@article {pmid38634789,
year = {2024},
author = {Li, B and Xiong, W and Zuo, W and Shi, Y and Wang, T and Chang, L and Wu, Y and Ma, H and Bian, Q and Chang, ACY},
title = {Proximal telomeric decompaction due to telomere shortening drives FOXC1-dependent myocardial senescence.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkae274},
pmid = {38634789},
issn = {1362-4962},
support = {82070248//National Natural Science Foundation of China/ ; 0900000024//Shanghai Institutions of Higher Learning/ ; },
abstract = {Telomeres, TTAGGGn DNA repeat sequences located at the ends of eukaryotic chromosomes, play a pivotal role in aging and are targets of DNA damage response. Although we and others have demonstrated presence of short telomeres in genetic cardiomyopathic and heart failure cardiomyocytes, little is known about the role of telomere lengths in cardiomyocyte. Here, we demonstrate that in heart failure patient cardiomyocytes, telomeres are shortened compared to healthy controls. We generated isogenic human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) with short telomeres (sTL-CMs) and normal telomeres (nTL-CMs) as model. Compared to nTL-CMs, short telomeres result in cardiac dysfunction and expression of senescent markers. Using Hi-C and RNASeq, we observe that short telomeres induced TAD insulation decrease near telomeric ends and this correlated with a transcription upregulation in sTL-CMs. FOXC1, a key transcription factor involved in early cardiogenesis, was upregulated in sTL-CMs and its protein levels were negatively correlated with telomere lengths in heart failure patients. Overexpression of FOXC1 induced hiPSC-CM aging, mitochondrial and contractile dysfunction; knockdown of FOXC1 rescued these phenotypes. Overall, the work presented demonstrate that increased chromatin accessibility due to telomere shortening resulted in the induction of FOXC1-dependent expression network responsible for contractile dysfunction and myocardial senescence.},
}
@article {pmid38634106,
year = {2024},
author = {Garcia-Medina, JS and Sienkiewicz, K and Narayanan, SA and Overbey, EG and Grigorev, K and Ryon, KA and Burke, M and Proszynski, J and Tierney, B and Schmidt, CM and Mencia-Trinchant, N and Klotz, R and Ortiz, V and Foox, J and Chin, C and Najjar, D and Matei, I and Chan, I and Cruchaga, C and Kleinman, A and Kim, J and Lucaci, A and Loy, C and Mzava, O and De Vlaminck, I and Singaraju, A and Taylor, LE and Schmidt, JC and Schmidt, MA and Blease, K and Moreno, J and Boddicker, A and Zhao, J and Lajoie, B and Altomare, A and Kruglyak, S and Levy, S and Yu, M and Hassane, DC and Bailey, SM and Bolton, K and Mateus, J and Mason, CE},
title = {Genome and clonal hematopoiesis stability contrasts with immune, cfDNA, mitochondrial, and telomere length changes during short duration spaceflight.},
journal = {Precision clinical medicine},
volume = {7},
number = {1},
pages = {pbae007},
pmid = {38634106},
issn = {2516-1571},
abstract = {BACKGROUND: The Inspiration4 (I4) mission, the first all-civilian orbital flight mission, investigated the physiological effects of short-duration spaceflight through a multi-omic approach. Despite advances, there remains much to learn about human adaptation to spaceflight's unique challenges, including microgravity, immune system perturbations, and radiation exposure.<br><br>METHODS: To provide a detailed genetics analysis of the mission, we collected dried blood spots pre-, during, and post-flight for DNA extraction. Telomere length was measured by quantitative PCR, while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations. A robust bioinformatic pipeline was used for data analysis, including variant calling to assess mutational burden.<br><br>RESULT: Telomere elongation occurred during spaceflight and shortened after return to Earth. Cell-free DNA analysis revealed increased immune cell signatures post-flight. No significant clonal hematopoiesis of indeterminate potential (CHIP) or whole-genome instability was observed. The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight.<br><br>CONCLUSION: Our findings provide valuable insights into the physiological consequences of short-duration spaceflight, with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth. CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts, an understudied phenomenon as previous studies have focused on career astronauts. This study will serve as a reference point for future commercial and non-commercial spaceflight, low Earth orbit (LEO) missions, and deep-space exploration.},
}
@article {pmid38633384,
year = {2024},
author = {Yu, HJ and Byun, YH and Park, CK},
title = {Techniques for assessing telomere length: A methodological review.},
journal = {Computational and structural biotechnology journal},
volume = {23},
number = {},
pages = {1489-1498},
pmid = {38633384},
issn = {2001-0370},
abstract = {Telomeres are located at the ends of chromosomes and have specific sequences with a distinctive structure that safeguards genes. They possess capping structures that protect chromosome ends from fusion events and ensure chromosome stability. Telomeres shorten in length during each cycle of cell division. When this length reaches a certain threshold, it can lead to genomic instability, thus being implicated in various diseases, including cancer and neurodegenerative disorders. The possibility of telomeres serving as a biomarker for aging and age-related disease is being explored, and their significance is still under study. This is because post-mitotic cells, which are mature cells that do not undergo mitosis, do not experience telomere shortening due to age. Instead, other causes, for example, exposure to oxidative stress, can directly damage the telomeres, causing genomic instability. Nonetheless, a general agreement has been established that measuring telomere length offers valuable insights and forms a crucial foundation for analyzing gene expression and epigenetic data. Numerous approaches have been developed to accurately measure telomere lengths. In this review, we summarize various methods and their advantages and limitations for assessing telomere length.},
}
@article {pmid38631323,
year = {2024},
author = {de Punder, K and Salinas-Manrique, J and Dietrich, DE and Karabatsiakis, A},
title = {Serum levels of the steroid hormone dehydroepiandrosterone (DHEA) are associated with psychological trauma and lymphocyte telomere integrity in women suffering from depression.},
journal = {Neuroimmunomodulation},
volume = {},
number = {},
pages = {},
doi = {10.1159/000538893},
pmid = {38631323},
issn = {1423-0216},
abstract = {INTRODUCTION: Emerging studies highlight the telomere system as an aging mechanism underlying the association between exposure to psychological trauma and the development of a wide range of physical and mental disorders, including major depressive disorder (MDD). Here, we investigated associations of circulating levels of the steroid hormone dehydroepiandrosterone (DHEA) with immune cell telomere length (TL) in the context of lifetime trauma exposure and MDD.<br><br>METHODS: Lifetime traumatic events (trauma load) were assessed using the Essener Trauma Inventory (ETI) in n=22 postmenopausal female inpatients with MDD and n=22 non-depressed controls. All women completed the Beck's Depression Inventory-II to assess the severity of current depressive symptoms. DHEA concentration in serum was measured by immunoassay and TL was quantified in kilobase units using quantitative fluorescent in situ hybridization (qFISH) in total peripheral blood mononuclear cells (PBMC) and in selected T cell subpopulations isolated by FACS separation.<br><br>RESULTS: Higher trauma load was significantly associated with lower DHEA concentration, which in turn was linked to more depression-related fatigue. Furthermore, DHEA concentration was positively and significantly associated with TL in memory CD4+ T cells as well as in na&#xef;ve and memory CD8+ T cells, but not in na&#xef;ve CD4+ T cells and total PBMC. Mediational analysis suggested that DHEA concentration is a mediator in the relationship between trauma load and memory CD8+ T cell TL.<br><br>CONCLUSION: The current findings suggest a potential role of DHEA as a biological resilience factor that may exert beneficial effects on telomere integrity, especially in conditions related to distress.},
}
@article {pmid38631073,
year = {2024},
author = {Zhong, M and Salberg, S and Sampangi, S and van der Walt, A and Butzkueven, H and Mychasiuk, R and Jokubaitis, V},
title = {Leukocyte telomere length in multiple sclerosis: relationship between disability severity and pregnancy history.},
journal = {Multiple sclerosis and related disorders},
volume = {86},
number = {},
pages = {105607},
doi = {10.1016/j.msard.2024.105607},
pmid = {38631073},
issn = {2211-0356},
abstract = {BACKGROUND: Aging-related processes contribute to neurodegeneration and disability in multiple sclerosis (MS). Biomarkers of biological aging such as leukocyte telomere length (LTL) could help personalise prognosis. Pregnancy has been shown to be protective against disability accumulation in women with MS, though it is unclear if this effect relates to aging mechanisms or LTL.<br><br>OBJECTIVES: This study aimed to cross-sectionally characterise LTL in a cohort of individuals with MS, and to correlate LTL with disability severity and pregnancy history.<br><br>METHODS: We extracted DNA from the whole blood of 501 people with MS in Melbourne, Australia. Expanded Disability Status Scale (EDSS) score and demographic data, as well as pregnancy history for 197 females, were obtained at sample collection. Additional data were extracted from the MSBase Registry. LTL was determined in base pairs (bp) using real-time quantitative polymerase chain reaction.<br><br>RESULTS: A relationship between EDSS score and shorter LTL was robust to multivariable adjustment for demographic and clinical factors including chronological age, with an adjusted LTL reduction per 1.0 increase in EDSS of 97.1 bp (95 % CI = 9.7-184.5 bp, p = 0.030). Adjusted mediation analysis found chronological age accounted for 33.6 % of the relationship between LTL and EDSS score (p = 0.018). In females with pregnancy data, history of pregnancy was associated with older age (median 49.7 vs 33.0 years, p < 0.001). There were no significant relationships between adjusted LTL and any history of pregnancy (LTL increase of 65.3 bp, 95 % CI = -471.0-601.5 bp, p = 0.81) or number of completed pregnancies (LTL increase of 14.6 bp per pregnancy, 95 % CI = -170.3-199.6 bp, p = 0.87).<br><br>CONCLUSIONS: The correlation between LTL and disability independent of chronological age and other factors points to a link between neurological reserve in MS and biological aging, and a potential research target for pathophysiological and therapeutic mechanisms. Although LTL did not significantly differ by pregnancy history, longitudinal analyses could help identify interactions with prospectively captured pregnancy effects.},
}
@article {pmid38629454,
year = {2024},
author = {Liang, X and Aouizerat, BE and So-Armah, K and Cohen, MH and Marconi, VC and Xu, K and Justice, AC},
title = {DNA methylation-based telomere length is associated with HIV infection, physical frailty, cancer, and all-cause mortality.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e14174},
doi = {10.1111/acel.14174},
pmid = {38629454},
issn = {1474-9726},
support = {R01-DA035616/DA/NIDA NIH HHS/United States ; R01-DA038632/DA/NIDA NIH HHS/United States ; R01-DA047063/DA/NIDA NIH HHS/United States ; R01-DA047820/DA/NIDA NIH HHS/United States ; R03-DA039745/DA/NIDA NIH HHS/United States ; U01-AA020790/AA/NIAAA NIH HHS/United States ; U01-AA020795/AA/NIAAA NIH HHS/United States ; U01-AA020799/AA/NIAAA NIH HHS/United States ; U10-AA013566/AA/NIAAA NIH HHS/United States ; U24-AA020794/AA/NIAAA NIH HHS/United States ; },
abstract = {Telomere length (TL) is an important indicator of cellular aging. Shorter TL is associated with several age-related diseases including coronary heart disease, heart failure, diabetes, osteoporosis, and cancer. Recently, a DNA methylation-based TL (DNAmTL) estimator has been developed as an alternative method for directly measuring TL. In this study, we examined the association of DNAmTL with cancer prevalence and mortality risk among people with and without HIV in the Veterans Aging Cohort Study Biomarker Cohort (VACS, N = 1917) and Women's Interagency HIV Study Cohort (WIHS, N = 481). We profiled DNAm in whole blood (VACS) or in peripheral blood mononuclear cells (WIHS) using an array-based method. Cancer prevalence was estimated from electronic medical records and cancer registry data. The VACS Index was used as a measure of physiologic frailty. Models were adjusted for self-reported race and ethnicity, batch, smoking status, alcohol consumption, and five cell types (CD4, CD8, NK, B cell, and monocyte). We found that people with HIV had shorter average DNAmTL than those without HIV infection [beta = -0.25, 95% confidence interval (-0.32, -0.18), p = 1.48E-12]. Greater value of VACS Index [beta = -0.002 (-0.003, -0.001), p = 2.82E-05] and higher cancer prevalence [beta = -0.07 (-0.10, -0.03), p = 1.37E-04 without adjusting age] were associated with shortened DNAmTL. In addition, one kilobase decrease in DNAmTL was associated with a 40% increase in mortality risk [hazard ratio: 0.60 (0.44, 0.82), p = 1.42E-03]. In summary, HIV infection, physiologic frailty, and cancer are associated with shortening DNAmTL, contributing to an increased risk of all-cause mortality.},
}
@article {pmid38621495,
year = {2024},
author = {Moura, HF and Schuch, JB and Ornell, F and Bandeira, CE and Massuda, R and Dotto Bau, CH and Grevet, EH and Kessler, FHP and von Diemen, L},
title = {Association between telomere length with alcohol use disorder and internalizing/externalizing comorbidities in a Brazilian male sample.},
journal = {Alcohol (Fayetteville, N.Y.)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.alcohol.2024.04.004},
pmid = {38621495},
issn = {1873-6823},
abstract = {BACKGROUND: Shortening telomere length (TL) is an important ageing marker associated with substance use disorder (SUD). However, the influence of psychiatric and clinical comorbidities and alcohol-related outcomes has not been much explored in the context of TL in individuals with alcohol use disorder (AUD) and may be a source of heterogeneity in AUD studies. Therefore, our aim was to investigate the influence of AUD, alcohol-related outcomes, and common psychiatric comorbidities on TL in men with AUD and healthy controls (HC).<br><br>METHODS: Men with AUD (n=108, mean age=52.4, SD=8.6) were recruited in a detoxification unit, and HC (n=80, mean age=50.04, SD=9.1) from the blood bank, both located in Brazil. HC had no current or lifetime diagnosis of any substance use disorder. Psychiatric comorbidities were assessed using SCID-I. TL ratio was measured in triplicates using quantitative multiplex PCR.<br><br>RESULTS: Telomere length did not differ between individuals with AUD and HC (p=0.073) or was associated with AUD-related outcomes, trauma, or clinical comorbidities. Individuals with externalizing disorders had longer TL when comparing with those with internalizing disorders (p=0.018) or without comorbidity (p=0.018).<br><br>CONCLUSION: Our findings indicate that TL was influenced by the presence of psychiatric comorbidity rather than case or control status. These results were adjusted for potential confounders, such as age.},
}
@article {pmid38617276,
year = {2024},
author = {Greshnova, A and Pál, K and Martinez, JFI and Canzar, S and Makova, KD},
title = {Transcript Isoform Diversity of Y Chromosome Ampliconic Genes of Great Apes Uncovered Using Long Reads and Telomere-to-Telomere Reference Genome Assemblies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.02.587783},
pmid = {38617276},
abstract = {Y chromosomes of great apes harbor A mpliconic G enes (YAGs)-multi-copy gene families (BPY2 , CDY , DAZ , HSFY , PRY , RBMY , TSPY , VCY , and XKRY) that encode proteins important for spermatogenesis. Previous work assembled YAG transcripts based on their targeted sequencing but not using reference genome assemblies, potentially resulting in an incomplete transcript repertoire. Here we used the recently produced gapless telomere-to-telomere (T2T) Y chromosome assemblies of great ape species (bonobo, chimpanzee, human, gorilla, Bornean orangutan, and Sumatran orangutan) and analyzed RNA data from whole-testis samples for the same species. We generated hybrid transcriptome assemblies by combining targeted long reads (Pacific Biosciences), untargeted long reads (Pacific Biosciences) and untargeted short reads (Illumina)and mapping them to the T2T reference genomes. Compared to the results from the reference-free approach, average transcript length was more than two times higher, and the total number of transcripts decreased three times, improving the quality of the assembled transcriptome. The reference-based transcriptome assemblies allowed us to differentiate transcripts originating from different Y chromosome gene copies and from their non-Y chromosome homologs. We identified two sources of transcriptome diversity-alternative splicing and gene duplication with subsequent diversification of gene copies. For each gene family, we detected transcribed pseudogenes along with protein-coding gene copies. We revealed previously unannotated gene copies of YAGs as compared to currently available NCBI annotations, as well as novel isoforms for annotated gene copies. This analysis paves the way for better understanding Y chromosome gene functions, which is important given their role in spermatogenesis.},
}
@article {pmid38615081,
year = {2024},
author = {Li, Z and Yang, J and Ji, X and Liu, J and Yin, C and Bhadauria, V and Zhao, W and Peng, YL},
title = {First telomere-to-telomere gapless assembly of the rice blast fungus Pyricularia oryzae.},
journal = {Scientific data},
volume = {11},
number = {1},
pages = {380},
pmid = {38615081},
issn = {2052-4463},
abstract = {Rice blast caused by Pyricularia oryzae (syn., Magnaporthe oryzae) was one of the most destructive diseases of rice throughout the world. Genome assembly was fundamental to genetic variation identification and critically impacted the understanding of its ability to overcome host resistance. Here, we report a gapless genome assembly of rice blast fungus P. oryzae strain P131 using PacBio, Illumina and high throughput chromatin conformation capture (Hi-C) sequencing data. This assembly contained seven complete chromosomes (43,237,743 bp) and a circular mitochondrial genome (34,866 bp). Approximately 14.31% of this assembly carried repeat sequences, significantly greater than its previous assembled version. This assembly had a 99.9% complement in BUSCO evaluation. A total of 14,982 genes protein-coding genes were predicted. In summary, we assembled the first telomere-to-telomere gapless genome of P. oryzae, which would be a valuable genome resource for future research on the genome evolution and host adaptation.},
}
@article {pmid38615017,
year = {2024},
author = {Li, J and Yang, C and Zhang, Y and Li, Q and Liu, X and Zhang, Y and Zhao, Y},
title = {Study of association of leptin with leukocyte telomere length in a Chinese rural population.},
journal = {Lipids in health and disease},
volume = {23},
number = {1},
pages = {103},
pmid = {38615017},
issn = {1476-511X},
support = {U22A20360//National Natural Science Foundation of China/ ; 82060592//National Natural Science Foundation of China/ ; 2021BEG02026//key R&amp;D projects in Ningxia Hui Autonomous Region/ ; },
abstract = {BACKGROUND: Previous studies have demonstrated the relationship between adipocyte factors, insulin resistance, and other indicators with telomere length. However, these studies did not consider the influence of changes in different indicators on telomere length over time. Therefore, the aim of this study is to elucidate the impact of changes in adipocyte factors, HOMA-IR, and other indicators on the dynamic variation of telomere length.<br><br>METHODS: The data were from a cohort study conducted in Ningxia, China. A total of 1624 subjects were analyzed. Adipokines and relative leukocyte telomere length (RLTL) were measured, and changes in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), Homeostatic Model Assessment for &#x3b2;-Cell Function (HOMA-&#x3b2;), and Quantitative Insulin Sensitivity Check Index (QUICKI) were calculated. Generalized linear models evaluated associations between changes in adipokines and RLTL changes. Furthermore, univariate analyses examined the effects of changes in adipokines and insulin resistance indicators on &#x394;RLTL.<br><br>RESULTS: The research findings indicate that females generally have shorter telomeres compared to males. In comparison to the low-level group of &#x394;leptin (LEP), the high-level group of &#x394;LEP shows a negative correlation with &#x394;RLTL (B=-1.32, 95% CI (-2.38, -0.27)). Even after multivariable adjustments, this relationship persists (B=-1.31, 95% CI (-2.24, -0.23)). Further analysis reveals that after adjusting for &#x394;HOMA-IR, &#x394;HOMA-&#x3b2;, and &#x394;QUICKI, the high-level group of &#x394;LEP still exhibits a significant negative correlation with &#x394;RLTL (B=-1.37, 95% CI (-2.43, -0.31)). However, the interaction effects between &#x394;HOMA-IR, &#x394;HOMA-&#x3b2;, &#x394;QUICKI, and &#x394;LEP do not affect &#x394;RLTL.<br><br>CONCLUSIONS: Elevated levels of leptin were significantly correlated with shortened telomere length. This suggests that increased leptin levels may impact overall individual health by affecting telomere length, underscoring the importance of measures to reduce leptin levels to mitigate the onset and progression of related diseases.},
}
@article {pmid38611064,
year = {2024},
author = {Wakita, H and Lu, Y and Li, X and Kobayashi, T and Hachiya, T and Ide, H and Horie, S},
title = {Evaluating Leukocyte Telomere Length and Myeloid-Derived Suppressor Cells as Biomarkers for Prostate Cancer.},
journal = {Cancers},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/cancers16071386},
pmid = {38611064},
issn = {2072-6694},
abstract = {BACKGROUND: Leukocyte telomere length (LTL) and myeloid-derived suppressor cells (MDSC) are associated with aging and the development and progression of cancer. However, the exact nature of this relationship remains unclear. Our study aimed to investigate the potential of LTL and MDSC as diagnostic biomarkers for prostate cancer while also seeking to deepen our understanding of the relationship of these potential biomarkers to each other.<br><br>METHODS: Our study involved patients undergoing a prostate biopsy. We analyzed the relative LTL in genomic DNA obtained from peripheral blood leukocytes as well as the percentage of MDSC and their subtypes in peripheral blood mononuclear cells (PBMC). Our evaluation focused on examining the relationship between LTL and MDSC and pathological diagnoses as well as investigating the correlation between LTL and MDSC levels.<br><br>RESULTS: In our study of 102 participants, 56 were pathologically diagnosed with localized prostate cancer (cancer group), while 46 tested negative (control group). The cancer group exhibited significantly shorter LTL in comparison to the control group (p = 0.024). Additionally, the cancer group showed a tendency towards a higher percentage of monocytic MDSC (M-MDSC), although this difference did not reach statistical significance (p = 0.056). Our multivariate logistic regression analysis revealed that patients with shorter LTL and higher percentages of M-MDSC had a 2.98-fold (95% CI = 1.001-8.869, p = 0.049) and 3.03-fold (95% CI = 1.152-7.977, p = 0.025) increased risk of prostate cancer diagnosis, respectively. There was also a significant negative correlation between LTL and M-MDSC. (r = -0.347, p < 0.001).<br><br>CONCLUSIONS: Our research has established a correlation between LTL and MDSC in patients undergoing biopsy for prostate cancer. Notably, we observed that individuals with localized prostate cancer tend to have shorter LTL and a higher percentage of M-MDSC prior to their diagnosis. These findings suggest that LTL and M-MDSC could potentially serve as adjunctive biomarkers for the early diagnosis of prostate cancer.},
}
@article {pmid38610915,
year = {2024},
author = {Moustakli, E and Zikopoulos, A and Skentou, C and Dafopoulos, S and Stavros, S and Dafopoulos, K and Drakakis, P and Georgiou, I and Zachariou, A},
title = {Association of Obesity with Telomere Length in Human Sperm.},
journal = {Journal of clinical medicine},
volume = {13},
number = {7},
pages = {},
doi = {10.3390/jcm13072150},
pmid = {38610915},
issn = {2077-0383},
abstract = {Background: Telomere attrition and mitochondrial dysfunction are two fundamental aspects of aging. Calorie restriction (CR) is the best strategy to postpone aging since it can enhance telomere attrition, boost antioxidant capacity, and lower the generation of reactive oxygen species (ROS). Since ROS is produced by mitochondria and can readily travel to cell nuclei, it is thought to be a crucial molecule for information transfer between mitochondria and cell nuclei. Important variables that affect the quality and functionality of sperm and may affect male reproductive health and fertility include telomere length, mitochondrial content, and the ratio of mitochondrial DNA (mtDNA) to nuclear DNA (nDNA). Telomere damage results from mitochondrial failure, whereas nuclear DNA remains unaffected. This research aims to investigate potential associations between these three variables and how they might relate to body mass index. Methods: Data were collected from 82 men who underwent IVF/ICSI at the University Hospital of Ioannina's IVF Unit in the Obstetrics and Gynecology Department. Evaluations included sperm morphology, sperm count, sperm motility, and participant history. To address this, male participants who were categorized into three body mass index (ΒΜΙ) groups-normal, overweight, and obese-had their sperm samples tested. Results: For both the normal and overweight groups, our results show a negative connection between relative telomere length and ΒΜI. As an illustration of a potential connection between mitochondrial health and telomere maintenance, a positive correlation was found for the obese group. Only the obese group's results were statistically significant (p < 0.05). More evidence that longer telomeres are associated with lower mitochondrial content can be found in the negative connection between telomere length and mitochondrial content in both the normal and overweight groups. However, the obese group showed a positive association. The data did not reach statistical significance for any of the three groups. These associations may affect sperm quality since telomere length and mitochondrial concentration are indicators of cellular integrity and health. Moreover, the ratio of mtDNA to nDNA was positively correlated with the relative telomere lengths of the obese group, but negatively correlated with the normal and overweight groups. In every group that was studied, the results were not statistically significant. According to this, male fertility may be negatively impacted by an imbalance in the copy number of the mitochondrial genome compared to the nuclear DNA in sperm. Conclusions: Essentially, the goal of our work is to determine whether mitochondria and telomere length in human sperm interact. Understanding these connections may aid in the explanation of some male infertility causes and possibly contribute to the creation of new treatment modalities for problems pertaining to reproductive health. The functional implications of these connections and their applications in therapeutic settings require further investigation.},
}
@article {pmid38607251,
year = {2024},
author = {Wang, B and Xiong, Y and Li, R and Zhang, J and Zhang, S},
title = {Shorter telomere length increases the risk of lymphocyte immunodeficiency: A Mendelian randomization study.},
journal = {Immunity, inflammation and disease},
volume = {12},
number = {4},
pages = {e1251},
doi = {10.1002/iid3.1251},
pmid = {38607251},
issn = {2050-4527},
support = {2020SF-072//Key project of Research and development program of Shaanxi Province/ ; YXJLRH2022062//Innovation project for medical Integration in Xi'an Jiaotong University/ ; 2020YJ(ZYTS)018//Free exploration project of the second affiliated hospital of Xi'an Jiaotong University/ ; },
abstract = {BACKGROUND: For a long time, the prevailing viewpoint suggests that shorter telomere contribute to chromosomal instability, which is a shared characteristic of both aging and cancer. The newest research presented that T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to some cancers. However, the relationship between genetically determined telomere length (TL) and immune cells remains unclear.<br><br>METHODS: The two-sample Mendelian randomization analysis was conducted to elucidate the potential causal relationship. The genetic data of TL and immune cells were obtained from the Genome-Wide Association Study. The inverse variance weighted (IVW) method was used to estimate the effects primarily and another four methods were as a supplement. Sensitivity analysis was used to test the results.<br><br>RESULTS: The IVW method showed a significant correlation between TL and the percentage of T cells in lymphocytes (odds ratio [OR]: 1.222, 95% confidence interval [CI]: 1.014-1.472, p&#x2009;=&#x2009;.035), indicating that shorter TL significantly increases the risk of low T cell percentage. Further analysis of T cell subsets indicated that shorter TL may primarily lead to a lower percentage of Natural Killer T cells (OR: 1.574, 95% CI: 1.281-1.935, p&#x2009;<&#x2009;.001). Analysis of B cell subsets revealed that shorter TL may be associated with a higher percentage of Naive-mature B cells, and a lower percentage of Memory B cells. And the sensitivity analysis indicated the validity and robustness of our findings.<br><br>CONCLUSION: In summary, our findings suggest that shorter TL may be associated with a decline in the percentage of T cell, as well as impediments in the differentiation of B cell, consequently leading to the onset of immunosenescence and immunodeficiency. The relevant mechanisms and potential therapeutic avenues still need further investigation.},
}
@article {pmid38606545,
year = {2024},
author = {Nitschke, NJ and Jelsig, AM and Lautrup, C and Lundsgaard, M and Severinsen, MT and Cowland, JB and Maroun, LL and Andersen, MK and Grønbæk, K},
title = {Expanding the understanding of telomere biology disorder with reports from two families harboring variants in ZCCHC8 and TERC.},
journal = {Clinical genetics},
volume = {},
number = {},
pages = {},
doi = {10.1111/cge.14534},
pmid = {38606545},
issn = {1399-0004},
support = {//Rigshospitalet/ ; R302-A17259//Kr&#xe6;ftens Bek&#xe6;mpelse/ ; R223-A13071//Kr&#xe6;ftens Bek&#xe6;mpelse/ ; },
abstract = {Telomere biology disorder (TBD) can present within a wide spectrum of symptoms ranging from severe congenital malformations to isolated organ dysfunction in adulthood. Diagnosing TBD can be challenging given the substantial variation in symptoms and age of onset across generations. In this report, we present two families, one with a pathogenic variant in ZCCHC8 and another with a novel variant in TERC. In the literature, only one family has previously been reported with a ZCCHC8 variant and TBD symptoms. This family had multiple occurrences of pulmonary fibrosis and one case of bone marrow failure. In this paper, we present a second family with the same ZCCHC8 variant (p.Pro186Leu) and symptoms of TBD including pulmonary fibrosis, hematological disease, and elevated liver enzymes. The suspicion of TBD was confirmed with the measurement of short telomeres in the proband. In another family, we report a novel likely pathogenic variant in TERC. Our comprehensive description encompasses hematological manifestations, as well as pulmonary and hepatic fibrosis. Notably, there are no other reports which associate this variant to disease. The families expand our understanding of the clinical implications and genetic causes of TBD.},
}
@article {pmid38605518,
year = {2024},
author = {Jia, KH and Zhang, X and Li, LL and Shi, TL and Liu, D and Yang, Y and Cong, Y and Li, R and Pu, Y and Gong, Y and Chen, X and Si, YJ and Tian, R and Qian, Z and Ding, H and Li, N},
title = {Telomere-to-telomere cultivated and wild soybean genome assembly provides insights into evolution and domestication under structural variation.},
journal = {Plant communications},
volume = {},
number = {},
pages = {100919},
doi = {10.1016/j.xplc.2024.100919},
pmid = {38605518},
issn = {2590-3462},
}
@article {pmid38603928,
year = {2024},
author = {Chang, CH and Hwang, PA},
title = {Low-molecular-weight fucoidan increases telomere length and immunostimulatory effects on NK-92 cells following inhaled anesthetic injury.},
journal = {Mutation research},
volume = {828},
number = {},
pages = {111857},
doi = {10.1016/j.mrfmmm.2024.111857},
pmid = {38603928},
issn = {1873-135X},
abstract = {Inhaled anesthetics, such as isoflurane, may cause side effects, including short-term immunosuppression and DNA damage. In contrast, low molecular weight fucoidan (LMF), derived from brown seaweed, exhibits promising immunomodulatory effects. In this study, we determined the effect of isoflurane on telomeres and examined the potential of LMF to ameliorate the harmful effects of isoflurane. Male Lewis rats, the mouse lymphoma cell line YAC-1, and the human nature killer cell line NK-92 MI were exposed to isoflurane. The relative telomere length (T/S) ratio and mRNA expression were determined by quantitative PCR. The viability assay was used to assess cell viability. In vivo, 2% isoflurane exposure, which is a clinically relevant concentration, reduced telomere length, and correlated with exposure frequency and duration. Isoflurane concentrations above 2% shortened YAC-1 telomeres, with minimal impact on cell viability. LMF pre-treatment enhanced NK-92 MI cell survival resulting from isoflurane exposure and exerted superior telomere protection compared with LMF post-treatment. Furthermore, adding LMF during isoflurane exposure resulted in a significant increase in IFN-γ, TNF-α, and IL-10 mRNA compared with the untreated group. LMF protected against isoflurane-induced telomere shortening, enhanced NK cell viability, and modulated cytokine expression, thus mitigating postoperative immune suppression and risk of tumor metastasis.},
}
@article {pmid38603523,
year = {2024},
author = {Karimian, K and Groot, A and Huso, V and Kahidi, R and Tan, KT and Sholes, S and Keener, R and McDyer, JF and Alder, JK and Li, H and Rechtsteiner, A and Greider, CW},
title = {Human telomere length is chromosome end-specific and conserved across individuals.},
journal = {Science (New York, N.Y.)},
volume = {},
number = {},
pages = {eado0431},
doi = {10.1126/science.ado0431},
pmid = {38603523},
issn = {1095-9203},
abstract = {Short telomeres cause age-related disease and long telomeres predispose to cancer; however, the mechanisms regulating telomere length are unclear. We developed a nanopore-based method, Telomere Profiling, to determine telomere length at nearly single nucleotide resolution. Mapping telomere reads to chromosome ends showed chromosome end-specific length distributions that could differ by more than six kilobases. Telomere lengths in 147 individuals showed certain chromosome ends were consistently longer or shorter. The same rank order was found in newborn cord blood, suggesting that telomere length is determined at birth and chromosome end-specific telomere length differences are maintained as telomeres shorten with age. Telomere Profiling makes precision investigation of telomere length widely accessible for laboratory, clinical, and drug discovery efforts and will allow deeper insights into telomere biology.},
}
@article {pmid38600880,
year = {2024},
author = {Gao, Y and Xu, DD and Hu, Z},
title = {Telomere-to-telomere genome assembly of Oldenlandia diffusa.},
journal = {DNA research : an international journal for rapid publication of reports on genes and genomes},
volume = {},
number = {},
pages = {},
doi = {10.1093/dnares/dsae012},
pmid = {38600880},
issn = {1756-1663},
abstract = {We report the complete telomere-to-telomere genome assembly of Oldenlandia diffusa which renowned in traditional Chinese medicine, comprising 16 chromosomes and spanning 499.7 Mb. The assembly showcases 28 telomeres and minimal gaps, with a total of only five. Repeat sequences constitute 46.41% of the genome, and 49,701 potential protein-coding genes have been predicted. Compared with O. corymbosa, O. diffusa exhibits chromosome duplication and fusion events, diverging 20.34 million years ago. Additionally, a total of 11 clusters of terpene synthase have been identified. The comprehensive genome sequence, gene catalog, and terpene synthase clusters of O. diffusa detailed in this study will significantly contribute to advancing research in this species' genetic, genomic, and pharmacological aspects.},
}
@article {pmid38600443,
year = {2024},
author = {Wang, B and Jia, Y and Dang, N and Yu, J and Bush, SJ and Gao, S and He, W and Wang, S and Guo, H and Yang, X and Ma, W and Ye, K},
title = {Near telomere-to-telomere genome assemblies of two Chlorella species unveil the composition and evolution of centromeres in green algae.},
journal = {BMC genomics},
volume = {25},
number = {1},
pages = {356},
pmid = {38600443},
issn = {1471-2164},
support = {32200510//National Natural Science Foundation of China/ ; 2022YFC3400300//National Key Research and Development Program of China/ ; },
abstract = {BACKGROUND: Centromeres play a crucial and conserved role in cell division, although their composition and evolutionary history in green algae, the evolutionary ancestors of land plants, remains largely unknown.<br><br>RESULTS: We constructed near telomere-to-telomere (T2T) assemblies for two Trebouxiophyceae species, Chlorella sorokiniana NS4-2 and Chlorella pyrenoidosa DBH, with chromosome numbers of 12 and 13, and genome sizes of 58.11 Mb and 53.41 Mb, respectively. We identified and validated their centromere sequences using CENH3 ChIP-seq and found that, similar to humans and higher plants, the centromeric CENH3 signals of green algae display a pattern of hypomethylation. Interestingly, the centromeres of both species largely comprised transposable elements, although they differed significantly in their composition. Species within the Chlorella genus display a more diverse centromere composition, with major constituents including members of the LTR/Copia, LINE/L1, and LINE/RTEX families. This is in contrast to green algae including Chlamydomonas reinhardtii, Coccomyxa subellipsoidea, and Chromochloris zofingiensis, in which centromere composition instead has a pronounced single-element composition. Moreover, we observed significant differences in the composition and structure of centromeres among chromosomes with strong collinearity within the Chlorella genus, suggesting that centromeric sequence evolves more rapidly than sequence in non-centromeric regions.<br><br>CONCLUSIONS: This study not only provides high-quality genome data for comparative genomics of green algae but gives insight into the composition and evolutionary history of centromeres in early plants, laying an important foundation for further research on their evolution.},
}
@article {pmid38593805,
year = {2024},
author = {Jiang, H and Zhang, T and Kaur, H and Shi, T and Krishnan, A and Kwon, Y and Sung, P and Greenberg, RA},
title = {BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage response.},
journal = {Molecular cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molcel.2024.03.011},
pmid = {38593805},
issn = {1097-4164},
abstract = {The Bloom syndrome (BLM) helicase is critical for alternative lengthening of telomeres (ALT), a homology-directed repair (HDR)-mediated telomere maintenance mechanism that is prevalent in cancers of mesenchymal origin. The DNA substrates that BLM engages to direct telomere recombination during ALT remain unknown. Here, we determine that BLM helicase acts on lagging strand telomere intermediates that occur specifically in ALT-positive cells to assemble a replication-associated DNA damage response. Loss of ATRX was permissive for BLM localization to ALT telomeres in S and G2, commensurate with the appearance of telomere C-strand-specific single-stranded DNA (ssDNA). DNA2 nuclease deficiency increased 5'-flap formation in a BLM-dependent manner, while telomere C-strand, but not G-strand, nicks promoted ALT. These findings define the seminal events in the ALT DNA damage response, linking aberrant telomeric lagging strand DNA replication with a BLM-directed HDR mechanism that sustains telomere length in a subset of human cancers.},
}
@article {pmid38594465,
year = {2024},
author = {Shou, S and Li, Y and Chen, J and Zhang, X and Zhang, C and Jiang, X and Liu, F and Yi, L and Zhang, X and Geer, E and Pu, Z and Pang, B},
title = {Understanding, diagnosing, and treating pancreatic cancer from the perspective of telomeres and telomerase.},
journal = {Cancer gene therapy},
volume = {},
number = {},
pages = {},
pmid = {38594465},
issn = {1476-5500},
abstract = {Telomerase is associated with cellular aging, and its presence limits cellular lifespan. Telomerase by preventing telomere shortening can extend the number of cell divisions for cancer cells. In adult pancreatic cells, telomeres gradually shorten, while in precancerous lesions of cancer, telomeres in cells are usually significantly shortened. At this time, telomerase is still in an inactive state, and it is not until before and after the onset of cancer that telomerase is reactivated, causing cancer cells to proliferate. Methylation of the telomerase reverse transcriptase (TERT) promoter and regulation of telomerase by lactate dehydrogenase B (LDHB) is the mechanism of telomerase reactivation in pancreatic cancer. Understanding the role of telomeres and telomerase in pancreatic cancer will help to diagnose and initiate targeted therapy as early as possible. This article reviews the role of telomeres and telomerase as biomarkers in the development of pancreatic cancer and the progress of research on telomeres and telomerase as targets for therapeutic intervention.},
}
@article {pmid38593475,
year = {2024},
author = {Teixeira, GA and Travenzoli, NM and Tavares, MG},
title = {Chromosomal organization of different repetitive sequences in four wasp species of the genus Trypoxylon Latreille (Hymenoptera: Crabronidae) and insights into the composition of wasp telomeres.},
journal = {Genome},
volume = {},
number = {},
pages = {},
doi = {10.1139/gen-2023-0132},
pmid = {38593475},
issn = {1480-3321},
abstract = {This study characterizes the chromosomal organization of DNA repetitive sequences and the karyotypic evolution in four representatives of the solitary wasp genus Trypoxylon using conventional and molecular cytogenetic techniques. Our findings present the first cytogenetic data for T. rogenhoferi (2n=30) and T. albonigrum (2n=32) while the karyotypes of T. nitidum (2n=30) and T. lactitarse (2n=30) were similar to those described previously. Fluorochrome staining and microsatellite distribution data revealed differences in the constitutive heterochromatin composition among species. Trypoxylon nitidum and T. albonigrum exhibited a single rRNA gene site, potentially representing an ancestral pattern for aculeate Hymenoptera, while T. rogenhoferi and T. lactitarse showed two pericentromeric rRNA gene sites, suggesting amplification events in their ancestral clade. The (TCAGG)n motif hybridized in the terminal regions of the chromosomes in all four Trypoxylon species, which may suggest that this sequence is part of their telomeres. Notably, the presence of this repetitive sequence in the centromeric regions of certain chromosome pairs in two species supports the hypothesis of chromosomal fusions or inversions in the ancestral karyotype of Trypoxylon. The study expands the chromosomal mapping data of repetitive sequences in wasps and offers insights into the dynamic evolutionary landscape of karyotypes in these insects.},
}
@article {pmid38593055,
year = {2024},
author = {Karadağ, A and Dirican, E and Özmerdiven, &#xc7;G and Özen, A and Ayan, S and Kabadere, S},
title = {Evaluation of miR-130b-3p and miR-375 levels and telomere length with telomerase activity in prostate cancer.},
journal = {Nucleosides, nucleotides &amp; nucleic acids},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/15257770.2024.2334896},
pmid = {38593055},
issn = {1532-2335},
abstract = {Prostate cancer (PC) is the most frequent cancer in males, as well as the second highest cause of cancer-related deaths in men. Differences in expression levels of miRNAs were linked with prostat cancer pathogenesis. qPCR was used to evaluate the expression of miR-130b-3p and miR-375 in Benign Prostate Hyperplasia (BPH (n = 20) and PC (n = 22, pre- and post-operative) patients plasma. Relative telomere lengths (RLTs) in genomic DNA isolated from plasma were measured with qPCR, and telomerase activity analyzed by the ELISA method. PSA levels of PC patients were greater than of BPH patients (p = 0.0473). miR-130b-3p and miR-375 levels were significantly lower in pre-operative specimens of PC patients according to BPH (p = 0,0362, p = 0.0168, respectively). Similarly, post-operative miR-375 levels were lower in PC patients than in BPH patients (p = 0.1866). BPH patients had shorter RTLs than PC patients in both pre- (p=0.0438) and post-operative (p=0.0297) specimens. Telomerase activity was higher in PC patients than BPH(p = 0.0129). Interestingly, telomerase activity was further increased after surgery (p = 0.0003). We aim to identify the levels of miR-130b-3p and miR-375 expression and their relationship with telomerase activity in PC patients. Our data suggest that miRNAs and telomere length (TL) with telomerase activity may play a role in regulating prostate tumorgenesis and may be used as biomarkers for PC diagnosis.},
}
@article {pmid38588482,
year = {2024},
author = {de la Rosa, R and Le, A and Holm, S and Ye, M and Bush, NR and Hessler, D and Koita, K and Bucci, M and Long, D and Thakur, N},
title = {Associations Between Early-Life Adversity, Ambient Air Pollution, and Telomere Length in Children.},
journal = {Psychosomatic medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/PSY.0000000000001276},
pmid = {38588482},
issn = {1534-7796},
abstract = {OBJECTIVE: Examine the independent associations and interaction between early-life adversity and residential ambient air pollution exposure on relative buccal telomere length (rBTL).<br><br>METHODS: Experiences of abuse, neglect, household challenges, and related life events were identified in a cross-sectional sample of children ages 1-11 years (n = 197) using the 17-item Pediatric ACEs and Related Life Event Screener (PEARLS) tool. The PEARLS tool was analyzed both as a total score and across established domains (Maltreatment, Household Challenges, and Social Context). Ground-level fine particulate matter (PM2.5) concentrations were matched to residential locations for the one and twelve months prior to biospecimen collection. We used multivariable linear regression models to examine for independent associations between continuous PM2.5 exposure and PEARLS score/domains with rBTL. Additionally, effect modification by PEARLS scores and domains on associations between PM2.5 exposure and rBTL was examined.<br><br>RESULTS: Study participants were 47% girls, with mean age = 5.9 years [standard deviation: 3.4] median reported PEARLS score of 2 [interquartile range (IQR): 4], median 12-month prior PM2.5 concentrations of 11.8 &#x3bc;g/m3 [IQR: 2.7], median 1-month prior PM2.5 concentrations of 10.9 &#x3bc;g/m3 [IQR: 5.8], and rBTL of 0.1 [IQR: 0.03]. Mean 12-month prior PM2.5 exposure was inversely associated with rBTL (&#xdf; = -0.02, 95% CI: -0.04, -0.01). While reported PEARLS scores and domains were not independently associated with rBTL, we observed a greater decrement in rBTL with increment of average annual PM2.5 as reported Social Context domain items increased (p-interaction<0.05).<br><br>CONCLUSION: Our results suggest that adverse Social Context factors may accelerate the association between chronic PM2.5 exposure on telomere shortening during childhood.},
}
@article {pmid38588418,
year = {2024},
author = {Padmanaban, S and Lambacher, NJ and Tesmer, VM and Zhang, J and Shibuya, H and Nandakumar, J},
title = {Caenorhabditis elegans telomere-binding proteins TEBP-1 and TEBP-2 adapt the Myb module to dimerize and bind telomeric DNA.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {121},
number = {16},
pages = {e2316651121},
doi = {10.1073/pnas.2316651121},
pmid = {38588418},
issn = {1091-6490},
support = {R01HD108809//HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/ ; R35GM148276//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 211377Pj//Cancerfonden (Swedish Cancer Society)/ ; },
abstract = {Protecting chromosome ends from misrecognition as double-stranded (ds) DNA breaks is fundamental to eukaryotic viability. The protein complex shelterin prevents a DNA damage response at mammalian telomeres. Mammalian shelterin proteins TRF1 and TRF2 and their homologs in yeast and protozoa protect telomeric dsDNA. N-terminal homodimerization and C-terminal Myb-domain-mediated dsDNA binding are two structural hallmarks of end protection by TRF homologs. Yet our understanding of how Caenorhabditis elegans protects its telomeric dsDNA is limited. Recently identified C. elegans proteins TEBP-1 (also called DTN-1) and TEBP-2 (also called DTN-2) are functional homologs of TRF proteins, but how they bind DNA and whether or how they dimerize is not known. TEBP-1 and TEBP-2 harbor three Myb-containing domains (MCDs) and no obvious dimerization domain. We demonstrate biochemically that only the third MCD binds DNA. We solve the X-ray crystal structure of TEBP-2 MCD3 with telomeric dsDNA to reveal the structural mechanism of telomeric dsDNA protection in C. elegans. Mutagenesis of the DNA-binding site of TEBP-1 and TEBP-2 compromises DNA binding in vitro, and increases DNA damage signaling, lengthens telomeres, and decreases brood size in vivo. Via an X-ray crystal structure, biochemical validation of the dimerization interface, and SEC-MALS analysis, we demonstrate that MCD1 and MCD2 form a composite dimerization module that facilitates not only TEBP-1 and TEBP-2 homodimerization but also heterodimerization. These findings provide fundamental insights into C. elegans telomeric dsDNA protection and highlight how different eukaryotes have evolved distinct strategies to solve the chromosome end protection problem.},
}
@article {pmid38587381,
year = {2024},
author = {Martin, NA and McLester-Davis, LWY and Roy, TR and Magruder, MG and Hastings, WJ and Drury, SS},
title = {Monochrome Multiplex Quantitative PCR Telomere Length Measurement.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {205},
pages = {},
doi = {10.3791/66545},
pmid = {38587381},
issn = {1940-087X},
abstract = {Telomeres are ribonucleoprotein structures at the end of all eukaryotic chromosomes that protect DNA from damage and preserve chromosome stability. Telomere length (TL) has been associated with various exposures, biological processes, and health outcomes. This article describes the monochrome multiplex quantitative polymerase chain reaction (MMqPCR) assay protocol routinely conducted in our laboratory for measuring relative mean TL from human DNA. There are several different PCR-based TL measurement methods, but the specific protocol for the MMqPCR method presented in this publication is repeatable, efficient, cost-effective, and suitable for population-based studies. This detailed protocol outlines all information necessary for investigators to establish this assay in their laboratory. In addition, this protocol provides specific steps to increase the reproducibility of TL measurement by this assay, defined by the intraclass correlation coefficient (ICC) across repeated measurements of the same sample. The ICC is a critical factor in evaluating expected power for a specific study population; as such, reporting cohort-specific ICCs for any TL assay is a necessary step to enhance the overall rigor of population-based studies of TL. Example results utilizing DNA samples extracted from peripheral blood mononuclear cells demonstrate the feasibility of generating highly repeatable TL data using this MMqPCR protocol.},
}
@article {pmid38587189,
year = {2024},
author = {Lee, JJ and Kim, H and Park, H and Lee, U and Kim, C and Lee, M and Shin, Y and Jung, JJ and Lee, HB and Han, W and Lee, H},
title = {Disruption of G-quadruplex dynamicity by BRCA2 abrogation instigates phase separation and break-induced replication at telomeres.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkae251},
pmid = {38587189},
issn = {1362-4962},
support = {2020R1A5A1018081//National Research Foundation of Korea/ ; //Hyundai Motor Chung Mong-Koo Foundation/ ; },
abstract = {Dynamic interaction between BRCA2 and telomeric G-quadruplexes (G4) is crucial for maintaining telomere replication homeostasis. Cells lacking BRCA2 display telomeric damage with a subset of these cells bypassing senescence to initiate break-induced replication (BIR) for telomere synthesis. Here we show that the abnormal stabilization of telomeric G4 following BRCA2 depletion leads to telomeric repeat-containing RNA (TERRA)-R-loop accumulation, triggering liquid-liquid phase separation (LLPS) and the assembly of Alternative Lengthening of Telomeres (ALT)-associated promyelocytic leukemia (PML) bodies (APBs). Disruption of R-loops abolishes LLPS and impairs telomere synthesis. Artificial engineering of telomeric LLPS restores telomere synthesis, underscoring the critical role of LLPS in ALT. TERRA-R-loops also recruit Polycomb Repressive Complex 2 (PRC2), leading to tri-methylation of Lys27 on histone H3 (H3K27me3) at telomeres. Half of paraffin-embedded tissue sections from human breast cancers exhibit APBs and telomere length heterogeneity, suggesting that BRCA2 mutations can predispose individuals to ALT-type tumorigenesis. Overall, BRCA2 abrogation disrupts the dynamicity of telomeric G4, producing TERRA-R-loops, finally leading to the assembly of telomeric liquid condensates crucial for ALT. We propose that modulating the dynamicity of telomeric G4 and targeting TERRA-R-loops in telomeric LLPS maintenance may represent effective therapeutic strategies for treating ALT-like cancers with APBs, including those with BRCA2 disruptions.},
}
@article {pmid38584235,
year = {2024},
author = {Lagunas-Rangel, FA},
title = {Giardia telomeres and telomerase.},
journal = {Parasitology research},
volume = {123},
number = {4},
pages = {179},
pmid = {38584235},
issn = {1432-1955},
abstract = {Giardia duodenalis, the protozoan responsible for giardiasis, is a significant contributor to millions of diarrheal diseases worldwide. Despite the availability of treatments for this parasitic infection, therapeutic failures are alarmingly frequent. Thus, there is a clear need to identify new therapeutic targets. Giardia telomeres were previously identified, but our understanding of these structures and the critical role played by Giardia telomerase in maintaining genomic stability and its influence on cellular processes remains limited. In this regard, it is known that all Giardia chromosomes are capped by small telomeres, organized and protected by specific proteins that regulate their functions. To counteract natural telomere shortening and maintain high proliferation, Giardia exhibits constant telomerase activity and employs additional mechanisms, such as the formation of G-quadruplex structures and the involvement of transposable elements linked to telomeric repeats. Thus, this study aims to address the existing knowledge gap by compiling the available information (until 2023) about Giardia telomeres and telomerase, focusing on highlighting the distinctive features within this parasite. Furthermore, the potential feasibility of targeting Giardia telomeres and/or telomerase as an innovative therapeutic strategy is discussed.},
}
@article {pmid38581556,
year = {2024},
author = {Mason, CE and Sierra, MA and Feng, HJ and Bailey, SM},
title = {Telomeres and aging: on and off the planet!.},
journal = {Biogerontology},
volume = {25},
number = {2},
pages = {313-327},
pmid = {38581556},
issn = {1573-6768},
abstract = {Improving human healthspan in our rapidly aging population has never been more imperative. Telomeres, protective "caps" at the ends of linear chromosomes, are essential for maintaining genome stability of eukaryotic genomes. Due to their physical location and the "end-replication problem" first envisioned by Dr. Alexey Olovnikov, telomeres shorten with cell division, the implications of which are remarkably profound. Telomeres are hallmarks and molecular drivers of aging, as well as fundamental integrating components of the cumulative effects of genetic, lifestyle, and environmental factors that erode telomere length over time. Ongoing telomere attrition and the resulting limit to replicative potential imposed by cellular senescence serves a powerful tumor suppressor function, and also underlies aging and a spectrum of age-related degenerative pathologies, including reduced fertility, dementias, cardiovascular disease and cancer. However, very little data exists regarding the extraordinary stressors and exposures associated with long-duration space exploration and eventual habitation of other planets, nor how such missions will influence telomeres, reproduction, health, disease risk, and aging. Here, we briefly review our current understanding, which has advanced significantly in recent years as a result of the NASA Twins Study, the most comprehensive evaluation of human health effects associated with spaceflight ever conducted. Thus, the Twins Study is at the forefront of personalized space medicine approaches for astronauts and sets the stage for subsequent missions. We also extrapolate from current understanding to future missions, highlighting potential biological and biochemical strategies that may enable human survival, and consider the prospect of longevity in the extreme environment of space.},
}
@article {pmid38580193,
year = {2024},
author = {Yun, JJ and Unai, S and Budev, MM and Anandamurthy, B and Almeida, F and Turowski, J and McCurry, KR and Pettersson, G},
title = {Salvage Lung Retransplantation: En-Bloc Double Lung with Bronchial Artery Revascularization For Bronchial Dehiscence Related to Short Telomeres.},
journal = {The Journal of thoracic and cardiovascular surgery},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jtcvs.2024.03.026},
pmid = {38580193},
issn = {1097-685X},
}
@article {pmid38577209,
year = {2024},
author = {Rodseth, E and Sumasgutner, P and Tate, G and Nilsson, JF and Watson, H and Maritz, MF and Ingle, RA and Amar, A},
title = {Pleiotropic effects of melanin pigmentation: haemoparasite infection intensity but not telomere length is associated with plumage morph in black sparrowhawks.},
journal = {Royal Society open science},
volume = {11},
number = {4},
pages = {230370},
pmid = {38577209},
issn = {2054-5703},
abstract = {There is increasing recognition of the potential pleiotropic effects of melanin pigmentation, particularly on immunity, with reports of variation in haemoparasite infection intensity and immune responses between the morphs of colour-polymorphic bird species. In a population of the black sparrowhawk (Accipiter melanoleucus) in western South Africa, light morphs have a higher haemoparasite infection intensity, but no physiological effects of this are apparent. Here, we investigate the possible effects of haemoparasite infection on telomere length in this species and explore whether relative telomere length is associated with either plumage morph or sex. Using quantitative polymerase chain reaction analysis, we confirmed that dark morphs had a lower haemoparasite infection intensity than light morphs. However, we found no differences in telomere length associated with either the haemoparasite infection status or morph in adults, although males have longer telomeres than females. While differences in haemoparasite intensity between morphs are consistent with pleiotropic effects of melanin pigmentation in the black sparrowhawk, we found no evidence that telomere length was associated with haemoparasite infection. Further work is needed to investigate the implications of possible pleiotropic effects of plumage morph and their potential role in the maintenance of colour polymorphism in this species.},
}
@article {pmid38577142,
year = {2024},
author = {Prasad, R and Kaur, G},
title = {Recent Domains in Telomere and Telomerase Targeting for Accomplished Cancer Therapy.},
journal = {Indian journal of clinical biochemistry : IJCB},
volume = {39},
number = {2},
pages = {151-153},
pmid = {38577142},
issn = {0970-1915},
}
@article {pmid38574731,
year = {2024},
author = {LaBella, KA and Hsu, WH and Li, J and Qi, Y and Liu, Y and Liu, J and Wu, CC and Liu, Y and Song, Z and Lin, Y and Blecher, JM and Jiang, S and Shang, X and Han, J and Spring, DJ and Zhang, J and Xia, Y and DePinho, RA},
title = {Telomere dysfunction alters intestinal stem cell dynamics to promote cancer.},
journal = {Developmental cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.devcel.2024.03.020},
pmid = {38574731},
issn = {1878-1551},
abstract = {Telomere dynamics are linked to aging hallmarks, and age-associated telomere loss fuels the development of epithelial cancers. In Apc-mutant mice, the onset of DNA damage associated with telomere dysfunction has been shown to accelerate adenoma initiation via unknown mechanisms. Here, we observed that Apc-mutant mice engineered to experience telomere dysfunction show accelerated adenoma formation resulting from augmented cell competition and clonal expansion. Mechanistically, telomere dysfunction induces the repression of EZH2, resulting in the derepression of Wnt antagonists, which causes the differentiation of adjacent stem cells and a relative growth advantage to Apc-deficient telomere dysfunctional cells. Correspondingly, in this mouse model, GSK3β inhibition countered the actions of Wnt antagonists on intestinal stem cells, resulting in impaired adenoma formation of telomere dysfunctional Apc-mutant cells. Thus, telomere dysfunction contributes to cancer initiation through altered stem cell dynamics, identifying an interception strategy for human APC-mutant cancers with shortened telomeres.},
}
@article {pmid38566416,
year = {2024},
author = {Amiard, S and Feit, L and Vanrobays, E and Simon, L and Le Goff, S and Loizeau, L and Wolff, L and Butter, F and Bourbousse, C and Barneche, F and Tatout, C and Probst, AV},
title = {The TELOMERE REPEAT BINDING proteins TRB4 and TRB5 function as transcriptional activators of PRC2-controlled genes to regulate plant development.},
journal = {Plant communications},
volume = {},
number = {},
pages = {100890},
doi = {10.1016/j.xplc.2024.100890},
pmid = {38566416},
issn = {2590-3462},
abstract = {Plant-specific transcriptional regulators called TELOMERE REPEAT BINDING proteins (TRBs) combine two DNA-binding domains, the GH1 domain, which binds to linker DNA and is shared with H1 histones, and the Myb/SANT domain, which specifically recognizes the telobox DNA-binding site motif. TRB1, TRB2, and TRB3 proteins recruit Polycomb group complex 2 (PRC2) to deposit H3K27me3 and JMJ14 to remove H3K4me3 at gene promoters containing telobox motifs to repress transcription. Here, we demonstrate that TRB4 and TRB5, two related paralogs belonging to a separate TRB clade conserved in spermatophytes, regulate the transcription of several hundred genes involved in developmental responses to environmental cues. Indeed, TRB4 binds to several thousand sites in the genome, mainly at TSS and promoter regions of transcriptionally active and H3K4me3-marked genes, but unlike TRB1 it is not enriched at H3K27me3-marked gene bodies. Yet, TRB4 can physically interact with the catalytic components of PRC2, SWINGER and CURLY LEAF (CLF). Unexpectedly, we show that TRB4 and TRB5 are required for distinctive phenotypic traits observed in clf mutant plants and accordingly function as transcriptional activators of several hundred of CLF-controlled genes, including key flowering genes. We further demonstrate that TRB4 shares multiple target genes with TRB1 and physically and genetically interacts with members of both TRB clades. Collectively, this study uncovers that TRB proteins engage in both positive and negative interactions with other members of the family to regulate plant development through both PRC2-dependent and independent mechanisms.},
}
@article {pmid38565156,
year = {2024},
author = {Ravindran, S and Underwood, SL and Dorrens, J and Seeker, LA and Watt, K and Wilbourn, RV and Sparks, AM and Sinclair, R and Chen, Z and Pilkington, JG and McNeilly, TN and Harrington, L and Pemberton, JM and Nussey, DH and Froy, H},
title = {No correlative evidence of costs of infection or immunity on leucocyte telomere length in a wild population of Soay sheep.},
journal = {Proceedings. Biological sciences},
volume = {291},
number = {2020},
pages = {20232946},
doi = {10.1098/rspb.2023.2946},
pmid = {38565156},
issn = {1471-2954},
abstract = {Telomere length (TL) is a biomarker hypothesized to capture evolutionarily and ecologically important physiological costs of reproduction, infection and immunity. Few studies have estimated the relationships among infection status, immunity, TL and fitness in natural systems. The hypothesis that short telomeres predict reduced survival because they reflect costly consequences of infection and immune investment remains largely untested. Using longitudinal data from a free-living Soay sheep population, we tested whether leucocyte TL was predicted by infection with nematode parasites and antibody levels against those parasites. Helminth parasite burdens were positively associated with leucocyte TL in both lambs and adults, which is not consistent with TL reflecting infection costs. We found no association between TL and helminth-specific IgG levels in either young or old individuals which suggests TL does not reflect costs of an activated immune response or immunosenescence. Furthermore, we found no support for TL acting as a mediator of trade-offs between infection, immunity and subsequent survival in the wild. Our results suggest that while variation in TL could reflect short-term variation in resource investment or environmental conditions, it does not capture costs of infection and immunity, nor does it behave like a marker of an individual's helminth-specific antibody immune response.},
}
@article {pmid38565848,
year = {2024},
author = {Muoio, D and Laspata, N and Dannenberg, RL and Curry, C and Darkoa-Larbi, S and Hedglin, M and Uttam, S and Fouquerel, E},
title = {PARP2 promotes Break Induced Replication-mediated telomere fragility in response to replication stress.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {2857},
pmid = {38565848},
issn = {2041-1723},
support = {R35GM142982//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; },
abstract = {PARP2 is a DNA-dependent ADP-ribosyl transferase (ARTs) enzyme with Poly(ADP-ribosyl)ation activity that is triggered by DNA breaks. It plays a role in the Base Excision Repair pathway, where it has overlapping functions with PARP1. However, additional roles for PARP2 have emerged in the response of cells to replication stress. In this study, we demonstrate that PARP2 promotes replication stress-induced telomere fragility and prevents telomere loss following chronic induction of oxidative DNA lesions and BLM helicase depletion. Telomere fragility results from the activity of the break-induced replication pathway (BIR). During this process, PARP2 promotes DNA end resection, strand invasion and BIR-dependent mitotic DNA synthesis by orchestrating POLD3 recruitment and activity. Our study has identified a role for PARP2 in the response to replication stress. This finding may lead to the development of therapeutic approaches that target DNA-dependent ART enzymes, particularly in cancer cells with high levels of replication stress.},
}
@article {pmid38565642,
year = {2024},
author = {Huang, R and Bornman, MSR and Stricker, PD and Simoni Brum, I and Mutambirwa, SBA and Jaratlerdsiri, W and Hayes, VM},
title = {The impact of telomere length on prostate cancer aggressiveness, genomic instability and health disparities.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {7706},
pmid = {38565642},
issn = {2045-2322},
support = {International Research Training Program Scholarship//Australian Government/ ; APP2001098//National Health and Medical Research Council/ ; APP2001098//National Health and Medical Research Council/ ; PC210168//Congressionally Directed Medical Research Programs/ ; PC210168//Congressionally Directed Medical Research Programs/ ; Petre Chair//Petre Foundation/ ; },
abstract = {The telomere repetitive TTAGGG motif at the ends of chromosomes, serves to preserve genomic integrity and chromosomal stability. In turn, genomic instability is a hallmark of cancer-implicating telomere disturbance. Prostate cancer (PCa) shows significant ancestral disparities, with men of African ancestry at the greatest risk for aggressive disease and associated genomic instability. Yet, no study has explored the role of telomere length (TL) with respect to ancestrally driven PCa health disparities. Patient- and technically-matched tumour-blood whole genome sequencing data for 179 ancestrally defined treatment naïve PCa patients (117 African, 62 European), we assessed for TL (blood and tumour) associations. We found shortened tumour TL to be associated with aggressive PCa presentation and elevated genomic instabilities, including percentage of genome alteration and copy number gains, in men of African ancestry. For European patients, tumour TL showed significant associations with PCa driver genes PTEN, TP53, MSH2, SETBP1 and DDX11L1, while shorter blood TL (< 3200 base pairs) and tumour TL (< 2861 base pairs) were correlated with higher risk for biochemical recurrence. Concurring with previous studies linking TL to PCa diagnosis and/or prognosis, for the first time we correlated TL differences with patient ancestry with important implications for future treatments targeting telomere dysfunction.},
}
@article {pmid38559121,
year = {2024},
author = {Estrem, B and Davis, RE and Wang, J},
title = {End resection and telomere healing of DNA double-strand breaks during nematode programmed DNA elimination.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.03.15.585292},
pmid = {38559121},
abstract = {Most DNA double-strand breaks (DSBs) are harmful to genome integrity. However, some forms of DSBs are essential to biological processes, such as meiotic recombination and V(D)J recombination. DSBs are also required for programmed DNA elimination (PDE) in ciliates and nematodes. In nematodes, the DSBs are healed with telomere addition. While telomere addition sites have been well-characterized, little is known regarding the DSBs that fragment nematode chromosomes. Here, we used embryos from the nematode Ascaris to study the timing of PDE breaks and examine the DSBs and their end processing. Using END-seq, we characterize the DSB ends and demonstrate that DNA breaks are introduced before mitosis, followed by extensive end resection. The resection profile is unique for each break site, and the resection generates 3' overhangs before the addition of telomeres. Interestingly, telomere healing occurs much more frequently on retained DSB ends than on eliminated ends. This biased repair of the DSB ends in Ascaris may be due to the sequestration of the eliminated DNA into micronuclei, preventing their ends from telomere healing. Additional DNA breaks occur within the eliminated DNA in both Ascaris and Parascaris , ensuring chromosomal breakage and providing a fail-safe mechanism for nematode PDE.},
}
@article {pmid38553835,
year = {2024},
author = {Kirk, B and Kuo, CL and Liu, P and Xiang, M and Earp, JE and Kositsawat, J and Kuchel, GA and Duque, G},
title = {Leukocyte telomere length is associated with MRI-thigh fat-free muscle volume: data from 16 356 UK Biobank adults.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {},
number = {},
pages = {},
doi = {10.1002/jcsm.13461},
pmid = {38553835},
issn = {2190-6009},
support = {NR018963-01A1//National Institute of Nursing Research, National Institute of Health, USA/ ; P30AG067988//National Institute on Aging, National Institute of Health, USA./ ; //TSI Pharmaceuticals/ ; ICG001874//Australian Government (Department of Industry, Science and Resources)/ ; },
abstract = {BACKGROUND: Telomere attrition may share common biological mechanisms with bone and muscle loss with aging. Here, we investigated the association between these hallmarks of aging using data from UK Biobank, a large observational study.<br><br>METHODS: Leukocyte telomere length (LTL as T/S ratio) was measured using a multiplex qPCR assay at baseline (2006-2010). Bone mineral density (whole body and regional; via dual-energy X-ray absorptiometry), trabecular bone score (via lumbar-spine dual-energy X-ray absorptiometry images), fat-free muscle volume (thighs; via magnetic resonance imaging), and muscle fat infiltration (thighs; via magnetic resonance imaging) were measured during the imaging visit (2014-2018). Regression models were used to model LTL against a muscle or bone outcome, unadjusted and adjusted for covariates.<br><br>RESULTS: A total of 16&#xa0;356 adults (mean age: 62.8&#xa0;&#xb1;&#xa0;7.5&#xa0;years, 50.5% women) were included. In the fully adjusted model, thigh fat-free muscle volume was associated with LTL in the overall sample (adjusted standardized &#x3b2; (a&#x3b2;)&#xa0;=&#xa0;0.017, 95% CI 0.009 to 0.026, P&#xa0;<&#xa0;0.001, per SD increase in LTL), with stronger associations in men (a&#x3b2;&#xa0;=&#xa0;0.022, 95% CI 0.010 to 0.034, P&#xa0;<&#xa0;0.001) than in women (a&#x3b2;&#xa0;=&#xa0;0.013, 95% CI 0.000 to 0.025, P&#xa0;=&#xa0;0.041) (sex-LTL P&#xa0;=&#xa0;0.028). The adjusted odds ratio (aOR) for low thigh fat-free muscle volume (body mass index-adjusted, sex-specific bottom 20%) was 0.93 per SD increase in LTL (95% CI 0.89 to 0.96, P&#xa0;<&#xa0;0.001) in the overall sample, with stronger associations in men (aOR&#xa0;=&#xa0;0.92, 95% CI 0.87 to 0.99, P&#xa0;=&#xa0;0.008) than women (aOR&#xa0;=&#xa0;0.93, 95% CI 0.88 to 0.98, P&#xa0;=&#xa0;0.009), although the sex difference was not statistically significant in this model (sex-LTL P&#xa0;=&#xa0;0.37). LTL was not associated with bone mineral density, trabecular bone score, or muscle fat infiltration in the overall or subgroup analyses (P&#xa0;>&#xa0;0.05).<br><br>CONCLUSIONS: LTL was consistently associated with thigh fat-free muscle volume in men and women. Future research should investigate moderating effects of lifestyle factors (e.g., physical activity, nutrition, or chronic diseases) in the association between LTL and muscle volume.},
}
@article {pmid38552826,
year = {2024},
author = {Dehdashti, B and Miri, M and Khanahmad, H and Feizi, A and Mohammadi, F and Rouholamin, S and Amin, MM},
title = {In-Utero exposure to potential sources of indoor air pollution and umbilical cord blood leukocyte telomere length.},
journal = {Environmental research},
volume = {},
number = {},
pages = {118791},
doi = {10.1016/j.envres.2024.118791},
pmid = {38552826},
issn = {1096-0953},
abstract = {Indoor air pollution (IAP) has been associated with various adverse health effects. However, the evidence regarding such an association with leukocyte telomere length (LTL) in cord blood samples is still scarce. Therefore, the present study aimed to assess the relationship between exposure to indicators of IAP and LTL in umbilical cord blood samples. This cross-sectional study was based on 188 mother-newborn pairs who participated in our study between 2020 and 2022 in Isfahan, Iran. Umbilical LTL was measured by quantitative real-time polymerase chain reaction (qRT-PCR) technique. Linear mixed-effect models were used to assess the relationship between IAP indicators and umbilical LTL, adjusted for relevant covariates. The median (interquartile range (IQR)) of umbilical LTL was 0.92 (0.47). In fully adjusted models, frequency of using degreasing spray during pregnancy (times per month) (β = -0.047, 95% CI:0.09, -0.05, P-value = 0.02), using air freshener spray during pregnancy (β = -0.26, 95% CI: -0.5, -0.02, P-value = 0.03) and frequency of using insecticides during pregnancy (times per month) (β = -0.025, 95% CI: -0.047, -0.003, P-value = 0.02) were significantly associated with shorter umbilical LTL. There was a positive significant relationship between the frequency of using cleaning spray during pregnancy (times per month) with umbilical LTL (β = 0.019, 95% CI: 0.005, 0.033, P-value = 0.01). Furthermore, the direct connection of the parking with home and the frequency of using barbecue (times per week) were marginally associated with shorter umbilical LTL. For other indicators of IAP, we did not observe any statistically significant associations. Overall, this study suggested a negative association between prenatal exposure to IAP during pregnancy and umbilical LTL.},
}
@article {pmid38550590,
year = {2024},
author = {Kraft, BD and Verhulst, S and Lai, TP and Sullenger, BA and Wang, Y and Rountree, W and Chen, L and Woods, CW and Denny, TN and Aviv, A},
title = {T-cell count and T-cell telomere length in patients with severe COVID-19.},
journal = {Frontiers in immunology},
volume = {15},
number = {},
pages = {1356638},
doi = {10.3389/fimmu.2024.1356638},
pmid = {38550590},
issn = {1664-3224},
abstract = {Lymphocyte telomere length (TL) is highly variable and shortens with age. Short telomeres may impede TL-dependent T-cell clonal expansion with viral infection. As SARS-CoV-2 infection can induce prolonged and severe T-cell lymphopenia, infected adults, and particularly older adults with short telomeres, may display severe T-cell lymphopenia. To examine the relationship between T-cell TL parameters and T-cell counts, we studied 40 patients hospitalized with severe COVID-19. T-cells were isolated from lymphocytes, counted using flow cytometry, and their TL parameters were measured using the Telomere Shortest Length Assay. The cohort (median age = 62 years, 27% female) was racially and ethnically diverse (33% White, 35% Black, and 33% Other). On intensive care unit study day 1, T-cell count (mean=1.03 x10[9]/L) was inversely related to age (p=0.007) and higher in females than males (p=0.025). Mean TL was 3.88 kilobases (kb), and 45.3% of telomeres were shorter than 3 kb. Using multiple regression analysis and adjusting for age and sex, T-cell count decreased with increased proportion of T-cell telomeres shorter than 3 kb (p=0.033) and increased with mean TL (p=0.052). Our findings suggest an association between the buildup of short telomeres within T-cells and explain in part reduced peripheral blood T-cell counts in patients with severe COVID-19. Shortened T-cell telomeres may be a risk factor for COVID-19-associated T-cell lymphopenia.},
}
@article {pmid38542157,
year = {2024},
author = {Pochechueva, TV and Schwenzer, N and Kohl, T and Brandenburg, S and Kaltenecker, G and Wollnik, B and Lehnart, SE},
title = {3D Super-Resolution Nuclear Q-FISH Imaging Reveals Cell-Cycle-Related Telomere Changes.},
journal = {International journal of molecular sciences},
volume = {25},
number = {6},
pages = {},
doi = {10.3390/ijms25063183},
pmid = {38542157},
issn = {1422-0067},
support = {EXC 2067//Deutsche Forschungsgemeinschaft/ ; },
abstract = {We present novel workflows for Q-FISH nanoscopy with the potential for prognostic applications and resolving novel chromatin compaction changes. DNA-fluorescence in situ hybridization (DNA-FISH) is a routine application to visualize telomeres, repetitive terminal DNA sequences, in cells and tissues. Telomere attrition is associated with inherited and acquired diseases, including cancer and cardiomyopathies, and is frequently analyzed by quantitative (Q)-FISH microscopy. Recently, nanoscopic imaging techniques have resolved individual telomere dimensions and their compaction as a prognostic marker, in part leading to conflicting conclusions still unresolved to date. Here, we developed a comprehensive Q-FISH nanoscopy workflow to assess telomeres with PNA telomere probes and 3D-Stimulated Emission Depletion (STED) microscopy combined with Dynamic Intensity Minimum (DyMIN) scanning. We achieved single-telomere resolution at high, unprecedented telomere coverage. Importantly, our approach revealed a decrease in telomere signal density during mitotic cell division compared to interphase. Innovatively expanding FISH-STED applications, we conducted double FISH targeting of both telomere- and chromosome-specific sub-telomeric regions and accomplished FISH-STED in human cardiac biopsies. In summary, this work further advanced Q-FISH nanoscopy, detected a new aspect of telomere compaction related to the cell cycle, and laid the groundwork for future applications in complex cell types such as post-mitotic neurons and muscle cells.},
}
@article {pmid38540683,
year = {2024},
author = {Olson, CL and Wuttke, DS},
title = {Guardians of the Genome: How the Single-Stranded DNA-Binding Proteins RPA and CST Facilitate Telomere Replication.},
journal = {Biomolecules},
volume = {14},
number = {3},
pages = {},
doi = {10.3390/biom14030263},
pmid = {38540683},
issn = {2218-273X},
support = {R01 GM139274/NH/NIH HHS/United States ; },
abstract = {Telomeres act as the protective caps of eukaryotic linear chromosomes; thus, proper telomere maintenance is crucial for genome stability. Successful telomere replication is a cornerstone of telomere length regulation, but this process can be fraught due to the many intrinsic challenges telomeres pose to the replication machinery. In addition to the famous "end replication" problem due to the discontinuous nature of lagging strand synthesis, telomeres require various telomere-specific steps for maintaining the proper 3' overhang length. Bulk telomere replication also encounters its own difficulties as telomeres are prone to various forms of replication roadblocks. These roadblocks can result in an increase in replication stress that can cause replication forks to slow, stall, or become reversed. Ultimately, this leads to excess single-stranded DNA (ssDNA) that needs to be managed and protected for replication to continue and to prevent DNA damage and genome instability. RPA and CST are single-stranded DNA-binding protein complexes that play key roles in performing this task and help stabilize stalled forks for continued replication. The interplay between RPA and CST, their functions at telomeres during replication, and their specialized features for helping overcome replication stress at telomeres are the focus of this review.},
}
@article {pmid38540177,
year = {2024},
author = {Younoussa, H and Gadji, M and Soumboundou, M and Colicchio, B and Said, A and Ndoye, NA and Junker, S and Plesch, A and Heidingsfelder, L and Diagne, NR and Dieterlen, A and Voisin, P and Carde, P and Jeandidier, E and M'kacher, R},
title = {Telomere Dysfunction in Pediatric Patients with Differences/Disorders of Sexual Development.},
journal = {Biomedicines},
volume = {12},
number = {3},
pages = {},
doi = {10.3390/biomedicines12030565},
pmid = {38540177},
issn = {2227-9059},
abstract = {UNLABELLED: Differences/Disorders of sex development (DSDs) are conditions in which the development of chromosomal, gonadal, and anatomical sexes is atypical. DSDs are relatively rare, but their incidence is becoming alarmingly common in sub-Saharan Africa (SSA). Their etiologies and mechanisms are poorly understood. Therefore, we have investigated cytogenetic profiles, including telomere dysfunction, in a retrospective cohort of Senegalese DSD patients.<br><br>MATERIALS AND METHODS: Peripheral blood lymphocytes were sampled from 35 DSD patients (mean age: 3.3 years; range 0-18 years) admitted to two hospital centers in Dakar. Peripheral blood lymphocytes from 150 healthy donors were used as a control. Conventional cytogenetics, telomere, and centromere staining followed by multiplex FISH, as well as FISH with SRY-specific probes, were employed.<br><br>RESULTS: Cytogenetic analysis identified 19 male and 13 female patients with apparently normal karyotypes, two patients with Turner syndrome, and one patient with Klinefelter syndrome. Additional structural chromosome aberrations were detected in 22% of the patients (8/35). Telomere analysis revealed a reduction in mean telomere lengths of DSD patients compared to those of healthy donors of similar age. This reduction in telomere length was associated with an increased rate of telomere aberrations (telomere loss and the formation of telomere doublets) and the presence of additional chromosomal aberrations.<br><br>CONCLUSIONS: To the best of our knowledge, this study is the first to demonstrate a correlation between telomere dysfunction and DSDs. Further studies may reveal the link between telomere dysfunction and possible mechanisms involved in the disease itself, such as DNA repair deficiency or specific gene mutations. The present study demonstrates the relevance of implementing telomere analysis in prenatal tests as well as in diagnosed genetic DSD disorders.},
}
@article {pmid38540151,
year = {2024},
author = {Duseikaite, M and Vilkeviciute, A and Kunceviciene, E and Gedvilaite, G and Kriauciuniene, L and Liutkeviciene, R},
title = {Associations between ZNF676, CTC1 Gene Polymorphisms and Relative Leukocyte Telomere Length with Myopia and Its Degree.},
journal = {Biomedicines},
volume = {12},
number = {3},
pages = {},
doi = {10.3390/biomedicines12030538},
pmid = {38540151},
issn = {2227-9059},
abstract = {BACKGROUND: The interaction between environmental and genetic factors that influence eye growth, regulated by vision, contributes to the development and progression of myopia. This dynamic interaction significantly contributes to the multifaceted development and progression of myopia, a prevalent ocular condition. Our study delves into the associations between ZNF676 and CTC1 gene polymorphisms and their impact on the relative leukocyte telomere length (relative LTL) in myopia, as well as its degree. By unravelling these underpinnings in conjunction with environmental influences, we aim to enhance our understanding of the complex mechanisms that drive the onset and severity of myopia.<br><br>METHODS: This study included patients with myopia and ophthalmologically healthy subjects. DNA was extracted from peripheral venous blood by the salting out method. Genotyping of ZNF676 rs412658 and CTC1 rs3027234, as well as the measurement of relative LTL, were conducted using a real-time polymerase chain reaction method (RT-PCR). The data obtained were statistically analyzed using the "IBM SPSS Statistics 29.0" software program.<br><br>RESULTS: The results show that myopic patients who are homozygous for the rs3027234 rare allele genotype of the CTC1 gene have statistically significantly shorter relative LTL compared to patients with the CC and CT genotypes. Also, men with the CTC1 rs3027234 TT genotype have statistically significantly longer leukocyte telomeres than women with the same genotype. The respective median (IQR) of the relative LTL for women and men is 0.280 (0.463) vs. 0.696 (0.440), with a p-value of 0.027. The myopia group with the ZNF676 rs412658 CC genotype has statistically significantly shorter leukocyte telomeres than the control group with the same genotype (age &#x2264; 29), and the p-value is 0.011. Also, the myopia group with the ZNF676 rs412658 CT and CTC1 rs3027234 CT genotypes have statistically significantly longer leukocyte telomeres than the control group with the same genotypes (age > 29), with p-values that are, respectively, 0.016 and 0.012. The evaluation of the genotype distributions of the polymorphisms in the myopia patients showed that ZNF676 rs412658 CT genotype carriers have 4-fold decreased odds of high myopia occurrence (OR = 0.250; CI: 0.076-0.826; p = 0.023). Also, the evaluation of the allele distributions of the polymorphism under the additive genetic model in the myopia group showed that the ZNF676 rs412658 T allele was associated with similar odds of high myopia (OR = 0.269; 95% CI: 0.090-0.807; p = 0.019). The comprehensive p-value, assessing the relative LTL of subjects across the different levels of myopia, signifies a statistical difference in the relative LTL among individuals with varying degrees of myopia. There was a statistically significant difference in relative LTL between mild and moderate myopia degrees (0.819 (1.983) vs. 0.083 (0.930), p = 0.007).<br><br>CONCLUSIONS: CTC1 rs3027234 TT may be considered a protective genotype for telomere shortening in men, while the overall telomere shortening might be linked to the worse myopia degree. The ZNF676 rs412658 T allele may protect against a high myopia occurrence.},
}
@article {pmid38539016,
year = {2024},
author = {Mutz, J and Wong, WLE and Powell, TR and Young, AH and Dawe, GS and Lewis, CM},
title = {The duration of lithium use and biological ageing: telomere length, frailty, metabolomic age and all-cause mortality.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {38539016},
issn = {2509-2723},
abstract = {Lithium is an established first-line treatment for bipolar disorder. Beyond its therapeutic effect as a mood stabiliser, lithium exhibits potential anti-ageing effects. This study aimed to examine the relationship between the duration of lithium use, biological ageing and mortality. The UK Biobank is an observational study of middle-aged and older adults. We tested associations between the duration of lithium use (number of prescriptions, total duration of use and duration of the first prescription period) and telomere length, frailty, metabolomic age (MileAge) delta, pulse rate and all-cause mortality. Five hundred ninety-one individuals (mean age = 57.49 years; 55% females) had been prescribed lithium. There was no evidence that the number of prescriptions (β = - 0.022, 95% CI - 0.081 to 0.037, p = 0.47), the total duration of use (β = - 0.005, 95% CI - 0.023 to 0.013, p = 0.57) or the duration of the first prescription period (β = - 0.018, 95% CI - 0.051 to 0.015, p = 0.29) correlated with telomere length. There was also no evidence that the duration of lithium use correlated with frailty or MileAge delta. However, a higher prescription count and a longer duration of use was associated with a lower pulse rate. The duration of lithium use did not predict all-cause mortality. We observed no evidence of associations between the duration of lithium use and biological ageing markers, including telomere length. Our findings suggest that the potential anti-ageing effects of lithium do not differ by the duration of use.},
}
@article {pmid38533417,
year = {2024},
author = {Xu, B and Ren, J and Zhu, S and Ding, Y and Zhou, W and Guo, Q and Fang, Y and Zheng, J},
title = {Causal relationship between telomere length and risk of intracranial aneurysm: a bidirectional Mendelian randomization study.},
journal = {Frontiers in neurology},
volume = {15},
number = {},
pages = {1355895},
pmid = {38533417},
issn = {1664-2295},
abstract = {BACKGROUND: Telomere length is closely linked to the aging phenotype, where cellular aging results in the production of a cascade of cell factors and the senescence-associated secretory phenotype (SASP), leading to an inflammatory response. The presence of inflammation plays a crucial role in the formation of intracranial aneurysms. Nevertheless, the relationship between telomere length and intracranial aneurysms remains unclear. This study aims to explore the causal connection between telomere length and intracranial aneurysms through the utilization of Mendelian randomization (MR) analysis.<br><br>METHODS: Data on telomere length were obtained from the genome-wide association studies conducted on the UK Biobank, comprising a total of 472,174 participants. Data on intracranial aneurysms were obtained from the summary dataset of the Global Genome-wide Association Study (GWAS) conducted by the International Stroke Genetics Consortium. The dataset consisted of 7,495 cases and 71,934 controls, all of European descent. Initially, the linkage disequilibrium score was used to investigate the connection between telomere length and intracranial aneurysms. Subsequently, a bidirectional MR was conducted using two-sample analysis to assess whether there is a causal connection between telomere length and intracranial aneurysm risk. The results were analyzed utilizing five MR methods, with the inverse variance weighted method serving as the main methodology. In addition, we did various analyses to evaluate the presence of heterogeneity, pleiotropy, and sensitivity in the study results. A reverse MR analysis was conducted to investigate potential reverse causal links.<br><br>RESULTS: In the forward MR analysis, it was observed that both the inverse variance-weighted and weighted median analyses implied a potential causal relationship between longer telomere length and a decreased incidence of intracranial aneurysms (IVW: OR&#x2009;=&#x2009;0.66, 95% CI: 0.47-0.92, p&#x2009;=&#x2009;1.49&#x2009;&#xd7;&#x2009;10[-2]). There was no heterogeneity or horizontal pleiotropy. The findings were verified to be robust through the utilization of leave-one-out analysis. The use of reverse MR analysis did not establish a potential causal link between the occurrence of intracranial aneurysms and telomere length.<br><br>CONCLUSION: There may exist a potential correlation between longer telomere length and a decreased likelihood of intracranial aneurysms within the European population. The present study offers novel insights into the correlation between telomere length and intracranial aneurysms. Additional research is required to clarify the underlying mechanisms and validate our discoveries in diverse populations.},
}
@article {pmid38525449,
year = {2024},
author = {Chauhan, VS and Sibin, MK and Yadav, P and Sharma, M},
title = {To study childhood trauma in patients with bipolar affective disorder and its association with leucocyte telomere length.},
journal = {Medical journal, Armed Forces India},
volume = {80},
number = {2},
pages = {184-191},
pmid = {38525449},
issn = {0377-1237},
abstract = {BACKGROUND: Childhood traumatic (CT) events are more frequent in Bipolar Affective Disorder (BD) than in healthy individuals. As per existing studies, telomere shortening might be associated with psychiatric illnesses and aging-related disorders. One basis could be CT in BD aiding in telomere shortening.<br><br>METHODS: 100 BD patients and 100 healthy controls (HC) were matched for age and sex. All the participants were administered Childhood Trauma Questionnaire (CTQ). Subsequently, Quantitative Polymerase Chain Reaction (q-PCR) was performed in order to verify leukocyte telomere length (LTL) for both cases and controls.<br><br>RESULTS: Presence of subtypes of moderate to severe CT among cases revealed emotional abuse in 35%, physical abuse in 16%, and sexual abuse in 15%. BD patients had significantly shorter telomeres in comparison to HC. BD patients with CT had significantly shorter LTL as compared to healthy controls with CT. The association between CT and LTL was not statistically significant in cases as well as in controls.<br><br>CONCLUSIONS: Our study revealed presence of CT (moderate to severe) in 46% of BD patients and 12% in age and sex-matched healthy controls. All CT subtypes except sexual abuse were significantly higher among cases than in healthy controls. Mean score of LTL among cases including that with CT was significantly lower than the healthy controls.},
}
@article {pmid38519061,
year = {2024},
author = {Lieber, SB and Lipschultz, RA and Syed, S and Rajan, M and Venkatraman, S and Lin, M and Reid, MC and Lue, NF and Mandl, LA},
title = {Association of phenotypic frailty and hand grip strength with telomere length in SLE.},
journal = {Lupus science &amp; medicine},
volume = {11},
number = {1},
pages = {},
doi = {10.1136/lupus-2023-001008},
pmid = {38519061},
issn = {2053-8790},
abstract = {OBJECTIVE: Frailty and objective hand grip strength (one of the components of the frailty phenotype) are both risk factors for worse health outcomes in SLE. Whether telomere length, an established cellular senescence marker, is a biologic correlate of the frailty phenotype and hand grip strength in patients with SLE is not clear. First, we aimed to evaluate differences in telomere length between frail and non-frail women with SLE and then assessed whether frailty or hand grip strength is differentially associated with telomere length after adjusting for relevant confounders.<br><br>METHODS: Women &#x2265;18 years of age with validated SLE enrolled at a single medical centre. Fried frailty status (which includes hand grip strength), clinical characteristics and telomere length were assessed cross-sectionally. Differences between frail and non-frail participants were evaluated using Fisher's exact or Wilcoxon rank-sum tests. The associations between frailty and hand grip strength and telomere length were determined using linear regression.<br><br>RESULTS: Of the 150 enrolled participants, 131 had sufficient data for determination of frailty classification; 26% were frail with a median age of 45 years. There was a non-significant trend towards shorter telomere length in frail versus non-frail participants (p=0.07). Hand grip strength was significantly associated with telomere length (beta coefficient 0.02, 95%&#x2009;CI 0.004, 0.04), including after adjustment for age, SLE disease activity and organ damage, and comorbidity (beta coefficient 0.02, 95%&#x2009;CI 0.002, 0.04).<br><br>CONCLUSIONS: Decreased hand grip strength, but not frailty, was independently associated with shortened telomere length in a cohort of non-elderly women with SLE. Frailty in this middle-aged cohort may be multifactorial rather than strictly a manifestation of accelerated ageing.},
}
@article {pmid38518608,
year = {2024},
author = {Wei, B and Zhou, Y and Li, Q and Zhen, S and Wu, Q and Xiao, Z and Liao, J and Zhu, B and Duan, J and Yang, X and Liang, F},
title = {Outdoor fine particulate matter exposure and telomere length in humans: A systematic review and meta-analysis.},
journal = {Ecotoxicology and environmental safety},
volume = {275},
number = {},
pages = {116206},
doi = {10.1016/j.ecoenv.2024.116206},
pmid = {38518608},
issn = {1090-2414},
abstract = {Although the association between changes in human telomere length (TL) and ambient fine particulate matter (PM2.5) has been documented, there remains disagreement among the related literature. Our study conducted a systematic review and meta-analysis of epidemiological studies to investigate the health effects of outdoor PM2.5 exposure on human TL after a thorough database search. To quantify the overall effect estimates of TL changes associated with every 10 μg/m[3] increase in PM2.5 exposure, we focused on two main topics, which were outdoor long-term exposure and prenatal exposure of PM2.5. Additionally, we included a summary of short-term PM2.5 exposure and its impact on TL due to limited data availability. Our qualitative analysis included 20 studies with 483,600 participants. The meta-analysis showed a statistically significant association between outdoor PM2.5 exposure and shorter human TL, with pooled impact estimates (β) of -0.12 (95% CI: -0.20, -0.03, I[2]= 95.4%) for general long-term exposure and -0.07 (95% CI: -0.15, 0.00, I[2]= 74.3%) for prenatal exposure. In conclusion, our findings suggest that outdoor PM2.5 exposure may contribute to TL shortening, and noteworthy associations were observed in specific subgroups, suggesting the impact of various research variables. Larger, high-quality studies using standardized methodologies are necessary to strengthen these conclusions further.},
}
@article {pmid38516039,
year = {2024},
author = {Carver, AJ and Hing, B and Elser, BA and Lussier, SJ and Yamanashi, T and Howard, MA and Kawasaki, H and Shinozaki, G and Stevens, HE},
title = {Correlation of telomere length in brain tissue with peripheral tissues in living human subjects.},
journal = {Frontiers in molecular neuroscience},
volume = {17},
number = {},
pages = {1303974},
doi = {10.3389/fnmol.2024.1303974},
pmid = {38516039},
issn = {1662-5099},
abstract = {Telomeres are important to chromosomal stability, and changes in their length correlate with disease, potentially relevant to brain disorders. Assessing telomere length in human brain is invasive, but whether peripheral tissue telomere length correlates with that in brain is not known. Saliva, buccal, blood, and brain samples were collected at time points before, during, and after subjects undergoing neurosurgery (n = 35) for intractable epilepsy. DNA was isolated from samples and average telomere length assessed by qPCR. Correlations of telomere length between tissue samples were calculated across subjects. When data were stratified by sex, saliva telomere length correlated with brain telomere length in males only. Buccal telomere length correlated with brain telomere length when males and females were combined. These findings indicate that in living subjects, telomere length in peripheral tissues variably correlates with that in brain and may be dependent on sex. Peripheral tissue telomere length may provide insight into brain telomere length, relevant to assessment of brain disorder pathophysiology.},
}
@article {pmid38515829,
year = {2024},
author = {Chien, CW and Tang, YA and Jeng, SL and Pan, HA and Sun, HS},
title = {Blastocyst telomere length predicts successful implantation after frozen-thawed embryo transfer.},
journal = {Human reproduction open},
volume = {2024},
number = {2},
pages = {hoae012},
doi = {10.1093/hropen/hoae012},
pmid = {38515829},
issn = {2399-3529},
abstract = {STUDY QUESTION: Do embryos with longer telomere length (TL) at the blastocyst stage have a higher capacity to survive after frozen-thawed embryo transfer (FET)?<br><br>SUMMARY ANSWER: Digitally estimated TL using low-pass whole genome sequencing (WGS) data from the preimplantation genetic testing for aneuploidy (PGT-A) process demonstrates that blastocyst TL is the most essential factor associated with likelihood of implantation.<br><br>WHAT IS KNOWN ALREADY: The lifetime TL is established in the early cleavage cycles following fertilization through a recombination-based lengthening mechanism and starts erosion beyond the blastocyst stage. In addition, a telomerase-mediated slow erosion of TL in human fetuses has been observed from a gestational age of 6-11&#x2009;weeks. Finally, an abnormal shortening of telomeres is likely involved in embryo loss during early development.<br><br>STUDY DESIGN SIZE DURATION: Blastocyst samples were obtained from patients who underwent PGT-A and FET in an IVF center from March 2015 to May 2018. Digitally estimated mitochondrial copy number (mtCN) and TL were used to study associations with the implantation potential of each embryo.<br><br>In total, 965 blastocysts from 232 cycles (164 patients) were available to investigate the biological and clinical relevance of TL. A WGS-based workflow was applied to determine the ploidy of each embryo. Data from low-pass WGS-PGT-A were used to estimate the mtCN and TL for each embryo. Single-variant and multi-variant logistic regression, decision tree, and random forest models were applied to study various factors in association with the implantation potential of each embryo.<br><br>Of the 965 blastocysts originally available, only 216 underwent FET. While mtCN from the transferred embryos is significantly associated with the ploidy call of each embryo, mtCN has no role in impacting IVF outcomes after an embryo transfer in these women. The results indicate that mtCN is a marker of embryo aneuploidy. On the other hand, digitally estimated TL is the most prominent univariant factor and showed a significant positive association with pregnancy outcomes (P&#x2009;<&#x2009;0.01, odds ratio 79.1). We combined several maternal and embryo parameters to study the joint effects on successful implantation. The machine learning models, namely decision tree and random forest, were trained and yielded classification accuracy of 0.82 and 0.91, respectively. Taken together, these results support the vital role of TL in governing implantation potential, perhaps through the ability to control embryo survival after transfer.<br><br>The small sample size limits our study as only 216 blastocysts were transferred. The number was further reduced to 153 blastocysts, where pregnancy outcomes could be accurately traced. The other limitation of this study is that all data were collected from a single IVF center. The uniform and controlled operation of IVF cycles in a single center may cause selection bias.<br><br>We present novel findings to show that digitally estimated TL at the blastocyst stage is a predictor of pregnancy capacity after a FET cycle. As elective single-embryo transfer has become the mainstream direction in reproductive medicine, prioritizing embryos based on their implantation potential is crucial for clinical infertility treatment in order to reduce twin pregnancy rate and the time to pregnancy in an IVF center. The AI-powered, random forest prediction model established in this study thus provides a way to improve clinical practice and optimize the chances for people with fertility problems to achieve parenthood.<br><br>This study was supported by a grant from the National Science and Technology Council, Taiwan (MOST 108-2321-B-006-013 -). There were no competing interests.<br><br>TRIAL REGISTRATION NUMBER: N/A.},
}
@article {pmid38512957,
year = {2024},
author = {An, G and Zhao, X and Zhao, C},
title = {Unraveling the causal association between leukocyte telomere length and infertility: A two-sample Mendelian randomization study.},
journal = {PloS one},
volume = {19},
number = {3},
pages = {e0298997},
doi = {10.1371/journal.pone.0298997},
pmid = {38512957},
issn = {1932-6203},
abstract = {Infertility is a significant challenge in modern society, and observed studies have reported the association between telomere length and infertility. Whether this relationship is causal remains controversial.We employed two-sample mendelian randomization (MR) to investigate the causal relationship between leukocyte telomere length (LTL) and major causes of infertility, including male and female infertility, sperm abnormalities, and endometriosis. MR analyses were mainly performed using the inverse variance weighted (IVW) method and complemented with other MR methods.Our findings demonstrate a causal association between LTL and endometriosis (OR1.304, 95% CI (1.122,1.517), p = 0.001), suggesting its potential as a biomarker for this condition. However, we did not observe a significant causal relationship between LTL and other infertility causes.Our study presents compelling evidence on the relationship between LTL and endometriosis. Meanwhile, our study demonstrates that there is no causal relationship between LTL and infertility. This research contributes to the field by shedding light on the importance of LTL in the early diagnosis and intervention of endometriosis.},
}
@article {pmid38510147,
year = {2024},
author = {Keller, D and Stinus, S and Umlauf, D and Gourbeyre, E and Biot, E and Olivier, N and Mahou, P and Beaurepaire, E and Andrey, P and Crabbe, L},
title = {Non-random spatial organization of telomeres varies during the cell cycle and requires LAP2 and BAF.},
journal = {iScience},
volume = {27},
number = {4},
pages = {109343},
pmid = {38510147},
issn = {2589-0042},
abstract = {Spatial genome organization within the nucleus influences major biological processes and is impacted by the configuration of linear chromosomes. Here, we applied 3D spatial statistics and modeling on high-resolution telomere and centromere 3D-structured illumination microscopy images in cancer cells. We found a multi-scale organization of telomeres that dynamically evolved from a mixed clustered-and-regular distribution in early G1 to a purely regular distribution as cells progressed through the cell cycle. In parallel, our analysis revealed two pools of peripheral and internal telomeres, the proportions of which were inverted during the cell cycle. We then conducted a targeted screen using MadID to identify the molecular pathways driving or maintaining telomere anchoring to the nuclear envelope observed in early G1. Lamina-associated polypeptide (LAP) proteins were found transiently localized to telomeres in anaphase, a stage where LAP2α initiates the reformation of the nuclear envelope, and impacted telomere redistribution in the next interphase together with their partner barrier-to-autointegration factor (BAF).},
}
@article {pmid38509838,
year = {2024},
author = {Wolf, SE and Woodruff, MJ and Chang van Oordt, DA and Clotfelter, ED and Cristol, DA and Derryberry, EP and Ferguson, SM and Stanback, MT and Taff, CC and Vitousek, MN and Westneat, DF and Rosvall, KA},
title = {Among-population variation in telomere regulatory proteins and their potential role as hidden drivers of intraspecific variation in life history.},
journal = {The Journal of animal ecology},
volume = {},
number = {},
pages = {},
doi = {10.1111/1365-2656.14071},
pmid = {38509838},
issn = {1365-2656},
support = {T32 HD049336/NH/NIH HHS/United States ; },
abstract = {Biologists aim to explain patterns of growth, reproduction and ageing that characterize life histories, yet we are just beginning to understand the proximate mechanisms that generate this diversity. Existing research in this area has focused on telomeres but has generally overlooked the telomere's most direct mediator, the shelterin protein complex. Shelterin proteins physically interact with the telomere to shape its shortening and repair. They also regulate metabolism and immune function, suggesting a potential role in life history variation in the wild. However, research on shelterin proteins is uncommon outside of biomolecular work. Intraspecific analyses can play an important role in resolving these unknowns because they reveal subtle variation in life history within and among populations. Here, we assessed ecogeographic variation in shelterin protein abundance across eight populations of tree swallow (Tachycineta bicolor) with previously documented variation in environmental and life history traits. Using the blood gene expression of four shelterin proteins in 12-day-old nestlings, we tested the hypothesis that shelterin protein gene expression varies latitudinally and in relation to both telomere length and life history. Shelterin protein gene expression differed among populations and tracked non-linear variation in latitude: nestlings from mid-latitudes expressed nearly double the shelterin mRNA on average than those at more northern and southern sites. However, telomere length was not significantly related to latitude. We next assessed whether telomere length and shelterin protein gene expression correlate with 12-day-old body mass and wing length, two proxies of nestling growth linked to future fecundity and survival. We found that body mass and wing length correlated more strongly (and significantly) with shelterin protein gene expression than with telomere length. These results highlight telomere regulatory shelterin proteins as potential mediators of life history variation among populations. Together with existing research linking shelterin proteins and life history variation within populations, these ecogeographic patterns underscore the need for continued integration of ecology, evolution and telomere biology, which together will advance understanding of the drivers of life history variation in nature.},
}
@article {pmid38504468,
year = {2024},
author = {Hastings, WJ and Ye, Q and Wolf, SE and Ryan, CP and Das, SK and Huffman, KM and Kobor, MS and Kraus, WE and MacIsaac, JL and Martin, CK and Racette, SB and Redman, LM and Belsky, DW and Shalev, I},
title = {Effect of long-term caloric restriction on telomere length in healthy adults: CALERIE™ 2 trial analysis.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e14149},
doi = {10.1111/acel.14149},
pmid = {38504468},
issn = {1474-9726},
abstract = {Caloric restriction (CR) modifies lifespan and aging biology in animal models. The Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE™) 2 trial tested translation of these findings to humans. CALERIE™ randomized healthy, nonobese men and premenopausal women (age 21-50y; BMI 22.0-27.9 kg/m[2]), to 25% CR or ad-libitum (AL) control (2:1) for 2 years. Prior analyses of CALERIE™ participants' blood chemistries, immunology, and epigenetic data suggest the 2-year CR intervention slowed biological aging. Here, we extend these analyses to test effects of CR on telomere length (TL) attrition. TL was quantified in blood samples collected at baseline, 12-, and 24-months by quantitative PCR (absolute TL; aTL) and a published DNA-methylation algorithm (DNAmTL). Intent-to-treat analysis found no significant differences in TL attrition across the first year, although there were trends toward increased attrition in the CR group for both aTL and DNAmTL measurements. When accounting for adherence heterogeneity with an Effect-of-Treatment-on-the-Treated analysis, greater CR dose was associated with increased DNAmTL attrition during the baseline to 12-month weight-loss period. By contrast, both CR group status and increased CR were associated with reduced aTL attrition over the month 12 to month 24 weight maintenance period. No differences were observed when considering TL change across the study duration from baseline to 24-months, leaving it unclear whether CR-related effects reflect long-term detriments to telomere fidelity, a hormesis-like adaptation to decreased energy availability, or measurement error and insufficient statistical power. Unraveling these trends will be a focus of future CALERIE™ analyses and trials.},
}
@article {pmid38503134,
year = {2024},
author = {Dos Santos, GA and Viana, NI and Pimenta, R and de Camargo, JA and Guimaraes, VR and Romão, P and Candido, P and Dos Santos, VG and Ghazarian, V and Reis, ST and Leite, KRM and Srougi, M},
title = {Upregulation of shelterin and CST genes and longer telomeres are associated with unfavorable prognostic characteristics in prostate cancer.},
journal = {Cancer genetics},
volume = {284-285},
number = {},
pages = {20-29},
doi = {10.1016/j.cancergen.2024.03.006},
pmid = {38503134},
issn = {2210-7762},
abstract = {INTRODUCTION: Search for new clinical biomarkers targets in prostate cancer (PC) is urgent. Telomeres might be one of these targets. Telomeres are the extremities of linear chromosomes, essential for genome stability and control of cell divisions. Telomere homeostasis relies on the proper functioning of shelterin and CST complexes. Telomeric dysfunction and abnormal expression of its components are reported in most cancers and are associated with PC. Despite this, there are only a few studies about the expression of the main telomere complexes and their relationship with PC progression. We aimed to evaluate the role of shelterin (POT1, TRF2, TPP1, TIN2, and RAP1) and CST (CTC1, STN1, and TEN1) genes and telomere length in the progression of PC.<br><br>METHODS: We evaluated genetic alterations of shelterin and CST by bioinformatics in samples of localized (n = 499) and metastatic castration-resistant PC (n = 444). We also analyzed the expression of the genes using TCGA (localized PC n = 497 and control n = 152) and experimental approaches, with surgical specimens (localized PC n = 81 and BPH n = 10) and metastatic cell lines (LNCaP, DU145, PC3 and PNT2 as control) by real-time PCR. Real-time PCR also determined the telomere length in the same experimental samples. All acquired data were associated with clinical parameters.<br><br>RESULTS: Genetic alterations are uncommon in PC, but POT1, TIN2, and TEN1 showed significantly more amplifications in the metastatic cancer. Except for CTC1 and TEN1, which are differentially expressed in localized PC samples, we did not detect an expression pattern relative to control and cell lines. Nevertheless, except for TEN1, the upregulation of all genes is associated with a worse prognosis in localized PC. We also found that increased telomere length is associated with disease aggressiveness in localized PC.<br><br>CONCLUSION: The upregulation of shelterin and CST genes creates an environment that favors telomere elongation, giving selective advantages for localized PC cells to progress to more aggressive stages of the disease.},
}
@article {pmid38499533,
year = {2024},
author = {Li, Y and Chen, J and Sun, T and Chen, Y and Fu, R and Liu, X and Xue, F and Liu, W and Ju, M and Dai, X and Dong, H and Li, H and Wang, W and Chi, Y and Zhang, L},
title = {Genetically determined telomere length and risk for haematologic diseases: results from large prospective cohorts and Mendelian Randomization analysis.},
journal = {Blood cancer journal},
volume = {14},
number = {1},
pages = {48},
pmid = {38499533},
issn = {2044-5385},
}
@article {pmid38498288,
year = {2024},
author = {Gürel, S and Pak, EN and Tek, NA},
title = {Aging Processes Are Affected by Energy Balance: Focused on the Effects of Nutrition and Physical Activity on Telomere Length.},
journal = {Current nutrition reports},
volume = {},
number = {},
pages = {},
pmid = {38498288},
issn = {2161-3311},
abstract = {PURPOSE OF REVIEW: The number and proportion of individuals aged 60 and over are increasing globally. The increase in the elderly population has important social and economic effects. Telomere length is an important marker for healthy aging. Here, we review the relevance between telomere length and energy balance by determining the effects of physical activity, nutrients, dietary patterns, and foods on healthy aging and telomere length with related studies.<br><br>RECENT FINDINGS: Evidence emphasizes the importance of telomere length and integrity for healthy aging. It also focuses on the importance of potential interventions such as physical activity and a healthy diet to improve this process. We suggest that ensuring energy balance with regular physical activity and healthy diets can contribute to the aging process by protecting telomere length. In addition, different methods in studies, short and inconsistent durations, different types of exercise, different diet patterns, and non-standard foods have led to conflicting results. More studies are needed to elucidate molecular-based mechanisms.},
}
@article {pmid38493659,
year = {2024},
author = {Zhang, Y and Zhu, Y and Zhang, X and Li, C and Fu, H and Lin, L and Yang, Z and Zhang, B},
title = {The association of sleep duration and leukocyte telomere length in middle-aged and young-old adults: A cross-sectional study of UK Biobank.},
journal = {Sleep medicine},
volume = {117},
number = {},
pages = {18-24},
doi = {10.1016/j.sleep.2024.02.043},
pmid = {38493659},
issn = {1878-5506},
abstract = {BACKGROUND: The relationships between sleep duration and aging-associated diseases are intricate. Leukocyte telomere length (LTL) is a biomarker of aging, while the association of sleep duration and LTL is unclear.<br><br>METHODS: The 310,091 study participants from UK Biobank were enrolled in this cross-sectional study. Restricted cubic splines (RCS) analysis was firstly performed to assess the nonlinear relationship between sleep duration and LTL. Sleep duration was then categorized into three groups: <7&#xa0;h (short sleep duration), 7-8&#xa0;h (reference group), and >8&#xa0;h (long sleep duration) and multiple linear regression was applied to analyze the association of short sleep and long sleep duration with LTL. We further performed subgroup analyses stratified by sex, age, chronotype and snoring.<br><br>RESULTS: RCS showed an inverted J-shaped relationship between sleep duration and LTL. Compared with the reference group, the inverse association of long sleep duration and LTL was statistically significant in fully-adjusted model (P&#xa0;=&#xa0;0.001). Subgroup analyses showed that this association was more apparent in people over 50 years (51-60&#xa0;y: P&#xa0;=&#xa0;0.002; >60&#xa0;y: P&#xa0;=&#xa0;0.005), in men (P&#xa0;=&#xa0;0.022), and in people preferred evening chronotype (P&#xa0;=&#xa0;0.001).<br><br>CONCLUSION: Compared with participants sleeping 7-8&#xa0;h, those sleep longer than 8&#xa0;h had shorter LTL in middle-aged and young-old adults. The negative association between long sleep duration and LTL was more apparent in older people, in men, and in people preferred evening chronotype.},
}
@article {pmid38493352,
year = {2024},
author = {Závodník, M and Pavlištová, V and Machelová, A and Lyčka, M and Mozgová, I and Caklová, K and Dvořáčková, M and Fajkus, J},
title = {KU70 and CAF-1 in Arabidopsis: Divergent roles in rDNA stability and telomere homeostasis.},
journal = {The Plant journal : for cell and molecular biology},
volume = {},
number = {},
pages = {},
doi = {10.1111/tpj.16718},
pmid = {38493352},
issn = {1365-313X},
support = {20-01331X//Grantov&#xe1; Agentura &#x10c;esk&#xe9; Republiky/ ; 23-06643S//Grantov&#xe1; Agentura &#x10c;esk&#xe9; Republiky/ ; },
abstract = {Deficiency in chromatin assembly factor-1 (CAF-1) in plants through dysfunction of its components, FASCIATA1 and 2 (FAS1, FAS2), leads to the specific and progressive loss of rDNA and telomere repeats in plants. This loss is attributed to defective repair mechanisms for the increased DNA breaks encountered during replication, a consequence of impaired replication-dependent chromatin assembly. In this study, we explore the role of KU70 in these processes. Our findings reveal that, although the rDNA copy number is reduced in ku70 mutants when compared with wild-type plants, it is not markedly affected by diverse KU70 status in fas1 mutants. This is consistent with our previous characterisation of rDNA loss in fas mutants as a consequence part of the single-strand annealing pathway of homology-dependent repair. In stark contrast to rDNA, KU70 dysfunction fully suppresses the loss of telomeres in fas1 plants and converts telomeres to their elongated and heterogeneous state typical for ku70 plants. We conclude that the alternative telomere lengthening pathway, known to be activated in the absence of KU70, overrides progressive telomere loss due to CAF-1 dysfunction.},
}
@article {pmid38493287,
year = {2024},
author = {Ojeda-Rodriguez, A and Rangel-Zuñiga, OA and Arenas-de Larriva, AP and Gutierrez-Mariscal, FM and Torres-Peña, JD and Romero-Cabrera, JL and Podadera-Herreros, A and García-Fernandez, H and Porras-Pérez, E and Luque, RM and Kales, SN and Perez-Martinez, P and Delgado-Lista, J and Yubero-Serrano, EM and Lopez-Miranda, J},
title = {Telomere length as biomarker of nutritional therapy for prevention of type 2 diabetes mellitus development in patients with coronary heart disease: CORDIOPREV randomised controlled trial.},
journal = {Cardiovascular diabetology},
volume = {23},
number = {1},
pages = {98},
pmid = {38493287},
issn = {1475-2840},
support = {MCIN/AEI/10.13039/501100011033//Ministerio de Ciencia e Innovaci&#xf3;n/ ; Grant PY20/00256//Consejer&#xed;a de Transformaci&#xf3;n Econ&#xf3;mica, Industria, Conocimiento y Universidades/ ; },
abstract = {BACKGROUND: Telomere Length (TL), a marker of cellular aging, holds promise as a biomarker to elucidate the molecular mechanism of diabetes. This study aimed to investigate whether shorter telomeres are associated with a higher risk of type 2 diabetes mellitus (T2DM) incidence in patients with coronary heart disease; and to determine whether the most suitable dietary patterns, particularly a Mediterranean diet or a low-fat diet, can mitigate the development of diabetes in these patients after a follow-up period of five years.<br><br>METHODS: The CORonary Diet Intervention with Olive oil and cardiovascular PREVention study (CORDIOPREV study) was a single-centre, randomised clinical trial done at the Reina Sofia University Hospital in C&#xf3;rdoba, Spain. Patients with established coronary heart disease (aged 20-75 years) were randomly assigned in a 1:1 ratio by the Andalusian School of Public Health to receive two healthy diets. Clinical investigators were masked to treatment assignment; participants were not. Quantitative-PCR was used to assess TL measurements.<br><br>FINDINGS: 1002 patients (59.5&#xa0;&#xb1;&#xa0;8.7&#xa0;years and 82.5% men) were enrolled into Mediterranean diet (n&#x2009;=&#x2009;502) or a low-fat diet (n&#x2009;=&#x2009;500) groups. In this analysis, we included all 462 patients who did not have T2DM at baseline. Among them, 107 patients developed T2DM after a median of 60 months. Cox regression analyses showed that patients at risk of short telomeres (TL&#x2009;<&#x2009;percentile 20th) are more likely to experience T2DM than those at no risk of short telomeres (HR 1.65, p-value 0.023). In terms of diet, patients at high risk of short telomeres had a higher risk of T2DM incidence after consuming a low-fat diet compared to patients at no risk of short telomeres (HR 2.43, 95CI% 1.26 to 4.69, p-value 0.008), while no differences were observed in the Mediterranean diet group.<br><br>CONCLUSION: Patients with shorter TL presented a higher risk of developing T2DM. This association could be mitigated with a specific dietary pattern, in our case a Mediterranean diet, to prevent T2DM in patients with coronary heart disease.<br><br>TRIAL REGISTRATION: Clinicaltrials.gov number NCT00924937.},
}
@article {pmid38489874,
year = {2024},
author = {Liu, CC and Capart, MMM and Lin, JJ},
title = {Mismatch repair enzymes regulate telomere recombination in Saccharomycescerevisiae.},
journal = {Biochemical and biophysical research communications},
volume = {707},
number = {},
pages = {149768},
doi = {10.1016/j.bbrc.2024.149768},
pmid = {38489874},
issn = {1090-2104},
abstract = {DNA mismatch repair (MMR) is a crucial mechanism that ensures chromosome stability and prevents the development of various human cancers. Apart from its role in correcting mismatches during DNA replication, MMR also plays a significant role in regulating recombination between non-identical sequences, a process known as homeologous recombination. Telomeres, the protective ends of eukaryotic chromosomes, possess sequences that are not perfectly homologous. While telomerase primarily maintains telomere length in the yeast Saccharomyces cerevisiae, recombination between telomeres becomes a major pathway for length maintenance in cells lacking telomerase. This study investigates the participation of MMR in telomere recombination. Our findings reveal that mutations in MMR genes activate type I recombination. Notably, among the MMR proteins, MutSα (Msh2 and Msh6) and MutLα (Mlh1 and Pms1) exerted the most pronounced effects on telomere recombination. We also found that yeast cells containing simple human telomeric TTAGGG DNA sequences preferentially utilize type II recombination to maintain their telomeres, highlighting the influence of the heterogeneous nature of yeast telomeric sequences on type II recombination. Furthermore, our observations indicate that MMR activity is indispensable for its impact on telomere recombination. Collectively, these results contribute to a more comprehensive understanding of the role of MMR in telomere recombination.},
}
@article {pmid38487628,
year = {2024},
author = {, },
title = {Retraction: Obesity accelerates leukocyte telomere length shortening in apparently healthy adults: a meta-analysis.},
journal = {Frontiers in nutrition},
volume = {11},
number = {},
pages = {1390502},
doi = {10.3389/fnut.2024.1390502},
pmid = {38487628},
issn = {2296-861X},
abstract = {[This retracts the article DOI: 10.3389/fnut.2022.812846.].},
}
@article {pmid38485951,
year = {2024},
author = {Zhang, J and Ruiz, M and Bergh, PO and Henricsson, M and Stojanović, N and Devkota, R and Henn, M and Bohlooly-Y, M and Hernández-Hernández, A and Alsheimer, M and Borén, J and Pilon, M and Shibuya, H},
title = {Regulation of meiotic telomere dynamics through membrane fluidity promoted by AdipoR2-ELOVL2.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {2315},
pmid = {38485951},
issn = {2041-1723},
support = {StG-801659//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; 2018-03426//Vetenskapsr&#xe5;det (Swedish Research Council)/ ; KAW2019.0180//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; Al 1090/4-2//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 426173797 (INST 93/1003-1 FUGG)//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; },
abstract = {The cellular membrane in male meiotic germ cells contains a unique class of phospholipids and sphingolipids that is required for male reproduction. Here, we show that a conserved membrane fluidity sensor, AdipoR2, regulates the meiosis-specific lipidome in mouse testes by promoting the synthesis of sphingolipids containing very-long-chain polyunsaturated fatty acids (VLC-PUFAs). AdipoR2 upregulates the expression of a fatty acid elongase, ELOVL2, both transcriptionally and post-transcriptionally, to synthesize VLC-PUFA. The depletion of VLC-PUFAs and subsequent accumulation of palmitic acid in AdipoR2 knockout testes stiffens the cellular membrane and causes the invagination of the nuclear envelope. This condition impairs the nuclear peripheral distribution of meiotic telomeres, leading to errors in homologous synapsis and recombination. Further, the stiffened membrane impairs the formation of intercellular bridges and the germ cell syncytium, which disrupts the orderly arrangement of cell types within the seminiferous tubules. According to our findings we propose a framework in which the highly-fluid membrane microenvironment shaped by AdipoR2-ELOVL2 underpins meiosis-specific chromosome dynamics in testes.},
}
@article {pmid38481135,
year = {2024},
author = {Alanazi, AFR and Parkinson, GN and Haider, S},
title = {Structural Motifs at the Telomeres and Their Role in Regulatory Pathways.},
journal = {Biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biochem.4c00023},
pmid = {38481135},
issn = {1520-4995},
abstract = {Telomeres are specialized structures, found at the ends of linear chromosomes in eukaryotic cells, that play a crucial role in maintaining the stability and integrity of genomes. They are composed of repetitive DNA sequences, ssDNA overhangs, and several associated proteins. The length of telomeres is linked to cellular aging in humans, and deficiencies in their maintenance are associated with various diseases. Key structural motifs at the telomeres serve to protect vulnerable chromosomal ends. Telomeric DNA also has the ability to form diverse complex DNA higher-order structures, including T-loops, D-loops, R-loops, G-loops, G-quadruplexes, and i-motifs, in the complementary C-rich strand. While many essential proteins at telomeres have been identified, the intricacies of their interactions and structural details are still not fully understood. This Perspective highlights recent advancements in comprehending the structures associated with human telomeres. It emphasizes the significance of telomeres, explores various telomeric structural motifs, and delves into the structural biology surrounding telomeres and telomerase. Furthermore, telomeric loops, their topologies, and the associated proteins that contribute to the safeguarding of telomeres are discussed.},
}
@article {pmid38478320,
year = {2024},
author = {Du, X and Guo, C and Zhang, C and Xu, B},
title = {Causal Association of Telomere Length and Loss of Bone: a Directional Mendelian Randomization Study of Multi-Outcomes.},
journal = {Applied biochemistry and biotechnology},
volume = {},
number = {},
pages = {},
pmid = {38478320},
issn = {1559-0291},
support = {Nos.82072491//National Natural Science Foundation of China/ ; Nos. 20JCYBJC00820//Natural Science Foundation of Tianjin City/ ; },
abstract = {This study employed a genome-wide association study (GWAS) to investigate the relationship between telomere length and marginal bone loss (MBL), a marker of bone health and aging. Telomere length, a biological indicator of aging, was analyzed alongside several serum markers of bone loss. Following a screen for appropriate instrumental variables, telomere length was designated as the exposure variable. We conducted the main analysis using random-effects inverse variance weighting (IVW) and supplemented it with MR Egger, weighted median, simple mode, and weighted mode analyses, employing a total of five methods. Positive outcomes underwent scrutiny through heterogeneity analysis, horizontal multiplicity analysis, and leave-one-out plot. Subsequently, the effective gene locus was chosen for a reverse MR analysis, with positive results serving as the exposure variable. We found a causal relationship between telomere length and the expression of osteocalcin (OC), matrix metalloproteinase-3 (MMP-3), and matrix metalloproteinase-12 (MMP-12), key markers of bone metabolism. Our findings suggest that telomere wear and shortening may contribute to increased activity of OC, MMP-3, and MMP-12, thus affecting bone metabolism. However, reverse Mendelian randomization analysis did not indicate a significant impact of OC, MMP-3, and MMP-12 on telomere length, implying a unidirectional relationship. Overall, this meta-analysis underscores the association between telomere length and bone loss, highlighting the importance of timing and duration of telomere wear and shortening in influencing bone metabolism.},
}
@article {pmid38475941,
year = {2024},
author = {Gao, Z and Santos, RB and Rupert, J and Van Drunen, R and Yu, Y and Eckel-Mahan, K and Kolonin, MG},
title = {Endothelial-specific telomerase inactivation causes telomere-independent cell senescence and multi-organ dysfunction characteristic of aging.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e14138},
doi = {10.1111/acel.14138},
pmid = {38475941},
issn = {1474-9726},
support = {1R01DK125922/DK/NIDDK NIH HHS/United States ; },
abstract = {It has remained unclear how aging of endothelial cells (EC) contributes to pathophysiology of individual organs. Cell senescence results in part from inactivation of telomerase (TERT). Here, we analyzed mice with Tert knockout specifically in EC. Tert loss in EC induced transcriptional changes indicative of senescence and tissue hypoxia in EC and in other cells. We demonstrate that EC-Tert-KO mice have leaky blood vessels. The blood-brain barrier of EC-Tert-KO mice is compromised, and their cognitive function is impaired. EC-Tert-KO mice display reduced muscle endurance and decreased expression of enzymes responsible for oxidative metabolism. Our data indicate that Tert-KO EC have reduced mitochondrial content and function, which results in increased dependence on glycolysis. Consistent with this, EC-Tert-KO mice have metabolism changes indicative of increased glucose utilization. In EC-Tert-KO mice, expedited telomere attrition is observed for EC of adipose tissue (AT), while brain and skeletal muscle EC have normal telomere length but still display features of senescence. Our data indicate that the loss of Tert causes EC senescence in part through a telomere length-independent mechanism undermining mitochondrial function. We conclude that EC-Tert-KO mice is a model of expedited vascular senescence recapitulating the hallmarks aging, which can be useful for developing revitalization therapies.},
}
@article {pmid38475782,
year = {2024},
author = {Li, J and Wang, W and Yang, Z and Qiu, L and Ren, Y and Wang, D and Li, M and Li, W and Gao, F and Zhang, J},
title = {Causal association of obesity with epigenetic aging and telomere length: a bidirectional mendelian randomization study.},
journal = {Lipids in health and disease},
volume = {23},
number = {1},
pages = {78},
pmid = {38475782},
issn = {1476-511X},
support = {C12021A03005//Scientific and technological innovation project of China Academy of Chinese Medical Sciences/ ; C12021A03005//Scientific and technological innovation project of China Academy of Chinese Medical Sciences/ ; },
abstract = {BACKGROUND: In observational studies, there exists an association between obesity and epigenetic age as well as telomere length. However, varying and partially conflicting outcomes have notably arisen from distinct studies on this topic. In the present study, two-way Mendelian randomization was used to identify potential causal associations between obesity and epigenetic age and telomeres.<br><br>METHODS: A genome-wide association study was conducted using data from individuals of European ancestry to investigate bidirectional Mendelian randomization (MR) regarding the causal relationships between obesity, as indicated by three obesity indicators (body mass index or BMI, waist circumference adjusted for BMI or WCadjBMI, and waist-to-hip ratio adjusted for BMI or WHRadjBMI), and four epigenetic age measures (HannumAge, HorvathAge, GrimAge, PhenoAge), as well as telomere length. To assess these causal associations, various statistical methods were employed, including Inverse Variance Weighted (IVW), Weighted Median, MR Egger, Weighted Mode, and Simple Mode. To address the issue of multiple testing, we applied the Bonferroni correction. These methods were used to determine whether there is a causal link between obesity and epigenetic age, as well as telomere length, and to explore potential bidirectional relationships. Forest plots and scatter plots were generated to show causal associations between exposures and outcomes. For a comprehensive visualization of the results, leave-one-out sensitivity analysis plots, individual SNP-based forest plots for MR analysis, and funnel plots were included in the presentation of the results.<br><br>RESULTS: A strong causal association was identified between obesity and accelerated HannumAge, GrimAge, PhenoAge and telomere length shrinkage. The causal relationship between WCadjBMI and PhenoAge acceleration (OR: 2.099, 95%CI: 1.248-3.531, p&#x2009;=&#x2009;0.005) was the strongest among them. However, only the p-values for the causal associations of obesity with GrimAge, PhenoAge, and telomere length met the criteria after correction using the Bonferroni multiple test. In the reverse MR analysis, there were statistically significant causal associations between HorvathAge, PhenoAge and GrimAge and BMI, but these associations exhibited lower effect sizes, as indicated by their Odds Ratios (ORs). Notably, sensitivity analysis revealed the robustness of the study results.<br><br>CONCLUSIONS: The present findings reveal a causal relationship between obesity and the acceleration of epigenetic aging as well as the reduction of telomere length, offering valuable insights for further scientific investigations aimed at developing strategies to mitigate the aging process in humans.},
}
@article {pmid38467834,
year = {2024},
author = {Chen, S and Pan, C and Huang, J and Liu, T},
title = {ATR limits Rad18-mediated PCNA monoubiquitination to preserve replication fork and telomerase-independent telomere stability.},
journal = {The EMBO journal},
volume = {},
number = {},
pages = {},
pmid = {38467834},
issn = {1460-2075},
support = {2022YFA1302800//MOST | National Key Research and Development Program of China (NKPs)/ ; 2021YFA1101000//MOST | National Key Research and Development Program of China (NKPs)/ ; 31961160725//MOST | National Natural Science Foundation of China (NSFC)/ ; 31730021//MOST | National Natural Science Foundation of China (NSFC)/ ; 31971220//MOST | National Natural Science Foundation of China (NSFC)/ ; 32270769//MOST | National Natural Science Foundation of China (NSFC)/ ; 31970664//MOST | National Natural Science Foundation of China (NSFC)/ ; 31822031//MOST | National Natural Science Foundation of China (NSFC)/ ; },
abstract = {Upon replication fork stalling, the RPA-coated single-stranded DNA (ssDNA) formed behind the fork activates the ataxia telangiectasia-mutated and Rad3-related (ATR) kinase, concomitantly initiating Rad18-dependent monoubiquitination of PCNA. However, whether crosstalk exists between these two events and the underlying physiological implications of this interplay remain elusive. In this study, we demonstrate that during replication stress, ATR phosphorylates human Rad18 at Ser403, an adjacent residue to a previously unidentified PIP motif (PCNA-interacting peptide) within Rad18. This phosphorylation event disrupts the interaction between Rad18 and PCNA, thereby restricting the extent of Rad18-mediated PCNA monoubiquitination. Consequently, excessive accumulation of the tumor suppressor protein SLX4, now characterized as a novel reader of ubiquitinated PCNA, at stalled forks is prevented, contributing to the prevention of stalled fork collapse. We further establish that ATR preserves telomere stability in alternative lengthening of telomere (ALT) cells by restricting Rad18-mediated PCNA monoubiquitination and excessive SLX4 accumulation at telomeres. These findings shed light on the complex interplay between ATR activation, Rad18-dependent PCNA monoubiquitination, and SLX4-associated stalled fork processing, emphasizing the critical role of ATR in preserving replication fork stability and facilitating telomerase-independent telomere maintenance.},
}
@article {pmid38466631,
year = {2024},
author = {Stevers, NO and Costello, JF},
title = {Telomeres in glioma: Maintenance mechanisms to therapeutic potential.},
journal = {Neuro-oncology},
volume = {},
number = {},
pages = {},
doi = {10.1093/neuonc/noae052},
pmid = {38466631},
issn = {1523-5866},
}
@article {pmid38466455,
year = {2024},
author = {Eisenberg, DTA and Ryan, CP and Lee, NR and Carba, DB and MacIsaac, JL and Dever, K and Atashzay, P and Kobor, MS and Kuzawa, C},
title = {DNA methylation-based estimators of telomere length show low correspondence with paternal age at conception and other measures of external validity of telomere length.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {38466455},
issn = {2509-2723},
support = {R01AG061006//Office of Extramural Research, National Institutes of Health/ ; DK056350//Office of Extramural Research, National Institutes of Health/ ; DK078150//Office of Extramural Research, National Institutes of Health/ ; ES10126//Office of Extramural Research, National Institutes of Health/ ; RR20649//Office of Extramural Research, National Institutes of Health/ ; TW05596//Office of Extramural Research, National Institutes of Health/ ; BCS- 0962282//National Science Foundation/ ; BCS-1519110//National Science Foundation/ ; 8111//Wenner-Gren Foundation/ ; },
abstract = {In humans, DNA methylation (DNAm) based estimators of telomere length (TL) have been shown to better predict TL-associated variables (e.g., age, sex, and mortality) than TL itself. The biological significance of DNAm-based estimators of TL (DNAmTL) is unclear. In vitro DNAmTL shortens with cell replications, even when telomerase is maintaining TL. Telomerase is typically suppressed in humans, except in testes. Accordingly, sperm TL increases with age, and offspring with greater paternal age at conception (PAC) have longer TL. Thus, we expect that PAC associations with DNAmTL can shed light on whether in vivo cell replications in the presence of high telomerase activity (production of sperm) shorten DNAmTL or if PAC-lengthened TL causes lengthened DNAmTL. In a pre-registered analysis, using data from 1733 blood samples from the Philippines, we examined the association between paternal age at conception (PAC) and offspring DNAmTL. We did not find an association between PAC and DNAmTL but found a positive association of paternal grandfather's age at father's conception predicting grandchild's DNAmTL. In post hoc analyses, we examined how DNAmTL versus qPCR-measured TL (qPCR-TL) correlated with measures typically associated with TL. Contrary to previous findings, on almost all measures of external validity (correlations with parental TLs, southern blot TL, and age), qPCR-TL outperformed DNAmTL. The "kilobase" units of DNAm-based estimators of TL showed considerable deviations from southern blot-derived kilobase measures. Our findings suggest that DNAmTL is not a reliable index of inherited aspects of TL and underscores uncertainty about the biological meaning of DNAmTL.},
}
@article {pmid38466418,
year = {2024},
author = {Blanco, MB and Smith, DL and Greene, LK and Yoder, AD and Ehmke, EE and Lin, J and Klopfer, PH},
title = {Telomere dynamics during hibernation in a tropical primate.},
journal = {Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology},
volume = {},
number = {},
pages = {},
pmid = {38466418},
issn = {1432-136X},
abstract = {Hibernation is a widespread metabolic strategy among mammals for surviving periods of food scarcity. During hibernation, animals naturally alternate between metabolically depressed torpor bouts and energetically expensive arousals without ill effects. As a result, hibernators are promising models for investigating mechanisms that buffer against cellular stress, including telomere protection and restoration. In non-hibernators, telomeres, the protective structural ends of chromosomes, shorten with age and metabolic stress. In temperate hibernators, however, telomere shortening and elongation can occur in response to changing environmental conditions and associated metabolic state. We investigate telomere dynamics in a tropical hibernating primate, the fat-tailed dwarf lemur (Cheirogaleus medius). In captivity, these lemurs can hibernate when maintained under cold temperatures (11-15 °C) with limited food provisioning. We study telomere dynamics in eight fat-tailed dwarf lemurs at the Duke Lemur Center, USA, from samples collected before, during, and after the hibernation season and assayed via qPCR. Contrary to our predictions, we found that telomeres were maintained or even lengthened during hibernation, but shortened immediately thereafter. During hibernation, telomere lengthening was negatively correlated with time in euthermia. Although preliminary in scope, our findings suggest that there may be a preemptive, compensatory mechanism to maintain telomere integrity in dwarf lemurs during hibernation. Nevertheless, telomere shortening immediately afterward may broadly result in similar outcomes across seasons. Future studies could profitably investigate the mechanisms that offset telomere shortening within and outside of the hibernation season and whether those mechanisms are modulated by energy surplus or crises.},
}
@article {pmid38464183,
year = {2024},
author = {Smoom, R and May, CL and Skordalakes, E and Kaestner, KH and Tzfati, Y},
title = {Separation of telomere protection from length regulation by two different point mutations at amino acid 492 of RTEL1.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.02.26.582005},
pmid = {38464183},
abstract = {RTEL1 is an essential DNA helicase that plays multiple roles in genome stability and telomere length regulation. A variant of RTEL1 with a lysine at position 492 is associated with short telomeres in Mus spretus , while a conserved methionine at this position is found in M. musculus, which has ultra-long telomeres. In humans, a missense mutation at this position (RTEL1 [M492I]) causes a fatal telomere biology disease termed Hoyeraal-Hreidarsson syndrome (HHS). We previously described a M. musculus mouse model termed 'Telomouse', in which changing methionine 492 to a lysine (M492K) shortened the telomeres to their length in humans. Here, we report on the derivation of a mouse strain carrying the M492I mutation, termed 'HHS mouse'. The HHS mouse telomeres are not as short as those of Telomice but nevertheless they display higher levels of telomeric DNA damage, fragility and recombination, associated with anaphase bridges and micronuclei. These observations indicate that the two mutations separate critical functions of RTEL1: M492K mainly reduces the telomere length setpoint, while M492I predominantly disrupts telomere protection. The two mouse models enable dissecting the mechanistic roles of RTEL1 and the different contributions of short telomeres and DNA damage to telomere biology diseases, genomic instability, cancer, and aging.},
}
@article {pmid38463993,
year = {2024},
author = {Zhao, R and Xu, M and Wondisford, AR and Lackner, RM and Salsman, J and Dellaire, G and Chenoweth, DM and O'Sullivan, RJ and Zhao, X and Zhang, H},
title = {SUMO Promotes DNA Repair Protein Collaboration to Support Alterative Telomere Lengthening in the Absence of PML.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.02.29.582813},
pmid = {38463993},
abstract = {Alternative lengthening of telomeres (ALT) pathway maintains telomeres in a significant fraction of cancers associated with poor clinical outcomes. A better understanding of ALT mechanisms can provide a basis for developing new treatment strategies for ALT cancers. SUMO modification of telomere proteins plays a critical role in the formation of ALT telomere-associated PML bodies (APBs), where telomeres are clustered and DNA repair proteins are enriched to promote homology-directed telomere DNA synthesis in ALT. However, whether and how SUMO contributes to ALT beyond APB formation remains elusive. Here, we report that SUMO promotes collaboration among DNA repair proteins to achieve APB-independent telomere maintenance. By using ALT cancer cells with PML protein knocked out and thus devoid of APBs, we show that sumoylation is required for manifesting ALT features, including telomere clustering and telomeric DNA synthesis, independent of PML and APBs. Further, small molecule-induced telomere targeting of SUMO produces signatures of phase separation and ALT features in PML null cells in a manner depending on both sumoylation and SUMO interaction with SUMO interaction motifs (SIMs). Mechanistically, SUMO-induced effects are linked to the enrichment of DNA repair proteins, including Rad52, Rad51AP1, and BLM, to the SUMO-containing telomere foci. Finally, we find that Rad52 can undergo phase separation, enrich SUMO on telomeres, and promote telomere DNA synthesis in collaboration with the BLM helicase in a SUMO-dependent manner. Collectively, our findings suggest that, in addition to forming APBs, SUMO also promotes collaboration among DNA repair proteins to support telomere maintenance in ALT cells. Given the promising effects of sumoylation inhibitors in cancer treatment, our findings suggest their potential use in perturbing telomere maintenance in ALT cancer cells.},
}
@article {pmid38463625,
year = {2024},
author = {Jian, X and Sun, W and Zhang, J and Zhang, Q and Meng, X and Lu, H and Zheng, D and Wu, L and Wang, Y},
title = {Frailty mediating the causality between leucocyte telomere length and mortality: a cohort study of 440,551 UK Biobank participants.},
journal = {The EPMA journal},
volume = {15},
number = {1},
pages = {99-110},
pmid = {38463625},
issn = {1878-5077},
abstract = {INTRODUCTION: Previous studies reported leucocyte telomere length (LTL) and frailty were associated with mortality, but it remains unclear whether frailty serves as a mediator in the relationship between leucocyte telomere length and mortality risk. This study aimed to evaluate how measuring LTL and frailty can support early monitoring and prevention of risk of mortality from the prospective of predictive, preventive, and personalized medicine (PPPM/3PM).<br><br>METHODS: We included 440,551 participants from the UK Biobank between the baseline visit (2006-2010) and November 30, 2022. The time-dependent Cox proportional hazards model was conducted to assess the association between LTL and frailty index with the risk of mortality. Furthermore, we conducted causal mediation analyses to examine the extent to which frailty mediated the association between LTL and mortality.<br><br>RESULTS: During a median follow-up of 13.74&#xa0;years, each SD increase in LTL significantly decreased the risk of all-cause [hazard ratio (HR): 0.94, 95% confidence interval (CI): 0.93-0.95] and CVD-specific mortality (HR: 0.92, 95% CI: 0.90-0.95). The SD increase in FI elevated the risk of all-cause (HR: 1.35, 95% CI: 1.34-1.36), CVD-specific (HR: 1.47, 95% CI: 1.44-1.50), and cancer-specific mortality (HR: 1.22, 95% CI: 1.20-1.24). Frailty mediated approximately 10% of the association between LTL and all-cause and CVD-specific mortality.<br><br>CONCLUSIONS: Our results indicate that frailty mediates the effect of LTL on all-cause and CVD-specific mortality. There findings might be valuable to predict, prevent, and reduce mortality through primary prevention and healthcare in context of PPPM.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-024-00355-7.},
}
@article {pmid38461301,
year = {2024},
author = {Xu, M and Senanayaka, D and Zhao, R and Chigumira, T and Tripathi, A and Tones, J and Lackner, RM and Wondisford, AR and Moneysmith, LN and Hirschi, A and Craig, S and Alishiri, S and O'Sullivan, RJ and Chenoweth, DM and Reiter, NJ and Zhang, H},
title = {TERRA-LSD1 phase separation promotes R-loop formation for telomere maintenance in ALT cancer cells.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {2165},
pmid = {38461301},
issn = {2041-1723},
support = {U01CA260851//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; },
abstract = {The telomere repeat-containing RNA (TERRA) forms R-loops to promote homology-directed DNA synthesis in the alternative lengthening of telomere (ALT) pathway. Here we report that TERRA contributes to ALT via interacting with the lysine-specific demethylase 1A (LSD1 or KDM1A). We show that LSD1 localizes to ALT telomeres in a TERRA dependent manner and LSD1 function in ALT is largely independent of its demethylase activity. Instead, LSD1 promotes TERRA recruitment to ALT telomeres via RNA binding. In addition, LSD1 and TERRA undergo phase separation, driven by interactions between the RNA binding properties of LSD1 and the G-quadruplex structure of TERRA. Importantly, the formation of TERRA-LSD1 condensates enriches the R-loop stimulating protein Rad51AP1 and increases TERRA-containing R-loops at telomeres. Our findings suggest that LSD1-TERRA phase separation enhances the function of R-loop regulatory molecules for ALT telomere maintenance, providing a mechanism for how the biophysical properties of histone modification enzyme-RNA interactions impact chromatin function.},
}
@article {pmid38459464,
year = {2024},
author = {Li, Y and Lai, S and Kan, X},
title = {Causal relationship between immune cells and telomere length: mendelian randomization analysis.},
journal = {BMC immunology},
volume = {25},
number = {1},
pages = {19},
pmid = {38459464},
issn = {1471-2172},
support = {TJYX2DXK-068C//Tianjin Key Medical Discipline (Specialty) Construction Project/ ; TJYX2DXK-068C//Tianjin Key Medical Discipline (Specialty) Construction Project/ ; TJYX2DXK-068C//Tianjin Key Medical Discipline (Specialty) Construction Project/ ; 22ZYYLCCG03//Tianjin Medical University General Hospital Clinical Research Program/ ; 22ZYYLCCG03//Tianjin Medical University General Hospital Clinical Research Program/ ; 22ZYYLCCG03//Tianjin Medical University General Hospital Clinical Research Program/ ; },
abstract = {BACKGROUND: The causal relationship between immune cells and telomere length remains controversial.<br><br>METHODS: Data on the immune cells were obtained from a previous study with 3,757 participants. Data on telomere length were obtained from the OpenGWAS database. Genome-Wide Association Study (GWAS) data were obtained and screened for eligible instrumental variables (IVs) using the TwoSampleMR package and the Phenoscanner database. To investigate the genetic causality between immune cells and telomere length, Mendelian randomization (MR) analysis and Bayesian weighted Mendelian randomization (BWMR) analysis were used.<br><br>RESULTS: MR analysis showed that there is indeed a genetic causal relationship between immune cells and telomere length. A total of 16 immune cells were successfully validated. A positive correlation was found between telomere length and immune cells such as CD28&#x2009;+&#x2009;CD45RA&#x2009;+&#x2009;CD8br %CD8br (OR&#x2009;=&#x2009;1.002, 95%CI: 1.000-1.003). A negative correlation was found between telomere length and immune cells such as Transitional AC (OR&#x2009;=&#x2009;0.991, 95%CI: 0.984-0.997) (P&#x2009;<&#x2009;0.05). Reverse MR analysis similarly confirmed that telomere length can affect four types of immune cells, including CD25 on IgD&#x2009;+&#x2009;CD24- (OR&#x2009;=&#x2009;1.291, 95%CI: 1.060-1.571), at the genetic level.<br><br>CONCLUSION: There is indeed a mutual genetic causality between immune cells and telomere length, which will provide theoretical basis and support for more subsequent clinical studies.},
}
@article {pmid38459383,
year = {2024},
author = {Darian, JC and Kundu, R and Rajaby, R and Sung, WK},
title = {Constructing telomere-to-telomere diploid genome by polishing haploid nanopore-based assembly.},
journal = {Nature methods},
volume = {},
number = {},
pages = {},
pmid = {38459383},
issn = {1548-7105},
abstract = {Draft genomes generated from Oxford Nanopore Technologies (ONT) long reads are known to have a higher error rate. Although existing genome polishers can enhance their quality, the error rate (including mismatches, indels and switching errors between paternal and maternal haplotypes) can be significant. Here, we develop two polishers, hypo-short and hypo-hybrid to address this issue. Hypo-short utilizes Illumina short reads to polish an ONT-based draft assembly, resulting in a high-quality assembly with low error rates and switching errors. Expanding on this, hypo-hybrid incorporates ONT long reads to further refine the assembly into a diploid representation. Leveraging on hypo-hybrid, we have created a diploid genome assembly pipeline called hypo-assembler. Hypo-assembler automates the generation of highly accurate, contiguous and nearly complete diploid assemblies using ONT long reads, Illumina short reads and optionally Hi-C reads. Notably, our solution even allows for the production of telomere-to-telomere diploid genomes with additional manual steps. As a proof of concept, we successfully assembled a fully phased telomere-to-telomere diploid genome of HG00733, achieving a quality value exceeding 50.},
}
@article {pmid38457472,
year = {2024},
author = {Gao, C},
title = {Investigating the association between blood metabolites and telomere length: A mendelian randomization study.},
journal = {PloS one},
volume = {19},
number = {3},
pages = {e0298172},
doi = {10.1371/journal.pone.0298172},
pmid = {38457472},
issn = {1932-6203},
abstract = {BACKGROUND: Telomere length refers to the protective cap at the end of chromosomes, and it plays a crucial role in many diseases. The objective of this study is to explore the relationship between blood metabolites and telomere length, aiming to identify novel biological factors that influence telomere length.<br><br>METHODS: In this study, we extracted genome-wide association study (GWAS) data for blood metabolites from a sample of 7824 Europeans. Additionally, GWAS data for telomere length were obtained from the Open GWAS database (GWAS ID: ieu-b-4879). The primary analysis of this study utilized the random inverse variance weighted (IVW) method. Complementary analyses were also conducted using the MR-Egger and weighted median approaches. Sensitivity analyses were performed to assess the robustness of the findings. These included the Cochran Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis. To investigate the possibility of reverse causation, reverse MR analysis was conducted. Additionally, multivariable MR was utilized to evaluate the direct effect of metabolites on telomere length.<br><br>RESULTS: The results suggested a potential association between 15-methylpalmitate, taurocholate, levulinate, and X-12712 and telomere length. MVMR analysis further showed that 15-methylpalmitate, taurocholate, and levulinate can directly influence telomere length, regardless of other metabolites.<br><br>CONCLUSIONS: This study suggests that 15-methylpalmitate, taurocholate, and levulinate are likely factors correlated with telomere length. These findings will contribute to the development of strategies for protecting telomeres, preventing related diseases, and establishing a new biological foundation for achieving healthy aging.},
}
@article {pmid38455184,
year = {2024},
author = {Praengam, K and Tuntipopipat, S and Muangnoi, C and Jangwangkorn, C and Piamkulvanich, O},
title = {Efficacy of a dietary supplement derived from five edible plants on telomere length in Thai adults: A randomized, double-blind, placebo-controlled trial.},
journal = {Food science &amp; nutrition},
volume = {12},
number = {3},
pages = {1592-1604},
doi = {10.1002/fsn3.3851},
pmid = {38455184},
issn = {2048-7177},
abstract = {Mylife/Mylife100® is a dietary supplement consisting of black sesame seed, guava fruit, mangosteen aril, pennywort leaves, and soy protein. These edible plants contain multiple high-potential bioactive compounds exerting various vital biological functions including antioxidants which contribute to delaying the rate of telomere shortening. Telomere length is associated with cellular aging and age-related diseases. This study aimed to assess the efficacy of Mylife/Mylife100® on telomere length through a randomized, double-blind placebo-controlled trial. The trial assessed the alteration of leukocyte telomere length after 32 adults aged 50-65 years received either Mylife/Mylife100® or placebo (five capsules/day) for 8-week supplementation. The results demonstrated a significant increase in mean telomere length from baseline (6313 bp) to the 8-week supplementation period (6655 bp; p < 0.05) in the group receiving the product, whereas no significant change was observed in the placebo group. Additionally, the product group exhibited a significant improvement in plasma total antioxidant capacity levels compared to the placebo group (mean change, +35 vs -38; p = 0.006). This study also showed a significant correlation between telomere length and % CD4 + T cells (r = +0.325; p = 0.00003), % CD8 + T cells (r = +0.156; p = 0.048), and visceral fat (r = - 0.349; p = 0.000006). The findings suggest that consuming this dietary supplement (Mylife/Mylife100®) for 8 weeks has a positive effect on cellular aging by lengthening telomeres possible through their antioxidant capacities. Oxidative stress and cellular aging are underlying predisease mechanisms that might be alleviated by supplementing with this product.},
}
@article {pmid38451181,
year = {2024},
author = {Fang, T and Zhang, Z and Ren, K and Zou, L},
title = {Genetically determined telomere length as a risk factor for hematological malignancies: evidence from Mendelian randomization analysis.},
journal = {Aging},
volume = {16},
number = {},
pages = {},
doi = {10.18632/aging.205625},
pmid = {38451181},
issn = {1945-4589},
abstract = {BACKGROUND: Over the past years, the exact correlation between telomere length and hematological malignancies was still not fully understood.<br><br>METHODS: We performed a two-sample Mendelian randomization study to investigate the causal relationship between telomere length and hematological malignancies. We selected genetic instruments associated with telomere length. The genetic associations for lymphoid and hematopoietic malignant neoplasms were obtained from the most recent publicly accessible FinnGen study R9 data. Inverse variant weighted (IVW) analysis was adopted as the primary method, and we also performed the weighted-median method and the MR-Egger, and MRPRESSO methods as sensitive analysis.<br><br>RESULTS: Significant associations have been observed between telomere length and primary lymphoid (IVW: OR = 1.52, P = 2.11 &#xd7; 10[-6]), Hodgkin lymphoma (IVW: OR = 1.64, P = 0.014), non-Hodgkin lymphoma (IVW: OR = 1.70, P = 0.002), B-cell lymphoma (IVW: OR = 1.57, P = 0.015), non-follicular lymphoma (IVW: OR = 1.58, P = 1.7 &#xd7; 10[-3]), mantle cell lymphoma (IVW: OR = 3.13, P = 0.003), lymphoid leukemia (IVW: OR = 2.56, P = 5.92E-09), acute lymphocytic leukemia (IVW: OR = 2.65, P = 0.021) and chronic lymphocytic leukemia (IVW: OR = 2.80, P = 8.21 &#xd7; 10[-6]), along with multiple myeloma (IVW: OR = 1.85, P = 0.016).<br><br>CONCLUSION: This MR study found a significant association between telomere length and a wide range of hematopoietic malignancies. But no substantial impact of lymphoma and hematopoietic malignancies on telomere length has been detected.},
}
@article {pmid38451028,
year = {2024},
author = {Etherington, GJ and Wu, PS and Oliferenko, S and Uhlmann, F and Nieduszynski, CA},
title = {Telomere-to-telomere Schizosaccharomyces japonicus genome assembly reveals hitherto unknown genome features.},
journal = {Yeast (Chichester, England)},
volume = {},
number = {},
pages = {},
doi = {10.1002/yea.3912},
pmid = {38451028},
issn = {1097-0061},
support = {/CRUK_/Cancer Research UK/United Kingdom ; cc2137/WT_/Wellcome Trust/United Kingdom ; },
abstract = {Schizosaccharomyces japonicus belongs to the single-genus class Schizosaccharomycetes, otherwise known as "fission yeasts." As part of a composite model system with its widely studied S. pombe sister species, S. japonicus has provided critical insights into the workings and the evolution of cell biological mechanisms. Furthermore, its divergent biology makes S. japonicus a valuable model organism in its own right. However, the currently available genome assembly contains gaps and has been unable to resolve centromeres and other repeat-rich chromosomal regions. Here we present a telomere-to-telomere long-read genome assembly of the S. japonicus genome. This includes the three megabase-length chromosomes, with centromeres hundreds of kilobases long, rich in 5S ribosomal RNA genes, transfer RNA genes, long terminal repeats, and short repeats. We identify a gene-sparse region on chromosome 2 that resembles a 331 kb centromeric duplication. We revise the genome size of S. japonicus to at least 16.6 Mb and possibly up to 18.12 Mb, at least 30% larger than previous estimates. Our whole genome assembly will support the growing S. japonicus research community and facilitate research in new directions, including centromere and DNA repeat evolution, and yeast comparative genomics.},
}
@article {pmid38450924,
year = {2024},
author = {Guo, X and Li, J and Qi, Y and Chen, J and Jiang, M and Zhu, L and Liu, Z and Wang, H and Wang, G and Wang, X},
title = {Telomere length and micronuclei trajectories in APP/PS1 mouse model of Alzheimer's disease: Correlating with cognitive impairment and brain amyloidosis in a sexually dimorphic manner.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e14121},
doi = {10.1111/acel.14121},
pmid = {38450924},
issn = {1474-9726},
support = {31900410//National Natural Science Foundation of China/ ; 32260148//National Natural Science Foundation of China/ ; 31860301//National Natural Science Foundation of China/ ; 202001AU070055//Yunnan Fundamental Research Projects/ ; 202101AT070112//Yunnan Fundamental Research Projects/ ; },
abstract = {Although studies have demonstrated that genome instability is accumulated in patients with Alzheimer's disease (AD), the specific types of genome instability linked to AD pathogenesis remain poorly understood. Here, we report the first characterization of the age- and sex-related trajectories of telomere length (TL) and micronuclei in APP/PS1 mice model and wild-type (WT) controls (C57BL/6). TL was measured in brain (prefrontal cortex, cerebellum, pituitary gland, and hippocampus), colon and skin, and MN was measured in bone marrow in 6- to 14-month-old mice. Variation in TL was attributable to tissue type, age, genotype and, to a lesser extent, sex. Compared to WT, APP/PS1 had a significantly shorter baseline TL across all examined tissues. TL was inversely associated with age in both genotypes and TL shortening was accelerated in brain of APP/PS1. Age-related increase of micronuclei was observed in both genotypes but was accelerated in APP/PS1. We integrated TL and micronuclei data with data on cognition performance and brain amyloidosis. TL and micronuclei were linearly correlated with cognition performance or Aβ40 and Aβ42 levels in both genotypes but to a greater extent in APP/PS1. These associations in APP/PS1 mice were dominantly driven by females. Together, our findings provide foundational knowledge to infer the TL and micronuclei trajectories in APP/PS1 mice during disease progression, and strongly support that TL attrition and micronucleation are tightly associated with AD pathogenesis in a female-biased manner.},
}
@article {pmid38447517,
year = {2024},
author = {Mu, C and Lin, M and Shao, Y and Liao, Q and Liang, J and Yu, C and Wu, X and Chen, M and Tang, Y and Zhou, L and Qiu, X and Pan, D and Huang, D},
title = {Associations between maternal serum neonicotinoid pesticide exposure during pregnancy and newborn telomere length: Effect modification by sampling season.},
journal = {Ecotoxicology and environmental safety},
volume = {273},
number = {},
pages = {116164},
doi = {10.1016/j.ecoenv.2024.116164},
pmid = {38447517},
issn = {1090-2414},
abstract = {BACKGROUND: An increasing amount of evidence suggests that telomere length (TL) at birth can predict lifespan and is associated with chronic diseases later in life, but newborn TL may be affected by environmental pollutants. Neonicotinoids (NEOs) are widely used worldwide, and despite an increasing number of studies showing that they may have adverse effects on birth in mammals and even humans, few studies have examined the effect of NEO exposure on newborn TLs.<br><br>OBJECTIVE: To investigate the effects of prenatal exposure to NEOs and the interactions between NEOs and sampling season on newborn TL.<br><br>METHODS: We conducted a prospective cohort study of 500 mother-newborn pairs from the Guangxi Zhuang Birth Cohort. Ultraperformance liquid chromatographymass spectrometry was used to detect ten NEOs in maternal serum, and fluorescence quantitative PCR was used to estimate the newborn TL. A generalized linear model (GLM) was used to evaluate the relationships between individual NEO exposures and TLs&#xa0;, and quantile g-computation (Qgcomp) model and Bayesian kernel machine regression (BKMR) model were used to evaluate the combined effect of mixtures of components.<br><br>RESULTS: The results of the GLM showed that compared with maternal TMX levels < LOD, maternal TMX levels < median were negatively correlated with newborn TL (-6.93%, 95% CI%: -11.92%, -1.66%), and the decrease in newborn TL was more pronounced in girls (-9.60%, 95% CI: -16.84%, -1.72%). Moreover, different kinds of maternal NEO exposure had different effects on newborn TL in different sampling seasons, and the effect was statistically significant in all seasons except in autumn. Mixed exposure analysis revealed a potential positive trend between NEOs and newborn TL, but the association was not statistically significant.<br><br>CONCLUSION: Prenatal exposure to TMX may&#xa0;shorten newborn TL, and this effect is more pronounced among female newborns. Furthermore, the relationship between NEO exposure and TL may be modified by the sampling season.},
}
@article {pmid38445359,
year = {2024},
author = {Azzalin, CM},
title = {TERRA and the alternative lengthening of telomeres: a dangerous affair.},
journal = {FEBS letters},
volume = {},
number = {},
pages = {},
doi = {10.1002/1873-3468.14844},
pmid = {38445359},
issn = {1873-3468},
support = {LCF/PR/HP21/52310016//'la Caixa' Foundation/ ; 2021.00143.CEECIND//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; PTDC/BIA-MOL/6624/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; PTDC/MED-ONC/7864/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; //Sturtup company/ ; },
abstract = {Eukaryotic telomeres are transcribed into the long noncoding RNA TERRA. A fraction of TERRA remains associated with telomeres by forming RNA:DNA hybrids dubbed telR-loops. TERRA and telR-loops are essential to promote telomere elongation in human cancer cells that maintain telomeres through a homology-directed repair pathway known as alternative lengthening of telomeres or ALT. However, TERRA and telR-loops compromise telomere integrity and cell viability if their levels are not finely tuned. The study of telomere transcription in ALT cells will enormously expand our understanding of the ALT mechanism and of how genome integrity is maintained. Moreover, telomere transcription, TERRA and telR-loops are likely to become exceptionally suited targets for the development of novel anti-cancer therapies.},
}
@article {pmid38443473,
year = {2024},
author = {Xu, J and Zhu, G and Zhang, H},
title = {Causal relationship between telomere length and sepsis: a bidirectional Mendelian randomization study.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {5397},
pmid = {38443473},
issn = {2045-2322},
support = {SKLKF202008//Open Project of the State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University/ ; 20181BAB205041//Jiangxi Provincial Natural Science Foundation/ ; },
abstract = {Numerous observational studies have elucidated a connection between leukocyte telomere length (LTL) and sepsis, yet its fundamental cause remains enigmatic. Thus, the current study's objective is to employ a bidirectional Mendelian randomization (MR) approach to scrutinize the causality between LTL and sepsis. We selected single nucleotide polymorphisms (SNPs) associated with LTL (n = 472,174) and sepsis from a genome-wide association study (GWAS), including Sepsis (n = 486,484, ncase = 11,643), Sepsis (28 day death in critical care) (n = 431,365, ncase = 347), Sepsis (under 75) (n = 462,869, ncase = 11,568), Sepsis (28 day death) (n = 486,484, ncase = 1896), and Sepsis (critical care) (n = 431,365, ncase = 1380), as instrumental variables (IVs). The inverse variance weighted (IVW) MR method was employed as the primary approach, and various sensitivity analyses were conducted to assess the validity of this instrument and potential pleiotropy. Using the IVW method, we uncovered a potential causal relationship between genetically predicted LTL reduction and increased susceptibility to sepsis, with an odds ratio (OR) of 1.161 [95% confidence interval (CI) 1.039-1.297, p = 0.008]. However, reverse MR analysis did not indicate any impact of sepsis on LTL. Our forward MR study highlights a potential causal relationship between LTL as an exposure and increased susceptibility to sepsis. Specifically, our findings suggest that individuals with genetically determined shorter LTL may be at an increased risk of developing sepsis. This may contribute to the development of novel diagnostic and therapeutic strategies for the prevention, diagnosis, and treatment of sepsis.},
}
@article {pmid38442010,
year = {2024},
author = {Souza-Talarico, JN and Chesak, S and Elizalde, N and Liu, W and Moon, C and Oberfrank, NDCF and Rauer, AJ and Takao, CL and Shaw, C and Saravanan, A and Longhi Palacio, FG and Buck, H},
title = {Exploring the interplay of psychological and biological components of stress response and telomere length in the transition from middle age to late adulthood: A systematic review.},
journal = {Stress and health : journal of the International Society for the Investigation of Stress},
volume = {},
number = {},
pages = {e3389},
doi = {10.1002/smi.3389},
pmid = {38442010},
issn = {1532-2998},
abstract = {Ageing and chronic stress have been linked to reduced telomere length (TL) in mixed-age groups. Whether stress response components are linked to TL during the midlife-to-late adulthood transition remains unclear. Our study aimed to synthesise evidence on the relationship between psychological and biological components of stress response on TL in middle-aged and older adults. We conducted a systematic review of studies obtained from six databases (PubMed, CINAHL, EMBASE, PsycINFO, Web of Science, and Scopus) and evaluated by two independent reviewers. Original research measuring psychological and biological components of stress response and TL in human individuals were included. From an initial pool of 614 studies, 15 were included (n = 9446 participants). Synthesis of evidence showed that higher psychological components of the stress response (i.e., global perceived stress or within a specific life domain and cognitive appraisal to social-evaluative stressors) were linked to shorter TL, specifically in women or under major life stressors. For the biological stress response, cortisol, dehydroepiandrosterone sulphate and IGF-1/cortisol imbalance, IL-6, MCP-1, blood pressure, and heart rate presented a significant association with TL, but this relationship depended on major life stressors and the stress context (manipulated vs. non-manipulated conditions). This comprehensive review showed that psychological and biological components of the stress response are linked to shorter TL, but mainly in women or those under a major life stressor and stress-induced conditions. The interaction between stressor attributes and psychological and biological reactions in the transition from middle to late adulthood still needs to be fully understood, and examining it is a critical step to expanding our understanding of stress's impact on ageing trajectories.},
}
@article {pmid38441835,
year = {2024},
author = {Olovnikov, IA},
title = {Telomeres in health and longevity: special issue in memory of Alexey Olovnikov.},
journal = {Biogerontology},
volume = {},
number = {},
pages = {},
pmid = {38441835},
issn = {1573-6768},
abstract = {In this special issue we commemorate theoretical biologist Alexey Olovnikov (1936-2022), whose theory of marginotomy has laid the foundation for the new field of biology that studies the molecular structure of telomeres and its role in health, longevity and aging. This issue contains a collection of reviews and research articles that discuss different aspects of telomere and telomerase research, ranging from telomere length dynamics in wild animal populations to problems of telomere maintenance during human space flight.},
}
@article {pmid38441152,
year = {2024},
author = {Henriques, CM and Ferreira, MG},
title = {Telomere length is an epigenetic trait - Implications for the use of telomerase-deficient organisms to model human disease.},
journal = {Disease models &amp; mechanisms},
volume = {17},
number = {3},
pages = {},
doi = {10.1242/dmm.050581},
pmid = {38441152},
issn = {1754-8411},
support = {/WT_/Wellcome Trust/United Kingdom ; },
abstract = {Telomere length, unlike most genetic traits, is epigenetic, in the sense that it is not fully coded by the genome. Telomeres vary in length and randomly assort to the progeny leaving some individuals with longer and others with shorter telomeres. Telomerase activity counteracts this by extending telomeres in the germline and during embryogenesis but sizeable variances remain in telomere length. This effect is exacerbated by the absence of fully active telomerase. Telomerase heterozygous animals (tert+/-) have reduced telomerase activity and their telomeres fail to be elongated to wild-type average length, meaning that - with every generation - they decrease. After a given number of successive generations of telomerase-insufficient crosses, telomeres become critically short and cause organismal defects that, in humans, are known as telomere biology disorders. Importantly, these defects also occur in wild-type (tert+/+) animals derived from such tert+/- incrosses. Despite these tert+/+ animals being proficient for telomerase, they have shorter than average telomere length and, although milder, develop phenotypes that are similar to those of telomerase mutants. Here, we discuss the impact of this phenomenon on human pathologies associated with telomere length, provide a brief overview of telomere biology across species and propose specific measures for working with telomerase-deficient zebrafish.},
}
@article {pmid38438580,
year = {2024},
author = {Qiu, YD and Yan, Q and Wang, Y and Ye, YF and Wang, Y and Wang, MY and Wang, PP and Zhang, SY and Wang, DL and Yan, H and Ruan, J and Zhao, YJ and Huang, LH and Cho, N and Wang, K and Zheng, XH and Liu, ZG},
title = {Discovery of a selective TRF2 inhibitor FKB04 induced telomere shortening and senescence in liver cancer cells.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {38438580},
issn = {1745-7254},
abstract = {Telomere repeat binding factor 2 (TRF2), a critical element of the shelterin complex, plays a vital role in the maintenance of genome integrity. TRF2 overexpression is found in a wide range of malignant cancers, whereas its down-regulation could cause cell death. Despite its potential role, the selectively small-molecule inhibitors of TRF2 and its therapeutic effects on liver cancer remain largely unknown. Our clinical data combined with bioinformatic analysis demonstrated that TRF2 is overexpressed in liver cancer and that high expression is associated with poor prognosis. Flavokavain B derivative FKB04 potently inhibited TRF2 expression in liver cancer cells while having limited effects on the other five shelterin subunits. Moreover, FKB04 treatment induced telomere shortening and increased the amounts of telomere-free ends, leading to the destruction of T-loop structure. Consequently, FKB04 promoted liver cancer cell senescence without modulating apoptosis levels. In corroboration with these findings, FKB04 inhibited tumor cell growth by promoting telomeric TRF2 deficiency-induced telomere shortening in a mouse xenograft tumor model, with no obvious side effects. These results demonstrate that TRF2 is a potential therapeutic target for liver cancer and suggest that FKB04 may be a selective small-molecule inhibitor of TRF2, showing promise in the treatment of liver cancer.},
}
@article {pmid38435987,
year = {2024},
author = {Lunghi, E and Bilandžija, H},
title = {Telomere length and dynamics in Astyanax mexicanus cave and surface morphs.},
journal = {PeerJ},
volume = {12},
number = {},
pages = {e16957},
doi = {10.7717/peerj.16957},
pmid = {38435987},
issn = {2167-8359},
abstract = {BACKGROUND: Telomeres are non-coding DNA repeats at the chromosome ends and their shortening is considered one of the major causes of aging. However, they also serve as a biomarker of environmental exposures and their length and attrition is affected by various stressors. In this study, we examined the average telomere length in Astyanax mexicanus, a species that has both surface-dwelling and cave-adapted populations. The cave morph descended from surface ancestors and adapted to a markedly different environment characterized by specific biotic and abiotic stressors, many of which are known to affect telomere length. Our objective was to explore whether telomere length differs between the two morphs and whether it serves as a biological marker of aging or correlates with the diverse environments the morphs are exposed to.<br><br>METHODS: We compared telomere length and shortening between laboratory-reared Pach&#xf3;n cavefish and Rio Choy surface fish of A. mexicanus across different tissues and ages.<br><br>RESULTS: Astyanax mexicanus surface fish exhibited longer average telomere length compared to cavefish. In addition, we did not observe telomere attrition in either cave or surface form as a result of aging in adults up to 9 years old, suggesting that efficient mechanisms prevent telomere-mediated senescence in laboratory stocks of this species, at least within this time frame. Our results suggest that telomere length in Astyanax may be considered a biomarker of environmental exposures. Cavefish may have evolved shorter and energetically less costly telomeres due to the absence of potential stressors known to affect surface species, such as predator pressure and ultra-violet radiation. This study provides the first insights into telomere dynamics in Astyanax morphs and suggests that shorter telomeres may have evolved as an adaptation to caves.},
}
@article {pmid38435019,
year = {2024},
author = {Taylor, GT and McQueen, A and Eastwood, JR and Dupoué, A and Wong, BBM and Verhulst, S and Peters, A},
title = {No effect of testosterone or sexual ornamentation on telomere dynamics: A case study and meta-analyses.},
journal = {Ecology and evolution},
volume = {14},
number = {3},
pages = {e11088},
doi = {10.1002/ece3.11088},
pmid = {38435019},
issn = {2045-7758},
abstract = {Life-history theory predicts that reproductive investments are traded-off against self-maintenance. Telomeres, the protective caps on the ends of chromosomes, offer a promising avenue for assessing life-history trade-offs, as they shorten in response to stressors and are predictive of the remaining lifespan. In males, testosterone frequently mediates life-history trade-offs, in part, through its effects on sexual ornamentation, which is an important aspect of reproductive investment. However, studies of within-individual associations between telomere dynamics and sexual ornamentation are limited in number and have produced mixed results. Furthermore, most such studies have been observational, making it difficult to discern the nature of any causal relationship. To address this, we used short-acting testosterone implants in free-living male superb fairy-wrens (Malurus cyaneus) to stimulate the production of a sexual ornament: early moult into a costly blue breeding plumage. We found no evidence that elevated testosterone, and the consequent earlier moult into breeding plumage, accelerated telomere shortening. We therefore followed up with a systematic review and two meta-analyses (28 studies, 54 effect sizes) exploring the associations between telomeres and (1) testosterone and (2) sexual ornamentation. In line with our experimental findings, neither meta-analysis showed an overall correlation of testosterone or sexual ornamentation with telomere length or telomere dynamics. However, meta-regression showed that experimental, compared to observational, studies reported greater evidence of trade-offs. Our meta-analyses highlight the need for further experimental studies to better understand potential responses of telomere length or telomere dynamics to testosterone or sexual ornamentation.},
}
@article {pmid38434436,
year = {2024},
author = {Barcenilla, BB and Kundel, I and Hall, E and Hilty, N and Ulianich, P and Cook, J and Turley, J and Yerram, M and Min, JH and Castillo-González, C and Shippen, DE},
title = {Telomere dynamics and oxidative stress in Arabidopsis grown in lunar regolith simulant.},
journal = {Frontiers in plant science},
volume = {15},
number = {},
pages = {1351613},
doi = {10.3389/fpls.2024.1351613},
pmid = {38434436},
issn = {1664-462X},
abstract = {NASA envisions a future where humans establish a thriving colony on the Moon by 2050. Plants will be essential for this endeavor, but little is known about their adaptation to extraterrestrial bodies. The capacity to grow plants in lunar regolith would represent a major step towards this goal by minimizing the reliance on resources transported from Earth. Recent studies reveal that Arabidopsis thaliana can germinate and grow on genuine lunar regolith as well as on lunar regolith simulant. However, plants arrest in vegetative development and activate a variety of stress response pathways, most notably the oxidative stress response. Telomeres are hotspots for oxidative damage in the genome and a marker of fitness in many organisms. Here we examine A. thaliana growth on a lunar regolith simulant and the impact of this resource on plant physiology and on telomere dynamics, telomerase enzyme activity and genome oxidation. We report that plants successfully set seed and generate a viable second plant generation if the lunar regolith simulant is pre-washed with an antioxidant cocktail. However, plants sustain a higher degree of genome oxidation and decreased biomass relative to conventional Earth soil cultivation. Moreover, telomerase activity substantially declines and telomeres shorten in plants grown in lunar regolith simulant, implying that genome integrity may not be sustainable over the long-term. Overcoming these challenges will be an important goal in ensuring success on the lunar frontier.},
}
@article {pmid38431573,
year = {2024},
author = {Ding, K and Zhangwang, J and Lei, M and Xiong, C},
title = {Insight into telomere regulation: road to discovery and intervention in plasma drug-protein targets.},
journal = {BMC genomics},
volume = {25},
number = {1},
pages = {231},
pmid = {38431573},
issn = {1471-2164},
abstract = {BACKGROUND: Telomere length is a critical metric linked to aging, health, and disease. Currently, the exploration of target proteins related to telomere length is usually limited to the context of aging and specific diseases, which limits the discovery of more relevant drug targets. This study integrated large-scale plasma cis-pQTLs data and telomere length GWAS datasets. We used Mendelian randomization(MR) to identify drug target proteins for telomere length, providing essential clues for future precision therapy and targeted drug development.<br><br>METHODS: Using plasma cis-pQTLs data from a previous GWAS study (3,606 Pqtls associated with 2,656 proteins) and a GWAS dataset of telomere length (sample size: 472,174; GWAS ID:&#xa0;ieu-b-4879) from UK Biobank, using MR, external validation, and reverse causality testing, we identified essential drug target proteins for telomere length. We also&#xa0;performed co-localization, Phenome-wide association studies and enrichment analysis, protein-protein interaction network construction, search for existing intervening drugs, and potential drug/compound prediction for these critical targets to strengthen and expand our findings.<br><br>RESULTS: After Bonferron correction (p&#x2009;<&#x2009;0.05/734), RPN1 (OR: 0.96; 95%CI: (0.95, 0.97)), GDI2 (OR: 0.94; 95%CI: (0.92, 0.96)), NT5C (OR: 0.97; 95%CI: (0.95, 0.98)) had a significant negative causal association with telomere length; TYRO3 (OR: 1.11; 95%CI: (1.09, 1.15)) had a significant positive causal association with telomere length.&#xa0;GDI2 shared the same genetic variants with telomere length (coloc.abf-PPH 4&#x2009;>&#x2009;0.8).<br><br>CONCLUSION: Genetically determined plasma RPN1, GDI2, NT5C, and TYRO3 have significant causal effects on telomere length and can potentially be drug targets. Further exploration of the role and mechanism of these proteins/genes in regulating telomere length is needed.},
}
@article {pmid38431123,
year = {2024},
author = {Di, D and Zhou, H and Cui, Z and Zhang, J and Liu, Q and Yuan, T and Zhou, T and Luo, X and Ling, D and Wang, Q},
title = {Early-life tobacco smoke elevating later-life osteoporosis risk: Mediated by telomere length and interplayed with genetic predisposition.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2024.02.021},
pmid = {38431123},
issn = {2090-1224},
abstract = {INTRODUCTION: The growing prevalence of osteoporosis (OP) in an aging global population presents a significant public health concern. Tobacco smoke negatively affects bone turnover, leading to reduced bone mass and heightened OP and fracture risk. However, the impact of early-life tobacco smoke exposure on later-life OP risk remains unclear.<br><br>OBJECTIVES: This study was to explore the effects of early-life tobacco smoke exposure on incident OP risk in later life. The mediating role of telomere length (TL) and the interaction with genetic predisposition were also studied.<br><br>METHODS: Data on in utero tobacco smoke exposure (IUTSE) status and age of tobacco use initiation from the UK Biobank were used to estimate early-life tobacco smoke exposure. Incident OP cases were identified according to health-related records. Linear, Cox, and Laplace regression models were mainly used for data analysis.<br><br>RESULTS: Individuals with IUTSE showed a higher OP risk [hazard ratio (HR): 1.06, 95&#x202f;% confidence interval (CI): 1.01, 1.11] and experienced earlier OP onset by 0.30&#x202f;years [50th percentile difference&#x202f;=&#x202f;-0.30, 95&#x202f;% CI: -0.51, -0.09] compared to those without. Participants initiating tobacco smoke in childhood, adolescence, and adulthood had 1.41 times (95&#x202f;% CI: 1.23, 1.61), 1.17 times (95&#x202f;% CI:1.10, 1.24), and 1.14 times (95&#x202f;% CI: 1.07, 1.20) the risk of OP, respectively, compared to never smokers. They also experienced earlier OP onset by 2.16, 0.95, and 0.71&#x202f;years, sequentially. The TL significantly mediated the early-life tobacco exposure and OP association. Significant joint and interactive effects were detected between early-life tobacco smoke exposure and genetic elements.<br><br>CONCLUSIONS: Our findings implicate that early-life tobacco smoke exposure elevates the later-life OP risk, mediated by telomere length and interplayed with genetic predisposition. These findings highlight the importance of early-life intervention against tobacco smoke exposure and ageing status for precise OP prevention, especially in individuals with a high genetic risk.},
}
@article {pmid38430974,
year = {2024},
author = {Bories, C and Lejour, T and Adolphe, F and Kermasson, L and Couvé, S and Tanguy, L and Luszczewska, G and Watzky, M and Poillerat, V and Garnier, P and Groisman, R and Ferlicot, S and Richard, S and Saparbaev, M and Revy, P and Gad, S and Renaud, F},
title = {DCLRE1B/Apollo germline mutations associated with renal cell carcinoma impair telomere protection.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {},
number = {},
pages = {167107},
doi = {10.1016/j.bbadis.2024.167107},
pmid = {38430974},
issn = {1879-260X},
abstract = {Hereditary renal cell carcinoma (RCC) is caused by germline mutations in a subset of genes, including VHL, MET, FLCN, and FH. However, many familial RCC cases do not harbor mutations in the known predisposition genes. Using Whole Exome Sequencing, we identified two germline missense variants in the DCLRE1B/Apollo gene (Apollo[N246I] and Apollo[Y273H]) in two unrelated families with several RCC cases. Apollo encodes an exonuclease involved in DNA Damage Response and Repair (DDRR) and telomere integrity. We characterized these two functions in the human renal epithelial cell line HKC8. The decrease or inhibition of Apollo expression sensitizes these cells to DNA interstrand crosslink damage (ICLs). HKC8 Apollo[-/-] cells appear defective in the DDRR and present an accumulation of telomere damage. Wild-type and mutated Apollo forms could interact with TRF2, a shelterin protein involved in telomere protection. However, only Apollo[WT] can rescue the telomere damage in HKC8 Apollo[-/-] cells. Our results strongly suggest that Apollo[N246I] and Apollo[Y273H] are loss-of-function mutants that cause impaired telomere integrity and could lead to genomic instability. Altogether, our results suggest that mutations in Apollo could induce renal oncogenesis.},
}
@article {pmid38429270,
year = {2024},
author = {Spano, L and Marie-Claire, C and Godin, O and Lebras, A and Courtin, C and Laplanche, JL and Leboyer, M and Aouizerate, B and Lefrere, A and Belzeaux, R and Courtet, P and Olié, E and Dubertret, C and Schwan, R and Aubin, V and Roux, P and Polosan, M and Samalin, L and Haffen, E and , and Bellivier, F and Etain, B},
title = {Decreased telomere length in a subgroup of young individuals with bipolar disorders: replication in the FACE-BD cohort and association with the shelterin component POT1.},
journal = {Translational psychiatry},
volume = {14},
number = {1},
pages = {131},
pmid = {38429270},
issn = {2158-3188},
support = {2018//Fondation de France/ ; },
mesh = {Humans ; Aged ; Adult ; *Bipolar Disorder/genetics ; Telomere/genetics ; Telomere Shortening/genetics ; Aging ; *Aging, Premature ; Shelterin Complex ; Telomere-Binding Proteins/genetics ; },
abstract = {Bipolar disorder (BD) has been associated with premature cellular aging with shortened telomere length (TL) as compared to the general population. We recently identified a subgroup of young individuals with prematurely shortened TL. The aims of the present study were to replicate this observation in a larger sample and analyze the expression levels of genes associated with age or TL in a subsample of these individuals. TL was measured on peripheral blood DNA using quantitative polymerase chain reaction in a sample of 542 individuals with BD and clustering analyses were performed. Gene expression level of 29 genes, associated with aging or with telomere maintenance, was analyzed in RNA samples from a subsample of 129 individuals. Clustering analyses identified a group of young individuals (mean age 29.64 years), with shorter TL. None of the tested clinical variables were significantly associated with this subgroup. Gene expression level analyses showed significant downregulation of MYC, POT1, and CD27 in the prematurely aged young individuals compared to the young individuals with longer TL. After adjustment only POT1 remained significantly differentially expressed between the two groups of young individuals. This study confirms the existence of a subgroup of young individuals with BD with shortened TL. The observed decrease of POT1 expression level suggests a newly described cellular mechanism in individuals with BD, that may contribute to telomere shortening.},
}
@article {pmid38426330,
year = {2024},
author = {Bosquet Enlow, M and De Vivo, I and Petty, CR and Nelson, CA},
title = {Temperament and sex as moderating factors of the effects of exposure to maternal depression on telomere length in early childhood.},
journal = {Development and psychopathology},
volume = {},
number = {},
pages = {1-14},
doi = {10.1017/S0954579424000518},
pmid = {38426330},
issn = {1469-2198},
abstract = {Individual differences in sensitivity to context are posited to emerge early in development and to influence the effects of environmental exposures on a range of developmental outcomes. The goal of the current study was to examine the hypothesis that temperament characteristics and biological sex confer differential vulnerability to the effects of exposure to maternal depression on telomere length in early childhood. Telomere length has emerged as a potentially important biomarker of current and future health, with possible mechanistic involvement in the onset of various disease states. Participants comprised a community sample of children followed from infancy to age 3 years. Relative telomere length was assessed from DNA in saliva samples collected at infancy, 2 years, and 3 years. Maternal depressive symptoms and the child temperament traits of negative affectivity, surgency/extraversion, and regulation/effortful control were assessed via maternal report at each timepoint. Analyses revealed a 3-way interaction among surgency/extraversion, sex, and maternal depressive symptoms, such that higher surgency/extraversion was associated with shorter telomere length specifically among males exposed to elevated maternal depressive symptoms. These findings suggest that temperament and sex influence children's susceptibility to the effects of maternal depression on telomere dynamics in early life.},
}
@article {pmid38422914,
year = {2024},
author = {Kam, MLW and Chong, ST and Chan, SH and Swigris, JJ and Chew, EL and Tan, YH and Ngeow, JYY and Low, SY},
title = {First ever characterisation of the effects of short telomeres in a Singapore interstitial lung disease cohort.},
journal = {Respiratory investigation},
volume = {62},
number = {3},
pages = {348-355},
doi = {10.1016/j.resinv.2024.02.004},
pmid = {38422914},
issn = {2212-5353},
abstract = {BACKGROUND: Differences in disease behaviour and genotypes are described in Asian and Western interstitial lung disease (ILD) cohorts. Short leukocyte telomere length (LTL) correlates with poor outcomes in Western ILD cohorts but its significance in Asian populations is unknown. We aim to characterise the burden and clinical implications of short LTL in Singaporean ILD patients.<br><br>METHODS: Patients diagnosed with ILD at Singapore General Hospital were prospectively recruited and compared against 36 healthy controls. The primary outcome was transplant-free survival. Genomic DNA from peripheral blood was extracted and LTL measured using quantitative polymerase chain reaction assay (qPCR).<br><br>RESULTS: Amongst 165 patients, 37% had short LTL. There was a higher proportion of combined pulmonary fibrosis and emphysema (CPFE) patients with short LTL (n&#xa0;=&#xa0;21, 34.4% vs n&#xa0;=&#xa0;16, 15.4%; p&#xa0;<&#xa0;0.001). Short LTL patients had reduced survival at 12-, 24- and 36-months and median survival of 24 months (p&#xa0;<&#xa0;0.001) which remained significant following adjustment for smoking, GAP Stage and radiological UIP pattern (Hazard Ratio (HR), 2.74; 95%CI:1.46, 5.11; p&#xa0;=&#xa0;0.002). They had increased respiratory-related mortality and acute exacerbation incidences. Despite similar baseline lung function, short LTL patients had a faster decline in absolute forced vital capacity (FVC) of -105.3 (95% CI: 151.4, -59.1) mL/year compared to -58.2 (95% CI: 82.9, -33.6) mL/year (p&#xa0;<&#xa0;0.001) in normal LTL patients.<br><br>CONCLUSION: Short LTL correlated with increased mortality and faster lung function decline in our Singaporean ILD cohort with a magnitude similar to that in Western ILD cohorts. Further research is needed to integrate LTL assessment into clinical practice.},
}
@article {pmid38418884,
year = {2024},
author = {Takai, H and Aria, V and Borges, P and Yeeles, JTP and de Lange, T},
title = {CST-polymerase α-primase solves a second telomere end-replication problem.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {38418884},
issn = {1476-4687},
support = {R01 CA076027/CA/NCI NIH HHS/United States ; R50 CA243771/CA/NCI NIH HHS/United States ; },
abstract = {Telomerase adds G-rich telomeric repeats to the 3' ends of telomeres[1], counteracting telomere shortening caused by loss of telomeric 3' overhangs during leading-strand DNA synthesis ('the end-replication problem'[2]). Here we report a second end-replication problem that originates from the incomplete duplication of the C-rich telomeric repeat strand (C-strand) by lagging-strand DNA synthesis. This problem is resolved by fill-in synthesis mediated by polymerase α-primase bound to Ctc1-Stn1-Ten1 (CST-Polα-primase). In vitro, priming for lagging-strand DNA replication does not occur on the 3' overhang and lagging-strand synthesis stops in a zone of approximately 150 nucleotides (nt) more than 26 nt from the end of the template. Consistent with the in vitro data, lagging-end telomeres of cells lacking CST-Polα-primase lost 50-60 nt of telomeric CCCTAA repeats per population doubling. The C-strands of leading-end telomeres shortened by around 100 nt per population doubling, reflecting the generation of 3' overhangs through resection. The measured overall C-strand shortening in the absence of CST-Polα-primase fill-in is consistent with the combined effects of incomplete lagging-strand synthesis and 5' resection at the leading ends. We conclude that canonical DNA replication creates two telomere end-replication problems that require telomerase to maintain the G-rich strand and CST-Polα-primase to maintain the C-strand.},
}
@article {pmid38409427,
year = {2024},
author = {Inomata, S and Arima, H and Fukuda, T and Ozawa, H and Yamamoto, T},
title = {Smoking and diabetes cause telomere shortening among alcohol use disorder patients.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {4701},
pmid = {38409427},
issn = {2045-2322},
support = {19H05737//Grants-in-Aid for Scientific Research (KAKENHI)/ ; },
mesh = {Humans ; Telomere Shortening ; *Alcoholism/genetics ; Alcohol Drinking/adverse effects ; Smoking/adverse effects/genetics ; Telomere/genetics ; *Diabetes Mellitus/genetics ; Leukocytes ; },
abstract = {The length of telomeres located at the ends of chromosomes has attracted attention as an indicator of cellular and individual aging. Various diseases or stresses cause telomere shortening, and it has been reported that alcohol use disorder patients actually have shorter telomeres than healthy patients. However, the factors that contribute to the reduction in telomere length among alcohol use disorder patients have not been clarified in detail. Therefore, in this study, we explored the factors that reduce telomere length in alcohol use disorder patients. A questionnaire survey and a measurement of leukocyte telomere length were conducted among alcohol use disorder patients. The mean telomere length of leukocyte was measured by ∆∆Ct analysis using a real-time PCR. We compared the telomere length between alcohol use disorder patients and the control group (Japanese special health check-up examinee). Moreover, we searched for factors associated with telomere length from drinking/smoking characteristics and history of comorbidities. A total of 74 subjects had alcohol use disorder, and 68 were in the control group. Compared to the control group, alcohol use disorder patients had significantly shorter telomere lengths (p < 0.001). A multivariate analysis revealed that a longer duration of smoking resulted in a significantly shorter telomere length (p = 0.0129). In addition, a comparison of the telomere length between the groups with and without a history of suffering from each disease revealed that telomere length was significantly shorter in the group with diabetes than in the group without diabetes (p = 0.0371). This study reveals that in individuals with alcohol dependence, particularly, prolonged smoking habits and the presence of diabetes contribute to telomere shortening. Medication and support for abstinence from alcohol has been mainly provided for alcohol use disorder patients. Our findings demonstrate a potential support approach via smoking cessation programs and controlling diabetes, which may be helpful to suppress the shortening of healthy life expectancy among alcohol use disorder patients.},
}
@article {pmid38407308,
year = {2024},
author = {Sonmez, C and Toia, B and Eickhoff, P and Matei, AM and El Beyrouthy, M and Wallner, B and Douglas, ME and de Lange, T and Lottersberger, F},
title = {DNA-PK controls Apollo's access to leading-end telomeres.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkae105},
pmid = {38407308},
issn = {1362-4962},
support = {AG016642/NH/NIH HHS/United States ; },
abstract = {The complex formed by Ku70/80 and DNA-PKcs (DNA-PK) promotes the synapsis and the joining of double strand breaks (DSBs) during canonical non-homologous end joining (c-NHEJ). In c-NHEJ during V(D)J recombination, DNA-PK promotes the processing of the ends and the opening of the DNA hairpins by recruiting and/or activating the nuclease Artemis/DCLRE1C/SNM1C. Paradoxically, DNA-PK is also required to prevent the fusions of newly replicated leading-end telomeres. Here, we describe the role for DNA-PK in controlling Apollo/DCLRE1B/SNM1B, the nuclease that resects leading-end telomeres. We show that the telomeric function of Apollo requires DNA-PKcs's kinase activity and the binding of Apollo to DNA-PK. Furthermore, AlphaFold-Multimer predicts that Apollo's nuclease domain has extensive additional interactions with DNA-PKcs, and comparison to the cryo-EM structure of Artemis bound to DNA-PK phosphorylated on the ABCDE/Thr2609 cluster suggests that DNA-PK can similarly grant Apollo access to the DNA end. In agreement, the telomeric function of DNA-PK requires the ABCDE/Thr2609 cluster. These data reveal that resection of leading-end telomeres is regulated by DNA-PK through its binding to Apollo and its (auto)phosphorylation-dependent positioning of Apollo at the DNA end, analogous but not identical to DNA-PK dependent regulation of Artemis at hairpins.},
}
@article {pmid38404592,
year = {2024},
author = {Xu, D and Ye, Z and Huang, Y and Zhu, K and Xu, H and Yu, J and Feng, Y and Zhao, X and Wang, L and Xu, H and Li, Q and Qin, M and Tang, Y and Zhang, X and Zhao, Y},
title = {Haplotype-resolved genome assembly of Corydalis yanhusuo, a traditional Chinese medicine with unusual telomere motif.},
journal = {Horticulture research},
volume = {11},
number = {2},
pages = {uhad296},
pmid = {38404592},
issn = {2662-6810},
}
@article {pmid38398126,
year = {2024},
author = {Gorria, T and Crous, C and Pineda, E and Hernandez, A and Domenech, M and Sanz, C and Jares, P and Muñoz-Mármol, AM and Arpí-Llucía, O and Melendez, B and Gut, M and Esteve, A and Esteve-Codina, A and Parra, G and Alameda, F and Carrato, C and Aldecoa, I and Mallo, M and de la Iglesia, N and Balana, C},
title = {The C250T Mutation of TERTp Might Grant a Better Prognosis to Glioblastoma by Exerting Less Biological Effect on Telomeres and Chromosomes Than the C228T Mutation.},
journal = {Cancers},
volume = {16},
number = {4},
pages = {},
pmid = {38398126},
issn = {2072-6694},
support = {665/C/2013//Fundaci&#xf3; La Marat&#xf3; TV3/ ; PI118/01062//Instituto de Salud Carlos III/ ; },
abstract = {UNLABELLED: The aim of this study was to determine how TERTp mutations impact glioblastoma prognosis.<br><br>MATERIALS AND METHODS: TERTp mutations were assessed in a retrospective cohort of 258 uniformly treated glioblastoma patients. RNA-sequencing and whole exome sequencing results were available in a subset of patients.<br><br>RESULTS: Overall, there were no differences in outcomes between patients with mutated TERTp-wt or TERTp. However, we found significant differences according to the type of TERTp mutation. Progression-free survival (mPFS) was 9.1 months for those with the C250T mutation and 7 months for those with either the C228T mutation or TERTp-wt (p = 0.016). Overall survival (mOS) was 21.9 and 15 months, respectively (p = 0.026). This differential effect was more pronounced in patients with MGMTp methylation (mPFS: p = 0.008; mOS: p = 0.021). Multivariate analysis identified the C250T mutation as an independent prognostic factor for longer mOS (HR 0.69; p = 0.044). We found no differences according to TERTp mutation status in molecular alterations common in glioblastoma, nor in copy number variants in genes related to alternative lengthening of telomeres. Nevertheless, in the gene enrichment analysis adjusted for MGMTp methylation status, some Reactome gene sets were differentially enriched, suggesting that the C250T mutation may exert a lesser effect on telomeres or chromosomes.<br><br>CONCLUSIONS: In our series, patients exhibiting the C250T mutation had a more favorable prognosis compared to those with either TERPp-wt or TERTp C228T mutations. Additionally, our findings suggest a reduced involvement of the C250T mutation in the underlying biological mechanisms related to telomeres.},
}
@article {pmid38397754,
year = {2024},
author = {Córdoba-Lanús, E and Montuenga, LM and Domínguez-de-Barros, A and Oliva, A and Mayato, D and Remírez-Sanz, A and Gonzalvo, F and Celli, B and Zulueta, JJ and Casanova, C},
title = {Oxidative Damage and Telomere Length as Markers of Lung Cancer Development among Chronic Obstructive Pulmonary Disease (COPD) Smokers.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {2},
pages = {},
pmid = {38397754},
issn = {2076-3921},
support = {PI 12/00355//Instituto de Salud Carlos III/ ; PI 13/007//Sociedad Espa&#xf1;ola de Neumolog&#xed;a y Cirug&#xed;a Tor&#xe1;cica/ ; Agust&#xed;n de Betancourt program//Cabildo de Tenerife/ ; CB21/13/00100//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red en Enfermedades Infecciosas/ ; 2018//Menarini S.A./ ; },
abstract = {Lung cancer (LC) constitutes an important cause of death among patients with Chronic Obstructive Pulmonary Disease (COPD). Both diseases may share pathobiological mechanisms related to oxidative damage and cellular senescence. In this study, the potential value of leucocyte telomere length, a hallmark of aging, and 8-OHdG concentrations, indicative of oxidative DNA damage, as risk biomarkers of LC was evaluated in COPD patients three years prior to LC diagnosis. Relative telomere length measured using qPCR and serum levels of 8-OHdG were determined at the baseline in 99 COPD smokers (33 with LC and 66 age-matched COPD without LC as controls). Of these, 21 COPD with LC and 42 controls had the biomarkers measured 3 years before. Single nucleotide variants (SNVs) in TERT, RTEL, and NAF1 genes were also determined. COPD cases were evaluated, which showed greater telomere length (p < 0.001) and increased serum 8-OHdG levels (p = 0.004) three years prior to LC diagnosis compared to the controls. This relationship was confirmed at the time of LC diagnosis. No significant association was found between the studied SNVs in cases vs. controls. In conclusion, this preliminary study shows that longer leucocyte telomere length and increased 8-OHdG serum levels can be useful as early biomarkers of the risk for future lung cancer development among COPD patients.},
}
@article {pmid38393686,
year = {2024},
author = {Wang, Y and Liu, Q and Liang, S and Yao, M and Zheng, H and Hu, D and Wang, Y},
title = {Genetically predicted telomere length and the risk of 11 hematological diseases: a Mendelian randomization study.},
journal = {Aging},
volume = {16},
number = {},
pages = {},
doi = {10.18632/aging.205583},
pmid = {38393686},
issn = {1945-4589},
abstract = {OBJECTIVE: Previous studies have demonstrated that various hematologic diseases (HDs) induce alterations in telomere length (TL). The aim of this study is to investigate whether genetically predicted changes in TL have an impact on the risk of developing HDs.<br><br>METHODS: GWAS data for TL and 11 HDs were extracted from the database. The R software package "TwoSampleMR" was employed to conduct a two-sample Mendelian randomization (MR) analysis, in order to estimate the influence of TL changes on the risk of developing the 11 HDs.<br><br>RESULTS: We examined the effect of TL changes on the risk of developing the 11 HDs. The IVW results revealed a significant causal association between genetically predicted longer TL and the risk of developing acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MANTLE), and hodgkin lymphoma (HODGKIN). However, there was no significant causal relationship observed between TL changes and the risk of developing chronic myeloid leukemia (CML), diffuse large b-cell lymphoma (DLBCL), marginal zone b-cell lymphoma (MARGINAL), follicular lymphoma (FOLLICULAR), monocytic leukemia (MONOCYTIC), and mature T/NK-cell lymphomas (TNK).<br><br>CONCLUSIONS: The MR analysis revealed a positive association between genetically predicted longer TL and an increased risk of developing ALL, AML, CLL, MANTLE, and HODGKIN. This study further supports the notion that cells with longer TL have greater proliferative and mutational potential, leading to an increased risk of certain HDs.},
}
@article {pmid38393627,
year = {2024},
author = {Kogure, GS and Verruma, CG and Santana, BA and Calado, RT and Ferriani, RA and Furtado, CLM and Dos Reis, RM},
title = {Obesity contributes to telomere shortening in polycystic ovary syndrome.},
journal = {Reproductive sciences (Thousand Oaks, Calif.)},
volume = {},
number = {},
pages = {},
pmid = {38393627},
issn = {1933-7205},
support = {2019/17618-3//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 2012/11566-2//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 2012/11069-9//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 2015/14031-0//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; },
abstract = {Polycystic ovary syndrome (PCOS) is a multifactorial disorder and obesity occurs in 38% to 88% of these women. Although hyperandrogenism may contribute to telomere lengthening, increased body mass index (BMI) is associated with telomere erosion. We sought to compare leukocyte telomere length (LTL) in PCOS women with normal, overweight, and obese BMI. We evaluated the relationship between LTL and clinical variables of PCOS and inflammatory biomarkers independent of BMI. A total of 348 women (243 PCOS and 105 non-PCOS) were evaluated for anthropometric measures, total testosterone, androstenedione, estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone-binding globulin (SHBG), free androgen index (FAI), fasting insulin and glycemia, lipid profile, homocysteine, C-reactive protein (CRP) and homeostatic model of insulin resistance (HOMA-IR). LTL was measured by qPCR. The PCOS group presented higher weight, waist circumference, BMI, testosterone, LH, fasting insulin, FAI, and HOMA-IR, and lower E2, SHBG, and fasting glycemia measures compared with the non-PCOS. When stratified by BMI, LTL was increased in all subgroups in PCOS compared to non-PCOS. However, in the PCOS group, LTL was lower in overweight (P = 0.0187) and obese (P = 0.0018) compared to normal-weight women. The generalized linear model showed that BMI, androstenedione, homocysteine, and CRP were associated with telomere biology. Women with PCOS had longer LTL, however, overweight or obesity progressively contributes to telomere shortening and may affect reproductive outcomes of PCOS, while androstenedione may increase LTL.},
}
@article {pmid38389866,
year = {2024},
author = {Choudhary, D and Lekshmon, KS and Singh, C and Subramani, VN and Singh, Y and Mitra, S and Sekar, A and Malik, M and Bhagat, N and Shiva Kumar, SP and Taneja, S and Gupta, V and Ramachandran, R and Singh, S and Nada, R and Kenwar, D and Duseja, AK and Yadav, TD and Malhotra, P and Sharma, A},
title = {Simultaneous Liver and Kidney Transplantation in a Patient With Telomere Biology Disorder: A Case Study.},
journal = {Journal of clinical and experimental hepatology},
volume = {14},
number = {3},
pages = {101355},
pmid = {38389866},
issn = {0973-6883},
abstract = {Organ transplantation is the primary therapy for organ failure caused by telomere biology disorder (TBD). We describe the first documented case of simultaneous liver and kidney transplantation (SLKTx) for TBD, although the diagnosis of TBD was reached only three months following SLKTx. The patient was born prematurely, displayed growth retardation, and developed chronic kidney and liver diseases. His pre-SLKTx autoimmune, metabolic, and viral assessments were negative, and persistent pancytopenia (bone marrow cellularity 70-80%) was attributed to renal disease-associated bone marrow changes. Following SLKTx, he was discharged with stable graft function on tacrolimus and prednisolone. Although mycophenolate mofetil was discontinued on the second postoperative day, his pancytopenia persisted. Despite extensive evaluations, including drug, immune, nutritional, and viral assessments, all results were negative. A bone marrow biopsy conducted three months post-transplant revealed significant hypocellularity (40-50%). Whole genome sequencing revealed a likely pathogenic variant of the TINF2 gene. The patient was subsequently treated with danazol. At the nine-month follow-up post-SLKTx, he exhibited stable graft function and improved cell counts while maintaining triple-drug immunosuppression. Given the lack of uniform diagnostic criteria for TBD, healthcare providers must be vigilant with patients presenting with multi-organ failure and persistent cytopenias. Effective pre-transplant screening for TBD can lead to timely diagnoses, better management, and improved post-transplant outcomes.},
}
@article {pmid38386656,
year = {2024},
author = {Wolf, SE and Hastings, WJ and Ye, Q and Etzel, L and Apsley, AT and Chiaro, C and Heim, CC and Heller, T and Noll, JG and Schreier, HMC and Shenk, CE and Shalev, I},
title = {Cross-tissue comparison of telomere length and quality metrics of DNA among individuals aged 8 to 70 years.},
journal = {PloS one},
volume = {19},
number = {2},
pages = {e0290918},
pmid = {38386656},
issn = {1932-6203},
mesh = {Humans ; Child ; Adolescent ; *Leukocytes, Mononuclear/metabolism ; Cross-Sectional Studies ; *Mouth Mucosa ; Telomere/genetics ; DNA/genetics/metabolism ; },
abstract = {Telomere length (TL) is an important biomarker of cellular aging, yet its links with health outcomes may be complicated by use of different tissues. We evaluated within- and between-individual variability in TL and quality metrics of DNA across five tissues using a cross-sectional dataset ranging from 8 to 70 years (N = 197). DNA was extracted from all tissue cells using the Gentra Puregene DNA Extraction Kit. Absolute TL (aTL) in kilobase pairs was measured in buccal epithelial cells, saliva, dried blood spots (DBS), buffy coat, and peripheral blood mononuclear cells (PBMCs) using qPCR. aTL significantly shortened with age for all tissues except saliva and buffy coat, although buffy coat was available for a restricted age range (8 to 15 years). aTL did not significantly differ across blood-based tissues (DBS, buffy coat, PBMC), which had significantly longer aTL than buccal cells and saliva. Additionally, aTL was significantly correlated for the majority of tissue pairs, with partial Spearman's correlations controlling for age and sex ranging from ⍴ = 0.18 to 0.51. We also measured quality metrics of DNA including integrity, purity, and quantity of extracted DNA from all tissues and explored whether controlling for DNA metrics improved predictions of aTL. We found significant tissue variation: DNA from blood-based tissues had high DNA integrity, more acceptable A260/280 and A260/230 values, and greater extracted DNA concentrations compared to buccal cells and saliva. Longer aTL was associated with lower DNA integrity, higher extracted DNA concentrations, and higher A260/230, particularly for saliva. Model comparisons suggested that incorporation of quality DNA metrics improves models of TL, although relevant metrics vary by tissue. These findings highlight the merits of using blood-based tissues and suggest that incorporation of quality DNA metrics as control variables in population-based studies can improve TL predictions, especially for more variable tissues like buccal and saliva.},
}
@article {pmid38379260,
year = {2024},
author = {Margiana, R and Gupta, R and Al-Jewari, WM and Hjazi, A and Alsaab, HO and Mustafa, YF and Singh, R and Thaibt, R and Alkhayyat, S and Ibrahim, AJ},
title = {Evaluation of telomere length, reactive oxygen species, and apoptosis in spermatozoa of patients with oligospermia.},
journal = {Cell biochemistry and function},
volume = {42},
number = {2},
pages = {e3935},
doi = {10.1002/cbf.3935},
pmid = {38379260},
issn = {1099-0844},
mesh = {Humans ; Male ; *Oligospermia/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Catalase/genetics/metabolism ; *Azoospermia/metabolism ; Semen/metabolism ; Spermatozoa/metabolism ; *Infertility, Male/genetics/diagnosis/metabolism ; Antioxidants/metabolism ; DNA Fragmentation ; Apoptosis ; Superoxide Dismutase/genetics/metabolism ; Telomere/metabolism ; RNA, Messenger/metabolism ; },
abstract = {50% of cases of infertility are caused by male factor, which acquired or congenital problems may bring on. Male infertility can be caused by oligospermia and asthenozoospermia, which are common. Since the same mutations that cause azoospermia in some people also cause oligozoospermia in others, oligozoospermia may be thought of as a less severe form of azoospermia. Studies have demonstrated telomere length, catalase activity, super oxide dismutase (SOD), and DNA fragmentation can be influential factors for male infertility. The amount of apoptosis, oxidative stress factors, telomere length, and DNA fragmentation were some aspects of healthy sperm that we chose to look into in this study and compare to oligospermia individuals. Oligospermia patients (n = 24) and fertile men (n = 27) semen samples were collected, and the apoptosis rate of sperms in both groups was analyzed (Flow cytometry). Also, gene expression of apoptotic and antiapoptotic markers and telomere length were examined (real-time polymerase chain reaction). The sperm DNA fragmentation kit was used to determine DNA fragmentation and to evaluate catalase and SOD activity; the specific kits and methods were utilized. Higher expression levels of caspase3 (p = .0042), caspase8 (p = .0145), caspase9 (p = .0275), and BAX (p = .0202) mRNA were observed in patients who had oligospermia. In contrast, lower mRNA expression of BCL-2 (p = .0009) was detected in this group. In addition, telomere length was decreased in the oligospermia group (p < .0001) compared to the health group. Moreover, the frequency of apoptosis is induced in patients (p = .0026). The catalase activity is low (p = .0008), but the SOD activity is high (p = .0015) in the patient group. As a result of our findings, we may list the sperm cell apoptosis rate, telomere length, the degree of sperm DNA fragmentation, and lastly, the measurement of significant and efficient oxidative stress markers like SOD and catalase in semen plasma among the principal diagnostic characteristics for oligospermia. Future studies will be better able to treat oligospermia by showing whether these indicators are rising or falling.},
}
@article {pmid38378028,
year = {2024},
author = {Mervic, A and Goricar, K and Blagus, T and Franko, A and Trebusak-Podkrajsek, K and Fikfak, MD and Dolzan, V and Kovac, V},
title = {Telomere length and TERT polymorphisms as biomarkers in asbestos-related diseases.},
journal = {Radiology and oncology},
volume = {58},
number = {1},
pages = {87-98},
pmid = {38378028},
issn = {1581-3207},
mesh = {Humans ; *Telomerase/genetics ; Case-Control Studies ; Retrospective Studies ; Polymorphism, Single Nucleotide ; Biomarkers ; Telomere/genetics ; Disease Progression ; },
abstract = {BACKGROUND: Asbestos exposure has been proposed as a risk factor for shorter telomere length. The aim of our study was to investigate whether telomere length in leukocytes and hTERT genetic polymorphisms may serve as potential biomarkers for the risk of developing asbestos-related diseases and as biomarkers of progression and chemotherapy response rate in malignant mesothelioma (MM).<br><br>SUBJECTS AND METHODS: We conducted two retrospective studies. In the first study, a case-control study, telomere length and hTERT polymorphisms were determined in patients with MM, subjects with pleural plaques and controls without the asbestos related disease, who were occupationally exposed to asbestos. In the second study, a longitudinal observational study, telomere length was also determined in samples from MM patients before and after chemotherapy. Telomere length was determined by monochromatic multiplex quantitative polymerase chain reaction (PCR), while competitive allele-specific PCR was used to genotype hTERT rs10069690, rs2736100 and rs2736098. Logistic regression and survival analysis were used in statistical analysis.<br><br>RESULTS: Patients with MM had shorter telomere length than subjects with pleural plaques (p < 0.001). After adjustment for age, rs2736098 CT, and rs10069690 TT and CT+TT genotypes were significantly associated with a higher risk of MM (padj = 0.023; padj = 0.026 and padj = 0.017), while rs2736100 AA and CA+AA genotypes conferred to a lower risk for MM compared to all other subjects (padj = 0.017, and padj = 0.026). Telomere length was not associated with a response to chemotherapy (p > 0.05) or time to disease progression (p > 0.05). Carriers of one or two polymorphic rs10069690 T alleles had a good response to chemotherapy (p = 0.039, and p = 0.048), these associations remained statistically significant after adjustment for age (padj = 0.019; padj = 0.017). Carriers of two polymorphic rs2736100 A alleles had a longer time to disease progression (p = 0.038).<br><br>CONCLUSIONS: Shorter telomere length and hTERT polymorphisms may serve as a biomarker for the risk of developing MM. Additionally, rs10069690 and rs2736100 polymorphisms, but not telomere length, were associated with a chemotherapy response or MM progression.},
}
@article {pmid38376914,
year = {2024},
author = {Choi, H and Cho, SW and Kim, HH and Yi, KH and Park, DJ and Park, YJ},
title = {Shortened telomere length in peripheral blood leukocytes is associated with cumulative radioactive iodine doses in patients with differentiated thyroid carcinoma.},
journal = {Cancer},
volume = {},
number = {},
pages = {},
doi = {10.1002/cncr.35256},
pmid = {38376914},
issn = {1097-0142},
support = {5120200513755//Ministry of Education of Korea/ ; NRF-2019R1A2C2084332//National Research Foundation of Korea/ ; 03-2014-0130//Seoul National University Hospital/ ; },
abstract = {BACKGROUND: Telomere length is associated with cancer risk and cancer aggressiveness. Radioactive iodine (RAI) therapy for thyroid cancer has raised concerns for second primary malignancy (SPM) in patients with high cumulative doses. The association between RAI dose and peripheral blood leukocyte telomere length was examined.<br><br>METHODS: A total of 425 patients were included who underwent total thyroidectomy and were followed up for at least 1&#xa0;year with or without RAI treatment. The relative telomere length (RTL) of the patients was assessed via a quantitative polymerase chain reaction amplification method. RAI doses were divided into five groups on the basis of cumulative dose, and a comparison was made among these groups.<br><br>RESULTS: The number of patients with RAI treatment was 287 (67.5%), and the cumulative RAI dose was 3.33&#xa0;GBq (range, 1.11-131.35 GBq). The mean RTL was significantly shorter in the highest RAI group (>22.2&#xa0;GBq) compared to both the no-RAI and lower dose groups. The association between RAI dose and RTL was positive in the lower RAI group (1.1-3.7&#xa0;GBq) and negative in the highest RAI group in both univariate and multivariate analyses. We observed 59 (13.9%) SPMs and 20 (4.7%) mortalities, and RTL did not show a significant risk effect for all-cause, thyroid cancer-specific, or SPM-specific mortality.<br><br>CONCLUSIONS: In patients with thyroid cancer who underwent total thyroidectomy, peripheral blood leukocyte telomere length exhibited a significant association with cumulative RAI dose higher than 22.2&#xa0;GBq. These results suggest the possibility of telomere length shortening in patients who undergo high-dose RAI treatment.},
}
@article {pmid38373547,
year = {2024},
author = {Shoeb, M and Meighan, T and Kodali, VK and Abadin, H and Faroon, O and Zarus, GM and Erdely, A and Antonini, JM},
title = {TERT-independent telomere elongation and shelterin dysregulation after pulmonary exposure to stainless-steel welding fume in-vivo.},
journal = {Environmental research},
volume = {250},
number = {},
pages = {118515},
doi = {10.1016/j.envres.2024.118515},
pmid = {38373547},
issn = {1096-0953},
abstract = {Telomeres are inert DNA sequences (TTAGGG) at the end of chromosomes that protect genetic information and maintain DNA integrity. Emerging evidence has demonstrated that telomere alteration can be closely related to occupational exposure and the development of various disease conditions, including cancer. However, the functions and underlying molecular mechanisms of telomere alteration and shelterin dysregulation after welding fume exposures have not been broadly defined. In this study, we analyzed telomere length and shelterin complex proteins in peripheral blood mononuclear cells (PBMCs) and in lung tissue recovered from male Sprague-Dawley rats following exposure by intratracheal instillation (ITI) to 2 mg/rat of manual metal arc-stainless steel (MMA-SS) welding fume particulate or saline (vehicle control). PBMCs and lung tissue were harvested at 30 d after instillation. Our study identified telomere elongation and shelterin dysregulation in PBMCs and lung tissue after welding fume exposure. Mechanistically, telomere elongation was independent of telomerase reverse transcriptase (TERT) activation. Collectively, our findings demonstrated that welding fume-induced telomere elongation was (a) TERT-independent and (b) associated with shelterin complex dysregulation. It is possible that an alteration of telomere length and its regulatory proteins may be utilized as predictive biomarkers for various disease conditions after welding fume exposure. This needs further investigation.},
}
@article {pmid38372947,
year = {2024},
author = {Warsame, F and Simonetto, DA},
title = {Telomere Biology Disorder: A Focus on Gastrointestinal and Hepatic Manifestations.},
journal = {Current hematologic malignancy reports},
volume = {19},
number = {2},
pages = {75-81},
pmid = {38372947},
issn = {1558-822X},
mesh = {Humans ; *Liver Cirrhosis ; Mutation ; *Hypertension, Portal ; Telomere/genetics ; Biology ; },
abstract = {PURPOSE OF REVIEW: Telomere biology disorders (TBD) encompass several illnesses caused by underlying mutations in telomere maintenance leading to premature telomere attrition and telomere dysfunction. These disorders have unique features but share common disease manifestations including pulmonary fibrosis, cirrhosis, and bone marrow failure. The goals of this article are to provide an overview of the gastrointestinal and hepatic manifestations of TBD, focusing on their pathophysiology, clinical disease states, and current management strategies.<br><br>RECENT FINDINGS: Telomere shortening has been observed in patients with chronic liver disease and is associated with a higher risk of progression to cirrhosis and portal hypertension. While the directionality of the association between telomere dysfunction and senescence on liver disease is not fully understood, research in TBD may provide clarity and could lead to future therapies for this increasingly prevalent disease. While treatment options remain limited in TBD-associated liver disease, recent studies point to the safety and efficacy of liver transplantation among patients with end-stage liver disease.},
}
@article {pmid38372835,
year = {2024},
author = {Wang, D and Lin, D and Yang, X and Wu, D and Li, P and Zhang, Z and Zhang, W and Guo, Y and Fu, S and Zhang, N},
title = {Alterations in leukocyte telomere length and mitochondrial DNA copy number in benzene poisoning patients.},
journal = {Molecular biology reports},
volume = {51},
number = {1},
pages = {309},
pmid = {38372835},
issn = {1573-4978},
support = {No.SZGSP015//Shenzhen Fund for Guangdong Provincial High- level Clinical Key Specialties/ ; No.KCXFZ20201221173602007//Science and Technology Planning Project of Shenzhen Municipality/ ; No.JCYJ20190808174815278//Science and Technology Planning Project of Shenzhen Municipality/ ; },
mesh = {Humans ; *DNA, Mitochondrial/genetics ; *Benzene ; DNA Copy Number Variations/genetics ; Leukocytes ; Hemoglobins ; Telomere/genetics ; },
abstract = {OBJECTIVE: The aim of this study is to examine and evaluate the impact of benzene poisoning on the relative content of the mitochondrial MT-ND1 gene and telomere length in individuals with occupational chronic benzene poisoning (CBP) compared to a control group. The study will analyze and gather data on the mitochondrial gene content and telomere length in cases of benzene poisoning, and investigate the relationship with blood routine parameters in order to contribute scientific experimental data for the prevention and treatment of CBP.<br><br>METHOD: The case group comprised 30 individuals diagnosed with occupational chronic benzene poisoning, whereas the control group consisted of 60 healthy individuals who underwent physical examinations at our hospital concurrently. Blood routine indicators were detected and analyzed, and the PCR method was employed to measure changes in mitochondrial MT-ND1 content and telomere length. Subsequently, a comparison and analysis of the aforementioned indicators was conducted.<br><br>RESULT: The case group exhibited a higher mitochondrial gene content (median 366.2, IQR 90.0 rate) compared to the control group (median 101.5, IQR 12.0 rate), with a statistically significant difference between the two groups (P&#x2009;<&#x2009;0.05). Additionally, the case group demonstrated lower white blood cell levels (3.78&#x2009;&#xb1;&#x2009;1.387&#x2009;&#xd7;&#x2009;10[9]/L) compared to the control group (5.74&#x2009;&#xb1;&#x2009;1.41&#x2009;&#xd7;&#x2009;10[9]/L), with a significant difference between the two groups (P&#x2009;<&#x2009;0.05). Furthermore, the case group displayed lower red blood cell levels (3.86&#x2009;&#xb1;&#x2009;0.65&#x2009;&#xd7;&#x2009;10[12]/L) compared to the control group (4.89&#x2009;&#xb1;&#x2009;0.65&#x2009;&#xd7;&#x2009;10[12]/L), with a significant difference between the two groups (P&#x2009;<&#x2009;0.05). The hemoglobin level in the case group (113.33&#x2009;&#xb1;&#x2009;16.34&#xa0;g/L) was lower than that in the control group (138.22&#x2009;&#xb1;&#x2009;13.22&#xa0;g/L). There was a significant difference between the two groups (P&#x2009;<&#x2009;0.05). Platelet levels in the case group (153.80&#x2009;&#xb1;&#x2009;58.31&#x2009;&#xd7;&#x2009;10[9]/L) is smaller than the control group (244.92&#x2009;&#xb1;&#x2009;51.99&#x2009;&#xd7;&#x2009;10[9]/L), there was a significant difference between the two groups (P&#x2009;<&#x2009;0.05). The average telomere length of the normal control group was 1.451&#x2009;&#xb1;&#x2009;0.475 (rate); The mean telomere length of individuals in the case group diagnosed with benzene poisoning was determined to be 1.237&#x2009;&#xb1;&#x2009;0.457 (rate). No significant correlation was observed between telomere length and three blood routine parameters, namely white blood cells (WBC), hemoglobin (HB), and platelets (PLT). However, a significant correlation was found between telomere length and red blood cell count (RBC). Additionally, a negative correlation was observed between mitochondrial gene content and white blood cell count (r&#x2009;=&#x2009;-&#x2009;0.314, P&#x2009;=&#x2009;0.026), as well as between mitochondrial gene content and red blood cell count (r&#x2009;=&#x2009;-&#x2009;0.226, P&#x2009;=&#x2009;0.032). Furthermore, a negative correlation was identified between mitochondrial gene content and hemoglobin (r = - 0.314, P = 0.028), and platelets (r = - 0.445, P = 0.001).<br><br>CONCLUSION: Individuals diagnosed with occupational chronic benzene poisoning exhibit a reduction in telomere length and an elevation in the relative content of the mitochondrial MT-ND1 gene. Moreover, a negative correlation is observed between the content of the mitochondrial MT-ND1 gene and four blood routine parameters, namely white blood cells (WBC), red blood cells (RBC), hemoglobin (HB), and platelets (PLT). Consequently, benzene exposure may potentially contribute to the onset of premature aging.},
}
@article {pmid38371225,
year = {2024},
author = {Shi, ZF and Li, KK and Chan, DT and Mao, Y and Ng, HK},
title = {Alternative lengthening of telomeres is seen in a proportion of oligodendrogliomas and is associated with a worse prognosis.},
journal = {Neuro-oncology advances},
volume = {6},
number = {1},
pages = {vdae006},
pmid = {38371225},
issn = {2632-2498},
}
@article {pmid38365850,
year = {2024},
author = {Hackenhaar, FS and Josefsson, M and Adolfsson, AN and Landfors, M and Kauppi, K and Hultdin, M and Adolfsson, R and Degerman, S and Pudas, S},
title = {Correction: Short leukocyte telomeres predict 25-year Alzheimer's disease incidence in non-APOE ε4-carriers.},
journal = {Alzheimer's research &amp; therapy},
volume = {16},
number = {1},
pages = {39},
pmid = {38365850},
issn = {1758-9193},
}
@article {pmid38365769,
year = {2024},
author = {Chen, M and Wang, Z and Xu, H and Teng, P and Li, W and Ma, L},
title = {Association between modifiable lifestyle factors and telomere length: a univariable and multivariable Mendelian randomization study.},
journal = {Journal of translational medicine},
volume = {22},
number = {1},
pages = {160},
pmid = {38365769},
issn = {1479-5876},
support = {82200269//Natural Science Foundation for Youth of China/ ; 82271812//Natural Science Foundation of China/ ; },
mesh = {Humans ; *Diabetes Mellitus, Type 2 ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Sleep Initiation and Maintenance Disorders ; Telomere/genetics ; Polymorphism, Single Nucleotide ; },
abstract = {BACKGROUND: Telomere length has long been recognized as a valuable biomarker of aging and is inversely correlated with chronological age. Various lifestyle factors have been implicated in telomere shortening or preservation; however, the association between lifestyle factors and telomere length remains controversial. To address this issue, we conducted a Mendelian randomization (MR) analysis to investigate the potential causal associations between multiple lifestyle factors and telomere length.<br><br>METHODS: Independent genetic variants strongly associated with lifestyle factors (tobacco smoking, sleep duration, insomnia, and physical activity) were selected as instrumental variables from corresponding genome-wide association studies (GWASs). Summary-level data for telomere length was obtained from a GWAS comprising 472,174 European ancestries. Univariable and multivariable MR analyses were performed to assess the relationships.<br><br>RESULTS: The genetic liability to lifetime smoking was robustly associated with shorter telomere length (odd ratio [OR]: 0.882; 95% confidence interval [CI]: 0.847-0.918). Genetically predicted insomnia was also linked to shorter telomere length (OR: 0.972; 95% CI: 0.959-0.985), while no significant association was observed between sleep duration and telomere length. Furthermore, a suggestive association was found between moderate-to-vigorous physical activity and longer telomere length (OR: 1.680; 95% CI: 1.115-2.531). In multivariable MR analyses, adjusting for potential mediators such as body mass index, type 2 diabetes, alcohol consumption, and alcohol use disorder, the associations of lifetime smoking and insomnia with telomere length remained robust.<br><br>CONCLUSION: Our findings suggest that smoking and insomnia may contribute to telomere shortening, while physical activity may play a role in telomere length maintenance. These findings underscore the importance of managing positive risk factors and adopting a healthy lifestyle to promote telomere health.},
}
@article {pmid38359982,
year = {2024},
author = {Azeroglu, B and Ozbun, L and Pegoraro, G and Lazzerini Denchi, E},
title = {Native FISH: A low- and high-throughput assay to analyze the alternative lengthening of telomere (ALT) pathway.},
journal = {Methods in cell biology},
volume = {182},
number = {},
pages = {265-284},
doi = {10.1016/bs.mcb.2022.10.010},
pmid = {38359982},
issn = {0091-679X},
mesh = {Humans ; Animals ; *High-Throughput Screening Assays ; *Neoplasms ; DNA ; Telomere/genetics ; Fishes/genetics ; },
abstract = {Alternative lengthening of telomeres (ALT) is a telomerase-independent and recombination-based mechanism used by approximately 15% of human cancers to maintain telomere length and to sustain proliferation. ALT-positive cells display unique features that could be exploited for tailored cancer therapies. A key limitation for the development of ALT-specific treatments is the lack of an assay to detect ALT-positive cells that is easy to perform and that can be scaled up. One of the most broadly used assays for ALT detection, CCA (C-circle assay), does not provide single-cell information and it is not amenable to High-Throughput Screening (HTS). To overcome these limitations, we developed Native-FISH (N-FISH) as an alternative method to visualize ALT-specific single-stranded telomeric DNA. N-FISH produces single-cell data, can be applied to fixed tissues, does not require DNA isolation or amplification steps, and it can be miniaturized in a 384-well format. This protocol details the steps to perform N-FISH protocol both in a low- and high-throughput format to analyze ALT. While low-throughput N-FISH is useful to assay the ALT state of cell lines, we expect that the miniaturized N-FISH assay coupled with high-throughput imaging will be useful in functional genomics and chemical screens to identify novel cellular factors that regulate ALT and potential ALT therapeutic targets for cancer therapies directed against ALT-positive tumors, respectively.},
}
@article {pmid38359122,
year = {2024},
author = {Kinzig, CG and Zakusilo, G and Takai, KK and Myler, LR and de Lange, T},
title = {ATR blocks telomerase from converting DNA breaks into telomeres.},
journal = {Science (New York, N.Y.)},
volume = {383},
number = {6684},
pages = {763-770},
doi = {10.1126/science.adg3224},
pmid = {38359122},
issn = {1095-9203},
mesh = {Humans ; *Ataxia Telangiectasia Mutated Proteins/genetics/metabolism ; *DNA Breaks, Double-Stranded ; *Telomerase/genetics ; *Telomere/genetics/metabolism ; Genetic Techniques ; CRISPR-Associated Protein 9 ; HeLa Cells ; },
abstract = {Telomerase, the enzyme that maintains telomeres at natural chromosome ends, should be repressed at double-strand breaks (DSBs), where neotelomere formation can cause terminal truncations. We developed an assay to detect neotelomere formation at Cas9- or I-SceI-induced DSBs in human cells. Telomerase added telomeric repeats to DSBs, leading to interstitial telomeric repeat insertions or the formation of functional neotelomeres accompanied by terminal deletions. The threat that telomerase poses to genome integrity was minimized by ataxia telangiectasia and Rad3-related (ATR) kinase signaling, which inhibited telomerase at resected DSBs. In addition to acting at resected DSBs, telomerase used the extruded strand in the Cas9 enzyme-product complex as a primer for neotelomere formation. We propose that although neotelomere formation is detrimental in normal human cells, it may allow cancer cells to escape from breakage-fusion-bridge cycles.},
}
@article {pmid38357955,
year = {2024},
author = {Vazifehmand, R and Saeed Ali, D and Monem Homaie, F and Molaei Jalalvand, F and Othman, Z and Deming, C and Stanslas, J and Sekawi, Z},
title = {Effects of HSV-G47Δ Oncolytic Virus on Telomerase and Telomere Length Alterations in Glioblastoma Multiforme Cancer Stem Cells Under Hypoxia and Normoxia Conditions.},
journal = {Current cancer drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680096274769240115165344},
pmid = {38357955},
issn = {1873-5576},
abstract = {BACKGROUND: Due to the existence of tumor stem cells with tumorigenicity properties and resistance patterns, treatment of glioblastoma is not easy. Hypoxia is a major concern in glioblastoma therapy. Telomerase activity and telomere length alterations have been known to play a critical role in glioblastoma progression and invasion.<br><br>OBJECTIVE: This study aimed to investigate the effects of HSV-G47&#x394; oncolytic virus on telomerase and telomere length alterations in U251GBMCSCs (U251-Glioblastoma cancer stem cells) under hypoxia and normoxia conditions.<br><br>METHODS: U251-CSCs were exposed to the HSV-G47&#x394; virus in optimized MOI (Multiplicity of infection= 1/14 hours). An absolute telomere length and gene expression of telomerase subunits were determined using an absolute human telomere length quantification PCR assay. Furthermore, a bioinformatics pathway analysis was carried out to evaluate physical and genetic interactions between dysregulated genes with other potential genes and pathways.<br><br>RESULTS: Data revealed that U251CSCs had longer telomeres when exposed to HSV-G47&#x394; in normoxic conditions but had significantly shorter telomeres in hypoxic conditions. Furthermore, hTERC, DKC1, and TEP1 genes were significantly dysregulated in hypoxic and normoxic microenvironments. The analysis revealed that the expression of TERF2 was significantly reduced in both microenvironments, and two critical genes from the MRN complex, MER11 and RAD50, were significantly upregulated in normoxic conditions. RAD50 showed a significant downregulation pattern in the hypoxic niche. Our results suggested that repair complex in the telomeric structure could be targeted by HSV-G47&#x394; in both microenvironments.<br><br>CONCLUSION: In the glioblastoma treatment strategy, telomerase and telomere complex could be potential targets for HSV-G47&#x394; in both microenvironments.},
}
@article {pmid38349865,
year = {2024},
author = {Cozzolino, M and Ergun, Y and Ristori, E and Garg, A and Imamoglu, G and Seli, E},
title = {Disruption of mitochondrial unfolded protein response results in telomere shortening in mouse oocytes and somatic cells.},
journal = {Aging},
volume = {16},
number = {3},
pages = {2047-2060},
doi = {10.18632/aging.205543},
pmid = {38349865},
issn = {1945-4589},
mesh = {Humans ; Female ; Animals ; Mice ; Telomere Shortening ; Oocytes/metabolism ; Aging/genetics ; Telomere/genetics/metabolism ; *Infertility, Female/metabolism ; Unfolded Protein Response/genetics ; *Telomerase/metabolism ; },
abstract = {Caseinolytic peptidase P (CLPP) plays a central role in mitochondrial unfolded protein response (mtUPR) by promoting the breakdown of misfolded proteins and setting in motion a cascade of reactions to re-establish protein homeostasis. Global germline deletion of Clpp in mice results in female infertility and accelerated follicular depletion. Telomeres are tandem repeats of 5'-TTAGGG-3' sequences found at the ends of the chromosomes. Telomeres are essential for maintaining chromosome stability during somatic cell division and their shortening is associated with cellular senescence and aging. In this study, we asked whether the infertility and ovarian aging phenotype caused by global germline deletion of Clpp is associated with somatic aging, and tested telomere length in tissues of young and aging mice. We found that impaired mtUPR caused by the lack of CLPP is associated with accelerated telomere shortening in both oocytes and somatic cells of aging mice. In addition, expression of several genes that maintain telomere integrity was decreased, and double-strand DNA breaks were increased in telomeric regions. Our results highlight how impaired mtUPR can affect telomere integrity and demonstrate a link between loss of mitochondrial protein hemostasis, infertility, and somatic aging.},
}
@article {pmid38349660,
year = {2023},
author = {Schnurr, E and Volz, KU and Mosetter, K and Ghanaati, S and Hueber, R and Preussler, C},
title = {Interaction of Telomere Length and Inflammatory Biomarkers Following Zirconia Implant Placement: A Case Series.},
journal = {The Journal of oral implantology},
volume = {49},
number = {5},
pages = {524-531},
doi = {10.1563/aaid-joi-D-22-00236},
pmid = {38349660},
issn = {0160-6972},
mesh = {Humans ; *Dental Implants ; Esthetics, Dental ; Biomarkers ; Cytokines ; Inflammation ; Anti-Inflammatory Agents ; *Zirconium ; },
abstract = {Zirconia implants have gained popularity for their aesthetic appeal and biocompatibility, making them a preferred choice for anterior teeth replacement. This study explores the interaction between telomere length and inflammatory biomarkers in seven cases of zirconia implant placement to gain insights into postoperative cellular aging, inflammatory responses, and long-term outcomes. Zirconia implants offer advantages over titanium implants, as they do not corrode or release metal ions, leading to potential inflammation and implant failure. Monitoring immune and inflammatory biomarkers is essential to assess inflammation initiation, severity, and progression. C-reactive protein (CRP) and pro-inflammatory cytokines, like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), play crucial roles in host immune responses, while anti-inflammatory cytokines, including interleukin-10 (IL-10), regulate and dampen immune responses. Achieving a delicate balance between pro- and anti-inflammatory cytokines is vital for maintaining a healthy immune response and preventing chronic inflammatory conditions. Telomeres, protective structures present at chromosome ends, influence cellular aging and mitochondrial function. Shorter telomeres are associated with impaired mitochondrial function, increased oxidative stress, and cellular senescence, while longer telomeres are linked to reduced inflammation and improved immune function. Understanding these mechanisms is essential for addressing age-related conditions and promoting overall well-being. In this case series, we investigated the interaction between telomere length and inflammatory biomarkers in patients who received zirconia dental implants. The study aims to improve our understanding of postoperative cellular aging, inflammatory responses, and the biocompatibility of zirconia implants, potentially leading to improved treatment protocols and patient outcomes. This innovative assessment of telomere length and inflammatory biomarkers in the context of zirconia implants provides novel insights into the field of dental implantology. By exploring the effects of zirconia implants on cellular health and inflammation, this study contributes to advancements in implant technology and patient care.},
}
@article {pmid38345296,
year = {2024},
author = {Connor, A and Deschamps, A and Busque, L and Tardif, JC and Bourgoin, V and Dubé, MP and Busseuil, D and D'Antono, B},
title = {Childhood maltreatment and leukocyte telomere length: Cardiac vagal activity influences the relation in older adults.},
journal = {Psychosomatic medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/PSY.0000000000001290},
pmid = {38345296},
issn = {1534-7796},
abstract = {OBJECTIVE: Childhood maltreatment is associated with shorter leukocyte telomere length (LTL). However, the influence of cardiac vagal control on this relation is unknown. We examined whether cardiac vagal control at rest and in response to stress moderates or cross-sectionally mediates the relationship between childhood maltreatment and LTL.<br><br>METHODS: Participants were 1179 men and women (aged 65 &#xb1; 7.2 years) suffering from coronary artery disease (CAD) or non-cardiovascular chronic disease. They completed a childhood maltreatment questionnaire and underwent a stress protocol while ECG was monitored. HF-HRV measures were obtained at rest, during stress, and post-stress in absolute and normalized units (nu). LTL was measured using qPCR. Mediation and moderation analyses were performed.<br><br>RESULTS: HF-HRV and HFnu measures did not mediate the childhood maltreatment-LTL relation. However, baseline HFnu (p = .027) and HFnu reactivity (p = .051) moderated the relation. Specifically, maltreatment was associated with significantly lower LTL among those with baseline HFnu at (b = -.059, p = .003) or below the mean (b = -.103, p < .001), but not among those with higher baseline HFnu. It was also associated with significantly lower LTL among participants who showed either blunted (b = -.058, p = .004) or increased HFnu (b = -.099, p = .001) responses to stress but not in those with large decreases in HFnu.<br><br>CONCLUSIONS: Childhood maltreatment was associated with lower LTL in those who showed a distinct cardiac vagal profile at baseline and in response to stress. The mechanisms and implications remain to be determined.},
}
@article {pmid38344651,
year = {2024},
author = {Wang, Z and Zhou, J and Pan, J and Cheng, W and Fang, J and Lv, Q and Lin, X and Cheng, W and Zhang, L and Cheng, K},
title = {Insights into the Superrosids phylogeny and flavonoid synthesis from the telomere-to-telomere gap-free genome assembly of Penthorum chinense Pursh.},
journal = {Horticulture research},
volume = {11},
number = {2},
pages = {uhad274},
pmid = {38344651},
issn = {2662-6810},
abstract = {The completion of the first telomere-to-telomere (T2T) genome assembly of Penthorum chinense Pursh (PC), a prominent medicinal plant in China, represents a significant achievement. This assembly spans a length of 257.5 Mb and consists of nine chromosomes. PC's notably smaller genome size in Saxifragales, compared to that of Paeonia ostii, can be attributed to the low abundance of transposable elements. By utilizing single-copy genes from 30 species, including 28 other Superrosids species, we successfully resolved a previously debated Superrosids phylogeny. Our findings unveiled Saxifragales as the sister group to the core rosids, with both being the sister group to Vitales. Utilizing previously characterized cytochrome P450 (CYP) genes, we predicted the compound classes that most CYP genes of PC are involved in synthesizing, providing insight into PC's potential metabolic diversity. Metabolomic and transcriptomic data revealed that the richest sources of the three most noteworthy medicinal components in PC are young leaves and flowers. We also observed higher activity of upstream genes in the flavonoid synthesis pathway in these plant parts. Additionally, through weighted gene co-expression network analysis, we identified gene regulatory networks associated with the three medicinal components. Overall, these findings deepen our understanding of PC, opening new avenues for further research and exploration.},
}
@article {pmid38344410,
year = {2024},
author = {Muthumalage, T and Goracci, C and Rahman, I},
title = {Club cell-specific telomere protection protein 1 (TPP1) protects against tobacco smoke-induced lung inflammation, xenobiotic metabolic dysregulation, and injurious responses.},
journal = {FASEB bioAdvances},
volume = {6},
number = {2},
pages = {53-71},
pmid = {38344410},
issn = {2573-9832},
abstract = {Inhaling xenobiotics, such as tobacco smoke is a major risk factor for pulmonary diseases, e.g., COPD/emphysema, interstitial lung disease, and pre-invasive diseases. Shelterin complex or telosome provides telomeric end protection during replication. Telomere protection protein 1 (TPP1) is one of the main six subunits of the shelterin complex supporting the telomere stability and genomic integrity. Dysfunctional telomeres and shelterin complex are associated as a disease mechanism of tobacco smoke-induced pulmonary damage and disease processes. The airway epithelium is critical to maintaining respiratory homeostasis and is implicated in lung diseases. Club cells (also known as clara cells) play an essential role in the immune response, surfactant production, and metabolism. Disrupted shelterin complex may lead to dysregulated cellular function, DNA damage, and disease progression. However, it is unknown if the conditional removal of TPP1 from Club cells can induce lung disease pathogenesis caused by tobacco smoke exposure. In this study, conditional knockout of Club-cell specific TPP1 demonstrated the instability of other shelterin protein subunits, such as TRF1, dysregulation of cell cycle checkpoint proteins, p53 and downstream targets, and dysregulation of telomeric genes. This was associated with age-dependent senescence-associated genes, increased DNA damage, and upregulated RANTES/IL13/IL33 mediated lung inflammation and injury network by cigarette smoke (CS). These phenomena are also associated with alterations in cytochrome P450 and glutathione transferases, upregulated molecular pathways promoting lung lesions, bronchial neoplasms, and adenocarcinomas. These findings suggest a pivotal role of TPP1 in maintaining lung homeostasis and injurious responses in response to CS. Thus, these data TPP1 may have therapeutic value in alleviating telomere-related chronic lung diseases.},
}
@article {pmid38340585,
year = {2024},
author = {Chen, Y and Ding, X and Aierken, A and Chen, Y and Li, Y},
title = {Related risk factors for age-dependent telomere shortening change with age from the perspective of life course.},
journal = {Archives of gerontology and geriatrics},
volume = {121},
number = {},
pages = {105349},
doi = {10.1016/j.archger.2024.105349},
pmid = {38340585},
issn = {1872-6976},
abstract = {BACKGROUND: Many related factors can accelerate the age-dependent telomere shortening, but some problems remain unresolved. This study aimed to assess the risk factors of telomere attrition at different age stages.<br><br>METHODS: This study was a population-based nationally representative survey study. All data were collected using a standard methodology by the national surveillance system. Quantitative polymerase chain reaction was used to measure relative leukocyte telomere length. Multiple linear regression analysis with age stratification was used to estimate the association of shortened telomere length with risk factors at the different age stages. Covariance analysis was used to compare the telomere length of category variables, and the model was adjusted for potentially confounders.<br><br>RESULTS: A total of 7,659 eligible participants aged 20 years or older with DNA specimens participated in the study. Related risk factors for age-dependent telomere shortening included gender, race-ethnicity, education levels, family income, health insurance, marital status, physical activity, smoking status, alcohol use, and self-reported greatest weight, which were associated with change in telomere length at different age stages.<br><br>CONCLUSIONS AND IMPLICATIONS: Related risk factors of telomere attrition were changed with age in life course. The evaluation of related risk factors for telomere attrition in terms of age may be a more accurate evaluation comparison with the specific age.},
}
@article {pmid38339395,
year = {2024},
author = {Gedvilaite, G and Kriauciuniene, L and Tamasauskas, A and Liutkeviciene, R},
title = {The Influence of Telomere-Related Gene Variants, Serum Levels, and Relative Leukocyte Telomere Length in Pituitary Adenoma Occurrence and Recurrence.},
journal = {Cancers},
volume = {16},
number = {3},
pages = {},
pmid = {38339395},
issn = {2072-6694},
abstract = {In this study, we examined 130 patients with pituitary adenomas (PAs) and 320 healthy subjects, using DNA samples from peripheral blood leukocytes purified through the DNA salting-out method. Real-time polymerase chain reaction (RT-PCR) was used to assess single nucleotide polymorphisms (SNPs) and relative leukocyte telomere lengths (RLTLs), while enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of TERF1, TERF2, TNKS2, CTC1, and ZNF676 in blood serum. Our findings reveal several significant associations. Genetic associations with pituitary adenoma occurrence: the TERF1 rs1545827 CT + TT genotypes were linked to 2.9-fold decreased odds of PA occurrence. Conversely, the TNKS2 rs10509637 GG genotype showed 6.5-fold increased odds of PA occurrence. Gender-specific genetic associations with PA occurrence: in females, the TERF1 rs1545827 CC + TT genotypes indicated 3.1-fold decreased odds of PA occurrence, while the TNKS2 rs10509637 AA genotype was associated with 4.6-fold increased odds. In males, the presence of the TERF1 rs1545827 T allele was associated with 2.2-fold decreased odds of PA occurrence, while the TNKS2 rs10509637 AA genotype was linked to a substantial 10.6-fold increase in odds. Associations with pituitary adenoma recurrence: the TNKS2 rs10509637 AA genotype was associated with 4.2-fold increased odds of PA recurrence. On the other hand, the TERF1 rs1545827 CT + TT genotypes were linked to 3.5-fold decreased odds of PA without recurrence, while the TNKS2 rs10509637 AA genotype was associated with 6.4-fold increased odds of PA without recurrence. Serum TERF2 and TERF1 levels: patients with PA exhibited elevated serum TERF2 levels compared to the reference group. Conversely, patients with PA had decreased TERF1 serum levels compared to the reference group. Relative leukocyte telomere length (RLTL): a significant difference in RLTL between the PA group and the reference group was observed, with PA patients having longer telomeres. Genetic associations with telomere shortening: the TERF1 rs1545827 T allele was associated with 1.4-fold decreased odds of telomere shortening. In contrast, the CTC1 rs3027234 TT genotype was linked to 4.8-fold increased odds of telomere shortening. These findings suggest a complex interplay between genetic factors, telomere length, and pituitary adenoma occurrence and recurrence, with potential gender-specific effects. Furthermore, variations in TERF1 and TNKS2 genes may play crucial roles in telomere length regulation and disease susceptibility.},
}
@article {pmid38338706,
year = {2024},
author = {Borghini, A and Ndreu, R and Canale, P and Campolo, J and Marinaro, I and Mercuri, A and Turchi, S and Andreassi, MG},
title = {Telomere Length, Mitochondrial DNA, and Micronucleus Yield in Response to Oxidative Stress in Peripheral Blood Mononuclear Cells.},
journal = {International journal of molecular sciences},
volume = {25},
number = {3},
pages = {},
pmid = {38338706},
issn = {1422-0067},
mesh = {*DNA, Mitochondrial/metabolism ; *Leukocytes, Mononuclear/metabolism ; Hydrogen Peroxide/toxicity ; DNA Copy Number Variations ; Mitochondria/genetics/metabolism ; Telomere Shortening ; Telomere/genetics/metabolism ; Oxidative Stress ; },
abstract = {Telomere shortening, chromosomal damage, and mitochondrial dysfunction are major initiators of cell aging and biomarkers of many diseases. However, the underlying correlations between nuclear and mitochondrial DNA alterations remain unclear. We investigated the relationship between telomere length (TL) and micronucleus (MN) and their association with mitochondrial DNA copy number (mtDNAcn) in peripheral blood mononuclear cells (PBMCs) in response to 100 μM and 200 μM of hydrogen peroxide (H2O2) at 44, 72, and 96 h. Significant TL shortening was observed after both doses of H2O2 and at all times (all p < 0.05). A concomitant increase in MN was found at 72 h (p < 0.01) and persisted at 96 h (p < 0.01). An increase in mtDNAcn (p = 0.04) at 200 µM of H2O2 was also found. In PBMCs treated with 200 µM H2O2, a significant inverse correlation was found between TL and MN (r = -0.76, p = 0.03), and mtDNA content was directly correlated with TL (r = 0.6, p = 0.04) and inversely related to MN (r = -0.78, p = 0.02). Telomere shortening is the main triggering mechanism of chromosomal damage in stimulated T lymphocytes under oxidative stress. The significant correlations between nuclear DNA damage and mtDNAcn support the notion of a telomere-mitochondria axis that might influence age-associated pathologies and be a target for the development of relevant anti-aging drugs.},
}
@article {pmid38337920,
year = {2024},
author = {Valeeva, LR and Sannikova, AV and Shafigullina, NR and Abdulkina, LR and Sharipova, MR and Shakirov, EV},
title = {Telomere Length Variation in Model Bryophytes.},
journal = {Plants (Basel, Switzerland)},
volume = {13},
number = {3},
pages = {},
pmid = {38337920},
issn = {2223-7747},
support = {GM127402/NH/NIH HHS/United States ; },
abstract = {The ends of linear chromosomes of most eukaryotes consist of protein-bound DNA arrays called telomeres, which play essential roles in protecting genome integrity. Despite general evolutionary conservation in function, telomeric DNA is known to drastically vary in length and sequence between different eukaryotic lineages. Bryophytes are a group of early diverging land plants that include mosses, liverworts, and hornworts. This group of ancient land plants recently emerged as a new model for important discoveries in genomics and evolutionary biology, as well as for understanding plant adaptations to a terrestrial lifestyle. We measured telomere length in different ecotypes of model bryophyte species, including Physcomitrium patens, Marchantia polymorpha, Ceratodon purpureus, and in Sphagnum isolates. Our data indicate that all analyzed moss and liverwort genotypes have relatively short telomeres. Furthermore, all analyzed ecotypes and isolates of model mosses and liverworts display evidence of substantial natural variation in telomere length. Interestingly, telomere length also differs between male and female strains of the dioecious liverwort M. polymorpha and dioecious moss C. purpureus. Given that bryophytes are extraordinarily well adapted to different ecological niches from polar to tropical environments, our data will contribute to understanding the impact of natural telomere length variation on evolutionary adaptations in this ancient land plant lineage.},
}
@article {pmid38336161,
year = {2024},
author = {Pili, MP and Cagliero, L and Panichi, V and Bordoni, M and Pansarasa, O and Cremaschi, G and Tonga, EB and Cappelletti, F and Provenzi, L},
title = {Exposure to pollution during the first thousand days and telomere length regulation: A literature review.},
journal = {Environmental research},
volume = {249},
number = {},
pages = {118323},
doi = {10.1016/j.envres.2024.118323},
pmid = {38336161},
issn = {1096-0953},
abstract = {Telomere length (TL) is a biomarker for cellular senescence and TL erosion is predictive of the risk for age-related diseases. Despite being genetically determined at birth, TL may be susceptible to modifications through epigenetic mechanisms. Pollutant agents are considered one of the major threats to both human and planetary health. Their ability to cross the placental barrier and induce oxidative stress in fetal cells is particularly concerning and it may be associated with early TL erosion. In consideration of the timely relevance of this topic, we conducted a literature review on the impact of prenatal exposure to pollutant agents on newborn TL. The search yielded a total of 1099 records, of which only 32 met the inclusion criteria for the review. These criteria included the participation of human subjects, a longitudinal design or collection of longitudinal data, reporting of original TL data, and a focus on exposure to pollutant agents. The majority of the studies reported a significant inverse association between prenatal exposure to pollutant agents and TL. Furthermore, the second trimester of pregnancy emerged as a special sensitive period for the occurrence of pollutant agent-driven TL modifications. Sex differences were inconsistently reported across studies. This review contributes to highlighting biochemical pathways for the threats of environmental pollution to human health. Future research is warranted to further highlight potential buffering mechanisms.},
}
@article {pmid38333665,
year = {2024},
author = {Schellnegger, M and Hofmann, E and Carnieletto, M and Kamolz, LP},
title = {Unlocking longevity: the role of telomeres and its targeting interventions.},
journal = {Frontiers in aging},
volume = {5},
number = {},
pages = {1339317},
pmid = {38333665},
issn = {2673-6217},
abstract = {Average life expectancy has been steadily increasing in developed countries worldwide. These demographic changes are associated with an ever-growing social and economic strain to healthcare systems as well as society. The aging process typically manifests as a decline in physiological and cognitive functions, accompanied by a rise in chronic diseases. Consequently, strategies that both mitigate age-related diseases and promote healthy aging are urgently needed. Telomere attrition, characterized by the shortening of telomeres with each cell division, paradoxically serves as both a protective mechanism and a contributor to tissue degeneration and age-related ailments. Based on the essential role of telomere biology in aging, research efforts aim to develop approaches designed to counteract telomere attrition, aiming to delay or reduce age-related diseases. In this review, telomere biology and its role in aging and age-related diseases is summarized along with recent approaches to interfere with telomere shortening aiming at well- and healthy-aging as well as longevity. As aging research enters a new era, this review emphasizes telomere-targeting therapeutics, including telomerase activators and tankyrase inhibitors, while also exploring the effects of antioxidative and anti-inflammatory agents, along with indirectly related approaches like statins.},
}
@article {pmid38332494,
year = {2024},
author = {Legan, AW and Mehl, HL and Wissotski, M and Adhikari, BN and Callicott, KA},
title = {Telomere-to-telomere genome assembly of the aflatoxin biocontrol agent Aspergillus flavus isolate La3279 isolated from maize in Nigeria.},
journal = {Microbiology resource announcements},
volume = {},
number = {},
pages = {e0069623},
doi = {10.1128/mra.00696-23},
pmid = {38332494},
issn = {2576-098X},
abstract = {Here, we report the complete genome of the non-aflatoxigenic Aspergillus flavus isolate La3279, which is an active ingredient of the aflatoxin biocontrol product Aflasafe. The chromosome-scale assembly clarifies the deletion pattern in the aflatoxin biosynthesis gene cluster and corrects a misidentified assembly previously published for this isolate.},
}
@article {pmid38326475,
year = {2024},
author = {Ohadi, H and Khalili, P and Abasnezhad Kasrineh, F and Esmaeili, OS and Esmaeili Ranjbar, F and Manshoori, A and Hajizadeh, MR and Jalali, Z},
title = {Umbilical cord blood thyroid hormones are inversely related to telomere length and mitochondrial DNA copy number.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {3164},
pmid = {38326475},
issn = {2045-2322},
mesh = {Humans ; Infant, Newborn ; Animals ; Male ; Female ; Pregnancy ; Child, Preschool ; *DNA, Mitochondrial/genetics ; *Fetal Blood ; DNA Copy Number Variations ; Thyroid Hormones ; Telomere/genetics ; Thyrotropin/genetics ; },
abstract = {Hypothyroidism has been linked to reduced mortality rate and increased lifespan and health span. Telomere shortening, enhanced oxidative stress, and reduced cellular mitochondrial content are important hallmarks of aging shown to be related to age-associated diseases. It was proposed that the status of these markers in early life can be predictive of lifespan and the predisposition to certain age-associated disease in adulthood. Animal studies indicated that prenatal injection of thyroid hormones affects postnatal telomere length. Here, we sought to determine whether thyroid hormones TSH and fT4 are related to the telomere length, mitochondrial DNA copy number (mtDNAcn), and oxidative stress resistance marker GPX in the cord blood of newborns. In this study, we analyzed 70 mothers (18-42 years) and neonate dyads born in 2022 at the Nik Nafs maternity Hospital in Rafsanjan. The relative telomere length (RTL) and mtDNAcn were measured in the genomic DNA of cord blood leukocytes using real-time PCR. GPX enzyme activity was measured in the serum using colorimetric assays. In this study the correlation between these markers and the cord blood TSH and fT4 hormones were assessed using regression models. We found a reverse relationship between TSH levels and RTL in the cord blood of neonates. Additionally, our results displayed increased TSH levels associated with enhanced GPX activity. Regarding the mitochondrial DNA copy number, we found an indirect relationship between fT4 level and mtDNAcn only in male newborns. Future analyses of various oxidative stress markers, mitochondrial biogenesis status, telomerase activity, and the level of DNA damage are warranted to demonstrate the underlying mechanism of our observations.},
}
@article {pmid38326339,
year = {2024},
author = {Sun, Z and Li, S and Liu, Y and Li, W and Liu, K and Cao, X and Lin, J and Wang, H and Wang, Q and Shao, C},
title = {Telomere-to-telomere gapless genome assembly of the Chinese sea bass (Lateolabrax maculatus).},
journal = {Scientific data},
volume = {11},
number = {1},
pages = {175},
pmid = {38326339},
issn = {2052-4463},
mesh = {Animals ; *Bass/genetics ; Genome ; Telomere/genetics ; Computational Biology ; Seafood ; },
abstract = {Chinese sea bass (Lateolabrax maculatus) is a highly sought-after commercial seafood species in Asian regions due to its excellent nutritional value. With the rapid advancement of bioinformatics, higher standards for genome analysis compared to previously published reference genomes are now necessary. This study presents a gapless assembly of the Chinese sea bass genome, which has a length of 632.75 Mb. The sequences were assembled onto 24 chromosomes with a coverage of over 99% (626.61 Mb), and telomeres were detected on 34 chromosome ends. Analysis using Merqury indicated a high level of accuracy, with an average consensus quality value of 54.25. The ONT ultralong and PacBio HiFi data were aligned with the assembly using minimap2, resulting in a mapping rate of 99.9%. The study also identified repeating elements in 20.90% (132.25 Mb) of the genome and inferred 22,014 protein-coding genes. These results establish meaningful groundwork for exploring the evolution of the Chinese sea bass genome and advancing molecular breeding techniques.},
}
@article {pmid38321948,
year = {2024},
author = {Audry, J and Zhang, H and Kerr, C and Berkner, KL and Runge, KW},
title = {Ccq1 restrains Mre11-mediated degradation to distinguish short telomeres from double-strand breaks.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkae044},
pmid = {38321948},
issn = {1362-4962},
support = {R01 HL152678/HL/NHLBI NIH HHS/United States ; R01 HL158007/HL/NHLBI NIH HHS/United States ; R01AG051601/NH/NIH HHS/United States ; },
abstract = {Telomeres protect chromosome ends and are distinguished from DNA double-strand breaks (DSBs) by means of a specialized chromatin composed of DNA repeats bound by a multiprotein complex called shelterin. We investigated the role of telomere-associated proteins in establishing end-protection by studying viable mutants lacking these proteins. Mutants were studied using a Schizosaccharomyces pombe model system that induces cutting of a 'proto-telomere' bearing telomere repeats to rapidly form a new stable chromosomal end, in contrast to the rapid degradation of a control DSB. Cells lacking the telomere-associated proteins Taz1, Rap1, Poz1 or Rif1 formed a chromosome end that was stable. Surprisingly, cells lacking Ccq1, or impaired for recruiting Ccq1 to the telomere, converted the cleaved proto-telomere to a rapidly degraded DSB. Ccq1 recruits telomerase, establishes heterochromatin and affects DNA damage checkpoint activation; however, these functions were separable from protection of the new telomere by Ccq1. In cells lacking Ccq1, telomere degradation was greatly reduced by eliminating the nuclease activity of Mre11 (part of the Mre11-Rad50-Nbs1/Xrs2 DSB processing complex), and higher amounts of nuclease-deficient Mre11 associated with the new telomere. These results demonstrate a novel function for S. pombe Ccq1 to effect end-protection by restraining Mre11-dependent degradation of the DNA end.},
}
@article {pmid38315384,
year = {2024},
author = {Pennington, KM and Simonetto, D and Taner, T and Mangaonkar, AA},
title = {Pulmonary, Hepatic, and Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Telomere Biology Disorders.},
journal = {Current hematologic malignancy reports},
volume = {},
number = {},
pages = {},
pmid = {38315384},
issn = {1558-822X},
abstract = {PURPOSE OF THE REVIEW: This study aimed to summarize evidence and provide consensus-based guidelines for management of transplantation in patients with telomere biology disorders (TBD). Specifically, this review focuses on clinical management of lung, liver, and bone marrow transplantation in TBD patients.<br><br>RECENT FINDINGS: TBD patients have specific unique biological vulnerabilities such as T cell immunodeficiency, susceptibility to infections, hypersensitivity to chemotherapy and radiation, and cytopenias. Furthermore, multiple organ involvement at diagnosis makes clinical management especially challenging due to higher degree of organ damage, and stress-induced telomeric crisis. Sequential and combined organ transplants, development of novel radiation and alkylator-free conditioning regimen, and use of novel drugs for graft-versus-host disease prophylaxis are some of the recent updates in the field. Multidisciplinary management is essential to optimize transplant outcomes in patients with TBD. In this review, we provide consensus-based transplant management guidelines for clinical management of transplant in TBD.},
}
@article {pmid38310618,
year = {2024},
author = {Borges, G and Benslimane, Y and Harrington, L},
title = {A CRISPR base editing approach for the functional assessment of telomere biology disorder-related genes in human health and aging.},
journal = {Biogerontology},
volume = {},
number = {},
pages = {},
pmid = {38310618},
issn = {1573-6768},
support = {FRN148936/CAPMC/CIHR/Canada ; },
abstract = {Telomere Biology Disorders (TBDs) are a group of rare diseases characterized by the presence of short and/or dysfunctional telomeres. They comprise a group of bone marrow failure syndromes, idiopathic pulmonary fibrosis, and liver disease, among other diseases. Genetic alterations (variants) in the genes responsible for telomere homeostasis have been linked to TBDs. Despite the number of variants already identified as pathogenic, an even more significant number must be better understood. The study of TBDs is challenging since identifying these variants is difficult due to their rareness, it is hard to predict their impact on the disease onset, and there are not enough samples to study. Most of our knowledge about pathogenic variants comes from assessing telomerase activity from patients and their relatives affected by a TBD. However, we still lack a cell-based model to identify new variants and to study the long-term impact of such variants on the genes involved in TBDs. Herein, we present a cell-based model using CRISPR base editing to mutagenize the endogenous alleles of 21 genes involved in telomere biology. We identified key residues in the genes encoding 17 different proteins impacting cell growth. We provide functional evidence for variants of uncertain significance in patients with TBDs. We also identified variants resistant to telomerase inhibition that, similar to cells expressing wild-type telomerase, exhibited increased tumorigenic potential using an in vitro tumour growth assay. We believe that such cell-based approaches will significantly advance our understanding of the biology of TBDs and may contribute to the development of new therapies for this group of diseases.},
}
@article {pmid38307343,
year = {2024},
author = {Ozturk, S},
title = {The close relationship between oocyte aging and telomere shortening, and possible interventions for telomere protection.},
journal = {Mechanisms of ageing and development},
volume = {218},
number = {},
pages = {111913},
doi = {10.1016/j.mad.2024.111913},
pmid = {38307343},
issn = {1872-6216},
abstract = {As women delay childbearing due to socioeconomic reasons, understanding molecular mechanisms decreasing oocyte quantity and quality during ovarian aging becomes increasingly important. The ovary undergoes biological aging at a higher pace when compared to other organs. As is known, telomeres play crucial roles in maintaining genomic integrity, and their shortening owing to increased reactive oxygen species, consecutive cellular divisions, genetic and epigenetic alterations is associated with loss of developmental competence of oocytes. Novel interventions such as antioxidant treatments and regulation of gene expression are being investigated to prevent or rescue telomere attrition and thereby oocyte aging. Herein, potential factors and molecular mechanisms causing telomere shortening in aging oocytes were comprehensively reviewed. For the purpose of extending reproductive lifespan, possible therapeutic interventions to protect telomere length were also discussed.},
}
@article {pmid38296763,
year = {2024},
author = {Akkar, I and Koyuncuoglu, G and Turgut, ZI and Dogan, MH and Kizilarslanoglu, MC},
title = {Comment on: Effect of a 3-year lifestyle intervention on telomere length in participants from PREDIMED-Plus.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.clnu.2024.01.018},
pmid = {38296763},
issn = {1532-1983},
}
@article {pmid38293941,
year = {2024},
author = {Salih, AM and Galazzo, IB and Menegaz, G and Altmann, A},
title = {Leukocyte Telomere Length and Cardiac Structure and Function: A Mendelian Randomization Study.},
journal = {Journal of the American Heart Association},
volume = {13},
number = {3},
pages = {e032708},
doi = {10.1161/JAHA.123.032708},
pmid = {38293941},
issn = {2047-9980},
mesh = {*Mendelian Randomization Analysis/methods ; *Heart ; Leukocytes ; Telomere/genetics ; Genome-Wide Association Study ; },
abstract = {BACKGROUND: Existing research demonstrates the association of shorter leukocyte telomere length with increased risk of age-related health outcomes including cardiovascular diseases. However, the direct causality of these relationships has not been definitively established. Cardiovascular aging at an organ level may be captured using image-derived phenotypes of cardiac anatomy and function.<br><br>METHODS AND RESULTS: In the current study, we use 2-sample Mendelian randomization to assess the causal link between leukocyte telomere length and 54 cardiac magnetic resonance imaging measures representing structure and function across the 4 cardiac chambers. Genetically predicted shorter leukocyte telomere length was causally linked to smaller ventricular cavity sizes including left ventricular end-systolic volume, left ventricular end-diastolic volume, lower left ventricular mass, and pulmonary artery. The association with left ventricular mass (&#x3b2;&#x2009;=0.217, Pfalse discovery rate=0.016) remained significant after multiple testing adjustment, whereas other associations were attenuated.<br><br>CONCLUSIONS: Our findings support a causal role for shorter leukocyte telomere length and faster cardiac aging, with the most prominent relationship with left ventricular mass.},
}
@article {pmid38288254,
year = {2024},
author = {Wang, X and Tu, M and Wang, Y and Zhang, Y and Yin, W and Fang, J and Gao, M and Li, Z and Zhan, W and Fang, Y and Song, J and Xi, Z and Wang, X},
title = {Telomere-to-telomere and gap-free genome assembly of a susceptible grapevine species (Thompson Seedless) to facilitate grape functional genomics.},
journal = {Horticulture research},
volume = {11},
number = {1},
pages = {uhad260},
pmid = {38288254},
issn = {2662-6810},
abstract = {Grapes are globally recognized as economically significant fruit trees. Among grape varieties, Thompson Seedless holds paramount influence for fresh consumption and for extensive applications in winemaking, drying, and juicing. This variety is one of the most efficient genotypes for grape genetic modification. However, the lack of a high-quality genome has impeded effective breeding efforts. Here, we present the high-quality reference genome of Thompson Seedless with all 19 chromosomes represented as 19 contiguous sequences (N50 = 27.1 Mb) with zero gaps and prediction of all telomeres and centromeres. Compared with the previous assembly (TSv1 version), the new assembly incorporates an additional 31.5 Mb of high-quality sequenced data with annotation of a total of 30 397 protein-coding genes. We also performed a meticulous analysis to identify nucleotide-binding leucine-rich repeat genes (NLRs) in Thompson Seedless and two wild grape varieties renowned for their disease resistance. Our analysis revealed a significant reduction in the number of two types of NLRs, TIR-NB-LRR (TNL) and CC-NB-LRR (CNL), in Thompson Seedless, which may have led to its sensitivity to many fungal diseases, such as powdery mildew, and an increase in the number of a third type, RPW8 (resistance to powdery mildew 8)-NB-LRR (RNL). Subsequently, transcriptome analysis showed significant enrichment of NLRs during powdery mildew infection, emphasizing the pivotal role of these elements in grapevine's defense against powdery mildew. The successful assembly of a high-quality Thompson Seedless reference genome significantly contributes to grape genomics research, providing insight into the importance of seedlessness, disease resistance, and color traits, and these data can be used to facilitate grape molecular breeding efforts.},
}
@article {pmid38285162,
year = {2024},
author = {Waitkus, MS and Erman, EN and Reitman, ZJ and Ashley, DM},
title = {Mechanisms of telomere maintenance and associated therapeutic vulnerabilities in malignant gliomas.},
journal = {Neuro-oncology},
volume = {},
number = {},
pages = {},
doi = {10.1093/neuonc/noae016},
pmid = {38285162},
issn = {1523-5866},
support = {K22 CA258965/CA/NCI NIH HHS/United States ; },
abstract = {A majority of cancers (~85%) activate the enzyme telomerase to maintain telomere length over multiple rounds of cellular division. Telomerase-negative cancers activate a distinct, telomerase-independent mechanism of telomere maintenance termed Alternative lengthening of telomeres (ALT). ALT uses homologous recombination to maintain telomere length and exhibits features of break-induced DNA replication. In malignant gliomas, the activation of either telomerase or ALT is nearly ubiquitous in pediatric and adult tumors, and the frequency with which these distinct telomere maintenance mechanisms is activated varies according to genetically-defined glioma subtypes. In this review, we summarize the current state of the field of telomere maintenance mechanisms (TMMs) and their relevance to glioma biology and therapy. We review the genetic alterations and molecular mechanisms leading to telomerase activation or ALT induction in pediatric and adult gliomas. With this background, we review emerging evidence on strategies for targeting TMMs for glioma therapy. Finally, we comment on critical gaps and issues for moving the field forward to translate our improved understanding of glioma telomere maintenance into better therapeutic strategies for patients.},
}
@article {pmid38279807,
year = {2024},
author = {Pereira, FSM and Thomasini, RL and Pereira, DS and Silva, TJ and Leite, CA and Reis, LGO and Câmara, VAA and da Costa, MBR and Bakir, JVS and Xavier, LS and Pereira, LSM and Parentoni, AN and Lacerda, ACR},
title = {Association Between the Length of Leukocyte Telomeres and Functional Performance of Older Adults: Observational Study.},
journal = {Rejuvenation research},
volume = {},
number = {},
pages = {},
doi = {10.1089/rej.2023.0050},
pmid = {38279807},
issn = {1557-8577},
abstract = {Despite current literature pointing to a link between shortened telomeres and aging, chronic diseases, and geriatric syndromes, the precise implications of this connection remain unclear. The aim of this exploratory, cross-sectional, observational study was to investigate the association between the relative telomere length (RTL) of peripheral blood leukocyte subtypes (mononuclear cells and granulocytes) and physical performance using the Short Physical Performance Battery (SPPB) in older adults. A cohort of 95 participants was recruited, which included men and women aged over 60 years (70.48 ± 5.5 years). It was found that mononuclear cell RTL was significantly lower than that of granulocytes (p < 0.0001). Moreover, individuals with good SPPB performance exhibited lower mononuclear cell RTL compared with those with moderate or poor performance. However, no significant differences were observed in granulocyte RTL between different SPPB performance groups. The global SPPB score showed an inverse correlation with mononuclear cell RTL, but this correlation was not present with granulocyte RTL. Similarly, the SPPB sit-to-stand domain correlated with mononuclear cell RTL, but no such correlation was found with granulocyte RTL. Our findings challenge conventional expectations, suggesting that shorter mononuclear cell RTL may be associated with favorable functional capacity. The variations in RTL between mononuclear cells and granulocytes highlight their distinct biological roles and turnover rates. A history of immune responses may influence mononuclear cell RTL dynamics, while telomerase activity may protect granulocyte RTL from significant shortening. The unexpected associations observed in mononuclear cell RTL emphasize the complex interplay between immune responses, cellular aging, and functional capacity in older adults.},
}
@article {pmid38278953,
year = {2024},
author = {Bi, G and Zhao, S and Yao, J and Wang, H and Zhao, M and Sun, Y and Hou, X and Haas, FB and Varshney, D and Prigge, M and Rensing, SA and Jiao, Y and Ma, Y and Yan, J and Dai, J},
title = {Near telomere-to-telomere genome of the model plant Physcomitrium patens.},
journal = {Nature plants},
volume = {10},
number = {2},
pages = {327-343},
pmid = {38278953},
issn = {2055-0278},
mesh = {*Centromere/genetics ; *Telomere/genetics ; Genome, Plant ; },
abstract = {The model plant Physcomitrium patens has played a pivotal role in enhancing our comprehension of plant evolution and development. However, the current genome harbours numerous regions that remain unfinished and erroneous. To address these issues, we generated an assembly using Oxford Nanopore reads and Hi-C mapping. The assembly incorporates telomeric and centromeric regions, thereby establishing it as a near telomere-to-telomere genome except a region in chromosome 1 that is not fully assembled due to its highly repetitive nature. This near telomere-to-telomere genome resolves the chromosome number at 26 and provides a gap-free genome assembly as well as updated gene models to aid future studies using this model organism.},
}
@article {pmid38276581,
year = {2024},
author = {Aon-Im, P and Monthakantirat, O and Daodee, S and Chulikhit, Y and Sriya, N and Boonyarat, C and Chumwangwapee, T and Khamphukdee, C and Kijjoa, A},
title = {Evaluation of the Impact of Alternanthera philoxeroides (Mart.) Griseb. Extract on Memory Impairment in D-Galactose-Induced Brain Aging in Mice through Its Effects on Antioxidant Enzymes, Neuroinflammation, and Telomere Shortening.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {2},
pages = {},
pmid = {38276581},
issn = {1420-3049},
support = {RGNS 64-041//Office of the Permanent Secretary, Ministry of Higher Education, Science, Research and Innova-tion, Thailand/ ; },
mesh = {Mice ; Animals ; *Antioxidants/metabolism ; *Galactose/metabolism ; Telomere Shortening ; Neuroinflammatory Diseases ; Maze Learning ; Aging ; Brain/metabolism ; Memory Disorders/chemically induced/drug therapy/metabolism ; Superoxide Dismutase/metabolism ; Cytokines/metabolism ; Oxidative Stress ; },
abstract = {Aging is a well-known factor that accelerates brain deterioration, resulting in impaired learning and memory functions. This current study evaluated the potential of an extract of Alternanthera philoxeroides (AP), an edible flavonoid-rich plant, to ameliorate D-galactose-induced brain aging in male mice. Chronic administration of D-galactose (150 mg/kg/day) in mice mimicked the characteristics of aging by accelerating senescence via downregulation of the following telomere-regulating factors: mouse telomerase reverse transcriptase (mTERT) and mouse telomeric repeat-binding factors 1 (mTRF1) and 2 (mTRF2). D-galactose also decreased the activities of the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD), while increasing expression of neuroinflammatory cytokines in the frontal cortex and hippocampus. Daily treatment of D-galactose-induced aging mice with AP at 250 and 500 mg/kg/day or vitamin E (100 mg/kg/day) significantly increased the activities of SOD and CAT, as well as expression of mTERT, mTRF1, and mTRF2, which are involved in telomere stabilization, but decreased the levels of proinflammatory cytokines IL-1β, IL-6, and TNF-α. In the behavioral portion of the study, AP improved aging-related cognitive deficits in short-term memory as shown by the Y-maze task and the novel object recognition test (NORT) and long-term memory as shown by the Morris water maze test (MWMT). The flavones kaempferol-O-glucoside (1), quercetin (2), alternanthin B (3), demethyltorosaflavone D (4), and chrysoeriol-7-O-rhamnoside (5), which could be responsible for the observed effects of AP in the D-galactose-induced aging mice, were identified by HPLC analysis.},
}
@article {pmid38275650,
year = {2024},
author = {Ojeda-Rodriguez, A and Alcala-Diaz, JF and Rangel-Zuñiga, OA and Arenas-de Larriva, AP and Gutierrez-Mariscal, FM and Torres-Peña, JD and Mora-Ortiz, M and Romero-Cabrera, JL and Luque, RM and Ordovas, JM and Perez-Martinez, P and Delgado-Lista, J and Yubero-Serrano, EM and Lopez-Miranda, J},
title = {Telomere Maintenance Is Associated with Type 2 Diabetes Remission in Response to a Long-Term Dietary Intervention without Non-Weight Loss in Patients with Coronary Heart Disease: From the CORDIOPREV Randomized Controlled Trial.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {1},
pages = {},
pmid = {38275650},
issn = {2076-3921},
support = {CEAS, 1/2016//Fundaci&#xf3;n Patrimonio Comunal Olivarero/ ; Grant AGL2015-67896-P; PID2019-104362RB-I00//Ministerio de Ciencia e Innovaci&#xf3;n/ ; Grant P20/00256//Consejer&#xed;a de Transformaci&#xf3;n Econ&#xf3;mica, Industria, Conocimiento y Universidades/ ; },
abstract = {In order to evaluate whether telomere maintenance is associated with type 2 diabetes remission, newly diagnosed type 2 diabetes patients without glucose-lowering treatment (183 out of 1002) from the CORDIOPREV study (NCT00924937) were randomized to consume a Mediterranean or low-fat diet. Patients were classified as Responders, those who reverted from type 2 diabetes during the 5 years of dietary intervention (n = 69), and Non-Responders, who did not achieve diabetes remission by the end of the follow-up period (n = 104). We found no differences in diabetes remission between the two diets, and we determined telomere length (TL) by measuring qPCR, telomerase activity using the TRAP assay, and direct redox balance based on the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSH) via colorimetric assay. Responders exhibited higher baseline TL in comparison with Non-Responders (p = 0.040), and a higher TL at baseline significantly predicted a higher probability of type 2 diabetes remission (OR 2.13; 95% CI, 1.03 to 4.41). After the dietary intervention, Non-Responders showed significant telomere shortening (-0.19, 95% CI -0.32 to 0.57; p = 0.005). Telomere shortening was significantly pronounced in type 2 diabetes patients with a worse profile of insulin resistance and/or beta-cell functionality: high hepatic insulin resistance fasting, a high disposition index (-0.35; 95% CI, -0.54 to -0.16; p < 0.001), and a low disposition index (-0.25; 95% CI, -0.47 to -0.01; p = 0.037). In addition, changes in TL were correlated to the GSH/GSSG ratio. Responders also showed increased telomerase activity compared with baseline (p = 0.048), from 0.16 (95% CI, 0.08 to 0.23) to 0.28 (95% CI, 0.15 to 0.40), with a more marked increase after the dietary intervention compared with Non-Responders (+0.07; 95% CI, -0.06-0.20; p = 0.049). To conclude, telomere maintenance may play a key role in the molecular mechanisms underlying type 2 diabetes remission in newly diagnosed patients. However, further larger-scale prospective studies are necessary to corroborate our findings.},
}
@article {pmid38270117,
year = {2023},
author = {Liao, P and Yan, B and Wang, C and Lei, P},
title = {Telomeres: Dysfunction, Maintenance, Aging and Cancer.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2023.1128},
pmid = {38270117},
issn = {2152-5250},
abstract = {Aging has emerged at the forefront of scientific research due to the growing social and economic costs associated with the growing aging global population. The defining features of aging involve a variety of molecular processes and cellular systems, which are interconnected and collaboratively contribute to the aging process. Herein, we analyze how telomere dysfunction potentially amplifies or accelerates the molecular and biochemical mechanisms underpinning each feature of aging and contributes to the emergence of age-associated illnesses, including cancer and neurodegeneration, via the perspective of telomere biology. Furthermore, the recently identified novel mechanistic actions for telomere maintenance offer a fresh viewpoint and approach to the management of telomeres and associated disorders. Telomeres and the defining features of aging are intimately related, which has implications for therapeutic and preventive approaches to slow aging and reduce the prevalence of age-related disorders.},
}
@article {pmid38269293,
year = {2024},
author = {Liao, Z and Zhang, T and Lei, W and Wang, Y and Yu, J and Wang, Y and Chai, K and Wang, G and Zhang, H and Zhang, X},
title = {A telomere-to-telomere reference genome of ficus (Ficus hispida) provides new insights into sex determination.},
journal = {Horticulture research},
volume = {11},
number = {1},
pages = {uhad257},
pmid = {38269293},
issn = {2662-6810},
abstract = {A high-quality reference genome is indispensable for resolving biologically essential traits. Ficus hispida is a dioecious plant. A complete Ficus reference genome will be crucial for understanding their sex evolution and important biological characteristics, such as aerial roots, mutualistic symbiosis with ficus-wasps, and fruiting from old stems. Here, we generated a telomere-to-telomere (T2T) genome for F. hispida using PacBio HiFi and Oxford Nanopore Ultra-long sequencing technologies. The genome contiguity and completeness has shown improvement compared with the previously released genome, with the annotation of six centromeres and 28 telomeres. We have refined our previously reported 2-Mb male-specific region into a 7.2-Mb genomic region containing 51 newly predicted genes and candidate sex-determination genes AG2 and AG3. Many of these genes showed extremely low expression, likely attributed to hypermethylation in the gene body and promoter regions. Gene regulatory networks (GRNs) revealed that AG2 and AG3 are related to the regulation of stamen development in male flowers, while the AG1 gene is responsible for regulating female flowers' defense responses and secondary metabolite processes. Comparative analysis of GRNs showed that the NAC, WRKY, and MYB transcription factor families dominate the female GRN, whereas the MADS and MYB transcription factor families are prevalent in the male GRN.},
}
@article {pmid38267053,
year = {2024},
author = {Aburada, N and Ito, J and Inoue, Y and Yamamoto, T and Hayashi, M and Teramoto, N and Okada, Y and Koshiishi, Y and Shirasuna, K and Iwata, H},
title = {Effect of paternal aging and vitrification on mitochondrial DNA copy number and telomere length of mouse blastocysts.},
journal = {The Journal of reproduction and development},
volume = {},
number = {},
pages = {},
doi = {10.1262/jrd.2023-079},
pmid = {38267053},
issn = {1348-4400},
abstract = {In this study, we examined the effects of paternal aging on the mitochondrial DNA copy number (mt-cn), telomere length (TL), and gene expression in mouse embryos. The effects of vitrification on the mt-cn and TL of the embryos derived from young and aged male parents (YF and AF, respectively) were examined. C57BL/6N male mice were used for embryo production at 13-23 and 50-55 weeks of age. Two-cell stage embryos were collected from the oviducts of superovulated female mice (8-15 weeks old) and cultured for 24 h until the 8-cell stage, followed by embryo vitrification. Fresh and vitrified-warmed embryos were incubated for 2 days until the blastocyst stage, and mt-cn and TL were investigated. The cell-free mitochondrial DNA copy number (cf-mt-cn) in the spent culture medium (SCM) of the embryos was then investigated. RNA sequencing of blastocysts revealed that metabolic pathways, including oxidative phosphorylation and mTOR pathways, were enriched in differentially expressed genes. The mt-cn and TL of AF-derived blastocysts were lower and shorter, respectively, than those of YF-derived blastocysts. Paternal aging did not affect the blastocyst rate after vitrification. Vitrification of the 8-cell stage embryos did not affect the mt-cn of the blastocysts. However, it increased the cf-mt-cn (cell-free mt-cn) in the SCM of both YF- and AF-derived embryos. Vitrification did not affect the TL of either YF- or AF-derived embryos. Thus, paternal aging affected the mt-cn and TL of the embryos, but vitrification did not affect these parameters in either age groups.},
}
@article {pmid38262198,
year = {2024},
author = {Lu, G and Fang, T and Li, X and Zhang, X and Li, H and Wu, N and Liu, F and Hao, W and Ye, QN and Cheng, L and Li, J and Li, F},
title = {Methamphetamine use shortens telomere length in male adults and rats.},
journal = {Drug and alcohol dependence},
volume = {256},
number = {},
pages = {111094},
doi = {10.1016/j.drugalcdep.2024.111094},
pmid = {38262198},
issn = {1879-0046},
mesh = {Humans ; Adult ; Animals ; Rats ; Male ; *Aging ; Diagnostic and Statistical Manual of Mental Disorders ; Leukocytes ; *Methamphetamine/pharmacology ; Telomere ; },
abstract = {BACKGROUND: Methamphetamine (MA) use increases the risk of age-related diseases. However, it remains uncertain whether MA use exhibits accelerated biological aging, as indicated by telomere length (TL), a proposed marker of aging. Here we conducted studies in both humans and rats to investigate the association between MA use and TL.<br><br>METHODS: We recruited 125 male MA users and 66 healthy controls, aged 30-40 years. MA users were diagnosed using DSM-5 criteria and categorized into two groups: non-severe (n = 78) and severe (n = 47) MA use disorder (MUD). MA-treated conditioned place preference (CPP) rats were utilized to validate our clinical investigations. TL was assessed using real-time polymerase chain reaction.<br><br>RESULTS: At clinical levels, MA users exhibited significantly shorter leukocyte TL compared to healthy controls. Among MA users, individuals with severe MUD had significantly shorter leukocyte TL than those with non-severe MUD. Importantly, both univariate and multivariate linear regression analyses demonstrated a negative association between the severity of MA use and leukocyte TL. In a rat model of MA-induced CPP, leukocyte TL was also significantly shortened after MA administration, especially in rats with higher CPP expression or reinstatement scores.<br><br>CONCLUSION: MA use shortened TL, and the severity of MA use was negatively correlated with TL. These findings provide new insights into the pathophysiology of accelerated aging caused by MA use and may have implications for identifying biomarkers and developing novel treatment strategies for MUD.},
}
@article {pmid38260456,
year = {2024},
author = {Cheng, D and Zhang, F and Porter, KI and Wang, S and Zhang, H and Davis, CJ and Robertson, GP and Zhu, J},
title = {Humanization of the mouse Tert gene reset telomeres to human length.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {38260456},
support = {R01 AG073423/AG/NIA NIH HHS/United States ; R21 OD021432/OD/NIH HHS/United States ; R35 GM149529/GM/NIGMS NIH HHS/United States ; },
abstract = {Telomeres undergo shortening with each cell division, serving as biomarkers of human aging, which is characterized by short telomeres and restricted telomerase expression in adult tissues. Contrarily, mice, featuring their longer telomeres and widespread telomerase activity, present limitations as models for understanding telomere-related human biology and diseases. To bridge this gap, we engineered a mouse strain with a humanized mTert gene, hmTert, wherein specific non-coding sequences were replaced with their human counterparts. The hmTert gene, encoding the wildtype mTert protein, was repressed in adult tissues beyond the gonads and thymus, closely resembling the regulatory pattern of the human TERT gene. Remarkably, the hmTert gene rescued telomere dysfunction in late generations of mTert-knockout mice. Through successive intercrosses of Tert[h/-] mice, telomere length progressively declined, stabilizing below 10-kb. Tert[h/h] mice achieved a human-like average telomere length of 10-12 kb, contrasting with the 50-kb length in wildtype C57BL/6J mice. Despite shortened telomeres, Tert[h/h] mice maintained normal body weight and cell homeostasis in highly proliferative tissues. Notably, colonocyte proliferation decreased significantly in Tert[h/h] mice during dextran sodium sulfate-induced ulcerative colitis-like pathology, suggesting limitations on cellular renewal due to short telomeres. Our findings underscore the genetic determination of telomere homeostasis in mice by the Tert gene. These mice, exhibiting humanized telomere homeostasis, serve as a valuable model for exploring fundamental questions related to human aging and cancer.},
}
@article {pmid38258326,
year = {2024},
author = {Romero-Haro, A&#xc1; and Mulder, E and Haussmann, MF and Tschirren, B},
title = {The association between age and telomere length is age-dependent: Evidence for a threshold model of telomere length maintenance.},
journal = {Journal of experimental zoology. Part A, Ecological and integrative physiology},
volume = {},
number = {},
pages = {},
doi = {10.1002/jez.2785},
pmid = {38258326},
issn = {2471-5646},
support = {/SNSF_/Swiss National Science Foundation/Switzerland ; },
abstract = {Telomere length and dynamics are commonly used biomarkers of somatic state, yet the role of telomeres underlying the aging process is still debated. Indeed, to date, empirical evidence for an association between age and telomere length is mixed. Here, we test if the age-dependency of the association between age and telomere length can provide a potential explanation for the reported inconsistencies across studies. To this end, we quantified telomere length by telomere restriction fragment analysis in two groups of Japanese quail (Coturnix japonica) that differed in their age distribution. One group consisted of young adults only, whereas the second group consisted of adults across a wide range of ages. In the young adults group, there was a highly significant negative association between telomere length and age, whereas no association between age and telomere length was found in the all-ages adults group. This difference between groups was not due to telomere length-dependent selective disappearance. Our results shows that the association between telomere length and age is age-dependent and suggest that the costs and benefits associated with telomere maintenance are dynamic across an individual's life course.},
}
@article {pmid38255792,
year = {2024},
author = {Dhillon, VS and Shahid, M and Deo, P and Fenech, M},
title = {Reduced SIRT1 and SIRT3 and Lower Antioxidant Capacity of Seminal Plasma Is Associated with Shorter Sperm Telomere Length in Oligospermic Men.},
journal = {International journal of molecular sciences},
volume = {25},
number = {2},
pages = {},
pmid = {38255792},
issn = {1422-0067},
mesh = {Humans ; Male ; Semen ; *Oligospermia/genetics ; Antioxidants ; *Sirtuin 3/genetics ; Sirtuin 1/genetics ; Spermatozoa ; Protamines ; Superoxide Dismutase/genetics ; },
abstract = {Infertility affects millions of couples worldwide and has a profound impact not only on their families, but also on communities. Telomere attrition has been associated with infertility, DNA damage and fragmentation. Oxidative stress has been shown to affect sperm DNA integrity and telomere length. Sirtuins such as SIRT1 and SIRT3 are involved in aging and oxidative stress response. The aim of the present study is to determine the role of SIRT1 and SIRT3 in regulating oxidative stress, telomere shortening, and their association with oligospermia. Therefore, we assessed the protein levels of SIRT1 and SIRT3, total antioxidant capacity (TAC), superoxide dismutase (SOD), malondialdehyde (MDA) and catalase activity (CAT) in the seminal plasma of 272 patients with oligospermia and 251 fertile men. We also measured sperm telomere length (STL) and leukocyte telomere length (LTL) using a standard real-time quantitative PCR assay. Sperm chromatin and protamine deficiency were also measured as per standard methods. Our results for oligospermic patients demonstrate significant reductions in semen parameters, shorter STL and LTL, lower levels of SOD, TAC, CAT, SIRT1 and SIRT3 levels, and also significant protamine deficiency and higher levels of MDA and DNA fragmentation. We conclude that a shorter TL in sperms and leukocytes is associated with increased oxidative stress that also accounts for high levels of DNA fragmentation in sperms. Our results support the hypothesis that various sperm parameters in the state of oligospermia are associated with or caused by reduced levels of SIRT1 and SIRT3 proteins.},
}
@article {pmid38254712,
year = {2024},
author = {Musmaker, K and Wells, J and Tsai, MC and Comeron, JM and Malkova, A},
title = {Alternative Lengthening of Telomeres in Yeast: Old Questions and New Approaches.},
journal = {Biomolecules},
volume = {14},
number = {1},
pages = {},
pmid = {38254712},
issn = {2218-273X},
support = {R01 AG081263/AG/NIA NIH HHS/United States ; R01AG081263/AG/NIA NIH HHS/United States ; },
mesh = {*Saccharomyces cerevisiae/genetics ; *Telomere/genetics ; Computer Simulation ; DNA Repair ; Recombination, Genetic ; },
abstract = {Alternative lengthening of telomeres (ALT) is a homologous recombination-based pathway utilized by 10-15% of cancer cells that allows cells to maintain their telomeres in the absence of telomerase. This pathway was originally discovered in the yeast Saccharomyces cerevisiae and, for decades, yeast has served as a robust model to study ALT. Using yeast as a model, two types of ALT (RAD51-dependent and RAD51-independent) have been described. Studies in yeast have provided the phenotypic characterization of ALT survivors, descriptions of the proteins involved, and implicated break-induced replication (BIR) as the mechanism responsible for ALT. Nevertheless, many questions have remained, and answering them has required the development of new quantitative methods. In this review we discuss the historic aspects of the ALT investigation in yeast as well as new approaches to investigating ALT, including ultra-long sequencing, computational modeling, and the use of population genetics. We discuss how employing new methods contributes to our current understanding of the ALT mechanism and how they may expand our understanding of ALT in the future.},
}
@article {pmid38254667,
year = {2024},
author = {Li, B},
title = {Unwrap RAP1's Mystery at Kinetoplastid Telomeres.},
journal = {Biomolecules},
volume = {14},
number = {1},
pages = {},
pmid = {38254667},
issn = {2218-273X},
support = {R01 AI066095/AI/NIAID NIH HHS/United States ; R01 AI179972/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; *Telomere/genetics ; Epigenomics ; Eukaryota ; *RNA, Long Noncoding ; Mammals ; },
abstract = {Although located at the chromosome end, telomeres are an essential chromosome component that helps maintain genome integrity and chromosome stability from protozoa to mammals. The role of telomere proteins in chromosome end protection is conserved, where they suppress various DNA damage response machineries and block nucleolytic degradation of the natural chromosome ends, although the detailed underlying mechanisms are not identical. In addition, the specialized telomere structure exerts a repressive epigenetic effect on expression of genes located at subtelomeres in a number of eukaryotic organisms. This so-called telomeric silencing also affects virulence of a number of microbial pathogens that undergo antigenic variation/phenotypic switching. Telomere proteins, particularly the RAP1 homologs, have been shown to be a key player for telomeric silencing. RAP1 homologs also suppress the expression of Telomere Repeat-containing RNA (TERRA), which is linked to their roles in telomere stability maintenance. The functions of RAP1s in suppressing telomere recombination are largely conserved from kinetoplastids to mammals. However, the underlying mechanisms of RAP1-mediated telomeric silencing have many species-specific features. In this review, I will focus on Trypanosoma brucei RAP1's functions in suppressing telomeric/subtelomeric DNA recombination and in the regulation of monoallelic expression of subtelomere-located major surface antigen genes. Common and unique mechanisms will be compared among RAP1 homologs, and their implications will be discussed.},
}
@article {pmid38253555,
year = {2024},
author = {Eglenen-Polat, B and Kowash, RR and Huang, HC and Siteni, S and Zhu, M and Chen, K and Bender, ME and Mender, I and Stastny, V and Drapkin, BJ and Raj, P and Minna, JD and Xu, L and Shay, JW and Akbay, EA},
title = {A telomere-targeting drug depletes cancer initiating cells and promotes anti-tumor immunity in small cell lung cancer.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {672},
pmid = {38253555},
issn = {2041-1723},
support = {R01 CA276058/CA/NCI NIH HHS/United States ; U01 CA213338/CA/NCI NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Animals ; Mice ; *Small Cell Lung Carcinoma/drug therapy ; *Lung Neoplasms/drug therapy ; *Telomerase ; Drug Delivery Systems ; Telomere ; Deoxyguanosine/*analogs &amp; derivatives ; *Thionucleosides ; },
abstract = {There are few effective treatments for small cell lung cancer (SCLC) underscoring the need for innovative therapeutic approaches. This study focuses on exploiting telomerase, a critical SCLC dependency as a therapeutic target. A prominent characteristic of SCLC is their reliance on telomerase activity, a key enzyme essential for their continuous proliferation. Here we utilize a nucleoside analog, 6-Thio-2'-deoxyguanosine (6TdG) currently in phase II clinical trials, that is preferentially incorporated by telomerase into telomeres leading to telomere dysfunction. Using preclinical mouse and human derived models we find low intermittent doses of 6TdG inhibit tumor growth and reduce metastatic burden. Anti-tumor efficacy correlates with a reduction in a subpopulation of cancer initiating like cells (CICs) identified by their expression of L1CAM/CD133 and highest telomerase activity. 6TdG treatment also leads to activation of innate and adaptive anti-tumor responses. Mechanistically, 6TdG depletes CICs and induces type-I interferon signaling leading to tumor immune visibility by activating tumor cell STING signaling. We also observe increased sensitivity to irradiation after 6TdG treatment in both syngeneic and humanized SCLC xenograft models both of which are dependent on the presence of host immune cells. This study underscores the immune-enhancing and metastasis-reducing effects of 6TdG, employing a range of complementary in vitro and in vivo SCLC preclinical models providing a potential therapeutic approach to SCLC.},
}
@article {pmid38252370,
year = {2024},
author = {Monaghan, P},
title = {Linking telomere dynamics to evolution, life history and environmental change: perspectives, predictions and problems.},
journal = {Biogerontology},
volume = {},
number = {},
pages = {},
pmid = {38252370},
issn = {1573-6768},
support = {Adg 101020037//H2020 European Research Council/ ; },
abstract = {This perspectives paper considers the value of studying telomere biology outside of a biomedical context. I provide illustrative examples of the kinds of questions that evolutionary ecologists have addressed in studies of telomere dynamics in non-model species, primarily metazoan animals, and what this can contribute to our understanding of their evolution, life histories and health. I also discuss why the predicted relationships between telomere dynamics and life history traits, based on the detailed cellular studies in humans and model organisms, are not always found in studies in other species.},
}
@article {pmid38248925,
year = {2023},
author = {Wang, M and Meng, G and Yang, Y and Wang, X and Xie, R and Dong, C},
title = {Telomere-to-Telomere Genome Assembly of Tibetan Medicinal Mushroom Ganoderma leucocontextum and the First Copia Centromeric Retrotransposon in Macro-Fungi Genome.},
journal = {Journal of fungi (Basel, Switzerland)},
volume = {10},
number = {1},
pages = {},
pmid = {38248925},
issn = {2309-608X},
support = {2022YFD1200602//the National Key Research and Development Program of China project/ ; 21322916D//the Key Research and Development Program of Hebei Province/ ; KFJ-PTXM-016//CAS Engineering Laboratory for Advanced Microbial Technology of Agriculture/ ; },
abstract = {A complete telomere-to-telomere (T2T) genome has been a longstanding goal in the field of genomic research. By integrating high-coverage and precise long-read sequencing data using multiple assembly strategies, we present here the first T2T gap-free genome assembly of Ganoderma leucocontextum strain GL72, a Tibetan medicinal mushroom. The T2T genome, with a size of 46.69 Mb, consists 13 complete nuclear chromosomes and typical telomeric repeats (CCCTAA)n were detected at both ends of 13 chromosomes. The high mapping rate, uniform genome coverage, a complete BUSCOs of 99.7%, and base accuracy exceeding 99.999% indicate that this assembly represents the highest level of completeness and quality. Regions characterized by distinct structural attributes, including highest Hi-C interaction intensity, high repeat content, decreased gene density, low GC content, and minimal or no transcription levels across all chromosomes may represent potential centromeres. Sequence analysis revealed the first Copia centromeric retrotransposon in macro-fungi genome. Phylogenomic analysis identified that G. leucocontextum and G. tsugae diverged from the other Ganoderma species approximately 9.8-17.9 MYA. The prediction of secondary metabolic clusters confirmed the capability of this fungus to produce a substantial quantity of metabolites. This T2T gap-free genome will contribute to the genomic 'dark matter' elucidation and server as a great reference for genetics, genomics, and evolutionary studies of G. leucocontextum.},
}
@article {pmid38246982,
year = {2024},
author = {Campos-Sánchez, I and Navarrete-Muñoz, EM and Hurtado-Pomares, M and Júlvez, J and Lertxundi, N and Martens, DS and Fernández-Somoano, A and Riaño-Galán, I and Guxens, M and Ibarluzea, JM and Nawrot, T and Valera-Gran, D},
title = {Association between telomere length and neuropsychological function at 4-5 years in children from the INMA project: a cross-sectional study.},
journal = {European child &amp; adolescent psychiatry},
volume = {},
number = {},
pages = {},
pmid = {38246982},
issn = {1435-165X},
abstract = {Shortened telomere length (TL) has been associated with lower cognitive performance, different neurological diseases in adults, and certain neurodevelopmental disorders in children. However, the evidence about the association between TL and neuropsychological developmental outcomes in children from the general population is scarce. Therefore, this study aimed to explore the association between TL and neuropsychological function in children 4-5 years of age. We included 686 children from the INMA Project, a population-based birth cohort in Spain. Leucocyte TL was determined by quantitative PCR method, and neuropsychological outcomes were measured using the McCarthy Scales of Children's Abilities (MCSA). Multiple linear regression models were used to estimate associations adjusted for potential confounding variables. Main findings showed that a longer TL was associated with a higher mean working memory score (β = 4.55; 95% CI = 0.39, 8.71). In addition, longer TL was associated with a higher mean global quantitative score (β = 3.85; 95% CI = -0.19, 7.89), although the association was marginally significant. To our knowledge, this is the first study that shows a positive association between TL and better neuropsychological outcomes in children. Although further research is required to confirm these results, this study supports the hypothesis that TL is essential in protecting and maintaining a child's health, including cognitive functions such as working memory.},
}
@article {pmid38244620,
year = {2024},
author = {Sabol, A and Zhou, Y and Zhang, W and Ferreira, BCLB and Chen, J and Leblanc, RM and Catenazzi, A},
title = {Carbon nitride dots do not impair the growth, development, and telomere length of tadpoles.},
journal = {The Science of the total environment},
volume = {916},
number = {},
pages = {170176},
doi = {10.1016/j.scitotenv.2024.170176},
pmid = {38244620},
issn = {1879-1026},
mesh = {Animals ; Larva ; *Ecosystem ; *Wastewater ; Zebrafish ; Metamorphosis, Biological ; Anura ; Carbon/toxicity ; Telomere ; *Nitriles ; },
abstract = {Carbon nanoparticles, or carbon dots, can have many beneficial uses. However, we must consider whether they may have any potential negative side effects on wildlife or the ecosystem when these particles end up in wastewater. Early development stages of amphibians are particularly sensitive to contaminants, and exposure to carbon dots could disrupt their development and cause morbidity or death. Past studies have investigated short-term exposure to certain types of nanoparticles, but if these particles get into wastewater exposure may not be short term. Therefore, we tested whether chronic exposure to different concentrations of carbon dots affects the growth, metamorphosis, and telomere length of Cuban tree frog (Osteopilus septentrionalis) tadpoles. We exposed 12 groups of five tadpoles each to different concentrations of carbon dots and a control for three months and tracked survival, growth and metamorphosis. We used carbon nitride dots approximately 2 nm in size at concentrations of 0.01 mg/ml and 0.02 mg/ml, known to interrupt development in zebrafish embryos. After three months, we measured telomere length from tissue samples. We found no difference in tadpole survivorship, growth, development rate, or telomere length among any of the groups, suggesting that carbon dots at these concentrations do not disrupt tadpole development.},
}
@article {pmid38242305,
year = {2024},
author = {Zhou, G and Chai, J and Li, Q and Sun, P and Wang, Y and Wu, J and Zhang, J and Li, Y and Dong, W and Zhang, C and Yu, F and Yan, X and Ba, Y},
title = {U-shaped relationship between ozone exposure and preterm birth risk associated with preconception telomere length.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {344},
number = {},
pages = {123366},
doi = {10.1016/j.envpol.2024.123366},
pmid = {38242305},
issn = {1873-6424},
mesh = {Infant, Newborn ; Female ; Pregnancy ; Humans ; *Premature Birth/chemically induced/epidemiology ; *Air Pollutants/toxicity ; Environmental Monitoring ; *Ozone/toxicity ; Telomere ; },
abstract = {There are conflicting findings regarding the association of ozone (O3) exposure with preterm birth (PTB) occurrence. In the present study, two cohorts were combined to explore the relationship between maternal O3 exposure during pregnancy and PTB risk, and analyze the underlying mechanisms of this relationship in terms of alterations in the preconception telomere length. Cohort 1 included mothers who participated in the National Free Preconception Health Examination Project in Henan Province from 2014 to 2018 along with their newborns (n = 1,066,696). Cohort 2 comprised mothers who conceived between 2016 and 2018 and their newborns (n = 1871) from six areas in Henan Province. The telomere length was assessed in the peripheral blood of mothers at the preconception stage. Data on air pollutant concentrations were collected from environmental monitoring stations and individual exposures were assessed using an inverse distance-weighted model. O3 concentrations (100.60 ± 14.13 μg/m[3]) were lower in Cohort 1 than in Cohort 2 (114.09 ± 15.17 μg/m[3]). Linear analyses showed that PTB risk decreased with increasing O3 exposure concentrations in Cohort 1 but increased with increasing O3 exposure concentrations in Cohort 2. Nonlinear analyses revealed that PTB risk tended to decrease and then increase with increasing O3 exposure concentrations in both cohorts. Besides, PTB risk was reduced by 88% for each-unit increase in telomere length in those exposed to moderate O3 concentrations (92.4-123.7 μg/m[3], P < 0.05). While no significant association was observed between telomere length and PTB at extreme O3 concentration exposure during entire pregnancy (<92.4 or >123.7 μg/m[3], P > 0.05) in Cohort 2. These findings reveal a nonlinear (U-shaped) relationship between O3 exposure and PTB risk. Furthermore, telomere with elevated length was associated with decreased risk of PTB only when exposed to moderate concentrations of O3, but not when exposed to extreme concentrations of O3 during pregnancy.},
}
@article {pmid38240992,
year = {2024},
author = {Papageorgakopoulou, MA and Bania, A and Lagogianni, IA and Birmpas, K and Assimakopoulou, M},
title = {The Role of Glia Telomere Dysfunction in the Pathogenesis of Central Nervous System Diseases.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {38240992},
issn = {1559-1182},
abstract = {Maintaining the telomere length is decisive for the viability and homeostasis process of all the cells of an organism, including human glial cells. Telomere shortening of microglial cells has been widely associated with the onset and progression of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Additionally, traumatic brain injury appears to have a positive correlation with the telomere-shortening process of microglia, and telomere length can be used as a non-invasive biomarker for the clinical management of these patients. Moreover, telomere involvement through telomerase reactivation and homologous recombination also known as the alternative lengthening of telomeres (ALT) has been described in gliomagenesis pathways, and particular focus has been given in the translational significance of these mechanisms in gliomas diagnosis and prognostic classification. Finally, glia telomere shortening is implicated in some psychiatric diseases. Given that telomere dysfunction of glial cells is involved in the central nervous system (CNS) disease pathogenesis, it represents a promising drug target that could lead to the incorporation of new tools in the medicinal arsenal for the management of so far incurable conditions.},
}
@article {pmid38238005,
year = {2024},
author = {Wong, JY and Blechter, B and Hubbard, AK and Machiela, MJ and Shi, J and Gadalla, SM and Hu, W and Rahman, ML and Rothman, N and Lan, Q},
title = {Phenotypic and genetically predicted leucocyte telomere length and lung cancer risk in the prospective UK Biobank.},
journal = {Thorax},
volume = {79},
number = {3},
pages = {274-278},
doi = {10.1136/thorax-2023-220076},
pmid = {38238005},
issn = {1468-3296},
mesh = {Humans ; *Lung Neoplasms/epidemiology/genetics ; Biological Specimen Banks ; Prospective Studies ; UK Biobank ; Telomere Homeostasis/genetics ; *Adenocarcinoma ; Leukocytes ; Telomere/genetics ; },
abstract = {We investigated phenotypic leucocyte telomere length (LTL), genetically predicted LTL (gTL), and lung cancer risk among 371 890 participants, including 2829 incident cases, from the UK Biobank. Using multivariable Cox regression, we found dose-response relationships between longer phenotypic LTL (p-trendcontinuous=2.6×10[-5]), longer gTL predicted using a polygenic score with 130 genetic instruments (p-trendcontinuous=4.2×10[-10]), and overall lung cancer risk, particularly for adenocarcinoma. The associations were prominent among never smokers. Mendelian Randomization analyses supported causal associations between longer telomere length and lung cancer (HRper 1 SD gTL=1.87, 95% CI: 1.49 to 2.36, p=4.0×10[-7]), particularly adenocarcinoma (HRper 1 SD gTL=2.45, 95%CI: 1.69 to 3.57, p=6.5×10[-6]).},
}
@article {pmid38237997,
year = {2024},
author = {Zhang, D and Adegunsoye, A and Oldham, JM and Wolters, PJ and Garcia, CK and Newton, CA},
title = {Reply: Telomere length and immunosuppression in non-idiopathic pulmonary fibrosis interstitial lung disease.},
journal = {The European respiratory journal},
volume = {63},
number = {1},
pages = {},
doi = {10.1183/13993003.02146-2023},
pmid = {38237997},
issn = {1399-3003},
mesh = {Humans ; *Pulmonary Fibrosis/genetics ; *Lung Diseases, Interstitial ; Immunosuppression Therapy ; Telomere ; },
}
@article {pmid38237995,
year = {2024},
author = {Mackintosh, JA and Chambers, DC},
title = {Telomere length and immunosuppression in non-idiopathic pulmonary fibrosis interstitial lung disease.},
journal = {The European respiratory journal},
volume = {63},
number = {1},
pages = {},
doi = {10.1183/13993003.01806-2023},
pmid = {38237995},
issn = {1399-3003},
mesh = {Humans ; *Pulmonary Fibrosis/genetics ; *Lung Diseases, Interstitial/genetics ; Immunosuppression Therapy ; Telomere ; },
}
@article {pmid38237857,
year = {2024},
author = {Das, A and Giri, AK and Bhattacharjee, P},
title = {Targeting 'histone mark': Advanced approaches in epigenetic regulation of telomere dynamics in cancer.},
journal = {Biochimica et biophysica acta. Gene regulatory mechanisms},
volume = {1867},
number = {1},
pages = {195007},
doi = {10.1016/j.bbagrm.2024.195007},
pmid = {38237857},
issn = {1876-4320},
mesh = {Animals ; *Histones/metabolism ; *Epigenesis, Genetic ; Histone Code/genetics ; Telomere/genetics/metabolism ; Carcinogenesis/genetics ; Mammals/genetics ; },
abstract = {Telomere integrity is required for the maintenance of genome stability and prevention of oncogenic transformation of cells. Recent evidence suggests the presence of epigenetic modifications as an important regulator of mammalian telomeres. Telomeric and subtelomeric regions are rich in epigenetic marks that regulate telomere length majorly through DNA methylation and post-translational histone modifications. Specific histone modifying enzymes play an integral role in establishing telomeric histone codes necessary for the maintenance of structural integrity. Alterations of crucial histone moieties and histone modifiers cause deregulations in the telomeric chromatin leading to carcinogenic manifestations. This review delves into the significance of histone modifications and their influence on telomere dynamics concerning cancer. Additionally, it highlights the existing research gaps that hold the potential to drive the development of therapeutic interventions targeting the telomere epigenome.},
}
@article {pmid38237741,
year = {2024},
author = {Saxena, P and Srivastava, J and Rai, B and Tripathy, NK and Raza, S and Sinha, RA and Gupta, R and Yadav, S and Nityanand, S and Chaturvedi, CP},
title = {Elevated senescence in the bone marrow mesenchymal stem cells of acquired aplastic anemia patients: A possible implication of DNA damage responses and telomere attrition.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {1870},
number = {3},
pages = {167025},
doi = {10.1016/j.bbadis.2024.167025},
pmid = {38237741},
issn = {1879-260X},
mesh = {Humans ; *Anemia, Aplastic/genetics/metabolism ; *Telomerase/genetics/metabolism ; *Mesenchymal Stem Cells/metabolism ; Telomere/genetics ; DNA Repair ; },
abstract = {BACKGROUND: Bone marrow mesenchymal stem cells (BM-MSC) are an integral part of the BM niche that is essential to maintain hematopoietic homeostasis. In aplastic anemia (AA), a few studies have reported phenotypic defects in the BM-MSC, such as reduced proliferation, imbalanced differentiation, and apoptosis; however, the alterations at the molecular level need to be better characterized. Therefore, the current study aims to identify the causative factors underlying the compromised functions of AA BM-MSC that might eventually be contributing to the AA pathobiology.<br><br>METHODS: We performed RNA sequencing (RNA-Seq) using the Illumina platform to comprehend the distinction between the transcriptional landscape of AA and control BM-MSC. Further, we validated the alterations observed in senescence by Senescence- associated beta-galactosidase (SA -&#x3b2;-gal) assay, DNA damage by &#x3b3;H2AX staining, and telomere attrition by relative telomere length assessment and telomerase activity assay. We used qRT-PCR to analyze changes in some of the genes associated with these molecular mechanisms.<br><br>RESULTS: The transcriptome profiling revealed enrichment of senescence-associated genes and pathways in AA BM-MSC. The senescent phenotype of AA BM-MSC was accompanied by enhanced SA -&#x3b2;-gal activity and elevated expression of senescence associated genes TP53, PARP1, and CDKN1A. Further, we observed increased &#x3b3;H2AX foci indicating DNA damage, reduced telomere length, and diminished telomerase activity in the AA BM-MSC.<br><br>CONCLUSION: Our results highlight that AA BM-MSC have a senescent phenotype accompanied by other cellular defects like DNA damage and telomere attrition, which are most likely driving the senescent phenotype of AA BM-MSC thus hampering their hematopoiesis supporting properties as observed in AA.},
}
@article {pmid38236501,
year = {2024},
author = {Bukic, E and Dragovic, G and Toljic, B and Obradovic, B and Jadzic, J and Jevtovic, D and Milasin, JM},
title = {TERT single nucleotide polymorphism rs2736098 but not rs2736100 is associated with telomere length in HIV-infected patients on cART.},
journal = {Molecular biology reports},
volume = {51},
number = {1},
pages = {147},
pmid = {38236501},
issn = {1573-4978},
support = {200110/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Humans ; Polymorphism, Single Nucleotide/genetics ; *Telomerase/genetics ; Cross-Sectional Studies ; *HIV Infections/drug therapy/genetics ; Telomere/genetics ; },
abstract = {BACKGROUND: Continuous application of "combination antiretroviral therapy" (cART) has transformed Human immunodeficiency virus (HIV) infection into a manageable chronic disease; however, due to lasting inflammation and cumulative toxicity, progressive pathophysiological changes do occur and potentially lead to accelerated aging, among others, contributing to telomere shortening. The single nucleotide polymorphisms (SNP) rs2736100 and rs2736098 are particularly important for human telomerase (TERT) gene expression. The objective of this study was to evaluate the effects of clinical parameters and single nucleotide polymorphisms in TERT (rs2736100 and rs2736098) on telomere length in HIV-infected patients.<br><br>METHODS AND RESULTS: This cross-sectional study included 176 patients diagnosed with HIV infection. Relative telomere length (RTL) was determined by real-time polymerase chain reaction (qPCR), whereas genotyping was performed by polymerase chain reaction, followed by restriction fragment length polymorphism analysis (PCR-RFLP). The mean age of the patients (p&#x2009;=&#x2009;.904), time since HIV diagnosis (p&#x2009;=&#x2009;.220), therapy-related variables such as the cART regimen (0.761), and total cART duration (p&#x2009;=&#x2009;.096) did not significantly affect RTL. TERT rs2736100 genotype showed no association with RTL. However, TERT rs2736098 heterozygotes (GA) had significantly longer telomeres (P&#x2009;=&#x2009;.049) than both homozygotes (GG and AA).<br><br>CONCLUSIONS: Our findings support the fact that cellular aging in HIV-infected patients is influenced by the TERT rs2736098 polymorphism.},
}
@article {pmid38235989,
year = {2024},
author = {Kuszel, L and Trzeciak, T and Begier-Krasinska, B and Richter, M and Li, J and Czarny-Ratajczak, M},
title = {Sex-specific differences in telomere length of patients with primary knee osteoarthritis.},
journal = {Journal of cellular and molecular medicine},
volume = {28},
number = {3},
pages = {e18107},
pmid = {38235989},
issn = {1582-4934},
support = {P20 GM103629/GM/NIGMS NIH HHS/United States ; P20GM103629/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; *Osteoarthritis, Knee ; Telomere Shortening ; Telomere ; Leukocytes ; Pain ; },
abstract = {Accelerated telomere shortening is associated with age-related diseases, including osteoarthritis (OA). We aimed to determine the relative telomere length (TL) in leukocytes and cartilage of patients with primary knee OA and to investigate factors that may affect TL in OA. Relative TL measurements were performed using qPCR in leukocytes of 612 individuals (310 patients with primary knee OA undergoing total knee arthroplasty (TKA) and 302 unaffected controls). We also analysed cartilage in 57 of the 310 OA patients, measuring relative TL in severely affected and less affected (control) cartilage collected from the same knee. Cartilage TLs were compared to leukocyte TLs in all 57 patients. A significant sex-by-disease-status interaction was found in regard to relative TL. Controlling for age, the average difference of leukocyte TL between female OA patients versus female controls was 0.217 units greater than that between male OA patients versus male controls (95% CI; [0.014, 0.421]). Relative TL comparison of severely and less affected cartilage samples from the same joint showed attrition of telomeres corresponding to disease severity (0.345 mean TL difference with 95% CI of [0.151, 0.539]) in the joint. We also noted that both severely and less affected cartilage had shorter telomeres than leukocytes collected from the same patient. Severe and moderate pain in OA patients was associated with shorter TL in leukocytes, but there was no association with depression or smoking in leukocytes and cartilage. Our study indicates that sex is an important factor in OA contributing to leukocyte and cartilage TL and that pain in OA shows an inverse association only with leukocyte TL.},
}
@article {pmid38230426,
year = {2024},
author = {Hansson, A and Wapstra, E and While, GM and Olsson, M},
title = {Sex and early-life conditions shape telomere dynamics in an ectotherm.},
journal = {The Journal of experimental biology},
volume = {227},
number = {3},
pages = {},
doi = {10.1242/jeb.246512},
pmid = {38230426},
issn = {1477-9145},
support = {F20-0401//Helge Ax:son Johnsons Stiftelse/ ; //Nilsson-Ehle Endowments/ ; //Herbert &amp; Karin Jacobssons Foundation/ ; //Vetenskapsradet/ ; //Australian Research Council/ ; //Vetenskapsr&#xe5;det/ ; //G&#xf6;teborgs Universitet/ ; },
mesh = {Humans ; Animals ; Male ; Female ; *Telomerase/genetics ; Longevity/genetics ; Telomere Shortening ; *Lizards/metabolism ; Telomere/genetics/metabolism ; Telomere Homeostasis ; },
abstract = {Telomeres, the repetitive DNA regions that protect the ends of chromosomes, and their shortening have been linked to key life history trade-offs among growth, reproduction and lifespan. In contrast to most endotherms, many ectotherms can compensate for telomere shortening throughout life by upregulation of telomerase in somatic tissues. However, during development, marked by rapid growth and an increased sensitivity to extrinsic factors, the upregulation of telomerase may be overwhelmed, resulting in long-term impacts on telomere dynamics. In ectotherms, one extrinsic factor that may play a particularly important role in development is temperature. Here, we investigated the influence of developmental temperature and sex on early-life telomere dynamics in an oviparous ectotherm, Lacerta agilis. While there was no effect of developmental temperature on telomere length at hatching, there were subsequent effects on telomere maintenance capacity, with individuals incubated at warm temperatures exhibiting less telomere maintenance compared with cool-incubated individuals. Telomere dynamics were also sexually dimorphic, with females having longer telomeres and greater telomere maintenance compared with males. We suggest that selection drives this sexual dimorphism in telomere maintenance, in which females maximise their lifetime reproductive success by investing in traits promoting longevity such as maintenance, while males invest in short-term reproductive gains through a polygynous mating behaviour. These early-life effects, therefore, have the potential to mediate life-long changes to life histories.},
}
@article {pmid38229191,
year = {2024},
author = {Koemel, NA and Laouali, N and Senior, AM and Celermajer, DS and Grech, A and Solon-Biet, SM and Simpson, SJ and Raubenheimer, D and Gill, TP and Skilton, MR},
title = {The Relationship between Dietary Macronutrient Composition and Telomere Length Among US Adults.},
journal = {Advanced biology},
volume = {},
number = {},
pages = {e2300619},
doi = {10.1002/adbi.202300619},
pmid = {38229191},
issn = {2701-0198},
support = {GNT1149976//National Health and Medical Research Council/ ; },
abstract = {The role of dietary macronutrients and energy intake in the aging process has been well-established. However, previous research has mainly focused on the association between leukocyte telomere length (LTL) and individual macronutrients, while the effects of macronutrient composition on LTL remain unclear. This cross-sectional analysis involved 4130 US adults (44.8 ± 17.0 years; 51% female) from the National Health and Nutrition Examination Survey during 1999-2002. A single 24-h dietary recall is used to collect dietary data. The relationship between dietary macronutrient composition and LTL wasexamined using three-dimensional generalized additive models. After adjustment for age, sex, ethnicity, education, physical activity, BMI, and dietary quality, a three-dimensional association of macronutrient composition with LTL (P = 0.02) is revealed. Diets lower in protein (5-10%), higher in carbohydrates (75%), and lower in fat (15-20%) are associated with the longest LTL corresponding to 7.7 years of slower biological aging. Diets lowest in protein (5%) and carbohydrate (40%), while highest in dietary fat (55%) are associated with the shortest LTL, corresponding to accelerated biological aging of 4.4 years. The associations appeared magnified with higher energy intake. These findings support a complex relationship between dietary macronutrients and biological aging independent of diet quality.},
}
@article {pmid38225981,
year = {2024},
author = {Lan, L and Leng, L and Liu, W and Ren, Y and Reeve, W and Fu, X and Wu, Z and Zhang, X},
title = {The haplotype-resolved telomere-to-telomere carnation (Dianthus caryophyllus) genome reveals the correlation between genome architecture and gene expression.},
journal = {Horticulture research},
volume = {11},
number = {1},
pages = {uhad244},
pmid = {38225981},
issn = {2662-6810},
abstract = {Carnation (Dianthus caryophyllus) is one of the most valuable commercial flowers, due to its richness of color and form, and its excellent storage and vase life. The diverse demands of the market require faster breeding in carnations. A full understanding of carnations is therefore required to guide the direction of breeding. Hence, we assembled the haplotype-resolved gap-free carnation genome of the variety 'Baltico', which is the most common white standard variety worldwide. Based on high-depth HiFi, ultra-long nanopore, and Hi-C sequencing data, we assembled the telomere-to-telomere (T2T) genome to be 564 479 117 and 568 266 215 bp for the two haplotypes Hap1 and Hap2, respectively. This T2T genome exhibited great improvement in genome assembly and annotation results compared with the former version. The improvements were seen when different approaches to evaluation were used. Our T2T genome first informs the analysis of the telomere and centromere region, enabling us to speculate about specific centromere characteristics that cannot be identified by high-order repeats in carnations. We analyzed allele-specific expression in three tissues and the relationship between genome architecture and gene expression in the haplotypes. This demonstrated that the length of the genes, coding sequences, and introns, the exon numbers and the transposable element insertions correlate with gene expression ratios and levels. The insertions of transposable elements repress expression in gene regulatory networks in carnation. This gap-free finished T2T carnation genome provides a valuable resource to illustrate the genome characteristics and for functional genomics analysis in further studies and molecular breeding.},
}
@article {pmid38225201,
year = {2024},
author = {Speer, H and McKune, AJ and Woodward, AP},
title = {The long and the short of it: Salivary telomere length as a candidate biomarker for hypertension and age-related changes in blood pressure.},
journal = {Physiological reports},
volume = {12},
number = {1},
pages = {e15910},
pmid = {38225201},
issn = {2051-817X},
mesh = {Female ; Humans ; Aged ; Blood Pressure ; Bayes Theorem ; *Hypertension/diagnosis ; Biomarkers ; Telomere ; Telomere Shortening ; },
abstract = {Hypertension becomes more prevalent with increasing age. Telomere length (TL) has been proposed as a candidate biomarker and can be accessibly extracted from saliva. However, clarity is needed to evaluate the suitability of using TL as a predictor in such instances. This study investigated salivary TL in a cohort of older adults from the 2008 Health and Retirement Study (n = 3329; F: 58%, mean age: 69.4, SD: 10.3 years) to examine any associations with blood pressure (BP). A Bayesian robust regression model was fit using weakly informative priors to predict the effects of TL with age, sex, systolic BP (SBP), diastolic BP (DBP), and treatment status. There were small effects of treatment (β: -0.07, 95% CrI [-0.33, 0.19], pd: 71.91%) and sex (β: -0.10, 95% CrI [-0.27, 0.07], pd: >86.78%). Population effects showed a reduction of 0.01 log2 units in TL with each year of advancing age (95% CrI [-0.01, -0.00]). Conditional posterior predictions suggest that females, and treated individuals, experience greater change in TL with increasing age. Bayes R[2] was ~2%. TL declines with increasing age, differs between sexes, and appears to be influenced by antihypertensive drugs. Overall, all effects were weak. The data do not currently support the suitability of salivary TL as a biomarker to predict or understand any age-related changes in BP.},
}
@article {pmid38224126,
year = {2024},
author = {Dong, T and Yu, P and Zhao, J and Wang, J},
title = {Site specifically probing the unfolding process of human telomere i-motif DNA using vibrationally enhanced alkynyl stretch.},
journal = {Physical chemistry chemical physics : PCCP},
volume = {26},
number = {5},
pages = {3857-3868},
doi = {10.1039/d3cp05328h},
pmid = {38224126},
issn = {1463-9084},
mesh = {Humans ; *DNA/chemistry ; Base Pairing ; Temperature ; *Telomere ; Cytosine/chemistry ; Nucleic Acid Conformation ; },
abstract = {The microscopic unfolding process of a cytosine-rich DNA forming i-motif by hemi-protonated base pairs is related to gene regulation. However, the detailed thermal unfolding mechanism and the protonation/deprotonation status of site-specific cytosine in DNA in a physiological environment are still obscure. To address this issue, a vibration-enhanced C(?)C probe tagged on 5'E terminal cytosine of human telomere i-motif DNA was examined using linear and nonlinear infrared (IR) spectroscopies and quantum-chemistry calculations. The C(?)C probe extended into the major groove of the i-motif was found using nonlinear IR results only to introduce a minor steric effect on both steady-state structure and local structure dynamics; however, its IR absorption profile effectively reports the cleavage of the hemi-protonated base pair of C1-C13 upon the unfolding with C1 remaining protonated. The temperature mid-point (Tm) of the local transition reported using the C(?)C tag was slightly lower than the Tm of global transition, and the enthalpy of the former exceeds 60% of the global transition. It is shown that the base-pair unraveling is noncooperative, with outer base pairs breaking first and being likely the rate limiting step. Our results offered an in-depth understanding of the macroscopic unfolding characteristics of the i-motif DNA and provided a nonlinear IR approach to monitoring the local structural transition and dynamics of DNA and its complexes.},
}
@article {pmid38223236,
year = {2024},
author = {Burenkova, OV and Naumova, OY and Church, JA and Juranek, J and Fletcher, JM and Grigorenko, EL},
title = {Associations between telomere length, glucocorticoid receptor gene DNA methylation, volume of stress-related brain structures, and academic performance in middle-school-age children.},
journal = {Comprehensive psychoneuroendocrinology},
volume = {17},
number = {},
pages = {100223},
pmid = {38223236},
issn = {2666-4976},
support = {P20 HD091005/HD/NICHD NIH HHS/United States ; P50 HD052117/HD/NICHD NIH HHS/United States ; },
abstract = {BACKGROUND: The biological embedding theory posits that early life experiences can lead to enduring physiological and molecular changes impacting various life outcomes, notably academic performance. Studying previously revealed and objective biomarkers of early life stress exposure, such as telomere length (TL), glucocorticoid receptor gene DNA methylation (DNAme), and the volume of brain structures involved in the regulation of HPA axis functioning (the hippocampus, the amygdala, and the medial prefrontal cortex), in relation to academic performance is crucial. This approach provides an objective measure that surpasses the limitations of self-reported early life adversity and reveals potential molecular and neurological targets for interventions to enhance academic outcomes.<br><br>METHODS: The participants were 52 children of Mexican or Central American origin aged 11.6-15.6 years. DNA methylation levels and TL were analyzed in three cell sources: saliva, whole blood, and T cells derived from whole blood.<br><br>RESULTS: Overall, the concordance across three systems of stress-related biomarkers (TL, DNAme, and the brain) was observed to some extent, although it was less pronounced than we expected; no consistency in different cell sources was revealed. Each of the academic domains that we studied was characterized by a unique and distinct complex of associations with biomarkers, both in terms of the type of biomarker, the directionality of the observed effects, and the cell source of biomarkers. Furthermore, there were biomarker-by-sex interaction effects in predicting academic performance measures.<br><br>CONCLUSIONS: Assessed in an understudied youth sample, these preliminary data present new essential evidence for a deepened understanding of the biological mechanisms behind associations between exposure to early life stress and academic performance.},
}
@article {pmid38219218,
year = {2024},
author = {Ma, B and Martínez, P and Sánchez-Vázquez, R and Blasco, MA},
title = {Telomere dynamics in human pluripotent stem cells.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/15384101.2023.2285551},
pmid = {38219218},
issn = {1551-4005},
abstract = {Pluripotent stem cells (PSCs) are a promising source of stem cells for regenerative therapies. Stem cell function depends on telomere maintenance mechanisms that provide them with the proliferative capacity and genome stability necessary to multiply and regenerate tissues. We show here that established human embryonic stem cells (hESCs) have stable telomere length that is dependent on telomerase but not on alternative mechanisms based on homologous recombination pathways. Here, we show that human-induced pluripotent stem cells (hiPSCs) reprogrammed from somatic cells show progressive telomere lengthening until reaching a length similar to ESCs. hiPSCs also acquire telomeric chromatin marks of ESCs including decreased abundance of tri-methylated histone H3K9 and H4K20 and HP1 heterochromatic marks, as well as of the shelterin component TRF2. These chromatin features are accompanied with increased abundance of telomere transcripts or TERRAs. We also found that telomeres of both hESCs and hiPSCs are well protected from DNA damage during telomere elongation and once full telomere length is achieved, and exhibit stable genomes. Collectively, this study highlights that hiPSCs acquire ESC features during reprogramming and reveals the telomere biology in human pluripotent stem cells (hPSCs).},
}
@article {pmid38214116,
year = {2024},
author = {Liu, X and Yuan, J and Liu, S and Wang, X and Tang, M and Meng, X and Li, Y and Chai, Y and Wang, Y and Tian, G and Liu, X and Zhou, H and Kou, C and Zhang, L and Yuan, Z and Zhang, H},
title = {The causal relationship between autoimmune thyroid disorders and telomere length: A Mendelian randomization and colocalization study.},
journal = {Clinical endocrinology},
volume = {100},
number = {3},
pages = {294-303},
doi = {10.1111/cen.15004},
pmid = {38214116},
issn = {1365-2265},
support = {82173624//National Natural Science Foundation of China/ ; 81872712//National Natural Science Foundation of China/ ; 82370793//National Natural Science Foundation of China/ ; 81670721//National Natural Science Foundation of China/ ; ZR2019ZD02//Natural Science Foundation of Shandong Province/ ; //Taishan Scholar Project of Shandong Province/ ; //Cheeloo Young Talent Program of Shandong University/ ; },
mesh = {Humans ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Graves Disease ; Telomere/genetics ; *Hypothyroidism/genetics ; *Thyroiditis, Autoimmune ; *Hashimoto Disease ; },
abstract = {This study aimed to evaluate whether there is a causal relationship between autoimmune thyroid disorders (AITDs) and telomere length (TL) in the European population and whether there is reverse causality. In this study, Mendelian randomization (MR) and colocalization analysis were conducted to assess the potential causal relationship between AITDs and TL using summary statistics from large-scale genome-wide association studies, followed by analysis of the relationship between TL and thyroid stimulating hormone and free thyroxine (FT4) to help interpret the findings. The inverse variance weighted (IVW) method was used to estimate the causal estimates. The weighted median, MR-Egger and leave-one-out methods were used as sensitivity analyses. The IVW method results showed a significant causal relationship between autoimmune hyperthyroidism and TL (β = -1.93 × 10[-2] ; p = 4.54 × 10[-5]). There was no causal relationship between autoimmune hypothyroidism and TL (β = -3.99 × 10[-3] ; p = 0.324). The results of the reverse MR analysis showed that genetically TL had a significant causal relationship on autoimmune hyperthyroidism (IVW: odds ratio (OR) = 0.49; p = 2.83 × 10[-4]) and autoimmune hypothyroidism (IVW: OR = 0.86; p = 7.46 × 10[-3]). Both horizontal pleiotropy and heterogeneity tests indicated the validity of our bidirectional MR study. Finally, colocalization analysis suggested that there were shared causal variants between autoimmune hyperthyroidism and TL, further highlighting the robustness of the results. In conclusion, autoimmune hyperthyroidism may accelerate telomere attrition, and telomere attrition is a causal factor for AITDs.},
}
@article {pmid38213617,
year = {2024},
author = {Lu, R and Nelson, CB and Rogers, S and Cesare, AJ and Sobinoff, AP and Pickett, HA},
title = {Distinct modes of telomere synthesis and extension contribute to Alternative Lengthening of Telomeres.},
journal = {iScience},
volume = {27},
number = {1},
pages = {108655},
pmid = {38213617},
issn = {2589-0042},
abstract = {Alternative lengthening of telomeres (ALT) is a homology-directed repair mechanism that becomes activated in a subset of cancers to maintain telomere length. One of the defining features of ALT cells is the prevalence of extrachromosomal telomeric repeat (ECTR) DNA. Here, we identify that ALT cells engage in two modes of telomere synthesis. Non-productive telomere synthesis occurs during the G2 phase of the cell cycle and is characterized by newly synthesized internal telomeric regions that are not retained in the subsequent G1, coinciding with an induction of ECTR DNA. Productive telomere synthesis occurs specifically during the transition from G2 to mitosis and is defined as the extension of the telomere termini. While many proteins associated with break-induced telomere synthesis function in both non-productive and productive telomere synthesis, POLH specifically promotes productive telomere lengthening and suppresses non-productive telomere synthesis. These findings delineate the mechanism and cell cycle regulation of ALT-mediated telomere synthesis and extension.},
}
@article {pmid38213291,
year = {2024},
author = {Barade, A and Lakshmi, KM and Korula, A and Abubacker, FN and Kulkarni, UP and Abraham, A and Mathews, V and George, B and Edison, ES},
title = {Comparison of telomere length in patients with bone marrow failure syndromes and healthy controls.},
journal = {European journal of haematology},
volume = {},
number = {},
pages = {},
doi = {10.1111/ejh.14173},
pmid = {38213291},
issn = {1600-0609},
support = {BT/PR17415/MED/12/724/2016//Department of Biotechnology, Ministry of Science and Technology, India/ ; },
abstract = {INTRODUCTION: During normal aging, telomeric DNA is gradually lost in dividing somatic cells, and critically short telomeres lead to replicative senescence, apoptosis, or chromosomal instability. We studied telomere length in bone marrow failure syndromes (BMFS) compared to normal healthy population.<br><br>METHODS: Peripheral blood was collected from the participants, and genomic DNA was extracted. Relative telomere length was measured using a quantitative polymerase chain reaction. Statistical analysis was performed using SPSS and GraphPad Prism 8.2 software.<br><br>RESULTS: The median age of normal Indian population was 31 (0-60) years. As expected, telomere length (TL) showed a decline with age and no difference in TL between males and females. The median age of 650 patients with aplastic anemia (AA) was 30 (1-60) years. TL was significantly shorter in patients with AA compared to healthy controls (p&#x2009;<&#x2009;.001). In FA and MDS patients, TL was significantly shorter than age-matched healthy controls (p&#x2009;=&#x2009;.028; p&#x2009;<&#x2009;.001), respectively. There was no difference between the median TL in age-matched AA and FA patients (p&#x2009;=&#x2009;.727). However, patients with MDS had shorter TL than age-matched AA (p&#x2009;=&#x2009;.031).<br><br>CONCLUSION: TL in BMF syndrome patients was significantly shorter than age-matched healthy controls.},
}
@article {pmid38205251,
year = {2024},
author = {Xue, J and Liu, Z and Liao, Y and Zhang, X and Liu, Y and Mo, L and Dong, R and Li, Q and Sun, X and Xie, J and Yang, P},
title = {Undersized telomeres in regulatory T cells link to the pathogenesis of allergic rhinitis.},
journal = {iScience},
volume = {27},
number = {1},
pages = {108615},
pmid = {38205251},
issn = {2589-0042},
abstract = {Telomeres are an important biomarker in the cell destiny. The relationship between telomeres and regulatory T cells (Tregs) has not yet been investigated. The objective of this study is to evaluate the link between Tregs' telomere length and allergic rhinitis (AR)'s pathogenesis. Here, we report that low telomerase activity and high endoplasmic reticulum stress status were observed in Tregs from AR patients, as shown in the results. Immune regulatory molecules levels were correlated with the length of Tregs' telomeres. The immune-suppressive functions of Tregs were associated with the telomere length/Telomerase reverse transcriptase/Telomerase protein component 1 status in Tregs. The levels of telomere length/telomerase in airway Tregs were reduced by sensitization. Endoplasmic reticulum stress signaling pathway of proline-rich receptor-like protein kinase-eukaryotic translation initiation factor 2A (eIF2a) was associated with the regulation of telomerase. Inhibiting eIF2a had an effect on upregulating telomerase activity in Tregs and mitigating experimental AR.},
}
@article {pmid38203842,
year = {2024},
author = {Vaquero-Sedas, MI and Vega-Palas, MA},
title = {A Nested PCR Telomere Fusion Assay Highlights the Widespread End-Capping Protection of Arabidopsis CTC1.},
journal = {International journal of molecular sciences},
volume = {25},
number = {1},
pages = {},
pmid = {38203842},
issn = {1422-0067},
support = {PID2020-115720GB-100//Ministerio de Ciencia e Innovaci&#xf3;n/ ; },
mesh = {*Arabidopsis/genetics ; In Situ Hybridization, Fluorescence ; Polymerase Chain Reaction ; Shelterin Complex ; *Telomere/genetics ; *Telomere-Binding Proteins/genetics ; *Arabidopsis Proteins/genetics ; },
abstract = {Telomeres protect the ends of linear eukaryotic chromosomes from being recognized as DNA double-strand breaks. Two major protein complexes are involved in the protection of telomeres: shelterin and CST. The dysfunction of these complexes can challenge the function of telomeres and lead to telomere fusions, breakage-fusion-bridge cycles, and cell death. Therefore, monitoring telomere fusions helps to understand telomeres biology. Telomere fusions are often analyzed by Fluorescent In Situ Hybridization (FISH) or PCR. Usually, both methods involve hybridization with a telomeric probe, which allows the detection of fusions containing telomeric sequences, but not of those lacking them. With the aim of detecting both types of fusion events, we have developed a nested PCR method to analyze telomere fusions in Arabidopsis thaliana. This method is simple, accurate, and does not require hybridization. We have used it to analyze telomere fusions in wild-type and mutant plants altered in CTC1, one of the three components of the Arabidopsis CST telomere capping complex. Our results show that null ctc1-2 mutant plants display fusions between all telomeric regions present in Arabidopsis chromosomes 1, 3 and 5, thus highlighting the widespread end-capping protection achieved by CTC1.},
}
@article {pmid38202757,
year = {2023},
author = {Xu, Y and Komiyama, M},
title = {G-Quadruplexes in Human Telomere: Structures, Properties, and Applications.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {1},
pages = {},
pmid = {38202757},
issn = {1420-3049},
mesh = {Humans ; *G-Quadruplexes ; Guanine ; RNA/genetics ; Telomere/genetics ; DNA/genetics ; },
abstract = {G-quadruplexes, intricate four-stranded structures composed of G-tetrads formed by four guanine bases, are prevalent in both DNA and RNA. Notably, these structures play pivotal roles in human telomeres, contributing to essential cellular functions. Additionally, the existence of DNA:RNA hybrid G-quadruplexes adds a layer of complexity to their structural diversity. This review provides a comprehensive overview of recent advancements in unraveling the intricacies of DNA and RNA G-quadruplexes within human telomeres. Detailed insights into their structural features are presented, encompassing the latest developments in chemical approaches designed to probe these G-quadruplex structures. Furthermore, this review explores the applications of G-quadruplex structures in targeting human telomeres. Finally, the manuscript outlines the imminent challenges in this evolving field, setting the stage for future investigations.},
}
@article {pmid38198169,
year = {2024},
author = {Koh, JYP and Li, S and Koh, AS},
title = {Precision Measurement of Telomere Length as a Future Guide to Improve CVD Interventions.},
journal = {JAMA cardiology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamacardio.2023.5006},
pmid = {38198169},
issn = {2380-6591},
}
@article {pmid38194261,
year = {2024},
author = {Sánchez-González, JL and Sánchez-Rodríguez, JL and Varela-Rodríguez, S and González-Sarmiento, R and Rivera-Picón, C and Juárez-Vela, R and Tejada-Garrido, CI and Martín-Vallejo, J and Navarro-López, V},
title = {Effects of Physical Exercise on Telomere Length in Healthy Adults: Systematic Review, Meta-Analysis, and Meta-Regression.},
journal = {JMIR public health and surveillance},
volume = {10},
number = {},
pages = {e46019},
pmid = {38194261},
issn = {2369-2960},
mesh = {Adult ; Humans ; Databases, Factual ; *Exercise ; *Health Status ; Telomere ; },
abstract = {BACKGROUND: Physical exercise is one of the main nonpharmacological treatments for most pathologies. In addition, physical exercise is beneficial in the prevention of various diseases. The impact of physical exercise has been widely studied; however, existing meta-analyses have included diverse and heterogeneous samples. Therefore, to our knowledge, this is the first meta-analysis to evaluate the impact of different physical exercise modalities on telomere length in healthy populations.<br><br>OBJECTIVE: In this review, we aimed to determine the effect of physical exercise on telomere length in a healthy population through a meta-analysis of randomized controlled trials.<br><br>METHODS: A systematic review with meta-analysis and meta-regression of the published literature on the impact of physical exercise on telomere length in a healthy population was performed. PubMed, Cochrane Library, SCOPUS, Web of Science, and Embase databases were searched for eligible studies. Methodological quality was evaluated using the Risk Of Bias In Nonrandomized Studies of Interventions and the risk-of-bias tool for randomized trials. Finally, the certainty of our findings (closeness of the estimated effect to the true effect) was evaluated using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE).<br><br>RESULTS: We included 9 trials that met the inclusion criteria with fair methodological quality. Random-effects model analysis was used to quantify the difference in telomere length between the exercise and sham groups. Meta-analysis showed that exercise did not significantly increase telomere length compared with the control intervention (mean difference=0.0058, 95% CI -0.05 to 0.06; P=.83). Subgroup analysis suggested that high-intensity interventional exercise significantly increased telomere length compared with the control intervention in healthy individuals (mean difference=0.15, 95% CI 0.03-0.26; P=.01). Furthermore, 56% of the studies had a high risk of bias. Certainty was graded from low to very low for most of the outcomes.<br><br>CONCLUSIONS: The findings of this systematic review and meta-analysis suggest that high-intensity interval training seems to have a positive effect on telomere length compared with other types of exercise such as resistance training or aerobic exercise in a healthy population.<br><br>TRIAL REGISTRATION: PROSPERO CRD42022364518; http://tinyurl.com/4fwb85ff.},
}
@article {pmid38192544,
year = {2024},
author = {Farrukh, S and Baig, S and Hussain, R and Imad, R and Kulsoom, O and Yousaf Rana, M},
title = {Identification of polymorphic alleles in TERC and TERT gene reprogramming the telomeres of newborn and legacy with parental health.},
journal = {Saudi journal of biological sciences},
volume = {31},
number = {2},
pages = {103897},
pmid = {38192544},
issn = {1319-562X},
abstract = {Telomere and telomerase genes (TERC and TERT) highlighted many novel genetic polymorphisms related to common diseases. This study explored the polymorphic alleles of TERC and TERT gene in parents-newborn (triad) and its association with telomere length (TL) and parental diseases (mother: Gestational Diabetes Mellitus (GDM), Preeclampsia, fathers: Diabetes, Hypertension). In this cross-sectional study, the blood samples (n = 612) were collected from parents-newborn triad (204 each) for TL (T/S ratio) quantification by using qPCR, and gene (TERC and TERT) polymorphism was detected by Sanger sequencing. The correlation analysis was used to find an association between paternal TL (T/S ratio) and newborn TL. The multivariate linear regression was applied to determine the effect of parents genes and diseases on newborn TL. A positive association (r = 0.42,0.39) (p < 0.0001) among parents and newborn TL was observed. In the diseased group, both TERC (rs10936599) and TERT (rs2736100) genes had a high frequency of allele C in newborns (OR = 0.94, P = 0.90, OR = 4.24, P = 0.012). However, among parents, TERT gene [Mother CC (B = 0.575; P = 0.196), Father CC (B = -0.739; P = 0.071)] was found significant contributing factor for Newborn TL. Diseased parents with T/T and A/C genotypes had longer newborn TL (2.82 ± 2.43, p < 0.022; 1.80 ± 1.20, p < 0.00) than the C/C genotype. Therefore, the study, confirmed that major allele C of TERC and TERT genes is associated with smaller TL in diseased parents-newborns of the targeted population.},
}
@article {pmid38190874,
year = {2024},
author = {Li, R and Wang, J and Wang, Y and Lin, X and Sun, C and Xu, L},
title = {Telomere length as a modifier in the relationship between phthalate metabolites exposure and glucose homeostasis.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {344},
number = {},
pages = {123309},
doi = {10.1016/j.envpol.2024.123309},
pmid = {38190874},
issn = {1873-6424},
mesh = {Environmental Exposure ; Nutrition Surveys ; Bayes Theorem ; Cross-Sectional Studies ; *Phthalic Acids/metabolism ; Glucose ; Homeostasis ; Telomere ; *Insulins ; *Environmental Pollutants/analysis ; },
abstract = {Given the rising concern over the potential impact of environmental factors on metabolic heath, we conducted a cross-sectional analysis among 645 adults aged 20 and older in the National Health and Nutrition Examination Survey (NHANES), examining the association between nine phthalate metabolites (Mono-n-butyl phthalate (MBP), Mono-ethyl phthalate (MEP), Mono-(2-ethyl)-hexyl phthalate (MEHP), Mono-benzyl phthalate (MBzP), Mono-n-methyl phthalate (MnMP), Mono-(3-carboxy propyl) phthalate (MCPP), Mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), Mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), Mono-isobutyl phthalate (MiBP)) and six glucose homeostasis indices (fasting glucose, fasting insulin, hemoglobin A1C (HbA1C), homeostatic model assessment of insulin resistance (HOMA-IR), single Point Insulin Sensitivity Estimator (SPISE), and HOMA-β). Latent Class Analysis identified three phthalate metabolites exposure patterns: high MEP-low MEOHP (n = 282), high MBzP-low MEHHP (n = 214), and high MEHHP, MEOHP (n = 149). The high MBzP-low MEHHP and high MEHHP, MEOHP, versus the high MEP-low MEOHP, exposure groups showed significantly higher levels of fasting insulin (β = 0.126, 95% CI: 0.023-0.228), SPISE (β = 0.091, 95% CI: 0.018-0.164), and HOMA-IR (β = 0.091, 95% CI: 0.018-0.164). In the shorter telomere length group, high MEHHP, MEOHP exposure showed an increase in SPISE levels (β = 0.153, 95% CI: 0.037-0.269), while in the overweight/obese subgroup, high MEHHP, MEOHP exposure was significantly positively associated with HOMA-IR (β = 0.392, 95% CI: 0.150-0.735). Bayesian kernel machine regression analyses showed positive associations between higher combined phthalate exposure and increased glucose homeostasis indices (fasting glucose, HbA1C, fasting insulin, SPISE, and HOMA-IR). The quantile of g-calculation analysis also supported the positive associations with HbA1C, HOMA-IR, and fasting insulin. Our findings indicate that phthalate exposure was positively associated with glucose homeostasis indices, which strengthen the call for proactive measures to reduce phthalate exposure and mitigate potential risks to glucose metabolism.},
}
@article {pmid38189870,
year = {2023},
author = {Kurashova, NA and Dashiev, BG and Kolesnikov, SI and Kolesnikova, LI},
title = {Oxidative Stress, Telomere Length and Telomerase Activity in Spermatogenesis Disorders (Review of Scientific Activity).},
journal = {Bulletin of experimental biology and medicine},
volume = {176},
number = {2},
pages = {115-122},
pmid = {38189870},
issn = {1573-8221},
mesh = {Humans ; Male ; *Infertility, Male/genetics ; Oxidative Stress/genetics ; Spermatogenesis/genetics ; *Telomerase/genetics ; Telomere/genetics/metabolism ; },
abstract = {The paper systematizes the available data on the study of oxidative stress, the relative length of telomeres, and telomerase activity in male infertility and disorders of spermatogenesis. The study of telomeres, the structures that protect chromosome ends and genome integrity, is of interest for researchers in various fields, from cell biology and epidemiology to ecology and evolutionary biology. The review includes our own data on the study of the relative length of telomeres, oxidative stress, and telomerase activity and reflects modern ideas about the importance of these structures both in the maintenance of genome stability during cell division and in gametogenesis and reproduction. Many studies indicate the role of oxidative stress in the pathogenesis of various diseases, including male infertility. In turn, studies of telomeres as a biomarker of male infertility are insufficient, and the results obtained are extremely controversial and require deeper knowledge about the mechanisms underlying the dynamics of telomere length.},
}
@article {pmid38187739,
year = {2024},
author = {Karimian, K and Groot, A and Huso, V and Kahidi, R and Tan, KT and Sholes, S and Keener, R and McDyer, JF and Alder, JK and Li, H and Rechtsteiner, A and Greider, CW},
title = {Human telomere length is chromosome specific and conserved across individuals.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38187739},
support = {R35 CA209974/CA/NCI NIH HHS/United States ; T32 GM133391/GM/NIGMS NIH HHS/United States ; },
abstract = {Short telomeres cause age-related disease and long telomeres predispose to cancer; however, the mechanisms regulating telomere length are unclear. To probe these mechanisms, we developed a nanopore sequencing method, Telomere Profiling, that is easy to implement, precise, and cost effective with broad applications in research and the clinic. We sequenced telomeres from individuals with short telomere syndromes and found similar telomere lengths to the clinical FlowFISH assay. We mapped telomere reads to specific chromosome end and identified both chromosome end-specific and haplotype-specific telomere length distributions. In the T2T HG002 genome, where the average telomere length is 5kb, we found a remarkable 6kb difference in lengths between some telomeres. Further, we found that specific chromosome ends were consistently shorter or longer than the average length across 147 individuals. The presence of conserved chromosome end-specific telomere lengths suggests there are new paradigms in telomere biology that are yet to be explored. Understanding the mechanisms regulating length will allow deeper insights into telomere biology that can lead to new approaches to disease.},
}
@article {pmid38181239,
year = {2024},
author = {Zhang, Y and Wang, J and Zheng, M and Qu, H and Yang, S and Han, F and Yao, N and Li, W and Qu, J},
title = {Causal association between telomere length and colorectal polyps: A bidirectional two-sample Mendelian randomization study.},
journal = {Medicine},
volume = {103},
number = {1},
pages = {e36867},
pmid = {38181239},
issn = {1536-5964},
mesh = {Humans ; *Colonic Polyps/genetics ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Causality ; Telomere ; },
abstract = {We performed a bidirectional 2-sample Mendelian randomization (MR) design to explore the causal relation between telomere length (TL) and colorectal polyps. Genome-wide association study summary data of TL and colorectal polyps were extracted from the IEU open genome-wide association study database. Single nucleotide polymorphisms were served as instrumental variables at the significance threshold of P < 5 × 10-8. The inverse variance weighted method, MR-Egger method, and weight median method were performed for causal estimation in MR. Cochran Q test, MR-Egger intercept test, and leave-one-out analyses were performed to evaluate the pleiotropy of the MR results. One hundred and twenty-four single nucleotide polymorphisms were selected as instrumental variables. We found significant casual association between TL and colorectal polyps. Long TL increased the risk of colorectal polyps using the inverse variance weighted method [ukb-a-521: odds ratio (OR): 1.004, 95% confidence interval (CI): 1.001-1.007, P = .004; ukb-d-D12: OR: 1.008, CI: 1.004-1.012, P < .001; finn-b-CD2_BENIGN_COLORECANI_EXALLC2: OR: 1.170, CI: 1.027-1.332, P = .018]. Sensitivity analyses validated that the causality between TL and colorectal polyps was robust. The study provided a causal association between TL and colorectal polyps which indicated that TL might be served as a potential biomarker of colorectal polyps for screening and prevention. Nonetheless, the conclusions need further validation.},
}
@article {pmid38180812,
year = {2024},
author = {Vaid, R and Thombare, K and Mendez, A and Burgos-Panadero, R and Djos, A and Jachimowicz, D and Lundberg, KI and Bartenhagen, C and Kumar, N and Tümmler, C and Sihlbom, C and Fransson, S and Johnsen, JI and Kogner, P and Martinsson, T and Fischer, M and Mondal, T},
title = {METTL3 drives telomere targeting of TERRA lncRNA through m6A-dependent R-loop formation: a therapeutic target for ALT-positive neuroblastoma.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkad1242},
pmid = {38180812},
issn = {1362-4962},
support = {2018-02224//Swedish Research Council/ ; 22-2341//Cancerfonden/ ; PR 2019-077//Barncancerfonden/ ; //Svenska L&#xe4;kares&#xe4;llskapet/ ; //&#xc5;ke Wibergs Stiftelse/ ; //Kungl Vetenskaps- och Vitterhets-Samh&#xe4;llet/ ; TJ 2019-0077//Barncancerfonden/ ; 23-0753 PT//Cancerfonden/ ; //Tore Nilsons Stiftelse and Bollan scholarship/ ; //Assar Gabrielsson Fond/ ; },
abstract = {Telomerase-negative tumors maintain telomere length by alternative lengthening of telomeres (ALT), but the underlying mechanism behind ALT remains poorly understood. A proportion of aggressive neuroblastoma (NB), particularly relapsed tumors, are positive for ALT (ALT+), suggesting that a better dissection of the ALT mechanism could lead to novel therapeutic opportunities. TERRA, a long non-coding RNA (lncRNA) derived from telomere ends, localizes to telomeres in a R-loop-dependent manner and plays a crucial role in telomere maintenance. Here we present evidence that RNA modification at the N6 position of internal adenosine (m6A) in TERRA by the methyltransferase METTL3 is essential for telomere maintenance in ALT+ cells, and the loss of TERRA m6A/METTL3 results in telomere damage. We observed that m6A modification is abundant in R-loop enriched TERRA, and the m6A-mediated recruitment of hnRNPA2B1 to TERRA is critical for R-loop formation. Our findings suggest that m6A drives telomere targeting of TERRA via R-loops, and this m6A-mediated R-loop formation could be a widespread mechanism employed by other chromatin-interacting lncRNAs. Furthermore, treatment of ALT+ NB cells with a METTL3 inhibitor resulted in compromised telomere targeting of TERRA and accumulation of DNA damage at telomeres, indicating that METTL3 inhibition may represent a therapeutic approach for ALT+ NB.},
}
@article {pmid38180375,
year = {2023},
author = {Maximov, VN and Ivanova, AA and Orlov, PS and Titarenko, AV and Maksimova, SV and Simonova, GI and Chervova, OA and Voevoda, MI and Malyutina, SK},
title = {[The relationship between the relative length of leukocyte telomeres and mtDNA copy number and acute coronary syndrome in a 15-year follow-up.].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {36},
number = {5},
pages = {748-755},
pmid = {38180375},
issn = {1561-9125},
mesh = {Aged ; Humans ; Middle Aged ; DNA, Mitochondrial/genetics ; *Acute Coronary Syndrome ; DNA Copy Number Variations ; Follow-Up Studies ; Telomere/genetics ; Leukocytes ; *Neoplasms ; },
abstract = {to study the association of relative leukocyte DNA telomere length with death from natural causes during a 15-year follow-up in a middle-aged and elderly Siberian population. Study of the association of the relative length of leukocyte telomeres (LTL) with fatal outcomes during a 15-year follow-up of a random population sample formed in 2003-2005 (n=9 360, 45-69 years old, Novosibirsk, HAPIEE project). The main group included the persons died from natural causes (except external) without a previous history of CVD and cancer (n=609); controls were stratified by sex and age (n=799). The analysis of relative LTL at baseline was performed using quantitative real-time PCR. We estimated the odds ratio of all-cause death per 1 decile shortening of LTD as a continuous variable in a multivariable-adjusted logistic regression. The carriers of shorter telomere carriers had an increased risk of death from natural causes over the next 15 years (OR=1,37, 95% CI 1,31-1,44) per decile of LTL decrease, regardless of other factors. The risk coefficients were similar for death from CVD (1,39), cancer (1,42), and other non-external causes (1,51). In studied middle-aged and elderly Siberian (Caucasoid) population cohort the LTL was an independent inverse predictor of the 15-year risk of death from natural causes.},
}
@article {pmid38176734,
year = {2024},
author = {Bertrand, A and Ba, I and Kermasson, L and Pirabakaran, V and Chable, N and Lainey, E and Ménard, C and Kallel, F and Picard, C and Hadiji, S and Coolen-Allou, N and Blanchard, E and de Villartay, JP and Moshous, D and Roelens, M and Callebaut, I and Kannengiesser, C and Revy, P},
title = {Characterization of novel mutations in the TEL-patch domain of the telomeric factor TPP1 associated with telomere biology disorders.},
journal = {Human molecular genetics},
volume = {},
number = {},
pages = {},
doi = {10.1093/hmg/ddad210},
pmid = {38176734},
issn = {1460-2083},
support = {ANR-10-IAHU-01//Agence Nationale de la Recherche/ ; //Fondation de la recherche m&#xe9;dicale/ ; //Centre National de la Recherche Scientifique/ ; },
abstract = {Telomeres are nucleoprotein structures that protect the chromosome ends from degradation and fusion. Telomerase is a ribonucleoprotein complex essential to maintain the length of telomeres. Germline defects that lead to short and/or dysfunctional telomeres cause telomere biology disorders (TBDs), a group of rare and heterogeneous Mendelian diseases including pulmonary fibrosis, dyskeratosis congenita, and Høyeraal-Hreidarsson syndrome. TPP1, a telomeric factor encoded by the gene ACD, recruits telomerase at telomere and stimulates its activity via its TEL-patch domain that directly interacts with TERT, the catalytic subunit of telomerase. TBDs due to TPP1 deficiency have been reported only in 11 individuals. We here report four unrelated individuals with a wide spectrum of TBD manifestations carrying either heterozygous or homozygous ACD variants consisting in the recurrent and previously described in-frame deletion of K170 (K170∆) and three novel missense mutations G179D, L184R, and E215V. Structural and functional analyses demonstrated that the four variants affect the TEL-patch domain of TPP1 and impair telomerase activity. In addition, we identified in the ACD gene several motifs associated with small deletion hotspots that could explain the recurrence of the K170∆ mutation. Finally, we detected in a subset of blood cells from one patient, a somatic TERT promoter-activating mutation that likely provides a selective advantage over non-modified cells, a phenomenon known as indirect somatic genetic rescue. Together, our results broaden the genetic and clinical spectrum of TPP1 deficiency and specify new residues in the TEL-patch domain that are crucial for length maintenance and stability of human telomeres in vivo.},
}
@article {pmid38171574,
year = {2024},
author = {Sakamoto, Y and Shiraishi, K and Kodama, S},
title = {Enhanced induction of abnormal telomere FISH signals in response to oxidative DNA damage.},
journal = {Journal of radiation research},
volume = {},
number = {},
pages = {},
doi = {10.1093/jrr/rrad102},
pmid = {38171574},
issn = {1349-9157},
support = {JP24651051//Japan Society for the Promotion of Science London/ ; },
abstract = {Telomere dysfunction induces chromosomal instability, which is a driving force in the development of cancers. To examine X-irradiation's effect on telomere integrity, we investigated X-ray-induced abnormalities in telomere signals detected by fluorescence in situ hybridization (telomere FISH) in mouse embryo fibroblast cells. The abnormalities were categorized as either extra telomere signals (ETSs) or loss of telomere signals (LTSs). The results indicated that low doses (0.3-0.5 Gy) of X-rays significantly induced ETS but not LTS and that ETS induction was saturated at doses above 0.5 Gy. In addition, treatment with hydrogen peroxide also induced ETS but not LTS. To clarify the involvement of radicals in inducing ETS, we examined the effect of ascorbic acid (AsA) on telomere FISH signals and found that pre-treatment with AsA (5 mM, 2 h), but not post-treatment, significantly suppressed the induction of ETS by X-irradiation. Importantly, neither pre- nor post-treatment with AsA affected X-ray-induced chromosome aberrations. These results suggest that oxidative DNA damage induced by radicals is involved in the induction of ETS. Furthermore, combined treatment with aphidicolin, a DNA replication inhibitor, elevated the induction of ETS by X-irradiation. This observation suggests that DNA replication stress, potentially triggered by oxidative DNA lesions within telomeres, may contribute to the induction of ETS resulting from X-irradiation. Based on these results, we propose that ETS is a sensitive biological marker of oxidative DNA damage in telomere structures.},
}
@article {pmid38167290,
year = {2024},
author = {Muyas, F and Rodriguez, MJG and Cascão, R and Afonso, A and Sauer, CM and Faria, CC and Cortés-Ciriano, I and Flores, I},
title = {The ALT pathway generates telomere fusions that can be detected in the blood of cancer patients.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {82},
pmid = {38167290},
issn = {2041-1723},
support = {/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Humans ; Telomere Homeostasis/genetics ; *Telomerase/genetics/metabolism ; *Neoplasms/genetics ; Telomere/genetics/metabolism ; Genomics ; },
abstract = {Telomere fusions (TFs) can trigger the accumulation of oncogenic alterations leading to malignant transformation and drug resistance. Despite their relevance in tumour evolution, our understanding of the patterns and consequences of TFs in human cancers remains limited. Here, we characterize the rates and spectrum of somatic TFs across >30 cancer types using whole-genome sequencing data. TFs are pervasive in human tumours with rates varying markedly across and within cancer types. In addition to end-to-end fusions, we find patterns of TFs that we mechanistically link to the activity of the alternative lengthening of telomeres (ALT) pathway. We show that TFs can be detected in the blood of cancer patients, which enables cancer detection with high specificity and sensitivity even for early-stage tumours and cancers of high unmet clinical need. Overall, we report a genomic footprint that enables characterization of the telomere maintenance mechanism of tumours and liquid biopsy analysis.},
}
@article {pmid38166713,
year = {2024},
author = {Zhao, XX and Bai, LL},
title = {Correlation between telomere shortening in maternal peripheral blood and fetal aneuploidy.},
journal = {BMC pregnancy and childbirth},
volume = {24},
number = {1},
pages = {2},
pmid = {38166713},
issn = {1471-2393},
support = {81660542//This work was supported by the Natural Science Foundation of China/ ; 2018MS08091//the Inner Mongolia Natural Science Fund/ ; },
mesh = {Female ; Humans ; *Trisomy/diagnosis/genetics ; *Down Syndrome/diagnosis/genetics ; Telomere Shortening ; Aneuploidy ; Fetus ; Fetal Blood ; },
abstract = {BACKGROUND: This study aimed to assess whether maternal telomere length is a more accurate predictor of trisomy 21 than maternal age while also exploring the factors influencing maternal and fetal telomere length.<br><br>METHODS: Forty mothers with fetuses carrying extra maternal copies of chromosome 21 were defined as trisomy 21 cases, and 18 mothers with normal karyotype fetuses were defined as controls. Telomere lengths of maternal blood lymphocytes and amniotic fluid cells were determined using real-time polymerase chain reaction. Fetal and maternal telomere lengths were compared between the two groups. Moreover, we analyzed the factors influencing maternal and fetal telomere length in the trisomy 21 pedigree. A logistic regression model was used to analyze the correlation between maternal telomere length and trisomy 21 risk. In addition, receiver operating characteristic (ROC) curve analysis was used to determine the accuracy of using maternal telomere length as an indicator of trisomy 21 risk.<br><br>RESULTS: The study revealed that both maternal and fetal telomere lengths were significantly shorter in trisomy 21 cases than in the controls. In the trisomy 21 group, the maternal age, occupation, and nationality showed no significant correlation with their telomere length; fetal telomere length exhibited a positive correlation with maternal telomere length. Furthermore, maternal telomere length shortening is associated with trisomy 21 (OR&#x2009;=&#x2009;0.311; 95% CI, 0.109-0.885, P&#x2009;<&#x2009;0.05). The results of ROC curve analysis indicated that a combined assessment of maternal age and maternal telomere length predicted fetal chromosome trisomy more effectively than a single assessment (area under the curve 0.808, 95% CI, 0.674-0.941, P&#x2009;<&#x2009;0.001).<br><br>CONCLUSION: Maternal age combined with maternal telomere length proved to be a superior predictor of trisomy risk. Additionally, maternal telomere length was found to influence fetal telomere length.},
}
@article {pmid38166034,
year = {2024},
author = {Wang, D and Li, C and Zhang, X and Li, Y and He, J and Guo, X},
title = {Leukocyte telomere length and sarcopenia-related traits: A bidirectional Mendelian randomization study.},
journal = {PloS one},
volume = {19},
number = {1},
pages = {e0296063},
pmid = {38166034},
issn = {1932-6203},
mesh = {Humans ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Sarcopenia/genetics ; Leukocytes ; Telomere/genetics ; *Diabetes Mellitus, Type 2 ; },
abstract = {Accumulating evidence indicated that leukocyte telomere length (LTL) was related to sarcopenia. However, it is still not clear whether the association of changes in LTL with sarcopenia is likely to be causal, or could be explained by reverse causality. Thus, we carried on bidirectional Mendelian randomization (MR) and multivariable MR analyses to identify the causal relationship between LTL and sarcopenia-related traits. Summary-level data and independent variants used as instruments came from large genome-wide association studies of LTL (472,174 participants), appendicular lean mass (450,243 participants), low grip strength (256,523 participants), and walking pace (450,967 participants). We identified suggestive association of longer LTL with larger appendicular lean mass [odds ratio (OR) = 1.053; 95% confidence interval (CI), 1.009-1.099; P = 0.018], and causal association of longer LTL with a lower risk of low grip strength (OR = 0.915; 95% CI, 0.860-0.974; P = 0.005). In the reverse MR analysis, we also observed a positive causal association between walking pace and LTL (OR = 1.252; 95% CI, 1.121-1.397; P < 0.001). Similar results can be repeated in sensitivity analyses. While in the multivariable MR analysis, the estimate of the impact of walking pace on LTL underwent a transformation after adjusting for T2DM (OR = 1.141; 95%CI: 0.989-1.317; P = 0.070). The current MR analysis supported a causal relationship between shorter telomere length and both low muscle mass and strength. Additionally, walking pace may affect LTL through T2DM.},
}
@article {pmid38165952,
year = {2024},
author = {Piani, LL and Reschini, M and Somigliana, E and Ferrari, S and Busnelli, A and Viganò, P and Favero, C and Albetti, B and Hoxha, M and Bollati, V},
title = {Correction: Peripheral mitochondrial DNA, telomere length and DNA methylation as predictors of live birth in in vitro fertilization cycles.},
journal = {PloS one},
volume = {19},
number = {1},
pages = {e0296603},
pmid = {38165952},
issn = {1932-6203},
abstract = {[This corrects the article DOI: 10.1371/journal.pone.0261591.].},
}
@article {pmid38165506,
year = {2024},
author = {Tire, B and Talibova, G and Ozturk, S},
title = {The crosstalk between telomeres and DNA repair mechanisms: an overview to mammalian somatic cells, germ cells, and preimplantation embryos.},
journal = {Journal of assisted reproduction and genetics},
volume = {41},
number = {2},
pages = {277-291},
pmid = {38165506},
issn = {1573-7330},
mesh = {Humans ; Animals ; Male ; Female ; *DNA Repair/genetics ; *Telomere/genetics ; DNA Damage ; Germ Cells ; Blastocyst ; Mammals ; },
abstract = {Telomeres are located at the ends of linear chromosomes and play a critical role in maintaining genomic stability by preventing premature activation of DNA repair mechanisms. Because of exposure to various genotoxic agents, telomeres can undergo shortening and genetic changes. In mammalian cells, the basic DNA repair mechanisms, including base excision repair, nucleotide excision repair, double-strand break repair, and mismatch repair, function in repairing potential damages in telomeres. If these damages are not repaired correctly in time, the unfavorable results such as apoptosis, cell cycle arrest, and cancerous transition may occur. During lifespan, mammalian somatic cells, male and female germ cells, and preimplantation embryos experience a number of telomeric damages. Herein, we comprehensively reviewed the crosstalk between telomeres and the DNA repair mechanisms in the somatic cells, germ cells, and embryos. Infertility development resulting from possible defects in this crosstalk is also discussed in the light of existing studies.},
}
@article {pmid38163559,
year = {2024},
author = {Li, C and Yang, J and Chu, L and Tian, J and Xiao, J and Huang, Y and Wang, Q and Guo, B and Huang, L and Hu, Y and Luo, Y},
title = {The function of Bazhen decoction in rescuing progeroid cell senescence via facilitating G-quadruplex resolving and telomere elongation.},
journal = {Journal of ethnopharmacology},
volume = {323},
number = {},
pages = {117694},
doi = {10.1016/j.jep.2023.117694},
pmid = {38163559},
issn = {1872-7573},
mesh = {Animals ; Mice ; *Werner Syndrome/genetics ; DNA Damage ; Telomere ; Cellular Senescence ; DNA Helicases/genetics ; },
abstract = {The Bazhen decoction is one of the most extensively used Traditional Chinese medicine (TCM) prescriptions for treatment of aging related diseases. However, due to the complexity of the components, the pharmacological mechanism of Bazhen decoction is still limited.<br><br>AIM OF THE STUDY: In this study, with the aim of helping the clinical precision medicine of TCM, we try out a systematic analysis for dissecting the molecular mechanism of complicated TCM prescription: Bazhen decoction. We identify the pharmacological mechanism of Bazhen decoction in telomere elongation as revealed by systematic analysis.<br><br>MATERIALS AND METHODS: By RNA sequencing and transcriptome analysis of Bazhen decoction treated wild type cells, we reveal the transcriptome profile induced by Bazhen decoction. We utilized the cells derived from Werner syndrome (WS) mice, which is known to be dysfunctional in telomere elongation due to the deficiency of DNA helicase Wrn. By Western blot, qPCR, Immunofluorescence, flow cytometry, telomere FISH, and SA-&#x3b2;-Gal staining, we verify the transcriptome data and confirm the pharmacological function of Bazhen decoction and its drug containing serum in telomere elongation and reversing progeroid cell senescence.<br><br>RESULTS: We reveal that Bazhen decoction may systematically regulate multiple anti-aging pathways, including stem cell regulation, protein homeostasis, cardiovascular function, neuronal function, anti-inflammation, anti-DNA damage induced stress, DNA helicase activity and telomere lengthening. We find that Bazhen decoction and its drug containing serum could up-regulate multiple DNA helicases and telomere regulating proteins. The increased DNA helicases promote the resolving of G-quadruplex (G4) structures, and facilitate DNA replication and telomere elongation. These improvements also endow the cellular resistance to DNA damages induced by replication stress, and rescue the WS caused cellular senescence.<br><br>CONCLUSIONS: Together these data suggest that Bazhen decoction up-regulate the expression of DNA helicases, thus facilitate G4 resolving and telomere maintenance, which rescue the progeroid cellular senescence and contribute to its anti-aging properties. Our data reveal a new molecular mechanism of Bazhen decoction in anti-aging related diseases via elongating telomere, this may shed light in the application of Bazhen decoction in multiple degenerative diseases caused by telomere erosion.},
}
@article {pmid38163245,
year = {2024},
author = {Zhu, Y and Meng, Y and Zhang, Y and Karlsson, IK and Hägg, S and Zhan, Y},
title = {Genetically determined telomere length and its association with chronic obstructive pulmonary disease and interstitial lung disease in biobank Japan: A Mendelian randomization study.},
journal = {Heliyon},
volume = {10},
number = {1},
pages = {e23415},
pmid = {38163245},
issn = {2405-8440},
abstract = {IMPORTANCE: Chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) have been linked to shorter telomere length (TL). While understanding this association has critical clinical implications for respiratory diseases, previous studies exploring these associations were conducted in European populations. The present study aims to investigate this relationship in an Asian population.<br><br>OBJECTIVE: To examine the causal relationship between leukocyte TL and COPD and ILD in an Asian population.<br><br>DESIGN: Setting, and Participants: We used a genome-wide association study summary statistics-based two-sample Mendelian randomization (MR) design to investigate the association between leukocyte TL, genetically predicted by nine single-nucleotide polymorphisms and the risk of COPD and ILD. Participants were Japanese individuals enrolled in the Biobank Japan Project, including 3315 COPD patients and 806 ILD patients.<br><br>EXPOSURE: Leukocyte TL was genetically predicted by nine single-nucleotide polymorphisms.<br><br>RESULTS: The inverse-variance weighted estimates showed a significant inverse association between leukocyte TL and COPD (odds ratio [OR]&#xa0;=&#xa0;0.78; 95&#xa0;% confidence interval [CI]: 0.64, 0.95; P&#xa0;=&#xa0;0.01) and ILD (OR&#xa0;=&#xa0;0.29; 95&#xa0;% CI: 0.14, 0.61; P&#xa0;=&#xa0;0.001), respectively. All sensitivity analyses yielded consistent results. The MR-Egger regression intercept test showed no evidence of horizontal pleiotropy (Pintercept: COPD, 0.56; ILD: 0.70).<br><br>CONCLUSION: and Relevance: Our findings suggest that leukocyte telomere shortening may causally increase the risk of COPD and ILD. These results highlight the potential importance of TL for these respiratory diseases.},
}
@article {pmid38159192,
year = {2023},
author = {Del Valle, KT and Carmona, EM},
title = {Diagnosis and Management of Pulmonary Manifestations of Telomere Biology Disorders.},
journal = {Current hematologic malignancy reports},
volume = {},
number = {},
pages = {},
pmid = {38159192},
issn = {1558-822X},
abstract = {PURPOSE OF REVIEW: Telomere biology disorders (TBD) are a group of genetic disorders characterized by premature shortening of telomeres, resulting in accelerated aging of somatic cells. This often leads to major multisystem organ dysfunction, and TBDs have become increasingly recognized as a significant contributor to numerous disease processes within the past 10-15 years. Both research and clinical practice in this field are rapidly evolving.<br><br>RECENT FINDINGS: A subset of patients with TBD suffers from interstitial lung disease, most commonly pulmonary fibrosis. Often, the clinical presentation is indistinguishable from other forms of lung fibrosis. There are no pathognomonic radiographic or histological features, and a high level of suspicion is therefore required. Telomere evaluation is thus crucial to establishing the diagnosis. This review details the clinical presentation, objective evaluation, indicated genetic testing, and recommended management strategies for patients affected by interstitial lung disease associated with TBDs. Our goal is to empower pulmonologists and other healthcare professionals who care for these patients to provide appropriate and personalized care for this population.},
}
@article {pmid38150087,
year = {2023},
author = {Eppard, M and Passos, JF and Victorelli, S},
title = {Telomeres, cellular senescence, and aging: past and future.},
journal = {Biogerontology},
volume = {},
number = {},
pages = {},
pmid = {38150087},
issn = {1573-6768},
support = {R01AG068048/NH/NIH HHS/United States ; R01AG082708/NH/NIH HHS/United States ; },
abstract = {Over half a century has passed since Alexey Olovnikov's groundbreaking proposal of the end-replication problem in 1971, laying the foundation for our understanding of telomeres and their pivotal role in cellular senescence. This review paper delves into the intricate and multifaceted relationship between cellular senescence, the influence of telomeres in this process, and the far-reaching consequences of telomeres in the context of aging and age-related diseases. Additionally, the paper investigates the various factors that can influence telomere shortening beyond the confines of the end-replication problem and how telomeres can exert their impact on aging, even in the absence of significant shortening. Ultimately, this paper stands as a tribute to the pioneering work of Olovnikov, whose seminal contributions established the solid foundation upon which our ongoing explorations of telomeres and the aging process are based.},
}
@article {pmid38145728,
year = {2023},
author = {Zhang, X and Colicino, E and Cowell, W and Enlow, MB and Kloog, I and Coull, BA and Schwartz, JD and Wright, RO and Wright, RJ},
title = {Prenatal exposure to air pollution and BWGA Z-score: Modifying effects of placenta leukocyte telomere length and infant sex.},
journal = {Environmental research},
volume = {246},
number = {},
pages = {117986},
doi = {10.1016/j.envres.2023.117986},
pmid = {38145728},
issn = {1096-0953},
support = {R21 ES021318/ES/NIEHS NIH HHS/United States ; P30 ES023515/ES/NIEHS NIH HHS/United States ; UH3 OD023337/OD/NIH HHS/United States ; R01 HL095606/HL/NHLBI NIH HHS/United States ; R01 HL114396/HL/NHLBI NIH HHS/United States ; },
abstract = {BACKGROUND: Air pollutants, such as fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3), have been associated with adverse birth outcomes, including low birth weight, often exhibiting sex-specific effects. However, the modifying effect of placental telomere length (TL), reflecting cumulative lifetime oxidative stress in mothers, remains unexplored.<br><br>METHOD: Using data from a Northeastern U.S. birth cohort (n&#xa0;=&#xa0;306), we employed linear regression and weighted quantile sum models to assess trimester-average air pollution exposures and birth weight for gestational age (BWGA) z-scores. Placental TL, categorized by median split, was considered as an effect modifier. Interactions among air pollutants, placental TL, infant sex, and BWGA z-score were evaluated.<br><br>RESULTS: Without placental TL as a modifier, only 1[st] trimester O3 was significantly associated with BWGA z-scores (coefficient: 0.33, 95% CI: 0.03, 0.63). In models considering TL interactions, a significant modifying effect was observed between 3[rd] trimester NO2 and BWGA z-scores (interaction p-value&#xa0;=&#xa0;0.02). Specifically, a one interquartile range (1-IQR) increase in 3[rd] trimester NO2 was linked to a 0.28 (95% CI: 0.06, 0.52) change in BWGA z-score among shorter placental TL group, with no significant association among longer TL group. Among male infants, there were significant associations between 3[rd] trimester PM2.5 exposure and BWGA z-scores in the longer TL group (coefficient: -0.34, 95% CI: -0.61, -0.02), and between 1[st] trimester O3 exposure and BWGA z-scores among males in the shorter TL group (coefficient: 0.59, 95% CI: 0.06, 1.08). For females, only a negative association in 2[nd] trimester mixture model was observed within the longer TL group (coefficient: -0.10, 95% CI: -0.21, -0.01).<br><br>CONCLUSION: These findings highlight the need to consider the complex interactions among prenatal air pollutant exposures, placental TL, and fetal sex to better elucidate those at greatest risk for adverse birth outcomes.},
}
@article {pmid38144537,
year = {2023},
author = {, },
title = {Expression of concern: MRE11 and UBR5 co-operate to suppress RNF168-mediated fusion of dysfunctional telomeres.},
journal = {Frontiers in oncology},
volume = {13},
number = {},
pages = {1308554},
doi = {10.3389/fonc.2023.1308554},
pmid = {38144537},
issn = {2234-943X},
}
@article {pmid38141917,
year = {2024},
author = {Mishra, S and Stukken, CV and Drury, S and Nawrot, TS and Martens, DS},
title = {Prenatal air pollution exposure in relation to the telomere-mitochondrial axis of aging at birth: A systematic review.},
journal = {Environmental research},
volume = {244},
number = {},
pages = {117990},
doi = {10.1016/j.envres.2023.117990},
pmid = {38141917},
issn = {1096-0953},
mesh = {Infant, Newborn ; Pregnancy ; Female ; Humans ; Systematic Reviews as Topic ; Meta-Analysis as Topic ; *Air Pollution/adverse effects/analysis ; *Air Pollutants/toxicity/analysis ; Particulate Matter/analysis ; Telomere ; DNA, Mitochondrial ; Maternal Exposure/adverse effects ; Environmental Exposure/analysis ; },
abstract = {BACKGROUND: Telomere length (TL) and mitochondrial DNA (mtDNA) are central markers of vital biological mechanisms, including cellular aging. Prenatal air pollution exposure may impact molecular markers of aging leading to adverse health effects.<br><br>OBJECTIVE: To perform a systematic review on human population-based studies investigating the association between prenatal air pollution exposure and TL or mtDNA content at birth.<br><br>METHODOLOGY: Searches were undertaken on PubMed and Web of Science until July 2023. The framework of the review was based on the PRISMA-P guidelines.<br><br>RESULTS: Nineteen studies studied prenatal air pollution and TL or mtDNA content at birth. Studies investigating TL or mtDNA content measured at any other time or did not evaluate prenatal air pollution were excluded. Twelve studies (including 4381 participants with study sample range: 97 to 743 participants) investigated newborn TL and eight studies (including 3081 participants with study sample range: 120 to 743 participants) investigated mtDNA content at birth. Seven studies focused on particulate matter (PM2.5) exposure and newborn TL of which all, except two, showed an inverse association in at least one of the gestational trimesters. Of the eight studies on mtDNA content, four focused on PM2.5 air pollution with two of them reporting an inverse association. For PM2.5 exposure, observations on trimester-specific effects were inconsistent. Current literature showing associations with other prenatal air pollutants (including nitrogen oxides, sulfur dioxide, carbon monoxide and ozone) is inconsistent.<br><br>CONCLUSION: This review provides initial evidence that prenatal PM2.5 exposure impacts the telomere-mitochondrial axis of aging at birth. The current evidence did not reveal harmonious observations for trimester-specific associations nor showed consistent effects of other air pollutants. Future studies should elucidate the specific contribution of prenatal exposure to pollutants other than PM in relation to TL and mtDNA content at birth, and the potential later life health consequences.},
}
@article {pmid38137478,
year = {2023},
author = {Tesolato, S and Vicente-Valor, J and Jarabo, JR and Calatayud, J and Sáiz-Pardo, M and Nieto, A and Álvaro-Álvarez, D and Linares, MJ and Fraile, CA and Hernándo, F and Iniesta, P and Gómez-Martínez, AM},
title = {Role of Telomere Length in Survival of Patients with Idiopathic Pulmonary Fibrosis and Other Interstitial Lung Diseases.},
journal = {Biomedicines},
volume = {11},
number = {12},
pages = {},
pmid = {38137478},
issn = {2227-9059},
support = {2019 and 2020, respectively//"Neumomadrid" (Sociedad Madrile&#xf1;a de Neumolog&#xed;a y Cirug&#xed;a Tor&#xe1;cica), and "C&#xe1;tedra EPID Futuro UAM-Roche"./ ; },
abstract = {Interstitial lung diseases (ILDs) constitute a group of more than 200 disorders, with idiopathic pulmonary fibrosis (IPF) being one of the most frequent. Telomere length (TL) shortening causes loss of function of the lung parenchyma. However, little is known about its role as a prognostic factor in ILD patients. With the aim of investigating the role of TL and telomerase activity in the prognosis of patients affected by ILDs, we analysed lung tissue samples from 61 patients. We measured relative TL and telomerase activity by conventional procedures. Both clinical and molecular parameters were associated with overall survival by the Kaplan-Meier method. Patients with IPF had poorer prognosis than patients with other ILDs (p = 0.034). When patients were classified according to TL, those with shortened telomeres reported lower overall survival (p = 0.085); differences reached statistical significance after excluding ILD patients who developed cancer (p = 0.021). In a Cox regression analysis, TL behaved as a risk-modifying variable for death associated with rheumatic disease (RD) co-occurrence (p = 0.029). Also, in patients without cancer, ferritin was significantly increased in cases with RD and IPF co-occurrence (p = 0.032). In relation to telomerase activity, no significant differences were detected. In conclusion, TL in lung tissue emerges as a prognostic factor in ILD patients. Specifically, in cases with RD and IPF co-occurrence, TL can be considered as a risk-modifying variable for death.},
}
@article {pmid38136279,
year = {2023},
author = {Djos, A and Thombare, K and Vaid, R and Gaarder, J and Umapathy, G and Reinsbach, SE and Georgantzi, K and Stenman, J and Carén, H and Ek, T and Mondal, T and Kogner, P and Martinsson, T and Fransson, S},
title = {Telomere Maintenance Mechanisms in a Cohort of High-Risk Neuroblastoma Tumors and Its Relation to Genomic Variants in the TERT and ATRX Genes.},
journal = {Cancers},
volume = {15},
number = {24},
pages = {},
pmid = {38136279},
issn = {2072-6694},
support = {20-1213//the Swedish Cancer Society/ ; 19-566//the Swedish Cancer Society/ ; 19-139//the Swedish Childhood Cancer Foundation/ ; 22-156//the Swedish Childhood Cancer Foundation/ ; 17-122//the Swedish Childhood Cancer Foundation/ ; 18-99//the Swedish Childhood Cancer Foundation/ ; ALFGBG-447171//the Swedish state under the LUA/ALF agreement/ ; RB13-0204//the Swedish Foundation for Strategic Research/ ; SF//Sahlgrenska University hospital and Laboratory medicine research and development grant/ ; KAW 2018.0057//the Knut and Alice Wallenberg foundation/ ; },
abstract = {Tumor cells are hallmarked by their capacity to undergo unlimited cell divisions, commonly accomplished either by mechanisms that activate TERT or through the alternative lengthening of telomeres pathway. Neuroblastoma is a heterogeneous pediatric cancer, and the aim of this study was to characterize telomere maintenance mechanisms in a high-risk neuroblastoma cohort. All tumor samples were profiled with SNP microarrays and, when material was available, subjected to whole genome sequencing (WGS). Telomere length was estimated from WGS data, samples were assayed for the ALT biomarker c-circles, and selected samples were subjected to methylation array analysis. Samples with ATRX aberration in this study were positive for c-circles, whereas samples with either MYCN amplification or TERT re-arrangement were negative for c-circles. Both ATRX aberrations and TERT re-arrangement were enriched in 11q-deleted samples. An association between older age at diagnosis and 1q-deletion was found in the ALT-positive group. TERT was frequently placed in juxtaposition to a previously established gene in neuroblastoma tumorigenesis or cancer in general. Given the importance of high-risk neuroblastoma, means for mitigating active telomere maintenance must be therapeutically explored.},
}
@article {pmid38136206,
year = {2023},
author = {D'Angelo, S},
title = {Diet and Aging: The Role of Polyphenol-Rich Diets in Slow Down the Shortening of Telomeres: A Review.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {12},
pages = {},
pmid = {38136206},
issn = {2076-3921},
support = {DM737 of 25-06-2021; grant number: CUPI53C22001990001//Miur/ ; },
abstract = {The ends of human chromosomes are defended by DNA-protein complexes named telomeres, which inhibit the chromosomes from fusing with each other and from being known as a double-strand break by DNA reparation proteins. Telomere length is a marker of biological aging, and disfunction of telomeres is related to age-related syndromes. Telomere attrition has been shown to be accelerated by oxidative stress and inflammation. Telomere length has been proven to be positively linked with nutritional status in human and animal scientific research as several nutrients influence it through mechanisms that imitate their function in cellular roles including oxidative stress and inflammation. Data reported in this article support the idea that following a low-in-fat and rich-plant polyphenols food diet seems to be able to slow down the shortening of telomeres.},
}
@article {pmid38135140,
year = {2024},
author = {Wai, KM and Swe, T and Su Hninn, TS and Paing, AM and Naing, YL and Htay, ZW and Ihara, K},
title = {Prenatal exposure to environmental heavy metals and newborn telomere length: A systematic review and meta-analysis.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {343},
number = {},
pages = {123192},
doi = {10.1016/j.envpol.2023.123192},
pmid = {38135140},
issn = {1873-6424},
mesh = {Pregnancy ; Female ; Infant, Newborn ; Humans ; Cadmium/toxicity ; *Prenatal Exposure Delayed Effects ; Likelihood Functions ; Cohort Studies ; Telomere ; *Metals, Heavy/toxicity ; },
abstract = {Exposure to environmental heavy metals is associated with telomere length (TL) alteration. Available information regarding the effect of prenatal exposure to environmental pollutants on newborn TL is controversial. The aim of this study is to systematically review and conduct a meta-analysis of the existing epidemiological studies on the associations between prenatal metal exposure and newborn TL. A comprehensive literature search was performed using the online databases of PubMed, Web of Science, and ScienceDirect from their inception to December 1, 2023. Thirteen eligible studies were included from the overall initial identification of 3559 records. The effect size was expressed as standardized beta coefficients with 95% confidence intervals (CIs) by the restricted maximum-likelihood approach with a weighted random-effects model. Prenatal exposure to environmental heavy metals was associated with a shorter newborn TL (standardized beta = -0.04; 95% CI: -0.08, 0.00; p = 0.05). Subgroup analysis showed that prenatal exposure to cadmium was significantly, negatively associated with TL in newborns (standardized beta = -0.05; 95% CI: -0.10, -0.01; p = 0.021). Heavy metal exposure during the third trimester was significantly associated with a shorter TL in newborns (standardized beta = -0.05; 95% CI: -0.11, -0.01; p = 0.045). No significant association was found between the newborn's sex and exposure sample type. This study provides evidence for the negative effect of prenatal exposure to heavy metals on newborn TL. In particular, cadmium exposure and exposure during the third trimester of pregnancy are critical factors associated with heavy metal-induced TL shortening.},
}
@article {pmid38134301,
year = {2023},
author = {Niu, B and Wu, JX and Huang, XL and Lei, SF and Deng, FY},
title = {Telomere length is a driving hallmark for aging-related biochemical hallmarks: evidence from the shared genetic effect and causal inference.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glad275},
pmid = {38134301},
issn = {1758-535X},
abstract = {Telomere shortening is an important sign and driving factor of aging, but its association mechanisms and causal effects with other aging-related biochemical hallmarks are largely unknown. This study first performed comprehensive genetic analyses (e.g., shared genetic analysis, pleiotropic analysis, gene enrichment analysis) to detect the underlying molecular mechanisms for the associations between TL and aging-related biochemical hallmarks. Then, further bidirectional MR analyses investigated the causal effects between TL and other biochemical hallmarks. The genetic correlations were negative between TL and GDF15 (P = 0.024), CRP (P = 0.007), HbA1c (P = 0.007) and RBC (P = 0.022), but positive between TL and IGF-1 (P = 0.002) and WBC (P = 0.007). The increased TL has causal effects on the low levels of GDF15 (P = 3.73E-06), SHBG (P = 6.30E-06), testosterone (P = 5.56E-07), FI (P = 2.67E-05), and RBC (P = 1.54E-05), but the higher levels of IGF-1 (P = 3.24E-07). In conclusion, the observed phenotypic correlations between TL and aging-related biochemical hallmarks may arise from a combination of shared genetic components and causal effects. TL is regarded as a driving hallmark for aging-related biochemical hallmarks.},
}
@article {pmid38129441,
year = {2023},
author = {Chang, Y and Zhou, Y and Zhou, J and Li, W and Cao, J and Jing, Y and Zhang, S and Shen, Y and Lin, Q and Fan, X and Yang, H and Dong, X and Zhang, S and Yi, X and Shuai, L and Shi, L and Liu, Z and Yang, J and Ma, X and Hao, J and Chen, K and Li, MJ and Wang, F and Huang, D},
title = {Unraveling the causal genes and transcriptomic determinants of human telomere length.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {8517},
pmid = {38129441},
issn = {2041-1723},
support = {32270717//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
mesh = {Adult ; Humans ; Female ; Pregnancy ; *Genome-Wide Association Study ; *Placenta/metabolism ; Telomere Shortening ; Telomere/genetics ; Gene Expression Profiling ; },
abstract = {Telomere length (TL) shortening is a pivotal indicator of biological aging and is associated with many human diseases. The genetic determinates of human TL have been widely investigated, however, most existing studies were conducted based on adult tissues which are heavily influenced by lifetime exposure. Based on the analyses of terminal restriction fragment (TRF) length of telomere, individual genotypes, and gene expressions on 166 healthy placental tissues, we systematically interrogate TL-modulated genes and their potential functions. We discover that the TL in the placenta is comparatively longer than in other adult tissues, but exhibiting an intra-tissue homogeneity. Trans-ancestral TL genome-wide association studies (GWASs) on 644,553 individuals identify 20 newly discovered genetic associations and provide increased polygenic determination of human TL. Next, we integrate the powerful TL GWAS with placental expression quantitative trait locus (eQTL) mapping to prioritize 23 likely causal genes, among which 4 are functionally validated, including MMUT, RRM1, KIAA1429, and YWHAZ. Finally, modeling transcriptomic signatures and TRF-based TL improve the prediction performance of human TL. This study deepens our understanding of causal genes and transcriptomic determinants of human TL, promoting the mechanistic research on fine-grained TL regulation.},
}
@article {pmid38110867,
year = {2023},
author = {Wang, H and Chen, X and Wang, S and Zhang, H},
title = {Exploration of the causal effects of leukocyte telomere length and four gastrointestinal diseases: a two-sample bidirectional Mendelian randomization study.},
journal = {BMC gastroenterology},
volume = {23},
number = {1},
pages = {446},
pmid = {38110867},
issn = {1471-230X},
support = {2020A1515011379//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2020A1515011379//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2020A1515011379//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2020A1515011379//Basic and Applied Basic Research Foundation of Guangdong Province/ ; },
mesh = {Humans ; *Irritable Bowel Syndrome/genetics ; Mendelian Randomization Analysis ; *Gastrointestinal Diseases/genetics ; *Gastroesophageal Reflux ; Leukocytes ; Telomere ; },
abstract = {BACKGROUND: To explore the underlying causality between leukocyte telomere length (LTL) and four gastrointestinal diseases, we designed a two-sample bidirectional Mendelian randomization study.<br><br>METHODS: Two-sample Mendelian randomization (MR) was used to explore genetic causality between LTL and four gastrointestinal diseases, including irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), gastrointestinal ulcers disease (GUD), and nonalcoholic fatty liver disease (NAFLD). We utilized inverse-variance weighted (IVW) as the primary method for MR analysis. Supplementary analyses were conducted using methods such as MR-Egger regression, weighted-median, Maximum Likelihood (MaxLik), Robust adjusted profile score (MR-RAPS), Contamination mixture (ConMix), and MR-mix. Cochran's Q was calculated to check for heterogeneity. The MR-Egger regression and MR pleiotropy residual sum and outlier (MR-PRESSO) were detected for pleiotropy.<br><br>RESULTS: The IVW analysis suggests that there may be a potential causal relationship between LTL and two diseases (odds ratio (OR): 1.062; 95% confidence interval (CI): 1.003, 1.124; p&#x2009;=&#x2009;0.038 for IBS and OR: 0.889; 95% CI: 0.798, 0.990; p&#x2009;=&#x2009;0.032 for GERD). However, other methods do not entirely align with the results of the IVW analysis. In the reverse MR analysis, we did not find statistically significant associations between LTL and these four diseases.<br><br>CONCLUSION: The current evidence does not definitively rule out a causal relationship between LTL and these four gastrointestinal diseases but suggests a potential association between LTL and IBS, or LTL and GERD. Exploring the relationship between gastrointestinal diseases and LTL may offer new insights into the onset, progression, and treatment of these diseases.},
}
@article {pmid38109000,
year = {2023},
author = {Savage, SA},
title = {Telomere length and cancer risk: finding Goldilocks.},
journal = {Biogerontology},
volume = {},
number = {},
pages = {},
pmid = {38109000},
issn = {1573-6768},
abstract = {Telomeres are the nucleoprotein complex at chromosome ends essential in genomic stability. Baseline telomere length (TL) is determined by rare and common germline genetic variants but shortens with age and is susceptible to certain environmental exposures. Cellular senescence or apoptosis are normally triggered when telomeres reach a critically short length, but cancer cells overcome these protective mechanisms and continue to divide despite chromosomal instability. Rare germline variants in telomere maintenance genes cause exceedingly short telomeres for age (< 1st percentile) and the telomere biology disorders, which are associated with elevated risks of bone marrow failure, myelodysplastic syndrome, acute myeloid leukemia, and squamous cell carcinoma of the head/neck and anogenital regions. Long telomeres due to rare germline variants in the same or different telomere maintenance genes are associated with elevated risks of other cancers, such as chronic lymphocytic leukemia or sarcoma. Early epidemiology studies of TL in the general population lacked reproducibility but new methods, including creation of a TL polygenic score using common variants, have found longer telomeres associated with excess risks of renal cell carcinoma, glioma, lung cancer, and others. It has become clear that when it comes to TL and cancer etiology, not too short, not too long, but "just right" telomeres are important in minimizing cancer risk.},
}
@article {pmid38106000,
year = {2023},
author = {Kumawat, S and Martinez, I and Logeswaran, D and Chen, H and Coughlan, JM and Chen, JJ and Yuan, Y and Sobel, JM and Choi, JY},
title = {Transposition, duplication, and divergence of the telomerase RNA underlies the evolution of Mimulus telomeres.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38106000},
abstract = {Telomeres are nucleoprotein complexes with a crucial role of protecting chromosome ends. It consists of simple repeat sequences and dedicated telomere-binding proteins. Because of its vital functions, components of the telomere, for example its sequence, should be under strong evolutionary constraint. But across all plants, telomere sequences display a range of variation and the evolutionary mechanism driving this diversification is largely unknown. Here, we discovered in Monkeyflower (Mimulus) the telomere sequence is even variable between species. We investigated the basis of Mimulus telomere sequence evolution by studying the long noncoding telomerase RNA (TR), which is a core component of the telomere maintenance complex and determines the telomere sequence. We conducted total RNA-based de novo transcriptomics from 16 Mimulus species and analyzed reference genomes from 6 species, and discovered Mimulus species have evolved at least three different telomere sequences: (AAACCCT)n, (AAACCCG)n, and (AAACCG)n. Unexpectedly, we discovered several species with TR duplications and the paralogs had functional consequences that could influence telomere evolution. For instance, M. lewisii had two sequence-divergent TR paralogs and synthesized a telomere with sequence heterogeneity, consisting of AAACCG and AAACCCG repeats. Evolutionary analysis of the M. lewisii TR paralogs indicated it had arisen from a transposition-mediate duplication process. Further analysis of the TR from multiple Mimulus species showed the gene had frequently transposed and inserted into new chromosomal positions during Mimulus evolution. From our results, we propose the TR transposition, duplication, and divergence model to explain the evolutionary sequence turnovers in Mimulus and potentially all plant telomeres.},
}
@article {pmid38105195,
year = {2023},
author = {Kalmykova, AI and Sokolova, OA},
title = {Retrotransposons and Telomeres.},
journal = {Biochemistry. Biokhimiia},
volume = {88},
number = {11},
pages = {1739-1753},
doi = {10.1134/S0006297923110068},
pmid = {38105195},
issn = {1608-3040},
mesh = {Animals ; Humans ; *Retroelements ; Drosophila melanogaster/genetics ; RNA, Small Interfering/metabolism ; Drosophila/genetics ; *Drosophila Proteins/metabolism ; Telomere/genetics/metabolism ; DNA Transposable Elements ; },
abstract = {Transposable elements (TEs) comprise a significant part of eukaryotic genomes being a major source of genome instability and mutagenesis. Cellular defense systems suppress the TE expansion at all stages of their life cycle. Piwi proteins and Piwi-interacting RNAs (piRNAs) are key elements of the anti-transposon defense system, which control TE activity in metazoan gonads preventing inheritable transpositions and developmental defects. In this review, we discuss various regulatory mechanisms by which small RNAs combat TE activity. However, active transposons persist, suggesting these powerful anti-transposon defense mechanisms have a limited capacity. A growing body of evidence suggests that increased TE activity coincides with genome reprogramming and telomere lengthening in different species. In the Drosophila fruit fly, whose telomeres consist only of retrotransposons, a piRNA-mediated mechanism is required for telomere maintenance and their length control. Therefore, the efficacy of protective mechanisms must be finely balanced in order not only to suppress the activity of transposons, but also to maintain the proper length and stability of telomeres. Structural and functional relationship between the telomere homeostasis and LINE1 retrotransposon in human cells indicates a close link between selfish TEs and the vital structure of the genome, telomere. This relationship, which permits the retention of active TEs in the genome, is reportedly a legacy of the retrotransposon origin of telomeres. The maintenance of telomeres and the execution of other crucial roles that TEs acquired during the process of their domestication in the genome serve as a type of payment for such a "service."},
}
@article {pmid38105192,
year = {2023},
author = {Yegorov, YE},
title = {Olovnikov, Telomeres, and Telomerase. Is It Possible to Prolong a Healthy Life?.},
journal = {Biochemistry. Biokhimiia},
volume = {88},
number = {11},
pages = {1704-1718},
doi = {10.1134/S0006297923110032},
pmid = {38105192},
issn = {1608-3040},
mesh = {*Telomerase/genetics/metabolism ; Cellular Senescence/genetics ; Telomere Homeostasis ; Telomere/genetics/metabolism ; },
abstract = {The science of telomeres and telomerase has made tremendous progress in recent decades. In this review, we consider it first in a historical context (the Carrel-Hayflick-Olovnikov-Blackburn chain of discoveries) and then review current knowledge on the telomere structure and dynamics in norm and pathology. Central to the review are consequences of the telomere shortening, including telomere position effects, DNA damage signaling, and increased genetic instability. Cell senescence and role of telomere length in its development are discussed separately. Therapeutic aspects and risks of telomere lengthening methods including use of telomerase and other approaches are also discussed.},
}
@article {pmid38102621,
year = {2023},
author = {Moshfeghinia, R and Torabi, A and Mostafavi, S and Rahbar, S and Moradi, MS and Sadeghi, E and Mootz, J and Vardanjani, HM},
title = {Maternal psychological stress during pregnancy and newborn telomere length: a systematic review and meta-analysis.},
journal = {BMC psychiatry},
volume = {23},
number = {1},
pages = {947},
pmid = {38102621},
issn = {1471-244X},
mesh = {Infant ; Pregnancy ; Female ; Humans ; Infant, Newborn ; *Mothers ; *Telomere ; Stress, Psychological/complications ; Telomere Shortening ; Research Design ; },
abstract = {INTRODUCTION: Telomeres protect the ends of chromosomes, and shorter leukocyte telomeres are associated with major group diseases. Maternal psychological stress may be related to the shortening of telomeres in infants. This systematic review and meta-analysis set out to consolidate the varying effect sizes found in studies of maternal psychological stress and telomere length (TL) in newborns and identify moderators of the relationship between stress during pregnancy and newborn TL.<br><br>METHODS: Our systematic review was registered in Prospero. Six databases (PubMed, Scopus, Embase, PsycINFO, Web of Science, and CINAHL Complete) were searched for records in English from inception to February 10, 2023. Observational studies were included that measured the relationship of psychological stress of the mother during pregnancy on the TL of the newborn. The Newcastle-Ottawa quality assessment scale was used to assess the quality of the included studies. A random-effect model was selected. Statistical analysis performed by Stata software version 17.<br><br>RESULTS: Eight studies were included for qualitative and four for quantitative analysis. There was an inverse statistically significant relationship between maternal stress and newborn TL; A one score increase in maternal psychological stress resulted in a 0.04 decrease in the TL of the newborn (B&#x2009;=&#x2009;-0.04, 95% CI&#x2009;=&#x2009;[-0.08, 0.00], p&#x2009;=&#x2009;0.05). Selectivity analysis showed that the pooled effect size was sensitive to one study; After removing this study, the pooled effect size remained significant (B&#x2009;=&#x2009;-0.06, 95% CI&#x2009;=&#x2009;[-0. 10, -0.02], p&#x2009;<&#x2009;0.001).<br><br>CONCLUSION: Physiological and environmental factors can significantly affect the TL of newborns. Our results support a significant impact of maternal psychological stress on the TL of a newborn. This association demonstrates the significance of stress in influencing the telomere length, which can be a contributing factor in the infant's future. Therefore, recognizing this association is crucial for understanding and addressing potential health risks and necessitates the need for additional future studies to validate our findings.},
}
@article {pmid38099139,
year = {2023},
author = {Gómez-Blanco, D and Tobler, M and Hasselquist, D},
title = {Why and when should organisms elongate their telomeres? Elaborations on the 'excess resources elongation' and 'last resort elongation' hypotheses.},
journal = {Ecology and evolution},
volume = {13},
number = {12},
pages = {e10825},
pmid = {38099139},
issn = {2045-7758},
abstract = {Telomere length and telomere shortening are thought to be critical cellular attributes and processes that are related to an individual's life span and fitness. The general pattern across most taxa is that after birth telomere length gradually decreases with age. Telomere protection and restoration mechanisms are usually assumed to reduce the rate of shortening or at most keep telomere length constant. However, here we have compiled a list of 26 articles showing that there is an increasing number of studies reporting apparent elongation of telomeres (i.e., a net increase in TL from timet to timet+1) often in a considerable proportion of the individuals studied. Moreover, the few studies which have studied telomere elongation in detail show that increases in telomere length are unlikely to be due to measurement error alone. In this article, we argue that episodes of telomere elongation deserve more attention as they could reflect individual strategies to optimise life histories and maximise fitness, which may not be reflected in the overall telomere dynamics patterns. We propose that patterns of telomere (net) elongation may be partly determined by other factors than those causing telomere shortening, and therefore deserve analyses specifically targeted to investigate the occurrence of telomere elongation. We elaborate on two ecological hypotheses that have been proposed to explain patterns of telomere elongation (the 'excess resources elongation' and the 'last resort elongation' hypothesis) and we discuss the current evidence for (or against) these hypotheses and propose ways to test them.},
}
@article {pmid38095828,
year = {2024},
author = {Lasho, T and Patnaik, MM},
title = {Adaptive and Maladaptive Clonal Hematopoiesis in Telomere Biology Disorders.},
journal = {Current hematologic malignancy reports},
volume = {19},
number = {1},
pages = {35-44},
pmid = {38095828},
issn = {1558-822X},
mesh = {Humans ; *Telomerase/genetics/metabolism ; Clonal Hematopoiesis/genetics ; Telomere/genetics/metabolism ; Hematopoiesis/genetics ; Biology ; },
abstract = {PURPOSE OF REVIEW: Telomere biology disorders (TBDs) are germline-inherited conditions characterized by reduction in telomerase function, accelerated shortening of telomeres, predisposition to organ-failure syndromes, and increased risk of neoplasms, especially myeloid malignancies. In normal cells, critically short telomeres trigger apoptosis and/or cellular senescence. However, the evolutionary mechanism by which TBD-related telomerase-deficient cells can overcome this fitness constraint remains elusive.<br><br>RECENT FINDINGS: Preliminary data suggests the existence of adaptive somatic mosaic states characterized by variants in TBD-related genes and maladaptive somatic mosaic states that attempt to overcome hematopoietic fitness constraints by alternative methods leading to clonal hematopoiesis. TBDs are both rare and highly heterogeneous in presentation, and the association of TBD with malignant transformation is unclear. Understanding the clonal complexity and mechanisms behind TBD-associated molecular signatures that lead to somatic adaptation in the setting of defective hematopoiesis will help inform therapy and treatment for this set of diseases.},
}
@article {pmid38088914,
year = {2023},
author = {Kidd, E and Meimaridou, E and Williams, J and Metherell, LA and Walley, AJ and Fairbrother, UL},
title = {Choice of gDNA isolation method has a significant impact on average murine Telomere Length estimates.},
journal = {Preparative biochemistry &amp; biotechnology},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/10826068.2023.2288572},
pmid = {38088914},
issn = {1532-2297},
abstract = {Telomere Length (TL) and integrity is significantly associated with age-related disease, multiple genetic and environmental factors. We observe mouse genomic DNA (gDNA) isolation methods to have a significant impact on average TL estimates. The canonical qPCR method does not measure TL directly but via the ratio of telomere repeats to a single copy gene (SCG) generating a T/S ratio. We use a monochromatic-multiplex-qPCR (mmqPCR) method which multiplexes the PCR and enables quantification of the target and the single copy gene within the same qPCR reaction. We demonstrate that TL measurements, from murine gDNA, isolated via Spin Columns (SC) and Magnetic Beads (MB), generate significantly smaller T/S ratios compared to gDNA isolated via traditional phenol/chloroform methods. The former methods may impede correct TL estimation by producing non representative fragment sets and reducing qPCR efficacy. This work highlights discrepancies in TL measurements due to different extraction techniques. We recommend the use of gDNA isolation methods that are shown to preserve DNA length and integrity, such as phenol/chloroform isolation. We propose that widely used high throughput DNA isolation methodologies can create spurious associations within a sample set, thus creating misleading data. We suggest that published TL associations should be revisited in the light of these data.},
}
@article {pmid38088000,
year = {2024},
author = {Rivosecchi, J and Jurikova, K and Cusanelli, E},
title = {Telomere-specific regulation of TERRA and its impact on telomere stability.},
journal = {Seminars in cell &amp; developmental biology},
volume = {157},
number = {},
pages = {3-23},
doi = {10.1016/j.semcdb.2023.11.001},
pmid = {38088000},
issn = {1096-3634},
mesh = {*RNA, Long Noncoding/genetics ; Chromatin ; DNA ; Telomere/genetics ; },
abstract = {TERRA is a class of telomeric repeat-containing RNAs that are expressed from telomeres in multiple organisms. TERRA transcripts play key roles in telomere maintenance and their physiological levels are essential to maintain the integrity of telomeric DNA. Indeed, deregulated TERRA expression or its altered localization can impact telomere stability by multiple mechanisms including fueling transcription-replication conflicts, promoting resection of chromosome ends, altering the telomeric chromatin, and supporting homologous recombination. Therefore, a fine-tuned control of TERRA is important to maintain the integrity of the genome. Several studies have reported that different cell lines express substantially different levels of TERRA. Most importantly, TERRA levels markedly vary among telomeres of a given cell type, indicating the existence of telomere-specific regulatory mechanisms which may help coordinate TERRA functions. TERRA molecules contain distinct subtelomeric sequences, depending on their telomere of origin, which may instruct specific post-transcriptional modifications or mediate distinct functions. In addition, all TERRA transcripts share a repetitive G-rich sequence at their 3' end which can form DNA:RNA hybrids and fold into G-quadruplex structures. Both structures are involved in TERRA functions and can critically affect telomere stability. In this review, we examine the mechanisms controlling TERRA levels and the impact of their telomere-specific regulation on telomere stability. We compare evidence obtained in different model organisms, discussing recent advances as well as controversies in the field. Furthermore, we discuss the importance of DNA:RNA hybrids and G-quadruplex structures in the context of TERRA biology and telomere maintenance.},
}
@article {pmid38086788,
year = {2023},
author = {Braun, H and Xu, Z and Chang, F and Viceconte, N and Rane, G and Levin, M and Lototska, L and Roth, F and Hillairet, A and Fradera-Sola, A and Khanchandani, V and Sin, ZW and Yong, WK and Dreesen, O and Yang, Y and Shi, Y and Li, F and Butter, F and Kappei, D},
title = {ZNF524 directly interacts with telomeric DNA and supports telomere integrity.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {8252},
pmid = {38086788},
issn = {2041-1723},
mesh = {Humans ; *Telomeric Repeat Binding Protein 2/genetics ; *Telomere/genetics/metabolism ; Shelterin Complex ; Telomere-Binding Proteins/metabolism ; DNA/genetics/metabolism ; },
abstract = {Telomeres are nucleoprotein structures at the ends of linear chromosomes. In humans, they consist of TTAGGG repeats, which are bound by dedicated proteins such as the shelterin complex. This complex blocks unwanted DNA damage repair at telomeres, e.g. by suppressing nonhomologous end joining (NHEJ) through its subunit TRF2. Here, we describe ZNF524, a zinc finger protein that directly binds telomeric repeats with nanomolar affinity, and reveal base-specific sequence recognition by cocrystallization with telomeric DNA. ZNF524 localizes to telomeres and specifically maintains the presence of the TRF2/RAP1 subcomplex at telomeres without affecting other shelterin members. Loss of ZNF524 concomitantly results in an increase in DNA damage signaling and recombination events. Overall, ZNF524 is a direct telomere-binding protein involved in the maintenance of telomere integrity.},
}
@article {pmid38085929,
year = {2024},
author = {Lv, K and Wu, Y and Yang, G and Hao, X and Huang, S and Song, T and Yuan, Q},
title = {Leukocyte Telomere Length and the Risk of Prostate Cancer and Benign Prostatic Hyperplasia: Insights From UK Biobank and Mendelian Randomization Study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {79},
number = {3},
pages = {},
doi = {10.1093/gerona/glad272},
pmid = {38085929},
issn = {1758-535X},
support = {20220484230//Beijing NOVA Program/ ; 2021YFC2009304//National Key Research and Development Program of China/ ; 23BJZ29//Logistics Health Special Project/ ; 22QNC016//Youth Innovation Science Foundation of PLA/ ; },
mesh = {Male ; Humans ; *Prostatic Hyperplasia/genetics ; Mendelian Randomization Analysis ; Biological Specimen Banks ; Reproducibility of Results ; UK Biobank ; *Prostatic Neoplasms/epidemiology/genetics ; Leukocytes ; Telomere ; Genome-Wide Association Study ; },
abstract = {BACKGROUND: Previous observational studies have been controversial regarding the association of leukocyte telomere length (LTL) with prostate cancer (PCa) and benign prostatic hyperplasia (BPH).<br><br>METHODS: First, we conducted an observational study utilizing UK Biobank data. The correlation between LTL and the risk of PCa and BPH was evaluated via multivariate-adjusted logistic regression. Then, we conducted a 2-sample Mendelian randomization to examine causal links between LTL (472&#xa0;174 individuals) and PCa as well as BPH. To verify the reliability of the primary analysis, we conducted a second analysis and sensitivity analyses.<br><br>RESULTS: In the UK Biobank study, individuals in the longer quartiles of LTL were observed to have a higher risk of PCa (1.155-fold to 1.349-fold, all p&#x2005;<&#x2005;.001) and BPH (1.119-fold to 1.212-fold, all p&#x2005;<&#x2005;.001) compared to those in the lowest quartile in multivariate-adjusted logistic regression. We observed that genetically predicted longer LTL resulted in a 1.427-fold risk of PCa (odds ratio [OR]&#x2005;=&#x2005;1.427, 95% confidence interval [CI]&#x2005;=&#x2005;1.197-1.702, p&#x2005;<&#x2005;.001) and 1.539-fold risk of BPH (OR&#x2005;=&#x2005;1.539, 95% CI&#x2005;=&#x2005;1.387-1.707, p&#x2005;<&#x2005;.001) in the primary analysis. In the second analysis, the results also indicated that longer LTL increased the genetic liability to both PCa (OR&#x2005;=&#x2005;1.338, 95% CI&#x2005;=&#x2005;1.189-1.507, p&#x2005;<&#x2005;.001) and BPH (OR&#x2005;=&#x2005;1.006, 95% CI&#x2005;=&#x2005;1.003-1.008, p&#x2005;<&#x2005;.001). Sensitivity analyses also supported the reliability of the results.<br><br>CONCLUSIONS: Our study provides convincing evidence supporting that longer LTL increases the risk of PCa and BPH in European individuals. Large-scale studies are needed to elucidate the potential mechanisms of LTL in PCa and BPH occurrence.},
}
@article {pmid38084376,
year = {2024},
author = {Sun, K and Li, M and Wu, Y and Wu, Y and Zeng, Y and Zhou, S and Peng, L and Shen, B},
title = {Exploring Causal Relationships between Leukocyte Telomere Length, Sex Hormone-Binding Globulin Levels, and Osteoporosis Using Univariable and Multivariable Mendelian Randomization.},
journal = {Orthopaedic surgery},
volume = {16},
number = {2},
pages = {320-328},
pmid = {38084376},
issn = {1757-7861},
support = {81974347//National Natural Science Foundation of China/ ; 82272561//National Natural Science Foundation of China/ ; 23NSFSC4104//Natural Science Foundation of Sichuan Province/ ; 2021M702351//Postdoctoral Research Foundation of China/ ; 2022YFS0050//Science and Technology Department of Sichuan Province/ ; 2022YFS0061//Science and Technology Department of Sichuan Province/ ; },
mesh = {Humans ; *Mendelian Randomization Analysis ; Sex Hormone-Binding Globulin/genetics ; Leukocytes ; *Osteoporosis/genetics ; Gonadal Steroid Hormones ; Telomere ; },
abstract = {OBJECTIVE: Recent evidence supports that leukocyte telomere length (LTL) may be positively associated with healthy living and inversely correlated with the risk of age-related diseases, including osteoporosis. Furthermore, it is important to note that sex hormone-binding globulin (SHBG) levels play a crucial role in the regulation of osteoporosis by influencing the availability of sex hormones. Hence, this study holds significant importance as it aims to unravel the roles of LTL and SHBG levels and determine which one acts as a predominant intermediary factor in influencing osteoporosis. Using Mendelian randomization (MR), we can gain valuable insights into the intricate relationships between aging, sex hormones, and bone health.<br><br>METHODS: Univariable and multivariable and MR analyses were employed in this study. First, we used genetic variants associated with both LTL, as determined from a study involving 472,174 European participants by Codd et al., and SHBG levels, as identified in a study conducted by Ruth et al. with 370,125 participants, as instrumental variables (IVs). Then we aimed to establish a causal relationship between LTL and SHBG levels and their potential impact on osteoporosis using univariable MR. Finally, we conducted multivariable MR to provide insights into the independent and combined effects of LTL, SHBG levels on osteoporosis risk. We used various MR methods, with the primary analysis employing the inverse-variance weighted (IVW) model.<br><br>RESULTS: Univariable MR analysis reveals a potential causal effect of longer LTL on reduced risk of osteoporosis [odds ratio (OR): 0.85; 95% confidence interval (CI): 0.73-0.99; p&#x2009;=&#x2009;0.03]. Conversely, higher genetically determined SHBG levels affect the risk of osteoporosis positively. (OR: 1.38; 95% CI: 1.09-1.75; p&#x2009;<&#x2009;0.01). We observed a negative causal effect for LTL on the occurrence of SHBG (OR: 0.96; 95% CI 0.94-0.98, p&#x2009;<&#x2009;0.01). After adjustment of using multivariable MR, the causal effect of LTL on osteoporosis (OR: 0.92; 95% CI: 0.84-1.03; p&#x2009;=&#x2009;0.14), and the effect of SHBG on osteoporosis (OR: 1.43; 95% CI: 1.16-1.75; p&#x2009;<&#x2009;0.01) were observed.<br><br>CONCLUSION: Longer LTL may confer a protective effect against osteoporosis. Additionally, the levels of SHBG appear to play a crucial role in mediating the relationship between LTL and osteoporosis. By understanding the interplay between these factors, we can gain valuable insights into the mechanisms underlying bone health and aging and potentially identify new avenues for prevention and intervention strategies.},
}
@article {pmid38077053,
year = {2023},
author = {Sanchez, SE and Gu, J and Golla, A and Martin, A and Shomali, W and Hockemeyer, D and Savage, SA and Artandi, SE},
title = {Digital telomere measurement by long-read sequencing distinguishes healthy aging from disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38077053},
support = {R35 CA197563/CA/NCI NIH HHS/United States ; },
abstract = {Telomere length is an important biomarker of organismal aging and cellular replicative potential, but existing measurement methods are limited in resolution and accuracy. Here, we deploy digital telomere measurement by nanopore sequencing to understand how distributions of human telomere length change with age and disease. We measure telomere attrition and de novo elongation with unprecedented resolution in genetically defined populations of human cells, in blood cells from healthy donors and in blood cells from patients with genetic defects in telomere maintenance. We find that human aging is accompanied by a progressive loss of long telomeres and an accumulation of shorter telomeres. In patients with defects in telomere maintenance, the accumulation of short telomeres is more pronounced and correlates with phenotypic severity. We apply machine learning to train a binary classification model that distinguishes healthy individuals from those with telomere biology disorders. This sequencing and bioinformatic pipeline will advance our understanding of telomere maintenance mechanisms and the use of telomere length as a clinical biomarker of aging and disease.},
}
@article {pmid38077026,
year = {2023},
author = {Tan, KT and Slevin, MK and Leibowitz, ML and Garrity-Janger, M and Li, H and Meyerson, M},
title = {Neotelomeres and Telomere-Spanning Chromosomal Arm Fusions in Cancer Genomes Revealed by Long-Read Sequencing.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38077026},
support = {R01 HG010040/HG/NHGRI NIH HHS/United States ; R35 CA197568/CA/NCI NIH HHS/United States ; U01 HG010961/HG/NHGRI NIH HHS/United States ; U41 HG010972/HG/NHGRI NIH HHS/United States ; },
abstract = {Alterations in the structure and location of telomeres are key events in cancer genome evolution. However, previous genomic approaches, unable to span long telomeric repeat arrays, could not characterize the nature of these alterations. Here, we applied both long-read and short-read genome sequencing to assess telomere repeat-containing structures in cancers and cancer cell lines. Using long-read genome sequences that span telomeric repeat arrays, we defined four types of telomere repeat variations in cancer cells: neotelomeres where telomere addition heals chromosome breaks, chromosomal arm fusions spanning telomere repeats, fusions of neotelomeres, and peri-centromeric fusions with adjoined telomere and centromere repeats. Analysis of lung adenocarcinoma genome sequences identified somatic neotelomere and telomere-spanning fusion alterations. These results provide a framework for systematic study of telomeric repeat arrays in cancer genomes, that could serve as a model for understanding the somatic evolution of other repetitive genomic elements.},
}
@article {pmid38074328,
year = {2023},
author = {Galindo-Lalana, C and Hoelzl, F and Zahn, S and Habold, C and Cornils, JS and Giroud, S and Smith, S},
title = {Seasonal variation in telomerase activity and telomere dynamics in a hibernating rodent, the garden dormouse (Eliomys quercinus).},
journal = {Frontiers in physiology},
volume = {14},
number = {},
pages = {1298505},
pmid = {38074328},
issn = {1664-042X},
abstract = {Telomere dynamics in hibernating species are known to reflect seasonal changes in somatic maintenance. Throughout hibernation, the periodic states of rewarming, known as inter-bout euthermia or arousals, are associated with high metabolic costs including shortening of telomeres. In the active season, if high energetic resources are available, telomere length can be restored in preparation for the upcoming winter. The mechanism for telomere elongation has not been clearly demonstrated, although the action of the ribonucleoprotein complex, telomerase, has been implicated in many species. Here we tested for levels of telomerase activity in the garden dormouse (Eliomys quercinus) at different seasonal time points throughout the year and across ages from liver tissues of male juveniles to adults. We found that telomerase is active at high levels across seasons (during torpor and inter-bout euthermia, plus in the active season) but that there was a substantial decrease in activity in the month prior to hibernation. Telomerase levels were consistent across age groups and were independent of feeding regime and time of birth (early or late born). The changes in activity levels that we detected were broadly associated with changes in telomere lengths measured in the same tissues. We hypothesise that i) telomerase is the mechanism used by garden dormice for maintenance of telomeres and that ii) activity is kept at high levels throughout the year until pre-hibernation when resources are diverted to increasing fat reserves for overwintering. We found no evidence for a decrease in telomerase activity with age or a final increase in telomere length which has been detected in other hibernating rodents.},
}
@article {pmid38074093,
year = {2023},
author = {Li, B},
title = {Telomere maintenance in African trypanosomes.},
journal = {Frontiers in molecular biosciences},
volume = {10},
number = {},
pages = {1302557},
pmid = {38074093},
issn = {2296-889X},
support = {R01 AI066095/AI/NIAID NIH HHS/United States ; R01 AI127562/AI/NIAID NIH HHS/United States ; R01 GM147378/GM/NIGMS NIH HHS/United States ; },
abstract = {Telomere maintenance is essential for genome integrity and chromosome stability in eukaryotic cells harboring linear chromosomes, as telomere forms a specialized structure to mask the natural chromosome ends from DNA damage repair machineries and to prevent nucleolytic degradation of the telomeric DNA. In Trypanosoma brucei and several other microbial pathogens, virulence genes involved in antigenic variation, a key pathogenesis mechanism essential for host immune evasion and long-term infections, are located at subtelomeres, and expression and switching of these major surface antigens are regulated by telomere proteins and the telomere structure. Therefore, understanding telomere maintenance mechanisms and how these pathogens achieve a balance between stability and plasticity at telomere/subtelomere will help develop better means to eradicate human diseases caused by these pathogens. Telomere replication faces several challenges, and the "end replication problem" is a key obstacle that can cause progressive telomere shortening in proliferating cells. To overcome this challenge, most eukaryotes use telomerase to extend the G-rich telomere strand. In addition, a number of telomere proteins use sophisticated mechanisms to coordinate the telomerase-mediated de novo telomere G-strand synthesis and the telomere C-strand fill-in, which has been extensively studied in mammalian cells. However, we recently discovered that trypanosomes lack many telomere proteins identified in its mammalian host that are critical for telomere end processing. Rather, T. brucei uses a unique DNA polymerase, PolIE that belongs to the DNA polymerase A family (E. coli DNA PolI family), to coordinate the telomere G- and C-strand syntheses. In this review, I will first briefly summarize current understanding of telomere end processing in mammals. Subsequently, I will describe PolIE-mediated coordination of telomere G- and C-strand synthesis in T. brucei and implication of this recent discovery.},
}
@article {pmid38071573,
year = {2024},
author = {Doyle, TJ and Juge, PA and Peljto, AL and Lee, S and Walts, AD and Esposito, AJ and Poli, S and Gill, R and Hatabu, H and Nishino, M and Dellaripa, PF and Weinblatt, ME and Shadick, NA and Demoruelle, MK and Sparks, JA and Rosas, IO and Granger, B and Deane, KD and Crestani, B and Wolters, PJ and Dieudé, P and Lee, JS},
title = {Short peripheral blood leukocyte telomere length in rheumatoid arthritis-interstitial lung disease.},
journal = {Thorax},
volume = {79},
number = {2},
pages = {182-185},
doi = {10.1136/thorax-2023-220022},
pmid = {38071573},
issn = {1468-3296},
support = {R01 HL155522/HL/NHLBI NIH HHS/United States ; R03 HL148484/HL/NHLBI NIH HHS/United States ; K23 HL119558/HL/NHLBI NIH HHS/United States ; R01 HL139897/HL/NHLBI NIH HHS/United States ; L30 HL149048/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; Telomere Shortening ; Telomere/genetics ; *Arthritis, Rheumatoid/genetics/complications ; *Lung Diseases, Interstitial/complications ; Smoking ; },
abstract = {Shortened telomere lengths (TLs) can be caused by single nucleotide polymorphisms and loss-of-function mutations in telomere-related genes (TRG), as well as ageing and lifestyle factors such as smoking. Our objective was to determine if shortened TL is associated with interstitial lung disease (ILD) in individuals with rheumatoid arthritis (RA). This is the largest study to demonstrate and replicate that shortened peripheral blood leukocytes-TL is associated with ILD in patients with RA compared with RA without ILD in a multinational cohort, and short PBL-TL was associated with baseline disease severity in RA-ILD as measured by forced vital capacity percent predicted.},
}
@article {pmid38068836,
year = {2023},
author = {Lis, N and Lamnisos, D and Bograkou-Tzanetakou, A and Hadjimbei, E and Tzanetakou, IP},
title = {Preterm Birth and Its Association with Maternal Diet, and Placental and Neonatal Telomere Length.},
journal = {Nutrients},
volume = {15},
number = {23},
pages = {},
pmid = {38068836},
issn = {2072-6643},
mesh = {Infant, Newborn ; Humans ; Pregnancy ; Female ; *Placenta ; *Premature Birth/epidemiology ; Diet/adverse effects ; Family ; Telomere ; },
abstract = {Preterm birth (PTB), a multi-causal syndrome, is one of the global epidemics. Maternal nutrition, but also neonatal and placental telomere length (TL), are among the factors affecting PTB risk. However, the exact relationship between these factors and the PTB outcome, remains obscure. The aim of this review was to investigate the association between PTB, maternal nutrition, and placental-infant TL. Observational studies were sought with the keywords: maternal nutrition, placental TL, newborn, TL, and PTB. No studies were found that included all of the keywords simultaneously, and thus, the keywords were searched in dyads, to reach assumptive conclusions. The findings show that maternal nutrition affects PTB risk, through its influence on maternal TL. On the other hand, maternal TL independently affects PTB risk, and at the same time PTB is a major determinant of offspring TL regulation. The strength of the associations, and the extent of the influence from covariates, remains to be elucidated in future research. Furthermore, the question of whether maternal TL is simply a biomarker of maternal nutritional status and PTB risk, or a causative factor of PTB, to date, remains to be answered.},
}
@article {pmid38066848,
year = {2023},
author = {Niewisch, MR and Beier, F and Savage, SA},
title = {Clinical manifestations of telomere biology disorders in adults.},
journal = {Hematology. American Society of Hematology. Education Program},
volume = {2023},
number = {1},
pages = {563-572},
pmid = {38066848},
issn = {1520-4383},
mesh = {Adult ; Humans ; Germ-Line Mutation ; *Hematologic Diseases ; *Neoplasms/diagnosis/genetics ; Telomere/genetics ; Biology ; },
abstract = {Telomere biology disorders (TBDs) are a spectrum of inherited bone marrow failure syndromes caused by impaired telomere function due to pathogenic germline variants in genes involved in telomere maintenance. TBDs can affect many organ systems and are often thought of as diseases of childhood. However, TBDs may present in mid- or even late adulthood with features similar to but not always the same as the childhood-onset TBDs. Adult-onset TBDs are often cryptic with isolated pulmonary, liver, or hematologic disease, or cancer, and may lack the classic disease-defining triad of abnormal skin pigmentation, nail dysplasia, and oral leukoplakia. Diagnostics include detection of very short leukocyte telomeres and germline genetic testing. Notably, adult-onset TBDs may show telomeres in the 1st to 10th percentile for age, and some cases may not have an identifiable genetic cause. TBD genetic etiology includes all modes of inheritance, with autosomal dominant the most frequent in adult-onset disease. Variable symptom onset due to incomplete penetrance, variable expressivity, and genetic anticipation add to the diagnostic challenges. Adult-onset TBDs are likely underrecognized, but their correct identification is of utmost importance, since affected patients are faced with numerous clinical complications, including but not limited to an increased risk of malignancies requiring close surveillance for early detection. Currently lung, liver, or hematopoietic cell transplants are the only curative therapeutic approaches but can be complicated by comorbidities, despite improved medical care. This review highlights the challenges of identifying adult-onset TBDs and addresses currently recommended clinical screening measures and therapy options.},
}
@article {pmid38066331,
year = {2023},
author = {Zhai, T and Zilli Vieira, CL and Vokonas, P and Baccarelli, AA and Nagel, ZD and Schwartz, J and Koutrakis, P},
title = {Annual space weather fluctuations and telomere length dynamics in a longitudinal cohort of older men: the Normative Aging Study.},
journal = {Journal of exposure science &amp; environmental epidemiology},
volume = {},
number = {},
pages = {},
pmid = {38066331},
issn = {1559-064X},
abstract = {BACKGROUND: Space weather has been associated with increased risk of cardiovascular diseases in space and flight crew. However, limited research has focused on the ground population, particularly among the elderly who are vulnerable to aging-related diseases.<br><br>OBJECTIVE: We evaluated the association between space weather alterations and biological aging using leukocyte telomere length as a biomarker in healthy elderly men.<br><br>METHODS: We used data from the Normative Aging Study, a longitudinal cohort of healthy elderly men in Massachusetts, USA. Leukocyte telomere length and health information were measured at in-person examinations approximately every three years, contributing to a total of 1,850 visits from 791 participants. Regional space weather information was collected daily, including cosmic ray-induced ionization, neutrons, sunspot number, interplanetary magnetic field, and Kp-index as our exposure of interest. We used mixed-effects models with a random intercept per individual to evaluate the associations between annual averages of space weather indicators and relative telomere length while accounting for participant demographics, environmental parameters, and secular trends.<br><br>RESULTS: The mean age at baseline was 72.36 years. A one-year increment in age is associated with a 1.21% reduction in leukocyte telomere length. In the fully adjusted model accounting for individual and environmental factors, an interquartile range (IQR) increase of annual cosmic ray induced ionization (110.0 ion pairs cm[-3] sec[-1]) was associated with a 17.64% (95%CI: -27.73%, -7.55%) decrease in leukocyte telomere length, equivalent to 15-years age increment. Solar and geomagnetic activities were associated with increased leukocyte telomere length, but the association became absent after adjusting for cosmic ray indicators.<br><br>IMPACT: Galactic cosmic rays may accelerate the aging process in populations on the Earth, despite the protection by the Earth's atmosphere and magnetic field. This research enhances our understanding of how changes in space weather can impact health, highlights potential risks from space to Earth's inhabitants, and helps inform health strategies for vulnerable populations.},
}
@article {pmid38065483,
year = {2024},
author = {Yang, X and Feng, F and Gao, D and Cai, L and Wan, C and Zhou, X and Zeng, Z},
title = {Analysis of telomere length and the relationship with neurocognitive functions in euthymic bipolar disorder: A cross-sectional pilot study.},
journal = {Journal of affective disorders},
volume = {347},
number = {},
pages = {630-634},
doi = {10.1016/j.jad.2023.12.021},
pmid = {38065483},
issn = {1573-2517},
mesh = {Humans ; *Bipolar Disorder/complications/genetics ; Pilot Projects ; Telomere Shortening ; Cross-Sectional Studies ; Telomere/genetics ; Biomarkers ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Telomere shortening has been considered a potential biological marker related to disease susceptibility and aging in psychiatric disorders. However, the relationship between telomere length and bipolar disorder (BD-I and BD-II) is uncertain. Moreover, whether telomere shortening is an independent factor of cognitive impairment in BD patients is still inconclusive.<br><br>METHODS: We explore telomere length and cognitive function in patients with bipolar disorder and the relationship between them. We enrolled three groups (35 patients with euthymic BD-I, 18 with euthymic BD-II, and 38 healthy controls). Telomere length was measured by fluorescent quantitative polymerase chain reaction (q-PCR), and cognitive function was evaluated by the MATRICS Consensus Cognitive Battery (MCCB). SPSS 24.0 was used for statistical analysis.<br><br>RESULTS: The telomere length of euthymic patients with BD-I and BD-II was shorter than that of healthy controls (F&#xa0;=&#xa0;8.228, P&#xa0;=&#xa0;0.001, &#x3b7;[2]&#xa0;=&#xa0;0.176). Telomere length was not significantly different between BD-I and BD-II. Compared to HCs, poor performance was detected in attention and vigilance in BD-I patients (F&#xa0;=&#xa0;3.473, P&#xa0;=&#xa0;0.036). Working memory was positively correlated with telomere length in BD-II patients (Beta&#xa0;=&#xa0;0.5, P&#xa0;=&#xa0;0.041, Adjusted R[2]&#xa0;=&#xa0;0.2).<br><br>CONCLUSIONS: The current study provided evidence of shortened telomere length in euthymic BD patients, indicating that telomere shortening might be a promising biomarker of susceptibility to bipolar disorder. The telomere length predicted the working memory in BD-II patients. Further studies are needed to clarify the role of accelerated aging on cognitive functioning in a young group of patients with BD.},
}
@article {pmid38063002,
year = {2023},
author = {Belić, M and Sopić, M and Roksandić-Milenković, M and Ćeriman, V and Guzonijić, A and Vukašinović, A and Ostanek, B and Dimić, N and Jovanović, D and Kotur-Stevuljević, J},
title = {Correlation of Short Leukocyte Telomeres and Oxidative Stress with the Presence and Severity of Lung Cancer Explored by Principal Component Analysis.},
journal = {Folia biologica},
volume = {69},
number = {2},
pages = {59-68},
doi = {10.14712/fb2023069020059},
pmid = {38063002},
issn = {0015-5500},
support = {451-03-9/2021-14/200161//Ministarstvo Prosvete, Nauke i Tehnolo&#x161;kog Razvoja/ ; },
mesh = {Humans ; *Telomere Shortening ; *Lung Neoplasms/genetics/metabolism ; Principal Component Analysis ; Leukocytes/metabolism ; Oxidative Stress ; Telomere ; },
abstract = {Lung cancer (LC) is the second most common malignancy and leading cause of cancer death. The potential "culprit" for local and systemic telomere shortening in LC patients is oxidative stress. We investigated the correlation between the peripheral blood leukocyte (PBL) telomere length (TL) and the presence/severity of LC and oxidative stress, and its usefulness as LC diagnostic marker. PBL TL was measured in 89 LC patients and 83 healthy subjects using the modified Cawthon RTq-PCR method. The relative PBL TL, found to be a potential diagnostic marker for LC with very good accuracy (P < 0.001), was significantly shorter in patients compared to the control group (CG) (P < 0.001). Significantly shorter telomeres were found in patients with LC TNM stage IV than in patients with stages I-III (P = 0.014), in patients without therapy compared to those on therapy (P = 0.008), and in patients with partial response and stable/progressive disease compared to those with complete response (P = 0.039). The total oxidant status (TOS), advanced oxidation protein products (AOPP), prooxidant-antioxidant balance (PAB) and C-reactive protein (CRP) were significantly higher in patients compared to CG (P < 0.001) and correlated negatively with TL in both patients and CG (P < 0.001). PCA showed a relation between PAB and TL, and between the EGFR status and TL. Oxidative stress and PBL telomere shortening are probably associated with LC development and progression.},
}
@article {pmid38054014,
year = {2023},
author = {Pelletier, D and Blier, PU and Vézina, F and Dufresne, F and Paquin, F and Christen, F and Guillemette, M},
title = {Under pressure-exploring partner changes, physiological responses and telomere dynamics in northern gannets across varying breeding conditions.},
journal = {PeerJ},
volume = {11},
number = {},
pages = {e16457},
pmid = {38054014},
issn = {2167-8359},
mesh = {Humans ; Animals ; *Antioxidants ; *Birds/genetics ; Telomere/genetics ; Weight Loss/genetics ; Breeding ; Inflammation/genetics ; Oxygen ; },
abstract = {BACKGROUND: Life history theory predicts trade-offs between reproduction and survival in species like the northern gannet (Morus bassanus). During breeding, demanding foraging conditions lead them to expand their foraging range and diversify their diet, increasing the risk of reproductive failure. Changing partners may enhance breeding success but lead to more physiological costs.<br><br>METHODS: To investigate the physiological costs of reproduction upon partner changes, we measured and compared 21 biomarkers related to telomere dynamics, oxidative stress, inflammation, hematology, nutritional status, and muscle damage. We used a longitudinal approach with gannets (n&#xa0;=&#xa0;38) over three contrasting years (2017, 2018 and 2019).<br><br>RESULTS: Our results suggest that annual breeding conditions exert a greater influence on physiological changes than partnership status. Individuals that changed partner experienced greater short-term stress than retained partners. This transient increase in stress was marked by short-term increases in oxidative lipid damage, lower antioxidant capacity, signs of inflammation, and greater weight loss than individuals that retained partners. During favorable conditions, individuals that changed mates had stabilized telomere length, decreased antioxidant capacity, glucose concentration, and muscle damage, along with increased oxygen transport capacity. Conversely, unfavorable breeding conditions led to increased telomere attrition, stabilized antioxidant capacity, decreased inflammation susceptibility, diminished oxygen transport capacity, and increased muscle damage. In the cases where partners were retained, distinct physiological changes were observed depending on the year's conditions, yet the telomere dynamics remained consistent across both partnership status categories. During the favorable year, there was an increase in unsaturated fatty acids and oxygen transport capacity in the blood, coupled with a reduction in inflammation potential and protein catabolism. In contrast, during the unfavorable year in the retained mates, we observed an increase in oxidative DNA damage, antioxidant capacity, weight loss, but a decrease in inflammation susceptibility as observed in changed mates.<br><br>DISCUSSION: Our study shows that behavioral flexibility such as mate switching can help seabirds cope with the challenges of food scarcity during reproduction, but these coping strategies may have a negative impact on physiological status at the individual level. In addition, the marked reduction in telomere length observed during harsh conditions, coupled with the stabilization of telomere length in favorable conditions, highlights the long-term physiological impact of annual breeding conditions on seabirds. These findings underscore the effect on their potential survival and fitness, emphasizing that the influence of annual breeding conditions is greater than that of partnership status.},
}
@article {pmid38052712,
year = {2024},
author = {Volders, ELD and Meijer, C and Steeneken, LS and Lubberts, S and Zwart, N and van Roon, AM and Lefrandt, JD and de Jong, IJ and Demaria, M and Nuver, J and Gietema, JA},
title = {Change in telomere length and cardiovascular risk factors in testicular cancer survivors.},
journal = {Urologic oncology},
volume = {42},
number = {1},
pages = {24.e1-24.e8},
doi = {10.1016/j.urolonc.2023.10.010},
pmid = {38052712},
issn = {1873-2496},
mesh = {Male ; Humans ; *Cardiovascular Diseases/genetics ; *Metabolic Syndrome/complications/genetics ; *Testicular Neoplasms/drug therapy/genetics ; Prospective Studies ; Cisplatin/adverse effects ; Risk Factors ; Telomere Shortening ; Heart Disease Risk Factors ; Triglycerides ; Survivors ; Telomere/genetics ; *Hypogonadism/complications/genetics ; },
abstract = {BACKGROUND: Testicular cancer (TC) survivors cured with chemotherapy (CT) are prone to develop cardiovascular diseases, as part of an accelerated aging phenotype. A mechanism contributing to these events can be telomere shortening.<br><br>PATIENTS AND METHODS: In a prospective cohort of patients with disseminated TC who received cisplatin-based CT, mean absolute leukocyte telomere length (TL) was measured before and 1 year after start of treatment. Cardiovascular risk factors, including development of the metabolic syndrome and hypogonadism, were assessed before and up to 5 years after CT.<br><br>RESULTS: For the whole group (n&#x202f;=&#x202f;55), TL did not change 1 year after CT (5.7 (2.2-13.4) vs. 5.8 kb (1.6-19.2), P&#x202f;=&#x202f;0.335). At baseline, patients with a BMI >30 kg/m[2] (n = 12) had shorter TL (4.9 (2.2-13.4) vs. 6.3 kb (3.1-12.9), P = 0.045), while no age-dependent differences were measured. Patients with TL shortening after 1 year (n = 7) showed a significant increase in diastolic blood pressure (P = 0.007) and triglycerides (P = 0.003), compared to those with unchanged TL. There was no association between telomere shortening after 1 year or short TL at baseline (n = 7+11) and development of metabolic syndrome (25% vs. 21%; P = 0.777), or hypogonadism (38% vs. 17%; P = 0.120) after 5 years.<br><br>CONCLUSIONS: A small subset of TC patients treated with cisplatin-based CT showed telomere shortening 1 year after treatment. This shortening was associated to a rise in diastolic blood pressure and triglycerides, but not to newly developed metabolic syndrome and hypogonadism after 5 years.},
}
@article {pmid38047504,
year = {2024},
author = {Pepke, ML},
title = {Telomere length is not a useful tool for chronological age estimation in animals.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {46},
number = {2},
pages = {e2300187},
doi = {10.1002/bies.202300187},
pmid = {38047504},
issn = {1521-1878},
mesh = {Animals ; *Telomere Shortening/genetics ; *Vertebrates/genetics ; Cell Division ; Oxidative Stress ; Telomere/genetics ; },
abstract = {Telomeres are short repetitive DNA sequences capping the ends of chromosomes. Telomere shortening occurs during cell division and may be accelerated by oxidative damage or ameliorated by telomere maintenance mechanisms. Consequently, telomere length changes with age, which was recently confirmed in a large meta-analysis across vertebrates. However, based on the correlation between telomere length and age, it was concluded that telomere length can be used as a tool for chronological age estimation in animals. Correlation should not be confused with predictability, and the current data and studies suggest that telomeres cannot be used to reliably predict individual chronological age. There are biological reasons for why there is large individual variation in telomere dynamics, which is mainly due to high susceptibility to a wide range of environmental, but also genetic factors, rendering telomeres unfeasible as a tool for age estimation. The use of telomeres for chronological age estimation is largely a misguided effort, but its occasional reappearance in the literature raises concerns that it will mislead resources in wildlife conservation.},
}
@article {pmid38047499,
year = {2024},
author = {Rai, R and Sodeinde, T and Boston, A and Chang, S},
title = {Telomeres cooperate with the nuclear envelope to maintain genome stability.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {46},
number = {2},
pages = {e2300184},
doi = {10.1002/bies.202300184},
pmid = {38047499},
issn = {1521-1878},
support = {RO1GM141350/GF/NIH HHS/United States ; RO1GM141350/GM/NIGMS NIH HHS/United States ; RO1GM141350/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Humans ; *Nuclear Envelope/metabolism ; *Telomere/genetics/metabolism ; Telomere-Binding Proteins/chemistry/genetics/metabolism ; DNA/metabolism ; Genomic Instability ; Mammals/genetics ; },
abstract = {Mammalian telomeres have evolved safeguards to prevent their recognition as DNA double-stranded breaks by suppressing the activation of various DNA sensing and repair proteins. We have shown that the telomere-binding proteins TRF2 and RAP1 cooperate to prevent telomeres from undergoing aberrant homology-directed recombination by mediating t-loop protection. Our recent findings also suggest that mammalian telomere-binding proteins interact with the nuclear envelope to maintain chromosome stability. RAP1 interacts with nuclear lamins through KU70/KU80, and disruption of RAP1 and TRF2 function result in nuclear envelope rupture, promoting telomere-telomere recombination to form structures termed ultrabright telomeres. In this review, we discuss the importance of the interactions between shelterin components and the nuclear envelope to maintain telomere homeostasis and genome stability.},
}
@article {pmid38041119,
year = {2023},
author = {Xiong, L and Yang, G and Guo, T and Zeng, Z and Liao, T and Li, Y and Li, Y and Chen, F and Yang, S and Kang, L and Liang, Z},
title = {17-year follow-up of association between telomere length and all-cause mortality, cardiovascular mortality in individuals with metabolic syndrome: results from the NHANES database prospective cohort study.},
journal = {Diabetology &amp; metabolic syndrome},
volume = {15},
number = {1},
pages = {247},
pmid = {38041119},
issn = {1758-5996},
support = {No. 2021A374//administration of Traditional Chinese Medicine of Jiangxi Province, China (grant No. 2021A374)/ ; No. KCXFZ20201221173600001 and JCYJ20220818102605013//the Science and Technology Planning Project of Shenzhen City, Guangdong Province, China/ ; No. KCXFZ20201221173600001 and JCYJ20220818102605013//the Science and Technology Planning Project of Shenzhen City, Guangdong Province, China/ ; },
abstract = {BACKGROUND: The relationship between leukocyte telomere length (LTL) and mortality risk in individuals with metabolic syndrome (MetS) remains poorly understood. This study aimed to investigate the association between telomere length and long-term all-cause mortality, and cardiovascular disease (CVD) mortality, in individuals with MetS in the United States.<br><br>METHODS: A total of 1980 participants with MetS aged 18 years or older from the National Health and Nutrition Examination Survey (NHANES) prospective cohort study (1999-2002) were included in this cohort study. Medical records review was used to identify the cause of deaths as of December 2018. We employed Kaplan-Meier curves, fitted curves, and Cox proportional hazards regression models to estimate hazard ratios (HRs) for all-cause and CVD mortality, stratified by tertiles of LTL.<br><br>RESULTS: Over a median follow-up of 17.75 years of participants with metabolic syndrome, 819 deaths occurred, including 231 cardiovascular deaths. After adjusting for multiple covariates, participants with shorter telomere length had a significantly higher risk of all-cause mortality (HR, 1.33; 95% CI, 1.11-1.6) and CVD mortality (HR, 1.36; 95% CI, 0.96-1.93) compared with those in the highest tertile of telomere length. All-cause mortality (P&#x2009;<&#x2009;0.001) and cardiovascular disease mortality (P&#x2009;=&#x2009;0.028) followed a similar pattern across tertiles of telomere length.<br><br>CONCLUSION: In individuals with MetS, shorter telomere length is associated with increased risks of death from cardiovascular disease and all causes. The underlying mechanisms and clinical implications of these findings require additional investigation.},
}
@article {pmid38040384,
year = {2024},
author = {Prévot D'Alvise, N and Ascensio, E and Richard, S},
title = {Influence of EE2 exposure, age and sex on telomere length in European long-snouted seahorse (Hippocampus guttulatus).},
journal = {General and comparative endocrinology},
volume = {346},
number = {},
pages = {114419},
doi = {10.1016/j.ygcen.2023.114419},
pmid = {38040384},
issn = {1095-6840},
mesh = {Humans ; Male ; Animals ; Female ; Aged ; *Telomerase/genetics/metabolism ; *Smegmamorpha/genetics/metabolism ; Telomere Homeostasis ; Telomere/genetics/metabolism ; RNA, Messenger ; },
abstract = {After a Telomere Lengthening in juvenile stage, a progressive telomere shortening occurs with age despite higher telomerase level. Telomere Length (TL) may also reflect past physiological state such as a chronic chemical stress. Several studies have revealed a correlation between TL, ageing and/or sex in vertebrates, including teleosts; however, the patterns of telomere dynamics with telomerase mRNA expression, sex, lifespan or chemical stress in teleosts are unclear. The first aim of this study is to verify if telomere length is age and sex-dependent. The second aim is to consider if TL is a useful indicator of stress response in European long-snouted seahorse, Hippocampus guttulatus, an ectothermic and non-model system. We showed that after telomere lengthening during the juvenile stage, a telomeric attrition became significant in sexually mature individuals (p = 0.042). TL decreased in older seahorses despite the presence of somatic telomerase mRNA expression at all life stages studied. There was no difference in TL between males and females, but telomerase mRNA expression was consistently higher in females than males. Exposure to EE2 had no effect on TL in young seahorses, but was correlated with a significant increase in telomerase mRNA expression and various physiological disruptions. Here, a growth retardation of -10 % for body length (p = 0.016) and approximately -45 % for mass (p = 0.001) compared to healthy juvenile seahorses was observed. Our data suggest that telomere dynamics alone should not be used as a marker of EE2 exposure in juvenile seahorses.},
}
@article {pmid38039691,
year = {2024},
author = {Zhang, Y and Zhang, C and Zhang, C and Bin, X and Jiang, J and Huang, C},
title = {Leukocyte telomere length mediates the association between cadmium exposure and cognitive function in US older adults.},
journal = {Journal of psychiatric research},
volume = {169},
number = {},
pages = {166-173},
doi = {10.1016/j.jpsychires.2023.11.023},
pmid = {38039691},
issn = {1879-1379},
mesh = {Male ; Humans ; United States ; Middle Aged ; Aged ; Female ; Nutrition Surveys ; *Cadmium/toxicity ; *Cognition ; Leukocytes ; Telomere ; },
abstract = {BACKGROUND: Long-term exposure to cadmium-polluted environments may lead to shortened leukocyte telomere length and cognitive decline. This study aims to investigate (1) the associations among blood cadmium levels, leukocyte telomere length, and cognitive function, and (2) the mediating role of leukocyte telomere length between blood cadmium levels and cognitive function among older adults in the United States.<br><br>METHODS: Using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. Cadmium exposure level was assessed by measuring cadmium levels in blood samples. Leukocyte telomere length was measured by quantitative polymerase chain reaction, and cognitive function was measured by the digit symbol substitution test (DSST).<br><br>RESULTS: A total of 2185 older adults aged over 60 were included in this study, comprising 1109 (49.65%) males. Elevated blood cadmium levels were significantly associated with the risk of a decline in cognitive function (&#x3b2;&#xa0;=&#xa0;- 2.842, p&#xa0;=&#xa0;0.018). Shorter leukocyte telomere lengths were significantly associated with a higher risk of a decline in cognitive function (&#x3b2;&#xa0;=&#xa0;4.144, p&#xa0;=&#xa0;0.020). The total indirect effect on the blood cadmium level and cognitive function via leukocyte telomere length was - 0.218 (p&#xa0;=&#xa0;0.012). The mediation effect was estimated to be 0.218/2.084&#xa0;&#xd7;&#xa0;100%&#xa0;=&#xa0;10.46%.<br><br>CONCLUSION: The findings suggest that cadmium exposure may increase the risk of cognitive impairment by causing shortened leukocyte telomere length.},
}
@article {pmid38035695,
year = {2023},
author = {Cottin, V and Kolb, M},
title = {Leukocyte telomere length: the dawn of a new era of personalised medicine in fibrotic interstitial lung diseases?.},
journal = {The European respiratory journal},
volume = {62},
number = {5},
pages = {},
doi = {10.1183/13993003.01852-2023},
pmid = {38035695},
issn = {1399-3003},
mesh = {Humans ; *Pulmonary Fibrosis/genetics/therapy ; Precision Medicine ; *Lung Diseases, Interstitial/genetics/therapy ; Fibrosis ; Leukocytes ; Immunosuppression Therapy ; Telomere/genetics ; },
}
@article {pmid38034012,
year = {2023},
author = {Bai, C and Shen, Z and Qiu, B and Zhang, S},
title = {Leukocyte telomere length is associated with increased risk of endometriosis: a bidirectional two-sample Mendelian randomization study.},
journal = {Frontiers in endocrinology},
volume = {14},
number = {},
pages = {1272200},
pmid = {38034012},
issn = {1664-2392},
mesh = {Female ; Humans ; *Endometriosis/genetics ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Leukocytes ; Telomere ; },
abstract = {BACKGROUND: Endometriosis (EMs) is a common gynecological disorder. Observational studies on the relationship between leukocyte telomere length (LTL) and EMs have shown conflicting results. The purpose of this study was to evaluate the precise causal relationship between LTL and EMs using Mendelian randomization (MR) methodology.<br><br>METHODS: We employed MR to assess the causal relationship between LTL and EMs. Summary data from several large-scale genome-wide association studies (GWAS) were used for bidirectional two-sample MR analysis. Sensitivity analyses were conducted to ensure the robustness of our results. All analyses were also replicated in another completely independent EMs dataset.<br><br>RESULTS: Our MR analysis indicated that genetically predicted longer LTL increased the risk of EMs (IVW: discovery, OR=1.169, 95%CI: 1.059-1.290, p=0.002; validation, OR=1.302, 95%CI: 1.140-1.487, p=0.000), while EMs had no causal impact on LTL (IVW: discovery, OR=1.013, 95%CI: 1.000-1.027, p=0.056; IVW: validation, OR=1.005, 95%CI: 0.995-1.015, p=0.363). Causal estimates were supported by various calculation models (including MR-Egger, Weighted median, MR-PRESSO, and MR-RAPS). Heterogeneity and pleiotropy analyses also indicated robustness of the results.<br><br>CONCLUSION: Our findings substantiate the idea that a genetically predicted longer LTL elevates the risk of EMs, with no influence of EMs on LTL risk. This research bolsters the causal link between LTL and EMs, overcoming the constraints of earlier observational studies. It implies that LTL may potentially function as a biomarker for EMs, opening up novel possibilities for EMs prevention and treatment.},
}
@article {pmid38030615,
year = {2023},
author = {Barcenilla, BB and Meyers, AD and Castillo-González, C and Young, P and Min, JH and Song, J and Phadke, C and Land, E and Canaday, E and Perera, IY and Bailey, SM and Aquilano, R and Wyatt, SE and Shippen, DE},
title = {Arabidopsis telomerase takes off by uncoupling enzyme activity from telomere length maintenance in space.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {7854},
pmid = {38030615},
issn = {2041-1723},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; },
mesh = {Telomere Homeostasis ; *Arabidopsis/metabolism ; *Telomerase/genetics/metabolism ; *Arabidopsis Proteins/genetics/metabolism ; Telomere-Binding Proteins/metabolism ; Telomere/genetics/metabolism ; Plants/metabolism ; },
abstract = {Spaceflight-induced changes in astronaut telomeres have garnered significant attention in recent years. While plants represent an essential component of future long-duration space travel, the impacts of spaceflight on plant telomeres and telomerase have not been examined. Here we report on the telomere dynamics of Arabidopsis thaliana grown aboard the International Space Station. We observe no changes in telomere length in space-flown Arabidopsis seedlings, despite a dramatic increase in telomerase activity (up to 150-fold in roots), as well as elevated genome oxidation. Ground-based follow up studies provide further evidence that telomerase is induced by different environmental stressors, but its activity is uncoupled from telomere length. Supporting this conclusion, genetically engineered super-telomerase lines with enhanced telomerase activity maintain wildtype telomere length. Finally, genome oxidation is inversely correlated with telomerase activity levels. We propose a redox protective capacity for Arabidopsis telomerase that may promote survivability in harsh environments.},
}
@article {pmid38029531,
year = {2024},
author = {Zhou, Q and Wang, Y and Xin, C and Wei, X and Yao, Y and Xia, L},
title = {Identification of telomere-associated gene signatures to predict prognosis and drug sensitivity in glioma.},
journal = {Computers in biology and medicine},
volume = {168},
number = {},
pages = {107750},
doi = {10.1016/j.compbiomed.2023.107750},
pmid = {38029531},
issn = {1879-0534},
mesh = {Humans ; *Glioma/drug therapy/genetics ; Telomere/genetics ; *Brain Neoplasms/drug therapy/genetics ; Cluster Analysis ; Tumor Microenvironment ; Dual-Specificity Phosphatases ; Mitogen-Activated Protein Kinase Phosphatases ; },
abstract = {OBJECTIVE: Gliomas are a heterogeneous group of brain tumors with distinct biological and clinical properties, leading to significant mortality and morbidity. Emerging evidence shows telomere maintenance has implicated in glioma susceptibility and prognosis. In this study, we comprehensively analyzed gene signatures related to telomere maintenance in glioma and their predictive values for predicting the prognosis and drug sensitivity in glioma.<br><br>METHODS: We initially identified telomere-related genes differentially expressed between low-grade glioma (LGG) and glioblastoma (GBM) and accordingly developed a risk model by univariate and multivariate Cox analysis to assess the expressions of telomere-related genes across the risk groups. Finally, to assess these genes in immune function the anti-tumor medications often used in the clinical treatment of glioma, we computed immune cell infiltration analysis and drug sensitivity analysis.<br><br>RESULTS: The consensus clustering analysis identified 20 telomere-related genes which split LGG patients into two distinct subtypes. The patient survival, the expressions of key telomere-related DEGs, and immune cell infiltration significantly differed between Cluster 1 and Cluster 2. The LASSO risk model [riskScore=(0.086)*HOXA7+(0.242)*WEE1+(0.247)*IGF2BP3+(0.052)*DUSP10] showed significant differences regarding the 1-, 3-, 5-year overall survival, immune cell infiltration, and drug sensitivity between high- and low-risk groups. The predictive nomogram constructed to quantify the survival probability of each sample at 1, 3, and 5 years was consistent with the actual patient survival.<br><br>CONCLUSION: Our comprehensive characterization of telomere-associated gene signatures in glioma reveals their possible roles in the development, tumor microenvironment, and prognosis. The study provides some suggestive relationships between four telomere-related genes (HOXA7, WEE1, IGF2BP3, and DUSP10) and glioma prognosis.},
}
@article {pmid38029511,
year = {2024},
author = {Benites-Zapata, VA and Ulloque-Badaracco, JR and Alarcón-Braga, EA and Fernández-Alonso, AM and López-Baena, MT and Pérez-López, FR},
title = {Telomerase activity and telomere length in women with breast cancer or without malignancy: A systematic review and meta-analysis.},
journal = {Maturitas},
volume = {180},
number = {},
pages = {107882},
doi = {10.1016/j.maturitas.2023.107882},
pmid = {38029511},
issn = {1873-4111},
mesh = {Humans ; Female ; *Breast Neoplasms/genetics ; *Telomerase/metabolism ; Telomere/metabolism ; },
abstract = {AIM: We performed a systematic review and meta-analysis to assess whether telomerase activity and telomere length are associated with breast cancer.<br><br>METHODS: PubMed, Web of Science, Embase, LILACS, Scielo, Embase, and CNKI databases were searched to obtain relevant articles published through May 10, 2023, following PRISMA guidelines and a registered PROSPERO protocol (CRD42022335402). We included observational studies reporting telomerase activity or telomere length in patients with breast cancer compared with women with benign lesions or normal tissue (control women). The Newcastle-Ottawa Scale was used to evaluate the quality of studies. Data were expressed as odds ratios (OR) and 95&#xa0;% confidence intervals (CI). Random effects and inverse variance methods were used to meta-analyze associations. The I[2] test was used to assess heterogeneity.<br><br>RESULTS: The meta-analysis of telomerase shows significantly greater activity in patients with breast cancer than in those without malignancies (OR&#xa0;=&#xa0;23.46, 95&#xa0;% CI 14.07-39.11, p&#xa0;<&#xa0;0.00001, I[2]&#xa0;=&#xa0;72&#xa0;%). There were non-significant differences in relative telomere length (OR&#xa0;=&#xa0;1.16, 95&#xa0;% CI&#xa0;=&#xa0;0.90-1.49, p&#xa0;=&#xa0;0.26, I[2]&#xa0;=&#xa0;86&#xa0;%) and leukocyte telomere length (OR&#xa0;=&#xa0;2.32, 95&#xa0;% CI&#xa0;=&#xa0;0.89-6.08, p&#xa0;=&#xa0;0.09, I[2]&#xa0;=&#xa0;98&#xa0;%) between women with and without breast cancer. In subgroup analyses by world regions of studies, both telomerase activity and telomere length displayed the same trends as in their respective meta-analyses. In sensitivity analyses, variables showed their respective same trends.<br><br>CONCLUSION: Telomerase activity is higher in patients with breast cancer than in women without malignancies. There were no significant differences in either relative telomere length or leukocyte telomere length in women with and without breast cancer. PROSPERO protocol CRD42022335402.},
}
@article {pmid38028989,
year = {2023},
author = {Qin, B},
title = {Can Antidiabetic Medications Affect Telomere Length in Patients with Type 2 Diabetes? A Mini-Review.},
journal = {Diabetes, metabolic syndrome and obesity : targets and therapy},
volume = {16},
number = {},
pages = {3739-3750},
pmid = {38028989},
issn = {1178-7007},
abstract = {The fight against aging is an eternal pursuit of humankind. The aging rate of patients with type 2 diabetes mellitus (T2DM) is higher than that of healthy individuals. Reducing the aging rate of patients with T2DM and extending their life expectancy are challenges that endocrinologists are eager to overcome. Many studies have shown that antidiabetic medications have potent anti-aging potential. Telomeres are repetitive DNA sequences located at the ends of chromosomes, and telomere shortening is a hallmark of aging. This review summarizes clinical trials that have explored the association between antidiabetic medications and telomere length (TL) in patients with T2DM and explore the mystery of delaying aging in patients with T2DM from the perspective of telomeres. Various antidiabetic medications may have different effects on TL in patients with T2DM. Metformin and sitagliptin may protect telomeres in patients with T2DM, while exogenous insulin may promote telomere shortening in patients with T2DM. The effect of acarbose and glyburide on TL in patients with T2DM is still uncertain due to the absence of evidence from longitudinal studies.},
}
@article {pmid38026244,
year = {2023},
author = {Almuraikhy, S and Sellami, M and Al-Amri, HS and Domling, A and Althani, AA and Elrayess, MA},
title = {Impact of Moderate Physical Activity on Inflammatory Markers and Telomere Length in Sedentary and Moderately Active Individuals with Varied Insulin Sensitivity.},
journal = {Journal of inflammation research},
volume = {16},
number = {},
pages = {5427-5438},
pmid = {38026244},
issn = {1178-7031},
abstract = {INTRODUCTION: Physical activity-associated immune response plays a crucial role in the aging process. This study aimed to determine the impact of short-term moderate physical activity on cytokine levels, oxidative stress markers, and telomere length in lean/overweight young subjects.<br><br>METHODS: Fasting blood samples were collected from 368 participants at Qatar Biobank. Based on their homeostatic model assessment of insulin resistance (HOMA-IR), participants were categorized as insulin sensitive (IS) or insulin resistant (IR). Subsequently, they were divided into four groups: sedentary IS (n = 90), sedentary IR (n = 90), moderately active IS (n = 94), and moderately active IR (n = 94). Moderate physical activity was defined as walking at least two days per week for more than 150 minutes, as determined by physical activity questionnaires. Serum samples were analyzed for circulating inflammatory cytokines (IL-1&#x3b2;, IL-1RA, IL-6, IL-10, IL-22, MCP-1/CCL2, TNF-&#x3b1;), as well as antioxidant enzyme levels (SOD and catalase). Telomere lengths were measured in the respective DNA samples.<br><br>RESULTS: Moderately active IR participants exhibited significantly lower SOD activity, while catalase activity did not show significant differences. Moderately active IS participants had higher IL-6 and IL-10 levels compared to sedentary IS participants, with no significant differences observed in the IR counterparts. Telomere length did not significantly differ between the physically active and sedentary groups.<br><br>CONCLUSION: This study highlights the potential anti-inflammatory and anti-oxidative stress effects of moderate physical activity in individuals with insulin sensitivity and insulin resistance. However, no significant changes in telomere length were observed, suggesting a complex relationship between physical activity and the aging process. Further research is needed to fully understand the underlying mechanisms and optimize the balance between anti-inflammation and anti-oxidation through exercise and lifestyle adjustments.},
}
@article {pmid38024356,
year = {2023},
author = {Messerlian, N and Zgheib, N and Chokor, FAZ and Nasrallah, M and Tamim, H and Nasreddine, L},
title = {Fructose intake and its association with relative telomere length: an exploratory study among healthy Lebanese adults.},
journal = {Frontiers in nutrition},
volume = {10},
number = {},
pages = {1270124},
pmid = {38024356},
issn = {2296-861X},
abstract = {INTRODUCTION: Shorter relative telomere length (RTL) has been associated with increased incidence of morbidity. Although still disputed, available evidence suggests that dietary factors, including sugar-sweetened beverages (SSB) may be linked with shorter RTL. It was argued that the link between SSB and RTL may be explained by the sugar content of these beverages, and specifically fructose given its impact on oxidative stress and the inflammatory response. However, none of the existing studies have examined the specific link between fructose intake and RTL. This exploratory study aimed at (1) assessing the intake of dietary fructose (total, added and natural) in Lebanese healthy adults and (2) examining dietary fructose as a predictor of short telomere length.<br><br>METHODS: Following a cross-sectional design (n = 282), anthropometric and biochemical data were collected. RTL was assessed by utilizing real-time polymerase chain reaction (RT-qPCR) to amplify both telomere and single-copy gene segments. Dietary intake was evaluated using a culture-specific food frequency questionnaire (FFQ). Intakes of added fructose, naturally-occurring fructose, and total fructose were estimated.<br><br>RESULTS: Mean intakes of added and natural fructose were of 39.03 &#xb1; 34.12 and 12.28 &#xb1; 8.59 g/day, respectively, representing 4.80 &#xb1; 3.56 and 1.78 &#xb1; 1.41% of total energy intake (EI). Mean total fructose intake was of 51.31 &#xb1; 35.55 g/day, contributing 6.58 &#xb1; 3.71% EI. Higher intakes of total and added fructose were significantly associated with shorter RTL 2nd RTL tertile as compared to the 3rd RTL tertile; relative risk ratio (RRR) = 3.10 [95% confidence interval (CI): 1.38, 6.94] and RRR = 2.33 (95% CI: 1.02, 5.36), respectively after adjustment for confounders identified using a directed acyclic graph (DAG).<br><br>CONCLUSION: In conclusion, although we could not observe a dose-dependent relation between fructose intakes and RTL shortening and although the study is limited by its small sample size, the findings suggest that total and added dietary fructose intakes may be associated with shorter RTL. Larger studies, of longitudinal nature, are needed to further confirm the study findings.},
}
@article {pmid38023918,
year = {2023},
author = {Wang, L and Li, LL and Chen, L and Zhang, RG and Zhao, SW and Yan, H and Gao, J and Chen, X and Si, YJ and Chen, Z and Liu, H and Xie, XM and Zhao, W and Han, B and Qin, X and Jia, KH},
title = {Telomere-to-telomere and haplotype-resolved genome assembly of the Chinese cork oak (Quercus variabilis).},
journal = {Frontiers in plant science},
volume = {14},
number = {},
pages = {1290913},
pmid = {38023918},
issn = {1664-462X},
abstract = {The Quercus variabilis, a deciduous broadleaved tree species, holds significant ecological and economical value. While a chromosome-level genome for this species has been made available, it remains riddled with unanchored sequences and gaps. In this study, we present a nearly complete comprehensive telomere-to-telomere (T2T) and haplotype-resolved reference genome for Q. variabilis. This was achieved through the integration of ONT ultra-long reads, PacBio HiFi long reads, and Hi-C data. The resultant two haplotype genomes measure 789 Mb and 768 Mb in length, with a contig N50 of 65 Mb and 56 Mb, and were anchored to 12 allelic chromosomes. Within this T2T haplotype-resolved assembly, we predicted 36,830 and 36,370 protein-coding genes, with 95.9% and 96.0% functional annotation for each haplotype genome. The availability of the T2T and haplotype-resolved reference genome lays a solid foundation, not only for illustrating genome structure and functional genomics studies but also to inform and facilitate genetic breeding and improvement of cultivated Quercus species.},
}
@article {pmid38023478,
year = {2023},
author = {Sun, M and Yao, C and Shu, Q and He, Y and Chen, G and Yang, G and Xu, S and Liu, Y and Xue, Z and Wu, J},
title = {Telomere-to-telomere pear (Pyrus pyrifolia) reference genome reveals segmental and whole genome duplication driving genome evolution.},
journal = {Horticulture research},
volume = {10},
number = {11},
pages = {uhad201},
pmid = {38023478},
issn = {2662-6810},
abstract = {Previously released pear genomes contain a plethora of gaps and unanchored genetic regions. Here, we report a telomere-to-telomere (T2T) gap-free genome for the red-skinned pear, 'Yunhong No. 1' (YH1; Pyrus pyrifolia), which is mainly cultivated in Yunnan Province (southwest China), the pear's primary region of origin. The YH1 genome is 501.20 Mb long with a contig N50 length of 29.26 Mb. All 17 chromosomes were assembled to the T2T level with 34 characterized telomeres. The 17 centromeres were predicted and mainly consist of centromeric-specific monomers (CEN198) and long terminal repeat (LTR) Gypsy elements (≥74.73%). By filling all unclosed gaps, the integrity of YH1 is markedly improved over previous P. pyrifolia genomes ('Cuiguan' and 'Nijisseiki'). A total of 1531 segmental duplication (SD) driven duplicated genes were identified and enriched in stress response pathways. Intrachromosomal SDs drove the expansion of disease resistance genes, suggesting the potential of SDs in adaptive pear evolution. A large proportion of duplicated gene pairs exhibit dosage effects or sub-/neo-functionalization, which may affect agronomic traits like stone cell content, sugar content, and fruit skin russet. Furthermore, as core regulators of anthocyanin biosynthesis, we found that MYB10 and MYB114 underwent various gene duplication events. Multiple copies of MYB10 and MYB114 displayed obvious dosage effects, indicating role differentiation in the formation of red-skinned pear fruit. In summary, the T2T gap-free pear genome provides invaluable resources for genome evolution and functional genomics.},
}
@article {pmid38023477,
year = {2023},
author = {Xu, XD and Zhao, RP and Xiao, L and Lu, L and Gao, M and Luo, YH and Zhou, ZW and Ye, SY and Qian, YQ and Fan, BL and Shang, X and Shi, P and Zeng, W and Cao, S and Wu, Z and Yan, H and Chen, LL and Song, JM},
title = {Telomere-to-telomere assembly of cassava genome reveals the evolution of cassava and divergence of allelic expression.},
journal = {Horticulture research},
volume = {10},
number = {11},
pages = {uhad200},
pmid = {38023477},
issn = {2662-6810},
abstract = {Cassava is a crucial crop that makes a significant contribution to ensuring human food security. However, high-quality telomere-to-telomere cassava genomes have not been available up to now, which has restricted the progress of haploid molecular breeding for cassava. In this study, we constructed two nearly complete haploid resolved genomes and an integrated, telomere-to-telomere gap-free reference genome of an excellent cassava variety, 'Xinxuan 048', thereby providing a new high-quality genomic resource. Furthermore, the evolutionary history of several species within the Euphorbiaceae family was revealed. Through comparative analysis of haploid genomes, it was found that two haploid genomes had extensive differences in linear structure, transcriptome features, and epigenetic characteristics. Genes located within the highly divergent regions and differentially expressed alleles are enriched in the functions of auxin response and the starch synthesis pathway. The high heterozygosity of cassava 'Xinxuan 048' leads to rapid trait segregation in the first selfed generation. This study provides a theoretical basis and genomic resource for molecular breeding of cassava haploids.},
}
@article {pmid38023474,
year = {2023},
author = {Zeng, T and He, Z and He, J and Lv, W and Huang, S and Li, J and Zhu, L and Wan, S and Zhou, W and Yang, Z and Zhang, Y and Luo, C and He, J and Wang, C and Wang, L},
title = {The telomere-to-telomere gap-free reference genome of wild blueberry (Vaccinium duclouxii) provides its high soluble sugar and anthocyanin accumulation.},
journal = {Horticulture research},
volume = {10},
number = {11},
pages = {uhad209},
pmid = {38023474},
issn = {2662-6810},
abstract = {Vaccinium duclouxii, endemic to southwestern China, is a berry-producing shrub or small tree belonging to the Ericaceae family, with high nutritive, medicinal, and ornamental value, abundant germplasm resources, and good edible properties. In addition, V. duclouxii exhibits strong tolerance to adverse environmental conditions, making it a promising candidate for research and offering wide-ranging possibilities for utilization. However, the lack of V. duclouxii genome sequence has hampered its development and utilization. Here, a high-quality telomere-to-telomere genome sequence of V. duclouxii was de novo assembled and annotated. All of 12 chromosomes were assembled into gap-free single contigs, providing the highest integrity and quality assembly reported so far for blueberry. The V. duclouxii genome is 573.67 Mb, which encodes 41 953 protein-coding genes. Combining transcriptomics and metabolomics analyses, we have uncovered the molecular mechanisms involved in sugar and acid accumulation and anthocyanin biosynthesis in V. duclouxii. This provides essential molecular information for further research on the quality of V. duclouxii. Moreover, the high-quality telomere-to-telomere assembly of the V. duclouxii genome will provide insights into the genomic evolution of Vaccinium and support advancements in blueberry genetics and molecular breeding.},
}
@article {pmid38022874,
year = {2023},
author = {Farrukh, S and Baig, S},
title = {Parental telomeres implications on immune senescence of newborns.},
journal = {American journal of clinical and experimental immunology},
volume = {12},
number = {5},
pages = {81-86},
pmid = {38022874},
issn = {2164-7712},
abstract = {Telomere, the biological chronometer, and its effect on the immune system considerably varies among individuals. During pregnancy, multiple risk factors affect telomere reprogramming during fetal life which can lead to health disparities in newborns. These changes may cause a long-term impact on the telomere genetics of the newborn and become a reason for lifelong health implications and immune senescence. Therefore, telomere shortening in parents due to genetic variation may act as a hallmark of immune senescence and aging in their newborns.},
}
@article {pmid38021281,
year = {2022},
author = {Srikanth, P and Chowdhury, AR and Low, GKM and Saraswathy, R and Fujimori, A and Banerjee, B and Martinez-Lopez, W and Hande, MP},
title = {Oxidative Damage Induced Telomere Mediated Genomic Instability in Cells from Ataxia Telangiectasia Patients.},
journal = {Genome integrity},
volume = {13},
number = {},
pages = {2},
pmid = {38021281},
issn = {2041-9414},
abstract = {Our cellular genome is susceptible to cytotoxic lesions which include single strand breaks and double strand breaks among other lesions. Ataxia telangiectasia mutated (ATM) protein was one of the first DNA damage sensor proteins to be discovered as being involved in DNA repair and as well as in telomere maintenance. Telomeres help maintain the stability of our chromosomes by protecting the ends from degradation. Cells from ataxia telangiectasia (AT) patients lack ATM and accumulate chromosomal alterations. AT patients display heightened susceptibility to cancer. In this study, cells from AT patients (called as AT [-/-] and AT [+/-] cells) were characterized for genome stability status and it was observed that AT [-/-] cells show considerable telomere attrition. Furthermore, DNA damage and genomic instability were compared between normal (AT [+/+] cells) and AT [-/-] cells exhibiting increased frequencies of spontaneous DNA damage and genomic instability markers. Both AT [-/-] and AT [+/-] cells were sensitive to sodium arsenite (1.5 and 3.0 μg/ml) and ionizing radiation-induced (2 Gy, gamma rays) oxidative stress. Interestingly, telomeric fragments were detected in the comet tails as revealed by comet-fluorescence in situ hybridization analysis, suggestive of telomeric instability in AT [-/-] cells upon exposure to sodium arsenite or radiation. Besides, there was an increase in the number of chromosome alterations in AT [-/-] cells following arsenite treatment or irradiation. In addition, complex chromosome aberrations were detected by multicolor fluorescence in situ hybridization in AT [-/-] cells in comparison to AT [+/-] and normal cells. Telomere attrition and chromosome alterations were detected even at lower doses of sodium arsenite. Peptide nucleic acid - FISH analysis revealed defective chromosome segregation in cells lacking ATM proteins. The data obtained in this study substantiates the role of ATM in telomere stability under oxidative stress.},
}
@article {pmid38020928,
year = {2023},
author = {Fernández-Álvarez, A},
title = {Beyond tradition: exploring the non-canonical functions of telomeres in meiosis.},
journal = {Frontiers in cell and developmental biology},
volume = {11},
number = {},
pages = {1278571},
pmid = {38020928},
issn = {2296-634X},
abstract = {The telomere bouquet is a specific chromosomal configuration that forms during meiosis at the zygotene stage, when telomeres cluster together at the nuclear envelope. This clustering allows cytoskeleton-induced movements to be transmitted to the chromosomes, thereby facilitating homologous chromosome search and pairing. However, loss of the bouquet results in more severe meiotic defects than can be attributed solely to recombination problems, suggesting that the bouquet's full function remains elusive. Despite its transient nature and the challenges in performing in vivo analyses, information is emerging that points to a remarkable suite of non-canonical functions carried out by the bouquet. Here, we describe how new approaches in quantitative cell biology can contribute to establishing the molecular basis of the full function and plasticity of the bouquet, and thus generate a comprehensive picture of the telomeric control of meiosis.},
}
@article {pmid38019799,
year = {2023},
author = {Balouchi, M and Huang, SH and McGrath, SL and Kobryn, K},
title = {The telomere resolvase, TelA, utilizes an underwound pre-cleavage intermediate to promote hairpin telomere formation.},
journal = {PloS one},
volume = {18},
number = {11},
pages = {e0294732},
pmid = {38019799},
issn = {1932-6203},
mesh = {*Recombinases/genetics ; *Bacterial Proteins/genetics ; DNA/chemistry ; Telomere/genetics ; Phosphates ; },
abstract = {The telomere resolvase, TelA, forms the hairpin telomeres of the linear chromosome of Agrobacterium tumefaciens in a process referred to as telomere resolution. Telomere resolution is a unique DNA cleavage and rejoining reaction that resolves replicated telomere junctions into a pair of hairpin telomeres. Telomere resolvases utilize a reaction mechanism with similarities to that of topoisomerase-IB enzymes and tyrosine recombinases. The reaction proceeds without the need for high-energy cofactors due to the use of a covalent, enzyme-cleaved DNA intermediate that stores the bond energy of the cleaved bonds in 3'-phosphotyrosyl linkages. The cleaved DNA strands are then refolded into a hairpin conformation and the 5'-OH ends of the refolded strands attack the 3'-phosphotyrosine linkages in order to rejoin the DNA strands into hairpin telomeres. Because this kind of reaction mechanism is, in principle, reversible it is unclear how TelA controls the direction of the reaction and propels the reaction to completion. We present evidence that TelA forms and/or stabilizes a pre-cleavage intermediate that features breakage of the four central basepairs between the scissile phosphates prior to DNA cleavage to help propel the reaction forwards, thus preventing abortive cleavage and rejoining cycles that regenerate the substrate DNA. We identify eight TelA sidechains, located in the hairpin-binding module and catalytic domains of TelA, implicated in this process. These mutants were deficient for telomere resolution on parental replicated telomere junctions but were rescued by introduction of substrate modifications that mimic unwinding of the DNA between the scissile phosphates.},
}
@article {pmid38018863,
year = {2024},
author = {Mostafa, H and Gutierrez-Tordera, L and Mateu-Fabregat, J and Papandreou, C and Bulló, M},
title = {Dietary fat, telomere length and cognitive function: unravelling the complex relations.},
journal = {Current opinion in lipidology},
volume = {35},
number = {1},
pages = {33-40},
pmid = {38018863},
issn = {1473-6535},
mesh = {Humans ; *Dietary Fats/adverse effects ; *Fatty Acids ; Fatty Acids, Monounsaturated ; Cognition ; Telomere/genetics ; },
abstract = {PURPOSE OF REVIEW: The review aims to explore the recent evidence on the associations between different dietary fat intake and cognitive function, and to understand the role of telomere length in this relationship.<br><br>RECENT FINDINGS: Clinical and preclinical studies included in this review suggest that dietary fat intake is associated with cognitive function and telomere length. High intake of saturated fats and trans fats, commonly found in ultra-processed foods, appears to have negative effects on cognitive function and telomere length, while other dietary fats, such as omega-3 polyunsaturated fatty acids and monounsaturated fatty acids are associated with improved cognitive performance and reduced telomere attrition. Controversial results related to omega-6 polyunsaturated fatty acids intake and its impact on cognitive function were found. Dietary fats may affect telomere length and cognition through oxidative stress, inflammation, and insulin resistance.<br><br>SUMMARY: The current review illustrated the relationship between dietary fat and cognitive function by focusing on the role of telomere length as a potential intermediator. More future studies are required, however, in order to develop targeted interventions aimed at preserving cognitive well-being throughout life.},
}
@article {pmid38017164,
year = {2023},
author = {Le Bras, A},
title = {Short telomeres in Telomice.},
journal = {Lab animal},
volume = {52},
number = {12},
pages = {285},
doi = {10.1038/s41684-023-01297-9},
pmid = {38017164},
issn = {1548-4475},
mesh = {*Telomere Shortening ; Telomere/genetics ; *Telomerase ; },
}
@article {pmid38014526,
year = {2023},
author = {Valipour, B and Davari, S and Farahzadi, R and Pourrasol, S and Mehran, N and Dizaji Asl, K and Altaha, SM and Hojjati, Z and Nozad Charoudeh, H},
title = {Inhibition of mitochondria induces apoptosis and reduces telomere length and activity in acute myeloid leukemia stem cells.},
journal = {Cell biochemistry and function},
volume = {41},
number = {8},
pages = {1477-1487},
doi = {10.1002/cbf.3888},
pmid = {38014526},
issn = {1099-0844},
support = {//Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran/ ; },
mesh = {Adult ; Child ; Humans ; Caspase 9/genetics ; bcl-2-Associated X Protein/metabolism ; *Tumor Suppressor Protein p53/metabolism ; Tigecycline/pharmacology/metabolism ; *Leukemia, Myeloid, Acute/genetics ; Apoptosis ; Antigens, CD34/metabolism ; Neoplastic Stem Cells/metabolism ; Mitochondria/metabolism ; Telomere/metabolism/pathology ; },
abstract = {Acute myeloid leukemia (AML) is a highly lethal hematological malignancy in adults and children. Abnormal proliferation of leukemia stem cells (LSC) with CD34[+] and CD38[-] phenotypes are the main clinical features of AML. Patients with AML face drug resistance and treatment failure due to a default in stem and progenitor cells. Therefore, defining LSC properties is necessary for targeting leukemia-initiating cells. Mitochondrial mass and activity increase in AML initiating cells compared with normal stem cells. This idea has offered the inhibition of the mitochondrial translation machinery to reduce the number of leukemia-initiating cells in patients with AML Tigecycline is an FDA-approved microbial antibiotic that inhibits oxidative phosphorylation in mitochondria, resulting in the suppression of leukemia cell proliferation with little toxicity to normal cells. Thus, the present study was conducted to evaluate whether LSC is influenced by mitochondrial inhibition. We measured the IC50 of tigecycline in KG-1a AML cell lines. KG-1a AML cell lines were separated into CD34[+] and CD34[-] cells by MACS. In the following, these cells were treated with 20 µM (IC50) tigecycline. The expression of Annexin/PI, Caspase 3, apoptotic genes (BCL2, BCLX, BAX, BAD, and P53) and proteins (P53, BAX, BCL2 and Caspase 9) was evaluated in CD34[+] , CD34[-] and KG-1a AML cells. In addition, the telomere length and expression of hTERT were evaluated in this study. The results indicated that BCl2 (gene and protein) and BCLX gene dramatically decreased. In addition, BAD, BAX, and P53 gene and protein expression significantly increased in CD34[+] AML cells compared to CD34[-] AML cells. The results also suggested that tigecycline induced intrinsic (Cleaved-caspase 9/Pro-Caspase 9 ratio) and p53-mediated apoptosis. Furthermore, hTERT gene expression and telomere length decreased in the tigecycline-treated groups. Taken together, our findings indicate that inhibition of mitochondrial activity with tigecycline can induce apoptosis in cancer stem cells and can be used as a novel method for cancer therapy.},
}
@article {pmid38008763,
year = {2023},
author = {San-Cristobal, R and de Toro-Martín, J and Guénard, F and Pérusse, L and Biron, S and Marceau, S and Lafortune Payette, A and Vohl, MC},
title = {Impact of maternal cardiometabolic status after bariatric surgery on the association between telomere length and adiposity in offspring.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {20771},
pmid = {38008763},
issn = {2045-2322},
mesh = {Child ; Female ; Humans ; Adiposity/genetics ; Obesity/complications ; *Bariatric Surgery ; Body Mass Index ; Telomere/genetics ; *Cardiovascular Diseases/genetics/complications ; },
abstract = {The impact of bariatric surgery on metabolic and inflammatory status are reflected in the epigenetic profile and telomere length mediated by the changes in the metabolic status of the patients. This study compared the telomere length of children born before versus after maternal bariatric surgery as a surrogate to test the influence of the mother's metabolic status on children's telomere length. DNA methylation telomere length (DNAmTL) was estimated from Methylation-EPIC BeadChip array data from a total of 24 children born before and after maternal bariatric surgery in the greater Quebec City area. DNAmTL was inversely associated with chronological age in children (r = - 0.80, p < 0.001) and significant differences were observed on age-adjusted DNAmTL between children born before versus after the maternal bariatric surgery. The associations found between body mass index and body fat percentage with DNAmTL in children born after the surgery were influenced by maternal triglycerides, TG/HDL-C ratio and TyG index. This study reports the impact of maternal bariatric surgery on offspring telomere length. The influence of maternal metabolic status on the association between telomere length and markers of adiposity in children suggests a putative modulating effect of bariatric surgery on the cardiometabolic risk in offspring.},
}
@article {pmid38008503,
year = {2023},
author = {Yu, TN and Cheng, EH and Lin, YP and Chen, YC and Huang, CC and Lee, TH and Lee, MS},
title = {Significantly shortened telomere length and altered androgen receptor level in cumulus cells from women with polycystic ovary syndrome.},
journal = {Taiwanese journal of obstetrics &amp; gynecology},
volume = {62},
number = {6},
pages = {845-851},
doi = {10.1016/j.tjog.2023.07.035},
pmid = {38008503},
issn = {1875-6263},
mesh = {Female ; Humans ; Aged ; Adult ; Cumulus Cells ; *Polycystic Ovary Syndrome/genetics/complications ; Receptors, Androgen/genetics ; *Infertility, Female/genetics/complications ; Prospective Studies ; Telomere Shortening/genetics ; Telomere/genetics ; RNA, Messenger ; Hormones ; },
abstract = {OBJECTIVE: The aim of this study was to investigate the correlation between hormone receptor levels and telomere length (TL) in infertile women with and without polycystic ovary syndrome (PCOS).<br><br>MATERIALS AND METHODS: This prospective cohort study recruited a total of 431 cumulus oocyte complex (COC) from 88 infertile women between July 2012 and June 2014. The participants were divided into three groups: young age (<38 years, n&#xa0;=&#xa0;42 and 227 COC), advanced age (&#x2265;38 years, n&#xa0;=&#xa0;33 and 107 COC) and PCOS patients (n&#xa0;=&#xa0;13 and 97 COC). Cumulus cells were collected from individual follicle during oocyte pick-up, and the mRNA levels of hormone receptors and TL were measured using real-time PCR.<br><br>RESULTS: The cumulus cells of PCOS patients demonstrated lower mRNA levels of LH receptor (75.57&#xa0;&#xb1;&#xa0;138.10 vs. 171.07&#xa0;&#xb1;&#xa0;317.68; p&#xa0;<&#xa0;0.01) and androgen receptor (1.13&#xa0;&#xb1;&#xa0;1.52 vs. 4.08&#xa0;&#xb1;&#xa0;9.57; p&#xa0;<&#xa0;0.01), as well as a shorter TL (2.39&#xa0;&#xb1;&#xa0;2.58 vs. 3.96&#xa0;&#xb1;&#xa0;4.72; p&#xa0;<&#xa0;0.01) compared to those of the young age group. In the young age group, only androgen receptor mRNA level showed a significant association with TL (rho&#xa0;=&#xa0;0.148, p&#xa0;=&#xa0;0.026), while FSH receptor mRNA level was the only factor associated with TL (rho&#xa0;=&#xa0;0.247, p&#xa0;=&#xa0;0.015) in PCOS patients. For advanced-aged patients, no significant relationship was observed between hormone receptor mRNA levels and TL. Alternative splicing of androgen receptors was identified in some PCOS patients but not in young age controls.<br><br>CONCLUSION: The findings suggest that the androgen receptor level and function may be altered in the cumulus cells of PCOS patients, leading to a shorter TL in cumulus cells in PCOS patients.},
}
@article {pmid38003036,
year = {2023},
author = {Tao, Y and He, C and Lin, D and Gu, Z and Pu, W},
title = {Comprehensive Identification of Mitochondrial Pseudogenes (NUMTs) in the Human Telomere-to-Telomere Reference Genome.},
journal = {Genes},
volume = {14},
number = {11},
pages = {},
pmid = {38003036},
issn = {2073-4425},
support = {82003360//Young Scientists Fund of the National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Pseudogenes/genetics ; *Mitochondria/genetics ; DNA, Mitochondrial/genetics ; Genome, Human ; Telomere ; },
abstract = {Practices related to mitochondrial research have long been hindered by the presence of mitochondrial pseudogenes within the nuclear genome (NUMTs). Even though partially assembled human reference genomes like hg38 have included NUMTs compilation, the exhaustive NUMTs within the only complete reference genome (T2T-CHR13) remain unknown. Here, we comprehensively identified the fixed NUMTs within the reference genome using human pan-mitogenome (HPMT) from GeneBank. The inclusion of HPMT serves the purpose of establishing an authentic mitochondrial DNA (mtDNA) mutational spectrum for the identification of NUMTs, distinguishing it from the polymorphic variations found in NUMTs. Using HPMT, we identified approximately 10% of additional NUMTs in three human reference genomes under stricter thresholds. And we also observed an approximate 6% increase in NUMTs in T2T-CHR13 compared to hg38, including NUMTs on the short arms of chromosomes 13, 14, and 15 that were not assembled previously. Furthermore, alignments based on 20-mer from mtDNA suggested the presence of more mtDNA-like short segments within the nuclear genome, which should be avoided for short amplicon or cell free mtDNA detection. Finally, through the assay of transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) on cell lines before and after mtDNA elimination, we concluded that NUMTs have a minimal impact on bulk ATAC-seq, even though 16% of sequencing data originated from mtDNA.},
}
@article {pmid38001857,
year = {2023},
author = {Coltell, O and Asensio, EM and Sorlí, JV and Ortega-Azorín, C and Fernández-Carrión, R and Pascual, EC and Barragán, R and González, JI and Estruch, R and Alzate, JF and Pérez-Fidalgo, A and Portolés, O and Ordovas, JM and Corella, D},
title = {Associations between the New DNA-Methylation-Based Telomere Length Estimator, the Mediterranean Diet and Genetics in a Spanish Population at High Cardiovascular Risk.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {11},
pages = {},
pmid = {38001857},
issn = {2076-3921},
support = {CIBER 06/03/035//The Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Econom&#xed;a y Competitividad-Fondo Europeo de Desarrollo Regional (FEDER)/ ; PI21/00001//CIBER Fisiopatolog&#xed;a de la Obesidad y Nutrici&#xf3;n, Instituto de Salud Carlos III/ ; PROMETEO/2021/021//The Generalitat Valenciana/ ; PID2019-108858RB-I00//AEI 10.13039/501100011033 and by "ERDF A way of making Europe"/ ; },
abstract = {Biological aging is a relevant risk factor for chronic diseases, and several indicators for measuring this factor have been proposed, with telomere length (TL) among the most studied. Oxidative stress may regulate telomere shortening, which is implicated in the increased risk. Using a novel estimator for TL, we examined whether adherence to the Mediterranean diet (MedDiet), a highly antioxidant-rich dietary pattern, is associated with longer TL. We determined TL using DNA methylation algorithms (DNAmTL) in 414 subjects at high cardiovascular risk from Spain. Adherence to the MedDiet was assessed by a validated score, and genetic variants in candidate genes and at the genome-wide level were analyzed. We observed several significant associations (p < 0.05) between DNAmTL and candidate genes (TERT, TERF2, RTEL1, and DCAF4), contributing to the validity of DNAmTL as a biomarker in this population. Higher adherence to the MedDiet was associated with lower odds of having a shorter TL in the whole sample (OR = 0.93; 95% CI: 0.85-0.99; p = 0.049 after fully multivariate adjustment). Nevertheless, this association was stronger in women than in men. Likewise, in women, we observed a direct association between adherence to the MedDiet score and DNAmTL as a continuous variable (beta = 0.015; SE: 0.005; p = 0.003), indicating that a one-point increase in adherence was related to an average increase of 0.015 ± 0.005 kb in TL. Upon examination of specific dietary items within the global score, we found that fruits, fish, "sofrito", and whole grains exhibited the strongest associations in women. The novel score combining these items was significantly associated in the whole population. In the genome-wide association study (GWAS), we identified ten polymorphisms at the suggestive level of significance (p < 1 × 10[-5]) for DNAmTL (intergenics, in the IQSEC1, NCAPG2, and ABI3BP genes) and detected some gene-MedDiet modulations on DNAmTL. As this is the first study analyzing the DNAmTL estimator, genetics, and modulation by the MedDiet, more studies are needed to confirm these findings.},
}
@article {pmid38000989,
year = {2024},
author = {Qi, M and Yu, J and Ping, F and Xu, L and Li, W and Zhang, H and Li, Y},
title = {Leukocyte telomere length independently predicts hyperuricemia risk in a longitudinal study of the Chinese population.},
journal = {Nutrition, metabolism, and cardiovascular diseases : NMCD},
volume = {34},
number = {1},
pages = {230-234},
doi = {10.1016/j.numecd.2023.10.004},
pmid = {38000989},
issn = {1590-3729},
mesh = {Humans ; Longitudinal Studies ; Prospective Studies ; *Uric Acid ; *Hyperuricemia/diagnosis/epidemiology/genetics ; Leukocytes ; Telomere/genetics ; },
abstract = {BACKGROUND AND AIMS: Leukocyte telomere length (LTL) has been correlated with uric acid levels, although results are inconsistent, and prospective studies are lacking. In this longitudinal, prospective cohort study, we aimed to assess whether a shorter LTL predicts the risk of hyperuricemia.<br><br>METHODS AND RESULTS: We conducted a longitudinal study in a Chinese cohort of 599 participants. Of these, 266 participants completed a 5.9-year follow-up from June 2014 to December 2021. LTL was assessed at baseline using real-time polymerase chain reaction. Hyperuricemia was defined as serum uric acid &#x2265;420&#xa0;mmol/L according to Chinese guidelines for diagnosis and treatment of hyperuricemia and gout. Participants who had developed hyperuricemia during follow-up (n&#xa0;=&#xa0;17) had shorter LTL at baseline. Baseline LTL was independently associated with the development of hyperuricemia at follow-up after adjusting for conventional hyperuricemia risk factors (odds ratio [OR] 2.347 [95% confidence interval [CI] 1.123, 4.906]; P&#xa0;=&#xa0;0.023). After grouping according to LTL tertiles, the incidence of hyperuricemia was 18.334-fold higher for the first than for the third tertile (OR 18.334 [95%CI 1.786, 191.272]; P&#xa0;=&#xa0;0.014, P for trend&#xa0;=&#xa0;0.050).<br><br>CONCLUSION: Our findings in a prospective cohort suggest that LTL could predict hyperuricemia risk, which might inform the timely prevention and treatment of hyperuricemia.},
}
@article {pmid37997988,
year = {2023},
author = {Zhang, N and Baker, EC and Welsh, TH and Riley, DG},
title = {Telomere Dynamics in Livestock.},
journal = {Biology},
volume = {12},
number = {11},
pages = {},
pmid = {37997988},
issn = {2079-7737},
support = {2019-67015-2957//United States Department of Agriculture/ ; },
abstract = {Telomeres are repeated sequences of nucleotides at the end of chromosomes. They deteriorate across mitotic divisions of a cell. In Homo sapiens this process of lifetime reduction has been shown to correspond with aspects of organismal aging and exposure to stress or other insults. The early impetus to characterize telomere dynamics in livestock related to the concern that aged donor DNA would result in earlier cell senescence and overall aging in cloned animals. Telomere length investigations in dairy cows included breed effects, estimates of additive genetic control (heritability 0.12 to 0.46), and effects of external stressors on telomere degradation across animal life. Evaluation of telomeres with respect to aging has also been conducted in pigs and horses, and there are fewer reports of telomere biology in beef cattle, sheep, and goats. There were minimal associations of telomere length with animal productivity measures. Most, but not all, work in livestock has documented an inverse relationship between peripheral blood cell telomere length and age; that is, a longer telomere length was associated with younger age. Because livestock longevity affects productivity and profitability, the role of tissue-specific telomere attrition in aging may present alternative improvement strategies for genetic improvement while also providing translational biomedical knowledge.},
}
@article {pmid37997496,
year = {2024},
author = {Park, S and Kim, DK},
title = {Comment on "Causal linkage of tobacco smoking with ageing: Mendelian randomization analysis towards telomere attrition and sarcopenia" by Park et al. - The authors reply.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {15},
number = {1},
pages = {453-454},
pmid = {37997496},
issn = {2190-6009},
mesh = {Humans ; *Sarcopenia ; Mendelian Randomization Analysis ; Tobacco Smoking ; Aging ; Telomere ; },
}
@article {pmid37994393,
year = {2024},
author = {Setia, N and Del Gaudio, D and Kandikatla, P and Arndt, K and Tjota, M and Wang, P and Segal, J and Alikhan, M and Hart, J},
title = {A novel telomere biology disease-associated gastritis identified through a whole exome sequencing-driven approach.},
journal = {The journal of pathology. Clinical research},
volume = {10},
number = {1},
pages = {e349},
pmid = {37994393},
issn = {2056-4538},
mesh = {Humans ; *Gastritis, Atrophic/genetics/pathology ; Exome Sequencing ; *Gastritis/genetics/pathology ; Biopsy ; Biology ; Exodeoxyribonucleases ; },
abstract = {A whole exome sequencing (WES)-driven approach to uncover the etiology of unexplained inflammatory gastritides has been underutilized by surgical pathologists. Here, we discovered the pathobiology of an unusual chronic atrophic gastritis in two unrelated patients using this approach. The gastric biopsies were notable for an unusual pattern of gastritis with persistent dense inflammation, loss of both parietal and neuroendocrine cells in the oxyntic mucosa, and sparing of the antral mucosa. The patients were found to harbor pathogenic variants in telomeropathic genes (POT1 and DCLRE1B). Clonality testing for one of the patients showed evidence of evolving clonality of TCR-gene rearrangement. Both patients showed significantly decreased numbers of stem/progenitor cells by immunohistochemistry, which appears to be responsible for the development of mucosal atrophy. No such cases of unusual chronic atrophic gastritis in the setting of telomeropathy have been previously reported. The loss of stem/progenitor cells suggests that stem/progenitor cell exhaustion in the setting of telomere dysfunction is the likely mechanism for development of this unusual chronic atrophic gastritis. The results underscore the need for close monitoring of these gastric lesions, with special regard to their neoplastic potential. This combined WES-driven approach has promise to identify the cause and mechanism of other uncharacterized gastrointestinal inflammatory disorders.},
}
@article {pmid37993053,
year = {2024},
author = {Robinson, LG and Kalmbach, K and Sumerfield, O and Nomani, W and Wang, F and Liu, L and Keefe, DL},
title = {Telomere dynamics and reproduction.},
journal = {Fertility and sterility},
volume = {121},
number = {1},
pages = {4-11},
doi = {10.1016/j.fertnstert.2023.11.012},
pmid = {37993053},
issn = {1556-5653},
mesh = {Male ; Female ; Humans ; Mice ; Animals ; Aged ; *Telomerase/genetics/metabolism ; Semen/metabolism ; Reproduction/genetics ; Aging/genetics ; Oocytes/metabolism ; Telomere/genetics ; },
abstract = {The oocyte, a long-lived, postmitotic cell, is the locus of reproductive aging in women. Female germ cells replicate only during fetal life and age throughout reproductive life. Mechanisms of oocyte aging include the accumulation of oxidative damage, mitochondrial dysfunction, and disruption of proteins, including cohesion. Nobel Laureate Bob Edwards also discovered a "production line" during oogonial replication in the mouse, wherein the last oocytes to ovulate in the adult-derived from the last oogonia to exit mitotic replication in the fetus. On the basis of this, we proposed a two-hit "telomere theory of reproductive aging" to integrate the myriad features of oocyte aging. The first hit was that oocytes remaining in older women traversed more cell cycles during fetal oogenesis. The second hit was that oocytes accumulated more environmental and endogenous oxidative damage throughout the life of the woman. Telomeres (Ts) could mediate both of these aspects of oocyte aging. Telomeres provide a "mitotic clock," with T attrition an inevitable consequence of cell division because of the end replication problem. Telomere's guanine-rich sequence renders them especially sensitive to oxidative damage, even in postmitotic cells. Telomerase, the reverse transcriptase that restores Ts, is better at maintaining than elongating T. Moreover, telomerase remains inactive during much of oogenesis and early development. Oocytes are left with short Ts, on the brink of viability. In support of this theory, mice with induced T attrition and women with naturally occurring telomeropathy suffer diminished ovarian reserve, abnormal embryo development, and infertility. In contrast, sperm are produced throughout the life of the male by a telomerase-active progenitor, spermatogonia, resulting in the longest Ts in the body. In mice, cleavage-stage embryos elongate Ts via "alternative lengthening of telomeres," a recombination-based mechanism rarely encountered outside of telomerase-deficient cancers. Many questions about Ts and reproduction are raised by these findings: does the "normal" T attrition observed in human oocytes contribute to their extraordinarily high rate of meiotic nondisjunction? Does recombination-based T elongation render embryos susceptible to mitotic nondisjunction (and mosaicism)? Can some features of Ts serve as markers of oocyte quality?},
}
@article {pmid37991243,
year = {2023},
author = {Wang, C and Huang, Y and Yang, Y and Li, R and Li, Y and Qiu, H and Wu, J and Shi, G and Ma, W and Songyang, Z},
title = {ILF3 safeguards telomeres from aberrant homologous recombination as a telomeric R-loop reader.},
journal = {Protein &amp; cell},
volume = {},
number = {},
pages = {},
doi = {10.1093/procel/pwad054},
pmid = {37991243},
issn = {1674-8018},
abstract = {Telomeres are specialized structures at the ends of linear chromosomes that protect genome stability. The telomeric repeat-containing RNA (TERRA) that is transcribed from subtelomeric regions can invade into double-stranded DNA regions and form RNA:DNA hybrid-containing structure called R-loop. In tumor cells, R-loop formation is closely linked to gene expression and the alternative lengthening of telomeres (ALT) pathway. Dysregulated R-loops can cause stalled replication forks and telomere instability. However, how R-loops are recognized and regulated, particularly at telomeres, is not well understood. We discovered that ILF3 selectively associates with telomeric R-loops and safeguards telomeres from abnormal homologous recombination. Knocking out ILF3 results in excessive R-loops at telomeres and triggers telomeric DNA damage responses (DDR). In addition, ILF3 deficiency disrupts telomere homeostasis and causes abnormalities in the ALT pathway. Using the proximity-dependent biotin identification (BioID) technology, we mapped the ILF3 interactome and discovered that ILF3 could interact with several DNA/RNA helicases, including DHX9. Importantly, ILF3 may aid in the resolution of telomeric R-loops through its interaction with DHX9. Our findings suggest that ILF3 may function as a reader of telomeric R-loops, helping to prevent abnormal homologous recombination and maintain telomere homeostasis.},
}
@article {pmid37988290,
year = {2023},
author = {Colin, L and Reyes, C and Berthezene, J and Maestroni, L and Modolo, L and Toselli, E and Chanard, N and Schaak, S and Cuvier, O and Gachet, Y and Coulon, S and Bernard, P and Tournier, S},
title = {Condensin positioning at telomeres by shelterin proteins drives sister-telomere disjunction in anaphase.},
journal = {eLife},
volume = {12},
number = {},
pages = {},
pmid = {37988290},
issn = {2050-084X},
support = {ANR-16-CE12-0015-TeloMito//Agence Nationale de la Recherche/ ; PJA20161204921//Fondation ARC pour la Recherche sur le Cancer/ ; PhD studentship//La ligue contre le cancer/ ; PJA 20191209370//Fondation ARC pour la Recherche sur le Cancer/ ; PhD studentship//La fondtion pour la recherche medicale/ ; },
mesh = {Shelterin Complex ; Anaphase ; Telomere-Binding Proteins/genetics/metabolism ; Telomere/metabolism ; *Schizosaccharomyces/genetics/metabolism ; *Schizosaccharomyces pombe Proteins/genetics/metabolism ; },
abstract = {The localization of condensin along chromosomes is crucial for their accurate segregation in anaphase. Condensin is enriched at telomeres but how and for what purpose had remained elusive. Here, we show that fission yeast condensin accumulates at telomere repeats through the balancing acts of Taz1, a core component of the shelterin complex that ensures telomeric functions, and Mit1, a nucleosome remodeler associated with shelterin. We further show that condensin takes part in sister-telomere separation in anaphase, and that this event can be uncoupled from the prior separation of chromosome arms, implying a telomere-specific separation mechanism. Consistent with a cis-acting process, increasing or decreasing condensin occupancy specifically at telomeres modifies accordingly the efficiency of their separation in anaphase. Genetic evidence suggests that condensin promotes sister-telomere separation by counteracting cohesin. Thus, our results reveal a shelterin-based mechanism that enriches condensin at telomeres to drive in cis their separation during mitosis.},
}
@article {pmid37987889,
year = {2023},
author = {Harley, J and Santosa, MM and Ng, CY and Grinchuk, OV and Hor, JH and Liang, Y and Lim, VJ and Tee, WW and Ong, DST and Ng, SY},
title = {Telomere shortening induces aging-associated phenotypes in hiPSC-derived neurons and astrocytes.},
journal = {Biogerontology},
volume = {},
number = {},
pages = {},
pmid = {37987889},
issn = {1573-6768},
abstract = {Telomere shortening is a well-established hallmark of cellular aging. Telomerase reverse transcriptase (TERT) plays a crucial role in maintaining the length of telomeres, which are specialised protective caps at the end of chromosomes. The lack of in vitro aging models, particularly for the central nervous system (CNS), has impeded progress in understanding aging and age-associated neurodegenerative diseases. In this study, we aimed to explore the possibility of inducing aging-associated features in cell types of the CNS using hiPSC (human induced pluripotent stem cell) technology. To achieve this, we utilised CRISPR/Cas9 to generate hiPSCs with a loss of telomerase function and shortened telomeres. Through directed differentiation, we generated motor neurons and astrocytes to investigate whether telomere shortening could lead to age-associated phenotypes. Our findings revealed that shortened telomeres induced age-associated characteristics in both motor neurons and astrocytes including increased cellular senescence, heightened inflammation, and elevated DNA damage. We also observed cell-type specific age-related morphology changes. Additionally, our study highlighted the fundamental role of TERT and telomere shortening in neural progenitor cell (NPC) proliferation and neuronal differentiation. This study serves as a proof of concept that telomere shortening can effectively induce aging-associated phenotypes, thereby providing a valuable tool to investigate age-related decline and neurodegenerative diseases.},
}
@article {pmid37986934,
year = {2023},
author = {Pierpoint, M and Floyd, W and Wisdom, AJ and Luo, L and Ma, Y and Waitkus, MS and Kirsch, DG},
title = {Loss of function of Atrx leads to activation of alternative lengthening of telomeres in a primary mouse model of sarcoma.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {37986934},
support = {R35 CA197616/CA/NCI NIH HHS/United States ; },
abstract = {The development of a telomere maintenance mechanism is essential for immortalization in human cancer. While most cancers elongate their telomeres by expression of telomerase, 10-15% of human cancers use a pathway known as alternative lengthening of telomeres (ALT). In this work, we developed a genetically engineered primary mouse model of sarcoma in CAST/EiJ mice which displays multiple molecular features of ALT activation after CRISPR/Cas9 introduction of oncogenic Kras[G12D] and loss of function mutations of Trp53 and Atrx. In this model, we demonstrate that the loss of Atrx contributes to the development of ALT in an autochthonous tumor, and this process occurs independently of telomerase function by variation of mTR alleles. Furthermore, we find that telomere shortening from the loss of telomerase leads to higher chromosomal instability while loss of Atrx and activation of ALT lead to an increase in telomeric instability, telomere sister chromatid exchange, c-circle production, and formation of ALT-associated promyelocytic leukemia bodies (APBs). The development of this primary mouse model of ALT could enable future investigations into therapeutic vulnerabilities of ALT activation and its mechanism of action.},
}
@article {pmid37986388,
year = {2023},
author = {Zhang, W},
title = {Big data analysis identified a telomere-related signature predicting the prognosis and drug sensitivity in lung adenocarcinoma.},
journal = {Medicine},
volume = {102},
number = {46},
pages = {e35526},
pmid = {37986388},
issn = {1536-5964},
mesh = {Humans ; *RNA, Long Noncoding/genetics ; Prognosis ; *MicroRNAs/genetics ; Data Analysis ; *Adenocarcinoma ; Lung ; *Lung Neoplasms/drug therapy/genetics ; },
abstract = {Telomeres exert a critical role in chromosome stability and aberrant regulation of telomerase may result in telomeres dysfunction and genomic instability, which are involved in the occurrence of cancers. However, limited studies have been performed to fully clarify the immune infiltration and clinical significance of telomeres-related genes (TRGs) in lung adenocarcinoma (LUAD). The number of clusters of LUAD was determined by consensus clustering analysis. The prognostic signature was constructed and verified using TCGA and GSE42127 dataset with Least Absolute Shrinkage and Selection Operator cox regression analysis. The correlation between different clusters and risk-score and drug therapy response was analyzed using TIDE and IMvigor210 dataset. Using several miRNA and lncRNA related databases, we constructed a lncRNA-miRNA-mRNA regulatory axis. We identified 2 telomeres-related clusters in LUAD, which had distinct differences in prognostic stratification, TMB score, TIDE score, immune characteristics and signal pathways and biological effects. A prognostic model was developed based on 21 TRGs, which had a better performance in risk stratification and prognosis prediction compared with other established models. TRGs-based risk score could serve as an independent risk factor for LUAD. Survival prediction nomogram was also developed to promote the clinical use of TRGs risk score. Moreover, LUAD patients with high risk score had a high TMB score, low TIDE score and IC50 value of common drugs, suggesting that high risk score group might benefit from receiving immunotherapy, chemotherapy and target therapy. We also developed a lncRNA KCNQ1QT1/miR-296-5p/PLK1 regulatory axis. Our study identified 2 telomeres-related clusters and a prognostic model in LUAD, which could be helpful for risk stratification, prognosis prediction and treatment approach selection.},
}
@article {pmid37986353,
year = {2023},
author = {Li, W and Liu, C and Chen, Y and Dong, S and Zhang, M and Sun, J and Zhao, Z and Zuo, Y and Chen, S},
title = {Assessment of the relationship between telomere length and atherosclerosis: A Mendelian randomization study.},
journal = {Medicine},
volume = {102},
number = {46},
pages = {e35875},
pmid = {37986353},
issn = {1536-5964},
mesh = {Humans ; Mendelian Randomization Analysis ; *Atherosclerosis/genetics ; *Coronary Artery Disease/genetics ; Heart ; *Intracranial Arteriosclerosis ; Telomere/genetics ; Genome-Wide Association Study ; },
abstract = {To evaluate the causal relationship between genetically determined telomere length (TL) and atherosclerosis (AS). We performed a 2-sample Mendelian randomization (MR) study to assess the potential causal relationship between TL and AS (coronary AS, cerebral AS, peripheral atherosclerosis (PAD), and AS, excluding cerebral, coronary, and PAD). The TL phenotype contained 472,174 participants, and the 4 subtypes of AS had 361,194, 218,792, 168,832, and 213,140 participants, all of European ancestries. The single nucleotide polymorphisms (SNPs) of TL strongly associated with the 4 atherosclerotic subtypes included in this study were 101, 92, 91, and 92, respectively. The odds ratios (ORs) and 95% confidence interval (CI) between TL and coronary AS calculated using inverse variance weighted (IVW) were 0.993 (0.988, 0.997), and the results were statistically significant (P < .05). The results between TL and cerebral AS, PAD, and AS (excluding cerebral, coronary, and PAD) were not statistically significant (P > .05). "Egger-intercept test" showed that there was no horizontal pleiotropy (P > .05); "leave-one-out analysis" sensitivity analysis showed that the results were stable and there were no instrumental variables with strong effects on the results; "MR- pleiotropy residual sum and outlier (PRESSO) test" showed 1 outlier for coronary AS and no outliers for the remaining subgroups. The results of the 2-sample MR analysis showed a causal association between TL and coronary AS but not with cerebral AS, PAD, and AS (excluding cerebral, coronary, and PAD). This may elucidate the observation that various vascular regions can be affected by AS but highlights the propensity of coronary arteries to be more susceptible to AS development.},
}
@article {pmid37985967,
year = {2023},
author = {Serrano-León, IM and Prieto, P and Aguilar, M},
title = {Correction: Telomere and subtelomere high polymorphism might contribute to the specifcity of homologous recognition and pairing during meiosis in barley in the context of breeding.},
journal = {BMC genomics},
volume = {24},
number = {1},
pages = {694},
pmid = {37985967},
issn = {1471-2164},
}
@article {pmid37985282,
year = {2024},
author = {Mulet, A and González-Cabo, P and Pallardó, FV and Signes-Costa, J},
title = {Persistent Pulmonary Fibrotic Sequelae in Patients With Telomere Shortening One Year After Severe COVID-19.},
journal = {Archivos de bronconeumologia},
volume = {60},
number = {1},
pages = {62-64},
doi = {10.1016/j.arbres.2023.11.003},
pmid = {37985282},
issn = {1579-2129},
mesh = {Humans ; Telomere Shortening ; *COVID-19 ; *Idiopathic Pulmonary Fibrosis/genetics ; Disease Progression ; },
}
@article {pmid37983765,
year = {2023},
author = {Schmidt, KA and Simonetto, DA},
title = {The telomere tango: Liver disease in the genomic spotlight.},
journal = {Hepatology (Baltimore, Md.)},
volume = {},
number = {},
pages = {},
pmid = {37983765},
issn = {1527-3350},
}
@article {pmid37979607,
year = {2024},
author = {Garg, A and Seli, E},
title = {Leukocyte telomere length and DNA methylome as biomarkers of ovarian reserve and embryo aneuploidy: the intricate relationship between somatic and reproductive aging.},
journal = {Fertility and sterility},
volume = {121},
number = {1},
pages = {26-33},
doi = {10.1016/j.fertnstert.2023.11.011},
pmid = {37979607},
issn = {1556-5653},
mesh = {Female ; Humans ; *Ovarian Reserve/genetics ; Epigenome ; Aneuploidy ; Leukocytes/physiology ; *Infertility, Female/diagnosis/genetics ; Telomere/genetics ; Biomarkers ; },
abstract = {The average childbearing age among women continues to rise, leading to an increased prevalence of infertility and a subsequent increased use of assisted reproductive technologies (ARTs). Ovarian aging, especially diminished ovarian reserve and poor ovarian response, have been implicated as common causes of infertility. Telomere length and DNA methylation-based epigenetic clocks are established hallmarks of cellular aging; however, the interplay between somatic and ovarian aging remains unclear. There appears to be a lack of correlation between leukocyte telomere length and the DNA methylation age of somatic and ovarian cells. Both the telomere length and methylome of follicular somatic cells (granulosa and cumulus) appear to be unaffected by chronologic age, infertility, or processes that result in diminished ovarian reserve and poor ovarian response. As such, they are unlikely candidates as surrogate biomarkers of reproductive potential, response to stimulation, or ART outcome. Meanwhile, telomere or methylome changes in leukocytes associated with aging seem to correlate with reproductive function and may have the potential to aid the characterization of women with reproductive decline; however, current data are limited and larger studies evaluating this within an ART setting are warranted.},
}
@article {pmid37978541,
year = {2023},
author = {Liu, L and Luo, H and Sheng, Y and Kang, X and Peng, H and Luo, H and Fan, LL},
title = {A novel mutation of CTC1 leads to telomere shortening in a chinese family with interstitial lung disease.},
journal = {Hereditas},
volume = {160},
number = {1},
pages = {37},
pmid = {37978541},
issn = {1601-5223},
support = {82070003 and 82000079//National Natural Science Foundation of China/ ; 2021JJ30943, 2021JJ40849, 2023JJ20078//Natural Science Foundation of Hunan province/ ; 202203023480, 202103050563, and 202104022248//Hunan Province Health Commission Scientific Research Project/ ; },
mesh = {Humans ; *Telomere Shortening ; Telomere-Binding Proteins/genetics/metabolism ; East Asian People ; Mutation ; *Lung Diseases, Interstitial/genetics ; Telomere/genetics ; },
abstract = {Interstitial lung diseases (ILDs), or diffuse pulmonary lung disease, are a subset of lung diseases that primarily affect lung alveoli and the space around interstitial tissue and bronchioles. It clinically manifests as progressive dyspnea, and patients often exhibit a varied decrease in pulmonary diffusion function. Recently, variants in telomere biology-related genes have been identified as genetic lesions of ILDs. Here, we enrolled 82 patients with interstitial pneumonia from 2017 to 2021 in our hospital to explore the candidate gene mutations of these patients via whole-exome sequencing. After data filtering, a novel heterozygous mutation (NM_025099: p.Gly131Arg) of CTC1 was identified in two affected family members. As a component of CST (CTC1-STN1-TEN1) complex, CTC1 is responsible for maintaining telomeric structure integrity and has also been identified as a candidate gene for IPF, a special kind of chronic ILD with insidious onset. Simultaneously, real-time PCR revealed that two affected family members presented with short telomere lengths, which further confirmed the effect of the mutation in the CTC1 gene. Our study not only expanded the mutation spectrum of CTC1 and provided epidemiological data on ILDs caused by CTC1 mutations but also further confirmed the relationship between heterozygous mutations in CTC1 and ILDs, which may further contribute to understanding the mechanisms underlying ILDs.},
}
@article {pmid37976300,
year = {2023},
author = {Campa, D and Felici, A and Corradi, C and Peduzzi, G and Gentiluomo, M and Farinella, R and Rizzato, C},
title = {Long or short? Telomere length and pancreatic cancer and its precursor lesions, a narrative review.},
journal = {Mutagenesis},
volume = {},
number = {},
pages = {},
doi = {10.1093/mutage/gead034},
pmid = {37976300},
issn = {1464-3804},
abstract = {Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal form of pancreatic cancer, with a survival approaching only 11% at five years after diagnosis. In the last 15 years, telomere length measured in leukocyte (LTL) has been studied in relation to PDAC risk. The majority of the studies reported an association between short LTL and increased PDAC risk, but the results are heterogeneous. Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) in the telomerase reverse transcriptase (TERT) gene as susceptibility loci for PDAC. Polygenic risk scores (PRS) computed using SNPs associated with LTL have been tested in relation to PDAC susceptibility with various methods and giving contrasting results. The aim of this review is to analyze all publications carried out specifically on LTL, considering LTL measured with qPCR and with genetic proxies, and PDAC risk. Additionally, we will give an overview of the most relevant associations between SNPs in telomere associated genes and PDAC, to answer the question shorter or longer? Which one of the two is associated with PDAC risk?},
}
@article {pmid37976136,
year = {2023},
author = {Zhao, Z and Shen, X and Zhao, S and Wang, J and Tian, Y and Wang, X and Tang, B},
title = {A novel telomere-related genes model for predicting prognosis and treatment responsiveness in diffuse large B-cell lymphoma.},
journal = {Aging},
volume = {15},
number = {22},
pages = {12927-12951},
pmid = {37976136},
issn = {1945-4589},
mesh = {Humans ; Prognosis ; *Lymphoma, Large B-Cell, Diffuse/drug therapy/genetics/pathology ; Monocytes ; Killer Cells, Natural ; Telomere/genetics/pathology ; Nuclear Proteins/genetics ; },
abstract = {Diffuse large B cell lymphoma (DLBCL) is a highly heterogeneous disease with diverse clinical and molecular features. Telomere maintenance is widely present in tumors, but there is a lack of relevant reports on the role of telomere-related genes (TRGs) in DLBCL. In this study, we used consensus clustering based on TRGs expression to identify two molecular clusters with distinct prognoses and immune cell infiltration. We developed a TRGs scoring model using univariate Cox regression and LASSO regression in the GSE10846 training cohort. DLBCL patients in the high-risk group had a worse prognosis than those in the low-risk group, as revealed by Kaplan-Meier curves. The scoring model was validated in the GSE10846 testing cohort and GSE87371 cohort, respectively. The high-risk group was characterized by elevated infiltration of activated DCs, CD56 dim natural killer cells, myeloid-derived suppressor cells, monocytes, and plasmacytoid DCs, along with reduced infiltration of activated CD4 T cells, Type 2 T helper cells, γδ T cells, NK cells, and neutrophils. Overexpression of immune checkpoints, such as PDCD1, CD274, and LAG3, was observed in the high-risk group. Furthermore, high-risk DLBCL patients exhibited increased sensitivity to bortezomib, rapamycin, AZD6244, and BMS.536924, while low-risk DLBCL patients showed sensitivity to cisplatin and ABT.263. Using RT-qPCR, we found that three protective model genes, namely TCEAL7, EPHA4, and ELOVL4, were down-regulated in DLBCL tissues compared with control tissues. In conclusion, our novel TRGs-based model has great predictive value for the prognosis of DLBCL patients and provides a promising direction for treatment optimization.},
}
@article {pmid37975773,
year = {2023},
author = {Tomé, S},
title = {[Nanopore and telomeres].},
journal = {Medecine sciences : M/S},
volume = {39 Hors s&#xe9;rie n&#xb0; 1},
number = {},
pages = {64},
doi = {10.1051/medsci/2023141},
pmid = {37975773},
issn = {1958-5381},
mesh = {Humans ; *Nanopores ; Telomere/genetics ; },
}
@article {pmid37971759,
year = {2023},
author = {},
title = {Boyraz B, Bellomo CM, Fleming MD, Cutler CS, Agarwal S. A novel TERC CR4/CR5 domain mutation causes telomere disease via decreased TERT binding. Blood. 2016;128(16):2089-2092.},
journal = {Blood},
volume = {142},
number = {20},
pages = {1758},
doi = {10.1182/blood.2023022677},
pmid = {37971759},
issn = {1528-0020},
mesh = {*RNA/genetics ; *Telomerase/metabolism ; Mutation ; Telomere/genetics/metabolism ; },
}
@article {pmid37971645,
year = {2024},
author = {Khaleda, L and Begum, SK and Apu, MAR and Chowdhury, RH and Alam, MJ and Datta, A and Rahman, MZ and Hosain, N and Al-Forkan, M},
title = {Arsenic-Induced Cardiovascular Diseases and their Correlation with Mitochondrial DNA Copy Number, Deletion, and Telomere Length in Bangladeshi Population.},
journal = {Cardiovascular toxicology},
volume = {24},
number = {1},
pages = {27-40},
pmid = {37971645},
issn = {1559-0259},
mesh = {Humans ; DNA, Mitochondrial/genetics ; *Arsenic/toxicity ; DNA Copy Number Variations ; *Cardiovascular Diseases/chemically induced/diagnosis/genetics ; Telomere/genetics ; },
abstract = {Arsenic contamination is a global health concern, primarily through contaminated groundwater and its entry into the food chain. The association between arsenic exposure and cardiovascular diseases (CVDs) is particularly alarming due to CVDs being the leading cause of death worldwide. Arsenic exposure has also been linked to changes in telomere length, mitochondrial DNA copy number (mtDNAcn), and deletion, further increasing the risk of CVDs. We aimed to determine whether arsenic exposure alters telomere length and mtDNAcn and deletion in a total of 50 CVD patients who underwent open heart surgery hailed from known arsenic-affected and unaffected areas in Bangladesh. Amount of arsenic was determined from the collected nails and cardiac tissues. Relative telomere length and mtDNAcn and deletion were quantified by qRT-PCR. The patients from arsenic-contaminated areas had higher average arsenic deposits in their fingers and toenails (P < 0.05) and higher cardiac tissue injury scores (P < 0.05). Moreover, approximately 1.5-fold shorter telomere length (P < 0.05, r = - 0.775), 1.2-fold decreased mtDNAcn (P < 0.05, r = - 0.797), and an 81-fold higher amount of mitochondrial DNA deletion (P < 0.05, r = 0.784) were observed in the patients who had higher arsenic deposition in their nails. Higher levels of arsenic exposure were found to be linked to shorter telomere length, decreased mtDNAcn, and increased mitochondrial DNA deletion in the patients from As-affected areas. It can also be anticipated that the correlation of arsenic exposure with telomere length, mtDNAcn, and deletion can be used as biomarkers for early diagnosis of arsenic-induced cardiovascular diseases.},
}
@article {pmid37966130,
year = {2024},
author = {Zavala-Paez, M and Holliday, J and Hamilton, JA},
title = {Leveraging whole-genome sequencing to estimate telomere length in plants.},
journal = {Molecular ecology resources},
volume = {24},
number = {2},
pages = {e13899},
doi = {10.1111/1755-0998.13899},
pmid = {37966130},
issn = {1755-0998},
support = {//Department of Ecosystem Science and Management at Pennsylvania State University/ ; //Huck Institutes of the Life Sciences/ ; NSF-PGR-1856450//National Science Foundation (NSF)/ ; //Pennsylvania State University's Intercollege Graduate Degree Program in Ecology/ ; //Schatz Center for Tree Molecular Genetics/ ; PEN04809//USDA National Institute of Food and Agriculture and Hatch Appropriations/ ; 7003639//USDA National Institute of Food and Agriculture and Hatch Appropriations/ ; },
mesh = {Humans ; *Plant Breeding ; Whole Genome Sequencing/methods ; *Genome ; Genotype ; Telomere/genetics ; },
abstract = {Changes in telomere length are increasingly used to indicate species' response to environmental stress across diverse taxa. Despite this broad use, few studies have explored telomere length in plants. Thus, evaluation of new approaches for measuring telomeres in plants is needed. Rapid advances in sequencing approaches and bioinformatic tools now allow estimation of telomere content from whole-genome sequencing (WGS) data, a proxy for telomere length. While telomere content has been quantified extensively using quantitative polymerase chain reaction (qPCR) and WGS in humans, no study to date has compared the effectiveness of WGS in estimating telomere length in plants relative to qPCR approaches. In this study, we use 100 Populus clones re-sequenced using short-read Illumina sequencing to quantify telomere length comparing three different bioinformatic approaches (Computel, K-seek and TRIP) in addition to qPCR. Overall, telomere length estimates varied across different bioinformatic approaches, but were highly correlated across methods for individual genotypes. A positive correlation was observed between WGS estimates and qPCR, however, Computel estimates exhibited the greatest correlation. Computel incorporates genome coverage into telomere length calculations, suggesting that genome coverage is likely important to telomere length quantification when using WGS data. Overall, telomere estimates from WGS provided greater precision and accuracy of telomere length estimates relative to qPCR. The findings suggest WGS is a promising approach for assessing telomere length and, as the field of telomere ecology evolves, may provide added value to assaying response to biotic and abiotic environments for plants needed to accelerate plant breeding and conservation management.},
}
@article {pmid37964387,
year = {2023},
author = {Kmiołek, T and Filipowicz, G and Bogucka, D and Wajda, A and Ejma-Multański, A and Stypińska, B and Modzelewska, E and Kaliberda, Y and Radkowski, M and Targowski, T and Wrona, J and Paradowska-Gorycka, A},
title = {Aging and the impact of global DNA methylation, telomere shortening, and total oxidative status on sarcopenia and frailty syndrome.},
journal = {Immunity &amp; ageing : I &amp; A},
volume = {20},
number = {1},
pages = {61},
pmid = {37964387},
issn = {1742-4933},
abstract = {Aging is a biological event that influences many organs and systems. Both sarcopenia and frailty syndrome refer to geriatric conditions with overlapping phenotypes. Many mechanisms are involved in the aging process such as DNA methylation telomeres which are susceptible to oxidative stress, and inflammations which result in telomere shortening, leading to chromosomal instability. The study aimed to determine the associations between these processes, frailty and sarcopenia syndrome. Global DNA methylation was analyzed using the ELISA method. Telomere length was analyzed using qPCR. Total oxidative status (TOS) was analyzed using a colorimetric method. The present study revealed that the main factor affecting methylation, telomeres length and level of total oxidant stress was age.},
}
@article {pmid37962763,
year = {2023},
author = {Liang, Y and Huang, P},
title = {Associations of telomere length with risk of mortality from influenza and pneumonia in US adults: a prospective cohort study of NHANES 1999-2002.},
journal = {Aging clinical and experimental research},
volume = {35},
number = {12},
pages = {3115-3125},
pmid = {37962763},
issn = {1720-8319},
mesh = {Humans ; Male ; Female ; Prospective Studies ; Nutrition Surveys ; *Influenza, Human/genetics ; *Pneumonia/genetics ; Telomere/genetics ; },
abstract = {BACKGROUND: Due to the ongoing Coronavirus disease 2019 (COVID-19) pandemic, interest has arisen to realize the relationship between telomere length (TL) and influenza and pneumonia mortality.<br><br>AIM: Our study attempted to investigate this correlation by analyzing information gathered from the National Health and Nutrition Examination Survey (NHANES) 1999-2002.<br><br>METHODS: A total of 7229 participants were involved in the conducted research. We utilized Cox proportional risk model analysis to determine the hazard ratio (HR) and 95% confidence interval (CI) for TL and influenza and pneumonia mortality.<br><br>RESULTS: During the average follow-up time of 204.10&#x2009;&#xb1;&#x2009;51.26 months, 33 (0.45%) participants died from influenza and pneumonia. After adjusting for multiple variables, shorter TL was associated with higher influenza-pneumonia mortality. In subgroup analyses stratified by sex, men exhibited stronger associations with influenza-pneumonia mortality than women (Model 1: HRmale: 0.014 vs HRfemale: 0.054; Model 2: HRmale: 0.082 vs HRfemale: 0.890; Model 3: HRmale: 0.072 vs HRfemale: 0.776). For subgroup analyses by visceral adiposity index (VAI), all statistically significant (P&#x2009;<&#x2009;0.05) models displayed an inverse relationship between TL and influenza and pneumonia mortality.<br><br>CONCLUSIONS: Our research provides further proof for the connection between shorter telomeres and higher influenza-pneumonia mortality. Larger prospective researches are essential to support our results and explain the underlying mechanisms.},
}
@article {pmid37962459,
year = {2023},
author = {Gold, NM and Okeke, MN and He, Y},
title = {Involvement of Inheritance in Determining Telomere Length beyond Environmental and Lifestyle Factors.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2023.1023},
pmid = {37962459},
issn = {2152-5250},
abstract = {All linear chromosomal ends have specific DNA-protein complexes called telomeres. Telomeres serve as a "molecular clock" to estimate the potential length of cell replication. Shortening of telomere length (TL) is associated with cellular senescence, aging, and various age-related diseases in humans. Here we reviewed the structure, function, and regulation of telomeres and the age-related diseases associated with telomere attrition. Among the various determinants of TL, we highlight the connection between TL and heredity to provide a new overview of genetic determinants for TL. Studies across multiple species have shown that maternal and paternal TL influence the TL of their offspring, and this may affect life span and their susceptibility to age-related diseases. Hence, we reviewed the linkage between TL and parental influences and the proposed mechanisms involved. More in-depth studies on the genetic mechanism for TL attrition are needed due to the potential application of this knowledge in human medicine to prevent premature frailty at its earliest stage, as well as promote health and longevity.},
}
@article {pmid37961611,
year = {2024},
author = {Takai, H and Aria, V and Borges, P and Yeeles, JTP and de Lange, T},
title = {CST-Polymeraseα-primase solves a second telomere end-replication problem.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {37961611},
support = {R01 AG016642/AG/NIA NIH HHS/United States ; R35 CA210036/CA/NCI NIH HHS/United States ; R50 CA243771/CA/NCI NIH HHS/United States ; },
abstract = {Telomerase adds G-rich telomeric repeats to the 3' ends of telomeres[1], counteracting telomere shortening caused by loss of telomeric 3' overhangs during leading-strand DNA synthesis ("the end-replication problem"[2]). We report a second end-replication problem that originates from the incomplete duplication of the C-rich telomeric repeat strand by lagging-strand synthesis. This problem is solved by CST-Polymeraseα(Polα)-primase fill-in synthesis. In vitro, priming for lagging-strand DNA replication does not occur on the 3' overhang and lagging-strand synthesis stops in an ~150-nt zone more than 26 nt from the end of the template. Consistent with the in vitro data, lagging-end telomeres of cells lacking CST-Polα-primase lost ~50-60 nt of CCCTAA repeats per population doubling (PD). The C-strands of leading-end telomeres shortened by ~100 nt/PD, reflecting the generation of 3' overhangs through resection. The measured overall C-strand shortening in absence of CST-Polα-primase fill-in is consistent with the combined effects of incomplete lagging-strand synthesis and 5' resection at the leading-ends. We conclude that canonical DNA replication creates two telomere end-replication problems that require telomerase to maintain the G-strand and CST-Polα-primase to maintain the C-strand.},
}
@article {pmid37961382,
year = {2023},
author = {Agabekian, IA and Abdulkina, LR and Lushnenko, AY and Young, PG and Valeeva, LR and Boskovic, O and Lilly, EG and Sharipova, MR and Shippen, DE and Juenger, TE and Shakirov, EV},
title = {Arabidopsis AN3 and OLIGOCELLULA genes link telomere maintenance mechanisms with cell division and expansion control.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {37961382},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; R01 GM127402/GM/NIGMS NIH HHS/United States ; },
abstract = {Telomeres are conserved chromosomal structures necessary for continued cell division and proliferation. In addition to the classical telomerase pathway, multiple other genes including those involved in ribosome metabolism and chromatin modification contribute to telomere length maintenance. We previously reported that Arabidopsis thaliana ribosome biogenesis genes OLI2/NOP2A, OLI5/RPL5A and OLI7/RPL5B have critical roles in telomere length regulation. These three OLIGOCELLULA genes were also shown to function in cell proliferation and expansion control and to genetically interact with the transcriptional co-activator ANGUSTIFOLIA3 (AN3). Here we show that AN3-deficient plants progressively lose telomeric DNA in early homozygous mutant generations, but ultimately establish a new shorter telomere length setpoint by the fifth mutant generation with a telomere length similar to oli2/nop2a - deficient plants. Analysis of double an3 oli2 mutants indicates that the two genes are epistatic for telomere length control. Telomere shortening in an3 and oli mutants is not caused by telomerase inhibition; wild type levels of telomerase activity are detected in all analyzed mutants in vitro. Late generations of an3 and oli mutants are prone to stem cell damage in the root apical meristem, implying that genes regulating telomere length may have conserved functional roles in stem cell maintenance mechanisms. Multiple instances of anaphase fusions in late generations of oli5 and oli7 mutants were observed, highlighting an unexpected effect of ribosome biogenesis factors on chromosome integrity. Overall, our data implicate AN3 transcription coactivator and OLIGOCELLULA proteins in the establishment of telomere length set point in plants and further suggest that multiple regulators with pleiotropic functions can connect telomere biology with cell proliferation and cell expansion pathways.},
}
@article {pmid37960914,
year = {2023},
author = {Xing, B and Yu, J and Liu, Y and He, S and Chen, X and Li, Z and He, L and Yang, N and Ping, F and Xu, L and Li, W and Zhang, H and Li, Y},
title = {High Dietary Zinc Intake Is Associated with Shorter Leukocyte Telomere Length, Mediated by Tumor Necrosis Factor-α: A Study of China Adults.},
journal = {The journal of nutrition, health &amp; aging},
volume = {27},
number = {10},
pages = {904-910},
doi = {10.1007/s12603-023-1992-z},
pmid = {37960914},
issn = {1760-4788},
mesh = {Humans ; *Tumor Necrosis Factor-alpha ; *Zinc ; Cross-Sectional Studies ; Diet ; Inflammation ; Superoxide Dismutase ; Leukocytes ; Telomere ; },
abstract = {OBJECTIVES: Diet can influence peripheral leukocyte telomere length (LTL), and various micronutrients have been reported to correlate with it. Zinc is known for its antioxidant properties and immunomodulatory effects. However, there are few epidemiological investigations on the relationship between dietary zinc intake and LTL. This study analyzed the association between dietary zinc and LTL and the potential role of inflammation and oxidative stress among them.<br><br>DESIGN: Cross-sectional and community-based study.<br><br>SETTING AND PARTICIPANTS: 599 participants from rural communities in the Changping suburb of Beijing, China, were recruited.<br><br>MEASUREMENTS: Serum lipid profile, glycosylated hemoglobin (HbA1c), oxidative stress marker, and inflammatory cytokines levels were measured. Detailed dietary data were obtained using a 24 h food recall. LTL was assessed using a real-time PCR assay. Spearman analysis, restricted cubic splines (RCS), and general linear regression models were used to determine the association between dietary zinc intake and LTL. Simple regulatory models were also applied to analyze the role of inflammation and oxidative stress among them.<br><br>RESULTS: A total of 482 subjects were ultimately included in this analysis. Spearman analysis showed that dietary zinc intake and zinc intake under energy density were negatively correlated with LTL (r=-0.142 and -0.126, all P <0.05) and positively correlated with tumor necrosis factor-&#x3b1; (TNF-&#x3b1;) (r=0.138 and 0.202, all P <0.05) while only dietary zinc without energy adjustment had a positive correlation with superoxide dismutase (SOD). RCS (P for non-linearity=0.933) and multiple linear regression (B=-0.084, P=0.009) indicated a negative linear association between dietary zinc and LTL. The adjustment of TNF-&#x3b1; rather than SOD could abolish the relationship. The mediation model suggested that the unfavorable effect of dietary zinc on LTL was mediated by TNF-&#x3b1;.<br><br>CONCLUSIONS: High dietary zinc may correlate with telomere attrition, and TNF-&#x3b1; can act as a mediator in this relationship. In the future, more extensive cohort studies are needed to further explore the relationship between dietary zinc and cellular aging and the specific mechanisms.},
}
@article {pmid37960150,
year = {2023},
author = {Zhu, G and Xu, J and Guo, G and Zhu, F},
title = {Association between Lipids, Apolipoproteins and Telomere Length: A Mendelian Randomization Study.},
journal = {Nutrients},
volume = {15},
number = {21},
pages = {},
pmid = {37960150},
issn = {2072-6643},
support = {81701899//Guanghua Guo/ ; 82160376//Guanghua Guo/ ; 2019YFA0110601//Feng Zhu/ ; },
mesh = {Cholesterol, LDL ; *Mendelian Randomization Analysis ; *Apolipoproteins/genetics ; Apolipoproteins B ; Triglycerides ; Telomere/genetics ; Genome-Wide Association Study ; },
abstract = {(1) Background: The relationship between lipids, apolipoproteins, and telomere length (TL) has been explored in previous studies; however, the causal relationship between the two remains unclear. This study aims to assess the causal relationship between lipids, apolipoproteins, and TL using the two-sample Mendelian randomization (MR) approach; (2) Methods: This study comprehensively employed both univariate MR (uvMR) and multivariate MR (mvMR) methods to genetically evaluate the associations between 21 exposures related to lipids and apolipoproteins and the outcome of TL. During the analysis process, we utilized various statistical methods, including Inverse Variance Weighting (IVW), Weighted Median, MR-Egger regression, MR-PRESSO, and outlier tests. Furthermore, to confirm the robustness of the results, we conducted several sensitivity analyses to explore potential heterogeneity; (3) Results: The uvMR analysis indicated that an increase in MUFA, MUFA/FA ratio, LDL-C, VLDL-C, total cholesterol, ApoB, and triglycerides (TG) was associated with an increase in TL. However, this relationship did not manifest in the mvMR analysis, suggesting that this association may be based on preliminary evidence; (4) Conclusions: MR analysis results suggest potential suggestive positive causal relationships between genetically predicted MUFA, MUFA/FA ratio, LDL-C, VLDL-C, total cholesterol, ApoB, and TG with TL.},
}
@article {pmid37958962,
year = {2023},
author = {Kalmykova, A},
title = {Telomere Checkpoint in Development and Aging.},
journal = {International journal of molecular sciences},
volume = {24},
number = {21},
pages = {},
pmid = {37958962},
issn = {1422-0067},
support = {075-15-2020-773/9//the Ministry of Science and Higher Education of the Russian Federation/ ; },
mesh = {Animals ; *RNA/metabolism ; *Telomere Homeostasis ; Drosophila/genetics ; Aging/genetics ; Telomere/genetics ; Genomic Instability ; },
abstract = {The maintenance of genome integrity through generations is largely determined by the stability of telomeres. Increasing evidence suggests that telomere dysfunction may trigger changes in cell fate, independently of telomere length. Telomeric multiple tandem repeats are potentially highly recombinogenic. Heterochromatin formation, transcriptional repression, the suppression of homologous recombination and chromosome end protection are all required for telomere stability. Genetic and epigenetic defects affecting telomere homeostasis may cause length-independent internal telomeric DNA damage. Growing evidence, including that based on Drosophila research, points to a telomere checkpoint mechanism that coordinates cell fate with telomere state. According to this scenario, telomeres, irrespective of their length, serve as a primary sensor of genome instability that is capable of triggering cell death or developmental arrest. Telomeric factors released from shortened or dysfunctional telomeres are thought to mediate these processes. Here, we discuss a novel signaling role for telomeric RNAs in cell fate and early development. Telomere checkpoint ensures genome stability in multicellular organisms but aggravates the aging process, promoting the accumulation of damaged and senescent cells.},
}
@article {pmid37958686,
year = {2023},
author = {Grzeczka, A and Graczyk, S and Kordowitzki, P},
title = {DNA Methylation and Telomeres-Their Impact on the Occurrence of Atrial Fibrillation during Cardiac Aging.},
journal = {International journal of molecular sciences},
volume = {24},
number = {21},
pages = {},
pmid = {37958686},
issn = {1422-0067},
mesh = {Humans ; Female ; *Atrial Fibrillation ; DNA Methylation ; Aging/pathology ; Heart Atria/pathology ; Telomere/genetics/pathology ; },
abstract = {Atrial fibrillation (AF) is the most common arrhythmia in humans. AF is characterized by irregular and increased atrial muscle activation. This high-frequency activation obliterates the synchronous work of the atria and ventricles, reducing myocardial performance, which can lead to severe heart failure or stroke. The risk of developing atrial fibrillation depends largely on the patient's history. Cardiovascular diseases are considered aging-related pathologies; therefore, deciphering the role of telomeres and DNA methylation (mDNA), two hallmarks of aging, is likely to contribute to a better understanding and prophylaxis of AF. In honor of Prof. Elizabeth Blackburn's 75th birthday, we dedicate this review to the discovery of telomeres and her contribution to research on aging.},
}
@article {pmid37958573,
year = {2023},
author = {Rodriguez-Martin, I and Villanueva-Martin, G and Guillen-Del-Castillo, A and Ortego-Centeno, N and Callejas, JL and Simeón-Aznar, CP and Martin, J and Acosta-Herrera, M},
title = {Contribution of Telomere Length to Systemic Sclerosis Onset: A Mendelian Randomization Study.},
journal = {International journal of molecular sciences},
volume = {24},
number = {21},
pages = {},
pmid = {37958573},
issn = {1422-0067},
support = {RD21/0002/0039//Instituto de Salud Carlos III/ ; CP21/00132//Instituto de Salud Carlos III/ ; PRE2019-087586//Ministerio de Ciencia e Innovaci&#xf3;n/ ; FPU21/02746//Ministerio de Universidades/ ; },
mesh = {Humans ; *Genome-Wide Association Study ; Mendelian Randomization Analysis ; Leukocytes ; *Scleroderma, Systemic/genetics ; Telomere/genetics ; Polymorphism, Single Nucleotide ; },
abstract = {Although previous studies have suggested a relationship between telomere shortening and systemic sclerosis (SSc), the association between these two traits remains poorly understood. The objective of this study was to assess the causal relationship between telomere length in leukocytes (LTL) and SSc using the two-sample Mendelian randomization approach, with the genome-wide association study data for both LTL and SSc. The results of inverse-variance weighted regression (OR = 0.716 [95% CI 0.528-0.970], p = 0.031) and the Mendelian randomization pleiotropy residual sum and outlier method (OR = 0.716 [95% CI 0.563-0.911], p = 0.035) indicate an association between telomere length and SSc. Specifically, longer genetically predicted LTL is associated with a reduced risk of SSc. Sensitivity tests highlight the significant roles of the variants rs10936599 and rs2736100 annotated to the TERC and TERT genes, respectively. Our findings suggest an influence of telomere length in leukocytes on the development of SSc.},
}
@article {pmid37957036,
year = {2024},
author = {Lu, X and Liu, L},
title = {Genome stability from the perspective of telomere length.},
journal = {Trends in genetics : TIG},
volume = {40},
number = {2},
pages = {175-186},
doi = {10.1016/j.tig.2023.10.013},
pmid = {37957036},
issn = {0168-9525},
mesh = {Animals ; *Retroelements ; Telomere/metabolism ; Genomic Instability ; Cell Division ; *Telomerase ; Cellular Senescence ; Mammals ; },
abstract = {Telomeres and their associated proteins protect the ends of chromosomes to maintain genome stability. Telomeres undergo progressive shortening with each cell division in mammalian somatic cells without telomerase, resulting in genome instability. When telomeres reach a critically short length or are recognized as a damage signal, cells enter a state of senescence, followed by cell cycle arrest, programmed cell death, or immortalization. This review provides an overview of recent advances in the intricate relationship between telomeres and genome instability. Alongside well-established mechanisms such as chromosomal fusion and telomere fusion, we will delve into the perspective on genome stability by examining the role of retrotransposons. Retrotransposons represent an emerging pathway to regulate genome stability through their interactions with telomeres.},
}
@article {pmid37953281,
year = {2023},
author = {Carvalho Borges, PC and Bouabboune, C and Escandell, JM and Matmati, S and Coulon, S and Ferreira, MG},
title = {Pot1 promotes telomere DNA replication via the Stn1-Ten1 complex in fission yeast.},
journal = {Nucleic acids research},
volume = {51},
number = {22},
pages = {12325-12336},
pmid = {37953281},
issn = {1362-4962},
support = {PTDC/BEX-BCM/5179/14//FCT/ ; //Howard Hughes Medical Institute IECS/ ; Action 2 - 2019//Universit&#xe9; C&#xf4;te d'Azur - Acad&#xe9;mie 4/ ; EQU201903007804//Fondation pour la Recherche M&#xe9;dicale/ ; //'Ligue Nationale Contre le Cancer' (LNCC)/ ; ANR-16-CE12 TeloMito//Agence Nationale de la Research/ ; },
mesh = {*DNA Replication ; DNA-Binding Proteins/metabolism ; *Schizosaccharomyces/metabolism ; *Schizosaccharomyces pombe Proteins/metabolism ; Shelterin Complex ; *Telomere/metabolism ; Telomere-Binding Proteins/metabolism ; *Chromosomes, Fungal/metabolism ; },
abstract = {Telomeres are nucleoprotein complexes that protect the chromosome-ends from eliciting DNA repair while ensuring their complete duplication. Pot1 is a subunit of telomere capping complex that binds to the G-rich overhang and inhibits the activation of DNA damage checkpoints. In this study, we explore new functions of fission yeast Pot1 by using a pot1-1 temperature sensitive mutant. We show that pot1 inactivation impairs telomere DNA replication resulting in the accumulation of ssDNA leading to the complete loss of telomeric DNA. Recruitment of Stn1 to telomeres, an auxiliary factor of DNA lagging strand synthesis, is reduced in pot1-1 mutants and overexpression of Stn1 rescues loss of telomeres and cell viability at restrictive temperature. We propose that Pot1 plays a crucial function in telomere DNA replication by recruiting Stn1-Ten1 and Polα-primase complex to telomeres via Tpz1, thus promoting lagging-strand DNA synthesis at stalled replication forks.},
}
@article {pmid37951311,
year = {2023},
author = {Banaszak, LG and Smith-Simmer, K and Shoger, K and Lovrien, L and Malik, A and Sandbo, N and Sultan, S and Guzy, R and Lowery, EM and Churpek, JE},
title = {Implementation of a prospective screening strategy to identify adults with a telomere biology disorder among those undergoing lung transplant evaluation for interstitial lung disease.},
journal = {Respiratory medicine},
volume = {220},
number = {},
pages = {107464},
doi = {10.1016/j.rmed.2023.107464},
pmid = {37951311},
issn = {1532-3064},
mesh = {Adult ; Humans ; Prospective Studies ; *Lung Diseases, Interstitial/diagnosis/genetics/surgery ; Telomere/genetics ; *Lung Transplantation ; Biology ; },
abstract = {INTRODUCTION: Patients with interstitial lung disease (ILD) secondary to telomere biology disorders (TBD) experience increased morbidity after lung transplantation. Identifying patients with TBD may allow for personalized management to facilitate better outcomes. However, establishing a TBD diagnosis in adults is challenging.<br><br>METHODS: A TBD screening questionnaire was introduced prospectively into the lung transplant evaluation. Patients with ILD screening positive were referred for comprehensive TBD phenotyping and concurrent telomere length measurement and germline genetic testing.<br><br>RESULTS: Of 98 patients, 32 (33%) screened positive. Eight patients (8% of total; 25% of patients with a positive screen) met strict TBD diagnostic criteria, requiring either critically short lymphocyte telomeres (<1st percentile) (n&#xa0;=&#xa0;4), a pathogenic variant in a TBD-associated gene (n&#xa0;=&#xa0;1), or both (n&#xa0;=&#xa0;3) along with a TBD clinical phenotype. Additional patients not meeting strict diagnostic criteria had histories consistent with TBD along with telomere lengths <10th percentile and/or rare variants in TBD-associated genes, highlighting a critical need to refine TBD diagnostic criteria for this patient population.<br><br>CONCLUSION: A TBD phenotype screening questionnaire in patients with ILD undergoing lung transplant evaluation has a diagnostic yield of 25%. Additional gene discovery, rare variant functional testing, and refined TBD diagnostic criteria are needed to realize the maximum benefit of testing for TBD in patients undergoing lung transplantation.},
}
@article {pmid37951043,
year = {2024},
author = {Nassour, J and Przetocka, S and Karlseder, J},
title = {Telomeres as hotspots for innate immunity and inflammation.},
journal = {DNA repair},
volume = {133},
number = {},
pages = {103591},
pmid = {37951043},
issn = {1568-7856},
support = {R01 CA227934/CA/NCI NIH HHS/United States ; R01 CA234047/CA/NCI NIH HHS/United States ; R01 AG077324/AG/NIA NIH HHS/United States ; R00 CA252447/CA/NCI NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; R01 CA228211/CA/NCI NIH HHS/United States ; K99 CA252447/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; *Aging/genetics ; *Telomere ; Inflammation ; Immunity, Innate ; Cellular Senescence ; },
abstract = {Aging is marked by the gradual accumulation of deleterious changes that disrupt organ function, creating an altered physiological state that is permissive for the onset of prevalent human diseases. While the exact mechanisms governing aging remain a subject of ongoing research, there are several cellular and molecular hallmarks that contribute to this biological process. This review focuses on two factors, namely telomere dysfunction and inflammation, which have emerged as crucial contributors to the aging process. We aim to discuss the mechanistic connections between these two distinct hallmarks and provide compelling evidence highlighting the loss of telomere protection as a driver of pro-inflammatory states associated with aging. By reevaluating the interplay between telomeres, innate immunity, and inflammation, we present novel perspectives on the etiology of aging and its associated diseases.},
}
@article {pmid37950187,
year = {2023},
author = {Hassanpour, H and Mirshokraei, P and Salehpour, M and Amiri, K and Ghareghani, P and Nasiri, L},
title = {Canine sperm motility is associated with telomere shortening and changes in expression of shelterin genes.},
journal = {BMC veterinary research},
volume = {19},
number = {1},
pages = {236},
pmid = {37950187},
issn = {1746-6148},
mesh = {Male ; Dogs ; Animals ; *Shelterin Complex ; *Telomere-Binding Proteins/genetics/metabolism ; Telomere Shortening ; Sperm Motility/genetics ; Semen ; },
abstract = {BACKGROUND: Motion quality is a critical property for essential functions. Several endogenous and exogenous factors are involved in sperm motility. Here, we measured the relative telomere length and evaluated the gene expression of its binding-proteins, shelterin complex (TRF1, TRF2, RAP1, POT1, TIN2, and TPP1) in sperm of dogs using relative quantitative real-time PCR. We compared them between two sperm subpopulations with poor and good motion qualities (separated by swim-up method). Telomere shortening and alterations of shelterin gene expression result from ROS, genotoxic insults, and genetic predisposition.<br><br>RESULTS: Sperm kinematic parameters were measured in two subpopulations and then telomeric index of each parameter was calculated. Telomeric index for linearity, VSL, VCL, STR, BCF, and ALH were significantly higher in sperms with good motion quality than in sperms with poor quality. We demonstrated that poor motion quality is associated with shorter telomere, higher expression of TRF2, POT1, and TIN2 genes, and lower expression of the RAP1 gene in dog sperm. The levels of TRF1 and TPP1 gene expression remained consistent despite variations in sperm quality and telomere length.<br><br>CONCLUSION: Data provided evidence that there are considerable changes in gene expression of many shelterin components (TRF2, TIN2, POT1and RAP1) associated with shortening telomere in the spermatozoa with poor motion quality. Possibly, the poor motion quality is the result of defects in the shelterin complex and telomere length. Our data suggests a new approach in the semen assessment and etiologic investigations of subfertility or infertility in male animals.},
}
@article {pmid37949346,
year = {2024},
author = {Randell, Z and Dehghanbanadaki, H and Fendereski, K and Jimbo, M and Aston, K and Hotaling, J},
title = {Sperm telomere length in male-factor infertility and reproduction.},
journal = {Fertility and sterility},
volume = {121},
number = {1},
pages = {12-25},
doi = {10.1016/j.fertnstert.2023.11.001},
pmid = {37949346},
issn = {1556-5653},
mesh = {Male ; Humans ; *Semen ; *Infertility, Male/diagnosis/genetics ; Spermatozoa ; Reproduction ; Telomere/genetics ; },
abstract = {The underlying reasons for male-factor infertility are often unknown. 30% of all men have unexplained semen analysis abnormalities. Moreover, 15%-40% of infertile men have normal semen analyses. There have been increasing efforts to identify causes and associations that may explain idiopathic male-factor infertility. Telomeres have become an area of considerable interest in the field because of the essential roles they have in cellular division and genome integrity. Research to date most consistently supports that men with infertility have shorter sperm telomere length (STL); however, associations between shorter STL and meaningful reproductive health outcomes are less consistent. There is a major need for additional studies to better identify the role of STL in male reproductive health and use the information to improve the counseling and treatment of couples with idiopathic male-factor infertility.},
}
@article {pmid37947937,
year = {2023},
author = {Ferrer, A and Stephens, ZD and Kocher, JA},
title = {Experimental and Computational Approaches to Measure Telomere Length: Recent Advances and Future Directions.},
journal = {Current hematologic malignancy reports},
volume = {18},
number = {6},
pages = {284-291},
pmid = {37947937},
issn = {1558-822X},
mesh = {Humans ; Forecasting ; *Telomere/genetics ; },
abstract = {PURPOSE OF REVIEW: The length of telomeres, protective structures at the chromosome ends, is a well-established biomarker for pathological conditions including multisystemic syndromes called telomere biology disorders. Approaches to measure telomere length (TL) differ on whether they estimate average, distribution, or chromosome-specific TL, and each presents their own advantages and limitations.<br><br>RECENT FINDINGS: The development of long-read sequencing and publication of the telomere-to-telomere human genome reference has allowed for scalable and high-resolution TL estimation in pre-existing sequencing datasets but is still impractical as a dedicated TL test. As sequencing costs continue to fall and strategies for selectively enriching telomere regions prior to sequencing improve, these approaches may become a promising alternative to classic methods. Measurement methods rely on probe hybridization, qPCR or more recently, computational methods using sequencing data. Refinements of existing techniques and new approaches have been recently developed but a test that is accurate, simple, and scalable is still lacking.},
}
@article {pmid37946752,
year = {2023},
author = {Yan, J and Jin, T and Wang, L},
title = {Hematopoietic stem cell transplantation of aplastic anemia by relative with mutations and normal telomere length: A case report.},
journal = {World journal of clinical cases},
volume = {11},
number = {29},
pages = {7200-7206},
pmid = {37946752},
issn = {2307-8960},
abstract = {BACKGROUND: Immunosuppressive therapy and matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) are the preferred treatments for aplastic anemia (AA).<br><br>CASE SUMMARY: In this report, we describe a 43-year-old male patient with severe AA who carried BRIP1 (also known as FANCJ), TINF2, and TCIRG1 mutations. Screening of the family pedigree revealed the same TINF2 mutation in his mother and older brother, with his older brother also carrying the BRIP1 variant and demonstrating normal telomere length and hematopoietic function. The patient was successfully treated with oral cyclosporine A, eltrombopag, and acetylcysteine, achieving remission 4 years after receiving MSD-HSCT from his older brother.<br><br>CONCLUSION: This case provides a valuable clinical reference for individuals with suspected pathogenic gene mutations, normal telomere length, and hematopoietic function, highlighting them as potential donors for patients with AA.},
}
@article {pmid37944684,
year = {2023},
author = {Rolles, B and Caballero-Oteyza, A and Proietti, M and Goldacker, S and Warnatz, K and Camacho-Ordonez, N and Prader, S and Schmid, JP and Vieri, M and Isfort, S and Meyer, R and Kirschner, M and Brümmendorf, TH and Beier, F and Grimbacher, B},
title = {Telomere biology disorders may manifest as common variable immunodeficiency (CVID).},
journal = {Clinical immunology (Orlando, Fla.)},
volume = {257},
number = {},
pages = {109837},
doi = {10.1016/j.clim.2023.109837},
pmid = {37944684},
issn = {1521-7035},
mesh = {Adult ; Humans ; *Common Variable Immunodeficiency/genetics ; *Telomerase/genetics/metabolism ; *Primary Immunodeficiency Diseases ; Telomere/genetics/metabolism/pathology ; *Dyskeratosis Congenita/genetics/diagnosis/pathology ; Biology ; },
abstract = {Telomere biology disorders (TBD) are caused by germline pathogenic variants in genes related to telomere maintenance and are characterized by critically short telomeres. In contrast to classical dyskeratosis congenita (DC), which is typically diagnosed in infancy, adult or late onset TBD frequently lack the typical DC triad and rather show variable organ manifestations and a cryptic disease course, thus complicating its diagnosis. Common variable immunodeficiency (CVID), on the other hand, is a primary antibody deficiency (PAD) syndrome. PADs are a heterogenous group of diseases characterized by hypogammaglobulinemia which occurs due to dysfunctional B lymphocytes and additional autoimmune and autoinflammatory complications. Genetic screening reveals a monogenic cause in a subset of CVID patients (15-35%). In our study, we screened the exomes of 491 CVID patients for the occurrence of TBD-related variants in 13 genes encoding for telomere/telomerase-associated proteins, which had previously been linked to the disease. We found 110/491 patients (22%) carrying 91 rare candidate variants in these 13 genes. Following the American College of Medical Genetics and Genomics (ACMG) guidelines, we classified two variants as benign, two as likely benign, 64 as variants of uncertain significance (VUS), four as likely pathogenic, and one heterozygous variant in an autosomal recessive disease gene as pathogenic. We performed telomere length measurement in 42 of the 110 patients with candidate variants and CVID. Two of these 42 patients showed significantly shorter telomeres compared to controls in both lymphocytes and granulocytes. Following the evaluation of the published literature and the patient's manifestations, we re-classified two VUS as likely pathogenic variants. Thus, 0.5-1% of all CVID patients in our study carry possibly pathogenic variants in telomere/telomerase-associated genes. Our data adds CVID to the broad clinical spectrum of cryptic adult-onset TBD. As the molecular diagnosis greatly impacts patient management and treatment strategies, we advise inclusion of all TBD-associated genes-despite their low prevalence-into the molecular screening of patients with antibody deficiencies.},
}
@article {pmid37943179,
year = {2023},
author = {Sato, MP and Iwakami, S and Fukunishi, K and Sugiura, K and Yasuda, K and Isobe, S and Shirasawa, K},
title = {Telomere-to-telomere genome assembly of an allotetraploid pernicious weed, Echinochloa phyllopogon.},
journal = {DNA research : an international journal for rapid publication of reports on genes and genomes},
volume = {30},
number = {5},
pages = {},
pmid = {37943179},
issn = {1756-1663},
support = {19H02955//KAKENHI/ ; //Kazusa DNA Research Institute Foundation/ ; },
mesh = {*Echinochloa ; Telomere/genetics ; *Oryza/genetics ; Phenotype ; Tetraploidy ; },
abstract = {Echinochloa phyllopogon is an allotetraploid pernicious weed species found in rice fields worldwide that often exhibit resistance to multiple herbicides. An accurate genome sequence is essential to comprehensively understand the genetic basis underlying the traits of this species. Here, the telomere-to-telomere genome sequence of E. phyllopogon was presented. Eighteen chromosome sequences spanning 1.0 Gb were constructed using the PacBio highly fidelity long technology. Of the 18 chromosomes, 12 sequences were entirely assembled into telomere-to-telomere and gap-free contigs, whereas the remaining six sequences were constructed at the chromosomal level with only eight gaps. The sequences were assigned to the A and B genome with total lengths of 453 and 520 Mb, respectively. Repetitive sequences occupied 42.93% of the A genome and 48.47% of the B genome, although 32,337, and 30,889 high-confidence genes were predicted in the A and B genomes, respectively. This suggested that genome extensions and gene disruptions caused by repeated sequence accumulation often occur in the B genome before polyploidization to establish a tetraploid genome. The highly accurate and comprehensive genome sequence could be a milestone in understanding the molecular mechanisms of the pernicious traits and in developing effective weed control strategies to avoid yield loss in rice production.},
}
@article {pmid37942318,
year = {2023},
author = {Pan, R and Xiao, M and Wu, Z and Liu, J and Wan, L},
title = {Associations of genetically predicted circulating levels of cytokines with telomere length: a Mendelian randomization study.},
journal = {Frontiers in immunology},
volume = {14},
number = {},
pages = {1276257},
pmid = {37942318},
issn = {1664-3224},
mesh = {Humans ; *Cytokines/genetics ; *Interleukin-7 ; Interleukin-2 Receptor alpha Subunit ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Reproducibility of Results ; Telomere/genetics ; },
abstract = {BACKGROUND: Telomere length (TL) has been regarded as a biomarker of aging, and TL shortening is associated with numerous chronic illnesses. The mounting evidence has shown that inflammatory cytokines are involved in maintaining or shortening TL, the causality of cytokines with TL remains unknown. Therefore, we performed a two-sample Mendelian randomization (MR) analysis to estimate the underlying correlations of circulating inflammatory cytokines with TL.<br><br>METHODS: Genetic instrumental variables for inflammatory cytokines were identified through a genome-wide association study (GWAS) involving 8,293 European individuals. Summary statistics of TL were derived from a UK Bio-bank cohort comprising 472,174 samples of individuals with European descent. We employed the inverse-variance weighted (IVW) approach as our main analysis, and to ensure the reliability of our findings, we also conducted additional analyses including the weighted median, MR-Egger, MR pleiotropy residual sum and outlier test, and weighted model. Lastly, the reverse MR analyses were performed to estimate the likelihood of inverse causality between TL and the cytokines identified in the forward MR analysis. Cochran's Q test were employed to quantify the degree of heterogeneity.<br><br>RESULTS: After applying Bonferroni correction, a higher circulating level of Interleukin-7 (IL-7) was suggestively associated with TL maintaining (OR:1.01, 95%CI:1.00-1.02, P=0.032 by IVW method). The study also revealed suggestive evidence indicating the involvement of Interleukin-2 receptor, alpha subunit (IL-2R&#x3b1;) level was negatively associated with TL maintaining (OR:0.98, 95%CI:0.96-1.00, P=0.045 by IVW method), and the weighted median approach was consistent (OR:0.99, 95%CI:0.97-1.00, P=0.035). According to the findings of reverse MR analysis, no significant causal relationship between TL and cytokines was explored. Our analysis did not reveal any substantial heterogeneity in the Single nucleotide polymorphisms or horizontal pleiotropy.<br><br>CONCLUSIONS: Our MR analysis yielded suggestive evidence supporting the causality between circulating IL-7 and IL-2R&#x3b1; and telomere length, necessitating further investigations to elucidate the mechanisms by which these inflammatory cytokines may impact the progression of telomeres.},
}
@article {pmid37940980,
year = {2023},
author = {Tang, L and Li, D and Ma, Y and Cui, F and Wang, J and Tian, Y},
title = {The association between telomere length and non-alcoholic fatty liver disease: a prospective study.},
journal = {BMC medicine},
volume = {21},
number = {1},
pages = {427},
pmid = {37940980},
issn = {1741-7015},
mesh = {Humans ; *Non-alcoholic Fatty Liver Disease/epidemiology/genetics/complications ; Prospective Studies ; Risk Factors ; *Air Pollution ; Telomere/genetics ; },
abstract = {BACKGROUND: Research on the association between telomere length (TL) and incident non-alcoholic fatty liver disease (NAFLD) is limited. This study examined this association and further assessed how TL contributes to the association of NAFLD with its known risk factors.<br><br>METHODS: Quantitative PCR (polymerase chain reaction) was employed to assess leucocyte telomere length. Polygenic risk score (PRS) for NAFLD, air pollution score, and lifestyle index were constructed. Cox proportional hazard models were conducted to estimate the hazard ratios (HRs) and 95% confidence intervals.<br><br>RESULTS: Among 467,848 participants in UK Biobank, we identified 4809 NAFLD cases over a median follow-up of 12.83&#xa0;years. We found that long TL was associated with decreased risk of incident NAFLD, as each interquartile range increase in TL resulted in an HR of 0.93 (95% CI 0.89, 0.96). TL partly mediated the association between age and NAFLD (proportion mediated: 15.52%). When assessing the joint effects of TL and other risk factors, the highest risk of NAFLD was found in participants with low TL and old age, low TL and high air pollution score, low TL and unfavorable lifestyle, and low TL and high PRS, compared to each reference group. A positive addictive interaction was observed between high PRS and low TL, accounting for 14.57% (2.51%, 27.14%) of the risk of NAFLD in participants with low telomere length and high genetic susceptibility.<br><br>CONCLUSIONS: Long telomere length was associated with decreased risk of NAFLD incidence. Telomere length played an important role in NAFLD.},
}
@article {pmid37939053,
year = {2023},
author = {Kotecha, EA and Zhang, L and Aboklaish, A and Cousins, M and Hart, K and Kotecha, SJ and Watkins, WJ and Kotecha, S},
title = {Association of early and current life factors with telomere length in preterm-born children.},
journal = {PloS one},
volume = {18},
number = {11},
pages = {e0293589},
pmid = {37939053},
issn = {1932-6203},
support = {MR/M022552/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Infant, Newborn ; Male ; Infant ; Female ; Humans ; Child ; *Infant, Premature ; Gestational Age ; *Bronchopulmonary Dysplasia ; Fetal Growth Retardation ; Telomere/genetics ; },
abstract = {BACKGROUND: Telomeres shorten after each cell division. Since preterm-born babies are delivered early and often suffer from inflammatory conditions such as bronchopulmonary dysplasia (BPD), their telomere length may be altered.<br><br>OBJECTIVES: We assessed associations of early and current life factors with telomere length in saliva samples obtained from 7-12-year-old children born at &#x2264;34 weeks' gestation and term-born controls.<br><br>STUDY DESIGN: Relative telomere length was measured by qPCR on extracted DNA. Groups were compared using independent t-tests or ANOVA with post-hoc correction. Linear regression analysis was also used.<br><br>RESULTS: 534 children had satisfactory telomere data including 383 who were preterm-born (mean (SD) birthweight 1732g (558g), gestation 31.1 (2.6) weeks) and 151 term-born (3464g (510g); 39.8 (1.3) weeks). Telomere length was longer in children who had intrauterine growth restriction (IUGR) at birth: mean (SD): 464.6 (166.3) vs. 418.6 (110.7) in the no-IUGR group; in females: 440.2 (130.1) vs. 405.7 (101.5) in males; and in the least deprived group (397.8 (95.0) vs. 437.6 (121.9) most vs least deprivation quintile). Differences were most notable in females with IUGR. However, telomere length was not different between the preterm and term groups; the BPD and no BPD groups nor was it related to lung function or cardiovascular measurements. In multivariable regression analyses, telomere length was associated with sex, IUGR and deprivation with the greatest difference observed in females with IUGR.<br><br>CONCLUSIONS: Telomere length was associated with sex, IUGR and deprivation, especially in females with IUGR, but not with prematurity, BPD, lung function or cardiovascular measurements.},
}
@article {pmid37934624,
year = {2023},
author = {Sidali, S and Borie, R and Sicre de Fontbrune, F and El Husseini, K and Rautou, PE and Lainey, E and Goria, O and Crestani, B and Cadranel, J and Cottin, V and Bunel, V and Dumortier, J and Jacquemin, E and Reboux, N and Hirschi, S and Bourdin, A and Meszaros, M and Dharancy, S and Hilaire, S and Mallet, V and Reynaud-Gaubert, M and Terriou, L and Gottrand, F and Abou Chahla, W and Khan, JE and Carrier, P and Saliba, F and Rubbia-Brandt, L and Aubert, JD and Elkrief, L and de Lédinghen, V and Abergel, A and Olivier, T and Houssel, P and Jouneau, S and Wemeau, L and Bergeron, A and Leblanc, T and Ollivier-Hourmand, I and Nguyen Khac, E and Morisse-Pradier, H and Ba, I and Boileau, C and Roudot-Thoraval, F and Vilgrain, V and Bureau, C and Nunes, H and Naccache, JM and Durand, F and Francoz, C and Roulot, D and Valla, D and Paradis, V and Kannengiesser, C and Plessier, A},
title = {Liver disease in germline mutations of telomere-related genes: Prevalence, clinical, radiological, pathological features, outcome, and risk factors.},
journal = {Hepatology (Baltimore, Md.)},
volume = {},
number = {},
pages = {},
doi = {10.1097/HEP.0000000000000667},
pmid = {37934624},
issn = {1527-3350},
abstract = {BACKGROUND AND AIM: Germline mutations of telomere-related genes (TRG) induce multiorgan dysfunction, and liver-specific manifestations have not been clearly outlined. We aimed to describe TRG mutations-associated liver diseases.<br><br>APPROACH AND RESULTS: Retrospective multicenter analysis of liver disease (transaminases > 30 IU/L and/or abnormal liver imaging) in patients with TRG mutations. Main measurements were characteristics, outcomes, and risk factors of liver disease in a TRG mutations cohort. The prevalence of liver disease was compared to a community-based control group (n = 1190) stratified for age and matched 1:3 for known risk factors of liver disease. Among 132 patients with TRG mutations, 95 (72%) had liver disease, with associated lung, blood, skin, rheumatological, and ophthalmological TRG diseases in 82%, 77%, 55%, 39%, and 30% of cases, respectively. Liver biopsy was performed in 52/95 patients, identifying porto-sinusoidal vascular disease in 48% and advanced fibrosis/cirrhosis in 15%. After a follow-up of 21 months (12-54), ascites, hepato-pulmonary syndrome, variceal bleeding, and HCC occurred in 14%, 13%, 13%, and 2% of cases, respectively. Five-year liver transplantation-free survival was 69%. A FIB-4 score &#x2265; 3&#xb7;25 and &#x2265;1 risk factor for cirrhosis were associated with poor liver transplantation-free survival. Liver disease was more frequent in patients with TRG mutations than in the paired control group [80/396, (20%)], OR 12.9 (CI 95%: 7.8-21.3, p < 0.001).<br><br>CONCLUSIONS: TRG mutations significantly increase the risk of developing liver disease. Although symptoms may be mild, they may be associated with severe disease. Porto-sinusoidal vascular disease and cirrhosis were the most frequent lesions, suggesting that the mechanism of action is multifactorial.},
}
@article {pmid37930826,
year = {2023},
author = {Wang, Y and Zhu, W and Jang, Y and Sommers, JA and Yi, G and Puligilla, C and Croteau, DL and Yang, Y and Kai, M and Liu, Y},
title = {The RNA-binding motif protein 14 regulates telomere integrity at the interface of TERRA and telomeric R-loops.},
journal = {Nucleic acids research},
volume = {51},
number = {22},
pages = {12242-12260},
pmid = {37930826},
issn = {1362-4962},
support = {/AG/NIA NIH HHS/United States ; /AG/NIA NIH HHS/United States ; },
mesh = {Humans ; DNA/genetics ; R-Loop Structures ; RNA/genetics/metabolism ; RNA, Long Noncoding/genetics ; RNA-Binding Motifs ; *Telomere/genetics/metabolism ; *Telomere Homeostasis ; Neoplasms/genetics ; },
abstract = {Telomeric repeat-containing RNA (TERRA) and its formation of RNA:DNA hybrids (or TERRA R-loops), influence telomere maintenance, particularly in human cancer cells that use homologous recombination-mediated alternative lengthening of telomeres. Here, we report that the RNA-binding motif protein 14 (RBM14) is associated with telomeres in human cancer cells. RBM14 negatively regulates TERRA expression. It also binds to TERRA and inhibits it from forming TERRA R-loops at telomeres. RBM14 depletion has several effects, including elevated TERRA levels, telomeric R-loops, telomere dysfunction-induced DNA damage foci formation, particularly in the presence of DNA replication stress, pRPA32 accumulation at telomeres and telomere signal-free ends. Thus, RBM14 protects telomere integrity via modulating TERRA levels and its R-loop formation at telomeres.},
}
@article {pmid37927407,
year = {2023},
author = {He, S and Weng, D and Zhang, Y and Kong, Q and Wang, K and Jing, N and Li, F and Ge, Y and Xiong, H and Wu, L and Xie, DY and Feng, S and Yu, X and Wang, X and Shu, S and Mei, Z},
title = {A telomere-to-telomere reference genome provides genetic insight into the pentacyclic triterpenoid biosynthesis in Chaenomeles speciosa.},
journal = {Horticulture research},
volume = {10},
number = {10},
pages = {uhad183},
pmid = {37927407},
issn = {2662-6810},
abstract = {Chaenomeles speciosa (2n = 34), a medicinal and edible plant in the Rosaceae, is commonly used in traditional Chinese medicine. To date, the lack of genomic sequence and genetic studies has impeded efforts to improve its medicinal value. Herein, we report the use of an integrative approach involving PacBio HiFi (third-generation) sequencing and Hi-C scaffolding to assemble a high-quality telomere-to-telomere genome of C. speciosa. The genome comprised 650.4 Mb with a contig N50 of 35.5 Mb. Of these, 632.3 Mb were anchored to 17 pseudo-chromosomes, in which 12, 4, and 1 pseudo-chromosomes were represented by a single contig, two contigs, and four contigs, respectively. Eleven pseudo-chromosomes had telomere repeats at both ends, and four had telomere repeats at a single end. Repetitive sequences accounted for 49.5% of the genome, while a total of 45 515 protein-coding genes have been annotated. The genome size of C. speciosa was relatively similar to that of Malus domestica. Expanded or contracted gene families were identified and investigated for their association with different plant metabolisms or biological processes. In particular, functional annotation characterized gene families that were associated with the biosynthetic pathway of oleanolic and ursolic acids, two abundant pentacyclic triterpenoids in the fruits of C. speciosa. Taken together, this telomere-to-telomere and chromosome-level genome of C. speciosa not only provides a valuable resource to enhance understanding of the biosynthesis of medicinal compounds in tissues, but also promotes understanding of the evolution of the Rosaceae.},
}
@article {pmid37926899,
year = {2024},
author = {Zhao, L and Jin, W and Zhang, T and Lu, Y and Liu, Q and Cai, J and Luo, L and Teng, K and Guan, Q and Wu, S and Rong, J and Liang, YJ and Cao, J and Qin, L and Huang, C and Wang, X and Li, Y and Zhang, Z and Qin, J},
title = {Association between the dietary antioxidant index and relative telomere length of leucocytes in the Chinese population.},
journal = {The British journal of nutrition},
volume = {131},
number = {6},
pages = {1031-1040},
doi = {10.1017/S0007114523002544},
pmid = {37926899},
issn = {1475-2662},
mesh = {Humans ; Male ; Female ; *Antioxidants ; Cross-Sectional Studies ; *Vitamin E ; Telomere ; China ; },
abstract = {Dietary antioxidant indices (DAI) may be potentially associated with relative telomere length (RTL) of leucocytes. This study aimed to investigate the relationship between DAI and RTL. A cross-sectional study involving 1656 participants was conducted. A generalised linear regression model and a restricted cubic spline model were used to assess the correlation of DAI and its components with RTL. Generalised linear regression analysis revealed that DAI (β = 0·005, P = 0·002) and the intake of its constituents vitamin C (β = 0·043, P = 0·027), vitamin E (β = 0·088, P < 0·001), Se (β = 0·075, P = 0·003), and Zn (β = 0·075, P = 0·023) were significantly and positively correlated with RTL. Sex-stratified analysis showed that DAI (β = 0·006, P = 0·005) and its constituents vitamin E (β = 0·083, P = 0·012), Se (β = 0·093, P = 0·006), and Zn (β = 0·092, P = 0·034) were significantly and positively correlated with RTL among females. Meanwhile, among males, only vitamin E intake (β = 0·089, P = 0·013) was significantly and positively associated with RTL. Restricted cubic spline analysis revealed linear positive associations between DAI and its constituents' (vitamin E, Se and Zn) intake and RTL in the total population. Sex-stratified analysis revealed a linear positive correlation between DAI and its constituents' (vitamin E, Se and Zn) intake and RTL in females. Our study found a significant positive correlation between DAI and RTL, with sex differences.},
}
@article {pmid37926112,
year = {2023},
author = {Elbadry, MI and Tawfeek, A and Hirano, T and El-Mokhtar, MA and Kenawey, M and Helmy, AM and Ogawa, S and Mughal, MZ and Nannya, Y},
title = {A rare homozygous variant in TERT gene causing variable bone marrow failure, fragility fractures, rib anomalies and extremely short telomere lengths with high serum IgE.},
journal = {British journal of haematology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bjh.19176},
pmid = {37926112},
issn = {1365-2141},
abstract = {By whole exome sequencing, we identified a homozygous c.2086 C→T (p.R696C) TERT mutation in patients who present with a spectrum of variable bone marrow failure (BMF), raccoon eyes, dystrophic nails, rib anomalies, fragility fractures (FFs), high IgE level, extremely short telomere lengths (TLs), and skewed numbers of cytotoxic T cells with B and NK cytopenia. Haploinsufficiency in the other family members resulted in short TL and osteopenia. These patients also had the lowest bone mineral density Z-score compared to other BMF-patients. Danazol/zoledronic acid improved the outcomes of BMF and FFs. This causative TERT variant has been observed in one family afflicted with dyskeratosis congenita (DC), and thus, we also define a second report and new phenotype related to the variant which should be suspected in severe cases of DC with co-existent BMF, FFs, high IgE level and rib anomalies.},
}
@article {pmid37922882,
year = {2023},
author = {Miga, KH and Eichler, EE},
title = {Envisioning a new era: Complete genetic information from routine, telomere-to-telomere genomes.},
journal = {American journal of human genetics},
volume = {110},
number = {11},
pages = {1832-1840},
pmid = {37922882},
issn = {1537-6605},
support = {R01 HG010169/HG/NHGRI NIH HHS/United States ; R01 HG011274/HG/NHGRI NIH HHS/United States ; U01 HG010971/HG/NHGRI NIH HHS/United States ; U24 HG007497/HG/NHGRI NIH HHS/United States ; },
mesh = {Humans ; *Genomics ; Sequence Analysis, DNA ; *High-Throughput Nucleotide Sequencing ; Genome, Human/genetics ; Telomere/genetics ; },
abstract = {Advances in long-read sequencing and assembly now mean that individual labs can generate phased genomes that are more accurate and more contiguous than the original human reference genome. With declining costs and increasing democratization of technology, we suggest that complete genome assemblies, where both parental haplotypes are phased telomere to telomere, will become standard in human genetics. Soon, even in clinical settings where rigorous sample-handling standards must be met, affected individuals could have reference-grade genomes fully sequenced and assembled in just a few hours given advances in technology, computational processing, and annotation. Complete genetic variant discovery will transform how we map, catalog, and associate variation with human disease and fundamentally change our understanding of the genetic diversity of all humans.},
}
@article {pmid37925537,
year = {2023},
author = {Rosso, I and Jones-Weinert, C and Rossiello, F and Cabrini, M and Brambillasca, S and Munoz-Sagredo, L and Lavagnino, Z and Martini, E and Tedone, E and Garre', M and Aguado, J and Parazzoli, D and Mione, M and Shay, JW and Mercurio, C and d'Adda di Fagagna, F},
title = {Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {7086},
pmid = {37925537},
issn = {2041-1723},
support = {P30 CA142543/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; },
mesh = {*Telomere Homeostasis/genetics ; DNA Replication ; RNA ; Cell Survival/genetics ; Telomere/genetics/metabolism ; *Telomerase/genetics/metabolism ; },
abstract = {Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism activated in ~10-15% of cancers, characterized by telomeric damage. Telomeric damage-induced long non-coding RNAs (dilncRNAs) are transcribed at dysfunctional telomeres and contribute to telomeric DNA damage response (DDR) activation and repair. Here we observed that telomeric dilncRNAs are preferentially elevated in ALT cells. Inhibition of C-rich (teloC) dilncRNAs with antisense oligonucleotides leads to DNA replication stress responses, increased genomic instability, and apoptosis induction selectively in ALT cells. Cell death is dependent on DNA replication and is increased by DNA replication stress. Mechanistically, teloC dilncRNA inhibition reduces RAD51 and 53BP1 recruitment to telomeres, boosts the engagement of BIR machinery, and increases C-circles and telomeric sister chromatid exchanges, without increasing telomeric non-S phase synthesis. These results indicate that teloC dilncRNA is necessary for a coordinated recruitment of DDR factors to ALT telomeres and it is essential for ALT cancer cells survival.},
}
@article {pmid37924942,
year = {2024},
author = {Scorza, FA and Finsterer, J and Beltramim, L and Bombardi, LM and de Almeida, AG},
title = {Telomere Length and Pesticide Residues in Food: A Causal Link?.},
journal = {Journal of the Academy of Nutrition and Dietetics},
volume = {124},
number = {3},
pages = {311-312},
doi = {10.1016/j.jand.2023.11.002},
pmid = {37924942},
issn = {2212-2672},
mesh = {Humans ; *Pesticide Residues/analysis ; Fruit ; Telomere ; Food Contamination/analysis ; },
}
@article {pmid37921058,
year = {2023},
author = {Tsatsakis, A and Renieri, E and Tsoukalas, D and Buga, AM and Sarandi, E and Vakonaki, E and Fragkiadaki, P and Alegakis, A and Nikitovic, D and Calina, D and Spandidos, DA and Docea, AO},
title = {A novel nutraceutical formulation increases telomere length and activates telomerase activity in middle‑aged rats.},
journal = {Molecular medicine reports},
volume = {28},
number = {6},
pages = {},
pmid = {37921058},
issn = {1791-3004},
mesh = {Rats ; Animals ; *Telomerase/metabolism ; Leukocytes, Mononuclear/metabolism ; Telomere Shortening ; Dietary Supplements ; Telomere/metabolism ; },
abstract = {Telomeres are major contributors to cell fate and aging through their involvement in cell cycle arrest and senescence. The accelerated attrition of telomeres is associated with aging‑related diseases, and agents able to maintain telomere length (TL) through telomerase activation may serve as potential treatment strategies. The aim of the present study was to assess the potency of a novel telomerase activator on TL and telomerase activity in vivo. The administration of a nutraceutical formulation containing Centella asiatica extract, vitamin C, zinc and vitamin D3 in 18‑month‑old rats for a period of 3 months reduced the telomere shortening rate at the lower supplement dose and increased mean the TL at the higher dose, compared to pre‑treatment levels. TL was determined using the Q‑FISH method in peripheral blood mononuclear cells collected from the tail vein of the rats and cultured with RPMI‑1640 medium. In both cases, TLs were significantly longer compared to the untreated controls (P≤0.001). In addition, telomerase activity was increased in the peripheral blood mononuclear cells of both treatment groups. On the whole, the present study demonstrates that the nutraceutical formulation can maintain or even increase TL and telomerase activity in middle‑aged rats, indicating a potential role of this formula in the prevention and treatment of aging‑related diseases.},
}
@article {pmid37919818,
year = {2023},
author = {Prasad, A and Lin, J and Jelliffe-Pawlowski, L and Coleman-Phox, K and Rand, L and Wojcicki, JM},
title = {Sub-optimal maternal gestational gain is associated with shorter leukocyte telomere length at birth in a predominantly Latinx cohort of newborns.},
journal = {Maternal health, neonatology and perinatology},
volume = {9},
number = {1},
pages = {14},
pmid = {37919818},
issn = {2054-958X},
support = {Wojcicki//UCSF Preterm Birth Initiative/ ; Wojcicki//Little Giraffe Foundation/ ; },
abstract = {OBJECTIVE: To assess in utero exposures associated with leukocyte telomere length (LTL) at birth and maternal LTL in a primarily Latinx birth cohort.<br><br>STUDY DESIGN: Mothers and newborns were recruited postnatally before 24&#xa0;h of life. Newborn LTL was collected via heelstick at birth and maternal LTL was collected postnatally. LTL was determined by quantitative PCR. Using a longitudinal design, we evaluated associations between neonatal and maternal LTL and appropriate maternal gestational gain as indicated by the American College of Obstetrics and Gynecology (ACOG).<br><br>RESULT: Mean infant LTL was 2.02&#x2009;&#xb1;&#x2009;0.30&#xa0;T/S (n&#x2009;=&#x2009;386) and maternal LTL was 1.54&#x2009;&#xb1;&#x2009;0.26&#xa0;T/S (n&#x2009;=&#x2009;58). Independent risk factors for shorter LTL at birth included longer gestational duration (Coeff:-0.03, 95%CI: -0.05-0.01;p&#x2009;<&#x2009;0.01) and maternal gestational weight gain below ACOG recommendations (Coeff:-0.10, 95%CI: -0.18 - -0.02; p&#x2009;=&#x2009;0.01).<br><br>CONCLUSION: Gestational weight gain below ACOG recommendations may adversely impact neonatal health in Latinx infants as indicated by shorter LTL at birth.},
}
@article {pmid37919072,
year = {2023},
author = {Liu, J and Sha, S and Wang, J and Gu, X and Du, M and Lu, X},
title = {Development and Validation of a Prognosis-Prediction Signature for Patients with Lung Adenocarcinoma Based on 11 Telomere-Related Genes.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {28},
number = {10},
pages = {254},
doi = {10.31083/j.fbl2810254},
pmid = {37919072},
issn = {2768-6698},
mesh = {Humans ; *Adenocarcinoma of Lung/genetics ; *Lung Neoplasms/diagnosis/genetics ; Telomere/genetics ; B-Lymphocytes ; Tumor Microenvironment ; },
abstract = {BACKGROUND: The occurrence and progression of lung cancer are correlated with telomeres and telomerase. Telomere length is reduced in the majority of tumors, including lung cancers. Telomere length variations have been associated with lung cancer risk and may serve as therapeutic targets as well as predictive biomarkers for lung cancer. Nevertheless, the effects of telomere-associated genes on lung cancer prognosis have not been thoroughly studied. We aim to investigate the relationship between telomere-associated genes and lung cancer prognosis.<br><br>METHODS: The Cancer Genome Atlas and Genotype-Tissue Expression databases were used as training sets to build a predictive model. Three integrated Gene Expression Omnibus datasets served as validation sets. Using cluster consistency analysis and regression with the least absolute shrinkage and selection operator, we developed a telomere-related gene risk signature (TMGsig) based on 11 overall survival-related genes (RBBP8, PLK1, DSG2, HOXA7, ANAPC4, CSNK1E, SYAP1, ALDOA, PHF1, MUTYH, and PGS1).<br><br>RESULTS: The results indicated a negative outcome for the high-risk score group. Immunological microenvironment and somatic mutations differed between the high- and low-risk groups. A statistically significant difference existed between the low-risk and high-risk groups in terms of the expression levels of B cells and CD4 cells, and the risk score was essentially inversely linked with immune cell expression.<br><br>CONCLUSIONS: TMGsig can predict outcomes in patients with lung adenocarcinoma.},
}
@article {pmid37918674,
year = {2023},
author = {Ulak, M and Kvestad, I and Chandyo, RK and Schwinger, C and Basnet, S and Shrestha, M and Ranjitkar, S and Nguyen, LV and Corona-Pérez, D and De Vivo, I and Ueland, PM and McCann, A and Strand, TA},
title = {The Effect of Vitamin B12 Supplementation on Leukocyte Telomere Length in Mildly Stunted Nepalese Children: A Secondary Outcome of a Randomized Controlled Trial.},
journal = {The Journal of nutrition},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tjnut.2023.10.015},
pmid = {37918674},
issn = {1541-6100},
abstract = {BACKGROUND: Vitamin B12 is essential for deoxyribonucleic acid synthesis and genome stability. A deficiency of vitamin B12 is associated with telomere shortening, genomic aging, and increased risk of chronic disease and mortality.<br><br>OBJECTIVES: The study aims to determine the effect of vitamin B12 supplementation on leukocyte telomere length (LTL) in infants at risk of vitamin B12 deficiency.<br><br>METHODS: The study was a predefined secondary analysis of a randomized controlled trial enrolling 600 Nepalese infants aged 6 -11 mo, who were supplemented with 2 &#x3bc;g (2-3 recommended daily allowances) vitamin B12 or placebo daily for 1 y. At the end of the study, LTL was measured in 497 participants. Mean LTL was compared between the treatment arms in the full sample and predefined subgroups based on markers of vitamin B12 status, hemoglobin, sex, and growth indices.<br><br>RESULTS: LTL at end-study did not differ between the vitamin B12 and placebo arm with a standardized mean difference (95% confidence interval) of 0.04 (-0.14, 0.21). There was no effect of vitamin B12 on LTL in any of the subgroups.<br><br>CONCLUSIONS: Providing daily vitamin B12 for 1 y during infancy in a population at risk of vitamin B12 deficiency does not affect LTL. This trial was registered at clinicaltrials.gov as NCT02272842.},
}
@article {pmid37917279,
year = {2023},
author = {Medoro, A and Saso, L and Scapagnini, G and Davinelli, S},
title = {NRF2 signaling pathway and telomere length in aging and age-related diseases.},
journal = {Molecular and cellular biochemistry},
volume = {},
number = {},
pages = {},
pmid = {37917279},
issn = {1573-4919},
abstract = {The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is well recognized as a critical regulator of redox, metabolic, and protein homeostasis, as well as the regulation of inflammation. An age-associated decline in NRF2 activity may allow oxidative stress to remain unmitigated and affect key features associated with the aging phenotype, including telomere shortening. Telomeres, the protective caps of eukaryotic chromosomes, are highly susceptible to oxidative DNA damage, which can accelerate telomere shortening and, consequently, lead to premature senescence and genomic instability. In this review, we explore how the dysregulation of NRF2, coupled with an increase in oxidative stress, might be a major determinant of telomere shortening and age-related diseases. We discuss the relevance of the connection between NRF2 deficiency in aging and telomere attrition, emphasizing the importance of studying this functional link to enhance our understanding of aging pathologies. Finally, we present a number of compounds that possess the ability to restore NRF2 function, maintain a proper redox balance, and preserve telomere length during aging.},
}
@article {pmid37917220,
year = {2023},
author = {Chebly, A and Khalil, C and Kuzyk, A and Beylot-Barry, M and Chevret, E},
title = {T-cell lymphocytes' aging clock: telomeres, telomerase and aging.},
journal = {Biogerontology},
volume = {},
number = {},
pages = {},
pmid = {37917220},
issn = {1573-6768},
abstract = {Aging is the decline of physiological capabilities required for life maintenance and reproduction over time. The human immune cells, including T-cells lymphocytes, undergo dramatic aging-related changes, including those related to telomeres and telomerase. It was demonstrated that telomeres and telomerase play crucial roles in T-cell differentiation, aging, and diseases, including a well-documented link between short telomeres and telomerase activation demonstrated in several T-cells malignancies. Herein, we provide a comprehensive review of the literature regarding T-cells' telomeres and telomerase in health and age related-diseases.},
}
@article {pmid37915500,
year = {2023},
author = {Wei, M and Huang, Y and Mo, C and Wang, H and Zeng, Q and Yang, W and Chen, J and Zhang, X and Kong, Q},
title = {Telomere-to-telomere genome assembly of melon (Cucumis melo L. var. inodorus) provides a high-quality reference for meta-QTL analysis of important traits.},
journal = {Horticulture research},
volume = {10},
number = {10},
pages = {uhad189},
pmid = {37915500},
issn = {2662-6810},
abstract = {Melon is an important horticultural crop with extensive diversity in many horticultural groups. To explore its genomic diversity, it is necessary to assemble more high-quality complete genomes from different melon accessions. Meanwhile, a large number of QTLs have been mapped in several studies. Integration of the published QTLs onto a complete genome can provide more accurate information for candidate gene cloning. To address these problems, a telomere-to-telomere (T2T) genome of the elite melon landrace Kuizilikjiz (Cucumis melo L. var. inodorus) was de novo assembled and all the published QTLs were projected onto it in this study. The results showed that a high-quality Kuizilikjiz genome with the size of 379.2 Mb and N50 of 31.7 Mb was de novo assembled using the combination of short reads, PacBio high-fidelity long reads, Hi-C data, and a high-density genetic map. Each chromosome contained the centromere and telomeres at both ends. A large number of structural variations were observed between Kuizilikjiz and the other published genomes. A total of 1294 QTLs published in 67 studies were collected and projected onto the T2T genome. Several clustered, co-localized, and overlapped QTLs were determined. Furthermore, 20 stable meta-QTLs were identified, which significantly reduced the mapping intervals of the initial QTLs and greatly facilitated identification of the candidate genes. Collectively, the T2T genome assembly together with the numerous projected QTLs will not only broaden the high-quality genome resources but also provide valuable and abundant QTL information for cloning the genes controlling important traits in melon.},
}
@article {pmid37914069,
year = {2024},
author = {Pirtea, P and Keefe, DL and Ayoubi, JM and de Ziegler, D},
title = {Telomere length: a marker for reproductive aging?.},
journal = {Fertility and sterility},
volume = {121},
number = {1},
pages = {1-3},
doi = {10.1016/j.fertnstert.2023.10.027},
pmid = {37914069},
issn = {1556-5653},
mesh = {Female ; Humans ; *Aging/genetics ; *Reproduction/genetics ; Cellular Senescence/genetics ; Oocytes ; Telomere/genetics ; },
abstract = {The improvements accomplished in assisted reproductive technology have emphasized more than ever the role played by chronological age, notably for predicting oocyte quality. Studies in cellular aging have directed research on telomere length measurements as possible markers of functional aging and, notably, female reproductive outcomes. Although further research is still needed, encouraging results are already available on the possibility that leucocyte telomere length may be a useful parameter for assessing reproductive potential in aging women.},
}
@article {pmid37913757,
year = {2023},
author = {Al Awadhi, R and Alwehaidah, MS and Al Roomy, MS and Kapila, K},
title = {Relative Telomere length in cervical exfoliated cells among women with high- risk human papillomavirus.},
journal = {Pathobiology : journal of immunopathology, molecular and cellular biology},
volume = {},
number = {},
pages = {},
doi = {10.1159/000534917},
pmid = {37913757},
issn = {1423-0291},
abstract = {INTRODUCTION: This study investigates and compares the relative telomere length (RTL) outcome of high-risk (hr) human papillomavirus (HPV)-infected normal, low-grade squamous intraepithelial lesion (LSIL), and high-grade squamous intraepithelial lesion (HSIL) cervical samples to HPV-free normal cervical samples.<br><br>METHODS: This study used archived cervical samples and obtained cytology and histology data. HPV genotyping was conducted using Sanger sequencing and RTL was performed using real-time quantitative polymerase chain reaction.<br><br>RESULTS: This study investigated 287 cervical samples, including 100 normal and hr-HPV-negative samples from the control group, 44 normal and hr-HPV-infected samples, and 143 SIL and hr-HPV-infected samples. The RTL in hr-HPV-infected samples, including the SIL and normal sample groups, were significantly longer than that in the control group. RTL in HSIL (5.13 &#xb1; 3.22) and LSIL (2.86 &#xb1; 2.81) were significantly different (P < 0.001). The RTL of cervical intraepithelial neoplasia (CIN1) lesion (3.53 &#xb1; 2.53) differed significantly (P < 0.001) when compared to CIN2 and CIN3 lesions combined. The risk of developing cervical cancer was associated with RTL and was decreased with RTL.<br><br>CONCLUSION: This study revealed the strong potential of the RTL test in identifying women at risk of developing cervical cancer.},
}
@article {pmid37903596,
year = {2024},
author = {Wang, F and Chang, L and Zhang, X and Jia, T and Wang, Y and Wang, Y and Liu, G},
title = {Effects of Polycyclic Aromatic Hydrocarbon Exposure and Telomere Length and their Interaction on Blood Lipids in Coal Miners.},
journal = {Journal of occupational and environmental medicine},
volume = {66},
number = {2},
pages = {111-117},
doi = {10.1097/JOM.0000000000003002},
pmid = {37903596},
issn = {1536-5948},
mesh = {Humans ; *Polycyclic Aromatic Hydrocarbons/adverse effects ; Bayes Theorem ; Telomere ; *Dyslipidemias ; Coal ; Biomarkers ; *Phenanthrenes ; },
abstract = {OBJECTIVE: This study aimed to investigate the effects of polycyclic aromatic hydrocarbon (PAH) exposure and telomere length on lipids in coal miners.<br><br>METHODS: Basic personal information of 637 coal miners was collected by questionnaire survey. Logistic regression, the Bayesian kernel machine regression model, and weighted quantile sum regression were used to analyze the effects of PAH metabolites and telomere length and their interactions on blood lipids.<br><br>RESULTS: High exposure to 9-hydroxyphenanthrene (OR = 1.586, 95% CI: 1.011-2.487) and telomere shortening (OR = 1.413, 95% CI: 1.005-1.985) were associated with dyslipidemia. Weighted quantile sum results showed that 9-hydroxyphenanthrene accounted for the largest proportion of dyslipidemia (weight = 0.66). The interaction results showed that high 9-hydroxyphenanthrene exposure and short telomeres were risk factors for dyslipidemia in coal miners (OR = 2.085, 95% CI: 1.121-3.879). Conclusions: Our findings suggest that 9-hydroxyphenanthrene and shorter telomeres are risk factors for dyslipidemia, and their interaction increases the risk of dyslipidemia.},
}
@article {pmid37900433,
year = {2023},
author = {Aghajanyan, V and Bhupathy, S and Sheikh, S and Nausheen, F},
title = {A Narrative Review of Telomere Length Modulation Through Diverse Yoga and Meditation Styles: Current Insights and Prospective Avenues.},
journal = {Cureus},
volume = {15},
number = {9},
pages = {e46130},
pmid = {37900433},
issn = {2168-8184},
abstract = {Mindfulness practices have demonstrated the potential to positively impact various aspects of human health associated with telomere length (TL) - a recognized marker of healthy aging and susceptibility to age-related diseases. This review seeks to conduct an in-depth comparative analysis, examining methodological variations, outcome assessments, strengths, weaknesses, and gaps across mindfulness-focused studies concerning TL and attrition rates. While emerging data tentatively suggest a positive connection between mindfulness practices and TL, a notable research gap pertains to establishing the clinically recommended dosage of yoga/meditation and mindfulness interventions to effectively influence TL. To address this gap, upcoming research should prioritize meticulous structuring, pedagogical precision, and vigilant monitoring of mindfulness interventions to yield psychological and physiological benefits across an appropriate timeframe and intensity. The amalgamation of yoga/meditation or mindfulness emerges as a promising avenue for enhancing the quality of life while counteracting the influence of telomere attrition in the spectrum of age-related diseases. The core objective of this review is to meticulously investigate the interplay between yoga/meditation and mindfulness practices and their potential impact on TL - an essential biomarker indicative of age-related health and well-being. To achieve this, our study methodically compares various methodological approaches, outcome measures, strengths, and limitations within relevant research endeavors focused on TL and attrition rates. Through this scrutiny, we highlight prevailing research gaps. Our analysis underscores the need for comprehensive research efforts aimed at establishing the optimal therapeutic regimen for yielding significant clinical effects on TL and overall health. In summation, our exploration emphasizes the urgency of further studies to unravel the most effective approaches for positively influencing TL and its implications for holistic health.},
}
@article {pmid37899647,
year = {2023},
author = {Yu, M and Yang, D and Chen, C and Xia, H},
title = {Effects of SETD2 on telomere length and malignant transformation property of Met-5A after one-month crocidolite exposure.},
journal = {Journal of environmental science and health. Part C, Toxicology and carcinogenesis},
volume = {41},
number = {3-4},
pages = {121-134},
doi = {10.1080/26896583.2023.2271822},
pmid = {37899647},
issn = {2689-6591},
mesh = {Humans ; *Aminobenzoates/metabolism/pharmacology ; *Asbestos, Crocidolite/toxicity/metabolism ; Cell Transformation, Neoplastic/chemically induced/metabolism/pathology ; Epithelium/metabolism/pathology ; Naphthalenes/metabolism/pharmacology ; *Histone-Lysine N-Methyltransferase/metabolism ; *Telomere Homeostasis ; },
abstract = {Crocidolite is a carcinogen contributing to the pathogenesis of malignant mesothelioma. This study aimed to characterize the possible telomere-related events mediating the malignant transformation of mesothelial cells with and without SETD2 under crocidolite exposure. The crocidolite concentration resulting in 90% viable SETD2 knockout Met-5A (Met-5A[SETD2-KO]) and Met-5A were estimated to be 0.71 μg/cm[2] and 1.8 μg/cm[2], respectively, during 72 h of exposure, which was further employed in chronical crocidolite exposure during a 72 h exposure interval per time up to 1 month. Chronical crocidolite-exposed Met-5A[SETD2-KO] (chronical Cro-Met-5A[SETD2-KO]) had higher colony formation and increased telomerase reverse transcriptase (TERT) protein levels than chronical crocidolite-exposed Met-5A (chronical Cro-Met-5A) and Met-5A[SETD2-KO]. Chronical Cro-Met-5A[SETD2-KO] had longer telomere length (TL) than chronical Cro-Met-5A, although there were no changes in TL for either chronical Cro-Met-5A or chronical Cro-Met-5A[SETD2-KO] compared with their corresponding cells without crocidolite exposure. BIBR 1532, an inhibitor targeting TERT, partially reduced colony formation and TL for chronical Cro-Met-5A[SETD2-KO], while BIBR 1532 reduced TL but had no effect on colony formation for chronical Cro-Met-5A. Therefore, SETD2 deficient mesothelial cells are susceptible to malignant transformation during chronical crocidolite exposure, and TERT-dependent TL modification likely partially drives SETD2 loss-mediated early onset of mesothelial malignant transformation.},
}
@article {pmid37897613,
year = {2024},
author = {Luo, H and Wang, X and You, C and Wu, X and Pan, D and Lv, Z and Li, T and Zhang, D and Shen, Z and Zhang, X and Liu, G and He, K and Ye, Q and Jia, Y and Zhao, Q and Deng, X and Cao, X and Song, X and Huang, G},
title = {Telomere-to-telomere genome of the allotetraploid legume Sesbania cannabina reveals transposon-driven subgenome divergence and mechanisms of alkaline stress tolerance.},
journal = {Science China. Life sciences},
volume = {67},
number = {1},
pages = {149-160},
pmid = {37897613},
issn = {1869-1889},
mesh = {*Sesbania/genetics ; *Fabaceae ; Manure ; Soil ; Vegetables/genetics ; Alkalies ; Telomere/genetics ; },
abstract = {Alkaline soils pose an increasing problem for agriculture worldwide, but using stress-tolerant plants as green manure can improve marginal land. Here, we show that the legume Sesbania cannabina is very tolerant to alkaline conditions and, when used as a green manure, substantially improves alkaline soil. To understand genome evolution and the mechanisms of stress tolerance in this allotetraploid legume, we generated the first telomere-to-telomere genome assembly of S. cannabina spanning ∼2,087 Mb. The assembly included all centromeric regions, which contain centromeric satellite repeats, and complete chromosome ends with telomeric characteristics. Further genome analysis distinguished A and B subgenomes, which diverged approximately 7.9 million years ago. Comparative genomic analysis revealed that the chromosome homoeologs underwent large-scale inversion events (>10 Mb) and a significant, transposon-driven size expansion of the chromosome 5A homoeolog. We further identified four specific alkali-induced phosphate transporter genes in S. cannabina; these may function in alkali tolerance by relieving the deficiency in available phosphorus in alkaline soil. Our work highlights the significance of S. cannabina as a green tool to improve marginal lands and sheds light on subgenome evolution and adaptation to alkaline soils.},
}
@article {pmid37896796,
year = {2023},
author = {Bräuer, JA and Hammerl, JA and El-Mustapha, S and Fuhrmann, J and Barac, A and Hertwig, S},
title = {The Novel Yersinia enterocolitica Telomere Phage vB_YenS_P840 Is Closely Related to PY54, but Reveals Some Striking Differences.},
journal = {Viruses},
volume = {15},
number = {10},
pages = {},
pmid = {37896796},
issn = {1999-4915},
mesh = {*Bacteriophages/genetics ; *Yersinia enterocolitica/genetics ; Prophages/genetics ; Lysogeny ; Telomere ; },
abstract = {Telomere phages are a small group of temperate phages, whose prophages replicate as a linear plasmid with covalently closed ends. They have been isolated from some Enterobacteriaceae and from bacterial species living in aquatic environments. Phage PY54 was the first Yersinia (Y.) enterocolitica telomere phage isolated from a nonpathogenic O:5 strain, but recently a second telomeric Yersinia phage (vB_YenS_P840) was isolated from a tonsil of a wild boar in Germany. Both PY54 and vB_YenS_P840 (P840) have a siphoviridal morphology and a similar genome organization including the primary immunity region immB and telomere resolution site telRL. However, whereas PY54 only possesses one prophage repressor for the lysogenic cycle, vB_YenS_P840 encodes two. The telRL region of this phage was shown to be processed by the PY54 protelomerase under in vivo conditions, but unlike with PY54, a flanking inverted repeat was not required for processing. A further substantial difference between the phages is their host specificity. While PY54 infects Y. enterocolitica strains belonging to the serotypes O:5 and O:5,27, vB_YenS_P840 exclusively lyses O:3 strains. As the tail fiber and tail fiber assembly proteins of the phages differ significantly, we introduced the corresponding genes of vB_YenS_P840 by transposon mutagenesis into the PY54 genome and isolated several mutants that were able to infect both serotypes, O:5,27 and O:3.},
}
@article {pmid37895262,
year = {2023},
author = {Ortega-Vázquez, A and Sánchez-Badajos, S and Ramírez-García, M&#xc1; and Alvarez-Luquín, D and López-López, M and Adalid-Peralta, LV and Monroy-Jaramillo, N},
title = {Longitudinal Changes in Mitochondrial DNA Copy Number and Telomere Length in Patients with Parkinson's Disease.},
journal = {Genes},
volume = {14},
number = {10},
pages = {},
pmid = {37895262},
issn = {2073-4425},
mesh = {Humans ; *DNA, Mitochondrial/genetics ; Case-Control Studies ; DNA Copy Number Variations/genetics ; *Parkinson Disease/genetics ; Telomere/genetics ; Mitochondria/genetics ; Biomarkers ; },
abstract = {Parkinson's disease (PD) pathophysiology includes mitochondrial dysfunction, neuroinflammation, and aging as its biggest risk factors. Mitochondrial DNA copy number (mtDNA-CN) and telomere length (TL) are biological aging markers with inconclusive results regarding their association with PD. A case-control study was used to measure TL and mtDNA-CN using qPCR in PBMCs. PD patients were naive at baseline (T0) and followed-up at one (T1) and two (T2) years after the dopaminergic treatment (DRT). Plasmatic cytokines were determined by ELISA in all participants, along with clinical parameters of patients at T0. While TL was shorter in patients vs. controls at all time points evaluated (p < 0.01), mtDNA-CN showed no differences. An increase in mtDNA-CN and TL was observed in treated patients vs. naive ones (p < 0.001). Our statistical model analyzed both aging markers with covariates, showing a strong correlation between them (r = 0.57, p < 0.01), and IL-17A levels positively correlating with mtDNA-CN only in untreated patients (r = 0.45, p < 0.05). TL and mtDNA-CN could be useful markers for monitoring inflammation progression or treatment response in PD. DRT might modulate TL and mtDNA-CN, reflecting a compensatory mechanism to counteract mitochondrial dysfunction in PD, but this needs further investigation.},
}
@article {pmid37892448,
year = {2023},
author = {Sato, M and Wai, KM and Itoh, K and Yang, Y and Uchikawa, Y and Ito, Y and Nakaji, S and Ihara, K},
title = {Does the Protective Effect of Zinc on Telomere Length Depend on the Presence of Hypertension or Type 2 Diabetes? Results from the Iwaki Health Promotion Project, Japan.},
journal = {Nutrients},
volume = {15},
number = {20},
pages = {},
pmid = {37892448},
issn = {2072-6643},
support = {JPMJCE1302//Japan Science and Technology Agency/ ; COI accelerating grant JPMJCA2201//Hirosaki University/ ; },
mesh = {Humans ; *Diabetes Mellitus, Type 2 ; Zinc/pharmacology ; Cross-Sectional Studies ; Japan ; *Hypertension ; Telomere ; },
abstract = {Telomeres, repeated TTAGGG sequences at chromosomal ends, shorten with age and indicate cellular lifespan. Zinc can protect against telomere damage through its anti-oxidative effect. Meanwhile, telomere shortening was correlated with metabolic diseases of hypertension and type 2 diabetes. The objective of this study was to investigate whether the association between zinc and telomere length differs by the presence or absence of hypertension/type 2 diabetes. This is a cross-sectional study with 1064 participants of the Iwaki area, Japan. Multiple linear regression models were performed to test the hypothesis. A higher serum zinc concentration was significantly associated with a longer G-tail length (β = 48.11, 95% confidence intervals [CI]: 25.69, 70.54, p < 0.001). By multivariate linear regression analysis, there was a significant positive association between zinc and G-tail length in both hypertensive (β = 46.84, 95%CI: 9.69, 84.0, p = 0.014) and non-hypertensive groups (β = 49.47, 95%CI: 20.75, 78.18, p = 0.001), while the association was significant only in the non-diabetes group (β = 50.82, 95%CI: 27.54, 74.11, p < 0.001). In conclusion, higher zinc concentration was significantly associated with longer G-tail length. The protective effect of zinc on G-tail did not differ by hypertension status; however, it disappeared in individuals with type 2 diabetes.},
}
@article {pmid37891926,
year = {2023},
author = {Reljic, D and Koller, A and Herrmann, HJ and Ekici, AB and Neurath, MF and Zopf, Y},
title = {Differential Effects of Very-Low-Volume Exercise Modalities on Telomere Length, Inflammation, and Cardiometabolic Health in Obese Metabolic Syndrome Patients: A Subanalysis from Two Randomized Controlled Trials.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {10},
pages = {},
pmid = {37891926},
issn = {2076-3921},
support = {MED1710//Hector-Stiftung/ ; N.N.//Manfred Roth Foundation/ ; N.N.//Research Foundation for Medicine at the University Hospital Erlangen/ ; N.N.//Deutsche Forschungsgemeinschaft and Friedrich-Alexander-University Erlangen-N&#xfc;rnberg: Funding program "Open Access Publication Funding"/ ; },
abstract = {Oxidative stress (OS) and inflammation are features of metabolic syndrome (MetS) that can contribute to the shortening of telomere length (TL), a marker of cellular ageing. Research indicates that exercise can positively influence MetS-associated conditions and TL. However, the effects of low-volume exercise types on TL are still unknown. We investigated the impact of very-low-volume high-intensity interval training (LV-HIIT), one-set resistance training (1-RT), and whole-body electromyostimulation (WB-EMS) on TL, inflammation, and cardiometabolic indices in 167 MetS patients. Data were derived from two randomized controlled trials where patients were allocated to an exercise group (2 sessions/week, for 12 weeks) or a control group. All groups received standard-care nutritional weight loss counselling. TL was determined as the T/S ratio (telomere to single-copy gene amount). All groups significantly reduced body weight (p < 0.05), but the T/S-ratio (p < 0.001) only increased with LV-HIIT. OS-related inflammatory markers (C-reactive protein, interleukin-6, and lipopolysaccharide-binding protein) only decreased (p < 0.05) following LV-HIIT. The MetS severity z-score improved with LV-HIIT (p < 0.001) and 1-RT (p = 0.014) but not with WB-EMS. In conclusion, very-low-volume exercise modalities have differential effects on telomeres, inflammation, and cardiometabolic health. Only LV-HIIT but not strength-based low-volume exercise increased TL in MetS patients, presumably due to superior effects on OS-related inflammatory markers.},
}
@article {pmid37890990,
year = {2024},
author = {Mori, JO and Keegan, J and Flynn, RL and Heaphy, CM},
title = {Alternative lengthening of telomeres: mechanism and the pathogenesis of cancer.},
journal = {Journal of clinical pathology},
volume = {77},
number = {2},
pages = {82-86},
doi = {10.1136/jcp-2023-209005},
pmid = {37890990},
issn = {1472-4146},
mesh = {Humans ; Telomere Homeostasis ; X-linked Nuclear Protein/genetics ; *Telomerase/genetics ; Telomere/genetics/metabolism ; *Neoplasms/genetics ; DNA Helicases/genetics ; Carrier Proteins ; },
abstract = {Telomere maintenance and elongation allows cells to gain replicative immortality and evade cellular senescence during cancer development. While most cancers use telomerase to maintain telomere lengths, a subset of cancers engage the alternative lengthening of telomeres (ALT) pathway for telomere maintenance. ALT is present in 5%-10% of all cancers, although the prevalence is dramatically higher in certain cancer types, including complex karyotype sarcomas, isocitrate dehydrogenase-mutant astrocytoma (WHO grade II-IV), pancreatic neuroendocrine tumours, neuroblastoma and chromophobe hepatocellular carcinomas. ALT is maintained through a homology-directed DNA repair mechanism. Resembling break-induced replication, this aberrant process results in dramatic cell-to-cell telomere length heterogeneity, widespread chromosomal instability and chronic replication stress. Additionally, ALT-positive cancers frequently harbour inactivating mutations in either chromatin remodelling proteins (ATRX, DAXX and H3F3A) or DNA damage repair factors (SMARCAL1 and SLX4IP). ALT can readily be detected in tissue by assessing the presence of unique molecular characteristics, such as large ultrabright nuclear telomeric foci or partially single-stranded telomeric DNA circles (C-circles). Importantly, ALT has been validated as a robust diagnostic and prognostic biomarker for certain cancer types and may even be exploited as a therapeutic target via small molecular inhibitors and/or synthetic lethality approaches.},
}
@article {pmid37886996,
year = {2023},
author = {Crocco, P and De Rango, F and Dato, S and La Grotta, R and Maletta, R and Bruni, AC and Passarino, G and Rose, G},
title = {The Shortening of Leukocyte Telomere Length Contributes to Alzheimer's Disease: Further Evidence from Late-Onset Familial and Sporadic Cases.},
journal = {Biology},
volume = {12},
number = {10},
pages = {},
pmid = {37886996},
issn = {2079-7737},
support = {PA.CRO.DE." PON ARS01_00568//Ministry of Education, University and Research/ ; },
abstract = {Telomeres are structures at the ends of eukaryotic chromosomes that help maintain genomic stability. During aging, telomere length gradually shortens, producing short telomeres, which are markers of premature cellular senescence. This may contribute to age-related diseases, including Alzheimer's disease (AD), and based on this, several studies have hypothesized that telomere shortening may characterize AD. Current research, however, has been inconclusive regarding the direction of the association between leukocyte telomere length (LTL) and disease risk. We assessed the association between LTL and AD in a retrospective case-control study of a sample of 255 unrelated patients with late-onset AD (LOAD), including 120 sporadic cases and 135 with positive family history for LOAD, and a group of 279 cognitively healthy unrelated controls, who were all from Calabria, a southern Italian region. Following regression analysis, telomeres were found significantly shorter in LOAD cases than in controls (48% and 41% decrease for sporadic and familial cases, respectively; p < 0.001 for both). Interestingly, LTL was associated with disease risk independently of the presence of conventional risk factors (e.g., age, sex, MMSE scores, and the presence of the APOE-ε4 allele). Altogether, our findings lend support to the notion that LTL shortening may be an indicator of the pathogenesis of LOAD.},
}
@article {pmid37884878,
year = {2023},
author = {Serrano-León, IM and Prieto, P and Aguilar, M},
title = {Telomere and subtelomere high polymorphism might contribute to the specificity of homologous recognition and pairing during meiosis in barley in the context of breeding.},
journal = {BMC genomics},
volume = {24},
number = {1},
pages = {642},
pmid = {37884878},
issn = {1471-2164},
support = {(N&#xba; expediente administrativo subvenci&#xf3;n: POEJ00028/ N.&#xba; expediente: AND21_IAS_M2_064) from Garant&#xed;a Juvenil-Andaluc&#xed;a 2022//Consejer&#xed;a de Universidad, Investigaci&#xf3;n e Innovaci&#xf3;n, Secretar&#xed;a General de Investigaci&#xf3;n e Innovaci&#xf3;n, Junta de Andaluc&#xed;a/Cofinanciaci&#xf3;n FEDER 91%/ ; },
mesh = {*Hordeum/genetics ; Chromosome Pairing ; Plant Breeding ; Meiosis/genetics ; Telomere/genetics ; Heterochromatin ; },
abstract = {Barley (Hordeum vulgare) is one of the most popular cereal crops globally. Although it is a diploid species, (2n = 2x = 14) the study of its genome organization is necessary in the framework of plant breeding since barley is often used in crosses with other cereals like wheat to provide them with advantageous characters. We already have an extensive knowledge on different stages of the meiosis, the cell division to generate the gametes in species with sexual reproduction, such as the formation of the synaptonemal complex, recombination, and chromosome segregation. But meiosis really starts with the identification of homologous chromosomes and pairing initiation, and it is still unclear how chromosomes exactly choose a partner to appropriately pair for additional recombination and segregation. In this work we present an exhaustive molecular analysis of both telomeres and subtelomeres of barley chromosome arms 2H-L, 3H-L and 5H-L. As expected, the analysis of multiple features, including transposable elements, repeats, GC content, predicted CpG islands, recombination hotspots, G4 quadruplexes, genes and targeted sequence motifs for key DNA-binding proteins, revealed a high degree of variability both in telomeres and subtelomeres. The molecular basis for the specificity of homologous recognition and pairing occurring in the early chromosomal interactions at the start of meiosis in barley may be provided by these polymorphisms. A more relevant role of telomeres and most distal part of subtelomeres is suggested.},
}
@article {pmid37883989,
year = {2023},
author = {, },
title = {Retraction: Zinc sulfate contributes to promote telomere length extension via increasing telomerase gene expression, telomerase activity and change in the TERT gene promoter CpG island methylation status of human adipose-derived mesenchymal stem cells.},
journal = {PloS one},
volume = {18},
number = {10},
pages = {e0292985},
pmid = {37883989},
issn = {1932-6203},
}
@article {pmid37882647,
year = {2024},
author = {Shiraishi, K and Takahashi, A and Momozawa, Y and Daigo, Y and Kaneko, S and Kawaguchi, T and Kunitoh, H and Matsumoto, S and Horinouchi, H and Goto, A and Honda, T and Shimizu, K and Torasawa, M and Takayanagi, D and Saito, M and Saito, A and Ohe, Y and Watanabe, SI and Goto, K and Tsuboi, M and Tsuchihara, K and Takata, S and Aoi, T and Takano, A and Kobayashi, M and Miyagi, Y and Tanaka, K and Suzuki, H and Maeda, D and Yamaura, T and Matsuda, M and Shimada, Y and Mizuno, T and Sakamoto, H and Yoshida, T and Goto, Y and Yoshida, T and Yamaji, T and Sonobe, M and Toyooka, S and Yoneda, K and Masago, K and Tanaka, F and Hara, M and Fuse, N and Nishizuka, SS and Motoi, N and Sawada, N and Nishida, Y and Kumada, K and Takeuchi, K and Tanno, K and Yatabe, Y and Sunami, K and Hishida, T and Miyazaki, Y and Ito, H and Amemiya, M and Totsuka, H and Nakayama, H and Yokose, T and Ishigaki, K and Nagashima, T and Ohtaki, Y and Imai, K and Takasawa, K and Minamiya, Y and Kobayashi, K and Okubo, K and Wakai, K and Shimizu, A and Yamamoto, M and Iwasaki, M and Matsuda, K and Inazawa, J and Shiraishi, Y and Nishikawa, H and Murakami, Y and Kubo, M and Matsuda, F and Kamatani, Y and Hamamoto, R and Matsuo, K and Kohno, T},
title = {Identification of telomere maintenance gene variations related to lung adenocarcinoma risk by genome-wide association and whole genome sequencing analyses.},
journal = {Cancer communications (London, England)},
volume = {44},
number = {2},
pages = {287-293},
pmid = {37882647},
issn = {2523-3548},
support = {JP15ck0106096//Japan Agency for Medical Research and Development/ ; JP20km0105001//Japan Agency for Medical Research and Development/ ; JP20km0105002//Japan Agency for Medical Research and Development/ ; JP20km0105003//Japan Agency for Medical Research and Development/ ; JP20km0105004//Japan Agency for Medical Research and Development/ ; JPMJCR1689//Japan Science and Technology Agency/ ; JPMJCR18Y4//Japan Science and Technology Agency/ ; 17H06162//Japan Society for the Promotion of Science/ ; 20H03695//Japan Society for the Promotion of Science/ ; 17015018//Japan Society for the Promotion of Science/ ; 221S0001//Japan Society for the Promotion of Science/ ; 16H06277//Japan Society for the Promotion of Science/ ; 2020-J4//National Cancer Center Research and Development Fund/ ; 1989-2010//Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan/ ; },
mesh = {Humans ; Genome-Wide Association Study ; *Adenocarcinoma of Lung/genetics ; *Lung Neoplasms/genetics/pathology ; Whole Genome Sequencing ; Telomere/genetics/pathology ; },
}
@article {pmid37881605,
year = {2023},
author = {Kakridonis, F and Pneumatikos, SG and Vakonaki, E and Berdiaki, A and Tzatzarakis, MN and Fragkiadaki, P and Spandidos, DA and Baliou, S and Ioannou, P and Hatzidaki, E and Nikitovic, D and Tsatsakis, A and Vasiliadis, E},
title = {Telomere length as a predictive biomarker in osteoporosis (Review).},
journal = {Biomedical reports},
volume = {19},
number = {5},
pages = {87},
pmid = {37881605},
issn = {2049-9442},
abstract = {Telomeres are the ends of chromosomes that protect them from DNA damage. There is evidence to suggest that telomere shortening appears with advanced age. Since aging is a significant risk factor for developing age-related complications, it is plausible that telomere shortening may be involved in the development of osteoporosis. The present review summarizes the potential of telomere shortening as a biomarker for detecting the onset of osteoporosis. For the purposes of the present review, the following scientific databases were searched for relevant articles: PubMed/NCBI, Cochrane Library of Systematic Reviews, Scopus, Embase and Google Scholar. The present review includes randomized and non-randomized controlled studies and case series involving humans, irrespective of the time of their publication. In six out of the 11 included studies providing data on humans, there was at least a weak association between telomere length and osteoporosis, with the remaining studies exhibiting no such association. As a result, telomere shortening may be used as a biomarker or as part of a panel of biomarkers for tracking the onset and progression of osteoporosis.},
}
@article {pmid37879860,
year = {2023},
author = {Chrisman, B and He, C and Jung, JY and Stockham, N and Paskov, K and Washington, P and Petereit, J and Wall, DP},
title = {Localizing unmapped sequences with families to validate the Telomere-to-Telomere assembly and identify new hotspots for genetic diversity.},
journal = {Genome research},
volume = {33},
number = {10},
pages = {1734-1746},
pmid = {37879860},
issn = {1549-5469},
support = {U24 MH081810/MH/NIMH NIH HHS/United States ; R01 NS070911/NS/NINDS NIH HHS/United States ; R01 NS101158/NS/NINDS NIH HHS/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; P20 GM103440/GM/NIGMS NIH HHS/United States ; R01 MH064547/MH/NIMH NIH HHS/United States ; R01 NS095824/NS/NINDS NIH HHS/United States ; R01 NS101665/NS/NINDS NIH HHS/United States ; U54 GM104944/GM/NIGMS NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; S10 OD011939/OD/NIH HHS/United States ; },
mesh = {Humans ; *Genomics ; *Genome, Human ; Algorithms ; Telomere/genetics ; Genetic Variation ; Sequence Analysis, DNA ; },
abstract = {Although it is ubiquitous in genomics, the current human reference genome (GRCh38) is incomplete: It is missing large sections of heterochromatic sequence, and as a singular, linear reference genome, it does not represent the full spectrum of human genetic diversity. To characterize gaps in GRCh38 and human genetic diversity, we developed an algorithm for sequence location approximation using nuclear families (ASLAN) to identify the region of origin of reads that do not align to GRCh38. Using unmapped reads and variant calls from whole-genome sequences (WGSs), ASLAN uses a maximum likelihood model to identify the most likely region of the genome that a subsequence belongs to given the distribution of the subsequence in the unmapped reads and phasings of families. Validating ASLAN on synthetic data and on reads from the alternative haplotypes in the decoy genome, ASLAN localizes >90% of 100-bp sequences with >92% accuracy and ∼1 Mb of resolution. We then ran ASLAN on 100-mers from unmapped reads from WGS from more than 700 families, and compared ASLAN localizations to alignment of the 100-mers to the recently released T2T-CHM13 assembly. We found that many unmapped reads in GRCh38 originate from telomeres and centromeres that are gaps in GRCh38. ASLAN localizations are in high concordance with T2T-CHM13 alignments, except in the centromeres of the acrocentric chromosomes. Comparing ASLAN localizations and T2T-CHM13 alignments, we identified sequences missing from T2T-CHM13 or sequences with high divergence from their aligned region in T2T-CHM13, highlighting new hotspots for genetic diversity.},
}
@article {pmid37873898,
year = {2023},
author = {Rehkopf, DH and Wojcicki, JM and Haydel, KF and Lin, J and Smith, DL and Kapphahn, KI and Robinson, TN},
title = {Changes in leukocyte telomere length among children with obesity participating in a behavioural weight control program.},
journal = {Pediatric obesity},
volume = {18},
number = {12},
pages = {e13082},
pmid = {37873898},
issn = {2047-6310},
support = {R01 HL096015/HL/NHLBI NIH HHS/United States ; UL1 TR001085/TR/NCATS NIH HHS/United States ; ULI TR001085/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; Female ; Child ; Male ; *Obesity/therapy ; Body Mass Index ; *Leukocytes ; Behavior Therapy ; Telomere ; },
abstract = {OBJECTIVE: To examine changes in leukocyte telomere length (LTL) during and after a behavioural weight control program for children with obesity.<br><br>METHODS: We measured LTL among a cohort of 158 children 8-12&#x2009;years of age with a body mass index greater than or equal to the 95th percentile for age and sex. Children were 55% female, 29% white, 52% Latinx, 8% Asian and 11% Pacific Islander, other or multiethnic. All children participated in a 6-month, family-based, group behavioural weight control program and were assessed before treatment, after treatment and 1&#x2009;year after the end of treatment. To test the sample population slope of LTL over the intervention and maintenance time periods, we fit spline mixed-effect regression models.<br><br>RESULTS: LTL increased an average of 0.09&#x2009;T/S&#x2009;units per year (95% confidence interval [CI] 0.04 to 0.13; p&#x2009;=&#x2009;0.0001) during the weight control program intervention period, followed by an average decline of -0.05&#x2009;T/S&#x2009;units per year (95% CI -0.08 to -0.03; p&#x2009;<&#x2009;0.0001) during the 1&#x2009;year of follow-up after the completion of the intervention. Among 26 social, psychological, behavioural and physiological factors we examined, we did not find any predictors of these changes.<br><br>CONCLUSIONS: LTL increased in response to a behavioural weight control program among children with obesity, suggesting an impact on biological health and cellular aging from participation in a behavioural weight control intervention. LTL may be a useful biomarker for assessing changes in response to behavioural interventions.},
}
@article {pmid37873235,
year = {2023},
author = {Paul, S and McCourt, PM and Le, LTM and Ryu, J and Czaja, W and Bode, AM and Contreras-Galindo, R and Dong, Z},
title = {Fyn-mediated phosphorylation of Menin disrupts telomere maintenance in stem cells.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {37873235},
support = {R01 GM143428/GM/NIGMS NIH HHS/United States ; R21 CA259630/CA/NCI NIH HHS/United States ; },
abstract = {Telomeres protect chromosome ends and determine the replication potential of dividing cells. The canonical telomere sequence TTAGGG is synthesized by telomerase holoenzyme, which maintains telomere length in proliferative stem cells. Although the core components of telomerase are well-defined, mechanisms of telomerase regulation are still under investigation. We report a novel role for the Src family kinase Fyn, which disrupts telomere maintenance in stem cells by phosphorylating the scaffold protein Menin. Fyn phosphorylates Menin at tyrosine 603 (Y603), which increases Menin's SUMO1 modification, C-terminal stability, and importantly, its association with the telomerase RNA component (TR). We show that SUMO1-Menin decreases TR's association with telomerase subunit Dyskerin, suggesting that Fyn's phosphorylation of Menin induces telomerase subunit mislocalization and may compromise telomerase function at telomeres. Importantly, we find that Fyn inhibition reduces accelerated telomere shortening in human iPSCs harboring mutations for dyskeratosis congenita.},
}
@article {pmid37872177,
year = {2023},
author = {Smoom, R and May, CL and Ortiz, V and Tigue, M and Kolev, HM and Rowe, M and Reizel, Y and Morgan, A and Egyes, N and Lichtental, D and Skordalakes, E and Kaestner, KH and Tzfati, Y},
title = {Telomouse-a mouse model with human-length telomeres generated by a single amino acid change in RTEL1.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {6708},
pmid = {37872177},
issn = {2041-1723},
support = {R01 CA249929/CA/NCI NIH HHS/United States ; P30 DK019525/DK/NIDDK NIH HHS/United States ; R37 DK053839/DK/NIDDK NIH HHS/United States ; P30 DK050306/DK/NIDDK NIH HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Mice ; Animals ; Disease Models, Animal ; *Genome ; Telomere/genetics ; Cell Proliferation ; *Neoplasms/genetics ; DNA Helicases/genetics ; },
abstract = {Telomeres, the ends of eukaryotic chromosomes, protect genome integrity and enable cell proliferation. Maintaining optimal telomere length in the germline and throughout life limits the risk of cancer and enables healthy aging. Telomeres in the house mouse, Mus musculus, are about five times longer than human telomeres, limiting the use of this common laboratory animal for studying the contribution of telomere biology to aging and cancer. We identified a key amino acid variation in the helicase RTEL1, naturally occurring in the short-telomere mouse species M. spretus. Introducing this variation into M. musculus is sufficient to reduce the telomere length set point in the germline and generate mice with human-length telomeres. While these mice are fertile and appear healthy, the regenerative capacity of their colonic epithelium is compromised. The engineered Telomouse reported here demonstrates a dominant role of RTEL1 in telomere length regulation and provides a unique model for aging and cancer.},
}
@article {pmid37872100,
year = {2024},
author = {Radhakrishna, U and Ratnamala, U and Jhala, DD and Uppala, LV and Vedangi, A and Saiyed, N and Patel, M and Vadsaria, N and Shah, SR and Rawal, RM and Mercuri, SR and McGonagle, D and Jemec, GBE and Damiani, G},
title = {Hidradenitis suppurativa associated telomere-methylome dysregulations in blood.},
journal = {Journal of the European Academy of Dermatology and Venereology : JEADV},
volume = {38},
number = {2},
pages = {393-403},
doi = {10.1111/jdv.19586},
pmid = {37872100},
issn = {1468-3083},
mesh = {Humans ; *Hidradenitis Suppurativa/genetics/epidemiology ; Epigenome ; Leukocytes, Mononuclear ; Comorbidity ; *Neoplasms ; Telomere/genetics ; Ligases ; },
abstract = {BACKGROUND: Hidradenitis suppurativa (HS) is a chronic debilitating disease with a significant burden of both organic and psychological comorbidities. It has been shown that certain telomere-related genes (TRGs) affect a wide range of diseases, including HS and its associated comorbidities, but their exact role in HS pathogenesis is still unknown.<br><br>OBJECTIVES: To determine whether TRG methylomes can be used as biomarkers in HS.<br><br>METHODS: Using the Illumina HumanMethylation450 BeadChip array, we examined methylation variations associated with TRGs in HS cases and age-, sex- and ethnicity-matched healthy controls. The study utilized integrated bioinformatics statistical methods, such as a false discovery rate (FDR), the area under the receiver operating characteristic curve (AUC) and principal component analysis.<br><br>RESULTS: There were a total of 585 different differentially methylated CpG sites identified in 585 TRGs associated with HS (474 hypomethylated and 111 hypermethylated) (FDR p-value&#x2009;<&#x2009;0.05). A number of these CpGs have been identified as being involved in increased pain sensitivity including EPAS1, AHR, CSNK1D, DNMT1, IKBKAP, NOS3, PLCB1 and PRDM16 genes; GABRB3 as a potential alcohol addiction marker; DDB1, NSMCE2 and HNRNPA2B1 associated with cancers. Pathway analysis identified 67 statistically significant pathways, including DNA repair, telomere maintenance, mismatch repair and cell cycle control (p&#x2009;<&#x2009;0.001).<br><br>CONCLUSION: The disruption of TRGs leads to the shortening of telomeres, which is associated with HS progression, ageing, cellular senescence and an increased risk of various diseases, including cancer and associated comorbidities, such as metabolic syndrome, cardiovascular disease and inflammatory disorders. Further research is necessary to better understand the underlying mechanisms and establish causal links between TRGs and HS. The present study is the first effort to comprehend potential pathomechanisms of sporadic HS cases concentrating on PBMC methylome since ours.},
}
@article {pmid37870657,
year = {2024},
author = {Zhou, D and Sun, Y and Dong, C and Wang, Z and Zhao, J and Li, Z and Huang, G and Li, W},
title = {Folic acid alleviated oxidative stress-induced telomere attrition and inhibited apoptosis of neurocytes in old rats.},
journal = {European journal of nutrition},
volume = {63},
number = {1},
pages = {291-302},
pmid = {37870657},
issn = {1436-6215},
support = {81730091//National Natural Science Foundation of China/ ; 2021YJSB280//Tianjin Research Innovation Project for Postgraduate Students/ ; },
mesh = {Rats ; Male ; Animals ; *Folic Acid/pharmacology ; *Antioxidants/pharmacology ; Reactive Oxygen Species ; Rats, Sprague-Dawley ; Oxidative Stress ; Apoptosis ; 8-Hydroxy-2'-Deoxyguanosine ; Telomere ; },
abstract = {PURPOSE: Oxidative stress has been reported to cause telomere attrition, which triggers cell apoptosis. Apoptosis of neurocytes may play an essential role in the pathogenesis of neurodegenerative diseases. This study hypothesized that folic acid (FA) supplementation decreased neurocyte apoptosis by alleviating oxidative stress-induced telomere attrition in 25-month-old Sprague Dawley (SD) rats.<br><br>METHODS: Three-month-old male SD rats were randomly divided into four diet groups by different concentrations of folic acid in equal numbers, with intervention for 22&#xa0;months. Folate, homocysteine (Hcy), reactive oxygen species (ROS) levels, antioxidant activities, and telomere length in the brain tissues were tested at 11, 18, and 22&#xa0;months of intervention, and 8-hydroxy-deoxyguanosine (8-OHdG) levels, neurocyte apoptosis and telomere length in the cerebral cortex and hippocampal regions were tested during the 22-month intervention. An automated chemiluminescence system, auto-chemistry analyzer, Q-FISH, qPCR, and TUNEL assay were used in this study.<br><br>RESULTS: The rats had lower folate concentrations and higher Hcy, ROS, and 8-OHdG concentrations in brain tissue with aging. However, FA supplementation increased folate concentrations and antioxidant activities while decreasing Hcy, ROS, and 8-OHdG levels in rat brain tissue after 11, 18, and 22&#xa0;months of intervention. Furthermore, FA supplementation alleviated telomere length shortening and inhibited neurocyte apoptosis during the 22-month intervention.<br><br>CONCLUSION: FA supplementation alleviated oxidative stress-induced telomere attrition and inhibited apoptosis of neurocytes in 25-month-old rats.},
}
@article {pmid37864645,
year = {2023},
author = {Sung, JY and Lee, JW},
title = {Telomere maintenance mechanism subtype reveals different immune activity in vestibular schwannoma.},
journal = {Journal of neuro-oncology},
volume = {165},
number = {1},
pages = {113-126},
pmid = {37864645},
issn = {1573-7373},
mesh = {Humans ; *Telomerase/genetics/metabolism ; *Neuroma, Acoustic ; Telomere ; Telomere Homeostasis ; },
abstract = {BACKGROUND: The immortality of cancer cells relies on maintaining the length of telomeres, which prevents cellular senescence and enables unlimited replication. However, little is currently known about telomerase activity and the alternative lengthening of telomeres (ALT) in vestibular schwannomas. In this study we aimed to elucidate the role that telomerase and ALTs play in vestibular schwannomas.<br><br>METHODS: To address this gap, we conducted a study where we used the gene set variation analysis algorithm with bulk RNA-seq and single-cell RNA-seq to identify the characteristics of each group of patients with vestibular schwannomas, based on their telomere maintenance mechanism subtype.<br><br>RESULTS: Our findings suggest that patients with relatively high ALT-like groups have a better prognosis than those with relatively high telomerase groups. Specifically, we found that the high telomerase group had relatively higher antigen-presenting cell (APC) activity than the high ALT like group. At the single-cell level, microglia, neutrophils, and fibroblasts showed high telomerase activity and relatively high APC activity compared to other cell types. In addition, Schwann cells in the group with low ALT levels exhibited elevated immune activity at the single-cell level.<br><br>CONCLUSION: These results suggest that personalized drug therapy could be developed from the perspective of precision medicine for patients with relatively high telomerase activity and a high ALT-like group.},
}
@article {pmid37864620,
year = {2023},
author = {Ma, C and Li, X and Ding, W and Zhang, X and Chen, H and Feng, Y},
title = {Effects of hTERT transfection on the telomere and telomerase of Periplaneta americana cells in vitro.},
journal = {AMB Express},
volume = {13},
number = {1},
pages = {118},
pmid = {37864620},
issn = {2191-0855},
support = {32170168//National Natural Science Foundation of China/ ; 2019FB043//Yunnan Fundamental Research Projects/ ; },
abstract = {Telomere and telomerase are crucial factors in cell division and chromosome stability. Telomerase activity in most cells depends on the transcription control by the telomerase reverse transcriptase (TERT). The introduction of an exogenous human TERT (hTERT) in cultured cells could enhance telomerase activity and elongate the lifespan of various cells. Telomere elongation mechanisms vary between insects and are complex and unusual. Whether the use of exogenous hTERT can immortalize primary insect cells remains to be investigated. In this study, we used a recombinant virus expressing hTERT to infect primary cultured cells of Periplaneta americana and evaluated its effects on insect cell immortalization. We found that hTERT was successfully expressed and promoted the growth of P. americana cells, shortening their doubling time. This was due to the ability of hTERT to increase the activity of telomerase in P. americana cells, thus prolonging the telomeres. Our study lays the foundation for understanding the mechanisms of telomere elongation in P. americana, and suggests that the introduction of hTERT into insect cells could be an efficient way to establish certain insect cell lines.},
}
@article {pmid37864609,
year = {2023},
author = {Vaurs, M and Dolu, EB and Decottignies, A},
title = {Mitochondria and telomeres: hand in glove.},
journal = {Biogerontology},
volume = {},
number = {},
pages = {},
pmid = {37864609},
issn = {1573-6768},
abstract = {Born as an endosymbiont, the bacteria engulfed by the proto-eukaryotic cell more than 1.45 billion years ago progressively evolved as an important organelle with multiple interactions with the host cell. In particular, strong connections between mitochondria and the chromosome ends, the telomeres, led to propose a new theory of ageing in which dysfunctional telomeres and mitochondria are the main actors of a vicious circle reducing cell fitness and promoting cellular ageing. We review the evidences that oxidative stress and dysfunctional mitochondria damage telomeres and further discuss the interrelationship between telomere biology and mitochondria through the lens of telomerase which shuttles between the nucleus and mitochondria. Finally, we elaborate on the possible role of the mitochondrial genome on the inheritance of human telomere length through the expression of mitochondrial gene variants.},
}
@article {pmid37864481,
year = {2023},
author = {Badás, EP and Bauch, C and Boonekamp, JJ and Mulder, E and Verhulst, S},
title = {Ectoparasite presence and brood size manipulation interact to accelerate telomere shortening in nestling jackdaws.},
journal = {Molecular ecology},
volume = {32},
number = {24},
pages = {6913-6923},
doi = {10.1111/mec.17177},
pmid = {37864481},
issn = {1365-294X},
support = {8444403//European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie/ ; BA 5422/1-1//DFG fellowship/ ; 823.01.009//NWO/ ; 823.01.006//NWO/ ; },
mesh = {Animals ; *Crows ; Telomere Shortening/genetics ; Stress, Physiological ; Telomere/genetics ; },
abstract = {Early-life conditions impact fitness, but whether the combined effect of extrinsic stressors is additive or synergistic is not well known. This is a major knowledge gap because exposure to multiple stressors is frequent. Telomere dynamics may be instrumental when testing how stressors interact because many factors affect telomere shortening, and telomere shortening predicts survival. We evaluated the effect of manipulated brood size and natural infestation by the carnid fly Carnus hemapterus on nestling growth and telomere shortening of wild jackdaws (Corvus monedula). Telomere length, measured in blood using TRF, shortened on average by 264 bp, and on average, Carnus infection induced more telomere shortening. Further analyses showed that in enlarged broods, nestlings' telomeres shortened more when parasitized, while in reduced broods there was no effect of infection on telomere shortening. We conclude that there is a synergistic effect of number of siblings and Carnus infection on telomere shortening rate: blood-sucking parasites may negatively impact telomeres by increasing cell proliferation and/or physiological stress, and coping with infection may be less successful in enlarged broods with increased sibling competition. Larger nestlings had shorter telomeres independent of age, brood manipulation or infection. Growth was independent of infestation but in enlarged broods, nestlings were lighter at fledging. Our findings indicate that (i) evaluating consequences of early-life environmental conditions in isolation may not yield a full picture due to synergistic effects, and (ii) effects of environmental conditions may be cryptic, for example, on telomeres, with fitness consequences expressed beyond the temporal framework of the study.},
}
@article {pmid37859695,
year = {2023},
author = {Qi, M and Yu, J and Ping, F and Xu, L and Li, W and Zhang, H and Li, Y},
title = {Tumor necrosis factor-alpha mediates the negative association between telomere length and kidney dysfunction.},
journal = {International journal of medical sciences},
volume = {20},
number = {12},
pages = {1592-1599},
pmid = {37859695},
issn = {1449-1907},
mesh = {Humans ; Adult ; Middle Aged ; *Tumor Necrosis Factor-alpha/genetics/metabolism ; Prospective Studies ; Albuminuria/genetics ; Inflammation/pathology ; *Hypertension/genetics ; Kidney ; Telomere/genetics ; Leukocytes/metabolism/pathology ; },
abstract = {Aim/hypothesis: The relationship between peripheral blood leukocyte telomere length (LTL) and kidney dysfunction, especially in people with hypertension, remains unclear. No clinical study has explored the role of inflammation and oxidative stress in the relationship between LTL and kidney dysfunction. Therefore, we examined the relationship between baseline LTL and albuminuria progression and/or rapid renal function decline in Chinese patients with or without hypertension and investigated whether inflammation and oxidative stress played a mediating role in this relationship. Methods: We conducted a prospective study including 262 patients in a 7-year follow-up period from 2014 to 2021. Data on LTL, inflammation, oxidative markers, renal function, and urine protein levels were assessed. Kidney dysfunction was defined as either albuminuria progression, rapid decline in renal function, or the composite endpoint (albuminuria progression and rapid decline in renal function). Logistic regression and simple mediation models were used for the analysis. Results: In this cohort (mean age, 54.3±9.7 years; follow-up period, 5.9±1.1 years), 42(16.0%), 21(8.0%), and 59(22.5%) patients developed albuminuria progression, rapid eGFR decline, and the composite endpoint of kidney dysfunction, respectively. Logistic regression analysis showed that each standard deviation decrease of baseline LTL and the lower quartile (Q) of baseline LTL were significantly correlated with an increased risk of rapid decline in renal function (OR=1.83 [95% CI 1.07, 3.27] per 1SD, P=0.03; OR=7.57 [95% CI 1.25, 145.88] for Q1 vs. Q4, P for trend=0.031); and the composite endpoint of kidney dysfunction (OR=1.37 [95% CI 0.97, 1.96] per 1SD, borderline positive P=0.072; OR=2.96[95% CI 1.15, 8.2] for Q1 vs. Q4, P for trend=0.036). The mediating analysis showed that tumor necrosis factor (TNF)-a partly mediated the relationship between LTL and rapid decline in renal function (direct effect: β=0.046 95%CI [0.006, 0.090],P=0.02; indirect effect: β=0.013 95%CI [0.003, 0.020]), and the mediating proportion was 22.4%.In subgroup analyses, LTL was inversely associated with rapid decline in renal function or the composite endpoint of kidney dysfunction only in patients with hypertension (OR=49.07[3.72,211.12] vs.1.32[0.69,2.58] per 1SD, P for interaction=0.045;OR=3.10 [1.48, 7.52] vs.1.08[0.92,1.63] per 1SD, P for interaction=0.036). Conclusion: Baseline LTL could independently predict kidney dysfunction at follow-up, especially in participants with hypertension. TNF-a partially mediated the negative association between LTL and kidney dysfunction.},
}
@article {pmid37858982,
year = {2023},
author = {Rizzo, A and Maresca, C and D'Angelo, C and Porru, M and Di Vito, S and Salvati, E and Sacconi, A and Berardinelli, F and Sgura, A and Kuznetsov, S and Potdar, S and Hassinen, A and Stoppacciaro, A and Zizza, P and Biroccio, A},
title = {Drug repositioning strategy for the identification of novel telomere-damaging agents: A role for NAMPT inhibitors.},
journal = {Aging cell},
volume = {22},
number = {11},
pages = {e13944},
pmid = {37858982},
issn = {1474-9726},
support = {21579//Associazione Italiana per la Ricerca sul Cancro/ ; Ricerca Corrente 2022//Ministero della Salute/ ; },
mesh = {Humans ; *Triple Negative Breast Neoplasms ; Drug Repositioning ; Cell Death ; Apoptosis ; Telomere ; Telomeric Repeat Binding Protein 2/genetics ; Cell Line, Tumor ; },
abstract = {Drug repositioning strategy represents a valid tool to accelerate the pharmacological development through the identification of new applications for already existing compounds. In this view, we aimed at discovering molecules able to trigger telomere-localized DNA damage and tumor cell death. By applying an automated high-content spinning-disk microscopy, we performed a screening aimed at identifying, on a library of 527 drugs, molecules able to negatively affect the expression of TRF2, a key protein in telomere maintenance. FK866, resulting from the screening as the best candidate hit, was then validated at biochemical and molecular levels and the mechanism underlying its activity in telomere deprotection was elucidated both in vitro and in vivo. The results of this study allow us to discover a novel role of FK866 in promoting, through the production of reactive oxygen species, telomere loss and deprotection, two events leading to an accumulation of DNA damage and tumor cell death. The ability of FK866 to induce telomere damage and apoptosis was also demonstrated in advanced preclinical models evidencing the antitumoral activity of FK866 in triple-negative breast cancer-a particularly aggressive breast cancer subtype still orphan of targeted therapies and characterized by high expression levels of both NAMPT and TRF2. Overall, our findings pave the way to the development of novel anticancer strategies to counteract triple-negative breast cancer, based on the use of telomere deprotecting agents, including NAMPT inhibitors, that would rapidly progress from bench to bedside.},
}
@article {pmid37858268,
year = {2023},
author = {Sauty, SM and Yankulov, K},
title = {Analyses of POL30 (PCNA) reveal positional effects in transient repression or bi-modal active/silent state at the sub-telomeres of S. cerevisiae.},
journal = {Epigenetics &amp; chromatin},
volume = {16},
number = {1},
pages = {40},
pmid = {37858268},
issn = {1756-8935},
mesh = {Histone Chaperones/metabolism ; Histones/metabolism ; *Proliferating Cell Nuclear Antigen/genetics/metabolism ; *Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; *Telomere/genetics/metabolism ; },
abstract = {BACKGROUND: Classical studies on position effect variegation in Drosophila have demonstrated the existence of bi-modal Active/Silent state of the genes juxtaposed to heterochromatin. Later studies with irreversible methods for the detection of gene repression have revealed a similar phenomenon at the telomeres of Saccharomyces cerevisiae and other species. In this study, we used dual reporter constructs and a combination of reversible and non-reversible methods to present evidence for the different roles of PCNA and histone chaperones in the stability and the propagation of repressed states at the sub-telomeres of S. cerevisiae.<br><br>RESULTS: We show position dependent transient repression or bi-modal expression of reporter genes at the VIIL sub-telomere. We also show that mutations in the replicative clamp POL30 (PCNA) or the deletion of the histone chaperone CAF1 or the RRM3 helicase lead to transient de-repression, while the deletion of the histone chaperone ASF1 causes a shift from transient de-repression to a bi-modal state of repression. We analyze the physical interaction of CAF1 and RRM3 with PCNA and discuss the implications of these findings for our understanding of the stability and transmission of the epigenetic state of the genes.<br><br>CONCLUSIONS: There are distinct modes of gene silencing, bi-modal and transient, at the sub-telomeres of S. cerevisiae. We characterise the roles of CAF1, RRM3 and ASF1 in these modes of gene repression. We suggest that the interpretations of past and future studies should consider the existence of the dissimilar states of gene silencing.},
}
@article {pmid37857729,
year = {2023},
author = {Devrajani, T and Abid, S and Shaikh, H and Shaikh, I and Devrajani, DB and Memon, SM and Waryah, AM and Ujjan, ID and Syed, BM},
title = {Relationship between aging and control of metabolic syndrome with telomere shortening: a cross-sectional study.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {17878},
pmid = {37857729},
issn = {2045-2322},
mesh = {Humans ; Aged ; Adult ; Middle Aged ; *Telomere Shortening ; *Metabolic Syndrome/genetics/epidemiology ; Cross-Sectional Studies ; Aging/genetics ; Risk Factors ; Telomere/genetics ; },
abstract = {Aging is considered one of the major risk factors for several human disorders. The telomere plays a crucial role in regulating cellular responsiveness to stress and growth stimuli as well as maintaining the integrity of the Deoxyribonucleic Acid (DNA), and aging leads to the progressive decline in the telomere length (TL) due to continuous cell division. The aim of this study was to determine the relationship between TL and advancing age and the impact of metabolic syndrome (MetS) on TL. Firstly, we determined the association of advancing age and TL, by measuring telomere length (T/S ratio) in healthy volunteers (n = 90). The TL was compared between normal population and patients with metabolic syndrome (n = 298). The age matched controlled and uncontrolled MetS patients (n = 149) were also compared for their TL T/S ratio. The TL showed negative correlation with advancing age, whereas the significant change was observed at the cut-offs of 40 and 70 years defining 40 with longer TL and 70 as shorter TL. The longest T/S ratio at 2.46 was measured at the age range of 1 year in healthy volunteers, while elderly population showed considerably shorter TL. The patients older than 60 years with poor or uncontrolled MetS had shorter TL, as compared to the controlled MetS. In conclusion our findings suggest that TL was negatively correlated with advancing age. Uncontrolled metabolic syndrome appeared to have worsening effects on TL. Telomere length appears to have potential to be used a parameter to determine age. However, further large scale studies are recommended to make firm guidelines.},
}
@article {pmid37857262,
year = {2023},
author = {Yeung, SSY and Ma, SL and Wang, X and Chen, Y and Tsui, SKW and Tang, NLS and Woo, J},
title = {Telomere Length among Chinese Aged 75+ Years.},
journal = {Gerontology},
volume = {69},
number = {12},
pages = {1414-1423},
pmid = {37857262},
issn = {1423-0003},
mesh = {Male ; Female ; Humans ; Aged ; Aged, 80 and over ; *Sarcopenia/epidemiology/genetics ; *Frailty/epidemiology/genetics ; Cross-Sectional Studies ; East Asian People ; Biomarkers ; Telomere/genetics ; Telomere Shortening ; },
abstract = {INTRODUCTION: Telomere length (TL) is generally regarded as a biomarker of aging. TL, which is influenced by sociodemographic factors, has been shown to be inversely associated with morbidity. However, most studies examined the youngest, and whether the findings can be extended to older individuals is less clear. Further, few studies have examined these questions in Chinese older adults. This cross-sectional study examined TL and its associated factors in Chinese aged 75+ years in Hong Kong.<br><br>METHODS: Participants were from the Mr. and Ms. Osteoporosis cohort. A structured interview on sociodemographic factors and physical measurement was conducted. Frailty and sarcopenia status were respectively determined by Fried's criteria and the Asian Working Group for Sarcopenia definition. TL was measured by a molecular inversion probe-quantitative PCR assay and expressed as a novel telomere/a single copy reference gene (T/S) ratio. Adjusted binary logistic regressions were used to examine the associations between TL and the presence of multimorbidity, age-related diseases, frailty, and sarcopenia.<br><br>RESULTS: Among 555 participants (mean age 83.6 &#xb1; 3.8 years, 41.3% females), the mean T/S ratio was 1.01 &#xb1; 0.20. Males had a lower T/S ratio (0.97 &#xb1; 0.20) compared with females (1.07 &#xb1; 0.18) (p < 0.001). A lower education level was related to a longer TL (p = 0.016). Being a current smoker was related to a shorter TL (p = 0.007). TL was not significantly different across categories of age, subjective socioeconomic status, drinking status, physical activity level, and body mass index (p > 0.05). There were no associations between TL and the presence of multimorbidity, diabetes, stroke, cardiovascular diseases, cognitive impairment, frailty, and sarcopenia.<br><br>CONCLUSION: Among Chinese aged 75+ years, males had shorter TL compared with females. TL was not associated with age-related diseases, frailty, and sarcopenia in this age group. TL may not be a biological marker of aging among older individuals.},
}
@article {pmid37853446,
year = {2023},
author = {Liu, X and Ma, T and Yang, C and Li, J and Zhang, Y and Zhao, Y},
title = {Persistent dyslipidemia increases the longitudinal changes in telomere length.},
journal = {Lipids in health and disease},
volume = {22},
number = {1},
pages = {173},
pmid = {37853446},
issn = {1476-511X},
support = {2021BEG02026//the key R&amp;D projects in Ningxia Hui Autonomous Region/ ; No. 82060592//the National Natural Science Foundation of China/ ; },
mesh = {Humans ; Cross-Sectional Studies ; *Aging/genetics ; Real-Time Polymerase Chain Reaction ; *Leukocytes ; Telomere/genetics ; Lipids ; Longitudinal Studies ; },
abstract = {BACKGROUND AND AIMS: Leukocyte telomere length (LTL) as a 'biological clock' of aging is closely related to human health, its association with an aging-related disease, dyslipidemia, has been less studied and mainly focused on cross-sectional investigations.<br><br>METHODS: Two rounds of information and blood collections were conducted on a cohort of 1624 individuals residing in rural Ningxia, located in northwest China, with an average time gap of 9.8 years. The relative telomere length (RTL) of peripheral blood leukocytes was assessed using real-time quantitative PCR. To investigate the association between dyslipidemia, blood lipid levels, and alterations in RTL, multiple linear regression and generalized linear models were employed.<br><br>RESULTS: After conducting the follow-up analysis, it was observed that 83.3% of the participants in the study exhibited a reduction in telomere length, while 16.7% experienced an increase in telomere length. The results suggested that dyslipidemia at baseline or follow-up may increase longitudinal changes in telomere length, but it was more significant in the healthy group, especially in those aged &#x2265; 60 years. Furthermore, HDL-C levels in baseline and follow-up were found to be associated with longitudinal changes in telomere length, and lower HDL-C levels may be associated with increased longitudinal changes in telomere length.<br><br>CONCLUSIONS: The change in telomere length is correlated with dyslipidemia and its lipid indicators especially HDL-C. Persistent dyslipidemia and a reduction in HDL-C levels may be associated with elevated longitudinal fluctuations in telomere length.},
}
@article {pmid37851888,
year = {2023},
author = {Armanios, M},
title = {Familial Clonal Hematopoiesis in a Long Telomere Syndrome. Reply.},
journal = {The New England journal of medicine},
volume = {389},
number = {16},
pages = {1535-1536},
doi = {10.1056/NEJMc2309139},
pmid = {37851888},
issn = {1533-4406},
mesh = {Humans ; *Clonal Hematopoiesis ; *Hematopoiesis/genetics ; Mutation ; Telomere/genetics ; },
}
@article {pmid37851887,
year = {2023},
author = {Nakao, T and Natarajan, P},
title = {Familial Clonal Hematopoiesis in a Long Telomere Syndrome.},
journal = {The New England journal of medicine},
volume = {389},
number = {16},
pages = {1535},
pmid = {37851887},
issn = {1533-4406},
support = {K99 HL165024/HL/NHLBI NIH HHS/United States ; R01 HL148050/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; *Clonal Hematopoiesis ; *Hematopoiesis/genetics ; Mutation ; Telomere ; },
}
@article {pmid37849074,
year = {2024},
author = {Ertunc, O and Smearman, E and Zheng, Q and Hicks, JL and Brosnan-Cashman, JA and Jones, T and Gomes-Alexandre, C and Trabzonlu, L and Meeker, AK and De Marzo, AM and Heaphy, CM},
title = {Chromogenic detection of telomere lengths in situ aids the identification of precancerous lesions in the prostate.},
journal = {The Prostate},
volume = {84},
number = {2},
pages = {148-157},
pmid = {37849074},
issn = {1097-0045},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; P50 CA058236/CA/NCI NIH HHS/United States ; U01 CA196390/CA/NCI NIH HHS/United States ; U54 CA274370/CA/NCI NIH HHS/United States ; },
mesh = {Male ; Humans ; In Situ Hybridization, Fluorescence/methods ; *Prostate ; In Situ Hybridization ; *Precancerous Conditions/diagnosis/genetics ; Telomere ; },
abstract = {BACKGROUND: Telomeres are terminal chromosomal elements that are essential for the maintenance of genomic integrity. The measurement of telomere content provides useful diagnostic and prognostic information, and fluorescent methods have been developed for this purpose. However, fluorescent-based tissue assays are cumbersome for investigators to undertake, both in research and clinical settings.<br><br>METHODS: A robust chromogenic in situ hybridization (CISH) approach was developed to visualize and quantify telomere content at single cell resolution in human prostate tissues, both frozen and formalin-fixed, paraffin-embedded (FFPE).<br><br>RESULTS: This new assay (telomere chromogenic in situ hybridization ["Telo-CISH"]) produces permanently stained slides that are viewable with a standard light microscope, thus avoiding the need for specialized equipment and storage. The assay is compatible with standard immunohistochemistry, thereby allowing simultaneous assessment of histomorphology, identification of specific cell types, and assessment of telomere status. In addition, Telo-CISH eliminates the problem of autofluorescent interference that frequently occurs with fluorescent-based methods. Using this new assay, we demonstrate successful application of Telo-CISH to help identify precancerous lesions in the prostate by the presence of markedly short telomeres specifically in the luminal epithelial cells.<br><br>CONCLUSIONS: In summary, with fewer restrictions on the types of tissues that can be tested, and increased histologic information provided, the advantages presented by this novel chromogenic assay should extend the applicability of tissue-based telomere length assessment in research and clinical settings.},
}
@article {pmid37848852,
year = {2023},
author = {Houminer-Klepar, N and Bord, S and Epel, E and Baron-Epel, O},
title = {Are pregnancy and parity associated with telomere length? A systematic review.},
journal = {BMC pregnancy and childbirth},
volume = {23},
number = {1},
pages = {733},
pmid = {37848852},
issn = {1471-2393},
mesh = {Pregnancy ; Child ; Humans ; Female ; *Aging ; *Reproduction ; Telomere ; Postpartum Period ; Biomarkers ; },
abstract = {BACKGROUND: Women's reproduction requires increased energy demands, which consequently may lead to cellular damage and aging. Hence, Telomere Length (TL), a biomarker of biological aging and health status may possibly serve as a biomarker of reproductive effort. The aim of this systematic review is to evaluate telomere dynamics throughout pregnancy and the association between parity and TL.<br><br>METHODS: A systematic search was conducted across seven databases including CINAHL, Cochrane, PsycINFO, Proquest, PubMed; Scopus; and Web of Science, using keywords and MeSH descriptors of parity and TL. Predefined inclusion and exclusion criteria were used to screen abstracts and titles. After the removal of duplicates, 3431 articles were included in the primary screening, narrowed to 194 articles included in the full-text screening. Consensus was reached for the&#xa0;14 studies that were included in the final review, and the Newcastle-Ottawa scale (NOS) was utilized to assess the quality of the selected studies. A mini meta-analysis utilized JASP 0.17.3 software and included 4 applicable studies, comprising a total of 2564 participants to quantitatively assess the estimated effect size of parity on TL.<br><br>RESULTS: Of the 11 studies reviewed on parity and TL, four demonstrated a negative correlation; one - a positive correlation and six -found no correlation. Studies demonstrating a negative correlation encompassed rigorous methodological practices possibly suggesting having more children is associated with enhanced telomere attrition. Of the four longitudinal studies assessing telomere dynamics throughout pregnancy, most found no change in TL from early pregnancy to postpartum suggesting pregnancy does not affect TL from early pregnancy to early postpartum. The meta-analysis revealed a negative, yet, non-significant effect, of the estimated effect size of parity on TL(ES&#x2009;=&#x2009;-0.009, p&#x2009;=&#x2009;0.126, CI -0.021, 0.03).<br><br>CONCLUSIONS: Studies assessing pregnancy, parity and TL yielded mixed results, most likely due to the different research methods utilized in each study. Improvements in study design to better understand the short-term effects of pregnancy on TL and the effect of parity on TL over time, include precise definitions of parity, comparisons of different age groups, inclusion of reproductive lifespan and statistically adjusting for potential confounders in the parity and TL relationship.},
}
@article {pmid37847171,
year = {2023},
author = {Chen, J and Zhang, D and Ren, X and Wang, P},
title = {A comprehensive prognostic and immunological analysis of telomere-related lncRNAs in kidney renal clear cell carcinoma.},
journal = {Aging},
volume = {15},
number = {20},
pages = {11012-11032},
pmid = {37847171},
issn = {1945-4589},
mesh = {Humans ; Prognosis ; *RNA, Long Noncoding/genetics ; *Carcinoma, Renal Cell/genetics ; Telomere/genetics ; *Kidney Neoplasms/genetics ; Kidney ; Tumor Microenvironment/genetics ; },
abstract = {Kidney renal clear cell carcinoma (KIRC) is one of the most prevalent malignant tumors of the urinary system, with a high recurrence and metastasis rate. Telomeres and long non-coding RNAs (lncRNAs) have been documented playing critical roles in cancer progression. However, the prognostic significance of telomere-related lncRNA (TRLs) in KIRC is less well-defined. The Cancer Genome Atlas database was applied to retrieve the expression profiles and corresponding clinical information of KIRC patients. To create the TRLs prognostic signature, univariate Cox regression, least absolute shrinkage and selection operator analyses were performed. The prognostic signature, comprised of nine prognostic TRLs, was developed and demonstrated superior prognostic ability for KIRC patients. Additionally, the risk score acted as an independent prognostic indicator. A nomogram incorporating age, grade, stage, and signature-based risk scores was also developed and exhibited excellent predictive accuracy. Several immune activities were associated with the signature, as determined by gene function analysis. Further analysis revealed differences in the status of immunity and the tumor microenvironment between low- and high-risk groups. Notably, KIRC patients with high-risk scores were more responsive to immunotherapy and chemotherapy. To summarize, our study developed a new prognostic signature consisting of nine telomere-related lncRNA that can precisely predict the prognosis of KIRC patients. The signature was shown to be of substantial value for the tumor microenvironment and tumor mutation burden, thereby contributing to a framework for the individualized treatment of patients.},
}
@article {pmid37844405,
year = {2023},
author = {Zhang, F and Du, H and Hu, C and Song, Y},
title = {A new prognostic risk model for acute myeloid leukemia patients based on telomere-related genes.},
journal = {Leukemia research},
volume = {135},
number = {},
pages = {107404},
doi = {10.1016/j.leukres.2023.107404},
pmid = {37844405},
issn = {1873-5835},
mesh = {Humans ; Prognosis ; *Leukemia, Myeloid, Acute/diagnosis/genetics/drug therapy ; Risk Factors ; Kaplan-Meier Estimate ; ROC Curve ; Aldehyde Dehydrogenase, Mitochondrial ; },
abstract = {Telomere maintenance is critical to ensure unlimited cancer cell proliferation, but the role of telomere-related genes in acute myeloid leukemia (AML) has not yet been thoroughly discussed. This study aims to develop a new prognostic risk model based on telomere-related genes and analyze potential mechanisms and targets. Cox regression analyses were used to build the prognostic risk model. Kaplan-Meier (KM) survival analysis and receiver operating characteristic (ROC) curve were used to assess the model performance. At the same time, we analyzed the relationship between the risk score and chemotherapy and immunotherapy and preliminarily explored possible mechanisms of immune resistance. The real-time polymerase chain reaction (PCR) was used to detect the prognosis gene expression levels. Finally, a prognostic signature of six telomere-related genes (TGPS6) including ALDH2, CDK18, DNMT3B, FRAT2, LGALSL, and RBL2 was constructed. The TGPS6 score was confirmed as an independent prognostic factor (HR 2.74, CI [2.13-3.53], p < 0.001) in AML and the five-year area under the ROC curve (AUC) value of the score in the training and validation set reached 0.74, 0.81 respectively. In addition, the TGPS6 perfected the European LeukemiaNet (ELN) 2017 prognosis risk stratification and performed well in both AML and cytogenetically normal AML (CN-AML) cohorts. The TGPS6 score also provided a reference for chemotherapy and immunotherapy in patients with AML.},
}
@article {pmid37843976,
year = {2023},
author = {Sze, S and Bhardwaj, A and Fnu, P and Azarm, K and Mund, R and Ring, K and Smith, S},
title = {TERRA R-loops connect and protect sister telomeres in mitosis.},
journal = {Cell reports},
volume = {42},
number = {10},
pages = {113235},
pmid = {37843976},
issn = {2211-1247},
support = {R01 GM129780/GM/NIGMS NIH HHS/United States ; R01 GM141292/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; *Tankyrases/genetics/metabolism ; R-Loop Structures ; Telomere/metabolism ; Mitosis ; RNA ; DNA ; },
abstract = {Resolution of cohesion between sister telomeres in human cells depends on TRF1-mediated recruitment of the polyADP-ribosyltransferase tankyrase to telomeres. In human aged cells, due to insufficient recruitment of TRF1/tankyrase to shortened telomeres, sisters remain cohered in mitosis. This persistent cohesion plays a protective role, but the mechanism by which sisters remain cohered is not well understood. Here we show that telomere repeat-containing RNA (TERRA) holds sister telomeres together through RNA-DNA hybrid (R-loop) structures. We show that a tankyrase-interacting partner, the RNA-binding protein C19orf43, is required for repression of TERRA R-loops. Persistent telomere cohesion in C19orf43-depleted cells is counteracted by RNaseH1, confirming that RNA-DNA hybrids hold sisters together. Consistent with a protective role for persistent telomere cohesion, depletion of C19orf43 in aged cells reduces DNA damage and delays replicative senescence. We propose that the inherent inability of shortened telomeres to recruit R-loop-repressing machinery permits a controlled onset of senescence.},
}
@article {pmid37843740,
year = {2024},
author = {Thai, NQN and LaCroix, AZ and Haring, B and Wactawski-Wende, J and Manson, JE and Posis, AIB and Shadyab, AH},
title = {The association of leukocyte telomere length with exceptional longevity among older women.},
journal = {GeroScience},
volume = {46},
number = {2},
pages = {2083-2092},
pmid = {37843740},
issn = {2509-2723},
support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; },
mesh = {Humans ; Female ; Aged ; Aged, 80 and over ; *Longevity/genetics ; Prospective Studies ; Telomere ; Leukocytes ; *Stroke/epidemiology/genetics ; },
abstract = {The association of leukocyte telomere length (LTL) with survival to late life with intact mobility has not been adequately studied. This prospective cohort study consisted of 1451 postmenopausal women from a Women's Health Initiative ancillary study, who were eligible, because of birth year, to survive to age 90 as of March 6, 2021. LTL was measured by Southern blot at baseline (1993-1998). Associations between LTL and survival to age 90 were evaluated using logistic regression models adjusted for socio-demographic characteristics, health factors, and lifestyle factors. Multinominal logistic regression was utilized to examine associations of LTL with survival to age 90 with or without intact mobility. Mediation analysis examined the extent to which incident coronary heart disease and stroke-mediated the association between LTL and longevity. Overall, 76.7% of women were White, and 23.3% were Black; average age at baseline was 70.4±3.5 years. Relative to death before age 90, the odds of survival to age 90 were 60% higher (OR, 1.60; 95% CI, 1.28-2.01), the odds of survival to age 90 with mobility limitation were 72% higher (OR, 1.72; 95% CI, 1.33-2.21), and the odds of survival to age 90 with intact mobility were 44% higher (OR, 1.44; 95% CI, 1.06-1.95) for every one kilobase longer LTL. Absence of CHD, stroke, or CHD/stroke mediated the association of LTL with survival to age 90 by 11.1%, 37.4%, and 31.3%, respectively; however, these findings were not significant. Longer LTL was associated with higher odds of survival to age 90 among older women.},
}
@article {pmid37837282,
year = {2023},
author = {Westneat, DF and Young, RC and Cones, AG and Kucera, AC and Anacleto, A and Heidinger, BJ},
title = {Early-life telomeres are influenced by environments acting at multiple temporal and spatial scales.},
journal = {Molecular ecology},
volume = {32},
number = {22},
pages = {5959-5970},
doi = {10.1111/mec.17166},
pmid = {37837282},
issn = {1365-294X},
support = {IBN0542097//Division of Integrative Organismal Systems/ ; IBN9816989//Division of Integrative Organismal Systems/ ; IOS1257718//Division of Integrative Organismal Systems/ ; IOS1656194//Division of Integrative Organismal Systems/ ; IOS1656212//Division of Integrative Organismal Systems/ ; },
mesh = {Humans ; Animals ; *Telomere Shortening/genetics ; *Telomere/genetics ; Seasons ; Longevity ; },
abstract = {An individual's telomere length early in life may reflect or contribute to key life-history processes sensitive to environmental variation. Yet, the relative importance of genetic and environmental factors in shaping early-life telomere length is not well understood as it requires samples collected from multiple generations with known developmental histories. We used a confirmed pedigree and conducted an animal model analysis of telomere lengths obtained from nestling house sparrows (Passer domesticus) sampled over a span of 22 years. We found significant additive genetic variation for early-life telomere length, but it comprised a small proportion (9%) of the total biological variation. Three sources of environmental variation were important: among cohorts, among-breeding attempts within years, and among nestmates. The magnitude of variation among breeding attempts and among nestmates also differed by cohort, suggesting that interactive effects of environmental factors across time or spatial scales were important, yet we were unable to identify the specific causes of these interactions. The mean amount of precipitation during the breeding season positively predicted telomere length, but neither weather during a given breeding attempt nor date in the breeding season contributed to an offspring's telomere length. At the level of individual nestlings, offspring sex, size and mass at 10 days of age also did not predict telomere length. Environmental effects appear especially important in shaping early-life telomere length in some species, and more focus on how environmental factors that interact across scales may help to explain some of the variation observed among studies.},
}
@article {pmid37836587,
year = {2023},
author = {Petermann-Rocha, F and Valera-Gran, D and Prieto-Botella, D and Martens, DS and Gonzalez-Palacios, S and Riaño-Galán, I and Murcia, M and Irizar, A and Julvez, J and Santa-Marina, L and Tardón, A and Sunyer, J and Vioque, J and Nawrot, T and Navarrete-Muñoz, EM},
title = {Folic Acid Supplementation during Pregnancy and Its Association with Telomere Length in Children at Four Years: Results from the INMA Birth Cohort Study.},
journal = {Nutrients},
volume = {15},
number = {19},
pages = {},
pmid = {37836587},
issn = {2072-6643},
support = {27307C0010/ES/NIEHS NIH HHS/United States ; },
mesh = {Male ; Pregnancy ; Female ; Humans ; Child ; Cohort Studies ; *Folic Acid ; *Dietary Supplements ; Surveys and Questionnaires ; Telomere ; },
abstract = {This study examined the association between folic acid supplements (FAs) during different periods of pregnancy and offspring telomere length (TL) at age four in 666 children from the INMA study. FAs were self-reported using food-structured questionnaires during three periods of pregnancy (the first three months of pregnancy, from month fourth onward, and the whole pregnancy). For each period, the average daily dosage of FAs was categorised into (i) <400 μg/d, (ii) ≥400 to 999 μg/d, (iii) ≥1000 to 4999 μg/d, and (iv) ≥5000 μg/d. Leucocyte TL at age four was measured using quantitative PCR methods. Multiple robust linear log-level regression models were used to report the % difference among FA categories. During the first period, and compared with children whose mothers were classified in the reference group (<400 μg/d), children whose mothers took higher dosages of FAs showed shorter TL at age four (≥5000 μg/d). When the first and the second periods were mutually adjusted, children whose mothers self-reported ≥5000 μg/d during the first period of pregnancy had a statistically significant shorter TL than their counterparts (% difference: -7.28% [95% CI: -14.42 to -0.13]). Similar trends were observed for the whole period of pregnancy. When the analysis was stratified by sex, the association was more evident in boys (% difference: -13.5% [95% CI: -23.0 to -4.04]), whereas no association was observed in girls. This study suggests that high dosages of FAs in the first pregnancy period may be associated with a shorter TL in children at age four, particularly among boys. Further studies should confirm these results.},
}
@article {pmid37828426,
year = {2023},
author = {Liu, W and Chen, S and Xie, W and Wang, Q and Luo, Q and Huang, M and Gu, M and Lan, P and Chen, D},
title = {MCCC2 is a novel mediator between mitochondria and telomere and functions as an oncogene in colorectal cancer.},
journal = {Cellular &amp; molecular biology letters},
volume = {28},
number = {1},
pages = {80},
pmid = {37828426},
issn = {1689-1392},
support = {31970703//National Natural Science Foundation of China/ ; 2021A1515010544//Natural Science Foundation of Guangdong Province/ ; 2022A1515012472//Natural Science Foundation of Guangdong Province/ ; },
mesh = {Humans ; *Colorectal Neoplasms/genetics/metabolism ; Telomere/genetics/metabolism ; Oncogenes ; Mitochondria/metabolism ; Kaplan-Meier Estimate ; Cell Proliferation/genetics ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Cell Movement/genetics ; },
abstract = {BACKGROUND: The mitochondrial gene MCCC2, a subunit of the heterodimer of 3-methylcrotonyl-CoA carboxylase, plays a pivotal role in catabolism of leucine and isovaleric acid. The molecular mechanisms and prognostic value still need to be explored in the context of specific cancers, including colorectal cancer (CRC).<br><br>METHODS: In vitro and in vivo cell-based assays were performed to explore the role of MCCC2 in CRC cell proliferation, invasion, and migration. Mitochondrial morphology, membrane potential, intracellular reactive oxygen species (ROS), telomerase activity, and telomere length were examined and analyzed accordingly. Protein complex formation was detected by co-immunoprecipitation (CO-IP). Mitochondrial morphology was observed by transmission electron microscopy (TEM). The Cancer Genome Atlas (TCGA) CRC cohort analysis, qRT-PCR, and immunohistochemistry (IHC) were used to examine the MCCC2 expression level. The association between MCCC2 expression and various clinical characteristics was analyzed by chi-square tests. CRC patients' overall survival (OS) was analyzed by Kaplan-Meier analysis.<br><br>RESULTS: Ectopic overexpression of MCCC2 promoted cell proliferation, invasion, and migration, while MCCC2 knockdown (KD) or knockout (KO) inhibited cell proliferation, invasion, and migration. MCCC2 KD or KO resulted in reduced mitochondria numbers, but did not affect the gross ATP production in the cells. Mitochondrial fusion markers MFN1, MFN2, and OPA1 were all upregulated in MCCC2 KD or KO cells, which is in line with a phenomenon of more prominent mitochondrial fusion. Interestingly, telomere lengths of MCCC2 KD or KO cells were reduced more than control cells. Furthermore, we found that MCCC2 could specifically form a complex with telomere binding protein TRF2, and MCCC2 KD or KO did not affect the expression or activity of telomerase reverse transcriptase (TERT). Finally, MCCC2 expression was heightened in CRC, and patients with higher MCCC2 expression had favorable prognosis.<br><br>CONCLUSIONS: Together, we identified MCCC2 as a novel mediator between mitochondria and telomeres, and provided an additional biomarker for CRC stratification.},
}
@article {pmid37827695,
year = {2023},
author = {Wang, Q and Hou, K and Yang, J and Li, H and Li, C and Zhang, Y and Tian, J and Li, C and Guo, B and Jia, S and Luo, Y},
title = {Modified iPOND revealed the role of mutant p53 in promoting helicase function and telomere maintenance.},
journal = {Aging},
volume = {15},
number = {19},
pages = {10767-10784},
pmid = {37827695},
issn = {1945-4589},
mesh = {Animals ; Mice ; *DNA Replication ; Tumor Suppressor Protein p53/genetics/metabolism ; Werner Syndrome Helicase/genetics ; DNA Helicases/genetics/metabolism ; DNA/genetics ; Telomere/genetics/metabolism ; *Werner Syndrome ; RecQ Helicases/genetics/metabolism ; },
abstract = {The G-rich DNA, such as telomere, tends to form G-quadruplex (G4) structure, which slows down the replication fork progression, induces replication stress, and becomes the chromosome fragile sites. Here we described a molecular strategy that cells developed to overcome the DNA replication stress via DNA helicase regulation. The p53N236S (p53S) mutation has been found in the Werner syndrome mouse embryo fibroblast (MEFs) escaped from senescence, could be the driving force for cell escaping senescence. We revealed that the p53S could transcriptionally up-regulate DNA helicases expression, including Wrn, Blm, Timeless, Ddx, Mcm, Gins, Fanc, as well as telomere specific proteins Terf1, Pot1, through which p53S promoted the unwinding of G4 structures, and protected the cells from DNA replication stress induced by G4 stabilizer. By modified iPOND (isolation of proteins on nascent DNA) assay and telomere assay, we demonstrated that the p53S could promote the recruitment of those helicases to the DNA replication forks, facilitated the maintenance of telomere, and prevent the telomere dysfunction induced by G4 stabilizer. Interestingly, we did not observe the function of promoting G4 resolving and facilitating telomere lengthening in the cells with Li-Fraumeni Syndrome mutation-p53R172H (p53H), which suggests that this is the specific gain of function for p53S. Together our data suggest that the p53S could gain the new function of releasing the replication stress via regulating the helicase function and G4 structure, which benefits telomere lengthening. This strategy could be applied to the treatment of diseases caused by telomere replication stress.},
}
@article {pmid37826871,
year = {2023},
author = {Bernardinello, N and Crestani, B and Spagnolo, P and Ghanem, M and Homps-Legrand, M and Morer, L and Goletto, T and Frija-Masson, J and Bancal, C and Hurtado-Nedelec, M and de Chaisemartin, L and Debray, MP and Neukirch, C and Taillé, C and Ba, I and Kannengiesser, C and Lainey, E and Abels, A and Vankann, L and Beier, F and Borie, R},
title = {Is telomere length a predictor of long-term survival in patients with COVID-19 pneumonia?.},
journal = {Respiratory medicine and research},
volume = {84},
number = {},
pages = {101048},
doi = {10.1016/j.resmer.2023.101048},
pmid = {37826871},
issn = {2590-0412},
mesh = {Humans ; *COVID-19 ; Aging ; Telomere/genetics ; },
}
@article {pmid37824094,
year = {2023},
author = {Aviv, A},
title = {The "telomereless" erythrocytes and telomere-length dependent erythropoiesis.},
journal = {Aging cell},
volume = {22},
number = {12},
pages = {e13997},
pmid = {37824094},
issn = {1474-9726},
support = {U01 AG066529/AG/NIA NIH HHS/United States ; 1R56AG073226/NH/NIH HHS/United States ; U01AG066529/NH/NIH HHS/United States ; 1R01HL134840/NH/NIH HHS/United States ; },
mesh = {Adult ; Humans ; *Erythropoiesis/genetics ; *Erythrocytes ; Leukocytes ; Longevity ; Telomere ; },
abstract = {Approximately 25 trillion erythrocytes (red blood cells) circulate in the bloodstream of an adult human, surpassing the number of circulating leukocytes (white blood cells) by a factor of about 1000. Moreover, the erythrocyte turnover rate accounts for approximately 76% of the turnover rate of all circulating blood cells. This simple math shows that the hematopoietic system principally spends its telomere length-dependent replicative capacity on building and maintaining the erythrocyte blood pool. Erythropoiesis (red blood cell production) is thus the principal cause of telomere shortening with age in hematopoietic cells (HCs), a conclusion that holds significant implications for linking telomere length dynamics in HCs to health and lifespan of modern humans.},
}
@article {pmid37817598,
year = {2023},
author = {Power, ML and Ransome, RD and Riquier, S and Romaine, L and Jones, G and Teeling, EC},
title = {Hibernation telomere dynamics in a shifting climate: insights from wild greater horseshoe bats.},
journal = {Proceedings. Biological sciences},
volume = {290},
number = {2008},
pages = {20231589},
pmid = {37817598},
issn = {1471-2954},
mesh = {Humans ; Animals ; *Hibernation ; *Chiroptera/genetics ; Cross-Sectional Studies ; Body Temperature ; Telomere ; },
abstract = {Hibernation is linked with various hypotheses to explain the extended lifespan of hibernating mammals compared with their non-hibernating counterparts. Studies on telomeres, markers of ageing and somatic maintenance, suggest telomere shortening slows during hibernation, and lengthening may reflect self-maintenance with favourable conditions. Bats in temperate zones adjust body temperatures during winter torpor to conserve energy and exploit mild conditions for foraging. Climate change may impact the hibernation cycle of bats, but more research is needed regarding the role of telomeres in understanding their response to a changing climate. Here, relative telomere length (rTL) was measured in the long-lived greater horseshoe bat Rhinolophus ferrumequinum (n = 223 individuals) over three winters, considering climatic conditions. Cross-sectional analyses revealed between-individual variation in rTL with a strong year effect, likely linked to varying weather conditions and foraging success. Additionally, within-individual increases of rTL occurred in 51% of consecutive measurements, with evidence of increasing telomerase expression during hibernation in this species. These findings highlight the beneficial effects of hibernation on telomeres and potential consequences of changing climatic conditions for long-lived temperate bats. Understanding the interplay between hibernation, telomeres, and climate can provide insights into the adaptive capacity and survival of bat populations facing environmental challenges.},
}
@article {pmid37806951,
year = {2023},
author = {Veiko, NN and Ershova, ES and Porokhovnik, LN and Klimenko, MP and Klimenko, PA and Umriukhin, PE and Kostyuk, &#x415;V and Kurtser, MA and Agafonova, ON and Salimova, TA and Kutsev, SI and Izhevskaya, VL and Kostyuk, SV},
title = {Ribosomal, Telomere, and Mitochondrial Repeat Copy Number Variations in Female Genomes during Ovarian Stimulation and the Prediction of In Vitro Fertilization Outcome: A Pilot Study.},
journal = {Frontiers in bioscience (Scholar edition)},
volume = {15},
number = {3},
pages = {9},
doi = {10.31083/j.fbs1503009},
pmid = {37806951},
issn = {1945-0524},
support = {FGFF-2022-0007//State assignment of the Ministry of Science and Higher Education/ ; },
mesh = {Pregnancy ; Female ; Humans ; *DNA Copy Number Variations/genetics ; Pilot Projects ; *Fertilization in Vitro ; DNA, Mitochondrial/genetics ; DNA, Ribosomal ; Telomere ; Ovulation Induction/methods ; },
abstract = {INTRODUCTION: Individual risk assessment of assisted reproductive technologies is essential for personalized treatment strategies. Genetic and genomic indicators of the response to stress by cells could provide individual prognostic indicators for in vitro fertilization (IVF) success. Such indicators include the copy number of ribosomal genes (rDNA), which modulates the level of protein synthesis, and the abundance of mitochondrial DNA (mtDNA), which provides the cell with energy, while the content of telomere repeats (TRs) indicate the biological age.<br><br>MATERIALS AND METHODS: The contents of the three repeats in DNA isolated from blood leukocytes of 40 women before and after ovarian stimulation were assayed prior to IVF. Then, we divided the women into a successful IVF group, IVF+ (N = 17, 7 cases of twins), and a group of failed cases, IVF- (N = 23). The control group included 17 non-pregnant women with natural childbirth in the past. The nonradioactive quantitative hybridization (NQH) method was applied to assay the genome repeat contents.<br><br>RESULTS: The number of rDNA copies in the IVF+ group was significantly higher than in the IVF- group (p < 10-8). The number of mtDNA copies in the IVF+ group also exceeded those in the IVF- group (p < 0.001), whereas the TR content in the two groups differed, albeit, non-significantly (p < 0.03). Following the ovarian stimulation, the rDNA copy numbers did not change, while the contents of the mtDNA and TR varied significantly.<br><br>CONCLUSIONS: This pilot study has shown that rDNA abundance in blood leukocytes can be considered a stable and effective predictor. Very low numbers of ribosomal repeat copies (<330) entail a high risk of IVF failure. However, a combination of numerous mtDNA and TRs, provided that rDNA content is not very low, increases the probability of multiple pregnancies.},
}
@article {pmid37803147,
year = {2023},
author = {Hu, J and Lu, J and Lu, Q and Weng, W and Guan, Z and Wang, Z},
title = {Mendelian randomization and colocalization analyses reveal an association between short sleep duration or morning chronotype and altered leukocyte telomere length.},
journal = {Communications biology},
volume = {6},
number = {1},
pages = {1014},
pmid = {37803147},
issn = {2399-3642},
mesh = {*Sleep Duration ; *Chronotype ; Genome-Wide Association Study/methods ; Mendelian Randomization Analysis/methods ; Sleep/genetics ; Leukocytes ; Telomere/genetics ; },
abstract = {Observational studies suggest certain sleep traits are associated with telomere length, but the causal nature of these associations is unclear. The study aimed to determine the causal associations between 11 sleep-related traits and leukocyte telomere length (LTL) through two-sample Mendelian randomization and colocalization analyses using the summary statistics from large-scale genome-wide association studies. Univariable Mendelian randomization indicates that genetically determined short sleep is associated with decreased LTL, while morning chronotype is associated with increased LTL. Multivariable Mendelian randomization further supports the findings and colocalization analysis identifies shared common genetic variants for these two associations. No genetic evidence is observed for associations between other sleep-related traits and LTL. Sensitivity MR methods, reverse MR and re-running MR after removing potential pleiotropic genetic variants enhance the robustness of the results. These findings indicate that prioritizing morning chronotype and avoiding short sleep is beneficial for attenuating telomere attrition. Consequently, addressing sleep duration and chronotype could serve as practical intervention strategies.},
}
@article {pmid37802318,
year = {2023},
author = {Sienkiewicz, M and Sroka, K and Binienda, A and Jurk, D and Fichna, J},
title = {A new face of old cells: An overview about the role of senescence and telomeres in inflammatory bowel diseases.},
journal = {Ageing research reviews},
volume = {91},
number = {},
pages = {102083},
doi = {10.1016/j.arr.2023.102083},
pmid = {37802318},
issn = {1872-9649},
mesh = {Humans ; *Inflammatory Bowel Diseases/genetics/drug therapy ; Inflammation/pathology ; Cellular Senescence/genetics ; Aging/genetics/pathology ; Telomere/pathology ; },
abstract = {Cellular senescence is a pivotal factor contributing to aging and the pathophysiology of age-related diseases. Despite the presence of inflammation and abnormal immune system function in both inflammatory bowel diseases (IBD) and senescence, the relationship between the two remains largely unexplored. Therefore, our study aimed to investigate the intricate connection between cellular senescence, telomeres, and IBD. The review highlights the presence of senescence markers, particularly p16 and p21, in IBD patients, suggesting their potential association with disease progression and mucosal inflammation. We emphasize the critical role of macrophages in eliminating senescent cells and how disturbance in effective clearance may contribute to persistent senescence and inflammation in IBD. Additionally, we shed light on the involvement of telomeres in IBD, as their dysfunction impairs enterocyte function and disrupts colonic barrier integrity, potentially exacerbating the pathogenesis of the disease. Targeting senescence and telomere dysfunctions holds promise for the development of innovative therapeutic approaches to mitigate intestinal inflammation and alleviate symptoms in IBD patients. By unraveling the precise role of senescence in IBD, we can pave the way for the discovery of novel therapeutic interventions that effectively address the underlying mechanisms of intestinal inflammation, offering hope for improved management and treatment of IBD patients.},
}
@article {pmid37801568,
year = {2023},
author = {Butts, B and Hope, C and Herring, C and Mueller, K and Gary, RA},
title = {The Effects of Exercise on Telomere Length in Persons With Heart Failure.},
journal = {The Journal of cardiovascular nursing},
volume = {},
number = {},
pages = {},
pmid = {37801568},
issn = {1550-5049},
support = {T32 NR012715/NR/NINR NIH HHS/United States ; },
abstract = {BACKGROUND: Telomere length is reduced in persons with heart failure (HF). Inflammation is a putative mechanism contributing to telomere shortening. Although physical activity is known to increase telomere length, its effects in HF are unknown.<br><br>OBJECTIVE: The aim of this study was to examine the effects of exercise on telomere length and its relationship with interleukin (IL)-1&#x3b2; in persons with HF.<br><br>METHODS: This secondary analysis of a 3-month home-based aerobic exercise intervention measured total telomere length and IL-1&#x3b2; levels in persons with HF (69% with reduced ejection fraction).<br><br>RESULTS: Total telomere length increased and plasma IL-1&#x3b2; levels decreased in the exercise group from baseline to 3 months. Total telomere length was negatively associated with IL-1&#x3b2; at baseline (r = -0.441 P = .001).<br><br>CONCLUSIONS: The association between telomere length and IL-1&#x3b2; suggests a relationship between inflammation and cellular aging. Moderate-intensity exercise may help maintain cellular functions. Further research is needed to examine the effects on outcomes in persons with HF.},
}
@article {pmid37793222,
year = {2024},
author = {Yadav, PS and Kumar, D and Saini, M and Sharma, RK and Dua, S and Selokar, NL and Bansal, S and Punetha, M and Gupta, A and Kumar, R and Kumar, P},
title = {Evaluation of postnatal growth, hematology, telomere length and semen attributes of multiple clones and re-clone of superior buffalo breeding bulls.},
journal = {Theriogenology},
volume = {213},
number = {},
pages = {24-33},
doi = {10.1016/j.theriogenology.2023.09.024},
pmid = {37793222},
issn = {1879-3231},
mesh = {Male ; Female ; Animals ; Cattle/genetics ; *Semen ; Buffaloes/genetics ; Sperm Motility ; Spermatozoa ; *Hematology ; Telomere ; Semen Analysis/veterinary ; },
abstract = {The present study comprehensively evaluates the postnatal growth, hematology, telomere length, and semen attributes of multiple clones and re-clone derived from superior buffalo breeding bulls. To the best of our knowledge, we successfully produced multiple clones and a re-clone of an earlier cloned buffalo bull from an embryo developed from an adult bull's skin-derived cell for the first time. The cloned bulls' growth, blood hematology, plasma biochemistry, and telomere length were all shown to be normal at various stages of development. The bulls were used for semen production after being screened for testicular growth and training. Semen characteristics such as volume, concentration, and initial motility of fresh sperm as well as motility and kinetics characteristics such as straightness (STR), average lateral head displacement (ALH), and beat cross frequency (BCF) of frozen-thawed sperms of the cloned bulls were found to be similar to those of non-cloned bulls, including the donor bulls. Additionally, it was found that cloned bulls' functional sperm attributes, including acrosome intactness, mitochondrial membrane potential, and superoxide anion status, were comparable to those of non-cloned bulls. These characteristics are necessary for sperm to pass through the female reproductive system, penetrate the oocyte, and efficiently fertilize. Finally, this study adds to our understanding of the postnatal development, hematology, telomere length, and sperm characteristics of superior buffalo breeding bulls that have been cloned and re-cloned. The findings provide the groundwork for improving cloning practices, refining reproductive procedures, and optimizing the use of cloned genetic material in animal breeding and conservation.},
}
@article {pmid37792396,
year = {2023},
author = {Morbiato, E and Cattelan, S and Pilastro, A and Grapputo, A},
title = {Sperm production is negatively associated with muscle and sperm telomere length in a species subjected to strong sperm competition.},
journal = {Molecular ecology},
volume = {32},
number = {21},
pages = {5812-5822},
doi = {10.1111/mec.17158},
pmid = {37792396},
issn = {1365-294X},
support = {20178T2PSW//Ministry of University and Research/ ; C93C22002810006//NBFC-PNRR/ ; //PRID 2020/ ; },
mesh = {Animals ; Male ; *Semen ; Spermatozoa/physiology ; Sexual Behavior, Animal ; Reproduction/genetics ; Muscles ; *Poecilia/genetics ; },
abstract = {Life-history theory suggests that ageing is one of the costs of reproduction. Accordingly, a higher reproductive allocation is expected to increase the deterioration of both the somatic and the germinal lines through enhanced telomere attrition. In most species, males' reproductive allocation mainly regards traits that increase mating and fertilization success, that is sexually selected traits. In this study, we tested the hypothesis that a higher investment in sexually selected traits is associated with a reduced relative telomere length (RTL) in the guppy (Poecilia reticulata), an ectotherm species characterized by strong pre- and postcopulatory sexual selection. We first measured telomere length in both the soma and the sperm over guppies' lifespan to see whether there was any variation in telomere length associated with age. Second, we investigated whether a greater investment in pre- and postcopulatory sexually selected traits is linked to shorter telomere length in both the somatic and the sperm germinal lines, and in young and old males. We found that telomeres lengthened with age in the somatic tissue, but there was no age-dependent variation in telomere length in the sperm cells. Telomere length in guppies was significantly and negatively correlated with sperm production in both tissues and life stages considered in this study. Our findings indicate that telomere length in male guppies is strongly associated with their reproductive investment (sperm production), suggesting that a trade-off between reproduction and maintenance is occurring at each stage of males' life in this species.},
}
@article {pmid37790308,
year = {2024},
author = {Ahlers, NE and Lin, J and Weiss, SJ},
title = {WITHDRAWN: Exposure to Ambient Particulate Matter during Pregnancy: Implications for Infant Telomere Length.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.09.17.23295692},
pmid = {37790308},
abstract = {This manuscript has been withdrawn by the authors as it was submitted and made public without the full consent of all the authors. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author. The authors have an approved version for citation that is peer reviewed. Ahlers, N.E.; Lin, J.; Weiss, S.J. Exposure to Ambient Particulate Matter during Pregnancy: Implications for Infant Telomere Length. Air 2024, 2, 24-37. https://doi.org/10.3390/air2010002.},
}
@article {pmid37789444,
year = {2023},
author = {Wang, Y and Dong, M and Wu, Y and Zhang, F and Ren, W and Lin, Y and Chen, Q and Zhang, S and Yue, J and Liu, Y},
title = {Telomere-to-telomere and haplotype-resolved genome of the kiwifruit Actinidia eriantha.},
journal = {Molecular horticulture},
volume = {3},
number = {1},
pages = {4},
pmid = {37789444},
issn = {2730-9401},
support = {31972474//National Natural Science Foundation of China/ ; 31471157//National Natural Science Foundation of China/ ; },
abstract = {Actinidia eriantha is a characteristic fruit tree featuring with great potential for its abundant vitamin C and strong disease resistance. It has been used in a wide range of breeding programs and functional genomics studies. Previously published genome assemblies of A. eriantha are quite fragmented and not highly contiguous. Using multiple sequencing strategies, we get the haplotype-resolved and gap-free genomes of an elite breeding line "Midao 31" (MD), termed MDHAPA and MDHAPB. The new assemblies anchored to 29 pseudochromosome pairs with a length of 619.3 Mb and 611.7 Mb, as well as resolved 27 and 28 gap-close chromosomes in a telomere-to-telomere (T2T) manner. Based on the haplotype-resolved genome, we found that most alleles experienced purifying selection and coordinately expressed. Owing to the high continuity of assemblies, we defined the centromeric regions of A. eriantha, and identified the major repeating monomer, which is designated as Ae-CEN153. This resource lays a solid foundation for further functional genomics study and horticultural traits improvement in kiwifruit.},
}
@article {pmid37787873,
year = {2023},
author = {Ongie, L and Raj, HA and Stevens, KB},
title = {Genetic Counseling and Family Screening Recommendations in Patients with Telomere Biology Disorders.},
journal = {Current hematologic malignancy reports},
volume = {18},
number = {6},
pages = {273-283},
pmid = {37787873},
issn = {1558-822X},
mesh = {Humans ; *Genetic Counseling ; Telomere/genetics/metabolism ; *Telomerase/genetics/metabolism ; Genetic Testing ; Mutation ; },
abstract = {PURPOSE OF REVIEW: Telomere biology disorders (TBDs) encompass a spectrum of genetic diseases with a common pathogenesis of defects in telomerase function and telomere maintenance causing extremely short telomere lengths. Here, we review the current literature surrounding genetic testing strategies, cascade testing, reproductive implications, and the role of genetic counseling.<br><br>RECENT FINDINGS: The understanding of the genetic causes and clinical symptoms of TBDs continues to expand while genetic testing and telomere length testing are nuanced tools utilized in the diagnosis of this condition. Access to genetic counseling is becoming more abundant and is valuable in supporting patients and their families in making informed decisions. Patient resources and support groups are valuable to this community. Defining which populations should be offered genetic counseling and testing is imperative to provide proper diagnoses and medical management for not only the primary patient, but also their biological relatives.},
}
@article {pmid37786729,
year = {2023},
author = {Wang, YH and Liu, PZ and Liu, H and Zhang, RR and Liang, Y and Xu, ZS and Li, XJ and Luo, Q and Tan, GF and Wang, GL and Xiong, AS},
title = {Telomere-to-telomere carrot (Daucus carota) genome assembly reveals carotenoid characteristics.},
journal = {Horticulture research},
volume = {10},
number = {7},
pages = {uhad103},
pmid = {37786729},
issn = {2662-6810},
abstract = {Carrot (Daucus carota) is an Apiaceae plant with multi-colored fleshy roots that provides a model system for carotenoid research. In this study, we assembled a 430.40 Mb high-quality gapless genome to the telomere-to-telomere (T2T) level of "Kurodagosun" carrot. In total, 36 268 genes were identified and 34 961 of them were functionally annotated. The proportion of repeat sequences in the genome was 55.3%, mainly long terminal repeats. Depending on the coverage of the repeats, 14 telomeres and 9 centromeric regions on the chromosomes were predicted. A phylogenetic analysis showed that carrots evolved early in the family Apiaceae. Based on the T2T genome, we reconstructed the carotenoid metabolic pathway and identified the structural genes that regulate carotenoid biosynthesis. Among the 65 genes that were screened, 9 were newly identified. Additionally, some gene sequences overlapped with transposons, suggesting replication and functional differentiation of carotenoid-related genes during carrot evolution. Given that some gene copies were barely expressed during development, they might be functionally redundant. Comparison of 24 cytochrome P450 genes associated with carotenoid biosynthesis revealed the tandem or proximal duplication resulting in expansion of CYP gene family. These results provided molecular information for carrot carotenoid accumulation and contributed to a new genetic resource.},
}
@article {pmid37782440,
year = {2024},
author = {Liu, D and Aziz, NA and Imtiaz, MA and Pehlivan, G and Breteler, MMB},
title = {Associations of measured and genetically predicted leukocyte telomere length with vascular phenotypes: a population-based study.},
journal = {GeroScience},
volume = {46},
number = {2},
pages = {1947-1970},
pmid = {37782440},
issn = {2509-2723},
support = {432325352//Deutsche Forschungsgemeinschaft/ ; EXC 2151 - 390873048//Deutsche Forschungsgemeinschaft/ ; 2017006100345//China Scholarship Council/ ; },
mesh = {Humans ; Female ; Aged ; Aged, 80 and over ; Male ; Cohort Studies ; Longitudinal Studies ; Phenotype ; *Leukocytes/metabolism ; *Telomere/genetics ; },
abstract = {Shorter leukocyte telomere length (LTL) is associated with cardiovascular dysfunction. Whether this association differs between measured and genetically predicted LTL is still unclear. Moreover, the molecular processes underlying the association remain largely unknown. We used baseline data of the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany [56.2% women, age: 55.5 ± 14.0 years (range 30 - 95 years)]. We calculated genetically predicted LTL in 4180 participants and measured LTL in a subset of 1828 participants with qPCR. Using multivariable regression, we examined the association of measured and genetically predicted LTL, and the difference between measured and genetically predicted LTL (ΔLTL), with four vascular functional domains and the overall vascular health. Moreover, we performed epigenome-wide association studies of three LTL measures. Longer measured LTL was associated with better microvascular and cardiac function. Longer predicted LTL was associated with better cardiac function. Larger ΔLTL was associated with better microvascular and cardiac function and overall vascular health, independent of genetically predicted LTL. Several CpGs were associated (p < 1e-05) with measured LTL (n = 5), genetically predicted LTL (n = 8), and ΔLTL (n = 27). Genes whose methylation status was associated with ΔLTL were enriched in vascular endothelial signaling pathways and have been linked to environmental exposures, cardiovascular diseases, and mortality. Our findings suggest that non-genetic causes of LTL contribute to microvascular and cardiac function and overall vascular health, through an effect on the vascular endothelial signaling pathway. Interventions that counteract LTL may thus improve vascular function.},
}
@article {pmid37781376,
year = {2023},
author = {Roger, L and Miners, KL and Leonard, L and Grimstead, JW and Price, DA and Baird, DM and Ladell, K},
title = {T cell memory revisited using single telomere length analysis.},
journal = {Frontiers in immunology},
volume = {14},
number = {},
pages = {1100535},
pmid = {37781376},
issn = {1664-3224},
support = {/WT_/Wellcome Trust/United Kingdom ; C17199/A18246/CRUK_/Cancer Research UK/United Kingdom ; 093053/Z/10/Z/WT_/Wellcome Trust/United Kingdom ; 100326/Z/12/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {*Memory T Cells ; Cell Differentiation ; Leukocyte Common Antigens/metabolism ; *Lymphocyte Activation ; Telomere/genetics ; },
abstract = {The fundamental basis of T cell memory remains elusive. It is established that antigen stimulation drives clonal proliferation and differentiation, but the relationship between cellular phenotype, replicative history, and longevity, which is likely essential for durable memory, has proven difficult to elucidate. To address these issues, we used conventional markers of differentiation to identify and isolate various subsets of CD8[+] memory T cells and measured telomere lengths in these phenotypically defined populations using the most sensitive technique developed to date, namely single telomere length analysis (STELA). Naive cells were excluded on the basis of dual expression of CCR7 and CD45RA. Memory subsets were sorted as CD27[+]CD45RA[+], CD27[int]CD45RA[+], CD27[-]CD45RA[+], CD27[+]CD45RA[int], CD27[-]CD45RA[int], CD27[+]CD45RA[-], and CD27[-]CD45RA[-] at >98% purity. The shortest median telomere lengths were detected among subsets that lacked expression of CD45RA, and the longest median telomere lengths were detected among subsets that expressed CD45RA. Longer median telomere lengths were also a feature of subsets that expressed CD27 in compartments defined by the absence or presence of CD45RA. Collectively, these data suggested a disconnect between replicative history and CD8[+] memory T cell differentiation, which is classically thought to be a linear process that culminates with revertant expression of CD45RA.},
}
@article {pmid37780571,
year = {2023},
author = {Chi, Z and Bai, X and Zhang, Z},
title = {Risk relationship between leukocyte telomere length and constipation: a Mendelian randomization study.},
journal = {Frontiers in medicine},
volume = {10},
number = {},
pages = {1177785},
pmid = {37780571},
issn = {2296-858X},
abstract = {OBJECTIVE: Some epidemiological studies have investigated the associations between aging and constipation, yet their outcomes are inconclusive, so we strive to ascertain whether aging is the cause of constipation.<br><br>METHODS: We conducted a two-sample Mendelian randomization (MR) analysis using publicly accessible genome-wide association study (GWAS) summary statistics. As a marker of cellular and biological aging, we employed 15 single-nucleotide polymorphisms as instrumental variables for leukocyte telomere length (LTL) as exposure and a GWAS for constipation in the Finnish database as an outcome. To select the instrumental variables strongly associated with the phenotype, we eliminated confounding factors and direct effects outcomes to determine the causal relationship of exposure factors on the outcome; the analysis was mainly performed using the random-effect inverse variance weighting method, MR-Egger, weighted median, and sensitivity analysis of the results.<br><br>RESULTS: Random effect inverse variance weighted odds ratio = 1.035 (95% CI 0.907-1.180), but p = 0.612, which was not statistically significant. Other statistical methods, such as MR-Egger and weighted median, also yielded non-significant results.<br><br>CONCLUSION: LTL as a proxy for aging does not necessarily indicate an increased likelihood of constipation. Further research is needed to explore the specific mechanisms of constipation.},
}
@article {pmid37777139,
year = {2023},
author = {Ogletree, SS and Huang, JH and Reif, D and Yang, L and Dunstan, C and Osakwe, N and Oh, JI and Hipp, JA},
title = {The relationship between greenspace exposure and telomere length in the National Health and Nutrition Examination Survey.},
journal = {The Science of the total environment},
volume = {905},
number = {},
pages = {167452},
doi = {10.1016/j.scitotenv.2023.167452},
pmid = {37777139},
issn = {1879-1026},
mesh = {Humans ; Nutrition Surveys ; *Parks, Recreational ; *Environmental Exposure ; Risk Factors ; Telomere ; },
abstract = {The exposome, reflecting the range of environmental exposures individuals encounter throughout their life, can influence a variety of health outcomes and can play a role in how the environment impacts our genes. Telomeres, genetic structures regulating cell growth and senescence, are one pathway through which the exposome may impact health. Greenspace exposure, representing the amount of green areas in one's neighborhood, is one component of the exposome and has been associated with multiple health benefits. To investigate the potential link between greenspace exposure and telomere length, we analyzed data from the 1999-2001 National Health and Nutrition Examination Survey (NHANES) sample. Our study examined individual, risk, and contextual factors. We found that greater greenspace exposure in one's neighborhood was associated with longer telomere lengths when considering individual and risk factors, suggesting a positive effect of living in greener neighborhoods. However, this relationship became non-significant when contextual factors, such as air pollution and deprivation, were included in the analysis. These findings highlight a complex relationship between greenspace and telomere length, warranting further research to explore contextual factors in detail.},
}
@article {pmid37773482,
year = {2023},
author = {Hou, X and Li, R and Wang, J and Wei, D and Yang, X and Liao, W and Yuchi, Y and Liu, X and Huo, W and Mao, Z and Liu, J and Wang, C and Hou, J},
title = {Gender-specific associations between mixture of polycyclic aromatic hydrocarbons and telomere length.},
journal = {Environmental geochemistry and health},
volume = {45},
number = {12},
pages = {9583-9598},
pmid = {37773482},
issn = {1573-2983},
support = {21IRTSTHN029//Science and Technology Innovation Team Support Plan of Colleges and Universities in Henan Province/ ; 222102320029//the Science and Technique Foundation of Henan Province/ ; 2016YFC0900803//the Foundation of National Key Program of Research and Development of China/ ; 2019M662548, 2021M702934//China Postdoctoral Science Foundation/ ; 2020GWFJJ01//the open project of Key Laboratory of Environment and health, ministry of Education/ ; },
mesh = {Male ; Humans ; Female ; *Polycyclic Aromatic Hydrocarbons/analysis ; Cohort Studies ; Gas Chromatography-Mass Spectrometry ; *Environmental Pollutants/toxicity/analysis ; Telomere/chemistry ; },
abstract = {Evidence shows the relationships of individual environmental PAHs by their urinary metabolites with relative telomere length (RTL), which may be affected by biological gender differences. Since plasma parent PAHs are not metabolized, it may reflect human exposure to PAHs more realistically in daily life. Thus, exploring joint associations between plasma parent PAHs and RTL is urgent, which may identify the major contributor to its adverse effect. In this study, 2577 participants were obtained from the Henan Rural Cohort. The level of PAHs in blood samples was detected by gas chromatography coupled with tandem mass spectrometry. RTL in blood samples was detected by quantitative polymerase chain reaction. Generalized linear models or quantile g-computation were performed to evaluate the associations between the individual or a mixture of PAHs and RTL. Results from generalized linear models showed that each unit increment in BghiP value corresponded to a 0.098 (95%CI: 0.067, 0.129) increment in RTL for men; each unit increment in BaP, BghiP and Flu value corresponded to a 0.041 (95%CI: 0.014, 0.068), 0.081 (95%CI: 0.055, 0.107) and 0.016 (95%CI: 0.005, 0.027) increment in RTL for women. Results from quantile-g computation revealed that each one-quantile increment in the mixture of 10 PAHs corresponded to a 0.057 (95%CI: 0.021, 0.094) and 0.047 (95%CI: 0.003, 0.091) increment in RTL values of women and men, but these associations were mainly ascribed to three PAHs for women (BaP, Flu and BghiP) and men (BaP, BghiP and Pyr), respectively. Similar results were found in smoking men and cooking women without smoking. Our study found that exposure to 10 PAHs mixture was positively associated with RTL across gender, mainly attributed to Flu, BaP and BghiP, implicating that gender-specific associations may be ascribed to tobacco and cooking smoke pollution. The findings provided clues for effective measures to control PAHs pollutants-related aging disease.Clinical trial registration The Henan Rural Cohort Study has been registered at the Chinese Clinical Trial Register (Registration number: ChiCTR-OOC-15006699). Date of registration: 06 July 2015. http://www.chictr.org.cn/showproj.aspx?proj=11375 .},
}
@article {pmid37773274,
year = {2023},
author = {Dutta, S},
title = {Unveiling the telomere-p53-PGC ageing axis.},
journal = {Nature reviews. Endocrinology},
volume = {19},
number = {12},
pages = {686},
pmid = {37773274},
issn = {1759-5037},
}
@article {pmid37771090,
year = {2023},
author = {Estep, KN and Tobias, JW and Fernandez, RJ and Beveridge, BM and Johnson, FB},
title = {Telomeric DNA breaks in human induced pluripotent stem cells trigger ATR-mediated arrest and telomerase-independent telomere damage repair.},
journal = {Journal of molecular cell biology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jmcb/mjad058},
pmid = {37771090},
issn = {1759-4685},
abstract = {Although mechanisms of telomere protection are well-defined in differentiated cells, it is poorly understood how stem cells sense and respond to telomere dysfunction. In particular, the broader impact of telomeric double-strand breaks (DSBs) in these cells is poorly characterized. Here, we report on DNA damage signaling, cell cycle, and transcriptome-level changes in human induced pluripotent stem cells (iPSCs) in response to telomere-internal DSBs. We engineered human iPSCs with an inducible TRF1-FokI fusion protein to acutely induce DSBs at telomeres. Using this model, we demonstrate that TRF1-FokI DSBs activate an ATR-dependent DDR, which leads to p53-independent cell cycle arrest in G2. Using CRISPR-Cas9 to cripple the catalytic domain of telomerase, we show that telomerase is largely dispensable for survival and lengthening of TRF1-FokI-cleaved telomeres, which instead are effectively repaired by robust homologous recombination (HR). In contrast to HR-based telomere maintenance in mouse embryonic stem cells, we find neither evidence that HR causes extension of telomeres beyond their initial lengths, nor an apparent role for ZSCAN4 in this process. Rather, HR-based repair of telomeric breaks is sufficient to maintain iPSC telomeres at a normal length which is compatible with sustained survival of the cells over several days of TRF1-FokI induction. Our findings suggest a previously unappreciated role for HR in telomere maintenance in telomerase-positive iPSCs and reveal distinct iPSC-specific responses to targeted telomeric damage.},
}
@article {pmid37770147,
year = {2023},
author = {Sutterlüty, H and Bargl, M and Holzmann, K},
title = {Quantifying telomere transcripts as tool to improve risk assessment for genetic instability and genotoxicity.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {891},
number = {},
pages = {503690},
doi = {10.1016/j.mrgentox.2023.503690},
pmid = {37770147},
issn = {1879-3592},
mesh = {Reactive Oxygen Species ; *Telomere/genetics ; *RNA, Long Noncoding/genetics ; DNA ; DNA Damage ; Risk Assessment ; },
abstract = {Telomere repeat-containing RNAs (TERRA) are transcribed from telomeres as long non-coding RNAs and are part of the telomere structure with protective function. The genetic stability of cells requires telomeric repeats at the ends of chromosomes. Maintenance of telomere length (TL) is essential for proliferative capacity and chromosomal integrity. In contrast, telomere shortening is a recognized risk factor for carcinogenesis and a biomarker of aging due to the cumulative effects of environmental exposures and life experiences such as trauma or stress. In this context, telomere repeats are lost due to cell proliferation, but are also susceptible to stress factors including reactive oxygen species (ROS) inducing oxidative base damage. Quantitative PCR (qPCR) of genomic DNA is an established method to analyze TL as a tool to detect genotoxic events. That same qPCR method can be applied to RNA converted into cDNA to quantify TERRA as a useful tool to perform high-throughput screenings. This short review summarizes relevant qPCR studies using both TL and TERRA quantification, provides an overall view of the molecular mechanisms of telomere protection against ROS by TERRA, and summarizes the presented studies comparing the results at DNA and RNA levels, which indicate that fluctuations at transcript level might reflect a short-term response. Therefore, we conclude that performing both of these measurements together will improve genotoxicity studies.},
}
@article {pmid37768599,
year = {2023},
author = {Bosquet Enlow, M and De Vivo, I and Petty, CR and Cayon, N and Nelson, CA},
title = {Associations among temperament characteristics and telomere length and attrition rate in early childhood.},
journal = {Developmental psychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/dev0001635},
pmid = {37768599},
issn = {1939-0599},
support = {/NH/NIH HHS/United States ; },
abstract = {There is growing interest in telomere length as an indicator of current and future health. Although early childhood is a period of rapid telomere attrition, little is known about the factors that influence telomere biology during this time. Adult research suggests that telomere length is influenced by psychological characteristics. This study's goal was to test associations among repeated measures of temperament and telomere length in a community sample of children (N = 602; 52% male, 73% non-Hispanic White, middle-to-high socioeconomic status) from infancy to age 3 years. Relative telomere length was assessed from DNA in saliva samples collected at infancy (M = 8.4 months), 2 years (M = 24.9 months), and 3 years (M = 37.8 months). Temperament was assessed via maternal report questionnaires administered at infancy (Infant Behavior Report Questionnaire-Revised) and ages 2 and 3 years (Early Childhood Behavior Questionnaire). Temperament was operationalized in two ways: using the established domains of negative affectivity, surgency/extraversion, and regulation/effortful control and using person-centered scores that identified three groups of children with similar profiles across domains (emotionally and behaviorally regulated; emotionally and behaviorally dysregulated; introverted and overcontrolled). Analyses revealed that greater regulation/effortful control was associated with longer telomere length across time points. Additionally, higher surgency/extraversion, beginning in infancy, was associated with decreased rate of telomere attrition. There were no sex differences in the relations between temperament and telomere measures. These findings suggest that, as early as infancy, temperament may influence telomere biology, with a potential protective effect of positive temperament characteristics on telomere erosion. (PsycInfo Database Record (c) 2023 APA, all rights reserved).},
}
@article {pmid37767563,
year = {2023},
author = {Loe, TK and Lazzerini Denchi, E and Tricola, GM and Azeroglu, B},
title = {ALTercations at telomeres: stress, recombination and extrachromosomal affairs.},
journal = {Biochemical Society transactions},
volume = {51},
number = {5},
pages = {1935-1946},
doi = {10.1042/BST20230265},
pmid = {37767563},
issn = {1470-8752},
support = {ZIA BC011815/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Humans ; *Telomere Homeostasis ; *Telomere ; Recombination, Genetic ; },
abstract = {Approximately 15% of human cancers depend on the alternative lengthening of telomeres (ALT) pathway to maintain telomeres and proliferate. Telomeres that are elongated using ALT display unique features raising the exciting prospect of tailored cancer therapies. ALT-mediated telomere elongation shares several features with recombination-based DNA repair. Strikingly, cells that use the ALT pathway display abnormal levels of replication stress at telomeres and accumulate abundant extrachromosomal telomeric DNA. In this review, we examine recent findings that shed light on the ALT mechanisms and the strategies currently available to suppress this telomere elongation mechanism.},
}
@article {pmid37767490,
year = {2023},
author = {Sivasangari, K and Sivamaruthi, BS and Chaiyasut, C and Rajan, KE},
title = {Maternal stress-induced changes in adolescent and adult offspring: Neurobehavioural improvement and telomere maintenance.},
journal = {Heliyon},
volume = {9},
number = {10},
pages = {e20385},
pmid = {37767490},
issn = {2405-8440},
abstract = {Maternal stress (MS) during gestation is known to increase the risk for the development of behavioural and physiological disorders and advances cellular aging. In this study, we investigated whether the supplementation of standardized Bacopa monnieri extract (CDRI-08/BME) or l-Carnosine (L-C) to the mother exposed to social stress during gestation modify the effect on their offspring's neurobehaviour, antioxidant defence gene expression, telomere length, and telomere biology. To test this, timed pregnant rats were subjected to social stress during the gestational day (GD) 16-18. A subset of stressed pregnant rats received either BME [80 mg/kg in 0.5% gum acacia (per-orally; p.o)] or L-C [1 mg/kg (p.o)] every day from GD-10 to until their pup's attained postnatal day (PND)-23. We observed that MS induced anxiety-like behaviour, altered inter-limb coordination, antioxidant defence genes [Superoxide dismutase (SOD1,2), Catalase (CAT), Glutathione peroxidase-3 (GPX3)], telomerase reverse transcriptase (TERT), shelterin complex subunits (TRF1, RAP1B, POT1) protein level and shorten telomere length. Notably, supplementation of BME/L-C dampens the MS, thus the effect on neurobehaviour, antioxidant defence gene expression, and telomere biology is minimized in their offspring. Together, our results suggest that supplementation of BME/L-C during gestation dampens the MS and reduced oxidative stress-mediated changes in telomere shortening/biology and associated neurobehaviour in offspring born following MS.},
}
@article {pmid37762611,
year = {2023},
author = {Vukašinović, A and Klisic, A and Ostanek, B and Kafedžić, S and Zdravković, M and Ilić, I and Sopić, M and Hinić, S and Stefanović, M and Bogavac-Stanojević, N and Marc, J and Nešković, AN and Kotur-Stevuljević, J},
title = {Redox Status and Telomere-Telomerase System Biomarkers in Patients with Acute Myocardial Infarction Using a Principal Component Analysis: Is There a Link?.},
journal = {International journal of molecular sciences},
volume = {24},
number = {18},
pages = {},
pmid = {37762611},
issn = {1422-0067},
mesh = {Humans ; Antioxidants ; *Telomerase ; Biomarkers ; Serum Albumin ; Oxidation-Reduction ; *Myocardial Infarction ; },
abstract = {In the present study, we examined redox status parameters in arterial and venous blood samples, its potential to predict the prognosis of acute myocardial infarction (AMI) patients assessed through its impact on the comprehensive grading SYNTAX score, and its clinical accuracy. Potential connections between common blood biomarkers, biomarkers of redox status, leukocyte telomere length, and telomerase enzyme activity in the acute myocardial infarction burden were assessed using principal component analysis (PCA). This study included 92 patients with acute myocardial infarction. Significantly higher levels of advanced oxidation protein products (AOPP), superoxide anion (O2[•-]), ischemia-modified albumin (IMA), and significantly lower levels of total oxidant status (TOS) and total protein sulfhydryl (SH-) groups were found in arterial blood than in the peripheral venous blood samples, while biomarkers of the telomere-telomerase system did not show statistical significance in the two compared sample types (p = 0.834 and p = 0.419). To better understand the effect of the examined biomarkers in the AMI patients on SYNTAX score, those biomarkers were grouped using PCA, which merged them into the four the most contributing factors. The "cholesterol-protein factor" and "oxidative-telomere factor" were independent predictors of higher SYNTAX score (OR = 0.338, p = 0.008 and OR = 0.427, p = 0.035, respectively), while the ability to discriminate STEMI from non-STEMI patients had only the "oxidative-telomere factor" (AUC = 0.860, p = 0.008). The results show that traditional cardiovascular risk factors, i.e., high total cholesterol together with high total serum proteins and haemoglobin, are associated with severe disease progression in much the same way as a combination of redox biomarkers (pro-oxidant-antioxidant balance, total antioxidant status, IMA) and telomere length.},
}
@article {pmid37762576,
year = {2023},
author = {Han, X and Hirschel, A and Tsapekos, M and Perez, D and Vollmer, D},
title = {In Vitro Assessment of Gold Nanoparticles on Telomerase Activity and Telomere Length in Human Fibroblasts.},
journal = {International journal of molecular sciences},
volume = {24},
number = {18},
pages = {},
pmid = {37762576},
issn = {1422-0067},
support = {GF-AntiAging001//4Life Research/ ; },
mesh = {Infant, Newborn ; Humans ; Gold/pharmacology ; *Metal Nanoparticles ; *Telomerase/genetics ; Fibroblasts ; Telomere/genetics ; },
abstract = {Telomerase activity coincides with lengthening of the ends of chromosomes known as telomeres. Telomere length is used as a marker for cellular aging. Telomeres shorten over time as cells divide, and certain bioactive compounds such as gold nanoparticles (AuNPs) may slow the shortening of telomeres by increasing telomerase activity. The objective of the present study is to assess the effect of AuNPs on telomerase activity and telomere length in human fibroblasts. Telomerase activity was measured using enzyme-linked immunosorbent assay (ELISA) in primary human lung fibroblasts (IMR90) and using quantitative PCR-based telomeric repeat amplification protocol (Q-TRAP) in primary human dermal fibroblasts, neonatal (HDFn). Telomere length was determined by Telomere Analysis Technology (TAT[®])assay in HDFn. In IMR90, all AuNP treatments showed significant increases in telomerase activity when compared to earlier passages. HDFn treated with AuNPs at 0 ppm, 0.05 ppm, 0.5 ppm, or 5 ppm did not show significant differences in telomerase activity compared to the control group. Significant differences in telomere length in HDFn were observed at 2 weeks of 0.05 and 0.5 ppm AuNPs under oxidative culture conditions as compared to the control group. The study showed preliminary evidence that AuNPs may increase telomerase activity and decelerate the shortening of telomeres in human fibroblasts, suggesting its potential anti-aging effects, which warrants further investigation.},
}
@article {pmid37762556,
year = {2023},
author = {Hou, J and Yun, Y and Jeon, B and Baek, J and Kim, S},
title = {Ginsenoside F1-Mediated Telomere Preservation Delays Cellular Senescence.},
journal = {International journal of molecular sciences},
volume = {24},
number = {18},
pages = {},
pmid = {37762556},
issn = {1422-0067},
support = {2011-0031955//Intelligent Synthetic Biology Center of the Global Frontier Project, funded by the Ministry of Education, Science and Technology/ ; NRF-2021M3A9C4001028//Bio-Synergy Research Project of the Ministry of Sci-ence, ICT and Future Planning through the National Research Foundation/ ; P0014633//Advancement of Active Biomedical material Project, funded by the Ministry of Trade/ ; 321109041SB010//development of industrialization technology for crop virus and pest Project, funded by the Min-istry of Agriculture, Food and Rural Affairs/ ; 2021-153-0028-0019-002B//Multi-Department Research and Business Development Program, funded by Sejong city/ ; none//the KAIST Cross-Generation Collaborative Lab project/ ; P0021532//Center for mRNA/DNA Therapeutics Development and Production Project/ ; },
mesh = {Humans ; *Ginsenosides/pharmacology ; Cellular Senescence ; Preservation, Biological ; Syndrome ; },
abstract = {Telomeres play pivotal roles in processes closely related to somatic senescence and aging, making them a compelling target for interventions aimed at combating aging and age-related pathologies. Ginsenoside, a natural compound, has emerged as a potential remedy for promoting healthy aging, yet how it protects telomeres remains incompletely understood. Here, we show that treatment of F1 can effectively restore the level of TRF2, thereby preserving telomere integrity. This restoration leads to inhibition of the DNA damage response and improvements in mitochondrial function and, ultimately, delays in cellular senescence. Conversely, depletion of TRF2 causes mitochondrial dysfunction, accompanied by increased oxidative stress, autophagy inhibition, insufficient energy metabolism, and the onset of cellular senescence. These observations underscore the critical role of TRF2 in maintaining telomere integrity and direct association with the initiation of cellular senescence. We conduct a further analysis, suggesting F1 could bind in proximity to the TRF2 heterodimer interface, potentially enhancing dimerization stability. These findings suggest that F1 may be a promising natural remedy for anti-aging, and restoring TRF2 could potentially prevent telomere-dependent diseases commonly associated with the aging process.},
}
@article {pmid37759609,
year = {2023},
author = {Bukic, E and Milasin, J and Toljic, B and Jadzic, J and Jevtovic, D and Obradovic, B and Dragovic, G},
title = {Association between Combination Antiretroviral Therapy and Telomere Length in People Living with Human Immunodeficiency Virus.},
journal = {Biology},
volume = {12},
number = {9},
pages = {},
pmid = {37759609},
issn = {2079-7737},
abstract = {Long-term exposure to combination antiretroviral therapy (cART) may be associated with accelerated ageing. Telomere length is considered to be reliable aging biomarker. The aim of this study was to compare patients' relative telomere length (RTL) between and within different cART classes and to estimate the impact of certain HIV-related variables on RTL. The study was conducted in 176 HIV-infected male patients receiving cART, with ≤50 copies HIV RNA/mL plasma. RTL was determined from mononuclear cells by quantitative polymerase chain reaction. Standard statistical tests and unsupervised machine learning were performed. The mean RTL was 2.50 ± 1.87. There was no difference (p = 0.761) in RTL between therapeutic groups: two nucleoside reverse transcriptase inhibitors as the backbone treatment, combined with either integrase inhibitor, protease inhibitor, or non-nucleoside reverse transcriptase inhibitor (NNRTI). Machine learning results suggested duration of HIV infection, CD4+ T-cell count, and cART, including NNRTI, as potentially significant variables impacting RTL. Kendall's correlation test excluded duration of HIV infection (p = 0.220) and CD4+ T-cell count (p = 0.536) as significant. The Mann-Whitney test confirmed that cART containing NNRTI impacted RTL (p = 0.018). This was the first study to show that patients using efavirenz within cART had significantly shorter telomeres than patients using nevirapine.},
}
@article {pmid37757453,
year = {2023},
author = {},
title = {Correction to: Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells.},
journal = {Neuro-oncology},
volume = {25},
number = {11},
pages = {2105},
doi = {10.1093/neuonc/noad180},
pmid = {37757453},
issn = {1523-5866},
support = {K22 CA258965/CA/NCI NIH HHS/United States ; 1K22CA258965-01A1/NH/NIH HHS/United States ; },
}
@article {pmid37756323,
year = {2023},
author = {Liu, J and Zheng, T and Chen, D and Huang, J and Zhao, Y and Ma, W and Liu, H},
title = {RBMX involves in telomere stability maintenance by regulating TERRA expression.},
journal = {PLoS genetics},
volume = {19},
number = {9},
pages = {e1010937},
pmid = {37756323},
issn = {1553-7404},
mesh = {*Exosomes/genetics ; Heterochromatin ; Nuclear Proteins ; *RNA, Long Noncoding/genetics ; Telomere/genetics ; Humans ; },
abstract = {Telomeric repeat-containing RNA (TERRA) is a class of long noncoding RNAs (lncRNAs) that are transcribed from subtelomeric to telomeric region of chromosome ends. TERRA is prone to form R-loop structures at telomeres by invading into telomeric DNA. Excessive telomere R-loops result in telomere instability, so the TERRA level needs to be delicately modulated. However, the molecular mechanisms and factors controlling TERRA level are still largely unknown. In this study, we report that the RNA binding protein RBMX is a novel regulator of TERRA level and telomere integrity. The expression level of TERRA is significantly elevated in RBMX depleted cells, leading to enhanced telomere R-loop formation, replication stress, and telomere instability. We also found that RBMX binds to TERRA and the nuclear exosome targeting protein ZCCHC8 simultaneously, and that TERRA degradation slows down upon RBMX depletion, implying that RBMX promotes TERRA degradation by regulating its transportation to the nuclear exosome, which decays nuclear RNAs. Altogether, these findings uncover a new role of RBMX in TERRA expression regulation and telomere integrity maintenance, and raising RBMX as a potential target of cancer therapy.},
}
@article {pmid37754816,
year = {2023},
author = {Borghini, A and Mercuri, A and Campolo, J and Parolini, M and Ndreu, R and Turchi, S and Andreassi, MG},
title = {Influence of Chromosome 9p21.3 rs1333049 Variant on Telomere Length and Their Interactive Impact on the Prognosis of Coronary Artery Disease.},
journal = {Journal of cardiovascular development and disease},
volume = {10},
number = {9},
pages = {},
pmid = {37754816},
issn = {2308-3425},
abstract = {BACKGROUND: Both telomere shortening and the chromosome 9p21.3 (Chr9p21) rs1333049 (G/C) variant are involved in coronary artery disease (CAD) risk, likely affecting mechanisms related to cell cycle arrest and vascular senescence. The aim of the study was to examine the link between Chr9p21 rs1333049 variant and leucocyte telomere length (LTL), as well as their interactive effect on the risk of major adverse cardiovascular events (MACEs).<br><br>METHODS: A cohort of 472 patients with angiographically proven and clinically stable CAD were included in the study. At baseline, the LTL, biochemical parameters, and genotype analysis of Chr9p21 rs1333049 variant were measured in all patients. The primary endpoint of this study was the occurrence of MACE defined as a composite of coronary-related death, nonfatal MI, and coronary revascularization.<br><br>RESULTS: On multivariable linear regression analysis, age (p = 0.02) and Chr9p21 rs1333049 variant (p = 0.002) were the only independent predictors of LTL levels. Carriers of the CC genotype of this SNP had shorter telomeres than GC carriers (p = 0.02) and GG carriers (p = 0.0005). After a follow-up with a mean period of 62 &#xb1; 19 months, 90 patients (19.1%) had MACE. Short LTL was an independent prognostic factor of MACE incidence (HR:2.2; 95% CI: 1.3-3.7; p = 0.005) after adjustment for potential confounders. There was a significant interaction (p = 0.01) between the LTL and rs1333049 variant, with patients with risk-allele C and short LTL having a higher risk (HR:5.8; 95% CI: 1.8-19.2; p = 0.004).<br><br>CONCLUSION: A strong relationship between LTL and Chr9p21 rs1333049 variant was identified, and they interactively affect the risk of poor prognosis in CAD patients.},
}
@article {pmid37754262,
year = {2023},
author = {Torres-Montaner, A},
title = {Interactions between the DNA Damage Response and the Telomere Complex in Carcinogenesis: A Hypothesis.},
journal = {Current issues in molecular biology},
volume = {45},
number = {9},
pages = {7582-7616},
pmid = {37754262},
issn = {1467-3045},
abstract = {Contrary to what was once thought, direct cancer originating from normal stem cells seems to be extremely rare. This is consistent with a preneoplastic period of telomere length reduction/damage in committed cells that becomes stabilized in transformation. Multiple observations suggest that telomere damage is an obligatory step preceding its stabilization. During tissue turnover, the telomeres of cells undergoing differentiation can be damaged as a consequence of defective DNA repair caused by endogenous or exogenous agents. This may result in the emergence of new mechanism of telomere maintenance which is the final outcome of DNA damage and the initial signal that triggers malignant transformation. Instead, transformation of stem cells is directly induced by primary derangement of telomere maintenance mechanisms. The newly modified telomere complex may promote survival of cancer stem cells, independently of telomere maintenance. An inherent resistance of stem cells to transformation may be linked to specific, robust mechanisms that help maintain telomere integrity.},
}
@article {pmid37753451,
year = {2023},
author = {Romero-Haro, AA and Figuerola, J and Alonso-Alvarez, C},
title = {Low Antioxidant Glutathione Levels Lead to Longer Telomeres: A Sex-Specific Link to Longevity?.},
journal = {Integrative organismal biology (Oxford, England)},
volume = {5},
number = {1},
pages = {obad034},
pmid = {37753451},
issn = {2517-4843},
abstract = {Telomeres are repetitive DNA sequences at the end of chromosomes that protect them from degradation. They have been the focus of intense research because short telomeres would predict accelerated ageing and reduced longevity in vertebrates. Oxidative stress is considered a physiological driver of the telomere shortening and, consequently, short lifespan. Among molecules fighting against oxidative stress, glutathione is involved in many antioxidant pathways. Literature supports that oxidative stress may trigger a compensatory "hormetic" response increasing glutathione levels and telomere length. Here, we tested the link between total glutathione concentration and telomere length in captive birds (zebra finches; Taeniopygia guttata). Total glutathione levels were experimentally decreased during birds' growth using a specific inhibitor of glutathione synthesis (buthionine sulfoximine; BSO). We monitored the birds' reproductive performance in an outdoor aviary during the first month of life, and their longevity for almost 9 years. Among control individuals, erythrocyte glutathione levels during development positively predicted erythrocyte telomere length in adulthood. However, BSO-treated females, but not males, showed longer telomeres than control females in adulthood. This counterintuitive finding suggests that females mounted a compensatory response. Such compensation agrees with precedent findings in the same population where the BSO treatment increased growth and adult body mass in females but not males. BSO did not influence longevity or reproductive output in any sex. However, early glutathione levels and adult telomere length interactively predicted longevity only among control females. Those females with "naturally" low (non-manipulated) glutathione levels at the nestling age but capable of producing longer telomeres in adulthood seem to live longer. The results suggest that the capability to mount a hormetic response triggered by low early glutathione levels can improve fitness via telomere length. Overall, the results may indicate a sex-specific link between glutathione and telomere values. Telomerase activity and sexual steroids (estrogens) are good candidates to explain the sex-biased mechanism underlying the early-life impact of oxidative stress on adult telomere length.},
}
@article {pmid37752708,
year = {2023},
author = {Shin, YA and Kim, JH},
title = {Effects of Cardiorespiratory Fitness on Cardiovascular Disease Risk Factors and Telomere Length by Age and Obesity.},
journal = {Journal of obesity &amp; metabolic syndrome},
volume = {32},
number = {3},
pages = {259-268},
pmid = {37752708},
issn = {2508-7576},
abstract = {BACKGROUND: This study investigates differences in telomere length according to obesity, cardiovascular disease (CVD) risk factors, and fitness level in South Korean males.<br><br>METHODS: The subjects of this study were males in their 10s to 50s (n=249). We measured obesity indices, CVD risk factors, leukocyte telomere length (LTL), and cardiorespiratory fitness (CRF). Correlation and regression analyses were performed to analyze the data.<br><br>RESULTS: Measurement of participants' obesity indices, CVD risk factors, and maximum oxygen intake and analyzing their correlations with LTL revealed that LTL and CRF decreased with age and the levels and numbers of obesity indices and CVD risk factors increased. The LTL showed differences according to whether subjects exhibited obesity or dyslipidemia and by CRF level. When all the variables that influence the LTL were adjusted, the LTL became shorter as the age and low-density lipoprotein cholesterol (LDL-C) level increased, and it became longer as the maximum rate of oxygen utilization (VO2max) increased. When the age and CVD risk factors that influence the LTL were adjusted according to obesity and CRF for the obese group, the LTL became shorter as the age and LDL-C level increased (P<0.01), and it became longer as VO2max increased (P<0.01).<br><br>CONCLUSION: We found that obesity influenced the LTL by increasing the levels of CVD risk factors and decreasing CRF, whereas maintaining high CRF could alleviate the effects of obesity and CVD risk factors according to age while maintaining and influencing the elongation of LTL.},
}
@article {pmid37752451,
year = {2023},
author = {Belyayev, A and Kalendar, R and Josefiová, J and Paštová, L and Habibi, F and Mahelka, V and Mandák, B and Krak, K},
title = {Telomere sequence variability in genotypes from natural plant populations: unusual block-organized double-monomer terminal telomeric arrays.},
journal = {BMC genomics},
volume = {24},
number = {1},
pages = {572},
pmid = {37752451},
issn = {1471-2164},
support = {20-20286S//Grantov&#xe1; Agentura &#x10c;esk&#xe9; Republiky/ ; },
mesh = {Humans ; *Arabidopsis/genetics ; In Situ Hybridization, Fluorescence ; Telomere/genetics ; Genotype ; Eukaryota ; },
abstract = {BACKGROUND: Telomeres are the nucleoprotein complexes that physically cap the ends of eukaryotic chromosomes. Most plants possess Arabidopsis-type telomere sequences (TSs). In addition to terminal TSs, more diverse interstitial TSs exists in plants. Although telomeres have been sufficiently studied, the actual diversity of TSs in land plants is underestimated.<br><br>RESULTS: We investigate genotypes from seven natural populations with contrasting environments of four Chenopodium species to reveal the variability in TSs by analyzing Oxford Nanopore reads. Fluorescent in situ hybridization was used to localize telomeric repeats on chromosomes. We identified a number of derivative monomers that arise in part of both terminal and interstitial telomeric arrays of a single genotype. The former presents a case of block-organized double-monomer telomers, where blocks of Arabidopsis-type TTTAGGG motifs were interspersed with blocks of derivative TTTAAAA motifs. The latter is an integral part of the satellitome with transformations specific to the inactive genome fraction.<br><br>CONCLUSIONS: We suggested two alternative models for the possible formation of derivative monomers from telomeric heptamer motifs of Arabidopsis-type. It was assumed that derivatization of TSs is a ubiquitous process in the plant genome but occurrence and frequencies of derivatives may be genotype-specific. We also propose that the formation of non-canonical arrays of TSs, especially at chromosomal termini, may be a source for genomic variability in nature.},
}
@article {pmid37751005,
year = {2023},
author = {Li, X and Duan, X and Wang, M and Wang, W},
title = {MEG3 polymorphisms associated with leukocyte telomere length in workers exposed to polycyclic aromatic hydrocarbons.},
journal = {Environmental science and pollution research international},
volume = {30},
number = {50},
pages = {108596-108605},
pmid = {37751005},
issn = {1614-7499},
mesh = {Humans ; *Polycyclic Aromatic Hydrocarbons/analysis ; *Occupational Exposure/analysis ; Telomere ; Leukocytes ; Polymorphism, Single Nucleotide ; *Coke/analysis ; },
abstract = {Long non-coding RNA maternally expressed gene 3 (MEG3) has been revealed to be involved in telomere length (TL) maintenance and homeostasis. However, it is unknown whether single-nucleotide polymorphisms (SNPs) in MEG3 could regulate TL in populations exposed to polycyclic aromatic hydrocarbons (PAHs). This study aimed to explore the effect of MEG3 genetic polymorphisms on TL in PAH-exposed populations. This study recruited 544 coke oven workers and 238 controls using random cluster sampling. The concentrations of four urinary OH-PAHs were measured by employing high-performance liquid chromatography. TL was measured by a quantitative polymerase chain reaction assay. The MEG3 genetic polymorphisms were detected using a Sequenom MassARRAY matrix-assisted laser desorption/ionization-time of flight mass spectrometry platform. The concentrations of four urinary OH-PAHs in the exposure group were significantly higher than those in the control group (P < 0.001). TL in the exposure group (4.57 ± 0.84) was significantly lower than in the control (5.00 ± 0.75), and TL had a negative correlation with OH-PAHs. The generalized linear model found that PAH exposure [β(95% CI) = -0.409(-0.537, -0.282), P < 0.001] and the CT+TT genotype in MEG3 rs10132552 [β(95% CI) = -0.299(-0.582, -0.017), P = 0.038] were associated with the decreased TL. In conclusion, PAH exposure and the CT+TT genotype in MEG3 rs10132552 may be the risk factors for TL reduction.},
}
@article {pmid37747680,
year = {2024},
author = {Kertes, DA and Clendinen, C and Duan, K and Rabinowitz, JA and Browning, C and Kvam, P},
title = {The Social Environment Matters for Telomere Length and Internalizing Problems During Adolescence.},
journal = {Journal of youth and adolescence},
volume = {53},
number = {1},
pages = {21-35},
pmid = {37747680},
issn = {1573-6601},
support = {R01 DA032371/DA/NIDA NIH HHS/United States ; R01DA032371/DA/NIDA NIH HHS/United States ; },
mesh = {Humans ; Adolescent ; Female ; *Depression/psychology ; *Emotions ; Anxiety/psychology ; Social Environment ; Telomere ; },
abstract = {Depression and anxiety symptoms are on the rise among adolescents. With increasing evidence that cellular aging may be associated with depressive and anxiety symptoms, there is an urgent need to identify the social environment context that may moderate this link. This study addresses this research gap by investigating the moderating role of the social environment on the relation between telomere length and emotional health among adolescents. Participants were 411 non-Hispanic (88.56%) Black (100%) adolescents (M = 14.23 years, SD = 1.85, female = 54%) in a major metropolitan city. Youth and parents reported on an array of social risk and protective factors, and youth provided DNA samples for telomere length measurement. Results demonstrated that the association of telomere length and anxiety symptoms was stronger among youth with higher perceived stress or lower school belongingness, and the association of telomere length with depressive symptoms was stronger under conditions of higher parent inter-partner psychological aggression. The results enhance our understanding of the complex associations between biological aging, the social environment, and mental health in adolescence.},
}
@article {pmid37745694,
year = {2023},
author = {Nonaka, K and Takubo, K and Aida, J and Watai, Y and Komatsu, A and Gomi, F and Shichi, Y and Yamazaki, Y and Ishiwata, T and Sasano, H and Arai, T},
title = {Accelerated telomere shortening in adrenal zona reticularis in patients with prolonged critical illness.},
journal = {Frontiers in endocrinology},
volume = {14},
number = {},
pages = {1244553},
pmid = {37745694},
issn = {1664-2392},
mesh = {Male ; Humans ; Female ; Aged, 80 and over ; Aged ; *Zona Reticularis ; *Critical Illness ; In Situ Hybridization, Fluorescence ; Telomere Shortening ; Cholesterol Esters ; },
abstract = {BACKGROUND: The number of patients with prolonged critical illness (PCI) has been increasing in many countries, and the adrenal gland plays an important role in maintaining homeostasis during PCI. Chronic disease burden is reportedly associated with shorter telomere lengths in human tissues. Telomere shortening in human somatic cells is largely dependent on cell divisions, and critically short telomeres lead to cellular dysfunction and aging. However, the association between PCI and telomere lengths in human adrenal cells is poorly understood. In this study, we investigated this association to assess whether the burden of PCI could accelerate the aging process in adrenal cells.<br><br>METHODS: Adrenocortical tissues from patients who died after PCI usually show a diffuse pattern of intracellular cholesterol ester depletion (i.e., lipid depletion). This study examined near-normal adrenal glands obtained from autopsied patients who died suddenly (control group) and lipid-depleted adrenal glands obtained from autopsied patients who died after PCI (PCI group). The control group included 7 men aged 80 to 94 years (mean age: 85.3 years) and 7 women aged 84 to 94 years (mean age: 87.7 years). The PCI group included 10 men aged 71 to 88 years (mean age: 78.8 years) and 8 women aged 77 to 95 years (mean age: 85.6 years). By using quantitative fluorescence in situ hybridization, relative telomere lengths (RTLs) were determined in the parenchymal cells of the three adrenocortical zones (zona glomerulosa, zona fasciculata, and zona reticularis [ZR]) and in the chromaffin cells of the medulla. The number of adrenal parenchymal cells was determined by immunohistochemistry and digital image analysis.<br><br>RESULTS: RTLs in ZR cells were significantly shorter in the PCI group than in the control group for both men and women (P = 0.0001 for men and P = 0.0012 for women). However, RTLs in the remaining three types of adrenal cells did not differ between the control and PCI groups for both men and women. The number of ZR cells was higher in the PCI group than in the control group for both men and women (P < 0.0001 for both men and women). The proportion of the number of ZR cells to the total number of adrenocortical parenchymal cells was also higher in the PCI group than in the control group (P < 0.0001 for both men and women). The Ki-67 proliferation index in ZR cells was higher in the PCI group than in the control group (P = 0.0039 for men and P = 0.0063 for women).<br><br>CONCLUSIONS: This study demonstrated ZR cell-specific telomere shortening in patients with adrenal lipid depletion who died after PCI. Our results suggest that the reactive proliferation of ZR cells accelerates the telomere shortening and aging process in ZR cells in these patients. The results of our study may contribute to the understanding of adrenal aging during PCI.},
}
@article {pmid37744360,
year = {2023},
author = {Guo, Y and Zhao, H and Wang, F and Xu, H and Liu, X and Hu, T and Wu, D},
title = {Telomere length as a marker of changes in body composition and fractures-an analysis of data from the NHANES 2001-2002.},
journal = {Frontiers in immunology},
volume = {14},
number = {},
pages = {1181544},
pmid = {37744360},
issn = {1664-3224},
mesh = {Humans ; Nutrition Surveys ; *Fractures, Bone/epidemiology ; Bone Density ; Body Composition ; Telomere ; },
abstract = {PURPOSE: There has been an association between changes in body composition, fracture incidence, and age in previous studies. Telomere length (TL) has been proposed as a biomarker of aging. However, the relationship between body composition, fractures, and TL has rarely been studied. Therefore, this study aimed to investigate the correlation between TL and body composition and fractures.Patients and methods: 20950 participants from the 2001-2002 National Health and Nutrition Examination Survey (NHANES) were included in the final analysis. In NHANES, body compositions were measured with DXA, and TL was determined with quantitative PCR. Correlation analysis of TL and body composition was conducted using multivariate weighted linear regression and logistic regression models.<br><br>RESULTS: The results showed that TL positively correlated with bone mineral density (BMD) and bone mineral content (BMC) in most body parts. However, BMD and BMC were negatively connected with TL in the upper limbs and skull. Fat content was negatively associated with TL, while muscle content was positively linked to TL. In addition, TL's trend analysis results were consistent with the regression model when transformed from a continuous to a classified variable. An increase in TL was associated with a higher incidence of wrist fractures, while a decrease in spine fractures. The above correlation also has a certain degree of sex specificity.<br><br>CONCLUSION: Our study indicate that TL is associated with body composition as well as fractures, but further research is needed to confirm these contrasting associations in the skull, upper limbs, and wrists.},
}
@article {pmid37741970,
year = {2023},
author = {Moreno, E and Martínez-Sanz, J and Martín-Mateos, R and Díaz-Álvarez, J and Serrano-Villar, S and Burgos-Santamaría, D and Luna, L and Vivancos, MJ and Moreno-Zamora, A and Pérez-Elías, MJ and Moreno, S and Dronda, F and Montes, ML and Sánchez-Conde, M},
title = {Global DNA methylation and telomere length as markers of accelerated aging in people living with HIV and non-alcoholic fatty liver disease.},
journal = {BMC genomics},
volume = {24},
number = {1},
pages = {567},
pmid = {37741970},
issn = {1471-2164},
mesh = {Humans ; DNA Methylation ; *Non-alcoholic Fatty Liver Disease/genetics ; *HIV Infections/complications/genetics ; Leukocytes, Mononuclear ; Prospective Studies ; Aging/genetics ; *Aging, Premature ; Telomere/genetics ; },
abstract = {Metabolic-dysfunction-associated fatty liver disease (MAFLD) is a comorbidity that generally increases in people living with HIV (PLWH). This condition is usually accompanied by persistent inflammation and premature immune system aging. In this prospective cohort study, we describe a straightforward methodology for quantifying biomarkers of aging, such as DNA methylation and telomere length, in PLWH and in the context of another relevant condition, such as MAFLD. Fifty-seven samples in total, thirty-eight from PLWH and nineteen from non-PLWH participants with or without MAFLD, were obtained and subjected to DNA extraction from peripheral blood mononuclear cells (PBMCs). Global DNA methylation and telomere length quantification were performed using an adapted enzyme-linked immunosorbent assay (ELISA) and qPCR, respectively. The quantification results were analysed and corrected by clinically relevant variables in this context, such as age, sex, and metabolic syndrome. Our results show an increased association of these biomarkers in PLWH regardless of their MAFLD status. Thus, we propose including the quantification of these age-related factors in studies of comorbidities. This will allow a better understanding of the effect of comorbidities of HIV infection and MAFLD and prevent their effects in these populations in the future.},
}
@article {pmid37737586,
year = {2023},
author = {Wood, ML and Neumann, R and Roy, P and Nair, V and Royle, NJ},
title = {Characterization of integrated Marek's disease virus genomes supports a model of integration by homology-directed recombination and telomere-loop-driven excision.},
journal = {Journal of virology},
volume = {97},
number = {10},
pages = {e0071623},
pmid = {37737586},
issn = {1098-5514},
support = {MIBTP 1645656//BBSRC-MIBTP/ ; },
mesh = {Animals ; *Chickens/virology ; *Genome, Viral/genetics ; *Herpesvirus 2, Gallid/genetics ; *Homologous Recombination ; *Marek Disease/genetics/virology ; Poultry Diseases/genetics/virology ; *Telomere/genetics ; Viral Vaccines/immunology ; Virus Activation ; Virus Latency ; *Virus Integration/genetics ; },
abstract = {Marek's disease virus (MDV) is a ubiquitous chicken pathogen that inflicts a large economic burden on the poultry industry, despite worldwide vaccination programs. MDV is only partially controlled by available vaccines, and the virus retains the ability to replicate and spread between vaccinated birds. Following an initial infection, MDV enters a latent state and integrates into host telomeres and this may be a prerequisite for malignant transformation, which is usually fatal. To understand the mechanism that underlies the dynamic relationship between integrated-latent and reactivated MDV, we have characterized integrated MDV (iMDV) genomes and their associated telomeres. This revealed a single orientation among iMDV genomes and the loss of some terminal sequences that is consistent with integration by homology-directed recombination and excision via a telomere-loop-mediated process.},
}
@article {pmid37737335,
year = {2023},
author = {Dratwa, M and Łacina, P and Butrym, A and Porzuczek, D and Mazur, G and Bogunia-Kubik, K},
title = {Telomere length and hTERT genetic variants as potential prognostic markers in multiple myeloma.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {15792},
pmid = {37737335},
issn = {2045-2322},
mesh = {Humans ; *Multiple Myeloma/genetics ; Prognosis ; Plasma Cells ; Alleles ; Telomere/genetics ; },
abstract = {Telomere dysfunction is a notable event observed in many cancers contributing to their genomic instability. A major factor controlling telomere stability is the human telomerase reverse transcriptase catalytic subunit (hTERT). Telomere shortening has been observed in multiple myeloma (MM), a plasma cell malignancy with a complex and heterogeneous genetic background. In the present study, we aimed to analyse telomere length and hTERT genetic variants as potential markers of risk and survival in 251 MM patients. We found that telomere length was significantly shorter in MM patients than in healthy individuals, and patients with more advanced disease (stage III according to the International Staging System) had shorter telomeres than patients with less advanced disease. MM patients with hTERT allele rs2736100 T were characterized with significantly shorter progression-free survival (PFS). Moreover, allele rs2736100 T was also found to be less common in patients with disease progression in response to treatment. hTERT rs2853690 T was associated with higher haemoglobin blood levels and lower C-reactive protein. In conclusion, our results suggest that telomere length and hTERT genetic variability may affect MM development and can be potential prognostic markers in this disease.},
}
@article {pmid37735501,
year = {2023},
author = {Ochi, S and Roy, B and Prall, K and Shelton, RC and Dwivedi, Y},
title = {Strong associations of telomere length and mitochondrial copy number with suicidality and abuse history in adolescent depressed individuals.},
journal = {Molecular psychiatry},
volume = {28},
number = {9},
pages = {3920-3929},
pmid = {37735501},
issn = {1476-5578},
support = {R01 MH107183/MH/NIMH NIH HHS/United States ; R01 MH124248/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Humans ; Adolescent ; Child ; Suicidal Ideation ; *Depressive Disorder, Major/genetics ; DNA Copy Number Variations/genetics ; *Suicide ; DNA, Mitochondrial/genetics ; Telomere/genetics ; },
abstract = {Major depressive disorder (MDD) is highly prevalent in adolescents and is a major risk factor for suicidality. Recent evidence shows that accelerated cellular senescence/aging is associated with psychiatric illness, including depression, in adults. The present study examined if the relationships of telomere length (TL) and mitochondrial DNA copy number (mtDNAcn), two critical indicators of cellular senescence/aging, are altered in depressed adolescents and whether these alterations are associated with suicidality, early-life adversities, and other co-occuring factors. In genomic DNA isolated from 53 adolescents (ages 16-19, 19 MDD with suicide attempt/suicidal ideation [MDD + SI/SA], 14 MDD without SA/SI [MDD-SI/SA], and 20 healthy controls [HC]), TL and mtDNAcn were measured as the ratio between the number of telomere repeats and that of a single-copy nuclear-hemoglobin [HBG] gene or the amount of mtDNA (NADH dehydrogenase, subunit 1) relative to HBG. Our data show that TL was significantly lower, and mtDNAcn was significantly higher in the total MDD group than HC. TL was significantly lower and mtDNAcn was significantly higher in the MDD + SA/SI group than in the HC, whereas there were no differences in the MDD-SI/SA group. TL was positively correlated with mtDNAcn in both HC and MDD-SA/SI groups; however, TL was negatively correlated with mtDNAcn in MDD + SA/SI. Furthermore, TL was negatively correlated with the severity of both depression and anxiety, while mtDNAcn was positively correlated with the severity of prior emotional abuse. Our study indicates that cellular senescence is more advanced in depressed adolescents with suicidal ideation and that childhood emotional abuse may participate in such a process.},
}
@article {pmid37734859,
year = {2023},
author = {Lima, SM and Ren, X and Mu, L and Ochs-Balcom, HM and Palermo, T},
title = {Food Insecurity, telomere length and the potential modifying effects of social support in National Health and Nutrition Examination Survey.},
journal = {Public health nutrition},
volume = {26},
number = {12},
pages = {3005-3012},
pmid = {37734859},
issn = {1475-2727},
mesh = {Adult ; Humans ; Middle Aged ; Aged ; Nutrition Surveys ; Cross-Sectional Studies ; *Food Supply ; *Food Insecurity ; Social Support ; Telomere ; },
abstract = {OBJECTIVE: Telomere length (TL) is a posited pathway through which chronic stress results in biological dysregulation and subsequent adverse health outcomes. Food insecurity is associated with shorter TL. Social support, which is defined by the size and function of an individual's social network, is associated with better health outcomes. The present study assesses whether social support modifies the relationship between food security and TL.<br><br>DESIGN: Cross-sectional study design. Linear regression was used to assess the association between food insecurity and TL, stratified by social support level. A multiplicative interacted model was used to formally test modification.<br><br>SETTING: Data come from the National Health and Nutrition Examination Survey 1999-2000 and 2001-2002 waves.<br><br>PARTICIPANTS: Adults aged 60 years and older who have measurements for TL.<br><br>RESULTS: Our sample comprised 2674 participants, and 63&#xb7;5 % of the total sample had low social support, with 13&#xb7;3 % being food insecure. In fully adjusted models, food insecurity was negatively though modestly associated (P = 0&#xb7;13) with TL. Associations between food insecurity and TL were significantly modified by social support (interaction P = 0&#xb7;026), whereby food insecurity had a stronger effect among individuals with high social support (coefficient = -0&#xb7;099 (95 % CI: -0&#xb7;161, -0&#xb7;038)) compared to low social support (coefficient = -0&#xb7;001, (95 % CI: -0&#xb7;033, 0&#xb7;032)).<br><br>CONCLUSION: Food insecurity is modestly associated with shorter TL. Contrary to our hypothesis, food insecurity had more deleterious effects on TL among participants with high social support than low social support. Results may indicate that the food insecure population is a higher needs population, and increased social support reflects these needs rather than providing protective effects.},
}
@article {pmid37732945,
year = {2023},
author = {Gellert-Kristensen, H and Bojesen, SE and Tybjærg Hansen, A and Stender, S},
title = {Telomere length and risk of cirrhosis, hepatocellular carcinoma, and cholangiocarcinoma in 63,272 individuals from the general population.},
journal = {Hepatology (Baltimore, Md.)},
volume = {},
number = {},
pages = {},
pmid = {37732945},
issn = {1527-3350},
abstract = {BACKGROUND AND AIMS: Inherited short telomeres are associated with a risk of liver disease, whereas longer telomeres predispose to cancer. The association between telomere length and risk of HCC and cholangiocarcinoma remains unknown.<br><br>APPROACH AND RESULTS: We measured leukocyte telomere length using multiplex PCR in 63,272 individuals from the Danish general population. Telomere length and plasma ALT concentration were not associated (&#x3b2; = 4 &#xd7;10 -6 , p -value = 0.06) in a linear regression model, without any signs of a nonlinear relationship. We tested the association between telomere length and risk of cirrhosis, HCC, and cholangiocarcinoma using Cox regression. During a median follow-up of 11 years, 241, 76, and 112 individuals developed cirrhosis, HCC, and cholangiocarcinoma, respectively. Telomere length and risk of cirrhosis were inversely and linearly associated (p -value = 0.004, p for nonlinearity = 0.27). Individuals with telomeres in the shortest vs. longest quartile had a 2.25-fold higher risk of cirrhosis. Telomere length and risk of HCC were nonlinearly associated (p -value = 0.009, p -value for nonlinearity = 0.01). This relationship resembled an inverted J-shape, with the highest risk observed in individuals with short telomeres. Individuals with telomeres in the shortest versus longest quartile had a 2.29-fold higher risk of HCC. Telomere length was inversely and linearly associated with the risk of cholangiocarcinoma. Individuals with telomeres in the shortest versus longest quartile had a 1.86-fold higher risk of cholangiocarcinoma.<br><br>CONCLUSIONS: Shorter telomere length is associated with a higher risk of cirrhosis, HCC, and cholangiocarcinoma.},
}
@article {pmid37732532,
year = {2023},
author = {Hao, Y and Lv, M and Peng, J and Kuang, D and Zhang, Z and Zhang, Z and Wang, T and Yang, B and Wei, Z and Zhou, P and Zhang, Z and Cao, Y},
title = {Alteration of relative telomere length and telomerase reverse transcriptase expression in the granulosa cells of women during aging and assessment of in vitro fertilization outcomes.},
journal = {Molecular medicine reports},
volume = {28},
number = {5},
pages = {},
pmid = {37732532},
issn = {1791-3004},
mesh = {Adult ; Aged ; Female ; Humans ; Male ; Pregnancy ; Aging/genetics ; Aneuploidy ; Fertilization in Vitro ; Granulosa Cells ; Retrospective Studies ; Semen ; *Telomerase/genetics ; },
abstract = {Telomere attrition plays a critical role in the reproductive aging process in humans. Telomere length (TL) is typically regulated by telomerase, the main component of which is telomerase reverse transcriptase (TERT). The aim of the present study was to investigate the changes of relative TL (RTL) and TERT expression in granulosa cells (GCs) during aging and its association with reproduction. Clinical data on the frozen‑thawed embryo transfer cycles of older (>35 year old) and younger (≤35 year old) women from a single center over a 3‑year period were retrospectively analyzed. Preimplantation genetic testing for chromosome aneuploidies in older women during the same period was also analyzed. Following the analysis of the data, several biological characteristics of senescent GCs were explored. In addition, a total of 160 women who were undergoing their first fresh cycle of in vitro fertilization (IVF) or intracytoplasmic sperm injection were included in the study. GCs were collected from all participants. The changes of RTL and TERT expression in GCs during aging were investigated using quantitative PCR and western blotting. The associations of RTL and TERT with IVF outcomes were also assessed. The clinical data demonstrated that the pregnancy and live birth rates of women aged >35 years were ~20% lower than those of women aged ≤35 years, and the number of embryos with aneuploidy was 7‑fold of that without euploidy in the older age group. An aging‑induced change in follicle stimulating hormone receptor expression was observed. A shorter TL and increased TERT expression were detected in the older women. A significant inverse correlation between the expression levels of TERT and oocyte yield was identified. However, no association of RTL and TERT with blastocyst formation rate and the probability of clinical pregnancy was detected. It may be concluded that RTL and TERT alterations in GCs are potential determinants of ovarian aging. TERT expression in GCs appears to be a potential biomarker for the prediction of ovarian response, which provides a novel strategy for the assessment of female fertility.},
}
@article {pmid37732319,
year = {2023},
author = {, },
title = {Retraction: Leukocyte telomere length and obesity in children and adolescents: a systematic review and meta-analysis.},
journal = {Frontiers in genetics},
volume = {14},
number = {},
pages = {1285214},
doi = {10.3389/fgene.2023.1285214},
pmid = {37732319},
issn = {1664-8021},
abstract = {[This retracts the article DOI: 10.3389/fgene.2022.861101.].},
}
@article {pmid37727982,
year = {2024},
author = {Zhang, J and Zhang, F and Porter, KI and Dakup, PP and Wang, S and Robertson, GP and Gaddameedhi, S and Zhu, J},
title = {Telomere dysfunction in Tert knockout mice delays Braf[V600E] -induced melanoma development.},
journal = {International journal of cancer},
volume = {154},
number = {3},
pages = {548-560},
pmid = {37727982},
issn = {1097-0215},
support = {R01 AG073423/AG/NIA NIH HHS/United States ; R01 ES030113/ES/NIEHS NIH HHS/United States ; R35 GM149529/GM/NIGMS NIH HHS/United States ; 579152/MRA/Melanoma Research Alliance/United States ; },
mesh = {Animals ; Mice ; *Melanoma/genetics/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Mutation ; *Proto-Oncogene Proteins B-raf/genetics/metabolism ; *Telomerase/genetics/metabolism ; Telomere/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; Ultraviolet Rays/adverse effects ; },
abstract = {Telomerase activation is a crucial step in melanomagenesis, often occurring because of ultraviolet radiation (UVR)-induced mutations at the telomerase gene (TERT) promoter and rendering TERT transcription in response to the activated Raf-MAP kinase pathway by BRAF[V600E] mutation. Due to the excessively long telomeres in mice, this process does not occur during melanomagenesis in mouse models. To investigate the impact of telomere dysfunction on melanomagenesis, Braf[V600E] was induced in generations 1 and 4 (G1 and G4) of Tert[-/-] mice. Our findings revealed that, regardless of UVR exposure, melanoma development was delayed in G4 mice, which had shorter telomeres compared to G1 and wild-type C57BL/6J (G0) mice. Moreover, many G4 tumors displayed an accumulation of excessive DNA damage, as evidenced by increased γH2A.X staining. Tumors from UVR-exposed mice exhibited elevated p53 protein expression. Cultured tumor cells isolated from G4 mice displayed abundant chromosomal fusions and rearrangements, indicative of telomere dysfunction in these cells. Additionally, tumor cells derived from UVB-exposed mice exhibited constitutively elevated expression of mutant p53 proteins, suggesting that p53 was a target of UVB-induced mutagenesis. Taken together, our findings suggest that telomere dysfunction hampers melanomagenesis, and targeting telomere crisis-mediated genomic instability may hold promise for the prevention and treatment of melanoma.},
}
@article {pmid37725415,
year = {2024},
author = {Hassler, EM and Almer, G and Reishofer, G and Deutschmann, H and Mangge, H and Herrmann, M and Leber, SL and Gunzer, F and Langsenlehner, T and Renner, W},
title = {A sex-specific association of leukocyte telomere length with thigh muscle mass.},
journal = {Clinical chemistry and laboratory medicine},
volume = {62},
number = {1},
pages = {150-156},
pmid = {37725415},
issn = {1437-4331},
mesh = {Humans ; Male ; Female ; *Thigh ; *Telomere/genetics ; Leukocytes ; Muscles ; DNA/metabolism ; },
abstract = {OBJECTIVES: Telomeres are DNA-protein complexes at the ends of linear chromosomes that protect against DNA degradation. Telomeres shorten during normal cell divisions and therefore, telomere length is an indicator of mitotic-cell age. In humans, telomere shortening is a potential biomarker for disease risk, progression and premature death. Physical activity has been associated with longer leukocyte telomere length (LTL) in some studies. In the current study the relationship between LTL, thigh muscle mass and adipose tissue distribution was explored.<br><br>METHODS: We performed anthropometric measurements and magnetic resonance imaging (MRI) measurements of the thigh in 149 healthy subjects (77 male, 72 female). LTL was measured using qPCR. Additionally, the subjects answered a questionnaire concerning their training behaviour.<br><br>RESULTS: In male subjects, LTL was significantly associated with thigh muscle mass, independent of age and body mass index (p=0.006). In addition, a slight association of LTL with weekly endurance units in the male group was found. These relations could not be observed in females.<br><br>CONCLUSIONS: In conclusion, we observed a sex-specific association of LTL and thigh muscle mass in healthy males. The reason of this sex-specific association is currently unclear, but could be related to different training effects and/or hormonal pathways in men and women.},
}
@article {pmid37725013,
year = {2023},
author = {Liang, J and Cui, J and Cheng, J and Pan, Y and Zhang, R and Yang, S and Zou, L},
title = {SIRT6 Knockdown in Buffalo Fetal Fibroblasts Exacerbates Premature Senescence Caused by DNA and Telomere Damage.},
journal = {Cellular reprogramming},
volume = {25},
number = {6},
pages = {277-287},
doi = {10.1089/cell.2023.0048},
pmid = {37725013},
issn = {2152-4998},
mesh = {Animals ; *Buffaloes/genetics ; Cellular Senescence ; Fibroblasts/metabolism ; Fetus ; DNA/metabolism ; Telomere/metabolism ; *Sirtuins/genetics/metabolism ; },
abstract = {As a gene with antiaging functions, sirtuin6 (SIRT6) belonging to the sirtuin family plays a vital role in DNA repair, telomerase function, and cellular senescence, as well as maintains epigenomic stability and promotes longevity. However, its role in cell senescence in large animals, such as buffaloes, remains unknown. Fibroblasts are commonly used for somatic reprogramming, and their physiological characteristics affect the efficiency of this process. We aimed to elucidate the role of SIRT6 in cellular senescence and proliferation and analyze its effect on the biological function of buffalo fibroblasts to help improve the efficiency of buffalo somatic cell reprogramming. The expression of SIRT6 and related DNA damage was measured in buffalo fibroblasts obtained at different developmental stages (in the fetus and at 3 and 10 years of age), and the effect of SIRT6 knockdown on the senescence of buffalo fetal fibroblast was investigated. An inverse relationship was observed between SIRT6 expression and senescence in buffalo fibroblasts obtained from animals of various ages. This was accompanied by decreased cell growth, viability, and increased DNA damage. Short hairpin RNA-mediated SIRT6 knockdown accelerated the senescence of buffalo fetal fibroblasts. It blocked the cell cycle during in vitro cell culture, which further enhanced DNA damage, particularly with respect to the telomeres. Collectively, our findings suggest that SIRT6 expression was closely associated with buffalo senescence in fibroblasts. These findings serve as a foundation to better understand the cellular functions of SIRT6 and also aid in selecting donor cells for buffalo somatic cell reprogramming.},
}
@article {pmid37721487,
year = {2023},
author = {Wong, JYY and Shu, XO and Hu, W and Blechter, B and Shi, J and Wang, K and Cawthon, R and Cai, Q and Yang, G and Rahman, ML and Ji, BT and Gao, Y and Zheng, W and Rothman, N and Lan, Q},
title = {Associations between Longer Leukocyte Telomere Length and Increased Lung Cancer Risk among Never Smokers in Urban China.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {32},
number = {12},
pages = {1734-1737},
pmid = {37721487},
issn = {1538-7755},
support = {ZIA HL006285/ImNIH/Intramural NIH HHS/United States ; UM1 CA173640/CA/NCI NIH HHS/United States ; R01 CA070867/CA/NCI NIH HHS/United States ; Z99 HL999999/ImNIH/Intramural NIH HHS/United States ; R01 CA082729/CA/NCI NIH HHS/United States ; ZIA CP010120/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Male ; Humans ; Female ; *Lung Neoplasms/etiology/genetics ; Prospective Studies ; China/epidemiology ; Smokers ; Telomere Homeostasis/genetics ; Leukocytes ; Lung ; Telomere/genetics ; Carcinogenesis ; },
abstract = {BACKGROUND: The complex relationship between measured leukocyte telomere length (LTL), genetically predicted LTL (gTL), and carcinogenesis is exemplified by lung cancer. We previously reported associations between longer pre-diagnostic LTL, gTL, and increased lung cancer risk among European and East Asian populations. However, we had limited statistical power to examine the associations among never smokers by gender and histology.<br><br>METHODS: To investigate further, we conducted nested case-control analyses on an expanded sample of never smokers from the prospective Shanghai Women's Health Studies (798 cases and 792 controls) and Shanghai Men's Health Studies (161 cases and 162 controls). We broke the case-control matching and used multivariable unconditional logistic regression models to estimate the ORs and 95% confidence intervals (CI) of incident lung cancer and adenocarcinoma (LUAD), in relation to LTL measured using quantitative PCR and gTL determined using a polygenic score. In addition, we conducted Mendelian randomization (MR) using MR-PRESSO.<br><br>RESULTS: We found striking dose-response relationships between longer LTL and gTL, and increased lung cancer risk among never-smoking women (P trendLTL = 4&#xd7;10-6; P trendgTL = 3&#xd7;10-4). Similarly, among never-smoking men, longer measured LTL was associated with over triple the risk compared with those with the shortest (OR, 3.48; 95% CI, 1.85-6.57). The overall results were similar for LUAD among women and men. MR analyses supported causal associations with LUAD among women (OR1 SD gTL, 1.19; 95% CI, 1.03-1.37; P = 0.03).<br><br>CONCLUSIONS: Longer pre-diagnostic LTL is associated with increased lung cancer risk among never smokers.<br><br>IMPACT: Our findings firmly support the role of longer telomeres in lung carcinogenesis.},
}
@article {pmid37718447,
year = {2023},
author = {Bhat, GR and Jamwal, RS and Sethi, I and Bhat, A and Shah, R and Verma, S and Sharma, M and Sadida, HQ and Al-Marzooqi, SK and Masoodi, T and Mirza, S and Haris, M and Macha, MA and Akil, ASA and Bhat, AA and Kumar, R},
title = {Associations between telomere attrition, genetic variants in telomere maintenance genes, and non-small cell lung cancer risk in the Jammu and Kashmir population of North India.},
journal = {BMC cancer},
volume = {23},
number = {1},
pages = {874},
pmid = {37718447},
issn = {1471-2407},
mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/genetics ; *Lung Neoplasms/epidemiology/genetics ; Telomere/genetics ; India/epidemiology ; Mass Spectrometry ; },
abstract = {BACKGROUND: Telomeres are repetitive DNA sequences located at the ends of chromosomes, playing a vital role in maintaining chromosomal integrity and stability. Dysregulation of telomeres has been implicated in the development of various cancers, including non-small cell lung cancer (NSCLC), which is the most common type of lung cancer. Genetic variations within telomere maintenance genes may influence the risk of developing NSCLC. The present study aimed to evaluate the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India, and to investigate the relationship between telomere length and NSCLC risk.<br><br>METHODS: We employed the cost-effective and high-throughput MassARRAY MALDI-TOF platform to assess the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India. Additionally, we used TaqMan genotyping to validate our results. Furthermore, we investigated telomere length variation and its relation to NSCLC risk in the same population using dual-labeled fluorescence-based qPCR.<br><br>RESULTS: Our findings revealed significant associations of TERT rs10069690 and POT1 rs10228682 with NSCLC risk (adjusted p-values&#x2009;=&#x2009;0.019 and 0.002, respectively), while TERF2 rs251796 and rs2975843 showed no significant associations. The TaqMan genotyping validation further substantiated the associations of TERT rs10069690 and rs2242652 with NSCLC risk (adjusted p-values&#x2009;=&#x2009;0.02 and 0.003, respectively). Our results also demonstrated significantly shorter telomere lengths in NSCLC patients compared to controls (p&#x2009;=&#x2009;0.0004).<br><br>CONCLUSION: This study highlights the crucial interplay between genetic variation in telomere maintenance genes, telomere attrition, and NSCLC risk in the Jammu and Kashmir population of North India. Our findings suggest that TERT and POT1 gene variants, along with telomere length, may serve as potential biomarkers and therapeutic targets for NSCLC in this population. Further research is warranted to elucidate the underlying mechanisms and to explore the potential clinical applications of these findings.},
}
@article {pmid37716992,
year = {2023},
author = {Liu, X and Arshad, R and Wang, X and Li, WM and Zhou, Y and Ge, XJ and Huang, HR},
title = {The phased telomere-to-telomere reference genome of Musa acuminata, a main contributor to banana cultivars.},
journal = {Scientific data},
volume = {10},
number = {1},
pages = {631},
pmid = {37716992},
issn = {2052-4463},
support = {32070237, 31261140366//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
mesh = {Haploidy ; *Musa/genetics ; Telomere/genetics ; *Genome, Plant ; },
abstract = {Musa acuminata is a main wild contributor to banana cultivars. Here, we reported a haplotype-resolved and telomere-to-telomere reference genome of M. acuminata by incorporating PacBio HiFi reads, Nanopore ultra-long reads, and Hi-C data. The genome size of the two haploid assemblies was estimated to be 469.83 Mb and 470.21 Mb, respectively. Multiple assessments confirmed the contiguity (contig N50: 16.53 Mb and 18.58 Mb; LAI: 20.18 and 19.48), completeness (BUSCOs: 98.57% and 98.57%), and correctness (QV: 45.97 and 46.12) of the genome. The repetitive sequences accounted for about half of the genome size. In total, 40,889 and 38,269 protein-coding genes were annotated in the two haploid assemblies, respectively, of which 9.56% and 3.37% were newly predicted. Genome comparison identified a large reciprocal translocation involving 3 Mb and 10 Mb from chromosomes 01 and 04 within M. acuminata. This reference genome of M. acuminata provides a valuable resource for further understanding of subgenome evolution of Musa species, and precise genetic improvement of banana.},
}
@article {pmid37714858,
year = {2023},
author = {Tichy, ED and Lee, JH and Li, G and Estep, KN and Brad Johnson, F and Mourkioti, F},
title = {Impacts of radiation exposure, hindlimb unloading, and recovery on murine skeletal muscle cell telomere length.},
journal = {NPJ microgravity},
volume = {9},
number = {1},
pages = {76},
pmid = {37714858},
issn = {2373-8065},
support = {P30 AR069619/AR/NIAMS NIH HHS/United States ; R01 AR075914/AR/NIAMS NIH HHS/United States ; R01 HL146662/HL/NHLBI NIH HHS/United States ; },
abstract = {Astronauts are exposed to harsh conditions, including cosmic radiation and microgravity. Spaceflight elongates human telomeres in peripheral blood, which shorten upon return to Earth and approach baseline levels during postflight recovery. Astronauts also encounter muscle atrophy, losing up to 20% loss of muscle mass on spaceflights. Telomere length changes in muscle cells of astronauts remain unexplored. This study investigates telomere alterations in grounded mice experiencing radiation exposure and muscle atrophy, via a hindlimb unloading spaceflight mimicking model. We find telomere lengthening is present in muscle stem cells and in myofiber nuclei, but not in muscle-resident endothelial cells. We further assessed telomere length in the model following hindlimb unloading recovery. We find that telomere length failed to return to baseline values. Our results suggest a role for telomeres in muscle acclimatization, which is relevant for the well-being of astronauts in space, and upon their return to Earth.},
}
@article {pmid37713629,
year = {2023},
author = {Manzato, C and Larini, L and Oss Pegorar, C and Dello Stritto, MR and Jurikova, K and Jantsch, V and Cusanelli, E},
title = {TERRA expression is regulated by the telomere-binding proteins POT-1 and POT-2 in Caenorhabditis elegans.},
journal = {Nucleic acids research},
volume = {51},
number = {19},
pages = {10681-10699},
pmid = {37713629},
issn = {1362-4962},
support = {P40 OD010440/OD/NIH HHS/United States ; },
mesh = {Animals ; Caenorhabditis elegans/genetics/metabolism ; *Caenorhabditis elegans Proteins/genetics/metabolism ; DNA-Binding Proteins/genetics ; Meiosis ; *RNA, Long Noncoding/genetics ; *Telomerase/genetics ; Telomere/genetics/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Several aspects of telomere biology are regulated by the telomeric repeat-containing RNA TERRA. While TERRA expression is conserved through evolution, species-specific mechanisms regulate its biogenesis and function. Here we report on the expression of TERRA in Caenorhabditis elegans. We show that C. elegans TERRA is regulated by the telomere-binding proteins POT-1 and POT-2 which repress TERRA in a telomere-specific manner. C. elegans TERRA transcripts are heterogeneous in length and form discrete nuclear foci, as detected by RNA FISH, in both postmitotic and germline cells; a fraction of TERRA foci localizes to telomeres. Interestingly, in germ cells, TERRA is expressed in all stages of meiotic prophase I, and it increases during pachytene, a stage in meiosis when homologous recombination is ongoing. We used the MS2-GFP system to study the spatiotemporal dynamics of single-telomere TERRA molecules. Single particle tracking revealed different types of motilities, suggesting complex dynamics of TERRA transcripts. Finally, we unveiled distinctive features of C. elegans TERRA, which is regulated by telomere shortening in a telomere-specific manner, and it is upregulated in the telomerase-deficient trt-1; pot-2 double mutant prior to activation of the alternative lengthening mechanism ALT. Interestingly, in these worms TERRA displays distinct dynamics with a higher fraction of fast-moving particles.},
}
@article {pmid37707950,
year = {2023},
author = {Jalan-Sakrikar, N and Anwar, A and Yaqoob, U and Gan, C and Lagnado, AB and Wixom, AQ and Jurk, D and Huebert, RC},
title = {Telomere dysfunction promotes cholangiocyte senescence and biliary fibrosis in primary sclerosing cholangitis.},
journal = {JCI insight},
volume = {8},
number = {20},
pages = {},
pmid = {37707950},
issn = {2379-3708},
support = {KL2 TR002379/TR/NCATS NIH HHS/United States ; P30 DK084567/DK/NIDDK NIH HHS/United States ; R01 DK117861/DK/NIDDK NIH HHS/United States ; },
mesh = {Humans ; Animals ; Mice ; *Cholangitis, Sclerosing/genetics/metabolism/pathology ; Liver/metabolism ; Bile Ducts/metabolism ; Fibrosis ; Telomere ; },
abstract = {Cellular senescence and biliary fibrosis are prototypical features of obliterative cholangiopathies, such as primary sclerosing cholangitis (PSC). Telomere dysfunction can lead to senescence either through telomere erosion or damaged telomeres. Our goal was to investigate a mechanistic relationship between telomere damage and biliary fibrosis in PSC. Telomere attrition was observed in the bile ducts of patients with PSC along with a reduction in telomerase reverse transcriptase (TERT) expression, compared with that in normal livers. Similarly, liver tissue from mouse models of biliary fibrosis showed telomere attrition with increased damage at telomeres measured as telomere-associated foci (TAF). Cellular models of senescence induction increased the TAF in cholangiocytes. This coincided with decreased TERT expression and increased senescence, which was rescued by modulating TERT levels. Epigenetic analysis revealed increased acquisition of repressive histone methylation at the TERT promoter, which correlated with decreased TERT transcription. Cholangiocyte-selective deletion of TERT in mice exacerbated fibrosis, whereas androgen therapy toward telomerase rescued liver fibrosis and liver function in a genetic mouse model of PSC. Our results demonstrate a mechanistic role for telomere dysfunction in cellular senescence and fibrosis that characterize PSC. This suggests that PSC may be, in part, a telomere biology disorder, and identifies TERT as a potential therapeutic target.},
}
@article {pmid37705928,
year = {2023},
author = {Cao, Z and Hou, Y and Xu, C},
title = {Leucocyte telomere length, brain volume and risk of dementia: a prospective cohort study.},
journal = {General psychiatry},
volume = {36},
number = {4},
pages = {e101120},
pmid = {37705928},
issn = {2517-729X},
abstract = {BACKGROUND: The evidence regarding the association between leucocyte telomere length (LTL) and brain health is sparse and inconclusive.<br><br>AIMS: To investigate the associations of LTL with brain structure and the risk of dementia based on a large-scale prospective study.<br><br>METHODS: LTL in the peripheral blood was measured by the quantitative polymerase chain reaction (qPCR) assay from 439&#x2009;961 individuals in the UK Biobank recruited between 2006 and 2010 and followed up until 2020. Electronic health records were used to record the incidence of dementia, including Alzheimer's disease (AD) and vascular dementia (VD). The brain structure, including total and regional brain volume, of 38&#x2009;740 participants was then assessed by magnetic resonance imaging (MRI).<br><br>RESULTS: During a median follow-up of 11.6 years, a total of 5 820 (1.3%) dementia cases were documented. The restricted cubic spline model showed significant overall associations between LTL and the risk of dementia and AD (p for overall <0.05). The multivariable adjusted hazard ratios (HRs) for the lowest LTL tertile compared with the highest LTL tertile were 1.14 (95% confidence interval (CI): 1.06 to 1.21) for dementia, 1.28 (95% CI: 1.12 to 1.46) for AD and 1.18 (95% CI: 0.98 to 1.42) for VD. Furthermore, we found that shorter LTL was associated with smaller total brain volume (&#x3b2;=-0.012 8, p=0.003), white matter volume (&#x3b2;=-0.022 4, p<0.001), hippocampus volume (&#x3b2;=-0.017 2, p<0.001), thalamus volume (&#x3b2;=-0.023 9, p<0.001) and accumbens (&#x3b2;=-0.015 5, p=0.001).<br><br>CONCLUSIONS: Shorter LTL is associated with total and regional brain structure and a higher risk of incident dementia and AD, implying the potential of telomere length as a predictive biomarker of brain health.},
}
@article {pmid37705399,
year = {2023},
author = {Houminer-Klepar, N and Bord, S and Epel, E and Lin, J and Sultan, L and Baron-Epel, O},
title = {Working Status of First-Time Postpartum Mothers and Telomere Length-A 1-Year Prospective Study.},
journal = {Journal of occupational and environmental medicine},
volume = {65},
number = {12},
pages = {1036-1044},
pmid = {37705399},
issn = {1536-5948},
mesh = {Female ; Humans ; *Mothers ; Prospective Studies ; *Postpartum Period ; Employment ; Telomere ; },
abstract = {OBJECTIVE: Transitioning to motherhood can create work family conflicts affecting mothers' health. Although employment is generally associated with longer telomeres, this may diminish during the early years of child-rearing. This study aimed to assess the impact of work reentry on telomere length (TL) among first-time mothers.<br><br>METHODS: In this 1-year prospective study, a total of 103 first-time postpartum mothers participated from two medical institutions in Northern Israel; they completed validated questionnaires, reported their current working status, and provided dried blood spots measuring TL.<br><br>RESULTS: We found that working status significantly predicted change in TL and was negatively correlated with change in TL over time (&#x3b2; = -0.245; 95% confidence interval, -0.169, -0.018; P = 0.016).<br><br>CONCLUSIONS: Identifying ideal timing of work reentry is recommended for first-time postpartum mother's optimal health and TL.},
}
@article {pmid37702332,
year = {2023},
author = {Rahman, ST and Waterhouse, M and Pham, H and Duarte Romero, B and Baxter, C and McLeod, DSA and English, DR and Ebeling, PR and Hartel, G and Armstrong, BK and O'Connell, RL and van der Pols, JC and Venn, AJ and Webb, PM and Wells, JK and Whiteman, DC and Pickett, HA and Neale, RE},
title = {Effects of Vitamin D Supplementation on Telomere Length: An Analysis of Data from the Randomised Controlled D-Health Trial.},
journal = {The journal of nutrition, health &amp; aging},
volume = {27},
number = {8},
pages = {609-616},
doi = {10.1007/s12603-023-1948-3},
pmid = {37702332},
issn = {1760-4788},
mesh = {Humans ; Aged ; Australia ; *Vitamins/pharmacology/therapeutic use ; *Vitamin D ; Calcifediol ; Telomere ; Dietary Supplements ; Randomized Controlled Trials as Topic ; },
abstract = {OBJECTIVES: Observational studies have suggested that a higher 25-hydroxyvitamin D concentration may be associated with longer telomere length; however, this has not been investigated in randomised controlled trials. We conducted an ancillary study within a randomised, double-blind, placebo-controlled trial of monthly vitamin D (the D-Health Trial) for the prevention of all-cause mortality, conducted from 2014 to 2020, to assess the effect of vitamin D supplementation on telomere length (measured as the telomere to single copy gene (T/S) ratio).<br><br>Participants were Australians aged 60-84 years and we randomly selected 1,519 D-Health participants (vitamin D: n=744; placebo: n=775) for this analysis. We used quantitative polymerase chain reaction to measure the relative telomere length (T/S ratio) at 4 or 5 years after randomisation. We compared the mean T/S ratio between the vitamin D and placebo groups to assess the effect of vitamin D supplementation on relative telomere length, using a linear regression model with adjustment for age, sex, and state which were used to stratify the randomisation.<br><br>RESULTS: The mean T/S ratio was 0.70 for both groups (standard deviation 0.18 and 0.16 for the vitamin D and placebo groups respectively). The adjusted mean difference (vitamin D minus placebo) was -0.001 (95% CI -0.02 to 0.02). There was no effect modification by age, sex, body mass index, or predicted baseline 25-hydroxyvitamin D concentration.<br><br>CONCLUSION: In conclusion, routinely supplementing older adults, who are largely vitamin D replete, with monthly doses of vitamin D is unlikely to influence telomere length.},
}
@article {pmid37701454,
year = {2023},
author = {Huang, HR and Liu, X and Arshad, R and Wang, X and Li, WM and Zhou, Y and Ge, XJ},
title = {Telomere-to-telomere haplotype-resolved reference genome reveals subgenome divergence and disease resistance in triploid Cavendish banana.},
journal = {Horticulture research},
volume = {10},
number = {9},
pages = {uhad153},
pmid = {37701454},
issn = {2662-6810},
abstract = {Banana is one of the most important crops of the world. Cavendish-type bananas, which have a monospecific Musa acuminata origin (AAA), account for around half of the global banana production, thereby are of great significance for human societies. However, until now, the high-quality haplotype-resolved reference genome was still undecoded for banana cultivars. Here, we reported the telomere-to-telomere (T2T) and haplotype-resolved reference genome of 'Baxijiao' (Cavendish) consisting of three haploid assemblies. The sizes of the three haploid assemblies were estimated to be 477.16 Mb, 477.18 Mb, and 469.57 Mb, respectively. Although with monospecific origins, the three haploid assemblies showed great differences with low levels of sequence collinearity. Several large reciprocal translocations were identified among chromosomes 1, 4, and 7. An expansion of gene families that might affect fruit quality and aroma was detected, such as those belonging to sucrose/disaccharide/oligosaccharide catabolic processes, sucrose metabolic process, starch metabolic process, and aromatic compound biosynthetic process. Besides, an expansion of gene families related to anther and pollen development was observed, which could be associated with parthenocarpy and sterility of the Cavendish cultivar. Finally, much fewer resistance genes were identified in 'Baxijiao' than in M. acuminata, particularly in the gene clusters in chromosomes 3 and 10, providing potential targets to explore for molecular analysis of disease resistance in banana. This T2T haplotype-resolved reference genome will thus be a valuable genetic resource for biological studies, molecular breeding, and genetic improvement of banana.},
}
@article {pmid37696218,
year = {2023},
author = {Han, D and Zhu, Y and Choudhry, AA and Cheng, J and Liang, H and Lin, F and Chang, Q and Liu, H and Pan, P and Zhang, Y},
title = {Association of telomere length with risk of lung cancer: A large prospective cohort study from the UK Biobank.},
journal = {Lung cancer (Amsterdam, Netherlands)},
volume = {184},
number = {},
pages = {107358},
doi = {10.1016/j.lungcan.2023.107358},
pmid = {37696218},
issn = {1872-8332},
mesh = {Female ; Humans ; *Lung Neoplasms/epidemiology/genetics ; Biological Specimen Banks ; Prospective Studies ; *Adenocarcinoma ; *Carcinoma, Squamous Cell ; Telomere/genetics ; United Kingdom/epidemiology ; },
abstract = {OBJECTIVES: Leukocyte telomere length (LTL) is associated with a wide variety of diseases, including cancer. However, findings regarding the association between LTL and the risk for lung cancer have been inconclusive and inconsistent across previous observational studies.<br><br>METHODS: This prospective cohort study included data from 425,146 participants 37-73&#xa0;years of age housed in the UK Biobank. Quantitative polymerase chain reaction (qPCR) was used to measure LTL in baseline DNA samples. A multivariate Cox proportional hazards model was used to evaluate the relationship between LTL and the risk for lung cancer.<br><br>RESULTS: An increase in LTL per interquartile range (IQR) was associated with a 9% increase in the risk for lung cancer (hazard ratio [HR] 1.09 [95% confidence interval (CI) 1.03-1.16]). Participants in the highest LTL quintile exhibited an approximately 25% elevated risk for developing lung cancer (HR 1.25 [95% CI 1.09-1.45]) compared with those in the lowest quintile. The relationship between per IQR increase in LTL and elevated risk for lung cancer was greater in the histological subtype of adenocarcinoma (HR 1.30 [95% CI 1.18-1.43]), female sex (HR 1.16 [95% CI 1.06-1.26]), non-smokers (HR 1.45 [95% CI 1.23-1.71]), and individuals with high genetic risk for lung cancer (HR 1.18 [95% CI 1.03-1.34]), respectively. Surprisingly, a per IQR increase in LTL was associated with increased risks for both lung adenocarcinoma (HR 1.56 [95% CI 1.24-1.96]) and squamous cell carcinoma (HR 2.01 [95% CI 1.13-3.56]) in never smokers.<br><br>CONCLUSIONS: Longer LTL was associated with an elevated risk for lung cancer, particularly for adenocarcinoma and squamous cell carcinoma in never smokers. The results suggest the potential of telomeres as non-invasive biomarkers for the early screening of lung cancer, particularly in non-smokers, who are typically overlooked.},
}
@article {pmid37693759,
year = {2023},
author = {Yu, W and Mei, Y and Lu, Z and Zhou, L and Jia, F and Chen, S and Wang, Z},
title = {The causal relationship between genetically determined telomere length and meningiomas risk.},
journal = {Frontiers in neurology},
volume = {14},
number = {},
pages = {1178404},
pmid = {37693759},
issn = {1664-2295},
abstract = {BACKGROUND: Studies have shown that longer leukocyte telomere length (LTL) is significantly associated with increased risk of meningioma. However, there is limited evidence concerning the causal association of LTL with benign and malignant meningiomas or with the location of benign tumors.<br><br>METHODS: We used three LTL datasets from different sources, designated by name and sample size as LTL-78592, LTL-9190, and LTL-472174. The linkage disequilibrium score (LDSC) was used to explore the association between LTL and meningioma. We utilized two-sample bidirectional Mendelian randomization (TSMR) to evaluate whether LTL is causally related to meningioma risk. We adjusted for confounders by conducting multivariable Mendelian randomization (MVMR).<br><br>RESULTS: In the LTL-78592, longer LTL was significantly associated with increased risk of malignant [odds ratio (OR)&#x2009;=&#x2009;5.14, p&#x2009;=&#x2009;1.04&#x2009;&#xd7;&#x2009;10[-5]], benign (OR&#x2009;=&#x2009;4.81, p&#x2009;<&#x2009;0.05), benign cerebral (OR&#x2009;=&#x2009;5.36, p&#x2009;<&#x2009;0.05), and benign unspecified meningioma (OR&#x2009;=&#x2009;8.26, p&#x2009;<&#x2009;0.05). The same results were obtained for the LTL-9190. In the LTL-472174, longer LTL was significantly associated with increased risk of malignant (OR&#x2009;=&#x2009;4.94, p&#x2009;<&#x2009;0.05), benign (OR&#x2009;=&#x2009;3.14, p&#x2009;<&#x2009;0.05), and benign cerebral meningioma (OR&#x2009;=&#x2009;3.59, p&#x2009;<&#x2009;0.05). Similar results were obtained in the MVMR. In contrast, only benign cerebral meningioma displayed a possible association with longer LTL (OR&#x2009;=&#x2009;1.01, p&#x2009;<&#x2009;0.05). No heterogeneity or horizontal pleiotropy was detected.<br><br>CONCLUSION: In brief, genetically predicted longer LTL may increase the risk of benign, malignant, and benign cerebral meningiomas, regardless of the LTL measure, in European populations.},
}
@article {pmid37690790,
year = {2023},
author = {},
title = {"Interstitial lung abnormalities are associated with decreased mean telomere length." R.K. Putman, G.T. Axelsson, S.Y. Ash, et al. Eur Respir J 2022; 60: 2101814.},
journal = {The European respiratory journal},
volume = {62},
number = {3},
pages = {},
doi = {10.1183/13993003.51814-2021},
pmid = {37690790},
issn = {1399-3003},
}
@article {pmid37689117,
year = {2023},
author = {Martinez, S and Jones, JD},
title = {A pilot study examining the relationship between chronic heroin use and telomere length among individuals of African ancestry.},
journal = {Pharmacology, biochemistry, and behavior},
volume = {231},
number = {},
pages = {173631},
pmid = {37689117},
issn = {1873-5177},
support = {R21 DA043199/DA/NIDA NIH HHS/United States ; T32 DA007294/DA/NIDA NIH HHS/United States ; },
mesh = {Humans ; Female ; Middle Aged ; Male ; *Telomere Shortening ; Pilot Projects ; *Heroin ; Cross-Sectional Studies ; Bayes Theorem ; Telomere/genetics ; },
abstract = {BACKGROUND: Prior research has suggested a possible link between heroin use and shortened telomere length (TL), a marker of cellular aging and genomic stability. We sought to replicate these findings by examining the relationship between TL and heroin use among individuals of African ancestry.<br><br>METHODS: This cross-sectional study examined TL among 57 participants [17.5&#xa0;% female; mean age 48.0 (&#xb1;6.80) years] of African ancestry with Opioid Use Disorder (OUD) and a mean heroin use duration of 18.2 (&#xb1;10.7) years. Quantitative polymerase chain reaction (qPCR) was used to calculate TL as the ratio between telomere repeat copy number (T) and a single-copy gene, copy number (S). The primary dependent variable was TL (T/S Ratio) measured in kilobase pairs. Covariates included heroin use years and personality traits. Using a hybrid approach, multiple linear regression and Bayesian linear regression examined the association of chronological age, heroin use years and personality traits with TL.<br><br>RESULTS: The multiple linear regression model fit the data well, R[2]&#xa0;=&#xa0;0.265, F(7,49)&#xa0;=&#xa0;2.53, p&#xa0;<&#xa0;.026. Chronological age (&#x3b2;&#xa0;=&#xa0;-0.36, p&#xa0;=&#xa0;.017), neuroticism (&#x3b2;&#xa0;=&#xa0;0.46, p&#xa0;=&#xa0;.044), and conscientiousness (&#x3b2;&#xa0;=&#xa0;0.52, p&#xa0;=&#xa0;.040) were significant predictors of TL. Bayesian linear regression provided moderate support for the alternate hypothesis that chronological age and TL are associated, BF[10]&#xa0;=&#xa0;5.77, R[2]&#xa0;=&#xa0;0.120. The posterior summary of the coefficient was M&#xa0;=&#xa0;0.719 (SD&#xa0;=&#xa0;0.278, 95&#xa0;% credible interval [-1.28, -0.163]).<br><br>CONCLUSIONS: Contrary to prior studies, these findings suggest that heroin use duration may not be significantly associated with TL among individuals of African ancestry, highlighting the need for more rigorous research to elucidate the complexity of this relationship.},
}
@article {pmid37688329,
year = {2023},
author = {Sullivan, DI and Bello, FM and Silva, AG and Redding, KM and Giordano, L and Hinchie, AM and Loughridge, KE and Mora, AL and Königshoff, M and Kaufman, BA and Jurczak, MJ and Alder, JK},
title = {Intact mitochondrial function in the setting of telomere-induced senescence.},
journal = {Aging cell},
volume = {22},
number = {10},
pages = {e13941},
pmid = {37688329},
issn = {1474-9726},
support = {F32 HL152503/HL/NHLBI NIH HHS/United States ; R01 DK114012/DK/NIDDK NIH HHS/United States ; R01 HL135062/HL/NHLBI NIH HHS/United States ; U54 AG075931/AG/NIA NIH HHS/United States ; },
mesh = {*Telomere/genetics ; *Telomere-Binding Proteins/metabolism ; Mitochondria/genetics/metabolism ; Cellular Senescence/genetics ; Fibroblasts/metabolism ; },
abstract = {Mitochondria play essential roles in metabolic support and signaling within all cells. Congenital and acquired defects in mitochondria are responsible for several pathologies, including premature entrance to cellar senescence. Conversely, we examined the consequences of dysfunctional telomere-driven cellular senescence on mitochondrial biogenesis and function. We drove senescence in vitro and in vivo by deleting the telomere-binding protein TRF2 in fibroblasts and hepatocytes, respectively. Deletion of TRF2 led to a robust DNA damage response, global changes in transcription, and induction of cellular senescence. In vitro, senescent cells had significant increases in mitochondrial respiratory capacity driven by increased cellular and mitochondrial volume. Hepatocytes with dysfunctional telomeres maintained their mitochondrial respiratory capacity in vivo, whether measured in intact cells or purified mitochondria. Induction of senescence led to the upregulation of overlapping and distinct genes in fibroblasts and hepatocytes, but transcripts related to mitochondria were preserved. Our results support that mitochondrial function and activity are preserved in telomere dysfunction-induced senescence, which may facilitate continued cellular functions.},
}
@article {pmid37686490,
year = {2023},
author = {Kreilmeier-Berger, T and Aupperle-Lellbach, H and Reifinger, M and Hörstke, NV and Holzmann, K and Kleiter, M},
title = {Alternative Lengthening of Telomeres Is Rare in Canine Histiocytic Sarcoma.},
journal = {Cancers},
volume = {15},
number = {17},
pages = {},
pmid = {37686490},
issn = {2072-6694},
abstract = {Cancer cells activate telomere maintenance mechanisms (TMMs) to overcome senescence and thus are targets for TMM-specific therapies. Telomerase-independent alternative lengthening of telomeres (ALT) is frequently utilized as a TMM in human sarcoma subtypes. Histiocytic sarcoma (HS) is a rare but aggressive tumor of hematopoietic origin with unknown ALT incidence in humans. ALT has been identified in canine HS, a tumor type comparable to human HS that occurs with high rates in certain canine breeds such as Bernese mountain dogs (BMDs). This retrospective study characterized the frequency of ALT in BMD and non-BMD patients diagnosed with HS as surrogates for humans. Formalin-fixed paraffin-embedded tumor samples from 63 dogs at two centers, including 47 BMDs, were evaluated for their ALT activity and relative telomere content (TC) using a radiolabel C-circle assay (CCA). Known ALT-positive samples served as controls. CCA-positive cases were validated via FISH. Two BMD samples showed ALT activity of 1-14% compared to controls. All other samples were ALT-negative. The TC did not correlate with the CCA results. ALT positivity was validated by the appearance of ultrabright telomere foci. Low ALT activity was present in 4% of BMDs with HS and therefore does not appear to be a common target for therapeutic approaches but can have diagnostic value.},
}
@article {pmid37682379,
year = {2023},
author = {Benitez-Roig, V and Martínez-Carpio, PA and Trelles, MA and Cosmina-Timircan, A and Arias-Salgado, EG and Perona, R},
title = {Clinical and laboratory results in vaginal wall restoration using a fractional-pixel-CO2 laser: histological findings and changes in the Ki67 protein and telomere length.},
journal = {Lasers in medical science},
volume = {38},
number = {1},
pages = {206},
pmid = {37682379},
issn = {1435-604X},
support = {PI20-00335//Instituto de Salud Carlos III/ ; },
mesh = {Humans ; Female ; *Carbon Dioxide ; *Hyaluronic Acid ; Ki-67 Antigen/genetics ; Prospective Studies ; Telomere/genetics ; },
abstract = {Thermal deposition of laser energy in the vaginal epithelium in genitourinary syndrome of menopause (GSM) results in clinical and biological effects, but many cellular and molecular changes indicating cell proliferation or senescence inhibition are unknown. The aim of this study is to evaluate the clinical efficacy of the fractional-pixel-CO2 laser in the possible improvement of GMS signs and symptoms that can be correlated with histological changes or with cellular or molecular indicators of restoration. A detailed prospective study was designed to assess 17 women diagnosed with GSM who were treated intravaginally with two laser sessions. Seven non-treated women diagnosed with GSM were used as controls. Three validated outcome questionnaires for assessment of quality of sexual life and urinary incontinence were performed. Vaginal biopsies were collected before the first laser treatment and 4 months following the second session. Histological status, elastin, collagen, and hyaluronic acid content of the biopsies were also evaluated. Cell proliferation was assessed by Ki67 staining. Telomere length (TL) was measured by qPCR. The results show an improvement of the clinical symptoms of GSM (p < 0.05), vaginal epithelium recovery and enhancement of collagen (p < 0.05), elastic fibers (p < 0.005), and hyaluronic acid (p < 0.0005) content in the lamina propria after fractional-pixel-CO2 laser treatment. The laser treatment induced a significant rise on the TL of vaginal epithelial cells (VECs), and a positive correlation was found between the improvements of the collagen and hyaluronic acid content and TL changes (r = 0.82, p < 0.05; r = 0.38, p < 0.05). The percentage of proliferative Ki67-positive VECs was increased in patients whose vaginal TL lengthened after laser treatment (p < 0.05). In conclusion, the results indicate that laser treatment may induce restoration of the vaginal epithelium which is associated to increased TL and proliferation in the VECs. Performing a TL assay could be a suitable tool to evaluate the efficacy of vaginal laser treatment.},
}
@article {pmid37673133,
year = {2023},
author = {Yin, F and Zhou, Y and Xie, D and Hu, J and Luo, X},
title = {Effects of nanomaterial exposure on telomere dysfunction, hallmarks of mammalian and zebrafish cell senescence, and zebrafish mortality.},
journal = {Ageing research reviews},
volume = {91},
number = {},
pages = {102062},
doi = {10.1016/j.arr.2023.102062},
pmid = {37673133},
issn = {1872-9649},
mesh = {Animals ; Humans ; *Zebrafish/metabolism ; *Telomerase/genetics ; Telomere/metabolism ; Shelterin Complex ; Cellular Senescence ; Mammals/metabolism ; },
abstract = {Environmental and occupational exposure to hazardous substances accelerates biological aging. However, the toxic effects of nanomaterials on telomere and cellular senescence (major hallmarks of the biological aging) remained controversial. This study was to synthesize all published evidence to explore the effects of nanomaterial exposure on the telomere change, cellular senescence and mortality of model animals. Thirty-five studies were included by searching electronic databases (PubMed, Embase and Web of Science). The pooled analysis by Stata 15.0 software showed that compared with the control, nanomaterial exposure could significantly shorten the telomere length [measured as kbp: standardized mean difference (SMD) = -1.88; 95% confidence interval (CI) = -3.13 - - 0.64; % of control: SMD = -1.26; 95%CI = -2.11- - 0.42; < 3 kbp %: SMD = 5.76; 95%CI = 2.92 - 8.60), increase the telomerase activity (SMD = -1.00; 95%CI = -1.74 to -0.26), senescence-associated β-galactosidase levels in cells (SMD = 8.20; 95%CI = 6.05 - 10.34) and zebrafish embryos (SMD = 7.32; 95%CI = 4.70 - 9.94) as well as the mortality of zebrafish (SMD = 3.83; 95%CI = 2.94 - 4.72)]. The expression levels of telomerase TERT, shelterin components (TRF1, TRF2 and POT1) and senescence biomarkers (p21, p16) were respectively identified to be decreased or increased in subgroup analyses. In conclusion, this meta-analysis demonstrates that nanomaterial exposure is associated with telomere attrition, cell senescence and organismal death.},
}
@article {pmid37671590,
year = {2023},
author = {Fan, G and Liu, Q and Bi, J and Qin, X and Fang, Q and Wang, Y and Song, L},
title = {Association between female-specific reproductive factors and leukocyte telomere length.},
journal = {Human reproduction (Oxford, England)},
volume = {38},
number = {11},
pages = {2239-2246},
doi = {10.1093/humrep/dead176},
pmid = {37671590},
issn = {1460-2350},
mesh = {Pregnancy ; Female ; Humans ; *Abortion, Spontaneous ; Stillbirth ; Leukocytes ; *Menopause, Premature ; Live Birth ; Contraceptives, Oral ; Menstruation Disturbances ; Telomere ; Chronic Disease ; },
abstract = {STUDY QUESTION: What are the associations between female-specific reproductive factors and leukocyte telomere length (LTL)?<br><br>SUMMARY ANSWER: Early menarche, early menopause, short reproductive lifespan, early age at first birth, multiparity, and use of oral contraceptives (OCs) and hormone replacement therapy (HRT) were associated with shorter LTL.<br><br>WHAT IS KNOWN ALREADY: Reproductive factors have been associated with age-related diseases, but their associations with cellular aging, as indicated by LTL, are unclear.<br><br>STUDY DESIGN, SIZE, DURATION: This population-based study included 224&#x200a;965 women aged 40-69&#x2009;years from the UK Biobank between 2006 and 2010.<br><br>Women aged 40-69 were included. Female-specific reproductive factors, including age at menarche, age at natural menopause, reproductive lifespan, number of live births, age at first live birth, history of stillbirth, history of miscarriage, and use of OCs and HRT were self-reported. LTL was measured using a validated polymerase chain reaction method. Multiple linear regression and restricted cubic spline models were applied to explore the association between each reproductive factor and LTL.<br><br>After adjustment for potential confounders, early menarche (<12&#x2009;years; percent change, per unit change in LTL Z score: -1.29%, 95% CI: -2.32%, -0.26%), early menopause (<45&#x2009;years; percent change: -7.18%, 95% CI: -8.87%, -5.45%), short reproductive lifespan (<30&#x2009;years; percent change: -6.10%, 95% CI: -8.14%, -4.01%), multiparity (percent change: -3.38%, 95% CI: -4.38%, -2.37%), early age at first live birth (<20&#x2009;years; percent change: -4.46%, 95% CI: -6.00%, -2.90%), and use of OCs (percent change: -1.10%, 95% CI: -2.18%, -0.02%) and HRT (percent change: -3.72%, 95% CI: -4.63%, -2.80%) were all significantly associated with shorter LTL. However, no significant association was found for history of miscarriage and stillbirth. We observed nonlinear relationships of age at menarche, age at natural menopause, reproductive lifespan, and age at first live birth with LTL (Pnonlinear < 0.05).<br><br>Considering that the participants were predominantly of European ethnicity, the findings may not be generalizable to women of other ethnic backgrounds.<br><br>Our findings suggest that early menarche, early menopause, short reproductive lifespan, early age at first birth, multiparity, and use of OCs and HRT were associated with shorter LTL, which has been linked to various chronic diseases. The accelerated shortening of telomeres may potentially contribute to the development of chronic diseases related to reproductive factors.<br><br>This study was funded by the National Natural Science Foundation of China (82003479, 82073660), Hubei Provincial Natural Science Foundation of China (2023AFB663), and the China Postdoctoral Science Foundation (2019M662646, 2020T130220). The authors have no competing interests to disclose.<br><br>TRIAL REGISTRATION NUMBER: N/A.},
}
@article {pmid37665761,
year = {2023},
author = {Ferrer, A and Lasho, T and Fernandez, JA and Steinauer, NP and Simon, RA and Finke, CM and Carmona, EM and Wylam, ME and Ongie, LJ and Burnap, BN and Arana Yi, C and Sproat, LZ and Foran, J and Badar, T and Mangaonkar, AA and Patnaik, MM},
title = {Patients with telomere biology disorders show context specific somatic mosaic states with high frequency of U2AF1 variants.},
journal = {American journal of hematology},
volume = {98},
number = {12},
pages = {E357-E359},
doi = {10.1002/ajh.27086},
pmid = {37665761},
issn = {1096-8652},
mesh = {Humans ; Splicing Factor U2AF/genetics ; *Telomere/genetics/metabolism ; Biology ; *Telomerase/genetics/metabolism ; },
abstract = {Somatic mosaic states in telomere biology disorders are characterized by somatic variants in the spliceosome and DNA damage response and repair pathways. A likely maladaptive response to short telomeres that may lead to increased hematological cancer.},
}
@article {pmid37662954,
year = {2023},
author = {Han, X and Yan, Z and Fan, K and Guan, X and Hu, B and Li, X and Ou, Y and Cui, B and An, L and Zhang, Y and Gong, J},
title = {The combined signatures of telomere and immune cell landscape provide a prognostic and therapeutic biomarker in glioma.},
journal = {Frontiers in immunology},
volume = {14},
number = {},
pages = {1220100},
pmid = {37662954},
issn = {1664-3224},
mesh = {Adult ; Humans ; Prognosis ; Biomarkers ; *Telomere/genetics ; *Glioma/diagnosis/genetics/therapy ; Central Nervous System ; Tumor Microenvironment/genetics ; },
abstract = {BACKGROUND: Gliomas, the most prevalent primary malignant tumors of the central nervous system in adults, exhibit slow growth in lower-grade gliomas (LGG). However, the majority of LGG cases progress to high-grade gliomas, posing challenges for prognostication. The tumor microenvironment (TME), characterized by telomere-related genes and immune cell infiltration, strongly influences glioma growth and therapeutic response. Therefore, our objective was to develop a Telomere-TME (TM-TME) classifier that integrates telomere-related genes and immune cell landscape to assess prognosis and therapeutic response in glioma.<br><br>METHODS: This study encompassed LGG patients from the TCGA and CCGA databases. TM score and TME score were derived from the expression signatures of telomere-related genes and the presence of immune cells in LGG, respectively. The TM-TME classifier was established by combining TM and TME scores to effectively predict prognosis. Subsequently, we conducted Kaplan-Meier survival estimation, univariate Cox regression analysis, and receiver operating characteristic curves to validate the prognostic prediction capacity of the TM-TME classifier across multiple cohorts. Gene Ontology (GO) analysis, biological processes, and proteomaps were performed to annotate the functional aspects of each subgroup and visualize the cellular signaling pathways.<br><br>RESULTS: The TM_low+TME_high subgroup exhibited superior prognosis and therapeutic response compared to other subgroups (P<0.001). This finding could be attributed to distinct tumor somatic mutations and cancer cellular signaling pathways. GO analysis indicated that the TM_low+TME_high subgroup is associated with the neuronal system and modulation of chemical synaptic transmission. Conversely, the TM_high+TME_low subgroup showed a strong association with cell cycle and DNA metabolic processes. Furthermore, the classifier significantly differentiated overall survival in the TCGA LGG cohort and served as an independent prognostic factor for LGG patients in both the TCGA cohort (P<0.001) and the CGGA cohort (P<0.001).<br><br>CONCLUSION: Overall, our findings underscore the significance of the TM-TME classifier in predicting prognosis and immune therapeutic response in glioma, shedding light on the complex immune landscape within each subgroup. Additionally, our results suggest the potential of integrating risk stratification with precision therapy for LGG.},
}
@article {pmid37660722,
year = {2024},
author = {Zhou, HH and Jin, B and Liao, Y and Hu, Y and Li, P and YangLha, T and Liu, Y and Xu, J and Wang, B and Zhu, M and Xiao, J and Liu, J and Nüssler, AK and Liu, L and Hao, X and Chen, J and Peng, Z and Yang, W},
title = {Associations of Various Physical Activities with Mortality and Life Expectancy are Mediated by Telomere Length.},
journal = {Journal of the American Medical Directors Association},
volume = {25},
number = {3},
pages = {431-438.e15},
doi = {10.1016/j.jamda.2023.08.002},
pmid = {37660722},
issn = {1538-9375},
mesh = {Adult ; Humans ; Middle Aged ; Prospective Studies ; *Exercise ; *Life Expectancy ; Longevity ; Telomere ; },
abstract = {OBJECTIVES: Physical activity (PA) and telomeres both contribute to healthy aging and longevity. To investigate the optimal dosage of various PA for longevity and the role of telomere length in PA and mortality.<br><br>DESIGN: Prospective cohort study.<br><br>SETTING AND PARTICIPANTS: A total of 333,865 adults (mean age of 56&#xa0;years) from the UK Biobank were analyzed.<br><br>METHODS: Walking, moderate PA (MPA), and vigorous PA (VPA) were self-reported via questionnaire, and leukocyte telomere length (LTL) was measured. Cox proportional hazards regression was used to predict all-cause mortality risk. A flexible parametric Royston-Parmar survival model was used to estimate life expectancy.<br><br>RESULTS: During a median follow-up of 13.8&#xa0;years, 19,789 deaths were recorded. Compared with the no-walking group, 90 to 720&#xa0;minutes/week of walking was similarly associated with 27% to 31% of lower mortality and about 6&#xa0;years of additional life expectancy. We observed nearly major benefits for mortality and life expectancy among those meeting the PA guidelines [151-300&#xa0;minutes/wk for MPA: hazard ratio (HR) 0.80, 95% CI 0.75-0.85, 3.40-3.42 additional life years; 76-150&#xa0;minutes/wk for VPA: HR 0.78, 95% CI 0.75-0.82, 2.61&#xa0;years (2.33-2.89)] vs the no-PA group. Similar benefits were also observed at 76-150 and 301-375&#xa0;minutes/wk of MPA (18%-19% lower mortality, 3.20-3.42 gained years) or 151-300&#xa0;minutes/wk of VPA (20%-26% lower mortality, 2.41-2.61 gained years). The associations between MPA, VPA, and mortality risk were slightly mediated by LTL (&#x2248;1% mediation proportion, both P < .001).<br><br>CONCLUSIONS AND IMPLICATIONS: Our study suggests a more flexible range of PA than the current PA guidelines, which could gain similar benefits and is easier to achieve: 90 to 720&#xa0;minutes/wk of walking, 75 to 375&#xa0;minutes/wk of MPA, and 75 to 300&#xa0;minutes/wk of VPA. Telomeres might be a potential mechanism by which PA promotes longevity.},
}
@article {pmid37658759,
year = {2023},
author = {Casagrande, S and Loveland, JL and Oefele, M and Boner, W and Lupi, S and Stier, A and Hau, M},
title = {Dietary nucleotides can prevent glucocorticoid-induced telomere attrition in a fast-growing wild vertebrate.},
journal = {Molecular ecology},
volume = {32},
number = {19},
pages = {5429-5447},
doi = {10.1111/mec.17114},
pmid = {37658759},
issn = {1365-294X},
mesh = {Humans ; Animals ; Adult ; *Telomere/genetics ; Glucocorticoids ; Nucleotides ; *Passeriformes/genetics ; Adenosine Triphosphate ; Telomere Shortening ; },
abstract = {Telomeres are chromosome protectors that shorten during eukaryotic cell replication and in stressful conditions. Developing individuals are susceptible to telomere erosion when their growth is fast and resources are limited. This is critical because the rate of telomere attrition in early life is linked to health and life span of adults. The metabolic telomere attrition hypothesis (MeTA) suggests that telomere dynamics can respond to biochemical signals conveying information about the organism's energetic state. Among these signals are glucocorticoids, hormones that promote catabolic processes, potentially impairing costly telomere maintenance, and nucleotides, which activate anabolic pathways through the cellular enzyme target of rapamycin (TOR), thus preventing telomere attrition. During the energetically demanding growth phase, the regulation of telomeres in response to two contrasting signals - one promoting telomere maintenance and the other attrition - provides an ideal experimental setting to test the MeTA. We studied nestlings of a rapidly developing free-living passerine, the great tit (Parus major), that either received glucocorticoids (Cort-chicks), nucleotides (Nuc-chicks) or a combination of both (NucCort-chicks), comparing these with controls (Cnt-chicks). As expected, Cort-chicks showed telomere attrition, while NucCort- and Nuc-chicks did not. NucCort-chicks was the only group showing increased expression of a proxy for TOR activation (the gene TELO2), of mitochondrial enzymes linked to ATP production (cytochrome oxidase and ATP-synthase) and a higher efficiency in aerobically producing ATP. NucCort-chicks had also a higher expression of telomere maintenance genes (shelterin protein TERF2 and telomerase TERT) and of enzymatic antioxidant genes (glutathione peroxidase and superoxide dismutase). The findings show that nucleotide availability is crucial for preventing telomere erosion during fast growth in stressful environments.},
}
@article {pmid37653240,
year = {2023},
author = {Roisné-Hamelin, F and Marcand, S},
title = {All roads lead to MRN regulation at telomeres: different paths to one solution.},
journal = {Nature structural &amp; molecular biology},
volume = {30},
number = {9},
pages = {1242-1243},
pmid = {37653240},
issn = {1545-9985},
}
@article {pmid37653239,
year = {2023},
author = {Myler, LR and Toia, B and Vaughan, CK and Takai, K and Matei, AM and Wu, P and Paull, TT and de Lange, T and Lottersberger, F},
title = {DNA-PK and the TRF2 iDDR inhibit MRN-initiated resection at leading-end telomeres.},
journal = {Nature structural &amp; molecular biology},
volume = {30},
number = {9},
pages = {1346-1356},
pmid = {37653239},
issn = {1545-9985},
support = {R01 AG016642/AG/NIA NIH HHS/United States ; R01 GM138548/GM/NIGMS NIH HHS/United States ; R35 CA210036/CA/NCI NIH HHS/United States ; R56 AG016642/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Mice ; *DNA-Activated Protein Kinase ; *DNA Breaks ; Endonucleases ; Telomere ; DNA ; },
abstract = {Telomeres replicated by leading-strand synthesis lack the 3' overhang required for telomere protection. Surprisingly, resection of these blunt telomeres is initiated by the telomere-specific 5' exonuclease Apollo rather than the Mre11-Rad50-Nbs1 (MRN) complex, the nuclease that acts at DNA breaks. Without Apollo, leading-end telomeres undergo fusion, which, as demonstrated here, is mediated by alternative end joining. Here, we show that DNA-PK and TRF2 coordinate the repression of MRN at blunt mouse telomeres. DNA-PK represses an MRN-dependent long-range resection, while the endonuclease activity of MRN-CtIP, which could cleave DNA-PK off of blunt telomere ends, is inhibited in vitro and in vivo by the iDDR of TRF2. AlphaFold-Multimer predicts a conserved association of the iDDR with Rad50, potentially interfering with CtIP binding and MRN endonuclease activation. We propose that repression of MRN-mediated resection is a conserved aspect of telomere maintenance and represents an ancient feature of DNA-PK and the iDDR.},
}
@article {pmid37650705,
year = {2023},
author = {Liu, M and Lan, Y and Zhang, H and Zhang, X and Wu, M and Yang, L and Zhou, J and Tong, M and Leng, L and Zheng, H and Li, J and Mi, X},
title = {Telomere length is associated with increased risk of cutaneous melanoma: a Mendelian randomization study.},
journal = {Melanoma research},
volume = {33},
number = {6},
pages = {475-481},
doi = {10.1097/CMR.0000000000000917},
pmid = {37650705},
issn = {1473-5636},
mesh = {Humans ; *Melanoma/genetics ; *Skin Neoplasms/genetics ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Telomere/genetics ; Melanoma, Cutaneous Malignant ; },
abstract = {The MR analysis using two TL GWAS datasets revealed strong and consistent evidence that long TL is causally associated with an increased risk of CM. The analysis of the Codd et al. dataset found that long TL significantly predicted an elevated risk of CM (IVW OR = 2.411, 95% CI 2.092-2.780, P = 8.05E-34). Similarly, the analysis of the Li et al. dataset yielded consistent positive results across all MR methods, providing further robustness to the causal relationship (IVW OR = 2.324, 95% CI 1.516-3.565, P = 1.11E-04). The study provides evidence for a causal association between TL and CM susceptibility, indicating that longer TL increases the risk of developing CM and providing insight into the unique telomere biology in melanoma pathogenesis. Telomere maintenance pathways may be a potential target for preventing and treating CM.},
}
@article {pmid37648073,
year = {2023},
author = {Greenland, JR and Guo, R and Lee, S and Tran, L and Kapse, B and Kukreja, J and Hays, SR and Golden, JA and Calabrese, DR and Singer, JP and Wolters, PJ},
title = {Short airway telomeres are associated with primary graft dysfunction and chronic lung allograft dysfunction.},
journal = {The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation},
volume = {42},
number = {12},
pages = {1700-1709},
pmid = {37648073},
issn = {1557-3117},
support = {R01 HL161048/HL/NHLBI NIH HHS/United States ; R01 HL139897/HL/NHLBI NIH HHS/United States ; U01 HL145435/HL/NHLBI NIH HHS/United States ; I01 CX002011/CX/CSRD VA/United States ; R01 HL151552/HL/NHLBI NIH HHS/United States ; IK2 BX005301/BX/BLRD VA/United States ; R01 HL134851/HL/NHLBI NIH HHS/United States ; U01 HL163242/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; *Primary Graft Dysfunction/genetics ; Lung ; *Lung Transplantation/adverse effects ; Allografts ; Fibrosis ; Telomere ; Retrospective Studies ; },
abstract = {Primary graft dysfunction (PGD) is a major risk factor for chronic lung allograft dysfunction (CLAD) following lung transplantation, but the mechanisms linking these pathologies are poorly understood. We hypothesized that the replicative stress induced by PGD would lead to erosion of telomeres, and that this telomere dysfunction could potentiate CLAD. In a longitudinal cohort of 72 lung transplant recipients with >6 years median follow-up time, we assessed tissue telomere length, PGD grade, and freedom from CLAD. Epithelial telomere length and fibrosis-associated gene expression were assessed on endobronchial biopsies taken at 2 to 4 weeks post-transplant by TeloFISH assay and nanoString digital RNA counting. Negative-binomial mixed-effects and Cox-proportional hazards models accounted for TeloFISH staining batch effects and subject characteristics including donor age. Increasing grade of PGD severity was associated with shorter airway epithelial telomere lengths (p = 0.01). Transcriptomic analysis of fibrosis-associated genes showed alteration in fibrotic pathways in airway tissue recovering from PGD, while telomere dysfunction was associated with inflammation and impaired remodeling. Shorter tissue telomere length was in turn associated with increased CLAD risk, with a hazard ratio of 1.89 (95% CI 1.16-3.06) per standard deviation decrease in airway telomere length, after adjusting for subject characteristics. PGD may accelerate telomere dysfunction, potentiating immune responses and dysregulated repair. Epithelial cell telomere dysfunction may represent one of several mechanisms linking PGD to CLAD.},
}
@article {pmid37645045,
year = {2023},
author = {Li, H and Durbin, R},
title = {Genome assembly in the telomere-to-telomere era.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {37645045},
issn = {2331-8422},
support = {/WT_/Wellcome Trust/United Kingdom ; R01 HG010040/HG/NHGRI NIH HHS/United States ; },
abstract = {De novo assembly is the process of reconstructing the genome sequence of an organism from sequencing reads. Genome sequences are essential to biology, and assembly has been a central problem in bioinformatics for four decades. Until recently, genomes were typically assembled into fragments of a few megabases at best but technological advances in long-read sequencing now enable near complete chromosome-level assembly, also known as telomere-to-telomere assembly, for many organisms. Here we review recent progress on assembly algorithms and protocols. We focus on how to derive near telomere-to-telomere assemblies and discuss potential future developments.},
}
@article {pmid37641324,
year = {2023},
author = {Häussler, S and Ghaffari, MH and Seibt, K and Sadri, H and Alaedin, M and Huber, K and Frahm, J and Dänicke, S and Sauerwein, H},
title = {Blood and liver telomere length, mitochondrial DNA copy number, and hepatic gene expression of mitochondrial dynamics in mid-lactation cows supplemented with l-carnitine under systemic inflammation.},
journal = {Journal of dairy science},
volume = {106},
number = {12},
pages = {9822-9842},
doi = {10.3168/jds.2023-23556},
pmid = {37641324},
issn = {1525-3198},
mesh = {Female ; Cattle ; Animals ; *Lactation/physiology ; Lipopolysaccharides/adverse effects ; Carnitine/metabolism ; DNA, Mitochondrial ; DNA Copy Number Variations ; Mitochondrial Dynamics ; Inflammation/veterinary ; Dietary Supplements ; Liver/metabolism ; Milk/metabolism ; Diet/veterinary ; Gene Expression ; Fibrinogen/adverse effects/metabolism ; RNA, Messenger/metabolism ; Mitochondrial Proteins/metabolism ; Telomere ; *Cattle Diseases/metabolism ; },
abstract = {The current study was conducted to examine the effect of l-carnitine (LC) supplementation on telomere length and mitochondrial DNA copy number (mtDNAcn) per cell in mid-lactation cows challenged by lipopolysaccharide (LPS) in blood and liver. The mRNA abundance of 31 genes related to inflammation, oxidative stress, and the corresponding stress response mechanisms, the mitochondrial quality control and the protein import system, as well as the phosphatidylinositol 3-kinase/protein kinase B pathway, were assessed using microfluidics integrated fluidic circuit chips (96.96 dynamic arrays). In addition to comparing the responses in cows with or without LC, our objectives were to characterize the oxidative and inflammatory status by assessing the circulating concentration of lactoferrin (Lf), haptoglobin (Hp), fibrinogen, derivates of reactive oxygen metabolites (dROM), and arylesterase activity (AEA), and to extend the measurement of Lf and Hp to milk. Pluriparous Holstein cows were assigned to either a control group (CON, n = 26) or an LC-supplemented group (CAR; 25 g LC/cow per day; d 42 ante partum to d 126 postpartum (PP), n = 27). On d 111 PP, each cow was injected intravenously with LPS (Escherichia coli O111:B4, 0.5 µg/kg). The mRNA abundance was examined in liver biopsies of d -11 and +1 relative to LPS administration. Plasma and milk samples were frequently collected before and after the challenge. After LPS administration, circulating plasma fibrinogen and serum dROM concentrations increased, whereas AEA decreased. Moreover, serum P4 initially increased by 3 h after LPS administration and declined thereafter irrespective of grouping. The Lf concentrations increased in both groups after LPS administration, with the CAR group showing greater concentrations in serum and milk than the CON group. After LPS administration, telomere length in blood increased, whereas mtDNAcn per cell decreased; however, both remained unaffected in liver. For mitochondrial protein import genes, the hepatic mRNA abundance of the translocase of the mitochondrial inner membrane (TIM)-17B was increased in CAR cows. Moreover, TIM23 increased in both groups after LPS administration. Regarding the mRNA abundance of genes related to stress response mechanisms, 7 out of 14 genes showed group × time interactions, indicating a (local) protective effect due to the dietary LC supplementation against oxidative stress in mid-lactating dairy cows. For mtDNAcn and telomere length, the effects of the LPS-induced inflammation were more pronounced than the dietary supplementation of LC. Dietary LC supplementation affected the response to LPS primarily by altering mitochondrial dynamics. Regarding mRNA abundance of genes related to the mitochondrial protein import system, the inner mitochondrial membrane translocase (TIM complex) seemed to be more sensitive to dietary LC than the outer mitochondrial membrane translocase (TOM complex).},
}
@article {pmid37634078,
year = {2023},
author = {Wang, L and Zhang, M and Li, M and Jiang, X and Jiao, W and Song, Q},
title = {A telomere-to-telomere gap-free assembly of soybean genome.},
journal = {Molecular plant},
volume = {16},
number = {11},
pages = {1711-1714},
doi = {10.1016/j.molp.2023.08.012},
pmid = {37634078},
issn = {1752-9867},
mesh = {*Glycine max/genetics ; *Telomere/genetics ; },
}
@article {pmid37628647,
year = {2023},
author = {Igoshin, AV and Yudin, NS and Romashov, GA and Larkin, DM},
title = {A Multibreed Genome-Wide Association Study for Cattle Leukocyte Telomere Length.},
journal = {Genes},
volume = {14},
number = {8},
pages = {},
pmid = {37628647},
issn = {2073-4425},
mesh = {Animals ; Cattle/genetics ; Cell Division ; *Genome-Wide Association Study ; *Leukocytes/physiology ; *Telomere/genetics/physiology ; },
abstract = {Telomeres are terminal DNA regions of chromosomes that prevent chromosomal fusion and degradation during cell division. In cattle, leukocyte telomere length (LTL) is associated with longevity, productive lifespan, and disease susceptibility. However, the genetic basis of LTL in this species is less studied than in humans. In this study, we utilized the whole-genome resequencing data of 239 animals from 17 cattle breeds for computational leukocyte telomere length estimation and subsequent genome-wide association study of LTL. As a result, we identified 42 significant SNPs, of which eight were found in seven genes (EXOC6B, PTPRD, RPS6KC1, NSL1, AGBL1, ENSBTAG00000052188, and GPC1) when using covariates for two major breed groups (Turano-Mongolian and European). Association analysis with covariates for breed effect detected 63 SNPs, including 13 in five genes (EXOC6B, PTPRD, RPS6KC1, ENSBTAG00000040318, and NELL1). The PTPRD gene, demonstrating the top signal in analysis with breed effect, was previously associated with leukocyte telomere length in cattle and likely is involved in the mechanism of alternative lengthening of telomeres. The single nucleotide variants found could be tested for marker-assisted selection to improve telomere-length-associated traits.},
}
@article {pmid37615075,
year = {2023},
author = {Ha, SJ and Kwag, E and Kim, S and Park, JH and Park, SJ and Yoo, HS},
title = {Effect of Traditional Korean Medicine Oncotherapy on the Survival, Quality of Life, and Telomere Length: A Prospective Cohort Study.},
journal = {Integrative cancer therapies},
volume = {22},
number = {},
pages = {15347354231154267},
pmid = {37615075},
issn = {1552-695X},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; },
mesh = {Female ; Humans ; *Quality of Life ; Prospective Studies ; Progression-Free Survival ; *Medicine, Korean Traditional ; Telomere/genetics ; Republic of Korea ; },
abstract = {A 4-year prospective cohort study on patients with lung, gastric, hepatic, colorectal, breast, uterine, and ovarian cancer was conducted at the East-West Cancer Center (EWCC) of Daejeon Korean Medicine Hospital in Daejeon, Korea. We divided patients into 2 groups based on how long they had been receiving TKM oncotherapy and compared event-free survival (EFS), telomere length change, and quality of life (QoL). The study collected data on 83 patients from October 2016 to June 2020 and discovered no statistical differences in EFS based on the duration of TKM oncotherapy. In the analysis of changes in QoL outcomes, there were no statistically significant group differences between the groups. After controlling for covariates that could affect telomere length, the long-term TKM oncotherapy group had a higher daily telomere attrition rate. The study of the relationship between telomere length and prognostic factors discovered that patients with advanced N stage at the time of diagnosis and who had previously received radiotherapy had shorter telomere length. When examining associations between SNP genotype and percentile score of telomere length, this study was able to confirm an association between telomere length and rs4387287. This study is significant because it is the first to assess the effects of TKM oncotherapy and investigate telomere length-related factors. To assess the effects of TKM oncotherapy on cancer patients' survival and QoL, a longer-term observational study with a larger sample size is required.},
}
@article {pmid37611374,
year = {2023},
author = {Dupoué, A and Mello, DF and Trevisan, R and Dubreuil, C and Queau, I and Petton, S and Huvet, A and Guével, B and Com, E and Pernet, F and Salin, K and Fleury, E and Corporeau, C},
title = {Intertidal limits shape covariation between metabolic plasticity, oxidative stress and telomere dynamics in Pacific oyster (Crassostrea gigas).},
journal = {Marine environmental research},
volume = {191},
number = {},
pages = {106149},
doi = {10.1016/j.marenvres.2023.106149},
pmid = {37611374},
issn = {1879-0291},
abstract = {In intertidal zones, species such as sessile shellfish exhibit extended phenotypic plasticity to face rapid environmental changes, but whether frequent exposure to intertidal limits of the distribution range impose physiological costs for the animal remains elusive. Here, we explored how phenotypic plasticity varied along foreshore range at multiple organization levels, from molecular to cellular and whole organism acclimatization, in the Pacific oyster (Crassostrea gigas). We exposed 7-month-old individuals for up to 16 months to three foreshore levels covering the vertical range for this species, representing 20, 50 and 80% of the time spent submerged monthly. Individuals at the upper range limit produced energy more efficiently, as seen by steeper metabolic reactive norms and unaltered ATP levels despite reduced mitochondrial density. By spending most of their time emerged, oysters mounted an antioxidant shielding concomitant with lower levels of pro-oxidant proteins and postponed age-related telomere attrition. Instead, individuals exposed at the lower limit range near subtidal conditions showed lower energy efficiencies, greater oxidative stress and shorter telomere length. These results unraveled the extended acclimatization strategies and the physiological costs of living too fast in subtidal conditions for an intertidal species.},
}
@article {pmid37610666,
year = {2023},
author = {Frydrychová, R&#x10c; and Konopová, B and Peska, V and Brejcha, M and Sábová, M},
title = {Telomeres and telomerase: active but complex players in life-history decisions.},
journal = {Biogerontology},
volume = {},
number = {},
pages = {},
pmid = {37610666},
issn = {1573-6768},
support = {LUAUS23128//Ministry of Education/ ; },
abstract = {Studies on human telomeres have established that telomeres exert a significant influence on lifespan and health of organisms. However, recent research has indicated that the original idea that telomeres affect lifespan in a universal and central manner across all eukaryotic species is an oversimplification. Indeed, findings from a variety of animal species revealed that the role of telomere biology in aging is more subtle and intricate than previously recognized. Here, we show how telomere biology varies depending on the taxon. We also show how telomere biology corresponds to basic life history traits and affects the life table of a species and investments in growth, body size, reproduction, and lifespan; telomeres are hypothesized to shape evolutionary perspectives for species in an active but complex manner. Our evaluation is based on telomere biology data from many examples from throughout the animal kingdom that vary according to the degree of organismal complexity and life history strategies.},
}
@article {pmid37608257,
year = {2023},
author = {Liu, C and Ding, K and Abdul, M and Sun, QC and Zhang, ZF and Dong, MM and Han, L and Dai, MS and Guan, HL and Han, Y and Liu, H and Chen, XF and Cao, JL},
title = {The relationship between longer leukocyte telomeres and dNCR in non-cardiac surgery patients: a retrospective analysis.},
journal = {BMC anesthesiology},
volume = {23},
number = {1},
pages = {284},
pmid = {37608257},
issn = {1471-2253},
mesh = {Aged ; Humans ; Retrospective Studies ; *Aging ; *Cognitive Dysfunction ; Leukocytes ; Telomere ; },
abstract = {BACKGROUND: Cognitive decline following surgery is a common concern among elderly individuals. Leukocyte telomere length (LTL) can be assessed as a biological clock connected to an individual lifespan. However, the mechanisms causing this inference are still not fully understood. As a result of this, LTL has the potential to be useful as an aging-related biomarker for assessing delayed neurocognitive recovery (dNCR) and related diseases.<br><br>METHODS: For this study, 196 individuals over 60 who were scheduled due to major non-cardiac surgical operations attended neuropsychological testing before surgery, followed by additional testing one week later. The finding of dNCR was based on a measured Z-score&#x2009;&#x2264;&#x2009;-1.96 on two or more separate tests. The frequency of dNCR was presented as the primary outcome of the study. Secondly, we evaluated the association between dNCR and preoperative LTL.<br><br>RESULTS: Overall, 20.4% [40/196; 95% confidence interval (CI), 14.7-26.1%] of patients exhibited dNCR 1-week post-surgery. Longer LTL was identified as a predictor for the onset of early cognitive impairment resulting in postoperative cognitive decline [odds ratio (OR), 14.82; 95% CI, 4.01-54.84; P&#x2009;<&#x2009;0.001], following adjustment of age (OR, 12.33; 95% CI, 3.29-46.24; P&#x2009;<&#x2009;0.001). The dNCR incidence based on LTL values of these patients, the area under the receiver operating characteristic (ROC) curve was 0.79 (95% CI, 0.722-0.859; P&#x2009;<&#x2009;0.001). At an optimal cut-off value of 0.959, LTL values offered respective specificity and sensitivity values of 64.7% and 87.5%.<br><br>CONCLUSIONS: In summary, the current study revealed that the incidence of dNCR was strongly associated with prolonged LTL. Furthermore, this biomarker could help identify high-risk patients and offer insight into the pathophysiology of dNCR.},
}
@article {pmid37606092,
year = {2023},
author = {Eastwood, JR and Dupoué, A and Verhulst, S and Cockburn, A and Peters, A},
title = {Cool, dry nights and short heatwaves during growth result in longer telomeres in temperate songbird nestlings.},
journal = {Molecular ecology},
volume = {32},
number = {19},
pages = {5382-5393},
doi = {10.1111/mec.17107},
pmid = {37606092},
issn = {1365-294X},
mesh = {Animals ; *Songbirds/genetics ; Climate ; Temperature ; *Passeriformes ; Telomere/genetics ; },
abstract = {Exposure to rising sublethal temperatures can affect development and somatic condition, and thereby Darwinian fitness. In the context of climate warming, these changes could have implications for population viability, but they can be subtle and consequently difficult to quantify. Using telomere length (TL) as a known biomarker of somatic condition in early life, we investigated the impact of pre-hatching and nestling climate on six cohorts of wild nestling superb fairy wrens (Malurus cyaneus) in temperate south-eastern Australia. Models incorporating only climate information from the nestling phase were best supported compared to those including the (pre-)laying to incubation phase (previously shown to affect mass) or both phases combined. This implies that nestling TL is most sensitive to ambient climate in the nestling phase. The top model showed a negative relationship between early-life TL and nestling mean daily minimum temperature when rainfall was low which gradually became positive with increasing rainfall. In addition, there was a positive relationship between TL and the frequency of hot days (daily maximum temperature ≥35°C), although these temperatures were rare and short-term. Including other pre-hatching and nestling period, climate variables (e.g., mean daily maximum temperature and mean diurnal temperature variability) did not improve the prediction of nestling TL. Overall, our results suggest that cooler nights when conditions are dry and short-term temperature spikes above 35°C during development are conducive for somatic maintenance. While these findings indicate a potential pathway for climate warming to impact wildlife fitness, they emphasize the need to elucidate the mechanisms underlying these complex associations.},
}
@article {pmid37602392,
year = {2024},
author = {Lyčka, M and Bubeník, M and Závodník, M and Peska, V and Fajkus, P and Demko, M and Fajkus, J and Fojtová, M},
title = {TeloBase: a community-curated database of telomere sequences across the tree of life.},
journal = {Nucleic acids research},
volume = {52},
number = {D1},
pages = {D311-D321},
pmid = {37602392},
issn = {1362-4962},
support = {20-01331X//Czech Science Foundation/ ; //CzechElib/ ; },
mesh = {Nucleotide Motifs ; Plants/genetics ; *Telomerase/genetics ; Telomere/genetics/metabolism ; *Databases, Genetic ; },
abstract = {Discoveries over the recent decade have demonstrated the unexpected diversity of telomere DNA motifs in nature. However, currently available resources, 'Telomerase database' and 'Plant rDNA database', contain just fragments of all relevant literature published over decades of telomere research as they have a different primary focus and limited updates. To fill this gap, we gathered data about telomere DNA sequences from a thorough literature screen as well as by analysing publicly available NGS data, and we created TeloBase (http://cfb.ceitec.muni.cz/telobase/) as a comprehensive database of information about telomere motif diversity. TeloBase is supplemented by internal taxonomy utilizing popular on-line taxonomic resources that enables in-house data filtration and graphical visualisation of telomere DNA evolutionary dynamics in the form of heat tree plots. TeloBase avoids overreliance on administrators for future data updates by having a simple form and community-curation system for application and approval, respectively, of new telomere sequences by users, which should ensure timeliness of the database and topicality. To demonstrate TeloBase utility, we examined telomere motif diversity in species from the fungal genus Aspergillus, and discovered (TTTATTAGGG)n sequence as a putative telomere motif in the plant family Chrysobalanaceae. This was bioinformatically confirmed by analysing template regions of identified telomerase RNAs.},
}
@article {pmid37601866,
year = {2023},
author = {Gorsi, HS and Gallardo-Rios, M and Savaşan, S},
title = {Short telomere length in autoimmune neutropenia of childhood: A mere coincidence or an association?.},
journal = {EJHaem},
volume = {4},
number = {3},
pages = {827-828},
pmid = {37601866},
issn = {2688-6146},
}
@article {pmid37600718,
year = {2023},
author = {Han, X and Wu, T and Liu, CY},
title = {Univariable and multivariable Mendelian randomization investigating the effects of telomere length on the risk of adverse pregnancy outcomes.},
journal = {Frontiers in endocrinology},
volume = {14},
number = {},
pages = {1225600},
pmid = {37600718},
issn = {1664-2392},
mesh = {Infant, Newborn ; Female ; Pregnancy ; Humans ; Pregnancy Outcome ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Premature Birth ; *Abortion, Spontaneous ; *Diabetes, Gestational ; Fetal Growth Retardation ; *Pre-Eclampsia/epidemiology/genetics ; Telomere/genetics ; },
abstract = {BACKGROUND: Numerous observational studies have revealed a correlation between telomere length (TL) and adverse pregnancy outcomes (APOs). However, the impacts of TL on APOs are still unclear.<br><br>METHODS: Mendelian randomization (MR) was carried out using summary data from genome-wide association studies (GWAS). Inverse variance weighted (IVW) was employed as the primary analysis to explore the causal relationship between TL and APOs. The exposure data came from a GWAS dataset of IEU analysis of the United Kingdom Biobank phenotypes consisting of 472,174 European participants. Summary-level data for five APOs were obtained from the GWAS datasets of the FinnGen consortium. We also performed multivariate MR (MVMR), adjusting for smoking, alcohol intake, body mass index (BMI), and number of live births. In addition, we conducted a series of rigorous analyses to further examine the validity of our MR findings.<br><br>RESULTS: After Bonferroni correction and rigorous quality control, univariable MR (UVMR) demonstrated that a shorter TL was significantly associated with an increased risk of spontaneous abortion (SA) (odds ratio [OR]: 0.815; 95% confidence interval [CI]: 0.714-0.930; P = 0.002) and preterm birth (PTB) (OR: 0.758; 95% CI: 0.632-0.908; P = 0.003) in the IVW model. There was a nominally significant relationship between TL and preeclampsia (PE) in the IVW model (OR: 0.799; 95% CI: 0.651-0.979; P = 0.031). However, no significant association was found between TL and gestational diabetes mellitus (GDM) (OR: 0.950; 95% CI: 0.804-1.122; P = 0.543) or fetal growth restriction (FGR) (OR: 1.187; 95% CI: 0.901-1.565; P = 0.223) among the five statistical models. Furthermore, we did not find a significant causal effect of APOs on TL in the reverse MR analysis. MVMR analysis showed that the causal effects of TL on SA remained significant after accounting for smoking, alcohol intake, BMI, and number of live births.<br><br>CONCLUSION: Our MR study provides robust evidence that shorter telomeres were associated with an increased risk of SA. Further work is necessary to investigate the potential mechanisms. UVMR and MVMR findings showed limited evidence that TL affects the risk of PTB, PE, GDM, and FGR, illustrating that the outcomes of previous observational studies may have been confounded.},
}
@article {pmid37599304,
year = {2023},
author = {Mo, W and Shu, Y and Liu, B and Long, Y and Li, T and Cao, X and Deng, X and Zhai, J},
title = {Single-molecule targeted accessibility and methylation sequencing of centromeres, telomeres and rDNAs in Arabidopsis.},
journal = {Nature plants},
volume = {9},
number = {9},
pages = {1439-1450},
pmid = {37599304},
issn = {2055-0278},
mesh = {*Arabidopsis/genetics ; Centromere/genetics ; Telomere/genetics ; DNA Methylation ; Chromatin/genetics ; DNA, Ribosomal ; },
abstract = {The short read-length of next-generation sequencing makes it challenging to characterize highly repetitive regions (HRRs) such as centromeres, telomeres and ribosomal DNAs. Based on recent strategies that combined long-read sequencing and exogenous enzymatic labelling of open chromatin, we developed single-molecule targeted accessibility and methylation sequencing (STAM-seq) in plants by further integrating nanopore adaptive sampling to investigate the HRRs in wild-type Arabidopsis and DNA methylation mutants that are defective in CG- or non-CG methylation. We found that CEN180 repeats show higher chromatin accessibility and lower DNA methylation on their forward strand, individual rDNA units show a negative correlation between their DNA methylation and accessibility, and both accessibility and CHH methylation levels are lower at telomere compared to adjacent subtelomeric region. Moreover, DNA methylation-deficient mutants showed increased chromatin accessibility at HRRs, consistent with the role of DNA methylation in maintaining heterochromatic status in plants. STAM-seq can be applied to study accessibility and methylation of repetitive sequences across diverse plant species.},
}
@article {pmid37598977,
year = {2023},
author = {Stylianakis, E and Chan, JPK and Law, PP and Jiang, Y and Khadayate, S and Karimi, MM and Festenstein, R and Vannier, JB},
title = {Mouse HP1γ regulates TRF1 expression and telomere stability.},
journal = {Life sciences},
volume = {331},
number = {},
pages = {122030},
doi = {10.1016/j.lfs.2023.122030},
pmid = {37598977},
issn = {1879-0631},
support = {MC_UP_1102/14/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; Humans ; Mice ; Chromatin ; DNA ; *Fibroblasts/metabolism ; RNA/genetics/metabolism ; *Telomere/genetics/metabolism ; Transcription Factors/genetics ; Telomeric Repeat Binding Protein 1/metabolism ; },
abstract = {AIMS: Telomeric repeat-containing RNAs are long non-coding RNAs generated from the telomeres. TERRAs are essential for the establishment of heterochromatin marks at telomeres, which serve for the binding of members of the heterochromatin protein 1 (HP1) protein family of epigenetic modifiers involved with chromatin compaction and gene silencing. While HP1γ is enriched on gene bodies of actively transcribed human and mouse genes, it is unclear if its transcriptional role is important for HP1γ function in telomere cohesion and telomere maintenance. We aimed to study the effect of mouse HP1γ on the transcription of telomere factors and molecules that can affect telomere maintenance.<br><br>MAIN METHODS: We investigated the telomere function of HP1&#x3b3; by using HP1&#x3b3; deficient mouse embryonic fibroblasts (MEFs). We used gene expression analysis of HP1&#x3b3; deficient MEFs and validated the molecular and mechanistic consequences of HP1&#x3b3; loss by telomere FISH, immunofluorescence, RT-qPCR and DNA-RNA immunoprecipitation (DRIP).<br><br>KEY FINDINGS: Loss of HP1&#x3b3; in primary MEFs led to a downregulation of various telomere and telomere-accessory transcripts, including the shelterin protein TRF1. Its downregulation is associated with increased telomere replication stress and DNA damage (&#x3b3;H2AX), effects more profound in females. We suggest that the source for the impaired telomere maintenance is a consequence of increased telomeric DNA-RNA hybrids and TERRAs arising at and from mouse chromosomes 18 and X.<br><br>SIGNIFICANCE: Our results suggest an important transcriptional control by mouse HP1&#x3b3; of various telomere factors including TRF1 protein and TERRAs that has profound consequences on telomere stability, with a potential sexually dimorphic nature.},
}
@article {pmid37598517,
year = {2023},
author = {Zhang, D and Chen, X and Huang, K and Zheng, Q and Fu, Y and Ma, J and Ren, X and Xu, B and Liu, P and Liu, J and Lu, S},
title = {Urinary essential and toxic metal mixtures, and type 2 diabetes mellitus: Telomere shortening as an intermediary factor?.},
journal = {Journal of hazardous materials},
volume = {459},
number = {},
pages = {132329},
doi = {10.1016/j.jhazmat.2023.132329},
pmid = {37598517},
issn = {1873-3336},
mesh = {Adult ; Humans ; *Diabetes Mellitus, Type 2 ; Mediation Analysis ; Telomere Shortening ; Bayes Theorem ; Cadmium/toxicity ; Cross-Sectional Studies ; Lead ; },
abstract = {The joint effect of metal mixtures on telomere function and type 2 diabetes mellitus (T2DM) is unclear. This large-scale cross-sectional study sought to assess the role of telomere length (TL) in the relationship between urinary essential and toxic metal mixtures, and T2DM in 7410 Chinese adults ≥ 60 years of age. Essential (Cr, Cu, Zn, Se) and non-essential metals (V, Al, Sb, Sn, Cd, Pb) in urine samples were quantified, while leukocyte TL was measured from blood samples. Restricted cubic splines regression showed nonlinear relationships between single metal and T2DM, and between TL and T2DM. Bayesian kernel machine regression and quantile-based g-computation showed that the overall status of urinary metals was positively associated with risk of developing T2DM, which was mainly explained by exposure to Pb, Cd, and Sb, excessive Se intake, and high excretion of Zn. Mediation analyses showed that shortened TL mediated 27.9% of the overall positive effect of metal exposure on T2DM, and this mediation was mainly explained by toxic metal exposure and excessive Se intake. Tobacco smoke exposure, extensive cooking at home, and black tea consumption were found to be important contributors of toxic metal exposures. Further studies are needed to explore the recommended Zn dosage for T2DM patients at different stages, which may ameliorate pancreatic senescence and glycemic progression.},
}
@article {pmid37596879,
year = {2023},
author = {Zhang, Y and Zhu, Y and Ye, M and Mao, Y and Zhan, Y},
title = {Telomere length and its association with systemic lupus erythematosus in an Asian population: A Mendelian randomization study.},
journal = {Lupus},
volume = {32},
number = {10},
pages = {1222-1226},
doi = {10.1177/09612033231195953},
pmid = {37596879},
issn = {1477-0962},
mesh = {Humans ; Asian ; Genome-Wide Association Study ; *Lupus Erythematosus, Systemic/genetics ; Mendelian Randomization Analysis ; *Telomere/genetics ; Telomere Shortening/genetics ; Genetic Predisposition to Disease ; },
abstract = {OBJECTIVES: To investigate whether shorter telomere length is a causal risk factor for systemic lupus erythematosus (SLE) in the Asian population.<br><br>METHODS: We applied the two-sample Mendelian randomization (MR) method to the pooled statistics from a genome-wide association study (GWAS) of 6,707 SLE cases and 16,047 controls. We selected nine single-nucleotide polymorphisms (SNPs) with genome-wide significance as instrumental variables for telomere length. The main analysis was carried out by the random-effects inverse-variance weighted (IVW) method. Horizontal pleiotropy was evaluated by the intercept of MR-Egger regression.<br><br>RESULTS: A potentially causal relationship between longer genetically predicted telomere length and increased risk of systemic lupus erythematosus (OR = 1.72, 95%CI: 1.21, 2.46, p = 0.01) was observed. The MR-Egger regression demonstrated an intercept proximal to zero (intercept = 0.017, p = 0.69), which does not provide evidence of the presence of horizontal pleiotropy.<br><br>CONCLUSIONS: Our findings provided evidence supporting a potential causal relationship between longer telomere length and increased risk of systemic lupus erythematosus.},
}
@article {pmid37595788,
year = {2023},
author = {He, Y and Chu, Y and Guo, S and Hu, J and Li, R and Zheng, Y and Ma, X and Du, Z and Zhao, L and Yu, W and Xue, J and Bian, W and Yang, F and Chen, X and Zhang, P and Wu, R and Ma, Y and Shao, C and Chen, J and Wang, J and Li, J and Wu, J and Hu, X and Long, Q and Jiang, M and Ye, H and Song, S and Li, G and Wei, Y and Xu, Y and Ma, Y and Chen, Y and Wang, K and Bao, J and Xi, W and Wang, F and Ni, W and Zhang, M and Yu, Y and Li, S and Kang, Y and Gao, Z},
title = {T2T-YAO: A Telomere-to-telomere Assembled Diploid Reference Genome for Han Chinese.},
journal = {Genomics, proteomics &amp; bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.gpb.2023.08.001},
pmid = {37595788},
issn = {2210-3244},
abstract = {Since its initial release in 2001, the human reference genome has undergone continuous improvement in quality, and the recently released telomere-to-telomere version-T2T-CHM13-reaches its highest level of continuity and accuracy after 20 years of effort by working on a simplified, nearly homozygous genome of a hydatidiform mole cell line. To provide an authentic complete diploid human genome reference for the Han Chinese, the largest population in the world, we have assembled the genome of a male Han Chinese individual, T2T-YAO, which includes telomere-to-telomere assemblies of all the 22+X+M and 22+Y chromosomes in both haploid. The quality of T2T-YAO is much better than all currently available diploid assemblies, and its haploid version, T2T-YAO-hp, generated by selecting the better assembly for each autosome, reaches the top quality of fewer than one error per 29.5 Mb, even higher than that of T2T-CHM13. Derived from an individual living in the aboriginal region of the Han population, T2T-YAO shows clear ancestry and potential genetic continuity from the ancient ancestors. Each haplotype of T2T-YAO possesses ∼330 Mb exclusive sequences, ∼3100 unique genes, and tens of thousands of nucleotide and structural variations as compared to CHM13, highlighting the necessity of population-stratified reference genome. The construction of T2T-YAO, a truly accurate and authentic representative of the Chinese population, would enable precise delineation of genomic variations and advance our understandings in the hereditability of diseases and phenotypes, especially within the context of the unique variations of the Chinese population.},
}
@article {pmid37594236,
year = {2023},
author = {Rinne, GR and Carroll, JE and Guardino, CM and Shalowitz, MU and Ramey, SL and Schetter, CD},
title = {Parental preconception posttraumatic stress symptoms and maternal prenatal inflammation prospectively predict shorter telomere length in children.},
journal = {Psychosomatic medicine},
volume = {},
number = {},
pages = {},
pmid = {37594236},
issn = {1534-7796},
support = {U01 HD044207/HD/NICHD NIH HHS/United States ; R03 HD059584/HD/NICHD NIH HHS/United States ; R01 HD072021/HD/NICHD NIH HHS/United States ; U01 HD054791/HD/NICHD NIH HHS/United States ; U01 HD044245/HD/NICHD NIH HHS/United States ; U01 HD044253/HD/NICHD NIH HHS/United States ; U01 HD044226/HD/NICHD NIH HHS/United States ; U01 HD044219/HD/NICHD NIH HHS/United States ; T32 MH015750/MH/NIMH NIH HHS/United States ; U01 NR008929/NR/NINR NIH HHS/United States ; },
abstract = {OBJECTIVE: Parental trauma exposure and trauma-related distress can increase risk for adverse health outcomes in offspring, but the pathways implicated in intergenerational transmission are not fully explicated. Accelerated biological aging may be one mechanism underlying less favorable health in trauma-exposed individuals and their offspring. This study examines associations of preconception maternal and paternal posttraumatic stress disorder (PTSD) symptoms with child telomere length, and maternal prenatal C-reactive protein (CRP) as a biological mechanism.<br><br>METHODS: Mothers (n = 127) and a subset of the fathers (n = 84) reported on PTSD symptoms before conception. Mothers provided blood spots in the second and third trimester that were assayed for CRP. At age 4, children provided buccal cells for measurement of telomere length. Models adjusted for parental age, socioeconomic status, maternal pre-pregnancy BMI, child biological sex, and child age.<br><br>RESULTS: Mothers' PTSD symptoms were significantly associated with shorter child telomere length (&#x3b2; = -0.22, SE = 0.10, p = .023). Fathers' PTSD symptoms were also inversely associated with child telomere length (&#x3b2; = -0.21, SE = 0.11), though nonsignificant (p = .065). There was no significant indirect effect of mothers' PTSD symptoms on child telomere length through CRP in pregnancy, but higher second trimester CRP was significantly associated with shorter child telomere length (&#x3b2; = -0.35, SE = 0.18, p = .048).<br><br>CONCLUSIONS: Maternal symptoms of PTSD prior to conception and second trimester inflammation were associated with shorter telomere length in offspring in early childhood, independent of covariates. Findings indicate intergenerational transmission of parental trauma may occur in part through accelerated biological aging processes and provide further evidence that prenatal pro-inflammatory processes program child telomere length.Open Science Framework Pre-registration:https://osf.io/7c2d5/?view_only=cd0fb81f48db4b8f9c59fc8bb7b0ef97.},
}
@article {pmid37593897,
year = {2023},
author = {Luo, X and Ruan, Z and Liu, L},
title = {Causal relationship between telomere length and epilepsy: A bidirectional Mendelian randomization study.},
journal = {Epilepsia open},
volume = {8},
number = {4},
pages = {1432-1439},
pmid = {37593897},
issn = {2470-9239},
support = {2021A378//Science and Technology program of Jiangxi Provincial Administration of Traditional Chinese Medicine/ ; },
mesh = {Humans ; *Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Epilepsy/genetics ; Causality ; Telomere/genetics ; },
abstract = {OBJECTIVE: Observational studies have suggested a link between telomere length (TL) and epilepsy, but the direction of the effect and whether it is causal or not is still being debated. The objective of this study was to investigate the causal relationship between TL and epilepsy using Mendelian randomization (MR) analysis.<br><br>METHODS: We performed a bidirectional two-sample MR analysis using pooled statistics from genome-wide association studies (GWAS) of TL and epilepsy. Additionally, we conducted a replication analysis using data from another GWAS study on epilepsy to validate our findings. The final results were analyzed using five MR methods, with the inverse-variance weighted (IVW) method as the primary outcome. We applied methods such as radial MR, MR pleiotropy residual and outlier test and MR Steiger filters to exclude outliers. Sensitivity analyses were also conducted to assess heterogeneity and pleiotropy.<br><br>RESULTS: Our analysis found no evidence of a causal relationship between epilepsy and TL (all p-values >0.05). The sensitivity analysis confirms the robustness of these results.<br><br>SIGNIFICANCE: In summary, our study contradicts existing observational reports by not finding any evidence to support a causal relationship between epilepsy and TL. Further research is necessary to determine the underlying mechanism behind the association observed in observational studies.},
}
@article {pmid37592749,
year = {2023},
author = {Huang, X},
title = {A complete telomere-to-telomere assembly provides new reference genome for rice.},
journal = {Molecular plant},
volume = {16},
number = {9},
pages = {1370-1372},
doi = {10.1016/j.molp.2023.08.007},
pmid = {37592749},
issn = {1752-9867},
mesh = {*Oryza/genetics ; Telomere/genetics ; },
}
@article {pmid37591536,
year = {2023},
author = {Zhang, D and Adegunsoye, A and Oldham, JM and Kozlitina, J and Garcia, N and Poonawalla, M and Strykowski, R and Linderholm, AL and Ley, B and Ma, SF and Noth, I and Strek, ME and Wolters, PJ and Garcia, CK and Newton, CA},
title = {Telomere length and immunosuppression in non-idiopathic pulmonary fibrosis interstitial lung disease.},
journal = {The European respiratory journal},
volume = {62},
number = {5},
pages = {},
pmid = {37591536},
issn = {1399-3003},
support = {K23 HL146942/HL/NHLBI NIH HHS/United States ; UL1 TR001105/TR/NCATS NIH HHS/United States ; R01 HL093096/HL/NHLBI NIH HHS/United States ; R01 HL139897/HL/NHLBI NIH HHS/United States ; UG3 HL145266/HL/NHLBI NIH HHS/United States ; K23 HL138190/HL/NHLBI NIH HHS/United States ; R56 HL158935/HL/NHLBI NIH HHS/United States ; K23 HL148498/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; Azathioprine/adverse effects ; Retrospective Studies ; *Lung Diseases, Interstitial ; *Idiopathic Pulmonary Fibrosis ; Immunosuppressive Agents/therapeutic use ; *Connective Tissue Diseases ; Immunosuppression Therapy ; Telomere ; },
abstract = {BACKGROUND: Studies suggest a harmful pharmacogenomic interaction exists between short leukocyte telomere length (LTL) and immunosuppressants in idiopathic pulmonary fibrosis (IPF). It remains unknown if a similar interaction exists in non-IPF interstitial lung disease (ILD).<br><br>METHODS: A retrospective, multicentre cohort analysis was performed in fibrotic hypersensitivity pneumonitis (fHP), unclassifiable ILD (uILD) and connective tissue disease (CTD)-ILD patients from five centres. LTL was measured by quantitative PCR for discovery and replication cohorts and expressed as age-adjusted percentiles of normal. Inverse probability of treatment weights based on propensity scores were used to assess the association between mycophenolate or azathioprine exposure and age-adjusted LTL on 2-year transplant-free survival using weighted Cox proportional hazards regression incorporating time-dependent immunosuppressant exposure.<br><br>RESULTS: The discovery and replication cohorts included 613 and 325 patients, respectively. In total, 40% of patients were exposed to immunosuppression and 22% had LTL <10th percentile of normal. fHP and uILD patients with LTL <10th percentile experienced reduced survival when exposed to either mycophenolate or azathioprine in the discovery cohort (mortality hazard ratio (HR) 4.97, 95% CI 2.26-10.92; p<0.001) and replication cohort (mortality HR 4.90, 95% CI 1.74-13.77; p=0.003). Immunosuppressant exposure was not associated with differential survival in patients with LTL &#x2265;10th percentile. There was a significant interaction between LTL <10th percentile and immunosuppressant exposure (discovery pinteraction=0.013; replication pinteraction=0.011). Low event rate and prevalence of LTL <10th percentile precluded subgroup analyses for CTD-ILD.<br><br>CONCLUSION: Similar to IPF, fHP and uILD patients with age-adjusted LTL <10th percentile may experience reduced survival when exposed to immunosuppression.},
}
@article {pmid37591348,
year = {2023},
author = {Naudé, PJW and Stein, DJ and Lin, J and Zar, HJ},
title = {Investigating the association of prenatal psychological adversities with mother and child telomere length and neurodevelopment.},
journal = {Journal of affective disorders},
volume = {340},
number = {},
pages = {675-685},
doi = {10.1016/j.jad.2023.08.074},
pmid = {37591348},
issn = {1573-2517},
support = {222020/Z/20/Z/WT_/Wellcome Trust/United Kingdom ; U01 MH115484/MH/NIMH NIH HHS/United States ; },
mesh = {Female ; Humans ; Infant ; Infant, Newborn ; Pregnancy ; *Adverse Childhood Experiences ; Black People ; *Mothers ; Telomere ; Telomere Shortening ; Vitamins ; },
abstract = {BACKGROUND: Exposure to prenatal maternal psychological adversities can negatively affect the offspring's developing brain. Shortened telomere length (TL) has been implicated as a mechanism for the transgenerational effects of maternal psychological adversities on offspring. This study aimed to determine associations between prenatal psychological stressors and distress with maternal and early life TL, and associations between maternal, newborn and child TL with neurodevelopmental outcomes at 2 years of age.<br><br>METHODS: Follow-up TL was measured in a subgroup of African mothers (n&#xa0;=&#xa0;138) and their newborns (n&#xa0;=&#xa0;142) and children (n&#xa0;=&#xa0;96) at 2-years in the Drakenstein Child Health Study. Prenatal symptoms of depression, distress, intimate partner violence, posttraumatic stress-disorder and childhood trauma were measured at 27&#xa0;weeks gestation. Neurodevelopment was assessed at 2&#xa0;years using the Bayley Scales of Infant and Toddler Development III. TLs were measured in whole bloods from mothers and their children at 2-years, and cord bloods in newborns.<br><br>RESULTS: Maternal prenatal stressors and distress were not significantly associated with TL in mothers or their children at birth or at 2-years. Furthermore, maternal psychological measures were not associated with early-life attrition of TL. Longer TL in children at 2-years was associated (p&#xa0;=&#xa0;0.04) with higher motor functioning.<br><br>LIMITATIONS: Limited numbers of participants and single time-point psychological measures.<br><br>CONCLUSIONS: This study is the first to provide information on the association of early life TL with prenatal psychological adversities and neurodevelopmental outcomes in a population of low-income African mothers and their children.},
}
@article {pmid37591176,
year = {2023},
author = {Lu, ZH and Sun, B and Wang, YX and Wu, YR and Chen, YJ and Sun, SZ and Liang, SJ and Xu, S and Chang, H and Chen, HG and Zhang, J},
title = {Ozone exposure associates with sperm quality indicators: Sperm telomere length as a potential mediating factor.},
journal = {Journal of hazardous materials},
volume = {459},
number = {},
pages = {132292},
doi = {10.1016/j.jhazmat.2023.132292},
pmid = {37591176},
issn = {1873-3336},
mesh = {Humans ; Male ; *Semen Analysis ; Mediation Analysis ; Quality Indicators, Health Care ; Semen ; Spermatozoa ; Telomere ; *Ozone/toxicity ; },
abstract = {Evidence linking O3 exposure and human semen quality is limited and conflicting and the mechanism underlying the association remains unclear. Therefore, we investigated the associations between ambient O3 exposure and sperm quality parameters and explored the mediating role of sperm mitochondrial DNA copy number (mtDNAcn) and sperm telomere length (STL) among 1068 potential sperm donors who provided 5002 repeated semen samples over approximately 90 days. We found that every 10 μg/m[3] increase in O3 exposure was associated with a decrease in STL, sperm concentration, total count, total motile sperm number, and semen volume. However, O3 exposure was associated with increased total motility and progressive motility. The association for sperm quality parameters was stronger when exposure was measured at spermatogenesis stages I and II. For STL, the strongest association was observed when exposure was measured at spermatogenesis stage II. Additionally, we found that approximately 9% and 8% of the association between O3 exposure and sperm concentration and count was mediated by STL, respectively. In summary, our findings suggest that O3 pollution may affect sperm telomere length, eventually leading to reduced semen quality.},
}
@article {pmid37590305,
year = {2023},
author = {Vellingiri, B and Balasubramani, K and Iyer, M and Raj, N and Elangovan, A and Song, K and Yeo, HC and Jayakumar, N and Kinoshita, M and Thangarasu, R and Narayanasamy, A and Dayem, AA and Prajapati, VK and Gopalakrishnan, AV and Cho, SG},
title = {Role of Telomeres and Telomerase in Parkinson's Disease-A New Theranostics?.},
journal = {Advanced biology},
volume = {7},
number = {12},
pages = {e2300097},
doi = {10.1002/adbi.202300097},
pmid = {37590305},
issn = {2701-0198},
support = {340/2021//DST/INT/JSPS/P-/ ; 120217720//JPJSBP/ ; //technology exchange grant from Nakatani Foundation/ ; },
mesh = {Humans ; Aged ; *Parkinson Disease/diagnosis/genetics/therapy ; *Telomerase/genetics/metabolism ; Leukocytes, Mononuclear/metabolism ; Precision Medicine ; Telomere/genetics/metabolism ; },
abstract = {Parkinson's disease (PD) is a complex condition that is significantly influenced by oxidative stress and inflammation. It is also suggested that telomere shortening (TS) is regulated by oxidative stress which leads to various diseases including age-related neurodegenerative diseases like PD. Thus, it is anticipated that PD would result in TS of peripheral blood mononuclear cells (PBMCs). Telomeres protect the ends of eukaryotic chromosomes preserving them against fusion and destruction. The TS is a normal process because DNA polymerase is unable to replicate the linear ends of the DNA due to end replication complications and telomerase activity in various cell types counteracts this process. PD is usually observed in the aged population and progresses over time therefore, disparities among telomere length in PBMCs of PD patients are recorded and it is still a question whether it has any useful role. Here, the likelihood of telomere attrition in PD and its implications concerning microglia activation, ageing, oxidative stress, and the significance of telomerase activators are addressed. Also, the possibility of telomeres and telomerase as a diagnostic and therapeutic biomarker in PD is discussed.},
}
@article {pmid37589509,
year = {2023},
author = {Chen, H and Liang, W and Zheng, W and Li, F and Pan, X and Lu, Y},
title = {A novel telomere-related gene prognostic signature for survival and drug treatment efficiency prediction in lung adenocarcinoma.},
journal = {Aging},
volume = {15},
number = {16},
pages = {7956-7973},
pmid = {37589509},
issn = {1945-4589},
mesh = {Humans ; Prognosis ; Proteomics ; *Adenocarcinoma of Lung ; *Lung Neoplasms ; *Adenocarcinoma ; Aldehyde Dehydrogenase, Mitochondrial ; },
abstract = {OBJECTIVE: Telomere-related genes (TRGs) play a critical role in various types of tumors. However, there is a lack of comprehensive exploration of their relevance in lung cancer. This research aimed to verify the relationship between TRGs gene expression and the prognosis of patients with lung adenocarcinoma (LUAD), as well as the prediction of drug treatment efficiency.<br><br>METHODS: A total of 2093 TRGs were acquired from TelNet. The clinical information including age, tumor stage, follow up and outcome (death/survival) and TRGs expression profile of LUAD were obtained from the patients in The Cancer Genome Atlas (TCGA) database and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. The two databases were used to construct and verify a prognostic model based on the expression of hubTRGs. The tumor mutation burden, immune infiltration and subtypes, as well as IC50 prediction of multiple targeted drugs were also evaluated in TRGs-divided risk groups.<br><br>RESULTS: A total of 335 TRGs were significantly differentially expressed in LUAD as compared with normal control. Among them, 9 TRGs (ABCC2, ABCC8, ALDH2, FOXP3, GNMT, JSRP1, MACF1, PLCD3, SULT4A1) were finally identified as hubGenes and used to construct a TRG risk score. The TRG risk score showed favorable performance in constructing a prognostic nomogram in predicting survival of LUAD, and the ROC curves at 1, 3 and 5 years were plotted and the AUROC values were 0.743, 0.754 and 0.735, respectively. Higher TRGs risk score correlated with worse immune subtypes and higher tumor mutation burden in LUAD tissues. In addition, the patients in TRG high risk group harbored a lower TIDE score which indicated potentially better response to immunotherapy.<br><br>CONCLUSION: This study proposed a broad molecular signature of telomere-related genes that can be used in further functional and therapeutic investigations, and also represents an integrated modality for characterizing critical molecules when exploring novel targets for lung cancer immunotherapy.},
}
@article {pmid37588048,
year = {2023},
author = {Zhu, S and Yang, M and Wang, T and Ding, Z},
title = {Causal relationships between telomere length and liver disease: a Mendelian randomization study.},
journal = {Frontiers in genetics},
volume = {14},
number = {},
pages = {1164024},
pmid = {37588048},
issn = {1664-8021},
abstract = {Background: Leukocyte telomere length and hepatic disorders have been linked in various research studies, although their causative association has not been clarified. This study investigated the causal relationship between the length of telomeres on peripheral blood leukocytes and certain liver disorders. Methods: Mendelian randomization (MR) analysis was used to examine the relationship between leukocyte telomere length and risk of liver disease using the publicly accessible worldwide gene-wide association study (GWAS) database. The weighted mode, weighted median, and inverse variance weighted (IVW) methods were employed as supplements to the IVW approach, which is the main analytical method. Results: Leukocytes with longer telomeres may have a lower risk of developing cirrhosis [OR = 0.645 (0.524, 0.795), p = 3.977E-05] and a higher chance of developing benign liver tumors [OR = 3.087 (1.721, 5.539), p = 1.567E-04]. There was no direct link between telomere length and fatty liver, hepatic fibrosis, or liver cancer. Our findings in the replication analysis agreed with those of the previous studies. Conclusion: Further research is needed to examine the mechanisms underlying the probable causal association between the length of leukocyte telomeres and cirrhosis and benign liver cancer.},
}
@article {pmid37586999,
year = {2023},
author = {He, Q and Lim, CJ},
title = {Models for human telomere C-strand fill-in by CST-Polα-primase.},
journal = {Trends in biochemical sciences},
volume = {48},
number = {10},
pages = {860-872},
pmid = {37586999},
issn = {0968-0004},
support = {DP2 GM150023/GM/NIGMS NIH HHS/United States ; R00 GM131023/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; *DNA Primase ; *Telomerase ; Telomere ; Shelterin Complex ; Eukaryota ; },
abstract = {Telomere maintenance is essential for the genome integrity of eukaryotes, and this function is underpinned by the two-step telomeric DNA synthesis process: telomere G-overhang extension by telomerase and complementary strand fill-in by DNA polymerase alpha-primase (polα-primase). Compared to the telomerase step, the telomere C-strand fill-in mechanism is less understood. Recent studies have provided new insights into how telomeric single-stranded DNA-binding protein CTC1-STN1-TEN1 (CST) and polα-primase coordinate to synthesize the telomeric C-strand for telomere overhang fill-in. Cryogenic electron microscopy (cryo-EM) structures of CST-polα-primase complexes have provided additional insights into how they assemble at telomeric templates and de novo synthesize the telomere C-strand. In this review, we discuss how these latest findings coalesce with existing understanding to develop a human telomere C-strand fill-in mechanism model.},
}
@article {pmid37580799,
year = {2023},
author = {Brown, RL and Epel, EE and Lin, J and Dubal, DB and Prather, AA},
title = {Associations between klotho and telomere biology in high stress caregivers.},
journal = {Aging},
volume = {15},
number = {15},
pages = {7381-7396},
pmid = {37580799},
issn = {1945-4589},
support = {T32 MH019391/MH/NIMH NIH HHS/United States ; R21 HL117727/HL/NHLBI NIH HHS/United States ; R56 AG030424/AG/NIA NIH HHS/United States ; K08 HL112961/HL/NHLBI NIH HHS/United States ; K08 AG034531/AG/NIA NIH HHS/United States ; R01 AG030424/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Female ; *Caregivers ; *Autism Spectrum Disorder ; Aging/genetics ; Biomarkers ; Telomere ; Biology ; Telomere Shortening ; },
abstract = {Aging biomarkers may be related to each other through direct co-regulation and/or through being regulated by common processes associated with chronological aging or stress. Klotho is an aging regulator that acts as a circulating hormone with critical involvement in regulating insulin signaling, phosphate homeostasis, oxidative stress, and age-related inflammatory functioning. Both klotho and telomere length are biomarkers of biological aging and decrease with age; however, the relationship between them is not well understood. Here we test the association between klotho levels and the telomere length of specific sorted immune cells among a healthy sample of mothers caregiving for a child with autism spectrum disorder (ASD; i.e., experiencing higher caregiving stress) or a child without ASD, covarying age and body mass index, in order to understand if high stress associated with caregiving for a child with an ASD may be involved in any association between these aging biomarkers. In 178 caregiving women (n = 90 high-stress mothers of children with ASD, n = 88 low-stress mothers of neurotypical children), we found that klotho levels were positively associated with telomere length in PBMCs (an effect driven by CD4+ and CD8+CD28- T cells) among high-stress mothers of children with an ASD but not among low-stress mothers of neurotypical children. There were no significant associations between klotho and telomerase activity in either group, across cell types assessed here. Our results suggest that klotho levels and telomere length may be associated through a coordinated downregulation of longevity factors occurring under higher stress caregiving conditions.},
}
@article {pmid37577643,
year = {2023},
author = {Lee, J and Lee, J and Sohn, EJ and Taglialatela, A and O'Sullivan, RJ and Ciccia, A and Min, J},
title = {Extrachromosomal Telomeres Derived from Excessive Strand Displacements.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {37577643},
support = {K22 CA245259/CA/NCI NIH HHS/United States ; R01 CA197774/CA/NCI NIH HHS/United States ; R01 CA207209/CA/NCI NIH HHS/United States ; R01 CA262316/CA/NCI NIH HHS/United States ; },
abstract = {Alternative Lengthening of Telomeres (ALT) is a telomere maintenance mechanism mediated by break-induced replication (BIR), evident in approximately 15% of human cancers. A characteristic feature of ALT cancers is the presence of C-circles, circular single-stranded telomeric DNAs composed of C-rich sequences. Despite the fact that extrachromosomal C-rich single-stranded DNAs (ssDNAs), unique to ALT cells, are considered potential precursors of C-circles, their generation process remains undefined. Here, we introduce a highly sensitive method to detect single stranded telomeric DNA, called 4SET (Strand-Specific Southern-blot for Single-stranded Extrachromosomal Telomeres) assay. Utilizing 4SET, we are able to capture C-rich single stranded DNAs that are near 200 to 1500 nucleotides in size. Both linear C-rich ssDNAs and C-circles are abundant in the fractions of cytoplasm and nucleoplasm, which supports the idea that linear C-rich ssDNA accumulation may indeed precede C-circle formation. We also found that C-rich ssDNAs originate during Okazaki fragment processing during lagging strand DNA synthesis. The generation of C-rich ssDNA requires CST-PP (CTC1/STN1/TEN1-PRIMASE-Polymerase alpha) complex-mediated priming of the C-strand DNA synthesis and subsequent excessive strand displacement of the C-rich strand mediated by the DNA Polymerase delta and the BLM helicase. Our work proposes a new model for the generation of C-rich ssDNAs and C-circles during ALT-mediated telomere elongation.},
}
@article {pmid37570635,
year = {2023},
author = {Yamaguchi, I and Ikawa, K and Takimiya, N and Wang, A},
title = {Tetraphenylethene Derivatives Bearing Alkylammonium Substituents: Synthesis, Chemical Properties, and Application as BSA, Telomere DNA, and Hydroxyl Radical Sensors.},
journal = {Molecules (Basel, Switzerland)},
volume = {28},
number = {15},
pages = {},
pmid = {37570635},
issn = {1420-3049},
support = {20231181//Cooperative Research Program of "NJRC Mater. &amp; Dev."/ ; },
mesh = {*Serum Albumin, Bovine ; *Hydroxyl Radical ; DNA ; Telomere ; },
abstract = {Tetraphenylethene derivatives (TPEs) are used as luminescence probes for the detection of metal ions and biomolecules. These sensors function by monitoring the increase in the photoluminescence (PL) intensity of the TPEs resulting from aggregation-induced emission (AIE) upon interaction with the analytes. The AIE behavior of the sensors was investigated by measuring their PL. In this study, PL, PL lifetime, and confocal laser scanning microscopy measurements were carried out as part of our in-depth investigation of AIE behavior of TPEs for the detection of biomolecules and radical species. We used 1,1,2,2-tetrakis(4-((trimethylammonium)alkoxy)phenyl)tetraphenylethene tetrabromide (TPE-C(m)N[+]Me3Br[-], m = 2, 4, and 6, where m denotes the number of methylene groups in the alkyl chain) and TPE-C(m)N[+]Me3TCNQ[-•] (TCNQ[-•] is the 7,7',8,8'-tetracyanoquinodimethane anion radical) as luminescent probes for the detection of bovine serum albumin (BSA), DNA, and the hydroxyl radical ([•]OH) generated from Fenton's reagent. The sensing performance of TPE-C(m)N[+]Me3Br[-] for BSA and DNA was found to depend on the length of the alkyl chains (m). UV-vis and PL measurements revealed that the responses of TPE-C(m)N[+]Me3Br[-] and TPE-C(4)N[+]TCNQ[-•] to Fenton's reagent depended on the solvent. The electrochemical properties of the TPE derivatives prepared in this study were additionally investigated via cyclic voltammetry.},
}
@article {pmid37569497,
year = {2023},
author = {Li, XH and Sun, MH and Jiang, WJ and Zhou, D and Lee, SH and Heo, G and Chen, Z and Cui, XS},
title = {ZSCAN4 Regulates Zygotic Genome Activation and Telomere Elongation in Porcine Parthenogenetic Embryos.},
journal = {International journal of molecular sciences},
volume = {24},
number = {15},
pages = {},
pmid = {37569497},
issn = {1422-0067},
support = {2022R1A2C300769//National Research Foundation of Korea/ ; },
mesh = {Animals ; Mice ; Swine ; *Transcription Factors/genetics/metabolism ; *Telomere/genetics/metabolism ; Telomere Shortening ; DNA-Binding Proteins/metabolism ; Zygote/metabolism ; Embryonic Development/genetics ; Gene Expression Regulation, Developmental ; },
abstract = {Zinc finger and SCAN domain-containing 4 (ZSCAN4), a DNA-binding protein, maintains telomere length and plays a key role in critical aspects of mouse embryonic stem cells, including maintaining genomic stability and defying cellular senescence. However, the effect of ZSCAN4 in porcine parthenogenetic embryos remains unclear. To investigate the function of ZSCAN4 and the underlying mechanism in porcine embryo development, ZSCAN4 was knocked down via dsRNA injection in the one-cell stage. ZSCAN4 was highly expressed in the four- and five- to eight-cell stages in porcine embryos. The percentage of four-cell stage embryos, five- to eight-cell stage embryos, and blastocysts was lower in the ZSCAN4 knockdown group than in the control group. Notably, depletion of ZSCAN4 induced the protein expression of DNMT1 and 5-Methylcytosine (5mC, a methylated form of the DNA base cytosine) in the four-cell stage. The H3K27ac level and ZGA genes expression decreased following ZSCAN4 knockdown. Furthermore, ZSCAN4 knockdown led to DNA damage and shortened telomere compared with the control. Additionally, DNMT1-dsRNA was injected to reduce DNA hypermethylation in ZSCAN4 knockdown embryos. DNMT1 knockdown rescued telomere shortening and developmental defects caused by ZSCAN4 knockdown. In conclusion, ZSCAN4 is involved in the regulation of transcriptional activity and is essential for maintaining telomere length by regulating DNMT1 expression in porcine ZGA.},
}
@article {pmid37567392,
year = {2023},
author = {Ye, Q and Apsley, AT and Etzel, L and Hastings, WJ and Kozlosky, JT and Walker, C and Wolf, SE and Shalev, I},
title = {Telomere length and chronological age across the human lifespan: A systematic review and meta-analysis of 414 study samples including 743,019 individuals.},
journal = {Ageing research reviews},
volume = {90},
number = {},
pages = {102031},
pmid = {37567392},
issn = {1872-9649},
support = {T32 AG049676/AG/NIA NIH HHS/United States ; U01 ES030949/ES/NIEHS NIH HHS/United States ; U24 AG066528/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Humans ; *Longevity ; Cross-Sectional Studies ; *Telomere Shortening ; Aging/genetics ; Telomere ; },
abstract = {Telomere attrition is a proposed hallmark of aging. To evaluate the association of telomere length (TL) with chronological age across the human lifespan, we conducted a systematic review and meta-analysis of 414 study samples comprising 743,019 individuals aged 0-112 years. We examined both cross-sectional and longitudinal data, and evaluated the impact of various biological and methodological factors including sex, health status, tissue types, DNA extraction procedures, and TL measurement methods. The pooled corrected correlation between TL and age from cross-sectional samples was -0.19 (95%CI: -0.22 to -0.15), which weakened with increased chronological age (β = 0.003, p < 0.001). Z-score change rates of TL across the lifespan showed a gradual decrease in shortening rate until around age 50 and remained at a relatively stable rate towards the elderly period. A greater attrition rate was observed in longitudinal than cross-sectional evaluations. For TL measured in base pairs, the median change rate of TL was -23 bp/year in cross-sectional samples and -38 bp/year in longitudinal samples. Methodological factors including TL measurement methods and tissue types impacted the TL-age correlation, while sex or disease status did not. This meta-analysis revealed the non-linear shortening trend of TL across the human lifespan and provides a reference value for future studies. Results also highlight the importance of methodological considerations when using TL as an aging biomarker.},
}
@article {pmid37564879,
year = {2023},
author = {Nose, D and Shiga, Y and Takahashi, RU and Yamamoto, Y and Suematsu, Y and Kuwano, T and Sugihara, M and Kanda, M and Tahara, H and Miura, SI},
title = {Association Between Telomere G-Tail Length and Coronary Artery Disease or Statin Treatment in Patients With Cardiovascular Risks - A Cross-Sectional Study.},
journal = {Circulation reports},
volume = {5},
number = {8},
pages = {338-347},
pmid = {37564879},
issn = {2434-0790},
abstract = {Background: The utility of telomere G-tail length to predict coronary artery disease (CAD) remains controversial. CAD results from coronary artery narrowing due to cholesterol and lipid accumulation, augmented by inflammatory cells and other factors. This study explored the significance of telomere G-tail length in suspected CAD patients. Methods and Results: In all, 95 patients with suspected CAD or ≥1 cardiac risk factor underwent coronary computed tomography angiography (CCTA). We measured leukocyte telomere length and G-tail length using a hybrid protection method, and diagnosed the presence of CAD using CCTA. Associations between G-tail length and the presence of CAD, the number of stenosed coronary arteries, and brachial-ankle pulse wave velocity (baPWV) were analyzed. No significant difference was observed in G-tail length when comparing groups with or without CAD or statin treatment. However, in the non-statin group, G-tail length was significantly shorter in patients with 3-vessel disease compared with 1-vessel disease. Dividing the group using a baPWV of 1,300 cm/s, telomere G-tail length was significantly shorter in the high-risk (baPWV ≥1,300 cm/s) group. Conclusions: The clinical utility of telomere G-tail length as a CAD risk indicator seems limited. There was a trend for longer telomere G-tail length in the statin-treated group. Moreover, telomere G-tail length was reduced in patients at high-risk of cardiovascular events, aligning with the trend of a shortening in telomere G-tail length with CAD severity.},
}
@article {pmid37560909,
year = {2023},
author = {Takasugi, T and Gu, P and Liang, F and Staco, I and Chang, S},
title = {Pot1b -/- tumors activate G-quadruplex-induced DNA damage to promote telomere hyper-elongation.},
journal = {Nucleic acids research},
volume = {51},
number = {17},
pages = {9227-9247},
pmid = {37560909},
issn = {1362-4962},
support = {R01 GM141350/GM/NIGMS NIH HHS/United States ; T32 GM007205/GM/NIGMS NIH HHS/United States ; F30 CA254123/CA/NCI NIH HHS/United States ; },
mesh = {Mice ; Humans ; Animals ; *Shelterin Complex ; Telomere-Binding Proteins/genetics/metabolism ; Telomere/genetics/metabolism ; DNA Damage ; Replication Protein A/metabolism ; *Sarcoma ; DNA-Binding Proteins/genetics ; },
abstract = {Malignant cancers must activate telomere maintenance mechanisms to achieve replicative immortality. Mutations in the human Protection of Telomeres 1 (POT1) gene are frequently detected in cancers with abnormally long telomeres, suggesting that the loss of POT1 function disrupts the regulation of telomere length homeostasis to promote telomere elongation. However, our understanding of the mechanisms leading to elongated telomeres remains incomplete. The mouse genome encodes two POT1 proteins, POT1a and POT1b possessing separation of hPOT1 functions. We performed serial transplantation of Pot1b-/- sarcomas to better understand the role of POT1b in regulating telomere length maintenance. While early-generation Pot1b-/- sarcomas initially possessed shortened telomeres, late-generation Pot1b-/- cells display markedly hyper-elongated telomeres that were recognized as damaged DNA by the Replication Protein A (RPA) complex. The RPA-ATR-dependent DNA damage response at telomeres promotes telomerase recruitment to facilitate telomere hyper-elongation. POT1b, but not POT1a, was able to unfold G-quadruplex present in hyper-elongated telomeres to repress the DNA damage response. Our findings demonstrate that the repression of the RPA-ATR DDR is conserved between POT1b and human POT1, suggesting that similar mechanisms may underly the phenotypes observed in human cancers harboring human POT1 mutations.},
}
@article {pmid37560336,
year = {2023},
author = {Teng, Y and Huang, DQ and Li, RX and Yi, C and Zhan, YQ},
title = {Association Between Telomere Length and Risk of Lung Cancer in an Asian Population: A Mendelian Randomization Study.},
journal = {World journal of oncology},
volume = {14},
number = {4},
pages = {277-284},
pmid = {37560336},
issn = {1920-454X},
abstract = {BACKGROUND: Several traditional observational studies and Mendelian randomization (MR) studies have indicated an association between leukocyte telomere length (LTL) and the risk of lung cancer in the European population. However, the results in the Asian population are still unclear. The objective was to reveal the genetic causal association between LTL and the risk of lung cancer in the Asian population.<br><br>METHODS: We conducted a two-sample MR analysis using summary statistics. Instrumental variables (IVs) were obtained from the genome-wide association studies (GWAS) of LTL (n = 23,096) and lung cancer (n = 212,453) of Asian ancestry. We applied the random-effects inverse-variance weighted (IVW) model as the main method. As well, several other models were performed as complementary methods to assess the impact of potential MR assumption violations, including MR-Egger regression, weighted median, and weighted mode models.<br><br>RESULTS: We included eight single-nucleotide polymorphisms (SNPs) as IVs for LTL and found that LTL was significantly associated with the risk of lung cancer in the IVW model (odds ratio (OR): 1.60; 95% confidence interval (CI): 1.31 - 1.97; P = 5.96 &#xd7; 10[-6]), which was in line with the results in the weighted median and weighted mode models. However, the relationship was not statistically significant in the MR-Egger regression model (OR: 1.44; 95% CI: 0.92 - 2.26; P = 0.160). Sensitivity analyses indicated the robustness of the results.<br><br>CONCLUSIONS: This two-sample MR study confirmed that longer telomere length significantly increased the risk of lung cancer in the Asian population, which was in accord with findings in the Western population.},
}
@article {pmid37560017,
year = {2023},
author = {Lin, Y and Ye, C and Li, X and Chen, Q and Wu, Y and Zhang, F and Pan, R and Zhang, S and Chen, S and Wang, X and Cao, S and Wang, Y and Yue, Y and Liu, Y and Yue, J},
title = {quarTeT: a telomere-to-telomere toolkit for gap-free genome assembly and centromeric repeat identification.},
journal = {Horticulture research},
volume = {10},
number = {8},
pages = {uhad127},
pmid = {37560017},
issn = {2662-6810},
abstract = {A high-quality genome is the basis for studies on functional, evolutionary, and comparative genomics. The majority of attention has been paid to the solution of complex chromosome structures and highly repetitive sequences, along with the emergence of a new 'telomere-to-telomere (T2T) assembly' era. However, the bioinformatic tools for the automatic construction and/or characterization of T2T genome are limited. Here, we developed a user-friendly web toolkit, quarTeT, which currently includes four modules: AssemblyMapper, GapFiller, TeloExplorer, and CentroMiner. First, AssemblyMapper is designed to assemble phased contigs into the chromosome-level genome by referring to a closely related genome. Then, GapFiller would endeavor to fill all unclosed gaps in a given genome with the aid of additional ultra-long sequences. Finally, TeloExplorer and CentroMiner are applied to identify candidate telomere and centromere as well as their localizations on each chromosome. These four modules can be used alone or in combination with each other for T2T genome assembly and characterization. As a case study, by adopting the entire modular functions of quarTeT, we have achieved the Actinidia chinensis genome assembly that is of a quality comparable to the reported genome Hongyang v4.0, which was assembled with the addition of manual handling. Further evaluation of CentroMiner by searching centromeres in Arabidopsis thaliana and Oryza sativa genomes showed that quarTeT is capable of identifying all the centromeric regions that have been previously detected by experimental methods. Collectively, quarTeT is an efficient toolkit for studies of large-scale T2T genomes and can be accessed at http://www.atcgn.com:8080/quarTeT/home.html without registration.},
}
@article {pmid37550565,
year = {2023},
author = {Tang, L and Li, D and Wang, J and Su, B and Tian, Y},
title = {Ambient air pollution, genetic risk and telomere length in UK biobank.},
journal = {Journal of exposure science &amp; environmental epidemiology},
volume = {},
number = {},
pages = {},
pmid = {37550565},
issn = {1559-064X},
abstract = {BACKGROUND: Telomere length (TL) is a biomarker of genomic aging. The evidence on the association between TL and air pollution was inconsistent. Besides, the modification effect of genetic susceptibility on the air pollution-TL association remains unknown.<br><br>OBJECTIVE: We aimed to evaluate the association of ambient air pollution with TL and further assess the modification effect of genetic susceptibility.<br><br>METHODS: 433,535 participants with complete data of TL and air pollutants in UK Biobank were included. Annual average exposure of NO2, NOx, PM10 and PM2.5 was estimated by&#xa0;applying land use regression models. Genetic risk score (GRS) was constructed using reported telomere-related SNPs. Leukocyte TL was measured by quantitative polymerase chain reaction (qPCR). Multivariable linear regression models were employed to conduct associational analyses.<br><br>RESULTS: Categorical exposure models and RCS models both indicated U-shaped (for NO2 and NOx) and L-shaped (for PM10 and PM2.5) correlations between air pollution and TL. In comparison to the lowest quartile, the 2nd and 3rd quartile of NO2 (q2: -1.3% [-2.1%, -0.4%]; q3: -1.2% [-2.0%, -0.3%], NOx (q2: -1.3% [-2.1%, -0.5%]; q3: -1.4% [-2.2%, -0.5%]), PM2.5 (q2: -0.8% [-1.7%, 0.0%]; q3: -1.3% [-2.2%, -0.5%]), and the third quartile of PM10 (q3: -1.1% [-1.9%, -0.2%]) were inversely associated with TL. The highest quartile of NO2 was positively correlated with TL (q4: 1.0% [0.0%, 2.0%]), whereas the negative correlation between the highest quartile of other pollutants and TL was also attenuated and no longer significant. In the genetic analyses, synergistic interactions were observed between the 4th quartile of three air pollutants (NO2, NOx, and PM2.5) and genetic risk.<br><br>IMPACT STATEMENT: Our study for the first time revealed a non-linear trend for the association between air pollution and telomere length. The genetic analyses suggested synergistic interactions between air pollution and genetic risk on the&#xa0;air pollution-TL association. These findings may shed new light on air pollution's health effects, offer suggestions for identifying at-risk individuals, and provide hints regarding further investigation into gene-environment interactions.},
}
@article {pmid37549582,
year = {2023},
author = {Ojeda-Rodriguez, A and Alcala-Diaz, JF and Rangel-Zuñiga, OA and Arenas-de Larriva, AP and Gutierrez-Mariscal, FM and Gómez-Luna, P and Torres-Peña, JD and Garcia-Rios, A and Romero-Cabrera, JL and Malagon, MM and Perez-Martinez, P and Ordovas, JM and Delgado-Lista, J and Yubero-Serrano, EM and Lopez-Miranda, J},
title = {Association between telomere length and intima-media thickness of both common carotid arteries in patients with coronary heart disease: From the CORDIOPREV randomized controlled trial.},
journal = {Atherosclerosis},
volume = {380},
number = {},
pages = {117193},
doi = {10.1016/j.atherosclerosis.2023.117193},
pmid = {37549582},
issn = {1879-1484},
mesh = {Humans ; Carotid Intima-Media Thickness ; *Carotid Artery Diseases/diagnostic imaging/epidemiology/complications ; Risk Factors ; *Coronary Disease/complications ; Carotid Artery, Common/diagnostic imaging ; *Diet, Mediterranean ; Telomere ; Carotid Arteries/diagnostic imaging ; },
abstract = {BACKGROUND AND AIMS: A critical telomere length (TL) is associated with cardiovascular mortality. Dietary habits have been demonstrated to affect cardiovascular risk. However, it remains unclear how exactly TL determines the response to specific dietary approaches in the reduction of arterial injury. We aimed to evaluate whether TL was associated with the progression of arterial injury (assessed by intima-media thickness of both common carotid arteries: IMT-CC), after long-term consumption of two healthy dietary models in patients with coronary heart disease (CHD).<br><br>METHODS: From the 1002 CHD patients of the CORDIOPREV study, 903 completed IMT-CC and TL evaluation at baseline and were randomized to follow a Mediterranean diet or a low-fat diet for 5 years.<br><br>RESULTS: Patients at risk of short TL (TL&#xa0;<&#xa0;20th percentile) presented an elevated IMT-CC, (0.79&#xa0;&#xb1;&#xa0;0.17 vs patients at non-risk 0.74&#xa0;&#xb1;&#xa0;0.17 p&#xa0;<&#xa0;0.001). TL and IMT-CC showed an inverse association (&#x3b2;&#xa0;=&#xa0;-0.035, p&#xa0;=&#xa0;0.002). Patients who consumed a Mediterranean diet, regardless of the risk of short TL, showed a significant decrease in IMT-CC, with a higher reduction in those patients with risk of short TL (-0.03&#xa0;&#xb1;&#xa0;0.11, p&#xa0;=&#xa0;0.036). TL (&#x3b2;&#xa0;=&#xa0;0.019, p&#xa0;=&#xa0;0.024), age (&#x3b2;&#xa0;=&#xa0;-0.001, p&#xa0;=&#xa0;0.031), energy intake (&#x3b2;&#xa0;=&#xa0;-0.000, p&#xa0;=&#xa0;0.036), use of statins (&#x3b2;&#xa0;=&#xa0;-0.027, p&#xa0;=&#xa0;0.028) and allocation into the Mediterranean diet (vs low-fat diet) (&#x3b2;&#xa0;=&#xa0;-0.024, p&#xa0;=&#xa0;0.003) were significant contributors to changes in IMT-CC.<br><br>CONCLUSIONS: Patients who had a reduced TL exhibited a greater decrease in IMT-CC after consuming a Mediterranean diet.},
}
@article {pmid37548940,
year = {2023},
author = {Kordowitzki, P and Graczyk, S and Mechsner, S and Sehouli, J},
title = {Shedding Light on the Interaction Between Rif1 and Telomeres in Ovarian Cancer.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2023.0716},
pmid = {37548940},
issn = {2152-5250},
abstract = {Ovarian cancer, more precisely high-grade serous ovarian cancer, is one of the most lethal ageindependent gynecologic malignancies in women worldwide, regardless of age. There is mounting evidence that there is a link between telomeres and the RIF1 protein and the proliferation of cancer cells. Telomeres are hexameric (TTAGGG) tandem repeats at the tip of chromosomes that shorten as somatic cells divide, limiting cell proliferation and serving as an important barrier in preventing cancer. RIF1 (Replication Time Regulation Factor 1) plays, among other factors, an important role in the regulation of telomere length. Interestingly, RIF1 appears to influence the DNA double-strand break (DSB) repair pathway. However, detailed knowledge regarding the interplay between RIF1 and telomeres and their degree of engagement in epithelial ovarian cancer (EOC) is still elusive, despite the fact that such knowledge could be of relevance in clinical practice to find novel biomarkers. In this review, we provide an update of recent literature to elucidate the relation between telomere biology and the RIF1 protein during the development of ovarian cancer in women.},
}
@article {pmid37548421,
year = {2023},
author = {Tahara, T and Shijimaya, T and Yamazaki, J and Tomiyama, T and Fukui, T and Naganuma, M},
title = {Telomere Shortening of Barrett's Esophagus and Esophageal Adenocarcinoma in Japanese Patients.},
journal = {Cancer investigation},
volume = {41},
number = {7},
pages = {640-645},
doi = {10.1080/07357907.2023.2245897},
pmid = {37548421},
issn = {1532-4192},
mesh = {Humans ; *Barrett Esophagus/pathology ; Telomere Shortening ; East Asian People ; Telomere/pathology ; *Esophageal Neoplasms/pathology ; *Adenocarcinoma/pathology ; },
abstract = {Telomere shortening is deeply involved in many types of cancer. Telomere length of esophageal adenocarcinoma (EAC) and Barrett's esophagus (BE) was examined in Japanese patients. Among BE from cancer free patients (Cancer free), BE from patients with EAC (Adjacent) and EAC tissue (Cancer), Cancer free group presented the longest telomeres, while Cancer group presented the shortest telomeres and Adjacent group presented intermediate telomeres. Direction of endoscopic biopsy, 2 o'clock direction was also significantly associated with shorter telomere length in non-neoplastic BE (p = 0.027). Shortened telomere highlighted the impact of this molecular change in early carcinogenesis in EAC.},
}
@article {pmid37544968,
year = {2024},
author = {Xiang, M and Pilling, LC and Melzer, D and Kirk, B and Duque, G and Liu, R and Kuchel, GA and Wood, AR and Metcalf, B and Diniz, BS and Hillsdon, M and Kuo, CL},
title = {Does physical activity moderate the association between shorter leukocyte telomere length and incident coronary heart disease? Data from 54,180 UK Biobank participants.},
journal = {GeroScience},
volume = {46},
number = {1},
pages = {1331-1342},
pmid = {37544968},
issn = {2509-2723},
support = {P30 AG067988/AG/NIA NIH HHS/United States ; R21 NR018963/NR/NINR NIH HHS/United States ; P30AG067988/AG/NIA NIH HHS/United States ; R21NR018963-01A1/NR/NINR NIH HHS/United States ; },
mesh = {Humans ; *Biological Specimen Banks ; UK Biobank ; *Coronary Disease/epidemiology/genetics ; Leukocytes ; Telomere/genetics ; Exercise ; },
abstract = {Telomere shortening is a biological aging hallmark. The effect of short telomere length may be targeted by increased physical activity to reduce the risk of multiple aging-related diseases, including coronary heart disease (CHD). The objective was to assess the moderation effect of accelerometer-based physical activity (aPA) on the association between shorter leukocyte telomere length (LTL) relatively in the population sample and incident CHD. Data were from the UK Biobank participants with well-calibrated accelerometer data for at least 6.5 days (n = 54,180). Relative mean LTL at baseline (5-6 years prior to aPA assessment) was measured in T/S ratio, using a multiplex quantitative polymerase chain reaction (qPCR) technology, by comparing the amount of the telomere amplification product (T) to that of a single-copy gene (S). aPA measures included total number of events (at least 10-s continued physical activity > 32 milligravities [mg]), total volume, mean duration, mean intensity, and peak intensity of all events. LTL, aPA measures, and their interactions were associated with incident CHD (mean follow-up 6.8 years) using Cox proportional hazards models adjusting for covariates. Longer LTL (relative to the sample distribution) was associated with reduced incidence of CHD (adjusted hazard ratio [aHR] = 0.94 per standard deviation [SD] increase in LTL, [95% CI, 0.90 to 0.99], P = .010). Incidence of CHD was reduced by higher total volume of aPA (aHR = 0.82 per SD increase in LTL, [95% CI, 0.71 to 0.95], P = .010) but increased by higher total number of events (aHR = 1.11 per SD increase in LTL, [95% CI, 1.02 to 1.21], P = .020) after controlling for other aPA measures and covariates. However, none of the interactions between LTL and aPA measures was statistically significant (P = .171).},
}
@article {pmid37544465,
year = {2023},
author = {Snyder, ME and Anderson, MR and Benvenuto, LJ and Sutton, RM and Bondonese, A and Koshy, R and Burke, R and Clifford, S and Craig, A and Iasella, CJ and Hannan, SJ and Popescu, I and Zhang, Y and Sanchez, PG and Alder, JK and McDyer, JF},
title = {Impact of age and telomere length on circulating T cells and rejection risk after lung transplantation for idiopathic pulmonary fibrosis.},
journal = {The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation},
volume = {42},
number = {12},
pages = {1666-1677},
pmid = {37544465},
issn = {1557-3117},
support = {R00 HL151750/HL/NHLBI NIH HHS/United States ; R01 HL135062/HL/NHLBI NIH HHS/United States ; R01 HL133184/HL/NHLBI NIH HHS/United States ; R01 HL167901/HL/NHLBI NIH HHS/United States ; K23 HL151759/HL/NHLBI NIH HHS/United States ; R35 HL139860/HL/NHLBI NIH HHS/United States ; K99 HL151750/HL/NHLBI NIH HHS/United States ; R01 HL166265/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; Infant ; Leukocytes, Mononuclear ; CD8-Positive T-Lymphocytes ; *Idiopathic Pulmonary Fibrosis/genetics/surgery ; *Lung Transplantation ; Telomere ; Receptors, Antigen, T-Cell/genetics ; },
abstract = {BACKGROUND: Most idiopathic pulmonary fibrosis (IPF) lung transplant recipients (IPF-LTRs) have short telomere (ST) length. Inherited mutations in telomere-related genes are associated with the development of T cell immunodeficiency. Despite this, IPF-LTRs with telomere-related rare variants are not protected from acute cellular rejection (ACR). We set out to determine the impact of both age and telomere length on the circulating T cell compartment and ACR burden of IPF-LTRs.<br><br>METHODS: We identified 106 IPF-LTRs who had telomere length testing using flowFISH (57 with short telomeres and 49 with long telomeres) as well as a subset from both cohorts who had cryopreserved PBMC at least 1 time point, 6 months posttransplantation. Circulating T cells from before transplantation and at 6 and 12 months posttransplantation were analyzed using multiparameter flow cytometry to study phenotype and functional capacity, and bulk T cell receptor sequencing was performed to study repertoire diversity. Linear regression was used to study the relationship of age and telomere length on early (within 1 year) and late (between 1 and 2 years) ACR.<br><br>RESULTS: IPF-LTRs with ST were found to have premature "aging" of their circulating T cell compartment, with age-agnostic elevations in posttransplant terminal differentiation of CD8[+] T cells, increased granzyme B positivity of both CD8[+] and CD4[+] T cells, upregulation of the exhaustion marker, CD57, and chemotactic protein CCR5, and enhanced T cell receptor clonal expansion. Additionally, we found a significant decline in early ACR burden with increasing age, but only in the ST cohort.<br><br>CONCLUSIONS: IPF-LTRs with ST have premature "aging" of their circulating T cell compartment posttransplantation and a clear age-related decline in ACR burden.},
}
@article {pmid37543795,
year = {2023},
author = {Zou, J and Chu, S and Bao, Q and Zhang, Y},
title = {Telomere maintenance genes-derived prognosis signature characterizes immune landscape and predicts prognosis of head and neck squamous cell carcinoma.},
journal = {Medicine},
volume = {102},
number = {31},
pages = {e34586},
pmid = {37543795},
issn = {1536-5964},
mesh = {Humans ; Squamous Cell Carcinoma of Head and Neck/genetics ; Prognosis ; *Nomograms ; Immunotherapy ; *Head and Neck Neoplasms/genetics/therapy ; },
abstract = {Telomere dysfunction has been identified as a biological marker of cancer progression in several types of cancer, including Head and Neck Squamous Cell Carcinoma (HNSCC). This study aimed to characterize the telomere maintenance genes (TMG)-related signature in prognosis and treatment response in HNSCC. The transcriptome and clinical data of HNSCC were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases, respectively. Non-negative matrix factorization (NMF) was used to identify molecular subtypes derived from TMG. Gene set enrichment analysis (GSEA) was performed to analyze the differentially expressed pathways between subtypes, and a risk score model derived from TMG was established. Kaplan-Meier survival analysis was used to evaluate inter-group prognostic features, and the correlation between TMG-derived molecular subtypes and risk score model with immune infiltration, immunotherapy, and chemosensitivity was assessed. Two HNSCC subtypes were identified based on 59 TMG-related genes, which exhibit significant heterogeneity in prognosis, immune cell infiltration, and treatment response. Additionally, a TMG-derived risk signature containing 9 genes was developed to assess the prognosis of HNSCC patients. The signature had significant predictive ability for HNSCC prognosis and was significantly correlated with immune cell infiltration and immunotherapy response. A nomogram integrating the risk signature, N stage and radiotherapy was constructed to predict 1-, 3-, and 5-year overall survival (OS) of HNSCC patients, which had better performance than other prognostic models and included TMG-derived risk score, radiotherapy, and N stage. This study identified TMG-derived molecular subtypes in HNSCC and developed a novel prognostic score model, highlighting the potential value of TMG in HNSCC prognosis and immunotherapy.},
}
@article {pmid37543429,
year = {2023},
author = {Jiang, T and Mo, X and Zhan, R and Zhang, Y},
title = {Causal pathway from telomere length to occurrence and 28-day mortality of sepsis: an observational and mendelian randomization study.},
journal = {Aging},
volume = {15},
number = {15},
pages = {7727-7740},
pmid = {37543429},
issn = {1945-4589},
mesh = {Humans ; *Mendelian Randomization Analysis/methods ; Genome-Wide Association Study ; Causality ; Polymorphism, Single Nucleotide ; Telomere/genetics ; *Sepsis/genetics ; },
abstract = {BACKGROUND: Telomeres are considered to be a physiological marker of aging. Elucidating relationship between telomere length and sepsis is an essential step towards understanding the biological processes involved in sepsis and its salvation. Mendelian randomization studies based on SNPs have given us new insights into genetic susceptibility to disease.<br><br>OBJECTIVES: To explore the causal pathway from telomere length to occurrence and 28-day mortality of sepsis.<br><br>METHODS: Leveraging genetic information resource of UK Biobank, we captured three groups of large-scale GWAS data: leukocyte telomere length (LTL), sepsis and all-cause death of 28-day. Study design consisted of three parts: forward analysis, reverse analysis and one-way analysis. Genetic instrumental variables were selected for different analyses under the premise that three MR core assumptions were satisfied. Causality was determined by means of IVW.<br><br>RESULTS: In forward analysis, we did not observe a significant causal pathway from sepsis to LTL under IVW model: &#x3b2; (SE) was -0.0051 (0.0075) with a p-value of 0.499. In reverse analysis, based on the IVW model, the OR (95% CI) was 0.89 (0.80-0.99) and the p-values was 0.043; based on the results of leave out method and single SNP analysis, we obtained seven key SNPs. There were results of IVW model in the one-way analysis: &#x3b2; (SE) was -0.0287(0.1261).<br><br>CONCLUSIONS: Short LTL increases susceptibility to sepsis, but sepsis does not shorten telomere length. LTL does not affect sepsis 28-day all-cause mortality and does not serve as a causal intermediate in gene regulation during the progression of sepsis to 28-day death.},
}
@article {pmid37534393,
year = {2023},
author = {Lombardi, F and Sanfilippo, A and Fabbiani, M and Borghetti, A and Ciccullo, A and Tamburrini, E and Di Giambenedetto, S},
title = {Blood telomere length gain in people living with HIV switching to dolutegravir plus lamivudine versus continuing triple regimen: a longitudinal, prospective, matched, controlled study.},
journal = {The Journal of antimicrobial chemotherapy},
volume = {78},
number = {9},
pages = {2315-2322},
pmid = {37534393},
issn = {1460-2091},
mesh = {Adult ; Humans ; Lamivudine/therapeutic use/pharmacology ; *HIV Infections/drug therapy ; *Anti-HIV Agents/therapeutic use/pharmacology ; Prospective Studies ; Oxazines/pharmacology ; Heterocyclic Compounds, 3-Ring/therapeutic use/pharmacology ; Pyridones/pharmacology ; Telomere ; Viral Load ; },
abstract = {BACKGROUND: Blood telomere length (BTL) is a validated biomarker of aging. ART reduces immunosenescence and has benefits in terms of BTL in people living with HIV (PLWH). However, it has also been observed that ART containing NRTIs, such as tenofovir or abacavir, which are potent inhibitors of human telomerase activity in vitro, might negatively affect BTL. Here we investigated the effects on BTL 1 year after switching to a dual therapy (DT) with dolutegravir + lamivudine versus maintaining a standard triple therapy (TT) with a two-NRTI backbone and an anchor drug.<br><br>METHODS: This was a longitudinal, prospective, matched, controlled study that included virologically suppressed adults on stable three-drug ART who either switched at baseline (BL) to DT or maintained TT. The DT and TT groups were 1:1 matched for age, sex, years since HIV diagnosis, years on ART and anchor drug. BTL was assessed by a monochrome multiplex qPCR at BL and after 48 weeks (W48).<br><br>RESULTS: We enrolled 120 PLWH, i.e. 60 participants in each group. At BL, the BTL means were comparable between the two groups (P&#x200a;=&#x200a;0.973). At W48, viro-immunological status was stable and an overall increase in the mean BTL was observed, i.e., +0.161 (95%CI, 0.054-0.268) (P&#x200a;=&#x200a;0.004). However, the within-group analysis showed a significant mean BTL gain in the DT group (P&#x200a;=&#x200a;0.003) but not in the TT group (P&#x200a;=&#x200a;0.656).<br><br>CONCLUSIONS: In this setting of virologically suppressed PLWH, simplifying to dolutegravir&#x200a;+&#x200a;lamivudine was associated with a higher gain in BTL than maintaining triple therapy after the 1 year follow-up. These findings suggest that as a simplification strategy dolutegravir&#x200a;+&#x200a;lamivudine might have a positive effect on BTL.},
}
@article {pmid37534392,
year = {2023},
author = {Naspolini, NF and Sichieri, R and Barbosa Cunha, D and Alves Pereira, R and Faerstein, E},
title = {Dietary patterns, obesity markers and leukocyte telomere length among Brazilian civil servants: cross-sectional results from the Pro-Saude study - CORRIGENDUM.},
journal = {Public health nutrition},
volume = {26},
number = {10},
pages = {2180},
pmid = {37534392},
issn = {1475-2727},
}
@article {pmid37532653,
year = {2024},
author = {Hourvitz, N and Awad, A and Tzfati, Y},
title = {The many faces of the helicase RTEL1 at telomeres and beyond.},
journal = {Trends in cell biology},
volume = {34},
number = {2},
pages = {109-121},
doi = {10.1016/j.tcb.2023.07.002},
pmid = {37532653},
issn = {1879-3088},
mesh = {Humans ; *DNA Helicases/genetics/metabolism ; *Genome ; Phenotype ; Telomere/genetics/metabolism ; },
abstract = {Regulator of telomere elongation 1 (RTEL1) is known as a DNA helicase that is important for telomeres and genome integrity. However, the diverse phenotypes of RTEL1 dysfunction, the wide spectrum of symptoms caused by germline RTEL1 mutations, and the association of RTEL1 mutations with cancers suggest that RTEL1 is a complex machine that interacts with DNA, RNA, and proteins, and functions in diverse cellular pathways. We summarize the proposed functions of RTEL1 and discuss their implications for telomere maintenance. Studying RTEL1 is crucial for understanding the complex interplay between telomere maintenance and other nuclear pathways, and how compromising these pathways causes telomere biology diseases, various aging-associated pathologies, and cancer.},
}
@article {pmid37531260,
year = {2023},
author = {Sullivan, SM and Cole, B and Lane, J and Meredith, JJ and Langer, E and Hooten, AJ and Roesler, M and McGraw, KL and Pankratz, N and Poynter, JN},
title = {Predicted leukocyte telomere length and risk of myeloid neoplasms.},
journal = {Human molecular genetics},
volume = {32},
number = {20},
pages = {2996-3005},
pmid = {37531260},
issn = {1460-2083},
support = {R01 CA142714/CA/NCI NIH HHS/United States ; R01 CA142714/NH/NIH HHS/United States ; },
mesh = {Humans ; *Genome-Wide Association Study ; Genetic Predisposition to Disease ; Risk Factors ; Leukocytes/metabolism ; Genetic Risk Score ; Telomere/genetics ; *Leukemia, Myeloid, Acute/genetics/metabolism ; Mendelian Randomization Analysis ; },
abstract = {Maintenance of telomere length has long been established to play a role in the biology of cancer and several studies suggest that it may be especially important in myeloid malignancies. To overcome potential bias in confounding and reverse causation of observational studies, we use both a polygenic risk score (PRS) and inverse-variance weighted (IVW) Mendelian randomization (MR) analyses to estimate the relationship between genetically predicted leukocyte telomere length (LTL) and acute myeloid leukemia (AML) risk in 498 cases and 2099 controls and myelodysplastic syndrome (MDS) risk in 610 cases and 1759 controls. Genetic instruments derived from four recent studies explaining 1.23-4.57% of telomere variability were considered. We used multivariable logistic regression to estimate odds ratios (OR, 95% confidence intervals [CI]) as the measure of association between individual single-nucleotide polymorphisms and myeloid malignancies. We observed a significant association between a PRS of longer predicted LTL and AML using three genetic instruments (OR = 4.03 per ~1200 base pair [bp] increase in LTL, 95% CI: 1.65, 9.85 using Codd et al. [Codd, V., Nelson, C.P., Albrecht, E., Mangino, M., Deelen, J., Buxton, J.L., Hottenga, J.J., Fischer, K., Esko, T., Surakka, I. et al. (2013) Identification of seven loci affecting mean telomere length and their association with disease. Nat. Genet., 45, 422-427 427e421-422.], OR = 3.48 per one-standard deviation increase in LTL, 95% CI: 1.74, 6.97 using Li et al. [Li, C., Stoma, S., Lotta, L.A., Warner, S., Albrecht, E., Allione, A., Arp, P.P., Broer, L., Buxton, J.L., Alves, A.D.S.C. et al. (2020) Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length. Am. J. Hum. Genet., 106, 389-404.] and OR = 2.59 per 1000 bp increase in LTL, 95% CI: 1.03, 6.52 using Taub et al. [Taub, M.A., Conomos, M.P., Keener, R., Iyer, K.R., Weinstock, J.S., Yanek, L.R., Lane, J., Miller-Fleming, T.W., Brody, J.A., Raffield, L.M. et al. (2022) Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed. Cell Genom., 2.] genetic instruments). MR analyses further indicated an association between LTL and AML risk (PIVW ≤ 0.049) but not MDS (all PIVW ≥ 0.076). Findings suggest variation in genes relevant to telomere function and maintenance may be important in the etiology of AML but not MDS.},
}
@article {pmid37530521,
year = {2023},
author = {Singh, P and Gazy, I and Kupiec, M},
title = {Control of telomere length in yeast by SUMOylated PCNA and the Elg1 PCNA unloader.},
journal = {eLife},
volume = {12},
number = {},
pages = {},
pmid = {37530521},
issn = {2050-084X},
mesh = {Saccharomyces cerevisiae/genetics/metabolism ; Proliferating Cell Nuclear Antigen/genetics ; *Telomerase/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Protein Binding ; Telomere/metabolism ; *Saccharomyces cerevisiae Proteins/metabolism ; Carrier Proteins/metabolism ; },
abstract = {Telomeres cap and protect the linear eukaryotic chromosomes. Telomere length is determined by an equilibrium between positive and negative regulators of telomerase activity. A systematic screen for yeast mutants that affect telomere length maintenance in the yeast Saccharomyces cerevisiae revealed that mutations in any of ~500 genes affects telomere length. One of the genes that, when mutated, causes telomere elongation is ELG1, which encodes an unloader of PCNA, the processivity factor for replicative DNA polymerases. PCNA can undergo SUMOylation on two conserved residues, K164 and K127, or ubiquitination at lysine 164. These modifications have already been implicated in genome stability processes. We report that SUMOylated PCNA acts as a signal that positively regulates telomerase activity. We also uncovered physical interactions between Elg1 and the CST (Cdc13-Stn1-Ten) complex and addressed the mechanism by which Elg1 and Stn1 negatively regulates telomere elongation, coordinated by SUMO. We discuss these results with respect to how chromosomal replication and telomere elongation are coordinated.},
}
@article {pmid37527721,
year = {2023},
author = {Sebastiano, M and Jouanneau, W and Blévin, P and Angelier, F and Parenteau, C and Pallud, M and Ribout, C and Gernigon, J and Lemesle, JC and Robin, F and Pardon, P and Budzinski, H and Labadie, P and Chastel, O},
title = {Physiological effects of PFAS exposure in seabird chicks: A multi-species study of thyroid hormone triiodothyronine, body condition and telomere length in South Western France.},
journal = {The Science of the total environment},
volume = {901},
number = {},
pages = {165920},
doi = {10.1016/j.scitotenv.2023.165920},
pmid = {37527721},
issn = {1879-1026},
abstract = {There is growing evidence that poly and perfluoroalkyl substances (PFAS) exposure leads to the disruption of thyroid hormones including thyroxine (T4) and triiodothyronine (T3), and may affect telomeres, repetitive nucleotide sequences which protect chromosome ends. Many seabird species are long-lived top predators thus exhibit high contaminant levels, and PFAS-disrupting effects on their physiology have been documented especially in relation to the endocrine system in adults. On the contrary, studies on the developmental period (i.e., chicks), during which exposure to environmental contaminants may have a greater impact on physiological traits, remain scarce to this date. We carried out a multi-species study with the aim to assess whether and to which extent chicks of four gull species (herring gull, great and lesser black-backed gull, yellow-legged gull) in South Western France are contaminated by PFAS, and to bring further evidence about their potential physiological consequences. Linear PFOS showed concentrations of concern as it was generally >10 times higher than the other PFAS, and exceeded a threshold toxicity level (calculated from previous studies in birds) in almost all sampled chicks. Nonetheless, in herring gull male chicks, total T3 levels were significantly and negatively associated with perfluorodecanoate (PFDA) and perfluorododecanoate (PFDoDA) and positively associated with perfluorotetradecanoate (PFTeDA) in female chicks. Total T3 levels were also positively associated with PFDoDA in great black backed gull male chicks and with perfluorotridecanoate (PFTrDA) in lesser black backed gull chicks. In lesser and great black-backed gulls, both females and males showed significant negative associations between several PFAS and their body condition, and a positive association between telomere length and L-PFOS in the yellow-legged gull was also found. These results corroborate previous findings and need to be further explored as they suggest that PFAS may interfere with the physiological status of chicks during the developmental period, potentially inducing long-lasting consequences.},
}
@article {pmid37526508,
year = {2023},
author = {Zhao, P and Deng, B and Kang, Q and Ni, M and Yang, B and Xue, M and Zhang, Y and Gao, R and Chen, Y and Li, Y and Zhang, L and Cheng, W and Zhao, M and Wang, J},
title = {Recipients with acute myeloid leukemia with a long telomere and donors with a short telomere have a higher relapse rate within 1-year post-transplantation.},
journal = {Minerva medica},
volume = {},
number = {},
pages = {},
doi = {10.23736/S0026-4806.23.08742-6},
pmid = {37526508},
issn = {1827-1669},
}
@article {pmid37526331,
year = {2023},
author = {Guo, M and Songyang, Z and Xiong, Y},
title = {ChArmTelo Enables Large-Scale Chromosome Arm-Level Telomere Analysis across Human Populations and in Cancer Patients.},
journal = {Small methods},
volume = {7},
number = {11},
pages = {e2300385},
doi = {10.1002/smtd.202300385},
pmid = {37526331},
issn = {2366-9608},
support = {92249303//National Natural Science Foundation of China/ ; 2021A1515110972//Guangdong Basic and Applied Basic Research Foundation/ ; },
mesh = {Animals ; Humans ; *Arm ; Telomere/genetics ; DNA Replication ; Algorithms ; *Liver Neoplasms ; },
abstract = {Telomeres are structures protecting chromosome ends. However, a scalable and cost-effective method to investigate chromosome arm-level (ChArm) telomeres (Telos) in large-scale projects is still lacking, hindering intensive investigation of high-resolution telomeres across cancers and other diseases. Here, ChArmTelo, the first computational toolbox to analyze telomeres at chromosome arm level in human and other animal species, using 10X linked-read and similar technologies, is presented. ChArmTelo currently consists of two algorithms, TeloEM and TeloKnow, for arm-level telomere length (TL) analysis. The algorithms are demonstrated by comprehensive analysis of chromosome arm-level telomere lengths (chArmTLs) in nearly 400 whole genome sequencing samples (WGS) from human populations and animals, including healthy and cancer samples. Notably, considerable performance improvement contributed by using the latest complete telomere-to-telomere reference genome (CHM13v2), compared to hg38, is shown. ChArmTelo reveals population-specific chArmTL differences and liver cancer signatures of chArmTLs and that DNA replication origin disruption may contribute to cancer by affecting TLs. Importantly, ChArmTelo can be readily applied to tens of thousands of cancer and healthy samples with published WGS data.},
}
@article {pmid37524789,
year = {2023},
author = {O'Donnell, S and Yue, JX and Saada, OA and Agier, N and Caradec, C and Cokelaer, T and De Chiara, M and Delmas, S and Dutreux, F and Fournier, T and Friedrich, A and Kornobis, E and Li, J and Miao, Z and Tattini, L and Schacherer, J and Liti, G and Fischer, G},
title = {Telomere-to-telomere assemblies of 142 strains characterize the genome structural landscape in Saccharomyces cerevisiae.},
journal = {Nature genetics},
volume = {55},
number = {8},
pages = {1390-1399},
pmid = {37524789},
issn = {1546-1718},
mesh = {*Saccharomyces cerevisiae/genetics ; Phylogeny ; *Genome ; Genomics ; Telomere/genetics ; },
abstract = {Pangenomes provide access to an accurate representation of the genetic diversity of species, both in terms of sequence polymorphisms and structural variants (SVs). Here we generated the Saccharomyces cerevisiae Reference Assembly Panel (ScRAP) comprising reference-quality genomes for 142 strains representing the species' phylogenetic and ecological diversity. The ScRAP includes phased haplotype assemblies for several heterozygous diploid and polyploid isolates. We identified circa (ca.) 4,800 nonredundant SVs that provide a broad view of the genomic diversity, including the dynamics of telomere length and transposable elements. We uncovered frequent cases of complex aneuploidies where large chromosomes underwent large deletions and translocations. We found that SVs can impact gene expression near the breakpoints and substantially contribute to gene repertoire evolution. We also discovered that horizontally acquired regions insert at chromosome ends and can generate new telomeres. Overall, the ScRAP demonstrates the benefit of a pangenome in understanding genome evolution at population scale.},
}
@article {pmid37519381,
year = {2023},
author = {Dasanayaka, NN and Sirisena, ND and Samaranayake, N},
title = {Associations of meditation with telomere dynamics: a case-control study in healthy adults.},
journal = {Frontiers in psychology},
volume = {14},
number = {},
pages = {1222863},
pmid = {37519381},
issn = {1664-1078},
abstract = {INTRODUCTION: Telomeres are protective end caps of chromosomes which naturally shorten with each cell division and thus with age. Short telomeres have been associated with many age-related diseases. Meditation has come to the fore as a mind-body practice which could influence the telomere dynamics underlying these phenomena. We previously reported meditation to be associated with higher telomerase levels, mindfulness and quality of life. Here, reporting on the same study population, we describe associations between long-term meditation and telomere length (TL), expression of hTERT and hTR genes and methylation of the promoter region of hTERT gene.<br><br>METHODS: Thirty healthy meditators and matched non-meditators were recruited. TL was measured using quantitative PCR, gene expression was assessed using reverse transcriptase PCR, and methylation level was quantified by bisulfite-specific PCR followed by Sanger sequencing. Comparisons between meditators and controls were carried out using t-tests, while Pearson correlation was used to identify correlations, and regression was used to identify predictors.<br><br>RESULTS: Males comprised 63.4% of each group with an average age of 43&#x2009;years. On average, they had meditated daily for 5.82&#x2009;h (&#xb1;3.45) for 6.8&#x2009;years (&#xb1;3.27). Meditators had longer relative TLs (p =&#x2009;0.020), and TL decreased with age (p <&#x2009;0.001) but was not associated with other socio-demographic variables. Regression analysis showed that age (p <&#x2009;0.001) and duration of meditation (p =&#x2009;0.003) significantly predicted TL. The meditators showed higher relative expression of hTERT (p =&#x2009;0.020) and hTR (p =&#x2009;0.029) genes while the methylation level of the promoter region of hTERT gene was significantly lower when compared to non-meditators (p <&#x2009;0.001). Negative correlations were identified between the methylation level of the promoter region of hTERT gene and the expression of the hTERT gene (p =&#x2009;0.001) and duration of meditation (p =&#x2009;0.001).<br><br>CONCLUSION: The findings suggest that meditation as a lifestyle practice has multi-level beneficial effects on telomere dynamics with potential to promote healthy aging.},
}
@article {pmid37515613,
year = {2023},
author = {Cai, Y and Guo, H and Zhou, J and Zhu, G and Qu, H and Liu, L and Shi, T and Ge, S and Qu, Y},
title = {An alternative extension of telomeres related prognostic model to predict survival in lower grade glioma.},
journal = {Journal of cancer research and clinical oncology},
volume = {149},
number = {15},
pages = {13575-13589},
pmid = {37515613},
issn = {1432-1335},
support = {81630027//National Natural Science Foundation of China/ ; },
abstract = {OBJECTIVE: The alternative extension of the telomeres (ALT) mechanism is activated in lower grade glioma (LGG), but the role of the ALT mechanism has not been well discussed. The primary purpose was to demonstrate the significance of the ALT mechanism in prognosis estimation for LGG patients.<br><br>METHOD: Gene expression and clinical data of LGG patients were collected from the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) cohort, respectively. ALT-related genes obtained from the TelNet database and potential prognostic genes related to ALT were selected by LASSO regression to calculate an ALT-related risk score. Multivariate Cox regression analysis was performed to construct a prognosis signature, and a nomogram was used to represent this signature. Possible pathways of the ALT-related risk score are explored by enrichment analysis.<br><br>RESULT: The ALT-related risk score was calculated based on the LASSO regression coefficients of 22 genes and then divided into high-risk and low-risk groups according to the median. The ALT-related risk score is an independent predictor of LGG (HR and 95% CI in CGGA cohort: 5.70 (3.79, 8.58); in TCGA cohort: 1.96 (1.09, 3.54)). ROC analysis indicated that the model contained ALT-related risk score was superior to conventional clinical features (AUC: 0.818 vs 0.729) in CGGA cohorts. The results in the TCGA cohort also shown a powerful ability of ALT-related risk score (AUC: 0.766 vs 0.691). The predicted probability and actual probability of the nomogram are consistent. Enrichment analysis demonstrated that the ALT mechanism was involved in the cell cycle, DNA repair, immune processes, and others.<br><br>CONCLUSION: ALT-related risk score based on the 22-gene is an important factor in predicting the prognosis of LGG patients.},
}
@article {pmid37511119,
year = {2023},
author = {Dmitrenko, OP and Abramova, OI and Karpova, NS and Nurbekov, MK and Arshinova, ES},
title = {Relative Telomere Length Is Associated with the Risk of Development and Severity of the Course of Age-Related Macular Degeneration in the Russian Population.},
journal = {International journal of molecular sciences},
volume = {24},
number = {14},
pages = {},
pmid = {37511119},
issn = {1422-0067},
support = {&#x2116; FGFU-2022-0011: &#xab;Identification of significant bioindicators of various disorders of body functions&#xbb;.//The work was carried out within the framework of the state task of the Federal State Budgetary Institution "Research Institute of Pathology and Pathophysiology" &#x2116; FGFU-2022-0011: &#xab;Identification of significant bioindicators of various disorders of body fu/ ; },
mesh = {Male ; Humans ; Female ; *Telomere/genetics ; Aging/pathology ; Risk Factors ; *Macular Degeneration/genetics ; Biomarkers ; Disease Progression ; },
abstract = {One of the most significant factors for age-related macular degeneration (AMD) development is considered to be aging, the processes of which are closely associated with telomere shortening. The different forms, indicators of aggressiveness, and intensities of AMD can be observed in the same age group, confirming the need to find a biomarker for early diagnosis and be capable of monitoring the progression of the pathological process. Therefore, we investigated whether the relative telomere length (RTL) has any connection with the risk of development of disease and its progression. RTL was measured using RT-PCR in 166 people, including 96 patients with AMD. RTL was significantly lower in patients with AMD. Women were more likely to develop AMD than men (odds ratio (OR) = 9.53 × 10[6] vs. OR = 1.04 × 10[8], respectively). The decrease in RTL in patients reliably correlated with the progression of AMD, and the smallest RTL was observed in late-stage patients. RTL < 0.8 is a significant risk factor for disease progression. The results of our research showed that RTL may be considered as a potential biomarker and a promising predictor of disease progression in patients with early AMD.},
}
@article {pmid37508101,
year = {2023},
author = {O'Daniel, SE and Kochan, KJ and Long, CR and Riley, DG and Randel, RD and Welsh, TH},
title = {Comparison of Telomere Length in Age-Matched Primiparous and Multiparous Brahman Cows.},
journal = {Animals : an open access journal from MDPI},
volume = {13},
number = {14},
pages = {},
pmid = {37508101},
issn = {2076-2615},
support = {USDA-NIFA grant 2019-67015-2957//United States Department of Agriculture/ ; },
abstract = {Physiological and psychological stressors have been associated with the attrition of telomeres, which are the protective caps of chromosomes. This study compares the telomere length (TL) in 4-year-old Brahman cows grouped by the first parity (n = 8) and the second parity (n = 11). The cows were bled via jugular venipuncture, weighed, and had their body condition scores recorded at Day -28 prior to calving and at Day + 7 and Day + 28 post-calving. The duration of labor (Dlabor) and parturition ease were recorded. The peripheral leukocytes were isolated, the leukocyte blood count with differential was recorded, and the genomic DNA was extracted. The relative quantity of telomere products, which is proportional to the average TL, was determined via multiplex quantitative PCR using the ratio (T/S ratio) of bovine telomere and β-globulin DNA. Standards of the bovine telomere (10[12]-10[7] dilution series) and β-globulin (10[9]-10[4] dilution series) genes were utilized to produce relative copy numbers. The samples were assayed in triplicate and were included if the triplicate Cq difference was less than 0.25 cycles. The parity was the fixed effect, and the random effects included the sire and day repeated with the cow as the subject. Statistical significance was not observed in the leukocyte number or type (p > 0.1). A reduction in the TL of approximately 9225 telomeric copies was found between Parity 1 and Parity 2 (p = 0.02). A trend was found between the TL and Dlabor (p = 0.06). The stress of parturition and raising the first calf of a cow's life may be responsible for TL attenuation. Parity may be considered a stressor of cow longevity.},
}
@article {pmid37502897,
year = {2023},
author = {Bazan, N and Bhattacharjee, S and Kala-Bhattacharjee, S and Ledet, A and Mukherjee, P},
title = {Elovanoids are neural resiliency epigenomic regulators targeting histone modifications, DNA methylation, tau phosphorylation, telomere integrity, senescence programming, and dendrite integrity.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {37502897},
support = {R01 EY005121/EY/NEI NIH HHS/United States ; },
abstract = {Cellular identity, developmental reorganization, genomic structure modulation, and susceptibility to diseases are determined by epigenomic regulation by multiple signaling interplay. Here we demonstrate that elovanoids (ELVs), mediators derived from very-long-chain polyunsaturated fatty acids (VLC-PUFAs, n-3, C > 28), and their precursors in neurons in culture overcome the damage triggered by oligomeric amyloid-beta (OAβ), erastin (ferroptosis-dependent cell death), or other insults that target epigenomic signaling. We uncover that ELVs counteract damage targeting histones H3K9 and H3K27 methylation and acetylation; tau hyperphosphorylation (pThr181, pThr217, pThr231, and pSer202/pThr205 (AT8)); senescence gene programming (p16INK4a, p27KIP, p21CIP1, and p53); DNA methylation (DNAm) modifying enzymes: TET (DNA hydroxymethylase), DNA methyltransferase, DNA demethylase, and DNAm (5mC) phenotype. Moreover, ELVs revert OAβ-triggered telomere length (TL) attrition as well as upregulation of telomerase reverse transcriptase (TERT) expression fostering dendrite protection and neuronal survival. Thus, ELVs modulate epigenomic resiliency by pleiotropic interrelated signaling.},
}
@article {pmid37496110,
year = {2023},
author = {Sung, S and Kim, E and Niida, H and Kim, C and Lee, J},
title = {Distinct characteristics of two types of alternative lengthening of telomeres in mouse embryonic stem cells.},
journal = {Nucleic acids research},
volume = {51},
number = {17},
pages = {9122-9143},
pmid = {37496110},
issn = {1362-4962},
mesh = {Animals ; Mice ; *Mouse Embryonic Stem Cells/metabolism ; Mutation ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; Telomere Homeostasis ; },
abstract = {Telomere length must be maintained in actively dividing cells to avoid cellular arrest or death. In the absence of telomerase activity, activation of alternative lengthening of telomeres (ALT) allows the maintenance of telomeric length and prolongs the cellular lifespan. Our previous studies have established two types of ALT survivors from mouse embryonic stem cells. The key differences between these ALT survivors are telomere-constituting sequences: non-telomeric sequences and canonical telomeric repeats, with each type of ALT survivors being referred to as type I and type II, respectively. We explored how the characteristics of the two types of ALT lines reflect their fates using multi-omics approaches. The most notable gene expression signatures of type I and type II ALT cell lines were chromatin remodelling and DNA repair, respectively. Compared with type II cells, type I ALT cells accumulated more mutations and demonstrated persistent telomere instability. These findings indicate that cells of the same origin have separate routes for survival, thus providing insights into the plasticity of crisis-suffering cells and cancers.},
}
@article {pmid37495394,
year = {2023},
author = {Cai, SW and de Lange, T},
title = {CST-Polα/Primase: the second telomere maintenance machine.},
journal = {Genes &amp; development},
volume = {37},
number = {13-14},
pages = {555-569},
pmid = {37495394},
issn = {1549-5477},
support = {R35 CA210036/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Humans ; *Telomerase/metabolism ; DNA Primase/genetics ; Telomere-Binding Proteins/genetics/metabolism ; Telomere/genetics/metabolism ; Telomere Homeostasis ; DNA Replication ; Mammals/genetics ; },
abstract = {It has been known for decades that telomerase extends the 3' end of linear eukaryotic chromosomes and dictates the telomeric repeat sequence based on the template in its RNA. However, telomerase does not mitigate sequence loss at the 5' ends of chromosomes, which results from lagging strand DNA synthesis and nucleolytic processing. Therefore, a second enzyme is needed to keep telomeres intact: DNA polymerase α/Primase bound to Ctc1-Stn1-Ten1 (CST). CST-Polα/Primase maintains telomeres through a fill-in reaction that replenishes the lost sequences at the 5' ends. CST not only serves to maintain telomeres but also determines their length by keeping telomerase from overelongating telomeres. Here we discuss recent data on the evolution, structure, function, and recruitment of mammalian CST-Polα/Primase, highlighting the role of this complex and telomere length control in human disease.},
}
@article {pmid37494011,
year = {2023},
author = {Aung, N and Wang, Q and van Duijvenboden, S and Burns, R and Stoma, S and Raisi-Estabragh, Z and Ahmet, S and Allara, E and Wood, A and Di Angelantonio, E and Danesh, J and Munroe, PB and Young, A and Harvey, NC and Codd, V and Nelson, CP and Petersen, SE and Samani, NJ},
title = {Association of Longer Leukocyte Telomere Length With Cardiac Size, Function, and Heart Failure.},
journal = {JAMA cardiology},
volume = {8},
number = {9},
pages = {808-815},
pmid = {37494011},
issn = {2380-6591},
support = {MR/L003120/1/MRC_/Medical Research Council/United Kingdom ; BRC-1215-20014/DH_/Department of Health/United Kingdom ; RE/18/1/34212/BHF_/British Heart Foundation/United Kingdom ; FS/17/81/33318/BHF_/British Heart Foundation/United Kingdom ; PG/21/10619/BHF_/British Heart Foundation/United Kingdom ; BTRU-2014-10024/DH_/Department of Health/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; SP/16/4/32697/BHF_/British Heart Foundation/United Kingdom ; BCDSA\100005/BHF_/British Heart Foundation/United Kingdom ; MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; MC_PC_21001/MRC_/Medical Research Council/United Kingdom ; NIHR203312/DH_/Department of Health/United Kingdom ; RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom ; BRC-1215-20010/DH_/Department of Health/United Kingdom ; RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom ; MC_PC_21003/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Male ; Middle Aged ; Humans ; Female ; Cross-Sectional Studies ; Phenotype ; *Heart Failure/genetics ; Leukocytes ; Telomere/genetics ; },
abstract = {IMPORTANCE: Longer leukocyte telomere length (LTL) is associated with a lower risk of adverse cardiovascular outcomes. The extent to which variation in LTL is associated with intermediary cardiovascular phenotypes is unclear.<br><br>OBJECTIVE: To evaluate the associations between LTL and a diverse set of cardiovascular imaging phenotypes.<br><br>This is a population-based cross-sectional study of UK Biobank participants recruited from 2006 to 2010. LTL was measured using a quantitative polymerase chain reaction method. Cardiovascular measurements were derived from cardiovascular magnetic resonance using machine learning. The median (IQR) duration of follow-up was 12.0 (11.3-12.7) years. The associations of LTL with imaging measurements and incident heart failure (HF) were evaluated by multivariable regression models. Genetic associations between LTL and significantly associated traits were investigated by mendelian randomization. Data were analyzed from January to May 2023.<br><br>EXPOSURE: LTL.<br><br>MAIN OUTCOMES AND MEASURES: Cardiovascular imaging traits and HF.<br><br>RESULTS: Of 40&#x202f;459 included participants, 19 529 (48.3%) were men, and the mean (SD) age was 55.1 (7.6) years. Longer LTL was independently associated with a pattern of positive cardiac remodeling (higher left ventricular mass, larger global ventricular size and volume, and higher ventricular and atrial stroke volumes) and a lower risk of incident HF (LTL fourth quartile vs first quartile: hazard ratio, 0.86; 95% CI, 0.81-0.91; P&#x2009;=&#x2009;1.8&#x2009;&#xd7;&#x2009;10-6). Mendelian randomization analysis suggested a potential causal association between LTL and left ventricular mass, global ventricular volume, and left ventricular stroke volume.<br><br>CONCLUSIONS AND RELEVANCE: In this cross-sectional study, longer LTL was associated with a larger heart with better cardiac function in middle age, which could potentially explain the observed lower risk of incident HF.},
}
@article {pmid37493024,
year = {2023},
author = {Li, T and Zhang, M and Li, Y and Han, X and Tang, L and Ma, T and Zhao, X and Zhao, R and Wang, Y and Bai, X and Zhang, K and Geng, X and Sui, L and Feng, X and Zhang, Q and Zhao, Y and Liu, Y and Stewart, JA and Wang, F},
title = {Cooperative interaction of CST and RECQ4 resolves G-quadruplexes and maintains telomere stability.},
journal = {EMBO reports},
volume = {24},
number = {9},
pages = {e55494},
pmid = {37493024},
issn = {1469-3178},
mesh = {Humans ; *DNA Replication ; Telomere-Binding Proteins/genetics ; *G-Quadruplexes ; Telomere Homeostasis ; Telomere/metabolism ; },
abstract = {Human CST (CTC1-STN1-TEN1) is a ssDNA-binding complex that interacts with the replisome to aid in stalled fork rescue. We previously found that CST promotes telomere replication to maintain genomic integrity via G-quadruplex (G4) resolution. However, the detailed mechanism by which CST resolves G4s in vivo and whether additional factors are involved remains unclear. Here, we identify RECQ4 as a novel CST-interacting partner and show that RECQ4 can unwind G4 structures in vitro using a FRET assay. Moreover, G4s accumulate at the telomere after RECQ4 depletion, resulting in telomere dysfunction, including the formation of MTSs, SFEs, and TIFs, suggesting that RECQ4 is crucial for telomere integrity. Furthermore, CST is also required for RECQ4 telomere or chromatin localization in response to G4 stabilizers. RECQ4 is involved in preserving genomic stability by CST and RECQ4 disruption impairs restart of replication forks stalled by G4s. Overall, our findings highlight the essential roles of CST and RECQ4 in resolving G-rich regions, where they collaborate to resolve G4-induced replication deficiencies and maintain genomic homeostasis.},
}
@article {pmid37491556,
year = {2024},
author = {Pérez-López, FR and López-Baena, MT and Ulloque-Badaracco, JR and Benites-Zapata, VA},
title = {Telomere Length in Patients with Gestational Diabetes Mellitus and Normoglycemic Pregnant Women: a Systematic Review and Meta-analysis.},
journal = {Reproductive sciences (Thousand Oaks, Calif.)},
volume = {31},
number = {1},
pages = {45-55},
pmid = {37491556},
issn = {1933-7205},
mesh = {Infant ; Humans ; Pregnancy ; Female ; *Diabetes, Gestational/diagnosis ; Pregnant Women ; Birth Weight ; Cholesterol ; Telomere ; },
abstract = {We performed a systematic review and meta-analysis of studies assessing telomere length in blood leukocytes or mononuclear cells in women with gestational diabetes mellitus (GDM) and normoglycemic pregnant women (NPW) and their infants. The review protocol was registered in PROSPERO (CRD42022300950). Searches were conducted in PubMed, Embase, LILACS, CNKI, and Wang Fang, from inception through November 2022. The primary outcomes were maternal and offspring telomere length. The Newcastle-Ottawa Scale was used to assess the quality of included studies. Random-effect meta-analyses were applied to estimate standardized mean differences (SMDs) and their 95% confidence interval (CI). The meta-analysis of four studies showed no significant maternal telomere length difference (SMD = -0.80, 95% CI: -1.66, 0.05) in women with GDM compared to NPW. In the sensibility analysis omitting one study with a small sample of women, the telomere length becomes significantly reduced in women with GDM (SMD = -1.10, 95% CI: -2.18, -0.02). GDM patients had increased glucose (SMD = 0.28, 95% CI: 0.09, 0.46) and glycosylated hemoglobin than NPW (SMD = 0.62, 95% CI: 0.23, 1.01) while total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides did not display differences between women with and without GDM. There was no significant difference in cord blood telomere length in offspring from women with GDM and NPW (SMD = 0.11, 95% CI: -0.52, 0.30). Cord blood insulin levels (SMD = 0.59, 95% CI: 0.33, 0.85) and birthweight (SMD = 0.59, 95% CI: 0.39, 0.79) were higher in offspring from pregnant women with GDM than in those from NPW. There were no significant differences in maternal and offspring telomere length between pregnancies with and without GDM.},
}
@article {pmid37489893,
year = {2023},
author = {Hoferichter, F and Jentsch, A and Maas, L and Hageman, G},
title = {Burnout among high school students is linked to their telomere length and relatedness with peers.},
journal = {Stress (Amsterdam, Netherlands)},
volume = {26},
number = {1},
pages = {2240909},
doi = {10.1080/10253890.2023.2240909},
pmid = {37489893},
issn = {1607-8888},
mesh = {Female ; Humans ; Male ; *Burnout, Psychological/genetics ; *Students ; Telomere/genetics ; Adolescent ; Interpersonal Relations ; Peer Group ; },
abstract = {School burnout is a serious concern, as it impairs students' health and academic success. According to the Conservation of Resources Theory, burnout results from the depletion of personal coping resources and can be counteracted by supportive social relationships. However, it is not yet clear how students' relatedness with their peers is linked to their burnout. Next to students' self-reported fatigue, biomarkers such as telomere length (TL), which presents an indicator of aging, complement stress research. To identify school-related factors that may prevent students from experiencing burnout and to link TL to students' self-reported burnout, the current study investigated how relatedness with peers as well as TL at the beginning of the school year explained students' burnout at the end of the school year. The sample included 78 students (Mage = 13.7 ± 0.7 years; 48% girls). Results of multilevel analysis in Mplus indicate that, over the school year, students with higher TL and those who experienced relatedness with their peers reported lower levels of burnout. Moreover, students who felt related to their peers exhibited a longer TL. The study implies that students' relatedness with their peers may be a promising setscrew to prevent students' burnout and support their physical health. This is one of the first studies to link TL with school-related variables such as burnout and relatedness to peers in a non-clinical student sample, providing a baseline for interventions and future interdisciplinary studies in the field of education and stress.},
}
@article {pmid37489536,
year = {2023},
author = {Schuermans, A and Nakao, T and Uddin, MM and Hornsby, W and Ganesh, S and Shadyab, AH and Liu, S and Haring, B and Shufelt, CL and Taub, MA and Mathias, RA and Kooperberg, C and Reiner, AP and Bick, AG and Manson, JE and Natarajan, P and Honigberg, MC},
title = {Age at Menopause, Leukocyte Telomere Length, and Coronary Artery Disease in Postmenopausal Women.},
journal = {Circulation research},
volume = {133},
number = {5},
pages = {376-386},
pmid = {37489536},
issn = {1524-4571},
support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; R01 HL130733/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; K08 HL166687/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; HHSN268201500014C/HL/NHLBI NIH HHS/United States ; R01 HL141944/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; R01 HL146500/HL/NHLBI NIH HHS/United States ; HHSN268201000001I/HL/NHLBI NIH HHS/United States ; DP5 OD029586/OD/NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL148050/HL/NHLBI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; },
mesh = {Adult ; Female ; Humans ; *Coronary Artery Disease/epidemiology/genetics ; Leukocytes ; Menopause/genetics ; *Menopause, Premature ; Postmenopause/genetics ; Telomere/genetics ; },
abstract = {BACKGROUND: Premature menopause is a risk factor for accelerated cardiovascular aging, but underlying mechanisms remain incompletely understood. This study investigated the role of leukocyte telomere length (LTL), a marker of cellular aging and genomic instability, in the association of premature menopause with cardiovascular disease.<br><br>METHODS: Participants from the UK Biobank and Women's Health Initiative with complete reproductive history and LTL measurements were included. Primary analyses tested the association between age at menopause and LTL using multivariable-adjusted linear regression. Secondary analyses stratified women by history of gynecologic surgery. Mendelian randomization was used to infer causal relationships between LTL and age at natural menopause. Multivariable-adjusted Cox regression and mediation analyses tested the joint associations of premature menopause and LTL with incident coronary artery disease.<br><br>RESULTS: This study included 130&#x2005;254 postmenopausal women (UK Biobank: n=122&#x2005;224; Women's Health Initiative: n=8030), of whom 4809 (3.7%) had experienced menopause before age 40. Earlier menopause was associated with shorter LTL (meta-analyzed &#xdf;=-0.02 SD/5 years of earlier menopause [95% CI, -0.02 to -0.01]; P=7.2&#xd7;10[-12]). This association was stronger and significant in both cohorts for women with natural/spontaneous menopause (meta-analyzed &#xdf;=-0.04 SD/5 years of earlier menopause [95% CI, -0.04 to -0.03]; P<2.2&#xd7;10[-16]) and was independent of hormone therapy use. Mendelian randomization supported a causal association of shorter genetically predicted LTL with earlier age at natural menopause. LTL and age at menopause were independently associated with incident coronary artery disease, and mediation analyses indicated small but significant mediation effects of LTL in the association of menopausal age with coronary artery disease.<br><br>CONCLUSIONS: Earlier age at menopause is associated with shorter LTL, especially among women with natural menopause. Accelerated telomere shortening may contribute to the heightened cardiovascular risk associated with premature menopause.},
}
@article {pmid37487414,
year = {2023},
author = {Sun, P and Wei, P and Liu, H and Wu, J and Gross, ND and Sikora, AG and Wei, Q and Shete, S and Zafereo, ME and Liu, J and Li, G},
title = {GWAS-identified telomere length associated genetic variants predict risk of recurrence of HPV-positive oropharyngeal cancer after definitive radiotherapy.},
journal = {EBioMedicine},
volume = {94},
number = {},
pages = {104722},
pmid = {37487414},
issn = {2352-3964},
mesh = {Humans ; Genome-Wide Association Study ; *Papillomavirus Infections/complications/genetics ; *Oropharyngeal Neoplasms/genetics ; Squamous Cell Carcinoma of Head and Neck ; *Carcinoma, Squamous Cell/genetics ; *Head and Neck Neoplasms ; Telomere/genetics ; Polymorphism, Single Nucleotide ; Leukocytes ; },
abstract = {BACKGROUND: Lymphocyte telomere length (LTL)-related genetic variants may modulate LTL and affect recurrence of squamous cell carcinoma of the oropharynx (SCCOP).<br><br>METHODS: A total of 1013 patients with incident SCCOP were recruited and genotyped for 16 genome-wide association study (GWAS)-identified TL-related polymorphisms. Of these patients, 489 had tumour HPV16 status determination. Univariate and multivariate analyses were performed to evaluate associations.<br><br>FINDINGS: Of the 16&#xa0;TL-related polymorphisms, four were significantly associated with LTL: rs1920116, rs3027234, rs6772228, and rs11125529, and the patients with putatively favourable genotypes had approximately 1.5-3 times the likelihood of shorter LTL compared with patients with the corresponding risk genotypes. Moreover, patients with one to four favourable genotypes of the four combined polymorphisms had approximately 3-11 times the likelihood of shorter LTL compared with patients with no favourable genotype. The four LTL-related polymorphisms were significantly associated with approximately 40% reduced risk (for favourable genotypes) or doubled risk (for risk genotypes) of recurrence, and similar but more pronounced associations were observed in patients with tumour HPV16-positive SCCOP. Similarly, patients with one to four risk genotypes had significantly approximately 2.5-4 times increased recurrence risk compared with patients with no risk genotype, and similar but more pronounced associations were observed in patients with tumour HPV16-positive SCCOP.<br><br>INTERPRETATION: Four LTL-related polymorphisms individually or jointly modify LTL and risk of recurrence of SCCOP, particularly HPV-positive SCCOP. These LTL-related polymorphisms could have potential to further stratify patients with HPV-positive SCCOP for individualized treatment and better survival.<br><br>FUNDING: Not applicable.},
}
@article {pmid37478811,
year = {2023},
author = {Marti, A and Fernández de la Puente, M and Canudas, S and Zalba, G and Razquin, C and Valle-Hita, C and Fitó, M and Martínez-González, M&#xc1; and García-Calzón, S and Salas-Salvadó, J},
title = {Effect of a 3-year lifestyle intervention on telomere length in participants from PREDIMED-Plus: A randomized trial.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {42},
number = {9},
pages = {1581-1587},
doi = {10.1016/j.clnu.2023.06.030},
pmid = {37478811},
issn = {1532-1983},
mesh = {Male ; Humans ; Female ; Middle Aged ; Aged ; Risk Factors ; *Cardiovascular Diseases/prevention &amp; control ; *Metabolic Syndrome ; Life Style ; Telomere ; *Diet, Mediterranean ; },
abstract = {BACKGROUND &amp; AIMS: Short telomeres have been observed in chronic disease patients. Identifying environmental and lifestyle factors that could reduce telomere attrition is crucial for disease prevention. The aim of this work was to determine whether weight-loss induced by an energy-reduced Mediterranean diet (erMedDiet) and physical activity (PA) could modify telomere length (TL).<br><br>METHODS: In 317 randomized non-smoker participants (mean age, 65.8&#xa0;&#xb1;&#xa0;4.98 years) with metabolic syndrome from two "Prevenci&#xf3;n con Dieta Mediterr&#xe1;nea-Plus" (PREDIMED-Plus) trial centers, we evaluated MedDiet adherence, PA, anthropometric variables and TL at baseline and after a 3-year intervention using an intensive lifestyle program (IG) with an erMedDiet and PA or an unrestricted MedDiet without PA promotion (CG).<br><br>RESULTS: Participants in the IG displayed greater 3-year weight reductions (-3.7&#xa0;&#xb1;&#xa0;4&#xa0;kg, P&#xa0;<&#xa0;0.001) compared to those in the CG. No differences in TL changes between groups were observed in the cohort as a whole. However, an interaction was observed between the intervention group and sex for TL changes (pinteraction&#xa0;=&#xa0;0.039). Women in the IG showed an increase in TL after 3-y (+0.25&#xa0;&#xb1;&#xa0;0.9, relative units) compared to women in the CG (-0.07&#xa0;&#xb1;&#xa0;1.0) (pANCOVA&#xa0;=&#xa0;0.036), whereas no differences between groups were observed in men. Women in the IG had a lower risk of telomere shortening after the intervention (OR&#xa0;=&#xa0;0.17, 95%CI: 0.05-0.64, p&#xa0;=&#xa0;0.008) compared to women in the CG.<br><br>CONCLUSIONS: A 3-year lifestyle intervention based on an erMedDiet and PA slowed telomere shortening in women but not in men.<br><br>TRIAL REGISTRATION: ISRCTN, ISRCTN89898870. Registered 24 July 2014- Retrospectively registered, https://www.isrctn.com/ISRCTN89898870.},
}
@article {pmid37477674,
year = {2023},
author = {Çakır, S},
title = {The Effect of Royal Jelly on Telomere Length and Some Biochemical Parameters in Wistar Albino Rats with Liver Damage Caused by Carbon Tetrachloride.},
journal = {Journal of medicinal food},
volume = {26},
number = {8},
pages = {580-585},
doi = {10.1089/jmf.2023.0042},
pmid = {37477674},
issn = {1557-7600},
mesh = {Rats ; Animals ; Bees ; Rats, Wistar ; *Carbon Tetrachloride/adverse effects ; Cholesterol, LDL ; *Liver Diseases/drug therapy ; Antioxidants/pharmacology/therapeutic use ; Liver ; Aspartate Aminotransferases ; },
abstract = {Royal jelly (RJ) is a natural bee product that has been used for therapeutic purposes since ancient times. The therapeutic properties of this product, which has rich biological content, are still being investigated with new approaches. In this study, the effect of RJ on telomere length, some antioxidant parameters, and lipid profile was examined. This study will contribute to the literature as it is the first to evaluate the effect of RJ on the length of telomeres in damaged liver tissues. In the study, the levels of serum triglyceride, total cholesterol (TC), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), aspartate transaminase (AST), alanine transaminase (ALT), telomerase, 8'-hydroxy-2'-deoxyguanosine (8-OHdG), and paraoxonase-1 (PON1) were investigated with enzyme-linked immunosorbent assay method and telomere lengths were investigated by real-time quantitative polymerase chain reaction. The increased TC, LDL-C levels, and AST and ALT activities in the serum after carbon tetrachloride (CCl4) administration approached the control level after RJ administration. PON1 activity decreased in groups with CCl4. PON1 activity increased after RJ administration. The level of 8-OHdG, which increased groups with CCl4, decreased after RJ administration. According to the results of telomere length analysis in liver tissues, telomere lengths in damaged tissues were significantly shortened with CCl4 application and increased with RJ application. Based on the findings of the study, it was concluded that RJ may have therapeutic effects on telomere lengths and some biochemistry parameters.},
}
@article {pmid37477641,
year = {2023},
author = {Reddy, V and Hwang, C and Reddy, GP and Kim, SH},
title = {A Novel Role of Prostate-Specific Membrane Antigen in Telomere Stability in Prostate Cancer Cells.},
journal = {Molecular cancer research : MCR},
volume = {21},
number = {11},
pages = {1176-1185},
doi = {10.1158/1541-7786.MCR-23-0075},
pmid = {37477641},
issn = {1557-3125},
support = {W81XWH-17-1-0305//U.S. Department of Defense (DOD)/ ; W81XWH-22-1-0400//U.S. Department of Defense (DOD)/ ; },
mesh = {Male ; Humans ; *Prostate/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Antigens, Surface/genetics ; Glutamate Carboxypeptidase II/genetics ; *Prostatic Neoplasms/metabolism ; Phosphorylation ; Telomere/genetics/metabolism ; Cell Line, Tumor ; },
abstract = {UNLABELLED: Prostate-specific membrane antigen (PSMA) expression increases with prostate cancer grade and progression; however, the role of PSMA in prostate cancer progression remains poorly understood. Telomere stability is essential for the survival and genome stability of cancer cells. We found massive telomere DNA damage in PSMA-negative prostate cancer cells (PC-3 and DU145) compared with PSMA-positive prostate cancer (LNCaP) cells. The ectopic expression of PSMA suppressed telomere DNA damage in PC3 cells. PSMA inhibitor, 2-PMPA, and PSMA knockdown induced telomere DNA damage in PSMA-positive LNCaP cells but not in PSMA-negative PC-3 cells, suggesting that PSMA plays a critical role in telomere stability in prostate cancer cells. In addition, we observed that inhibition of PSMA or inhibition of glutamate receptor, which mediates PSMA-dependent activation of AKT, suppressed AKT phosphorylation, and caused telomere DNA damage. Furthermore, 2-PMPA-induced telomere DNA damage in LNCaP cells was associated with telomere aberrations, such as telomere-telomere fusions, sister-chromatid telomere fusions, and telomere breakages. AKT is reported to promote cell growth by stabilizing telomere association with telomere-binding proteins TRF1 and TPP1. We observed that TRF1 and TPP1 transfection of LNCaP cells attenuated the inhibitory effect of 2-PMPA on cell growth and telomere DNA damage. Together, these observations indicate that PSMA role in maintaining telomere stability in prostate cancer cells is mediated by AKT. Thus, these studies reveal an important role of PSMA in maintaining telomere stability that can promote cell survival and, thereby, prostate cancer progression.<br><br>IMPLICATIONS: Role of PSMA in telomere stability suggests a strong correlation between PSMA expression and prostate cancer progression.},
}
@article {pmid37477196,
year = {2023},
author = {Aoulad Fares, D and Wiegel, RE and Eggink, AJ and van Meurs, JBJ and Willemsen, SP and Danser, AHJ and Steegers-Theunissen, RPM},
title = {First-trimester maternal renin-angiotensin-aldosterone system activation and the association with maternal telomere length after natural and IVF/ICSI conceived pregnancies: the Rotterdam periconception cohort.},
journal = {Hypertension in pregnancy},
volume = {42},
number = {1},
pages = {2238086},
doi = {10.1080/10641955.2023.2238086},
pmid = {37477196},
issn = {1525-6065},
mesh = {Pregnancy ; Male ; Female ; Humans ; Pregnancy Trimester, First ; *Sperm Injections, Intracytoplasmic ; *Renin-Angiotensin System ; Renin ; Aldosterone ; Semen ; Fertilization ; Fertilization in Vitro ; Telomere ; },
abstract = {OBJECTIVE: To study associations between the first-trimester maternal determinants of renin-angiotensin-aldosterone system (RAAS) activation and telomere length (TL) in pregnancies conceived natural and after IVF/ICSI.<br><br>METHODS: In 145 pregnancies of the Rotterdam Periconception cohort renin, prorenin and aldosterone concentrations were measured in maternal blood at 9 weeks gestational age (GA). TL was measured by qPCR at 20 weeks GA.<br><br>RESULTS: A significantly negative correlation was found between renin and TL, which was attenuated for prorenin but not observed for aldosterone. Maternal TL was significantly shorter in pregnancies conceived after in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) compared to natural pregnancies.<br><br>CONCLUSION: The negative association between first-trimester maternal renin and maternal TL, and the shorter maternal TL in women after IVF/ICSI treatment compared to natural pregnancies, substantiates the role of excessive RAAS activation.},
}
@article {pmid37474692,
year = {2023},
author = {Kurashova, NA and Vanyarkina, AS and Petrova, AG and Rychkova, LV and Kolesnikov, SI and Darenskaya, MA and Moskaleva, EV and Kolesnikova, LI},
title = {Length of Leukocyte Telomeres in Newborns of HIV-Infected Mothers.},
journal = {Bulletin of experimental biology and medicine},
volume = {175},
number = {2},
pages = {260-264},
pmid = {37474692},
issn = {1573-8221},
mesh = {Pregnancy ; Female ; Infant, Newborn ; Humans ; Mothers ; Infectious Disease Transmission, Vertical/prevention &amp; control ; Cross-Sectional Studies ; *HIV Infections/drug therapy/genetics/prevention &amp; control ; Leukocytes ; Telomere/genetics ; *Pregnancy Complications, Infectious/genetics ; },
abstract = {We studied the relative length of telomeres in newborns with unrealized perinatal transmission of HIV (zero viral load according to PCR results). A cross-sectional survey of 62 newborns of HIV-infected mothers (Apgar score 8); the control group consisted of 80 healthy newborns (Apgar score 8). DNA extracted from whole venous blood samples was analyzed. In newborns of HIV-infected mothers, the relative length of telomeres was significantly lower (0.69 (0.66; 0.72)) than in newborns of the control group (1.1 (0.97; 1.22)) (p<0.001). No significant differences in the relative length of telomeres were found between newborns of mothers with a viral load at the time of delivery and with undetectable viral load: 0.69 (0.66; 0.73) and 0.69 (0.63; 0.72). These findings indicate that HIV-infection in mothers or exposure to antiretroviral therapy has an impact on the relative telomere length in leukocytes of newborns.},
}
@article {pmid37469277,
year = {2023},
author = {Lee, GO and Mora-Plazas, M and Marín, C and Villamor, E},
title = {Leukocyte telomere length predicts subsequent infectious morbidity among Colombian schoolchildren.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {35},
number = {10},
pages = {e23966},
doi = {10.1002/ajhb.23966},
pmid = {37469277},
issn = {1520-6300},
support = {//ASISA Foundation/ ; },
abstract = {OBJECTIVE: Telomere length (TL) attrition is related to chronic disease risk. However, less is known on whether TL predicts infectious outcomes, especially in childhood. We examined whether leukocyte TL (LTL) was associated with subsequent infectious morbidity in schoolchildren.<br><br>METHODS: We assessed LTL in 717 Colombian children 5-12&#x2009;years-old at the beginning of a school year and followed them through the year for daily occurrence of common infection symptoms and doctor visits. We estimated adjusted incidence rate ratios (IRR) with 95% confidence intervals (CI) of gastrointestinal and respiratory syndromes for quartiles of standardized LTL Z score and per unit LTL Z score.<br><br>RESULTS: A longer LTL was associated with increased incidence of all infectious morbidity syndromes considered. Adjusted IRR (95% CI) per unit LTL Z score were 1.55 (1.20, 2.00) for diarrhea with vomiting, 1.34 (1.13, 1.60) for cough with fever, 1.70 (1.28, 2.28) for ear infection, and 1.66 (1.36, 2.02) for doctor visits with symptoms.<br><br>CONCLUSIONS: Longer LTL is related to increased incidence of common infectious morbidities in middle childhood.},
}
@article {pmid37463174,
year = {2023},
author = {Zhou, H and Xie, C and Xie, Y and He, Y and Chen, Y and Zhang, C and Zhang, Y and Zhao, Y and Liu, H},
title = {UBQLN1 deficiency mediates telomere shortening and IPF through interacting with RPA1.},
journal = {PLoS genetics},
volume = {19},
number = {7},
pages = {e1010856},
pmid = {37463174},
issn = {1553-7404},
mesh = {Humans ; Animals ; Mice ; *Telomere Shortening/genetics ; HeLa Cells ; *Idiopathic Pulmonary Fibrosis/genetics/epidemiology/pathology ; Telomere Homeostasis ; Telomere/genetics ; Replication Protein A/genetics ; Autophagy-Related Proteins/genetics ; Adaptor Proteins, Signal Transducing/genetics ; },
abstract = {Premature telomere shortening is a known factor correlated to idiopathic pulmonary fibrosis (IPF) occurrence, which is a chronic, progressive, age-related disease with high mortality. The etiology of IPF is still unknown. Here, we found that UBQLN1 plays a key role in telomere length maintenance and is potentially relevant to IPF. UBQLN1 involves in DNA replication by interacting with RPA1 and shuttling it off from the replication fork. The deficiency of UBQLN1 retains RPA1 at replication fork, hinders replication and thus causes cell cycle arrest and genome instability. Especially at telomere regions of the genome, where more endogenous replication stress exists because of G rich sequences, UBQLN1 depletion leads to rapid telomere shortening in HeLa cells. It revealed that UBQLN1 depletion also shortens telomere length at mouse lung and accelerates mouse lung fibrosis. In addition, the UBQLN1 expression level in IPF patients is downregulated and correlated to poor prognosis. Altogether, these results uncover a new role of UBQLN1 in ensuring DNA replication and maintaining telomere stability, which may shed light on IPF pathogenesis and prevention.},
}
@article {pmid37459977,
year = {2023},
author = {Mlakar, V and Birkenæs, V and Elvsaashagen, T and Ormerod, MBEG and Quintana, DS and Ueland, T and Melle, I and Lagerberg, TV and Djurovic, S and Martin-Ruiz, C and Steen, NE and Andreassen, OA and Aas, M},
title = {Telomere length and verbal learning in bipolar disorders.},
journal = {Journal of affective disorders},
volume = {339},
number = {},
pages = {555-560},
doi = {10.1016/j.jad.2023.07.087},
pmid = {37459977},
issn = {1573-2517},
support = {MR/WO27720/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; *Bipolar Disorder/drug therapy ; Telomere Shortening ; Telomere ; Neuropsychological Tests ; Memory, Short-Term ; Verbal Learning ; },
abstract = {INTRODUCTION: Recent studies indicate accelerated ageing processes, shorter telomere length and poorer cognitive functioning in patients with bipolar disorder. The neurobiology underlying cognitive function in bipolar disorder is yet to be established. We anticipated that accelerated ageing as indicated by shortened telomere length, would be associated with reduced cognitive performance in bipolar disorder, particularly for ageing sensitive functions such as memory and learning.<br><br>METHODS: The study consisted of 647 participants (bipolar disorder [n&#xa0;=&#xa0;246] and healthy controls [n&#xa0;=&#xa0;401]). All participants underwent a standardized neuropsychological test battery, including working memory, executive functioning, processing speed, verbal learning, and verbal memory. Leucocyte telomere length was measured via blood and determined by quantitative real-time Polymerase Chain Reaction (qPCR) providing a telomere to single copy ratio (T/S ratio). The T/S ratio was used as an estimate of the mean telomere length of each participant. All analyses were adjusted for medication, Daily Defined Dose (DDD), chronological age, sex, and ethnicity.<br><br>RESULTS: Patients had shorter telomere lengths than healthy controls (Cohen's d&#xa0;=&#xa0;0.11, p&#xa0;=&#xa0;0.01). Within patients', a positive association was observed for verbal learning and telomere length (&#x3b2;&#xa0;=&#xa0;0.14, p&#xa0;=&#xa0;0.025), along with a trend for verbal memory and telomere length (&#x3b2;&#xa0;=&#xa0;0.11, p&#xa0;=&#xa0;0.07). No other associations were observed for telomere length and cognitive functioning in the patient or the control group (p&#xa0;>&#xa0;0.1).<br><br>CONCLUSION: Our study may suggest poorer brain health in bipolar disorder as indexed by shorter telomere length and reduced learning correlates. However, the role of telomere length on cognitive functioning in bipolar disorder seems limited.},
}
@article {pmid37455385,
year = {2023},
author = {Neyaz, A and Crotty, R and Rickelt, S and Pankaj, A and Stojanova, M and Michelakos, TP and Sekigami, Y and Kontos, F and Parrack, PH and Patil, DT and Heaphy, CM and Ferrone, CR and Deshpande, V},
title = {Predicting recurrence in pancreatic neuroendocrine tumours: role of ARX and alternative lengthening of telomeres (ALT).},
journal = {Histopathology},
volume = {83},
number = {4},
pages = {546-558},
doi = {10.1111/his.14996},
pmid = {37455385},
issn = {1365-2559},
mesh = {Humans ; *Neuroendocrine Tumors/diagnosis/pathology ; *Pancreatic Neoplasms/diagnosis/pathology ; Disease-Free Survival ; Telomere/pathology ; Transcription Factors ; Homeodomain Proteins ; },
abstract = {BACKGROUND: While many pancreatic neuroendocrine tumours (PanNET) show indolent behaviour, predicting the biological behaviour of small nonfunctional PanNETs remains a challenge. Nonfunctional PanNETs with an epigenome and transcriptome that resemble islet alpha cells (ARX-positive) are more aggressive than neoplasms that resemble islet beta cells (PDX1-positive). In this study, we explore the ability of immunohistochemistry for ARX and PDX1 and telomere-specific fluorescence in situ hybridisation (FISH) for alternative lengthening of telomeres (ALT) to predict recurrence.<br><br>METHODS: Two hundred fifty-six patients with PanNETs were identified, and immunohistochemistry for ARX and PDX1 was performed. Positive staining was defined as strong nuclear staining in >5% of tumour cells. FISH for ALT was performed in a subset of cases.<br><br>RESULTS: ARX reactivity correlated with worse disease-free survival (DFS) (P&#x2009;=&#x2009;0.011), while there was no correlation between PDX1 reactivity and DFS (P&#x2009;=&#x2009;0.52). ALT-positive tumours (n&#x2009;=&#x2009;63, 31.8%) showed a significantly lower DFS (P&#x2009;<&#x2009;0.0001) than ALT-negative tumours (n&#x2009;=&#x2009;135, 68.2%). ARX reactivity correlated with ALT positivity (P&#x2009;<&#x2009;0.0001). Among nonfunctional tumours, recurrence was noted in 18.5% (30/162) of ARX-positive tumours and 7.5% (5/67) of ARX-negative tumours. Among WHO grade 1 and 2 PanNETs with &#x2264;2&#x2009;cm tumour size, 14% (6/43) of ARX-positive tumours recurred compared to 0 of 33 ARX-negative tumours and 33.3% (3/9) ALT-positive tumours showed recurrence versus 4.4% (2/45) ALT-negative tumours.<br><br>CONCLUSION: Immunohistochemistry for ARX and ALT FISH status may aid in distinguishing biologically indolent cases from aggressive small low-grade PanNETs, and help to identify patients who may preferentially benefit from surgical intervention.},
}
@article {pmid37454741,
year = {2023},
author = {Zhou, M and Cui, Y and Zuo, S and Peng, Q and Liu, Y and Li, X and Yang, Y and He, Q and Yu, X and Zhou, J and He, Z and He, Q},
title = {ZBTB40 is a telomere-associated protein and protects telomeres in human ALT cells.},
journal = {The Journal of biological chemistry},
volume = {299},
number = {9},
pages = {105053},
pmid = {37454741},
issn = {1083-351X},
mesh = {Humans ; Cell Line, Tumor ; *Telomere/genetics/metabolism ; Telomere Homeostasis/genetics ; Protein Binding ; DNA/metabolism ; Nuclear Bodies/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Gene Knockdown Techniques ; Gene Knockout Techniques ; Apoptosis/genetics ; },
abstract = {Alternative lengthening of telomeres (ALTs) mechanism is activated in some somatic, germ cells, and human cancer cells. However, the key regulators and mechanisms of the ALT pathway remain elusive. Here we demonstrated that ZBTB40 is a novel telomere-associated protein and binds to telomeric dsDNA through its N-terminal BTB (BR-C, ttk and bab) or POZ (Pox virus and Zinc finger) domain in ALT cells. Notably, the knockout or knockdown of ZBTB40 resulted in the telomere dysfunction-induced foci and telomere lengthening in the ALT cells. The results also show that ZBTB40 is associated with ALT-associated promyelocytic leukemia nuclear bodies, and the loss of ZBTB40 induces the accumulation of the ALT-associated promyelocytic leukemia nuclear bodies in U2OS cells. Taken together, our results implicate that ZBTB40 is a key player of telomere protection and telomere lengthening regulation in human ALT cells.},
}
@article {pmid37452322,
year = {2023},
author = {Yue, K and Yao, X},
title = {Prognostic model based on telomere-related genes predicts the risk of oral squamous cell carcinoma.},
journal = {BMC oral health},
volume = {23},
number = {1},
pages = {484},
pmid = {37452322},
issn = {1472-6831},
mesh = {Humans ; Squamous Cell Carcinoma of Head and Neck/genetics ; *Carcinoma, Squamous Cell/pathology ; *Mouth Neoplasms/pathology ; Prognosis ; Biomarkers, Tumor/genetics ; *Head and Neck Neoplasms/genetics ; Gene Expression Regulation, Neoplastic/genetics ; },
abstract = {BACKGROUND: This study investigated a potential prognostic model based on telomere-related genes (TRGs) for the clinical prediction of oral squamous cell carcinoma (OSCC).<br><br>METHODS: Gene expression data and associated clinical phenotypes were obtained from online databases. Differentially expressed (DE)-TRGs were identified between OSCC and normal samples, followed by protein-protein interaction and enrichment analyses. Subsequently, the prognostic genes explored based on the DE-TRGs and survival data were applied in the establishment of the current prognostic model, and an integrated analysis was performed between high- and low-risk groups using a prognostic model. The expression of certain prognostic genes identified in the present study was validated using qPCR analysis and/or western blot in OSCC cell lines and clinical samples.<br><br>RESULTS: 169 DE-TRGs were identified between the OSCC samples and controls. DE-TRGs are mainly involved in functions such as hypoxia response and pathways such as the cell cycle. Eight TRGs (CCNB1, PDK4, PLOD2, RACGAP1, MET, PLK1, KPNA2, and CCNA2) associated with OSCC survival and prognosis were used to construct a prognostic model. qPCR analysis and western blot showed that most of the eight prognostic genes were consistent with the current bioinformatics results. Analysis of the high- and low-risk groups for OSCC determined by the prognostic model showed that the current prognostic model was reliable.<br><br>CONCLUSIONS: A novel prognostic model for OSCC was constructed by TRGs. PLOD2 and APLK1 may participate in the progression of OSCC via responses to hypoxia and cell cycle pathways, respectively. TRGs, including KPNA2 and CCNA2, may serve as novel prognostic biomarkers for OSCC.},
}
@article {pmid37447170,
year = {2023},
author = {Ren, Q and Zhang, G and Dong, C and Li, Z and Zhou, D and Huang, L and Li, W and Huang, G and Yan, J},
title = {Parental Folate Deficiency Inhibits Proliferation and Increases Apoptosis of Neural Stem Cells in Rat Offspring: Aggravating Telomere Attrition as a Potential Mechanism.},
journal = {Nutrients},
volume = {15},
number = {13},
pages = {},
pmid = {37447170},
issn = {2072-6643},
support = {82003439//National Natural Science Foundation of China/ ; 2019KJ166//Scientific Research Program of Tianjin Municipal Education Commission/ ; 2022KJ203//Scientific Research Program of Tianjin Municipal Education Commission/ ; },
mesh = {Animals ; Rats ; *Telomerase ; Telomere Shortening ; Telomere ; Folic Acid/pharmacology ; *Folic Acid Deficiency ; *Neural Stem Cells ; Apoptosis ; Cell Proliferation ; },
abstract = {The effect of maternal folate status on the fetal central nervous system (CNS) is well recognized, while evidence is emerging that such an association also exists between fathers and offspring. The biological functions of telomeres and telomerase are also related to neural cell proliferation and apoptosis. The study aimed to investigate the effect of parental folate deficiency on the proliferation and apoptosis of neural stem cells (NSCs) in neonatal offspring and the role of telomeres in this effect. In this study, rats were divided into four groups: maternal folate-deficient and paternal folate-deficient diet (D-D) group; maternal folate-deficient and paternal folate-normal diet (D-N) group; maternal folate-normal and paternal folate-deficient diet (N-D) group; and the maternal folate-normal and paternal folate-normal diet (N-N) group. The offspring were sacrificed at postnatal day 0 (PND0), and NSCs were cultured from the hippocampus and striatum tissues of offspring for future assay. The results revealed that parental folate deficiency decreased folate levels, increased homocysteine (Hcy) levels of the offspring's brain tissue, inhibited proliferation, increased apoptosis, shortened telomere length, and aggravated telomere attrition of offspring NSCs in vivo and in vitro. In vitro experiments further showed that offspring NSCs telomerase activity was inhibited due to parental folate deficiency. In conclusion, parental folate deficiency inhibited the proliferation and increased apoptosis of offspring NSCs, maternal folate deficiency had more adverse effects than paternal, and the mechanisms may involve the telomere attrition of NSCs.},
}
@article {pmid37445605,
year = {2023},
author = {Pendina, AA and Krapivin, MI and Sagurova, YM and Mekina, ID and Komarova, EM and Tikhonov, AV and Golubeva, AV and Gzgzyan, AM and Kogan, IY and Efimova, OA},
title = {Telomere Length in Human Spermatogenic Cells as a New Potential Predictor of Clinical Outcomes in ART Treatment with Intracytoplasmic Injection of Testicular Spermatozoa.},
journal = {International journal of molecular sciences},
volume = {24},
number = {13},
pages = {},
pmid = {37445605},
issn = {1422-0067},
support = {18-75-10046//Russian Science Foundation/ ; },
mesh = {Pregnancy ; Female ; Humans ; Male ; *Azoospermia/genetics/therapy/pathology ; Sperm Retrieval ; Retrospective Studies ; Semen ; Spermatozoa ; Testis/pathology ; },
abstract = {Predicting the clinical outcomes of intracytoplasmic sperm injection (ICSI) cycles that use the testicular spermatozoa of azoospermic patients presents a challenge. Thus, the development of additional approaches to assessing the competence of a testicular-sperm-derived embryo without causing damage to gametes or the embryo is necessary. One of the key parameters in determining such developmental competence is telomere length (TL). We aimed to analyze TLs in spermatogenic cells from the testicular biopsy samples of azoospermic patients and determine how this parameter influences embryo competence for pre- and post-implantation development. Using Q-FISH, we studied the TL of the chromosomes in spermatogonia and spermatocytes I from the TESE biopsy samples of 30 azoospermic patients. An increase in TL was detected during the differentiation from spermatogonia to spermatocytes I. The patients' testicular spermatozoa were used in 37 ICSI cycles that resulted in 22 embryo transfers. Nine pregnancies resulted, of which, one was ectopic and eight ended in birth. The analysis of embryological outcomes revealed a dependence between embryo competence for development to the blastocyst stage and the TL in spermatogenic cells. The TLs in spermatogonia and spermatocytes I in the testicular biopsy samples were found to be higher in patients whose testicular sperm ICSI cycles resulted in a birth. Therefore, the length of telomeres in spermatogenic cells can be considered as a potential prognostic criterion in assessing the competence of testicular-sperm-derived embryos for pre- and post-implantation development. The results of this study provide the basis for the development of a laboratory test for the prediction of testicular sperm ICSI cycle outcomes.},
}
@article {pmid37444460,
year = {2023},
author = {Dhillon, VS and Deo, P and Fenech, M},
title = {The Relationship between Telomere Length and Nucleoplasmic Bridges and Severity of Disease in Prostate Cancer Patients.},
journal = {Cancers},
volume = {15},
number = {13},
pages = {},
pmid = {37444460},
issn = {2072-6694},
abstract = {Telomeres are repetitive nucleotide (TTAGGG) sequences that stabilize the chromosome ends and play an important role in the prevention of cancer initiation and progression. Nucleoplasmic bridges (NPBs) are formed when chromatids remain joined together during mitotic anaphase either due to mis-repair of DNA breaks or due to chromatid end fusion as a result of telomere loss or telomere dysfunction. We tested the hypotheses that (i) telomere length (TL) is shorter in prostate cancer (PC) patients relative to healthy age-matched individuals, (ii) TL differs in different stages of PC and (iii) shorter TL is significantly correlated with NPBs formation in PC cases. TL was measured in whole blood by well-established quantitative PCR method and the frequency of NPBs was measured in lymphocytes using cytokinesis-block micronucleus cytome (CBMNcyt) assay. Our results indicate that TL is shorter and NPBs are increased in PC patients relative to age-matched healthy controls. Furthermore, TL was significantly shorter (p = 0.03) in patients with a Gleason score more than 7 and there was also a significant trend of decreasing TL across all three stages (p trend = 0.01; Gleason score <7, 7 and >7). Furthermore, TL was significantly inversely correlated with NPB frequency in PC patients (r = -0.316; p = 0.001) but not in controls (r = 0.163; p = 0.06) and their relationships became stronger with higher Gleason scores. More studies are required that can confirm our observations and explore mechanistic differences in the role of telomeres in NPB formation in PC cases relative to non-cancer cases.},
}
@article {pmid37433812,
year = {2023},
author = {Zhang, X and Yu, Q and Wu, Y and Zhang, Y and He, Y and Wang, R and Yu, X and Li, S},
title = {Glc7/PP1 dephosphorylates histone H3T11 to regulate autophagy and telomere silencing in response to nutrient availability.},
journal = {Cell discovery},
volume = {9},
number = {1},
pages = {71},
pmid = {37433812},
issn = {2056-5968},
support = {31970578//National Natural Science Foundation of China (National Science Foundation of China)/ ; 31872812//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2021CFA013//Natural Science Foundation of Hubei Province (Hubei Provincial Natural Science Foundation)/ ; 2019CFA077//Natural Science Foundation of Hubei Province (Hubei Provincial Natural Science Foundation)/ ; },
abstract = {How cells adapt their gene expression to nutritional changes remains poorly understood. Histone H3T11 is phosphorylated by pyruvate kinase to repress gene transcription. Here, we identify the protein phosphatase 1 (PP1), Glc7 as the enzyme that specifically dephosphorylates H3T11. We also characterize two novel Glc7-containing complexes and reveal their roles in regulating gene expression upon glucose starvation. Specifically, the Glc7-Sen1 complex dephosphorylates H3T11 to activate the transcription of autophagy-related genes. The Glc7-Rif1-Rap1 complex dephosphorylates H3T11 to derepress the transcription of telomere-proximal genes. Upon glucose starvation, Glc7 expression is up-regulated and more Glc7 translocates into the nucleus to dephosphorylate H3T11, leading to induction of autophagy and derepressed transcription of telomere-proximal genes. Furthermore, the functions of PP1/Glc7 and the two Glc7-containing complexes are conserved in mammals to regulate autophagy and telomere structure. Collectively, our results reveal a novel mechanism that regulate gene expression and chromatin structure in response to glucose availability.},
}
@article {pmid37433224,
year = {2023},
author = {Ibrahim, KG and Chivandi, E and Erlwanger, KH and Brooksbank, RL},
title = {Neonatal administration of fenofibrate had no developmental programming effect on the lipid profile and relative leucocyte telomere lengths of adolescent rats fed a high-fructose diet postnatally.},
journal = {Canadian journal of physiology and pharmacology},
volume = {101},
number = {11},
pages = {565-573},
doi = {10.1139/cjpp-2022-0528},
pmid = {37433224},
issn = {1205-7541},
mesh = {Male ; Rats ; Animals ; Female ; *Fenofibrate/pharmacology ; Fructose/adverse effects ; Rats, Sprague-Dawley ; Diet ; Cholesterol ; Triglycerides ; },
abstract = {Telomere length, a marker of ageing, is susceptible to developmental programming that may cause its accelerated attrition. Metabolic syndrome triggers telomere attrition. Fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, is protective against telomere attrition. We investigated the impact of fenofibrate administered during suckling on the lipid profile and leucocyte telomere lengths of rats fed a high-fructose diet post-weaning. Suckling Sprague-Dawley pups (n = 119) were allocated to four groups and gavaged with either 10 mL·kg[-1] body mass 0.5% dimethyl sulfoxide, 100 mg·kg[-1] body mass fenofibrate, fructose (20%, w / v), or a combination of fenofibrate and fructose for 15 days. Upon weaning, each of the initial groups was split into two subgroups: one had plain water while the other had fructose solution (20%, w / v) to drink for 6 weeks. Blood was collected for DNA extraction and relative leucocyte telomere length determination by real-time PCR. Plasma triglycerides and cholesterol were also quantified. The treatments had no effect (p > 0.05) on body mass, cholesterol concentration, and relative leucocyte telomere lengths in both sexes. Post-weaning fructose increased triglyceride concentrations (p < 0.05) in female rats. Fenofibrate administered during suckling did not affect ageing nor did it prevent high fructose-induced hypertriglyceridaemia in female rats.},
}
@article {pmid37432588,
year = {2023},
author = {Yung, Y and Maydan, SA and Bart, Y and Orvieto, R and Aizer, A},
title = {Human granulosa cells of poor ovarian responder patients display telomeres shortening.},
journal = {Journal of assisted reproduction and genetics},
volume = {40},
number = {8},
pages = {1943-1947},
pmid = {37432588},
issn = {1573-7330},
mesh = {Female ; Humans ; Aged ; *Fertilization in Vitro ; *Granulosa Cells ; Ovary ; Oocyte Retrieval ; Telomere/genetics ; Ovulation Induction ; },
abstract = {OBJECTIVE: We aimed to compare the telomere length in granulosa cells of the young normal and poor ovarian responder patients and elderly patients undergoing ovarian stimulation for IVF.<br><br>METHODS: The main outcome measures granulosa cells telomere Length in the 3 study groups of patients undergoing IVF treatment in our center. 1) young normal responder patients (<&#x2009;35&#xa0;years); 2) young (<&#x2009;35&#xa0;years) poor ovarian responder patients; and 3) Elderly patients (40-45&#xa0;years). Granulosa cells were obtained at the time of oocyte retrieval. Granulosa cells telomere length was assessed by absolute human telomere length quantification qPCR Assay.<br><br>RESULTS: The telomere length of the young normal responder was significantly longer as compared to young poor ovarian responder (15.5 vs 9.6&#xa0;KB, p&#x2009;<&#x2009;0.001) and the elderly patients (15.5 vs 10.66&#xa0;KB, p&#x2009;<&#x2009;0.002). No significant difference was observed in the telomere length between the young poor ovarian responder and the elderly patients.<br><br>CONCLUSIONS: Granulosa cells telomere length of the young normal responder was found to be significantly longer than young poor ovarian responder or elderly patients, highlighting the role of telomere length as a predictor, or contributor to poor oocyte yield following IVF treatment.},
}
@article {pmid37424625,
year = {2023},
author = {Karaviti, E and Kontogiannis, A and Anastopoulos, A and Kotteas, E and Gomatou, G},
title = {An overview of the role of telomeres and telomerase in pre‑neoplastic lesions (Review).},
journal = {Molecular and clinical oncology},
volume = {19},
number = {2},
pages = {61},
pmid = {37424625},
issn = {2049-9469},
abstract = {Telomeres are tandem repeats of DNA sequences protecting the end of linear chromosomes. Replicative senescence due to telomere attrition is considered a tumor-preventing mechanism in differentiated somatic cells. However, telomere shortening is associated with genome instability and several disease entities. During carcinogenesis, the development of a telomere maintenance mechanism, predominately through the activation of the telomerase enzyme, represents a hallmark of cancer, since it enables cancer cells to avert senescence and divide indefinitely. Although research of the involvement of telomeres and telomerase in various malignant neoplasms has gained a large amount of interest, the timing and relevance of their role in pre-neoplastic lesions remain to be determined. The present narrative review aims to summarize the evidence regarding the role of telomeres and telomerase in pre-neoplasia across different types of tissues.},
}
@article {pmid37421961,
year = {2023},
author = {Luo, S and Wong, ICK and Chui, CSL and Zheng, J and Huang, Y and Schooling, CM and Yeung, SLA},
title = {Effects of putative metformin targets on phenotypic age and leukocyte telomere length: a mendelian randomisation study using data from the UK Biobank.},
journal = {The lancet. Healthy longevity},
volume = {4},
number = {7},
pages = {e337-e344},
doi = {10.1016/S2666-7568(23)00085-5},
pmid = {37421961},
issn = {2666-7568},
mesh = {Humans ; *Metformin/pharmacology/therapeutic use ; *Diabetes Mellitus, Type 2/drug therapy/genetics/metabolism ; Biological Specimen Banks ; Cross-Sectional Studies ; Biomarkers ; Hemoglobin A/genetics ; Transcription Factors/genetics/therapeutic use ; Telomere/genetics/metabolism ; United Kingdom ; },
abstract = {BACKGROUND: Metformin, a first-line medication for type 2 diabetes, might also have a protective effect against ageing-related diseases, but so far little experimental evidence is available. We sought to assess the target-specific effect of metformin on biomarkers of ageing in the UK Biobank.<br><br>METHODS: In this drug target mendelian randomisation study, we assessed the target-specific effect of four putative targets of metformin (AMPK, ETFDH, GPD1, and PEN2), involving ten genes. Genetic variants with evidence of causation of gene expression, glycated haemoglobin A1c (HbA1c), and colocalisation were used as instruments mimicking the target-specific effect of metformin via HbA1c lowering. The biomarkers of ageing considered were phenotypic age (PhenoAge) and leukocyte telomere length. To triangulate the evidence, we also assessed the effect of HbA1c on the outcomes using a polygenic mendelian randomisation design and assessed the effect of metformin use on these outcomes using a cross-sectional observational design.<br><br>FINDINGS: GPD1-induced HbA1c lowering was associated with younger PhenoAge (&#x3b2; -5&#xb7;26, 95% CI -6&#xb7;69 to -3&#xb7;83) and longer leukocyte telomere length (&#x3b2; 0&#xb7;28, 0&#xb7;03 to 0&#xb7;53), and AMPK&#x3b3;2 (PRKAG2)-induced HbA1c lowering was associated with younger PhenoAge (&#x3b2; -4&#xb7;88, -7&#xb7;14 to -2&#xb7;62) but not with longer leukocyte telomere length. Genetically predicted HbA1c lowering was associated with younger PhenoAge (&#x3b2; -0&#xb7;96 per SD lowering of HbA1c, 95% CI -1&#xb7;19 to -0&#xb7;74) but not associated with leukocyte telomere length. In the propensity score matched analysis, metformin use was associated with younger PhenoAge (&#x3b2; -0&#xb7;36, 95% CI -0&#xb7;59 to -0&#xb7;13) but not with leukocyte telomere length.<br><br>INTERPRETATION: This study provides genetic validation evidence that metformin might promote healthy ageing via targets GPD1 and AMPK&#x3b3;2 (PRKAG2), and the effect could be in part due to its glycaemic property. Our findings support further clinical research into metformin and longevity.<br><br>FUNDING: Healthy Longevity Catalyst Award, National Academy of Medicine, and Seed Fund for Basic Research, The University of Hong Kong.},
}
@article {pmid37419142,
year = {2024},
author = {Heleniak, C and Goff, B and Gabard-Durnam, LJ and Telzer, EH and Humphreys, KL and Lumian, DS and Flannery, JE and Caldera, C and Shapiro, M and Louie, JY and Shen, F and Vannucci, A and Jain, M and Glatt, CE and Tottenham, N},
title = {Telomere Erosion and Depressive Symptoms Across Development Following Institutional Care.},
journal = {Journal of the American Academy of Child and Adolescent Psychiatry},
volume = {63},
number = {3},
pages = {365-375},
doi = {10.1016/j.jaac.2023.06.011},
pmid = {37419142},
issn = {1527-5418},
mesh = {Adult ; Child ; Child, Preschool ; Adolescent ; Humans ; *Depression/genetics/diagnosis ; Longitudinal Studies ; *Telomere Shortening ; Psychopathology ; Telomere ; },
abstract = {OBJECTIVE: A large literature has identified exposure to early caregiving adversities as a potent risk for developing affective psychopathology, with depression, in particular, increasing across childhood into adolescence. Evidence suggests telomere erosion, a marker of biological aging, may underlie associations between adverse early-life experiences and later depressive behavior; yet, little is understood about this association during development.<br><br>METHOD: The current accelerated longitudinal study examined concurrent telomere length and depressive symptoms concurrently, 2 and 4 years later, from the preschool period through adolescence among children exposed (n&#xa0;=116) and not exposed (n&#xa0;= 242) to early previous institutional (PI) care.<br><br>RESULTS: PI care was associated with shorter telomeres on average and with quadratic age-related growth in depressive symptoms, indicating a steeper association between PI care and depressive symptoms in younger age groups that leveled off in adolescence. Contrary to studies in adult samples, telomere length was not associated with depressive symptoms, and it did not predict future symptoms.<br><br>CONCLUSION: These findings indicate that early caregiving disruptions increase the risk for both accelerated biological aging and depressive symptoms, although these variables did not correlate with each other during this age range.},
}
@article {pmid37415075,
year = {2023},
author = {Loh, NY and Rosoff, D and Noordam, R and Christodoulides, C},
title = {Investigating the impact of metabolic syndrome traits on telomere length: a Mendelian randomization study.},
journal = {Obesity (Silver Spring, Md.)},
volume = {31},
number = {8},
pages = {2189-2198},
pmid = {37415075},
issn = {1930-739X},
support = {FS/16/45/32359/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Humans ; *Metabolic Syndrome/epidemiology/genetics/metabolism ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Aging ; Telomere/genetics ; Leukocytes/metabolism ; },
abstract = {OBJECTIVE: Observational studies have reported bidirectional associations between metabolic syndrome (MetS) traits and short leukocyte telomere length (LTL), a TL marker in somatic tissues and a proposed risk factor for age-related degenerative diseases. However, in Mendelian randomization studies, longer LTL has been paradoxically associated with higher MetS risk. This study investigated the hypothesis that shorter LTL might be a consequence of metabolic dysfunction.<br><br>METHODS: This study undertook univariable and multivariable Mendelian randomization. As instrumental variables for MetS traits, all of the genome-wide significant independent signals identified in genome-wide association studies for anthropometric, glycemic, lipid, and blood pressure traits conducted in European individuals were used. Summary-level data for LTL were obtained from a genome-wide association study conducted in the UK Biobank.<br><br>RESULTS: Higher BMI was associated with shorter LTL (&#x3b2;&#x2009;=&#x2009;-0.039, 95% CI:&#x2009;-0.058 to -0.020, p&#x2009;=&#x2009;5&#x2009;&#xd7;&#x2009;10[-5]) equivalent to 1.70&#x2009;years of age-related LTL change. In contrast, higher low-density lipoprotein cholesterol was associated with longer LTL (&#x3b2;&#x2009;=&#x2009;0.022, 95% CI:&#x2009;0.007 to 0.037, p&#x2009;=&#x2009;0.003) equivalent to 0.96&#x2009;years of age-related LTL change. Mechanistically, increased low-grade systemic inflammation, as measured by circulating C-reactive protein, and lower circulating linoleic acid levels might link higher BMI to shorter LTL.<br><br>CONCLUSIONS: Overweight and obesity might promote the development of aging-related degenerative diseases by accelerating telomere shortening.},
}
@article {pmid37405953,
year = {2023},
author = {},
title = {Erratum: Fluorescence In Situ Hybridization on DNA Halo Preparations to Reveal Whole Chromosomes, Telomeres and Gene Loci.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {196},
pages = {},
doi = {10.3791/6564},
pmid = {37405953},
issn = {1940-087X},
abstract = {An erratum was issued for: Fluorescence In Situ Hybridization on DNA Halo Preparations to Reveal Whole Chromosomes, Telomeres and Gene Loci. The Authors section was updated from: Lauren S. Godwin[1] Joanna M. Bridger[1] Helen A. Foster[2] [1]Laboratory of Nuclear and Genomic Health, Centre for Genome Engineering and Maintenance, Division of Biosciences, Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London [2]Biosciences, Department of Clinical, Pharmaceutical and Biological Science, School of Life and Medical Sciences, University of Hertfordshire to: Lauren S. Godwin[1] Emily Roberts[2] Joanna M. Bridger[1] Helen A. Foster[2] [1]Laboratory of Nuclear and Genomic Health, Centre for Genome Engineering and Maintenance, Division of Biosciences, Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London [2]Biosciences, Department of Clinical, Pharmaceutical and Biological Science, School of Life and Medical Sciences, University of Hertfordshire.},
}
@article {pmid37400833,
year = {2023},
author = {Tire, B and Ozturk, S},
title = {Potential effects of assisted reproductive technology on telomere length and telomerase activity in human oocytes and early embryos.},
journal = {Journal of ovarian research},
volume = {16},
number = {1},
pages = {130},
pmid = {37400833},
issn = {1757-2215},
mesh = {Humans ; *Telomerase/genetics ; Oocytes/metabolism ; Germ Cells/metabolism ; Reproductive Techniques, Assisted ; Telomere/genetics/metabolism ; },
abstract = {Telomeres are repetitive DNA sequences at eukaryotic chromosome ends and function in maintaining genome integrity and stability. These unique structures undergo shortening due to various factors including biological aging, consecutive DNA replication, oxidative stress, and genotoxic agents. Shortened telomeres can be lengthened by the enzyme telomerase and alternative lengthening of telomeres in germ cells, early embryos, stem cells, and activated lymphocytes. If telomeres reach to critical length, it may lead to genomic instability, chromosome segregation defects, aneuploidy, and apoptosis. These phenotypes also occur in the oocytes and early embryos, produced using assisted reproductive technologies (ARTs). Thus, a number of studies have examined the potential effects of ART applications such as ovarian stimulation, culture conditions, and cryopreservation procedures on telomeres. Herein, we comprehensively reviewed impacts of these applications on telomere length and telomerase activity in ART-derived oocytes and embryos. Further, we discussed use of these parameters in ART centers as a biomarker in determining oocyte and embryo quality.},
}
@article {pmid37397566,
year = {2023},
author = {Kung, SC and Dixon, O and Kentwell, S and Vasireddy, RS and Rodgers, J and Ding, Y and Rahman, T and Tallis, C and Yang, IA and Mackintosh, JA},
title = {Telomere biology disorder presenting acutely with pulmonary fibrosis and hepatopulmonary syndrome in a young adult male.},
journal = {Respirology case reports},
volume = {11},
number = {8},
pages = {e01182},
pmid = {37397566},
issn = {2051-3380},
abstract = {A 33-year-old man presented with acute dyspnoea and profound hypoxaemia, and had clubbing, greying of hair, orthodeoxia and fine inspiratory crackles. CT chest showed established pulmonary fibrosis in a usual interstitial pneumonia pattern. Additional investigations revealed a small patent foramen ovale, pancytopenia, and oesophageal varices and portal hypertensive gastropathy from liver cirrhosis. Telomere length testing demonstrated short telomeres (<1st percentile), confirming the diagnosis of a telomere biology disorder. An interstitial lung disease gene panel identified a pathogenic variant in TERT (c.1700C>T, p.(Thr567Met)) and a variant of uncertain significance in PARN (c.1159G>A, p.(Gly387Arg)). Combined lung and liver transplantation was deemed not suitable due to frailty and severe hepatopulmonary syndrome, and he died 56 days after presentation. Early recognition of the short telomere syndrome is important, and its multi-organ involvement poses challenges to management. Genetic screening may be important in younger patients with pulmonary fibrosis or in unexplained liver cirrhosis.},
}
@article {pmid37395529,
year = {2023},
author = {Ton, R and Boner, W and Raveh, S and Monaghan, P and Griffith, SC},
title = {Effects of heat waves on telomere dynamics and parental brooding effort in nestlings of the zebra finch (Taeniopygia castanotis) transitioning from ectothermy to endothermy.},
journal = {Molecular ecology},
volume = {32},
number = {17},
pages = {4911-4920},
doi = {10.1111/mec.17064},
pmid = {37395529},
issn = {1365-294X},
mesh = {Animals ; Hot Temperature ; *Passeriformes/physiology ; Body Temperature Regulation ; Telomere/genetics ; *Finches/genetics ; },
abstract = {Heat waves are predicted to be detrimental for organismal physiology with costs for survival that could be reflected in markers of biological state such as telomeres. Changes in early life telomere dynamics driven by thermal stress are of particular interest during the early post-natal stages of altricial birds because nestlings quickly shift from being ectothermic to endothermic after hatching. Telomeres of ectothermic and endothermic organisms respond differently to environmental temperature, but few investigations within species that transition from ectothermy to endothermy are available. Also, ambient temperature influences parental brooding behaviour, which will alter the temperature experienced by offspring and thereby, potentially, their telomeres. We exposed zebra finch nestlings to experimental heat waves and compared their telomere dynamics to that of a control group at 5, 12 and 80 days of age that encapsulate the transition from the ectothermic to the endothermic thermoregulatory stage; we also recorded parental brooding, offspring sex, mass, growth rates, brood size and hatch order. Nestling mass showed an inverse relationship with telomere length, and nestlings exposed to heat waves showed lower telomere attrition during their first 12 days of life (ectothermic stage) compared to controls. Additionally, parents of heated broods reduced the time they spent brooding offspring (at 5 days old) compared to controls. Our results indicate that the effect of heat waves on telomere dynamics likely varies depending on age and thermoregulatory stage of the offspring in combination with parental brooding behaviour during growth.},
}
@article {pmid37392813,
year = {2023},
author = {Hannan, SJ and Iasella, CJ and Sutton, RM and Popescu, ID and Koshy, R and Burke, R and Chen, X and Zhang, Y and Pilewski, JM and Hage, CA and Sanchez, PG and Im, A and Farah, R and Alder, JK and McDyer, JF},
title = {Lung transplant recipients with telomere-mediated pulmonary fibrosis have increased risk for hematologic complications.},
journal = {American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons},
volume = {23},
number = {10},
pages = {1590-1602},
doi = {10.1016/j.ajt.2023.06.014},
pmid = {37392813},
issn = {1600-6143},
support = {R01 HL135062/HL/NHLBI NIH HHS/United States ; R01 HL166265/HL/NHLBI NIH HHS/United States ; R01 HL133184/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; Retrospective Studies ; Transplant Recipients ; *Telomerase/genetics/metabolism ; Lung/metabolism ; *Idiopathic Pulmonary Fibrosis/genetics/surgery/pathology ; Telomere/genetics/metabolism/pathology ; },
abstract = {Idiopathic pulmonary fibrosis lung transplant recipients (IPF-LTRs) are enriched for short telomere length (TL) and telomere gene rare variants. A subset of patients with nontransplant short-TL are at increased risk for bone marrow (BM) dysfunction. We hypothesized that IPF-LTRs with short-TL and/or rare variants would be at increased risk for posttransplant hematologic complications. Data were extracted from a retrospective cohort of 72 IPF-LTRs and 72 age-matched non-IPF-LTR controls. Genetic assessment was done using whole genome sequencing or targeted sequence panel. TL was measured using flow cytometry and fluorescence in-situ hybridization (FlowFISH) and TelSeq software. The majority of the IPF-LTR cohort had short-TL, and 26% of IPF-LTRs had rare variants. Compared to non-IPF controls, short-TL IPF-LTRs were more likely to have immunosuppression agents discontinued due to cytopenias (P = .0375), and BM dysfunction requiring BM biopsy was more prevalent (29% vs 4%, P = .0003). IPF-LTRs with short-TL and rare variants had increased requirements for transfusion and growth factor support. Multivariable logistic regression demonstrated that short-TL, rare variants, and lower pretransplant platelet counts were associated with BM dysfunction. Pretransplant TL measurement and genetic testing for rare telomere gene variants identified IPF-LTRs at increased risk for hematologic complications. Our findings support stratification for telomere-mediated pulmonary fibrosis in lung transplant candidates.},
}
@article {pmid37392033,
year = {2023},
author = {Zhang, R and Wu, M and Ma, M and Liu, B and Zhang, X and Wei, N and Wang, T and Lv, Y and Xu, C and Wang, J and Zhang, Y and Liu, F},
title = {Genetic evidence for the causal linkage between telomere length and aortic aneurysm risk: A Mendelian randomisation study.},
journal = {European journal of clinical investigation},
volume = {53},
number = {11},
pages = {e14056},
doi = {10.1111/eci.14056},
pmid = {37392033},
issn = {1365-2362},
support = {2022JZ-47//Key Basic Natural Science Foundation of Shaanxi Province/ ; 2020ZDLSF01-08//Key Industrial Innovation Chain Project in Shaanxi Province of China/ ; 2021ZDLSF02-03//Key Industrial Innovation Chain Project in Shaanxi Province of China/ ; 2021-03-22-001//Key Program for the Traditional Chinese Medicine Inheritance and Innovation and "Qin Medicine" Development/ ; 2022SF-476//Natural Science Foundation of Shaanxi Province/ ; 2021JQ-911//Natural Science Foundation of Shaanxi Province/ ; 2022D024//Shaanxi Provincial Health and Health Research Fund Project/ ; },
abstract = {BACKGROUND: Evidence of a clear causal relationship between telomere length and aortic aneurysms is limited by the potential for confounding or reverse causation effects. In this study, we used a Mendelian randomisation (MR) approach to investigate this putative causal association.<br><br>METHODS: In total, 118 telomere length-associated single-nucleotide polymorphisms, identified in 472,174 individuals of European ancestry, were used as the instrumental variables. Summary statistics for genome-wide association studies of aortic aneurysms were obtained from the FinnGen consortium. For the primary MR analyses, the inverse-variance weighted random-effects method was used and was supplemented with multivariable MR, weighted median and MR-Egger approaches. The MR-Egger intercept test, Cochran's Q test and 'leave-one-out' sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneity and stability of the genetic variants. Forward and reverse MR analyses were performed.<br><br>RESULTS: All forward univariable MR analyses showed that longer telomere lengths decreased aortic aneurysm risks (total aortic aneurysms: OR&#x2009;=&#x2009;0.80, 95% CI 0.67-0.96, p&#x2009;=&#x2009;.015; thoracic aortic aneurysms: OR&#x2009;=&#x2009;0.82, 95% CI 0.68-0.98, p&#x2009;=&#x2009;.026; abdominal aortic aneurysms: OR&#x2009;=&#x2009;0.525, 95% CI 0.398-0.69, p&#x2009;<&#x2009;.001), whereas all reverse MR analyses suggested the absence of aortic aneurysm liability on telomere length. The sensitivity analysis results were robust, and no evidence of horizontal pleiotropy was observed.<br><br>CONCLUSIONS: Our results support a possible causal association between telomere length and aortic aneurysms, providing new insights into the involvement of telomere biology in this condition and offering a potential avenue for targeted therapeutic interventions.},
}
@article {pmid37391893,
year = {2023},
author = {Závodník, M and Fajkus, P and Franek, M and Kopecký, D and Garcia, S and Dodsworth, S and Orejuela, A and Kilar, A and Ptáček, J and Mátl, M and Hýsková, A and Fajkus, J and Peška, V},
title = {Telomerase RNA gene paralogs in plants - the usual pathway to unusual telomeres.},
journal = {The New phytologist},
volume = {239},
number = {6},
pages = {2353-2366},
doi = {10.1111/nph.19110},
pmid = {37391893},
issn = {1469-8137},
mesh = {*Telomerase/genetics/metabolism ; Telomere/genetics ; RNA/genetics/metabolism ; Plants/metabolism ; },
abstract = {Telomerase, telomeric DNA and associated proteins together represent a complex, finely tuned and functionally conserved mechanism that ensures genome integrity by protecting and maintaining chromosome ends. Changes in its components can threaten an organism's viability. Nevertheless, molecular innovation in telomere maintenance has occurred multiple times during eukaryote evolution, giving rise to species/taxa with unusual telomeric DNA sequences, telomerase components or telomerase-independent telomere maintenance. The central component of telomere maintenance machinery is telomerase RNA (TR) as it templates telomere DNA synthesis, its mutation can change telomere DNA and disrupt its recognition by telomere proteins, thereby leading to collapse of their end-protective and telomerase recruitment functions. Using a combination of bioinformatic and experimental approaches, we examine a plausible scenario of evolutionary changes in TR underlying telomere transitions. We identified plants harbouring multiple TR paralogs whose template regions could support the synthesis of diverse telomeres. In our hypothesis, formation of unusual telomeres is associated with the occurrence of TR paralogs that can accumulate mutations, and through their functional redundancy, allow for the adaptive evolution of the other telomere components. Experimental analyses of telomeres in the examined plants demonstrate evolutionary telomere transitions corresponding to TR paralogs with diverse template regions.},
}
@article {pmid37391503,
year = {2023},
author = {Chen, S and Hu, S and Zhou, B and Cheng, B and Tong, H and Su, D and Li, X and Chen, Y and Zhang, G},
title = {Telomere-related prognostic biomarkers for survival assessments in pancreatic cancer.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {10586},
pmid = {37391503},
issn = {2045-2322},
mesh = {Humans ; Prognosis ; *Pancreatic Neoplasms/diagnosis/genetics ; Telomere/genetics ; Biomarkers ; Tumor Microenvironment/genetics ; },
abstract = {Human telomeres are linked to genetic instability and a higher risk of developing cancer. Therefore, to improve the dismal prognosis of pancreatic cancer patients, a thorough investigation of the association between telomere-related genes and pancreatic cancer is required. Combat from the R package "SVA" was performed to correct the batch effects between the TCGA-PAAD and GTEx datasets. After differentially expressed genes (DEGs) were assessed, we constructed a prognostic risk model through univariate Cox regression, LASSO-Cox regression, and multivariate Cox regression analysis. Data from the ICGC, GSE62452, GSE71729, and GSE78229 cohorts were used as test cohorts for validating the prognostic signature. The major impact of the signature on the tumor microenvironment and its response to immune checkpoint drugs was also evaluated. Finally, PAAD tissue microarrays were fabricated and immunohistochemistry was performed to explore the expression of this signature in clinical samples. After calculating 502 telomere-associated DEGs, we constructed a three-gene prognostic signature (DSG2, LDHA, and RACGAP1) that can be effectively applied to the prognostic classification of pancreatic cancer patients in multiple datasets, including TCGA, ICGC, GSE62452, GSE71729, and GSE78229 cohorts. In addition, we have screened a variety of tumor-sensitive drugs targeting this signature. Finally, we also found that protein levels of DSG2, LDHA, and RACGAP1 were upregulated in pancreatic cancer tissues compared to normal tissues by immunohistochemistry analysis. We established and validated a telomere gene-related prognostic signature for pancreatic cancer and confirmed the upregulation of DSG2, LDHA, and RACGAP1 expression in clinical samples, which may provide new ideas for individualized immunotherapy.},
}
@article {pmid37382785,
year = {2023},
author = {Berteli, TS and Wang, F and Navarro, PA and Kohlrausch, FB and Keefe, DL},
title = {A pilot study of LINE-1 copy number and telomere length with aging in human sperm.},
journal = {Journal of assisted reproduction and genetics},
volume = {40},
number = {8},
pages = {1845-1854},
pmid = {37382785},
issn = {1573-7330},
support = {88887.371487/2019-00//Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior/ ; 88887.597054/2021-00//Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior/ ; 204747/2018-0//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; },
mesh = {Humans ; Male ; Aged ; Pilot Projects ; *DNA Copy Number Variations ; *Semen ; Spermatozoa/physiology ; Telomere/genetics ; Telomere Homeostasis/genetics ; },
abstract = {PURPOSE: Unlike other cells in the body, in sperm, telomere length (TL) increases with age. TL can regulate nearby genes, and the subtelomeric region is rich in retrotransposons. We hypothesized that age-related telomere lengthening in sperm might suppress Long Interspersed Element 1 (LINE-1/L1), the only competent retrotransposon in humans.<br><br>METHODS: We measured L1 copy number (L1-CN) and sperm telomere length (STL) from young and older men to evaluate the relationship between age, TL and L1-CN. We also evaluated L1-CN and TL in individual sperm to determine whether these variables influence sperm morphology. STL was assayed by Multiplex quantitative polymerase chain reaction method (mmqPCR) and L1-CN by Quantitative polymerase chain reaction (qPCR).<br><br>RESULTS: We found that STL increased, and L1-CN decreased significantly with paternal age. STL in normal single sperm was significantly higher than in abnormal sperm. L1-CN did not differ between normal and abnormal sperm. Furthermore, morphologically normal sperm have longer telomeres than abnormal sperm.<br><br>CONCLUSIONS: Elongation of telomeres in the male germline could repress retrotransposition, which tends to increase with cellular aging. More studies in larger cohorts across a wide age span are needed to confirm our conclusions and explore their biological and clinical significance.},
}
@article {pmid37380710,
year = {2023},
author = {Thayer, Z and Becares, L and Marks, E and Ly, K and Walker, C},
title = {Maternal racism experience and cultural identity in relation to offspring telomere length.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {10458},
pmid = {37380710},
issn = {2045-2322},
mesh = {Child, Preschool ; Female ; Humans ; Pregnancy ; *Maori People ; Mothers ; Parents ; *Racism ; *Social Identification ; *Telomere ; },
abstract = {Racism is a determinant of individual and offspring health. Accelerated telomere shortening, an indicator of cellular aging, is a potential mechanism through which parental experience of racism could affect offspring. Here we longitudinally evaluated the relationship between maternal lifetime experience of an ethnically-motivated verbal or physical attack, as reported in pregnancy, with offspring telomere length in 4.5-year-old children. We also explored the potential association between positive feelings about one's culture and offspring telomere length. Data come from a nationally representative, multi-ethnic birth cohort in Aotearoa New Zealand (NZ) (Māori N = 417, Pacific N = 364, Asian N = 381). In models adjusting for covariates, including socioeconomic status and health status, Māori mothers who experienced an ethnically-motivated physical attack had children with significantly shorter telomere length than children of Māori mothers who did not report an attack (B = - 0.20, p = 0.01). Conversely, Māori mothers who had positive feelings about their culture had offspring with significantly longer telomeres (B = 0.25, p = 0.02). Our results suggest that ethnicity-based health inequities are shaped by racism, with impacts for clinical care and policy. Future research should also evaluate the potential protective effects of positive cultural identity.},
}
@article {pmid37380632,
year = {2023},
author = {Silva, B and Arora, R and Bione, S and Azzalin, CM},
title = {Author Correction: TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {3829},
doi = {10.1038/s41467-023-39584-1},
pmid = {37380632},
issn = {2041-1723},
}
@article {pmid37376725,
year = {2023},
author = {Hu, Y and You, X and Zhang, Z and Zhao, H},
title = {Telomere-Associated Gene Signatures Correlate with Prognosis, Tumor Microenvironment, and Chemosensitivity in Breast Cancer.},
journal = {Medical science monitor : international medical journal of experimental and clinical research},
volume = {29},
number = {},
pages = {e939921},
pmid = {37376725},
issn = {1643-3750},
mesh = {Humans ; Female ; *Breast Neoplasms/drug therapy/genetics ; Tumor Microenvironment/genetics ; Prognosis ; Breast ; Cluster Analysis ; },
abstract = {BACKGROUND Telomeres are strongly associated with cancer, as their shortening over time is associated with an increased risk of tumor growth and progression. However, the prognostic value of telomere-related genes (TRGs) in breast cancer has not been systematically elucidated. MATERIAL AND METHODS The transcriptome and clinical data of breast cancer were downloaded from TCGA and GEO databases, and prognostic TRGs were identified by differential expression analysis and univariate and multivariate Cox regression analyses. Gene set enrichment analysis (GSEA) of different risk groups was performed. Molecular subtypes of breast cancer were constructed by consensus clustering analysis, and the differences in immune infiltration and chemotherapy sensitivity between subtypes were analyzed. RESULTS Differential expression analysis revealed 86 significantly differentially expressed TRGs in breast cancer, of which 43 were significantly associated with breast cancer prognosis. A predictive risk signature consisting of 6 tumor-related genes (TRGs) was developed, which can accurately stratify patients with breast cancer into 2 distinct groups with significantly different prognoses. Significantly different risk scores were found among different racial groups, treatment groups, and pathological features groups. GSEA results showed that patients in the low-risk group had activated immune responses and repressed cilium-related biological processes. Consistent clustering analysis based on these 6 TRGs obtained 2 molecular models with significant prognosis differences, which revealed distinct immune infiltration and chemotherapy sensitivity. CONCLUSIONS This study conducted a systematic investigation of the expression pattern of TRGs in breast cancer and its prognostic and clustering implications, thereby offering a reference for utilizing it to predict prognosis and evaluate treatment response.},
}
@article {pmid37374216,
year = {2023},
author = {Abu-Awwad, SA and Craina, M and Gluhovschi, A and Ciordas, PD and Marian, C and Boscu, L and Bernad, E and Iurciuc, M and Abu-Awwad, A and Iurciuc, S and Maghiari, AL},
title = {Linking Pregnancy and Long-Term Health: The Impact of Cardiovascular Risk on Telomere Shortening in Pregnant Women.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {59},
number = {6},
pages = {},
pmid = {37374216},
issn = {1648-9144},
mesh = {Child ; Humans ; Female ; Pregnancy ; *Pregnant Women ; Telomere Shortening ; *Cardiovascular Diseases/genetics ; Cesarean Section ; Risk Factors ; Heart Disease Risk Factors ; },
abstract = {Background and Objectives: Telomeres are repetitive DNA sequences located at the end of chromosomes that play a crucial role in maintaining chromosomal stability. Shortening of telomeres has been associated with an increased risk of cardiovascular disease. The aim of this study was to investigate whether the length of telomeres in pregnant women with cardiovascular risk is shorter compared to those without cardiovascular risk. Materials and Methods: A total of 68 participants were enrolled, including 30 pregnant women with cardiovascular risk and 38 without cardiovascular risk, who were followed-up during their pregnancy between 2020 and 2022 at the Obstetrical and Gynecology Department of the "Pius Brînzeu" Emergency County Clinical Hospital in Timişoara, Romania. All included women underwent delivery via cesarean section at the same medical institution. The telomere length was measured in each participant using quantitative Polymerase chain reaction (PCR). Results: The results showed that the telomere length was negatively correlated with cardiovascular risk in pregnant women, with significantly shorter telomeres observed in the cardiovascular risk group (mean telomere length = 0.3537) compared to the group without cardiovascular risk (mean telomere length = 0.5728) (p = 0.0458). Conclusions: These findings suggest that cardiovascular risk during pregnancy may be associated with accelerated telomere shortening, which could have implications for the long-term health of both the mother and the child. Further research is needed to investigate the potential mechanisms underlying this association and to identify interventions that may mitigate the negative effects of cardiovascular risk on the telomere length during pregnancy.},
}
@article {pmid37373801,
year = {2023},
author = {Coskun, M and Altinova, AE and Babayeva, A and Sel, AT and Yapar, D and Karaca, M and Yalcin, MM and Akturk, M and Toruner, FB and Karakoc, MA and Yetkin, I},
title = {Leukocyte Telomere Length and Neuregulin-4 Levels in Female Patients with Acromegaly: The Relationship between Disease Activity and Body Fat Distribution.},
journal = {Journal of clinical medicine},
volume = {12},
number = {12},
pages = {},
pmid = {37373801},
issn = {2077-0383},
support = {123-21//Endocrinology and Metabolism Training Coordination Association/ ; },
abstract = {The study aimed to examine leukocyte telomere length (LTL) and serum neuregulin-4 levels and their relationship with disease activity, co-morbidities and body fat distribution in female acromegaly patients. Forty female patients with acromegaly and thirty-nine age and body mass index (BMI) similar healthy female volunteers were included in the study. Patients were classified into two groups: active acromegaly (AA) and controlled acromegaly (CA). The quantitative polymerase chain reaction (PCR) method was used to study LTL, and T/S ratio < 1 was accepted as shortened telomere length. Neuregulin-4 was studied by ELISA. There was no difference in median LTL between acromegaly and the control group (p = 0.530). The percentage of T/S < 1 in patients with acromegaly (60.0%) was similar to that of the control group (43.6%) (p = 0.144). However, serum neuregulin-4 was significantly higher in patients with acromegaly than those in the control group (p = 0.037). There were no significant differences concerning LTL, percentage of T/S < 1 and neuregulin-4 levels between active and controlled acromegaly groups (p > 0.05). Neuregulin-4 correlated positively with fasting glucose, triglyceride (TG), triglyceride/glucose (TyG) index, and lean body mass in the acromegaly group. A negative correlation was observed between LTL and neuregulin-4 in the control group (p = 0.039). When the factors affecting neuregulin-4 were evaluated by multivariate linear regression analysis with an enter method, TG (β: 0.316, p = 0.025) was independently and positively associated with neuregulin-4. Our findings indicate that acromegaly is associated with unchanged LTL and high neuregulin-4 levels in female patients. However, the relationship between acromegaly, the aging process, and neuregulin-4 involves complex mechanisms, and further studies are needed.},
}
@article {pmid37373080,
year = {2023},
author = {Saretzki, G},
title = {Role of Telomeres and Telomerase in Cancer and Aging.},
journal = {International journal of molecular sciences},
volume = {24},
number = {12},
pages = {},
pmid = {37373080},
issn = {1422-0067},
mesh = {Humans ; *Telomerase/genetics/metabolism ; Aging/genetics ; Telomere/genetics/metabolism ; *Neoplasms/genetics ; },
abstract = {Seventeen papers published in 2019 and early 2020 demonstrate the ongoing interest and research concerning telomeres and telomerase in aging and cancer [...].},
}
@article {pmid37372458,
year = {2023},
author = {Raseley, K and Jinwala, Z and Zhang, D and Xiao, M},
title = {Single-Molecule Telomere Assay via Optical Mapping (SMTA-OM) Can Potentially Define the ALT Positivity of Cancer.},
journal = {Genes},
volume = {14},
number = {6},
pages = {},
pmid = {37372458},
issn = {2073-4425},
mesh = {Humans ; Telomere Homeostasis/genetics ; *Telomerase/genetics/metabolism ; Cell Line ; *Neoplasms/genetics ; DNA Replication ; },
abstract = {Telomeres play an essential role in protecting the ends of linear chromosomes and maintaining the integrity of the human genome. One of the key hallmarks of cancers is their replicative immortality. As many as 85-90% of cancers activate the expression of telomerase (TEL+) as the telomere maintenance mechanism (TMM), and 10-15% of cancers utilize the homology-dependent repair (HDR)-based Alternative Lengthening of Telomere (ALT+) pathway. Here, we performed statistical analysis of our previously reported telomere profiling results from Single Molecule Telomere Assay via Optical Mapping (SMTA-OM), which is capable of quantifying individual telomeres from single molecules across all chromosomes. By comparing the telomeric features from SMTA-OM in TEL+ and ALT+ cancer cells, we demonstrated that ALT+ cancer cells display certain unique telomeric profiles, including increased fusions/internal telomere-like sequence (ITS+), fusions/internal telomere-like sequence loss (ITS-), telomere-free ends (TFE), super-long telomeres, and telomere length heterogeneity, compared to TEL+ cancer cells. Therefore, we propose that ALT+ cancer cells can be differentiated from TEL+ cancer cells using the SMTA-OM readouts as biomarkers. In addition, we observed variations in SMTA-OM readouts between different ALT+ cell lines that may potentially be used as biomarkers for discerning subtypes of ALT+ cancer and monitoring the response to cancer therapy.},
}
@article {pmid37372380,
year = {2023},
author = {Wang, F and McCulloh, DH and Chan, K and Wiltshire, A and McCaffrey, C and Grifo, JA and Keefe, DL},
title = {The Landscape of Telomere Length and Telomerase in Human Embryos at Blastocyst Stage.},
journal = {Genes},
volume = {14},
number = {6},
pages = {},
pmid = {37372380},
issn = {2073-4425},
mesh = {Humans ; *Telomerase/genetics/metabolism ; Blastocyst/metabolism ; Embryo, Mammalian/metabolism ; Aneuploidy ; Telomere/genetics/metabolism ; },
abstract = {The telomere length of human blastocysts exceeds that of oocytes and telomerase activity increases after zygotic activation, peaking at the blastocyst stage. Yet, it is unknown whether aneuploid human embryos at the blastocyst stage exhibit a different profile of telomere length, telomerase gene expression, and telomerase activity compared to euploid embryos. In present study, 154 cryopreserved human blastocysts, donated by consenting patients, were thawed and assayed for telomere length, telomerase gene expression, and telomerase activity using real-time PCR (qPCR) and immunofluorescence (IF) staining. Aneuploid blastocysts showed longer telomeres, higher telomerase reverse transcriptase (TERT) mRNA expression, and lower telomerase activity compared to euploid blastocysts. The TERT protein was found in all tested embryos via IF staining with anti-hTERT antibody, regardless of ploidy status. Moreover, telomere length or telomerase gene expression did not differ in aneuploid blastocysts between chromosomal gain or loss. Our data demonstrate that telomerase is activated and telomeres are maintained in all human blastocyst stage embryos. The robust telomerase gene expression and telomere maintenance, even in aneuploid human blastocysts, may explain why extended in vitro culture alone is insufficient to cull out aneuploid embryos during in vitro fertilization.},
}
@article {pmid37371908,
year = {2023},
author = {Warman, DJ and Jia, H and Kato, H},
title = {Effects of Thyme (Thymus vulgaris L.) Essential Oil on Aging-Induced Brain Inflammation and Blood Telomere Attrition in Chronologically Aged C57BL/6J Mice.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {6},
pages = {},
pmid = {37371908},
issn = {2076-3921},
abstract = {Chronological aging is commonly accompanied by chronic low-grade inflammation (or "inflammaging"), a contributor to the development of age-related chronic diseases. Aging increases oxidative stress that accelerates telomere shortening, leading to cell senescence and the generation of senescence-associated secretory phenotype (SASP) that exacerbates inflammation. Dietary antioxidants may help protect telomeres and attenuate inflammation. Thyme essential oil (TEO), reported for its potency against neuroinflammation, was fed to chronologically aged C57BL/6J mice for 24 weeks. The TEO diet showed notable impacts on the hippocampus, indicated by lower expression of the aging-related gene p16[INK4A] (p = 0.0783) and significantly lower expression of cyclin D kinase Cdk4 and Cdk6 (p < 0.05) compared to the age-matched control mice. The TEO group also showed significantly lower gene expression of the pro-inflammatory cytokine Il6 (p < 0.05) in the hippocampus and lower Il1b expression in the liver and cerebellum (p < 0.05). In vitro experiments conducted on NIH-3T3 cells expressing SASP revealed the dose-dependent anti-inflammatory activity of TEO. Remarkably, TEO diet-fed mice showed higher survival rates and significantly longer blood telomere lengths than the control mice. Monoterpene antioxidants in TEO, particularly thymol and p-cymene, may primarily contribute to the anti-inflammatory and telomere-protecting activities of TEO.},
}
@article {pmid37371596,
year = {2023},
author = {Kuse, R and Ishii, K},
title = {Flexible Attachment and Detachment of Centromeres and Telomeres to and from Chromosomes.},
journal = {Biomolecules},
volume = {13},
number = {6},
pages = {},
pmid = {37371596},
issn = {2218-273X},
mesh = {*Centromere/genetics ; *Telomere/genetics ; Cell Division ; },
abstract = {Accurate transmission of genomic information across multiple cell divisions and generations, without any losses or errors, is fundamental to all living organisms. To achieve this goal, eukaryotes devised chromosomes. Eukaryotic genomes are represented by multiple linear chromosomes in the nucleus, each carrying a centromere in the middle, a telomere at both ends, and multiple origins of replication along the chromosome arms. Although all three of these DNA elements are indispensable for chromosome function, centromeres and telomeres possess the potential to detach from the original chromosome and attach to new chromosomal positions, as evident from the events of telomere fusion, centromere inactivation, telomere healing, and neocentromere formation. These events seem to occur spontaneously in nature but have not yet been elucidated clearly, because they are relatively infrequent and sometimes detrimental. To address this issue, experimental setups have been developed using model organisms such as yeast. In this article, we review some of the key experiments that provide clues as to the extent to which these paradoxical and elusive features of chromosomally indispensable elements may become valuable in the natural context.},
}
@article {pmid37370681,
year = {2023},
author = {Umaru, B and Sengupta, S and Senthil Kumar, S and Drissi, R},
title = {Alternative Lengthening of Telomeres in Pediatric High-Grade Glioma and Therapeutic Implications.},
journal = {Cancers},
volume = {15},
number = {12},
pages = {},
pmid = {37370681},
issn = {2072-6694},
support = {None//The Cure Starts Now Foundation/ ; },
abstract = {Pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine glioma (DIPG), are highly aggressive tumors with dismal prognoses despite multimodal therapy including surgery, radiation therapy, and chemotherapy. To achieve cellular immortality cancer cells must overcome replicative senescence and apoptosis by activating telomere maintenance mechanisms (TMMs) through the reactivation of telomerase activity or using alternative lengthening of telomere (ALT) pathways. Although the ALT phenotype is more prevalent in pHGGs compared to adult HGGs, the molecular pathway and the prognostic significance of ALT activation are not well understood in pHGGs. Here, we report the heterogeneity of TMM in pHGGs and their association with genetic alterations. Additionally, we show that sensitivity to the protein kinase ataxia telangiectasia- and RAD3-related protein (ATR) inhibitor and the ATR downstream target CHK1 is not specific to pHGG ALT-positive cells. Together, these findings underscore the need for novel therapeutic strategies to target ALT in pHGG tumors.},
}
@article {pmid37368589,
year = {2023},
author = {Kuo, CL and Liu, R and Godoy, LDC and Pilling, LC and Fortinsky, RH and Brugge, D},
title = {Association between Residential Exposure to Air Pollution and Incident Coronary Heart Disease Is Not Mediated by Leukocyte Telomere Length: A UK Biobank Study.},
journal = {Toxics},
volume = {11},
number = {6},
pages = {},
pmid = {37368589},
issn = {2305-6304},
support = {R21 NR018963/NR/NINR NIH HHS/United States ; R01ES030289/ES/NIEHS NIH HHS/United States ; P30AG067988/AG/NIA NIH HHS/United States ; R21NR018963-01A1/NR/NINR NIH HHS/United States ; P30 AG067988/AG/NIA NIH HHS/United States ; R01 ES030289/ES/NIEHS NIH HHS/United States ; },
abstract = {Higher air pollution exposure and shorter leukocyte telomere length (LTL) are both associated with increased risk of coronary heart disease (CHD), and share plausible mechanisms, including inflammation. LTL may serve as a biomarker of air pollution exposure and may be intervened with to reduce the risk of CHD. To the best of our knowledge, we are the first to test the mediation effect of LTL in the relationship between air pollution exposure and incident CHD. Using the UK Biobank (UKB) data (n = 317,601), we conducted a prospective study linking residential air pollution exposure (PM2.5, PM10, NO2, NOx) and LTL to incident CHD during a mean follow-up of 12.6 years. Cox proportional hazards models and generalized additive models with penalized spline functions were used to model the associations of pollutant concentrations and LTL with incident CHD. We found non-linear associations of air pollution exposure with LTL and CHD. Pollutant concentrations in the lower range were decreasingly associated with longer LTL and reduced risk of CHD. The associations between lower pollutant concentrations and reduced risk of CHD, however, were minimally mediated by LTL (<3%). Our findings suggest that air pollution influences CHD through pathways that do not involve LTL. Replication is needed with improved measurements of air pollution that more accurately assesses personal exposure.},
}
@article {pmid37360685,
year = {2023},
author = {Boyle, C and Lansdorp, PM and Edelstein-Keshet, L},
title = {Predicting the number of lifetime divisions for hematopoietic stem cells from telomere length measurements.},
journal = {iScience},
volume = {26},
number = {7},
pages = {107053},
pmid = {37360685},
issn = {2589-0042},
abstract = {How many times does a typical hematopoietic stem cell (HSC) divide to maintain a daily production of over 1011 blood cells over a human lifetime? It has been predicted that relatively few, slowly dividing HSCs occupy the top of the hematopoietic hierarchy. However, tracking HSCs directly is extremely challenging due to their rarity. Here, we utilize previously published data documenting the loss of telomeric DNA repeats in granulocytes, to draw inferences about HSC division rates, the timing of major changes in those rates, as well as lifetime division totals. Our method uses segmented regression to identify the best candidate representations of the telomere length data. Our method predicts that, on average, an HSC divides 56 times over an 85-year lifespan (with lower and upper bounds of 36 and 120, respectively), with half of these divisions during the first 24 years of life.},
}
@article {pmid37356355,
year = {2023},
author = {Caria, P and Pilotto, S and D'Alterio, MN and Fronza, M and Murgia, F and Frau, J and Fenu, G and Dettori, T and Frau, DV and Atzori, L and Angioni, S and Cocco, E and Lorefice, L},
title = {Leukocyte telomere length in women with multiple sclerosis: Comparison with healthy women during pregnancy and puerperium.},
journal = {Journal of neuroimmunology},
volume = {381},
number = {},
pages = {578137},
doi = {10.1016/j.jneuroim.2023.578137},
pmid = {37356355},
issn = {1872-8421},
mesh = {Pregnancy ; Female ; Humans ; *Multiple Sclerosis/genetics ; In Situ Hybridization, Fluorescence ; Postpartum Period ; Leukocytes ; Telomere ; },
abstract = {OBJECTIVES: Several studies indicated leukocyte telomere length (LTL) as a biomarker of multiple sclerosis (MS) evolution. This study aimed to investigate LTL in women with multiple sclerosis (MS) compared to that in healthy women (HW) across different reproductive phases, and to evaluate its relationship with MS activity.<br><br>METHODS: Blood samples were collected from women with MS and HW during the fertile phase, pregnancy, and puerperium. LTL was determined using quantitative fluorescence in situ hybridization (Q-FISH).<br><br>RESULTS: Blood samples from 68 women with MS (22 during fertile life, 23 during pregnancy, and 23 post-partum) and 52 HW (23 during fertile life, 20 during pregnancy, and 9 post-partum) were analyzed. During pregnancy, LTL in MS women and HW was 84.7&#xa0;&#xb1;&#xa0;10.5 and 77.6&#xa0;&#xb1;&#xa0;11.5, respectively (p&#xa0;<&#xa0;0.005). Regression analysis showed that shorter LTL was associated with pregnancy in HW (p&#xa0;=&#xa0;0.021); this relationship was not observed in MS women, for whom shorter LTL was related to a higher EDSS (p&#xa0;=&#xa0;0.036). A longitudinal analysis was performed in eight MS women, showing LTL shortening from pregnancy to puerperium (p&#xa0;=&#xa0;0.003), which was related to MS reactivation (p&#xa0;=&#xa0;0.042).<br><br>CONCLUSION: Our results highlight the possible associations between LTL, reproductive biological phases, and MS activity after delivery.},
}
@article {pmid37354000,
year = {2023},
author = {Raj, HA and Lai, TP and Niewisch, MR and Giri, N and Wang, Y and Spellman, SR and Aviv, A and Gadalla, SM and Savage, SA},
title = {The distribution and accumulation of the shortest telomeres in telomere biology disorders.},
journal = {British journal of haematology},
volume = {203},
number = {5},
pages = {820-828},
pmid = {37354000},
issn = {1365-2141},
support = {ZIA CP010144/ImNIH/Intramural NIH HHS/United States ; Z01 CP010144/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Humans ; Biology ; *Bone Marrow Failure Disorders ; *Dyskeratosis Congenita/genetics ; *Pancytopenia ; Telomere/genetics ; Telomere Shortening ; },
abstract = {Individuals with telomere biology disorders (TBDs) have very short telomeres, high risk of bone marrow failure (BMF), and reduced survival. Using data from TBD patients, a mean leukocyte Southern blot telomere length (TL) of 5 kilobases (kb) was estimated as the 'telomere brink' at which human survival is markedly reduced. However, the shortest telomere, not the mean TL, signals replicative senescence. We used the Telomere Shortest Length Assay (TeSLA) to tally TL of all 46 chromosomes in blood-derived DNA and examined its relationship with TBDs. Patients (n = 18) had much shorter mean TL (TeSmTL) (2.54 ± 0.41 kb vs. 4.48 ± 0.52 kb, p < 0.0001) and more telomeres <3 kb than controls (n = 22) (70.43 ± 8.76% vs. 33.05 ± 6.93%, p < 0.0001). The proportion of ultrashort telomeres (<1.6 kb) was also higher in patients than controls (39.29 ± 10.69% vs. 10.40 ± 4.09%, p < 0.0001). TeS <1.6 kb was associated with severe (n = 11) compared with non-severe (n = 7) BMF (p = 0.027). Patients with multi-organ manifestations (n = 10) had more telomeres <1.6 kb than those with one affected organ system (n = 8) (p = 0.029). Findings suggest that TBD clinical manifestations are associated with a disproportionately higher number of haematopoietic cell telomeres reaching a telomere brink, whose length at the single telomere level is yet to be determined.},
}
@article {pmid37353495,
year = {2023},
author = {Rampersaud, R and Wu, GWY and Reus, VI and Lin, J and Blackburn, EH and Epel, ES and Hough, CM and Mellon, SH and Wolkowitz, OM},
title = {Shorter telomere length predicts poor antidepressant response and poorer cardiometabolic indices in major depression.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {10238},
pmid = {37353495},
issn = {2045-2322},
support = {R01 MH083784/MH/NIMH NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; TL1 TR001871/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; *Depressive Disorder, Major/drug therapy/genetics ; Leukocytes, Mononuclear/metabolism ; Depression ; *Telomerase/genetics ; Telomere Shortening ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; Antidepressive Agents/therapeutic use ; Telomere/metabolism ; *Cardiovascular Diseases/drug therapy ; },
abstract = {Telomere length (TL) is a marker of biological aging, and shorter telomeres have been associated with several medical and psychiatric disorders, including cardiometabolic dysregulation and Major Depressive Disorder (MDD). In addition, studies have shown shorter TL to be associated with poorer response to certain psychotropic medications, and our previous work suggested shorter TL and higher telomerase activity (TA) predicts poorer response to Selective Serotonin Reuptake Inhibitor (SSRI) treatment. Using a new group of unmedicated medically healthy individuals with MDD (n = 48), we sought to replicate our prior findings demonstrating that peripheral blood mononuclear cell (PBMC) TL and TA predict response to SSRI treatment and to identify associations between TL and TA with biological stress mediators and cardiometabolic risk indices. Our results demonstrate that longer pre-treatment TL was associated with better response to SSRI treatment (β = .407 p = .007). Additionally, we observed that TL had a negative relationship with allostatic load (β = - .320 p = .017) and a cardiometabolic risk score (β = - .300 p = .025). Our results suggest that PBMC TL reflects, in part, the cumulative effects of physiological stress and cardiovascular risk in MDD and may be a biomarker for predicting SSRI response.},
}
@article {pmid37352282,
year = {2023},
author = {Wan, B and Lu, L and Lv, C},
title = {Mendelian randomization study on the causal relationship between leukocyte telomere length and prostate cancer.},
journal = {PloS one},
volume = {18},
number = {6},
pages = {e0286219},
pmid = {37352282},
issn = {1932-6203},
mesh = {Male ; Humans ; *Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Prostatic Neoplasms/genetics ; Leukocytes ; Polymorphism, Single Nucleotide ; Telomere/genetics ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) is related to prostate cancer (PCa). However, the causal relationship between them remains unknown. This study was aimed at identifying the causal direction between LTL and PCa with Mendelian randomization (MR).<br><br>METHODS: Single-nucleotide polymorphisms associated with LTL were identified from a genome-wide association study (GWAS) involving 472,174 individuals. Summary-level data of PCa-related GWAS were extracted from four cohorts comprising 456,717 individuals. An inverse-variance-weighted (IVW) algorithm was used for MR. Sensitivity analyses were performed with MR-Egger regression, IVW regression, leave-one-out test, and MR-Pleiotropy Residual Sum and Outlier analyses. A meta-analysis was also performed to compute the average genetically determined effect of LTL on PCa.<br><br>RESULTS: A long LTL was associated with an increased risk of PCa in all cohorts, with odds ratios of 1.368 (95% confidence interval [CI]: 1.247 to 1.500, P = 2.84&#xd7;10-11), 1.503 (95% CI: 1.243 to 1.816, P = 2.57&#xd7;10-5), 1.722 (95% CI: 1.427 to 2.077, P = 1.48&#xd7;10-8), and 1.358 (95% CI: 1.242 to 1.484, P = 1.73&#xd7;10-11) in the IVW analysis. Sensitivity analyses showed that the genetically determined effect of LTL on PCa was stable and reliable. The meta-analysis showed that the genetically determined per 1-standard deviation rise in LTL correlated significantly with an average 40.6% increase in the PCa risk, with an average odds ratio of 1.406 (95% CI: 1.327 to 1.489, P < 0.001).<br><br>CONCLUSION: The results of this study supported the causal hypothesis that the genetically determined longer LTL was associated with a higher risk of PCa. This finding could serve as a basis for therapeutic strategies for PCa.},
}
@article {pmid37352164,
year = {2023},
author = {Gao, S and Rohr, JK and de Vivo, I and Ramsay, M and Krieger, N and Kabudula, CW and Farrell, MT and Bassil, DT and Harriman, NW and Corona-Perez, D and Pesic, K and Berkman, LF},
title = {Telomere Length, Health, and Mortality in a Cohort of Older Black South African Adults.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {78},
number = {11},
pages = {1983-1990},
pmid = {37352164},
issn = {1758-535X},
support = {069683/Z/02/Z/WT_/Wellcome Trust/United Kingdom ; 085477/Z/08/Z/WT_/Wellcome Trust/United Kingdom ; 058893/Z/99/A/WT_/Wellcome Trust/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; P01 AG041710/AG/NIA NIH HHS/United States ; 085477/B/08/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Humans ; Female ; Aged ; Longitudinal Studies ; South Africa/epidemiology ; *Aging/genetics ; *Life Expectancy ; Biomarkers ; Telomere ; },
abstract = {Telomere length (TL) may be a biomarker of aging processes as well as age-related diseases. However, most studies of TL and aging are conducted in high-income countries. Less is known in low- and middle-income countries (LMICs) such as South Africa, where life expectancy remains lower despite population aging. We conducted a descriptive analysis of TL in a cohort of older adults in rural South Africa. TL was assayed from venous blood draws using quantitative polymerase chain reaction (T/S ratio). We examined the correlation between TL and biomarkers, demographic characteristics, mental/cognitive health measures, and physical performance measures in a subsample of the Wave 1 2014-2015 "Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa" (HAALSI) cohort (n = 510). We used logistic regression to measure the association between TL and mortality through Wave 3 (2021-2022). In bivariate analyses, TL was significantly correlated with age (r = -0.29, p < .0001), self-reported female sex (r = 0.13, p = .002), mortality (r = -0.1297, p = .003), diastolic blood pressure (r = 0.09, p = .037), pulse pressure (r = -0.09, p = .045), and being a grandparent (r = -0.17, p = .0001). TL was significantly associated with age (β = -0.003; 95% confidence interval [CI] = -0.005, -0.003). TL was significantly associated in unadjusted multivariate analyses with mortality, but the relationship between TL and mortality was attenuated after adjusting for age (odds ratio [OR] = 0.19; 95% CI = 0.03, 1.27) and other covariates (OR = 0.17; 95% CI = 0.02, 1.19). Our study is the first analysis of TL in an older adult South African population. Our results corroborate existing relationships between TL and age, sex, cardiometabolic disease, and mortality found in higher-income countries.},
}
@article {pmid37351101,
year = {2023},
author = {Xie, Q and Liu, T and Zhang, X and Ding, Y and Fan, X},
title = {Construction of a telomere-related gene signature to predict prognosis and immune landscape for glioma.},
journal = {Frontiers in endocrinology},
volume = {14},
number = {},
pages = {1145722},
pmid = {37351101},
issn = {1664-2392},
mesh = {Humans ; *Endothelial Cells ; Prognosis ; *Glioma/genetics ; Immunotherapy ; B-Lymphocytes ; },
abstract = {BACKGROUND: Glioma is one of the commonest malignant tumors of the brain. However, glioma present with a poor clinical prognosis. Therefore, specific detection markers and therapeutic targets need to be explored as a way to promote the survival rate of BC patients. Therefore, we need to search for quality immune checkpoints to support the efficacy of immunotherapy for glioma.<br><br>METHODS: We first recognized differentially expressed telomere-related genes (TRGs) and accordingly developed a risk model by univariate and multivariate Cox analysis. The accuracy of the model is then verified. We evaluated the variations in immune function and looked at the expression levels of immune checkpoint genes. Finally, to assess the anti-tumor medications often used in the clinical treatment of glioma, we computed the half inhibitory concentration of pharmaceuticals.<br><br>RESULTS: We finally identified nine TRGs and built a risk model. Through the validation of the model, we found good agreement between the predicted and observed values. Then, we found 633 differentially expressed genes between various risk groups to identify the various molecular pathways between different groups. The enrichment of CD4+ T cells, CD8+ T cells, fibroblasts, endothelial cells, macrophages M0, M1, and M2, mast cells, myeloid dendritic cells, and neutrophils was favorably correlated with the risk score, but the enrichment of B cells and NK cells was negatively correlated with the risk score. The expression of several immune checkpoint-related genes differed significantly across the risk groups. Finally, in order to create individualized treatment plans for diverse individuals, we searched for numerous chemotherapeutic medications for patients in various groups.<br><br>CONCLUSION: The findings of this research provide evidence that TRGs may predict a patient's prognosis for glioma, assist in identifying efficient targets for glioma immunotherapy, and provide a foundation for an efficient, customized approach to treating glioma patients.},
}
@article {pmid37350340,
year = {2023},
author = {Vohra, V and Cheng, MZ and Xue, QL and Simonsick, EM and Lane, AP and Agrawal, Y and Rowan, NR},
title = {The Association of Multiple Sensory Impairment and Telomere Length: The Health ABC Study.},
journal = {The Laryngoscope},
volume = {133},
number = {11},
pages = {3132-3138},
pmid = {37350340},
issn = {1531-4995},
support = {P30 AG021334/AG/NIA NIH HHS/United States ; R01 DC016106/DC/NIDCD NIH HHS/United States ; ZIA AG000964/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Humans ; Aged ; Aged, 80 and over ; Cross-Sectional Studies ; *Aging ; *Hearing ; Smell ; Telomere ; },
abstract = {OBJECTIVES: The objective of this study was to characterize the associations of sensory impairments, including olfaction (OI), vision (VI), hearing (HI), and touch (TI), with telomere length (TL) in a group of community-dwelling older adults who participated in the Health ABC study.<br><br>METHODS: Across 1603 participants, OI was classified with the Brief Smell Identification Test (<11), HI with pure-tone averages (<25 dB), VI with visual acuity (20/50 or worse), and TI with monofilament testing (inability to detect three of four touches). Shorter TL was defined as the lowest quartile of sample TLs. Adjusted multivariable regressions were used to examine the cross-sectional association between the modality, severity, and number of sensory impairments with TL.<br><br>RESULTS: Participants had an average age of 77.4&#x2009;&#xb1;&#x2009;2.84&#x2009;years, and 89.7% (n&#x2009;=&#x2009;1438) had at least one or more sensory impairments. Severe OI (odds ratio [OR]&#x2009;=&#x2009;1.73, 95% confidence interval [CI]&#x2009;=&#x2009;[1.19, 2.6]) was independently associated with increased odds of shorter TL. Additionally, having one (OR&#x2009;=&#x2009;2.79, 95% CI&#x2009;=&#x2009;[1.69, 4.70]), two (OR&#x2009;=&#x2009;2.5, 95% CI&#x2009;=&#x2009;[1.51, 4.26]), three (OR&#x2009;=&#x2009;3.04, 95% CI&#x2009;=&#x2009;[1.79, 5.36]), or four impairments (OR&#x2009;=&#x2009;3.72, 95% CI&#x2009;=&#x2009;[1.52, 7.33]) was associated with increased odds of shorter TL in a dose-dependent manner.<br><br>CONCLUSION: Severe OI and TI appear to be particularly robust markers of shortened TL. Additionally, multiple sensory impairment is strongly associated with shortened TL, suggesting that sensory dysfunction may represent a unique biomarker of unhealthy aging.<br><br>LEVEL OF EVIDENCE: Level II Laryngoscope, 133:3132-3138, 2023.},
}
@article {pmid37348955,
year = {2023},
author = {Jessberger, R},
title = {Rolf Jessberger: cohesin, telomeres, &amp; germ cells.},
journal = {Life science alliance},
volume = {6},
number = {7},
pages = {},
pmid = {37348955},
issn = {2575-1077},
mesh = {Male ; Humans ; *Germ Cells ; *Telomere/genetics ; Cohesins ; },
abstract = {Rolf Jessberger is Professor and Chairman at the Institute of Physiological Chemistry, and Faculty of Medicine at the Technische Universität Dresden. We asked him about his recent article published in Life Science Alliance (LSA) and his experience in science thus far.},
}
@article {pmid37345011,
year = {2023},
author = {Amin, A and Morello, M and Petrara, MR and Rizzo, B and Argenton, F and De Rossi, A and Giunco, S},
title = {Short-Term TERT Inhibition Impairs Cellular Proliferation via a Telomere Length-Independent Mechanism and Can Be Exploited as a Potential Anticancer Approach.},
journal = {Cancers},
volume = {15},
number = {10},
pages = {},
pmid = {37345011},
issn = {2072-6694},
support = {5x1000 2017 - Cancer Genomics Research Platform//Istituto Oncologico Veneto/ ; Department of Surgery, Oncology and Gastroenterology DOR 2021 and BIRD 2021 to SG//University of Padua/ ; },
abstract = {Telomerase reverse transcriptase (TERT), the catalytic component of telomerase, may also contribute to carcinogenesis via telomere-length independent mechanisms. Our previous in vitro and in vivo studies demonstrated that short-term telomerase inhibition by BIBR1532 impairs cell proliferation without affecting telomere length. Here, we show that the impaired cell cycle progression following short-term TERT inhibition by BIBR1532 in in vitro models of B-cell lymphoproliferative disorders, i.e., Epstein-Barr virus (EBV)-immortalized lymphoblastoid cell lines (LCLs), and B-cell malignancies, i.e., Burkitt's lymphoma (BL) cell lines, is characterized by a significant reduction in NF-κB p65 nuclear levels leading to the downregulation of its target gene MYC. MYC downregulation was associated with increased expression and nuclear localization of P21, thus promoting its cell cycle inhibitory function. Consistently, treatment with BIBR1532 in wild-type zebrafish embryos significantly decreased Myc and increased p21 expression. The combination of BIBR1532 with antineoplastic drugs (cyclophosphamide or fludarabine) significantly reduced xenografted cells' proliferation rate compared to monotherapy in the zebrafish xenograft model. Overall, these findings indicate that short-term inhibition of TERT impairs cell growth through the downregulation of MYC via NF-κB signalling and supports the use of TERT inhibitors in combination with antineoplastic drugs as an efficient anticancer strategy.},
}
@article {pmid37342644,
year = {2023},
author = {Thakur, M and Patil, Y and Philip, ST and Hamdule, T and Thimmapuram, J and Vyas, N and Thakur, K},
title = {Impact of Heartfulness meditation practice on anxiety, perceived stress, well-being, and telomere length.},
journal = {Frontiers in psychology},
volume = {14},
number = {},
pages = {1158760},
pmid = {37342644},
issn = {1664-1078},
abstract = {OBJECTIVE: Exhaustion, stress, and burnout have all been found to be reduced using techniques like yoga and meditation. This study was carried out to check the effectiveness of Heartfulness practice (a form of meditation) on certain psychological and genetic variables.<br><br>METHODS: A total of 100 healthy individuals (aged 18-24) were recruited and randomized into two groups-Heartfulness intervention and control group. The intervention was carried out for 03&#x2009;months. Participants from both groups were analysed for their cortisol levels and telomere length before and after the intervention. Psychometric measures of anxiety, perceived stress, well-being and mindfulness were carried out using Beck Anxiety Inventory (BAI), Perceived Stress Scale (PSS), WHO-Well-being Index (WHO-WBI) and Five Facet Mindfulness Questionnaire (FFMQ).<br><br>RESULTS: The cortisol levels in the meditators group significantly decreased (p&#x2009;<&#x2009;0.001) after the intervention as compared to the non-meditators group, whereas, the telomere length increased in the mediators group. This increase was not significant (p&#x2009;>&#x2009;0.05). Anxiety and perceived stress also decreased post intervention, and well-being as well as mindfulness increased, as assessed by the questionnaire tools, although the decrease in perceived stress was statistically insignificant (p&#x2009;>&#x2009;0.05). A negative correlation was observed between telomere length and cortisol (stress biomarker), whereas a positive correlation was found between telomere length and well-being.<br><br>CONCLUSION: Our data provide evidence that Heartfulness meditation practice can improve our mental health. Additionally, telomere length is shown to be affected by cortisol levels, and this meditation practice can also help to increase telomere length, and thereby slow down cellular aging. However, future studies with larger sample size are required to confirm our observations.},
}
@article {pmid37342445,
year = {2023},
author = {Li, K and Dai, M and Sacirovic, M and Zemmrich, C and Pagonas, N and Ritter, O and Grisk, O and Lubomirov, LT and Lauxmann, MA and Bramlage, P and Persson, AB and Buschmann, E and Buschmann, I and Hillmeister, P},
title = {Leukocyte telomere length and mitochondrial DNA copy number associate with endothelial function in aging-related cardiovascular disease.},
journal = {Frontiers in cardiovascular medicine},
volume = {10},
number = {},
pages = {1157571},
pmid = {37342445},
issn = {2297-055X},
abstract = {BACKGROUND: We investigated the association between leukocyte telomere length, mitochondrial DNA copy number, and endothelial function in patients with aging-related cardiovascular disease (CVD).<br><br>METHODS: In total 430 patients with CVD and healthy persons were enrolled in the current study. Peripheral blood was drawn by routine venipuncture procedure. Plasma and peripheral blood mononuclear cells (PBMCs) were collected. Cell-free genomic DNA (cfDNA) and leukocytic genomic DNA (leuDNA) were extracted from plasma and PBMCs, respectively. Relative telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN) were analyzed using quantitative polymerase chain reaction. Endothelial function was evaluated by measuring flow-mediated dilation (FMD). The correlation between TL of cfDNA (cf-TL), mtDNA-CN of cfDNA (cf-mtDNA), TL of leuDNA (leu-TL), mtDNA-CN of leuDNA (leu-mtDNA), age, and FMD were analyzed based on Spearman's rank correlation. The association between cf-TL, cf-mtDNA, leu-TL, leu-mtDNA, age, gender, and FMD were explored using multiple linear regression analysis.<br><br>RESULTS: cf-TL positively correlated with cf-mtDNA (r&#x2009;=&#x2009;0.1834, P&#x2009;=&#x2009;0.0273), and leu-TL positively correlated with leu-mtDNA (r&#x2009;=&#x2009;0.1244, P&#x2009;=&#x2009;0.0109). In addition, both leu-TL (r&#x2009;=&#x2009;0.1489, P&#x2009;=&#x2009;0.0022) and leu-mtDNA (r&#x2009;=&#x2009;0.1929, P&#x2009;<&#x2009;0.0001) positively correlated with FMD. In a multiple linear regression analysis model, both leu-TL (&#x3b2;&#x2009;=&#x2009;0.229, P&#x2009;=&#x2009;0.002) and leu-mtDNA (&#x3b2;&#x2009;=&#x2009;0.198, P&#x2009;=&#x2009;0.008) were positively associated with FMD. In contrast, age was inversely associated with FMD (&#x3b2;&#x2009;=&#x2009;-0.426, P&#x2009;<&#x2009;0.0001).<br><br>CONCLUSION: TL positively correlates mtDNA-CN in both cfDNA and leuDNA. leu-TL and leu-mtDNA can be regarded as novel biomarkers of endothelial dysfunction.},
}
@article {pmid37342232,
year = {2023},
author = {Kliszczak, M and Moralli, D and Jankowska, JD and Bryjka, P and Subha Meem, L and Goncalves, T and Hester, SS and Fischer, R and Clynes, D and Green, CM},
title = {Loss of FAM111B protease mutated in hereditary fibrosing poikiloderma negatively regulates telomere length.},
journal = {Frontiers in cell and developmental biology},
volume = {11},
number = {},
pages = {1175069},
pmid = {37342232},
issn = {2296-634X},
abstract = {Hereditary fibrosing poikiloderma (HFP) is a rare human dominant negative disorder caused by mutations in the FAM111B gene that encodes a nuclear trypsin-like serine protease. HFP patients present with symptoms including skin abnormalities, tendon contractures, myopathy and lung fibrosis. We characterized the cellular roles of human FAM111B using U2OS and MCF7 cell lines and report here that the protease interacts with components of the nuclear pore complex. Loss of FAM111B expression resulted in abnormal nuclear shape and reduced telomeric DNA content suggesting that FAM111B protease is required for normal telomere length; we show that this function is independent of telomerase or recombination driven telomere extension. Even though FAM111B-deficient cells were proficient in DNA repair, they showed hallmarks of genomic instability such as increased levels of micronuclei and ultra-fine DNA bridges. When mutated as in HFP, FAM111B was more frequently localized to the nuclear envelope, suggesting that accumulation of the mutated protease at the nuclear periphery may drive the disease pathology.},
}
@article {pmid37340856,
year = {2023},
author = {Chen, C and Yang, K and Nan, H and Unverzagt, F and McClure, LA and Irvin, MR and Judd, S and Cushman, M and Kamin Mukaz, D and Klaunig, JE and D'Alton, ME and Kahe, K},
title = {Associations of Telomere Length and Change With Cognitive Decline Were Modified by Sex and Race: The REGARDS Study.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {38},
number = {},
pages = {15333175231175797},
doi = {10.1177/15333175231175797},
pmid = {37340856},
issn = {1938-2731},
support = {RF1 AG056111/AG/NIA NIH HHS/United States ; U01 NS041588/NS/NINDS NIH HHS/United States ; },
mesh = {Female ; Humans ; Biomarkers ; *Cognition ; Executive Function ; *Cognitive Dysfunction/genetics ; Telomere/genetics ; },
abstract = {INTRODUCTION: We examined the associations of baseline telomere length (TL) and TL change with cognitive function over time in older US adults, as well as differences by sex and race.<br><br>METHODS: A total of 1820 cognitively healthy individuals (median baseline age: 63&#xa0;years) were included. Telomere length was measured using qPCR-based method at baseline and among 614 participants in the follow-up examination 10&#xa0;years later. Cognitive function was assessed by a four-test battery every 2&#xa0;years.<br><br>RESULTS: In multivariable-adjusted linear mixed models, longer baseline TL and smaller attrition/lengthening of TL over time were associated with better Animal Fluency Test score. Longer baseline TL was also linearly associated with better Letter Fluency Test score. The observed associations were consistently more pronounced in women than men and in Black compared to White participants.<br><br>DISCUSSION: Telomere length may be a biomarker that predicts long-term verbal fluency and executive function, particularly in women and Black Americans.},
}
@article {pmid37338562,
year = {2023},
author = {Polonio, AM and Medrano, M and Chico-Sordo, L and Córdova-Oriz, I and Cozzolino, M and Montans, J and Herraiz, S and Seli, E and Pellicer, A and García-Velasco, JA and Varela, E},
title = {Impaired telomere pathway and fertility in Senescence-Accelerated Mice Prone 8 females with reproductive senescence.},
journal = {Aging},
volume = {15},
number = {11},
pages = {4600-4624},
pmid = {37338562},
issn = {1945-4589},
mesh = {Male ; Female ; Mice ; Animals ; *Telomerase/genetics/metabolism ; Aging/genetics ; Fertility/physiology ; *Infertility ; Telomere/metabolism ; },
abstract = {Ovarian aging is the main cause of infertility and telomere attrition is common to both aging and fertility disorders. Senescence-Accelerated Mouse Prone 8 (SAMP8) model has shortened lifespan and premature infertility, reflecting signs of reproductive senescence described in middle-aged women. Thus, our objective was to study SAMP8 female fertility and the telomere pathway at the point of reproductive senescence. The lifespan of SAMP8 and control mice was monitored. Telomere length (TL) was measured by in situ hybridization in blood and ovary. Telomerase activity (TA) was analyzed by telomere-repeat amplification protocol, and telomerase expression, by real-time quantitative PCR in ovaries from 7-month-old SAMP8 and controls. Ovarian follicles at different stages of maturation were evaluated by immunohistochemistry. Reproductive outcomes were analyzed after ovarian stimulation. Unpaired t-test or Mann-Whitney test were used to calculate p-values, depending on the variable distribution. Long-rank test was used to compare survival curves and Fisher's exact test was used in contingency tables. Median lifespan of SAMP8 females was reduced compared to SAMP8 males (p = 0.0138) and control females (p < 0.0001). In blood, 7-month-old SAMP8 females presented lower mean TL compared to age-matched controls (p = 0.041). Accordingly, the accumulation of short telomeres was higher in 7-month-old SAMP8 females (p = 0.0202). Ovarian TA was lower in 7-month-old SAMP8 females compared to controls. Similarly, telomerase expression was lower in the ovaries of 7-month-old SAMP8 females (p = 0.04). Globally, mean TL in ovaries and granulosa cells (GCs) were similar. However, the percentage of long telomeres in ovaries (p = 0.004) and GCs (p = 0.004) from 7-month-old SAMP8 females was lower compared to controls. In early-antral and antral follicles, mean TL of SAMP8 GCs was lower than in age-matched controls (p = 0.0156 for early-antral and p = 0.0037 for antral follicles). Middle-aged SAMP8 showed similar numbers of follicles than controls, although recovered oocytes after ovarian stimulation were lower (p = 0.0068). Fertilization rate in oocytes from SAMP8 was not impaired, but SAMP8 mice produced significantly more morphologically abnormal embryos than controls (27.03% in SAMP8 vs. 1.22% in controls; p < 0.001). Our findings suggest telomere dysfunction in SAMP8 females, at the time of reproductive senescence.},
}
@article {pmid37335484,
year = {2023},
author = {Lyčka, M and Fajkus, P and Jenner, LP and Sýkorová, E and Fojtová, M and Peska, V},
title = {Identification of the Sequence and the Length of Telomere DNA.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2672},
number = {},
pages = {285-302},
pmid = {37335484},
issn = {1940-6029},
mesh = {*DNA/genetics ; *Telomere/genetics ; Telomere-Binding Proteins/genetics ; DNA Breaks, Double-Stranded ; },
abstract = {Telomeres are essential nucleoprotein structures at the very ends of linear eukaryote chromosomes. They shelter the terminal genome territories against degradation and prevent the natural chromosome ends from being recognized by repair mechanisms as double-strand DNA breaks.There are two basic characteristics of telomeric DNA, its sequence and its length. The telomere sequence is important as a "landing area" for specific telomere-binding proteins, which function as signals and moderate the interactions required for correct telomere function. While the sequence forms the proper "landing surface" of telomeric DNA, its length is similarly important. Too short or exceptionally long telomere DNA cannot perform its function properly. In this chapter, methods for the investigation of these two basic telomere DNA characteristics are described, namely, telomere motif identification and telomere length measurement.},
}
@article {pmid37333916,
year = {2023},
author = {Zhang, T and Sun, Y and Wei, J and Zhao, G and Hao, W and Lv, Z and Chen, X and Liu, Y and Wei, F},
title = {Shorter telomere length in children with autism spectrum disorder is associated with oxidative stress.},
journal = {Frontiers in psychiatry},
volume = {14},
number = {},
pages = {1209638},
pmid = {37333916},
issn = {1664-0640},
abstract = {OBJECTIVE: Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder caused by a complex interaction between genetic and environmental risk factors. The balance between antioxidant capacity and oxidative stress (OS) induced free radicals may be crucial during the pathophysiological development of ASD.<br><br>METHODS: In this study, 96 children with ASD who met the diagnostic and statistical manual of mental disorders were collected, and the number of children in the typical development (TD) group was matched by 1:1. Digital PCR (dPCR) for telomere length (TL) expression in ASD in peripheral blood leukocytes. Urine levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) content were measured by tandem triple quadrupole mass spectrometry and corrected by urinary creatinine levels. The levels of superoxide dismutase (SOD), catalase (CAT), and capacity (AOC) were detected by kits.<br><br>RESULTS: The TL of the ASD group was shorter than the TD group (p&#x2009;<&#x2009;0.01) and had some accurate predictive significance for the identification of ASD (AUC&#x2009;=&#x2009;0.632, 95% CI: 0.533-0.710, p =&#x2009;0.002). Both 8-OHdG content and SOD activity in the ASD group were significantly higher than those in the TD group (p&#x2009;<&#x2009;0.05). Shortened TL (Monofactor: 2.20 (1.22, 3.96), p =&#x2009;0.009; Multifactor: 2.22 (1.22, 4.00), p =&#x2009;0.008) and reduced CAT activity (Monofactor: 2.31 (1.28, 4.17), p =&#x2009;0.006; Multifactor: 2.31 (1.28, 4.18), p =&#x2009;0.006) are risk factors for the development of ASD, while reduced 8-OHdG content (Monofactor: 0.29 (0.14, 0.60), p =&#x2009;0.001; Multifactor: 0.27 (0.13, 0.57), p =&#x2009;0.001) and reduced SOD activity (Monofactor: 0.55 (0.31, 0.98), p =&#x2009;0.042; Multifactor: 0.54 (0.30, 0.98), p =&#x2009;0.042) are protective factors for the development of ASD.<br><br>CONCLUSION: In this study, TL and OS were significantly different between the ASD group and the TD group. As guanine-rich telomere sequences were likely damaged by oxygen free radicals, creating OS, which is a factor in the incidence and progression of ASDs. In conclusion, oxidative damage occurs in the bodies of children with ASD, which may lead to sustained disease progression and severe clinical manifestations. We assume that timely supplementation of antioxidants is very likely to be a potential treatment for early intervention in children with ASD. Identification and detection of OS-related biomarkers may contribute to early diagnosis and timely interventions in young patients with ASD.},
}
@article {pmid37332563,
year = {2023},
author = {Cheng, H and Asri, M and Lucas, J and Koren, S and Li, H},
title = {Scalable telomere-to-telomere assembly for diploid and polyploid genomes with double graph.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {37332563},
issn = {2331-8422},
support = {K99 HG012798/HG/NHGRI NIH HHS/United States ; R01 HG010040/HG/NHGRI NIH HHS/United States ; U01 HG010971/HG/NHGRI NIH HHS/United States ; U41 HG010972/HG/NHGRI NIH HHS/United States ; },
abstract = {Despite recent advances in the length and the accuracy of long-read data, building haplotype-resolved genome assemblies from telomere to telomere still requires considerable computational resources. In this study, we present an efficient de novo assembly algorithm that combines multiple sequencing technologies to scale up population-wide telomere-to-telomere assemblies. By utilizing twenty-two human and two plant genomes, we demonstrate that our algorithm is around an order of magnitude cheaper than existing methods, while producing better diploid and haploid assemblies. Notably, our algorithm is the only feasible solution to the haplotype-resolved assembly of polyploid genomes.},
}
@article {pmid37329271,
year = {2023},
author = {Barcın-Güzeldere, HK and Aksoy, M and Demircan, T and Yavuz, M and Beler, M},
title = {Association between the anthropometric measurements and dietary habits on telomere shortening in healthy older adults: A-cross-sectional study.},
journal = {Geriatrics &amp; gerontology international},
volume = {23},
number = {7},
pages = {565-572},
doi = {10.1111/ggi.14620},
pmid = {37329271},
issn = {1447-0594},
mesh = {Male ; Humans ; Female ; Aged ; *Telomere Shortening ; Cross-Sectional Studies ; *Diet ; Feeding Behavior ; Leukocytes ; Telomere/genetics ; },
abstract = {AIM: This study aimed to evaluate the effect of anthropometric measurements and dietary habits on telomere length in healthy older residents in rural and urban areas.<br><br>METHODS: This was a cross-sectional study. The study population included 81 healthy older individuals aged &#x2265;80&#x2009;years. A quantitative food frequency questionnaire was used to determine dietary habits. Anthropometric measurements were taken by researchers. The telomere length of individuals was determined from leukocytes using quantitative polymerase chain reaction.<br><br>RESULTS: Urban women had longer telomeres than rural women (P&#x2009;<&#x2009;0.05). Rural men had significantly higher hip circumference, middle-upper arm circumference and fat-free mass than urban men (P&#x2009;<&#x2009;0.05). It was shown that while fresh vegetable consumption was higher in rural areas, carbonated drink consumption was higher in urban areas (P&#x2009;<&#x2009;0.05). In women, homemade bread and sugar consumption were higher in rural areas, and honey consumption was higher in urban (P&#x2009;<&#x2009;0.05). Red meat, milk-based dessert and pastry consumption explain telomere shortening by 22.5%, 24.8% and 17.9%, respectively. In addition, the model based on anthropometric measurements also contributes to explaining telomere shortening by 42.9%.<br><br>CONCLUSION: Red meat, milk-based dessert and pastry consumption, and waist circumference, hip circumference, waist-to-hip ratio and waist-to-height ratio are associated with telomere length. Longer telomeres are associated with a healthy, balanced, adequate diet and maintaining a healthy body weight/proportion, and they are crucial for achieving healthy aging. Geriatr Gerontol Int 2023; 23: 565-572.},
}
@article {pmid37328426,
year = {2024},
author = {Fernández de la Puente, M and Salas-Huetos, A and Valle-Hita, C and Babio, N and Murphy, MM and Canudas, S and Salas-Salvadó, J},
title = {Is telomere length a biomarker of sperm quality? A systematic review and meta-analysis of observational studies.},
journal = {Andrology},
volume = {12},
number = {2},
pages = {277-288},
doi = {10.1111/andr.13482},
pmid = {37328426},
issn = {2047-2927},
support = {CEX2021-001234-M//MICIN/AEI/FEDER, UE/ ; PI21/01447//Instituto de Salud Carlos III/ ; PI21/01447//European Union/ ; 2021/11-No.Exp.8004330008-2021-0022642//Diputaci&#xf3; de Tarragona/ ; },
mesh = {Humans ; Male ; *Semen Analysis ; Semen ; Cross-Sectional Studies ; Spermatozoa ; *Infertility, Male/diagnosis/genetics ; Telomere ; Biomarkers ; },
abstract = {BACKGROUND: Telomeres are essential for the integrity of chromosome ends during cell division and their involvement in different processes linked to aging has been established. These chromosome components are involved in spermatogenesis and seem to play an important role in fertilization and embryo development. Telomere length is shortened with each cell division. Recently, short sperm telomere length has been proposed as a potential biomarker of male infertility.<br><br>OBJECTIVES: To conduct a systematic review and meta-analysis of studies exploring the association between spermatozoa and/or leukocyte telomere length with sperm quality parameters and different infertility conditions.<br><br>MATERIAL AND METHODS: A systematic review and meta-analysis was conducted with studies from Medline-PUBMED and Cochrane Library databases until May 2022. Eligible studies included cohort, cross-sectional and case-control studies, and telomere length in spermatozoa and/or leukocytes cells was defined as the exposure. Semen quality parameters or infertility conditions (e.g., oligozoospermia, asthenozoospermia, teratozoospermia, or other spermatogenic impairment combinations) were defined as the outcomes.<br><br>RESULTS: Twenty-three observational studies were included. In the qualitative analysis, high heterogeneity was observed between studies regarding the associations between telomere length and semen parameters in different normozoospermic/fertile and oligozoospermic/infertile populations. In the meta-analysis, spermatozoa and leukocyte telomere length were shorter in infertile individuals than in fertile individuals (mean difference [95% confidence interval]: -1.43 [-1.66 to -1.21], p-value <0.001&#xa0;and -1.67 [-2.02 to -1.31], p-value <0.001, respectively). Moreover, in terms of sperm telomere length, these differences were also significant between individuals with a normal seminogram and individuals with a low quantity of spermatozoa in the ejaculate (-0.97 [-1.32, -0.61], p-value <0.001).<br><br>CONCLUSION: The current systematic review and meta-analysis suggests the potential role of spermatozoa or leukocyte telomere length as a reliable biomarker of semen quality, which may help distinguish between infertility conditions beyond the routine semen analysis.},
}
@article {pmid37322622,
year = {2023},
author = {Ma, TL and Chang, KF and Huang, XF and Lai, HC and Hsiao, CY and Tsai, NM},
title = {Angelica sinensis extract induces telomere dysfunction, cell cycle arrest, and mitochondria-mediated apoptosis in human glioblastoma cells.},
journal = {The Chinese journal of physiology},
volume = {66},
number = {3},
pages = {119-128},
doi = {10.4103/cjop.CJOP-D-23-00024},
pmid = {37322622},
issn = {0304-4920},
mesh = {Humans ; Mice ; Animals ; *Glioblastoma/drug therapy/metabolism/pathology ; *Telomerase/metabolism/pharmacology/therapeutic use ; Apoptosis ; Cell Cycle Checkpoints ; Cell Cycle ; Cell Proliferation ; Telomere/metabolism/pathology ; Mitochondria ; Cell Line, Tumor ; },
abstract = {Glioblastoma (GB) is one of the most aggressive and malignant tumors of the central nervous system. Conventional treatment for GB requires surgical resection followed by radiotherapy combined with temozolomide chemotherapy; however, the median survival time is only 12-15 months. Angelica sinensis Radix (AS) is commonly used as a traditional medicinal herb or a food/dietary supplement in Asia, Europe, and North America. This study aimed to investigate the effect of AS-acetone extract (AS-A) on the progression of GB and the potential mechanisms underlying its effects. The results indicated that AS-A used in this study showed potency in growth inhibition of GB cells and reduction of telomerase activity. In addition, AS-A blocked the cell cycle at the G0/G1 phase by regulating the expression of p53 and p16. Furthermore, apoptotic morphology, such as chromatin condensation, DNA fragmentation, and apoptotic bodies, was observed in AS-A-treated cells, induced by the activation of the mitochondria-mediated pathway. In an animal study, AS-A reduced tumor volume and prolonged lifespans of mice, with no significant changes in body weight or obvious organ toxicity. This study confirmed the anticancer effects of AS-A by inhibiting cell proliferation, reducing telomerase activity, altering cell cycle progression, and inducing apoptosis. These findings suggest that AS-A has great potential for development as a novel agent or dietary supplement against GB.},
}
@article {pmid37322399,
year = {2023},
author = {Tang, W and Zhan, W and Chen, Q},
title = {The mediating role of telomere length in multi-pollutant exposure associated with metabolic syndrome in adults.},
journal = {Environmental science and pollution research international},
volume = {30},
number = {34},
pages = {82068-82082},
doi = {10.1007/s11356-023-28017-7},
pmid = {37322399},
issn = {1614-7499},
mesh = {Telomere ; *Environmental Pollutants ; *Metabolic Syndrome/epidemiology ; *Environmental Pollution ; Humans ; Male ; Female ; Polycyclic Aromatic Hydrocarbons/analysis ; *Environmental Exposure/statistics &amp; numerical data ; Nutrition Surveys ; Metals ; },
abstract = {Metabolic syndrome is a chronic and complex disease characterized by environmental and genetic factors. However, the underlying mechanisms remain unclear. This study assessed the relationship between exposure to a mixture of environmental chemicals and metabolic syndrome (MetS) and further examined whether telomere length (TL) moderated these relationships. A total of 1265 adults aged > 20 years participated in the study. Data on multiple pollutants (polycyclic aromatic hydrocarbons, phthalates, and metals), MetS, leukocyte telomere length (LTL), and confounders were provided in the 2001-2002 National Health and Nutrition Examination Survey. The correlations between multi-pollutant exposure, TL, and MetS in the males and females were separately assessed using principal component analysis (PCA), logistic and extended linear regression models, Bayesian kernel machine regression (BKMR), and mediation analysis. Four factors were generated in PCA that accounted for 76.2% and 77.5% of the total environmental pollutants in males and females, respectively. The highest quantiles of PC2 and PC4 were associated with the risk of TL shortening (P < 0.05). We observed that the relationship between PC2, PC4, and MetS risk was significant in the participants with median TL levels (P for trend = 0.04 for PC2, and P for trend = 0.01 for PC4). Furthermore, mediation analysis revealed that TL could explain 26.1% and 17.1% of the effects of PC2 and PC4 associated with MetS in males, respectively. The results of BKMR model revealed that these associations were mainly driven by 1-PYE (cPIP = 0.65) and Cd (cPIP = 0.29) in PC2. Meanwhile, TL could explain 17.7% of the mediation effects of PC2 associated with MetS in the females. However, the relationships between pollutants and MetS were sparse and inconsistent in the females. Our findings suggest that the effects of the risk of MetS associated with mixed exposure to multiple pollutants are mediated by TL, and this mediating effect in the males is more pronounced than that in the females.},
}
@article {pmid37322109,
year = {2023},
author = {Chen, J and Wang, Z and Tan, K and Huang, W and Shi, J and Li, T and Hu, J and Wang, K and Wang, C and Xin, B and Zhao, H and Song, W and Hufford, MB and Schnable, JC and Jin, W and Lai, J},
title = {A complete telomere-to-telomere assembly of the maize genome.},
journal = {Nature genetics},
volume = {55},
number = {7},
pages = {1221-1231},
pmid = {37322109},
issn = {1546-1718},
mesh = {*Zea mays/genetics ; *Genomics ; Repetitive Sequences, Nucleic Acid/genetics ; Genome, Plant ; Telomere/genetics ; Sequence Analysis, DNA ; High-Throughput Nucleotide Sequencing ; },
abstract = {A complete telomere-to-telomere (T2T) finished genome has been the long pursuit of genomic research. Through generating deep coverage ultralong Oxford Nanopore Technology (ONT) and PacBio HiFi reads, we report here a complete genome assembly of maize with each chromosome entirely traversed in a single contig. The 2,178.6 Mb T2T Mo17 genome with a base accuracy of over 99.99% unveiled the structural features of all repetitive regions of the genome. There were several super-long simple-sequence-repeat arrays having consecutive thymine-adenine-guanine (TAG) tri-nucleotide repeats up to 235 kb. The assembly of the entire nucleolar organizer region of the 26.8 Mb array with 2,974 45S rDNA copies revealed the enormously complex patterns of rDNA duplications and transposon insertions. Additionally, complete assemblies of all ten centromeres enabled us to precisely dissect the repeat compositions of both CentC-rich and CentC-poor centromeres. The complete Mo17 genome represents a major step forward in understanding the complexity of the highly recalcitrant repetitive regions of higher plant genomes.},
}
@article {pmid37316451,
year = {2023},
author = {Liu, M and Yang, C and Pan, Y and Sun, G},
title = {Comment on 'Causal linkage of tobacco smoking with ageing: Mendelian randomization analysis towards telomere attrition and sarcopenia' by Park et al.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {14},
number = {4},
pages = {1912-1914},
pmid = {37316451},
issn = {2190-6009},
mesh = {Humans ; *Sarcopenia ; Mendelian Randomization Analysis ; Tobacco Smoking ; Aging ; Telomere ; },
}
@article {pmid37299586,
year = {2023},
author = {Novau-Ferré, N and Rojas, M and Gutierrez-Tordera, L and Arcelin, P and Folch, J and Papandreou, C and Bulló, M},
title = {Lipoprotein Particle Profiles Associated with Telomere Length and Telomerase Complex Components.},
journal = {Nutrients},
volume = {15},
number = {11},
pages = {},
pmid = {37299586},
issn = {2072-6643},
mesh = {Humans ; *Telomerase/metabolism ; Telomere Shortening ; Cellular Senescence/genetics ; Oxidative Stress ; Telomere/metabolism ; },
abstract = {Telomere length (TL) is a well-known marker of age-related diseases. Oxidative stress and inflammation increase the rate of telomere shortening, triggering cellular senescence. Although lipoproteins could have anti-inflammatory and proinflammatory functional properties, the relationship between lipoprotein particles with TL and telomerase activity-related genes has not been investigated much. In this study, we assessed the associations of lipoprotein subfractions with telomere length, TERT, and WRAP53 expression in a total of 54 pre-diabetic subjects from the EPIRDEM study. We regressed TL, TERT, and WRAP53 on 12 lipoprotein subclasses, employing a Gaussian linear regression method with Lasso penalty to determine a lipoprotein profile associated with telomere-related parameters. The covariates included age, sex, body mass index (BMI), dyslipidemia, statin consumption, and physical activity leisure time. We identified a lipoprotein profile composed of four lipoprotein subfractions associated with TL (Pearson r = 0.347, p-value = 0.010), two lipoprotein subfractions associated with TERT expression (Pearson r = 0.316, p-value = 0.020), and five lipoprotein subfractions associated with WRAP53 expression (Pearson r = 0.379, p-value =0.005). After adjusting for known confounding factors, most lipoprotein profiles maintained the association with TL, TERT, and WRAP53. Overall, medium and small-sized HDL particles were associated with shorter telomeres and lower expression of TERT and WRAP53. Large HDL particles were associated with longer telomere and lower expression of WRAP53, but not with TERT. Our results suggest that the lipoprotein profiles are associated with telomere length, TERT, and WRAP53 expression and should be considered when assessing the risk of chronic diseases.},
}
@article {pmid37299559,
year = {2023},
author = {Uziel, O and Dickstein, H and Beery, E and Lewis, Y and Loewenthal, R and Uziel, E and Shochat, Z and Weizman, A and Stein, D},
title = {Differences in Telomere Length between Adolescent Females with Anorexia Nervosa Restricting Type and Anorexia Nervosa Binge-Purge Type.},
journal = {Nutrients},
volume = {15},
number = {11},
pages = {},
pmid = {37299559},
issn = {2072-6643},
mesh = {Humans ; Female ; Adolescent ; *Anorexia Nervosa/psychology ; *Feeding and Eating Disorders ; Hospitalization ; Surveys and Questionnaires ; Telomere ; *Bulimia Nervosa/psychology ; },
abstract = {Physiological and psychological distress may accelerate cellular aging, manifested by shortening of telomere length (TL). The present study focused on TL shortening in anorexia nervosa (AN), an illness combining physiological and psychological distress. For that purpose, we measured TL in 44 female adolescents with AN at admission to inpatient treatment, in a subset of 18 patients also at discharge, and in 22 controls. No differences in TL were found between patients with AN and controls. At admission, patients with AN-binge/purge type (AN-B/P; n = 18) showed shorter TL compared with patients with AN-restricting type (AN-R; n = 26). No change in TL was found from admission to discharge, despite an improvement in body mass index standard deviation score (BMI-SDS) following inpatient treatment. Older age was the only parameter assessed to be correlated with greater TL shortening. Several methodological changes have to be undertaken to better understand the putative association of shorter TL with B/P behaviors, including increasing the sample size and the assessment of the relevant pathological eating disorder (ED) and non-ED psychological correlates in the two AN subtypes.},
}
@article {pmid37298208,
year = {2023},
author = {Feng, SW and Wu, ZS and Chiu, YL and Huang, SM},
title = {Exploring the Functional Roles of Telomere Maintenance 2 in the Tumorigenesis of Glioblastoma Multiforme and Drug Responsiveness to Temozolomide.},
journal = {International journal of molecular sciences},
volume = {24},
number = {11},
pages = {},
pmid = {37298208},
issn = {1422-0067},
support = {MND-MAB-D-112069 to S-M Huang//the Ministry of National Defense-Medical Affairs Bureau/ ; A1111035 to S-M Huang//Teh-Tzer Study Group for Human Medical Research Foundation/ ; },
mesh = {Adult ; Humans ; Temozolomide/pharmacology/therapeutic use ; *Glioblastoma/drug therapy/genetics/metabolism ; Reactive Oxygen Species/metabolism ; *Telomerase/genetics/metabolism ; *Glioma/metabolism ; *Brain Neoplasms/drug therapy/genetics/metabolism ; *Central Nervous System Neoplasms/drug therapy ; Carcinogenesis/genetics ; Cell Transformation, Neoplastic ; RNA, Messenger ; Telomere/metabolism ; Cell Line, Tumor ; Antineoplastic Agents, Alkylating/pharmacology/therapeutic use ; Drug Resistance, Neoplasm/genetics ; },
abstract = {Glioblastoma multiforme (GBM) is a grade IV human glioma. It is the most malignant primary central nervous system tumor in adults, accounting for around 15% of intracranial neoplasms and 40-50% of all primary malignant brain tumors. However, the median survival time of GBM patients is still less than 15 months, even after treatment with surgical resection, concurrent chemoradiotherapy, and adjuvant chemotherapy with temozolomide (TMZ). Telomere maintenance 2 (TELO2) mRNA is highly expressed in high-grade glioma patients, and its expression correlates with shorter survival outcomes. Hence, it is urgent to address the functional role of TELO2 in the tumorigenesis and TMZ treatment of GBM. In this study, we knocked down TELO2 mRNA in GBM8401 cells, a grade IV GBM, compared with TELO2 mRNA overexpression in human embryonic glial SVG p12 cells and normal human astrocyte (NHA) cells. We first analyzed the effect of TELO2 on the Elsevier pathway and Hallmark gene sets in GBM8401, SVG p12, and NHA via an mRNA array analysis. Later, we further examined and analyzed the relationship between TELO2 and fibroblast growth factor receptor 3, cell cycle progression, epithelial-mesenchymal transient (EMT), reactive oxygen species (ROS), apoptosis, and telomerase activity. Our data showed that TELO2 is involved in several functions of GBM cells, including cell cycle progression, EMT, ROS, apoptosis, and telomerase activity. Finally, we examined the crosstalk between TELO2 and the responsiveness of TMZ or curcumin mediated through the TELO2-TTI1-TTI2 complex, the p53-dependent complex, the mitochondrial-related complex, and signaling pathways in GBM8401 cells. In summary, our work provides new insight that TELO2 might modulate target proteins mediated through the complex of phosphatidylinositol 3-kinase-related kinases in its involvement in cell cycle progression, EMT, and drug response in GBM patients.},
}
@article {pmid37294548,
year = {2023},
author = {Martínez, P and Sánchez-Vazquez, R and Saha, A and Rodriguez-Duque, MS and Naranjo-Gonzalo, S and Osorio-Chavez, JS and Villar-Ramos, AV and Blasco, MA},
title = {Short telomeres in alveolar type II cells associate with lung fibrosis in post COVID-19 patients with cancer.},
journal = {Aging},
volume = {15},
number = {11},
pages = {4625-4641},
pmid = {37294548},
issn = {1945-4589},
mesh = {Humans ; Mice ; Animals ; *Pulmonary Fibrosis/pathology ; *COVID-19/pathology ; SARS-CoV-2 ; Alveolar Epithelial Cells ; Lung/pathology ; *Neoplasms/pathology ; Telomere/pathology ; },
abstract = {The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic. The severity of COVID-19 increases with each decade of life, a phenomenon that suggest that organismal aging contributes to the fatality of the disease. In this regard, we and others have previously shown that COVID-19 severity correlates with shorter telomeres, a molecular determinant of aging, in patient's leukocytes. Lung injury is a predominant feature of acute SARS-CoV-2 infection that can further progress to lung fibrosis in post-COVID-19 patients. Short or dysfunctional telomeres in Alveolar type II (ATII) cells are sufficient to induce pulmonary fibrosis in mouse and humans. Here, we analyze telomere length and the histopathology of lung biopsies from a cohort of alive post-COVID-19 patients and a cohort of age-matched controls with lung cancer. We found loss of ATII cellularity and shorter telomeres in ATII cells concomitant with a marked increase in fibrotic lung parenchyma remodeling in post- COVID-19 patients compared to controls. These findings reveal a link between presence of short telomeres in ATII cells and long-term lung fibrosis sequel in Post-COVID-19 patients.},
}
@article {pmid37293446,
year = {2023},
author = {Ignatieva, EV and Yudin, NS and Larkin, DM},
title = {Compilation and functional classification of telomere length-associated genes in humans and other animal species.},
journal = {Vavilovskii zhurnal genetiki i selektsii},
volume = {27},
number = {3},
pages = {283-292},
doi = {10.18699/VJGB-23-34},
pmid = {37293446},
issn = {2500-0462},
abstract = {Telomeres are the terminal regions of chromosomes that ensure their stability while cell division. Telomere shortening initiates cellular senescence, which can lead to degeneration and atrophy of tissues, so the process is associated with a reduction in life expectancy and predisposition to a number of diseases. An accelerated rate of telomere attrition can serve as a predictor of life expectancy and health status of an individual. Telomere length is a complex phenotypic trait that is determined by many factors, including the genetic ones. Numerous studies (including genome-wide association studies, GWAS) indicate the polygenic nature of telomere length control. The objective of the present study was to characterize the genetic basis of the telomere length regulation using the GWAS data obtained during the studies of various human and other animal populations. To do so, a compilation of the genes associated with telomere length in GWAS experiments was collected, which included information on 270 human genes, as well as 23, 22, and 9 genes identified in the cattle, sparrow, and nematode, respectively. Among them were two orthologous genes encoding a shelterin protein (POT1 in humans and pot-2 in C. elegans). Functional analysis has shown that telomere length can be influenced by genetic variants in the genes encoding: (1) structural components of telomerase; (2) the protein components of telomeric regions (shelterin and CST complexes); (3) the proteins involved in telomerase biogenesis and regulating its activity; (4) the proteins that regulate the functional activity of the shelterin components; (5) the proteins involved in telomere replication and/or capping; (6) the proteins involved in the alternative telomere lengthening; (7) the proteins that respond to DNA damage and are responsible for DNA repair; (8) RNA-exosome components. The human genes identified by several research groups in populations of different ethnic origins are the genes encoding telomerase components such as TERC and TERT as well as STN1 encoding the CST complex component. Apparently, the polymorphic loci affecting the functions of these genes may be the most reliable susceptibility markers for telomere-related diseases. The systematized data about the genes and their functions can serve as a basis for the development of prognostic criteria for telomere length-associated diseases in humans. Information about the genes and processes that control telomere length can be used for marker-assisted and genomic selection in the farm animals, aimed at increasing the duration of their productive lifetime.},
}
@article {pmid37290379,
year = {2023},
author = {Ford, JL and Pickler, R and Browning, CR and Tarrence, J and Anderson, AM and Kertes, DA},
title = {Associations of depression and anxiety and adolescent telomere length.},
journal = {Psychoneuroendocrinology},
volume = {155},
number = {},
pages = {106310},
pmid = {37290379},
issn = {1873-3360},
support = {R01 DA032371/DA/NIDA NIH HHS/United States ; P2C HD058484/HD/NICHD NIH HHS/United States ; P2C HD042849/HD/NICHD NIH HHS/United States ; R21 DA034960/DA/NIDA NIH HHS/United States ; R01 NR019008/NR/NINR NIH HHS/United States ; R01 MD011727/MD/NIMHD NIH HHS/United States ; },
mesh = {Adult ; Humans ; Male ; Adolescent ; Female ; Child ; *Depression/genetics ; Prospective Studies ; *Anxiety/genetics ; Cellular Senescence ; Telomere ; Telomere Shortening ; },
abstract = {BACKGROUND: Telomere length (TL), a biomarker of cellular aging, is influenced by adverse life experiences. Although depression and anxiety are associated with shorter TL in adults, the relationship in younger ages has received little attention. We examined relationships between depression and anxiety diagnoses and symptomatology and TL in adolescence, an important developmental window for early intervention. Sex differences in relationships were also examined.<br><br>METHODS: Wave 1 survey and TL data from the Adolescent Health and Development in Context study were analyzed (N&#xa0;=&#xa0;995). Depression and anxiety diagnosis were parent-reported measures categorized as: current diagnosis, prior diagnosis, and never diagnosed (reference category). Depressive symptoms were measured via adolescent-report using nine items from the Center for Epidemiologic Studies-Depression scale, short form. Anxiety symptoms were measured via adolescent-report using eight items from the pediatric anxiety scale obtained from the Patient-Reported Outcomes Measurement Information System. Genomic DNA was isolated from 500&#xa0;&#x3bc;L saliva via ethanol precipitation. Genomic DNA TL was assessed using monoplexed quantitative polymerase chain reactions. Relative T/S quantities were calculated in accordance with established procedures. Covariates included sociodemographic factors (sex, age, race/ethnicity, caregiver marital status and education level, and household income), pubertal development, and season of collection. Descriptive and multivariable linear regression analyses were conducted, including an examination of sex as a moderator in the relationships between depression, anxiety, and TL.<br><br>RESULTS: In multivariable analysis, adolescents with a current depression diagnosis (b = -0.26, p&#xa0;<&#xa0;.05), but not a prior diagnosis (b =0.05, p&#xa0;>&#xa0;.05) had shorter TL than those who were never diagnosed; higher depressive symptom scores were associated with shorter TL (b = -0.12, p&#xa0;<&#xa0;.05). No significant associations were found between anxiety diagnosis and TL; however, higher anxiety symptom scores were associated with shorter TL (b = -0.14, p&#xa0;<&#xa0;.01). Sex did not significantly moderate any of the relationships between depression, anxiety and TL.<br><br>CONCLUSIONS: Depression and anxiety were associated with shorter TL in this diverse community sample of adolescents and the findings highlight the potential for impaired mental health to contribute to cellular senescence as early as adolescence. Prospective research on the long-term effect of depression and anxiety occurring earlier in the life span on TL over time is needed, including examination of potential mechanisms that may accelerate or buffer the negative effects of impaired mental health on TL.},
}
@article {pmid37288975,
year = {2023},
author = {Kim, JJ and Ahn, A and Ying, J and Hickman, E and Ludlow, AT},
title = {Exercise as a Therapy to Maintain Telomere Function and Prevent Cellular Senescence.},
journal = {Exercise and sport sciences reviews},
volume = {51},
number = {4},
pages = {150-160},
pmid = {37288975},
issn = {1538-3008},
support = {R00 CA197672/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; *Telomerase/genetics/metabolism ; Telomere/metabolism ; Cellular Senescence/genetics ; },
abstract = {Exercise transiently impacts the expression, regulation, and activity of TERT/telomerase to maintain telomeres and protect the genome from insults. By protecting the telomeres (chromosome ends) and the genome, telomerase promotes cellular survival and prevents cellular senescence. By increasing cellular resiliency, via the actions of telomerase and TERT, exercise promotes healthy aging.},
}
@article {pmid37288004,
year = {2022},
author = {Wang, Z and Li, J and Liu, J and Wang, L and Lu, Y and Liu, JP},
title = {Molecular mechanism of anionic stabilizer for telomere G-quadruplex.},
journal = {Biophysics reports},
volume = {8},
number = {4},
pages = {225-238},
pmid = {37288004},
issn = {2364-3420},
abstract = {Telomere DNA assumes a high-order G-quadruplex (G4) structure, stabilization of which prevents telomere lengthening by telomerase in cancer. Through applying combined molecular simulation methods, an investigation on the selective binding mechanism of anionic phthalocyanine 3,4',4'',4'''-tetrasulfonic acid (APC) and human hybrid (3 + 1) G4s was firstly performed at the atomic level. Compared to the groove binding mode of APC and the hybrid type I (hybrid-I) telomere G4, APC preferred to bind to the hybrid type II (hybrid-II) telomere G4 via end-stacking interactions, which showed much more favorable binding free energies. Analyses of the non-covalent interaction and binding free energy decomposition revealed a decisive role of van der Waals interaction in the binding of APC and telomere hybrid G4s. And the binding of APC and hybrid-II G4 that showed the highest binding affinity adopted the end-stacking binding mode to form the most extensive van der Waals interactions. These findings add new knowledge to the design of selective stabilizers targeting telomere G4 in cancer.},
}
@article {pmid37286532,
year = {2023},
author = {Rai, R and Biju, K and Sun, W and Sodeinde, T and Al-Hiyasat, A and Morgan, J and Ye, X and Li, X and Chen, Y and Chang, S},
title = {Author Correction: Homology directed telomere clustering, ultrabright telomere formation and nuclear envelope rupture in cells lacking TRF2[B] and RAP1.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {3319},
doi = {10.1038/s41467-023-39144-7},
pmid = {37286532},
issn = {2041-1723},
support = {R01 GM141350/GM/NIGMS NIH HHS/United States ; },
}
@article {pmid37284908,
year = {2023},
author = {Altundag, K},
title = {The association of telomere length with exercise and diet might be time-dependent in breast cancer survivors.},
journal = {Breast cancer research and treatment},
volume = {200},
number = {3},
pages = {401},
pmid = {37284908},
issn = {1573-7217},
mesh = {Humans ; Female ; *Breast Neoplasms/genetics/complications ; *Cancer Survivors ; Diet ; Exercise ; Telomere/genetics ; },
}
@article {pmid37284700,
year = {2023},
author = {Martha, SR and Tolentino, EJ and Bugajski, AA and Thompson, HJ},
title = {Telomere Length Associates With Symptom Severity After Mild Traumatic Brain Injury in Older Adults.},
journal = {Neurotrauma reports},
volume = {4},
number = {1},
pages = {350-358},
pmid = {37284700},
issn = {2689-288X},
abstract = {The objectives were to compare differences in telomere length (TL) among younger (21-54 years) and older adults (≥55) with mild traumatic brain injury (mTBI) to non-injured controls and to examine the association between TL and the severity of post-concussive symptoms over time. We performed a quantitative polymerase chain reaction to determine the TL (Kb/genome) of peripheral blood mononuclear cell samples (day 0, 3 months, and 6 months) from 31 subjects. The Rivermead Post-Concussion Symptoms Questionnaire was used to assess symptoms. Group-by-time comparisons of TL and symptom severity were evaluated with repeated-measures analysis of variance. Multiple linear regression examined the relationship between TL, group (mTBI and non-injured controls), and symptom severity total and subscale scores. Significant aging-related differences in TL were found within mTBI groups by time (day 0, 3 months, and 6 months; p = 0.025). Older adults with mTBI experienced significant worsening of changes in total symptom severity scores over time (day 0, 3 months, and 6 months; p = 0.016). Shorter TLs were associated with higher total symptom burden among each of the four groups at day 0 (baseline; p = 0.035) and 3 months (p = 0.038). Shorter TL was also associated with higher cognitive symptom burden among the four groups at day 0 (p = 0.008) and 3 months (p = 0.008). Shorter TL was associated with higher post-injury symptom burden to 3 months in both older and younger persons with mTBI. Large-scale, longitudinal studies of factors associated with TL may be useful to delineate the mechanistic underpinnings of higher symptom burden in adults with mTBI.},
}
@article {pmid37284584,
year = {2023},
author = {Zhang, X and Tong, G},
title = {Antigen-presenting cells maintain T cells proliferation through vesicle transfer of telomeres: A new approach to telomere extension.},
journal = {MedComm},
volume = {4},
number = {3},
pages = {e270},
pmid = {37284584},
issn = {2688-2663},
}
@article {pmid37278929,
year = {2023},
author = {Diukov, Y and Bachinskaya, N and Dzobak, A and Kholin, V and Kyriachenko, Y and Barsukov, O and Zabuha, O and Krasnienkov, D},
title = {Association of Telomere Length with Cognitive Impairment.},
journal = {Journal of molecular neuroscience : MN},
volume = {73},
number = {6},
pages = {448-455},
pmid = {37278929},
issn = {1559-1166},
mesh = {Male ; Humans ; Female ; Aged ; Leukocytes, Mononuclear ; *Depressive Disorder, Major ; *Cognitive Dysfunction/genetics ; *Alzheimer Disease/genetics/diagnosis ; Telomere/genetics ; },
abstract = {Telomere attrition is attributed to Alzheimer's disease (AD), major depressive disorder, stress levels, physical inactivity, short sleep duration, and reduced educational abilities. In this article, we tried to assess the association between the telomere length in peripheral blood leukocytes and level of cognitive impairment and its dependence on age and sex. Healthy subjects and patients with amnestic mild cognitive impairment (aMCI) and different AD stages were recruited in the study. All patients were assessed by the same standard diagnostic procedure, including neurological examination-Mini-Mental State Examination (MMSE). Blood samples from 66 subjects (18 men and 48 women, mean age 71.2 ± 0.56 years) were collected for DNA extraction from peripheral mononuclear cells (PBMC). Relative telomere length (RTL) was measured by monochrome multiplex polymerase chain reaction. The data obtained in the study indicate that RTL in PBMCs has a statistically significant association with MMSE score (p < 0.02). Moreover, the sex-specific difference was observed for the association between telomere length and various parameters of MMSE. Also, it has been found that a decrease in RTL by one unit is associated with an increase in the odds to get AD at a ratio of 2.54 (95% CI, 1.25 to 5.17). The results obtained in this research are in coherence with other studies that telomere length may be a valuable biomarker of cognitive decline. However, the potential need for longitudinal studies of telomere length, in order to estimate the influence of hereditary and environmental factors, remains.},
}
@article {pmid37277368,
year = {2023},
author = {Kroupa, M and Kubecek, O and Tomasova, K and Hanak, P and Krupova, M and Cervena, K and Siskova, A and Rosendorf, J and Hosek, P and Vodickova, L and Vodicka, P and Liska, V and John, S and Vymetalkova, V and Petera, J},
title = {The dynamics of telomere length in primary and metastatic colorectal cancer lesions.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {9097},
pmid = {37277368},
issn = {2045-2322},
mesh = {Humans ; *Colonic Neoplasms ; *Rectal Neoplasms ; Prognosis ; *Liver Neoplasms ; Telomere/genetics/pathology ; *Colorectal Neoplasms/pathology ; Telomere Shortening ; },
abstract = {Telomeric sequences, the structures comprised of hexanucleotide repeats and associated proteins, play a pivotal role in chromosome end protection and preservation of genomic stability. Herein we address telomere length (TL) dynamics in primary colorectal cancer (CRC) tumour tissues and corresponding liver metastases. TL was measured by multiplex monochrome real-time qPCR in paired samples of primary tumours and liver metastases along with non-cancerous reference tissues obtained from 51 patients diagnosed with metastatic CRC. Telomere shortening was observed in the majority of primary tumour tissues compared to non-cancerous mucosa (84.1%, p < 0.0001). Tumours located within the proximal colon had shorter TL than those in the rectum (p < 0.05). TL in liver metastases was not significantly different from that in primary tumours (p = 0.41). TL in metastatic tissue was shorter in the patients diagnosed with metachronous liver metastases than in those diagnosed with synchronous liver metastases (p = 0.03). The metastatic liver lesions size correlated with the TL in metastases (p < 0.05). Following the neoadjuvant treatment, the patients with rectal cancer had shortened telomeres in tumour tissue than prior to the therapy (p = 0.01). Patients with a TL ratio between tumour tissue and the adjacent non-cancerous mucosa of ≥ 0.387 were associated with increased overall survival (p = 0.01). This study provides insights into TL dynamics during progression of the disease. The results show TL differences in metastatic lesions and may help in clinical practice to predict the patient's prognosis.},
}
@article {pmid37276942,
year = {2023},
author = {Rafiq, M and Liaquat, A and Javed, A and Ullah Shah, S and Hussain, R and Akram, Z and Jawad Khan, M},
title = {Association of leukocyte telomere attrition in coronary artery disease in Pakistani population: A case-control study with meta-analysis.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {547},
number = {},
pages = {117416},
doi = {10.1016/j.cca.2023.117416},
pmid = {37276942},
issn = {1873-3492},
mesh = {Humans ; *Coronary Artery Disease/diagnosis/genetics ; Case-Control Studies ; Pakistan ; Telomere/genetics ; Leukocytes ; Cholesterol ; },
abstract = {BACKGROUND: Coronary arteries disease (CAD) is one of the primary causes of mortality worldwide. Genetic, epigenetic and environmental factors have been hypothesized in the pathogenesis of CAD. Leukocyte telomere length (LTL) has been proposed as a potential biomarker for early detection of atherosclerosis. Telomere is the DNA-Protein structure that maintains stability and integrity of chromosomes and is associated with the aging-related cellular mechanisms. This study is designed to investigate the association of LTL with CAD pathogenesis.<br><br>MATERIAL AND METHOD: This prospective case-control study included 100 patients and 100 control individuals. DNA was extracted from the peripheral blood samples, and LTL was measured using real-time PCR. Data were normalized with single copy gene and presented as relative telomere length T/S ratio. Comprehensive meta-analysis was conducted to ascertain the pivotal role of telomere length in CAD pathology across multiple populations.<br><br>RESULTS: Our results showed shorter telomere length in CAD patients as compared to control. The correlation analysis revealed a significant (P-value <0.01) negative correlation between telomere length with basal metabolic index (BMI), total cholesterol, and low-density lipoprotein cholesterol (LDL-C) and a positive correlation with high-density lipoprotein cholesterol (HDL-C). Meta-analysis results indicated a significantly shorter telomere length in the Asian population and a non-significant shorter telomere length in other populations. Receiver operator curve (ROC) analysis demonstrated an area under the curve (AUC) of 0.814 with cut-off value of 0.691 exhibited sensitivity of 72.2%, and specificity of 79.1%, for the diagnosis of CAD.<br><br>CONCLUSION: In conclusion, LTL is associated with the onset of CAD and could be used as a diagnostic predictor to screen individuals with CAD.},
}
@article {pmid37274248,
year = {2023},
author = {Roka, K and Solomou, EE and Kattamis, A},
title = {Telomere biology: from disorders to hematological diseases.},
journal = {Frontiers in oncology},
volume = {13},
number = {},
pages = {1167848},
pmid = {37274248},
issn = {2234-943X},
abstract = {Variations in the length of telomeres and pathogenic variants involved in telomere length maintenance have been correlated with several human diseases. Recent breakthroughs in telomere biology knowledge have contributed to the identification of illnesses named "telomeropathies" and revealed an association between telomere length and disease outcome. This review emphasizes the biology and physiology aspects of telomeres and describes prototype diseases in which telomeres are implicated in their pathophysiology. We also provide information on the role of telomeres in hematological diseases ranging from bone marrow failure syndromes to acute and chronic leukemias.},
}
@article {pmid37273887,
year = {2023},
author = {Mahmoodpoor, A and Sanaie, S and Eskandari, M and Behrouzi, N and Taghizadeh, M and Roudbari, F and Emamalizadeh, B and Sohrabifar, N and Kazeminasab, S},
title = {Association between leukocyte telomere length and COVID-19 severity.},
journal = {The Egyptian journal of medical human genetics},
volume = {24},
number = {1},
pages = {37},
pmid = {37273887},
issn = {2090-2441},
abstract = {BACKGROUND: Inter-individual variations in the clinical manifestations of SARS-CoV-2 infection are among the challenging features of COVID-19. The known role of telomeres in cell proliferation and immune competency highlights their possible function in infectious diseases. Variability in telomere length is an invaluable parameter in the heterogeneity of the clinical presentation of diseases.<br><br>RESULT: In this study, our aim was to investigate the possible association between leukocyte telomere length (LTL) and COVID-19 severity. LTL was measured in 100 patients with moderate and severe forms of COVID-19 using the quantitative PCR (q-PCR) method. Statistical analysis confirmed a strong inverse correlation between relative LTL and COVID-19 severity.<br><br>CONCLUSIONS: These findings suggest that LTL can be a useful parameter for predicting disease severity in patients, as individuals with short telomeres may have a higher risk of developing severe COVID-19.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s43042-023-00415-z.},
}
@article {pmid37268182,
year = {2023},
author = {Wolf, SE and Shalev, I},
title = {The shelterin protein expansion of telomere dynamics: Linking early life adversity, life history, and the hallmarks of aging.},
journal = {Neuroscience and biobehavioral reviews},
volume = {152},
number = {},
pages = {105261},
pmid = {37268182},
issn = {1873-7528},
support = {R01 NR019610/NR/NINR NIH HHS/United States ; R03 AG071549/AG/NIA NIH HHS/United States ; T32 AG049676/AG/NIA NIH HHS/United States ; U01 ES030949/ES/NIEHS NIH HHS/United States ; },
mesh = {Humans ; *Adverse Childhood Experiences ; Shelterin Complex ; Telomere/metabolism ; Telomere-Binding Proteins/genetics/chemistry/metabolism ; Proteins/metabolism ; Aging/genetics ; },
abstract = {Aging is characterized by functional decline occurring alongside changes to several hallmarks of aging. One of the hallmarks includes attrition of repeated DNA sequences found at the ends of chromosomes called telomeres. While telomere attrition is linked to morbidity and mortality, whether and how it causally contributes to lifelong rates of functional decline is unclear. In this review, we propose the shelterin-telomere hypothesis of life history, in which telomere-binding shelterin proteins translate telomere attrition into a range of physiological outcomes, the extent of which may be modulated by currently understudied variation in shelterin protein levels. Shelterin proteins may expand the breadth and timing of consequences of telomere attrition, e.g., by translating early life adversity into acceleration of the aging process. We consider how the pleiotropic roles of shelterin proteins provide novel insights into natural variation in physiology, life history, and lifespan. We highlight key open questions that encourage the integrative, organismal study of shelterin proteins that enhances our understanding of the contribution of the telomere system to aging.},
}
@article {pmid37263999,
year = {2023},
author = {Rouan, A and Pousse, M and Djerbi, N and Porro, B and Bourdin, G and Carradec, Q and Hume, BC and Poulain, J and Lê-Hoang, J and Armstrong, E and Agostini, S and Salazar, G and Ruscheweyh, HJ and Aury, JM and Paz-García, DA and McMinds, R and Giraud-Panis, MJ and Deshuraud, R and Ottaviani, A and Morini, LD and Leone, C and Wurzer, L and Tran, J and Zoccola, D and Pey, A and Moulin, C and Boissin, E and Iwankow, G and Romac, S and de Vargas, C and Banaigs, B and Boss, E and Bowler, C and Douville, E and Flores, M and Reynaud, S and Thomas, OP and Troublé, R and Thurber, RV and Planes, S and Allemand, D and Pesant, S and Galand, PE and Wincker, P and Sunagawa, S and Röttinger, E and Furla, P and Voolstra, CR and Forcioli, D and Lombard, F and Gilson, E},
title = {Telomere DNA length regulation is influenced by seasonal temperature differences in short-lived but not in long-lived reef-building corals.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {3038},
pmid = {37263999},
issn = {2041-1723},
mesh = {Animals ; *Anthozoa/genetics ; Coral Reefs ; Temperature ; Seasons ; DNA/genetics ; },
abstract = {Telomeres are environment-sensitive regulators of health and aging. Here,we present telomere DNA length analysis of two reef-building coral genera revealing that the long- and short-term water thermal regime is a key driver of between-colony variation across the Pacific Ocean. Notably, there are differences between the two studied genera. The telomere DNA lengths of the short-lived, more stress-sensitive Pocillopora spp. colonies were largely determined by seasonal temperature variation, whereas those of the long-lived, more stress-resistant Porites spp. colonies were insensitive to seasonal patterns, but rather influenced by past thermal anomalies. These results reveal marked differences in telomere DNA length regulation between two evolutionary distant coral genera exhibiting specific life-history traits. We propose that environmentally regulated mechanisms of telomere maintenance are linked to organismal performances, a matter of paramount importance considering the effects of climate change on health.},
}
@article {pmid37262296,
year = {2023},
author = {Puglisi, CJ and McDonough, J and Bianco-Miotto, T and Grieger, JA},
title = {General Practitioners perspectives on infant telomere length screening after a pregnancy complication: a qualitative analysis.},
journal = {Family practice},
volume = {},
number = {},
pages = {},
doi = {10.1093/fampra/cmad064},
pmid = {37262296},
issn = {1460-2229},
support = {APP2000905//National Health and Medical Research Council/ ; },
abstract = {BACKGROUND: Pregnancy complications can impact the mother and child's health in the short and longterm resulting in an increased risk of chronic disease later in life. Telomere length is a biomarker of future cardiometabolic diseases and may offer a novel way of identifying offspring most at risk for future chronic diseases.<br><br>OBJECTIVE(S): To qualitatively explore General Practitioners' (GPs) perspectives on the feasibility and uptake for recommending a telomere screening test in children who were born after a pregnancy complication.<br><br>METHODS: Twelve semi-structured interviews were conducted with GPs within metropolitan Adelaide, South Australia. Interviews were audio recorded, transcribed verbatim, and analysed for codes and themes.<br><br>RESULTS: Two themes were generated: ethical considerations and practical considerations. Ethically, the GP participants discussed barriers including consenting on behalf of a child, parental guilt, and the impact of health insurance, whereas viewing it for health promotion was a facilitator. For practical considerations, barriers included the difficulty in identifying people eligible for screening, maintaining medical communication between service providers, and time and financial constraints, whereas linking screening for telomere length with existing screening would facilitate uptake.<br><br>CONCLUSIONS: GPs were generally supportive of potential telomere screening in infants, particularly via a saliva test that could be embedded in current antenatal care. However, several challenges, such as lack of knowledge, ethical considerations, and time and financial constraints, need to be overcome before such a test could be implemented into practice.},
}
@article {pmid37261700,
year = {2023},
author = {Haridoss, M and Ayyasamy, L and Bagepally, BS},
title = {Is COVID-19 severity associated with telomere length? A systematic review and meta-analysis.},
journal = {Virus genes},
volume = {59},
number = {4},
pages = {489-498},
pmid = {37261700},
issn = {1572-994X},
mesh = {Humans ; *COVID-19 ; Telomere Shortening/genetics ; Telomere/genetics ; },
abstract = {Telomere shortening, a marker of cellular aging, has been linked to hospitalization and the severity of COVID-19. In this systematic review and meta-analysis, the mean difference in telomere length between non-severe and severe COVID-19 individuals was pooled to determine the association between short telomeres and COVID-19 severity. Relevant studies were retrieved through searches conducted in PubMed-Medline, Scopus, EMBASE, Medrxiv, Biorxiv, EuroPMC, and SSRN databases up to November 2022. Selected studies were systematically reviewed and assessed for risk of bias using AXIS tool. The standardized mean difference in telomere length between non-severe and severe COVID-19 was pooled using random-effects model. A total of thirteen studies were included in the review, out of which seven (1332 patients with the severe COVID-19 disease and 6321 patients with non-severe COVID-19) were eligible for meta-analysis. The estimated pooled mean difference in Leukocyte telomere length between severe COVID-19 and non-severe COVID-19 was 0.39 (95% CI - 0.02 to 0.81, I[2] = 93.5%) with substantial heterogeneity. Our findings do not provide clear evidence for association of shorter telomere length and severe COVID-19 disease. More extensive studies measuring absolute telomere length with age and gender adjustments are needed to draw definitive conclusions on the potential causal association between telomere shortening and COVID-19 severity.},
}
@article {pmid37260287,
year = {2023},
author = {Kim, Y and Lin, J and Epel, ES and Carver, CS},
title = {A Lens on Caregiver Stress in Cancer: Longitudinal Investigation of Cancer-Related Stress and Telomere Length Among Family Caregivers of Adult Patients With Cancer.},
journal = {Psychosomatic medicine},
volume = {85},
number = {6},
pages = {527-534},
pmid = {37260287},
issn = {1534-7796},
support = {R01 NR016838/NR/NINR NIH HHS/United States ; },
mesh = {Humans ; Adult ; Female ; Middle Aged ; Male ; *Caregivers/psychology ; Stress, Psychological/psychology ; Cellular Senescence ; Family ; Telomere ; *Colorectal Neoplasms ; },
abstract = {OBJECTIVE: Family members are typically the primary caregivers of patients with chronic illnesses. Family caregivers of adult relatives with cancer are a fast-growing population, yet the physical consequences of their stress due to the cancer in the family have been poorly understood. This study examined the bidirectional relations of the perceived stress of family caregivers of individuals recently diagnosed with cancer and leukocyte cellular aging indexed by telomere length for 2 years.<br><br>METHODS: Family caregivers (N = 168; mean age = 51 years, 70% female, 46% Hispanic, 36% spouse to the patient) of patients with colorectal cancer provided psychological data and peripheral blood samples approximately 4 (T1), 12 (T2), and 21 months (T3) after diagnosis. Time-lagged cross-panel modeling was used to test the associations of perceived cancer-related stress and telomere length, controlling for age, sex, and body mass index.<br><br>RESULTS: Cancer-related stress was highest at T1 and decreased by 1 year. Greater cancer-related stress predicted longer telomere length at subsequent assessments for 2 years (&#x3b2; &#x2265; 0.911, p &#x2264; .019). However, telomere length did not change significantly for 2 years overall and did not prospectively predict cancer-related stress over this period.<br><br>CONCLUSIONS: Findings suggest the need to better understand how the perceived stress of colorectal cancer caregivers, which tends to be intense for a relatively short period compared with dementia caregiving, may impact immune cell distributions and telomere length. These findings emphasize the need for further knowledge about psychobiological mechanisms of how cancer caregiving may impact cellular aging.},
}
@article {pmid37259830,
year = {2023},
author = {Nichele, S and Bonfim, C and Junior, LGD and Loth, G and Kuwahara, C and Trennephol, J and Funke, VAM and Marinho, DE and Koliski, A and Rodrigues, AM and Mousquer, RTG and Fasth, A and Lima, ACM and Calado, RT and Pasquini, R},
title = {Hematopoietic cell transplantation for telomere biology diseases: A retrospective single-center cohort study.},
journal = {European journal of haematology},
volume = {111},
number = {3},
pages = {423-431},
doi = {10.1111/ejh.14023},
pmid = {37259830},
issn = {1600-0609},
mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Retrospective Studies ; Cohort Studies ; *Graft vs Host Disease/etiology ; Unrelated Donors ; Telomere/genetics ; Biology ; Transplantation Conditioning/adverse effects ; },
abstract = {BACKGROUND: Telomere biology diseases (TBD) result from defective telomere maintenance, leading to bone marrow failure. The only curative treatment for aplastic anemia related to TBD is a hematopoietic cell transplant (HCT). Although reduced-intensity conditioning (RIC) regimens decrease transplant-related mortality, non-hematological phenotypes represent a major challenge and are associated with poor long-term follow-up outcomes.<br><br>OBJECTIVE: To describe the outcome of TBD patients transplanted for marrow failure.<br><br>STUDY DESIGN: This is a retrospective, single-center study describing the outcomes of 32 consecutive transplants on 29 patients between 1993 and 2019.<br><br>RESULTS: The median age at transplantation was 14&#x2009;years (range, 3-30&#x2009;years). Most patients received a RIC regimen (n&#x2009;=&#x2009;28) and bone marrow (BM) from an unrelated donor (n&#x2009;=&#x2009;16). Four patients received a haploidentical transplant. Chimerism was available for 27 patients with a median time to neutrophil recovery of 20&#x2009;days (13-36&#x2009;days). Primary graft failure occurred in one patient, whereas second graft failure occurred in two. Acute GVHD grade II-IV and moderate to severe chronic GVHD occurred in 22% of patients at risk. Fourteen patients were alive after HCT at the last follow-up (median, 6&#x2009;years; 1.4-19&#x2009;years). The 5-year overall survival was better after matched sibling donor (MSD) transplantation compared to other hematopoietic stem cell sources (88.9% vs. 47.7%; p&#x2009;=&#x2009;.05; CI&#x2009;=&#x2009;95%). Overall, 15 patients died after HCT, most of them (n&#x2009;=&#x2009;11) after the first year of transplant, due to non-hematological disease progression or complication of chronic GVHD.<br><br>CONCLUSIONS: Hematopoietic cell transplantation is a potentially curative treatment option for TBD, nonetheless the poor outcome reflects the progression of non-hematologic disease manifestations, which should be considered when transplantation is indicated.},
}
@article {pmid37259606,
year = {2023},
author = {Bloom, SI and Liu, Y and Tucker, JR and Islam, MT and Machin, DR and Abdeahad, H and Thomas, TG and Bramwell, RC and Lesniewski, LA and Donato, AJ},
title = {Endothelial cell telomere dysfunction induces senescence and results in vascular and metabolic impairments.},
journal = {Aging cell},
volume = {22},
number = {8},
pages = {e13875},
pmid = {37259606},
issn = {1474-9726},
support = {F31 AG076312/AG/NIA NIH HHS/United States ; R00 AT010017/AT/NCCIH NIH HHS/United States ; R01 AG048366/AG/NIA NIH HHS/United States ; R01 AG060395/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Animals ; Mice ; *Endothelial Cells/metabolism ; *Telomere ; Cellular Senescence/genetics ; Shelterin Complex ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Inflammation/genetics/metabolism ; },
abstract = {In advanced age, increases in oxidative stress and inflammation impair endothelial function, which contributes to the development of cardiovascular disease (CVD). One plausible source of this oxidative stress and inflammation is an increase in the abundance of senescent endothelial cells. Cellular senescence is a cell cycle arrest that occurs in response to various damaging stimuli. In the present study, we tested the hypothesis that advanced age results in endothelial cell telomere dysfunction that induces senescence. In both human and mouse endothelial cells, advanced age resulted in an increased abundance of dysfunctional telomeres, characterized by activation of DNA damage signaling at telomeric DNA. To test whether this results in senescence, we selectively reduced the telomere shelterin protein telomere repeat binding factor 2 (Trf2) from endothelial cells of young mice. Trf2 reduction increased endothelial cell telomere dysfunction and resulted in cellular senescence. Furthermore, induction of endothelial cell telomere dysfunction increased inflammatory signaling and oxidative stress, resulting in impairments in endothelial function. Finally, we demonstrate that endothelial cell telomere dysfunction-induced senescence impairs glucose tolerance. This likely occurs through increases in inflammatory signaling in the liver and adipose tissue, as well as reductions in microvascular density and vasodilation to metabolic stimuli. Cumulatively, the findings of the present study identify age-related telomere dysfunction as a mechanism that leads to endothelial cell senescence. Furthermore, these data provide compelling evidence that senescent endothelial cells contribute to age-related increases in oxidative stress and inflammation that impair arterial and metabolic function.},
}
@article {pmid37258936,
year = {2023},
author = {Huang, P and Li, Q},
title = {Comments on the effects of exercise and diet on oxidative stress and telomere length in breast cancer survivors.},
journal = {Breast cancer research and treatment},
volume = {200},
number = {3},
pages = {399},
pmid = {37258936},
issn = {1573-7217},
mesh = {Humans ; Female ; *Breast Neoplasms/genetics ; *Cancer Survivors ; Diet ; Oxidative Stress ; Telomere/genetics ; },
}
@article {pmid37258109,
year = {2023},
author = {Ashe, JJ and Evans, MK and Zonderman, AB and Waldstein, SR},
title = {Absent Relations of Religious Coping to Telomere Length in African American and White Women and Men.},
journal = {Experimental aging research},
volume = {},
number = {},
pages = {1-23},
pmid = {37258109},
issn = {1096-4657},
support = {R01 AG034161/AG/NIA NIH HHS/United States ; ZIA AG000513/ImNIH/Intramural NIH HHS/United States ; },
abstract = {OBJECTIVES: This study investigated whether race and sex moderated the relations of religious coping to telomere length (TL), a biomarker of cellular aging implicated in race-related health disparities.<br><br>METHODS: Participant data were drawn from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study, which included 252 socioeconomically diverse African American and White men and women aged (30-64&#x2009;years old). Cross-sectional multivariable regression analyses examined interactive associations of religious coping, race, and sex to TL, adjusting for other sociodemographic characteristics.<br><br>RESULTS: Religious coping was unrelated to TL in this sample (p's > .05). There were no notable race or sex differences. Post hoc exploratory analyses similarly found that neither secular social support coping use nor substance use coping was associated with TL.<br><br>CONCLUSION: There was no evidence to support that religious coping use provided protective effects to TL in this sample of African American and White women and men. Nevertheless, future studies should use more comprehensive assessments of religious coping and intersectional identities to provide an in-depth examination of religiosity/spirituality as a potential culturally salient protective factor in cellular aging among African Americans in the context of specific chronic stressors such as discrimination.},
}
@article {pmid37254630,
year = {2023},
author = {Liu, R and Xiang, M and Pilling, LC and Melzer, D and Wang, L and Manning, KJ and Steffens, DC and Bowden, J and Fortinsky, RH and Kuchel, GA and Rhee, TG and Diniz, BS and Kuo, CL},
title = {Mid-life leukocyte telomere length and dementia risk: An observational and mendelian randomization study of 435,046 UK Biobank participants.},
journal = {Aging cell},
volume = {22},
number = {7},
pages = {e13808},
pmid = {37254630},
issn = {1474-9726},
support = {P30 AG067988/AG/NIA NIH HHS/United States ; R21 NR018963/NR/NINR NIH HHS/United States ; R21NR018963-01A1S1/NR/NINR NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; Mendelian Randomization Analysis ; Biological Specimen Banks ; Leukocytes ; Telomere/genetics/pathology ; United Kingdom ; },
abstract = {Telomere attrition is one of biological aging hallmarks and may be intervened to target multiple aging-related diseases, including Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). The objective of this study was to assess associations of leukocyte telomere length (TL) with AD/ADRD and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging (MRI) phenotypes. Data from European-ancestry participants in the UK Biobank (n = 435,046) were used to evaluate whether mid-life leukocyte TL is associated with incident AD/ADRD over a mean follow-up of 12.2 years. In a subsample without AD/ADRD and with brain imaging data (n = 43,390), we associated TL with brain MRI phenotypes related to AD or vascular dementia pathology. Longer TL was associated with a lower risk of incident AD/ADRD (adjusted Hazard Ratio [aHR] per SD = 0.93, 95% CI 0.90-0.96, p = 3.37 × 10[-7]). Longer TL also was associated with better cognitive performance in specific cognitive domains, larger hippocampus volume, lower total volume of white matter hyperintensities, and higher fractional anisotropy and lower mean diffusivity in the fornix. In conclusion, longer TL is inversely associated with AD/ADRD, cognitive impairment, and brain structural lesions toward the development of AD/ADRD. However, the relationships between genetically determined TL and the outcomes above were not statistically significant based on the results from Mendelian randomization analysis results. Our findings add to the literature of prioritizing risk for AD/ADRD. The causality needs to be ascertained in mechanistic studies.},
}
@article {pmid37246640,
year = {2023},
author = {Fernandes, RV and Lingner, J},
title = {The THO complex counteracts TERRA R-loop-mediated telomere fragility in telomerase+ cells and telomeric recombination in ALT+ cells.},
journal = {Nucleic acids research},
volume = {51},
number = {13},
pages = {6702-6722},
pmid = {37246640},
issn = {1362-4962},
mesh = {Humans ; *Telomerase/genetics/metabolism ; R-Loop Structures ; Telomere/genetics/metabolism ; Telomere Homeostasis ; *RNA, Long Noncoding/genetics ; Recombination, Genetic ; },
abstract = {Telomeres are the nucleoprotein structures at the ends of linear chromosomes. Telomeres are transcribed into long non-coding Telomeric Repeat-Containing RNA (TERRA), whose functions rely on its ability to associate with telomeric chromatin. The conserved THO complex (THOC) was previously identified at human telomeres. It links transcription with RNA processing, decreasing the accumulation of co-transcriptional DNA:RNA hybrids throughout the genome. Here, we explore the role of THOC at human telomeres, as a regulator of TERRA localization to chromosome ends. We show that THOC counteracts TERRA association with telomeres via R-loops formed co-transcriptionally and also post-transcriptionally, in trans. We demonstrate that THOC binds nucleoplasmic TERRA, and that RNaseH1 loss, which increases telomeric R-loops, promotes THOC occupancy at telomeres. Additionally, we show that THOC counteracts lagging and mainly leading strand telomere fragility, suggesting that TERRA R-loops can interfere with replication fork progression. Finally, we observed that THOC suppresses telomeric sister-chromatid exchange and C-circle accumulation in ALT cancer cells, which maintain telomeres by recombination. Altogether, our findings reveal crucial roles of THOC in telomeric homeostasis through the co- and post-transcriptional regulation of TERRA R-loops.},
}
@article {pmid37245595,
year = {2023},
author = {Zhu, X and Li, Z and Wang, Z and Guo, C and Qian, Y and Wang, Z and Li, X and Wei, Y},
title = {Associations between exposure to ambient air pollution and changes in blood telomeres in young people: A repeated-measure study.},
journal = {Chemosphere},
volume = {336},
number = {},
pages = {139053},
doi = {10.1016/j.chemosphere.2023.139053},
pmid = {37245595},
issn = {1879-1298},
mesh = {Humans ; Adolescent ; Nitrogen Dioxide/analysis ; Environmental Exposure/analysis ; *Air Pollution/analysis ; *Air Pollutants/toxicity/analysis ; Particulate Matter/toxicity/analysis ; *Ozone/toxicity/analysis ; Sulfur Dioxide/analysis ; Telomere ; China ; },
abstract = {Telomere length (TL) is one of the early biomarkers of aging. Air pollutants play an important role in promoting the aging process. However, few studies have explored how they adversely affect human health by altering telomeres. This study aims to investigate the associations between telomere alterations and exposure to ambient air pollutants, thereby shedding light on the intrinsic and profound link between these pollutants and aging. We recruited 26 healthy young people and conducted 7 repeated measure studies from 2019 to 2021, and TL and telomerase (TA) in the blood samples. We analyzed the associations between air pollutants, including ozone (O3), particulate matter in diameter smaller than 2.5 μm (PM2.5) and 10 μm (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO) and telomere variability, and explored the lagged effects by linear mixed-effects model. The result showed that short-term exposure to O3 was negatively associated with TL, and this effect in the lag days went up to around 0. In contrast, the associations between O3 and TA presented positive tendency and gradually decreased to around 0 in the lag days. The association between PM2.5 and TL showed positive tendency and gradually decreased to negative. There was no statistically significant association between PM2.5 and TA. Other pollutants (PM10, NO2, SO2, CO) showed similar patterns of variation to that of PM2.5. Our findings suggest that short-term exposure to O3 shortens TL, which can be gradually recovered through activating TA activity, while exposure to PM2.5, PM10, NO2, SO2 and CO lengthens TL and then becomes shorter over time. This implies that the human body has some ability to self-repair telomere changes after exposure to air pollutants, and predictably, when this exposure exceeds a certain threshold, it cannot be repaired, leading to aging of the body.},
}
@article {pmid37239399,
year = {2023},
author = {Gouhier, C and Pons-Rejraji, H and Dollet, S and Chaput, L and Bourgne, C and Berger, M and Pereira, B and Tchirkov, A and Brugnon, F},
title = {Freezing Does Not Alter Sperm Telomere Length despite Increasing DNA Oxidation and Fragmentation.},
journal = {Genes},
volume = {14},
number = {5},
pages = {},
pmid = {37239399},
issn = {2073-4425},
mesh = {Male ; Animals ; Freezing ; *Spermatozoa ; *Semen Analysis/methods ; DNA ; Telomere/genetics ; },
abstract = {Correlations were reported between sperm telomere length (STL) and male fertility, sperm DNA fragmentation, and oxidation. Sperm freezing is widely used for assisted reproductive techniques, fertility preservation, and sperm donation. However, its impact on STL remains unknown. For this study, semen surplus from patients who underwent routine semen analysis were used. The impact of slow freezing on STL was analyzed by performing qPCR before and after freezing. Sperm populations with different STL were evaluated using Q-FISH. The relationship between sperm DNA oxidation, DNA fragmentation, and STL was assessed in fresh and frozen sperm samples. No significant impact of slow freezing on STL was observed, neither measured by qPCR nor Q-FISH. However, Q-FISH allowed for the distinguishing of sperm populations with different STLs within individual sperm samples. Slow freezing induced different STL distributions for some of the analyzed sperm samples, but no correlation was found between STL and sperm DNA fragmentation or oxidation. Slow freezing does not alter STL despite increasing sperm DNA oxidation and fragmentation. As STL alterations could be transmitted to offspring, the lack of impact of the slow freezing method on STL ensures the safety of this procedure.},
}
@article {pmid37239390,
year = {2023},
author = {Hill, C and Duffy, S and Kettyle, LM and McGlynn, L and Sandholm, N and Salem, RM and Thompson, A and Swan, EJ and Kilner, J and Rossing, P and Shiels, PG and Lajer, M and Groop, PH and Maxwell, AP and McKnight, AJ and On Behalf Of The Genie Consortium, },
title = {Differential Methylation of Telomere-Related Genes Is Associated with Kidney Disease in Individuals with Type 1 Diabetes.},
journal = {Genes},
volume = {14},
number = {5},
pages = {},
pmid = {37239390},
issn = {2073-4425},
support = {MC_PC_20026/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; Aged ; *Diabetes Mellitus, Type 1/complications/genetics ; *Diabetic Nephropathies/genetics/metabolism ; *Kidney Failure, Chronic/genetics ; DNA Methylation/genetics ; Telomere/genetics/metabolism ; },
abstract = {Diabetic kidney disease (DKD) represents a major global health problem. Accelerated ageing is a key feature of DKD and, therefore, characteristics of accelerated ageing may provide useful biomarkers or therapeutic targets. Harnessing multi-omics, features affecting telomere biology and any associated methylome dysregulation in DKD were explored. Genotype data for nuclear genome polymorphisms in telomere-related genes were extracted from genome-wide case-control association data (n = 823 DKD/903 controls; n = 247 end-stage kidney disease (ESKD)/1479 controls). Telomere length was established using quantitative polymerase chain reaction. Quantitative methylation values for 1091 CpG sites in telomere-related genes were extracted from epigenome-wide case-control association data (n = 150 DKD/100 controls). Telomere length was significantly shorter in older age groups (p = 7.6 × 10[-6]). Telomere length was also significantly reduced (p = 6.6 × 10[-5]) in DKD versus control individuals, with significance remaining after covariate adjustment (p = 0.028). DKD and ESKD were nominally associated with telomere-related genetic variation, with Mendelian randomisation highlighting no significant association between genetically predicted telomere length and kidney disease. A total of 496 CpG sites in 212 genes reached epigenome-wide significance (p ≤ 10[-8]) for DKD association, and 412 CpG sites in 193 genes for ESKD. Functional prediction revealed differentially methylated genes were enriched for Wnt signalling involvement. Harnessing previously published RNA-sequencing datasets, potential targets where epigenetic dysregulation may result in altered gene expression were revealed, useful as potential diagnostic and therapeutic targets for intervention.},
}
@article {pmid37238614,
year = {2023},
author = {Chieffi Baccari, G and Iurato, G and Santillo, A and Dale, B},
title = {Male Germ Cell Telomeres and Chemical Pollutants.},
journal = {Biomolecules},
volume = {13},
number = {5},
pages = {},
pmid = {37238614},
issn = {2218-273X},
mesh = {Male ; Humans ; *Seeds ; Telomere/genetics ; Germ Cells/metabolism ; Spermatozoa ; *Infertility, Male ; },
abstract = {In recent decades, male infertility has been correlated with the shortening of sperm telomeres. Telomeres regulate the reproductive lifespan by mediating the synapsis and homologous recombination of chromosomes during gametogenesis. They are composed of thousands of hexanucleotide DNA repeats (TTAGGG) that are coupled to specialized shelterin complex proteins and non-coding RNAs. Telomerase activity in male germ cells ensures that the telomere length is maintained at maximum levels during spermatogenesis, despite telomere shortening due to DNA replication or other genotoxic factors such as environmental pollutants. An emerging body of evidence has associated an exposure to pollutants with male infertility. Although telomeric DNA may be one of the important targets of environmental pollutants, only a few authors have considered it as a conventional parameter for sperm function. The aim of this review is to provide comprehensive and up-to-date data on the research carried out so far on the structure/function of telomeres in spermatogenesis and the influence of environmental pollutants on their functionality. The link between pollutant-induced oxidative stress and telomere length in germ cells is discussed.},
}
@article {pmid37236462,
year = {2023},
author = {Zhang, Q and Han, XZ and Burraco, P and Hao, X and Teng, LW and Liu, ZS and Zhang, FS and Du, WG},
title = {Telomere length, oxidative stress and their links with growth and survival in a lizard facing climate warming.},
journal = {The Science of the total environment},
volume = {891},
number = {},
pages = {164424},
doi = {10.1016/j.scitotenv.2023.164424},
pmid = {37236462},
issn = {1879-1026},
mesh = {Humans ; Animals ; *Lizards/physiology ; Telomere Shortening ; Telomere ; Temperature ; Climate Change ; Oxidative Stress ; },
abstract = {Higher temperatures enhance ectothermic metabolism and development, which can reduce individual health and life expectancy, and therefore increase their vulnerability to climate warming. However, the mechanistic causes and consequences of such a temperature-driven impact remain unclear. Our study aimed to address two questions: (1) does climate warming alter early-life growth and physiology, and, if so, what are the associated carry-over effects in terms of reduced survival, increased oxidative stress and telomere shortening? (2) can oxidative stress and telomere dynamics at early life stages predict the effect of climate warming on individual survival? To answer these questions, we conducted a longitudinal experiment under semi-natural conditions where we exposed multiocellated racerunner (Eremias multiocellata) to warming conditions from juvenile to adult stages. We found that exposure to climate warming enhanced growth rates, induced oxidative stress, and shortened telomere length of juvenile lizards. Warming conditions did not induce carry-over effects in terms of altered growth rate or physiology but resulted in increased mortality risk in the later life. Intriguingly, telomere shortening in young individuals was associated with mortality risk later in life. This study improves our mechanistic understanding of how global warming impacts on ectotherms' life-history traits, which encourages the inclusion of physiological information in assessing species vulnerability to climate change.},
}
@article {pmid37235262,
year = {2023},
author = {Zhou, F and Guo, C and Wang, L and Zhang, G and Wang, J and Chen, W and Cui, K and Tan, Y and Zhou, Z},
title = {Mono-(2-ethylhexyl) Phthalate (MEHP)-Induced Telomere Structure and Function Disorder Mediates Cell Cycle Dysregulation and Apoptosis via c-Myc and Its Upstream Transcription Factors in a Mouse Spermatogonia-Derived (GC-1) Cell Line.},
journal = {Toxics},
volume = {11},
number = {5},
pages = {},
pmid = {37235262},
issn = {2305-6304},
support = {2018YFC1004201//Ministry of Science and Technology/ ; },
abstract = {As a typical environmental endocrine disrupting chemical (EDC), di-(2-ethylhexyl) phthalate (DEHP) is thought to be related to reproductive disorders, especially in males. Growing evidence suggests that various EDCs may result in an impaired telomere structure and function, which is associated with male infertility. However, the adverse effect of DEHP on telomeres in male reproductive cells has rarely been studied, and the related mechanisms remain unclear. In this study, we tested the effects of mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of DEHP, on telomere dysfunction in mouse spermatogonia-derived cells (GC-1) and the potential role of TERT and c-Myc in MEHP-induced spermatogenic cell damage. Results showed that MEHP induced cell viability inhibition, G0/G1 phase cell cycle arrest, and apoptosis in GC-1 cells in a dose-dependent manner. Shortened telomeres, reduced telomerase activity, and decreased expression of TERT, c-Myc, and upstream transcription factors of c-Myc were also observed in the MEHP-treated cells. In conclusion, it can be concluded that TERT-mediated telomere dysfunction may contribute to MEHP-induced G0/G1 phase cell cycle arrest and apoptosis in GC-1 cells through the impairment of c-Myc and its upstream transcription factors.},
}
@article {pmid37232505,
year = {2023},
author = {Chen, B and Yan, Y and Wang, H and Xu, J},
title = {Association between genetically determined telomere length and health-related outcomes: A systematic review and meta-analysis of Mendelian randomization studies.},
journal = {Aging cell},
volume = {22},
number = {7},
pages = {e13874},
pmid = {37232505},
issn = {1474-9726},
mesh = {Humans ; Mendelian Randomization Analysis/methods ; *Arthritis, Rheumatoid ; *Glioma ; *Hypertension ; Telomere/genetics ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; },
abstract = {Emerging evidence has shown that leukocyte telomere length (LTL) is associated with various health-related outcomes, while the causality of these associations remains unclear. We performed a systematic review and meta-analysis of current evidence from Mendelian randomization (MR) studies on the association between LTL and health-related outcomes. We searched PubMed, Embase, and Web of Science up to April 2022 to identify eligible MR studies. We graded the evidence level of each MR association based on the results of the main analysis and four sensitive MR methods, MR-Egger, weighted median, MR-PRESSO, and multivariate MR. Meta-analyses of published MR studies were also performed. A total of 62 studies with 310 outcomes and 396 MR associations were included. Robust evidence level was observed for the association between longer LTL and increased risk of 24 neoplasms (the strongest magnitude for osteosarcoma, GBM, glioma, thyroid cancer, and non-GBM glioma), six genitourinary and digestive system outcomes of excessive or abnormal growth, hypertension, metabolic syndrome, multiple sclerosis, and clonal hematopoiesis of indeterminate potential. Robust inverse association was observed for coronary heart disease, chronic kidney disease, rheumatoid arthritis, juvenile idiopathic arthritis, idiopathic pulmonary fibrosis, and facial aging. Meta-analyses of MR studies suggested that genetically determined LTL was associated with 12 neoplasms and 9 nonneoplasm outcomes. Evidence from published MR studies supports that LTL plays a causal role in various neoplastic and nonneoplastic diseases. Further research is required to elucidate the underlying mechanisms and to bring insight into the potential prediction, prevention, and therapeutic applications of telomere length.},
}
@article {pmid37232367,
year = {2023},
author = {Tsatsakis, A and Oikonomopoulou, T and Nikolouzakis, TK and Vakonaki, E and Tzatzarakis, M and Flamourakis, M and Renieri, E and Fragkiadaki, P and Iliaki, E and Bachlitzanaki, M and Karzi, V and Katsikantami, I and Kakridonis, F and Hatzidaki, E and Tolia, M and Svistunov, AA and Spandidos, DA and Nikitovic, D and Tsiaoussis, J and Berdiaki, A},
title = {Role of telomere length in human carcinogenesis (Review).},
journal = {International journal of oncology},
volume = {63},
number = {1},
pages = {},
pmid = {37232367},
issn = {1791-2423},
mesh = {Humans ; *Neoplasms/genetics/pathology ; Telomere/genetics/metabolism ; Carcinogenesis ; Chromosomal Instability ; DNA ; *Telomerase/genetics ; },
abstract = {Cancer is considered the most important clinical, social and economic issue regarding cause‑specific disability‑adjusted life years among all human pathologies. Exogenous, endogenous and individual factors, including genetic predisposition, participate in cancer triggering. Telomeres are specific DNA structures positioned at the end of chromosomes and consist of repetitive nucleotide sequences, which, together with shelterin proteins, facilitate the maintenance of chromosome stability, while protecting them from genomic erosion. Even though the connection between telomere status and carcinogenesis has been identified, the absence of a universal or even a cancer‑specific trend renders consent even more complex. It is indicative that both short and long telomere lengths have been associated with a high risk of cancer incidence. When evaluating risk associations between cancer and telomere length, a disparity appears to emerge. Even though shorter telomeres have been adopted as a marker of poorer health status and an older biological age, longer telomeres due to increased cell growth potential are associated with the acquirement of cancer‑initiating somatic mutations. Therefore, the present review aimed to comprehensively present the multifaceted pattern of telomere length and cancer incidence association.},
}
@article {pmid37231745,
year = {2023},
author = {Naspolini, NF and Sichieri, R and Barbosa Cunha, D and Alves Pereira, R and Faerstein, E},
title = {Dietary patterns, obesity markers and leukocyte telomere length among Brazilian civil servants: cross-sectional results from the Pro-Saude study.},
journal = {Public health nutrition},
volume = {26},
number = {10},
pages = {2076-2082},
pmid = {37231745},
issn = {1475-2727},
mesh = {Humans ; Cross-Sectional Studies ; *Leptin ; Brazil ; Cohort Studies ; *Adiponectin ; Obesity ; Diet ; Leukocytes ; Telomere ; Feeding Behavior ; },
abstract = {OBJECTIVE: Dietary patterns express the combination and variety of foods in the diet. The partial least squares method allows extracting dietary patterns related to a specific health outcome. Few studies have evaluated obesity-related dietary patterns associated with telomeres length. This study aims to identify dietary patterns explaining obesity markers and to assess their association with leukocyte telomere length (LTL), a biological marker of the ageing process.<br><br>DESIGN: Cross-sectional study.<br><br>SETTING: University campuses in the state of Rio de Janeiro, Brazil.<br><br>PARTICIPANTS: 478 participants of a civil servants' cohort study with data on food consumption, obesity measurements (total body fat, visceral fat, BMI, leptin and adiponectin) and blood samples.<br><br>RESULTS: Three dietary patterns were extracted: (1) fast food and meat; (2) healthy and (3) traditional pattern, which included rice and beans, the staple foods most consumed in Brazil. All three dietary patterns explained 23&#xb7;2 % of food consumption variation and 10&#xb7;7 % of the obesity-related variables. The fast food and meat pattern were the first factor extracted, explaining 11-13 % variation of the obesity-related response variables (BMI, total body fat and visceral fat), leptin and adiponectin showed the lowest percentage (4&#xb7;5-0&#xb7;1 %). The healthy pattern mostly explained leptin and adiponectin variations (10&#xb7;7 and 3&#xb7;3 %, respectively). The traditional pattern was associated with LTL (&#x3b2; = 0&#xb7;0117; 95 % CI 0&#xb7;0001, 0&#xb7;0233) after adjustment for the other patterns, age, sex, exercise practice, income and energy intake.<br><br>CONCLUSION: Leukocyte telomere length was longer among participants eating a traditional dietary pattern that combines fruit, vegetables and beans.},
}
@article {pmid37231173,
year = {2023},
author = {Jacome Burbano, MS and Robin, JD and Bauwens, S and Martin, M and Donati, E and Martínez, L and Lin, P and Sacconi, S and Magdinier, F and Gilson, E},
title = {Non-canonical telomere protection role of FOXO3a of human skeletal muscle cells regulated by the TRF2-redox axis.},
journal = {Communications biology},
volume = {6},
number = {1},
pages = {561},
pmid = {37231173},
issn = {2399-3642},
mesh = {Humans ; *Telomere ; *Telomeric Repeat Binding Protein 2/genetics ; Cellular Senescence ; Aging/metabolism ; Muscle Fibers, Skeletal ; Muscle, Skeletal ; },
abstract = {Telomeric repeat binding factor 2 (TRF2) binds to telomeres and protects chromosome ends against the DNA damage response and senescence. Although the expression of TRF2 is downregulated upon cellular senescence and in various aging tissues, including skeletal muscle tissues, very little is known about the contribution of this decline to aging. We previously showed that TRF2 loss in myofibers does not trigger telomere deprotection but mitochondrial dysfunction leading to an increased level of reactive oxygen species. We show here that this oxidative stress triggers the binding of FOXO3a to telomeres where it protects against ATM activation, revealing a previously unrecognized telomere protective function of FOXO3a, to the best of our knowledge. We further showed in transformed fibroblasts and myotubes that the telomere properties of FOXO3a are dependent on the C-terminal segment of its CR2 domain (CR2C) but independent of its Forkhead DNA binding domain and of its CR3 transactivation domain. We propose that these non-canonical properties of FOXO3a at telomeres play a role downstream of the mitochondrial signaling induced by TRF2 downregulation to regulate skeletal muscle homeostasis and aging.},
}
@article {pmid37230863,
year = {2023},
author = {Liu, Q and Song, L and Fan, G and Wu, M and Bi, J and Xu, L and Xiong, C and Xia, W and Cao, Z and Xu, S and Wang, Y},
title = {Associations of self-reported sleep duration and sleep quality during pregnancy with newborn telomere length.},
journal = {Sleep health},
volume = {9},
number = {4},
pages = {475-481},
doi = {10.1016/j.sleh.2023.03.001},
pmid = {37230863},
issn = {2352-7226},
mesh = {Child ; Pregnancy ; Humans ; Infant, Newborn ; Female ; Cohort Studies ; Self Report ; *Sleep Quality ; *Sleep Duration ; Parturition ; Telomere ; },
abstract = {BACKGROUND: Telomere length (TL) at birth is considered a potential biomarker for lifelong health. Although maternal sleep disturbance has been linked to a series of adverse pregnancy outcomes, evidence on the effect of maternal sleep on newborn TL remains scarce. Therefore, we aim to investigate the association of maternal sleep duration and sleep quality with newborn TL.<br><br>METHODS: A total of 742 mother-newborn pairs were recruited from Wuhan Children's Hospital between November 2013 and March 2015. Cord blood TL was measured using real-time quantitative polymerase chain reaction. Maternal sleep duration and quality during late pregnancy were obtained via questionnaires. Multivariate linear regression models were used to estimate the effects of maternal sleep duration and sleep quality on newborn TL.<br><br>RESULTS: A total of 742 maternal-newborn pairs were included in the analyses. Mothers sleeping &#x2265;10&#xa0;hours had a 9.30% (95% CI: 2.09%, 15.99%) shorter newborn TL than those sleeping 7-<9&#xa0;hours. However, the association in mothers with short sleep duration (<7&#xa0;hours) did not reach statistical significance. Compared to mothers with good sleep quality, those with poor sleep quality had a 9.91% (95% CI: 4.06%, 15.40%) shorter newborn TL. We observed a joint effect of sleep duration and sleep quality on newborn telomere shortening. Women with sleep duration &#x2265;10&#xa0;hours and poor sleep quality were most likely to have newborns with short TL (percent change:-19.66%, 95% CI: -28.42, -9.84%).<br><br>CONCLUSIONS: Long sleep duration and poor sleep quality during late pregnancy were associated with shorter newborn TL.},
}
@article {pmid37230028,
year = {2023},
author = {Giunco, S and Padovan, M and Angelini, C and Cavallin, F and Cerretti, G and Morello, M and Caccese, M and Rizzo, B and d'Avella, D and Puppa, AD and Chioffi, F and De Bonis, P and Zagonel, V and De Rossi, A and Lombardi, G},
title = {Prognostic role and interaction of TERT promoter status, telomere length and MGMT promoter methylation in newly diagnosed IDH wild-type glioblastoma patients.},
journal = {ESMO open},
volume = {8},
number = {3},
pages = {101570},
pmid = {37230028},
issn = {2059-7029},
mesh = {Humans ; Prognosis ; *Glioblastoma/genetics ; Isocitrate Dehydrogenase/genetics ; Retrospective Studies ; Methylation ; Prospective Studies ; *Brain Neoplasms/diagnosis ; Telomere ; *Telomerase/genetics ; DNA Modification Methylases/genetics ; Tumor Suppressor Proteins/genetics ; DNA Repair Enzymes/genetics ; },
abstract = {BACKGROUND: The clinical relevance of promoter mutations and single nucleotide polymorphism rs2853669 of telomerase reverse transcriptase (TERT) and telomere length in patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) patients remains unclear. Moreover, some studies speculated that TERT promoter status might influence the prognostic role of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation in newly diagnosed GBM. We carried out a large study to investigate their clinical impact and their interaction in newly diagnosed GBM patients.<br><br>PATIENTS AND METHODS: We included 273 newly diagnosed IDH wild-type GBM patients who started treatment at Veneto Institute of Oncology IOV - IRCCS (Padua, Italy) from December 2016 to January 2020. TERT promoter mutations (-124 C>T and&#xa0;-146 C>T) and SNP rs2853669 (-245 T>C), relative telomere length (RTL) and MGMT methylation status were retrospectively assessed in this prospective cohort of patients.<br><br>RESULTS: Median overall survival (OS) of 273 newly diagnosed IDH wild-type GBM patients was 15 months. TERT promoter was mutated in 80.2% of patients, and most had the rs2853669 single nucleotide polymorphism as T/T genotype (46.2%). Median RTL was 1.57 (interquartile range 1.13-2.32). MGMT promoter was methylated in 53.4% of cases. At multivariable analysis, RTL and TERT promoter mutations were not associated with OS or progression-free survival (PFS). Notably, patients C carrier of rs2853669 (C/C+C/T genotypes) showed a better PFS compared with those with the T/T genotype (hazard ratio 0.69, P&#xa0;= 0.007). In terms of OS and PFS, all interactions between MGMT, TERT and RTL and between TERT and rs2853669 genotype were not statistically significant.<br><br>CONCLUSIONS: Our findings suggest the presence of the C variant allele at the rs2853669 of the TERT promoter as an attractive independent prognostic biomarker of disease progression in IDH wild-type GBM patients. RTL and TERT promoter mutational status were not correlated to survival regardless of MGMT methylation status.},
}
@article {pmid37230009,
year = {2023},
author = {Pan, Y and Hu, C and Hou, LJ and Chen, YL and Shi, J and Liu, JC and Zhou, JQ},
title = {Swc4 protects nucleosome-free rDNA, tDNA and telomere loci to inhibit genome instability.},
journal = {DNA repair},
volume = {127},
number = {},
pages = {103512},
doi = {10.1016/j.dnarep.2023.103512},
pmid = {37230009},
issn = {1568-7856},
mesh = {Humans ; *Nucleosomes ; Histones/metabolism ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; DNA, Ribosomal ; Chromatin ; Saccharomyces cerevisiae/genetics/metabolism ; Telomere/genetics/metabolism ; Genomic Instability ; Chromatin Assembly and Disassembly ; Histone Acetyltransferases/genetics ; Transcription Factors/genetics ; },
abstract = {In the baker's yeast Saccharomyces cerevisiae, NuA4 and SWR1-C, two multisubunit complexes, are involved in histone acetylation and chromatin remodeling, respectively. Eaf1 is the assembly platform subunit of NuA4, Swr1 is the assembly platform and catalytic subunit of SWR1-C, while Swc4, Yaf9, Arp4 and Act1 form a functional module, and is present in both NuA4 and SWR1 complexes. ACT1 and ARP4 are essential for cell survival. Deletion of SWC4, but not YAF9, EAF1 or SWR1 results in a severe growth defect, but the underlying mechanism remains largely unknown. Here, we show that swc4Δ, but not yaf9Δ, eaf1Δ, or swr1Δ cells display defects in DNA ploidy and chromosome segregation, suggesting that the defects observed in swc4Δ cells are independent of NuA4 or SWR1-C integrity. Swc4 is enriched in the nucleosome-free regions (NFRs) of the genome, including characteristic regions of RDN5s, tDNAs and telomeres, independently of Yaf9, Eaf1 or Swr1. In particular, rDNA, tDNA and telomere loci are more unstable and prone to recombination in the swc4Δ cells than in wild-type cells. Taken together, we conclude that the chromatin associated Swc4 protects nucleosome-free chromatin of rDNA, tDNA and telomere loci to ensure genome integrity.},
}
@article {pmid37226085,
year = {2023},
author = {Raee, P and Shams Mofarahe, Z and Nazarian, H and Abdollahifar, MA and Ghaffari Novin, M and Aghamiri, S and Ghaffari Novin, M},
title = {Male obesity is associated with sperm telomere shortening and aberrant mRNA expression of autophagy-related genes.},
journal = {Basic and clinical andrology},
volume = {33},
number = {1},
pages = {13},
pmid = {37226085},
issn = {2051-4190},
abstract = {BACKGROUND: Obesity is regarded a global public health crisis. It has been implicated in a variety of health problems, but when it comes to male fertility, how and to what extent obesity affects it are poorly understood. Accordingly, semen samples from 32 individuals with obesity (body mass index (BMI) ≥ 30 kg/m[2]) and 32 individuals with normal weight (BMI: 18.5-25 kg/m[2]) were obtained. Here, for the first time, we examined the association between obesity, relative sperm telomere length (STL) and autophagy-related mRNA levels such as Beclin1, AMPKa1, ULK1, BAX, and BCL2. Each group was also evaluated for conventional semen parameters, sperm apoptotic changes, DNA fragmentation index (DFI), sperm chromatin maturation, and reactive oxygen species (ROS) levels.<br><br>RESULTS: Based on our findings, there was a marked reduction in relative STL in individuals with obesity as compared to the normal-weight group. We also found a significant negative correlation between relative STL and age, BMI, DFI, percentage of sperm with immature chromatin, and intracellular ROS levels in patients with obesity. In the normal-weight group, relative STL was only negatively correlated with DFI and intracellular ROS levels. Regarding mRNA expression, there was considerable upregulation of Beclin1, ULK1, and BCL2 in the group with obesity compared to the normal-weight group. Obesity was also found to be associated with a considerable decline in semen volume, total sperm count, progressive motility, and viability in comparison to normal-weight individuals. Furthermore, obesity was associated with considerably higher percentages of DFI, sperm with immature chromatin, late-stage apoptosis, and elevated ROS levels.<br><br>CONCLUSION: According to our findings, obesity is associated with sperm telomere shortening and aberrant autophagy-related mRNA expression. It should be emphasized that telomere shortening in sperm may be an indirect consequence of obesity due to the oxidative stress associated with the condition. Nevertheless, further investigation is required for a more comprehensive understanding.},
}
@article {pmid37216436,
year = {2023},
author = {Aix, E and Gallinat, A and Yago-Díez, C and Lucas, J and Gómez, MJ and Benguría, A and Freitag, P and Cortez-Toledo, E and Fernández de Manuel, L and García-Cuasimodo, L and Sánchez-Iranzo, H and Montoya, MC and Dopazo, A and Sánchez-Cabo, F and Mercader, N and López, JE and Fleischmann, BK and Hesse, M and Flores, I},
title = {Telomeres Fuse During Cardiomyocyte Maturation.},
journal = {Circulation},
volume = {147},
number = {21},
pages = {1634-1636},
doi = {10.1161/CIRCULATIONAHA.122.062229},
pmid = {37216436},
issn = {1524-4539},
mesh = {Humans ; *Myocytes, Cardiac ; Cell Proliferation ; *Telomere/genetics ; },
}
@article {pmid37216007,
year = {2023},
author = {Allaire, P and He, J and Mayer, J and Moat, L and Gerstenberger, P and Wilhorn, R and Strutz, S and Kim, DSL and Zeng, C and Cox, N and Shay, JW and Denny, J and Bastarache, L and Hebbring, S},
title = {Genetic and clinical determinants of telomere length.},
journal = {HGG advances},
volume = {4},
number = {3},
pages = {100201},
pmid = {37216007},
issn = {2666-2477},
support = {R01 GM130715/GM/NIGMS NIH HHS/United States ; R01 LM010685/LM/NLM NIH HHS/United States ; UL1 TR002373/TR/NCATS NIH HHS/United States ; R01 GM114128/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; Aged ; *Leukocytes ; *Telomere/genetics ; Calcium-Binding Proteins/genetics ; Eye Proteins/genetics ; Membrane Proteins/genetics ; },
abstract = {Many epidemiologic studies have identified important relationships between leukocyte telomere length (LTL) with genetics and health. Most of these studies have been significantly limited in scope by focusing predominantly on individual diseases or restricted to GWAS analysis. Using two large patient populations derived from Vanderbilt University and Marshfield Clinic biobanks linked to genomic and phenomic data from medical records, we investigated the inter-relationship between LTL, genomics, and human health. Our GWAS confirmed 11 genetic loci previously associated with LTL and two novel loci in SCNN1D and PITPNM1. PheWAS of LTL identified 67 distinct clinical phenotypes associated with both short and long LTL. We demonstrated that several diseases associated with LTL were related to one another but were largely independent from LTL genetics. Age of death was correlated with LTL independent of age. Those with very short LTL (<-1.5 standard deviation [SD]) died 10.4 years (p < 0.0001) younger than those with average LTL (±0.5 SD; mean age of death = 74.2 years). Likewise, those with very long LTL (>1.5 SD) died 1.9 years (p = 0.0175) younger than those with average LTL. This is consistent with the PheWAS results showing diseases associating with both short and long LTL. Finally, we estimated that the genome (12.8%) and age (8.5%) explain the largest proportion of LTL variance, whereas the phenome (1.5%) and sex (0.9%) explained a smaller fraction. In total, 23.7% of LTL variance was explained. These observations provide the rationale for expanded research to understand the multifaceted correlations between TL biology and human health over time, leading to effective LTL usage in medical applications.},
}
@article {pmid37215005,
year = {2023},
author = {Cai, SW and Takai, H and Walz, T and de Lange, T},
title = {POT1 recruits and regulates CST-Polα/Primase at human telomeres.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {37215005},
support = {R35 CA210036/CA/NCI NIH HHS/United States ; R50 CA243771/CA/NCI NIH HHS/United States ; },
abstract = {Telomere maintenance requires extension of the G-rich telomeric repeat strand by telomerase and fill-in synthesis of the C-rich strand by Polα/Primase. Telomeric Polα/Primase is bound to Ctc1-Stn1-Ten1 (CST), a single-stranded DNA-binding complex. Like mutations in telomerase, mutations affecting CST-Polα/Primase result in pathological telomere shortening and cause a telomere biology disorder, Coats plus (CP). We determined cryogenic electron microscopy structures of human CST bound to the shelterin heterodimer POT1/TPP1 that reveal how CST is recruited to telomeres by POT1. Phosphorylation of POT1 is required for CST recruitment, and the complex is formed through conserved interactions involving several residues mutated in CP. Our structural and biochemical data suggest that phosphorylated POT1 holds CST-Polα/Primase in an inactive auto-inhibited state until telomerase has extended the telomere ends. We propose that dephosphorylation of POT1 releases CST-Polα/Primase into an active state that completes telomere replication through fill-in synthesis.},
}
@article {pmid37214874,
year = {2023},
author = {Granger, SL and Sharma, R and Kaushik, V and Razzaghi, M and Honda, M and Bhat, DS and Wlodarski, MW and Antony, E and Spies, M},
title = {Human hnRNPA1 reorganizes telomere-bound Replication Protein A.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.05.09.540056},
pmid = {37214874},
support = {R01 GM130746/GM/NIGMS NIH HHS/United States ; R01 GM133967/GM/NIGMS NIH HHS/United States ; R35 GM149320/GM/NIGMS NIH HHS/United States ; S10 OD030343/OD/NIH HHS/United States ; },
abstract = {UNLABELLED: Human replication protein A (RPA) is a heterotrimeric ssDNA binding protein responsible for many aspects of cellular DNA metabolism. The binding and dissociation of the four individual DNA binding domains (DBDs) from DNA result in configurational dynamics of the RPA-DNA complexes. This dynamics is essential for replacement of RPA by downstream proteins in various cellular metabolic pathways. RPA plays several important functions at telomeres where it binds to and melts telomeric G-quadruplexes, non-canonical DNA structures formed at the G-rich telomeric ssDNA overhangs. Here, we combine single-molecule total internal reflection fluorescence microscopy (smTIRFM) and mass photometry (MP) with biophysical and biochemical analyses to demonstrate that heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) specifically remodels RPA bound to telomeric ssDNA by dampening the RPA configurational dynamics and forming a stable ternary complex. Uniquely, among hnRNPA1 target RNAs, telomeric repeat-containing RNA (TERRA) is selectively capable of releasing hnRNPA1 from the RPA-telomeric DNA complex. We speculate that this telomere specific RPA-DNA-hnRNPA1 complex is an important structure in telomere protection.<br><br>ONE SENTENCE SUMMARY: At the single-stranded ends of human telomeres, the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) binds to and modulates conformational dynamics of the ssDNA binding protein RPA forming a ternary complex which is controlled by telomeric repeat-containing RNA (TERRA).},
}
@article {pmid37213605,
year = {2023},
author = {Cai, X and Ning, C and Fan, L and Li, Y and Wang, L and He, H and Dong, T and Cai, Y and Zhang, M and Lu, Z and Chen, C and Shi, K and Ye, T and Zhong, R and Tian, J and Li, H and Li, H and Zhu, Y and Miao, X},
title = {Triclosan is associated with breast cancer via oxidative stress and relative telomere length.},
journal = {Frontiers in public health},
volume = {11},
number = {},
pages = {1163965},
pmid = {37213605},
issn = {2296-2565},
mesh = {Humans ; Female ; *Triclosan/adverse effects ; *Breast Neoplasms ; Leukocytes, Mononuclear ; Case-Control Studies ; Oxidative Stress ; 8-Hydroxy-2'-Deoxyguanosine ; Telomere ; },
abstract = {INTRODUCTION: Triclosan (TCS), a widely prescribed broad-spectrum antibacterial agent, is an endocrine-disrupting chemical. The relationship and biological mechanisms between TCS exposure and breast cancer (BC) are disputed. We aimed to examine the correlation between urinary TCS exposure and BC risk and estimated the mediating effects of oxidative stress and relative telomere length (RTL) in the above association.<br><br>METHODS: This case-control study included 302 BC patients and 302 healthy individuals in Wuhan, China. We detected urinary TCS, three common oxidative stress biomarkers [8-hydroxy-2-deoxyguanosine (8-OHdG), 8-iso-prostaglandin F2&#x3b1; (8-isoPGF2&#x3b1;), 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)], and RTL in peripheral blood mononuclear cells.<br><br>RESULTS: Significant associations were observed between log-transformed urinary concentrations of TCS, 8-OHdG, HNE-MA, 8-isoPGF2&#x3b1;, RTL, and BC risk, with the odds ratios (95% confidence intervals) being 1.58 (1.32-1.91), 3.08 (1.55-6.23), 3.39 (2.45-4.77), 3.99 (2.48-6.54), and 1.67 (1.35-2.09), respectively. Continuous TCS exposure was significantly positively correlated with RTL, HNE-MA, and 8-isoPGF2&#x3b1; (all p<0.05) but not with 8-OHdG (p = 0.060) after adjusting for covariates. The mediated proportions of 8-isoPGF22&#x3b1; and RTL in the relationship between TCS and BC risk were 12.84% and 8.95%, respectively (all p<0.001).<br><br>DISCUSSION: In conclusion, our study provides epidemiological evidence to confirmed the deleterious effects of TCS on BC and indicated the mediating effect of oxidative stress and RTL on the correlation between TCS and BC risk. Moreover, exploring the contribution of TCS to BC can clarify the biological mechanisms of TCS exposure, provide new clues for the pathogenesis of BC, which is of great significance to improving public health systems.},
}
@article {pmid37211520,
year = {2023},
author = {Ämmälä, AJ and Suvisaari, J and Kananen, L and Lönnqvist, J and Ripatti, S and Pirkola, S and Paunio, T and Hovatta, I},
title = {Corrigendum to Childhood adversities are associated with shorter leukocyte telomere length at adult age in a population-based study [Psychoneuroendocrinology (2021) 130 105276].},
journal = {Psychoneuroendocrinology},
volume = {153},
number = {},
pages = {106286},
doi = {10.1016/j.psyneuen.2023.106286},
pmid = {37211520},
issn = {1873-3360},
}
@article {pmid37211230,
year = {2023},
author = {Gu, Z and Niu, Z and Yan, Z and Fan, Y and Sun, J and Zhao, X and Duan, X and Yao, W and Yang, Y and Wang, W},
title = {Chain-mediating effect of interaction between telomeres and mitochondria under oxidative stress in coke oven workers.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {331},
number = {Pt 1},
pages = {121855},
doi = {10.1016/j.envpol.2023.121855},
pmid = {37211230},
issn = {1873-6424},
mesh = {Humans ; Antioxidants/analysis ; *Coke/analysis ; DNA, Mitochondrial/genetics ; Mitochondria/genetics ; *Occupational Exposure/analysis ; Oxidative Stress ; *Polycyclic Aromatic Hydrocarbons/analysis ; Telomere ; },
abstract = {Coke oven emissions (COEs) exposure leads to oxidative stress, an imbalance between oxidant production and antioxidant defence in the body, which then leads to shortened relative telomere length (RTL) and reduced mitochondrial DNA copy number (mtDNAcn), ultimately leading to ageing and disease. By analysing the relationship among COEs, oxidative stress, RTL and mtDNAcn, we investigated the chain-mediating effects of oxidative stress and telomeres on mitochondrial damage and mitochondria on telomere damage in coke oven workers. A total of 779 subjects were included in the study. Cumulative COEs exposure concentrations were estimated, and the RTL and mtDNAcn of peripheral blood leukocytes were measured using real-time fluorescence quantitative PCR. Total antioxidant capacity (T-AOC) was measured to reflect the level of oxidative stress. The data were statistically analysed using SPSS 21.0 software and discussed using mediation effect analysis. After adjusting for age, sex, smoking, drinking and BMI, generalised linear model revealed dose-response associations between COEs and T-AOC, RTL and mtDNAcn, respectively. (Ptrend < 0.05). The results of chain-mediating effect showed that the proportion of the chain-mediating effect of "CED-COEs→T-AOC→ RTL→mtDNAcn" was 0.82% (β = -0.0005, 95% CI = [-0.0012, -0.0001]), and the proportion of the chain-mediating effect of "CED-COEs→T-AOC→ mtDNAcn → RTL ″ was 2.64% (β = -0.0013, 95% CI = [-0.0025, -0.0004]). After oxidative stress is induced by COEs, mitochondria and telomeres may interact with each other while leading further to potential bodily damage. This study provides clues to explore the association between mitochondria and telomeres.},
}
@article {pmid37209418,
year = {2024},
author = {Wang, W and Huang, N and Zhuang, Z and Song, Z and Li, Y and Dong, X and Xiao, W and Zhao, Y and Jia, J and Liu, Z and Qi, L and Huang, T},
title = {Identifying Potential Causal Effects of Telomere Length on Health Outcomes: A Phenome-Wide Investigation and Mendelian Randomization Study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {79},
number = {1},
pages = {},
doi = {10.1093/gerona/glad128},
pmid = {37209418},
issn = {1758-535X},
support = {2020YFC2003401//National Key Research and Development Program of China/ ; },
mesh = {Humans ; *Genome-Wide Association Study ; Mendelian Randomization Analysis ; Phenotype ; *Myocardial Infarction/epidemiology/genetics ; Telomere/genetics ; Polymorphism, Single Nucleotide ; },
abstract = {BACKGROUND: Telomere length has been linked to various health outcomes. To comprehensively investigate the causal effects of telomere length throughout the human disease spectrum, we conducted a phenome-wide Mendelian randomization study (MR-PheWAS) and a systematic review of MR studies.<br><br>METHODS: We conducted a PheWAS to screen for associations between telomere length and 1 035 phenotypes in the UK Biobank (n = 408 354). The exposure of interest was the genetic risk score (GRS) of telomere length. Observed associations passing multiple testing corrections were assessed for causality by 2-sample MR analysis. A systematic review of MR studies on telomere length was performed to harmonize the published evidence and complement our findings.<br><br>RESULTS: Of the 1 035 phenotypes tested, PheWAS identified 29 and 78 associations of telomere length GRS at a Bonferroni- and false discovery rate-corrected threshold; 24 and 66 distinct health outcomes were causal in the following principal MR analysis. The replication MR using data from the FinnGen study provided evidence of causal effects of genetically instrumented telomere length on 28 out of 66 outcomes, including decreased risks of 5 diseases in respiratory diseases, digestive diseases, and myocardial infarction, and increased risks of 23 diseases, mainly comprised neoplasms, diseases of the genitourinary system, and essential hypertension. A systematic review of 53 MR studies found evidence to support 16 out of the 66 outcomes.<br><br>CONCLUSIONS: This large-scale MR-PheWAS identified a wide range of health outcomes that were possibly affected by telomere length, and suggested that susceptibility to telomere length may vary across disease categories.},
}
@article {pmid37204126,
year = {2023},
author = {Liao, S and Zhou, Q and Zhang, Y},
title = {Association of ABCA1 R219K polymorphism and telomere length in a Chinese rural population: possible linking to systemic inflammation.},
journal = {Journal of genetics},
volume = {102},
number = {},
pages = {},
pmid = {37204126},
issn = {0973-7731},
mesh = {Humans ; Gene Frequency ; *East Asian People ; *Rural Population ; Genetic Predisposition to Disease ; Polymorphism, Genetic ; Genotype ; Inflammation ; Polymorphism, Single Nucleotide ; ATP Binding Cassette Transporter 1/genetics ; },
abstract = {The ATP-binding cassette transporter A1 (ABCA1) gene polymorphisms have been shown to be associated with various human diseases and pathological conditions such as cardiovascular disease and Alzheimer's disease. However, these associations remain unclear and inconclusive. Interestingly, short telomere length was also observed in these diseases. In the present study, our aims were to investigate the interaction between two selected ABCA1 polymorphisms (-565C/T and R219K) and telomere length in a Chinese rural population including 1629 subjects and explore the underlying mechanisms. Genotyping was conducted using Taqman SNP Genotyping Assays. Mean relative leukocyte telomere length was measured using monochrome multiplex quantitative PCR method. We found that the telomere length of R219K RR genotype was significantly shorter than RK or KK genotypes (1.242 ± 0.198 vs 1.271 ± 0.207, P = 0.027 and 1.242 ± 0.198 vs 1.276 ± 0.209, P = 0.021, respectively). While the neutrophil to lymphocyte ratio (NLR) of R219K RR genotype was significantly higher than KK genotype (1.929 ± 0.826 vs 1.768 ± 0.893, P = 0.019). In the general linear models after adjustments for confounding factors, the KK and RK genotypes were both significantly associated with telomere length and NLR. A significant association was also observed for K allele carrier genotypes when compared with RR genotype for telomere length and NLR. In conclusion, the R219K polymorphism of ABCA1 was independently associated with telomere length. R219K K allele could be protective against shortening of telomeres and inflammation.},
}
@article {pmid37193737,
year = {2023},
author = {Carlund, O and Norberg, A and Osterman, P and Landfors, M and Degerman, S and Hultdin, M},
title = {DNA methylation variations and epigenetic aging in telomere biology disorders.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {7955},
pmid = {37193737},
issn = {2045-2322},
mesh = {*DNA Methylation ; *DNA ; Epigenesis, Genetic ; Telomere/genetics ; Biology ; },
abstract = {Telomere Biology Disorders (TBDs) are characterized by mutations in telomere-related genes leading to short telomeres and premature aging but with no strict correlation between telomere length and disease severity. Epigenetic alterations are also markers of aging and we aimed to evaluate whether DNA methylation (DNAm) could be part of the pathogenesis of TBDs. In blood from 35 TBD cases, genome-wide DNAm were analyzed and the cases were grouped based on relative telomere length (RTL): short (S), with RTL close to normal controls, and extremely short (ES). TBD cases had increased epigenetic age and DNAm alterations were most prominent in the ES-RTL group. Thus, the differentially methylated (DM) CpG sites could be markers of short telomeres but could also be one of the mechanisms contributing to disease phenotype since DNAm alterations were observed in symptomatic, but not asymptomatic, cases with S-RTL. Furthermore, two or more DM-CpGs were identified in four genes previously linked to TBD or telomere length (PRDM8, SMC4, VARS, and WNT6) and in three genes that were novel in telomere biology (MAS1L, NAV2, and TM4FS1). The DM-CpGs in these genes could be markers of aging in hematological cells, but they could also be of relevance for the progression of TBD.},
}
@article {pmid37191632,
year = {2023},
author = {Bhala, S and Savage, SA},
title = {What is the future of telomere length testing in telomere biology disorders?.},
journal = {Expert review of hematology},
volume = {16},
number = {7},
pages = {475-478},
pmid = {37191632},
issn = {1747-4094},
support = {ZIA CP010144/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Humans ; Telomere/genetics/metabolism ; *Telomerase ; Biology ; *Dyskeratosis Congenita ; },
}
@article {pmid37189188,
year = {2023},
author = {Byrjalsen, A and Brainin, AE and Lund, TK and Andersen, MK and Jelsig, AM},
title = {Size matters in telomere biology disorders ‒ expanding phenotypic spectrum in patients with long or short telomeres.},
journal = {Hereditary cancer in clinical practice},
volume = {21},
number = {1},
pages = {7},
pmid = {37189188},
issn = {1731-2302},
abstract = {The end of each chromosome consists of a DNA region termed the telomeres. The telomeres serve as a protective shield against degradation of the coding DNA sequence, as the DNA strand inevitably ‒ with each cell division ‒ is shortened. Inherited genetic variants cause telomere biology disorders when located in genes (e.g. DKC1, RTEL1, TERC, TERT) playing a role in the function and maintenance of the telomeres. Subsequently patients with telomere biology disorders associated with both too short or too long telomeres have been recognized. Patients with telomere biology disorders associated with short telomeres are at increased risk of dyskeratosis congenita (nail dystrophy, oral leukoplakia, and hyper- or hypo-pigmentation of the skin), pulmonary fibrosis, hematologic disease (ranging from cytopenia to leukemia) and in rare cases very severe multiorgan manifestations and early death. Patients with telomere biology disorders associated with too long telomeres have in recent years been found to confer an increased risk of melanoma and chronic lymphocytic leukemia. Despite this, many patients have an apparently isolated manifestation rendering telomere biology disorders most likely underdiagnosed. The complexity of telomere biology disorders and many causative genes makes it difficult to design a surveillance program which will ensure identification of early onset disease manifestation without overtreatment.},
}
@article {pmid37188431,
year = {2023},
author = {Li, S and Liu, Z and Zhang, J and Li, L},
title = {Links between telomere dysfunction and hallmarks of aging.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {888},
number = {},
pages = {503617},
doi = {10.1016/j.mrgentox.2023.503617},
pmid = {37188431},
issn = {1879-3592},
mesh = {Humans ; Aging/genetics ; *Neoplasms/genetics ; Telomere/genetics ; *Telomerase ; },
abstract = {Aging is characterized by the gradual loss of physiological integrity, leading to impaired function and increased risk of death. This deterioration is the main risk factor for the great majority of chronic diseases, which account for most of the morbidity, death and medical expenses. The hallmarks of aging comprise diverse molecular mechanisms and cell systems, which are interrelated and coordinated to drive the aging process. This review focuses on telomere to analyze the interrelationships between telomere dysfunction and other aging hallmarks and their relative contributions to the initiation and progression of age-related diseases (such as neurodegeneration, cardiovascular disease, and cancer), which will contribute to determine drug targets, improve human health in the aging process with minimal side effects and provide information for the prevention and treatment of age-related diseases.},
}
@article {pmid37186136,
year = {2023},
author = {Kurokochi, H and Tajima, N and Sato, MP and Yoshitake, K and Asakawa, S and Isobe, S and Shirasawa, K},
title = {Telomere-to-telomere genome assembly of matsutake (Tricholoma matsutake).},
journal = {DNA research : an international journal for rapid publication of reports on genes and genomes},
volume = {30},
number = {3},
pages = {},
pmid = {37186136},
issn = {1756-1663},
abstract = {Here, we report the first telomere-to-telomere genome assembly of matsutake (Tricholoma matsutake), which consists of 13 sequences (spanning 161.0 Mb) and a 76 kb circular mitochondrial genome. All the 13 sequences were supported with telomeric repeats at the ends. GC-rich regions are located at the middle of the sequences and are enriched with long interspersed nuclear elements (LINEs). Repetitive sequences including long-terminal repeats (LTRs) and LINEs occupy 71.6% of the genome. A total of 21,887 potential protein-coding genes were predicted. The genomic data reported in this study served not only matsutake gene sequences but also genome structures and intergenic sequences. The information gained would be a great reference for exploring the genetics, genomics, and evolutionary study of matsutake in the future, and ultimately facilitate the conservation of this vulnerable genetic resource.},
}
@article {pmid37185424,
year = {2023},
author = {Delmonico, L and Bines, J and Nascimento, CMD and Fernandes, PV and Barbosa, IS and Ribeiro, GB and de Paula, BHR and Silvestre, RT and Ornellas, MHF and Alves, G and Lage, C},
title = {Nuclear and Cytoplasmic hTERT, Tumor-Infiltrating Lymphocytes, and Telomere Elongation Leukocytes Are Independent Factors in the Response to Neoadjuvant Treatment in HER2-Enriched Breast Cancer.},
journal = {Current oncology (Toronto, Ont.)},
volume = {30},
number = {4},
pages = {4094-4109},
pmid = {37185424},
issn = {1718-7729},
mesh = {Female ; Humans ; *Breast Neoplasms/drug therapy/genetics/pathology ; Lymphocytes, Tumor-Infiltrating/metabolism/pathology ; Neoadjuvant Therapy/methods ; Prognosis ; Receptor, ErbB-2/genetics/metabolism ; },
abstract = {HER2-enriched tumors are responsible for 20% of breast tumors and have high rates of immune infiltrates in the tumor stroma that respond favorably to neoadjuvant chemotherapy. In the context of tumors, telomeres control cell death and prevent tumor cells from replicating discontinuously, leading to their immortalization. This study aimed to evaluate the presence of tumor-infiltrating lymphocytes, hTERT expression, hTERT promoter mutation, and leukocyte telomere length in HER2-enriched breast tumors. A total of 103 cases were evaluated, 19 with pathologic complete response. The TILs percentage was above ≥10 in 44 cases (43%) and significantly present in patients ≥50 years of age. hTERT staining positivity was mostly nuclear, significantly present in the non-pCR group, and associated with a lower survival rate. Leukocyte telomeres were elongated for HER2-enriched tumors, and in multivariate analysis, shortening was associated with an increased risk of death. Overall, our results show that the nuclear and cytoplasmic presence of hTERT may indicate a worse prognosis and that leukocyte telomere elongation is a protective factor.},
}
@article {pmid37184208,
year = {2023},
author = {Vittal, A and Niewisch, MR and Bhala, S and Kudaravalli, P and Rahman, F and Hercun, J and Kleiner, DE and Savage, SA and Koh, C and Heller, T and Giri, N},
title = {Progression of liver disease and portal hypertension in dyskeratosis congenita and related telomere biology disorders.},
journal = {Hepatology (Baltimore, Md.)},
volume = {78},
number = {6},
pages = {1777-1787},
pmid = {37184208},
issn = {1527-3350},
support = {ZIA CP010190/ImNIH/Intramural NIH HHS/United States ; ZIA DK075008/ImNIH/Intramural NIH HHS/United States ; ZIA DK075150/ImNIH/Intramural NIH HHS/United States ; ZIC BC010685/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; *Dyskeratosis Congenita/complications/genetics ; *Digestive System Diseases ; Telomere/metabolism ; *Hypertension, Portal/genetics/complications ; *Vascular Diseases/complications ; Disease Progression ; Biology ; Mutation ; *Telomerase/genetics/metabolism ; },
abstract = {BACKGROUND AND AIMS: Dyskeratosis congenita (DC) and related telomere biology disorders (TBD) are characterized by very short telomeres and multisystem organ involvement including liver disease. Our study aimed to characterize baseline hepatic abnormalities in patients with DC/TBD and determine risk factors associated with liver disease progression.<br><br>APPROACH AND RESULTS: A retrospective review was performed on a cohort of 58 patients (39 males) with DC/TBD who were prospectively evaluated at a single institute from 2002 to 2019. The median age at initial assessment was 18 (1.4-67.6) years, and median follow-up duration was 6 (1.4-8.2) years. Patients with autosomal or X-linked recessive inheritance and those with heterozygous TINF2 DC were significantly younger, predominantly male, and more likely to have DC-associated mucocutaneous triad features and severe bone marrow failure compared with autosomal dominant-non- TINF2 DC/TBD patients. Liver abnormality (defined at baseline assessment by laboratory and/or radiological findings) was present in 72.4% of patients with predominantly cholestatic pattern of liver enzyme elevation. Clinically significant liver disease and portal hypertension developed in 17.2% of patients during the 6-year follow-up; this progression was mainly seen in patients with recessive or TINF2 -associated DC. Significant risk factors associated with progression included the presence of pulmonary or vascular disease.<br><br>CONCLUSIONS: Our experience shows a high prevalence of cholestatic pattern of liver abnormality with progression to portal hypertension in patients with DC/TBD. Presence of pulmonary and/or vascular disease in patients with recessive or TINF2 DC was an important predictor of liver disease progression, suggesting the need for increased vigilance and monitoring for complications in these patients.},
}
@article {pmid37183325,
year = {2023},
author = {Zade, NH and Khattar, E},
title = {POT1 mutations cause differential effects on telomere length leading to opposing disease phenotypes.},
journal = {Journal of cellular physiology},
volume = {238},
number = {6},
pages = {1237-1255},
doi = {10.1002/jcp.31034},
pmid = {37183325},
issn = {1097-4652},
mesh = {Mutation/genetics ; Phenotype ; *Shelterin Complex ; *Telomere/genetics/metabolism ; *Telomere-Binding Proteins/genetics/metabolism ; Humans ; },
abstract = {The protection of telomere protein (POT1) is a telomere-binding protein and is an essential component of the six-membered shelterin complex, which is associated with the telomeres. POT1 directly binds to the 3' single-stranded telomeric overhang and prevents the activation of DNA damage response at telomeres thus preventing the telomere-telomere fusions and genomic instability. POT1 also plays a pivotal role in maintaining telomere length by regulating telomerase-mediated telomere elongation. Mutations in POT1 proteins result in three different telomere phenotypes, which include long, short, or aberrant telomere length. Long telomeres predispose individuals to cancer, while short or aberrant telomere phenotypes result in pro-aging diseases referred to as telomeropathies. Here, we review the function of POT1 proteins in telomere length hemostasis and how the spectrum of mutations reported in POT1 can be segregated toward developing very distinct disease phenotypes of cancer and telomeropathies.},
}
@article {pmid37179160,
year = {2023},
author = {De Rosa, M and Opresko, PL},
title = {Translating the telomeres.},
journal = {Trends in genetics : TIG},
volume = {39},
number = {8},
pages = {593-595},
doi = {10.1016/j.tig.2023.04.009},
pmid = {37179160},
issn = {0168-9525},
mesh = {*RNA, Long Noncoding/genetics ; Telomere/genetics/metabolism ; },
abstract = {Telomeres are transcribed into long noncoding telomeric repeat-containing RNA (TERRA). Or so we thought. Recently, Al-Turki and Griffith provided evidence that TERRA can code for valine-arginine (VR) or glycine-leucine (GL) dipeptide repeat proteins by undergoing repeat-associated non-ATG (RAN) translation. This finding uncovers a new mechanism by which telomeres can impact cellular function.},
}
@article {pmid37173827,
year = {2023},
author = {Morland, F and Ewen, JG and Simons, MJP and Brekke, P and Hemmings, N},
title = {Early-life telomere length predicts life-history strategy and reproductive senescence in a threatened wild songbird.},
journal = {Molecular ecology},
volume = {32},
number = {14},
pages = {4031-4043},
doi = {10.1111/mec.16981},
pmid = {37173827},
issn = {1365-294X},
support = {216405/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Female ; Longevity ; *Songbirds/genetics ; Aging ; *Passeriformes ; Telomere/genetics ; Reproduction/genetics ; Telomere Shortening/genetics ; },
abstract = {Telomeres are well known for their associations with lifespan and ageing across diverse taxa. Early-life telomere length can be influenced by developmental conditions and has been shown positively affect lifetime reproductive success in a limited number of studies. Whether these effects are caused by a change in lifespan, reproductive rate or perhaps most importantly reproductive senescence is unclear. Using long-term data on female breeding success from a threatened songbird (the hihi, Notiomystis cincta), we show that the early-life telomere length of individuals predicts the presence and rate of future senescence of key reproductive traits: clutch size and hatching success. In contrast, senescence of fledging success is not associated with early-life telomere length, which may be due to the added influence of biparental care at this stage. Early-life telomere length does not predict lifespan or lifetime reproductive success in this species. Females may therefore change their reproductive allocation strategy depending on their early developmental conditions, which we hypothesise are reflected in their early-life telomere length. Our results offer new insights on the role that telomeres play in reproductive senescence and individual fitness and suggest telomere length can be used as a predictor for future life history in threatened species.},
}
@article {pmid37172909,
year = {2023},
author = {McLester-Davis, LWY and Estrada, P and Hastings, WJ and Kataria, LA and Martin, NA and Siebeneicher, JT and Tristano, RI and Mayne, CV and Horlick, RP and O'Connell, SS and Drury, SS},
title = {A review and meta-analysis: Cross-tissue telomere length correlations in healthy humans.},
journal = {Ageing research reviews},
volume = {88},
number = {},
pages = {101942},
doi = {10.1016/j.arr.2023.101942},
pmid = {37172909},
issn = {1872-9649},
support = {U24 AG066528/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Databases, Factual ; *Telomere ; },
abstract = {BACKGROUND AND AIM: Tissue source has been shown to exert a significant effect on the magnitude of associations between telomere length and various health outcomes and exposures. The purpose of the present qualitative review and meta-analysis is to describe and investigate the impact of study design and methodological features on the correlation between telomere lengths measured in different tissues from the same healthy individual.<br><br>METHODS: This meta-analysis included studies published from 1988 to 2022. Databases searched included PubMed, Embase, and Web of Science and studies were identified using the keywords "telomere length" and "tissues" or "tissue." A total of 220 articles of 7856 initially identified studies met inclusion criteria for qualitative review, of which 55 met inclusion criteria for meta-analysis in R RESULTS: Studies meeting inclusion criteria for meta-analysis tended to have enhanced demographic and methodological reporting relative to studies only included in the qualitative review. A total of 463 pairwise correlations reported for 4324 unique individuals and 102 distinct tissues were extracted from the 55 studies and subject to meta-analysis, resulting in a significant effect size z&#xa0;=&#xa0;0.66 (p&#xa0;<&#xa0;0.0001) and meta-correlation coefficient of r&#xa0;=&#xa0;0.58. Meta-correlations were significantly moderated by sample size and telomere length measurement methodology, with studies of smaller size and those using hybridization-based analyses exhibiting the largest meta-correlation. Tissue source also significantly moderated the meta-correlation, wherein correlations between samples of a different lineage (e.g., blood vs. non-blood) or collection method (e.g., peripheral vs. surgical) were lower than correlations between samples of the same lineage or collection method.<br><br>CONCLUSION: These results suggest that telomere lengths measured within individuals are generally correlated, but future research should be intentional in selecting a tissue for telomere length measurement that is most biologically relevant to the exposure or outcome investigated and balance this with the feasibility of obtaining the sample in sufficient numbers of individuals.},
}
@article {pmid37170112,
year = {2023},
author = {Wu, W and Li, C and Zhu, X and Liu, X and Li, P and Wan, R and Wu, X and Chen, S},
title = {Genetic association of telomere length, obesity and tobacoo smoking with idiopathic pulmonary fibrosis risk.},
journal = {BMC public health},
volume = {23},
number = {1},
pages = {868},
pmid = {37170112},
issn = {1471-2458},
mesh = {Humans ; *Genome-Wide Association Study ; Obesity/epidemiology/genetics ; *Idiopathic Pulmonary Fibrosis/epidemiology/genetics ; Smoking/adverse effects/epidemiology ; Tobacco Smoking ; Telomere/genetics ; Polymorphism, Single Nucleotide ; },
abstract = {BACKGROUND: Due to the inadequacy of published evidence, association of telomere length (TL), obesity and tobacco smoking with idiopathic pulmonary fibrosis (IPF) remains unclear. The aim of the study was to explore whether these exposures genetically affected the risk of the disease.<br><br>METHODS: Genetic variants from genome-wide association studies for TL, body mass index (BMI), body fat percentage (BFP) and tobacco smoking (including maternal smoking) were used as instrumental variables. Inverse-variance weighted were mainly adopted to determine the genetic association of these exposures with IPF. All analyses were conducted by R-software (version 3.6.1).<br><br>RESULTS: Firstly, longer TL was associated with the decreased risk of IPF (OR&#x2009;=&#x2009;0.475 per SD increase in TL, 95%CI&#x2009;=&#x2009;0.336&#x2009;~&#x2009;0.670, P<0.001). Secondly, higher levels of BMI and BFP were related to the increased risk of the disease (OR&#x2009;=&#x2009;1.425 per SD increase in BMI level, 95%CI&#x2009;=&#x2009;1.114&#x2009;~&#x2009;1.823, P&#x2009;=&#x2009;0.005; OR&#x2009;=&#x2009;1.702 per SD increase in BFP level, 95%CI&#x2009;=&#x2009;1.202&#x2009;~&#x2009;2.409, P&#x2009;=&#x2009;0.003). Thirdly, maternal smoking was implicated in the increased risk of the disease (OR&#x2009;=&#x2009;13.183 per SD increase in the prevalence of maternal smoking, 95%CI&#x2009;=&#x2009;1.820&#x2009;~&#x2009;95.484, P&#x2009;=&#x2009;0.011).<br><br>CONCLUSION: TL should be a genetic risk factor for IPF. Obesity and exposure to tobacco smoking as a fetus might also contribute to the development of this fibrotic diseases. These findings should be verified by future studies.},
}
@article {pmid37169669,
year = {2023},
author = {Mastrosimini, MG and Manfrin, E and Remo, A and De Bellis, M and Parisi, A and Pedron, S and Luchini, C and Brunelli, M and Ammendola, S and Bernardoni, L and Conti Bellocchi, MC and Gabbrielli, A and Facciorusso, A and Pea, A and Landoni, L and Scarpa, A and Crinò, SF},
title = {Endoscopic ultrasound fine-needle biopsy to assess DAXX/ATRX expression and alternative lengthening of telomeres status in non-functional pancreatic neuroendocrine tumors.},
journal = {Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]},
volume = {23},
number = {4},
pages = {429-436},
doi = {10.1016/j.pan.2023.05.002},
pmid = {37169669},
issn = {1424-3911},
mesh = {Humans ; X-linked Nuclear Protein/genetics/metabolism ; *Neuroendocrine Tumors/diagnosis/genetics/surgery ; Retrospective Studies ; Biopsy, Fine-Needle ; In Situ Hybridization, Fluorescence ; *Intellectual Disability ; *alpha-Thalassemia ; Reproducibility of Results ; *Pancreatic Neoplasms/diagnosis/genetics/surgery ; Telomere/genetics/metabolism/pathology ; Molecular Chaperones/genetics ; Co-Repressor Proteins/genetics ; },
abstract = {BACKGROUND/OBJECTIVES: Death domain-associated protein (DAXX) and/or α-thalassemia/mental retardation X-linked (ATRX) chromatin remodeling genes mutations and alternative lengthening of telomeres (ALT) activation are associated with more aggressive behavior of non-functional pancreatic neuroendocrine tumors (NF-PanNETs). We aimed to evaluate the reliability of such markers on endoscopic-ultrasound fine-needle biopsy (EUS-FNB) specimens.<br><br>METHODS: Patients who underwent EUS-FNB and subsequent surgical resection for PanNETs between January 2017 and December 2019 were retrospectively identified. Immunohistochemistry (IHC) to evaluate DAXX/ATRX expression and fluorescence in situ hybridization (FISH) for ALT status were performed. Primary outcome was the concordance rate of markers expression between EUS-FNB and surgical specimens. Secondary aims were association between markers and lesion aggressiveness, their diagnostic performance in predicting aggressiveness, and agreement of preoperative and post-surgical Ki67-based grading.<br><br>RESULTS: Forty-one NF-PanNETs (mean diameter 36.1&#xa0;&#xb1;&#xa0;26.5&#xa0;mm) were included. Twenty-four showed features of lesion aggressiveness. Concordance of expressions of DAXX, ATRX, and ALT status between EUS-FNB and surgical specimens were 95.1% (&#x3ba;&#xa0;=&#xa0;0.828; p&#xa0;<&#xa0;0.001), 92.7% (&#x3ba;&#xa0;=&#xa0;0.626; p&#xa0;<&#xa0;0.001), and 100% (&#x3ba;&#xa0;=&#xa0;1; p&#xa0;<&#xa0;0.001), respectively. DAXX/ATRX loss and ALT-positivity were significantly (p&#xa0;<&#xa0;0.05) associated with metastatic lymphnodes and lymphovascular invasion. The combination of all tumor markers (DAXX/ATRX loss&#xa0;+&#xa0;ALT-positivity&#xa0;+&#xa0;grade 2) reached an accuracy of 73.2% (95%CI 57.1-85.8) in identifying aggressive lesions. Pre- and post-operative ki-67-based grading was concordant in 80.5% of cases (k&#xa0;=&#xa0;0.573; p&#xa0;<&#xa0;0.001).<br><br>CONCLUSION: DAXX/ATRX expression and ALT status can be accurately evaluated in a preoperative setting on EUS-FNB samples, potentially improving the identification of patients with increased risk and poorer prognosis.},
}
@article {pmid37165507,
year = {2023},
author = {Maiese, K},
title = {The Implications of Telomere Length: Advanced Aging, Cell Senescence, MRI Phenotypes, Stem Cells and Alzheimer's Disease.},
journal = {Current neurovascular research},
volume = {20},
number = {2},
pages = {171-174},
doi = {10.2174/1567202620666230510150337},
pmid = {37165507},
issn = {1875-5739},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/genetics ; Cellular Senescence ; Phenotype ; Telomere ; Stem Cells ; },
}
@article {pmid37165138,
year = {2023},
author = {Mannherz, W and Agarwal, S},
title = {Publisher Correction: Thymidine nucleotide metabolism controls human telomere length.},
journal = {Nature genetics},
volume = {55},
number = {7},
pages = {1251},
doi = {10.1038/s41588-023-01418-7},
pmid = {37165138},
issn = {1546-1718},
}
@article {pmid37163741,
year = {2023},
author = {Ida, CM and Jenkins, RB},
title = {SMARCAL1: Expanding the spectrum of genes associated with alternative lengthening of telomeres.},
journal = {Neuro-oncology},
volume = {25},
number = {9},
pages = {1576-1577},
pmid = {37163741},
issn = {1523-5866},
mesh = {Humans ; *Telomerase/genetics ; *Glioblastoma ; Telomere/genetics/metabolism ; Mutation ; Carcinogenesis ; DNA Helicases/genetics/metabolism ; },
}
@article {pmid37160859,
year = {2023},
author = {Yang, D and Chen, X and Cao, W and Xu, C and Chang, L and Long, G},
title = {Association between mixed exposure of polycyclic aromatic hydrocarbons and telomere length in general population: NHANES 2001-2002.},
journal = {Environmental science and pollution research international},
volume = {30},
number = {27},
pages = {71131-71140},
pmid = {37160859},
issn = {1614-7499},
mesh = {Adult ; Humans ; Young Adult ; *Polycyclic Aromatic Hydrocarbons/metabolism ; Nutrition Surveys ; Bayes Theorem ; *Phenanthrenes ; Fluorenes ; Telomere ; Biomarkers ; },
abstract = {Although an association between single polycyclic aromatic hydrocarbons (PAHs) adult exposure and telomere length has been reported, the evidence of mixed PAHs (1-napthol, 2-napthol, 3-fluorene, 2-fluorene, 3-phenanthrene, 1-phenanthrene, 2-phenanthrene, and 1-pyrene) exposure and telomere length in the adult general population is still not clear. A total of 1460 adults over the age of 20 years provided urine information on 8 PAHs and selected covariates from the 2001-2002 National Health and Nutrition Examination Survey (NHANES). Bayesian nuclear machine regression (BKMR) was conducted to analyze these associations of telomere length in multiple PAH-exposed environments. Linear regression is mainly used for correlation analysis of PAHs with selected covariate adjustments. Restricted cubic spline (RCS) is used to estimate the correlation between selected PAHs and telomere length. After adjusting for potential covariates, PAHs mixed exposure was negatively associated with telomere length. The linear regression results showed that 2-napthol and 2-fluorene were negatively correlated with telomere length. Telomere length decreased by 1.0% in the fully adjusted model per increment of one unit in the base-10-logarithm-transformed 2-napthol and 2-fluorene concentrations (P = 0.030 and 0.049, respectively). However, the other 6 PAH metabolites were not significantly different. In addition, RCS results showed that 2-napthol has a marginal dose effect relationship with telomere length. Our present study suggested that PAHs are negatively associated with telomere length in the general population of the USA. Considering that the low level of PAHs exposure in the general population can also induce reduced telomere length and potential health risks, future research is needed to explore potential mechanisms.},
}
@article {pmid37160312,
year = {2023},
author = {Biswas, U and Deb Mallik, T and Pschirer, J and Lesche, M and Sameith, K and Jessberger, R},
title = {Cohesin SMC1β promotes closed chromatin and controls TERRA expression at spermatocyte telomeres.},
journal = {Life science alliance},
volume = {6},
number = {7},
pages = {},
pmid = {37160312},
issn = {2575-1077},
mesh = {Male ; *Chromatin/genetics ; *RNA, Long Noncoding/genetics ; Spermatocytes ; Telomere/genetics ; Animals ; *Cell Cycle Proteins ; Cohesins ; },
abstract = {Previous data showed that meiotic cohesin SMC1β protects spermatocyte telomeres from damage. The underlying reason, however, remained unknown as the expressions of telomerase and shelterin components were normal in Smc1β [-/-] spermatocytes. Here. we report that SMC1β restricts expression of the long noncoding RNA TERRA (telomeric repeat containing RNA) in spermatocytes. In somatic cell lines increased TERRA was reported to cause telomere damage through altering telomere chromatin structure. In Smc1β [-/-] spermatocytes, we observed strongly increased levels of TERRA which accumulate on damaged chromosomal ends, where enhanced R-loop formation was found. This suggested a more open chromatin configuration near telomeres in Smc1β [-/-] spermatocytes, which was confirmed by ATAC-seq. Telomere-distal regions were not affected by the absence of SMC1β but RNA-seq revealed increased transcriptional activity in telomere-proximal regions. Thus, SMC1β promotes closed chromatin specifically near telomeres and limits TERRA expression in spermatocytes.},
}
@article {pmid37156332,
year = {2023},
author = {Hart, M and Conrad, J and Barrett, E and Legg, K and Ivey, G and Lee, PHU and Yung, YC and Shim, JW},
title = {X-linked hydrocephalus genes: Their proximity to telomeres and high A + T content compared to Parkinson's disease.},
journal = {Experimental neurology},
volume = {366},
number = {},
pages = {114433},
pmid = {37156332},
issn = {1090-2430},
support = {P20 GM103434/GM/NIGMS NIH HHS/United States ; P20 GM121299/GM/NIGMS NIH HHS/United States ; U54 GM104942/GM/NIGMS NIH HHS/United States ; },
mesh = {Mice ; Rats ; Humans ; Animals ; *Parkinson Disease/genetics ; Thymine ; Genes, X-Linked ; Telomere/genetics ; *Hydrocephalus/genetics ; Mutation ; },
abstract = {Proximity to telomeres (i) and high adenine and thymine (A + T) content (ii) are two factors associated with high mutation rates in human chromosomes. We have previously shown that >100 human genes when mutated to cause congenital hydrocephalus (CH) meet either factor (i) or (ii) at 91% matching, while two factors are poorly satisfied in human genes associated with familial Parkinson's disease (fPD) at 59%. Using the sets of mouse, rat, and human chromosomes, we found that 7 genes associated with CH were located on the X chromosome of mice, rats, and humans. However, genes associated with fPD were in different autosomes depending on species. While the contribution of proximity to telomeres in the autosome was comparable in CH and fPD, high A + T content played a pivotal contribution in X-linked CH (43% in all three species) than in fPD (6% in rodents or 13% in humans). Low A + T content found in fPD cases suggests that PARK family genes harbor roughly 3 times higher chances of methylations in CpG sites or epigenetic changes than X-linked genes.},
}
@article {pmid37154569,
year = {2023},
author = {Jain, M and Madeka, S and Khattar, E},
title = {Optimization of Performance Parameters of the TAGGG Telomere Length Assay.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {194},
pages = {},
doi = {10.3791/65288},
pmid = {37154569},
issn = {1940-087X},
mesh = {Humans ; *Aging ; Telomere/genetics/metabolism ; *Telomerase/genetics/metabolism ; Oxidative Stress ; },
abstract = {Telomeres are repetitive sequences which are present at chromosomal ends; their shortening is a characteristic feature of human somatic cells. Shortening occurs due to a problem with end replication and the absence of the telomerase enzyme, which is responsible for maintaining telomere length. Interestingly, telomeres also shorten in response to various internal physiological processes, like oxidative stress and inflammation, which may be impacted due to extracellular agents like pollutants, infectious agents, nutrients, or radiation. Thus, telomere length serves as an excellent biomarker of aging and various physiological health parameters. The TAGGG telomere length assay kit is used to quantify average telomere lengths using the telomere restriction fragment (TRF) assay and is highly reproducible. However, it is an expensive method, and because of this, it is not employed routinely for large sample numbers. Here, we describe a detailed protocol for an optimized and cost-effective measurement of telomere length using Southern blots or TRF analysis and non-radioactive chemiluminescence-based detection.},
}
@article {pmid37150235,
year = {2023},
author = {Gregório, C and Thakur, S and Camara Rivero, R and Márcia Dos Santos Machado, S and Cuenin, C and Carreira, C and White, V and Cree, IA and Vukojevic, K and Glavina Durdov, M and Bersch Osvaldt, A and Ashton-Prolla, P and Herceg, Z and Talukdar, FR},
title = {Telomere length assessment and molecular characterization of TERT gene promoter in periampullary carcinomas.},
journal = {Gene},
volume = {873},
number = {},
pages = {147460},
doi = {10.1016/j.gene.2023.147460},
pmid = {37150235},
issn = {1879-0038},
mesh = {Humans ; *Telomerase/genetics/metabolism ; *Carcinoma/genetics ; Telomere Shortening ; Promoter Regions, Genetic ; Telomere/genetics/metabolism ; Mutation ; Telomere Homeostasis/genetics ; },
abstract = {Genetic and epigenetic alterations of the telomere maintenance machinery like telomere length and telomerase reverse transcriptase (encoded by TERT gene) are reported in several human malignancies. However, there is limited knowledge on the status of the telomere machinery in periampullary carcinomas (PAC) which are rare and heterogeneous groups of cancers arising from different anatomic sites around the ampulla of Vater. In the current study, we investigated the relative telomere length (RTL) and the most frequent genetic and epigenetic alterations in the TERT promoter in PAC and compared it with tumor-adjacent nonpathological duodenum (NDu). We found shorter RTLs (1.27 vs 1.33, P = 0.01) and lower TERT protein expression (p = 0.04) in PAC tissues as compared to the NDu. Although we did not find any mutation at two reactivating hotspot mutation sites of the TERT promoter, we detected polymorphism in 45% (9/20) of the cases at rs2853669 (T > C). Also, we found a hypermethylated region in the TERT promoter of PACs consisting of four CpGs (cg10896616 with Δβ 7%; cg02545192 with Δβ 9%; cg03323598 with Δβ 19%; and cg07285213 with Δβ 15%). In conclusion, we identified shorter telomeres with DNA hypermethylation in the TERT promoter region and lower TERT protein expression in PAC tissues. These results could be used further to investigate molecular pathology and develop theranostics for PAC.},
}
@article {pmid37149932,
year = {2023},
author = {Carson, LM and Flynn, RL},
title = {Highlighting vulnerabilities in the alternative lengthening of telomeres pathway.},
journal = {Current opinion in pharmacology},
volume = {70},
number = {},
pages = {102380},
pmid = {37149932},
issn = {1471-4973},
support = {R01 CA201446/CA/NCI NIH HHS/United States ; R01 CA214880/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; *Telomere Homeostasis ; DNA Replication ; *Neoplasms/drug therapy/genetics/metabolism ; Telomere/metabolism ; },
abstract = {The alternative lengthening of telomeres (ALT) pathway is a telomere elongation mechanism found in a small but often aggressive subset of cancers. Dependent on break-induced replication, telomere extension in ALT-positive cells relies on a baseline level of DNA replication stress to initiate elongation events. This results in an elevated level of DNA damage and presents a possible vulnerability to be exploited in the development of ALT-targeted cancer therapies. Currently, there are no treatment options that target the ALT mechanism or that are specific for ALT-positive tumors. Here, we review recent developments and promising directions in the development of ALT-targeted therapeutics, many of which involve tipping the balance towards inhibition or exacerbation of ALT activity to selectively target these cells.},
}
@article {pmid37149272,
year = {2023},
author = {Deregowska, A and Lewinska, A and Warzybok, A and Stoklosa, T and Wnuk, M},
title = {Telomere loss is accompanied by decreased pool of shelterin proteins TRF2 and RAP1, elevated levels of TERRA and enhanced glycolysis in imatinib-resistant CML cells.},
journal = {Toxicology in vitro : an international journal published in association with BIBRA},
volume = {90},
number = {},
pages = {105608},
doi = {10.1016/j.tiv.2023.105608},
pmid = {37149272},
issn = {1879-3177},
mesh = {Humans ; *Shelterin Complex ; Imatinib Mesylate/pharmacology ; Telomere-Binding Proteins/genetics/metabolism ; Telomeric Repeat Binding Protein 2 ; Telomere/metabolism ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy ; },
abstract = {Telomere length may be maintained by telomerase nucleoprotein complex and shelterin complex, namely TRF1, TRF2, TIN2, TPP1, POT1 and RAP1 proteins and modulated by TERRA expression. Telomere loss is observed during progression of chronic myeloid leukemia (CML) from the chronic phase (CML-CP) to the blastic phase (CML-BP). The introduction of tyrosine kinase inhibitors (TKIs), such as imatinib (IM), has changed outcome for majority of patients, however, a number of patients treated with TKIs may develop drug resistance. The molecular mechanisms underlying this phenomenon are not fully understood and require further investigation. In the present study, we demonstrate that IM-resistant BCR::ABL1 gene-positive CML K-562 and MEG-A2 cells are characterized by decreased telomere length, lowered protein levels of TRF2 and RAP1 and increased expression of TERRA in comparison to corresponding IM-sensitive CML cells and BCR::ABL1 gene-negative HL-60 cells. Furthermore, enhanced activity of glycolytic pathway was observed in IM-resistant CML cells. A negative correlation between a telomere length and advanced glycation end products (AGE) was also revealed in CD34[+] cells isolated from CML patients. In conclusion, we suggest that affected expression of shelterin complex proteins, namely TRF2 and RAP1, TERRA levels, and glucose consumption rate may promote telomere dysfunction in IM-resistant CML cells.},
}
@article {pmid37146910,
year = {2023},
author = {Thompson, AJ and Henrich, CC},
title = {Maternal depression and child telomere length: The role of genetic sensitivity.},
journal = {Journal of affective disorders},
volume = {334},
number = {},
pages = {77-82},
doi = {10.1016/j.jad.2023.04.103},
pmid = {37146910},
issn = {1573-2517},
support = {R01 HD036916/HD/NICHD NIH HHS/United States ; R01 HD039135/HD/NICHD NIH HHS/United States ; R01 HD040421/HD/NICHD NIH HHS/United States ; },
mesh = {Humans ; Child ; Child, Preschool ; Female ; *Telomere Shortening/genetics ; *Family ; Telomere/genetics ; Mothers/psychology ; },
abstract = {BACKGROUND: The stress of a mother's depression may increasingly tax psychobiological systems that help children with self-regulation, increasing children's allostatic load over time. Some evidence supports children exposed to maternal depression tend to have shorter telomeres and tend to have more somatic and psychological problems. Children having one or more A1 alleles of dopamine receptor 2 (DRD2, rs1800497), tend to have greater sensitivity to maternal depression and could experience more adverse child outcomes that contribute to greater allostatic load.<br><br>METHODS: Using the Future Families and Child Wellbeing dataset, secondary-data analyses were used to test the effect of repeated exposure to maternal depression during early childhood on children's telomere length during middle childhood moderated by children's DRD2 genotype (N&#xa0;=&#xa0;2884).<br><br>RESULTS: Greater maternal depression was not significantly associated with shorter child telomere length and this association was not moderated by DRD2 genotypes while controlling for factors associated with child telomere length.<br><br>IMPLICATIONS: The effect of maternal depression on children's TL may not be significant in populations from diverse racial-ethnic and family backgrounds during middle childhood. These findings could help further our current understanding psychobiological systems affected by maternal depression that result in adverse child outcomes.<br><br>LIMITATIONS: Even though this study used a relatively large and diverse sample, replication of DRD2 moderation in even larger samples is an important next step.},
}
@article {pmid37142951,
year = {2023},
author = {Mascarenhas Dos Santos, AC and Julian, AT and Liang, P and Juárez, O and Pombert, JF},
title = {Telomere-to-Telomere genome assemblies of human-infecting Encephalitozoon species.},
journal = {BMC genomics},
volume = {24},
number = {1},
pages = {237},
pmid = {37142951},
issn = {1471-2164},
support = {R15AI128627//National Institute of Allergy and Infectious Diseases/ ; R15AI128627//National Institute of Allergy and Infectious Diseases/ ; R15AI128627//National Institute of Allergy and Infectious Diseases/ ; },
mesh = {Humans ; *Encephalitozoon/genetics ; Epigenesis, Genetic ; Heterochromatin/genetics ; Genome, Fungal ; *Microsporidia ; Telomere/genetics ; },
abstract = {BACKGROUND: Microsporidia are diverse spore forming, fungal-related obligate intracellular pathogens infecting a wide range of hosts. This diversity is reflected at the genome level with sizes varying by an order of magnitude, ranging from less than 3 Mb in Encephalitozoon species (the smallest known in eukaryotes) to more than 50 Mb in Edhazardia spp. As a paradigm of genome reduction in eukaryotes, the small Encephalitozoon genomes have attracted much attention with investigations revealing gene dense, repeat- and intron-poor genomes characterized by a thorough pruning of molecular functions no longer relevant to their obligate intracellular lifestyle. However, because no Encephalitozoon genome has been sequenced from telomere-to-telomere and since no methylation data is available for these species, our understanding of their overall genetic and epigenetic architectures is incomplete.<br><br>METHODS: In this study, we sequenced the complete genomes from telomere-to-telomere of three human-infecting Encephalitozoon spp. -E. intestinalis ATCC 50506, E. hellem ATCC 50604 and E. cuniculi ATCC 50602- using short and long read platforms and leveraged the data generated as part of the sequencing process to investigate the presence of epigenetic markers in these genomes. We also used a mixture of sequence- and structure-based computational approaches, including protein structure prediction, to help identify which Encephalitozoon proteins are involved in telomere maintenance, epigenetic regulation, and heterochromatin formation.<br><br>RESULTS: The Encephalitozoon chromosomes were found capped by TTAGG 5-mer telomeric repeats followed by telomere associated repeat elements (TAREs) flanking hypermethylated ribosomal RNA (rRNA) gene loci featuring 5-methylcytosines (5mC) and 5-hemimethylcytosines (5hmC), themselves followed by lesser methylated subtelomeres and hypomethylated chromosome cores. Strong nucleotide biases were identified between the telomeres/subtelomeres and chromosome cores with significant changes in GC/AT, GT/AC and GA/CT contents. The presence of several genes coding for proteins essential to telomere maintenance, epigenetic regulation, and heterochromatin formation was further confirmed in the Encephalitozoon genomes.<br><br>CONCLUSION: Altogether, our results strongly support the subtelomeres as sites of heterochromatin formation in Encephalitozoon genomes and further suggest that these species might shutdown their energy-consuming ribosomal machinery while dormant as spores by silencing of the rRNA genes using both 5mC/5hmC methylation and facultative heterochromatin formation at these loci.},
}
@article {pmid37141574,
year = {2023},
author = {Wang, Z and Liu, J and Chen, H and Qiu, X and Xie, L and Kaniskan, H&#xdc; and Chen, X and Jin, J and Wei, W},
title = {Telomere Targeting Chimera Enables Targeted Destruction of Telomeric Repeat-Binding Factor Proteins.},
journal = {Journal of the American Chemical Society},
volume = {145},
number = {19},
pages = {10872-10879},
doi = {10.1021/jacs.3c02783},
pmid = {37141574},
issn = {1520-5126},
support = {R35 CA253027/CA/NCI NIH HHS/United States ; R01 CA218600/CA/NCI NIH HHS/United States ; R01 CA230854/CA/NCI NIH HHS/United States ; R01 CA260666/CA/NCI NIH HHS/United States ; R01 CA268384/CA/NCI NIH HHS/United States ; R01 CA268519/CA/NCI NIH HHS/United States ; S10 OD025132/OD/NIH HHS/United States ; S10 OD028504/OD/NIH HHS/United States ; },
mesh = {*Telomeric Repeat Binding Protein 1/genetics/metabolism ; *Telomere/metabolism ; Proteins/genetics ; Cell Line ; Proteasome Endopeptidase Complex/metabolism ; },
abstract = {Telomeres are naturally shortened after each round of cell division in noncancerous normal cells, while the activation of telomerase activity to extend telomere in the cancer cell is essential for cell transformation. Therefore, telomeres are regarded as a potential anticancer target. In this study, we report the development of a nucleotide-based proteolysis-targeting chimera (PROTAC) designed to degrade TRF1/2 (telomeric repeat-binding factor 1/2), which are the key components of the shelterin complex (telosome) that regulates the telomere length by directly interacting with telomere DNA repeats. The prototype telomere-targeting chimeras (TeloTACs) efficiently degrade TRF1/2 in a VHL- and proteosome-dependent manner, resulting in the shortening of telomeres and suppressed cancer cell proliferation. Compared to the traditional receptor-based off-target therapy, TeloTACs have potential application in a broad spectrum of cancer cell lines due to their ability to selectively kill cancer cells that overexpress TRF1/2. In summary, TeloTACs provide a nucleotide-based degradation approach for shortening the telomere and inhibiting tumor cell growth, representing a promising avenue for cancer treatment.},
}
@article {pmid37140180,
year = {2023},
author = {Robertson, CM and Xue, Y and Chowdhury, S and Maringele, L},
title = {A CDK-Dependent Phosphorylation of a Novel Domain of Rif1 Regulates its Function during Telomere Damage and Other Types of Stress.},
journal = {Molecular and cellular biology},
volume = {43},
number = {5},
pages = {185-199},
pmid = {37140180},
issn = {1098-5549},
support = {/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {DNA Replication ; Phosphorylation ; *Repressor Proteins/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; *Telomere/metabolism ; *Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Rif1 mediates telomere length, DNA replication, and DNA damage responses in budding yeast. Previous work identified several posttranslational modifications of Rif1, however none of these was shown to mediate the molecular or cellular responses to DNA damage, including telomere damage. We searched for such modifications using immunoblotting methods and the cdc13-1 and tlc1Δ models of telomere damage. We found that Rif1 is phosphorylated during telomere damage, and that serines 57 and 110 within a novel phospho-gate domain (PGD) of Rif1 are important for this modification, in cdc13-1 cells. The phosphorylation of Rif1 appeared to inhibit its accumulation on damaged chromosomes and the proliferation of cells with telomere damage. Moreover, we found that checkpoint kinases were upstream of this Rif1 phosphorylation and that the Cdk1 activity was essential for maintaining it. Apart from telomere damage, S57 and S110 were essential for Rif1 phosphorylation during the treatment of cells with genotoxic agents or during mitotic stress. We propose a speculative "Pliers" model to explain the role of the PGD phosphorylation during telomere and other types of damage.},
}
@article {pmid37140166,
year = {2023},
author = {DeBoy, EA and Tassia, MG and Schratz, KE and Yan, SM and Cosner, ZL and McNally, EJ and Gable, DL and Xiang, Z and Lombard, DB and Antonarakis, ES and Gocke, CD and McCoy, RC and Armanios, M},
title = {Familial Clonal Hematopoiesis in a Long Telomere Syndrome.},
journal = {The New England journal of medicine},
volume = {388},
number = {26},
pages = {2422-2433},
pmid = {37140166},
issn = {1533-4406},
support = {T32 GM136577/GM/NIGMS NIH HHS/United States ; R01 CA225027/CA/NCI NIH HHS/United States ; R01CA225027/CA/NCI NIH HHS/United States ; F31 HG012495/HG/NHGRI NIH HHS/United States ; K08 HL163468/HL/NHLBI NIH HHS/United States ; R01 HL119476/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; *Aging/genetics ; *Clonal Hematopoiesis/genetics ; Heterozygote ; Loss of Function Mutation/genetics ; Mutation ; *Neoplasms/genetics ; Shelterin Complex/genetics ; Syndrome ; *Telomere/genetics/physiology ; Telomere Homeostasis/genetics ; Telomere-Binding Proteins/genetics ; },
abstract = {BACKGROUND: Telomere shortening is a well-characterized cellular aging mechanism, and short telomere syndromes cause age-related disease. However, whether long telomere length is advantageous is poorly understood.<br><br>METHODS: We examined the clinical and molecular features of aging and cancer in persons carrying heterozygous loss-of-function mutations in the telomere-related gene POT1 and noncarrier relatives.<br><br>RESULTS: A total of 17 POT1 mutation carriers and 21 noncarrier relatives were initially included in the study, and a validation cohort of 6 additional mutation carriers was subsequently recruited. A majority of the POT1 mutation carriers with telomere length evaluated (9 of 13) had long telomeres (>99th percentile). POT1 mutation carriers had a range of benign and malignant neoplasms involving epithelial, mesenchymal, and neuronal tissues in addition to B- and T-cell lymphoma and myeloid cancers. Five of 18 POT1 mutation carriers (28%) had T-cell clonality, and 8 of 12 (67%) had clonal hematopoiesis of indeterminate potential. A predisposition to clonal hematopoiesis had an autosomal dominant pattern of inheritance, as well as penetrance that increased with age; somatic DNMT3A and JAK2 hotspot mutations were common. These and other somatic driver mutations probably arose in the first decades of life, and their lineages secondarily accumulated a higher mutation burden characterized by a clocklike signature. Successive generations showed genetic anticipation (i.e., an increasingly early onset of disease). In contrast to noncarrier relatives, who had the typical telomere shortening with age, POT1 mutation carriers maintained telomere length over the course of 2 years.<br><br>CONCLUSIONS: POT1 mutations associated with long telomere length conferred a predisposition to a familial clonal hematopoiesis syndrome that was associated with a range of benign and malignant solid neoplasms. The risk of these phenotypes was mediated by extended cellular longevity and by the capacity to maintain telomeres over time. (Funded by the National Institutes of Health and others.).},
}
@article {pmid37140164,
year = {2023},
author = {Vassiliou, G},
title = {Telomere Length and Clonal Hematopoiesis.},
journal = {The New England journal of medicine},
volume = {388},
number = {26},
pages = {2481-2484},
doi = {10.1056/NEJMe2303022},
pmid = {37140164},
issn = {1533-4406},
mesh = {Humans ; *Clonal Hematopoiesis/genetics ; *Hematopoiesis/genetics ; Mutation ; *Telomere/genetics ; Telomere Homeostasis/genetics ; },
}
@article {pmid37140004,
year = {2023},
author = {Gavia-García, G and Rosado-Pérez, J and Arista-Ugalde, TL and Aguiñiga-Sánchez, I and Santiago-Osorio, E and Mendoza-Núñez, VM},
title = {The consumption of Sechium edule (chayote) has antioxidant effect and prevents telomere attrition in older adults with metabolic syndrome.},
journal = {Redox report : communications in free radical research},
volume = {28},
number = {1},
pages = {2207323},
pmid = {37140004},
issn = {1743-2928},
mesh = {Humans ; Aged ; *Antioxidants/therapeutic use/metabolism ; *Metabolic Syndrome/drug therapy ; Lipid Peroxides ; Hydrogen Peroxide ; Telomere/metabolism ; },
abstract = {OBJECTIVE: To determine the effect of the consumption of Sechium edule (1.5 g/day) for six months on oxidative stress (OxS) and inflammation markers and its association with telomere length (TL) in older adults with metabolic syndrome (MetS).<br><br>METHODS: The study was conducted in a sample of 48 older adults: placebo (EP) and experimental (EG) groups. Lipoperoxides, protein carbonylation, 8-OHdG, total oxidant status (TOS), SOD, GPx, H2O2 inhibition, total antioxidant status (TAS), inflammatory cytokines (IL6, IL10, TNF-&#x3b1;), and TL were measured before and six months post-treatment.<br><br>RESULTS: We found a significant decrease in the levels of lipoperoxides, protein carbonylation, 8-OHdG, TOS in the EG in comparison PG. Likewise, a significante increase of TAS, IL-6, and IL-10 levels was found at six months post-treatment in EG in comparison with PG. TL showed a statistically significant decrease in PG compared to post-treatment EG.<br><br>CONCLUSIONS: Our findigns showed that the supplementation of Sechium edule has antioxidant, and anti-inflammatory effects, and diminushion of shortening of telomeric DNA in older adults with MetS. This would be the first study that shows that the intervention with Sechium edule has a possible geroprotective effect by preventing telomeres from shortening as usually happens in these patients. Therefore, suggesting a protection of telomeric DNA and genomic DNA.},
}
@article {pmid37139235,
year = {2023},
author = {Whittemore, K and Fossel, M},
title = {Editorial: Telomere length and species lifespan.},
journal = {Frontiers in genetics},
volume = {14},
number = {},
pages = {1199667},
pmid = {37139235},
issn = {1664-8021},
}
@article {pmid37139230,
year = {2023},
author = {Liu, M and Luo, P and Liu, L and Wei, X and Bai, X and Li, J and Wu, L and Luo, M},
title = {Immune-mediated inflammatory diseases and leukocyte telomere length: A Mendelian randomization study.},
journal = {Frontiers in genetics},
volume = {14},
number = {},
pages = {1129247},
pmid = {37139230},
issn = {1664-8021},
abstract = {Objective: To elucidate the potential causality of leukocyte telomere length (LTL) with immune-mediated inflammatory diseases (IMIDs), we conducted a Mendelian randomization (MR) study. Methods: The genetically predicted causation between LTL and IMIDs was evaluated using a two-sample MR method. We analyzed 16 major IMIDs, which included systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), ankylosing spondylitis (AS), sicca syndrome (SS), rheumatoid arthritis (RA), type 1 diabetes (T1D), primary sclerosing cholangitis (PSC), idiopathic pulmonary fibrosis (IPF), atopic dermatitis (AD), sarcoidosis, hypothyroidism, hyperthyroidism, psoriasis, and childhood asthma. The random-effects inverse-variance weighted (IVW) method was performed as the main analytical approach in MR. Various sensitivity analyses, including MR-Egger, MR robust adjusted profile score (MR-RAPS), weighted median, MR pleiotropy residual sum and outlier (MR-PRESSO) methods, weighted mode, radial plot, and radial regression, were used to guarantee the robustness of the results and detect horizontal pleiotropy. Cochran's Q value was calculated to check for heterogeneity, and the MR Steiger approach was used to test the causal direction. Results: The MR results indicated significant inverse associations of LTL with risks of psoriasis (OR: 0.77, 95% CI: 0.66-0.89, and p = 3.66 × 10[-4]), SS (OR: 0.75, CI: 0.58-0.98, and p = 0.03), RA (OR: 0.77, 95% CI: 0.68-0.88, and p = 9.85 × 10[-5]), hypothyroidism (OR: 0.84, 95% CI: 0.78-0.91, and p = 7,08 × 10[-6]), hyperthyroidism (OR: 0.60, 95% CI: 0.44-0.83, and p = 1.90 × 10[-3]), sarcoidosis (OR: 0.67, 95% CI: 0.54-0.83, and p = 2.60 × 10[-4]), and IPF (OR: 0.41, 95% CI: 0.29-0.58, and p = 4.11 × 10[-7]) in the FinnGen study. We observed that longer LTL was associated with an increased risk of AS susceptibility (OR: 1.51, 95% CI: 1.18-1.94, and p = 9.66 × 10[-4]). The results of the IVW method showed no causal relationship between TL and SLE (OR: 0.92, 95% CI: 0.62-1.38, and p = 0.69) in the FinnGen study; however, a significantly positive correlation was shown between LTL and SLE in another larger GWAS (OR: 1.87, 95% CI: 1.37-2.54, and p = 8.01 × 10[-5]). Conclusion: Our findings reveal that abnormal LTL has the potential to increase the risk of IMIDs. Therefore, it could be treated as a predictor and may provide new potential treatment targets for IMIDs. However, the change of LTL may not be the direct cause of IMIDs. Further studies should aim at the pathogenic mechanism or potential protective effects of LTL in IMIDs.},
}
@article {pmid37132239,
year = {2023},
author = {Voituron, Y and Guillaume, O and Dumet, A and Zahn, S and Criscuolo, F},
title = {Temperature-independent telomere lengthening with age in the long-lived human fish (Proteus anguinus).},
journal = {Proceedings. Biological sciences},
volume = {290},
number = {1998},
pages = {20230503},
pmid = {37132239},
issn = {1471-2954},
mesh = {Animals ; Humans ; Adult ; *Longevity ; *Telomere Homeostasis ; Temperature ; Telomere ; Telomere Shortening ; Mammals ; Fishes ; },
abstract = {Despite a number of studies showing a negative relationship between age and telomere length, the universality of this pattern has been recently challenged, mainly in ectothermic animals exhibiting diverse effects of age on telomere shortening. However, data on ectotherms may be strongly affected by the thermal history of the individuals. We thus investigated the age-related changes in relative telomere length in the skin of a small but long-lived amphibian living naturally in a stable thermal environment over its entire life, allowing comparison with other homeothermic animals like birds and mammals. The present data showed a positive relation between telomere length and individual age, independent of sex and body size. A segmented analysis highlighted a breakpoint in the telomere length-age relationship, suggesting that telomere length reached a plateau at the age of 25 years. Further studies focusing on the biology of animals that live much longer than expected based on body mass will contribute to our better understanding of how ageing processes evolved and may also bring innovation for extending human health span.},
}
@article {pmid37131110,
year = {2023},
author = {Kalal, AA and Shetty, RA and Manjappa, AB and Kulkarni, NV and Shetty, P},
title = {Prognostic significance of dysregulation of shelterin complex and its correlation with telomere length and cytogenetics in multiple myeloma.},
journal = {Journal, genetic engineering &amp; biotechnology},
volume = {21},
number = {1},
pages = {50},
pmid = {37131110},
issn = {2090-5920},
abstract = {BACKGROUND: MM (multiple myeloma) is a bone marrow disease with the accumulation of malignant plasma cells characterized by the neoplastic transformation of differentiated B cells. The onset and progression of cancer are greatly influenced by telomere dysfunction. We aimed to study the biomarker potential and prognostic significance of shelterin complex and hTERT. Telomere length and gene expression were measured using real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR), and these results were further correlated with clinical parameters.<br><br>RESULTS: Our study showed increased expression of all genes in complex, hTERT, and TL in MM (n&#x2009;=&#x2009;72) in comparison with controls (n&#x2009;=&#x2009;31). TRF2 (P&#x2009;=&#x2009;0.025) and hTERT (P&#x2009;=&#x2009;0.0002) displayed significant association among cytogenetic analysis. The receiver operative curve showed POT1 and RAP1 with a greater area under the curve (AUC). RAP1 (P&#x2009;=&#x2009;0.020) and hTERT (P&#x2009;=&#x2009;0.037) displayed to be independent prognostic markers for overall survival. Clinical parameters and genes were observed to be significantly correlated.<br><br>CONCLUSION: Our study findings showed variation in telomere-associated genes and suggest the participation of these genes as prognostic markers in MM. These results all together highlight the evaluation and role of genes involved in telomeric alteration and TL, providing the opportunity to study new therapeutic approaches in patients with MM.},
}
@article {pmid37130870,
year = {2023},
author = {Zhao, N and Yin, G and Liu, C and Zhang, W and Shen, Y and Wang, D and Lin, Z and Yang, J and Mao, J and Guo, R and Zhang, Y and Wang, F and Liu, Z and Lu, X and Liu, L},
title = {Critically short telomeres derepress retrotransposons to promote genome instability in embryonic stem cells.},
journal = {Cell discovery},
volume = {9},
number = {1},
pages = {45},
pmid = {37130870},
issn = {2056-5968},
support = {32030033//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32070858//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Telomeres, at the ends of chromosomes, protect chromosomes from fusion and preserve genomic stability. However, the molecular mechanisms underlying telomere attrition-induced genome instability remain to be understood. We systematically analyzed the expression of retrotransposons and performed genomic sequencing of different cell and tissue types with telomeres of varying lengths due to telomerase deficiency. We found that critically short telomeres altered retrotransposon activity to promote genomic instability in mouse embryonic stem cells, as evidenced by elevated numbers of single nucleotide variants, indels and copy number variations (CNVs). Transpositions of retrotransposons such as LINE1 resulting from the short telomeres can also be found in these genomes with elevated number of mutations and CNVs. Retrotransposon activation is linked to increased chromatin accessibility, and reduced heterochromatin abundance correlates with short telomeres. Re-elongation of telomeres upon recovery of telomerase partly represses retrotransposons and heterochromatin accumulation. Together, our findings suggest a potential mechanism by which telomeres maintain genomic stability by suppressing chromatin accessibility and retrotransposon activity.},
}
@article {pmid37129365,
year = {2023},
author = {Schreglmann, SR and Goncalves, T and Grant-Peters, M and Kia, DA and Soreq, L and Ryten, M and Wood, NW and Bhatia, KP and Tomita, K},
title = {Age-related telomere attrition in the human putamen.},
journal = {Aging cell},
volume = {22},
number = {7},
pages = {e13861},
pmid = {37129365},
issn = {1474-9726},
support = {C36439/A12097/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Humans ; *Putamen ; Cross-Sectional Studies ; *Telomere Shortening ; Risk Factors ; Telomere/genetics ; },
abstract = {Age is a major risk factor for neurodegenerative diseases. Shortening of leucocyte telomeres with advancing age, arguably a measure of "biological" age, is a known phenomenon and epidemiologically correlated with age-related disease. The main mechanism of telomere shortening is cell division, rendering telomere length in post-mitotic cells presumably stable. Longitudinal measurement of human brain telomere length is not feasible, and cross-sectional cortical brain samples so far indicated no attrition with age. Hence, age-related changes in telomere length in the brain and the association between telomere length and neurodegenerative diseases remain unknown. Here, we demonstrate that mean telomere length in the putamen, a part of the basal ganglia, physiologically shortens with age, like leukocyte telomeres. This was achieved by using matched brain and leukocyte-rich spleen samples from 98 post-mortem healthy human donors. Using spleen telomeres as a reference, we further found that mean telomere length was brain region-specific, as telomeres in the putamen were significantly shorter than in the cerebellum. Expression analyses of genes involved in telomere length regulation and oxidative phosphorylation revealed that both region- and age-dependent expression pattern corresponded with region-dependent telomere length dynamics. Collectively, our results indicate that mean telomere length in the human putamen physiologically shortens with advancing age and that both local and temporal gene expression dynamics correlate with this, pointing at a potential mechanism for the selective, age-related vulnerability of the nigro-striatal network.},
}
@article {pmid37128641,
year = {2023},
author = {Aguilera, P and Dubarry, M and Géli, V and Simon, MN},
title = {NPCs and APBs: two HUBs of non-canonical homology-based recombination at telomeres?.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {22},
number = {10},
pages = {1163-1168},
pmid = {37128641},
issn = {1551-4005},
mesh = {Humans ; *Saccharomyces cerevisiae/genetics/metabolism ; Nuclear Pore/metabolism ; *Telomerase/metabolism ; Homologous Recombination ; Telomere/genetics/metabolism ; Telomere Homeostasis ; },
abstract = {Apart from a few rare exceptions, the maintenance of functional telomeres by recombination-based mechanisms is restricted to accidental and/or pathological situations. Originally described in the yeast S. cerevisiae, this mode of telomere repair has gained interest with the discovery of telomerase negative cancers that use alternative lengthening of telomeres (ALT cancer) dependent on homologous recombination. In both yeast and humans, it has been shown that recombination at telomeres is spatially regulated and occurs preferentially at the nuclear pore complexes (NPCs) in yeast and at ALT-associated promyelocytic leukemia nuclear bodies (APBs) in human cells. Here, we discuss the potential relationships between these two membrane-less structures and their role in enabling unconventional recombination pathways.},
}
@article {pmid37127563,
year = {2023},
author = {Doherty, T and Dempster, E and Hannon, E and Mill, J and Poulton, R and Corcoran, D and Sugden, K and Williams, B and Caspi, A and Moffitt, TE and Delany, SJ and Murphy, TM},
title = {A comparison of feature selection methodologies and learning algorithms in the development of a DNA methylation-based telomere length estimator.},
journal = {BMC bioinformatics},
volume = {24},
number = {1},
pages = {178},
pmid = {37127563},
issn = {1471-2105},
support = {18/CRT/6183/SFI_/Science Foundation Ireland/Ireland ; },
mesh = {Algorithms ; *Telomere Homeostasis ; *DNA Methylation ; *Epigenomics/methods ; Regression Analysis ; Machine Learning ; Humans ; },
abstract = {BACKGROUND: The field of epigenomics holds great promise in understanding and treating disease with advances in machine learning (ML) and artificial intelligence being vitally important in this pursuit. Increasingly, research now utilises DNA methylation measures at cytosine-guanine dinucleotides (CpG) to detect disease and estimate biological traits such as aging. Given the challenge of high dimensionality of DNA methylation data, feature-selection techniques are commonly employed to reduce dimensionality and identify the most important subset of features. In this study, our aim was to test and compare a range of feature-selection methods and ML algorithms in the development of a novel DNA methylation-based telomere length (TL) estimator. We utilised both nested cross-validation and two independent test sets for the comparisons.<br><br>RESULTS: We found that principal component analysis in advance of elastic net regression led to the overall best performing estimator when evaluated using a nested cross-validation analysis and two independent test cohorts. This approach achieved a correlation between estimated and actual TL of 0.295 (83.4% CI [0.201, 0.384]) on the EXTEND test data set. Contrastingly, the baseline model of elastic net regression with no prior feature reduction stage performed less well in general-suggesting a prior feature-selection stage may have important utility. A previously developed TL estimator, DNAmTL, achieved a correlation of 0.216 (83.4% CI [0.118, 0.310]) on the EXTEND data. Additionally, we observed that different DNA methylation-based TL estimators, which have few common CpGs, are associated with many of the same biological entities.<br><br>CONCLUSIONS: The variance in performance across tested approaches shows that estimators are sensitive to data set heterogeneity and the development of an optimal DNA methylation-based estimator should benefit from the robust methodological approach used in this study. Moreover, our methodology which utilises a range of feature-selection approaches and ML algorithms could be applied to other biological markers and disease phenotypes, to examine their relationship with DNA methylation and predictive value.},
}
@article {pmid37122888,
year = {2023},
author = {Fattahi, M and Maghsudlu, M and Hasan Sheikhha, M},
title = {Is sperm telomere length altered in teratozoospermia specimens? A case-control study.},
journal = {International journal of reproductive biomedicine},
volume = {21},
number = {3},
pages = {229-236},
pmid = {37122888},
issn = {2476-4108},
abstract = {BACKGROUND: Male factor infertility is a multifactorial defect, and many of its etiologies are unknown. Teratozoospermia is determined by the existence of over 85% morphologically abnormal spermatozoa in semen which are almost incompetent in fertilization function. One of the most novel issues in genetic alterations studies is the variation of sperm telomere lengths (STL) and its collaboration with male infertility. The present study has been focused on STL alterations in teratozoospermia.<br><br>OBJECTIVE: Investigation of differences in telomere length of teratozoospermia specimens and sperms with normal parameters.<br><br>MATERIALS AND METHODS: In this case-control study, 60 men referred to Arak Fertility Clinic, Markazi province, Iran from November 2017 to February 2018 were categorized into teratozoospermia and normozoospermic groups. Sperm genomic DNA extraction was conducted, and STL were evaluated using quantitative polymerase chain reaction.<br><br>RESULTS: Statistical evaluation of relative telomere length was calculated by the ratio of telomere to single-copy gene for teratozoospermia and normal specimens. Results significantly demonstrated that relative telomere length in teratozoospermia samples is nearly 3 times shorter than in normal samples (p > 0.001).<br><br>CONCLUSION: Our results represent the reduction of telomeres length in teratozoospermia and suggest that this alteration might be one of the factors contributing to the sperm fertility potential of this kind of specimen. However, defining relevant molecular processes requires further detailed investigations.},
}
@article {pmid37119805,
year = {2023},
author = {Ngo, K and Gittens, TH and Gonzalez, DI and Hatmaker, EA and Plotkin, S and Engle, M and Friedman, GA and Goldin, M and Hoerr, RE and Eichman, BF and Rokas, A and Benton, ML and Friedman, KL},
title = {A comprehensive map of hotspots of de novo telomere addition in Saccharomyces cerevisiae.},
journal = {Genetics},
volume = {224},
number = {2},
pages = {},
pmid = {37119805},
issn = {1943-2631},
support = {T32 GM137793/GM/NIGMS NIH HHS/United States ; R01 AI153356/AI/NIAID NIH HHS/United States ; R35 GM136401/GM/NIGMS NIH HHS/United States ; T34 GM136451/GM/NIGMS NIH HHS/United States ; R01 GM123292/GM/NIGMS NIH HHS/United States ; F31 EY033235/EY/NEI NIH HHS/United States ; },
mesh = {Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Telomere/genetics/metabolism ; DNA Repair ; *Telomerase/genetics/metabolism ; },
abstract = {Telomere healing occurs when telomerase, normally restricted to chromosome ends, acts upon a double-strand break to create a new, functional telomere. De novo telomere addition (dnTA) on the centromere-proximal side of a break truncates the chromosome but, by blocking resection, may allow the cell to survive an otherwise lethal event. We previously identified several sequences in the baker's yeast, Saccharomyces cerevisiae, that act as hotspots of dnTA [termed Sites of Repair-associated Telomere Addition (SiRTAs)], but the distribution and functional relevance of SiRTAs is unclear. Here, we describe a high-throughput sequencing method to measure the frequency and location of telomere addition within sequences of interest. Combining this methodology with a computational algorithm that identifies SiRTA sequence motifs, we generate the first comprehensive map of telomere-addition hotspots in yeast. Putative SiRTAs are strongly enriched in subtelomeric regions where they may facilitate formation of a new telomere following catastrophic telomere loss. In contrast, outside of subtelomeres, the distribution and orientation of SiRTAs appears random. Since truncating the chromosome at most SiRTAs would be lethal, this observation argues against selection for these sequences as sites of telomere addition per se. We find, however, that sequences predicted to function as SiRTAs are significantly more prevalent across the genome than expected by chance. Sequences identified by the algorithm bind the telomeric protein Cdc13, raising the possibility that association of Cdc13 with single-stranded regions generated during the response to DNA damage may facilitate DNA repair more generally.},
}
@article {pmid37119246,
year = {2023},
author = {Kong, PL and Looi, LM and Cheah, PL},
title = {Potential utility of telomere length assessment in breast cancer in a diagnostic histopathology setting.},
journal = {The Malaysian journal of pathology},
volume = {45},
number = {1},
pages = {51-63},
pmid = {37119246},
issn = {0126-8635},
mesh = {Humans ; Female ; *Breast Neoplasms/diagnosis/genetics/metabolism ; In Situ Hybridization, Fluorescence ; Prognosis ; Telomere/metabolism/pathology ; Receptors, Antigen, T-Cell ; },
abstract = {INTRODUCTION: Telomeres shorten with cell cycling but are restored above mortality threshold in many cancers making them potentially exploitable for differentiating malignant from benign tissues, and for cancer evaluation.<br><br>MATERIALS AND METHODS: We assessed telomeres in a diagnostic histopathology setting using quantitative fluorescence in situ hybridisation on 33 fibroadenoma (FA) and 73 invasive breast carcinoma of no special type (IBC-NST) (prototypes of benign and malignant breast tumours, respectively) with paired benign, non-lesional breast tissues (BNL). Telomere lengths were expressed as telomere/chromosome-2-centromere ratio (TCR). The telomere length cut-off for malignancy was also determined.<br><br>RESULTS: Mean TCR of IBC-NST was significantly shorter than FA and BNL (p<0.001). Mean TCR of FA was shorter than BNL but not significantly (p>0.05). TCR cut-off for IBC-NST based on FA was &#x2264;0.29 (sensitivity=75.3%; specificity=78.8%), and &#x2264;0.30 based on BNL (sensitivity=76.7%; specificity=89.0%). TCR of IBC-NST did not differ in relation to histological grade, nodal and hormonal status (p>0.05) but was significantly shorter in HER2-overexpressing cancers (p<0.05).<br><br>CONCLUSION: We have demonstrated a first-step to the development of methodologybased cut-off values of mean telomere length for distinguishing benign from malignant breast tissues. Telomere length may not value-add to the standard prognostic and predictive parameters, but has potential in relation to HER2.},
}
@article {pmid37118904,
year = {2023},
author = {Lai, TP and Verhulst, S and Savage, SA and Gadalla, SM and Benetos, A and Toupance, S and Factor-Litvak, P and Susser, E and Aviv, A},
title = {Buildup from birth onward of short telomeres in human hematopoietic cells.},
journal = {Aging cell},
volume = {22},
number = {6},
pages = {e13844},
pmid = {37118904},
issn = {1474-9726},
support = {R21 ES023582/ES/NIEHS NIH HHS/United States ; KL2 TR003018/TR/NCATS NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; U01 AG066529/AG/NIA NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; },
mesh = {Male ; Aged, 80 and over ; Female ; Humans ; *Telomere Shortening ; *Longevity ; Cell Division ; Telomere/genetics ; },
abstract = {Telomere length (TL) limits somatic cell replication. However, the shortest among the telomeres in each nucleus, not mean TL, is thought to induce replicative senescence. Researchers have relied on Southern blotting (SB), and techniques calibrated by SB, for precise measurements of TL in epidemiological studies. However, SB provides little information on the shortest telomeres among the 92 telomeres in the nucleus of human somatic cells. Therefore, little is known about the accumulation of short telomeres with age, or whether it limits the human lifespan. To fill this knowledge void, we used the Telomere-Shortest-Length-Assay (TeSLA), a method that tallies and measures single telomeres of all chromosomes. We charted the age-dependent buildup of short telomeres (<3 kb) in human hematopoietic cells from 334 individuals (birth-89 years) from the general population, and 18 patients with dyskeratosis congenita-telomere biology disorders (DC/TBDs), whose hematopoietic cells have presumably reached or are close to their replicative limit. For comparison, we also measured TL with SB. We found that in hematopoietic cells, the buildup of short telomeres occurs in parallel with the shortening with age of mean TL. However, the proportion of short telomeres was lower in octogenarians from the general population than in patients with DC/TBDs. At any age, mean TL was longer and the proportion of short telomeres lower in females than in males. We conclude that though converging to the TL-mediated replicative limit, hematopoietic cell telomeres are unlikely to reach this limit during the lifespan of most contemporary humans.},
}
@article {pmid37115645,
year = {2023},
author = {Singh, M and MacKenzie, D and Desai, S and Batista, N and Zhang, D},
title = {Diagnostic Biomarkers and Therapeutic Targets of Alternative Lengthening of Telomeres-Positive Cancers.},
journal = {Genetic testing and molecular biomarkers},
volume = {27},
number = {4},
pages = {123-125},
doi = {10.1089/gtmb.2023.29069.mas},
pmid = {37115645},
issn = {1945-0257},
mesh = {Humans ; *Neoplasms/diagnosis/genetics/therapy ; Telomere/genetics/metabolism ; Biomarkers ; *Telomerase/genetics/metabolism ; },
}
@article {pmid37114543,
year = {2023},
author = {Moraes, IB and Paiva, IM and Moreira-Júnior, RE and Sartori, BM and Franco, RR and Espindola, FS and Murgas, LDS and Brunialti-Godard, AL},
title = {Ethanol Preference Leads to Alterations in Telomere Length, Mitochondria Copy Number, and Antioxidant Enzyme Activity in Zebrafish Brains.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {28},
number = {4},
pages = {73},
doi = {10.31083/j.fbl2804073},
pmid = {37114543},
issn = {2768-6698},
mesh = {Animals ; *Antioxidants/pharmacology ; Zebrafish/genetics/metabolism ; *Alcoholism ; DNA Copy Number Variations ; Catalase/genetics/metabolism/pharmacology ; Superoxide Dismutase/genetics/metabolism ; Ethanol ; Brain/metabolism ; Mitochondria/metabolism ; DNA, Mitochondrial/genetics ; Telomere/genetics/metabolism ; Oxidative Stress ; },
abstract = {BACKGROUND: The motivations for and effects of ethanol consumption vary considerably among individuals, and as such, a significant proportion of the population is prone to substance abuse and its negative consequences in the physical, social, and psychological spheres. In a biological context, the characterization of these phenotypes provides clues for understanding the neurological complexity associated with ethanol abuse behavior. Therefore, the objective of this research was to characterize four ethanol preference phenotypes described in zebrafish: Light, Heavy, Inflexible, and Negative Reinforcement.<br><br>METHODS: To do this, we evaluated the telomere length, mtDNA copy number using real-time quantitative PCR (qPCR), and the activity of these antioxidant enzymes: catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the brain, and the interactions between these biomarkers. Changes observed in these parameters were associated with ethanol consumption and alcohol abuse.<br><br>RESULTS: The Heavy, Inflexible, and Negative Reinforcement phenotypes showed ethanol preference. This was particularly the case with the Inflexible phenotype, which was the group with the greatest ethanol preference. These three phenotypes showed telomere shortening as well as high SOD/CAT and/or GPx activities, while the Heavy phenotype also showed an increase in the mtDNA copy number. However, the Light phenotype, containing individuals without ethanol preference, did not demonstrate any changes in the analyzed parameters even after being exposed to the drug. Additionally, the PCA analysis showed a tendency to cluster the Light and Control groups differently from the other ethanol preference phenotypes. There was also a negative correlation between the results of the relative telomere length and SOD and CAT activity, providing further evidence of the biological relationship between these parameters.<br><br>CONCLUSIONS: Our results showed differential molecular and biochemistry patterns in individuals with ethanol preference, suggesting that the molecular and biochemical basis of alcohol abuse behavior extends beyond its harmful physiological effects, but rather is correlated with preference phenotypes.},
}
@article {pmid37113976,
year = {2023},
author = {Duncan, E and Papatheodoulou, M and Metcalfe, NB and McLennan, D},
title = {Does pre-spawning catch and release angling affect offspring telomere dynamics in Atlantic salmon?.},
journal = {Conservation physiology},
volume = {11},
number = {1},
pages = {coad018},
pmid = {37113976},
issn = {2051-1434},
abstract = {The practice of 'catch and release' (C&amp;R) angling confers a balance between animal welfare, conservation efforts and preserving the socio-economic interests of recreational angling. However, C&amp;R angling can still cause exhaustion and physical injury, and often exposes the captured fish to the stress of air exposure. Therefore, the true conservation success of C&amp;R angling depends on whether the angled individuals then survive to reproduction and whether there are any persisting effects on subsequent generations. Here we tested the hypothesis that the stress of C&amp;R angling is then passed on to offspring. We experimentally manipulated the C&amp;R experience of wild adult salmon prior to the spawning season. These parental fish either underwent a C&amp;R simulation (which involved exercise with/without air exposure) or were left as control individuals. We then measured the telomere length of the arising offspring (at the larval stage of development) since previous studies have linked a shorter telomere length with reduced fitness/longevity and the rate of telomere loss is thought to be influenced by stress. Family-level telomere length was positively related to rate of growth. However, the telomere lengths of the salmon offspring were unrelated to the C&amp;R experience of their parents. This may be due to there being no intergenerational effect of parental stress exposure on offspring telomeres, or to any potential effects being buffered by the significant telomere elongation mechanisms that are thought to occur during the embryonic and larval stages of development. While this may suggest that C&amp;R angling has a minimal intergenerational effect on offspring fitness, there have been numerous other reports of negative C&amp;R effects, therefore we should still be aiming to mitigate and refine such practices, in order to minimize their impacts on fish populations.},
}
@article {pmid37113742,
year = {2023},
author = {Yang, Q and Nie, Z and Zhu, Y and Hao, M and Liu, S and Ding, X and Wang, F and Wang, F and Geng, X},
title = {Inhibition of TRF2 Leads to Ferroptosis, Autophagic Death, and Apoptosis by Causing Telomere Dysfunction.},
journal = {Oxidative medicine and cellular longevity},
volume = {2023},
number = {},
pages = {6897268},
pmid = {37113742},
issn = {1942-0994},
mesh = {Apoptosis/genetics ; *Autophagic Cell Death ; Cell Proliferation ; *Ferroptosis/genetics ; Telomere ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {BACKGROUND: Gastric cancer (GC) is an aggressive malignancy with a high mortality rate and poor prognosis. Telomeric repeat-binding factor 2 (TRF2) is a critical telomere protection protein. Emerging evidence indicates that TRF2 may be an essential treatment option for GC; however, the exact mechanism remains largely unknown.<br><br>OBJECTIVE: We aimed to explore the role of TRF2 in GC cells. The function and molecular mechanisms of TRF2 in the pathogenesis of GC were mainly discussed in this study.<br><br>METHODS: Relevant data from GEPIA and TCGA databases regarding TRF2 gene expression and its prognostic significance in GC samples were analyzed. Analysis of 53BP1 foci at telomeres by immunofluorescence, metaphase spreads, and telomere-specific FISH analysis was carried out to explore telomere damage and dysfunction after TRF2 depletion. CCK8 cell proliferation, trypan blue staining, and colony formation assay were performed to evaluate cell survival. Apoptosis and cell migration were determined with flow cytometry and scratch-wound healing assay, respectively. qRT-PCR and Western blotting were carried out to analyze the mRNA and protein expression levels after TRF2 depletion on apoptosis, autophagic death, and ferroptosis.<br><br>RESULTS: By searching with GEPIA and TCGA databases, the results showed that the expression levels of TRF2 were obviously elevated in the samples of GC patients, which was associated with adverse prognosis. Knockdown of TRF2 suppressed the cell growth, proliferation, and migration in GC cells, causing significant telomere dysfunction. Apoptosis, autophagic death, and ferroptosis were also triggered in this process. The pretreatment of chloroquine (autophagy inhibitor) and ferrostatin-1 (ferroptosis inhibitor) improved the survival phenotypes of GC cells.<br><br>CONCLUSION: Our data suggest that TRF2 depletion can inhibit cell growth, proliferation, and migration through the combined action of ferroptosis, autophagic death, and apoptosis in GC cells. The results indicate that TRF2 might be used as a potential target to develop therapeutic strategies for treating GC.},
}
@article {pmid37113487,
year = {2023},
author = {Wang, X and Wen, J and Qu, Q and Gu, S and Zhang, L and Li, Y and Qi, X},
title = {Association of weight range with telomere length: A retrospective cohort study.},
journal = {Frontiers in endocrinology},
volume = {14},
number = {},
pages = {1106283},
pmid = {37113487},
issn = {1664-2392},
mesh = {Adult ; Humans ; Nutrition Surveys ; Retrospective Studies ; *Aging ; *Telomere Shortening ; Telomere/genetics ; },
abstract = {OBJECTIVE: Previous research has shown a significant association between weight and telomere length, but did not take into consideration weight range. The study was to investigate the association of weight range with telomere length.<br><br>METHODS: Data of 2918 eligible participants aged 25-84 years from the National Health and Nutrition Examination Survey (NHANES) 1999-2000 cycle were analyzed. Information about demographic variables, lifestyle factors, anthropometric variables, and medical comorbidities were included. Univariate and multivariate linear regression model with adjustments for potential confounders were employed to determine the association between weight range and telomere length. A non-parametrically restricted cubic spline model was used to illustrate the possible non-linear relationship.<br><br>RESULTS: In univariate linear regression, BMImax, BMI range, and weight range all revealed significant negative associations with telomere length. However, annual rate of BMI/weight range showed a significant positive associations with telomere length. There was no significant association between telomere length and BMImin. After adjusting for potential confounders, the inverse associations persisted in BMImax (&#x3b2;=-0.003, P<0.001), BMI range (&#x3b2;=-0.002, P=0.003), and weight range (&#x3b2;=-0.001, P=0.001). Furthermore, annual rate of BMI range (&#x3b2;=-0.026, P=0.009) and weight range (&#x3b2;=-0.010, P=0.007) presented negative associations with telomere length, after adjusting for covariates in Model 2-4. The association between BMImin (&#x3b2; =-0.002, P=0.237) and telomere length still could not reach statistical significance in multivariate linear regression model. The results of restricted cubic spline analysis showed that BMImax (P for nonlinear =0.026), BMI range (P for nonlinear =0.022), weight range (P for nonlinear =0.035), annual rate of BMI range (P for nonlinear =0.030), and annual rate of weight range (P for nonlinear =0.027) all had nonlinear inverse associations with telomere length.<br><br>CONCLUSIONS: The study suggests that weight range is inversely associated with telomere length in U.S. adults. Larger weight fluctuation may accelerate telomere shortening and aging.},
}
@article {pmid37107603,
year = {2023},
author = {Adwan Shekhidem, H and Sharvit, L and Huffman, DM and Manov, I and Atzmon, G and Shams, I},
title = {Damage-Free Shortening of Telomeres Is a Potential Strategy Supporting Blind Mole-Rat Longevity.},
journal = {Genes},
volume = {14},
number = {4},
pages = {},
pmid = {37107603},
issn = {2073-4425},
mesh = {Animals ; Telomere Shortening/genetics ; Mole Rats/genetics/metabolism ; *Spalax/genetics/metabolism ; Longevity/genetics ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; Shelterin Complex ; },
abstract = {Telomere shortening or loss of shelterin components activates DNA damage response (DDR) pathways, leading to a replicative senescence that is usually coupled with a senescence-associated secretory phenotype (SASP). Recent studies suggested that telomere aberration that activates DDR may occur, irrespective of telomere length or loss of shelterin complex. The blind mole-rat (Spalax) is a subterranean rodent with exceptional longevity, and its cells demonstrate an uncoupling of senescence and SASP inflammatory components. Herein, we evaluated Spalax relative telomere length, telomerase activity, and shelterin expression, along with telomere-associated DNA damage foci (TAFs) levels with cell passage. We show that telomeres shorten in Spalax fibroblasts similar to the process in rats, and that the telomerase activity is lower. Moreover, we found lower DNA damage foci at the telomeres and a decline in the mRNA expression of two shelterin proteins, known as ATM/ATR repressors. Although additional studies are required for understanding the underling mechanism, our present results imply that Spalax genome protection strategies include effective telomere maintenance, preventing early cellular senescence induced by persistent DDR, thereby contributing to its longevity and healthy aging.},
}
@article {pmid37107534,
year = {2023},
author = {Pennarun, G and Picotto, J and Bertrand, P},
title = {Close Ties between the Nuclear Envelope and Mammalian Telomeres: Give Me Shelter.},
journal = {Genes},
volume = {14},
number = {4},
pages = {},
pmid = {37107534},
issn = {2073-4425},
mesh = {Animals ; Humans ; *Nuclear Envelope/genetics/metabolism ; *Telomere/genetics/metabolism ; DNA Replication/genetics ; Telomere-Binding Proteins/genetics/metabolism ; Meiosis ; Mammals/genetics/metabolism ; },
abstract = {The nuclear envelope (NE) in eukaryotic cells is essential to provide a protective compartment for the genome. Beside its role in connecting the nucleus with the cytoplasm, the NE has numerous important functions including chromatin organization, DNA replication and repair. NE alterations have been linked to different human diseases, such as laminopathies, and are a hallmark of cancer cells. Telomeres, the ends of eukaryotic chromosomes, are crucial for preserving genome stability. Their maintenance involves specific telomeric proteins, repair proteins and several additional factors, including NE proteins. Links between telomere maintenance and the NE have been well established in yeast, in which telomere tethering to the NE is critical for their preservation and beyond. For a long time, in mammalian cells, except during meiosis, telomeres were thought to be randomly localized throughout the nucleus, but recent advances have uncovered close ties between mammalian telomeres and the NE that play important roles for maintaining genome integrity. In this review, we will summarize these connections, with a special focus on telomere dynamics and the nuclear lamina, one of the main NE components, and discuss the evolutionary conservation of these mechanisms.},
}
@article {pmid37106187,
year = {2023},
author = {Lanna, A and D'Ambra, C},
title = {Detection of Telomere Transfer at Immunological Synapse.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2654},
number = {},
pages = {251-261},
pmid = {37106187},
issn = {1940-6029},
mesh = {*Immunological Synapses/metabolism ; Telomere/genetics/metabolism ; DNA Replication ; Telomere-Binding Proteins/metabolism ; Cellular Senescence ; *Telomerase/genetics ; },
abstract = {Eukaryotes solve the DNA-end replication problem synthesizing hexameric chromosome ends known as telomeres. Recent studies have uncovered unexpected functions of telomeres in linking synaptic signaling and vesicle transport, with at least one pathway directly involved in transferring telomeres through the immune synapse. These emerging forms of cellular communication may originate a new class of antiaging interventions based on telomere transplants.},
}
@article {pmid37105990,
year = {2023},
author = {Broderick, R and Cherdyntseva, V and Nieminuszczy, J and Dragona, E and Kyriakaki, M and Evmorfopoulou, T and Gagos, S and Niedzwiedz, W},
title = {Pathway choice in the alternative telomere lengthening in neoplasia is dictated by replication fork processing mediated by EXD2's nuclease activity.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {2428},
pmid = {37105990},
issn = {2041-1723},
support = {A24881/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Humans ; Telomere Homeostasis ; DNA Replication ; Telomere Shortening ; DNA Repair ; *Telomerase/genetics ; Telomere/genetics/metabolism ; *Neoplasms/genetics ; DNA Helicases/genetics/metabolism ; },
abstract = {Telomerase-independent cancer proliferation via the alternative lengthening of telomeres (ALT) relies upon two distinct, largely uncharacterized, break-induced-replication (BIR) processes. How cancer cells initiate and regulate these terminal repair mechanisms is unknown. Here, we establish that the EXD2 nuclease is recruited to ALT telomeres to direct their maintenance. We demonstrate that EXD2 loss leads to telomere shortening, elevated telomeric sister chromatid exchanges, C-circle formation as well as BIR-mediated telomeric replication. We discover that EXD2 fork-processing activity triggers a switch between RAD52-dependent and -independent ALT-associated BIR. The latter is suppressed by EXD2 but depends specifically on the fork remodeler SMARCAL1 and the MUS81 nuclease. Thus, our findings suggest that processing of stalled replication forks orchestrates elongation pathway choice at ALT telomeres. Finally, we show that co-depletion of EXD2 with BLM, DNA2 or POLD3 confers synthetic lethality in ALT cells, identifying EXD2 as a potential druggable target for ALT-reliant cancers.},
}
@article {pmid37105911,
year = {2023},
author = {Dang, MJ and Li, T and Zhao, LL and Li, Y and Wang, XY and Wu, YL and Lu, JL and Lu, ZW and Yang, Y and Feng, YX and Wang, HY and Jian, YT and Fan, SH and Jiang, Y and Zhang, GL},
title = {Leukocyte Telomere Length and Lacunar Stroke: A Mendelian Randomization Study.},
journal = {Biomedical and environmental sciences : BES},
volume = {36},
number = {4},
pages = {367-370},
doi = {10.3967/bes2023.042},
pmid = {37105911},
issn = {2214-0190},
mesh = {Humans ; *Stroke, Lacunar ; Mendelian Randomization Analysis ; Leukocytes ; Telomere/genetics ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; },
}
@article {pmid37104965,
year = {2023},
author = {de Punder, K and Heim, C and Martens, DS and Wadhwa, PD and Entringer, S},
title = {Maximal telomerase activity capacity (mTAC) underlies the link between the cortisol response to stress and telomere length.},
journal = {Psychoneuroendocrinology},
volume = {153},
number = {},
pages = {106120},
pmid = {37104965},
issn = {1873-3360},
support = {R01 AG050455/AG/NIA NIH HHS/United States ; R01 HD060628/HD/NICHD NIH HHS/United States ; R01 HD065825/HD/NICHD NIH HHS/United States ; },
mesh = {Male ; Humans ; Female ; *Telomerase/metabolism ; Leukocytes, Mononuclear/metabolism ; Hydrocortisone ; Telomere/metabolism ; },
abstract = {Exposure to various forms of stress has been associated with shorter telomere length (TL). However, the molecular underpinnings of this effect are poorly understood. Based on an understanding of the key role of the reverse transcriptase enzyme telomerase in regulating TL, and building upon our previous work in developing and validating a biomarker of the capacity of cells to express telomerase (maximal telomerase activity capacity (mTAC)), we examine here the hypotheses that mTAC is positively associated with TL and that the effect of stress on TL is mediated by individual differences in mTAC. In a proof-of-principle study of 28 healthy women and men we quantified the cortisol response to a standardized stress challenge, the Trier Social Stress Test (TSST), and we concurrently assessed peripheral blood mononuclear cell (PBMC) mTAC and TL. Our results indicated that higher mTAC levels were associated with longer TL (r = 0.50, p = .01). Moreover, mediational analysis suggested that the effect of the cortisol stress response on TL was mediated by mTAC (completely standardized β = -0.17, bootstrap CI95 %: -0.44 to -0.01). Thus, our findings support the premise that individual differences in the capacity of cells to up-regulate telomerase may represent a key mediator in the link between stress and TL.},
}
@article {pmid37104389,
year = {2023},
author = {McKnight, I and Raines, R and White, H and Nosoudi, N and Lee, C and Lee, PHU and Shim, JW},
title = {Mutability of druggable kinases and pro-inflammatory cytokines by their proximity to telomeres and A+T content.},
journal = {PloS one},
volume = {18},
number = {4},
pages = {e0283470},
pmid = {37104389},
issn = {1932-6203},
support = {P20 GM103434/GM/NIGMS NIH HHS/United States ; P20 GM121299/GM/NIGMS NIH HHS/United States ; U54 GM104942/GM/NIGMS NIH HHS/United States ; },
mesh = {Child ; Humans ; Animals ; Mice ; *Cytokines/genetics/therapeutic use ; Genomics/methods ; Mutation ; *Neoplasms/genetics ; Telomere/genetics ; },
abstract = {Mutations of protein kinases and cytokines are common and can cause cancer and other diseases. However, our understanding of the mutability in these genes remains rudimentary. Therefore, given previously known factors which are associated with high mutation rates, we analyzed how many genes encoding druggable kinases match (i) proximity to telomeres or (ii) high A+T content. We extracted this genomic information using the National Institute of Health Genome Data Viewer. First, among 129 druggable human kinase genes studied, 106 genes satisfied either factors (i) or (ii), resulting in an 82% match. Moreover, a similar 85% match rate was found in 73 genes encoding pro-inflammatory cytokines of multisystem inflammatory syndrome in children. Based on these promising matching rates, we further compared these two factors utilizing 20 de novo mutations of mice exposed to space-like ionizing radiation, in order to determine if these seemingly random mutations were similarly predictable with this strategy. However, only 10 of these 20 murine genetic loci met (i) or (ii), leading to only a 50% match. When compared with the mechanisms of top-selling FDA approved drugs, this data suggests that matching rate analysis on druggable targets is feasible to systematically prioritize the relative mutability-and therefore therapeutic potential-of the novel candidates.},
}
@article {pmid37102475,
year = {2023},
author = {Penrice, DD and Jalan-Sakrikar, N and Jurk, D and Passos, JF and Simonetto, DA},
title = {Telomere dysfunction in chronic liver disease: The link from aging.},
journal = {Hepatology (Baltimore, Md.)},
volume = {},
number = {},
pages = {},
pmid = {37102475},
issn = {1527-3350},
support = {KL2 TR002379/TR/NCATS NIH HHS/United States ; U01 DK130181/DK/NIDDK NIH HHS/United States ; U01 AA026886/AA/NIAAA NIH HHS/United States ; R01 AG068182/AG/NIA NIH HHS/United States ; UG3 CA268103/CA/NCI NIH HHS/United States ; R01 AG068048/AG/NIA NIH HHS/United States ; P30 DK084567/DK/NIDDK NIH HHS/United States ; },
}
@article {pmid37096215,
year = {2023},
author = {Tometten, M and Kirschner, M and Meyer, R and Begemann, M and Halfmeyer, I and Vieri, M and Kricheldorf, K and Maurer, A and Platzbecker, U and Radsak, M and Schafhausen, P and Corbacioglu, S and Höchsmann, B and Matthias Wilk, C and Hinze, C and Chromik, J and Heuser, M and Kreuter, M and Koschmieder, S and Panse, J and Isfort, S and Kurth, I and Brümmendorf, TH and Beier, F},
title = {Identification of Adult Patients With Classical Dyskeratosis Congenita or Cryptic Telomere Biology Disorder by Telomere Length Screening Using Age-modified Criteria.},
journal = {HemaSphere},
volume = {7},
number = {5},
pages = {e874},
pmid = {37096215},
issn = {2572-9241},
abstract = {Telomere biology disorders (TBD) result from premature telomere shortening due to pathogenic germline variants in telomere maintenance-associated genes. In adults, TBD are characterized by mono/oligosymptomatic clinical manifestations (cryptic TBD) contributing to severe underdiagnosis. We present a prospective multi-institutional cohort study where telomere length (TL) screening was performed in either newly diagnosed patients with aplastic anemia (AA) or if TBD was clinically suspected by the treating physician. TL of 262 samples was measured via flow-fluorescence in situ hybridization (FISH). TL was considered suspicious once below the 10th percentile of normal individuals (standard screening) or if below 6.5 kb in patients >40 years (extended screening). In cases with shortened TL, next generation sequencing (NGS) for TBD-associated genes was performed. The patients referred fell into 6 different screening categories: (1) AA/paroxysmal nocturnal hemoglobinuria, (2) unexplained cytopenia, (3) dyskeratosis congenita, (4) myelodysplastic syndrome/acute myeloid leukemia, (5) interstitial lung disease, and (6) others. Overall, TL was found to be shortened in 120 patients (n = 86 standard and n = 34 extended screening). In 17 of the 76 (22.4%) standard patients with sufficient material for NGS, a pathogenic/likely pathogenic TBD-associated gene variant was identified. Variants of uncertain significance were detected in 17 of 76 (22.4%) standard and 6 of 29 (20.7%) extended screened patients. Expectedly, mutations were mainly found in TERT and TERC. In conclusion, TL measured by flow-FISH represents a powerful functional in vivo screening for an underlying TBD and should be performed in every newly diagnosed patient with AA as well as other patients with clinical suspicion for an underlying TBD in both children and adults.},
}
@article {pmid37094463,
year = {2023},
author = {Ruan, Y and Lv, W and Li, S and Cheng, Y and Wang, D and Zhang, C and Shimizu, K},
title = {Identification of telomere-related genes associated with aging-related molecular clusters and the construction of a diagnostic model in Alzheimer's disease based on a bioinformatic analysis.},
journal = {Computers in biology and medicine},
volume = {159},
number = {},
pages = {106922},
doi = {10.1016/j.compbiomed.2023.106922},
pmid = {37094463},
issn = {1879-0534},
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism ; *Neurodegenerative Diseases ; Aging/genetics ; Telomere/genetics/metabolism/pathology ; Computational Biology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that is strongly associated with aging. Telomeres are DNA sequences that protect chromosomes from damage and shorten with age. Telomere-related genes (TRGs) may play a role in AD's pathogenesis.<br><br>OBJECTIVES: To identify TRGs related to aging clusters in AD patients, explore their immunological characteristics, and build a TRG-based prediction model for AD and AD subtypes.<br><br>METHODS: We analyzed the gene expression profiles of 97 AD samples from the GSE132903 dataset, using aging-related genes (ARGs) as clustering variables. We also assessed immune-cell infiltration in each cluster. We performed a weighted gene co-expression network analysis to identify cluster-specific differentially expressed TRGs. We compared four machine-learning models (random forest, generalized linear model [GLM], gradient boosting model, and support vector machine) for predicting AD and AD subtypes based on TRGs and validated TRGs by conducting an artificial neural network (ANN) analysis and a nomogram model.<br><br>RESULTS: We identified two aging clusters in AD patients with distinct immunological features: Cluster A had higher immune scores than Cluster B. Cluster A and the immune system are intimately associated, and this association could affect immunological function and result in AD via the digestive system. The GLM predicted AD and AD subtypes most accurately and was validated by the ANN analysis and nomogram model.<br><br>CONCLUSION: Our analyses revealed novel TRGs associated with aging clusters in AD patients and their immunological characteristics. We also developed a promising prediction model based on TRGs for assessing AD risk.},
}
@article {pmid37090094,
year = {2023},
author = {Zhou, Y and Xiong, J and Shu, Z and Dong, C and Gu, T and Sun, P and He, S and Jiang, M and Xia, Z and Xue, J and Khan, WU and Chen, F and Cheng, ZM},
title = {The telomere-to-telomere genome of Fragaria vesca reveals the genomic evolution of Fragaria and the origin of cultivated octoploid strawberry.},
journal = {Horticulture research},
volume = {10},
number = {4},
pages = {uhad027},
pmid = {37090094},
issn = {2662-6810},
abstract = {Fragaria vesca, commonly known as wild or woodland strawberry, is the most widely distributed diploid Fragaria species and is native to Europe and Asia. Because of its small plant size, low heterozygosity, and relative ease of genetic transformation, F. vesca has been a model plant for fruit research since the publication of its Illumina-based genome in 2011. However, its genomic contribution to octoploid cultivated strawberry remains a long-standing question. Here, we de novo assembled and annotated a telomere-to-telomere, gap-free genome of F. vesca 'Hawaii 4', with all seven chromosomes assembled into single contigs, providing the highest completeness and assembly quality to date. The gap-free genome is 220 785 082 bp in length and encodes 36 173 protein-coding gene models, including 1153 newly annotated genes. All 14 telomeres and seven centromeres were annotated within the seven chromosomes. Among the three previously recognized wild diploid strawberry ancestors, F. vesca, F. iinumae, and F. viridis, phylogenomic analysis showed that F. vesca and F. viridis are the ancestors of the cultivated octoploid strawberry F. × ananassa, and F. vesca is its closest relative. Three subgenomes of F. × ananassa belong to the F. vesca group, and one is sister to F. viridis. We anticipate that this high-quality, telomere-to-telomere, gap-free F. vesca genome, combined with our phylogenomic inference of the origin of cultivated strawberry, will provide insight into the genomic evolution of Fragaria and facilitate strawberry genetics and molecular breeding.},
}
@article {pmid37087699,
year = {2023},
author = {Voirin, CJ and Tsunekage, T and Liu, Y and Alexy, KF and Levin, II},
title = {Brood size is associated with apparent telomere lengthening in nestling barn swallows.},
journal = {Oecologia},
volume = {202},
number = {1},
pages = {29-40},
pmid = {37087699},
issn = {1432-1939},
support = {1856254//Division of Integrative Organismal Systems/ ; },
mesh = {Animals ; *Swallows ; Telomere Homeostasis ; Telomere ; Reproduction ; Telomere Shortening ; },
abstract = {Early life for animals is often a time of rapid growth and development. In a resource-limited environment, life history theory predicts that there must be trade-offs between resource sinks in ways that optimize future survival and reproductive success. Telomeres have emerged as putative indicators of these early life trade-offs, but there are conflicting accounts as to how developmental traits and conditions impact telomere length and dynamics. For 2 years, we studied the nestlings of a breeding population of barn swallows from day 6 to day 12 of life, measuring various ontogenetic factors to understand to what extent they explain variation in telomere length and dynamics. We unexpectedly found that telomeres lengthened between the two sampling points. Nestlings in large broods had shorter telomeres, but surprisingly, individuals that grew faster from day 6 to day 12 had longer telomeres and more telomere lengthening. Nestlings with higher mass relative to their nestmates on d6 had shorter telomeres, suggesting that the relatively fast growth barn swallows experience early in development is more costly than the relatively slower growth later in development. These effects were only found in the first year of study. Telomere lengthening may be due to the initiation of new hematopoietic cell lines during development or the expression of telomerase early in life. Favorable early life conditions and high parental investment could allow for more growth with little to no cost to telomere length or dynamics.},
}
@article {pmid37085672,
year = {2023},
author = {Piñeiro-Hermida, S and Bosso, G and Sánchez-Vázquez, R and Martínez, P and Blasco, MA},
title = {Telomerase deficiency and dysfunctional telomeres in the lung tumor microenvironment impair tumor progression in NSCLC mouse models and patient-derived xenografts.},
journal = {Cell death and differentiation},
volume = {30},
number = {6},
pages = {1585-1600},
pmid = {37085672},
issn = {1476-5403},
mesh = {Humans ; Mice ; Animals ; *Carcinoma, Non-Small-Cell Lung/genetics/pathology ; *Lung Neoplasms/pathology ; *Telomerase/genetics/metabolism ; Heterografts ; Tumor Microenvironment ; Telomere/metabolism ; Lung/metabolism ; Cell Line, Tumor ; },
abstract = {Non-small cell lung cancer (NSCLC) is a leading cause of cancer death. Tumor progression depends on interactions of cancer cells with the tumor microenvironment. Here, we find increased copy number and mRNA expression of the catalytic subunit of telomerase, TERT, in tumors from NSCLC patients, contributing to a lower survival. Moreover, TERT expression in NSCLC patients from the TCGA cohort is mainly associated to the reduced infiltration of CD8[+] T lymphocytes, as well as to increased infiltration of myeloid-derived suppressor cells (MDSCs). We also show that TERT deficiency and dysfunctional telomeres induced by 6-thio-dG treatment in mice reduced lung tumor implantation and vascularization, increased DNA damage response, cell cycle arrest and apoptosis, as well as reduced proliferation, inflammation, lung tumor immunosupression and invasion upon induction of a Lewis lung carcinoma (LLC). Furthermore, 6-thio-dG-treated human NSCLC xenografts exhibited increased telomere damage, cell cycle arrest and apoptosis, as well as reduced proliferation, resulting in a reduced tumor growth. Our results show that targeting telomeres might be an effective therapeutic strategy in NSCLC.},
}
@article {pmid37083294,
year = {2023},
author = {},
title = {Telomere Shortening Induces T-cell Dysfunction and Squamous Cell Cancers.},
journal = {Cancer discovery},
volume = {13},
number = {6},
pages = {1287},
doi = {10.1158/2159-8290.CD-RW2023-059},
pmid = {37083294},
issn = {2159-8290},
mesh = {Humans ; Telomere Shortening ; *Carcinoma, Squamous Cell/genetics/pathology ; T-Lymphocytes/metabolism ; Telomere/genetics/metabolism/pathology ; *Telomerase/genetics/metabolism ; },
abstract = {Patients with short telomere syndromes are predisposed to squamous cell carcinomas due to T-cell dysfunction.},
}
@article {pmid37079368,
year = {2023},
author = {Cortez Cardoso Penha, R and Smith-Byrne, K and Atkins, JR and Haycock, PC and Kar, S and Codd, V and Samani, NJ and Nelson, C and Milojevic, M and Gabriel, AAG and Amos, C and Brennan, P and Hung, RJ and Kachuri, L and Mckay, JD},
title = {Common genetic variations in telomere length genes and lung cancer: a Mendelian randomisation study and its novel application in lung tumour transcriptome.},
journal = {eLife},
volume = {12},
number = {},
pages = {},
pmid = {37079368},
issn = {2050-084X},
support = {K99 CA246076/CA/NCI NIH HHS/United States ; U19 CA203654/CA/NCI NIH HHS/United States ; C18281/A29019/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Humans ; Female ; Male ; Transcriptome ; Genome-Wide Association Study ; Risk Factors ; *Lung Neoplasms/genetics/metabolism ; *Adenocarcinoma of Lung/genetics/metabolism ; Leukocytes/metabolism ; Telomere/genetics/metabolism ; Genetic Variation ; RNA Splicing Factors/metabolism ; Transcription Factors/metabolism ; },
abstract = {BACKGROUND: Genome-wide association studies (GWASs) have identified genetic susceptibility variants for both leukocyte telomere length (LTL) and lung cancer susceptibility. Our study aims to explore the shared genetic basis between these traits and investigate their impact on somatic environment of lung tumours.<br><br>METHODS: We performed genetic correlation, Mendelian randomisation (MR), and colocalisation analyses using the largest available GWASs summary statistics of LTL (N=464,716) and lung cancer (N=29,239 cases and 56,450 controls). Principal components analysis based on RNA-sequencing data was used to summarise gene expression profile in lung adenocarcinoma cases from TCGA (N=343).<br><br>RESULTS: Although there was no genome-wide genetic correlation between LTL and lung cancer risk, longer LTL conferred an increased risk of lung cancer regardless of smoking status in the MR analyses, particularly for lung adenocarcinoma. Of the 144 LTL genetic instruments, 12 colocalised with lung adenocarcinoma risk and revealed novel susceptibility loci, including MPHOSPH6, PRPF6, and POLI. The polygenic risk score for LTL was associated with a specific gene expression profile (PC2) in lung adenocarcinoma tumours. The aspect of PC2 associated with longer LTL was also associated with being female, never smokers, and earlier tumour stages. PC2 was strongly associated with cell proliferation score and genomic features related to genome stability, including copy number changes and telomerase activity.<br><br>CONCLUSIONS: This study identified an association between longer genetically predicted LTL and lung cancer and sheds light on the potential molecular mechanisms related to LTL in lung adenocarcinomas.<br><br>FUNDING: Institut National du Cancer (GeniLuc2017-1-TABAC-03-CIRC-1-TABAC17-022), INTEGRAL/NIH (5U19CA203654-03), CRUK (C18281/A29019), and Agence Nationale pour la Recherche (ANR-10-INBS-09).},
}
@article {pmid37077333,
year = {2023},
author = {Zheng, B and Fu, J},
title = {Telomere dysfunction in some pediatric congenital and growth-related diseases.},
journal = {Frontiers in pediatrics},
volume = {11},
number = {},
pages = {1133102},
pmid = {37077333},
issn = {2296-2360},
abstract = {Telomere wear and dysfunction may lead to aging-related diseases. Moreover, increasing evidence show that the occurrence, development, and prognosis of some pediatric diseases are also related to telomere dysfunction. In this review, we systematically analyzed the relationship between telomere biology and some pediatric congenital and growth-related diseases and proposed new theoretical basis and therapeutic targets for the treatment of these diseases.},
}
@article {pmid37074465,
year = {2023},
author = {Saradadevi, GP and Fultz, D and Ramgopal, MK and Subramanian, AT and Prince, G and Thakur, V and Mohannath, G},
title = {Structural variation among assembled genomes facilitates development of rapid and low-cost NOR-linked markers and NOR-telomere junction mapping in Arabidopsis.},
journal = {Plant cell reports},
volume = {42},
number = {6},
pages = {1059-1069},
pmid = {37074465},
issn = {1432-203X},
support = {SB-S2-RJN-062-2017//DST-SERB, Government of India/ ; CRG/2020/002855//DST-SERB, Government of India/ ; BT/RLF/Re-Entry/47/2015//Department of Biotechnology, Ministry of Science and Technology, India/ ; },
mesh = {*Arabidopsis/genetics ; Genome-Wide Association Study ; Chromosome Mapping ; Base Sequence ; Telomere ; },
abstract = {Genome-wide structural variants we identified and new NOR-linked markers we developed would be useful for future genome-wide association studies (GWAS), and for new gene/trait mapping purposes. Bioinformatic alignment of the assembled genomes of Col-0 and Sha ecotypes of Arabidopsis thaliana revealed ~ 13,000 genome-wide structural variants involving simple insertions or deletions and repeat contractions or expansions. Using some of these structural variants, we developed new, rapid, and low-cost PCR-based molecular markers that are genetically linked to the nucleolus organizer regions (NORs). A. thaliana has two NORs, one each on chromosome 2 (NOR2) and chromosome 4 (NOR4). Both NORs are ~ 4 Mb each, and hundreds of 45S ribosomal RNA (rRNA) genes are tandemly arrayed at these loci. Using previously characterized recombinant inbred lines (RILs) derived from Sha x Col-0 crosses, we validated the utility of the newly developed NOR-linked markers in genetically mapping rRNA genes and the associated telomeres to either NOR2 or NOR4. Lastly, we sequenced Sha genome using Oxford Nanopore Technology (ONT) and used the data to obtain sequences of NOR-telomere junctions, and with the help of RILs, we mapped them as new genetic markers to their respective NORs (NOR2-TEL2N and NOR4-TEL4N). The structural variants obtained from this study would serve as valuable data for genome-wide association studies (GWAS), and to rapidly design more genome-wide genetic (molecular) markers for new gene/trait mapping purposes.},
}
@article {pmid37070671,
year = {2023},
author = {Mender, I and Siteni, S and Barron, S and Flusche, AM and Kubota, N and Yu, C and Cornelius, C and Tedone, E and Maziveyi, M and Grichuk, A and Venkateswaran, N and Conacci-Sorrell, M and Hoshida, Y and Kang, R and Tang, D and Gryaznov, S and Shay, JW},
title = {Activating an Adaptive Immune Response with a Telomerase-Mediated Telomere Targeting Therapeutic in Hepatocellular Carcinoma.},
journal = {Molecular cancer therapeutics},
volume = {22},
number = {6},
pages = {737-750},
pmid = {37070671},
issn = {1538-8514},
support = {P50 CA070907/CA/NCI NIH HHS/United States ; R01CA229275/NH/NIH HHS/United States ; R01CA211070/NH/NIH HHS/United States ; R01 CA255621/CA/NCI NIH HHS/United States ; R01 CA233794/CA/NCI NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; R01CA245548/BC/NCI NIH HHS/United States ; R01CA160417/NH/NIH HHS/United States ; },
mesh = {Humans ; *Carcinoma, Hepatocellular/drug therapy/genetics ; *Telomerase/genetics ; *Liver Neoplasms/drug therapy/genetics ; Telomere/genetics ; Adaptive Immunity ; },
abstract = {A select group of patients with hepatocellular carcinomas (HCC) benefit from surgical, radiologic, and systemic therapies that include a combination of anti-angiogenic and immune-checkpoint inhibitors. However, because HCC is generally asymptomatic in its early stages, this not only leads to late diagnosis, but also to therapy resistance. The nucleoside analogue 6-thio-dG (THIO) is a first-in-class telomerase-mediated telomere-targeting anticancer agent. In telomerase expressing cancer cells, THIO is converted into the corresponding 5'-triphosphate, which is efficiently incorporated into telomeres by telomerase, activating telomere damage responses and apoptotic pathways. Here, we show how THIO is effective in controlling tumor growth and, when combined with immune checkpoint inhibitors, is even more effective in a T-cell-dependent manner. We also show telomere stress induced by THIO increases both innate sensing and adaptive antitumor immunity in HCC. Importantly, the extracellular high-mobility group box 1 protein acts as a prototypical endogenous DAMP (Damage Associated Molecular Pattern) in eliciting adaptive immunity by THIO. These results provide a strong rationale for combining telomere-targeted therapy with immunotherapy.},
}
@article {pmid37066381,
year = {2023},
author = {Ertunc, O and Smearman, E and Zheng, Q and Hicks, JL and Brosnan-Cashman, JA and Jones, T and Gomes-Alexandre, C and Trabzonlu, L and Meeker, AK and De Marzo, AM and Heaphy, CM},
title = {Chromogenic detection of telomere lengths in situ aids the identification of precancerous lesions in the prostate.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {37066381},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; P50 CA058236/CA/NCI NIH HHS/United States ; U01 CA196390/CA/NCI NIH HHS/United States ; U54 CA274370/CA/NCI NIH HHS/United States ; },
abstract = {Telomeres are terminal chromosomal elements that are essential for the maintenance of genomic integrity. The measurement of telomere content provides useful diagnostic and prognostic information, and fluorescent methods have been developed for this purpose. However, fluorescent-based tissue assays are cumbersome for investigators to undertake, both in research and clinical settings. Here, a robust chromogenic in situ hybridization (CISH) approach was developed to visualize and quantify telomere content at single cell resolution in human prostate tissues, both frozen and formalin-fixed, paraffin-embedded (FFPE). This new assay ("Telo-CISH") produces permanently stained slides that are viewable with a standard light microscope, thus avoiding the need for specialized equipment and storage. The assay is compatible with standard immunohistochemistry, thereby allowing simultaneous assessment of histomorphology, identification of specific cell types, and assessment of telomere status. In addition, Telo-CISH eliminates the problem of autofluorescent interference that frequently occurs with fluorescent-based methods. Using this new assay, we demonstrate successful application of Telo-CISH to help identify precancerous lesions in the prostate by the presence of markedly short telomeres specifically in the luminal epithelial cells. In summary, with fewer restrictions on the types of tissues that can be tested, and increased histologic information provided, the advantages presented by this novel chromogenic assay should extend the applicability of tissue-based telomere length assessment in research and clinical settings.},
}
@article {pmid37065841,
year = {2023},
author = {Francis, M and Lindrose, A and O'Connell, S and Tristano, RI and McGarvey, C and Drury, S},
title = {The interaction of socioeconomic stress and race on telomere length in children: A systematic review and meta-analysis.},
journal = {SSM - population health},
volume = {22},
number = {},
pages = {101380},
pmid = {37065841},
issn = {2352-8273},
support = {U24 AG066528/AG/NIA NIH HHS/United States ; },
abstract = {RATIONALE: Proposed mechanisms relating early life exposures to poor health suggest that biologic indicators of risk are observable in childhood. Telomere length (TL) is a biomarker of aging, psychosocial stress, and a range of environmental exposures. In adults, exposure to early life adversity, including low socioeconomic status (SES), is predictive of shorter TL. However, results in pediatric populations have been mixed. Defining the true relation between TL and SES in childhood is expected to enhance the understanding of the biological pathways through which socioeconomic factors influence health across the life span.<br><br>OBJECTIVE: The aim of this meta-analysis was to systematically review and quantitatively assess the published literature to better understand how SES, race, and TL are related in pediatric populations.<br><br>METHODS: Studies in the United States in any pediatric population with any measure of SES were included and identified through the following electronic databases: PubMed, EMBASE, Web of Science, Medline, Socindex, CINAHL, and Psychinfo. Analysis utilized a multi-level random-effects meta-analysis accounting for multiple effect sizes within a study.<br><br>RESULTS: Thirty-two studies were included with a total of 78 effect sizes that were categorized into income-based, education-based, and composite indicators. Only three studies directly tested the relation between SES and TL as the primary study aim. In the full model, there was a significant relation between SES and TL (r&#xa0;=&#xa0;0.0220 p&#xa0;=&#xa0;0.0286). Analysis by type of SES categorization identified a significant moderating effect of income on TL (r&#xa0;=&#xa0;0.0480, 95% CI: 0.0155 to 0.0802, p&#xa0;=&#xa0;0.0045) but no significant effect for education or composite SES.<br><br>CONCLUSIONS: There is an overall association between SES and TL that is predominately due to the association with income-based SES measures implicating income disparities as a key target for efforts to address health inequity across the life span. Identification of associations between family income and biological changes in children that predict life-span health risk provides key data to support public health policies addressing economic inequality in families and presents a unique opportunity to assess the effect of prevention efforts at the biologic level.},
}
@article {pmid37061546,
year = {2023},
author = {Lai, KY and Webster, C and Kumari, S and Gallacher, JEJ and Sarkar, C},
title = {The associations of socioeconomic status with incident dementia and Alzheimer's disease are modified by leucocyte telomere length: a population-based cohort study.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {6163},
pmid = {37061546},
issn = {2045-2322},
support = {MR/T0333771/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology/genetics ; Cohort Studies ; Aging ; Social Class ; Telomere/genetics ; },
abstract = {Socio-economic status (SES) and biological aging are risk factors for dementia, including Alzheimer's disease, however, it is less clear if the associations with SES vary sufficiently across different biological age strata. We used data from 331,066 UK Biobank participants aged 38-73 with mean follow-up of 12 years to examine if associations between SES (assessed by educational attainment, employment status and household income) and dementia and Alzheimer's disease are modified by biological age (assessed by leucocyte telomere length: LTL). Diagnosis of events was ascertained through hospital admissions data. Cox regressions were used to estimate hazard ratios [HRs]. A consistent dose-response relationship was found, with participants in low SES and shorter LTL strata (double-exposed group) reporting 3.28 (95% confidence interval [CI] 2.57-4.20) and 3.44 (95% CI 2.35-5.04) times higher risks of incident dementia and Alzheimer's disease respectively, compared to those of high SES and longer LTL (least-exposed group). Of interest is a synergistic interaction between SES and LTL to increase risk of dementia (RERI 0.57, 95% CI 0.07-1.06) and Alzheimer's disease (RERI 0.79, 95% CI 0.02-1.56). Our findings that SES and biological age (LTL) are synergistic risk factors of dementia and Alzheimer's disease may suggest the need to target interventions among vulnerable sub-groups.},
}
@article {pmid37060569,
year = {2023},
author = {Savoca, V and Rivosecchi, J and Gaiatto, A and Rossi, A and Mosca, R and Gialdini, I and Zubovic, L and Tebaldi, T and Macchi, P and Cusanelli, E},
title = {TERRA stability is regulated by RALY and polyadenylation in a telomere-specific manner.},
journal = {Cell reports},
volume = {42},
number = {4},
pages = {112406},
doi = {10.1016/j.celrep.2023.112406},
pmid = {37060569},
issn = {2211-1247},
mesh = {*RNA, Long Noncoding/metabolism ; Polyadenylation ; RNA, Messenger/genetics/metabolism ; Telomere/metabolism ; },
abstract = {Telomeric repeat-containing RNA (TERRA) is a long non-coding RNA transcribed from telomeres that plays key roles in telomere maintenance. A fraction of TERRA is polyadenylated, and the presence of the poly(A) tail influences TERRA localization and stability. However, the mechanisms of TERRA biogenesis remain mostly elusive. Here, we show that the stability of TERRA transcripts is regulated by the RNA-binding protein associated with lethal yellow mutation (RALY). RALY depletion results in lower TERRA levels, impaired localization of TERRA at telomeres, and ultimately telomere damage. Importantly, we show that TERRA polyadenylation is telomere specific and that RALY preferentially stabilizes non-polyadenylated TERRA transcripts. Finally, we report that TERRA interacts with the poly(A)-binding protein nuclear 1 (PABPN1). Altogether, our results indicate that TERRA stability is regulated by the interplay between RALY and PABPN1, defined by the TERRA polyadenylation state. Our findings also suggest that different telomeres may trigger distinct TERRA-mediated responses.},
}
@article {pmid37059728,
year = {2023},
author = {Rai, R and Biju, K and Sun, W and Sodeinde, T and Al-Hiyasat, A and Morgan, J and Ye, X and Li, X and Chen, Y and Chang, S},
title = {Homology directed telomere clustering, ultrabright telomere formation and nuclear envelope rupture in cells lacking TRF2[B] and RAP1.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {2144},
pmid = {37059728},
issn = {2041-1723},
support = {5R01GM141350/GM/NIGMS NIH HHS/United States ; R01 CA202816/CA/NCI NIH HHS/United States ; },
mesh = {Lamin Type A/metabolism ; *Nuclear Envelope/metabolism ; Telomere/genetics/metabolism ; Telomere-Binding Proteins/metabolism ; *Telomeric Repeat Binding Protein 2/genetics/metabolism ; rap1 GTP-Binding Proteins/metabolism ; },
abstract = {Double-strand breaks (DSBs) due to genotoxic stress represent potential threats to genome stability. Dysfunctional telomeres are recognized as DSBs and are repaired by distinct DNA repair mechanisms. RAP1 and TRF2 are telomere binding proteins essential to protect telomeres from engaging in homology directed repair (HDR), but how this occurs remains unclear. In this study, we examined how the basic domain of TRF2 (TRF2[B]) and RAP1 cooperate to repress HDR at telomeres. Telomeres lacking TRF2[B] and RAP1 cluster into structures termed ultrabright telomeres (UTs). HDR factors localize to UTs, and UT formation is abolished by RNaseH1, DDX21 and ADAR1p110, suggesting that they contain DNA-RNA hybrids. Interaction between the BRCT domain of RAP1 and KU70/KU80 is also required to repress UT formation. Expressing TRF2[∆B] in Rap1[-/-] cells resulted in aberrant lamin A localization in the nuclear envelope and dramatically increased UT formation. Expressing lamin A phosphomimetic mutants induced nuclear envelope rupturing and aberrant HDR-mediated UT formation. Our results highlight the importance of shelterin and proteins in the nuclear envelope in repressing aberrant telomere-telomere recombination to maintain telomere homeostasis.},
}
@article {pmid37046606,
year = {2023},
author = {Sohn, EJ and Goralsky, JA and Shay, JW and Min, J},
title = {The Molecular Mechanisms and Therapeutic Prospects of Alternative Lengthening of Telomeres (ALT).},
journal = {Cancers},
volume = {15},
number = {7},
pages = {},
pmid = {37046606},
issn = {2072-6694},
support = {K22 CA245259/CA/NCI NIH HHS/United States ; },
abstract = {As detailed by the end replication problem, the linear ends of a cell's chromosomes, known as telomeres, shorten with each successive round of replication until a cell enters into a state of growth arrest referred to as senescence. To maintain their immortal proliferation capacity, cancer cells must employ a telomere maintenance mechanism, such as telomerase activation or the Alternative Lengthening of Telomeres pathway (ALT). With only 10-15% of cancers utilizing the ALT mechanism, progress towards understanding its molecular components and associated hallmarks has only recently been made. This review analyzes the advances towards understanding the ALT pathway by: (1) detailing the mechanisms associated with engaging the ALT pathway as well as (2) identifying potential therapeutic targets of ALT that may lead to novel cancer therapeutic treatments. Collectively, these studies indicate that the ALT molecular mechanisms involve at least two distinct pathways induced by replication stress and damage at telomeres. We suggest exploiting tumor dependency on ALT is a promising field of study because it suggests new approaches to ALT-specific therapies for cancers with poorer prognosis. While substantial progress has been made in the ALT research field, additional progress will be required to realize these advances into clinical practices to treat ALT cancers and improve patient prognoses.},
}
@article {pmid37046137,
year = {2023},
author = {Kuan, XY and Fauzi, NSA and Ng, KY and Bakhtiar, A},
title = {Exploring the Causal Relationship Between Telomere Biology and Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {60},
number = {8},
pages = {4169-4183},
pmid = {37046137},
issn = {1559-1182},
support = {FRGS/1/2021/SKK03/MUSM/03/1//Kementerian Pendidikan Malaysia/ ; REU00335//Monash University Malaysia/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism ; Telomere/genetics/metabolism ; Aging/genetics ; Telomere Shortening ; Biology ; },
abstract = {Telomeres, also known as the "protective caps" of our chromosomes, shorten with each cell cycle due to the end replication problem. This process, termed telomere attrition, is associated with many age-related disorders, such as Alzheimer's disease (AD). Despite the numerous studies conducted in this field, the role of telomere attrition in the onset of the disease remains unclear. To investigate the causal relationship between short telomeres and AD, this review aims to highlight the primary factors that regulate telomere length and maintain its integrity, with an additional outlook on the role of oxidative stress, which is commonly associated with aging and molecular damage. Although some findings thus far might be contradictory, telomere attrition likely plays a crucial role in the progression of AD due to its close association with oxidative stress. The currently available treatments for AD are only symptomatic without affecting the progression of the disease. The components of telomere biology discussed in this paper have previously been studied as an alternative treatment option for several diseases and have exhibited promising in vitro and in vivo results. Hence, this should provide a basis for future research to develop a potential therapeutic strategy for AD. (Created with BioRender.com).},
}
@article {pmid37042812,
year = {2023},
author = {Sosa Ponce, ML and Remedios, MH and Moradi-Fard, S and Cobb, JA and Zaremberg, V},
title = {SIR telomere silencing depends on nuclear envelope lipids and modulates sensitivity to a lysolipid.},
journal = {The Journal of cell biology},
volume = {222},
number = {7},
pages = {},
pmid = {37042812},
issn = {1540-8140},
support = {MOP-82736//CIHR/Canada ; },
mesh = {Membrane Proteins/metabolism ; *Nuclear Envelope/genetics/metabolism ; Phospholipid Ethers/metabolism ; Repressor Proteins/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; *Telomere/genetics/metabolism ; Transcription Factors/genetics/metabolism ; },
abstract = {The nuclear envelope (NE) is important in maintaining genome organization. The role of lipids in communication between the NE and telomere regulation was investigated, including how changes in lipid composition impact gene expression and overall nuclear architecture. Yeast was treated with the non-metabolizable lysophosphatidylcholine analog edelfosine, known to accumulate at the perinuclear ER. Edelfosine induced NE deformation and disrupted telomere clustering but not anchoring. Additionally, the association of Sir4 at telomeres decreased. RNA-seq analysis showed altered expression of Sir-dependent genes located at sub-telomeric (0-10 kb) regions, consistent with Sir4 dispersion. Transcriptomic analysis revealed that two lipid metabolic circuits were activated in response to edelfosine, one mediated by the membrane sensing transcription factors, Spt23/Mga2, and the other by a transcriptional repressor, Opi1. Activation of these transcriptional programs resulted in higher levels of unsaturated fatty acids and the formation of nuclear lipid droplets. Interestingly, cells lacking Sir proteins displayed resistance to unsaturated-fatty acids and edelfosine, and this phenotype was connected to Rap1.},
}
@article {pmid37041499,
year = {2023},
author = {Baird, A and Gomes, M and Souza, CA and Magner, K and Alvarez, G},
title = {Short Telomere Syndrome presenting with pulmonary fibrosis, liver cirrhosis and hepatopulmonary syndrome: a case report.},
journal = {BMC pulmonary medicine},
volume = {23},
number = {1},
pages = {114},
pmid = {37041499},
issn = {1471-2466},
mesh = {Male ; Humans ; *Hepatopulmonary Syndrome/complications/therapy ; Telomere Shortening ; Telomere ; Liver Cirrhosis/complications ; Fibrosis ; *Idiopathic Pulmonary Fibrosis/complications ; *Lung Diseases, Interstitial/complications ; },
abstract = {BACKGROUND: Idiopathic pulmonary fibrosis is thought to result from aberrant post-injury activation of epithelial cells leading to fibroblast proliferation and activation. A number of genetic aetiologies have been implicated in this disease process, including, among others, the short telomere syndromes. Short telomere syndromes follow an autosomal dominant pattern of inheritance resulting in shortened telomere length, which consequently leads to accelerated cell death. Organs with rapid cell turnover are most affected.<br><br>CASE PRESENTATION: We describe a case of a 53-year-old man with a chief complaint of cough and dyspnea on exertion. His presentation was otherwise significant for features of accelerated aging, including a history of osteoporosis and early greying, and a family history of pulmonary fibrosis in his father. Pulmonary function testing revealed a restrictive pattern with severely reduced diffusion capacity and high resolution CT of the chest showed diffuse lung disease with mild fibrosis, in pattern suggesting an alternative diagnosis to IPF. Biopsy of the lung was in keeping with&#xa0;chronic fibrosing interstitial pneumonia. Imaging of the abdomen showed splenomegaly, hepatic cirrhosis and portal hypertension. Transthoracic contrast echocardiogram showed intrapulmonary shunting consistent with hepatopulmonary syndrome. Given the constellation of early aging, idiopathic pulmonary fibrosis, cryptogenic cirrhosis and a family history of pulmonary fibrosis in this patient, the Short Telomere Syndrome was suspected. Peripheral blood was sent for Flow-cytometry FISH, which demonstrated granulocyte telomere length below the 10[th] percentile for the patient's age, consistent with a diagnosis of Short Telomere Syndrome in this clinical context. Targeted genetic testing of mutations known to be associated with short telomere was negative though it was acknowledged that the full spectrum of disease-causing mutations remains unknown. Given the extensive fibrosis on biopsy and his progressive hypoxemia he was treated with mycophenolate and prednisone. Ultimately, he developed progressive respiratory failure and underwent double lung and concurrent liver transplant 18&#xa0;months after the initial diagnosis was made.<br><br>CONCLUSIONS: Short Telomere Syndrome is a rare cause of end stage organ disease and testing lacks sensitivity making diagnosis challenging. Organ transplant is still the mainstay of treatment. Nevertheless, disease identification is important because of implications for family member screening and the possibility of future treatment options.},
}
@article {pmid37037617,
year = {2023},
author = {Schratz, KE and Flasch, DA and Atik, CC and Cosner, ZL and Blackford, AL and Yang, W and Gable, DL and Vellanki, PJ and Xiang, Z and Gaysinskaya, V and Vonderheide, RH and Rooper, LM and Zhang, J and Armanios, M},
title = {T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to squamous cancers.},
journal = {Cancer cell},
volume = {41},
number = {4},
pages = {807-817.e6},
pmid = {37037617},
issn = {1878-3686},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; R01 CA225027/CA/NCI NIH HHS/United States ; F32 HL142207/HL/NHLBI NIH HHS/United States ; T32 CA009071/CA/NCI NIH HHS/United States ; R01 CA229803/CA/NCI NIH HHS/United States ; T32 GM007309/GM/NIGMS NIH HHS/United States ; K08 HL163468/HL/NHLBI NIH HHS/United States ; R01 HL119476/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Mice ; Telomere/genetics/metabolism ; *Carcinoma, Squamous Cell/genetics ; Chromosomal Instability ; Mutation ; *Telomerase/genetics/metabolism ; T-Lymphocytes/metabolism ; },
abstract = {Patients with short telomere syndromes (STS) are predisposed to developing cancer, believed to stem from chromosome instability in neoplastic cells. We tested this hypothesis in a large cohort assembled over the last 20 years. We found that the only solid cancers to which patients with STS are predisposed are squamous cell carcinomas of the head and neck, anus, or skin, a spectrum reminiscent of cancers seen in patients with immunodeficiency. Whole-genome sequencing showed no increase in chromosome instability, such as translocations or chromothripsis. Moreover, STS-associated cancers acquired telomere maintenance mechanisms, including telomerase reverse transcriptase (TERT) promoter mutations. A detailed study of the immune status of patients with STS revealed a striking T cell immunodeficiency at the time of cancer diagnosis. A similar immunodeficiency that impaired tumor surveillance was documented in mice with short telomeres. We conclude that STS patients’ predisposition to solid cancers is due to T cell exhaustion rather than autonomous defects in the neoplastic cells themselves.},
}
@article {pmid37034403,
year = {2023},
author = {Howpay Manage, SA and Zhu, J and Fleming, AM and Burrows, CJ},
title = {Promoters vs. telomeres: AP-endonuclease 1 interactions with abasic sites in G-quadruplex folds depend on topology.},
journal = {RSC chemical biology},
volume = {4},
number = {4},
pages = {261-270},
pmid = {37034403},
issn = {2633-0679},
support = {P30 CA042014/CA/NCI NIH HHS/United States ; R01 CA090689/CA/NCI NIH HHS/United States ; R35 GM145237/GM/NIGMS NIH HHS/United States ; },
abstract = {The DNA repair endonuclease APE1 is responsible for the cleavage of abasic sites (AP) in DNA as well as binding AP in promoter G-quadruplex (G4) folds in some genes to regulate transcription. The present studies focused on the topological properties of AP-bearing G4 folds and how they impact APE1 interaction. The human telomere sequence with a tetrahydrofuran model (F) of an AP was folded in K[+]- or Na[+]-containing buffers to adopt hybrid- or basket-folds, respectively. Endonuclease and binding assays were performed with APE1 and the G4 substrates, and the data were compared to prior work with parallel-stranded VEGF and NEIL3 promoter G4s to identify topological differences. The APE1-catalyzed endonuclease assays led to the conclusion that telomere G4 folds were slightly better substrates than the promoter G4s, but the yields were all low compared to duplex DNA. In the binding assays, G4 topological differences were observed in which APE1 bound telomere G4s with dissociation constants similar to single-stranded DNA, and promoter G4s were bound with nearly ten-fold lower values similar to duplex DNA. An in-cellulo assay with the telomere G4 in a model promoter bearing a lesion failed to regulate transcription. These data support a hypothesis that G4 topology in gene promoters is a critical feature that APE1 recognizes for gene regulation.},
}
@article {pmid37033949,
year = {2023},
author = {Wei, D and Jiang, Y and Cheng, J and Wang, H and Sha, K and Zhao, J},
title = {Assessing the association of leukocyte telomere length with ankylosing spondylitis and rheumatoid arthritis: A bidirectional Mendelian randomization study.},
journal = {Frontiers in immunology},
volume = {14},
number = {},
pages = {1023991},
pmid = {37033949},
issn = {1664-3224},
mesh = {Humans ; *Spondylitis, Ankylosing/genetics/complications ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Arthritis, Rheumatoid/genetics ; Leukocytes ; Telomere/genetics ; },
abstract = {BACKGROUND: Telomere length shortening can cause senescence and apoptosis in various immune cells, resulting in immune destabilization and ageing of the organism. In this study, we aimed to systematically assess the causal relationship of leukocyte telomere length (LTL) with ankylosing spondylitis (AS) and rheumatoid arthritis (RA) using a Mendelian randomization study.<br><br>METHODS: LTL (n=472174) was obtained from the UK Biobank genome-wide association study pooled data. AS (n=229640), RA (n=212472) were obtained from FinnGen database. MR-Egger, inverse variance weighting, and weighted median methods were used to estimate the effects of causes. Cochran's Q test, MR Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots were used to look at sensitivity, heterogeneity, and multiple effects. Forward MR analysis considered LTL as the exposure and AS, RA as the outcome. Reverse MR analysis considered AS, RA as the exposure and LTL as the outcome.<br><br>RESULTS: In the forward MR analysis, inverse variance-weighted and weighted median analysis results indicated that longer LTL might be associated with increased risk of AS (IVW: OR = 1.55, 95% CI: 1.14-2.11, p = 0.006). MR Egger regression analysis showed no pleiotropy between instrumental variables (IVs) (Egger intercept= 0.008, p = 0.294). The leave-one-out analysis showed that each single nucleotide polymorphism (SNP) of AS was robust to each outcome. No significant causal effects were found between AS, RA and LTL in the reverse MR analysis.<br><br>CONCLUSION: Longer LTL may be related with an increased risk of developing AS, and these findings provide a foundation for future clinical research on the causal association between LTL and AS.},
}
@article {pmid37031574,
year = {2023},
author = {Flor-Alemany, M and Acosta-Manzano, P and Migueles, JH and Varela-López, A and Baena-García, L and Quiles, JL and Aparicio, VA},
title = {Influence of an exercise intervention plus an optimal Mediterranean diet adherence during pregnancy on the telomere length of the placenta. The GESTAFIT project.},
journal = {Placenta},
volume = {136},
number = {},
pages = {42-45},
doi = {10.1016/j.placenta.2023.04.002},
pmid = {37031574},
issn = {1532-3102},
mesh = {Humans ; Female ; Pregnancy ; *Placenta ; *Diet, Mediterranean ; Telomere Shortening ; Telomere ; Exercise Therapy ; },
abstract = {We aimed to investigate whether the effects of exercise on placental relative telomere length (RTL) after delivery are modulated by the Mediterranean diet [MD] adherence in 65 pregnant women (control n = 34, exercise n = 31). No differences were found in placental RTL between the exercise and the control groups (p = 0.557). The interaction-term between exercise and MD adherence with placental RTL was significant (p = 0.001). Specifically, women in the exercise group showed longer placental RTL after birth compared to controls (referent group), only for those women with a high MD adherence (mean difference = 0.467, p=0.010). A concurrent-exercise training plus an optimal MD adherence during pregnancy might prevent the placental RTL shortening.},
}
@article {pmid37028414,
year = {2023},
author = {Gaela, VM and Chen, LY},
title = {Ends end it via mitochondria: A telomere-dependent tumor suppressive mechanism acts during replicative crisis.},
journal = {Molecular cell},
volume = {83},
number = {7},
pages = {1027-1029},
doi = {10.1016/j.molcel.2023.03.012},
pmid = {37028414},
issn = {1097-4164},
mesh = {Humans ; Telomere/metabolism ; DNA Replication ; *RNA, Long Noncoding ; *Neoplasms/metabolism ; Mitochondria/metabolism ; },
abstract = {Nassour et al.[1] report that telomere dysfunction communicates with mitochondria via the ZBP1-TERRA-MAVS axis. This pathway activates a detrimental innate immune response that may promote the elimination of cells prone to oncogenic transformation during replicative crisis, thus serving as a telomere-dependent tumor-suppressive mechanism.},
}
@article {pmid37025175,
year = {2023},
author = {González-Amor, M and Dorado, B and Andrés, V},
title = {Emerging roles of interferon-stimulated gene-15 in age-related telomere attrition, the DNA damage response, and cardiovascular disease.},
journal = {Frontiers in cell and developmental biology},
volume = {11},
number = {},
pages = {1128594},
pmid = {37025175},
issn = {2296-634X},
abstract = {Population aging and age-related cardiovascular disease (CVD) are becoming increasingly prevalent worldwide, generating a huge medical and socioeconomic burden. The complex regulation of aging and CVD and the interaction between these processes are crucially dependent on cellular stress responses. Interferon-stimulated gene-15 (ISG15) encodes a ubiquitin-like protein expressed in many vertebrate cell types that can be found both free and conjugated to lysine residues of target proteins via a post-translational process termed ISGylation. Deconjugation of ISG15 (deISGylation) is catalyzed by the ubiquitin-specific peptidase 18 (USP18). The ISG15 pathway has mostly been studied in the context of viral and bacterial infections and in cancer. This minireview summarizes current knowledge on the role of ISG15 in age-related telomere shortening, genomic instability, and DNA damage accumulation, as well as in hypertension, diabetes, and obesity, major CVD risk factors prevalent in the elderly population.},
}
@article {pmid37024489,
year = {2023},
author = {Kusuma, FK and Prabhu, A and Tieo, G and Ahmed, SM and Dakle, P and Yong, WK and Pathak, E and Madan, V and Jiang, YY and Tam, WL and Kappei, D and Dröge, P and Koeffler, HP and Jeitany, M},
title = {Signalling inhibition by ponatinib disrupts productive alternative lengthening of telomeres (ALT).},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {1919},
pmid = {37024489},
issn = {2041-1723},
support = {R01 CA200992/CA/NCI NIH HHS/United States ; },
mesh = {*Telomere ; Cell Survival ; *Signal Transduction/drug effects ; Gene Expression Regulation ; DNA Repair ; DNA Replication ; JNK Mitogen-Activated Protein Kinases/metabolism ; Humans ; Animals ; Mice ; Cell Line, Tumor ; },
abstract = {Alternative lengthening of telomeres (ALT) supports telomere maintenance in 10-15% of cancers, thus representing a compelling target for therapy. By performing anti-cancer compound library screen on isogenic cell lines and using extrachromosomal telomeric C-circles, as a bona fide marker of ALT activity, we identify a receptor tyrosine kinase inhibitor ponatinib that deregulates ALT mechanisms, induces telomeric dysfunction, reduced ALT-associated telomere synthesis, and targets, in vivo, ALT-positive cells. Using RNA-sequencing and quantitative phosphoproteomic analyses, combined with C-circle level assessment, we find an ABL1-JNK-JUN signalling circuit to be inhibited by ponatinib and to have a role in suppressing telomeric C-circles. Furthermore, transcriptome and interactome analyses suggest a role of JUN in DNA damage repair. These results are corroborated by synergistic drug interactions between ponatinib and either DNA synthesis or repair inhibitors, such as triciribine. Taken together, we describe here a signalling pathway impacting ALT which can be targeted by a clinically approved drug.},
}
@article {pmid37021555,
year = {2023},
author = {Wang, H and Ma, T and Zhang, X and Chen, W and Lan, Y and Kuang, G and Hsu, SJ and He, Z and Chen, Y and Stewart, J and Bhattacharjee, A and Luo, Z and Price, C and Feng, X},
title = {CTC1 OB-B interaction with TPP1 terminates telomerase and prevents telomere overextension.},
journal = {Nucleic acids research},
volume = {51},
number = {10},
pages = {4914-4928},
pmid = {37021555},
issn = {1362-4962},
support = {R01 GM041803/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; Cell Line ; DNA, Single-Stranded/genetics ; Mutation ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {CST (CTC1-STN1-TEN1) is a telomere associated complex that binds ssDNA and is required for multiple steps in telomere replication, including termination of G-strand extension by telomerase and synthesis of the complementary C-strand. CST contains seven OB-folds which appear to mediate CST function by modulating CST binding to ssDNA and the ability of CST to recruit or engage partner proteins. However, the mechanism whereby CST achieves its various functions remains unclear. To address the mechanism, we generated a series of CTC1 mutants and studied their effect on CST binding to ssDNA and their ability to rescue CST function in CTC1-/- cells. We identified the OB-B domain as a key determinant of telomerase termination but not C-strand synthesis. CTC1-ΔB expression rescued C-strand fill-in, prevented telomeric DNA damage signaling and growth arrest. However, it caused progressive telomere elongation and the accumulation of telomerase at telomeres, indicating an inability to limit telomerase action. The CTC1-ΔB mutation greatly reduced CST-TPP1 interaction but only modestly affected ssDNA binding. OB-B point mutations also weakened TPP1 association, with the deficiency in TPP1 interaction tracking with an inability to limit telomerase action. Overall, our results indicate that CTC1-TPP1 interaction plays a key role in telomerase termination.},
}
@article {pmid37021005,
year = {2023},
author = {Domínguez-de-Barros, A and Sifaoui, I and Borecka, Z and Dorta-Guerra, R and Lorenzo-Morales, J and Castro-Fuentes, R and Córdoba-Lanús, E},
title = {An approach to the effects of longevity, sexual maturity, and reproduction on telomere length and oxidative stress in different Psittacidae species.},
journal = {Frontiers in genetics},
volume = {14},
number = {},
pages = {1156730},
pmid = {37021005},
issn = {1664-8021},
abstract = {Introduction: Aging is a multifactorial process that includes molecular changes such as telomere shortening. Telomeres shorten progressively with age in vertebrates, and their shortening rate has a significant role in determining the lifespan of a species. However, DNA loss can be enhanced by oxidative stress. The need for novel animal models has recently emerged as a tool to gather more information about the human aging process. Birds live longer than other mammals of the same size, and Psittacidae species are the most persevering of them, due to special key traits. Methods: We aimed to determine telomere length by qPCR, and oxidative stress status using colorimetric and fluorescence methods in different species of the order Psittaciformes with different lifespans. Results: We found that telomeres shorten with age for both long- and short-lived birds (p < 0.001 and p = 0.004, respectively), with long-lived birds presenting longer telomeres than short-lived ones (p = 0.001). In addition, short-lived birds accumulated more oxidative stress products than long-lived birds (p = 0.013), who showed a better antioxidant capacity (p < 0.001). Breeding was found related to telomere shortening in all species (p < 0.001 and p = 0.003 for long- and short-lived birds). Short-lived birds, especially breeding females, increased their oxidative stress products when breeding (p = 0.021), whereas long-lived birds showed greater resistance and even increased their antioxidant capacity (p = 0.002). Conclusion: In conclusion, the relationship between age and telomere length in Psittacidae was verified. The influence of breeding increased cumulative oxidative damage in short-lived species, while long-lived species may counteract this damage.},
}
@article {pmid37020849,
year = {2023},
author = {Lu, L and Zeng, H and Wan, B and Sun, M},
title = {Leukocyte telomere length and bipolar disorder risk: evidence from Mendelian randomization analysis.},
journal = {PeerJ},
volume = {11},
number = {},
pages = {e15129},
pmid = {37020849},
issn = {2167-8359},
mesh = {Humans ; *Bipolar Disorder ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Leukocytes ; Telomere ; },
abstract = {OBJECTIVE: We aim to test whether leukocyte telomere length (LTL) is causally associated with the risk of bipolar disorder (BD) using the Mendelian randomization (MR) method.<br><br>METHODS: Results of a genome-wide association study (GWAS) conducted with 472,174 individuals of European descent were used to screen for single-nucleotide polymorphisms (SNPs) related with LTL traits. Summary-level data for BD (7,647 cases and 27,303 controls) were obtained from UK Biobank. An inverse-variance-weighted (IVW) method was employed as the primary MR analysis. Sensitivity analyses were conducted via MR-Egger, maximum likelihood, MR-pleiotropy residual sum outlier (MR-PRESSO), and MR-robust adjusted profile score (MR-RAPS) methods. Finally, the MR Steiger test was utilized to validate the hypothesized relationship between exposure and outcome.<br><br>RESULTS: Two-sample MR analysis revealed inverse relationships between genetically predicted LTL and BD risk (IVW OR [odds ratio] = 0.800, 95% CI [0.647-0.989] P = 0.039). Genetically predicted LTL exhibits a consistent connection with BD across five MR methods. Sensitivity analyses showed that the genetically determined effect of LTL on BD was stable and reliable. Furthermore, the MR Steiger test demonstrated that LTL was causal for BD rather than the opposite (P < 0.001).<br><br>CONCLUSION: Our findings show that genetically determined LTL reduces the risk of BD. More research is required to clarify the mechanisms underlying this apparent causal connection. In addition, these findings may be useful for developing strategies for the prevention and treatment of BD.},
}
@article {pmid37018627,
year = {2023},
author = {Ling, X and Cui, H and Chen, Q and Yang, W and Zou, P and Yang, H and Zhou, N and Deng, J and Liu, J and Cao, J and Ao, L},
title = {Sperm telomere length is associated with sperm nuclear DNA integrity and mitochondrial DNA abnormalities among healthy male college students in Chongqing, China.},
journal = {Human reproduction (Oxford, England)},
volume = {38},
number = {6},
pages = {1036-1046},
doi = {10.1093/humrep/dead065},
pmid = {37018627},
issn = {1460-2350},
mesh = {Humans ; Male ; *DNA, Mitochondrial/genetics/metabolism ; *Semen ; Prospective Studies ; Follow-Up Studies ; Cross-Sectional Studies ; Spermatozoa/metabolism ; Semen Analysis ; Mitochondria/genetics ; Telomere ; Students ; },
abstract = {STUDY QUESTION: Is sperm telomere length (STL) associated with sperm nuclear DNA damage and mitochondrial DNA abnormalities?<br><br>SUMMARY ANSWER: Sperm telomere length is related to sperm nuclear DNA integrity and mitochondrial DNA abnormalities in healthy young college students.<br><br>WHAT IS KNOWN ALREADY: Many studies have revealed the correlations between sperm genetic alterations in both the nucleus and mitochondria and sperm functionality, however, the possible associations between the telomere, an important component of chromosome, and conventional indicators of mitochondrial DNA and nuclear DNA changes have not been investigated.<br><br>STUDY DESIGN, SIZE, DURATION: A prospective cohort study, Male Reproductive Health in Chongqing College Students (MARHCS), was conducted from June 2013 to June 2015. We pooled data collected from the follow-up study in 2014 and a total of 444 participants were included.<br><br>STL was measured by quantitative (Q)-PCR. Sperm nuclear DNA integrity was determined using sperm chromatin structure assay (SCSA) and comet assay. Mitochondrial DNA damage was assessed by mitochondrial DNA copy number (mtDNAcn) evaluated with Q-PCR, and mtDNA integrity was determined with long PCR.<br><br>The univariable-linear regression analysis revealed that STL was significantly positively correlated with markers of sperm nuclear DNA damage including the DNA fragmentation index (DFI) and comet parameters (the percentage of DNA in the tail, tail length, comet length, and tail moment). Additionally, STL was also significantly positively correlated with mtDNAcn and significantly negatively correlated with mtDNA integrity. After adjustment for potential confounders, these relationships remained appreciable. Moreover, we investigated potential effects of biometric factors, including age, parental age at conception, and BMI on STL and found that STL was increased with paternal age at conception.<br><br>A mechanistic explanation of the correlation between STL, sperm nuclear DNA integrity, and mtDNA abnormalities cannot be provided with a cross-sectional study design, so well-designed longitudinal studies are still necessary. In addition, a single semen samples were provided and were not all obtained at the same time point, which may increase the intraindividual bias in this study.<br><br>The findings extend the literature including assessment of mitochondrial dysfunction, sperm nuclear DNA damage, and telomere length and provide new insights into the relevance of STL in male reproduction.<br><br>This work was supported by the National Natural Science Foundation of China (No. 82073590), the National Natural Science Foundation of China (No. 81903363), the National Natural Science Foundation of China (No. 82130097), and the National Key R&amp;D Program of China (2022YFC2702900). The authors declare no conflicts of interest.<br><br>TRIAL REGISTRATION NUMBER: N/A.},
}
@article {pmid37014460,
year = {2023},
author = {Salem, S and Ashaat, E},
title = {Association of Relative Telomere Length and LINE-1 Methylation with Autism but not with Severity.},
journal = {Journal of autism and developmental disorders},
volume = {},
number = {},
pages = {},
pmid = {37014460},
issn = {1573-3432},
support = {33432//Science and Technology Development Fund (STDF)/ Egypt/ ; },
abstract = {Autism is associated with genomic instability, which is regulated by telomere length (TL) and index of global methylation (LINE-1). This study will determine relative TL (RTL) and LINE-1 methylation percentage for 69 patients and 33 control subjects to evaluate their potential role as biomarkers for autism. The results displayed a significant decrease of both RTL and LINE-1 methylation in autistic cases relative to controls (P < 0.001). Analysis of receiver operating characteristics curve revealed that both of RTL and LINE-1 methylation percentage have the ability to serve as autism biomarkers (area under the curve = 0.817 and 0.889, respectively). The statistical analysis revealed positive correlation between the two biomarkers (correlation coefficient = 0.439 and P < 0.001).},
}
@article {pmid37013192,
year = {2023},
author = {Moreno, SP and Fusté, JM and Kaiser, M and Li, JSZ and Nassour, J and Haggblom, C and Denchi, EL and Karlseder, J},
title = {TZAP overexpression induces telomere dysfunction and ALT-like activity in ATRX/DAXX-deficient cells.},
journal = {iScience},
volume = {26},
number = {4},
pages = {106405},
pmid = {37013192},
issn = {2589-0042},
support = {R01 CA234047/CA/NCI NIH HHS/United States ; },
abstract = {The appropriate regulation of telomere length homeostasis is crucial for the maintenance of genome integrity. The telomere-binding protein TZAP has been suggested to regulate telomere length by promoting t-circle and c-circle excisions through telomere trimming, yet the molecular mechanisms by which TZAP functions at telomeres are not understood. Using a system based on TZAP overexpression, we show that efficient TZAP recruitment to telomeres occurs in the context of open telomeric chromatin caused by loss of ATRX/DAXX independently of H3.3 deposition. Moreover, our data indicate that TZAP binding to telomeres induces telomere dysfunction and ALT-like activity, resulting in the generation of t-circles and c-circles in a Bloom-Topoisomerase IIIα-RMI1-RMI2 (BTR)-dependent manner.},
}
@article {pmid37012261,
year = {2023},
author = {Wojcicki, JM and Gill, RM and Wilson, L and Lin, J and Rosenthal, P},
title = {Shorter leukocyte telomere length protects against NAFLD progression in children.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {5446},
pmid = {37012261},
issn = {2045-2322},
support = {U01 DK061732/DK/NIDDK NIH HHS/United States ; U01 DK061718/DK/NIDDK NIH HHS/United States ; U01 DK061737/DK/NIDDK NIH HHS/United States ; U01 DK061713/DK/NIDDK NIH HHS/United States ; U01 DK061738/DK/NIDDK NIH HHS/United States ; U01 DK061728/DK/NIDDK NIH HHS/United States ; U01 DK061734/DK/NIDDK NIH HHS/United States ; U24 DK061730/DK/NIDDK NIH HHS/United States ; U01 DK061730/DK/NIDDK NIH HHS/United States ; P30 DK098722/DK/NIDDK NIH HHS/United States ; },
mesh = {Adult ; Child ; Humans ; Disease Progression ; Inflammation/pathology ; Leukocytes/pathology ; Liver Cirrhosis/complications ; *Non-alcoholic Fatty Liver Disease/pathology ; Telomere/genetics/pathology ; },
abstract = {Leukocyte telomere length (LTL) gets shorter with each cell division and is also sensitive to reactive oxygen species damage and inflammatory processes. Studies in adults with non-alcoholic fatty liver disease (NAFLD) have found that increased fibrosis but not ALT levels are associated with shorter LTL. Few pediatric studies have been conducted; as such, we sought to evaluate potential associations between LTL and liver disease and liver disease progression in pediatric patients. Using data from the Treatment of NAFLD in Children (TONIC) randomized controlled trial, we assessed the potential predictive relationship between LTL and liver disease progression based on two successive liver biopsies over 96 weeks. We assessed the potential relationship between LTL and child age, sex, and race/ethnicity and features of liver disease including components of histology. We subsequently evaluated predictors for improvement in non-alcoholic steatohepatitis (NASH) at 96 weeks including LTL. We also assessed predictors of lobular inflammation improvement at 96 weeks using multivariable models. Mean LTL at baseline was 1.33 ± 0.23 T/S. Increasing lobular and portal inflammation were associated with longer LTL. In multivariable models, greater lobular inflammation at baseline was associated with longer LTL (Coeff 0.03, 95% CI 0.006-0.13; p = 0.03). Longer LTL at baseline was associated with worsening lobular inflammation at 96 weeks (Coeff 2.41, 95% CI 0.78-4.04; p < 0.01). There was no association between liver fibrosis and LTL. The association between LTL and pediatric NASH does not parallel adults with no association between fibrosis stage and NASH. Conversely, longer LTL was associated with more lobular inflammation at baseline and increased lobular inflammation over the 96-week period. Longer LTL in children may indicate greater risk for future complications from NASH.},
}
@article {pmid37010429,
year = {2023},
author = {Zhu, M and Wu, C and Wu, X and Song, G and Li, M and Wang, Q},
title = {POP1 promotes the progression of breast cancer through maintaining telomere integrity.},
journal = {Carcinogenesis},
volume = {44},
number = {3},
pages = {252-262},
doi = {10.1093/carcin/bgad017},
pmid = {37010429},
issn = {1460-2180},
mesh = {Female ; Humans ; *Apoptosis Regulatory Proteins/metabolism ; Cell Cycle Checkpoints ; Cell Line, Tumor ; Cell Proliferation/genetics ; *Endoribonucleases ; Gene Expression Regulation, Neoplastic ; *Ribonucleoproteins/metabolism ; Telomere/genetics ; *Triple Negative Breast Neoplasms/genetics ; },
abstract = {Breast cancer is one of the most common and disastrous neoplasm for women worldwide, especially triple-negative breast cancer (TNBC). Emerging evidences have demonstrated that RNase subunits are closely related to the occurrence and development of malignant tumors. However, the functions and underlying molecular mechanisms of Processing of Precursor 1 (POP1), a core component of RNase subunits, in breast cancer development have not been fully defined. Our study identified the POP1was upregulated in breast cancer cell lines and tissues and patients with higher POP1 expression were associated with poor outcomes. Overexpression of POP1 promoted cell progression in breast cancer cells, whereas silencing of POP1 induced cell cycle arrest. Moreover, Xenograft model reproduced its growth regulatory roles in breast cancer in vivo. Mechanistically, POP1 interacted and activated the telomerase complex by stabilizing the telomerase RNA component (TERC), thus protecting telomeres from shortening during division. Collectively, our findings demonstrate POP1 may as a novel prognostic marker and a therapeutic target for the management of breast cancer.},
}
@article {pmid37003649,
year = {2023},
author = {Luna-Carrascal, J and Olivero-Verbel, J and Acosta-Hoyos, AJ and Quintana-Sosa, M},
title = {Auto repair workers exposed to PM2.5 particulate matter in Barranquilla, Colombia: Telomere length and hematological parameters.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {887},
number = {},
pages = {503597},
doi = {10.1016/j.mrgentox.2023.503597},
pmid = {37003649},
issn = {1879-3592},
mesh = {Humans ; *Particulate Matter/toxicity ; Colombia ; Glutathione Transferase/genetics ; Polymorphism, Genetic ; Polymorphism, Restriction Fragment Length ; *Occupational Exposure/adverse effects/analysis ; Genotype ; Telomere ; },
abstract = {Exposure to 2.5 µm particulate matter (PM2.5) in automotive repair shops is associated with risks to health. We evaluated the effects of occupational exposure to PM2.5 among auto repair-shop workers. Blood and urine samples were collected from 110 volunteers from Barranquilla, Colombia: 55 active workers and 55 controls. PM2.5 concentrations were assessed at each of the sampling sites and chemical content was analyzed by SEM-EDS electron microscopy. The biological samples obtained were peripheral blood (hematological profiling, DNA extraction) and urine (malondialdehyde concentration). Telomere length was assessed by qPCR and polymorphisms in the glutathione transferase genes GSTT1 and GSTM1 by PCR-RFLP, with confirmation by allelic exclusion. White blood cell (WBC), lymphocyte (LYM%) and platelet (PLT) counts and the malondialdehyde concentration were higher (4.10 ± 0.93) in the exposed group compared to the control group (1.56 ± 0.96). TL was shorter (5071 ± 891) in the exposed individuals compared to the control group (6271 ± 805). White blood cell (WBC) and platelet counts were positively associated with exposure. Age and TBARS were correlated with TL in exposed individuals. The GSTT1 gene alleles were not in Hardy-Weinberg (H-W) equilibrium. The GSTM1 gene alleles were in H-W equilibrium and allelic exclusion analysis confirmed the presence of heterozygous GSTM1 genotypes. SEM-EDS analysis showed the presence of potentially toxic elements, including Mg, Al, Fe, Mn, Rh, Zn, and Cu. Auto repair shop workers showed effects that may be associated with exposure to mixtures of pollutants present in PM2.5. The GSTM1 and GSTT1 genes had independent modulatory effects.},
}
@article {pmid37003504,
year = {2023},
author = {Jones, CY and Williams, CL and Moreno, SP and Morris, DK and Mondello, C and Karlseder, J and Bertuch, AA},
title = {Hyperextended telomeres promote formation of C-circle DNA in telomerase positive human cells.},
journal = {The Journal of biological chemistry},
volume = {299},
number = {5},
pages = {104665},
pmid = {37003504},
issn = {1083-351X},
support = {R01 CA211653/CA/NCI NIH HHS/United States ; R01 CA228211/CA/NCI NIH HHS/United States ; R01 CA234047/CA/NCI NIH HHS/United States ; T32 GM008307/GM/NIGMS NIH HHS/United States ; R01 CA227934/CA/NCI NIH HHS/United States ; R01 AG077324/AG/NIA NIH HHS/United States ; R01 GM077509/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; DNA Helicases/metabolism ; *DNA, Circular ; *Telomerase/metabolism ; *Telomere/genetics/metabolism ; Telomere Homeostasis ; Cell Line ; HeLa Cells ; DNA Replication ; Hydroxyurea ; DNA Repair ; },
abstract = {Telomere length maintenance is crucial to cancer cell immortality. Up to 15% of cancers utilize a telomerase-independent, recombination-based mechanism termed alternative lengthening of telomeres (ALT). Currently, the primary ALT biomarker is the C-circle, a type of circular DNA with extrachromosomal telomere repeats (cECTRs). How C-circles form is not well characterized. We investigated C-circle formation in the human cen3tel cell line, a long-telomere, telomerase+ (LTT+) cell line with progressively hyper-elongated telomeres (up to ∼100 kb). cECTR signal was observed in 2D gels and C-circle assays but not t-circle assays, which also detect circular DNA with extrachromosomal telomere repeats. Telomerase activity and C-circle signal were not separable in the analysis of clonal populations, consistent with C-circle production occurring within telomerase+ cells. We observed similar cECTR results in two other LTT+ cell lines, HeLa1.3 (∼23 kb telomeres) and HeLaE1 (∼50 kb telomeres). In LTT+ cells, telomerase activity did not directly impact C-circle signal; instead, C-circle signal correlated with telomere length. LTT+ cell lines were less sensitive to hydroxyurea than ALT+ cell lines, suggesting that ALT status is a stronger contributor to replication stress levels than telomere length. Additionally, the DNA repair-associated protein FANCM did not suppress C-circles in LTT+ cells as it does in ALT+ cells. Thus, C-circle formation may be driven by telomere length, independently of telomerase and replication stress, highlighting limitations of C-circles as a stand-alone ALT biomarker.},
}
@article {pmid37002420,
year = {2023},
author = {Zlotorynski, E},
title = {RPA dynamics at telomeres.},
journal = {Nature reviews. Molecular cell biology},
volume = {24},
number = {5},
pages = {310},
pmid = {37002420},
issn = {1471-0080},
mesh = {*Telomere/genetics/metabolism ; *DNA-Binding Proteins/metabolism ; DNA, Single-Stranded ; },
}
@article {pmid36999631,
year = {2023},
author = {Liu, CC and Chan, HR and Su, GC and Hsieh, YZ and Lei, KH and Kato, T and Yu, TY and Kao, YW and Cheng, TH and Chi, P and Lin, JJ},
title = {Flap endonuclease Rad27 cleaves the RNA of R-loop structures to suppress telomere recombination.},
journal = {Nucleic acids research},
volume = {51},
number = {9},
pages = {4398-4414},
pmid = {36999631},
issn = {1362-4962},
mesh = {DNA Helicases/genetics ; DNA, Single-Stranded ; *Flap Endonucleases/genetics/metabolism ; *R-Loop Structures ; Recombination, Genetic ; RNA/genetics ; Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {The long non-coding telomeric RNA transcript TERRA, in the form of an RNA-DNA duplex, regulates telomere recombination. In a screen for nucleases that affects telomere recombination, mutations in DNA2, EXO1, MRE11 and SAE2 cause severe delay in type II survivor formation, indicating that type II telomere recombination is mediated through a mechanism similar to repairing double-strand breaks. On the other hand, mutation in RAD27 results in early formation of type II recombination, suggesting that RAD27 acts as a negative regulator in telomere recombination. RAD27 encodes a flap endonuclease that plays a role in DNA metabolism, including replication, repair and recombination. We demonstrate that Rad27 suppresses the accumulation of the TERRA-associated R-loop and selectively cleaves TERRA of R-loop and double-flapped structures in vitro. Moreover, we show that Rad27 negatively regulates single-stranded C-rich telomeric DNA circles (C-circles) in telomerase-deficient cells, revealing a close correlation between R-loop and C-circles during telomere recombination. These results demonstrate that Rad27 participates in telomere recombination by cleaving TERRA in the context of an R-loop or flapped RNA-DNA duplex, providing mechanistic insight into how Rad27 maintains chromosome stability by restricting the accumulation of the R-loop structure within the genome.},
}
@article {pmid36999210,
year = {2023},
author = {Gao, M and Zheng, G and Li, Y and Zhang, Y and Hu, P and Pan, Y},
title = {Telomere length in multiple cancer: insight into recurrence risk from a meta-analysis.},
journal = {Journal of gastroenterology and hepatology},
volume = {38},
number = {6},
pages = {844-853},
doi = {10.1111/jgh.16186},
pmid = {36999210},
issn = {1440-1746},
support = {82004039//National Natural Science Foundation of China/ ; 82204420//National Natural Science Foundation of China/ ; BK20220474//Natural Science Foundation of Jiangsu Province/ ; 22KJB310004//Natural Science Foundation of the Jiangsu Higher Education Institutions of China/ ; SKLNMKF202202//Open Project of the State Key Laboratory of Natural Medicines/ ; NZY82004039//Natural Science Foundation for Young Scholars of Nanjing University of Chinese Medicine/ ; XPT82204420//Funding Supporting Projects of National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Neoplasm Recurrence, Local/genetics ; *Gastrointestinal Neoplasms/genetics ; Telomere/genetics ; },
abstract = {BACKGROUND: Several studies have revealed the relationships between telomere length and the risk and mortality of numerous cancers. This meta-analysis aims to insightfully clarify the potential relationship between telomere length and the recurrence of multiple cancers.<br><br>METHODS: PubMed database was used to search and identify interrelated citations. These reports investigated the relationship between telomere length and various cancer recurrences. Meta-analysis pooled data from studies that reported risk ratio (RR) of 95 (CI&#xa0;=&#xa0;95%) confidence intervals and/or P-values. The cancer recurrence was investigated from an overall standpoint to the multiple levels of subtypes of cancers.<br><br>RESULTS: The meta-analysis involved 5907 recurrent multiple cancer patients from 13 cohort studies. Compared to these cancer recurrence cases and the telomere length differences, there was no significant correlation between telomere length and cancer recurrence risk (short telomeres vs long telomeres; RR&#xa0;=&#xa0;0.93, 95% CI: 0.72-1.20, P&#xa0;=&#xa0;0.59). Additionally, a negative association was observed between telomere length and cancer recurrence in gastrointestinal cancer and a positive association in head and neck cancer, while telomere length had little effect on the recurrence of hematological malignancies and genitourinary cancer in this analysis.<br><br>CONCLUSION: There was no significant relationship between recurrence and telomere length in 5907 cases in 13 studies. However, there was a correlation between specific tumors. These results suggested that telomere length as a recurrence marker or telomere length to determine the possibility of recurrence must be evaluated on the specific type of cancer.},
}
@article {pmid36997693,
year = {2023},
author = {Bryan, TM},
title = {Nucleotide metabolism regulates human telomere length via telomerase activation.},
journal = {Nature genetics},
volume = {55},
number = {4},
pages = {532-533},
pmid = {36997693},
issn = {1546-1718},
mesh = {Humans ; *Telomerase/genetics ; Telomere Homeostasis/genetics ; Telomere/genetics ; Nucleotides/genetics ; },
}
@article {pmid36993206,
year = {2023},
author = {Ngo, K and Gittens, TH and Gonzalez, DI and Hatmaker, EA and Plotkin, S and Engle, M and Friedman, GA and Goldin, M and Hoerr, RE and Eichman, BF and Rokas, A and Benton, ML and Friedman, KL},
title = {A comprehensive map of hotspots of de novo telomere addition in Saccharomyces cerevisiae.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {36993206},
support = {T34 GM136451/GM/NIGMS NIH HHS/United States ; R35 GM136401/GM/NIGMS NIH HHS/United States ; T32 GM137793/GM/NIGMS NIH HHS/United States ; R01 AI153356/AI/NIAID NIH HHS/United States ; R01 GM123292/GM/NIGMS NIH HHS/United States ; F31 EY033235/EY/NEI NIH HHS/United States ; },
abstract = {Telomere healing occurs when telomerase, normally restricted to chromosome ends, acts upon a double-strand break to create a new, functional telomere. De novo telomere addition on the centromere-proximal side of a break truncates the chromosome but, by blocking resection, may allow the cell to survive an otherwise lethal event. We previously identified several sequences in the baker’s yeast, Saccharomyces cerevisiae , that act as hotspots of de novo telomere addition (termed Sites of Repair-associated Telomere Addition or SiRTAs), but the distribution and functional relevance of SiRTAs is unclear. Here, we describe a high-throughput sequencing method to measure the frequency and location of telomere addition within sequences of interest. Combining this methodology with a computational algorithm that identifies SiRTA sequence motifs, we generate the first comprehensive map of telomere-addition hotspots in yeast. Putative SiRTAs are strongly enriched in subtelomeric regions where they may facilitate formation of a new telomere following catastrophic telomere loss. In contrast, outside of subtelomeres, the distribution and orientation of SiRTAs appears random. Since truncating the chromosome at most SiRTAs would be lethal, this observation argues against selection for these sequences as sites of telomere addition per se. We find, however, that sequences predicted to function as SiRTAs are significantly more prevalent across the genome than expected by chance. Sequences identified by the algorithm bind the telomeric protein Cdc13, raising the possibility that association of Cdc13 with single-stranded regions generated during the response to DNA damage may facilitate DNA repair more generally.},
}
@article {pmid36991019,
year = {2023},
author = {Li, F and Wang, Y and Hwang, I and Jang, JY and Xu, L and Deng, Z and Yu, EY and Cai, Y and Wu, C and Han, Z and Huang, YH and Huang, X and Zhang, L and Yao, J and Lue, NF and Lieberman, PM and Ying, H and Paik, J and Zheng, H},
title = {Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {1756},
pmid = {36991019},
issn = {2041-1723},
support = {P30 CA010815/CA/NCI NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Cell Line ; DNA ; Telomere Homeostasis/genetics ; Telomere/genetics/metabolism ; *Neoplasms/genetics ; *Telomerase/genetics ; Cysteine Endopeptidases/metabolism ; *F-Box Proteins/genetics ; Jumonji Domain-Containing Histone Demethylases/genetics/metabolism ; },
abstract = {Telomere length maintenance is essential for cellular immortalization and tumorigenesis. 5% - 10% of human cancers rely on a recombination-based mechanism termed alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet there are currently no targeted therapies. Through CRISPR/Cas9-based genetic screens in an ALT-immortalized isogenic cellular model, here we identify histone lysine demethylase KDM2A as a molecular vulnerability selectively for cells contingent on ALT-dependent telomere maintenance. Mechanistically, we demonstrate that KDM2A is required for dissolution of the ALT-specific telomere clusters following recombination-directed telomere DNA synthesis. We show that KDM2A promotes de-clustering of ALT multitelomeres through facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Inactivation of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and thus dissolution of ALT telomere clusters, leading to gross chromosome missegregation and mitotic cell death. These findings together establish KDM2A as a selective molecular vulnerability and a promising drug target for ALT-dependent cancers.},
}
@article {pmid36989559,
year = {2023},
author = {Ali, JH and Abdeen, Z and Azmi, K and Berman, T and Jager, K and Barnett-Itzhaki, Z and Walter, M},
title = {Influence of exposure to pesticides on telomere length and pregnancy outcome: Diethylphosphates but not Dimethylphosphates are associated with accelerated telomere attrition in a Palestinian cohort.},
journal = {Ecotoxicology and environmental safety},
volume = {256},
number = {},
pages = {114801},
doi = {10.1016/j.ecoenv.2023.114801},
pmid = {36989559},
issn = {1090-2414},
mesh = {Humans ; Female ; Pregnancy ; *Pesticides/metabolism ; Birth Weight ; Arabs ; *Environmental Pollutants/metabolism ; Organophosphorus Compounds/urine ; Organophosphates/metabolism ; Vegetables/metabolism ; },
abstract = {Exposure to environmental pesticides during pregnancy is associated with adverse health outcomes such as low birth weight and impaired neuro-development. In this study, we assessed maternal leukocyte telomere lengths (TL) in Palestinian pregnant women and compared the data with urinary organophosphate concentrations, demographic, lifestyle and dietary factors, birth weight, body length, gestational age, and head circumference. Women with high urine levels of creatinine adjusted diethylphosphate(DE)derived pesticide metabolites DEP, DETP or DEDTP had shorter telomeres (p = 0.05). Women living in proximity to agricultural fields had shorter telomeres compared to women not living in proximity to agricultural fields (p = 0.011). Regular consumption of organic food was associated with shorter telomeres (p = 0.01), whereas the consumption of other vegetables such as artichokes was rather associated with longer telomeres. By contrast, urine levels of dimethylphosphate(DM)-derived pesticide metabolites DMTP and DMDTP were associated with lower birth weight (p = 0.05) but not with shrter telomeres. In conclusion organophosphate pesticides and living in proximity to agriculture are associated with shorter TL, likely due to higher consumption of contaminated fruits and vegetables and/or the transport of pesticides to non-treatment sites. DE and DM substituted pesticides seem to have different effects on telomeres and development.},
}
@article {pmid36989538,
year = {2023},
author = {Valeeva, LR and Abdulkina, LR and Agabekian, IA and Shakirov, EV},
title = {Telomere biology and ribosome biogenesis: structural and functional interconnections.},
journal = {Biochemistry and cell biology = Biochimie et biologie cellulaire},
volume = {101},
number = {5},
pages = {394-409},
doi = {10.1139/bcb-2022-0383},
pmid = {36989538},
issn = {1208-6002},
mesh = {Humans ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; Mutation ; Ribosomes/genetics/metabolism ; Eukaryota/genetics ; Biology ; },
abstract = {Telomeres are nucleoprotein structures that play a pivotal role in the protection and maintenance of eukaryotic chromosomes. Telomeres and the enzyme telomerase, which replenishes telomeric DNA lost during replication, are important factors necessary to ensure continued cell proliferation. Cell proliferation is also dependent on proper and efficient protein synthesis, which is carried out by ribosomes. Mutations in genes involved in either ribosome biogenesis or telomere biology result in cellular abnormalities and can cause human genetic diseases, defined as ribosomopathies and telomeropathies, respectively. Interestingly, recent discoveries indicate that many of the ribosome assembly and rRNA maturation factors have additional noncanonical functions in telomere biology. Similarly, several key proteins and enzymes involved in telomere biology, including telomerase, have unexpected roles in rRNA transcription and maturation. These observations point to an intriguing cross-talk mechanism potentially explaining the multiple pleiotropic symptoms of mutations in many causal genes identified in various telomeropathy and ribosomopathy diseases. In this review, we provide a brief summary of eukaryotic telomere and rDNA loci structures, highlight several universal features of rRNA and telomerase biogenesis, evaluate intriguing interconnections between telomere biology and ribosome assembly, and conclude with an assessment of overlapping features of human diseases of telomeropathies and ribosomopathies.},
}
@article {pmid36986204,
year = {2023},
author = {Kuo, CL and Kirk, B and Xiang, M and Pilling, LC and Kuchel, GA and Kremer, R and Duque, G},
title = {Very Low and High Levels of Vitamin D Are Associated with Shorter Leukocyte Telomere Length in 148,321 UK Biobank Participants.},
journal = {Nutrients},
volume = {15},
number = {6},
pages = {},
pmid = {36986204},
issn = {2072-6643},
support = {NR018963-01A1/NH/NIH HHS/United States ; },
mesh = {Humans ; Middle Aged ; Aged ; *Biological Specimen Banks ; *Vitamin D ; Vitamins ; Leukocytes ; Telomere ; United Kingdom ; },
abstract = {Background: Shorter leukocyte telomere length (LTL) is observed in multiple age-related diseases, which are also associated with vitamin D deficiency (i.e., osteosarcopenia, neurocognitive disorders, cancer, osteoarthritis, etc.), suggesting a close association between vitamin D and LTL. In this study, we examined the relationship between vitamin D levels and LTL in older participants of the UK Biobank. Methods: Data were collected from the UK Biobank. Participants aged 60 and older (n = 148,321) were included. Baseline LTL was measured using a multiplex qPCR technique and expressed as the ratio of the telomere amplification product (T) to that of a single-copy gene (S) (T/S ratio). Serum 25-hydroxyvitamin D (25OHD) was stratified by z score and linked to LTL in a linear regression model adjusting for covariates. Results: Compared to the medium level, a low (in the range of 16.6 nmol/L, 29.7 nmol/L) or extremely low (≤16.6 nmol/L) level of serum 25OHD was associated with shorter LTL: 0.018 SD (standardized β = -0.018, 95% CI -0.033 to -0.003, p = 0.022) and 0.048 SD (standardized β = -0.048, 95% CI -0.083 to -0.014, p = 0.006), respectively. Additionally, the high serum 25OHD groups (>95.9 nmol/L) had 0.038 SD (standardized β = -0.038, 95% CI -0.072 to -0.004, p = 0.030) shorter mean LTL than the group with medium 25OHD levels. The associations above were adjusted for multiple variables. Conclusions: In this population-based study, we identified an inverted U-shape relationship between LTL and vitamin D status. Our findings could be affected by unmeasured confounders. Whether high or low vitamin D-associated shorter LTL is mechanistically related to age-related conditions remains to be elucidated.},
}
@article {pmid36986083,
year = {2023},
author = {Wei, Y and Li, Z and Lai, H and Lu, P and Zhang, B and Song, L and Zhang, L and Shen, M},
title = {Instant Coffee Is Negatively Associated with Telomere Length: Finding from Observational and Mendelian Randomization Analyses of UK Biobank.},
journal = {Nutrients},
volume = {15},
number = {6},
pages = {},
pmid = {36986083},
issn = {2072-6643},
support = {12171387//National Natural Science Foundation of China/ ; 2018M631134//China Postdoctoral Science Foundation/ ; 2020T130095ZX//China Postdoctoral Science Foundation/ ; 20210307//Young Talent Support Program of Shaanxi University Association for Science and Technology/ ; },
mesh = {Humans ; *Aging/genetics ; Biological Specimen Banks ; Genome-Wide Association Study ; *Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; *Telomere/genetics ; United Kingdom ; *Coffee/adverse effects ; },
abstract = {Telomere length, as a biomarker of accelerated aging, is closely related to many chronic diseases. We aimed to explore the association between coffee consumption and telomere length. Our study included 468,924 participants from the UK Biobank. Multivariate linear models (observational analyses) were conducted to evaluate the associations of coffee intake, instant coffee intake, and filtered coffee intake with telomere length. In addition, we evaluated the causality of these associations in Mendelian randomization (MR) analyses by four methods (inverse-variance weighted (IVW), MR pleiotropy residual sum and outlier (MR-PRESSO), MR-Egger, and weighted median). Observational analyses indicated that coffee intake and instant coffee intake were negatively correlated with telomere length, which was equal to 0.12 year of age-related decrease in telomere length for each additional cup of coffee intake (p < 0.001), and 0.38 year of age-related decrease in telomere length for each additional cup of instant coffee intake (p < 0.001), respectively. There was no significant correlation between filtered coffee and telomere length (p = 0.862). Mendelian randomization analyses supported the results of observational analyses. Coffee intake was found to have a causal effect on telomere length through weighted median analysis (p = 0.022), and instant coffee intake had a causal effect on telomere length through IVW analysis (p = 0.019) and MR-PRESSO analysis (p = 0.028). No causal relationship was found between filtered coffee intake and telomere length (p > 0.05). Coffee intake, particularly instant coffee, was found to have an important role in shortening telomere length.},
}
@article {pmid36982772,
year = {2023},
author = {M'Kacher, R and Colicchio, B and Junker, S and El Maalouf, E and Heidingsfelder, L and Plesch, A and Dieterlen, A and Jeandidier, E and Carde, P and Voisin, P},
title = {High Resolution and Automatable Cytogenetic Biodosimetry Using In Situ Telomere and Centromere Hybridization for the Accurate Detection of DNA Damage: An Overview.},
journal = {International journal of molecular sciences},
volume = {24},
number = {6},
pages = {},
pmid = {36982772},
issn = {1422-0067},
mesh = {Humans ; Cytogenetics ; *Centromere/genetics ; *Telomere/genetics ; Chromosome Aberrations ; Radiometry/methods ; DNA Damage/genetics ; Cytogenetic Analysis ; Lymphocytes ; },
abstract = {In the event of a radiological or nuclear accident, or when physical dosimetry is not available, the scoring of radiation-induced chromosomal aberrations in lymphocytes constitutes an essential tool for the estimation of the absorbed dose of the exposed individual and for effective triage. Cytogenetic biodosimetry employs different cytogenetic assays including the scoring of dicentrics, micronuclei, and translocations as well as analyses of induced premature chromosome condensation to define the frequency of chromosome aberrations. However, inherent challenges using these techniques include the considerable time span from sampling to result, the sensitivity and specificity of the various techniques, and the requirement of highly skilled personnel. Thus, techniques that obviate these challenges are needed. The introduction of telomere and centromere (TC) staining have successfully met these challenges and, in addition, greatly improved the efficiency of cytogenetic biodosimetry through the development of automated approaches, thus reducing the need for specialized personnel. Here, we review the role of the various cytogenetic dosimeters and their recent improvements in the management of populations exposed to genotoxic agents such as ionizing radiation. Finally, we discuss the emerging potentials to exploit these techniques in a wider spectrum of medical and biological applications, e.g., in cancer biology to identify prognostic biomarkers for the optimal triage and treatment of patients.},
}
@article {pmid36982042,
year = {2023},
author = {Prieto-Botella, D and Martens, DS and Valera-Gran, D and Subiza-Pérez, M and Tardón, A and Lozano, M and Casas, M and Bustamante, M and Jimeno-Romero, A and Fernández-Somoano, A and Llop, S and Vrijheid, M and Nawrot, TS and Navarrete-Muñoz, EM},
title = {Sedentary Behaviour and Telomere Length Shortening during Early Childhood: Evidence from the Multicentre Prospective INMA Cohort Study.},
journal = {International journal of environmental research and public health},
volume = {20},
number = {6},
pages = {},
pmid = {36982042},
issn = {1660-4601},
mesh = {Child ; Humans ; Child, Preschool ; Cohort Studies ; *Sedentary Behavior ; Prospective Studies ; Longitudinal Studies ; *Telomere ; Leukocytes ; },
abstract = {Sedentary behaviour (SB) may be related to telomere length (TL) attrition due to a possible pro-inflammatory effect. This study examined the association between parent-reported sedentary behaviour (SB) and leukocyte TL at the age of 4 and telomere tracking from 4 to 8 years. In the Spanish birth cohort Infancia y Medio Ambiente (INMA) project, we analysed data from children who attended follow-up visits at age 4 (n = 669) and 8 (n = 530). Multiple robust regression models were used to explore the associations between mean daily hours of SB (screen time, other sedentary activities, and total SB) at 4 years categorised into tertiles and TL at 4 years and difference in TL rank between age 4 and 8, respectively. At the age of 4, the results showed that children with the highest screen time (1.6-5.0 h/day) had a shorter TL of -3.9% (95% CI: -7.4, -0.4; p = 0.03) compared with children in the lowest tertile (0.0-1.0 h/day). Between 4 and 8 years, a higher screen time (highest tertile group vs. lowest tertile) was associated with a decrease in the LTL rank of -1.9% (95% CI: -3.8, -0.1; p = 0.03) from 4 to 8 years. Children exposed to a higher screen time at 4 years were more prone to have shorter TL at 4 and between 4 and 8 years of age. This study supports the potential negative effect of SB during childhood on cellular longevity.},
}
@article {pmid36981836,
year = {2023},
author = {Duchaine, CS and Brisson, C and Diorio, C and Talbot, D and Maunsell, E and Carmichael, PH and Giguère, Y and Gilbert-Ouimet, M and Trudel, X and Ndjaboué, R and Vézina, M and Milot, A and Mâsse, B and Dionne, CE and Laurin, D},
title = {Work-Related Psychosocial Factors and Global Cognitive Function: Are Telomere Length and Low-Grade Inflammation Potential Mediators of This Association?.},
journal = {International journal of environmental research and public health},
volume = {20},
number = {6},
pages = {},
pmid = {36981836},
issn = {1660-4601},
support = {201403MOP-32544-BCA-CFBA-52569 to DL and CB, and 201810GSD-422016-DRB-CFBA-280487 to CSD//CIHR/Canada ; },
mesh = {Male ; Humans ; Female ; Longitudinal Studies ; *Stress, Psychological/psychology ; *Cognition ; Inflammation ; Telomere ; },
abstract = {The identification of modifiable factors that could maintain cognitive function is a public health priority. It is thought that some work-related psychosocial factors help developing cognitive reserve through high intellectual complexity. However, they also have well-known adverse health effects and are considered to be chronic psychosocial stressors. Indeed, these stressors could increase low-grade inflammation and promote oxidative stress associated with accelerated telomere shortening. Both low-grade inflammation and shorter telomeres have been associated with a cognitive decline. This study aimed to evaluate the total, direct, and indirect effects of work-related psychosocial factors on global cognitive function overall and by sex, through telomere length and an inflammatory index. A random sample of 2219 participants followed over 17 years was included in this study, with blood samples and data with cognitive function drawn from a longitudinal study of 9188 white-collar workers (51% female). Work-related psychosocial factors were evaluated according to the Demand-Control-Support and the Effort-Reward Imbalance (ERI) models. Global cognitive function was evaluated with the validated Montreal Cognitive Assessment (MoCA). Telomere length and inflammatory biomarkers were measured using standardised protocols. The direct and indirect effects were estimated using a novel mediation analysis method developed for multiple correlated mediators. Associations were observed between passive work or low job control, and shorter telomeres among females, and between low social support at work, ERI or iso-strain, and a higher inflammatory index among males. An association was observed with higher cognitive performance for longer telomeres, but not for the inflammatory index. Passive work overall, and low reward were associated with lower cognitive performance in males; whereas, high psychological demand in both males and females and high job strain in females were associated with a higher cognitive performance. However, none of these associations were mediated by telomere length or the inflammatory index. This study suggests that some work-related psychosocial factors could be associated with shorter telomeres and low-grade inflammation, but these associations do not explain the relationship between work-related psychosocial factors and global cognitive function. A better understanding of the biological pathways, by which these factors affect cognitive function, could guide future preventive strategies to maintain cognitive function and promote healthy aging.},
}
@article {pmid36980987,
year = {2023},
author = {Holesova, Z and Krasnicanova, L and Saade, R and Pös, O and Budis, J and Gazdarica, J and Repiska, V and Szemes, T},
title = {Telomere Length Changes in Cancer: Insights on Carcinogenesis and Potential for Non-Invasive Diagnostic Strategies.},
journal = {Genes},
volume = {14},
number = {3},
pages = {},
pmid = {36980987},
issn = {2073-4425},
mesh = {Humans ; *Neoplasms/diagnosis/genetics ; Carcinogenesis/genetics ; Telomere Homeostasis/genetics ; DNA ; Telomere/genetics ; },
abstract = {Telomere dynamics play a crucial role in the maintenance of chromosome integrity; changes in telomere length may thus contribute to the development of various diseases including cancer. Understanding the role of telomeric DNA in carcinogenesis and detecting the presence of cell-free telomeric DNA (cf-telDNA) in body fluids offer a potential biomarker for novel cancer screening and diagnostic strategies. Liquid biopsy is becoming increasingly popular due to its undeniable benefits over conventional invasive methods. However, the organization and function of cf-telDNA in the extracellular milieu are understudied. This paper provides a review based on 3,398,017 cancer patients, patients with other conditions, and control individuals with the aim to shed more light on the inconsistent nature of telomere lengthening/shortening in oncological contexts. To gain a better understanding of biological factors (e.g., telomerase activation, alternative lengthening of telomeres) affecting telomere homeostasis across different types of cancer, we summarize mechanisms responsible for telomere length maintenance. In conclusion, we compare tissue- and liquid biopsy-based approaches in cancer assessment and provide a brief outlook on the methodology used for telomere length evaluation, highlighting the advances of state-of-the-art approaches in the field.},
}
@article {pmid36980962,
year = {2023},
author = {da Mota, THA and Camargo, R and Biojone, ER and Guimarães, AFR and Pittella-Silva, F and de Oliveira, DM},
title = {The Relevance of Telomerase and Telomere-Associated Proteins in B-Acute Lymphoblastic Leukemia.},
journal = {Genes},
volume = {14},
number = {3},
pages = {},
pmid = {36980962},
issn = {2073-4425},
mesh = {Child ; Humans ; *Telomerase/genetics/metabolism ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Telomere Shortening ; Telomere/genetics/metabolism ; },
abstract = {Telomeres and telomerase are closely linked to uncontrolled cellular proliferation, immortalization and carcinogenesis. Telomerase has been largely studied in the context of cancer, including leukemias. Deregulation of human telomerase gene hTERT is a well-established step in leukemia development. B-acute lymphoblastic leukemia (B-ALL) recovery rates exceed 90% in children; however, the relapse rate is around 20% among treated patients, and 10% of these are still incurable. This review highlights the biological and clinical relevance of telomerase for B-ALL and the implications of its canonical and non-canonical action on signaling pathways in the context of disease and treatment. The physiological role of telomerase in lymphocytes makes the study of its biomarker potential a great challenge. Nevertheless, many works have demonstrated that high telomerase activity or hTERT expression, as well as short telomeres, correlate with poor prognosis in B-ALL. Telomerase and related proteins have been proven to be promising pharmacological targets. Likewise, combined therapy with telomerase inhibitors may turn out to be an alternative strategy for B-ALL.},
}
@article {pmid36980890,
year = {2023},
author = {Zeinoun, B and Teixeira, MT and Barascu, A},
title = {TERRA and Telomere Maintenance in the Yeast Saccharomyces cerevisiae.},
journal = {Genes},
volume = {14},
number = {3},
pages = {},
pmid = {36980890},
issn = {2073-4425},
mesh = {*Saccharomyces cerevisiae/genetics/metabolism ; *RNA, Long Noncoding/metabolism ; Transcription, Genetic ; Telomere/genetics/metabolism ; Heterochromatin ; },
abstract = {Telomeres are structures made of DNA, proteins and RNA found at the ends of eukaryotic linear chromosomes. These dynamic nucleoprotein structures protect chromosomal tips from end-to-end fusions, degradation, activation of damage checkpoints and erroneous DNA repair events. Telomeres were thought to be transcriptionally silent regions because of their constitutive heterochromatin signature until telomeric long non-coding RNAs (LncRNAs) were discovered. One of them, TERRA (TElomeric Repeat-containing RNA), starts in the subtelomeric regions towards the chromosome ends from different telomeres and has been extensively studied in many evolutionarily distant eukaryotes. Changes in TERRA's expression can lead to telomeric dysfunction, interfere with the replicative machinery and impact telomere length. TERRA also co-localizes in vivo with telomerase, and can form RNA:DNA hybrid structures called R-loops, which have been implicated in the onset of senescence and the alternative lengthening of telomere (ALT) pathway. Yet, the molecular mechanisms involving TERRA, as well as its function, remain elusive. Here, we review the current knowledge of TERRA transcription, structure, expression, regulation and its multiple telomeric and extra-telomeric functions in the budding yeast Saccharomyces cerevisiae.},
}
@article {pmid36980881,
year = {2023},
author = {Hill, C and Duffy, S and Coulter, T and Maxwell, AP and McKnight, AJ},
title = {Harnessing Genomic Analysis to Explore the Role of Telomeres in the Pathogenesis and Progression of Diabetic Kidney Disease.},
journal = {Genes},
volume = {14},
number = {3},
pages = {},
pmid = {36980881},
issn = {2073-4425},
support = {MC_PC_15025/MRC_/Medical Research Council/United Kingdom ; MC_PC_20026/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; *Diabetic Nephropathies/genetics/metabolism ; Gene Expression Regulation ; Epigenesis, Genetic/genetics ; Epigenomics ; Telomere/genetics/metabolism ; *Diabetes Mellitus/genetics ; },
abstract = {The prevalence of diabetes is increasing globally, and this trend is predicted to continue for future decades. Research is needed to uncover new ways to manage diabetes and its co-morbidities. A significant secondary complication of diabetes is kidney disease, which can ultimately result in the need for renal replacement therapy, via dialysis or transplantation. Diabetic kidney disease presents a substantial burden to patients, their families and global healthcare services. This review highlights studies that have harnessed genomic, epigenomic and functional prediction tools to uncover novel genes and pathways associated with DKD that are useful for the identification of therapeutic targets or novel biomarkers for risk stratification. Telomere length regulation is a specific pathway gaining attention recently because of its association with DKD. Researchers are employing both observational and genetics-based studies to identify telomere-related genes associated with kidney function decline in diabetes. Studies have also uncovered novel functions for telomere-related genes beyond the immediate regulation of telomere length, such as transcriptional regulation and inflammation. This review summarises studies that have revealed the potential to harness therapeutics that modulate telomere length, or the associated epigenetic modifications, for the treatment of DKD, to potentially slow renal function decline and reduce the global burden of this disease.},
}
@article {pmid36979904,
year = {2023},
author = {Caslini, C and Serna, A},
title = {Telomere Transcription in MLL-Rearranged Leukemia Cell Lines: Increased Levels of TERRA Associate with Lymphoid Lineage and Are Independent of Telomere Length and Ploidy.},
journal = {Biomedicines},
volume = {11},
number = {3},
pages = {},
pmid = {36979904},
issn = {2227-9059},
abstract = {Telomere transcription into telomeric repeat-containing RNA (TERRA) is an integral component of all aspects of chromosome end protection consisting of telomerase- or recombination-dependent telomere elongation, telomere capping, and the preservation of the (sub)telomeric heterochromatin structure. The chromatin modifier and transcriptional regulator MLL binds to telomeres and regulates TERRA transcription in telomere length homeostasis and response to telomere dysfunction. MLL fusion proteins (MLL-FPs), the product of MLL rearrangements in leukemia, also bind to telomeric chromatin. However, an effect on telomere transcription in MLL-rearranged (MLL-r) leukemia has not yet been evaluated. Here, we show increased UUAGGG repeat-containing RNA levels in MLL-r acute lymphoblastic leukemia (ALL) when compared to non-MLL-r ALL and myeloid leukemia. MLL rearrangements do not affect telomere length and UUAGGG repeat-containing RNA levels correlate with mean telomere length and reflect increased levels of TERRA. Furthermore, high levels of TERRA in MLL-r ALL occur in the presence of telomerase activity and are independent of ploidy, an underestimated source of variation on the overall transcriptome size in a cell. This MLL rearrangement-dependent and lymphoid lineage-associated increase in levels of TERRA supports a sustained telomere transcription by MLL-FPs that correlates with marked genomic stability previously reported in pediatric MLL-r ALL.},
}
@article {pmid36979709,
year = {2023},
author = {Cuevas Diaz, P and Nicolini, H and Nolasco-Rosales, GA and Juarez Rojop, I and Tovilla-Zarate, CA and Rodriguez Sanchez, E and Genis-Mendoza, AD},
title = {Telomere Shortening in Three Diabetes Mellitus Types in a Mexican Sample.},
journal = {Biomedicines},
volume = {11},
number = {3},
pages = {},
pmid = {36979709},
issn = {2227-9059},
abstract = {This study aimed to explore the role of telomere length in three different diabetes types: latent autoimmune diabetes of adulthood (LADA), latent autoimmune diabetes in the young (LADY), and type 2 diabetes mellitus (T2DM). A total of 115 patients were included, 72 (62.61%) had LADA, 30 (26.09%) had T2DM, and 13 (11.30%) had LADY. Telomere length was measured using real-time Polymerase Chain Reaction. For statistical analysis, we used the ANOVA test, X2 test, and the Mann-Whitney U test. Patients with T2DM had higher BMI compared to LADA and LADY groups, with a BMI average of 31.32 kg/m[2] (p = 0.0235). While the LADA group had more patients with comorbidities, there was not a statistically significant difference (p = 0.3164, p = 0.3315, p = 0.3742 for each of the previously mentioned conditions). There was a difference between those patients with T2DM who took metformin plus any other oral antidiabetic agent and those who took metformin plus insulin, the ones who had longer telomeres. LADA patients had shorter telomeres compared to T2DM patients but not LADY patients. Furthermore, T2DM may have longer telomeres thanks to the protective effects of both metformin and insulin, despite the higher BMI in this group.},
}
@article {pmid36979008,
year = {2023},
author = {Ferk, F and Mišík, M and Ernst, B and Prager, G and Bichler, C and Mejri, D and Gerner, C and Bileck, A and Kundi, M and Langie, S and Holzmann, K and Knasmueller, S},
title = {Impact of Bariatric Surgery on the Stability of the Genetic Material, Oxidation, and Repair of DNA and Telomere Lengths.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {3},
pages = {},
pmid = {36979008},
issn = {2076-3921},
support = {AP00692OFF//Richard and Ethel Herzfeld Foundation/ ; CA15132//European Cooperation in Science and Technology/ ; },
abstract = {Obesity causes genetic instability, which plays a key-role in the etiology of cancer and aging. We investigated the impact of bariatric surgery (BS) on DNA repair, oxidative DNA damage, telomere lengths, alterations of antioxidant enzymes and, selected proteins which reflect inflammation. The study was realized with BS patients (n = 35). DNA damage, base oxidation, BER, and NER were measured before and 1 month and 6 months after surgery with the single-cell gel electrophoresis technique. SOD and GPx were quantified spectrophotometrically, malondealdehyde (MDA) was quantified by HPLC. Telomere lengths were determined with qPCR, and plasma proteome profiling was performed with high-resolution mass spectrophotometry. Six months after the operations, reduction of body weight by 27.5% was observed. DNA damage decreased after this period, this effect was paralleled by reduced formation of oxidized DNA bases, a decline in the MDA levels and of BER and NER, and an increase in the telomere lengths. The activities of antioxidant enzymes were not altered. Clear downregulation of certain proteins (CRP, SAA1) which reflect inflammation and cancer risks was observed. Our findings show that BS causes reduced oxidative damage of DNA bases, possibly as a consequence of reduction of inflammation and lipid peroxidation, and indicate that the surgery has beneficial long-term health effects.},
}
@article {pmid36978826,
year = {2023},
author = {Levstek, T and Trebušak Podkrajšek, K},
title = {Telomere Attrition in Chronic Kidney Diseases.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {3},
pages = {},
pmid = {36978826},
issn = {2076-3921},
support = {P1-0170//Slovenian Research Agency/ ; },
abstract = {Telomeres are dynamic DNA nucleoprotein structures located at the end of chromosomes where they maintain genomic stability. Due to the end replication problem, telomeres shorten with each cell division. Critically short telomeres trigger cellular senescence, which contributes to various degenerative and age-related diseases, including chronic kidney diseases (CKDs). Additionally, other factors such as oxidative stress may also contribute to accelerated telomere shortening. Indeed, telomeres are highly susceptible to oxidative damage due to their high guanine content. Here, we provide a comprehensive review of studies examining telomere length (TL) in CKDs to highlight the association between TL and the development and progression of CKDs in humans. We then focus on studies investigating TL in patients receiving kidney replacement therapy. The mechanisms of the relationship between TL and CKD are not fully understood, but a shorter TL has been associated with decreased kidney function and the progression of nephropathy. Interestingly, telomere lengthening has been observed in some patients in longitudinal studies. Hemodialysis has been shown to accelerate telomere erosion, whereas the uremic milieu is not reversed even in kidney transplantation patients. Overall, this review aims to provide insights into the biological significance of telomere attrition in the pathophysiology of kidney disease, which may contribute to the development of new strategies for the management of patients with CKDs.},
}
@article {pmid36973214,
year = {2023},
author = {Zhang, KJ and Zhang, ZH},
title = {[Progress in the study of alternative lengthening of telomeres and prognosis of pancreatic neuroendocrine tumors].},
journal = {Zhonghua bing li xue za zhi = Chinese journal of pathology},
volume = {52},
number = {4},
pages = {431-434},
doi = {10.3760/cma.j.cn112151-20220701-00570},
pmid = {36973214},
issn = {0529-5807},
mesh = {Humans ; *Neuroendocrine Tumors/genetics ; Prognosis ; X-linked Nuclear Protein/genetics ; *Pancreatic Neoplasms/genetics/pathology ; Telomere/genetics/pathology ; },
}
@article {pmid36968845,
year = {2023},
author = {Zhang, H and Kong, W and Xie, Y and Zhao, X and Luo, D and Chen, S and Pan, Z},
title = {Telomere-related genes as potential biomarkers to predict endometriosis and immune response: Development of a machine learning-based risk model.},
journal = {Frontiers in medicine},
volume = {10},
number = {},
pages = {1132676},
pmid = {36968845},
issn = {2296-858X},
abstract = {INTRODUCTION: Endometriosis (EM) is an aggressive, pleomorphic, and common gynecological disease. Its clinical presentation includes abnormal menstruation, dysmenorrhea, and infertility, which seriously affect the patient's quality of life. However, the pathogenesis underlying EM and associated regulatory genes are unknown.<br><br>METHODS: Telomere-related genes (TRGs) were uploaded from TelNet. RNA-sequencing (RNA-seq) data of EM patients were obtained from three datasets (GSE5108, GSE23339, and GSE25628) in the GEO database, and a random forest approach was used to identify telomere signature genes and build nomogram prediction models. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis were used to identify the pathways involved in the action of the signature genes. Finally, the CAMP database was used to screen drugs for potential use in EM treatment.<br><br>RESULTS: Fifteen total genes were screened as EM-telomere differentially expressed genes. Further screening by machine learning obtained six genes as characteristic predictive of EM. Immuno-infiltration analysis of the telomeric genes showed that expressions including macrophages and natural killer cells were significantly higher in cluster A. Further enrichment analysis showed that the differential genes were mainly enriched in biological pathways like cell cycle and extracellular matrix. Finally, the Connective Map database was used to screen 11 potential drugs for EM treatment.<br><br>DISCUSSION: TRGs play a crucial role in EM development, and are associated with immune infiltration and act on multiple pathways, including the cell cycle. Telomere signature genes can be valuable predictive markers for EM.},
}
@article {pmid36967999,
year = {2023},
author = {Wan, B and Ma, N and Lv, C},
title = {Identifying effects of genetic obesity exposure on leukocyte telomere length using Mendelian randomization.},
journal = {PeerJ},
volume = {11},
number = {},
pages = {e15085},
pmid = {36967999},
issn = {2167-8359},
mesh = {Humans ; *Genome-Wide Association Study ; *Mendelian Randomization Analysis ; Leukocytes ; Obesity/genetics ; Telomere/genetics ; },
abstract = {BACKGROUND: Observational studies have shown that obesity is closely associated with leukocyte telomere length (LTL). However, the causal relationship between obesity and LTL remains unclear. This study investigated the causal relationship between obesity and LTL through the Mendelian randomization approach.<br><br>MATERIALS AND METHODS: The genome-wide association study (GWAS) summary data of several studies on obesity-related traits with a sample size of more than 600,000 individuals were extracted from the UK Biobank cohort. The summary-level data of LTL-related GWAS (45 6,717 individuals) was obtained from the IEU Open GWAS database. An inverse-variance-weighted (IVW) algorithm was utilized as the primary MR analysis method. Sensitivity analyses were conducted via MR-Egger regression, IVW regression, leave-one-out test, MR-pleiotropy residual sum, and outlier methods.<br><br>RESULTS: High body mass index was correlated with a short LTL, and the odds ratio (OR) was 0.957 (95% confidence interval [CI] 0.942-0.973, p = 1.17E-07). The six body fat indexes (whole body fat mass, right leg fat mass, left leg fat mass, right arm fat mass, left arm fat mass, and trunk fat mass) were consistently inversely associated with LTL. Multiple statistical sensitive analysis approaches showed that the adverse effect of obesity on LTL was steady and dependable.<br><br>CONCLUSION: The current study provided robust evidence supporting the causal assumption that genetically caused obesity is negatively associated with LTL. The findings may facilitate the formulation of persistent strategies for maintaining LTL.},
}
@article {pmid36966355,
year = {2023},
author = {Wang, H and Ni, J and Guo, X and Xue, J and Wang, X},
title = {Effects of folate on telomere length and chromosome stability of human fibroblasts and melanoma cells in vitro: a comparison of folic acid and 5-methyltetrahydrofolate.},
journal = {Mutagenesis},
volume = {38},
number = {3},
pages = {160-168},
doi = {10.1093/mutage/gead007},
pmid = {36966355},
issn = {1464-3804},
mesh = {Humans ; Folic Acid/pharmacology ; *Telomerase/genetics/metabolism ; Telomere/metabolism ; Chromosomal Instability ; Fibroblasts/metabolism ; *Melanoma ; },
abstract = {Telomere length (TL), which is maintained by human telomerase reverse transcriptase (hTERT; component of telomerase) and/or TRF1/TRF2 (core components of shelterin) via different mechanisms, is essential for chromosomal stability and cell survival. Folates comprise a group of essential B9 vitamin that involve in DNA synthesis and methylation. This study aimed to evaluate the effects of folic acid (FA) and 5-methyltetrahydrofolate (5-MeTHF) on TL, chromosome stability, and cell survival of telomerase-negative BJ and telomerase-positive A375 cells in vitro. BJ and A375 cells were cultured in modified medium with FA or 5-MeTHF (22.6 or 2260 nM) for 28 days. TL and mRNA expression were determined by RT-qPCR. Chromosome instability (CIN) and cell death were measured by CBMN-Cyt assay. Results showed that abnormal TL elongation was observed in FA and 5-MeTHF deficient BJ cells. The TL of A375 cells showed no obvious alterations under the FA-deficient condition but was significantly elongated under the 5-MeTHF-deficient condition. In both BJ and A375 cells, FA and 5-MeTHF deficiency caused decreased TRF1, TRF2, and hTERT expression, increased CIN and cell death; while a high concentration of 5-MeTHF induced elongated TL, elevated CIN, increased TRF1 and TRF2 expression and decreased hTERT expression, when compared with the FA counterpart. These findings concluded that folate deficiency induced TL instability in both telomerase-negative and -positive cells, and FA was more efficient in maintaining TL and chromosome stability compared with 5-MeTHF.},
}
@article {pmid36960859,
year = {2023},
author = {Maggio, J and Cardama, GA and Armando, RG and Balcone, L and Sobol, NT and Gomez, DE and Mengual Gómez, DL},
title = {Key role of PIN1 in telomere maintenance and oncogenic behavior in a human glioblastoma model.},
journal = {Oncology reports},
volume = {49},
number = {5},
pages = {},
doi = {10.3892/or.2023.8528},
pmid = {36960859},
issn = {1791-2431},
mesh = {Humans ; Animals ; Mice ; *Glioblastoma/pathology ; NF-kappa B/genetics/metabolism ; *Telomerase/metabolism ; Polymerase Chain Reaction ; Telomere/genetics/metabolism ; Cell Line, Tumor ; NIMA-Interacting Peptidylprolyl Isomerase/genetics/metabolism ; },
abstract = {PIN1 is the only known enzyme capable of recognizing and isomerizing the phosphorylated Serine/Threonine‑Proline motif. Through this mechanism, PIN1 controls diverse cellular functions, including telomere maintenance. Both PIN1 overexpression and its involvement in oncogenic pathways are involved in several cancer types, including glioblastoma (GBM), a lethal disease with poor therapeutic resources. However, knowledge of the role of PIN1 in GBM is limited. Thus, the present work aimed to study the role of PIN1 as a telomere/telomerase regulator and its contribution to tumor biology. PIN1 knockout (KO) LN‑229 cell variant using CRISPR/Cas9 was developed and compared with PIN1 LN‑229 expressing cells. To study the effect of PIN1 absence, status of NF‑κB pathway was evaluated by luciferase reporter gene assay and quantitative PCR. Results revealed that PIN1 deletion in GBM cells diminished the active levels of NF‑κB and decrease the transcription of il‑8 and htert genes. Then, telomere/telomerase related processes were studied by RQ‑TRAP assay and telomere length determination by qPCR, obtaining a reduction both in telomerase activity as in telomere length in PIN1 KO cells. In addition, measurement of SA β‑galactosidase and caspase‑3 activities revealed that loss of PIN1 triggers senescence and apoptosis. Finally, migration, cell cycle progression and tumorigenicity were studied by flow cytometry/western blot, Transwell assay and in vivo experiments, respectively. PIN1 deletion decreased migration as well as cell cycle progression by increasing doubling time and also resulted in the loss of LN‑229 cell ability to form tumors in mice. These results highlight the role of PIN1 in telomere homeostasis and GBM progression, which supports PIN1 as a potential molecular target for the development of novel therapeutic agents for GBM treatment.},
}
@article {pmid36959362,
year = {2023},
author = {Mannherz, W and Agarwal, S},
title = {Thymidine nucleotide metabolism controls human telomere length.},
journal = {Nature genetics},
volume = {55},
number = {4},
pages = {568-580},
pmid = {36959362},
issn = {1546-1718},
support = {R33 HL154133/HL/NHLBI NIH HHS/United States ; T32 GM007753/GM/NIGMS NIH HHS/United States ; T32 GM007226/GM/NIGMS NIH HHS/United States ; T32 GM144273/GM/NIGMS NIH HHS/United States ; R01 DK107716/DK/NIDDK NIH HHS/United States ; },
mesh = {Humans ; *Telomerase/genetics ; SAM Domain and HD Domain-Containing Protein 1/genetics/metabolism ; Nucleotides/genetics ; Telomere Homeostasis/genetics ; Thymidine ; Telomere/genetics ; },
abstract = {Telomere length in humans is associated with lifespan and severe diseases, yet the genetic determinants of telomere length remain incompletely defined. Here we performed genome-wide CRISPR-Cas9 functional telomere length screening and identified thymidine (dT) nucleotide metabolism as a limiting factor in human telomere maintenance. Targeted genetic disruption using CRISPR-Cas9 revealed multiple telomere length control points across the thymidine nucleotide metabolism pathway: decreasing dT nucleotide salvage via deletion of the gene encoding nuclear thymidine kinase (TK1) or de novo production by knockout of the thymidylate synthase gene (TYMS) decreased telomere length, whereas inactivation of the deoxynucleoside triphosphohydrolase-encoding gene SAMHD1 lengthened telomeres. Remarkably, supplementation with dT alone drove robust telomere elongation by telomerase in cells, and thymidine triphosphate stimulated telomerase activity in a substrate-independent manner in vitro. In induced pluripotent stem cells derived from patients with genetic telomere biology disorders, dT supplementation or inhibition of SAMHD1 promoted telomere restoration. Our results demonstrate a critical role of thymidine metabolism in controlling human telomerase and telomere length, which may be therapeutically actionable in patients with fatal degenerative diseases.},
}
@article {pmid36949104,
year = {2023},
author = {Meesters, M and Van Eetvelde, M and Martens, DS and Nawrot, TS and Dewulf, M and Govaere, J and Opsomer, G},
title = {Prenatal environment impacts telomere length in newborn dairy heifers.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {4672},
pmid = {36949104},
issn = {2045-2322},
mesh = {Pregnancy ; Humans ; Animals ; Cattle ; Female ; Animals, Newborn ; Parity ; *Parturition ; Humidity ; *Telomere/genetics ; Lactation ; },
abstract = {Telomere length is associated with longevity and survival in multiple species. In human population-based studies, multiple prenatal factors have been described to be associated with a newborn's telomere length. In the present study, we measured relative leukocyte telomere length in 210 Holstein Friesian heifers, within the first ten days of life. The dam's age, parity, and milk production parameters, as well as environmental factors during gestation were assessed for their potential effect on telomere length. We found that for both primi- and multiparous dams, the telomere length was 1.16% shorter for each day increase in the calf's age at sampling (P = 0.017). The dam's age at parturition (P = 0.045), and the median temperature-humidity index (THI) during the third trimester of gestation (P = 0.006) were also negatively associated with the calves' TL. Investigating multiparous dams separately, only the calf's age at sampling was significantly and negatively associated with the calves' TL (P = 0.025). Results of the present study support the hypothesis that in cattle, early life telomere length is influenced by prenatal factors. Furthermore, the results suggest that selecting heifers born in winter out of young dams might contribute to increased longevity in dairy cattle.},
}
@article {pmid36947528,
year = {2023},
author = {Topiwala, A and Nichols, TE and Williams, LZJ and Robinson, EC and Alfaro-Almagro, F and Taschler, B and Wang, C and Nelson, CP and Miller, KL and Codd, V and Samani, NJ and Smith, SM},
title = {Telomere length and brain imaging phenotypes in UK Biobank.},
journal = {PloS one},
volume = {18},
number = {3},
pages = {e0282363},
pmid = {36947528},
issn = {1932-6203},
support = {216462/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; 215573/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; 202788/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; R01 EB026859/EB/NIBIB NIH HHS/United States ; BRC-1215-20014/DH_/Department of Health/United Kingdom ; 100309/Z/12/Z/WT_/Wellcome Trust/United Kingdom ; MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; /BHF_/British Heart Foundation/United Kingdom ; BRC-1215-20010/DH_/Department of Health/United Kingdom ; },
mesh = {Humans ; *Neurodegenerative Diseases ; Biological Specimen Banks ; Brain/diagnostic imaging ; Phenotype ; Telomere/genetics ; Neuroimaging ; United Kingdom ; *Dementia/diagnostic imaging/genetics ; Leukocytes ; },
abstract = {Telomeres form protective caps at the ends of chromosomes, and their attrition is a marker of biological aging. Short telomeres are associated with an increased risk of neurological and psychiatric disorders including dementia. The mechanism underlying this risk is unclear, and may involve brain structure and function. However, the relationship between telomere length and neuroimaging markers is poorly characterized. Here we show that leucocyte telomere length (LTL) is associated with multi-modal MRI phenotypes in 31,661 UK Biobank participants. Longer LTL is associated with: i) larger global and subcortical grey matter volumes including the hippocampus, ii) lower T1-weighted grey-white tissue contrast in sensory cortices, iii) white-matter microstructure measures in corpus callosum and association fibres, iv) lower volume of white matter hyperintensities, and v) lower basal ganglia iron. Longer LTL was protective against certain related clinical manifestations, namely all-cause dementia (HR 0.93, 95% CI: 0.91-0.96), but not stroke or Parkinson's disease. LTL is associated with multiple MRI endophenotypes of neurodegenerative disease, suggesting a pathway by which longer LTL may confer protective against dementia.},
}
@article {pmid36946056,
year = {2023},
author = {Zhou, Z and Lo, CKM and Chan, KL and Chung, RSY and Pell, JP and Minnis, H and Shiels, PG and Ip, P and Ho, FK},
title = {Child maltreatment and telomere length in middle and older age: retrospective cohort study of 141 748 UK Biobank participants.},
journal = {The British journal of psychiatry : the journal of mental science},
volume = {223},
number = {2},
pages = {377-381},
doi = {10.1192/bjp.2023.33},
pmid = {36946056},
issn = {1472-1465},
mesh = {Adult ; Aged ; Humans ; Middle Aged ; Biological Specimen Banks ; Retrospective Studies ; *Telomere ; United Kingdom/epidemiology ; *Adult Survivors of Child Abuse ; },
abstract = {BACKGROUND: There is evidence that child maltreatment is associated with shorter telomere length in early life.<br><br>AIMS: This study aims to examine if child maltreatment is associated with telomere length in middle- and older-age adults.<br><br>METHOD: This was a retrospective cohort study of 141 748 UK Biobank participants aged 37-73 years at recruitment. Leukocyte telomere length was measured with quantitative polymerase chain reaction, and log-transformed and scaled to have unit standard deviation. Child maltreatment was recalled by participants. Linear regression was used to analyse the association.<br><br>RESULTS: After adjusting for sociodemographic characteristics, participants with three or more types of maltreatment presented with the shortest telomere lengths (&#x3b2; = -0.05, 95% CI -0.07 to -0.03; P < 0.0001), followed by those with two types of maltreatment (&#x3b2; = -0.02, 95% CI -0.04 to 0.00; P = 0.02), referent to those who had none. When adjusted for depression and post-traumatic stress disorder, the telomere lengths of participants with three or more types of maltreatment were still shorter (&#x3b2; = -0.04, 95% CI -0.07 to -0.02; P = 0.0008). The telomere lengths of those with one type of maltreatment were not significantly different from those who had none. When mutually adjusted, physical abuse (&#x3b2; = -0.05, 95% CI -0.07 to -0.03; P < 0.0001) and sexual abuse (&#x3b2; = -0.02, 95% CI -0.04 to 0.00; P = 0.02) were independently associated with shorter telomere length.<br><br>CONCLUSIONS: Our findings showed that child maltreatment is associated with shorter telomere length in middle- and older-aged adults, independent of sociodemographic and mental health factors.},
}
@article {pmid36944821,
year = {2023},
author = {Herrera-Moreno, JF and Prada, D and Baccarelli, AA},
title = {Early Environment and Telomeres: a Long-Term Toxic Relationship.},
journal = {Current environmental health reports},
volume = {10},
number = {2},
pages = {112-124},
pmid = {36944821},
issn = {2196-5412},
support = {R01 ES025225/ES/NIEHS NIH HHS/United States ; R01 ES032242/ES/NIEHS NIH HHS/United States ; R35 ES031688/ES/NIEHS NIH HHS/United States ; R01 AG069120/AG/NIA NIH HHS/United States ; R01 AG058704/AG/NIA NIH HHS/United States ; R01 ES027747/ES/NIEHS NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; },
mesh = {Child ; Female ; Pregnancy ; Humans ; Child, Preschool ; Aged ; Environmental Exposure/adverse effects/analysis ; *Air Pollutants/analysis ; *Polycyclic Aromatic Hydrocarbons/toxicity/analysis ; Aging/genetics ; Telomere/chemistry ; },
abstract = {PURPOSE OF REVIEW: Telomere length (TL) shortening is a hallmark of biological aging. While studies have extensively focused on the impact of environmental exposures on TL in older populations, consistent evidence indicates that prenatal environmental exposures to air pollutants, polycyclic aromatic hydrocarbons, metals, and endocrine-disrupting chemicals influence TL shortening. Here, we summarize evidence linking prenatal environmental exposures with children's TL and discuss potential long-term effects.<br><br>RECENT FINDINGS: Current evidence shows that prenatal environmental exposures alter TL and identify pregnancy as a critical window of susceptibility for telomere damage in children. However, results vary across studies, possibly depending on the source, exposure time window, and stage evaluated. Additional research is needed to investigate whether early TL alterations mediate long-term health effects of offspring. Prenatal environmental exposures induce early childhood changes in TL. Based on known links between TL and biological aging, these alterations may have long-term impact on individuals' health throughout life.},
}
@article {pmid36943406,
year = {2023},
author = {Connor, A and Starnino, L and Busque, L and Tardif, JC and Bourgoin, V and Dubé, MP and Busseuil, D and D'Antono, B},
title = {Childhood maltreatment and leukocyte telomere length in men and women with chronic illness: an evaluation of moderating and mediating influences.},
journal = {Psychological medicine},
volume = {53},
number = {13},
pages = {6242-6252},
pmid = {36943406},
issn = {1469-8978},
support = {MOP # 111015//CIHR/Canada ; },
mesh = {Male ; Humans ; Female ; Aged ; Child ; Aging ; *Coronary Artery Disease ; Chronic Disease ; Leukocytes/physiology ; Telomere ; *Child Abuse ; },
abstract = {BACKGROUND: Childhood maltreatment can result in lifelong psychological and physical sequelae, including coronary artery disease (CAD). Mechanisms leading to increased risk of illness may involve emotional dysregulation and shortened leukocyte telomere length (LTL).<br><br>METHODS: To evaluate whether (1) childhood maltreatment is associated with shorter LTL among older adults with CAD or other chronic illnesses; (2) sex and/or CAD status influence these results; and (3) symptoms of anxiety, depression, and stress moderate or mediate the association between childhood maltreatment and LTL, men and women (N = 1247; aged 65 &#xb1; 7.2 years) with and without CAD completed validated questionnaires on childhood maltreatment, symptoms of depression, anxiety, and perceived stress. LTL was measured using quantitative polymerase chain reaction. Analyses included bivariate correlations, hierarchical regressions, and moderation/mediation analyses, controlling for sociodemographic and lifestyle variables.<br><br>RESULTS: Childhood maltreatment was associated with significantly shorter LTL (r = -0.059, p = 0.038, b = -0.016, p = 0.005). This relation was not moderated by depression, anxiety, nor perceived stress, though there was mitigated evidence for absence of a maltreatment-LTL relation in men with CAD. Stress perception (but not anxiety or depression) partially mediated the relation between childhood maltreatment and LTL [Indirect effect, b = -0.0041, s.e. = 0.002, 95% CI (-0.0085 to -0.0002)].<br><br>CONCLUSIONS: Childhood maltreatment was associated with accelerated biological aging independently of patient characteristics. Emotional dysregulation resulting in chronic stress may contribute to this process. Whether stress management or other interventions may help prevent or slow premature aging in those who have suffered maltreatment requires study.},
}
@article {pmid36943300,
year = {2023},
author = {Wang, B and Shi, X and Gao, J and Liao, R and Fu, J and Bai, J and Cui, H},
title = {SCARECROW maintains the stem cell niche in Arabidopsis roots by ensuring telomere integrity.},
journal = {Plant physiology},
volume = {192},
number = {2},
pages = {1115-1131},
pmid = {36943300},
issn = {1532-2548},
mesh = {*Arabidopsis/genetics/metabolism ; *Arabidopsis Proteins/genetics/metabolism ; Plant Roots/genetics/metabolism ; Stem Cell Niche/genetics ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {Stem cells are the ultimate source of cells for various tissues and organs and thus are essential for postembryonic plant growth and development. SCARECROW (SCR) is a plant-specific transcription regulator well known for its role in stem cell renewal in plant roots, but the mechanism by which SCR exerts this function remains unclear. To address this question, we carried out a genetic screen for mutants that no longer express SCR in the stem cell niche of Arabidopsis (Arabidopsis thaliana) roots and characterized 1 of these mutants. Molecular genetics methods allowed us to pinpoint the causal mutation in this mutant in TELOMERIC PATHWAYS IN ASSOCIATION WITH STN 1 (TEN1), encoding a factor that protects telomere ends. Interestingly, TEN1 expression was dramatically reduced in the scr mutant. Telomerase and STN1 and CONSERVED TELOMERE MAINTENANCE COMPONENT 1 (CTC1), components of the same protein complex as TEN1, were also dramatically downregulated in scr. Loss of STN1, CTC1, and telomerase caused defects in root stem cells. These results together suggest that SCR maintains root stem cells by promoting expression of genes that ensure genome integrity. Supporting this conclusion, we demonstrated that the scr mutant accumulates more DNA damage than wild-type Arabidopsis and that this problem is aggravated after exposure to zeocin, a DNA damage reagent. Finally, we identified 2 previously uncharacterized motifs in TEN1 and provide evidence that a conserved amino acid residue in 1 of the motifs is indispensable for TEN1 function. SCR thus provides a connection between genome integrity and stem cell maintenance in Arabidopsis roots.},
}
@article {pmid36940725,
year = {2023},
author = {Rose, AM and Goncalves, T and Cunniffe, S and Geiller, HEB and Kent, T and Shepherd, S and Ratnaweera, M and O'Sullivan, RJ and Gibbons, RJ and Clynes, D},
title = {Induction of the alternative lengthening of telomeres pathway by trapping of proteins on DNA.},
journal = {Nucleic acids research},
volume = {51},
number = {13},
pages = {6509-6527},
pmid = {36940725},
issn = {1362-4962},
support = {P30 CA047904/CA/NCI NIH HHS/United States ; /MRC_/Medical Research Council/United Kingdom ; R01 CA207209/CA/NCI NIH HHS/United States ; /DH_/Department of Health/United Kingdom ; R01 CA262316/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; DNA ; *Neoplasms/genetics ; Telomerase/genetics ; *Telomere/genetics/metabolism ; Telomere Homeostasis ; X-linked Nuclear Protein/genetics/metabolism ; },
abstract = {Telomere maintenance is a hallmark of malignant cells and allows cancers to divide indefinitely. In some cancers, this is achieved through the alternative lengthening of telomeres (ALT) pathway. Whilst loss of ATRX is a near universal feature of ALT-cancers, it is insufficient in isolation. As such, other cellular events must be necessary - but the exact nature of the secondary events has remained elusive. Here, we report that trapping of proteins (such as TOP1, TOP2A and PARP1) on DNA leads to ALT induction in cells lacking ATRX. We demonstrate that protein-trapping chemotherapeutic agents, such as etoposide, camptothecin and talazoparib, induce ALT markers specifically in ATRX-null cells. Further, we show that treatment with G4-stabilising drugs cause an increase in trapped TOP2A levels which leads to ALT induction in ATRX-null cells. This process is MUS81-endonuclease and break-induced replication dependent, suggesting that protein trapping leads to replication fork stalling, with these forks being aberrantly processed in the absence of ATRX. Finally, we show ALT-positive cells harbour a higher load of genome-wide trapped proteins, such as TOP1, and knockdown of TOP1 reduced ALT activity. Taken together, these findings suggest that protein trapping is a fundamental driving force behind ALT-biology in ATRX-deficient malignancies.},
}
@article {pmid36934410,
year = {2023},
author = {D'Aronco, G and Ferraro, P and Sassano, V and Dagostino, C and Biancotto, M and Palumbo, E and Presot, E and Russo, A and Bianchi, V and Rampazzo, C},
title = {SAMHD1 restricts the deoxyguanosine triphosphate pool contributing to telomere stability in telomerase-positive cells.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {37},
number = {4},
pages = {e22883},
doi = {10.1096/fj.202300122R},
pmid = {36934410},
issn = {1530-6860},
mesh = {Humans ; Deoxyguanine Nucleotides ; *Monomeric GTP-Binding Proteins/metabolism ; *SAM Domain and HD Domain-Containing Protein 1/genetics ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {SAMHD1 (Sterile alpha motif and histidine/aspartic acid domain-containing protein 1) is a dNTP triphosphohydrolase crucial in the maintenance of balanced cellular dNTP pools, which support genome integrity. In SAMHD1 deficient fibroblasts isolated from Aicardi-Goutières Syndrome (AGS) patients, all four DNA precursors are increased and markedly imbalanced with the largest effect on dGTP, a key player in the modulation of telomerase processivity. Here, we present data showing that SAMHD1, by restricting the dGTP pool, contributes to telomere maintenance in hTERT-immortalized human fibroblasts from AGS patients as well as in telomerase positive cancer cell lines. Only in cells expressing telomerase, the lack of SAMHD1 causes excessive lengthening of telomeres and telomere fragility, whereas primary fibroblasts lacking both SAMHD1 and telomerase enter normally into senescence. Telomere lengthening observed in SAMHD1 deficient but telomerase proficient cells is a gradual process, in accordance with the intrinsic property of telomerase of adding only a few tens of nucleotides for each cycle. Therefore, only a prolonged exposure to high dGTP content causes telomere over-elongation. hTERT-immortalized AGS fibroblasts display also high fragility of chromosome ends, a marker of telomere replication stress. These results not only demonstrate the functional importance of dGTP cellular level but also reveal the critical role played by SAMHD1 in restraining telomerase processivity and safeguarding telomere stability.},
}
@article {pmid36933050,
year = {2023},
author = {Brown, JC and Sturgeon, K and Sarwer, DB and Troxel, AB and DeMichele, AM and Denlinger, CS and Schmitz, KH},
title = {The effects of exercise and diet on oxidative stress and telomere length in breast cancer survivors.},
journal = {Breast cancer research and treatment},
volume = {199},
number = {1},
pages = {109-117},
pmid = {36933050},
issn = {1573-7217},
support = {U54 CA155850/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Female ; *Breast Neoplasms/genetics/therapy ; *Cancer Survivors ; Diet ; Oxidative Stress ; Telomere/genetics ; },
abstract = {PURPOSE: Cancer and its treatments accelerate biological aging. This analysis tested the hypothesis that exercise and diet reduce oxidative stress and prevent telomere shortening in breast cancer survivors.<br><br>METHODS: In a 2&#xa0;&#xd7;&#xa0;2 factorial design, 342 breast cancer survivors who were insufficiently physically active and had overweight or obesity at enrollment were randomized to one of four treatment groups for 52&#xa0;weeks: control, exercise alone, diet alone, or exercise plus diet. The endpoints of this analysis were the change from baseline to week 52 in 8-iso-prostaglandin F2&#x3b1; (8-iso-PGF2&#x3b1;) and lymphocyte telomere length.<br><br>RESULTS: Baseline telomere length was shorter than age-adjusted normative values (median difference:&#x2009;-&#x2009;1.8 kilobases; 95% CI&#x2009;-&#x2009;2.4,&#x2009;-&#x2009;1.1); equivalent to 21&#xa0;years (95% CI 17, 25) of accelerated chronological aging. Compared to control, exercise alone did not change 8-iso-PGF2&#x3b1; [9.9%; 95% confidence interval (CI)&#x2009;-&#x2009;1.0, 20.8] or telomere length (13.8%; 95% CI&#x2009;-&#x2009;15.6, 43.3). Compared to control, diet alone was associated with reduced 8-iso-PGF2&#x3b1; (-&#x2009;10.5%; 95% CI&#x2009;-&#x2009;19.5,&#x2009;-&#x2009;1.5) but did not change telomere length (12.1%; 95% CI&#xa0;-&#x2009;17.2, 41.3). Compared to control, exercise plus diet was associated with reduced 8-iso-PGF2&#x3b1; (-&#x2009;9.8%; 95% CI&#x2009;-&#x2009;18.7,&#x2009;-&#x2009;0.9) but did not change telomere length (-&#x2009;8.5%; 95% CI&#x2009;-&#x2009;32.1, 15.2). Change in 8-iso-PGF2&#x3b1; did not correlate with change in telomere length (r&#x2009;=&#x2009;0.07; 95% CI&#x2009;-&#x2009;0.07, 0.20).<br><br>CONCLUSION: In breast cancer survivors, diet alone or exercise plus diet were associated with reduced oxidative stress but did not change telomere length. This analysis may inform future trials that aim to optimize healthy aging in cancer survivors.},
}
@article {pmid36933034,
year = {2023},
author = {Meng, Q and Shao, B and Zhao, D and Fu, X and Wang, J and Li, H and Zhou, Q and Gao, T},
title = {Loss of SUN1 function in spermatocytes disrupts the attachment of telomeres to the nuclear envelope and contributes to non-obstructive azoospermia in humans.},
journal = {Human genetics},
volume = {142},
number = {4},
pages = {531-541},
pmid = {36933034},
issn = {1432-1203},
support = {82201762//National Natural Science Foundation of China/ ; 82201765//National Natural Science Foundation of China/ ; BK20220200//Natural Science Foundation of Jiangsu Province/ ; LCZX202109//Suzhou science and technology development plan/ ; CJ20220143//the Science and Technology Project of Changzhou/ ; Z2021048//the Science and Technology Project of Jiangsu Health Committee/ ; },
mesh = {Male ; Humans ; *Nuclear Envelope/genetics ; *Azoospermia/pathology ; Microtubule-Associated Proteins/genetics ; Spermatocytes/metabolism/pathology ; Telomere/pathology ; Membrane Proteins/genetics/metabolism ; Nuclear Proteins/genetics/metabolism ; },
abstract = {One of the most severe forms of infertility in humans, caused by gametogenic failure, is non-obstructive azoospermia (NOA). Approximately, 20-30% of men with NOA may have single-gene mutations or other genetic variables that cause this disease. While a range of single-gene mutations associated with infertility has been identified in prior whole-exome sequencing (WES) studies, current insight into the precise genetic etiology of impaired human gametogenesis remains limited. In this paper, we described a proband with NOA who experienced hereditary infertility. WES analyses identified a homozygous variant in the SUN1 (Sad1 and UNC84 domain containing 1) gene [c. 663C > A: p.Tyr221X] that segregated with infertility. SUN1 encodes a LINC complex component essential for telomeric attachment and chromosomal movement. Spermatocytes with the observed mutations were incapable of repairing double-strand DNA breaks or undergoing meiosis. This loss of SUN1 functionality contributes to significant reductions in KASH5 levels within impaired chromosomal telomere attachment to the inner nuclear membrane. Overall, our results identify a potential genetic driver of NOA pathogenesis and provide fresh insight into the role of the SUN1 protein as a regulator of prophase I progression in the context of human meiosis.},
}
@article {pmid36932659,
year = {2023},
author = {Wang, H and Ni, J and Guo, X and Xue, J and Wang, X},
title = {Effects of folate on telomere length and chromosome stability of human fibroblasts and melanoma cells in vitro: a comparison of folic acid and 5-methyltetrahydrofolate.},
journal = {Mutagenesis},
volume = {38},
number = {2},
pages = {100-108},
doi = {10.1093/mutage/gead004},
pmid = {36932659},
issn = {1464-3804},
mesh = {Humans ; Folic Acid/pharmacology ; *Telomerase/genetics/metabolism ; Telomere/metabolism ; Chromosomal Instability ; Fibroblasts/metabolism ; *Melanoma ; },
abstract = {Telomere length (TL), which is maintained by human telomerase reverse transcriptase (hTERT; component of telomerase) and/or TRF1/TRF2 (core components of shelterin) via different mechanisms, is essential for chromosomal stability and cell survival. Folates comprise a group of essential B9 vitamin that involve in DNA synthesis and methylation. This study aimed to evaluate the effects of folic acid (FA) and 5-methyltetrahydrofolate (5-MeTHF) on TL, chromosome stability, and cell survival of telomerase-negative BJ and telomerase-positive A375 cells in vitro. BJ and A375 cells were cultured in modified medium with FA or 5-MeTHF (22.6 or 2260 nM) for 28 days. TL and mRNA expression were determined by RT-qPCR. Chromosome instability (CIN) and cell death were measured by CBMN-Cyt assay. Results showed that abnormal TL elongation was observed in FA- and 5-MeTHF-deficient BJ cells. The TL of A375 cells showed no obvious alterations under the FA-deficient condition but was significantly elongated under the 5-MeTHF-deficient condition. In both BJ and A375 cells, FA and 5-MeTHF deficiency caused decreased TRF1, TRF2, and hTERT expression, increased CIN and cell death; while a high concentration of 5-MeTHF induced elongated TL, elevated CIN, increased TRF1 and TRF2 expression, and decreased hTERT expression, when compared with the FA counterpart. These findings concluded that folate deficiency induced TL instability in both telomerase-negative and -positive cells, and FA was more efficient in maintaining TL and chromosome stability compared with 5-MeTHF.},
}
@article {pmid36932145,
year = {2023},
author = {Adegunsoye, A and Newton, CA and Oldham, JM and Ley, B and Lee, CT and Linderholm, AL and Chung, JH and Garcia, N and Zhang, D and Vij, R and Guzy, R and Jablonski, R and Bag, R and Voogt, RS and Ma, SF and Sperling, AI and Raghu, G and Martinez, FJ and Strek, ME and Wolters, PJ and Garcia, CK and Pierce, BL and Noth, I},
title = {Telomere length associates with chronological age and mortality across racially diverse pulmonary fibrosis cohorts.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {1489},
pmid = {36932145},
issn = {2041-1723},
support = {K23 HL148498/HL/NHLBI NIH HHS/United States ; R01 HL139897/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; *Pulmonary Fibrosis ; Ethnicity ; Proportional Hazards Models ; Racial Groups ; Telomere/genetics ; Leukocytes ; },
abstract = {Pulmonary fibrosis (PF) is characterized by profound scarring and poor survival. We investigated the association of leukocyte telomere length (LTL) with chronological age and mortality across racially diverse PF cohorts. LTL measurements among participants with PF stratified by race/ethnicity were assessed in relation to age and all-cause mortality, and compared to controls. Generalized linear models were used to evaluate the age-LTL relationship, Cox proportional hazards models were used for hazard ratio estimation, and the Cochran-Armitage test was used to assess quartiles of LTL. Standardized LTL shortened with increasing chronological age; this association in controls was strengthened in PF (R = -0.28; P < 0.0001). In PF, age- and sex-adjusted LTL below the median consistently predicted worse mortality across all racial groups (White, HR = 2.21, 95% CI = 1.79-2.72; Black, HR = 2.22, 95% CI = 1.05-4.66; Hispanic, HR = 3.40, 95% CI = 1.88-6.14; and Asian, HR = 2.11, 95% CI = 0.55-8.23). LTL associates uniformly with chronological age and is a biomarker predictive of mortality in PF across racial groups.},
}
@article {pmid36922555,
year = {2023},
author = {Pepke, ML and Kvalnes, T and Wright, J and Araya-Ajoy, YG and Ranke, PS and Boner, W and Monaghan, P and Sæther, BE and Jensen, H and Ringsby, TH},
title = {Longitudinal telomere dynamics within natural lifespans of a wild bird.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {4272},
pmid = {36922555},
issn = {2045-2322},
mesh = {Animals ; *Animals, Wild/genetics ; *Longevity/genetics ; Birds/genetics ; Telomere Homeostasis ; Telomere Shortening/genetics ; Telomere/genetics ; },
abstract = {Telomeres, the nucleotide sequences that protect the ends of eukaryotic chromosomes, shorten with each cell division and telomere loss may be influenced by environmental factors. Telomere length (TL) decreases with age in several species, but little is known about the sources of genetic and environmental variation in the change in TL (∆TL) in wild animals. In this study, we tracked changes in TL throughout the natural lifespan (from a few months to almost 9 years) of free-living house sparrows (Passer domesticus) in two different island populations. TL was measured in nestlings and subsequently up to four times during their lifetime. TL generally decreased with age (senescence), but we also observed instances of telomere lengthening within individuals. We found some evidence for selective disappearance of individuals with shorter telomeres through life. Early-life TL positively predicted later-life TL, but the within-individual repeatability in TL was low (9.2%). Using genetic pedigrees, we found a moderate heritability of ∆TL (h[2] = 0.21), which was higher than the heritabilities of early-life TL (h[2] = 0.14) and later-life TL measurements (h[2] = 0.15). Cohort effects explained considerable proportions of variation in early-life TL (60%), later-life TL (53%), and ∆TL (37%), which suggests persistent impacts of the early-life environment on lifelong telomere dynamics. Individual changes in TL were independent of early-life TL. Finally, there was weak evidence for population differences in ∆TL that may be linked to ecological differences in habitat types. Combined, our results show that individual telomere biology is highly dynamic and influenced by both genetic and environmental variation in natural conditions.},
}
@article {pmid36911306,
year = {2023},
author = {Wolf, SE and Zhang, S and Clotfelter, ED},
title = {Experimental ectoparasite removal has a sex-specific effect on nestling telomere length.},
journal = {Ecology and evolution},
volume = {13},
number = {3},
pages = {e9861},
pmid = {36911306},
issn = {2045-7758},
abstract = {Parasites are a strong selective force that can influence fitness-related traits. The length of chromosome-capping telomeres can be used to assess the long-term costs of parasitism, as telomere loss accelerates in response to environmental stressors and often precedes poorer survival prospects. Here, we explored the sex-specific effects of ectoparasite removal on morphology and telomere length in nestling tree swallows (Tachycineta bicolor). To do so, we experimentally removed blow fly (Protocalliphora spp.) larvae from nests using Permethrin, a broad-spectrum insecticide. Compared to water-treated controls, insecticide treatment of nests had a sex-biased effect on blood telomere length: ectoparasite removal resulted in significantly longer telomeres in males but not females. While this treatment did not influence nestling body mass, it was associated with reduced feather development regardless of sex. This may reflect a relaxed pressure to fledge quickly in the absence of parasites, or alternatively, could be a negative side effect of permethrin on morphology. Exploring robust sex-specific telomere dynamics in response to early-life environmental pressures such as parasitism will shed light on sexual dimorphism in adult life histories and aging.},
}
@article {pmid36910209,
year = {2023},
author = {Liu, J and Zhao, S and Li, Z and Zhang, Z and Zhao, B and Guan, G and Yin, H and Luo, J},
title = {Activation of telomerase activity and telomere elongation of host cells by Theileria annulata infection.},
journal = {Frontiers in microbiology},
volume = {14},
number = {},
pages = {1128433},
pmid = {36910209},
issn = {1664-302X},
abstract = {Theileria annulata-transformed cells share many phenotypes with cancer cells, including uncontrolled proliferation, immortalization, and dissemination. Telomeres are DNA-protein complex at the end of eukaryotic chromosomes that function to maintain genome stability and cell replicative capacity. Telomere length maintenance is primarily dependent on telomerase activity. In up to 90% of human cancer cells, telomerase is reactivated through expression of its catalytic subunit TERT. However, the effect of T. annulata infection on telomere and telomerase activity in bovine cells has not yet been described. In the present study, we confirmed that telomere length and telomerase activity are upregulated after T. annulata infection in three types of cell lines. This change depends on the presence of parasites. After eliminating Theileria from cells with antitheilerial drug buparvaquone, telomerase activity and the expression level of bTERT were decreased. In addition, inhibition of bHSP90 by novobiocin led to decreased AKT phosphorylation levels and telomerase activity, indicating that the bHSP90-AKT complex is a potent factor modulates telomerase activity in T. annulata-infected cells.},
}
@article {pmid36902458,
year = {2023},
author = {Shepelev, N and Dontsova, O and Rubtsova, M},
title = {Post-Transcriptional and Post-Translational Modifications in Telomerase Biogenesis and Recruitment to Telomeres.},
journal = {International journal of molecular sciences},
volume = {24},
number = {5},
pages = {},
pmid = {36902458},
issn = {1422-0067},
support = {21-64-00006//Russian Science Foundation/ ; },
mesh = {Animals ; Humans ; *Telomerase/metabolism ; *Neoplasms ; Saccharomyces cerevisiae/metabolism ; Telomere/metabolism ; Protein Processing, Post-Translational ; },
abstract = {Telomere length is associated with the proliferative potential of cells. Telomerase is an enzyme that elongates telomeres throughout the entire lifespan of an organism in stem cells, germ cells, and cells of constantly renewed tissues. It is activated during cellular division, including regeneration and immune responses. The biogenesis of telomerase components and their assembly and functional localization to the telomere is a complex system regulated at multiple levels, where each step must be tuned to the cellular requirements. Any defect in the function or localization of the components of the telomerase biogenesis and functional system will affect the maintenance of telomere length, which is critical to the processes of regeneration, immune response, embryonic development, and cancer progression. An understanding of the regulatory mechanisms of telomerase biogenesis and activity is necessary for the development of approaches toward manipulating telomerase to influence these processes. The present review focuses on the molecular mechanisms involved in the major steps of telomerase regulation and the role of post-transcriptional and post-translational modifications in telomerase biogenesis and function in yeast and vertebrates.},
}
@article {pmid36894693,
year = {2023},
author = {Spegg, V and Panagopoulos, A and Stout, M and Krishnan, A and Reginato, G and Imhof, R and Roschitzki, B and Cejka, P and Altmeyer, M},
title = {Phase separation properties of RPA combine high-affinity ssDNA binding with dynamic condensate functions at telomeres.},
journal = {Nature structural &amp; molecular biology},
volume = {30},
number = {4},
pages = {451-462},
pmid = {36894693},
issn = {1545-9985},
mesh = {*Replication Protein A/chemistry ; *Telomere/metabolism ; RNA/metabolism ; DNA, Single-Stranded ; Protein Binding ; DNA Replication ; },
abstract = {RPA has been shown to protect single-stranded DNA (ssDNA) intermediates from instability and breakage. RPA binds ssDNA with sub-nanomolar affinity, yet dynamic turnover is required for downstream ssDNA transactions. How ultrahigh-affinity binding and dynamic turnover are achieved simultaneously is not well understood. Here we reveal that RPA has a strong propensity to assemble into dynamic condensates. In solution, purified RPA phase separates into liquid droplets with fusion and surface wetting behavior. Phase separation is stimulated by sub-stoichiometric amounts of ssDNA, but not RNA or double-stranded DNA, and ssDNA gets selectively enriched in RPA condensates. We find the RPA2 subunit required for condensation and multi-site phosphorylation of the RPA2 N-terminal intrinsically disordered region to regulate RPA self-interaction. Functionally, quantitative proximity proteomics links RPA condensation to telomere clustering and integrity in cancer cells. Collectively, our results suggest that RPA-coated ssDNA is contained in dynamic RPA condensates whose properties are important for genome organization and stability.},
}
@article {pmid36890798,
year = {2023},
author = {Moustakli, E and Zikopoulos, A and Sakaloglou, P and Bouba, I and Sofikitis, N and Georgiou, I},
title = {Functional association between telomeres, oxidation and mitochondria.},
journal = {Frontiers in reproductive health},
volume = {5},
number = {},
pages = {1107215},
pmid = {36890798},
issn = {2673-3153},
abstract = {Prior research has substantiated the vital role of telomeres in human fertility. Telomeres are prerequisites for maintaining the integrity of chromosomes by preventing the loss of genetic material following replication events. Little is known about the association between sperm telomere length and mitochondrial capacity involving its structure and functions. Mitochondria are structurally and functionally distinct organelles that are located on the spermatozoon's midpiece. Mitochondria produce adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS), which is necessary for sperm motility and generate reactive oxygen species (ROS). While a moderate concentration of ROS is critical for egg-sperm fusion, and fertilization, excessive ROS generation is primarily related to telomere shortening, sperm DNA fragmentation, and alterations in the methylation pattern leading to male infertility. This review aims to highlight the functional connection between mitochondria biogenesis and telomere length in male infertility, as mitochondrial lesions have a damaging impact on telomere length, leading both to telomere lengthening and reprogramming of mitochondrial biosynthesis. Furthermore, it aims to shed light on how both inositol and antioxidants can positively affect male fertility.},
}
@article {pmid36890680,
year = {2023},
author = {Chen, Z and Shen, Y and He, J and Shen, Y and Zhu, W and Wu, X and Xiao, M},
title = {Longer leukocyte telomere length increases cardiovascular mortality in type 2 diabetes patients.},
journal = {Journal of diabetes},
volume = {15},
number = {4},
pages = {325-331},
pmid = {36890680},
issn = {1753-0407},
mesh = {Humans ; *Diabetes Mellitus, Type 2/complications ; Nutrition Surveys ; *Cardiovascular Diseases ; *Neoplasms ; Leukocytes ; Telomere/genetics ; },
abstract = {AIMS: Leukocyte telomere length (LTL), as a biomarker of biological aging, is associated with the prevalence and complications of diabetes. This study aims to investigate the associations between LTL and all-cause and cause-specific mortality in patients with type 2 diabetes.<br><br>METHODS: All participants with baseline LTL records were included from the National Health and Nutrition Examination Survey 1999-2002. Death status and its causes were ascertained for National Death Index based on International Classification of Diseases, Tenth Revision code. Cox proportional hazards regression models were established to estimate the hazard ratios (HRs) of LTL associating with all-cause and cause-specific mortality.<br><br>RESULTS: The study enrolled 804 diabetic patients with the mean follow-up of 14.9&#x2009;&#xb1;&#x2009;2.59&#x2009;years. There were 367 (45.6%) all-cause deaths, 80 (10.0%) cardiovascular deaths, and 42 (5.2%) cancer-related deaths. Longer LTL was associated with reduced all-cause mortality, whereas this association disappeared after adjusting for other variables. Compared with the lowest tertiles of LTL, the multivariable-adjusted hazard ratio of cardiovascular mortality was 2.11 (95% confidence interval [CI] 1.31-3.39; p&#x2009;<&#x2009;.05) in the highest tertiles. In terms of cancer mortality, the highest tertile was negatively correlated with the risk of cancer mortality (HR 0.58 [95% CI 0.37, 0.91], p&#x2009;<&#x2009;.05).<br><br>CONCLUSION: In conclusion, LTL was independently associated with the risk of cardiovascular mortality in patients with type 2 diabetes and was negatively correlated with the risk of cancer mortality. Telomere length may be a predictor of cardiovascular mortality in diabetes.},
}
@article {pmid36883676,
year = {2023},
author = {Becher, OJ},
title = {A new path to alternative lengthening of telomeres?.},
journal = {Neuro-oncology},
volume = {25},
number = {7},
pages = {1343-1344},
pmid = {36883676},
issn = {1523-5866},
support = {R01 CA197313/CA/NCI NIH HHS/United States ; R01 CA258636/CA/NCI NIH HHS/United States ; R01s CA197313/GF/NIH HHS/United States ; },
mesh = {Humans ; Child ; DNA Mismatch Repair ; Telomere/genetics/metabolism ; *Telomerase/genetics/metabolism ; Mutation ; *Glioma ; X-linked Nuclear Protein/genetics ; },
}
@article {pmid36880214,
year = {2023},
author = {Yang, C and Wu, X and Chen, S and Xiang, B},
title = {Association between telomere length and hepatocellular carcinoma risk: A Mendelian randomization study.},
journal = {Cancer medicine},
volume = {12},
number = {8},
pages = {9937-9944},
pmid = {36880214},
issn = {2045-7634},
mesh = {Humans ; *Carcinoma, Hepatocellular/genetics ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; *Liver Neoplasms/genetics ; Polymorphism, Single Nucleotide ; Telomere/genetics ; },
abstract = {BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer threatening the public health globally. Although HCC has been associated with the telomere length (TL), the causal relationship between them is not well understood. Therefore, we attempted to explore the linear causal relationship between TL and HCC through Mendelian randomization (MR) analysis among Asian and European populations.<br><br>METHODS: The summary statistics of TL-associated single nucleotide polymorphisms (SNPs) were obtained from a genome-wide association study (GWAS) in the Asian population (N = 23,096). The data of TL-associated SNPs in the European population (N&#xa0;=&#xa0;472,174) and the GWAS summary statistics of HCC in the Asian population (1866 cases, 195,745 controls) as well as the European population (168 cases, 372,016 controls) were downloaded from the public GWAS database. Two-sample MR was performed using inverse variance weighting (IVW), weighted median estimate, MR-Egger regression, weighted-mode estimate, and simple-mode estimate methods. Sensitivity analysis was performed to text the primary results' robustness.<br><br>RESULTS: Nine SNPs associated with TL in Asian populations and 98 SNPs in European populations were selected as instrumental variables. No linear causal relationship between heritable TL and the HCC risk was recorded in the Asian (IVW analysis odds ratio [OR]&#xa0;=&#xa0;1.023, 95% confidence interval [CI] 0.745, 1.405, p&#xa0;=&#xa0;0.887) and European populations (IVW analysis OR&#xa0;=&#xa0;0.487, 95% CI 0.180, 1.320, p&#xa0;=&#xa0;0.157). Other methods also achieved similar outcomes. Sensitivity analysis was performed and revealed no heterogeneity and horizontal pleiotropy.<br><br>CONCLUSIONS: No linear causal association was recorded between heritable TL and HCC in Asian and European populations.},
}
@article {pmid36879937,
year = {2023},
author = {Kumari, R and Suneja, A and Mehndiratta, M and Guleria, K and Malik, R},
title = {Maternal Serum Vitamin E Levels and its Association with Cord Blood Telomere Length and Mitochondrial DNA Copy Number in Preterm Premature Rupture of Membranes.},
journal = {Journal of obstetrics and gynaecology of India},
volume = {73},
number = {1},
pages = {9-14},
pmid = {36879937},
issn = {0971-9202},
abstract = {BACKGROUND AND OBJECTIVE: Oxidative stress is one of the pathophysiological factors of pPROM and Vit. E being antioxidant may have preventive role. Study was conducted to estimate maternal serum vitamin E levels and cord blood oxidative stress markers in pPROM cases.<br><br>METHODS: This was a case-control study including 40 pPROM cases and 40 controls. Maternal serum vitamin E levels were measured at recruitment. Cord blood was collected at delivery for estimation of telomere length and mtDNA copy number as oxidative stress markers. Levels were compared using student's t test or Mann Whitney test. For correlation Pearson coefficient was used.<br><br>RESULTS: Maternal serum vitamin E levels were normal in pPROM cases. Cord blood telomere length was more in pPROM than controls (428.99&#x2009;&#xb1;&#x2009;290.65 vs 322.35&#x2009;&#xb1;&#x2009;180.33) (p value 0.05). Cord blood mtDNA copy number was more in pPROM than controls (516.46&#x2009;&#xb1;&#x2009;443.55 vs 384.77&#x2009;&#xb1;&#x2009;328.27) (p value 0.13) though it was not significant. mtDNA copy number had negative correlation with Vit. E levels but it was statistically not significant (p value 0.49). There was no association of vitamin E levels with telomere length (p value 0.95).<br><br>INTERPRETATION AND CONCLUSION: pPROM was not associated with vitamin E deficiency. There was insignificant oxidative stress in cord blood as measured by mtDNA copy number but cord blood telomere length measurement did not detect any oxidative stress in pPPROM cases.},
}
@article {pmid36876055,
year = {2023},
author = {Goldstein, AM and Qin, R and Chu, EY and Elder, DE and Massi, D and Adams, DJ and Harms, PW and Robles-Espinoza, CD and Newton-Bishop, JA and Bishop, DT and Harland, M and Holland, EA and Cust, AE and Schmid, H and Mann, GJ and Puig, S and Potrony, M and Alos, L and Nagore, E and Millán-Esteban, D and Hayward, NK and Broit, N and Palmer, JM and Nathan, V and Berry, EG and Astiazaran-Symonds, E and Yang, XR and Tucker, MA and Landi, MT and Pfeiffer, RM and Sargen, MR},
title = {Association of germline variants in telomere maintenance genes (POT1, TERF2IP, ACD, and TERT) with spitzoid morphology in familial melanoma: A multi-center case series.},
journal = {JAAD international},
volume = {11},
number = {},
pages = {43-51},
pmid = {36876055},
issn = {2666-3287},
support = {MR/V000292/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {BACKGROUND: Spitzoid morphology in familial melanoma has been associated with germline variants in POT1, a telomere maintenance gene (TMG), suggesting a link between telomere biology and spitzoid differentiation.<br><br>OBJECTIVE: To assess if familial melanoma cases associated with germline variants in TMG (POT1, ACD, TERF2IP, and TERT) commonly exhibit spitzoid morphology.<br><br>METHODS: In this case series, melanomas were classified as having spitzoid morphology if at least 3 of 4 dermatopathologists reported this finding in &#x2265;25% of tumor cells. Logistic regression was used to calculate odds ratios (OR) of spitzoid morphology compared to familial melanomas from unmatched noncarriers that were previously reviewed by a National Cancer Institute dermatopathologist.<br><br>RESULTS: Spitzoid morphology was observed in 77% (23 of 30), 75% (3 of 4), 50% (2 of 4), and 50% (1 of 2) of melanomas from individuals with germline variants in POT1, TERF2IP, ACD, and TERT, respectively. Compared to noncarriers (n&#xa0;=&#xa0;139 melanomas), POT1 carriers (OR&#xa0;=&#xa0;225.1, 95% confidence interval: 51.7-980.5; P&#xa0;<&#xa0;.001) and individuals with TERF2IP, ACD, and TERT variants (OR&#xa0;=&#xa0;82.4, 95% confidence interval: 21.3-494.6; P&#xa0;<&#xa0;.001) had increased odds of spitzoid morphology.<br><br>LIMITATIONS: Findings may not be generalizable to nonfamilial melanoma cases.<br><br>CONCLUSION: Spitzoid morphology in familial melanoma could suggest germline alteration of TMG.},
}
@article {pmid36873417,
year = {2023},
author = {Sha, Z and Hou, T and Zhou, T and Dai, Y and Bao, Y and Jin, Q and Ye, J and Lu, Y and Wu, L},
title = {Causal relationship between atrial fibrillation and leukocyte telomere length: A two sample, bidirectional Mendelian randomization study.},
journal = {Frontiers in cardiovascular medicine},
volume = {10},
number = {},
pages = {1093255},
pmid = {36873417},
issn = {2297-055X},
abstract = {BACKGROUND: Atrial fibrillation (AF) is an age-related disease, while telomeres play a central role in aging. But the relationship between AF and telomere length (LTL) is still controversial. This study aims to examine the potential causal association between AF and LTL by using Mendelian randomization (MR).<br><br>METHODS: Bidirectional two-sample MR, expression and protein quantitative trait loci (eQTL and pQTL)-based MR were performed using genetic variants from United Kingdom Biobank, FinnGen, and a meta-analysis study, which comprised nearly 1 million participants in the Atrial Fibrillation Study and 470,000 participants in the Telomere Length Study. Apart from the inverse variance weighted (IVW) approach as the main MR analysis, complementary analysis approaches and sensitivity analysis were applied.<br><br>RESULTS: The forward MR revealed a significant causal estimate for the genetically predicted AF with LTL shortening [IVW: odds ratio (OR)&#x2009;=&#x2009;0.989, p&#x2009;=&#x2009;0.007; eQTL-IVW: OR&#x2009;=&#x2009;0.988, p&#x2009;=&#x2009;0.005; pQTL-IVW: OR&#x2009;=&#x2009;0.975, p&#x2009;<&#x2009;0.005]. But in the reverse MR analysis, genetically predicted LTL has no significant correlation with AF (IVW: OR&#x2009;=&#x2009;0.995, p&#x2009;=&#x2009;0.916; eQTL-IVW: OR&#x2009;=&#x2009;0.999, p&#x2009;=&#x2009;0.995; pQTL-IVW: OR&#x2009;=&#x2009;1.055, p&#x2009;=&#x2009;0.570). The FinnGen replication data yielded similar findings. Sensitivity analysis ensured the stability of the results.<br><br>CONCLUSION: The presence of AF leads to LTL shortening rather than the other way around. Aggressive intervention for AF may delay the telomere attrition.},
}
@article {pmid36871092,
year = {2023},
author = {Deręgowska, A and Pępek, M and Solarska, I and Machnicki, MM and Pruszczyk, K and Dudziński, M and Niesiobędzka-Krężel, J and Seferyńska, I and Sawicki, W and Wnuk, M and Stokłosa, T},
title = {The interplay between telomeric complex members and BCR::ABL1 oncogenic tyrosine kinase in the maintenance of telomere length in chronic myeloid leukemia.},
journal = {Journal of cancer research and clinical oncology},
volume = {149},
number = {10},
pages = {7103-7112},
pmid = {36871092},
issn = {1432-1335},
support = {2015/19/B/NZ5/03501//Narodowe Centrum Nauki/ ; },
mesh = {Humans ; Bone Marrow/metabolism ; Cell Cycle Proteins/genetics ; Fusion Proteins, bcr-abl/genetics ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics/pathology ; Nuclear Proteins/genetics ; *Tankyrases/genetics/metabolism ; *Telomerase/genetics/metabolism ; Telomere/metabolism ; },
abstract = {PURPOSE: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by recurrent genetic aberration in leukemic stem cells, namely Philadelphia chromosome caused by reciprocal translocation t(9;22)(q34;q11). In our study, we analyzed the telomeric complex expression and function in the molecular pathogenesis of CML.<br><br>METHODS: We employed CD34+&#x2009;primary leukemic cells, comprising both leukemic stem and progenitor cell populations, isolated from peripheral blood or bone marrow of CML patients in chronic and blastic phase to analyze the telomere length and telomeric-associated proteins.<br><br>RESULTS: The reduction in telomere length during disease progression was correlated with increased expression of BCR::ABL1 transcript and the dynamic changes were neither associated with the enzymatic activity of telomerase nor with gene copy number and expression of telomerase subunits. Increased expression of BCR::ABL1 was positively correlated with expression of TRF2, RAP1, TPP1, DKC1, TNKS1, and TNKS2 genes.<br><br>CONCLUSIONS: The dynamics of telomere length changes in CD34+&#x2009;CML cells is dependent on the expression level of BCR::ABL, which promotes the expression of certain shelterins including RAP1 and TRF2, as well as TNKS, and TNKS2, and results in telomere shortening regardless of telomerase activity. Our results may allow better understanding of the mechanisms responsible for the genomic instability of leukemic cells and CML progression.},
}
@article {pmid36868694,
year = {2023},
author = {Chakraborty, A and Roy, S and Hande, MP and Banerjee, B},
title = {Telomere attrition and genomic instability in unexplained recurrent pregnancy loss in humans: A preliminary study.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {886},
number = {},
pages = {503580},
doi = {10.1016/j.mrgentox.2022.503580},
pmid = {36868694},
issn = {1879-3592},
mesh = {Female ; Pregnancy ; Humans ; Retrospective Studies ; *Genomic Instability ; Mutation ; *DNA Damage ; Telomere ; },
abstract = {Genome instability is defined as an elevated rate of DNA damage and mutations as a result of exposure to potential direct and indirect mutagens. This current investigation was designed to elucidate the genomic instability among couples experiencing unexplained recurrent pregnancy loss (uRPL). A cohort of 1272 individuals with history of unexplained RPL with normal karyotype was retrospectively screened for levels of intracellular ROS production, baseline genomic instability and telomere functionality. The experimental outcome was compared with 728 fertile control individuals. In this study, it was perceived that individuals with uRPL exhibited higher intracellular oxidative stress, along with higher basal levels of genomic instability as compared with the fertile controls. This observation elucidates the role of genomic instability as well as involvement of telomeres in cases of uRPL. It was also observed that higher oxidative stress might be associated with DNA damage and telomere dysfunction resulting in genomic instability among subjects with unexplained RPL. This study highlighted the assessment of genomic instability status in individuals experiencing uRPL.},
}
@article {pmid36864251,
year = {2023},
author = {Maresca, C and Dello Stritto, A and D'Angelo, C and Petti, E and Rizzo, A and Vertecchi, E and Berardinelli, F and Bonanni, L and Sgura, A and Antoccia, A and Graziani, G and Biroccio, A and Salvati, E},
title = {PARP1 allows proper telomere replication through TRF1 poly (ADP-ribosyl)ation and helicase recruitment.},
journal = {Communications biology},
volume = {6},
number = {1},
pages = {234},
pmid = {36864251},
issn = {2399-3642},
support = {21579//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; 17121//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; },
mesh = {ADP-Ribosylation ; DNA Damage ; DNA Helicases ; *Shelterin Complex ; *Telomere/genetics ; Poly (ADP-Ribose) Polymerase-1/metabolism ; },
abstract = {Telomeres are nucleoprotein structures at eukaryotic chromosome termini. Their stability is preserved by a six-protein complex named shelterin. Among these, TRF1 binds telomere duplex and assists DNA replication with mechanisms only partly clarified. Here we found that poly (ADP-ribose) polymerase 1 (PARP1) interacts and covalently PARylates TRF1 in S-phase modifying its DNA affinity. Therefore, genetic and pharmacological inhibition of PARP1 impairs the dynamic association of TRF1 and the bromodeoxyuridine incorporation at replicating telomeres. Inhibition of PARP1 also affects the recruitment of WRN and BLM helicases in TRF1 containing complexes during S-phase, triggering replication-dependent DNA-damage and telomere fragility. This work unveils an unprecedented role for PARP1 as a "surveillant" of telomere replication, which orchestrates protein dynamics at proceeding replication fork.},
}
@article {pmid36860927,
year = {2023},
author = {Sun, H and Chen, G and Guo, B and Lv, S and Yuan, G},
title = {Potential clinical treatment prospects behind the molecular mechanism of alternative lengthening of telomeres (ALT).},
journal = {Journal of Cancer},
volume = {14},
number = {3},
pages = {417-433},
pmid = {36860927},
issn = {1837-9664},
abstract = {Normal somatic cells inevitably experience replicative stress and senescence during proliferation. Somatic cell carcinogenesis can be prevented in part by limiting the reproduction of damaged or old cells and removing them from the cell cycle [1, 2]. However, Cancer cells must overcome the issues of replication pressure and senescence as well as preserve telomere length in order to achieve immortality, in contrast to normal somatic cells [1, 2]. Although telomerase accounts for the bulk of telomere lengthening methods in human cancer cells, there is a non-negligible portion of telomere lengthening pathways that depend on alternative lengthening of telomeres (ALT) [3]. For the selection of novel possible therapeutic targets for ALT-related disorders, a thorough understanding of the molecular biology of these diseases is crucial [4]. The roles of ALT, typical ALT tumor cell traits, the pathophysiology and molecular mechanisms of ALT tumor disorders, such as adrenocortical carcinoma (ACC), are all summarized in this work. Additionally, this research compiles as many of its hypothetically viable but unproven treatment targets as it can (ALT-associated PML bodies (APB), etc.). This review is intended to contribute as much as possible to the development of research, while also trying to provide a partial information for prospective investigations on ALT pathways and associated diseases.},
}
@article {pmid36859557,
year = {2023},
author = {Chen, J and Wu, S and Wu, Y and Zhuang, P and Zhang, Y and Jiao, J},
title = {Long-term dietary DHA intervention prevents telomere attrition and lipid disturbance in telomerase-deficient male mice.},
journal = {European journal of nutrition},
volume = {62},
number = {4},
pages = {1867-1878},
pmid = {36859557},
issn = {1436-6215},
support = {LR18C200001//Natural Science Foundation of Zhejiang Province/ ; },
mesh = {Animals ; Mice ; Male ; *Docosahexaenoic Acids/pharmacology ; *Telomerase/genetics ; Glycerol ; Mice, Inbred C57BL ; Telomere ; Phosphates ; Mice, Knockout ; Mammals/genetics/metabolism ; },
abstract = {PURPOSE: Previous evidence indicated anti-ageing potential of docosahexaenoic acid (DHA), but the underlying mechanism remains unclear. We investigated protective effect of DHA on telomere attrition and lipid disturbance in male mice with premature ageing caused by telomerase deficiency.<br><br>METHODS: Wild-type (WT) and fourth-generation telomerase-deficient (G4 Terc[-/-], Terc knockout, KO) male mice (C57BL/6, 2&#xa0;months old) were fed control diet (WT-C and KO-C groups) or DHA-enriched diet containing 0.80% DHA by weight (WT-DHA and KO-DHA groups) for 10&#xa0;months. The ageing phenotypes and metabolic level [carbon dioxide emission, oxygen consumption, and respiratory exchange ratio (RER)] were assessed at the end of the experiment. Telomere length in various tissues and the hepatic gene and protein expression for regulating lipid synthesis and lipolysis were measured. Data were tested using one- or two-factor ANOVA.<br><br>RESULTS: In KO male mice, DHA prevented weight loss, corrected high RER, and reduced fat loss. Telomere shortening was reduced by 22.3%, 25.5%, and 13.5% in heart, liver, and testes of the KO-DHA group compared with those in the KO-C group. The KO-DHA group exhibited higher gene transcription involved in glycerol-3-phosphate pathway [glycerol-3-phosphate acyltransferase (Gpat)], lower gene expression of &#x3b2;-oxidation [carnitine palmitoyltransferase 1a (Cpt1a)], and upregulation of proteins in lipid synthesis [mammalian target of rapamycin complex 1 (mTORC1) and sterol responsive element binding protein 1 (SREBP1)] in liver than the KO-C group.<br><br>CONCLUSION: Long-term DHA intervention attenuates telomere attrition and promotes lipid synthesis via the tuberous sclerosis complex 2 (TSC2)-mTORC1-SREBP1 pathway in KO male mice.},
}
@article {pmid36855016,
year = {2023},
author = {Chen, X and Hao, Z and Pan, H and Liu, W and Lu, L and Zhang, M and He, X and Yi, H and Tang, S},
title = {Relationship between common telomere length-related genetic variations, telomere length, and risk of antituberculosis drug-induced hepatotoxicity in Chinese Han population: As assessed for causality using the updated Roussel Uclaf Causality Assessment Method.},
journal = {Fundamental &amp; clinical pharmacology},
volume = {37},
number = {4},
pages = {858-867},
doi = {10.1111/fcp.12885},
pmid = {36855016},
issn = {1472-8206},
support = {82073614//National Natural Science Foundation of China/ ; 2021//Zhenjiang "Jinshan Doctor" Talent Training Program/ ; SH2021055//Zhenjiang Key Technologies Research and Development Program (Social Development)/ ; },
mesh = {Humans ; *Antitubercular Agents/adverse effects ; Case-Control Studies ; *Chemical and Drug Induced Liver Injury/etiology/genetics ; East Asian People ; Genetic Predisposition to Disease ; Leukocytes ; Polymorphism, Single Nucleotide ; Telomere/genetics ; Causality ; },
abstract = {Antituberculosis drug-induced hepatotoxicity (ATDH) is a significant threat to tuberculosis control, and two recent studies indicated that leukocyte telomere length (LTL) might be a potential biomarker for ATDH. This study aimed to investigate the relationship between common telomere length-related genetic variations, LTL, and risk of ATDH in Eastern Chinese antituberculosis treatment patients. A 1:4 matched case-control study was conducted among 79 ATDH cases assessed for causality using the updated RUCAM and 316 controls. LTL was determined by quantitative real-time PCR, and nine SNPs involved in telomere biology reported by previous GWAS were assessed. Conditional logistic regression model was used to estimate the association between genotypes and risk of ATDH with odds ratios (ORs) and 95% confidence intervals (CIs). The average RUCAM score of cases was 7.1. The average LTL in cases was significantly shorter than that in controls (median = 1.239 vs. 1.481, P = 0.032). Differences in the distribution of LTL were statistically significant among three genotypes of SNP rs2736098 (CC vs. CT vs. TT, median = 1.544 vs. 1.356 vs. 1.337, P = 0.026) and rs2853677 (AA vs. AG vs. GG, median = 1.511 vs. 1.544 vs. 1.159, P = 0.005) in TERT. SNP rs7675998 in NAF1 was statistically associated with the risk of ATDH under the dominant model (adjusted OR = 1.725, 95% CI: 1.021-2.913, P = 0.042). This is the first study to investigate the relationship of LTL, common telomere length-related variations, and risk of ATDH. SNP rs2736098 and rs2853677 in TERT were significantly associated with LTL, and SNP rs7675998 in NAF1 may be associated with ATDH in Chinese population.},
}
@article {pmid36852686,
year = {2023},
author = {Zhang, H and Lai, X and Fang, Q and Ma, L and Liu, M and Yang, H and Guo, W and He, M and Yang, L and Zhang, X},
title = {Independent and Joint Association of Leukocyte Telomere Length and Lifestyle Score With Incident Stroke.},
journal = {Stroke},
volume = {54},
number = {5},
pages = {e199-e200},
doi = {10.1161/STROKEAHA.122.041126},
pmid = {36852686},
issn = {1524-4628},
mesh = {Humans ; *Aging ; Life Style ; *Stroke ; Leukocytes ; Telomere ; },
}
@article {pmid36851065,
year = {2023},
author = {Wu, X and Li, P and Tao, J and Chen, X and Zhang, A},
title = {Subchronic Low-Dose Methylmercury Exposure Accelerated Cerebral Telomere Shortening in Relevant with Declined Urinary aMT6s Level in Rats.},
journal = {Toxics},
volume = {11},
number = {2},
pages = {},
pmid = {36851065},
issn = {2305-6304},
support = {U1812403//National Natural Science Foundation of China/ ; },
abstract = {Methylmercury (MeHg) is a global pollutant with established toxic effects on the central nervous system (CNS). However, early events and early-warning biomarkers of CNS damage following exposure to low-dose MeHg are still lacking. This study aimed to investigate whether subchronic low-dose MeHg exposure had adverse effects on the cerebral telomere length, as well as serum melatonin and its urinary metabolite 6-sulfatoxymelatonin (aMT6s) in rats. Sixteen male Sprague Dawley rats were divided into two groups. Group I was the control group. In group II, rats were exposed to MeHg by gavage at a dose of 0.1 mg/kg/day for 3 months. This study revealed that MeHg exposure resulted in impairment of learning and memory ability, a slightly reduced number of neurons and an irregular arrangement of neurons in the hippocampus. It also significantly accelerated telomere shortening in the cerebral cortex, hippocampus and hypothalamus. Moreover, MeHg exposure decreased the levels of melatonin in serum and aMT6s in urine, partly by suppressing the synthesis of 5-hydroxytryptamine (5-HT) in the brain but promoted the expression of melatonin-catalyzing AANAT and ASMT. Importantly, cerebral telomere length was positively correlated with MT and aMT6s after MeHg exposure. These results suggested that the shortened telomere length in the brain may be an early event in MeHg-induced CNS toxicity, and the level of aMT6s in urine may serve as an early-warning biomarker for MeHg-induced CNS damage.},
}
@article {pmid36849001,
year = {2023},
author = {Liu, S and Nong, W and Ji, L and Zhuge, X and Wei, H and Luo, M and Zhou, L and Chen, S and Zhang, S and Lei, X and Huang, H},
title = {The regulatory feedback of inflammatory signaling and telomere/telomerase complex dysfunction in chronic inflammatory diseases.},
journal = {Experimental gerontology},
volume = {174},
number = {},
pages = {112132},
doi = {10.1016/j.exger.2023.112132},
pmid = {36849001},
issn = {1873-6815},
mesh = {Humans ; *Telomerase/metabolism ; NF-kappa B ; Feedback ; Telomere ; Inflammation ; },
abstract = {Inflammation is believed to play a role in the progression of numerous human diseases. Research has shown that inflammation and telomeres are involved in a feedback regulatory loop: inflammation increases the rate of telomere attrition, leading to telomere dysfunction, while telomere components also participate in regulating the inflammatory response. However, the specific mechanism behind this feedback loop between inflammatory signaling and telomere/telomerase complex dysfunction has yet to be fully understood. This review presents the latest findings on this topic, with a particular focus on the detailed regulation and molecular mechanisms involved in the progression of aging, various chronic inflammatory diseases, cancers, and different stressors. Several feedback loops between inflammatory signaling and telomere/telomerase complex dysfunction, including NF-κB-TERT feedback, NF-κB-RAP1 feedback, NF-κB-TERC feedback, STAT3-TERT feedback, and p38 MAPK-shelterin complex-related gene feedback, are summarized. Understanding the latest discoveries of this feedback regulatory loop can help identify novel potential drug targets for the suppression of various inflammation-associated diseases.},
}
@article {pmid36847305,
year = {2024},
author = {Levy, MA and Tian, J and Gandelman, M and Cheng, H and Tsapekos, M and Crego, SR and Maddela, R and Sinnott, R},
title = {A Multivitamin Mixture Protects against Oxidative Stress-Mediated Telomere Shortening.},
journal = {Journal of dietary supplements},
volume = {21},
number = {1},
pages = {53-70},
doi = {10.1080/19390211.2023.2179153},
pmid = {36847305},
issn = {1939-022X},
mesh = {Humans ; *Telomere Shortening ; *Hydrogen Peroxide ; Oxidative Stress ; Vitamins/pharmacology ; Aging/metabolism ; },
abstract = {Telomeres are nucleotide repeat sequences located at the end of chromosomes that protect them from degradation and maintain chromosomal stability. Telomeres shorten with each cell division; hence telomere length is associated with aging and longevity. Numerous lifestyle factors have been identified that impact the rate of telomere shortening; high vitamin consumption has been associated with longer telomere length, whereas oxidative stress is associated with telomere shortening. In this paper, we sought to determine if a multivitamin mixture containing both vitamins and a blend of polyphenolic compounds, could reduce telomere shortening consequent to an oxidative stress (10 uM H2O2 for 8 weeks) in a primary fibroblast cell culture model. Under conditions of oxidative stress, the median and 20[th] percentile telomere length were significantly greater (p < 0.05), and the percentage of critically short telomeres (<3000 bp) was significantly less (p < 0.05) in cells treated with the multivitamin mixture at 4, 15 and 60 ug/ml compared to control (0 ug/ml). Median and 20[th] percentile telomere shortening rate was also reduced under the same conditions (p < 0.05). Taken together, these findings demonstrate that the multivitamin mixture protects against oxidative stress-mediated telomere shortening in cell culture, findings which may have implications in human health.},
}
@article {pmid36847070,
year = {2023},
author = {Pepke, ML and Ringsby, TH and Eisenberg, DTA},
title = {The evolution of early-life telomere length, pace-of-life and telomere-chromosome length dynamics in birds.},
journal = {Molecular ecology},
volume = {32},
number = {11},
pages = {2898-2912},
doi = {10.1111/mec.16907},
pmid = {36847070},
issn = {1365-294X},
mesh = {*Birds/classification/genetics ; Animals ; *Telomere Homeostasis ; *Chromosome Structures/genetics ; *Phylogeny ; Genome Size/genetics ; Cytogenetic Analysis ; *Life History Traits ; },
abstract = {Telomeres, the short DNA sequences that protect chromosome ends, are an ancient molecular structure, which is highly conserved across most eukaryotes. Species differ in their telomere lengths, but the causes of this variation are not well understood. Here, we demonstrate that mean early-life telomere length is an evolutionary labile trait across 57 bird species (representing 35 families in 12 orders) with the greatest trait diversity found among passerines. Among these species, telomeres are significantly shorter in fast-lived than in slow-lived species, suggesting that telomere length may have evolved to mediate trade-offs between physiological requirements underlying the diversity of pace-of-life strategies in birds. This association was attenuated when excluding studies that may include interstitial telomeres in the estimation of mean telomere length. Curiously, within some species, larger individual chromosome size predicts longer telomere lengths on that chromosome, leading to the hypothesis that telomere length also covaries with chromosome length across species. We show that longer mean chromosome length or genome size tends to be associated with longer mean early-life telomere length (measured across all chromosomes) within a phylogenetic framework constituting up to 31 bird species. These associations were strengthened when excluding highly influential outliers. However, sensitivity analyses suggested that they were susceptible to sample size effects and not robust to the exclusion of studies that may include interstitial telomeres. Combined, our analyses generalize patterns previously found within a few species and provide potential adaptive explanations for the 10-fold variation in telomere lengths observed among birds.},
}
@article {pmid36843839,
year = {2023},
author = {Zhang, X and Zhang, C and Zhou, D and Zhang, T and Chen, X and Ren, J and He, C and Meng, F and Zhou, Q and Yang, Q and Dai, C and Lin, G and Zeng, S and Leng, L},
title = {Telomeres cooperate in zygotic genome activation by affecting DUX4/Dux transcription.},
journal = {iScience},
volume = {26},
number = {3},
pages = {106158},
pmid = {36843839},
issn = {2589-0042},
abstract = {Zygotic genome activation (ZGA) is initiated once the genome chromatin state is organized in the newly formed zygote. Telomeres are specialized chromatin structures at the ends of chromosomes and are reset during early embryogenesis, while the details and significance of telomere changes in preimplantation embryos remain unclear. We demonstrated that the telomere length was shortened in the minor ZGA stage and significantly elongated in the major ZGA stage of human and mouse embryos. Expression of the ZGA pioneer factor DUX4/Dux was negatively correlated with the telomere length. ATAC sequencing data revealed that the chromatin accessibility peaks on the DUX4 promoter region (i.e., the subtelomere of chromosome 4q) were transiently augmented in human minor ZGA. Reduction of telomeric heterochromatin H3K9me3 in the telomeric region also synergistically activated DUX4 expression with p53 in human embryonic stem cells. We propose herein that telomeres regulate the expression of DUX4/Dux through chromatin remodeling and are thereby involved in ZGA.},
}
@article {pmid36834938,
year = {2023},
author = {Martel-Martel, A and Corchete, LA and Martí, M and Vidal-Tocino, R and Hurtado, E and Álvaro, E and Jiménez, F and Jiménez-Toscano, M and Balaguer, F and Sanz, G and López, I and Hernández-Villafranca, S and Ballestero, A and Vivas, A and Melone, S and Pastor, C and Brandáriz, L and Gómez-Marcos, MA and Cruz-Hernández, JJ and Perea, J and González-Sarmiento, R},
title = {Telomere Length as a New Risk Marker of Early-Onset Colorectal Cancer.},
journal = {International journal of molecular sciences},
volume = {24},
number = {4},
pages = {},
pmid = {36834938},
issn = {1422-0067},
support = {PI20/0974//Instituto de Salud Carlos III/ ; PI20/01569//Instituto de Salud Carlos III/ ; },
mesh = {Humans ; Middle Aged ; *Colorectal Neoplasms/diagnosis/genetics ; Incidence ; *Telomere/genetics/metabolism ; Biomarkers, Tumor ; *Early Detection of Cancer/methods ; },
abstract = {Early-onset colorectal cancer (EOCRC; age younger than 50 years) incidence has been steadily increasing in recent decades worldwide. The need for new biomarkers for EOCRC prevention strategies is undeniable. In this study, we aimed to explore whether an aging factor, such as telomere length (TL), could be a useful tool in EOCRC screening. The absolute leukocyte TL from 87 microsatellite stable EOCRC patients and 109 healthy controls (HC) with the same range of age, was quantified by Real Time Quantitative PCR (RT-qPCR). Then, leukocyte whole-exome sequencing (WES) was performed to study the status of the genes involved in TL maintenance (hTERT, TERC, DKC1, TERF1, TERF2, TERF2IP, TINF2, ACD, and POT1) in 70 sporadic EOCRC cases from the original cohort. We observed that TL was significantly shorter in EOCRC patients than in healthy individuals (EOCRC mean: 122 kb vs. HC mean: 296 kb; p < 0.001), suggesting that telomeric shortening could be associated with EOCRC susceptibility. In addition, we found a significant association between several SNPs of hTERT (rs79662648), POT1 (rs76436625, rs10263573, rs3815221, rs7794637, rs7784168, rs4383910, and rs7782354), TERF2 (rs251796 and rs344152214), and TERF2IP (rs7205764) genes and the risk of developing EOCRC. We consider that the measurement of germline TL and the status analysis of telomere maintenance related genes polymorphisms at early ages could be non-invasive methods that could facilitate the early identification of individuals at risk of developing EOCRC.},
}
@article {pmid36834592,
year = {2023},
author = {Fujiwara-Tani, R and Takagi, T and Mori, S and Kishi, S and Nishiguchi, Y and Sasaki, T and Ikeda, M and Nagai, K and Bhawal, UK and Ohmori, H and Fujii, K and Kuniyasu, H},
title = {Short Telomere Lesions with Dysplastic Metaplasia Histology May Represent Precancerous Lesions of Helicobacter pylori-Positive Gastric Mucosa.},
journal = {International journal of molecular sciences},
volume = {24},
number = {4},
pages = {},
pmid = {36834592},
issn = {1422-0067},
support = {19K16564//Ministry of Education, Culture, Sports, Science and Technology/ ; 20K21659//Ministry of Education, Culture, Sports, Science and Technology/ ; 20K18007//Ministry of Education, Culture, Sports, Science and Technology/ ; 21K10143//Ministry of Education, Culture, Sports, Science and Technology/ ; },
mesh = {Humans ; *Helicobacter pylori ; *Stomach Neoplasms/pathology ; *Helicobacter Infections/complications ; In Situ Hybridization, Fluorescence ; Gastric Mucosa/metabolism ; *Precancerous Conditions/pathology ; Hyperplasia/metabolism ; Metaplasia/metabolism ; Telomere/pathology ; },
abstract = {Gastric cancers are strongly associated with Helicobacter pylori infection, with intestinal metaplasia characterizing the background mucosa in most cases. However, only a subset of intestinal metaplasia cases proceed to carcinogenesis, and the characteristics of high-risk intestinal metaplasia that link it with gastric cancer are still unclear. We examined telomere reduction in five gastrectomy specimens using fluorescence in situ hybridization, and identified areas with localized telomere loss (outside of cancerous lesions), which were designated as short telomere lesions (STLs). Histological analyses indicated that STLs were characteristic of intestinal metaplasia accompanied by nuclear enlargement but lacking structural atypia, which we termed dysplastic metaplasia (DM). A review of gastric biopsy specimens from 587 H. pylori-positive patients revealed 32 cases of DM, 13 of which were classified as high-grade based on the degree of nuclear enlargement. All high-grade DM cases exhibited a telomere volume reduced to less than 60% of that of lymphocytes, increased stemness, and telomerase reverse transcriptase (TERT) expression. Two patients (15%) exhibited low levels of p53 nuclear retention. After a 10-year follow-up, 7 (54%) of the high-grade DM cases had progressed to gastric cancer. These results suggest that DM is characterized by telomere shortening, TERT expression, and stem cell proliferation, and high-grade DM is a high-grade intestinal metaplasia that likely represents a precancerous lesion of gastric cancer. High-grade DM is expected to effectively prevent progression to gastric cancer in H. pylori-positive patients.},
}
@article {pmid36834587,
year = {2023},
author = {Deng, S and Yang, M and Su, J and Cui, N and Wu, S and Zhang, G and Wang, L and Hou, Y and Chai, Y and Yu, B},
title = {Heat-Killed Staphylococcus aureus Induces Bone Mass Loss through Telomere Erosion.},
journal = {International journal of molecular sciences},
volume = {24},
number = {4},
pages = {},
pmid = {36834587},
issn = {1422-0067},
support = {81830079//the Major Program of National Natural Science Foundation of China/ ; 82102623//the National Natural Science Foundation of China/ ; 82002352//the National Natural Science Foundation of China/ ; 2020A1515010145//Natural Science Foundation of Guangdong Province/ ; 2019A1515110053//Natural Science Foundation of Guangdong Province/ ; 2020M682798//China Postdoctoral Science Foundation/ ; 202201011340//the Science and Technology Program of Guangzhou/ ; },
mesh = {Animals ; Mice ; Staphylococcus aureus ; Hot Temperature ; *Staphylococcal Infections ; Inflammation ; Bone Marrow Cells ; Telomere ; *Telomerase ; Cellular Senescence ; },
abstract = {The mechanism of systemic osteoporosis caused by chronic infection is not completely clear, and there is a lack of reasonable interventions for this disease. In this study, heat-killed S. aureus (HKSA) was applied to simulate the inflammation caused by the typical clinical pathogen and to explore the mechanism of systemic bone loss caused by it. In this study, we found that the systemic application of HKSA caused bone loss in mice. Further exploration found that HKSA caused cellular senescence, telomere length shortening, and telomere dysfunction-induced foci (TIF) in limb bones. As a well-known telomerase activator, cycloastragenol (CAG) significantly alleviated HKSA-induced telomere erosion and bone loss. These results suggested that telomere erosion in bone marrow cells is a possible mechanism of HKSA-induced bone loss. CAG may protect against HKSA-induced bone loss by alleviating telomere erosion in bone marrow cells.},
}
@article {pmid36833352,
year = {2023},
author = {Fattet, AJ and Chaillot, M and Koscinski, I},
title = {Telomere Length, a New Biomarker of Male (in)Fertility? A Systematic Review of the Literature.},
journal = {Genes},
volume = {14},
number = {2},
pages = {},
pmid = {36833352},
issn = {2073-4425},
mesh = {Humans ; Male ; *Semen ; *Infertility, Male ; Fertility ; Telomere ; Biomarkers ; },
abstract = {Male factors are suspected in around half cases of infertility, of which up to 40% are diagnosed as idiopathic. In the context of a continuously increased resort to ART and increased decline of semen parameters, it is of greatest interest to evaluate an additional potential biomarker of sperm quality. According to PRISMA guidelines, this systematic review of the literature selected studies evaluating telomere length in sperm and/or in leukocytes as a potential male fertility biomarker. Twenty-two publications (3168 participants) were included in this review of experimental evidence. For each study, authors determined if there was a correlation between telomere length and semen parameters or fertility outcomes. Of the 13 studies concerning sperm telomere length (STL) and semen parameters, ten found an association between short STL and altered parameters. Concerning the impact of STL on ART results, the data are conflicting. However, eight of the 13 included studies about fertility found significantly longer sperm telomeres in fertile men than in infertile men. In leukocytes, the seven studies reported conflicting findings. Shorter sperm telomeres appear to be associated with altered semen parameters or male infertility. Telomere length may be considered as a new molecular marker of spermatogenesis and sperm quality, and thus is related to male fertility potential. However, additional studies are needed to define the place of the STL in the assessment of individual fertility.},
}
@article {pmid36833275,
year = {2023},
author = {Barnes, RP and Thosar, SA and Opresko, PL},
title = {Telomere Fragility and MiDAS: Managing the Gaps at the End of the Road.},
journal = {Genes},
volume = {14},
number = {2},
pages = {},
pmid = {36833275},
issn = {2073-4425},
support = {R35 ES030396/ES/NIEHS NIH HHS/United States ; K99 ES033771/ES/NIEHS NIH HHS/United States ; R01 CA207342/CA/NCI NIH HHS/United States ; },
mesh = {*DNA Replication ; *DNA/metabolism ; Mitosis ; Phenotype ; Telomere/metabolism ; },
abstract = {Telomeres present inherent difficulties to the DNA replication machinery due to their repetitive sequence content, formation of non-B DNA secondary structures, and the presence of the nucleo-protein t-loop. Especially in cancer cells, telomeres are hot spots for replication stress, which can result in a visible phenotype in metaphase cells termed "telomere fragility". A mechanism cells employ to mitigate replication stress, including at telomeres, is DNA synthesis in mitosis (MiDAS). While these phenomena are both observed in mitotic cells, the relationship between them is poorly understood; however, a common link is DNA replication stress. In this review, we will summarize what is known to regulate telomere fragility and telomere MiDAS, paying special attention to the proteins which play a role in these telomere phenotypes.},
}
@article {pmid36831502,
year = {2023},
author = {Pauleck, S and Sinnott, JA and Zheng, YL and Gadalla, SM and Viskochil, R and Haaland, B and Cawthon, RM and Hoffmeister, A and Hardikar, S},
title = {Association of Telomere Length with Colorectal Cancer Risk and Prognosis: A Systematic Review and Meta-Analysis.},
journal = {Cancers},
volume = {15},
number = {4},
pages = {},
pmid = {36831502},
issn = {2072-6694},
support = {K07 CA222060//National Cancer Institute/ ; U01ES031786//National Cancer Institute/ ; P30CA042014//National Cancer Institute/ ; intramural program//National Cancer Institute/ ; Promotionsstipendium//DGHO/ ; Promotionsstipendium//Stiftung Lebensblicke/ ; },
abstract = {(1) Background: Colorectal cancer risk and survival have previously been associated with telomere length in peripheral blood leukocytes and tumor tissue. A systematic review and meta-analysis of the literature was conducted. The PubMed, Embase, and Web of Science databases were searched through March 2022. (2) Methods: Relevant studies were identified through database searching following PRISMA guidelines. Risk estimates were extracted from identified studies; meta-analyses were conducted using random effects models. (3) Results: Fourteen studies were identified (eight on risk; six on survival) through systematic review. While no association was observed between circulating leukocyte telomere length and the risk of colorectal cancer [overall OR (95% CI) = 1.01 (0.82-1.24)], a worse survival for those with shorter telomeres in leukocytes and longer telomeres in tumor tissues was observed [Quartile1/Quartile2-4 overall HR (95% CI) = 1.41 (0.26-7.59) and 0.82 (0.69-0.98), respectively]. (4) Conclusions: Although there was no association with colorectal cancer risk, a poorer survival was observed among those with shorter leukocyte telomere length. Future larger studies evaluating a potentially non-linear relationship between telomeres and colorectal cancer are needed.},
}
@article {pmid36831134,
year = {2023},
author = {Hernández-Álvarez, D and Rosado-Pérez, J and Gavia-García, G and Arista-Ugalde, TL and Aguiñiga-Sánchez, I and Santiago-Osorio, E and Mendoza-Núñez, VM},
title = {Aging, Physical Exercise, Telomeres, and Sarcopenia: A Narrative Review.},
journal = {Biomedicines},
volume = {11},
number = {2},
pages = {},
pmid = {36831134},
issn = {2227-9059},
abstract = {Human aging is a gradual and adaptive process characterized by a decrease in the homeostatic response, leading to biochemical and molecular changes that are driven by hallmarks of aging, such as oxidative stress (OxS), chronic inflammation, and telomere shortening. One of the diseases associated with the hallmarks of aging, which has a great impact on functionality and quality of life, is sarcopenia. However, the relationship between telomere length, sarcopenia, and age-related mortality has not been extensively studied. Moderate physical exercise has been shown to have a positive effect on sarcopenia, decreasing OxS and inflammation, and inducing protective effects on telomeric DNA. This results in decreased DNA strand breaks, reduced OxS and IA, and activation of repair pathways. Higher levels of physical activity are associated with an apparent increase in telomere length. This review aims to present the current state of the art of knowledge on the effect of physical exercise on telomeric maintenance and activation of repair mechanisms in sarcopenia.},
}
@article {pmid36830739,
year = {2023},
author = {Ueno, M},
title = {Exploring Genetic Interactions with Telomere Protection Gene pot1 in Fission Yeast.},
journal = {Biomolecules},
volume = {13},
number = {2},
pages = {},
pmid = {36830739},
issn = {2218-273X},
support = {20K06488//MEXT/JSPS KAKENHI/ ; },
mesh = {Humans ; *Schizosaccharomyces/metabolism ; Shelterin Complex ; *Schizosaccharomyces pombe Proteins/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Chromosomes, Fungal ; Telomere/metabolism ; },
abstract = {The regulation of telomere length has a significant impact on cancer risk and aging in humans. Circular chromosomes are found in humans and are often unstable during mitosis, resulting in genome instability. Some types of cancer have a high frequency of a circular chromosome. Fission yeast is a good model for studying the formation and stability of circular chromosomes as deletion of pot1 (encoding a telomere protection protein) results in rapid telomere degradation and chromosome fusion. Pot1 binds to single-stranded telomere DNA and is conserved from fission yeast to humans. Loss of pot1 leads to viable strains in which all three fission yeast chromosomes become circular. In this review, I will introduce pot1 genetic interactions as these inform on processes such as the degradation of uncapped telomeres, chromosome fusion, and maintenance of circular chromosomes. Therefore, exploring genes that genetically interact with pot1 contributes to finding new genes and/or new functions of genes related to the maintenance of telomeres and/or circular chromosomes.},
}
@article {pmid36829978,
year = {2023},
author = {Péntek, S and Várnagy, &#xc1; and Farkas, B and Mauchart, P and Gödöny, K and Varjas, T and Kőszegi, T and Kaltenecker, P and Jakabfi-Csepregi, R and Kovács, K and Bódis, J and Sulyok, E},
title = {Telomere Length and Telomerase Activity of Granulosa Cells and Follicular Fluid in Women Undergoing In Vitro Fertilization.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {2},
pages = {},
pmid = {36829978},
issn = {2076-3921},
abstract = {This study aimed to evaluate the interrelationship between telomere length, telomerase activity and oxidative DNA damage in patients undergoing in vitro fertilization (IVF). This single-center, observational clinical study comprised 102 unselected, consecutive patients with various infertility diagnoses. Granulosa cells (GCs) and follicular fluid (FF) were analyzed simultaneously for telomere functions and for the marker of oxidative DNA damage, 8-hydroxy-2-deoxyguanosine (8-OHdG). An Absolute Human Telomere Lengths Quantification qPCR Assay kit and Telomerase Activity Quantification qPCR Assay kit (Nucleotestbio, Budapest, Hungary), as well as an 8-OHdG ELISA kit (Abbexa Ltd., Cambridge, United Kingdom) were used for analyses. Similar telomere lengths were found in GCs and FF, however telomerase activity was markedly depressed, while 8-OHdG levels were markedly elevated in FF compared with those in GCs (p < 0.01). Telomere lengths were independent of telomerase activity both in GCs and FF. However, GC 8-OHdG was inversely related to telomerase activity in GCs and FF (p < 0.05). Importantly, 8-OHdG levels both in GCs and FF had significant negative impact on the number of the retrieved and MII oocytes (p < 0.01), whereas FF 8-OHdG was negatively related further to the number of fertilized oocytes and blastocysts (p < 0.01). In conclusion, we could not confirm the direct association of telomere function and reproductive potential. However, oxidative DNA damage, as mainly reflected by 8-OHdG, adversely affected early markers of IVF outcome and clinical pregnancies.},
}
@article {pmid36826621,
year = {2023},
author = {Stock, AJ and Ayyar, S and Kashyap, A and Wang, Y and Yanai, H and Starost, MF and Tanaka-Yano, M and Bodogai, M and Sun, C and Wang, Y and Gong, Y and Puligilla, C and Fang, EF and Bohr, VA and Liu, Y and Beerman, I},
title = {Boosting NAD ameliorates hematopoietic impairment linked to short telomeres in vivo.},
journal = {GeroScience},
volume = {45},
number = {4},
pages = {2213-2228},
pmid = {36826621},
issn = {2509-2723},
support = {Intramural Funding/AG/NIA NIH HHS/United States ; Intramural Funding/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Animals ; Mice ; NAD ; Telomere/metabolism ; *Dyskeratosis Congenita/genetics/metabolism ; Inflammation ; *Hematopoietic Stem Cell Transplantation ; },
abstract = {Short telomeres are a defining feature of telomere biology disorders (TBDs), including dyskeratosis congenita (DC), for which there is no effective general cure. Patients with TBDs often experience bone marrow failure. NAD, an essential metabolic coenzyme, is decreased in models of DC. Herein, using telomerase reverse transcriptase null (Tert[-/-]) mice with critically short telomeres, we investigated the effect of NAD supplementation with the NAD precursor, nicotinamide riboside (NR), on features of health span disrupted by telomere impairment. Our results revealed that NR ameliorated body weight loss in Tert[-/-] mice and improved telomere integrity and telomere dysfunction-induced systemic inflammation. NR supplementation also mitigated myeloid skewing of Tert[-/-] hematopoietic stem cells. Furthermore, NR alleviated villous atrophy and inflammation in the small intestine of Tert[-/-] transplant recipient mice. Altogether, our findings support NAD intervention as a potential therapeutic strategy to enhance aspects of health span compromised by telomere attrition.},
}
@article {pmid36811398,
year = {2023},
author = {Eastwood, JR and Dupoué, A and Delhey, K and Verhulst, S and Cockburn, A and Peters, A},
title = {When does early-life telomere length predict survival? A case study and meta-analysis.},
journal = {Molecular ecology},
volume = {32},
number = {11},
pages = {3000-3013},
doi = {10.1111/mec.16894},
pmid = {36811398},
issn = {1365-294X},
mesh = {Animals ; *Longevity/genetics ; Telomere Shortening ; Telomere/genetics ; *Songbirds/genetics ; Research Design ; Mammals/genetics ; },
abstract = {Suboptimal conditions during development can shorten telomeres, the protective DNA caps on the end of chromosomes. Shorter early-life telomere length (TL) can indicate reduced somatic maintenance, leading to lower survival and shorter lifespan. However, despite some clear evidence, not all studies show a relationship between early-life TL and survival or lifespan, which may be due to differences in biology or study design (e.g., survival period measured). In superb fairy-wrens (Malurus cyaneus), we assessed whether early-life TL predicts mortality across different life-history stages (fledgling, juvenile, adult). However, in contrast to a similar study on a congener, early-life TL did not predict mortality across any life stage in this species. We then performed a meta-analysis including 32 effect sizes from 23 studies (15 birds and three mammals) to quantify the effect of early-life TL on mortality whilst taking into consideration potential sources of biological and methodological variation. Overall, the effect of early-life TL on mortality was significant, corresponding to a 15% reduction in mortality risk with each standard deviation increase in TL. However, the effect became weaker when correcting for publication bias. Contrary to our predictions, there was no evidence that effects of early-life TL on mortality varied with species lifespan or the period over which survival was measured. However, negative effects of early-life TL on mortality risk were pervasive throughout life. These results imply that effects of early-life TL on mortality are more likely to be context-dependent than age-dependent, although substantial power and publication bias issues highlight the need for more research.},
}
@article {pmid36810772,
year = {2023},
author = {Strzyz, P},
title = {From shortening telomeres to replicative crisis.},
journal = {Nature reviews. Molecular cell biology},
volume = {24},
number = {4},
pages = {239},
pmid = {36810772},
issn = {1471-0080},
mesh = {*Telomere/genetics/metabolism ; Cellular Senescence ; DNA Replication/genetics ; Telomere Shortening ; *Telomerase/metabolism ; },
}
@article {pmid36809211,
year = {2023},
author = {Li, Z and Cai, K and Sun, Y and Zhou, D and Yan, J and Luo, S and Huang, G and Gao, Y and Li, W},
title = {Folic acid protects against age-associated apoptosis and telomere attrition of neural stem cells in senescence-accelerated mouse prone 8.},
journal = {Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme},
volume = {48},
number = {5},
pages = {393-402},
doi = {10.1139/apnm-2022-0111},
pmid = {36809211},
issn = {1715-5320},
mesh = {Mice ; Male ; Animals ; *Folic Acid/pharmacology ; In Situ Hybridization, Fluorescence ; Aging ; *Neural Stem Cells ; Apoptosis ; Telomere ; },
abstract = {Folic acid (FA) could improve cognitive performance and attenuate brain cell injury in the aging brain; FA supplementation is also associated with inhibiting neural stem cell (NSC) apoptosis. However, its role in age-associated telomere attrition remains unclear. We hypothesized that FA supplementation attenuates age-associated apoptosis of NSCs in mice via alleviating telomere attrition in senescence-accelerated mouse prone 8 (SAMP8). In this study, 4-month-old male SAMP8 mice were assigned equal numbers to four different diet groups (n = 15). Fifteen age-matched senescence-accelerated mouse resistant 1 mice, fed with the FA-normal diet, were used as the standard aging control group. After FA treatment for 6 months, all mice were sacrificed. NSC apoptosis, proliferation, oxidative damage, and telomere length were evaluated by immunofluorescence and Q-fluorescent in situ hybridization. The results showed that FA supplementation inhibited age-associated NSC apoptosis and prevented telomere attrition in the cerebral cortex of SAMP8 mice. Importantly, this effect might be explained by the decreased levels of oxidative damage. In conclusion, we demonstrate it may be one of the mechanisms by which FA inhibits age-associated NSC apoptosis by alleviating telomere length shortening.},
}
@article {pmid36805596,
year = {2023},
author = {Turkalo, TK and Maffia, A and Schabort, JJ and Regalado, SG and Bhakta, M and Blanchette, M and Spierings, DCJ and Lansdorp, PM and Hockemeyer, D},
title = {A non-genetic switch triggers alternative telomere lengthening and cellular immortalization in ATRX deficient cells.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {939},
pmid = {36805596},
issn = {2041-1723},
mesh = {Humans ; Telomere Homeostasis/genetics ; Telomere/genetics ; Cell Differentiation/genetics ; *Telomerase/genetics ; *Pluripotent Stem Cells ; X-linked Nuclear Protein/genetics ; },
abstract = {Alternative Lengthening of Telomeres (ALT) is an aberrant DNA recombination pathway which grants replicative immortality to approximately 10% of all cancers. Despite this high prevalence of ALT in cancer, the mechanism and genetics by which cells activate this pathway remain incompletely understood. A major challenge in dissecting the events that initiate ALT is the extremely low frequency of ALT induction in human cell systems. Guided by the genetic lesions that have been associated with ALT from cancer sequencing studies, we genetically engineered primary human pluripotent stem cells to deterministically induce ALT upon differentiation. Using this genetically defined system, we demonstrate that disruption of the p53 and Rb pathways in combination with ATRX loss-of-function is sufficient to induce all hallmarks of ALT and results in functional immortalization in a cell type-specific manner. We further demonstrate that ALT can be induced in the presence of telomerase, is neither dependent on telomere shortening nor crisis, but is rather driven by continuous telomere instability triggered by the induction of differentiation in ATRX-deficient stem cells.},
}
@article {pmid36805537,
year = {2023},
author = {Han, MH and Lee, EH and Park, HH and Choi, SH and Koh, SH},
title = {Relationship between telomere shortening and early subjective depressive symptoms and cognitive complaints in older adults.},
journal = {Aging},
volume = {15},
number = {4},
pages = {914-931},
pmid = {36805537},
issn = {1945-4589},
mesh = {Aged ; Humans ; Cognition ; *Cognitive Dysfunction/psychology ; *Depression/psychology ; Surveys and Questionnaires ; Telomere ; Telomere Shortening ; Middle Aged ; },
abstract = {Telomere length (TL) has been reported to be associated with depression and cognitive impairment in elderly. Early detection of depression and cognitive impairment is important to delay disease progression. Therefore, we aimed to identify whether TL is associated with early subjective depressive symptoms and cognitive complaints among healthy elderly subjects. This study was a multicenter, outcome assessor-blinded, 24-week, randomized controlled trial (RCT). Measurement of questionnaire and physical activity scores and blood sample analyses were performed at baseline and after six months of follow-up in all study participants. Linear regression analyses were performed to identify whether early subjective depressive symptoms, cognitive complaints, and several blood biomarkers are associated with TL. Altogether, 137 relatively healthy elderly individuals (60-79 years old) were enrolled in this prospective RCT. We observed an approximate decrease of 0.06 and 0.11-0.14 kbps of TL per one point increase in the geriatric depression scale and cognitive complaint interview scores, respectively, at baseline and after six months of follow-up. We also found an approximate decrease of 0.08-0.09 kbps of TL per one point increase in interleukin (IL)-6 levels at baseline and after six months of follow-up. Our study showed that both early subjective depressive symptoms and cognitive complaints were associated with a relatively shorter TL in relatively healthy elderly individuals. In addition, based on our findings, we believe that IL-6 plays an important role in the relationship between shortening TL and early subjective depressive symptoms and cognitive complaints.},
}
@article {pmid36798520,
year = {2022},
author = {Li, Y and Yang, S and Liao, M and Zheng, Z and Li, M and Wei, X and Liu, M and Yang, L},
title = {Association between genetically predicted leukocyte telomere length and non-scarring alopecia: A two-sample Mendelian randomization study.},
journal = {Frontiers in immunology},
volume = {13},
number = {},
pages = {1072573},
pmid = {36798520},
issn = {1664-3224},
mesh = {Humans ; *Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Alopecia Areata ; Leukocytes ; Telomere/genetics ; },
abstract = {BACKGROUND: The most commonly acknowledged non-scarring alopecia are androgenetic alopecia (AGA) and alopecia areata (AA). Previous studies have revealed various risk factors associated with alopecia. However, the relationship between leukocyte telomere length (LTL) and non-scarring alopecia remains unclear.<br><br>METHODS: A two-sample Mendelian randomization (MR) analysis was performed to evaluate the causality between genetically predicted LTL and the risk of non-scarring alopecia. MR analyses were performed using the inverse variance-weighted (IVW) method and complemented with other MR methods.<br><br>RESULTS: The summary statistics of the genome-wide association studies (GWAS) for AGA and AA were obtained from the FinnGen biobank, which included 119,185 and 211,428 individuals, respectively. A total of 126 single nucleotide polymorphisms (SNPs) with genome-wide significance were selected as the instrumental variables for LTL. The MR analyses suggested a causal relationship between LTL and AGA, and the risk of AGA increased by 3.19 times as the genetically predicted LTL was shortened by one standard deviation in log transformed form under the IVW method (OR&#xa0;=&#xa0;4.19, 95% CI&#xa0;=&#xa0;1.20-14.61, p&#xa0;=&#xa0;0.024). The other MR methods also demonstrated a similar trend of the effect of LTL on AGA. There was no causal relationship between LTL and AA (p&#xa0;>&#xa0;0.05). Sensitivity analyses further demonstrated that the current results were less likely to be affected by confounders and bias.<br><br>CONCLUSION: Our results suggested a potential causal relationship between LTL and AGA, and shortened LTL was associated with an increased risk of AGA.},
}
@article {pmid36798426,
year = {2023},
author = {Li, F and Wang, Y and Hwang, I and Jang, JY and Xu, L and Deng, Z and Yu, EY and Cai, Y and Wu, C and Han, Z and Huang, YH and Huang, X and Zhang, L and Yao, J and Lue, NF and Lieberman, PM and Ying, H and Paik, J and Zheng, H},
title = {Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.02.10.528023},
pmid = {36798426},
abstract = {Telomere length maintenance is essential for cellular immortalization and tumorigenesis. 5% - 10% of human cancers rely on a recombination-based mechanism termed alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet there are currently no targeted therapies. Through CRISPR/Cas9-based genetic screens in an ALT-immortalized isogenic cellular model, here we identify histone lysine demethylase KDM2A as a molecular vulnerability selectively for cells contingent on ALT-dependent telomere maintenance. Mechanistically, we demonstrate that KDM2A is required for dissolution of the ALT-specific telomere clusters following homology-directed telomere DNA synthesis. We show that KDM2A promotes de-clustering of ALT multitelomeres through facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Inactivation of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and thus dissolution of ALT telomere clusters, leading to gross chromosome missegregation and mitotic cell death. These findings together establish KDM2A as a selective molecular vulnerability and a promising drug target for ALT-dependent cancers.},
}
@article {pmid36797576,
year = {2023},
author = {Han, M and Liu, S and Ji, JR and Wu, YF and Chang, KW and Zhang, JY and Wei, JN},
title = {[Interaction of polycyclic aromatic hydrocarbon DNA adducts and telomere length on missed abortion].},
journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]},
volume = {57},
number = {2},
pages = {193-199},
doi = {10.3760/cma.j.cn112150-20220322-00274},
pmid = {36797576},
issn = {0253-9624},
support = {201901D111206//Shanxi Provincial Basic Research Project of China/ ; 2020086//Shanxi Provincial Health Commission Scientific Research Project of China/ ; },
mesh = {Humans ; Female ; Pregnancy ; Young Adult ; Adult ; DNA Adducts ; *Abortion, Missed/chemically induced ; *Polycyclic Aromatic Hydrocarbons ; *Abortion, Spontaneous/chemically induced ; Telomere/chemistry ; },
abstract = {Objective: To analyze the contribution and interaction of polycyclic aromatic hydrocarbons (PAH)-DNA adducts and changes of telomere length (TL) on missed abortion. Methods: From March to December 2019, patients with missed abortion in the First Hospital of Shanxi Medical University and pregnant women with normal pregnancy but voluntary abortion in the same department during the same period were selected and divided into a case group and a control group. Questionnaire was used to investigate the general situation and the pregnancy situation of the subjects. The abortion villi were collected and the content of PAH-DNA adducts and TL was detected. Logistic regression model was used to analyze the associated factors of missed abortion. R epiR package and Mediation package were used to analyze the effect and relationship between PAH-DNA adducts and TL on missed abortion. Results: The age of the subjects was(29.92±5.69)years old. The M(Q1,Q3)of PAH-DNA adducts was 453.75(404.61, 504.72) pg/ml. The M(Q1,Q3)of TL was 1.21(0.77, 1.72). The content of PAH-DNA adducts in the case group was higher than that in the control group (Z=-2.10, P=0.036), while the TL was lower than that in the control group (Z=-4.05, P<0.001). Multivariate logistic regression showed that low, medium and high levels of PAH-DNA adducts (OR=3.17,95%CI:1.41-7.14;OR=2.85,95%CI:1.25-6.52;OR=2.46,95%CI:1.07-5.64), and long, medium and short levels of TL (OR=2.50,95%CI:1.11-5.63;OR=3.32,95%CI:1.45-7.56;OR=3.22,95%CI:1.42-7.26) were all risk factors for missed abortion. The medium level of PAH-DNA adducts had a 2.76-fold higher risk of shortened TL than those with the lowest level, and no mediating role of TL was found. The stratified analysis showed that when the TL level was longer (>1.21), the low and high levels of PAH-DNA adducts were associated with missed abortion (all P<0.05); when the TL level was shorter (<1.21), the medium level of PAH-DNA adducts was associated with abortion (P=0.025). At lower levels of PAH-DNA adducts, no effect of TL on missed abortion was observed, while, at higher levels, TL was strongly associated with missed abortion (OR=7.50,95%CI:1.95-28.82;OR=6.04,95%CI:1.54-23.65;OR=9.05,95%CI:2.34-35.04). The interaction analysis found that the AP was 0.72 (95%CI: 0.46-0.99), and the SI was 5.21 (95%CI: 2.30-11.77). Conclusion: The high level of PAH-DNA adducts and shortened TL may increase the risk of missed abortion, and there may be a positive additive interaction between the two factors on missed abortion.},
}
@article {pmid36797493,
year = {2023},
author = {Rautiainen, M and Nurk, S and Walenz, BP and Logsdon, GA and Porubsky, D and Rhie, A and Eichler, EE and Phillippy, AM and Koren, S},
title = {Telomere-to-telomere assembly of diploid chromosomes with Verkko.},
journal = {Nature biotechnology},
volume = {41},
number = {10},
pages = {1474-1482},
pmid = {36797493},
issn = {1546-1696},
support = {F32 GM134558/GM/NIGMS NIH HHS/United States ; R01 HG010169/HG/NHGRI NIH HHS/United States ; Z99 HG999999/ImNIH/Intramural NIH HHS/United States ; R01 HG002385/HG/NHGRI NIH HHS/United States ; },
mesh = {Humans ; Sequence Analysis, DNA/methods ; *Diploidy ; *Genomics/methods ; Genome, Human/genetics ; Telomere/genetics ; High-Throughput Nucleotide Sequencing/methods ; },
abstract = {The Telomere-to-Telomere consortium recently assembled the first truly complete sequence of a human genome. To resolve the most complex repeats, this project relied on manual integration of ultra-long Oxford Nanopore sequencing reads with a high-resolution assembly graph built from long, accurate PacBio high-fidelity reads. We have improved and automated this strategy in Verkko, an iterative, graph-based pipeline for assembling complete, diploid genomes. Verkko begins with a multiplex de Bruijn graph built from long, accurate reads and progressively simplifies this graph by integrating ultra-long reads and haplotype-specific markers. The result is a phased, diploid assembly of both haplotypes, with many chromosomes automatically assembled from telomere to telomere. Running Verkko on the HG002 human genome resulted in 20 of 46 diploid chromosomes assembled without gaps at 99.9997% accuracy. The complete assembly of diploid genomes is a critical step towards the construction of comprehensive pangenome databases and chromosome-scale comparative genomics.},
}
@article {pmid36779965,
year = {2023},
author = {Bountziouka, V and Hansell, AL and Nelson, CP and Codd, V and Samani, NJ},
title = {Large-Scale Analysis of the Association between Air Pollutants and Leucocyte Telomere Length in the UK Biobank.},
journal = {Environmental health perspectives},
volume = {131},
number = {2},
pages = {27701},
pmid = {36779965},
issn = {1552-9924},
support = {MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; SP/16/4/32697/BHF_/British Heart Foundation/United Kingdom ; BRC-1215-20010/DH_/Department of Health/United Kingdom ; },
mesh = {*Air Pollutants ; Biological Specimen Banks ; Telomere ; United Kingdom ; Leukocytes ; },
}
@article {pmid36778189,
year = {2023},
author = {Yue, J and Chen, Q and Wang, Y and Zhang, L and Ye, C and Wang, X and Cao, S and Lin, Y and Huang, W and Xian, H and Qin, H and Wang, Y and Zhang, S and Wu, Y and Wang, S and Yue, Y and Liu, Y},
title = {Telomere-to-telomere and gap-free reference genome assembly of the kiwifruit Actinidia chinensis.},
journal = {Horticulture research},
volume = {10},
number = {2},
pages = {uhac264},
pmid = {36778189},
issn = {2662-6810},
abstract = {Kiwifruit is an economically and nutritionally important fruit crop with extremely high contents of vitamin C. However, the previously released versions of kiwifruit genomes all have a mass of unanchored or missing regions. Here, we report a highly continuous and completely gap-free reference genome of Actinidia chinensis cv. 'Hongyang', named Hongyang v4.0, which is the first to achieve two de novo haploid-resolved haplotypes, HY4P and HY4A. HY4P and HY4A have a total length of 606.1 and 599.6 Mb, respectively, with almost the entire telomeres and centromeres assembled in each haplotype. In comparison with Hongyang v3.0, the integrity and contiguity of Hongyang v4.0 is markedly improved by filling all unclosed gaps and correcting some misoriented regions, resulting in ~38.6-39.5 Mb extra sequences, which might affect 4263 and 4244 protein-coding genes in HY4P and HY4A, respectively. Furthermore, our gap-free genome assembly provides the first clue for inspecting the structure and function of centromeres. Globally, centromeric regions are characterized by higher-order repeats that mainly consist of a 153-bp conserved centromere-specific monomer (Ach-CEN153) with different copy numbers among chromosomes. Functional enrichment analysis of the genes located within centromeric regions demonstrates that chromosome centromeres may not only play physical roles for linking a pair of sister chromatids, but also have genetic features for participation in the regulation of cell division. The availability of the telomere-to-telomere and gap-free Hongyang v4.0 reference genome lays a solid foundation not only for illustrating genome structure and functional genomics studies but also for facilitating kiwifruit breeding and improvement.},
}
@article {pmid36776610,
year = {2023},
author = {Cai, Y and Zhong, YD and Zhang, H and Lu, PL and Liang, YY and Hu, B and Wu, H},
title = {Association between dietary vitamin C and telomere length: A cross-sectional study.},
journal = {Frontiers in nutrition},
volume = {10},
number = {},
pages = {1025936},
pmid = {36776610},
issn = {2296-861X},
abstract = {BACKGROUND: Currently, telomere length is known to reflect the replication potential and longevity of cells, and many studies have reported that telomere length is associated with age-related diseases and biological aging. Studies have also shown that vitamin C acts as an oxidant and free radical scavenger to protect cells from oxidative stress and telomere wear, thus achieving anti-aging effects. At present, there are few and incomplete studies on the relationship between vitamin C and telomere length, so this study aims to explore the relationship between vitamin C and telomere length.<br><br>METHODS: This study used cross-sectional data from the National Health and Nutrition Examination Surveys (NHANES) database from 1999 to 2002, a total of 7,094 participants were selected from all races in the United States. Male participants accounted for 48.2% and female participants accounted for 51.8%. The correlation between vitamin C and telomere length was assessed using a multiple linear regression model, and the effect of dietary vitamin C on telomere length was obtained after adjusting for confounding factors such as age, gender, race, body mass index (BMI), and poverty income ratio (PIR).<br><br>RESULTS: This cross-sectional study showed that vitamin C was positively correlated with telomere length, with greater dietary vitamin C intake associated with longer telomeres (&#x3b2; = 0.03, 95% CI: 0.01-0.05, P = 0.003).<br><br>CONCLUSION: This study shows that vitamin C intake is positively correlated with human telomere length, which is of guiding significance for our clinical guidance on people's health care, but our study need to be confirmed by more in-depth and comprehensive other research results.},
}
@article {pmid36767300,
year = {2023},
author = {Pasha, Q and Rain, M and Tasnim, S and Kanipakam, H and Thinlas, T and Mohammad, G},
title = {The Telomere-Telomerase System Is Detrimental to Health at High-Altitude.},
journal = {International journal of environmental research and public health},
volume = {20},
number = {3},
pages = {},
pmid = {36767300},
issn = {1660-4601},
mesh = {Humans ; Altitude ; *Altitude Sickness/genetics ; Biomarkers ; Case-Control Studies ; *Telomerase/genetics ; *Telomere/genetics ; *DNA Damage/genetics ; },
abstract = {The hypobaric-hypoxia environment at high-altitude (HA, >2500 m) may influence DNA damage due to the production of reactive molecular species and high UV radiation. The telomere system, vital to chromosomal integrity and cellular viability, is prone to oxidative damages contributing to the severity of high-altitude disorders such as high-altitude pulmonary edema (HAPE). However, at the same time, it is suggested to sustain physical performance. This case-control study, comprising 210 HAPE-free (HAPE-f) sojourners, 183 HAPE-patients (HAPE-p) and 200 healthy highland natives (HLs) residing at ~3500 m, investigated telomere length, telomerase activity, and oxidative stress biomarkers. Fluidigm SNP genotyping screened 65 single nucleotide polymorphisms (SNPs) in 11 telomere-maintaining genes. Significance was attained at p ≤ 0.05 after adjusting for confounders and correction for multiple comparisons. Shorter telomere length, decreased telomerase activity and increased oxidative stress were observed in HAPE patients; contrarily, longer telomere length and elevated telomerase activity were observed in healthy HA natives compared to HAPE-f. Four SNPs and three haplotypes are associated with HAPE, whereas eight SNPs and nine haplotypes are associated with HA adaptation. Various gene-gene interactions and correlations between/among clinical parameters and biomarkers suggested the presence of a complex interplay underlining HAPE and HA adaptation physiology. A distinctive contribution of the telomere-telomerase system contributing to HA physiology is evident in this study. A normal telomere system may be advantageous in endurance training.},
}
@article {pmid36759506,
year = {2023},
author = {Falcinelli, M and Dell'Omo, G and Grassi, E and Mariella, E and Leto, SM and Scardellato, S and Lorenzato, A and Arena, S and Bertotti, A and Trusolino, L and Bardelli, A and d'Adda di Fagagna, F},
title = {Colorectal cancer patient-derived organoids and cell lines harboring ATRX and/or DAXX mutations lack Alternative Lengthening of Telomeres (ALT).},
journal = {Cell death &amp; disease},
volume = {14},
number = {2},
pages = {96},
pmid = {36759506},
issn = {2041-4889},
mesh = {Humans ; X-linked Nuclear Protein/genetics/metabolism ; *Intellectual Disability ; Telomere Homeostasis/genetics ; *alpha-Thalassemia ; Co-Repressor Proteins/genetics/metabolism ; *Telomerase/genetics/metabolism ; Mutation/genetics ; Cell Line ; Telomere/genetics/metabolism ; Organoids/metabolism ; *Colorectal Neoplasms/genetics ; Molecular Chaperones/genetics/metabolism ; },
abstract = {Telomere maintenance is necessary to maintain cancer cell unlimited viability. However, the mechanisms maintaining telomere length in colorectal cancer (CRC) have not been extensively investigated. Telomere maintenance mechanisms (TMM) include the re-expression of telomerase or alternative lengthening of telomeres (ALT). ALT is genetically associated with somatic alterations in alpha-thalassemia/mental retardation X-linked (ATRX) and death domain-associated protein (DAXX) genes. Cells displaying ALT present distinctive features including C-circles made of telomeric DNA, long and heterogenous telomeric tracts, and telomeric DNA co-localized with promyelocytic leukemia (PML) bodies forming so-called ALT-associated PML bodies (APBs). Here, we identified mutations in ATRX and/or DAXX genes in an extensive collection of CRC samples including 119 patient-derived organoids (PDOs) and 232 established CRC cell lines. C-circles measured in CRC PDOs and cell lines showed low levels overall. We also observed that CRC PDOs and cell lines did not display a significant accumulation of APBs or long telomeres with no appreciable differences between wild-type and mutated ATRX/DAXX samples. Overall, our extensive analyses indicate that CRC is not prone to engage ALT, even when carrying genetic lesions in ATRX and/or DAXX, and support the notion that ATRX/DAXX genomic footprints are not reliable predictors of ALT.},
}
@article {pmid36758285,
year = {2023},
author = {Vostatek, R and Hohensinner, P and Nopp, S and Haider, P and Englisch, C and Pointner, J and Pabinger, I and Ay, C},
title = {Association of telomere length and mitochondrial DNA copy number, two biomarkers of biological aging, with the risk of venous thromboembolism.},
journal = {Thrombosis research},
volume = {223},
number = {},
pages = {168-173},
doi = {10.1016/j.thromres.2023.01.031},
pmid = {36758285},
issn = {1879-2472},
mesh = {Male ; Humans ; Female ; *DNA, Mitochondrial/genetics ; *Venous Thromboembolism ; DNA Copy Number Variations ; Case-Control Studies ; Telomere ; Aging/genetics ; Mitochondria ; Biomarkers ; },
abstract = {BACKGROUND: Venous thromboembolism (VTE) is the third most common cardiovascular disease and occurs in all age groups, albeit the risk increases considerably with age. Previous research indicates mitochondrial dysfunction and telomere shortening in cardiovascular aging. However, in the context of VTE this has not been investigated in detail.<br><br>AIM: We aimed to explore biomarkers reflecting biological aging (i.e. human mitochondrial DNA copy number (mtDNA) and telomere length) and their association with VTE.<br><br>METHODS: mtDNA and telomere length were measured in a case-control study of 116 patients with a history of VTE and 128 age- and sex-matched healthy individuals from isolated blood using a qPCR-based assay kit. Cases had at least one unprovoked VTE event and were enrolled no earlier than 3&#xa0;months after the last VTE event.<br><br>RESULTS: The mtDNA copy number was significantly lower in VTE cases compared to controls (median [IQR]: 663 per diploid cells [78.75-2204.5] vs. 2832 per diploid cells [724-4350]; p&#xa0;<&#xa0;0.001). After adjustment for age, sex, BMI, and smoking, mtDNA copy number was independently associated with VTE risk (odds ratio per increase in 400 mtDNA per diploid cell: 0.889, 95%CI 0.834-0.947). mtDNA copy numbers were significantly different between women and men (2375 [455-3737] women vs. 893 [152-3154] men; p&#xa0;<&#xa0;0.001). The analysis of telomere length showed no significant difference between patients and healthy controls.<br><br>CONCLUSION: Lower mtDNA levels were found in patients with VTE compared to controls, indicating an association of biological aging with risk of VTE.},
}
@article {pmid36755096,
year = {2023},
author = {Nassour, J and Aguiar, LG and Correia, A and Schmidt, TT and Mainz, L and Przetocka, S and Haggblom, C and Tadepalle, N and Williams, A and Shokhirev, MN and Akincilar, SC and Tergaonkar, V and Shadel, GS and Karlseder, J},
title = {Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis.},
journal = {Nature},
volume = {614},
number = {7949},
pages = {767-773},
pmid = {36755096},
issn = {1476-4687},
support = {P01 AG073084/AG/NIA NIH HHS/United States ; RF1 AG064049/AG/NIA NIH HHS/United States ; R01 CA228211/CA/NCI NIH HHS/United States ; R01 CA234047/CA/NCI NIH HHS/United States ; P30 AG068635/AG/NIA NIH HHS/United States ; R01 AR069876/AR/NIAMS NIH HHS/United States ; P30 AR041940/AR/NIAMS NIH HHS/United States ; K99 CA252447/CA/NCI NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; R01 AG077324/AG/NIA NIH HHS/United States ; R01 CA227934/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; DNA/biosynthesis/genetics/metabolism ; *DNA Replication ; *Mitochondria/genetics/metabolism ; Neoplasms/genetics/pathology ; RNA, Long Noncoding/biosynthesis/genetics/metabolism ; *Telomere/genetics/metabolism ; Interferons ; Immunity, Innate ; Autophagy ; *Signal Transduction ; },
abstract = {Cancers arise through the accumulation of genetic and epigenetic alterations that enable cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative crisis-an autophagy-dependent program that eliminates checkpoint-deficient cells with unstable telomeres and other cancer-relevant chromosomal aberrations[1,2]. However, little is known about the molecular events that regulate the onset of this important tumour-suppressive barrier. Here we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as a regulator of the crisis program. A crisis-associated isoform of ZBP1 is induced by the cGAS-STING DNA-sensing pathway, but reaches full activation only when associated with telomeric-repeat-containing RNA (TERRA) transcripts that are synthesized from dysfunctional telomeres. TERRA-bound ZBP1 oligomerizes into filaments on the outer mitochondrial membrane of a subset of mitochondria, where it activates the innate immune adapter protein mitochondrial antiviral-signalling protein (MAVS). We propose that these oligomerization properties of ZBP1 serve as a signal amplification mechanism, where few TERRA-ZBP1 interactions are sufficient to launch a detrimental MAVS-dependent interferon response. Our study reveals a mechanism for telomere-mediated tumour suppression, whereby dysfunctional telomeres activate innate immune responses through mitochondrial TERRA-ZBP1 complexes to eliminate cells destined for neoplastic transformation.},
}
@article {pmid36751991,
year = {2023},
author = {Marriott, RJ and Murray, K and Budgeon, CA and Codd, V and Hui, J and Arscott, GM and Beilby, JP and Hankey, GJ and Wittert, GA and Wu, FCW and Yeap, BB},
title = {Serum testosterone and sex hormone-binding globulin are inversely associated with leucocyte telomere length in men: a cross-sectional analysis of the UK Biobank study.},
journal = {European journal of endocrinology},
volume = {188},
number = {2},
pages = {},
doi = {10.1093/ejendo/lvad015},
pmid = {36751991},
issn = {1479-683X},
support = {//Western Australian Health Translation Network/ ; //University of Western Australia/ ; //Government of Western Australia/ ; },
mesh = {Humans ; Male ; Middle Aged ; *Biological Specimen Banks ; Cross-Sectional Studies ; *Sex Hormone-Binding Globulin/analysis ; Telomere ; Testosterone ; United Kingdom ; },
abstract = {OBJECTIVE: Older men on an average have lower testosterone concentrations, compared with younger men, and more age-related comorbidities. Whether lower testosterone concentrations contribute to biological ageing remains unclear. Shorter telomeres are a marker for biological age. We tested the hypothesis that testosterone concentrations are associated with leucocyte telomere length (LTL), in middle- to older-aged men.<br><br>DESIGN: Cross-sectional analysis of the UK Biobank study, involving community-dwelling men aged 40-69 years.<br><br>METHODS: Serum testosterone and sex hormone-binding globulin (SHBG) were assayed. Free testosterone was calculated (cFT). Leucocyte telomere length was measured using polymerase chain reaction. Multivariable models were used to assess associations of hormones with standardised LTL.<br><br>RESULTS: In 167 706 men, median age 58 years, adjusting for sociodemographic, lifestyle, and medical factors, total testosterone was inversely associated with standardised LTL, which was 0.09 longer (95% confidence interval [CI], 0.08-0.10, P < .001) in men with total testosterone at median of lowest quintile [Q1] vs highest [Q5]. This relationship was attenuated after additional adjustment for SHBG (0.03 longer, CI = 0.02-0.05, P = .003). The association between cFT and LTL was similar in direction but lower in magnitude. In multivariable analysis, SHBG was inversely associated with standardised LTL, which was 0.12 longer (CI = 0.10-0.13, P < .001) for SHBG at median Q1 vs Q5. Results were similar with testosterone included in the model (0.10 longer, CI = 0.08-0.12, P < .001).<br><br>CONCLUSIONS: Total testosterone and SHBG were independently and inversely associated with LTL. Men with higher testosterone or SHBG had shorter telomeres, arguing against a role for testosterone to slow biological ageing in men.},
}
@article {pmid36750187,
year = {2023},
author = {Burraco, P and Hernandez-Gonzalez, M and Metcalfe, NB and Monaghan, P},
title = {Ageing across the great divide: tissue transformation, organismal growth and temperature shape telomere dynamics through the metamorphic transition.},
journal = {Proceedings. Biological sciences},
volume = {290},
number = {1992},
pages = {20222448},
pmid = {36750187},
issn = {1471-2954},
mesh = {Animals ; Temperature ; *Aging ; *Metamorphosis, Biological ; Larva ; Telomere ; },
abstract = {Telomere attrition is considered a useful indicator of cellular and whole-organism ageing rate. While approximately 80% of animal species undergo metamorphosis that includes extensive tissue transformations (involving cell division, apoptosis, de-differentiation and de novo formation of stem cells), the effect on telomere dynamics is unknown. We measured telomeres in Xenopus laevis developing from larvae to adults under contrasting environmental temperatures. Telomere dynamics were linked to the degree of tissue transformation during development. Average telomere length in gut tissue increased dramatically during metamorphosis, when the gut shortens by 75% and epithelial cells de-differentiate into stem cells. In the liver (retained from larva) and hindlimb muscle (newly formed before metamorphosis), telomeres gradually shortened until adulthood, likely due to extensive cell division. Tail muscle telomere lengths were constant until tail resorption, and those in heart (retained from larva) showed no change over time. Telomere lengths negatively correlated with larval growth, but for a given growth rate, telomeres were shorter in cooler conditions, suggesting that growing in the cold is more costly. Telomere lengths were not related to post-metamorphic growth rate. Further research is now needed to understand whether telomere dynamics are a good indicator of ageing rate in species undergoing metamorphosis.},
}
@article {pmid36747763,
year = {2023},
author = {Jones, CY and Williams, CL and Moreno, SP and Morris, DK and Mondello, C and Karlseder, J and Bertuch, AA},
title = {Hyperextended telomeres promote C-circle formation in telomerase positive human cells.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {36747763},
abstract = {Telomere length maintenance is crucial to cancer cell immortality. Up to 15% of cancers utilize a telomerase-independent, recombination-based mechanism termed alternative lengthening of telomeres (ALT). The primary ALT biomarker is the C-circle, a type of circular DNA with extrachromosomal telomere repeats (cECTRs). How C-circles form is not well characterized. To investigate C-circle formation in telomerase+ cells, we studied the human cen3tel cell line, in which telomeres progressively hyper-elongated post TERT -immortalization. cECTR signal was observed in 2D gels and C-circle assays but not t-circle assays, which also detect cECTRs. Telomerase activity and C-circle signal were not separable in the analysis of clonal populations, consistent with C-circle production occurring within telomerase+ cells. Two other long telomere, telomerase+ (LTT+) cell lines, HeLa1.3 (~23 kb telomeres) and HeLaE1 (~50 kb telomeres), had similar cECTR properties. Telomerase activity did not directly impact C-circle signal in LTT+ cells; instead, C-circle signal correlated with telomere length. LTT+ lines were less sensitive to hydroxyurea than an ALT+ cell line, suggesting that ALT status is a stronger contributor to replication stress levels than telomere length. Additionally, FANCM did not suppress C-circles in LTT+ cells as it does in ALT+ cells. Thus, C-circle formation may be driven by telomere length, independently of telomerase and replication stress, highlighting limitations of C-circles as a stand-alone ALT biomarker.},
}
@article {pmid36747657,
year = {2023},
author = {Landa, I and Thornton, CE and Xu, B and Haase, J and Krishnamoorthy, GP and Hao, J and Knauf, JA and Herbert, ZT and Blasco, MA and Ghossein, R and Fagin, JA},
title = {Telomerase reactivation induces progression of mouse Braf [V600E] -driven thyroid cancers without telomere lengthening.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {36747657},
support = {R01 CA050706/CA/NCI NIH HHS/United States ; K22 CA230381/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA249663/CA/NCI NIH HHS/United States ; P30 CA006516/CA/NCI NIH HHS/United States ; },
abstract = {Mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are the paradigm of a cross-cancer alteration in a non-coding region. TERT promoter mutations (TPMs) are biomarkers of poor prognosis in several tumors, including thyroid cancers. TPMs enhance TERT transcription, which is otherwise silenced in adult tissues, thus reactivating a bona fide oncoprotein. To study TERT deregulation and its downstream consequences, we generated a Tert mutant promoter mouse model via CRISPR/Cas9 engineering of the murine equivalent locus (Tert [-123C>T]) and crossed it with thyroid-specific Braf [V600E] -mutant mice. We also employed an alternative model of Tert overexpression (K5-Tert). Whereas all Braf [V600E] animals developed well-differentiated papillary thyroid tumors, 29% and 36% of Braf [V600E] +Tert [-123C>T] and Braf [V600E] +K5-Tert mice progressed to poorly differentiated thyroid cancers at week 20, respectively. Braf+Tert tumors showed increased mitosis and necrosis in areas of solid growth, and older animals from these cohorts displayed anaplastic-like features, i.e., spindle cells and macrophage infiltration. Murine Tert promoter mutation increased Tert transcription in vitro and in vivo , but temporal and intra-tumoral heterogeneity was observed. RNA-sequencing of thyroid tumor cells showed that processes other than the canonical Tert-mediated telomere maintenance role operate in these specimens. Pathway analysis showed that MAPK and PI3K/AKT signaling, as well as processes not previously associated with this tumor etiology, involving cytokine and chemokine signaling, were overactivated. Braf+Tert animals remained responsive to MAPK pathway inhibitors. These models constitute useful pre-clinical tools to understand the cell-autonomous and microenvironment-related consequences of Tert-mediated progression in advanced thyroid cancers and other aggressive tumors carrying TPMs.},
}
@article {pmid36729832,
year = {2023},
author = {Pires, VB and Lohner, N and Wagner, T and Wagner, CB and Wilkens, M and Hajikazemi, M and Paeschke, K and Butter, F and Luke, B},
title = {RNA-DNA hybrids prevent resection at dysfunctional telomeres.},
journal = {Cell reports},
volume = {42},
number = {2},
pages = {112077},
doi = {10.1016/j.celrep.2023.112077},
pmid = {36729832},
issn = {2211-1247},
mesh = {*RNA/genetics ; *Telomere/genetics ; DNA ; Telomere Shortening ; DNA, Single-Stranded ; },
abstract = {At critically short telomeres, stabilized TERRA RNA-DNA hybrids drive homology-directed repair (HDR) to delay replicative senescence. However, even at long- and intermediate-length telomeres, not subject to HDR, transient TERRA RNA-DNA hybrids form, suggestive of additional roles. We report that telomeric RNA-DNA hybrids prevent Exo1-mediated resection when telomeres become non-functional. We used the well-characterized cdc13-1 allele, where telomere resection can be induced in a temperature-dependent manner, to demonstrate that ssDNA generation at telomeres is either prevented or augmented when RNA-DNA hybrids are stabilized or destabilized, respectively. The viability of cdc13-1 cells is affected by the presence or absence of hybrids accordingly. Telomeric hybrids do not affect the shortening rate of bulk telomeres. We suggest that TERRA hybrids require dynamic regulation to drive HDR at short telomeres; hybrid presence may initiate HDR through replication stress, whereby their removal allows strand resection.},
}
@article {pmid36726239,
year = {2023},
author = {Van Ommen, CE and Hsieh, AYY and Albert, AY and Kimmel, ER and Cote, HCF and Maan, EJ and Prior, JC and Pick, N and Murray, MCM and , },
title = {Lower anti-Müllerian hormone levels are associated with HIV in reproductive age women and shorter leukocyte telomere length among late reproductive age women.},
journal = {AIDS (London, England)},
volume = {37},
number = {5},
pages = {769-778},
pmid = {36726239},
issn = {1473-5571},
support = {//CIHR/Canada ; },
mesh = {Pregnancy ; Humans ; Female ; Adult ; Aged ; Child ; Adolescent ; Young Adult ; Middle Aged ; *Anti-Mullerian Hormone ; Cross-Sectional Studies ; *HIV Infections ; Leukocytes ; Telomere ; },
abstract = {OBJECTIVES: We sought to better understand factors associated with ovarian aging in women with HIV (WWH).<br><br>DESIGN: HIV has been associated with diminished fertility, younger age at menopause, and shorter leukocyte telomere length (LTL), a marker of cellular aging. We herein examine cross-sectional and longitudinal associations between LTL, anti-M&#xfc;llerian hormone (AMH), and HIV.<br><br>METHODS: We included WWH and HIV-negative women 12-50&#x200a;years of age in the CARMA cohort with one or more study visit(s). LTL and AMH were measured by qPCR and ELISA, respectively. Women were analyzed in peak reproductive (<35&#x200a;years) vs. late reproductive (&#x2265;35&#x200a;years) life phases. Using multivariable mixed-effect linear or logistic regressions, we assessed factors associated with AMH and &#x394;AMH/year while adjusting for relevant confounders.<br><br>RESULTS: WWH had shorter LTL and lower AMH levels compared to HIV-negative controls despite being of similar age. After adjusting for relevant factors, HIV was associated with 20% lower AMH levels in women under 35 years of age and shorter LTL was associated with AMH levels below 2&#x200a;ng/ml among women aged 35 years or older. Longitudinally, &#x394;AMH/year was largely related to initial AMH level among older women, and to age in younger women.<br><br>CONCLUSIONS: Factors associated with AMH change across women's reproductive lifespan. Lower AMH among peak reproductive aged WWH suggests that HIV may have an initial detrimental effect on ovarian reserve, an observation that may warrant counseling around pregnancy planning. In women aged 35 years or older, the association between shorter LTL and lower AMH suggests that the immune and reproductive aging connections are more important in this age group.},
}
@article {pmid36719921,
year = {2023},
author = {Eguchi, A and Gonzalez, AFGS and Torres-Bigio, SI and Koleckar, K and Birnbaum, F and Zhang, JZ and Wang, VY and Wu, JC and Artandi, SE and Blau, HM},
title = {TRF2 rescues telomere attrition and prolongs cell survival in Duchenne muscular dystrophy cardiomyocytes derived from human iPSCs.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {120},
number = {6},
pages = {e2209967120},
pmid = {36719921},
issn = {1091-6490},
support = {R01 HL159340/HL/NHLBI NIH HHS/United States ; R01 HL130020/HL/NHLBI NIH HHS/United States ; R25 HL147666/HL/NHLBI NIH HHS/United States ; R01 HL126527/HL/NHLBI NIH HHS/United States ; R01 HL123968/HL/NHLBI NIH HHS/United States ; R01 HL146690/HL/NHLBI NIH HHS/United States ; UL1 TR003142/TR/NCATS NIH HHS/United States ; R01 HL134776/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; *Cardiomyopathy, Dilated/genetics ; Cell Survival ; Dystrophin/genetics ; *Heart Failure/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Muscular Dystrophy, Duchenne/metabolism ; Myocytes, Cardiac/metabolism ; Telomere/genetics/metabolism ; },
abstract = {Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by the lack of dystrophin. Heart failure, driven by cardiomyocyte death, fibrosis, and the development of dilated cardiomyopathy, is the leading cause of death in DMD patients. Current treatments decrease the mechanical load on the heart but do not address the root cause of dilated cardiomyopathy: cardiomyocyte death. Previously, we showed that telomere shortening is a hallmark of DMD cardiomyocytes. Here, we test whether prevention of telomere attrition is possible in cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPSC-CMs) and if preventing telomere shortening impacts cardiomyocyte function. We observe reduced cell size, nuclear size, and sarcomere density in DMD iPSC-CMs compared with healthy isogenic controls. We find that expression of just one telomere-binding protein, telomeric repeat-binding factor 2 (TRF2), a core component of the shelterin complex, prevents telomere attrition and rescues deficiencies in cell size as well as sarcomere density. We employ a bioengineered platform to micropattern cardiomyocytes for calcium imaging and perform Southern blots of telomere restriction fragments, the gold standard for telomere length assessments. Importantly, preservation of telomere lengths in DMD cardiomyocytes improves their viability. These data provide evidence that preventing telomere attrition ameliorates deficits in cell morphology, activation of the DNA damage response, and premature cell death, suggesting that TRF2 is a key player in DMD-associated cardiac failure.},
}
@article {pmid36717449,
year = {2022},
author = {Morgunova, VV and Sokolova, OA and Sizova, TV and Malaev, LG and Babaev, DS and Kwon, DA and Kalmykova, AI},
title = {Dysfunction of Lamin B and Physiological Aging Cause Telomere Instability in Drosophila Germline.},
journal = {Biochemistry. Biokhimiia},
volume = {87},
number = {12},
pages = {1600-1610},
doi = {10.1134/S000629792212015X},
pmid = {36717449},
issn = {1608-3040},
mesh = {Animals ; *Lamin Type B/genetics/metabolism ; *Drosophila/genetics ; Heterochromatin ; Drosophila melanogaster/genetics ; Aging/genetics ; Telomere/genetics/metabolism ; Germ Cells ; },
abstract = {Chromatin spatial organization in the nucleus is essential for the genome functioning and regulation of gene activity. The nuclear lamina and lamina-associated proteins, lamins, play a key role in this process. Lamin dysfunction leads to the decompaction and transcriptional activation of heterochromatin, which is associated with the premature aging syndrome. In many cell types, telomeres are located at the nuclear periphery, where their replication and stability are ensured by the nuclear lamina. Moreover, diseases associated with defects in lamins and telomeres have similar manifestations and resemble physiological aging. Understanding molecular changes associated with aging at the organismal level is especially important. In this study, we compared the effects caused by the mutation in lamin B and physiological aging in the germline of the model organism Drosophila melanogaster. We have shown that the impaired localization of lamin B leads to the heterochromatin decompaction and transcriptional activation of some transposable elements and telomeric repeats. Both DNA damage and activation of homologous recombination in the telomeres were observed in the germ cells of lamin B mutants. The instability of repeat-enriched heterochromatin can be directly related to the genome destabilization, germ cell death, and sterility observed in lamin B mutants. Similar processes were observed in Drosophila germline in the course of physiological aging, which indicates a close link between the maintenance of the heterochromatin stability at the nuclear periphery and mechanisms of aging.},
}
@article {pmid36714994,
year = {2023},
author = {Hsu, BY and Cossin-Sevrin, N and Stier, A and Ruuskanen, S},
title = {Prenatal thyroid hormones accelerate postnatal growth and telomere shortening in wild great tits.},
journal = {The Journal of experimental biology},
volume = {226},
number = {6},
pages = {},
pmid = {36714994},
issn = {1477-9145},
mesh = {Pregnancy ; Animals ; Female ; Telomere Shortening ; Aging ; Fetal Development ; *Passeriformes ; *Songbirds ; Vitamins ; Telomere ; Thyroid Hormones ; Hormones ; },
abstract = {The early-life environment is known to affect later-life health and disease, which could be mediated by the early-life programming of telomere length, a key hallmark of ageing. According to the fetal programming of telomere biology hypothesis, variation in prenatal exposure to hormones is likely to influence telomere length. Yet, the contribution of key metabolic hormones, i.e. thyroid hormones (THs), has been largely ignored. We recently showed that in contrast to predictions, exposure to elevated prenatal THs increased postnatal telomere length in wild collared flycatchers, but the generality of such effect, the underlying proximate mechanisms and consequences for survival have not been investigated. We therefore conducted a comprehensive study evaluating the impact of THs on potential drivers of telomere dynamics (growth, post-natal THs, mitochondria and oxidative stress), telomere length and medium-term survival using wild great tits as a model system. While prenatal THs did not significantly affect telomere length a week after hatching (i.e. day 7), they influenced postnatal telomere shortening (i.e. shorter telomeres at day 14 and the following winter) but not apparent survival. Circulating THs, mitochondrial density or oxidative stress biomarkers were not significantly influenced, whereas the TH-supplemented group showed accelerated growth, which may explain the observed delayed effect on telomeres. We discuss several alternative hypotheses that may explain the contrast with our previous findings in flycatchers. Given that shorter telomeres in early life tend to be carried until adulthood and are often associated with decreased survival prospects, the effects of prenatal THs on telomeres may have long-lasting effects on senescence.},
}
@article {pmid36714598,
year = {2022},
author = {Yuan, Y and Tan, Y and Qiu, X and Luo, H and Li, Y and Li, R and Yang, X},
title = {Sperm telomere length as a novel biomarker of male infertility and embryonic development: A systematic review and meta-analysis.},
journal = {Frontiers in endocrinology},
volume = {13},
number = {},
pages = {1079966},
pmid = {36714598},
issn = {1664-2392},
mesh = {Pregnancy ; Female ; Humans ; Male ; *Semen Analysis ; Semen ; *Infertility, Male/diagnosis/genetics ; Spermatozoa ; Telomere ; Biomarkers ; Observational Studies as Topic ; },
abstract = {BACKGROUND: Telomeres have an essential role in maintaining the integrity and stability of the human chromosomal genome and preserving essential DNA biological functions. Several articles have been published on the association of STL with male semen parameters and clinical pregnancy. The results, however, are either inconclusive or inconsistent. Therefore, this meta-analysis aimed to systematically assess the accuracy and clinical value of sperm telomere length (STL) as a new marker for diagnosing male infertility and predicting the quality of embryonic development.<br><br>METHODS: We performed a comprehensive systematic search for relevant publications in PubMed, the Cochrane Library, Web of Science, Embase, Scopus, and Ovid, from database build to August 2022. All experimental studies exploring the association of STL with male semen quality, male infertility, or embryonic development were included.<br><br>RESULTS: Overall, Twelve prospective observational cohort studies (1700 patients) were eligible for inclusion in the meta-analysis. The meta-analysis showed a positive linear correlation between STL and semen parameters. The optimal cut-off value for STL diagnosing male infertility was 1.0, with a sensitivity and specificity of 80%. Regarding STL and embryonic development, the clinical pregnancy rate was associated with longer STL, and there was no significant difference between the two groups regarding fertilization rate.<br><br>CONCLUSION: Our study showed that STL has good diagnostic and predictive value for male fertility and clinical pregnancy and could be used as a new biomarker for diagnosing male infertility and predicting embryonic development.<br><br>https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022303333.},
}
@article {pmid36707451,
year = {2023},
author = {Valdiani, A and Ofoghi, H},
title = {Enzymatic approaches against SARS-CoV-2 infection with an emphasis on the telomere-associated enzymes.},
journal = {Biotechnology letters},
volume = {45},
number = {3},
pages = {333-345},
pmid = {36707451},
issn = {1573-6776},
mesh = {Humans ; *COVID-19 ; SARS-CoV-2/genetics ; Pandemics/prevention &amp; control ; *Middle East Respiratory Syndrome Coronavirus ; },
abstract = {The pandemic phase of coronavirus disease 2019 (COVID-19) appears to be over in most countries. However, the unexpected behaviour and unstable nature of coronaviruses, including temporary hiatuses, re-emergence, emergence of new variants, and changing outbreak epicentres during the COVID-19 pandemic, have been frequently reported. The mentioned trend shows the fact that in addition to vaccine development, different strategies should be considered to deal effectively with this disease, in long term. In this regard, the role of enzymes in regulating immune responses to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has recently attracted much attention. Moreover, several reports confirm the association of short telomeres with sever COVID-19 symptoms. This review highlights the role of several enzymes involved in telomere length (TL) regulation and explains their relevance to SARS-CoV-2 infection. Apparently, inhibition of telomere shortening (TS) through inhibition and/or activation of these enzymes could be a potential target in the treatment of COVID-19, which may also lead to a reduction in disease severity.},
}
@article {pmid36705478,
year = {2023},
author = {},
title = {Heritable Defects in Mitotic and Telomere Function Confer Sarcoma Risk.},
journal = {Cancer discovery},
volume = {13},
number = {3},
pages = {529},
doi = {10.1158/2159-8290.CD-RW2023-016},
pmid = {36705478},
issn = {2159-8290},
mesh = {Humans ; *Sarcoma/genetics ; Telomere/genetics ; },
abstract = {Mitotic and telomere function pathways were identified to play a role in sarcoma susceptibility.},
}
@article {pmid36703827,
year = {2022},
author = {Wai, KM and Swe, T and Myar, MT and Aisyah, CR and Hninn, TSS},
title = {Telomeres susceptibility to environmental arsenic exposure: Shortening or lengthening?.},
journal = {Frontiers in public health},
volume = {10},
number = {},
pages = {1059248},
pmid = {36703827},
issn = {2296-2565},
mesh = {*Arsenic/metabolism ; *Telomerase/genetics/metabolism ; Telomere/metabolism ; },
abstract = {Maintaining telomere length plays a crucial role in regulating cellular life span. Telomere lengthening or shortening is one of the important biomarkers which could predict the preceding or present diseases. Meanwhile, the impact of environmental arsenic exposure on telomere length has increasingly concerned. Although previous studies demonstrated the effects of arsenic on telomere length, the findings were unclear on whether telomere shortens or lengthens by arsenic exposure. Thus, this manuscript summarized and discussed the telomere length alteration following arsenic exposure and the possible does-response effect of arsenic on telomere length. The present review suggested that different age groups may respond differently to arsenic exposure, and the dose-response effect of arsenic could be a critical factor in its effect on telomere length. Moreover, speciation analysis of arsenic could be more informative in identifying the effect of arsenic on telomere length.},
}
@article {pmid36702776,
year = {2023},
author = {Hoerr, RE and Eng, A and Payen, C and Di Rienzi, SC and Raghuraman, MK and Dunham, MJ and Brewer, BJ and Friedman, KL},
title = {Hotspot of de novo telomere addition stabilizes linear amplicons in yeast grown in sulfate-limiting conditions.},
journal = {Genetics},
volume = {224},
number = {2},
pages = {},
pmid = {36702776},
issn = {1943-2631},
support = {R01 GM123292/GM/NIGMS NIH HHS/United States ; R35 GM122497/GM/NIGMS NIH HHS/United States ; T32 GM137793/GM/NIGMS NIH HHS/United States ; R01GM123292/NH/NIH HHS/United States ; },
mesh = {Humans ; Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; *Telomerase/genetics/metabolism ; Sulfates/metabolism ; DNA Copy Number Variations ; Telomere-Binding Proteins/genetics ; Telomere/genetics/metabolism ; Sulfate Transporters/genetics/metabolism ; },
abstract = {Evolution is driven by the accumulation of competing mutations that influence survival. A broad form of genetic variation is the amplification or deletion of DNA (≥50 bp) referred to as copy number variation (CNV). In humans, CNV may be inconsequential, contribute to minor phenotypic differences, or cause conditions such as birth defects, neurodevelopmental disorders, and cancers. To identify mechanisms that drive CNV, we monitored the experimental evolution of Saccharomyces cerevisiae populations grown under sulfate-limiting conditions. Cells with increased copy number of the gene SUL1, which encodes a primary sulfate transporter, exhibit a fitness advantage. Previously, we reported interstitial inverted triplications of SUL1 as the dominant rearrangement in a haploid population. Here, in a diploid population, we find instead that small linear fragments containing SUL1 form and are sustained over several generations. Many of the linear fragments are stabilized by de novo telomere addition within a telomere-like sequence near SUL1 (within the SNF5 gene). Using an assay that monitors telomerase action following an induced chromosome break, we show that this region acts as a hotspot of de novo telomere addition and that required sequences map to a region of <250 base pairs. Consistent with previous work showing that association of the telomere-binding protein Cdc13 with internal sequences stimulates telomerase recruitment, mutation of a four-nucleotide motif predicted to associate with Cdc13 abolishes de novo telomere addition. Our study suggests that internal telomere-like sequences that stimulate de novo telomere addition can contribute to adaptation by promoting genomic plasticity.},
}
@article {pmid36702689,
year = {2023},
author = {Heaphy, CM and Singhi, AD},
title = {Reprint of: The Diagnostic and Prognostic Utility of Incorporating DAXX, ATRX, and Alternative Lengthening of Telomeres (ALT) to the Evaluation of Pancreatic Neuroendocrine Tumors (PanNETs).},
journal = {Human pathology},
volume = {132},
number = {},
pages = {1-11},
pmid = {36702689},
issn = {1532-8392},
support = {R37 CA263622/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; *Neuroendocrine Tumors/diagnosis/genetics/pathology ; Prognosis ; X-linked Nuclear Protein/genetics ; In Situ Hybridization, Fluorescence ; *Intellectual Disability ; *alpha-Thalassemia ; Nuclear Proteins/genetics ; *Pancreatic Neoplasms/diagnosis/genetics/metabolism ; Telomere/pathology ; Co-Repressor Proteins ; Telomere Homeostasis ; Molecular Chaperones ; },
abstract = {Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of neoplasms with increasing incidence and an ill-defined pathobiology. Although many PanNETs are indolent and remain stable for years, a subset may behave aggressively and metastasize widely. Thus, the increasing and frequent detection of PanNETs presents a treatment dilemma. Current prognostic systems are susceptible to interpretation errors, sampling issues, and do not accurately reflect the clinical behavior of these neoplasms. Hence, additional biomarkers are needed to improve the prognostic stratification of patients diagnosed with a PanNET. Recent studies have identified alterations in death domain-associated protein 6 (DAXX) and alpha-thalassemia/mental retardation X-linked (ATRX), as well as alternative lengthening of telomeres (ALT), as promising prognostic biomarkers. This review summarizes the identification, clinical utility, and specific nuances in testing for DAXX/ATRX by immunohistochemistry and ALT by telomere-specific fluorescence in situ hybridization in PanNETs. Furthermore, a discussion on diagnostic indications for DAXX, ATRX, and ALT status is provided to include the distinction between PanNETs and pancreatic neuroendocrine carcinomas (PanNECs), and determining pancreatic origin for metastatic neuroendocrine tumors in the setting of an unknown primary.},
}
@article {pmid36700322,
year = {2023},
author = {Uzuncakmak, SK and Dirican, E and Ozcan, H and Takim, U},
title = {Relation of ATPase6 Mutations and Telomere Length in Schizophrenia Patients.},
journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology},
volume = {21},
number = {1},
pages = {162-170},
pmid = {36700322},
issn = {1738-1088},
abstract = {OBJECTIVE: Schizophrenia is a serious mental disorder. Mutations in mitochondrial genes can change energy metabolism. Telomere is a tandem sequence at the end of chromosomes. Shorter telomere length has been shown in schizophrenia. The aim of this study was to determine the relationship between ATPase6 gene mutations and telomere length in schizophrenia patients.<br><br>METHODS: Blood samples of 34 patients and 34 healthy controls were used. In this study conventional PCR, Sanger sequencing technic and real-time PCR were utilized.<br><br>RESULTS: Five different mutations (A8860G, A8836, G8697A, C8676T, and A8701G) in the ATPase6 gene were identified in schizophrenia patients. The most seen mutation was A8860G (94%). Telomere length analysis indicated the relation of ATPase6 gene mutations and telomere length variations (p = 0.001). Patients carrying the A8860G mutation had shorter telomere lengths than patients carrying other mutations. Comparing telomere length between schizophrenia patients and healthy controls revealed that the mean telomere length of schizophrenia patients was shorter than healthy controls (p = 0.006). The demographic analysis demonstrated a significant relationship between marital status and telomere length (p = 0.011). Besides that, the duration of the illness is another factor that impacts telomere length (p = 0.044). There is no significant relation between telomere length and other clinical and demographic characteristics including education status, age, gender, etc.<br><br>CONCLUSION: In conclusion, telomere length and ATPase6 gene mutations have a significant relation. Studies with larger patient populations and investigation of other mitochondrial gene mutations will make the clearer link between telomere length and mitochondrial mutations.},
}
@article {pmid36699384,
year = {2022},
author = {Holmes, O and Nones, K and Tang, YH and Loffler, KA and Lee, M and Patch, AM and Dagg, RA and Lau, LMS and Leonard, C and Wood, S and Xu, Q and Pickett, HA and Reddel, RR and Barbour, AP and Grimmond, SM and Waddell, N and Pearson, JV},
title = {qmotif: determination of telomere content from whole-genome sequence data.},
journal = {Bioinformatics advances},
volume = {2},
number = {1},
pages = {vbac005},
pmid = {36699384},
issn = {2635-0041},
abstract = {MOTIVATION: Changes in telomere length have been observed in cancer and can be indicative of mechanisms involved in carcinogenesis. Most methods used to estimate telomere length require laboratory analysis of DNA samples. Here, we present qmotif, a fast and easy tool that determines telomeric repeat sequences content as an estimate of telomere length directly from whole-genome sequencing.<br><br>RESULTS: qmotif shows similar results to quantitative PCR, the standard method for high-throughput clinical telomere length quantification. qmotif output correlates strongly with the output of other tools for determining telomere sequence content, TelSeq and TelomereHunter, but can run in a fraction of the time-usually under a minute.<br><br>qmotif is implemented in Java and source code is available at https://github.com/AdamaJava/adamajava, with instructions on how to build and use the application available from https://adamajava.readthedocs.io/en/latest/.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics Advances online.},
}
@article {pmid36696951,
year = {2023},
author = {Park, S and Kim, SG and Lee, S and Kim, Y and Cho, S and Kim, K and Kim, YC and Han, SS and Lee, H and Lee, JP and Joo, KW and Lim, CS and Kim, YS and Kim, DK},
title = {Causal linkage of tobacco smoking with ageing: Mendelian randomization analysis towards telomere attrition and sarcopenia.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {14},
number = {2},
pages = {955-963},
pmid = {36696951},
issn = {2190-6009},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; 3020220160//Seoul National University Hospital/ ; //Ministry of Health &amp; Welfare, Republic of Korea/ ; 2021R1A2C2094586//Korean government (MSIT, Ministry of Science and ICT)/ ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; Mendelian Randomization Analysis ; *Sarcopenia ; Hand Strength ; *Frailty ; Tobacco Smoking ; Telomere/genetics ; },
abstract = {BACKGROUND: Ageing traits and frailty are important health issues in modern medicine. Evidence supporting the causal effects of tobacco smoking on various ageing traits is required.<br><br>METHODS: This study performed Mendelian randomization (MR) analysis instrumenting 377 genetic variants associated with being an ever-smoker at a genome-wide significance level to test the causal estimates from tobacco smoking. The outcome data were obtained from 337&#x2009;138 white British ancestry participants from the UK Biobank. Leucocyte telomere length, appendicular lean mass index, subjective walking pace, handgrip strength,&#xa0;and wristband accelerometry-determined physical activity degree were collected as ageing-related outcomes. Summary-level MR analysis was performed using the inverse variance-weighted method and pleiotropy-robust MR methods, including weighted median and MR-Egger. Observational association between the outcome traits and phenotypically being an ever-smoker was also investigated.<br><br>RESULTS: Summary-level MR analysis indicated that a higher genetic predisposition for tobacco smoking was significantly associated with shorter leucocyte telomere length (twofold increase in prevalence of smoking towards standardized Z-score, -0.041 [-0.054, -0.028]), lower appendicular lean mass index (-0.007 [-0.010, -0.005]), slower walking pace (ordinal category, -0.047 [-0.054, -0.033]) and lower time spent on moderate-to-vigorous physical activity (hours per week, -0.39 [-0.56, -0.23]). The causal estimates were non-significant towards handgrip strength phenotype (kg, 0.074 [-0.055, 0.204]). Pleiotropy-robust MR results generally supported the main causal estimates. The observational findings also showed significant association between being an ever-smoker and the ageing traits.<br><br>CONCLUSIONS: Genetically predicted and observational tobacco smoking status are significantly associated with poor ageing phenotypes. Healthcare providers may continue to reduce tobacco use, which may be helpful in reducing the burden of ageing and frailty.},
}
@article {pmid36691437,
year = {2023},
author = {Sabot, D and Lovegrove, R and Stapleton, P},
title = {The association between sleep quality and telomere length: A systematic literature review.},
journal = {Brain, behavior, &amp; immunity - health},
volume = {28},
number = {},
pages = {100577},
pmid = {36691437},
issn = {2666-3546},
abstract = {Several sleep parameters present an elevated risk for processes that contribute to cellular aging. Short sleep duration, sleep apnoea, and insomnia are significantly associated with shorter telomeres, a biological marker of cellular aging. However, there has been no review or analysis of studies that have examined the association between the psychological construct of sleep quality and telomere length. The present study aimed to provide a systematic review of the association between sleep quality and telomere length. A systematic review of English articles was conducted using MEDLINE/PubMed, PsycINFO, Google Scholar, and Web of Science electronic databases, with the final search conducted on 3rd September 2021. Search terms included sleep quality, poor sleep, insomnia, sleep difficulties, sleep issue*, non-restorative sleep, telomere*, cellular aging, and immune cell telomere length. Study eligibility criteria included human participants aged 18 years or older and a reproducible methodology. Study appraisal and synthesis were completed using a systematic search in line with a PICOS approach (P = Patient, problem, or population; I = Intervention, prognostic factor, exposure; C = Comparison, control, or comparator; O = Outcomes; S = Study designs). Twenty-two studies met review inclusion criteria. Qualitative synthesis of the literature indicated insufficient evidence overall to support a significant association between sleep quality and telomere length. Limitations across studies were addressed, such as the assessment of examined constructs. Findings highlight important targets for future research, including the standardised operationalisation of the sleep quality construct and experimental study designs. Research in this area has clinical significance by identifying possible mechanisms that increase the risk for age-related disease and mortality. PROSPERO Registration No.: CRD 42021233139.},
}
@article {pmid36690926,
year = {2023},
author = {Kim, JS and Manichaikul, AW and Hoffman, EA and Balte, P and Anderson, MR and Bernstein, EJ and Madahar, P and Oelsner, EC and Kawut, SM and Wysoczanski, A and Laine, AF and Adegunsoye, A and Ma, JZ and Taub, MA and Mathias, RA and Rich, SS and Rotter, JI and Noth, I and Garcia, CK and Barr, RG and Podolanczuk, AJ},
title = {MUC5B, telomere length and longitudinal quantitative interstitial lung changes: the MESA Lung Study.},
journal = {Thorax},
volume = {78},
number = {6},
pages = {566-573},
pmid = {36690926},
issn = {1468-3296},
support = {K23 HL140199/HL/NHLBI NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; K23 HL146942/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01HC95168/HL/NHLBI NIH HHS/United States ; R01 HL077612/HL/NHLBI NIH HHS/United States ; N01HC95162/HL/NHLBI NIH HHS/United States ; HHSN268201000021C/HL/NHLBI NIH HHS/United States ; N01HC95165/HL/NHLBI NIH HHS/United States ; N01HC95167/HL/NHLBI NIH HHS/United States ; N01HC95163/HL/NHLBI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; HHSN268201000001I/HL/NHLBI NIH HHS/United States ; N01HC95161/HL/NHLBI NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; P30 ES005605/ES/NIEHS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; R01 HL093081/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; R01 HL121270/HL/NHLBI NIH HHS/United States ; K23 AR075112/AR/NIAMS NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; N01HC95164/HL/NHLBI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; N01HC95166/HL/NHLBI NIH HHS/United States ; K23 HL150301/HL/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; R01 HL131565/HL/NHLBI NIH HHS/United States ; N01HC95160/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Humans ; *Lung/diagnostic imaging ; *Lung Diseases, Interstitial/diagnostic imaging/genetics/complications ; Genotype ; Telomere/genetics ; Mucin-5B/genetics ; },
abstract = {BACKGROUND: The MUC5B promoter variant (rs35705950) and telomere length are linked to pulmonary fibrosis and CT-based qualitative assessments of interstitial abnormalities, but their associations with longitudinal quantitative changes of the lung interstitium among community-dwelling adults are unknown.<br><br>METHODS: We used data from participants in the Multi-Ethnic Study of Atherosclerosis with high-attenuation areas (HAAs, Examinations 1-6 (2000-2018)) and MUC5B genotype (n=4552) and telomere length (n=4488) assessments. HAA was defined as the per cent of imaged lung with attenuation of -600 to -250 Hounsfield units. We used linear mixed-effects models to examine associations of MUC5B risk allele (T) and telomere length with longitudinal changes in HAAs. Joint models were used to examine associations of longitudinal changes in HAAs with death and interstitial lung disease (ILD).<br><br>RESULTS: The MUC5B risk allele (T) was associated with an absolute change in HAAs of 2.60% (95% CI 0.36% to 4.86%) per 10 years overall. This association was stronger among those with a telomere length below an age-adjusted percentile of 5% (p value for interaction=0.008). A 1% increase in HAAs per year was associated with 7% increase in mortality risk (rate ratio (RR)=1.07, 95%&#x2009;CI 1.02 to 1.12) for overall death and 34% increase in ILD (RR=1.34, 95%&#x2009;CI 1.20 to 1.50). Longer baseline telomere length was cross-sectionally associated with less HAAs from baseline scans, but not with longitudinal changes in HAAs.<br><br>CONCLUSIONS: Longitudinal increases in HAAs were associated with the MUC5B risk allele and a higher risk of death and ILD.},
}
@article {pmid36689342,
year = {2023},
author = {Liu, H and Xu, C and Diplas, BH and Brown, A and Strickland, LM and Yao, H and Ling, J and McLendon, RE and Keir, ST and Ashley, DM and He, Y and Waitkus, MS},
title = {Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells.},
journal = {Neuro-oncology},
volume = {25},
number = {9},
pages = {1563-1575},
pmid = {36689342},
issn = {1523-5866},
support = {K22 CA258965/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; *Telomerase/genetics/metabolism ; *Glioblastoma/genetics ; Telomere Homeostasis ; Mutation ; Telomere/genetics/metabolism ; Carcinogenesis ; Cell Transformation, Neoplastic/genetics ; DNA Helicases/genetics/metabolism ; },
abstract = {BACKGROUND: Telomere maintenance mechanisms are required to enable the replicative immortality of malignant cells. While most cancers activate the enzyme telomerase, a subset of cancers uses telomerase-independent mechanisms termed alternative lengthening of telomeres (ALT). ALT occurs via homology-directed-repair mechanisms and is frequently associated with ATRX mutations. We previously showed that a subset of adult glioblastoma (GBM) patients with ATRX-expressing ALT-positive tumors harbored loss-of-function mutations in the SMARCAL1 gene, which encodes an annealing helicase involved in replication fork remodeling and the resolution of replication stress. However, the causative relationship between SMARCAL1 deficiency, tumorigenesis, and de novo telomere synthesis is not understood.<br><br>METHODS: We used a patient-derived ALT-positive GBM cell line with native SMARCAL1 deficiency to investigate the role of SMARCAL1 in ALT-mediated de novo telomere synthesis, replication stress, and gliomagenesis in vivo.<br><br>RESULTS: Inducible rescue of SMARCAL1 expression suppresses ALT indicators and inhibits de novo telomere synthesis in GBM and osteosarcoma cells, suggesting that SMARCAL1 deficiency plays a functional role in ALT induction in cancers that natively lack SMARCAL1 function. SMARCAL1-deficient ALT-positive cells can be serially propagated in vivo in the absence of detectable telomerase activity, demonstrating that the SMARCAL1-deficient ALT phenotype maintains telomeres in a manner that promotes tumorigenesis.<br><br>CONCLUSIONS: SMARCAL1 deficiency is permissive to ALT and promotes gliomagenesis. Inducible rescue of SMARCAL1 in ALT-positive cell lines permits the dynamic modulation of ALT activity, which will be valuable for future studies aimed at understanding the mechanisms of ALT and identifying novel anticancer therapeutics that target the ALT phenotype.},
}
@article {pmid36689071,
year = {2023},
author = {Yin, H and Pickering, JG},
title = {Telomere Length: Implications for Atherogenesis.},
journal = {Current atherosclerosis reports},
volume = {25},
number = {3},
pages = {95-103},
pmid = {36689071},
issn = {1534-6242},
support = {FDN-143326//CIHR/Canada ; PJT-180604//CIHR/Canada ; },
mesh = {Humans ; *Atherosclerosis/genetics ; Telomere Shortening ; *Cardiovascular System ; Risk Factors ; Telomere ; Leukocytes ; },
abstract = {PURPOSE OF REVIEW: The purpose of the study is to explore the evidence linking telomere length with atherosclerotic ischemic disease.<br><br>RECENT FINDINGS: There has been a recent expansion in strategies for measuring telomere length, including analyzing genome sequence data and capitalizing on genomic loci that associate with telomere length. These, together with more established approaches, have been used to generate a more complete picture of telomere length relationships with ischemic disease. Whereas earlier meta-analyses suggested an association between short leukocyte telomeres and ischemic disease, several recent large population studies now provide particularly compelling data, including an association with cardiovascular mortality. In addition, whether short leukocyte telomeres might be causally related to ischemic disease has been interrogated using Mendelian randomization strategies, which point to shorter leukocyte telomeres as a determining risk factor. Importantly however, the wide, interindividual variability in telomere length still means that a single assessment of leukocyte telomere length in an individual does not reliably report on a biological aging process. In this regard, recent multi-tissue analyses of telomere length dynamics are providing both new mechanistic insights into how telomere length and shortening rates may participate in atherogenesis and risk prediction opportunities. The balance of evidence indicates that short leukocyte telomeres confer a risk for atherosclerotic cardiovascular disease. Moreover, an integrated analysis of telomere lengths in leukocytes and other tissues may provide a window into individualized telomere dynamics, raising new prospects for risk management.},
}
@article {pmid36685927,
year = {2022},
author = {Xiao, Y and Xu, D and Jiang, C and Huili, Y and Nie, S and Zhu, H and Fan, G and Guan, X},
title = {Telomere maintenance-related genes are important for survival prediction and subtype identification in bladder cancer.},
journal = {Frontiers in genetics},
volume = {13},
number = {},
pages = {1087246},
pmid = {36685927},
issn = {1664-8021},
abstract = {Background: Bladder cancer ranks among the top three in the urology field for both morbidity and mortality. Telomere maintenance-related genes are closely related to the development and progression of bladder cancer, and approximately 60%-80% of mutated telomere maintenance genes can usually be found in patients with bladder cancer. Methods: Telomere maintenance-related gene expression profiles were obtained through limma R packages. Of the 359 differential genes screened, 17 prognostically relevant ones were obtained by univariate independent prognostic analysis, and then analysed by LASSO regression. The best result was selected to output the model formula, and 11 model-related genes were obtained. The TCGA cohort was used as the internal group and the GEO dataset as the external group, to externally validate the model. Then, the HPA database was used to query the immunohistochemistry of the 11 model genes. Integrating model scoring with clinical information, we drew a nomogram. Concomitantly, we conducted an in-depth analysis of the immune profile and drug sensitivity of the bladder cancer. Referring to the matrix heatmap, delta area plot, consistency cumulative distribution function plot, and tracking plot, we further divided the sample into two subtypes and delved into both. Results: Using bioinformatics, we obtained a prognostic model of telomere maintenance-related genes. Through verification with the internal and the external groups, we believe that the model can steadily predict the survival of patients with bladder cancer. Through the HPA database, we found that three genes, namely ABCC9, AHNAK, and DIP2C, had low expression in patients with tumours, and eight other genes-PLOD1, SLC3A2, RUNX2, RAD9A, CHMP4C, DARS2, CLIC3, and POU5F1-were highly expressed in patients with tumours. The model had accurate predictive power for populations with different clinicopathological features. Through the nomogram, we could easily assess the survival rate of patients. Clinicians can formulate targeted diagnosis and treatment plans for patients based on the prediction results of patient survival, immunoassays, and drug susceptibility analysis. Different subtypes help to further subdivide patients for better treatment purposes. Conclusion: According to the results obtained by the nomogram in this study, combined with the results of patient immune-analysis and drug susceptibility analysis, clinicians can formulate diagnosis and personalized treatment plans for patients. Different subtypes can be used to further subdivide the patient for a more precise treatment plan.},
}
@article {pmid36684585,
year = {2022},
author = {Semeraro, MD and Beltrami, AP and Kharrat, F and Almer, G and Sedej, S and Renner, W and Gruber, HJ and Curcio, F and Herrmann, M},
title = {The impact of moderate endurance exercise on cardiac telomeres and cardiovascular remodeling in obese rats.},
journal = {Frontiers in cardiovascular medicine},
volume = {9},
number = {},
pages = {1080077},
pmid = {36684585},
issn = {2297-055X},
abstract = {INTRODUCTION: Hypercaloric nutrition and physical inactivity cause obesity, a potential driver of myocardial apoptosis and senescence that may accelerate cardiac aging. Although physical activity reduces mortality, its impact on myocardial aging is insufficiently understood. Here we investigated the effects of a hypercaloric high-fat diet (HFD) and regular exercise training on cardiac cells telomeres and histomorphometric indices of cardiac aging.<br><br>METHODS: Ninety-six 4-months old female Sprague-Dawley rats were fed for 10 months normal (ND) or a HFD diet. Half of the animals in each group performed 30 min treadmill-running sessions on 5 consecutive days per week. At study end, cardiomyocyte cross-sectional area (CSA), interstitial collagen content, vascular density, apoptotic and senescent cells, relative telomere length (RTL), and expression of telomerase-reverse transcriptase (Tert) as marker of telomere-related senescence and apoptosis were analyzed.<br><br>RESULTS: Compared to ND, the HFD group developed obesity, higher CSA, lower capillary density and tended to have more apoptotic cardiomyocytes and interstitials cells. Myocardial RTL and the expression of Terf-1 and Terf-2 were comparable in sedentary HFD and ND animals. In the HFD group, regular moderate endurance exercise improved myocardial vascularization, but had no effect on CSA or apoptosis. Notably, the combination of exercise and HFD increased senescence when compared to sedentary ND or HFD, and reduced RTL when compared to exercise ND animals. Exercising HFD animals also showed a trend toward higher Tert expression compared to all other groups. In addition, exercise reduced Terf-1 expression regardless of diet.<br><br>CONCLUSION: HFD-induced obesity showed no effects on myocardial telomeres and induced only mild morphologic alterations. Summarized, long-term moderate endurance exercise partially reverses HFD-induced effects but may even trigger cardiac remodeling in the context of obesity.},
}
@article {pmid36674498,
year = {2023},
author = {Dhillon, VS and Deo, P and Thomas, P and Fenech, M},
title = {Low Magnesium in Conjunction with High Homocysteine and Less Sleep Accelerates Telomere Attrition in Healthy Elderly Australian.},
journal = {International journal of molecular sciences},
volume = {24},
number = {2},
pages = {},
pmid = {36674498},
issn = {1422-0067},
mesh = {Humans ; Aged ; *Magnesium ; Australia ; *Vitamin B 12 ; Folic Acid ; Telomere/genetics ; Sleep ; Micronutrients ; Homocysteine ; },
abstract = {The relationship between sleep and micronutrients, including magnesium, is implicated in its regulation. The effects of low magnesium and other micronutrients on sleep disruption and telomere loss are not well understood. The present study was carried out in 172 healthy elderly subjects from South Australia. Plasma micronutrients including magnesium were measured. Each participant provided information about their sleep hours (<7 h or ≥7 h). Lymphocyte telomere length (TL) was measured by real-time qPCR assay. Plasma magnesium level was significantly low in subjects who sleep less than 7 h (p = 0.0002). TL was significantly shorter in people who are low in magnesium and sleep less than 7 h (p = 0.01). Plasma homocysteine (Hcy) is negatively associated with magnesium (r = −0.299; p < 0.0001). There is a significant interaction effect of magnesium and Hcy on sleep duration (p = 0.04) and TL (p = 0.003). Our results suggest that inadequate magnesium levels have an adverse impact on sleep and telomere attrition rate in cognitively normal elderly people, and this may be exacerbated by low levels of vitamin B12 and folate that elevate Hcy concentration.},
}
@article {pmid36674427,
year = {2023},
author = {López-Armas, GDC and Ramos-Márquez, ME and Navarro-Meza, M and Macías-Islas, M&#xc1; and Saldaña-Cruz, AM and Zepeda-Moreno, A and Siller-López, F and Cruz-Ramos, JA},
title = {Leukocyte Telomere Length Predicts Severe Disability in Relapsing-Remitting Multiple Sclerosis and Correlates with Mitochondrial DNA Copy Number.},
journal = {International journal of molecular sciences},
volume = {24},
number = {2},
pages = {},
pmid = {36674427},
issn = {1422-0067},
support = {259639//University of Guadalajara/ ; },
mesh = {Humans ; *Multiple Sclerosis, Relapsing-Remitting/genetics ; *Multiple Sclerosis/genetics ; DNA, Mitochondrial/genetics ; DNA Copy Number Variations ; Leukocytes ; Telomere/genetics ; },
abstract = {Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease that affects the nervous system. Peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-CN) are potential biomarkers of neurological disability and neural damage. Our objective was to assess the LTL and mtDNA-CN in relapsing-remitting MS (RRMS). We included 10 healthy controls, 75 patients with RRMS, 50 of whom had an Expanded Disability Status Scale (EDSS) from 0 to 3 (mild to moderate disability), and 25 had an EDSS of 3.5 to 7 (severe disability). We use the Real-Time Polymerase Chain Reaction (qPCR) technique to quantify absolute LTL and absolute mtDNA-CN. ANOVA test show differences between healthy control vs. severe disability RRMS and mild-moderate RRMS vs. severe disability RRMS (p = 0.0130). LTL and mtDNA-CN showed a linear correlation in mild-moderate disability RRMS (r = 0.378, p = 0.007). Furthermore, we analyzed LTL between RRMS groups with a ROC curve, and LTL can predict severe disability (AUC = 0.702, p = 0.0018, cut-off < 3.0875 Kb, sensitivity = 75%, specificity = 62%), whereas the prediction is improved with a logistic regression model including LTL plus age (AUC = 0.762, p = 0.0001, sensitivity = 79.17%, specificity = 80%). These results show that LTL is a biomarker of disability in RRMS and is correlated with mtDNA-CN in mild-moderate RRMS patients.},
}
@article {pmid36669753,
year = {2023},
author = {Bountziouka, V and Nelson, CP and Wang, Q and Musicha, C and Codd, V and Samani, NJ},
title = {Dietary Patterns and Practices and Leucocyte Telomere Length: Findings from the UK Biobank.},
journal = {Journal of the Academy of Nutrition and Dietetics},
volume = {123},
number = {6},
pages = {912-922.e26},
doi = {10.1016/j.jand.2023.01.008},
pmid = {36669753},
issn = {2212-2672},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; BRC-1215-20010/DH_/Department of Health/United Kingdom ; SP/16/4/32697/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Humans ; Cross-Sectional Studies ; *Biological Specimen Banks ; *Diet, Mediterranean ; Telomere ; United Kingdom ; },
abstract = {BACKGROUND: Shorter telomere length (TL) is associated with risk of several age-related diseases and decreased life span, but the extent to which dietary patterns and practices associate with TL is uncertain.<br><br>OBJECTIVE: This study aimed to investigate the association of dietary patterns and practices and leucocyte TL (LTL).<br><br>DESIGN: This was a cross-sectional study.<br><br>PARTICIPANTS AND SETTING: Data collected voluntarily from up to 422,797 UK Biobank participants, during 2006-2010.<br><br>MAIN OUTCOME MEASURES: LTL was measured as a ratio of the telomere repeat number to a single-copy gene and was loge-transformed and standardized (z-LTL).<br><br>Adherence a priori to a Mediterranean-style diet was assessed through the MedDietScore. Principal component analysis was used to a posteriori extract the "Meat" and "Prudent" dietary patterns. Additional dietary practices considered were the self-reported adherence to "Vegetarian" diet, "Eating 5-a-day of fruit and vegetables" and "Abstaining from eggs/dairy/wheat/sugar." Associations between quintiles of dietary patterns or adherence to dietary practices with z-LTL were investigated through multivariable linear regression models (adjusted for demographic, lifestyle, and clinical characteristics).<br><br>RESULTS: Adherence to the "Mediterranean" and the "Prudent" patterns, was positively associated with LTL, with an effect magnitude in z-LTL of 0.020 SD and 0.014 SD, respectively, for the highest vs the lowest quintile of adherence to the pattern (both P values < 0.05). Conversely, a reversed association between quintile of the "Meat" pattern and LTL was observed, with z-LTL being on average shorter by 0.025 SD (P&#xa0;= 6.12&#xd7;10[-05]) for participants in the highest quintile of the pattern compared with the lowest quintile. For adherents to "5-a-day" z-LTL was on average longer by 0.027 SD (P&#xa0;= 5.36&#xd7;10[-09]), and for "abstainers," LTL was shorter by 0.016 SD (P&#xa0;= 2.51&#xd7;10[-04]). The association of LTL with a vegetarian diet was nonsignificant after adjustment for demographic, lifestyle, and clinical characteristics.<br><br>CONCLUSIONS: Several dietary patterns and practices associated with beneficial health effects are significantly associated with longer LTL. However, the magnitude of the association was small, and any clinical relevance is uncertain.},
}
@article {pmid36658792,
year = {2023},
author = {Park, HS and Im, K and Shin, DY and Yoon, SS and Kwon, S and Kim, SW and Lee, DS},
title = {Telomere integrated scoring system of myelodysplastic syndrome.},
journal = {Journal of clinical laboratory analysis},
volume = {37},
number = {3},
pages = {e24839},
pmid = {36658792},
issn = {1098-2825},
support = {NRF-2017R1A2A1A17069780//National Research Foundation of Korea/ ; NRF-2020R1A3B3079653//Ministry of Science and ICT(MSIT) of the Republic of Korea and the National Research Foundation of Korea/ ; },
mesh = {Humans ; Aged ; Retrospective Studies ; Prognosis ; *Myelodysplastic Syndromes ; Mutation ; Telomere ; },
abstract = {INTRODUCTION: Recently, multigene target sequencing is widely performed for the purpose of prognostic prediction and application of targeted therapy. Here, we proposed a new scoring system that encompasses gene variations, telomere length, and Revised International Prognostic Scoring System (IPSS-R) together in Asian myelodysplastic syndrome.<br><br>METHODS: We developed a new scoring model of these variables: age&#xa0;&#x2265;&#x2009;65&#x2009;years&#x2009;+&#x2009;IPSS-R score&#x2009;+&#x2009;ASXL1 mutation&#x2009;+&#x2009;TP53 mutation&#x2009;+&#x2009;Telomere length (<5.37). According to this new scoring system, patients were divided into four groups: very good score cutoff (&#x2264;3.0), good (3.0-4.5), poor (4.5-7.0), and very poor (>7.0).<br><br>RESULTS: The median OS was 170.1, 100.4, 46.0, and 12.0&#xa0;months for very good, good, poor, and very poor, retrospectively (p&#x2009;<&#x2009;0.001). Meanwhile, according to the conventional IPSS-R scoring system, the median OS was 141.3, 50.2, 93.0, 36.0, and 16.2&#xa0;months for very low, low, intermediate, high, and very high, retrospectively (p&#x2009;<&#x2009;0.001).<br><br>CONCLUSIONS: The newly developed model incorporating molecular variations and TL yielded more clear separations of the survival curves. By adding the presence of gene mutation and telomere length to the existing IPSS-R, its predictive ability can be further improved in myelodysplastic syndrome.},
}
@article {pmid36657619,
year = {2023},
author = {Armstrong, E and Boonekamp, J},
title = {Does oxidative stress shorten telomeres in vivo? A meta-analysis.},
journal = {Ageing research reviews},
volume = {85},
number = {},
pages = {101854},
doi = {10.1016/j.arr.2023.101854},
pmid = {36657619},
issn = {1872-9649},
mesh = {Humans ; *Oxidative Stress ; *Aging/genetics ; Telomere ; Telomere Shortening ; },
abstract = {Telomere attrition is considered a hallmark of ageing. Untangling the proximate causes of telomere attrition may therefore reveal important aspects about the ageing process. In a landmark paper in 2002 Thomas von Zglinicki demonstrated that oxidative stress accelerates telomere attrition in cell culture. In the next 20 years, oxidative stress became firmly embedded into modern theories of ageing and telomere attrition. However, a recent surge of in vivo studies reveals an inconsistent pattern questioning the unequivocal role of oxidative stress in telomere length and telomere attrition (henceforth referred to as telomere dynamics), in living organisms. Here we report the results of the first formal meta-analysis on the association between oxidative stress and telomere dynamics in vivo, representing 37 studies, 4969 individuals, and 18,677 correlational measurements. The overall correlation between oxidative stress markers and telomere dynamics was indistinguishable from zero (r = 0.027). This result was independent of the type of oxidative stress marker, telomere dynamic, or taxonomic group. However, telomere measurement method affected the analysis and the subset of TRF-based studies showed a significant overall correlation (r = 0.09), supporting the prediction that oxidative stress accelerates telomere attrition. The correlation was more pronounced in short-lived species and during the adult life phase, when ageing becomes apparent. We then performed an additional meta-analysis of interventional studies (n = 7) manipulating oxidative stress. This revealed a significant effect of treatment on telomere dynamics (d=0.36). Our findings provide new support for the hypothesis that oxidative stress causes telomere attrition in living organisms.},
}
@article {pmid36656928,
year = {2023},
author = {Ballinger, ML and Pattnaik, S and Mundra, PA and Zaheed, M and Rath, E and Priestley, P and Baber, J and Ray-Coquard, I and Isambert, N and Causeret, S and van der Graaf, WTA and Puri, A and Duffaud, F and Le Cesne, A and Seddon, B and Chandrasekar, C and Schiffman, JD and Brohl, AS and James, PA and Kurtz, JE and Penel, N and Myklebost, O and Meza-Zepeda, LA and Pickett, H and Kansara, M and Waddell, N and Kondrashova, O and Pearson, JV and Barbour, AP and Li, S and Nguyen, TL and Fatkin, D and Graham, RM and Giannoulatou, E and Green, MJ and Kaplan, W and Ravishankar, S and Copty, J and Powell, JE and Cuppen, E and van Eijk, K and Veldink, J and Ahn, JH and Kim, JE and Randall, RL and Tucker, K and Judson, I and Sarin, R and Ludwig, T and Genin, E and Deleuze, JF and , and Haber, M and Marshall, G and Cairns, MJ and Blay, JY and , and Thomas, DM and Tattersall, M and Neuhaus, S and Lewis, C and Tucker, K and Carey-Smith, R and Wood, D and Porceddu, S and Dickinson, I and Thorne, H and James, P and Ray-Coquard, I and Blay, JY and Cassier, P and Le Cesne, A and Duffaud, F and Penel, N and Isambert, N and Kurtz, JE and Puri, A and Sarin, R and Ahn, JH and Kim, JE and Ward, I and Judson, I and van der Graaf, W and Seddon, B and Chandrasekar, C and Rickar, R and Hennig, I and Schiffman, J and Randall, RL and Silvestri, A and Zaratzian, A and Tayao, M and Walwyn, K and Niedermayr, E and Mang, D and Clark, R and Thorpe, T and MacDonald, J and Riddell, K and Mar, J and Fennelly, V and Wicht, A and Zielony, B and Galligan, E and Glavich, G and Stoeckert, J and Williams, L and Djandjgava, L and Buettner, I and Osinki, C and Stephens, S and Rogasik, M and Bouclier, L and Girodet, M and Charreton, A and Fayet, Y and Crasto, S and Sandupatla, B and Yoon, Y and Je, N and Thompson, L and Fowler, T and Johnson, B and Petrikova, G and Hambridge, T and Hutchins, A and Bottero, D and Scanlon, D and Stokes-Denson, J and Génin, E and Campion, D and Dartigues, JF and Deleuze, JF and Lambert, JC and Redon, R and Ludwig, T and Grenier-Boley, B and Letort, S and Lindenbaum, P and Meyer, V and Quenez, O and Dina, C and Bellenguez, C and Le Clézio, CC and Giemza, J and Chatel, S and Férec, C and Le Marec, H and Letenneur, L and Nicolas, G and Rouault, K},
title = {Heritable defects in telomere and mitotic function selectively predispose to sarcomas.},
journal = {Science (New York, N.Y.)},
volume = {379},
number = {6629},
pages = {253-260},
doi = {10.1126/science.abj4784},
pmid = {36656928},
issn = {1095-9203},
support = {P50 CA272170/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; *Genetic Predisposition to Disease ; Genetic Variation ; Germ Cells ; Melanoma/genetics ; *Mitosis/genetics ; *Sarcoma/genetics ; Shelterin Complex/genetics ; *Telomere/genetics ; *Germ-Line Mutation ; },
abstract = {Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases and 3205 matched healthy elderly controls. Using an extreme phenotype design, a combined rare-variant burden and ontologic analysis identified two sarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes are linked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, whereas heritable defects in the shelterin complex link susceptibility to sarcoma, melanoma, and thyroid cancers. These studies indicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas.},
}
@article {pmid36652742,
year = {2023},
author = {Lv, BB and Yang, CL and Tan, ZX and Zheng, L and Li, MD and Jiang, YL and Liu, L and Tang, MM and Hua, DX and Yang, J and Xu, DX and Zhao, H and Fu, L},
title = {Association between cadmium exposure and pulmonary function reduction: Potential mediating role of telomere attrition in chronic obstructive pulmonary disease patients.},
journal = {Ecotoxicology and environmental safety},
volume = {251},
number = {},
pages = {114548},
doi = {10.1016/j.ecoenv.2023.114548},
pmid = {36652742},
issn = {1090-2414},
mesh = {Humans ; Cadmium/toxicity ; *Telomerase ; Forced Expiratory Volume ; *Pulmonary Disease, Chronic Obstructive ; Lung ; },
abstract = {BACKGROUND: Environmental cadmium (Cd) exposure is linked to pulmonary function injury in the general population. But, the association between blood Cd concentration and pulmonary function has not been investigated thoroughly in chronic obstructive pulmonary disease (COPD) patients, and the potential mechanisms are unclear.<br><br>METHODS: All eligible 789 COPD patients were enrolled from Anhui COPD cohort. Blood specimens and clinical information were collected. Pulmonary function test was conducted. The subunit of telomerase, telomerase reverse transcriptase (TERT), was determined through enzyme linked immunosorbent assay (ELISA). Blood Cd was measured via inductively coupled-mass spectrometer (ICP-MS).<br><br>RESULTS: Blood Cd was negatively and dose-dependently associated with pulmonary function. Each 1-unit increase of blood Cd was associated with 0.861&#xa0;L decline in FVC, 0.648&#xa0;L decline in FEV1, 5.938 % decline in FEV1/FVC %, and 22.098 % decline in FEV1 % among COPD patients, respectively. Age, current-smoking, self-cooking and higher smoking amount aggravated Cd-evoked pulmonary function decrease. Additionally, there was an inversely dose-response association between Cd concentration and TERT in COPD patients. Elevated TERT obviously mediated 29.53 %, 37.50 % and 19.48 % of Cd-evoked FVC, FEV1, and FEV1 % declines in COPD patients, respectively.<br><br>CONCLUSION: Blood Cd concentration is strongly associated with the decline of pulmonary function and telomerase activity among COPD patients. Telomere attrition partially mediates Cd-induced pulmonary function decline, suggesting an underlying mechanistic role of telomere attrition in pulmonary function decline from Cd exposure in COPD patients.},
}
@article {pmid36651908,
year = {2023},
author = {James, EN and Sagi-Kiss, V and Bennett, M and Mycielska, ME and Karen-Ng, LP and Roberts, T and Matta, S and Dokal, I and Bundy, JG and Parkinson, EK},
title = {Dyskeratosis Congenita Links Telomere Attrition to Age-Related Systemic Energetics.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {78},
number = {5},
pages = {780-789},
pmid = {36651908},
issn = {1758-535X},
support = {MR/P018440/1/MRC_/Medical Research Council/United Kingdom ; R452/1115/DMT_/The Dunhill Medical Trust/United Kingdom ; },
mesh = {Humans ; Animals ; Mice ; *Dyskeratosis Congenita/genetics/metabolism ; *Telomerase/genetics/metabolism ; *Diabetes Mellitus, Type 2 ; Telomere/genetics/metabolism ; Mutation ; Citrates ; Lactates ; Nuclear Proteins/metabolism ; Cell Cycle Proteins/genetics/metabolism ; },
abstract = {The underlying mechanisms of plasma metabolite signatures of human aging and age-related diseases are not clear but telomere attrition and dysfunction are central to both. Dyskeratosis congenita (DC) is associated with mutations in the telomerase enzyme complex (TERT, TERC, and DKC1) and progressive telomere attrition. We analyzed the effect of telomere attrition on senescence-associated metabolites in fibroblast-conditioned media and DC patient plasma. Samples were analyzed by gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry. We showed extracellular citrate was repressed by canonical telomerase function in vitro and associated with DC leukocyte telomere attrition in vivo, leading to the hypothesis that altered citrate metabolism detects telomere dysfunction. However, elevated citrate and senescence factors only weakly distinguished DC patients from controls, whereas elevated levels of other tricarboxylic acid cycle (TCA) metabolites, lactate, and especially pyruvate distinguished them with high significance. The DC plasma signature most resembled that of patients with loss of function pyruvate dehydrogenase complex mutations and that of older subjects but significantly not those of type 2 diabetes, lactic acidosis, or elevated mitochondrial reactive oxygen species. Additionally, our data are consistent with further metabolism of citrate and lactate in the liver and kidneys. Citrate uptake in certain organs modulates age-related disease in mice and our data have similarities with age-related disease signatures in humans. Our results have implications for the role of telomere dysfunction in human aging in addition to its early diagnosis and the monitoring of anti-senescence therapeutics, especially those designed to improve telomere function.},
}
@article {pmid36651296,
year = {2023},
author = {Storchova, R and Palek, M and Palkova, N and Veverka, P and Brom, T and Hofr, C and Macurek, L},
title = {Phosphorylation of TRF2 promotes its interaction with TIN2 and regulates DNA damage response at telomeres.},
journal = {Nucleic acids research},
volume = {51},
number = {3},
pages = {1154-1172},
pmid = {36651296},
issn = {1362-4962},
mesh = {DNA Damage ; Phosphorylation ; Proteomics ; *Shelterin Complex ; Telomere/metabolism ; *Telomere-Binding Proteins/metabolism ; *Telomeric Repeat Binding Protein 2 ; Humans ; },
abstract = {Protein phosphatase magnesium-dependent 1 delta (PPM1D) terminates the cell cycle checkpoint by dephosphorylating the tumour suppressor protein p53. By targeting additional substrates at chromatin, PPM1D contributes to the control of DNA damage response and DNA repair. Using proximity biotinylation followed by proteomic analysis, we identified a novel interaction between PPM1D and the shelterin complex that protects telomeric DNA. In addition, confocal microscopy revealed that endogenous PPM1D localises at telomeres. Further, we found that ATR phosphorylated TRF2 at S410 after induction of DNA double strand breaks at telomeres and this modification increased after inhibition or loss of PPM1D. TRF2 phosphorylation stimulated its interaction with TIN2 both in vitro and at telomeres. Conversely, induced expression of PPM1D impaired localisation of TIN2 and TPP1 at telomeres. Finally, recruitment of the DNA repair factor 53BP1 to the telomeric breaks was strongly reduced after inhibition of PPM1D and was rescued by the expression of TRF2-S410A mutant. Our results suggest that TRF2 phosphorylation promotes the association of TIN2 within the shelterin complex and regulates DNA repair at telomeres.},
}
@article {pmid36650155,
year = {2023},
author = {Tham, CY and Poon, L and Yan, T and Koh, JYP and Ramlee, MK and Teoh, VSI and Zhang, S and Cai, Y and Hong, Z and Lee, GS and Liu, J and Song, HW and Hwang, WYK and Teh, BT and Tan, P and Xu, L and Koh, AS and Osato, M and Li, S},
title = {High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {281},
pmid = {36650155},
issn = {2041-1723},
mesh = {Humans ; *Telomere/genetics ; *Shelterin Complex ; Aging ; },
abstract = {Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes. The progressive shortening of steady-state telomere length in normal human somatic cells is a promising biomarker for age-associated diseases. However, there remain substantial challenges in quantifying telomere length due to the lack of high-throughput method with nucleotide resolution for individual telomere. Here, we describe a workflow to capture telomeres using newly designed telobaits in human culture cell lines as well as clinical patient samples and measure their length accurately at nucleotide resolution using single-molecule real-time (SMRT) sequencing. Our results also reveal the extreme heterogeneity of telomeric variant sequences (TVSs) that are dispersed throughout the telomere repeat region. The presence of TVSs disrupts the continuity of the canonical (5'-TTAGGG-3')n telomere repeats, which affects the binding of shelterin complexes at the chromosomal ends and telomere protection. These findings may have profound implications in human aging and diseases.},
}
@article {pmid36649908,
year = {2023},
author = {Lambert-Lanteigne, P and Young, A and Autexier, C},
title = {Complex interaction network revealed by mutation of human telomerase 'insertion in fingers' and essential N-terminal domains and the telomere protein TPP1.},
journal = {The Journal of biological chemistry},
volume = {299},
number = {3},
pages = {102916},
pmid = {36649908},
issn = {1083-351X},
support = {PJT-166130//CIHR/Canada ; },
mesh = {Humans ; Cell Line ; Mutation ; *Telomerase/chemistry/metabolism ; Telomere/chemistry/metabolism ; *Telomere-Binding Proteins/chemistry/metabolism ; *Shelterin Complex/chemistry/metabolism ; },
abstract = {In the majority of human cancer cells, cellular immortalization depends on the maintenance of telomere length by telomerase. An essential step required for telomerase function is its recruitment to telomeres, which is regulated by the interaction of the telomere protein, TPP1, with the telomerase essential N-terminal (TEN) domain of the human telomerase reverse transcriptase, hTERT. We previously reported that the hTERT 'insertion in fingers domain' (IFD) recruits telomerase to telomeres in a TPP1-dependent manner. Here, we use hTERT truncations and the IFD domain containing mutations in conserved residues or premature aging disease-associated mutations to map the interactions between the IFD and TPP1. We find that the hTERT-IFD domain can interact with TPP1. However, deletion of the IFD motif in hTERT lacking the N-terminus and the C-terminal extension does not abolish interaction with TPP1, suggesting the IFD is not essential for hTERT interaction with TPP1. Several conserved residues in the central IFD-TRAP region that we reported regulate telomerase recruitment to telomeres, and cell immortalization compromise interaction of the hTERT-IFD domain with TPP1 when mutated. Using a similar approach, we find that the IFD domain interacts with the TEN domain but is not essential for intramolecular hTERT interactions with the TEN domain. IFD-TEN interactions are not disrupted by multiple amino acid changes in the IFD or TEN, thus highlighting a complex regulation of IFD-TEN interactions as suggested by recent cryo-EM structures of human telomerase.},
}
@article {pmid36649354,
year = {2023},
author = {Schneper, LM and Drake, AJ and Dunstan, T and Kotenko, I and Notterman, DA and Piyasena, C},
title = {Characteristics of salivary telomere length shortening in preterm infants.},
journal = {PloS one},
volume = {18},
number = {1},
pages = {e0280184},
pmid = {36649354},
issn = {1932-6203},
support = {R01 HD076592/HD/NICHD NIH HHS/United States ; },
mesh = {Infant ; Female ; Humans ; Infant, Newborn ; *Infant, Premature ; *Telomere Shortening ; Gestational Age ; Maternal Age ; Telomere/genetics ; },
abstract = {OBJECTIVE: To examine the association between gestational age, telomere length (TL) and rate of shortening in newborns.<br><br>STUDY DESIGN: Genomic DNA was isolated from buccal samples of 39 term infants at birth and one year and 32 preterm infants at birth, term-adjusted age (40 weeks post-conception) and age one-year corrected for gestational duration. Telomere length was measured by quantitative real-time PCR. Demographic and clinical data were collected during clinic or research visits and from hospital records. Socioeconomic status was estimated using the deprivation category (DEPCAT) scores derived from the Carstairs score of the subject's postal code.<br><br>RESULTS: At birth, preterm infants had longer telomeres than infants born at term. However, there was no difference in telomere length between preterm infants and term infants at one year of age, implying that the rate of telomere shortening was greater in pre-term than term infants. Interestingly, TL at age 40 weeks post-conception in preterm infants was significantly longer than term infant TL at birth, suggesting that time since conception is not the only factor that affects rate of shortening. Several factors, including sex, fetal growth restriction, maternal age, maternal booking body mass index (BMI), mother education level and DEPCAT score, also differed between the preterm and term groups.<br><br>CONCLUSIONS: Preterm infants have longer telomeres than term infants at birth. In the studied cohort, the rate of telomere shortening was greater in the premature group compared with the term infants. This finding agrees with previous studies using cord blood, suggesting that the longer TL in premature infants detected at birth do not persist and demonstrating that use of saliva DNA is acceptable for studies of telomere dynamics in infants. However, that the TL at age 40 weeks post-conception in preterm is longer than term infants at birth suggests that biological factors other than time since conception also affect rate of shortening.},
}
@article {pmid36643758,
year = {2023},
author = {Fu, A and Zheng, Y and Guo, J and Grierson, D and Zhao, X and Wen, C and Liu, Y and Li, J and Zhang, X and Yu, Y and Ma, H and Wang, Q and Zuo, J},
title = {Telomere-to-telomere genome assembly of bitter melon (Momordica charantia L. var. abbreviata Ser.) reveals fruit development, composition and ripening genetic characteristics.},
journal = {Horticulture research},
volume = {10},
number = {1},
pages = {uhac228},
pmid = {36643758},
issn = {2662-6810},
abstract = {Momordica charantia L. var. abbreviata Ser. (Mca), known as bitter gourd or bitter melon, is a Momordica variety with medicinal value and belongs to the Cucurbitaceae family. In view of the lack of genomic information on bitter gourd and other Momordica species and to promote Mca genomic research, we assembled a 295.6-Mb telomere-to-telomere (T2T) high-quality Mca genome with six gap-free chromosomes after Hi-C correction. This genome is anchored to 11 chromosomes, which is consistent with the karyotype information, and comprises 98 contigs (N50 of 25.4 Mb) and 95 scaffolds (N50 of 25.4 Mb). The Mca genome harbors 19 895 protein-coding genes, of which 45.59% constitute predicted repeat sequences. Synteny analysis revealed variations involved in fruit quality during the divergence of bitter gourd. In addition, assay for transposase-accessible chromatin by high-throughput sequencing and metabolic analysis showed that momordicosides and other substances are characteristic of Mca fruit pulp. A combined transcriptomic and metabolomic analysis revealed the mechanisms of pigment accumulation and cucurbitacin biosynthesis in Mca fruit peels, providing fundamental molecular information for further research on Mca fruit ripening. This report provides a new genetic resource for Momordica genomic studies and contributes additional insights into Cucurbitaceae phylogeny.},
}
@article {pmid36642039,
year = {2023},
author = {Zong, ZQ and Chen, SW and Wu, Y and Gui, SY and Zhang, XJ and Hu, CY},
title = {Ambient air pollution exposure and telomere length: a systematic review and meta-analysis.},
journal = {Public health},
volume = {215},
number = {},
pages = {42-55},
doi = {10.1016/j.puhe.2022.11.022},
pmid = {36642039},
issn = {1476-5616},
mesh = {Child ; Adult ; Female ; Pregnancy ; Humans ; Nitrogen Dioxide/analysis ; Environmental Exposure ; *Air Pollution/analysis ; *Air Pollutants/adverse effects/analysis ; Particulate Matter/adverse effects/analysis ; Telomere/chemistry ; },
abstract = {OBJECTIVE: This study aimed to provide evidence of the associations between pre- and post-birth and adulthood air pollution exposure with telomere length.<br><br>STUDY DESIGN: The databases of PubMed, Embase, and Web of Science were searched up to June 1st, 2022 in order to include relevant observational studies and perform a systematic review and meta-analysis.<br><br>METHODS: The random-effects meta-analysis was grouped by air pollutant and exposure window (pre- and post-birth and adulthood) to evaluate the summary effect estimate. Cochran's Q and I[2] statistics were used to evaluate the heterogeneity among the included studies. The quality of individual studies was evaluated using the national toxicology program/office of health assessment and translation risk of bias rating tool.<br><br>RESULTS: We identified 18 studies, covering 8506 children and 2263 adults from multiple countries. We found moderate evidence that particulate matter less than 2.5&#xa0;&#x3bc;m (PM2.5) exposure during the entire pregnancy (-0.043, 95% CI:&#xa0;-0.067,&#xa0;-0.018), nitrogen dioxide (NO2) exposure during the first trimester (-0.016, 95% confidence interval [CI]:&#xa0;-0.027,&#xa0;-0.005), long-term adulthood PM2.5 exposure were associated with shortening telomere length. Mild to high between-study heterogeneity was observed for the most tested air pollutant-telomere length combinations in different exposure windows.<br><br>CONCLUSIONS: This systematic review and meta-analysis provides the evidence which strongly supports that prenatal PM2.5 and NO2 exposures were related to reduced telomere length, while prenatal sulfur dioxide (SO2) and carbon monoxide (CO) exposures, childhood PM2.5, particulate matter less than 10&#xa0;&#x3bc;m (PM10), NO2 exposures and short-term adulthood PM2.5 and PM10 exposures were not associated with telomere length. Further high-quality studies are needed to elaborate our suggestive associations.},
}
@article {pmid36641077,
year = {2023},
author = {Siegel, SR and Ulrich, M and Logue, SF},
title = {Comparison qPCR study for selecting a valid single copy gene for measuring absolute telomere length.},
journal = {Gene},
volume = {860},
number = {},
pages = {147192},
doi = {10.1016/j.gene.2023.147192},
pmid = {36641077},
issn = {1879-0038},
mesh = {Humans ; Gene Dosage ; *Interferon-beta/genetics ; *Polymerase Chain Reaction/methods ; Reference Standards ; *Telomere/genetics ; *Telomere Shortening/genetics ; },
abstract = {Telomere shortening is a well-known biomarker for biological aging. A previous review of the methods used to measure telomere length (TL) noted how challenging it is to compare results from different studies using diverse methodological techniques. The most commonly used high throughput method for measuring average TL is the quantitative PCR (qPCR) method, where there are two protocols available; the relative TL and the absolute TL (aTL) method. All qPCR methods have similarities in that they use two different primer sets to measure the telomere repeat sequence (TTAGGG)n and a single copy gene region to calculate the average TL, (T/S) ratio. The difference between the relative TL and the aTL assay lies with the introduction of duplex oligomer standards to identify TL in kilobase pairs rather than using the traditional relative TL, T/S ratio method. Problems were noted using 36B4 (RPLP0), which was originally used as a suitable single copy gene qPCR assay. A previous aTL publication attempted to replace the 36B4 (RPLP0) single copy gene using the Interferon beta 1 gene (IFNB1) but results showed a lack of agreement with the TL results when compared to the DNAmTL assay. Here, we compare the two single copy gene assays previously used for the aTL assay and offer an alternative IFNB1 single copy gene assay without non-specific priming amplification to provide more consistent diploid copy number determination and a more robust and reproducible assay for measuring absolute TL.},
}
@article {pmid36636341,
year = {2023},
author = {Guo, YZ and Zhang, Y and Wang, Q and Yu, J and Wan, QH and Huang, J and Fang, SG},
title = {Alternative telomere maintenance mechanism in Alligator sinensis provides insights into aging evolution.},
journal = {iScience},
volume = {26},
number = {1},
pages = {105850},
pmid = {36636341},
issn = {2589-0042},
abstract = {Lifespan is a life-history trait that undergoes natural selection. Telomeres are hallmarks of aging, and shortening rate predicts species lifespan, making telomere maintenance mechanisms throughout different lifespans a worthy topic for study. Alligators are suitable for the exploration of anti-aging molecular mechanisms, because they exhibit low or even negligible mortality in adults and no significant telomere shortening. Telomerase reverse transcriptase (TERT) expression is absent in the adult Alligator sinensis, as in humans. Selection analyses on telomere maintenance genes indicated that ATM, FANCE, SAMHD1, HMBOX1, NAT10, and MAP3K4 experienced positive selection on A. sinensis. Repressed pleiotropic ATM kinase in A. sinensis suggests their fitness optimum shift. In ATM downstream, Alternative Lengthening of Telomeres (ALT)-related genes were clustered in a higher expression pattern in A. sinensis, which covers 10-15% of human cancers showing no telomerase activities. In summary, we demonstrated how telomere shortening, telomerase activities, and ALT contributed to anti-aging strategies.},
}
@article {pmid36635307,
year = {2023},
author = {Romero-Zamora, D and Hayashi, MT},
title = {A non-catalytic N-terminus domain of WRN prevents mitotic telomere deprotection.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {645},
pmid = {36635307},
issn = {2045-2322},
mesh = {Werner Syndrome Helicase/genetics/metabolism ; *Exodeoxyribonucleases/genetics ; *Telomeric Repeat Binding Protein 2 ; RecQ Helicases/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {Telomeric ends form a loop structure (T-loop) necessary for the repression of ATM kinase activation throughout the normal cell cycle. However, cells undergoing a prolonged mitotic arrest are prone to lose the T-loop, resulting in Aurora B kinase-dependent mitotic telomere deprotection, which was proposed as an anti-tumor mechanism that eliminates precancerous cells from the population. The mechanism of mitotic telomere deprotection has not been elucidated. Here, we show that WRN, a RECQ helicase family member, can suppress mitotic telomere deprotection independently of its exonuclease and helicase activities. Truncation of WRN revealed that N-terminus amino acids 168-333, a region that contains a coiled-coil motif, is sufficient to suppress mitotic telomere deprotection without affecting both mitotic Aurora B-dependent spindle checkpoint and ATM kinase activity. The suppressive activity of the WRN[168-333] fragment is diminished in cells partially depleted of TRF2, while WRN is required for complete suppression of mitotic telomere deprotection by TRF2 overexpression. Finally, we found that phosphomimetic but not alanine mutations of putative Aurora B target sites in the WRN[168-333] fragment abolished its suppressive effect. Our findings reveal a non-enzymatic function of WRN, which may be regulated by phosphorylation in cells undergoing mitotic arrest. We propose that WRN enhances the protective function of TRF2 to counteract the hypothetical pathway that resolves the mitotic T-loop.},
}
@article {pmid36634459,
year = {2023},
author = {Vulsteke, JB and Smith, V and Bonroy, C and Derua, R and Blockmans, D and De Haes, P and Vanderschueren, S and Lenaerts, JL and Claeys, KG and Wuyts, WA and Verschueren, P and Vanhandsaeme, G and Piette, Y and De Langhe, E and Bossuyt, X},
title = {Identification of new telomere- and telomerase-associated autoantigens in systemic sclerosis.},
journal = {Journal of autoimmunity},
volume = {135},
number = {},
pages = {102988},
doi = {10.1016/j.jaut.2022.102988},
pmid = {36634459},
issn = {1095-9157},
mesh = {Humans ; Autoantigens ; *Telomerase/metabolism ; *Scleroderma, Systemic ; Autoantibodies ; Telomere ; Nuclear Proteins/metabolism ; Cell Cycle Proteins/metabolism ; ATPases Associated with Diverse Cellular Activities/metabolism ; Carrier Proteins ; DNA Helicases/metabolism ; DNA-Binding Proteins/metabolism ; RNA-Binding Proteins ; },
abstract = {PURPOSE: In up to 20% of patients with systemic sclerosis (SSc) no known autoantibody specificity can be identified. Recently discovered autoantigens, such as telomeric repeat binding factor 1 (TERF1), as well as established autoantigens, like RuvBL1/2, are associated with telomere and telomerase biology. We aimed to identify new telomere- and telomerase-associated autoantigens in patients with SSc without known autoantibody specificity.<br><br>METHODS: Unlabelled protein immunoprecipitation combined with gel-free liquid chromatography-tandem mass spectrometry (IP-MS) was performed with sera of 106 patients with SSc from two tertiary referral centres that had a nuclear pattern on HEp-2 indirect immunofluorescence without previously identified autoantibody. Telomere- or telomerase-associated proteins or protein complexes precipitated by individual sera were identified. Candidate autoantigens were confirmed through immunoprecipitation-western blot (IP-WB). A custom Luminex xMAP assay for 5 proteins was evaluated with sera from persons with SSc (n&#xa0;=&#xa0;467), other systemic autoimmune rheumatic diseases (n&#xa0;=&#xa0;923), non-rheumatic disease controls (n&#xa0;=&#xa0;187) and healthy controls (n&#xa0;=&#xa0;199).<br><br>RESULTS: Eight telomere- and telomerase-associated autoantigens were identified in a total of 11 index patients, including the THO complex (n&#xa0;=&#xa0;3, all with interstitial lung disease and two with cardiac involvement), telomeric repeat-binding factor 2 (TERF2, n&#xa0;=&#xa0;1), homeobox-containing protein 1 (HMBOX1, n&#xa0;=&#xa0;2), regulator of chromosome condensation 1 (RCC1, n&#xa0;=&#xa0;1), nucleolar and coiled-body phosphoprotein 1 (NOLC1, n&#xa0;=&#xa0;1), dyskerin (DKC1, n&#xa0;=&#xa0;1), probable 28S rRNA (cytosine(4447)-C(5))-methyltransferase (NOP2, n&#xa0;=&#xa0;1) and nuclear valosin-containing protein-like (NVL, n&#xa0;=&#xa0;2). A Luminex xMAP assay for THO complex subunit 1 (THOC1), TERF2, NOLC1, NOP2 and NVL revealed high reactivity in all index patients, but also in other patients with SSc and disease controls. However, the reactivity by xMAP assay in these other patients was not confirmed by IP-WB.<br><br>CONCLUSION: IP-MS revealed key telomere- and telomerase-associated proteins and protein complexes as autoantigens in patients with SSc.},
}
@article {pmid36627320,
year = {2023},
author = {Sohn, I and Shin, C and Baik, I},
title = {Associations of green tea, coffee, and soft drink consumption with longitudinal changes in leukocyte telomere length.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {492},
pmid = {36627320},
issn = {2045-2322},
mesh = {Male ; Humans ; Female ; *Coffee ; *Tea ; Carbonated Beverages ; Leukocytes ; Telomere ; },
abstract = {Whether beverage consumption is associated with longitudinal observation of telomere length remains unclear. We evaluated the association of green tea, coffee, and soft drink consumption with 6-year changes in leukocyte telomere length (LTL). The study included 1952 participants who provided whole blood samples for LTL assays during the baseline (year 2011-2012) and follow-up (year 2017-2018) periods and reported baseline information on consumption of green tea, coffee, and soft drinks. Robust regression analysis was used to analyze the association adjusted for potential confounding variables. In the results, an inverse association between green tea consumption and LTL changes from baseline, which indicate telomere shortening, was found; regression coefficient [95% confidence interval] was - 0.097 [- 0.164, - 0.029] for participants who daily consumed at least 1 cup of green tea compared with non-consumers (p value = 0.006). This association was stronger among women (versus men) and younger participants aged 50-64 years (versus older). However, a positive association between soft drink consumption and LTL shortening was observed among women (p value < 0.05). Coffee consumption was not associated with LTL changes. These findings suggested that green tea consumption may be protective against telomere shortening reflecting biological aging whereas coffee and soft drink consumption may not.},
}
@article {pmid36617609,
year = {2023},
author = {Montoya, M and Uchino, BN},
title = {Social support and telomere length: a meta-analysis.},
journal = {Journal of behavioral medicine},
volume = {46},
number = {4},
pages = {556-565},
pmid = {36617609},
issn = {1573-3521},
support = {R01 HL137606/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; *Social Support ; *Telomere ; },
abstract = {Previous studies have shown that lower social support is associated with higher all-cause mortality (Holt-Lunstad et al. in PLoS ONE Medicine 7:e1000316, 2010). While social support has been associated with system-specific biological measures (e.g., cardiovascular), there is the need to elucidate more general biological mechanisms linking social support to health risk across a number of diseases. In this meta-analytic review, the link between social support and telomere length (Cawthon et al. in Lancet 361:393-395, 2003) was conducted based on the updated PRISMA guidelines (Page et al., 2021). Across 17 studies, higher social support was not significantly related to longer telomere length (Zr = 0.010, 95% CI [- 0.028, 0.047], p > 0.05). The confidence interval indicated that the bulk of plausible values were small to null associations. Little evidence for bias was found as shown by funnel plots and Kendall's Tau. Moderator analyses focusing on the measure of support, health of sample, age, type of assay specimen, and gender were not significant. In conclusion, this review showed no significant relationship between social support and telomere length and highlights important future directions.},
}
@article {pmid36612286,
year = {2022},
author = {Faugeras, E and Véronèse, L and Jeannin, G and Janicot, H and Bailly, S and Bay, JO and Pereira, B and Cayre, A and Penault-Llorca, F and Cachin, F and Merle, P and Tchirkov, A},
title = {Telomere Status of Advanced Non-Small-Cell Lung Cancer Offers a Novel Promising Prognostic and Predictive Biomarker.},
journal = {Cancers},
volume = {15},
number = {1},
pages = {},
pmid = {36612286},
issn = {2072-6694},
abstract = {Telomere length appears to correlate with survival in early non-small-cell lung cancer (NSCLC), but the prognostic impact of telomere status in advanced NSCLC remains undetermined. Our purpose was to evaluate telomere parameters as prognostic and predictive biomarkers in advanced NSCLC. In 79 biopsies obtained before treatment, we analyzed the telomere length and expression of TERT and shelterin complex genes (TRF1, TRF2, POT1, TPP1, RAP1, and TIN2), using quantitative PCR. Non-responders to first-line chemotherapy were characterized by shorter telomeres and low RAP1 expression (p = 0.0035 and p = 0.0069), and tended to show higher TERT levels (p = 0.058). In multivariate analysis, short telomeres were associated with reduced event-free (EFS, p = 0.0023) and overall survival (OS, p = 0.00041). TERT and TRF2 overexpression correlated with poor EFS (p = 0.0069 and p = 0.00041) and OS (p = 0.0051 and p = 0.007). Low RAP1 and TIN2 expression-levels were linked to reduced EFS (p = 0.00032 and p = 0.0069) and OS (p = 0.000051 and p = 0.02). Short telomeres were also associated with decreased survival after nivolumab therapy (p = 0.097). Evaluation of telomere status in advanced NSCLC emerges as a useful biomarker that allows for the selection of patient groups with different clinical evolutions, to establish personalized treatment.},
}
@article {pmid36612269,
year = {2022},
author = {García-Martínez, S and González-Gamo, D and Tesolato, SE and Barabash, A and de la Serna, SC and Domínguez-Serrano, I and Dziakova, J and Rivera, D and Torres, AJ and Iniesta, P},
title = {Telomere Length and Telomerase Activity in Subcutaneous and Visceral Adipose Tissues from Obese and Non-Obese Patients with and without Colorectal Cancer.},
journal = {Cancers},
volume = {15},
number = {1},
pages = {},
pmid = {36612269},
issn = {2072-6694},
support = {PI15/01199 and PI19/00073//Instituto de Salud Carlos III/ ; },
abstract = {To investigate the molecular mechanisms that link obesity and colorectal cancer (CRC), we analyzed parameters related to telomere function in subcutaneous and visceral adipose tissues (SAT and VAT), including subjects with and without CRC, who were classified according to their body mass index (BMI). Adipose tissues were obtained from 147 patients who had undergone surgery. A total of 66 cases corresponded to CRC patients, and 81 subjects were not affected by cancer. Relative telomere length was established by qPCR, and telomerase activity was determined by a method based on the telomeric repeat amplification protocol. Our results indicated longer telomeres in patients affected by CRC, both in SAT and VAT, when compared to the group of subjects without CRC. Tumor local invasion was associated with telomere length (TL) in SAT. Considering the BMI values, significant differences were found in the TL of both adipose tissues between subjects affected by CRC and those without cancer. Overweight subjects showed the greatest differences, with longer telomeres in the group of CRC patients, and a higher number of cases with telomerase reactivation in the VAT of subjects without cancer. In conclusion, parameters related to telomere function in adipose tissue could be considered as potential biomarkers in the evaluation of CRC and obesity.},
}
@article {pmid36609582,
year = {2023},
author = {Rolles, B and Ferreira, MSV and Vieri, M and Rheinwalt, KP and Schmitz, SM and Alizai, PH and Neumann, U and Brümmendorf, TH and Beier, F and Ulmer, TF and Tometten, M},
title = {Telomere length dynamics measured by flow-FISH in patients with obesity undergoing bariatric surgery.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {304},
pmid = {36609582},
issn = {2045-2322},
mesh = {Humans ; *Quality of Life ; Obesity/surgery ; *Bariatric Surgery ; Telomere ; },
abstract = {Obesity has negative effects on comorbidities, health-related quality of life and survival. Telomere length (TL) changes after bariatric surgery have been reported, but the studies are contradictory, and analyses using state-of-the art techniques for TL measurement, such as flow-FISH, are sparse. We measured TL dynamics via flow-FISH in patients undergoing bariatric surgery and compared their TL with 105 healthy individuals. Patients with obesity who underwent bariatric surgery were included. Lymphocyte and granulocyte absolute and age-adjusted (aa) TL were analyzed by flow-FISH before (preoperative cohort, n = 45) and after surgery (follow-up cohort, n = 35) at month 5.5 ± 3.9 (mean ± standard deviation [SD]). The initial lymphocyte aaTL was significantly shorter (-0.37 kb ± 0.18 kb, P = 0.045) in patients with obesity, while the granulocyte aaTL was not different from that in the healthy comparison population (0.28 kb ± 0.17 kb, P = 0.11). The telomere dynamics after surgery showed an increase in mean TL in both lymphocytes and granulocytes of patients with a pronounced BMI loss of ≥ 10 kg/m[2]. We did not find any association between TL increase after surgery and age, sex or the type of procedure selected for bariatric surgery. We confirmed that patients suffering from obesity have significantly shorter lymphocyte TL using flow-FISH. Along with and dependent on the degree of weight reduction after bariatric surgery, TL significantly increased in both lymphocytes and granulocytes after a mean of 5.5 months. Our results show that bariatric surgery affects not only body weight but also biomarkers of aging, such as TL.},
}
@article {pmid36607563,
year = {2023},
author = {Troxel, WM and Madrigano, J and Haas, AC and Dubowitz, T and Rosso, AL and Prather, AA and Ghosh-Dastidar, M and Weinstein, AM and Butters, MA and Presto, A and Gary-Webb, TL},
title = {Examining the Cross-sectional Association Between Neighborhood Conditions, Discrimination, and Telomere Length in a Predominantly African American Sample.},
journal = {Journal of racial and ethnic health disparities},
volume = {10},
number = {6},
pages = {3159-3167},
pmid = {36607563},
issn = {2196-8837},
support = {R01 HL131531/HL/NHLBI NIH HHS/United States ; R01-HL131531-S2/HL/NHLBI NIH HHS/United States ; R01 AG072652/AG/NIA NIH HHS/United States ; K23 AG076663/AG/NIA NIH HHS/United States ; AG072652/AG/NIA NIH HHS/United States ; NHLBI R01 HL131531/HL/NHLBI NIH HHS/United States ; R01 CA149105/CA/NCI NIH HHS/United States ; NHLBI R01 HL131531/HL/NHLBI NIH HHS/United States ; R01-HL131531-S2/HL/NHLBI NIH HHS/United States ; AG072652/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Humans ; *Aging ; *Black or African American ; Cross-Sectional Studies ; Particulate Matter ; *Telomere ; *Neighborhood Characteristics ; *Racism ; Air Pollution ; },
abstract = {Disproportionate exposure to adverse neighborhood conditions and greater discrimination may contribute to health disparities among African Americans (AAs). We examined whether adverse neighborhood conditions, alone or in conjunction with discrimination, associate with shorter leukocyte telomere length among a predominantly AA cohort. The sample included 200 residents from two low-income neighborhoods (96% AA; mean age = 67 years). Perceived neighborhood conditions and discrimination were surveyed in 2018, and objective neighborhood conditions (total crime rate, neighborhood walkability, ambient air pollution (PM2.5, black carbon)) were collected in 2017/2018. Relative telomere length (T/S; ratio of telomeric DNA to a single-gene copy) was assessed from blood samples. Linear regression models estimated the main effects of each neighborhood condition and discrimination and their interactions on the T/S ratio. Less walkable neighborhoods were associated with shorter telomeres. Higher air pollution (PM2.5) was associated with shorter telomeres among those experiencing greater discrimination. Findings highlight the importance of understanding the intersecting influences of historic and contemporary sources of systemic racism and how they contribute to accelerated aging among adults.},
}
@article {pmid36607418,
year = {2023},
author = {Hassanpour, H and Farhadi, N and Bahadoran, S and Akbari, MR},
title = {Cardiac telomere attrition following changes in the expression of shelterin genes in pulmonary hypertensive chickens.},
journal = {British poultry science},
volume = {64},
number = {3},
pages = {370-376},
doi = {10.1080/00071668.2022.2163877},
pmid = {36607418},
issn = {1466-1799},
mesh = {Animals ; *Chickens/genetics/metabolism ; *Telomere-Binding Proteins/genetics/metabolism ; Shelterin Complex ; Telomere/metabolism ; Heart ; },
abstract = {1. The alterations of relative telomere length and expression of shelterin genes (TRF1, TRF2, RAP1, POT1, and TPP1) were evaluated from the chickens' right heart ventricle in the early and last stages of cold-induced pulmonary hypertension (PHS) at 21 and 42 d of age.2. The relative telomere length in the right ventricular tissues was significantly shorter in the PHS group of broilers than in the control group at 42 d, but did not statistically change at 21 d of age. There was a significant negative correlation between relative telomere length and RV:TV ratio in the broilers at 42 d of age.3. The relative expression of POT1, RAP1 and TPP1 genes in the right ventricular tissues was significantly lower in the PHS group than in the control group at 21 d. The relative expression of the TRF2 gene was only higher in the PHS group of broilers than control at 42 d. The mRNA level of the TRF2 gene exhibited a significant positive correlation with RV:TV ratio at 42 d.4. It was concluded that most shelterin genes are dysregulated in the early stage of PHS (right ventricular hypertrophy) while telomere attrition occurs only at the last stage (heart dilation/failure).},
}
@article {pmid36605550,
year = {2022},
author = {Ask, TF and Sütterlin, S},
title = {Prefrontally modulated vagal neuroimmunomodulation is associated with telomere length.},
journal = {Frontiers in neuroscience},
volume = {16},
number = {},
pages = {1063162},
pmid = {36605550},
issn = {1662-4548},
abstract = {BACKGROUND: Accumulated senescent cells are proposed to be one of the main drivers of age-related pathology such as dementia and cancer through disruption of tissue structure and function. We recently proposed the Neuro-Immuno-Senescence Integrative Model (NISIM), which relates prefrontally modulated vagal tone and subsequent balance between vagal and sympathetic input to the spleen to inflammatory responses leading to generation of reactive oxygen species and oxidative telomere damage.<br><br>AIM: In this study, we assess inflammation as a mediator in the relationship between prefrontally modulated vagal tone and leukocyte telomere length (LTL). We also assess the relationship between a recently proposed index of vagal neuroimmunomodulation (vagal tone/inflammation ratio; NIM index) and telomere length.<br><br>METHODS: This study uses participant data from a large nationally representative longitudinal study since 1974 with a total of 45,000 Norwegian residents so far. A sub-sample of 131 participants from which ultrashort recordings (30 s) of vagal tone, c reactive protein, and LTL could be obtained were included in the study. Relationships were analyzed with Pearson's correlations and hierarchical multiple linear regression using either vagal tone and CRP or the NIM index to predict telomere length.<br><br>RESULTS: Vagal tone was a significant positive predictor of telomere length but this was not mediated by c reactive protein, even after controlling for confounders. The NIM index was a significant positive predictor of telomere length, also when controlling for confounders. In a follow-up analysis simultaneously comparing telomere length between groups with high and low values of vagal tone, and between groups with high and low NIM index values, telomere length was only significantly different between NIM index groups.<br><br>CONCLUSION: This is the first study suggesting that prefrontally modulated vagal neuroimmunomodulation is associated with telomere length thus supporting the NISIM. Results indicate that the NIM index is a more sensitive indicator of vagal neuroimmunomodulation than vagal tone and CRP in isolation.},
}
@article {pmid36604719,
year = {2023},
author = {Liu, Q and Li, Z and Huang, L and Zhou, D and Fu, J and Duan, H and Wang, Z and Yang, T and Zhao, J and Li, W and Liu, H and Ma, F and Sun, C and Wang, G and Du, Y and Zhang, M and Chen, Y and Huang, G},
title = {Telomere and mitochondria mediated the association between dietary inflammatory index and mild cognitive impairment: A prospective cohort study.},
journal = {Immunity &amp; ageing : I &amp; A},
volume = {20},
number = {1},
pages = {1},
pmid = {36604719},
issn = {1742-4933},
abstract = {BACKGROUND: Diet and chronic inflammation might play a major role in the pathogenesis of mild cognitive impairment (MCI). In addition, peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) might mediate the relationship between inflammation and MCI risk. The purpose of the present study is to evaluate whether inflammatory potential of diet assessed by dietary inflammatory index (DII), chronic inflammation, peripheral blood LTL, and mtDNAcn were associated with the risk of MCI.<br><br>RESULTS: A population-based cohort study was conducted with a total of 2944 participants. During a median follow-up of 2 years, 438 (14.90%) individuals were new-onset MCI. After adjustment, a higher score of DII (hazard ratio [HR]: 1.056, 95% CI: 1.005, 1.109), a higher log systemic immune inflammation index (SII) (HR: 1.333, 95% CI: 1.089, 1.633) and log system inflammation response index (SIRI) (HR: 1.487, 95% CI: 1.024, 2.161) predicted elevated risk of MCI. An increased mtDNAcn (HR: 0.843, 95% CI: 0.712, 0.997), but not LTL, predicted a decreased risk of MCI. Negative associations of log SII with LTL (&#x3b2;:-0.359, 95% CI: -0.445, -0.273) and mtDNAcn (&#x3b2;:-0.048, 95% CI: -0.090, -0.006) were found. Additionally, negative associations of log SIRI with LTL (&#x3b2;: -0.035, 95% CI: -0.052, -0.017) and mtDNAcn (&#x3b2;:-0.136, 95% CI: -0.216, -0.056) were also found. Path analysis suggested that SIRI, LTL, and mtDNAcn, in series, have mediation roles in the association between DII score and MCI risk.<br><br>CONCLUSIONS: Higher DII, SII, and SIRI might predict a greater risk of MCI, while a longer LTL and an increased mtDNAcn were linked to a reduced risk of MCI among the older population. LTL and mtDNAcn could play mediation roles in the association between DII and MCI risk.},
}
@article {pmid36603485,
year = {2023},
author = {Duan, X and Huang, T and Zhang, D and Wei, Y and Li, L and Yao, W and Cui, L and Zhou, X and Yang, Y and Wang, W and Zhao, J},
title = {Effect and interaction of TNKS genetic polymorphisms and environmental factors on telomere damage in COEs-exposure workers.},
journal = {Ecotoxicology and environmental safety},
volume = {250},
number = {},
pages = {114489},
doi = {10.1016/j.ecoenv.2022.114489},
pmid = {36603485},
issn = {1090-2414},
mesh = {Humans ; *Coke/adverse effects ; DNA Damage ; *Occupational Exposure/adverse effects/analysis ; *Polycyclic Aromatic Hydrocarbons/toxicity/analysis ; Polymorphism, Genetic ; *Tankyrases/genetics ; Telomere/genetics ; },
abstract = {Coke oven emissions (COEs) contain many carcinogenic polycyclic aromatic hydrocarbons (PAHs). Telomere damage is an early biological marker reflecting long-term COEs-exposure. Whereas, whether the genetic variations of telomere-regulated gene TNKS have an effect on the COEs-induced telomere damage is unknown. So we detected the environmental exposure levels, relative telomere length (RTL), and TNKS genetic polymorphisms among 544 COEs-exposure workers and 238 healthy participants. We found that the RTL of the wild homozygous GG genotype in rs1055328 locus was statistically shorter compared with the CG+CC genotype for the healthy participants using covariance analysis(P = 0.008). In the Generalized linear model (GLM) analysis, TNKS rs1055328 GG could accelerate telomere shortening (P = 0.011); and the interaction between TNKS rs1055328 GG and COEs-exposure had an effect on RTL (P = 0.002). In conclusion, this study was the first to discover the role of TNKS rs1055328 locus in COEs-induced telomere damage, and proved that chromosomal damage was a combined consequence of environmental and genetic factors.},
}
@article {pmid36601105,
year = {2022},
author = {Hu, J and Song, J and Chen, Z and Yang, J and Shi, Q and Jin, F and Pang, Q and Chang, X and Tian, Y and Luo, Y and Chen, L},
title = {Reverse causal relationship between periodontitis and shortened telomere length: Bidirectional two-sample Mendelian random analysis.},
journal = {Frontiers in immunology},
volume = {13},
number = {},
pages = {1057602},
pmid = {36601105},
issn = {1664-3224},
mesh = {Humans ; Causality ; *Chronic Periodontitis ; *Genome-Wide Association Study ; Telomere/genetics ; Telomere Shortening ; },
abstract = {BACKGROUND: Observational studies have demonstrated a link between shortened telomere lengths(TL) and chronic periodontitis. However, whether the shortened TL is the cause or the result of periodontitis is unknown.Therefore, our objective was to investigate a bidirectional causal relationship between periodontitis and TL using a two-sample Mendel randomized (MR) study.<br><br>METHODS: A two-sample bidirectional MR analysis using publicly available genome-wide association study (GWAS) data was used. As the primary analysis, inverse variance weighting (IVW) was employed. To identify pleiotropy, we used leave-one-out analysis, MR-Egger, Weighted median, Simple mode, Weighted mode, and MR pleiotropy residual sum and outlier (MR-PRESSO).<br><br>RESULTS: In reverse MR results, a genetic prediction of short TL was causally associated with a higher risk of periodontitis (IVW: odds ratio [OR]: 1.0601, 95% confidence interval [CI]: 1.0213 to 1.1002; P =0.0021) and other complementary MR methods. In the forward MR analysis, periodontitis was shown to have no significant effect on TL (IVW: p = 0.7242), with consistent results for the remaining complementary MR. No pleiotropy was detected in sensitivity analysis (all P>0.05).<br><br>CONCLUSION: Our MR studies showed a reverse causal relationship, with shorten TL being linked to a higher risk of periodontitis, rather than periodontitis shorten that TL. Future research is needed to investigate the relationship between cell senescence and the disease.},
}
@article {pmid36592269,
year = {2023},
author = {Seki, Y and Aczel, D and Torma, F and Jokai, M and Boros, A and Suzuki, K and Higuchi, M and Tanisawa, K and Boldogh, I and Horvath, S and Radak, Z},
title = {No strong association among epigenetic modifications by DNA methylation, telomere length, and physical fitness in biological aging.},
journal = {Biogerontology},
volume = {24},
number = {2},
pages = {245-255},
pmid = {36592269},
issn = {1573-6768},
mesh = {Humans ; Aged ; Aged, 80 and over ; *DNA Methylation ; *Aging/physiology ; Epigenesis, Genetic ; Physical Fitness ; Telomere ; },
abstract = {Cellular senescence is greatly accelerated by telomere shortening, and the steps forward in human aging are strongly influenced by environmental and lifestyle factors, whether DNA methylation (DNAm) is affected by exercise training, remains unclear. In the present study, we investigated the relationships between physiological functions, maximal oxygen uptake (VO2max), vertical jump, working memory, telomere length (TL) assessed by RT-PCR, DNA methylation-based estimation of TL (DNAmTL), and DNA methylation-based biomarkers of aging of master rowers (N = 146) and sedentary subjects (N = 95), aged between 37 and 85 years. It was found that the TL inversely correlated with chronological age. We could not detect an association between telomere length and VO2max, vertical jump, and working memory by RT-PCR method, while these physiological test results showed a correlation with DNAmTL. DNAmGrimAge and DNAmPhenoAge acceleration were inversely associated with telomere length assessed by both methods. It appears that there are no strong beneficial effects of exercise or physiological fitness on telomere shortening, however, the degree of DNA methylation is associated with telomere length.},
}
@article {pmid36591268,
year = {2022},
author = {Lv, Z and Cui, J and Zhang, J},
title = {Associations between serum urate and telomere length and inflammation markers: Evidence from UK Biobank cohort.},
journal = {Frontiers in immunology},
volume = {13},
number = {},
pages = {1065739},
pmid = {36591268},
issn = {1664-3224},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; Biological Specimen Banks ; Biomarkers/blood ; Genome-Wide Association Study ; *Hyperuricemia/blood/genetics/immunology ; *Inflammation/blood/genetics/immunology ; Insulin-Like Growth Factor I ; Interleukin-6 ; *Telomere/genetics/immunology ; Tumor Necrosis Factor-alpha ; United Kingdom ; *Uric Acid/blood/immunology ; *Gout/blood/immunology ; },
abstract = {OBJECTIVE: Hyperuricemia and gout have become gradually more common. The effect of serum urate on organism aging and systematic inflammation is not determined. This study aims to evaluate whether serum urate is causally associated with cellular aging markers and serum inflammation markers.<br><br>METHODS: A Mendelian randomization study was performed on summary-level data from the largest published genome-wide association studies. Single nucleotide polymorphisms with a genome-wide significance level were selected as instrumental variables for leukocyte telomere length (LTL), and serum soluble makers of inflammation (CRP, IL-6, TNF-&#x3b1;, and IGF-1). Standard inverse variance weighted (IVW) method was used as the primary statistical method. The weighted median, MR-Egger regression, and MR-PRESSO methods were used for sensitivity analysis.<br><br>RESULTS: An inverse causal association of genetically predicted serum urate levels and LTL was found using IVW method (OR: 0.96, 95%CI 0.95, 0.97; &#x3b2;=-0.040; SE=0.0072; P=4.37&#xd7;10[-8]). The association was also supported by MR results using MR-Egger method and weighted median method. The MR-PRESSO analysis and leave-one-out sensitivity analysis supported the robustness of the combined results. In terms of other aging-related serum biomarkers, there was no evidence supporting a causal effect of serum urate on CRP, IL-6, TNF-&#x3b1;, or IGF-1 levels.<br><br>CONCLUSIONS: Serum urate levels are negatively associated with telomere length but are not associated with serum soluble indicators of inflammation. Telomere length may be a critical marker that reflects urate-related organismal aging and may be a mechanism in the age-related pathologies and mortality caused by hyperuricemia.},
}
@article {pmid36589292,
year = {2022},
author = {Al Khleifat, A and Iacoangeli, A and Jones, AR and van Vugt, JJFA and Moisse, M and Shatunov, A and Zwamborn, RAJ and van der Spek, RAA and Cooper-Knock, J and Topp, S and van Rheenen, W and Kenna, B and Van Eijk, KR and Kenna, K and Byrne, R and López, V and Opie-Martin, S and Vural, A and Campos, Y and Weber, M and Smith, B and Fogh, I and Silani, V and Morrison, KE and Dobson, R and van Es, MA and McLaughlin, RL and Vourc'h, P and Chio, A and Corcia, P and de Carvalho, M and Gotkine, M and Panades, MP and Mora, JS and Shaw, PJ and Landers, JE and Glass, JD and Shaw, CE and Basak, N and Hardiman, O and Robberecht, W and Van Damme, P and van den Berg, LH and Veldink, JH and Al-Chalabi, A},
title = {Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data.},
journal = {Frontiers in cellular neuroscience},
volume = {16},
number = {},
pages = {1050596},
pmid = {36589292},
issn = {1662-5102},
support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; R56 NS073873/NS/NINDS NIH HHS/United States ; R01 NS073873/NS/NINDS NIH HHS/United States ; MC_PC_17214/MRC_/Medical Research Council/United Kingdom ; 171/ALZS_/Alzheimer's Society/United Kingdom ; MCLAUGHLIN/OCT15/957-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive weakness of voluntary muscles, with death following from neuromuscular respiratory failure, typically within 3 to 5 years. There is a strong genetic contribution to ALS risk. In 10% or more, a family history of ALS or frontotemporal dementia is obtained, and the Mendelian genes responsible for ALS in such families have now been identified in about 50% of cases. Only about 14% of apparently sporadic ALS is explained by known genetic variation, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication, differ between sexes, and shorten naturally with age. Sex and age are risk factors for ALS and we therefore investigated telomere length in ALS.<br><br>METHODS: Samples were from Project MinE, an international ALS whole genome sequencing consortium that includes phenotype data. For validation we used donated brain samples from motor cortex from people with ALS and controls. Ancestry and relatedness were evaluated by principal components analysis and relationship matrices of DNA microarray data. Whole genome sequence data were from Illumina HiSeq platforms and aligned using the Isaac pipeline. TelSeq was used to quantify telomere length using whole genome sequence data. We tested the association of telomere length with ALS and ALS survival using Cox regression.<br><br>RESULTS: There were 6,580 whole genome sequences, reducing to 6,195 samples (4,315 from people with ALS and 1,880 controls) after quality control, and 159 brain samples (106 ALS, 53 controls). Accounting for age and sex, there was a 20% (95% CI 14%, 25%) increase of telomere length in people with ALS compared to controls (p = 1.1 &#xd7; 10[-12]), validated in the brain samples (p = 0.03). Those with shorter telomeres had a 10% increase in median survival (p = 5.0&#xd7;10[-7]). Although there was no difference in telomere length between sporadic ALS and familial ALS (p=0.64), telomere length in 334 people with ALS due to expanded C9orf72 repeats was shorter than in those without expanded C9orf72 repeats (p = 5.0&#xd7;10[-4]).<br><br>DISCUSSION: Although telomeres shorten with age, longer telomeres are a risk factor for ALS and worsen prognosis. Longer telomeres are associated with ALS.},
}
@article {pmid38426924,
year = {2023},
author = {Timina, MF and Pavlova, LE and Kirgintsev, RM and Agumava, AA},
title = {[Changes in telomere length in leukocytes of male rhesus macaques of different ages.].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {36},
number = {6},
pages = {859-863},
pmid = {38426924},
issn = {1561-9125},
mesh = {Humans ; Animals ; Male ; *Aging/genetics ; Macaca mulatta/genetics ; Phylogeny ; *Telomere/genetics ; Leukocytes ; DNA ; },
abstract = {Telomeres are specialized terminal sections of chromosomes that ensure the stability of the latter. DNA duplication during cell division is associated with telomere shortening due to the phenomenon of terminal underreplication. As cells divide, shortening of telomere length is considered to be one of the most important causes of cell aging. Estimation of telomere length still remains the subject of scientific research in gerontology and it is not used in clinical practice. Most often, rodents are used as a model object for studying the aging process, but the neuroendocrine mechanisms that influence, among other things, the regulation of the aging process differ in rodents and humans. The model objects closest in phylogenetic relation to humans are monkeys. In particular, Rhesus macaques is one of the representatives of the Old World most often used in biomedical research. However, data on age-related changes in telomere length in monkeys are extremely scarce. We studied the absolute average length of telomeres in DNA from blood leukocytes of 29 clinically healthy male rhesus monkeys aged from 4 to 24 years using quantitative PCR-method. The data obtained did not correspond to the normal distribution and the correlation analysis showed the absence of a significant dependence of telomere length on the age of the animals (rs=0,27; p>0,05). Thus, our study does not confirm the dependence of changes in the average length of telomeres of blood leukocytes with age.},
}
@article {pmid36586020,
year = {2023},
author = {Liu, Y and Song, L and Wu, M and Bi, J and Wang, L and Liu, Q and Xiong, C and Cao, Z and Xu, S and Wang, Y},
title = {Association between rare earth element exposure during pregnancy and newborn telomere length.},
journal = {Environmental science and pollution research international},
volume = {30},
number = {13},
pages = {38751-38760},
pmid = {36586020},
issn = {1614-7499},
support = {82073660//National Natural Science Foundation of China/ ; 82003479//National Natural Science Foundation of China/ ; 2019M662646//Postdoctoral Research Foundation of China/ ; 2020T130220//Postdoctoral Research Foundation of China/ ; },
mesh = {Pregnancy ; Infant, Newborn ; Female ; Humans ; *Maternal Exposure ; Cohort Studies ; Parturition ; Mothers ; *Metals, Rare Earth ; Telomere ; China ; },
abstract = {Telomere length (TL) is considered a marker of biological aging and lifetime health, and some epidemiological studies report that the environmental exposures may influence TL at birth. We aimed to investigate the associations between prenatal rare earth elements (REE) exposure and newborn TL. A total of 587 mother-newborn pairs were recruited during 2013 to 2015 in Wuhan, China. Maternal urinary concentrations of REE collected during three trimesters were measured by inductively coupled plasma mass spectrometry. Quantitative real-time polymerase chain reaction was used to measure relative cord blood TL. The trimester-specific associations between prenatal REE exposure and cord blood TL were evaluated using multiple informant models. Weighted quantile sum regression was used to estimate the mixture effect of urinary REE on cord blood TL. After adjustment for potential confounders, per doubling of urinary REE (Dy, Yb, Pr, Nd, and Tm) concentrations (μg/g creatinine) during the second trimester was respectively associated with 1.94% (95% CI 0.19%, 3.72%), 2.10% (95% CI 0.31%, 3.92%), 2.11% (95% CI 0.35%, 3.89%), 2.08% (95% CI 0.01%, 4.20%), and 1.38% (95% CI 0.09%, 2.70%) increase in cord blood TL. Furthermore, exposure to the mixture of REE during the second trimester was also significantly associated with increased cord blood TL (percent change 1.20%, 95% CI 0.30%, 2.11%). However, these associations were not statistically significant in the first and third trimesters. This study provides new evidence on the potential effect of prenatal REE exposure on the initial (newborn) setting of offspring's telomere biology. Further epidemiological studies are warranted to confirm our findings.},
}
@article {pmid36585257,
year = {2023},
author = {Mei, Q and Yu, Q and Li, X and Chen, J and Yu, X},
title = {Regulation of telomere silencing by the core histones-autophagy-Sir2 axis.},
journal = {Life science alliance},
volume = {6},
number = {3},
pages = {},
pmid = {36585257},
issn = {2575-1077},
mesh = {*Histones/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; Gene Silencing ; Saccharomyces cerevisiae/genetics/metabolism ; Telomere/genetics/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Sirtuin 2/genetics/metabolism ; Histone-Lysine N-Methyltransferase/metabolism ; },
abstract = {Telomeres contain compacted heterochromatin, and genes adjacent to telomeres are subjected to transcription silencing. Maintaining telomere structure integrity and transcription silencing is important to prevent the occurrence of premature aging and aging-related diseases. How telomere silencing is regulated during aging is not well understood. Here, we find that the four core histones are reduced during yeast chronological aging, leading to compromised telomere silencing. Mechanistically, histone loss promotes the nuclear export of Sir2 and its degradation by autophagy. Meanwhile, reducing core histones enhances the autophagy pathway, which further accelerates autophagy-mediated Sir2 degradation. By screening the histone mutant library, we identify eight histone mutants and one histone modification (histone methyltransferase Set1-catalyzed H3K4 trimethylation) that regulate telomere silencing by modulating the core histones-autophagy-Sir2 axis. Overall, our findings reveal core histones and autophagy as causes of aging-coupled loss of telomere silencing and shed light on dynamic regulation of telomere structure during aging.},
}
@article {pmid36582083,
year = {2022},
author = {Dondoladze, K and Nikolaishvili, M and Museliani, T and Jikia, G},
title = {EFFECT OF RADIATION ON AGING PROCESSES AND TELOMERE LENGTH.},
journal = {Problemy radiatsiinoi medytsyny ta radiobiolohii},
volume = {27},
number = {},
pages = {107-119},
doi = {10.33145/2304-8336-2022-27-107-119},
pmid = {36582083},
issn = {2313-4607},
mesh = {*Antioxidants ; *Cellular Senescence/genetics ; Oxidative Stress ; Telomere/genetics ; },
abstract = {Telomeres are the ending areas of chromosomes - protective «caps» that ensure the stability of chromosomes. Telomere shortening is one of the most important biological signs of aging and is involved in cellular aging and the «mitotic clock» mechanism. One of the known mechanisms of the impact of radiation on the aging process is damage to telomeres by free radicals. Oxidative stress has a toxic effect on telomere length. The increase in free radicals occurs under the action of both ionizing and nonionizing radiation, although antioxidant mechanisms are often able to neutralize harmful free radicals. Low doses of nonionizing and ionizing radiation even cause the activation of antioxidant systems, however, when the body is exposed to radiation at a high dose or for a long time, or if pathological processes with oxidative stress occur in the body, damage to cells becomes more noticeable, and aging processes accelerate. Maintaining telomere length and a normal rate of aging is important for health. In this review, we want to discuss the role of ionizing and nonionizing radiation in cellular aging, in particular, in the shortening of telomere length.},
}
@article {pmid36579443,
year = {2023},
author = {Clé, DV and Catto, LFB and Gutierrez-Rodrigues, F and Donaires, FS and Pinto, AL and Santana, BA and Darrigo, LG and Valera, ET and Koenigkam-Santos, M and Baddini-Martinez, J and Young, NS and Martinez, EZ and Calado, RT},
title = {Effects of nandrolone decanoate on telomere length and clinical outcome in patients with telomeropathies: a prospective trial.},
journal = {Haematologica},
volume = {108},
number = {5},
pages = {1300-1312},
pmid = {36579443},
issn = {1592-8721},
mesh = {Humans ; In Situ Hybridization, Fluorescence ; *Lung Diseases, Interstitial ; Nandrolone Decanoate ; Prospective Studies ; Retrospective Studies ; Telomere ; },
abstract = {Androgens have been reported to elongate telomeres in retrospective and prospective trials with patients with telomeropathies, mainly with bone marrow failure. In our single-arm prospective clinical trial (clinicaltrials gov. Identifier: NCT02055456), 17 patients with short telomeres and/or germline pathogenic variants in telomere biology genes associated with at least one cytopenia and/or radiologic diagnosis of interstitial lung disease were treated with 5 mg/kg of intramuscular nandrolone decanoate every 15 days for 2 years. Ten of 13 evaluable patients (77%) showed telomere elongation at 12 months by flow-fluorescence in situ hybridization (average increase, 0.87 kb; 95% confidence interval: 0.20-1.55 kb; P=0.01). At 24 months, all ten evaluable patients showed telomere elongation (average increase, 0.49 kb; 95% confidence interval: 0.24-1.23 kb; P=0.18). Hematologic response was achieved in eight of 16 patients (50%) with marrow failure at 12 months, and in ten of 16 patients (63%) at 24 months. Seven patients had interstitial lung disease at baseline, and two and three had pulmonary response at 12 and 24 months, respectively. Two patients died due to pulmonary failure during treatment. In the remaining evaluable patients, the pulmonary function remained stable or improved, but showed consistent decline after cessation of treatment. Somatic mutations in myeloid neoplasm-related genes were present in a minority of patients and were mostly stable during drug treatment. The most common adverse events were elevations in liver function test levels in 88%, acne in 59%, and virilization in 59%. No adverse events grade ≥4 was observed. Our findings indicate that nandrolone decanoate elongates telomeres in patients with telomeropathies, which correlated with clinical improvement in some cases and tolerable adverse events.},
}
@article {pmid36579149,
year = {2022},
author = {Wang, J and Hao, Y and Zhu, Z and Liu, B and Zhang, X and Wei, N and Wang, T and Lv, Y and Xu, C and Ma, M and Zhang, Y and Liu, F},
title = {Causality of telomere length associated with calcific aortic valvular stenosis: A Mendelian randomization study.},
journal = {Frontiers in medicine},
volume = {9},
number = {},
pages = {1077686},
pmid = {36579149},
issn = {2296-858X},
abstract = {BACKGROUND: Observational studies have shown that calcific aortic valve stenosis (CAVS) is associated with a shorter telomere length (TL). However, the results of observational studies are often influenced by confounding factors and reverse causal associations; it is unclear whether there is a causal relationship between TL and CAVS. This study aimed to investigate the causal relationship between TL and CAVS.<br><br>MATERIALS AND METHODS: Genome-wide association study (GWAS) data on TL (n = 472,174) and CAVS (n = 311,437) were used to assess the effect of TL on CAVS. All the participants were of European ancestry. Three Mendelian randomization (MR) methods, namely, MR-Egger, weighted median, and inverse variance weighted (IVW), were used to assess the potential causal effect of TL on CAVS. Heterogeneity was assessed using Cochran's Q statistic. Leave-one-out and MR-Egger regression methods were used for sensitivity and pleiotropy analyses. Forward and reverse MR analyses were performed.<br><br>RESULTS: In total, 118 valid and independent TL genetic instrumental variants were extracted from the GWAS dataset. MR analysis showed that TL was negatively associated with CAVS (odds ratios [OR] = 0.727, 95% confidence interval [CI]: 0.565-0.936, and P = 0.013 by weighted median; OR = 0.763, 95% CI: 0.634-0.920, and P = 0.005 by IVW; OR = 0.757, 95% CI: 0.549-1.044, and P = 0.055 by MR-Egger). Sensitivity and pleiotropy analyses showed that the results of this study were relatively stable and that there was no significant pleiotropy. Reverse MR analyses consistently suggested the absence of causal effects of CAVS liability on TL levels.<br><br>CONCLUSION: A causal relationship between the shortening of TL and the development of CAVS in the European population was suggested in this study, and a theoretical basis was provided to investigate the pathogenesis of CAVS.},
}
@article {pmid36575046,
year = {2022},
author = {Yang, X and Benny, PA and Cervera-Marzal, E and Wu, B and Lassiter, CB and Astern, J and Garmire, LX},
title = {Placental telomere length shortening is not associated with severe preeclampsia but the gestational age.},
journal = {Aging},
volume = {15},
number = {2},
pages = {353-370},
pmid = {36575046},
issn = {1945-4589},
mesh = {Pregnancy ; Humans ; Female ; *Placenta ; *Pre-Eclampsia/genetics ; Retrospective Studies ; Gestational Age ; Telomere Shortening ; Telomere ; },
abstract = {Variations in telomere length (TL) have been associated with aging, stress, and many diseases. Placenta TL is an essential molecular component influencing the outcome of birth. Previous investigations into the relationship between placenta TL and preeclampsia (PE) have produced conflicting findings. We conducted a retrospective case-control analysis in this study to address the disparity. We used placenta samples from 224 births received from Hawaii Biorepository (HiBR) between 2006 and 2013, comprising 129 healthy full-term controls and 95 severe PE samples. The average absolute placental TL was calculated using the quantitative polymerase chain reaction (qPCR) technique. We utilized multiple linear regressions to associate placental TL with severe PE and other demographic, clinical and physiological data. The outcome demonstrates that the placental TL of severe PE cases did not significantly differ from that of healthy controls. Instead, there is a strong correlation between gestational age and placenta TL shortening. Placental TL also exhibits racial differences: (1) Latino moms' TL is significantly longer than non-Latino mothers' (p=0.009). (2) Caucasian patients with severe PE have shorter TL than non-Caucasian patients (p=0.0037). This work puts the long-standing question of whether severe PE influences placental TL to rest. Placental TL is not related to severe PE but is negatively associated with gestational age and is also affected by race.},
}
@article {pmid36574746,
year = {2023},
author = {Van Der Stukken, C and Nawrot, TS and Wang, C and Lefebvre, W and Vanpoucke, C and Plusquin, M and Roels, HA and Janssen, BG and Martens, DS},
title = {The association between ambient particulate matter exposure and the telomere-mitochondrial axis of aging in newborns.},
journal = {Environment international},
volume = {171},
number = {},
pages = {107695},
doi = {10.1016/j.envint.2022.107695},
pmid = {36574746},
issn = {1873-6750},
mesh = {Humans ; Infant, Newborn ; Female ; Pregnancy ; Particulate Matter/analysis ; Tumor Suppressor Protein p53/analysis/pharmacology ; Placenta/chemistry ; Maternal Exposure/adverse effects ; *Air Pollution/adverse effects/analysis ; Aging ; Mitochondria/chemistry ; DNA, Mitochondrial/analysis ; Telomere ; *Air Pollutants/analysis ; },
abstract = {BACKGROUND: Particulate matter (PM) is associated with aging markers at birth, including telomeres and mitochondria. It is unclear whether markers of the core-axis of aging, i.e. tumor suppressor p53 (p53) and peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), are associated with prenatal air pollution and whether there are underlying mechanisms.<br><br>METHODS: 556 mother-newborn pairs from the ENVIRONAGE birth cohort were recruited at the East Limburg Hospital in Genk (Belgium). In placenta and cord blood, telomere length (TL) and mitochondrial DNA content (mtDNAc) were measured using quantitative real-time polymerase chain reaction (qPCR). In cord plasma, p53 and PGC-1&#x3b1; protein levels were measured using ELISA. Daily ambient PM2.5 concentrations during gestation were calculated using a spatial temporal interpolation model. Distributed lag models (DLMs) were applied to assess the association between prenatal PM2.5 exposure and each molecular marker. Mediation analysis was performed to test for underlying mechanisms.<br><br>RESULTS: A 5&#xa0;&#xb5;g/m[3] increment in PM2.5 exposure was associated with -11.23&#xa0;% (95&#xa0;% CI: -17.36&#xa0;% to -4.65&#xa0;%, p&#xa0;=&#xa0;0.0012) and -7.34&#xa0;% (95&#xa0;% CI: -11.56&#xa0;% to -2.92&#xa0;%, p&#xa0;=&#xa0;0.0014) lower placental TL during the entire pregnancy and second trimester respectively, and with -12.96&#xa0;% (95&#xa0;% CI: -18.84&#xa0;% to -6.64&#xa0;%, p&#xa0;<&#xa0;0.001) lower placental mtDNAc during the third trimester. Furthermore, PM2.5&#xa0;exposure was associated with a 12.42&#xa0;% (95&#xa0;% CI: -1.07&#xa0;% to 27.74&#xa0;%, p&#xa0;=&#xa0;0.059) higher cord plasma p53 protein level and a -3.69&#xa0;% (95&#xa0;% CI: -6.97&#xa0;% to -0.31&#xa0;%, p&#xa0;=&#xa0;0.033) lower cord plasma PGC-1&#x3b1; protein level during the third trimester. Placental TL mediated 65&#xa0;% of the negative and 17&#xa0;% of the positive association between PM2.5 and placental mtDNAc and cord plasma p53 protein levels, respectively.<br><br>CONCLUSION: Ambient PM2.5 exposure during pregnancy is associated with markers of the core-axis of aging, with TL as a mediating factor. This study strengthens the hypothesis of the air pollution induced core-axis of aging, and may unravel a possible underlying mediating mechanism in an early-life epidemiological context.},
}
@article {pmid36573392,
year = {2023},
author = {Ardestani, SK and Jamali, T and Taravati, A and Behboudi, H and Vaez-Mahdavi, MR and Faghihzadeh, E and Ghazanfari, T},
title = {Changes in hormones, Leukocyte Telomere Length (LTL), and p16[INK4a] expression in SM-exposed individuals in favor of the cellular senescence.},
journal = {Drug and chemical toxicology},
volume = {46},
number = {6},
pages = {1235-1241},
doi = {10.1080/01480545.2022.2150205},
pmid = {36573392},
issn = {1525-6014},
mesh = {Humans ; Male ; *Mustard Gas/toxicity ; Cyclin-Dependent Kinase Inhibitor p16/genetics/metabolism ; Hydrocortisone/metabolism ; Iran ; Cellular Senescence ; Leukocytes/metabolism ; Telomere ; Testosterone/metabolism ; },
abstract = {Sulfur mustard (SM) is a chemical warfare agent with well-known severe toxic effects and may cause long-term debilitating injuries. We aimed to evaluate aging and longevity in Iranian SM-exposed survivors using some endocrine and molecular biomarkers for the first time. Dehydroepiandrosterone (DHEA), prolactin (PRL), cortisol, testosterone, and luteinizing hormone (LH) were measured in 289 male SM-veterans and 66 age-matched males using the ELISA method. Leukocyte Telomere Length (LTL) measurement and p16[INK4a] expression were measured in the peripheral blood leukocytes of 55 males who were exposed to SM. We found a significantly lower serum DHEAS level and higher serum PRL level in SM-exposed groups (without any related to the severity of lung injuries) compared to healthy controls, but no significant difference in serum levels of cortisol, testosterone, and LH. The molar ratio of DHEAS/cortisol was significantly higher in controls compared to the SM-exposed individuals especially those with severe lung damage. Some biological parameters of allostatic load score such as DHEAS and DHEAS/cortisol ratio significantly decreased long-term after the SM exposure. Additionally, we found that LTL was shorter in SM-exposed veterans rather than unexposed controls while p16[INK4a] gene expression significantly increased in these groups. It seems that DHEAS, DHEAS/cortisol ratio, LTL, and p16[INK4a] gene expression have changed significantly in favor of cellular senescence in SM-exposed patients. Therefore, it seems that SM exposure increases biological age compared to chronological age in SM-exposed survivors.},
}
@article {pmid36567450,
year = {2023},
author = {Matsuda, Y and Ye, J and Yamakawa, K and Mukai, Y and Azuma, K and Wu, L and Masutomi, K and Yamashita, T and Daigo, Y and Miyagi, Y and Yokose, T and Oshima, T and Ito, H and Morinaga, S and Kishida, T and Minamoto, T and Kojima, M and Kaneko, S and Haba, R and Kontani, K and Kanaji, N and Okano, K and Muto-Ishizuka, M and Yokohira, M and Saoo, K and Imaida, K and Suizu, F},
title = {Association of longer telomere length in cancer cells and cancer-associated fibroblasts with worse prognosis.},
journal = {Journal of the National Cancer Institute},
volume = {115},
number = {2},
pages = {208-218},
pmid = {36567450},
issn = {1460-2105},
mesh = {Humans ; *Carcinoma, Renal Cell ; *Cancer-Associated Fibroblasts/pathology ; In Situ Hybridization, Fluorescence ; Prognosis ; Telomere Shortening ; Telomere ; *Carcinoma, Squamous Cell/pathology ; *Liver Neoplasms/pathology ; *Kidney Neoplasms ; Telomere Homeostasis ; },
abstract = {BACKGROUND: Telomere dysfunction has been reported to be directly involved in carcinogenesis owing to chromosomal instability and immortalization; however, the clinicopathological significance of telomeres remains controversial. We have shown that telomere shortening occurs in normal-appearing duct cells at initiation and then continues during the progression of pancreatic cancer. In this study, we determined the clinicopathological and prognostic value of telomere length (TL) in cancer progression.<br><br>METHODS: TL in both cancer cells and cancer-associated fibroblasts (CAFs) was analyzed by high-throughput quantitative fluorescence in situ hybridization using a previously reported cohort comprising 1434 cases of adenocarcinoma (ADC), squamous cell carcinoma (SCC), adenosquamous carcinoma, hepatocellular carcinoma, and renal cell carcinoma (RCC), which are known cancers with a statistically significantly low incidence of alternative lengthening of telomeres. Cases were divided into 2 groups as follows: longer and shorter telomeres, according to the median TL of cancer cells and CAFs. The statistical significance of TL in cancer cells and CAFs on clinicopathological characteristics and prognosis was analyzed.<br><br>RESULTS: There was a close association between TL in cancer cells and CAFs. Longer telomeres in cancer cells and CAFs were associated with aggressive features such as advanced stage, high mitosis score and nuclear score, poorly differentiated cancer, and desmoplastic stroma in ADC. Furthermore, a longer TL was an independent prognostic factor for ADC, SCC, and RCC.<br><br>CONCLUSIONS: Longer telomeres are associated with worse prognosis in ADC, SCC, and RCC. Thus, TL is a novel biomarker for the diagnosis of aggressive cancers with poor prognoses.},
}
@article {pmid36563016,
year = {2023},
author = {D'Angiolo, M and Yue, JX and De Chiara, M and Barré, BP and Giraud Panis, MJ and Gilson, E and Liti, G},
title = {Telomeres are shorter in wild Saccharomyces cerevisiae isolates than in domesticated ones.},
journal = {Genetics},
volume = {223},
number = {3},
pages = {},
pmid = {36563016},
issn = {1943-2631},
mesh = {*Saccharomyces cerevisiae/genetics/metabolism ; Telomere/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/genetics ; Telomere-Binding Proteins/genetics ; Base Sequence ; },
abstract = {Telomeres are ribonucleoproteins that cap chromosome-ends and their DNA length is controlled by counteracting elongation and shortening processes. The budding yeast Saccharomyces cerevisiae has been a leading model to study telomere DNA length control and dynamics. Its telomeric DNA is maintained at a length that slightly varies between laboratory strains, but little is known about its variation at the species level. The recent publication of the genomes of over 1,000 S. cerevisiae strains enabled us to explore telomere DNA length variation at an unprecedented scale. Here, we developed a bioinformatic pipeline (YeaISTY) to estimate telomere DNA length from whole-genome sequences and applied it to the sequenced S. cerevisiae collection. Our results revealed broad natural telomere DNA length variation among the isolates. Notably, telomere DNA length is shorter in those derived from wild rather than domesticated environments. Moreover, telomere DNA length variation is associated with mitochondrial metabolism, and this association is driven by wild strains. Overall, these findings reveal broad variation in budding yeast's telomere DNA length regulation, which might be shaped by its different ecological life-styles.},
}
@article {pmid36555658,
year = {2022},
author = {Sagris, M and Theofilis, P and Antonopoulos, AS and Tsioufis, K and Tousoulis, D},
title = {Telomere Length: A Cardiovascular Biomarker and a Novel Therapeutic Target.},
journal = {International journal of molecular sciences},
volume = {23},
number = {24},
pages = {},
pmid = {36555658},
issn = {1422-0067},
mesh = {Humans ; *Cardiovascular System ; Telomere Shortening ; *Atherosclerosis/genetics ; Biomarkers ; *Telomerase/genetics ; Telomere/genetics ; },
abstract = {Coronary artery disease (CAD) is a multifactorial disease with a high prevalence, particularly in developing countries. Currently, the investigation of telomeres as a potential tool for the early detection of the atherosclerotic disease seems to be a promising method. Telomeres are repetitive DNA sequences located at the extremities of chromosomes that maintain genetic stability. Telomere length (TL) has been associated with several human disorders and diseases while its attrition rate varies significantly in the population. The rate of TL shortening ranges between 20 and 50 bp and is affected by factors such as the end-replication phenomenon, oxidative stress, and other DNA-damaging agents. In this review, we delve not only into the pathophysiology of TL shortening but also into its association with cardiovascular disease and the progression of atherosclerosis. We also provide current and future treatment options based on TL and telomerase function, trying to highlight the importance of these cutting-edge developments and their clinical relevance.},
}
@article {pmid36541551,
year = {2023},
author = {Stundon, JL and Ijaz, H and Gaonkar, KS and Kaufman, RS and Jin, R and Karras, A and Vaksman, Z and Kim, J and Corbett, RJ and Lueder, MR and Miller, DP and Guo, Y and Santi, M and Li, M and Lopez, G and Storm, PB and Resnick, AC and Waanders, AJ and MacFarland, SP and Stewart, DR and Diskin, SJ and Rokita, JL and Cole, KA},
title = {Alternative lengthening of telomeres (ALT) in pediatric high-grade gliomas can occur without ATRX mutation and is enriched in patients with pathogenic germline mismatch repair (MMR) variants.},
journal = {Neuro-oncology},
volume = {25},
number = {7},
pages = {1331-1342},
pmid = {36541551},
issn = {1523-5866},
support = {HHSN261200800001C/RC/CCR NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; K12 HD043245/HD/NICHD NIH HHS/United States ; U2C-CA233285/NH/NIH HHS/United States ; },
mesh = {Humans ; Child ; DNA Mismatch Repair ; Telomere Homeostasis/genetics ; X-linked Nuclear Protein/genetics ; *Glioma/genetics ; *Brain Neoplasms/genetics/pathology ; Mutation ; Telomere/genetics/pathology ; },
abstract = {BACKGROUND: To achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available.<br><br>METHODS: We performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n&#xa0;=&#xa0;40/579) of these tumors and completed additional validation by ultrabright telomeric foci in situ on a subset of these tumors. We used CCA to validate TelomereHunter for computational prediction of ALT status and focus subsequent analyses on pediatric high-grade gliomas (pHGGs) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations.<br><br>RESULTS: ALT is common in pHGGs (n&#xa0;=&#xa0;24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (<3%). Somatic ATRX mutations occur in 50% of ALT+ pHGGs and in 30% of ALT- pHGGs. Rare pathogenic germline variants in mismatch repair (MMR) genes are significantly associated with an increased occurrence of ALT.<br><br>CONCLUSIONS: We demonstrate that ATRX is mutated in only a subset of ALT+ pHGGs, suggesting other mechanisms of ATRX loss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with the development of ALT in patients with pHGG.},
}
@article {pmid36536359,
year = {2022},
author = {Wong, KK and Cheng, F and Lim, CKP and Tam, CHT and Tutino, G and Yuen, LY and Wang, CC and Hou, Y and Chan, MHM and Ho, CS and Joglekar, MV and Hardikar, AA and Jenkins, AJ and Metzger, BE and Lowe, WL and Tam, WH and Ma, RCW},
title = {Early emergence of sexual dimorphism in offspring leukocyte telomere length was associated with maternal and children's glucose metabolism-a longitudinal study.},
journal = {BMC medicine},
volume = {20},
number = {1},
pages = {490},
pmid = {36536359},
issn = {1741-7015},
support = {R01 HD034242/HD/NICHD NIH HHS/United States ; R01 HD034243/HD/NICHD NIH HHS/United States ; },
mesh = {Male ; Pregnancy ; Female ; Humans ; Adult ; Child ; Longitudinal Studies ; *Diabetes Mellitus, Type 2 ; Sex Characteristics ; Leukocytes ; Insulin/metabolism ; Glucose/metabolism ; Telomere ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) is suggested to be a biomarker of biological age and reported to be associated with metabolic diseases such as type 2 diabetes. Glucose metabolic traits including glucose and insulin levels have been reported to be associated with LTL in adulthood. However, there is relatively little research focusing on children's LTL and the association with prenatal exposures. This study investigates the relationship between maternal and offspring glucose metabolism with offspring LTL in early life.<br><br>METHODS: This study included 882 mother-child pairs from the HAPO Hong Kong Field Centre, with children evaluated at age 7.0 &#xb1; 0.4 (mean &#xb1; SD) years. Glucose metabolic traits including maternal post-load glucose during pregnancy, children's glucose and insulin levels, and their derived indices at follow-up were measured or calculated. Offspring LTL was assessed using real-time polymerase chain reaction.<br><br>RESULTS: Sex- and age-adjusted children's LTL was found to be associated with children's HOMA-IR (&#x3b2;=-0.046 &#xb1; 0.016, p=0.005). Interestingly, both children's and maternal post-load glucose levels were positively associated with children's LTL. However, negative associations were observed between children's LTL and children's OGTT insulin levels. In addition, the LTL in females was more strongly associated with pancreatic beta-cell function whilst LTL in males was more strongly associated with OGTT glucose levels.<br><br>CONCLUSIONS: Our findings suggest a close association between maternal and offspring glucose metabolic traits with early life LTL, with the offspring sex as an important modifier of the disparate relationships in insulin production and response.},
}
@article {pmid36533316,
year = {2023},
author = {Derenzini, E and Gueli, A and Risso, A and Bruna, R and Gottardi, D and Cignetti, A and Pileri, S and Avvedimento, EV and Tarella, C},
title = {Long telomeres at baseline and male sex are main determinants of telomere loss following chemotherapy exposure in lymphoma patients.},
journal = {Hematological oncology},
volume = {41},
number = {3},
pages = {335-342},
doi = {10.1002/hon.3118},
pmid = {36533316},
issn = {1099-1069},
support = {//Fondazione Cariplo/ ; //Piaggio/ ; //Banca del Piemonte/ ; },
mesh = {Adult ; Humans ; Male ; Female ; Young Adult ; Middle Aged ; Aged ; *Lymphoma/drug therapy/genetics ; Telomere Shortening ; Telomere ; },
abstract = {Although chemotherapy (CHT) exposure is an established cause of telomere attrition, determinants of telomere length (TL) dynamics after chemotherapy are poorly defined. In this study, we analyzed granulocyte telomere dynamics in 34 adult lymphoma patients undergoing first-line CHT. TL was measured by southern blot at each CHT cycle and after 1 year from CHT completion. Median age was 59 yrs (range 22-77). Median number of CHT cycles was 6 (range 3-6). The majority of patients (79%, n = 27) experienced TL shortening following CHT exposure. Mean telomere loss was 673 base pairs (bp) by cycle 6. Telomere shortening was an early event as 87% of the total telomere loss (mean 586 bp) occurred by the end of cycle 3, with no significant recovery after 1 year. A significant correlation was observed between baseline TL and total or fractional telomere loss (p < 0.001), with telomere shortening by cycle 3 observed predominantly in male patients with long telomeres at pre-treatment evaluation. Stratifying the analysis by gender and age only young women (<51 years of age) did not show significant telomere shortening following chemotherapy exposure. These findings indicate that gender and baseline TL are major determinants of TL dynamics following chemotherapy exposure in lymphoma patients.},
}
@article {pmid36526187,
year = {2023},
author = {Zamora-Camacho, FJ and Burraco, P and Zambrano-Fernández, S and Aragón, P},
title = {Ammonium effects on oxidative stress, telomere length, and locomotion across life stages of an anuran from habitats with contrasting land-use histories.},
journal = {The Science of the total environment},
volume = {862},
number = {},
pages = {160924},
doi = {10.1016/j.scitotenv.2022.160924},
pmid = {36526187},
issn = {1879-1026},
mesh = {Animals ; Humans ; *Ammonium Compounds/pharmacology ; Antioxidants ; Ecosystem ; Hydrogen Peroxide ; Larva ; Life Cycle Stages ; Locomotion/physiology ; *Oxidative Stress/physiology ; Ranidae ; *Telomere/metabolism ; },
abstract = {Understanding the mechanistic implications behind wildlife responses to global changes is a central topic in eco-evolutionary research. In particular, anthropic pollution is known to impact wild populations across the globe, which may have even stronger consequences for species with complex life cycles. Among vertebrates, amphibians represent a paradigmatic example of metamorphosis, and their characteristics make them highly vulnerable to pollution. Here, we tested for differences in the redox status, telomere length, and locomotor performance across life stages of green frogs (Pelophylax perezi) from agrosystem and natural habitats, both constitutively and in response to an experimental ammonium exposure (10 mg/L). We found that larvae from the agrosystem constitutively showed an enhanced redox status (better antioxidant balance against H2O2, lower lipid peroxidation) but shorter telomeres as compared to larvae from the natural environment. The larval redox response to ammonium was, overall, similar in both habitats. In contrast, after metamorphosis, the redox status of individuals from the natural habitat seemed to cope better with ammonium exposure (denoted by lower lipid peroxidation), and differences between habitats in telomere length were no longer present. Intriguingly, while the swimming performance of larvae did not correlate with individual's physiology, metamorphs with lower glutathione reductase activity and longer telomeres had a better jumping performance. This may suggest that locomotor performance is both traded off with the production of reactive oxygen species and potentiated directly by longer telomeres or indirectly by the mechanisms that buffer their shortening. Overall, our study suggests that contrasting land-use histories can drive divergence in physiological pathways linked to individual health and lifespan. Since this pattern was life-stage dependent, divergent habitat conditions can have contrasting implications across the ontogenetic development of species with complex life cycles.},
}
@article {pmid36525974,
year = {2023},
author = {Warecki, B and Bast, I and Tajima, M and Sullivan, W},
title = {Connections between sister and non-sister telomeres of segregating chromatids maintain euploidy.},
journal = {Current biology : CB},
volume = {33},
number = {1},
pages = {58-74.e5},
pmid = {36525974},
issn = {1879-0445},
support = {R35 GM139595/GM/NIGMS NIH HHS/United States ; S10 OD023528/OD/NIH HHS/United States ; },
mesh = {Animals ; *Chromatids/genetics ; Drosophila melanogaster/genetics ; Telomere/genetics ; Anaphase ; DNA ; Chromosome Segregation ; Cell Cycle Proteins/genetics ; *Drosophila Proteins/genetics ; },
abstract = {The complete separation of sister chromatids during anaphase is a fundamental requirement for successful mitosis. Therefore, divisions with either persistent DNA-based connections or lagging chromosome fragments threaten aneuploidy if unresolved. Here, we demonstrate the existence of an anaphase mechanism in normally dividing cells in which pervasive connections between telomeres of segregating chromosomes aid in rescuing lagging chromosome fragments. We observe that in a large proportion of Drosophila melanogaster neuronal stem cell divisions, early anaphase sister and non-sister chromatids remain connected by thin telomeric DNA threads. Normally, these threads are resolved in mid-to-late anaphase via a spatial mechanism. However, we find that the presence of a nearby unrepaired DNA break recruits histones, BubR1 kinase, Polo kinase, Aurora B kinase, and BAF to the telomeric thread of the broken chromosome, stabilizing it. Stabilized connections then aid lagging chromosome rescue. These results suggest a model in which pervasive anaphase telomere-telomere connections that are normally resolved quickly can instead be stabilized to retain wayward chromosome fragments. Thus, the liability of persistent anaphase inter-chromosomal connections in normal divisions may be offset by their ability to maintain euploidy in the face of chromosome damage and genome loss.},
}
@article {pmid36522605,
year = {2022},
author = {Wang, C and Gu, Y and Zhou, J and Zang, J and Ling, X and Li, H and Hu, L and Xu, B and Zhang, B and Qin, N and Lv, H and Duan, W and Jiang, Y and He, Y and Jiang, T and Chen, C and Han, X and Zhou, K and Xu, B and Liu, X and Tao, S and Jiang, Y and Du, J and Dai, J and Diao, F and Lu, C and Guo, X and Huo, R and Liu, J and Lin, Y and Xia, Y and Jin, G and Ma, H and Shen, H and Hu, Z},
title = {Leukocyte telomere length in children born following blastocyst-stage embryo transfer.},
journal = {Nature medicine},
volume = {28},
number = {12},
pages = {2646-2653},
pmid = {36522605},
issn = {1546-170X},
mesh = {Pregnancy ; Humans ; Female ; Animals ; Mice ; *Pregnancy Outcome ; *Premature Birth ; Embryo Transfer ; Reproductive Techniques, Assisted ; Blastocyst ; Leukocytes ; Telomere/genetics ; },
abstract = {Perinatal and childhood adverse outcomes associated with assisted reproductive technology (ART) has been reported, but it remains unknown whether the initial leukocyte telomere length (LTL), which is an indicator of age-related phenotypes in later life, is affected. Here, we estimated the LTLs of 1,137 individuals from 365 families, including 202 children conceived by ART and 205 children conceived spontaneously from two centers of the China National Birth Cohort, using whole-genome sequencing (WGS) data. One-year-old children conceived by ART had shorter LTLs than those conceived spontaneously (beta, -0.36; P = 1.29 × 10[-3]) after adjusting for plurality, sex and other potential confounding factors. In particular, blastocyst-stage embryo transfer was associated with shorter LTL (beta, -0.54, P = 2.69 × 10[-3]) in children conceived by ART. The association was validated in 586 children conceived by ART from five centers using different LTL quantification methods (that is, WGS or qPCR). Blastocyst-stage embryo transfer resulted in shorter telomere lengths in mice at postnatal day 1 (P = 2.10 × 10[-4]) and mice at 6 months (P = 0.042). In vitro culturing of mice embryos did not result in shorter telomere lengths in the late cleavage stage, but it did suppress telomerase activity in the early blastocyst stage. Our findings demonstrate the need to evaluate the long-term consequences of ART, particularly for aging-related phenotypes, in children conceived by ART.},
}
@article {pmid36514516,
year = {2022},
author = {Akay, GG},
title = {Telomeres and Psychological Stress: Perspective on Psychopathologies.},
journal = {Noro psikiyatri arsivi},
volume = {59},
number = {4},
pages = {330-337},
pmid = {36514516},
issn = {1300-0667},
abstract = {INTRODUCTION: Telomeres are specialized DNA-protein complexes located at the ends of all chromosomes and act as a "molecular clock" to determine the replicative lifespan of the cells. Recent studies indicate that life-long exposure to stress, starting from the prenatal period, causes many diseases to emerge at an early age, and telomeres may be possible mediators in this process. This article aims to review the relationship between the stress-telomere-disease triad and the potential role of telomere dysfunction in psychopathologies in the light of current literature.<br><br>METHODS: A literature search was conducted along the lines of a narrative review. PubMed and Web of Science databases were used to identify all types of articles published from inception to January 2022. After the title/abstract search, articles available in full text and English were selected based on key findings, the applicability of the method used to test the hypothesis, limitations, interpretation of the results, and impact of the results in the field. A total of 73 records were included in this narrative review.<br><br>RESULTS: The fact that some age-related chronic diseases, such as cardiovascular diseases and type 2 diabetes, are seen more frequently and at an earlier age in certain psychopathologies including depression, bipolar disorder, and schizophrenia suggests that these disorders are premature ageing syndromes. Although there are some conflicting results in the literature, in line with this hypothesis, the presence of shortened telomeres reported in these psychopathologies and the impact of lifelong exposure to stress on this process are remarkable.<br><br>CONCLUSION: Many of the studies point to an association and do not tell much about the causality. Hence, the elucidation of the biological processes underlying the relationship between psychological stress, dysfunctional telomeres and complex, common age-related diseases, as well as psychiatric disorders is important and further studies are needed at the cellular level.},
}
@article {pmid36513246,
year = {2023},
author = {Ito, J and Kageyama, M and Hara, S and Sato, T and Shirasuna, K and Iwata, H},
title = {Paternal aging impacts mitochondrial DNA content and telomere length in mouse embryos.},
journal = {Mitochondrion},
volume = {68},
number = {},
pages = {105-113},
doi = {10.1016/j.mito.2022.12.002},
pmid = {36513246},
issn = {1872-8278},
mesh = {Male ; Animals ; Cattle ; Mice ; *DNA, Mitochondrial/genetics ; *Telomere/genetics ; Mitochondria/genetics ; Aging/genetics ; Blastocyst ; },
abstract = {Mitochondrial DNA (mtDNA) copy number and telomere length (TL) in blastocysts derived from the same male mice at young (10-19-week-old) and aged (40-49-week-old) time points and mtDNA and TL in the hearts of offspring derived from young and aged male mice were examined. Paternal aging correlated with reduced mtDNA and TL in blastocysts. mtDNA and TL were significantly correlated, which was also observed in bovine blastocysts. Moreover, mtDNA in the heart of offspring was reduced in male mice with paternal aging. In conclusion, paternal aging affects embryonic mtDNA and TL, potentially impacting their offspring.},
}
@article {pmid36513120,
year = {2022},
author = {Misino, S and Busch, A and Wagner, CB and Bento, F and Luke, B},
title = {TERRA increases at short telomeres in yeast survivors and regulates survivor associated senescence (SAS).},
journal = {Nucleic acids research},
volume = {50},
number = {22},
pages = {12829-12843},
pmid = {36513120},
issn = {1362-4962},
mesh = {Humans ; *RNA, Long Noncoding/genetics ; *Saccharomyces cerevisiae/genetics/metabolism ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; *Telomere Shortening ; },
abstract = {Cancer cells achieve immortality by employing either homology-directed repair (HDR) or the telomerase enzyme to maintain telomeres. ALT (alternative lengthening of telomeres) refers to the subset of cancer cells that employ HDR. Many ALT features are conserved from yeast to human cells, with the yeast equivalent being referred to as survivors. The non-coding RNA TERRA, and its ability to form RNA-DNA hybrids, has been implicated in ALT/survivor maintenance by promoting HDR. It is not understood which telomeres in ALT/survivors engage in HDR, nor is it clear which telomeres upregulate TERRA. Using yeast survivors as a model for ALT, we demonstrate that HDR only occurs at telomeres when they become critically short. Moreover, TERRA levels steadily increase as telomeres shorten and decrease again following HDR-mediated recombination. We observe that survivors undergo cycles of senescence, in a similar manner to non-survivors following telomerase loss, which we refer to as survivor associated senescence (SAS). Similar to 'normal' senescence, we report that RNA-DNA hybrids slow the rate of SAS, likely through the elongation of critically short telomeres, however decreasing the rate of telomere shortening may contribute to this effect. In summary, TERRA RNA-DNA hybrids regulate telomere dysfunction-induced senescence before and after survivor formation.},
}
@article {pmid36508921,
year = {2023},
author = {Nasiri, L and Vaez-Mahdavi, MR and Hassanpour, H and Ghazanfari, T and Kaboudanian Ardestani, S and Askari, N and Mohseni Majd, MA and Rahimlou, B},
title = {Increased serum lipofuscin associated with leukocyte telomere shortening in veterans: a possible role for sulfur mustard exposure in delayed-onset accelerated cellular senescence.},
journal = {International immunopharmacology},
volume = {114},
number = {},
pages = {109549},
doi = {10.1016/j.intimp.2022.109549},
pmid = {36508921},
issn = {1878-1705},
mesh = {Humans ; Male ; *Mustard Gas/toxicity ; *Chemical Warfare Agents/toxicity ; Telomere Shortening ; Lipofuscin ; *Veterans ; Leukocytes ; Cellular Senescence ; Transforming Growth Factor beta ; },
abstract = {BACKGROUND: Sulfur mustard (SM) is a toxic gas that causes chronic inflammation and oxidative stress leading to cell senescence. This study aimed to evaluate two indicators of biological aging (i.e., serum lipofuscin level and leukocyte telomere length) and assess their relationship based on the severity of SM exposure in the long term.<br><br>METHODS: The study was performed on two groups of male participants. 1) SM-exposed group (exposed to SM once in 1987), 73 volunteers. 2) Non-exposed group, 16 healthy volunteers. The SM-exposed group was categorized into three subgroups based on the severity of SM exposure and body damage (asymptom, mild, and severe). The blood sample was prepared from members of each group. The serum lipofuscin, TGF-&#x3b2;, malondialdehyde (MDA), c-reactive protein (CRP), and leukocyte telomere length (TL) were measured in all participants.<br><br>RESULTS: The MDA level was increased in the SM-exposed group (mean = 39.6 &#xb5;M, SD = 16.5) compared to the non-exposed group (mean = 21.1 &#xb5;M, SD = 10.3) (P < 0.05). The CRP level was also increased in the SM-exposed group (mean = 5.12 mg/l, SD = 3.36) compared to the non-exposed group (mean = 3.51 mg/l, SD = 1.21), while the TGF-&#x3b2; level was decreased (P < 0.05) in the SM-exposed group (mean = 52.6 pg/ml, SD = 18.7) compared to the non-exposed group (mean = 68.9 pg/ml, SD = 13.8). The relative TL was shorter in the SM-exposed group (mean = 0.40, SD = 0.28) than in the non-exposed group (mean = 2.25, SD = 1.41) (P < 0.05). The lipofuscin level was higher in the total SM-exposed group (mean = 1.44 ng/ml, SD = 0.685) than in the non-exposed group (mean = 0.88 ng/ml, SD = 0.449) (P < 0.05). The MDA and CRP levels were increased in the SM-exposed subgroups of asymptom, mild, and severe than the non-exposed group, while TGF-&#x3b2; level and TL were decreased in those subgroups. The lipofuscin level was higher in the SM-exposed subgroups of mild and severe than in the non-exposed group. The regression analysis determined a negative correlation between lipofuscin level and TL. The lipofuscin/TL ratio was higher in the total SM-exposed group (mean = 6.36, SD = 5.342) than in the non-exposed group (mean = 0.51, SD=0.389). This ratio was also higher in the SM-exposed subgroups of asymptom, mild, and severe than in the non-exposed group. The lipofuscin/TL ratio did not differ between mild and severe subgroups.<br><br>CONCLUSION: The delayed toxicity of SM is associated with chronic oxidative stress, continuous inflammatory stimulation, increased lipofuscin, and telomere shortening. Future studies are needed to verify the suitability of serum lipofuscin to telomere length ratio in determining the severity of SM toxicity.},
}
@article {pmid36502996,
year = {2023},
author = {Zhang, Y and Liu, J and Li, X and Zhou, G and Sang, Y and Zhang, M and Gao, L and Xue, J and Zhao, M and Yu, H and Zhou, X},
title = {Dietary selenium excess affected spermatogenesis via DNA damage and telomere-related cell senescence and apoptosis in mice.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {171},
number = {},
pages = {113556},
doi = {10.1016/j.fct.2022.113556},
pmid = {36502996},
issn = {1873-6351},
mesh = {Mice ; Male ; Animals ; *Selenium/pharmacology ; Semen ; Spermatogenesis ; Cellular Senescence ; Apoptosis ; DNA Damage ; *Malnutrition ; Telomere ; },
abstract = {Selenium (Se) is a vital microelement for spermatogenesis and male fertility. The aim of this study was to investigate the effects of Se on the male reproductive function and possible mechanisms. Fourty male mice were randomly divided into 0, 0.1, 0.3 and 0.9 mg/kg Se supplementation groups and given with Se dietary intervention for 12 weeks. Our data showed that excessive Se intake damaged the tissue structure of testes and epididymides of the mice, resulting in decreased sperm quality and quantity. Moreover, excessive Se induced oxidative stress, causing DNA damage and activated DNA damage repair factors (Mre11/Rad50/Nbs1), and also disrupted telomere function by shortening telomere length and decreasing TERT expression. Se excess activated the senescence pathway p53/p21/p16, leading to germ cell senescence, and inhibited cell proliferation by suppressing the Sirt1/Foxo1/c-Myc pathway. All of this led to spermatogenic cell apoptosis, thereby causing a decrease of sperm quantity and quality. In conclusion, excessive Se caused reproductive toxicity via inducing telomere dysfunction due to DNA damage, leading to germ cellular senescence and apoptosis in the testes of male mice. Our research provide new proof to explain the underlying mechanism of male reproductive toxicity triggered by excessive Se intake.},
}
@article {pmid36501220,
year = {2022},
author = {Toupance, S and Karampatsou, SI and Labat, C and Genitsaridi, SM and Tragomalou, A and Kassari, P and Soulis, G and Hollander, A and Charmandari, E and Benetos, A},
title = {Longitudinal Association of Telomere Dynamics with Obesity and Metabolic Disorders in Young Children.},
journal = {Nutrients},
volume = {14},
number = {23},
pages = {},
pmid = {36501220},
issn = {2072-6643},
support = {ANR-15-IDEX-04-LUE//Agence Nationale de la Recherche/ ; FHU project CARTAGE-PROFILES//French National Alliance for Life Sciences and Health/ ; },
mesh = {Adult ; Adolescent ; Child ; Humans ; Child, Preschool ; *Pediatric Obesity/genetics/metabolism ; Telomere ; Telomere Shortening ; Leukocytes/metabolism ; *Diabetes Mellitus, Type 2/genetics/metabolism ; },
abstract = {In adults, short leukocyte telomere length (LTL) is associated with metabolic disorders, such as obesity and diabetes mellitus type 2. These associations could stem from early life interactions between LTL and metabolic disorders. To test this hypothesis, we explored the associations between LTL and metabolic parameters as well as their evolution over time in children with or without obesity at baseline. Seventy-three (n = 73) children attending our Outpatient Clinic for the Prevention and Management of Overweight and Obesity in Childhood and Adolescence, aged 2-10 years (mean ± SD: 7.6 ± 2.0 years), were followed for 2 to 4 years. Anthropometric, clinical, and biological (including LTL by Southern blot) measurements were performed annually. Baseline LTL correlated negatively with BMI (p = 0.02), fat percentage (p = 0.01), and blood glucose (p = 0.0007). These associations persisted after adjustments for age and sex. No associations were found between LTL attrition during the follow-up period and any of the metabolic parameters. In young children, obesity and metabolic disturbances were associated with shorter telomeres but were not associated with more pronounced LTL attrition. These results suggest that short telomeres contribute to the development of obesity and metabolic disorders very early in life, which can have a major impact on health.},
}
@article {pmid36498467,
year = {2022},
author = {Mulet, A and Signes-Costa, J},
title = {Idiopathic Pulmonary Fibrosis and Telomeres.},
journal = {Journal of clinical medicine},
volume = {11},
number = {23},
pages = {},
pmid = {36498467},
issn = {2077-0383},
abstract = {Idiopathic pulmonary fibrosis is an interstitial lung disease of unknown etiology with a highly compromised prognosis and a significant mortality rate within a few years of diagnosis. Despite being idiopathic, it has been shown that telomeric shortening could play an important role in its etiopathogenesis. Mutations in telomere-related genes have been identified, but they are not always present despite telomere shortening. On the other hand, this telomeric shortening has been linked to a worse prognosis of the disease independently of other clinical factors, implying it may serve as a biomarker.},
}
@article {pmid36497103,
year = {2022},
author = {Vilkeviciute, A and Gedvilaite, G and Banevicius, M and Kriauciuniene, L and Zaliuniene, D and Dobiliene, O and Liutkeviciene, R},
title = {Relative Leukocyte Telomere Length and Genetic Variants in Telomere-Related Genes and Serum Levels Role in Age-Related Macular Degeneration.},
journal = {Cells},
volume = {11},
number = {23},
pages = {},
pmid = {36497103},
issn = {2073-4409},
mesh = {Humans ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; *Telomerase/genetics/metabolism ; Leukocytes/metabolism ; *Macular Degeneration/genetics ; DNA ; *Tankyrases ; },
abstract = {UNLABELLED: Telomere shortening is well known to be associated with ageing. Age is the most decisive risk factor for age-related macular degeneration (AMD) development. The older the individual, the higher the AMD risk. For this reason, we aimed to find any associations between telomere length, distribution of genetic variants in telomere-related genes (TERT, TERT-CLPTM1, TRF1, TRF2, and TNKS2), and serum TERF-1 and TERF2 levels on AMD development.<br><br>METHODS: Our study enrolled 342 patients with AMD and 177 healthy controls. Samples of DNA from peripheral blood leukocytes were extracted by DNA salting-out method. The genotyping of TERT rs2736098, rs401681 in TERT-CLPTM1 locus, TRF1 rs1545827, rs10107605, TNKS2 rs10509637, rs10509639, and TRF2 rs251796 and relative leukocyte telomere length (T/S) measurement were carried out using the real-time polymerase chain reaction method. Serum TERF-1 and TERF2 levels were measured by enzymatic immunoassay (ELISA).<br><br>RESULTS: We found longer telomeres in early AMD patients compared to the control group. Additionally, we revealed that minor allele C at TRF1 rs10107605 was associated with decreases the odds of both early and exudative AMD. Each minor allele G at TRF2 rs251796 and TRF1 rs1545827 C/T genotype and C/T+T/T genotypes, compared to the C/C genotype, increases the odds of having shorter telomeres. Furthermore, we found elevated TERF1 serum levels in the early AMD group compared to the control group.<br><br>CONCLUSIONS: In conclusion, these results suggest that relative leukocyte telomere length and genetic variants of TRF1 and TRF2 play a role in AMD development. Additionally, TERF1 is likely to be associated with early AMD.},
}
@article {pmid36497039,
year = {2022},
author = {Farrukh, S and Baig, S and Hussain, R and Imad, R and Khalid, M},
title = {Parental Genetics Communicate with Intrauterine Environment to Reprogram Newborn Telomeres and Immunity.},
journal = {Cells},
volume = {11},
number = {23},
pages = {},
pmid = {36497039},
issn = {2073-4409},
support = {Ref No. 20-15896/NRPU/R&amp;D/HEC/2021 2021//Higher Education Commission/ ; Ref no. Biochemistry.242.14/5/21)//ziauddin university/ ; },
mesh = {Female ; Humans ; Infant, Newborn ; Pregnancy ; Genotype ; Mothers ; *Telomerase/genetics ; *Telomere/genetics ; Telomere Shortening/genetics ; Fathers ; Male ; *Immunity/genetics ; Maternal Inheritance ; Paternal Inheritance ; },
abstract = {Telomeres, markers for cellular senescence, have been found substantially influenced by parental inheritance. It is well known that genomic stability is preserved by the DNA repair mechanism through telomerase. This study aimed to determine the association between parents−newborn telomere length (TL) and telomerase gene (TERT), highlighting DNA repair combined with TL/TERT polymorphism and immunosenescence of the triad. The mother−father−newborn triad blood samples (n = 312) were collected from Ziauddin Hospitals, Pakistan, between September 2021 and June 2022. The telomere length (T/S ratio) was quantified by qPCR, polymorphism was identified by Sanger sequencing, and immunosenescence by flow cytometry. The linear regression was applied to TL and gene association. The newborns had longest TL (2.51 ± 2.87) and strong positive association (R = 0.25, p ≤ 0.0001) (transgenerational health effects) with mothers’ TL (1.6 ± 2.00). Maternal demographics—socioeconomic status, education, and occupation—showed significant effects on TL of newborns (p < 0.015, 0.034, 0.04, respectively). The TERT risk genotype CC (rs2736100) was predominant in the triad (0.6, 0.5, 0.65, respectively) with a strong positive association with newborn TL (β = 2.91, <0.0011). Further analysis highlighted the expression of KLRG 1+ in T-cells with shorter TL but less frequent among newborns. The study concludes that TERT, parental TL, antenatal maternal health, and immunity have a significantly positive effect on the repair of newborn TL.},
}
@article {pmid36496180,
year = {2023},
author = {Nelson, N and Feurstein, S and Niaz, A and Truong, J and Holien, JK and Lucas, S and Fairfax, K and Dickinson, J and Bryan, TM},
title = {Functional genomics for curation of variants in telomere biology disorder associated genes: A systematic review.},
journal = {Genetics in medicine : official journal of the American College of Medical Genetics},
volume = {25},
number = {3},
pages = {100354},
doi = {10.1016/j.gim.2022.11.021},
pmid = {36496180},
issn = {1530-0366},
mesh = {Humans ; *Genetic Variation/genetics ; *Genetic Testing ; Genome, Human ; Genomics ; Telomere/genetics ; },
abstract = {PURPOSE: Patients with an underlying telomere biology disorder (TBD) have variable clinical presentations, and they can be challenging to diagnose clinically. A genomic diagnosis for patients presenting with TBD is vital for optimal treatment. Unfortunately, many variants identified during diagnostic testing are variants of uncertain significance. This complicates management decisions, delays treatment, and risks nonuptake of potentially curative therapies. Improved application of functional genomic evidence may reduce variants of uncertain significance classifications.<br><br>METHODS: We systematically searched the literature for published functional assays interrogating TBD gene variants. When possible, established likely benign/benign and likely pathogenic/pathogenic variants were used to estimate the assay sensitivity, specificity, positive predictive value, negative predictive value, and odds of pathogenicity.<br><br>RESULTS: In total, 3131 articles were screened and 151 met inclusion criteria. Sufficient data to enable a PS3/BS3 recommendation were available for TERT variants only. We recommend that PS3 and BS3 can be applied at a moderate and supportive level, respectively. PS3/BS3 application was limited by a lack of assay standardization and limited inclusion of benign variants.<br><br>CONCLUSION: Further assay standardization and assessment of benign variants are required for optimal use of the PS3/BS3 criterion for TBD gene variant classification.},
}
@article {pmid36485133,
year = {2022},
author = {Savage, SA},
title = {Dyskeratosis congenita and telomere biology disorders.},
journal = {Hematology. American Society of Hematology. Education Program},
volume = {2022},
number = {1},
pages = {637-648},
pmid = {36485133},
issn = {1520-4383},
mesh = {Humans ; Child ; *Dyskeratosis Congenita/genetics/pathology ; Telomere/genetics/pathology ; Germ-Line Mutation ; Bone Marrow Failure Disorders ; *Anemia, Aplastic ; },
abstract = {Numerous genetic discoveries and the advent of clinical telomere length testing have led to the recognition of a spectrum of telomere biology disorders (TBDs) beyond the classic dyskeratosis congenita (DC) triad of nail dysplasia, abnormal skin pigmentation, and oral leukoplakia occurring with pediatric bone marrow failure. Patients with DC/TBDs have very short telomeres for their age and are at high risk of bone marrow failure, cancer, pulmonary fibrosis (PF), pulmonary arteriovenous malformations, liver disease, stenosis of the urethra, esophagus, and/or lacrimal ducts, avascular necrosis of the hips and/or shoulders, and other medical problems. However, many patients with TBDs do not develop classic DC features; they may present in middle age and/or with just 1 feature, such as PF or aplastic anemia. TBD-associated clinical manifestations are progressive and attributed to aberrant telomere biology caused by the X-linked recessive, autosomal dominant, autosomal recessive, or de novo occurrence of pathogenic germline variants in at least 18 different genes. This review describes the genetics and clinical manifestations of TBDs and highlights areas in need of additional clinical and basic science research.},
}
@article {pmid36483815,
year = {2022},
author = {Picos-Cárdenas, VJ and Beltrán-Ontiveros, SA and Cruz-Ramos, JA and Contreras-Gutiérrez, JA and Arámbula-Meraz, E and Angulo-Rojo, C and Guadrón-Llanos, AM and Leal-León, EA and Cedano-Prieto, DM and Meza-Espinoza, JP},
title = {Novel TINF2 gene mutation in dyskeratosis congenita with extremely short telomeres: A case report.},
journal = {World journal of clinical cases},
volume = {10},
number = {33},
pages = {12440-12446},
pmid = {36483815},
issn = {2307-8960},
abstract = {BACKGROUND: Dyskeratosis congenita is a rare disease characterized by bone marrow failure and a clinical triad of oral leukoplakia, nail dystrophy, and abnormal skin pigmentation. The genetics of dyskeratosis congenita include mutations in genes involved in telomere maintenance, including TINF2.<br><br>CASE SUMMARY: Here, we report a female patient who presented thrombocytopenia, anemia, reticulate hyperpigmentation, dystrophy in fingernails and toenails, and leukoplakia on the tongue. A histopathological study of the skin showed dyskeratocytes; however, a bone marrow biopsy revealed normal cell morphology. The patient was diagnosed with dyskeratosis congenita, but her family history did not reveal significant antecedents. Whole-exome sequencing showed a novel heterozygous punctual mutation in exon 6 from the TINF2 gene, namely, NM_001099274.1:c.854delp.(Val285Alafs*32). An analysis of telomere length showed short telomeres relative to the patient's age.<br><br>CONCLUSION: The disease in this patient was caused by a germline novel mutation of TINF2 in one of her parents.},
}
@article {pmid36481818,
year = {2022},
author = {Sieverling, L and Hong, C and Koser, SD and Ginsbach, P and Kleinheinz, K and Hutter, B and Braun, DM and Cortés-Ciriano, I and Xi, R and Kabbe, R and Park, PJ and Eils, R and Schlesner, M and , and Brors, B and Rippe, K and Jones, DTW and Feuerbach, L and , },
title = {Author Correction: Genomic footprints of activated telomere maintenance mechanisms in cancer.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {7574},
doi = {10.1038/s41467-022-32328-7},
pmid = {36481818},
issn = {2041-1723},
}
@article {pmid36473858,
year = {2022},
author = {He, F and Yu, Q and Wang, M and Wang, R and Gong, X and Ge, F and Yu, X and Li, S},
title = {SESAME-catalyzed H3T11 phosphorylation inhibits Dot1-catalyzed H3K79me3 to regulate autophagy and telomere silencing.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {7526},
pmid = {36473858},
issn = {2041-1723},
mesh = {*Histones ; *Sesamum ; Autophagy ; },
abstract = {The glycolytic enzyme, pyruvate kinase Pyk1 maintains telomere heterochromatin by phosphorylating histone H3T11 (H3pT11), which promotes SIR (silent information regulator) complex binding at telomeres and prevents autophagy-mediated Sir2 degradation. However, the exact mechanism of action for H3pT11 is poorly understood. Here, we report that H3pT11 directly inhibits Dot1-catalyzed H3K79 tri-methylation (H3K79me3) and uncover how this histone crosstalk regulates autophagy and telomere silencing. Mechanistically, Pyk1-catalyzed H3pT11 directly reduces the binding of Dot1 to chromatin and inhibits Dot1-catalyzed H3K79me3, which leads to transcriptional repression of autophagy genes and reduced autophagy. Despite the antagonism between H3pT11 and H3K79me3, they work together to promote the binding of SIR complex at telomeres to maintain telomere silencing. Furthermore, we identify Reb1 as a telomere-associated factor that recruits Pyk1-containing SESAME (Serine-responsive SAM-containing Metabolic Enzyme) complex to telomere regions to phosphorylate H3T11 and prevent the invasion of H3K79me3 from euchromatin into heterochromatin to maintain telomere silencing. Together, these results uncover a histone crosstalk and provide insights into dynamic regulation of silent heterochromatin and autophagy in response to cell metabolism.},
}
@article {pmid36469522,
year = {2022},
author = {Martinez, D and Lavebratt, C and Millischer, V and de Jesus R de Paula, V and Pires, T and Michelon, L and Camilo, C and Esteban, N and Pereira, A and Schalling, M and Vallada, H},
title = {Shorter telomere length and suicidal ideation in familial bipolar disorder.},
journal = {PloS one},
volume = {17},
number = {12},
pages = {e0275999},
pmid = {36469522},
issn = {1932-6203},
mesh = {Humans ; *Bipolar Disorder/genetics ; Suicidal Ideation ; Telomere/genetics ; Leukocytes ; *Suicide ; Telomere Shortening/genetics ; },
abstract = {Bipolar Disorder (BD) has recently been related to a process of accelerated aging, with shortened leukocyte telomere length (LTL) in this population. It has also been observed that the suicide rate in BD patients is higher than in the general population, and more recently the telomere length variation has been described as shorter in suicide completers compared with control subjects. Objectives The aim of the present study was to investigate if there is an association between LTL and BD in families where two or more members have BD including clinical symptomatology variables, along with suicide behavior. Methods Telomere length and single copy gene ratio (T/S ratio) was measured using quantitative polymerase chain reaction in a sample of 143 relatives from 22 families, of which 60 had BD. The statistical analysis was performed with a polygenic mixed model. Results LTL was associated with suicidal ideation (p = 0.02) as that there is an interaction between suicidal ideation and course of the disorder (p = 0.02). The estimated heritability for LTL in these families was 0.68. In addition, covariates that relate to severity of disease, i.e. suicidal ideation and course of the disorder, showed an association with shorter LTL in BD patients. No difference in LTL between BD patients and healthy relatives was observed. Conclusion LTL are shorter in subjects with familial BD suggesting that stress related sub-phenotypes possibly accelerate the process of cellular aging and correlate with disease severity and suicidal ideation.},
}
@article {pmid36466397,
year = {2022},
author = {Shi, H and Li, X and Yu, H and Shi, W and Lin, Y and Zhou, Y},
title = {Potential effect of dietary zinc intake on telomere length: A cross-sectional study of US adults.},
journal = {Frontiers in nutrition},
volume = {9},
number = {},
pages = {993425},
pmid = {36466397},
issn = {2296-861X},
abstract = {BACKGROUND: Telomere length, which is related to chronic diseases and premature mortality, is influenced by dietary factors. Zinc is known as a dietary antioxidant micronutrient, however, its impact on telomere length remains unclear.<br><br>OBJECTIVE: We aimed to examine the potential effect of dietary zinc intake on telomere length among middle-aged and older individuals in the US.<br><br>MATERIALS AND METHODS: Our study included 3,793 US participants aged 45 years and older from the 1999 to 2002 National Health and Nutrition Examination Survey (NHANES). 24-h dietary recall interviews were employed to evaluate zinc consumption. Leukocyte telomere length was assessed by real-time quantitative polymerase chain reaction (qPCR). We adopted generalized linear models to investigate the effect of dietary zinc intake on telomere length, and subgroup analyses were further applied. We further evaluated the dose-response relationship using restricted cubic spline analysis.<br><br>RESULTS: Among the 3,793 participants, the average telomere length was 0.926 &#xb1; 0.205 (T/S ratio) or 5509.5 &#xb1; 494.9 (bp). After adjusting for major confounders, every 5 mg increment in dietary zinc consumption was related to 0.64% (95% CI: 0.17%, 1.10%) longer telomere length. In the subgroup analyses, significant relationships were found in females (Percentage change: 1.11%; 95% CI: 0.48%, 1.75%), obese (Percentage change: 0.88%; 95% CI: 0.26%, 1.50%), and low energy intake individuals (Percentage change: 0.99%; 95% CI: 0.51%, 1.46%). Additionally, we revealed a positive linear relationship between dietary zinc intake and telomere length (P for non-linearity = 0.636).<br><br>CONCLUSION: Our study revealed that elevated dietary zinc intake was significantly related to longer telomere length among adults aged 45 years and older in the US. And the association was more pronounced in females, obese, and low energy intake individuals.},
}
@article {pmid36466075,
year = {2022},
author = {Krasnienkov, DS and Gorodna, OV and Kaminska, TM and Podolskiy, VV and Podolskiy, VV and Nechyporenko, MV and Antypkin, YG and Livshits, LA},
title = {Analysis of Relative Average Length of Telomeres in Leukocytes of Women with COVID-19.},
journal = {Cytology and genetics},
volume = {56},
number = {6},
pages = {526-529},
pmid = {36466075},
issn = {0095-4527},
abstract = {Coronavirus disease (COVID-19) is an acute infectious disease of the respiratory tract caused by a new SARS-CoV-2 coronavirus. A global vaccination program against SARS-CoV-2 continues, and the incidence of COVID-19 worldwide is significantly decreasing. However, among millions of those who survived COVID-19, numerous groups will need assistance due to increased clinical consequences after COVID-19. Currently, there is a need to search for molecular biomarkers for monitoring the onset and progression of post-COVID syndrome. For this purpose, the relative average length of chromosome regions was studied in the groups of women of reproductive age: in the group of patients (n = 64) recovered from COVID-19 and in the control group (n = 42) of women of the same age. The analysis was carried out using a method of multiplex monochrome quantitative real-time PCR on DNA samples isolated from the peripheral blood leukocytes. According to the results of the study, it was established that the relative average length of chromosomes in the peripheral blood leukocytes was statistically significantly lower in the group of patients with COVID-19 than in the control group (p < 0.05). The results obtained allow one to state that the observed shortening of the relative average length of telomeres in the group of patients that recovered from COVID-19 can indicate that SARS-CoV-2 infection can directly cause the erosion of telomeres in the blood cells, particularly, in leukocytes. Thus, the determination of the relative average length of telomeres can be an informative prognostic marker for estimating the risk of the severity of COVID-19 disease and the development of post-COVID syndrome.},
}
@article {pmid36462796,
year = {2022},
author = {Zizza, A and Panico, A and Grassi, T and Recchia, V and Grima, P and De Giglio, O and Bagordo, F},
title = {Is telomere length in buccal or salivary cells a useful biomarker of exposure to air pollution? A review.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {883-884},
number = {},
pages = {503561},
doi = {10.1016/j.mrgentox.2022.503561},
pmid = {36462796},
issn = {1879-3592},
mesh = {Adult ; Child ; Humans ; *Air Pollution/adverse effects ; Biomarkers ; Soot ; Telomere ; *Pesticides ; Carbon ; },
abstract = {Telomeres are repetitive DNA-protein sequences located at the end of chromosomes and play an essential role in preserving information in our genome by protecting against end-to-end fusion, nucleolytic degradation, breakage, and inappropriate recombination. The telomeres shorten with aging and this process can be affected by oxidative stress and inflammation. Environmental and occupational factors may contribute to telomere length (TL) shortening, as demonstrated by an increasing number of studies. In particular, air pollution was associated with aging-related health outcomes and molecular alterations, such as telomeric shortening. Leukocytes are widely used for TL measurement. However, buccal and salivary cells have more intimate contact with airborne pollutants and are easier to sample. The objective of this review was to identify whether salivary or buccal TL represents a valid marker for evaluating the effects of pollution on health. The reviewed studies investigated the association between TL and occupational exposure (genotoxic substances in mechanical workers, and pesticides in pesticides applicators), residential traffic exposure (NOx, NO2, PM2.5, PM10, and black carbon), and household air pollution (PM2.5 and black carbon from biomass stoves). The studies involved adults and children. Although few studies have yet been carried out, almost all reported a negative association between salivary or buccal TL and exposure to air pollutants stating that it could be a good indicator of occupational or airborne pollution exposure. However, further research is needed to evaluate the effect of acute versus long-term exposure on salivary or buccal TL as well as the role of confounding factors. Moreover, most of the reviewed studies were conducted on healthy adults, so it is important to deeply investigate how TL is associated with all-cause mortality such as cancer, diabetes, cardiovascular disease, and respiratory disease, how it can be affected during childhood, and which changes over time can be associated with diseases' onset in adulthood.},
}
@article {pmid36461827,
year = {2023},
author = {Safaee, MM and Lin, J and Smith, DL and Fury, M and Scheer, JK and Burke, JF and Bravate, C and Lambert, D and Ames, CP},
title = {Association of telomere length with risk of complications in adult spinal deformity surgery: a pilot study of 43 patients.},
journal = {Journal of neurosurgery. Spine},
volume = {38},
number = {3},
pages = {331-339},
doi = {10.3171/2022.10.SPINE22605},
pmid = {36461827},
issn = {1547-5646},
mesh = {Humans ; Adult ; Female ; Aged ; Middle Aged ; Pilot Projects ; Follow-Up Studies ; *Frailty ; *Scoliosis/surgery ; Postoperative Complications ; Quality of Life ; Retrospective Studies ; },
abstract = {OBJECTIVE: Risk stratification is a critical element of surgical planning. Early tools were fairly crude, while newer instruments incorporate disease-specific elements and markers of frailty. It is unknown if discrepancies between chronological and cellular age can guide surgical planning or treatment. Telomeres are DNA-protein complexes that serve an important role in protecting genomic DNA. Their shortening is a consequence of aging and environmental exposures, with well-established associations with diseases of aging and mortality. There are compelling data to suggest that telomere length can provide insight toward overall health. The authors sought to determine potential associations between telomere length and postoperative complications.<br><br>METHODS: Adults undergoing elective surgery for spinal deformity were prospectively enrolled. Telomere length was measured from preoperative whole blood using quantitative polymerase chain reaction and expressed as the ratio of telomere (T) to single-copy gene (S) abundance (T/S ratio), with higher T/S ratios indicating longer telomere length. Demographic and patient data included age, BMI, and results for the following rating scales: the Adult Spinal Deformity Frailty Index (ASD-FI), Oswestry Disability Index (ODI), Scoliosis Research Society-22r (SRS-22r), American Society of Anesthesiology (ASA) classification, and Charlson Comorbidity Index (CCI). Operative and postoperative complication data (medical or surgical within 90 days) were also collected.<br><br>RESULTS: Forty-three patients were enrolled, including 31 women (53%), with a mean age of 66 years and a mean BMI of 28.5. The mean number of levels fused was 11, with 21 (48.8%) combined anterior-posterior approaches. Twenty-two patients (51.2%) had a medical or surgical complication. Patients with a postoperative complication had a significantly lower T/S ratio (0.712 vs 0.813, p = 0.008), indicating shorter telomere length, despite a mild difference in age compared with patients without a postoperative complication (68 vs 63 years, p = 0.069). Patients with complications also had higher CCI scores than patients without complications (2.3 vs 3.8, p = 0.004). There were no significant differences in sex, BMI, ASD-FI score, ASA class, preoperative ODI and SRS-22r scores, number of levels fused, or use of three-column osteotomies. In a multivariate model including age, frailty, ASA class, use of an anterior-posterior approach, CCI score, and telomere length, the authors found that short telomere length was significantly associated with postoperative complications. Patients whose telomere length fell in the shortest quartile had the highest risk (OR 18.184, p = 0.030).<br><br>CONCLUSIONS: Short telomere length was associated with an increased risk of postoperative complications despite only a mild difference in chronological age. Increasing comorbidity scores also trended toward significance. Larger prospective studies are needed; however, these data provide a compelling impetus to investigate the role of biological aging as a component of surgical risk stratification.},
}
@article {pmid36458548,
year = {2023},
author = {Virseda-Berdices, A and Concostrina-Martinez, L and Martínez-González, O and Blancas, R and Resino, S and Ryan, P and Martin-Vicente, M and Brochado-Kith, O and Blanca-López, N and Mallol Poyato, MJ and López Matamala, B and Martín Parra, C and Jiménez-Sousa, M&#xc1; and Fernández-Rodríguez, A},
title = {Relative telomere length impact on mortality of COVID-19: Sex differences.},
journal = {Journal of medical virology},
volume = {95},
number = {1},
pages = {e28368},
pmid = {36458548},
issn = {1096-9071},
mesh = {Humans ; Male ; Female ; Aged ; *Sex Characteristics ; *COVID-19 ; Prognosis ; Telomere Shortening ; Telomere ; },
abstract = {Increasing age is associated with severity and higher mortality of COVID-19. Telomere shortening is associated with higher risk of infections and may be used to identify those patients who are more likely to die. We evaluated the association between relative telomere length (RTL) and COVID-19 mortality. RTL was measured in patients hospitalized because of COVID-19. We used Kaplan-Meier method to analyze survival probabilities, and Cox regression to investigate the association between RTL and mortality (30 and 90 days). Six hundred and eight patients were included in the analysis (mean age =72.5 years, 41.1% women, and 53.8% Caucasic). During the study period, 75 people died from COVID-19 and 533 survived. Lower RTL was associated with a higher risk of death in women either at 30 (adjusted hazard ratio [HR] (aHR) = 3.33; 95% confidence interval [CI] = 1.05-10.00; p = 0.040) and at 90 days (aHR = 3.57; 95%CI = 1.23-11.11; p = 0.019). Lower RTL was associated with a higher risk of dying of COVID-19 in women. This finding suggests that RTL has an essential role in the prognosis of this subset of the population.},
}
@article {pmid36457292,
year = {2023},
author = {Mayer, SE and Guan, J and Lin, J and Hamlat, E and Parker, JE and Brownell, K and Price, C and Mujahid, M and Tomiyama, AJ and Slavich, GM and Laraia, BA and Epel, ES},
title = {Intergenerational effects of maternal lifetime stressor exposure on offspring telomere length in Black and White women.},
journal = {Psychological medicine},
volume = {53},
number = {13},
pages = {6171-6182},
pmid = {36457292},
issn = {1469-8978},
support = {R01 HD073568/HD/NICHD NIH HHS/United States ; R00 AG062778/AG/NIA NIH HHS/United States ; R56 HL141878/HL/NHLBI NIH HHS/United States ; R01 AG059677/AG/NIA NIH HHS/United States ; K99 AG062778/AG/NIA NIH HHS/United States ; K12 HD051958/HD/NICHD NIH HHS/United States ; R56 AG059677/AG/NIA NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Child ; Female ; Humans ; Pregnancy ; Maternal Exposure ; *Mothers/psychology ; Prospective Studies ; Telomere/physiology ; *Telomere Shortening/physiology ; White People/psychology ; Intergenerational Relations/ethnology ; Black or African American/psychology ; Young Adult ; Middle Aged ; },
abstract = {BACKGROUND: Although maternal stressor exposure has been associated with shorter telomere length (TL) in offspring, this literature is based largely on White samples. Furthermore, timing of maternal stressors has rarely been examined. Here, we examined how maternal stressors occurring during adolescence, pregnancy, and across the lifespan related to child TL in Black and White mothers.<br><br>METHOD: Mothers (112 Black; 110 White; Mage = 39) and their youngest offspring (n = 222; Mage = 8) were part of a larger prospective cohort study, wherein mothers reported their stressors during adolescence (assessed twice during adolescence for the past year), pregnancy (assessed in midlife for most recent pregnancy), and across their lifespan (assessed in midlife). Mother and child provided saliva for TL measurement. Multiple linear regression models examined the interaction of maternal stressor exposure and race in relation to child TL, controlling for maternal TL and child gender and age. Race-stratified analyses were also conducted.<br><br>RESULTS: Neither maternal adolescence nor lifespan stressors interacted with race in relation to child TL. In contrast, greater maternal pregnancy stressors were associated with shorter child TL, but this effect was present for children of White but not Black mothers. Moreover, this effect was significant for financial but not social pregnancy stressors. Race-stratified models revealed that greater financial pregnancy stressors predicted shorter telomeres in offspring of White, but not Black mothers.<br><br>CONCLUSIONS: Race and maternal stressors interact and are related to biological aging across generations, but these effects are specific to certain races, stressors, and exposure time periods.},
}
@article {pmid36447745,
year = {2021},
author = {Aiello, A and Accardi, G and Alì, S and Caruso, C and Chen, M and De Vivo, I and Ligotti, ME and Scapagnini, G and Davinelli, S and Candore, G},
title = {Possible Association of Telomere Length With Sleep Duration. A Preliminary Pilot Study in a Sicilian Cohort with Centenarians.},
journal = {Translational medicine @ UniSa},
volume = {24},
number = {1},
pages = {24-29},
pmid = {36447745},
issn = {2239-9747},
abstract = {Telomere length (TL) is considered a biomarker of ageing although this topic is still debated. Also, sleep pattern changes are physiological part of the normal ageing process. In fact, it is widely recognized that sleep duration declines with age, leading to dysregulation of circadian rhythms. The aim of our study was to analyse the possible association of sleep duration with TL in a sample of 135 subjects with ages ranging from 20 to 111 years, recruited from Palermo and neighbouring municipalities in Sicily (Italy). Preliminary data suggest that relative TL (RTL) decreases with age in both men and women. However, at older ages, the difference between men and women tends to narrow. Nonagenarian and centenarian women do not show RTL values significantly different from those observed in adult and old women (40-89 years aged). Moreover, to analyse the relationship between TL and sleep, we stratified sleep duration into greater or lesser than 8-h periods. We found that centenarians, who daily sleep 8 hours or more, have longer RTL than centenarians who sleep fewer than 8 hours. Although the relatively small sample size of centenarians, we provide preliminary evidence that sleep duration may affect the RTL of centenarians. To the best of our knowledge, this is the first study to examine the relationship between centenarians, RTL and sleep duration. Further studies with greater sample size of centenarians are required to replicate and extend these data.},
}
@article {pmid36442845,
year = {2022},
author = {Ni, W and Wolf, K and Breitner, S and Zhang, S and Nikolaou, N and Ward-Caviness, CK and Waldenberger, M and Gieger, C and Peters, A and Schneider, A},
title = {Higher Daily Air Temperature Is Associated with Shorter Leukocyte Telomere Length: KORA F3 and KORA F4.},
journal = {Environmental science &amp; technology},
volume = {56},
number = {24},
pages = {17815-17824},
pmid = {36442845},
issn = {1520-5851},
mesh = {Adult ; Humans ; *Air Pollution/analysis ; Temperature ; Cohort Studies ; Leukocytes ; Telomere ; },
abstract = {Higher air temperature is associated with increased age-related morbidity and mortality. To date, short-term effects of air temperature on leukocyte telomere length have not been investigated in an adult population. We aimed to examine the short-term associations between air temperature and leukocyte telomere length in an adult population-based setting, including two independent cohorts. This population-based study involved 5864 participants from the KORA F3 (2004-2005) and F4 (2006-2008) cohort studies conducted in Augsburg, Germany. Leukocyte telomere length was assessed by a quantitative PCR-based method. We estimated air temperature at each participant's residential address through a highly resolved spatiotemporal model. We conducted cohort-specific generalized additive models to explore the short-term effects of air temperature on leukocyte telomere length at lags 0-1, 2-6, 0-6, and 0-13 days separately and pooled the estimates by fixed-effects meta-analysis. Our study found that between individuals, an interquartile range (IQR) increase in daily air temperature was associated with shorter leukocyte telomere length at lags 0-1, 2-6, 0-6, and 0-13 days (%change: -2.96 [-4.46; -1.43], -2.79 [-4.49; -1.07], -4.18 [-6.08; -2.25], and -6.69 [-9.04; -4.27], respectively). This meta-analysis of two cohort studies showed that between individuals, higher daily air temperature was associated with shorter leukocyte telomere length.},
}
@article {pmid36440190,
year = {2022},
author = {Lan, B and Bai, Y and Chang, X and Zhang, X},
title = {Independent and joint effect of relative telomere length and type 2 diabetes on all-cause mortality in American adults.},
journal = {Frontiers in endocrinology},
volume = {13},
number = {},
pages = {1035017},
pmid = {36440190},
issn = {1664-2392},
mesh = {Adult ; Humans ; Male ; United States ; Female ; *Diabetes Mellitus, Type 2/genetics ; Nutrition Surveys ; Telomere/genetics ; Leukocytes ; Proportional Hazards Models ; },
abstract = {OBJECTIVE: The joint effect of leukocyte telomere length (LTL) and type 2 diabetes (T2D) on the risk of all-cause death has been sparsely explored. The study designed to examine the joint effect of T2D and LTL on the probability of death in American adults.<br><br>METHODS: A cohort of 6862 adults with LTL measurements and with or without T2D from the NHANES 1999-2002 with follow-up information until 2015 was studied. Quantitative PCR was used to measure the length of telomeres relative to standard reference DNA (T/S ratio). Individuals were grouped into three tertiles according to the LTL levels, with the first tertile demonstrating the lowest one and used as the reference group. The effects of LTL and T2D status on death were evaluated using Kaplan-Meier curves along with log-rank test. Three Cox proportional hazards models with adjustment for various confounders were used to examine the links between TL and all-cause death possibility using adjusted hazard ratios (HRs).<br><br>RESULTS: Adults in the sample averaged 45.54 years of age, with 49.51% being male. After a median follow-up period of 14.4 years, 1543 (22.5%) individuals died from all cause. The probability of all-cause mortality was higher among individuals with LTL in the highest tertile than individuals in the lowest tertile (aHR = 0.89; 95%CI: 0.77-1.03); however, the difference did not reach the level of statistical significance (P = 0.11). Conversely, the individuals with T2D had a higher probability of death than individuals without (aHR = 1.26; 95%CI: 1.06-1.50; P = 0.0092). When LTL and T2D status were investigated jointly, subjects in the highest TLT tertile and with T2D had the highest probability of mortality compared with their counterparts (aHR = 1.34; 95%CI: 1.07-1.68; P = 0.0101). However, there was no independent effect of low TLT on mortality as demonstrated among individuals with diabetes (aHR = 1.14; 95%CI: 0.95-1.38; P = 0.1662).<br><br>CONCLUSION: The joint effect of TLT and T2D was larger than the sum of the independent effects on the risk of all-cause death. Participants with high TLT and diabetes showed the highest possibility of death compared with other groups.},
}
@article {pmid36437769,
year = {2022},
author = {Zhao, G and Guo, D and Li, L and Yang, C and Dong, J},
title = {The Association between Dietary Magnesium Intake and Telomere Length in Adults with Hypertension.},
journal = {The journal of nutrition, health &amp; aging},
volume = {26},
number = {11},
pages = {1010-1015},
doi = {10.1007/s12603-022-1856-y},
pmid = {36437769},
issn = {1760-4788},
mesh = {Male ; Humans ; Female ; Nutrition Surveys ; *Magnesium ; *Hypertension/genetics ; Uric Acid ; Telomere ; },
abstract = {BACKGROUND: Dietary micronutrients are significantly associated with telomere length, as shown in multiple studies. However, no study has investigated the association between magnesium intake and telomere length in adults with hypertension.<br><br>METHODS: Participants were included from the National Health and Nutrition Examination Survey (NHANES) in 1999-2000 and 2001-2002. Dietary magnesium intake was assessed using the 24 - hour recall method and the telomere length of leukocytes was measured using polymerase chain reaction (PCR). A multivariate regression model was then used to assess the association between dietary magnesium intake and telomere length in adults with hypertension.<br><br>RESULTS: Our final analysis included 2199 hypertensive adults (46.79% males) with a mean dietary magnesium intake of 254.82&#xb1;133.47 mg/day. Linear regression, adjusted for race, sex, age, smoking, uric acid, and other variables, showed that every 1 mg increase in dietary magnesium intake was associated with a 0.20 (95% CI: 0.01, 0.39, p = 0.043) longer telomere length in all participants. In the &#x2265;45 years age group, there was a statistically significant association between the telomere length and dietary magnesium (95% CI: 0.16, 0.63, p <0.001).<br><br>CONCLUSIONS: This study suggests that increased magnesium intake is associated with a longer telomere length in hypertensive adults, especially in those &#x2265;45 years of age. However, further research is needed to determine a causal relationship.},
}
@article {pmid36437244,
year = {2022},
author = {Maciejewska, N and Olszewski, M and Jurasz, J and Baginski, M and Stasevych, M and Zvarych, V and Folini, M and Zaffaroni, N},
title = {Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres.},
journal = {Cell death &amp; disease},
volume = {13},
number = {11},
pages = {1005},
pmid = {36437244},
issn = {2041-4889},
mesh = {Humans ; *Telomerase ; Telomere ; DNA Damage ; *Lung Neoplasms ; Anthraquinones/pharmacology ; Cell Line, Tumor ; *Bone Neoplasms ; },
abstract = {Telomerase reactivation is one of the hallmarks of cancer, which plays an important role in cellular immortalization and the development and progression of the tumor. Chemical telomerase inhibitors have been shown to trigger replicative senescence and apoptotic cell death both in vitro and in vivo. Due to its upregulation in various cancers, telomerase is considered a potential target in cancer therapy. In this study, we identified potent, small-molecule telomerase inhibitors using a telomerase repeat amplification protocol assay. The results of the assay are the first evidence of telomerase inhibition by anthraquinone derivatives that do not exhibit G-quadruplex-stabilizing properties. The stability of telomerase in the presence of its inhibitor was evaluated under nearly physiological conditions using a cellular thermal shift assay. Our data showed that the compound induced aggregation of the catalytic subunit (hTERT) of human telomerase, and molecular studies confirmed the binding of the hit compound with the active site of the enzyme. The ability of new derivatives to activate DNA double-strand breaks (DSBs) was determined by high-resolution microscopy and flow cytometry in tumor cell lines differing in telomere elongation mechanism. The compounds triggered DSBs in TERT-positive A549 and H460 lung cancer cell lines, but not in TERT-negative NHBE normal human bronchial epithelial and ALT-positive U2OS osteosarcoma cell lines, which indicates that the induction of DSBs was dependent on telomerase inhibition. The observed DNA damage activated DNA damage response pathways involving ATM/Chk2 and ATR/Chk1 cascades. Additionally, the compounds induced apoptotic cell death through extrinsic and intrinsic pathways in lung cancer cells. Taken together, our study demonstrated that anthraquinone derivatives can be further developed into novel telomerase-related anticancer agents.},
}
@article {pmid36435475,
year = {2023},
author = {Tao, HY and He, SM and Zhao, CY and Wang, Y and Sheng, WJ and Zhen, YS},
title = {Antitumor efficacy of a recombinant EGFR-targeted fusion protein conjugate that induces telomere shortening and telomerase downregulation.},
journal = {International journal of biological macromolecules},
volume = {226},
number = {},
pages = {1088-1099},
doi = {10.1016/j.ijbiomac.2022.11.225},
pmid = {36435475},
issn = {1879-0003},
mesh = {Animals ; Mice ; Humans ; Recombinant Fusion Proteins/genetics/pharmacology/metabolism ; *Telomerase/genetics/metabolism ; ErbB Receptors/metabolism ; Down-Regulation ; Telomere Shortening ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; *Immunoconjugates/pharmacology ; Telomere/metabolism ; },
abstract = {OBJECTIVE: To prepare a recombinant EGFR-targeted fusion protein drug conjugate acting on telomere and telomerase; and evaluate its antitumor efficacy.<br><br>METHODS: We prepared a recombinant fusion protein Fv-LDP-D3 which consists of the Fv fragment of an anti-EGFR monoclonal antibody (MAb), the apoprotein of lidamycin (LDP), and the third domain (D3) of human serum albumin (HSA); then generated the conjugate Fv-LDP-D3&#x223c;AE by integrating the active enediyne chomophore (AE) of lidamycin. Accordingly, in vitro and in vivo experiments were performed.<br><br>RESULTS: As shown, Fv-LDP-D3 specifically bound to EGFR highly-expressing cancer cells and intensely entered K-Ras mutant cells via enhanced macropinocytosis. By in vivo imaging, Fv-LDP-D3 displayed intense accumulation and persistent retention in tumor-site. Furthermore, the conjugate Fv-LDP-D3&#x223c;AE displayed highly potent cytotoxicity to cancer cells with IC50 at 0.1&#xa0;nM level. The conjugate induced telomere shortening and downregulation of telomerase and EGFR pathway related proteins. Fv-LDP-D3&#x223c;AE exhibited prominent antitumor efficacy against human colorectal cancer xenograft accompanying with significant increase of serum IFN-&#x3b2; in athymic mice.<br><br>CONCLUSION: The recombinant fusion protein conjugate that exhibits the capability of tumor-targeting drug delivery can induce telomere shortening and telomerase downregulation. The investigation may lay the foundation for the development of MAb-HSA domain-based fusion protein drug conjugates.},
}
@article {pmid36427630,
year = {2022},
author = {Jenkins, AJ and Syreeni, A and Mutter, S and Januszewski, AS and Groop, PH},
title = {Telomeres in clinical diabetes research - Moving towards precision medicine in diabetes care?.},
journal = {Diabetes research and clinical practice},
volume = {194},
number = {},
pages = {110178},
doi = {10.1016/j.diabres.2022.110178},
pmid = {36427630},
issn = {1872-8227},
mesh = {Humans ; *Precision Medicine ; Telomere/genetics ; Telomere Shortening ; *Diabetes Mellitus/genetics/therapy ; Biomarkers ; },
abstract = {The early prediction of health outcomes for people with diabetes mellitus is desirable, as are adjunct therapies to reduce the related chronic complications and risk of premature death. The length of telomeres, protective caps on chromosome ends, is influenced by genetic and acquired factors, and shorter telomeres have been associated with and predictive of adverse cardiometabolic outcomes. Many studies have shown associations between telomere length in white blood cells (WBC) and diabetes per se and its chronic complications, and some studies show that telomeres do not always progressively shorten in people with diabetes. With the pandemic of diabetes and taking into consideration the calculations of residual risk using existent risk equations, additional tests to stratify subject risk are desirable. In this evolving era of precision medicine for people with diabetes, this 'global biomarker' of WBC telomere length may be useful to help predict health outcomes, to monitor health status, and may be a therapeutic target. We comment on the field of telomere investigations in diabetes, including recommending areas for further clinical research.},
}
@article {pmid36427074,
year = {2023},
author = {Goswami, J and MacArthur, TA and Ramachandran, D and Mahony, CR and Howick, AS and Price-Troska, T and Thompson, RJ and Spears, GM and Bailey, KR and Patnaik, MS and Passos, JF and Park, MS and Ferrer, A},
title = {TELOMERE LENGTH OF PERIPHERAL BLOOD MONONUCLEAR CELLS IS ASSOCIATED WITH DISCHARGE DISPOSITION IN OLDER TRAUMA PATIENTS.},
journal = {Shock (Augusta, Ga.)},
volume = {59},
number = {3},
pages = {327-333},
pmid = {36427074},
issn = {1540-0514},
support = {R38 HL150086/HL/NHLBI NIH HHS/United States ; T32 AG049672/AG/NIA NIH HHS/United States ; UM1 HL120877/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; Male ; Aged ; Female ; *Leukocytes, Mononuclear ; *Thrombin ; Patient Discharge ; Blood Coagulation ; Telomere ; },
abstract = {Introduction: Little is known regarding peripheral blood mononuclear cell telomere length (PBMC-TL) and response to traumatic injury. The objective of this study was to characterize the role of PBMC-TL in coagulation and clinical outcomes after injury. Methods: Plasma and buffy coats were prospectively collected from trauma patients and healthy volunteers. DNA was purified and PBMC-TL quantified by quantitative polymerase chain reaction. Thrombin generation kinetics were expressed as lag time (in minutes), peak height (in nanometers), time to peak (in minutes), and endogenous thrombin potential (in nM × min). Results are in median and quartiles [Q1, Q3]. P < 0.05 was considered significant (Wilcoxon rank sum testing). Results: Forty-two younger patients (21 [20, 22] years, 69% were male) and 39 older patients (62 [61, 64] years, 79% were male) were included. There was no significant difference in Clinical Frailty Scores between groups. Younger patients had longer total PBMC-TL (0.40 Mb [0.30, 0.49] vs. 0.29 Mb [0.23, 0.33], P < 0.001) and longer average PBMC-TL per chromosome (4.3 kb [3.3, 5.3] vs. 3.2 kb [2.5, 3.7], P < 0.001). When older patients were stratified by 50th percentile of PBMC-TL, there were no differences in thrombin generation; however, those with shorter telomeres were less likely to be discharged home (29% vs. 77%, P = 0.004). Older patients in the bottom quartile of PBMC-TL had shorter lag time (2.78 min [2.33, 3.00] vs. 3.33 min [3.24, 3.89], P = 0.030) and were less likely to be discharged home (22% vs. 90%, P = 0.006) than those in the top quartile of PBMC-TL. Multivariable logistic regression models revealed both increased age and shorter PBMC-TL to be independent predictors of discharge disposition other than home. Conclusion: In older trauma patients, shorter PBMC-TL is associated with accelerated initiation of thrombin generation and lower likelihood of being discharged to home.},
}
@article {pmid36421025,
year = {2023},
author = {PerezGrovas-Saltijeral, A and Ochoa-Morales, A and Jara-Prado, A and Velázquez-Cruz, R and Rivera-Paredez, B and Dávila-OrtizdeMontellano, D and Benítez-Alonso, EO and Santamaría-Olmedo, M and Sevilla-Montoya, R and Marfil-Marín, E and Valdés-Flores, M and Martínez-Ruano, L and Camacho-Molina, A and Hidalgo-Bravo, A},
title = {Unraveling the role of relative telomere length and CAG expansion on initial symptoms of juvenile Huntington disease.},
journal = {European journal of neurology},
volume = {30},
number = {3},
pages = {612-621},
doi = {10.1111/ene.15644},
pmid = {36421025},
issn = {1468-1331},
mesh = {Adult ; Humans ; *Huntington Disease/genetics/diagnosis ; Trinucleotide Repeats/genetics ; Telomere ; Age of Onset ; },
abstract = {BACKGROUND AND PURPOSE: Juvenile-onset Huntington disease (JHD) is defined when symptoms initiate before 20 years of age. Mechanisms explaining differences between juvenile and adult onset are not fully understood. Our aim was to analyze the distribution of initial symptoms in a cohort of JHD patients and to explore its relationship with CAG expansion and relative telomere length (RTL).<br><br>METHODS: A total of 84 JHD patients and 54 neurologically healthy age and sex matched individuals were recruited. CAG length was measured by southern blot or triplet repeat primed polymerase chain reaction. RTL was measured using the Cawthon method.<br><br>RESULTS: Psychiatric symptoms were most frequent when considering the entire cohort. When divided into onset before or after 10&#x2009;years, cognitive symptoms were more frequent in the youngest, whilst in the older group psychiatric symptoms prevailed. Motor symptoms were rare in the youngest and epilepsy was observed only in this group as well as a larger CAG expansion. RTL analysis revealed shorter telomeres in JHD patients compared to controls. This difference is not influenced by age, initial symptoms, time of disease or CAG expansion.<br><br>CONCLUSIONS: To the best of our knowledge this is the largest cohort of JHD patients reported. Psychiatric manifestations deserve special attention when JHD is suspected and epilepsy is especially important in the youngest patients. Initial symptoms seem to be influenced by CAG expansion and therefore age of onset. RTL is significantly reduced in JHD patients which can influence the characteristic neurodegeneration of JHD and contribute to the clinical discrepancy between adult and juvenile forms of Huntington disease.},
}
@article {pmid36416860,
year = {2023},
author = {Jezek, M and Sun, W and Negesse, MY and Smith, ZM and Orosz, A and Green, EM},
title = {Set1 regulates telomere function via H3K4 methylation-dependent and -independent pathways and calibrates the abundance of telomere maintenance factors.},
journal = {Molecular biology of the cell},
volume = {34},
number = {1},
pages = {ar6},
pmid = {36416860},
issn = {1939-4586},
support = {R01 GM124342/GM/NIGMS NIH HHS/United States ; R25 GM055036/GM/NIGMS NIH HHS/United States ; T32 GM144876/GM/NIGMS NIH HHS/United States ; },
mesh = {Methylation ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; Histone-Lysine N-Methyltransferase/genetics/metabolism ; Histones/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Telomere/metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Set1 is an H3K4 methyltransferase that comprises the catalytic subunit of the COMPASS complex and has been implicated in transcription, DNA repair, cell cycle control, and numerous other genomic functions. Set1 also promotes proper telomere maintenance, as cells lacking Set1 have short telomeres and disrupted subtelomeric gene repression; however, the precise role for Set1 in these processes has not been fully defined. In this study, we have tested mutants of Set1 and the COMPASS complex that differentially alter H3K4 methylation status, and we have attempted to separate catalytic and noncatalytic functions of Set1. Our data reveal that Set1-dependent subtelomeric gene repression relies on its catalytic activity toward H3K4, whereas telomere length is regulated by Set1 catalytic activity but likely independent of the H3K4 substrate. Furthermore, we uncover a role for Set1 in calibrating the abundance of critical telomere maintenance proteins, including components of the telomerase holoenzyme and members of the telomere capping CST (Cdc13-Stn1-Ten1) complex, through both transcriptional and posttranscriptional pathways. Altogether, our data provide new insights into the H3K4 methylation-dependent and -independent roles for Set1 in telomere maintenance in yeast and shed light on possible roles for Set1-related methyltransferases in other systems.},
}
@article {pmid36406126,
year = {2022},
author = {Peretz, I and Kupiec, M and Sharan, R},
title = {A comparative analysis of telomere length maintenance circuits in fission and budding yeast.},
journal = {Frontiers in genetics},
volume = {13},
number = {},
pages = {1033113},
pmid = {36406126},
issn = {1664-8021},
abstract = {The natural ends of the linear eukaryotic chromosomes are protected by telomeres, which also play an important role in aging and cancer development. Telomere length varies between species, but it is strictly controlled in all organisms. The process of Telomere Length Maintenance (TLM) involves many pathways, protein complexes and interactions that were first discovered in budding and fission yeast model organisms (Saccharomyces cerevisiae, Schizosaccharomyces pombe). In particular, large-scale systematic genetic screens in budding yeast uncovered a network of ≈ 500 genes that, when mutated, cause telomeres to lengthen or to shorten. In contrast, the TLM network in fission yeast remains largely unknown and systematic data is still lacking. In this work we try to close this gap and develop a unified interpretable machine learning framework for TLM gene discovery and phenotype prediction in both species. We demonstrate the utility of our framework in pinpointing the pathways by which TLM homeostasis is maintained and predicting novel TLM genes in fission yeast. The results of this study could be used for better understanding of telomere biology and serve as a step towards the adaptation of computational methods based on telomeric data for human prognosis.},
}
@article {pmid36404192,
year = {2023},
author = {Vinayagamurthy, S and Bagri, S and Mergny, JL and Chowdhury, S},
title = {Telomeres expand sphere of influence: emerging molecular impact of telomeres in non-telomeric functions.},
journal = {Trends in genetics : TIG},
volume = {39},
number = {1},
pages = {59-73},
pmid = {36404192},
issn = {0168-9525},
support = {IA/S/18/2/504021/WTDBT_/DBT-Wellcome Trust India Alliance/India ; },
mesh = {*Telomere/genetics/metabolism ; DNA/metabolism ; *G-Quadruplexes ; Heterochromatin ; },
abstract = {Although the impact of telomeres on physiology stands well established, a question remains: how do telomeres impact cellular functions at a molecular level? This is because current understanding limits the influence of telomeres to adjacent subtelomeric regions despite the wide-ranging impact of telomeres. Emerging work in two distinct aspects offers opportunities to bridge this gap. First, telomere-binding factors were found with non-telomeric functions. Second, locally induced DNA secondary structures called G-quadruplexes are notably abundant in telomeres, and gene regulatory regions genome wide. Many telomeric factors bind to G-quadruplexes for non-telomeric functions. Here we discuss a more general model of how telomeres impact the non-telomeric genome - through factors that associate at telomeres and genome wide - and influence cell-intrinsic functions, particularly aging, cancer, and pluripotency.},
}
@article {pmid36402910,
year = {2022},
author = {Roberts, EK and Boss, J and Mukherjee, B and Salerno, S and Zota, A and Needham, BL},
title = {Persistent organic pollutant exposure contributes to Black/White differences in leukocyte telomere length in the National Health and Nutrition Examination Survey.},
journal = {Scientific reports},
volume = {12},
number = {1},
pages = {19960},
pmid = {36402910},
issn = {2045-2322},
support = {R01 AG033592/AG/NIA NIH HHS/United States ; U24 AG066528/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Adult ; Persistent Organic Pollutants ; *Polychlorinated Biphenyls/toxicity ; Nutrition Surveys ; Cross-Sectional Studies ; White People ; Leukocytes ; *Environmental Pollutants/toxicity ; Telomere/genetics ; },
abstract = {Despite racial disparities in diseases of aging and premature mortality, non-Hispanic Black Americans tend to have longer leukocyte telomere length (LTL), a biomarker of cellular aging, than non-Hispanic White Americans. Previous findings suggest that exposure to certain persistent organic pollutants (POPs) is both racially-patterned and associated with longer LTL. We examine whether Black/White differences in LTL are explained by differences in exposure to 15 POPs by estimating the indirect effect (IE) of self-reported race on LTL that is mediated through nine polychlorinated biphenyls (PCBs), three furans, and three dioxins, as well as their mixtures. Our study population includes 1,251 adults from the 1999-2000 and 2001-2002 cycles of the cross-sectional National Health and Nutrition Examination Survey. We characterized single-pollutant mediation effects by constructing survey-weighted linear regression models. We also implemented various approaches to quantify a global mediation effect of all POPs, including unpenalized linear regression, ridge regression, and examination of three summary exposure scores. We found support for the hypothesis that exposure to PCBs partially mediates Black/White differences in LTL. In single-pollutant models, there were significant IEs of race on LTL through six individual PCBs (118, 138, 153, 170, 180, and 187). Ridge regression (0.013, CI 0.001, 0.023; 26.0% mediated) and models examining summative exposure scores with linear combinations derived from principal components analysis (0.019, CI 0.009, 0.029; 34.8% mediated) and Toxic Equivalency Quotient (TEQ) scores (0.016, CI 0.005, 0.026; 28.8% mediated) showed significant IEs when incorporating survey weights. Exposures to individual POPs and their mixtures, which may arise from residential and occupational segregation, may help explain why Black Americans have longer LTL than their White counterparts, providing an environmental explanation for counterintuitive race differences in cellular aging.},
}
@article {pmid36401358,
year = {2022},
author = {Wang, L and Yin, H and Huang, S and Huang, S and Huang, C and Zhang, Z and Liu, H},
title = {Bortezomib induces cellular senescence in A549 lung cancer cells by stimulating telomere shortening.},
journal = {Human &amp; experimental toxicology},
volume = {41},
number = {},
pages = {9603271221124094},
doi = {10.1177/09603271221124094},
pmid = {36401358},
issn = {1477-0903},
mesh = {Humans ; Bortezomib/pharmacology/therapeutic use ; *Lung Neoplasms/drug therapy/genetics ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics ; A549 Cells ; Telomere Shortening ; *Antineoplastic Agents/pharmacology/therapeutic use ; Cell Line, Tumor ; Cellular Senescence ; },
abstract = {Bortezomib (BTZ) is a first-generation proteasome inhibitor with anti-tumor properties for multiple myeloma and mantle cell lymphoma. Increasing evidence has shown that BTZ exhibits toxic effects on diverse tumor cells, including non-small cell lung cancer (NSCLC) cells. However, the mechanism has not been fully evaluated. Here, we examined the regulatory effect of BTZ on cellular senescence, a potent tumor suppressive mechanism, in NSCLC cell lines. SA-β-gal staining assay showed that BTZ caused a significant increase in β-Gal positive A549 cells. BTZ also induced cell cycle arrest on G0/G1 phase in A549 cells. Furthermore, telomerase activity was markedly reduced in A549 cells treated with BTZ. BTZ reduced the expression levels of hTERT, and the key proteins binding to telomeric DNA, including POT1 and TIN2. It also induced the expressions of the cell cycle-associated tumor suppressors p53 and p21 in A549 cells. Moreover, hTERT overexpression abolished the effects of BTZ on A549 cells. These results show that BTZ induced cellular senescence by stimulating telomere shortening. Our results provide experimental data for the potential clinical application of BTZ in NSCLC treatment.},
}
@article {pmid36400982,
year = {2023},
author = {Jin, M and Huang, JD},
title = {New mechanism to promote long-term T-cell immunity by telomere transfer from antigen-presenting cells.},
journal = {Cellular &amp; molecular immunology},
volume = {20},
number = {2},
pages = {117-118},
pmid = {36400982},
issn = {2042-0226},
mesh = {*T-Lymphocytes ; *Antigen-Presenting Cells ; Antigen Presentation ; Telomere ; },
}
@article {pmid36399511,
year = {2022},
author = {Chen, L and Zhang, C and Ma, W and Huang, J and Zhao, Y and Liu, H},
title = {METTL3-mediated m6A modification stabilizes TERRA and maintains telomere stability.},
journal = {Nucleic acids research},
volume = {50},
number = {20},
pages = {11619-11634},
pmid = {36399511},
issn = {1362-4962},
mesh = {*RNA, Long Noncoding/genetics/metabolism ; Telomere/genetics/metabolism ; Telomere Shortening ; Homologous Recombination ; DNA ; Telomere Homeostasis ; },
abstract = {Telomeric repeat-containing RNA (TERRA) is a type of long non-coding RNA transcribed from telomeres, and it forms R-loops by invasion into telomeric DNA. Since either an excessive or inadequate number of R-loops leads to telomere instability, the TERRA levels need to be delicately modulated. In this study, we found that m6A modification presents on the subtelomeric regions of TERRA and stabilizes it, and the loss of METTL3 impacts telomere stability. Mechanically, the m6A modification on TERRA is catalyzed by METTL3, recognized and stabilized by the m6A reader YTHDC1. Knockdown of either METTL3 or YTHDC1 enhances TERRA degradation. The m6A-modified TERRA forms R-loops and promotes homologous recombination which is essential for the alternative lengthening of telomeres (ALT) pathway in cancer cells. METTL3 depletion leads to R-loop reduction, telomere shortening and instability. Altogether, these findings reveal that METTL3 protects telomeres by catalyzing m6A modification on TERRA, indicating that inhibition or deletion of METTL3 is potentially a new avenue for ALT cancer therapy.},
}
@article {pmid36399449,
year = {2022},
author = {Salih, A and Galazzo, IB and Petersen, SE and Lekadir, K and Radeva, P and Menegaz, G and Altmann, A},
title = {Telomere length is causally connected to brain MRI image derived phenotypes: A mendelian randomization study.},
journal = {PloS one},
volume = {17},
number = {11},
pages = {e0277344},
pmid = {36399449},
issn = {1932-6203},
support = {MR/L016311/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {*Mendelian Randomization Analysis ; *Brain/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; Phenotype ; Telomere ; },
abstract = {Recent evidence suggests that shorter telomere length (TL) is associated with neuro degenerative diseases and aging related outcomes. The causal association between TL and brain characteristics represented by image derived phenotypes (IDPs) from different magnetic resonance imaging (MRI) modalities remains unclear. Here, we use two-sample Mendelian randomization (MR) to systematically assess the causal relationships between TL and 3,935 brain IDPs. Overall, the MR results suggested that TL was causally associated with 193 IDPs with majority representing diffusion metrics in white matter tracts. 68 IDPs were negatively associated with TL indicating that longer TL causes decreasing in these IDPs, while the other 125 were associated positively (longer TL leads to increased IDPs measures). Among them, ten IDPs have been previously reported as informative biomarkers to estimate brain age. However, the effect direction between TL and IDPs did not reflect the observed direction between aging and IDPs: longer TL was associated with decreases in fractional anisotropy and increases in axial, radial and mean diffusivity. For instance, TL was positively associated with radial diffusivity in the left perihippocampal cingulum tract and with mean diffusivity in right perihippocampal cingulum tract. Our results revealed a causal role of TL on white matter integrity which makes it a valuable factor to be considered when brain age is estimated and investigated.},
}
@article {pmid36396857,
year = {2023},
author = {Hong, Z and Lin, X and Zhou, Y and Zheng, G and Liao, X and Wei, Q and Zhang, Z and Liang, J},
title = {Lean body mass but not body fat mass is related with leukocyte telomere length in children.},
journal = {International journal of obesity (2005)},
volume = {47},
number = {1},
pages = {67-74},
pmid = {36396857},
issn = {1476-5497},
mesh = {Male ; Female ; Humans ; Child ; Cross-Sectional Studies ; *Body Composition/physiology ; *Bone Density/physiology ; Absorptiometry, Photon ; Telomere ; },
abstract = {OBJECTIVES: The aim of this study was to investigate the relationship between body composition and leukocyte telomere length (LTL) in healthy Chinese children aged 6-11 years.<br><br>METHODS: This cross-sectional study enrolled 406 healthy children (175 girls and 231 boys). The relative telomere length in their peripheral blood leukocytes was determined via quantitative polymerase chain reaction. Dual-energy X-ray absorptiometry was used to determine body fat content and regional fat distribution, appendicular skeletal muscle mass (ASM), bone mineral density (BMD) and bone mineral content (BMC) at the total body (TB) and total body less head (TBLH) levels, and total body lean mass (TBLM) was then determined. ASM/height[2] (ASMI) was also calculated.<br><br>RESULTS: After adjusting for potential covariates, multiple linear regression analyses revealed that neither body fat content nor regional body fat distribution were significantly associated with LTL (&#x3b2;&#x2009;=&#x2009;-8.48&#x2009;&#xd7;&#x2009;10[-6]-1.44&#x2009;&#xd7;&#x2009;10[-1], p&#x2009;=&#x2009;0.227-0.959). However, ASM, ASMI, TB BMC/TB BMD, TBLH BMC/TBLH BMD and TBLM were positively associated with LTL (&#x3b2;&#x2009;=&#x2009;8.95&#x2009;&#xd7;&#x2009;10[-6]-4.95&#x2009;&#xd7;&#x2009;10[-1], p&#x2009;=&#x2009;0.005-0.035). Moreover, analysis of covariance revealed there was a statistically significant dose-dependent positive association between LTL and ASM, TB BMC/BMD, TBLH BMC/BMD, and TBLM (p-trend&#x2009;=&#x2009;0.002-0.025).<br><br>CONCLUSIONS: Skeletal muscle mass and bone mass but not body fat content or distribution were significantly associated with LTL in this pediatric population.},
}
@article {pmid36394537,
year = {2022},
author = {Vicari, MR and Bruschi, DP and Cabral-de-Mello, DC and Nogaroto, V},
title = {Telomere organization and the interstitial telomeric sites involvement in insects and vertebrates chromosome evolution.},
journal = {Genetics and molecular biology},
volume = {45},
number = {3 Suppl 1},
pages = {e20220071},
pmid = {36394537},
issn = {1415-4757},
abstract = {Telomere has a central role in chromosomal stability events. Chromosome ends organized in telomere-loop prevent activation of DNA damage response (DDR) mechanisms, thus keeping the chromosome structure organized. On the other hand, free chromosome ends, dysfunctional telomeres, and interstitial telomeric sequences (ITS) can trigger chromosome rearrangements. Here, the telomere organization, function, and maintenance mechanisms, in addition to ITS types and their involvement in chromosome changes, were revisited. Despite a general (TTAGGG)n sequence being present in vertebrate telomeres, insects show more diversification of their telomere motif. The relation between ITS and chromosome rearrangements was observed in insects and vertebrates, demonstrating different types of genome organization and distribution. Some ITS cannot be considered relicts of chromosome rearrangements because probable they were inserted during a double-strand break repair mechanism. On the other hand, the involvement of telomere sequences participating or triggering chromosome rearrangements or organizing satellite DNA components in several species groups is evident. The genomic assembling advances and applying other methodologies over ITS, and their flanking regions, can help to understand the telomere participation in the chromosomal evolution in species groups with highly diversified karyotypes.},
}
@article {pmid36394204,
year = {2022},
author = {Yuan, X and Yuan, H and Zhang, N and Liu, T and Xu, D},
title = {Thyroid carcinoma-featured telomerase activation and telomere maintenance: Biology and translational/clinical significance.},
journal = {Clinical and translational medicine},
volume = {12},
number = {11},
pages = {e1111},
pmid = {36394204},
issn = {2001-1326},
mesh = {Humans ; *Telomerase/genetics/metabolism ; *Thyroid Neoplasms/diagnosis/genetics ; Telomere/genetics/metabolism ; Telomere Homeostasis/genetics ; Biology ; },
abstract = {BACKGROUND: Telomerase is a ribonucleoprotein complex consisting of a catalytic component telomerase reverse transcriptase (TERT), internal RNA template and other co-factors, and its essential function is to synthesize telomeric DNA, repetitive TTAGGG sequences at the termini of linear chromosomes. Telomerase is silent in normal human follicular thyroid cells, primarily due to the TERT gene being tightly repressed. During the development and progression of thyroid carcinomas (TCs), TERT induction and telomerase activation is in general required to maintain telomere length, thereby conferring TC cells with immortal and aggressive phenotypes.<br><br>METHODS: The genomic alterations of the TERT loci including TERT promoter's gain-of-function mutations, copy number gain, fusion and rearrangements, have recently been identified in TCs as mechanisms to induce TERT expression and to activate telomerase. Importantly, numerous studies have consistently shown that TERT promoter mutations and TERT expression occur in all TC subtypes, and are robustly associated with TC malignancy, aggressiveness, treatment failure and poor outcomes. Therefore, the assessment of TERT promoter mutations and TERT expression is highly valuable in TC diagnostics, prognosis, treatment decision, and follow-up design. In addition, the TERT promoter is frequently hypermethylated in TC cells and tumors, which is required to activate TERT transcription and telomerase. Dysregulation of other components in the telomerase complex similarly upregulate telomerase. Moreover, shortened telomeres lead to altered gene expression and metabolism, thereby actively promoting TC aggressiveness. Here we summarize recent findings in TCs to provide the landscape of TC-featured telomere/telomerase biology and discuss underlying implications in TC precision medicine.<br><br>CONCLUSION: Mechanistic insights into telomerase activation and TERT induction in TCs are important both biologically and clinically. The TERT gene aberration and expression-based molecular classification of TCs is proposed, and for such a purpose, the standardization of the assay and evaluation system is required. Moreover, the TERT-based system and 2022 WHO TC classification may be combined to improve TC care.},
}
@article {pmid36385813,
year = {2022},
author = {Liu, Y and Ye, X and Wang, Z and Zong, S and Cui, Y},
title = {In Situ Super-Resolution Imaging of Telomeres with DNA-PAINT.},
journal = {ACS omega},
volume = {7},
number = {44},
pages = {40512-40519},
pmid = {36385813},
issn = {2470-1343},
abstract = {Telomeres are located at the ends of chromosomes and play an important role in maintaining the integrity of chromosomes and controlling the cycle of cell division. Studies have shown that abnormal telomere length may lead to the occurrence of some diseases. Therefore, accurate measurement of telomere length will be helpful for the prediction and diagnosis of related diseases. DNA point accumulation for imaging in nanoscale topography (PAINT) is an optical super-resolution technology that relies on the instantaneous binding of the fluorescent DNA imaging strand to the target epitope. Here, we present the first demonstration of DNA-PAINT-based in situ super-resolution imaging of telomeres as well as centromeres. For DNA-PAINT imaging, Cy5-labeled telomere DNA (5'-Cy5-TTTTTCCCTAACCCTAA-3') and Cy3-labeled centromere DNA (5'-Cy3-TTTTTAGCTTCTGTCTAGTTT-3') are utilized as the imager strands. Through an improved permeabilization strategy that we proposed, the imager strands can bind with intracellular telomeres and centromeres with high specificity, realizing super-resolution imaging of telomeres and centromeres. To check the applicability of DNA-PAINT in evaluating telomere length, we conducted an experiment using azidothymidine (AZT)-treated tumor cells as the imaging target. The DNA-PAINT imaging results clearly revealed the telomerase inhibition effect of AZT. Compared with single-molecule localization microscopy (SMLM) with peptide nucleic acid (PNA)-based fluorescence in situ hybridization (FISH), our method has the advantages of low cost, low toxicity, and simple equipment. Such a DNA-PAINT-based imaging strategy holds great potential in measuring telomere length with high accuracy, which would play an important role in the study of telomere-related diseases such as cancer.},
}
@article {pmid36374285,
year = {2022},
author = {Kohlrausch, FB and Wang, F and Luo, D and Mahn, R and Keefe, DL},
title = {Telomere fusions as a signal of term placental aging? A pilot study.},
journal = {Reproduction &amp; fertility},
volume = {3},
number = {4},
pages = {L9-L11},
pmid = {36374285},
issn = {2633-8386},
mesh = {Animals ; Humans ; Female ; Pregnancy ; Pilot Projects ; *Placenta ; },
abstract = {The placenta plays an essential role at the beginning of life, nourishing and supporting the fetus, but its life span is limited. In late pregnancy, the placenta develops signs of aging, including inflammation and impaired function, which may complicate pregnancy. Placentas also show another sign of aging - cells with extra or missing chromosomes. Chromosomally abnormal cells could gather in the placenta if they get stranded there and/or if the cells do not separate normally. Chromosome separation goes wrong in aging cells when the DNA sequences, which protect the ends of the chromosomes, erode. When chromosomes lose their protective caps, they fuse which leads to abnormal numbers of chromosomes. In this pilot study, for the first time, we found fusions between the caps in a human placenta when it reaches full term. More studies are needed to decide whether this has an influence on how the placenta works and outcomes of pregnancy.},
}
@article {pmid36372149,
year = {2023},
author = {Liu, C and Chen, YJ and Sun, B and Chen, HG and Mustieles, V and Messerlian, C and Sun, Y and Meng, TQ and Lu, WQ and Pan, XF and Xiong, CL and Hou, J and Wang, YX},
title = {Blood trihalomethane concentrations in relation to sperm mitochondrial DNA copy number and telomere length among 958 healthy men.},
journal = {Environmental research},
volume = {216},
number = {Pt 4},
pages = {114737},
doi = {10.1016/j.envres.2022.114737},
pmid = {36372149},
issn = {1096-0953},
mesh = {Humans ; Male ; *Semen Analysis ; Semen/chemistry ; DNA, Mitochondrial ; DNA Copy Number Variations ; Trihalomethanes/toxicity ; Spermatozoa ; Telomere ; *Water Pollutants, Chemical/analysis ; },
abstract = {BACKGROUND: In animal and human studies, exposure to trihalomethanes (THMs) has been associated with reduced semen quality. However, the underlying mechanisms remain poorly understood.<br><br>OBJECTIVE: To investigate the associations of blood THM concentrations with sperm mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) among healthy men.<br><br>METHODS: We recruited 958 men who volunteered as potential sperm donors. A single blood sample was collected from each participant at recruitment and measured for chloroform (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and bromoform (TBM) concentrations. Within a 90-day follow-up, the last semen sample provided by each participant was quantified for sperm mtDNAcn and TL. We used multivariable linear regression models to assess the associations between blood THM concentrations and sperm mtDNAcn and TL. We also performed stratified analyses according to the time intervals between baseline blood THM determinations and semen collection (i.e., 0-9, 10-14, 15-69, or >69 days) to explore potential windows of susceptibility.<br><br>RESULTS: After adjusting for potential confounders, we found inverse associations between quartiles (or categories) of blood TBM, brominated THM (Br-THM, the sum of BDCM, DBCM, and TBM), and total THM (TTHM, the sum of all four THMs) concentrations and sperm mtDNAcn (all P for trend&#x2264;0.03). Besides, we found inverse associations between quartiles of blood TCM, Br-THM, chlorinated THM (Cl-THM, the sum of TCM, BDCM, and DBCM), and TTHM concentrations and sperm TL (all P for trend<0.10). Stratified analyses showed stronger associations between Br-THM concentrations and sperm mtDNAcn determined 15-69 days since baseline exposure determinations, and between blood TCM and TTHM concentrations and sperm TL determined >69 days since baseline exposure determinations.<br><br>CONCLUSION: Exposure to THMs may be associated with sperm mitochondrial and telomeric dysfunction.},
}
@article {pmid36371747,
year = {2023},
author = {Yu, HJ and Ho, M and Chau, PH and Geng, L and Fong, DYT},
title = {Salivary telomere length and the risks of prediabetes and diabetes among middle-aged and older adults: findings from the Health and Retirement Study.},
journal = {Acta diabetologica},
volume = {60},
number = {2},
pages = {273-283},
pmid = {36371747},
issn = {1432-5233},
mesh = {Male ; Middle Aged ; Humans ; Aged ; Retirement ; Overweight ; *Prediabetic State/epidemiology/genetics ; Obesity/complications/epidemiology ; *Diabetes Mellitus/epidemiology/genetics ; Telomere Shortening ; Telomere/genetics ; *Cardiovascular Diseases ; },
abstract = {AIM: To assess the association of telomere length (TL) with prediabetes/diabetes and to explore the potential factors affecting TL among individuals with prediabetes/diabetes by weight status.<br><br>METHODS: This study included 3,379 eligible adults (aged 45-85&#xa0;years, males: 42%) from the US Health and Retirement Study in 2008. TL was assayed using quantitative PCR of saliva (T/S ratio). Linear and nonlinear associations between TL and prediabetes/diabetes were assessed using the logistic regression and restricted cubic spline model, respectively, adjusting for TL-plate numbers, age, sex, race, body mass index, lifestyles, diabetes medications, and cardiometabolic parameters (blood pressure, C-reactive protein, and total cholesterol). Multiple linear regression was used for testing any factors associated with TL.<br><br>RESULTS: Among 3,379 participants, 868 (25.7%) had prediabetes with a mean TL of 1.34&#x2009;&#xb1;&#x2009;0.37 (T/S ratio) and 858 (25.4%) had diabetes with a mean TL of 1.36&#x2009;&#xb1;&#x2009;0.43 (T/S ratio). Neither linear nor nonlinear association of TL with prediabetes/diabetes was significant by weight status. Age was negatively associated with TL in both normal-weight (&#x3b2;&#x2009;=&#x2009;-&#x2009;0.002, p&#x2009;=&#x2009;0.025) and overweight/obese (&#x3b2;&#x2009;=&#x2009;-&#x2009;0.002, p&#x2009;=&#x2009;0.006) prediabetes, but non-significant in normal-weight and overweight/obese diabetes. BMI and cardiometabolic parameters were not associated with TL in prediabetes/diabetes by weight status.<br><br>CONCLUSIONS: Salivary TL was not associated with prediabetes/diabetes among the US middle-aged and older adults. Further longitudinal studies are required to establish the link between TL and diabetes development and to identify potential factors affecting TL shortening, particularly in normal-weight diabetic patients.},
}
@article {pmid36370823,
year = {2023},
author = {Yasir, S and Thompson, S and Chen, ZE and Knudson, R and Knutson, D and Kloft-Nelson, S and Graham, RP and Jain, D and Simon, SM and Wu, TT and Torbenson, M},
title = {Alternative lengthening of telomeres in primary hepatic neoplasms.},
journal = {Human pathology},
volume = {131},
number = {},
pages = {79-86},
pmid = {36370823},
issn = {1532-8392},
support = {P50 CA210964/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; *Carcinoma, Hepatocellular/genetics/pathology ; *Hemangiosarcoma/genetics/pathology ; In Situ Hybridization, Fluorescence ; *Liver Neoplasms/genetics/pathology ; *Cholangiocarcinoma/genetics/pathology ; *Carcinosarcoma/pathology ; Bile Ducts, Intrahepatic/pathology ; *Bile Duct Neoplasms/genetics/pathology ; Telomere/genetics/pathology ; },
abstract = {The alternative lengthening of telomeres (ALT) phenotype is characterized by ultra-bright telomeres on fluorescence in situ hybridization (FISH) and is a marker of a unique mechanism of telomere maintenance in tumors. ALT does not occur in normal tissues. ALT has been described in hepatocellular carcinoma (5-10%) and in primary hepatic angiosarcomas (75%). To study the frequency of ALT in other primary hepatic tumors, a wide range of primary hepatic neoplasms were retrieved. The tumors included the following: intrahepatic and hilar cholangiocarcinomas (N = 110), hepatic adenomas (N = 35), hepatocellular carcinomas (N = 30), fibrolamellar carcinomas (n = 11), combined cholangiocarcinoma-hepatocellular carcinomas (N = 8), carcinosarcoma (N = 10), hepatoblastomas (N = 5), hemangiomas (N = 4), angiosarcomas (N = 8), epithelioid hemangioendotheliomas (N = 10), calcified nested stromal epithelial tumor (N = 2), embryonal sarcoma (N = 2), rhabdoid tumor (N = 1), bile duct adenoma (N = 1), and angiomyolipoma (N = 1). For epithelial tumors, ALT-FISH was positive in one carcinosarcoma (10% of cases), one cholangiocarcinoma (1% of cases), and one combined hepatocellular carcinoma-cholangiocarcinoma (13% of cases). In the hepatocellular carcinoma component of both the carcinosarcoma and the combined hepatocellular carcinoma-cholangiocarcinoma, the tumor cells showed patchy marked nuclear pleomorphism akin to that described previously for chromophobe hepatocellular carcinoma, which are typically ALT FISH positive. The ALT-positive cholangiocarcinoma also showed patchy, striking nuclear pleomorphism. For soft tissue tumors, ALT was positive in two angiosarcomas (N = 2; 25% of cases). In summary, this study shows that ALT-FISH is positive in rare carcinosarcomas, cholangiocarcinomas, and combined cholangiocarcinoma-hepatocellular carcinoma. ALT is not a significant mechanism of telomere maintenance in hepatocellular adenomas or fibrolamellar carcinomas and was negative in all other tested primary hepatic neoplasms. ALT-FISH is also positive in a subset of primary hepatic angiosarcomas.},
}
@article {pmid36364907,
year = {2022},
author = {Nonsa-Ard, R and Aneknan, P and Tong-Un, T and Honsawek, S and Leelayuwat, N},
title = {Effects of Irvingia gabonensis Extract on Metabolism, Antioxidants, Adipocytokines, Telomere Length, and Aerobic Capacity in Overweight/Obese Individuals.},
journal = {Nutrients},
volume = {14},
number = {21},
pages = {},
pmid = {36364907},
issn = {2072-6643},
support = {N/A//Blackmores Limited and Exercise and Sport Sciences Development and Research Group, Khon Kaen University, Khon Kaen, Thailand./ ; },
mesh = {Humans ; Adipokines ; Adiponectin ; *Antioxidants/therapeutic use ; Ascorbic Acid/therapeutic use ; Dietary Supplements ; Double-Blind Method ; Inflammation/drug therapy ; Obesity/drug therapy ; *Overweight ; Plant Extracts/pharmacology/therapeutic use ; Polyesters/therapeutic use ; Telomere ; },
abstract = {We investigated the effects of Irvingia gabonensis (IG) kernel extract on the metabolism, adiposity indices, redox status, inflammation, adipocytokines, blood leukocyte relative telomere length (RTL), and aerobic capacity of overweight/obese individuals. All participants used the first 12-week phase to monitor body weight. They were then randomly divided into two groups: (1) 300 mg IG or (2) placebo (PLA). Both groups took one tablet per day for 12 weeks. The variables were measured before supplementation and after 3, 6, and 12 weeks of supplementation. RTL and aerobic capacity were measured before and after 12 weeks. Compared with the PLA, the IG increased plasma vitamin C after supplementation at 6 (p < 0.01) and 12 weeks (p < 0.05) and serum adiponectin after 3 weeks (p < 0.05). Compared with before supplementation, plasma malondialdehyde in the IG and serum leptin in the PLA were decreased after 12-week supplementation, without any differences between the groups. There were no differences between groups with respect to metabolism, inflammation, RTL, and aerobic capacity after the supplementation. We suggest that 12-week daily IG supplementation improved plasma vitamin C and adiponectin. The findings show the possible mechanism contributing to the effect of IG supplementation on a reduction in obesity-related complications.},
}
@article {pmid36362235,
year = {2022},
author = {Scarabino, D and Veneziano, L and Mantuano, E and Arisi, I and Fiore, A and Frontali, M and Corbo, RM},
title = {Leukocyte Telomere Length as Potential Biomarker of HD Progression: A Follow-Up Study.},
journal = {International journal of molecular sciences},
volume = {23},
number = {21},
pages = {},
pmid = {36362235},
issn = {1422-0067},
support = {2018; 2019//Sapienza University of Rome/ ; grant 0942//EHDN seed fund/ ; 2020//AICH/ ; 2019-2021//Fondo Ordinario Enti (FOE D.M 865/2019) in the framework of a collaboration agreement between CNR and EBRI/ ; },
mesh = {Humans ; *Huntington Disease/diagnosis/genetics ; Follow-Up Studies ; Telomere/genetics ; Leukocytes, Mononuclear ; Leukocytes ; Biomarkers ; },
abstract = {The identification of biomarkers for neurodegenerative disorders such as Huntington's disease (HD) is crucial for monitoring disease progression and therapeutic trial outcomes, especially in the pre-manifest disease stage (pre-HD). In a previous study, we observed that leukocyte telomere length (LTL) was strongly correlated with the estimated time to clinical onset in pre-HD subjects. To validate this hypothesis, we designed a follow-up study in which we analyzed LTL in 45 pre-HD stage subjects at baseline (T0) and then again after clinical onset at follow-up (T1); the follow-up interval was about 3 years, and the CAG range was 39-51 repeats; 90 peripheral blood mononuclear cell samples (PBMCs) were obtained from the Enroll-HD biorepository. In pre-HD subjects at T0, LTL was significantly reduced by 22% compared to the controls and by 14% from T0 at T1. No relationship was observed between the LTL and CAG numbers in subjects carrying different CAG repeats at T0 and at T1, suggesting that LTL reduction occurs independently of CAG number in pre-HD subjects. ROC curve analysis was used to test the validity of LTL as a potential biomarker of HD progression and showed that LTL measurement is extremely accurate in discriminating pre-HD subjects from the controls and even pre-HD from manifest HD, thus yielding a robust prognostic value in pre-HD subjects.},
}
@article {pmid36362129,
year = {2022},
author = {Nonsa-Ard, R and Aneknan, P and Tong-Un, T and Honsawek, S and Leelayuwat, C and Leelayuwat, N},
title = {Telomere Length Is Correlated with Resting Metabolic Rate and Aerobic Capacity in Women: A Cross-Sectional Study.},
journal = {International journal of molecular sciences},
volume = {23},
number = {21},
pages = {},
pmid = {36362129},
issn = {1422-0067},
support = {PHD/0005/2559//The Royal Golden Jubilee (RGJ) Ph.D. Program/ ; },
mesh = {Humans ; Female ; *Basal Metabolism ; Cross-Sectional Studies ; *Obesity ; Energy Intake ; Telomere ; Body Composition ; },
abstract = {This study investigated the associations between relative telomere length (RTL) and resting metabolic rate (RMR), resting fat oxidation (RFO), and aerobic capacity and whether oxidative stress and inflammation are the underlying mechanisms in sedentary women. We also aimed to determine whether the correlations depend on age and obesity. Sixty-eight normal weight and 66 obese women participated in this study. After adjustment for age, energy expenditure, energy intake, and education level, the RTL of all participants was negatively correlated with absolute RMR (RMRAB) and serum high-sensitivity C-reactive protein (hsCRP) concentration, and positively correlated with maximum oxygen consumption (V˙O2max) (all p < 0.05). After additional adjustment for adiposity indices and fat-free mass (FFM), RTL was positively correlated with plasma vitamin C concentration (p < 0.05). Furthermore, after adjustment for fasting blood glucose concentration, RTL was negatively correlated with age and positively correlated with V˙O2max (mL/kg FFM/min). We found that normal weight women had longer RTL than obese women (p < 0.001). We suggest that RTL is negatively correlated with RMRAB and positively correlated with aerobic capacity, possibly via antioxidant and anti-inflammatory mechanisms. Furthermore, age and obesity influenced the associations. We provide useful information for the management of promotion strategies for health-related physical fitness in women.},
}
@article {pmid36359878,
year = {2022},
author = {Reddy, HM and Randall, TA and Cipressa, F and Porrazzo, A and Cenci, G and Frydrychova, RC and Mason, JM},
title = {Identification of the Telomere elongation Mutation in Drosophila.},
journal = {Cells},
volume = {11},
number = {21},
pages = {},
pmid = {36359878},
issn = {2073-4409},
mesh = {Animals ; *Drosophila/genetics ; *Drosophila melanogaster/genetics ; Gene Products, gag/genetics ; Telomere/genetics ; Mutation/genetics ; },
abstract = {Telomeres in Drosophila melanogaster, which have inspired a large part of Sergio Pimpinelli work, are similar to those of other eukaryotes in terms of their function. Yet, their length maintenance relies on the transposition of the specialized retrotransposons Het-A, TART, and TAHRE, rather than on the activity of the enzyme telomerase as it occurs in most other eukaryotic organisms. The length of the telomeres in Drosophila thus depends on the number of copies of these transposable elements. Our previous work has led to the isolation of a dominant mutation, Tel[1], that caused a several-fold elongation of telomeres. In this study, we molecularly identified the Tel[1] mutation by a combination of transposon-induced, site-specific recombination and next-generation sequencing. Recombination located Tel[1] to a 15 kb region in 92A. Comparison of the DNA sequence in this region with the Drosophila Genetic Reference Panel of wild-type genomic sequences delimited Tel[1] to a 3 bp deletion inside intron 8 of Ino80. Furthermore, CRISPR/Cas9-induced deletions surrounding the same region exhibited the Tel[1] telomere phenotype, confirming a strict requirement of this intron 8 gene sequence for a proper regulation of Drosophila telomere length.},
}
@article {pmid36359738,
year = {2022},
author = {Sung, JY and Cheong, JH},
title = {Single Cell Analysis of Gastric Cancer Reveals Non-Defined Telomere Maintenance Mechanism.},
journal = {Cells},
volume = {11},
number = {21},
pages = {},
pmid = {36359738},
issn = {2073-4409},
mesh = {Humans ; *Stomach Neoplasms/genetics ; Single-Cell Analysis ; Ubiquitin-Protein Ligases/metabolism ; Telomere/metabolism ; Tumor Necrosis Factor-alpha ; Homeostasis ; },
abstract = {Telomere maintenance mechanisms (TMMs) are important for cell survival and homeostasis. However, most related cancer research studies have used heterogenous bulk tumor tissue, which consists of various single cells, and the cell type properties cannot be precisely recognized. In particular, cells exhibiting non-defined TMM (NDTMM) indicate a poorer prognosis than those exhibiting alternative lengthening of telomere (ALT)-like mechanisms. In this study, we used bioinformatics to classify TMMs by cell type in gastric cancer (GC) in single cells and compared the biological processes of each TMM. We elucidated the pharmacological vulnerabilities of NDTMM type cells, which are associated with poor prognosis, based on molecular mechanisms. We analyzed differentially expressed genes in cells exhibiting different TMMs in two single-cell GC cohorts and the pathways enriched in single cells. NDTMM type cells showed high stemness, epithelial-mesenchymal transition, cancer hallmark activity, and metabolic reprogramming with mitochondrial abnormalities. Nuclear receptor subfamily 4 group A member 1 (NR4A1) activated parkin-dependent mitophagy in association with tumor necrosis factor-alpha (TNFA) to maintain cellular homeostasis without TMM. NR4A1 overexpression affected TNFA-induced GC cell apoptosis by inhibiting Jun N-terminal kinase/parkin-dependent mitophagy. Our findings also revealed that NR4A1 is involved in cell cycle mediation, inflammation, and apoptosis to maintain cell homeostasis, and is a novel potential therapeutic target in recalcitrant GC.},
}
@article {pmid36359275,
year = {2022},
author = {Macek, P and Poreba, R and Gac, P and Bogunia-Kubik, K and Dratwa, M and Wieckiewicz, M and Wojakowska, A and Michalek-Zrabkowska, M and Mazur, G and Martynowicz, H},
title = {Genetic Variants of the TERT Gene and Telomere Length in Obstructive Sleep Apnea.},
journal = {Biomedicines},
volume = {10},
number = {11},
pages = {},
pmid = {36359275},
issn = {2227-9059},
support = {STM.A210.20.006//Wroc&#x142;aw Medical University/ ; },
abstract = {Introduction: Obstructive sleep apnea (OSA) is a worldwide breathing disorder that has been diagnosed globally in almost 1 billion individuals aged 30−69 years. It is characterized by repeated upper airway collapses during sleep. Telomerase reverse transcriptase (TERT) is involved in the prevention of telomere shortening. This prospective, observational study aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) of TERT and the severity of OSA, taking into account hypertension and diabetes prevalence. Methods: A total of 149 patients with OSA were diagnosed using one-night video-polysomnography based on the American Academy of Sleep Medicine guidelines. The TERT SNPs and telomere length (TL) were detected using real-time quantitative polymerase chain reaction. Results: Statistical analysis showed that there is no relationship between the rs2853669 and rs2736100 polymorphisms of TERT, and the severity of OSA (p > 0.05). Moreover, no relationship between TL and the severity of OSA was observed. The G allele in the locus of rs2736100 TERT was associated with hypertension prevalence and was more prevalent in hypertensives patients (46.00% vs. 24.49%, p = 0.011). The prevalence of hypertension was higher in patients with the C allele in the locus of rs2853669 than in patients without this allele (50.79% vs. 30.23%, p = 0.010). Moreover, a lower prevalence of diabetes was observed in homozygotes of rs2736100 TERT than in heterozygotes (5.63% vs. 15.38%, p = 0.039). Conclusion: This study showed no relationship between OSA and TERT SNPs. However, SNPs of the TERT gene (rs2736100 and rs2853669) were found to affect arterial hypertension and diabetes prevalence.},
}
@article {pmid36357941,
year = {2022},
author = {Shin, DY and Lim, KM and Park, HS and Kwon, S and Yoon, SS and Lee, DS},
title = {The importance of critically short telomere in myelodysplastic syndrome.},
journal = {Biomarker research},
volume = {10},
number = {1},
pages = {79},
pmid = {36357941},
issn = {2050-7771},
support = {NRF-2020R1A3B3079653//National Research Foundation of Korea/ ; },
abstract = {A few critically short telomeres trigger genomic instability regardless of average telomere length (TL). Recently, the telomere shortest length assay (TeSLA) was developed to detect critically short telomeres and measure absolute telomeres. Using TeSLA with the internally labeled biotin probe, we measured the TL of bone marrow (BM) aspirates from 52 patients with myelodysplastic syndrome (MDS). A percentage of shortest telomeres (< 1.0 kb (ShTL1.0)) were calculated. ShTL1.0 was correlated to IPSS-R risk (spearman's rho = 0.35 and p = 0.0196), and ShTL1.0 and BM blast (2.61% in < 5% blast, 4.15% in 5-10% blast, and 6.80% in 10-20% blast, respectively, p = 0.0332). Interestingly, MDS patients with a shortest TL ≥ 0.787 kb at the time of diagnosis showed better overall survival (OS) and progression-free survival (PFS) than patients with a shortest TL < 0.787 kb in the multivariate analyses (HR = 0.13 and 0.30, p = 0.011 and 0.048 for OS and PFS, respectively). Our results clearly show the presence and abundance of critically short telomeres in MDS patients. These pathologic telomeres are associated with IPSS-R which is a validated prognostic scoring system in MDS. Furthermore, they are independent prognostic factors for OS in MDS patients. Future prospective studies are needed to validate our results.},
}
@article {pmid36356143,
year = {2022},
author = {Chun-On, P and Hinchie, AM and Beale, HC and Gil Silva, AA and Rush, E and Sander, C and Connelly, CJ and Seynnaeve, BKN and Kirkwood, JM and Vaske, OM and Greider, CW and Alder, JK},
title = {TPP1 promoter mutations cooperate with TERT promoter mutations to lengthen telomeres in melanoma.},
journal = {Science (New York, N.Y.)},
volume = {378},
number = {6620},
pages = {664-668},
pmid = {36356143},
issn = {1095-9203},
support = {R01 HL135062/HL/NHLBI NIH HHS/United States ; R35 CA209974/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; *Melanoma/genetics ; Mutation ; *Promoter Regions, Genetic/genetics ; *Shelterin Complex/genetics ; *Skin Neoplasms/genetics ; *Telomerase/genetics ; Telomere/genetics/metabolism ; *Telomere Homeostasis/genetics ; *Telomere-Binding Proteins/genetics ; Transcriptional Activation ; },
abstract = {Overcoming replicative senescence is an essential step during oncogenesis, and the reactivation of TERT through promoter mutations is a common mechanism. TERT promoter mutations are acquired in about 75% of melanomas but are not sufficient to maintain telomeres, suggesting that additional mutations are required. We identified a cluster of variants in the promoter of ACD encoding the shelterin component TPP1. ACD promoter variants are present in about 5% of cutaneous melanoma and co-occur with TERT promoter mutations. The two most common somatic variants create or modify binding sites for E-twenty-six (ETS) transcription factors, similar to mutations in the TERT promoter. The variants increase the expression of TPP1 and function together with TERT to synergistically lengthen telomeres. Our findings suggest that TPP1 promoter variants collaborate with TERT activation to enhance telomere maintenance and immortalization in melanoma.},
}
@article {pmid36352846,
year = {2022},
author = {Deng, Y and Li, Q and Zhou, F and Li, G and Liu, J and Lv, J and Li, L and Chang, D},
title = {Telomere length and the risk of cardiovascular diseases: A Mendelian randomization study.},
journal = {Frontiers in cardiovascular medicine},
volume = {9},
number = {},
pages = {1012615},
pmid = {36352846},
issn = {2297-055X},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; },
abstract = {BACKGROUND: The causal direction and magnitude of the associations between telomere length (TL) and cardiovascular diseases (CVDs) remain uncertain due to susceptibility of reverse causation and confounding. This study aimed to investigate the associations between TL and CVDs using Mendelian randomization (MR).<br><br>MATERIALS AND METHODS: In this two-sample MR study, we identified 154 independent TL-associated genetic variants from a genome-wide association study (GWAS) consisting of 472,174 individuals (aged 40-69) in the UK Biobank. Summary level data of CVDs were obtained from different GWASs datasets. Methods of inverse variance weighted (IVW), Mendelian Randomization-Egger (MR-Egger), Mendelian Randomization robust adjusted profile score (MR-RAPS), maximum likelihood estimation, weighted mode, penalized weighted mode methods, and Mendelian randomization pleiotropy residual sum and outlier test (MR-PRESSO) were conducted to investigate the associations between TL and CVDs.<br><br>RESULTS: Our findings indicated that longer TL was significantly associated with decreased risk of coronary atherosclerosis [odds ratio (OR), 0.85; 95% confidence interval (CI), 0.75-0.95; P = 4.36E-03], myocardial infarction (OR, 0.72; 95% CI, 0.63-0.83; P = 2.31E-06), ischemic heart disease (OR, 0.87; 95% CI, 0.78-0.97; P = 1.01E-02), stroke (OR, 0.87; 95% CI, 0.79-0.95; P = 1.60E-03), but an increased risk of hypertension (OR, 1.12; 95% CI, 1.02-1.23; P = 2.00E-02). However, there was no significant association between TL and heart failure (OR, 0.94; 95% CI, 0.87-1.01; P = 1.10E-01), atrial fibrillation (OR, 1.01; 95% CI, 0.93-1.11; P = 7.50E-01), or cardiac death (OR, 0.95; 95% CI, 0.82-1.10; P = 4.80E-01). Both raw and outlier corrected estimates from MR-PRESSO were consistent with those of IVW results. The sensitivity analyses showed no evidence of pleiotropy (MR-Egger intercept, P > 0.05), while Cochran's Q test and MR-Egger suggested different degrees of heterogeneity.<br><br>CONCLUSION: Our MR study suggested that longer telomeres were associated with decreased risk of several CVDs, including coronary atherosclerosis, myocardial infarction, ischemic heart disease, and stroke, as well as an increased risk of hypertension. Future studies are still warranted to validate the results and investigate the mechanisms underlying these associations.},
}
@article {pmid36350851,
year = {2022},
author = {Geiller, HEB and Harvey, A and Jones, RE and Grimstead, JW and Cleal, K and Hendrickson, EA and Baird, DM},
title = {ATRX modulates the escape from a telomere crisis.},
journal = {PLoS genetics},
volume = {18},
number = {11},
pages = {e1010485},
pmid = {36350851},
issn = {1553-7404},
support = {29202/CRUK_/Cancer Research UK/United Kingdom ; R01 CA266524/CA/NCI NIH HHS/United States ; A18246/A29202/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Humans ; *Telomerase/genetics/metabolism ; Telomere Homeostasis/genetics ; X-linked Nuclear Protein/genetics ; *alpha-Thalassemia/genetics ; Telomere/genetics/metabolism ; *Neoplasms ; },
abstract = {Telomerase activity is the principal telomere maintenance mechanism in human cancers, however 15% of cancers utilise a recombination-based mechanism referred to as alternative lengthening of telomeres (ALT) that leads to long and heterogenous telomere length distributions. Loss-of-function mutations in the Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) gene are frequently found in ALT cancers. Here, we demonstrate that the loss of ATRX, coupled with telomere dysfunction during crisis, is sufficient to initiate activation of the ALT pathway and that it confers replicative immortality in human fibroblasts. Additionally, loss of ATRX combined with a telomere-driven crisis in HCT116 epithelial cancer cells led to the initiation of an ALT-like pathway. In these cells, a rapid and precise telomeric elongation and the induction of C-circles was observed; however, this process was transient and the telomeres ultimately continued to erode such that the cells either died or the escape from crisis was associated with telomerase activation. In both of these instances, telomere sequencing revealed that all alleles, irrespective of whether they were elongated, were enriched in variant repeat types, that appeared to be cell-line specific. Thus, our data show that the loss of ATRX combined with telomere dysfunction during crisis induces the ALT pathway in fibroblasts and enables a transient activation of ALT in epithelial cells.},
}
@article {pmid36350415,
year = {2022},
author = {Bloom, SI and Tucker, JR and Lim, J and Thomas, TG and Stoddard, GJ and Lesniewski, LA and Donato, AJ},
title = {Aging results in DNA damage and telomere dysfunction that is greater in endothelial versus vascular smooth muscle cells and is exacerbated in atheroprone regions.},
journal = {GeroScience},
volume = {44},
number = {6},
pages = {2741-2755},
pmid = {36350415},
issn = {2509-2723},
support = {R01 AG060395/AG/NIA NIH HHS/United States ; F31 AG076312/AG/NIA NIH HHS/United States ; UL1 TR002538/TR/NCATS NIH HHS/United States ; UL1 TR001067/TR/NCATS NIH HHS/United States ; R01 AG050238/AG/NIA NIH HHS/United States ; R01 AG048366/AG/NIA NIH HHS/United States ; T32 HL007576/HL/NHLBI NIH HHS/United States ; UL1 RR025764/RR/NCRR NIH HHS/United States ; UL1 TR000105/TR/NCATS NIH HHS/United States ; R44 AG053131/AG/NIA NIH HHS/United States ; },
mesh = {*Muscle, Smooth, Vascular ; *Endothelial Cells ; Telomere/genetics ; DNA Damage ; },
abstract = {Aging increases the risk of atherosclerotic cardiovascular disease which is associated with arterial senescence; however, the mechanisms responsible for the development of cellular senescence in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) remain elusive. Here, we study the effect of aging on arterial DNA damage and telomere dysfunction. Aging resulted in greater DNA damage in ECs than VSMCs. Further, telomere dysfunction-associated DNA damage foci (TAF: DNA damage signaling at telomeres) were elevated with aging in ECs but not VMSCs. Telomere length was modestly reduced in ECs with aging and not sufficient to induce telomere dysfunction. DNA damage and telomere dysfunction were greatest in atheroprone regions (aortic minor arch) versus non-atheroprone regions (thoracic aorta). Collectively, these data demonstrate that aging results in DNA damage and telomere dysfunction that is greater in ECs than VSMCs and elevated in atheroprone aortic regions.},
}
@article {pmid36347948,
year = {2023},
author = {Bussa, RM and Mora-Plazas, M and Marín, C and Villamor, E},
title = {Vitamin D status and leukocyte telomere length in middle childhood.},
journal = {European journal of clinical nutrition},
volume = {77},
number = {2},
pages = {295-297},
pmid = {36347948},
issn = {1476-5640},
mesh = {Male ; Female ; Humans ; Child ; Child, Preschool ; Cross-Sectional Studies ; *Vitamin D ; *Vitamins ; Leukocytes ; Telomere ; },
abstract = {Short telomere length is associated with chronic diseases and decreased lifespan. Vitamin D and its binding protein (DBP) may maintain telomeres through anti-inflammatory actions, yet the role of vitamin D on telomere length is uncertain, especially in children. We assessed the cross-sectional associations of plasma 25-hydroxy vitamin D (25(OH)D) and DBP with leukocyte telomere length (LTL) in a group of 447 children ages 5-12 years from the Bogotá School Children Cohort. We compared the distribution of age-standardized LTL (z-score) between 25(OH)D categories and between DBP quartiles overall and by sex. Overall, 25(OH)D was not significantly associated with LTL. Nonetheless, among boys, 25(OH)D < 50 nmol/L was related to an adjusted 0.36 shorter LTL z-score (95% CI: -0.71, -0.01; P = 0.046) compared with 25(OH)D ≥ 75 nmol/L. There was no association among girls. DBP was not significantly related to LTL. Intervention studies are warranted to determine whether increasing vitamin D status enhances telomere length.},
}
@article {pmid36347559,
year = {2022},
author = {Glousker, G and Lingner, J},
title = {TFIIH moonlighting at telomeres.},
journal = {Genes &amp; development},
volume = {36},
number = {17-18},
pages = {951-953},
pmid = {36347559},
issn = {1549-5477},
mesh = {*Telomeric Repeat Binding Protein 1 ; Telomere/genetics/metabolism ; Telomere Shortening ; Telomere-Binding Proteins/metabolism ; *Telomerase/metabolism ; Shelterin Complex ; },
abstract = {Although telomeres are essential for chromosome stability, they represent fragile structures in our genome. Telomere shortening occurs during aging in cells lacking telomerase due to the end replication problem. In addition, recent work uncovered that the bulk of telomeric DNA poses severe hurdles for the semiconservative DNA replication machinery, requiring the assistance of an increasing number of specialized factors that prevent accidental telomere loss or damage events. In this issue of Genes &amp; Development, Yang and colleagues (pp. 956-969) discover that TFIIH, a basic component of the PolII transcription initiation and nucleotide excision repair machinery, facilitates telomere replication. TFIIH is recruited to telomeres by the shelterin component TRF1, taking on at telomeres a moonlighting function.},
}
@article {pmid36347449,
year = {2023},
author = {Wu, S and Wu, Y and Chen, J and Zhuang, P and Zhang, Y and Jiao, J},
title = {Lifelong docosahexaenoic acid intervention ameliorates aging in the telomere-DNA-mitochondria axis in telomerase-deficient mice.},
journal = {The Journal of nutritional biochemistry},
volume = {112},
number = {},
pages = {109202},
doi = {10.1016/j.jnutbio.2022.109202},
pmid = {36347449},
issn = {1873-4847},
mesh = {Female ; Animals ; Male ; Mice ; *Telomerase/genetics/metabolism ; Docosahexaenoic Acids/pharmacology/therapeutic use ; Cellular Senescence ; Aging/genetics ; *Fatty Acids, Omega-3 ; Inflammation ; DNA, Mitochondrial ; Mitochondria/metabolism ; Telomere/metabolism ; },
abstract = {The health benefits of n-3 polyunsaturated fatty acids (PUFAs) in multiple age-related diseases are associated with telomere length. Telomerase is intimately related to inflammation and oxidative stress, but whether the underlying function of n-3 PUFAs on telomere maintenance is based on telomerase activation or related mechanisms remains unclear. Herein, we utilized late-generation (G4) telomerase-deficient (Terc[-/-]) mice to perform a lifelong docosahexaenoic acid (DHA) intervention to determine the potential of DHA in telomere maintenance and health promotion. Unfortunately, DHA failed to prolong mouse longevity in either intrinsic or premature aging. However, intriguingly, lifelong dietary DHA intervention slowed the aging phenotypes and profoundly attenuated telomere attrition in blood leukocytes and multiple tissues, consistent with decreased β-galactosidase activity and other senescence hallmarks with no observed sex differences. Notably, DHA intervention alleviated telomere attrition-induced γ-H2AX accumulation dependent on poly (ADP-ribose) polymerase 1 (PARP1) recruitment, and further regulated mitochondrial dysfunction critically involved in the DNA damage response. Together with the improvement of mitochondria function, the blocked reactive oxygen species (ROS) accumulation and suppression of the nuclear factor-κB (NF-κB)/nucleotide-binding domain-like receptor protein 3 (NLRP3)/caspase-1 pathways partially indicated anti-oxidative and anti-inflammatory effects of DHA. These data revealed a regulatory paradigm involving DHA in the telomere-DNA-mitochondria feedback loop mediated by DNA damage response and inflammation in alleviating senescence, which may hold potential as a translatable intervention in telomere-related diseases during aging.},
}
@article {pmid36345036,
year = {2022},
author = {Rodríguez-Fernández, B and Vilor-Tejedor, N and Arenaza-Urquijo, EM and Sánchez-Benavides, G and Suárez-Calvet, M and Operto, G and Minguillón, C and Fauria, K and Kollmorgen, G and Suridjan, I and de Moura, MC and Piñeyro, D and Esteller, M and Blennow, K and Zetterberg, H and De Vivo, I and Molinuevo, JL and Navarro, A and Gispert, JD and Sala-Vila, A and Crous-Bou, M and , },
title = {Genetically predicted telomere length and Alzheimer's disease endophenotypes: a Mendelian randomization study.},
journal = {Alzheimer's research &amp; therapy},
volume = {14},
number = {1},
pages = {167},
pmid = {36345036},
issn = {1758-9193},
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid ; Mendelian Randomization Analysis ; Endophenotypes ; Biomarkers/cerebrospinal fluid ; Apolipoproteins E/genetics ; Telomere ; tau Proteins/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; },
abstract = {Telomere length (TL) is associated with biological aging, consequently influencing the risk of age-related diseases such as Alzheimer's disease (AD). We aimed to evaluate the potential causal role of TL in AD endophenotypes (i.e., cognitive performance, N = 2233; brain age and AD-related signatures, N = 1134; and cerebrospinal fluid biomarkers (CSF) of AD and neurodegeneration, N = 304) through a Mendelian randomization (MR) analysis. Our analysis was conducted in the context of the ALFA (ALzheimer and FAmilies) study, a population of cognitively healthy individuals at risk of AD. A total of 20 single nucleotide polymorphisms associated with TL were used to determine the effect of TL on AD endophenotypes. Analyses were adjusted by age, sex, and years of education. Stratified analyses by APOE-ɛ4 status and polygenic risk score of AD were conducted. MR analysis revealed significant associations between genetically predicted longer TL and lower levels of CSF Aβ and higher levels of CSF NfL only in APOE-ɛ4 non-carriers. Moreover, inheriting longer TL was associated with greater cortical thickness in age and AD-related brain signatures and lower levels of CSF p-tau among individuals at a high genetic predisposition to AD. Further observational analyses are warranted to better understand these associations.},
}
@article {pmid36342193,
year = {2023},
author = {Coutelier, H and Ilioaia, O and Le Peillet, J and Hamon, M and D'Amours, D and Teixeira, MT and Xu, Z},
title = {The Polo kinase Cdc5 is regulated at multiple levels in the adaptation response to telomere dysfunction.},
journal = {Genetics},
volume = {223},
number = {1},
pages = {},
pmid = {36342193},
issn = {1943-2631},
support = {FDN-167265//CIHR/Canada ; },
mesh = {*Protein Serine-Threonine Kinases/genetics/metabolism ; Cell Cycle Proteins/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; Protein Kinases/genetics ; Phosphorylation ; Saccharomyces cerevisiae/metabolism ; Checkpoint Kinase 2/genetics ; DNA Damage ; Telomere/genetics/metabolism ; },
abstract = {Telomere dysfunction activates the DNA damage checkpoint to induce a cell cycle arrest. After an extended period of time, however, cells can bypass the arrest and undergo cell division despite the persistence of the initial damage, a process called adaptation to DNA damage. The Polo kinase Cdc5 in Saccharomyces cerevisiae is essential for adaptation and for many other cell cycle processes. How the regulation of Cdc5 in response to telomere dysfunction relates to adaptation is not clear. Here, we report that Cdc5 protein level decreases after telomere dysfunction in a Mec1-, Rad53- and Ndd1-dependent manner. This regulation of Cdc5 is important to maintain long-term cell cycle arrest but not for the initial checkpoint arrest. We find that both Cdc5 and the adaptation-deficient mutant protein Cdc5-ad are heavily phosphorylated and several phosphorylation sites modulate adaptation efficiency. The PP2A phosphatases are involved in Cdc5-ad phosphorylation status and contribute to adaptation mechanisms. We finally propose that Cdc5 orchestrates multiple cell cycle pathways to promote adaptation.},
}
@article {pmid36341901,
year = {2022},
author = {Fan, G and Song, L and Liu, Q and Wu, M and Bi, J and Xu, L and Xiong, C and Cao, Z and Xu, S and Wang, Y},
title = {Association of maternal folic acid supplementation during pregnancy with newborn telomere length.},
journal = {Reproductive toxicology (Elmsford, N.Y.)},
volume = {114},
number = {},
pages = {52-56},
doi = {10.1016/j.reprotox.2022.10.006},
pmid = {36341901},
issn = {1873-1708},
mesh = {Humans ; Infant, Newborn ; Female ; Pregnancy ; Cohort Studies ; China ; *Dietary Supplements ; *Folic Acid ; Telomere ; },
abstract = {This study aimed to explore the associations between maternal folic acid (FA) supplementation during different trimesters of pregnancy and newborn telomere length (TL). Data were collected from a birth cohort study of 746 mother-newborn pairs conducted from November 2013 to March 2015 in Wuhan, China. After adjustment for potential confounders, maternal FA supplementation after the first trimester and throughout pregnancy were associated with longer newborn TL [β = 0.29, 95 % confidence interval (CI): 0.20, 0.38 and β = 0.24, 95 % CI: 0.16, 0.32, respectively]. No significant association was found between maternal FA supplementation in the first trimester and newborn TL. In conclusion, a possible association between maternal FA supplementation during pregnancy with longer newborn TL was suggested in the present study. This study provides insight into the benefit of newborn TL by maternal FA supplementation during pregnancy.},
}
@article {pmid36338739,
year = {2022},
author = {Li, Y and Ma, L},
title = {Relationship between telomere length and the prognosis of breast cancer based on estrogen receptor status: A Mendelian randomization study.},
journal = {Frontiers in oncology},
volume = {12},
number = {},
pages = {1024772},
pmid = {36338739},
issn = {2234-943X},
abstract = {OBJECTIVE: To identify the relationship between telomere length and the prognosis of breast cancer with different status of estrogen receptor (ER).<br><br>METHODS: We collected single nucleotide polymorphisms (SNPs) associated with telomere length and breast cancer prognosis from the MRCIEU GWAS database and the dataset of a large meta-analysis conducted by the Breast Cancer Association Consortium (BCAC), respectively. The relationship was identified using inverse-variance weighted (IVW), MR-Egger, weighted median, penalized weighted median, and maximum likelihood methods. IVW, MR-Egger, and MR-PRESSO methods were used to perform sensitivity analysis to assess the accuracy of the results.<br><br>RESULTS: Telomere length was negatively associated with the prognosis of total breast cancer (odds ratio [OR]=1.84, 95% confidence interval [CI]=1.08-3.14, IVW method), especially with ER- breast cancer (OR=1.89, 95% CI=1.11-3.22, IVW method). No similar relationship was found between telomere length and the prognosis of ER+ breast cancer (OR=0.99, 95% CI=0.62-1.58, IVW method). The findings from other methods were consistent with the results shown by the IVW method. The Mendelian randomization assumptions did not appear to be violated. Sensitivity analysis indicated that the result was robust, and no bias was observed in the study.<br><br>CONCLUSION: Telomere length is associated with the prognosis of total breast cancer, especially with ER- breast cancer. There is no significant correlation between telomere length and the prognosis of ER+ breast cancer. These findings add to the evidence that long telomere could predict a poor prognosis of ER- breast cancer.},
}
@article {pmid36334946,
year = {2022},
author = {Lansdorp, PM},
title = {Telomeres, Telomerase and Cancer.},
journal = {Archives of medical research},
volume = {53},
number = {8},
pages = {741-746},
doi = {10.1016/j.arcmed.2022.10.004},
pmid = {36334946},
issn = {1873-5487},
mesh = {Animals ; Humans ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; *Neoplasms/genetics ; Aging/genetics ; },
abstract = {Telomeres and telomerase play a crucial role in human aging and cancer. Three "drivers" of human aging can be identified. The developmental program encoded in DNA is the primary determinant of lifespan. Faithful execution of the developmental program requires stability of the (epi-)genome which is challenged throughout life by damage to DNA as well as epigenetic 'scars' from error-free DNA repair and stochastic errors made during the establishment and maintenance of the "epigenome". Over time (epi-)mutations accumulate, compromising cellular function and causing (pre-)malignant alterations. Damage to the genome and epigenome can be considered the second "driver" of aging. A third driver of the aging process, important to suppress tumors in long-lived animals, is caused by progressive loss of telomeric DNA. Telomere erosion protects against cancer early in life but limits cell renewal late in life, in agreement with the Antagonistic Pleiotropy theory on the evolutionary origin of aging. Malignant tumors arise when mutations and/or epimutations in cells (clock 2) corrupt the developmental program (clock 1) as well as tumor suppression by telomere erosion (clock 3). In cancer cells clock 3 is typically inactivated by loss of p53 as well as increased expression of telomerase. Taken together, aging in humans can be described by the ticking of three clocks: the clock that directs development, the accumulation of (epi-)mutations over time and the telomere clock that limits the number of cell divisions in normal stem and immune cells.},
}
@article {pmid36332602,
year = {2022},
author = {Decottignies, A},
title = {TERRA and RAD51AP1 at the R&amp;D-loop department of ALT telomeres.},
journal = {Molecular cell},
volume = {82},
number = {21},
pages = {3963-3965},
doi = {10.1016/j.molcel.2022.10.006},
pmid = {36332602},
issn = {1097-4164},
mesh = {*Telomere Homeostasis ; Telomere/genetics ; R-Loop Structures ; *RNA, Long Noncoding/genetics ; Chromatin ; },
abstract = {In this issue of Molecular Cell, Kaminski et al. and Yadav et al. demonstrate that RAD51AP1 and TERRA non-coding RNA positively regulate the alternative mechanism of telomere maintenance by promoting D-loop formation and chromatin-directed mechanisms to suppress transcription-collision events during ALT telomere synthesis.},
}
@article {pmid36330920,
year = {2022},
author = {Vaurs, M and Audry, J and Runge, KW and Géli, V and Coulon, S},
title = {A proto-telomere is elongated by telomerase in a shelterin-dependent manner in quiescent fission yeast cells.},
journal = {Nucleic acids research},
volume = {50},
number = {20},
pages = {11682-11695},
pmid = {36330920},
issn = {1362-4962},
support = {R01 HL158007/HL/NHLBI NIH HHS/United States ; R01 AG051601/AG/NIA NIH HHS/United States ; },
mesh = {*Schizosaccharomyces/genetics/metabolism ; *Schizosaccharomyces pombe Proteins/genetics/metabolism ; *Shelterin Complex ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; *Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Telomere elongation is coupled with genome replication, raising the question of the repair of short telomeres in post-mitotic cells. We investigated the fate of a telomere-repeat capped end that mimics a single short telomere in quiescent fission yeast cells. We show that telomerase is able to elongate this single short telomere during quiescence despite the binding of Ku to the proto-telomere. While Taz1 and Rap1 repress telomerase in vegetative cells, both shelterin proteins are required for efficient telomere extension in quiescent cells, underscoring a distinct mode of telomerase control. We further show that Rad3ATR and Tel1ATM are redundantly required for telomere elongation in quiescence through the phosphorylation of Ccq1 and that Rif1 and its associated-PP1 phosphatases negatively regulate telomerase activity by opposing Ccq1 phosphorylation. The distinct mode of telomerase regulation in quiescent fission yeast cells may be relevant to that in human stem and progenitor cells.},
}
@article {pmid36330807,
year = {2022},
author = {Wu, Y and Zhang, Y and Jiao, J},
title = {The relationship between n-3 polyunsaturated fatty acids and telomere: A review on proposed nutritional treatment against metabolic syndrome and potential signaling pathways.},
journal = {Critical reviews in food science and nutrition},
volume = {},
number = {},
pages = {1-20},
doi = {10.1080/10408398.2022.2142196},
pmid = {36330807},
issn = {1549-7852},
abstract = {Metabolic syndrome (MetS), a cluster of metabolic abnormalities composed of central obesity, elevated blood pressure, glucose disturbances, hypercholesterolemia and dyslipidaemia, has increasingly become a public health problem in the 21st century worldwide. The dysfunction of telomeres, the repetitive DNA with highly conserved sequences (5'-TTAGGG-3'), is remarkably correlated with organismal aging, even suggesting a causal relationship with metabolic disorders. The health benefits of n-3 polyunsaturated fatty acids (PUFAs) in multiple disorders are associated with telomere length in evidence, which have recently drawn wide attention. However, functional targets and pathways for the associations of n-3 PUFAs and telomere with MetS remain scare. Few studies have summarized the role of n-3 PUFAs in DNA damage repair pathways, anti-inflammatory pathways, and redox balance, linking with telomere biology, and other potential telomere-related signaling pathways. This review aims to (i) elucidate how n-3 PUFAs ameliorate telomere attrition in the context of anti-oxidation and anti-inflammation; (ii) unravel the role of n-3 PUFAs in modulating telomere-related neuron dysfunction and regulating the neuro-endocrine-immunological network in MetS; (iii) epidemiologically implicate the associations of metabolic disorders and n-3 PUFAs with telomere length; and (iv) suggest promising biochemical approaches and advancing methodologies to overcome the inter-variation problem helpful for future research.},
}
@article {pmid36330668,
year = {2022},
author = {Monaghan, P and Olsson, M and Richardson, DS and Verhulst, S and Rogers, SM},
title = {Integrating telomere biology into the ecology and evolution of natural populations: Progress and prospects.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {5909-5916},
doi = {10.1111/mec.16768},
pmid = {36330668},
issn = {1365-294X},
mesh = {*Ecology ; *Biological Evolution ; Telomere/genetics ; },
}
@article {pmid36319514,
year = {2023},
author = {Beranek, M and Borsky, P and Fiala, Z and Andrys, C and Hamakova, K and Chmelarova, M and Kovarikova, H and Karas, A and Kremlacek, J and Palicka, V and Borska, L},
title = {Telomere length, oxidative and epigenetic changes in blood DNA of patients with exacerbated psoriasis vulgaris.},
journal = {Anais brasileiros de dermatologia},
volume = {98},
number = {1},
pages = {68-74},
pmid = {36319514},
issn = {1806-4841},
mesh = {Female ; Humans ; *Metabolic Syndrome ; 5-Methylcytosine ; Epigenesis, Genetic ; Oxidative Stress/genetics ; RNA/metabolism ; Telomere/genetics/metabolism ; DNA/metabolism ; *Psoriasis/genetics ; },
abstract = {BACKGROUND: The pathogenesis of psoriasis vulgaris involves changes in DNA molecules, genomic instability, telomere attrition, and epigenetic alterations among them. These changes are also considered important mechanisms of aging in cells and tissues.<br><br>OBJECTIVE: This study dealt with oxidation damage, telomere length and methylation status in DNA originating from peripheral blood of 41 psoriatic patients and 30 healthy controls.<br><br>METHODS: Oxidative damage of serum DNA/RNA was determined immunochemically. Real-time PCR was used for the analysis of the telomere length. ELISA technique determined levels of 5-methylcytosine in blood cells' DNA.<br><br>RESULTS: Oxidative damage of serum DNA/RNA was higher in patients than in controls (median, 3758 vs. 2286pg/mL, p<0.001). A higher length of telomeres per chromosome was found in patients whole-cell DNA than in controls (3.57 vs. 3.04 kilobases, p=0.011). A negative correlation of the length of telomeres with an age of the control subjects was revealed (Spearman's rho=-0.420, p=0.028). Insignificantly different levels of 5-methylcytosine in patients and controls were observed (33.20 vs. 23.35%, p=0.234). No influences of sex, smoking, BMI, PASI score, and metabolic syndrome on the methylation status were found.<br><br>STUDY LIMITATIONS: i) A relatively small number of the participants, particularly for reliable subgroup analyses, ii) the Caucasian origin of the participants possibly influencing the results of the parameters determined, and iii) Telomerase activity was not directly measured in serum or blood cells.<br><br>CONCLUSION: The study demonstrated increased levels of oxidized DNA/RNA molecules in the serum of patients with exacerbated psoriasis vulgaris. The results were minimally influenced by sex, the presence of metabolic syndrome, or cigarette smoking. In the psoriatic blood cells' DNA, the authors observed longer telomeres compared to healthy controls, particularly in females. Insignificantly higher global DNA methylation in psoriasis cases compared to the controls indicated marginal clinical importance of this epigenetic test performed in the blood cells' DNA.},
}
@article {pmid36319501,
year = {2022},
author = {Ramírez-Sanabria, M and Martínez-Magaña, J and Nicolini-Sánchez, H and Guzmán-Sánchez, R and Genis-Mendoza, AD},
title = {[Association between telomere length and cognitive impairment in older adults].},
journal = {Revista espanola de geriatria y gerontologia},
volume = {57},
number = {6},
pages = {320-324},
doi = {10.1016/j.regg.2022.09.006},
pmid = {36319501},
issn = {1578-1747},
mesh = {Humans ; *Telomere Shortening ; Telomere ; *Cognitive Dysfunction/genetics ; Biomarkers ; },
abstract = {INTRODUCTION: Cognitive impairment is a transition stage between normal aging and dementia, the prevalence of last one increases with age; the damage of the functions and physical integrity, places the older adult in a greater susceptibility to get sick. Telomere length is a hallmark of aging to characterize this phenotype, as well as a biomarker that reflects the underlying state of the cell. In this work, the relative length of telomeres in older adults with cognitive impairment was correlated.<br><br>MATERIAL AND METHODS: Observational-analytical study, in samples of adult patients older than 65 years with and without cognitive impairment, in whom the relative length of telomeres was measured.<br><br>RESULTS: Ninety samples of older adults were included in the study and in the association analysis according to multivariate logistic models, cognitive impairment showed almost five times more risk for telomere shortening in relation to the presence of the diagnosis of cognitive impairment (Odds ratio 4.88, p=0.027).<br><br>CONCLUSIONS: When correlating the relative length of telomeres in older adults diagnosed with cognitive impairment, this association was confirmed for shorter.},
}
@article {pmid36311861,
year = {2022},
author = {de Mendonça Filho, EJ and Frechette, A and Pokhvisneva, I and Arcego, DM and Barth, B and Tejada, CV and Sassi, R and Wazana, A and Atkinson, L and Meaney, MJ and Silveira, PP},
title = {Examining attachment, cortisol secretion, and cognitive neurodevelopment in preschoolers and its predictive value for telomere length at age seven.},
journal = {Frontiers in behavioral neuroscience},
volume = {16},
number = {},
pages = {954977},
pmid = {36311861},
issn = {1662-5153},
abstract = {BACKGROUND: Secure attachment reflects caregiver-child relationship in which the caregiver is responsive when support and comforting are needed by the child. This pattern of bond has an important buffering role in the response to stress by the reduction of the negative experience and its associated physiological response. Disruption of the physiological stress system is thought to be a central mechanism by which early care impacts children. Early life stress causes cellular and molecular changes in brain regions associated with cognitive functions that are fundamental for early learning.<br><br>METHODS: The association between attachment, cortisol response before and after the Strange Situation Experiment, and neurodevelopment was examined in a sample of 107 preschoolers at age three. Also, the predictive effect of cortisol reactivity and attachment on telomere length at age seven was investigated in a followed-up sample of 77 children.<br><br>RESULTS: Children with insecure attachment had higher cortisol secretion and poorer neurodevelopmental skills at age three. A significant cortisol change was observed across the experiment with non-significant interaction with attachment. The attachment and neurodevelopment association was not mediated by cortisol secretion. Preschoolers' attachment and cortisol did not associate nor interacted to predict telomere length at age seven.<br><br>CONCLUSION: These findings add evidence to the detrimental effects of insecure attachment as an aggravator of the physiological response to stress and poorer neurodevelopment during the preschool period. Although attachment and cortisol were not predictive of telomere length, intervention policies that promote secure attachment are more likely to positively echo on several health domains.},
}
@article {pmid36311538,
year = {2022},
author = {Carvalho, VS and Gomes, WR and Calado, RT},
title = {Recent advances in understanding telomere diseases.},
journal = {Faculty reviews},
volume = {11},
number = {},
pages = {31},
pmid = {36311538},
issn = {2732-432X},
abstract = {Germline genetic defects impairing telomere length maintenance may result in severe medical conditions in humans, from aplastic anemia and myeloid neoplasms to interstitial lung disease and liver cirrhosis, from childhood (dyskeratosis congenita) to old age (pulmonary fibrosis). The molecular mechanisms underlying these clinically distinct disorders are pathologically excessive telomere erosion, limiting cell proliferation and differentiation, tissue regeneration, and increasing genomic instability. Recent findings also indicate that telomere shortening imbalances stem cell fate and is associated with an abnormal inflammatory response and the senescent-associated secretory phenotype. Bone marrow failure is the most common phenotype in patients with telomere diseases. Pulmonary fibrosis is a typical phenotype in older patients, and disease progression appears faster than in pulmonary fibrosis not associated with telomeropathies. Liver cirrhosis may present in isolation or in combination with other phenotypes. Diagnosis is based on clinical suspicion and may be confirmed by telomere length measurement and genetic testing. Next-generation sequencing (NGS) techniques have improved genetic testing; today, at least 16 genes have been implicated in telomeropathies. NGS also allows tracking of clonal hematopoiesis and malignant transformation. Patients with telomere diseases are at high risk of developing cancers, including myeloid neoplasms and head and neck cancer. However, treatment options are still limited. Transplant modalities (bone marrow, lung, and liver) may be definitive to the respective organ involvement but limited by donor availability, comorbidities, and impact on other affected organs. In clinical trials, androgens elongate telomeres of peripheral blood leukocytes and improve hematopoiesis. Further understanding of how telomere erosion impairs organ function and how somatic mutations evolve in the hematopoietic tissue may help develop new strategies to treat and prevent telomere diseases.},
}
@article {pmid36311389,
year = {2022},
author = {Dobson, FS and Schull, Q and Criscuolo, F},
title = {Two aspects of longevity are associated with rates of loss of telomeres in birds.},
journal = {Ecology and evolution},
volume = {12},
number = {10},
pages = {e9364},
pmid = {36311389},
issn = {2045-7758},
abstract = {Telomeres, the terminal repetitive DNA sequences at the ends of linear chromosomes, have strong associations with longevity in some major taxa. Longevity has been linked to rate of decline in telomere length in birds and mammals, and absolute telomere length seems to be associated with body mass in mammals. Using a phylogenetic comparative method and 30 species of birds, we examined longevity (reflected by maximum lifespan), absolute telomere length, the rate of change in telomere length (TROC), and body mass (often strongly associated with longevity) to ascertain their degree of association. We divided lifespan into two life-history components, one reflected by body size (measured as body mass) and a component that was statistically independent of body mass. While both lifespan and body mass were strongly associated with a family tree of the species (viz., the phylogeny of the species), telomere measures were not. Telomere length was not significantly associated with longevity or body mass or our measure of mass-independent lifespan. TROC, however, was strongly associated with mass-independent lifespan, but only to a much lesser degree at best with body mass-predicted lifespan. Our results supported an association of TROC and longevity, in particular longevity that was independent of body size and part of the pace-of-life syndrome of life histories.},
}
@article {pmid36304436,
year = {2022},
author = {Castro-Diehl, C and Smith, JA and Zhao, W and Wang, X and Mukherjee, B and Seeman, T and Needham, BL},
title = {Prediction of telomere length and telomere attrition using a genetic risk score: The multi-ethnic study of atherosclerosis (MESA).},
journal = {Frontiers in aging},
volume = {3},
number = {},
pages = {1021051},
pmid = {36304436},
issn = {2673-6217},
abstract = {Background: Short telomere length (TL) and telomere attrition (TA) have been associated with age-related diseases. Objective: We assessed whether a genetic risk score for short TL (GRS-TL) combining seven TL-associated genetic variants identified in a European-ancestry genome-wide association study (GWAS) was associated with TL and TA over 10 years. Methods: Relative TL (T/S ratio) was measured by the quantitative polymerase chain reaction method for a sample of white, African American, and Hispanic participants, who attended Exam 1 and/or 5 of the Multi-Ethnic Study of Atherosclerosis (MESA). Our final sample included 1,227 participants for the TL analysis and 1,138 for the TA analysis. Participants were 45-84 years at Exam 1. We used a linear mixed effects model and adjusted for age, sex, and population structure. Models were stratified by race/ethnicity. Results: In the TL analysis, higher GRS-TL significantly predicted shorter TL (estimates = -0.18 [S.E. = 0.08], p = 0.02 for white; -0.18 [0.07], p < 0.01 for African American; and -0.13 [0.05], p = 0.02 for Hispanic) in fully adjusted models. In the TA analysis, no association between GRS-TL and TA over 10 years was found. Conclusion: Although GRS-TL was developed in European-ancestry populations, it was significantly associated with TL (but not TA) in all three race/ethnic groups examined.},
}
@article {pmid36302456,
year = {2022},
author = {Katz, R and Gay, EL and Kuipers, AL and Lee, JH and Honig, LS and Christensen, K and Feitosa, MF and Wojczynski, MK and Glynn, NW and , },
title = {Association of leukocyte telomere length with perceived physical fatigability.},
journal = {Experimental gerontology},
volume = {170},
number = {},
pages = {111988},
doi = {10.1016/j.exger.2022.111988},
pmid = {36302456},
issn = {1873-6815},
support = {U19 AG063893/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Female ; Aged ; Aged, 80 and over ; Male ; Longitudinal Studies ; *Telomere/genetics ; *Leukocytes ; Fatigue/genetics ; Aging/genetics ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) is a potential genomic marker of biological aging, but its relation to fatigability, a prognostic indicator of phenotypic aging (e.g., functional decline) is unknown. We hypothesized shorter LTL would predict greater perceived physical fatigability, but that this association would be attenuated by adjusting for chronological age.<br><br>METHODS: Two generations of participants (N&#xa0;=&#xa0;1997; 309 probands, 1688 offspring) were from the Long Life Family Study (age&#xa0;=&#xa0;73.7&#xa0;&#xb1;&#xa0;10.4, range 60-108, 54.4&#xa0;% women), a longitudinal cohort study of aging. LTL was assayed at baseline. Perceived physical fatigability was measured 8.0&#xa0;&#xb1;&#xa0;1.1&#xa0;years later using the validated, self-administered 10-item Pittsburgh Fatigability Scale (PFS, 0-50, higher scores&#xa0;=&#xa0;greater fatigability). Generalized estimating equations were generated to model the association between LTL and PFS Physical scores.<br><br>RESULTS: Prevalence of greater physical fatigability (PFS scores&#x2265;15) was 41.9&#xa0;%. Using generalized estimating equations, a one kilobase pair shorter LTL was associated with higher PFS Physical scores (&#x3b2;&#xa0;=&#xa0;1.8, p&#xa0;<&#xa0;.0001), accounting for family structure, and adjusting for field center, follow-up time, sex, and follow-up body mass index, physical activity, and chronic health conditions. When age was included as a covariate, the association was fully attenuated (&#x3b2;&#xa0;=&#xa0;0.1, p&#xa0;=&#xa0;.78).<br><br>CONCLUSION: LTL may provide an alternative method for estimating an individual's lifetime exposure to chronic stressors, but does not appear to provide additional information not captured by chronological age. Further research is needed to characterize the interaction between age, LTL, and perceived fatigability, and develop a method of identifying individuals at risk for deleterious aging.},
}
@article {pmid36296977,
year = {2022},
author = {Cancello, R and Rey, F and Carelli, S and Cattaldo, S and Fontana, JM and Goitre, I and Ponzo, V and Merlo, FD and Zuccotti, G and Bertoli, S and Capodaglio, P and Bo, S and Brunani, A},
title = {Telomere Length and Mitochondrial DNA Copy Number Variations in Patients with Obesity: Effect of Diet-Induced Weight Loss-A Pilot Study.},
journal = {Nutrients},
volume = {14},
number = {20},
pages = {},
pmid = {36296977},
issn = {2072-6643},
mesh = {Humans ; *DNA Copy Number Variations ; Pilot Projects ; *Telomere/genetics ; Antioxidants ; Obesity/genetics ; DNA, Mitochondrial/genetics ; Weight Loss/genetics ; },
abstract = {Background: Telomere length (TL) and mitochondrial DNA (mtDNA) copy number shifts are linked to metabolic abnormalities, and possible modifications by diet-induced weight loss are poorly explored. We investigated the variations before (T0) and after a 1-year (T12) lifestyle intervention (diet + physical activity) in a group of outpatients with obesity. Methods: Patients aged 25−70 years with BMI ≥ 30 kg/m2 were enrolled. Clinical and biochemical assessments (including a blood sample for TL, mtDNA copy number and total antioxidant capacity, and TAC determinations) were performed at T0 and T12. Results: The change in TL and the mtDNA copy number was heterogeneous and not significantly different at T12. Patients were then divided by baseline TL values into lower than median TL (L-TL) and higher than median TL (H-TL) groups. The two groups did not differ at baseline for anthropometric, clinical, and laboratory characteristics. At T12, the L-TL group when compared to H-TL showed TL elongation (respectively, +0.57 ± 1.23 vs. −2.15 ± 1.13 kbp, p = 0.04), higher mtDNA copy number (+111.5 ± 478.5 vs. −2314.8 ± 724.2, respectively, p < 0.001), greater weight loss (−8.1 ± 2.7 vs. −6.1 ± 4.6 Kg, respectively, p = 0.03), fat mass reduction (−1.42 ± 1.3 vs. −1.22 ± 1.5%, respectively, p = 0.04), and increased fat-free mass (+57.8 ± 6.5 vs. +54.9 ± 5.3%, respectively, p = 0.04) and TAC levels (+58.5 ± 18.6 vs. +36.4 ± 24.1 µM/L, respectively, p = 0.04). Conclusions: TL and the mtDNA copy number significantly increased in patients with obesity and with lower baseline TL values after a 1-year lifestyle intervention. Larger longitudinal studies are needed to confirm the results of this pilot study.},
}
@article {pmid36294653,
year = {2022},
author = {Xu, F and Li, X and Ren, H and Zeng, R and Wang, Z and Hu, H and Bao, J and Que, Y},
title = {The First Telomere-to-Telomere Chromosome-Level Genome Assembly of Stagonospora tainanensis Causing Sugarcane Leaf Blight.},
journal = {Journal of fungi (Basel, Switzerland)},
volume = {8},
number = {10},
pages = {},
pmid = {36294653},
issn = {2309-608X},
support = {CARS-17//Modern Agriculture Technology of China/ ; CXZX2020083A//Special Fund for Science and Technology Innovation of Fujian Agriculture and Forestry University/ ; },
abstract = {The sexual morph Leptosphaeria taiwanensis Yen and Chi and its asexual morph Stagonospora tainanensis W. H. Hsieh is an important necrotrophic fungal phytopathogen, which causes sugarcane leaf blight, resulting in loss of cane tonnage and sucrose in susceptible sugarcane varieties. Decoding the genome and understanding of the basis of virulence is vitally important for devising effective disease control strategies. Here, we present a 38.25-Mb high-quality genome assembly of S. tainanensis strain StFZ01, denovo assembled with 10.19 Gb Nanopore sequencing long reads (~267×) and 3.82 Gb Illumina short reads (~100×). The genome assembly consists of 12 contigs with N50 of 2.86 Mb of which 5 belong to the telomere to telomere (T2T) chromosome. It contains 13.20% repeat sequences, 12,543 proteins, and 12,206 protein-coding genes with the BUSCO completeness 99.18% at fungi (n = 758) and 99.87% at ascomycota (n = 1706), indicating the high accuracy and completeness of our gene annotations. The virulence analysis in silico revealed the presence of 2379 PHIs, 599 CAZys, 248 membrane transport proteins, 191 cytochrome P450 enzymes, 609 putative secreted proteins, and 333 effectors in the StFZ01 genome. The genomic resources presented here will not only be helpful for development of specific molecular marker and diagnosis technique, population genetics, molecular taxonomy, and disease managements, it can also provide a significant precise genomic reference for investigating the ascomycetous genome, the necrotrophic lifestyle, and pathogenicity in the future.},
}
@article {pmid36292740,
year = {2022},
author = {Dlouha, D and Vymetalova, J and Novakova, S and Huckova, P and Lanska, V and Hubacek, JA},
title = {Posttransplant Complications and Genetic Loci Involved in Telomere Maintenance in Heart Transplant Patients.},
journal = {Genes},
volume = {13},
number = {10},
pages = {},
pmid = {36292740},
issn = {2073-4425},
mesh = {Humans ; Adult ; Middle Aged ; *Telomere/genetics ; Leukocytes/metabolism ; *Heart Transplantation/adverse effects ; Genetic Loci ; DNA/metabolism ; },
abstract = {Reaching critically short telomeres induces cellular senescence and ultimately cell death. Cellular senescence contributes to the loss of tissue function. We aimed to determine the association between variants within genes involved in telomere length maintenance, posttransplant events, and aortic telomere length in heart transplant patients. DNA was isolated from paired aortic samples of 383 heart recipients (age 50.7 ± 11.9 years) and corresponding donors (age 38.7 ± 12.0 years). Variants within the TERC (rs12696304), TERF2IP (rs3784929 and rs8053257), and OBCF1 (rs4387287) genes were genotyped, and telomere length was measured using qPCR. We identified similar frequencies of genotypes in heart donors and recipients. Antibody-mediated rejection (AMR) was more common (p < 0.05) in carriers of at least one G allele within the TERF2IP locus (rs3784929). Chronic graft dysfunction (CGD) was associated with the TERC (rs12696304) GG donor genotype (p = 0.05). The genetic risk score did not determine posttransplant complication risk prediction. No associations between the analyzed polymorphisms and telomere length were detected in either donor or recipient DNA. In conclusion, possible associations between donor TERF2IP (rs3784929) and AMR and between TERC (rs12696304) and CGD were found. SNPs within the examined genes were not associated with telomere length in transplanted patients.},
}
@article {pmid36292646,
year = {2022},
author = {M'Kacher, R and Miguet, M and Maillard, PY and Colicchio, B and Scheidecker, S and Najar, W and Arnoux, M and Oudrhiri, N and Borie, C and Biehler, M and Plesch, A and Heidingsfelder, L and Bennaceur-Griscelli, A and Dieterlen, A and Voisin, P and Junker, S and Carde, P and Jeandidier, E},
title = {A Central Role of Telomere Dysfunction in the Formation of a Unique Translocation within the Sub-Telomere Region Resulting in Duplication and Partial Trisomy.},
journal = {Genes},
volume = {13},
number = {10},
pages = {},
pmid = {36292646},
issn = {2073-4425},
mesh = {Humans ; *Trisomy/genetics ; In Situ Hybridization, Fluorescence ; Chromosome Banding ; *Translocation, Genetic/genetics ; Chromosome Aberrations ; Telomere/genetics ; },
abstract = {Telomeres play a major role in maintaining genome stability and integrity. Putative involvement of telomere dysfunction in the formation of various types of chromosomal aberrations is an area of active research. Here, we report a case of a six-month-old boy with a chromosomal gain encompassing the 11q22.3q25 region identified by SNP array analysis. The size of the duplication is 26.7 Mb and contains 170 genes (OMIM). The duplication results in partial trisomy of the region in question with clinical consequences, including bilateral renal dysplasia, delayed development, and a heart defect. Moreover, the karyotype determined by R-banding and chromosome painting as well as by hybridization with specific sub-telomere probes revealed the presence of an unbalanced t(9;11)(p24;q22.3) translocation with a unique breakpoint involving the sub-telomere region of the short arm of chromosome 9. The karyotypes of the parents were normal. Telomere integrity in circulating lymphocytes from the child and from his parents was assessed using an automated high-throughput method based on fluorescence in situ hybridization (FISH) with telomere- and centromere-specific PNA probes followed by M-FISH multicolor karyotyping. Very short telomeres, as well as an increased frequency of telomere loss and formation of telomere doublets, were detected in the child's cells. Interestingly, similar telomere profiles were found in the circulating lymphocytes of the father. Moreover, an assessment of clonal telomere aberrations identified chromosomes 9 and 11 with particularly high frequencies of such aberrations. These findings strongly suggest that telomere dysfunction plays a central role in the formation of this specific unbalanced chromosome rearrangement via chromosome end-to-end fusion and breakage-fusion-bridge cycles.},
}
@article {pmid36290385,
year = {2022},
author = {Dorador, AP and Dalikova, M and Cerbin, S and Stillman, CM and Zych, MG and Hawley, RS and Miller, DE and Ray, DA and Funikov, SY and Evgen'ev, MB and Blumenstiel, JP},
title = {Paramutation-like Epigenetic Conversion by piRNA at the Telomere of Drosophila virilis.},
journal = {Biology},
volume = {11},
number = {10},
pages = {},
pmid = {36290385},
issn = {2079-7737},
support = {1413532//National Science Foundation/ ; P20 GM103418/GM/NIGMS NIH HHS/United States ; 22-74-10050//Russian Science Foundation/ ; P20GM103418//National Institute of Health/ ; P20 GM103638/GM/NIGMS NIH HHS/United States ; NA//University of Kansas/ ; NA//Stowers Institute for Medical Research/ ; P30 GM145499/GM/NIGMS NIH HHS/United States ; 2025197//National Science Foundation/ ; P20GM103638//National Institute of Health/ ; },
abstract = {First discovered in maize, paramutation is a phenomenon in which one allele can trigger an epigenetic conversion of an alternate allele. This conversion causes a genetically heterozygous individual to transmit alleles that are functionally the same, in apparent violation of Mendelian segregation. Studies over the past several decades have revealed a strong connection between mechanisms of genome defense against transposable elements by small RNA and the phenomenon of paramutation. For example, a system of paramutation in Drosophila melanogaster has been shown to be mediated by piRNAs, whose primary function is to silence transposable elements in the germline. In this paper, we characterize a second system of piRNA-mediated paramutation-like behavior at the telomere of Drosophila virilis. In Drosophila, telomeres are maintained by arrays of retrotransposons that are regulated by piRNAs. As a result, the telomere and sub-telomeric regions of the chromosome have unique regulatory and chromatin properties. Previous studies have shown that maternally deposited piRNAs derived from a sub-telomeric piRNA cluster can silence the sub-telomeric center divider gene of Drosophila virilis in trans. In this paper, we show that this silencing can also be maintained in the absence of the original silencing allele in a subsequent generation. The precise mechanism of this paramutation-like behavior may be explained by either the production of retrotransposon piRNAs that differ across strains or structural differences in the telomere. Altogether, these results show that the capacity for piRNAs to mediate paramutation in trans may depend on the local chromatin environment and proximity to the uniquely structured telomere regulated by piRNAs. This system promises to provide significant insights into the mechanisms of paramutation.},
}
@article {pmid36289653,
year = {2022},
author = {Rangel-Pozzo, A and Wechsler, J and Groult, J and Da Meda, L and Lebbe, C and Mai, S},
title = {Telomere-Associated Changes in Nuclear Architecture of Cancer-Associated Macrophage-like Cells in Liquid Biopsies from Melanoma Patients.},
journal = {Biomedicines},
volume = {10},
number = {10},
pages = {},
pmid = {36289653},
issn = {2227-9059},
abstract = {During phagocytosis, tumor-associated macrophages (TAMs) can incorporate genetic material from tumor cells. The incorporation of extra genetic material may be responsible for advanced malignant behavior observed in some TAMs, making TAMs potentially important players in cancer progression. More recently, similar cells were described in the blood as cancer-associated macrophage-like cells (CAMLs). CAMLs may be equivalent to TAMs cells in the blood, and they express macrophage markers. However, their origin is still unclear. In a previous study, we showed for the first time the distinct telomere 3D structure of circulating tumor cells (CTCs) in melanoma and other cancers. In the present pilot study, we investigated, comparatively, the 3D telomere structure of CAMLs, CTCs and leucocytes from nine melanoma patients with metastatic cutaneous melanoma stage IV. CTC capture was performed by size-based filtration followed by cytological and immunocytological evaluation. Three-dimensional Quantitative Fluorescent in situ Hybridization was performed to measure differences in five 3D telomere parameters. Telomere parameters, such as number, length, telomere aggregates, nuclear volume, and a/c ratio, were compared among different cellular types (CTCs, CAMLs, and normal leucocytes). Three telomere parameters were significantly different between CAMLs and leucocytes. The combination of two telomere parameters (telomere length against the number of telomeres) resulted in the identification of two CAMLs subpopulations with different levels of genomic instability. Those populations were classified as profile 1 and 2. Profile 2, characterized by a high number of short telomeres, was observed in four of the nine melanoma patients. To our knowledge, this is the first pilot study to investigate 3D telomere parameters as hallmarks of nuclear architecture in CAMLs' population in comparison to leucocytes from the same patient. Further studies involving a larger patient sample size are necessary to validate these findings and explore their potential prognostic value.},
}
@article {pmid36289597,
year = {2022},
author = {Lupatov, AY and Yarygin, KN},
title = {Telomeres and Telomerase in the Control of Stem Cells.},
journal = {Biomedicines},
volume = {10},
number = {10},
pages = {},
pmid = {36289597},
issn = {2227-9059},
support = {122022800499-5//Program for Basic Research in the Russian Federation for a long-term period (2021-2030)/ ; },
abstract = {Stem cells serve as a source of cellular material in embryogenesis and postnatal growth and regeneration. This requires significant proliferative potential ensured by sufficient telomere length. Telomere attrition in the stem cells and their niche cells can result in the exhaustion of the regenerative potential of high-turnover organs, causing or contributing to the onset of age-related diseases. In this review, stem cells are examined in the context of the current telomere-centric theory of cell aging, which assumes that telomere shortening depends not just on the number of cell doublings (mitotic clock) but also on the influence of various internal and external factors. The influence of the telomerase and telomere length on the functional activity of different stem cell types, as well as on their aging and prospects of use in cell therapy applications, is discussed.},
}
@article {pmid36285820,
year = {2022},
author = {Iannarelli, NJ and Wade, TJ and Dempster, KS and Moore, J and MacNeil, AJ and O'Leary, DD},
title = {No Mediation Effect of Telomere Length or Mitochondrial DNA Copy Number on the Association Between Adverse Childhood Experiences (ACEs) and Central Arterial Stiffness.},
journal = {Journal of the American Heart Association},
volume = {11},
number = {21},
pages = {e026619},
pmid = {36285820},
issn = {2047-9980},
support = {363774//CIHR/Canada ; 399332//CIHR/Canada ; RFN 167014//CIHR/Canada ; },
mesh = {Young Adult ; Humans ; Female ; Adult ; DNA, Mitochondrial/genetics ; *Vascular Stiffness ; *Adverse Childhood Experiences ; DNA Copy Number Variations ; Pulse Wave Analysis ; Biomarkers/metabolism ; Telomere/genetics/metabolism ; *Cardiovascular Diseases/diagnosis/epidemiology/genetics ; },
abstract = {Background Adverse childhood experiences (ACEs) have been linked to increased cardiovascular disease (CVD) risk. Previous reports have suggested that accelerated biological aging-indexed by telomere length (TL) and mitochondrial DNA copy number (mtDNAcn)-may contribute to associations between ACEs and cardiovascular health outcomes. Here, we examine the potential mediating effects of TL and mtDNAcn on the association between ACEs and central arterial stiffness-an intermediate cardiovascular health outcome-as a novel pathway linking ACEs to CVD risk among young adults. Methods and Results One hundred and eighty-five (n=102 women; mean age, 22.5±1.5 years) individuals provided information on ACEs. TL (kb per diploid cell) and mtDNAcn (copies per diploid cell) were quantified using quantitative polymerase chain reaction techniques. Central arterial stiffness was measured as carotid-femoral pulse wave velocity (cfPWV; m/s). Multiple linear regression analyses were used to examine the associations between ACEs, TL, mtDNAcn, and cfPWV. ACEs were positively associated with cfPWV (β=0.147, P=0.035). TL (β=-0.170, P=0.011) and mtDNAcn (β=-0.159, P=0.019) were inversely associated with cfPWV. Neither TL (β=-0.027, P=0.726) nor mtDNAcn (β=0.038, P=0.620) was associated with ACEs. Neither marker mediated the association between ACEs and cfPWV. Conclusions An increasing number of ACEs were associated with a faster cfPWV and thus, a greater degree of central arterial stiffness. ACEs were not associated with either TL or mtDNAcn, suggesting that these markers do not represent a mediating pathway linking ACEs to central arterial stiffness.},
}
@article {pmid36283531,
year = {2023},
author = {Li, X and Liu, H and Wan, H and Li, Y and Xu, S and Xiao, H and Xia, W},
title = {Sex-specific associations between legacy and novel per- and polyfluoroalkyl substances and telomere length in newborns in Wuhan, China: Mixture and single pollutant associations.},
journal = {The Science of the total environment},
volume = {857},
number = {Pt 3},
pages = {159676},
doi = {10.1016/j.scitotenv.2022.159676},
pmid = {36283531},
issn = {1879-1026},
mesh = {Pregnancy ; Female ; Male ; Infant, Newborn ; Humans ; *Fluorocarbons/analysis ; *Environmental Pollutants/analysis ; *Alkanesulfonic Acids/analysis ; China ; Telomere ; },
abstract = {Telomere length (TL) at birth predicts later life TL and is related to health. Prenatal exposure to environmental pollutants might affect TL, but the associations between intrauterine per- and polyfluoroalkyl substances (PFASs) exposure and neonatal TL remained inconclusive. This study aimed to explore the single pollutant and mixture associations between legacy and novel PFASs and TL in newborns. In 908 mother-newborn pairs from Wuhan, China, thirteen PFASs were measured in cord serum, and TL was determined in cord leukocytes. Weighted quantile sum (WQS) regression and generalized linear model (GLM) were utilized to analyze the associations between PFASs mixture and single PFASs and TL in newborns. Furthermore, stratified and interaction analyses were performed to evaluate if there were sex-specific associations. The concentrations of perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA) ranked the highest (geometric mean, 4.12, 1.61, and 0.77 ng/mL, respectively) among the 13 measured PFASs. Each unit increase in WQS index of PFASs mixture was associated with -5.19 % change (95% CI, -9.44, -0.73) of neonatal TL, and 8:2 Cl-PFESA contributed most (32.59 %) to the mixture association. In stratified analyses by neonatal sex, PFOS (-4.73 % change, 95% CI, -8.40, -0.93 for per doubling concentration) and 8:2 Cl-PFESA (-4.52 % change, 95% CI, -8.20, -0.70) were negatively associated with neonatal TL in male newborns, but no significant association appeared in females. In summary, intrauterine exposure to PFASs in mixture was associated with shorter neonatal TL, and the negative associations of 8:2 Cl-PFESA and PFOS with neonatal TL were observed only in boys. Future risk assessments are needed to pay more attention to the health effects of novel PFASs.},
}
@article {pmid36282763,
year = {2022},
author = {Kertes, DA and Leri, J and Duan, K and Tarrence, J and Browning, C and Pickler, R and Ford, J},
title = {Demographic and health predictors of telomere length during adolescence.},
journal = {Developmental psychobiology},
volume = {64},
number = {7},
pages = {e22311},
pmid = {36282763},
issn = {1098-2302},
support = {R01 DA032371/DA/NIDA NIH HHS/United States ; P2C HD058484/HD/NICHD NIH HHS/United States ; R21 DA034960/DA/NIDA NIH HHS/United States ; R01 NR019008/NR/NINR NIH HHS/United States ; R01 MD011727/MD/NIMHD NIH HHS/United States ; },
mesh = {Adult ; Adolescent ; Humans ; *Telomere Shortening ; *Telomere ; Body Mass Index ; DNA ; Demography ; },
abstract = {Telomere length (TL) is proposed to play a mechanistic role in how the exposome affects health outcomes. Little is known about TL during adolescence, a developmental period during which precursors of adult-onset health problems often emerge. We examined health and demographic sources of variation in TL in 899 youth aged 11-17. Demographic and health information included age, sex, race, household income, caregiver age and marital status, youth tobacco exposure, body mass index, pubertal status, health problems, medication use, and season of data collection. Genomic DNA was extracted from saliva, and T/S ratios were computed following qPCR. Age, race, season of data collection, and household income were associated with the telomere to single copy (T/S) ratio. We found that T/S ratios were larger at younger ages, among Black youth, for saliva collected during autumn and winter, and among households with higher income. Analyses stratified by race revealed that the association between age and T/S ratio was present for Black youth, that season of collection was present across races, but that family demographic associations with T/S ratio varied by race. The results provide information for future telomere research and highlight adolescence as a potentially important developmental phase for racial disparities in telomere shortening and health.},
}
@article {pmid36276465,
year = {2022},
author = {Mishra, R and Haldar, S and Biondi, S and Bhari, VK and Singh, G and Bhowmick, NA},
title = {TGF-β controls stromal telomere length through epigenetic modifications.},
journal = {3 Biotech},
volume = {12},
number = {11},
pages = {290},
pmid = {36276465},
issn = {2190-572X},
support = {I01 BX001040/BX/BLRD VA/United States ; P01 CA233452/CA/NCI NIH HHS/United States ; },
abstract = {UNLABELLED: Telomere length is primarily controlled by the enzyme telomerase, but being chromatin structures, telomeres undergo epigenetic regulation for their maintenance and function. Altered telomere length among cancer cells combined with shorter telomere length in cancer-associated stromal cells, strongly implicated with progression to prostate cancer metastasis and cancer death and providing a novel target for therapeutics. Transforming growth factor-β (TGF-β) signaling pathways are well-recognized for their role in stromal-epithelial interactions responsible for prostate androgen responsiveness, promoting tumorigenesis. However, the underlying mechanism remains unclear. We sought to establish a role for TGF-β in the regulation of telomere length in mouse and human prostate fibroblast. Polymerase chain reaction (PCR)-based telomere length measuring methods are widely used due to their repeatability and reproducibility. Using real-time RT-PCR-based telomere length measuring method, we identified that TGF-beta regulates telomere length via increased expression of histone methyltransferase, Suv39h1, which in turn affected histone methylation levels at the telomeric ends. Moreover, treatment of DAPT and non-steroidal antiandrogen bicalutamide demonstrated that notch and androgen signaling co-operated with TGF-ß in regulating stromal telomere length. Telomere variation in tumor cells and non-tumor cells within the tumor microenvironment greatly facilitates the clinical assessment of prostate cancer; therefore, understanding stromal telomere length regulation mechanism will hold significant prospects for cancer treatment, diagnosis, and prognosis.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-022-03346-5.},
}
@article {pmid36270567,
year = {2022},
author = {Tang, P and He, W and Shao, Y and Liu, B and Huang, H and Liang, J and Liao, Q and Tang, Y and Mo, M and Zhou, Y and Li, H and Huang, D and Liu, S and Zeng, X and Qiu, X},
title = {Associations between prenatal multiple plasma metal exposure and newborn telomere length: Effect modification by maternal age and infant sex.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {315},
number = {},
pages = {120451},
doi = {10.1016/j.envpol.2022.120451},
pmid = {36270567},
issn = {1873-6424},
mesh = {Infant ; Infant, Newborn ; Humans ; Pregnancy ; Female ; *Arsenic ; Lead ; Maternal Age ; Prospective Studies ; Telomere ; Bayes Theorem ; Barium ; Cohort Studies ; China ; Maternal Exposure ; },
abstract = {Exposure to metals during pregnancy may affect maternal and infant health. However, studies on the combined effects of metals on the telomere length (TL) of newborns are limited. A prospective cohort study was conducted among 1313 mother-newborn pairs in the Guangxi Zhuang Birth Cohort. The concentrations of metals in maternal plasma during the first trimester were measured using inductively coupled plasma-mass spectrometry. We explored the associations between nine plasma metals and newborn TL using generalized linear models (GLMs), principal component analysis (PCA), quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR). The GLMs revealed the inverse association between plasma arsenic (percent change, -5.56%; 95% CI: -7.69%, -3.38%) and barium concentrations (-9.84%; 95% CI: -13.81%, -5.68%) and newborn TL. Lead levels were related to significant decreases in newborn TL only in females. The PCA revealed a negative association between the PC3 and newborn TL (-4.52%; 95% CI: -6.34%, -2.68%). In the BKMR, the joint effect of metals was negatively associated with newborn TL. Qgcomp indicated that each one-tertile increase in metal mixture levels was associated with shorter newborn TL (-9.39%; 95% CI: -14.32%, -4.18%). The single and joint effects of multiple metals were more pronounced among pregnant women carrying female fetuses and among pregnant women <28 years of age. The finding suggests that prenatal exposure to arsenic, barium, antimony, and lead and mixed metals may shorten newborn TLs. The relationship between metal exposures and newborn TL may exhibit heterogeneities according to infant sex and maternal age.},
}
@article {pmid36267401,
year = {2022},
author = {Wang, C and Alfano, R and Reimann, B and Hogervorst, J and Bustamante, M and De Vivo, I and Plusquin, M and Nawrot, TS and Martens, DS},
title = {Genetic regulation of newborn telomere length is mediated and modified by DNA methylation.},
journal = {Frontiers in genetics},
volume = {13},
number = {},
pages = {934277},
pmid = {36267401},
issn = {1664-8021},
abstract = {Telomere length at birth determines later life telomere length and potentially predicts ageing-related diseases. However, the genetic and epigenetic settings of telomere length in newborns have not been analyzed. In addition, no study yet has reported how the interplay between genetic variants and genome-wide cytosine methylation explains the variation in early-life telomere length. In this study based on 281 mother-newborn pairs from the ENVIRONAGE birth cohort, telomere length and whole-genome DNA methylation were assessed in cord blood and 26 candidate single nucleotide polymorphism related to ageing or telomere length were genotyped. We identified three genetic variants associated with cord blood telomere length and 57 cis methylation quantitative trait loci (cis-mQTLs) of which 22 mQTLs confirmed previous findings and 35 were newly identified. Five SNPs were found to have significant indirect effects on cord blood telomere length via the mediating CpGs. The association between rs911874 (SOD2) and newborn telomere length was modified by nearby DNA methylation indicated by a significant statistical interaction. Our results suggest that DNA methylation in cis might have a mediation or modification effect on the genetic difference in newborn telomere length. This novel approach warrants future follow-up studies that are needed to further confirm and extend these findings.},
}
@article {pmid36266468,
year = {2022},
author = {Asghar, M and Odeh, A and Fattahi, AJ and Henriksson, AE and Miglar, A and Khosousi, S and Svenningsson, P},
title = {Mitochondrial biogenesis, telomere length and cellular senescence in Parkinson's disease and Lewy body dementia.},
journal = {Scientific reports},
volume = {12},
number = {1},
pages = {17578},
pmid = {36266468},
issn = {2045-2322},
mesh = {Humans ; *Parkinson Disease/genetics/complications ; *Lewy Body Disease/genetics ; *Dementia/etiology ; Organelle Biogenesis ; Levodopa ; Cellular Senescence/genetics ; DNA, Mitochondrial/genetics ; Telomere/genetics ; },
abstract = {Progressive age is the single major risk factor for neurodegenerative diseases. Cellular aging markers during Parkinson's disease (PD) have been implicated in previous studies, however the majority of studies have investigated the association of individual cellular aging hallmarks with PD but not jointly. Here, we have studied the association of PD with three aging hallmarks (telomere attrition, mitochondrial dysfunction, and cellular senescence) in blood and the brain tissue. Our results show that PD patients had 20% lower mitochondrial DNA copies but 26% longer telomeres in blood compared to controls. Moreover, telomere length in blood was positively correlated with medication (Levodopa Equivalent Daily Dose, LEDD) and disease duration. Similar results were found in brain tissue, where patients with Parkinson's disease (PD), Parkinson's disease dementia (PDD) and Dementia with Lewy Bodies (DLB) showed (46-95%) depleted mtDNA copies, but (7-9%) longer telomeres compared to controls. In addition, patients had lower mitochondrial biogenesis (PGC-1α and PGC-1β) and higher load of a cellular senescence marker in postmortem prefrontal cortex tissue, with DLB showing the highest effect among the patient groups. Our results suggest that mitochondrial dysfunction (copy number and biogenesis) in blood might be a valuable marker to assess the risk of PD. However, further studies with larger sample size are needed to evaluate these findings.},
}
@article {pmid36265486,
year = {2022},
author = {Yadav, T and Zhang, JM and Ouyang, J and Leung, W and Simoneau, A and Zou, L},
title = {TERRA and RAD51AP1 promote alternative lengthening of telomeres through an R- to D-loop switch.},
journal = {Molecular cell},
volume = {82},
number = {21},
pages = {3985-4000.e4},
pmid = {36265486},
issn = {1097-4164},
support = {R01 CA218856/CA/NCI NIH HHS/United States ; R35 CA263934/CA/NCI NIH HHS/United States ; },
mesh = {Telomere Homeostasis ; Telomere/genetics/metabolism ; *Telomerase/genetics/metabolism ; R-Loop Structures/genetics ; DNA Repair ; *RNA, Long Noncoding ; },
abstract = {Alternative lengthening of telomeres (ALT), a telomerase-independent process maintaining telomeres, is mediated by break-induced replication (BIR). RAD52 promotes ALT by facilitating D-loop formation, but ALT also occurs through a RAD52-independent BIR pathway. Here, we show that the telomere non-coding RNA TERRA forms dynamic telomeric R-loops and contributes to ALT activity in RAD52 knockout cells. TERRA forms R-loops in vitro and at telomeres in a RAD51AP1-dependent manner. The formation of R-loops by TERRA increases G-quadruplexes (G4s) at telomeres. G4 stabilization enhances ALT even when TERRA is depleted, suggesting that G4s act downstream of R-loops to promote BIR. In vitro, the telomeric R-loops assembled by TERRA and RAD51AP1 generate G4s, which persist after R-loop resolution and allow formation of telomeric D-loops without RAD52. Thus, the dynamic telomeric R-loops formed by TERRA and RAD51AP1 enable the RAD52-independent ALT pathway, and G4s orchestrate an R- to D-loop switch at telomeres to stimulate BIR.},
}
@article {pmid36263045,
year = {2022},
author = {Lai, TP and Verhulst, S and Dagnall, CL and Hutchinson, A and Spellman, SR and Howard, A and Katki, HA and Levine, JE and Saber, W and Aviv, A and Gadalla, SM},
title = {Decoupling blood telomere length from age in recipients of allogeneic hematopoietic cell transplant in the BMT-CTN 1202.},
journal = {Frontiers in immunology},
volume = {13},
number = {},
pages = {966301},
pmid = {36263045},
issn = {1664-3224},
support = {U01 AG066529/AG/NIA NIH HHS/United States ; KL2 TR003018/TR/NCATS NIH HHS/United States ; U01 AG066529/AG/NIA NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Humans ; *Hematopoietic Stem Cell Transplantation ; Telomere/genetics ; Tissue Donors ; *Transplants ; },
abstract = {The age of allogeneic hematopoietic cell transplant (HCT) donors and their hematopoietic cell telomere length (TL) might affect recipients' outcomes. Our goals were to examine the possible effect of these donors' factors on the recipients' hematopoietic cell TL and quantify hematopoietic cell TL shortening in the critical first three-month post-HCT. We measured hematopoietic cell TL parameters in 75 recipient-donor pairs, from the Blood and Marrow Transplant Clinical Trials Network (protocol#1202), by Southern blotting (SB), the Telomeres Shortest Length Assay (TeSLA), and quantitative PCR (qPCR). Recipients' hematopoietic cell TL parameters post-HCT correlated with donors' age (p<0.001 for all methods), but not recipients' own age, and with donors' pre-HCT hematopoietic cell TL (p<0.0001 for all). Multivariate analyses showed that donors' hematopoietic cell TL pre-HCT, independent of donors' age, explained most of the variability in recipients' hematopoietic cell TL post-HCT (81% for SB, 56% for TeSLA, and 65% for qPCR; p>0.0001 for all). SB and TeSLA detected hematopoietic cell TL shortening in all recipients post-HCT (mean=0.52kb and 0.47kb, respectively; >15-fold the annual TL shortening in adults; p<0.00001 for both), but qPCR detected shortening only in 57.5% of recipients. TeSLA detected a buildup of post-HCT of telomeres <3 kb in 96% of recipients (p<0.0001). In conclusion, HCT decouples hematopoietic cell TL in the recipients from their own age to reflect the donors' age. The potential donors' age effect on outcomes of HCT might be partially mediated by short hematopoietic cell TL in older donors. qPCR-based TL measurement is suboptimal for detecting telomere shortening post-HCT.},
}
@article {pmid36254044,
year = {2022},
author = {Sung, MK and Koh, E and Kang, Y and Lee, JH and Park, JY and Kim, JY and Shin, SY and Kim, YH and Setou, N and Lee, US and Yang, HJ},
title = {Three months-longitudinal changes in relative telomere length, blood chemistries, and self-report questionnaires in meditation practitioners compared to novice individuals during midlife.},
journal = {Medicine},
volume = {101},
number = {41},
pages = {e30930},
pmid = {36254044},
issn = {1536-5964},
mesh = {Alanine Transaminase ; Aspartate Aminotransferases ; Glucose ; Humans ; Lipoproteins, HDL ; *Meditation/methods ; Self Report ; Surveys and Questionnaires ; Telomere ; Triglycerides ; },
abstract = {Aging accelerates during midlife. Researches have shown the health benefits of mind-body intervention (MBI). However, whether MBI is involved with aging process has not been well understood. In this study, we approach to examine the relations of MBI with this process by investigating an aging marker of the peripheral blood, blood chemistry, and self-report questionnaires. A quasi-experimental design was applied. Experienced MBI practitioners participated in a 3-month intensive meditation training, while the age, gender-matched MBI-naïve controls led a normal daily life. Measurements were taken at before and after the 3 months for relative telomere length (RTL), blood chemistry, and self-report questionnaires including items about sleep quality, somatic symptoms, depression, anxiety, stress, emotional intelligence (EI), and self-regulation. For RTL, the repeated measures analysis of variance showed a significant group*time interaction (P = .013) with a significant post hoc result (P = .030) within the control group: RTL was significantly reduced in the control while it was maintained in the meditation group. In repeated measures analysis of variance for blood chemistries, there were significant group differences between the groups in glucose and total protein. In the post hoc comparison analysis, at post measurements, the meditation group exhibited significantly lower values than the control group in both glucose and total protein. There were significant group-wise differences in the correlations of RTL with triglyceride (TG), high-density lipoprotein (HDL), glutamic oxaloacetic transaminase and glutamic pyruvic transaminase. Any of self-report results did not show significant changes in group*time interaction. However, there were group differences with significant (P < .05) or a tendency (.05 < P < .1) level. There were significant improvements in depression, stress and EI as well as tendencies of improvement in sleep quality and anxiety, in the meditation group compared to the control group. Our results suggest that meditation practice may have a potential to modify aging process in molecular cellular level combined with changes in psychological dimension.},
}
@article {pmid36253798,
year = {2022},
author = {Squassina, A and Meloni, A and Congiu, D and Bosganas, P and Patrinos, GP and Lin, R and Turecki, G and Severino, G and Ardau, R and Chillotti, C and Pisanu, C},
title = {Analysis on in vitro effect of lithium on telomere length in lymphoblastoid cell lines from bipolar disorder patients with different clinical response to long-term lithium treatment.},
journal = {Human genomics},
volume = {16},
number = {1},
pages = {45},
pmid = {36253798},
issn = {1479-7364},
mesh = {*Bipolar Disorder/diagnosis/drug therapy/genetics ; Cell Line ; Humans ; Lithium/pharmacology/therapeutic use ; Lithium Chloride/pharmacology/therapeutic use ; Lithium Compounds/pharmacology/therapeutic use ; *Neural Stem Cells/metabolism ; Telomere/genetics ; },
abstract = {BACKGROUND: It has been suggested that bipolar disorder (BD) is associated with clinical and biological features of accelerated aging. In our previous studies, we showed that long-term lithium treatment was correlated with longer leukocyte telomere length (LTL) in BD patients. A recent study explored the role of TL in BD using patients-derived lymphoblastoid cell lines (LCLs), showing that baseline TL was shorter in BD compared to controls and that lithium in vitro increased TL but only in BD. Here, we used the same cell system (LCLs) to explore if a 7-day treatment protocol with lithium chloride (LiCl) 1 mM was able to highlight differences in TL between BD patients clinically responders (Li-R; n = 15) or non-responders (Li-NR; n = 15) to lithium, and if BD differed from non-psychiatric controls (HC; n = 15).<br><br>RESULTS: There was no difference in TL between BD patients and HC. Moreover, LiCl did not influence TL in the overall sample, and there was no difference between diagnostic or clinical response groups. Likewise, LiCl did not affect TL in neural precursor cells from healthy donors.<br><br>CONCLUSIONS: Our findings suggest that a 7-day lithium treatment protocol and the use of LCLs might not represent a suitable approach to deepen our understanding on the role of altered telomere dynamics in BD as previously suggested by studies in vivo.},
}
@article {pmid36253342,
year = {2023},
author = {Hassani, MA and Murid, J and Yan, J},
title = {Regulator of telomere elongation helicase 1 gene and its association with malignancy.},
journal = {Cancer reports (Hoboken, N.J.)},
volume = {6},
number = {1},
pages = {e1735},
pmid = {36253342},
issn = {2573-8348},
mesh = {Humans ; DNA ; *Neoplasms/genetics ; *Telomere/genetics ; Tumor Microenvironment ; *DNA Helicases/genetics ; },
abstract = {BACKGROUND: With the progression of next-generation sequencing technologies, researchers have identified numerous variants of the regulator of telomere elongation helicase 1 (RTEL1) gene that are associated with a broad spectrum of phenotypic manifestations, including malignancies. At the molecular level, RTEL1 is involved in the regulation of the repair, replication, and transcription of deoxyribonucleic acid (DNA) and the maintenance of telomere length. RTEL1 can act both as a promotor and inhibitor of tumorigenesis. Here, we review the potential mechanisms implicated in the malignant transformation of tissues under conditions of RTEL1 deficiency or its aberrant overexpression.<br><br>RECENT FINDINGS: A major hemostatic challenge during RTEL1 dysfunction could arise from its unbalanced activity for unwinding guanine-rich quadruplex DNA (G4-DNA) structures. In contrast, RTEL1 deficiency leads to alterations in telomeric and genome-wide DNA maintenance mechanisms, ribonucleoprotein metabolism, and the creation of an inflammatory and immune-deficient microenvironment, all promoting malignancy. Additionally, we hypothesize that functionally similar molecules could act to compensate for the deteriorated functions of RTEL1, thereby facilitating the survival of malignant cells. On the contrary, RTEL1 over-expression was directed toward G4-unwinding, by promoting replication fork progression and maintaining intact telomeres, may facilitate malignant transformation and proliferation of various pre-malignant cellular compartments.<br><br>CONCLUSIONS: Therefore, restoring the equilibrium of RTEL1 functions could serve as a therapeutic approach for preventing and treating malignancies.},
}
@article {pmid36249518,
year = {2021},
author = {Albosale, AH and Mashkina, EV},
title = {Association of Relative Telomere Length and Risk of High Human Papillomavirus Load in Cervical Epithelial Cells.},
journal = {Balkan journal of medical genetics : BJMG},
volume = {24},
number = {2},
pages = {65-70},
pmid = {36249518},
issn = {1311-0160},
abstract = {Importunate high-risk HPV (HR-HPV) infection is the most common trigger for the cervical carcinogenesis process. In this respect, the presence of cancer can be imputed to telomere lengthening or shortening. This paper explores the possible correlation between relative telomere length and viral load in two groups of women, namely: those with high-risk HPV infection and those who do not have this infection. Thus, samples comprising of 50 women in each group were evaluated for this research. The Amplisens HPV HCR screen-titre-FRT PCR kite was employed for quantitative analysis. Relative telomere length was quantified by real-time PCR. In each of the two HPV load groups, there was no correlation between age and telomere length. Telomere shortening was found in the cervical cell samples of women with high HPV loads, compared with women in the control group. Telomere shortening is associated with elevated HPV loads.},
}
@article {pmid36248806,
year = {2022},
author = {Ye, M and Wang, Y and Zhan, Y},
title = {Genetic association of leukocyte telomere length with Graves' disease in Biobank Japan: A two-sample Mendelian randomization study.},
journal = {Frontiers in immunology},
volume = {13},
number = {},
pages = {998102},
pmid = {36248806},
issn = {1664-3224},
mesh = {Biological Specimen Banks ; Genome-Wide Association Study ; *Graves Disease/genetics ; Humans ; Japan/epidemiology ; Leukocytes ; *Mendelian Randomization Analysis ; Telomere ; },
abstract = {BACKGROUND: Telomere length (TL) has been recognized to be fundamental to the risk of autoimmune disorders. However, the role of leukocyte TL in Graves' disease has not yet been fully elucidated. In the study, we exploited the two-sample Mendelian randomization (MR) design to evaluate the causal effect of leukocyte TL on the risk of Graves' disease.<br><br>METHODS: Genome-wide association study (GWAS) data of leukocyte TL from the Singapore Chinese Health Study (SCHS) cohort and Graves' disease from Biobank Japan (BBJ, 2176 cases and 210,277 controls) were analyzed. Nine single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) for TL. We used the inverse variance weighted (IVW) approach as the main estimator and MR-Egger regression, weighted median, simple mode, and weighed mode methods as complementary estimators. Horizontal pleiotropy was assessed using the intercept from MR-Egger.<br><br>RESULTS: The analysis demonstrated that genetically predicted longer leukocyte TL was causally associated with a lower risk of Graves' disease using the IVW method (odds ratio [OR]: 1.64, 95% confidence interval [CI]: 1.23-2.17, P=2.27e-04, and other complementary MR approaches&#xa0;achieved similar results. The intercept from the MR-Egger analysis provided no noticeable evidence of horizontal pleiotropy (&#x3b2;=0.02, P=0.641).&#xa0;MR-PRESSO method reported no outliers (P=0.266).<br><br>CONCLUSIONS: Our results provided evidence to support a genetic predisposition to shorter leukocyte TL with an increased risk of Graves' disease. Further studies are warranted to explore the mechanism underlying the association.},
}
@article {pmid36235538,
year = {2022},
author = {Valera-Gran, D and Prieto-Botella, D and Hurtado-Pomares, M and Baladia, E and Petermann-Rocha, F and Sánchez-Pérez, A and Navarrete-Muñoz, EM},
title = {The Impact of Foods, Nutrients, or Dietary Patterns on Telomere Length in Childhood and Adolescence: A Systematic Review.},
journal = {Nutrients},
volume = {14},
number = {19},
pages = {},
pmid = {36235538},
issn = {2072-6643},
support = {VIPROY21/8//Miguel Hernandez University/ ; GVA/2021/191//Generalitat Valenciana/ ; PI18/00825//Instituto de Salud Carlos III/ ; },
mesh = {Animals ; *Antioxidants ; *Diet ; Feeding Behavior ; Monosaccharides ; Nutrients ; Telomere ; Vegetables ; },
abstract = {Environmental factors such as diet can affect telomere length (TL) dynamics. However, the role that children's and adolescents' diets play in maintaining TL is not well understood. Thus, we conducted a systematic review to examine the association between the intake of nutrients, foods, food groups, and/or dietary patterns and TL in childhood and adolescence. Following the PRISMA guidelines, we searched MEDLINE via PubMed, Embase, and Cochrane databases and additional registers and methods. The five selected studies were cross-sectional and conducted in children and adolescents aged 2 to 18 years. The main results suggest that a higher consumption of fish, nuts and seeds, fruits and vegetables, green leafy and cruciferous vegetables, olives, legumes, polyunsaturated fatty acids, and an antioxidant-rich diet might positively affect TL. On the contrary, a higher intake of dairy products, simple sugar, sugar-sweetened beverages, cereals, especially white bread, and a diet high in glycaemic load were factors associated with TL shortening. To our knowledge, this is the first systematic review examining the impact of dietary intake factors on TL in childhood and adolescence. Although limited, these results are consistent with previous studies in different adult populations. Further research is needed to ascertain potential nutritional determinants of TL in childhood and adolescence.},
}
@article {pmid36233645,
year = {2022},
author = {Zia, S and Khan, N and Tehreem, K and Rehman, N and Sami, R and Baty, RS and Tayeb, FJ and Almashjary, MN and Alsubhi, NH and Alrefaei, GI and Shahid, R},
title = {Transcriptomic Analysis of Conserved Telomere Maintenance Component 1 (CTC1) and Its Association with Leukemia.},
journal = {Journal of clinical medicine},
volume = {11},
number = {19},
pages = {},
pmid = {36233645},
issn = {2077-0383},
abstract = {Telomere length (TEL) regulation is important for genome stability and is governed by the coordinated role of shelterin proteins, telomerase (TERT), and CST (CTC1/OBFC1/TEN1) complex. Previous studies have shown the association of telomerase expression with the risk of acute lymphoblastic leukemia (ALL). However, no data are available for CST association with the ALL. The current pilot study was designed to evaluate the CST expression levels in ALL. In total, 350 subjects were recruited, including 250 ALL cases and 100 controls. The subjects were stratified by age and categorized into pediatrics (1-18 years) and adults (19-54 years). TEL and expression patterns of CTC1, OBFC1, and TERT genes were determined by qPCR. The univariable logistic regression analysis was performed to determine the association of gene expression with ALL, and the results were adjusted for age and sex in multivariable analyses. Pediatric and adult cases did not reflect any change in telomere lengths relative to controls. However, expression of CTC1, OBFC1, and TERT genes were induced among ALL cases. Multivariable logistic regression analyses showed association of CTC1 with ALL in pediatric [β estimate (standard error (SE)= -0.013 (0.007), p = 0.049, and adults [0.053 (0.023), p = 0.025]. The association of CTC1 remained significant when taken together with OBFC1 and TERT in a multivariable model. Furthermore, CTC1 showed significant association with B-cell ALL [-0.057(0.017), p = 0.002) and T-cell ALL [-0.050 (0.018), p = 0.008] in pediatric group while no such association was noted in adults. Together, our findings demonstrated that telomere modulating genes, particularly CTC1, are strongly associated with ALL. Therefore, CTC1 can potentially be used as a risk biomarker for the identification of ALL in both pediatrics and adults.},
}
@article {pmid36231453,
year = {2022},
author = {Chen, XY and Lo, CKM and Chan, KL and Leung, WC and Ip, P},
title = {Association between Childhood Exposure to Family Violence and Telomere Length: A Meta-Analysis.},
journal = {International journal of environmental research and public health},
volume = {19},
number = {19},
pages = {},
pmid = {36231453},
issn = {1660-4601},
mesh = {Child ; *Domestic Violence ; Humans ; *Intimate Partner Violence ; Telomere ; },
abstract = {The aims of this meta-analysis were to examine the association between childhood exposure to family violence and telomere length and the moderating variables that influence this association. Relevant works published on or before 1st September 2022 were identified through a search in five major databases in English and 19 articles (N = 18,977) finally met the inclusion criteria. A meta-analysis was conducted to compute the pooled effect size (correlation; r), and moderator analyses were performed using a random effects meta-analytic model. The studies yielded a significant inverse association between childhood exposure to family violence and telomere length, with a small effect size (r = -0.038, 95% CI [-0.070, -0.005], p = 0.025). Furthermore, the strength of this association was stronger in studies examining the co-occurrence of multiple types of violence than in those examining just one type (Q = 8.143, p = 0.004). These findings suggested that victims' telomere length may be negatively influenced by childhood exposure to family violence and that such impairment appears to be stronger for those who are exposed to multiple types of violence. Future studies are necessary to examine the moderating and mediating factors underlying the association between childhood exposure to family violence and telomere length.},
}
@article {pmid36230999,
year = {2022},
author = {Shokr, H and Lush, V and Dias, IH and Ekárt, A and De Moraes, G and Gherghel, D},
title = {The Use of Retinal Microvascular Function and Telomere Length in Age and Blood Pressure Prediction in Individuals with Low Cardiovascular Risk.},
journal = {Cells},
volume = {11},
number = {19},
pages = {},
pmid = {36230999},
issn = {2073-4409},
mesh = {Adult ; Aged ; Biomarkers ; Blood Pressure/physiology ; *Cardiovascular Diseases ; Heart Disease Risk Factors ; Humans ; Middle Aged ; Risk Factors ; Telomere ; },
abstract = {Ageing represents a major risk factor for many pathologies that limit human lifespan, including cardiovascular diseases. Biological ageing is a good biomarker to assess early individual risk for CVD. However, finding good measurements of biological ageing is an ongoing quest. This study aims to assess the use retinal microvascular function, separate or in combination with telomere length, as a predictor for age and systemic blood pressure in individuals with low cardiovascular risk. In all, 123 healthy participants with low cardiovascular risk were recruited and divided into three groups: group 1 (less than 30 years old), group 2 (31-50 years old) and group 3 (over 50 years old). Relative telomere length (RTL), parameters of retinal microvascular function, CVD circulatory markers and blood pressure (BP) were measured in all individuals. Symbolic regression- analysis was used to infer chronological age and systemic BP measurements using either RTL or a combination of RTL and parameters for retinal microvascular function. RTL decreased significantly with age (p = 0.010). There were also age-related differences between the study groups in retinal arterial time to maximum dilation (p = 0.005), maximum constriction (p = 0.007) and maximum constriction percentage (p = 0.010). In the youngest participants, the error between predicted versus actual values for the chronological age were smallest in the case of using both retinal vascular functions only (p = 0.039) or the combination of this parameter with RTL (p = 0.0045). Systolic BP was better predicted by RTL also only in younger individuals (p = 0.043). The assessment of retinal arterial vascular function is a better predictor than RTL for non-modifiable variables such as age, and only in younger individuals. In the same age group, RTL is better than microvascular function when inferring modifiable risk factors for CVDs. In older individuals, the accumulation of physiological and structural biological changes makes such predictions unreliable.},
}
@article {pmid36229075,
year = {2022},
author = {Yang, Z and Sharma, K and de Lange, T},
title = {TRF1 uses a noncanonical function of TFIIH to promote telomere replication.},
journal = {Genes &amp; development},
volume = {36},
number = {17-18},
pages = {956-969},
pmid = {36229075},
issn = {1549-5477},
support = {R01 AG016642/AG/NIA NIH HHS/United States ; R35 CA210036/CA/NCI NIH HHS/United States ; R56 AG016642/AG/NIA NIH HHS/United States ; },
mesh = {*Telomeric Repeat Binding Protein 1 ; *Telomere/genetics/metabolism ; DNA Replication/genetics ; DNA Helicases/genetics/metabolism ; DNA/metabolism ; },
abstract = {Telomeric DNA challenges the replisome and requires TRF1 for efficient duplication. TRF1 recruits the BLM helicase, but BLM loss does not explain the extensive telomere fragility, ATR signaling, and sister telomere associations (STAs) induced by TRF1 deletion. Here, we document that Helix2 of the TRFH domain and Helix1 of the Myb domain of TRF1 are required for efficient telomere replication. Mutation of both helices generated a TRF1 separation-of-function mutant (TRF1-E83K/LW-TI) that induced severe telomere replication defects but no ATR signaling or STAs. We identified the transcription and nucleotide excision repair (NER) factor TFIIH as a critical effector of TRF1. Loss of TFIIH subunits, but no other NER factors, caused the same telomere replication phenotypes as the TRF1-E83K/LW-TI mutant independent of the effects on TRF1 expression. TFIIH subunits coimmunoprecipitated with wild-type TRF1 but not with TRF1-E83K/LW-TI. These results establish that the major mechanism by which TRF1 ensures telomere replication involves a noncanonical function of TFIIH.},
}
@article {pmid36222081,
year = {2023},
author = {Sheikh-Wu, SF and Liang, Z and Downs, CA},
title = {The Relationship Between Telomeres, Cognition, Mood, and Physical Function: A Systematic Review.},
journal = {Biological research for nursing},
volume = {25},
number = {2},
pages = {227-239},
doi = {10.1177/10998004221132287},
pmid = {36222081},
issn = {1552-4175},
mesh = {Humans ; *Oxidative Stress ; *Diet ; Risk Factors ; Cognition/physiology ; Telomere ; },
abstract = {Background and Purpose: Cognitive, affective, and physical symptoms and alterations in their function are seen across chronic illnesses. Data suggest that environmental, psychological, and physiological factors contribute to symptom experience, potentially through loss of telomeres (telomere attrition), structures at the ends of chromosomes. Telomere length is affected by many factors including environmental (e.g., exercise, diet, smoking) and physiological (e.g., response to stress), as well as from oxidative damage and inflammation that occurs in many disease processes. Moreover, telomere attrition is associated with chronic disease (cancer, cardiovascular disease, Alzheimer's disease) and predicts higher morbidity and mortality rates. However, findings are inconsistent among telomere roles and relationships with health outcomes. This article aims to synthesize the current state-of-the-science of telomeres and their relationship with cognitive, affective, and physical function and symptoms. Method: A comprehensive literature search was performed in two databases: CINAHL and PUBMED. A total of 33 articles published between 2000 and 2022 were included in the final analysis. Results: Telomere attrition is associated with various changes in cognitive, affective, and physical function and symptoms. However, findings are inconsistent. Interventional studies (e.g., meditation and exercise) may affect telomere attrition, potentially impacting health outcomes. Conclusion: Nursing research and practice are at the forefront of furthering the understanding of telomeres and their relationships with cognitive, affective, and physical function and symptoms. Future interventions targeting modifiable risk factors may be developed to improve health outcomes across populations.},
}
@article {pmid36221106,
year = {2022},
author = {Sanchez, M and Kannengiesser, C and Hoang, S and Potier, L and Fumeron, F and Venteclef, N and Scheen, A and Gautier, JF and Hadjadj, S and Marre, M and Roussel, R and Mohammedi, K and Velho, G},
title = {Leukocyte telomere length, allelic variations in related genes and risk of coronary heart disease in people with long-standing type 1 diabetes.},
journal = {Cardiovascular diabetology},
volume = {21},
number = {1},
pages = {206},
pmid = {36221106},
issn = {1475-2840},
mesh = {Adaptor Proteins, Signal Transducing/genetics ; Adult ; *Coronary Disease/diagnosis/epidemiology/genetics ; Cytoskeletal Proteins/genetics ; *Diabetes Mellitus, Type 1/diagnosis/epidemiology/genetics ; Humans ; Leukocytes ; *Myocardial Infarction/complications ; Prospective Studies ; Telomere/genetics ; },
abstract = {BACKGROUND: Type 1 diabetes is associated with accelerated vascular aging and advanced atherosclerosis resulting in increased rates of cardiovascular disease and premature death. We evaluated associations between Leukocyte telomere length (LTL), allelic variations (SNPs) in LTL-related genes and the incidence of coronary heart disease (CHD) in adults with long-standing type 1 diabetes.<br><br>METHODS: We assessed associations of LTL, measured at baseline by RT-PCR, and of SNPs in 11 LTL-related genes with the risk of coronary heart disease (CHD: myocardial infarction or coronary revascularization) and all-cause death during follow-up in two multicenter French-Belgian prospective cohorts of people with long-standing type 1 diabetes.<br><br>RESULTS: In logistic and Cox analyses, the lowest tertile of LTL distribution (short telomeres) at baseline was associated with the prevalence of myocardial infarction at baseline and with increased risk of CHD (Hazard ratio 3.14 (1.39-7.70), p&#x2009;=&#x2009;0.005, for shorter vs longer tertile of LTL) and all-cause death (Hazard ratio 1.63 (95% CI 1.04-2.55), p&#x2009;=&#x2009;0.03, for shorter vs combined intermediate and longer tertiles of LTL) during follow-up. Allelic variations in six genes related to telomere biology (TERC, NAF1, TERT, TNKS, MEN1 and BICD1) were also associated with the incidence of CHD during follow-up. The associations were independent of sex, age, duration of diabetes, and a range of relevant confounding factors at baseline.<br><br>CONCLUSIONS: Our results suggest that short LTL is an independent risk factor for CHD in people with type 1 diabetes.},
}
@article {pmid36219936,
year = {2022},
author = {Hatse, S and Serena, M and Vulsteke, C and Punie, K and Neven, P and Smeets, A and Laenen, A and Wildiers, H},
title = {Impact of baseline telomere length on survival and chemotherapy related toxicity in breast cancer patients receiving (neo)adjuvant anthracycline containing chemotherapy.},
journal = {Translational oncology},
volume = {26},
number = {},
pages = {101551},
pmid = {36219936},
issn = {1936-5233},
abstract = {PURPOSE: The aim of this study is to assess baseline mean leukocyte telomere length (TL) as a potential predictive factor for chemotherapy toxicity and a prognostic marker for long-term outcome in early breast cancer (BC) patients.<br><br>METHODS: 445 BC patients were selected, diagnosed between 2007 and 2010 with early BC and treated with (neo)adjuvant fluorouracil, epirubicin and cyclophosphamide (FEC) or with FEC and Docetaxel (FEC-D). RT-qPCR was performed on germline DNA samples collected at diagnosis before any treatment, to measure mean leukocyte TL. Uni- and multivariable logistic regression or Cox proportional hazard regression analyses were carried out to assess correlation between baseline TL and toxicity parameters (derived from the medical chart) or longer-term outcome.<br><br>RESULTS: Baseline TL correlated with age as expected (p&#xa0;=&#xa0;0.005), but not with febrile neutropenia (n&#xa0;=&#xa0;97), left ventricular ejection fraction >10% decrease (n&#xa0;=&#xa0;17) nor other toxicity endpoints measured (all p&#xa0;>&#xa0;0.05). TL was neither associated with overall survival, breast cancer specific survival or distant disease-free survival (all p&#xa0;>&#xa0;0.05).<br><br>CONCLUSIONS: Baseline TL is not associated with chemotherapy-related toxicity nor long-term outcome in BC patients.},
}
@article {pmid36218957,
year = {2023},
author = {Vaquero-Sedas, MI and Vega-Palas, MA},
title = {Epigenetic nature of Arabidopsis thaliana telomeres.},
journal = {Plant physiology},
volume = {191},
number = {1},
pages = {47-55},
pmid = {36218957},
issn = {1532-2548},
mesh = {*Arabidopsis/genetics ; Epigenesis, Genetic ; Telomere/genetics ; Heterochromatin/genetics ; },
abstract = {The epigenetic features of defined chromosomal domains condition their biochemical and functional properties. Therefore, there is considerable interest in studying the epigenetic marks present at relevant chromosomal loci. Telomeric regions, which include telomeres and subtelomeres, have been traditionally considered heterochromatic. However, whereas the heterochromatic nature of subtelomeres has been widely accepted, the epigenetic status of telomeres remains controversial. Here, we studied the epigenetic features of Arabidopsis (Arabidopsis thaliana) telomeres by analyzing multiple genome-wide ChIP-seq experiments. Our analyses revealed that Arabidopsis telomeres are not significantly enriched either in euchromatic marks like H3K4me2, H3K9ac, and H3K27me3 or in heterochromatic marks such as H3K27me1 and H3K9me2. Thus, telomeric regions in Arabidopsis have a bimodal chromatin organization with telomeres lacking significant levels of canonical euchromatic and heterochromatic marks followed by heterochromatic subtelomeres. Since heterochromatin is known to influence telomere function, the heterochromatic modifications present at Arabidopsis subtelomeres could play a relevant role in telomere biology.},
}
@article {pmid36216345,
year = {2023},
author = {Baser, E and Inandiklioglu, N and Aydogan Kırmızı, D and Ercan, F and Caniklioğlu, A and Kara, M and Onat, T and Yalvac, ES},
title = {Placental and Umbilical Cord Blood Oxidative Stress Level and Telomere Homeostasis in Early Onset Severe Preeclampsia.},
journal = {Zeitschrift fur Geburtshilfe und Neonatologie},
volume = {227},
number = {2},
pages = {112-119},
doi = {10.1055/a-1938-0010},
pmid = {36216345},
issn = {1439-1651},
mesh = {Infant, Newborn ; Pregnancy ; Humans ; Female ; *Placenta ; Telomere Homeostasis ; *Pre-Eclampsia/diagnosis ; Fetal Blood ; Oxidative Stress ; },
abstract = {OBJECTIVE: Although the etiopathogenesis of preeclampsia (PE) is unknown, evidence suggests that it may be associated with increased oxidative stress. Studies have shown that oxidative stress can affect DNA fragments called telomeres. However, the interactions of PE, oxidative stress, and telomere length are not clearly known. This study aims to evaluate the oxidative/anti-oxidative stress balance in the placenta and umbilical cord and examine the effect of oxidative stress on telomeres.<br><br>MATERIALS-METHOD: Cord blood and placental samples were collected from 27 pregnant women with severe PE (28[0/7]-33[6/7] gestational weeks) and 53 healthy pregnant women. Telomere length (TL) was measured by real-time PCR in the cord blood and placenta tissue. Total antioxidant status (TAS) and total oxidant status (TOS) levels were measured in the cord blood and placenta tissue using a colorimetric method.<br><br>RESULTS: No significant differences were found between groups regarding age, BMI, gravida, parity, and newborn gender (p>0.05). Cord blood and placental TL of PE patients were significantly shorter than the control group, while cord blood and placental TAS and TOS levels were higher (p<0.05). The results of a multivariate logistic regression analysis showed that the level of placental TOS in PE patients (OR=1.212, 95% CI=1.068-1.375) was an independent risk factor affecting PE.<br><br>CONCLUSION: This study found that oxidative stress is an independent risk factor in the development of PE and shortens TL in both placental and umbilical cord blood. Future research on telomere homeostasis may offer a new perspective for the treatment of PE.},
}
@article {pmid36214766,
year = {2023},
author = {Liang, Z and Saugar, EE and Alamian, A and Ferreira, T and Downs, CA},
title = {Changes in Telomere Length and Indicators of Oxidative Stress in Critically Ill Mechanically Ventilated Adults - A Pilot Study.},
journal = {Biological research for nursing},
volume = {25},
number = {2},
pages = {282-288},
doi = {10.1177/10998004221133395},
pmid = {36214766},
issn = {1552-4175},
mesh = {Humans ; Adult ; Male ; Middle Aged ; Aged ; Female ; Pilot Projects ; *Critical Illness ; *Respiration, Artificial ; Leukocytes, Mononuclear ; Glutathione Disulfide ; Intensive Care Units ; Telomere ; Oxidative Stress ; },
abstract = {BACKGROUND: Telomeres are structures at the end of chromosomes that shorten with each cell division. The purpose of this pilot project is to report changes in telomere length (T/S ratio), indicators of oxidative stress (serum protein carbonyl, vitamin C, GSH:GSSG, and total antioxidant capacity) from Intensive Care Unit (ICU) admission to ICU discharge, and to explore their association with ICU-related morbidities among critically ill mechanically ventilated adults.<br><br>METHODS: Blood was collected from mechanically ventilated patients (n = 25) at enrollment and within 48 hours of ICU discharge. Telomere length from peripheral blood mononuclear cells (PBMCs) was determined using RTqPCR. ELISAs were used to measure indicators of oxidative stress. Descriptive analysis, paired t-tests, and Pearson's correlations were performed.<br><br>RESULTS: Mean age was 62.0 &#xb1; 12.3&#xa0;years, 28.6% were male, and 76.2% were White with disease severity using APACHE III (74.6 &#xb1; 24.6) and SOFA (7.6 &#xb1; 3.2). Mean T/S ratios shortened (ICU: 0.712, post-ICU: 0.683, p < 0.001, n = 19) and serum protein carbonyl increased (ICU: 7437&#xa0;nmol/mg &#xb1; 3328, post-ICU: 10,254&#xa0;nmol/mg &#xb1; 3962, p < 0.005) as did the oxidative stress index (protein carbonyl/GSH:GSSG, ICU: 1049.972 &#xb1; 420.923, post-ICU: 1348.971 &#xb1; 417.175, p = 0.0104). T/S ratio was positively associated with APACHE III scores (ICU: r = 0.474, post-ICU: r = 0.628, p < 0.05).<br><br>CONCLUSIONS: Pilot findings suggest that critical illness significantly correlates with telomere attrition, perhaps due to increased oxidative stress. Future larger and longitudinal studies investigating mechanisms of telomere attrition and associations with clinical outcomes are needed to identify potential modifiable factors for subsequent intervention to improve outcomes for critically ill patients.},
}
@article {pmid36214364,
year = {2023},
author = {Hope, SF and Angelier, F and Ribout, C and Groffen, J and Kennamer, RA and Hopkins, WA},
title = {Warmer incubation temperatures and later lay-orders lead to shorter telomere lengths in wood duck (Aix sponsa) ducklings.},
journal = {Journal of experimental zoology. Part A, Ecological and integrative physiology},
volume = {339},
number = {1},
pages = {101-111},
doi = {10.1002/jez.2659},
pmid = {36214364},
issn = {2471-5646},
mesh = {Animals ; *Ducks/genetics ; Temperature ; *Embryonic Development/physiology ; Hot Temperature ; Telomere ; },
abstract = {The environment that animals experience during development shapes phenotypic expression. In birds, two important aspects of the early-developmental environment are lay-order sequence and incubation. Later-laid eggs tend to produce weaker offspring, sometimes with compensatory mechanisms to accelerate their growth rate to catch-up to their siblings. Further, small decreases in incubation temperature slow down embryonic growth rates and lead to wide-ranging negative effects on many posthatch traits. Recently, telomeres, noncoding DNA sequences at the end of chromosomes, have been recognized as a potential proxy for fitness because longer telomeres are positively related to lifespan and individual quality in many animals, including birds. Although telomeres appear to be mechanistically linked to growth rate, little is known about how incubation temperature and lay-order may influence telomere length. We incubated wood duck (Aix sponsa) eggs at two ecologically-relevant temperatures (34.9°C and 36.2°C) and measured telomere length at hatch and 1 week after. We found that ducklings incubated at the lower temperature had longer telomeres than those incubated at the higher temperature both at hatch and 1 week later. Further, we found that later-laid eggs produced ducklings with shorter telomeres than those laid early in the lay-sequence, although lay-order was not related to embryonic developmental rate. This study contributes to our broader understanding of how parental effects can affect telomere length early in life. More work is needed to determine if these effects on telomere length persist until adulthood, and if they are associated with effects on fitness in this precocial species.},
}
@article {pmid36213488,
year = {2022},
author = {Bürgin, D and Clemens, V and Varghese, N and Eckert, A and Huber, M and Bruttin, E and Boonmann, C and Unternährer, E and O'Donovan, A and Schmid, M},
title = {Adverse and traumatic exposures, posttraumatic stress disorder, telomere length, and hair cortisol - Exploring associations in a high-risk sample of young adult residential care leavers.},
journal = {Brain, behavior, &amp; immunity - health},
volume = {26},
number = {},
pages = {100524},
pmid = {36213488},
issn = {2666-3546},
abstract = {BACKGROUND: Childhood adversities (CAs), potentially traumatic exposures (PTEs), and posttraumatic stress disorder (PTSD) are known to increase the risk for poor health outcomes, including diseases of aging and early mortality. Telomere length (TL) and hair cortisol concentrations (HCC) are biomarkers known to be associated with CA and PTEs, and PTSD, but there is considerable heterogeneity in findings.<br><br>OBJECTIVES: This study aims to investigate the association of CAs, PTEs, and PTSD with TL and HCC in a high-risk sample of young adults who were previously placed in youth residential care institutions throughout Switzerland.<br><br>METHOD: Our sample includes 130 participants (30.8% women, M Age&#xa0;=&#xa0;26.5&#xa0;&#xb1;&#xa0;3.7 years) with previous youth residential care placements (MPlacements=&#xa0;3.9). CAs and PTEs, as well as PTSD, were assessed with self-reported questionnaires and semi-structured clinical interviews. Immune cell TL was measured with quantitative polymerase chain reaction (qPCR) in whole blood. Hair samples were collected for HCC measurement and assayed with high-sensitivity ELISA. Multivariate regression models were fitted to describe the associations between CAs, PTEs, and PTSD with TL and HCC, adjusting for covariates.<br><br>RESULTS: In our high-risk sample, a higher burden of CAs, PTEs, Criterion A trauma, and PTSD was associated with longer TL. PTEs, Criterion A trauma, and PTSD were associated with lower HCC, however no significant associations between CAs and HCC were found. The magnitude of these effects varied depending on the dimensional or categorical nature of the stress-phenotype and the specific measure used.<br><br>CONCLUSIONS: Our findings are in contrast with many, but not all, previous studies of associations between adversity and both TL and HCC. For instance, our findings are in line with other studies that find a state of hypocortisolism in PTSD. Better measurement of adversities and trauma, multisystem biomarker approaches, and more research in larger high-risk samples at the upper end of the adversity-continuum is warranted.},
}
@article {pmid36210421,
year = {2022},
author = {Xu, L and Qiu, Z and Cong, YS},
title = {Comparison of Telomere Length between Buccal Cells and Blood Cells.},
journal = {Bulletin of experimental biology and medicine},
volume = {173},
number = {5},
pages = {677-679},
pmid = {36210421},
issn = {1573-8221},
mesh = {*Blood Cells ; DNA/genetics ; Humans ; *Mouth Mucosa ; Reproducibility of Results ; Telomere/genetics ; Telomere Homeostasis ; },
abstract = {Telomere length (TL) in blood cells is commonly used as a proxy for TL in other tissue types. The source of DNA of adequate quality and quantity is important for TL analysis. Compared to blood cells, buccal cells easy for genomic DNA preparation would facilitate the rapid and reliable TL analysis. However, the feasibility of buccal cells for TL analysis remains yet unestablished. We characterized TL of buccal cells and blood cells collected from 52 individuals using buccal cell swabs and fingertip sticks. Relative TL (RTL) determined by quantitative PCR showed that there is a strong correlation between buccal RTL and blood RTL (r=0.877, p<0.001), suggesting that buccal cells are adequate sources of DNA for TL analysis. The validity of sampling using buccal cell swabs provides simple operation and good reproducibility for TL analysis, that overcomes the discomfort and risk of infection caused by blood sampling.},
}
@article {pmid36208022,
year = {2022},
author = {Olsson, M and Bererhi, B and Miller, E and Schwartz, T and Rollings, N and Lindsay, W and Wapstra, E},
title = {Inbreeding effects on telomeres in hatchling sand lizards (Lacerta agilis): An optimal family affair?.},
journal = {Molecular ecology},
volume = {31},
number = {24},
pages = {6605-6616},
pmid = {36208022},
issn = {1365-294X},
mesh = {Pregnancy ; Animals ; Female ; Humans ; *Inbreeding ; *Lizards/genetics ; Telomere/genetics ; Telomere Shortening ; Genotype ; },
abstract = {Telomeres are nucleotide-protein caps, predominantly at the ends of Metazoan linear chromosomes, showing complex dynamics with regard to their lengthening and shortening through life. Their complexity has entertained the idea that net telomere length and attrition could be valuable biomarkers of phenotypic and genetic quality of their bearer. Intuitively, those individuals could be more heterozygous and, hence, less inbred. However, some inbred taxa have longer, not shorter, telomeres. To understand the role of inbreeding in this complex scenario we need large samples across a range of genotypes with known maternity and paternity in telomere-screened organisms under natural conditions. We assessed the effects of parental and hatchling inbreeding on telomere length in >1300 offspring from >500 sires and dams in a population of sand lizards (Lacerta agilis). Maternal and paternal ID and their interactions predict hatchling telomere length at substantial effect sizes (R[2] > .50). Deviation from mean maternal heterozygosity statistically predicts shorter offspring telomeres but this only when sibship is controlled for by paternal ID, and then is still limited (R[2] = .06). Raw maternal heterozygosity scores, ignoring absolute deviation from the mean, explained 0.07% of the variance in hatchling telomere length. In conclusion, inbreeding is not a driver of telomere dynamics in the sand lizard (Lacerta agilis) study system.},
}
@article {pmid36206470,
year = {2022},
author = {Miki, A and Matsuda, Y and Aida, J and Watanabe, J and Sanada, Y and Sakuma, Y and Lefor, AK and Fukushima, N and Sata, N and Arai, T and Takubo, K and Ishiwata, T},
title = {Telomere Attrition in Intraductal Papillary Mucinous Neoplasms of the Pancreas Associated With Carcinogenesis and Aging.},
journal = {Pancreas},
volume = {51},
number = {6},
pages = {678-683},
doi = {10.1097/MPA.0000000000002081},
pmid = {36206470},
issn = {1536-4828},
mesh = {*Adenocarcinoma, Mucinous/pathology ; Aging ; Carcinogenesis ; *Carcinoma, Pancreatic Ductal/pathology ; *Carcinoma, Papillary/pathology ; Humans ; In Situ Hybridization, Fluorescence ; Pancreas/pathology ; *Pancreatic Intraductal Neoplasms/pathology ; *Pancreatic Neoplasms/pathology ; Telomere/genetics ; },
abstract = {OBJECTIVES: It is challenging to preoperatively distinguish malignant and benign forms of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. The aims of this study were to investigate whether telomere length is associated with pathological grade of IPMNs and age and to clarify the utility of telomere length as a marker to identify malignant IPMNs.<br><br>METHODS: Pancreas tissue was obtained from 28 patients after resection. We measured the telomere lengths of tumor cells in IPMNs and normal duct cells by quantitative fluorescence in situ hybridization. The association of normalized telomere-centromere ratio (NTCR) to pathological grade of IPMNs and age were determined.<br><br>RESULTS: The NTCR showed a gradual decrease with increasing pathological grade of IPMNs. The NTCR in intermediate- and high-grade dysplasia and adenocarcinoma lesions was significantly shorter than in normal pancreatic ducts (P < 0.05). In multivariate analysis, telomere length was most associated with carcinogenesis. When the cutoff value of NTCR was set to 0.74, the sensitivity for detection of high-grade dysplasia and adenocarcinoma was 82.8%, with a specificity of 87.5%.<br><br>CONCLUSIONS: Telomere shortening occurs with carcinogenesis and aging. A significant reduction of telomere length in IPMNs may be useful for surgical decision making.},
}
@article {pmid36205590,
year = {2022},
author = {Madsen, T and Klaassen, M and Raven, N and Dujon, AM and Jennings, G and Thomas, F and Hamede, R and Ujvari, B},
title = {Transmissible cancer and longitudinal telomere dynamics in Tasmanian devils (Sarcophilus harrisii).},
journal = {Molecular ecology},
volume = {31},
number = {24},
pages = {6531-6540},
pmid = {36205590},
issn = {1365-294X},
mesh = {Animals ; Animals, Wild/genetics ; *Facial Neoplasms/epidemiology/genetics/pathology ; *Marsupialia/genetics ; Telomere/genetics ; },
abstract = {A plethora of intrinsic and environmental factors have been shown to influence the length of telomeres, the protector of chromosome ends. Despite the growing interest in infection-telomere interactions, there is very limited knowledge on how transmissible cancers influence telomere maintenance. An emblematic example of transmissible cancer occurs in the Tasmanian devil (Sarcophilus harrisii), whose populations have been dramatically reduced by infectious cancer cells. To investigate associations between telomere dynamics and the transmissible cancer, we used longitudinal data from a Tasmanian devil population that has been exposed to the disease for over 15 years. We detected substantial temporal variation in individual telomere length (TL), and a positive significant association between TL and age, as well as a marginally significant trend for devils with devil facial tumour disease (DFTD) having longer telomeres. A proportional hazard analysis yielded no significant effect of TL on the development of DFTD. Like previous studies, we show the complexity that TL dynamics may exhibit across the lifetime of organisms. Our work highlights the importance of long-term longitudinal sampling for understanding the effects of wildlife diseases on TL.},
}
@article {pmid36203452,
year = {2022},
author = {Tomasova, K and Kroupa, M and Zinkova, A and Korabecna, M and Vymetalkova, V and Skrobanek, P and Sojka, L and Levy, M and Hemminki, K and Liska, V and Hosek, P and Kumar, R and Vodickova, L and Vodicka, P},
title = {Monitoring of telomere dynamics in peripheral blood leukocytes in relation to colorectal cancer patients' outcomes.},
journal = {Frontiers in oncology},
volume = {12},
number = {},
pages = {962929},
pmid = {36203452},
issn = {2234-943X},
abstract = {We investigated the possible associations between leukocyte telomere length, therapy outcomes, and clinicopathological features in patients with colorectal cancer. Additionally, telomerase reverse transcriptase (TERT) expression was evaluated. Telomere length was measured using singleplex qPCR in 478 consecutive leukocyte DNA samples from 198 patients. Blood was drawn at diagnosis prior to any therapy and then at 6-month intervals for 18 months. Following diagnosis, the telomeres gradually shortened during the course of the treatment regardless of the patient's age. The most pronounced decrease was observed 12 months after the diagnosis (p < 0.0001). Based on tumor localization, the decrease in telomere length one year after the diagnosis followed different trajectories (p = 0.03). In patients treated with adjuvant therapy, telomere length correlated with the time elapsed after completion of therapy (p = 0.03). TERT expression did not correlate with the telomere length; however, it was higher in women than men (1.35-fold, 95% CI 1.11-1.65, p = 0.003) and in smokers than non-smokers (1.27-fold, 95% CI 1.01-1.61, p = 0.04). Leukocyte telomere length declines naturally during aging, but the accelerated shortening observed in our patients was age-independent. Telomere length manifestly reflected chemotherapy impact and could be linked to therapy toxicity.},
}
@article {pmid36202783,
year = {2022},
author = {Piñeiro-Hermida, S and Martínez, P and Bosso, G and Flores, JM and Saraswati, S and Connor, J and Lemaire, R and Blasco, MA},
title = {Consequences of telomere dysfunction in fibroblasts, club and basal cells for lung fibrosis development.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {5656},
pmid = {36202783},
issn = {2041-1723},
mesh = {Animals ; Bleomycin/toxicity ; Female ; Fibroblasts/metabolism ; Male ; Mice ; *Pulmonary Fibrosis/chemically induced/genetics/pathology ; Telomere/metabolism ; *Telomeric Repeat Binding Protein 1/genetics ; },
abstract = {TRF1 is an essential component of the telomeric protective complex or shelterin. We previously showed that dysfunctional telomeres in alveolar type II (ATII) cells lead to interstitial lung fibrosis. Here, we study the lung pathologies upon telomere dysfunction in fibroblasts, club and basal cells. TRF1 deficiency in lung fibroblasts, club and basal cells induced telomeric damage, proliferative defects, cell cycle arrest and apoptosis. While Trf1 deletion in fibroblasts does not spontaneously lead to lung pathologies, upon bleomycin challenge exacerbates lung fibrosis. Unlike in females, Trf1 deletion in club and basal cells from male mice resulted in lung inflammation and airway remodeling. Here, we show that depletion of TRF1 in fibroblasts, Club and basal cells does not lead to interstitial lung fibrosis, underscoring ATII cells as the relevant cell type for the origin of interstitial fibrosis. Our findings contribute to a better understanding of proper telomere protection in lung tissue homeostasis.},
}
@article {pmid36202131,
year = {2022},
author = {Aviv, A},
title = {The bullwhip effect, T-cell telomeres, and SARS-CoV-2.},
journal = {The lancet. Healthy longevity},
volume = {3},
number = {10},
pages = {e715-e721},
pmid = {36202131},
issn = {2666-7568},
support = {R01 HL134840/HL/NHLBI NIH HHS/United States ; R56 AG073226/AG/NIA NIH HHS/United States ; U01 AG066529/AG/NIA NIH HHS/United States ; },
mesh = {Adaptive Immunity ; Aged ; *COVID-19 ; Humans ; *SARS-CoV-2/genetics ; T-Lymphocytes ; Telomere/genetics ; },
abstract = {Both myeloid cells, which contribute to innate immunity, and lymphoid cells, which dominate adaptive immunity, partake in defending against SARS-CoV-2. In response to the virus, the otherwise slow haematopoietic production supply chain quickly unleashes its preconfigured myeloid element, which largely resists a bullwhip-like effect. By contrast, the lymphoid element risks a bullwhip-like effect when it produces T cells and B cells that are specifically designed to clear the virus. As T-cell production is telomere-length dependent and telomeres shorten with age, older adults are at higher risk of a T-cell shortfall when contracting SARS-CoV-2 than are younger adults. A poorly calibrated adaptive immune response, stemming from a bullwhip-like effect, compounded by a T-cell deficit, might thus contribute to the propensity of people with inherently short T-cell telomeres to develop severe COVID-19. The immune systems of these individuals might also generate an inadequate T-cell response to anti-SARS-CoV-2 vaccination.},
}
@article {pmid36196242,
year = {2022},
author = {Wilson, C and Murnane, JP},
title = {High-throughput screen to identify compounds that prevent or target telomere loss in human cancer cells.},
journal = {NAR cancer},
volume = {4},
number = {4},
pages = {zcac029},
pmid = {36196242},
issn = {2632-8674},
abstract = {Chromosome instability (CIN) is an early step in carcinogenesis that promotes tumor cell progression and resistance to therapy. Using plasmids integrated adjacent to telomeres, we have previously demonstrated that the sensitivity of subtelomeric regions to DNA double-strand breaks (DSBs) contributes to telomere loss and CIN in cancer. A high-throughput screen was created to identify compounds that affect telomere loss due to subtelomeric DSBs introduced by I-SceI endonuclease, as detected by cells expressing green fluorescent protein (GFP). A screen of a library of 1832 biologically-active compounds identified a variety of compounds that increase or decrease the number of GFP-positive cells following activation of I-SceI. A curated screen done in triplicate at various concentrations found that inhibition of classical nonhomologous end joining (C-NHEJ) increased DSB-induced telomere loss, demonstrating that C-NHEJ is functional in subtelomeric regions. Compounds that decreased DSB-induced telomere loss included inhibitors of mTOR, p38 and tankyrase, consistent with our earlier hypothesis that the sensitivity of subtelomeric regions to DSBs is a result of inappropriate resection during repair. Although this assay was also designed to identify compounds that selectively target cells experiencing telomere loss and/or chromosome instability, no compounds of this type were identified in the current screen.},
}
@article {pmid36193690,
year = {2023},
author = {Spano, L and Etain, B and Laplanche, JL and Leboyer, M and Gard, S and Bellivier, F and Marie-Claire, C},
title = {Telomere length and mitochondrial DNA copy number in bipolar disorder: A sibling study.},
journal = {The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry},
volume = {24},
number = {5},
pages = {449-456},
doi = {10.1080/15622975.2022.2131907},
pmid = {36193690},
issn = {1814-1412},
mesh = {Humans ; *DNA, Mitochondrial/genetics ; *Bipolar Disorder/genetics ; Siblings ; DNA Copy Number Variations ; Biomarkers ; Telomere/genetics ; },
abstract = {OBJECTIVES: An accelerated cellular ageing has been observed in bipolar disorder (BD) using biomarkers such as telomere length (TL) and mitochondrial DNA copy number (mtDNAcn). Several risk factors might drive premature ageing in individuals with BD, including a familial predisposition. This study compared TL and mtDNAcn between individuals with BD and their (un)-affected siblings, and explored factors that may explain proband-sibling differences.<br><br>METHODS: Sixty individuals with BD and seventy-four siblings (34 affected with BD or mood disorders and 40 unaffected) were included. Quantitative polymerase chain reaction (qPCR) was used to measure TL and mtDNAcn from peripheral blood genomic DNA.<br><br>RESULTS: TL and mtDNAcn did not significantly differ between probands and their siblings, whatever these latter were affected or not with mood disorders. However, the correlation plots of TL or mtDNAcn in proband-sibling pairs suggested that some pairs were discordant. The within proband-sibling pairs differences for TL and mtDNAcn were not explained by differences in all tested factors.<br><br>CONCLUSIONS: This study shows that probands with BD and their siblings are concordant for TL and mtDNAcn suggesting that they may share some environmental or genetic determinants of these two biomarkers of cellular ageing.},
}
@article {pmid36189312,
year = {2022},
author = {Li, SC and Jia, ZK and Yang, JJ and Ning, XH},
title = {Telomere-related gene risk model for prognosis and drug treatment efficiency prediction in kidney cancer.},
journal = {Frontiers in immunology},
volume = {13},
number = {},
pages = {975057},
pmid = {36189312},
issn = {1664-3224},
mesh = {*Carcinoma, Renal Cell/drug therapy/genetics/pathology ; Humans ; Immune Checkpoint Inhibitors ; *Kidney Neoplasms/drug therapy/genetics/pathology ; NIMA-Related Kinases/genetics ; Prognosis ; Protein Kinase C-theta/genetics ; Proteomics ; RNA ; Risk Factors ; Telomere/genetics ; },
abstract = {Kidney cancer is one of the most common urological cancers worldwide, and kidney renal clear cell cancer (KIRC) is the major histologic subtype. Our previous study found that von-Hippel Lindau (VHL) gene mutation, the dominant reason for sporadic KIRC and hereditary kidney cancer-VHL syndrome, could affect VHL disease-related cancers development by inducing telomere shortening. However, the prognosis role of telomere-related genes in kidney cancer has not been well discussed. In this study, we obtained the telomere-related genes (TRGs) from TelNet. We obtained the clinical information and TRGs expression status of kidney cancer patients in The Cancer Genome Atlas (TCGA) database, The International Cancer Genome Consortium (ICGC) database, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. Totally 353 TRGs were differential between tumor and normal tissues in the TCGA-KIRC dataset. The total TCGA cohort was divided into discovery and validation TCGA cohorts and then using univariate cox regression, lasso regression, and multivariate cox regression method to conduct data analysis sequentially, ten TRGs (ISG15, RFC2, TRIM15, NEK6, PRKCQ, ATP1A1, ELOVL3, TUBB2B, PLCL1, NR1H3) risk model had been constructed finally. The kidney patients in the high TRGs risk group represented a worse outcome in the discovery TCGA cohort (p<0.001), and the result was validated by these four cohorts (validation TCGA cohort, total TCGA cohort, ICGC cohort, and CPTAC cohort). In addition, the TRGs risk score is an independent risk factor for kidney cancer in all these five cohorts. And the high TRGs risk group correlated with worse immune subtypes and higher tumor mutation burden in cancer tissues. In addition, the high TRGs risk group might benefit from receiving immune checkpoint inhibitors and targeted therapy agents. Moreover, the proteins NEK6, RF2, and ISG15 were upregulated in tumors both at the RNA and protein levels, while PLCL1 and PRKCQ were downregulated. The other five genes may display the contrary expression status at the RNA and protein levels. In conclusion, we have constructed a telomere-related genes risk model for predicting the outcomes of kidney cancer patients, and the model may be helpful in selecting treatment agents for kidney cancer patients.},
}
@article {pmid36186140,
year = {2022},
author = {Liu, Y and Huang, Y and Liu, C and Liu, Q},
title = {Longer Leukocyte Telomere Length Increases the Risk of Atrial Fibrillation: A Mendelian Randomization Study.},
journal = {Aging and disease},
volume = {13},
number = {5},
pages = {1311-1313},
pmid = {36186140},
issn = {2152-5250},
}
@article {pmid36184605,
year = {2022},
author = {Guh, CY and Shen, HJ and Chen, LW and Chiu, PC and Liao, IH and Lo, CC and Chen, Y and Hsieh, YH and Chang, TC and Yen, CP and Chen, YY and Chen, TW and Chen, LY and Wu, CS and Egly, JM and Chu, HC},
title = {XPF activates break-induced telomere synthesis.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {5781},
pmid = {36184605},
issn = {2041-1723},
mesh = {DNA ; Endonucleases/metabolism ; RNA ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; Telomere Homeostasis ; },
abstract = {Alternative Lengthening of Telomeres (ALT) utilizes a recombination mechanism and break-induced DNA synthesis to maintain telomere length without telomerase, but it is unclear how cells initiate ALT. TERRA, telomeric repeat-containing RNA, forms RNA:DNA hybrids (R-loops) at ALT telomeres. We show that depleting TERRA using an RNA-targeting Cas9 system reduces ALT-associated PML bodies, telomere clustering, and telomere lengthening. TERRA interactome reveals that TERRA interacts with an extensive subset of DNA repair proteins in ALT cells. One of TERRA interacting proteins, the endonuclease XPF, is highly enriched at ALT telomeres and recruited by telomeric R-loops to induce DNA damage response (DDR) independent of CSB and SLX4, and thus triggers break-induced telomere synthesis and lengthening. The attraction of BRCA1 and RAD51 at telomeres requires XPF in FANCM-deficient cells that accumulate telomeric R-loops. Our results suggest that telomeric R-loops activate DDR via XPF to promote homologous recombination and telomere replication to drive ALT.},
}
@article {pmid36182724,
year = {2022},
author = {He, D and Meng, P and Li, C and Jia, Y and Wen, Y and Pan, C and Zhang, Z and Zhang, J and Zhang, H and Chen, Y and Zhao, Y and Qin, X and Cai, Q and Wei, W and Shi, S and Chu, X and Zhang, N and Zhang, F},
title = {Association between telomere length and insomnia: A mendelian randomization and colocalization study.},
journal = {Sleep medicine},
volume = {100},
number = {},
pages = {304-310},
doi = {10.1016/j.sleep.2022.09.002},
pmid = {36182724},
issn = {1878-5506},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Female ; Humans ; *Mendelian Randomization Analysis ; Genome-Wide Association Study/methods ; *Sleep Initiation and Maintenance Disorders/genetics ; Polymorphism, Single Nucleotide/genetics ; Telomere/genetics ; },
abstract = {BACKGROUND: Previous studies have suggested a potential association between sleep and telomere length (TL), but its genetic basis remains unclear. In this study, we aimed to explore the genetic correlation and potential causal association between TL and insomnia.<br><br>METHODS: The genome-wide association study (GWAS) datasets of TL and insomnia-related traits were used, including insomnia, snoring, daytime dozing and napping. Based on the polygenic risk scores (PRS) of TL, linear regression and linkage disequilibrium score (LDSC) regression were used to preliminarily explore the association between TL and insomnia parameters in the UK Biobank cohort. Then, we investigated the causal association between TL and insomnia by mendelian randomization (MR) analysis and colocalization analysis.<br><br>RESULTS: In the UK Biobank cohort, the association between TL and insomnia was observed in the female samples (t&#xa0;=&#xa0;2.968, P&#xa0;=&#xa0;3.00&#xa0;&#xd7;&#xa0;10[-3]). LDSC detected a genetic correlation between short TL and insomnia (Rg&#xa0;=&#xa0;-9.27&#xa0;&#xd7;&#xa0;10[-2], P&#xa0;=&#xa0;8.00&#xa0;&#xd7;&#xa0;10[-4]). We found no evidence supporting significant causal association between insomnia and TL in IVW method (b&#xa0;=&#xa0;-5.95&#xa0;&#xd7;&#xa0;10[-3], P&#xa0;=&#xa0;0.57), with horizontal pleiotropy and heterogeneity tests indicating the validity of our MR study. Finally, rs12638862 was classified as colocalized by COLOC (PP4&#xa0;=&#xa0;0.99), and TERC may be involved in regulating the association between insomnia and TL.<br><br>CONCLUSIONS: Our study found no evidence for causal association between insomnia and TL in individuals of European ancestry. We detected a candidate gene associated with both insomnia and TL, providing novel clues for understanding the roles of this association.},
}
@article {pmid36182046,
year = {2022},
author = {Hanis, F and Chung, ELT and Kamalludin, MH and Idrus, Z},
title = {Blood Profile, Hormones, and Telomere Responses: Potential Biomarkers in Horses Exhibiting Abnormal Oral Behavior.},
journal = {Journal of equine veterinary science},
volume = {118},
number = {},
pages = {104130},
doi = {10.1016/j.jevs.2022.104130},
pmid = {36182046},
issn = {0737-0806},
mesh = {Animals ; *Leptin ; *Ghrelin ; Hydrocortisone ; Creatine Kinase ; Biomarkers ; Telomere/genetics ; },
abstract = {The high prevalence of abnormal oral behavior (AOB) in working horses has been linked to management issues and the pathophysiology of this behavior remains unclear. Therefore, this study aims to elucidate the blood profile, hormones, and telomere length responses between low and high levels of AOB among different horse working groups. A total of 207 healthy horses from various breeds were initially selected from four working groups (leisure riding, equestrian, endurance, and patrolling) and observed for the time spent on AOB. Then, six horses each with higher and lower AOB than the population means were randomly selected from each of the working groups and categorized as high and low AOB horses, respectively. Blood samples were collected for hematology, biochemistry, cortisol, ghrelin, leptin, and relative telomere length analyzes. High AOB horses notably had higher values of glucose, alanine aminotransferase (ALT), alkaline phosphatase (ALP), and creatine kinase (CK) compared to low AOB horses. High AOB horses also recorded higher plasma cortisol and ghrelin, but lower leptin concentrations. Among working groups, both endurance and patrolling horses presented the highest values in sodium, potassium, chloride, phosphate, ALT, and CK. While patrolling horses had the lowest levels of urea, ALP, and albumin levels, equestrian and leisure horses recorded the highest and lowest plasma cortisol and leptin concentrations, respectively. Finally, the telomere length of endurance and patrolling horses were significantly greater than leisure and equestrian horses. The present findings suggest that AOB horses had distinctive physiological characteristics that could be linked to improper diet and a demanding workload, while ghrelin and leptin hormones could be potential biomarkers for this behavior.},
}
@article {pmid36181470,
year = {2023},
author = {Raftopoulou, C and Abawi, O and Sommer, G and Binou, M and Paltoglou, G and Flück, CE and van den Akker, ELT and Charmandari, E},
title = {Leukocyte Telomere Length in Children With Congenital Adrenal Hyperplasia.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {108},
number = {2},
pages = {443-452},
doi = {10.1210/clinem/dgac560},
pmid = {36181470},
issn = {1945-7197},
mesh = {Female ; Humans ; Child ; Adolescent ; Male ; *Adrenal Hyperplasia, Congenital/drug therapy/genetics/complications ; Hydrocortisone/therapeutic use ; Glucocorticoids/pharmacology/therapeutic use ; Prospective Studies ; Prednisolone/therapeutic use ; Telomere/genetics ; },
abstract = {CONTEXT: Exposure to chronic stress and hypercortisolism is associated with decreased leukocyte telomere length (LTL), a marker for biological aging and cardiovascular disease. Children with congenital adrenal hyperplasia (CAH) are treated with glucocorticoids.<br><br>OBJECTIVE: To investigate LTL in children with CAH.<br><br>METHODS: In this prospective observational cohort study, conducted at 4 academic pediatric endocrinology outpatient clinics, children with genetically confirmed CAH were assessed at 2 follow-up visits (mean 4.1 &#xb1; 0.7 months apart). At each visit, LTL was determined by quantitative real-time PCR. All subjects underwent detailed clinical and endocrinologic evaluation and were classified as undertreated, optimally treated, or overtreated, accordingly. The influence of clinical factors on LTL was investigated using linear mixed models adjusted for age, sex, and BMI-z.<br><br>RESULTS: We studied 76 patients, of whom 31 (41%) were girls, 63 (83%) had classic CAH, 67 (88%) received hydrocortisone, and 8 (11%) prednisolone. Median age at first visit was 12.0 years (IQR, 6.3-15.1), and median BMI-z was 0.51 (IQR, -0.12 to 1.43). LTL was shorter in patients with classic vs nonclassic CAH (-0.29, P = 0.012), in overtreated than in optimally treated patients (-0.07, P = 0.002), and patients receiving prednisolone compared with hydrocortisone (-0.34, P < 0.001). LTL was not associated with undertreatment or daily hydrocortisone-equivalent dose (P > 0.05).<br><br>CONCLUSION: LTL is shorter in patients with classic than nonclassic CAH, and in those who are overtreated with hydrocortisone or treated with long-acting glucocorticoids. These findings may be attributed to chronic exposure to supraphysiologic glucocorticoid concentrations and indicate that LTL may be used as a biomarker for monitoring glucocorticoid treatment.},
}
@article {pmid36177720,
year = {2022},
author = {Akinnibosun, OA and Maier, MC and Eales, J and Tomaszewski, M and Charchar, FJ},
title = {Telomere therapy for chronic kidney disease.},
journal = {Epigenomics},
volume = {14},
number = {17},
pages = {1039-1054},
doi = {10.2217/epi-2022-0073},
pmid = {36177720},
issn = {1750-192X},
mesh = {Animals ; Fibrosis ; Longitudinal Studies ; Nucleoproteins/genetics ; *Renal Insufficiency, Chronic/genetics/therapy ; *Telomere/genetics ; },
abstract = {Chronic kidney disease (CKD) is estimated to affect almost 10% of individuals worldwide and is one of the leading causes of morbidity and mortality. Renal fibrosis, a central pathway in CKD progression (irrespective of etiology), is associated with shortened or dysfunctional telomeres in animal studies. Telomeres are specialized nucleoprotein structures located at the chromosome end that maintain genomic integrity. The mechanisms of associations between telomere length and CKD have not yet been fully elucidated, however, CKD patients with shorter telomere length may have decreased renal function and a higher mortality rate. A plethora of ongoing research has focused on possible therapeutic applications of telomeres with the overall goal to preserve telomere length as a therapy to treat CKD.},
}
@article {pmid36175852,
year = {2022},
author = {de Oliveira, FM and Jamur, VR and Merfort, LW and Pozzo, AR and Mai, S},
title = {Three-dimensional nuclear telomere architecture and differential expression of aurora kinase genes in chronic myeloid leukemia to measure cell transformation.},
journal = {BMC cancer},
volume = {22},
number = {1},
pages = {1024},
pmid = {36175852},
issn = {1471-2407},
mesh = {Aurora Kinase A/genetics ; Blast Crisis ; Chromosome Aberrations ; *Graft vs Host Disease ; Humans ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics ; *Leukemia, Myeloid ; RNA, Messenger ; Telomere/genetics ; },
abstract = {BACKGROUND: Telomere dysfunction results in aneuploidy, and ongoing chromosomal abnormalities. The three-dimensional (3D) nuclear organization of telomeres allows for a distinction between normal and tumor cells. On the other hand, aurora kinase genes (AURKA and AURKB) play an important role regulating the cell cycle. A correlation between overexpression of aurora kinase genes and clinical aggressiveness has been demonstrated in different types of neoplasias. To better understand cellular and molecular mechanisms of CML evolution, it was examined telomere dysfunction (alterations in the 3D nuclear telomere architecture), and the expression levels of AURKA and AURKB genes in two clinical distinct subgroups of CML samples, from the same patient.<br><br>METHODS: Eighteen CML patients, in total, 36 bone marrow samples (18 patients, chronic vs. accelerated/blast phase) were eligible for 3D telomeric investigations. Quantitative 3D imaging, cytologic diagnosis and cytogenetic determination of additional chromosomal abnormalities were assessed according to standard protocols.<br><br>RESULTS: Using TeloView software, two CML subgroups were defined based on their 3D telomeric profiles, reflecting the different stages of the disease (chronic vs. accelerated/blast phase). Statistical analyses showed significant differences between the CML subgroups (p&#x2009;<&#x2009;0.001). We also found that AURKA and AURKB mRNA were expressed at significantly higher levels in both CML subgroups, when compared with healthy donors. Our findings suggest that the evolution of CML progresses from a low to a high level of telomere dysfunction, that is, from an early stage to a more aggressive stage, followed by disease transformation, as demonstrated by telomere, additional chromosomal abnormalities, and gene expression profile dynamics.<br><br>CONCLUSIONS: Thus, we demonstrated that 3D telomere organization, in accordance with the genomic instability observed in CML samples were able to distinguish subgroup CML patients. Classifying CML patients based on these characteristics might represent an important strategy to define better therapeutic strategies.},
}
@article {pmid36175503,
year = {2022},
author = {Bird, L},
title = {Gift of life: APC to T cell telomere transfer.},
journal = {Nature reviews. Immunology},
volume = {22},
number = {11},
pages = {653},
pmid = {36175503},
issn = {1474-1741},
mesh = {Humans ; *T-Lymphocytes ; *Telomere/genetics ; },
}
@article {pmid36175493,
year = {2022},
author = {Porrazzo, A and Cipressa, F and De Gregorio, A and De Pittà, C and Sales, G and Ciapponi, L and Morciano, P and Esposito, G and Tabocchini, MA and Cenci, G},
title = {Author Correction: Low dose rate γ-irradiation protects fruit fly chromosomes from double strand breaks and telomere fusions by reducing the esi-RNA biogenesis factor Loquacious.},
journal = {Communications biology},
volume = {5},
number = {1},
pages = {1033},
doi = {10.1038/s42003-022-03984-8},
pmid = {36175493},
issn = {2399-3642},
}
@article {pmid36174712,
year = {2022},
author = {Zhu, X and Fu, H and Sun, J and Di, Q and Xu, Q},
title = {N6-methyladenosine modification on Hmbox1 is related to telomere dysfunction in DEHP-induced male reproductive injury.},
journal = {Life sciences},
volume = {309},
number = {},
pages = {121005},
doi = {10.1016/j.lfs.2022.121005},
pmid = {36174712},
issn = {1879-0631},
mesh = {Animals ; Male ; Mice ; *Diethylhexyl Phthalate/toxicity ; *Telomerase/metabolism ; Telomere/genetics ; Adenosine ; Homeodomain Proteins/metabolism ; },
abstract = {AIMS: Di (2-ethylhexyl) phthalate (DEHP), as an environmental endocrine-disrupting chemical (EDC), can induce male reproductive injury. N6-methyladenosine (m6A) plays a vital role in environmental exposure-induced diseases by regulating gene expression. Therefore, we aim to investigate the role of m6A in DEHP-induced reproductive injury.<br><br>MAIN METHODS: We established an in vivo model of mice exposed to DEHP to explore the effect of DEHP on reproductive injury and m6A. To further explore the molecular mechanism of DEHP toxicity, we built a model of GC-2 cells exposed to mono-(2-ethylhexyl) phthalate (MEHP) in vitro and further silenced Mettl3 in GC-2cells. Besides, we also conducted MeRIP-qPCR and RIP assays to identify the target genes for m6A modification.<br><br>KEY FINDINGS: DEHP induced testicular injury and senescence. And telomeres shortening, reduced levels of telomere repeat-binding factor 1 (TRF1), TRF2, protection of telomeres 1 (POT1), and telomerase reverse transcriptase (TERT) can be observed in DEHP-treated testes. MEHP also induced GC-2 cellular senescence and telomere dysfunction. Besides, increased m6A mediated by METTL3 stabilized homeobox containing 1 (Hmbox1) in an m6A-dependent manner in MEHP-exposed GC-2 cells. Mettl3 knockdown led to lower m6A modification and reduced Hmbox1 stability, resulting in further shortening of telomere length.<br><br>SIGNIFICANCE: our work uncovered that DEHP led to male reproductive injury by telomere dysfunction and m6A modified Hmbox1 contributed to maintaining telomere homeostasis in this process, suggesting that accurate regulation of m6A modification level by drugs has potential value in the treatment of DEHP-induced male reproductive injury.},
}
@article {pmid36172207,
year = {2022},
author = {Xia, F and Li, Q and Luo, X and Wu, J},
title = {Association between urinary metals and leukocyte telomere length involving an artificial neural network prediction: Findings based on NHANES 1999-2002.},
journal = {Frontiers in public health},
volume = {10},
number = {},
pages = {963138},
pmid = {36172207},
issn = {2296-2565},
mesh = {Adult ; Aged ; *Cadmium ; Humans ; Leukocytes/physiology ; Molybdenum ; Neural Networks, Computer ; Nutrition Surveys ; *Telomere ; },
abstract = {OBJECTIVE: Leukocytes telomere length (LTL) was reported to be associated with cellular aging and aging related disease. Urine metal also might accelerate the development of aging related disease. We aimed to analyze the association between LTL and urinary metals.<br><br>METHODS: In this research, we screened all cycles of National Health and Nutrition Examination Survey (NHANES) dataset, and download the eligible dataset in NHANES 1999-2002 containing demographic, disease history, eight urine metal, and LTL. The analysis in this research had three steps including baseline difference comparison, multiple linear regression (MLR) for hazardous urine metals, and artificial neural network (ANN, based on Tensorflow framework) to make LTL prediction.<br><br>RESULTS: The MLR results showed that urinary cadmium (Cd) was negatively correlated with LTL in the USA population [third quantile: -9.36, 95% confidential interval (CI) = (-19.7, -2.32)], and in the elderly urinary molybdenum (Mo) was positively associated with LTL [third quantile: 24.37, 95%CI = (5.42, 63.55)]. An ANN model was constructed, which had 24 neurons, 0.375 exit rate in the first layer, 15 neurons with 0.53 exit rate in the second layer, and 7 neurons with 0.86 exit rate in the third layer. The squared error loss (LOSS) and mean absolute error (MAE) in the ANN model were 0.054 and 0.181, respectively, which showed a low error rate.<br><br>CONCLUSION: In conclusion, in adults especially the elderly, the relationships between urinary Cd and Mo might be worthy of further research. An accurate prediction model based on ANN could be further analyzed.},
}
@article {pmid36169361,
year = {2022},
author = {Maximov, VN and Orlov, PS and Gurazeva, AA and Melnikova, ES and Gafarov, VV and Chervova, OA and Voevoda, MI and Malyutina, SK},
title = {[The relationship between the relative length of leukocyte telomeres and mtDNA copy number and acute coronary syndrome in a 15-year follow-up.].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {35},
number = {3},
pages = {351-360},
pmid = {36169361},
issn = {1561-9125},
mesh = {*Acute Coronary Syndrome/diagnosis/genetics ; Aged ; Biomarkers ; DNA Copy Number Variations ; DNA, Mitochondrial/genetics ; Female ; Follow-Up Studies ; Humans ; Leukocytes ; Male ; Middle Aged ; *Myocardial Infarction ; Telomere/genetics ; },
abstract = {We studied the relationship between the leucocyte telomere length (LTL) and the copy number of mitochondrial DNA (CNmtDNA) and the development of acute coronary syndrome during 15 years of follow-up. A random population sample was examined at baseline in 2003-2005 (n=9 360, men and women 45-69 years old, Novosibirsk, the HAPIEE project) and followed-up for 15 years. In the frame of nested case-control design, we selected cases - incident myocardial infarction/acute coronary syndrome (MI/ACS) among those free from baseline CVD (n=256) and sex- and age-stratified control among those free from baseline CVD and cancer and alive by the end of follow-up (n=799). The relative LTL and CNmtDNA were assessed using quantitative real-time PCR. Results. The carriers of shorter telomeres had increased 15-year risk of MI/ACS with adjusted OR=1,87 (95% CI 1,70-2,06) per 1 LTL decile independent of other factors. Fewer CNmtDNA was associated with increased risk of MI/ACS with adjusted OR=1,19 (95% CI 1,12-1,26) per 1 CNmtDNA decile. The identified associations were confirmed in tertile analysis and in stepwise analysis with continuous variables of both biomarkers. All associations persisted after adjusting for gender, age, and traditional CVD risk factors. Conclusion. The LTL and CNmtDNA were independent predictors of the 15-year risk of MI/ACS in the middle- and elderly Siberian (Caucasoid) population cohort. These findings highlight the need for further research to elucidate the mechanisms by which LTL and mtDNA copy number may affect human health.},
}
@article {pmid36168042,
year = {2022},
author = {Carey, A and Niedernhofer, L and Camell, C},
title = {Telomeres are a life-extending gift.},
journal = {Nature cell biology},
volume = {24},
number = {10},
pages = {1449-1450},
pmid = {36168042},
issn = {1476-4679},
mesh = {*Telomere/genetics ; Cellular Senescence ; },
}
@article {pmid36160016,
year = {2022},
author = {Kahrizi, MS and Patra, I and Jalil, AT and Achmad, H and Alesaeidi, S and Al-Gazally, ME and Alesaeidi, S},
title = {Leukocyte telomere length and obesity in children and adolescents: A systematic review and meta-analysis.},
journal = {Frontiers in genetics},
volume = {13},
number = {},
pages = {861101},
pmid = {36160016},
issn = {1664-8021},
abstract = {Background: Several studies have revealed the negative effects of adiposity on telomere length shortening. However, the results of the studies assessing the negative relationship between obesity and leukocyte telomere length (LTL) are not consistent. This systematic review and meta-analysis are aimed to pool the results of articles assessing the relationship between obesity and LTL among children and adolescents. Methods: To retrieve the related studies, four online databases including PubMed, Embase, ProQuest, and Scopus were searched until May 2022. Observational studies evaluating the relationship between obesity and LTL among apparently healthy children and adolescents (aged ≤18 years) were included in the study. We considered the studies that had reported a mean ± standard deviation of LTL. The random-effects model was used to assess the pooled weighted mean difference (WMD) and a 95% confidence interval (CI). Results: The search yielded seven studies from an initial 3,403 records identified. According to the results of seven articles with 4,546 participants, obesity was associated with LTL shortening among children and adolescents (WMD = -0.081; 95% CI: -0.137 to -0.026; p = 0.004; I[2] = 99.9%). Also, no publication bias was observed. According to the results of subgrouping, significant results were only attributed to the studies conducted in Europe, with high quality scores, among overweight and obese adolescents, with a baseline LTL lower than 1, and performed in community-based school settings. Also, according to the subgrouping and meta-regression results, the obesity definition criteria and baseline LTL were the possible sources of between-study heterogeneity. Conclusion: We observed shorter LTL among overweight and obese children and adolescents. To obtain more reliable results, further longitudinal prospective studies with large sample sizes and more consistent and accurate definitions of obesity are required.},
}
@article {pmid36159052,
year = {2022},
author = {Krishna, M and Shetty, A and Manjappa, AB and Shetty, V and Hegde, MN and Kumar, BM},
title = {Comparative characterization and analysis of telomere length in stem cells derived from deciduous and permanent teeth.},
journal = {Dental research journal},
volume = {19},
number = {},
pages = {64},
pmid = {36159052},
issn = {1735-3327},
abstract = {BACKGROUND: Understanding the influence of age on growth kinetics and telomere length in dental stem cells is essential for the successful development of cell therapies. Hence, the present study compared the basic cellular and phenotypical characteristics of stem cells from human exfoliated deciduous teeth (SHEDs) and dental pulp stem cells (DPSCs) of permanent teeth and their telomere lengths using quantitative real-time polymerase chain reaction.<br><br>MATERIALS AND METHODS: The study is an in vitro original research article. Primary cultures of SHED and DPSCs (n = 6 each) were successfully established in vitro, and the parameters analyzed were the morphology, viability, proliferation rate, population doubling time (PDT), phenotypic markers expression, and the relative telomere lengths. Data were analyzed by analysis of variance and P < 0.05 was considered statistically significant.<br><br>RESULTS: SHED and DPSCs exhibited a small spindle-shaped fibroblast-like morphology with >90% viability. The proliferation assay showed that the cells had a typical growth pattern. The PDT values of SHED and DPSCs were 29.03 &#xb1; 9.71 h and 32.05 &#xb1; 9.76 h, respectively. Both cells were positive for surface markers CD29, CD44, and CD90. However, they were negative for CD45 and human leukocyte antigen DR. Although the differences in relative telomere lengths between the individual cell lines of SHED and DPSCs were observed, no significant (P > 0.05) variations were found for the mean T/S ratios of both the cells.<br><br>CONCLUSION: SHED and DPSCs displayed similar morphology, proliferation rates, and phenotypic features. The relative telomere lengths were slightly shorter in DPSCs than SHED, but the values were not significantly different. Thus, SHED and DPSCs can be considered as recognized sources for regenerative applications in dentistry.},
}
@article {pmid36153564,
year = {2022},
author = {Meeser, A and Bartenhagen, C and Werr, L and Hellmann, AM and Kahlert, Y and Hemstedt, N and Nürnberg, P and Altmüller, J and Ackermann, S and Hero, B and Simon, T and Peifer, M and Fischer, M and Rosswog, C},
title = {Reliable assessment of telomere maintenance mechanisms in neuroblastoma.},
journal = {Cell &amp; bioscience},
volume = {12},
number = {1},
pages = {160},
pmid = {36153564},
issn = {2045-3701},
support = {FI 1926/2-1//Deutsche Forschungsgemeinschaft/ ; as part of the SFB1399//Deutsche Forschungsgemeinschaft/ ; BA 6984/1-1//Deutsche Forschungsgemeinschaft/ ; 2016-Kolleg-19//Else Kr&#xf6;ner-Fresenius-Stiftung/ ; 01ZX1303//Bundesministerium f&#xfc;r Bildung und Forschung/ ; 01ZX1603//Bundesministerium f&#xfc;r Bildung und Forschung/ ; 01ZX1307//Bundesministerium f&#xfc;r Bildung und Forschung/ ; 01ZX1607//Bundesministerium f&#xfc;r Bildung und Forschung/ ; K&#xf6;ln Fortune Program/Faculty of Medicine//Universit&#xe4;t zu K&#xf6;ln/ ; },
abstract = {BACKGROUND: Telomere maintenance mechanisms (TMM) are a hallmark of high-risk neuroblastoma, and are conferred by activation of telomerase or alternative lengthening of telomeres (ALT). However, detection of TMM is not yet part of the clinical routine, and consensus on TMM detection, especially on ALT assessment, remains to be achieved.<br><br>METHODS: Whole genome sequencing (WGS) data of 68 primary neuroblastoma samples were analyzed. Telomere length was calculated from WGS data or by telomere restriction fragment analysis (n&#x2009;=&#x2009;39). ALT was assessed by C-circle assay (CCA, n&#x2009;=&#x2009;67) and detection of ALT-associated PML nuclear bodies (APB) by combined fluorescence in situ hybridization and immunofluorescence staining (n&#x2009;=&#x2009;68). RNA sequencing was performed (n&#x2009;=&#x2009;64) to determine expression of TERT and telomeric long non-coding RNA (TERRA). Telomerase activity was examined by telomerase repeat amplification protocol (TRAP, n&#x2009;=&#x2009;15).<br><br>RESULTS: Tumors were considered as telomerase-positive if they harbored a TERT rearrangement, MYCN amplification or high TERT expression (45.6%, 31/68), and ALT-positive if they were positive for APB and CCA (19.1%, 13/68). If all these markers were absent, tumors were considered TMM-negative (25.0%, 17/68). According to these criteria, the majority of samples were classified unambiguously (89.7%, 61/68). Assessment of additional ALT-associated parameters clarified the TMM status of the remaining seven cases with high likelihood: ALT-positive tumors had higher TERRA expression, longer telomeres, more telomere insertions, a characteristic pattern of telomere variant repeats, and were associated with ATRX mutations.<br><br>CONCLUSIONS: We here propose a workflow to reliably detect TMM in neuroblastoma. We show that unambiguous classification is feasible following a stepwise approach that determines both, activation of telomerase and ALT. The workflow proposed in this study can be used in clinical routine and provides a framework to systematically and reliably determine telomere maintenance mechanisms for risk stratification and treatment allocation of neuroblastoma patients.},
}
@article {pmid36151328,
year = {2023},
author = {Revy, P and Kannengiesser, C and Bertuch, AA},
title = {Genetics of human telomere biology disorders.},
journal = {Nature reviews. Genetics},
volume = {24},
number = {2},
pages = {86-108},
pmid = {36151328},
issn = {1471-0064},
support = {R01 HL131744/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; *Telomere/genetics/metabolism ; Aging/genetics ; Telomere Homeostasis ; Genomic Instability ; Biology ; *Telomerase/genetics ; },
abstract = {Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that prevent the activation of DNA damage response and repair pathways. Numerous factors localize at telomeres to regulate their length, structure and function, to avert replicative senescence or genome instability and cell death. In humans, Mendelian defects in several of these factors can result in abnormally short or dysfunctional telomeres, causing a group of rare heterogeneous premature-ageing diseases, termed telomeropathies, short-telomere syndromes or telomere biology disorders (TBDs). Here, we review the TBD-causing genes identified so far and describe their main functions associated with telomere biology. We present molecular aspects of TBDs, including genetic anticipation, phenocopy, incomplete penetrance and somatic genetic rescue, which underlie the complexity of these diseases. We also discuss the implications of phenotypic and genetic features of TBDs on fundamental aspects related to human telomere biology, ageing and cancer, as well as on diagnostic, therapeutic and clinical approaches.},
}
@article {pmid36146670,
year = {2022},
author = {Wight, DJ and Aimola, G and Beythien, G and Flamand, L and Kaufer, BB},
title = {Impact of Host Telomere Length on HHV-6 Integration.},
journal = {Viruses},
volume = {14},
number = {9},
pages = {},
pmid = {36146670},
issn = {1999-4915},
support = {Stg 677673/ERC_/European Research Council/International ; },
mesh = {Child ; HeLa Cells ; *Herpesvirus 6, Human/genetics ; Humans ; In Situ Hybridization, Fluorescence ; *Roseolovirus Infections/genetics ; Telomere ; Virus Integration ; },
abstract = {Human herpesvirus 6A and 6B are two closely related viruses that infect almost all humans. In contrast to most herpesviruses, HHV-6A/B can integrate their genomes into the telomeres during the infection process. Both viruses can also integrate in germ cells and subsequently be inherited in children. How HHV-6A/B integrate into host telomeres and the consequences of this remain a subject of active research. Here, we developed a method to measure telomere length by quantitative fluorescence in situ hybridization, confocal microscopy, and computational processing. This method was validated using a panel of HeLa cells having short or long telomeres. These cell lines were infected with HHV-6A, revealing that the virus could efficiently integrate into telomeres independent of their length. Furthermore, we assessed the telomere lengths after HHV-6A integration and found that the virus-containing telomeres display a variety of lengths, suggesting that either telomere length is restored after integration or telomeres are not shortened by integration. Our results highlight new aspects of HHV-6A/B biology and the role of telomere length on virus integration.},
}
@article {pmid36145097,
year = {2022},
author = {Ogłuszka, M and Lipiński, P and Starzyński, RR},
title = {Effect of Omega-3 Fatty Acids on Telomeres-Are They the Elixir of Youth?.},
journal = {Nutrients},
volume = {14},
number = {18},
pages = {},
pmid = {36145097},
issn = {2072-6643},
support = {2020/39/B/NZ5/02469//National Science Center/ ; 2015/17/N/NZ9/01105//National Science Center/ ; },
mesh = {Animals ; Cellular Senescence ; Cross-Sectional Studies ; *Fatty Acids, Omega-3/pharmacology ; Humans ; Inflammation ; Rats ; *Telomere ; Telomere Shortening ; },
abstract = {Telomeres are complexes consisting of tandem repeat DNA combined with associated proteins that play a key role in protecting the ends of chromosomes and maintaining genome stability. They are considered a biological clock, as they shorten in parallel with aging. Furthermore, short telomeres are associated with several age-related diseases. However, the variability in telomere shortening independent of chronological age suggests that it is a modifiable factor. In fact, it is regulated inter alia by genetic damage, cell division, aging, oxidative stress, and inflammation. A key question remains: how can we prevent accelerated telomere attrition and subsequent premature replicative senescence? A number of studies have explored the possible impact of omega-3 fatty acids on telomere shortening. This review summarizes published cross-sectional studies, randomized controlled trials, and rodent studies investigating the role of omega-3 fatty acids in telomere biology. It also covers a broad overview of the mechanism, currently favored in the field, that explains the impact of omega-3 fatty acids on telomeres-the food compound's ability to modulate oxidative stress and inflammation. Although the results of the studies performed to date are not consistent, the vast majority indicate a beneficial effect of omega-3 fatty acids on telomere length.},
}
@article {pmid36143917,
year = {2022},
author = {Liutkeviciene, R and Mikalauskaite, R and Gedvilaite, G and Glebauskiene, B and Kriauciuniene, L and Žemaitienė, R},
title = {Relative Leukocyte Telomere Length and Telomerase Complex Regulatory Markers Association with Leber's Hereditary Optic Neuropathy.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {58},
number = {9},
pages = {},
pmid = {36143917},
issn = {1648-9144},
mesh = {Adult ; Aged ; Case-Control Studies ; DNA, Mitochondrial/genetics ; Female ; Humans ; Leukocytes ; Male ; *Optic Atrophy, Hereditary, Leber/diagnosis/genetics/therapy ; *Telomerase/genetics ; Telomere/genetics ; },
abstract = {Background and Objectives: To evaluate the association of relative leukocyte telomere length (RLTL) and telomerase complex regulatory markers with Leber’s hereditary optic neuropathy (LHON). Material and Methods: A case-control study was performed in patients with LHON (≥18 years) and healthy subjects. The diagnosis of LHON was based on a genetic blood test (next-generation sequencing with Illumina MiSeq, computer analysis: BWA2.1 Illumina BaseSpace, Alamut, and mtDNA Variant analyzer 1000 were performed) and diagnostic criteria approved by the LHON disease protocol. Statistical analysis was performed using the standard statistical software package, IBM SPSS Statistics 27. Statistically significant results were considered when p < 0.05. Results: Significantly longer RLTL was observed in LHON patients than in healthy controls (p < 0.001). RLTL was significantly longer in women and men with LOHN than in healthy women and men in the control group (p < 0.001 and p = 0.003, respectively). In the elderly group (>32 years), RLTL was statistically significantly longer in LHON patients compared with healthy subjects (p < 0.001). The GG genotype of the TERC rs12696304 polymorphism was found to be statistically significantly higher in the LHON group (p = 0.041), and the C allele in the TERC rs12696304 polymorphism was found to be statistically significantly less common in the LHON group (p < 0.001). The RLTL of LHON patients was found to be statistically significantly longer in the TERC rs12696304 polymorphism in all tested genotypes (CC, p = 0.005; CG, p = 0.008; GG, p = 0.025), TEP1 rs1760904 polymorphism in the GA genotype (p < 0.001), and TEP1 gene rs1713418 in the AA and AG genotypes (p = 0.011 and p < 0.001, respectively). Conclusions: The RLTL in LHON patients was found to be longer than in healthy subjects regardless of treatment with idebenone. The TERC rs12696304 polymorphism, of all studied polymorphisms, was the most significantly associated with changes in LHON and telomere length.},
}
@article {pmid36140830,
year = {2022},
author = {Jenner, LP and Peska, V and Fulnečková, J and Sýkorová, E},
title = {Telomeres and Their Neighbors.},
journal = {Genes},
volume = {13},
number = {9},
pages = {},
pmid = {36140830},
issn = {2073-4425},
mesh = {Base Sequence ; DNA ; *DNA, Satellite ; Humans ; Repetitive Sequences, Nucleic Acid ; *Telomere/genetics ; },
abstract = {Telomeres are essential structures formed from satellite DNA repeats at the ends of chromosomes in most eukaryotes. Satellite DNA repeat sequences are useful markers for karyotyping, but have a more enigmatic role in the eukaryotic cell. Much work has been done to investigate the structure and arrangement of repetitive DNA elements in classical models with implications for species evolution. Still more is needed until there is a complete picture of the biological function of DNA satellite sequences, particularly when considering non-model organisms. Celebrating Gregor Mendel's anniversary by going to the roots, this review is designed to inspire and aid new research into telomeres and satellites with a particular focus on non-model organisms and accessible experimental and in silico methods that do not require specialized equipment or expensive materials. We describe how to identify telomere (and satellite) repeats giving many examples of published (and some unpublished) data from these techniques to illustrate the principles behind the experiments. We also present advice on how to perform and analyse such experiments, including details of common pitfalls. Our examples are a selection of recent developments and underexplored areas of research from the past. As a nod to Mendel's early work, we use many examples from plants and insects, especially as much recent work has expanded beyond the human and yeast models traditional in telomere research. We give a general introduction to the accepted knowledge of telomere and satellite systems and include references to specialized reviews for the interested reader.},
}
@article {pmid36139914,
year = {2022},
author = {Konstantinidou, F and Budani, MC and Marconi, GD and Gonnella, F and Sarra, A and Trubiani, O and Stuppia, L and Tiboni, GM and Gatta, V},
title = {The Aftermath of Long-Term Cigarette Smoking on Telomere Length and Mitochondrial DNA Copy Number in Human Cumulus Cells Prior to In Vitro Fertilization-A Pilot Study.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {11},
number = {9},
pages = {},
pmid = {36139914},
issn = {2076-3921},
abstract = {Cigarette smoking among women of reproductive age is known to take a toll on systemic health and fertility potential by severely impacting ovarian tissues and cells, such as granulosa and cumulus cells (CCs). The purpose of this study was to determine the potential damage caused by tobacco smoke at a molecular level in the CCs of females who had undergone in vitro fertilization. The level of intracellular damage was determined by estimating the average telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN), as well as the expression profile of telomere maintenance genes TERF1, TERF2, POT1 and microRNAs miR-155, miR-23a and miR-185. Western blotting analysis was performed to detect consequent protein levels of TERF1, TERF2 and POT1. Our results evidenced significantly lower relative TL and mtDNA-CN and a down-regulation pattern for all three described genes and corresponding proteins in the CCs of smokers compared with controls (p < 0.05). No significant differences were found in the miRNAs’ modulation. Combined, our data add another piece to the puzzle of the complex regulatory molecular networks controlling the general effects of tobacco smoke in CCs. This pilot study extends the until now modest number of studies simultaneously investigating the mtDNA-CN and TL pathways in the human CCs of smoking women.},
}
@article {pmid36138138,
year = {2023},
author = {Chandyo, RK and Schwinger, C and Kvestad, I and Ulak, M and Ranjitkar, S and Shrestha, M and Nguyen, LV and Corona-Perez, D and DeVivo, I and Shrestha, L and Strand, TA},
title = {The association between household biomass fuel use and leukocyte telomere length among toddlers in Bhaktapur, Nepal.},
journal = {Journal of exposure science &amp; environmental epidemiology},
volume = {33},
number = {3},
pages = {448-454},
pmid = {36138138},
issn = {1559-064X},
mesh = {Adult ; Humans ; Child, Preschool ; *Air Pollution, Indoor/adverse effects/analysis ; Nepal ; Prospective Studies ; *Petroleum ; Cooking ; Leukocytes ; Telomere ; },
abstract = {BACKGROUND: Biomass fuels are still in use for cooking by many households in resource poor countries such as Nepal and is a major source of household air pollution (HAP). Chronic exposure to HAP has been shown to be associated with shorter telomere length in adults.<br><br>OBJECTIVES: To measure the association between exposure related to household biomass fuel in infancy and leukocyte telomere length (LTL) at 18-23 months of age among 497 children from Bhaktapur, Nepal.<br><br>METHODS: In a prospective cohort study design, we have collected information on household cooking fuel use and several clinical, anthropometric, demographic, and socioeconomic variables. We estimated the association between biomass fuel use and the relative LTL in multiple linear regression models.<br><br>RESULTS: Most of the families (78%) reported liquified petroleum gas (LPG) as the primary cooking fuel, and 18.7% used biomass. The mean relative (SD) LTL was 1.03 (0.19). Children living in households using biomass fuel had on average 0.09 (95% CI: 0.05 to 0.13) units shorter LTL than children in households with no biomass fuel use. The observed association was unaltered after adjusting for relevant confounders. The association between LTL and biomass use was strongest among children from households with &#x2264;2 rooms and without separate kitchen.<br><br>SIGNIFICANCE: Exposure to biomass fuel use in early life might have consequences for longevity, and risk of chronic illnesses reflected in shortening of the telomeres. Our findings support the ongoing effort to reduce exposure to biomass fuel in low-resource settings.<br><br>IMPACT STATEMENTS: Biomass for cooking is a leading source of household air pollution in low and middle-income countries, contributing to many chronic diseases and premature deaths. Chronic exposure to biomass fuel through oxidative stress and inflammation has been associated with a shortening of the telomeres, a "biological marker" of longevity. This prospective cohort study describes the association between household biomass fuel use and leukocyte telomere length among 497 toddlers. Leukocyte telomere length was significantly shorter among children living in households with biomass fuel than in children from homes where mainly LPG was used for cooking.<br><br>CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT02272842, registered October 21, 2014, Universal Trial Number: U1111-1161-5187 (September 8, 2014).},
}
@article {pmid36137363,
year = {2022},
author = {Verma, AK and Singh, P and Al-Saeed, FA and Ahmed, AE and Kumar, S and Kumar, A and Dev, K and Dohare, R},
title = {Unravelling the role of telomere shortening with ageing and their potential association with diabetes, cancer, and related lifestyle factors.},
journal = {Tissue &amp; cell},
volume = {79},
number = {},
pages = {101925},
doi = {10.1016/j.tice.2022.101925},
pmid = {36137363},
issn = {1532-3072},
mesh = {Humans ; Telomere Shortening/genetics ; Telomere/genetics/metabolism ; *Telomerase/genetics/metabolism ; Aging/genetics ; *Neoplasms ; Life Style ; *Diabetes Mellitus ; RNA, Messenger ; },
abstract = {Telomeres are often considered as the 'ageing clock' that determines the lifespan at the cellular level, forming the ends of a chromosome, which shorten each time the cell divides itself to the point where they become so short the cell is unable to divide itself further. Telomere length alteration is often linked with lifestyle factors such as age, obesity, exposure to pesticides and pollution, depression, unhealthy diet, lack of exercise, and stress. The current review discusses the mechanism of telomere shortening in relation to ageing and lifestyle factors in general and its association with chronic diseases like diabetes which may influence the health and lifespan of an individual by increasing telomere shortening. Accelerated or excessive telomere shortening is also associated with the early onset of age-related disorders globally and, hence, reduced lifespan of individuals. Upregulated Telomerase activity and reactivation of telomeres is observed in > 70 % of cancer patients by TERT point mutations, rearrangements, DNA amplifications, and transcript fusions, making it a useful marker in diagnosis and prognosis of various cancers. The study presents a systematic review of the unregulated Telomere activity with progression of various cancer and extrapolation of suitable pathways and prognostic information correlated with mRNA levels of TERT, which are critical among thymic epithelial tumors (TETs). In most cancers, unlimited proliferation is due to the reactivation of reverse transcriptase gene TERT. All these observations are comprehensively presented in the paper and might be useful for researchers working in the field of telomere dynamics and finding the correlation of age shortening with mRNA expression profiling.},
}
@article {pmid36136831,
year = {2022},
author = {Chico-Sordo, L and Polonio, AM and Córdova-Oriz, I and Medrano, M and Herraiz, S and Bronet, F and García-Velasco, JA and Varela, E},
title = {Telomeres and oocyte maturation rate are not reduced by COVID-19 except in severe cases.},
journal = {Reproduction (Cambridge, England)},
volume = {164},
number = {5},
pages = {259-267},
doi = {10.1530/REP-22-0243},
pmid = {36136831},
issn = {1741-7899},
mesh = {*COVID-19 ; Female ; Humans ; Leukocytes, Mononuclear ; Male ; Oocytes ; Prospective Studies ; SARS-CoV-2 ; Telomere ; },
abstract = {IN BRIEF: COVID-19 does not affect the telomeres or fertility outcomes in mild cases. However, in women with severe symptoms, telomeres of granulosa cells are shorter, and the oocyte maturation rate is decreased.<br><br>ABSTRACT: The coronavirus SARS-CoV-2 causes COVID-19 disease and affects primarily the lungs and also other organs, causing accelerated cell aging. One of the main pathways involved in aging is telomere attrition, which ultimately leads to defective tissue regeneration and organ dysfunction. Indeed, short telomeres in aged people aggravate the COVID-19 symptoms, and COVID-19 survivors showed shorter telomeres in blood cells. The SARS-CoV-2 has been detected in testis, but the ovaries, which express the viral entry factors, have not been fully explored. Our objective was to analyze telomeres and reproductive outcomes in women who had COVID-19 and controls. In this prospective cohort study, granulosa cells (GCs) and blood were collected from 65 women. Telomere length (TL) was measured by high-throughput in situ hybridization. Mean TL of GCs and peripheral blood mononuclear cells (PBMCs) was alike in control and mild cases. However, mean TL of GCs was lower in severe cases compared to controls (P = 0.017). Control and COVID groups had similar ovarian reserve and number of total oocytes after puncture. However, the oocyte maturation rate was lower in severe cases (P = 0.018). Interestingly, a positive correlation between the oocyte maturation rate and TL of GCs was found in the control group (P = 0.024). Our findings point to a potential impact of the coronavirus infection on telomeres and reproductive outcomes in severe cases. This might be considered upon possible new SARS-CoV threats, to favor treatments that enhance oocyte maturation in women severely affected by coronavirus undergoing ART.},
}
@article {pmid36130485,
year = {2022},
author = {McKinney, AM and Mathur, R and Stevers, NO and Molinaro, AM and Chang, SM and Phillips, JJ and Costello, JF},
title = {GABP couples oncogene signaling to telomere regulation in TERT promoter mutant cancer.},
journal = {Cell reports},
volume = {40},
number = {12},
pages = {111344},
pmid = {36130485},
issn = {2211-1247},
support = {F31 CA243187/CA/NCI NIH HHS/United States ; P01 CA118816/CA/NCI NIH HHS/United States ; P50 CA097257/CA/NCI NIH HHS/United States ; R01 CA244838/CA/NCI NIH HHS/United States ; },
mesh = {AMP-Activated Protein Kinases/metabolism ; Adenosine Monophosphate ; ErbB Receptors/genetics/metabolism ; GA-Binding Protein Transcription Factor/metabolism ; *Glioblastoma/genetics ; Humans ; Mutation/genetics ; Oncogenes ; RNA, Messenger ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {Telomerase activation counteracts senescence and telomere erosion caused by uncontrolled proliferation. Epidermal growth factor receptor (EGFR) amplification drives proliferation while telomerase reverse transcriptase promoter (TERTp) mutations underlie telomerase reactivation through recruitment of GA-binding protein (GABP). EGFR amplification and TERTp mutations typically co-occur in glioblastoma, the most common and aggressive primary brain tumor. To determine if these two frequent alterations driving proliferation and immortality are functionally connected, we combine analyses of copy number, mRNA, and protein data from tumor tissue with pharmacologic and genetic perturbations. We demonstrate that proliferation arrest decreases TERT expression in a GABP-dependent manner and elucidate a critical proliferation-to-immortality pathway from EGFR to TERT expression selectively from the mutant TERTp through activation of AMP-mediated kinase (AMPK) and GABP upregulation. EGFR-AMPK signaling promotes telomerase activity and maintains telomere length. These results define how the tumor cell immortality mechanism keeps pace with persistent oncogene signaling and cell cycling.},
}
@article {pmid36130216,
year = {2022},
author = {Seo, B and Yang, K and Kahe, K and Qureshi, AA and Chan, AT and De Vivo, I and Cho, E and Giovannucci, EL and Nan, H},
title = {Association of omega-3 and omega-6 fatty acid intake with leukocyte telomere length in US males.},
journal = {The American journal of clinical nutrition},
volume = {116},
number = {6},
pages = {1759-1766},
pmid = {36130216},
issn = {1938-3207},
support = {U01 CA167552/CA/NCI NIH HHS/United States ; U01 CA167552/GF/NIH HHS/United States ; },
mesh = {Male ; Humans ; Cross-Sectional Studies ; *Telomere ; Case-Control Studies ; Follow-Up Studies ; Leukocytes ; *Fatty Acids, Omega-3/pharmacology ; Fatty Acids, Omega-6 ; Fatty Acids ; },
abstract = {BACKGROUND: Omega-3 (n-3) and omega-6 (n-6) fatty acids may contribute to oxidative stress and inflammation, which are related to telomere shortening. Evidence supporting an association between intake of n-3 or n-6 fatty acids and leukocyte telomere length (LTL) in males has been limited.<br><br>OBJECTIVES: We conducted a cross-sectional study to examine the associations of total or individual n-3 or total n-6 fatty acid intake with LTL in US males.<br><br>METHODS: We included 2,494 US males with LTL measurement from 4 nested case-control studies within the Health Professionals Follow-Up Study. Individuals with previous histories of cancers, diabetes, and cardiovascular diseases at or before blood collection were excluded. Blood collection was performed between 1993 and 1995, and relevant information including n-3 and n-6 intake was collected in 1994 by questionnaire. The LTL was log-transformed and Z scores of the LTL were calculated for statistical analyses by standardizing the LTL in comparison with the mean within each selected nested case-control study.<br><br>RESULTS: We found that consumption of DHA (22:6n-3) was positively associated with LTL. In the multivariable-adjusted model, compared with individuals who had the lowest intake of DHA (i.e., first quartile group), the percentage differences (95% CIs) of LTL were -3.7 (-13.7, 7.5), 7.0 (-4.3, 19.7), and 8.2 (-3.5, 21.3) for individuals in the second, third, and fourth quartiles of consumption, respectively (P-trend&#xa0;=&#xa0;0.0498). We did not find significant associations between total n-3 or total n-6 fatty acid intakes and LTL. In addition, we found that males who consumed canned tuna had longer LTL than those who did not; in the multivariable-adjusted model, the percentage difference of LTL was 10.5 (95% CI: 1.3, 20.4) (P&#xa0;=&#xa0;0.02).<br><br>CONCLUSIONS: Our results suggest that higher intakes of DHA and canned tuna consumption are associated with longer LTL.},
}
@article {pmid36126117,
year = {2022},
author = {Foley, JF},
title = {Telomeres to go.},
journal = {Science signaling},
volume = {15},
number = {752},
pages = {eade9136},
doi = {10.1126/scisignal.ade9136},
pmid = {36126117},
issn = {1937-9145},
mesh = {*Cellular Senescence/genetics ; *Telomere/genetics ; },
abstract = {By acquiring telomeres from antigen-presenting cells, some T cells are protected from senescence.},
}
@article {pmid36125668,
year = {2023},
author = {Tian, C and Heng, D and Zhao, N and Liu, L and Sheng, X and Chen, J and Liu, L},
title = {Short telomeres impede germ cell specification by upregulating MAPK and TGFβ signaling.},
journal = {Science China. Life sciences},
volume = {66},
number = {2},
pages = {324-339},
pmid = {36125668},
issn = {1869-1889},
mesh = {Animals ; Mice ; Chromatin/metabolism ; *Germ Cells/metabolism ; Telomerase/genetics/metabolism ; *Telomere/genetics/metabolism ; Transforming Growth Factor beta/metabolism ; MAP Kinase Signaling System/physiology ; },
abstract = {Functional telomeres protect chromosome ends and play important roles in stem cell maintenance and differentiation. Short telomeres negatively impact germ cell development and can contribute to age-associated infertility. Moreover, telomere syndrome resulting from mutations of telomerase or telomere-associated genes exhibits short telomeres and reduced fertility. It remains elusive whether and how telomere lengths affect germ cell specification. We report that functional telomere is required for the coordinated germ cell and somatic cell fate decisions. Using telomerase gene Terc deficient mice as a model, we show that short telomeres restrain germ cell specification of epiblast cells but promote differentiation towards somatic lineage. Short telomeres increase chromatin accessibility to elevate TGFβ and MAPK/ERK signaling for somatic cell differentiation. Notably, elevated Fst expression in TGFβ pathway represses the BMP4-pSmad signaling pathway, thus reducing germ cell formation. Re-elongation of telomeres by targeted knock-in of Terc restores normal chromatin accessibility to suppress TGFβ and MAPK signaling, thereby facilitating germ cell formation. Taken together, our data reveal that functional telomeres are required for germ cell specification by repressing TGFβ and MAPK signaling.},
}
@article {pmid36125233,
year = {2023},
author = {Park, HS and Son, BR and Kwon, J},
title = {Usefulness of Genetic Aberration and Shorter Telomere Length in Myelodysplastic Syndrome: A Pilot Study.},
journal = {Laboratory medicine},
volume = {54},
number = {2},
pages = {199-205},
doi = {10.1093/labmed/lmac100},
pmid = {36125233},
issn = {1943-7730},
support = {//Chonbuk National University Hospital/ ; },
mesh = {Humans ; Pilot Projects ; *Myelodysplastic Syndromes/diagnosis/genetics ; Prognosis ; Real-Time Polymerase Chain Reaction ; Telomere/genetics ; },
abstract = {OBJECTIVE: We aimed to evaluate the clinical usefulness of genetic aberration and shorter telomere length (TL) in individuals with myelodysplastic syndrome (MDS).<br><br>METHODS: A targeted sequencing panel with 49 genes and TL measurement by quantitative real-time polymerase chain reaction were performed for 46 subjects.<br><br>RESULTS: According to the revised International Prognostic Scoring System (IPSS-R) subtypes, the mutation frequency was 33.3%, 57.9%, and 100% in the very low/low, intermediate, and very high/high risk groups, respectively. A shorter telomere was detected in 43.5%. We defined group 1 as IPSS-R-high or -very high risk, group 2 as having 1 or more genetic aberrations, group 3 as having a shorter TL, and group 4 as having a longer TL than the age-matched reference. Group 1 and group 2 showed an adverse prognosis. The TL was not strongly correlated with MDS prognosis. However, it may be related to a poor long-term prognosis.<br><br>CONCLUSION: Genetic variation and shorter TL may be helpful in reclassifying non-high-risk groups.},
}
@article {pmid36122232,
year = {2022},
author = {Silva, B and Arora, R and Azzalin, CM},
title = {The alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restricted.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {119},
number = {39},
pages = {e2208669119},
pmid = {36122232},
issn = {1091-6490},
mesh = {DNA ; Endonucleases/metabolism ; Humans ; *RNA, Long Noncoding ; *Telomerase/genetics ; Telomere/genetics/metabolism ; },
abstract = {A substantial number of human cancers are telomerase-negative and elongate physiologically damaged telomeres through a break-induced replication (BIR)-based mechanism known as alternative lengthening of telomeres (ALT). We recently demonstrated that inhibiting the transcription of the telomeric long noncoding RNA TERRA suppresses telomere damage and ALT features, indicating that telomere transcription is a main trigger of ALT activity. Here we show that experimentally increased TERRA transcription not only increases ALT features, as expected, but also causes rapid loss of telomeric DNA through a pathway that requires the endonuclease Mus81. Our data indicate that the ALT mechanism can endanger telomere integrity if not properly controlled and point to TERRA transcription as a uniquely versatile target for therapy.},
}
@article {pmid36121249,
year = {2022},
author = {Sharqawi, M and Hantisteanu, S and Bilgory, A and Aslih, N and Shibli Abu Raya, Y and Atzmon, Y and Estrada, D and Limonad, O and Meisel-Sharon, S and Shalom-Paz, E},
title = {The Impact of Lifestyle on Sperm Function, Telomere Length, and IVF Outcomes.},
journal = {American journal of men's health},
volume = {16},
number = {5},
pages = {15579883221119931},
pmid = {36121249},
issn = {1557-9891},
mesh = {Female ; Fertilization in Vitro ; Humans ; Life Style ; Male ; Pregnancy ; *Semen ; *Sperm Motility ; Spermatozoa ; Telomere ; },
abstract = {Many risk factors can potentially influence sperm quality. Telomeres confer stability on the chromosome and their dysfunction has been implicated in conditions such as cancer, aging, and lifestyle. The impact of lifestyle on sperm cell telomeres is unclear. The objectives of this study were to evaluate the impact of lifestyle behaviors on telomere length in sperm and to follow the correlation with pregnancy outcomes in patients undergoing in vitro fertilization (IVF). In this prospective observational study, sperm was analyzed for telomere length (TL). Men were asked to report lifestyle behaviors including occupation (physical or sedentary), smoking duration and amount, physical activity, dietary habits, and where they keep their cellular phone (bag, pants, or shirt pocket). Correlations among semen analysis, TL, men's habits, and embryo quality and pregnancy outcomes were evaluated. Among 34 patients recruited, 12 had longer TL and 13 shorter TL. Sperm motility was negatively correlated with TL (Pearson correlation = -.588, p = .002). Smoking adversely affected native sperm motility (53% motility in nonsmokers vs. 37% in smokers; p = .006). However, there was no significant impact on TL. The group with longer telomeres demonstrated significant association with healthy diet (10/12 vs. 6/13; p = .05) and a trend toward more sports activity, weekly (16/84 vs. 7/91; p = .04) compared with the shorter telomeres group. This study suggests that lifestyle, healthy diet, and sports activity are associated with long telomeres in sperm. Sperm quality is also influenced by patients' habits. The study strongly recommends maintaining a healthy lifestyle to preserve general health and fertility.},
}
@article {pmid36119151,
year = {2022},
author = {Kazantseva, AV and Davydova, YD and Enikeeva, RF and Mustafin, RN and Lobaskova, MM and Malykh, SB and Khusnutdinova, EK},
title = {Individual Differences in Relative Telomere Length in Mentally Healthy Subjects: The Effect of TERT Gene Polymorphism and Urban Residency.},
journal = {Russian journal of genetics},
volume = {58},
number = {9},
pages = {1135-1144},
pmid = {36119151},
issn = {1022-7954},
abstract = {The changes in the telomere length caused by the terminal underreplication in the existing literature are related to depressive disorders. However, the use of the telomere length as a biomarker of depressive states is ambiguous, which is due to the effect of various environmental factors on both the psychoemotional state and cellular aging of an organism. In order to identify the possible use of the relative telomere length (RTL) measured in peripheral blood leukocytes as a biomarker of enhanced liability to depression prior to the clinical symptoms, as well as to determine the link between telomere length, sociodemographic factors, allelic variants of the genes involved in the regulation of telomere elongation, and depression level, the association analysis of reverse transcriptase (TERT rs7726159), telomerase RNA component (TERC rs1317082), and the CST complex encoding protein (OBFC1 rs2487999) gene polymorphisms was performed with RTL and depression level in mentally healthy individuals (N = 1065) aged 18-25 years. Together with genetic variants, the examined regression models included various sociodemographic parameters as predictors. As a result of statistical analysis, we failed to observe the association between RTL and individual differences in depression level in the studied sample. Nevertheless, multiple regression analysis allowed us to construct a statistically significant model of individual variance in RTL (P = 4.3е-4; r [2] = 0.018), which included rs7726159 in the TERT gene (P = 0.020; β = 0.078) and such environmental predictors as age (P = 0.001; β = -0.027) and place of residence in childhood (urban/rural area) (P = 0.048; β = 0.063). The data obtained confirm the involvement of TERT gene variants and age in telomere length in mentally healthy individuals aged 18-25 years and indicate a negative effect of urban residency on telomere length shortening, which reflects the cellular aging of an organism.},
}
@article {pmid36116241,
year = {2022},
author = {Saini, D and Jain, V and Das, B},
title = {Evaluation of natural chronic low dose radiation exposure on telomere length and transcriptional response of shelterin complex in individuals residing in Kerala coast, India.},
journal = {Mutation research},
volume = {825},
number = {},
pages = {111797},
doi = {10.1016/j.mrfmmm.2022.111797},
pmid = {36116241},
issn = {1873-135X},
mesh = {Humans ; Male ; Shelterin Complex ; Leukocytes, Mononuclear/radiation effects ; Background Radiation ; Telomere/genetics/metabolism ; *Radiation Exposure/adverse effects ; X-ray Repair Cross Complementing Protein 1/metabolism ; Cell Cycle Proteins/metabolism ; *DNA Glycosylases/metabolism ; },
abstract = {The high level natural radiation areas (HLNRA) of Kerala coast provide unique opportunity to study the biological effect of chronic low dose ionizing radiation (LDIR) on human population below 100 mSv. The radiation level in this area varies from < 1.0-45 mGy /year due to patchy distribution of monazite in the sand, which contains [232]Th (8-10%), [238]U (0.3%), and their decay products. Telomere length attrition has been correlated to DNA damage due to genotoxic agents. The objective of the present study is to evaluate the effect of natural chronic LDIR exposure on telomere length and transcriptional response of telomere specific and DNA damage repair genes in peripheral blood mononuclear cells (PBMCs) of individuals from normal level natural radiation areas (NLNRA) and HLNRA of Kerala coast, southwest India. Blood samples were collected from 71 random male donors (24-80 years) from NLNRA (≤1.50 mGy/year; N = 19) and two HLNRA dose groups [1.51-10 mGy/year (N = 17); > 10 mGy/year, (N = 35)]. Genomic DNA was isolated from PBMCs and relative telomere length (RTL) was determined using real time q-PCR. Radio-adaptive response (RAR) study was carried out in PBMCs of 40 random males from NLNRA (N = 20) and HLNRA (>10 mGy/year; N = 20), where PBMCs were given a challenged dose of 2.0 Gy gamma radiation at 4 h. Transcriptional profile of telomere specific (TRF1, TRF2, POT1, TIN2, TPP1, RAP1), DNA damage response (RAD17, ATM, CHEK1) and base excision repair pathway (BER) (OGG1, XRCC1, NTH1, NEIL1, MUTYH, MBD4) genes were analysed at basal level and after a challenge dose of 2.0 Gy at 4 h. Our results did not show any significant effect of chronic LDR on RTL among the individuals from NLNRA and two HLNRA groups (p = 0.195). However, influence of age on RTL was clearly evident among NLNRA and HLNRA individuals. At basal level, TRF1, TRF2, TIN2, MBD4, NEIL1 and RAD17 showed significant up-regulation, whereas XRCC1 was significantly down regulated in HLNRA individuals. After a challenge dose of 2.0 Gy, significant transcriptional up-regulation was observed at telomere specific (TRF2, POT1) and BER (MBD4, NEIL1) genes in HLNRA individuals as compared to NLNRA suggesting their role in RAR. In conclusion, elevated level of natural chronic LDR exposure did not have any adverse effect on telomere length in Kerala coast. Significant transcriptional response at TRF2, MBD4 and NEIL1 at basal level and with a challenge dose of 2.0 Gy suggested their active involvement in efficient repair and telomere maintenance in individuals from HLNRA of Kerala coast.},
}
@article {pmid36110146,
year = {2022},
author = {Panelli, DM and Diwan, M and Cruz, GI and Leonard, SA and Chueh, J and Gotlib, IH and Bianco, K},
title = {An exploratory analysis of leukocyte telomere length among pregnant and non-pregnant people.},
journal = {Brain, behavior, &amp; immunity - health},
volume = {25},
number = {},
pages = {100506},
pmid = {36110146},
issn = {2666-3546},
abstract = {BACKGROUND: Leukocyte telomere length (LTL) is a biomarker that is affected by older age, psychosocial stress, and medical comorbidities. Despite the relevance of these factors to obstetric practice, little is known about LTL in pregnancy. Our study explored longitudinal LTL dynamics in pregnant and non-pregnant people.<br><br>OBJECTIVE: This pilot study compares changes in LTL between pregnant and non-pregnant people over time, explores potential correlations between LTL and mental health measures, and investigates associations between short first-trimester LTL and adverse pregnancy outcomes.<br><br>STUDY DESIGN: This was a prospective pilot cohort study of nulliparous pregnant and non-pregnant people between ages 18 and 50 who presented for care at a single institution from January to November 2020. Pregnant people were enrolled between 10 and 14 weeks gestation. Participants had two blood samples drawn for LTL; the first on the day of enrollment and the second on postpartum day 1 (pregnant cohort) or 7 months later (non-pregnant cohort). LTL was measured using quantitative PCR. The primary outcome was the difference between pregnant and non-pregnant people in LTL change between the two timepoints (basepair difference per 30-day period). Secondary outcomes included differences in responses to the Patient Health Questionnaire-9 (PHQ-9) and a survey about stress related to COVID-19. Differences in LTL were tested using t-tests and linear regression models, both crude and adjusted for age. A subgroup analysis was conducted within the pregnant cohort to examine whether shorter first-trimester LTL was associated with adverse pregnancy outcomes. We conducted t-tests to compare LTL between people with and without each categorical outcome and computed Pearson correlation coefficients between LTL and continuous outcomes such as gestational age at delivery.<br><br>RESULTS: 46 pregnant and 30 non-pregnant people were enrolled; 44 pregnant and 18 non-pregnant people completed all LTL assessments. There were no between-group differences in LTL change (-4.2&#xa0;&#xb1;&#xa0;22.2 bp per 30 days pregnant versus -6.4&#xa0;&#xb1;&#xa0;11.2 bp per 30 days non-pregnant, adjusted beta 2.1, 95% CI -9.0-13.2, p&#xa0;=&#xa0;0.60). The prevalence of depression and pandemic-related stress were both low overall. The two groups did not differ in PHQ-9 scores, and no correlations were significant between LTL and PHQ-9 scores. Among the 44 pregnant people, shorter first-trimester LTL was significantly correlated with earlier gestational age at delivery (r&#xa0;=&#xa0;0.35, p&#xa0;=&#xa0;0.02).<br><br>CONCLUSION: In this exploratory pilot cohort of reproductive-aged people with low levels of psychological stress, we described baseline changes in LTL over time in pregnant and non-pregnant participants. We found a correlation between shorter first-trimester LTL and earlier gestational age at delivery, which warrants further investigation in a larger cohort.},
}
@article {pmid36109671,
year = {2022},
author = {Lanna, A and Vaz, B and D'Ambra, C and Valvo, S and Vuotto, C and Chiurchiù, V and Devine, O and Sanchez, M and Borsellino, G and Akbar, AN and De Bardi, M and Gilroy, DW and Dustin, ML and Blumer, B and Karin, M},
title = {An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory.},
journal = {Nature cell biology},
volume = {24},
number = {10},
pages = {1461-1474},
pmid = {36109671},
issn = {1476-4679},
support = {100262Z/12/Z/WT_/Wellcome Trust/United Kingdom ; 110229/WT_/Wellcome Trust/United Kingdom ; MR/P00184X/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; MR/M003833/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {*Telomerase/genetics/metabolism ; Immunologic Memory ; T-Lymphocytes/metabolism ; Telomere/genetics/metabolism ; Cellular Senescence/genetics ; },
abstract = {The common view is that T lymphocytes activate telomerase to delay senescence. Here we show that some T cells (primarily naïve and central memory cells) elongated telomeres by acquiring telomere vesicles from antigen-presenting cells (APCs) independently of telomerase action. Upon contact with these T cells, APCs degraded shelterin to donate telomeres, which were cleaved by the telomere trimming factor TZAP, and then transferred in extracellular vesicles at the immunological synapse. Telomere vesicles retained the Rad51 recombination factor that enabled telomere fusion with T-cell chromosome ends lengthening them by an average of ~3,000 base pairs. Thus, there are antigen-specific populations of T cells whose ageing fate decisions are based on telomere vesicle transfer upon initial contact with APCs. These telomere-acquiring T cells are protected from senescence before clonal division begins, conferring long-lasting immune protection.},
}
@article {pmid36104328,
year = {2022},
author = {Bowyer, P and Currin, A and Delneri, D and Fraczek, MG},
title = {Telomere-to-telomere genome sequence of the model mould pathogen Aspergillus fumigatus.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {5394},
pmid = {36104328},
issn = {2041-1723},
support = {208396/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; /DH_/Department of Health/United Kingdom ; },
mesh = {*Aspergillus fumigatus/genetics ; DNA Transposable Elements/genetics ; *Fungi ; Humans ; Sequence Analysis, DNA ; Telomere/genetics ; },
abstract = {The pathogenic fungus Aspergillus fumigatus is a major etiological agent of fungal invasive and chronic diseases affecting tens of millions of individuals worldwide. Draft genome sequences of two clinical isolates (Af293 and A1163) are commonly used as reference genomes for analyses of clinical and environmental strains. However, the reference sequences lack coverage of centromeres, an accurate sequence for ribosomal repeats, and a comprehensive annotation of chromosomal rearrangements such as translocations and inversions. Here, we used PacBio Single Molecule Real-Time (SMRT), Oxford Nanopore and Illumina HiSeq sequencing for de novo genome assembly and polishing of two laboratory reference strains of A. fumigatus, CEA10 (parental isolate of A1163) and its descendant A1160. We generated full length chromosome assemblies and a comprehensive telomere-to-telomere coverage for CEA10 and near complete assembly of A1160 including ribosomal repeats and the sequences of centromeres, which we discovered to be composed of long transposon elements. We envision these high-quality reference genomes will become fundamental resources to study A. fumigatus biology, pathogenicity and virulence, and to discover more effective treatments against diseases caused by this fungus.},
}
@article {pmid36103374,
year = {2022},
author = {Barbosa, ARC and Nunes, DP and Lima, DB and Colombo, FA and Nunes, JB and Santos Orlandi, AAD and Rocha, GDS and Pereira, DS and Corona, LP and Brito, TRP},
title = {Association of Social Support Network with Telomere Length: A Cross-Sectional Study with Community-Dwelling Older Adults.},
journal = {Rejuvenation research},
volume = {25},
number = {6},
pages = {253-259},
doi = {10.1089/rej.2022.0037},
pmid = {36103374},
issn = {1557-8577},
mesh = {Humans ; Aged ; *Independent Living ; Cross-Sectional Studies ; *Activities of Daily Living ; Social Support ; Telomere ; },
abstract = {Considering that telomere length can be determined not only by issues related to cell biology but also by aspects related to social factors and environmental exposures, studies on the relationship between social aspects and telomere length can help to better understand the still scarcely known aspects of the human aging process. Thus, this research seeks to verify whether social support networks are associated with telomere length in older adults. This is a cross-sectional study conducted with 448 individuals aged at least 60 years living in the urban area of an inland Brazilian municipality. Relative quantification of telomere length was obtained through real-time qPCR. Social support was assessed through the Medical Outcomes Study Social Support Scale. Descriptive statistics and multiple logistic regression were used in data analysis. The evaluated social support networks for older adults consist in a mean of 16.4 people, and the percentage of older adults who reported up to five members in their network was 27.75%. Shorter telomere length was identified in 25% of the participants, and the older adults who reported having up to five members in their support network were more likely to have a shorter telomere length than those who reported more numerous networks (odds ratio: 1.89, p = 0.011) regardless of gender, age, household arrangement, cognitive decline, and dependence for basic and instrumental activities of daily living, which suggests that measures that stimulate the creation and maintenance of social support networks should be implemented to improve older adults' health.},
}
@article {pmid36098743,
year = {2022},
author = {Liu, Z and Wei, X and Gao, Y and Gao, X and Li, X and Zhong, Y and Wang, X and Liu, C and Shi, T and Lv, J and Liu, T},
title = {Zbtb34 promotes embryonic stem cell proliferation by elongating telomere length.},
journal = {Aging},
volume = {14},
number = {17},
pages = {7126-7136},
pmid = {36098743},
issn = {1945-4589},
mesh = {Animals ; Mice ; Alanine/genetics ; Cell Proliferation ; DNA ; DNA, Complementary ; *DNA, Single-Stranded ; DNA-Binding Proteins/genetics ; Embryonic Stem Cells/metabolism ; *Repressor Proteins/metabolism ; Shelterin Complex ; Telomere/genetics/metabolism ; *Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Zbtb34 is a novel zinc finger protein, which is revealed by biological software analysis to have 3 zinc fingers, but its functions remain unknown. In this study, mouse Zbtb34 cDNA was amplified by PCR and inserted into the plasmid pEGFP-N1 to generate Zbtb34-EGFP fusion protein. The upregulation of Zbtb34 in mouse embryonic stem cells promoted telomere elongation and increased cell proliferation. In order to understand the above phenomena, the telomere co-immunoprecipitation technique was employed to investigate the relationship between Zbtb34 and telomeres. The results indicated that Zbtb34 could bind to the DNA sequences of the telomeres. Alanine substitution of the third zinc finger abolished such binding. Since Pot1 is the only protein binding to the single-stranded DNA at the end of the telomeres, we further investigated the relationship between Zbtb34 and Pot1. The results revealed that the upregulation of Zbtb34 decreased the binding of Pot1b to the telomeres. Through the upregulation of Pot1b, the binding of Zbtb34 to the telomeres was also reduced. In conclusion, we showed that the main biological function of Zbtb34 was to bind telomere DNA via its third ZnF, competing with Pot1b for the binding sites, resulting in telomere elongation and cell proliferation.},
}
@article {pmid36091172,
year = {2022},
author = {Fiesco-Roa, M&#xd3; and García-de Teresa, B and Leal-Anaya, P and van 't Hek, R and Wegman-Ostrosky, T and Frías, S and Rodríguez, A},
title = {Fanconi anemia and dyskeratosis congenita/telomere biology disorders: Two inherited bone marrow failure syndromes with genomic instability.},
journal = {Frontiers in oncology},
volume = {12},
number = {},
pages = {949435},
pmid = {36091172},
issn = {2234-943X},
abstract = {Inherited bone marrow failure syndromes (IBMFS) are a complex and heterogeneous group of genetic diseases. To date, at least 13 IBMFS have been characterized. Their pathophysiology is associated with germline pathogenic variants in genes that affect hematopoiesis. A couple of these diseases also have genomic instability, Fanconi anemia due to DNA damage repair deficiency and dyskeratosis congenita/telomere biology disorders as a result of an alteration in telomere maintenance. Patients can have extramedullary manifestations, including cancer and functional or structural physical abnormalities. Furthermore, the phenotypic spectrum varies from cryptic features to patients with significantly evident manifestations. These diseases require a high index of suspicion and should be considered in any patient with abnormal hematopoiesis, even if extramedullary manifestations are not evident. This review describes the disrupted cellular processes that lead to the affected maintenance of the genome structure, contrasting the dysmorphological and oncological phenotypes of Fanconi anemia and dyskeratosis congenita/telomere biology disorders. Through a dysmorphological analysis, we describe the phenotypic features that allow to make the differential diagnosis and the early identification of patients, even before the onset of hematological or oncological manifestations. From the oncological perspective, we analyzed the spectrum and risks of cancers in patients and carriers.},
}
@article {pmid36087937,
year = {2022},
author = {Svyryd, Y and Pascual-Ramos, V and Contreras-Yañez, I and Muñoz-Tellez, LA and Luna-Muñoz, L and López-Hernández, MA and Aguayo-Gómez, A and Mutchinick, OM},
title = {Telomeres Length Variations in a Rheumatoid Arthritis Patients Cohort at Early Disease Onset and after Follow-Up.},
journal = {Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion},
volume = {74},
number = {4},
pages = {202-211},
doi = {10.24875/RIC.22000048},
pmid = {36087937},
issn = {0034-8376},
mesh = {Humans ; *Arthritis, Rheumatoid/genetics ; Follow-Up Studies ; Telomere/genetics ; Telomere Shortening ; },
abstract = {BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovial joint inflammation, progressive disability, premature immune aging, and telomere length (TL) shortening.<br><br>OBJECTIVES: The objective of the study was to study TL changes in patients at early disease onset and after follow-up.<br><br>METHODS: Relative leukocyte TL (rLTL) was measured by quantitative polymerase chain reaction (qPCR) in 88 at-admission patients (AAP) with < 1 year of symptoms onset, self-compared after follow-up, and a reference group of sex- and age-matched healthy individuals. Correlations between rLTL percentage change after variable disease exposure time (DET) and clinical laboratory disease activity markers and treatments were assessed. Non-parametrical statistics were applied, considering < 0.05 p-value significant.<br><br>RESULTS: The median (p25, p75) rLTL was lower in patients after DET (0.61, 0.49-0.70) than in AAP (0.64, 0.50-0.77), p = 0.017. Furthermore, telomeres at early stages of RA were shorter than in the reference group (0.77, 0.59-0.92; p = 0.003). HLA-DRB1*04 allele carrier status did not significantly affect rLTL at an early stage and after follow-up. The patients' rLTL shortening was mainly associated with longer at-admission telomeres (OR 16.2, 95%CI: 3.5-74.4; p < 0.0001).<br><br>CONCLUSIONS: At follow-up, RA patients showed significantly shorter rLTL than AAP, particularly in those AAP with longer telomeres, disregarding disease activity and treatments, denoting an rLTL shortening effect influenced by age, DET, and native rLTL.},
}
@article {pmid36085441,
year = {2023},
author = {Qureshi, F and Aris, IM and Rifas-Shiman, SL and Perng, W and Oken, E and Rich-Edwards, J and Cardenas, A and Baccarelli, AA and Enlow, MB and Belfort, MB and Tiemeier, H},
title = {Associations of cord blood leukocyte telomere length with adiposity growth from infancy to adolescence.},
journal = {Pediatric obesity},
volume = {18},
number = {1},
pages = {e12977},
pmid = {36085441},
issn = {2047-6310},
support = {R03 AG067064/AG/NIA NIH HHS/United States ; T32 CA009001/CA/NCI NIH HHS/United States ; R24 ES030894/ES/NIEHS NIH HHS/United States ; R01 HD034568/HD/NICHD NIH HHS/United States ; P30 DK048520/DK/NIDDK NIH HHS/United States ; R01 HD082078/HD/NICHD NIH HHS/United States ; R01 ES031259/ES/NIEHS NIH HHS/United States ; UH3 OD023286/OD/NIH HHS/United States ; },
mesh = {Child ; Infant, Newborn ; Male ; Infant ; Adolescent ; Female ; Humans ; *Adiposity ; *Fetal Blood ; Obesity ; Body Mass Index ; Leukocytes ; Telomere ; Biomarkers ; },
abstract = {OBJECTIVE: Leukocyte telomere length (LTL) may be a biomarker for chronic disease susceptibility, but no work has tested this hypothesis directly. Our study investigated associations of LTL at birth with markers of adiposity growth that are linked with cardiometabolic health later in life.<br><br>METHODS: Participants were 375 children in Project Viva (48% female, 71% White). Body mass index (BMI) trajectories from birth to 18&#x2009;years were tracked using repeated measures of BMI collected in physical examinations and via medical records, then used to predict age (months) and magnitude (kg/m[2]) of BMI peak and rebound. LTL was measured from cord blood via duplex quantitative PCR. A binary variable indicating LTL shorter than the reference population average was the primary exposure.<br><br>RESULTS: LTL was unrelated to BMI at peak or rebound, but associations were apparent with the timing of BMI growth milestones. Short LTL was related to a later age of peak for females (&#x3b2;&#xa0;=&#xa0;0.99, 95% CI&#xa0;=&#xa0;0.16, 1.82; psex interaction &#xa0;=&#xa0;0.015) and an earlier age of rebound for both males and females (&#x3b2;combined &#xa0;=&#xa0;-5.26, 95% CI&#xa0;=&#xa0;-9.44, -1.08).<br><br>CONCLUSION: LTL at birth may be an early biomarker of altered adiposity growth. Newborn telomere biology may shed new insight into the developmental origins of health and disease.},
}
@article {pmid36078786,
year = {2022},
author = {Montiel Ishino, FA and Rowan, CE and Villalobos, K and Rajbhandari-Thapa, J and Williams, F},
title = {A Time-Varying Effect Model (TVEM) of the Complex Association of Tobacco Use and Smoke Exposure on Mean Telomere Length: Differences between Racial and Ethnic Groups Assessed in the National Health and Nutrition Examination Survey.},
journal = {International journal of environmental research and public health},
volume = {19},
number = {17},
pages = {},
pmid = {36078786},
issn = {1660-4601},
mesh = {Adult ; Aged ; *Cotinine ; Ethnicity ; Humans ; Middle Aged ; Nutrition Surveys ; Telomere ; *Tobacco Smoke Pollution ; Tobacco Use ; },
abstract = {Telomere length is affected by lifestyle and environmental factors and varies between racial and ethnic groups; however, studies are limited, with mixed findings. This study examined the effects of tobacco use and smoke exposure on mean telomere length to identify critical age periods by race/ethnicity. We used time-varying effect modeling on the National Health and Nutrition Examination Survey for continuous years 1999-2002 to observe the effects of active tobacco use and environmental tobacco smoke-measured through serum cotinine-and mean telomere length for adults 19 to 85 and older (N = 7826). Models were run for Mexican American, other Hispanic, non-Hispanic White, non-Hispanic Black, and other/multi-race categories to allow for time-varying group differences, and controlled for biological sex, socioeconomic status, education, and ever-smoker status. Serum cotinine was found to have an increasing effect on telomere length from age 37 to approximately age 74 among Mexican Americans. Among other/multi-race individuals serum cotinine was found to have a decreasing effect at approximately age 42, and among Blacks, it had an overall decreasing effect from age 61 to 78. Findings reveal a further need to focus additional support and resources to intervene regarding disparate health effects from tobacco use and environmental smoke exposure for already vulnerable groups at particular ages.},
}
@article {pmid36077523,
year = {2022},
author = {Jitjumnong, M and Chalermkitpanit, P and Suantawee, T and Dechsupa, S and Vajarintarangoon, L and Honsawek, S},
title = {Telomere Shortening and Increased Oxidative Stress in Lumbar Disc Degeneration.},
journal = {International journal of molecular sciences},
volume = {23},
number = {17},
pages = {},
pmid = {36077523},
issn = {1422-0067},
support = {CUGR 63953002//Fundamental Fund, Ratchadapiseksompotch Fund/ ; },
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Antioxidants ; Case-Control Studies ; Humans ; *Intervertebral Disc Degeneration/genetics ; Oxidative Stress/genetics ; Telomere/genetics ; *Telomere Shortening ; },
abstract = {Lumbar disc degeneration (LDD) contributes to low back pain. This study aimed to determine relative telomere length (RTL), oxidative stress status, and antioxidant levels and examine the relationships between RTL, oxidative stress, and the severity in LDD patients. A total of 100 subjects, 50 LDD patients and 50 healthy controls, were enrolled in the case−control study. Blood leukocyte RTL was analyzed using quantitative real-time polymerase chain reaction. Lipid peroxidation was determined by malondialdehyde (MDA) assay. Plasma 8-hydroxy 2′-deoxyguanosine (8-OHdG) values were determined using enzyme-linked immunosorbent assay. Total antioxidant capacity (TAC) and ferric reducing antioxidant power (FRAP) in plasma were also measured. The LDD patients had significantly shorter telomeres than the healthy controls (p = 0.04). Blood leukocyte RTL was inversely correlated with the LDD severity (r = −0.41, p = 0.005). Additionally, plasma MDA and 8-OHdG levels were markedly greater in LDD patients than in the controls (p = 0.01 and p = 0.002, respectively). Furthermore, the plasma MDA level showed a positive correlation with the radiographic severity (r = 0.49, p = 0.001). There was a positive correlation between plasma 8-OHdG and the severity (r = 0.60, p < 0.001). Moreover, plasma TAC and FRAP levels were significantly lower in LDD patients than in the controls (p = 0.04). No significant differences in plasma TAC and FRAP were observed among the three groups of LDD severity. We found that RTL was negatively correlated with the severity while plasma MDA and 8-OHdG levels were positively correlated with the severity. These findings suggest that blood leukocyte RTL, plasma MDA, and 8-OHdG may have potential as noninvasive biomarkers for the assessment of severity in LDD.},
}
@article {pmid36074986,
year = {2022},
author = {Andrés, V and Díez, J},
title = {Failing Hypertensive Heart: a Question of Altered Telomere Biology?.},
journal = {Hypertension (Dallas, Tex. : 1979)},
volume = {79},
number = {10},
pages = {2185-2187},
doi = {10.1161/HYPERTENSIONAHA.122.19937},
pmid = {36074986},
issn = {1524-4563},
mesh = {Biology ; Heart ; *Heart Failure/genetics ; Humans ; *Hypertension/genetics ; Telomere/genetics ; },
}
@article {pmid36074951,
year = {2022},
author = {Pölönen, J and Pinola, P and Ronkainen, J and Blakemore, AI and Buxton, JL and Tapanainen, JS and Franks, S and Piltonen, TT and Sebert, S and Morin-Papunen, L},
title = {Polycystic ovary syndrome and leukocyte telomere length: cross-sectional and longitudinal changes.},
journal = {European journal of endocrinology},
volume = {187},
number = {5},
pages = {651-661},
pmid = {36074951},
issn = {1479-683X},
mesh = {Adult ; Biomarkers ; Cohort Studies ; Cross-Sectional Studies ; DNA ; Female ; Humans ; Leukocytes ; Longitudinal Studies ; Middle Aged ; *Polycystic Ovary Syndrome/epidemiology/genetics ; Telomere ; },
abstract = {OBJECTIVE: Telomeres are DNA-protein complexes that protect chromosome ends from DNA damage and are surrogate biomarkers of cellular aging. Current evidence, almost entirely from cross-sectional observations, supports negative associations between leukocyte telomere length (LTL) and adverse lifestyle factors and cardiometabolic risk factors. Polycystic ovary syndrome (PCOS), the most common gynecological endocrine disorder, is associated with inflammation and oxidative stress, both factors associated with accelerated telomere attrition. We therefore hypothesized that LTL would be shorter and decrease more rapidly in women with PCOS in comparison to a control population.<br><br>DESIGN: This is a population-based cohort study comprising women of Northern Finland Birth Cohort 1966, with clinical examinations at ages 31 and 46. The sample included self-reported PCOS (age 31, n = 190; age 46, n = 207) and referent women (age 31, n = 1054; age 46, n = 1324) with data on LTL.<br><br>METHODS: The association between LTL and PCOS at ages 31 and 46 was analyzed by linear regression models adjusted for BMI, smoking, alcohol consumption and socioeconomic status at the corresponding age.<br><br>RESULTS: Women with PCOS had similar mean LTL at ages 31 and 46 (P > 0.4 for both). The mean LTL change between ages 31 and 46 did not differ between groups (P = 0.19). However, we observed a significant LTL attrition between ages 31 and 46 in the reference population (P < 0.001), but not in women with PCOS (P = 0.96).<br><br>CONCLUSIONS: This finding may suggest a difference in the LTL attrition rate in women with PCOS, an unexpected finding that might affect their risk of age-related disease. Further research is needed to clarify the underlying mechanisms.},
}
@article {pmid36070080,
year = {2022},
author = {Faingelernt, Y and Nassar, R and Ling, G and Kodman, Y and Feuerstein, T and Yerushalmi, B},
title = {Early-life liver cirrhosis and variable clinical presentation in telomere disease.},
journal = {Acta paediatrica (Oslo, Norway : 1992)},
volume = {111},
number = {12},
pages = {2416-2421},
doi = {10.1111/apa.16539},
pmid = {36070080},
issn = {1651-2227},
mesh = {Child, Preschool ; Humans ; *Telomerase/genetics/metabolism ; Telomere/genetics ; Liver Cirrhosis/genetics ; Mutation ; Phenotype ; },
abstract = {AIM: Telomeres are DNA sequences of tandem TTAGGG repeats that protect chromosome ends from degradation and instability. Constitutional loss-of-function telomerase mutations result in rapid telomere shortening, premature senescence and cell death. Liver cirrhosis is rare and has only been reported in adults. We present five family members of Bedouin-Muslim origin, all of which carry the same mutation, and yet demonstrate an extremely variable phenotypical presentation, including liver cirrhosis during early childhood.<br><br>METHODS: A multidisciplinary long-term follow-up of two healthy and three affected patients was analysed. The mutation (r.95G>C) was identified in all patients using Sanger sequencing. Telomere length samples were obtained and analysed.<br><br>RESULTS: Clinical phenotypes were extremely variable, including age at first symptoms, organ involvement, disease severity and patient prognosis. The most prominent clinical phenotype is liver involvement, including end-stage liver disease early in life, which affects three members of the family. Affected patients had markedly shorter telomeres.<br><br>CONCLUSION: We describe an unusual presentation of early liver failure in telomere disease patients. Little, if any, is known about the association between the genotype and phenotype among children with telomere disease and whether the mutation we have described (r.95G>C) is predisposed to early severe hepatic involvement.},
}
@article {pmid36069016,
year = {2022},
author = {Young, RC and Westneat, DF and Vangorder-Braid, J and Sirman, AE and Siller, SJ and Kittilson, J and Ghimire, A and Heidinger, BJ},
title = {Stressors interact across generations to influence offspring telomeres and survival.},
journal = {Proceedings. Biological sciences},
volume = {289},
number = {1982},
pages = {20220868},
pmid = {36069016},
issn = {1471-2954},
mesh = {Animals ; Longevity ; *Sparrows/physiology ; Telomere ; },
abstract = {Parental stress often has long-term consequences for offspring. However, the mechanisms underlying these effects and how they are shaped by conditions offspring subsequently experience are poorly understood. Telomeres, which often shorten in response to stress and predict longevity, may contribute to, and/or reflect these cross-generational effects. Traditionally, parental stress is expected to have negative effects on offspring telomeres, but experimental studies in captive animals suggest that these effects may depend on the subsequent conditions that offspring experience. Yet, the degree to which parental stress influences and interacts with stress experienced by offspring to affect offspring telomeres and survival in free-living organisms is unknown. To assess this, we experimentally manipulated the stress exposure of free-living parent and offspring house sparrows (Passer domesticus). We found a weak, initial, negative effect of parental stress on offspring telomeres, but this effect was no longer evident at the end of post-natal development. Instead, the effects of parental stress depended on the natural sources of stress that offspring experienced during post-natal development whereby some outcomes were improved under more stressful rearing conditions. Thus, the effects of parental stress on offspring telomeres and survival are context-dependent and may involve compensatory mechanisms of potential benefit under some circumstances.},
}
@article {pmid36067971,
year = {2022},
author = {Assavanopakun, P and Sapbamrer, R and Kumfu, S and Chattipakorn, N and Chattipakorn, SC},
title = {Effects of air pollution on telomere length: Evidence from in vitro to clinical studies.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {312},
number = {},
pages = {120096},
doi = {10.1016/j.envpol.2022.120096},
pmid = {36067971},
issn = {1873-6424},
mesh = {*Air Pollutants/analysis/toxicity ; *Air Pollution/adverse effects/analysis ; Cellular Senescence ; Environmental Exposure/adverse effects/analysis ; Humans ; *Occupational Exposure ; Particulate Matter/analysis ; Telomere ; },
abstract = {Air pollution remains the major environmental problem globally. There is extensive evidence showing that the variety of air pollutants from environmental and occupational exposures cause adverse effects to our health. The clinical symptoms of those effects may present at a late stage, so surveillance is difficult to manage. Several biomarkers have been used for the early detection of health issues following exposure to air pollution, including the use of telomere length which indicates cellular senescence in response to oxidative stress. Oxidative stress is one of the most plausible mechanisms associated with exposure to air pollutants. Some specific contexts including age groups, gender, ethnicity, occupations, and health conditions, showed significant alterations in telomere length after exposure to air pollutants. Several reports demonstrated both negative and positive associations between telomere length and air pollution, the studies using different concentrations and exposure times to air pollution on the study of telomere lengths. Surprisingly, some studies reported that low levels of exposure to air pollutants (lower than regulated levels) caused the alterations in telomere length. Those findings suggest that telomere length could be one of most practical biomarkers in air pollution surveillance. Therefore, this review aimed to summarize and discuss the relationship between telomere length and exposure to air pollution. The knowledge from this review will be beneficial for the planning of public health to reduce health problems in the general population, particularly in vulnerable people, who still live in areas with high air pollution.},
}
@article {pmid36066716,
year = {2023},
author = {Kato, TA},
title = {Nontraditional Method for Telomere Staining by PNA Probes.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2519},
number = {},
pages = {111-116},
pmid = {36066716},
issn = {1940-6029},
mesh = {DNA Probes/genetics ; In Situ Hybridization, Fluorescence/methods ; *Peptide Nucleic Acids/chemistry ; Telomere/genetics ; },
abstract = {The standard FISH uses DNA probes to hybridize to the designated complementary strands. This is DNA-DNA interaction, and it usually takes much longer time to obtain detectable signals compared to other reactions such as immunochemical reactions and simple chemical reactions. Certain proteins bind to specific DNA sequences and regulate the biological function of DNA. These DNA-binding proteins have specific domains to interact with single- or double-stranded DNA. Some of telomere proteins apparently bind to telomere sequence and form nucleoprotein complex to protect chromosome ends. Using telomere PNA probes, probes can be accumulated at the telomere sites in a non-hybridization manner. This chapter introduces nontraditional PNA telomere staining protocol without DNA-DNA hybridization to visualize telomere locations on metaphase chromosomes.},
}
@article {pmid36066715,
year = {2023},
author = {Kato, TA},
title = {Telomere Aberration Detection by PNA FISH Probe.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2519},
number = {},
pages = {105-110},
pmid = {36066715},
issn = {1940-6029},
mesh = {DNA Probes ; In Situ Hybridization, Fluorescence/methods ; *Repetitive Sequences, Nucleic Acid ; *Telomere/genetics ; },
abstract = {Telomere is a structure of the end cap of chromosomes. Telomere gets shorter as cell aging and progressing cell division. Shorter telomere may cause telomere fusion, thus inducing genomic instability. Telomere dysfunction can be visualized by PNA FISH probe against telomere repeat sequence (TTAGGG)n. PNA probes have higher hybridization affinity than DNA probes. The traditional FISH or modified FISH protocol can stain telomere relatively easier than whole-chromosome painting probes. This chapter introduces PNA telomere FISH protocol to visualize telomere signals on metaphase chromosomes.},
}
@article {pmid37881560,
year = {2023},
author = {Mutz, J and Lewis, CM},
title = {Telomere Length Associations With Clinical Diagnosis, Age, and Polygenic Risk Scores for Anxiety Disorder, Depression, and Bipolar Disorder.},
journal = {Biological psychiatry global open science},
volume = {3},
number = {4},
pages = {1012-1020},
pmid = {37881560},
issn = {2667-1743},
abstract = {BACKGROUND: Accelerated biological aging might contribute to the lower life expectancy of individuals with mental disorders. The aim of this study was to characterize telomere length, a biological hallmark of aging, in individuals with mental disorders.<br><br>METHODS: The UK Biobank is a multicenter community-based observational study that recruited >500,000 middle-aged and older adults. Average leukocyte telomere length (telomere repeat copy number/single-copy gene ratio) was measured using quantitative polymerase chain reaction. Polygenic risk scores (PRSs) were calculated for individuals of European ancestry. We estimated differences in telomere length between individuals with anxiety disorder, depression, or bipolar disorder and people without mental disorders and examined associations with psychotropic medication use, age, and PRSs for these 3 disorders.<br><br>RESULTS: The analyses included up to 308,725 participants. Individuals with depression had shorter telomeres than people without mental disorders (&#x3b2;&#xa0;=&#xa0;-0.011, 95% CI,&#xa0;-0.019 to&#xa0;-0.004, Bonferroni-corrected&#xa0;p&#xa0;= .027). Associations between bipolar disorder and telomere length differed by lithium use. There was limited evidence that individuals with an anxiety disorder had shorter telomeres. There was no evidence that associations between age and telomere length differed between individuals with and without these disorders. PRSs for depression, but not anxiety disorder or bipolar disorder, were associated with shorter telomeres (&#x3b2;&#xa0;=&#xa0;-0.006, 95% CI,&#xa0;-0.010 to&#xa0;-0.003, Bonferroni-corrected&#xa0;p&#xa0;= .001).<br><br>CONCLUSIONS: Differences in telomere length were observed primarily for individuals with depression or bipolar disorder and in individuals with a higher PRS for depression. There was no evidence that the association between age and telomere length differed between individuals with and without an anxiety disorder, depression, or bipolar disorder.},
}
@article {pmid36060975,
year = {2022},
author = {Ghoussaini, R and Tamim, H and Elbejjani, M and Makki, M and Nasreddine, L and Ismaeel, H and Nasrallah, MP and Zgheib, NK},
title = {C-peptide is a predictor of telomere shortening: A five-year longitudinal study.},
journal = {Frontiers in endocrinology},
volume = {13},
number = {},
pages = {978747},
pmid = {36060975},
issn = {1664-2392},
mesh = {C-Peptide ; Humans ; Longitudinal Studies ; Risk Factors ; *Telomere/genetics ; *Telomere Shortening ; },
abstract = {AIM: Relative telomere length (RTL) predicts the development of many age-related diseases. Yet, few studies have evaluated their longitudinal effect on RTL. We investigated longitudinally the association between cardiometabolic risk factors and RTL.<br><br>METHODS: This was a longitudinal study with a 5-year follow-up period, based on data collected in 2014 and 2019. Of 478 participants in 2014, 198 consented to be followed-up in 2019. The associations between RTL and risk factors were analyzed using t-test, ANOVA or simple linear regression as applicable.<br><br>RESULTS: RTL was significantly shortened after 5 years (P<0.001). Older age (P=0.018) and gender (P=0.05) were significantly associated with shorter RTL at follow-up. Higher baseline C-peptide correlated with shorter RTL (P=0.04) and shortening of RTL (P=0.03) after 5 years. Multivariate linear regression including both age and gender revealed a significant trend for C-peptide and change in RTL after 5 years (P=0.04). Interestingly, there was a trend of shorter RTL at follow-up with diabetes, though the findings were not statistically significant.<br><br>CONCLUSIONS: Higher C-peptide level contributes to telomere shortening over time, suggesting that metabolic dysregulation may play a role in early aging. Further understanding of this relationship and addressing high C-peptide levels can be important to prevent premature aging.},
}
@article {pmid36059259,
year = {2022},
author = {Pan, L and Tormey, D and Bobon, N and Baumann, P},
title = {Rap1 prevents fusions between long telomeres in fission yeast.},
journal = {The EMBO journal},
volume = {41},
number = {20},
pages = {e110458},
pmid = {36059259},
issn = {1460-2075},
support = {//Howard Hughes Medical Institute (HHMI)/ ; },
mesh = {Amino Acids/metabolism ; *Schizosaccharomyces/genetics/metabolism ; *Schizosaccharomyces pombe Proteins/genetics/metabolism ; Shelterin Complex ; Telomere/genetics/metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {The conserved Rap1 protein is part of the shelterin complex that plays critical roles in chromosome end protection and telomere length regulation. Previous studies have addressed how fission yeast Rap1 contributes to telomere length maintenance, but the mechanism by which the protein inhibits end fusions has remained elusive. Here, we use a mutagenesis screen in combination with high-throughput sequencing to identify several amino acid positions in Rap1 that have key roles in end protection. Interestingly, mutations at these sites render cells susceptible to genome instability in a conditional manner, whereby longer telomeres are prone to undergoing end fusions, while telomeres within the normal length range are sufficiently protected. The protection of long telomeres is in part dependent on their nuclear envelope attachment mediated by the Rap1-Bqt4 interaction. Our data demonstrate that long telomeres represent a challenge for the maintenance of genome integrity, thereby providing an explanation for species-specific upper limits on telomere length.},
}
@article {pmid36057868,
year = {2022},
author = {Schellnegger, M and Lin, AC and Hammer, N and Kamolz, LP},
title = {Physical Activity on Telomere Length as a Biomarker for Aging: A Systematic Review.},
journal = {Sports medicine - open},
volume = {8},
number = {1},
pages = {111},
pmid = {36057868},
issn = {2199-1170},
abstract = {BACKGROUND: Overall life expectancy continues to rise, approaching 80 years of age in several developed countries. However, healthy life expectancy lags far behind, which has, in turn, contributed to increasing costs in healthcare. One way to improve health and attenuate the socio-economic impact of an aging population is to increase overall fitness through physical activity. Telomere attrition or shortening is a well-known molecular marker in aging. As such, several studies have focused on whether exercise influences health and aging through telomere biology. This systematic review examines the recent literature on the effect of physical activity on telomere length (TL) and/or telomerase activity as molecular markers of aging.<br><br>METHODS: A focused search was performed in the databases PubMed and Web of Science for retrieving relevant articles over the past ten years. The search contained the following keywords: exercise, sport, physical activity, fitness, sedentary, physical inactivity, telomere, telomere length, t/s ratio, and telomerase. PRISMA guidelines for systematic reviews were observed.<br><br>RESULTS: A total of 43 articles were identified and categorized into randomized controlled trials (RCT), observational or interventional studies. RCTs (n&#x2009;=&#x2009;8) showed inconsistent findings of increased TL length with physical activity in, e.g. obese, post-menopausal women. In comparison with a predominantly sedentary lifestyle, observational studies (n&#x2009;=&#x2009;27) showed significantly longer TL with exercise of moderate to vigorous intensity; however, there was no consensus on the duration and type of physical activity and training modality. Interventional studies (n&#x2009;=&#x2009;8) also showed similar findings of significantly longer TL prior to exercise intervention; however, these studies had smaller numbers of enrolled participants (mostly of high-performance athletes), and the physical activities covered a range of exercise intensities and duration. Amongst the selected studies, aerobic training of moderate to vigorous intensity is most prevalent. For telomere biology analysis, TL was determined mainly from leukocytes using qPCR. In some cases, especially in RCT and interventional studies, different sample types such as saliva, sperm, and muscle biopsies were analyzed; different leukocyte cell types and potential genetic markers in regulating telomere biology were also investigated.<br><br>CONCLUSIONS: Taken together, physical activity with regular aerobic training of moderate to vigorous intensity appears to help preserve TL. However, the optimal intensity, duration of physical activity, as well as type of exercise still need to be further elucidated. Along with TL or telomerase activity, participants' fitness level, the type of physical activity, and training modality should be assessed at different time points in future studies, with the plan for long-term follow-up. Reducing the amount of sedentary behavior may have a positive effect of preserving and increasing TL. Further molecular characterization of telomere biology in different cell types and tissues is required in order to draw definitive causal conclusions on how physical activity affects TL and aging.},
}
@article {pmid36057690,
year = {2022},
author = {Porrazzo, A and Cipressa, F and De Gregorio, A and De Pittà, C and Sales, G and Ciapponi, L and Morciano, P and Esposito, G and Tabocchini, MA and Cenci, G},
title = {Low dose rate γ-irradiation protects fruit fly chromosomes from double strand breaks and telomere fusions by reducing the esi-RNA biogenesis factor Loquacious.},
journal = {Communications biology},
volume = {5},
number = {1},
pages = {905},
pmid = {36057690},
issn = {2399-3642},
mesh = {Animals ; Dose-Response Relationship, Radiation ; *Drosophila melanogaster/genetics/radiation effects ; Gamma Rays ; Humans ; RNA ; *Telomere/genetics ; },
abstract = {It is still continuously debated whether the low-dose/dose-rate (LDR) of ionizing radiation represents a hazard for humans. Model organisms, such as fruit flies, are considered valuable systems to reveal insights into this issue. We found that, in wild-type Drosophila melanogaster larval neuroblasts, the frequency of Chromosome Breaks (CBs), induced by acute γ-irradiation, is considerably reduced when flies are previously exposed to a protracted dose of 0.4 Gy delivered at a dose rate of 2.5 mGy/h. This indicates that this exposure, which is associated with an increased expression of DNA damage response proteins, induces a radioadaptive response (RAR) that protects Drosophila from extensive DNA damage. Interestingly, the same exposure reduces the frequency of telomere fusions (TFs) from Drosophila telomere capping mutants suggesting that the LDR can generally promote a protective response on chromatin sites that are recognized as DNA breaks. Deep RNA sequencing revealed that RAR is associated with a reduced expression of Loquacious D (Loqs-RD) gene that encodes a well-conserved dsRNA binding protein required for esiRNAs biogenesis. Remarkably, loss of Loqs mimics the LDR-mediated chromosome protection as it decreases the IR-induced CBs and TFs frequency. Thus, our molecular characterization of RAR identifies Loqs as a key factor in the cellular response to LDR and in the epigenetic routes involved in radioresistance.},
}
@article {pmid36057525,
year = {2022},
author = {Batista, LFZ and Dokal, I and Parker, R},
title = {Telomere biology disorders: time for moving towards the clinic?.},
journal = {Trends in molecular medicine},
volume = {28},
number = {10},
pages = {882-891},
pmid = {36057525},
issn = {1471-499X},
support = {MR/P018440/1/MRC_/Medical Research Council/United Kingdom ; R01 CA258386/CA/NCI NIH HHS/United States ; R01 HL137793/HL/NHLBI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Biology ; Cell Cycle Proteins/genetics/metabolism ; *Dyskeratosis Congenita/genetics/metabolism ; Humans ; Mutation ; Nuclear Proteins/genetics ; RNA/metabolism ; RNA-Binding Proteins/genetics ; *Telomerase/genetics/metabolism ; Telomere/genetics ; },
abstract = {Telomere biology disorders (TBDs) are a group of rare diseases caused by mutations that impair telomere maintenance. Mutations that cause reduced levels of TERC/hTR, the telomerase RNA component, are found in most TBD patients and include loss-of-function mutations in hTR itself, in hTR-binding proteins [NOP10, NHP2, NAF1, ZCCHC8, and dyskerin (DKC1)], and in proteins required for hTR processing (PARN). These patients show diverse clinical presentations that most commonly include bone marrow failure (BMF)/aplastic anemia (AA), pulmonary fibrosis, and liver cirrhosis. There are no curative therapies for TBD patients. An understanding of hTR biogenesis, maturation, and degradation has identified pathways and pharmacological agents targeting the poly(A) polymerase PAPD5, which adds 3'-oligoadenosine tails to hTR to promote hTR degradation, and TGS1, which modifies the 5'-cap structure of hTR to enhance degradation, as possible therapeutic approaches. Critical next steps will be clinical trials to establish the effectiveness and potential side effects of these compounds in TBD patients.},
}
@article {pmid36055854,
year = {2022},
author = {Seibt, KD and Ghaffari, MH and Scheu, T and Koch, C and Sauerwein, H},
title = {Effects of different feeding levels during a 14-week preweaning phase in dairy heifer calves on telomere length and mitochondrial DNA copy number in blood.},
journal = {Journal of dairy science},
volume = {105},
number = {10},
pages = {8509-8522},
doi = {10.3168/jds.2022-21891},
pmid = {36055854},
issn = {1525-3198},
mesh = {*Animal Feed/analysis ; Animals ; Cattle ; DNA Copy Number Variations ; DNA, Mitochondrial ; *Diet/veterinary ; Female ; Milk/metabolism ; Mitochondria ; Reactive Oxygen Species/metabolism ; Telomere ; Weaning ; },
abstract = {Telomeres cap the ends of eukaryotic chromosomes, and the telomere length (TL) is related to cellular age. The mitochondrial DNA copy number (mtDNAcn) reflects the abundance of mitochondria in a cell. In addition to generating energy, mitochondria are also the main producers of reactive oxygen species, which in turn can accelerate TL attrition and impair mitochondrial function. Nutrition in early life could influence mtDNAcn and TL in later life. In the present study, we investigated the effects of feeding different levels of milk replacer (MR) on TL shortening and energetic status by examining mtDNAcn of heifers during their first year of life. In this study, whole blood samples were obtained from German Holstein heifer calves 36 to 48 h after birth (wk 1) and at wk 12 and wk 16 of life (n = 37), as well as from 31 calves when reaching 1 yr of age. Calves were fed either a high level of MR (14% solids) at 10 L/d (1.4 kg of MR/d; n = 18) or a restrictive low level at 5.7 L/d (0.8 kg of MR/d; n = 19) until linear weaning in wk 13 to 14 of life. Additional whole blood samples were taken from their respective dams 36 to 48 h after calving. Relative TL (qT) and mtDNAcn in cells from whole blood were measured by multiplex quantitative PCR. The greatest qT values were observed in neonates (36-48 h after birth), with decreasing qT values thereafter. Delta qT values were calculated as ΔqT = qT (first year of life) - initial qT (36-48 h after birth). We found no effect of the feeding regimen on qT values, but qT decreased with age. The mtDNAcn was lowest in neonates, increased until wk 12 of life, and then remained at a constant level until after weaning (wk 16). After the first year of life, mtDNAcn was decreased and returned to levels comparable to those of the neonatal stage. No differences in mtDNAcn were detectable between feeding groups within each time point. When comparing the values of qT and mtDNAcn between the calves and their dams after calving (36-48 h after birth and after calving), greater values were observed in calves than in dams. Delta qT values were negative in all but 2 calves (on the restricted diet), indicating that the change in TL with age was not uniform among individual animals, whereas no difference in mean ΔqT values occurred between the feeding groups. Additional analyses of the correlation between qT, mtDNAcn, and various indicators of oxidative status from birth until wk 16 of life did not indicate major interactions between oxidative status, qT and mtDNAcn. The results of this study support an age-dependent decrease of TL in calves independent of the MR feeding level and show the dynamic changes of mtDNAcn in early life.},
}
@article {pmid36054116,
year = {2022},
author = {Chen, L and Dickerhoff, J and Sakai, S and Yang, D},
title = {DNA G-Quadruplex in Human Telomeres and Oncogene Promoters: Structures, Functions, and Small Molecule Targeting.},
journal = {Accounts of chemical research},
volume = {55},
number = {18},
pages = {2628-2646},
pmid = {36054116},
issn = {1520-4898},
support = {U01 CA240346/CA/NCI NIH HHS/United States ; R01 CA122952/CA/NCI NIH HHS/United States ; R01 CA177585/CA/NCI NIH HHS/United States ; S10 RR016649/RR/NCRR NIH HHS/United States ; R01 CA153821/CA/NCI NIH HHS/United States ; P30 CA023168/CA/NCI NIH HHS/United States ; K01 CA083886/CA/NCI NIH HHS/United States ; R01 GM083117/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatin ; DNA/chemistry ; *G-Quadruplexes ; Guanine/chemistry ; Humans ; Ligands ; Oncogenes ; Proto-Oncogene Proteins c-bcl-2/genetics ; Receptors, Drug/genetics ; Telomere/genetics ; Vascular Endothelial Growth Factor A ; },
abstract = {DNA G-quadruplex secondary structures formed in guanine-rich human telomeres and oncogene promoters are functionally important and have emerged as a promising new class of cancer-specific drug targets. These globular intramolecular structures are stabilized by K[+] or Na[+] and form readily under physiological solution conditions. Moreover, G-quadruplexes are epigenetic features and can alter chromatin structure and function together with interactive proteins. Here, we discuss our efforts over the last two decades to understand the structures and functions of DNA G-quadruplexes formed in key oncogene promoters and human telomeres and their interactions with small molecules. Using high-field NMR spectroscopy, we determined the high-resolution structures of physiologically relevant telomeric G-quadruplexes in K[+] solution with a major form (hybrid-2) and a minor form (hybrid-1), as well as a two-tetrad intermediate. The intrinsic structural polymorphism of telomeric DNA may be important for the biology of human telomeres, and we proposed a model for the interconversion. More recently, we have worked on G-quadruplexes of MYC, BCL2, PDGFR-β, VEGF, and k-RAS oncogene promoters. We determined the structure of the major G-quadruplex formed in the MYC promoter, a prototype for parallel G-quadruplexes. It is the first example of the parallel-stranded G3NG3 structure motif with a 1-nt loop, which is prevalent in promoter sequences and likely evolutionarily selected to initiate folding. Remarkably, the parallel MYC promoter G-quadruplexes are highly stable. Additionally, we determined the molecular structures of G-quadruplexes formed in human BCL2, VEGF, and PDGFR-β promoters, each adopting a unique structure. For example, the BCL2 promoter contains distinct interchangeable G-quadruplexes in two adjacent regions, suggesting precise regulation by different proteins. The PDGFR-β promoter adopts unique "broken-strand" and vacancy G-quadruplexes, which can be recognized by cellular guanine metabolites for a potential regulatory role.Structural information on G-quadruplexes in complex with small-molecules is critical for understanding specific recognition and structure-based rational drug design. Our studies show that many G-quadruplexes contain unique structural features such as capping and loop structures, allowing specific recognition by drugs and protein. This represents a paradigm shift in understanding DNA as a drug target: Rather than a uniform, nonselective binding site in duplex DNA, the G-quadruplex is being pursued as a new class of selectively targetable drug receptors. We focus on targeting the biologically relevant MYC promoter G-quadruplex (MycG4) with small molecules and have determined its first and additional drug complex structures. Very recently, we have discovered clinically tested indenoisoquinolines as strong MycG4 binders and potent MYC inhibitors. We have also discovered drugs targeting the unique dGMP-bound-vG4 formed in the PDGFR-β promoter. Moreover, we determined the complex structures of the first small molecules that specifically recognize the physiologically relevant human telomeric G-quadruplexes. Unlike the previously recognized dogma that the optimal G-quadruplex ligands are large aromatic or cyclic compounds, our results suggest that smaller asymmetric compounds with appropriate functional groups are better choices to specifically bind G-quadruplexes. This body of work lays a strong foundation for future work aimed at understanding the cellular functions of G-quadruplexes and G-quadruplex-targeted drug design.},
}
@article {pmid36051868,
year = {2022},
author = {Rodríguez-Fernández, B and Gispert, JD and Guigo, R and Navarro, A and Vilor-Tejedor, N and Crous-Bou, M},
title = {Genetically predicted telomere length and its relationship with neurodegenerative diseases and life expectancy.},
journal = {Computational and structural biotechnology journal},
volume = {20},
number = {},
pages = {4251-4256},
pmid = {36051868},
issn = {2001-0370},
abstract = {Telomere length (TL) is a biomarker of biological aging. Shorter telomeres have been associated with mortality and increased rates of age-related diseases. However, observational studies are unable to conclude whether TL is causally associated with those outcomes. Mendelian randomization (MR) was developed for assessing causality using genetic variants in epidemiological research. The objective of this study was to test the potential causal role of TL in neurodegenerative disorders and life expectancy through MR analysis. Summary level data were extracted from the most recent genome-wide association studies for TL, Alzheimer's disease (AD), Parkinson's disease, Frontotemporal dementia, Amyotrophic Lateral Sclerosis, Progressive Supranuclear Palsy and life expectancy. MR estimates revealed that longer telomeres inferred a protective effect on risk of AD (OR = 0.964; adjusted p-value = 0.039). Moreover, longer telomeres were significantly associated with increased life expectancy (βIVW = 0.011; adjusted p-value = 0.039). Sensitivity analyses suggested evidence for directional pleiotropy in AD analyses. Our results showed that genetically predicted longer TL may increase life expectancy and play a protective causal effect on AD. We did not observe significant causal relationships between longer TL and other neurodegenerative diseases. This suggests that the involvement of TL on specific biological mechanisms might differ between AD and life expectancy, with respect to that in other neurodegenerative diseases. Moreover, the presence of pleiotropy may reflect the complex interplay between TL homeostasis and AD pathophysiology. Further observational studies are needed to confirm these results.},
}
@article {pmid36047552,
year = {2022},
author = {Coukos, A and Daccord, C and Lazor, R and Blum, S and Naveiras, O and Unger, S and Vionnet, J and Gaide, O and Koutsokera, A and Moschouri, E and Sempoux, C and Good, JM and Moradpour, D and Baerlocher, GM and Fraga, M},
title = {[Short telomere syndrome in adults: a rare entity that should be evoked].},
journal = {Revue medicale suisse},
volume = {18},
number = {793},
pages = {1606-1613},
doi = {10.53738/REVMED.2022.18.793.1606},
pmid = {36047552},
issn = {1660-9379},
mesh = {Adult ; *Bone Marrow Diseases/genetics/pathology ; Child ; Growth Disorders ; Humans ; Hypercalcemia ; Metabolic Diseases ; *Nephrocalcinosis ; Syndrome ; Telomere/genetics/pathology ; },
abstract = {Short telomere syndrome (STS) is a group of rare, often underrecognized, diseases caused by defects in telomere-maintenance genes, leading to abnormal telomere shortening and associated with diverse multi-organ manifestations. In pediatric patients, STS typically presents with mucocutaneous or gastrointestinal lesions, bone marrow failure and neoplasia. In adulthood, aplastic bone marrow disease, liver disease and pulmonary fibrosis are classic clinical manifestations. At present, medical treatment options for STS remain limited. Danazol, a synthetic androgenic hormone, can slow down telomere shortening and thus limit the progression of the disease. Finally, hematopoietic, hepatic and pulmonary transplantation, sometimes combined, may be discussed in a multidisciplinary setting in certain situations.},
}
@article {pmid36041576,
year = {2022},
author = {Dey, A and Pandav, K and Nath, M and Barthwal, R and Prasad, R},
title = {Molecular rec§ognition of telomere DNA sequence by 2, 6 anthraquinone derivatives leads to thermal stabilization and induces apoptosis in cancer cells.},
journal = {International journal of biological macromolecules},
volume = {221},
number = {},
pages = {355-370},
doi = {10.1016/j.ijbiomac.2022.08.156},
pmid = {36041576},
issn = {1879-0003},
mesh = {Base Sequence ; Telomere/genetics/metabolism ; *G-Quadruplexes ; Anthraquinones/pharmacology ; *Telomerase/genetics ; DNA/chemistry ; Apoptosis ; Anthracenes ; *Neoplasms/drug therapy/genetics ; },
abstract = {According to current research, anti-cancer anthraquinones impact telomere disruption and may interact with G-quadruplex DNA that triggers signaling to apoptosis. The present study represents the biophysical investigation of oxidative stress, late apoptosis, and induced senescence among cancer cells after binding laboratory synthesized piperidine-based anthraquinone derivatives, 2, 6- Bis [(3-piperidino)acetamido)]anthracene-9,10-dione (N1P) and 2, 6-Bis [piperidino)propionamido]anthracene-9,10-dione (N2P), with G-quadruplex DNA. We employed biophysical approaches to explore the interaction of synthetic anthraquinone derivatives with quadruplex DNA sequences to influence biological activities in the presence of K[+] and Na[+] cations. The binding affinity for N2P and N1P are Kb = 5.8 × 10[6] M[-1] and Kb = 1.0 × 10[6] M[-1], respectively, leading to hypo-/hyper-chromism with 5-7 nm red shift and significant fluorescence quenching and changes in ellipticity resulting in external binding of both the ligands to G-quadruplex DNA. Ligand binding induced enhancement of thermostability of G4 DNA is greater in Na[+] environment (ΔTm = 34 °C) as compared to that in K[+] environment (ΔTm = 21 °C), thereby restricting telomerase binding access to telomeres. Microscopic images of treated cells indicated cellular shape, nuclear condensation, and fragmentation alterations. The findings pave the path for therapeutic research, given the great potential of modifying anthraquinone substituent groups towards improved efficacy, ROS generation, and G-quadruplex DNA selectivity.},
}
@article {pmid36038949,
year = {2022},
author = {Kille, B and Balaji, A and Sedlazeck, FJ and Nute, M and Treangen, TJ},
title = {Multiple genome alignment in the telomere-to-telomere assembly era.},
journal = {Genome biology},
volume = {23},
number = {1},
pages = {182},
pmid = {36038949},
issn = {1474-760X},
support = {P01 AI152999/AI/NIAID NIH HHS/United States ; T15 LM007093/LM/NLM NIH HHS/United States ; },
mesh = {*Genome, Human ; *Genomics/methods ; Humans ; Nucleotides ; Telomere/genetics ; },
abstract = {With the arrival of telomere-to-telomere (T2T) assemblies of the human genome comes the computational challenge of efficiently and accurately constructing multiple genome alignments at an unprecedented scale. By identifying nucleotides across genomes which share a common ancestor, multiple genome alignments commonly serve as the bedrock for comparative genomics studies. In this review, we provide an overview of the algorithmic template that most multiple genome alignment methods follow. We also discuss prospective areas of improvement of multiple genome alignment for keeping up with continuously arriving high-quality T2T assembled genomes and for unlocking clinically-relevant insights.},
}
@article {pmid36038827,
year = {2022},
author = {Fohringer, C and Hoelzl, F and Allen, AM and Cayol, C and Ericsson, G and Spong, G and Smith, S and Singh, NJ},
title = {Large mammal telomere length variation across ecoregions.},
journal = {BMC ecology and evolution},
volume = {22},
number = {1},
pages = {105},
pmid = {36038827},
issn = {2730-7182},
mesh = {Animals ; Animals, Wild/genetics ; *Deer/genetics ; *Ecosystem ; Female ; Humans ; Male ; Seasons ; Telomere/genetics ; },
abstract = {BACKGROUND: Telomere length provides a physiological proxy for accumulated stress in animals. While there is a growing consensus over how telomere dynamics and their patterns are linked to life history variation and individual experience, knowledge on the impact of exposure to different stressors at a large spatial scale on telomere length is still lacking. How exposure to different stressors at a regional scale interacts with individual differences in life history is also poorly understood. To better understand large-scale regional influences, we investigated telomere length variation in moose (Alces alces) distributed across three ecoregions. We analyzed 153 samples of 106 moose representing moose of both sexes and range of ages to measure relative telomere lengths (RTL) in white blood cells.<br><br>RESULTS: We found that average RTL was significantly shorter in a northern (montane) and southern (sarmatic) ecoregion where moose experience chronic stress related to severe summer and winter temperatures as well as high anthropogenic land-use compared to the boreal region. Our study suggests that animals in the northern boreal forests, with relatively homogenous land use, are less disturbed by environmental and anthropogenic stressors. In contrast, animals in areas experiencing a higher rate of anthropogenic and environmental change experience increased stress.<br><br>CONCLUSION: Although animals can often adapt to predictable stressors, our data suggest that some environmental conditions, even though predictable and ubiquitous, can generate population level differences of long-term stress. By measuring RTL in moose for the first time, we provide valuable insights towards our current understanding of telomere biology in free-ranging wildlife in human-modified ecosystems.},
}
@article {pmid36037299,
year = {2022},
author = {Jentsch, A and Hoferichter, F and Raufelder, D and Hageman, G and Maas, L},
title = {The relation between sensory processing sensitivity and telomere length in adolescents.},
journal = {Brain and behavior},
volume = {12},
number = {9},
pages = {e2751},
pmid = {36037299},
issn = {2162-3279},
mesh = {Adolescent ; Biomarkers ; Body Mass Index ; Humans ; Perception ; *Telomere ; *Telomere Shortening ; },
abstract = {BACKGROUND: In the present study, we investigated the association between sensory processing sensitivity (SPS) and telomere length (TL), which is considered a biomarker of cellular aging. SPS is an individual characteristic describing increased perception and procession of inner or outer stimuli, and is positively related to self-perceived stress.<br><br>METHODS: We recruited 82 healthy adolescents aged 13-16 from secondary schools in Germany. SPS was measured with the Highly Sensitive Person Scale, and TL was determined by a multiplex quantitative PCR method.<br><br>RESULTS: Our results show that students with higher values of SPS are likely to have shorter telomeres (&#x3b2;&#xa0;=&#xa0;0.337, p&#xa0;=&#xa0;.001), when adjusting for sex, socioeconomic status, age, and body mass index. These findings are also independent of the negative impact of stress students might have perceived shortly before data collection.<br><br>CONCLUSIONS: Our analysis suggests that students who struggle with low sensory threshold are likely to have shorter telomeres.},
}
@article {pmid36036734,
year = {2023},
author = {Salisbury, ML and Markin, CR and Wu, P and Cogan, JD and Mitchell, DB and Liu, Q and Loyd, JE and Lancaster, LH and Kropski, JA and Blackwell, TS},
title = {Peripheral Blood Telomere Attrition in Persons at Risk for Familial Pulmonary Fibrosis.},
journal = {American journal of respiratory and critical care medicine},
volume = {207},
number = {2},
pages = {208-211},
pmid = {36036734},
issn = {1535-4970},
support = {P01 HL092870/HL/NHLBI NIH HHS/United States ; K23 HL141539/HL/NHLBI NIH HHS/United States ; K08HL130595/HL/NHLBI NIH HHS/United States ; P01HL092870/HL/NHLBI NIH HHS/United States ; R01 HL151016/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; *Idiopathic Pulmonary Fibrosis ; Mutation ; Telomere/genetics ; },
}
@article {pmid36036284,
year = {2023},
author = {Khalil, D and Giurgescu, C and Misra, DP and Templin, T and Jenuwine, E and Drury, SS},
title = {Psychosocial Factors and Telomere Length Among Parents and Infants of Immigrant Arab American Families.},
journal = {Biological research for nursing},
volume = {25},
number = {1},
pages = {137-149},
pmid = {36036284},
issn = {1552-4175},
support = {U24 AG066528/AG/NIA NIH HHS/United States ; },
mesh = {Infant ; Female ; Humans ; Child, Preschool ; Cross-Sectional Studies ; Pilot Projects ; *Mothers/psychology ; *Emigrants and Immigrants ; Arabs ; Telomere ; },
abstract = {Background: Immigrant Arab American families face multiple stressors related to migration and resettlement. Telomere length (TL) is an established biomarker of aging and psychosocial stress. No published studies have concurrently examined the association between maternal and paternal psychosocial factors and infants' TL. The purpose of this study was to: (1) compare mother, father, and infant TLs; (2) explore the association of maternal and paternal psychosocial factors (acculturative stress and depressive symptoms) with maternal and paternal TL; and (3) explore the association of maternal and paternal psychosocial factors with infants' TL among Arab American immigrants. Method: Using a cross-sectional exploratory design, a sample of 52 immigrant Arab American mother-father-infant triads were recruited from community centers. Data were collected in a single home visit when the infant was 6-24 months old. Each parent completed the study questionnaires addressing their psychosocial factors (acculturative stress, and depressive symptoms), then parents and infants provided buccal cell for TL measurement. Results: Maternal TL was positively correlated to infants' TL (r = .31, p = .04) and significantly shorter (p < .001). Paternal TL was not correlated with infant TL but was significantly shorter than infant's TL (p < .001). Maternal depression was significantly correlated with mothers' TL (r = .4, p = .007). Higher levels of maternal depressive symptoms were significantly associated with shorter infant TL when controlling for background characteristics. Conclusions: Our pilot study is the first study to examine maternal and paternal psychosocial factors related to migration and infants' TL. More research is needed to advance our understanding of the effects of immigration on the intergenerational transfer of stress and trauma.},
}
@article {pmid36035793,
year = {2022},
author = {Wang, Y and Ferrucci, L and Seidman, MM and Liu, Y},
title = {An optimized proximity ligation assay to detect telomere dysfunction induced foci in human and mouse cells.},
journal = {STAR protocols},
volume = {3},
number = {3},
pages = {101610},
pmid = {36035793},
issn = {2666-1667},
mesh = {Animals ; Fluorescent Antibody Technique ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; *Telomere ; },
abstract = {Telomere dysfunction-induced foci (TIF) can be measured by immunofluorescence, combined with telomere-fluorescent in situ hybridization. We modified this approach by combining the proximity ligation assay (PLA), which detects colocalization of two molecules in proximity through a signal amplification step and improves the fidelity and sensitivity of TIF detection in human and mouse cells. The protocol includes cell preparation, permeabilization, fixation, and blocking PLA detection of DNA damage response proteins within proximity with telomeres and optional PLA verification by immunofluorescence-based technique.},
}
@article {pmid36031719,
year = {2022},
author = {Maher, TM},
title = {A clinical short-cut to identifying short telomeres in idiopathic pulmonary fibrosis?.},
journal = {Respirology (Carlton, Vic.)},
volume = {27},
number = {11},
pages = {916-917},
doi = {10.1111/resp.14355},
pmid = {36031719},
issn = {1440-1843},
mesh = {Humans ; *Idiopathic Pulmonary Fibrosis/diagnosis/genetics ; *Telomerase/genetics ; Telomere/genetics/metabolism ; Telomere Shortening ; },
}
@article {pmid36030273,
year = {2022},
author = {Yu, EY and Cheung, NV and Lue, NF},
title = {Connecting telomere maintenance and regulation to the developmental origin and differentiation states of neuroblastoma tumor cells.},
journal = {Journal of hematology &amp; oncology},
volume = {15},
number = {1},
pages = {117},
pmid = {36030273},
issn = {1756-8722},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; },
mesh = {Cell Differentiation ; Cell Proliferation ; Child ; Humans ; *Neuroblastoma ; *Telomerase ; Telomere ; Telomere Homeostasis ; },
abstract = {A cardinal feature that distinguishes clinically high-risk neuroblastoma from low-risk tumors is telomere maintenance. Specifically, neuroblastoma tumors with either active telomerase or alternative lengthening of telomeres exhibit aggressive growth characteristics that lead to poor outcomes, whereas tumors without telomere maintenance can be managed with observation or minimal treatment. Even though the need for cancer cells to maintain telomere DNA-in order to sustain cell proliferation-is well established, recent studies suggest that the neural crest origin of neuroblastoma may enforce unique relationships between telomeres and tumor malignancy. Specifically in neuroblastoma, telomere structure and telomerase activity are correlated with the adrenergic/mesenchymal differentiation states, and manipulating telomerase activity can trigger tumor cell differentiation. Both findings may reflect features of normal neural crest development. This review summarizes recent advances in the characterization of telomere structure and telomere maintenance mechanisms in neuroblastoma and discusses the findings in the context of relevant literature on telomeres during embryonic and neural development. Understanding the canonical and non-canonical roles of telomere maintenance in neuroblastoma could reveal vulnerabilities for telomere-directed therapies with potential applications to other pediatric malignancies.},
}
@article {pmid36028900,
year = {2022},
author = {Tan, KT and Slevin, MK and Meyerson, M and Li, H},
title = {Identifying and correcting repeat-calling errors in nanopore sequencing of telomeres.},
journal = {Genome biology},
volume = {23},
number = {1},
pages = {180},
pmid = {36028900},
issn = {1474-760X},
support = {U41 HG010972/HG/NHGRI NIH HHS/United States ; U01 HG010961/HG/NHGRI NIH HHS/United States ; R01 HG010040/HG/NHGRI NIH HHS/United States ; U01 HG010971/HG/NHGRI NIH HHS/United States ; R35 CA197568/CA/NCI NIH HHS/United States ; },
mesh = {Genomics ; High-Throughput Nucleotide Sequencing ; *Nanopore Sequencing ; *Nanopores ; Repetitive Sequences, Nucleic Acid ; Sequence Analysis, DNA ; Telomere ; },
abstract = {Nanopore long-read sequencing is an emerging approach for studying genomes, including long repetitive elements like telomeres. Here, we report extensive basecalling induced errors at telomere repeats across nanopore datasets, sequencing platforms, basecallers, and basecalling models. We find that telomeres in many organisms are frequently miscalled. We demonstrate that tuning of nanopore basecalling models leads to improved recovery and analysis of telomeric regions, with minimal negative impact on other genomic regions. We highlight the importance of verifying nanopore basecalls in long, repetitive, and poorly defined regions, and showcase how artefacts can be resolved by improvements in nanopore basecalling models.},
}
@article {pmid36014852,
year = {2022},
author = {Opstad, TB and Alexander, J and Aaseth, JO and Larsson, A and Seljeflot, I and Alehagen, U},
title = {Selenium and Coenzyme Q10 Intervention Prevents Telomere Attrition, with Association to Reduced Cardiovascular Mortality-Sub-Study of a Randomized Clinical Trial.},
journal = {Nutrients},
volume = {14},
number = {16},
pages = {},
pmid = {36014852},
issn = {2072-6643},
support = {N/A//Stein Erik Hagen Foundation for Clinical Heart Research, Oslo, Norway and County Council of &#xd6;sterg&#xf6;tland, Link&#xf6;ping University, Sweden./ ; },
mesh = {Aged ; Aged, 80 and over ; *Cardiovascular Diseases/mortality/physiopathology/prevention &amp; control ; Dietary Supplements ; Humans ; Leukocytes ; Prospective Studies ; *Selenium/pharmacology/therapeutic use ; *Telomere/drug effects/physiology ; *Ubiquinone/pharmacology/therapeutic use ; },
abstract = {Short telomeres have been associated with ageing and cardiovascular disease. The influence on leukocyte telomere length (LTL) of long-term intervention with combined selenium and coenzyme Q10 is unknown. Our aim was to determine whether 42 months of selenium and coenzyme Q10 supplementation prevented telomere attrition and further cardiovascular mortality. The investigation is an explorative sub-study of a double-blind, placebo-controlled, randomized trial. Swedish citizens low in selenium (n = 118), aged 70−80 years, were included. Intervention time was 4 years, with 10 years’ follow-up time. LTL was relatively quantified with PCR at baseline and after 42 months. At baseline, LTL (SD) was 0.954 (0.260) in the active treatment group and 1.018 (0.317) in the placebo group (p = 0.23). At 42 months, less shortening of LTL was observed after active treatment compared with placebo (+0.019 vs. −0.129, respectively, p = 0.02), with a significant difference in change basing the analysis on individual changes in LTL (p < 0.001). Subjects suffering future death presented with significantly shorter LTL at 42 months than survivors [0.791 (0.190) vs. 0.941 (0.279), p = 0.01], with a significant difference in change of LTL according to cardiovascular mortality and survival (p = 0.03). To conclude, preservation of LTL after selenium and coenzyme Q10 supplementation associated with reduced cardiovascular mortality.},
}
@article {pmid36011306,
year = {2022},
author = {Oudrhiri, N and M'kacher, R and Chaker, D and Colicchio, B and Borie, C and Jeandidier, E and Dieterlen, A and Griscelli, F and Bennaceur-Griscelli, A and Turhan, AG},
title = {Patient-Derived iPSCs Reveal Evidence of Telomere Instability and DNA Repair Deficiency in Coats Plus Syndrome.},
journal = {Genes},
volume = {13},
number = {8},
pages = {},
pmid = {36011306},
issn = {2073-4425},
mesh = {Ataxia ; Brain Neoplasms ; Calcinosis ; Central Nervous System Cysts ; *DNA Repair-Deficiency Disorders ; Humans ; *Induced Pluripotent Stem Cells/metabolism ; Leukoencephalopathies ; Muscle Spasticity ; Retinal Diseases ; Seizures ; *Telomerase/genetics ; Telomere/genetics/metabolism ; Telomere Homeostasis/genetics ; },
abstract = {Coats plus (CP) syndrome is an inherited autosomal recessive condition that results from mutations in the conserved telomere maintenance component 1 gene (CTC1). The CTC1 protein functions as a part of the CST protein complex, a protein heterotrimer consisting of CTC1-STN1-TEN1 which promotes telomere DNA synthesis and inhibits telomerase-mediated telomere elongation. However, it is unclear how CTC1 mutations may have an effect on telomere structure and function. For that purpose, we established the very first induced pluripotent stem cell lines (iPSCs) from a compound heterozygous patient with CP carrying deleterious mutations in both alleles of CTC1. Telomere dysfunction and chromosomal instability were assessed in both circulating lymphocytes and iPSCs from the patient and from healthy controls of similar age. The circulating lymphocytes and iPSCs from the CP patient were characterized by their higher telomere length heterogeneity and telomere aberrations compared to those in control cells from healthy donors. Moreover, in contrast to iPSCs from healthy controls, the high levels of telomerase were associated with activation of the alternative lengthening of telomere (ALT) pathway in CP-iPSCs. This was accompanied by inappropriate activation of the DNA repair proteins γH2AX, 53BP1, and ATM, as well as with accumulation of DNA damage, micronuclei, and anaphase bridges. CP-iPSCs presented features of cellular senescence and increased radiation sensitivity. Clonal dicentric chromosomes were identified only in CP-iPSCs after exposure to radiation, thus mirroring the role of telomere dysfunction in their formation. These data demonstrate that iPSCs derived from CP patients can be used as a model system for molecular studies of the CP syndrome and underscores the complexity of telomere dysfunction associated with the defect of DNA repair machinery in the CP syndrome.},
}
@article {pmid36010691,
year = {2022},
author = {Derevyanko, A and Skowronska, A and Skowronski, MT and Kordowitzki, P},
title = {The Interplay between Telomeres, Mitochondria, and Chronic Stress Exposure in the Aging Egg.},
journal = {Cells},
volume = {11},
number = {16},
pages = {},
pmid = {36010691},
issn = {2073-4409},
mesh = {*Aging/genetics ; Female ; Humans ; Mitochondria/genetics/metabolism ; Oocytes/metabolism ; Pregnancy ; *Telomere ; Telomere Shortening ; },
abstract = {While at the organismal level, biological aging can be estimated by telomere length and DNA methylation signatures, reliable biomarkers that can predict reproductive age are much needed to gauge the quality of an oocyte. Reproductive medicine and fertility centers often merely quantitate the ovarian reserve to predict the likelihood of fertilization and pregnancy in women of advanced reproductive age. It is highly important to address the level of age-related decline in oocyte quality since it leads to an increased risk of miscarriages and aneuploidy. Conversely, the pathways behind oocyte aging remain, in large part, elusive. Telomere shortening upon chronic stress exposure regulates mitochondria function and biogenesis by various pathways; therefore, establishing a link between these two important players and extrapolating them for the aging of oocytes will be the purpose of our commentary.},
}
@article {pmid36009574,
year = {2022},
author = {Opstad, TB and Solheim, S and Pettersen, AR and Kalstad, AA and Arnesen, H and Seljeflot, I},
title = {TERT and TET2 Genetic Variants Affect Leukocyte Telomere Length and Clinical Outcome in Coronary Artery Disease Patients-A Possible Link to Clonal Hematopoiesis.},
journal = {Biomedicines},
volume = {10},
number = {8},
pages = {},
pmid = {36009574},
issn = {2227-9059},
abstract = {Inherited and acquired mutations in hematopoietic stem cells can cause clonal expansion with increased risk of cardiovascular disease (CVD), a condition known for the clonal hematopoiesis of indeterminate potential (CHIP). Inherited genetic variants in two CHIP-associated genome loci, the telomerase gene telomerase enzyme reverse transcriptase (TERT) (rs7705526) and the epigenetic regulator ten−eleven translocation 2 (TET2) (rs2454206), were investigated in 1001 patients with stable coronary artery disease (CAD) (mean age 62 years, 22% women), with regards to cardiovascular outcome, comorbidities, and leukocyte telomere length. Over 2 years, mutated TERT increased the risk two-fold for major clinical events (MACEs) in all patients (p = 0.004), acute myocardial infarction (AMI) in male patients (p = 0.011), and stroke in female patients (p < 0.001). Mutated TET2 correlated with type 2 diabetes (p < 0.001), the metabolic syndrome (p = 0.002), as well as fasting glucose, HbA1c, and shorter telomeres (p = 0.032, p = 0.003, and p = 0.016, respectively). In conclusion, our results from stable CAD patients highlight TERTs’ role in CVD, and underline TET2s’ role in the epigenetic regulation of lifestyle-related diseases.},
}
@article {pmid36006930,
year = {2022},
author = {Sharaf, R and Frampton, GM and Albacker, LA},
title = {Mutations in the TERC template sequence can be incorporated into the telomeres of human tumors.},
journal = {PloS one},
volume = {17},
number = {8},
pages = {e0272707},
pmid = {36006930},
issn = {1932-6203},
mesh = {Humans ; Mutation ; *Neoplasms/genetics ; RNA/genetics/metabolism ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {Telomerase-mediated lengthening is a mechanism by which some cancer cells avoid senescence-mediated cell cycle arrest due to shortened telomeres. By reverse transcribing an RNA template, encoded by TERC, the enzyme telomerase synthesizes the elongation of telomeric DNA using the 3' end of the chromosome as a primer. TERC harbors a highly conserved template region consisting of 11 nucleotides spanning hg19 coordinates chr3:169482793-169482803. In human cell lines, when TERC was mutated to alter its template region, telomerase generated the predicted mutant telomeric repeats. However, it is unknown if this can occur in human clinical samples. Here, we report on the rare occurrence of two tumor samples where TERC template mutations were reflected in telomeric repeats.},
}
@article {pmid36005153,
year = {2022},
author = {Tacheva, T and Zienolddiny-Narui, S and Dimov, D and Vlaykova, D and Miteva, I and Vlaykova, T},
title = {The Leucocyte Telomere Length, GSTM1 and GSTT1 Null Genotypes and the Risk of Chronic Obstructive Pulmonary Disease.},
journal = {Current issues in molecular biology},
volume = {44},
number = {8},
pages = {3757-3769},
pmid = {36005153},
issn = {1467-3045},
support = {3/2019//Medical Faculty, Trakia University, Stara Zagora, Bulgaria/ ; },
abstract = {Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and oxidative stress both in the airways and blood and other organs. Elevated oxidative stress and inflammation have been reported to affect leucocyte telomere length (LTL). Glutathione S-transferase (GST) enzymes are a large family of xenobiotic-metabolizing enzymes that utilize different ROS products. We aimed to explore the link between GSTM1 and GSTT1 gene polymorphisms, LTL and COPD risk. For GSTM1, we genotyped 152 COPD patients and 131 non-affected controls; for GSTT1, we genotyped 149 COPD patients and 130 controls. We were able to assess TL for 91 patients and 88 controls. There was a significant difference in the GSTM1 null genotype frequency between the patients and controls (0.59 vs. 0.38, p ≤ 0.000), but such was not found for GSTT1 (p = 0.192). When combining both polymorphisms, we obtained a significantly greater presence of at least one null genotype among patients (0.12 vs. 0.05, p = 0.027). An association between GSTT1 and LTL was not found. COPD patients carrying the GSTM1 null genotype had shorter telomeres compared to those carrying the non-null genotype (15,720 bp vs. 22,442 bp, p = 0.008); as for the controls, it was the opposite (31,354 bp vs. 17,800 bp, p = 0.020). The significance in both groups remained when combining GSTM1 and GSTT1 (COPD (at least one null) 16,409 bp vs. COPD (non-null) 22,092 bp, p = 0.029; control (at least one null) 29,666 bp vs. control (non-null) 16,370 bp, p = 0.027). The total glutathione level in GSTM1 non-null controls was higher compared to the null genotype (15.39 ng/mL vs. 5.53 ng/mL, p = 0.002). In COPD patients, we found no association (p = 0.301). In conclusion, according to our results, GSTM1, but not GSTT1, null genotypes might play a role in leucocyte telomere shortening, and thus be involved in the pathogenesis of COPD.},
}
@article {pmid35996190,
year = {2022},
author = {Retuerto, M and Lledó, A and Fernandez-Varas, B and Guerrero-López, R and Usategui, A and Lalueza, A and García-García, R and Mancebo, E and Paz-Artal, E and Sastre, L and Perona, R and Pablos, JL},
title = {Shorter telomere length is associated with COVID-19 hospitalization and with persistence of radiographic lung abnormalities.},
journal = {Immunity &amp; ageing : I &amp; A},
volume = {19},
number = {1},
pages = {38},
pmid = {35996190},
issn = {1742-4933},
abstract = {BACKGROUND: Age and comorbidity are the main determinants of COVID-19 outcome. Shorter leukocyte telomere length (TL), a hallmark of biological aging, has been associated with worse COVID-19 outcomes. We sought to determine TL in patients with severe COVID-19 requiring hospitalization to analyze whether clinical outcomes and post-COVID-19 manifestations are associated with shorter TL.<br><br>RESULTS: We analyzed 251 patients with PCR-confirmed COVID-19, hospitalized in the first months of the pandemics. We determined TL in PBL at admission by quantitative-PCR (qPCR) analysis in patients. A healthy cohort from the same area with a similar age range (n&#x2009;=&#x2009;169) was used to calculate TL Z-scores. After hospital discharge, 144 COVID-19 survivors were followed-up for persistent COVID-19 manifestations. A second TL determination was performed in a smaller group of 63 patients 1&#x2009;year later and compared with baseline TL. Hospitalized COVID-19 patients had a decreased baseline age-adjusted TL Z-score compared to the reference group. No differences in Z-scores were observed in patients with different COVID-19 outcomes, classified as WHO ordinal scores. In 144 patients, followed for a median of 8&#x2009;months, post-COVID manifestations were not associated to differences in TL. Persistence of lung radiographic abnormalities was associated with shorter baseline TL. In patients with a second TL determination, further telomere shortening (TS) was observed in 35% and telomere lengthening in 49%. Patients with further TS had suffered a more severe disease.<br><br>CONCLUSION: Shorter TL is associated with COVID-19 hospitalization but not with hospital clinical outcomes nor with persistent post-COVID-19 manifestations. Delayed resolution of radiographic lung abnormalities was also associated with shorter TL.},
}
@article {pmid35992857,
year = {2022},
author = {Li, JH and Tao, YF and Shen, CH and Li, RD and Wang, Z and Xing, H and Ma, ES and Xue, HY and Zhang, QB and Ma, ZY and Wang, ZX},
title = {Integrated multi-omics analysis identifies ENY2 as a predictor of recurrence and a regulator of telomere maintenance in hepatocellular carcinoma.},
journal = {Frontiers in oncology},
volume = {12},
number = {},
pages = {939948},
pmid = {35992857},
issn = {2234-943X},
abstract = {Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has a high recurrence rate. Accurate prediction of recurrence risk is urgently required for tailoring personalized treatment programs for individual HCC patients in advance. In this study, we analyzed a gene expression dataset from an HCC cohort with 247 samples and identified five genes including ENY2, GPAA1, NDUFA4L2, NEDD9, and NRP1 as the variables for the prediction of HCC recurrence, especially the early recurrence. The Cox model and risks score were validated in two public HCC cohorts (GSE76427 and The Cancer Genome Atlas (TCGA)) and one cohort from Huashan Hospital, which included a total of 641 samples. Moreover, the multivariate Cox regression analysis revealed that the risk score could serve as an independent prognostic factor in the prediction of HCC recurrence. In addition, we found that ENY2, GPAA1, and NDUFA4L2 were significantly upregulated in HCC of the two validation cohorts, and ENY2 had significantly higher expression levels than another four genes in malignant cells, suggesting that ENY2 might play key roles in malignant cells. The cell line analysis revealed that ENY2 could promote cell cycle progression, cell proliferation, migration, and invasion. The functional analysis of the genes correlated with ENY2 revealed that ENY2 might be involved in telomere maintenance, one of the fundamental hallmarks of cancer. In conclusion, our data indicate that ENY2 may regulate the malignant phenotypes of HCC via activating telomere maintenance.},
}
@article {pmid35988638,
year = {2022},
author = {Lynn, SE and Kern, MD and Serrurier, B and Sirman, A and Heidinger, BJ},
title = {Chill out: Environmentally relevant cooling challenge does not increase telomere loss during early life.},
journal = {General and comparative endocrinology},
volume = {329},
number = {},
pages = {114108},
doi = {10.1016/j.ygcen.2022.114108},
pmid = {35988638},
issn = {1095-6840},
mesh = {Animals ; Female ; *Corticosterone ; Stress, Physiological ; Telomere ; Telomere Shortening ; *Songbirds/physiology ; },
abstract = {In vertebrates, exposure to diverse stressors during early life activates a stress response that can initiate compensatory mechanisms or promote cellular damage with long-term fitness consequences. A growing number of studies associate exposure to stressors during early life with increased damage to telomeres (i.e., promoting the shortening of these highly conserved, repeating sequences of non-coding DNA at chromosome ends). However, some studies show no such relationship, suggesting that the nature, timing, and context of these challenges may determine the degree to which physiological mediators of the stress response act in a damage-mitigating or damage promoting way in relation to telomere dynamics. In free-living eastern bluebirds (Sialia sialis), we have previously demonstrated that bouts of offspring cooling that occur when brooding females leave the nest increase at least one such physiological mediator of the stress response (circulating glucocorticoids), suggesting that variation in patterns of maternal brooding may result in different impacts on telomere dynamics at a young age. Here we experimentally tested whether repeated bouts of ecologically relevant offspring cooling affected telomere dynamics during post-natal development. Rates of telomere shortening during the nestling stage were not affected by experimental cooling, but they were affected by brood size and the rate of growth during the nestling stage. Our data suggest that the effects of developmental stress exposure on offspring telomeres are often context-dependent and that not all challenges that increase physiological mediators of stress result in damage to telomeres. Under some conditions, physiological mediators of stress may instead act as protective regulators, allowing for optimization of fitness outcomes in the face of environmental challenges.},
}
@article {pmid35987624,
year = {2022},
author = {Wang, T and Jia, Z and Li, S and Li, Y and Yu, T and Lu, T and Shi, Y},
title = {The association between leukocyte telomere length and chronic obstructive pulmonary disease is partially mediated by inflammation: a meta-analysis and population-based mediation study.},
journal = {BMC pulmonary medicine},
volume = {22},
number = {1},
pages = {320},
pmid = {35987624},
issn = {1471-2466},
mesh = {Aging ; Humans ; Inflammation/genetics ; Leukocytes ; Nutrition Surveys ; *Pulmonary Disease, Chronic Obstructive ; *Smoking ; Telomere ; },
abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of the major health issues worldwide. Pathophysiological changes in COPD are mainly reflected in the deterioration of lung function with aging.<br><br>METHODS: Considering that telomere length is a hallmark of biological aging, we first performed a meta-analysis to summarize the current knowledge about the relationship between telomere length and COPD and then employed individual-level data from the continuous National Health and Nutrition Examination Survey (NHANES) to investigate whether telomere length could reflect accelerated aging in COPD and serve as an independent predictor. A mediation study was further performed to examine whether the association between telomeres and COPD could be mediated by inflammation, as one of the most important etiologies and characteristics of COPD.<br><br>RESULTS: The four studies included in our meta-analysis were with high heterogeneity (I[2]&#x2009;=&#x2009;95.7%, Phet&#x2009;<&#x2009;0.001), and the pooled relative risk for COPD comparing the shortest tertile versus the longest tertile was 4.06 (95% CI&#x2009;=&#x2009;1.38 to 11.96). Of the 6,378 subjects in the individual-level data analyses using NHANES, 455 were diagnosed with COPD, and multivariable-adjusted logistic regression also indicated that short telomere length was associated with COPD. Consistently, cubic regression spline analyses showed that long telomeres exhibited a significant association with a decreased risk of COPD. In the subsequent mediation analyses, C-reactive protein concentration, white blood cells count and blood neutrophil count, as inflammatory biomarkers, showed a significant indirect effect on the relationship between telomere length and COPD.<br><br>CONCLUSION: Accelerated aging in COPD could be characterized by excessive telomere shortening, and inflammatory response might be involved in the underlying mechanisms of COPD pathogenesis promoted by short telomere length. Telomere length measurement may facilitate clinical translational research and targeted therapy of COPD.},
}
@article {pmid37519465,
year = {2023},
author = {Ratanatharathorn, A and Roberts, AL and Chibnik, LB and Choi, KW and De Vivo, I and Kim, Y and Nishimi, K and Rimm, EB and Sumner, JA and Kubzansky, LD and Koenen, KC},
title = {Posttraumatic Stress Disorder, Depression, and Accelerated Aging: Leukocyte Telomere Length in the Nurses' Health Study II.},
journal = {Biological psychiatry global open science},
volume = {3},
number = {3},
pages = {510-518},
pmid = {37519465},
issn = {2667-1743},
abstract = {BACKGROUND: Exposure to trauma, posttraumatic stress disorder (PTSD), and depression have been independently associated with leukocyte telomere length (LTL), a cellular marker of aging associated with mortality and age-related diseases. However, the joint contributions of trauma and its psychological sequelae on LTL have not been examined.<br><br>METHODS: We conducted an analysis of LTL in a subset of women from the Nurses' Health Study II (N = 1868). Lifetime exposure to traumatic events, PTSD, and depression was assessed with validated measures. DNA was extracted from peripheral blood leukocytes and telomere repeat copy number to single gene copy number was determined by quantitative real-time polymerase chain reaction telomere assay. Linear regression models assessed the association of trauma, PTSD, and depression with LTL after adjustment for health behaviors and medical conditions.<br><br>RESULTS: Trauma, PTSD, and depression were not independently associated with LTL in mutually adjusted models. However, individuals with severe psychological distress-characterized by comorbid PTSD and depression-had shorter LTL equivalent to being 7.62 years older (95% CI, 0.02 to 17.97) than participants who had never experienced a traumatic event and were not depressed. Further examination found only an association among individuals with the highest number of PTSD symptoms and comorbid depression equivalent to 9.71 additional years of aging (95% CI, 1.36 to 20.49). No effect was found among individuals meeting the minimum threshold for probable PTSD with comorbid depression.<br><br>CONCLUSIONS: Severe psychological distress, as indicated by the presence of comorbid PTSD and depression, may be associated with shorter LTL.},
}
@article {pmid37117760,
year = {2022},
author = {Codd, V and Denniff, M and Swinfield, C and Warner, SC and Papakonstantinou, M and Sheth, S and Nanus, DE and Budgeon, CA and Musicha, C and Bountziouka, V and Wang, Q and Bramley, R and Allara, E and Kaptoge, S and Stoma, S and Jiang, T and Butterworth, AS and Wood, AM and Di Angelantonio, E and Thompson, JR and Danesh, JN and Nelson, CP and Samani, NJ},
title = {Measurement and initial characterization of leukocyte telomere length in 474,074 participants in UK Biobank.},
journal = {Nature aging},
volume = {2},
number = {2},
pages = {170-179},
pmid = {37117760},
issn = {2662-8465},
support = {MR/L003120/1/MRC_/Medical Research Council/United Kingdom ; RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom ; SP/16/4/32697/BHF_/British Heart Foundation/United Kingdom ; RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom ; MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; CH/12/2/29428/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Infant, Newborn ; Humans ; Male ; Female ; *Biological Specimen Banks ; *Ethnicity ; Leukocytes ; Telomere/genetics ; United Kingdom ; },
abstract = {Leukocyte telomere length (LTL) is a proposed marker of biological age. Here we report the measurement and initial characterization of LTL in 474,074 participants in UK Biobank. We confirm that older age and male sex associate with shorter LTL, with women on average ~7 years younger in 'biological age' than men. Compared to white Europeans, LTL is markedly longer in African and Chinese ancestries. Older paternal age at birth is associated with longer individual LTL. Higher white cell count is associated with shorter LTL, but proportions of white cell subtypes show weaker associations. Age, ethnicity, sex and white cell count explain ~5.5% of LTL variance. Using paired samples from 1,351 participants taken ~5 years apart, we estimate the within-individual variability in LTL and provide a correction factor for this. This resource provides opportunities to investigate determinants and biomedical consequences of variation in LTL.},
}
@article {pmid37117759,
year = {2022},
author = {Hägg, S and Zhan, Y},
title = {Telomere research entering the big data era.},
journal = {Nature aging},
volume = {2},
number = {2},
pages = {102-104},
pmid = {37117759},
issn = {2662-8465},
support = {U24 AG066528/AG/NIA NIH HHS/United States ; },
mesh = {*Big Data ; *Telomere/genetics ; Databases, Factual ; },
}
@article {pmid36324603,
year = {2022},
author = {Ridout, KK and Syed, SA and Kao, HT and Porton, B and Rozenboym, AV and Tang, J and Fulton, S and Perera, T and Jackowski, AP and Kral, JG and Tyrka, AR and Coplan, J},
title = {Relationships Between Telomere Length, Plasma Glucagon-like Peptide 1, and Insulin in Early-Life Stress-Exposed Nonhuman Primates.},
journal = {Biological psychiatry global open science},
volume = {2},
number = {1},
pages = {54-60},
pmid = {36324603},
issn = {2667-1743},
abstract = {BACKGROUND: Early-life stress is associated with alterations in telomere length, a marker of accumulated stress and aging, and a risk factor for psychiatric disorders. Nonhuman primate maternal variable foraging demand (VFD) is a validated early-life stress model, resulting in anxiety- and depressive-like symptoms in offspring. Previous studies reported increased plasma glucagon-like peptide 1 (pGLP-1) along with insulin resistance in this model. We investigated whether VFD rearing related to adult telomere length and to these neuroendocrine markers.<br><br>METHODS: Adult leukocyte telomere length was measured in VFD-reared (12 males, 13 females) and non-VFD-reared (9 males, 26 females) bonnet macaques. Associations between adult telomere length and adolescent fasting pGLP-1 or insulin resistance in VFD-reared versus non-VFD-reared groups were examined using regression modeling, controlling for sex, weight, and age.<br><br>RESULTS: VFD subjects had relatively longer telomeres than non-VFD subjects (p&#xa0;= .017), and females relatively longer than males (p&#xa0;= .0004). Telomere length was positively associated with pGLP-1 (p&#xa0;= .0009) and with reduced insulin sensitivity (p < .0001) in both sexes, but not as a function of rearing group.<br><br>CONCLUSIONS: Unexpectedly, VFD was associated with longer adult telomere length. Insulin resistance may lead to higher pGLP-1 levels in adolescence, which could protect telomere length in VFD offspring as adults. Associations between adult telomere length and adolescent insulin resistance and high pGLP-1 may reflect an adaptive, compensatory response after early-life stress exposure.},
}
@article {pmid37034531,
year = {2023},
author = {Vukašinović, A and Ostanek, B and Klisic, A and Kafedžić, S and Zdravković, M and Ilić, I and Sopić, M and Hinić, S and Stefanović, M and Memon, L and Gaković, B and Bogavac-Stanojević, N and Spasojević-Kalimanovska, V and Marc, J and Nešković, AN and Kotur-Stevuljević, J},
title = {Telomere-telomerase system status in patients with acute myocardial infarction with ST-segment elevation - relationship with oxidative stress.},
journal = {Archives of medical science : AMS},
volume = {19},
number = {2},
pages = {313-323},
pmid = {37034531},
issn = {1734-1922},
abstract = {INTRODUCTION: Telomeres are protective chromosomal ends. Short telomeres are a proven biomarker of biological aging. We aimed to find an association of telomere length and telomerase activity in circulating leukocytes and thromboaspirates of patients with acute myocardial infarction. Furthermore, association of the telomere-telomerase system with oxidative stress markers (as common risk factors for coronary artery disease (CAD)) was tested.<br><br>MATERIAL AND METHODS: Patients were selected from the patients admitted to the intensive care unit with acute myocardial infarction with ST-segment elevation (STEMI), with the following inclusion criteria - STEMI patients between 18 and 80 years old of both genders and candidates for primary percutaneous coronary intervention, with infarction pain present for a maximum of 12 h. In all the patients leukocyte telomere length, telomerase activity and scores related to oxidative-stress status (Protective, Damage and OXY) were evaluated.<br><br>RESULTS: Patients were divided into different groups: with stable angina pectoris (AP) (n = 22), acute myocardial infarction with: STEMI (n = 93), non-obstructive coronary arteries (MINOCA) (n = 7), blood vessel rupture (n = 6) at three time points, and compared to the group of 84 healthy subjects. Telomerase activity was significantly higher in all CAD sub-groups compared to the control group (AP = 0.373 (0.355-0.386), STEMI = 0.375 (0.349-0.395), MINOCA = 0.391 (0.366-0.401), blood vessel rupture = 0.360 (0.352-0.385) vs. CG = 0.069 (0.061-0.081), p < 0.001), while telomeres were significantly shorter in STEMI, MINOCA and blood vessel rupture groups compared to the control group (STEMI = 1.179 (0.931-1.376), MINOCA = 1.026 (0.951-1.070), blood vessel rupture = 1.089 (0.842-1.173) vs. CG = 1.329 (1.096-1.624), p = 0.030]. Values of OXY score were significantly higher in STEMI and MINOCA patients compared to the control group and AP patients (5.83 (4.55-7.54) and 10.28 (9.19-10.72) vs. 4.94 (3.29-6.18) and 4.18 (2.58-4.86), p < 0.001). Longer telomeres and higher telomerase activity were found in thromboaspirates, compared to the peripheral blood leukocytes in the same patients (1.25 (1.01-1.84) vs. 1.18 (0.909-1.516), p = 0.036; and 0.366 (0.367-0.379) vs. 0.366 (0.367-0.379), p < 0.001, respectively). In addition, telomere length and telomerase activity had good diagnostic ability to separate STEMI patients from healthy persons.<br><br>CONCLUSIONS: Leukocyte telomere length and telomerase activity can differentiate CAD patients from healthy persons, and relate CAD to oxidative stress.},
}
@article {pmid37118410,
year = {2021},
author = {Saraswati, S and Martínez, P and Graña-Castro, O and Blasco, MA},
title = {Short and dysfunctional telomeres sensitize the kidneys to develop fibrosis.},
journal = {Nature aging},
volume = {1},
number = {3},
pages = {269-283},
pmid = {37118410},
issn = {2662-8465},
mesh = {Mice ; Animals ; Humans ; *Telomerase/genetics ; Telomere/genetics ; Shelterin Complex ; Fibrosis ; Kidney/metabolism ; Folic Acid ; },
abstract = {Accumulation of short telomeres is a hallmark of aging. Mutations in telomerase or telomere-binding proteins lead to telomere shortening or dysfunction and are at the origin of human pathologies known as 'telomere syndromes', which are characterized by loss of the regenerative capacity of tissues and fibrotic pathologies. Here, we generated two mouse models of kidney fibrosis, either by combining telomerase deficiency to induce telomere shortening and a low dose of folic acid, or by conditionally deleting Trf1, a component of the shelterin telomere protective complex, from the kidneys. We find that short telomeres sensitize the kidneys to develop fibrosis in response to folic acid and exacerbate the epithelial-to-mesenchymal transition (EMT) program. Trf1 deletion in kidneys led to fibrosis and EMT activation. Our findings suggest that telomere shortening or dysfunction may contribute to pathological, age-associated renal fibrosis by influencing the EMT program.},
}
@article {pmid35986545,
year = {2022},
author = {Zafirovic, S and Macvanin, M and Stanimirovic, J and Obradovic, M and Radovanovic, J and Melih, I and Isenovic, E},
title = {Association Between Telomere Length and Cardiovascular Risk: Pharmacological Treatments Affecting Telomeres and Telomerase Activity.},
journal = {Current vascular pharmacology},
volume = {20},
number = {6},
pages = {465-474},
doi = {10.2174/1570161120666220819164240},
pmid = {35986545},
issn = {1875-6212},
mesh = {Humans ; *Telomerase/genetics/metabolism ; *Cardiovascular Diseases/diagnosis/drug therapy/genetics ; Risk Factors ; Telomere/genetics/metabolism ; Heart Disease Risk Factors ; },
abstract = {Telomeres represent the ends of chromosomes, and they are composed of an extensive number of - TTAGGG nucleotide sequence repeats in humans. Telomeres prevent chromosome degradation, participate in stabilization, and regulate the DNA repair system. Inflammation and oxidative stress have been identified as important processes causing cardiovascular disease and accelerating telomere shortening rate. This review investigates the link between telomere length and pathological vascular conditions from experimental and human studies. Also, we discuss pharmacological treatments affecting telomeres and telomerase activity.},
}
@article {pmid35983406,
year = {2022},
author = {Hoffmann, J and Tabata, N and Mas-Peiro, S and Spyridopoulos, I and Sinning, JM and Berkowitsch, A and Martin-Ruiz, C and Al-Kassou, B and Herrmann, E and Dimmeler, S and Zeiher, AM and Vasa-Nicotera, M},
title = {Longer leukocyte telomere length is associated with myeloid inflammation and increased mortality after transcatheter aortic valve replacement.},
journal = {European heart journal open},
volume = {2},
number = {4},
pages = {oeac045},
pmid = {35983406},
issn = {2752-4191},
abstract = {AIMS: Inflammatory activation of leukocytes may limit prognosis of patients (pts) with severe aortic valve stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Leukocyte telomere length (LTL) is a marker of proliferative capacity and inflammatory responsiveness but the impact of LTL on the prognosis in AS remains elusive. The aim of this study was to analyse the association of LTL with inflammatory markers and prognosis of pts undergoing TAVR.<br><br>METHODS AND RESULTS: LTL was analysed using quantitative real-time PCR in 285 consecutive pts (median age 82 years) undergoing TAVR and correlated with 18-month all-cause mortality. C-reactive protein was significantly elevated in pts with the longest LTL (P&#x2009;=&#x2009;0.017), paralleled by increased procalcitonin (PCT) serum levels (P&#x2009;=&#x2009;0.0006). This inflammatory reaction was accompanied by increased myeloid cells in the highest LTL tertile, mainly a rise in circulating neutrophils (P&#x2009;=&#x2009;0.0025) and monocytes (P&#x2009;=&#x2009;0.01). Multivariate analysis revealed LTL (HR 2.6, 95%CI 1.4-5.1, &#x2009;P=&#x2009;0.004) and PCT levels (HR 4.3, 95%CI 1.7-11.0, P&#x2009;=&#x2009;0.003) as independent predictors of mortality.<br><br>CONCLUSIONS: Longer LTL is associated with increased mortality after TAVR. This might be explained by enhanced proliferative capacity of cells resulting in myeloid and systemic inflammation. Our findings suggest that targeting the specific inflammation pathways could present a novel strategy to augment survival in selected patients with degenerative aortic stenosis.},
}
@article {pmid35977791,
year = {2022},
author = {Romero-Haro, A&#xc1; and Morger, J and Haussmann, MF and Tschirren, B},
title = {Reproductive Strategies Affect Telomere Dynamics across the Life Course.},
journal = {The American naturalist},
volume = {200},
number = {3},
pages = {373-382},
doi = {10.1086/720440},
pmid = {35977791},
issn = {1537-5323},
mesh = {Adult ; Aging/genetics ; Animals ; *Coturnix/genetics ; Humans ; Infant, Newborn ; *Life Change Events ; Male ; Reproduction ; Telomere ; },
abstract = {AbstractBecause parental care has a heritable basis, the benefits of receiving increased parental provisioning early in life are genetically linked to the costs of providing increased parental provisioning at adulthood. Reproductive strategies thus result in distinct cost-benefit syndromes across the life course that may shape individual health and aging trajectories. Here we used an artificial selection approach in Japanese quail (Coturnix japonica) to test how reproductive strategies affect telomere length, a biomarker of somatic state, at different life stages. We show that males but not females from lines selected for low maternal investment (i.e., developing in a relatively small egg) had shorter telomeres at birth. These patterns were still weakly present at the end of the juvenile growth period. In contrast, significantly shorter telomeres were found in reproductively active adult birds from the high-investment lines, suggesting that telomere attrition was accelerated in these individuals once they had become reproductively active. Our study shows that reproductive strategies differentially affect telomere dynamics across the life course, highlighting the role of cross-generational constraints in shaping individual aging trajectories.},
}
@article {pmid35974160,
year = {2023},
author = {Petermann-Rocha, F and Valera-Gran, D and Fernández-Pires, P and Martens, DS and Júlvez, J and Rodríguez-Dehli, C and Andiarena, A and Lozano, M and Fernández-Somoano, A and Lertxundi, A and Llop, S and Guxens, M and Nawrot, TS and Navarrete-Muñoz, EM},
title = {Children who sleep more may have longer telomeres: evidence from a longitudinal population study in Spain.},
journal = {Pediatric research},
volume = {93},
number = {5},
pages = {1419-1424},
pmid = {35974160},
issn = {1530-0447},
mesh = {Humans ; Child ; Child, Preschool ; Cohort Studies ; Spain ; Cross-Sectional Studies ; *Sleep ; *Telomere ; },
abstract = {BACKGROUND: Inadequate sleep duration has been suggested as a chronic stressor associated with changes in telomere length (TL). This study aimed to explore the association between sleep duration and TL using the INMA birth cohort study data.<br><br>METHODS: A total of 1014 children were included in this study (cross-sectional: 686; longitudinal: 872). Sleep duration (h/day) was reported by caregivers at 4 years and classified into tertiles (7-10&#x2009;h/day; >10-11&#x2009;h/day; >11-14&#x2009;h/day). Leucocyte TL at 4 and 7-9 years were measured using quantitative PCR methods. Multiple robust linear regression models, through log-level regression models, were used to report the % of difference among tertiles of sleep duration.<br><br>RESULTS: In comparison to children who slept between >10 and 11&#x2009;h/day, those in the highest category (more than 11&#x2009;h/day) had 8.5% (95% CI: 3.56-13.6) longer telomeres at 4 years. Longitudinal analysis showed no significant association between sleep duration at 4 years and TL at 7-9 years.<br><br>CONCLUSION: Children who slept more hours per day had longer TL at 4 years independently of a wide range of confounder factors. Environmental conditions, such as sleep duration, might have a major impact on TL during the first years of life.<br><br>IMPACT: Telomere length was longer in children with longer sleep duration (>11&#x2009;h/day) independently of a wide range of confounder factors at age 4 and remained consistent by sex. Sleep routines are encouraged to promote positive child development, like the number of hours of sleep duration. Considering the complex biology of telomere length, future studies still need to elucidate which biological pathways might explain the association between sleep duration and telomere length.},
}
@article {pmid35968296,
year = {2022},
author = {Maroon, JC},
title = {The effect of hyperbaric oxygen therapy on cognition, performance, proteomics, and telomere length-The difference between zero and one: A case report.},
journal = {Frontiers in neurology},
volume = {13},
number = {},
pages = {949536},
pmid = {35968296},
issn = {1664-2295},
abstract = {INTRODUCTION: Hyperbaric oxygen (HBO2) therapy has recently been suggested for the treatment of different brain injuries as well as for physical and cognitive enhancement. The author recently carried out a self-experiment to obtain objective information on the effects of HBO2 therapy on neurocognition, cardiopulmonary function, neuroimaging and its effect on novel biomarkers such as telomere length and proteomics. In the following case report, the author will present and discuss the results and the differences between zero and one.<br><br>METHODS: This is a personal case report on a single subject, myself, who underwent a protocol of 60 daily HBO2 therapy sessions within 3 months. Pre- and post-therapy objective evaluation measured included computerized cognitive assessment, brain imaging, cardiopulmonary exercise test, physical assessments and blood tests including telomere length and proteomics.<br><br>RESULTS: Neurocognitive results showed a 3.1-3.8% improvements in global cognitive function as well as all other cognitive function domains. In the perfusion MRI, there was a relative increase ranging from 43.3 to 52.3% in cerebral perfusion in various areas subserving memory, coordination, and visual motor cortex function. Similar improvements in cerebral perfusion were seen in the SPECT scans, which ranged from 8.79 to 16.12% increased perfusion in the temporal pole and entorhinal cortex subserving memory, as well as in the subcallosal area and lingual gyrus. MRI-DTI showed prominent increases in fractional anisotropy in several white matter areas including 9% in the body of the corpus callosum, 16.85% in for the fornix and 22.06% in the tapetum. In the physical domains, there were improvements in both anaerobic threshold, exercise endurance, muscle strength, gait speed and grip strength in the 7-15% range. The telomeres length was doubled and clusters of inflammatory proteins dropped around the 40th session and remained low at the 60th session.<br><br>CONCLUSION: The difference between zero and one in this single case study of HBO2 therapy confirmed improvement in objective biomarkers which measured cognition, memory, brain processing speed, athletic performance and neuroimaging modalities measuring cerebral perfusion, blood flow and tractography. Additional studies with larger sample size and randomized clinical trials using similar biomarkers are needed to confirm the results and to delineate the longevity of these improvements.},
}
@article {pmid35959813,
year = {2022},
author = {Byrjalsen, A and Bygum, A and Lautrup, CK and Frederiksen, AL and Fialla, AD and Raaschou-Jensen, K and Bendstrup, E and Madsen, TN and Klarskov, M and Jelsig, AM},
title = {[Telomere biology disorders].},
journal = {Ugeskrift for laeger},
volume = {184},
number = {28},
pages = {},
pmid = {35959813},
issn = {1603-6824},
mesh = {Adult ; Biology ; Child ; *Diet, Ketogenic ; *Epilepsy/therapy ; Humans ; Telomere ; *Vagus Nerve Stimulation ; },
abstract = {The end of the chromosomes consists of DNA referred to as telomeres. The telomeres protect chromosomal DNA against shortening when cells divide. Patients with telomere biology disorders carry pathogenic germline variants in a gene involved in telomere function. New technologic advances have enabled us to identify more patients with telomere biology disorders, which in turn have increased our understanding of the phenotypic spectrum. The latter have proved wider than previously thought, and now we know that e.g. patients with isolated lung fibrosis can have an underlying telomere biology disorder.},
}
@article {pmid35953846,
year = {2022},
author = {Kim, S and Chowdhury, T and Yu, HJ and Kahng, JY and Lee, CE and Choi, SA and Kim, KM and Kang, H and Lee, JH and Lee, ST and Won, JK and Kim, KH and Kim, MS and Lee, JY and Kim, JW and Kim, YH and Kim, TM and Choi, SH and Phi, JH and Shin, YK and Ku, JL and Lee, S and Yun, H and Lee, H and Kim, D and Kim, K and Hur, JK and Park, SH and Kim, SK and Park, CK},
title = {The telomere maintenance mechanism spectrum and its dynamics in gliomas.},
journal = {Genome medicine},
volume = {14},
number = {1},
pages = {88},
pmid = {35953846},
issn = {1756-994X},
mesh = {*Glioma/genetics ; Humans ; Mutation ; *Telomerase/genetics ; Telomere/genetics ; Telomere Homeostasis ; },
abstract = {BACKGROUND: The activation of the telomere maintenance mechanism (TMM) is one of the critical drivers of cancer cell immortality. In gliomas, TERT expression and TERT promoter mutation are considered to reliably indicate telomerase activation, while ATRX mutation and/or loss indicates an alternative lengthening of telomeres (ALT). However, these relationships have not been extensively validated in tumor tissues.<br><br>METHODS: Telomerase repeated amplification protocol (TRAP) and C-circle assays were used to profile and characterize the TMM cross-sectionally (n = 412) and temporally (n = 133) across glioma samples. WES, RNA-seq, and NanoString analyses were performed to identify and validate the genetic characteristics of the TMM groups.<br><br>RESULTS: We show through the direct measurement of telomerase activity and ALT in a large set of glioma samples that the TMM in glioma cannot be defined solely by the combination of telomerase activity and ALT, regardless of TERT expression, TERT promoter mutation, and ATRX loss. Moreover, we observed that a considerable proportion of gliomas lacked both telomerase activity and ALT. This telomerase activation-negative and ALT negative group exhibited evidence of slow growth potential. By analyzing a set of longitudinal samples from a separate cohort of glioma patients, we discovered that the TMM is not fixed and can change with glioma progression.<br><br>CONCLUSIONS: This study suggests that the TMM is dynamic and reflects the plasticity and oncogenicity of tumor cells. Direct measurement of telomerase enzyme activity and evidence of ALT should be considered when defining TMM. An accurate understanding of the TMM in glioma is expected to provide important information for establishing cancer management strategies.},
}
@article {pmid35950364,
year = {2022},
author = {Lundsgaard, NU and Cramp, RL and Franklin, CE},
title = {Early exposure to UV radiation causes telomere shortening and poorer condition later in life.},
journal = {The Journal of experimental biology},
volume = {225},
number = {17},
pages = {},
pmid = {35950364},
issn = {1477-9145},
support = {DP190102152//Australian Research Council/ ; //Australian Government/ ; //The University of Queensland/ ; },
mesh = {Animals ; Anura/genetics ; Australia ; Larva/genetics ; Metamorphosis, Biological ; *Telomere Shortening ; *Ultraviolet Rays/adverse effects ; },
abstract = {Determining the contribution of elevated ultraviolet-B radiation (UVBR; 280-315 nm) to amphibian population declines is being hindered by a lack of knowledge about how different acute UVBR exposure regimes during early life-history stages might affect post-metamorphic stages via long-term carryover effects. We acutely exposed tadpoles of the Australian green tree frog (Litoria caerulea) to a combination of different UVBR irradiances and doses in a multi-factorial laboratory experiment, and then reared them to metamorphosis in the absence of UVBR to assess carryover effects in subsequent juvenile frogs. Dose and irradiance of acute UVBR exposure influenced carryover effects into metamorphosis in somewhat opposing manners. Higher doses of UVBR exposure in larvae yielded improved rates of metamorphosis. However, exposure at a high irradiance resulted in frogs metamorphosing smaller in size and in poorer condition than frogs exposed to low and medium irradiance UVBR as larvae. We also demonstrate some of the first empirical evidence of UVBR-induced telomere shortening in vivo, which is one possible mechanism for life-history trade-offs impacting condition post-metamorphosis. These findings contribute to our understanding of how acute UVBR exposure regimes in early life affect later life-history stages, which has implications for how this stressor may shape population dynamics.},
}
@article {pmid35949423,
year = {2022},
author = {Yu, HJ and Koh, SH},
title = {Is Telomere Length Shortening a Risk Factor for Neurodegenerative Disorders?.},
journal = {Dementia and neurocognitive disorders},
volume = {21},
number = {3},
pages = {83-92},
pmid = {35949423},
issn = {2384-0757},
abstract = {Telomeres are located at the end of chromosomes. They are known to protect chromosomes and prevent cellular senescence. Telomere length shortening has been considered an important marker of aging. Many studies have reported this concept in connection with neurodegenerative disorders. Considering the role of telomeres, it seems that longer telomeres are beneficial while shorter telomeres are detrimental in preventing neurodegenerative disorders. However, several studies have shown that people with longer telomeres might also be vulnerable to neurodegenerative disorders. Before these conflicting results can be explained through large-scale longitudinal clinical studies on the role of telomere length in neurodegenerative disorders, it would be beneficial to simultaneously review these opposing results. Understanding these conflicting results might help us plan future studies to reveal the role of telomere length in neurodegenerative disorders. In this review, these contradictory findings are thoroughly discussed, with the aim to better understand the role of telomere length in neurodegenerative disorders.},
}
@article {pmid35948770,
year = {2022},
author = {Olson, CL and Barbour, AT and Wuttke, DS},
title = {Filling in the blanks: how the C-strand catches up to the G-strand at replicating telomeres using CST.},
journal = {Nature structural &amp; molecular biology},
volume = {29},
number = {8},
pages = {730-733},
pmid = {35948770},
issn = {1545-9985},
support = {R24 OD033699/OD/NIH HHS/United States ; T32 GM008759/GM/NIGMS NIH HHS/United States ; },
mesh = {*Telomerase/genetics/metabolism ; *Telomere/genetics/metabolism ; Telomere-Binding Proteins/metabolism ; },
}
@article {pmid35947933,
year = {2022},
author = {Natalini, JG and England, BR and Baker, JF and Chen, Q and Singh, N and Mahajan, TD and Roul, P and Thiele, GM and Sauer, BC and Mikuls, TR and Johnson, FB and Kawut, SM},
title = {Associations between shortened telomeres and rheumatoid arthritis-associated interstitial lung disease among U.S. Veterans.},
journal = {Respiratory medicine},
volume = {201},
number = {},
pages = {106943},
pmid = {35947933},
issn = {1532-3064},
support = {IK2 CX002203/CX/CSRD VA/United States ; I01 CX001703/CX/CSRD VA/United States ; IK6 BX004600/BX/BLRD VA/United States ; T32 HL007891/HL/NHLBI NIH HHS/United States ; K24 HL103844/HL/NHLBI NIH HHS/United States ; U54 GM115458/GM/NIGMS NIH HHS/United States ; I01 BX004660/BX/BLRD VA/United States ; },
mesh = {*Arthritis, Rheumatoid/complications/epidemiology/genetics ; Cross-Sectional Studies ; Female ; Humans ; *Lung Diseases, Interstitial/etiology/genetics ; Male ; Telomere/genetics ; Telomere Shortening ; *Veterans ; },
abstract = {BACKGROUND: Shortened telomeres are associated with several different subtypes of interstitial lung disease (ILD), although studies of telomere length and ILD in rheumatoid arthritis (RA) are lacking.<br><br>METHODS: Within the Veterans Affairs Rheumatoid Arthritis (VARA) registry, we performed cross-sectional and case-control studies of prevalent and incident ILD, respectively. We randomly selected a subset of RA patients with ILD and individually matched them to RA patients without ILD according to age, sex, and VARA enrollment date. Telomere length was measured on peripheral blood leukocytes collected at registry enrollment using quantitative PCR (T/S ratio). Short telomeres were defined as a T/S ratio in the lowest 10th percentile of the cohort.<br><br>RESULTS: Our cross-sectional study cohort was comprised of 54 RA-ILD patients and 92 RA-non-ILD patients. T/S ratios significantly differed between patients with and without prevalent ILD (1.56 [IQR 1.30, 1.78] vs. 1.96 [IQR 1.65, 2.27], p <&#xa0;0.001). Similarly, prevalence of ILD was significantly higher in patients with short vs. normal-length telomeres (73.3% vs. 32.8%, p&#xa0;=&#xa0;0.002). Short telomeres were independently associated with an increased odds of prevalent ILD compared to normal-length telomeres (adjusted OR 6.60, 95% CI 1.78-24.51, p&#xa0;=&#xa0;0.005). In our case-control analysis, comprised of 22 incident RA-ILD cases and 36 RA-non-ILD controls, short telomeres were not associated with incident RA-ILD (adjusted OR 0.90, 95% CI 0.06-13.4, p&#xa0;=&#xa0;0.94).<br><br>CONCLUSION: Short telomeres were strongly associated with prevalent but not incident ILD among patients with RA. Additional studies are needed to better understand telomere length dynamics among RA patients with and without ILD.},
}
@article {pmid35947641,
year = {2022},
author = {Macha, SJ and Koneru, B and Burrow, TA and Zhu, C and Savitski, D and Rahman, RL and Ronaghan, CA and Nance, J and McCoy, K and Eslinger, C and Reynolds, CP},
title = {Alternative Lengthening of Telomeres in Cancer Confers a Vulnerability to Reactivation of p53 Function.},
journal = {Cancer research},
volume = {82},
number = {18},
pages = {3345-3358},
pmid = {35947641},
issn = {1538-7445},
support = {R01 CA264949/CA/NCI NIH HHS/United States ; R01 CA217251/CA/NCI NIH HHS/United States ; R01 CA221957/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; *Carcinoma ; Humans ; Irinotecan ; Mice ; *Neuroblastoma/drug therapy/genetics ; *Sarcoma/genetics ; *Telomerase/genetics ; Telomere/genetics/metabolism ; Telomere Homeostasis/genetics ; Tumor Suppressor Protein p53/genetics/metabolism ; },
abstract = {UNLABELLED: A subset of cancers across multiple histologies with predominantly poor outcomes use the alternative lengthening of telomeres (ALT) mechanism to maintain telomere length, which can be identified with robust biomarkers. ALT has been reported to be prevalent in high-risk neuroblastoma and certain sarcomas, and ALT cancers are a major clinical challenge that lack targeted therapeutic approaches. Here, we found ALT in a variety of pediatric and adult cancer histologies, including carcinomas. Patient-derived ALT cancer cell lines from neuroblastomas, sarcomas, and carcinomas were hypersensitive to the p53 reactivator eprenetapopt (APR-246) relative to telomerase-positive (TA+) models. Constitutive telomere damage signaling in ALT cells activated ataxia-telangiectasia mutated (ATM) kinase to phosphorylate p53, which resulted in selective ALT sensitivity to APR-246. Treatment with APR-246 combined with irinotecan achieved complete responses in mice xenografted with ALT neuroblastoma, rhabdomyosarcoma, and breast cancer and delayed tumor growth in ALT colon cancer xenografts, while the combination had limited efficacy in TA+ tumor models. A large number of adult and pediatric cancers present with the ALT phenotype, which confers a uniquely high sensitivity to reactivation of p53. These data support clinical evaluation of a combinatorial approach using APR-246 and irinotecan in ALT patients with cancer.<br><br>SIGNIFICANCE: This work demonstrates that constitutive activation of ATM in chemotherapy-refractory ALT cancer cells renders them hypersensitive to reactivation of p53 function by APR-246, indicating a potential strategy to overcome therapeutic resistance.},
}
@article {pmid35947638,
year = {2022},
author = {Lemaître, JF and Gaillard, JM and Gilson, E},
title = {Telomeres as a sentinel of population decline in the context of global warming.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {119},
number = {35},
pages = {e2211349119},
pmid = {35947638},
issn = {1091-6490},
mesh = {Animals ; *Extinction, Biological ; *Global Warming ; *Lizards/genetics ; Population Dynamics ; Sentinel Species ; *Telomere/genetics ; },
}
@article {pmid35942347,
year = {2022},
author = {Zhang, JM and Zou, L},
title = {Protocol to stimulate and delineate alternative lengthening of telomeres in human U2OS cells.},
journal = {STAR protocols},
volume = {3},
number = {3},
pages = {101594},
pmid = {35942347},
issn = {2666-1667},
mesh = {DNA Replication ; Humans ; *Telomerase/genetics ; *Telomere/genetics ; },
abstract = {Alternative lengthening of telomeres (ALT) is a telomerase-independent but recombination-dependent pathway that maintains telomeres. Here, we describe a protocol to stimulate the formation of ALT-associated PML bodies (APBs) and ALT activity by tethering PML-IV to telomeres in human U2OS cells. Through immunofluorescence, in situ hybridization, and microscopy, we analyze dynamics of telomere clustering, visualize recruitment of DNA repair proteins to APBs, and measure telomere DNA synthesis during ALT. This protocol provides a unique approach to delineate the ALT pathway. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2021).},
}
@article {pmid35939862,
year = {2022},
author = {Woo, JMP and Parks, CG and Hyde, EE and Auer, PL and Simanek, AM and Konkel, RH and Taylor, J and Sandler, DP and Meier, HCS},
title = {Early life trauma and adult leucocyte telomere length.},
journal = {Psychoneuroendocrinology},
volume = {144},
number = {},
pages = {105876},
pmid = {35939862},
issn = {1873-3360},
support = {Z01 ES044005/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adult ; Child ; Female ; Humans ; Leukocytes ; Life Change Events ; Prospective Studies ; *Telomere ; *Telomere Shortening ; },
abstract = {BACKGROUND: Telomere length, a biomarker of cell division and cellular aging, has been associated with multiple chronic disease endpoints. Experienced trauma over the life course may contribute to telomere shortening via mechanisms of stress embodiment. However, it is unclear how patterns of co-occurring trauma during sensitive periods (e.g., early life) throughout the life course may influence telomere shortening. We examine the relationship between co-occurring early life trauma on adult telomere length and the extent to which adulthood trauma, socioeconomic position, and health and lifestyle factors may mediate this relationship.<br><br>METHODS: We use data from a sample of participants in the Sister Study (N&#xa0;=&#xa0;740, analytic sample: n&#xa0;=&#xa0;602), a prospective cohort of U.S. self-identified females aged 35-74 years at enrollment (2003-2009) for whom leukocyte telomere length was measured in baseline blood samples. Participants reported their experience of 20 different types of trauma, from which we identified patterns of co-occurring early life trauma (before age 18) using latent class analysis. We estimated the direct and indirect effects of early life trauma on leukocyte telomere length using structural equation modeling, allowing for mediating adult pathways.<br><br>RESULTS: Approximately 47 % of participants reported early life trauma. High early life trauma was associated with shorter telomere length compared to low early life trauma (&#x3b2;&#xa0;=&#xa0;-0.11; 95 % CI: -0.22, -0.004) after adjusting for age and childhood socioeconomic position. The inverse association between early life trauma and adult leukocyte telomere length was largely attributable to the direct effect of early life trauma on telomere length (&#x3b2;&#xa0;=&#xa0;-0.12; 95 %CI: -0.23, -0.01). Mediating indirect pathways via adult trauma, socioeconomic position, and health metrics did not substantively contribute the overall association.<br><br>CONCLUSIONS: These findings highlight the role of patterns of co-occurring early life trauma on shortened telomere length independent of adult pathways.},
}
@article {pmid35939680,
year = {2022},
author = {Dupoué, A and Blaimont, P and Angelier, F and Ribout, C and Rozen-Rechels, D and Richard, M and Miles, D and de Villemereuil, P and Rutschmann, A and Badiane, A and Aubret, F and Lourdais, O and Meylan, S and Cote, J and Clobert, J and Le Galliard, JF},
title = {Lizards from warm and declining populations are born with extremely short telomeres.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {119},
number = {33},
pages = {e2201371119},
pmid = {35939680},
issn = {1091-6490},
mesh = {*Aging/genetics ; Animals ; *Extinction, Biological ; Female ; *Global Warming ; *Lizards/genetics ; Population Dynamics ; Reproduction ; Risk ; *Telomere/genetics ; *Telomere Shortening ; },
abstract = {Aging is the price to pay for acquiring and processing energy through cellular activity and life history productivity. Climate warming can exacerbate the inherent pace of aging, as illustrated by a faster erosion of protective telomere DNA sequences. This biomarker integrates individual pace of life and parental effects through the germline, but whether intra- and intergenerational telomere dynamics underlies population trends remains an open question. Here, we investigated the covariation between life history, telomere length (TL), and extinction risk among three age classes in a cold-adapted ectotherm (Zootoca vivipara) facing warming-induced extirpations in its distribution limits. TL followed the same threshold relationships with population extinction risk at birth, maturity, and adulthood, suggesting intergenerational accumulation of accelerated aging rate in declining populations. In dwindling populations, most neonates inherited already short telomeres, suggesting they were born physiologically old and unlikely to reach recruitment. At adulthood, TL further explained females' reproductive performance, switching from an index of individual quality in stable populations to a biomarker of reproductive costs in those close to extirpation. We compiled these results to propose the aging loop hypothesis and conceptualize how climate-driven telomere shortening in ectotherms may accumulate across generations and generate tipping points before local extirpation.},
}
@article {pmid35939618,
year = {2022},
author = {Quque, M and Ferreira, C and Sosa, S and Schull, Q and Zahn, S and Criscuolo, F and Bleu, J and Viblanc, VA},
title = {Cascading Effects of Conspecific Aggression on Oxidative Status and Telomere Length in Zebra Finches.},
journal = {Physiological and biochemical zoology : PBZ},
volume = {95},
number = {5},
pages = {416-429},
doi = {10.1086/721252},
pmid = {35939618},
issn = {1537-5293},
mesh = {Aggression/physiology ; Animals ; *Finches/physiology ; Oxidative Stress ; *Physical Conditioning, Animal ; Telomere ; },
abstract = {Living in social groups may exacerbate interindividual competition for territory, food, and mates, leading to stress and possible health consequences. Unfavorable social contexts have been shown to elevate glucocorticoid levels (often used as biomarkers of individual stress), but the downstream consequences of socially stressful environments are rarely explored. Our study experimentally tests the mechanistic links between social aggression, oxidative stress, and somatic maintenance in captive zebra finches (Taeniopygia guttata). Over 64 d, we measured the effects of aggression (received or emitted) on the individual oxidative status, body condition, and changes in relative telomere length (rTL) of birds living in high- and low-social-density conditions. Using path analyses, we found that birds living at high social density increased their aggressive behavior. Birds receiving the highest number of aggressions exhibited the strongest activation of antioxidant defenses and highest plasmatic levels of reactive oxygen metabolites. In turn, this prevented birds from maintaining or restoring telomere length between the beginning and the end of the experiment. Received aggression also had a direct negative effect on changes in rTL, unrelated to oxidative stress. In contrast, emitted aggression had no significant effect on individual oxidative stress or changes in rTL. Body condition did not appear to affect the physiological response to aggression or oxidative stress. At low density, we found trends that were similar to those at high density but nonsignificant. Our study sheds light on the causal chain linking the social environment and aggressive behavior to individual oxidative stress and telomere length. The long-term consequences of socially induced stress on fitness remain to be characterized.},
}
@article {pmid35938805,
year = {2022},
author = {Moazamian, A and Gharagozloo, P and Aitken, RJ and Drevet, JR},
title = {OXIDATIVE STRESS AND REPRODUCTIVE FUNCTION: Sperm telomeres, oxidative stress, and infertility.},
journal = {Reproduction (Cambridge, England)},
volume = {164},
number = {6},
pages = {F125-F133},
doi = {10.1530/REP-22-0189},
pmid = {35938805},
issn = {1741-7899},
mesh = {Male ; Humans ; Reactive Oxygen Species/metabolism ; *Antioxidants/metabolism ; *Infertility, Male/metabolism ; Semen/metabolism ; Spermatozoa/metabolism ; Oxidative Stress ; Telomere/metabolism ; Guanine/metabolism ; DNA ; Deoxyguanosine/metabolism ; Biomarkers/metabolism ; },
abstract = {IN BRIEF: Oxidative stress is recognized as an underlying driving factor of both telomere dysfunction and human subfertility/infertility. This review briefly reassesses telomere integrity as a fertility biomarker before proposing a novel, mechanistic rationale for the role of oxidative stress in the seemingly paradoxical lengthening of sperm telomeres with aging.<br><br>ABSTRACT: The maintenance of redox balance in the male reproductive tract is critical to sperm health and function. Physiological levels of reactive oxygen species (ROS) promote sperm capacitation, while excess ROS exposure, or depleted antioxidant defenses, yields a state of oxidative stress which disrupts their fertilizing capacity and DNA structural integrity. The guanine moiety is the most readily oxidized of the four DNA bases and gets converted to the mutagenic lesion 8-hydroxy-deoxyguanosine (8-OHdG). Numerous studies have also confirmed oxidative stress as a driving factor behind accelerated telomere shortening and dysfunction. Although a clear consensus has not been reached, clinical studies also appear to associate telomere integrity with fertility outcomes in the assisted reproductive technology setting. Intriguingly, while sperm cellular and molecular characteristics make them more susceptible to oxidative insult than any other cell type, they are also the only cell type in which telomere lengthening accompanies aging. This article focuses on the oxidative stress response pathways to propose a mechanism for the explanation of this apparent paradox.},
}
@article {pmid35934479,
year = {2022},
author = {Paul, T and Myong, S},
title = {Helicase mediated vectorial folding of telomere G-quadruplex.},
journal = {Methods in enzymology},
volume = {672},
number = {},
pages = {283-297},
doi = {10.1016/bs.mie.2022.03.065},
pmid = {35934479},
issn = {1557-7988},
support = {R01 GM115631/GM/NIGMS NIH HHS/United States ; R01 CA207342/CA/NCI NIH HHS/United States ; RF1 NS113636/NS/NINDS NIH HHS/United States ; },
mesh = {DNA Helicases/metabolism ; *G-Quadruplexes ; Shelterin Complex ; *Telomerase/metabolism ; Telomere/genetics/metabolism ; Telomere-Binding Proteins/chemistry/genetics/metabolism ; },
abstract = {The G-rich single-stranded telomere overhang can self-fold into G-quadruplex (G4) structure both in vivo and in vitro. In somatic cells, telomeres shorten progressively due to the end-replication. In stem cells, however, telomeres are replenished by a special enzyme, telomerase which synthesizes single-stranded telomere overhang. The active extension by the telomerase releases G-rich overhang segmentally in 5' to 3' direction as the overhang folds into G4 structure after successive elongation. To replicate such vectorial G4 folding process, we employed a superhelicase, Rep-X to release the G-rich sequence gradually. Using single-molecule assay we demonstrated that the folded conformation achieved by the vectorial folding is inherently different from the post-folding where the entire overhang is allowed to fold at once. In addition, the vectorially folded overhangs are less stable and more accessible to a complementary C-rich strand and the telomere binding protein, POT1 compared to the post-folded state. The higher accessibility may have implications for the facile loading of shelterin proteins after DNA replication.},
}
@article {pmid35934145,
year = {2022},
author = {Lai, X and Yuan, Y and Liu, M and Xiao, Y and Ma, L and Guo, W and Fang, Q and Yang, H and Hou, J and Yang, L and Yang, H and He, MA and Guo, H and Zhang, X},
title = {Individual and joint associations of co-exposure to multiple plasma metals with telomere length among middle-aged and older Chinese in the Dongfeng-Tongji cohort.},
journal = {Environmental research},
volume = {214},
number = {Pt 3},
pages = {114031},
doi = {10.1016/j.envres.2022.114031},
pmid = {35934145},
issn = {1096-0953},
mesh = {Aged ; *Aluminum ; Bayes Theorem ; China ; Humans ; *Manganese ; Middle Aged ; Telomere ; Vanadium/toxicity ; },
abstract = {Studies on associations of metals with leucocyte telomere length (LTL) were mainly limited to several most common toxic metals and single-metal effect, but the impact of other common metals and especially the overall joint associations and interactions of metal mixture with LTL are largely unknown. We included 15 plasma metals and LTL among 4906 participants from Dongfeng-Tongji cohort. Multivariable linear regression was used to estimate associations of individual metals with LTL. We also applied Bayesian kernel machine regression (BKMR) and quantile g-computation regression (Q-g) to evaluate the overall association and interactions, and identified the major contributors as well as the potential modifications by major characteristics. Multivariable linear regression found vanadium, copper, arsenic, aluminum and nickel were negatively associated with LTL, and a 2-fold change was related to 1.9%-5.1% shorter LTL; while manganese and zinc showed 3.7% and 4.0% longer LTL (all P < 0.05) in multiple-metal models. BKMR confirmed above metals and revealed a linearly inverse joint association between 15 metals and LTL. Q-g regression further indicated each quantile increase in mixture was associated with 5.2% shorter LTL (95% CI: -8.1%, -2.3%). Furthermore, manganese counteracted against aluminum and vanadium respectively (Pint<0.05). In addition, associations of vanadium, aluminum and metal mixture with LTL were more prominent in overweight participants. Our results are among the first to provide a new comprehensive view of metal mixture exposure on LTL attrition in the general population, including identifying the major components, metals interactions and the overall effects.},
}
@article {pmid35933575,
year = {2022},
author = {Fan, Y and Guo, Y and Zhong, J and Chi, H and Zhao, X and Su, P and Gao, J and Chen, M},
title = {The association between visceral adiposity index and leukocyte telomere length in adults: results from National Health and Nutrition Examination Survey.},
journal = {Aging clinical and experimental research},
volume = {34},
number = {9},
pages = {2177-2183},
pmid = {35933575},
issn = {1720-8319},
support = {81870310//National Natural Science Foundation of China/ ; 81200194//National Natural Science Foundation of China/ ; },
mesh = {*Adiposity/genetics ; Humans ; *Leukocytes ; Nutrition Surveys ; Obesity, Abdominal ; Risk Factors ; Telomere/genetics ; United States ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) is a robust marker of biological aging, which is associated with obesity. Recently, the visceral adiposity index (VAI) has been proposed as an indicator of adipose distribution and function.<br><br>OBJECTIVE: To evaluated the association between VAI and LTL in adult Americans.<br><br>METHODS: There were 3193 participants in U.S. National Health and Nutrition Examination Surveys (1999-2002) included in this analysis. LTL was measured using quantitative PCR (qPCR) and expressed as telomere to single-gene copy ratio (T/S ratio). We performed multiple logistic regression models to explore the association between VAI and LTL by adjusting for potential confounders.<br><br>RESULTS: Among all participants, VAI was associated with the shorter LTL (&#x3b2;: &#x2009;-&#x2009;14.81, 95% CI &#x2009;-&#x2009;22.28 to &#x2009;-&#x2009;7.34, p&#x2009;<&#x2009;0.001). There were significant differences of LTL in VAI tertiles (p&#x2009;<&#x2009;0.001). Participants in the higher VAI tertile had the shorter LTL (1.26&#x2009;&#x2264;&#x2009;VAI&#x2009;<&#x2009;2.46: &#x3b2;&#x2009;=&#x2009;&#x2009;-&#x2009;130.16, 95% CI [&#x2009;-&#x2009;183.44, &#x2009;-&#x2009;76.87]; VAI&#x2009;&#x2265;&#x2009;2.46: &#x3b2;&#x2009;=&#x2009;&#x2009;-&#x2009;216.12, 95% CI [&#x2009;-&#x2009;216.12, &#x2009;-&#x2009;81.42], p for trend:&#x2009;<&#x2009;0.001) comparing with the lower VAI tertile. We also found a non-linear relationship between VAI and LTL. VAI was negatively correlated with LTL when VAI was less than 2.84.<br><br>CONCLUSIONS: The present study demonstrates that VAI is independently associated with telomere length. A higher VAI is associated with shorter LTL. The results suggest that VAI may provide prediction for LTL and account for accelerating the biological aging.},
}
@article {pmid35932977,
year = {2022},
author = {Zheng, Y and Zhang, N and Wang, Y and Wang, F and Li, G and Tse, G and Liu, T},
title = {Association between leucocyte telomere length and the risk of atrial fibrillation: An updated systematic review and meta-analysis.},
journal = {Ageing research reviews},
volume = {81},
number = {},
pages = {101707},
doi = {10.1016/j.arr.2022.101707},
pmid = {35932977},
issn = {1872-9649},
mesh = {*Atrial Fibrillation/epidemiology/genetics ; *Biological Products ; Female ; Humans ; Leukocytes ; Male ; Telomere/genetics ; Telomere Shortening ; },
abstract = {BACKGROUND AND AIMS: Advancing age is the most important risk factor of atrial fibrillation (AF). The shortening of telomere length is a biomarker of biologic aging. There is an increasing body of evidence that leucocyte telomere length (LTL) is associated with the risk of AF development. However, the results in these studies were controversial. The current systematic review and meta-analysis was conducted to examine the role of LTL in predicting the incidence of AF.<br><br>METHODS AND RESULTS: Observational studies reporting the association between LTL and the risk of AF were retrieved through 25th June, 2022 from PubMed and Embase. A total of twelve studies including 18,293 patients were included in the present analysis. Leucocyte telomere shortening was found to be an independent predictor of AF as a continuous variable in both univariate [OR:2.14; 95%CI(1.48,3.10); P&#xa0;<&#xa0;0.0001] and multivariate analyses [OR:1.41;95%CI(1.11,1.79); P&#xa0;=&#xa0;0.005], as well as categorical variable in multivariate analysis [OR:1.53; 95%CI(1.04,2.27); P&#xa0;=&#xa0;0.03]. Furthermore, leucocyte telomere shortening was significantly associated with recurrent AF [OR:4.32;95%CI(2.42,7.69); P&#xa0;<&#xa0;0.00001] but not new-onset AF [OR:1.14; 95%CI(0.90,1.45); P&#xa0;=&#xa0;0.29]. Leucocyte telomere shortening was also associated with an increased risk of persistent AF [OR:14.73;95%CI (3.16,68.67); P&#xa0;=&#xa0;0.0006] and paroxysmal AF [OR:2.74;95%CI(1.45,5.18); P&#xa0;=&#xa0;0.002]. Besides, LTL was an independent predictor for progression from paroxysmal AF to persistent AF [OR:3.2;95%CI(1.66,6.18); P&#xa0;=&#xa0;0.0005]. Differences between males [OR:1.99; 95%CI(1.29,3.06); P&#xa0;=&#xa0;0.002] and females [OR:0.86; 95%CI (0.29,2.56);P&#xa0;=&#xa0;0.79] were observed.<br><br>CONCLUSIONS: Leucocyte telomere shortening predicts the risk of AF, especially recurrent AF. The predictive value is more prominent in males than in females. Shortening in LTL can predict the progression from paroxysmal to persistent AF.},
}
@article {pmid35932478,
year = {2022},
author = {Chik, HYJ and Sparks, AM and Schroeder, J and Dugdale, HL},
title = {A meta-analysis on the heritability of vertebrate telomere length.},
journal = {Journal of evolutionary biology},
volume = {35},
number = {10},
pages = {1283-1295},
pmid = {35932478},
issn = {1420-9101},
support = {NE/P011284/1//Natural Environment Research Council/ ; },
mesh = {Animals ; Phylogeny ; *Telomere/genetics ; *Vertebrates/genetics ; },
abstract = {Telomere dynamics are linked with both cellular and organismal senescence, and life history, individual quality and health. Telomere dynamics, particularly telomere length, have therefore garnered much research interest in evolutionary biology. To examine the evolution of telomere length, it is important to quantify its heritability, the proportion of total variation explained by additive genetic effects. Many studies have quantified telomere length heritability, but estimates are varied, and no general conclusion has been drawn. Additionally, it is unclear whether biological and methodological factors influence telomere length heritability estimates. We present the first meta-analysis of telomere length heritability, using 104 estimates from 43 studies over 18 vertebrate species. We calculated an overall mean heritability and examined how estimates varied by study, phylogeny, species-specific ecology, environmental setting, age at sampling, laboratory methods, statistical methods, sex and repeated measurements. Overall heritability was moderate (44.9%, 95% CI: 25.2-64.7%), and there was considerable heterogeneity in heritability estimates, in particular among studies and estimates. Laboratory method influenced heritability estimates, with in-gel hybridization TRF yielding higher heritabilities than qPCR and Southern blot TRF. There was also an effect from statistical method, with twin-based and SNP-based estimates lower than correlation-based or pedigree-based estimates. Our results highlight an overall heritable basis of telomere length, and we recommend future research on a wider range of taxa, and the use of variance-partitioning methods with relatedness or SNP data over correlation methods to minimize heritability estimation bias.},
}
@article {pmid35931358,
year = {2022},
author = {Guo, Z and Zou, K and Li, X and Duan, X and Fan, Y and Liu, X and Wang, W},
title = {Relationship between miRNAs polymorphisms and peripheral blood leukocyte DNA telomere length in coke oven workers: A cross-sectional study.},
journal = {Environmental toxicology and pharmacology},
volume = {95},
number = {},
pages = {103941},
doi = {10.1016/j.etap.2022.103941},
pmid = {35931358},
issn = {1872-7077},
mesh = {*Coke/analysis ; Cross-Sectional Studies ; DNA ; DNA Damage ; Humans ; Leukocytes ; *MicroRNAs/genetics ; *Occupational Exposure/adverse effects/analysis ; *Polycyclic Aromatic Hydrocarbons/analysis ; Telomere/genetics ; },
abstract = {OBJECTIVE: The purpose of this study was to investigate the factors affecting telomere length (TL) in coke oven workers by analyzing the interaction between miRNAs polymorphisms and coke oven emissions (COEs) exposure.<br><br>METHODS: A total of 544 coke oven workers and 238 healthy controls were recruited. Peripheral blood was collected from the subjects, genomic DNA was extracted, leukocyte TL was detected by real-time quantitative polymerase chain reaction, and fifteen polymorphisms of eight miRNAs were genotyped by flight mass spectrometry.<br><br>RESULTS: Statistical analysis showed that the peripheral blood DNA TL in the exposure group was shorter than that in the control group (P&#xa0;<&#xa0;0.001). Generalized linear model found that COEs-exposure [&#x3b2; (95%CI) =&#xa0;-0.427 (-0.556, -0.299), P&#xa0;<&#xa0;0.001], genotype CC+CT for miR-612 rs1144925 [&#x3b2; (95%CI) =&#xa0;-0.367 (-0.630, -0.104), P&#xa0;=&#xa0;0.006], and the interaction of miR-181B1 rs12039395 TT genotype and COEs-exposure [&#x3b2; (95% CI) =&#xa0;0.564 (0.108, 1.020), P&#xa0;=&#xa0;0.015] were associated with the shortened TL.<br><br>CONCLUSION: COEs-exposure and miR-612 rs1144925 TT could promote telomere shortening in coke oven workers. The interaction of miR-181B1 rs12039395 TT genotype and COEs-exposure could protect telomere. This provides clues for further mechanistic studies between miRNA and telomere damage.},
}
@article {pmid35930283,
year = {2022},
author = {Martens, DS and Sleurs, H and Dockx, Y and Rasking, L and Plusquin, M and Nawrot, TS},
title = {Association of Newborn Telomere Length With Blood Pressure in Childhood.},
journal = {JAMA network open},
volume = {5},
number = {8},
pages = {e2225521},
pmid = {35930283},
issn = {2574-3805},
mesh = {Adult ; Blood Pressure ; Child ; Child, Preschool ; Cohort Studies ; Female ; Humans ; *Hypertension ; Infant, Newborn ; Male ; *Placenta ; Pregnancy ; Prospective Studies ; Telomere ; United States ; },
abstract = {IMPORTANCE: Adult telomere length (TL) is a biological marker of aging associated with vascular health. TL at birth is associated with later life TL and may contain early biological information of later life cardiovascular health and disease.<br><br>OBJECTIVE: To evaluate whether newborn TL is associated with early life blood pressure differences in childhood.<br><br>This cohort study was part of the ENVIRONAGE (Environmental Influence on Aging in Early Life) study, a birth cohort of Belgian mother-child pairs with recruitment at birth and a median follow-up of 4.5 years conducted between October 2014 and July 2021. Participants included for analysis provided full data for evaluation at follow-up visit. Data analysis was conducted between August and September 2021.<br><br>MAIN OUTCOMES AND MEASURES: Cord blood and placental average relative TL were measured at birth using quantitative polymerase chain reaction (qPCR). Systolic, diastolic, and mean arterial pressure (MAP) were evaluated at follow-up. High childhood blood pressure (standardized for child age, sex, and height) was defined following the 2017 American Academy of Pediatrics guidelines. Multivariable adjusted linear and logistic regression models were used to associate newborn TL and blood pressure indicators in childhood.<br><br>RESULTS: This study included 485 newborn children (52.8% girls) with a mean (SD) age of 4.6 (0.4) years at the follow-up visit. Newborn TL was associated with lower blood pressure in childhood. A 1-IQR increase in cord blood TL was associated with a -1.54 mm Hg (95% CI, -2.36 to -0.72 mm Hg) lower diastolic blood pressure and -1.18 mm Hg (95% CI, -1.89 to -0.46 mm Hg) lower MAP. No association was observed with systolic blood pressure. Furthermore, a 1-IQR increase in cord blood TL was associated with lower odds of having high blood pressure at the age of 4 to 6 years (adjusted OR, 0.72; 95% CI, 0.53 to 0.98). In placenta, a 1-IQR increase in TL was associated with a -0.96 mm Hg (95% CI, -1.72 to -0.21 mm Hg) lower diastolic, -0.88 mm Hg (95% CI, -1.54 to -0.22 mm Hg) lower MAP, and a lower adjusted OR of 0.69 (95% CI, 0.52 to 0.92) for having a high blood pressure in childhood.<br><br>CONCLUSIONS AND RELEVANCE: In this prospective birth cohort study, variation in early life blood pressure at school-age was associated with TL at birth. Cardiovascular health may to some extent be programmed at birth, and these results suggest that TL entails a biological mechanism in this programming.},
}
@article {pmid35929966,
year = {2022},
author = {Tummala, H and Walne, A and Dokal, I},
title = {The biology and management of dyskeratosis congenita and related disorders of telomeres.},
journal = {Expert review of hematology},
volume = {15},
number = {8},
pages = {685-696},
doi = {10.1080/17474086.2022.2108784},
pmid = {35929966},
issn = {1747-4094},
support = {14032/LLR_/Blood Cancer UK/United Kingdom ; MR/P018440/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Biology ; Danazol ; *Dyskeratosis Congenita/diagnosis/genetics/therapy ; Humans ; Mutation ; Oxymetholone ; *Telomerase ; Telomere/genetics/metabolism ; },
abstract = {BACKGROUND: Dyskeratosis congenita (DC) is a multisystem syndrome characterized by mucocutaneous abnormalities, bone marrow failure, and predisposition to cancer. Studies over the last 25 years have led to the identification of 18 disease genes. These have a principal role in telomere maintenance, and patients usually have very short/abnormal telomeres. The advances have also led to the unification of DC with a number of other diseases, now collectively referred to as the telomeropathies or telomere biology disorders.<br><br>WHAT IS COVERED: Clinical features, genetics, and biology of the different subtypes. Expert view on diagnosis, treatment of the hematological complications and future.<br><br>EXPERT VIEW: As these are very pleotropic disorders affecting multiple organs, a high index of suspicion is necessary to make the diagnosis. Telomere length measurement and genetic analysis of the disease genes have become useful diagnostic tools. Although hematological defects can respond to danazol/oxymetholone, the only current curative treatment for these is hematopoietic stem cell transplantation (HSCT) using fludarabine-based conditioning protocols. New therapies are needed where danazol/oxymetholone is ineffective and HSCT is not feasible.},
}
@article {pmid35923948,
year = {2022},
author = {Pepke, ML and Kvalnes, T and Ranke, PS and Araya-Ajoy, YG and Wright, J and Sæther, BE and Jensen, H and Ringsby, TH},
title = {Causes and consequences of variation in early-life telomere length in a bird metapopulation.},
journal = {Ecology and evolution},
volume = {12},
number = {8},
pages = {e9144},
pmid = {35923948},
issn = {2045-7758},
abstract = {Environmental conditions during early-life development can have lasting effects shaping individual heterogeneity in fitness and fitness-related traits. The length of telomeres, the DNA sequences protecting chromosome ends, may be affected by early-life conditions, and telomere length (TL) has been associated with individual performance within some wild animal populations. Thus, knowledge of the mechanisms that generate variation in TL, and the relationship between TL and fitness, is important in understanding the role of telomeres in ecology and life-history evolution. Here, we investigate how environmental conditions and morphological traits are associated with early-life blood TL and if TL predicts natal dispersal probability or components of fitness in 2746 wild house sparrow (Passer domesticus) nestlings from two populations sampled across 20 years (1994-2013). We retrieved weather data and we monitored population fluctuations, individual survival, and reproductive output using field observations and genetic pedigrees. We found a negative effect of population density on TL, but only in one of the populations. There was a curvilinear association between TL and the maximum daily North Atlantic Oscillation index during incubation, suggesting that there are optimal weather conditions that result in the longest TL. Dispersers tended to have shorter telomeres than non-dispersers. TL did not predict survival, but we found a tendency for individuals with short telomeres to have higher annual reproductive success. Our study showed how early-life TL is shaped by effects of growth, weather conditions, and population density, supporting that environmental stressors negatively affect TL in wild populations. In addition, shorter telomeres may be associated with a faster pace-of-life, as individuals with higher dispersal rates and annual reproduction tended to have shorter early-life TL.},
}
@article {pmid35920280,
year = {2022},
author = {Borges, G and Criqui, M and Harrington, L},
title = {Tieing together loose ends: telomere instability in cancer and aging.},
journal = {Molecular oncology},
volume = {16},
number = {18},
pages = {3380-3396},
pmid = {35920280},
issn = {1878-0261},
support = {148936//CIHR/Canada ; },
mesh = {Aging/genetics ; Cellular Senescence/genetics ; Genomic Instability ; Humans ; *Neoplasms/genetics ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {Telomere maintenance is essential for maintaining genome integrity in both normal and cancer cells. Without functional telomeres, chromosomes lose their protective structure and undergo fusion and breakage events that drive further genome instability, including cell arrest or death. One means by which this loss can be overcome in stem cells and cancer cells is via re-addition of G-rich telomeric repeats by the telomerase reverse transcriptase (TERT). During aging of somatic tissues, however, insufficient telomerase expression leads to a proliferative arrest called replicative senescence, which is triggered when telomeres reach a critically short threshold that induces a DNA damage response. Cancer cells express telomerase but do not entirely escape telomere instability as they often possess short telomeres; hence there is often selection for genetic alterations in the TERT promoter that result in increased telomerase expression. In this review, we discuss our current understanding of the consequences of telomere instability in cancer and aging, and outline the opportunities and challenges that lie ahead in exploiting the reliance of cells on telomere maintenance for preserving genome stability.},
}
@article {pmid35920237,
year = {2023},
author = {Gurvich, C and Thomas, N and Hudaib, AR and Van Rheenen, TE and Thomas, EHX and Tan, EJ and Neill, E and Carruthers, SP and Sumner, PJ and Romano-Silva, M and Bozaoglu, K and Kulkarni, J and Rossell, SL},
title = {The relationship between cognitive clusters and telomere length in bipolar-schizophrenia spectrum disorders.},
journal = {Psychological medicine},
volume = {53},
number = {11},
pages = {5119-5126},
doi = {10.1017/S0033291722002148},
pmid = {35920237},
issn = {1469-8978},
mesh = {Humans ; *Bipolar Disorder/genetics/complications ; *Schizophrenia/genetics/complications ; *Psychotic Disorders/genetics/complications ; Cognition ; Telomere ; },
abstract = {BACKGROUND: Schizophrenia and bipolar disorder are complex mental illnesses that are associated with cognitive deficits. There is considerable cognitive heterogeneity that exists within both disorders. Studies that cluster schizophrenia and bipolar patients into subgroups based on their cognitive profile increasingly demonstrate that, relative to healthy controls, there is a severely compromised subgroup and a relatively intact subgroup. There is emerging evidence that telomere shortening, a marker of cellular senescence, may be associated with cognitive impairments. The aim of this study was to explore the relationship between cognitive subgroups in bipolar-schizophrenia spectrum disorders and telomere length against a healthy control sample.<br><br>METHODS: Participants included a transdiagnostic group diagnosed with bipolar, schizophrenia or schizoaffective disorder (n = 73) and healthy controls (n = 113). Cognitive clusters within the transdiagnostic patient group, were determined using K-means cluster analysis based on current cognitive functioning (MATRICS Consensus Cognitive Battery scores). Telomere length was determined using quantitative PCRs genomic DNA extracted from whole blood. Emergent clusters were then compared to the healthy control group on telomere length.<br><br>RESULTS: Two clusters emerged within the patient group that were deemed to reflect a relatively intact cognitive group and a cognitively impaired subgroup. Telomere length was significantly shorter in the severely impaired cognitive subgroup compared to the healthy control group.<br><br>CONCLUSIONS: This study replicates previous findings of transdiagnostic cognitive subgroups and associates shorter telomere length with the severely impaired cognitive subgroup. These findings support emerging literature associating cognitive impairments in psychiatric disorders to accelerated cellular aging as indexed by telomere length.},
}
@article {pmid35920029,
year = {2022},
author = {Vernasco, BJ and Watts, HE},
title = {Telomere length predicts timing and intensity of migratory behaviour in a nomadic songbird.},
journal = {Biology letters},
volume = {18},
number = {8},
pages = {20220176},
pmid = {35920029},
issn = {1744-957X},
mesh = {Animal Migration/physiology ; Animals ; *Finches ; Psychomotor Agitation ; Seasons ; *Songbirds/genetics ; Telomere ; Telomere Shortening ; },
abstract = {Our understanding of state-dependent behaviour is reliant on identifying physiological indicators of condition. Telomeres are of growing interest for understanding behaviour as they capture differences in biological state and residual lifespan. To understand the significance of variable telomere lengths for behaviour and test two hypotheses describing the relationship between telomeres and behaviour (i.e. the causation and the selective adoption hypotheses), we assessed if telomere lengths are longitudinally repeatable traits related to spring migratory behaviour in captive pine siskins (Spinus pinus). Pine siskins are nomadic songbirds that exhibit highly flexible, facultative migrations, including a period of spring nomadism. Captive individuals exhibit extensive variation in spring migratory restlessness and are an excellent system for mechanistic studies of migratory behaviour. Telomere lengths were found to be significantly repeatable (R = 0.51) over four months, and shorter pre-migratory telomeres were associated with earlier and more intense expression of spring nocturnal migratory restlessness. Telomere dynamics did not vary with migratory behaviour. Our results describe the relationship between telomere length and migratory behaviour and provide support for the selective adoption hypothesis. More broadly, we provide a novel perspective on the significance of variable telomere lengths for animal behaviour and the timing of annual cycle events.},
}
@article {pmid35918419,
year = {2022},
author = {Huang, MY and Madhani, HD},
title = {Telomere transposon takeover in Cryptococcus.},
journal = {Nature microbiology},
volume = {7},
number = {8},
pages = {1108-1109},
pmid = {35918419},
issn = {2058-5276},
support = {T32 AI060537/AI/NIAID NIH HHS/United States ; },
mesh = {Automation ; *Cryptococcus/genetics ; Telomere ; },
}
@article {pmid35914599,
year = {2022},
author = {Passos, JDC and Felisbino, K and Laureano, HA and Guiloski, IC},
title = {Occupational exposure to pesticides and its association with telomere length - A systematic review and meta-analysis.},
journal = {The Science of the total environment},
volume = {849},
number = {},
pages = {157715},
doi = {10.1016/j.scitotenv.2022.157715},
pmid = {35914599},
issn = {1879-1026},
mesh = {Biomarkers ; Humans ; *Occupational Exposure/adverse effects/analysis ; *Pesticides/toxicity ; Telomere ; },
abstract = {BACKGROUND: Telomere length is a common biomarker for the cumulative effect of environmental factors on aging-related diseases, therefore an association has been hypothesized between occupational exposure to pesticides and shorter telomere length.<br><br>OBJECTIVE: This study is a systematic review and meta-analysis aiming to examine the association between telomere length and occupational exposure to pesticides.<br><br>METHODS: We systematically searched in SciELO, PubMed, Scopus, Embase, Cochrane, Lilacs, Science Direct, and Web of Science databases for all observational studies containing measurements of telomere length on groups occupationally exposed to pesticides. Data were synthesized through qualitative synthesis and meta-analysis. We estimated the associations between exposed and non-exposed groups by using the natural log of the response ratio (lnRR). Heterogeneity was quantified using the Cochran Q test and I[2] statistics.<br><br>RESULTS: Six studies were included in the qualitative synthesis and meta-analysis, with a total of 480 participants exposed to pesticides. The time of exposure evaluated 391 participants that had a range of 5 to >30 years of occupational exposure. Most studies presented shorter telomere length in the occupationally exposed group. From the six studies included in the meta-analysis, three presented telomere length measurement as a single copy gene (T/S), and three presented telomere length measurement as base pairs (bp). The statistical analysis pooled estimates (log ratio of means) of the telomere length in both measurements (T/S and bp) showed a shortening of telomere length in the exposed group when compared with the non-exposed (control) group. Two of six studies reported longer telomere length in the group exposed to pesticides.<br><br>DISCUSSION: Our findings suggest an association between occupational exposure to pesticides and shorter telomere length. However, we found a small number of studies to include in our meta-analysis, being required more high-quality studies to strengthen our findings and conclusions.},
}
@article {pmid35912187,
year = {2022},
author = {Mushtaq, I and Bhat, GR and Rah, B and Besina, S and Zahoor, S and Wani, MA and Shah, MA and Bashir, S and Farooq, M and Rather, RA and Afroze, D},
title = {Telomere Attrition With Concomitant hTERT Overexpression Involved in the Progression of Gastric Cancer May Have Prognostic and Clinical Implications in High-Risk Population Group From North India.},
journal = {Frontiers in oncology},
volume = {12},
number = {},
pages = {919351},
pmid = {35912187},
issn = {2234-943X},
abstract = {Genetic instabilities exacerbated by the dysfunction of telomeres can lead to the development of cancer. Nearly 90% of all human malignancies are linked with telomere dysregulation and overexpression of telomerase, an enzyme that catalyzes the synthesis of telomeric DNA repeats at the ends of chromosomes. The burden of gastric cancer continues to inflict a deterring impact on the global health scenario, accounting for over one million new cases in 2020. The disease is asymptomatic in its early stages of progression, which is attributed to the poor prognosis and overall surge in mortality rate worldwide. Exploiting telomere physiology can provide extensive mechanistic insight into telomere-associated gastric cancer progression and its use as a target in a variety of therapeutic interventions. In this study, we aimed to evaluate the clinical implications of c-Myc, human telomerase reverse transcriptase (hTERT) expression, and telomere length in patients with gastric cancer. A total of 57 gastric cancer cases and adjacent controls were included in the study. RT-PCR and immunohistochemistry were used to assess the expression levels of c-Myc and hTERT. The relative telomere length was measured by MMQPCR using the Cawthon method. Our results indicated that the shorter telomere and increased hTERT expression were associated with gastric cancer progression. The study also highlighted the role of short telomeres and increased expression of hTERT in gastric cancer progression and its association with various etiological risk factors, transcriptional activators, and overall survival among the ethnic Kashmiri population of North India.},
}
@article {pmid35911771,
year = {2022},
author = {Liao, Q and He, J and Tian, FF and Bi, FF and Huang, K},
title = {A causal relationship between leukocyte telomere length and multiple sclerosis: A Mendelian randomization study.},
journal = {Frontiers in immunology},
volume = {13},
number = {},
pages = {922922},
pmid = {35911771},
issn = {1664-3224},
mesh = {Genome-Wide Association Study ; Humans ; Leukocytes ; *Mendelian Randomization Analysis ; *Multiple Sclerosis/genetics ; Polymorphism, Single Nucleotide ; Telomere/genetics ; },
abstract = {OBJECTIVES: Multiple sclerosis (MS) is a chronic inflammatory autoimmune and degenerative disorder of the central nervous system. Telomeres are protective structures located at the ends of linear chromosomes, and leukocyte telomere length (LTL) is closely connected with cell aging and senescence. However, the relationship between LTL and the risk of MS remains unknown.<br><br>METHODS: We performed a two-sample Mendelian randomization (MR) to evaluate whether LTL was causally associated with MS risk.<br><br>RESULTS: In our MR analysis, 12 LTL-related variants were selected as valid instrumental variables, and a causal relationship between LTL and MS was suggested. The risk of MS nearly doubled as the genetically predicted LTL shortened by one standard deviation (SD) under the inverse variance weighted (IVW) fixed effect model (odds ratio (OR) = 2.00, 95% confidence interval (CI): 1.52-2.62, p = 6.01e-07). Similar estimated causal effects were also observed under different MR models. The MR-Egger regression test did not reveal any evidence of directional pleiotropy (intercept = -0.005, stand error (SE) = 0.03, p = 0.87). The Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analysis also indicated no directional pleiotropy or outliers for any LTL-related IVs (p-global test = 0.13). In addition, a leave-one-out sensitivity analysis showed similar findings, which further emphasized the validity and stability of the causal relationship.<br><br>CONCLUSIONS: Our results suggest a potential causal effect of LTL on the risk of MS. Genetically predicted shorter LTL could increase the risk of MS in the European population. LTL should be noted and emphasized in the pathogenesis and treatment of MS.},
}
@article {pmid35910300,
year = {2022},
author = {Aviv, A},
title = {The telomere tumult: meaning and metrics in population studies.},
journal = {The lancet. Healthy longevity},
volume = {3},
number = {5},
pages = {e308-e309},
pmid = {35910300},
issn = {2666-7568},
support = {R01 HL134840/HL/NHLBI NIH HHS/United States ; U01 AG066529/AG/NIA NIH HHS/United States ; },
mesh = {*Benchmarking ; *Biological Specimen Banks ; Health Behavior ; Leukocytes ; Telomere/genetics ; United Kingdom ; },
}
@article {pmid35903361,
year = {2022},
author = {Son, N and Cui, Y and Xi, W},
title = {Association Between Telomere Length and Skin Cancer and Aging: A Mendelian Randomization Analysis.},
journal = {Frontiers in genetics},
volume = {13},
number = {},
pages = {931785},
pmid = {35903361},
issn = {1664-8021},
abstract = {Background: Telomere shortening is a hallmark of cellular senescence. However, telomere length (TL)-related cellular senescence has varying effects in different cancers, resulting in a paradoxical relationship between senescence and cancer. Therefore, we used observational epidemiological studies to investigate the association between TL and skin cancer and aging, and to explore whether such a paradoxical relationship exists in skin tissue. Methods: This study employed two-sample Mendelian randomization (MR) to analyze the causal relationship between TL and skin cancer [melanoma and non-melanoma skin cancers (NMSCs)] and aging. We studied single nucleotide polymorphisms (SNPs) obtained from pooled data belonging to genome-wide association studies (GWAS) in the literature and biobanks. Quality control was performed using pleiotropy, heterogeneity, and sensitivity analyses. Results: We used five algorithms to analyze the causal relationship between TL and skin aging, melanoma, and NMSCs, and obtained consistent results. TL shortening reduced NMSC and melanoma susceptibility risk with specific odds ratios (ORs) of 1.0344 [95% confidence interval (CI): 1.0168-1.0524, p = 0.01] and 1.0127 (95% CI: 1.0046-1.0209, p = 6.36E-07), respectively. Conversely, TL shortening was validated to increase the odds of skin aging (OR = 0.96, 95% CI: 0.9332-0.9956, p = 0.03). Moreover, the MR-Egger, maximum likelihood, and inverse variance weighted (IVW) methods found significant heterogeneity among instrumental variable (IV) estimates (identified as MR-Egger skin aging Q = 76.72, p = 1.36E-04; melanoma Q = 97.10, p = 1.62E-07; NMSCsQ = 82.02, p = 1.90E-05). The leave-one-out analysis also showed that the SNP sensitivity was robust to each result. Conclusion: This study found that TL shortening may promote skin aging development and reduce the risk of cutaneous melanoma and NMSCs. The results provide a reference for future research on the causal relationship between skin aging and cancer in clinical practice.},
}
@article {pmid35902621,
year = {2022},
author = {Bae, JS and Lee, JW and Joung, JG and Cho, HW and Ju, HY and Yoo, KH and Koo, HH and Sung, KW},
title = {Clinical significance of germline telomere length and associated genetic factors in patients with neuroblastoma.},
journal = {Scientific reports},
volume = {12},
number = {1},
pages = {12954},
pmid = {35902621},
issn = {2045-2322},
mesh = {Genetic Markers ; *Genome-Wide Association Study ; Humans ; Leukocytes, Mononuclear ; *Neuroblastoma/genetics ; Polymorphism, Single Nucleotide ; Telomere/genetics ; },
abstract = {Studies investigating the relationship between germline telomere length and the clinical characteristics of tumors are very limited. This study evaluated the relationship between germline telomere length and the clinical characteristics of neuroblastoma. In addition, a genome-wide association study (GWAS) was performed to investigate the genetic factors associated with germline telomere length. The germline telomere length of peripheral blood mononuclear cells from 186 patients with neuroblastoma was measured by quantitative polymerase chain reaction. The association between germline telomere length and clinical characteristics, including long-term survival, was investigated. For the GWAS, genotyping was performed with a high-density bead chip (Illumina, San Diego, CA, USA). After strict quality-control checks of the samples, an association analysis was conducted. The result showed that longer germline telomeres were significantly associated with longer event-free survival (P = 0.032). To identify significantly assocated genetic markers for germline telomere length, genome wide association analysis was performed. As a result, several single nucleotide polymorphisms located in HIVEP3, LRRTM4, ADGRV1, RAB30, and CHRNA4 genes were discovered. During gene-based analysis (VEGAS2 tool), the CNTN4 gene had the most significant association with germline telomere length (P = 1.0E-06). During gene ontology analysis, susceptible genes associated with germline telomere length were mainly distributed in neurite morphogenesis and neuron development. A longer germline telomere length is associated with favorable prognostic factors at diagnosis and eventually better event-free survival in patients with neuroblastoma. In addition, the GWAS demonstrated that genetic markers and genes related to germline telomere length are associated with neurite morphogenesis and neuron development. Further research with larger cohorts of patients and functional investigations are needed.},
}
@article {pmid35897312,
year = {2022},
author = {Liu, Y and Liu, S and Xin, J and Qian, P and Guo, S and Xu, X and Wang, D and Yang, L},
title = {Telomere Length and Hearing Loss: A Two-Sample Mendelian Randomization.},
journal = {International journal of environmental research and public health},
volume = {19},
number = {15},
pages = {},
pmid = {35897312},
issn = {1660-4601},
mesh = {Genome-Wide Association Study ; *Hearing Loss/epidemiology/genetics ; Humans ; *Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; Telomere ; },
abstract = {BACKGROUND: Observational studies have suggested that there may be an association between telomere length (TL) and hearing loss (HL). However, inferring causality from observational studies is subject to residual confounding effects, reverse causation, and bias. This study adopted a two-sample Mendelian randomization (MR) approach to evaluate the causal relationship between TL and increased risk of HL.<br><br>METHODS: A total of 16 single nucleotide polymorphisms (SNPs) associated with TL were identified from a genome-wide association study (GWAS) meta-analysis of 78,592 European participants and applied to our modeling as instrumental variables. Summary-level data for hearing loss (HL), age-related hearing loss (ARHL), and noise-induced hearing loss (NIHL) were obtained from the recent largest available GWAS and five MR analyses were used to investigate the potential causal association of genetically predicted TL with increased risk for HL, including the inverse-variance-weighted (IVW), weighted median, MR-Egger regression, simple mode, and weighted mode. In addition, sensitivity analysis, pleiotropy, and heterogeneity tests were also used to evaluate the robustness of our findings.<br><br>RESULTS: There was no causal association between genetically predicted TL and HL or its subtypes (by the IVW method, HL: odds ratio (OR) = 1.216, p = 0.382; ARHL: OR = 0.934, p = 0.928; NIHL: OR = 1.003, p = 0.776). Although heterogenous sites rs2736176, rs3219104, rs8105767, and rs2302588 were excluded for NIHL, the second MR analysis was consistent with the first analysis (OR = 1.003, p = 0.572).<br><br>CONCLUSION: There was no clear causal relationship between shorter TLs and increased risk of HL or its subtypes in this dataset.},
}
@article {pmid35892638,
year = {2022},
author = {Scarabino, D and Veneziano, L and Fiore, A and Nethisinghe, S and Mantuano, E and Garcia-Moreno, H and Bellucci, G and Solanky, N and Morello, M and Zanni, G and Corbo, RM and Giunti, P},
title = {Leukocyte Telomere Length Variability as a Potential Biomarker in Patients with PolyQ Diseases.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {11},
number = {8},
pages = {},
pmid = {35892638},
issn = {2076-3921},
abstract = {SCA1, SCA2, and SCA3 are the most common forms of SCAs among the polyglutamine disorders, which include Huntington's Disease (HD). We investigated the relationship between leukocyte telomere length (LTL) and the phenotype of SCA1, SCA2, and SCA3, comparing them with HD. The results showed that LTL was significantly reduced in SCA1 and SCA3 patients, while LTL was significantly longer in SCA2 patients. A significant negative relationship between LTL and age was observed in SCA1 but not in SCA2 subjects. LTL of SCA3 patients depend on both patient's age and disease duration. The number of CAG repeats did not affect LTL in the three SCAs. Since LTL is considered an indirect marker of an inflammatory response and oxidative damage, our data suggest that in SCA1 inflammation is present already at an early stage of disease similar to in HD, while in SCA3 inflammation and impaired antioxidative processes are associated with disease progression. Interestingly, in SCA2, contrary to SCA1 and SCA3, the length of leukocyte telomeres does not reduce with age. We have observed that SCAs and HD show a differing behavior in LTL for each subtype, which could constitute relevant biomarkers if confirmed in larger cohorts and longitudinal studies.},
}
@article {pmid35887427,
year = {2022},
author = {Quenu, M and Treindl, AD and Lee, K and Takemoto, D and Thünen, T and Ashrafi, S and Winter, D and Ganley, ARD and Leuchtmann, A and Young, CA and Cox, MP},
title = {Telomere-to-Telomere Genome Sequences across a Single Genus Reveal Highly Variable Chromosome Rearrangement Rates but Absolute Stasis of Chromosome Number.},
journal = {Journal of fungi (Basel, Switzerland)},
volume = {8},
number = {7},
pages = {},
pmid = {35887427},
issn = {2309-608X},
abstract = {Genome rearrangements in filamentous fungi are prevalent but little is known about the modalities of their evolution, in part because few complete genomes are available within a single genus. To address this, we have generated and compared 15 complete telomere-to-telomere genomes across the phylogeny of a single genus of filamentous fungi, Epichloë. We find that the striking distinction between gene-rich and repeat-rich regions previously reported for isolated species is ubiquitous across the Epichloë genus. We built a species phylogeny from single-copy gene orthologs to provide a comparative framing to study chromosome composition and structural change through evolutionary time. All Epichloë genomes have exactly seven nuclear chromosomes, but despite this conserved ploidy, analyses reveal low synteny and substantial rearrangement of gene content across the genus. These rearrangements are highly lineage-dependent, with most occurring over short evolutionary distances, with long periods of structural stasis. Quantification of chromosomal rearrangements shows they are uncorrelated with numbers of substitutions and evolutionary distances, suggesting that different modes of evolution are acting to create nucleotide and chromosome-scale changes.},
}
@article {pmid35886017,
year = {2022},
author = {Zimnitskaya, OV and Petrova, MM and Lareva, NV and Cherniaeva, MS and Al-Zamil, M and Ivanova, AE and Shnayder, NA},
title = {Leukocyte Telomere Length as a Molecular Biomarker of Coronary Heart Disease.},
journal = {Genes},
volume = {13},
number = {7},
pages = {},
pmid = {35886017},
issn = {2073-4425},
mesh = {Adult ; Biomarkers ; *Cardiovascular Diseases ; *Coronary Disease/genetics ; Humans ; Leukocytes ; Telomere/genetics ; },
abstract = {BACKGROUND: This work is a review of preclinical and clinical studies of the role of telomeres and telomerase in the development and progression of coronary heart disease (CHD).<br><br>MATERIALS AND METHODS: A search for full-text publications (articles, reviews, meta-analyses, Cochrane reviews, and clinical cases) in English and Russian was carried out in the databases PubMed, Oxford University Press, Scopus, Web of Science, Springer, and E-library electronic library using keywords and their combinations. The search depth is 11 years (2010-2021).<br><br>RESULTS: The review suggests that the relative leukocyte telomere length (LTL) is associated with the development of socially significant and widespread cardiovascular diseases such as CHD and essential hypertension. At the same time, the interests of researchers are mainly focused on the study of the relative LTL in CHD.<br><br>CONCLUSIONS: Despite the scientific and clinical significance of the analyzed studies of the relative length of human LTL as a biological marker of cardiovascular diseases, their implementation in real clinical practice is difficult due to differences in the design and methodology of the analyzed studies, as well as differences in the samples by gender, age, race, and ethnicity. The authors believe that clinical studies of the role of the relative length of leukocyte telomeres in adult patients with coronary heart disease are the most promising and require large multicenter studies with a unified design and methodology.},
}
@article {pmid35884905,
year = {2022},
author = {Lauriola, A and Davalli, P and Marverti, G and Caporali, A and Mai, S and D'Arca, D},
title = {Telomere Dysfunction Is Associated with Altered DNA Organization in Trichoplein/Tchp/Mitostatin (TpMs) Depleted Cells.},
journal = {Biomedicines},
volume = {10},
number = {7},
pages = {},
pmid = {35884905},
issn = {2227-9059},
support = {MR/R014353/1/MRC_/Medical Research Council/United Kingdom ; MR/R014353/1//MRC-IMPC Pump Priming Award/ ; },
abstract = {Recently, we highlighted a novel role for the protein Trichoplein/TCHP/Mitostatin (TpMs), both as mitotic checkpoint regulator and guardian of chromosomal stability. TpMs-depleted cells show numerical and structural chromosome alterations that lead to genomic instability. This condition is a major driving force in malignant transformation as it allows for the cells acquiring new functional capabilities to proliferate and disseminate. Here, the effect of TpMs depletion was investigated in different TpMs-depleted cell lines by means of 3D imaging and 3D Structured illumination Microscopy. We show that TpMs depletion causes alterations in the 3D architecture of telomeres in colon cancer HCT116 cells. These findings are consistent with chromosome alterations that lead to genomic instability. Furthermore, TpMs depletion changes the spatial arrangement of chromosomes and other nuclear components. Modified nuclear architecture and organization potentially induce variations that precede the onset of genomic instability and are considered as markers of malignant transformation. Our present observations connect the tumor suppression ability of TpMs with its novel functions in maintaining the proper chromosomal segregation as well as the proper telomere and nuclear architecture. Further investigations will investigate the connection between alterations in telomeres and nuclear architecture with the progression of human tumors with the aim of developing personalized therapeutic interventions.},
}
@article {pmid35880304,
year = {2022},
author = {Curtis, EM and Codd, V and Nelson, C and D'Angelo, S and Wang, Q and Allara, E and Kaptoge, S and Matthews, PM and Tobias, JH and Danesh, J and Cooper, C and Samani, NJ and Harvey, NC},
title = {Telomere Length and Risk of Incident Fracture and Arthroplasty: Findings From UK Biobank.},
journal = {Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research},
volume = {37},
number = {10},
pages = {1997-2004},
pmid = {35880304},
issn = {1523-4681},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; 209233/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; MC_PC_15015/MRC_/Medical Research Council/United Kingdom ; MC_PC_21002/MRC_/Medical Research Council/United Kingdom ; MC_PC_21001/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; MC_PC_21003/MRC_/Medical Research Council/United Kingdom ; MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; MC_PC_21022/MRC_/Medical Research Council/United Kingdom ; 201268/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; /BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Female ; Male ; Humans ; Middle Aged ; Hand Strength ; *Arthroplasty, Replacement, Hip ; Biological Specimen Banks ; *Arthroplasty, Replacement, Knee ; *Fractures, Bone/epidemiology/genetics ; Bone Density ; Telomere ; United Kingdom/epidemiology ; Risk Factors ; *Osteoporotic Fractures/epidemiology ; *Hip Fractures/epidemiology ; },
abstract = {We investigated independent associations between telomere length and risk of fracture and arthroplasty in UK Biobank participants. Leukocyte telomere length (LTL) was measured in baseline samples using a validated polymerase chain reaction (PCR) method. We used, in men and women separately, Cox proportional hazards models to calculate the hazard ratio (HR) for incident fracture (any, osteoporotic) or arthroplasty (hip or knee) over 1,186,410 person-years of follow-up. Covariates included age, white cell count, ethnicity, smoking, alcohol, physical activity, and menopause (women). In further analyses we adjusted for either estimated bone mineral density (eBMD) from heel quantitative ultrasound, handgrip strength, gait speed, total fat mass (bioimpedance), or blood biomarkers, all measured at baseline (2006-2010). We studied 59,500 women and 51,895 men, mean ± standard deviation (SD) age 56.4 ± 8.0 and 57.0 ± 8.3 years, respectively. During follow-up there were 5619 fractures; 5285 hip and 4261 knee arthroplasties. In confounder-adjusted models, longer LTL was associated with reduced risk of incident knee arthroplasty in both men (HR/SD 0.93; 95% confidence interval [CI], 0.88-0.97) and women (0.92; 95% CI, 0.88-0.96), and hip arthroplasty in men (0.91; 95% CI, 0.87-0.95), but not women (0.98; 95% CI, 0.94-1.01). Longer LTL was weakly associated with reduced risk of any incident fracture in women (HR/SD 0.96; 95% CI, 0.93-1.00) with less evidence in men (0.98; 95% CI, 0.93-1.02). Associations with incident outcomes were not materially altered by adjustment for heel eBMD, grip strength, gait speed, fat mass, or blood biomarker measures. In this, the largest study to date, longer LTL was associated with lower risk of incident knee or hip arthroplasty, but only weakly associated with lower risk of fracture. The relative risks were low at a population level, but our findings suggest that common factors acting on the myeloid and musculoskeletal systems might influence later life musculoskeletal outcomes. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).},
}
@article {pmid35879401,
year = {2022},
author = {Topiwala, A and Taschler, B and Ebmeier, KP and Smith, S and Zhou, H and Levey, DF and Codd, V and Samani, NJ and Gelernter, J and Nichols, TE and Burgess, S},
title = {Alcohol consumption and telomere length: Mendelian randomization clarifies alcohol's effects.},
journal = {Molecular psychiatry},
volume = {27},
number = {10},
pages = {4001-4008},
pmid = {35879401},
issn = {1476-5578},
support = {204623/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom ; UL1 TR001863/TR/NCATS NIH HHS/United States ; MR/K013351/1/MRC_/Medical Research Council/United Kingdom ; BRC-1215-20010/DH_/Department of Health/United Kingdom ; I01 CX001849/CX/CSRD VA/United States ; MC_UU_00002/7/MRC_/Medical Research Council/United Kingdom ; MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; 216462/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; R21 CA252916/CA/NCI NIH HHS/United States ; CH/12/2/29428/BHF_/British Heart Foundation/United Kingdom ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; G1001354/MRC_/Medical Research Council/United Kingdom ; BRC-1215-20014/DH_/Department of Health/United Kingdom ; 100309/Z/12/Z/WT_/Wellcome Trust/United Kingdom ; R01 EB026859/EB/NIBIB NIH HHS/United States ; RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Humans ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Alcohol Drinking/genetics ; Ethanol ; Telomere/genetics ; },
abstract = {Alcohol's impact on telomere length, a proposed marker of biological aging, is unclear. We performed the largest observational study to date (in n = 245,354 UK Biobank participants) and compared findings with Mendelian randomization (MR) estimates. Two-sample MR used data from 472,174 participants in a recent genome-wide association study (GWAS) of telomere length. Genetic variants were selected on the basis of associations with alcohol consumption (n = 941,280) and alcohol use disorder (AUD) (n = 57,564 cases). Non-linear MR employed UK Biobank individual data. MR analyses suggested a causal relationship between alcohol traits, more strongly for AUD, and telomere length. Higher genetically-predicted AUD (inverse variance-weighted (IVW) β = -0.06, 95% confidence interval (CI): -0.10 to -0.02, p = 0.001) was associated with shorter telomere length. There was a weaker association with genetically-predicted alcoholic drinks weekly (IVW β = -0.07, CI: -0.14 to -0.01, p = 0.03). Results were consistent across methods and independent from smoking. Non-linear analyses indicated a potential threshold relationship between alcohol and telomere length. Our findings indicate that alcohol consumption may shorten telomere length. There are implications for age-related diseases.},
}
@article {pmid35878015,
year = {2022},
author = {Zhan, Y and Kang, X},
title = {Disentangling the Causal Effect of Telomere Length in Systemic Lupus Erythematosus Using Genetic Variants as Instruments.},
journal = {Arthritis &amp; rheumatology (Hoboken, N.J.)},
volume = {74},
number = {12},
pages = {1890-1892},
doi = {10.1002/art.42313},
pmid = {35878015},
issn = {2326-5205},
mesh = {Humans ; *Lupus Erythematosus, Systemic/genetics ; Telomere/genetics ; Causality ; },
}
@article {pmid35876482,
year = {2022},
author = {},
title = {Corrigendum to: TERT promoter C228T mutation in neural progenitors confers growth advantage following telomere shortening in vivo.},
journal = {Neuro-oncology},
volume = {24},
number = {11},
pages = {2008},
doi = {10.1093/neuonc/noac178},
pmid = {35876482},
issn = {1523-5866},
}
@article {pmid35872157,
year = {2022},
author = {Heaphy, CM and Singhi, AD},
title = {The diagnostic and prognostic utility of incorporating DAXX, ATRX, and alternative lengthening of telomeres to the evaluation of pancreatic neuroendocrine tumors.},
journal = {Human pathology},
volume = {129},
number = {},
pages = {11-20},
doi = {10.1016/j.humpath.2022.07.015},
pmid = {35872157},
issn = {1532-8392},
support = {R37 CA263622/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Adaptor Proteins, Signal Transducing/genetics/metabolism ; Biomarkers, Tumor/genetics ; Co-Repressor Proteins/metabolism ; In Situ Hybridization, Fluorescence ; Molecular Chaperones/metabolism ; *Neuroendocrine Tumors/diagnosis/genetics/pathology ; Nuclear Proteins/genetics/metabolism ; *Pancreatic Neoplasms/diagnosis/genetics/metabolism ; Prognosis ; *Telomere/pathology ; X-linked Nuclear Protein/genetics ; },
abstract = {Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of neoplasms with increasing incidence and an ill-defined pathobiology. Although many PanNETs are indolent and remain stable for years, a subset may behave aggressively and metastasize widely. Thus, the increasing and frequent detection of PanNETs presents a treatment dilemma. Current prognostic systems are susceptible to interpretation errors, sampling issues, and do not accurately reflect the clinical behavior of these neoplasms. Hence, additional biomarkers are needed to improve the prognostic stratification of patients diagnosed with a PanNET. Recent studies have identified alterations in death domain-associated protein 6 (DAXX) and alpha-thalassemia/mental retardation X-linked (ATRX), as well as alternative lengthening of telomeres (ALT), as promising prognostic biomarkers. This review summarizes the identification, clinical utility, and specific nuances in testing for DAXX/ATRX by immunohistochemistry and ALT by telomere-specific fluorescence in situ hybridization in PanNETs. Furthermore, a discussion on diagnostic indications for DAXX, ATRX, and ALT status is provided to include the distinction between PanNETs and pancreatic neuroendocrine carcinomas (PanNECs), and determining pancreatic origin for metastatic neuroendocrine tumors in the setting of an unknown primary.},
}
@article {pmid35862346,
year = {2022},
author = {Nadri, P and Ansari-Mahyari, S and Jafarpour, F and Mahdavi, AH and Tanhaei Vash, N and Lachinani, L and Dormiani, K and Nasr-Esfahani, MH},
title = {Melatonin accelerates the developmental competence and telomere elongation in ovine SCNT embryos.},
journal = {PloS one},
volume = {17},
number = {7},
pages = {e0267598},
pmid = {35862346},
issn = {1932-6203},
mesh = {Animals ; Blastocyst/metabolism ; Culture Media/metabolism ; Embryonic Development/genetics ; *Melatonin/metabolism/pharmacology ; *Nuclear Transfer Techniques/veterinary ; RNA, Messenger/metabolism ; Sheep/genetics ; Telomere ; },
abstract = {SCNT embryos suffer from poor developmental competence (both in vitro and in vivo) due to various defects such as oxidative stress, incomplete epigenetic reprogramming, and flaws in telomere rejuvenation. It is very promising to ameliorate all these defects in SCNT embryos by supplementing the culture medium with a single compound. It has been demonstrated that melatonin, as a multitasking molecule, can improve the development of SCNT embryos, but its function during ovine SCNT embryos is unclear. We observed that supplementation of embryonic culture medium with 10 nM melatonin for 7 days accelerated the rate of blastocyst formation in ovine SCNT embryos. In addition, the quality of blastocysts increased in the melatonin-treated group compared with the SCNT control groups in terms of ICM, TE, total cell number, and mRNA expression of NANOG. Mechanistic studies in this study revealed that the melatonin-treated group had significantly lower ROS level, apoptotic cell ratio, and mRNA expression of CASPASE-3 and BAX/BCL2 ratio. In addition, melatonin promotes mitochondrial membrane potential and autophagy status (higher number of LC3B dots). Our results indicate that melatonin decreased the global level of 5mC and increased the level of H3K9ac in the treated blastocyst group compared with the blastocysts in the control group. More importantly, we demonstrated for the first time that melatonin treatment promoted telomere elongation in ovine SCNT embryos. This result offers the possibility of better development of ovine SCNT embryos after implantation. We concluded that melatonin can accelerate the reprogramming of telomere length in sheep SCNT embryos, in addition to its various beneficial effects such as increasing antioxidant capacity, reducing DNA damage, and improving the quality of derived blastocysts, all of which led to a higher in vitro development rate.},
}
@article {pmid35862118,
year = {2022},
author = {Brandt, M and Dörschmann, H and Khraisat, S and Knopp, T and Ringen, J and Kalinovic, S and Garlapati, V and Siemer, S and Molitor, M and Göbel, S and Stauber, R and Karbach, SH and Münzel, T and Daiber, A and Wenzel, P},
title = {Telomere Shortening in Hypertensive Heart Disease Depends on Oxidative DNA Damage and Predicts Impaired Recovery of Cardiac Function in Heart Failure.},
journal = {Hypertension (Dallas, Tex. : 1979)},
volume = {79},
number = {10},
pages = {2173-2184},
doi = {10.1161/HYPERTENSIONAHA.121.18935},
pmid = {35862118},
issn = {1524-4563},
mesh = {Animals ; DNA ; *Heart Failure ; *Hypertension ; Mice ; NADPH Oxidases/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Superoxides/metabolism ; Telomere Shortening ; },
abstract = {BACKGROUND: Heart failure (HF) coincides with cardiomyocyte telomere shortening. Arterial hypertension is the most prominent risk factor for HF. Both HF and arterial hypertension are associated with dysregulation of the neurohormonal axis. How neurohormonal activation is linked to telomere shortening in the pathogenesis of HF is incompletely understood.<br><br>METHODS: Cardiomyocyte telomere length was assessed in a mouse model of hypertensive HF induced by excess neurohormonal activation (AngII [angiotensin II] infusion, high salt diet, and uninephrectomy), in AngII-stimulated cardiomyocytes and in endomyocardial biopsies from patients with HF. Superoxide production, expression of NOX2 (NADPH oxidase 2) and PRDX1 (peroxiredoxin 1) and HDAC6 (histone deacetylase 6) activity were assessed.<br><br>RESULTS: Telomere shortening occurred in vitro and in vivo, correlating with both left ventricular (LV) dilatation and LV systolic function impairment. Telomere shortening coincided with increased superoxide production, increased NOX2 expression, increased HDAC6 activity, loss of the telomere-specific antioxidant PRDX1, and increased oxidative DNA-damage. NOX2 knockout prevented PRDX1 depletion, DNA-damage and telomere shortening confirming this enzyme as a critical source of reactive oxygen species. Cotreatment with the NOX inhibitor apocynin ameliorated hypertensive HF and telomere shortening. Similarly, treatment with the HDAC6 inhibitor tubastatin A, which increases PRDX1 bioavailability, prevented telomere shortening in adult cardiomyocytes. To explore the clinical relevance of our findings, we examined endomyocardial biopsies from an all-comer population of patients with HF with reduced ejection fraction. Here, cardiomyocyte telomere length predicted the recovery of cardiac function.<br><br>CONCLUSIONS: Cardiomyocyte telomere shortening and oxidative damage in heart failure with reduced ejection fraction induced by excess neurohormonal activation depends on NOX2-derived superoxide and may help to stratify HF therapy.},
}
@article {pmid35861921,
year = {2022},
author = {Kayacık Günday, &#xd6; and Özdemir Erdoğan, M and Pehlivan, A and Yılmazer, M},
title = {The effect of metformin treatment on leukocyte telomere length in patients with polycystic ovary syndrome: a prospective case-control study.},
journal = {Journal of assisted reproduction and genetics},
volume = {39},
number = {9},
pages = {2153-2161},
pmid = {35861921},
issn = {1573-7330},
mesh = {Body Mass Index ; C-Reactive Protein/genetics/metabolism ; Case-Control Studies ; Female ; Humans ; Leukocytes/metabolism ; *Metformin/therapeutic use ; *Polycystic Ovary Syndrome/drug therapy/genetics ; Telomere/genetics ; },
abstract = {PURPOSE: The study aimed to investigate the effect of metformin treatment on leukocyte telomere length (LTL) and the relationship of LTL with C-reactive protein (CRP), homocysteine, albumin, complete blood count, and HOMA-IR values in patients with polycystic ovary syndrome (PCOS).<br><br>MATERIAL AND METHOD: A prospective case-control study consisting of 30 women with PCOS and 30 healthy women without PCOS was performed. The relationship between clinical and laboratory parameters and LTL was analyzed. PCOS patients were treated with metformin (850&#xa0;mg/day) for three months. Before treatment (BT) and after treatment (AT), each patient's LTL was evaluated and compared with the control group.<br><br>RESULTS: In the comparison between PCOS and control groups, the difference was significant for LTL, age, body mass index (BMI), and CRP (p&#x2009;=&#x2009;0.002; p&#x2009;<&#x2009;0.001; p&#x2009;=&#x2009;0.001; p&#x2009;=&#x2009;0.01, respectively). In PCOS patients, the difference between BT and AT, LTL was not statistically significant (BT: 6.06&#x2009;&#xb1;&#x2009;2.12; AT: 6.30&#x2009;&#xb1;&#x2009;1.93; p&#x2009;=&#x2009;0.623; 95% C.I:&#x2009;-&#x2009;1.22-0.74); however, the difference for weight was significant (BT: 83.78&#x2009;&#xb1;&#x2009;15.31; AT: 80.62&#x2009;&#xb1;&#x2009;15.40; p&#x2009;=&#x2009;0.02; 95% CI: 1.34-4.99). The logistic regression model established by BMI (group 1: 21-24, group 2: 24-29, group 3: 29-34, group 4:&#x2009;>&#x2009;34), age, and RDW, which predicted the PCOS group by affecting the LTL level, was statistically significant (p&#x2009;<&#x2009;0.001/PPV&#x2009;=&#x2009;96.3%; NPV&#x2009;=&#x2009;88.5%). Each unit reduction in telomere length increased women's probability of PCOS by 0.4 times (p&#x2009;=&#x2009;0.013; OR&#x2009;=&#x2009;0.419, 95% CI: 0.211-0.835).<br><br>CONCLUSION: Although statistically insignificant, LTL increased after metformin use in PCOS patients, and the mean weight loss reduction was statistically significant. Telomere shortening increased the likelihood of PCOS 0.4 times.},
}
@article {pmid35860550,
year = {2022},
author = {Lansdorp, P},
title = {Telomere Length Regulation.},
journal = {Frontiers in oncology},
volume = {12},
number = {},
pages = {943622},
pmid = {35860550},
issn = {2234-943X},
abstract = {The number of (TTAGGG)n repeats at the ends of chromosomes is highly variable between individual chromosomes, between different cells and between species. Progressive loss of telomere repeats limits the proliferation of pre-malignant human cells but also contributes to aging by inducing apoptosis and senescence in normal cells. Despite enormous progress in understanding distinct pathways that result in loss and gain of telomeric DNA in different cell types, many questions remain. Further studies are needed to delineate the role of damage to telomeric DNA, replication errors, chromatin structure, liquid-liquid phase transition, telomeric transcripts (TERRA) and secondary DNA structures such as guanine quadruplex structures, R-loops and T-loops in inducing gains and losses of telomere repeats in different cell types. Limitations of current telomere length measurements techniques and differences in telomere biology between species and different cell types complicate generalizations about the role of telomeres in aging and cancer. Here some of the factors regulating the telomere length in embryonic and adult cells in mammals are discussed from a mechanistic and evolutionary perspective.},
}
@article {pmid35858061,
year = {2022},
author = {Benowitz-Fredericks, ZM and Lacey, LM and Whelan, S and Will, AP and Hatch, SA and Kitaysky, AS},
title = {Telomere length correlates with physiological and behavioural responses of a long-lived seabird to an ecologically relevant challenge.},
journal = {Proceedings. Biological sciences},
volume = {289},
number = {1978},
pages = {20220139},
pmid = {35858061},
issn = {1471-2954},
mesh = {Animals ; *Charadriiformes/physiology ; *Corticosterone ; Food ; Male ; Reproduction/physiology ; Telomere ; },
abstract = {Determinants of individual variation in reallocation of limited resources towards self-maintenance versus reproduction are not well known. We tested the hypothesis that individual heterogeneity in long-term 'somatic state' (i) explains variation in endocrine and behavioural responses to environmental challenges, and (ii) is associated with variation in strategies for allocating to self-maintenance versus reproduction. We used relative telomere length as an indicator of somatic state and experimentally generated an abrupt short-term reduction of food availability (withdrawal of food supplementation) for free-living seabirds (black-legged kittiwakes, Rissa tridactyla). Incubating male kittiwakes responded to withdrawal by increasing circulating corticosterone and losing more weight compared to continuously supplemented controls. Males with longer telomeres increased time in directed travel regardless of treatment, while experiencing smaller increases in corticosterone. Males with longer telomeres fledged more chicks in the control group and tended to be more likely to return regardless of treatment. This study supports the hypothesis that somatic state can explain variation in short-term physiological and behavioural responses to challenges, and longer-term consequences for fitness. Male kittiwakes with longer telomeres appear to have prioritized investment in self over investment in offspring under challenging conditions.},
}
@article {pmid35854470,
year = {2022},
author = {Huang, D and Lin, S and He, J and Wang, Q and Zhan, Y},
title = {Association between COVID-19 and telomere length: A bidirectional Mendelian randomization study.},
journal = {Journal of medical virology},
volume = {94},
number = {11},
pages = {5345-5353},
pmid = {35854470},
issn = {1096-9071},
mesh = {*COVID-19/genetics ; Critical Illness ; *Genome-Wide Association Study ; Humans ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; Telomere/genetics ; },
abstract = {Several traditional observational studies suggested an association between COVID-19 and leukocyte telomere length (LTL), a biomarker for biological age. However, whether there was a causal association between them remained unclear. We aimed to investigate whether genetically predicted COVID-19 is related to the risk of LTL, and vice versa. We performed bidirectional Mendelian randomization (MR) study using summary statistics from the genome-wide association studies of critically ill COVID-19 (n = 1 388 342) and LTL (n = 472 174) of European ancestry. The random-effects inverse-variance weighted estimation method was applied as the primary method with several other estimators as complementary methods. Using six single-nucleotide polymorphisms (SNPs) of genome-wide significance as instrumental variables for critically ill COVID-19, we did not find a significant association of COVID-19 on LTL (β = 0.0075, 95% confidence interval [CI]: -0.018 to 0.021, p = 0.733). Likewise, using 97 SNPs of genome-wide significance as instrumental variables for LTL, we did not find a significant association of LTL on COVID-19 (odds ratio = 1.00, 95% CI: 0.79-1.28, p = 0.973). Comparable results were obtained using MR-Egger regression, weighted median, and weighted mode approaches. We did not find evidence to support a causal association between COVID-19 and LTL in either direction.},
}
@article {pmid35853584,
year = {2022},
author = {Hawks, RM and Kahn, LG and Fang, W and Keefe, D and Mehta-Lee, SS and Brubaker, S and Trasande, L},
title = {Prenatal phthalate exposure and placental telomere length.},
journal = {American journal of obstetrics &amp; gynecology MFM},
volume = {4},
number = {6},
pages = {100694},
pmid = {35853584},
issn = {2589-9333},
support = {R00 ES030403/ES/NIEHS NIH HHS/United States ; },
mesh = {Pregnancy ; Humans ; Female ; *Placenta ; *Phthalic Acids/toxicity ; Telomere/genetics ; },
}
@article {pmid35852986,
year = {2022},
author = {Chang, TR and Long, X and Shastry, S and Parks, JW and Stone, MD},
title = {Single-Molecule Mechanical Analysis of Strand Invasion in Human Telomere DNA.},
journal = {Biochemistry},
volume = {61},
number = {15},
pages = {1554-1560},
pmid = {35852986},
issn = {1520-4995},
support = {R01 GM095850/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA/chemistry ; DNA Replication ; *DNA, Single-Stranded ; *G-Quadruplexes ; Guanine ; Humans ; Telomere/genetics ; },
abstract = {Telomeres are essential chromosome end capping structures that safeguard the genome from dangerous DNA processing events. DNA strand invasion occurs during vital transactions at telomeres, including telomere length maintenance by the alternative lengthening of telomeres (ALT) pathway. During telomeric strand invasion, a single-stranded guanine-rich (G-rich) DNA invades at a complementary duplex telomere repeat sequence, forming a displacement loop (D-loop) in which the displaced DNA consists of the same G-rich sequence as the invading single-stranded DNA. Single-stranded G-rich telomeric DNA readily folds into stable, compact, structures called G-quadruplexes (GQs) in vitro and is anticipated to form within the context of a D-loop; however, evidence supporting this hypothesis is lacking. Here, we report a magnetic tweezers assay that permits the controlled formation of telomeric D-loops (TDLs) within uninterrupted duplex human telomere DNA molecules of physiologically relevant lengths. Our results are consistent with a model wherein the displaced single-stranded DNA of a TDL fold into a GQ. This study provides new insight into telomere structure and establishes a framework for the development of novel therapeutics designed to target GQs at telomeres in cancer cells.},
}
@article {pmid35841174,
year = {2022},
author = {Grigoryan, OR and Frolova, TM and Mikheev, RK and Sheremetyeva, EV and Absatarova, YS and Uzhegova, ZA and Andreeva, EN and Mokrysheva, NG},
title = {[The dual role of the menopausal hormonal therapy as the enhancer of pleiotropic telomere rejuvenation and the silencer of cellular aging (literature review)].},
journal = {Problemy endokrinologii},
volume = {68},
number = {3},
pages = {105-112},
pmid = {35841174},
issn = {2308-1430},
mesh = {Cellular Senescence/genetics ; Female ; Humans ; Menopause ; *Quality of Life ; *Rejuvenation ; Telomere/genetics ; },
abstract = {Present worldwide healthcare researches prove that female patients are more sensitive to the population aging. Menopause or climacteria (climax) - is not as ageing itself, but a physiological unstoppable process. The main task for a physician is to improve life quality for female despite of ageing problems. Menopausal hormone therapy (MHT) due to the estrogen component has an anti-inflammatory, antioxidant effect and promotes the expression of telomerase, which together changes the homeostasis and integrity of telomeres. The use of MHT for five years or more can not only significantly change the quality of life, but also increase its duration. Literature search was carried out in national (eLibrary, CyberLeninka.ru) and international (PubMed, Cochrane Library) databases in Russian and English. The priority was free access to the full text of articles. The choice of sources was prioritized for the period from 2019 to 2021. However, taking into account the insufficient knowledge of the chosen topic, the choice of sources dates back to 1989.},
}
@article {pmid35838223,
year = {2022},
author = {Daios, S and Anogeianaki, A and Kaiafa, G and Kontana, A and Veneti, S and Gogou, C and Karlafti, E and Pilalas, D and Kanellos, I and Savopoulos, C},
title = {Telomere Length as a Marker of Biological Aging: A Critical Review of Recent Literature.},
journal = {Current medicinal chemistry},
volume = {29},
number = {34},
pages = {5478-5495},
doi = {10.2174/0929867329666220713123750},
pmid = {35838223},
issn = {1875-533X},
mesh = {Aging/genetics/metabolism ; Biomarkers ; *Cardiovascular Diseases/genetics ; *Heart Diseases ; Humans ; *Stroke ; Telomere/genetics ; },
abstract = {INTRODUCTION: Aging is characterized as a syndrome of deleterious, progressive, universal, and irreversible function changes affecting every structural and functional aspect of the organism and accompanied by a generalized increase in mortality. Although a substantial number of candidates for biomarkers of aging have been proposed, none has been validated or universally accepted. Human telomeres constitute hexameric repetitive DNA sequence nucleoprotein complexes that cap chromosome ends, regulating gene expression and modulating stress-related pathways. Telomere length (TL) shortening is observed both in cellular senescence and advanced age, leading to the investigation of TL as a biomarker for aging and a risk factor indicator for the development and progression of the most common age-related diseases.<br><br>OBJECTIVE: The present review underlines the connection between TL and the pathophysiology of the diseases associated with telomere attrition.<br><br>METHODS: We performed a structured search of the PubMed database for peer-reviewed research of the literature regarding leukocyte TL and cardiovascular diseases (CVD), more specifically stroke and heart disease, and focused on the relevant articles published during the last 5 years. We also applied Hill's criteria of causation to strengthen this association.<br><br>RESULTS: We analyzed the recent literature regarding TL length, stroke, and CVD. Although approximately one-third of the available studies support the connection, the results of different studies seem to be rather conflicting as a result of different study designs, divergent methods of TL determination, small study samples, and patient population heterogeneity. After applying Hill's criteria, we can observe that the literature conforms to them weakly, with chronology being the only Hill criterion of causality that probably cannot be contested.<br><br>CONCLUSION: The present review attempted to examine the purported relation between leukocyte TL and age-related diseases such as CVD and more specific stroke and heart disease in view of the best established, comprehensive, medical and epidemiological criteria that have characterized the focused recent relevant research. Although several recommendations have been made that may contribute significantly to the field, a call for novel technical approaches and studies is mandatory to further elucidate the possible association.},
}
@article {pmid35836303,
year = {2022},
author = {Heaphy, CM and Joshu, CE and Barber, JR and Davis, C and Lu, J and Zarinshenas, R and Giovannucci, E and Mucci, LA and Stampfer, MJ and Han, M and De Marzo, AM and Lotan, TL and Platz, EA and Meeker, AK},
title = {The prostate tissue-based telomere biomarker as a prognostic tool for metastasis and death from prostate cancer after prostatectomy.},
journal = {The journal of pathology. Clinical research},
volume = {8},
number = {5},
pages = {481-491},
pmid = {35836303},
issn = {2056-4538},
support = {P50 CA058236/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; P30 CA006516/CA/NCI NIH HHS/United States ; P50 CA090381/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Male ; Prognosis ; *Prostate/pathology/surgery ; Prostatectomy/methods ; *Prostatic Neoplasms/pathology/surgery ; Risk Factors ; Telomere/pathology ; },
abstract = {Current biomarkers are inadequate prognostic predictors in localized prostate cancer making treatment decision-making challenging. Previously, we observed that the combination of more variable telomere length among prostate cancer cells and shorter telomere length in prostate cancer-associated stromal cells - the telomere biomarker - is strongly associated with progression to metastasis and prostate cancer death after prostatectomy independent of currently used pathologic indicators. Here, we optimized our method allowing for semi-automated telomere length determination in single cells in fixed tissue, and tested the telomere biomarker in five cohort studies of men surgically treated for clinically localized disease (N = 2,255). We estimated the relative risk (RR) of progression to metastasis (N = 311) and prostate cancer death (N = 85) using models appropriate to each study's design adjusting for age, prostatectomy stage, and tumor grade, which then we meta-analyzed using inverse variance weights. Compared with men who had less variable telomere length among prostate cancer cells and longer telomere length in prostate cancer-associated stromal cells, men with the combination of more variable and shorter telomere length had 3.76 times the risk of prostate cancer death (95% confidence interval [CI] 1.37-10.3, p = 0.01) and had 2.23 times the risk of progression to metastasis (95% CI 0.99-5.02, p = 0.05). The telomere biomarker was associated with prostate cancer death in men with intermediate risk disease (grade groups 2/3: RR = 9.18, 95% CI 1.14-74.0, p = 0.037) and with PTEN protein intact tumors (RR = 6.74, 95% CI 1.46-37.6, p = 0.015). In summary, the telomere biomarker is robust and associated with poor outcome independent of current pathologic indicators in surgically treated men.},
}
@article {pmid35835478,
year = {2022},
author = {Bhatt, SP and Misra, A and Pandey, RM and Upadhyay, AD},
title = {Shortening of leucocyte telomere length is independently correlated with high body mass index and subcutaneous obesity (predominantly truncal), in Asian Indian women with abnormal fasting glycemia.},
journal = {BMJ open diabetes research &amp; care},
volume = {10},
number = {4},
pages = {},
pmid = {35835478},
issn = {2052-4897},
mesh = {Body Mass Index ; *Fasting ; Female ; Glucose ; Humans ; *Obesity/epidemiology/genetics ; Telomere/genetics ; },
abstract = {INTRODUCTION: Leucocyte telomere length (LTL) is linked to accelerate aging and premature mortality. In this research, we aimed to explore the relations between biochemical and anthropometry markers and LTL in Asian Indian women with abnormal fasting glycemia (impaired fasting glucose).<br><br>RESEARCH DESIGN AND METHODS: In this study, 797 pre-diabetic women (obese, 492; non-obese, 305) were recruited. Demographic and clinical profiles, anthropometry, and fasting blood glucose were evaluated. LTL was quantified by a quantitative PCR. LTL was expressed as the relative telomere length or telomere repeat:single copy gene (T:S) ratio. The subjects were separated into quartiles according to the LTL.<br><br>RESULTS: The average LTL was significantly decreased with increasing age. The average LTL was significantly shorter in obese women with abnormal fasting glycemia (p<0.05). R-squared (R[2]) statistic for multivariable linear model after adjusted for age, family income, education and hypertension showed that LTL was inversely correlated with body mass index (BMI), waist and hip circumference, waist-hip and waist-to-height ratio, truncal skinfolds (subscapular, and subscapular/triceps ratio, central and total skinfolds), fat mass (kg) and % body fat. The relationship between obesity measures and LTL (using the LTL quartile 1 as reference) identified central skinfolds (R[2]=0.92, p<0.0001), &#x3a3;4SF (R[2]=0.90, p<0.0001), BMI (R[2]=0.93, p<0.0001) and % body fat (R[2]=0.91, p<0.0001) as independent predictors of LTL.<br><br>CONCLUSIONS: Besides age, obesity and subcutaneous adiposity (predominantly truncal) are major contributors to telomere shortening in Asian Indian women with abnormal fasting glycemia (impaired fasting glucose).},
}
@article {pmid35830881,
year = {2022},
author = {He, Q and Lin, X and Chavez, BL and Agrawal, S and Lusk, BL and Lim, CJ},
title = {Structures of the human CST-Polα-primase complex bound to telomere templates.},
journal = {Nature},
volume = {608},
number = {7924},
pages = {826-832},
pmid = {35830881},
issn = {1476-4687},
support = {75N91019D00024/CA/NCI NIH HHS/United States ; R00 GM131023/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA/metabolism ; *DNA Primase/chemistry/metabolism ; DNA Primers/biosynthesis ; DNA Replication ; Humans ; Protein Domains ; RNA/biosynthesis/metabolism ; *Shelterin Complex/chemistry/metabolism ; Substrate Specificity ; *Telomere/chemistry/genetics/metabolism ; *Templates, Genetic ; },
abstract = {The mammalian DNA polymerase-α-primase (Polα-primase) complex is essential for DNA metabolism, providing the de novo RNA-DNA primer for several DNA replication pathways[1-4] such as lagging-strand synthesis and telomere C-strand fill-in. The physical mechanism underlying how Polα-primase, alone or in partnership with accessory proteins, performs its complicated multistep primer synthesis function is unknown. Here we show that CST, a single-stranded DNA-binding accessory protein complex for Polα-primase, physically organizes the enzyme for efficient primer synthesis. Cryogenic electron microscopy structures of the CST-Polα-primase preinitiation complex (PIC) bound to various types of telomere overhang reveal that template-bound CST partitions the DNA and RNA catalytic centres of Polα-primase into two separate domains and effectively arranges them in RNA-DNA synthesis order. The architecture of the PIC provides a single solution for the multiple structural requirements for the synthesis of RNA-DNA primers by Polα-primase. Several insights into the template-binding specificity of CST, template requirement for assembly of the CST-Polα-primase PIC and activation are also revealed in this study.},
}
@article {pmid35830513,
year = {2022},
author = {Wang, XF and Xu, WJ and Wang, FF and Leng, R and Yang, XK and Ling, HZ and Fan, YG and Tao, JH and Shuai, ZW and Zhang, L and Ye, DQ and Leng, RX},
title = {Telomere Length and Development of Systemic Lupus Erythematosus: A Mendelian Randomization Study.},
journal = {Arthritis &amp; rheumatology (Hoboken, N.J.)},
volume = {74},
number = {12},
pages = {1984-1990},
doi = {10.1002/art.42304},
pmid = {35830513},
issn = {2326-5205},
mesh = {Humans ; *Mendelian Randomization Analysis ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; *Lupus Erythematosus, Systemic/epidemiology ; Telomere/genetics ; Autoantibodies/genetics ; },
abstract = {OBJECTIVE: Previous observational studies demonstrated that a subset of patients with systemic lupus erythematosus (SLE) have markedly short telomere length in leukocytes. This study was undertaken to test whether leukocyte telomere length is causally associated with risk of SLE.<br><br>METHODS: A 2-sample Mendelian randomization (MR) analysis was conducted to estimate causality of telomere length on SLE in European populations. A replication 2-sample MR study using Asian genetic data was also conducted. A reverse MR analysis was then performed to test the effects of SLE on telomere length. The autoantibodies targeting telomere-associated protein (telomeric repeat-binding factor 1 [TERF1] autoantibodies) were detected in patients with SLE, healthy controls, and patients with rheumatoid arthritis.<br><br>RESULTS: The results of the inverse variance-weighted method (odds ratio [OR] 2.96 [95% confidence interval (95% CI) 1.58-5.55], P&#x2009;<&#x2009;0.001) showed strong evidence for a causal relationship between longer telomere length and risk of SLE in people with European ancestry. The outcomes of MR-Egger regression analysis (OR 29.46 [95% CI 3.02-287.60], P&#xa0;=&#xa0;0.033) and MR pleiotropy residual sum and outlier analysis (OR 3.62 [95% CI 2.03-6.46], P&#xa0;=&#xa0;0.002) also showed that longer telomere length was significantly associated with increased risk of SLE in a European population. Sensitivity analyses using different methods and summary data sets showed that the results were still broadly consistent. A replication MR study using Asian genetic data yielded similar findings. However, the reverse MR analysis showed that genetically predicted SLE was not causally associated with telomere length. In addition, we found that TERF1 autoantibodies were present in 2 of 40 SLE patients (5.0%).<br><br>CONCLUSION: In contrast with previous observational studies, MR analyses show that longer telomere length is significantly associated with increased risk of SLE.},
}
@article {pmid35830448,
year = {2022},
author = {Edelson, PK and Sawyer, MR and Gray, KJ and Cantonwine, DE and McElrath, TF and Phillippe, M},
title = {Increase in short telomeres during the third trimester in human placenta.},
journal = {PloS one},
volume = {17},
number = {7},
pages = {e0271415},
pmid = {35830448},
issn = {1932-6203},
support = {K08 HL146963/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Female ; Gestational Age ; Humans ; Infant ; Mice ; *Placenta ; Pregnancy ; Pregnancy Trimester, Third ; Telomere/genetics ; *Telomere Shortening ; },
abstract = {An increase in telomere shortening in gestational tissues has been proposed as a mechanism involved in the timing for the initiation of parturition. An increase in very short telomeres with increasing gestational age has been observed in mice; this study sought to explore this phenomenon in human pregnancies. Specifically, this study addressed the hypothesis that prior to labor, the quantity of very short telomeres (<3 kilobase (kb) lengths) increases in human placental tissue as term gestation approaches. The primary outcome was the quantity of very short telomeres present in placental tissue. Quantitative measurements of very short telomeres were performed using real-time polymerase chain reaction (qPCR) adaptation of the telomere restriction fragment technique. Placental tissue from 69 pregnant individuals were included. Mean gestational age was 39.1 weeks (term) and 36.2 weeks (preterm). For term versus preterm placentas, the observed increase in very short telomeres were as follows: 500 bp telomeres increased by 1.67-fold (p < 0.03); 1 kb telomeres increased 1.67-fold (p < 0.08); and 3 kb telomeres increased 5.20-fold (p < 0.001). This study confirms a significant increase in very short telomeres in human placental tissue at term; thereby supporting the hypothesis that telomere shortening at term contributes to the mechanism that determine the length of pregnancy thereby leading to onset of parturition.},
}
@article {pmid35822010,
year = {2021},
author = {Stock, AJ and Liu, Y},
title = {NAD-Linked Metabolism and Intervention in Short Telomere Syndromes and Murine Models of Telomere Dysfunction.},
journal = {Frontiers in aging},
volume = {2},
number = {},
pages = {785171},
pmid = {35822010},
issn = {2673-6217},
abstract = {Telomeres are specialized nucleoprotein structures that form protective caps at the ends of chromosomes. Short telomeres are a hallmark of aging and a principal defining feature of short telomere syndromes, including dyskeratosis congenita (DC). Emerging evidence suggests a crucial role for critically short telomere-induced DNA damage signaling and mitochondrial dysfunction in cellular dysfunction in DC. A prominent factor linking nuclear DNA damage and mitochondrial homeostasis is the nicotinamide adenine dinucleotide (NAD) metabolite. Recent studies have demonstrated that patients with DC and murine models with critically short telomeres exhibit lower NAD levels, and an imbalance in the NAD metabolome, including elevated CD38 NADase and reduced poly (ADP-ribose) polymerase and SIRT1 activities. CD38 inhibition and/or supplementation with NAD precursors reequilibrate imbalanced NAD metabolism and alleviate mitochondrial impairment, telomere DNA damage, telomere dysfunction-induced DNA damage signaling, and cellular growth retardation in primary fibroblasts derived from DC patients. Boosting NAD levels also ameliorate chemical-induced liver fibrosis in murine models of telomere dysfunction. These findings underscore the relevance of NAD dysregulation to telomeropathies and demonstrate how NAD interventions may prove to be effective in combating cellular and organismal defects that occur in short telomere syndromes.},
}
@article {pmid35821228,
year = {2022},
author = {Bürgin, D and Varghese, N and Eckert, A and Clemens, V and Unternährer, E and Boonmann, C and O'Donovan, A and Schmid, M},
title = {Higher hair cortisol concentrations associated with shorter leukocyte telomere length in high-risk young adults.},
journal = {Scientific reports},
volume = {12},
number = {1},
pages = {11730},
pmid = {35821228},
issn = {2045-2322},
support = {K01 MH109871/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Female ; Hair ; Humans ; *Hydrocortisone ; *Leukocytes/physiology ; Male ; Pituitary-Adrenal System ; Telomere/genetics ; Young Adult ; },
abstract = {Chronic stress is associated with accelerated biological aging as indexed by short age-adjusted leukocyte telomere length (LTL). Exploring links of biological stress responses with LTL has proved challenging due to the lack of biological measures of chronic psychological stress. Hair cortisol concentration (HCC) has emerged as a measure of chronic hypothalamic pituitary adrenal (HPA) axis activation, allowing the examination of relationships between aggregate cortisol concentrations over time and LTL. Our sample includes 92 participants (38% women, Mage = 26 ± 3.7 years) from a high-risk sample of young adults with previous residential care placements. Two cm hair was collected for HCC, reflecting approximately eight weeks of cortisol secretion. LTL was measured with quantitative polymerase chain reaction (qPCR) in whole blood samples. All samples for LTL were run in triplicate and assayed twice. Linear and polynomial regression models were used to describe the association between HCC and LTL, adjusting for age and sex. HCC and LTL showed negative associations (std. ß = - 0.67, 95% CI [- 0.83, - 0.52], p < .001) in age- and sex-adjusted analyses, indicating that higher HCCs are associated with shorter LTL. Using polynomial regression, we found a curvilinear relationship indicating a stronger negative association at lower cortisol concentrations. Higher HCCs were associated with shorter LTL, supporting the hypothesized involvement of prolonged cortisol secretion in telomere attrition. Thus, HCC may prove useful as a biological indicator of chronic stress associated with aging-related processes in samples exposed to high levels of stress.},
}
@article {pmid35820929,
year = {2022},
author = {Ellis, PS and Martins, RR and Thompson, EJ and Farhat, A and Renshaw, SA and Henriques, CM},
title = {A subset of gut leukocytes has telomerase-dependent "hyper-long" telomeres and require telomerase for function in zebrafish.},
journal = {Immunity &amp; ageing : I &amp; A},
volume = {19},
number = {1},
pages = {31},
pmid = {35820929},
issn = {1742-4933},
support = {MR/M004864/1/MRC_/Medical Research Council/United Kingdom ; MR/M004864/1/MRC/MRC_/Medical Research Council/United Kingdom ; 206224/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; Vice Chancellor's Fellowship//University of Sheffield/ ; MR/P020941/1/MRC_/Medical Research Council/United Kingdom ; PhD Studentship//The University of Sheffield/ ; },
abstract = {BACKGROUND: Telomerase, the enzyme capable of elongating telomeres, is usually restricted in human somatic cells, which contributes to progressive telomere shortening with cell-division and ageing. T and B-cells cells are somatic cells that can break this rule and can modulate telomerase expression in a homeostatic manner. Whereas it seems intuitive that an immune cell type that depends on regular proliferation outbursts for function may have evolved to modulate telomerase expression it is less obvious why others may also do so, as has been suggested for macrophages and neutrophils in some chronic inflammation disease settings. The gut has been highlighted as a key modulator of systemic ageing and is a key tissue where inflammation must be carefully controlled to prevent dysfunction. How telomerase may play a role in innate immune subtypes in the context of natural ageing in the gut, however, remains to be determined.<br><br>RESULTS: Using the zebrafish model, we show that subsets of gut immune cells have telomerase-dependent"hyper-long" telomeres, which we identified as being predominantly macrophages and dendritics (mpeg1.1[+] and cd45[+]mhcII[+]). Notably, mpeg1.1[+] macrophages have much longer telomeres in the gut than in their haematopoietic tissue of origin, suggesting that there is modulation of telomerase in these cells, in the gut. Moreover, we show that a subset of gut mpeg1.1[+] cells express telomerase (tert) in young WT zebrafish, but that the relative proportion of these cells decreases with ageing. Importantly, this is accompanied by telomere shortening and DNA damage responses with ageing and a telomerase-dependent decrease in expression of autophagy and immune activation markers. Finally, these telomerase-dependent molecular alterations are accompanied by impaired phagocytosis of E. coli and increased gut permeability in vivo.<br><br>CONCLUSIONS: Our data show that limiting levels of telomerase lead to alterations in gut immunity, impacting on the ability to clear pathogens in vivo. These are accompanied by increased gut permeability, which, together, are likely contributors to local and systemic tissue degeneration and increased susceptibility to infection with ageing.},
}
@article {pmid35820392,
year = {2022},
author = {Olaya, I and Burgess, SM},
title = {When the anchor's away, meiotic telomeres go astray.},
journal = {Developmental cell},
volume = {57},
number = {13},
pages = {1563-1565},
doi = {10.1016/j.devcel.2022.06.014},
pmid = {35820392},
issn = {1878-1551},
support = {R25 GM116690/GM/NIGMS NIH HHS/United States ; R35 GM145244/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromosome Pairing ; Meiosis/genetics ; Microtubules ; *Telomere/genetics ; *Zebrafish/genetics ; },
abstract = {During meiosis, microtubules emanate from the centrosome to cluster telomeres in the bouquet configuration and facilitate chromosome pairing. In a recent issue of Science, Mytlis et al. establish that a cilium in zebrafish anchors the centrosome and is important for telomere clustering and germ cell development.},
}
@article {pmid35818177,
year = {2022},
author = {Inandiklioglu, N and Demir, V and Celik, Y and Demirtas, M},
title = {Leukocyte telomere length and lipid parameters in patients with myocardial infarction with non-obstructive coronary arteries.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {67},
number = {6},
pages = {346-352},
doi = {10.14715/cmb/2021.67.6.45},
pmid = {35818177},
issn = {1165-158X},
mesh = {Cholesterol, HDL ; *Coronary Artery Disease/diagnosis ; Coronary Vessels ; Humans ; Leukocytes ; MINOCA ; *Myocardial Infarction/genetics ; Risk Factors ; Telomere/genetics ; },
abstract = {Myocardial infarction with non-obstructive coronary arteries (MINOCA) is defined as stenosis of less than 50% or no stenosis on coronary angiography in a patient diagnosed with myocardial infarction. Telomere length is expressed by studies that it acts as a biomarker, especially for biological aging and cardiovascular diseases. In this study, we aimed to investigate whether there is a relationship between circulating leukocyte telomere length (LTL) and serum lipid values in MINOCA patients. Forty-five newly diagnosed patients with MINOCA were included in the study, along with 45 healthy controls who matched the patients in terms of age and gender. We determined the LTL value using the RT-PCR method. As a result of the study, we found LTL (p< 0.001) and serum lipid values (HDL-cholesterol (p< 0.001), LDL-cholesterol (p< 0.001), triglycerides (p< 0.05), and total cholesterol (p< 0.05)) to be significantly higher in the MINOCA group than in the control group. When the correlation relationship between LTL and lipid values in the MINOCA group was evaluated, a negative correlation was determined only between LTL and HDL (p=0.014, r=-0.362). This is the first study to evaluate telomere length in MINOCA patients in Turkey. Our results support the existence of short telomere length in MINOCA patients.},
}
@article {pmid35816887,
year = {2022},
author = {Ribas-Maynou, J and Llavanera, M and Mateo-Otero, Y and Ruiz, N and Muiño, R and Bonet, S and Yeste, M},
title = {Telomere length in bovine sperm is related to the production of reactive oxygen species, but not to reproductive performance.},
journal = {Theriogenology},
volume = {189},
number = {},
pages = {290-300},
doi = {10.1016/j.theriogenology.2022.06.025},
pmid = {35816887},
issn = {1879-3231},
mesh = {Animals ; Cattle ; Female ; Humans ; In Situ Hybridization, Fluorescence/veterinary ; Insemination, Artificial/veterinary ; Male ; Reactive Oxygen Species ; *Semen ; *Spermatozoa ; Telomere ; },
abstract = {Over the last decades, selection in cattle has mainly been based on milk production rather than on reproductive efficiency. While, when applied, focus on reproduction has involved females, attention has barely been paid to males and, if so, it has only looked at classical sperm quality parameters. In effect, variables such as telomere length have been missed, despite the fact that longer telomeres have been suggested to be linked to male fertility in humans. For this reason, the present study aimed to determine the length of telomeres in bovine sperm and their relationship with a) sperm quality evaluated through the conventional spermiogram and flow cytometry, and b) bull reproductive performance. For this purpose, 29 bulls were involved in this study. Sperm telomere length was evaluated through quantitative Fluorescent In Situ Hybridization (qFISH), and sperm quality was determined at 0 h and 4 h post-thaw. Bull fertility was assessed as non-return to estrus rates after 90 days of artificial insemination. Although the mean telomere length in bovine sperm was 12.06 ± 2.75 kb, the intra-individual variability in length led us to observe three different groups of telomeres in each sperm cell: short telomeres (7.14% ± 5.79% of telomeres; 8.29 ± 2.34 kb), medium telomeres (31.03% ± 12.92% of telomeres; 16.00 ± 2.72 kb) and long telomeres (61.93% ± 18.11% of telomeres; 30.13 ± 11.35 kb). Moreover, whereas reactive oxygen species (ROS) were found to be correlated to sperm telomere length (Rs = -0.492; P= 0.007), no correlation with other sperm quality parameters was found (P > 0.05). Reproductive performance after artificial insemination was not seen to be correlated to sperm telomere length (Rs = 0.123; P= 0.520). In conclusion, this study determined, for the first time, the mean telomere length in bovine sperm and also reported that there is a high variability within each sperm cell. Yet, while telomere length was found to be correlated to ROS generation, it was not related to bull reproductive performance.},
}
@article {pmid35812693,
year = {2022},
author = {Gupta, A and Hwang, BJ and Benyamien-Roufaeil, D and Jain, S and Liu, S and Gonzales, R and Brown, RA and Zalzman, M and Lu, AL},
title = {Mammalian MutY Homolog (MYH or MUTYH) is Critical for Telomere Integrity under Oxidative Stress.},
journal = {OBM geriatrics},
volume = {6},
number = {2},
pages = {},
pmid = {35812693},
issn = {2638-1311},
support = {R01 AR070819/AR/NIAMS NIH HHS/United States ; R01 GM118837/GM/NIGMS NIH HHS/United States ; },
abstract = {Telomeres consist of special features and proteins to protect the ends of each chromosome from deterioration and fusion. The telomeric DNA repeats are highly susceptible to oxidative damage that can accelerate telomere shortening and affect telomere integrity. Several DNA repair factors including MYH/MUTYH DNA glycosylase, its interacting partners Rad9/Rad1/Hus1 checkpoint clamp, and SIRT6 aging regulator, are associated with the telomeres. MYH prevents C:G to A:T mutation by removing adenine mispaired with a frequent oxidative DNA lesion, 8-oxoguanine. Here, we show that hMYH knockout (KO) human HEK-293T cells are more sensitive to H2O2 treatment, have higher levels of DNA strand breaks and shorter telomeres than the control hMYH [+/+] cells. SIRT6 foci increase at both the global genome and at telomeric regions in H2O2-treated hMYH [+/+] cells. However, in untreated hMYH KO HEK-293T cells, SIRT6 foci only increase at the global genome, but not at the telomeric regions. In addition, the hMYH KO HEK-293T cells have increased extra-chromosomal and intra-chromosomal telomeres compared to the control cells, even in the absence of H2O2 treatment. After H2O2 treatment, the frequency of extra-chromosomal telomeres increased in control HEK-293T cells. Remarkably, in H2O2-treated hMYH KO cells, the frequencies of extra-chromosomal telomeres, intra-chromosomal telomeres, and telomere fusions are further increased. We further found that the sensitivity to H2O2 and shortened telomeres of hMYH KO cells, are restored by expressing wild-type hMYH, and partially rescued by expressing hMYH[Q324H] mutant (defective in Hus1 interaction only), but not by expressing hMYH[V315A] mutant (defective in both SIRT6 and Hus1 interactions). Thus, MYH interactions with SIRT6 and Hus1 are critical for maintaining cell viability and telomeric stability. Therefore, the failure to coordinate 8-oxoG repair is detrimental to telomere integrity.},
}
@article {pmid35811822,
year = {2022},
author = {Giguere, DJ and Bahcheli, AT and Slattery, SS and Patel, RR and Browne, TS and Flatley, M and Karas, BJ and Edgell, DR and Gloor, GB},
title = {Telomere-to-telomere genome assembly of Phaeodactylum tricornutum.},
journal = {PeerJ},
volume = {10},
number = {},
pages = {e13607},
pmid = {35811822},
issn = {2167-8359},
mesh = {*Diatoms/genetics ; *Genome, Mitochondrial/genetics ; Telomere/genetics ; },
abstract = {Phaeodactylum tricornutum is a marine diatom with a growing genetic toolbox available and is being used in many synthetic biology applications. While most of the genome has been assembled, the currently available genome assembly is not a completed telomere-to-telomere assembly. Here, we used Oxford Nanopore long reads to build a telomere-to-telomere genome for Phaeodactylum tricornutum. We developed a graph-based approach to extract all unique telomeres, and used this information to manually correct assembly errors. In total, we found 25 nuclear chromosomes that comprise all previously assembled fragments, in addition to the chloroplast and mitochondrial genomes. We found that chromosome 19 has filtered long-read coverage and a quality estimate that suggests significantly less haplotype sequence variation than the other chromosomes. This work improves upon the previous genome assembly and provides new opportunities for genetic engineering of this species, including creating designer synthetic chromosomes.},
}
@article {pmid35810694,
year = {2022},
author = {Seo, SH and Shin, JH and Ham, DW and Shin, EH},
title = {PTEN/AKT signaling pathway related to hTERT downregulation and telomere shortening induced in Toxoplasma GRA16-expressing colorectal cancer cells.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {153},
number = {},
pages = {113366},
doi = {10.1016/j.biopha.2022.113366},
pmid = {35810694},
issn = {1950-6007},
mesh = {*Colorectal Neoplasms/genetics ; Down-Regulation/genetics ; Humans ; PTEN Phosphohydrolase/genetics/metabolism ; Protein Phosphatase 2/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction ; *Telomerase/metabolism ; Telomere/genetics/metabolism ; Telomere Shortening ; *Toxoplasma ; },
abstract = {This study investigated whether the molecular mechanism of granule protein 16 (GRA16), a dense granule protein of Toxoplasma gondii (T. gondii) that induces cancer cell apoptosis, results in telomere shortening in cancer cells. The molecular mechanism of GRA16 responsible for regulating telomerase reverse transcriptase (hTERT) activity and telomere shortening was investigated using GRA16-transferred HCT116 human colorectal cancer cells (GRA16-stable cells). GRA16 directly decreased hTERT expression by downregulating the expression and phosphorylation of hTERT transcriptional factors accompanied by decreased expression of shelterin complex molecules. Moreover, GRA16 resulted in cancer cell death through reduction of telomerase activity which leads to telomere shortening (decreased relative ratio of telomeric repeat-amplified sequence to that of a single-copy gene) (T/S ratio)), and at the same time gamma-H2A histone family member X (γ-H2A.X) stained nucleus was increased in the cells. The molecular mechanism between GRA16 and hTERT inactivation was revealed using inhibitors for phosphatase and tensin homolog (PTEN) and protein phosphatase 2A (PP2A) as well as siRNAs against PTEN and PP2A. hTERT dephosphorylation was induced effectively by the signaling pathway of HAUSP/PTEN/p-AKT(S473) but not by PP2A-B55/p-AKT(T308). Inhibition of the PTEN signaling pathway increased mRNA expressions in hTERT transcriptional factors, cell cycle activating factors, and apoptosis-inhibiting factors. When HCT116 cells were infected with T. gondii, the number of γ-H2A.X-stained nuclei also increased and p-hTERT/hTERT decreased as in GRA16-stable cells. Altogether, our results emphasize that GRA16 is a novel promising telomerase inhibitor that causes telomere shortening through telomerase inactivation by inducing the activation of the tumor suppressor PTEN.},
}
@article {pmid35807292,
year = {2022},
author = {Zou, T and Sato, Y and Kaneyoshi, S and Mano, K and Yasukawa, R and Nakano, Y and Fujii, S and Sato, S and Takenaka, S},
title = {Naphthalene Diimides Carrying Two β-Cyclodextrins Prefer Telomere RNA G-Quadruplex Recognition.},
journal = {Molecules (Basel, Switzerland)},
volume = {27},
number = {13},
pages = {},
pmid = {35807292},
issn = {1420-3049},
support = {19H02748//Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology,/ ; S.T.//Nakatani Foundation for advancement of measuring technologies in biomedical engineering/ ; },
mesh = {*G-Quadruplexes ; Imides/chemistry ; Ligands ; Naphthalenes ; RNA ; Telomere/genetics ; *beta-Cyclodextrins ; },
abstract = {Newly synthesized naphthalene diimide carrying two β-cyclodextrins (NDI-β-CyDs) showed improved specificity for the parallel G-quadruplex structure alongside the hybrid G-quadruplex structure. Specifically, the highest binding affinity of NDI-β-CyDs for the telomere RNA G-quadruplex was observed. The binding simulation indicated that β-cyclodextrins might be available for loop nucleobase inclusion under its complex.},
}
@article {pmid35805953,
year = {2022},
author = {Zhou, D and Li, Z and Sun, Y and Yan, J and Huang, G and Li, W},
title = {Early Life Stage Folic Acid Deficiency Delays the Neurobehavioral Development and Cognitive Function of Rat Offspring by Hindering De Novo Telomere Synthesis.},
journal = {International journal of molecular sciences},
volume = {23},
number = {13},
pages = {},
pmid = {35805953},
issn = {1422-0067},
support = {81602849//National Natural Science Foundation of China/ ; 81730091//National Natural Science Foundation of China/ ; 82003439//National Natural Science Foundation of China/ ; 19JCQNJC11700//Natural Science Foundation of Tianjin City/ ; },
mesh = {Animals ; Cognition ; Dietary Supplements ; Female ; Folic Acid/metabolism ; *Folic Acid Deficiency/complications/metabolism ; Rats ; Telomere/metabolism ; Uracil ; },
abstract = {Early life stage folate status may influence neurodevelopment in offspring. The developmental origin of health and disease highlights the importance of the period of the first 1000 days (from conception to 2 years) of life. This study aimed to evaluate the effect of early life stage folic acid deficiency on de novo telomere synthesis, neurobehavioral development, and the cognitive function of offspring rats. The rats were divided into three diet treatment groups: folate-deficient, folate-normal, and folate-supplemented. They were fed the corresponding diet from 5 weeks of age to the end of the lactation period. After weaning, the offspring rats were still fed with the corresponding diet for up to 100 days. Neurobehavioral tests, folic acid and homocysteine (Hcy) levels, relative telomere length in brain tissue, and uracil incorporation in telomere in offspring were measured at different time points. The results showed that folic acid deficiency decreased the level of folic acid, increased the level of Hcy of brain tissue in offspring, increased the wrong incorporation of uracil into telomeres, and hindered de novo telomere synthesis. However, folic acid supplementation increased the level of folic acid, reduced the level of Hcy of brain tissue in offspring, reduced the wrong incorporation of uracil into telomeres, and protected de novo telomere synthesis of offspring, which was beneficial to the development of early sensory-motor function, spatial learning, and memory in adolescence and adulthood. In conclusion, early life stage folic acid deficiency had long-term inhibiting effects on neurodevelopment and cognitive function in offspring.},
}
@article {pmid35805470,
year = {2022},
author = {Assis, V and de Sousa Neto, IV and Ribeiro, FM and de Cassia Marqueti, R and Franco, OL and da Silva Aguiar, S and Petriz, B},
title = {The Emerging Role of the Aging Process and Exercise Training on the Crosstalk between Gut Microbiota and Telomere Length.},
journal = {International journal of environmental research and public health},
volume = {19},
number = {13},
pages = {},
pmid = {35805470},
issn = {1660-4601},
mesh = {Dysbiosis ; Exercise ; *Gastrointestinal Microbiome ; Humans ; Inflammation ; Telomere ; },
abstract = {Aging is a natural process of organism deterioration, which possibly impairs multiple physiological functions. These harmful effects are linked to an accumulation of somatic mutations, oxidative stress, low-grade inflammation, protein damage, and mitochondrial dysfunction. It is known that these factors are capable of inducing telomere shortening, as well as intestinal dysbiosis. Otherwise, among the biological mechanisms triggered by physical exercise, the attenuation of pro-inflammatory mediators accompanied by redox state improvement can be the main mediators for microbiota homeostasis and telomere wear prevention. Thus, this review highlights how oxidative stress, inflammation, telomere attrition, and gut microbiota (GM) dysbiosis are interconnected. Above all, we provide a logical foundation for unraveling the role of physical exercise in this process. Based on the studies summarized in this article, exercise training can increase the biodiversity of beneficial microbial species, decrease low-grade inflammation and improve oxidative metabolism, these factors together possibly reduce telomeric shortening.},
}
@article {pmid35805162,
year = {2022},
author = {Min, S and Kwon, SM and Hong, J and Lee, YK and Park, TJ and Lim, SB and Yoon, G},
title = {Mitoribosomal Deregulation Drives Senescence via TPP1-Mediated Telomere Deprotection.},
journal = {Cells},
volume = {11},
number = {13},
pages = {},
pmid = {35805162},
issn = {2073-4409},
mesh = {Animals ; *Cellular Senescence/physiology ; Mice ; *Mitochondria/metabolism ; Rats ; *Ribosomes/metabolism ; *Shelterin Complex ; Telomere/metabolism ; *Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {While mitochondrial bioenergetic deregulation has long been implicated in cellular senescence, its mechanistic involvement remains unclear. By leveraging diverse mitochondria-related gene expression profiles derived from two different cellular senescence models of human diploid fibroblasts, we found that the expression of mitoribosomal proteins (MRPs) was generally decreased during the early-to-middle transition prior to the exhibition of noticeable SA-β-gal activity. Suppressed expression patterns of the identified senescence-associated MRP signatures (SA-MRPs) were validated in aged human cells and rat and mouse skin tissues and in aging mouse fibroblasts at single-cell resolution. TIN2- and POT1-interaction protein (TPP1) was concurrently suppressed, which induced senescence, accompanied by telomere DNA damage. Lastly, we show that SA-MRP deregulation could be a potential upstream regulator of TPP1 suppression. Our results indicate that mitoribosomal deregulation could represent an early event initiating mitochondrial dysfunction and serve as a primary driver of cellular senescence and an upstream regulator of shelterin-mediated telomere deprotection.},
}
@article {pmid35804173,
year = {2022},
author = {Magnano San Lio, R and Maugeri, A and La Rosa, MC and Giunta, G and Panella, M and Cianci, A and Caruso, MAT and Agodi, A and Barchitta, M},
title = {Nutrient intakes and telomere length of cell-free circulating DNA from amniotic fluid: findings from the Mamma &amp; Bambino cohort.},
journal = {Scientific reports},
volume = {12},
number = {1},
pages = {11671},
pmid = {35804173},
issn = {2045-2322},
mesh = {*Amniotic Fluid ; *Cell-Free Nucleic Acids/genetics ; Diet ; Eating ; Female ; Humans ; Magnesium ; Pregnancy ; Prospective Studies ; Telomere/genetics ; },
abstract = {Pregnancy represents a crucial period in which several exposures-and especially maternal diet-might shape children's health. Thus, identifying how maternal dietary intakes early affect biological aging in children represents a public health mission. We aimed to assess the relationship between maternal intake of nutrients in early pregnancy and telomere length of cell-free circulating DNA (cfDNA) from amniotic fluid. We used data and samples from the ongoing prospective "Mamma &amp; Bambino" study, which recruits mother-child pairs from Catania at the first prenatal visit. Maternal nutrient intakes were assessed using a Food Frequency Questionnaire, while relative telomere length of cfDNA was assessed by real-time polymerase chain reaction. Our analysis included 174 mother-child pairs. The intakes of iron, vitamin B1, and magnesium were positively correlated with relative telomere length (p-values < 0.05). However, only the intake of magnesium was positively associated with relative telomere length, after applying a linear regression model (β = 0.002; SE = 0.001; p = 0.024). Magnesium deficiency was negatively associated with relative telomere length after adjusting for the same covariates (β = -0.467; SE = 0.176; p = 0.009). To our knowledge, this is the first evidence of a positive relationship between maternal nutrient intake and telomere length of cfDNA. Further efforts are needed for deeply investigating the effect of maternal dietary intakes on telomere length, in order to develop effective public health strategies.},
}
@article {pmid35802889,
year = {2022},
author = {Zhou, J and Chen, F and Yan, A and Xia, X},
title = {Explore the molecular mechanism of angle-closure glaucoma in elderly patients induced telomere shortening of retinal ganglion cells through oxidative stress.},
journal = {Nucleosides, nucleotides &amp; nucleic acids},
volume = {41},
number = {10},
pages = {1024-1035},
doi = {10.1080/15257770.2022.2094947},
pmid = {35802889},
issn = {1532-2335},
mesh = {Animals ; Disease Models, Animal ; Fluorescent Dyes/metabolism ; *Glaucoma/metabolism/pathology ; *Glaucoma, Angle-Closure/metabolism/pathology ; Intraocular Pressure ; *Ketamine/metabolism ; Mice ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Retinal Ganglion Cells/metabolism/pathology ; *Telomerase ; Telomere Shortening ; Xylazine/metabolism ; beta-Galactosidase/metabolism ; },
abstract = {Senile glaucoma is a common ophthalmological disease in the elderly. It is a disease of visual papillary perfusion caused by elevated intraocular pressure, complicated by visual dysfunction. Glaucoma can cause serious damage to the normal vision of the elderly. Therefore, exploring the related molecular mechanisms of glaucoma is of great significance to the diagnosis and treatment of glaucoma. This is an exploratory study. Establish a mouse model and conduct experimental groupings. After one week of adaptive feeding, the mice were intraperitoneally injected with an anesthetic mixture: ketamine + xylazine. Then the mice were sacrificed by neck dissection, and the eyeball tissues were immediately dissected. HE staining was used to analyze the histopathological characteristics of the retina of each group of mice. MitoSOX fluorescent probe was used to analyze the content of ROS in retinal tissue. The ELISA analysis was used to detect the activation of β-galactosidase for the aging characteristics of retinal ganglion cells in retinal tissues. Immunohistochemistry experiments were used to analyze the expression of telomerase TERT in retinal tissues. Western blot analysis was used to determine the expression of proteins POT1, TERF1, TERF2, and TINF2 in retinal tissues. The HE staining experiment showed that the damage of retinal tissue decreased from group Glaucoma to group Old, group Old to group Young. The experimental results of MitoSOX fluorescent probe show that ROS content is positively correlated with the degree of tissue damage. ELISA analysis results showed that the expression trend of β-galactosidase was the same as the ROS content. The protein expression levels related to telomere protection (TRET, POT1, TREF1, TREF2 and TINF2) all increased from group Glaucoma to group Old, group Old to group Young. The increase in ROS content, the decrease in telomere protection-related protein expression (telomere shortening) induced by ROS, and the increase of the expression of β-galactosidase, are all potential molecular mechanisms for the occurrence of angle-closure glaucoma in elderly patients.},
}
@article {pmid35801658,
year = {2022},
author = {Tsai, LK and Ou-Yang, H and Xu, J and Chen, CM and Chang, WF and Sung, LY},
title = {Effects of Recloning on the Telomere Lengths of Mouse Terc[+/-] Nuclear Transfer-Derived Embryonic Stem Cells.},
journal = {Stem cells and development},
volume = {31},
number = {21-22},
pages = {720-729},
doi = {10.1089/scd.2022.0115},
pmid = {35801658},
issn = {1557-8534},
mesh = {Mice ; Animals ; *Telomerase/genetics/metabolism ; RNA/genetics ; Telomere/genetics ; Embryonic Stem Cells/metabolism ; },
abstract = {Haploinsufficiency of genes that participate in telomere elongation and maintenance processes, such as telomerase RNA component (Terc) and telomere reverse transcriptase (Tert), often leads to premature aging-related diseases such as dyskeratosis congenita and aplastic anemia. Previously, we reported that when mouse Terc[+/-] tail tip fibroblasts (TTFs) were used as donor cells for somatic cell nuclear transfer (SCNT, also known as cloning), the derivative embryonic stem cells (ntESCs) had elongated telomeres. In the present work, we are interested to know if an additional round of SCNT, or recloning, could lead to further elongation of telomeres. Terc[+/-] TTFs were used to derive the first-generation (G1) ntESCs, followed by a second round of SCNT using G1-Terc[+/-] ntESCs as donor cells to derive G2-Terc[+/-] ntESCs. Multiple lines of G1- and G2-Terc[+/-] ntESCs were efficiently established, and all expressed major pluripotent markers and supported efficient chondrocyte differentiation in vitro. Compared with donor TTFs, telomere lengths of G1 ntESCs were elongated to the level comparable with that in wild-type ntESCs. Interestingly, recloning did not further elongate the telomere lengths of Terc[+/-] ntESCs. Together, our work demonstrates that while a single round of SCNT is a viable means to reprogram Terc haploinsufficient cells to the ESC state, and to elongate these cells' telomere lengths, a second round of SCNT does not necessarily further elongate the telomeres.},
}
@article {pmid35795254,
year = {2022},
author = {Stinus, S and Bringas, FRR and Wanders, L and Chang, M},
title = {Investigating the role of G-quadruplexes at Saccharomyces cerevisiae telomeres.},
journal = {Microbial cell (Graz, Austria)},
volume = {9},
number = {6},
pages = {126-132},
pmid = {35795254},
issn = {2311-2638},
abstract = {The G-quadruplex consensus motif G≥3NxG≥3NxG≥3NxG≥3 is found at telomeres of many species, ranging from yeast to plants to humans, but the biological significance of this fact remains largely unknown. In this study, we examine the in vivo relevance of telomeric G-quadruplexes in the budding yeast Saccharomyces cerevisiae by expressing a mutant telomerase RNA subunit (tlc1-tm) that introduces mutant [(TG)0-4TGG]xATTTGG telomeric repeats instead of wild-type (TG)0-6TGGGTGTG(G)0-1 repeats to the distal ends of telomeres. The tlc1-tm telomere sequences lack the GGG motif present in every wild-type repeat and, therefore, are expected to be impaired in the formation of G-quadruplexes. Circular dichroism analysis of oligonucleotides consisting of tlc1-tm telomeric sequence is consistent with this hypothesis. We have previously shown that tlc1-tm cells grow similarly to wild-type cells, suggesting that the ability to form telomeric G-quadruplexes is not essential for telomere capping in S. cerevisiae cells.},
}
@article {pmid35791675,
year = {2024},
author = {Ma, Y and Wang, M and Chen, X and Ruan, W and Yao, J and Lian, X},
title = {Telomere length and multiple sclerosis: a Mendelian randomization study.},
journal = {The International journal of neuroscience},
volume = {134},
number = {3},
pages = {229-233},
doi = {10.1080/00207454.2022.2098737},
pmid = {35791675},
issn = {1563-5279},
mesh = {Humans ; *Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Multiple Sclerosis/genetics ; Odds Ratio ; Telomere/genetics ; },
abstract = {PURPOSE OF THE STUDY: Previous studies have established that telomere length is associated with multiple sclerosis (MS). However, confounding factors and reverse causality bias can impair observational research. Here, we conducted a two-sample MR study to see if telomere length is causally linked to MS using publically available GWAS summary statistics.<br><br>MATERIALS AND METHODS: We screened 13 independent single-nucleotide polymorphisms (SNPs) related to leukocyte telomere length in a recent genome-wide association meta-analysis, which was available for 78,592 samples of European ancestry. The summary statistics for MS were from the latest meta-analyses conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC), which included 115,803 European participants (47,429&#x2009;MS, 68,374 controls).<br><br>RESULTS: We found that leukocyte telomere length and MS are correlated (IVW estimate of odds ratio (OR): 2.13 per 1-SD increase in genetically determined telomere length, 95% confidence interval (CI): 1.55-2.92, p&#x2009;=&#x2009;3.18&#x2009;&#xd7;&#x2009;10[-6]).<br><br>CONCLUSION: Our MR study supported that leukocyte telomere length and MS have a positive causal relationship. Further researches are warranted to elucidate the physiological mechanism.},
}
@article {pmid35790854,
year = {2022},
author = {Gao, J and Pickett, HA},
title = {Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies.},
journal = {Nature reviews. Cancer},
volume = {22},
number = {9},
pages = {515-532},
pmid = {35790854},
issn = {1474-1768},
mesh = {DNA Replication ; Humans ; *Neoplasms/drug therapy/genetics ; *Telomerase/genetics ; Telomere/genetics/metabolism ; Telomere Homeostasis ; },
abstract = {Cancer cells establish replicative immortality by activating a telomere-maintenance mechanism (TMM), be it telomerase or the alternative lengthening of telomeres (ALT) pathway. Targeting telomere maintenance represents an intriguing opportunity to treat the vast majority of all cancer types. Whilst telomerase inhibitors have historically been heralded as promising anticancer agents, the reality has been more challenging, and there are currently no therapeutic options for cancer types that use ALT despite their aggressive nature and poor prognosis. In this Review, we discuss the mechanistic differences between telomere maintenance by telomerase and ALT, the current methods used to detect each mechanism, the utility of these tests for clinical diagnosis, and recent developments in the therapeutic strategies being employed to target both telomerase and ALT. We present notable developments in repurposing established therapeutic agents and new avenues that are emerging to target cancer types according to which TMM they employ. These opportunities extend beyond inhibition of telomere maintenance, by finding and exploiting inherent weaknesses in the telomeres themselves to trigger rapid cellular effects that lead to cell death.},
}
@article {pmid35789082,
year = {2022},
author = {Elam, KK and Johnson, SL and Ruof, A and Eisenberg, DTA and Rej, PH and Sandler, I and Wolchik, S},
title = {Examining the influence of adversity, family contexts, and a family-based intervention on parent and child telomere length.},
journal = {European journal of psychotraumatology},
volume = {13},
number = {1},
pages = {2088935},
pmid = {35789082},
issn = {2000-8066},
mesh = {Adolescent ; Child ; Divorce ; Family Conflict/psychology ; Humans ; *Parenting/psychology ; *Parents/psychology ; Telomere/genetics ; },
abstract = {UNLABELLED: Background: Exposure to adversity, trauma, and negative family environments can prematurely shorten telomeres, the protective caps at the ends of chromosomes. Conversely, some evidence indicates that positive environments and psychosocial interventions can buffer the shortening of telomere length (TL). However, most work has examined individual aspects of the family environment as predictive of TL with little work investigating multiple risk and protective factors. Further, most research has not examined parent TL relative to child TL despite its heritability. Objective: In the current study, we examined interparental conflict, positive parenting, alcohol use, adverse childhood experiences (ACEs), and a family-based intervention as predictive of parent TL. We also examined interparental conflict, positive parenting, ACEs, and a family-based intervention as predictive of child TL. Method: Parents and adolescents from a sample of divorced families participated in either a 10-session family-based intervention, the New Beginnings Programme (NBP), or a 2-week active control condition. Approximately six years after the intervention, a subsample of parents (n = 45) and adolescents (n = 41) were assessed for TL. Parents reported on interparental conflict, ACEs, and alcohol use. Children reported on interparental conflict, positive parenting, and ACEs. In separate models, these constructs and the NBP intervention condition were examined as predictors of parent TL and child TL. Results: Findings indicated that the family-based intervention was associated with longer TL in parents. Also, positive parenting was associated with longer TL in children. Conclusions: These findings have important implications for the role of the family and family-based preventive interventions in buffering parent and child biological stress.<br><br>HIGHLIGHTS: Across multiple indices of psychosocial functioning, we found a family-based intervention associated with longer telomere length in parents and positive parenting associated with longer telomere length in children.},
}
@article {pmid35787517,
year = {2022},
author = {von Falkenhausen, AS and Freudling, R and Waldenberger, M and Gieger, C and Peters, A and Müller-Nurasyid, M and Kääb, S and Sinner, MF},
title = {Common electrocardiogram measures are not associated with telomere length.},
journal = {Aging},
volume = {14},
number = {14},
pages = {5620-5627},
pmid = {35787517},
issn = {1945-4589},
mesh = {Aged ; Aging/genetics ; *Atrial Fibrillation/diagnosis/genetics ; Electrocardiography ; Female ; Humans ; Leukocytes ; Male ; Telomere/genetics ; *Telomere Shortening ; },
abstract = {AIMS: Aging is accompanied by telomere shortening. Increased telomere shortening is considered a marker of premature aging. Cardiac aging results in the development of cardiac pathologies. Electrocardiogram (ECG) measures reflect cardiac excitation, conduction, and repolarization. ECG measures also prolong with aging and are associated with cardiac pathologies including atrial fibrillation. As premature prolongation of ECG measures is observed, we hypothesized that such prolongation may be associated with telomere length.<br><br>METHODS AND RESULTS: We studied the large, community-based KORA F4 Study. Of 3,080 participants enrolled between 2006 and 2007 with detailed information on demographic, anthropometric, clinical, and ECG characteristics, 2,575 presented with available data on leukocyte telomere length. Telomere length was determined by real-time quantitative PCR and expressed relative to a single copy gene. We fitted multivariable adjusted linear regression models to associate the ECG measures RR-interval, PR-interval, QRS-duration, and heart rate corrected QTc with telomere length. In our cohort, the mean age was 54.9&#xb1;12.9 years and 46.6% were men. Increased age was associated with shorter telomere length (p<0.01), and men had shorter telomere length than women (p<0.05). In unadjusted models, heart rate (p=0.023), PR-interval (p<0.01), and QTc-interval (p<0.01) were significantly associated with shorter telomere length. However, no significant associations remained after accounting for age, sex, and covariates.<br><br>CONCLUSIONS: ECG measures are age-dependent, but not associated with shortened telomere length as a marker of biological aging. Further research is warranted to clarify if shortened telomeres are associated with clinical cardiac pathologies including atrial fibrillation.},
}
@article {pmid35784039,
year = {2022},
author = {van de Crommenacker, J and Hammers, M and Dugdale, HL and Burke, TA and Komdeur, J and Richardson, DS},
title = {Early-life conditions impact juvenile telomere length, but do not predict later life-history strategies or fitness in a wild vertebrate.},
journal = {Ecology and evolution},
volume = {12},
number = {6},
pages = {e8971},
pmid = {35784039},
issn = {2045-7758},
abstract = {Environmental conditions experienced during early life may have long-lasting effects on later-life phenotypes and fitness. Individuals experiencing poor early-life conditions may suffer subsequent fitness constraints. Alternatively, individuals may use a strategic "Predictive Adaptive Response" (PAR), whereby they respond-in terms of physiology or life-history strategy-to the conditions experienced in early life to maximize later-life fitness. Particularly, the Future Lifespan Expectation (FLE) PAR hypothesis predicts that when poor early-life conditions negatively impact an individual's physiological state, it will accelerate its reproductive schedule to maximize fitness during its shorter predicted life span. We aimed to measure the impact of early-life conditions and resulting fitness across individual lifetimes to test predictions of the FLE hypothesis in a wild, long-lived model species. Using a long-term individual-based dataset, we investigated how early-life conditions are linked with subsequent fitness in an isolated population of the Seychelles warbler Acrocephalus sechellensis. How individuals experience early-life environmental conditions may vary greatly, so we also tested whether telomere length-shorter telomers are a biomarker of an individual's exposure to stress-can provide an effective measure of the individual-specific impact of early-life conditions. Specifically, under the FLE hypothesis, we would expect shorter telomeres to be associated with accelerated reproduction. Contrary to expectations, shorter juvenile telomere length was not associated with poor early-life conditions, but instead with better conditions, probably as a result of faster juvenile growth. Furthermore, neither juvenile telomere length, nor other measures of early-life conditions, were associated with age of first reproduction or the number of offspring produced during early life in either sex. We found no support for the FLE hypothesis. However, for males, poor early-life body condition was associated with lower first-year survival and reduced longevity, indicating that poor early-life conditions pose subsequent fitness constraints. Our results also showed that using juvenile telomere length as a measure of early-life conditions requires caution, as it is likely to not only reflect environmental stress but also other processes such as growth.},
}
@article {pmid35782414,
year = {2022},
author = {Durand, M and Nagot, N and Michel, L and Le, SM and Duong, HT and Vallo, R and Vizeneux, A and Rapoud, D and Giang, HT and Quillet, C and Thanh, NTT and Hai Oanh, KT and Vinh, VH and Feelemyer, J and Vande Perre, P and Minh, KP and Laureillard, D and Des Jarlais, D and Molès, JP},
title = {Mental Disorders Are Associated With Leukocytes Telomere Shortening Among People Who Inject Drugs.},
journal = {Frontiers in psychiatry},
volume = {13},
number = {},
pages = {846844},
pmid = {35782414},
issn = {1664-0640},
abstract = {Premature biological aging, assessed by shorter telomere length (TL) and mitochondrial DNA (mtDNA) alterations, has been reported among people with major depressive disorders or psychotic disorders. However, these markers have never been assessed together among people who inject drugs (PWIDs), although mental disorders are highly prevalent in this population, which, in addition, is subject to other aggravating exposures. Diagnosis of mental disorders was performed by a psychiatrist using the Mini International Neuropsychiatric Interview test among active PWIDs in Haiphong, Vietnam. mtDNA copy number (MCN), mtDNA deletion, and TL were assessed by quantitative PCR and compared to those without any mental disorder. We next performed a multivariate analysis to identify risk factors associated with being diagnosed with a major depressive episode (MDE) or a psychotic syndrome (PS). In total, 130 and 136 PWIDs with and without psychiatric conditions were analyzed. Among PWIDs with mental disorders, 110 and 74 were diagnosed with MDE and PS, respectively. TL attrition was significantly associated with hepatitis C virus-infected PWIDs with MDE or PS (adjusted odds ratio [OR]: 0.53 [0.36; 0.80] and 0.59 [0.39; 0.88], respectively). TL attrition was even stronger when PWIDs cumulated at least two episodes of major depressive disorders. On the other hand, no difference was observed in mtDNA alterations between groups. The telomeric age difference with drug users without a diagnosis of psychiatric condition was estimated during 4.2-12.8 years according to the number of MDEs, making this group more prone to age-related diseases.},
}
@article {pmid35777725,
year = {2022},
author = {Gampawar, P and Schmidt, R and Schmidt, H},
title = {Telomere length and brain aging: A systematic review and meta-analysis.},
journal = {Ageing research reviews},
volume = {80},
number = {},
pages = {101679},
doi = {10.1016/j.arr.2022.101679},
pmid = {35777725},
issn = {1872-9649},
mesh = {Aged ; *Aging/genetics/psychology ; Brain ; Cognition ; Female ; Humans ; Leukocytes/chemistry ; *Telomere ; Telomere Shortening ; },
abstract = {The current evidence on the association of leukocyte telomere length (LTL) with age-related structural and cognitive changes in the brain is mixed. Herein conforming to PRISMA 2020 guidelines, we performed a systematic review and meta-analysis using data from 27 observational studies in non-demented individuals. We used effect size and p-value based meta-analysis methods considering marked heterogeneity among studies. We found that the longer LTL was associated with higher brain volume (β = 0.43, 95%CI: 0.36-0.50%, p = 0.008, N = 1102) and with higher global cognition (β = 0.01; 95%CI: 0.00-0.02, p = 0.03, N = 19609) by effect size based meta-analysis and with brain volume, hippocampal volume, global cognition, cognitive domains of attention/speed as well as executive functions by p-value based meta-analysis. No significant association of LTL with brain white matter hyperintensities was detected. Furthermore, the evidence strongly suggests a subgroup-specific canonical effect of telomeres, notably in older individuals and females. In conclusion, we provide meta-analytic evidence on the beneficial effect of telomeres on brain structure as well as cognition and advocate for a beneficial subgroup-specific effect that warrants further attention.},
}
@article {pmid35775462,
year = {2022},
author = {Iannuzzi, A and Albarella, S and Parma, P and Galdiero, G and D'Anza, E and Pistucci, R and Peretti, V and Ciotola, F},
title = {Characterization of telomere length in Agerolese cattle breed, correlating blood and milk samples.},
journal = {Animal genetics},
volume = {53},
number = {5},
pages = {676-679},
pmid = {35775462},
issn = {1365-2052},
mesh = {Aging ; Animals ; Cattle/genetics ; Dairying/methods ; Female ; Lactation ; *Longevity ; *Milk ; Telomere/genetics ; },
abstract = {Studies into telomere length in cattle are relatively recent and have focused mainly on the Holstein Friesian cattle breed, making it arduous to evaluate the correlation with ageing due to the early age of culling in this breed. Telomere length provides information about the productive lifespan and the quality of farm management, complying with the 'One Health' approach. This study evaluated telomere length in Agerolese cattle, an autochthonous dairy breed characterized by a long productive lifespan (13 years). Multiplex quantitative PCR estimated telomere length in DNA extracted from blood and milk matrices. Interestingly, the results showed longer telomeres in Agerolese (compared to the Holstein Friesian cattle control group), with a negative correlation between telomere length and increasing age and a synchronous trend between blood and milk samples, with a positive correlation between them.},
}
@article {pmid35773409,
year = {2022},
author = {Barnes, RP and de Rosa, M and Thosar, SA and Detwiler, AC and Roginskaya, V and Van Houten, B and Bruchez, MP and Stewart-Ornstein, J and Opresko, PL},
title = {Telomeric 8-oxo-guanine drives rapid premature senescence in the absence of telomere shortening.},
journal = {Nature structural &amp; molecular biology},
volume = {29},
number = {7},
pages = {639-652},
pmid = {35773409},
issn = {1545-9985},
support = {P30 CA047904/CA/NCI NIH HHS/United States ; R01 CA207342/CA/NCI NIH HHS/United States ; K99 ES033771/ES/NIEHS NIH HHS/United States ; R01 EB017268/EB/NIBIB NIH HHS/United States ; R35 ES030396/ES/NIEHS NIH HHS/United States ; F32 AG067710/AG/NIA NIH HHS/United States ; R35 ES031638/ES/NIEHS NIH HHS/United States ; },
mesh = {Cellular Senescence/genetics ; DNA/metabolism ; DNA Damage ; *Guanine ; Humans ; Oxidative Stress ; Telomere/metabolism ; *Telomere Shortening ; },
abstract = {Oxidative stress is a primary cause of cellular senescence and contributes to the etiology of numerous human diseases. Oxidative damage to telomeric DNA has been proposed to cause premature senescence by accelerating telomere shortening. Here, we tested this model directly using a precision chemoptogenetic tool to produce the common lesion 8-oxo-guanine (8oxoG) exclusively at telomeres in human fibroblasts and epithelial cells. A single induction of telomeric 8oxoG is sufficient to trigger multiple hallmarks of p53-dependent senescence. Telomeric 8oxoG activates ATM and ATR signaling, and enriches for markers of telomere dysfunction in replicating, but not quiescent cells. Acute 8oxoG production fails to shorten telomeres, but rather generates fragile sites and mitotic DNA synthesis at telomeres, indicative of impaired replication. Based on our results, we propose that oxidative stress promotes rapid senescence by producing oxidative base lesions that drive replication-dependent telomere fragility and dysfunction in the absence of shortening and shelterin loss.},
}
@article {pmid35769259,
year = {2022},
author = {Robinson, H and Ali, SI and Diaz-Hernandez, ME and Lopez-Gonzalez, R},
title = {Telomere Attrition in Induced Pluripotent Stem Cell-Derived Neurons From ALS/FTD-Related C9ORF72 Repeat Expansion Carriers.},
journal = {Frontiers in cell and developmental biology},
volume = {10},
number = {},
pages = {874323},
pmid = {35769259},
issn = {2296-634X},
abstract = {The GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dysregulated DNA damage response and the generation of reactive oxygen species (ROS) have been postulated as major drivers of toxicity in C9ORF72 pathogenesis. Telomeres are tandem-repeated nucleotide sequences that are located at the end of chromosomes and protect them from degradation. Interestingly, it has been established that telomeres are sensitive to ROS. Here, we analyzed telomere length in neurons and neural progenitor cells from several induced pluripotent stem cell (iPSC) lines from control subjects and C9ORF72 repeat expansion carriers. We found an age-dependent decrease in telomere length in two-month-old iPSC-derived motor neurons from C9ORF72 carriers as compared to control subjects and a dysregulation in the protein levels of shelterin complex members TRF2 and POT1.},
}
@article {pmid35769005,
year = {2022},
author = {Choi, BE and Lee, HT},
title = {DNA-RNA hybrid G-quadruplex tends to form near the 3' end of telomere overhang.},
journal = {Biophysical journal},
volume = {121},
number = {15},
pages = {2962-2980},
pmid = {35769005},
issn = {1542-0086},
mesh = {DNA/chemistry/genetics ; DNA, Single-Stranded ; *G-Quadruplexes ; *RNA/chemistry ; Telomere/genetics/metabolism ; },
abstract = {Telomeric repeat-containing RNA (TERRA) has been suggested to participate in telomere maintenance. TERRA consisting of UUAGGG repeats is capable of forming an intermolecular G-quadruplex (GQ) with single-stranded TTAGGG-repeat DNA in the telomere 3' overhang. To explore the structural features and potential functions of this DNA-RNA hybrid GQ (HGQ), we used single-molecule FRET to study the folding patterns of DNA with four to seven telomeric tandem repeats annealed with a short RNA consisting of two or five telomeric repeats. Our data highlight that RNA prefers to form DNA-RNA HGQ near the 3' end of telomeric DNA. Furthermore, the unfolding of secondary structures by a complementary C-rich sequence was observed for DNA GQ but not for DNA-RNA HGQ, which demonstrated the enhanced stability of the telomere 3' end via hybridization with RNA. These conformational and physical properties of telomeric DNA-RNA HGQ suggest that TERRA might limit access to the 3' end of the telomeric DNA overhang, which is known to be critical for the interaction with telomerase and other telomere-associated proteins.},
}
@article {pmid35760212,
year = {2022},
author = {Buttet, M and Bagheri, R and Ugbolue, UC and Laporte, C and Trousselard, M and Benson, A and Bouillon-Minois, JB and Dutheil, F},
title = {Effect of a lifestyle intervention on telomere length: A systematic review and meta-analysis.},
journal = {Mechanisms of ageing and development},
volume = {206},
number = {},
pages = {111694},
doi = {10.1016/j.mad.2022.111694},
pmid = {35760212},
issn = {1872-6216},
mesh = {Exercise ; Female ; Humans ; *Life Style ; Male ; Nutritional Status ; *Telomere ; },
abstract = {BACKGROUND: We conducted a systematic review and meta-analysis to assess the effects of lifestyle intervention on telomere length (TL).<br><br>METHOD: Four databases were searched for studies reporting TL in leukocytes, before and after a lifestyle intervention. We computed random-effects meta-analysis on TL within intervention and control group after versus before intervention, and on changes in TL between groups. Sensitivity analyses and Meta-regression were conducted.<br><br>RESULTS: We included 20 studies in the systematic review (2995 participants, mean 50.3 years old, 77% women, 2045 following an intervention and 950 controls) and 19 in the meta-analysis. TL were similar at baseline between intervention and control groups. The physical activity &#xb1;&#xa0;diet group had an increase in TL (Effect size 0.17, 95%CI 0.03-0.31, p&#xa0;=&#xa0;0.020) using changes within the intervention group, whereas TL shortened in the control group (-0.32, -0.61 to -0.02, p&#xa0;=&#xa0;0.037). TL was longer in the physical activity &#xb1;&#xa0;diet intervention group (0.24, 0.08-0.40, p&#xa0;=&#xa0;0.004) compared to controls after the intervention. Sensitivity analysis gave similar results. Meta-regressions demonstrated that combining strength and endurance exercise increased TL more than endurance alone or strength alone.<br><br>CONCLUSION: A lifestyle intervention with physical activity &#xb1;&#xa0;diet can increase telomere length, independently of population characteristics or baseline TL.},
}
@article {pmid35760210,
year = {2022},
author = {Llorente, H and Perez-Rivera, JA and Perez-Nieto, M and Cieza-Borrella, C and Pastor, I and Novo-Veleiro, I and Fernández-Mateos, J and Chamorro, AJ and Crecente-Otero, P and Laso, FJ and González-Sarmiento, R and Marcos, M},
title = {Genetic susceptibility to telomere shortening through the rs2293607 polymorphism is associated with a greater risk of alcohol use disorder.},
journal = {Mechanisms of ageing and development},
volume = {206},
number = {},
pages = {111693},
doi = {10.1016/j.mad.2022.111693},
pmid = {35760210},
issn = {1872-6216},
mesh = {*Alcoholism/genetics ; Genetic Predisposition to Disease ; Humans ; Male ; Polymorphism, Single Nucleotide ; RNA/genetics ; Telomerase/*genetics ; Telomere/genetics ; Telomere Shortening ; },
abstract = {Telomere shortening is usually considered a biomarker of ageing. Harmful alcohol use promotes accelerated biological ageing and alcohol use disorders (AUDs) are associated with short telomere length (TL). This study was conducted to examine the relationship of TL to AUD and determine whether single nucleotide polymorphisms (SNPs) in TERC and TERT modulate this association. For this purpose, we genotyped TERC SNPs rs2293607, rs12696304, and rs16847897 and TERT SNPs rs2735940, rs2736100, and rs2736098 in 308 male patients with AUD and 255 sex-matched healthy controls and measured TL in a subset of 99 patients and 99 controls paired by age and smoking status. Our results showed that the mean TL was shorter in patients with AUD than in controls. The area under the ROC curve was 0.70 (P < 0.001). The GG genotype of TERC rs2293607 was more common among patients with AUD than among controls (9.8% vs. 5.1%; P = 0.038). No difference was found for the other SNPs. Carriers of the GG genotype of rs2293607 had shorter telomeres than did allele A carriers. In conclusion, patients with AUD had shorter telomeres. Genetic susceptibility to telomere shortening through the rs2293607 SNP is associated with a greater risk of AUD.},
}
@article {pmid35759567,
year = {2022},
author = {Madaeva, IM and Kurashova, NA and Ukhinov, EB and Berdina, ON and Semenova, NV and Madaev, VV and Kolesnikova, LI and Kolesnikov, SI},
title = {[Changes in the telomeres length in patients with obstructive sleep apnea after continuous positive airway pressure therapy: a pilot study].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {122},
number = {5. Vyp. 2},
pages = {52-57},
doi = {10.17116/jnevro202212205252},
pmid = {35759567},
issn = {1997-7298},
mesh = {*Continuous Positive Airway Pressure ; Humans ; Hypoxia ; Male ; Middle Aged ; Pilot Projects ; *Sleep Apnea, Obstructive/diagnosis/genetics/therapy ; Telomere/genetics ; },
abstract = {OBJECTIVE: To evaluate a relative telomere length in patients with obstructive sleep apnea (OSA) before and after a 6-month course of continuous positive airway pressure (CPAP) therapy.<br><br>MATERIAL AND METHODS: Seventy-five men participated in the study, including 50 men with OSA (the main group 1) and 25 men without OSA (the control group). The average age in the total group was 53.4&#xb1;3.6 years. Thirty-five men completed the study (the main group 2). According to the design, night polysomnography (PSG) was performed for all the subjects, blood sampling to assess the length of telomeres was carried out in the morning according to the standard method. The values of the relative telomere length were obtained using the difference between the values of the threshold cycles for telomeric DNA and the reference gene albumin (&#x2206;CCt). After clarifying the diagnosis, CPAP was applied for 6 months.<br><br>RESULTS: Statistically significant indicators of PSG were revealed: a decrease in NREM 3 in patients with OSA compared to controls (89.3&#xb1;15.8 versus 150&#xb1;23.4 minutes), an increase in NREM1-2 in OSA (296.2&#xb1;31.1 and 170.1&#xb1;24.5, respectively), REM was 84.6&#xb1;15.4 in the main group and 118.5&#xb1;19.5 in the control group. CPAP therapy conducted for 6 months (at least 4-5 nights a week, lasting at least 5-6 hours of night sleep) demonstrated a significant improvement in the qualitative and quantitative parameters of sleep. In patients of the main group 1, there is a shortening of the telomere length compared with the control group (p<0.001). With the elimination of hypoxia and improvement of the structure of sleep after CPAP, there was an increase in the telomere lengths in the main group 1 from 0.28 [0.24-0.29] to 0.32 [0.30-0.34] in the main group 2 (p=0.03). The telomers length in the control group was 0.53 [0.50-0.55].<br><br>CONCLUSION: Intermittent hypoxia and fragmentation of sleep in OSA leads to shortening of telomeres. CPAP, by eliminating the pathophysiological triggers of OSA, contributes to an increase in telomeres lengths and can slow down the premature aging in OSA.},
}
@article {pmid35748695,
year = {2022},
author = {Zhang, Y and Fu, J and Wang, K and Han, X and Yan, T and Su, Y and Li, Y and Lin, Z and Qin, P and Fu, C and Deng, XW and Zhou, D and Yang, Y and He, H},
title = {The telomere-to-telomere gap-free genome of four rice parents reveals SV and PAV patterns in hybrid rice breeding.},
journal = {Plant biotechnology journal},
volume = {20},
number = {9},
pages = {1642-1644},
pmid = {35748695},
issn = {1467-7652},
mesh = {Genome, Plant/genetics ; Hybrid Vigor ; Hybridization, Genetic ; *Oryza/genetics ; Plant Breeding ; Telomere/genetics ; },
}
@article {pmid35747346,
year = {2022},
author = {Isehunwa, OO and Warner, ET and Spiegelman, D and Zhang, Y and Palmer, JR and Kanaya, AM and Cole, SA and Tworoger, SS and Shields, LO and Gu, Y and Kent, BV and De Vivo, I and Shields, AE},
title = {Depression, religiosity, and telomere length in the Study on Stress, Spirituality, and Health (SSSH).},
journal = {International journal of mental health and addiction},
volume = {20},
number = {3},
pages = {1465-1484},
pmid = {35747346},
issn = {1557-1874},
support = {U01 HL041642/HL/NHLBI NIH HHS/United States ; R01 HL093009/HL/NHLBI NIH HHS/United States ; U01 CA176726/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; U01 HL041652/HL/NHLBI NIH HHS/United States ; P30 DK098722/DK/NIDDK NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 HL109319/HL/NHLBI NIH HHS/United States ; P30 DK092924/DK/NIDDK NIH HHS/United States ; R01 HL109284/HL/NHLBI NIH HHS/United States ; U01 HL065521/HL/NHLBI NIH HHS/United States ; R01 HL109301/HL/NHLBI NIH HHS/United States ; R01 HL109282/HL/NHLBI NIH HHS/United States ; P30 DK063720/DK/NIDDK NIH HHS/United States ; U01 HL041654/HL/NHLBI NIH HHS/United States ; U01 CA164974/CA/NCI NIH HHS/United States ; R01 CA067262/CA/NCI NIH HHS/United States ; R01 CA098663/CA/NCI NIH HHS/United States ; R01 CA163451/CA/NCI NIH HHS/United States ; UL1 TR001872/TR/NCATS NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; UM1 CA176726/CA/NCI NIH HHS/United States ; R01 CA058420/CA/NCI NIH HHS/United States ; R01 HL109315/HL/NHLBI NIH HHS/United States ; R01 HL120725/HL/NHLBI NIH HHS/United States ; U01 HL065520/HL/NHLBI NIH HHS/United States ; },
abstract = {Prospective studies on the association between depression and telomere length have produced mixed results and have been largely limited to European ancestry populations. We examined the associations between depression and telomere length, and the modifying influence of religion and spirituality, in four cohorts, each representing a different race/ethnic population. Relative leukocyte telomere length (RTL) was measured by a quantitative polymerase chain reaction. Our result showed that depression was not associated with RTL (percent difference: 3.0 95% CI: -3.9, 10.5; p = 0.41; p-heterogeneity across studies = 0.67) overall or in cohort-specific analyses. However, in cohort-specific analyses, there was some evidence of effect modification by the extent of religiosity or spirituality, religious congregation membership, and group prayer. Further research is needed to investigate prospective associations between depression and telomere length, and the resources of resilience including dimensions of religion and spirituality that may impact such dynamics in diverse racial/ethnic populations.},
}
@article {pmid35746868,
year = {2022},
author = {Deng, Y and Liu, S and Zhang, Y and Tan, J and Li, X and Chu, X and Xu, B and Tian, Y and Sun, Y and Li, B and Xu, Y and Deng, XW and He, H and Zhang, X},
title = {A telomere-to-telomere gap-free reference genome of watermelon and its mutation library provide important resources for gene discovery and breeding.},
journal = {Molecular plant},
volume = {15},
number = {8},
pages = {1268-1284},
doi = {10.1016/j.molp.2022.06.010},
pmid = {35746868},
issn = {1752-9867},
mesh = {Chromosome Mapping ; *Citrullus/genetics ; Genetic Association Studies ; Genome, Plant/genetics ; INDEL Mutation ; Plant Breeding ; Telomere ; },
abstract = {Watermelon, Citrullus lanatus, is the world's third largest fruit crop. Reference genomes with gaps and a narrow genetic base hinder functional genomics and genetic improvement of watermelon. Here, we report the assembly of a telomere-to-telomere gap-free genome of the elite watermelon inbred line G42 by incorporating high-coverage and accurate long-read sequencing data with multiple assembly strategies. All 11 chromosomes have been assembled into single-contig pseudomolecules without gaps, representing the highest completeness and assembly quality to date. The G42 reference genome is 369 321 829 bp in length and contains 24 205 predicted protein-coding genes, with all 22 telomeres and 11 centromeres characterized. Furthermore, we established a pollen-EMS mutagenesis protocol and obtained over 200 000 M1 seeds from G42 . In a sampling pool, 48 monogenic phenotypic mutations, selected from 223 M1 and 78 M2 mutants with morphological changes, were confirmed. The average mutation density was 1 SNP/1.69 Mb and 1 indel/4.55 Mb per M1 plant and 1 SNP/1.08 Mb and 1 indel/6.25 Mb per M2 plant. Taking advantage of the gap-free G42 genome, 8039 mutations from 32 plants sampled from M1 and M2 families were identified with 100% accuracy, whereas only 25% of the randomly selected mutations identified using the 97103v2 reference genome could be confirmed. Using this library and the gap-free genome, two genes responsible for elongated fruit shape and male sterility (ClMS1) were identified, both caused by a single base change from G to A. The validated gap-free genome and its EMS mutation library provide invaluable resources for functional genomics and genetic improvement of watermelon.},
}
@article {pmid35741087,
year = {2022},
author = {Ebata, H and Loo, TM and Takahashi, A},
title = {Telomere Maintenance and the cGAS-STING Pathway in Cancer.},
journal = {Cells},
volume = {11},
number = {12},
pages = {},
pmid = {35741087},
issn = {2073-4409},
mesh = {Humans ; Membrane Proteins/metabolism ; *Neoplasms/metabolism ; Nucleotidyltransferases/metabolism ; *Telomerase/metabolism ; Telomere/metabolism ; Tumor Microenvironment ; },
abstract = {Cancer cells exhibit the unique characteristics of high proliferation and aberrant DNA damage response, which prevents cancer therapy from effectively eliminating them. The machinery required for telomere maintenance, such as telomerase and the alternative lengthening of telomeres (ALT), enables cancer cells to proliferate indefinitely. In addition, the molecules in this system are involved in noncanonical pro-tumorigenic functions. Of these, the function of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which contains telomere-related molecules, is a well-known contributor to the tumor microenvironment (TME). This review summarizes the current knowledge of the role of telomerase and ALT in cancer regulation, with emphasis on their noncanonical roles beyond telomere maintenance. The components of the cGAS-STING pathway are summarized with respect to intercell communication in the TME. Elucidating the underlying functional connection between telomere-related molecules and TME regulation is important for the development of cancer therapeutics that target cancer-specific pathways in different contexts. Finally, strategies for designing new cancer therapies that target cancer cells and the TME are discussed.},
}
@article {pmid35738556,
year = {2022},
author = {Miller, JG and Buthmann, JL and Gotlib, IH},
title = {Hippocampal volume indexes neurobiological sensitivity to the effect of pollution burden on telomere length in adolescents.},
journal = {New directions for child and adolescent development},
volume = {2022},
number = {181-182},
pages = {155-172},
pmid = {35738556},
issn = {1534-8687},
support = {R37 MH101495/MH/NIMH NIH HHS/United States ; Young Investigator Award 23819//Brain and Behavior Research Foundation/ ; R37MH1014945/NH/NIH HHS/United States ; //Klingenstein Third Generation Foundation/ ; },
mesh = {Adolescent ; Child ; Environmental Exposure/adverse effects ; *Environmental Pollutants ; Environmental Pollution ; Hippocampus ; Humans ; *Telomere/genetics ; },
abstract = {Exposure to environmental pollutants has been associated with cellular aging in children and adolescents. Individuals may vary, however, in their sensitivity or vulnerability to the effects of environmental pollutants. Larger hippocampal volume has emerged as a potential index of increased sensitivity to social contexts. In exploratory analyses (N = 214), we extend work in this area by providing evidence that larger hippocampal volume in early adolescence reflects increased sensitivity to the effect of neighborhood pollution burden on telomere length (standardized β = -0.40, 95% CI[-0.65, -0.15]). In contrast, smaller hippocampal volume appears to buffer this association (standardized β = 0.02). In youth with larger hippocampal volume, pollution burden was indirectly associated with shorter telomere length approximately 2 years later through shorter telomere length at baseline (indirect standardized β = -0.25, 95% CI[-0.40, 0.10]). For these youth, living in high or low pollution-burdened neighborhoods may predispose them to develop shorter or longer telomeres, respectively, later in adolescence.},
}
@article {pmid35736788,
year = {2022},
author = {Xiong, K and Ouyang, C and Liu, J and Karges, J and Lin, X and Chen, X and Chen, Y and Wan, J and Ji, L and Chao, H},
title = {Chiral Ru[II] -Pt[II] Complexes Inducing Telomere Dysfunction against Cisplatin-Resistant Cancer Cells.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {61},
number = {33},
pages = {e202204866},
doi = {10.1002/anie.202204866},
pmid = {35736788},
issn = {1521-3773},
mesh = {Animals ; *Antineoplastic Agents/pharmacology/therapeutic use ; Cisplatin/metabolism/pharmacology ; *Coordination Complexes/metabolism/pharmacology/therapeutic use ; DNA ; *G-Quadruplexes ; Mice ; *Neoplasms ; *Ruthenium/metabolism/pharmacology ; *Telomerase/genetics ; Telomere ; },
abstract = {The application of G-quadruplex stabilizers presents a promising anticancer strategy. However, the molecular crowding conditions within cells diminish the potency of current G-quadruplex stabilizers. Herein, chiral Ru[II] -Pt[II] dinuclear complexes were developed as highly potent G-quadruplex stabilizers even under challenging molecular crowding conditions. The compounds were encapsulated with biotin-functionalized DNA cages to enhance sub-cellular localization and provide cancer selectivity. The nanoparticles were able to efficiently inhibit the endogenous activities of telomerase in cisplatin-resistant cancer cells and cause cell death by apoptosis. The nanomaterials demonstrated high antitumor activity towards cisplatin-resistant tumor cells as well as tumor-bearing mice. To the best of our knowledge, this study presents the first example of a Ru[II] -Pt[II] dinuclear complex as a G-quadruplex stabilizer with an anti-cancer effect towards drug-resistant tumors inside an animal model.},
}
@article {pmid35733342,
year = {2022},
author = {Benelli, R and Weiss, M},
title = {Probing local chromatin dynamics by tracking telomeres.},
journal = {Biophysical journal},
volume = {121},
number = {14},
pages = {2684-2692},
pmid = {35733342},
issn = {1542-0086},
mesh = {*Chromatin ; Interphase ; Motion ; Polymers ; *Telomere ; },
abstract = {Chromatin dynamics is key for cell viability and replication. In interphase, chromatin is decondensed, allowing the transcription machinery to access a plethora of DNA loci. Yet, decondensed chromatin occupies almost the entire nucleus, suggesting that DNA molecules can hardly move. Recent reports have even indicated that interphase chromatin behaves like a solid body on mesoscopic scales. To explore the local chromatin dynamics, we have performed single-particle tracking on telomeres under varying conditions. We find that mobile telomeres feature, under all conditions, a strongly subdiffusive, antipersistent motion that is consistent with the monomer motion of a Rouse polymer in viscoelastic media. In addition, telomere trajectories show intermittent accumulations in local niches at physiological conditions, suggesting that the surrounding chromatin reorganizes on these timescales. Reducing the temperature or exposing cells to osmotic stress resulted in a significant reduction of mobile telomeres and the number of visited niches. Altogether, our data indicate a vivid local chromatin dynamics, akin to a semidilute polymer solution, unless perturbations enforce a more rigid or entangled state of chromatin.},
}
@article {pmid35732925,
year = {2022},
author = {Mao, Y and Zhang, G},
title = {Publisher Correction: A complete, telomere-to-telomere human genome sequence presents new opportunities for evolutionary genomics.},
journal = {Nature methods},
volume = {19},
number = {7},
pages = {899},
doi = {10.1038/s41592-022-01551-x},
pmid = {35732925},
issn = {1548-7105},
}
@article {pmid35730364,
year = {2022},
author = {Cozzolino, M and Seli, E},
title = {Mitochondrial dysfunction caused by targeted deletion of Mfn1 does not result in telomere shortening in oocytes.},
journal = {Zygote (Cambridge, England)},
volume = {30},
number = {5},
pages = {735-737},
doi = {10.1017/S0967199422000089},
pmid = {35730364},
issn = {1469-8730},
mesh = {Animals ; GTP Phosphohydrolases/genetics/metabolism ; *Infertility ; Mice ; Mitochondria/metabolism ; Oocytes/physiology ; Reactive Oxygen Species/metabolism ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; Telomere Shortening ; },
abstract = {Telomere shortening during oocyte growth and development is related to reproductive ageing and infertility. The main mechanism involved in the maintenance of telomeres is based on telomerase activity, a specialized enzyme complex, which is capable of adding TTAGGG repeats at the ends of the chromosomes. Mitochondrial dysfunction may cause progressive shortening of telomeres by promoting the generation of reactive oxygen species. Mitofusin-1 is a protein required for mitochondrial fusion. Mice with the mitofusin-1 (Mfn1) deletion in the oocyte are characterized by accelerated follicular depletion and infertility, associated with defective oocyte maturation and follicular development. We hypothesized whether mitochondrial dysfunction in oocytes with targeted deletion of Mfn1 causes telomere shortening. We analyzed telomere length in oocyte and somatic cells in 3-, 6- and 9-month-old Mfn1[-/-] and wild-type mice. Immunofluorescence in oocyte mice of TRF1 and H2A.X was assessed to evaluate the interplay between the end-protection functions and the response to DNA damage occurring inside the telomeric repeats. Mitochondrial dysfunction due to the deletion of Mfn1 does not seem to affect telomere length in mouse oocytes.},
}
@article {pmid35725832,
year = {2022},
author = {Qin, S and Chen, X and Xu, Z and Li, T and Zhao, S and Hu, R and Zhu, J and Li, Y and Yang, Y and Liu, M},
title = {Telomere G-triplex lights up Thioflavin T for RNA detection: new wine in an old bottle.},
journal = {Analytical and bioanalytical chemistry},
volume = {414},
number = {20},
pages = {6149-6156},
pmid = {35725832},
issn = {1618-2650},
support = {22174150//National Natural Science Foundation of China/ ; },
mesh = {Benzothiazoles ; *Biosensing Techniques/methods ; *COVID-19 ; DNA/genetics ; Fluorescent Dyes ; *G-Quadruplexes ; Humans ; Limit of Detection ; RNA ; SARS-CoV-2 ; Spectrometry, Fluorescence/methods ; Telomere ; },
abstract = {Few reports are found working on the features and functions of the human telomere G-triplex (ht-G3) though the telomere G-quadruplex has been intensely studied and widely implemented to develop various biosensors. We herein report that ht-G3 lights up Thioflavin T (ThT) and establish a sensitive biosensing platform for RNA detection by introducing a target recycling strategy. An optimal condition was selected out for ht-G3 to promote ThT to generate a strong fluorescence. Accordingly, an ht-G3-based molecular beacon was successfully designed against the corresponding RNA sequence of the SARS-CoV-2 N-gene. The sensitivity for the non-amplified RNA target achieves 0.01 nM, improved 100 times over the conventional ThT-based method. We believe this ht-G3/ThT-based label-free strategy could be widely applied for RNA detection.},
}
@article {pmid35721750,
year = {2022},
author = {Hu, L and Zhang, Q and Bai, Y and Hu, G and Li, J},
title = {Triglyceride-Glucose Index Correlate With Telomere Length in Healthy Adults From the National Health and Nutrition Examination Survey.},
journal = {Frontiers in endocrinology},
volume = {13},
number = {},
pages = {844073},
pmid = {35721750},
issn = {1664-2392},
mesh = {Adult ; Blood Glucose/analysis ; Glucose ; Humans ; *Insulin Resistance/genetics ; Nutrition Surveys ; Telomere/chemistry/genetics ; Triglycerides ; },
abstract = {AIM: The present investigation was designed to test the association between leukocyte telomere length (LTL) and two simple markers of insulin resistance, that is, homeostatic model assessment of insulin resistance (HOMA-IR) and triglyceride-glucose (TyG) index in U.S. adults without metabolic diseases.<br><br>METHODS: A total of 6489 U.S. adults without diabetes from NHANES 1999-2002 were analyzed. TyG index was calculated as ln [fasting triglycerides (mg/dL) &#xd7; fasting glucose (mg/dL)/2]. HOMA-Index was calculated as fasting plasma glucose (mmol/L) &#xd7; fasting serum insulin (mU/mL)/22.5. LTL was obtained using the quantitative polymerase chain reaction method. Multivariate linear regression analysis was assessed to evaluate the association of TyG index HOMA-IR with LTL. We further conducted a generalized additive model (GAM) and a fitted smoothing curve with penalized spline method.<br><br>RESULTS: It was found that the mean LTL was 5796.1 bp in the measured healthy adults. Overall, TyG index was significantly associated with LTL, while HOMA-IR was not. Compared with participants in tertile 1 of the TyG index, the &#x3b2; (95% CI) for those in the second (8.27 to 8.77) and third (&#x2265; 8.77) were -4.31 (95% CI: -48.12~39.49) and -95.98 (95% CI: -145.08~-46.89), respectively. Subjects with TyG index &#x2265; 8.77 had statistically significant shorter LTL (&#x3b2; = -93.33, 95%CI: -134.33~-52.32), compared with TyG index < 8.77. We further explored a dose-response relation between TyG index by a decile approach [&#x2264; 7.81 (reference), 7.81-8.04, 8.04-8.21, 8.21-8.37, 8.37-8.52, 8.52-8.68, 8.68-8.83, 8.83-9.03, 9.03-9.33, and >9.33] and LTL. Five subgroups (TyG index 7.81-8.04, 8.04-8.21, 8.21-8.37, 8.37-8.52, and 8.52-8.68) did not show significant effect on LTL; while there was a significantly shorter LTL for participants with the TyG index > 8.68, supporting a threshold effect of TyG index on LTL.<br><br>CONCLUSIONS: The results suggested that higher TyG index (> 8.68) was closely related to shorter LTL and the TyG index was better associated with LTL than HOMA-IR.},
}
@article {pmid35721024,
year = {2022},
author = {Long, L and Meng, Z and Jia, Z and Tang, X},
title = {Exploring the Association of Leukocyte Telomere Length and Hearing Threshold Shifts of Adults in the United States.},
journal = {Frontiers in aging neuroscience},
volume = {14},
number = {},
pages = {770159},
pmid = {35721024},
issn = {1663-4365},
abstract = {BACKGROUND: Although telomere length has a significant relationship with various age-related diseases, studies on its relationship with hearing status in adults are limited and equivocal. This study investigated the associations between mean telomere length (MTL) and low-, speech-, and high-frequency hearing threshold shifts of adults in the United States.<br><br>METHODS: A total of 2,027 adults, aged 20-69 years, from the National Health and Nutrition Examination Surveys (NHANES, 1999-2002) were included in the analytic sample. The quantitative polymerase chain reaction method was used for the MTL assay, and MTL was expressed using the telomere-to-single copy gene (T/S) ratio. Hearing loss was defined as a pure-tone average (PTA) for the better ear at &#x2265; 20 dB HL at frequencies 500, 1,000, 2,000, and 4,000 Hz. Univariate and multivariate linear regression analyses and smooth curve fittings were conducted to evaluate the correlation between MTL and low-, speech-, and high-frequency hearing levels.<br><br>RESULTS: The mean age of the participants was 40.60 &#xb1; 12.76 years, including 952 men (weighted, 48.67%) and 303 (weighted, 12.88%) participants with hearing loss. After adjusting for potential confounders in the multivariate linear regression model, the relationship between MTL and hearing thresholds was not statistically significant. Smooth curve fittings indicated a non-linear relationship between MTL and high-frequency PTA hearing threshold shifts. MTL was inversely related to high-frequency PTA to the turning point (T/S ratio = 0.82) (adjusted &#x3b2;-21.45, 95% CI -37.28, -5.62; P = 0.008). When the T/S ratio exceeded0.82, MTL was not associated with high-frequency PTA (adjusted &#x3b2;0.18, 95% CI -2.21, 2.57; P = 0.8809).<br><br>CONCLUSION: Our findings revealed that MTL was associated with high-frequency PTA hearing threshold shifts of adults in the United States in a non-linear manner.},
}
@article {pmid35719148,
year = {2022},
author = {Khosravaniardakani, S and Bokov, DO and Mahmudiono, T and Hashemi, SS and Nikrad, N and Rabieemotmaen, S and Abbasalizad-Farhangi, M},
title = {Obesity Accelerates Leukocyte Telomere Length Shortening in Apparently Healthy Adults: A Meta-Analysis.},
journal = {Frontiers in nutrition},
volume = {9},
number = {},
pages = {812846},
pmid = {35719148},
issn = {2296-861X},
abstract = {BACKGROUND: Shorter telomere length is associated with numerous comorbidities. Several studies have investigated the role of obesity in telomere shortening. In the current systematic review and meta-analysis, we summarized the results of studies that evaluated the association between obesity and telomere length.<br><br>METHODS: A systematic search from Scopus, PubMed, Embase, and ProQuest electronic databases up to 19 March 2021 without language restriction was performed and after data extraction and screening, 19 manuscripts were eligible to be included in the final meta-synthesis.<br><br>RESULTS: The highest category of telomere length was associated with an approximate 0.75 kg/m[2] reduction in body mass index (BMI; WMD = -0.75 kg/m[2]; CI = -1.19, -0.31; p < 0.001; I [2] = 99.4%). Moreover, overweight/obese individuals had 0.036 kbp shorter telomere length compared with non-overweight/obese adults (WMD = -0.036; CI = -0.05, -0.02; p = 0.030; I [2] = 100%). According to the results of subgroupings, continent, age, and sample size could be possible sources of heterogeneity.<br><br>CONCLUSION: From the results, it was clear that obesity was associated with shorter telomere length. Because of the observational design of included studies, the causality inference of results should be done with caution; thus, further longitudinal studies are warranted for better inference of causal association.},
}
@article {pmid35715571,
year = {2022},
author = {Courtney, MG and Roberts, J and Godde, K},
title = {Author Correction: How social/environmental determinants and inflammation affect salivary telomere length among middle-older adults in the health and retirement study.},
journal = {Scientific reports},
volume = {12},
number = {1},
pages = {10195},
doi = {10.1038/s41598-022-14839-x},
pmid = {35715571},
issn = {2045-2322},
}
@article {pmid35715316,
year = {2022},
author = {Guérin, C and Crestani, B and Dupin, C and Kawano-Dourado, L and Ba, I and Kannengiesser, C and Borie, R},
title = {[Telomeres and lung].},
journal = {Revue des maladies respiratoires},
volume = {39},
number = {7},
pages = {595-606},
doi = {10.1016/j.rmr.2022.03.011},
pmid = {35715316},
issn = {1776-2588},
mesh = {Cell Cycle Proteins/genetics ; Humans ; *Idiopathic Pulmonary Fibrosis/diagnosis/epidemiology/genetics ; Lung ; *Lung Diseases, Interstitial/diagnosis/epidemiology/genetics ; Nuclear Proteins/genetics ; Telomere ; Vital Capacity ; },
abstract = {Genetic studies of familial forms of interstitial lung disease (ILD) have led to the discovery of telomere-related gene (TRG) mutations (TERT, TERC, RTEL1, PARN, DKC1, TINF2, NAF1, NOP10, NHP2, ACD, ZCCH8) in approximately 30% of familial ILD forms. ILD patients with TRG mutation are also subject to extra-pulmonary (immune-hematological, hepatic and/or mucosal-cutaneous) manifestations. TRG mutations may be associated not only with idiopathic pulmonary fibrosis (IPF), but also with non-IPF ILDs, including idiopathic and secondary ILDs, such as hypersensitivity pneumonitis (HP). The presence of TRG mutation may also be associated with an accelerated decline of forced vital capacity (FVC) or poorer prognosis after lung transplantation, notwithstanding which, usual ILD treatments may be proposed. Lastly, patients and their relatives are called upon to reduce their exposure to environmental lung toxicity, and are likely to derive benefit from specific genetic counseling and pre-symptomatic genetic testing.},
}
@article {pmid35713713,
year = {2022},
author = {Viblanc, VA and Criscuolo, F and Sosa, S and Schull, Q and Boonstra, R and Saraux, C and Lejeune, M and Roth, JD and Uhlrich, P and Zahn, S and Dobson, FS},
title = {Telomere dynamics in female Columbian ground squirrels: recovery after emergence and loss after reproduction.},
journal = {Oecologia},
volume = {199},
number = {2},
pages = {301-312},
pmid = {35713713},
issn = {1432-1939},
support = {The present study was supported by a USIAS fellowship//University of Strasbourg/ ; by a Gutenberg Chair awarded to F.S. Dobson.//University of Strasbourg/ ; },
mesh = {Animals ; Female ; Longitudinal Studies ; Male ; Reproduction/physiology ; Sciuridae/genetics ; *Telomere ; *Telomere Homeostasis ; },
abstract = {Telomeres are specialized non-coding DNA sequences located at the end of chromosomes and that protect genetic information. Telomere loss over lifespan is generally viewed as a phenomenon associated with aging in animals. Recently, telomere elongation after hibernation has been described in several mammals. Whether this pattern is an adaptation to repair DNA damage caused during rewarming from torpor or if it coevolved as a mechanism to promote somatic maintenance in preparation for the upcoming reproductive effort remains unclear. In a longitudinal study measuring telomere length using buccal swabs, we tested if telomere elongation was related to reproductive success in wild adult female Columbian ground squirrels (Urocitellus columbianus) that were monitored from emergence from hibernation to the end of the reproductive season. We found three key results. First, female telomere length increased at the start of the breeding season, both in breeding and non-breeding individuals. Second, post-emergence telomere lengthening was unrelated to female future reproductive output. Third, telomere length decreased in breeding females during lactation, but remained stable in non-breeding females over a similar period. Within breeders, telomeres shortened more in females producing larger and heavier litters. We concluded that telomere lengthening after hibernation did not constrain immediate female reproductive capacities. It was more likely to be part of the body recovery process that takes place after hibernation. Telomere erosion that occurs after birth may constitute a physiological cost of female reproduction.},
}
@article {pmid35710461,
year = {2023},
author = {Liu, W and Wang, N and Zhu, J and Zhang, M and Lu, L and Pan, H and He, X and Yi, H and Tang, S},
title = {The relationship between relative telomere length and anti-tuberculosis drug-induced hepatitis : A case-control study.},
journal = {Therapie},
volume = {78},
number = {3},
pages = {259-266},
doi = {10.1016/j.therap.2022.05.007},
pmid = {35710461},
issn = {1958-5578},
mesh = {Humans ; Case-Control Studies ; *Antitubercular Agents/adverse effects ; Risk Factors ; *Hepatitis ; Telomere ; },
abstract = {AIM: Anti-tuberculosis drug-induced hepatitis (AT-DIH) is a common and serious adverse drug reaction of tuberculosis treatment. Evidence demonstrated that many factors could affect the occurrence of AT-DIH, such as ageing, smoking, alcohol, oxidative stress, etc., while these factors could also promote telomere shortening. Therefore, relative telomere length (RTL) is indirectly related to the occurrence of AT-DIH. The present study aimed to explore and validate this relationship in Chinese tuberculosis patients.<br><br>METHODS: A 1:4 matched case-control study was undertaken using 202 AT-DIH cases and 808 controls. Logistic regression models were used to estimate the association between RTL and AT-DIH with odds ratios (ORs) and 95% confidence intervals (CIs). The area under receiver operating characteristic curve (AUC) was calculated to estimate the discriminative performance for distinguishing AT-DIH cases from controls.<br><br>RESULTS: The average RTL in AT-DIH cases was significantly shorter than that in controls (1.24 vs. 1.46, P=0.002). Patients with longer RTL were at a reduced risk of AT-DIH (OR=0.79, 95% CI: 0.66-0.94, P=0.009), and a dose-response relationship also existed between RTL and lower AT-DIH risk (P for trend=0.012). Under the optimal RTL cut-off value of 1.22, the corresponding AUCs were 0.57 (95% CI: 0.53-0.62, P=0.001) in the univariate model and 0.62 (95% CI: 0.57-0.66, P<0.001) in the multivariate model.<br><br>CONCLUSION: This study showed that the shorter the RTL, the higher the risk of AT-DIH during an anti-tuberculosis treatment. The short RTL could potentially serve as a risk factor or a predictive test of the hepatotoxic risk associated with anti-tuberculosis treatments.},
}
@article {pmid35707279,
year = {2022},
author = {Gu, W and Lin, Z and Zhao, S and Wang, G and Shen, Z and Liu, W and Cai, Y and Wang, K and Wan, CC and Yan, T},
title = {Research Progress on G-Quadruplexes in Human Telomeres and Human Telomerase Reverse Transcriptase (hTERT) Promoter.},
journal = {Oxidative medicine and cellular longevity},
volume = {2022},
number = {},
pages = {2905663},
pmid = {35707279},
issn = {1942-0994},
mesh = {Animals ; *G-Quadruplexes ; Humans ; Ligands ; Mice ; Promoter Regions, Genetic/genetics ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {The upregulation telomerase activity is observed in over 85-90% of human cancers and provides an attractive target for cancer therapies. The high guanine content in the telomere DNA sequences and the hTERT promoter can form G-quadruplexes (G4s). Small molecules targeting G4s in telomeres and hTERT promoter could stabilize the G4s and inhibit hTERT expression and telomere extension. Several G4 ligands have shown inhibitory effects in cancer cells and xenograft mouse models, indicating these ligands have a potential for cancer therapies. The current review article describes the concept of the telomere, telomerase, and G4s. Moreover, the regulation of telomerase and G4s in telomeres and hTERT promoter is discussed as well. The summary of the small molecules targeting G4s in telomeric DNA sequences and the hTERT promoter will also be shown.},
}
@article {pmid35706406,
year = {2022},
author = {Zhang, Y and Fu, F and Zhang, L and Zhang, W and Chen, L and Zhang, Y and Chen, W and Du, Y and Chen, S and Zhan, Q and Feng, Z and Xu, H and Nie, Y},
title = {Telomere is shortened in patients with irritable bowel syndrome in the Chinese population.},
journal = {Journal of gastroenterology and hepatology},
volume = {37},
number = {9},
pages = {1749-1755},
doi = {10.1111/jgh.15912},
pmid = {35706406},
issn = {1440-1746},
support = {202002020012//Guangzhou Planned Project of Science and Technology/ ; //Guangzhou Postdoctoral Sciences Foundation/ ; },
mesh = {China ; Humans ; *Irritable Bowel Syndrome/genetics ; Leukocytes ; Telomere/genetics ; Telomere Shortening/genetics ; },
abstract = {BACKGROUND AND AIM: Telomere shortening is an accepted indicator of aging. Many studies have investigated an association between leukocyte telomere length (LTL) and psychiatric disorders. Mental or psychological factors could be an important cause of irritable bowel syndrome (IBS). However, there are currently few research evaluating correlations between LTL and IBS.<br><br>METHODS: We examined associations between LTL and IBS using quantitative polymerase chain reaction in independent cohorts, including 205 patients with IBS and 189 healthy controls. Furthermore, we examined whether mental or psychological factors, types of IBS, duration of IBS and antidepressants had an association with LTL in patients with IBS.<br><br>RESULTS: Among total samples, patients with IBS presented shorter LTL when compared to healthy controls (P&#xa0;<&#xa0;0.0001). Moreover, in subgroup analyses of patients with IBS, not only the LTL in patients with IBS caused by mental or psychological factors was shorter (P&#xa0;<&#xa0;0.0001), but also in patients with IBS that were caused by other factors (P&#xa0;=&#xa0;0.0082). Furthermore, LTL in patients with IBS who had taken antidepressants for more than 1&#xa0;month was longer than that in patients with IBS who did not take antidepressants or took for less than 1&#xa0;month (P&#xa0;<&#xa0;0.0001).<br><br>CONCLUSIONS: This is the first study to describe the relationship between LTL and IBS. This study showed significantly shorter telomeres in patients with IBS. Our findings suggest that LTL may hold the potential to serve as a predictor of IBS diagnosis.},
}
@article {pmid35705636,
year = {2022},
author = {Jung, J and McCartney, DL and Wagner, J and Rosoff, DB and Schwandt, M and Sun, H and Wiers, CE and de Carvalho, LM and Volkow, ND and Walker, RM and Campbell, A and Porteous, DJ and McIntosh, AM and Marioni, RE and Horvath, S and Evans, KL and Lohoff, FW},
title = {Alcohol use disorder is associated with DNA methylation-based shortening of telomere length and regulated by TESPA1: implications for aging.},
journal = {Molecular psychiatry},
volume = {27},
number = {9},
pages = {3875-3884},
pmid = {35705636},
issn = {1476-5578},
support = {ZIA AA000242/ImNIH/Intramural NIH HHS/United States ; 220857/Z/20/Z/WT_/Wellcome Trust/United Kingdom ; 104036/Z/14/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Humans ; Alcohol Drinking/genetics ; *Alcoholism/genetics ; DNA Methylation/genetics ; Genome-Wide Association Study ; Telomere/genetics ; *Telomere Shortening ; *Aging ; *Adaptor Proteins, Signal Transducing/genetics ; },
abstract = {Chronic heavy alcohol consumption is associated with increased mortality and morbidity and often leads to premature aging; however, the mechanisms of alcohol-associated cellular aging are not well understood. In this study, we used DNA methylation derived telomere length (DNAmTL) as a novel approach to investigate the role of alcohol use on the aging process. DNAmTL was estimated by 140 cytosine phosphate guanines (CpG) sites in 372 individuals with alcohol use disorder (AUD) and 243 healthy controls (HC) and assessed using various endophenotypes and clinical biomarkers. Validation in an independent sample of DNAmTL on alcohol consumption was performed (N = 4219). Exploratory genome-wide association studies (GWAS) on DNAmTL were also performed to identify genetic variants contributing to DNAmTL shortening. Top GWAS findings were analyzed using in-silico expression quantitative trait loci analyses and related to structural MRI hippocampus volumes of individuals with AUD. DNAmTL was 0.11-kilobases shorter per year in AUD compared to HC after adjustment for age, sex, race, and blood cell composition (p = 4.0 × 10[-12]). This association was partially attenuated but remained significant after additionally adjusting for BMI, and smoking status (0.06 kilobases shorter per year, p = 0.002). DNAmTL shortening was strongly associated with chronic heavy alcohol use (ps < 0.001), elevated gamma-glutamyl transferase (GGT), and aspartate aminotransferase (AST) (ps < 0.004). Comparison of DNAmTL with PCR-based methods of assessing TL revealed positive correlations (R = 0.3, p = 2.2 × 10[-5]), highlighting the accuracy of DNAmTL as a biomarker. The GWAS meta-analysis identified a single nucleotide polymorphism (SNP), rs4374022 and 18 imputed ones in Thymocyte Expressed, Positive Selection Associated 1(TESPA1), at the genome-wide level (p = 3.75 × 10[-8]). The allele C of rs4374022 was associated with DNAmTL shortening, lower hippocampus volume (p < 0.01), and decreased mRNA expression in hippocampus tissue (p = 0.04). Our study demonstrates DNAmTL-related aging acceleration in AUD and suggests a functional role for TESPA1 in regulating DNAmTL length, possibly via the immune system with subsequent biological effects on brain regions negatively affected by alcohol and implicated in aging.},
}
@article {pmid35704191,
year = {2022},
author = {Glousker, G and Fernandes, RV and Feretzaki, M and Lingner, J},
title = {Detection of TERRA R-Loops at Human Telomeres.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2528},
number = {},
pages = {159-171},
pmid = {35704191},
issn = {1940-6029},
mesh = {DNA/chemistry ; Humans ; Nucleic Acid Hybridization ; *R-Loop Structures ; *RNA, Long Noncoding/genetics ; Telomere/genetics ; },
abstract = {R-loops are three-stranded nucleic acid structures composed of a DNA-RNA hybrid and a displaced DNA strand. The long noncoding RNA TERRA forms R-loops at telomeres influencing the telomeric chromatin composition and impacting on telomere maintenance mechanisms by semiconservative DNA replication, homology directed DNA repair and telomerase. Here, we describe a method to detect R-loops at telomeres, which involves immunoprecipitation with the R-loop recognizing S9.6 antibody, followed by detection of telomeric DNA by either dot-blot hybridization with a radiolabeled telomeric probe, or qPCR using DNA primers that are specific for subtelomeric sequences.},
}
@article {pmid35704190,
year = {2022},
author = {Wagner, CB and Luke, B},
title = {DNA-RNA Hybrids at Telomeres in Budding Yeast.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2528},
number = {},
pages = {145-157},
pmid = {35704190},
issn = {1940-6029},
mesh = {DNA/genetics ; *RNA/genetics/metabolism ; Ribonuclease H/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomycetales/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {It has recently been demonstrated that budding yeast telomeres are transcribed into TERRA, a long noncoding RNA. Due to the G-rich nature of the coding strand, TERRA has a tendency to form DNA-RNA hybrids and potentially R-loops, which in turn, promote repair at short telomeres. Here, we report two methods to detect DNA-RNA hybrids at yeast telomeres, namely, DRIP, which employs the S9.6 hybrid-recognizing antibody, and R-ChIP, which takes advantage of a catalytic dead form of RNase H1 (Rnh1-cd). We use cross-linked material for both protocols as we have found that this does not negatively affect recovered material, and furthermore allows the precipitation of other proteins from the identical cross-linked material. Although both methods are successful in terms of detecting DNA-RNA hybrids at telomeres, the R-ChIP method yields an approximately ten-fold increased enrichment.},
}
@article {pmid35698093,
year = {2022},
author = {Zhang, R and Du, J and Xiao, Z and Jiang, Y and Jin, L and Weng, Q},
title = {Association between the peripartum maternal and fetal telomere lengths and mitochondrial DNA copy numbers and preeclampsia: a prospective case-control study.},
journal = {BMC pregnancy and childbirth},
volume = {22},
number = {1},
pages = {483},
pmid = {35698093},
issn = {1471-2393},
support = {81701475//National Natural Science Foundation of China/ ; 81701475//National Natural Science Foundation of China/ ; BK20211006//Natural Science Foundation of Jiangsu Province/ ; },
mesh = {Case-Control Studies ; DNA Copy Number Variations ; *DNA, Mitochondrial/genetics ; Female ; Humans ; Infant ; Peripartum Period ; *Pre-Eclampsia/genetics ; Pregnancy ; Telomere ; },
abstract = {PURPOSE: To explore changes in telomere length (TL) and mitochondrial copy number (mtDNA-CN) in preeclampsia (PE) and to evaluate the combined effect of maternal TL and mtDNA-CN on PE risk.<br><br>METHODS: A case-control study of 471 subjects (130 PE cases and 341 age frequency matched controls with gestational age rank from 24 to 42&#xa0;weeks) was conducted in Nanjing Drum Tower Hospital, Jiangsu Province of China. Relative telomere length (RTL) and mtDNA-CN were measured using quantitative polymerase chain reaction (qPCR), and PE risk was compared between groups by logistic regression analyses.<br><br>RESULTS: PE patients displayed longer RTL (0.48 versus 0.30) and higher mtDNA-CN (3.02 versus 2.00) in maternal blood as well as longer RTL (0.61 versus 0.35) but lower mtDNA-CN (1.69 versus 5.49) in cord blood (all p&#x2009;<&#x2009;0.001). Exercise during pregnancy exerted an obvious effect of maternal telomere length prolongation. Multiparous women with folic acid intake during early pregnancy and those who delivered vaginally showed longer telomere length, while those factors imposed no or opposite effect on RTL in PE cases. Furthermore, RTL and mtDNA-CN were positively correlated in controls (in maternal blood r&#x2009;=&#x2009;0.18, p&#x2009;<&#x2009;0.01; in cord blood r&#x2009;=&#x2009;0.19, p&#x2009;<&#x2009;0.001), but this correlation was disrupted in PE patients in both maternal blood and cord blood. Longer maternal RTL and higher mtDNA-CN were associated with a higher risk of PE, and the ROC curve of RTL and mtDNA-CN for predicting PE risk presented an AUC of 0.755 (95% CI: 0.698-0.812).<br><br>CONCLUSIONS: The interaction of TL and mtDNA-CN may play an important role in the pathogenesis of PE and could be a potential biomarker of PE risk.},
}
@article {pmid35697743,
year = {2022},
author = {Lee, J and Sung, K and Joo, SY and Jeong, JH and Kim, SK and Lee, H},
title = {Dynamic interaction of BRCA2 with telomeric G-quadruplexes underlies telomere replication homeostasis.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {3396},
pmid = {35697743},
issn = {2041-1723},
mesh = {DNA Replication ; *G-Quadruplexes ; Homeostasis ; Telomere/genetics ; Telomere Homeostasis ; },
abstract = {BRCA2-deficient cells precipitate telomere shortening upon collapse of stalled replication forks. Here, we report that the dynamic interaction between BRCA2 and telomeric G-quadruplex (G4), the non-canonical four-stranded secondary structure, underlies telomere replication homeostasis. We find that the OB-folds of BRCA2 binds to telomeric G4, which can be an obstacle during replication. We further demonstrate that BRCA2 associates with G-triplex (G3)-derived intermediates, which are likely to form during direct interconversion between parallel and non-parallel G4. Intriguingly, BRCA2 binding to G3 intermediates promoted RAD51 recruitment to the telomere G4. Furthermore, MRE11 resected G4-telomere, which was inhibited by BRCA2. Pathogenic mutations at the OB-folds abrogated the binding with telomere G4, indicating that the way BRCA2 associates with telomere is innate to its tumor suppressor activity. Collectively, we propose that BRCA2 binding to telomeric G4 remodels it and allows RAD51-mediated restart of the G4-driven replication fork stalling, simultaneously preventing MRE11-mediated breakdown of telomere.},
}
@article {pmid35697164,
year = {2022},
author = {Shen, Z and Zheng, R and Yang, H and Xing, S and Jin, X and Yan, H and Zhu, J and Mei, Y and Lin, F and Zheng, X},
title = {G-quadruplex stabilizer Tetra-Pt(bpy) disrupts telomere maintenance and impairs FAK-mediated migration of telomerase-positive cells.},
journal = {International journal of biological macromolecules},
volume = {213},
number = {},
pages = {858-870},
doi = {10.1016/j.ijbiomac.2022.06.015},
pmid = {35697164},
issn = {1879-0003},
mesh = {Animals ; *Antineoplastic Agents/pharmacology/therapeutic use ; *G-Quadruplexes ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; *Neoplasms/drug therapy ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {G-quadruplex regulates a wide spectrum of biological processes, including telomere maintenance, DNA replication and transcription. The development of small molecules to selectively target G-quadruplex and their application remain hotspots in cancer therapy. Here, we explored the biological effect of G-quadruplexes stabilizer Tetra-Pt(bpy) in telomerase-positive cancer cells. Telomere maintenance was evaluated by telomerase repeat amplification protocol, chromosome orientation fluorescence in situ hybridization and telomere restriction fragment assays. We found that Tetra-Pt(bpy) accelerates telomere shortening through dual inhibition of telomerase activity and telomere sister chromatin exchanges mediated by telomeric G-quadruplexes. Consequently, Tetra-Pt(bpy)-treated cancer cells became enriched with extremely short telomeres and produced a strong telomeric DNA damage response following long-term treatment, leading to cell proliferation inhibition and senescence. Experimental evidence from RNA seq and cell migration-related assays showed that Tetra-Pt(bpy) decreased cell-matrix adhesion and inhibited the migration of non-senescent tumor cells. Mechanistically, Tetra-Pt(bpy) induced the formation of G-quadruplexes in focal adhesion kinase (FAK)-encoding gene PTK2, resulting in FAK transcription inhibition. Tetra-Pt(bpy) reduced xenograft tumor formation and inhibited tumor cell growth and migration in mice. This study further elucidates the function of G-quadruplexes in the human genome and reveals the potential of Tetra-Pt(bpy) as a novel chemotherapeutic agent for targeting telomerase-positive cancer cells.},
}
@article {pmid35696588,
year = {2022},
author = {Eastwood, JR and Connallon, T and Delhey, K and Hall, ML and Teunissen, N and Kingma, SA and La Porte, AM and Verhulst, S and Peters, A},
title = {Hot and dry conditions predict shorter nestling telomeres in an endangered songbird: Implications for population persistence.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {119},
number = {25},
pages = {e2122944119},
pmid = {35696588},
issn = {1091-6490},
mesh = {Animals ; *Climate Change ; *Endangered Species ; *Extinction, Biological ; Hot Temperature ; *Longevity/genetics ; *Songbirds/genetics/growth &amp; development ; Telomere/genetics ; *Telomere Shortening ; Water ; },
abstract = {Climate warming is increasingly exposing wildlife to sublethal high temperatures, which may lead to chronic impacts and reduced fitness. Telomere length (TL) may link heat exposure to fitness, particularly at early-life stages, because developing organisms are especially vulnerable to adverse conditions, adversity can shorten telomeres, and TL predicts fitness. Here, we quantify how climatic and environmental conditions during early life are associated with TL in nestlings of wild purple-crowned fairy-wrens (Malurus coronatus), endangered songbirds of the monsoonal tropics. We found that higher average maximum air temperature (range 31 to 45 °C) during the nestling period was associated with shorter early-life TL. This effect was mitigated by water availability (i.e., during the wet season, with rainfall), but independent of other pertinent environmental conditions, implicating a direct effect of heat exposure. Models incorporating existing information that shorter early-life TL predicts shorter lifespan and reduced fitness showed that shorter TL under projected warming scenarios could lead to population decline across plausible future water availability scenarios. However, if TL is assumed to be an adaptive trait, population viability could be maintained through evolution. These results are concerning because the capacity to change breeding phenology to coincide with increased water availability appears limited, and the evolutionary potential of TL is unknown. Thus, sublethal climate warming effects early in life may have repercussions beyond individual fitness, extending to population persistence. Incorporating the delayed reproductive costs associated with sublethal heat exposure early in life is necessary for understanding future population dynamics with climate change.},
}
@article {pmid35691385,
year = {2022},
author = {De Ruyter, T and Martens, DS and Bijnens, EM and Nawrot, TS and De Henauw, S and Michels, N},
title = {A multi-exposure approach to study telomere dynamics in childhood: A role for residential green space and waist circumference.},
journal = {Environmental research},
volume = {213},
number = {},
pages = {113656},
doi = {10.1016/j.envres.2022.113656},
pmid = {35691385},
issn = {1096-0953},
mesh = {Child ; Cross-Sectional Studies ; Female ; Humans ; Longitudinal Studies ; Male ; *Parks, Recreational ; *Telomere ; Waist Circumference ; },
abstract = {BACKGROUND: Telomeres are vulnerable to various environmental exposures and lifestyle factors, encompassed in the exposome. Recent research shows that telomere length is substantially determined early in life and that exposures in childhood may have important consequences in setting later life telomere length.<br><br>OBJECTIVES: We explore in a child population the associations of 17 exposures with telomere length and longitudinal telomere change.<br><br>METHODS: Children (2.8-10.3y at baseline, 51.3% boys) were followed-up for five to seven years. Relative telomere length was measured at baseline and follow-up using quantitative real-time PCR. Exposures and lifestyle factors included: body composition (body mass index and waist circumference), dietary habits (sugar- and fat-rich food intake, vegetables and fruit intake), psychosocial stress (events, emotions, behaviour), sleep duration, physical activity, and residential environmental quality (longterm black carbon, particulate matter exposure, and residential green space). Cross-sectional (n=182) and longitudinal (n=150) analyses were assessed using linear regression models, adjusting for age, sex, socioeconomic status and multiple testing.<br><br>RESULTS: Our longitudinal analyses showed that higher residential green space at baseline was associated with (&#x3b2;=0.261, p=0.002) lower telomere attrition and that children with a higher waist circumference at baseline showed a higher telomere attrition (&#x3b2;=-0.287, p=0.001). These two predictors were confirmed via LASSO variable selection and correction for multiple testing. In addition, children with more unhealthy exposures at baseline had a significantly higher telomere attrition over the follow-up period compared to children with more healthy exposures (&#x3b2;=-0.200, p=0.017).<br><br>DISCUSSION: Waist circumference and residential green space were identified as predictors associated with telomere attrition in childhood. These results further support the advantages of a healthy lifestyle from early age onwards and the importance of a green environment to promote molecular longevity from childhood onwards.},
}
@article {pmid35689027,
year = {2022},
author = {Mao, Y and Zhang, G},
title = {A complete, telomere-to-telomere human genome sequence presents new opportunities for evolutionary genomics.},
journal = {Nature methods},
volume = {19},
number = {6},
pages = {635-638},
pmid = {35689027},
issn = {1548-7105},
mesh = {Base Sequence ; *Genome, Human ; *Genomics ; Humans ; Telomere/genetics ; },
}
@article {pmid35688856,
year = {2022},
author = {Massey, DJ and Koren, A},
title = {Telomere-to-telomere human DNA replication timing profiles.},
journal = {Scientific reports},
volume = {12},
number = {1},
pages = {9560},
pmid = {35688856},
issn = {2045-2322},
support = {DP2 GM123495/GM/NIGMS NIH HHS/United States ; DP2-GM123495/NH/NIH HHS/United States ; },
mesh = {*Centromere/genetics ; DNA Replication/genetics ; *DNA Replication Timing ; Genome, Human ; Humans ; Telomere/genetics ; },
abstract = {The spatiotemporal organization of DNA replication produces a highly robust and reproducible replication timing profile. Sequencing-based methods for assaying replication timing genome-wide have become commonplace, but regions of high repeat content in the human genome have remained refractory to analysis. Here, we report the first nearly-gapless telomere-to-telomere replication timing profiles in human, using the T2T-CHM13 genome assembly and sequencing data for five cell lines. We find that replication timing can be successfully assayed in centromeres and large blocks of heterochromatin. Centromeric regions replicate in mid-to-late S-phase and contain replication-timing peaks at a similar density to other genomic regions, while distinct families of heterochromatic satellite DNA differ in their bias for replicating in late S-phase. The high degree of consistency in centromeric replication timing across chromosomes within each cell line prompts further investigation into the mechanisms dictating that some cell lines replicate their centromeres earlier than others, and what the consequences of this variation are.},
}
@article {pmid35687934,
year = {2022},
author = {Sengupta, D and Sengupta, K},
title = {Lamin A and telomere maintenance in aging: Two to Tango.},
journal = {Mutation research},
volume = {825},
number = {},
pages = {111788},
doi = {10.1016/j.mrfmmm.2022.111788},
pmid = {35687934},
issn = {1873-135X},
mesh = {Humans ; Lamin Type A/genetics/metabolism ; *Progeria/genetics/metabolism ; Aging/genetics ; *Aging, Premature/genetics ; Telomere/genetics/metabolism ; Mutation ; },
abstract = {Lamin proteins which constitute the nuclear lamina in almost all higher eukaryotes, are mainly of two types A &amp; B encoded by LMNA and LMNB1/B2 genes respectively. While lamin A remains the principal product of LMNA gene, variants like lamin C, C2 and A∆10 are also formed as alternate splice products. Role of lamin A in aging has been highlighted in recent times due to its association with progeroid or premature aging syndromes which is classified as a type of laminopathy. Progeria caused by accelerated accumulation of lamin A Δ50 or progerin occurs due to a mutation in this LMNA gene leading to defects in post translational modification of lamin A. One of the most common and severe symptoms of progeroid laminopathy is accelerated cellular senescence or aging along with bone resorption, muscle weakness, lipodystrophy and cardiovascular disorders. On the other hand, progerin accumulation and telomere dysfunction merge as common traits in the process of chronological aging. Two major hallmarks of physiological aging in humans include loss of genomic integrity and telomere attrition which can result from defective laminar organization leading to deformed nuclear architecture and culminates into replicative senescence. This also adversely affects epigenetic landscape, mitochondrial dysfunction and several signalling pathways like DNA repair, mTOR, MAPK, TGFβ. In this review, we discuss the telomere-lamina interplay in the context of physiological aging and progeria.},
}
@article {pmid35687089,
year = {2022},
author = {Paul, T and Opresko, PL and Ha, T and Myong, S},
title = {Vectorial folding of telomere overhang promotes higher accessibility.},
journal = {Nucleic acids research},
volume = {50},
number = {11},
pages = {6271-6283},
pmid = {35687089},
issn = {1362-4962},
support = {R01 CA207342/CA/NCI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; RF1 NS113636/NS/NINDS NIH HHS/United States ; R35 GM122569/GM/NIGMS NIH HHS/United States ; R01 GM115631/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA/chemistry ; *G-Quadruplexes ; Humans ; Nucleic Acid Conformation ; Shelterin Complex ; Telomerase/metabolism ; *Telomere/chemistry/genetics ; Telomere-Binding Proteins/metabolism ; },
abstract = {Human telomere overhang composed of tandem repeats of TTAGGG folds into G-quadruplex (G4). Unlike in an experimental setting in the test tube in which the entire length is allowed to fold at once, inside the cell, the overhang is expected to fold as it is synthesized directionally (5' to 3') and released segmentally by a specialized enzyme, the telomerase. To mimic such vectorial G4 folding process, we employed a superhelicase, Rep-X which can unwind DNA to release the TTAGGG repeats in 5' to 3' direction. We demonstrate that the folded conformation achieved by the refolding of full sequence is significantly different from that of the vectorial folding for two to eight TTAGGG repeats. Strikingly, the vectorially folded state leads to a remarkably higher accessibility to complementary C-rich strand and the telomere binding protein POT1, reflecting a less stably folded state resulting from the vectorial folding. Importantly, our study points to an inherent difference between the co-polymerizing and post-polymerized folding of telomere overhang that can impact telomere architecture and downstream processes.},
}
@article {pmid35686443,
year = {2022},
author = {Gong, H and Yu, Q and Guo, D and Wang, Y and Duan, L and Huang, W and Zhou, J and Wang, J and Huang, P},
title = {The relationship between dietary selenium intake and telomere length among diabetes.},
journal = {The British journal of nutrition},
volume = {},
number = {},
pages = {1-7},
doi = {10.1017/S000711452200174X},
pmid = {35686443},
issn = {1475-2662},
abstract = {Se is an indispensable trace element for the human body, and telomere length is considered a marker of biological ageing. Previous studies have shown that dietary Se intake is associated with telomere length. However, the relationship between Se intake and telomere length in patients with diabetes has not been well studied. Therefore, this study aimed to investigate the relationship between dietary Se intake and telomere length in patients with diabetes. We extracted 878 participants with diabetes from the National Health and Nutrition Examination Survey database for 1990-2002. Dietary Se intake was assessed using the 24 h dietary recall method, and telomere length was measured using quantitative PCR. Generalised linear models were constructed to assess the relationship between dietary Se intake and telomere length. After controlling for the confounders, 1 μg increase in dietary Se intake in female patients with diabetes, and telomere length increased by 1·84 base pairs (β = 1·84 (95 % CI: 0·15, 3·53)), there was a line relationship between dietary Se intake and telomere length in female patients with diabetes and telomere length increased with increasing dietary Se intake within the range of 0-250 μg. The study demonstrates that dietary Se intake is significantly associated with telomere length only in the female population with diabetes in the USA. However, further prospective studies are required to confirm this finding.},
}
@article {pmid35685390,
year = {2022},
author = {Bountziouka, V and Musicha, C and Allara, E and Kaptoge, S and Wang, Q and Angelantonio, ED and Butterworth, AS and Thompson, JR and Danesh, JN and Wood, AM and Nelson, CP and Codd, V and Samani, NJ},
title = {Modifiable traits, healthy behaviours, and leukocyte telomere length: a population-based study in UK Biobank.},
journal = {The lancet. Healthy longevity},
volume = {3},
number = {5},
pages = {e321-e331},
pmid = {35685390},
issn = {2666-7568},
support = {MR/L003120/1/MRC_/Medical Research Council/United Kingdom ; MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom ; SP/16/4/32697/BHF_/British Heart Foundation/United Kingdom ; MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom ; CH/12/2/29428/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Biological Specimen Banks ; *Coronary Artery Disease ; Female ; Health Behavior ; Health Status ; Humans ; Leukocytes ; Male ; Mendelian Randomization Analysis ; *Telomere ; United Kingdom ; },
abstract = {BACKGROUND: Telomere length is associated with risk of several age-related diseases and cancers. We aimed to investigate the extent to which telomere length might be modifiable through lifestyle and behaviour, and whether such modification has any clinical consequences.<br><br>METHODS: In this population-based study, we included participants from UK Biobank who had leukocyte telomere length (LTL) measurement, ethnicity, and white blood cell count data. We investigated associations of LTL with 117 potentially modifiable traits, as well as two indices of healthy behaviours incorporating between them smoking, physical activity, diet, maintenance of a healthy bodyweight, and alcohol intake, using both available and imputed data. To help interpretation, associations were summarised as the number of equivalent years of age-related change in LTL by dividing the trait &#x3b2; coefficients with the age &#x3b2; coefficient. We used mendelian randomisation to test causality of selected associations. We investigated whether the associations of LTL with 22 diseases were modified by the number of healthy behaviours and the extent to which the associations of more healthy behaviours with greater life expectancy and lower risk of coronary artery disease might be mediated through LTL.<br><br>FINDINGS: 422&#x2008;797 participants were available for the analysis (227&#x2008;620 [53&#xb7;8%] were women and 400&#x2008;036 [94&#xb7;6%] were White). 71 traits showed significant (p<4&#xb7;27&#x2008;&#xd7;&#x2008;10[-4]) associations with LTL but most were modest, equivalent to less than 1 year of age-related change in LTL. In multivariable analyses of 17 traits with stronger associations (equivalent to &#x2265;2 years of age-related change in LTL), oily fish intake, educational attainment, and general health status retained a significant association of this magnitude, with walking pace and current smoking being additionally significant at this level of association in the imputed models. Mendelian randomisation analysis suggested that educational attainment and smoking behaviour causally affect LTL. Both indices of healthy behaviour were positively and linearly associated with LTL, with those with the most healthy behaviours having longer LTL equivalent to about 3&#xb7;5 years of age-related change in LTL than those with the least heathy behaviours (p<0&#xb7;001). However, healthy behaviours explained less than 0&#xb7;2% of the total variation in LTL and did not significantly modify the association of LTL with risk of any of the diseases studied. Neither the association of more healthy behaviours on greater life expectancy or lower risk of coronary artery disease were substantially mediated through LTL.<br><br>INTERPRETATION: Although several potentially modifiable traits and healthy behaviours have a quantifiable association with LTL, at least some of which are likely to be causal, these effects are not of a sufficient magnitude to substantially alter the association between LTL and various diseases or life expectancy. Attempts to change telomere length through lifestyle or behavioural changes might not confer substantial clinical benefit.<br><br>FUNDING: UK Medical Research Council, UK Biotechnology and Biological Sciences Research Council, and British Heart Foundation.},
}
@article {pmid35682685,
year = {2022},
author = {Alswady-Hoff, M and Erdem, JS and Aleksandersen, M and Anmarkrud, KH and Skare, &#xd8; and Lin, FC and Simensen, V and Arnoldussen, YJ and Skaug, V and Ropstad, E and Zienolddiny-Narui, S},
title = {Multiwalled Carbon Nanotubes Induce Fibrosis and Telomere Length Alterations.},
journal = {International journal of molecular sciences},
volume = {23},
number = {11},
pages = {},
pmid = {35682685},
issn = {1422-0067},
support = {19/00274//National Institute of Occupational Health, Norway/ ; NFR 204341/H10, fellowship Y.J.A.//Research Council of Norway/ ; FP7/2007-2013//EU Seventh Framework Programme, NANoREG project/ ; },
mesh = {Animals ; Epithelial Cells/metabolism ; Fibrosis ; Lung/pathology ; Mice ; *Nanotubes, Carbon/toxicity ; Telomere/genetics ; },
abstract = {Telomere shortening can result in cellular senescence and in increased level of genome instability, which are key events in numerous of cancer types. Despite this, few studies have focused on the effect of nanomaterial exposure on telomere length as a possible mechanism involved in nanomaterial-induced carcinogenesis. In this study, effects of exposure to multiwalled carbon nanotubes (MWCNT) on telomere length were investigated in mice exposed by intrapleural injection, as well as in human lung epithelial and mesothelial cell lines. In addition, cell cycle, apoptosis, and regulation of genes involved in DNA damage repair were assessed. Exposure to MWCNT led to severe fibrosis, infiltration of inflammatory cells in pleura, and mesothelial cell hyperplasia. These histological alterations were accompanied by deregulation of genes involved in fibrosis and immune cell recruitment, as well as a significant shortening of telomeres in the pleura and the lung. Assessment of key carcinogenic mechanisms in vitro confirmed that long-term exposure to the long MWCNT led to a prominent telomere shortening in epithelial cells, which coincided with G1-phase arrest and enhanced apoptosis. Altogether, our data show that telomere shortening resulting in cell cycle arrest and apoptosis may be an important mechanism in long MWCNT-induced inflammation and fibrosis.},
}
@article {pmid35681604,
year = {2022},
author = {Alessandrini, I and Percio, S and Naghshineh, E and Zuco, V and Stacchiotti, S and Gronchi, A and Pasquali, S and Zaffaroni, N and Folini, M},
title = {Telomere as a Therapeutic Target in Dedifferentiated Liposarcoma.},
journal = {Cancers},
volume = {14},
number = {11},
pages = {},
pmid = {35681604},
issn = {2072-6694},
support = {C56167/A29363/CRUK_/Cancer Research UK/United Kingdom ; 29363/CRUK_/Cancer Research UK/United Kingdom ; },
abstract = {BACKGROUND: Well-differentiated (WD)/dedifferentiated (DD) liposarcoma (LPS) accounts for ~60% of retroperitoneal sarcomas. WDLPS and DDLPS divergently evolve from a common precursor and are both marked by the amplification of the 12q13-q15 region, leading to the abnormal expression of MDM2, CDK4, and HMGA2 genes. DDLPS is a non-lipogenic disease associated with aggressive clinical behavior. Patients have limited therapeutic options, especially for advanced disease, and their outcome remains largely unsatisfactory. This evidence underlines the need for identifying and validating DDLPS-specific actionable targets to design novel biology-driven therapies.<br><br>METHODS: Following gene expression profiling of DDLPS clinical specimens, we observed the up-regulation of "telomere maintenance" (TMM) pathways in paired DD and WD components of DDLPS. Considering the relevance of TMM for LPS onset and progression, the activity of a telomeric G-quadruplex binder (RHPS4) was assessed in DDLPS patient-derived cell lines.<br><br>RESULTS: Equitoxic concentrations of RHPS4 in DDLPS cells altered telomeric c-circle levels, induced DNA damage, and resulted in the accumulation of &#x3b3;-H2AX-stained micronuclei. This evidence was paralleled by an RHPS4-mediated reduction of in vitro cell migration and induction of apoptosis/autophagy.<br><br>CONCLUSIONS: Our findings support telomere as an intriguing therapeutic target in DDLPS and suggest G-quadruplex binders as innovative therapeutic agents.},
}
@article {pmid35681050,
year = {2022},
author = {Andreu-Sánchez, S and Aubert, G and Ripoll-Cladellas, A and Henkelman, S and Zhernakova, DV and Sinha, T and Kurilshikov, A and Cenit, MC and Jan Bonder, M and Franke, L and Wijmenga, C and Fu, J and van der Wijst, MGP and Melé, M and Lansdorp, P and Zhernakova, A},
title = {Genetic, parental and lifestyle factors influence telomere length.},
journal = {Communications biology},
volume = {5},
number = {1},
pages = {565},
pmid = {35681050},
issn = {2399-3642},
mesh = {*Aging/genetics ; Epigenesis, Genetic ; Female ; Humans ; Life Style ; Parents ; Pregnancy ; *Telomere/genetics ; },
abstract = {The average length of telomere repeats (TL) declines with age and is considered to be a marker of biological ageing. Here, we measured TL in six blood cell types from 1046 individuals using the clinically validated Flow-FISH method. We identified remarkable cell-type-specific variations in TL. Host genetics, environmental, parental and intrinsic factors such as sex, parental age, and smoking are associated to variations in TL. By analysing the genome-wide methylation patterns, we identified that the association of maternal, but not paternal, age to TL is mediated by epigenetics. Single-cell RNA-sequencing data for 62 participants revealed differential gene expression in T-cells. Genes negatively associated with TL were enriched for pathways related to translation and nonsense-mediated decay. Altogether, this study addresses cell-type-specific differences in telomere biology and its relation to cell-type-specific gene expression and highlights how perinatal factors play a role in determining TL, on top of genetics and lifestyle.},
}
@article {pmid35679773,
year = {2022},
author = {Kuehl, LK and de Punder, K and Deuter, CE and Martens, DS and Heim, C and Otte, C and Wingenfeld, K and Entringer, S},
title = {Telomere length in individuals with and without major depression and adverse childhood experiences.},
journal = {Psychoneuroendocrinology},
volume = {142},
number = {},
pages = {105762},
doi = {10.1016/j.psyneuen.2022.105762},
pmid = {35679773},
issn = {1873-3360},
support = {R01 HD065825/HD/NICHD NIH HHS/United States ; R01 HD060628/HD/NICHD NIH HHS/United States ; R01 AG050455/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; *Adverse Childhood Experiences ; Depression ; *Depressive Disorder, Major/genetics ; Humans ; Leukocytes ; Male ; Telomere ; Telomere Shortening ; },
abstract = {Major depressive disorder (MDD) and adverse childhood experiences (ACE) are associated with poor physical and mental health in adulthood. One underlying mechanism might be accelerated cellular aging. For example, both conditions, MDD and ACE, have been related to a biological marker of cellular aging, accelerated shortening of telomere length (TL). Since MDD and ACE are confounded in many studies, we aimed with the current study to further disentangle the effects of MDD and ACE on TL using a full-factorial design including four carefully diagnosed groups of healthy participants and MDD patients with and without ACE (total N = 90, all without use of antidepressants). As dependent variable, TL was assessed in leukocytes. We found no group differences based on MDD and ACE exposure in TL. While TL was negatively associated with age and male sex, TL was not associated with any measure of severity of MDD, ACE or current stress. One possible explanation for our null result may be the comparatively good physical health status of our sample. Future research is needed to elucidate the relation of TL, MDD and ACE, taking potential effect modification by medication intake and physical health status into account.},
}
@article {pmid35677559,
year = {2022},
author = {Jiang, L and Tang, BS and Guo, JF and Li, JC},
title = {Telomere Length and COVID-19 Outcomes: A Two-Sample Bidirectional Mendelian Randomization Study.},
journal = {Frontiers in genetics},
volume = {13},
number = {},
pages = {805903},
pmid = {35677559},
issn = {1664-8021},
abstract = {Observational studies have found a relationship between directly measured short leukocyte telomere length (LTL) and severe coronavirus disease 19 (COVID-19). We investigated the causal association between genetically predicted LTL and COVID-19 susceptibility or severity. A previous genome-wide association study (GWAS) of 78,592 European-ancestry participants identified single nucleotidepolymorphisms (SNPs) that can be utilized to genetically predict LTL. Summary-level data for COVID-19 outcomes were analyzed from the COVID-19 Host Genetics Initiative. A two-sample bidirectional Mendelian randomization (MR) study was designed to evaluate these causal relationships. Using an inverse-weighted MR analysis and population-based controls, genetically predicted LTL did not reveal any significant association with COVID-19 susceptibility (odds ratio (OR): 0.94; 95% CI: 0.85-1.04; p = 0.202) or severity (OR: 0.85; 95% CI: 0.70-1.03; p = 0.099). Similar results were found for five other definitions of cases/controls and/or COVID-19 outcomes. Six additional MR methods and sensitivity analyses were conducted after removing variants with potential horizontal pleiotropy and including variants at a liberal significance level, which produced similar results. Using SNPs identified for the prediction of LTL from another GWAS study, we found a non-significant association for COVID-19 susceptibility or severity with narrower CIs toward the null hypothesis. No proof of genetically predicted COVID-19 phenotypes remained causally associated with genetically predicted LTL, and the null association was consistent with a lack of significant genetic correlation. Genetic evidence does not support shorter LTL as a causal risk factor for COVID-19 susceptibility or severity.},
}
@article {pmid35676815,
year = {2022},
author = {Fan, YH and Li, XL and Liu, XH and Guo, ZF and Yan, MQ and Duan, XR and Miao, WB and Wang, W},
title = {Association between Polymorphisms in Telomere-Associated Protein Genes and the Cholinesterase Activity of Omethoate-Exposed Workers.},
journal = {Biomedical and environmental sciences : BES},
volume = {35},
number = {5},
pages = {448-452},
doi = {10.3967/bes2022.060},
pmid = {35676815},
issn = {2214-0190},
mesh = {Cholinesterases/genetics ; *Dimethoate/analogs &amp; derivatives ; Humans ; *Occupational Exposure/adverse effects ; Polymorphism, Genetic ; Telomere ; },
}
@article {pmid35675759,
year = {2022},
author = {Giaccherini, M and Gentiluomo, M and Arcidiacono, PG and Falconi, M and Testoni, SGG and Apadula, L and Lauri, G and Di Franco, G and Fatucchi, LM and Petrone, MC and Corradi, C and Crippa, S and Morelli, L and Capurso, G and Campa, D},
title = {A polymorphic variant in telomere maintenance is associated with worrisome features and high-risk stigmata development in IPMNs.},
journal = {Carcinogenesis},
volume = {43},
number = {8},
pages = {728-735},
doi = {10.1093/carcin/bgac051},
pmid = {35675759},
issn = {1460-2180},
mesh = {*Carcinoma, Pancreatic Ductal/genetics/pathology ; Humans ; *Pancreatic Intraductal Neoplasms ; *Pancreatic Neoplasms/genetics/pathology ; Retrospective Studies ; Telomere/genetics ; },
abstract = {Intraductal papillary mucinous neoplasms (IPMNs) are nonobligatory precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The identification of molecular biomarkers able to predict the risk of progression of IPMNs toward malignancy is largely lacking and sorely needed. Telomere length (TL) is associated with the susceptibility of developing cancers, including PDAC. Moreover, several PDAC risk factors have been shown to be associated with IPMN transition to malignancy. TL is genetically determined, and the aim of this study was to use 11 SNPs, alone or combined in a score (teloscore), to estimate the causal relation between genetically determined TL and IPMNs progression. For this purpose, 173 IPMN patients under surveillance were investigated. The teloscore did not show any correlation, however, we observed an association between PXK-rs6772228-A and an increased risk of IPMN transition to malignancy (HR = 3.17; 95%CI 1.47-6.84; P = 3.24 × 10-3). This effect was also observed in a validation cohort of 142 IPMNs even though the association was not statistically significant. The combined analysis was consistent showing an association between PXK-rs6772228-A and increased risk of progression. The A allele of this SNP is strongly associated with shorter LTL that in turn have been reported to be associated with increased risk of developing PDAC. These results clearly highlight the importance of looking for genetic variants as potential biomarkers in this setting in order to further our understanding the etiopathogenesis of PDAC and suggest that genetically determined TL might be an additional marker of IPMN prognosis.},
}
@article {pmid35670038,
year = {2022},
author = {Carroll, JE and Olmstead, R and Haque, R and Irwin, MR},
title = {Accelerated mononuclear cell telomere attrition in breast cancer survivors with depression history: A 2-year longitudinal cohort study.},
journal = {Cancer},
volume = {128},
number = {16},
pages = {3109-3119},
doi = {10.1002/cncr.34329},
pmid = {35670038},
issn = {1097-0142},
support = {R01 CA160245/CA/NCI NIH HHS/United States ; R01 CA207130/CA/NCI NIH HHS/United States ; },
mesh = {*Breast Neoplasms/genetics ; *Cancer Survivors ; Cohort Studies ; Depression/epidemiology ; *Depressive Disorder, Major ; Female ; Humans ; Leukocytes, Mononuclear ; Longitudinal Studies ; Prospective Studies ; Telomere ; },
abstract = {BACKGROUND: Cancer treatments are thought to accelerate biological aging, although this trajectory is highly variable. Depression is more prevalent in breast cancer survivors and is thought to be a vulnerability factor for biological aging. A lifetime history of depression and cumulative lifetime number of depression episodes could hypothetically be associated with an accelerated rate of biological aging as indexed by attrition of telomere length in a prospective cohort of breast cancer survivors who were not currently depressed.<br><br>METHODS: Breast cancer survivors (n&#xa0;=&#xa0;206) without current depression were recruited from a large community-based health plan and were assessed for depression history by a structured diagnostic interview. Blood specimens were provided at baseline and every 8&#x2009;months over 24&#x2009;months to measure peripheral blood mononuclear cell (PBMC) telomere length. Mixed linear models examined associations of depression history and number of depression episodes with change in telomere length, adjusting for demographic, comorbidity, and cancer-specific factors.<br><br>RESULTS: In the fully adjusted model, depression history predicted attrition of PBMC telomere length over 24&#x2009;months (Beta [SE]&#xa0;=&#xa0;-.006 [.002], p&#xa0;=&#xa0;.001). Greater number of depressive episodes over the lifetime was also associated with accelerated attrition of PBMC telomere length over 24&#x2009;months (Beta [SE]&#xa0;=&#xa0;-.004 [.001], p&#xa0;=&#xa0;.001).<br><br>CONCLUSIONS: In breast cancer survivors without current depression, telomere attrition over 24&#x2009;months was greatest in those with a lifetime depression history, particularly those with the greatest number of episodes of major depressive disorder over their lifetime. Depression history and its cumulative burden may contribute to accelerated biological aging, with implications for risk of morbidity and mortality in breast cancer survivors.},
}
@article {pmid35666175,
year = {2022},
author = {Memaran, N and Wilke, H and Sugianto, RI and Baumann, U and Bauer, E and Swallow, M and Beuke, E and Junge, N and Pfister, ED and Grabitz, C and Richter, N and Goldschmidt, I and Schmidt, BMW and Melk, A},
title = {Telomere length is associated with intima-media thickness in pediatric liver transplant patients: A prospective cohort study.},
journal = {Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society},
volume = {28},
number = {11},
pages = {1766-1775},
doi = {10.1002/lt.26524},
pmid = {35666175},
issn = {1527-6473},
mesh = {Aspartate Aminotransferases ; *Atherosclerosis/epidemiology/etiology ; Carotid Intima-Media Thickness ; Child ; Humans ; Leukocytes ; *Liver Transplantation/adverse effects ; Prospective Studies ; Tacrolimus ; Telomere ; },
abstract = {Leukocyte telomere length (LTL) is a marker for biological age. Pediatric liver transplant recipients show a high rate of subclinical atherosclerosis, indicated by elevated intima-media thickness (IMT). We hypothesized that atherosclerosis is associated with biological age in these patients and investigated the course of LTL over time. We measured LTL from peripheral blood leukocytes by quantitative polymerase chain reaction and IMT from 97 pediatric patients after liver transplantation in a prospective cohort study. Of the patients, 71% (n = 69) had two or more assessments (total, 228 observations; median follow-up, 1.1 years). Lower LTL was associated with higher IMT (β = -0.701, p = 0.01) and higher aspartate aminotransferase (β = -0.001, p = 0.02), adjusted for age, sex, and age at transplantation. Of the patients, 45% showed decreasing LTL over time, whereas 55% exhibited stable LTL. Patients with stable LTL showed a decrease in IMT (median, -0.02 mm/year) and a decrease of tacrolimus trough levels (median, -0.08 μg/L/year). LTL is associated with IMT independent of age in pediatric liver transplant patients, suggesting that early aging contributes to the high burden of subclinical cardiovascular damage and may furthermore negatively affect the graft.},
}
@article {pmid35664481,
year = {2022},
author = {Carvalho, CM and Coimbra, BM and Xavier, G and Bugiga, AVG and Fonseca, T and Olff, M and Polimanti, R and Mello, AF and Ota, VK and Mello, MF and Belangero, SI},
title = {Shorter Telomeres Related to Posttraumatic Stress Disorder Re-experiencing Symptoms in Sexually Assaulted Civilian Women.},
journal = {Frontiers in psychiatry},
volume = {13},
number = {},
pages = {835783},
pmid = {35664481},
issn = {1664-0640},
abstract = {Telomeres are short tandem repeats of "TTAGGG" that protect the chromosome ends from deterioration or fusion of chromosomes. Their repeat length shortens with cell division acting as a biomarker of cellular aging. Traumatic stress events during adulthood or childhood have been associated with posttraumatic stress disorder (PTSD) and short leukocyte telomere length (LTL). This study investigated whether LTL was associated with PTSD in a Brazilian sample of sexually assaulted civilian women at two time points: baseline and 1-year follow-up. At baseline, we assessed 64 women with PTSD following sexual assault (cases) and 60 women with no previous history of sexual trauma or mental disorders (healthy controls - HC). At follow-up visit, 13 persistent PTSD cases, 11 HCs, and 11 PTSD remitters patients were evaluated. PTSD diagnosis and severity were assessed using Mini International Neuropsychiatric Interview (Diagnostic and Statistical Manual of Mental Disorders III/IV criteria) and Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), respectively. LTL was measured using multiplex real-time polymerase chain reaction (PCR). In the baseline analysis, we observed that LTL was associated with re-experiencing symptoms (B = -0.16; confidence interval (CI) 95% = -0.027--0.005; Bonferroni-adjusted p-value = 0.02), but no association was observed between other PTSD symptoms and LTL. In the longitudinal analysis, telomere shortening was no longer observed in patients with PTSD and PTSD remitters. In conclusion, our findings indicate that shorter baseline LTL is associated with early stage of PTSD re-experiencing symptoms in recently sexually assaulted women.},
}
@article {pmid35662923,
year = {2022},
author = {Hu, L and Bai, Y and Hu, G and Zhang, Y and Han, X and Li, J},
title = {Association of Dietary Magnesium Intake With Leukocyte Telomere Length in United States Middle-Aged and Elderly Adults.},
journal = {Frontiers in nutrition},
volume = {9},
number = {},
pages = {840804},
pmid = {35662923},
issn = {2296-861X},
abstract = {AIM: Magnesium supplementation may extend the life span; however, the biological mechanism is still unknown. Leukocyte telomere length (LTL) is a marker of cell aging and biological health in humans. Data concerning whether magnesium supplementation can maintain telomere length, thus prolonging life are limited. We aimed to investigate the association between dietary magnesium intake and LTL in United States middle-aged and elderly adults.<br><br>METHODS: A total of 4,039 United States adults aged &#x2265; 45 years from National Health and Nutrition Examination Survey (1999-2002). Dietary magnesium intake was collected by a trained interviewer using 24-h dietary recall method and LTL was obtained using the quantitative polymerase chain reaction method. Multiple linear regression analysis was performed to evaluate the crude and adjusted association of dietary magnesium intake with LTL.<br><br>RESULTS: The overall mean (SD) of LTL was 5.6 (0.6) kp. After adjusting potential confounders, every 1 mg increase in log-transformed dietary magnesium intake was associated with 0.20 kp (95% confidence intervals: 0.05-0.34) longer LTL. Participants with the highest tertile (&#x2265;299 mg) of dietary magnesium intake had statistically significant longer LTL (&#x3b2; = 0.07, P = 0.038) compared with the lowest tertile (<198 mg), with significant linear trends across tertiles. Moreover, the association between dietary magnesium intake and LTL was significantly stronger in participants with higher levels of education (&#x2265;high school compared with < high school, P for interaction = 0.002). E-value analysis suggested robustness to unmeasured confounding.<br><br>CONCLUSION: Our findings showed that increased dietary magnesium intake was associated with longer LTL, which suggested that magnesium was conducive to a longer life expectancy.},
}
@article {pmid35661999,
year = {2022},
author = {da Silva, A and Silveira, BKS and Hermsdorff, HHM and da Silva, W and Bressan, J},
title = {Effect of omega-3 fatty acid supplementation on telomere length and telomerase activity: A systematic review of clinical trials.},
journal = {Prostaglandins, leukotrienes, and essential fatty acids},
volume = {181},
number = {},
pages = {102451},
doi = {10.1016/j.plefa.2022.102451},
pmid = {35661999},
issn = {1532-2823},
mesh = {Clinical Trials as Topic ; *Diabetes Mellitus, Type 2/drug therapy ; Dietary Supplements ; *Fatty Acids, Omega-3/pharmacology/therapeutic use ; Humans ; *Telomerase/genetics/metabolism ; Telomere ; },
abstract = {Evidence suggests antioxidant and anti-inflammatory properties of omega-3 polyunsaturated fatty acids (n-3 PUFA). However, the effect of supplementation of this fatty acid profile on the telomere length and the telomerase enzyme activity was not revised yet. The PubMed and Embase® databases were used to search for clinical trials. A total of six clinical trials were revised. Omega-3 PUFA supplementation did not statistically affect telomere length in three out of three studies but affected telomerase activity in two out of four studies. The supplementation increased telomerase enzyme activity in subjects with first-episode schizophrenia. Besides, it decreased telomerase enzyme activity without modulating the effects of Pro12Ala polymorphism on the PPARγ gene in type 2 diabetes subjects. The methodological differences between the studies and the limited number of studies on the theme suggest that further studies are needed to elucidate the effects of n-3 PUFA supplementation on telomere length and telomerase enzyme activity in humans.},
}
@article {pmid35660961,
year = {2022},
author = {Lim, HF and Tan, NS and Dehghan, R and Shen, M and Liew, MF and Bee, SWL and Sia, YY and Liu, J and Khor, CC and Kwok, I and Ng, LG and Angeli, V and Dorajoo, R},
title = {Shortened Telomere Length in Sputum Cells of Bronchiectasis Patients is Associated with Dysfunctional Inflammatory Pathways.},
journal = {Lung},
volume = {200},
number = {3},
pages = {401-407},
pmid = {35660961},
issn = {1432-1750},
mesh = {*Bronchiectasis ; Humans ; Respiratory System ; *Sputum ; Telomere ; Telomere Shortening ; },
abstract = {Telomere attrition is an established ageing biomarker and shorter peripheral blood leukocyte telomere length has been associated with increased risks of respiratory diseases. However, whether telomere length in disease-relevant sputum immune cells of chronic respiratory disease patients is shortened and which pathways are dysfunctional are not clear. Here we measured telomere length from sputum samples of bronchiectasis and asthmatic subjects and determined that telomere length in sputum of bronchiectasis subjects was significantly shorter (Beta = - 1.167, PAdj = 2.75 × 10[-4]). We further performed global gene expression analysis and identified genes involved in processes such as NLRP3 inflammasome activation and regulation of adaptive immune cells when bronchiectasis sputum telomere length was shortened. Our study provides insights on dysfunctions related to shortened telomere length in sputum immune cells of bronchiectasis patients.},
}
@article {pmid35659559,
year = {2022},
author = {Morosinotto, C and Bensch, S and Tarka, M and Karell, P},
title = {Heritability and Parental Effects in Telomere Length in a Color Polymorphic Long-Lived Bird.},
journal = {Physiological and biochemical zoology : PBZ},
volume = {95},
number = {4},
pages = {350-364},
doi = {10.1086/720161},
pmid = {35659559},
issn = {1537-5293},
mesh = {Animals ; Birds ; Melanins/genetics ; *Physical Conditioning, Animal ; Telomere/genetics ; Telomere Shortening ; },
abstract = {AbstractRelative telomere length (RTL), an indicator of senescence, has been shown to be heritable but can also be affected by environmental factors, such as parental effects. Investigating heritability as well as parental effects and rearing environment can help us to understand the factors affecting offspring telomeres. Moreover, how phenotypic parental traits linked with fitness can impact offspring RTL is still unclear. A phenotypic marker closely associated with physiological traits and fitness is melanin-based color polymorphism, which in tawny owl (Strix aluco) is highly heritable and strongly associated with adult telomere shortening and survival. We studied narrow-sense heritability (h[2]) of RTL, as well as the impact of parental age and color morph and their interaction on offspring RTL. Offspring RTL at fledging was strongly positively correlated with both mother RTL and father RTL at breeding. Offspring RTL was also negatively associated with father age, suggesting that older fathers sired offspring with shorter telomeres. Parental color morph did not explain offspring RTL, and there were no interactive effects of parental morph and age, despite previously documented morph-specific senescence patterns. Our results suggest that RTL is highly heritable and affected by paternal age but not related to color polymorphism. This suggests that either morph-specific telomere shortening as an adult does not result in significantly shorter telomeres in their gametes, or that parents compensate morph-specific senescence via parental care. Morph-specific patterns of telomere dynamics in polymorphic species may thus emerge from different life history strategies adopted in adulthood.},
}
@article {pmid35657918,
year = {2022},
author = {Armstrong, ND and Irvin, MR and Haley, WE and Blinka, MD and Kamin Mukaz, D and Patki, A and Rutherford Siegel, S and Shalev, I and Durda, P and Mathias, RA and Walston, JD and Roth, DL},
title = {Telomere shortening and the transition to family caregiving in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study.},
journal = {PloS one},
volume = {17},
number = {6},
pages = {e0268689},
pmid = {35657918},
issn = {1932-6203},
support = {U01 NS041588/NS/NINDS NIH HHS/United States ; RF1 AG050609/AG/NIA NIH HHS/United States ; P30 AG021334/AG/NIA NIH HHS/United States ; },
mesh = {Cross-Sectional Studies ; Humans ; Race Factors ; Stress, Psychological/genetics ; *Stroke/genetics ; Telomere/genetics ; *Telomere Shortening ; },
abstract = {Telomere length (TL) is widely studied as a possible biomarker for stress-related cellular aging and decreased longevity. There have been conflicting findings about the relationship between family caregiving stress and TL. Several initial cross-sectional studies have found associations between longer duration of caregiving or perceived stressfulness of caregiving and shortened TL, suggesting that caregiving poses grave risks to health. Previous reviews have suggested the need for longitudinal methods to investigate this topic. This study examined the association between the transition to family caregiving and change in TL across ~9 years. Data was utilized from the Caregiving Transitions Study, an ancillary study to the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. TL was assayed using qPCR and analyzed as the telomere-to-single copy gene ratio for each participant at baseline and follow-up. General linear models examined the association between caregiving status and the change in TL for 208 incident caregivers and 205 controls, as well as associations between perceived stress and TL among caregivers. No association was found between TL change and caregiving (p = 0.494), and fully adjusted models controlling for health and socioeconomic factors did not change the null relationship (p = 0.305). Among caregivers, no association was found between perceived caregiving stress and change in TL (p = 0.336). In contrast to earlier cross-sectional studies, this longitudinal, population-based study did not detect a significant relationship between the transition into a family caregiving role and changes in TL over time. Given the widespread citation of previous findings suggesting that caregiving shortens telomeres and places caregivers at risk of early mortality, these results demonstrate the potential need of a more balanced narrative about caregiving.},
}
@article {pmid35656320,
year = {2022},
author = {Bennett, S and Girndt, A and Sánchez-Tójar, A and Burke, T and Simons, M and Schroeder, J},
title = {Evidence of Paternal Effects on Telomere Length Increases in Early Life.},
journal = {Frontiers in genetics},
volume = {13},
number = {},
pages = {880455},
pmid = {35656320},
issn = {1664-8021},
abstract = {Offspring of older parents in many species have decreased longevity, a faster ageing rate and lower fecundity than offspring born to younger parents. Biomarkers of ageing, such as telomeres, that tend to shorten as individuals age, may provide insight into the mechanisms of such parental age effects. Parental age may be associated with offspring telomere length either directly through inheritance of shortened telomeres or indirectly, for example, through changes in parental care in older parents affecting offspring telomere length. Across the literature there is considerable variation in estimates of the heritability of telomere length, and in the direction and extent of parental age effects on telomere length. To address this, we experimentally tested how parental age is associated with the early-life telomere dynamics of chicks at two time points in a captive population of house sparrows Passer domesticus. We experimentally separated parental age from sex effects, and removed effects of age-assortative mating, by allowing the parent birds to only mate with young, or old partners. The effect of parental age was dependent on the sex of the parent and the chicks, and was found in the father-daughter relationship only; older fathers produced daughters with longer telomere lengths post-fledging. Overall we found that chick telomere length increased between the age of 0.5 and 3 months at the population and individual level. This finding is unusual in birds with such increases more commonly associated with non-avian taxa. Our results suggest parental age effects on telomere length are sex-specific either through indirect or direct inheritance. The study of similar patterns in different species and taxa will help us further understand variation in telomere length and its evolution.},
}
@article {pmid35654175,
year = {2022},
author = {Bauch, C and Gatt, MC and Verhulst, S and Granadeiro, JP and Catry, P},
title = {Higher mercury contamination is associated with shorter telomeres in a long-lived seabird - A direct effect or a consequence of among-individual variation in phenotypic quality?.},
journal = {The Science of the total environment},
volume = {839},
number = {},
pages = {156359},
doi = {10.1016/j.scitotenv.2022.156359},
pmid = {35654175},
issn = {1879-1026},
mesh = {Aging/genetics ; Animals ; Birds ; Female ; Humans ; Male ; *Mercury/toxicity ; Telomere ; *Telomere Shortening ; },
abstract = {Mercury is a heavy metal, which is pervasive and persistent in the marine environment. It bioaccumulates within organisms and biomagnifies in the marine food chain. Due to its high toxicity, mercury contamination is a major concern for wildlife and human health. Telomere length is a biomarker of aging and health, because it predicts survival, making it a potential tool to investigate sublethal effects of mercury contamination. However, the relationship between telomeres and mercury contamination is unclear. We measured feather mercury concentration in Cory's Shearwaters Calonectris borealis, long-lived seabirds and top predators, between 9 and 35 years of age and related it to telomere length in erythrocytes. Cory's Shearwaters with higher mercury concentrations had shorter telomeres and the effect was sex-dependent, reaching significance in males only. This may be explained by the fact that males have longer telomeres and higher and more variable mercury concentrations than females in this population. The mercury effect on telomere length was stronger on longer telomeres in the genome within individuals. We discuss the hypotheses that the negative correlation could either be a direct effect of mercury on telomere shortening and/or a consequence of variation in phenotypic quality among individuals that results in a covariation between mercury contamination and telomere length.},
}
@article {pmid35649672,
year = {2022},
author = {Dos Santos, IC and da Silva, JT and Rohr, P and Lengert, AVH and de Lima, MA and Kahl, VFS and da Silva, J and Reis, RM and Silveira, HCS},
title = {Genomic instability evaluation by BMCyt and telomere length in Brazilian family farmers exposed to pesticides.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {878},
number = {},
pages = {503479},
doi = {10.1016/j.mrgentox.2022.503479},
pmid = {35649672},
issn = {1879-3592},
mesh = {Adult ; Brazil ; DNA Damage ; *Farmers ; Female ; Genomic Instability ; Humans ; Male ; Middle Aged ; *Pesticides/toxicity ; Telomere/genetics ; },
abstract = {Brazil is one of the largest consumers of pesticides in the world. This high consumption has resulted in higher potential health risk to agricultural farm workers due to occupational exposure. Hence, the aim of this study is to evaluate genomic instability, using Buccal Micronucleus Cytome (BMCyt) and telomere length (TL) measurement as biomarkers of occupational exposure to pesticides in rural workers living in the State of São Paulo, Brazil. Genomic instability was evaluated in 81 pesticide-exposed farm workers (69 males and 12 females) with a mean age of 49.16 ± 10.06 years and a mean time job of 30.00 ± 14.00 years,81 non-exposed individuals (62 males and 15 females) with a mean age of 47.87 ± 10.66 years. BMCyt results showed significantly higher levels of cell damage (micronuclei and binucleated cells) and cell death (karyorrhectic and condensed chromatin cells) in subjects exposed to pesticide when compared to those non-exposed (p < 0.05). Although our results did not show significant differences in TL among exposed and non-exposed groups, effects in TL due to pesticide exposure was found in a multivariable linear regression model when we stratified the groups by age (≤ 49 years and ≥ 50 years old; β = 11.21, p = 0.006). In addition, TL reduction on was identified in relation to an increase in cigarette pack consumption (β = -0.633, p = 0.045). Furthermore, exposure to specific pesticides presented different effects in TL. Cypermethrin exposure resulted in a reduction in TL (β = -18.039, p = 0.018), while abamectin exposure led to an increase in TL (β = 23.990, p = 0.007). Thus, our findings substantiate genomic instability due to pesticides exposure.},
}
@article {pmid35646972,
year = {2022},
author = {Shull, JG and Planas-Cerezales, L and Lara Compte, C and Perona, R and Molina-Molina, M},
title = {Harnessing PM2.5 Exposure Data to Predict Progression of Fibrotic Interstitial Lung Diseases Based on Telomere Length.},
journal = {Frontiers in medicine},
volume = {9},
number = {},
pages = {871898},
pmid = {35646972},
issn = {2296-858X},
abstract = {Cross-analysis of clinical and pollution factors could help calculate the risk of fibrotic interstitial lung disease (ILD) development and progression. The intent of this study is to build a body of knowledge around early detection and diagnosis of lung disease, harnessing new data sets generated for other purposes. We cross-referenced exposure levels to particulate matter 2.5 (PM2.5) with telomere length of a cohort of 280 patients with fibrotic ILD to weigh impact and associations. There was no linear correlation between PM2.5 and telomere length in our data sets, as the value of the correlation coefficient was 0.08. This exploratory study offers additional insights into methodologies for investigating the development and prognosis of pulmonary fibrosis.},
}
@article {pmid35645014,
year = {2022},
author = {Córdova-Oriz, I and Chico-Sordo, L and Varela, E},
title = {Telomeres, aging and reproduction.},
journal = {Current opinion in obstetrics &amp; gynecology},
volume = {34},
number = {3},
pages = {151-158},
doi = {10.1097/GCO.0000000000000779},
pmid = {35645014},
issn = {1473-656X},
mesh = {Aging/genetics ; Female ; Humans ; Infant, Newborn ; *Infertility, Female ; Pregnancy ; *Premature Birth ; Reproduction ; Telomere ; },
abstract = {PURPOSE OF REVIEW: Women's fertility decay starts at the mid 30 s. However, the current delay of childbearing leads to ovarian aging and the need of assisted reproduction technologies (ART). Telomere biology is one of the main pathways involved in organismal aging. Thus, this review will focus on the knowledge acquired during the last 2 years about the telomere pathway and its influence on female fertility and the consequences for the newborn.<br><br>RECENT FINDINGS: New research on telomere biology reaffirms the relationship of telomere attrition and female infertility. Shorter maternal telomeres, which could be aggravated by external factors, underly premature ovarian aging and other complications including preeclampsia, preterm birth and idiopathic pregnancy loss. Finally, the telomere length of the fetus or the newborn is also affected by external factors, such as stress and nutrition.<br><br>SUMMARY: Recent evidence shows that telomeres are implicated in most processes related to female fertility, embryo development and the newborn's health. Thus, telomere length and telomerase activity may be good biomarkers for early detection of ovarian and pregnancy failures, opening the possibility to use telomere therapies to try to solve the infertility situation.},
}
@article {pmid35628895,
year = {2022},
author = {Svikle, Z and Pahirko, L and Zariņa, L and Baumane, K and Kardonaite, D and Radzeviciene, L and Daugintyte-Petrusiene, L and Balciuniene, VJ and Verkauskiene, R and Tiščuka, A and Rovite, V and Sjakste, N and Sokolovska, J},
title = {Telomere Lengths and Serum Proteasome Concentrations in Patients with Type 1 Diabetes and Different Severities of Diabetic Retinopathy in Latvia and Lithuania.},
journal = {Journal of clinical medicine},
volume = {11},
number = {10},
pages = {},
pmid = {35628895},
issn = {2077-0383},
support = {"Novel biomarkers of diabetic retinopathy: epigenetic modifications of genes of ubiquitin-proteasome system, telomere length and proteasome concentration"//Mutual funds Taiwan - Latvia - Lithuania/ ; "Research of biomarkers and natural substances for acute and chronic diseases' diagnostics and personalized treatment"//University of Latvia/ ; },
abstract = {The aim of the study was to compare telomere lengths and circulating proteasome concentrations in patients with different stages of diabetic retinopathy and type 1 diabetes in Latvia and Lithuania. Methods. Patients with no diabetic retinopathy and with non-proliferative diabetic retinopathy were included in the NDR/NPDR group (n = 187). Patients with proliferative diabetic retinopathy and status post laser-photocoagulation were included int the PDR/LPC group (n = 119). Telomeres were evaluated by real-time quantitative polymerase chain reaction. Proteasome concentration was measured by ELISA. Results. Telomeres were longer in PDR/LPC (ΔCT 0.21 (0.12−0.28)) vs. NDR/NPDR (ΔCT 0.18 (0.1−0.28)), p = 0.036. In NDR/NPDR, telomeres were correlated negatively with age (R = −0.17, p = 0.019), BMI (R = −0.21, p = 0.004), waist/hip ratio (R = −0.21, p = 0.005), total cholesterol (R = −0.18, p = 0.021), and low-density cholesterol (R = −0.20, p = 0.010), and positively with estimated glomerular filtration rate (eGFR) (R = 0.28, p < 0.001). None of the above correlations were observed in PRD/LPC. Proteasome concentrations were lower in PDR/LPC (130 (90−210) ng/mL) vs. NDR/NPDR (150 (100−240) ng/mL), p = 0.024. This correlated negatively with eGFR (R = −0.17, p = 0.025) in the NDR/NPDR group and positively with age (R = 0.23, p = 0.014) and systolic blood pressure (R = 0.20, p = 0.032) in the PRD/LPC group. Telomere lengths did not correlate with proteasome concentrations. Conclusion. Longer telomeres and lower circulating proteasome concentrations are observed in patients with type 1 diabetes and advanced diabetic retinopathy.},
}
@article {pmid35627106,
year = {2022},
author = {Tung, KTS and Wong, RS and Tsang, HW and Wong, WHS and Tso, WWY and Yam, JC and Lum, TYS and Chan, GCF and Wong, ICK and Ip, P},
title = {Family Financial Pressure in Childhood and Telomere Length in Early Adolescence: A Prospective Study.},
journal = {Genes},
volume = {13},
number = {5},
pages = {},
pmid = {35627106},
issn = {2073-4425},
mesh = {Adolescent ; Female ; *Financial Stress ; Humans ; Male ; Prospective Studies ; Stress, Psychological/genetics ; *Telomere/genetics ; Telomere Shortening/genetics ; },
abstract = {Much research on children in high-risk environments has focused on the biological consequences of maltreatment, adversity, and trauma. Whether other early-life stress sources such as family financial hardship are implicated in the cellular mechanism of disease development remains unclear. This study investigated the long-term effect of childhood exposure to family financial pressure on telomere length. It involved two waves of data collection occurring when participants reached Grade 3 (W1) and 7 (W2), respectively. In W1, parents reported family demographics and perceived financial stressors and pressure. In W2, participants provided buccal swab samples for measurement of their telomere length. Data from 92 participants (Mage in W2 = 13.2 years; 56.5% male) were analyzed. The main type of stressors reported by parents who perceived high family financial pressure in W1 were child-level stressors including affordability of their medical and educational expenses. Participants exposed to high parent-perceived family financial pressure in W1 had shorter telomeres in W2 when compared to those exposed to low parent-perceived family financial pressure (β = -0.61, p = 0.042). Subgroup analyses revealed stronger associations in girls than boys. These findings reveal an important spillover effect between parental financial perceptions and stress and children's health at the cellular level.},
}
@article {pmid35626642,
year = {2022},
author = {Semeraro, MD and Almer, G and Renner, W and Gruber, HJ and Herrmann, M},
title = {Influences of Long-Term Exercise and High-Fat Diet on Age-Related Telomere Shortening in Rats.},
journal = {Cells},
volume = {11},
number = {10},
pages = {},
pmid = {35626642},
issn = {2073-4409},
mesh = {Animals ; Diet, High-Fat ; Female ; Leukocytes, Mononuclear ; Rats ; Rats, Sprague-Dawley ; *Telomerase/genetics ; *Telomere Shortening ; },
abstract = {(1) Obesity and exercise are believed to modify age-related telomere shortening by regulating telomerase and shelterins. Existing studies are inconsistent and limited to peripheral blood mononuclear cells (PBMCs) and selected solid tissues. (2) Female Sprague Dawley (SD) rats received either standard diet (ND) or high-fat diet (HFD). For 10 months, half of the animals from both diet groups performed 30 min running at 30 cm/s on five consecutive days followed by two days of rest (exeND, exeHFD). The remaining animals served as sedentary controls (coND, coHFD). Relative telomere length (RTL) and mRNA expression of telomerase (TERT) and the shelterins TERF-1 and TERF-2 were mapped in PBMCs and nine solid tissues. (3) At study end, coND and coHFD animals showed comparable RTL in most tissues with no systematic differences in TERT, TERF-1 and TERF-2 expression. Only visceral fat of coHFD animals showed reduced RTL and lower expression of TERT, TERF-1 and TERF-2. Exercise had heterogeneous effects on RTL in exeND and exeHFD animals with longer telomeres in aorta and large intestine, but shorter telomeres in PBMCs and liver. Telomere-regulating genes showed inconsistent expression patterns. (4) In conclusion, regular exercise or HFD cannot systematically modify RTL by regulating the expression of telomerase and shelterins.},
}
@article {pmid35622501,
year = {2022},
author = {Lee, BY and Kim, J and Lee, J},
title = {Long-read sequencing infers a mechanism for copy number variation of template for alternative lengthening of telomeres in a wild C. elegans strain.},
journal = {microPublication biology},
volume = {2022},
number = {},
pages = {},
pmid = {35622501},
issn = {2578-9430},
abstract = {Template for alternative lengthening of telomeres 1 (TALT1) is a specific sequence used to protect chromosomal ends from telomere damage first identified in the CB4856 strain of Caenorhabditis elegans . Here we assembled the genome of DL226, a wild strain with one more copy of TALT1-like sequences in its genome compared to those of CB4856, using long-read DNA sequencing. We found that a five-copy array of short telomeric repeats and TALT1s present in CB4856 were changed to a six-copy array due to the duplication of the third copy; there was an additional damage-repair trace in the new short telomeric repeat near the newly replicated TALT1.},
}
@article {pmid35619042,
year = {2022},
author = {Spano, L and Hennion, V and Marie-Claire, C and Bellivier, F and Scott, J and Etain, B},
title = {Associations between circadian misalignment and telomere length in BD: an actigraphy study.},
journal = {International journal of bipolar disorders},
volume = {10},
number = {1},
pages = {14},
pmid = {35619042},
issn = {2194-7511},
support = {Prix Face//Fondation FondaMental/ ; Prix Marcel Dassault//Fondation FondaMental/ ; C0829//Institut National de la Sant&#xe9; et de la Recherche M&#xe9;dicale/ ; GAN12//Assistance Publique - H&#xf4;pitaux de Paris/ ; },
abstract = {BACKGROUND: Life expectancy is significantly decreased in bipolar disorder (BD). This is associated with accelerated cellular aging which can be estimated by telomere length (TL). However, specific determinants of shorter TL in BD are under-explored. This study examines whether circadian misalignment (i.e. mismatch between preferred and actual phase of circadian activity rhythms) is associated with shorter TL in BD.<br><br>METHODS: Euthymic individuals with BD (n&#x2009;=&#x2009;101) undertook 21 consecutive days of actigraphy recording and completed the Composite Scale of Morningness (CSM) to assess phase preference for activities (chronotype). Polymerase chain reaction was used to measure TL in blood. Cluster analysis identified circadian aligned/misaligned subgroups as defined by preferred (CSM score) and actual phases of activity (actigraphically determined onset of active and inactive periods). We tested for any associations between TL and clusters, with adjustments for between-cluster differences in socio-demographic and illness factors.<br><br>RESULTS: We identified three clusters: an "Aligned Morning" cluster (n&#x2009;=&#x2009;31) with preferred and actual timing of activity in the morning, an "Aligned Evening" cluster (n&#x2009;=&#x2009;37) with preferred and actual timing of activity in the evening and a "Misaligned" cluster (n&#x2009;=&#x2009;32) with an evening chronotype, but an earlier objective onset of active periods. After adjustment for confounders, we found that TL was significantly associated with circadian misalignment and older age.<br><br>CONCLUSIONS: Circadian misalignment may partly explain shorter TL in BD and could contribute to accelerated aging in these individuals.},
}
@article {pmid35614304,
year = {2022},
author = {Courtney, MG and Roberts, J and Godde, K},
title = {How social/environmental determinants and inflammation affect salivary telomere length among middle-older adults in the health and retirement study.},
journal = {Scientific reports},
volume = {12},
number = {1},
pages = {8882},
pmid = {35614304},
issn = {2045-2322},
support = {R15 AG063330/AG/NIA NIH HHS/United States ; U01 AG009740/AG/NIA NIH HHS/United States ; R21 AG045625/AG/NIA NIH HHS/United States ; R15AG063330/AG/NIA NIH HHS/United States ; UL1 TR001086/TR/NCATS NIH HHS/United States ; P01 AG017625/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging ; *C-Reactive Protein/metabolism ; Humans ; *Inflammation/metabolism ; Middle Aged ; Retirement/statistics &amp; numerical data ; *Social Determinants of Health ; *Telomere/genetics/metabolism ; *Telomere Shortening/genetics/physiology ; },
abstract = {Social epidemiology posits that chronic stress from social determinants will lead to a prolonged inflammatory response that may induce accelerated aging as measured, for example, through telomere length (TL). In this paper, we hypothesize variables across demographic, health-related, and contextual/environmental domains influence the body's stress response, increase inflammation (as measured through high-sensitivity C-reactive protein (hs-CRP)), and thereby lead to shortening of telomeres. This population-based research uses data from the 2008 Health and Retirement Study on participants ages ≤ 54-95 + years, estimating logistic regression and Cox proportional hazards models of variables (with and without confounders) across the domains on shortened TL. A mediation analysis is also conducted. Contrary to expectations, hs-CRP is not associated with risk of shortened TL. Rather, factors related to accessing health care, underlying conditions of frailty, and social inequality appear to predict risk of shorter TL, and models demonstrate considerable confounding. Further, hs-CRP is not a mediator for TL. Therefore, the social determinants of health examined do not appear to follow an inflammatory pathway for shortened TL. The finding of a relationship to social determinants affecting access to health care and medical conditions underscores the need to address social determinants alongside primary care when examining health inequities.},
}
@article {pmid35612837,
year = {2022},
author = {Koller, A and Brandl, C and Lamina, C and Zimmermann, ME and Summerer, M and Stark, KJ and Würzner, R and Heid, IM and Kronenberg, F},
title = {Relative Telomere Length Is Associated With Age-Related Macular Degeneration in Women.},
journal = {Investigative ophthalmology &amp; visual science},
volume = {63},
number = {5},
pages = {30},
pmid = {35612837},
issn = {1552-5783},
support = {W 1253/FWF_/Austrian Science Fund FWF/Austria ; },
mesh = {Aged ; Aged, 80 and over ; Aging/physiology ; Cholesterol, HDL ; Female ; Humans ; *Macular Degeneration/genetics ; Male ; Odds Ratio ; Risk Factors ; *Telomere/genetics ; },
abstract = {PURPOSE: Relative telomere length (RTL) is a biomarker for physiological aging. Premature shortening of telomeres is associated with oxidative stress, which is one possible pathway that might contribute to age-related macular degeneration (AMD). We therefore aimed to investigate the association between RTL and AMD in a well-characterized group of elderly individuals.<br><br>METHODS: We measured RTL in participants of the AugUR study using a multiplex quantitative PCR-based assay determining the ratio between the telomere product and a single-copy gene product (T/S ratio). AMD was assessed by manual grading of color fundus images using the Three Continent AMD Consortium Severity Scale.<br><br>RESULTS: Among the 2262 individuals 70 to 95 years old (627 with AMD and 1635 without AMD), RTL was significantly shorter in individuals with AMD compared to AMD-free participants. In age- and sex-adjusted logistic regression analyses, we observed an 8% higher odds for AMD per 0.1 unit shorter RTL (odds ratio [OR] = 1.08; 95% confidence interval [CI], 1.02-1.14; P = 0.005). The estimates remained stable when adjusted for smoking, high-density lipoprotein cholesterol, cardiovascular disease, diabetes, and hypertension. Interestingly, this association was only present in women (OR = 1.14; 95% CI, 1.06-1.23; P < 0.001), but not in men (OR = 1.01; 95% CI, 0.93-1.10; P = 0.76). A significant sex-by-RTL interaction on AMD was detected (P = 0.043).<br><br>CONCLUSIONS: Our results show an association of RTL with AMD that was restricted to women. This is in line with altered reactive oxygen species levels and higher telomerase activity in women and provides an indication for a sex-differential pathway for oxidative stress and AMD.},
}
@article {pmid35609925,
year = {2022},
author = {Armanios, M},
title = {The Role of Telomeres in Human Disease.},
journal = {Annual review of genomics and human genetics},
volume = {23},
number = {},
pages = {363-381},
pmid = {35609925},
issn = {1545-293X},
support = {R01 CA225027/CA/NCI NIH HHS/United States ; R01 HL119476/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Genomic Instability ; Growth Disorders ; Humans ; Hypercalcemia ; Metabolic Diseases ; Mice ; *Neoplasms/genetics/pathology ; Nephrocalcinosis ; Syndrome ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism/pathology ; },
abstract = {Telomere biology was first studied in maize, ciliates, yeast, and mice, and in recent decades, it has informed understanding of common disease mechanisms with broad implications for patient care. Short telomere syndromes are the most prevalent premature aging disorders, with prominent phenotypes affecting the lung and hematopoietic system. Less understood are a newly recognized group of cancer-prone syndromes that are associated with mutations that lengthen telomeres. A large body of new data from Mendelian genetics and epidemiology now provides an opportunity to reconsider paradigms related to the role of telomeres in human aging and cancer, and in some cases, the findings diverge from what was interpreted from model systems. For example, short telomeres have been considered potent drivers of genome instability, but age-associated solid tumors are rare in individuals with short telomere syndromes, and T cell immunodeficiency explains their spectrum. More commonly, short telomeres promote clonal hematopoiesis, including somatic reversion, providing a new leukemogenesis paradigm that is independent of genome instability. Long telomeres, on the other hand, which extend the cellular life span in vitro, are now appreciated to be the most common shared germline risk factor for cancer in population studies. Through this contemporary lens, I revisit here the role of telomeres in human aging, focusing on how short and long telomeres drive cancer evolution but through distinct mechanisms.},
}
@article {pmid35608796,
year = {2023},
author = {Farladansky-Gershnabel, S and Dekel, N and Biron-Shental, T and Shechter-Maor, G and Amiel, A and Weisz, A and Benchetrit, S and Zitman-Gal, T},
title = {Spontaneous Preterm Birth: Elevated Galectin-3 and Telomere Shortening May Reflect a Common Pathway of Enhanced Inflammation and Senescence.},
journal = {Reproductive sciences (Thousand Oaks, Calif.)},
volume = {30},
number = {2},
pages = {487-493},
pmid = {35608796},
issn = {1933-7205},
mesh = {Pregnancy ; Female ; Infant, Newborn ; Humans ; *Premature Birth/metabolism ; Placenta/metabolism ; Telomere Shortening ; Galectin 3/metabolism ; *Obstetric Labor, Premature/metabolism ; Inflammation/metabolism ; },
abstract = {Preterm delivery complicates 5-12% of pregnancies and is the primary cause of neonatal morbidity and mortality. The pathophysiology of preterm labor and parturition is not fully known, although it is probably related to inflammation and placental senescence. Telomere shortening is related to senescence and galectin-3 (Gal-3) protein is involved in cell growth, differentiation, inflammation, and fibrosis. This study examined changes in Gal-3 expression and telomere homeostasis (which represent inflammatory and stress markers) in maternal blood and placental tissue of spontaneous preterm births (SPTB) and uncomplicated, spontaneous term pregnancies (NTP) during labor. Participants included 19 women with NTP and 11 with SPTB who were enrolled during admission for delivery. Maternal blood samples were obtained along with placental tissue for Gal-3 analysis and telomere length evaluation. Gal-3 protein expression in placental tissue was increased in SPTB compared to NTP (fold change: 1.89 ± 0.36, P < 0.05). Gal-3 immunohistochemistry demonstrated strong staining in placental extravillous trophoblast tissue from SPTB. Maternal blood levels of Gal-3 protein were elevated in SPTB compared to NTP (19.3 ± 1.3 ng/ml vs. 13.6 ± 1.07 ng/ml, P = 0.001). Placental samples from SPTB had a higher percentage of trophoblasts with short telomeres (47.6%) compared to NTP (15.6%, P < 0.0001). Aggregate formation was enhanced in SPTB (7.8%) compared to NTP (1.98%, P < 0.0001). Maternal blood and placental samples from SPTB had shorter telomeres and increased Gal-3 expression compared to NTP. These findings suggest that increased senescence and inflammation might be factors in the abnormal physiology of spontaneous preterm labor.},
}
@article {pmid35601455,
year = {2022},
author = {Roast, MJ and Eastwood, JR and Aranzamendi, NH and Fan, M and Teunissen, N and Verhulst, S and Peters, A},
title = {Telomere length declines with age, but relates to immune function independent of age in a wild passerine.},
journal = {Royal Society open science},
volume = {9},
number = {4},
pages = {212012},
pmid = {35601455},
issn = {2054-5703},
abstract = {Telomere length (TL) shortens with age but telomere dynamics can relate to fitness components independent of age. Immune function often relates to such fitness components and can also interact with telomeres. Studying the link between TL and immune function may therefore help us understand telomere-fitness associations. We assessed the relationships between erythrocyte TL and four immune indices (haptoglobin, natural antibodies (NAbs), complement activity (CA) and heterophil-lymphocyte (HL) ratio; n = 477-589), from known-aged individuals of a wild passerine (Malurus coronatus). As expected, we find that TL significantly declined with age. To verify whether associations between TL and immune function were independent of parallel age-related changes (e.g. immunosenescence), we statistically controlled for sampling age and used within-subject centring of TL to separate relationships within or between individuals. We found that TL positively predicted CA at the between-individual level (individuals with longer average TL had higher CA), but no other immune indices. By contrast, age predicted the levels of NAbs and HL ratio, allowing inference that respective associations between TL and age with immune indices are independent. Any links existing between TL and fitness are therefore unlikely to be strongly mediated by innate immune function, while TL and immune indices appear independent expressions of individual heterogeneity.},
}
@article {pmid35597826,
year = {2022},
author = {Zhang, JC and Li, SJ and Guo, JY and Zhang, GY and Kang, H and Shi, XJ and Zhou, H and Liang, YF and Shen, WT and Lei, LJ},
title = {Urinary cadmium and peripheral blood telomere length predict the risk of renal function impairment: a study of 547 community residents of Shanxi, China.},
journal = {Environmental science and pollution research international},
volume = {29},
number = {47},
pages = {71427-71438},
pmid = {35597826},
issn = {1614-7499},
support = {81872701//National Natural Science Foundation of China/ ; 81273040//National Natural Science Foundation of China/ ; },
mesh = {Acetylglucosaminidase/urine ; *Cadmium/toxicity/urine ; China ; Creatinine ; Cross-Sectional Studies ; Female ; Humans ; Kidney/physiology ; Male ; *Renal Insufficiency/chemically induced ; Telomere ; },
abstract = {Few reports have investigated the predictive value of urinary cadmium (UCd) and telomere length on renal function impairment. Therefore, we constructed nomogram models, using a cross-sectional survey to analyze the potential function of UCd and telomere length in renal function impairment risk. We randomly selected two community populations in Shanxi, China, and general information of the subjects was collected through face-to-face questionnaire surveys. Venous blood of subjects was collected to detect absolute telomere length (ATL) by real-time quantitative chain reaction (RT-PCR). Collecting urinary samples detected UCd and urinary N-acetyl-β-d-glucosaminidase (UNAG). Estimated glomerular filtration rate (eGFR) was obtained based on serum creatinine (SCr). Nomogram models on risk prediction analysis of renal function impairment was constructed. After adjusting for other confounding factors, UCd (β = 0.853, 95% confidence interval (CI): 0.739 ~ 0.986) and ATL (β = 1.803, 95%CI: 1.017 ~ 1.154) were independent risk influencing factors for increased UNAG levels, and the risk factors for eGFR reduction were UCd (β = 1.011, 95%CI: 1.187 ~ 1.471), age (β = 1.630, 95%CI: 1.303 ~ 2.038), and sex (β = 0.181, 95%CI: 0.105 ~ 0.310). Using UCd, ATL, sex, and age to construct the nomogram, and the C-statistics 0.584 (95%CI: 0.536 ~ 0.632) and 0.816 (95%CI: 0.781 ~ 0.851) were obtained by internal verification of the calibration curve, C-statistics revealed nomogram model validation was good and using decision curve analysis (DCA) confirmed a good predictive value of the nomogram models. In a nomogram model, ATL, UCd, sex, and age were detected as independent risk factors for renal function impairment, with UCd being the strongest predictor.},
}
@article {pmid35590036,
year = {2022},
author = {Dempsey, PC and Musicha, C and Rowlands, AV and Davies, M and Khunti, K and Razieh, C and Timmins, I and Zaccardi, F and Codd, V and Nelson, CP and Yates, T and Samani, NJ},
title = {Author Correction: Investigation of a UK biobank cohort reveals causal associations of self-reported walking pace with telomere length.},
journal = {Communications biology},
volume = {5},
number = {1},
pages = {498},
doi = {10.1038/s42003-022-03459-w},
pmid = {35590036},
issn = {2399-3642},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; },
}
@article {pmid35588569,
year = {2022},
author = {Bhargava, R and Lynskey, ML and O'Sullivan, RJ},
title = {New twists to the ALTernative endings at telomeres.},
journal = {DNA repair},
volume = {115},
number = {},
pages = {103342},
pmid = {35588569},
issn = {1568-7856},
support = {P30 CA047904/CA/NCI NIH HHS/United States ; R01 CA207209/CA/NCI NIH HHS/United States ; R01 CA262316/CA/NCI NIH HHS/United States ; R37 CA263622/CA/NCI NIH HHS/United States ; },
mesh = {Chromatin ; Histones/genetics ; *Telomerase/metabolism ; Telomere/metabolism ; *Telomere Homeostasis ; },
abstract = {Activation of a telomere maintenance mechanism is key to achieving replicative immortality. Alternative Lengthening of Telomeres (ALT) is a telomerase-independent pathway that hijacks the homologous recombination pathways to elongate telomeres. Commitment to ALT is often associated with several hallmarks including long telomeres of heterogenous lengths, mutations in histone H3.3 or the ATRX/DAXX histone chaperone complex, and incorporation of non-canonical telomere sequences. The consequences of these genetic and epigenetic changes include enhanced replication stress and the presence of transcriptionally permissive chromatin, which can result in replication-associated DNA damage. Here, we detail the molecular mechanisms that are critical to repairing DNA damage at ALT telomeres, including the BLM Helicase, which acts at several steps in the ALT process. Furthermore, we discuss the emerging findings related to the telomere-associated RNA, TERRA, and its roles in maintaining telomeric integrity. Finally, we review new evidence for therapeutic interventions for ALT-positive cancers which are rooted in understanding the molecular underpinnings of this process.},
}
@article {pmid35588001,
year = {2022},
author = {Wong, KK and Cheng, F and Mao, D and Lim, CKP and Tam, CHT and Wang, CC and Yuen, LY and Chan, MHM and Ho, CS and Joglekar, MV and Hardikar, AA and Jenkins, AJ and Metzger, BE and Lowe, WL and Tam, WH and Ma, RCW},
title = {Vitamin D Levels During Pregnancy Are Associated With Offspring Telomere Length: A Longitudinal Mother-Child Study.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {107},
number = {9},
pages = {e3901-e3909},
pmid = {35588001},
issn = {1945-7197},
support = {R01 HD034242/HD/NICHD NIH HHS/United States ; },
mesh = {Calcifediol ; Child ; Cohort Studies ; *Diabetes Mellitus, Type 2 ; Female ; Humans ; Male ; Mother-Child Relations ; Pregnancy ; Telomere ; Vitamin D ; *Vitamin D Deficiency/complications/epidemiology ; Vitamins ; },
abstract = {CONTEXT: Leukocyte telomere length (LTL) is a biomarker of biological aging and is associated with metabolic diseases such as type 2 diabetes. Insufficient maternal vitamin D was associated with increased risk for many diseases and adverse later life outcomes.<br><br>OBJECTIVE: This study investigates the relationship between vitamin D levels and offspring LTL at early life.<br><br>METHODS: This observational, longitudinal, hospital-based cohort study included eligible mother-child pairs from the HAPO Hong Kong Field Centre, with 853 offspring at age 6.96&#x2005;&#xb1;&#x2005;0.44 (mean&#x2005;&#xb1;&#x2005;SD) years. LTL was measured using real-time polymerase chain reaction while serum vitamin D metabolites 25(OH)D2, 25(OH)D3, and 3-epi-25(OH)D3 were measured in maternal blood (at gestation 24-32 weeks) and cord blood by liquid chromatography-mass spectrometry.<br><br>RESULTS: LTL at follow-up was significantly shorter in boys compared with girls (P&#x2005;<&#x2005;0.001) at age 7. Childhood LTL was negatively associated with childhood BMI (&#x3b2;&#x2005;&#xb1;&#x2005;SE&#x2005;=&#x2005;-0.016&#x2005;&#xb1;&#x2005;0.007)(P&#x2005;=&#x2005;0.02) and HOMA-IR (&#x3b2;&#x2005;&#xb1;&#x2005;SE&#x2005;=&#x2005;-0.065&#x2005;&#xb1;&#x2005;0.021)(P&#x2005;=&#x2005;0.002). Multiple linear regression was used to evaluate the relationship between 25(OH)D and LTL, with covariate adjustments. Childhood LTL was positively correlated with total maternal 25(OH)D (0.048&#x2005;&#xb1;&#x2005;0.017) (P&#x2005;=&#x2005;0.004) and maternal 3-epi-25(OH)D3 (0.05&#x2005;&#xb1;&#x2005;0.017) (P&#x2005;=&#x2005;0.003), even after adjustment for covariates. A similar association was also noted for cord 3-epi-25(OH)D3 (0.037&#x2005;&#xb1;&#x2005;0.018) (P&#x2005;=&#x2005;0.035) after adjustment for offspring sex and age.<br><br>CONCLUSION: Our findings suggest 25(OH)D3 and 3-epi-25(OH)D3 in utero may impact on childhood LTLs, highlighting a potential link between maternal vitamin D and biological aging.},
}
@article {pmid35587917,
year = {2022},
author = {Zahid, S and Aloe, S and Sutherland, JH and Holloman, WK and Lue, NF},
title = {Ustilago maydis telomere protein Pot1 harbors an extra N-terminal OB fold and regulates homology-directed DNA repair factors in a dichotomous and context-dependent manner.},
journal = {PLoS genetics},
volume = {18},
number = {5},
pages = {e1010182},
pmid = {35587917},
issn = {1553-7404},
support = {R01 GM107287/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Basidiomycota ; DNA/genetics ; DNA Repair/genetics ; Mammals/genetics ; Protein Binding ; *Telomere/genetics/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; *Ustilago/genetics ; },
abstract = {The telomere G-strand binding protein Pot1 plays multifaceted roles in telomere maintenance and protection. We examined the structure and activities of Pot1 in Ustilago maydis, a fungal model that recapitulates key features of mammalian telomere regulation. Compared to the well-characterized primate and fission yeast Pot1 orthologs, UmPot1 harbors an extra N-terminal OB-fold domain (OB-N), which was recently shown to be present in most metazoans. UmPot1 binds directly to Rad51 and regulates the latter's strand exchange activity. Deleting the OB-N domain, which is implicated in Rad51-binding, caused telomere shortening, suggesting that Pot1-Rad51 interaction facilitates telomere maintenance. Depleting Pot1 through transcriptional repression triggered growth arrest as well as rampant recombination, leading to multiple telomere aberrations. In addition, telomere repeat RNAs transcribed from both the G- and C-strand were dramatically up-regulated, and this was accompanied by elevated levels of telomere RNA-DNA hybrids. Telomere abnormalities of pot1-deficient cells were suppressed, and cell viability was restored by the deletion of genes encoding Rad51 or Brh2 (the BRCA2 ortholog), indicating that homology-directed repair (HDR) proteins are key mediators of telomere aberrations and cellular toxicity. Together, these observations underscore the complex physical and functional interactions between Pot1 and DNA repair factors, leading to context-dependent and dichotomous effects of HDR proteins on telomere maintenance and protection.},
}
@article {pmid35587764,
year = {2022},
author = {Gong, H and Yu, Q and Yuan, M and Jiang, Y and Wang, J and Huang, P and Zhou, J},
title = {The Relationship between Dietary Copper intake and Telomere Length in Hypertension.},
journal = {The journal of nutrition, health &amp; aging},
volume = {26},
number = {5},
pages = {510-514},
doi = {10.1007/s12603-022-1787-7},
pmid = {35587764},
issn = {1760-4788},
mesh = {Copper ; Humans ; *Hypertension/genetics ; Leukocytes ; Nutrition Surveys ; Prospective Studies ; *Telomere ; },
abstract = {BACKGROUND: More indications proved that diet might be involved in the telomere length, a marker of biological aging and chronic diseases. Copper is widely viewed as one of the essential elements in the diet. Therefore, this study aimed to evaluate the relationship between telomere length and dietary copper intake in hypertension and provide a basis for guiding dietary copper intake in patients with hypertension.<br><br>METHODS: The data was collected from the National Health and Nutrition Examination Survey (NHANES) in 1999-2000 and 2001-2002. The relevance between telomere length and dietary copper intake in hypertension is assessed using a multivariable linear regression model.<br><br>RESULTS: We gathered 1,867 participants with hypertension with assessed telomere length and dietary copper intake. We found that one unit increasing log-transformed dietary copper intake in hypertension was significantly associated with longer telomere length base pair (bp) (&#x3b2; = 112.20, 95% confidence interval [CI]: 5.48, 218.92), after controlling for covariates, including age, sex, ethnicity, body mass index (BMI), physical activity, and taking medication for hypertension. For the age group, we found that one unit increasing log-transformed dietary copper in hypertension was associated with longer telomere length (&#x3b2; = 237.95, 95% CI: 114.39, 361.51) in the age group >45 years. The grouping was based on whether the participants take medication for hypertension. We found that one unit increasing log-transformed dietary copper in hypertension was associated with longer telomere length (&#x3b2; = 116.47, 95% CI: 0.72, 232.21) in the group that takes medication for hypertension.<br><br>CONCLUSIONS: This study demonstrates that dietary copper intake was associated with longer telomere length in patients with hypertension, which provides evidence for guiding dietary copper intake in patients with hypertension. However, further studies are needed to evaluate the effect of copper supplementation on telomere length in patients with hypertension in well-designed random control studies and prospective studies.},
}
@article {pmid35585300,
year = {2022},
author = {Pearce, EE and Alsaggaf, R and Katta, S and Dagnall, C and Aubert, G and Hicks, BD and Spellman, SR and Savage, SA and Horvath, S and Gadalla, SM},
title = {Telomere length and epigenetic clocks as markers of cellular aging: a comparative study.},
journal = {GeroScience},
volume = {44},
number = {3},
pages = {1861-1869},
pmid = {35585300},
issn = {2509-2723},
mesh = {Biomarkers ; Cellular Senescence ; *DNA Methylation ; Epigenesis, Genetic ; *Epigenomics ; Humans ; Telomere/genetics ; },
abstract = {Telomere length (TL) and DNA methylation-based epigenetic clocks are markers of biological age, but the relationship between the two is not fully understood. Here, we used multivariable regression models to evaluate the relationships between leukocyte TL (LTL; measured by qPCR [n = 635] or flow FISH [n = 144]) and five epigenetic clocks (Hannum, DNAmAge pan-tissue, PhenoAge, SkinBlood, or GrimAge clocks), or their epigenetic age acceleration measures in healthy adults (age 19-61 years). LTL showed statistically significant negative correlations with all clocks (qPCR: r = - 0.26 to - 0.32; flow FISH: r = - 0.34 to - 0.49; p < 0.001 for all). Yet, models adjusted for age, sex, and race revealed significant associations between three of five clocks (PhenoAge, GrimAge, and Hannum clocks) and LTL by flow FISH (p < 0.01 for all) or qPCR (p < 0.001 for all). Significant associations between age acceleration measures for the same three clocks and qPCR or flow FISH TL were also found (p < 0.01 for all). Additionally, LTL (by qPCR or flow FISH) showed significant associations with extrinsic epigenetic age acceleration (EEAA: p < 0.0001 for both), but not intrinsic epigenetic age acceleration (IEAA; p > 0.05 for both). In conclusion, the relationships between LTL and epigenetic clocks were limited to clocks reflecting phenotypic age. The observed association between LTL and EEAA reflects the ability of both measures to detect immunosenescence. The observed modest correlations between LTL and epigenetic clocks highlight a possible benefit from incorporating both measures in understanding disease etiology and prognosis.},
}
@article {pmid35584004,
year = {2022},
author = {Mota, JIS and Silva-Júnior, RMP and Martins, CS and Bueno, AC and Wildemberg, LE and Antunes, XLDS and Ozaki, JGO and Coeli-Lacchini, FB and Garcia-Peral, C and Oliveira, AER and Santos, AC and Moreira, AC and Machado, HR and Dos Santos, MV and Colli, LM and Gadelha, MR and Antonini, SRR and de Castro, M},
title = {Telomere length and Wnt/β-catenin pathway in adamantinomatous craniopharyngiomas.},
journal = {European journal of endocrinology},
volume = {187},
number = {2},
pages = {219-230},
doi = {10.1530/EJE-21-1269},
pmid = {35584004},
issn = {1479-683X},
mesh = {Adolescent ; Child ; *Craniopharyngioma/genetics ; Cross-Sectional Studies ; Humans ; Mutation ; Retrospective Studies ; *Telomere/ultrastructure ; Wnt Signaling Pathway ; *beta Catenin/genetics ; },
abstract = {OBJECTIVES: To evaluate how telomere length behaves in adamantinomtous craniopharyngioma (aCP) and if it contributes to the pathogenesis of aCPs with and without CTNNB1 mutations.<br><br>DESIGN: Retrospective cross-sectional study enrolling 42 aCP patients from 2 tertiary institutions.<br><br>METHODS: Clinicopathological features were retrieved from the patient's charts. Fresh frozen tumors were used for RNA and DNA analyses. Telomere length was evaluated by qPCR (T/S ratio). Somatic mutations in TERT promoter (TERTp) and CTNNB1 were detected by Sanger and/or whole-exome sequencing. We performed RNA-Seq to identify differentially expressed genes in aCPs presenting with shorter or longer telomere lengths.<br><br>RESULTS: Mutations in CTNNB1 were detected in 29 (69%) tumors. There was higher frequency of CTNNB1 mutations in aCPs from patients diagnosed under the age of 15 years (85% vs 15%; P = 0.04) and a trend to recurrent disease (76% vs 24%; P = 0.1). No mutation was detected in the TERTp region. The telomeres were shorter in CTNNB1-mutated aCPs (0.441, IQR: 0.297-0.597vs 0.607, IQR: 0.445-0.778; P = 0.04), but it was neither associated with clinicopathological features nor with recurrence. RNAseq identified a total of 387 differentially expressed genes, generating two clusters, being one enriched for short telomeres and CTNNB1-mutated aCPs.<br><br>CONCLUSIONS: CTNNB1: mutations are more frequent in children and adolescents and appear to associate with progressive disease. CTNNB1-mutated aCPs have shorter telomeres, demonstrating a relationship between the Wnt/&#x3b2;-catenin pathway and telomere biology in the pathogenesis of aCPs.},
}
@article {pmid35580703,
year = {2022},
author = {Syreeni, A and Carroll, LM and Mutter, S and Januszewski, AS and Forsblom, C and Lehto, M and Groop, PH and Jenkins, AJ and , },
title = {Telomeres do not always shorten over time in individuals with type 1 diabetes.},
journal = {Diabetes research and clinical practice},
volume = {188},
number = {},
pages = {109926},
doi = {10.1016/j.diabres.2022.109926},
pmid = {35580703},
issn = {1872-8227},
mesh = {Cholesterol, HDL/genetics ; *Diabetes Mellitus, Type 1/drug therapy/genetics ; Humans ; Leukocytes ; Male ; Telomere/genetics ; Telomere Homeostasis ; },
abstract = {AIMS: We aimed to determine how white blood cell (WBC) telomeres and telomere length change over time are associated with health status in type 1 diabetes.<br><br>METHODS: Relative telomere length (rTL) was measured in WBC DNA from two time-points (median 6.8&#xa0;years apart) in 618 individuals from the Finnish Diabetic Nephropathy Study by quantitative PCR, with interassay CV&#xa0;&#x2264;&#xa0;4%.<br><br>RESULTS: Baseline rTL correlated inversely with age and was shorter in men. Individuals in the shortest vs. longest rTL tertile had adverse cardiometabolic profiles, worse renal function, and were prescribed more antihypertensive and lipid-lowering drugs. While overall rTL tended to decrease during the median 6.8-years of follow-up, telomeres shortened in 55.3% of subjects, lengthened in 40.0%, and did not change in 4.7%. Baseline rTL correlated inversely with rTL change. Telomere lengthening was associated with higher HDL-Cholesterol (HDL-C), HDL-C/ApoA1, and with antihypertensive drug and (inversely) with lipid-lowering drug commencement during follow-up. Correlates of rTL percentage change per-annum (adjusted model) were baseline BMI, eGFR, previous retinal laser treatment, HDL-C, and HDL-C/ApoA1.<br><br>CONCLUSIONS: Telomere length measurements may facilitate the treatment and monitoring of the health status of individuals with type 1 diabetes.},
}
@article {pmid35575903,
year = {2022},
author = {Tissier, ML and Bergeron, P and Garant, D and Zahn, S and Criscuolo, F and Réale, D},
title = {Telomere length positively correlates with pace-of-life in a sex- and cohort-specific way and elongates with age in a wild mammal.},
journal = {Molecular ecology},
volume = {31},
number = {14},
pages = {3812-3826},
doi = {10.1111/mec.16533},
pmid = {35575903},
issn = {1365-294X},
mesh = {Adult ; Aging/genetics ; Animals ; Female ; Humans ; *Longevity/genetics ; Male ; Mammals/genetics ; Telomere/genetics ; *Telomere Shortening ; },
abstract = {Understanding ageing and the diversity of life histories is a cornerstone in biology. Telomeres, the protecting caps of chromosomes, are thought to be involved in ageing, cancer risks and life-history strategies. They shorten with cell division and age in somatic tissues of most species, possibly limiting lifespan. The resource allocation trade-off hypothesis predicts that short telomeres have thus coevolved with early reproduction, proactive behaviour and reduced lifespan, that is, a fast pace-of-life syndrome (POLS). Conversely, since short telomeres may also reduce the risks of cancer, the anticancer hypothesis advances that they should be associated with slow POLS. Conclusion on which hypothesis best supports the role of telomeres as mediators of life-history strategies is hampered by a lack of study on wild short-lived vertebrates, apart from birds. Using seven years of data on wild Eastern chipmunks Tamias striatus, we highlighted that telomeres elongate with age (n = 204 and n = 20) and do not limit lifespan in this species (n = 51). Furthermore, short telomeres correlated with a slow POLS in a sex-specific way (n = 37). Females with short telomeres had a delayed age at first breeding and a lower fecundity rate than females with long telomeres, while we found no differences in males. Our findings support most predictions adapted from the anticancer hypothesis, but none of those from the resource allocation trade-off hypothesis. Results are in line with an increasing body of evidence suggesting that other evolutionary forces than resource allocation trade-offs shape the diversity of telomere length in adult somatic cells and the relationships between telomere length and life-histories.},
}
@article {pmid35567940,
year = {2022},
author = {Tang, L and Li, T and Chang, Y and Wang, Z and Li, Y and Wang, F and Sui, L},
title = {Diabetic oxidative stress-induced telomere damage aggravates periodontal bone loss in periodontitis.},
journal = {Biochemical and biophysical research communications},
volume = {614},
number = {},
pages = {22-28},
doi = {10.1016/j.bbrc.2022.04.039},
pmid = {35567940},
issn = {1090-2104},
mesh = {*Alveolar Bone Loss ; Animals ; *Diabetes Mellitus, Experimental/complications ; Mice ; Oxidative Stress ; Periodontal Ligament ; *Periodontitis/complications ; Reactive Oxygen Species ; Telomere ; },
abstract = {Periodontitis, one of the most common oral complications of diabetes mellitus (DM), causes a reduction in alveolar bone height and loss of alveolar bone mass. It has been shown that DM aggravates the progression of periodontitis, but the mechanism remains inconclusive. The hyperglycemic environment of DM has been proven to generate reactive oxygen species (ROS). Since telomeres, guanine-rich repeats, are highly susceptible to oxidative attack, we speculate that the excessive accumulation of ROS in DM could induce telomere damage resulting in dysfunction of periodontal ligament cells, especially periodontal ligament stem cells (PDLSCs), which reduces the ability of tissue repair and reconstruction in diabetic periodontitis. In this study, our current data revealed that oxidative telomere damage occurred in the periodontal ligaments of diabetic mice. And Micro-CT scans showed reduced alveolar bone height and impaired alveolar bone mass in a diabetic periodontitis model. Next, cultured mouse PDLSCs (mPDLSCs) were treated with the oxidant tert-butyl hydroperoxide (t-BHP) in vitro, as we expected telomere damage was observed and resulted in cellular senescence and dysfunction. Taken together, oxidative stress in DM causes telomere dysfunction and PDLSCs senescence, which influences periodontal bone tissue regeneration and reconstruction and ultimately exacerbates bone loss in periodontitis.},
}
@article {pmid35566652,
year = {2022},
author = {Min, J and Kim, JY and Choi, JY and Kong, ID},
title = {Association between Physical Activity and Telomere Length in Women with Breast Cancer: A Systematic Review.},
journal = {Journal of clinical medicine},
volume = {11},
number = {9},
pages = {},
pmid = {35566652},
issn = {2077-0383},
support = {NRF-2020R1I1A3070520//the National Research Foundation of Korea (NRF) grant/ ; },
abstract = {The association between physical activity and telomere length (TL) has been continuously reported. However, the interplay of physical activity and TL among women with breast cancer has not been elucidated. Thus, the purpose of this systematic review was to synthesize the evidence for the association of physical activity with TL in women with breast cancer. Systematic searches were conducted to identify quantified studies using MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and Clinical Trials.gov. Five studies were included in this systematic review. Three of the five studies reported that physical activity has a significant relationship in delaying TL shortening, but others observed no association between physical activity and TL in breast cancer survivors. Although the heterogeneous studies acted as limitations in drawing clear conclusions, physical activity strategies show encouraging impacts in delaying TL shortening. To understand the effects of physical activity on TL shortening in breast cancer survivors, further studies are needed considering the tissue site, treatments for breast cancer, DNA extraction methods, and tools for measuring physical activity.},
}
@article {pmid35565445,
year = {2022},
author = {Kjeldsen, E},
title = {Congenital Aneuploidy in Klinefelter Syndrome with B-Cell Acute Lymphoblastic Leukemia Might Be Associated with Chromosomal Instability and Reduced Telomere Length.},
journal = {Cancers},
volume = {14},
number = {9},
pages = {},
pmid = {35565445},
issn = {2072-6694},
abstract = {Rare congenital aneuploid conditions such as trisomy 13, trisomy 18, trisomy 21 and Klinefelter syndrome (KS, 47,XXY) are associated with higher susceptibility to developing cancer compared with euploid genomes. Aneuploidy frequently co-exists with chromosomal instability, which can be viewed as a "vicious cycle" where aneuploidy potentiates chromosomal instability, leading to further karyotype diversity, and in turn, paving the adaptive evolution of cancer. However, the relationship between congenital aneuploidy per se and tumor initiation and/or progression is not well understood. We used G-banding analysis, array comparative genomic hybridization analysis and quantitative fluorescence in situ hybridization for telomere length analysis to characterize the leukemic blasts of a three-year-old boy with KS and B-cell acute lymphoblastic leukemia (B-ALL), to gain insight into genomic evolution mechanisms in congenital aneuploidy and leukemic development. We found chromosomal instability and a significant reduction in telomere length in leukemic blasts when compared with the non-leukemic aneuploid cells. Reviewing published cases with KS and B-ALL revealed 20 additional cases with B-ALL diagnostic cytogenetics. Including our present case, 67.7% (14/21) had acquired two or more additional chromosomal aberrations at B-ALL diagnosis. The presented data indicate that congenital aneuploidy in B-ALL might be associated with chromosomal instability, which may be fueled by enhanced telomere attrition.},
}
@article {pmid35565379,
year = {2022},
author = {Kibriya, MG and Raza, M and Kamal, M and Haq, Z and Paul, R and Mareczko, A and Pierce, BL and Ahsan, H and Jasmine, F},
title = {Relative Telomere Length Change in Colorectal Carcinoma and Its Association with Tumor Characteristics, Gene Expression and Microsatellite Instability.},
journal = {Cancers},
volume = {14},
number = {9},
pages = {},
pmid = {35565379},
issn = {2072-6694},
support = {R24 ES028532/ES/NIEHS NIH HHS/United States ; P30 ES027792/ES/NIEHS NIH HHS/United States ; R35 ES028379/ES/NIEHS NIH HHS/United States ; },
abstract = {We compared tumor and adjacent normal tissue samples from 165 colorectal carcinoma (CRC) patients to study change in relative telomere length (RTL) and its association with different histological and molecular features. To measure RTL, we used a Luminex-based assay. We observed shorter RTL in the CRC tissue compared to paired normal tissue (RTL 0.722 ± SD 0.277 vs. 0.809 ± SD 0.242, p = 0.00012). This magnitude of RTL shortening (by ~0.08) in tumor tissue is equivalent to RTL shortening seen in human leukocytes over 10 years of aging measured by the same assay. RTL was shorter in cancer tissue, irrespective of age group, gender, tumor pathology, location and microsatellite instability (MSI) status. RTL shortening was more prominent in low-grade CRC and in the presence of microsatellite instability (MSI). In a subset of patients, we also examined differential gene expression of (a) telomere-related genes, (b) genes in selected cancer-related pathways and (c) genes at the genome-wide level in CRC tissues to determine the association between gene expression and RTL changes. RTL shortening in CRC was associated with (a) upregulation of DNA replication genes, cyclin dependent-kinase genes (anti-tumor suppressor) and (b) downregulation of "caspase executor", reducing apoptosis.},
}
@article {pmid35565323,
year = {2022},
author = {Hou, K and Yu, Y and Li, D and Zhang, Y and Zhang, K and Tong, J and Yang, K and Jia, S},
title = {Alternative Lengthening of Telomeres and Mediated Telomere Synthesis.},
journal = {Cancers},
volume = {14},
number = {9},
pages = {},
pmid = {35565323},
issn = {2072-6694},
support = {YNWRQNBJ-2019-240//Yunnan "Ten Thousand Talents Plan" Young Top Talent Project/ ; 202201AS070074//Yunnan Fundamental Research Project/ ; },
abstract = {Telomeres are DNA-protein complexes that protect eukaryotic chromosome ends from being erroneously repaired by the DNA damage repair system, and the length of telomeres indicates the replicative potential of the cell. Telomeres shorten during each division of the cell, resulting in telomeric damage and replicative senescence. Tumor cells tend to ensure cell proliferation potential and genomic stability by activating telomere maintenance mechanisms (TMMs) for telomere lengthening. The alternative lengthening of telomeres (ALT) pathway is the most frequently activated TMM in tumors of mesenchymal and neuroepithelial origin, and ALT also frequently occurs during experimental cellular immortalization of mesenchymal cells. ALT is a process that relies on homologous recombination (HR) to elongate telomeres. However, some processes in the ALT mechanism remain poorly understood. Here, we review the most recent understanding of ALT mechanisms and processes, which may help us to better understand how the ALT pathway is activated in cancer cells and determine the potential therapeutic targets in ALT pathway-stabilized tumors.},
}
@article {pmid35563554,
year = {2022},
author = {Dratwa, M and Wysoczanska, B and Brankiewicz, W and Stachowicz-Suhs, M and Wietrzyk, J and Matkowski, R and Ekiert, M and Szelachowska, J and Maciejczyk, A and Szajewski, M and Baginski, M and Bogunia-Kubik, K},
title = {Relationship between Telomere Length, TERT Genetic Variability and TERT, TP53, SP1, MYC Gene Co-Expression in the Clinicopathological Profile of Breast Cancer.},
journal = {International journal of molecular sciences},
volume = {23},
number = {9},
pages = {},
pmid = {35563554},
issn = {1422-0067},
support = {STRATEGMED3/306853//National Centre for Research and Development/ ; 2017/27/B/NZ5/01167//National Science Center/ ; },
mesh = {*Breast Neoplasms/genetics/pathology ; Female ; Genes, myc ; Humans ; Polymorphism, Single Nucleotide ; Sp1 Transcription Factor/genetics ; *Telomerase/genetics ; Telomere/pathology ; Tumor Suppressor Protein p53/genetics ; },
abstract = {The molecular mechanisms of telomerase reverse transcriptase (TERT) upregulation in breast cancer (BC) are complex. We compared genetic variability within TERT and telomere length with the clinical data of patients with BC. Additionally, we assessed the expression of the TERT, MYC, TP53 and SP1 genes in BC patients and in BC organoids (3D cell cultures obtained from breast cancer tissues). We observed the same correlation in the blood of BC patients and in BC organoids between the expression of TERT and TP53. Only in BC patients was a correlation found between the expression of the TERT and MYC genes and between TP53 and MYC. We found associations between TERT genotypes (rs2735940 and rs10069690) and TP53 expression and telomere length. BC patients with the TT genotype rs2735940 have a shorter telomere length, but patients with A allele rs10069690 have a longer telomere length. BC patients with a short allele VNTR-MNS16A showed higher expression of the SP1 and had a longer telomere. Our results bring new insight into the regulation of TERT, MYC, TP53 and SP1 gene expression related to TERT genetic variability and telomere length. Our study also showed for the first time a similar relationship in the expression of the above genes in BC patients and in BC organoids. These findings suggest that TERT genetic variability, expression and telomere length might be useful biomarkers for BC, but their prognostic value may vary depending on the clinical parameters of BC patients and tumor aggressiveness.},
}
@article {pmid35563512,
year = {2022},
author = {Libera, V and Bianchi, F and Rossi, B and D'Amico, F and Masciovecchio, C and Petrillo, C and Sacchetti, F and Paciaroni, A and Comez, L},
title = {Solvent Vibrations as a Proxy of the Telomere G-Quadruplex Rearrangements across Thermal Unfolding.},
journal = {International journal of molecular sciences},
volume = {23},
number = {9},
pages = {},
pmid = {35563512},
issn = {1422-0067},
support = {COAN:07.70.01.06.01 UA.PG.DFIG//PETCARESS/ ; },
mesh = {Circular Dichroism ; *G-Quadruplexes ; Gene Rearrangement ; Humans ; Solvents ; Telomere/genetics ; Vibration ; Water ; },
abstract = {G-quadruplexes (G4s) are noncanonical forms of DNA involved in many key genome functions. Here, we exploited UV Resonance Raman scattering to simultaneously explore the vibrational behavior of a human telomeric G4 (Tel22) and its aqueous solvent as the biomolecule underwent thermal melting. We found that the OH stretching band, related to the local hydrogen-bonded network of a water molecule, was in strict relation with the vibrational features of the G4 structure as a function of temperature. In particular, the modifications to the tetrahedral ordering of the water network were strongly coupled to the DNA rearrangements, showing changes in temperature that mirrored the multi-step melting process of Tel22. The comparison between circular dichroism and Raman results supported this view. The present findings provide novel insights into the impact of the molecular environment on G4 conformation. Improving current knowledge on the solvent structural properties will also contribute to a better understanding of the role played by water arrangement in the complexation of G4s with ligands.},
}
@article {pmid35563379,
year = {2022},
author = {Castillo-González, C and Barbero Barcenilla, B and Young, PG and Hall, E and Shippen, DE},
title = {Quantification of 8-oxoG in Plant Telomeres.},
journal = {International journal of molecular sciences},
volume = {23},
number = {9},
pages = {},
pmid = {35563379},
issn = {1422-0067},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; GM065383/NH/NIH HHS/United States ; },
mesh = {DNA/chemistry ; DNA Damage ; Guanine/analogs &amp; derivatives/chemistry ; *Telomerase/genetics/metabolism ; *Telomere/genetics/metabolism ; },
abstract = {Chemical modifications in DNA impact gene regulation and chromatin structure. DNA oxidation, for example, alters gene expression, DNA synthesis and cell cycle progression. Modification of telomeric DNA by oxidation is emerging as a marker of genotoxic damage and is associated with reduced genome integrity and changes in telomere length and telomerase activity. 8-oxoguanine (8-oxoG) is the most studied and common outcome of oxidative damage in DNA. The G-rich nature of telomeric DNA is proposed to make it a hotspot for oxidation, but because telomeres make up only a tiny fraction of the genome, it has been difficult to directly test this hypothesis by studying dynamic DNA modifications specific to this region in vivo. Here, we present a new, robust method to differentially enrich telomeric DNA in solution, coupled with downstream methods for determination of chemical modification. Specifically, we measure 8-oxoG in Arabidopsis thaliana telomeres under normal and oxidative stress conditions. We show that telomere length is unchanged in response to oxidative stress in three different wild-type accessions. Furthermore, we report that while telomeric DNA comprises only 0.02-0.07% of the total genome, telomeres contribute between 0.2 and 15% of the total 8-oxoG. That is, plant telomeres accumulate 8-oxoG at levels approximately 100-fold higher than the rest of the genome under standard growth conditions. Moreover, they are the primary targets of further damage upon oxidative stress. Interestingly, the accumulation of 8-oxoG in the chromosome body seems to be inversely proportional to telomere length. These findings support the hypothesis that telomeres are hotspots of 8-oxoG and may function as sentinels of oxidative stress in plants.},
}
@article {pmid35562991,
year = {2022},
author = {Pham, C and Vryer, R and O'Hely, M and Mansell, T and Burgner, D and Collier, F and Symeonides, C and Tang, MLK and Vuillermin, P and Gray, L and Saffery, R and Ponsonby, AL and On Behalf Of The Barwon Infant Study Investigator Group, },
title = {Shortened Infant Telomere Length Is Associated with Attention Deficit/Hyperactivity Disorder Symptoms in Children at Age Two Years: A Birth Cohort Study.},
journal = {International journal of molecular sciences},
volume = {23},
number = {9},
pages = {},
pmid = {35562991},
issn = {1422-0067},
support = {N/A//Murdoch Children's Research Institute/ ; N/A//Deakin University/ ; N/A//Barwon Health/ ; N/A//National Health and Medical Research Council of Australia/ ; N/A//The Jack Brockhoff Foundation/ ; N/A//Scobie Trust/ ; N/A//Shane O'Brien Memorial Asthma Foundation/ ; N/A//Our Women's Our Children's FundRaising Committee Barwon Health/ ; N/A//The Shepherd Foundation/ ; N/A//Rotary Club of Geelong/ ; N/A//Ilhan Food Allergy Foundation/ ; N/A//GMHBA Limited/ ; N/A//Percy Baxter Charitable Trust/ ; N/A//Perpetual Trustees/ ; N/A//Minderoo Foundation/ ; N/A//Cotton On Foundation/ ; N/A//CreativeForce/ ; N/A//Victorian Government's Operational Infrastructure Support Program/ ; APP1197234 to AL Ponsonby//NHMRC Investigator Grant/ ; 2018-984 to C Pham//Melbourne Children's Campus LifeCourse PhD Support Program/ ; },
mesh = {*Attention Deficit Disorder with Hyperactivity/genetics ; Birth Cohort ; Child ; Child, Preschool ; Cohort Studies ; Humans ; Infant ; Schools ; Telomere/genetics ; },
abstract = {Environmental factors can accelerate telomere length (TL) attrition. Shortened TL is linked to attention deficit/hyperactivity disorder (ADHD) symptoms in school-aged children. The onset of ADHD occurs as early as preschool-age, but the TL-ADHD association in younger children is unknown. We investigated associations between infant TL and ADHD symptoms in children and assessed environmental factors as potential confounders and/or mediators of this association. Relative TL was measured by quantitative polymerase chain reaction in cord and 12-month blood in the birth cohort study, the Barwon Infant Study. Early life environmental factors collected antenatally to two years were used to measure confounding. ADHD symptoms at age two years were evaluated by the Child Behavior Checklist Attention Problems (AP) and the Attention Deficit/Hyperactivity Problems (ADHP). Associations between early life environmental factors on TL or ADHD symptoms were assessed using multivariable regression models adjusted for relevant factors. Telomere length at 12 months (TL12), but not at birth, was inversely associated with AP (β = -0.56; 95% CI (-1.13, 0.006); p = 0.05) and ADHP (β = -0.66; 95% CI (-1.11, -0.21); p = 0.004). Infant secondhand smoke exposure at one month was independently associated with shorter TL12 and also higher ADHD symptoms. Further work is needed to elucidate the mechanisms that influence TL attrition and early neurodevelopment.},
}
@article {pmid35559731,
year = {2022},
author = {Fernandez, RJ and Gardner, ZJG and Slovik, KJ and Liberti, DC and Estep, KN and Yang, W and Chen, Q and Santini, GT and Perez, JV and Root, S and Bhatia, R and Tobias, JW and Babu, A and Morley, MP and Frank, DB and Morrisey, EE and Lengner, CJ and Johnson, FB},
title = {GSK3 inhibition rescues growth and telomere dysfunction in dyskeratosis congenita iPSC-derived type II alveolar epithelial cells.},
journal = {eLife},
volume = {11},
number = {},
pages = {},
pmid = {35559731},
issn = {2050-084X},
support = {R21 AG054209/AG/NIA NIH HHS/United States ; R01 HL148821/HL/NHLBI NIH HHS/United States ; T32 AG000255/AG/NIA NIH HHS/United States ; P30 DK050306/DK/NIDDK NIH HHS/United States ; P30 CA016520/CA/NCI NIH HHS/United States ; },
mesh = {Alveolar Epithelial Cells/metabolism ; *Dyskeratosis Congenita/genetics/pathology ; Glycogen Synthase Kinase 3 ; Humans ; *Induced Pluripotent Stem Cells/metabolism ; Mutation ; *Telomerase/genetics/metabolism ; Telomere/metabolism ; },
abstract = {Dyskeratosis congenita (DC) is a rare genetic disorder characterized by deficiencies in telomere maintenance leading to very short telomeres and the premature onset of certain age-related diseases, including pulmonary fibrosis (PF). PF is thought to derive from epithelial failure, particularly that of type II alveolar epithelial (AT2) cells, which are highly dependent on Wnt signaling during development and adult regeneration. We use human induced pluripotent stem cell-derived AT2 (iAT2) cells to model how short telomeres affect AT2 cells. Cultured DC mutant iAT2 cells accumulate shortened, uncapped telomeres and manifest defects in the growth of alveolospheres, hallmarks of senescence, and apparent defects in Wnt signaling. The GSK3 inhibitor, CHIR99021, which mimics the output of canonical Wnt signaling, enhances telomerase activity and rescues the defects. These findings support further investigation of Wnt agonists as potential therapies for DC-related pathologies.},
}
@article {pmid35546751,
year = {2023},
author = {Fathi, E and Montazersaheb, S and Sanaat, Z and Nakhlband, A and Vandghanooni, S and Farahzadi, R and Vietor, I},
title = {L-Carnitine Reduced Cellular Aging of Bone Marrow Resident C-Kit+ Hematopoietic Progenitor Cells Through Telomere Dependent Pathways.},
journal = {Current stem cell research &amp; therapy},
volume = {18},
number = {2},
pages = {231-236},
doi = {10.2174/1574888X17666220511141123},
pmid = {35546751},
issn = {2212-3946},
support = {63634//Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran/ ; },
mesh = {Humans ; *Bone Marrow ; *Carnitine/pharmacology/metabolism ; Cellular Senescence/genetics ; Hematopoietic Stem Cells ; Telomere/genetics ; Bone Marrow Cells ; },
abstract = {BACKGROUND: Increased oxygen species levels can induce mitochondrial DNA damage and chromosomal aberrations and cause defective stem cell differentiation, leading finally to senescence of stem cells. In recent years, several studies have reported that antioxidants can improve stem cell survival and subsequently affect the potency and differentiation of these cells. Finding factors, which reduce the senescence tendency of stem cells upon expansion, has great potential for cellular therapy in regenerative medicine. This study aimed to evaluate the effects of L-carnitine (LC) on the aging of C-kit+ hematopoietic progenitor cells (HPCs) via examining the expression of some signaling pathway components.<br><br>METHODS: For this purpose, bone marrow resident C-kit+ HPCs were enriched by the magnetic-activated cell sorting (MACS) method and were characterized using flow cytometry as well as immunocytochemistry. Cells were treated with LC, and at the end of the treatment period, the cells were subjected to the realtime PCR technique along with a western blotting assay for measurement of the telomere length and assessment of protein expression, respectively.<br><br>RESULTS: The results showed that 0.2 mM LC caused the elongation of the telomere length and increased the TERT protein expression. In addition, a significant increase was observed in the protein expression of p38, p53, BCL2, and p16 as key components of the telomere-dependent pathway.<br><br>CONCLUSION: It can be concluded that LC can increase the telomere length as an effective factor in increasing the cell survival and maintenance of the C-kit+ HPCs via these signaling pathway components.},
}
@article {pmid35534619,
year = {2023},
author = {Yang, Q and Liu, R and Gao, Y and Kang, H and Zhang, Z and Han, Z and Zhang, Y and Li, Y and Mu, L and Lei, L},
title = {Mediating effect of telomere length in a hypertension population exposed to cadmium: a case-control study.},
journal = {Journal of human hypertension},
volume = {37},
number = {5},
pages = {386-393},
pmid = {35534619},
issn = {1476-5527},
mesh = {Humans ; *Cadmium/adverse effects/urine ; Case-Control Studies ; *Hypertension ; Blood Pressure ; Telomere ; },
abstract = {Cadmium (Cd) is associated with telomere length and hypertension, respectively, but the mechanism behind its relationship is unclear. Our study aimed to clarify the role of telomere length in the relationship between Cd and hypertension. A 1:1 matched case-control study was conducted with 213 hypertensive patients and 213 normotensive controls in Taiyuan, Shanxi Province, China, from February and June 2016. General demographic characteristics information and lifestyle were collected using a structured questionnaire. Urine samples were collected to test urinary Cd (UCd) levels and corrected by urinary creatinine (UCr) levels. Peripheral leukocyte absolute telomere length (ATL) was measured using quantitative polymerase chain reaction. Logistic regression was used to screen the influencing factors of hypertension. A mediation effect analysis was used to explore the role of telomere length between Cd exposure and the risk of hypertension. We found that the hypertension group had a significantly higher UCd level compared to the control group (0.91 vs 0.80 μg/g Cr, P < 0.01), while ATL showed the opposite relationship (2.36 vs 2.65 kb, P < 0.01). The Regression analysis of hypertension identified these significant predictors: family history of hypertension (OR = 3.129, 95% confidence interval (95% CI): 1.767-5.540), Body mass index (BMI, OR = 1.088, 95% CI: 1.023-1.157), total cholesterol (TC, OR = 1.277, 95% CI: 1.024-1.592), UCd (OR = 2.092, 95% CI: 1.179-3.710), ATL (OR = 0.105, 95% CI: 0.025-0.453) and 8-hydroxy-2-deoxyguanosine (8-OHdG, OR = 7.864, 95% CI: 3.516-17.589). Mediating effect analysis revealed that ATL was a potential partial mediating factor between Cd and hypertension. Cd may induce hypertension by affecting telomere length, but this requires further exploration.},
}
@article {pmid35533552,
year = {2022},
author = {Nasiri, L and Vaez-Mahdavi, MR and Hassanpour, H and Askari, N and Ardestani, SK and Ghazanfari, T},
title = {Concomitant use of relative telomere length, biological health score and physical/social statuses in the biological aging evaluation of mustard-chemical veterans.},
journal = {International immunopharmacology},
volume = {109},
number = {},
pages = {108785},
doi = {10.1016/j.intimp.2022.108785},
pmid = {35533552},
issn = {1878-1705},
mesh = {Aging ; Humans ; *Mustard Gas/toxicity ; Mustard Plant ; Telomere ; Telomere Shortening ; *Veterans ; },
abstract = {Sulfur mustard (SM) is a toxic gas that has been used as a chemical weapon in wars. After many years, SM-exposed people are still suffering from its side effects such as biological and premature aging. This study was aimed to evaluate biological aging rate via involving biological health scoring (BHS), relative telomere length (TL) and different physical/social variables i.e. marital and smoking statuses, body mass index, salary and educational levels. BHS was calculated according to measurement of 18 biomarkers related to function of four physiological systems (endocrine, inflammatory, cardiovascular and metabolic systems) and two organs (liver and kidney). The volunteers were 442 individuals exposed to SM gas in 1987 and 119 healthy individuals as non-exposed group. Each group was divided based on leukocyte relative TL (short, intermediate and long). Our data showed an inverse correlation between BHS and relative TL in two groups. The BHS was significantly higher in SM-exposed group than non-exposed group, especially in the participants with short and intermediate TL. The BHS had also a positive correlation with smoking and BMI parameters, and a negative correlation with salary and educational levels in the participants with shorter telomeres; and SM strengthened these correlations in the shorter telomeres. It is concluded that the higher BHS along with shorter relative TL that are indices for lower health quality and biological aging, could be used in the health evaluation of non- and SM-exposed people; and involving of BHS, TL and physical/social covariates could be useful to make this evaluation more accurate.},
}
@article {pmid35532056,
year = {2022},
author = {Alder, JK and Armanios, M},
title = {Telomere-mediated lung disease.},
journal = {Physiological reviews},
volume = {102},
number = {4},
pages = {1703-1720},
pmid = {35532056},
issn = {1522-1210},
support = {R01 HL135062/HL/NHLBI NIH HHS/United States ; R01 CA225027/CA/NCI NIH HHS/United States ; R01 HL119476/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; *Idiopathic Pulmonary Fibrosis/genetics ; Lung/metabolism ; *Lung Diseases/genetics ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism/pathology ; },
abstract = {Parenchymal lung disease is the fourth leading cause of death in the United States; among the top causes, it continues on the rise. Telomeres and telomerase have historically been linked to cellular processes related to aging and cancer, but surprisingly, in the recent decade genetic discoveries have linked the most apparent manifestations of telomere and telomerase dysfunction in humans to the etiology of lung disease: both idiopathic pulmonary fibrosis (IPF) and emphysema. The short telomere defect is pervasive in a subset of IPF patients, and human IPF is the phenotype most intimately tied to germline defects in telomere maintenance. One-third of families with pulmonary fibrosis carry germline mutations in telomerase or other telomere maintenance genes, and one-half of patients with apparently sporadic IPF have short telomere length. Beyond explaining genetic susceptibility, short telomere length uncovers clinically relevant syndromic extrapulmonary disease, including a T-cell immunodeficiency and a propensity to myeloid malignancies. Recognition of this subset of patients who share a unifying molecular defect has provided a precision medicine paradigm wherein the telomere-mediated lung disease diagnosis provides more prognostic value than histopathology or multidisciplinary evaluation. Here, we critically evaluate this progress, emphasizing how the genetic findings put forth a new pathogenesis paradigm of age-related lung disease that links telomere abnormalities to alveolar stem senescence, remodeling, and defective gas exchange.},
}
@article {pmid35530816,
year = {2022},
author = {Taub, MA and Conomos, MP and Keener, R and Iyer, KR and Weinstock, JS and Yanek, LR and Lane, J and Miller-Fleming, TW and Brody, JA and Raffield, LM and McHugh, CP and Jain, D and Gogarten, SM and Laurie, CA and Keramati, A and Arvanitis, M and Smith, AV and Heavner, B and Barwick, L and Becker, LC and Bis, JC and Blangero, J and Bleecker, ER and Burchard, EG and Celedón, JC and Chang, YPC and Custer, B and Darbar, D and de Las Fuentes, L and DeMeo, DL and Freedman, BI and Garrett, ME and Gladwin, MT and Heckbert, SR and Hidalgo, BA and Irvin, MR and Islam, T and Johnson, WC and Kaab, S and Launer, L and Lee, J and Liu, S and Moscati, A and North, KE and Peyser, PA and Rafaels, N and Seidman, C and Weeks, DE and Wen, F and Wheeler, MM and Williams, LK and Yang, IV and Zhao, W and Aslibekyan, S and Auer, PL and Bowden, DW and Cade, BE and Chen, Z and Cho, MH and Cupples, LA and Curran, JE and Daya, M and Deka, R and Eng, C and Fingerlin, TE and Guo, X and Hou, L and Hwang, SJ and Johnsen, JM and Kenny, EE and Levin, AM and Liu, C and Minster, RL and Naseri, T and Nouraie, M and Reupena, MS and Sabino, EC and Smith, JA and Smith, NL and Su, JL and Taylor, JG and Telen, MJ and Tiwari, HK and Tracy, RP and White, MJ and Zhang, Y and Wiggins, KL and Weiss, ST and Vasan, RS and Taylor, KD and Sinner, MF and Silverman, EK and Shoemaker, MB and Sheu, WH and Sciurba, F and Schwartz, DA and Rotter, JI and Roden, D and Redline, S and Raby, BA and Psaty, BM and Peralta, JM and Palmer, ND and Nekhai, S and Montgomery, CG and Mitchell, BD and Meyers, DA and McGarvey, ST and , and Mak, AC and Loos, RJ and Kumar, R and Kooperberg, C and Konkle, BA and Kelly, S and Kardia, SL and Kaplan, R and He, J and Gui, H and Gilliland, FD and Gelb, BD and Fornage, M and Ellinor, PT and de Andrade, M and Correa, A and Chen, YI and Boerwinkle, E and Barnes, KC and Ashley-Koch, AE and Arnett, DK and , and , and , and Laurie, CC and Abecasis, G and Nickerson, DA and Wilson, JG and Rich, SS and Levy, D and Ruczinski, I and Aviv, A and Blackwell, TW and Thornton, T and O'Connell, J and Cox, NJ and Perry, JA and Armanios, M and Battle, A and Pankratz, N and Reiner, AP and Mathias, RA},
title = {Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed.},
journal = {Cell genomics},
volume = {2},
number = {1},
pages = {},
pmid = {35530816},
issn = {2666-979X},
support = {R01 HL104135/HL/NHLBI NIH HHS/United States ; U10 HL054472/HL/NHLBI NIH HHS/United States ; U01 HL054472/HL/NHLBI NIH HHS/United States ; R01 HL113264/HL/NHLBI NIH HHS/United States ; S10 OD017985/OD/NIH HHS/United States ; R01 HL080083/HL/NHLBI NIH HHS/United States ; OT3 HL142478/HL/NHLBI NIH HHS/United States ; UM1 HL098162/HL/NHLBI NIH HHS/United States ; R01 HL112064/HL/NHLBI NIH HHS/United States ; R01 ES021801/ES/NIEHS NIH HHS/United States ; UL1 TR000445/TR/NCATS NIH HHS/United States ; R01 HL095080/HL/NHLBI NIH HHS/United States ; U01 HL072496/HL/NHLBI NIH HHS/United States ; UM1 HL098123/HL/NHLBI NIH HHS/United States ; R01 HL133040/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL087698/HL/NHLBI NIH HHS/United States ; R01 HL046380/HL/NHLBI NIH HHS/United States ; R01 HL092217/HL/NHLBI NIH HHS/United States ; R01 HL121007/HL/NHLBI NIH HHS/United States ; R01 HL111249/HL/NHLBI NIH HHS/United States ; R01 HL071259/HL/NHLBI NIH HHS/United States ; U01 HL054527/HL/NHLBI NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; R01 HL069234/HL/NHLBI NIH HHS/United States ; UM1 HG008895/HG/NHGRI NIH HHS/United States ; R01 HL068986/HL/NHLBI NIH HHS/United States ; U01 HL130114/HL/NHLBI NIH HHS/United States ; R01 HL087660/HL/NHLBI NIH HHS/United States ; R01 AR048797/AR/NIAMS NIH HHS/United States ; R01 HL092577/HL/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; R01 HL085251/HL/NHLBI NIH HHS/United States ; U19 HL065962/HL/NHLBI NIH HHS/United States ; R01 HL066216/HL/NHLBI NIH HHS/United States ; U01 HL089897/HL/NHLBI NIH HHS/United States ; R01 HL113338/HL/NHLBI NIH HHS/United States ; U10 HL064307/HL/NHLBI NIH HHS/United States ; UH3 HL151865/HL/NHLBI NIH HHS/United States ; R01 AG058921/AG/NIA NIH HHS/United States ; R01 HL071250/HL/NHLBI NIH HHS/United States ; P30 AG028747/AG/NIA NIH HHS/United States ; S10 RR025141/RR/NCRR NIH HHS/United States ; R01 NS058700/NS/NINDS NIH HHS/United States ; U01 HL130045/HL/NHLBI NIH HHS/United States ; T32 HG000040/HG/NHGRI NIH HHS/United States ; UH3 OD023282/OD/NIH HHS/United States ; R01 HL141845/HL/NHLBI NIH HHS/United States ; R01 HL089856/HL/NHLBI NIH HHS/United States ; U10 HL064295/HL/NHLBI NIH HHS/United States ; OT3 HL142481/HL/NHLBI NIH HHS/United States ; U01 HL065962/HL/NHLBI NIH HHS/United States ; U10 HL064288/HL/NHLBI NIH HHS/United States ; U01 AI126614/AI/NIAID NIH HHS/United States ; U01 HL054464/HL/NHLBI NIH HHS/United States ; N01HC85086/HL/NHLBI NIH HHS/United States ; OT3 HL147154/HL/NHLBI NIH HHS/United States ; U10 HL064287/HL/NHLBI NIH HHS/United States ; R01 HL119443/HL/NHLBI NIH HHS/United States ; R37 HL066289/HL/NHLBI NIH HHS/United States ; U01 HL089856/HL/NHLBI NIH HHS/United States ; R01 HL067348/HL/NHLBI NIH HHS/United States ; R35 HL135818/HL/NHLBI NIH HHS/United States ; R25 GM062459/GM/NIGMS NIH HHS/United States ; I01 BX005295/BX/BLRD VA/United States ; R01 HL113326/HL/NHLBI NIH HHS/United States ; R01 HL071051/HL/NHLBI NIH HHS/United States ; U01 HL072524/HL/NHLBI NIH HHS/United States ; P01 ES011627/ES/NIEHS NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; U10 HL064305/HL/NHLBI NIH HHS/United States ; U01 HL054457/HL/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; R01 HD074711/HD/NICHD NIH HHS/United States ; R01 HL104608/HL/NHLBI NIH HHS/United States ; RC2 GM092618/GM/NIGMS NIH HHS/United States ; UG3 OD023282/OD/NIH HHS/United States ; P01 HL045522/HL/NHLBI NIH HHS/United States ; OT3 HL142480/HL/NHLBI NIH HHS/United States ; UM1 HL128761/HL/NHLBI NIH HHS/United States ; U01 HL072518/HL/NHLBI NIH HHS/United States ; P50 GM115305/GM/NIGMS NIH HHS/United States ; U10 HL109164/HL/NHLBI NIH HHS/United States ; HHSN268201500014C/HL/NHLBI NIH HHS/United States ; R01 HL133221/HL/NHLBI NIH HHS/United States ; 75N92021D00006/HL/NHLBI NIH HHS/United States ; R01 HL080467/HL/NHLBI NIH HHS/United States ; N01HC85082/HL/NHLBI NIH HHS/United States ; R01 HL068959/HL/NHLBI NIH HHS/United States ; U01 HL072507/HL/NHLBI NIH HHS/United States ; R01 HL132523/HL/NHLBI NIH HHS/United States ; R01 DK071891/DK/NIDDK NIH HHS/United States ; U01 HG006378/HG/NHGRI NIH HHS/United States ; R01 HL093093/HL/NHLBI NIH HHS/United States ; R01 HL087263/HL/NHLBI NIH HHS/United States ; R01 HL097163/HL/NHLBI NIH HHS/United States ; N01HC85083/HL/NHLBI NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; R01 HL117004/HL/NHLBI NIH HHS/United States ; R01 HL071205/HL/NHLBI NIH HHS/United States ; U01 HL054481/HL/NHLBI NIH HHS/United States ; R03 HL154284/HL/NHLBI NIH HHS/United States ; OT3 HL142479/HL/NHLBI NIH HHS/United States ; UL1 RR024975/RR/NCRR NIH HHS/United States ; UM1 HL128711/HL/NHLBI NIH HHS/United States ; R01 NS032830/NS/NINDS NIH HHS/United States ; UG1 HL139054/HL/NHLBI NIH HHS/United States ; U01 HG004798/HG/NHGRI NIH HHS/United States ; UL1 TR002243/TR/NCATS NIH HHS/United States ; U01 HL117721/HL/NHLBI NIH HHS/United States ; UM1 HL098147/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; N01HC85079/HL/NHLBI NIH HHS/United States ; U10 HL098112/HL/NHLBI NIH HHS/United States ; R01 HL090682/HL/NHLBI NIH HHS/United States ; R01 HL073410/HL/NHLBI NIH HHS/United States ; RC1 HL099355/HL/NHLBI NIH HHS/United States ; N01HC85080/HL/NHLBI NIH HHS/United States ; R01 HL118267/HL/NHLBI NIH HHS/United States ; R01 HL071258/HL/NHLBI NIH HHS/United States ; R01 HL055673/HL/NHLBI NIH HHS/United States ; R01 HL079915/HL/NHLBI NIH HHS/United States ; R01 HL056177/HL/NHLBI NIH HHS/United States ; R01 HL092301/HL/NHLBI NIH HHS/United States ; K01 HL135405/HL/NHLBI NIH HHS/United States ; N01HC85081/HL/NHLBI NIH HHS/United States ; U10 HL064313/HL/NHLBI NIH HHS/United States ; R01 HL091889/HL/NHLBI NIH HHS/United States ; },
abstract = {Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value <5×10[-9]) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes.},
}
@article {pmid35524933,
year = {2022},
author = {Ferrer, A and Mangaonkar, AA and Patnaik, MM},
title = {Clonal Hematopoiesis and Myeloid Neoplasms in the Context of Telomere Biology Disorders.},
journal = {Current hematologic malignancy reports},
volume = {17},
number = {3},
pages = {61-68},
pmid = {35524933},
issn = {1558-822X},
mesh = {Biology ; Clonal Hematopoiesis/genetics ; Humans ; *Leukemia, Myeloid, Acute ; Mutation ; *Myeloproliferative Disorders/genetics/therapy ; Telomere/genetics ; },
abstract = {PURPOSE OF REVIEW: Telomere biology disorders (TBDs) are cancer-predisposing multisystemic diseases that portend a higher risk of transforming into myeloid neoplasms (MNs). Due to the rarity and high variability of clinical presentations, TBD-specific characteristics of MN and the mechanisms behind this predisposition are not well defined. Herein, we review recent studies on TBD patient cohorts describing myeloid transformation events and summarize efforts to develop screening and treatment guidelines for these patients.<br><br>RECENT FINDINGS: Preliminary studies have indicated that TBD patients have a higher prevalence of somatic genetic alterations in hematopoietic cells, an age-related phenomenon, also known as clonal hematopoiesis; increasing predisposition to MN. The CH mutational landscape in TBD differs from that observed in non-TBD patients and preliminary data suggest a higher frequency of somatic mutations in the DNA repair mechanism pathway. Although initial studies did not observe specific features of MN in TBD patients, certain events are common in TBD, such as hypocellular bone marrows. The mechanisms of MN development need further elucidation. Current management options for MN-TBD patients need to be individualized and tailored as per the clinical context. Because of the high sensitivity to alkylator chemotherapy and radiation conferred by short telomeres, non-cytotoxic targeted therapies and immunotherapy are ideal therapeutic options, but these therapies are still being tested in clinical trials. Defining the mechanisms of CH evolution in TBD and identifying risk factors leading to MN evolution will allow for the development of screening and treatment guidelines for these patients.},
}
@article {pmid35511166,
year = {2022},
author = {Shakirov, EV and Chen, JJ and Shippen, DE},
title = {Plant telomere biology: The green solution to the end-replication problem.},
journal = {The Plant cell},
volume = {34},
number = {7},
pages = {2492-2504},
pmid = {35511166},
issn = {1532-298X},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; R01 GM127402/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Arabidopsis/genetics/metabolism ; Biology ; Plants/genetics/metabolism ; *Telomerase/genetics ; Telomere/genetics/metabolism ; },
abstract = {Telomere maintenance is a fundamental cellular process conserved across all eukaryotic lineages. Although plants and animals diverged over 1.5 billion years ago, lessons learned from plants continue to push the boundaries of science, revealing detailed molecular mechanisms in telomere biology with broad implications for human health, aging biology, and stress responses. Recent studies of plant telomeres have unveiled unexpected divergence in telomere sequence and architecture, and the proteins that engage telomeric DNA and telomerase. The discovery of telomerase RNA components in the plant kingdom and some algae groups revealed new insight into the divergent evolution and the universal core of telomerase across major eukaryotic kingdoms. In addition, resources cataloging the abundant natural variation in Arabidopsis thaliana, maize (Zea mays), and other plants are providing unparalleled opportunities to understand the genetic networks that govern telomere length polymorphism and, as a result, are uncovering unanticipated crosstalk between telomeres, environmental factors, organismal fitness, and plant physiology. Here we recap current advances in plant telomere biology and put this field in perspective relative to telomere and telomerase research in other eukaryotic lineages.},
}
@article {pmid35510763,
year = {2022},
author = {Ujvari, B and Raven, N and Madsen, T and Klaassen, M and Dujon, AM and Schultz, AG and Nunney, L and Lemaître, JF and Giraudeau, M and Thomas, F},
title = {Telomeres, the loop tying cancer to organismal life-histories.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6273-6285},
pmid = {35510763},
issn = {1365-294X},
mesh = {Humans ; *Ecosystem ; Telomere Shortening/genetics ; *Neoplasms/genetics ; Biological Evolution ; Telomere/genetics ; },
abstract = {Recent developments in telomere and cancer evolutionary ecology demonstrate a very complex relationship between the need of tissue repair and controlling the emergence of abnormally proliferating cells. The trade-off is balanced by natural and sexual selection and mediated via both intrinsic and environmental factors. Here, we explore the effects of telomere-cancer dynamics on life history traits and strategies as well as on the cumulative effects of genetic and environmental factors. We show that telomere-cancer dynamics constitute an incredibly complex and multifaceted process. From research to date, it appears that the relationship between telomere length and cancer risk is likely nonlinear with good evidence that both (too) long and (too) short telomeres can be associated with increased cancer risk. The ability and propensity of organisms to respond to the interplay of telomere dynamics and oncogenic processes, depends on the combination of its tissue environments, life history strategies, environmental challenges (i.e., extreme climatic conditions), pressure by predators and pollution, as well as its evolutionary history. Consequently, precise interpretation of telomere-cancer dynamics requires integrative and multidisciplinary approaches. Finally, incorporating information on telomere dynamics and the expression of tumour suppressor genes and oncogenes could potentially provide the synergistic overview that could lay the foundations to study telomere-cancer dynamics at ecosystem levels.},
}
@article {pmid35501726,
year = {2022},
author = {Panelli, DM and Leonard, SA and Wong, RJ and Becker, M and Mayo, JA and Wu, E and Girsen, AI and Gotlib, IH and Aghaeepour, N and Druzin, ML and Shaw, GM and Stevenson, DK and Bianco, K},
title = {Leukocyte telomere dynamics across gestation in uncomplicated pregnancies and associations with stress.},
journal = {BMC pregnancy and childbirth},
volume = {22},
number = {1},
pages = {381},
pmid = {35501726},
issn = {1471-2393},
support = {R35 GM138353/GM/NIGMS NIH HHS/United States ; },
mesh = {Adult ; Cohort Studies ; Female ; Humans ; Leukocytes ; Pilot Projects ; Pregnancy ; *Telomere ; *Telomere Shortening ; },
abstract = {BACKGROUND: Short leukocyte telomere length is a biomarker associated with stress and morbidity in non-pregnant adults. Little is known, however, about maternal telomere dynamics in pregnancy. To address this, we examined changes in maternal leukocyte telomere length (LTL) during uncomplicated pregnancies and explored correlations with perceived stress.<br><br>METHODS: In this pilot study, maternal LTL was measured in blood collected from nulliparas who delivered live, term, singleton infants between 2012 and 2018 at a single institution. Participants were excluded if they had diabetes or hypertensive disease. Samples were collected over the course of pregnancy and divided into three time periods: <&#x2009;20[0/7] weeks (Timepoint 1); 20[1/7] to 36[6/7] weeks (Timepoint 2); and 37[0/7] to 9-weeks postpartum (Timepoint 3). All participants also completed a survey assessing a multivariate profile of perceived stress at the time of enrollment in the first trimester. LTL was measured using quantitative polymerase chain reaction (PCR). Wilcoxon signed-rank tests were used to compare LTL differences within participants across all timepoint intervals. To determine whether mode of delivery affected LTL, we compared postpartum Timepoint 3 LTLs between participants who had vaginal versus cesarean birth. Secondarily, we evaluated the association of the assessed multivariate stress profile and LTL using machine learning analysis.<br><br>RESULTS: A total of 115 samples from 46 patients were analyzed. LTL (mean&#x2009;&#xb1;&#x2009;SD), expressed as telomere to single copy gene (T/S) ratios, were: 1.15&#x2009;&#xb1;&#x2009;0.26, 1.13&#x2009;&#xb1;&#x2009;0.23, and 1.07&#x2009;&#xb1;&#x2009;0.21 for Timepoints 1, 2, and 3, respectively. There were no significant differences in LTL between Timepoints 1 and 2 (LTL T/S change -&#x2009;0.03&#x2009;&#xb1;&#x2009;0.26, p&#x2009;=&#x2009;0.39); 2 and 3 (-&#x2009;0.07&#x2009;&#xb1;&#x2009;0.29, p&#x2009;=&#x2009;0.38) or Timepoints 1 and 3 (-&#x2009;0.07&#x2009;&#xb1;&#x2009;0.21, p&#x2009;=&#x2009;0.06). Participants who underwent cesareans had significantly shorter postpartum LTLs than those who delivered vaginally (T/S ratio: 0.94&#x2009;&#xb1;&#x2009;0.12 cesarean versus 1.12&#x2009;&#xb1;&#x2009;0.21 vaginal, p&#x2009;=&#x2009;0.01). In secondary analysis, poor sleep quality was the main stress construct associated with shorter Timepoint 1 LTLs (p&#x2009;=&#x2009;0.02) and shorter mean LTLs (p&#x2009;=&#x2009;0.03).<br><br>CONCLUSIONS: In this cohort of healthy pregnancies, maternal LTLs did not significantly change across gestation and postpartum LTLs were shorter after cesarean than after vaginal birth. Significant associations between sleep quality and short LTLs warrant further investigation.},
}
@article {pmid35500959,
year = {2022},
author = {Nickels, M and Mastana, S and Denniff, M and Codd, V and Akam, E},
title = {Pilates and telomere dynamics: A 12-month longitudinal study.},
journal = {Journal of bodywork and movement therapies},
volume = {30},
number = {},
pages = {118-124},
doi = {10.1016/j.jbmt.2022.02.013},
pmid = {35500959},
issn = {1532-9283},
mesh = {*Antioxidants ; *Body Composition/physiology ; Female ; Humans ; Longitudinal Studies ; RNA, Messenger ; Telomere ; },
abstract = {Telomeres are dynamic structures that appear to be positively influenced by healthy lifestyle factors such as exercise. Pilates is an increasingly popular exercise modality that is reported to exert beneficial physiological effects in the body, although the cellular mechanisms are poorly understood. The aim of the present study was to investigate the influence of Pilates exercise on telomere length. This longitudinal study followed experienced female Pilates practitioners (n = 11, 50.8 ± 7.5 years) and healthy age- and sex-matched sedentary controls (n = 11, 49.3 ± 6.1 years) over a 12-month period. Leukocyte telomere length was quantified using qPCR. Circulatory inflammatory markers, mRNA gene expression, body composition, physical performance, and mental well-being were also assessed. Telomere length was comparable between Pilates practitioners and controls at baseline (Pre) and 12-months (Post) (p > 0.0125). Pilates practitioners displayed enhanced mRNA gene expression of antioxidant enzymes (SOD2 and GPX1), and lower body fat percentage and visceral fat rating, compared with sedentary controls (p < 0.0125). Over the 12-month longitudinal period, Pilates participants significantly increased dynamic balance (p < 0.05). In conclusion, long-term Pilates participation does not appear to influence telomere length. Nonetheless, Pilates exercise appears to increase antioxidant enzyme gene expression, effectively manage body composition, and improve dynamic balance.},
}
@article {pmid35493096,
year = {2022},
author = {de Oliveira, BCD and Shiburah, ME and Paiva, SC and Vieira, MR and Morea, EGO and da Silva, MS and Alves, CS and Segatto, M and Gutierrez-Rodrigues, F and Borges, JC and Calado, RT and Cano, MIN},
title = {Corrigendum: Possible Involvement of Hsp90 in the Regulation of Telomere Length and Telomerase Activity During the Leishmania Amazonensis Developmental Cycle and Population Proliferation.},
journal = {Frontiers in cell and developmental biology},
volume = {10},
number = {},
pages = {894949},
doi = {10.3389/fcell.2022.894949},
pmid = {35493096},
issn = {2296-634X},
abstract = {[This corrects the article DOI: 10.3389/fcell.2021.713415.].},
}
@article {pmid35489708,
year = {2022},
author = {Kirk, B and Kuo, CL and Xiang, M and Duque, G},
title = {Associations between leukocyte telomere length and osteosarcopenia in 20,400 adults aged 60 years and over: Data from the UK Biobank.},
journal = {Bone},
volume = {161},
number = {},
pages = {116425},
doi = {10.1016/j.bone.2022.116425},
pmid = {35489708},
issn = {1873-2763},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; R21 NR018963/NR/NINR NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Biological Specimen Banks ; Bone Density/physiology ; *Bone Diseases, Metabolic/complications ; Female ; Hand Strength/physiology ; Humans ; Leukocytes ; Male ; Middle Aged ; *Osteoporosis/complications ; *Sarcopenia/complications/epidemiology/genetics ; Telomere/genetics ; United Kingdom/epidemiology ; },
abstract = {PURPOSE: Two mechanisms implicated in telomere shortening are oxidative stress and inflammation, both of which are linked to bone and muscle loss suggesting a pathological link between telomere attrition and osteosarcopenia. Using older adults aged 60 years and over in the UK Biobank, we examined the association between leukocyte telomere length and osteosarcopenia.<br><br>METHODS: Baseline leukocyte telomere length was measured using a multiplex qPCR technique and expressed as the amount of the telomere amplification product (T) to that of a single-copy gene (S) (T/S ratio). Osteosarcopenia data was from the first imaging visit and defined by WHO criteria (femoral neck bone density T score&#xa0;&#x2264;&#xa0;-1) for osteopenia/osteoporosis plus either the EWGSOP2 (low appendicular lean mass/height[2] and low grip strength) or SDOC (low grip strength and slow walking pace) criteria for sarcopenia. Binary or multinomial logistic regression models were used to associate telomere length and osteosarcopenia or its components, adjusting for the covariates: age, sex, race, education, Townsend deprivation index, alcohol, smoking, BMI/weight, physical activity levels.<br><br>RESULTS: Among 20,400 older adults (mean age: 67.79&#xa0;&#xb1;&#xa0;4.9&#xa0;years, 53% men), the prevalence of osteosarcopenia by EWGSOP2 (n&#xa0;=&#xa0;96, 0.47%) or SDOC (n&#xa0;=&#xa0;205, 1%) criteria was low at the first imaging visit (mean 8.82&#xa0;years after baseline). Baseline telomere length was not associated with osteosarcopenia by EWGSOP2 (Relative Risk (RR): 1.00, 95% CI: 0.82-1.23 comparing osteosarcopenia to normal (non-osteopenic, non-osteoporotic, and non-sarcopenic) per Standard Deviation (SD) increase in telomere length) or SDOC (RR: 0.95, 95% CI: 0.83-1.09) criteria. Longer telomere length was associated with a lower risk of slow walking pace (Odds Ratio: 0.92, 95% CI: 0.87-0.99 per SD increase in telomere length, p&#xa0;=&#xa0;0.021). Telomere length, however, was not associated with low grip strength, low bone density or low appendicular lean mass/height[2] (p&#xa0;>&#xa0;0.05).<br><br>CONCLUSIONS: In this population-based study, telomere length was not associated with osteosarcopenia; however, slow walking pace was. Further studies are needed to reexamine this relationship, including a greater number of the oldest-old (&#x2265;75&#xa0;years) where osteosarcopenia is more prevalent.},
}
@article {pmid35488763,
year = {2022},
author = {Mikheev, RK and Grigoryan, OR and Pankratova, MS and Andreeva, EN and Sheremetyeva, EV and Absatarova, YS and Mokrysheva, NG},
title = {[Telomere pathology in ontogenesis in patients with Turner syndrome].},
journal = {Problemy endokrinologii},
volume = {68},
number = {2},
pages = {128-132},
pmid = {35488763},
issn = {2308-1430},
mesh = {*Cardiovascular Abnormalities ; Female ; Humans ; Male ; Prospective Studies ; Proteomics ; Telomere/genetics/pathology ; *Turner Syndrome/complications/genetics/pathology ; },
abstract = {According to present medical databases there many trials to provide in vivo researches in vivo to confirm/refute shortening process of telomeres among patients with Turner syndrome. Despite the successful clinical experience of providing such patients with Turner syndrome, a lot of omics (proteomic and metabolomic) aspects still stay unclear. Main disadvantages of most researches are small volume and minimized mathematical correlation with chronic disease (coronary heart disease, essential hypertension, cardiovascular malformations). Finally, organization of international prospective multi-centered researches in vivo including patients with mosaic cariotype and co-operation between physicians and biologists are optimal solutions for this present problem.},
}
@article {pmid35484160,
year = {2022},
author = {Buemi, V and Schillaci, O and Santorsola, M and Bonazza, D and Broccia, PV and Zappone, A and Bottin, C and Dell'Omo, G and Kengne, S and Cacchione, S and Raffa, GD and Piazza, S and di Fagagna, FD and Benetti, R and Cortale, M and Zanconati, F and Del Sal, G and Schoeftner, S},
title = {TGS1 mediates 2,2,7-trimethyl guanosine capping of the human telomerase RNA to direct telomerase dependent telomere maintenance.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {2302},
pmid = {35484160},
issn = {2041-1723},
mesh = {Guanosine ; Humans ; RNA/genetics ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {Pathways that direct the selection of the telomerase-dependent or recombination-based, alternative lengthening of telomere (ALT) maintenance pathway in cancer cells are poorly understood. Using human lung cancer cells and tumor organoids we show that formation of the 2,2,7-trimethylguanosine (TMG) cap structure at the human telomerase RNA 5' end by the Trimethylguanosine Synthase 1 (TGS1) is central for recruiting telomerase to telomeres and engaging Cajal bodies in telomere maintenance. TGS1 depletion or inhibition by the natural nucleoside sinefungin impairs telomerase recruitment to telomeres leading to Exonuclease 1 mediated generation of telomere 3' end protrusions that engage in RAD51-dependent, homology directed recombination and the activation of key features of the ALT pathway. This indicates a critical role for 2,2,7-TMG capping of the RNA component of human telomerase (hTR) in enforcing telomerase-dependent telomere maintenance to restrict the formation of telomeric substrates conductive to ALT. Our work introduces a targetable pathway of telomere maintenance that holds relevance for telomere-related diseases such as cancer and aging.},
}
@article {pmid35483787,
year = {2022},
author = {Ng, GY and Hande, V and Ong, MH and Wong, BW and Loh, ZW and Ho, WD and Handison, LB and Tan, IMP and Fann, DY and Arumugam, TV and Hande, MP},
title = {Effects of dietary interventions on telomere dynamics.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {876-877},
number = {},
pages = {503472},
doi = {10.1016/j.mrgentox.2022.503472},
pmid = {35483787},
issn = {1879-3592},
mesh = {*DNA Damage ; Diet ; Humans ; Prospective Studies ; *Telomere/genetics ; },
abstract = {Telomeres play a critical role in maintaining cellular fate through tight regulation of cell division and DNA damage or repair. Over the years, it is established that biological ageing is defined by a gradual derangement in functionality, productivity, and robustness of biological processes. The link between telomeres and ageing is highlighted when derangement in telomere biology often leads to premature ageing and concomitant accompaniment of numerous age-associated diseases. Unfortunately, given that ageing is a biologically complicated intricacy, measures to reduce morbidity and improve longevity are still largely in the infancy stage. Recently, it was discovered that dietary habits and interventions might play a role in promoting successful healthy ageing. The intricate relationship between dietary components and its potential to protect the integrity of telomeres may provide unprecedented health benefits and protection against age-related pathologies. However, more focused prospective and follow-up studies with and without interventions are needed to unequivocally link dietary interventions with telomere maintenance in humans. This review aims to summarise recent findings that investigate the roles of nutrition on telomere biology and provide enough evidence for further studies to consider the topic of nutrigenomics and its contributions toward healthy ageing and concomitant strategy against age-associated diseases.},
}
@article {pmid35477473,
year = {2022},
author = {Howell, MP and Jones, CW and Herman, CA and Mayne, CV and Fernandez, C and Theall, KP and Esteves, KC and Drury, SS},
title = {Impact of prenatal tobacco smoking on infant telomere length trajectory and ADHD symptoms at 18 months: a longitudinal cohort study.},
journal = {BMC medicine},
volume = {20},
number = {1},
pages = {153},
pmid = {35477473},
issn = {1741-7015},
support = {R01 MH101533/MH/NIMH NIH HHS/United States ; T32 HL007713/HL/NHLBI NIH HHS/United States ; },
mesh = {*Attention Deficit Disorder with Hyperactivity/epidemiology/etiology ; Child ; Child, Preschool ; Cohort Studies ; Female ; Humans ; Infant ; Longitudinal Studies ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Telomere ; Tobacco Smoking ; },
abstract = {BACKGROUND: Prenatal maternal tobacco smoking is a predictor of child attention-deficit/hyperactivity disorder (ADHD) and is associated with offspring telomere length (TL). In this study, we examine the relationship between maternal prenatal smoking, infant TL, and maternal report of early childhood symptoms of ADHD.<br><br>METHODS: One-hundred and eighty-one mother-infant dyads were followed prospectively for the infant's first 18&#x2009;months of life. Prenatal smoking was assessed from maternal report and medical records. TL was measured from infant buccal swab DNA obtained across the first 18&#x2009;months of life. ADHD symptoms were obtained from maternal report on the Child Behavior Check List. Multiple regression models tested the relation between prenatal smoking and both ADHD symptoms and infant TL. Additional analyses tested whether the change in infant TL influenced the relation between prenatal smoking and ADHD symptoms.<br><br>RESULTS: Sixteen percent of mothers reported prenatal smoking. Infant TL at 4, 12, and 18&#x2009;months of age were correlated. Consistent with previous cross-sectional studies linking shorter offspring TL to maternal prenatal smoking, maternal prenatal smoking predicted greater telomere shortening from four to 18&#x2009;months of infant age (&#x3b2;&#x2009;=&#x2009;-&#x2009;5.797, 95% CI [-10.207, -1.386]; p&#x2009;=&#x2009;0.010). Maternal depression was positively associated with both prenatal smoking (odds ratio (OR): 4.614, 95% CI [1.733, 12.282]; p&#x2009;=&#x2009;0.002) and child ADHD symptoms (&#x3b2;&#x2009;=&#x2009;4.713, 95% CI [2.073, 7.354]; p&#x2009;=&#x2009;0.0006). To prevent confounding, analyses examined the relation between TL, ADHD symptoms, and prenatal smoking only in non-depressed mothers. In non-depressed mothers, infant TL attrition across the first 18&#x2009;months moderated the relation between smoking and child ADHD.<br><br>CONCLUSIONS: The findings extend previous studies linking prenatal smoking to shorter infant TL by providing data demonstrating the effect on TL trajectory. The relation between prenatal smoking and early infant ADHD symptoms was moderated by the change in TL. The findings provide novel initial evidence suggesting that TL dynamics are one mechanistic pathway influencing the relation between maternal prenatal smoking and ADHD.},
}
@article {pmid35477117,
year = {2022},
author = {Niaz, A and Truong, J and Manoleras, A and Fox, LC and Blombery, P and Vasireddy, RS and Pickett, HA and Curtin, JA and Barbaro, PM and Rodgers, J and Roy, J and Riley, LG and Holien, JK and Cohen, SB and Bryan, TM},
title = {Functional interaction between compound heterozygous TERT mutations causes severe telomere biology disorder.},
journal = {Blood advances},
volume = {6},
number = {12},
pages = {3779-3791},
pmid = {35477117},
issn = {2473-9537},
mesh = {Biology ; Humans ; Mutation ; RNA/genetics ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {Telomere biology disorders (TBDs) are a spectrum of multisystem inherited disorders characterized by bone marrow failure, resulting from mutations in the genes encoding telomerase or other proteins involved in maintaining telomere length and integrity. Pathogenicity of variants in these genes can be hard to evaluate, because TBD mutations show highly variable penetrance and genetic anticipation related to inheritance of shorter telomeres with each generation. Thus, detailed functional analysis of newly identified variants is often essential. Herein, we describe a patient with compound heterozygous variants in the TERT gene, which encodes the catalytic subunit of telomerase, hTERT. This patient had the extremely severe Hoyeraal-Hreidarsson form of TBD, although his heterozygous parents were clinically unaffected. Molecular dynamic modeling and detailed biochemical analyses demonstrate that one allele (L557P) affects association of hTERT with its cognate RNA component hTR, whereas the other (K1050E) affects the binding of telomerase to its DNA substrate and enzyme processivity. Unexpectedly, the data demonstrate a functional interaction between the proteins encoded by the two alleles, with wild-type hTERT rescuing the effect of K1050E on processivity, whereas L557P hTERT does not. These data contribute to the mechanistic understanding of telomerase, indicating that RNA binding in one hTERT molecule affects the processivity of telomere addition by the other molecule. This work emphasizes the importance of functional characterization of TERT variants to reach a definitive molecular diagnosis for patients with TBD, and, in particular, it illustrates the importance of analyzing the effects of compound heterozygous variants in combination, to reveal interallelic effects.},
}
@article {pmid35472852,
year = {2022},
author = {Gentiluomo, M and Capurso, G and Morelli, L and Ermini, S and Pasquali, C and Latiano, A and Tavano, F and Greenhalf, W and Milanetto, AC and Landi, S and Roth, S and Malecka-Wojciesko, E and Costello, E and Jamroziak, K and Perri, F and Boggi, U and Basso, D and Farinati, F and Kaaks, R and Vanella, G and Gais Zurcher, AJ and Archibugi, L and Lawlor, RT and Canzian, F and Campa, D},
title = {Genetically Determined Telomere Length Is Associated with Pancreatic Neuroendocrine Neoplasms Onset.},
journal = {Neuroendocrinology},
volume = {112},
number = {12},
pages = {1168-1176},
doi = {10.1159/000524659},
pmid = {35472852},
issn = {1423-0194},
support = {MR/N003284/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; Genome-Wide Association Study ; Case-Control Studies ; Telomere/genetics ; Polymorphism, Single Nucleotide/genetics ; *Neoplasms ; *Pancreatic Neoplasms/genetics ; Acid Anhydride Hydrolases/genetics ; },
abstract = {INTRODUCTION: Telomere length (TL) is a potential indicator of cancer predisposition; however, the multitude of techniques used to measure it causes the results to be heterogeneous and, in some cases, controversial. In the last years, several studies adopted a strategy based on TL-associated genetic variants to generate a polygenic score, often referred as teloscore, used in lieu of direct TL measurement. For pancreatic neuroendocrine neoplasms (PanNEN), this strategy has not been attempted yet.<br><br>METHODS: A teloscore was generated using 11 SNPs (NAF1-rs7675998, ZNF676-rs409627, TERC-rs10936599, CTC1-rs3027234, PXK-rs6772228, DHX35-rs6028466, OBFC1-rs9420907, ZNF208-rs8105767, ACYP2-rs11125529, TERT-rs2736100, and ZBTB46-rs755017), and 291 PanNEN cases and 1,686 controls collected by the PANcreatic Disease ReseArch (PANDoRA) consortium were genotyped to analyse the association of the teloscore and its individual SNPs with the risk of developing PanNEN.<br><br>RESULTS: An association between genetically determined long telomeres and the risk of developing PanNEN (OR = 1.99, CI: 1.33-2.98, p = 0.0008) for highest versus median (third) quintile was observed. In addition, two novel SNPs associated with PanNEN risk were identified: ZNF676-rs409627 (ORC/C_vs_G/G = 2.27, CI: 1.58-3.27, p = 8.80 &#xd7; 10-6) and TERT-rs2736100 (ORC/A_vs_C/C = 2.03, CI: 1.42-2.91, p = 1.06 &#xd7; 10-4).<br><br>CONCLUSION: In conclusion, this study provides for the first time a clear indication of the association between long genetically determined telomeres and increased risk of developing PanNEN.},
}
@article {pmid35472831,
year = {2022},
author = {Yu, J and Mathi Kanchi, M and Rawtaer, I and Feng, L and Kumar, AP and Kua, EH and Mahendran, R and , },
title = {Differences between multimodal brain-age and chronological-age are linked to telomere shortening.},
journal = {Neurobiology of aging},
volume = {115},
number = {},
pages = {60-69},
pmid = {35472831},
issn = {1558-1497},
support = {U01 AG024904/AG/NIA NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; //CIHR/Canada ; },
mesh = {Aging/genetics/psychology ; Brain ; *Cognitive Dysfunction ; Humans ; Machine Learning ; Telomere/genetics ; *Telomere Shortening ; },
abstract = {Telomere shortening is theorized to accelerate biological aging, however, this has not been tested in the brain and cognitive contexts. We used machine learning age-prediction models to determine brain/cognitive age and quantified the degree of accelerated aging as the discrepancy between brain and/or cognitive and chronological ages (i.e., age gap). We hypothesized these age gaps are associated with telomere length (TL). Using healthy participants from the ADNI-3 cohort (N = 196, Agemean=70.7), we trained age-prediction models using 4 modalities of brain features and cognitive scores, as well as a 'stacked' model combining all brain modalities. Then, these 6 age-prediction models were applied to an independent sample diagnosed with mild cognitive impairment (N = 91, Agemean=71.3) to determine, for each subject, the model-specific predicted age and age gap. TL was most strongly associated with age gaps from the resting-state functional connectivity model after controlling for confounding variables. Overall, telomere shortening was significantly related to older brain but not cognitive age gaps. In particular, functional relative to structural brain-age gaps, were more strongly implicated in telomere shortening.},
}
@article {pmid35469505,
year = {2023},
author = {Yan, M and Cheng, S and Wang, S and Duan, X and Mensah, AR and Li, L and Zhang, Y and Li, G and Zhao, J and Feng, F and Zhou, X and Wu, Y and Yang, Y and Wang, W},
title = {Association of Genetic Polymorphisms of TERT with Telomere Length in Coke Oven Emissions-Exposed Workers.},
journal = {International journal of environmental health research},
volume = {33},
number = {11},
pages = {1059-1069},
doi = {10.1080/09603123.2022.2069687},
pmid = {35469505},
issn = {1369-1619},
mesh = {Humans ; *Coke/adverse effects ; Genotype ; *Occupational Exposure/adverse effects/analysis ; *Polycyclic Aromatic Hydrocarbons/analysis ; Polymorphism, Genetic ; *Telomerase/genetics ; Telomere/chemistry ; },
abstract = {We explored the association between variations in the telomere maintenance genes and change in telomere length (TL) in workers. The TL of peripheral blood leukocytes from 544 coke oven workers and 238 controls were detected using the Real-time PCR method. Variations in four genes were then detected using the PCR based restriction fragment length polymorphism. The effects of environmental and genetic factors on TL were subsequently analyzed through covariance analysis and a generalized linear model .The TL of subjects with GG genotypes were longer than those with AG genotype in the TERT rs2736098 locus amongst the controls (P = .032). The combined effect of COEs exposure and AG+AA genotypes had a significant effect on TL (P < .001). The interaction between the COEs exposure factor and the rs2736098AG+AA genotypes had a significant effect on the TL (P < .05). The TL in coke oven workers is associated with the interactions between TERT rs2736098 AG+AA and COEs exposure.},
}
@article {pmid35466826,
year = {2023},
author = {Rohr, P and Campanelli Dos Santos, I and van Helvoort Lengert, A and Alves de Lima, M and Manuel Reis, R and Barbosa, F and Cesar Santejo Silveira, H},
title = {Absolute telomere length in peripheral blood lymphocytes of workers exposed to construction environment.},
journal = {International journal of environmental health research},
volume = {33},
number = {10},
pages = {949-957},
doi = {10.1080/09603123.2022.2066069},
pmid = {35466826},
issn = {1369-1619},
mesh = {Male ; Humans ; *Arsenic/toxicity ; Lead/toxicity ; Environmental Exposure ; Lymphocytes ; Telomere ; },
abstract = {Construction environment is composed of various substances classified as carcinogens. Thus, workers exposed in this environment can be susceptible to genomic instability that can be evaluated by absolute telomere length (TL). In this work, we evaluated TL in construction workers compared to a non-exposed group performed by qPCR assay. The TL was evaluated in 59 men exposed to the construction environment (10 years of exposure) and 49 men non-exposed. Our data showed that individuals exposed to the construction environment exhibited a significantly lower TL in relation to non-exposed group (p = 0.009). Also, on the multiple linear regression model, we observed that TL was significantly influenced by the construction environment exposure (p ≤ 0.001). Additionally, the arsenic exposure is associated to a shortening telomere (p ≤ 0.001), and the lead exposure caused an increase in TL (p ≤ 0.001). Thus, our findings suggest a modulation in TL by construction environment exposure, mainly by arsenic and lead exposure.},
}
@article {pmid35464834,
year = {2022},
author = {Pérez-Martínez, L and Wagner, T and Luke, B},
title = {Telomere Interacting Proteins and TERRA Regulation.},
journal = {Frontiers in genetics},
volume = {13},
number = {},
pages = {872636},
pmid = {35464834},
issn = {1664-8021},
abstract = {Telomere shortening rates inversely correlate with life expectancy and hence it is critical to understand how telomere shortening is regulated. Recently, the telomeric non-coding RNA, TERRA has been implicated in the regulation of replicative senescence. To better understand how TERRA is regulated we employed a proteomics approach to look for potential RNA regulators that associate with telomeric sequences. Based on the results, we have identified proteins that may regulate TERRA in both a positive and negative manner, depending on the state of the telomere. In this mini-review, we discuss and speculate about these data to expand our understanding of TERRA and telomere interactors with respect to telomere shortening dynamics.},
}
@article {pmid35460626,
year = {2022},
author = {Phillippe, M},
title = {Telomeres, oxidative stress, and timing for spontaneous term and preterm labor.},
journal = {American journal of obstetrics and gynecology},
volume = {227},
number = {2},
pages = {148-162},
doi = {10.1016/j.ajog.2022.04.024},
pmid = {35460626},
issn = {1097-6868},
mesh = {Adult ; Female ; Humans ; Infant, Newborn ; *Obstetric Labor, Premature ; Oxidative Stress ; Pregnancy ; *Premature Birth/epidemiology ; Telomere ; Vitamins ; },
abstract = {Telomeres are nucleoprotein complexes located at the distal ends of chromosomes. In adults, progressive telomere shortening occurs throughout the lifetime and is thought to contribute to progressive aging, physiological senescence, multiorgan dysfunction, and ultimately, death. As discussed in this review, multiple lines of evidence provide support for the biological plausibility that a telomere-based clock mechanism also determines the length of gestation, leading to the onset of labor (parturition). After telomere expansion at the beginning of pregnancy, the telomere lengths in the gestational tissues (ie, the placenta and fetal membranes) progressively shorten throughout the remainder of pregnancy. The rate of telomere shortening can be accelerated by conditions that affect the mother and result in oxidative stress. Preterm births in the United States are associated with multiple risk factors that are linked with increased oxidative stress. Antioxidant vitamins (ie, vitamins E and C) mitigate the effects of oxidative stress and delay or prevent telomere shortening. Clinical trials with vitamins E and C and with multivitamins started during the periconception period have been associated with reduced rates of preterm births. In the United States, African-American women have a 2-3-fold higher rate of preterm birth. African-American women have multiple risk factors for premature birth, all of which are distinct and potentially additive with regard to epigenetic telomere shortening. The "weathering effect" is the hypothesis to explain the increased rates of chronic illness, disabilities, and early death observed in African-Americans. With regard to pregnancy, accelerated weathering with the associated telomere shortening in the gestational tissues would not only explain the preterm birth disparity but could also explain why highly educated, affluent African-American women continue to have an increased rate of preterm birth. These studies suggest that the racial disparities in preterm birth are potentially mediated by telomere shortening produced by lifetime or even generational exposure to the effects of systemic racism and socioeconomic marginalization. In conclusion, this review presents multiple lines of evidence supporting a novel hypothesis regarding the biological clock mechanism that determines the length of pregnancy, and it opens the possibility of new approaches to prevent or reduce the rate of spontaneous preterm birth.},
}
@article {pmid35460064,
year = {2022},
author = {Gao, X and Yu, X and Zhang, C and Wang, Y and Sun, Y and Sun, H and Zhang, H and Shi, Y and He, X},
title = {Telomeres and Mitochondrial Metabolism: Implications for Cellular Senescence and Age-related Diseases.},
journal = {Stem cell reviews and reports},
volume = {18},
number = {7},
pages = {2315-2327},
pmid = {35460064},
issn = {2629-3277},
mesh = {Adenosine Triphosphate/metabolism ; Aged ; Aging/genetics ; Animals ; Cellular Senescence/genetics ; Humans ; Mice ; Mitochondria/genetics/metabolism ; Reactive Oxygen Species/metabolism ; *Telomerase/metabolism ; Telomere/genetics/metabolism ; },
abstract = {Cellular senescence is an irreversible cell arrest process, which is determined by a variety of complicated mechanisms, including telomere attrition, mitochondrial dysfunction, metabolic disorders, loss of protein homeostasis, epigenetic changes, etc. Cellular senescence is causally related to the occurrence and development of age-related disease. The elderly is liable to suffer from disorders such as neurodegenerative diseases, cancer, and diabetes. Therefore, it is increasingly imperative to explore specific countermeasures for the treatment of age-related diseases. Numerous studies on humans and mice emphasize the significance of metabolic imbalance caused by short telomeres and mitochondrial damages in the onset of age-related diseases. Although the experimental data are relatively independent, more and more evidences have shown that there is mutual crosstalk between telomeres and mitochondrial metabolism in the process of cellular senescence. This review systematically discusses the relationship between telomere length, mitochondrial metabolic disorder, as well as their underlying mechanisms for cellular senescence and age-related diseases. Future studies on telomere and mitochondrial metabolism may shed light on potential therapeutic strategies for age-related diseases. Graphical Abstract The characteristics of cellular senescence mainly include mitochondrial dysfunction and telomere attrition. Mitochondrial dysfunction will cause mitochondrial metabolic disorders, including decreased ATP production, increased ROS production, as well as enhanced cellular apoptosis. While oxidative stress reaction to produce ROS, leads to DNA damage, and eventually influences telomere length. Under the stimulation of oxidative stress, telomerase catalytic subunit TERT mainly plays an inhibitory role on oxidative stress, reduces the production of ROS and protects telomere function. Concurrently, mitochondrial dysfunction and telomere attrition eventually induce a range of age-related diseases, such as T2DM, osteoporosis, AD, etc. :increase; :reduce;⟝:inhibition.},
}
@article {pmid35456510,
year = {2022},
author = {Boniewska-Bernacka, E and Pańczyszyn, A and Hobot, J and Donizy, P and Ziembik, Z and Goc, A and Klinger, M},
title = {The Length of Leukocyte and Femoral Artery Telomeres in Patients with Peripheral Atherosclerosis.},
journal = {Genes},
volume = {13},
number = {4},
pages = {},
pmid = {35456510},
issn = {2073-4425},
mesh = {*Atherosclerosis/genetics ; *Femoral Artery ; Humans ; Leukocytes ; Telomere/genetics ; },
abstract = {The length of telomeres (TLs) that protect chromosome ends may reflect the age of cells as well as the degree of genetic material damage caused by external factors. Since leukocyte telomere length is associated with cardiovascular diseases, the aim of this study was to evaluate whether leukocyte TL reflects femoral artery wall telomeres of patients with atherosclerosis and lower limb ischemia. Samples of femoral artery wall and blood were collected from 32 patients qualified to surgical revascularization. The analysis included blood and artery wall telomere length measurement and biochemical parameters. The study indicated that there was a moderate correlation between artery wall TL and leukocyte TL. Leukocyte TL was, on average, two times shorter than artery wall TL and correlated with the number of white blood cells. In turn, artery TL was impacted by total cholesterol level. The results suggest that the length of leukocyte telomeres may reflect artery wall TL and indirectly reflect the processes taking place in the artery wall in patients with atherosclerosis.},
}
@article {pmid35455044,
year = {2022},
author = {Takahashi, S and Bhowmik, S and Sato, S and Takenaka, S and Sugimoto, N},
title = {Replication Control of Human Telomere G-Quadruplex DNA by G-Quadruplex Ligands Dependent on Solution Environment.},
journal = {Life (Basel, Switzerland)},
volume = {12},
number = {4},
pages = {},
pmid = {35455044},
issn = {2075-1729},
support = {JP17H06351, 18KK0164, and 19K05723//Japan Society for the Promotion of Science/ ; },
abstract = {The human telomere region is known to contain guanine-rich repeats and form a guanine-quadruplex (G4) structure. As telomeres play a role in the regulation of cancer progression, ligands that specifically bind and stabilize G4 have potential therapeutic applications. However, as the human telomere sequence can form G4 with various topologies due to direct interaction by ligands and indirect interaction by the solution environment, it is of great interest to study the topology-dependent control of replication by ligands. In the present study, a DNA replication assay of a template with a human telomere G4 sequence in the presence of various ligands was performed. Cyclic naphthalene diimides (cNDI1 and cNDI2) efficiently increased the replication stall of the template DNA at G4 with an anti-parallel topology. This inhibition was stability-dependent and topology-selective, as the replication of templates with hybrid or parallel G4 structures was not affected by the cNDI and cNDI2. Moreover, the G4 ligand fisetin repressed replication with selectivity for anti-parallel and hybrid G4 structures without stabilization. Finally, the method used, referred to as quantitative study of topology-dependent replication (QSTR), was adopted to evaluate the correlation between the replication kinetics and the stability of G4. Compared to previous results obtained using a modified human telomere sequence, the relationship between the stability of G4 and the effect on the topology-dependent replication varied. Our results suggest that native human telomere G4 is more flexible than the modified sequence for interacting with ligands. These findings indicate that the modification of the human telomeric sequence forces G4 to rigidly form a specific structure of G4, which can restrict the change in topology-dependent replication by some ligands.},
}
@article {pmid35447111,
year = {2022},
author = {McGrath, SL and Huang, SH and Kobryn, K},
title = {The N-terminal domain of the Agrobacterium tumefaciens telomere resolvase, TelA, regulates its DNA cleavage and rejoining activities.},
journal = {The Journal of biological chemistry},
volume = {298},
number = {5},
pages = {101951},
pmid = {35447111},
issn = {1083-351X},
mesh = {*Agrobacterium tumefaciens/enzymology/genetics ; Bacterial Proteins/genetics/metabolism ; DNA/metabolism ; DNA Cleavage ; *Recombinases/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {Linear replicons can be found in a minority of prokaryotic organisms, including Borrelia species and Agrobacterium tumefaciens. The problem with replicating the lagging strand end of linear DNAs is circumvented in these organisms by the presence of covalently closed DNA hairpin telomeres at the DNA termini. Telomere resolvases are enzymes responsible for generating these hairpin telomeres from a dimeric replication intermediate through a two-step DNA cleavage and rejoining reaction referred to as telomere resolution. It was previously shown that the agrobacterial telomere resolvase, TelA, possesses ssDNA annealing activity in addition to telomere resolution activity. The annealing activity derives, chiefly, from the N-terminal domain. This domain is dispensable for telomere resolution. In this study, we used activity analyses of an N-terminal domain deletion mutant, domain add back experiments, and protein-protein interaction studies and we report that the N-terminal domain of TelA is involved in inhibitory interactions with the remainder of TelA that are relieved by the binding of divalent metal ions. We also found that the regulation of telomere resolution by the N-terminal domain of TelA extends to suppression of inappropriate enzymatic activity, including hairpin telomere fusion (reaction reversal) and recombination between replicated telomeres to form a Holliday junction.},
}
@article {pmid35446515,
year = {2022},
author = {Giha, HA and Joatar, FE and AlDehaini, DMB and Malalla, ZHA and Ali, ME and Al Qarni, AA},
title = {Association of obesity in T2DM with differential polymorphism of ghrelin, growth hormone secretagogue receptor-1 and telomeres maintenance genes.},
journal = {Hormone molecular biology and clinical investigation},
volume = {43},
number = {3},
pages = {297-306},
doi = {10.1515/hmbci-2021-0063},
pmid = {35446515},
issn = {1868-1891},
mesh = {Acid Anhydride Hydrolases/genetics ; Carrier Proteins ; Cross-Sectional Studies ; *Diabetes Mellitus, Type 2/complications/genetics ; Ghrelin/genetics ; Humans ; Obesity/complications/genetics ; Polymorphism, Single Nucleotide ; *Receptors, Ghrelin/genetics ; Telomere/genetics ; },
abstract = {BACKGROUND: Although obesity and T2DM comorbidity is too frequent, the molecular basis of diabetic obesity is largely unexplained and barely investigated.<br><br>MATERIALS: Cross-sectional studies were conducted in Kingdom of Saudi Arabia (KSA) in 2013 and Kuwait in 2019. Fasting blood samples were obtained from a total of 216 T2DM patients (104 from KSA) and 193 nondiabetic subjects (93 from KSA) after their consents. Eight SNPs in 5 genes known to be associated with both obesity and T2DM, ghrelin (GHRL) and growth hormone secretagogue receptor -GHSR (KSA) and telomeres maintenance genes (Kuwait) were genotyped by rtPCR. Both patients and controls were grouped into obese and non-obese and sub-grouped into 4-BMI- grades: normal, overweight (OW), obese (OBS) and severely obese (SOBS).<br><br>RESULTS: Showed that the only SNP which was distinguished between all groups/subgroups in all study subjects was the ACYP2 rs6713088G/C, where the common CC genotype was under-expressed in the obese compared to non-obese diabetics (17.8% vs. 40.4%, p 0.01) and between the 4-BMI-grade (p 0.025). Interestingly the same genotype was over-expressed in obese compared to non-obese non-diabetics (50% vs. 27.6%, p 0.04). Furthermore, the GHRL (rs27647C/T), GHSR (rs509030G/C) and TERC (rs12696304G/C) MAFs were significantly low in normal BMI patients; p=0.034, 0.008 and 0.011, respectively.<br><br>CONCLUSIONS: This is the first report about the molecular distinction between the obese and non-obese diabetics, it showed the association of rs6713088G/C mutant allele with diabetic obesity, while the GHRL, GHSR and TERC SNPs were differentially expressed based on the BMI-grades.},
}
@article {pmid35446379,
year = {2022},
author = {Wlodarski, MW},
title = {The rise of Apollo, protector of telomeres.},
journal = {Blood},
volume = {139},
number = {16},
pages = {2415-2416},
doi = {10.1182/blood.2021015199},
pmid = {35446379},
issn = {1528-0020},
mesh = {*Telomere/genetics ; *Telomere-Binding Proteins/genetics ; },
}
@article {pmid35444173,
year = {2022},
author = {Dempsey, PC and Musicha, C and Rowlands, AV and Davies, M and Khunti, K and Razieh, C and Timmins, I and Zaccardi, F and Codd, V and Nelson, CP and Yates, T and Samani, NJ},
title = {Investigation of a UK biobank cohort reveals causal associations of self-reported walking pace with telomere length.},
journal = {Communications biology},
volume = {5},
number = {1},
pages = {381},
pmid = {35444173},
issn = {2399-3642},
support = {MC_UU_12015/3/MRC_/Medical Research Council/United Kingdom ; /BHF_/British Heart Foundation/United Kingdom ; MC_UU_00006/4/MRC_/Medical Research Council/United Kingdom ; MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; /DH_/Department of Health/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {*Biological Specimen Banks ; Humans ; Self Report ; Telomere/genetics ; United Kingdom ; *Walking Speed ; },
abstract = {Walking pace is a simple and functional form of movement and a strong predictor of health status, but the nature of its association with leucocyte telomere length (LTL) is unclear. Here we investigate whether walking pace is associated with LTL, which is causally associated with several chronic diseases and has been proposed as a marker of biological age. Analyses were conducted in 405,981 UK Biobank participants. We show that steady/average and brisk walkers had significantly longer LTL compared with slow walkers, with accelerometer-assessed measures of physical activity further supporting this through an association between LTL and habitual activity intensity, but not with total amount of activity. Bi-directional mendelian randomisation analyses suggest a causal link between walking pace and LTL, but not the other way around. A faster walking pace may be causally associated with longer LTL, which could help explain some of the beneficial effects of brisk walking on health status. Given its simple measurement and low heritability, self-reported walking pace may be a pragmatic target for interventions.},
}
@article {pmid35443468,
year = {2022},
author = {KrishnaKuchipudi, GS and Prabhu, M},
title = {Study of Association of Leptin and Leucocyte Telomere Length with Body Mass Index in Adult Indian Population a One Year Cross Sectional Study.},
journal = {The Journal of the Association of Physicians of India},
volume = {70},
number = {4},
pages = {11-12},
pmid = {35443468},
issn = {0004-5772},
mesh = {Adult ; Aged ; Body Mass Index ; Cross-Sectional Studies ; Humans ; *Leptin ; Middle Aged ; *Obesity/epidemiology ; Telomere ; Waist Circumference ; Waist-Hip Ratio ; },
abstract = {UNLABELLED: Obesity is a leading preventable cause of death and a growing health problem worldwide with increasing rate in both adults and children. Obesity is an important factor causing accelerated aging and various metabolic syndromes. Leptin role as proinflammatory adipokine in obesity is well established. Telomere length acts as a biological clock and a marker for cellular senescence. This study is aimed to quantify leucocyte telomere length &amp; its association with biochemical and anthropometric surrogates of obesity.<br><br>MATERIAL: This cross-sectional study was conducted for a duration of 1yr on patients admitted in the wards or attending OPD, fulfilling the inclusion criteria. After a written informed consent and a thorough history, patient's anthropometric measurements were taken following all guidelines. Based on the values obtained the participants were divided into categories based on age and BMI. Blood samples are collected for the assessment of Leucocyte Telomere length through qPCR technique, Leptin through ELIZA method and HBA1c through HPLC method.<br><br>OBSERVATION: In our present study, a total of 90 patients were included. These patients are equally divided in age groups of 25-39yrs, 40-54yrs and >=55yrs of age. The mean age of the patients was 48.84&#xb1;16.84yrs. The patients were further categorized equally in each age group into normal, overweight and obese. The mean BMI of the study subjects was 24.20&#xb1;3.32 kg/m2. Age is found to have a negative correlation with telomere length (r=-0.205). A significant negative correlation of BMI with telomere length is observed (r=-0.20, p<0.05). No significant correlation between leptin with telomere length (r=0.092, p=0.386) or other anthropometric variables is observed. Waist circumference has a positive correlation with waist/hip ratio (r=0.281) (p=0.007), BMI (r=0.640), weight (r=0.677) and neck circumference(r=0.687). Whereas Telomere length has a negative correlation with waist circumference (r= -0.171), neck circumference (r=--0.2266) (p=0.0318) and positive correlation with waist/hip ratio (r=0.043). In our study a negative correlation was observed between waist/ height ratio and telomere length. Waist hip ratio had a positive correlation with BMI (r= 0.138) and telomere length (r=0.232).<br><br>CONCLUSION: Telomere length showed a negative correlation with all anthropometric measures except WHR which showed a positive correlation. Leptin did not show any association with telomere length or anthropometric measures in our study. Our study shows that WHR is a better marker of central obesity than BMI. The notion of metabolically healthy obese also holds true in our study results.},
}
@article {pmid35441417,
year = {2022},
author = {Lansdorp, PM},
title = {Sex differences in telomere length, lifespan, and embryonic dyskerin levels.},
journal = {Aging cell},
volume = {21},
number = {5},
pages = {e13614},
pmid = {35441417},
issn = {1474-9726},
support = {PJT-159787//CIHR/Canada ; },
mesh = {Cell Cycle Proteins/metabolism ; *Dyskeratosis Congenita/genetics/pathology ; Female ; Humans ; Infant, Newborn ; Longevity/genetics ; Male ; Nuclear Proteins/genetics/metabolism ; Sex Characteristics ; *Telomerase/genetics/metabolism ; Telomere/metabolism ; },
abstract = {Telomerase levels in most human cells are insufficient to prevent loss of telomeric DNA with each replication cycle. The resulting "Hayflick" limit may have allowed lifespan to increase by suppressing the development of tumors early in life be it at the expense of compromised cellular responses late in life. At any given age, the average telomere length in leukocytes shows considerably variation between individuals with females having, on average, longer telomeres than males. Sex differences in average telomere length are already present at birth and correspond to reported differences in the average life expectancy between the sexes. Levels of telomerase RNA and dyskerin, encoded by DKC1, are known to limit telomerase activity in embryonic stem cells. X-linked DKC1 is expressed from both alleles in female embryo cells and higher levels of dyskerin and telomerase could elongate telomeres prior to embryo implantation. The hypothesis that embryonic telomerase levels set the stage for the sex differences in telomere length and lifespan deserves further study.},
}
@article {pmid35440402,
year = {2022},
author = {Brenner, KA and Nandakumar, J},
title = {Consequences of telomere replication failure: the other end-replication problem.},
journal = {Trends in biochemical sciences},
volume = {47},
number = {6},
pages = {506-517},
pmid = {35440402},
issn = {0968-0004},
support = {R01 GM120094/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; DNA Repair ; DNA Replication ; Genomic Instability ; Mammals ; *Telomerase/genetics/metabolism ; *Telomere/genetics/metabolism ; Telomere Homeostasis ; },
abstract = {Telomeres are chromosome-capping structures that protect ends of the linear genome from DNA damage sensors. However, these structures present obstacles during DNA replication. Incomplete telomere replication accelerates telomere shortening and limits replicative lifespan. Therefore, continued proliferation under conditions of replication stress requires a means of telomere repair, particularly in the absence of telomerase. It was recently revealed that replication stress triggers break-induced replication (BIR) and mitotic DNA synthesis (MiDAS) at mammalian telomeres; however, these mechanisms are error prone and primarily utilized in tumorigenic contexts. In this review article, we discuss the consequences of replication stress at telomeres and how use of available repair pathways contributes to genomic instability. Current research suggests that fragile telomeres are ultimately tumor-suppressive and thus may be better left unrepaired.},
}
@article {pmid35433791,
year = {2022},
author = {Chen, W and Shi, S and Jiang, Y and Chen, L and Liao, Y and Chen, K and Huang, K},
title = {Association Between Riboflavin Intake and Telomere Length: A Cross-Sectional Study From National Health and Nutrition Examination Survey 1999-2002.},
journal = {Frontiers in nutrition},
volume = {9},
number = {},
pages = {744397},
pmid = {35433791},
issn = {2296-861X},
abstract = {BACKGROUND: Dietary habits and dietary intake affect telomere length, a reliable marker of biological aging and a predictor of chronic disease. Riboflavin (RF) is known as a water-soluble antioxidant vitamin, but its role in telomere length maintenance has yet to be elucidated.<br><br>OBJECTIVE: The purpose of this study was to examine the relationship between dietary RF intake and telomere length in a nationally representative sample of adults.<br><br>METHODS: Using the NHANES (1999-2002), telomere data of 4,298 participants aged &#x2265;45 years were analyzed in a cross-sectional manner. Leukocyte telomere length was measured using the quantitative real-time polymerase chain reaction (qPCR). Dietary RF intake was assessed by a trained interviewer using 24-h dietary recall method. Generalized linear regressions were performed to evaluate the association between dietary RF intake and telomere length. Subgroup analyses were performed to further explore this relationship in sex and body mass index (BMI) subgroups.<br><br>RESULTS: Among the 3,788 participants included, the average telomere length was longer in females (P = 0.014), while they had a lower average RF intake compared to males (P < 0.001). There was a weak positive correlation between RF intake and telomere length both when unadjusted (&#x3b2; = 0.011; P = 0.037) and adjusted for age, sex, and ethnicity (&#x3b2; = 0.013; P = 0.033). Subgroup analyses showed a positive association between RF intake and the telomere length in female after adjusting for confounding factors (&#x3b2; = 0.029; P = 0.046). In the female subgroup, there were significant positive relationships between telomere length and RF intake in the obese group (&#x3b2; = 0.086, P = 0.022).<br><br>CONCLUSION: Increased dietary RF intake was significantly associated with longer telomere length in middle-aged and older American females, especially in low RF intake obese female.},
}
@article {pmid35427669,
year = {2022},
author = {Takahashi, T and Eguchi, A and Watanabe, M and Todaka, E and Sakurai, K and Mori, C},
title = {Association between telomere length in human umbilical cord tissues and polychlorinated biphenyls in maternal and cord serum.},
journal = {Chemosphere},
volume = {300},
number = {},
pages = {134560},
doi = {10.1016/j.chemosphere.2022.134560},
pmid = {35427669},
issn = {1879-1298},
mesh = {Cohort Studies ; *Environmental Pollutants/analysis ; Female ; Fetal Blood/chemistry ; Humans ; Infant, Newborn ; Male ; Maternal Exposure/adverse effects ; *Polychlorinated Biphenyls/analysis ; Pregnancy ; Telomere ; Umbilical Cord ; },
abstract = {Environmental exposure to persistent organic pollutants during pregnancy has potential adverse health effects on the fetus. One of the environmental pollutants is polychlorinated biphenyl (PCB). Earlier, we reported the presence of PCBs in fetal tissues such as the umbilical cord. Telomere length (TL) is a biomarker of aging because it shortens with each cell division. According to the Developmental Origins of Health and Disease hypothesis, fetal exposure to environmental pollutants during pregnancy affects the occurrence of non-communicable diseases in later life. In the current study, we investigated the association between cord tissue TL and serum levels of PCBs. The subjects were 114 mother-child pairs participating in a birth cohort study, the Chiba Study of Mother and Child Health (C-MACH). Maternal serum was collected during pregnancy, and cord serum and tissue were obtained at birth. TL was assessed by qPCR using genomic DNA extracted from the cord tissue. Maternal and cord serum PCB congener levels were assessed using gas chromatography and negative ion chemical ionization qMS. In male fetuses, serum levels of PCB74 in the cord blood were significantly associated with TL following covariate adjustment, but no significant association was found in female fetuses. These data suggest that the TL of the umbilical cord is affected by fetal exposure to PCBs.},
}
@article {pmid35426375,
year = {2022},
author = {Muralidharan, A and Sotocinal, SG and Yousefpour, N and Akkurt, N and Lima, LV and Tansley, S and Parisien, M and Wang, C and Austin, JS and Ham, B and Dutra, GM and Rousseau, P and Maldonado-Bouchard, S and Clark, T and Rosen, SF and Majeed, MR and Silva, O and Nejade, R and Li, X and Donayre Pimentel, S and Nielsen, CS and Neely, GG and Autexier, C and Diatchenko, L and Ribeiro-da-Silva, A and Mogil, JS},
title = {Long-term male-specific chronic pain via telomere- and p53‑mediated spinal cord cellular senescence.},
journal = {The Journal of clinical investigation},
volume = {132},
number = {8},
pages = {},
pmid = {35426375},
issn = {1558-8238},
support = {//CIHR/Canada ; },
mesh = {Animals ; Cellular Senescence ; *Chronic Pain/genetics/metabolism ; Female ; Hyperalgesia/metabolism ; Male ; Mice ; Microglia/metabolism ; *Neuralgia/genetics/metabolism ; Spinal Cord/metabolism ; Telomere/genetics/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; },
abstract = {Mice with experimental nerve damage can display long‑lasting neuropathic pain behavior. We show here that 4 months and later after nerve injury, male but not female mice displayed telomere length (TL) reduction and p53‑mediated cellular senescence in the spinal cord, resulting in maintenance of pain and associated with decreased lifespan. Nerve injury increased the number of p53‑positive spinal cord neurons, astrocytes, and microglia, but only in microglia was the increase male‑specific, matching a robust sex specificity of TL reduction in this cell type, which has been previously implicated in male‑specific pain processing. Pain hypersensitivity was reversed by repeated intrathecal administration of a p53‑specific senolytic peptide, only in male mice and only many months after injury. Analysis of UK Biobank data revealed sex-specific relevance of this pathway in humans, featuring male‑specific genetic association of the human p53 locus (TP53) with chronic pain and a male-specific effect of chronic pain on mortality. Our findings demonstrate the existence of a biological mechanism maintaining pain behavior, at least in males, occurring much later than the time span of virtually all extant preclinical studies.},
}
@article {pmid35425228,
year = {2022},
author = {S M N Mydin, RB and Sreekantan, S and Widera, D and Saharudin, KA and Hazan, R and Farid Wajidi, MF},
title = {Genome-nanosurface interaction of titania nanotube arrays: evaluation of telomere, telomerase and NF-κB activities on an epithelial cell model.},
journal = {RSC advances},
volume = {12},
number = {4},
pages = {2237-2245},
pmid = {35425228},
issn = {2046-2069},
abstract = {Titanium dioxide nanotube arrays (TNAs) provide a promising platform for medical implants and nanomedicine applications. The present cell-TNA study has provided profound understanding on protection of genome integrity via telomere, telomerase and NF-κB activities using an epithelial cell model. It has been revealed in this study that cell-TNA interaction triggers the telomere shortening activity and inhibition of telomerase activity at the mRNA and protein level. The present work supported that the cell-TNA stimulus might involve controlled transcription and proliferative activities via NBN and TERF21P mechanisms. Moreover, inhibition of NF-κB may promote molecular sensitivity via senescence-associated secretory phenotype activities and might result in reduced inflammatory response which would be good for cell and nanosurface adaptation activities. Thus, this nanomaterial-molecular knowledge is beneficial for further nanomaterial characterization and advanced medical application.},
}
@article {pmid35422196,
year = {2023},
author = {Zhang, X and Cheng, S and Li, Z and Gu, H and Jiang, Y and Li, H and Meng, X and Wang, Y},
title = {Telomere length and stroke recurrence after ischemic stroke and TIA.},
journal = {International journal of stroke : official journal of the International Stroke Society},
volume = {18},
number = {2},
pages = {208-214},
doi = {10.1177/17474930221096552},
pmid = {35422196},
issn = {1747-4949},
mesh = {Humans ; Aged ; *Stroke/epidemiology/genetics/complications ; *Ischemic Attack, Transient/epidemiology/genetics/complications ; *Ischemic Stroke/complications ; Risk Factors ; Telomere ; Recurrence ; },
abstract = {BACKGROUND AND OBJECTIVE: Shortening telomere length (TL), as an indicator of aging, has been associated with increased risk of cardiovascular disease and incident stroke. However, there are limited data relating to the association between TL and recurrent stroke.<br><br>METHODS: Patients from the Third China National Stroke Registry who had whole genome sequencing (WGS) were selected. TL was estimated using TelSeq based on binary sequence alignment/map files derived from WGS data. Cox proportional hazards regression models were performed to assess the association of TL with recurrent stroke.<br><br>RESULTS: A total of 8041 patients with ischemic stroke (IS) or transient ischemic attack (TIA) were included. Mean TL was 2.14&#x2009;&#xb1;&#x2009;0.82&#x2009;kb. Patients in the lowest tertile of TL had higher incidence of stroke recurrence compared to those in the middle and highest tertile (6.4% vs 5.9% vs 5.2%), but the difference was not longer significant after adjusting for age, sex, cardiovascular risk factors and stroke severity. Similarly, when analyzing TL as a continuous variable, the HR per 1000&#x2009;bp increase in TL was significant 0.88 (0.79-0.98), but after adjusting for co-variates, was no longer significant (0.91; 95% confidence interval (CI), 0.81-1.02). In patients aged&#x2009;>&#x2009;65&#x2009;years, but not in younger patients, after adjusting for co-variates, TL was significantly associated with stroke recurrence. Compared to the lowest tertile, HRs (95% CI) after adjustment for all co-variates for the middle and highest tertiles were 0.78 (0.55-1.10) and 0.67 (0.46-0.98), respectively, with p for trend of 0.03. In analyses using TL as a continuous variable, adjusted HR (95% CI) per 1000&#x2009;bp increase in TL was 0.80 (0.66-0.96). However, there was no significant interaction between TL and age on risk of stroke recurrence (p for interaction&#x2009;=&#x2009;0.09).<br><br>CONCLUSIONS: In Chinese IS or TIA patients, no independent association was found between TL and risk of stroke recurrence after adjusting for co-variates. We found a possible association in older patients but this needs replicating.},
}
@article {pmid35421215,
year = {2022},
author = {Choo, S and Lorbeer, FK and Regalado, SG and Short, SB and Wu, S and Rieser, G and Bertuch, AA and Hockemeyer, D},
title = {Editing TINF2 as a potential therapeutic approach to restore telomere length in dyskeratosis congenita.},
journal = {Blood},
volume = {140},
number = {6},
pages = {608-618},
pmid = {35421215},
issn = {1528-0020},
support = {R01 CA196884/CA/NCI NIH HHS/United States ; R01 HL131744/HL/NHLBI NIH HHS/United States ; },
mesh = {*Dyskeratosis Congenita/genetics/therapy ; Humans ; Mutation ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; Telomere Shortening/genetics ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Mutations in the TINF2 gene, encoding the shelterin protein TIN2, cause telomere shortening and the inherited bone marrow (BM) failure syndrome dyskeratosis congenita (DC). A lack of suitable model systems limits the mechanistic understanding of telomere shortening in the stem cells and thus hinders the development of treatment options for BM failure. Here, we endogenously introduced TIN2-DC mutations in human embryonic stem cells (hESCs) and human hematopoietic stem and progenitor cells (HSPCs) to dissect the disease mechanism and identify a gene-editing strategy that rescued the disease phenotypes. The hESCs with the T284R disease mutation exhibited the short telomere phenotype observed in DC patients. Yet, telomeres in mutant hESCs did not trigger DNA damage responses at telomeres or show exacerbated telomere shortening when differentiated into telomerase-negative cells. Disruption of the mutant TINF2 allele by introducing a frameshift mutation in exon 2 restored telomere length in stem cells and the replicative potential of differentiated cells. Similarly, we introduced TIN2-DC disease variants in human HSPCs to assess the changes in telomere length and proliferative capacity. Lastly, we showed that editing at exon 2 of TINF2 that restored telomere length in hESCs could be generated in TINF2-DC patient HSPCs. Our study demonstrates a simple genetic intervention that rescues the TIN2-DC disease phenotype in stem cells and provides a versatile platform to assess the efficacy of potential therapeutic approaches in vivo.},
}
@article {pmid35420632,
year = {2022},
author = {Kelich, J and Aramburu, T and van der Vis, JJ and Showe, L and Kossenkov, A and van der Smagt, J and Massink, M and Schoemaker, A and Hennekam, E and Veltkamp, M and van Moorsel, CHM and Skordalakes, E},
title = {Telomere dysfunction implicates POT1 in patients with idiopathic pulmonary fibrosis.},
journal = {The Journal of experimental medicine},
volume = {219},
number = {5},
pages = {},
pmid = {35420632},
issn = {1540-9538},
support = {R01 CA201312/CA/NCI NIH HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; R50 CA211199/CA/NCI NIH HHS/United States ; T32 CA009171/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; *Idiopathic Pulmonary Fibrosis/genetics ; Shelterin Complex ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; Telomere-Binding Proteins/genetics ; },
abstract = {Exonic sequencing identified a family with idiopathic pulmonary fibrosis (IPF) containing a previously unreported heterozygous mutation in POT1 p.(L259S). The family displays short telomeres and genetic anticipation. We found that POT1(L259S) is defective in binding the telomeric overhang, nuclear accumulation, negative regulation of telomerase, and lagging strand maintenance. Patient cells containing the mutation display telomere loss, lagging strand defects, telomere-induced DNA damage, and premature senescence with G1 arrest. Our data suggest POT1(L259S) is a pathogenic driver of IPF and provide insights into gene therapy options.},
}
@article {pmid35419815,
year = {2022},
author = {Hoffman, TW and van der Vis, JJ and Biesma, DH and Grutters, JC and van Moorsel, CHM},
title = {Extrapulmonary manifestations of a telomere syndrome in patients with idiopathic pulmonary fibrosis are associated with decreased survival.},
journal = {Respirology (Carlton, Vic.)},
volume = {27},
number = {11},
pages = {959-965},
doi = {10.1111/resp.14264},
pmid = {35419815},
issn = {1440-1843},
mesh = {Cohort Studies ; Humans ; *Idiopathic Pulmonary Fibrosis/genetics ; Retrospective Studies ; Telomere/genetics ; Telomere Shortening/genetics ; },
abstract = {BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a heterogenous disease with a median survival of 3-4 years. Patients with mutations in telomere-related genes exhibit extrapulmonary signs and symptoms. These patients represent a distinct phenotype of IPF with worse survival. As genetic analyses are not available for most patients with IPF, we sought to determine the predictive value of extrapulmonary signs and symptoms of a telomere syndrome in patients with IPF.<br><br>METHODS: We retrospectively studied 409 patients with IPF. Clinical characteristics, laboratory results and family history suggestive of a telomere syndrome were related to leukocyte telomere length measured by quantitative PCR and patient outcomes.<br><br>RESULTS: The cohort included 293 patients with sporadic IPF and 116 patients with a background of familial pulmonary fibrosis. Any or a combination of a clinical history (haematological disease, liver disease, early greying of hair, nail dystrophy, skin abnormalities), a family history or haematological laboratory abnormalities (macrocytosis, anaemia, thrombopenia or leukopenia) suggestive of a telomere syndrome was present in 27% of IPF patients and associated with shorter leukocyte telomere length and shorter survival (p&#x2009;=&#x2009;0.002 in a multivariate model). In sporadic IPF, having either a clinical history, family history or haematological laboratory abnormalities was not significantly associated with decreased survival (p&#x2009;=&#x2009;0.07 in a multivariate model).<br><br>CONCLUSION: Taking a careful clinical and family history focused on extrapulmonary manifestations of a telomere syndrome can provide important prognostic information in patients with IPF, as this is associated with shorter survival.},
}
@article {pmid35418675,
year = {2022},
author = {Liu, B and He, Y and Wang, Y and Song, H and Zhou, ZH and Feigon, J},
title = {Structure of active human telomerase with telomere shelterin protein TPP1.},
journal = {Nature},
volume = {604},
number = {7906},
pages = {578-583},
pmid = {35418675},
issn = {1476-4687},
support = {1S10 OD018111/NH/NIH HHS/United States ; 1S10 RR23057/NH/NIH HHS/United States ; R35 GM131901/GM/NIGMS NIH HHS/United States ; S10 OD018111/OD/NIH HHS/United States ; S10 RR023057/RR/NCRR NIH HHS/United States ; U24 GM116792/GM/NIGMS NIH HHS/United States ; R01 GM071940/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites ; Cryoelectron Microscopy ; Humans ; Protein Binding ; *Shelterin Complex/ultrastructure ; Tartrate-Resistant Acid Phosphatase ; *Telomerase/ultrastructure ; Telomere/genetics/metabolism ; *Telomere-Binding Proteins/metabolism/ultrastructure ; },
abstract = {Human telomerase is a RNA-protein complex that extends the 3' end of linear chromosomes by synthesizing multiple copies of the telomeric repeat TTAGGG[1]. Its activity is a determinant of cancer progression, stem cell renewal and cellular aging[2-5]. Telomerase is recruited to telomeres and activated for telomere repeat synthesis by the telomere shelterin protein TPP1[6,7]. Human telomerase has a bilobal structure with a catalytic core ribonuclear protein and a H and ACA box ribonuclear protein[8,9]. Here we report cryo-electron microscopy structures of human telomerase catalytic core of telomerase reverse transcriptase (TERT) and telomerase RNA (TER (also known as hTR)), and of telomerase with the shelterin protein TPP1. TPP1 forms a structured interface with the TERT-unique telomerase essential N-terminal domain (TEN) and the telomerase RAP motif (TRAP) that are unique to TERT, and conformational dynamics of TEN-TRAP are damped upon TPP1 binding, defining the requirements for recruitment and activation. The structures further reveal that the elements of TERT and TER that are involved in template and telomeric DNA handling-including the TEN domain and the TRAP-thumb helix channel-are largely structurally homologous to those in Tetrahymena telomerase[10], and provide unique insights into the mechanism of telomerase activity. The binding site of the telomerase inhibitor BIBR1532[11,12] overlaps a critical interaction between the TER pseudoknot and the TERT thumb domain. Numerous mutations leading to telomeropathies[13,14] are located at the TERT-TER and TEN-TRAP-TPP1 interfaces, highlighting the importance of TER-TERT and TPP1 interactions for telomerase activity, recruitment and as drug targets.},
}
@article {pmid35418123,
year = {2022},
author = {Sehl, ME and Henry, JE and Storniolo, AM and Horvath, S and Ganz, PA},
title = {The impact of reproductive factors on DNA methylation-based telomere length in healthy breast tissue.},
journal = {NPJ breast cancer},
volume = {8},
number = {1},
pages = {48},
pmid = {35418123},
issn = {2374-4677},
abstract = {Estrogen promotes breast tissue proliferation and telomerase activation. We investigated the effects of reproductive history on cell cycling and telomere length using a DNA methylation-based estimate of telomere length (DNAmTL) in breast and blood from healthy women donors. We demonstrate that DNAmTL is shorter in breast than in blood, and that nulliparous women have longer age-adjusted DNAmTL in both breast and blood, potentially explaining their higher risk of breast cancer.},
}
@article {pmid35416741,
year = {2022},
author = {Korkiakoski, A and Käräjämäki, AJ and Ronkainen, J and Auvinen, J and Hannuksela, J and Kesäniemi, YA and Ukkola, O},
title = {Nonalcoholic fatty liver disease and its prognosis associates with shorter leucocyte telomeres in a 21-year follow-up study.},
journal = {Scandinavian journal of clinical and laboratory investigation},
volume = {82},
number = {3},
pages = {173-180},
doi = {10.1080/00365513.2022.2059698},
pmid = {35416741},
issn = {1502-7686},
mesh = {Follow-Up Studies ; Humans ; Leukocytes ; Middle Aged ; *Non-alcoholic Fatty Liver Disease/diagnosis/genetics ; Prognosis ; Telomere/genetics ; },
abstract = {Leucocyte telomere length (LTL) has been associated with nonalcoholic fatty liver disease (NAFLD), but the evidence is imperfect. Furthermore, liver fibrosis has been shown to correlate with mortality and recent studies have also found associations with LTL and fibrosis suggesting that LTL may have additional prognostic value in liver diseases. Our objective was to study the association of LTL and NAFLD and evaluate the association of LTL in prognosis of NAFLD subjects. Study subjects (n = 847) were middle-aged hypertensive patients. All participants were evaluated for NAFLD and their LTL was measured at baseline. Outcomes were obtained from Finnish Causes-of-Death Register and the Care Register for Health Care in Statistics Finland to the end of 2014. An inverse association with NAFLD prevalence and LTL length was observed (p < .001 for trend). Shortest telomere tertile possessed statistically significantly more NAFLD subjects even with multivariate analysis (shortest vs. middle tertile HR 1.98 p = .006 and shortest vs. longest tertile HR 2.03 p = .007). For the study period, mortality of the study group showed statistically significant relation with telomere length in univariate but not for multivariate analysis. In subgroup analysis, LTL did not associate with prognosis of non-NAFLD subjects. However, LTL was inversely associated with overall mortality in the subjects with NAFLD in both univariate (HR 0.16 p = .007) and multivariate analysis (HR 0.20 p = .045). In middle-aged Caucasian cohort, shorter leucocyte telomeres associated independently with increased prevalence of NAFLD. Shorter LTL was not associated with mortality in non-NAFLD patients whereas it predicted mortality of NAFLD patients independently.},
}
@article {pmid35414715,
year = {2022},
author = {Yamakawa, K and Mukai, Y and Ye, J and Muto-Ishizuka, M and Ito, M and Tanimoto, M and Suizu, F and Asano, K and Kurose, A and Matsuda, Y},
title = {Telomere length was associated with grade and pathological features of meningioma.},
journal = {Scientific reports},
volume = {12},
number = {1},
pages = {6143},
pmid = {35414715},
issn = {2045-2322},
mesh = {Chromosomal Instability ; Humans ; In Situ Hybridization, Fluorescence ; Ki-67 Antigen/genetics ; *Meningeal Neoplasms/genetics/pathology ; *Meningioma/genetics/pathology ; Telomere/genetics/pathology ; },
abstract = {Telomeres are tandem repeats of the TTAGGG sequence at chromosomal ends and afford protection against chromosomal instability. To investigate the contribution of telomere dysfunction in meningiomas, here we estimate the associations between telomere length, tumor grade, and proliferation index in a series of 14 archived samples, using quantitative-fluorescence in situ hybridization, Ki67 immunostaining, and pathological analysis. The number of mitoses per 10 high-power fields (HPF) and Ki67 index was higher in grade III cases than in grade I or grade II cases. Telomere length was negatively associated with both the number of mitoses/10HPF and Ki67 index. Meningioma cases with atypical mitosis, a morphological marker of chromosomal instability, exhibited shortened telomeres. Among telomere-shortened meningioma cases, 40% were grade I, 20% were grade II, and 100% were grade III. In grade I or II meningiomas, shortened telomeres lacked high proliferation activity and atypical mitosis. In conclusion, telomere shortening might be pivotal in the development of high-grade meningioma. Analysis of telomere length might be a selective marker for meningiomas with high-grade malignant potential.},
}
@article {pmid35411811,
year = {2022},
author = {Ito, T and Saeki, H and Guo, X and Sysa-Shah, P and Tamashiro, KL and Lee, RS and Ishiyama, S and Orita, H and Sato, K and Brock, MV and Gabrielson, K},
title = {Prenatal stress enhances atherosclerosis and telomere shortening in ApoE knockout mouse offspring.},
journal = {American journal of physiology. Regulatory, integrative and comparative physiology},
volume = {323},
number = {1},
pages = {R68-R80},
doi = {10.1152/ajpregu.00201.2021},
pmid = {35411811},
issn = {1522-1490},
mesh = {Animals ; Aorta ; Apolipoproteins E/genetics ; *Atherosclerosis/genetics/pathology ; Female ; Humans ; Mice ; Mice, Knockout ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Stress, Psychological ; Telomere Shortening ; },
abstract = {Children born to women who experience stress during pregnancy have an increased risk of atherosclerosis in later life, but few animal models have explored mechanisms. To study this phenomenon, timed-bred ApoE knockout mice were determined pregnant with ultrasound and randomly assigned on gestation day 8.5 to either a control (no stress) or prenatal stress (PS) group using 2 h of restraint for five consecutive days. PS significantly increased plasma corticosterone levels in pregnant mice. The litters from PS mice showed increased neonatal mortality within the first week of life. Body weights (at euthanasia) of adult offspring at 25 wk from the PS group were significantly increased compared with weights of controls. Adult offspring from these pregnancies were serially imaged with ultrasound to measure plaque thickness and were compared with plaque macroscopic and microscopic pathology. PS groups had increased plaque thickness determined by ultrasound, gross, histological evaluation and increased aortic root and valve macrophage infiltration at 25 wk. Five-week-old mice from PS group had significant decrease in mean arterial pressure, yet blood pressure normalized by 10 wk. As prenatal stress induced increased atherosclerosis, and telomeres are susceptible to stress, aortas from 10-wk-old mice were compared for telomere lengths and were found to be significantly shorter in PS mice compared with control mice. These studies support future investigation of how stress impacts telomere shortening in animal models and human aortas. This model could be further used to investigate the role of prenatal stress, telomere biology, and atherosclerosis pathogenesis in adults.},
}
@article {pmid35411518,
year = {2022},
author = {Song, L and Wu, M and Wang, L and Bi, J and Cao, Z and Xu, S and Tian, Y and Xiong, C and Wang, Y},
title = {Ambient ozone exposure during pregnancy and telomere length in newborns: a prospective investigation in Wuhan, China.},
journal = {Environmental science and pollution research international},
volume = {29},
number = {41},
pages = {62662-62668},
pmid = {35411518},
issn = {1614-7499},
support = {82003479//National Natural Science Foundation of China/ ; 82073660//National Natural Science Foundation of China/ ; 2019M662646//China Postdoctoral Science Foundation/ ; 2020T130220//China Postdoctoral Science Foundation/ ; },
mesh = {China ; Cohort Studies ; Female ; Humans ; Infant, Newborn ; *Maternal Exposure ; *Ozone ; Pregnancy ; Prospective Studies ; Telomere ; },
abstract = {Recent studies suggest that environmental exposures, including air pollution, may influence initial (newborn) telomere length (TL), which has important implications for lifetime health. However, the effect of prenatal ozone exposure on newborn TL is unclear. This study aimed to examine the association of ozone exposure during pregnancy with newborn TL. We used data from a birth cohort study of 762 mother-newborn pairs performed in Wuhan, China, during 2013-2015. Land-use regression models were used to assess prenatal ozone exposure. Newborn TL was quantified in cord blood by qPCR assay. We applied multiple informant model to explore the relationship of prenatal ozone exposure with newborn TL. After adjustment for potential confounders, an interquartile range (IQR) increase in ozone exposure during the 2nd trimester, 3rd trimester, and whole pregnancy were associated with 6.00% (95% confidence interval [CI]: 1.59%, 10.62%), 12.64% (95% CI: 7.52%, 18.00%), and 7.10% (95% CI: 4.09%, 10.20%) longer cord blood TL, respectively. In contrast, an IQR increase in ozone exposure during the 1st trimester was associated with a 8.39% (95% CI: - 12.90%, - 3.65%) shorter cord blood TL. In multipollutant models, consistent associations were observed between ozone exposures during the 2nd trimester and whole pregnancy and cord blood TL, but not significant for the 1st and 3rd trimesters. In conclusion, our findings suggest positive associations of ozone exposure during the 2nd trimester, 3rd trimester, and whole pregnancy with newborn TL and a negative association during the 1st trimester. This study provides new evidence in humans for a potential "programming" mechanism linking maternal ozone exposure to the initial (newborn) setting of offspring's telomere biology.},
}
@article {pmid35410445,
year = {2022},
author = {Franzoni, LT and Garcia, EL and Motta, SB and Ahner, MM and Bertoletti, OA and Saffi, MAL and da Silveira, AD and Pereira, AA and Pereira, AH and Danzmann, LC and Stein, R},
title = {Aerobic exercise and telomere length in patients with systolic heart failure: protocol study for a randomized controlled trial.},
journal = {Trials},
volume = {23},
number = {1},
pages = {283},
pmid = {35410445},
issn = {1745-6215},
support = {180651//Hospital de Cl&#xed;nicas de Porto Alegre/ ; },
mesh = {Aged ; Aged, 80 and over ; Exercise/physiology ; Exercise Therapy/methods ; Female ; *Heart Failure/diagnosis/genetics/therapy ; *Heart Failure, Systolic ; Humans ; Male ; Middle Aged ; Quality of Life ; Randomized Controlled Trials as Topic ; Stroke Volume/physiology ; Telomere ; },
abstract = {BACKGROUND: Heart failure (HF) with reduced ejection fraction (HFrEF) is a syndrome that leads to fatigue and reduced functional capacity due to disease-related pathophysiological mechanisms. Aerobic exercise (AERO) plays a key role in improving HF outcomes, such as an increase in peak oxygen uptake (VO2peak). In addition, HF promotes cell senescence, which involves reducing telomere length. Several studies have shown that patients with a worse prognosis (i.e., reduced VO2 peak) also have shorter telomeres. However, the effects of AERO on telomere length in patients with HFrEF are still unknown. In an attempt to fill this gap, we designed a study to determine the effects of 16 weeks of aerobic training (32 sessions) on telomere length in HFrEF patients.<br><br>METHODS: In this single-center randomized controlled trial, men and women between 50 and 80&#x2009;years old will be allocated into two different groups: a moderate-intensity aerobic training and a control grouTelomere length, functional capacity, echocardiographic variables, endothelial function, and walking ability will be assessed before and after the 16-week intervention period.<br><br>DISCUSSION: Understanding the role of physical exercise in biological aging in HFrEF patients is relevant. Due to cell senescence, these individuals have shown a shorter telomere length. AERO can delay biological aging according to a balance in oxidative stress through antioxidant action. Positive telomere length results are expected for the aerobic training group.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT03856736 . Registered on February 27, 2019.},
}
@article {pmid35409143,
year = {2022},
author = {Vertecchi, E and Rizzo, A and Salvati, E},
title = {Telomere Targeting Approaches in Cancer: Beyond Length Maintenance.},
journal = {International journal of molecular sciences},
volume = {23},
number = {7},
pages = {},
pmid = {35409143},
issn = {1422-0067},
support = {17121//Italian Association for Cancer Research/ ; },
mesh = {Cellular Senescence ; DNA/metabolism ; DNA Damage ; Humans ; *Neoplasms/drug therapy/genetics ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; Telomere Homeostasis ; },
abstract = {Telomeres are crucial structures that preserve genome stability. Their progressive erosion over numerous DNA duplications determines the senescence of cells and organisms. As telomere length homeostasis is critical for cancer development, nowadays, telomere maintenance mechanisms are established targets in cancer treatment. Besides telomere elongation, telomere dysfunction impinges on intracellular signaling pathways, in particular DNA damage signaling and repair, affecting cancer cell survival and proliferation. This review summarizes and discusses recent findings in anticancer drug development targeting different "telosome" components.},
}
@article {pmid35407431,
year = {2022},
author = {Yu, TN and Cheng, EH and Tsai, HN and Lin, PY and Chen, CH and Huang, CC and Lee, TH and Lee, MS},
title = {Assessment of Telomere Length and Mitochondrial DNA Copy Number in Granulosa Cells as Predictors of Aneuploidy Rate in Young Patients.},
journal = {Journal of clinical medicine},
volume = {11},
number = {7},
pages = {},
pmid = {35407431},
issn = {2077-0383},
abstract = {Background: To identify the correlation among female age, cellular aging markers, and aneuploidy rate in in vitro fertilization (IVF) and the preimplantation genetic test for aneuploidy (PGT-A) cycles. Methods: This is a prospective cohort study recruiting 110 infertile women between August 2017 and July 2018. They were divided into young-age (<38 years, n = 60) and advanced-age (≥38 years, n = 50) groups. Peripheral leukocytes were assessed, and the granulosa cells were pooled during oocyte pickup. Mitochondrial DNA (mtDNA) copy number and telomere length (TL) were measured using real-time polymerase chain reaction. PGT-A was performed on the NGS platform. Results: mtDNA copy number and TL were positively correlated in both leukocytes (rho = 0.477, p < 0.001) and granulosa cells (rho = 0.361, p < 0.001), but the two parameters in leukocytes were not correlated with those in granulosa cells. In the young-age group, TL in the granulosa cells was the only factor correlated with the aneuploidy rate (rho = −0.283, p = 0.044), whereas in the advanced-age group, age was the main factor (rho = 0.358, p = 0.018). Conclusions: TL in the granulosa cells was negatively correlated with the aneuploidy rate in the young-age group, supporting the application of PGT-A in younger women.},
}
@article {pmid35402460,
year = {2022},
author = {Pavanello, S and Campisi, M and Rigotti, P and Bello, MD and Nuzzolese, E and Neri, F and Furian, L},
title = {DNA Methylation - and Telomere - Based Biological Age Estimation as Markers of Biological Aging in Donors Kidneys.},
journal = {Frontiers in medicine},
volume = {9},
number = {},
pages = {832411},
pmid = {35402460},
issn = {2296-858X},
abstract = {The biological age of an organ may represent a valuable tool for assessing its quality, especially in the elder. We examined the biological age of the kidneys [right (RK) and left kidney (LK)] and blood leukocytes in the same subject and compared these to assess whether blood mirrors kidney biological aging. Biological age was studied in n = 36 donors (median age: 72 years, range: 19-92; male: 42%) by exploring mitotic and non-mitotic pathways, using telomere length (TL) and age-methylation changes (DNAmAge) and its acceleration (AgeAcc). RK and LK DNAmAge are older than blood DNAmAge (RK vs. Blood, p = 0.0271 and LK vs. Blood, p = 0.0245) and RK and LK AgeAcc present higher score (this mean the AgeAcc is faster) than that of blood leukocytes (p = 0.0271 and p = 0.0245) in the same donor. TL of RK and LK are instead longer than that of blood (p = 0.0011 and p = 0.0098) and the increase in Remuzzi-Karpinski score is strongly correlated with kidney TL attrition (p = 0.0046). Finally, blood and kidney TL (p < 0.01) and DNAmAge (p < 0.001) were correlated. These markers can be evaluated in further studies as indicators of biological age of donor organ quality and increase the usage of organs from donors of advanced age therefore offering a potential translational research inkidney transplantation.},
}
@article {pmid35397997,
year = {2022},
author = {Balmori, C and Cordova-Oriz, I and De Alba, G and Medrano, M and Jiménez-Tormo, L and Polonio, AM and Chico-Sordo, L and Pacheco, A and García-Velasco, JA and Varela, E},
title = {Effects of age and oligoasthenozoospermia on telomeres of sperm and blood cells.},
journal = {Reproductive biomedicine online},
volume = {44},
number = {6},
pages = {1090-1100},
doi = {10.1016/j.rbmo.2021.10.010},
pmid = {35397997},
issn = {1472-6491},
mesh = {Adult ; Humans ; Leukocytes, Mononuclear/metabolism ; Male ; Middle Aged ; RNA, Messenger/genetics ; Spermatozoa/metabolism ; *Telomerase/genetics/metabolism ; Telomere ; *Telomeric Repeat Binding Protein 1/genetics/metabolism ; },
abstract = {RESEARCH QUESTION: How do age and normo- or oligoasthenozoospermia affect telomere length dynamics in spermatozoa and blood?<br><br>DESIGN: Sperm and blood samples were collected from a cohort of 37 men aged 25 and under and 40 men aged 40 and over, with either normozoospermia (NZ) or oligoasthenozoospermia (OAZ). Telomere length was evaluated using quantitative fluorescence in-situ hybridization. Telomerase mRNA (TERC and TERT) and shelterin (TRF1) gene expression were analysed using quantitative real-time polymerase chain reaction. TRF1 protein immunoreactivity was also evaluated using immunofluorescence.<br><br>RESULTS: Mean sperm telomere length (STL) increased with age in the NZ group; older NZ men accumulated the longest telomeres (P < 0.001). In peripheral blood mononuclear cells (PBMC), mean telomere length decreased with age in NZ groups, although not reaching statistical significance. Interestingly, the younger OAZ group had the shortest mean telomere length (versus young NZ, P&#x202f;=&#x202f;0.0081; versus old NZ, P&#x202f;=&#x202f;0.0116; versus old OAZ, P&#x202f;=&#x202f;0.0009) and accumulated the highest percentage of short telomeres compared with the other groups (overall P&#x202f;=&#x202f;0.0017). Analysis of TERC and TERT mRNA expression in spermatozoa and PBMC did not show significant differences among groups. Statistically significant positive correlations were found between STL and seminal parameters in younger NZ men (P&#x202f;=&#x202f;0.009 for sperm count and P&#x202f;=&#x202f;0.007 for total progressive motility). Protein immunoreactivity of TRF1 in blood was not significantly different in all groups analysed.<br><br>CONCLUSIONS: The OAZ group did not show the increase of STL with age that is seen in NZ individuals, suggesting that telomere length elongation mechanisms fail in OAZ patients. In PBMC, younger OAZ individuals showed significantly shorter mean telomere length, suggesting that this parameter could be a good biomarker of OAZ in younger OAZ patients. Telomerase gene and TRF1 mRNA expression and TRF1 protein immunoreactivity did not differ significantly between groups, and so these factors cannot be used as OAZ biomarkers.},
}
@article {pmid35393557,
year = {2022},
author = {Ayora, M and Fraguas, D and Abregú-Crespo, R and Recio, S and Blasco, MA and Moises, A and Derevyanko, A and Arango, C and Díaz-Caneja, CM},
title = {Leukocyte telomere length in patients with schizophrenia and related disorders: a meta-analysis of case-control studies.},
journal = {Molecular psychiatry},
volume = {27},
number = {7},
pages = {2968-2975},
pmid = {35393557},
issn = {1476-5578},
mesh = {Case-Control Studies ; Humans ; Leukocytes ; *Psychotic Disorders ; *Schizophrenia/genetics ; Telomere/genetics ; Telomere Shortening/genetics ; },
abstract = {CONTEXT: Telomere length may serve as a biomarker of cellular aging. The literature assessing telomere length in schizophrenia contains conflicting results.<br><br>OBJECTIVE: To assess differences in leukocyte telomere length (LTL) in peripheral blood in patients with schizophrenia and related disorders and healthy controls and to explore the effect of potential confounding variables.<br><br>DATA SOURCES: A search of Ovid MEDLINE, and Proquest databases was conducted to identify appropriate studies published from database inception through December 2020. The review protocol was registered with PROSPERO-ID: CRD42021233280.<br><br>STUDY SELECTION: The initial literature search yielded 192 studies. After study selection in 3 phases, we included 29 samples from 22 studies in the meta-analysis database.<br><br>DATA EXTRACTION: We used random effects and meta-regression models to derive Cohen d values with pooled 95% confidence intervals (CI) as estimates of effect size (ES) and to test effects of potential moderators.<br><br>RESULTS: The overall meta-analysis included 4145 patients with schizophrenia and related disorders and 4184 healthy controls and showed that LTL was significantly shorter in patients, with a small to medium effect size (ES, -0.388; 95% CI, -0.492 to -0.283; p&#x2009;<&#x2009;0.001). Subgroup meta-analyses did not find a significant effect of age or illness duration on differences in LTL in patients with psychosis relative to controls. Meta-regression analyses showed that none of the putative moderators had a significant effect on effect size estimates.<br><br>CONCLUSIONS: This meta-analysis find further support for the hypothesis of accelerated cellular aging in schizophrenia and related disorders and highlights the need for large longitudinal studies with repeated LTL measurements over time and appropriate assessments of associated factors.},
}
@article {pmid35391893,
year = {2022},
author = {Córdoba-Lanús, E and Falfán-Valencia, R},
title = {Editorial: Telomere Dysfunction and Lung Diseases.},
journal = {Frontiers in medicine},
volume = {9},
number = {},
pages = {861228},
pmid = {35391893},
issn = {2296-858X},
}
@article {pmid35390241,
year = {2022},
author = {Tričković, JF and Šobot, AV and Joksić, I and Joksić, G},
title = {Telomere fragility in radiology workers occupationally exposed to low doses of ionising radiation.},
journal = {Arhiv za higijenu rada i toksikologiju},
volume = {73},
number = {1},
pages = {23-30},
pmid = {35390241},
issn = {1848-6312},
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Chromosome Aberrations ; Humans ; *Occupational Exposure/adverse effects ; Radiation, Ionizing ; *Radiology ; Telomere ; },
abstract = {Ionising radiation damages DNA directly and indirectly through increased production of reactive oxygen species. Although telomeres have been reported as indicators of radiosensitivity, their maintenance in response to occupational exposure to low radiation doses is still a matter of debate. In this work we aimed to investigate telomere length and structure in hospital workers occupationally exposed to X-rays and to relate these findings to oxidation of biomolecules and chromosome aberrations. Blood samples of exposed participants and matching controls were taken during periodical check-ups. Chromosome aberrations and telomere length and structure were analysed in peripheral blood lymphocytes using Q-FISH, whereas oxidative stress parameters [pro/antioxidant balance (PAB), lipid peroxidation, and 8-oxo-dG] were measured in plasma samples. Based on the CA findings we divided the exposed group into two subgroups, of which one had chromosome aberrations in the first division metaphases and the other did not. There was no significant difference in telomere length between any of the groups. However, both subgroups showed significantly higher rate of fragile telomeres and higher lipid peroxidation product and 8-oxo-dG levels than controls. The rate of fragile telomeres significantly correlated with plasma levels of 8-oxo-dG, which suggests that continuous exposure to low radiation doses induces oxidative base damage of guanine resulting in telomere fragility.},
}
@article {pmid35385755,
year = {2022},
author = {Sakellariou, D and Bak, ST and Isik, E and Barroso, SI and Porro, A and Aguilera, A and Bartek, J and Janscak, P and Peña-Diaz, J},
title = {MutSβ regulates G4-associated telomeric R-loops to maintain telomere integrity in ALT cancer cells.},
journal = {Cell reports},
volume = {39},
number = {1},
pages = {110602},
doi = {10.1016/j.celrep.2022.110602},
pmid = {35385755},
issn = {2211-1247},
mesh = {DNA/metabolism ; Humans ; *Neoplasms/genetics ; R-Loop Structures ; *RNA, Long Noncoding/metabolism ; Telomere/metabolism ; Telomere Homeostasis ; },
abstract = {Up to 15% of human cancers maintain their telomeres through a telomerase-independent mechanism, termed "alternative lengthening of telomeres" (ALT) that relies on homologous recombination between telomeric sequences. Emerging evidence suggests that the recombinogenic nature of ALT telomeres results from the formation of RNA:DNA hybrids (R-loops) between telomeric DNA and the long-noncoding telomeric repeat-containing RNA (TERRA). Here, we show that the mismatch repair protein MutSβ, a heterodimer of MSH2 and MSH3 subunits, is enriched at telomeres in ALT cancer cells, where it prevents the accumulation of telomeric G-quadruplex (G4) structures and R-loops. Cells depleted of MSH3 display increased incidence of R-loop-dependent telomere fragility and accumulation of telomeric C-circles. We also demonstrate that purified MutSβ recognizes and destabilizes G4 structures in vitro. These data suggest that MutSβ destabilizes G4 structures in ALT telomeres to regulate TERRA R-loops, which is a prerequisite for maintenance of telomere integrity during ALT.},
}
@article {pmid35385311,
year = {2022},
author = {Nakao, T and Bick, AG and Taub, MA and Zekavat, SM and Uddin, MM and Niroula, A and Carty, CL and Lane, J and Honigberg, MC and Weinstock, JS and Pampana, A and Gibson, CJ and Griffin, GK and Clarke, SL and Bhattacharya, R and Assimes, TL and Emery, LS and Stilp, AM and Wong, Q and Broome, J and Laurie, CA and Khan, AT and Smith, AV and Blackwell, TW and Codd, V and Nelson, CP and Yoneda, ZT and Peralta, JM and Bowden, DW and Irvin, MR and Boorgula, M and Zhao, W and Yanek, LR and Wiggins, KL and Hixson, JE and Gu, CC and Peloso, GM and Roden, DM and Reupena, MS and Hwu, CM and DeMeo, DL and North, KE and Kelly, S and Musani, SK and Bis, JC and Lloyd-Jones, DM and Johnsen, JM and Preuss, M and Tracy, RP and Peyser, PA and Qiao, D and Desai, P and Curran, JE and Freedman, BI and Tiwari, HK and Chavan, S and Smith, JA and Smith, NL and Kelly, TN and Hidalgo, B and Cupples, LA and Weeks, DE and Hawley, NL and Minster, RL and , and Deka, R and Naseri, TT and de Las Fuentes, L and Raffield, LM and Morrison, AC and Vries, PS and Ballantyne, CM and Kenny, EE and Rich, SS and Whitsel, EA and Cho, MH and Shoemaker, MB and Pace, BS and Blangero, J and Palmer, ND and Mitchell, BD and Shuldiner, AR and Barnes, KC and Redline, S and Kardia, SLR and Abecasis, GR and Becker, LC and Heckbert, SR and He, J and Post, W and Arnett, DK and Vasan, RS and Darbar, D and Weiss, ST and McGarvey, ST and de Andrade, M and Chen, YI and Kaplan, RC and Meyers, DA and Custer, BS and Correa, A and Psaty, BM and Fornage, M and Manson, JE and Boerwinkle, E and Konkle, BA and Loos, RJF and Rotter, JI and Silverman, EK and Kooperberg, C and Danesh, J and Samani, NJ and Jaiswal, S and Libby, P and Ellinor, PT and Pankratz, N and Ebert, BL and Reiner, AP and Mathias, RA and Do, R and , and Natarajan, P},
title = {Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential.},
journal = {Science advances},
volume = {8},
number = {14},
pages = {eabl6579},
pmid = {35385311},
issn = {2375-2548},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; R35 HL135818/HL/NHLBI NIH HHS/United States ; R01 HL146860/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; DP2 HL157540/HL/NHLBI NIH HHS/United States ; KL2 TR002490/TR/NCATS NIH HHS/United States ; R01 DK124097/DK/NIDDK NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; DP5 OD029586/OD/NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL046380/HL/NHLBI NIH HHS/United States ; R01 EB015611/EB/NIBIB NIH HHS/United States ; RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL148565/HL/NHLBI NIH HHS/United States ; R01 HL113338/HL/NHLBI NIH HHS/United States ; R01 HL134892/HL/NHLBI NIH HHS/United States ; R01 HL142302/HL/NHLBI NIH HHS/United States ; R01 DK110113/DK/NIDDK NIH HHS/United States ; T32 HG000040/HG/NHGRI NIH HHS/United States ; R01 DK107786/DK/NIDDK NIH HHS/United States ; P01 HL132825/HL/NHLBI NIH HHS/United States ; R01 HL148050/HL/NHLBI NIH HHS/United States ; CH/12/2/29428/BHF_/British Heart Foundation/United Kingdom ; },
abstract = {Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.},
}
@article {pmid35368045,
year = {2022},
author = {Cigan, SS and Meredith, JJ and Kelley, AC and Yang, T and Langer, EK and Hooten, AJ and Lane, JA and Cole, BR and Krailo, M and Frazier, AL and Pankratz, N and Poynter, JN},
title = {Predicted leukocyte telomere length and risk of germ cell tumours.},
journal = {British journal of cancer},
volume = {127},
number = {2},
pages = {301-312},
pmid = {35368045},
issn = {1532-1827},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; R01 CA151284/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Child ; Female ; Humans ; Leukocytes ; *Neoplasms, Germ Cell and Embryonal/genetics ; *Telomere/genetics ; Telomere Homeostasis/genetics ; },
abstract = {BACKGROUND: Genetically predicted leukocyte telomere length (LTL) has been evaluated in several studies of childhood and adult cancer. We test whether genetically predicted longer LTL is associated with germ cell tumours (GCT) in children and adults.<br><br>METHODS: Paediatric GCT samples were obtained from a Children's Oncology Group study and state biobank programs in California and Michigan (N&#x2009;=&#x2009;1413 cases, 1220 biological parents and 1022 unrelated controls). Replication analysis included 396 adult testicular GCTs (TGCT) and 1589 matched controls from the UK Biobank. Mendelian randomisation was used to look at the association between genetically predicted LTL and GCTs and TERT variants were evaluated within GCT subgroups.<br><br>RESULTS: We identified significant associations between TERT variants reported in previous adult TGCT GWAS in paediatric GCT: TERT/rs2736100-C (OR&#x2009;=&#x2009;0.82; P&#x2009;=&#x2009;0.0003), TERT/rs2853677-G (OR&#x2009;=&#x2009;0.80; P&#x2009;=&#x2009;0.001), and TERT/rs7705526-A (OR&#x2009;=&#x2009;0.81; P&#x2009;=&#x2009;0.003). We also extended these findings to females and tumours outside the testes. In contrast, we did not observe strong evidence for an association between genetically predicted LTL by other variants and GCT risk in children or adults.<br><br>CONCLUSION: While TERT is a known susceptibility locus for GCT, our results suggest that LTL predicted by other variants is not strongly associated with risk in either children or adults.},
}
@article {pmid35367774,
year = {2022},
author = {Anderson, JJ and Susser, E and Arbeev, KG and Yashin, AI and Levy, D and Verhulst, S and Aviv, A},
title = {Telomere-length dependent T-cell clonal expansion: A model linking ageing to COVID-19 T-cell lymphopenia and mortality.},
journal = {EBioMedicine},
volume = {78},
number = {},
pages = {103978},
pmid = {35367774},
issn = {2352-3964},
support = {P2C HD042828/HD/NICHD NIH HHS/United States ; R56 AG073226/AG/NIA NIH HHS/United States ; U24 AG066528/AG/NIA NIH HHS/United States ; U01 AG066529/AG/NIA NIH HHS/United States ; RF1 AG046860/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging ; *COVID-19 ; Humans ; *Lymphopenia ; T-Lymphocytes ; Telomere/genetics ; Young Adult ; },
abstract = {BACKGROUND: Severe COVID-19 T-cell lymphopenia is more common among older adults and entails poor prognosis. Offsetting the decline in T-cell count during COVID-19 demands fast and massive T-cell clonal expansion, which is telomere length (TL)-dependent.<br><br>METHODS: We developed a model of TL-dependent T-cell clonal expansion capacity with age and virtually examined the relation of T-cell clonal expansion with COVID-19 mortality in the general population.<br><br>FINDINGS: The model shows that an individual with average hematopoietic cell TL (HCTL) at age twenty years maintains maximal T-cell clonal expansion capacity until the 6th decade of life when this capacity rapidly declines by more than 90% over the next ten years. The collapse in the T-cell clonal expansion capacity coincides with the steep increase in COVID-19 mortality with age.<br><br>INTERPRETATION: Short HCTL might increase vulnerability of many older adults, and some younger individuals with inherently short HCTL, to COVID-19 T-cell lymphopenia and severe disease.<br><br>FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.},
}
@article {pmid35366243,
year = {2022},
author = {Jin, JH and Kwon, HS and Choi, SH and Koh, SH and Lee, EH and Jeong, JH and Jang, JW and Park, KW and Kim, EJ and Kim, HJ and Hong, JY and Yoon, SJ and Yoon, B and Park, HH and Ha, J and Park, JE and Han, MH},
title = {Association between sleep parameters and longitudinal shortening of telomere length.},
journal = {Aging},
volume = {14},
number = {7},
pages = {2930-2944},
pmid = {35366243},
issn = {1945-4589},
support = {27398C0007/ES/NIEHS NIH HHS/United States ; },
mesh = {Aging/genetics ; Humans ; Leukocytes ; Longitudinal Studies ; Sleep ; *Telomere ; *Telomere Shortening ; },
abstract = {BACKGROUND: The relationship between sleep parameters and longitudinal shortening of telomere length is unclear. This study aimed to investigate the relationship between sleep parameters and the shortening of leukocyte telomere length (LTL) over a year.<br><br>METHODS: Among the participants in the validation cohort of the Korea Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease, participants who measured both baseline and follow-up (two years later) of LTL were analyzed. They were dichotomized according to the degree of LTL attrition over two years. Clinical characteristics were compared between the faster and slower LTL shortening groups (cut-off points: -0.710 kbp, n = 119 each). Multivariable logistic regression analyses were performed to determine independent relationships between faster shortening of LTL length and sleep parameters.<br><br>RESULTS: A total of 238 participants, aged 55-88 years, were included. Participants with faster LTL shortening had a shorter duration of sleep (P = 0.013) and longer sleep latency (P = 0.007). Among the components of the PSQI, subjective measures of sleep quality, sleep latency, sleep duration, and sleep efficiency were significantly worse in participants with faster LTL shortening. Multivariate logistic regression analysis showed that sleep duration (per hour, OR = 0.831, 95% CI = 0.698-0.989), sleep latency (per minute, OR = 1.013, 95% CI = 1.002-1.024), global PSQI score (OR = 1.134, 95% CI = 1.040-1.236), shortest sleep duration (OR = 5.173, 95% CI = 1.563-17.126), and lowest sleep efficiency (OR = 7.351, 95% CI = 1.943-27.946) were independently associated with faster LTL shortening.<br><br>CONCLUSIONS: Poor sleep quality, specifically short sleep duration, long sleep latency, and low sleep efficiency were associated with faster longitudinal shortening of LTL.},
}
@article {pmid35365597,
year = {2022},
author = {Spano, L and Etain, B and Meyrel, M and Hennion, V and Gross, G and Laplanche, JL and Bellivier, F and Marie-Claire, C},
title = {Telomere length and mitochondrial DNA copy number in bipolar disorder: identification of a subgroup of young individuals with accelerated cellular aging.},
journal = {Translational psychiatry},
volume = {12},
number = {1},
pages = {135},
pmid = {35365597},
issn = {2158-3188},
mesh = {Adult ; *Bipolar Disorder/genetics ; Cellular Senescence ; DNA Copy Number Variations ; *DNA, Mitochondrial/genetics ; Humans ; Telomere/genetics ; },
abstract = {The 10-15-years decrease in life expectancy observed in individuals with bipolar disorder (BD) has been linked to the concept of accelerated cellular aging. Telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) have been proposed as markers of cellular aging and comparisons between individuals with BD and healthy controls (HC) sometimes led to conflicting results. Previous studies had moderate sample sizes and studies combining these two markers into a single analysis are scarce. Using quantitative polymerase chain reaction, we measured both TL and mtDNAcn in DNA (peripheral blood) in a sample of 130 individuals with BD and 78 HC. Regression analyses, receiver operating characteristic (ROC), and clustering analyses were performed. We observed significantly lower TL and mtDNAcn in individuals with BD as compared to HC (respective decrease of 26.5 and 35.8%). ROC analyses showed that TL and mtDNAcn highly discriminated groups (AUC = 0.904 for TL and AUC = 0.931 for mtDNAcn). In the whole population, clustering analyses identified a group of young individuals (age around 36 years), with accelerated cellular aging (both shorter TL and lower mtDNAcn), which consisted mostly of individuals with BD (85.5%). The subgroup of patients with young age but accelerated aging was not characterized by specific clinical variables related to the course of BD or childhood maltreatment. However, patients in this subgroup were more frequently treated with anticonvulsants. Further characterization of this subgroup is required to better understand the molecular mechanisms and the risk factors of accelerated cellular aging in BD.},
}
@article {pmid35361931,
year = {2022},
author = {Mc Cartney, AM and Shafin, K and Alonge, M and Bzikadze, AV and Formenti, G and Fungtammasan, A and Howe, K and Jain, C and Koren, S and Logsdon, GA and Miga, KH and Mikheenko, A and Paten, B and Shumate, A and Soto, DC and Sović, I and Wood, JMD and Zook, JM and Phillippy, AM and Rhie, A},
title = {Chasing perfection: validation and polishing strategies for telomere-to-telomere genome assemblies.},
journal = {Nature methods},
volume = {19},
number = {6},
pages = {687-695},
pmid = {35361931},
issn = {1548-7105},
support = {R01 HG006677/HG/NHGRI NIH HHS/United States ; U01 HG010961/HG/NHGRI NIH HHS/United States ; WT206194/WT_/Wellcome Trust/United Kingdom ; U41 HG010972/HG/NHGRI NIH HHS/United States ; F32 GM134558/GM/NIGMS NIH HHS/United States ; OT2 OD026682/OD/NIH HHS/United States ; Z99 HG999999/ImNIH/Intramural NIH HHS/United States ; R01 HG011274/HG/NHGRI NIH HHS/United States ; R21 HG010548/HG/NHGRI NIH HHS/United States ; U01 HG010971/HG/NHGRI NIH HHS/United States ; U24 HG011853/HG/NHGRI NIH HHS/United States ; R01 HG010485/HG/NHGRI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; ZIA HG200398/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Female ; Genome, Human ; *High-Throughput Nucleotide Sequencing/methods ; Humans ; *Nanopores ; Pregnancy ; Sequence Analysis, DNA/methods ; Telomere/genetics ; },
abstract = {Advances in long-read sequencing technologies and genome assembly methods have enabled the recent completion of the first telomere-to-telomere human genome assembly, which resolves complex segmental duplications and large tandem repeats, including centromeric satellite arrays in a complete hydatidiform mole (CHM13). Although derived from highly accurate sequences, evaluation revealed evidence of small errors and structural misassemblies in the initial draft assembly. To correct these errors, we designed a new repeat-aware polishing strategy that made accurate assembly corrections in large repeats without overcorrection, ultimately fixing 51% of the existing errors and improving the assembly quality value from 70.2 to 73.9 measured from PacBio high-fidelity and Illumina k-mers. By comparing our results to standard automated polishing tools, we outline common polishing errors and offer practical suggestions for genome projects with limited resources. We also show how sequencing biases in both high-fidelity and Oxford Nanopore Technologies reads cause signature assembly errors that can be corrected with a diverse panel of sequencing technologies.},
}
@article {pmid35359435,
year = {2022},
author = {da Silva, MS and McCulloch, R and Cano, MIN},
title = {Editorial: Nuclear Genome Stability: DNA Replication, Telomere Maintenance, and DNA Repair.},
journal = {Frontiers in cell and developmental biology},
volume = {10},
number = {},
pages = {875749},
doi = {10.3389/fcell.2022.875749},
pmid = {35359435},
issn = {2296-634X},
}
@article {pmid35359323,
year = {2022},
author = {Joseph, NA and Chen, CF and Chen, JH and Chen, LY},
title = {Monitoring Telomere Maintenance During Regeneration of Annelids.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2450},
number = {},
pages = {467-478},
pmid = {35359323},
issn = {1940-6029},
mesh = {Animals ; *Annelida ; In Situ Hybridization, Fluorescence ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; Telomere Homeostasis ; },
abstract = {Telomere shortening is a hallmark of aging and eventually constrains the proliferative capacity of cells. The protocols discussed here are used for monitoring telomeres comprehensively in Aeolosoma viride, a model system for regeneration studies. We present methods for analyzing the activity of telomerase enzyme in regenerating tissue by telomeric repeat amplification protocol (TRAP) assay, for comparing telomere length between existing tissue and newly regenerated tissue by telomere restriction fragment (TRF) assay, as well as for visualizing telomeres by fluorescence in situ hybridization (FISH).},
}
@article {pmid35357925,
year = {2022},
author = {Hoyt, SJ and Storer, JM and Hartley, GA and Grady, PGS and Gershman, A and de Lima, LG and Limouse, C and Halabian, R and Wojenski, L and Rodriguez, M and Altemose, N and Rhie, A and Core, LJ and Gerton, JL and Makalowski, W and Olson, D and Rosen, J and Smit, AFA and Straight, AF and Vollger, MR and Wheeler, TJ and Schatz, MC and Eichler, EE and Phillippy, AM and Timp, W and Miga, KH and O'Neill, RJ},
title = {From telomere to telomere: The transcriptional and epigenetic state of human repeat elements.},
journal = {Science (New York, N.Y.)},
volume = {376},
number = {6588},
pages = {eabk3112},
pmid = {35357925},
issn = {1095-9203},
support = {U24 HG010263/HG/NHGRI NIH HHS/United States ; R35 GM128857/GM/NIGMS NIH HHS/United States ; T32 GM007445/GM/NIGMS NIH HHS/United States ; R21 CA240199/CA/NCI NIH HHS/United States ; R01 HG010169/HG/NHGRI NIH HHS/United States ; U01 CA253481/CA/NCI NIH HHS/United States ; R01 HG002939/HG/NHGRI NIH HHS/United States ; U01 HG010971/HG/NHGRI NIH HHS/United States ; P20 GM103546/GM/NIGMS NIH HHS/United States ; R01 HG002385/HG/NHGRI NIH HHS/United States ; R01 HG011274/HG/NHGRI NIH HHS/United States ; U24 HG006620/HG/NHGRI NIH HHS/United States ; U24 HG010136/HG/NHGRI NIH HHS/United States ; R21 HG010548/HG/NHGRI NIH HHS/United States ; R01 HG009909/HG/NHGRI NIH HHS/United States ; R01 GM123312/GM/NIGMS NIH HHS/United States ; R01 HG009190/HG/NHGRI NIH HHS/United States ; R24 DK106766/DK/NIDDK NIH HHS/United States ; R01 GM132600/GM/NIGMS NIH HHS/United States ; ZIA HG200398/ImNIH/Intramural NIH HHS/United States ; },
mesh = {*Epigenesis, Genetic ; *Genome, Human ; Humans ; *Repetitive Sequences, Nucleic Acid ; Telomere/*genetics ; *Transcription, Genetic ; },
abstract = {Mobile elements and repetitive genomic regions are sources of lineage-specific genomic innovation and uniquely fingerprint individual genomes. Comprehensive analyses of such repeat elements, including those found in more complex regions of the genome, require a complete, linear genome assembly. We present a de novo repeat discovery and annotation of the T2T-CHM13 human reference genome. We identified previously unknown satellite arrays, expanded the catalog of variants and families for repeats and mobile elements, characterized classes of complex composite repeats, and located retroelement transduction events. We detected nascent transcription and delineated CpG methylation profiles to define the structure of transcriptionally active retroelements in humans, including those in centromeres. These data expand our insight into the diversity, distribution, and evolution of repetitive regions that have shaped the human genome.},
}
@article {pmid35351386,
year = {2022},
author = {Nandavaram, S and Chandrashekaran, S and Gelman, AE},
title = {Short telomeres in lung transplantation: Known unknowns.},
journal = {The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation},
volume = {41},
number = {5},
pages = {664-666},
doi = {10.1016/j.healun.2022.02.001},
pmid = {35351386},
issn = {1557-3117},
mesh = {Humans ; *Lung Transplantation ; *Telomerase/genetics ; Telomere/genetics ; },
}
@article {pmid35348914,
year = {2022},
author = {Muoio, D and Laspata, N and Fouquerel, E},
title = {Functions of ADP-ribose transferases in the maintenance of telomere integrity.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {79},
number = {4},
pages = {215},
pmid = {35348914},
issn = {1420-9071},
support = {R00 ES027028/ES/NIEHS NIH HHS/United States ; R35 GM142982/GM/NIGMS NIH HHS/United States ; R35GM142982/GM/NIGMS NIH HHS/United States ; R00ES027028/ES/NIEHS NIH HHS/United States ; },
mesh = {*ADP Ribose Transferases/metabolism ; Adenosine Diphosphate Ribose/metabolism ; DNA Repair ; Genomic Instability ; Humans ; *Telomere/genetics/metabolism ; },
abstract = {The ADP-ribose transferase (ART) family comprises 17 enzymes that catalyze mono- or poly-ADP-ribosylation, a post-translational modification of proteins. Present in all subcellular compartments, ARTs are implicated in a growing number of biological processes including DNA repair, replication, transcription regulation, intra- and extra-cellular signaling, viral infection and cell death. Five members of the family, PARP1, PARP2, PARP3, tankyrase 1 and tankyrase 2 are mainly described for their crucial functions in the maintenance of genome stability. It is well established that the most describedrole of PARP1, 2 and 3 is the repair of DNA lesions while tankyrases 1 and 2 are crucial for maintaining the integrity of telomeres. Telomeres, nucleoprotein complexes located at the ends of eukaryotic chromosomes, utilize their unique structure and associated set of proteins to orchestrate the mechanisms necessary for their own protection and replication. While the functions of tankyrases 1 and 2 at telomeres are well known, several studies have also brought PARP1, 2 and 3 to the forefront of telomere protection. The singular quality of the telomeric environment has highlighted protein interactions and molecular pathways distinct from those described throughout the genome. The aim of this review is to provide an overview of the current knowledge on the multiple roles of PARP1, PARP2, PARP3, tankyrase 1 and tankyrase 2 in the maintenance and preservation of telomere integrity.},
}
@article {pmid35347712,
year = {2022},
author = {Aoulad Fares, D and Wiegel, RE and Eggink, AJ and Willemsen, SP and van Meurs, JBJ and Steegers-Theunissen, RPM},
title = {Shorter periconception maternal telomere length and the risk of congenital cardiac outflow defects in the offspring.},
journal = {European journal of clinical investigation},
volume = {52},
number = {8},
pages = {e13784},
pmid = {35347712},
issn = {1365-2362},
support = {//The Bo Hjelt Foundation for Spina Bifida in memory of Madeleine Hjelt/ ; },
mesh = {Female ; *Heart Defects, Congenital ; *Heart Septal Defects, Ventricular/genetics ; Humans ; Mothers ; Odds Ratio ; Telomere/genetics ; Telomere Shortening ; },
abstract = {BACKGROUND: Congenital cardiac outflow defects (COD) are the largest group of congenital heart defects, with ventricular septal defect (VSD) as the most prevalent phenotype. Increased maternal age, excessive oxidative stress and inflammation are involved in the pathophysiology of COD and enhance telomere length (TL) shortening. We investigated the association between periconception maternal TL and the risk of having a child with COD.<br><br>METHODS: From a multicentre case-control trial, 306 case mothers of a child with COD and 424 control mothers of a child without a congenital malformation were selected. Relative TL was measured by qPCR. Multivariable logistic regression was used to compute crude and adjusted odds ratios, per standard deviation decrease, between maternal T/S ratio and COD and VSD risk. Adjustments were made for maternal age. Additional adjustments were made in a second model.<br><br>RESULTS: Shorter maternal relative TL was significantly associated with an OR of 1.29 (95% CI 1.04-1.61), p&#xa0;=&#xa0;.02, for the risk of VSD in offspring, which remained significant after an adjustment for maternal age (adjOR 1.25(95% CI 1.01-1.55), p&#xa0;=&#xa0;.04). No association between maternal TL and the risk of overall COD in offspring was observed.<br><br>CONCLUSION: Shorter maternal relative TL is associated with an approximately 1.3-OR for the risk, per SD in relative TL shortening, of VSD in the offspring. These findings need further confirmation in other studies on the predictive value of maternal TL.},
}
@article {pmid35346819,
year = {2022},
author = {Gordon, CA and Madamanchi, NR and Runge, MS and Jarstfer, MB},
title = {Effect of oxidative stress on telomere maintenance in aortic smooth muscle cells.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {1868},
number = {7},
pages = {166397},
doi = {10.1016/j.bbadis.2022.166397},
pmid = {35346819},
issn = {1879-260X},
mesh = {Animals ; *Cardiovascular Diseases/pathology ; Mice ; Myocytes, Smooth Muscle/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase-1/genetics ; *Telomerase/genetics/metabolism ; Telomere/genetics ; },
abstract = {Reactive oxygen species (ROS) and telomere dysfunction are both associated with aging and the development of age-related diseases. Although there is evidence for a direct relationship between ROS and telomere dysfunction as well as an independent association of oxidative stress and telomere attrition with age-related disorders, there has not been sufficient exploration of how the interaction between oxidative stress and telomere function may contribute to the pathophysiology of cardiovascular diseases (CVD). To better understand the complex relationships between oxidative stress, telomerase biology and pathophysiology, we examined the telomere biology of aortic smooth muscle cells (ASMCs) isolated from mutant mouse models of oxidative stress. We discovered that telomere lengths were significantly shorter in ASMCs isolated from superoxide dismutase 2 heterozygous (Sod2[+/-]) mice, which exhibit increased arterial stiffness with aging, and the observed telomere attrition occurred over time. Furthermore, the telomere erosion occurred even though telomerase activity increased. In contrast, telomeres remained stable in wild-type and superoxide dismutase 1 heterozygous (Sod1[+/-]) mice, which do not exhibit CVD phenotypes. The data indicate that mitochondrial oxidative stress, in particular elevated superoxide levels and decreased hydrogen peroxide levels, induces telomere erosion in the ASMCs of the Sod2[+/-] mice. This reduction in telomere length occurs despite an increase in telomerase activity and correlates with the onset of disease phenotype. Our results suggest that the oxidative stress caused by imbalance in mitochondrial ROS, from deficient SOD2 activity as a model for mitochondrial dysfunction results in telomere dysfunction, which may contribute to pathogenesis of CVD.},
}
@article {pmid35342938,
year = {2022},
author = {Zhang, Y and Luo, S and Jia, Y and Zhang, X},
title = {Telomere maintenance mechanism dysregulation serves as an early predictor of adjuvant therapy response and a potential therapeutic target in human cancers.},
journal = {International journal of cancer},
volume = {151},
number = {2},
pages = {313-327},
doi = {10.1002/ijc.34007},
pmid = {35342938},
issn = {1097-0215},
mesh = {Genomic Instability ; Humans ; *Neoplasms/drug therapy/genetics ; Prognosis ; Telomere/metabolism ; Telomere Homeostasis ; },
abstract = {Telomere maintenance mechanisms (TMMs) rescue cells from telomere crisis, endow cells immortal property, stabilize genomic integrity. However, TMM-associated molecular profiles and their clinical outcomes in cancer remain elusive. Here, we performed a pan-cancer and integrated analysis of TMM gene expression profiles from 10 107 unique samples with clinicopathological, molecular and outcome features across seven malignancies from the same microarray platform (Affymetrix GPL570 platform). This resource was divided into case-control datasets for obtaining dysregulated TMM genes and survival datasets for evaluating clinical outcomes. Multidimensional data from The Cancer Genome Atlas (TCGA) were used to elucidate associations between TMM dysregulation and survival, genomic instability. Our results demonstrated that TMMs had a consistent dysregulation spectrum across cancers, based on which we developed the TMM-dysregulation signature TMS score (TMScore) that was positively associated with various tumor adverse features. Two opposite prognostic patterns of TMScore independent of clinicopathological and molecular characteristics were identified, which might be explained by genomic instability: breast and lung cancer patients with elevated TMScore had inferior outcomes, suggesting TMScore-related genes as potential therapeutic targets, on the contrary, colon and stomach cancer patients had superior outcomes. Most important, the prognostic value of TMScore was still significant regardless of whether patients had received adjuvant therapy, which was valuable for discriminating nonresponders from responders, and could predict the effectiveness of adjuvant therapy. In summary, our resources delineate TMMs dysregulated landscape across cancers, shed light on the impact of TMMs dysregulation on patient outcomes and adjuvant therapy, and provide novel therapeutic opportunities for cancer treatment.},
}
@article {pmid35339005,
year = {2022},
author = {Shu, MJ and Li, J and Zhu, YC},
title = {Genetically predicted telomere length and multiple sclerosis.},
journal = {Multiple sclerosis and related disorders},
volume = {60},
number = {},
pages = {103731},
doi = {10.1016/j.msard.2022.103731},
pmid = {35339005},
issn = {2211-0356},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; },
mesh = {*Genome-Wide Association Study ; Humans ; Mendelian Randomization Analysis ; *Multiple Sclerosis/genetics ; Polymorphism, Single Nucleotide ; Telomere/genetics ; },
abstract = {BACKGROUND: Previous epidemiological studies have indicated a role for telomere length in multiple sclerosis (MS) severity and phenotype. However, these studies failed to establish the causality between telomere length and MS susceptibility. Hence, we performed two-sample Mendelian randomization (MR) analysis to explore the causal relationship between telomere length and MS susceptibility.<br><br>METHODS: We used data of genetic variants associated with leukocyte telomere length as instrumental variables (IVs), which was identified from the largest and latest genome-wide association study (GWAS) from UK Biobank (UKB) with 472,174 participants. Summary data of MS was obtained from the International Multiple Sclerosis Genetics Consortium. We performed two-sample MR analyses using the inverse-variance weighted method as the primary approach. Other MR approaches, including the MR-Egger, the inverse variance weighted (multiplicative random effects), weighted median, simple median, weighted mode-based methods, and Causal Analysis Using Summary Effect estimates (CAUSE), were also conducted to detect the result robustness.<br><br>RESULTS: The genetic liability to longer telomere length was associated with a higher risk of MS susceptibility (odds ratio [OR] per one-SD telomere length, 1.91; 95% confidence interval [CI], 1.48-2.47; P&#xa0;=&#xa0;8.04&#xa0;&#xd7;&#xa0;10[-7]). The results remained consistent across multiple sensitivity analyses.<br><br>CONCLUSIONS: Our study supports the causal relationship between longer telomere length and increased risk of MS susceptibility.},
}
@article {pmid35338946,
year = {2022},
author = {Murkey, JA and Watkins, BX and Vieira, D and Boden-Albala, B},
title = {Disparities in allostatic load, telomere length and chronic stress burden among African American adults: A systematic review.},
journal = {Psychoneuroendocrinology},
volume = {140},
number = {},
pages = {105730},
doi = {10.1016/j.psyneuen.2022.105730},
pmid = {35338946},
issn = {1873-3360},
mesh = {Adult ; Black or African American ; *Allostasis/physiology ; Biomarkers ; Health Status Disparities ; Humans ; Stress, Psychological/complications ; Telomere ; },
abstract = {BACKGROUND: The chronic disease burden among African Americans has continued to rise. Although racial disparities in chronic disease risk are well documented, the role of chronic stress in risk disparities among racial and ethnic minorities is not well understood. This systematic review of studies reporting on the relationship between chronic stress, education, and/or income, and biomarkers of chronic stress (allostatic load and telomere length) longitudinally among African Americans, seeks to contribute to this knowledge gap.<br><br>OBJECTIVE: To use the existing literature to both examine the strength of two objective biomarkers--telomere length and allostatic load--as measures of the overactivation of physiological stress processes in African American adults; and determine if existing studies used these two biomarkers to assess the relationship between chronic stress, income and level of educational attainment among African Americans longitudinally.<br><br>METHODS: In order to identify English-language articles published prior to October 11, 2021, a comprehensive search strategy was developed using five databases: PubMed/Medline, EMBASE, Web of Science Plus, Global Health (Ovid), and PsycINFO. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method was used to record progress on the comprehensive search for studies reporting on allostatic load and/or telomere length biomarkers longitudinally within all bodily fluids and chronic stress among African American adults.<br><br>RESULTS: In total, 7 studies met the search criteria; 902 were excluded. Thus, less than 1% of all studies reporting on biomarkers of chronic stress longitudinally included African Americans. Each of the 7 studies described the relationship between telomere length and/or allostatic load among African Americans and chronic stress, education, and/or income. Higher chronic stress levels and experiences of racial discrimination were associated with telomere shortening while lower income and higher chronic stress levels were associated with an increase in allostatic load among African Americans.<br><br>DISCUSSION: Given the limited number of studies reporting on the association between allostatic load, telomere length, and/or the relationship between both in assessing chronic stress severity longitudinally among African American populations, it is impossible to determine whether one biomarker has greater predictive value than the other. However, based on the literature included in this review, higher chronic stress levels and experiences of racial discrimination were associated with shorter telomere length, while lower income and higher chronic stress levels are associated with an increase in allostatic load among African Americans.<br><br>CONCLUSION: These data illustrate a gap in the literature on the relationship between the biomarkers of telomere length and allostatic load combined as a potential measure for chronic stress among African Americans. To our knowledge, none the current literature describes the relationship between telomere length and allostatic load longitudinally among African American adults. As the field strives to develop a "gold standard" for measuring chronic stress, the combination of these biomarkers needs to be the subject of scientific inquiry and thus, fully examined. Future longitudinal studies among African Americans are needed to better understand which biomarker, or combination of biomarkers will provide the most accurate measure of physiological stress processes.},
}
@article {pmid35338551,
year = {2022},
author = {Navrátilová, P and Toegelová, H and Tulpová, Z and Kuo, YT and Stein, N and Doležel, J and Houben, A and Šimková, H and Mascher, M},
title = {Prospects of telomere-to-telomere assembly in barley: Analysis of sequence gaps in the MorexV3 reference genome.},
journal = {Plant biotechnology journal},
volume = {20},
number = {7},
pages = {1373-1386},
pmid = {35338551},
issn = {1467-7652},
mesh = {Chromosomes, Plant/genetics ; DNA, Ribosomal/genetics ; Genome, Plant/genetics ; *Hordeum/genetics ; Sequence Analysis, DNA ; Telomere/genetics ; },
abstract = {The first gapless, telomere-to-telomere (T2T) sequence assemblies of plant chromosomes were reported recently. However, sequence assemblies of most plant genomes remain fragmented. Only recent breakthroughs in accurate long-read sequencing have made it possible to achieve highly contiguous sequence assemblies with a few tens of contigs per chromosome, that is a number small enough to allow for a systematic inquiry into the causes of the remaining sequence gaps and the approaches and resources needed to close them. Here, we analyse sequence gaps in the current reference genome sequence of barley cv. Morex (MorexV3). Optical map and sequence raw data, complemented by ChIP-seq data for centromeric histone variant CENH3, were used to estimate the abundance of centromeric, ribosomal DNA, and subtelomeric repeats in the barley genome. These estimates were compared with copy numbers in the MorexV3 pseudomolecule sequence. We found that almost all centromeric sequences and 45S ribosomal DNA repeat arrays were absent from the MorexV3 pseudomolecules and that the majority of sequence gaps can be attributed to assembly breakdown in long stretches of satellite repeats. However, missing sequences cannot fully account for the difference between assembly size and flow cytometric genome size estimates. We discuss the prospects of gap closure with ultra-long sequence reads.},
}
@article {pmid35337624,
year = {2022},
author = {Praveen, G and Sivaprasad, M and Reddy, GB},
title = {Telomere length and vitamin B12.},
journal = {Vitamins and hormones},
volume = {119},
number = {},
pages = {299-324},
doi = {10.1016/bs.vh.2022.01.014},
pmid = {35337624},
issn = {0083-6729},
mesh = {Aging/genetics ; Cellular Senescence ; Humans ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; *Vitamin B 12 ; },
abstract = {Telomeres are non-coding nucleoprotein structures consisting of a highly conserved tandem repeat DNA sequence that caps the ends of chromosomes in eukaryotes. Telomeres confer chromosomal stability, protect the genome from nucleolytic degradation, avoid aberrant recombination and improper repair, and prevent random fusion of chromosomes. The end-replication problem results in telomere shortening with every cell division, eventually leading to cellular senescence and aging. Telomere length (TL) is thereby an ideal candidate for "biological aging." Telomeres possess guanine-rich repeats, which are highly susceptible to oxidative stress. Epidemiological studies have indicated the association of telomere attrition with mortality and various age-related diseases. Micronutrients comprising vitamins and minerals act as potential modulators of stress and can influence TL. Research has indicated that vitamin B12 (B12) regulates oxidative stress and maintains genomic stability, thereby influencing telomere integrity and cellular aging. The deficiency of B12 leads to elevated levels of homocysteine, which reduces the methylation potential and increases oxidative stress, thereby compromising the TL. Telomere shortening and mitochondrial dysfunction are independently linked to aging. However, they are connected through telomerase reverse transcriptase activity, which regulates mitochondrial biogenesis. Further, experimental evidence indicated the positive association of B12 with relative TL and mitochondrial DNA copy number, an indirect index of mitochondrial biogenesis. The present chapter provides some insights into the role of B12 in influencing TL. Exploring their association might open new avenues to understand the pathophysiology of aging and age-related diseases.},
}
@article {pmid35337612,
year = {2022},
author = {Wan, S and Zhao, X and Pei, J and Han, Z and Che, R and Qin, S and Hua, X},
title = {Association of age at benign hysterectomy with leukocyte telomere length in a nationally representative population.},
journal = {Maturitas},
volume = {159},
number = {},
pages = {46-51},
doi = {10.1016/j.maturitas.2022.01.002},
pmid = {35337612},
issn = {1873-4111},
mesh = {Cross-Sectional Studies ; Female ; Humans ; Hysterectomy/adverse effects ; *Leukocytes ; Nutrition Surveys ; *Telomere ; },
abstract = {OBJECTIVES: Hysterectomy is one of the most common gynecological surgical procedures, and most hysterectomies are performed for benign indications. Despite the frequency and known benefits of the procedure, it remains unclear whether it has potential adverse effects on long-term health and longevity. The aim of this study was to evaluate the association of age at benign hysterectomy with leukocyte telomere length, in data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002.<br><br>STUDY DESIGN: In total, 811 women who had a hysterectomy were included in this cross-sectional study.<br><br>MAIN OUTCOME MEASURES: To estimate the association of age at benign hysterectomy with telomere length, multivariate regression analyses adjusted for age, race/ ethnicity, education, marital status, income poverty ratio, body mass index (BMI), physical activity, smoking behavior, alcohol consumption, history of chronic disease and history of oophorectomy were conducted. Fitted smoothing curves were also evaluated.<br><br>RESULTS: We found leukocyte telomere length was positively correlated with age at benign hysterectomy after adjusting for other confounders in both a minimally adjusted model [&#x3b2;&#xa0;=&#xa0;4.18, 95%CI: (0.17,8.20)] and a fully adjusted model [&#x3b2;&#xa0;=&#xa0;4.63, 95% CI:(0.56,8.70)].<br><br>CONCLUSIONS: Earlier age at benign hysterectomy was associated with shorter telomere length in a nationally representative population of women. These data provide new information in pre-surgical counseling and decision-making.},
}
@article {pmid35334902,
year = {2022},
author = {Raftopoulou, C and Paltoglou, G and Charmandari, E},
title = {Association between Telomere Length and Pediatric Obesity: A Systematic Review.},
journal = {Nutrients},
volume = {14},
number = {6},
pages = {},
pmid = {35334902},
issn = {2072-6643},
support = {project code: T1EDK-01386, MIS: 5030543, Acronym: PEDOBESITY//This research was co-financed by the European Regional Development Fund of the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call RESEARCH-CREATE-INNOVATE/ ; },
mesh = {Adult ; Aging ; Child ; Humans ; *Pediatric Obesity ; Prospective Studies ; Telomere ; Telomere Homeostasis ; },
abstract = {OBJECTIVE: Telomere length (TL) is a robust marker of biological aging, and increased telomere attrition is noted in adults with obesity. The primary objective of this systematic review was to summarize current knowledge on the effects of childhood obesity in TL. The secondary objective was to assess the effect of weight management interventions in TL.<br><br>METHODS: The following databases were searched: PubMed, Scopus, Web of Science and Heal-link.gr from inception to September 2021. The search was performed using the following combinations of terms: "telomer*" [All Fields] AND ("length" [All Fields] OR "lengths" [All Fields]) AND "obes*" [All Fields] AND ("child*" [All Fields] OR "adolescen*" [All Fields]).<br><br>RESULTS: A total of 16 original articles were included in this systematic review. Eleven of them were cross-sectional and five were lifestyle interventions.<br><br>CONCLUSIONS: There was a tendency towards a negative association between childhood obesity and TL. Life-style interventions in children have been associated with increased TL peripherally, indicating a possible association of the redistribution of younger cells in the periphery with the favorable effect of these interventions. Further prospective studies with larger sample sizes that employ other markers of cell aging would potentially elucidate this important mechanistic relation.},
}
@article {pmid35334391,
year = {2022},
author = {Li, X and Cai, J and Yang, L and Zhang, X and Deng, W and Ni, P and Zhao, L and Du, XD and Li, T},
title = {Correlation between reduced telomere length and behavioural and emotional problems in left-behind children in a rural area in China.},
journal = {Psychoneuroendocrinology},
volume = {140},
number = {},
pages = {105732},
doi = {10.1016/j.psyneuen.2022.105732},
pmid = {35334391},
issn = {1873-3360},
mesh = {Adolescent ; Child ; China ; Humans ; *Mental Health ; *Self Concept ; Surveys and Questionnaires ; Telomere ; },
abstract = {Evidence shows that being left behind experience (LBE) during childhood may increase the risks of poor psychopathological outcomes. However, it is unclear to what extent the mental health is affected by the LBE. Telomere length (TL), one of the most extensively studied biological markers of cellular ageing, provides a valuable tool for exploring the potential effects of parent-child separation on psychological problems by integrating genetic and environmental factors. In this study, a total of 613 children (mean age = 10.77, SD = 1.92) were recruited from the rural area of Deyang, Sichuan Province, China. We used a self-designed questionnaire to assess LBE, and collected psychopathological outcomes by using the Piers-Harris Children's Self-concept Scale, the Teacher's Report Form 6/18 and the Youth Self-Report 11/18. Terminal restriction fragment analysis was used to measure TL in peripheral blood leukocytes. Analyses revealed that 342 out of 613 participants (55.79%) were Left-behind children. LBE was observed to associated with shorter TL, lower self-esteem, and increased behavioural and emotional problems. The cumulative effects of LBE may be reflected by greater altered telomere homeostasis, decreased self-esteem, and worsened behavioural and emotional problems. The association of the total time of being left behind with self-esteem and behavioural and emotional problems was significantly mediated by altered telomere homeostasis, with estimated effects of 14.19%, 47.95% and 45.13%, respectively. The LBE in childhood, especially prolonged parent-child separation, increases the risk of mental health problems in childhood and adolescence.},
}
@article {pmid35330058,
year = {2022},
author = {Sánchez-González, JL and Sánchez-Rodríguez, JL and Juárez-Vela, R and Ruiz de Viñaspre-Hernandez, R and González-Sarmiento, R and Martin-Vallejo, FJ},
title = {Analysis of Telomere Length and Its Implication in Neurocognitive Functions in Elderly Women.},
journal = {Journal of clinical medicine},
volume = {11},
number = {6},
pages = {},
pmid = {35330058},
issn = {2077-0383},
abstract = {During the normal aging process, a series of events occur, such as a decrease in telomere length and a decrease in various cognitive functions, such as attention, memory, or perceptual-motor speed. Several studies have attempted to establish a correlation between both variables; however, there is considerable controversy in the scientific literature. The aim of our study was to establish a correlation between the scores obtained in the following different cognitive tests: the Mini-Mental State Examination, the Benton Visual Retention Test, the Trail Making Test, the Rey Auditory Verbal Learning Test, the Stroop Test, and the measurement of telomere length. The sample consisted of a total of 41 physically active, healthy women, with a mean age of 71.21 (±4.32) and of 33 physically inactive, healthy women, with a mean age of 72.70 (±4.13). Our results indicate that there is no correlation between the scores obtained by the women in either group and their telomere length. Therefore, it is not possible to conclude that telomere length can be correlated with cognitive performance.},
}
@article {pmid35328692,
year = {2022},
author = {Oliva-Rico, D and Fabian-Morales, E and Cáceres-Gutiérrez, RE and Gudiño, A and Cisneros-Soberanis, F and Dominguez, J and Almaraz-Rojas, O and Arriaga-Canon, C and Castro-Hernández, C and De la Rosa, C and Reyes, JL and Herrera, LA},
title = {Methylation of Subtelomeric Chromatin Modifies the Expression of the lncRNA TERRA, Disturbing Telomere Homeostasis.},
journal = {International journal of molecular sciences},
volume = {23},
number = {6},
pages = {},
pmid = {35328692},
issn = {1422-0067},
support = {513107//Consejo Nacional de Ciencia y Tecnolog&#xed;a/ ; },
mesh = {Chromatin/genetics ; Heterochromatin ; Methylation ; *RNA, Long Noncoding/genetics/metabolism ; Telomere/genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {The long noncoding RNA (lncRNA) telomeric repeat-containing RNA (TERRA) has been associated with telomeric homeostasis, telomerase recruitment, and the process of chromosome healing; nevertheless, the impact of this association has not been investigated during the carcinogenic process. Determining whether changes in TERRA expression are a cause or a consequence of cell transformation is a complex task because studies are usually carried out using either cancerous cells or tumor samples. To determine the role of this lncRNA in cellular aging and chromosome healing, we evaluated telomeric integrity and TERRA expression during the establishment of a clone of untransformed myeloid cells. We found that reduced expression of TERRA disturbed the telomeric homeostasis of certain loci, but the expression of the lncRNA was affected only when the methylation of subtelomeric bivalent chromatin domains was compromised. We conclude that the disruption in TERRA homeostasis is a consequence of cellular transformation and that changes in its expression profile can lead to telomeric and genomic instability.},
}
@article {pmid35328421,
year = {2022},
author = {Porika, M and Tippani, R and Saretzki, GC},
title = {CRISPR/Cas: A New Tool in the Research of Telomeres and Telomerase as Well as a Novel Form of Cancer Therapy.},
journal = {International journal of molecular sciences},
volume = {23},
number = {6},
pages = {},
pmid = {35328421},
issn = {1422-0067},
mesh = {CRISPR-Cas Systems/genetics ; Gene Editing/methods ; *Neoplasms/genetics/therapy ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {Due to their close connection with senescence, aging, and disease, telomeres and telomerase provide a unique and vital research route for boosting longevity and health span. Despite significant advances during the last three decades, earlier studies into these two biological players were impeded by the difficulty of achieving real-time changes inside living cells. As a result of the clustered regularly interspaced short palindromic repeats (CRISPR)-associated system's (Cas) method, targeted genetic studies are now underway to change telomerase, the genes that govern it as well as telomeres. This review will discuss studies that have utilized CRISPR-related technologies to target and modify genes relevant to telomeres and telomerase as well as to develop targeted anti-cancer therapies. These studies greatly improve our knowledge and understanding of cellular and molecular mechanisms that underlie cancer development and aging.},
}
@article {pmid35325218,
year = {2022},
author = {Miki, S and Koga, T and Mckinney, AM and Parisian, AD and Tadokoro, T and Vadla, R and Marsala, M and Hevner, RF and Costello, JF and Furnari, F},
title = {TERT promoter C228T mutation in neural progenitors confers growth advantage following telomere shortening in vivo.},
journal = {Neuro-oncology},
volume = {24},
number = {12},
pages = {2063-2075},
pmid = {35325218},
issn = {1523-5866},
support = {F31 CA243187/CA/NCI NIH HHS/United States ; R01 CA258248/CA/NCI NIH HHS/United States ; P50 CA097257/CA/NCI NIH HHS/United States ; T32 GM008666/GM/NIGMS NIH HHS/United States ; R01 NS080939/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; Mice ; Animals ; Telomere Shortening/genetics ; *Induced Pluripotent Stem Cells ; *Telomerase/genetics ; Telomere/genetics ; *Glioblastoma/genetics ; Mutation ; Carcinogenesis ; },
abstract = {BACKGROUND: Heterozygous TERT (telomerase reverse transcriptase) promoter mutations (TPMs) facilitate TERT expression and are the most frequent mutation in glioblastoma (GBM). A recent analysis revealed this mutation is one of the earliest events in gliomagenesis. However, no appropriate human models have been engineered to study the role of this mutation in the initiation of these tumors.<br><br>METHOD: We established GBM models by introducing the heterozygous TPM in human induced pluripotent stem cells (hiPSCs) using a two-step targeting approach in the context of GBM genetic alterations, CDKN2A/B and PTEN deletion, and EGFRvIII overexpression. The impact of the mutation was evaluated through the in vivo passage and in vitro experiment and analysis.<br><br>RESULTS: Orthotopic injection of neuronal precursor cells (NPCs) derived from hiPSCs with the TPM into immunodeficient mice did not enhance tumorigenesis compared to TERT promoter wild type NPCs at initial in vivo passage presumably due to relatively long telomeres. However, the mutation recruited GA-Binding Protein and engendered low-level TERT expression resulting in enhanced tumorigenesis and maintenance of short telomeres upon secondary passage as observed in human GBM. These results provide the first insights regarding increased tumorigenesis upon introducing a TPM compared to isogenic controls without TPMs.<br><br>CONCLUSION: Our novel GBM models presented the growth advantage of heterozygous TPMs for the first time in the context of GBM driver mutations relative to isogenic controls, thereby allowing for the identification and validation of TERT promoter-specific vulnerabilities in a genetically accurate background.},
}
@article {pmid35323880,
year = {2022},
author = {Shimamura, A},
title = {Telomere biology disorders: ends and (genetic) means.},
journal = {Blood},
volume = {139},
number = {12},
pages = {1776-1777},
doi = {10.1182/blood.2021014855},
pmid = {35323880},
issn = {1528-0020},
mesh = {Biology ; *Telomerase/genetics/metabolism ; *Telomere/genetics/metabolism ; },
}
@article {pmid35323213,
year = {2022},
author = {Lister-Shimauchi, EH and McCarthy, B and Lippincott, M and Ahmed, S},
title = {Genetic and Epigenetic Inheritance at Telomeres.},
journal = {Epigenomes},
volume = {6},
number = {1},
pages = {},
pmid = {35323213},
issn = {2075-4655},
support = {R01 GM135470/GM/NIGMS NIH HHS/United States ; },
abstract = {Transgenerational inheritance can occur at telomeres in distinct contexts. Deficiency for telomerase or telomere-binding proteins in germ cells can result in shortened or lengthened chromosome termini that are transmitted to progeny. In human families, altered telomere lengths can result in stem cell dysfunction or tumor development. Genetic inheritance of altered telomeres as well as mutations that alter telomeres can result in progressive telomere length changes over multiple generations. Telomeres of yeast can modulate the epigenetic state of subtelomeric genes in a manner that is mitotically heritable, and the effects of telomeres on subtelomeric gene expression may be relevant to senescence or other human adult-onset disorders. Recently, two novel epigenetic states were shown to occur at C. elegans telomeres, where very low or high levels of telomeric protein foci can be inherited for multiple generations through a process that is regulated by histone methylation.Together, these observations illustrate that information relevant to telomere biology can be inherited via genetic and epigenetic mechanisms, although the broad impact of epigenetic inheritance to human biology remains unclear.},
}
@article {pmid35317118,
year = {2021},
author = {Fathi, E and Vandghanooni, S and Montazersaheb, S and Farahzadi, R},
title = {Mesenchymal stem cells promote caspase-3 expression of SH-SY5Y neuroblastoma cells via reducing telomerase activity and telomere length.},
journal = {Iranian journal of basic medical sciences},
volume = {24},
number = {11},
pages = {1583-1589},
pmid = {35317118},
issn = {2008-3866},
abstract = {OBJECTIVES: The use of mesenchymal stem cells in malignancies has attracted much attention due to their ability to deliver anticancer agents to tumors, including cytokines, chemokines, etc. This study aimed to investigate the effect of MSCs on the neuroblastoma SH-SY5Y cells through proliferation/apoptosis, senescence assessment, telomere length, and telomerase activity in vitro. BAX and BCL2 were also examined as potential signaling pathways in this process.<br><br>MATERIALS AND METHODS: For this reason, two cell populations (MSCs and SH-SY5Y cells) were co-cultured on trans-well plates for 7 days. In a subsequent step, SH-SY5Y cells were harvested from both control and experimental groups and subjected to flow cytometry, ELISA, real-time PCR, PCR-ELISA TRAP assay, and Western blotting assay for Ki67/Caspase3 investigation, &#x3b2;-Galactosidase assessment, telomere length, and telomerase activity assay. Also, expression of genes and proteins through real-time PCR and Western blotting demonstrated the involvement of the aforementioned signaling pathways in this process.<br><br>RESULTS: It was found that MSCs contributed significantly to decrease and increase of Ki-67 and Caspase-3, respectively. Also, MSCs dramatically reduced the length of telomere and telomerase activity and increased the &#x3b2;-Galactosidase activity in a significant manner. In addition, significant increase and decrease were also seen in BAX and BCL2 gene and protein expressions, respectively.<br><br>CONCLUSION: These findings revealed that close interaction between MSCs and neuroblastoma cells causes inhibition of the SH-SY5Y cell proliferation and promotes cell senescence via BAX and caspase-3 cascade pathways.},
}
@article {pmid35316424,
year = {2022},
author = {Berteli, TS and Wang, F and Kohlrausch, FB and Da Luz, CM and Oliveira, FV and Keefe, DL and Navarro, PA},
title = {Impact of superovulation and in vitro fertilization on LINE-1 copy number and telomere length in C57BL/6 J mice blastocysts.},
journal = {Molecular biology reports},
volume = {49},
number = {6},
pages = {4909-4917},
pmid = {35316424},
issn = {1573-4978},
support = {88887.371487/2019-00//Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior/ ; 204747/2018-0//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; },
mesh = {Animals ; Blastocyst ; *DNA Copy Number Variations/genetics ; Female ; Fertilization in Vitro ; Mice ; Mice, Inbred C57BL ; *Superovulation ; Telomere/genetics ; },
abstract = {OBJECTIVE: Millions of babies have been conceived by IVF, yet debate about its safety to offspring continues. We hypothesized that superovulation and in vitro fertilization (IVF) promote genomic changes, including altered telomere length (TL) and activation of the retrotransposon LINE-1 (L1), and tested this hypothesis in a mouse model.<br><br>MATERIAL AND METHODS: Experimental study analyzing TL and L1 copy number in C57BL/6&#xa0;J mouse blastocysts in vivo produced from natural mating cycles (N), in vivo produced following superovulation (S), or in vitro produced following superovulation (IVF). We also examined the effects of prolonged culture on TL and L1 copy number in the IVF group comparing blastocysts cultured 96&#xa0;h versus blastocysts cultured 120&#xa0;h. TL and L1 copy number were measured by Real Time PCR.<br><br>RESULTS: TL in S (n&#x2009;=&#x2009;77; Mean: 1.50&#x2009;&#xb1;&#x2009;1.15; p&#x2009;=&#x2009;0.0007) and IVF (n&#x2009;=&#x2009;82; Mean: 1.72&#x2009;&#xb1;&#x2009;1.44; p&#x2009;<&#x2009;0.0001) exceeded that in N (n&#x2009;=&#x2009;16; Mean: 0.61&#x2009;&#xb1;&#x2009;0.27). TL of blastocysts cultured 120&#xa0;h (n&#x2009;=&#x2009;15, Mean: 2.14&#x2009;&#xb1;&#x2009;1.05) was significantly longer than that of embryos cultured for 96&#xa0;h (n&#x2009;=&#x2009;67, Mean: 1.63&#x2009;&#xb1;&#x2009;1.50; p&#x2009;=&#x2009;0.0414). L1 copy number of blastocysts cultured for 120&#xa0;h (n&#x2009;=&#x2009;15, Mean: 1.71&#x2009;&#xb1;&#x2009;1.49) exceeded that of embryos cultured for 96&#xa0;h (n&#x2009;=&#x2009;67, Mean: 0.95&#x2009;&#xb1;&#x2009;1.03; p&#x2009;=&#x2009;0.0162).<br><br>CONCLUSIONS: Intriguingly ovarian stimulation, alone or followed by IVF, produced embryos with significantly longer telomeres compared to in vivo, natural cycle-produced embryos. The significance of this enriched telomere endowment for the health and longevity of offspring born from IVF merit future studies.},
}
@article {pmid35313074,
year = {2022},
author = {Lv, N and Zhao, Y and Liu, X and Ye, L and Liang, Z and Kang, Y and Dong, Y and Wang, W and Kolliputi, N and Shi, L},
title = {Dysfunctional telomeres through mitostress-induced cGAS/STING activation to aggravate immune senescence and viral pneumonia.},
journal = {Aging cell},
volume = {21},
number = {4},
pages = {e13594},
pmid = {35313074},
issn = {1474-9726},
mesh = {Animals ; *COVID-19 ; *Immunity, Innate ; Inflammation ; Membrane Proteins/genetics/metabolism ; Mice ; Nucleotidyltransferases/genetics/metabolism ; SARS-CoV-2 ; Signal Transduction ; Telomere/metabolism ; },
abstract = {Disproportionately high incidence and mortality of respiratory infection such as influenza A virus (IAV) and SARS-CoV-2 have been evidenced in the elderly, but the role and the mechanism of age-associated immune deregulation in disease exacerbation are not well defined. Using a late generation of mice deficient in telomerase RNA (Terc[-/-]), we herein demonstrated that aged mice were exquisitely susceptible to respiratory viral infection, with excessive inflammation and increased mortality. Furthermore, we identified the cGAS/STING pathway, which was essentially induced by the leaked mitochondrial DNA, as a biologically relevant mechanism contributing to exaggerated inflammation in Terc[-/-] mice following viral infection. Innate immune cells, mainly, macrophages with shortened telomeres, exhibited hallmarks of cellular senescence, mitochondrial distress, and aberrant activation of STING and NLRP3 inflammasome pathways, which predisposed mice to severe viral pneumonia during commonly mild infections. Application of STING inhibitor and, more importantly, senolytic agent, reduced the burden of stressed macrophages, improved mitochondrial integrity, and suppressed STING activation, thereby conferring the protection for Terc[-/-] mice against respiratory infection. Together, the findings expand our understanding of innate immune senescence and reveal the potential of the senolytics as a promising treatment to alleviate the symptom of viral pneumonia, particularly for the older population.},
}
@article {pmid35312207,
year = {2022},
author = {Wu, W and Du, Z and Wu, L},
title = {Dexmedetomidine attenuates hypoxia-induced cardiomyocyte injury by promoting telomere/telomerase activity: Possible involvement of ERK1/2-Nrf2 signaling pathway.},
journal = {Cell biology international},
volume = {46},
number = {7},
pages = {1036-1046},
doi = {10.1002/cbin.11799},
pmid = {35312207},
issn = {1095-8355},
mesh = {Apoptosis ; Cardiomegaly/metabolism ; *Dexmedetomidine/metabolism/pharmacology ; Humans ; Hypoxia/metabolism ; MAP Kinase Signaling System ; Myocytes, Cardiac/metabolism ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; RNA, Messenger/metabolism ; Signal Transduction ; *Telomerase/genetics ; Telomere/metabolism ; },
abstract = {Dexmedetomidine (Dex), an α2-adrenergic receptor (α2-AR) agonist, possesses cardioprotection against ischemic/hypoxic injury, but the exact mechanism is not fully elucidated. Since telomere/telomerase dysfunction is involved in myocardial ischemic damage, the present study aimed to investigate whether Dex ameliorates cobalt chloride (CoCl2; a hypoxia mimic agent in vitro)-induced the damage of H9c2 cardiomyocytes by improving telomere/telomerase dysfunction and further explored the underlying mechanism focusing on extracellular signal-regulated kinase (ERK1/2)-NF-E2-related factor 2 (Nrf2) signaling pathway. The result showed that Dex increased cell viability, decreased apoptosis, and reduced cardiomyocyte hypertrophy as illustrated by the decreases in cell surface area and the biomarker levels for cardiac hypertrophy including atrial natriuretic peptide, brain natriuretic peptide, and myosin heavy chain β messenger RNA (mRNA) and protein in CoCl2 -exposed H9c2 cells. Intriguingly, Dex increased the telomere length and telomerase activity as well as telomere reverse transcriptase protein and mRNA levels in H9c2 cells exposed to CoCl2 , indicating that Dex promotes telomere/telomerase function under hypoxia. In addition, Dex remarkably diminished the reactive oxygen species generation, reduced malondialdehyde content, and increased antioxidative signaling as evidenced by the increases in superoxide dismutase and plasma glutathione peroxidase activities. Furthermore, Dex increased the ratio of P-ERK1/2/T-ERK1/2 and P-Nrf2/T-Nrf2 and enhanced Nrf2 nuclear translocation in CoCl2 -subjected H9c2 cells, suggesting that Dex promotes the activation of the ERK1/2-Nrf2 signaling pathway. These novel findings indicated that Dex attenuates myocardial ischemic damage and reduces myocardial hypertrophy by promoting telomere/telomerase function, which may be associated with the activation of the ERK1/2-Nrf2 signaling pathway in vitro.},
}
@article {pmid35297226,
year = {2022},
author = {Bountziouka, V and Nelson, CP and Codd, V and Wang, Q and Musicha, C and Allara, E and Kaptoge, S and Di Angelantonio, E and Butterworth, AS and Thompson, JR and Curtis, EM and Wood, AM and Danesh, JN and Harvey, NC and Cooper, C and Samani, NJ},
title = {Association of shorter leucocyte telomere length with risk of frailty.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {13},
number = {3},
pages = {1741-1751},
pmid = {35297226},
issn = {2190-6009},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; MR/M012816/1//UK Medical Research Council (MRC)/ ; MR/L003120/1/MRC_/Medical Research Council/United Kingdom ; /BHF_/British Heart Foundation/United Kingdom ; MC_PC_21022/MRC_/Medical Research Council/United Kingdom ; MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Cross-Sectional Studies ; Female ; *Frailty/epidemiology/genetics ; Humans ; Leukocytes ; Male ; Risk Factors ; Telomere/genetics ; },
abstract = {BACKGROUND: Frailty is a multidimensional syndrome of decline that affects multiple systems and predisposes to adverse health outcomes. Although chronological age is the major risk factor, inter-individual variation in risk is not fully understood. Leucocyte telomere length (LTL), a proposed marker of biological age, has been associated with risk of many diseases. We sought to determine whether LTL is associated with risk of frailty.<br><br>METHODS: We utilized cross-sectional data from 441&#xa0;781 UK Biobank participants (aged 40-69&#xa0;years), with complete data on frailty indicators and LTL. Frailty was defined as the presence of at least three of five indicators: weaker grip strength, slower walking pace, weight loss in the past year, lower physical activity, and exhaustion in the past 2&#xa0;weeks. LTL was measured using a validated qPCR method and reported as a ratio of the telomere repeat number (T) to a single-copy gene (S) (T/S ratio). Association of LTL with frailty was evaluated using adjusted (chronological age, sex, deprivation, smoking, alcohol intake, body mass index, and multimorbidity) multinomial and ordinal regression models, and results are presented as relative risk (RRR) or odds ratios (OR), respectively, alongside the 95% confidence interval (CI). Mendelian randomization (MR), using 131 genetic variants associated with LTL, was used to assess if the association of LTL with frailty was causal.<br><br>RESULTS: Frail participants (4.6%) were older (median age difference (95% CI): 3 (2.5; 3.5) years, P&#xa0;=&#xa0;2.73&#xa0;&#xd7;&#xa0;10[-33]), more likely to be female (61%, P&#xa0;=&#xa0;1.97&#xa0;&#xd7;&#xa0;10[-129]), and had shorter LTL (-0.13SD vs. 0.03SD, P&#xa0;=&#xa0;5.43&#xa0;&#xd7;&#xa0;10[-111]) than non-frail. In adjusted analyses, both age and LTL were associated with frailty (RRR&#xa0;=&#xa0;1.03 (95% CI: 1.02; 1.04) per year of older chronological age, P&#xa0;=&#xa0;3.99&#xa0;&#xd7;&#xa0;10[-12] ; 1.10 (1.08; 1.11) per SD shorter LTL, P&#xa0;=&#xa0;1.46&#xa0;&#xd7;&#xa0;10[-30]). Within each age group (40-49, 50-59, 60-69&#xa0;years), the prevalence of frailty was about 33% higher in participants with shorter (-2SD) versus longer telomeres (+2SD). MR analysis showed an association of LTL with frailty that was directionally consistent with the observational association, but not statistically significant (MR-Median: OR (95% CI): 1.08 (0.98; 1.19) per SD shorter LTL, P&#xa0;=&#xa0;0.13).<br><br>CONCLUSIONS: Inter-individual variation in LTL is associated with the risk of frailty independently of chronological age and other risk factors. Our findings provide evidence for an additional biological determinant of frailty.},
}
@article {pmid35296692,
year = {2022},
author = {Törn, C and Liu, X and Onengut-Gumuscu, S and Counts, KM and Moreno, JL and Remedios, CL and Chen, WM and LeFaive, J and Butterworth, MD and Akolkar, B and Krischer, JP and Lernmark, &#xc5; and Rewers, M and She, JX and Toppari, J and Ziegler, AG and Ratan, A and Smith, AV and Hagopian, WA and Rich, SS and Parikh, HM and , },
title = {Telomere length is not a main factor for the development of islet autoimmunity and type 1 diabetes in the TEDDY study.},
journal = {Scientific reports},
volume = {12},
number = {1},
pages = {4516},
pmid = {35296692},
issn = {2045-2322},
support = {UC4 DK063836/DK/NIDDK NIH HHS/United States ; UC4 DK112243/DK/NIDDK NIH HHS/United States ; U01 DK063865/DK/NIDDK NIH HHS/United States ; U01 DK063821/DK/NIDDK NIH HHS/United States ; UC4 DK063821/DK/NIDDK NIH HHS/United States ; UC4 DK117483/DK/NIDDK NIH HHS/United States ; UL1 TR001082/TR/NCATS NIH HHS/United States ; U01 DK063836/DK/NIDDK NIH HHS/United States ; /JDRF/Juvenile Diabetes Research Foundation/United States ; U01 DK124166/DK/NIDDK NIH HHS/United States ; U01 DK128847/DK/NIDDK NIH HHS/United States ; U01 DK063861/DK/NIDDK NIH HHS/United States ; UC4 DK095300/DK/NIDDK NIH HHS/United States ; UC4 DK063865/DK/NIDDK NIH HHS/United States ; UC4 DK063863/DK/NIDDK NIH HHS/United States ; UC4 DK100238/DK/NIDDK NIH HHS/United States ; HHSN267200700014C/LM/NLM NIH HHS/United States ; U01 DK063790/DK/NIDDK NIH HHS/United States ; U01 DK063863/DK/NIDDK NIH HHS/United States ; UC4 DK063829/DK/NIDDK NIH HHS/United States ; UL1 TR000064/TR/NCATS NIH HHS/United States ; UC4 DK063861/DK/NIDDK NIH HHS/United States ; UC4 DK106955/DK/NIDDK NIH HHS/United States ; },
mesh = {Autoantibodies ; Autoimmunity/genetics ; Case-Control Studies ; Child ; *Diabetes Mellitus, Type 1 ; Female ; Genetic Predisposition to Disease ; Genotype ; Humans ; *Islets of Langerhans ; Telomere/genetics ; },
abstract = {The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8676 children, 3-4 months of age, born with HLA-susceptibility genotypes for islet autoimmunity (IA) and type 1 diabetes (T1D). Whole-genome sequencing (WGS) was performed in 1119 children in a nested case-control study design. Telomere length was estimated from WGS data using five tools: Computel, Telseq, Telomerecat, qMotif and Motif_counter. The estimated median telomere length was 5.10 kb (IQR 4.52-5.68 kb) using Computel. The age when the blood sample was drawn had a significant negative correlation with telomere length (P = 0.003). European children, particularly those from Finland (P = 0.041) and from Sweden (P = 0.001), had shorter telomeres than children from the U.S.A. Paternal age (P = 0.019) was positively associated with telomere length. First-degree relative status, presence of gestational diabetes in the mother, and maternal age did not have a significant impact on estimated telomere length. HLA-DR4/4 or HLA-DR4/X children had significantly longer telomeres compared to children with HLA-DR3/3 or HLA-DR3/9 haplogenotypes (P = 0.008). Estimated telomere length was not significantly different with respect to any IA (P = 0.377), IAA-first (P = 0.248), GADA-first (P = 0.248) or T1D (P = 0.861). These results suggest that telomere length has no major impact on the risk for IA, the first step to develop T1D. Nevertheless, telomere length was shorter in the T1D high prevalence populations, Finland and Sweden.},
}
@article {pmid35295138,
year = {2021},
author = {Mandakh, Y and Oudin, A and Erlandsson, L and Isaxon, C and Hansson, SR and Broberg, K and Malmqvist, E},
title = {Association of Prenatal Ambient Air Pollution Exposure With Placental Mitochondrial DNA Copy Number, Telomere Length and Preeclampsia.},
journal = {Frontiers in toxicology},
volume = {3},
number = {},
pages = {659407},
pmid = {35295138},
issn = {2673-3080},
abstract = {Background: Studies have shown that ambient air pollution is linked to preeclampsia (PE), possibly via generation of oxidative stress in the placenta. Telomere length and mitochondrial DNA copy number (mtDNAcn) are sensitive to oxidative stress damage. Objective: To study the association between prenatal exposure to ambient nitrogen oxides (NOx, a marker for traffic-related air pollution), and PE, as well as potential mediation effects by placental telomere length and mtDNAcn. Methods: This is a cross-sectional study of 42 preeclamptic and 95 arbitrarily selected normotensive pregnant women with gestational ambient NOx exposure assessment in southern Scania, Sweden. Hourly concentrations of NOx were estimated at the residential addresses by a Gaussian-plume dispersion model with 100 × 100 m spatial resolutions and aggregated into trimester-specific mean concentrations. Placental relative mtDNAcn and telomere length were measured using qPCR. Linear and logistic regression models were used to investigate associations, adjusted for perinatal and seasonal characteristics. Results: Exposure was categorized into low and high exposures by median cut-offs during first [11.9 μg/m[3]; interquartile range (IQR) 7.9, 17.9], second (11.6 μg/m[3]; IQR: 7.1, 21.1), third trimesters (11.9 μg/m[3]; IQR: 7.7, 19.5) and entire pregnancy (12.0 μg/m[3]; IQR: 7.6, 20.1). Increased risk of PE was found for high prenatal NOx exposure during the first trimester (OR 4.0; 95% CI: 1.4, 11.1; p = 0.008), and entire pregnancy (OR 3.7; 95% CI: 1.3, 10.4; p = 0.012). High exposed group during the first trimester had lower placental relative mtDNAcn compared with low exposed group (-0.20; 95% CI: -0.36, -0.04; p = 0.01). Changes in relative mtDNAcn did not mediate the association between prenatal NOx exposure and PE. No statistically significant association was found between placental relative telomere length, prenatal NOx exposure and PE. Conclusion: In this region with relatively low levels of air pollution, ambient NOx exposure during the first trimester was associated with reduced placental relative mtDNAcn and an increased risk of PE. However, we did not find any evidence that mtDNAcn or TL mediated the association between air pollution and PE. Future research should further investigate the role of mtDNAcn for pregnancy complications in relation to exposure to ambient air pollution during pregnancy.},
}
@article {pmid35294438,
year = {2022},
author = {Wei, H and Aucoin, J and Kuntapay, GR and Justice, A and Jones, A and Zhang, C and Santos, HP and Hall, LA},
title = {The prevalence of nurse burnout and its association with telomere length pre and during the COVID-19 pandemic.},
journal = {PloS one},
volume = {17},
number = {3},
pages = {e0263603},
pmid = {35294438},
issn = {1932-6203},
mesh = {Adult ; Burnout, Professional/*epidemiology/genetics/psychology ; COVID-19/complications/*epidemiology/psychology ; Clinical Competence ; Cross-Sectional Studies ; Female ; Humans ; Job Satisfaction ; Male ; Middle Aged ; Nursing Staff, Hospital/*psychology ; Prevalence ; Quality of Health Care ; Regression Analysis ; Telomere/*genetics ; Telomere Homeostasis ; Young Adult ; },
abstract = {BACKGROUND: Burnout is a work-related stress syndrome characterized by emotional exhaustion, depersonalization, and reduced personal accomplishment. Nurse burnout is related to nurses' deteriorating mental health and poorer patient care quality and thus, is a significant concern in healthcare. The Coronavirus Disease 2019 (COVID-19) pandemic has swept the world and distressed the healthcare systems. Because of the body's stress mechanism, it is vital to examine the current prevalence of nurse burnout and understand it at a biological level, using an epigenetic biomarker, telomere length.<br><br>PURPOSE: To determine the prevalence of burnout among nurses in the Peri-Operative and Labor &amp; Delivery settings pre and during the COVID-19 pandemic and to examine the effects of burnout on absolute telomere length.<br><br>METHODS: This is a cross-sectional study assessing the prevalence of nurses' burnout and the relationships between nurses' burnout and telomere length. Due to the COVID-19 pandemic, we had to stop the study during the mid of data collection. Even though the study was not designed to capture changes before and during the pandemic, we analyzed two groups' data before and during the pandemic. The study took place in a US hospital. Nurses in the hospital's Operating Room, Post-Anesthesia Care Unit, and Labor &amp; Delivery Unit participated in the study. Maslach Burnout Inventory survey and nurses' demographics were administered online. Telomere length was measured via finger-prick blood.<br><br>RESULTS: 146 nurses participated in the study, with 120 participants' blood samples collected. The high-level burnout rate was 70.5%. Correlation analysis did not reveal a direct correlation between nurse burnout and telomere length. However, in a multiple regression analysis, the final model contained the burnout subscale of emotional exhaustion, years as an RN, and work unit's nursing care quality. There was a low degree of departure from normality of the mean absolute telomere length in the pre-pandemic group and a substantial degree of departure in the during-pandemic group.<br><br>CONCLUSIONS: Nurse burnout is a prevalent phenomenon in healthcare, and this study indicates that nurses currently experience high levels of burnout. Nurses' cellular biomarker, telomere length, is shorter in the group of nurses during the COVID-19 pandemic than before. Appropriate measures should be implemented to decrease nurses' burnout symptoms and improve nurses' psychological and physical health. Nurses, especially those younger than 60, report higher burnout symptoms, particularly emotional exhaustion. This study indicates the need for intervention to promote nurses' health during the pandemic and beyond. If not appropriately managed, nurse burnout may continue to be a significant issue facing the healthcare system.},
}
@article {pmid35290636,
year = {2022},
author = {Barnes, RP and Thosar, SA and Fouquerel, E and Opresko, PL},
title = {Targeted Formation of 8-Oxoguanine in Telomeres.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2444},
number = {},
pages = {141-159},
pmid = {35290636},
issn = {1940-6029},
mesh = {Animals ; *DNA Damage ; Guanine/analogs &amp; derivatives/metabolism ; Mammals/genetics ; Oxidative Stress/genetics ; *Telomere/genetics/metabolism ; },
abstract = {Mammalian telomeres are guanine-rich sequences which cap the ends of linear chromosomes. While recognized as sites sensitive to oxidative stress, studies on the consequences of oxidative damage to telomeres have been primarily limited to experimental conditions which cause oxidative damage throughout the whole genome and cell. We developed a chemoptogenetic tool (FAP-mCER-TRF1) to specifically induce singlet oxygen at telomeres, resulting in the formation of the common oxidative lesion 8-oxo-guanine. Here, we describe this tool and detail how to generate cell lines which express FAP-mCER-TRF1 at telomeres and verify the formation of 8-oxo-guanine.},
}
@article {pmid35290406,
year = {2022},
author = {Shenouda, MM and Noyce, RS and Lee, SZ and Wang, JL and Lin, YC and Favis, NA and Desaulniers, MA and Evans, DH},
title = {The mismatched nucleotides encoded in vaccinia virus flip-and-flop hairpin telomeres serve an essential role in virion maturation.},
journal = {PLoS pathogens},
volume = {18},
number = {3},
pages = {e1010392},
pmid = {35290406},
issn = {1553-7374},
support = {PJT 159614//CIHR/Canada ; },
mesh = {Animals ; DNA ; Mice ; Mice, SCID ; *Nucleotides ; Telomere ; *Vaccinia virus/genetics ; Virion/genetics ; Virus Replication/genetics ; },
abstract = {Poxvirus genomes consist of a linear duplex DNA that ends in short inverted and complementary hairpin structures. These elements also encode loops and mismatches that likely serve a role in genome packaging and perhaps replication. We constructed mutant vaccinia viruses (VACV) where the native hairpins were replaced by altered forms and tested effects on replication, assembly, and virulence. Our studies showed that structure, not sequence, likely determines function as one can replace an Orthopoxvirus (VACV) hairpin with one copied from a Leporipoxvirus with no effect on growth. Some loops can be deleted from VACV hairpins with little effect, but VACV bearing too few mismatches grew poorly and we couldn't recover viruses lacking all mismatches. Further studies were conducted using a mutant bearing only one of six mismatches found in wild-type hairpins (SΔ1Δ3-6). This virus grew to ~20-fold lower titers, but neither DNA synthesis nor telomere resolution was affected. However, the mutant exhibited a particle-to-PFU ratio 10-20-fold higher than wild-type viruses and p4b/4b core protein processing was compromised, indicating an assembly defect. Electron microscopy showed that SΔ1Δ3-6 mutant development was blocked at the immature virus (IV) stage, which phenocopies known effects of I1L mutants. Competitive DNA binding assays showed that recombinant I1 protein had less affinity for the SΔ1Δ3-6 hairpin than the wild-type hairpin. The SΔ1Δ3-6 mutant was also attenuated when administered to SCID-NCR mice by tail scarification. Mice inoculated with viruses bearing wild-type hairpins exhibited a median survival of 30-37 days, while mice infected with SΔ1Δ3-6 virus survived >70 days. Persistent infections favor genetic reversion and genome sequencing detected one example where a small duplication near the hairpin tip likely created a new loop. These observations show that mismatches serve a critical role in genome packaging and provide new insights into how VACV "flip and flop" telomeres are arranged.},
}
@article {pmid35282254,
year = {2022},
author = {Méndez-Chacón, E},
title = {Gender Differences in Perceived Stress and Its Relationship to Telomere Length in Costa Rican Adults.},
journal = {Frontiers in psychology},
volume = {13},
number = {},
pages = {712660},
pmid = {35282254},
issn = {1664-1078},
support = {R01 AG031716/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: Stress is associated with disease and reduced leukocyte telomere length (LTL). The objective of this research is to determine if self-perceived stress is associated with telomere length in Costa Rican adults and the gender differences in this association. Findings may help explain how some populations in apparent socioeconomic disadvantage and with limited access to specialized medical services have a remarkably high life expectancy.<br><br>METHODOLOGY: Data come from the pre-retirement cohort of the Costa Rican Longevity and Healthy Aging Study (CRELES), a population based survey conducted in the households to 2,327 adults aged 53 to 66 years. The DNA to measure LTL was extracted from blood cells in laboratories of the University of Costa Rica whereas the Blackburn laboratory at the University of California performed the telomere length measurement applying the quantitative polymerase chain reaction (Q-PCR). The relationship between telomere length and perceived stress was measured using least-squares multiple regression. Perceived stress was measured by a set of questions about family, job, finances and, health reasons to be stressed. Models included the control variables: (1) age and sex of the participant, (2) whether he or she resides in the Nicoya area, a "blue zone" known for its high longevity, and (3) the aforementioned sociodemographic, health and lifestyles characteristics.<br><br>RESULTS: Stress perception and LTL are significantly different by sex. Women perceived higher stress levels than men in almost all aspects studied, except work. Women have significantly longer telomeres. Shorter telomeres are significantly associated with caregiving stress in men and with parental health concerns in women. Counter-intuitive telomere lengthenings were observed among women who feel stressed about caring for family members; and among men who feel stressed due to their family relationships as well as concerns about their own health.<br><br>DISCUSSION: Results confirm that people with self-perceived stress due to caregiving or health issues have shorter telomeres. The relationship between stress and telomere length differs between men and women. Gender relations exert a strong modifier effect on the relationship between stress and LTL: gender is related to perceived stress, telomere length, and apparently also to the way stress and LTL are related.},
}
@article {pmid35279598,
year = {2022},
author = {Yuan, H and Wu, Y and Wang, J and Qin, X and Huang, Y and Yan, L and Fana, Y and Zedenius, J and Juhlin, CC and Larsson, C and Lui, WO and Xu, D},
title = {Synergistic effects of telomerase reverse transcriptase and regulator of telomere elongation helicase 1 on aggressiveness and outcomes in adrenocortical carcinoma.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {149},
number = {},
pages = {112796},
doi = {10.1016/j.biopha.2022.112796},
pmid = {35279598},
issn = {1950-6007},
mesh = {*Adrenal Cortex Neoplasms/genetics ; *Adrenocortical Carcinoma/genetics ; Humans ; RNA, Messenger/genetics ; *Telomerase/genetics ; Telomere/genetics ; },
abstract = {Adrenocortical carcinoma (ACC) is one of the deadliest endocrine malignancies and telomere maintenance by activated telomerase is critically required for ACC development and progression. Because telomerase reverse transcriptase (TERT) and regulator of telomere elongation helicase 1 (RTEL1) play key roles in telomere homeostasis, we determined their effect on ACC pathogenesis and outcomes. Analyses of TCGA and GEO datasets showed significantly higher expression of RTEL1 but not TERT in ACC tumors, compared to their benign or normal counterparts. Furthermore, gains/amplifications of both TERT and RTEL1 genes were widespread in ACC tumors and their expression correlated with their gene copy numbers. Higher expression of either TERT or RTEL1 was associated with shorter overall and progression-free survival (OS and PFS) in the TCGA ACC patient cohort, and higher levels of both TERT and RTEL1 mRNA predicted the shortest patient OS and PFS. However, multivariate analyses showed that only RTEL1 independently predicted patient OS and PFS. Gene set enrichment analysis further showed enrichments of wnt/β-catenin, MYC, glycolysis, MTOR, and DNA repair signaling pathways in ACC tumors expressing high TERT and RTEL1 mRNA levels. Taken together, TERT and RTEL1 promote ACC aggressiveness synergistically and may serve as prognostic factors and therapeutic targets for ACC.},
}
@article {pmid35278080,
year = {2022},
author = {Chen, SS and Liao, XM and Wei, QZ and Zhou, YY and Su, MY and Hu, Y and Song, YY and Zhang, ZQ and Liang, JJ},
title = {Associations of the Gut Microbiota Composition and Fecal Short-Chain Fatty Acids with Leukocyte Telomere Length in Children Aged 6 to 9 Years in Guangzhou, China: A Cross-sectional Study.},
journal = {The Journal of nutrition},
volume = {152},
number = {6},
pages = {1549-1559},
doi = {10.1093/jn/nxac063},
pmid = {35278080},
issn = {1541-6100},
mesh = {Adult ; Child ; Cross-Sectional Studies ; Fatty Acids, Volatile/analysis ; Feces/chemistry ; *Gastrointestinal Microbiome/genetics ; Humans ; Leukocytes/chemistry ; RNA, Ribosomal, 16S/analysis/genetics ; Telomere ; Young Adult ; },
abstract = {BACKGROUND: Telomere length (TL) serves as a marker of cellular senescence and appears to plateau between the age of 4 y and young adulthood, after which the gut microbiota are supposed to be established. However, scarce data are available regarding the correlation between gut microbiota composition and TL in the pediatric population.<br><br>OBJECTIVES: We aimed to investigate whether the gut microbiota and the concentrations of SCFAs in feces are associated with leukocyte TL in children.<br><br>METHODS: In total, 401 children aged 6-9 y from Guangzhou were enrolled in this cross-sectional study. qPCR was used to determine relative TL in peripheral blood leukocytes. The gut microbiota was characterized by 16S ribosomal RNA amplicon sequencing and the fecal concentrations of total SCFAs and SCFA subtypes were determined using HPLC. The multivariate methods with an unbiased variable selection (MUVR) algorithm and partial least square models were used to select predictable operational taxonomic units (OTUs). Further correlation analyses were performed based on multiple linear regression models with adjustment for covariates and false discovery rate.<br><br>RESULTS: With the use of MUVR, 35 relevant and minimal optimal OTUs were finally selected. Multiple linear regression analysis showed that the abundance of several OTUs, including OTU334 (belonging to the genus Family XIII AD3011 group), OTU726 (belonging to the species Lachnoclostridium phocaeense), OTU1441 (belonging to the genus Ruminococcus torques group), OTU2553 (belonging to the genus Lachnospiraceae UCG-010), and OTU3375 (belonging to the family Lachnospiraceae), was negatively associated with leukocyte TL (&#x3b2;: -0.187 to -0.142; false discovery rate (FDR)-corrected P value (PFDR)&#xa0;=&#xa0;0.009-0.035]. However, neither SCFA subtype nor total SCFA content in feces exhibited significant associations with TL (&#x3b2;: -0.032 to 0.048; PFDR&#xa0;=&#xa0;0.915-0.969).<br><br>CONCLUSIONS: The gut microbiota, but not fecal SCFA concentration, was significantly associated with TL in this pediatric population.},
}
@article {pmid35274784,
year = {2022},
author = {Zhang, X and Shi, M and Zhao, X and Bin, E and Hu, Y and Tang, N and Dai, H and Wang, C},
title = {Telomere shortening impairs alveolar regeneration.},
journal = {Cell proliferation},
volume = {55},
number = {4},
pages = {e13211},
pmid = {35274784},
issn = {1365-2184},
support = {92068108//National Natural Science Foundation of China/ ; },
mesh = {Alveolar Epithelial Cells/metabolism ; Animals ; Cell Differentiation/physiology ; *Lung Injury/metabolism ; Mice ; Telomere/genetics ; Telomere Shortening ; },
abstract = {OBJECTIVES: Short telomeres in alveolar type 2 (AT2) cells have been associated with many lung diseases. The study aimed to investigate the regeneration capacity of AT2 cells with short telomeres by knocking out Tert in mice (G4 Tert[-/-]) from the whole to the cellular level.<br><br>MATERIALS AND METHODS: The lung injury model of mice was established by left pneumonectomy (PNX). The proliferation and differentiation of AT2 cells were observed by immunofluorescence staining in vivo and in vitro. The difference of the gene expression between control and G4 Tert[-/-] group during the regeneration of AT2 cells was compared by RNA sequencing. The expression of tubulin polymerization promoting protein 3 (TPPP3) was reduced by adeno-associated virus delivery.<br><br>RESULTS: The alveolar regeneration in G4 Tert[-/-] mice was impaired after PNX-induced lung injury. The regulation of cytoskeleton remodelling was defective in G4 Tert[-/-] AT2 cells. The expression of TPPP3 was gradually increased during AT2 cell differentiation. The expression level of TPPP3 was reduced in G4 Tert[-/-] AT2 cells. Reducing TPPP3 expression in AT2 cells limits the microtubule remodelling and differentiation of AT2 cells.<br><br>CONCLUSION: Short telomeres in AT2 cells result in the reduced expression level of TPPP3, leading to impaired regeneration capacity of AT2 cells.},
}
@article {pmid35273922,
year = {2022},
author = {Edwards-Smallbone, J and Jensen, AL and Roberts, LE and Totañes, FIG and Hart, SR and Merrick, CJ},
title = {Plasmodium falciparum GBP2 Is a Telomere-Associated Protein That Binds to G-Quadruplex DNA and RNA.},
journal = {Frontiers in cellular and infection microbiology},
volume = {12},
number = {},
pages = {782537},
pmid = {35273922},
issn = {2235-2988},
support = {MR/P010873/2/MRC_/Medical Research Council/United Kingdom ; BB/K009206/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MR/L008823/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {DNA/metabolism ; *G-Quadruplexes ; Plasmodium falciparum/genetics ; RNA ; Telomere/metabolism ; },
abstract = {In the early-diverging protozoan parasite Plasmodium, few telomere-binding proteins have been identified and several are unique. Plasmodium telomeres, like those of most eukaryotes, contain guanine-rich repeats that can form G-quadruplex structures. In model systems, quadruplex-binding drugs can disrupt telomere maintenance and some quadruplex-binding drugs are potent anti-plasmodial agents. Therefore, telomere-interacting and quadruplex-interacting proteins may offer new targets for anti-malarial therapy. Here, we report that P. falciparum GBP2 is such a protein. It was identified via 'Proteomics of Isolated Chromatin fragments', applied here for the first time in Plasmodium. In vitro, PfGBP2 binds specifically to G-rich telomere repeats in quadruplex form and it can also bind to G-rich RNA. In vivo, PfGBP2 partially colocalises with the known telomeric protein HP1 but is also found in the cytoplasm, probably due to its affinity for RNA. Consistently, its interactome includes numerous RNA-associated proteins. PfGBP2 is evidently a multifunctional DNA/RNA-binding factor in Plasmodium.},
}
@article {pmid35272158,
year = {2022},
author = {Li, P and Wang, ZY and Yueying Li, and Liu, LZ and Qiu, JG and Zhang, CY},
title = {Bsu polymerase-mediated fluorescence coding for rapid and sensitive detection of 8-oxo-7,8-dihydroguanine in telomeres of cancer cells.},
journal = {Talanta},
volume = {243},
number = {},
pages = {123340},
doi = {10.1016/j.talanta.2022.123340},
pmid = {35272158},
issn = {1873-3573},
mesh = {DNA Damage ; Fluorescence ; Guanine/analogs &amp; derivatives ; HeLa Cells ; Humans ; *Hydrogen Peroxide ; *Neoplasms/diagnosis/genetics ; Oxidation-Reduction ; Telomere/genetics ; },
abstract = {Guanine is the most susceptible to oxidation among all the DNA bases, and 8-oxo-7,8-dihydroguanine (OG) is one of main oxidation products that can occur in any part of chromosomal DNA. OG in the telomere sequence is associated with telomere shortening, cell aging, and dysfunction, and it may induce cancers. The accurate detection of OG in telomeres is important to early clinical diagnosis and molecular research. Herein, we develop a simple and rapid method to sensitively measure 8-oxo-7,8-dihydroguanine (OG) in telomeres of cancer cells by using Bsu polymerase-mediated fluorescence coding. This method is very simple without the requirement for any nucleic acid amplification or specific restriction enzyme recognition reaction, and Bsu polymerase can selectively incorporate Cy5-dATP into the opposite site of OG, endowing this method with good specificity. Moreover, the introduction of single-molecule detection significantly improves the sensitivity. This method can detect OG within 70 min with a limit of detection (LOD) of 2.45 × 10[-18] M, and it can detect OG in genomic DNA extracted from H2O2-treated HeLa cells with a LOD of 0.0094 ng, holding great potential in disease-specific gene damage research and early clinic diagnosis.},
}
@article {pmid35265860,
year = {2022},
author = {Lu, R and Allen, JAM and Galaviz, P and Pickett, HA},
title = {A DNA-fiber protocol for single molecule analysis of telomere (SMAT) length and extension events in cancer cells.},
journal = {STAR protocols},
volume = {3},
number = {1},
pages = {101212},
pmid = {35265860},
issn = {2666-1667},
mesh = {DNA/genetics ; In Situ Hybridization, Fluorescence/methods ; *Neoplasms/genetics ; *Single Molecule Imaging ; Telomere/genetics ; Telomere Homeostasis/genetics ; },
abstract = {Alternative lengthening of telomeres (ALT) is a homologous recombination-based telomere maintenance mechanism. It is active in approximately 10-15% of cancers. We present a DNA-fiber protocol, combining YOYO-1 staining of genomic DNA, telomere fluorescence in situ hybridization (FISH), and EdU labeling of nascent DNA, to measure telomere extension events in ALT cancer cells. The protocol can be used to delineate ALT-mediated telomere extension. For complete details on the use and execution of this protocol, please refer to Barroso-Gonzalez et al. (2021).},
}
@article {pmid35260310,
year = {2022},
author = {Vecoli, C and Basta, G and Borghini, A and Gaggini, M and Del Turco, S and Mercuri, A and Gastaldelli, A and Andreassi, MG},
title = {Advanced glycation end products, leukocyte telomere length, and mitochondrial DNA copy number in patients with coronary artery disease and alterations of glucose homeostasis: From the GENOCOR study.},
journal = {Nutrition, metabolism, and cardiovascular diseases : NMCD},
volume = {32},
number = {5},
pages = {1236-1244},
doi = {10.1016/j.numecd.2022.01.021},
pmid = {35260310},
issn = {1590-3729},
mesh = {Biomarkers ; Blood Glucose ; *Coronary Artery Disease/diagnosis/genetics ; DNA Copy Number Variations ; DNA, Mitochondrial/genetics ; *Diabetes Mellitus, Type 2 ; Glycation End Products, Advanced ; Homeostasis ; Humans ; Leukocytes ; Receptor for Advanced Glycation End Products/genetics ; Telomere/genetics ; },
abstract = {BACKGROUND AND AIM: Alterations of glucose homeostasis can increase advanced glycation end products (AGEs) that exacerbate vascular inflammatory disease and may increase vascular senescence and aging. This study examined the relationships between carboxymethyl-lysine (CML) and soluble receptor for AGEs (sRAGE) with leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn), as cell aging biomarkers, in patients with established coronary artery disease (CAD).<br><br>METHODS AND RESULTS: We studied 459 patients with CAD further categorized as having normal glucose homeostasis (NG, n&#xa0;=&#xa0;253), pre-diabetes (preT2D, n&#xa0;=&#xa0;85), or diabetes (T2D, n&#xa0;=&#xa0;121). All patients were followed up for the occurrence of major adverse cardiovascular events (MACEs). Plasma concentrations of sRAGE and CML were measured by ELISA. mtDNAcn and LTL were measured by qRT-PCR. CML levels were significantly higher in patients with preT2D (p&#xa0;<&#xa0;0.007) or T2D (p&#xa0;<&#xa0;0.003) compared with those with NG. mtDNAcn resulted lower in T2D vs preT2D (p&#xa0;=&#xa0;0.04). At multivariate Cox proportional hazard analysis, short LTL (HR: 2.89; 95% CI: 1.11-10.1; p&#xa0;=&#xa0;0.04) and high levels of sRAGE (HR: 2.20; 95% CI: 1.01-5.14; p&#xa0;=&#xa0;0.04) were associated with an increased risk for MACEs in patients with preT2D and T2D, respectively. T2D patients with both short LTL and high sRAGE levels had the highest risk of MACEs (HR: 3.11; 95% CI: 1.11-9.92; p&#xa0;=&#xa0;0.04).<br><br>CONCLUSIONS: High levels of sRAGE and short LTL were associated with an increased risk of MACEs, especially in patients with diabetes, supporting the usefulness of both biomarkers of glycemic impairment and aging in predicting cardiovascular outcomes in patients with CAD.},
}
@article {pmid35259951,
year = {2022},
author = {Lu, R and Pickett, HA},
title = {Telomeric replication stress: the beginning and the end for alternative lengthening of telomeres cancers.},
journal = {Open biology},
volume = {12},
number = {3},
pages = {220011},
pmid = {35259951},
issn = {2046-2441},
mesh = {DNA Repair ; DNA Replication ; Humans ; *Neoplasms/genetics ; Telomere/genetics ; *Telomere Homeostasis ; },
abstract = {Telomeres are nucleoprotein structures that cap the ends of linear chromosomes. Telomeric DNA comprises terminal tracts of G-rich tandem repeats, which are inherently difficult for the replication machinery to navigate. Structural aberrations that promote activation of the alternative lengthening of telomeres (ALT) pathway of telomere maintenance exacerbate replication stress at ALT telomeres, driving fork stalling and fork collapse. This form of telomeric DNA damage perpetuates recombination-mediated repair pathways and break-induced telomere synthesis. The relationship between replication stress and DNA repair is tightly coordinated for the purpose of regulating telomere length in ALT cells, but has been shown to be experimentally manipulatable. This raises the intriguing possibility that induction of replication stress can be used as a means to cause toxic levels of DNA damage at ALT telomeres, thereby selectively disrupting the viability of ALT cancers.},
}
@article {pmid35254177,
year = {2022},
author = {Tajada, M and Dieste-Pérez, P and Sanz-Arenal, A and Pérez-Roncero, G and López-Baena, MT and Pérez-López, FR},
title = {Leukocyte telomere length in women with and without polycystic ovary syndrome: a systematic review and meta-analysis.},
journal = {Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology},
volume = {38},
number = {5},
pages = {391-397},
doi = {10.1080/09513590.2022.2047922},
pmid = {35254177},
issn = {1473-0766},
mesh = {Body Mass Index ; Female ; Humans ; Leukocytes/metabolism ; *Polycystic Ovary Syndrome/metabolism ; Telomere/metabolism ; Testosterone ; },
abstract = {AIM: To study the telomere length and the telomerase activity in women with and without polycystic ovary syndrome (PCOS).<br><br>METHODS: Relevant studies were searched from PubMed, Embase, and LILACS online databases and manual screening. The mean differences (MDs) or standardized MDs (SMDs) with their 95% confidence intervals (CIs) were calculated. The methodological quality of included studies was evaluated with the Newcastle-Ottawa Scale (NOS), and heterogeneity with the I[2] and Tau[2] statistics.<br><br>RESULTS: Six studies including 2109 non-pregnant women with (n&#x2009;=&#x2009;1155) or without (n&#x2009;=&#x2009;954) PCOS assessed leukocyte telomere length. There was a non-significant leukocyte telomere length difference (SMD = 0.25, 95% CI: -0.01, 0.51, p&#x2009;=&#x2009;.06, I[2] = 81%, Tau[2] = 0.08) comparing PCOS patients with the control group. Studied PCOS women were younger (MD&#x2009;=&#x2009;-1.39, 95% CI: -2.47, -0.31&#x2009;years, I[2] = 83%), and had higher body mass index (BMI; MD = 3.66, 95% CI: 2.11, 5.20&#x2009;kg/m[2], I[2] = 94%). There were significantly higher testosterone (SMD = 0.88, 95% CI: 0.65, 1.10) and luteinizing hormone levels (SMD = 0.60, 95% CI: 0.12, 1.08) in women with PCOS as compared to controls. There was a low risk of bias and there were not sufficient studies to meta-analyze other cell types.<br><br>CONCLUSIONS: Leukocyte telomere length did not differ between women with and without PCOS. Further studies with large sample sizes and including other outcomes are warranted to further substantiate the reported evidence.},
}
@article {pmid35253187,
year = {2022},
author = {Liu, XG and Li, M and Mai, SJ and Cai, RJ},
title = {Telomere length-related signature as a novel biomarker of prognosis and immune response in non-small cell lung cancer.},
journal = {European review for medical and pharmacological sciences},
volume = {26},
number = {4},
pages = {1304-1319},
doi = {10.26355/eurrev_202202_28124},
pmid = {35253187},
issn = {2284-0729},
mesh = {Biomarkers, Tumor/genetics ; *Carcinoma, Non-Small-Cell Lung/diagnosis/genetics ; Gene Expression Regulation, Neoplastic ; Humans ; Immunity ; *Lung Neoplasms/diagnosis/genetics ; Prognosis ; Telomere/genetics ; },
abstract = {OBJECTIVE: Telomere length-related genes (TLRGs) play an important role in multiple tumors; however, there is a lack of systematic reporting about their relevance in non-small cell lung cancer (NSCLC). This study investigated the relation between TLRG gene expression and the immunotherapeutic response of patients with NSCLC.<br><br>MATERIALS AND METHODS: Differentially expressed TLRGs in tumor tissues and normal tissues were screened using Gene Expression Omnibus (GEO) datasets. A univariate Cox regression analysis was performed to identify the optimal prognosis-related genes. A prognostic risk model was constructed by using least absolute shrinkage, selection operator, and multivariate Cox regression analysis results. The model was then evaluated by a Kaplan-Meier analysis, functional enrichment annotation, and a receiver operating characteristic curve analysis; after which, it was validated in the TCGA dataset. The model was used to predict immunotherapeutic response and drug sensitivity.<br><br>RESULTS: An 18-gene prognostic signature was developed and used to stratify NSCLC patients into a low- or high-risk group in GEO cohorts. Patients in the low-risk group had better survival possibilities than those in the high-risk group, and showed significantly higher overall survival times in the TCGA cohort. The risk score was identified as an independent prognostic factor, when compared with other clinical factors. ssGSEA scores showed that the risk model was mainly linked to cancer- and immune-related pathways. Importantly, the candidate risk model was linked to tumor immunity and predicted a patient's response to PDL-1 blockade immune therapy. Several potential drugs that might target this model were identified.<br><br>CONCLUSIONS: This study provides broad molecular signatures that can be used in further functional and therapeutic studies of the telomere system, and also represents an integrated approach for characterizing key protein complexes when creating a prognosis and identifying new targets for cancer immunotherapy.},
}
@article {pmid35247880,
year = {2022},
author = {Rybicki, BA and Sadasivan, SM and Chen, Y and Loveless, I and Gupta, NS and Chitale, DA and Williamson, SR and Rundle, AG and Tang, DL},
title = {Race Differences in Telomere Length in Benign Prostate Biopsies and Subsequent Risk of Prostate Cancer.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {31},
number = {5},
pages = {991-998},
pmid = {35247880},
issn = {1538-7755},
support = {R01 ES011126/ES/NIEHS NIH HHS/United States ; },
mesh = {Biopsy ; Case-Control Studies ; Humans ; Leukocytes ; Male ; *Prostate ; *Prostatic Neoplasms/genetics ; Race Factors ; Risk Factors ; Telomere/genetics ; },
abstract = {BACKGROUND: Telomere shortening is linked to aging and may be associated with increased risk for cancer. Most cancer studies have used telomere length in leukocytes rather than in the target tissue of cancer origin.<br><br>METHODS: A case-control study of 524 case-control pairs with a benign prostate biopsy nested within a historical cohort of 10,478 men was conducted to determine whether premalignant prostate telomere length (assessed using a modified qRT-PCR) is associated with prostate cancer risk.<br><br>RESULTS: Telomere lengths in benign prostate biopsies of cases versus controls were similar (1.46 &#xb1; 0.38 vs. 1.45 &#xb1; 0.42; P = 0.49). African American (AA) men had significantly shorter telomeres compared with White men (1.51 &#xb1; 0.38 vs. 1.63 &#xb1; 0.39; P < 0.0001). In race-stratified analyses, increasing telomere length was more strongly associated with prostate cancer risk in White men, wherein those with telomere length in the highest quartile had 1.9-fold greater adjusted risk of prostate cancer compared with men with prostate telomere lengths in the lowest quartile [OR = 1.90; 95% confidence interval (CI) = 1.08-3.36]. Men in the highest telomere length quartile also had a greater risk of aggressive prostate cancer compared with men with telomere lengths in the lowest quartile (OR = 2.78; 95% CI = 1.25-6.19).<br><br>CONCLUSIONS: White men have longer telomeres in benign prostate tissue compared with AA men, and those with the longest telomeres may be at increased risk for prostate cancer, particularly the more aggressive form of the disease.<br><br>IMPACT: Race-specific telomere length measures may be an early biomarker of aggressive prostate cancer.},
}
@article {pmid35246468,
year = {2022},
author = {Huda, N and Kusumanchi, P and Perez, K and Jiang, Y and Skill, NJ and Sun, Z and Ma, J and Yang, Z and Liangpunsakul, S},
title = {Telomere length in patients with alcohol-associated liver disease: a brief report.},
journal = {Journal of investigative medicine : the official publication of the American Federation for Clinical Research},
volume = {70},
number = {6},
pages = {1438-1441},
pmid = {35246468},
issn = {1708-8267},
support = {UH2 AA026903/AA/NIAAA NIH HHS/United States ; R01 AA025208/AA/NIAAA NIH HHS/United States ; I01 CX000361/CX/CSRD VA/United States ; U01 AA026917/AA/NIAAA NIH HHS/United States ; K01 AA026385/AA/NIAAA NIH HHS/United States ; R24 AA025017/AA/NIAAA NIH HHS/United States ; UH3 AA026903/AA/NIAAA NIH HHS/United States ; },
mesh = {*Hepatitis, Alcoholic ; Humans ; Liver Cirrhosis, Alcoholic/genetics ; *Liver Diseases, Alcoholic/genetics ; *Telomerase/genetics/metabolism ; Telomere/metabolism ; Telomere Shortening ; },
abstract = {The intact telomere structure is essential for the prevention of the chromosome end-to-end fusions and maintaining genomic integrity. The maintenance of telomere length is critical for cellular homeostasis. The shortening of telomeres has been reported in patients with chronic liver diseases. The telomere length has not been systemically studied in patients with alcohol-associated liver disease (ALD) at different stages, such as alcoholic hepatitis and alcoholic cirrhosis. In this brief report, we observed evidence of telomere shortening without changes in the telomerase activity in the liver of patients with alcoholic hepatitis and alcoholic cirrhosis when compared with controls. The alterations in the genes associated with telomere binding proteins were only observed in patients with alcoholic cirrhosis. Future studies are required to determine the mechanism of how alcohol affects the length of the telomere and if the shortening impacts the disease progression in ALD.},
}
@article {pmid35246364,
year = {2022},
author = {Schürhoff, F and Corfdir, C and Pignon, B and Lajnef, M and Richard, JR and Marcos, E and Leboyer, M and Adnot, S and Jamain, S and Szöke, A},
title = {Shortening telomere is associated with psychotic dimensions in the general population.},
journal = {Schizophrenia research},
volume = {243},
number = {},
pages = {470-471},
doi = {10.1016/j.schres.2022.02.030},
pmid = {35246364},
issn = {1573-2509},
mesh = {Humans ; *Mental Disorders ; *Telomere/genetics ; Telomere Shortening ; },
}
@article {pmid35244708,
year = {2022},
author = {Goumy, C and Veronese, L and Stamm, R and Domas, Q and Hadjab, K and Gallot, D and Laurichesse, H and Delabaere, A and Gouas, L and Salaun, G and Perbel-Richard, C and Vago, P and Tchirkov, A},
title = {Reduced telomere length in amniocytes: an early biomarker of abnormal fetal development?.},
journal = {Human molecular genetics},
volume = {31},
number = {16},
pages = {2669-2677},
doi = {10.1093/hmg/ddac054},
pmid = {35244708},
issn = {1460-2083},
mesh = {Biomarkers ; Female ; *Fetal Development ; Fetal Growth Retardation/diagnosis/genetics ; Humans ; Pregnancy ; Telomere/genetics ; *Telomere Shortening/genetics ; },
abstract = {Telomeres protect chromosome ends and control cell division and senescence. During organogenesis, telomeres need to be long enough to ensure the cell proliferation necessary at this stage of development. Previous studies have shown that telomere shortening is associated with growth retardation and congenital malformations. However, these studies were performed in newborns or postnatally, and data on telomere length (TL) during the prenatal period are still very limited. We measured TL using quantitative PCR in amniotic fluid (AF) and chorionic villi (CV) samples from 69 control fetuses with normal ultrasound (52 AF and 17 CV) and 213 fetuses (165 AF and 48 CV) with intrauterine growth retardation (IUGR) or congenital malformations diagnosed by ultrasound. The samples were collected by amniocentesis at the gestational age (GA) of 25.0 ± 5.4 weeks and by CV biopsy at 18.1 ± 6.3 weeks. In neither sample type was TL influenced by GA or fetal sex. In AF, a comparison of abnormal versus normal fetuses showed a significant telomere shortening in cases of IUGR (reduction of 34%, P < 10-6), single (29%, P < 10-6) and multiple (44%, P < 10-6) malformations. Similar TL shortening was also observed in CV from abnormal fetuses but to a lesser extent (25%, P = 0.0002; 18%, P = 0.016; 20%, P = 0.004, respectively). Telomere shortening was more pronounced in cases of multiple congenital anomalies than in fetuses with a single malformation, suggesting a correlation between TL and the severity of fetal phenotype. Thus, TL measurement in fetal samples during pregnancy could provide a novel predictive marker of pathological development.},
}
@article {pmid35243342,
year = {2022},
author = {Machan, M and Tabor, JB and Wang, M and Sutter, B and Wiley, JP and Mychasiuk, R and Debert, CT},
title = {The Impact of Concussion, Sport, and Time in Season on Saliva Telomere Length in Healthy Athletes.},
journal = {Frontiers in sports and active living},
volume = {4},
number = {},
pages = {816607},
pmid = {35243342},
issn = {2624-9367},
abstract = {To date, sport-related concussion diagnosis and management is primarily based on subjective clinical tests in the absence of validated biomarkers. A major obstacle to clinical validation and application is a lack of studies exploring potential biomarkers in non-injured populations. This cross-sectional study examined the associations between saliva telomere length (TL) and multiple confounding variables in a healthy university athlete population. One hundred eighty-three (108 male and 75 female) uninjured varsity athletes were recruited to the study and provided saliva samples at either pre- or mid-season, for TL analysis. Multiple linear regression was used to determine the associations between saliva TL and history of concussion, sport contact type, time in season (pre vs. mid-season collection), age, and sex. Results showed no significant associations between TL and history of concussion, age, or sport contact type. However, TL from samples collected mid-season were longer than those collected pre-season [β = 231.4, 95% CI (61.9, 401.0), p = 0.008], and males had longer TL than females [β = 284.8, 95% CI (111.5, 458.2), p = 0.001] when adjusting for all other variables in the model. These findings population suggest that multiple variables may influence TL. Future studies should consider these confounders when evaluating saliva TL as a plausible fluid biomarker for SRC.},
}
@article {pmid35240880,
year = {2023},
author = {Siwik, CJ and Cash, E and Sephton, SE},
title = {Depressive symptoms and shorter survival in lung cancer: the role of leukocyte telomere length.},
journal = {Psychology &amp; health},
volume = {38},
number = {12},
pages = {1649-1664},
pmid = {35240880},
issn = {1476-8321},
support = {L30 AT011624/AT/NCCIH NIH HHS/United States ; T32 AT003997/AT/NCCIH NIH HHS/United States ; },
abstract = {OBJECTIVE: To examine the association between depressive symptoms, leukocyte telomere length-a marker of cellular ageing, and survival amongst lung cancer patients.<br><br>DESIGN: Patients with non-small cell lung cancer were recruited from a university-affiliated cancer center clinic.<br><br>MAIN OUTCOME: Patients (N&#x2009;=&#x2009;67) reported on depressive symptoms and provided a blood sample for leukocyte telomere length assessment at baseline and at a 3-month follow-up. Survival status was tracked over 3&#xa0;years.<br><br>RESULTS: Age at diagnosis and depressive symptoms, as measured by the CES-D, were associated with shorter leukocyte telomere length (p < .05), although only age at diagnosis contributed statistical significance to the model. Depressive symptoms predicted shorter survival from date of diagnosis (p < .01). Patients who reported experiencing clinically meaningful levels of depressive symptoms (CES-D scores &#x2265; 16) demonstrated shorter survival than those who reported sub-clinical levels of depressive symptoms (p < .05). Leukocyte telomere length did not emerge as a predictor of shorter survival.<br><br>CONCLUSION: Clinically meaningful levels of depressive symptoms are associated with shorter survival amongst lung cancer patients. These findings support the on-going efforts to screen all cancer patients for low mood and to investigate mechanisms linking depressive symptoms and shorter survival in cancer contexts.},
}
@article {pmid35234973,
year = {2021},
author = {Osnato, M},
title = {Searching for the link between telomere length and life history traits in plants.},
journal = {The Plant cell},
volume = {33},
number = {4},
pages = {1087-1088},
pmid = {35234973},
issn = {1532-298X},
mesh = {*Life History Traits ; Telomere/genetics ; Telomere Homeostasis ; },
}
@article {pmid35228641,
year = {2022},
author = {Ngwa, NE and Matsha, TE and Lombard, C and Levitt, N and Sobngwi, E and Kengne, AP and Peer, N},
title = {Cardiometabolic profile and leukocyte telomere length in a Black South African population.},
journal = {Scientific reports},
volume = {12},
number = {1},
pages = {3323},
pmid = {35228641},
issn = {2045-2322},
mesh = {Cholesterol, LDL ; Cross-Sectional Studies ; Female ; Humans ; *Hypertension/epidemiology/genetics ; *Leukocytes ; Male ; South Africa/epidemiology ; Telomere/genetics ; },
abstract = {Several studies have reported a possible association between leucocyte telomere length (LTL) and cardio-metabolic diseases (CMDs). However, studies investigating such association are lacking in South Africa despite having a very high prevalence of CMDs. We investigated the association between LTL and CMD risk profile in a black South African population. This was a cross-sectional study with participants > 21 years of age and residing in five townships in Cape Town. CMD markers were compared between men and women and across quartiles of LTL. Linear and logistic regressions relate increasing quartile and Log10LTL with CMD risk profile, with appropriate adjustment. Among 676-participants, diabetes, obesity and hypertension prevalence were 11.5%, 23.1% and 47.5%. Waist-circumference, hip-circumference and highly sensitive c-reactive protein values were significantly higher in women (all p < 0.001), while HDL-C (p = 0.023), creatinine (p = 0.005) and gamma glutamyl transferase (p < 0.001) values were higher in men. In age, sex and BMI adjusted linear regression model, Log10 of LTL was associated with low HDL-C (beta = 0.221; p = 0.041) while logistic regression showed a significant association between Log10LTL and prevalent dyslipidaemia characterised by high LDL-C. In this population, the relationship between LTL and CMD is weak given its association with only HDL-C and LDL-C.},
}
@article {pmid35227290,
year = {2022},
author = {Sharaf, R and Montesion, M and Hopkins, JF and Song, J and Frampton, GM and Albacker, LA},
title = {A pan-cancer landscape of telomeric content shows that RAD21 and HGF alterations are associated with longer telomeres.},
journal = {Genome medicine},
volume = {14},
number = {1},
pages = {25},
pmid = {35227290},
issn = {1756-994X},
mesh = {Cell Cycle Proteins/genetics ; DNA-Binding Proteins/genetics ; Hepatocyte Growth Factor/genetics/metabolism ; Humans ; *Neoplasms/genetics ; *Telomerase/genetics ; Telomere/genetics ; Telomere Homeostasis ; X-linked Nuclear Protein/genetics ; },
abstract = {BACKGROUND: Cancer cells can proliferate indefinitely through telomere maintenance mechanisms. These mechanisms include telomerase-dependent elongation, mediated by TERT activation, and alternative lengthening of telomeres (ALT), linked to loss of ATRX or DAXX.<br><br>METHODS: We analyzed the telomeric content of 89,959 tumor samples within the Foundation Medicine dataset and investigated the genomic determinants of high telomeric content, linking them to clinical outcomes, when available.<br><br>RESULTS: Telomeric content varied widely by disease type with leiomyosarcoma having the highest and Merkel cell carcinoma having the lowest telomeric content. In agreement with previous studies, telomeric content was significantly higher in samples with alterations in TERC, ATRX, and DAXX. We further identified that amplifications in two genes, RAD21 and HGF, were enriched in samples with high telomeric content, which was confirmed using the PCAWG/ICGC dataset. We identified the minimal amplified region associated with high telomeric content for RAD21 (8q23.1-8q24.12), which excludes MYC, and for HGF (7q21.11). Our results demonstrated that RAD21 and HGF exerted an additive telomere lengthening effect on samples with existing alterations in canonical genes previously associated with telomere elongation. Furthermore, patients with breast cancer who harbor RAD21 alterations had poor median overall survival and trended towards higher levels of Ki-67 staining.<br><br>CONCLUSIONS: This study highlights the importance of the role played by RAD21 (8q23.1-8q24.12) and HGF (7q21.11) in the lengthening of telomeres, supporting unlimited replication in tumors. These findings open avenues for work aimed at targeting this crucial pathway in tumorigenesis.},
}
@article {pmid35226812,
year = {2022},
author = {Fletcher, K and Shin, OH and Clark, KJ and Feng, C and Putman, AI and Correll, JC and Klosterman, SJ and Van Deynze, A and Michelmore, RW},
title = {Ancestral Chromosomes for Family Peronosporaceae Inferred from a Telomere-to-Telomere Genome Assembly of Peronospora effusa.},
journal = {Molecular plant-microbe interactions : MPMI},
volume = {35},
number = {6},
pages = {450-463},
doi = {10.1094/MPMI-09-21-0227-R},
pmid = {35226812},
issn = {0894-0282},
mesh = {*Oomycetes/genetics ; *Peronospora/genetics ; Plant Diseases/microbiology ; Spinacia oleracea ; Telomere/genetics ; },
abstract = {Downy mildew disease of spinach, caused by the oomycete Peronospora effusa, causes major losses to spinach production. In this study, the 17 chromosomes of P. effusa were assembled telomere-to-telomere, using Pacific Biosciences high-fidelity reads. Of these, 16 chromosomes are complete and gapless; chromosome 15 contains one gap bridging the nucleolus organizer region. This is the first telomere-to-telomere genome assembly for an oomycete. Putative centromeric regions were identified on all chromosomes. This new assembly enables a reevaluation of the genomic composition of Peronospora spp.; the assembly was almost double the size and contained more repeat sequences than previously reported for any Peronospora species. Genome fragments consistently underrepresented in six previously reported assemblies of P. effusa typically encoded repeats. Some genes annotated as encoding effectors were organized into multigene clusters on several chromosomes. Putative effectors were annotated on 16 of the 17 chromosomes. The intergenic distances between annotated genes were consistent with compartmentalization of the genome into gene-dense and gene-sparse regions. Genes encoding putative effectors were enriched in gene-sparse regions. The near-gapless assembly revealed apparent horizontal gene transfer from Ascomycete fungi. Gene order was highly conserved between P. effusa and the genetically oriented assembly of the oomycete Bremia lactucae; high levels of synteny were also detected with Phytophthora sojae. Extensive synteny between phylogenetically distant species suggests that many other oomycete species may have similar chromosome organization. Therefore, this assembly provides the foundation for genomic analyses of diverse oomycetes.[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.},
}
@article {pmid35222015,
year = {2021},
author = {Xu, X and Chen, Z and Wu, W and Tian, X},
title = {Polyadenylated Telomeric Noncoding RNA Functions as a Pivotal Therapeutic Target of Anti-Ageing to Stabilize Telomere Length of Chromosomes Via Collaborating With Zscan4c.},
journal = {Frontiers in pharmacology},
volume = {12},
number = {},
pages = {822779},
pmid = {35222015},
issn = {1663-9812},
abstract = {Telomeres are closely associated with the development of cell aging. Shortening or erosion of telomeres will cause cell mortality, suggesting that the maintenance of telomere integrity facilitates cell anti-senescence. However, the mechanism of how to keep the telomere length remains fragmentary. Here, we found that polyadenylated telomeric noncoding RNA (TERRA) can promote the self-renewal when overexpressed in mouse embryonic stem cells (mESCs), implying that TERRA with polyadenylation is critical for mESC maintenance. Further studies revealed that TERRA with a polyadenylated tail plays an important role in the sustenance of telomere length. High-throughput sequencing and quantitative real-time PCR show that zinc finger and SCAN domain containing 4C (Zscan4c) may be a potential target of TERRA. Zscan4c is negatively regulated by TERRA and collaborates with TERRA to stabilize the telomere length of chromosomes in mESCs. Our study not only identifies TERRA as a potential novel factor of telomere length regulation and uncovers the new molecular mechanism of cell anti-aging, but also indicates that Zscan4c could be a key therapeutic target candidate for therapy in dysfunctional chromosome diseases. These data will expand our understanding of the cell fate regulatory network and will be beneficial to drug discovery and theragnostics for antiaging and anticancer therapy in the future.},
}
@article {pmid35221117,
year = {2022},
author = {Ningarhari, M and Caruso, S and Hirsch, TZ and Bayard, Q and Franconi, A and Védie, AL and Noblet, B and Blanc, JF and Amaddeo, G and Ganne, N and Ziol, M and Paradis, V and Guettier, C and Calderaro, J and Morcrette, G and Kim, Y and MacLeod, AR and Nault, JC and Rebouissou, S and Zucman-Rossi, J},
title = {Corrigendum to: 'Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target' [J Hepatol 2021 (74) 1155-1166].},
journal = {Journal of hepatology},
volume = {76},
number = {5},
pages = {1242-1243},
doi = {10.1016/j.jhep.2022.01.019},
pmid = {35221117},
issn = {1600-0641},
}
@article {pmid35220523,
year = {2023},
author = {Panahi, Y and Salasar Moghaddam, F and Babaei, K and Eftekhar, M and Shervin Badv, R and Eskandari, MR and Vafaee-Shahi, M and Pezeshk, H and Pedram, M},
title = {Sexual Dimorphism in Telomere Length in Childhood Autism.},
journal = {Journal of autism and developmental disorders},
volume = {53},
number = {5},
pages = {2050-2061},
pmid = {35220523},
issn = {1573-3432},
support = {A-12-534/1-4//Zanjan University of Medical Sciences/ ; A-12-534/6-8//Zanjan University of Medical Sciences/ ; },
mesh = {Child ; Humans ; Male ; Female ; *Autistic Disorder/genetics ; *Autism Spectrum Disorder/genetics ; Sex Characteristics ; Biomarkers ; Telomere ; },
abstract = {Autism spectrum disorders (ASD) are strikingly more prevalent in males, but the molecular mechanisms responsible for ASD sex-differential risk are poorly understood. Abnormally shorter telomeres have been associated with autism. Examination of relative telomere lengths (RTL) among non-syndromic male (N = 14) and female (N = 10) children with autism revealed that only autistic male children had significantly shorter RTL than typically-developing controls (N = 24) and paired siblings (N = 10). While average RTL of autistic girls did not differ significantly from controls, it was substantially longer than autistic boys. Our findings indicate a sexually-dimorphic pattern of RTL in childhood autism and could have important implications for RTL as a potential biomarker and the role/s of telomeres in the molecular mechanisms responsible for ASD sex-biased prevalence and etiology.},
}
@article {pmid35220278,
year = {2022},
author = {Semeraro, MD and Almer, G and Renner, W and Gruber, HJ and Herrmann, M},
title = {Telomere length in leucocytes and solid tissues of young and aged rats.},
journal = {Aging},
volume = {14},
number = {4},
pages = {1713-1728},
pmid = {35220278},
issn = {1945-4589},
mesh = {Animals ; *Leukocytes, Mononuclear/metabolism ; RNA, Messenger/genetics ; Rats ; Rats, Sprague-Dawley ; *Telomerase/genetics/metabolism ; Telomere/metabolism ; },
abstract = {BACKGROUND: Telomeres are protective nucleoprotein structures at the end of chromosomes that shorten with age. Telomere length (TL) in peripheral blood mononuclear cells (PBMCs) has been proposed as surrogate marker for TL in the entire organism. Solid evidence that supports this concept is lacking.<br><br>METHODS: Relative TL (RTL) was measured in PBMCS and multiple solid tissues from 24 young (4 months) and 24 aged (14 months) Sprague-Dawley (SD) rats. The mRNA expression of telomerase (TERT) and shelterin proteins TERF-1 and TERF-2 was also measured.<br><br>RESULTS: Mean RTL in PBMCs and solid tissues of young rats ranged from 0.64 &#xb1; 0.26 in large intestine to 1.07 &#xb1; 0.22 in skeletal muscle. RTL in PBMCs correlated with that in kidney (r = 0.315, p = 0.008), skeletal muscle (r = 0.276, p = 0.022), liver (r = 0.269, p = 0.033), large intestine (r = -0.463, p = 7.035E-5) and aorta (r = -0.273, p = 0.028). A significant difference of RTL between young and aged animals was only observed in aorta (0.98 &#xb1; 0.15 vs. 0.76 &#xb1; 0.11, p = 1.987E-6), lung (0.76 &#xb1; 0.14 vs. 0.85 &#xb1; 0.14, p = 0.024) and visceral fat (0.83 &#xb1; 0.14 vs. 0.92 &#xb1; 0.15, p = 0.44). The expression of TERT significantly differed between the tested organs with highest levels in liver and kidney. Age-related differences in TERT expression were found in PBMCs, skeletal muscle, and visceral fat. mRNA expression of TERF-1 and TERF-2 was tissue-specific with the highest levels in liver. Age-related differences in TERF-1 and TERF-2 expression were inconsistent.<br><br>CONCLUSIONS: The present study questions the utility of RTL in PBMCs as a biomarker for the individual assessment of aging.},
}
@article {pmid35217318,
year = {2022},
author = {Almuwaqqat, Z and Wittbrodt, MT and Moazzami, K and Nye, JA and Lima, BB and Shah, AJ and Alkhalaf, J and Pearce, B and Sun, YV and Quyyumi, AA and Vaccarino, V and Bremner, JD},
title = {Neural correlates of stress and leucocyte telomere length in patients with coronary artery disease.},
journal = {Journal of psychosomatic research},
volume = {155},
number = {},
pages = {110760},
pmid = {35217318},
issn = {1879-1360},
support = {S10 RR016917/RR/NCRR NIH HHS/United States ; I01 RX003418/RX/RRD VA/United States ; R01 MH056120/MH/NIMH NIH HHS/United States ; K24 HL077506/HL/NHLBI NIH HHS/United States ; R01 HL125246/HL/NHLBI NIH HHS/United States ; T32 MH067547/MH/NIMH NIH HHS/United States ; TL1 TR002382/TR/NCATS NIH HHS/United States ; R01 MH120262/MH/NIMH NIH HHS/United States ; T32 HL130025/HL/NHLBI NIH HHS/United States ; K23 HL127251/HL/NHLBI NIH HHS/United States ; UL1 TR000454/TR/NCATS NIH HHS/United States ; P01 HL101398/HL/NHLBI NIH HHS/United States ; UG3 DA048502/DA/NIDA NIH HHS/United States ; KL2 TR000455/TR/NCATS NIH HHS/United States ; R01 HL109413/HL/NHLBI NIH HHS/United States ; K24 MH076955/MH/NIMH NIH HHS/United States ; R01 HL088726/HL/NHLBI NIH HHS/United States ; },
mesh = {*Coronary Artery Disease/genetics ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes ; Male ; Middle Aged ; Telomere ; Telomere Shortening ; },
abstract = {BACKGROUND: Accelerated biological aging, as indicated by telomere shortening, is associated with CAD pathogenesis. In a cross-sectional study, we investigated neural correlates of acute psychological stress and short telomeres in patients with CAD.<br><br>METHODS: Individuals with CAD (N&#xa0;=&#xa0;168) underwent a validated mental stress protocol including public speaking and mental arithmetic. Imaging of the brain with [O-15] water and high-resolution positron emission tomography (HR-PET) was performed during mental stress and control conditions. Blood flow during stressful tasks (average of speech and arithmetic) and control tasks were assessed. Telomere length in peripheral leucocytes was measured by quantitative polymerase chain reaction and expressed as Telomere/Single Copy Gene (T/S) ratio. Voxel-wise regression models were constructed to assess the association between brain areas and activity during rest and mental stress after adjustments for demographic factors and clinical characteristics.<br><br>RESULTS: The mean (SD) age of the sample was 62 (8) years, and 69% were men. Increased activation with mental stress in the lingual gyrus, cerebellum and superior and inferior frontal gyri were associated with reduced telomere length; 1.6 higher voxel activation of these areas was associated with 0.1&#xa0;T/S-units reduction in telomere length (P&#xa0;<&#xa0;0.005). Additionally, during neutral counting and speaking tasks, brain activity in the precentral, middle and superior frontal and middle temporal gyri was inversely associated with telomere length. Results remained consistent after adjustment for demographic and clinical risk factors.<br><br>CONCLUSION: Increased stress-induced activity in brain areas mediating the stress response was associated with shortened telomere length in CAD patients.},
}
@article {pmid35210806,
year = {2022},
author = {Zhang, J},
title = {Mendelian Randomization Study Implies Causal Linkage Between Telomere Length and Juvenile Idiopathic Arthritis in a European Population.},
journal = {Journal of inflammation research},
volume = {15},
number = {},
pages = {977-986},
pmid = {35210806},
issn = {1178-7031},
abstract = {BACKGROUND: Telomere maintenance is increasingly being considered as fundamental to the progression of immune-mediated inflammatory diseases. However, the causality underlying the purported relationship has not been fully elucidated. In the present work, we applied Mendelian randomization (MR) analysis to obtain estimates of the causal effect of telomere length (TL) on the risk of juvenile idiopathic arthritis (JIA) and JIA-associated iridocyclitis.<br><br>METHODS: Two-sample MR analysis was conducted using summary-level data from the largest genome-wide association studies concerning TL (78,592 individuals), JIA (6056 cases and 25,086 controls), and JIA-associated iridocyclitis (1430 cases and 9,2767 controls). All the participants were of European ancestry. The inverse variance weighted (IVW) method was applied to estimate the causal effects. Sensitivity analyses incorporating multiple complementary MR approaches were implemented to test the robustness of the association and examine potential bias from pleiotropy.<br><br>RESULTS: In our MR analysis, genetically predicted shorter TL was associated with an increased risk of JIA (IVW: odds ratio=1.68, 95% CI: 1.13-2.48, P=0.009), but not with the risk of JIA-associated iridocyclitis (IVW: odds ratio=1.75, 95% CI: 0.81-3.79, P=0.155). The other MR methods produced consistent results. Besides, a leave-one-out sensitivity analysis yielded similar findings and validated the robustness of the causal relationship. MR-Egger regression revealed no notable horizontal pleiotropy (intercept=0.046, P=0.175).<br><br>CONCLUSION: This work provides evidence of a negative association between TL and JIA risk, but not for the association between TL and the risk of JIA-associated iridocyclitis, in a European population. Future studies with larger sample sizes are warranted to elucidate the underlying role of TL in these diseases.},
}
@article {pmid35208566,
year = {2022},
author = {Song, S and Lee, E and Kim, H},
title = {Does Exercise Affect Telomere Length? A Systematic Review and Meta-Analysis of Randomized Controlled Trials.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {58},
number = {2},
pages = {},
pmid = {35208566},
issn = {1648-9144},
mesh = {*Exercise ; Humans ; *Life Style ; Randomized Controlled Trials as Topic ; Telomere/genetics ; },
abstract = {Background and objectives: Telomere length is an indicator of biological aging, and it shortens during cell division. A short telomere length is associated with various age-related diseases and mortality. It is suggested that physical activity has a positive effect on the rate of telomere length shortening. Materials and Methods: Related studies, published in electronic databases, were searched with keywords, including exercise, telomere length, and randomized controlled trial. The data were weighted and pooled through a fixed-effect model. Results: Of the total 49 studies searched, 7 studies with 939 participants were considered suitable, and were analyzed qualitatively and quantitatively. Exercise is beneficial to telomere length. Aerobic exercise was effective as the type of exercise (MD, -0.03; 95% CI, -0.04 to -0.01). In addition, exercise for more than 6 months, with a change in lifestyle, is beneficial for telomere length (MD, -0.02; 95% CI, -0.04 to -0.01). Conclusions: The type and duration of exercise for positive improvement in telomere length is aerobic exercise for more than 6 months.},
}
@article {pmid35205387,
year = {2022},
author = {Umriukhin, PE and Ershova, ES and Filev, AD and Agafonova, ON and Martynov, AV and Zakharova, NV and Veiko, RV and Porokhovnik, LN and Kostyuk, GP and Kutsev, SI and Veiko, NN and Kostyuk, SV},
title = {The Psychoemotional Stress-Induced Changes in the Abundance of SatIII (1q12) and Telomere Repeats, but Not Ribosomal DNA, in Human Leukocytes.},
journal = {Genes},
volume = {13},
number = {2},
pages = {},
pmid = {35205387},
issn = {2073-4425},
mesh = {*DNA Copy Number Variations ; DNA, Ribosomal/genetics ; Humans ; Leukocytes ; *Schizophrenia/genetics ; Telomere/genetics ; },
abstract = {INTRODUCTION: As shown earlier, copy number variations (CNV) in the human satellite III (1q12) fragment (f-SatIII) and the telomere repeat (TR) reflects the cell's response to oxidative stress. The contents of f-SatIII and TR in schizophrenic (SZ) patients were found to be lower than in healthy controls (HC) in previous studies. The major question of this study was: 'What are the f-SatIII and TR CNV dynamic changes in human leukocytes, depending on psychoemotional stress?'<br><br>MATERIALS AND METHODS: We chose a model of psychoemotional stress experienced by second-year medical students during their exams. Blood samples were taken in stressful conditions (exams) and in a control non-stressful period. Biotinylated probes were used for f-SatIII, rDNA, and TR quantitation in leukocyte DNA by non-radioactive quantitative hybridization in SZ patients (n = 97), HC (n = 97), and medical students (n = 17, n = 42). A flow cytometry analysis was used for the oxidative stress marker (NOX4, 8-oxodG, and &#x3b3;H2AX) detection in the lymphocytes of the three groups.<br><br>RESULTS: Oxidative stress markers increased significantly in the students' lymphocytes during psychoemotional stress. The TR and f-SatIII, but not the rDNA, contents significantly changed in the DNA isolated from human blood leukocytes. After a restoration period (post-examinational vacations), the f-SatIII content decreased, and the TR content increased. Changes in the blood cells of students during examinational stress were similar to those in SZ patients during an exacerbation of the disease.<br><br>CONCLUSIONS: Psychoemotional stress in students during exams triggers a universal mechanism of oxidative stress. The oxidative stress causes significant changes in the f-SatIII and TR contents, while the ribosomal repeat content remains stable. A hypothesis is proposed to explain the quantitative polymorphisms of f-SatIII and TR contents under transient (e.g., students' exams) or chronic (in SZ patients) stress. The changes in the f-SatIII and TR copy numbers are non-specific events, irrespective of the source of stress. Thus, our findings suggest that the psychoemotional stress, common in SZ patients and healthy students during exams, but not in a schizophrenia-specific event, was responsible for the changes in the repeat contents that we observed earlier in SZ patients.},
}
@article {pmid35205225,
year = {2022},
author = {Li, D and Hou, K and Zhang, K and Jia, S},
title = {Regulation of Replication Stress in Alternative Lengthening of Telomeres by Fanconi Anaemia Protein.},
journal = {Genes},
volume = {13},
number = {2},
pages = {},
pmid = {35205225},
issn = {2073-4425},
mesh = {DNA Repair/genetics ; Fanconi Anemia Complementation Group A Protein/genetics ; Fanconi Anemia Complementation Group Proteins/genetics ; *Telomere/genetics/metabolism ; *Telomere Homeostasis/genetics ; },
abstract = {Fanconi anaemia (FA)-related proteins function in interstrand crosslink (ICL) repair pathways and multiple damage repair pathways. Recent studies have found that FA proteins are involved in the regulation of replication stress (RS) in alternative lengthening of telomeres (ALT). Since ALT cells often exhibit high-frequency ATRX mutations and high levels of telomeric secondary structure, high levels of DNA damage and replicative stress exist in ALT cells. Persistent replication stress is required to maintain the activity of ALT mechanistically, while excessive replication stress causes ALT cell death. FA proteins such as FANCD2 and FANCM are involved in the regulation of this balance by resolving or inhibiting the formation of telomere secondary structures to stabilize stalled replication forks and promote break-induced repair (BIR) to maintain the survival of ALT tumour cells. Therefore, we review the role of FA proteins in replication stress in ALT cells, providing a rationale and direction for the targeted treatment of ALT tumours.},
}
@article {pmid35205052,
year = {2022},
author = {Armendáriz-Castillo, I and Hidalgo-Fernández, K and Pérez-Villa, A and García-Cárdenas, JM and López-Cortés, A and Guerrero, S},
title = {Identification of Key Proteins from the Alternative Lengthening of Telomeres-Associated Promyelocytic Leukemia Nuclear Bodies Pathway.},
journal = {Biology},
volume = {11},
number = {2},
pages = {},
pmid = {35205052},
issn = {2079-7737},
abstract = {Alternative lengthening of telomeres-associated promyelocytic leukemia nuclear bodies (APBs) are a hallmark of telomere maintenance. In the last few years, APBs have been described as the main place where telomeric extension occurs in ALT-positive cancer cell lines. A different set of proteins have been associated with APBs function, however, the molecular mechanisms behind their assembly, colocalization, and clustering of telomeres, among others, remain unclear. To improve the understanding of APBs in the ALT pathway, we integrated multiomics analyses to evaluate genomic, transcriptomic and proteomic alterations, and functional interactions of 71 APBs-related genes/proteins in 32 Pan-Cancer Atlas studies from The Cancer Genome Atlas Consortium (TCGA). As a result, we identified 13 key proteins which showed distinctive mutations, interactions, and functional enrichment patterns across all the cancer types and proposed this set of proteins as candidates for future ex vivo and in vivo analyses that will validate these proteins to improve the understanding of the ALT pathway, fill the current research gap about APBs function and their role in ALT, and be considered as potential therapeutic targets for the diagnosis and treatment of ALT-positive cancers in the future.},
}
@article {pmid35203522,
year = {2022},
author = {M'Kacher, R and Jaillet, M and Colicchio, B and Vasarmidi, E and Mailleux, A and Dieterlen, A and Kannengiesser, C and Borie, C and Oudrhiri, N and Junker, S and Voisin, P and Jeandidier, E and Carde, P and Fenech, M and Bennaceur-Griscelli, A and Crestani, B and Borie, R},
title = {Lung Fibroblasts from Idiopathic Pulmonary Fibrosis Patients Harbor Short and Unstable Telomeres Leading to Chromosomal Instability.},
journal = {Biomedicines},
volume = {10},
number = {2},
pages = {},
pmid = {35203522},
issn = {2227-9059},
abstract = {Idiopathic pulmonary fibrosis (IPF) is associated with several hallmarks of aging including telomere shortening, which can result from germline mutations in telomere related genes (TRGs). Here, we assessed the length and stability of telomeres as well as the integrity of chromosomes in primary lung fibroblasts from 13 IPF patients (including seven patients with pathogenic variants in TRGs) and seven controls. Automatized high-throughput detection of telomeric FISH signals highlighted lower signal intensity in lung fibroblasts from IPF patients, suggesting a telomere length defect in these cells. The increased detection of telomere loss and terminal deletion in IPF cells, particularly in TRG-mutated cells (IPF-TRG), supports the notion that these cells have unstable telomeres. Furthermore, fibroblasts from IPF patients with TRGs mutations exhibited dicentric chromosomes and anaphase bridges. Collectively, our study indicates that fibroblasts from IPF patients exhibit telomere and chromosome instability that likely contribute to the physiopathology.},
}
@article {pmid35202418,
year = {2022},
author = {Agirbasli, D and Kalyoncu, M and Muftuoglu, M and Aksungar, FB and Agirbasli, M},
title = {Leukocyte telomere length as a compensatory mechanism in vitamin D metabolism.},
journal = {PloS one},
volume = {17},
number = {2},
pages = {e0264337},
pmid = {35202418},
issn = {1932-6203},
mesh = {Aged ; Cohort Studies ; Female ; Humans ; Leukocytes, Mononuclear/*drug effects/ultrastructure ; Middle Aged ; Postmenopause ; Receptors, Calcitriol/blood ; Telomere/*drug effects ; Telomere Homeostasis/*drug effects ; Transcriptome ; Vitamin D/administration &amp; dosage/blood/*pharmacology ; Vitamin D Deficiency/*drug therapy/pathology ; },
abstract = {Vitamin D deficiency is common among postmenopausal women. Telomere length can be a potential protective mechanism for age-related diseases. The objective of our study is to examine the association of vitamin D supplementation on leukocyte telomere length (LTL) in healthy postmenopausal women with vitamin D deficiency. The study was designed as a placebo-controlled study to investigate the short-term effects of vitamin D supplementation and seasonal changes on vitamin D related parameters, including 25(OH)D, 1,25(OH)2D parathormone (PTH), Vitamin D binding protein (VDBP), vitamin D receptor (VDR), and telomere length in a cohort of postmenopausal women (n = 102). The group was divided as supplementation (n = 52) and placebo groups (n = 50). All parameters were measured before and after treatment. Serum VDBP levels were measured by ELISA method and VDR, GC (VDBP) gene expressions and relative telomere lengths were measured in peripheral blood mononuclear cells (PBMC) using a quantitative real-time PCR method. The results demonstrate that baseline levels were similar between the groups. After vitamin D supplementation 25(OH)D, 1,25(OH)2D, PTH and VDBP levels were changed significantly compared to the placebo group. At the end of the study period, LTL levels were significantly increased in both groups and this change was more prominent in placebo group. The change in GC expression was significant between treatment and placebo groups but VDR expression remained unchanged. Even though the study was designed to solely assess the effects of vitamin D supplementation, LTL was significantly increased in the whole study group in summer months suggesting that LTL levels are affected by sun exposure and seasonal changes rather than supplementation. The study displayed the short-term effect of Vitamin D supplementation on vitamin D, PTH levels, LTL and vitamin D associated gene expressions. The relation between Vitamin D and LTL is not linear and could be confounded by several factors such as the population differences, regional and seasonal changes in sun exposure.},
}
@article {pmid35189049,
year = {2022},
author = {Ali, S and Scapagnini, G and Davinelli, S},
title = {Effect of omega-3 fatty acids on the telomere length: A mini meta-analysis of clinical trials.},
journal = {Biomolecular concepts},
volume = {13},
number = {1},
pages = {25-33},
doi = {10.1515/bmc-2021-0024},
pmid = {35189049},
issn = {1868-503X},
mesh = {Antioxidants/pharmacology ; *Fatty Acids, Omega-3/pharmacology/therapeutic use ; Humans ; Inflammation ; Oxidative Stress ; Telomere ; },
abstract = {Telomeres are protective caps at the end of eukaryotic chromosomes, whose length is correlated with health and lifespan. Telomere attrition is a common feature of the aging process and can be accelerated by oxidative stress and chronic inflammation. Various nutrients influence the telomere length, partially due to their antioxidant and anti-inflammatory properties. The aim of this review was to meta-analytically assess the effect of omega-3 fatty acids on the telomere length. We searched four databases (PubMed, Web of Sciences, Scopus, and the Cochrane Library) from inception until November 2021. Of 573 records, a total of 5 clinical trials were included for the quantitative meta-analysis, comprising a total of 337 participants. The results revealed an overall beneficial effect of omega-3 fatty acids on the telomere length (mean difference = 0.16; 95% CI, 0.02, 0.30; p = 0.02). Despite a limited number of studies, the available evidence suggests that omega-3 fatty acids may positively affect the telomere length. However, larger clinical trials are needed to confirm our findings, along with studies aimed to clarify the underlying molecular mechanisms.},
}
@article {pmid35188570,
year = {2022},
author = {Frank, L and Rademacher, A and Mücke, N and Tirier, SM and Koeleman, E and Knotz, C and Schumacher, S and Stainczyk, SA and Westermann, F and Fröhling, S and Chudasama, P and Rippe, K},
title = {ALT-FISH quantifies alternative lengthening of telomeres activity by imaging of single-stranded repeats.},
journal = {Nucleic acids research},
volume = {50},
number = {11},
pages = {e61},
pmid = {35188570},
issn = {1362-4962},
mesh = {Cell Line ; DNA, Single-Stranded/genetics ; Humans ; In Situ Hybridization, Fluorescence ; Neoplasms/genetics ; Telomerase/genetics ; Telomere/genetics/*metabolism ; Telomere Homeostasis ; },
abstract = {Alternative lengthening of telomeres (ALT) occurs in ∼10% of cancer entities. However, little is known about the heterogeneity of ALT activity since robust ALT detection assays with high-throughput in situ readouts are lacking. Here, we introduce ALT-FISH, a method to quantitate ALT activity in single cells from the accumulation of single-stranded telomeric DNA and RNA. It involves a one-step fluorescent in situ hybridization approach followed by fluorescence microscopy imaging. Our method reliably identified ALT in cancer cell lines from different tumor entities and was validated in three established models of ALT induction and suppression. Furthermore, we successfully applied ALT-FISH to spatially resolve ALT activity in primary tissue sections from leiomyosarcoma and neuroblastoma tumors. Thus, our assay provides insights into the heterogeneity of ALT tumors and is suited for high-throughput applications, which will facilitate screening for ALT-specific drugs.},
}
@article {pmid35186180,
year = {2022},
author = {Zhang, W and Peng, SF and Chen, L and Chen, HM and Cheng, XE and Tang, YH},
title = {Association between the Oxidative Balance Score and Telomere Length from the National Health and Nutrition Examination Survey 1999-2002.},
journal = {Oxidative medicine and cellular longevity},
volume = {2022},
number = {},
pages = {1345071},
pmid = {35186180},
issn = {1942-0994},
mesh = {Adult ; Aged ; Aged, 80 and over ; Cross-Sectional Studies ; Female ; History, 20th Century ; History, 21st Century ; Humans ; Male ; Middle Aged ; Nutrition Surveys/*methods ; *Oxidation-Reduction ; Risk Factors ; Telomere Homeostasis/*immunology ; United States ; Young Adult ; },
abstract = {PURPOSE: Leukocyte telomere length (LTL) is an important biomarker of aging. The oxidative balance score (OBS) is used to assess the oxidative stress-related exposures of diet and lifestyle. This study is aimed at exploring if the OBS was associated with LTL.<br><br>METHODS: 3220 adults were included in this study from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. LTL was assayed from leukocyte DNA. Twenty dietary and lifestyle factors were selected to score the OBS. Survey-based multivariable linear regression was conducted to assess the association between the OBS and log-transformed LTL.<br><br>RESULTS: The association between the OBS and log-transformed LTL was positive in females but not males. For females, compared with the lowest OBS category as a reference, the multivariable-adjusted beta estimate (95% confidence interval, CI) for the highest OBS category was 0.0701 (0.0205-0.1197) (p for trend < 0.01), and the multivariable-adjusted beta estimate (95% CI) of the continuous OBS was 0.0039 (0.0014-0.0065). There was also the gender difference in the correlations of the dietary OBS and the lifestyle OBS with log-transformed LTL.<br><br>CONCLUSION: There was a positive association between the OBS and LTL in females. This result suggested that diet and lifestyle might affect LTL by regulating oxidative balance.},
}
@article {pmid35183942,
year = {2022},
author = {Pan, D and Shao, Y and Song, Y and Huang, D and Liu, S and Zeng, X and Liang, J and Juan Jennifer Tan, H and Qiu, X},
title = {Association between maternal per- and polyfluoroalkyl substance exposure and newborn telomere length: Effect modification by birth seasons.},
journal = {Environment international},
volume = {161},
number = {},
pages = {107125},
doi = {10.1016/j.envint.2022.107125},
pmid = {35183942},
issn = {1873-6750},
mesh = {*Alkanesulfonic Acids ; Bayes Theorem ; China ; Cohort Studies ; *Environmental Pollutants ; Female ; *Fluorocarbons/toxicity ; Humans ; Infant ; Infant, Newborn ; Maternal Exposure/adverse effects ; Pregnancy ; Seasons ; Telomere ; },
abstract = {BACKGROUND: Telomere length (TL) is an important biomarker of biological aging and disease that may be affected by prenatal exposure to environmental pollutants. Birth seasons have been linked to reproductive and immune-related diseases. Prenatal exposure to per- and polyfluoroalkyl substance (PFAS) has been associated with adverse birth outcomes, but the effects of PFAS and birth seasons on newborn TL are poorly understood.<br><br>OBJECTIVES: To explore the individual and combined effects of maternal PFAS exposure on newborn TL, with exploration of the interaction between PFAS and birth seasons on newborn TL.<br><br>METHODS: Between June 2015 and May 2018, a total of 499 mother-newborn pairs were recruited for a birth cohort study in Guangxi, China. Maternal blood samples were collected during pregnancy. Nine PFASs were measured by ultraperformance liquid chromatography-mass spectrometry. Newborn TL was assessed using quantitative real-time polymerase chain reaction. Modeling newborn TL as the outcome, multivariable linear regressions were performed for individual PFAS exposures, and Bayesian Kernel Machine Regressions were performed for PFAS mixtures. Furthermore, interaction analyses were conducted to evaluate the effect modification by birth seasons in these relationships.<br><br>RESULTS: For both single and multipollutant models, PFASs exposure were inversely associated with newborn TL, although none of the relationships were significant. The mixture of PFASs showed a potential positive trend of combined effect on newborn TL but non-statistically significant. Each ln-transformed unit concentration increase in PFOA was related to a 20.41% (95% CI: -30.44%, -8.93%) shorter TL in spring-born infants but not in those born in other birth seasons. Mothers in the middle and highest tertiles of PFOA exposure had 11.69% and 10.71% shorter TLs in spring-born infants, respectively.<br><br>CONCLUSION: Maternal PFAS exposure showed little association with newborn TL. The results suggested potential effect modification by birth season on the association between PFOA exposure and newborn TL.},
}
@article {pmid35179471,
year = {2022},
author = {Collin, V and Flamand, L},
title = {[The importance of telomeres in human herpesvirus-6A/B infections].},
journal = {Medecine sciences : M/S},
volume = {38},
number = {2},
pages = {168-176},
doi = {10.1051/medsci/2022008},
pmid = {35179471},
issn = {1958-5381},
mesh = {Genome, Viral ; *Herpesvirus 6, Human/genetics ; Humans ; *Roseolovirus Infections/genetics ; Telomere/genetics ; Virus Integration/genetics ; },
abstract = {Herpesviruses are undisputed masters of disguise. The ability to become invisible to the immune system effectors is a complex process resting on a variety of stealth approaches. Among these, human herpesviruses-6A and -6B (HHV-6A/B) have developed the unique ability to integrate their genome within the ends of chromosomes allowing viral persistence in the absence of viral protein expression. This aptitude, unique to HHV-6A/B among human herpesviruses, requires close interactions between the telomeric regions of chromosomes and the viral genome. In this review article, the biology of telomeres and the mechanisms responsible for viral integration are discussed. In closing, the possible biological consequences of HHV-6A/B integration into chromosomal DNA are discussed.},
}
@article {pmid35178897,
year = {2022},
author = {Bridges, J and Chung, KW and Martz, CD and Smitherman, EA and Drenkard, C and Wu, C and Lin, J and Lim, SS and Chae, DH},
title = {Leukocyte Telomere Length and Childhood Onset of Systemic Lupus Erythematosus in the Black Women's Experiences Living with Lupus Study.},
journal = {ACR open rheumatology},
volume = {4},
number = {5},
pages = {426-431},
pmid = {35178897},
issn = {2578-5745},
support = {U01DP005119/CC/CDC HHS/United States ; U01DP006488/CC/CDC HHS/United States ; U01DP005119/CC/CDC HHS/United States ; U01DP006488/CC/CDC HHS/United States ; },
abstract = {OBJECTIVE: The study objective was to compare leukocyte telomere length (LTL) among patients with systemic lupus erythematosus (SLE) diagnosed in childhood versus adulthood.<br><br>METHODS: Data are from the Black Women's Experiences Living with Lupus (BeWELL) study. Multivariable linear regression analyses that examined childhood diagnosis of SLE (diagnosed before 18&#x2009;years of age), age, and their interaction in relationship to LTL were conducted, adjusting for a range of demographic, socioeconomic, and health-related covariates.<br><br>RESULTS: The total analytic sample size was 415. Forty participants (9.6%) were diagnosed in childhood. There was no main effect of childhood diagnosis on LTL (b&#xa0;=&#x2009;0.007; 95% confidence interval [CI]: -0.089 to 0.103). However, the interaction between age and childhood diagnosis was significant (b&#xa0;=&#xa0;-0.008; 95% CI: -0.016 to -0.001), indicating a steeper inverse association between age and LTL among those diagnosed in childhood compared with those diagnosed in adulthood. This interaction remained statistically significant (P&#xa0;=&#x2009;0.024) after controlling for disease duration measured dichotomously (less than 10&#x2009;years vs. 10&#x2009;years or more); it was marginally significant (P&#xa0;=&#x2009;0.083) when controlling for disease duration measured continuously.<br><br>CONCLUSION: This cross-sectional analysis suggests that Black women with childhood-onset SLE may undergo accelerated LTL shortening compared with their adult-onset counterparts. This relationship persisted even after controlling for differences in SLE damage and disease duration. These findings inform research on immunosenescence mechanisms of SLE.},
}
@article {pmid35178191,
year = {2022},
author = {Sahm, V and Maurer, C and Baumeister, T and Anand, A and Strangmann, J and Schmid, RM and Wang, TC and Quante, M},
title = {Telomere shortening accelerates tumor initiation in the L2-IL1B mouse model of Barrett esophagus and emerges as a possible biomarker.},
journal = {Oncotarget},
volume = {13},
number = {},
pages = {347-359},
pmid = {35178191},
issn = {1949-2553},
mesh = {Adenocarcinoma ; Animals ; *Barrett Esophagus/genetics/pathology ; Biomarkers ; Cell Transformation, Neoplastic ; Disease Models, Animal ; *Esophageal Neoplasms/pathology ; Humans ; Interleukin-1beta ; Metaplasia ; Mice ; Telomere Shortening ; },
abstract = {Barrett's esophagus (BE) is a precursor of the esophageal adenocarcinoma (EAC). BE- development and its progression to cancer is associated with gastroesophageal reflux disease. However, there is currently no molecular risk prediction model that accurately identifies patients at high risk for EAC. Here, we investigated the impact of shortened telomeres in a mouse model for Barrett esophagus (L2-IL1B). The L2-IL1B mouse model is characterized by IL-1β-mediated inflammation, which leads to a Barrett-like metaplasia in the transition zone between the squamous forestomach and glandular cardia/stomach. Telomere shortening was achieved by mTERC knockout. In the second generation (G2) of mTERC knockout L2-IL1B.mTERC[-/-] G2 mice exhibited telomere dysfunction with significantly shorter telomeres as measured by qFISH compared to L2-IL1B mice, correlating with stronger DNA damage in the form of phosphorylation of H2AX (γH2AX). Macroscopically, tumor area along the squamocolumnar junction (SCJ) was increased in L2-IL1B.mTERC[-/-] G2 mice, along with increased histopathological dysplasia. In vitro studies indicated increased organoid formation capacity in BE tissue from L2-IL1B.mTERC[-/-] G2 mice. In addition, pilot studies of human BE-, dysplasia- and EAC tissue samples confirmed that BE epithelial cells with or without dysplasia (LGD) had shorter telomeres compared to gastric cardia tissue. Of note, differentiated goblet cells retained longer telomeres than columnar lined BE epithelium. In conclusion, our studies suggest that shortened telomeres are functionally important for tumor development in a mouse model of BE and are associated with proliferating columnar epithelium in human BE. We propose that shortened telomeres should be evaluated further as a possible biomarker of cancer risk in BE patients.},
}
@article {pmid35175322,
year = {2022},
author = {Savage, SA},
title = {Telomere biology disorders gain a family member.},
journal = {Blood},
volume = {139},
number = {7},
pages = {957-959},
pmid = {35175322},
issn = {1528-0020},
mesh = {Biology ; *Dyskeratosis Congenita ; Family ; Humans ; *Telomere/genetics ; },
}
@article {pmid35169632,
year = {2022},
author = {Costanzo, A and Ambrosini, R and Parolini, M and Caprioli, M and Secomandi, S and Rubolini, D and Fusani, L and Canoine, V},
title = {Telomere shortening is associated with corticosterone stress response in adult barn swallows.},
journal = {Current zoology},
volume = {68},
number = {1},
pages = {93-101},
pmid = {35169632},
issn = {1674-5507},
abstract = {When vertebrates face stressful events, the hypothalamic-pituitary-adrenal (HPA) axis is activated, generating a rapid increase in circulating glucocorticoid (GC) stress hormones followed by a return to baseline levels. However, repeated activation of HPA axis may lead to increase in oxidative stress. One target of oxidative stress is telomeres, nucleoprotein complexes at the end of chromosomes that shorten at each cell division. The susceptibility of telomeres to oxidizing molecules has led to the hypothesis that increased GC levels boost telomere shortening, but studies on this link are scanty. We studied if, in barn swallows Hirundo rustica, changes in adult erythrocyte telomere length between 2 consecutive breeding seasons are related to corticosterone (CORT) (the main avian GC) stress response induced by a standard capture-restraint protocol. Within-individual telomere length did not significantly change between consecutive breeding seasons. Second-year individuals showed the highest increase in circulating CORT concentrations following restraint. Moreover, we found a decline in female stress response along the breeding season. In addition, telomere shortening covaried with the stress response: a delayed activation of the negative feedback loop terminating the stress response was associated with greater telomere attrition. Hence, among-individual variation in stress response may affect telomere dynamics.},
}
@article {pmid35169104,
year = {2022},
author = {Van Der Stukken, C and Nawrot, TS and Alfano, R and Wang, C and Langie, SAS and Plusquin, M and Janssen, BG and Martens, DS},
title = {The telomere-mitochondrial axis of aging in newborns.},
journal = {Aging},
volume = {14},
number = {4},
pages = {1627-1650},
pmid = {35169104},
issn = {1945-4589},
mesh = {Aging/genetics ; DNA, Mitochondrial/genetics ; Female ; Fetal Blood ; Humans ; *Placenta ; Pregnancy ; Telomere/genetics ; *Tumor Suppressor Protein p53/genetics ; },
abstract = {Aging starts at the beginning of life as evidenced by high variability in telomere length (TL) and mitochondrial DNA content (mtDNAc) at birth. Whether p53 and PGC-1α are connected to these age-related markers in early life is unclear. In this study, we hypothesized that these hallmarks of aging are associated at birth. In 613 newborns from the ENVIRONAGE birth cohort, p53 and PGC-1α protein levels were measured in cord plasma, while TL and mtDNAc were measured in both cord blood and placental tissue. Cord blood methylation data of genes corresponding to the measured protein levels were available from the Human MethylationEPIC 850K BeadChip array. Pearson correlations and linear regression models were applied while accounting for selected covariates. In cord, a 10% increase in TL was associated with 5.22% (95% CI: 3.26 to 7.22; p < 0.0001) higher mtDNAc and -2.66% (95% CI: -5.04 to -0.23%; p = 0.032) lower p53 plasma level. In placenta, a 10% increase in TL was associated with 5.46% (95% CI: 3.82 to 7.13%; p < 0.0001) higher mtDNAc and -2.42% (95% CI: -4.29 to -0.52; p = 0.0098) lower p53 plasma level. Methylation level of TP53 was correlated with TL and mtDNAc in cord blood and with cord plasma p53 level. Our study suggests that p53 may be an important factor both at the protein and methylation level for the telomere-mitochondrial axis of aging at birth.},
}
@article {pmid35166828,
year = {2022},
author = {Long, W and Zheng, BX and Li, Y and Huang, XH and Lin, DM and Chen, CC and Hou, JQ and Ou, TM and Wong, WL and Zhang, K and Lu, YJ},
title = {Rational design of small-molecules to recognize G-quadruplexes of c-MYC promoter and telomere and the evaluation of their in vivo antitumor activity against breast cancer.},
journal = {Nucleic acids research},
volume = {50},
number = {4},
pages = {1829-1848},
pmid = {35166828},
issn = {1362-4962},
mesh = {Animals ; Antineoplastic Agents/*chemistry ; *Breast Neoplasms/drug therapy/genetics ; Drug Design ; Female ; *G-Quadruplexes ; Genes, myc ; Humans ; Ligands ; MCF-7 Cells ; Mice ; Promoter Regions, Genetic ; Telomere ; },
abstract = {DNA G4-structures from human c-MYC promoter and telomere are considered as important drug targets; however, the developing of small-molecule-based fluorescent binding ligands that are highly selective in targeting these G4-structures over other types of nucleic acids is challenging. We herein report a new approach of designing small molecules based on a non-selective thiazole orange scaffold to provide two-directional and multi-site interactions with flanking residues and loops of the G4-motif for better selectivity. The ligands are designed to establish multi-site interactions in the G4-binding pocket. This structural feature may render the molecules higher selectivity toward c-MYC G4s than other structures. The ligand-G4 interaction studied with 1H NMR may suggest a stacking interaction with the terminal G-tetrad. Moreover, the intracellular co-localization study with BG4 and cellular competition experiments with BRACO-19 may suggest that the binding targets of the ligands in cells are most probably G4-structures. Furthermore, the ligands that either preferentially bind to c-MYC promoter or telomeric G4s are able to downregulate markedly the c-MYC and hTERT gene expression in MCF-7 cells, and induce senescence and DNA damage to cancer cells. The in vivo antitumor activity of the ligands in MCF-7 tumor-bearing mice is also demonstrated.},
}
@article {pmid35165420,
year = {2022},
author = {Rossiello, F and Jurk, D and Passos, JF and d'Adda di Fagagna, F},
title = {Telomere dysfunction in ageing and age-related diseases.},
journal = {Nature cell biology},
volume = {24},
number = {2},
pages = {135-147},
pmid = {35165420},
issn = {1476-4679},
support = {P01 AG062413/AG/NIA NIH HHS/United States ; R01 AG068182/AG/NIA NIH HHS/United States ; UG3 CA268103/CA/NCI NIH HHS/United States ; UL1 TR002377/TR/NCATS NIH HHS/United States ; R01 AG068048/AG/NIA NIH HHS/United States ; P30 DK084567/DK/NIDDK NIH HHS/United States ; },
mesh = {Age Factors ; Aging/genetics/*metabolism/pathology ; Animals ; *Cellular Senescence ; DNA Damage ; Humans ; *Noncommunicable Diseases ; Telomere/genetics/*metabolism/pathology ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Ageing organisms accumulate senescent cells that are thought to contribute to body dysfunction. Telomere shortening and damage are recognized causes of cellular senescence and ageing. Several human conditions associated with normal ageing are precipitated by accelerated telomere dysfunction. Here, we systematize a large body of evidence and propose a coherent perspective to recognize the broad contribution of telomeric dysfunction to human pathologies.},
}
@article {pmid35159322,
year = {2022},
author = {Michaeli, J and Smoom, R and Serruya, N and El Ayoubi, H and Rotshenker-Olshinka, K and Srebnik, N and Michaeli, O and Eldar-Geva, T and Tzfati, Y},
title = {Leukocyte Telomere Length Correlates with Extended Female Fertility.},
journal = {Cells},
volume = {11},
number = {3},
pages = {},
pmid = {35159322},
issn = {2073-4409},
support = {2107/18//Israel Science Foundation/ ; Mirsky fund SZMC//Mirsky fund SZMC/ ; Kamla fund, HUJI//Kamla fund, HUJI/ ; Israel-UK-Palestine GROWTH Fellowship Scheme, the British Council//Israel-UK-Palestine GROWTH Fellowship Scheme, the British Council/ ; },
mesh = {Aging/genetics ; Female ; Fertility/genetics ; Humans ; *Leukocytes ; Longevity/genetics ; Pregnancy ; *Telomere/genetics ; },
abstract = {Current social trends of delayed reproduction to the fourth and fifth decade of life call for a better understanding of reproductive aging. Demographic studies correlated late reproduction with general health and longevity. Telomeres, the protective ends of eukaryotic chromosomes, were implicated in various aging-associated pathologies and longevity. To examine whether telomeres are also associated with reproductive aging, we measured by Southern analysis the terminal restriction fragments (TRF) in leukocytes of women delivering a healthy infant following a spontaneous pregnancy at 43-48 years of age. We compared them to age-matched previously fertile women who failed to conceive above age 41. The average TRF length in the extended fertility group (9350 bp) was significantly longer than in the normal fertility group (8850 bp; p-value = 0.03). Strikingly, excluding women with nine or more children increased the difference between the groups to over 1000 bp (9920 and 8880 bp; p-value = 0.0009). Nevertheless, we observed no apparent effects of pregnancy, delivery, or parity on telomere length. We propose that longer leukocyte telomere length reflects higher oocyte quality, which can compensate for other limiting physiological and behavioral factors and enable successful reproduction. Leukocyte telomere length should be further explored as a novel biomarker of oocyte quality for assessing reproductive potential and integrating family planning with demanding women's careers.},
}
@article {pmid35159266,
year = {2022},
author = {Dan, J and Zhou, Z and Wang, F and Wang, H and Guo, R and Keefe, DL and Liu, L},
title = {Zscan4 Contributes to Telomere Maintenance in Telomerase-Deficient Late Generation Mouse ESCs and Human ALT Cancer Cells.},
journal = {Cells},
volume = {11},
number = {3},
pages = {},
pmid = {35159266},
issn = {2073-4409},
support = {202001BC070001, 202102AA100053//Natural Science Foundation of Yunnan Province/ ; 2018YFA0107000//China National Key R&amp;D Program/ ; 31571546, 91749129//National Natural Science Foundation of China/ ; },
mesh = {Animals ; DNA Methylation/genetics ; DNA-Binding Proteins/metabolism ; Humans ; Mice ; Mouse Embryonic Stem Cells ; *Neoplasms/genetics/metabolism ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; Telomere Homeostasis ; Transcription Factors/metabolism ; },
abstract = {Proper telomere length is essential for indefinite self-renewal of embryonic stem (ES) cells and cancer cells. Telomerase-deficient late generation mouse ES cells and human ALT cancer cells are able to propagate for numerous passages, suggesting telomerase-independent mechanisms responding for telomere maintenance. However, the underlying mechanisms ensuring the telomere length maintenance are unclear. Here, using late generation telomerase KO (G4 Terc[-/-]) ESCs as a model, we show that Zscan4, highly upregulated in G4 Terc[-/-] ESCs, is responsible for the prolonged culture of these cells with stably short telomeres. Mechanistically, G4 Terc[-/-] ESCs showed reduced levels of DNA methylation and H3K9me3 at Zscan4 promoter and subtelomeres, which relieved the expression of Zscan4. Similarly, human ZSCAN4 was also derepressed by reduced H3K9me3 at its promoter in ALT U2 OS cells, and depletion of ZSCAN4 significantly shortened telomeres. Our results define a similar conserved pathway contributing to the telomere maintenance in telomerase-deficient late generation mESCs and human ALT U2OS cancer cells.},
}
@article {pmid35155512,
year = {2021},
author = {Liu, X and Shi, Q and Fan, X and Chen, H and Chen, N and Zhao, Y and Qi, K},
title = {Associations of Maternal Polyunsaturated Fatty Acids With Telomere Length in the Cord Blood and Placenta in Chinese Population.},
journal = {Frontiers in nutrition},
volume = {8},
number = {},
pages = {779306},
pmid = {35155512},
issn = {2296-861X},
abstract = {Few studies have investigated the correlation between maternal polyunsaturated fatty acids (PUFAs) and telomeres in offspring, and the underlying influential mechanisms. In this study, we assessed the associations of maternal PUFAs with telomere length (TL) and DNA methylation of the telomerase reverse transcriptase (TERT) promoter in the cord blood and the placenta. A total of 274 pregnant women and their newborn babies were enrolled in this study. Maternal blood before delivery, the cord blood, and the placenta at birth were collected. Fatty acids in maternal erythrocytes and cord blood cells were measured by gas chromatography (GC). TL in the cord blood and the placenta was determined using real-time quantitative PCR (qPCR) by calculating the product ratio of telomeric DNA to the single-copy gene β-globin. The TERT promoter methylation was analyzed by DNA bisulfite sequencing. The associations of maternal fatty acids with TL were analyzed by univariate and multivariate regression. We found that low concentrations of docosapentaenoci acid (DPA, C22: 5n-3) and total n-3 PUFAs, adrenic acid (ADA, C22: 4n-6), and osbond acid (OA, C22: 5n-6) and high concentrations of linoleic acid (LA, C18: 2n-6) in maternal erythrocytes were associated with the shortened TL in cord blood cells (estimated difference in univariate analysis -0.36 to -0.46 for extreme quintile compared with middle quintile), and that low concentrations of cord blood docosahexaenoic acid (DHA, C22: 6n-3) were related to the shortened TL in cord blood cells. Differently, high concentrations of α-linolenic acid (LNA, C18: 3n-3), eicosatrienoic acid (EA, C20: 3n-3), DHA, and γ-linoleic acid (GLA, C18:3n-6) in maternal erythrocytes were associated with the shortened TL in the placenta (estimated difference in univariate analysis -0.36 to -0.45 for higher quintiles compared with the middle quintile). Further examination demonstrated that the concentrations of DHA and total n-3 PUFAs in maternal erythrocytes had positive associations with DNA methylation of the TERT promoter in the cord blood instead of the placenta. These data suggest that maternal PUFAs are closely correlated to infant TL and the TERT promoter methylation, which are differently affected by maternal n-3 PUFAs between the cord blood and the placenta. Therefore, keeping higher levels of maternal n-3 PUFAs during pregnancy may help to maintain TL in the offspring, which is beneficial to long-term health.},
}
@article {pmid35155172,
year = {2021},
author = {Arjmand, B and Safari-Alighiarloo, N and Razzaghi, M and Rezaei Tavirani, M and Rostami Nejad, M and Rezaei Tavirani, M and Mansouri, V and Vafaee, R},
title = {Effect of UV Laser Radiation on "Positive Regulation of Telomere Maintenance" in Saccharomyces cerevisiae.},
journal = {Journal of lasers in medical sciences},
volume = {12},
number = {},
pages = {e87},
pmid = {35155172},
issn = {2008-9783},
abstract = {Introduction: Excessive exposure to ultraviolet (UV) radiation may cause a variety of skin cancers and damage to the eye lens. The assessment of different aspects of UV damage has attracted researchers' interest. UV radiation to simple biological models such as Saccharomyces cerevisiae of yeast family could help to find out different molecular changes resulting from radiation. The assessment and network analysis of gene expression data about yeast cells radiated by the UV laser was the aim of this study. Methods: The gene expression profiles of S. cerevisiae samples in the presence of the UV laser at 30 seconds radiation and 15 minutes' post-radiation time are compared with the control profiles. The significant expressed genes interacted and the central nodes and related biological terms were identified. Results: The main connected component of the network including 427 nodes was analyzed and 11 central differentially expressed genes (DEGs) were determined. RPN11, UBI4, HSP82, and HSC82 as critical DEGs and "positive regulation of telomere maintenance" as a related biological term were introduced. Conclusion: The finding has provided a new perspective on laser application in the rejuvenation process. It seems that the laser can be used as a suitable agent against the aging process which is a limiting factor in human life.},
}
@article {pmid35152597,
year = {2021},
author = {Fursova, AZ and Derbeneva, AS and Tarasov, MS and Nikulich, IF and Devyatkin, VA and Telegina, DV and Kolosova, NG and Kozhevnikova, OS},
title = {[Leukocyte telomere length and response to antiangiogenic therapy in patients with neovascular age-related macular degeneration.].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {34},
number = {6},
pages = {823-830},
pmid = {35152597},
issn = {1561-9125},
mesh = {Aged ; Angiogenesis Inhibitors ; Humans ; Leukocytes ; *Macular Degeneration/diagnosis/drug therapy/genetics ; Middle Aged ; Ranibizumab/therapeutic use ; Receptors, Vascular Endothelial Growth Factor/therapeutic use ; Retrospective Studies ; Telomere ; Treatment Outcome ; *Vascular Endothelial Growth Factor A ; Visual Acuity ; },
abstract = {Age-related macular degeneration (AMD) is becoming the leading cause of vision loss in people over 60 years of age. The neovascular form of AMD (nVMD) is characterized by choroidal neovascularization (CNV), the main trigger of which is vascular endothelial growth factor (VEGF), the inhibition of which is the current standard of treatment. Significant variability of response to anti-VEGF therapy determines the relevance of the search for biological markers - prognostic criteria of treatment response. We analyzed the response of 110 nVMD patients to anti-VEGF therapy depending on the functional and anatomical parameters of the retina (according to optical coherence tomography, OCT) and leukocyte telomere length (LTL, was assessed by quantitative PCR). Positive dynamics of best corrected visual acuity (BCVA) was observed in 100% of eyes. The central retinal thickness (CRT) decreased after the 3rd injection to 265 [234-306] µm, by the end of the observation period - to 211 [190-262] µm. The retention of activity of the subretinal neovascular membrane (SNM) at the end of the observation period correlated with lower values of the initial BCVA and high values of the initial CRT. An association of LTL with response to treatment was revealed: in patients with higher LTL the active form of SNM was more often switched to inactive after three injections, while with lower LTL, the activity of SNM was more often preserved, which determined the need for more intravitreal injections.},
}
@article {pmid35151422,
year = {2022},
author = {Rai, S and Badarinath, ARS and George, A and Sitaraman, S and Bronson, SC and Anandt, S and Babu, KT and Moses, A and Saraswathy, R and Hande, MP},
title = {Association of telomere length with diabetes mellitus and idiopathic dilated cardiomyopathy in a South Indian population: A pilot study.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {874-875},
number = {},
pages = {503439},
doi = {10.1016/j.mrgentox.2021.503439},
pmid = {35151422},
issn = {1879-3592},
mesh = {*Cardiomyopathy, Dilated/genetics ; *Diabetes Mellitus, Type 2/genetics ; Humans ; India ; Pilot Projects ; Stroke Volume ; *Telomere/genetics ; Ventricular Function, Left ; },
abstract = {Telomere shortening has been associated with ageing and with many age-related diseases including cancer, coronary artery disease, heart failure and diabetes. We sought to investigate the link between telomere shortening and age-related diseases like type 2 diabetes mellitus (DM) (without any complications: DM; with neuropathic complication: DN) and idiopathic dilated cardiomyopathy (IDCM) in south Indian population. We compared telomere lengths of blood lymphocytes taken from patients with associated age-related diseases, namely DM (n = 47), DN (n = 52) and IDCM (n = 34) and controls (n = 46). In addition, we evaluated the relationship between echocardiographic left ventricular ejection fraction (LVEF), left ventricular end diastolic and systolic diameters (LVEDd and LVESd) and telomere length in IDCM patients. Telomere length negatively correlated with age in the cohorts with diabetes and IDCM, and in controls. Average telomere length in diabetes and IDCM patients was significantly shorter than that of controls either before or after adjustments for age and sex. Duration of diabetes in patients with type 2 diabetes did not correlate with telomere length. No correlation was found between the length of telomeres and echocardiography parameters like LVEF, LVEDd and LVESd in IDCM patients. Though echocardiographic characteristics of IDCM did not correlate with telomere length, telomere shortening was found to be accelerated in diabetes (both DM and DN) and IDCM in a south Indian population. Neuropathic complication in diabetes had no effect on telomere shortening. While telomere shortening is a cause or a consequence of diabetic and cardiac pathology remains further investigation, the current study substantiates the usefulness of telomere length measurements as a marker in conjunction with other biochemical markers of age-related diseases.},
}
@article {pmid35150467,
year = {2022},
author = {Kauzálová, T and Tomášek, O and Mulder, E and Verhulst, S and Albrecht, T},
title = {Telomere length is highly repeatable and shorter in individuals with more elaborate sexual ornamentation in a short-lived passerine.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6172-6183},
doi = {10.1111/mec.16397},
pmid = {35150467},
issn = {1365-294X},
mesh = {Humans ; Male ; Animals ; Female ; *Sex Characteristics ; Sex ; *Swallows/genetics ; Feathers ; Telomere/genetics ; },
abstract = {Quantifying an individual's state as a fitness proxy has proven challenging, but accumulating evidence suggests that telomere length and attrition may indicate individual somatic state and success at self-maintenance, respectively. Sexual ornamentation is also thought to signal phenotypic quality, but links between telomeres and sexual ornamentation have been little explored. To address this issue, we examined whether telomere length and dynamics are predicted by the expression of a sexually selected ornament, the length of the outermost tail feathers (streamers), using longitudinal data from a population of European barn swallows (Hirundo rustica). In 139 adult individuals, each measured twice, we further assessed associations of telomere length with age, sex, breeding status and survival. Telomere length showed high individual repeatability (R = .97) across years while shortening with age in both sexes. Telomere length and dynamics were not significantly associated with survival to the next year, remaining lifespan or reproduction status (comparing breeding and nonbreeding yearlings). Tail streamer length, a sexually selected trait in barn swallows, was negatively associated with telomere length, independent of sex. Thus, telomere length may reflect the costs of carrying an elaborated sexual ornament, although ornament size did not significantly predict telomere shortening. In conclusion, telomere length in adult barn swallows is a highly consistent trait that shows a negative relationship with sexual ornamentation, suggesting a trade-off between sexual ornamentation and telomere length.},
}
@article {pmid35142846,
year = {2022},
author = {Lansdorp, PM},
title = {Telomeres, aging, and cancer: the big picture.},
journal = {Blood},
volume = {139},
number = {6},
pages = {813-821},
pmid = {35142846},
issn = {1528-0020},
support = {PJT-159787//CIHR/Canada ; },
mesh = {*Aging ; Animals ; DNA/genetics/metabolism ; DNA Damage ; Disease Models, Animal ; Humans ; Mutation ; Neoplasms/*genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; *Telomere Shortening ; },
abstract = {The role of telomeres in human health and disease is yet to be fully understood. The limitations of mouse models for the study of human telomere biology and difficulties in accurately measuring the length of telomere repeats in chromosomes and cells have diverted attention from many important and relevant observations. The goal of this perspective is to summarize some of these observations and to discuss the antagonistic role of telomere loss in aging and cancer in the context of developmental biology, cell turnover, and evolution. It is proposed that both damage to DNA and replicative loss of telomeric DNA contribute to aging in humans, with the differences in leukocyte telomere length between humans being linked to the risk of developing specific diseases. These ideas are captured in the Telomere Erosion in Disposable Soma theory of aging proposed herein.},
}
@article {pmid35141296,
year = {2021},
author = {Wang, Q and Liu, Z and Dong, Y and Yang, X and Chen, M and Gao, Y},
title = {Leukocyte Telomere Length Predicts Progression From Paroxysmal to Persistent Atrial Fibrillation in the Long Term After Catheter Ablation.},
journal = {Frontiers in cardiovascular medicine},
volume = {8},
number = {},
pages = {813390},
pmid = {35141296},
issn = {2297-055X},
abstract = {BACKGROUND: Aging is significantly associated with the incidence and progression of atrial fibrillation (AF) incidence. This study aimed to evaluate the potential predictive value of leukocyte telomere length (LTL) for progression from paroxysmal AF (PAF) to persistent AF (PsAF) after catheter ablation.<br><br>METHODS AND RESULTS: A total of 269 patients with AF (154 patients with PAF and 115 patients with PsAF, respectively) were prospectively enrolled, and all patients with PAF at baseline were regularly followed up to determine whether and when they should progress to PsAF after catheter ablation therapy. Baseline relative LTL was measured by quantitative real-time PCR (rt-PCT). There was a significant negative association between LTL and age (r = -0.23, p < 0.001). Patients with PsAF had significantly shorter LTL than those with PAF. After a mean follow-up of 854.9 &#xb1; 18.7 d, progression events occurred in 35 out of the 154 patients with PAF. Those progressed patients with PAF were older (70.9 &#xb1; 8.0 vs. 62.3 &#xb1; 10.3, p < 0.001) and had shorter LTL (1.2 &#xb1; 0.3 vs. 1.5 &#xb1; 0.3, p < 0.001) than those who did not. The receiver operating characteristic (ROC) curve analysis showed a significant value of LTL in distinguishing patients with PAF from patients with PsAF, with an area under the ROC curve (AUC) of 0.63 (95% CI 0.56-0.70, p < 0.001), and the optimal cut-off value of LTL was 1.175, with a sensitivity and specificity of 56.03 and 82.04%, respectively. All patients with PAF were divided into two subgroups according to the optimal cut-off point of LTL calculated by the ROC curve analysis: high LTL group (&#x2265;1.175) and low LTL group (<1.175). Kaplan-Meier curve analysis showed that PAF patients with shorter LTL had a significantly higher rate of progression after catheter ablation (40.5% vs. 18.8%, log-rank test p < 0.001). Multivariate Cox proportional-hazards model indicated that LTL [hazard ratio (HR): 2.71, 95% CI 1.36-5.42, p = 0.005] was an independent predictor for progression from PAF to PsAF after catheter ablation therapy, but HATCH score was not (HR: 1.02, 95% CI: 0.68-1.52, p = 0.923).<br><br>CONCLUSION: Leukocyte telomere length was significantly associated with AF types. LTL was independently associated with progression from PAF to PsAF after catheter ablation therapy.Chinese Clinical Trial Registry, Registration Number: ChiCTR1900021341.},
}
@article {pmid35140887,
year = {2022},
author = {Aramburu, T and Kelich, J and Rice, C and Skordalakes, E},
title = {POT1-TPP1 binding stabilizes POT1, promoting efficient telomere maintenance.},
journal = {Computational and structural biotechnology journal},
volume = {20},
number = {},
pages = {675-684},
pmid = {35140887},
issn = {2001-0370},
support = {P30 CA010815/CA/NCI NIH HHS/United States ; },
abstract = {Telomeric POT1-TPP1 binding is critical to telomere maintenance and disruption of this complex may lead to cancer. Current data suggests a reduction of intracellular POT1 levels in the absence of TPP1. Here we provide evidence of POT1 plasticity that contributes to its lack of stability in the absence of TPP1 binding. Structural data reveals inter- and intramolecular POT1C domain flexibility in the absence of TPP1. Thermostability and proteolytic resistance assays show that POT1C and the mutant complex POT1C(Q623H)-TPP1(PBD) are less stable than the wild type POT1C-TPP1(PBD), suggesting that TPP1 binding to POT1 stabilizes POT1C and makes it less accessible to proteasomal degradation in the cell. Disruption of the POT1-TPP1 complex such as through cancer-associated mutations leads to a reduction of intracellular POT1, telomere uncapping, and telomere associated DNA damage response (DDR). DDR in turn leads to senescence or genomic instability and oncogenesis.},
}
@article {pmid35129114,
year = {2022},
author = {Malyavko, AN and Petrova, OA and Zvereva, MI and Polshakov, VI and Dontsova, OA},
title = {Telomere length regulation by Rif1 protein from Hansenula polymorpha.},
journal = {eLife},
volume = {11},
number = {},
pages = {},
pmid = {35129114},
issn = {2050-084X},
mesh = {Cell Cycle Proteins/genetics/*metabolism ; DNA Replication ; Repressor Proteins/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Saccharomycetales/genetics/*metabolism ; Telomere/*ultrastructure ; Telomere Homeostasis ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Rif1 is a large multifaceted protein involved in various processes of DNA metabolism - from telomere length regulation and replication to double-strand break repair. The mechanistic details of its action, however, are often poorly understood. Here, we report functional characterization of the Rif1 homologue from methylotrophic thermotolerant budding yeast Hansenula polymorpha DL-1. We show that, similar to other yeast species, H. polymorpha Rif1 suppresses telomerase-dependent telomere elongation. We uncover two novel modes of Rif1 recruitment at H. polymorpha telomeres: via direct DNA binding and through the association with the Ku heterodimer. Both of these modes (at least partially) require the intrinsically disordered N-terminal extension - a region of the protein present exclusively in yeast species. We also demonstrate that Rif1 binds Stn1 and promotes its accumulation at telomeres in H. polymorpha.},
}
@article {pmid35127871,
year = {2021},
author = {Zhang, A and Fan, L and Bao, X and Xu, Z and Yin, Z and Zhuo, Y and Zhang, J and Gu, J and Chang, ACY and Fan, Y and Wang, C},
title = {Leukocyte Telomere Length Shortening Implies Plaque Instability and Major Adverse Cardiovascular Events in Patients With Angiographically Intermediate Lesions.},
journal = {Frontiers in cardiovascular medicine},
volume = {8},
number = {},
pages = {812363},
pmid = {35127871},
issn = {2297-055X},
abstract = {BACKGROUND: Telomere shortening, an indicator of aging, is associated with age-related diseases. This study aims to investigate the association between leukocyte telomere length (LTL) and thin-capped fibroatheromata (TCFA) and the impact of using LTL cutoff to determine the incidence of major adverse cardiovascular events (MACEs) in patients with angiographically intermediate coronary lesions.<br><br>METHODS: This was a signal-center retrospective study focusing on patients who underwent coronary angiography and optical coherence tomography (OCT). The degree of coronary stenosis was assessed by angiography. The presence of TCFA was determined by OCT imaging. A total of 156 patients with angiographically intermediate coronary lesions were enrolled.<br><br>RESULTS: Leukocyte telomere lengths were significantly shorter in the TCFA group compared with non-TCFA group [11.95 (10.56, 15.21) kb vs. 13.81 (12.06, 16.11) kb, p = 0.003]. The short-LTL group and long-LTL group were divided according to the optimal cut-off value which was determined by the receiver operating characteristic (ROC) curve analysis. Logistic regression model revealed that short-LTL was independently associated with TCFA incidence (odds ratio [OR] 4.387, 95% CI: 1.902-10.120, p = 0.001) after adjusting for confounding factors. Over a 24-months follow-up, the MACE incidence among patients with short-LTL was significantly higher than those in the long-LTL group (12.5 vs. 2.0%, p = 0.006 by log-rank test). Multivariable cox regression analysis indicated that short-LTL (hazard ratio [HR] 9.716, 95% CI: 1.995-47.319, p = 0.005) was an independent prognostic factor of MACE incidence in angiographically intermediate coronary lesions patients.<br><br>CONCLUSIONS: Short-LTL was independently associated with the incidence of TCFA and may serve as a prognostic factor for MACE risk on top of conventional risk factors.},
}
@article {pmid35123384,
year = {2022},
author = {Coimbra, BM and Carvalho, CM and van Zuiden, M and Williamson, RE and Ota, VK and Mello, AF and Belangero, SI and Olff, M and Mello, MF},
title = {The impact of neighborhood context on telomere length: A systematic review.},
journal = {Health &amp; place},
volume = {74},
number = {},
pages = {102746},
doi = {10.1016/j.healthplace.2022.102746},
pmid = {35123384},
issn = {1873-2054},
mesh = {Humans ; Residence Characteristics ; *Telomere ; *Telomere Shortening ; },
abstract = {A growing body of research demonstrates the association between neighborhood context and health. The underlying biological mechanisms of this association are not fully understood. We conducted a systematic review of studies that investigated the association between neighborhood context and telomere length (TL), a DNA-protein complex that shortens after cell division. Short TL is linked to age-related diseases and may be impacted by chronic stress. Nineteen eligible articles identified through PubMed and Scopus met inclusion criteria. Results demonstrated inconsistent support for the relationship between neighborhood disadvantage and short TL. However, findings across several studies provide evidence for an inverse association between perceived neighborhood problems and TL, suggesting that TL may be an important factor in understanding health vulnerabilities associated specifically with negative perceptions of the neighborhood context.},
}
@article {pmid35123339,
year = {2022},
author = {Incollingo Rodriguez, AC and Polcari, JJ and Nephew, BC and Harris, R and Zhang, C and Murgatroyd, C and Santos, HP},
title = {Acculturative stress, telomere length, and postpartum depression in Latinx mothers.},
journal = {Journal of psychiatric research},
volume = {147},
number = {},
pages = {301-306},
pmid = {35123339},
issn = {1879-1379},
support = {K23 NR017898/NR/NINR NIH HHS/United States ; UL1 TR001111/TR/NCATS NIH HHS/United States ; },
mesh = {Acculturation ; Adult ; Depression/psychology ; *Depression, Postpartum/epidemiology/genetics ; Female ; Hispanic or Latino ; Humans ; Mothers/psychology ; Pregnancy ; Stress, Psychological ; Telomere ; Telomere Shortening ; United States/epidemiology ; },
abstract = {Latinx mothers in the United States are highly vulnerable to psychosocial stressors, including discrimination and acculturative stress, which increase maternal health risks. Previous work in Latinx mothers indicates that prenatal discrimination influences epigenetic immune markers that may increase risk for postpartum depression. Discrimination and acculturative stress have also been linked to cellular aging, including telomere degradation, in Hispanic populations broadly, but not in this particularly vulnerable population. The present work addressed this gap in a sample of 150 Latinx mothers living in the United States (mean age 27.6 years). Psychosocial measures (including discrimination, stress, and mental health) and blood were collected at 24-32 weeks gestation. Psychosocial measures were re-evaluated at 4-6 weeks postpartum. First, we examined the relationship between maternal prenatal cultural stress (i.e., discrimination and acculturative stress) and telomere length (TL). Second, we tested whether TL predicted postpartum depression. Acculturative stress - but not discrimination - predicted shorter TL, especially among participants with high methylation of the FOXP3 promoter region. Further, shorter telomere measures during pregnancy predicted greater postpartum depression symptom severity. TL was not related to any sociodemographic characteristics such as age, income, country of origin, or years in the United States. These results highlight the uniquely impactful role of acculturative stress on Latinx maternal health and the potential interactive role of telomere length and epigenetic immune alterations in risk for maternal mental health concerns.},
}
@article {pmid35122449,
year = {2022},
author = {Marasco, V and Smith, S and Angelier, F},
title = {How does early-life adversity shape telomere dynamics during adulthood? Problems and paradigms.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {44},
number = {4},
pages = {e2100184},
doi = {10.1002/bies.202100184},
pmid = {35122449},
issn = {1521-1878},
support = {M 2520/FWF_/Austrian Science Fund FWF/Austria ; },
mesh = {*Adverse Childhood Experiences ; Longevity ; Telomere/genetics ; *Telomere Shortening ; Humans ; Animals ; *Stress, Physiological ; },
abstract = {Although early-life adversity has been associated with negative consequences during adulthood, growing evidence shows that such adversity can also lead to subsequent stress resilience and positive fitness outcomes. Telomere dynamics are relevant in this context because of the link with developmental conditions and longevity. However, few studies have assessed whether the effects of early-life adversity on developmental telomere dynamics may relate to adult telomere dynamics. We propose that the potential links between early-life adversity and adult telomere dynamics could be driven by developmental constraints (the Constraint hypothesis), by the nature/severity of developmental adversity (the Resilience hypothesis), or by developmental-mediated changes in individual life-history strategies (the Pace of Life hypothesis). We discuss these non-mutually exclusive hypotheses, explore future research directions, and propose specific studies to test these hypotheses. Our article aims to expand our understanding of the evolutionary role of developmental conditions on adult telomere dynamics, stress resilience and ageing.},
}
@article {pmid35119008,
year = {2022},
author = {Ngwa, NE and Peer, N and Matsha, TE and de Villiers, A and Sobngwi, E and Kengne, AP},
title = {Associations of leucocyte telomere length with cardio-metabolic risk profile in a South African HIV-infected population.},
journal = {Medicine},
volume = {101},
number = {5},
pages = {e28642},
pmid = {35119008},
issn = {1536-5964},
support = {Hypertension Grant #0169-04//Grand Challenges Canada/ ; Hypertension Grant #0169-04//South African Medical Research Council/ ; },
mesh = {Adult ; Cholesterol ; Cross-Sectional Studies ; *Diabetes Mellitus/epidemiology/genetics ; Female ; *HIV Infections/epidemiology ; Heart Disease Risk Factors ; Humans ; *Hypertension/epidemiology/genetics ; Leukocytes ; Male ; *Obesity/epidemiology/genetics ; Prospective Studies ; South Africa/epidemiology ; *Telomere/genetics ; Telomere Shortening ; },
abstract = {Leukocyte Telomere length (LTL) is an independent predictor of cardio-metabolic diseases (CMDs) and Human Immuno Virus (HIV) infection. However, studies are lacking on the association between LTL with CMD profile in people with HIV. Accordingly, we investigated the association between LTL and CMD profile in HIV-infected adult South Africans.This cross-sectional study included 728 HIV patients (20.6% men; median age 38 years) recruited across 17 public healthcare facilities in Cape Town. CMD markers were compared across quartiles of LTL, and spearman correlations assessed the continuous association of LTL with CMD markers. Linear and logistic regressions were then used to relate LTL with CMD risk profile, with appropriate adjustment for confounders.The prevalence of obesity, hypertension and diabetes were 34.8%, 36.8%, and 8.4%, respectively. In age, sex and body mass index adjusted models, increasing Log10LTL was associated with decreasing systolic (β = -10.52) and diastolic (β = -6.74) blood pressures, HOMA-β (β = -70.72), increasing total cholesterol (β = 0.544), non-high-density lipoprotein cholesterol (β = 0.472), and waist-to-height-ratio > 0.5 (odds ratio [OR] = 5.67), all P < .05. Compared to those in the bottom quarter, those in the top LTL quarter had lower prevalence of hypertension (OR = 0.65), and higher prevalence of total cholesterol > 5 mmol/L (OR = 1.94), and low-density lipoprotein-cholesterol > 3 mmol/L (OR = 1.62), all P < .05. LTL was not associated with diabetes nor general obesity. It was associated with Alanine Transaminase (ALT) and heart rate in univariable analyses.LTL shortening was associated with some CMD risk factors in HIV-infected adults on anti-retroviral therapy in South Africa. Prospective research is needed to explore the direction and implications of these associations.},
}
@article {pmid35116600,
year = {2021},
author = {Ye, X and Li, J and Song, C and Chen, W},
title = {Telomere in colorectal cancer associated with distant metastases and predicted a poor prognosis.},
journal = {Translational cancer research},
volume = {10},
number = {6},
pages = {2906-2917},
pmid = {35116600},
issn = {2219-6803},
abstract = {BACKGROUND: Telomere is essential for chromosomal stability and its length has been proven to be related to prognosis in many malignant tumors. This study aims to investigate the relevance of telomere length with clinical and pathologic features and its prognostic value in colorectal cancer (CRC).<br><br>METHODS: Telomere status of CRC and adenoma cells were measured by telomere-specific quantitative fluorescent in situ hybridization (Q-FISH). The relative telomere length (RTL) was calculated as the mean telomere fluorescent intensity units (TFUs) in carcinoma cell divided by the TFU in cancer-associated fibroblast cell (CAF).<br><br>RESULTS: One hundred CRC patients, who were received surgery treatment during 2013 to 2014 and fifty-seven patients who underwent the examination of colonoscope and were confirmed as adenoma were enrolled. TFUs of carcinoma cell and CAF were statistically significantly lower than in adjacent mucosa cell (P=0.0079). Although there was no difference between the three kinds of adenoma cells (P=0.5457), TFU in adenoma cells was significantly lower than in CAF (P<0.0001) and independent with age. TFU and the RTL were statistically significantly lower in adenoma cells than in carcinoma (all P<0.0001). TFU of carcinoma cell in distant metastases patients were significantly lower than that without distant metastases patients (P=0.002). When cut by the median value of TFU of carcinoma cell and RTL, patients with a lower TFU or RTL had statistically significantly poorer overall survival (OS) (P=0.0027, HR: 4.6, 95% CI: 1.9-11.0; P=0.0163, HR: 2.95, 95% CI: 1.22-7.12) and disease-free survival (DFS) (P=0.0057, HR: 3.14, 95% CI: 1.40-7.06; P=0.0271, HR: 2.49, 95% CI: 1.11-5.59, respectively) than those patients with higher TFU or RTL. On multivariate analysis, the TFU of carcinoma cell was proved to be an independent prognostic value both for OS and DFS (P=0.0005, HR: 4.975, 95% CI: 1.616-15.385; P=0.007, HR: 3.57, 95% CI: 1.410-9.010).<br><br>CONCLUSIONS: The length of telomere in carcinoma and adenoma cells were consistently shorter and the telomere changes were early carcinogenesis event, even the epithelial cells were morphologically not malignant. The length of telomere was associated with tumor metastases and prognosis, suggesting telomere probably was an important cue of the biological behavior of CRC.},
}
@article {pmid35115918,
year = {2021},
author = {Gao, X and Kong, Y and Li, S and Dong, S and Huang, X and Qi, D and Zhang, T and Yan, Y and Chen, W},
title = {Intermediate Effects of Body Mass Index and C-Reactive Protein on the Serum Cotinine- Leukocyte Telomere Length Association.},
journal = {Frontiers in aging neuroscience},
volume = {13},
number = {},
pages = {827465},
pmid = {35115918},
issn = {1663-4365},
abstract = {We aimed to examine the association between serum cotinine and leukocyte telomere length (LTL) and the intermediate effects of body mass index (BMI) and C-reactive protein (CRP) on modulating the association. This study included 4,047 adults from the 1999 to 2002 National Health and Nutrition Examination Survey. In the combined sample, after adjusting for age, race, sex, physical activity, and alcohol use, the total effect of serum cotinine on LTL was significant (standardized regression coefficient, β = -0.049, p = 0.001) without BMI and CRP included in the model. With inclusion of BMI but without CRP in the model, the direct effect of cotinine on LTL in its absolute value increased to β = -0.053 (p < 0.001), and the suppression effect of BMI was estimated at 8.8%. With inclusion of CRP but without BMI in the model, the direct effect of cotinine on LTL in its absolute value decreased to β = -0.040 (p = 0.008), and the mediation effect of CRP was estimated at 16.9%. With inclusion of both BMI and CRP in the model, BMI and CRP still had significant suppression and mediation effects, respectively, on the cotinine-LTL association. These findings suggest that weight and inflammation have different roles in the inverse association between serum cotinine and LTL.},
}
@article {pmid35115336,
year = {2022},
author = {Putman, RK and Axelsson, GT and Ash, SY and Sanders, JL and Menon, AA and Araki, T and Nishino, M and Yanagawa, M and Gudmundsson, EF and Qiao, D and San José Estépar, R and Dupuis, J and O'Connor, GT and Rosas, IO and Washko, GR and El-Chemaly, S and Raby, BA and Gudnason, V and DeMeo, DL and Silverman, EK and Hatabu, H and De Vivo, I and Cho, MH and Gudmundsson, G and Hunninghake, GM},
title = {Interstitial lung abnormalities are associated with decreased mean telomere length.},
journal = {The European respiratory journal},
volume = {60},
number = {2},
pages = {},
pmid = {35115336},
issn = {1399-3003},
support = {R01 HL122464/HL/NHLBI NIH HHS/United States ; R01 HL149877/HL/NHLBI NIH HHS/United States ; T32 HL007633/HL/NHLBI NIH HHS/United States ; R01 HL130974/HL/NHLBI NIH HHS/United States ; R21 HL140422/HL/NHLBI NIH HHS/United States ; R01 HL147148/HL/NHLBI NIH HHS/United States ; R01 HL116473/HL/NHLBI NIH HHS/United States ; R01 HL135142/HL/NHLBI NIH HHS/United States ; R01 HL137927/HL/NHLBI NIH HHS/United States ; K01 HL129039/HL/NHLBI NIH HHS/United States ; 75N92019D00031/HL/NHLBI NIH HHS/United States ; U01 HL089897/HL/NHLBI NIH HHS/United States ; U01 HL133232/HL/NHLBI NIH HHS/United States ; K08 HL140087/HL/NHLBI NIH HHS/United States ; R01 HL111024/HL/NHLBI NIH HHS/United States ; U01 HL089856/HL/NHLBI NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; K08 HL145118/HL/NHLBI NIH HHS/United States ; R01 CA203636/CA/NCI NIH HHS/United States ; U01 CA209414/CA/NCI NIH HHS/United States ; P01 HL132825/HL/NHLBI NIH HHS/United States ; R01 HL149861/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; Lung ; *Lung Diseases, Interstitial/epidemiology/genetics ; *Pulmonary Disease, Chronic Obstructive ; Telomere/genetics ; Tomography, X-Ray Computed ; },
abstract = {BACKGROUND: Interstitial lung abnormalities (ILA) share many features with idiopathic pulmonary fibrosis; however, it is not known if ILA are associated with decreased mean telomere length (MTL).<br><br>METHODS: Telomere length was measured with quantitative PCR in the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) and Age Gene/Environment Susceptibility Reykjavik (AGES-Reykjavik) cohorts and Southern blot analysis was used in the Framingham Heart Study (FHS). Logistic and linear regression were used to assess the association between ILA and MTL; Cox proportional hazards models were used to assess the association between MTL and mortality.<br><br>RESULTS: In all three cohorts, ILA were associated with decreased MTL. In the COPDGene and AGES-Reykjavik cohorts, after adjustment there was greater than twofold increase in the odds of ILA when comparing the shortest quartile of telomere length to the longest quartile (OR 2.2, 95% CI 1.5-3.4, p=0.0001, and OR 2.6, 95% CI 1.4-4.9, p=0.003, respectively). In the FHS, those with ILA had shorter telomeres than those without ILA (-767&#x2005;bp, 95% CI 76-1584&#x2005;bp, p=0.03). Although decreased MTL was associated with chronic obstructive pulmonary disease (OR 1.3, 95% CI 1.1-1.6, p=0.01) in COPDGene, the effect estimate was less than that noted with ILA. There was no consistent association between MTL and risk of death when comparing the shortest quartile of telomere length in COPDGene and AGES-Reykjavik (HR 0.82, 95% CI 0.4-1.7, p=0.6, and HR 1.2, 95% CI 0.6-2.2, p=0.5, respectively).<br><br>CONCLUSION: ILA are associated with decreased MTL.},
}
@article {pmid35114947,
year = {2022},
author = {Olbertova, H and Plevova, K and Pavlova, S and Malcikova, J and Kotaskova, J and Stranska, K and Spunarova, M and Trbusek, M and Navrkalova, V and Dvorackova, B and Tom, N and Pal, K and Jarosova, M and Brychtova, Y and Panovska, A and Doubek, M and Pospisilova, S},
title = {Evolution of TP53 abnormalities during CLL disease course is associated with telomere length changes.},
journal = {BMC cancer},
volume = {22},
number = {1},
pages = {137},
pmid = {35114947},
issn = {1471-2407},
support = {MH-CZ RVO 65269705//Ministerstvo Zdravotnictv&#xed; Cesk&#xe9; Republiky/ ; AZV NU21-08-00237//Ministerstvo Zdravotnictv&#xed; Cesk&#xe9; Republiky/ ; AZV NV19-03-00091//Ministerstvo Zdravotnictv&#xed; Cesk&#xe9; Republiky/ ; GACR 19-15737S//Grantov&#xe1; Agentura &#x10c;esk&#xe9; Republiky/ ; GACR 19-11299S//Grantov&#xe1; Agentura &#x10c;esk&#xe9; Republiky/ ; LM2018132//Technologick&#xe1; Agentura &#x10c;esk&#xe9; Republiky/ ; LM2018133//Technologick&#xe1; Agentura &#x10c;esk&#xe9; Republiky/ ; CZ.02.1.01/0.0/0.0/18_046/0015515//Ministerstvo &#x160;kolstv&#xed;, Ml&#xe1;de&#x17e;e a T&#x11b;lov&#xfd;chovy/ ; },
mesh = {Clonal Evolution/*genetics ; Female ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics ; Male ; Middle Aged ; Mutation ; Proto-Oncogene Proteins c-bcr/metabolism ; Signal Transduction ; Telomerase/genetics ; Telomere/*ultrastructure ; Tumor Suppressor Protein p53/*genetics ; },
abstract = {BACKGROUND: Telomeres are protective structures at chromosome ends which shorten gradually with increasing age. In chronic lymphocytic leukemia (CLL), short telomeres have been associated with unfavorable disease outcome, but the link between clonal evolution and telomere shortening remains unresolved.<br><br>METHODS: We investigated relative telomere length (RTL) in a well-characterized cohort of 198 CLL patients by qPCR and focused in detail on a subgroup 26 patients who underwent clonal evolution of TP53 mutations (evolTP53). In the evolTP53 subgroup we explored factors influencing clonal evolution and corresponding changes in telomere length through measurements of telomerase expression, lymphocyte doubling time, and BCR signaling activity.<br><br>RESULTS: At baseline, RTL of the evolTP53 patients was scattered across the entire RTL spectrum observed in our CLL cohort. RTL changed in the follow-up samples of 16/26 (62%) evolTP53 cases, inclining to reach intermediate RTL values, i.e., longer telomeres shortened compared to baseline while shorter ones prolonged. For the first time we show that TP53 clonal shifts are linked to RTL change, including unexpected RTL prolongation. We further investigated parameters associated with RTL changes. Unstable telomeres were significantly more frequent among younger patients (P&#x2009;=&#x2009;0.032). Shorter telomeres were associated with decreased activity of the B-cell receptor signaling components p-ERK1/2, p-ZAP-70/SYK, and p-NF&#x3ba;B (P&#x2009;=&#x2009;0.04, P&#x2009;=&#x2009;0.01, and P&#x2009;=&#x2009;0.02, respectively).<br><br>CONCLUSIONS: Our study revealed that changes of telomere length reflect evolution in leukemic subclone proportion, and are associated with specific clinico-biological features of the explored cohort.},
}
@article {pmid35101395,
year = {2022},
author = {Niu, Z and Wen, X and Wang, M and Tian, L and Mu, L},
title = {Personal exposure to benzene, toluene, ethylbenzene, and xylenes (BTEXs) mixture and telomere length: a cross-sectional study of the general US adult population.},
journal = {Environmental research},
volume = {209},
number = {},
pages = {112810},
doi = {10.1016/j.envres.2022.112810},
pmid = {35101395},
issn = {1096-0953},
support = {UL1 TR001412/TR/NCATS NIH HHS/United States ; R21 HD091515/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Bayes Theorem ; *Benzene/analysis/toxicity ; Benzene Derivatives/toxicity ; Cross-Sectional Studies ; Humans ; Middle Aged ; Nutrition Surveys ; Telomere ; Toluene/analysis ; *Xylenes/analysis/toxicity ; Young Adult ; },
abstract = {BACKGROUND: Benzene, Toluene, Ethylbenzene, and Xylenes (BTEXs) are a group of aromatic air pollutants from fossil fuels. There is no research on associations of the BTEXs mixture with telomere length (TL), a marker of cellular aging, in the general population.<br><br>METHODS: We analyzed a subsample of 549 US adults aged 20-59 years from the National Health and Nutrition Examination Survey 1999-2000. BTEXs samples were collected by passive exposure badges worn by participants for 48-72&#xa0;h. Levels of BTEXs were measured with gas chromatography/mass spectrometry. Leukocyte TL was measured with qPCR. We used Bayesian Kernel Machine Regression (BKMR) to examine the effect of the BTEXs mixture on TL adjusting for potential confounders. Analyses were stratified by tobacco smoking status (serum cotinine&#x2265;10&#xa0;ng/mL vs. <10&#xa0;ng/mL).<br><br>RESULTS: Levels of personal exposure to BTEXs were detectable in most participants and were relatively higher in the 150 smokers than in the 399 nonsmokers. The BTEXs were moderately or strongly intercorrelated (0.5&#xa0;<&#xa0;r&#xa0;&#x2264;&#xa0;0.9, P&#xa0;<&#xa0;0.05). All chemicals had weak, inverse correlations with TL (-0.1<r&#xa0;<&#xa0;0, P&#xa0;>&#xa0;0.05). In BKMR models among the nonsmokers, the BTEXs mixture was significantly inversely associated with TL at a low range of the BTEXs (20th-65th percentile) but was not associated with TL at a higher range (>65th percentile). Also, we found a U-shape association of benzene and a positive association of ethylbenzene with TL independent of other BTEXs. Among smokers, neither the BTEXs mixture nor any individual BTEXs were significantly associated with TL.<br><br>CONCLUSION: Within a low-to-middle range, exposure to the BTEXs mixture may be associated with shorter telomere length in the general nonsmoking population.},
}
@article {pmid35100428,
year = {2022},
author = {Ceschi, S and Berselli, M and Cozzaglio, M and Giantin, M and Toppo, S and Spolaore, B and Sissi, C},
title = {Vimentin binds to G-quadruplex repeats found at telomeres and gene promoters.},
journal = {Nucleic acids research},
volume = {50},
number = {3},
pages = {1370-1381},
pmid = {35100428},
issn = {1362-4962},
mesh = {*G-Quadruplexes ; Guanine/chemistry ; Intermediate Filaments ; *Promoter Regions, Genetic ; Telomere/*metabolism ; Vimentin/*metabolism ; },
abstract = {G-quadruplex (G4) structures that can form at guanine-rich genomic sites, including telomeres and gene promoters, are actively involved in genome maintenance, replication, and transcription, through finely tuned interactions with protein networks. In the present study, we identified the intermediate filament protein Vimentin as a binder with nanomolar affinity for those G-rich sequences that give rise to at least two adjacent G4 units, named G4 repeats. This interaction is supported by the N-terminal domains of soluble Vimentin tetramers. The selectivity of Vimentin for G4 repeats versus individual G4s provides an unprecedented result. Based on GO enrichment analysis performed on genes having putative G4 repeats within their core promoters, we suggest that Vimentin recruitment at these sites may contribute to the regulation of gene expression during cell development and migration, possibly by reshaping the local higher-order genome topology, as already reported for lamin B.},
}
@article {pmid35098380,
year = {2022},
author = {Wang, LN and Wang, L and Cheng, G and Dai, M and Yu, Y and Teng, G and Zhao, J and Xu, D},
title = {The association of telomere maintenance and TERT expression with susceptibility to human papillomavirus infection in cervical epithelium.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {79},
number = {2},
pages = {110},
pmid = {35098380},
issn = {1420-9071},
support = {ZR201702160271//Natural Science Foundation of Shandong Province/ ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Epithelium/metabolism/virology ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genetic Predisposition to Disease/*genetics ; HeLa Cells ; Humans ; Middle Aged ; Papillomavirus Infections/complications/*genetics/virology ; Polymorphism, Single Nucleotide ; Telomerase/*genetics/metabolism ; Telomere/enzymology/*genetics ; Uterine Cervical Neoplasms/complications/*genetics/metabolism ; Young Adult ; },
abstract = {The role of telomerase reverse transcriptase (TERT) induction and telomere maintenance in carcinogenesis including cervical cancer (CC) pathogenesis has been well established. However, it remains unclear whether they affect infection of high-risk human papillomavirus (hrHPV), an initiating event for CC development. Similarly, genetic variants at the TERT locus are shown to be associated with susceptibility to CC, but it is unclear whether these SNPs modify the risk for cervical HPV infection. Here we show that in CC-derived HeLa cells, TERT overexpression inhibits, while its depletion upregulates expression of Syndecan-1 (SDC-1), a key component for HPV entry receptors. The TCGA cohort of CC analyses reveals an inverse correlation between TERT and SDC-1 expression (R = -0.23, P = 0.001). We further recruited 1330 females (520 non-HPV and 810 hrHPV-infected) without CC or high-grade cervical intraepithelial neoplasia to analyze telomeres in cervical epithelial cells and SNPs at rs2736098, rs2736100 and rs2736108, previously identified TERT SNPs for CC risk. Non-infected females exhibited age-related telomere shortening in cervical epithelial cells and their telomeres were significantly longer than those in hrHPV-infected group (1.31 ± 0.62 vs 1.19 ± 0.48, P < 0.001). There were no differences in rs2736098 and rs2736100 genotypes, but non-infected individuals had significantly a higher C-allele frequency (associated with higher TERT expression) while lower T-allele levels at rs2736108 compared with those in the hrHPV group (P = 0.020). Collectively, appropriate telomere maintenance and TERT expression in normal cervical cells may prevent CC by modulating hrHPV infection predisposition, although they are required for CC development and progression.},
}
@article {pmid35097237,
year = {2022},
author = {Dorgaleleh, S and Naghipoor, K and Hajimohammadi, Z and Dastaviz, F and Oladnabi, M},
title = {Molecular insight of dyskeratosis congenita: Defects in telomere length homeostasis.},
journal = {Journal of clinical and translational research},
volume = {8},
number = {1},
pages = {20-30},
pmid = {35097237},
issn = {2424-810X},
abstract = {BACKGROUND: Dyskeratosis congenita (DC) is a rare disease and is a heterogenous disorder, with its inheritance patterns as autosomal dominant, autosomal recessive, and X-linked recessive. This disorder occurs due to faulty maintenance of telomeres in stem cells. This congenital condition is diagnosed with three symptoms: oral leukoplakia, nail dystrophy, and abnormal skin pigmentation. However, because it has a wide range of symptoms, it may have phenotypes similar to other diseases. For this reason, it is necessary to use methods of measuring the Telomere Length (TL) and determining the shortness of the telomere in these patients so that it can be distinguished from other diseases. Today, the Next Generation Sequencing technique accurately detects mutations in the target genes.<br><br>AIM: This work aims to review and summarize how each of the DC genes is involved in TL, and how to diagnose and differentiate the disease using clinical signs and methods to measure TL. It also offers treatments for DC patients, such as Hematopoietic Stem Cell Transplantation and Androgen therapy.<br><br>RELEVANCE FOR PATIENTS: In DC patients, the genes involved in telomere homeostasis are mutated. Because these patients may have an overlapping phenotype with other diseases, it is best to perform whole-exome sequencing after genetics counseling to find the relevant mutation. As DC is a multi-systemic disease, we need to monitor patients frequently through annual lung function tests, ultrasounds, gynecological examinations, and skin examinations.},
}
@article {pmid35092358,
year = {2022},
author = {Shinko, Y and Okazaki, S and Otsuka, I and Horai, T and Kim, S and Tanifuji, T and Hishimoto, A},
title = {Accelerated epigenetic age and shortened telomere length based on DNA methylation in Nicolaides-Baraitser syndrome.},
journal = {Molecular genetics &amp; genomic medicine},
volume = {10},
number = {3},
pages = {e1876},
pmid = {35092358},
issn = {2324-9269},
mesh = {*DNA Methylation ; Epigenesis, Genetic ; Facies ; Foot Deformities, Congenital ; Humans ; Hypotrichosis ; Intellectual Disability ; Telomere/genetics ; *Telomere Shortening ; },
abstract = {BACKGROUND: Nicolaides-Baraitser syndrome (NCBRS) is a rare disorder characterized by neurodevelopmental delays, seizures, and diverse physical characteristics. The DNA methylation (DNAm) profile in NCBRS is significantly different. DNAm is linked to the biological aging of cells and the health risks associated with biological aging. In this study, we examined changes in biological ages in NCBRS to provide insights into the prognosis and health risks of NCBRS.<br><br>METHODS: We used a publicly available dataset to examine biological aging in NCBRS using DNAm-based epigenetic ages, such as PhenoAge and GrimAge, as well as DNAm-based estimator of telomere length (DNAmTL). We investigated 12 cases, clinically diagnosed as NCBRS, and 27 controls.<br><br>RESULTS: Compared to controls, NCBRS cases exhibited significantly accelerated PhenoAge and GrimAge as well as significantly shortened DNAmTL.<br><br>CONCLUSION: These results suggest an acceleration of biological aging in NCBRS and provide insights into the prognosis and health risks of NCBRS.},
}
@article {pmid35088059,
year = {2021},
author = {Heard, E and Johnson, AD and Korbel, JO and Lee, C and Snyder, MP and Sturgill, D},
title = {The X chromosome from telomere to telomere: key achievements and future opportunities.},
journal = {Faculty reviews},
volume = {10},
number = {},
pages = {63},
pmid = {35088059},
issn = {2732-432X},
abstract = {While the human genome represents the most accurate vertebrate reference assembly to date, it still contains numerous gaps, including centromeric and other large repeat-containing regions - often termed the "dark side" of the genome - many of which are of fundamental biological importance. Miga et al.[1,2] present the first gapless assembly of the human X chromosome, with the help of ultra-long-read nanopore reads generated for the haploid complete hydatidiform mole (CHM13) genome. They reconstruct the ~3.1 megabase centromeric satellite DNA array and map DNA methylation patterns across complex tandem repeats and satellite arrays. This Telomere-to-Telomere assembly provides a superior human X chromosome reference enabling future sex-determination and X-linked disease research, and provides a path towards finishing the entire human genome sequence.},
}
@article {pmid35086525,
year = {2022},
author = {Usategui, A and Municio, C and Arias-Salgado, EG and Martín, M and Fernández-Varas, B and Del Rey, MJ and Carreira, P and González, A and Criado, G and Perona, R and Pablos, JL},
title = {Evidence of telomere attrition and a potential role for DNA damage in systemic sclerosis.},
journal = {Immunity &amp; ageing : I &amp; A},
volume = {19},
number = {1},
pages = {7},
pmid = {35086525},
issn = {1742-4933},
support = {PI19/01129//Instituto de Salud Carlos III/ ; RD16/0012 RETICS program//Instituto de Salud Carlos III/ ; },
abstract = {BACKGROUND: To investigate the role of cell senescence in systemic sclerosis (SSc), we analyzed telomere shortening (TS) in SSc patients and the effect of targeting DNA damage in the bleomycin model of skin fibrosis.<br><br>RESULTS: Telomere length (TL) in blood leukocytes of 174 SSc patients and 68 healthy controls was measured by Southern blot, and we found shorter age-standardized TL in SSc patients compared to healthy controls. TL was shorter in SSc patients with ILD compared to those without ILD and in anti-topoisomerase I positive compared to anti-centromere positive patients. To analyze the potential role of DNA damage in skin fibrosis, we evaluated the effects of the DNA protective GSE4 peptide in the bleomycin mouse model of scleroderma and the fibrotic response of cultured human dermal fibroblasts. Administration of GSE4-nanoparticles attenuated bleomycin-induced skin fibrosis as measured by Masson's staining of collagen and reduced Acta2 and Ctgf mRNA expression, whereas transduction of dermal fibroblasts with a lentiviral GSE4 expression vector reduced COL1A1, ACTA2 and CTGF gene expression after stimulation with bleomycin or TGF-&#x3b2;, in parallel to a reduction of the phospho-histone H2A.X marker of DNA damage.<br><br>CONCLUSIONS: SSc is associated with TS, particularly in patients with lung disease or anti-topoisomerase I antibodies. Administration of GSE4 peptide attenuated experimental skin fibrosis and reduced fibroblast expression of profibrotic factors, supporting a role for oxidative DNA damage in scleroderma.},
}
@article {pmid35085380,
year = {2022},
author = {Cheng, F and Luk, AO and Shi, M and Huang, C and Jiang, G and Yang, A and Wu, H and Lim, CKP and Tam, CHT and Fan, B and Lau, ESH and Ng, ACW and Wong, KK and Carroll, L and Lee, HM and Kong, AP and Keech, AC and Chow, E and Joglekar, MV and Tsui, SKW and So, WY and So, HC and Hardikar, AA and Jenkins, AJ and Chan, JCN and Ma, RCW},
title = {Shortened Leukocyte Telomere Length Is Associated With Glycemic Progression in Type 2 Diabetes: A Prospective and Mendelian Randomization Analysis.},
journal = {Diabetes care},
volume = {45},
number = {3},
pages = {701-709},
pmid = {35085380},
issn = {1935-5548},
mesh = {Cohort Studies ; *Diabetes Mellitus, Type 2/genetics ; Humans ; Leukocytes ; Mendelian Randomization Analysis ; Middle Aged ; Prospective Studies ; Telomere/genetics ; Telomere Shortening ; },
abstract = {OBJECTIVE: Several studies support associations between relative leukocyte telomere length (rLTL), a biomarker of biological aging and type 2 diabetes. This study investigates the relationship between rLTL and the risk of glycemic progression in patients with type 2 diabetes.<br><br>RESEARCH DESIGN AND METHODS: In this cohort study, consecutive Chinese patients with type 2 diabetes (N = 5,506) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied. rLTL was measured using quantitative PCR. Glycemic progression was defined as the new need for exogenous insulin.<br><br>RESULTS: The mean (SD) age of the 5,349 subjects was 57.0 (13.3) years, and mean (SD) follow-up was 8.8 (5.4) years. Baseline rLTL was significantly shorter in the 1,803 subjects who progressed to insulin requirement compared with the remaining subjects (4.43 &#xb1; 1.16 vs. 4.69 &#xb1; 1.20). Shorter rLTL was associated with a higher risk of glycemic progression (hazard ratio [95% CI] for each unit decrease [to &#x223c;0.2 kilobases]: 1.10 [1.06-1.14]), which remained significant after adjusting for confounders. Baseline rLTL was independently associated with glycemic exposure during follow-up (&#x3b2; = -0.05 [-0.06 to -0.04]). Each 1-kilobase decrease in absolute LTL was on average associated with a 1.69-fold higher risk of diabetes progression (95% CI 1.35-2.11). Two-sample Mendelian randomization analysis showed per 1-unit genetically decreased rLTL was associated with a 1.38-fold higher risk of diabetes progression (95% CI 1.12-1.70).<br><br>CONCLUSIONS: Shorter rLTL was significantly associated with an increased risk of glycemic progression in individuals with type 2 diabetes, independent of established risk factors. Telomere length may be a useful biomarker for glycemic progression in people with type 2 diabetes.},
}
@article {pmid35081355,
year = {2022},
author = {Zhang, K and Tarczykowska, A and Gupta, DK and Pendlebury, DF and Zuckerman, C and Nandakumar, J and Shibuya, H},
title = {The TERB1 MYB domain suppresses telomere erosion in meiotic prophase I.},
journal = {Cell reports},
volume = {38},
number = {4},
pages = {110289},
pmid = {35081355},
issn = {2211-1247},
support = {R01 GM120094/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Female ; Humans ; Male ; Meiotic Prophase I/*physiology ; Mice ; Mice, Inbred C57BL ; Protein Domains ; Telomere/*metabolism ; Telomere-Binding Proteins/*chemistry/*metabolism ; },
abstract = {The meiosis-specific telomere-binding protein TERB1 anchors telomeres to the nuclear envelope and drives chromosome movements for the pairing of homologous chromosomes. TERB1 has an MYB-like DNA-binding (MYB) domain, which is a hallmark of telomeric DNA-binding proteins. Here, we demonstrate that the TERB1 MYB domain has lost its canonical DNA-binding activity. The analysis of Terb1 point mutant mice expressing TERB1 lacking its MYB domain showed that the MYB domain is dispensable for telomere localization of TERB1 and the downstream TERB2-MAJIN complex, the promotion of homologous pairing, and even fertility. Instead, the TERB1 MYB domain regulates the enrichment of cohesin and promotes the remodeling of axial elements in the early-to-late pachytene transition, which suppresses telomere erosion. Considering its conservation across metazoan phyla, the TERB1 MYB domain is likely to be important for the maintenance of telomeric DNA and thus for genomic integrity by suppressing meiotic telomere erosion over long evolutionary timescales.},
}
@article {pmid35080073,
year = {2022},
author = {Salmón, P and Burraco, P},
title = {Telomeres and anthropogenic disturbances in wildlife: A systematic review and meta-analysis.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6018-6039},
pmid = {35080073},
issn = {1365-294X},
mesh = {Animals ; Humans ; *Animals, Wild/genetics ; *Telomere Shortening ; Anthropogenic Effects ; Telomere/genetics ; Biological Evolution ; },
abstract = {Human-driven environmental changes are affecting wildlife across the globe. These challenges do not influence species or populations to the same extent and therefore a comprehensive evaluation of organismal health is needed to determine their ultimate impact. Evidence suggests that telomeres (the terminal chromosomal regions) are sensitive to environmental conditions and have been posited as a surrogate for animal health and fitness. Evaluation of their use in an applied ecological context is still scarce. Here, using information from molecular and occupational biomedical studies, we aim to provide ecologists and evolutionary biologists with an accessible synthesis of the links between human disturbances and telomere length. In addition, we perform a systematic review and meta-analysis on studies measuring telomere length in wild/wild-derived animals facing anthropogenic disturbances. Despite the relatively small number of studies to date, our meta-analysis revealed a significant small negative association between disturbances and telomere length (-0.092 [-0.153, -0.031]; n = 28; k = 159). Yet, our systematic review suggests that the use of telomeres as a biomarker to understand the anthropogenic impact on wildlife is limited. We propose some research avenues that will help to broadly evaluate their suitability: (i) further causal studies on the link between human disturbances and telomeres; (ii) investigating the organismal implications, in terms of fitness and performance, of a given telomere length in anthropogenically disturbed scenarios; and (iii) better understanding of the underlying mechanisms of telomere dynamics. Future studies in these facets will help to ultimately determine their role as markers of health and fitness in wildlife facing anthropogenic disturbances.},
}
@article {pmid35079641,
year = {2022},
author = {Karlsen, TR and Olsen, MB and Kong, XY and Yang, K and Quiles-Jiménez, A and Kroustallaki, P and Holm, S and Lines, GT and Aukrust, P and Skarpengland, T and Bjørås, M and Dahl, TB and Nilsen, H and Gregersen, I and Halvorsen, B},
title = {NEIL3-deficient bone marrow displays decreased hematopoietic capacity and reduced telomere length.},
journal = {Biochemistry and biophysics reports},
volume = {29},
number = {},
pages = {101211},
pmid = {35079641},
issn = {2405-5808},
abstract = {Deficiency of NEIL3, a DNA repair enzyme, has significant impact on mouse physiology, including vascular biology and gut health, processes related to aging. Leukocyte telomere length (LTL) is suggested as a marker of biological aging, and shortened LTL is associated with increased risk of cardiovascular disease. NEIL3 has been shown to repair DNA damage in telomere regions in vitro. Herein, we explored the role of NEIL3 in telomere maintenance in vivo by studying bone marrow cells from atherosclerosis-prone NEIL3-deficient mice. We found shortened telomeres and decreased activity of the telomerase enzyme in bone marrow cells derived from Apoe [-/-] Neil3 [-/-] as compared to Apoe [-/-] mice. Furthermore, Apoe [-/-] Neil3 [-/-] mice had decreased leukocyte levels as compared to Apoe [-/-] mice, both in bone marrow and in peripheral blood. Finally, RNA sequencing of bone marrow cells from Apoe [-/-] Neil3 [-/-] and Apoe [-/-] mice revealed different expression levels of genes involved in cell cycle regulation, cellular senescence and telomere protection. This study points to NEIL3 as a telomere-protecting protein in murine bone marrow in vivo.},
}
@article {pmid35077681,
year = {2022},
author = {Jack, A and Kim, Y and Strom, AR and Lee, DSW and Williams, B and Schaub, JM and Kellogg, EH and Finkelstein, IJ and Ferro, LS and Yildiz, A and Brangwynne, CP},
title = {Compartmentalization of telomeres through DNA-scaffolded phase separation.},
journal = {Developmental cell},
volume = {57},
number = {2},
pages = {277-290.e9},
pmid = {35077681},
issn = {1878-1551},
support = {R35 GM136414/GM/NIGMS NIH HHS/United States ; T32 GM007388/GM/NIGMS NIH HHS/United States ; R01 GM120554/GM/NIGMS NIH HHS/United States ; U01 DA040601/DA/NIDA NIH HHS/United States ; F31 GM123655/GM/NIGMS NIH HHS/United States ; T32 GM008295/GM/NIGMS NIH HHS/United States ; K99 GM124463/GM/NIGMS NIH HHS/United States ; R00 GM124463/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; R01 GM118773/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line ; Chromatin/genetics ; DNA/metabolism ; DNA Damage/physiology ; DNA Repair/genetics/physiology ; Humans ; Optogenetics/methods ; Protein Binding/genetics/physiology ; Shelterin Complex/genetics/*metabolism/physiology ; Telomere/*metabolism/physiology ; Telomere-Binding Proteins/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; },
abstract = {Telomeres form unique nuclear compartments that prevent degradation and fusion of chromosome ends by recruiting shelterin proteins and regulating access of DNA damage repair factors. To understand how these dynamic components protect chromosome ends, we combine in vivo biophysical interrogation and in vitro reconstitution of human shelterin. We show that shelterin components form multicomponent liquid condensates with selective biomolecular partitioning on telomeric DNA. Tethering and anomalous diffusion prevent multiple telomeres from coalescing into a single condensate in mammalian cells. However, telomeres coalesce when brought into contact via an optogenetic approach. TRF1 and TRF2 subunits of shelterin drive phase separation, and their N-terminal domains specify interactions with telomeric DNA in vitro. Telomeric condensates selectively recruit telomere-associated factors and regulate access of DNA damage repair factors. We propose that shelterin mediates phase separation of telomeric chromatin, which underlies the dynamic yet persistent nature of the end-protection mechanism.},
}
@article {pmid35077392,
year = {2022},
author = {Hastings, WJ and Etzel, L and Heim, CM and Noll, JG and Rose, EJ and Schreier, HMC and Shenk, CE and Tang, X and Shalev, I},
title = {Comparing qPCR and DNA methylation-based measurements of telomere length in a high-risk pediatric cohort.},
journal = {Aging},
volume = {14},
number = {2},
pages = {660-677},
pmid = {35077392},
issn = {1945-4589},
support = {P50 HD089922/HD/NICHD NIH HHS/United States ; T32 AG049676/AG/NIA NIH HHS/United States ; U01 ES030949/ES/NIEHS NIH HHS/United States ; },
mesh = {Aged ; Aging/genetics ; Cohort Studies ; *DNA Methylation ; Humans ; Male ; Reproducibility of Results ; *Telomere/genetics ; },
abstract = {Various approaches exist to assess population differences in biological aging. Telomere length (TL) is one such measure, and is associated with disease, disability and early mortality. Yet, issues surrounding precision and reproducibility are a concern for TL measurement. An alternative method to estimate TL using DNA methylation (DNAmTL) was recently developed. Although DNAmTL has been characterized in adult and elderly cohorts, its utility in pediatric populations remains unknown. We examined the comparability of leukocyte TL measurements generated using qPCR (absolute TL; aTL) to those estimated using DNAmTL in a high-risk pediatric cohort (N = 269; age: 8-13 years, 83% investigated for maltreatment). aTL and DNAmTL measurements were correlated with one another (r = 0.20, p = 0.001), but exhibited poor measurement agreement and were significantly different in paired-sample t-tests (Cohen's d = 0.77, p < 0.001). Shorter DNAmTL was associated with older age (r = -0.25, p < 0.001), male sex (β = -0.27, p = 0.029), and White race (β = -0.74, p = 0.008). By contrast, aTL was less strongly associated with age (r = -0.13, p = 0.040), was longer in males (β = 0.31, p = 0.012), and was not associated with race (p = 0.820). These findings highlight strengths and limitations of high-throughput measures of TL; although DNAmTL replicated hypothesized associations, aTL measurements were positively skewed and did not replicate associations with external validity measures. These results also extend previous research in adults and suggest that DNAmTL is a sensitive TL measure for use in pediatric populations.},
}
@article {pmid35073935,
year = {2022},
author = {Chen, L and Tan, KML and Gong, M and Chong, MFF and Tan, KH and Chong, YS and Meaney, MJ and Gluckman, PD and Eriksson, JG and Karnani, N},
title = {Variability in newborn telomere length is explained by inheritance and intrauterine environment.},
journal = {BMC medicine},
volume = {20},
number = {1},
pages = {20},
pmid = {35073935},
issn = {1741-7015},
mesh = {Cohort Studies ; Female ; *Genome-Wide Association Study ; Humans ; Infant, Newborn ; Male ; Mothers ; Pregnancy ; *Telomere/genetics ; Telomere Homeostasis ; },
abstract = {BACKGROUND: Telomere length (TL) and its attrition are important indicators of physiological stress and biological aging and hence may vary among individuals of the same age. This variation is apparent even in newborns, suggesting potential effects of parental factors and the intrauterine environment on TL of the growing fetus.<br><br>METHODS: Average relative TLs of newborns (cord tissue, N = 950) and mothers (buffy coat collected at 26-28&#x2009;weeks of gestation, N = 892) were measured in a birth cohort. This study provides a comprehensive analysis of the effects of heritable factors, socioeconomic status, and in utero exposures linked with maternal nutrition, cardiometabolic health, and mental well-being on the newborn TL. The association between maternal TL and antenatal maternal health was also studied.<br><br>RESULTS: Longer maternal TL (&#x3b2; = 0.14, P = 1.99E-05) and higher paternal age (&#x3b2; = 0.10, P = 3.73E-03) were positively associated with newborn TL. Genome-wide association studies on newborn and maternal TLs identified 6 genetic variants in a strong linkage disequilibrium on chromosome 3q26.2 (Tag SNP-LRRC34-rs10936600: Pmeta = 5.95E-08). Mothers with higher anxiety scores, elevated fasting blood glucose, lower plasma insulin-like growth factor-binding protein 3 and vitamin B12 levels, and active smoking status during pregnancy showed a higher risk of giving birth to offspring with shorter TL. There were sex-related differences in the factors explaining newborn TL variation. Variation in female newborn TL was best explained by maternal TL, mental health, and plasma vitamin B12 levels, while that in male newborn TL was best explained by paternal age, maternal education, and metabolic health. Mother's TL was associated with her own metabolic health and nutrient status, which may have transgenerational effects on offspring TL.<br><br>CONCLUSIONS: Our findings provide a comprehensive understanding of the heritable and environmental factors and their relative contributions to the initial setting of TL and programing of longevity in early life. This study provides valuable insights for preventing in utero telomere attrition by improving the antenatal health of mothers via targeting the modifiable factors.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov , NCT01174875. Registered on 1 July 2010.},
}
@article {pmid35073322,
year = {2022},
author = {Li Piani, L and Reschini, M and Somigliana, E and Ferrari, S and Busnelli, A and Viganò, P and Favero, C and Albetti, B and Hoxha, M and Bollati, V},
title = {Peripheral mitochondrial DNA, telomere length and DNA methylation as predictors of live birth in in vitro fertilization cycles.},
journal = {PloS one},
volume = {17},
number = {1},
pages = {e0261591},
pmid = {35073322},
issn = {1932-6203},
mesh = {Adult ; Birth Rate ; *DNA Methylation ; DNA, Mitochondrial/*genetics ; Epigenesis, Genetic ; Female ; Fertilization in Vitro ; Humans ; Italy ; Long Interspersed Nucleotide Elements ; Maternal Age ; Mitochondria/*genetics ; Pregnancy ; Pregnancy Rate ; Prospective Studies ; *Telomere Homeostasis ; },
abstract = {OBJECTIVE: To evaluate whether telomere length (TL), mitochondrial-DNA (mt-DNA) or epigenetic age estimators based on DNA methylation (DNAm) pattern could be considered reliable predictors of in-vitro-fertilization (IVF) success in terms of live birth rate.<br><br>DESIGN: Prospective cohort study.<br><br>SETTING: Infertility Unit of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico.<br><br>PATIENTS: 181 women aged 37-39 years who underwent IVF at a single-centre between January 2017 and December 2018.<br><br>INTERVENTIONS: On the day of recruitment, blood samples were collected, and genomic DNA was isolated from white blood cells. TL, mt-DNA and DNAm assessment was performed using quantitative real-time polymerase chain reaction (qPCR). Biological age (DNAm age) was computed as the algorithm based on methylation pattern of five genes. Epigenetic age acceleration was estimated from the residuals of the linear model of epigenetic age regressed on chronological age. Long Interspersed Nuclear Elements (LINE)-1 methylation pattern was used as a surrogate for global DNA methylation.<br><br>MAIN OUTCOME MEASURES: This study investigated whether peripheral TL, mt-DNA and DNAm could predict live birth in IVF cycles.<br><br>RESULTS: TL, mt-DNA and LINE-1 methylation were not associated with IVF success. Conversely, DNAm age resulted significantly lower in women who had a live birth compared to women who did not (36.1 &#xb1; 4.2 and 37.3 &#xb1; 3.3 years, respectively, p = 0.04). For DNAm age, odds ratio (OR) for live birth per year of age was 0.90 (95%CI: 0.82-0.99, p = 0.036) after adjusting for FSH and antral follicle count (AFC) and 0.90 (95%CI: 0.82-0.99, p = 0.028) after adjusting also for number of oocytes retrieved. A significant association also emerged for epigenetic age acceleration after adjustments (OR = 0.91, 95%CI: 0.83-1.00, p = 0.048).<br><br>CONCLUSION: DNAm age is associated with IVF success but the magnitude of this association is insufficient to claim a clinical use. However, our findings are promising and warrant further investigation. Assessment of biological age using different epigenetic clocks or focusing on different tissues may reveal new predictors of IVF success.},
}
@article {pmid35063426,
year = {2022},
author = {Isaevska, E and Fiano, V and Asta, F and Stafoggia, M and Moirano, G and Popovic, M and Pizzi, C and Trevisan, M and De Marco, L and Polidoro, S and Gagliardi, L and Rusconi, F and Brescianini, S and Nisticò, L and Stazi, MA and Ronfani, L and Porta, D and Richiardi, L},
title = {Prenatal exposure to PM10 and changes in DNA methylation and telomere length in cord blood.},
journal = {Environmental research},
volume = {209},
number = {},
pages = {112717},
doi = {10.1016/j.envres.2022.112717},
pmid = {35063426},
issn = {1096-0953},
support = {MR/S019669/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Child ; DNA Methylation ; Female ; *Fetal Blood ; Humans ; Infant, Newborn ; Maternal Exposure/adverse effects ; Pregnancy ; *Prenatal Exposure Delayed Effects/chemically induced/genetics ; Telomere ; },
abstract = {BACKGROUND: Air pollution exposure in pregnancy can cause molecular level alterations that might influence later disease susceptibility.<br><br>OBJECTIVES: We investigated DNA methylation (DNAm) and telomere length (TL) in the cord blood in relation to gestational PM10 exposure and explored potential gestational windows of susceptibility.<br><br>METHODS: Cord blood epigenome-wide DNAm (N&#xa0;=&#xa0;384) and TL (N&#xa0;=&#xa0;500) were measured in children of the Italian birth cohort Piccolipi&#xf9;, using the Infinium Methylation EPIC BeadChip and qPCR, respectively. PM10 daily exposure levels, based on maternal residential address, were estimated for different gestational periods using models based on satellite data. Epigenome-wide analysis to identify differentially methylated probes (DMPs) and regions (DMRs) was conducted, followed by a pathway analysis and replication analysis in an second Piccolipi&#xf9; dataset. Distributed lag models (DLMs) using weekly exposures were used to study the association of PM10 exposure across pregnancy with telomere length, as well as with the DMPs that showed robust associations.<br><br>RESULTS: Gestational PM10 exposure was associated with the DNA methylation of more than 250 unique DMPs, most of them identified in early gestation, and 1 DMR. Out of 151 DMPs available in the replication dataset, ten DMPs showed robust associations: eight were associated with exposure during early gestation and 2 with exposure during the whole pregnancy. These exposure windows were supported by the DLM analysis. The PM10 exposure between 15th and 20th gestational week seem to be associated with shorter telomeres at birth, while exposure between 24th and 29th was associated with longer telomeres.<br><br>DISCUSSION: The early pregnancy period is a potential critical window during which PM10 exposure can influence cord blood DNA methylation. The results from the TL analysis were consistent with previous findings and merit further exploration in future studies. The study underlines the importance of considering gestational windows outside of the predefined trimesters that may not always overlap with biologically relevant windows of exposure.},
}
@article {pmid35063336,
year = {2022},
author = {Penev, A and Markiewicz-Potoczny, M and Sfeir, A and Lazzerini Denchi, E},
title = {Stem cells at odds with telomere maintenance and protection.},
journal = {Trends in cell biology},
volume = {32},
number = {6},
pages = {527-536},
pmid = {35063336},
issn = {1879-3088},
support = {F30 CA221285/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; U01 CA231019/CA/NCI NIH HHS/United States ; },
mesh = {Embryonic Stem Cells ; Genomic Instability ; Humans ; Shelterin Complex ; *Telomerase/chemistry/genetics/metabolism ; Telomere/metabolism ; },
abstract = {Telomeres are distinctive structures that protect the ends of linear chromosomes and ensure genome stability. They are composed of long tracks of repetitive and G-rich DNA that is bound by shelterin, a dedicated six-subunit protein complex. In somatic cells, shelterin protects telomeres from the DNA damage response and regulates telomere length. Telomere repeats are replenished by telomerase, a specialized ribonucleoprotein composed of telomerase reverse transcriptase and an integral RNA component. Telomere protection and telomerase regulation have been primarily studied in somatic cells. However, recent evidence points out striking differences in the context of embryonic stem cells (ESCs). In this review, we discuss insights into telomere protection in ESCs versus somatic cells and summarize findings on telomerase regulation as a function of pluripotency.},
}
@article {pmid35061898,
year = {2022},
author = {Rabbani, MAG and Tonini, ML and Afrin, M and Li, B},
title = {POLIE suppresses telomerase-mediated telomere G-strand extension and helps ensure proper telomere C-strand synthesis in trypanosomes.},
journal = {Nucleic acids research},
volume = {50},
number = {4},
pages = {2036-2050},
pmid = {35061898},
issn = {1362-4962},
support = {R01 AI127562/AI/NIAID NIH HHS/United States ; S10 OD025252/OD/NIH HHS/United States ; },
mesh = {DNA/metabolism ; Humans ; *Telomerase/genetics/metabolism ; *Telomere/genetics/metabolism ; Trypanosoma/genetics/*metabolism ; Variant Surface Glycoproteins, Trypanosoma/genetics ; },
abstract = {Trypanosoma brucei causes human African trypanosomiasis and sequentially expresses distinct VSGs, its major surface antigen, to achieve host immune evasion. VSGs are monoallelically expressed from subtelomeric loci, and telomere proteins regulate VSG monoallelic expression and VSG switching. T. brucei telomerase is essential for telomere maintenance, but no regulators of telomerase have been identified. T. brucei appears to lack OB fold-containing telomere-specific ssDNA binding factors that are critical for coordinating telomere G- and C-strand syntheses in higher eukaryotes. We identify POLIE as a telomere protein essential for telomere integrity. POLIE-depleted cells have more frequent VSG gene conversion-mediated VSG switching and an increased amount of telomeric circles (T-circles), indicating that POLIE suppresses DNA recombination at the telomere/subtelomere. POLIE-depletion elongates telomere 3' overhangs dramatically, indicating that POLIE is essential for coordinating DNA syntheses of the two telomere strands. POLIE depletion increases the level of telomerase-dependent telomere G-strand extension, identifying POLIE as the first T. brucei telomere protein that suppresses telomerase. Furthermore, depletion of POLIE results in an elevated telomeric C-circle level, suggesting that the telomere C-strand experiences replication stress and that POLIE may promote telomere C-strand synthesis. Therefore, T. brucei uses a novel mechanism to coordinate the telomere G- and C-strand DNA syntheses.},
}
@article {pmid35057533,
year = {2022},
author = {Alonso-Pedrero, L and Donat-Vargas, C and Bes-Rastrollo, M and Ojeda-Rodríguez, A and Zalba, G and Razquin, C and Martínez-González, MA and Marti, A},
title = {Dietary Exposure to Polychlorinated Biphenyls and Dioxins and Its Relationship to Telomere Length in Subjects Older Than 55 Years from the SUN Project.},
journal = {Nutrients},
volume = {14},
number = {2},
pages = {},
pmid = {35057533},
issn = {2072-6643},
support = {(27/2011, 45/2011, 122/2014)//University of Navarra and Navarra Regional Government/ ; (RD 06/0045, CIBER-OBN, and Fondo de Investigaciones sanitarias, Grants PI10/02658, PI10/02293, PI13/00615, PI14/01668, PI14/01798, PI14/01764, PI17/01795, PI20/00564 and G03/140)//Spanish Government-Instituto de Salud Carlos III and the European Regional Development Fund (FEDER)/ ; (2020/021)//PNDS (Plan Nacional sobre Drogas)/ ; },
mesh = {Cross-Sectional Studies ; Diet/*adverse effects/statistics &amp; numerical data ; Diet Surveys ; Dietary Exposure/*adverse effects ; Dioxins/*toxicity ; Female ; Humans ; Linear Models ; Male ; Middle Aged ; Polychlorinated Biphenyls/*toxicity ; Spain ; Telomere Homeostasis/drug effects ; Telomere Shortening/*drug effects ; },
abstract = {Exposure to persistent organic pollutants (POPs) may influence telomere length (TL), which is considered as a marker of biological age associated with the risk of chronic disease. We hypothesized that dietary exposure to polychlorinated biphenyls (PCBs) and dioxins could affect TL. Our aim was to evaluate the association of dietary exposure to PCBs and dioxins with TL. In this cross-sectional study of 886 subjects older than 55 y (mean age: 67.7; standard deviation (SD): 6.1; 27% women) from the "Seguimiento Universidad de Navarra" (SUN) project. TL was determined by real-time quantitative polymerase chain reaction and dietary PCBs and dioxins exposure was collected using a validated 136-item Food Frequency Questionnaire. Multivariable linear regression models were used to control for potential confounding factors. Shorter TL was associated with dietary total PCBs (SD of T/S ratio/(ng/day) = -0.30 × 10[-7]; 95% CI, -0.55 × 10[-7] to -0.06 × 10[-7]), dioxin-like PCBs (DL-PCBs) (SD of T/S ratio/(pg WHO TEQ (Toxic Equivalents)/day) = -6.17 × 10[-7]; 95% CI, -11.30 × 10[-7] to -1.03 × 10[-7]), and total TEQ exposure (SD of T/S ratio/(pg WHO TEQ/day) = -5.02 × 10[-7]; 95% CI, -9.44 × 10[-7] to -0.61 × 10[-7]), but not with dioxins (SD of T/S ratio/(pg WHO TEQ/day) = -13.90 × 10[-7]; 95% CI, -37.70 × 10[-7] to 9.79 × 10[-7]). In this sample of middle-aged and older Spanish adults, dietary exposure to total PCBs and DL-PCBs alone and together with dioxins was associated with shorter TL. Further longitudinal studies, preferably with POPs measured in biological samples, are needed to confirm this finding.},
}
@article {pmid35054812,
year = {2022},
author = {Button, L and Rogers, B and Thomas, E and Bradfield, A and Alnafakh, R and Drury, J and Hapangama, DK},
title = {Telomere and Telomerase-Associated Proteins in Endometrial Carcinogenesis and Cancer-Associated Survival.},
journal = {International journal of molecular sciences},
volume = {23},
number = {2},
pages = {},
pmid = {35054812},
issn = {1422-0067},
support = {NO//University of Liverpool (MRes studentships L.B, E.T., A.B.)/ ; N/A//Liverpool Women's Hospital NHS Trust (Research and development J.D.)/ ; N/A//Higher Committee for Education Development in Iraq (R.A.)/ ; grants RG1487 and RG2137//Wellbeing of Women's/ ; RDG2021.18//Northwest Cancer Research/ ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Carcinogenesis/*metabolism/*pathology ; Endometrial Neoplasms/genetics/*metabolism/*pathology ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Ki-67 Antigen/metabolism ; Middle Aged ; Neoplasm Proteins/genetics/*metabolism ; Receptors, Steroid ; Survival Analysis ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Risk of relapse of endometrial cancer (EC) after surgical treatment is 13% and recurrent disease carries a poor prognosis. Research into prognostic indicators is essential to improve EC management and outcome. "Immortality" of most cancer cells is dependent on telomerase, but the role of associated proteins in the endometrium is poorly understood. The Cancer Genome Atlas data highlighted telomere/telomerase associated genes (TTAGs) with prognostic relevance in the endometrium, and a recent in silico study identified a group of TTAGs and proteins as key regulators within a network of dysregulated genes in EC. We characterise relevant telomere/telomerase associated proteins (TTAPs) NOP10, NHP2, NOP56, TERF1, TERF2 and TERF2IP in the endometrium using quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). qPCR data demonstrated altered expression of multiple TTAPs; specifically, increased NOP10 (p = 0.03) and reduced NHP2 (p = 0.01), TERF2 (p = 0.01) and TERF2IP (p < 0.003) in EC relative to post-menopausal endometrium. Notably, we report reduced NHP2 in EC compared to post-menopausal endometrium in qPCR and IHC (p = 0.0001) data; with survival analysis indicating high immunoscore is favourable in EC (p = 0.0006). Our findings indicate a potential prognostic role for TTAPs in EC, particularly NHP2. Further evaluation of the prognostic and functional role of the examined TTAPs is warranted to develop novel treatment strategies.},
}
@article {pmid35052747,
year = {2021},
author = {Maugeri, A and Magnano San Lio, R and La Rosa, MC and Giunta, G and Panella, M and Cianci, A and Caruso, MAT and Agodi, A and Barchitta, M},
title = {The Relationship between Telomere Length and Gestational Weight Gain: Findings from the Mamma &amp; Bambino Cohort.},
journal = {Biomedicines},
volume = {10},
number = {1},
pages = {},
pmid = {35052747},
issn = {2227-9059},
support = {Programma ricerca di ateneo UNICT 2020-22 linea 2, PIAno di inCEntivi per la RIcerca di Ateneo 2020/2022//University of Catania/ ; },
abstract = {Inadequate gestational weight gain (GWG) affects a growing number of pregnancies, influencing intrauterine environment and long-term health. Uncovering molecular mechanisms associated with GWG could be helpful to develop public health strategies for tackling this issue. Here, our study aimed to understand the relationship of DNA telomere length with weigh gain during pregnancy, using data and samples from the ongoing prospective "Mamma &amp; Bambino" study (Catania, Italy). GWG was calculated according to the Institute of Medicine (IOM) guidelines. Relative telomere length was assessed by real-time quantitative polymerase chain reaction in 252 samples of maternal leucocyte DNA (mlDNA) and 150 samples of cell-free DNA (cfDNA) from amniotic fluid. We observed that relative telomere length of mlDNA seemed to weakly increase with GWG. In contrast, telomere length of cfDNA exhibited a U-shaped relationship with GWG. Women with adequate GWG showed longer telomere length than those who gained weight inadequately. Accordingly, the logistic regression model confirmed the association between telomere length of cfDNA and adequate GWG, after adjusting for potential confounders. Our findings suggest an early effect of GWG on telomere length of cfDNA, which could represent a molecular mechanism underpinning the effects of maternal behaviours on foetal well-being.},
}
@article {pmid35052422,
year = {2021},
author = {Gunnarsdottir, SR and Bjarnason, H and Thorvaldsdottir, B and Paland, F and Steinarsdottir, M and Eyfjörd, JE and Bödvarsdottir, SK},
title = {BRCA2 Haploinsufficiency in Telomere Maintenance.},
journal = {Genes},
volume = {13},
number = {1},
pages = {},
pmid = {35052422},
issn = {2073-4425},
mesh = {BRCA2 Protein/*genetics ; Breast Neoplasms/genetics/*pathology ; Female ; *Genetic Predisposition to Disease ; *Haploinsufficiency ; *Heterozygote ; Humans ; *Mutation ; *Telomere Shortening ; },
abstract = {Our previous studies showed an association between monoallelic BRCA2 germline mutations and dysfunctional telomeres in epithelial mammary cell lines and increased risk of breast cancer diagnosis for women with BRCA2 999del5 germline mutation and short telomeres in blood cells. In the current study, we analyzed telomere dysfunction in lymphoid cell lines from five BRCA2 999del5 mutation carriers and three Fanconi Anemia D1 patients by fluorescence in situ hybridization (FISH). Metaphase chromosomes were harvested from ten lymphoid cell lines of different BRCA2 genotype origin and analyzed for telomere loss (TL), multitelomeric signals (MTS), interstitial telomere signals (ITS) and extra chromosomal telomere signals (ECTS). TL, ITS and ECTS were separately found to be significantly increased gradually between the BRCA2[+/+], BRCA2[+/-] and BRCA2[-/-] lymphoid cell lines. MTS were found to be significantly increased between the BRCA2[+/+] and the BRCA2[+/-] heterozygous (p < 0.0001) and the BRCA2[-/-] lymphoid cell lines (p < 0.0001) but not between the BRCA2 mutated genotypes. Dysfunctional telomeres were found to be significantly increased in a stepwise manner between the BRCA2 genotypes indicating an effect of BRCA2 haploinsufficiency on telomere maintenance.},
}
@article {pmid35051766,
year = {2022},
author = {De Loma, J and Krais, AM and Lindh, CH and Mamani, J and Tirado, N and Gardon, J and Broberg, K},
title = {Arsenic exposure and biomarkers for oxidative stress and telomere length in indigenous populations in Bolivia.},
journal = {Ecotoxicology and environmental safety},
volume = {231},
number = {},
pages = {113194},
doi = {10.1016/j.ecoenv.2022.113194},
pmid = {35051766},
issn = {1090-2414},
mesh = {*Arsenic ; Biomarkers ; Bolivia ; Chromatography, Liquid ; Female ; Humans ; Indigenous Peoples ; Methyltransferases ; Oxidative Stress/genetics ; Tandem Mass Spectrometry ; Telomere/genetics ; },
abstract = {BACKGROUND: Women living in the Bolivian Andes are environmentally exposed to arsenic, yet there is scarce information about arsenic-related effects in this region. Several biomarkers for telomere length and oxidative stress (mitochondrial DNA copy number, mtDNAcn; 8-Oxo-2'-deoxyguanosine, 8-oxo-dG; and 4-hydroxy nonenal mercapturic acid, 4-HNE-MA) have been previously linked to arsenic, and some of which are prospective biomarkers for cancer risk.<br><br>OBJECTIVE AND HYPOTHESIS: To evaluate associations between arsenic exposure and telomere length, mtDNAcn, 8-oxo-dG, and 4-HNE-MA in Bolivians. Arsenic exposure was hypothesized to be positively associated with all four toxicity biomarkers, particularly in individuals with a less efficient arsenic metabolism.<br><br>METHODS: The study encompassed 193 indigenous women. Arsenic exposure was assessed in urine as the sum of inorganic arsenic metabolite concentrations (U-As) measured by HPLC-HG-ICP-MS, and in whole blood as total arsenic (B-As) measured by ICP-MS. Efficiency of arsenic metabolism was evaluated by a polymorphism (rs3740393) in the main arsenic methylating gene AS3MT measured by TaqMan allelic discrimination, and by the relative fractions of urinary inorganic arsenic metabolites. Telomere length and mtDNAcn were determined in peripheral blood leukocytes by quantitative PCR, and urinary 8-oxo-dG and 4-HNE-MA by LC-MS/MS.<br><br>RESULTS: U-As and B-As were associated with longer telomeres and higher mtDNAcn, particularly in women with a less efficient arsenic metabolism. Urinary 8-oxo-dG and 4-HNE-MA were positively associated with U-As, but only 4-HNE-MA was associated with B-As. Arsenic metabolism efficiency did not have a clear effect on the concentrations of either of these biomarkers.<br><br>CONCLUSION: Bolivian women showed indications of arsenic toxicity, measured by four different biomarkers. Telomere length, mtDNAcn, and 4-HNE-MA were positively associated with both U-As and B-As. The association of arsenic exposure with telomere length and mtDNAcn was only present in Bolivian women with a less efficient metabolism. These findings call for additional efforts to evaluate and reduce arsenic exposure in Bolivia.},
}
@article {pmid35051055,
year = {2022},
author = {Durham, T and Guo, J and Cowell, W and Riley, KW and Wang, S and Tang, D and Perera, F and Herbstman, JB},
title = {Prenatal PM2.5 Exposure in Relation to Maternal and Newborn Telomere Length at Delivery.},
journal = {Toxics},
volume = {10},
number = {1},
pages = {},
pmid = {35051055},
issn = {2305-6304},
support = {UG3OD023290/NH/NIH HHS/United States ; R01ES13163/ES/NIEHS NIH HHS/United States ; P50ES09600/ES/NIEHS NIH HHS/United States ; RD82702701/EPA/EPA/United States ; RD832141/EPA/EPA/United States ; R01ES014393/ES/NIEHS NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; P01ES09600/ES/NIEHS NIH HHS/United States ; Environmental Protection Agency/EPA/EPA/United States ; R01ES08977/ES/NIEHS NIH HHS/United States ; R03ES026416/NH/NIH HHS/United States ; P30ES009089/NH/NIH HHS/United States ; RD834509/EPA/EPA/United States ; },
abstract = {Particulate matter with an aerodynamic diameter of 2.5 μm or less (PM2.5) is a ubiquitous air pollutant that is increasingly threatening the health of adults and children worldwide. One health impact of elevated PM2.5 exposure is alterations in telomere length (TL)-protective caps on chromosome ends that shorten with each cell division. Few analyses involve prenatal PM2.5 exposure, and paired maternal and cord TL measurements. Here, we analyzed the association between average and trimester-specific prenatal PM2.5 exposure, and maternal and newborn relative leukocyte TL measured at birth among 193 mothers and their newborns enrolled in a New-York-City-based birth cohort. Results indicated an overall negative relationship between prenatal PM2.5 and maternal TL at delivery, with a significant association observed in the second trimester (β = -0.039, 95% CI: -0.074, -0.003). PM2.5 exposure in trimester two was also inversely related to cord TL; however, this result did not reach statistical significance (β = -0.037, 95% CI: -0.114, 0.039), and no clear pattern emerged between PM2.5 and cord TL across the different exposure periods. Our analysis contributes to a limited body of research on ambient air pollution and human telomeres, and emphasizes the need for continued investigation into how PM2.5 exposure during pregnancy influences maternal and newborn health.},
}
@article {pmid35050506,
year = {2022},
author = {Stout-Oswald, SA and Glynn, LM and Bisoffi, M and Demers, CH and Davis, EP},
title = {Prenatal exposure to maternal psychological distress and telomere length in childhood.},
journal = {Developmental psychobiology},
volume = {64},
number = {1},
pages = {e22238},
doi = {10.1002/dev.22238},
pmid = {35050506},
issn = {1098-2302},
support = {R01 MH109662/MH/NIMH NIH HHS/United States ; T32 MH015442/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Child ; Female ; Humans ; Infant, Newborn ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Prospective Studies ; *Psychological Distress ; Telomere ; Telomere Shortening ; },
abstract = {Telomere length (TL) is a biological marker of cellular aging, and shorter TL in adulthood is associated with increased morbidity and mortality risk. It is likely that these differences in TL are established long before adulthood, and there is growing evidence that TL can reflect prenatal experiences. Although maternal prenatal distress predicts newborn TL, it is unknown whether the relation between prenatal exposure to maternal distress and child TL persists through childhood. The purpose of the current longitudinal, prospective study is to examine the relation between prenatal exposure to maternal distress (perceived stress, depressive symptoms, pregnancy-related anxiety) and TL in childhood. Participants included 102 children (54 girls) and their mothers. Mothers' distress was assessed five times during pregnancy, at 12 weeks postpartum, and at the time of child telomere measurement between 6 and 16 years of age. Maternal distress during pregnancy predicted shorter offspring TL in childhood, even after accounting for postnatal exposure to maternal distress and other covariates. These findings indicate that maternal mental health predicts offspring TL biology later in childhood than previously observed. This study bolsters claims that telomere biology is subject to fetal programming and highlights the importance of supporting maternal mental health during pregnancy.},
}
@article {pmid35049825,
year = {2022},
author = {Ribas-Maynou, J and Mateo-Otero, Y and Sanchez-Quijada, M and Recuero, S and Delgado-Bermúdez, A and Llavanera, M and Yeste, M},
title = {Telomere Length in Pig Sperm Is Related to In Vitro Embryo Development Outcomes.},
journal = {Animals : an open access journal from MDPI},
volume = {12},
number = {2},
pages = {},
pmid = {35049825},
issn = {2076-2615},
support = {AGL2017-88329-R//Ministry of science and innovation, Spain/ ; 2017-SGR-1229//Generalitat de Catalunya/ ; 214/857-202039//La marat&#xf3; de TV3/ ; Tecniospring INDUSTRY; TECSPR-19-1-0003//European Union's Horizon 2020 research and innovation programme under the Marie Sk&#x142;odowska-Curie grant agreement No 801342/ ; },
abstract = {Telomere length has attracted much interest as a topic of study in human reproduction; furthermore, the link between sperm telomere length and fertility outcomes has been investigated in other species. This biomarker, however, has not been much explored in other animals, such as pigs, and whether it is related to sperm quality and fertility outcomes remains unknown. The present work aimed to determine the absolute value of telomere length in pig sperm, as well as its relationship to sperm quality parameters and embryo development. Telomere length was determined through quantitative fluorescence in situ hybridization (qFISH) in 23 pig sperm samples and data were correlated to quality parameters (motility, morphology, and viability) and in vitro fertilization outcomes. We found that the mean telomere length in pig sperm was 22.1 ± 3.6 kb, which is longer than that previously described in humans. Whilst telomere length was not observed to be correlated to sperm quality variables (p > 0.05), a significant correlation between telomere length and the percentage of morulae 6 days after in vitro fertilization was observed (rs = 0.559; 95% C.I. = (-0.007 to 0.854); p = 0.047). Interestingly, this correlation was not found when percentages of early blastocysts/blastocysts (rs = 0.410; 95% C.I. = (-0.200 to 0.791); p = 0.164) and of hatching/hatched blastocysts (rs = 0.356; 95% C.I. = (- 0.260 to 0.766); p = 0.233) were considered. Through the separation of the samples into two groups by the median value, statistically significant differences between samples with shorter telomeres than the median and samples with longer telomeres than the median were found regarding development to morula (11.5 ± 3.6 vs. 21.8 ± 6.9, respectively) and to early blastocyst/blastocysts (7.6 ± 1.4 vs. 17.9 ± 12.2, respectively) (p < 0.05). In the light of these results, sperm telomere length may be a useful biomarker for embryo development in pigs, as sperm with longer telomeres lead to higher rates of morulae and blastocysts.},
}
@article {pmid35045162,
year = {2022},
author = {Rodríguez-Centeno, J and Esteban-Cantos, A and Montejano, R and Stella-Ascariz, N and De Miguel, R and Mena-Garay, B and Saiz-Medrano, G and Alejos, B and Jiménez-González, M and Bernardino, JI and Cadiñanos, J and Castro-Alvarez, JM and Rodés, B and Arribas, JR},
title = {Effects of tenofovir on telomeres, telomerase and T cell maturational subset distribution in long-term aviraemic HIV-infected adults.},
journal = {The Journal of antimicrobial chemotherapy},
volume = {77},
number = {4},
pages = {1125-1132},
doi = {10.1093/jac/dkab492},
pmid = {35045162},
issn = {1460-2091},
support = {FI17/00194//Instituto de Salud Carlos III-Fondo Social Europeo/ ; CM17/00064//Instituto de Salud Carlos III-Fondo Social Europeo/ ; },
mesh = {Adult ; CD4-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes ; *HIV Infections ; Humans ; *Telomerase/metabolism ; Telomere/metabolism ; Tenofovir/therapeutic use ; },
abstract = {OBJECTIVES: To evaluate whether the negative impact of tenofovir on telomere length (TL) is due to immune reconstitution interference or inhibition of telomerase.<br><br>METHODS: One hundred and twenty-eight long-term aviraemic HIV adults treated with tenofovir-containing (n = 79) or tenofovir-sparing regimens (n = 49) were recruited to compare the following: TL in whole blood, PBMCs, CD4+ T cells and CD8+ T cells by quantitative PCR (qPCR); telomerase activity in PBMCs, CD4+ cells and CD8+ T cells using the TRAPeze RT Telomerase Detection Kit; and T cell maturational subset distribution by flow cytometry.<br><br>RESULTS: In an adjusted analysis, participants treated with tenofovir for at least 4 years had shorter TL in CD8+ T cells (P = 0.04) and lower telomerase activity in CD4+ (P = 0.012) and CD8+ T cells (P = 0.023). Tenofovir treatment was also associated with lower proportions of recent thymic emigrant (RTE) CD4+ cells (P = 0.031) and PD1 marker expression (P = 0.013).<br><br>CONCLUSIONS: In long-term aviraemic HIV adults, the inhibition of telomerase by tenofovir could explain telomere shortening in CD8+ T cells. There is no telomere shortening in the CD4+ compartment and the decrease in telomerase activity could be explained both by the inhibition by tenofovir and by the lower proportion of RTE CD4+cells.},
}
@article {pmid35044907,
year = {2022},
author = {Rosas Bringas, FR and Stinus, S and de Zoeten, P and Cohn, M and Chang, M},
title = {Rif2 protects Rap1-depleted telomeres from MRX-mediated degradation in Saccharomyces cerevisiae.},
journal = {eLife},
volume = {11},
number = {},
pages = {},
pmid = {35044907},
issn = {2050-084X},
mesh = {Multiprotein Complexes/*metabolism ; RNA/*metabolism ; RNA, Fungal/*metabolism ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/*metabolism ; Shelterin Complex/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*genetics/*metabolism ; Transcription Factors/*metabolism ; },
abstract = {Rap1 is the main protein that binds double-stranded telomeric DNA in Saccharomyces cerevisiae. Examination of the telomere functions of Rap1 is complicated by the fact that it also acts as a transcriptional regulator of hundreds of genes and is encoded by an essential gene. In this study, we disrupt Rap1 telomere association by expressing a mutant telomerase RNA subunit (tlc1-tm) that introduces mutant telomeric repeats. tlc1-tm cells grow similar to wild-type cells, although depletion of Rap1 at telomeres causes defects in telomere length regulation and telomere capping. Rif2 is a protein normally recruited to telomeres by Rap1, but we show that Rif2 can still associate with Rap1-depleted tlc1-tm telomeres, and that this association is required to inhibit telomere degradation by the MRX complex. Rif2 and the Ku complex work in parallel to prevent tlc1-tm telomere degradation; tlc1-tm cells lacking Rif2 and the Ku complex are inviable. The partially redundant mechanisms may explain the rapid evolution of telomere components in budding yeast species.},
}
@article {pmid35044242,
year = {2022},
author = {Yadav, S and Maurya, PK},
title = {Correlation Between Telomere Length and Biomarkers of Oxidative Stress in Human Aging.},
journal = {Rejuvenation research},
volume = {25},
number = {1},
pages = {25-29},
doi = {10.1089/rej.2021.0045},
pmid = {35044242},
issn = {1557-8577},
mesh = {Aged ; *Aging ; Biomarkers ; Female ; Humans ; Male ; Oxidative Stress ; *Telomere ; Telomere Shortening ; },
abstract = {The telomere length (TL) has increasingly been used as a biomarker of human aging because it has been shown to predict the chances of survival and longevity. Oxidative stress is presumed to be a major cause of telomere shortening, but the importance of oxidative stress as a determinant of telomere shortening remains less clear and has recently been questioned. We analyzed 105 healthy subjects of both sexes between the ages of 20-77 years. The TL and biomarkers of oxidative stress were estimated as per standard protocols. A significant (p < 0.001) age-dependent decline in TL was observed. TL was positively correlated with the ferric reducing ability of plasma value (r = 0.8811) and reduced glutathione (r = 0.8209), whereas negatively correlated with malondialdehyde (r = -0.7191). Our findings supported the idea of a possible correlation between the TL and biomarkers of oxidative stress in aging. The study has remarkable scope in medical science as the findings on correlation of TL with biomarkers of oxidative stress in aging are novel and they will help in further research against oxidative stress.},
}
@article {pmid35040871,
year = {2022},
author = {Schneider, CV and Schneider, KM and Teumer, A and Rudolph, KL and Hartmann, D and Rader, DJ and Strnad, P},
title = {Association of Telomere Length With Risk of Disease and Mortality.},
journal = {JAMA internal medicine},
volume = {182},
number = {3},
pages = {291-300},
pmid = {35040871},
issn = {2168-6114},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Aged ; Female ; Follow-Up Studies ; Humans ; Leukocytes/*physiology ; Longitudinal Studies ; Male ; Middle Aged ; Mortality/*trends ; Risk ; Telomere/*physiology ; United Kingdom ; },
abstract = {IMPORTANCE: Telomeres protect DNA from damage. Because they shorten with each mitotic cycle, leukocyte telomere length (LTL) serves as a mitotic clock. Reduced LTL has been associated with multiple human disorders.<br><br>OBJECTIVE: To determine the association between LTL and overall as well as disease-specific mortality and morbidity.<br><br>This multicenter, community-based cohort study conducted from March 2006 to December 2010 included longitudinal follow-up (mean [SD], 12 [2] years) for 472 432 English participants from the United Kingdom Biobank (UK Biobank) and analyzed morbidity and mortality. The data were analyzed in 2021.<br><br>MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) and odds ratios for mortality and morbidity associated with a standard deviation change in LTL, adjusted for age, sex, body mass index (calculated as weight in kilograms divided by height in meters squared), and ethnicity.<br><br>RESULTS: This study included a total of 472&#x202f;432 English participants, of whom 54% were women (mean age, 57 years). Reduced LTL was associated with increased overall (HR, 1.08; 95% CI, 1.07-1.09), cardiovascular (HR, 1.09; 95% CI, 1.06-1.12), respiratory (HR, 1.40; 95% CI, 1.34-1.45), digestive (HR, 1.26; 95% CI, 1.19-1.33), musculoskeletal (HR, 1.51; 95% CI, 1.35-1.92), and COVID-19 (HR, 1.15; 95% CI, 1.07-1.23) mortality, but not cancer-related mortality. A total of 214 disorders were significantly overrepresented and 37 underrepresented in participants with shorter LTL. Respiratory (11%), digestive/liver-related (14%), circulatory (18%), and musculoskeletal conditions (6%), together with infections (5%), accounted for most positive associations, whereas (benign) neoplasms and endocrinologic/metabolic disorders were the most underrepresented entities. Malignant tumors, esophageal cancer, and lymphoid and myeloid leukemia were significantly more common in participants with shorter LTL, whereas brain cancer and melanoma were less prevalent. While smoking and alcohol consumption were associated with shorter LTL, additional adjustment for both factors, as well as cognitive function/major comorbid conditions, did not significantly alter the results.<br><br>CONCLUSIONS AND RELEVANCE: This cohort study found that shorter LTL was associated with a small risk increase of overall mortality, but a higher risk of mortality was associated with specific organs and diseases.},
}
@article {pmid35038777,
year = {2022},
author = {Cuadrado, &#xc1; and Figueroa, RI and Sixto, M and Bravo, I and De Bustos, A},
title = {First record of the spatial organization of the nucleosome-less chromatin of dinoflagellates: The nonrandom distribution of microsatellites and bipolar arrangement of telomeres in the nucleus of Gambierdiscus australes (Dinophyceae).},
journal = {Journal of phycology},
volume = {58},
number = {2},
pages = {297-307},
doi = {10.1111/jpy.13236},
pmid = {35038777},
issn = {1529-8817},
mesh = {Cell Nucleus/genetics ; Chromatin/metabolism ; DNA/metabolism ; *Dinoflagellida/genetics/metabolism ; In Situ Hybridization, Fluorescence ; Microsatellite Repeats ; Nucleosomes/metabolism ; Telomere ; },
abstract = {Dinoflagellates are a group of protists whose exceptionally large genome is organized in permanently condensed nucleosome-less chromosomes. In this study, we examined the potential role of repetitive DNAs in both the structure of dinoflagellate chromosomes and the architecture of the dinoflagellate nucleus. Non-denaturing fluorescent in situ hybridization (ND-FSH) was used to determine the abundance and physical distribution of telomeric DNA and 16 microsatellites (1- to 4-bp repeats) in the nucleus of Gambierdiscus australes. The results showed an increased relative abundance of the different microsatellite motifs with increasing GC content. Two ND-FISH probes, (A)20 and (AAT)5 , did not yield signals whereas the remainder revealed a dispersed but nonrandom distribution of the microsatellites, mostly in clusters. The bean-shaped interphase nucleus of G. australes contained a region with a high density of trinucleotides. This nuclear compartment was located between the nucleolar organizer region (NOR), located on the concave side of the nucleus, and the convex side. Telomeric DNA was grouped in multiple foci and distributed in two polarized compartments: one associated with the NOR and the other peripherally located along the convex side of the nucleus. Changes in the position of the telomeres during cell division evidenced their dynamic distribution and thus that of the chromosomes during dinomitosis. These insights into the spatial organization of microsatellites and telomeres and thus into the nuclear architecture of G. australes will open up new lines of research into the structure and function of the nucleosome-less chromatin of dinoflagellates.},
}
@article {pmid35033923,
year = {2022},
author = {Yang, K and Prescott, J and Hazra, A and Meyerhardt, JA and Zhang, X and De Vivo, I and Chan, AT and Du, M and Giovannucci, EL and Nan, H},
title = {Pre-diagnostic telomere length and colorectal cancer risk.},
journal = {Cancer epidemiology},
volume = {77},
number = {},
pages = {102100},
pmid = {35033923},
issn = {1877-783X},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R35 CA253185/CA/NCI NIH HHS/United States ; },
mesh = {Case-Control Studies ; *Colorectal Neoplasms/diagnosis/epidemiology/genetics ; Follow-Up Studies ; Humans ; Leukocytes ; Risk Factors ; *Telomere/genetics ; },
abstract = {BACKGROUND: Progressive telomere shortening may be related to genomic instability and carcinogenesis. Prospective evidence relating telomere length (TL) with colorectal cancer (CRC) risk has been limited and inconsistent.<br><br>METHODS: We examined the association between pre-diagnostic peripheral blood leukocyte TL and CRC risk in two matched case-control studies nested within the Nurses' Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). Relative leukocyte TL was measured using qPCR among 356 incident CRC cases and 801 controls (NHS: 186/465, HPFS: 170/336).<br><br>RESULTS: We did not find a significant association between pre-diagnostic TL and CRC risk [in all participants, multivariable-adjusted odds ratio (OR) (95% CI) for TL Quartile 1 (shortest) vs. Quartile 4 (longest)&#xa0;=&#xa0;1.36 (0.85, 2.17), P-trend&#xa0;=&#xa0;0.27; OR (95% CI) per 1 SD decrease in TL&#xa0;=&#xa0;1.12 (0.92, 1.36)].<br><br>CONCLUSIONS: Our prospective analysis did not support a significant association between pre-diagnostic leukocyte TL and CRC risk.},
}
@article {pmid35032170,
year = {2022},
author = {Vetter, VM and Kalies, CH and Sommerer, Y and Spira, D and Drewelies, J and Regitz-Zagrosek, V and Bertram, L and Gerstorf, D and Demuth, I},
title = {Relationship Between 5 Epigenetic Clocks, Telomere Length, and Functional Capacity Assessed in Older Adults: Cross-Sectional and Longitudinal Analyses.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {77},
number = {9},
pages = {1724-1733},
doi = {10.1093/gerona/glab381},
pmid = {35032170},
issn = {1758-535X},
support = {DE 842/7-1//Deutsche Forschungsgemeinschaft/ ; #01UW0808//German Federal Ministry of Education and Research/ ; },
mesh = {*Activities of Daily Living ; Aged ; Aging/genetics ; Biomarkers ; Cross-Sectional Studies ; *DNA Methylation ; Epigenesis, Genetic ; Humans ; Telomere/genetics ; },
abstract = {DNA methylation age acceleration (DNAmAA, derived from an epigenetic clock) and relative leukocyte telomere length (rLTL) are widely accepted biomarkers of aging. Nevertheless, it is still unclear which aspects of aging they represent best. Here we evaluated longitudinal associations between baseline rLTL and DNAmAA (estimated with 7-CpG clock) and functional assessments covering different domains of aging. Additionally, we made use of cross-sectional data on these assessments and examined their association with DNAmAA estimated by 5 different DNAm age measures. Two-wave longitudinal data were available for 1 083 participants of the Berlin Aging Study II who were reexamined on average 7.4 years after baseline as part of the GendAge study. Functional outcomes were assessed with Fried's frailty score, Tinetti mobility test, falls in the past 12 months (yes/no), finger-floor distance, Mini-Mental State Examination, Center for Epidemiologic Studies-Depression scale, activities of daily living, instrumented ADL, and mini nutritional assessment. Overall, we found no evidence for an association between the molecular biomarkers measured at baseline, rLTL, and DNAmAA (7-CpG clock), and functional assessments assessed at follow-up. Similarly, a cross-sectional analysis of follow-up data did also not show evidence for associations of the various DNAmAA measures (7-CpG clock, Horvath's clock, Hannum's clock PhenoAge, and GrimAge) with functional assessments. In conclusion, neither rLTL nor 7-CpG DNAmAA was able to predict impairment in the analyzed assessments over a ~7-year time course. Similarly, DNAmAA estimated from 5 epigenetic clocks was not a good cross-sectional marker of health deterioration either.},
}
@article {pmid35024423,
year = {2022},
author = {Amin, V and Fletcher, JM and Sun, Z and Lu, Q},
title = {Higher educational attainment is associated with longer telomeres in midlife: Evidence from sibling comparisons in the UK Biobank.},
journal = {SSM - population health},
volume = {17},
number = {},
pages = {101018},
pmid = {35024423},
issn = {2352-8273},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; P30 AG017266/AG/NIA NIH HHS/United States ; R01 AG060109/AG/NIA NIH HHS/United States ; },
abstract = {Prior studies have established that higher educational attainment is associated with a longer telomere length (TL), a marker of cellular aging. However, it is unclear whether extant associations are causal, since they are likely confounded by unobserved genetic, early-life and family background factors that are correlated with education and TL. We leverage sibling differences in TL, education and measured genetics (polygenic scores for educational attainment and TL) to estimate associations between educational attainment and TL in midlife for European ancestry individuals in the UK Biobank, while controlling for unobserved confounders shared by siblings. After controlling for genetics and shared background between siblings, we find suggestive evidence that high school graduates have longer telomeres than high school dropouts, but we find no differences in TL between high school dropouts and college graduates.},
}
@article {pmid35022670,
year = {2022},
author = {Stephens, Z and Ferrer, A and Boardman, L and Iyer, RK and Kocher, JA},
title = {Telogator: a method for reporting chromosome-specific telomere lengths from long reads.},
journal = {Bioinformatics (Oxford, England)},
volume = {38},
number = {7},
pages = {1788-1793},
pmid = {35022670},
issn = {1367-4811},
support = {R01 CA204013/CA/NCI NIH HHS/United States ; },
mesh = {*Telomere/genetics ; *Repetitive Sequences, Nucleic Acid ; Haplotypes ; },
abstract = {MOTIVATION: Telomeres are the repetitive sequences found at the ends of eukaryotic chromosomes and are often thought of as a 'biological clock,' with their average length shortening during division in most cells. In addition to their association with senescence, abnormal telomere lengths are well known to be associated with multiple cancers, short telomere syndromes and as risk factors for a broad range of diseases. While a majority of methods for measuring telomere length will report average lengths across all chromosomes, it is known that aberrations in specific chromosome arms are biomarkers for certain diseases. Due to their repetitive nature, characterizing telomeres at this resolution is prohibitive for short read sequencing approaches, and is challenging still even with longer reads.<br><br>RESULTS: We present Telogator: a method for reporting chromosome-specific telomere length from long read sequencing data. We demonstrate Telogator's sensitivity in detecting chromosome-specific telomere length in simulated data across a range of read lengths and error rates. Telogator is then applied to 10 germline samples, yielding a high correlation with short read methods in reporting average telomere length. In addition, we investigate common subtelomere rearrangements and identify the minimum read length required to anchor telomere/subtelomere boundaries in samples with these haplotypes.<br><br>Telogator is written in Python3 and is available at github.com/zstephens/telogator.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid35018411,
year = {2022},
author = {Westbrook, A and Zhang, R and Shi, M and Razavi, AC and Huang, Z and Chen, J and He, J and Kelly, T and Shen, Y and Li, C},
title = {Association Between Baseline Buccal Telomere Length and Progression of Kidney Function: The Health and Retirement Study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {77},
number = {3},
pages = {471-476},
pmid = {35018411},
issn = {1758-535X},
support = {P20 GM109036/GM/NIGMS NIH HHS/United States ; U01 AG009740/AG/NIA NIH HHS/United States ; U01AG009740/AG/NIA NIH HHS/United States ; },
mesh = {Female ; Glomerular Filtration Rate ; Glycated Hemoglobin ; Humans ; *Kidney ; Male ; *Retirement ; Risk Factors ; Telomere/genetics ; },
abstract = {We aimed to evaluate associations of baseline telomere length with overall and annual change in estimated glomerular filtration rate (eGFR) and trajectory of kidney function during an 8-year follow-up. A total of 3 964 participants of the Health and Retirement Study were included. We identified 3 trajectory groups of kidney function: consistently normal (n = 1 163 or 29.3%), normal to impaired (n = 2 306 or 58.2%), and consistently impaired groups (n = 495 or 12.5%). After controlling for age, sex, race, education, smoking, drinking, diabetes, heart disease, blood pressure, body mass index, total cholesterol, and hemoglobin A1c, participants with longer telomere length were 20% less likely (odds ratio = 0.80, 95% confidence interval: 0.69-0.93, p = .003) to have a normal to impaired kidney function trajectory than a consistently normal function trajectory. Telomere length was not associated with changing rate of eGFR over 8 years (p = .45). Participants with longer telomere length were more likely to have consistently normal kidney function.},
}
@article {pmid35016866,
year = {2022},
author = {Hansen, E and Skotnes, T and Bustnes, JO and Helander, B and Eulaers, I and Sun, J and Covaci, A and Bårdsen, BJ and Zahn, S and Criscuolo, F and Bourgeon, S},
title = {Telomere length in relation to persistent organic pollutant exposure in white-tailed eagle (Haliaeetus albicilla) nestlings from Sweden sampled in 1995-2013.},
journal = {Environmental research},
volume = {208},
number = {},
pages = {112712},
doi = {10.1016/j.envres.2022.112712},
pmid = {35016866},
issn = {1096-0953},
mesh = {Animals ; *Eagles ; Environmental Monitoring ; *Environmental Pollutants ; Persistent Organic Pollutants ; Sweden ; Telomere ; },
abstract = {Telomeres are used as biomarkers of vertebrate health because of the link between their length, lifespan, and survival. Exposure to environmental stressors appears to alter telomere dynamics, but little is known about telomere length and persistent organic pollutant (POP) exposure in wildlife. The white-tailed eagle (WTE; Haliaeetus albicilla) is an avian top predator that accumulates high levels of POPs and may subsequently suffer adverse health effects. Here we study the Baltic WTE population that is well documented to have been exposed to large contaminant burdens, thereby making it a promising candidate species for analyzing pollutant-mediated effects on telomeres. We investigated telomere lengths in WTE nestlings (n = 168) over 19 years and examined legacy POP concentrations (organochlorines and polybrominated diphenyl ethers) in whole blood and serum as potential drivers of differences in telomere length. Although we detected significant year-to-year variations in telomere lengths among the WTE nestlings, telomere lengths did not correlate with any of the investigated POP concentrations of several classes. Given that telomere lengths did not associate with POP contamination in the Baltic WTE nestlings, we propose that other environmental and biological factors, which likely fluctuate on a year-to-year basis, could be more important drivers of telomere lengths in this population.},
}
@article {pmid35011817,
year = {2021},
author = {Barragán, R and Ortega-Azorín, C and Sorlí, JV and Asensio, EM and Coltell, O and St-Onge, MP and Portolés, O and Corella, D},
title = {Effect of Physical Activity, Smoking, and Sleep on Telomere Length: A Systematic Review of Observational and Intervention Studies.},
journal = {Journal of clinical medicine},
volume = {11},
number = {1},
pages = {},
pmid = {35011817},
issn = {2077-0383},
support = {PROMETEO 17/2017//Conselleria de Innovaci&#xf3;n, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana/ ; APOSTD/2019/136//Conselleria de Innovaci&#xf3;n, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana/ ; PI19/00781//Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Econom&#xed;a y Competitividad-Fondo Europeo de Desarrollo Regional (FEDER)/ ; SAF2016-80532-R//Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Econom&#xed;a y Competitividad-Fondo Europeo de Desarrollo Regional (FEDER)/ ; PID2019-108858RB-I00//Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Econom&#xed;a y Competitividad-Fondo Europeo de Desarrollo Regional (FEDER)/ ; UJI-B2018-69//Universitat Jaume I/ ; PROMETEO 21/2021//Generalitat Valenciana Conselleria de Innovaci&#xf3;n, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana/ ; PID2019-108858RB-I00//AEI 10.13039/501100011033 and, by "ERDF A way of making Europe"/ ; },
abstract = {Aging is a risk factor for several pathologies, restricting one's health span, and promoting chronic diseases (e.g., cardiovascular and neurodegenerative diseases), as well as cancer. Telomeres are regions of repetitive DNA located at chromosomal ends. Telomere length has been inversely associated with chronological age and has been considered, for a long time, a good biomarker of aging. Several lifestyle factors have been linked with telomere shortening or maintenance. However, the consistency of results is hampered by some methodological issues, including study design, sample size, measurement approaches, and population characteristics, among others. Therefore, we aimed to systematically review the current literature on the effects of three relevant lifestyle factors on telomere length in human adults: physical activity, smoking, and sleep. We conducted a qualitative systematic review of observational and intervention studies using the Preferred Reporting Item for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The systematic literature search covered articles published in MEDLINE and EMBASE databases (from 2010 to 2020). A total of 1400 studies were identified; 83 were included after quality control. Although fewer sedentary activities, optimal sleep habits, and non- or ex-smoker status have been associated with less telomere shortening, several methodological issues were detected, including the need for more targeted interventions and standardized protocols to better understand how physical activity and sleep can impact telomere length and aging. We discuss the main findings and current limitations to gain more insights into the influence of these lifestyle factors on the healthy aging process.},
}
@article {pmid35011715,
year = {2022},
author = {Haupt, S and Niedrist, T and Sourij, H and Schwarzinger, S and Moser, O},
title = {The Impact of Exercise on Telomere Length, DNA Methylation and Metabolic Footprints.},
journal = {Cells},
volume = {11},
number = {1},
pages = {},
pmid = {35011715},
issn = {2073-4409},
mesh = {Aged ; Aging/*genetics ; Cellular Senescence/*genetics ; DNA Methylation/*genetics ; Exercise/*genetics ; Humans ; Telomere Homeostasis/*physiology ; },
abstract = {Aging as a major risk factor influences the probability of developing cancer, cardiovascular disease and diabetes, amongst others. The underlying mechanisms of disease are still not fully understood, but research suggests that delaying the aging process could ameliorate these pathologies. A key biological process in aging is cellular senescence which is associated with several stressors such as telomere shortening or enhanced DNA methylation. Telomere length as well as DNA methylation levels can be used as biological age predictors which are able to detect excessive acceleration or deceleration of aging. Analytical methods examining aging are often not suitable, expensive, time-consuming or require a high level of technical expertise. Therefore, research focusses on combining analytical methods which have the potential to simultaneously analyse epigenetic, genomic as well as metabolic changes.},
}
@article {pmid35008850,
year = {2021},
author = {Ruiz, A and Flores-Gonzalez, J and Buendia-Roldan, I and Chavez-Galan, L},
title = {Telomere Shortening and Its Association with Cell Dysfunction in Lung Diseases.},
journal = {International journal of molecular sciences},
volume = {23},
number = {1},
pages = {},
pmid = {35008850},
issn = {1422-0067},
mesh = {Animals ; COVID-19/genetics/immunology ; Cellular Senescence/genetics ; Genetic Therapy/methods ; Humans ; Immunotherapy/methods ; Lung Diseases/drug therapy/*genetics/*immunology ; Telomere Shortening/*immunology ; },
abstract = {Telomeres are localized at the end of chromosomes to provide genome stability; however, the telomere length tends to be shortened with each cell division inducing a progressive telomere shortening (TS). In addition to age, other factors, such as exposure to pollutants, diet, stress, and disruptions in the shelterin protein complex or genes associated with telomerase induce TS. This phenomenon favors cellular senescence and genotoxic stress, which increases the risk of the development and progression of lung diseases such as idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, SARS-CoV-2 infection, and lung cancer. In an infectious environment, immune cells that exhibit TS are associated with severe lymphopenia and death, whereas in a noninfectious context, naïve T cells that exhibit TS are related to cancer progression and enhanced inflammatory processes. In this review, we discuss how TS modifies the function of the immune system cells, making them inefficient in maintaining homeostasis in the lung. Finally, we discuss the advances in drug and gene therapy for lung diseases where TS could be used as a target for future treatments.},
}
@article {pmid35006465,
year = {2021},
author = {Claude, E and de Lhoneux, G and Pierreux, CE and Marbaix, E and de Ville de Goyet, M and Boulanger, C and Van Damme, A and Brichard, B and Decottignies, A},
title = {Detection of alternative lengthening of telomeres mechanism on tumor sections.},
journal = {Molecular biomedicine},
volume = {2},
number = {1},
pages = {32},
pmid = {35006465},
issn = {2662-8651},
support = {7.6519.20//fonds de la recherche scientifique - fnrs/ ; 2018-072-project # FAF-F/208/1208//fondation contre le cancer (be)/ ; 2016-J1151710-206515//king baudouin foundation (be)/ ; },
abstract = {The vast majority of adult cancer cells achieve cellular immortality by activating a telomere maintenance mechanism (TMM). While this is mostly achieved by the de-silencing of hTERT telomerase gene expression, an alternative homologous recombination-based and telomerase-independent mechanism, known as ALT (Alternative Lengthening of Telomeres), is frequently activated in a subset of tumors, including paediatric cancers. Being absent from normal cells, the ALT mechanism offers interesting perspectives for new targeted cancer therapies. To date, however, the development of better translationally applicable tools for ALT detection in tumor sections is still needed. Here, using a newly derived ALT-positive cancer cell mouse xenograft model, we extensively examined how the previously known ALT markers could be used as reliable tools for ALT diagnosis in tumor sections. We found that, together with the detection of ultra-bright telomeric signals (UBS), an ALT hallmark, native telomeric FISH, that detects single-stranded C-rich telomeric DNA, provides a very sensitive and robust tool for ALT diagnosis in tissues. We applied these assays to paediatric tumor samples and readily identified three ALT-positive tumors for which the TMM was confirmed by the gold-standard C-circle amplification assay. Although the latter offers a robust assay for ALT detection in the context of research laboratories, it is more difficult to set up in histopathological laboratories and could therefore be conveniently replaced by the combination of UBS detection and native telomeric FISH.},
}
@article {pmid34998722,
year = {2022},
author = {Pauleck, S and Gigic, B and Cawthon, RM and Ose, J and Peoples, AR and Warby, CA and Sinnott, JA and Lin, T and Boehm, J and Schrotz-King, P and Li, CI and Shibata, D and Siegel, EM and Figueiredo, JC and Toriola, AT and Schneider, M and Ulrich, AB and Hoffmeister, A and Ulrich, CM and Hardikar, S},
title = {Association of circulating leukocyte telomere length with survival in patients with colorectal cancer.},
journal = {Journal of geriatric oncology},
volume = {13},
number = {4},
pages = {480-485},
pmid = {34998722},
issn = {1879-4076},
support = {R01 CA189184/CA/NCI NIH HHS/United States ; U01 CA206110/CA/NCI NIH HHS/United States ; R01 NR018762/NR/NINR NIH HHS/United States ; P30 CA042014/CA/NCI NIH HHS/United States ; R01 CA207371/CA/NCI NIH HHS/United States ; K07 CA222060/CA/NCI NIH HHS/United States ; },
mesh = {*Colorectal Neoplasms/genetics ; Disease-Free Survival ; Humans ; Kaplan-Meier Estimate ; Leukocytes ; *Telomere/genetics ; },
abstract = {INTRODUCTION: Telomere shortening, as seen with aging, can cause chromosomal instability and promote cancer progression. We investigated the association between circulating telomere length and overall and disease-free survival in a sub-cohort of patients with colorectal cancer.<br><br>METHODS: Baseline genomic DNA from blood leukocytes was extracted from N&#xa0;=&#xa0;92 newly diagnosed stage I-IV patients with colorectal cancer enrolled at the ColoCare Study site in Heidelberg, Germany. Detailed information on clinicodemographic (including age) and lifestyle risk factors, and clinical outcomes (including recurrence and survival) was collected. Telomere length was measured in DNA using multiplex quantitative polymerase chain reaction. Kaplan Meier survival curves were generated comparing shorter to longer telomere lengths with log-rank testing.<br><br>RESULTS: The mean T/S ratio for study patients was 0.5 (range: 0.3-0.9). Shorter telomeres were associated with older age at baseline. Patients with shorter telomeres experienced a worse overall and disease-free survival, although this association did not reach statistical significance. Kaplan-Meier survival curves for those with circulating telomere length below vs. above the median showed poorer overall (log-rank p&#xa0;=&#xa0;0.31) and disease-free survival (long-rank p&#xa0;=&#xa0;0.23).<br><br>CONCLUSIONS: Our results suggest that individuals with shorter telomeres, as seen with aging, may experience a worse overall and disease-free survival after colorectal cancer diagnosis. Larger sample sizes with longer follow-up are needed to further evaluate telomere length as a prognostic biomarker in colorectal cancer progression.},
}
@article {pmid34997994,
year = {2022},
author = {Pepke, ML and Kvalnes, T and Rønning, B and Jensen, H and Boner, W and Saether, BE and Monaghan, P and Ringsby, TH},
title = {Artificial size selection experiment reveals telomere length dynamics and fitness consequences in a wild passerine.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6224-6238},
doi = {10.1111/mec.16340},
pmid = {34997994},
issn = {1365-294X},
mesh = {Humans ; Male ; Female ; Animals ; *Longevity/genetics ; Selection, Genetic ; Telomere ; *Passeriformes/genetics ; Telomere Shortening/genetics ; },
abstract = {Telomere dynamics could underlie life-history trade-offs among growth, size and longevity, but our ability to quantify such processes in natural, unmanipulated populations is limited. We investigated how 4 years of artificial selection for either larger or smaller tarsus length, a proxy for body size, affected early-life telomere length (TL) and several components of fitness in two insular populations of wild house sparrows over a study period of 11 years. The artificial selection was expected to shift the populations away from their optimal body size and increase the phenotypic variance in body size. Artificial selection for larger individuals caused TL to decrease, but there was little evidence that TL increased when selecting for smaller individuals. There was a negative correlation between nestling TL and tarsus length under both selection regimes. Males had longer telomeres than females and there was a negative effect of harsh weather on TL. We then investigated whether changes in TL might underpin fitness effects due to the deviation from the optimal body size. Mortality analyses indicated disruptive selection on TL because both short and long early-life telomeres tended to be associated with the lowest mortality rates. In addition, there was a tendency for a negative association between TL and annual reproductive success, but only in the population where body size was increased experimentally. Our results suggest that natural selection for optimal body size in the wild may be associated with changes in TL during growth, which is known to be linked to longevity in some bird species.},
}
@article {pmid34995210,
year = {2022},
author = {Guo, L and Chen, Y and Li, H and Yin, F and Ge, M and Hu, L and Zi, M and Qin, Z and He, Y},
title = {Telomere length is maternally inherited and associated with lipid metabolism in Chinese population.},
journal = {Aging},
volume = {14},
number = {1},
pages = {354-367},
pmid = {34995210},
issn = {1945-4589},
mesh = {Aged ; Aged, 80 and over ; Aging ; Asian People/*genetics ; China ; Female ; Humans ; Lipid Metabolism/*genetics ; Male ; Middle Aged ; Telomere/*genetics/*physiology ; Young Adult ; },
abstract = {Telomere is a unique DNA-protein complex which covers the ends of chromosomes to avoid end fusion and maintain the stability and integrity of chromosomes. Telomere length (TL) shortening has been linked to aging and various age-related diseases in humans. Here we recruited a total of 1031 Chinese individuals aged between 12 and 111 years, including 108 families with parents and their offspring. DNA was extracted from peripheral white blood cells and TL was measured by quantitative PCR (qPCR). We explored the associations of TL with age, gender and clinical variables, and tested the parental effects on TL variation. First, we found that TL was shortened with age, however, TL was better maintained in females than males. Second, there was a robust association of TL between mother and offspring, but not between father and their offspring. In addition, TL was inversely associated with visceral fat index in females, and positively associated with apolipoprotein A levels. Knockdown of the key genes for lipid metabolism (PNPLA2 and CPT1) shortened the TL in HepG2 cells. These findings indicate that TL is maternally inherited, and impairment of lipid metabolism may contribute to the TL shortening in the Chinese population.},
}
@article {pmid34993885,
year = {2022},
author = {Alzoubi, H and Minasi, S and Gianno, F and Antonelli, M and Belardinilli, F and Giangaspero, F and Jaffrain-Rea, ML and Buttarelli, FR},
title = {Alternative Lengthening of Telomeres (ALT) and Telomerase Reverse Transcriptase Promoter Methylation in Recurrent Adult and Primary Pediatric Pituitary Neuroendocrine Tumors.},
journal = {Endocrine pathology},
volume = {33},
number = {4},
pages = {494-505},
pmid = {34993885},
issn = {1559-0097},
mesh = {Adult ; Child ; Humans ; In Situ Hybridization, Fluorescence ; Neoplasm Recurrence, Local/genetics ; *Neuroendocrine Tumors/genetics/pathology ; *Pituitary Neoplasms/genetics ; *Telomerase/genetics ; *Telomere/genetics/pathology ; Telomere Homeostasis/genetics ; X-linked Nuclear Protein/genetics ; DNA Methylation ; Promoter Regions, Genetic ; },
abstract = {Neoplastic cells acquire the ability to proliferate endlessly by maintaining telomeres via telomerase, or alternative lengthening of telomeres (ALT). The role of telomere maintenance in pituitary neuroendocrine tumors (PitNETs) has yet to be thoroughly investigated. We analyzed surgical samples of 24 adult recurrent PitNETs (including onset and relapses for 14 of them) and 12 pediatric primary PitNETs. The presence of ALT was assessed using telomere-specific fluorescence in situ hybridization, methylation of telomerase reverse transcriptase promoter (TERTp) by methylation-specific PCR, and ATRX expression by immunohistochemistry. Among the adult recurrent PitNETs, we identified 3/24 (12.5%) ALT-positive cases. ALT was present from the onset and maintained in subsequent relapses, suggesting that this mechanism occurs early in tumorigenesis and is stable during progression. ATRX loss was only seen in one ALT-positive case. Noteworthy, ALT was observed in 3 out of 5 aggressive PitNETs, including two aggressive corticotroph tumors, eventually leading to patient's death. ALT-negative tumors (87.5%) were classified according to their low (29.2%), medium (50%), and high (8.3%) telomere fluorescence intensity, with no significant differences emerging in their molecular, clinical, or pathological characteristics. TERTp methylation was found in 6/24 cases (25%), with a total concordance in methylation status between onset and recurrences, suggesting that this mechanism remains stable throughout disease progression. TERTp methylation did not influence telomere length. In the pediatric cohort of PitNETs, TERTp methylation was also observed in 4/12 cases (33.3%), but no case of ALT activation was observed. In conclusion, ALT is triggered at onset and maintained during tumor progression in a subset of adult PitNETs, suggesting that it could be used for clinical purposes, as a potential predictor of aggressive behavior.},
}
@article {pmid34988401,
year = {2022},
author = {Song, S and Ma, D and Xu, L and Wang, Q and Liu, L and Tong, X and Yan, H},
title = {Low-intensity pulsed ultrasound-generated singlet oxygen induces telomere damage leading to glioma stem cell awakening from quiescence.},
journal = {iScience},
volume = {25},
number = {1},
pages = {103558},
pmid = {34988401},
issn = {2589-0042},
abstract = {Cancer stem cells, quiescent and drug resistant, have become a therapeutic target. Unlike high-intensity focused ultrasound directly killing tumor, low-intensity pulsed ultrasound (LIPUS), a new noninvasive physical device, promotes pluripotent stem cell differentiation and is primarily applied in tissue engineering but rarely in oncotherapy. We explored the effect and mechanism of LIPUS on glioma stem cell (GSC) expulsion from quiescence. Here, we observed that LIPUS led to attenuated expression of GSC biomarkers, promoted GSC escape from G0 quiescence, and significantly weakened the Wnt and Hh pathways. Of note, LIPUS transferred sonomechanical energy into cytochrome c and B5 proteins, which converted oxygen molecules into singlet oxygen, triggering telomere crisis. The in vivo and in vitro results confirmed that LIPUS enhanced the GSC sensitivity to temozolomide. These results demonstrated that LIPUS "waked up" GSCs to improve their sensitivity to chemotherapy, and importantly, we confirmed the direct targeted proteins of LIPUS in GSCs.},
}
@article {pmid34988044,
year = {2021},
author = {Montiel Ishino, FA and McNab, P and Villalobos, K and Cohen, JH and Nápoles, AM and Williams, F},
title = {Hispanic/Latino Acculturation Profiles and Telomere Length: Latent Class Analysis on a Nationally Representative Sample.},
journal = {Frontiers in public health},
volume = {9},
number = {},
pages = {640226},
pmid = {34988044},
issn = {2296-2565},
mesh = {*Acculturation ; Child ; Hispanic or Latino ; Humans ; Latent Class Analysis ; Nutrition Surveys ; Telomere ; Telomere Shortening ; United States ; },
abstract = {Background: Acculturation profiles and their impact on telomere length among foreign-born Hispanics/Latinos living in the United States (US) are relatively unknown. The limited research available has linked acculturation with shortened telomere length. Objectives: To identify acculturation profiles among a US representative sample of Hispanics/Latinos and to then examine telomere length differences between profiles. Methods: We conducted a latent class analysis among a non-institutionalized US-representative sample of Hispanics/Latinos using the 1999-2002 National Health and Nutrition Examination Survey (N = 2,292). The latent variable of acculturation was assessed by length of time in the US and language used as a child, read and spoken, usually spoken at home, used to think, and used with friends (i.e., Spanish and/or English). Telomere length assessed from leukocytes was used as the distal continuous outcome. Results: We identified five profiles: (1) low acculturated [33.2% of sample]; (2) partially integrated [18.6% of sample]; (3) integrated [19.4% of sample]; (4) partially assimilated [15.1% of sample]; and (5) assimilated [13.7% of sample]. Acculturation profiles revealed nuanced differences in conditional probabilities with language use despite the length of time spent in the US. While telomere length did vary, there were no significant differences between profiles. Conclusion: Profiles identified revealed that possible life-course and generational effects may be at play in the partially assimilated and assimilated profiles. Our findings expand public health research using complex survey data to identify and assess the dynamic relationship of acculturation profiles and health biomarkers, while being among the first to examine this context using a person-centered approach.},
}
@article {pmid34977149,
year = {2021},
author = {Al-Muraikhy, S and Sellami, M and Domling, AS and Rizwana, N and Agouni, A and Al-Khelaifi, F and Donati, F and Botre, F and Diboun, I and Elrayess, MA},
title = {Metabolic Signature of Leukocyte Telomere Length in Elite Male Soccer Players.},
journal = {Frontiers in molecular biosciences},
volume = {8},
number = {},
pages = {727144},
pmid = {34977149},
issn = {2296-889X},
abstract = {Introduction: Biological aging is associated with changes in the metabolic pathways. Leukocyte telomere length (LTL) is a predictive marker of biological aging; however, the underlying metabolic pathways remain largely unknown. The aim of this study was to investigate the metabolic alterations and identify the metabolic predictors of LTL in elite male soccer players. Methods: Levels of 837 blood metabolites and LTL were measured in 126 young elite male soccer players who tested negative for doping abuse at anti-doping laboratory in Italy. Multivariate analysis using orthogonal partial least squares (OPLS), univariate linear models and enrichment analyses were conducted to identify metabolites and metabolic pathways associated with LTL. Generalized linear model followed by receiver operating characteristic (ROC) analysis were conducted to identify top metabolites predictive of LTL. Results: Sixty-seven metabolites and seven metabolic pathways showed significant associations with LTL. Among enriched pathways, lysophospholipids, benzoate metabolites, and glycine/serine/threonine metabolites were elevated with longer LTL. Conversely, monoacylglycerols, sphingolipid metabolites, long chain fatty acids and polyunsaturated fatty acids were enriched with shorter telomeres. ROC analysis revealed eight metabolites that best predict LTL, including glutamine, N-acetylglutamine, xanthine, beta-sitosterol, N2-acetyllysine, stearoyl-arachidonoyl-glycerol (18:0/20:4), N-acetylserine and 3-7-dimethylurate with AUC of 0.75 (0.64-0.87, p < 0.0001). Conclusion: This study characterized the metabolic activity in relation to telomere length in elite soccer players. Investigating the functional relevance of these associations could provide a better understanding of exercise physiology and pathophysiology of elite athletes.},
}
@article {pmid34976365,
year = {2021},
author = {Akash, C and Prabhu, M and Maldar, A and Akash, P and Mishra, S and Madhura, TK and Kumar, S and Patil, RS and Piplani, S and Smitha, KS},
title = {Association of Telomere Length and Serum Vitamin D Levels with Type 2 Diabetes Mellitus and its Related Complications: A Possible Future Perspective.},
journal = {Genome integrity},
volume = {12},
number = {},
pages = {2},
pmid = {34976365},
issn = {2041-9414},
abstract = {Evidence show that shortened telomere length (TL) and low Vitamin D levels can increase the risk of type 2 diabetes mellitus (T2DM) and its associated complications. T2DM has been considered as an age-related disease, it may be associated with TL. The study aimed to evaluate the association of TL and Vitamin D levels with complications of T2DM and the impact of Vitamin D on TL in patients with T2DM. This 1-year cross-sectional study was conducted at a tertiary care hospital on 90 patients. Height, weight, body mass index, waist-hip ratio was calculated. Fasting blood sugars, postprandial blood sugar, and glycated hemoglobin (HbA1c) were analyzed. Absolute TL was obtained from quantitative real-time polymerase chain reaction (qPCR). Vitamin D estimation was done by chemiluminescent immunoassay. Descriptive analysis of the data was done using R i386 3.6.3. The study found a positive correlation between TL and Vitamin D levels (r = 0.64; P < 0.0001). The interaction with high HbA1c levels and lower levels of Vitamin D led to the shortening of TL (P = 0.0001). The median of TL and mean of Vitamin D levels were significantly less in the diabetic group (P < 0.0001). Vitamin D levels positively affected the TL and its levels had an inverse relation with the HbA1c levels. This association had a significant effect on the shortening of TL. Vitamin D also had a significant association with other diabetic complications that instigated the shortening of TL. Therefore, assessing the role of Vitamin D levels on the shortening of TL can prove to be crucial biomarkers in managing optimal glycemic levels in T2DM patients.},
}
@article {pmid34965558,
year = {2021},
author = {Belyi, DO and Ilyenko, I and Nastina, O and Sydorenko, G and Gabulavichene, Z and Kursina, N and Bazyka, O and Bilaya, V and Kovaliov, O and Bazyka, D},
title = {RELATIVE TELOMERE LENGTH OF PERIPHERAL BLOOD LYMPHOCYTES AND STRUCTURAL AND FUNCTIONAL STATE OF THE LEFT VENTRICLE MYOCARDIUM IN CLEAN-UP WORKERS OF THE CHORNOBYL ACCIDENT WHO SUFFERED FROM STENOTIC CORONARY ATHEROSCLEROSIS.},
journal = {Problemy radiatsiinoi medytsyny ta radiobiolohii},
volume = {26},
number = {},
pages = {319-338},
doi = {10.33145/2304-8336-2021-26-319-338},
pmid = {34965558},
issn = {2313-4607},
mesh = {Abnormalities, Radiation-Induced/epidemiology/*physiopathology ; Adult ; Case-Control Studies ; Chernobyl Nuclear Accident ; Coronary Artery Disease/epidemiology/*physiopathology ; Emergency Responders/*statistics &amp; numerical data ; Heart Ventricles/*physiopathology/*radiation effects ; Humans ; Lymphocytes/*pathology ; Male ; Middle Aged ; Radiation Exposure/adverse effects ; Radiation Injuries/epidemiology ; Radioactive Hazard Release/statistics &amp; numerical data ; Telomere Shortening/*radiation effects ; Ukraine/epidemiology ; },
abstract = {UNLABELLED: The objective was to analyze the relative telomere length (RTL) of peripheral blood lymphocytes depending onmyocardium structural and functional state in emergency workers (EW) of the Chornobyl accident who suffered fromcoronary arteries stenotic atherosclerosis.<br><br>MATERIALS AND METHODS: There were examined 60 male EW who operated at the Chornobyl nuclear power plant at1986 and 25 male non-irradiated persons (control group - CG) with coronary heart disease (CHD). Everyone EW andCG patients were almost healthy before the accident. During the period 2016-2021, they underwent a comprehen-sive clinical and laboratory examination, echodopplercardiographic examination and determination of RTL by fluo-rescent hybridization in situ using laser flow cytometry.<br><br>RESULTS: EW almost did not differ from CG according to its clinical characteristics, the presence of risk factors,indices of systolic and diastolic heart functions, as well as RTL. The analysis of variance showed that RTL was influ-enced by the fact of irradiation in combination with obesity (p = 0.020). At normal body weight, RTL average valuein CG was significantly higher than in EW (p = 0.023). According to the results of hierarchical cluster analysis of twovariables as RTL and end-diastolic volume normalized by body surface area (EDV/BSA), EW and CG patients togeth-er were divided into two subgroups. The first subgroup (1st cluster) differed from the second (2nd cluster) by signi-ficantly larger average values of left ventricle (LV) EDV and end-systolic volume (ESV) as well as EDV/BSA andESV/BSA, LV myocardial mass (MM) and MM/BSA, reduced ejection fraction (EF). In patients of the 1st cluster telom-eres were significantly shorter than in the 2nd one (10,3 &#xb1; 1.7 vs. 14.3 &#xb1; 2.0 at p = 0.000). The increase of myocar-dial mass and LV wall thickness caused the development of its hypertrophy. The number of people with hypertrophyLV was significantly higher among patients of the 1st cluster (91.6 vs. 67.2 %, p < 0.001) due to eccentric hypertro-phy LV. Accordingly, concentric hypertrophy LV was more common among patients in the 2nd cluster (24.6 vs. 4.2 %at p < 0.01). Patients of the 1st cluster was characterized by a more severe course of heart failure.<br><br>CONCLUSIONS: In patients who suffered from CHD with stenotic atherosclerosis of the coronary arteries and wereexposed to radiation 30-35 years earlier, having normal body weight, there was a reduction in telomere. Hierarchicalcluster analysis proved to be a good tool that allows by the value of RTL and EDV/BSA to separate the group ofpatients with the most severe clinical course of CHD and LV systolic dysfunction among patients with the samepathology.},
}
@article {pmid34965251,
year = {2021},
author = {Poláková, E and Albanaz, ATS and Zakharova, A and Novozhilova, TS and Gerasimov, ES and Yurchenko, V},
title = {Ku80 is involved in telomere maintenance but dispensable for genomic stability in Leishmania mexicana.},
journal = {PLoS neglected tropical diseases},
volume = {15},
number = {12},
pages = {e0010041},
pmid = {34965251},
issn = {1935-2735},
mesh = {Genome, Protozoan ; *Genomic Instability ; Humans ; Ku Autoantigen/genetics/*metabolism ; Leishmania mexicana/*genetics/*metabolism ; Leishmaniasis, Cutaneous/parasitology ; Protozoan Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; Trypanosoma brucei brucei/genetics/metabolism ; },
abstract = {BACKGROUND: Telomeres are indispensable for genome stability maintenance. They are maintained by the telomere-associated protein complex, which include Ku proteins and a telomerase among others. Here, we investigated a role of Ku80 in Leishmania mexicana. Leishmania is a genus of parasitic protists of the family Trypanosomatidae causing a vector-born disease called leishmaniasis.<br><br>We used the previously established CRISPR/Cas9 system to mediate ablation of Ku80- and Ku70-encoding genes in L. mexicana. Complete knock-outs of both genes were confirmed by Southern blotting, whole-genome Illumina sequencing, and RT-qPCR. Resulting telomeric phenotypes were subsequently investigated using Southern blotting detection of terminal restriction fragments. The genome integrity in the Ku80- deficient cells was further investigated by whole-genome sequencing. Our work revealed that telomeres in the &#x394;Ku80 L. mexicana are elongated compared to those of the wild type. This is a surprising finding considering that in another model trypanosomatid, Trypanosoma brucei, they are shortened upon ablation of the same gene. A telomere elongation phenotype has been documented in other species and associated with a presence of telomerase-independent alternative telomere lengthening pathway. Our results also showed that Ku80 appears to be not involved in genome stability maintenance in L. mexicana.<br><br>CONCLUSION/SIGNIFICANCE: Ablation of the Ku proteins in L. mexicana triggers telomere elongation, but does not have an adverse impact on genome integrity.},
}
@article {pmid34964306,
year = {2022},
author = {Wolf, SE and Rosvall, KA},
title = {A multi-tissue view on telomere dynamics and postnatal growth.},
journal = {Journal of experimental zoology. Part A, Ecological and integrative physiology},
volume = {337},
number = {4},
pages = {346-355},
pmid = {34964306},
issn = {2471-5646},
support = {IOS-1656109//National Science Foundation/ ; //Indiana Academy of Science/ ; T32 HD049336/HD/NICHD NIH HHS/United States ; //The Society for Integrative &amp; Comparative Biology/ ; },
mesh = {Animals ; Biomarkers ; Longevity ; *Telomere ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Trade-offs between growth and self-maintenance are common in nature, such that early-life effects on growth can generate lasting consequences on survival and longevity. Telomeres-putative biomarkers of self-maintenance-may link early growth with these later phenotypic effects, but evidence for growth-telomere trade-offs is mixed. Null or even positive relationships between growth and telomeres may be driven by heterogeneity in resource availability or invariable allocation towards telomere maintenance within a population. We used nestling tree swallows (Tachycineta bicolor) to assess the directionality and timing of relationships between growth and telomere length in several tissues. We focused on two important phases of growth: first, the peak of postnatal growth occurring around 6 days old when nestlings grow by ~33% in a single day, and subsequently, the later phase of growth occurring as body mass plateaus near adult size at 12 days old. We quantified telomere attrition in blood during postnatal growth, as well as telomere length in the blood, brain, adrenals, and liver at 12 days old. Growth was unrelated to telomere length in the liver and telomere dynamics in blood. However, brain telomere length was positively correlated with peak growth, and adrenal telomere length was positively related to later growth, particularly for chicks that had experienced a temporary stressor. These observations suggest that variation in resource availability may mask trade-offs, generating positive correlations between growth and telomere length at the population level. They also provide insights into complex relationships between growth and self-maintenance that can be revealed by looking in multiple tissues.},
}
@article {pmid34959893,
year = {2021},
author = {Hakeem, S and Mendonça, N and Aspray, T and Kingston, A and Martin-Ruiz, C and Robinson, L and Hill, TR},
title = {The Association between 25-Hydroxyvitamin D Concentration and Telomere Length in the Very-Old: The Newcastle 85+ Study.},
journal = {Nutrients},
volume = {13},
number = {12},
pages = {},
pmid = {34959893},
issn = {2072-6643},
support = {MR/J50001X/1/MRC_/Medical Research Council/United Kingdom ; grant reference R124/0509//Dunhill Medical Trust/ ; grant reference G0500997/MRC_/Medical Research Council/United Kingdom ; grant reference G0500997/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Age Factors ; Aged, 80 and over ; Aging/blood/*genetics/*physiology ; Cross-Sectional Studies ; Female ; Humans ; Male ; Prospective Studies ; *Telomere Homeostasis ; Vitamin D/*analogs &amp; derivatives/blood ; },
abstract = {(1) Introduction: vitamin D may maintain the telomere length, either directly or via the inflammation effect and/or modulating the rate of cell proliferation. Whilst results from cross-sectional studies investigating the association between 25(OH)D concentration and telomere length have been mixed, there is a dearth of data from prospective studies which have assessed these associations. This study aimed to examine the association between 25(OH)D concentration in plasma and telomere length in blood cells in very-old adults (≥85 years old) at baseline, 18 months and 36 months by controlling for related lifestyle factors. (2) Methodology: our prospective cohort study comprised 775 participants from the Newcastle 85+ Study who had 25(OH)D measurements at baseline. Plasma 25(OH)D was stratified as <25 nmol/L (low), 25-50 nmol/L (moderate) and >50 nmol/L (high). Peripheral blood mononuclear cell telomere length was measured by quantitative real-time polymerase chain reaction at baseline, 18 and 36 months from baseline. (3) Results: a positive significant association was found between 25(OH)D concentration and telomere length amongst very-old participants at baseline (95% CI = 12.0-110.3, B = 61.2 ± 5.0, p = 0.015). This association was negative at 18 months (95% CI = -59.9--7.5, B = -33.7 ± 13.3, p = 0.012) but was non-significant at 36 months. (4) Conclusion: Circulating 25(OH)D concentration shows inconsistent relationships with telomere length over time in very-old (85+ year old) adults.},
}
@article {pmid34957928,
year = {2023},
author = {Liu, Q and Zhou, D and Duan, H and Zhu, Y and Du, Y and Sun, C and Lin, H and Jin, M and Fu, J and Gao, Y and Ma, F and Chen, Y and Zhang, M and Huang, G},
title = {Association of dietary inflammatory index and leukocyte telomere length with mild cognitive impairment in Chinese older adults.},
journal = {Nutritional neuroscience},
volume = {26},
number = {1},
pages = {50-59},
doi = {10.1080/1028415X.2021.2017660},
pmid = {34957928},
issn = {1476-8305},
mesh = {Aged ; Humans ; Middle Aged ; Cohort Studies ; Cross-Sectional Studies ; *East Asian People ; *Cognitive Dysfunction ; Leukocytes ; Telomere ; },
abstract = {BACKGROUND: There are minimal data on the relationship between DII and MCI in an elderly Chinese population and no research has assessed the potential effect of LTL.<br><br>OBJECTIVE: We investigated the association between DII and MCI while taking into account the potential effect of LTL.<br><br>METHODS: This cross-sectional study included 3,386 participants aged &#x2265; 60 years of age from the Tianjin Elderly Nutrition and Cognition Cohort study. DII score was constructed based on a validated self-administered food frequency questionnaire was calculated based on the method developed by Shivappa et al. LTL was measured by quantitative real-time polymerase chain reaction. Multivariable logistic regression analysis was used to analyze the association between DII, LTL and MCI. Moreover, mediation analysis was employed to test the mediation effect of LTL on the total effect of DII on MCI.<br><br>RESULTS: Compared with the participants in the lowest tertiles of LTL and DII score, the odds ratios (ORs) of MCI in the highest tertiles were 0.386(95% CI: 0.281-0.529) and 1.650 (95% CI: 1.232-2.209), respectively. The significant association between DII score and MCI persisted after further adjusting for LTL (OR: 1.595; 95% CI: 1.189-2.140). The link between DII score and MCI was mediated partially by LTL (&#x3b2;indirect effect= -0.008, P<0.05).<br><br>CONCLUSION: High DII score was positively associated with MCI prevalence in an elderly Chinese population and the link between DII scores and MCI seemed to be mediated partially by LTL.},
}
@article {pmid34955515,
year = {2022},
author = {Darvishi, FZ and Saadat, M},
title = {Morphine may have a role in telomere shortening.},
journal = {Psychiatric genetics},
volume = {32},
number = {2},
pages = {87-89},
pmid = {34955515},
issn = {1473-5873},
mesh = {Heroin/adverse effects ; Humans ; Leukocytes ; *Morphine/adverse effects ; Telomere/genetics ; *Telomere Shortening ; },
abstract = {Morphine/heroin may increase oxidative stress in drug-dependent persons. The imbalance between oxidative stress and antioxidant defense mechanisms can accelerate the shortening of telomere length. This article reports two sets of data; comparison of relative telomere length between heroin-dependent patients and healthy control group, as well as, investigation of the effect of morphine on the relative telomere length of human SH-SY5Y cells treated by morphine. Study participants were composed of 163 heroin-dependent patients and 166 unrelated healthy controls. SH-SY5Y cells were treated with (5 μM) morphine hydrochloride and incubated for 40 and 60 days. The relative telomere length was calculated as the T/S (telomere/single-copy gene) ratio using 36B4 as a reference for each sample, using quantitative real-time PCR. The mean (± SE) value of relative telomere length was 4.81 ± 0.21 and 6.38 ± 0.23 in leukocytes of heroin-dependent and control groups, respectively. The telomere length was significantly decreased in heroin-dependent participants (t = 4.97; df = 327; P < 0.0001). The relative telomere length in cells treated with morphine for 60 days was 4.50 ± 0.14 and in untreated cells was 5.75 ± 0.08. The difference was highly significant (t = 7.68; df = 4; P = 0.002). Our present findings indicate that morphine and dependency on heroin are significantly associated with shorter telomeres. The present findings may help to explain some of the adverse effects of drug dependency on health such as accelerating biologic processes related to aging.},
}
@article {pmid34949741,
year = {2022},
author = {Lim, YS and Nguyen, MTN and Pham, TX and Huynh, TTX and Park, EM and Choi, DH and Kang, SM and Tark, D and Hwang, SB},
title = {Hepatitis C Virus Nonstructural 5A Protein Interacts with Telomere Length Regulation Protein: Implications for Telomere Shortening in Patients Infected with HCV.},
journal = {Molecules and cells},
volume = {45},
number = {3},
pages = {148-157},
pmid = {34949741},
issn = {0219-1032},
mesh = {*Hepacivirus/physiology ; *Hepatitis C/genetics ; Humans ; RNA, Viral ; Telomere/genetics ; Telomere Shortening ; },
abstract = {Hepatitis C virus (HCV) is a major cause of chronic liver disease and is highly dependent on cellular proteins for viral propagation. Using protein microarray analysis, we identified 90 cellular proteins as HCV nonstructural 5A (NS5A) interacting partners, and selected telomere length regulation protein (TEN1) for further study. TEN1 forms a heterotrimeric complex with CTC and STN1, which is essential for telomere protection and maintenance. Telomere length decreases in patients with active HCV, chronic liver disease, and hepatocellular carcinoma. However, the molecular mechanism of telomere length shortening in HCV-associated disease is largely unknown. In the present study, protein interactions between NS5A and TEN1 were confirmed by immunoprecipitation assays. Silencing of TEN1 reduced both viral RNA and protein expression levels of HCV, while ectopic expression of the siRNA-resistant TEN1 recovered the viral protein level, suggesting that TEN1 was specifically required for HCV propagation. Importantly, we found that TEN1 is re-localized from the nucleus to the cytoplasm in HCV-infected cells. These data suggest that HCV exploits TEN1 to promote viral propagation and that telomere protection is compromised in HCV-infected cells. Overall, our findings provide mechanistic insight into the telomere shortening in HCV-infected cells.},
}
@article {pmid34947936,
year = {2021},
author = {Fan, HC and Chang, FW and Tsai, JD and Lin, KM and Chen, CM and Lin, SZ and Liu, CA and Harn, HJ},
title = {Telomeres and Cancer.},
journal = {Life (Basel, Switzerland)},
volume = {11},
number = {12},
pages = {},
pmid = {34947936},
issn = {2075-1729},
support = {TTMHH-R1100003 and TTMHH-R1100004.//Tungs' Taichung MetroHarbor Hospital/ ; },
abstract = {Telomeres cap the ends of eukaryotic chromosomes and are indispensable chromatin structures for genome protection and replication. Telomere length maintenance has been attributed to several functional modulators, including telomerase, the shelterin complex, and the CST complex, synergizing with DNA replication, repair, and the RNA metabolism pathway components. As dysfunctional telomere maintenance and telomerase activation are associated with several human diseases, including cancer, the molecular mechanisms behind telomere length regulation and protection need particular emphasis. Cancer cells exhibit telomerase activation, enabling replicative immortality. Telomerase reverse transcriptase (TERT) activation is involved in cancer development through diverse activities other than mediating telomere elongation. This review describes the telomere functions, the role of functional modulators, the implications in cancer development, and the future therapeutic opportunities.},
}
@article {pmid34945752,
year = {2021},
author = {Wai, KM and Kaori, S and Itoh, K and Shinya, O and Uchikawa, Y and Hayashi, S and Shiraki, A and Murashita, K and Nakaji, S and Ihara, K},
title = {Telomere Length and Arterial Stiffness Reflected by Brachial-Ankle Pulse Wave Velocity: A Population-Based Cross-Sectional Study.},
journal = {Journal of personalized medicine},
volume = {11},
number = {12},
pages = {},
pmid = {34945752},
issn = {2075-4426},
support = {JMPJCE1302//Japan Science and Technology Agency/ ; },
abstract = {Telomere (TL) is a biomarker of biological aging, and its shortening is associated with major risk factors for cardiovascular diseases (CVD). This study aimed to identify whether TL is associated with arterial stiffness as reflected by brachial-ankle pulse wave velocity (baPWV). This population-based cross-sectional study involved 1065 individuals in the Iwaki area, Japan. Total TL length and TL G-tail length were measured by hybridization protection assay. The baPWV was measured on the right and left sides using a non-invasive vascular screening device. The associations between TL and baPWV were assessed by multivariate linear regression. Compared with the shortest total TL tertile, the longest total TL group showed a significant decrease in baPWV (lowest vs. highest tertile: adjusted beta: -41.24, 95% confidence interval (CI): -76.81, -5.68). The mean baPWV decreased with a longer TL (TL G-tail length: p trend < 0.001, total TL: p trend < 0.001). TL G-tail and total TL lengths were inversely associated with baPWV, implicating TL shortening in the development of CVD. This study provides evidence of the factors influencing CVD risks at a very early stage when individuals can still take necessary precautions before CVD gives rise to a symptomatic health outcome.},
}
@article {pmid34944968,
year = {2021},
author = {Roy Choudhury, S and Ashby, C and Zhan, F and van Rhee, F},
title = {Epigenetic Deregulation of Telomere-Related Genes in Newly Diagnosed Multiple Myeloma Patients.},
journal = {Cancers},
volume = {13},
number = {24},
pages = {},
pmid = {34944968},
issn = {2072-6694},
support = {R01 CA236814/CA/NCI NIH HHS/United States ; },
abstract = {High-risk Multiple Myeloma (MM) patients were found to maintain telomere length (TL), below the margin of short critical length, consistent with proactive overexpression of telomerase. Previously, DNA methylation has been shown as a determinant of telomere-related gene (TRG) expression and TL to assess risk in different types of cancer. We mapped genome-wide DNA methylation in a cohort of newly diagnosed MM (NDMM; n = 53) patients of major molecular subgroups, compared to age-matched healthy donors (n = 4). Differential methylation and expression at TRG-loci were analyzed in combination with overlapping chromatin marks and underlying DNA-sequences. We observed a strong correlation (R[2] ≥ 0.5) between DNA methylation and expression amongst selective TRGs, such that demethylation at the promoters of DDX1 and TERF1 were associated to their oncogenic upregulation, while demethylation at the bodies of two key tumor suppressors ZNF208 and RAP1A led to downregulation of the genes. We demonstrated that TRG expression may be controlled by DNA methylation alone or in cooperation with chromatin modifications or CCCTC-binding factor at the regulatory regions. Additionally, we showed that hypomethylated DMRs of TRGs in NDMM are stabilized with G-quadruplex forming sequences, suggesting a crucial role of these epigenetically vulnerable loci in MM pathogenesis. We have identified a panel of five TRGs, which are epigenetically deregulated in NDMM patients and may serve as early detection biomarkers or therapeutic targets in the disease.},
}
@article {pmid34943011,
year = {2021},
author = {Hassler, E and Almer, G and Reishofer, G and Marsche, G and Mangge, H and Deutschmann, H and Herrmann, M and Leber, S and Gunzer, F and Renner, W},
title = {Sex-Specific Association of Serum Anti-Oxidative Capacity and Leukocyte Telomere Length.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {10},
number = {12},
pages = {},
pmid = {34943011},
issn = {2076-3921},
abstract = {Telomeres are a crucial factor in the preservation of genomic integrity, and an elevated risk for diseases such as cancer and cardiovascular events is related to shortened telomeres. However, telomere deterioration could be caused by factors such as chronic oxidative stress and inflammation, which are promoted by an imbalance among reactive oxygen species (ROS) and antioxidants. In this cross-sectional study, we investigated the relationship between telomeres and oxidative stress. The serum leucocyte telomer length (LTL), serum total antioxidant capacity (TAC) and the total serum lipid panel of 180 healthy athletic volunteers (90 males, 90 females) were measured Additionally, a questionnaire about sports behaviour and the type of training was completed. We observed a positive significant relation between serum LTL and TAC in the male group (cc = 3.4/p = 0.001) but not in females. There was no statistically significant correlation between age and physical activity and LTL in both groups. This is the first cross sectional study demonstrating an association between total serum TAC and LTL in healthy males, but interestingly, not in the females. Nevertheless, these results should be interpreted as preliminary, and further studies in independent cohorts are needed to investigate the sex-specific effects of oxidative stress on telomere length and telomerase activity.},
}
@article {pmid34941841,
year = {2021},
author = {Quimby, J and Erickson, A and Mcleland, S and Cianciolo, R and Maranon, D and Lunn, K and Elliott, J and Lawson, J and Hess, A and Paschall, R and Bailey, S},
title = {Renal Senescence, Telomere Shortening and Nitrosative Stress in Feline Chronic Kidney Disease.},
journal = {Veterinary sciences},
volume = {8},
number = {12},
pages = {},
pmid = {34941841},
issn = {2306-7381},
abstract = {Kidney tissues from cats with naturally occurring chronic kidney disease (CKD) and adult and senior cats without CKD were assessed to determine whether telomere shortening and nitrosative stress are associated with senescence in feline CKD. The histopathologic assessment of percent global glomerulosclerosis, inflammatory infiltrate, and fibrosis was performed. Senescence and nitrosative stress were evaluated utilizing p16 and iNOS immunohistochemistry, respectively. Renal telomere length was evaluated using telomere fluorescent in situ hybridization combined with immunohistochemistry. CKD cats were found to have significantly increased p16 staining in both the renal cortex and corticomedullary junction compared to adult and senior cats. Senior cats had significantly increased p16 staining in the corticomedullary junction compared to adult cats. p16 staining in both the renal cortex and corticomedullary junction were found to be significantly correlated with percent global glomerulosclerosis, cortical inflammatory infiltrate, and fibrosis scores. p16 staining also correlated with age in non-CKD cats. Average telomere length was significantly decreased in CKD cats compared to adult and senior cats. CKD cats had significantly increased iNOS staining compared to adult cats. Our results demonstrate increased renal senescence, telomere shortening, and nitrosative stress in feline CKD, identifying these patients as potential candidates for senolytic therapy with translational potential.},
}
@article {pmid34937532,
year = {2021},
author = {Libertini, G and Shubernetskaya, O and Corbi, G and Ferrara, N},
title = {Is Evidence Supporting the Subtelomere-Telomere Theory of Aging?.},
journal = {Biochemistry. Biokhimiia},
volume = {86},
number = {12},
pages = {1526-1539},
doi = {10.1134/S0006297921120026},
pmid = {34937532},
issn = {1608-3040},
mesh = {Aging/*genetics/metabolism ; Animals ; Cellular Senescence/*genetics ; *Epigenesis, Genetic ; Humans ; Inflammation/genetics/metabolism ; *Models, Genetic ; Oxidation-Reduction ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {The telomere theory tries to explain cellular mechanisms of aging as mainly caused by telomere shortening at each duplication. The subtelomere-telomere theory overcomes various shortcomings of telomere theory by highlighting the essential role of subtelomeric DNA in aging mechanisms. The present work illustrates and deepens the correspondence between assumptions and implications of subtelomere-telomere theory and experimental results. In particular, it is investigated the evidence regarding the relationships between aging and (i) epigenetic modifications; (ii) oxidation and inflammation; (iii) telomere protection; (iv) telomeric heterochromatin hood; (v) gradual cell senescence; (vi) cell senescence; and (vii) organism decline with telomere shortening. The evidence appears broadly in accordance or at least compatible with the description and implications of the subtelomere-telomere theory. In short, phenomena of cellular aging, by which the senescence of the whole organism is determined in various ways, appear substantially dependent on epigenetic modifications regulated by the subtelomere-telomere-telomeric hood-telomerase system. These phenomena appear to be not random, inevitable, and irreversible but rather induced and regulated by genetically determined mechanisms, and modifiable and reversible by appropriate methods. All this supports the thesis that aging is a genetically programmed and regulated phenoptotic phenomenon and is against the opposite thesis of aging as caused by random and inevitable degenerative factors.},
}
@article {pmid34933911,
year = {2022},
author = {Sui, JD and Tang, Z and Chen, BPC and Huang, P and Yang, MQ and Wang, NH and Yang, HN and Tu, HL and Jiang, QM and Zhang, J and Wang, Y and Wu, YZ},
title = {Protein Phosphatase 2A-Dependent Mitotic hnRNPA1 Dephosphorylation and TERRA Formation Facilitate Telomere Capping.},
journal = {Molecular cancer research : MCR},
volume = {20},
number = {4},
pages = {583-595},
doi = {10.1158/1541-7786.MCR-21-0581},
pmid = {34933911},
issn = {1557-3125},
mesh = {DNA-Binding Proteins ; Heterogeneous Nuclear Ribonucleoprotein A1/genetics/metabolism ; Humans ; *Protein Phosphatase 2/genetics/metabolism ; Replication Protein A/genetics/metabolism ; Telomere/genetics/metabolism ; *Telomere-Binding Proteins/genetics ; Transcription Factors ; },
abstract = {UNLABELLED: The heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), telomeric repeat-containing RNA (TERRA), and protection of telomeres 1 (POT1) have been reported to orchestrate to displace replication protein A (RPA) from telomeric overhangs, ensuring orderly telomere replication and capping. Our previous studies further demonstrated that DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-dependent hnRNPA1 phosphorylation plays a crucial role in the promotion of hnRNPA1 binding to telomeric overhangs and RPA displacement during G2-M phases. However, it is unclear that how the subsequent exchange between hnRNPA1 and POT1 is orchestrated. Here we report that the protein phosphatase 2A (PP2A) depends on its scaffold subunit, which is called PPP2R1A, to interact with and dephosphorylate hnRNPA1 in the late M phase. Furthermore, PP2A-mediated hnRNPA1 dephosphorylation and TERRA accumulation act in concert to promote the hnRNPA1-to-POT1 switch on telomeric single-stranded DNA. Consequently, defective PPP2R1A results in ataxia telangiectasia and Rad3-related (ATR)-mediated DNA damage response at telomeres as well as induction of fragile telomeres. Combined inhibition of ATR and PP2A induces entry into a catastrophic mitosis and leads to synthetic lethality of tumor cells. In addition, PPP2R1A levels correlate with clinical stages and prognosis of multiple types of cancers. Taken together, our results indicate that PP2A is critical for telomere maintenance.<br><br>IMPLICATIONS: This study demonstrates that the PP2A-dependent hnRNPA1 dephosphorylation and TERRA accumulation facilitates the formation of the protective capping structure of newly replicated telomeres, thus exerting essential oncogenic role in tumorigenesis.},
}
@article {pmid34933798,
year = {2022},
author = {Alder, JK and Sutton, RM and Iasella, CJ and Nouraie, M and Koshy, R and Hannan, SJ and Chan, EG and Chen, X and Zhang, Y and Brown, M and Popescu, I and Veatch, M and Saul, M and Berndt, A and Methé, BA and Morris, A and Pilewski, JM and Sanchez, PG and Morrell, MR and Shapiro, SD and Lindell, KO and Gibson, KF and Kass, DJ and McDyer, JF},
title = {Lung transplantation for idiopathic pulmonary fibrosis enriches for individuals with telomere-mediated disease.},
journal = {The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation},
volume = {41},
number = {5},
pages = {654-663},
pmid = {34933798},
issn = {1557-3117},
support = {R01 HL133184/HL/NHLBI NIH HHS/United States ; R01 HL135062/HL/NHLBI NIH HHS/United States ; R35 HL139860/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; *Idiopathic Pulmonary Fibrosis/genetics/surgery ; *Lung Diseases, Interstitial ; *Lung Transplantation ; Middle Aged ; Telomere/genetics ; Telomere Shortening/genetics ; },
abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common indication for lung transplantation in North America and variants in telomere-maintenance genes are the most common identifiable cause of IPF. We reasoned that younger IPF patients are more likely to undergo lung transplantation and we hypothesized that lung transplant recipients would be enriched for individuals with telomere-mediated disease due to the earlier onset and more severe disease in these patients.<br><br>METHODS: Individuals with IPF who underwent lung transplantation or were evaluated in an interstitial lung disease specialty clinic who did not undergo lung transplantation were examined. Genetic evaluation was completed via whole genome sequencing (WGS) of 426 individuals and targeted sequencing for 5 individuals. Rare variants in genes previously associated with IPF were classified using the American College of Medical Genetics guidelines. Telomere length from WGS data was measured using TelSeq software. Patient characteristics were collected via medical record review.<br><br>RESULTS: Of 431 individuals, 149 underwent lung transplantation for IPF. The median age of diagnosis of transplanted vs non-transplanted individuals was significantly younger (60 years vs 70 years, respectively, p<0.0001). IPF lung transplant recipients (IPF-LTRs) were twice as likely to have telomere-related rare variants compared to non-transplanted individuals (24% vs 12%, respectively, p=0.0013). IPF-LTRs had shorter telomeres than non-transplanted IPF patients (p=0.0028) and >85% had telomeres below the age-adjusted mean. Post-transplant survival and CLAD were similar amongst IPF-LTRs with rare variants in telomere-maintenance genes compared to those without, as well as in those with short telomeres versus longer telomeres.<br><br>CONCLUSIONS: There is an enrichment for telomere-maintenance gene variants and short telomeres among IPF-LTRs. However, transplant outcomes of survival and CLAD do not differ by gene variants or telomere length within IPF-LTRs. Our findings support individual with telomere-mediated disease should not be excluded from lung transplantation and focusing research efforts on therapies directed toward individuals with short-telomere mediated disease.},
}
@article {pmid34928768,
year = {2022},
author = {Abramson, DH and Cruz-Abrams, R and Francis, JH},
title = {Coats Disease and Premature Telomere Shortening.},
journal = {Journal of pediatric ophthalmology and strabismus},
volume = {59},
number = {4},
pages = {280},
doi = {10.3928/01913913-20211115-01},
pmid = {34928768},
issn = {1938-2405},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; },
mesh = {Female ; Humans ; *Premature Birth ; *Retinal Telangiectasis/diagnosis/genetics ; Telomere Shortening ; },
}
@article {pmid34924765,
year = {2021},
author = {Xie, Y and Lou, D and Zhang, D},
title = {Melatonin Alleviates Age-Associated Endothelial Injury of Atherosclerosis via Regulating Telomere Function.},
journal = {Journal of inflammation research},
volume = {14},
number = {},
pages = {6799-6812},
pmid = {34924765},
issn = {1178-7031},
abstract = {BACKGROUND: Atherosclerosis is an aging-related disease, partly attributed to telomerase dysfunction. This study aims to investigate whether telomere dysfunction-related vascular aging is involved in the protection mechanism of melatonin (MLT) in atherosclerosis.<br><br>METHODS: Young and aged ApoE[-/-] mice were used to establish atherosclerotic mice model. H&amp;E staining and immunofluorescence assay were performed to detect endothelial cell injury and apoptosis. Inflammatory cytokines and oxidative stress-related factors were determined using corresponding commercial assay kits. Telomerase activity was detected by TRAP assay, and SA-&#x3b2;-gal staining was conducted to evaluate cellular senescence. HUVECs were treated with H2O2 for 1 h to induce senescence. Western blot was performed to measure protein expression.<br><br>RESULTS: An obvious vascular endothelial injury, reflected by excessive production of inflammatory cytokines, elevated ROS, MDA and SOD levels, and more apoptotic endothelial cells, was found in atherosclerotic mice, especially in aged mice, which were then greatly suppressed by MLT. In addition, telomere dysfunction and senescence occurred in atherosclerosis, especially in aged mice, while MLT significantly alleviated the conditions. CYP1A1, one of the targeted genes of MLT, was verified to be upregulated in atherosclerotic mice but downregulated by MLT. Furthermore, H2O2 induced a senescence model in HUVECs, which was accompanied with a remarkably increased cell viability loss and apoptosis rate, and a downregulated telomerase activity of HUVECs, and this phenomenon was strengthened by RHPS4, an inhibitor of telomerase activity. However, MLT could partly abolish these changes in H2O2- and RHPS4-treated HUVECs, demonstrating that MLT alleviated vascular endothelial injury by regulating senescence and telomerase activity.<br><br>CONCLUSIONS: Collectively, this study provided evidence for the protective role of MLT in atherosclerosis through regulating telomere dysfunction-related vascular aging.},
}
@article {pmid34921825,
year = {2022},
author = {Herrera-Moreno, JF and Estrada-Gutierrez, G and Wu, H and Bloomquist, TR and Rosa, MJ and Just, AC and Lamadrid-Figueroa, H and Téllez-Rojo, MM and Wright, RO and Baccarelli, AA},
title = {Prenatal lead exposure, telomere length in cord blood, and DNA methylation age in the PROGRESS prenatal cohort.},
journal = {Environmental research},
volume = {205},
number = {},
pages = {112577},
doi = {10.1016/j.envres.2021.112577},
pmid = {34921825},
issn = {1096-0953},
support = {R00 ES027496/ES/NIEHS NIH HHS/United States ; R01 ES021357/ES/NIEHS NIH HHS/United States ; R01 ES032242/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; DNA Methylation ; Female ; *Fetal Blood ; Humans ; Infant, Newborn ; *Lead/toxicity ; Maternal Exposure/adverse effects ; Obesity ; Pregnancy ; Telomere ; Young Adult ; },
abstract = {BACKGROUND: Lead is a ubiquitous pollutant with deleterious effects on human health and remains a major current public health concern in developing countries. This heavy metal may interfere with nucleic acids via oxidative stress or epigenetic changes that affect biological markers of aging, e.g., telomere length and DNA methylation (DNAm). Telomere shortening associates with biological age in newborns, and DNA methylation at specific CpG sites can be used to calculate "epigenetic clocks".<br><br>OBJECTIVE: The aim of this study was to examine the associations of prenatal lead exposures with telomere length and DNA-methylation-based predictors of age in cord blood.<br><br>DESIGN: The study included 507 mother-child pairs from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, a birth cohort in Mexico City. Maternal blood (second trimester, third trimester and at delivery) and bone lead levels (one month postpartum) were measured using inductively coupled plasma-mass spectrometry and X-ray fluorescence, respectively. Cord blood leukocyte telomere length was measured using quantitative PCR and apparent age by DNA methylation biomarkers, i.e., Horvath's DNA methylation age and the Knight's predictor of gestational age.<br><br>RESULTS: Average maternal age was 28.5&#xa0;&#xb1;&#xa0;5.5 years, and 51.5% reported low socioeconomic status. Children's mean telomere length was 1.2&#xa0;&#xb1;&#xa0;1.3 relative units, and mean DNA methylation ages using the Horvath's and Knight's clocks were -2.6&#xa0;&#xb1;&#xa0;0.1 years and 37.9&#xa0;&#xb1;&#xa0;1.4 weeks (mean&#xa0;&#xb1;&#xa0;SD), respectively. No significant associations were found between maternal blood and bone lead concentrations with telomere length and DNAm age in newborns.<br><br>CONCLUSION: We found no associations of prenatal lead exposure with telomere length and DNA methylation age biomarkers.},
}
@article {pmid34919564,
year = {2021},
author = {Rahimi Mehdi Abad, F and Khalili, P and Jalali, F and Pirsadeghi, A and Esmaeili Nadimi, A and Manshoori, A and Jalali, Z},
title = {Maternal opioid use is reflected on leukocyte telomere length of male newborns.},
journal = {PloS one},
volume = {16},
number = {12},
pages = {e0261013},
pmid = {34919564},
issn = {1932-6203},
mesh = {Adolescent ; Adult ; Case-Control Studies ; Female ; Fetal Blood ; Humans ; Infant, Newborn ; Male ; Maternal Age ; Maternal Exposure ; Opioid-Related Disorders/complications/*genetics ; Pregnancy ; Pregnancy Complications/*genetics ; Prenatal Exposure Delayed Effects/*genetics ; *Telomere Shortening ; Young Adult ; },
abstract = {Opioid use accelerates normal aging in adults that raises a question on whether it may trans-generationally affect aging and aging biomarkers in the offspring of users as well? In the present research, we investigated the relative telomere length in umbilical cord blood of newborns born to opioid consuming mothers compared to normal controls. Telomere length shortening is a known biomarker of aging and aging related diseases. Its measure at birth or early in life is considered as a predictor of individual health in adulthood. Here, we performed a case-control study to investigate whether maternal opioid use affects newborns relative telomere length (RTL). 57 mother-newborn dyads were included in this study, 30 neonates with opioid using mothers (OM), and 27 with not-opioid using mothers (NOM)). RTL was measured in leukocyte cells genomic DNA using real-time PCR. The correlation of maternal opioid use with neonates telomer length was assessed using logistic regression analysis. The results displayed a significant association between odds ratio of long RTL and maternal opioid use when sensitivity analysis was performed by neonate sex; where the data indicates significantly increased odds ratio of long leukocyte RTL in association with maternal opioid use in male neonates only. Further work is necessary to assess this association in larger samples and test the potential underlying mechanisms for this observation.},
}
@article {pmid34915934,
year = {2021},
author = {Lu, Y and Liu, X and Zhao, Z and Ou, X and Yang, Y and Wei, Q and Chen, J and Jiang, J and Sun, Y and Zhao, H and Wu, S and He, Y},
title = {Telomere length in peripheral leukocytes is a sensitive marker for assessing genetic damage among workers exposed to isopropanol, lead and noise: the case of an electronics manufacturer.},
journal = {Genes and environment : the official journal of the Japanese Environmental Mutagen Society},
volume = {43},
number = {1},
pages = {57},
pmid = {34915934},
issn = {1880-7046},
support = {81472998//national natural science foundation of china/ ; 81872661//national natural science foundation of china/ ; },
abstract = {BACKGROUND: Workers in electronics manufacturers may be exposed to various occupational hazards such as isopropanol, lead, and noise. Telomeres are special segments of cap-like DNA protein complex at end of liner chromosomes in eukaryotic cells. Telomere length is a potential marker of genetic damage. The aim of this study is to evaluate the effect of occupational hazards on the relative telomere length (rTL) of peripheral blood cells of workers in an electronics manufacturer, and to explore whether relative telomere length could be a biomarker for assessing genetic damage in the electronics manufacturing industry.<br><br>METHODS: We investigated a large-scale electronics manufacturer in the Pearl River Delta Region. We ultimately collected 699 qualified workers (248 with isopropanol exposure, 182 with lead exposure, 157 with noise exposure, and 112 controls). During physical examination of the workers, we gave them questionnaires to understand their health statuses and living habits. We also collected peripheral blood samples from these workers to test exposure levels and rTL in the leucocytes.<br><br>RESULTS: The concentrations of air isopropanol in all monitored workshops was 25.3&#xa0;mg/m[3] and air lead smoke was 0.020&#xa0;mg/m[3]. The maximum equivalent continuous A sound level noise exposure position was 82.2dB (A). All were lower than those in the Occupational Exposure Limits in Workplaces in China. Urinary acetone in the isopropanol exposed group was 1.04 (0, 1.50) mg/L, and cumulative urinary acetone was 1.48 (0, 5.09) mg-years/L. Blood lead levels (BLLs) were 28.57 (22.77, 37.06) &#xb5;g/dL, and cumulative blood lead levels (CBLLs) were 92.75 (55.47, 165.13) &#xb5;g-years/dL. rTL was different between occupational exposed workers and controls: rTL was 0.140 units (95&#x2009;% CI: 0.022, 0.259) shorter in lead exposed workers and 0.467 units (95&#x2009;% CI: 0.276-0.658) shorter in noise exposed workers compared to the controls. There is no statistical difference in rTL between isopropanol exposure workers and the controls. In order to elucidate the relationship between rTL and occupational hazards exposure, we divided the isopropanol exposure workers into three groups (0, ~1.43&#xa0;mg/L, and >1.43&#xa0;mg/L). None of the rTL difference was statistically significant among exposed workers at different uroacetone levels (P>0.05). The groups with &#x2265;100&#xa0;&#xb5;g/dL blood lead had shorter rTL than the group with blood lead below 100&#xa0;&#xb5;g/dL (F=4.422, P=0.013). We incorporated age, gender, birthplace, race, education level, smoking, and alcohol consumption into the linear regression equation. Only blood lead concentration (X) was entered into the regression equation, yielding a multivariate linear regression equation of Y=0.397-0.124X (F=8.091, P=0.005). Workers with different hearing loss also had statistically significant differences in rTL (F=5.731, P=0.004). rTL was a protective factor for the occurrence of noise-induced hearing loss (NIHL). The longer the rTL, the lower the risk of NIHL [OR=0.64 (0.42, 0.98)].<br><br>CONCLUSIONS: rTL was shorter in lead exposed workers and noise exposed workers, and it was a protective factor for the occurrence of the noise-induced hearing loss. Thus, rTL of peripheral blood may be a sensitive marker of genetic damage among workers in environments with lead and noise exposure.},
}
@article {pmid34912838,
year = {2021},
author = {Niu, KM and Bao, T and Gao, L and Ru, M and Li, Y and Jiang, L and Ye, C and Wang, S and Wu, X},
title = {The Impacts of Short-Term NMN Supplementation on Serum Metabolism, Fecal Microbiota, and Telomere Length in Pre-Aging Phase.},
journal = {Frontiers in nutrition},
volume = {8},
number = {},
pages = {756243},
pmid = {34912838},
issn = {2296-861X},
abstract = {Aging is a natural process with concomitant changes in the gut microbiota and associate metabolomes. Beta-nicotinamide mononucleotide, an important NAD[+] intermediate, has drawn increasing attention to retard the aging process. We probed the changes in the fecal microbiota and metabolomes of pre-aging male mice (C57BL/6, age: 16 months) following the oral short-term administration of nicotinamide mononucleotide (NMN). Considering the telomere length as a molecular gauge for aging, we measured this in the peripheral blood mononuclear cells (PBMC) of pre-aging mice and human volunteers (age: 45-60 years old). Notably, the NMN administration did not influence the body weight and feed intake significantly during the 40 days in pre-aging mice. Metabolomics suggested 266 upregulated and 58 downregulated serum metabolites. We identified 34 potential biomarkers linked with the nicotinamide, purine, and proline metabolism pathways. Nicotinamide mononucleotide significantly reduced the fecal bacterial diversity (p < 0.05) with the increased abundance of Helicobacter, Mucispirillum, and Faecalibacterium, and lowered Akkermansia abundance associated with nicotinamide metabolism. We propose that this reshaped microbiota considerably lowered the predicated functions of aging with improved immune and cofactors/vitamin metabolism. Most notably, the telomere length of PBMC was significantly elongated in the NMN-administered mice and humans. Taken together, these findings suggest that oral NMN supplementation in the pre-aging stage might be an effective strategy to retard aging. We recommend further studies to unravel the underlying molecular mechanisms and comprehensive clinical trials to validate the effects of NMN on aging.},
}
@article {pmid34910909,
year = {2021},
author = {Liu, R and Kasowitz, SD and Homolka, D and Leu, NA and Shaked, JT and Ruthel, G and Jain, D and Lin, H and Keeney, S and Luo, M and Pillai, RS and Wang, PJ},
title = {YTHDC2 is essential for pachytene progression and prevents aberrant microtubule-driven telomere clustering in male meiosis.},
journal = {Cell reports},
volume = {37},
number = {11},
pages = {110110},
pmid = {34910909},
issn = {2211-1247},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; P50 HD068157/HD/NICHD NIH HHS/United States ; R01 HD069592/HD/NICHD NIH HHS/United States ; R35 GM118052/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Female ; Male ; *Meiosis ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microtubules/*physiology ; *Pachytene Stage ; RNA Helicases/*physiology ; Spermatocytes/*cytology/metabolism ; *Telomere ; *Transcriptome ; },
abstract = {Mechanisms driving the prolonged meiotic prophase I in mammals are poorly understood. RNA helicase YTHDC2 is critical for mitosis to meiosis transition. However, YTHDC2 is highly expressed in pachytene cells. Here we identify an essential role for YTHDC2 in meiotic progression. Specifically, YTHDC2 deficiency causes microtubule-dependent telomere clustering and apoptosis at the pachytene stage of prophase I. Depletion of YTHDC2 results in a massively dysregulated transcriptome in pachytene cells, with a tendency toward upregulation of genes normally expressed in mitotic germ cells and downregulation of meiotic transcripts. Dysregulation does not correlate with m[6]A status, and YTHDC2-bound mRNAs are enriched in genes upregulated in mutant germ cells, revealing that YTHDC2 primarily targets mRNAs for degradation. Furthermore, altered transcripts in mutant pachytene cells encode microtubule network proteins. Our results demonstrate that YTHDC2 regulates the pachytene stage by perpetuating a meiotic transcriptome and preventing microtubule network changes that could lead to telomere clustering.},
}
@article {pmid34910812,
year = {2022},
author = {Schoepf, IC and Thorball, CW and Ledergerber, B and Kootstra, NA and Reiss, P and Raffenberg, M and Engel, T and Braun, DL and Hasse, B and Thurnheer, C and Marzolini, C and Seneghini, M and Bernasconi, E and Cavassini, M and Buvelot, H and Arribas, JR and Kouyos, RD and Fellay, J and Günthard, HF and Tarr, PE},
title = {Telomere Length Declines in Persons With Human Immunodeficiency Virus Before Antiretroviral Therapy Start but Not After Viral Suppression: A Longitudinal Study Over &gt;17 Years.},
journal = {The Journal of infectious diseases},
volume = {225},
number = {9},
pages = {1581-1591},
doi = {10.1093/infdis/jiab603},
pmid = {34910812},
issn = {1537-6613},
support = {177499/SNSF_/Swiss National Science Foundation/Switzerland ; },
mesh = {Anti-Retroviral Agents/therapeutic use ; Cohort Studies ; HIV/genetics ; *HIV Infections ; Humans ; Leukocytes, Mononuclear ; Longitudinal Studies ; Telomere/genetics ; },
abstract = {BACKGROUND: In people with human immunodeficiency virus (PWH), long-term telomere length (TL) change without/with suppressive antiretroviral therapy (ART) and the contribution of genetic background to TL are incompletely understood.<br><br>METHODS: We measured TL change in peripheral blood mononuclear cells by quantitative polymerase chain reaction in 107 Swiss HIV Cohort Study participants with longitudinal samples available both before and during suppressive ART. We applied mixed-effects multilevel regression to obtain uni-/multivariable estimates for longitudinal TL dynamics including age, sex, and CD4/CD8 ratio. We assessed the effect of (1) individual antiretrovirals and (2) an individual TL-polygenic risk score ([TL-PRS] based on 239 single-nucleotide polymorphisms) on TL in 798 additional participants from our previous longitudinal studies.<br><br>RESULTS: During untreated human immunodeficiency virus (HIV) infection (median observation, 7.7; interquartile range [IQR], 4.7-11] years), TL declined significantly (median -2.12%/year; IQR, -3.48% to -0.76%/year; P&#x2005;=&#x2005;.002). During suppressive ART (median observation, 9.8; IQR, 7.1-11.1 years), there was no evidence of TL decline or increase (median&#x2005;+&#x2005;0.54%/year; IQR, -0.55% to&#x2005;+&#x2005;1.63%/year; P&#x2005;=&#x2005;.329). The TL-PRS contributed to TL change (global P&#x2005;=&#x2005;.019) but particular antiretrovirals did not (all P&#x2005;>&#x2005;.15).<br><br>CONCLUSIONS: In PWH, TL is associated with an individual PRS. Telomere length declined significantly during untreated chronic HIV infection, but no TL change occurred during suppressive ART.},
}
@article {pmid34906191,
year = {2021},
author = {Xia, K and Zhang, L and Zhang, G and Wang, Y and Huang, T and Fan, D},
title = {Leukocyte telomere length and amyotrophic lateral sclerosis: a Mendelian randomization study.},
journal = {Orphanet journal of rare diseases},
volume = {16},
number = {1},
pages = {508},
pmid = {34906191},
issn = {1750-1172},
mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Genome-Wide Association Study ; Humans ; Leukocytes ; Mendelian Randomization Analysis/methods ; Polymorphism, Single Nucleotide/genetics ; Telomere/genetics ; },
abstract = {BACKGROUND: Observational studies have suggested that telomere length is associated with amyotrophic lateral sclerosis (ALS). However, whether this association is causal remains unclear. In this study, we aimed to explore the causal relationship between leukocyte telomere length (LTL) and ALS by a two-sample Mendelian randomization (MR) approach. Single-nucleotide polymorphisms (SNPs) for LTL were identified through high-quality genome-wide association studies (GWASs). The ALS GWAS summary data (20,806 cases; 59,804 controls) with largest sample size to date was obtained. We adopted the inverse variance weighted (IVW) method to examine the effect of LTL on ALS and used the weighted median method, simple median method, MR Egger method and MR-PRESSO method to perform sensitivity analyses.<br><br>RESULTS: We found that genetically determined increased LTL was inversely associated with the risk of ALS (odds ratio (OR)&#x2009;=&#x2009;0.846, 95% confidence interval (CI): 0.744-0.962, P&#x2009;=&#x2009;0.011), which was mainly driven by rs940209 in the OBFC1 gene, suggesting a potential effect of OBFC1 on ALS. The results were further confirmed by sensitivity analysis with the MR Egger method (OR&#x2009;=&#x2009;0.647, 95% CI&#x2009;=&#x2009;0.447-0.936, P&#x2009;=&#x2009;0.050). Analyses by the weighted median method (OR&#x2009;=&#x2009;0.893, P&#x2009;=&#x2009;0.201) and simple median method (OR&#x2009;=&#x2009;0.935, P&#x2009;=&#x2009;0.535) also showed a similar trend. The MR Egger analysis did not suggest directional pleiotropy, with an intercept of 0.025 (P&#x2009;=&#x2009;0.168). Neither the influence of instrumental outliers nor heterogeneity was found.<br><br>CONCLUSIONS: Our results suggest that genetically predicted increased LTL has a causal relationship with a lower risk of ALS. Protecting against telomere loss may be of great importance in the prevention and treatment of ALS.},
}
@article {pmid34902558,
year = {2022},
author = {Engin, AB and Coleman, MD},
title = {Telomere attrition may be a more realistic toxicity test for both low and high dose exposure.},
journal = {Environmental toxicology and pharmacology},
volume = {90},
number = {},
pages = {103788},
doi = {10.1016/j.etap.2021.103788},
pmid = {34902558},
issn = {1872-7077},
mesh = {Aging ; Environmental Exposure/*adverse effects/analysis ; Environmental Pollutants/toxicity ; Humans ; Risk Assessment ; Telomerase/analysis/metabolism ; Telomere Shortening/*drug effects ; Toxicity Tests/*methods ; },
}
@article {pmid34901077,
year = {2021},
author = {Casas-Recasens, S and Mendoza, N and López-Giraldo, A and Garcia, T and Cosio, BG and Pascual-Guardia, S and Acosta-Castro, A and Borras-Santos, A and Gea, J and Garrabou, G and Agusti, A and Faner, R},
title = {Telomere Length but Not Mitochondrial DNA Copy Number Is Altered in Both Young and Old COPD.},
journal = {Frontiers in medicine},
volume = {8},
number = {},
pages = {761767},
pmid = {34901077},
issn = {2296-858X},
abstract = {Accelerated ageing is implicated in the pathogenesis of respiratory diseases as chronic obstructive pulmonary disease (COPD), but recent evidence indicates that the COPD can have roots early in life. Here we hypothesise that the accelerated ageing markers might have a role in the pathobiology of young COPD. The objective of this study was to compare two hallmarks of ageing, telomere length (TL), and mitochondrial DNA copy number (mtDNA-CN, as a surrogate marker of mitochondrial dysfunction) in young (≤ 50 years) and old (>50 years) smokers, with and without COPD. Both, TL and mtDNA-CN were measured in whole blood DNA by quantitative PCR [qPCR] in: (1) young ever smokers with (n = 81) or without (n = 166) COPD; and (2) old ever smokers with (n = 159) or without (n = 29) COPD. A multivariable linear regression was used to assess the association of TL and mtDNA-CN with lung function. We observed that in the entire study population, TL and mtDNA-CN decreased with age, and the former but not the latter related to FEV1/FVC (%), FEV1 (% ref.), and DLCO (% ref.). The short telomeres were found both in the young and old patients with severe COPD (FEV1 <50% ref.). In addition, we found that TL and mtDNA-CN were significantly correlated, but their relationship was positive in younger while negative in the older patients with COPD, suggesting a mitochondrial dysfunction. We conclude that TL, but not mtDNA-CN, is associated with the lung function impairment. Both young and old patients with severe COPD have evidence of accelerated ageing (shorter TL) but differ in the direction of the correlation between TL and mtDNA-CN in relation to age.},
}
@article {pmid34900979,
year = {2021},
author = {Nozaki, T and Chang, F and Weiner, B and Kleckner, N},
title = {High Temporal Resolution 3D Live-Cell Imaging of Budding Yeast Meiosis Defines Discontinuous Actin/Telomere-Mediated Chromosome Motion, Correlated Nuclear Envelope Deformation and Actin Filament Dynamics.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {687132},
pmid = {34900979},
issn = {2296-634X},
support = {R35 GM136322/GM/NIGMS NIH HHS/United States ; },
abstract = {Chromosome movement is prominent at mid-meiotic prophase and is proposed to enhance the efficiency and/or stringency of homolog pairing and/or to help prevent or resolve topological entanglements. Here, we combine fluorescent repressor operator system (FROS) labeling with three-dimensional (3D) live-cell imaging at high spatio-temporal resolution to define the detailed kinetics of mid-meiotic prophase motion for a single telomere-proximal locus in budding yeast. Telomere motions can be grouped into three general categories: (i) pauses, in which the telomere "jiggles in place"; (ii) rapid, straight/curvilinear motion which reflects Myo2/actin-mediated transport of the monitored telomere; and (iii) slower directional motions, most of which likely reflect indirectly promoted motion of the monitored telomere in coordination with actin-mediated motion of an unmarked telomere. These and other findings highlight the importance of dynamic assembly/disassembly of telomere/LINC/actin ensembles and also suggest important roles for nuclear envelope deformations promoted by actin-mediated telomere/LINC movement. The presented low-SNR (signal-to-noise ratio) imaging methodology provides opportunities for future exploration of homolog pairing and related phenomena.},
}
@article {pmid34900769,
year = {2021},
author = {Al-Thuwaini, TM},
title = {Association of antidiabetic therapy with shortened telomere length in middle-aged Type 2 diabetic patients.},
journal = {Journal of diabetes and metabolic disorders},
volume = {20},
number = {2},
pages = {1161-1168},
pmid = {34900769},
issn = {2251-6581},
abstract = {INTRODUCTION: A wide range of antidiabetic therapies have been developed to manage diabetes and limit its lifespan but each of them have adverse long-term drug reactions. This study was performed for the investigation of the possible association of antidiabetic therapy with shortened telomere length in middle-aged Type 2 diabetic patients.<br><br>MATERIALS AND METHODS: The subjects in this case-control study included 100 non-diabetic patients and 300 patients with Type 2 diabetes with ages in the range of 30-50&#xa0;years. The treated patients were further subdivided into diabetic patients using Doanil, those using insulin and those using both the therapies. The mean telomere length was determined using the southern-blotting technique. A logistic regression analysis was performed to predict the relationship between antidiabetic therapy and shortened telomere length.<br><br>RESULTS: The results revealed a significant increase (P&#x2009;<&#x2009;0.01) in the fasting blood glucose and lipid profile in non-treatment diabetic patients compared to diabetic patients with treatment, and also in diabetic patients with insulin therapy, compared to diabetic patients with Doanil or both therapies. The results showed that non-treatment diabetic patients had shorter telomere length, compared to the diabetic patients with treatment, and patients treated with insulin therapy had shorter telomere length, compared to the diabetic patients with Doanil or both therapies. The logistic regression analysis confirmed that insulin therapy was closely related to diabetic risk factors and shortened telomere length.<br><br>CONCLUSIONS: The results revealed that Doanil therapy was more effective in managing diabetic risk and limiting the shortening telomere length than insulin therapy.},
}
@article {pmid34895035,
year = {2022},
author = {Rungnirundorn, T and Krusong, K and Kalayasiri, R and Maes, M},
title = {Leukocyte telomere length is not shortened in methamphetamine dependence or methamphetamine-induced psychosis but is increased following traumatic events.},
journal = {The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry},
volume = {23},
number = {8},
pages = {613-621},
pmid = {34895035},
issn = {1814-1412},
support = {D43 TW006166/TW/FIC NIH HHS/United States ; K24 DA017899/DA/NIDA NIH HHS/United States ; },
mesh = {Humans ; *Methamphetamine/adverse effects ; *Tobacco Use Disorder/complications ; *Amphetamine-Related Disorders/complications ; *Substance Withdrawal Syndrome ; *Alcoholism/genetics/complications ; *Psychotic Disorders/genetics/complications ; Leukocytes ; Telomere/genetics ; },
abstract = {OBJECTIVE: This study aims to examine the effects of methamphetamine (MA) use and dependence and MA withdrawal symptoms on the telomere length and whether shortening of the latter is associated with MA-induced psychosis (MIP).<br><br>METHODS: This study included 185&#x2009;MA-abuse, 118&#x2009;MA-dependent, and 67 MIP patients, diagnosed using DSM-IV criteria. The Semi-structured Assessment for Drug Dependence and Alcoholism (SSADDA) questionnaire was employed to collect MA-related data. MIP was confirmed using the Methamphetamine Experience Questionnaire (MEQ). The leukocyte telomere length was measured using real-time polymerase chain reaction measuring the Telomere/Single gene ratio (T/S ratio). Data were analysed using multivariate statistical analyses.<br><br>RESULTS: There were no significant associations between the T/S ratio and severity of MA-use, MIP, and MA withdrawal symptoms. MIP was significantly predicted by alcohol dependence, antisocial personality disorder, and MA-use severity. There were significantly positive associations between the T/S ratio and previous traumatic and life-threatening events. The T/S ratio was not affected by alcohol and nicotine dependence. Alcohol and nicotine dependence, antisocial personality disorder, and severity of MA use increased risk of MA withdrawal symptoms.<br><br>CONCLUSION: MIP and MA-use severity are not associated with leukocyte telomere length, but previous traumatic and life-threatening events are associated with increased telomere length.},
}
@article {pmid34894710,
year = {2022},
author = {Zhang, A and Fan, L and Sun, T and Fan, Y and Xu, Z and Yin, Z and Zhuo, Y and Zhang, J and Gu, J and Chang, ACY and Wang, C},
title = {The association of leukocyte telomere length and intermediate coronary lesions-a retrospective study.},
journal = {Annals of palliative medicine},
volume = {11},
number = {4},
pages = {1210-1221},
doi = {10.21037/apm-21-2295},
pmid = {34894710},
issn = {2224-5839},
mesh = {Humans ; Leukocytes ; Lipids ; *Percutaneous Coronary Intervention/methods ; *Plaque, Atherosclerotic/diagnostic imaging/genetics ; Retrospective Studies ; Telomere/genetics ; Telomere Shortening ; },
abstract = {BACKGROUND: Intermediate coronary lesions (40-70% stenosis) present a higher risk for future cardiovascular events for instability of plaques. Shortened telomere is an indicator of cellular senescence, which is associated with age-related diseases. However, the relationship between telomere length and severity of intermediate coronary lesions remains largely unknown.<br><br>METHODS: A total of 121 lesions of 121 patients with intermediate coronary disease that underwent intravascular optical coherence tomography were enrolled. These patients were retrospectively divided into two groups according to whether accept percutaneous coronary intervention (PCI) treatment: non-PCI group and PCI group.<br><br>RESULTS: Leukocyte telomere length (LTL) in patients of PCI group were significantly shorter (12.54&#xb1;2.70 vs. 15.32&#xb1;3.72 kb, P<0.001) than non-PCI group. The PCI group had longer lipid length (17.17&#xb1;9.94 vs. 12.21&#xb1;10.15 mm, P=0.01) and greater lipid index (4,286.82&#xb1;3,012.54 vs. 2,444.87&#xb1;2,677.59 &#xb0;*mm, P<0.001). There was a significant difference in the prevalence of thin-cap fibroatheroma (36.6% vs. 16.0%, P=0.013), macrophages (56.3% vs. 38.0%, P=0.047), plaque rupture (23.9% vs. 6.0%, P=0.009), cholesterol crystal (49.3% vs. 30.0%, P=0.034), dissection (23.9% vs. 4.0%, P=0.003) between PCI and non-PCI group. Logistic regression revealed that LTL was independently associated with PCI after adjusting for confounding factors (OR 0.952, CI: 0.930-0.974, per 1unit increase, P<0.001). Receiver operating characteristic (ROC) analysis revealed a LTL area under the ROC curve (AUC) of 0.714 (95% CI: 0.619-0.808, P<0.001) in the study population. Furthermore, LTL was inversely correlated with lipid length (r =-0.190, P=0.037), lipid arc (r =-0.301, P=0.001), lipid index (r =-0.182, P=0.046), and positive correlation with FCT (r =0.213, P=0.034).<br><br>CONCLUSIONS: LTL was independently associated with possibility of receiving PCI in intermediate coronary lesion patients and LTL is also significantly related to plaque instability features that evaluated by optical coherence tomography. LTL may be as an indicator to assess the necessity of PCI in intermediate coronary lesion patients.},
}
@article {pmid34890718,
year = {2022},
author = {Womersley, JS and Xulu, KR and Sommer, J and Hinsberger, M and Kidd, M and Elbert, T and Weierstall, R and Kaminer, D and Malan-Müller, S and Seedat, S and M J Hemmings, S},
title = {Associations between telomere length and symptoms of posttraumatic stress disorder and appetitive aggression in trauma-exposed men.},
journal = {Neuroscience letters},
volume = {769},
number = {},
pages = {136388},
doi = {10.1016/j.neulet.2021.136388},
pmid = {34890718},
issn = {1872-7972},
mesh = {Adolescent ; Adult ; *Aggression ; *Appetitive Behavior ; Humans ; Male ; South Africa ; Stress Disorders, Post-Traumatic/epidemiology/*genetics/physiopathology ; *Telomere Homeostasis ; Violence/psychology/statistics &amp; numerical data ; },
abstract = {Exposure to community violence is common in South Africa and negatively impacts on biopsychosocial health. Posttraumatic stress disorder (PTSD) is characterised by symptoms of intrusion, avoidance, hypervigilance and negative alterations in cognition and mood, and can develop consequent to trauma exposure. Individuals who repeatedly experience and witness violence may also come to view it as appealing and rewarding. This appetitive aggression (AA) increases the likelihood of perpetrating violence. Telomeres are repetitive nucleotide sequences that protect the ends of chromosomes. Telomere length (TL) attrition is a stress-sensitive marker of biological aging that has been associated with a range of psychiatric disorders. This study investigated the cross-sectional relationship between TL and symptoms of PTSD and AA in South African men residing in areas with high community violence. PTSD and AA symptom severity was assessed in 290 men using the Posttraumatic Stress Disorder Symptom Scale - Interview (PSS-I) and Appetitive Aggression Scale (AAS), respectively. Quantitative polymerase chain reaction was performed on DNA extracted from saliva and used to calculate relative TL (rTL). Regression models were used to assess the relationships between rTL and PSS-I and AAS scores. Network analyses using EBIC glasso methods were performed using rTL and items from each of the AAS and PSS-I measures. Both PSS-I (p = 0.023) and AAS (p = 0.016) scores were positively associated with rTL. Network analyses indicated that rTL was weakly related to two PSS-I and five AAS items but performed poorly on indicators of centrality and was not strongly associated with measure items either directly or indirectly. The positive association between rTL and measures of AA and PTSD may be due to the induction of protective homeostatic mechanisms, which reduce TL attrition, following early life trauma exposure.},
}
@article {pmid34887119,
year = {2022},
author = {Kardeh, S and Saber, A and Mazloomrezaei, M and Hosseini, A},
title = {Telomere targeting is insufficient to ameliorate multifaceted hallmarks of aging in cultured keratinocytes.},
journal = {Burns : journal of the International Society for Burn Injuries},
volume = {48},
number = {2},
pages = {470-471},
doi = {10.1016/j.burns.2021.07.012},
pmid = {34887119},
issn = {1879-1409},
mesh = {Aging ; *Burns ; Cells, Cultured ; Humans ; Keratinocytes ; Telomere/genetics ; },
}
@article {pmid34884608,
year = {2021},
author = {Lee, KH and Kim, DY and Kim, W},
title = {Regulation of Gene Expression by Telomere Position Effect.},
journal = {International journal of molecular sciences},
volume = {22},
number = {23},
pages = {},
pmid = {34884608},
issn = {1422-0067},
support = {2021R1F1A1062392//National Research Foundation of Korea/ ; },
mesh = {*Aging ; Animals ; *Epigenesis, Genetic ; *Gene Expression Regulation ; Humans ; Neoplasms/genetics/*pathology ; Telomere/*chemistry/*genetics ; },
abstract = {Many diseases that involve malignant tumors in the elderly affect the quality of human life; therefore, the relationship between aging and pathogenesis in geriatric diseases must be under-stood to develop appropriate treatments for these diseases. Recent reports have shown that epigenetic regulation caused by changes in the local chromatin structure plays an essential role in aging. This review provides an overview of the roles of telomere shortening on genomic structural changes during an age-dependent shift in gene expression. Telomere shortening is one of the most prominent events that is involved in cellular aging and it affects global gene expression through genome rearrangement. This review provides novel insights into the roles of telomere shortening in disease-affected cells during pathogenesis and suggests novel therapeutic approaches.},
}
@article {pmid34882527,
year = {2022},
author = {Rangel-Pozzo, A and Dettori, T and Virginia Frau, D and Etzi, F and Gartner, J and Fisher, G and Vanni, R and Mai, S and Caria, P},
title = {Three-dimensional telomere profiles in papillary thyroid cancer variants: A pilot study.},
journal = {Bosnian journal of basic medical sciences},
volume = {22},
number = {3},
pages = {481-487},
pmid = {34882527},
issn = {1840-4812},
mesh = {*Adenocarcinoma, Follicular/metabolism/pathology ; Humans ; Pilot Projects ; Telomere/genetics ; Thyroid Cancer, Papillary/genetics/pathology ; *Thyroid Neoplasms/genetics/pathology ; },
abstract = {Besides the two main histologic types of papillary thyroid carcinoma (PTC), the classical PTC (CL-PTC) and the follicular variant PTC (FV-PTC), several other variants are described. The encapsulated FV-PTC variant was recently reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) due to its similarities to benign lesions. Specific molecular signatures, however, are still unavailable. It is well known that improper DNA repair of dysfunctional telomeres may cause telomere-related genome instability. The mechanisms involved in the damaged telomere repair processing may lead to detrimental outcomes, altering the three-dimensional (3D) nuclear telomere and genome organization in cancer cells. This pilot study aimed to evaluate whether a specific 3D nuclear telomere architecture might characterize NIFTP, potentially distinguishing it from other PTC histologic variants. Our findings demonstrate that 3D telomere profiles of CL-PTC and FV-PTC were different from NIFTP and that NIFTP more closely resembles follicular thyroid adenoma (FTA). NIFTP has longer telomeres than CL-PTC and FV-PTC samples, and the telomere length of NIFTP overlaps with that of the FTA histotype. In contrast, there was no association between BRAF expression and telomere length in all tested samples. These preliminary findings reinforce the view that NIFTP is closer to non-malignant thyroid nodules and confirm that PTC features short telomeres.},
}
@article {pmid34881184,
year = {2021},
author = {Tang, Y and Mukherjee, J and Pieper, RO},
title = {MRE11 and UBR5 Co-Operate to Suppress RNF168-Mediated Fusion of Dysfunctional Telomeres.},
journal = {Frontiers in oncology},
volume = {11},
number = {},
pages = {772233},
pmid = {34881184},
issn = {2234-943X},
support = {R01 CA265983/CA/NCI NIH HHS/United States ; },
abstract = {TRF2 is part of the shelterin complex that hides telomeric DNA ends and prevents the activation of the cNHEJ pathway that can lead to chromosomal fusion. TRF2, however, also actively suppresses the cNHEJ pathway by recruiting two proteins, MRE11 and UBR5. MRE11 binds BRCC3, which in turn deubiquitinates γH2AX deposited at exposed telomeric DNA ends and limits RNF168 recruitment to the telomere. UBR5, in contrast directly ubiquitinates and destroys RNF168. The loss of telomeric RNF168 in turn blocks the subsequent recruitment of 53BP1 and prevents the cNHEJ-mediated fusion of chromosomes with exposed telomeric DNA ends. Although MRE11 and UBR5 are both involved in the control of telomeric RNF168 levels and the chromosome fusion process, their relative contributions have not been directly addressed. To do so we genetically suppressed MRE11 and UBR5 alone or in combination in glioma cell lines which we previously showed contained dysfunctional telomeres that were dependent on TRF2 for suppression of telomeric fusion and monitored the effects on events associated with telomere fusion. We here show that while suppression of either MRE11 or UBR5 alone had minimal effects on RNF168 telomeric accumulation, 53BP1 recruitment, and telomeric fusion, their combined suppression led to significant increases in RNF168 and 53BP1 telomeric recruitment and telomeric fusion and eventually cell death, all of which were reversible by suppression of RNF168 itself. These results show that MRE11 and UBR5 co-operate to suppress fusion at dysfunctional telomeres.},
}
@article {pmid34879271,
year = {2021},
author = {Barroso-González, J and García-Expósito, L and Galaviz, P and Lynskey, ML and Allen, JAM and Hoang, S and Watkins, SC and Pickett, HA and O'Sullivan, RJ},
title = {Anti-recombination function of MutSα restricts telomere extension by ALT-associated homology-directed repair.},
journal = {Cell reports},
volume = {37},
number = {10},
pages = {110088},
pmid = {34879271},
issn = {2211-1247},
support = {P30 CA047904/CA/NCI NIH HHS/United States ; R01 CA207209/CA/NCI NIH HHS/United States ; R37 CA263622/CA/NCI NIH HHS/United States ; S10 OD019973/OD/NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; DNA Mismatch Repair ; DNA, Neoplasm/genetics/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Genomic Instability ; HeLa Cells ; Humans ; Models, Genetic ; MutS Homolog 2 Protein/genetics/*metabolism ; Neoplasms/*enzymology/genetics/pathology ; Nucleic Acid Conformation ; Nucleic Acid Heteroduplexes/genetics/*metabolism ; RecQ Helicases/genetics/metabolism ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; },
abstract = {Alternative lengthening of telomeres (ALT) is a telomere-elongation mechanism observed in ∼15% of cancer subtypes. Current models indicate that ALT is mediated by homology-directed repair mechanisms. By disrupting MSH6 gene expression, we show that the deficiency of MutSα (MSH2/MSH6) DNA mismatch repair complex causes striking telomere hyperextension. Mechanistically, we show MutSα is specifically recruited to telomeres in ALT cells by associating with the proliferating-cell nuclear antigen (PCNA) subunit of the ALT telomere replisome. We also provide evidence that MutSα counteracts Bloom (BLM) helicase, which adopts a crucial role in stabilizing hyper-extended telomeres and maintaining the survival of MutSα-deficient ALT cancer cells. Lastly, we propose a model in which MutSα deficiency impairs heteroduplex rejection, leading to premature initiation of telomere DNA synthesis that coincides with an accumulation of telomere variant repeats (TVRs). These findings provide evidence that the MutSα DNA mismatch repair complex acts to restrain unwarranted ALT.},
}
@article {pmid34875134,
year = {2022},
author = {Kärkkäinen, T and Laaksonen, T and Burgess, M and Cantarero, A and Martínez-Padilla, J and Potti, J and Moreno, J and Thomson, RL and Tilgar, V and Stier, A},
title = {Population differences in the length and early-life dynamics of telomeres among European pied flycatchers.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {5966-5978},
pmid = {34875134},
issn = {1365-294X},
mesh = {Animals ; *Songbirds/genetics ; Telomere Shortening/genetics ; Telomere/genetics ; Estonia ; Finland ; },
abstract = {Telomere length and shortening rate are increasingly being used as biomarkers for long-term costs in ecological and evolutionary studies because of their relationships with survival and fitness. Both early-life conditions and growth, and later-life stressors can create variation in telomere shortening rate. Studies on between-population telomere length and dynamics are scarce, despite the expectation that populations exposed to varying environmental constraints would present divergent telomere length patterns. The pied flycatcher (Ficedula hypoleuca) is a passerine bird breeding across Eurasia (from Spain to western Siberia) and migrating through the Iberian Peninsula to spend the nonbreeding period in sub-Saharan Africa. Thus, different populations show marked differences in migration distance. We studied the large-scale variation of telomere length and early-life dynamics in the pied flycatcher by comparing six European populations across a north-south gradient (Finland, Estonia, England and Spain) predicting a negative effect of migration distance on adult telomere length, and of nestling growth on nestling telomere dynamics. There were clear population differences in telomere length, with English birds from midlatitudes having the longest telomeres. Telomere length did not thus show consistent latitudinal variation and was not linearly linked to differences in migration distance. Early-life telomere shortening rate tended to vary between populations. Fast growth was associated with shorter telomeres in the early life, but faster nestling growth affected telomeres more negatively in northern than southern populations. While the sources of between-population differences in telomere-related biology remain to be more intensively studied, our study illustrates the need to expand telomere studies at the between-population level.},
}
@article {pmid34875050,
year = {2022},
author = {van der Spek, A and Karamujić-Čomić, H and Pool, R and Bot, M and Beekman, M and Garmaeva, S and Arp, PP and Henkelman, S and Liu, J and Alves, AC and Willemsen, G and van Grootheest, G and Aubert, G and , and Ikram, MA and Jarvelin, MR and Lansdorp, P and Uitterlinden, AG and Zhernakova, A and Slagboom, PE and Penninx, BWJH and Boomsma, DI and Amin, N and van Duijn, CM},
title = {Fat metabolism is associated with telomere length in six population-based studies.},
journal = {Human molecular genetics},
volume = {31},
number = {7},
pages = {1159-1170},
doi = {10.1093/hmg/ddab281},
pmid = {34875050},
issn = {1460-2083},
mesh = {Biomarkers/metabolism ; Cross-Sectional Studies ; Fatty Acids/metabolism ; Humans ; *Leukocytes/metabolism ; Lipids ; Telomere/genetics ; *Telomere Shortening ; },
abstract = {Telomeres are repetitive DNA sequences located at the end of chromosomes, which are associated to biological aging, cardiovascular disease, cancer and mortality. Lipid and fatty acid metabolism have been associated with telomere shortening. We have conducted an in-depth study investigating the association of metabolic biomarkers with telomere length (LTL). We performed an association analysis of 226 metabolic biomarkers with LTL using data from 11 775 individuals from six independent population-based cohorts (BBMRI-NL consortium). Metabolic biomarkers include lipoprotein lipids and subclasses, fatty acids, amino acids, glycolysis measures and ketone bodies. LTL was measured by quantitative polymerase chain reaction or FlowFISH. Linear regression analysis was performed adjusting for age, sex, lipid-lowering medication and cohort-specific covariates (model 1) and additionally for body mass index (BMI) and smoking (model 2), followed by inverse variance-weighted meta-analyses (significance threshold Pmeta = 6.5 × 10-4). We identified four metabolic biomarkers positively associated with LTL, including two cholesterol to lipid ratios in small VLDL (S-VLDL-C % and S-VLDL-CE %) and two omega-6 fatty acid ratios (FAw6/FA and LA/FA). After additionally adjusting for BMI and smoking, these metabolic biomarkers remained associated with LTL with similar effect estimates. In addition, cholesterol esters in very small VLDL (XS-VLDL-CE) became significantly associated with LTL (P = 3.6 × 10-4). We replicated the association of FAw6/FA with LTL in an independent dataset of 7845 individuals (P = 1.9 × 10-4). To conclude, we identified multiple metabolic biomarkers involved in lipid and fatty acid metabolism that may be involved in LTL biology. Longitudinal studies are needed to exclude reversed causation.},
}
@article {pmid34874050,
year = {2021},
author = {Hahn, MC and Werlang, ICR and Rechenmacher, C and Morais, RV and Barbé-Tuana, FM and Grun, LK and Guma, FTCR and Silva, CHD and Bernardi, JR and Michalowski, MB and Goldani, MZ},
title = {Telomere length in healthy newborns is not affected by adverse intrauterine environments.},
journal = {Genetics and molecular biology},
volume = {44},
number = {4},
pages = {e20200411},
pmid = {34874050},
issn = {1415-4757},
abstract = {Different intrauterine exposures are associated with different metabolic profiles leading to growth and development characteristics in children and also relate to health and disease patterns in adult life. The objective of this work was to evaluate the impact of four different intrauterine environments on the telomere length of newborns. This is a longitudinal observational study using a convenience sample of 222 mothers and their term newborns (>37 weeks of gestational age) from hospitals in Porto Alegre, Rio Grande do Sul (Brazil), from September 2011 to January 2016. Sample was divided into four groups: pregnant women with Gestational Diabetes Mellitus (DM) (n=38), smoking pregnant women (TOBACCO) (n=52), mothers with small-for-gestational age (SGA) children due to idiopathic intrauterine growth restriction (n=33), and a control group (n=99). Maternal and newborn genomic DNA were obtained from epithelial mucosal cells. Telomere length was assessed by qPCR, with the calculation of the telomere and single copy gene (T/S ratio). In this sample, there was no significant difference in telomere length between groups (p>0.05). There was also no association between childbirth weight and telomere length in children (p>0.05). For term newborns different intrauterine environments seems not to influence telomere length at birth.},
}
@article {pmid34873130,
year = {2022},
author = {da Silva, RS and de Moraes, LS and da Rocha, CAM and Ferreira-Fernandes, H and Yoshioka, FKN and Rey, JA and Pinto, GR and Burbano, RR},
title = {Telomere length and telomerase activity of leukocytes as biomarkers of selective serotonin reuptake inhibitor responses in patients with major depressive disorder.},
journal = {Psychiatric genetics},
volume = {32},
number = {1},
pages = {34-36},
doi = {10.1097/YPG.0000000000000305},
pmid = {34873130},
issn = {1473-5873},
mesh = {Biomarkers ; *Depressive Disorder, Major/drug therapy/genetics ; Humans ; Leukocytes/metabolism ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {We analyze the leukocyte telomere length (LTL) and telomerase activity in patients with major depressive disorder (MDD) before and after treatment with selective serotonin reuptake inhibitors (SSRIs). Before treatment, there was a reduction in the LTLs and expression levels of the human telomerase reverse transcriptase (hTERT) in the patients with MDD compared with controls. However, after 24 weeks of treatment with SSRIs, there was a significant increase in the LTLs and the expression levels of hTERT, with values approaching those observed in the controls. We conclude that SSRI antidepressant therapy can directly influence the increased expression levels of hTERT in patients.},
}
@article {pmid34869348,
year = {2021},
author = {De Rosa, M and Johnson, SA and Opresko, PL},
title = {Roles for the 8-Oxoguanine DNA Repair System in Protecting Telomeres From Oxidative Stress.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {758402},
pmid = {34869348},
issn = {2296-634X},
abstract = {Telomeres are protective nucleoprotein structures that cap linear chromosome ends and safeguard genome stability. Progressive telomere shortening at each somatic cell division eventually leads to critically short and dysfunctional telomeres, which can contribute to either cellular senescence and aging, or tumorigenesis. Human reproductive cells, some stem cells, and most cancer cells, express the enzyme telomerase to restore telomeric DNA. Numerous studies have shown that oxidative stress caused by excess reactive oxygen species is associated with accelerated telomere shortening and dysfunction. Telomeric repeat sequences are remarkably susceptible to oxidative damage and are preferred sites for the production of the mutagenic base lesion 8-oxoguanine, which can alter telomere length homeostasis and integrity. Therefore, knowledge of the repair pathways involved in the processing of 8-oxoguanine at telomeres is important for advancing understanding of the pathogenesis of degenerative diseases and cancer associated with telomere instability. The highly conserved guanine oxidation (GO) system involves three specialized enzymes that initiate distinct pathways to specifically mitigate the adverse effects of 8-oxoguanine. Here we introduce the GO system and review the studies focused on investigating how telomeric 8-oxoguanine processing affects telomere integrity and overall genome stability. We also discuss newly developed technologies that target oxidative damage selectively to telomeres to investigate roles for the GO system in telomere stability.},
}
@article {pmid34865259,
year = {2022},
author = {Tobler, M and Gómez-Blanco, D and Hegemann, A and Lapa, M and Neto, JM and Tarka, M and Xiong, Y and Hasselquist, D},
title = {Telomeres in ecology and evolution: A review and classification of hypotheses.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {5946-5965},
doi = {10.1111/mec.16308},
pmid = {34865259},
issn = {1365-294X},
mesh = {*Telomere Shortening/genetics ; Ecology ; Telomere/genetics ; *Life History Traits ; },
abstract = {Research on telomeres in the fields of ecology and evolution has been rapidly expanding over the last two decades. This has resulted in the formulation of a multitude of, often name-given, hypotheses related to the associations between telomeres and life-history traits or fitness-facilitating processes (and the mechanisms underlying them). However, the differences (or similarities) between the various hypotheses, which can originate from different research fields, are often not obvious. Our aim here is therefore to give an overview of the hypotheses that are of interest in ecology and evolution and to provide two frameworks that help discriminate among them. We group the hypotheses (i) based on their association with different research questions, and (ii) using a hierarchical approach that builds on the assumptions they make, such as about causality of telomere length/shortening and/or the proposed functional consequences of telomere shortening on organism performance. Both our frameworks show that there exist parallel lines of thoughts in different research fields. Moreover, they also clearly illustrate that there are in many cases competing hypotheses within clusters, and that some of these even have contradictory assumptions and/or predictions. We also touch upon two topics in telomere research that would benefit from further conceptualization. This review should help researchers, both those familiar with and those new to the subject, to identify future avenues of research.},
}
@article {pmid34859008,
year = {2021},
author = {Zhang, K and Xu, L and Cong, YS},
title = {Telomere Dysfunction in Idiopathic Pulmonary Fibrosis.},
journal = {Frontiers in medicine},
volume = {8},
number = {},
pages = {739810},
pmid = {34859008},
issn = {2296-858X},
abstract = {Idiopathic pulmonary fibrosis is an age-dependent progressive and fatal lung disease of unknown etiology, which is characterized by the excessive accumulation of extracellular matrix inside the interstitial layer of the lung parenchyma that leads to abnormal scar architecture and compromised lung function capacity. Recent genetic studies have attributed the pathological genes or genetic mutations associated with familial idiopathic pulmonary fibrosis (IPF) and sporadic IPF to telomere-related components, suggesting that telomere dysfunction is an important determinant of this disease. In this study, we summarized recent advances in our understanding of how telomere dysfunction drives IPF genesis. We highlighted the key role of alveolar stem cell dysfunction caused by telomere shortening or telomere uncapping, which bridged the gap between telomere abnormalities and fibrotic lung pathology. We emphasized that senescence-associated secretory phenotypes, innate immune cell infiltration, and/or inflammation downstream of lung stem cell dysfunction influenced the native microenvironment and local cell signals, including increased transforming growth factor-beta (TGF-β) signaling in the lung, to induce pro-fibrotic conditions. In addition, the failed regeneration of new alveoli due to alveolar stem cell dysfunction might expose lung cells to elevated mechanical tension, which could activate the TGF-β signaling loop to promote the fibrotic process, especially in a periphery-to-center pattern as seen in IPF patients. Understanding the telomere-related molecular and pathophysiological mechanisms of IPF would provide new insights into IPF etiology and therapeutic strategies for this fatal disease.},
}
@article {pmid34857839,
year = {2021},
author = {Dratwa, M and Wysoczańska, B and Butrym, A and Łacina, P and Mazur, G and Bogunia-Kubik, K},
title = {TERT genetic variability and telomere length as factors affecting survival and risk in acute myeloid leukaemia.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {23301},
pmid = {34857839},
issn = {2045-2322},
mesh = {Age Factors ; Female ; *Genetic Association Studies ; Humans ; Leukemia, Myeloid, Acute/*genetics/mortality ; Leukocyte Count ; Male ; Middle Aged ; Nucleophosmin/genetics ; Polymorphism, Genetic/*genetics ; Risk ; Survival Rate ; Telomerase/*genetics ; Telomere Homeostasis/*genetics ; fms-Like Tyrosine Kinase 3/genetics ; },
abstract = {Acute myeloid leukaemia (AML) is a neoplasm of immature myeloid cells characterized by various cytogenetic alterations. The present study showed that in addition to the FLT3-ITD and NPM1 mutation status, telomere length (TL) and telomerase reverse transcriptase (TERT) gene polymorphisms may affect risk and overall survival (OS) in AML. TL was longer in healthy controls than in AML patients and positively correlated with age in the patients, but not in healthy subjects. TL was found to be independently affected by the presence of the FLT3-ITD mutation. As for the TERT gene polymorphism, AML patients with the TERT rs2853669 CC genotype were characterized by significantly shorter OS than patients carrying the T allele. Another observation in our study is the difference in TL and OS in patients belonging to various risk stratification groups related to the FLT3-ITD and NPM1 mutation status. Patients with adverse risk classification (mutation in FLT3-ITD and lack of mutation in NPM1) presented with the shortest telomeres and significantly worse OS. In conclusion, OS of AML patients appears to be affected by TERT gene variability and TL in addition to other well-established factors such as age, WBC count, or FLT3-ITD and NPM1 mutation status.},
}
@article {pmid34857525,
year = {2021},
author = {Mackintosh, JA and Pietsch, M and Lutzky, V and Enever, D and Bancroft, S and Apte, SH and Tan, M and Yerkovich, ST and Dickinson, JL and Pickett, HA and Selvadurai, H and Grainge, C and Goh, NS and Hopkins, P and Glaspole, I and Reynolds, PN and Wrobel, J and Jaffe, A and Corte, TJ and Chambers, DC},
title = {TELO-SCOPE study: a randomised, double-blind, placebo-controlled, phase 2 trial of danazol for short telomere related pulmonary fibrosis.},
journal = {BMJ open respiratory research},
volume = {8},
number = {1},
pages = {},
pmid = {34857525},
issn = {2052-4439},
mesh = {Australia ; *COVID-19 ; Child ; Danazol/therapeutic use ; Humans ; *Pulmonary Fibrosis ; Telomere/genetics ; Treatment Outcome ; },
abstract = {INTRODUCTION: Recent discoveries have identified shortened telomeres and related mutations in people with pulmonary fibrosis (PF). There is evidence to suggest that androgens, including danazol, may be effective in lengthening telomeres in peripheral blood cells. This study aims to assess the safety and efficacy of danazol in adults and children with PF associated with telomere shortening.<br><br>METHODS AND ANALYSIS: A multi-centre, double-blind, placebo-controlled, randomised trial of danazol will be conducted in subjects aged >5 years with PF associated with age-adjusted telomere length &#x2264;10th centile measured by flow fluorescence in situ hybridisation; or in children, a diagnosis of dyskeratosis congenita. Adult participants will receive danazol 800&#x2009;mg daily in two divided doses or identical placebo capsules orally for 12 months, in addition to standard of care (including pirfenidone or nintedanib). Paediatric participants will receive danazol 2&#x2009;mg/kg/day orally in two divided doses or identical placebo for 6 months. If no side effects are encountered, the dose will be escalated to 4&#x2009;mg/kg/day (maximum 800&#x2009;mg daily) orally in two divided doses for a further 6 months. The primary outcome is change in absolute telomere length in base pairs, measured using the telomere shortest length assay (TeSLA), at 12 months in the intention to treat population.<br><br>ETHICS AND DISSEMINATION: Ethics approval has been granted in Australia by the Metro South Human Research Ethics Committee (HREC/2020/QMS/66385). The study will be conducted and reported according to Standard Protocol Items: Recommendations for Interventional Trials guidelines. Results will be published in peer-reviewed journals and presented at international and national conferences.<br><br>TRIAL REGISTRATION NUMBERS: NCT04638517; Australian New Zealand Clinical Trials Registry (ACTRN12620001363976p).},
}
@article {pmid34856024,
year = {2022},
author = {Choi, B and Messika, J and Courtwright, A and Mornex, JF and Hirschi, S and Roux, A and Le Pavec, J and Quêtant, S and Froidure, A and Lazor, R and Reynaud-Gaubert, M and Borgne, AL and Houlbracq, MP and Goldberg, H and El-Chemaly, S and Borie, R and , },
title = {Airway complications in lung transplant recipients with telomere-related interstitial lung disease.},
journal = {Clinical transplantation},
volume = {36},
number = {3},
pages = {e14552},
doi = {10.1111/ctr.14552},
pmid = {34856024},
issn = {1399-0012},
support = {R01-HL130272/NH/NIH HHS/United States ; },
mesh = {Constriction, Pathologic/complications ; Female ; Humans ; Lung ; *Lung Diseases, Interstitial/genetics/surgery ; *Lung Transplantation/adverse effects ; Retrospective Studies ; Telomere/genetics ; Transplant Recipients ; },
abstract = {INTRODUCTION: Patients with short telomere-related interstitial lung disease (ILD) have worse outcomes after lung transplantation. We hypothesized that post-transplant airway complications, including dehiscence and bronchial stenosis, would be more common in the short telomere ILD lung transplant population.<br><br>METHODS: We conducted a multi-institutional (Brigham and Women's Hospital, Groupe de Transplantation de la SPLF) retrospective cohort study of 63 recipients between 2009 and 2019 with ILD and short telomeres, compared to 4359 recipients from the Scientific Registry of Transplant Recipients with ILD and no known telomeropathy.<br><br>RESULTS: In the short telomere cohort, six recipients (9.5%) developed dehiscence and nine recipients (14.3%) developed stenosis, compared to 60 (1.4%) and 149 (3.4%) in the control, respectively. After adjusting for age, sex, and bilaterality, the presence of short telomeres was associated with higher odds of dehiscence (odds ratio (OR)&#xa0;=&#xa0;8.24, 95% confidence interval (CI)&#xa0;=&#xa0;3.34 20.29, p&#xa0;<&#xa0;.001) and stenosis (OR&#xa0;=&#xa0;4.63, 95% CI 2.21 9.69, p&#xa0;<&#xa0;.001).<br><br>CONCLUSION: The association between the presence of short telomeres and post-transplant dehiscence and stenosis suggest that airway complications may be a contributor to increased morbidity and mortality in patients with telomere-related ILD.},
}
@article {pmid34854526,
year = {2022},
author = {Sepe, S and Rossiello, F and Cancila, V and Iannelli, F and Matti, V and Cicio, G and Cabrini, M and Marinelli, E and Alabi, BR and di Lillo, A and Di Napoli, A and Shay, JW and Tripodo, C and d'Adda di Fagagna, F},
title = {DNA damage response at telomeres boosts the transcription of SARS-CoV-2 receptor ACE2 during aging.},
journal = {EMBO reports},
volume = {23},
number = {2},
pages = {e53658},
pmid = {34854526},
issn = {1469-3178},
support = {//Fondazione Umberto Veronesi (Umberto Veronesi Foundation)/ ; 835103//EC|H2020|H2020 Priority Excellent Science|H2020 European Research Council (ERC)/ ; 875139//EC|H2020|H2020 Priority Excellent Science|H2020 European Research Council (ERC)/ ; 21091//Associazione Italiana per la Ricerca sul Cancro (AIRC)/ ; P50 CA070907/CA/NCI NIH HHS/United States ; //Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (AriSLA)/ ; GGP17111//Fondazione Telethon (Telethon Foundation)/ ; 21762//Associazione Italiana per la Ricerca sul Cancro (AIRC)/ ; },
mesh = {Aged ; *Aging/genetics ; Angiotensin-Converting Enzyme 2/*genetics ; Animals ; *COVID-19 ; *DNA Damage ; Humans ; Mice ; SARS-CoV-2 ; *Telomere/genetics ; },
abstract = {The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19), known to be more common in the elderly, who also show more severe symptoms and are at higher risk of hospitalization and death. Here, we show that the expression of the angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 cell receptor, increases during aging in mouse and human lungs. ACE2 expression increases upon telomere shortening or dysfunction in both cultured mammalian cells and in vivo in mice. This increase is controlled at the transcriptional level, and Ace2 promoter activity is DNA damage response (DDR)-dependent. Both pharmacological global DDR inhibition of ATM kinase activity and selective telomeric DDR inhibition by the use of antisense oligonucleotides prevent Ace2 upregulation following telomere damage in cultured cells and in mice. We propose that during aging telomere dysfunction due to telomeric shortening or damage triggers DDR activation and this causes the upregulation of ACE2, the SARS-CoV-2 cell receptor, thus contributing to make the elderly more susceptible to the infection.},
}
@article {pmid34854357,
year = {2022},
author = {Huang, YC and Lin, PY and Lee, Y and Lee, CY and Lo, YC and Hung, CF and Chen, CS},
title = {Metabolic syndrome components and leukocyte telomere length in patients with major depressive disorder.},
journal = {The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry},
volume = {23},
number = {6},
pages = {483-492},
doi = {10.1080/15622975.2021.2013091},
pmid = {34854357},
issn = {1814-1412},
mesh = {Humans ; Female ; Adult ; Male ; *Metabolic Syndrome/genetics/epidemiology ; *Depressive Disorder, Major/genetics/metabolism ; Prospective Studies ; Leukocytes/metabolism ; Telomere ; },
abstract = {OBJECTIVES: The relationship between metabolic syndrome (MetS) components and leukocyte telomere length (LTL) attrition in major depressive disorder (MDD) remains unclear.<br><br>METHODS: We recruited 70 MDD patients (mean age: 44.6&#x2009;years, 60.0% female) and 51 age- and sex-matched controls (mean age: 41.2&#x2009;years, 68.6% female) to examine the associations of MetS components and LTL. Five MetS components-waist circumference, systolic/diastolic blood pressure, serum levels of fasting glucose, high-density lipoprotein cholesterol (HDL-C), and triglycerides-were assessed. LTL was measured through quantitative polymerase chain reaction.<br><br>RESULTS: MDD had higher prevalence of MetS (34.3 vs. 17.6%, p=.042), low HDL-C (25.7 vs. 7.8%, p=.009) and shorter LTL (-0.038&#x2009;&#xb1;&#x2009;0.169 vs. 0.033&#x2009;&#xb1;&#x2009;0.213, p=.042). Regression analysis revealed that MDD (p=.046) and age (p=.003) associated with LTL, while a significant interaction effect of group (MDD vs. controls) &#xd7; HDL-C (p=.037) was observed. Post-hoc analysis showed MDD with low HDL-C had greater LTL attrition than controls without low HDL-C (p=.020). In MDD, HDL-C dysregulation negatively correlated with LTL (p=.010); but no significance after Bonferroni correction.<br><br>CONCLUSIONS: HDL-C may be involved in accelerated ageing process regarding metabolic disturbance in MDD only. The relationship merits prospective investigations with larger sample size for clarification.},
}
@article {pmid34853825,
year = {2021},
author = {Estrada, N and Xicoy, B and Beier, F and Garcia, O and Morales, C and Boqué, C and Sagüés, M and Ventura Ferreira, MS and Vallansot, R and Marcé, S and Cabezón, M and Brümmendorf, TH and Zamora, L},
title = {Influence of Telomere Length on the Achievement of Deep Molecular Response With Imatinib in Chronic Myeloid Leukemia Patients.},
journal = {HemaSphere},
volume = {5},
number = {12},
pages = {e657},
pmid = {34853825},
issn = {2572-9241},
abstract = {Tyrosine kinase inhibitors have dramatically changed the outcome of chronic myeloid leukemia (CML), and nowadays, one of the main treatment goals is the achievement of deep molecular responses (DMRs), which can eventually lead to therapy discontinuation approaches. Few biological factors at diagnosis have been associated with this level of response. Telomere length (TL) in peripheral blood cells of patients with CML has been related to disease stage, response to therapy and disease progression, but little is known about its role on DMR. In this study, we analyzed if age-adjusted TL (referred as "delta-TL") at diagnosis of chronic phase (CP)-CML might correlate with the achievement of DMR under first-line imatinib treatment. TL from 96 CP-CML patients had been retrospectively analyzed at diagnosis by monochrome multiplex quantitative PCR. We observed that patients with longer age-adjusted telomeres at diagnosis had higher probabilities to achieve DMR with imatinib than those with shortened telomeres (P = 0.035 when delta-TL was studied as a continuous variable and P = 0.047 when categorized by the median). Moreover, patients carrying long telomeres also achieved major molecular response significantly earlier (P = 0.012). This study provides proof of concept that TL has a role in CML biology and when measured at diagnosis of CP-CML could help to identify patients likely to achieve DMR to first-line imatinib treatment.},
}
@article {pmid34852175,
year = {2022},
author = {Niewisch, MR and Giri, N and McReynolds, LJ and Alsaggaf, R and Bhala, S and Alter, BP and Savage, SA},
title = {Disease progression and clinical outcomes in telomere biology disorders.},
journal = {Blood},
volume = {139},
number = {12},
pages = {1807-1819},
pmid = {34852175},
issn = {1528-0020},
support = {ZIA CP010190/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Biology ; Disease Progression ; *Dyskeratosis Congenita/genetics/therapy ; Humans ; Male ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; Telomere Shortening ; },
abstract = {Dyskeratosis congenita related telomere biology disorders (DC/TBDs) are characterized by very short telomeres caused by germline pathogenic variants in telomere biology genes. Clinical presentations can affect all organs, and inheritance patterns include autosomal dominant (AD), autosomal recessive (AR), X-linked (XLR), or de novo. This study examined the associations between mode of inheritance with phenotypes and long-term clinical outcomes. Two hundred thirty-one individuals with DC/TBDs (144 male, 86.6% known genotype, median age at diagnosis 19.4 years [range 0 to 71.6]), enrolled in the National Cancer Institute's Inherited Bone Marrow Failure Syndrome Study, underwent detailed clinical assessments and longitudinal follow-up (median follow-up 5.2 years [range 0 to 36.7]). Patients were grouped by inheritance pattern, considering AD-nonTINF2, AR/XLR, and TINF2 variants separately. Severe bone marrow failure (BMF), severe liver disease, and gastrointestinal telangiectasias were more prevalent in AR/XLR or TINF2 disease, whereas pulmonary fibrosis developed predominantly in adults with AD disease. After adjusting for age at DC/TBD diagnosis, we observed the highest cancer risk in AR/XLR individuals. At last follow-up, 42% of patients were deceased with a median overall survival (OS) of 52.8 years (95% confidence interval [CI] 45.5-57.6), and the hematopoietic cell or solid organ transplant-free median survival was 45.3 years (95% CI 37.4-52.1). Significantly better OS was present in AD vs AR/XLR/TINF2 disease (P < .01), while patients with AR/XLR and TINF2 disease had similar survival probabilities. This long-term study of the clinical manifestations of DC/TBDs creates a foundation for incorporating the mode of inheritance into evidence-based clinical care guidelines and risk stratification in patients with DC/TBDs. This trial was registered at www.clinicaltrials.gov as #NCT00027274.},
}
@article {pmid34850488,
year = {2022},
author = {Sheldon, EL and Eastwood, JR and Teunissen, N and Roast, MJ and Aranzamendi, NH and Fan, M and Louise Hall, M and Kingma, SA and Verhulst, S and Peters, A},
title = {Telomere dynamics in the first year of life, but not later in life, predict lifespan in a wild bird.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6008-6017},
doi = {10.1111/mec.16296},
pmid = {34850488},
issn = {1365-294X},
mesh = {Animals ; Animals, Wild/genetics ; *Longevity/genetics ; Longitudinal Studies ; *Songbirds/genetics ; Telomere/genetics ; Telomere Shortening/genetics ; },
abstract = {Telomeres are protective, nucleoprotein structures at the end of chromosomes that have been associated with lifespan across taxa. However, the extent to which these associations can be attributed to absolute length vs. the rate of telomere shortening prior to sampling remains unresolved. In a longitudinal study, we examined the relationship between lifespan, telomere length and the rate of telomere shortening in wild, purple-crowned fairy-wrens (Malurus coronatus coronatus). To this end, we measured telomere length using quantitative polymerase chain reaction in the blood of 59 individuals sampled as nestlings and 4-14 months thereafter, and in 141 known-age individuals sampled on average three times across adulthood. We applied within-subject centring analyses to simultaneously test for associations between lifespan and average telomere length and telomere shortening. We reveal that the rate of telomere shortening and to a lesser extent telomere length in the first year of life independently predicted lifespan, with individuals with faster shortening rates and/or shorter telomeres living less long. In contrast, in adulthood neither telomere shortening nor telomere length predicted lifespan, despite a considerably larger data set. Our results suggest that telomere length measured very early in life (during development) and longitudinal assessments of telomere shortening during the first year of life constitute more useful biomarkers of total life expectancy than either telomere length measured after development, or telomere shortening later in adulthood.},
}
@article {pmid34849882,
year = {2021},
author = {Watson, JM and Trieb, J and Troestl, M and Renfrew, K and Mandakova, T and Fulnecek, J and Shippen, DE and Riha, K},
title = {A hypomorphic allele of telomerase uncovers the minimal functional length of telomeres in Arabidopsis.},
journal = {Genetics},
volume = {219},
number = {2},
pages = {},
pmid = {34849882},
issn = {1943-2631},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; R01-GM065383/NH/NIH HHS/United States ; },
mesh = {Arabidopsis ; Arabidopsis Proteins/genetics/*metabolism ; Mutation ; Telomerase/genetics/*metabolism ; Telomere/genetics ; *Telomere Homeostasis ; },
abstract = {Despite the essential requirement of telomeric DNA for genome stability, the length of telomere tracts between species substantially differs, raising the question of the minimal length of telomeric DNA necessary for proper function. Here, we address this question using a hypomorphic allele of the telomerase catalytic subunit, TERT. We show that although this construct partially restored telomerase activity to a tert mutant, telomeres continued to shorten over several generations, ultimately stabilizing at a bimodal size distribution. Telomeres on two chromosome arms were maintained at a length of 1 kb, while the remaining telomeres were maintained at 400 bp. The longest telomeres identified in this background were also significantly longer in wild-type populations, suggesting cis-acting elements on these arms either promote telomerase processivity or recruitment. Genetically disrupting telomerase processivity in this background resulted in immediate lethality. Thus, telomeres of 400 bp are both necessary and sufficient for Arabidopsis viability. As this length is the estimated minimal length for t-loop formation, our data suggest that telomeres long enough to form a t-loop constitute the minimal functional length.},
}
@article {pmid34848322,
year = {2022},
author = {Mahmoodpoor, A and Sanaie, S and Roudbari, F and Sabzevari, T and Sohrabifar, N and Kazeminasab, S},
title = {Understanding the role of telomere attrition and epigenetic signatures in COVID-19 severity.},
journal = {Gene},
volume = {811},
number = {},
pages = {146069},
pmid = {34848322},
issn = {1879-0038},
mesh = {COVID-19/*genetics/*immunology/*metabolism/virology ; DNA Methylation ; *Epigenesis, Genetic ; *Epigenomics ; Genetic Predisposition to Disease ; Humans ; Immunity ; MicroRNAs/metabolism ; SARS-CoV-2/immunology ; *Severity of Illness Index ; Telomere/*genetics ; },
abstract = {Within the past several decades, the emergence and spread of infectious diseases with pandemic potential have endangered human lives. Coronavirus disease 2019 (COVID-19) outbreak represents an unprecedented threat for all health systems worldwide. The clinical spectrum of COVID-19 is highly heterogeneous, ranging from asymptomatic and mild upper respiratory tract illness to severe interstitial pneumonia with respiratory failure and even death. Highly age-dependent patterns of immune response potentially explain the higher rates of the severe forms of COVID-19 in elderly patients. However, genetic and epigenetic architecture can influence multiple biological processes during the lifespan, therefore as far as our knowledge shows, vulnerability to viral infection concerning telomere length and epigenetic signature is not a new idea. This review aims is to summarize the current understanding of the role of telomere length and epigenetic mechanisms on the severity of COVID-19. The current knowledge highlights the significant association between the shorter telomere length and the higher risk of developing severe COVID-19. Differential DNA methylation patterns and miRNA expression profiles imply that these hallmarks can play a pivotal role in COVID- 19 pathogenesis. Understanding the causes of inter-individual variations in COVID-19 outcomes could provide clues to the development of the personalized therapeutic intervention.},
}
@article {pmid34845136,
year = {2022},
author = {Panelli, DM and Bianco, K},
title = {Cellular aging and telomere dynamics in pregnancy.},
journal = {Current opinion in obstetrics &amp; gynecology},
volume = {34},
number = {2},
pages = {57-61},
doi = {10.1097/GCO.0000000000000765},
pmid = {34845136},
issn = {1473-656X},
support = {K12 HD103084/HD/NICHD NIH HHS/United States ; },
mesh = {Cellular Senescence/genetics ; Female ; Humans ; Infant, Newborn ; Parturition ; *Placenta ; Pregnancy ; *Telomere ; Telomere Shortening ; },
abstract = {PURPOSE OF REVIEW: Telomere biology is an emerging area of scientific interest. Telomeres are deoxynucleic acid caps at the ends of chromosomes that naturally shorten over one's lifespan; because of this, short telomeres have been studied as a marker of cellular aging. Given the association between short telomeres and genetic and environmental factors, their role in pregnancy has become an intriguing area of research.<br><br>RECENT FINDINGS: This review describes recent data on telomeres in pregnancy. Specifically, we discuss the association between short maternal leukocyte telomeres and poor nutritional status, between short neonatal telomeres and greater maternal psychosocial stress, and between shorter fetal amniotic membrane telomeres and the spontaneous onset of parturition. We also review recent studies suggesting that events during pregnancy can impact telomeres in the offspring years into the future.<br><br>SUMMARY: Telomere length varies in maternal, placental, and neonatal cells, but within each of these compartments telomeres may play their own distinct role during pregnancy. Whether telomeres are reflective of the cumulative impact of stressors, or part of an as-yet unknown fetal programming mechanism is an area of interest. With future research, we may work toward a better understanding of gestational biology which could have far reaching intergenerational impacts.},
}
@article {pmid34845112,
year = {2021},
author = {Guerrero, EN and Vega, S and Fu, C and De León, R and Beltran, D and Solis, MA},
title = {Increased proliferation and differentiation capacity of placenta-derived mesenchymal stem cells from women of median maternal age correlates with telomere shortening.},
journal = {Aging},
volume = {13},
number = {22},
pages = {24542-24559},
pmid = {34845112},
issn = {1945-4589},
mesh = {Adolescent ; Adult ; Cell Differentiation/*physiology ; Cell Proliferation/physiology ; Female ; Humans ; *Maternal Age ; Mesenchymal Stem Cells/*physiology ; Placenta/*cytology ; Pregnancy ; Telomere Shortening/*physiology ; Young Adult ; },
abstract = {Mesenchymal stem cells (MSCs) experience functional decline with systemic aging, resulting in reduced proliferation, increased senescence, and lower differentiation potential. The placenta represents a valuable source of MSCs, but the possible effect of donor age on the properties of placenta-derived mesenchymal stem cells (PDMSCs) has not been thoroughly studied. Thus, the aim of this study was to underscore the effect of maternal age on the biological characteristics and stemness properties of PDMSCs. PDMSCs were isolated from 5 donor age groups (A: 18-21, B: 22-25, C: 26-30, D:31-35 and E: ≥36 years) for comparison of morphological, proliferative and differentiation properties. The pluripotency markers NANOG, OCT4, and SSEA4, as well as multipotency and differentiation markers, showed higher expression in PDMSCs from mothers aged 22-35 years, with up to a 7-fold increase in adipogenesis. Cumulative population doubling, cell growth curves, and colony-forming unit-fibroblast assays revealed higher self-renewal ability in donors 26-30 years old. An increase in the proliferative characteristics of PDMSCs correlated with increased telomere shortening, suggesting that shorter telomere lengths could be related to cellular division rather than aging. A clear understanding of the effect of maternal age on MSC regenerative potential will assist in increasing the effectiveness of future cell therapies.},
}
@article {pmid34842724,
year = {2021},
author = {Anifandis, G and Samara, M and Simopoulou, M and Messini, CI and Chatzimeletiou, K and Thodou, E and Daponte, A and Georgiou, I},
title = {Insights into the Role of Telomeres in Human Embryological Parameters. Opinions Regarding IVF.},
journal = {Journal of developmental biology},
volume = {9},
number = {4},
pages = {},
pmid = {34842724},
issn = {2221-3759},
abstract = {Telomeres promote genome integrity by protecting chromosome ends from the activation of the DNA damage response and protecting chromosomes from the loss of coding sequences due to the end replication problem. Telomere length (TL) is progressively shortened as age progresses, thus resulting in cellular senescence. Therefore, TL is in strong adverse linear correlation with aging. Mounting evidence supports the notion that telomeres and male/female infertility are in a close relationship, posing the biology of telomeres as a hot topic in the era of human-assisted reproduction. Specifically, the length of sperm telomeres is gradually increasing as men get older, while the telomere length of the oocytes seems not to follow similar patterns with that of sperm. Nonetheless, the telomere length of the embryos during the cleavage stages seems to have a paternal origin, but the telomere length can be further extended by telomerase activity during the blastocyst stage. The latter has been proposed as a new molecular biomarker with strong predictive value regarding male infertility. As far as the role of telomeres in assisted reproduction, the data is limited but the length of telomeres in both gametes seems to be affected mainly by the cause of infertility rather than the assisted reproductive therapy (ART) procedure itself. The present review aims to shed more light into the role of telomeres in human embryological parameters, including gametes and embryos and also presents opinions regarding the association between telomeres and in vitro fertilization (IVF).},
}
@article {pmid34834452,
year = {2021},
author = {Pisanu, C and Vitali, E and Meloni, A and Congiu, D and Severino, G and Ardau, R and Chillotti, C and Trabucchi, L and Bortolomasi, M and Gennarelli, M and Minelli, A and Squassina, A},
title = {Investigating the Role of Leukocyte Telomere Length in Treatment-Resistant Depression and in Response to Electroconvulsive Therapy.},
journal = {Journal of personalized medicine},
volume = {11},
number = {11},
pages = {},
pmid = {34834452},
issn = {2075-4426},
support = {Year 2019 and 2020//Fondo integrativo per la ricerca (Fir)/ ; RASSR57271//Autonomous Region of Sardinia ("Legge Regionale 7 agosto 2007, n. 7 - call 2017")/ ; P.O.R. Sardegna F.S.E. - Operational Programme of the Autonomous Region of Sardinia, European Social Fund 2014-2020//Sardinian Regional Government/ ; },
abstract = {Psychiatric disorders seem to be characterized by premature cell senescence. However, controversial results have also been reported. In addition, the relationship between accelerated aging and treatment-resistance has scarcely been investigated. In the current study, we measured leukocyte telomere length (LTL) in 148 patients with treatment-resistant depression (TRD, 125 with major depressive disorder, MDD, and 23 with bipolar disorder, BD) treated with electroconvulsive therapy (ECT) and analyzed whether LTL was associated with different response profiles. We also compared LTL between patients with TRD and 335 non-psychiatric controls. For 107 patients for which genome-wide association data were available, we evaluated whether a significant overlap among genetic variants or genes associated with LTL and with response to ECT could be observed. LTL was negatively correlated with age (Spearman's correlation coefficient = -0.25, p < 0.0001) and significantly shorter in patients with treatment-resistant MDD (Quade's F = 35.18, p < 0.0001) or BD (Quade's F = 20.84, p < 0.0001) compared to controls. Conversely, baseline LTL was not associated with response to ECT or remission. We did not detect any significant overlap between genetic variants or genes associated with LTL and response to ECT. Our results support previous findings suggesting premature cell senescence in patients with severe psychiatric disorders and suggest that LTL could not be a predictive biomarker of response to ECT.},
}
@article {pmid34831418,
year = {2021},
author = {Assis, LHC and Andrade-Silva, D and Shiburah, ME and de Oliveira, BCD and Paiva, SC and Abuchery, BE and Ferri, YG and Fontes, VS and de Oliveira, LS and da Silva, MS and Cano, MIN},
title = {Cell Cycle, Telomeres, and Telomerase in Leishmania spp.: What Do We Know So Far?.},
journal = {Cells},
volume = {10},
number = {11},
pages = {},
pmid = {34831418},
issn = {2073-4409},
support = {2018/04375-2 (MICANO) and 2019/10753-2 and 2020/10277-3 (MSdS)//S&#xe3;o Paulo Research Foundation/ ; 2021/04253-7 (LHCA), 2021/05523-8 (DAS), 2019/25985-6 (BCDO), 2020/00316-1 (MES), 2020/16480-5 (BEA), 2020/16465-6 (YGF), 2020/08162-3 (VSF)//S&#xe3;o Paulo Research Foundation/ ; SCP//Coordena&#xe7;&#xe3;o de Aperfeicoamento de Pessoal de N&#xed;vel Superior/ ; },
mesh = {*Cell Cycle ; Humans ; Leishmania/*cytology/*enzymology ; Models, Biological ; Phylogeny ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Leishmaniases belong to the inglorious group of neglected tropical diseases, presenting different degrees of manifestations severity. It is caused by the transmission of more than 20 species of parasites of the Leishmania genus. Nevertheless, the disease remains on the priority list for developing new treatments, since it affects millions in a vast geographical area, especially low-income people. Molecular biology studies are pioneers in parasitic research with the aim of discovering potential targets for drug development. Among them are the telomeres, DNA-protein structures that play an important role in the long term in cell cycle/survival. Telomeres are the physical ends of eukaryotic chromosomes. Due to their multiple interactions with different proteins that confer a likewise complex dynamic, they have emerged as objects of interest in many medical studies, including studies on leishmaniases. This review aims to gather information and elucidate what we know about the phenomena behind Leishmania spp. telomere maintenance and how it impacts the parasite's cell cycle.},
}
@article {pmid34830418,
year = {2021},
author = {Turkiewicz, S and Ditmer, M and Sochal, M and Białasiewicz, P and Strzelecki, D and Gabryelska, A},
title = {Obstructive Sleep Apnea as an Acceleration Trigger of Cellular Senescence Processes through Telomere Shortening.},
journal = {International journal of molecular sciences},
volume = {22},
number = {22},
pages = {},
pmid = {34830418},
issn = {1422-0067},
support = {564/5-000-00/564-20-054//Medical University of Lodz/ ; },
mesh = {Aging/genetics ; Cellular Senescence/*genetics/physiology ; Humans ; Leukocytes/metabolism ; Oxidative Stress/genetics ; Sleep Apnea, Obstructive/*genetics/pathology ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Obstructive sleep apnea (OSA) is chronic disorder which is characterized by recurrent pauses of breathing during sleep which leads to hypoxia and its two main pathological sequelae: oxidative stress and chronic inflammation. Both are also associated with cellular senescence. As OSA patients present with higher prevalence of age-related disorders, such as atrial hypertension or diabetes mellitus type 2, a relationship between OSA and accelerated aging is observable. Furthermore, it has been established that these OSA are associated with telomere shortening. This process in OSA is likely caused by increased oxidative DNA damage due to increased reactive oxygen species levels, DNA repair disruptions, hypoxia, chronic inflammation, and circadian clock disturbances. The aim of the review is to summarize study outcomes on changes in leukocyte telomere length (LTL) in OSA patients and describe possible molecular mechanisms which connect cellular senescence and the pathophysiology of OSA. The majority of OSA patients are characterized by LTL attrition due to oxidative stress, hypoxia and inflammation, which make a kind of positive feedback loop, and circadian clock disturbance.},
}
@article {pmid34829621,
year = {2021},
author = {Tarazón, E and Pérez-Carrillo, L and Giménez-Escamilla, I and Ramos-Castellanos, P and Martínez-Dolz, L and Portolés, M and Roselló-Lletí, E},
title = {Relationships of Telomere Homeostasis with Oxidative Stress and Cardiac Dysfunction in Human Ischaemic Hearts.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {10},
number = {11},
pages = {},
pmid = {34829621},
issn = {2076-3921},
support = {PI20/01469, PI20/00071, CP18/00145//Instituto de Salud Carlos III/ ; CB16/11/00261//Centro de Investigaci&#xf3;n en Red en Enfermedades Cardiovasculares/ ; ERDF, "A way to make Europe"//European Union/ ; },
abstract = {Although the roles of telomeres and oxidative stress in ischaemic cardiomyopathy (ICM) are known, mechanisms of telomere homeostasis and their relationship with oxidative stress are incompletely understood. We performed two RNA-seq analyses (mRNA n = 23; ncRNA n = 30) and protein validation on left ventricles of explanted hearts from ICM and control subjects. We observed dysregulation of the shelterin and cohesin complexes, which was related to an increase in the response to cellular oxidative stress. Moreover, we found alterations at mRNA level in the mechanisms of telomeric DNA repair. Specifically, increased RAD51D mRNA levels were correlated with left ventricular diameters. RAD51D protein levels were unaltered, however, and were inversely corelated with the miR-103a-3p upregulation. We also observed the overexpression of lncRNAs (TERRA and GUARDIN) involved in telomere protection in response to stress and alterations in their regulatory molecules. Expression of the TERRA transcription factor ATF7 was correlated with superoxide dismutase 1 expression and left ventricular diameters. The levels of GUARDIN and its transcription factor FOSL2 were correlated with those of catalase. Therefore, we showed specific alterations in the mechanisms of telomeric DNA repair and protection, and these alterations are related to an increase in the response mechanisms to oxidative stress and cardiac dysfunction in ICM.},
}
@article {pmid34828344,
year = {2021},
author = {Kent, T and Clynes, D},
title = {Alternative Lengthening of Telomeres: Lessons to Be Learned from Telomeric DNA Double-Strand Break Repair.},
journal = {Genes},
volume = {12},
number = {11},
pages = {},
pmid = {34828344},
issn = {2073-4425},
support = {MC_UU_12009/3/MRC_/Medical Research Council/United Kingdom ; MC_UU_12025/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Cell Cycle ; DNA/metabolism ; *DNA Breaks, Double-Stranded ; *DNA Repair ; *DNA Replication ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {The study of the molecular pathways underlying cancer has given us important insights into how breaks in our DNA are repaired and the dire consequences that can occur when these processes are perturbed. Extensive research over the past 20 years has shown that the key molecular event underpinning a subset of cancers involves the deregulated repair of DNA double-strand breaks (DSBs) at telomeres, which in turn leads to telomere lengthening and the potential for replicative immortality. Here we discuss, in-depth, recent major breakthroughs in our understanding of the mechanisms underpinning this pathway known as the alternative lengthening of telomeres (ALT). We explore how this gives us important insights into how DSB repair at telomeres is regulated, with relevance to the cell-cycle-dependent regulation of repair, repair of stalled replication forks and the spatial regulation of DSB repair.},
}
@article {pmid34828008,
year = {2021},
author = {Badmus, KA and Idrus, Z and Meng, GY and Mamat-Hamidi, K},
title = {Telomere Length, Apoptotic, and Inflammatory Genes: Novel Biomarkers of Gastrointestinal Tract Pathology and Meat Quality Traits in Chickens under Chronic Stress (Gallus gallus domesticus).},
journal = {Animals : an open access journal from MDPI},
volume = {11},
number = {11},
pages = {},
pmid = {34828008},
issn = {2076-2615},
support = {9629100//Universiti Putra Malaysia/ ; },
abstract = {This study was designed to examine the potentials of telomere length, mitochondria, and acute phase protein genes as novel biomarkers of gastrointestinal (GI) tract pathologies and meat quality traits. Chickens were fed a diet containing corticosterone (CORT) for 4 weeks and records on body weight, telomere length, GI tract and muscle histopathological test, meat quality traits, mitochondria, and acute phase protein genes were obtained at weeks 4 and 6 of age. The body weight of CORT-fed chickens was significantly suppressed (p < 0.05). CORT significantly altered the GI tract and meat quality traits. The interaction effect of CORT and age on body weight, duodenum and ileum crypt depth, pH, and meat color was significant (p < 0.05). CORT significantly (p < 0.05) shortened buffy coat telomere length. UCP3 and COX6A1 were diversely and significantly expressed in the muscle, liver, and heart of the CORT-fed chicken. Significant expression of SAAL1 and CRP in the liver and hypothalamus of the CORT-fed chickens was observed at week 4 and 6. Therefore, telomere lengths, mitochondria, and acute phase protein genes could be used as novel biomarkers for GI tract pathologies and meat quality traits.},
}
@article {pmid34827691,
year = {2021},
author = {Al-Daghri, NM and Abdi, S and Sabico, S and Alnaami, AM and Wani, KA and Ansari, MGA and Khattak, MNK and Khan, N and Tripathi, G and Chrousos, GP and McTernan, PG},
title = {Gut-Derived Endotoxin and Telomere Length Attrition in Adults with and without Type 2 Diabetes.},
journal = {Biomolecules},
volume = {11},
number = {11},
pages = {},
pmid = {34827691},
issn = {2218-273X},
mesh = {Aging ; *Diabetes Mellitus, Type 2 ; Endotoxins ; Humans ; Middle Aged ; Telomere ; },
abstract = {Premature aging, as denoted by a reduced telomere length (TL), has been observed in several chronic inflammatory diseases, such as obesity and type 2 diabetes mellitus (T2DM). However, no study to date has addressed the potential inflammatory influence of the gut-derived Gram-negative bacterial fragments lipopolysaccharide, also referred to as endotoxin, and its influence on TL in low-grade inflammatory states such as type 2 diabetes mellitus (T2DM). The current study therefore investigated the influence of endotoxin and inflammatory factors on telomere length (TL) in adults with (T2DM: n = 387) and without (non-diabetic (ND) controls: n = 417) obesity and T2DM. Anthropometric characteristics were taken, and fasted blood samples were used to measure biomarkers, TL, and endotoxin. The findings from this study highlighted across all participants that circulating endotoxin (r = -0.17, p = 0.01) was inversely associated with TL, noting that endotoxin and triglycerides predicted 18% of the variance perceived in TL (p < 0.001). Further stratification of the participants according to T2DM status and sex highlighted that endotoxin significantly predicted 19% of the variance denoted in TL among male T2DM participants (p = 0.007), where TL was notably influenced. The influence on TL was not observed to be impacted by anti-T2DM medications, statins, or anti-hypertensive therapies. Taken together, these results show that TL attrition was inversely associated with circulating endotoxin levels independent of the presence of T2DM and other cardiometabolic factors, suggesting that low-grade chronic inflammation may trigger premature biological aging. The findings further highlight the clinical relevance of mitigating the levels of circulating endotoxin (e.g., manipulation of gut microbiome) not only for the prevention of chronic diseases but also to promote healthy aging.},
}
@article {pmid34827416,
year = {2021},
author = {Sánchez-González, JL and Sánchez-Rodríguez, JL and Martín-Vallejo, J and Martel-Martel, A and González-Sarmiento, R},
title = {Effects of Physical Exercise on Cognition and Telomere Length in Healthy Older Women.},
journal = {Brain sciences},
volume = {11},
number = {11},
pages = {},
pmid = {34827416},
issn = {2076-3425},
abstract = {BACKGROUND: Physical exercise is an effective measure for preventing the onset of cognitive decline and has a direct influence on the aging process. The purpose of this study was to assess the effect of a 6-month physical exercise program on cognition and telomere length in adults over 65 years of age.<br><br>METHOD: Seventy-four healthy women were separated into two groups: 41 were included in the intervention group (IG) (72.70 &#xb1; 4.127 years and 8.18 &#xb1; 1.551 years of education) and 33 in the control group (CG) (71.21 &#xb1; 4.127 years and 8.42 &#xb1; 2.562). The participants included within the IG carried out three sessions of physical exercise per week for six months. Cognitive function was assessed using the Mini-Mental State Examination (MMSE), the Stroop test and the Trail Making Test (TMT). Saliva samples were taken and analyzed and relative telomere length was calculated. Those conducting the analysis were blind to the group to which the participants had been assigned.<br><br>RESULTS: An improvement was observed in global cognitive function, in both attentional and executive functions, in the group of adults doing physical exercise as compared to the control group. Six months after the physical exercise program had finished, relative telomere length was found to have increased in the participants in the intervention group.<br><br>CONCLUSION: Physical exercise programs can lead to an improvement in both cognitive functions and telomere length.},
}
@article {pmid34826177,
year = {2022},
author = {Reichard, M and Giannetti, K and Ferreira, T and Maouche, A and Vrtílek, M and Polačik, M and Blažek, R and Ferreira, MG},
title = {Lifespan and telomere length variation across populations of wild-derived African killifish.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {5979-5992},
doi = {10.1111/mec.16287},
pmid = {34826177},
issn = {1365-294X},
mesh = {Animals ; Female ; Male ; Longevity/genetics ; *Fundulidae/genetics ; Telomere Shortening/genetics ; *Cyprinodontiformes/genetics ; Telomere/genetics ; },
abstract = {Telomeres and telomerase prevent the continuous erosion of chromosome-ends caused by lifelong cell division. Shortened telomeres are associated with age-related pathologies. While short telomere length is positively correlated with increased lethality at the individual level, in comparisons across species short telomeres are associated with long (and not short) lifespans. Here, we tested this contradiction between individual and evolutionary patterns in telomere length using African annual killifish. We analysed lifespan and telomere length in a set of captive strains derived from well-defined wild populations of Nothobranchius furzeri and its sister species, N. kadleci, from sites along a strong gradient of aridity which ultimately determines maximum natural lifespan. Overall, males were shorter-lived than females, and also had shorter telomeres. Male lifespan (measured in controlled laboratory conditions) was positively associated with the amount of annual rainfall in the site of strain origin. However, fish from wetter climates had shorter telomeres. In addition, individual fish which grew largest over the juvenile period possessed shorter telomeres at the onset of adulthood. This demonstrates that individual condition and environmentally-driven selection indeed modulate the relationship between telomere length and lifespan in opposite directions, validating the existence of inverse trends within a single taxon. Intraindividual heterogeneity of telomere length (capable to detect very short telomeres) was not associated with mean telomere length, suggesting that the shortest telomeres are controlled by regulatory pathways other than those that determine mean telomere length. The substantial variation in telomere length between strains from different environments identifies killifish as a powerful system in understanding the adaptive value of telomere length.},
}
@article {pmid34826163,
year = {2022},
author = {Campitelli, BE and Razzaque, S and Barbero, B and Abdulkina, LR and Hall, MH and Shippen, DE and Juenger, TE and Shakirov, EV},
title = {Plasticity, pleiotropy and fitness trade-offs in Arabidopsis genotypes with different telomere lengths.},
journal = {The New phytologist},
volume = {233},
number = {4},
pages = {1939-1952},
pmid = {34826163},
issn = {1469-8137},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; R01 GM127402/GM/NIGMS NIH HHS/United States ; },
mesh = {*Arabidopsis ; Genetic Fitness ; Genotype ; Selection, Genetic ; Telomere/genetics ; },
abstract = {Telomere length has been implicated in the organismal response to stress, but the underlying mechanisms are unknown. Here we examine the impact of telomere length changes on the responses to three contrasting abiotic environments in Arabidopsis, and measure 32 fitness, developmental, physiological and leaf-level anatomical traits. We report that telomere length in wild-type and short-telomere mutants is resistant to abiotic stress, while the elongated telomeres in ku70 mutants are more plastic. We detected significant pleiotropic effects of telomere length on flowering time and key leaf physiological and anatomical traits. Furthermore, our data reveal a significant genotype by environment (G × E) interaction for reproductive fitness, with the benefits and costs to performance depending on the growth conditions. These results imply that life-history trade-offs between flowering time and reproductive fitness are impacted by telomere length variation. We postulate that telomere length in plants is subject to natural selection imposed by different environments.},
}
@article {pmid34825754,
year = {2022},
author = {Pepke, ML and Kvalnes, T and Lundregan, S and Boner, W and Monaghan, P and Saether, BE and Jensen, H and Ringsby, TH},
title = {Genetic architecture and heritability of early-life telomere length in a wild passerine.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6360-6381},
doi = {10.1111/mec.16288},
pmid = {34825754},
issn = {1365-294X},
mesh = {Animals ; *Genome-Wide Association Study ; Longevity/genetics ; Telomere/genetics ; *Passeriformes/genetics ; },
abstract = {Early-life telomere length (TL) is associated with fitness in a range of organisms. Little is known about the genetic basis of variation in TL in wild animal populations, but to understand the evolutionary and ecological significance of TL it is important to quantify the relative importance of genetic and environmental variation in TL. In this study, we measured TL in 2746 house sparrow nestlings sampled across 20 years and used an animal model to show that there is a small heritable component of early-life TL (h[2] = 0.04). Variation in TL among individuals was mainly driven by environmental (annual) variance, but also brood and parental effects. Parent-offspring regressions showed a large maternal inheritance component in TL (h maternal 2 = 0.44), but no paternal inheritance. We did not find evidence for a negative genetic correlation underlying the observed negative phenotypic correlation between TL and structural body size. Thus, TL may evolve independently of body size and the negative phenotypic correlation is likely to be caused by nongenetic environmental effects. We further used genome-wide association analysis to identify genomic regions associated with TL variation. We identified several putative genes underlying TL variation; these have been inferred to be involved in oxidative stress, cellular growth, skeletal development, cell differentiation and tumorigenesis in other species. Together, our results show that TL has a low heritability and is a polygenic trait strongly affected by environmental conditions in a free-living bird.},
}
@article {pmid34824901,
year = {2021},
author = {Tacheva, T and Zienolddiny, S and Dimov, D and Vlaykova, D and Vlaykova, T},
title = {The leukocyte telomere length, single nucleotide polymorphisms near TERC gene and risk of COPD.},
journal = {PeerJ},
volume = {9},
number = {},
pages = {e12190},
pmid = {34824901},
issn = {2167-8359},
abstract = {Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction and is associated with chronic local and systemic inflammation and oxidative stress. The enhanced oxidative stress and inflammation have been reported to affect telomere length (TL). Furthermore, a number of SNPs at loci encoding the main components of the telomerase genes, TERT and TERC have been shown to correlate with TL. We aimed to explore the leukocyte TL and genotypes for single nucleotide polymorphisms, rs12696304 (C > G) and rs10936599 (C > T) near TERC in COPD cases and matched healthy controls using q-PCR technologies. Successful assessment of TL was performed for 91 patients and 88 controls. The patients had shorter TL (17919.36 ± 1203.01 bp) compared to controls (21 271.48 ± 1891.36 bp) although not significant (p = 0.137). The TL did not associate with the gender, age, spirometric indexes, smoking habits but tended to correlate negatively with BMI (Rho = - 0.215, p = 0.076) in the controls, but not in COPD patients. The genotype frequencies of the SNPs rs12696304 and rs10936599 were compared between patients and controls and the odds ratios (OR) for developing COPD were calculated. The carriers of the common homozygous (CC) genotypes of the SNPs had higher risk for COPD, compared to carriers of the variants alleles (rs12696304 CG+GG vs. CC; OR: 0.615, 95% CI [0.424-0.894], p = 0.011 and for rs10936599 CT+TT vs. CC OR = 0.668, 95% CI [0.457-0.976], p = 0.044). Analysis on the combined effects of the TERC rs12696304 (C > G) and rs10936599 (C > T) genotypes, CC/CC genotype combination was associated with higher risk for COPD (p < 0.0001) and marginally lower FEV1% pr. in patients with GOLD II (p = 0.052). There was no association between the SNP genotypes and TL. In summary, our results suggest that COPD patients may have shorter TL, and rs12696304 and rs10936599 near TERC may affect the risk of COPD independently of TL.},
}
@article {pmid34824250,
year = {2021},
author = {Livingstone, J and Shiah, YJ and Yamaguchi, TN and Heisler, LE and Huang, V and Lesurf, R and Gebo, T and Carlin, B and Eng, S and Drysdale, E and Green, J and van der Kwast, T and Bristow, RG and Fraser, M and Boutros, PC},
title = {The telomere length landscape of prostate cancer.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {6893},
pmid = {34824250},
issn = {2041-1723},
support = {U24 CA248265/CA/NCI NIH HHS/United States ; U01 CA214194/CA/NCI NIH HHS/United States ; P50 CA092131/CA/NCI NIH HHS/United States ; P30 CA016042/CA/NCI NIH HHS/United States ; },
mesh = {DNA Copy Number Variations ; Epigenome ; Gene Fusion ; Genomics ; Humans ; Male ; Prostatic Neoplasms/*genetics/metabolism/pathology ; Proteome ; Telomerase/genetics/metabolism ; Telomere/*genetics ; Transcriptome ; },
abstract = {Replicative immortality is a hallmark of cancer, and can be achieved through telomere lengthening and maintenance. Although the role of telomere length in cancer has been well studied, its association to genomic features is less well known. Here, we report the telomere lengths of 392 localized prostate cancer tumours and characterize their relationship to genomic, transcriptomic and proteomic features. Shorter tumour telomere lengths are associated with elevated genomic instability, including single-nucleotide variants, indels and structural variants. Genes involved in cell proliferation and signaling are correlated with tumour telomere length at all levels of the central dogma. Telomere length is also associated with multiple clinical features of a tumour. Longer telomere lengths in non-tumour samples are associated with a lower rate of biochemical relapse. In summary, we describe the multi-level integration of telomere length, genomics, transcriptomics and proteomics in localized prostate cancer.},
}
@article {pmid34824242,
year = {2021},
author = {Thongon, N and Ma, F and Santoni, A and Marchesini, M and Fiorini, E and Rose, A and Adema, V and Ganan-Gomez, I and Groarke, EM and Gutierrez-Rodrigues, F and Chen, S and Lockyer, P and Schneider, S and Bueso-Ramos, C and Montalban-Bravo, G and Class, CA and Soltysiak, KA and Pellegrini, M and Sahin, E and Bertuch, AA and DiNardo, CD and Garcia-Manero, G and Young, NS and Dwyer, K and Colla, S},
title = {Hematopoiesis under telomere attrition at the single-cell resolution.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {6850},
pmid = {34824242},
issn = {2041-1723},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; P50 CA100632/CA/NCI NIH HHS/United States ; P50 CA211015/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Bone Marrow Failure Disorders/genetics/metabolism/pathology ; Cell Self Renewal ; Cellular Reprogramming ; Hematopoiesis/genetics/*physiology ; Hematopoietic Stem Cells/cytology/metabolism ; Humans ; Interferons/metabolism ; Megakaryocytes/cytology/metabolism ; Mice ; Nuclear Proteins/metabolism ; Oligodeoxyribonucleotides/metabolism ; Phosphoproteins/metabolism ; Signal Transduction ; Single-Cell Analysis ; Telomere/chemistry/physiology ; Telomere Shortening/genetics/*physiology ; },
abstract = {The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells' self-renewal capabilities and eventually leads to their exhaustion. Mechanistically, we demonstrate that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes interferon signaling activation in telomere-dysfunctional hematopoietic stem cells and these cells' skewed differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of hematopoietic stem cells by inducing apoptosis, autophagy, or senescence, and suggests that targeting IFI16 signaling axis might prevent hematopoietic stem cell functional decline in conditions affecting telomere maintenance.},
}
@article {pmid34817067,
year = {2022},
author = {Galati, A and Scatolini, L and Micheli, E and Bavasso, F and Cicconi, A and Maccallini, P and Chen, L and Roake, CM and Schoeftner, S and Artandi, SE and Gatti, M and Cacchione, S and Raffa, GD},
title = {The S-adenosylmethionine analog sinefungin inhibits the trimethylguanosine synthase TGS1 to promote telomerase activity and telomere lengthening.},
journal = {FEBS letters},
volume = {596},
number = {1},
pages = {42-52},
doi = {10.1002/1873-3468.14240},
pmid = {34817067},
issn = {1873-3468},
mesh = {*Methyltransferases ; },
abstract = {Mutations in many genes that control the expression, the function, or the stability of telomerase cause telomere biology disorders (TBDs), such as dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia. Mutations in a subset of the genes associated with TBDs cause reductions of the telomerase RNA moiety hTR, thus limiting telomerase activity. We have recently found that loss of the trimethylguanosine synthase TGS1 increases both hTR abundance and telomerase activity and leads to telomere elongation. Here, we show that treatment with the S-adenosylmethionine analog sinefungin inhibits TGS1 activity, increases the hTR levels, and promotes telomere lengthening in different cell types. Our results hold promise for restoring telomere length in stem and progenitor cells from TBD patients with reduced hTR levels.},
}
@article {pmid34813587,
year = {2021},
author = {Cui, M and Bai, Y and Li, K and Rong, YS},
title = {Taming active transposons at Drosophila telomeres: The interconnection between HipHop's roles in capping and transcriptional silencing.},
journal = {PLoS genetics},
volume = {17},
number = {11},
pages = {e1009925},
pmid = {34813587},
issn = {1553-7404},
mesh = {Animals ; Chromatin/genetics ; Chromosomal Proteins, Non-Histone/genetics ; DNA Transposable Elements/*genetics ; Drosophila Proteins/*genetics ; Drosophila melanogaster/genetics ; Female ; Genomic Instability/genetics ; Germ Cells/metabolism ; Heterochromatin/genetics ; Mutation ; RNA, Small Interfering/genetics ; Retroelements/*genetics ; Silencer Elements, Transcriptional/*genetics ; Telomere/*genetics ; },
abstract = {Drosophila chromosomes are elongated by retrotransposon attachment, a process poorly understood. Here we characterized a mutation affecting the HipHop telomere-capping protein. In mutant ovaries and the embryos that they produce, telomere retrotransposons are activated and transposon RNP accumulates. Genetic results are consistent with that this hiphop mutation weakens the efficacy of HP1-mediated silencing while leaving piRNA-based mechanisms largely intact. Remarkably, mutant females display normal fecundity suggesting that telomere de-silencing is compatible with germline development. Moreover, unlike prior mutants with overactive telomeres, the hiphop stock does not over-accumulate transposons for hundreds of generations. This is likely due to the loss of HipHop's abilities both to silence transcription and to recruit transposons to telomeres in the mutant. Furthermore, embryos produced by mutant mothers experience a checkpoint activation, and a further loss of maternal HipHop leads to end-to-end fusion and embryonic arrest. Telomeric retroelements fulfill an essential function yet maintain a potentially conflicting relationship with their Drosophila host. Our study thus showcases a possible intermediate in this arm race in which the host is adapting to over-activated transposons while maintaining genome stability. Our results suggest that the collapse of such a relationship might only occur when the selfish element acquires the ability to target non-telomeric regions of the genome. HipHop is likely part of this machinery restricting the elements to the gene-poor region of telomeres. Lastly, our hiphop mutation behaves as a recessive suppressor of PEV that is mediated by centric heterochromatin, suggesting its broader effect on chromatin not limited to telomeres.},
}
@article {pmid34813074,
year = {2022},
author = {Panasiak, L and Szubert, K and Polonis, M and Ocalewicz, K},
title = {Correction to: Telomere length variation does not correspond with the growth disturbances in the rainbow trout (Oncorhynchus mykiss).},
journal = {Journal of applied genetics},
volume = {63},
number = {1},
pages = {183},
doi = {10.1007/s13353-021-00671-y},
pmid = {34813074},
issn = {2190-3883},
}
@article {pmid34807303,
year = {2022},
author = {Cheng, F and Luk, AO and Wu, H and Tam, CHT and Lim, CKP and Fan, B and Jiang, G and Carroll, L and Yang, A and Lau, ESH and Ng, ACW and Lee, HM and Chow, E and Kong, APS and Keech, AC and Joglekar, MV and So, WY and Hardikar, AA and Chan, JCN and Jenkins, AJ and Ma, RCW},
title = {Relative leucocyte telomere length is associated with incident end-stage kidney disease and rapid decline of kidney function in type 2 diabetes: analysis from the Hong Kong Diabetes Register.},
journal = {Diabetologia},
volume = {65},
number = {2},
pages = {375-386},
pmid = {34807303},
issn = {1432-0428},
mesh = {Aged ; Diabetes Mellitus, Type 2/*physiopathology ; Female ; Glomerular Filtration Rate ; Hong Kong ; Humans ; Incidence ; Kidney/*physiopathology ; Kidney Failure, Chronic/*epidemiology/physiopathology ; Leukocytes/*metabolism ; Male ; Middle Aged ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; Registries ; Telomere/metabolism ; Telomere Shortening/*physiology ; },
abstract = {AIMS/HYPOTHESIS: Few large-scale prospective studies have investigated associations between relative leucocyte telomere length (rLTL) and kidney dysfunction in individuals with type 2 diabetes. We examined relationships between rLTL and incident end-stage kidney disease (ESKD) and the slope of eGFR decline in Chinese individuals with type 2 diabetes.<br><br>METHODS: We studied 4085 Chinese individuals with type 2 diabetes observed between 1995 and 2007 in the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data. rLTL was measured using quantitative PCR. ESKD was diagnosed based on the ICD-9 code and eGFR.<br><br>RESULTS: In this cohort (mean&#x2009;&#xb1;&#x2009;SD age 54.3&#x2009;&#xb1;&#x2009;12.6&#xa0;years) followed up for 14.1&#x2009;&#xb1;&#x2009;5.3&#xa0;years, 564 individuals developed incident ESKD and had shorter rLTL at baseline (4.2&#x2009;&#xb1;&#x2009;1.2 vs 4.7&#x2009;&#xb1;&#x2009;1.2, p&#xa0;<&#x2009;0.001) than the non-progressors (n&#x2009;=&#x2009;3521). On Cox regression analysis, each &#x2206;&#x2206;Ct decrease in rLTL was associated with an increased risk of incident ESKD (HR 1.21 [95% CI 1.13, 1.30], p&#xa0;<&#x2009;0.001); the association remained significant after adjusting for baseline age, sex, HbA1c, lipids, renal function and other risk factors (HR 1.11 [95% CI 1.03, 1.19], p&#x2009;=&#x2009;0.007). Shorter rLTL at baseline was associated with rapid decline in eGFR (>4% per year) during follow-up (unadjusted OR 1.22 [95% CI 1.15, 1.30], p&#xa0;<&#x2009;0.001; adjusted OR 1.09 [95% CI 1.01, 1.17], p&#x2009;=&#x2009;0.024).<br><br>CONCLUSIONS/INTERPRETATION: rLTL is independently associated with incident ESKD and rapid eGFR loss in individuals with type 2 diabetes. Telomere length may be a useful biomarker for the progression of kidney function and ESKD in type 2 diabetes.},
}
@article {pmid34803652,
year = {2021},
author = {Wang, Y and Jiao, F and Zheng, H and Kong, Q and Li, R and Zhang, X and Yan, L and Hao, Y and Wu, Y},
title = {Gender Difference in Associations Between Telomere Length and Risk Factors in Patients With Stroke.},
journal = {Frontiers in aging neuroscience},
volume = {13},
number = {},
pages = {719538},
pmid = {34803652},
issn = {1663-4365},
abstract = {Multiple risk factors of stroke are associated with telomere length shortening. Although leukocyte telomere length (LTL) is shorter in patients with stroke, the heterogeneity is high. Risk factors may be differentially associated with LTL in male and female patients contributing to the heterogeneity. However, the gender difference in associations between LTL and risk factors in stroke patients has not been investigated. In this study, we investigated the gender difference in associations between LTL and risk factors in 312 stroke patients. Real-time quantitative PCR was used to determine relative LTL, and multiple linear regression analysis was applied for association analyses. We found that LTL was negatively associated with triglyceride (TG) in all patients [β(95% CI) = -0.69 (-1.26, -0.11), P < 0.05] after adjusting confounders. Importantly, LTL was negatively associated with lack of exercise [β(95% CI) = -1.80 (-3.12, -0.49), P < 0.05] and LDL levels [β(95% CI) = -3.22 (-6.05, -0.390), P < 0.05] in male patients, while LTL was negatively associated with dyssomnia [β(95%CI) = -2.00 (-3.96, -0.07), P < 0.05] and diabetes [β(95%CI) = -2.13 (-4.10, -0.27), P < 0.01] in female patients. Our study showed that LTL is differently associated with risk factors in male and female patients with stroke, indicating that gender difference should be considered when LTL is potentially applied as an index of risk and prognosis for stroke. Our study also provides an insight into that gender differences should be considered when developing intervention strategies for stroke prevention and treatment.},
}
@article {pmid34798938,
year = {2021},
author = {Kahl, VFS and da Silva, J},
title = {Inorganic elements in occupational settings: A review on the effects on telomere length and biology.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {872},
number = {},
pages = {503418},
doi = {10.1016/j.mrgentox.2021.503418},
pmid = {34798938},
issn = {1879-3592},
mesh = {Humans ; Lead/toxicity ; *Occupational Exposure/adverse effects/analysis ; Particulate Matter ; *Telomere/genetics ; *Welding ; Xenobiotics ; },
abstract = {The past decades have shown that telomere crisis is highly affected by external factors. Effects of human exposure to xenobiotics on telomere length (TL), particularly in their workplace, have been largely studied. TL has been shown to be an efficient biomarker in occupational risk assessment. This is the first review focusing on studies about the effects on TL from occupational exposures to metals (lead [Pb] and mixtures), and particulate matter (PM) related to inorganic elements. Data from 15 studies were evaluated regarding occupational exposure to metals and PM-associated inorganic elements and impact on TL. Potential complementary analyses and subjects' background (age, length of employment and gender) were also assessed. There was limited information on the correlations between work length and TL dynamics, and that was also true for the correlation between age and TL. Results indicated that TL is affected differently across the types of occupational exposure investigated in this review, and even within the same exposure, a variety of effects can be observed. Fifty-three percent of the studies observed decreased TL in occupational exposure among welding fumes, open-cast coal mine, Pb and PM industries workers. Two studies focused particularly on the levels of metals and association with TL, and both linear and non-linear associations were found. Interestingly, TL modifications were accompanied by increase in DNA damage in 7 out of 8 studies that investigated it, measured either by Cytokinesis-block Micronucleus Assay or Comet assay. Five studies also investigated oxidative stress parameters, and 4 of them found increased levels of oxidative damage along with TL impairment. Oxidative stress is one of the main mechanisms by which telomeres are affected due to their high guanine content. Our review highlights the need of further studies accessing TL in simultaneous occupational exposure to mixtures of xenobiotics.},
}
@article {pmid34797948,
year = {2021},
author = {Dalzini, A and Ballin, G and Dominguez-Rodriguez, S and Rojo, P and Petrara, MR and Foster, C and Cotugno, N and Ruggiero, A and Nastouli, E and Klein, N and Rinaldi, S and Pahwa, S and Rossi, P and Giaquinto, C and Palma, P and De Rossi, A and , },
title = {Size of HIV-1 reservoir is associated with telomere shortening and immunosenescence in early-treated European children with perinatally acquired HIV-1.},
journal = {Journal of the International AIDS Society},
volume = {24},
number = {11},
pages = {e25847},
pmid = {34797948},
issn = {1758-2652},
mesh = {Adolescent ; CD4-Positive T-Lymphocytes ; Cross-Sectional Studies ; *HIV Infections/drug therapy ; *HIV-1/genetics ; Humans ; *Immunosenescence ; Telomere Shortening ; },
abstract = {INTRODUCTION: Persistence of HIV-1, causing chronic immune activation, is a key determinant of premature senescence. Early antiretroviral therapy (ART) has been associated with a reduced HIV-1 reservoir in children with perinatally acquired HIV-1 (PHIV), but its impact on the senescence process is an open question. We investigated the association between HIV-1 reservoir and biological and immune ageing profile in PHIV enrolled in the multicentre cross-sectional study CARMA (Child and Adolescent Reservoir Measurements on early suppressive ART) conducted within the EPIICAL (Early treated Perinatally HIV Infected individuals: Improving Children's Actual Life) consortium.<br><br>METHODS: Between September 2017 and June 2018, CARMA enrolled 40 PHIV who started ART before 2 years of age and had undetectable viremia for at least 5 years before sampling date. Samples from 37 children with a median age of 13.8 years were available for this study. HIV-1 DNA copies on CD4 cells, relative telomere length (marker of cellular senescence) and levels of T-cell receptor rearrangement excision circle (TREC, marker of thymic output) on CD4 and CD8 cells were quantified by qPCR. Immunological profile was assessed by flow cytometry. Associations between molecular and phenotypic markers, HIV-1 reservoir and age at ART initiation were explored using a multivariable Poisson regression.<br><br>RESULTS: Higher HIV-1 reservoir was associated (p<0.001) with telomere shortening (incidence rate ratio [IRR] = 0.15 [0.13-0.17]), immunosenescence (CD28[-] CD57[+] , IRR = 1.23 [1.21-1.26]) and immunoactivation (CD38[+] HLADR[+] , IRR = 7.29 [6.58-8.09]) of CD4 cells. Late ART initiation (after 6 months of age) correlated with higher HIV-1 reservoir levels (552 [303-1001] vs. 89 [56-365] copies/10[6] CD4 cells, p = 0.003) and percentage of CD4 senescent cells (2.89 [1.95-6.31] vs. 1.02 [0.45-2.69, p = 0.047). TREC levels in CD8 cells were inversely associated with HIV-1 reservoir (IRR = 0.77 [0.76-0.79]) and were significantly lower in late treated PHIV (1128 [486-1671] vs. 2278 [1425-3314], p = 0.042).<br><br>CONCLUSIONS: Later ART initiation is associated with higher HIV-1 reservoir size, which correlates with increased telomere shortening and senescence of CD4 cells. Timing of ART initiation in infancy has long-term consequences on the immune and biological ageing profile of children with perinatally acquired HIV-1.},
}
@article {pmid34797165,
year = {2021},
author = {Smith, AR and Lin, PD and Rifas-Shiman, SL and Rahman, ML and Gold, DR and Baccarelli, AA and Claus Henn, B and Amarasiriwardena, C and Wright, RO and Coull, B and Hivert, MF and Oken, E and Cardenas, A},
title = {Prospective Associations of Early Pregnancy Metal Mixtures with Mitochondria DNA Copy Number and Telomere Length in Maternal and Cord Blood.},
journal = {Environmental health perspectives},
volume = {129},
number = {11},
pages = {117007},
pmid = {34797165},
issn = {1552-9924},
support = {U2C ES026555/ES/NIEHS NIH HHS/United States ; U2C ES026561/ES/NIEHS NIH HHS/United States ; R01 HD034568/HD/NICHD NIH HHS/United States ; R01 ES031259/ES/NIEHS NIH HHS/United States ; UH3 OD023286/OD/NIH HHS/United States ; },
mesh = {Bayes Theorem ; Child ; DNA Copy Number Variations ; DNA, Mitochondrial/genetics ; Female ; *Fetal Blood ; Humans ; *Metals, Heavy ; Mitochondria ; Pregnancy ; Telomere ; },
abstract = {BACKGROUND: Metal exposure during pregnancy influences maternal and child health. Oxidative stress and inflammation may mediate adverse effects of heavy metals, whereas essential metals may act as antioxidants. Mitochondrial DNA is a prime target for metal-induced oxidative damage. Telomere dysfunction is attributed to imbalances between reactive oxidant species and antioxidants.<br><br>OBJECTIVES: We evaluated individual and joint associations of prenatal metals with mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) in maternal and cord blood as biomarkers of inflammation and oxidative stress.<br><br>METHODS: We measured six nonessential metals (arsenic, barium, cadmium, cesium, lead, mercury) and four essential metals (magnesium, manganese, selenium, zinc) in first-trimester maternal red blood cells in Project Viva, a U.S. prebirth cohort. We measured relative mtDNAcn (n=898) and TL (n=893) in second-trimester maternal blood and mtDNAcn (n=419) and TL (n=408) in cord blood. We used multivariable linear regression and quantile g-computation to estimate associations between prenatal metals and the biomarkers. We used generalized additive models and Bayesian kernel machine regression to examine nonlinearity and interactions.<br><br>RESULTS: A 2-fold increase in maternal magnesium was associated with lower maternal [&#x3b2;=-0.07, 95% confidence interval (CI): -0.10, -0.01] and cord blood (&#x3b2;=-0.08, 95% CI: -0.20, -0.01) mtDNAcn. Lead was associated with higher maternal mtDNAcn (&#x3b2;=0.04, 95% CI: 0.01, 0.06). Selenium was associated with longer cord blood TL (&#x3b2;=0.30, 95% CI: 0.01 0.50). An association was observed between the nonessential metal mixture and higher maternal mtDNAcn (&#x3b2;=0.04, 95% CI: 0.01, 0.07). There was a nonlinear relationship between cord blood mtDNAcn and magnesium; maternal mtDNAcn and barium, lead, and mercury; and maternal TL and barium.<br><br>DISCUSSION: Maternal exposure to metals such as lead, magnesium, and selenium was associated with mtDNAcn and TL in maternal second trimester and cord blood. Future work will evaluate whether these biomarkers are associated with child health. https://doi.org/10.1289/EHP9294.},
}
@article {pmid34794487,
year = {2021},
author = {Razazi, K and Marcos, E and Hüe, S and Boyer, L and Adnot, S and Mekontso Dessap, A},
title = {Telomere shortening during human septic shock: influence of sepsis mediators, role in organ failures, and septic myocardial dysfunction.},
journal = {Critical care (London, England)},
volume = {25},
number = {1},
pages = {401},
pmid = {34794487},
issn = {1466-609X},
mesh = {Cardiomyopathies ; Humans ; Multiple Organ Failure ; Sepsis ; *Shock, Septic/genetics/physiopathology ; *Telomere Shortening ; },
}
@article {pmid34789157,
year = {2021},
author = {Chung, D and Kwon, YM and Yang, Y},
title = {Telomere-to-telomere genome assembly of asparaginase-producing Trichoderma simmonsii.},
journal = {BMC genomics},
volume = {22},
number = {1},
pages = {830},
pmid = {34789157},
issn = {1471-2164},
mesh = {Asparaginase ; Genome ; Hypocreales ; Telomere ; *Trichoderma/genetics ; },
abstract = {BACKGROUND: Trichoderma is a genus of fungi in the family Hypocreaceae and includes species known to produce enzymes with commercial use. They are largely found in soil and terrestrial plants. Recently, Trichoderma simmonsii isolated from decaying bark and decorticated wood was newly identified in the Harzianum clade of Trichoderma. Due to a wide range of applications in agriculture and other industries, genomes of at least 12 Trichoderma spp. have been studied. Moreover, antifungal and enzymatic activities have been extensively characterized in Trichoderma spp. However, the genomic information and bioactivities of T. simmonsii from a particular marine-derived isolate remain largely unknown. While we screened for asparaginase-producing fungi, we observed that T. simmonsii GH-Sj1 strain isolated from edible kelp produced asparaginase. In this study, we report a draft genome of T. simmonsii GH-Sj1 using Illumina and Oxford Nanopore technologies. Furthermore, to facilitate biotechnological applications of this species, RNA-sequencing was performed to elucidate the transcriptional profile of T. simmonsii GH-Sj1 in response to asparaginase-rich conditions.<br><br>RESULTS: We generated ~&#x2009;14 Gb of sequencing data assembled in a&#x2009;~&#x2009;40&#x2009;Mb genome. The T. simmonsii GH-Sj1 genome consisted of seven telomere-to-telomere scaffolds with no sequencing gaps, where the N50 length was 6.4&#x2009;Mb. The total number of protein-coding genes was 13,120, constituting ~&#x2009;99% of the genome. The genome harbored 176 tRNAs, which encode a full set of 20 amino acids. In addition, it had an rRNA repeat region consisting of seven repeats of the 18S-ITS1-5.8S-ITS2-26S cluster. The T. simmonsii genome also harbored 7 putative asparaginase-encoding genes with potential medical applications. Using RNA-sequencing analysis, we found that 3 genes among the 7 putative genes were significantly upregulated under asparaginase-rich conditions.<br><br>CONCLUSIONS: The genome and transcriptome of T. simmonsii GH-Sj1 established in the current work represent valuable resources for future comparative studies on fungal genomes and asparaginase production.},
}
@article {pmid34786545,
year = {2021},
author = {Wang, Y and Chen, S and Feng, S and Wang, C and Jiang, H and Rong, S and Hermann, H and Chen, J and Zhang, P},
title = {Telomere shortening in patients on long-term hemodialysis.},
journal = {Chronic diseases and translational medicine},
volume = {7},
number = {4},
pages = {266-275},
pmid = {34786545},
issn = {2589-0514},
abstract = {BACKGROUND: Leukocyte telomere length shortening is a characteristic of premature senescence, a process that can be accelerated by oxidative stress. In general, patients with end-stage renal disease undergoing regular hemodialysis (HD) are repeatedly exposed to oxidative stress. Patients undergoing HD tend to have cardiovascular diseases associated with oxidative stress and inflammation. Therefore, we assumed that telomere length is associated with HD vintage and the degree of vascular calcification.<br><br>METHODS: A total of 144 patients undergoing regular HD before kidney transplantation and 62 patients on hemodialysis, but not undergoing kidney transplantation, were enrolled. We measured common laboratory values, such as calcium, phosphate, and hemoglobin levels, and assessed the degree of vascular calcification in the patients. The leukocyte telomere length was measured using reverse transcription polymerase chain reaction, and Spearman correlation was used for correlation analysis.<br><br>RESULTS: The leukocyte telomere length was negatively associated with age (rho&#xa0;=&#xa0;-0.306, P&#xff1c;0.01); it was shorter in middle-aged patients than in young patients (13.48&#xa0;&#xb1;&#xa0;4.80 vs. 15.86&#xa0;&#xb1;&#xa0;4.51, P&#xa0;<&#xa0;0.01). The telomere length was significantly different among patients aged 52-74 years in groups with different HD vintages. Additionally, the telomere length was positively associated with serum hemoglobin (Hb) levels in all patients (rho&#xa0;=&#xa0;0.290, P&#xa0;<&#xa0;0.01). There was a significant difference among patients divided into three groups according to the degree of anemia (17.09&#xa0;&#xb1;&#xa0;5.64 vs. 14.40&#xa0;&#xb1;&#xa0;4.07 vs. 13.99&#xa0;&#xb1;&#xa0;3.95, P&#xa0;<&#xa0;0.01). Further, a significant difference was observed in the telomere length among patients with different degrees of vascular calcification (16.79&#xa0;&#xb1;&#xa0;4.91 vs. 13.61&#xa0;&#xb1;&#xa0;2.82 vs. 14.62&#xa0;&#xb1;&#xa0;3.63 vs. 10.71&#xa0;&#xb1;&#xa0;3.74, P&#xa0;<&#xa0;0.01). The telomere length was shorter in the patients on hemodialysis who did not receive a kidney transplant than in the surgical patients (8.12&#xa0;&#xb1;&#xa0;1.83 vs. 14.33&#xa0;&#xb1;&#xa0;4.63, P&#xa0;<&#xa0;0.01).<br><br>CONCLUSION: This study demonstrated that the telomere length was significantly correlated with HD vintage in patients of a certain age group. The telomere length was shorter in patients on hemodialysis who matched for age and dialysis vintage with kidney transplant patients. It was also associated with vascular calcification and serum Hb levels in all patients undergoing HD.},
}
@article {pmid34784790,
year = {2021},
author = {Vedelek, B and Kovács, &#xc1; and Boros, IM},
title = {Evolutionary mode for the functional preservation of fast-evolving Drosophila telomere capping proteins.},
journal = {Open biology},
volume = {11},
number = {11},
pages = {210261},
pmid = {34784790},
issn = {2046-2441},
mesh = {Animals ; Chromosomal Proteins, Non-Histone/chemistry/genetics/*metabolism ; DNA Replication ; DNA, Single-Stranded/*metabolism ; Drosophila Proteins/chemistry/genetics/*metabolism ; Drosophila melanogaster/*genetics/metabolism ; Evolution, Molecular ; Models, Molecular ; Mutation ; Protein Conformation ; Structural Homology, Protein ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {DNA end protection is fundamental for the long-term preservation of the genome. In vertebrates the Shelterin protein complex protects telomeric DNA ends, thereby contributing to the maintenance of genome integrity. In the Drosophila genus, this function is thought to be performed by the Terminin complex, an assembly of fast-evolving subunits. Considering that DNA end protection is fundamental for successful genome replication, the accelerated evolution of Terminin subunits is counterintuitive, as conservation is supposed to maintain the assembly and concerted function of the interacting partners. This problem extends over Drosophila telomere biology and provides insight into the evolution of protein assemblies. In order to learn more about the mechanistic details of this phenomenon we have investigated the intra- and interspecies assemblies of Verrocchio and Modigliani, two Terminin subunits using in vitro assays. Based on our results and on homology-based three-dimensional models for Ver and Moi, we conclude that both proteins contain Ob-fold and contribute to the ssDNA binding of the Terminin complex. We propose that the preservation of Ver function is achieved by conservation of specific amino acids responsible for folding or localized in interacting surfaces. We also provide here the first evidence on Moi DNA binding.},
}
@article {pmid34782750,
year = {2021},
author = {Wan, F and Ding, Y and Zhang, Y and Wu, Z and Li, S and Yang, L and Yan, X and Lan, P and Li, G and Wu, J and Lei, M},
title = {Zipper head mechanism of telomere synthesis by human telomerase.},
journal = {Cell research},
volume = {31},
number = {12},
pages = {1275-1290},
pmid = {34782750},
issn = {1748-7838},
mesh = {DNA ; Holoenzymes/genetics ; Humans ; RNA ; Repetitive Sequences, Nucleic Acid ; *Telomerase/metabolism ; Telomere/genetics/metabolism ; },
abstract = {Telomerase, a multi-subunit ribonucleoprotein complex, is a unique reverse transcriptase that catalyzes the processive addition of a repeat sequence to extend the telomere end using a short fragment of its own RNA component as the template. Despite recent structural characterizations of human and Tetrahymena telomerase, it is still a mystery how telomerase repeatedly uses its RNA template to synthesize telomeric DNA. Here, we report the cryo-EM structure of human telomerase holoenzyme bound with telomeric DNA at resolutions of 3.5 Å and 3.9 Å for the catalytic core and biogenesis module, respectively. The structure reveals that a leucine residue Leu980 in telomerase reverse transcriptase (TERT) catalytic subunit functions as a zipper head to limit the length of the short primer-template duplex in the active center. Moreover, our structural and computational analyses suggest that TERT and telomerase RNA (hTR) are organized to harbor a preformed active site that can accommodate short primer-template duplex substrates for catalysis. Furthermore, our findings unveil a double-fingers architecture in TERT that ensures nucleotide addition processivity of human telomerase. We propose that the zipper head Leu980 is a structural determinant for the sequence-based pausing signal of DNA synthesis that coincides with the RNA element-based physical template boundary. Functional analyses unveil that the non-glycine zipper head plays an essential role in both telomerase repeat addition processivity and telomere length homeostasis. In addition, we also demonstrate that this zipper head mechanism is conserved in all eukaryotic telomerases. Together, our study provides an integrated model for telomerase-mediated telomere synthesis.},
}
@article {pmid34782395,
year = {2022},
author = {Man, TK and Aubert, G and Richard, MA and LeJeune, W and Hariri, E and Goltsova, T and Gaikwad, A and Chen, Y and Whitton, J and Leisenring, WM and Arnold, MA and Neglia, JP and Yasui, Y and Robison, LL and Armstrong, GT and Bhatia, S and Gramatges, MM},
title = {Short NK- and Naïve T-Cell Telomere Length Is Associated with Thyroid Cancer in Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Study.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {31},
number = {2},
pages = {453-460},
pmid = {34782395},
issn = {1538-7755},
support = {P30 CA021765/CA/NCI NIH HHS/United States ; R01 CA194473/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Cancer Survivors/*statistics &amp; numerical data ; Case-Control Studies ; Child ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Neoplasms, Second Primary/blood/*genetics ; Radiotherapy/adverse effects ; Surveys and Questionnaires ; T-Lymphocytes ; Telomere Shortening/*genetics ; Thyroid Neoplasms/blood/*genetics ; },
abstract = {BACKGROUND: Survivors of childhood cancer are at risk for therapy-related subsequent malignant neoplasms (SMN), including thyroid SMN. Telomere length (TL) is associated with cancer risk, but the relationship between TL and SMN risk among survivors is less clear.<br><br>METHODS: We conducted a nested, matched case-control study of radiation-exposed 15-year+ adult survivors of childhood cancer with thyroid SMN (cases) and without SMN (controls). Forty-six cases were matched to 46 controls by primary diagnosis, chemotherapy (yes/no), radiation field, and follow-up duration. Lymphocyte TL (LTL) was measured by telomere flow-FISH cytometry using blood samples banked at a mean of 38.9 years (cases), 39.2 years (controls). Genetic variation in telomere genes was assessed by whole genome sequencing. Point estimates for LTL <10th percentile were determined for cases and controls.<br><br>RESULTS: Cases had shorter median LTL than controls in three out of four leukocyte subsets. Cases were more likely to have NK cell LTL <10th percentile (P = 0.01), and 2.8-fold more likely to have na&#xef;ve T-cell LTL <10th percentile than controls (CI, 1.07-8.78). Five out of 15 cases with a rare indel or missense variant had na&#xef;ve T-cell LTL <10th percentile, compared with one out of eight controls.<br><br>CONCLUSIONS: Long-term survivors have shorter than expected LTL, a finding that is more pronounced among survivors with thyroid SMN.<br><br>IMPACT: The long-term impact of childhood cancer treatment on immune function is poorly understood. Our findings support immune function studies in larger survivor cohorts to assess long-term deficits in adaptive and innate immunity that may underlie SMN risk.},
}
@article {pmid34782052,
year = {2021},
author = {Cheng, S and Liu, B and Guo, ZF and Duan, XR and Liu, SX and Li, L and Yao, W and Yang, YL and Wang, W},
title = {Relationship between TERT Polymorphism and Telomere Length in Workers Exposed to Omethoate.},
journal = {Biomedical and environmental sciences : BES},
volume = {34},
number = {10},
pages = {838-841},
doi = {10.3967/bes2021.115},
pmid = {34782052},
issn = {2214-0190},
mesh = {Adult ; China ; Dimethoate/adverse effects/*analogs &amp; derivatives ; Farmers/statistics &amp; numerical data ; Female ; Humans ; Male ; Middle Aged ; *Occupational Exposure ; Pesticides/*adverse effects ; *Polymorphism, Single Nucleotide ; Telomerase/*genetics ; Telomere/*drug effects/physiology ; },
}
@article {pmid34781413,
year = {2022},
author = {Connelly, CJ and Vidal-Cardenas, S and Goldsmith, S and Greider, CW},
title = {The Bur1 cyclin-dependent kinase regulates telomere length in Saccharomyces cerevisiae.},
journal = {Yeast (Chichester, England)},
volume = {39},
number = {3},
pages = {177-192},
pmid = {34781413},
issn = {1097-0061},
mesh = {Cyclin-Dependent Kinases/genetics/*metabolism ; *Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomere/genetics/metabolism ; Transcription, Genetic ; },
abstract = {Telomere length regulation is essential for cell viability in eukaryotes. While many pathways that affect telomere length are known, we do not yet have a complete understanding of the mechanism of length regulation. To identify new pathways that might regulate telomere length, we carried out a genetic screen in yeast and identified the cyclin-dependent kinase complex Bur1/2 as a regulator of telomere length. Mutations in either BUR1 cyclin-dependent kinase or the associated BUR2 cyclin resulted in short telomeres. This regulation did not function through the known role of BUR1 in regulating histone modification as bur1∆ set2∆ and bur2∆ set2∆ double mutants rescued cell growth but did not rescue the telomere shortening effects. We found that both bur1∆ and bur2∆ set2∆ were also defective in de novo telomere addition, and deletion of SET2 did also not rescue this elongation defect. The Bur1/2 cyclin-dependent kinase regulates transcription of many genes. We found that TLC1 RNA levels were reduced in bur2∆ set2∆ mutants; however, overexpression of TLC1 restored the transcript levels but did not restore de novo telomere elongation or telomere length. These data suggest that the Bur1/2 kinase plays a role in telomere elongation separate from its role in transcription of telomerase components. Dissecting the role of the Bur1/2 kinase pathway at telomeres will help complete our understanding of the complex network of telomere length regulation.},
}
@article {pmid34781086,
year = {2021},
author = {Freimane, L and Barkane, L and Igumnova, V and Kivrane, A and Zole, E and Ranka, R},
title = {Telomere length and mitochondrial DNA copy number in multidrug-resistant tuberculosis.},
journal = {Tuberculosis (Edinburgh, Scotland)},
volume = {131},
number = {},
pages = {102144},
doi = {10.1016/j.tube.2021.102144},
pmid = {34781086},
issn = {1873-281X},
mesh = {Adult ; Aged ; Antitubercular Agents/therapeutic use ; *DNA Copy Number Variations ; DNA, Mitochondrial/*genetics/immunology ; Female ; Humans ; Male ; Middle Aged ; Risk Factors ; Telomere Homeostasis/*genetics/immunology ; Tuberculosis, Multidrug-Resistant/drug therapy/*genetics ; },
abstract = {Multidrug resistant tuberculosis (MDR-TB) is a severe disease that requires prolonged chemotherapy and is associated with an increased probability of treatment failure and death. MDR-TB is a state of heightened oxidative stress and inflammation, which could be related to the aging-related processes and immunosenescence. We, therefore, tested the hypothesis that MDR-TB is associated with alterations in aging biomarkers in peripheral blood cells. We investigated 51 MDR-TB patients and 57 healthy individuals and carried out an analysis of covariance to assess the possible impact of different variables on biomarker perturbations. The results showed that MDR-TB patients had significantly reduced telomere length (TL) and increased mitochondrial DNA copy number (mtDNA CN) (P < 0.05) in comparison to the controls, and MDR-TB infection was the main influencing factor. Male sex and extrapulmonary TB strongly influenced mtDNA CN increment, and MDR-TB patients with normal weight had longer telomeres than those who were underweight (P < 0.05). In conclusion, the evidence for shorter telomeres and higher mtDNA CN in the peripheral blood cells of MDR-TB patients was obtained indicating the connection between MDR-TB and aging biomarkers. The observed associations highlight a complicated interplay between MDR-TB and immunosenescence, thus further studies are required to achieve full understanding.},
}
@article {pmid34780645,
year = {2021},
author = {Brown, HA and Williams, CAC and Zhou, H and Rios-Szwed, D and Fernandez-Alonso, R and Mansoor, S and McMulkin, L and Toth, R and Gourlay, R and Peltier, J and Dieguez-Martinez, N and Trost, M and Lizcano, JM and Stavridis, MP and Findlay, GM},
title = {An ERK5-KLF2 signalling module regulates early embryonic gene expression and telomere rejuvenation in stem cells.},
journal = {The Biochemical journal},
volume = {478},
number = {23},
pages = {4119-4136},
pmid = {34780645},
issn = {1470-8728},
support = {211209/Z/18/Z/WT_/Wellcome Trust/United Kingdom ; MR/N000609/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; Kruppel-Like Transcription Factors/*metabolism ; Mice ; Mitogen-Activated Protein Kinase 7/*metabolism ; *Mouse Embryonic Stem Cells/cytology/metabolism ; },
abstract = {The ERK5 MAP kinase signalling pathway drives transcription of naïve pluripotency genes in mouse Embryonic Stem Cells (mESCs). However, how ERK5 impacts on other aspects of mESC biology has not been investigated. Here, we employ quantitative proteomic profiling to identify proteins whose expression is regulated by the ERK5 pathway in mESCs. This reveals a function for ERK5 signalling in regulating dynamically expressed early embryonic 2-cell stage (2C) genes including the mESC rejuvenation factor ZSCAN4. ERK5 signalling and ZSCAN4 induction in mESCs increases telomere length, a key rejuvenative process required for prolonged culture. Mechanistically, ERK5 promotes ZSCAN4 and 2C gene expression via transcription of the KLF2 pluripotency transcription factor. Surprisingly, ERK5 also directly phosphorylates KLF2 to drive ubiquitin-dependent degradation, encoding negative feedback regulation of 2C gene expression. In summary, our data identify a regulatory module whereby ERK5 kinase and transcriptional activities bi-directionally control KLF2 levels to pattern 2C gene transcription and a key mESC rejuvenation process.},
}
@article {pmid34778247,
year = {2021},
author = {de Oliveira, BCD and Shiburah, ME and Paiva, SC and Vieira, MR and Morea, EGO and da Silva, MS and Alves, CS and Segatto, M and Gutierrez-Rodrigues, F and Borges, JC and Calado, RT and Cano, MIN},
title = {Possible Involvement of Hsp90 in the Regulation of Telomere Length and Telomerase Activity During the Leishmania amazonensis Developmental Cycle and Population Proliferation.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {713415},
pmid = {34778247},
issn = {2296-634X},
abstract = {The Leishmania developmental cycle comprises three main life forms in two hosts, indicating that the parasite is continually challenged due to drastic environmental changes. The disruption of this cycle is critical for discovering new therapies to eradicate leishmaniasis, a neglected disease that affects millions worldwide. Telomeres, the physical ends of chromosomes, maintain genome stability and cell proliferation and are potential antiparasitic drug targets. Therefore, understanding how telomere length is regulated during parasite development is vital. Here, we show that telomeres form clusters spread in the nucleoplasm of the three parasite life forms. We also observed that amastigotes telomeres are shorter than metacyclic and procyclic promastigotes and that in parasites with continuous in vitro passages, telomere length increases over time. These observed differences in telomere length among parasite's life stages were not due to lack/inhibition of telomerase since enzyme activity was detected in all parasite life stages, although the catalysis was temperature-dependent. These data led us to test if, similar to other eukaryotes, parasite telomere length maintenance could be regulated by Hsp83, the ortholog of Hsp90 in trypanosomatids, and Leishmania (LHsp90). Parasites were then treated with the Hsp90 inhibitor 17AAG. The results showed that 17AAG disturbed parasite growth, induced accumulation into G2/M phases, and telomere shortening in a time-dependent manner. It has also inhibited procyclic promastigote's telomerase activity. Besides, LHsp90 interacts with the telomerase TERT component as shown by immunoprecipitation, strongly suggesting a new role for LHsp90 as a parasite telomerase component involved in controlling telomere length maintenance and parasite life span.},
}
@article {pmid34775545,
year = {2022},
author = {Panasiak, L and Szubert, K and Polonis, M and Ocalewicz, K},
title = {Telomere length variation does not correspond with the growth disturbances in the rainbow trout (Oncorhynchus mykiss).},
journal = {Journal of applied genetics},
volume = {63},
number = {1},
pages = {133-139},
pmid = {34775545},
issn = {2190-3883},
support = {2017/27/B/NZ9/00113//Narodowe Centrum Nauki/ ; },
mesh = {Animals ; Diploidy ; Female ; Haploidy ; Humans ; Infant ; Male ; *Oncorhynchus mykiss/genetics ; *Telomerase ; Telomere/genetics ; },
abstract = {Somatic growth is considered to affect pace of the telomere attrition in vertebrates. As normally developed and dwarf fish differ in the body size we have decided to compare telomere length in the rainbow trout (Oncorhynchus mykiss) with normal growth and with growth reduced due to the dwarf condition. Examined 1-year-old fish with normal and dwarf appearance were siblings originated from androgenetic fully homozygous doubled haploid (DH) line of rainbow trout. Particular dwarf individuals had body deformities such as humpback, kyphosis, and lordosis. Somatic cells of examined rainbow trout had an average telomere length between 17 and 20 kb, comparable in females and males. Dwarf rainbow trout exhibited significantly lower body length and weight than their normally developed siblings even though no differences in the telomere length were found between these fishes. Statistical analysis did not exhibit any correlation between body size and the telomere length. Equal length of telomeres observed in the studied normal and dwarf rainbow trout suggests morphological and physiological differences in fish with different growth rates do not affect dynamics of telomeric DNA. Or any variation in the telomere length might have been levelled by telomerase that in rainbow trout is active in all tissues irrespective of the individual developmental stage.},
}
@article {pmid34774607,
year = {2022},
author = {Kosmopoulos, M and Chiriacò, M and Stamatelopoulos, K and Tsioufis, C and Masci, PG and Kontogiannis, C and Mengozzi, A and Pugliese, NR and Taddei, S and Virdis, A and Masi, S and Georgiopoulos, G},
title = {The relationship between telomere length and putative markers of vascular ageing: A systematic review and meta-analysis.},
journal = {Mechanisms of ageing and development},
volume = {201},
number = {},
pages = {111604},
doi = {10.1016/j.mad.2021.111604},
pmid = {34774607},
issn = {1872-6216},
mesh = {Aging/*physiology ; *Blood Vessels/pathology/physiopathology ; Cardiovascular Physiological Phenomena ; Cellular Senescence/*physiology ; Humans ; Telomere Homeostasis/*physiology ; *Vascular Remodeling ; },
abstract = {Accelerated biological aging contributes to the evolution of cardiovascular disease. However, its influence on subclinical organ damage remains unclear. Leukocyte telomere length (LTL) is emerging as a marker of biological cardiovascular aging. We performed a systematic review and meta-analysis to assess the association between LTL and measures of end-organ damage. PubMed, Medline, Embase, Cinahl Plus, ClinicalTrials.gov, and grey literature databases were searched for studies that assessed the association of LTL with arterial pulse wave velocity (aPWV), carotid intima-media thickness (cIMT), left ventricular mass (LVM or LVMI), renal outcomes, coronary artery calcium (CAC) and presence of carotid plaques. In a sample of 7256 patients, we found that cIMT (pooled correlation coefficient (r) = -0.249; 95 %CI -0.37, -0.128) and aPWV (pooled r = -0.194; 95 % CI -0.290, -0.100) inversely correlate with LTL. Compared to aPWV, cIMT had a stronger correlation with LTL. Patients without carotid plaques had longer telomeres than patients with carotid plaques. Quantitative analyses documented LTL association with renal outcomes and CAC, but not with LVM/LVMI. Among measures of end-organ damage, cIMT and aPWV provide the most accurate information on the contribution of biological aging to the process of vascular remodeling/damage.},
}
@article {pmid34771533,
year = {2021},
author = {Chen, YY and Dagg, R and Zhang, Y and Lee, JHY and Lu, R and Martin La Rotta, N and Sampl, S and Korkut-Demirbaş, M and Holzmann, K and Lau, LMS and Reddel, RR and Henson, JD},
title = {The C-Circle Biomarker Is Secreted by Alternative-Lengthening-of-Telomeres Positive Cancer Cells inside Exosomes and Provides a Blood-Based Diagnostic for ALT Activity.},
journal = {Cancers},
volume = {13},
number = {21},
pages = {},
pmid = {34771533},
issn = {2072-6694},
support = {09CDF225//Cancer Institute NSW/ ; RG14-04//Cancer Council NSW/ ; },
abstract = {C-Circles, self-primed telomeric C-strand templates for rolling circle amplification, are the only known alternative-lengthening-of-telomeres (ALT)-specific molecule. However, little is known about the biology of C-Circles and if they may be clinically useful. Here we show that C-Circles are secreted by ALT+ cancer cells inside exosomes, and that a blood-based C-Circle Assay (CCA) can provide an accurate diagnostic for ALT activity. Extracellular vesicles were isolated by differential centrifugation from the growth media of lung adenocarcinoma, glioblastoma, neuroblastoma, osteosarcoma, and soft tissue sarcoma cell lines, and C-Circles were detected in the exosome fraction from all eleven ALT+ cancer cell lines and not in any extracellular fraction from the eight matching telomerase positive cancer cell lines or the normal fibroblast strain. The existence of C-Circles in ALT+ exosomes was confirmed with exosomes isolated by iodixanol gradient separation and CD81-immunoprecipitation, and C-Circles in the exosomes were protected from nucleases. On average, 0.4% of the total ALT+ intracellular C-Circles were secreted in the exosomes every 24 h. Comparing the serum-based and tumor-based CCAs in 35 high risk neuroblastoma patients divided randomly into ALT+ threshold derivation and validation groups, we found the serum-based CCA to have 100% sensitivity (6/6), 70% specificity (7/10), and 81% concordance (13/16). We conclude that the secretion of C-Circles by ALT+ cancer cells in the exosomes provides a stable blood-based biomarker and a potential clinical diagnostic for ALT activity.},
}
@article {pmid34769797,
year = {2021},
author = {Ribeiro, VB and Pedroso, DCC and Kogure, GS and Lopes, IP and Santana, BA and Dutra de Souza, HC and Ferriani, RA and Calado, RT and Furtado, CLM and Reis, RMD},
title = {Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study.},
journal = {International journal of environmental research and public health},
volume = {18},
number = {21},
pages = {},
pmid = {34769797},
issn = {1660-4601},
mesh = {Body Mass Index ; Exercise ; Female ; Humans ; *Insulin Resistance ; Obesity ; *Polycystic Ovary Syndrome ; Telomere ; Testosterone ; },
abstract = {Metabolic and hormonal outcomes of polycystic ovary syndrome (PCOS) have implications on telomere biology and physical activity may prevent telomere erosion. We sought to observe the effects of continuous (CAT) and intermittent (IAT) aerobic training on telomere length, inflammatory biomarkers, and its correlation with metabolic, hormonal, and anthropometric parameters of PCOS. This randomized controlled clinical trial study included 87 PCOS randomly stratified according to body mass index (BMI) in CAT (n = 28), IAT (n = 29) and non-training control group (CG, n = 30). The exercises were carried out on a treadmill, three times per week for 16 weeks. The participants' anthropometric characteristics and biochemical and hormonal concentrations were measured before and after aerobic training or observation period, as the telomere length that was evaluated using quantitative real-time PCR. Four months of aerobic exercises (CAT or IAT) did not alter telomere length and inflammatory biomarkers in PCOS women. Obesity index as BMI and waist circumference (WC), and inflammatory biomarkers negatively affect telomeres. The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC (p = 0.045), hip circumference (p = 0.032), serum cholesterol (p ≤ 0.001), and low-density lipoprotein (p = 0.030). Whereas, the IAT decreased WC (p = 0.014), waist-to-hip ratio (p = 0.012), free androgen index (FAI) (p = 0.037). WC (p = 0.049) and body fat (p = 0.015) increased in the non-training group while total cholesterol was reduced (p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers.},
}
@article {pmid34767620,
year = {2022},
author = {Sharma, R and Sahoo, SS and Honda, M and Granger, SL and Goodings, C and Sanchez, L and Künstner, A and Busch, H and Beier, F and Pruett-Miller, SM and Valentine, MB and Fernandez, AG and Chang, TC and Géli, V and Churikov, D and Hirschi, S and Pastor, VB and Boerries, M and Lauten, M and Kelaidi, C and Cooper, MA and Nicholas, S and Rosenfeld, JA and Polychronopoulou, S and Kannengiesser, C and Saintomé, C and Niemeyer, CM and Revy, P and Wold, MS and Spies, M and Erlacher, M and Coulon, S and Wlodarski, MW},
title = {Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.},
journal = {Blood},
volume = {139},
number = {7},
pages = {1039-1051},
pmid = {34767620},
issn = {1528-0020},
support = {P30 CA021765/CA/NCI NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; R35 GM131704/GM/NIGMS NIH HHS/United States ; U01 HG007709/HG/NHGRI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Bone Marrow Failure Disorders/etiology/metabolism/*pathology ; Cell Differentiation ; Child ; Female ; *Gain of Function Mutation ; *Heterozygote ; Humans ; Infant, Newborn ; Male ; Middle Aged ; Myelodysplastic Syndromes/etiology/metabolism/*pathology ; Replication Protein A/*genetics ; Telomere/*genetics ; *Telomere Shortening ; Young Adult ; },
abstract = {Human telomere biology disorders (TBD)/short telomere syndromes (STS) are heterogeneous disorders caused by inherited loss-of-function mutations in telomere-associated genes. Here, we identify 3 germline heterozygous missense variants in the RPA1 gene in 4 unrelated probands presenting with short telomeres and varying clinical features of TBD/STS, including bone marrow failure, myelodysplastic syndrome, T- and B-cell lymphopenia, pulmonary fibrosis, or skin manifestations. All variants cluster to DNA-binding domain A of RPA1 protein. RPA1 is a single-strand DNA-binding protein required for DNA replication and repair and involved in telomere maintenance. We showed that RPA1E240K and RPA1V227A proteins exhibit increased binding to single-strand and telomeric DNA, implying a gain in DNA-binding function, whereas RPA1T270A has binding properties similar to wild-type protein. To study the mutational effect in a cellular system, CRISPR/Cas9 was used to knock-in the RPA1E240K mutation into healthy inducible pluripotent stem cells. This resulted in severe telomere shortening and impaired hematopoietic differentiation. Furthermore, in patients with RPA1E240K, we discovered somatic genetic rescue in hematopoietic cells due to an acquired truncating cis RPA1 mutation or a uniparental isodisomy 17p with loss of mutant allele, coinciding with stabilized blood counts. Using single-cell sequencing, the 2 somatic genetic rescue events were proven to be independently acquired in hematopoietic stem cells. In summary, we describe the first human disease caused by germline RPA1 variants in individuals with TBD/STS.},
}
@article {pmid34764923,
year = {2021},
author = {Bhatt, SP and Guleria, R and Vikram, NK},
title = {The Effect of the Severity of Obstructive Sleep Apnea on Leukocyte Telomere Length, 25 Hydroxy Vitamin D, and Parathyroid Hormonal Concentrations in Asian Indians.},
journal = {Frontiers in neurology},
volume = {12},
number = {},
pages = {682739},
pmid = {34764923},
issn = {1664-2295},
abstract = {Background: Obstructive sleep apnea (OSA) is a common disorder in which breathing repeatedly stops during sleep. Leukocyte telomere length (LTL) and OSA are linked with an increased risk of oxidative stress and inflammation. The possible link between LTL and OSA in Asian Indians has not been evaluated. Thus, the present study aims to compare the link between LTL and OSA in Asian Indians. Methods: In this study, 300 subjects (120 obese with OSA, 110 obese without OSA, and 70 non-obese without OSA) were included after overnight polysomnography and a fasting blood sample. Clinical, anthropometry, metabolic markers, insulin, 25-hydroxyvitamin D [25(OH) D], and parathyroid hormones (PTH) levels were investigated. LTL was investigated by a QPCR. Univariate and stepwise multivariate linear regression analyses adjusting for age, gender, BMI, and % body fat were conducted while treating LTL as a dependent variable in relation to AHI and other covariates. Results: Obese subjects with OSA had significantly decreased 25(OH)D and increased PTH levels. The mean telomere length (T/S) ratio was significantly shorter in patients with OSA. The adjusted correlation analysis showed that shortening of telomere length correlated with increasing age, apnea-hypopnea index (AHI), oxygen desaturation index, and RDI. Univariate analysis showed that LTL revealed a trend toward a negative correlation with a mean age (β + SE, -0.015 + 0.0006; p = 0.01) and positive correlation with AHI [β +slandered error (SE), 0.042 + 0.017; p = 0.008]. In the multiple regression analysis, LTL was positively associated with AHI (β + SE, 0.281 + 0.04; p = 0.001) after adjusting for age, sex, BMI, and % body fat. Even when adjusted for confounding factors, 25(OH)D, and PTH levels, LTL still was related to AHI (β + SE, 0.446 + 0.02; p = 0.05). Conclusion: Our study indicates the presence of an association between LTL and OSA and a significant impact of OSA severity and telomeres shortening in Asian Indians.},
}
@article {pmid34761561,
year = {2022},
author = {Garfein, J and Flannagan, KSJ and Mora-Plazas, M and Oliveros, H and Marín, C and Villamor, E},
title = {Prospective associations between leukocyte telomere length and adiposity in childhood.},
journal = {Pediatric obesity},
volume = {17},
number = {4},
pages = {e12868},
doi = {10.1111/ijpo.12868},
pmid = {34761561},
issn = {2047-6310},
mesh = {*Adiposity/genetics ; Adolescent ; Child ; Child, Preschool ; Colombia ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes ; Male ; Models, Biological ; *Obesity/genetics ; Prospective Studies ; Sex Factors ; *Telomere/genetics ; Waist Circumference/genetics ; },
abstract = {Leukocyte telomere length (LTL) is associated with obesity and may be involved in its aetiology, but few studies have focused on children and most have been cross-sectional. We assessed the relation of LTL with adiposity development in a prospective study of Colombian children. We quantified LTL at enrollment in 722 children aged 5-12 years and measured anthropometry annually for a median 6 years. Using mixed effects models, we estimated changes in adiposity measures including BMI and waist circumference (WC)-for-age z-scores in relation to baseline LTL z-score. In girls, longer LTL was linearly related to a lower increase in WC z-score from age 6 to 16 years. Every 1 SD LTL was associated with an adjusted 0.13 units lower increase in WC (95% CI: -0.23, -0.03; p = 0.01). In conclusion, longer LTL among girls in middle childhood is associated with smaller increases in WC, an indicator of abdominal adiposity.},
}
@article {pmid34761263,
year = {2021},
author = {Higa, M and Matsuda, Y and Fujii, J and Sugimoto, N and Yoshida, K and Fujita, M},
title = {TRF2-mediated ORC recruitment underlies telomere stability upon DNA replication stress.},
journal = {Nucleic acids research},
volume = {49},
number = {21},
pages = {12234-12251},
pmid = {34761263},
issn = {1362-4962},
mesh = {Cell Line, Tumor ; DNA Damage ; DNA Replication/*genetics ; Gene Expression Regulation ; HCT116 Cells ; HEK293 Cells ; HeLa Cells ; Humans ; Microscopy, Fluorescence ; *Mutation ; Origin Recognition Complex/*genetics ; Protein Binding ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/*genetics/metabolism ; },
abstract = {Telomeres are intrinsically difficult-to-replicate region of eukaryotic chromosomes. Telomeric repeat binding factor 2 (TRF2) binds to origin recognition complex (ORC) to facilitate the loading of ORC and the replicative helicase MCM complex onto DNA at telomeres. However, the biological significance of the TRF2-ORC interaction for telomere maintenance remains largely elusive. Here, we employed a TRF2 mutant with mutations in two acidic acid residues (E111A and E112A) that inhibited the TRF2-ORC interaction in human cells. The TRF2 mutant was impaired in ORC recruitment to telomeres and showed increased replication stress-associated telomeric DNA damage and telomere instability. Furthermore, overexpression of an ORC1 fragment (amino acids 244-511), which competitively inhibited the TRF2-ORC interaction, increased telomeric DNA damage under replication stress conditions. Taken together, these findings suggest that TRF2-mediated ORC recruitment contributes to the suppression of telomere instability.},
}
@article {pmid34758087,
year = {2022},
author = {Kachuri, L and Walsh, KM},
title = {Long telomeres in need of a SNP: Germline contributions of telomere maintenance to glioma.},
journal = {Neuro-oncology},
volume = {24},
number = {2},
pages = {182-183},
pmid = {34758087},
issn = {1523-5866},
support = {P30 CA014236/CA/NCI NIH HHS/United States ; },
mesh = {*Glioma/genetics ; Humans ; *Telomere/genetics ; },
}
@article {pmid34754432,
year = {2021},
author = {Gurung, RL and Dorajoo, R and M, Y and Wang, L and Liu, S and Liu, JJ and Shao, YM and Chen, Y and Sim, X and Ang, K and Subramaniam, T and Tang, WE and Sum, CF and Liu, JJ and Lim, SC},
title = {Association of leukocyte telomere length with chronic kidney disease in East Asians with type 2 diabetes: a Mendelian randomization study.},
journal = {Clinical kidney journal},
volume = {14},
number = {11},
pages = {2371-2376},
pmid = {34754432},
issn = {2048-8505},
abstract = {BACKGROUND: Chronic kidney disease (CKD) is common among people with type 2 diabetes (T2D), and increases the risk of kidney failure and cardiovascular diseases. Shorter leukocyte telomere length (LTL) is associated with CKD in patients with T2D. We previously reported single-nucleotide polymorphisms (SNPs) associated with LTL in an Asian population. In this study, we elucidated the association of these SNPs with CKD in patients with T2D using the Mendelian randomization (MR) approach.<br><br>METHODS: The cross-sectional association of 16 LTL SNPs with CKD, defined as an estimated glomerular filtration rate of <60&#x2009;mL/min/1.73&#x2009;m[2], was assessed among 4768 (1628 cases and 3140 controls) participants in the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in T2D and Diabetic Nephropathy cohorts. MR analysis was performed using the random-effect inverse-variance weighted (IVW) method, the weighted median, MR-Egger and Radial MR adjusted for age and sex-stratified by cohorts and ethnicity (Chinese and Malays), then meta-analyzed.<br><br>RESULTS: Genetically determined shorter LTL was associated with increased risk of CKD in patients with T2D (meta-IVW adjusted odds ratio&#x2009;= 1.51, 95% confidence interval 1.12-2.12, P&#x2009;=&#x2009;0.007, Phet &#x2009;=&#x2009;0.547). Similar results were obtained following sensitivity analysis. MR-Egger analysis (intercept) suggested no evidence of horizontal pleiotropy (&#x3b2;&#x2009;=&#x2009;0.010, P&#x2009;=&#x2009;0.751).<br><br>CONCLUSIONS: Our findings suggest that genetically determined LTL is associated with CKD in patients with T2D. Further studies are warranted to elucidate the causal role of telomere length in CKD progression.},
}
@article {pmid34752684,
year = {2021},
author = {Wang, L and Lu, Z and Zhao, J and Schank, M and Cao, D and Dang, X and Nguyen, LN and Nguyen, LNT and Khanal, S and Zhang, J and Wu, XY and El Gazzar, M and Ning, S and Moorman, JP and Yao, ZQ},
title = {Selective oxidative stress induces dual damage to telomeres and mitochondria in human T cells.},
journal = {Aging cell},
volume = {20},
number = {12},
pages = {e13513},
pmid = {34752684},
issn = {1474-9726},
support = {S10 OD021572/OD/NIH HHS/United States ; I01 BX004281/BX/BLRD VA/United States ; R01 AI114748/AI/NIAID NIH HHS/United States ; R21 AI157909/AI/NIAID NIH HHS/United States ; I01 BX002670/BX/BLRD VA/United States ; R21 AI138598/AI/NIAID NIH HHS/United States ; R15 AG069544/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Mitochondria/*metabolism ; Oxidative Stress/*genetics ; T-Lymphocytes/*metabolism ; Telomere/*metabolism ; },
abstract = {Oxidative stress caused by excess reactive oxygen species (ROS) accelerates telomere erosion and mitochondrial injury, leading to impaired cellular functions and cell death. Whether oxidative stress-mediated telomere erosion induces mitochondrial injury, or vice versa, in human T cells-the major effectors of host adaptive immunity against infection and malignancy-is poorly understood due to the pleiotropic effects of ROS. Here we employed a novel chemoptogenetic tool that selectively produces a single oxygen ([1] O2) only at telomeres or mitochondria in Jurkat T cells. We found that targeted [1] O2 production at telomeres triggered not only telomeric DNA damage but also mitochondrial dysfunction, resulting in T cell apoptotic death. Conversely, targeted [1] O2 formation at mitochondria induced not only mitochondrial injury but also telomeric DNA damage, leading to cellular crisis and apoptosis. Targeted oxidative stress at either telomeres or mitochondria increased ROS production, whereas blocking ROS formation during oxidative stress reversed the telomeric injury, mitochondrial dysfunction, and cellular apoptosis. Notably, the X-ray repair cross-complementing protein 1 (XRCC1) in the base excision repair (BER) pathway and multiple mitochondrial proteins in other cellular pathways were dysregulated by the targeted oxidative stress. By confining singlet [1] O2 formation to a single organelle, this study suggests that oxidative stress induces dual injury in T cells via crosstalk between telomeres and mitochondria. Further identification of these oxidation pathways may offer a novel approach to preserve mitochondrial functions, protect telomere integrity, and maintain T cell survival, which can be exploited to combat various immune aging-associated diseases.},
}
@article {pmid34747482,
year = {2021},
author = {Lin, CG and Näger, AC and Lunardi, T and Vančevska, A and Lossaint, G and Lingner, J},
title = {The human telomeric proteome during telomere replication.},
journal = {Nucleic acids research},
volume = {49},
number = {21},
pages = {12119-12135},
pmid = {34747482},
issn = {1362-4962},
mesh = {*DNA Replication ; HEK293 Cells ; HeLa Cells ; Histones/metabolism ; Humans ; Shelterin Complex/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Shortening ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomere shortening can cause detrimental diseases and contribute to aging. It occurs due to the end replication problem in cells lacking telomerase. Furthermore, recent studies revealed that telomere shortening can be attributed to difficulties of the semi-conservative DNA replication machinery to replicate the bulk of telomeric DNA repeats. To investigate telomere replication in a comprehensive manner, we develop QTIP-iPOND - Quantitative Telomeric chromatin Isolation Protocol followed by isolation of Proteins On Nascent DNA - which enables purification of proteins that associate with telomeres specifically during replication. In addition to the core replisome, we identify a large number of proteins that specifically associate with telomere replication forks. Depletion of several of these proteins induces telomere fragility validating their importance for telomere replication. We also find that at telomere replication forks the single strand telomere binding protein POT1 is depleted, whereas histone H1 is enriched. Our work reveals the dynamic changes of the telomeric proteome during replication, providing a valuable resource of telomere replication proteins. To our knowledge, this is the first study that examines the replisome at a specific region of the genome.},
}
@article {pmid34745087,
year = {2021},
author = {Chuenwisad, K and More-Krong, P and Tubsaeng, P and Chotechuang, N and Srisa-Art, M and Storer, RJ and Boonla, C},
title = {Premature Senescence and Telomere Shortening Induced by Oxidative Stress From Oxalate, Calcium Oxalate Monohydrate, and Urine From Patients With Calcium Oxalate Nephrolithiasis.},
journal = {Frontiers in immunology},
volume = {12},
number = {},
pages = {696486},
pmid = {34745087},
issn = {1664-3224},
mesh = {Aged ; Aging, Premature/*etiology ; Calcium Oxalate/*pharmacology ; Cell Line ; Cyclin-Dependent Kinase Inhibitor p16/analysis ; DNA Damage ; Female ; Humans ; Hydrogen Peroxide/pharmacology ; Male ; Middle Aged ; Nephrolithiasis/etiology/*urine ; Oxalates/*pharmacology ; Oxidative Stress/*drug effects ; *Telomere Shortening ; Telomeric Repeat Binding Protein 1/genetics ; },
abstract = {Oxidative stress, a well-known cause of stress-induced premature senescence (SIPS), is increased in patients with calcium oxalate (CaOx) kidney stones (KS). Oxalate and calcium oxalate monohydrate (COM) induce oxidative stress in renal tubular cells, but to our knowledge, their effect on SIPS has not yet been examined. Here, we examined whether oxalate, COM, or urine from patients with CaOx KS could induce SIPS and telomere shortening in human kidney (HK)-2 cells, a proximal tubular renal cell line. Urine from age- and sex-matched individuals without stones was used as a control. In sublethal amounts, H2O2, oxalate, COM, and urine from those with KS evoked oxidative stress in HK-2 cells, indicated by increased protein carbonyl content and decreased total antioxidant capacity, but urine from those without stones did not. The proportion of senescent HK-2 cells, as indicated by SA-βgal staining, increased after treatment with H2O2, oxalate, COM, and urine from those with KS. Expression of p16 was higher in HK-2 cells treated with H2O2, oxalate, COM, and urine from those with KS than it was in cells treated with urine from those without stones and untreated controls. p16 was upregulated in the SA-βgal positive cells. Relative telomere length was shorter in HK-2 cells treated with H2O2, oxalate, COM, and urine from those with KS than that in cells treated with urine from those without stones and untreated controls. Transcript expression of shelterin components (TRF1, TRF2 and POT1) was decreased in HK-2 cells treated with H2O2, oxalate, COM, and urine from those with KS, in which case the expression was highest. Urine from those without KS did not significantly alter TRF1, TRF2, and POT1 mRNA expression in HK-2 cells relative to untreated controls. In conclusion, oxalate, COM, and urine from patients with CaOx KS induced SIPS and telomere shortening in renal tubular cells. SIPS induced by a lithogenic milieu may result from upregulation of p16 and downregulation of shelterin components, specifically POT1, and might contribute, at least in part, to the development of CaOx KS.},
}
@article {pmid34741234,
year = {2022},
author = {Li, Z and Li, W and Zhou, D and Zhao, J and Ma, Y and Huang, L and Dong, C and Wilson, JX and Huang, G},
title = {Alleviating Oxidative Damage-Induced Telomere Attrition: a Potential Mechanism for Inhibition by Folic Acid of Apoptosis in Neural Stem Cells.},
journal = {Molecular neurobiology},
volume = {59},
number = {1},
pages = {590-602},
pmid = {34741234},
issn = {1559-1182},
support = {81730091//National Natural Science Foundation of China/ ; 19JCQNJC11700//Natural Science Foundation of Tianjin City/ ; },
mesh = {Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Cell Proliferation/drug effects ; Corpus Striatum/drug effects/metabolism ; Folic Acid/*pharmacology ; Hippocampus/drug effects/metabolism ; Hydrogen Peroxide/pharmacology ; Neural Stem Cells/*drug effects/metabolism ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Telomere/*drug effects/metabolism ; },
abstract = {DNA oxidative damage can cause telomere attrition or dysfunction that triggers cell senescence and apoptosis. The hypothesis of this study is that folic acid decreases apoptosis in neural stem cells (NSCs) by preventing oxidative stress-induced telomere attrition. Primary cultures of NSCs were incubated for 9 days with various concentrations of folic acid (0-40 µM) and then incubated for 24 h with a combination of folic acid and an oxidant (100-µM hydrogen peroxide, H2O2), antioxidant (10-mM N-acetyl-L-cysteine, NAC), or vehicle. Intracellular folate concentration, apoptosis rate, cell proliferative capacity, telomere length, telomeric DNA oxidative damage, telomerase activity, intracellular reactive oxygen species (ROS) levels, cellular oxidative damage, and intracellular antioxidant enzyme activities were determined. The results showed that folic acid deficiency in NSCs decreased intracellular folate concentration, cell proliferation, telomere length, and telomerase activity but increased apoptosis, telomeric DNA oxidative damage, and intracellular ROS levels. In contrast, folic acid supplementation dose-dependently increased intracellular folate concentration, cell proliferative capacity, telomere length, and telomerase activity but decreased apoptosis, telomeric DNA oxidative damage, and intracellular ROS levels. Exposure to H2O2 aggravated telomere attrition and oxidative damage, whereas NAC alleviated the latter. High doses of folic acid prevented telomere attrition and telomeric DNA oxidative damage by H2O2. In conclusion, inhibition of telomeric DNA oxidative damage and telomere attrition in NSCs may be potential mechanisms of inhibiting NSC apoptosis by folic acid.},
}
@article {pmid34737398,
year = {2022},
author = {Goddard, T and Tsintzas, K and Stephan, BCM and Prado, CM and Mazidi, M and Siervo, M},
title = {Sarcopenic obesity is associated with telomere shortening: findings from the NHANES 1999-2002.},
journal = {International journal of obesity (2005)},
volume = {46},
number = {2},
pages = {437-440},
pmid = {34737398},
issn = {1476-5497},
mesh = {Absorptiometry, Photon/methods/statistics &amp; numerical data ; Adult ; Body Mass Index ; Female ; Humans ; Male ; Middle Aged ; Obesity/epidemiology/*etiology/physiopathology ; Risk Factors ; Sarcopenia/*complications/epidemiology/physiopathology ; Surveys and Questionnaires ; Telomere Shortening/*physiology ; },
abstract = {Sarcopenic obesity (SO) is characterised by the concurrent presence of sarcopenia and excess adiposity. Telomere shortening has been associated with sarcopenia and obesity alone but the association between SO and telomere length (TL) has not been investigated. This study aimed to investigate SO and TL in an adult population. Data were from 5397 individuals (mean age = 44.7 years, 51.3% male) enrolled in the National Health and Nutrition Examination Survey. Body composition (BC) was assessed by Dual Energy X-Ray Absorptiometry. Two models were used to assess SO: a BC model including four phenotypes derived from the combination of high or low adiposity and muscle mass; and, a truncal fat mass to appendicular skeletal mass ratio (TrFM/ASM). TL was assessed using quantitative polymerase chain reaction and expressed as base pairs. The mean TL, relative to the reference DNA, was calculated and expressed as the mean T/S ratio. A General Linear Model was applied to determine associations between TL for SO. In adjusted analysis, only individuals with SO, defined as the presence of high adiposity-low muscle mass (four-phenotype model), had significantly shorter telomeres (p = 0.05) than the reference group (i.e. low adiposity-high muscle mass), with a mean T/S ratio of 1.02 (95%CI: 0.98-1.05) compared to 1.05 (95%CI: 1.01-1.09), respectively. TrFM/ASM was not associated with TL. Preliminary findings suggest that sarcopenia and obesity may act synergistically to shorten telomeres.},
}
@article {pmid34737002,
year = {2022},
author = {Brázda, V and Bohálová, N and Bowater, RP},
title = {New telomere to telomere assembly of human chromosome 8 reveals a previous underestimation of G-quadruplex forming sequences and inverted repeats.},
journal = {Gene},
volume = {810},
number = {},
pages = {146058},
doi = {10.1016/j.gene.2021.146058},
pmid = {34737002},
issn = {1879-0038},
mesh = {*Chromosomes, Human, Pair 8 ; *G-Quadruplexes ; Genome, Human ; Humans ; Sequence Analysis, DNA ; *Sequence Inversion ; *Telomere ; },
abstract = {Taking advantage of evolving and improving sequencing methods, human chromosome 8 is now available as a gapless, end-to-end assembly. Thanks to advances in long-read sequencing technologies, its centromere, telomeres, duplicated gene families and repeat-rich regions are now fully sequenced. We were interested to assess if the new assembly altered our understanding of the potential impact of non-B DNA structures within this completed chromosome sequence. It has been shown that non-B secondary structures, such as G-quadruplexes, hairpins and cruciforms, have important regulatory functions and potential as targeted therapeutics. Therefore, we analysed the presence of putative G-quadruplex forming sequences and inverted repeats in the current human reference genome (GRCh38) and in the new end-to-end assembly of chromosome 8. The comparison revealed that the new assembly contains significantly more inverted repeats and G-quadruplex forming sequences compared to the current reference sequence. This observation can be explained by improved accuracy of the new sequencing methods, particularly in regions that contain extensive repeats of bases, as is preferred by many non-B DNA structures. These results show a significant underestimation of the prevalence of non-B DNA secondary structure in previous assembly versions of the human genome and point to their importance being not fully appreciated. We anticipate that similar observations will occur as the improved sequencing technologies fill in gaps across the genomes of humans and other organisms.},
}
@article {pmid34736994,
year = {2022},
author = {Lin, J and Epel, E},
title = {Stress and telomere shortening: Insights from cellular mechanisms.},
journal = {Ageing research reviews},
volume = {73},
number = {},
pages = {101507},
pmid = {34736994},
issn = {1872-9649},
support = {R01 HL128156/HL/NHLBI NIH HHS/United States ; R24 AG048024/AG/NIA NIH HHS/United States ; U01 AG064785/AG/NIA NIH HHS/United States ; U24 AG066528/AG/NIA NIH HHS/United States ; },
mesh = {Aging/genetics ; Cellular Senescence ; Female ; Humans ; Mitochondria/metabolism ; Pregnancy ; Reactive Oxygen Species ; *Telomerase/metabolism ; Telomere/metabolism ; *Telomere Shortening ; },
abstract = {Short telomeres confer risk of degenerative diseases. Chronic psychological stress can lead to disease through many pathways, and research from in vitro studies to human longitudinal studies has pointed to stress-induced telomere damage as an important pathway. However, there has not been a comprehensive model to describe how changes in stress physiology and neuroendocrine pathways can lead to changes in telomere biology. Critically short telomeres or the collapse of the telomere structure caused by displacement of telomere binding protein complex shelterin elicit a DNA damage response and lead to senescence or apoptosis. In this narrative review, we summarize the key roles glucocorticoids, reactive oxygen species (ROS) and mitochondria, and inflammation play in mediating the relationship between psychological stress and telomere maintenance. We emphasis that these mediators are interconnected and reinforce each other in positive feedback loops. Telomere length has not been studied across the lifespan yet, but the initial setting point at birth appears to be the most influential point, as it sets the lifetime trajectory, and is influenced by stress. We describe two types of intergenerational stress effects on telomeres - prenatal stress effects on telomeres during fetal development, and 'telotype transmission" -the directly inherited transmission of short telomeres from parental germline. It is clear that the initial simplistic view of telomere length as a mitotic clock has evolved into a far more complex picture of both transgenerational telomere influences, and of interconnected molecular and cellular pathways and networks, as hallmarks of aging where telomere maintenance is a key player interacting with mitochondria. Further mechanistic investigations testing this comprehensive model of stress mediators shaping telomere biology and the telomere-mitochondrial nexus will lead to better understanding from cell to human lifespan aging, and could lead to anti-aging interventions.},
}
@article {pmid34736527,
year = {2021},
author = {Torres-Montaner, A},
title = {The telomere complex and the origin of the cancer stem cell.},
journal = {Biomarker research},
volume = {9},
number = {1},
pages = {81},
pmid = {34736527},
issn = {2050-7771},
abstract = {Exquisite regulation of telomere length is essential for the preservation of the lifetime function and self-renewal of stem cells. However, multiple oncogenic pathways converge on induction of telomere attrition or telomerase overexpression and these events can by themselves trigger malignant transformation. Activation of NFκB, the outcome of telomere complex damage, is present in leukemia stem cells but absent in normal stem cells and can activate DOT1L which has been linked to MLL-fusion leukemias. Tumors that arise from cells of early and late developmental stages appear to follow two different oncogenic routes in which the role of telomere and telomerase signaling might be differentially involved. In contrast, direct malignant transformation of stem cells appears to be extremely rare. This suggests an inherent resistance of stem cells to cancer transformation which could be linked to a stem cell'specific mechanism of telomere maintenance. However, tumor protection of normal stem cells could also be conferred by cell extrinsic mechanisms.},
}
@article {pmid34727279,
year = {2023},
author = {Daoust, AR and Thakur, A and Kotelnikova, Y and Kleiber, ML and Singh, SM and Hayden, EP},
title = {Associations Between Children's Telomere Length, Parental Intrusiveness, and the Development of Early Externalizing Behaviors.},
journal = {Child psychiatry and human development},
volume = {54},
number = {3},
pages = {672-682},
pmid = {34727279},
issn = {1573-3327},
mesh = {*Telomere/metabolism ; *Parents/psychology ; *Child Behavior/psychology ; *Parenting/psychology ; Humans ; Male ; Female ; Child, Preschool ; Child ; *Acting Out ; Adverse Childhood Experiences/psychology ; Sex Characteristics ; Stress, Psychological/psychology ; Adult ; Attention ; Aggression ; Child Behavior Disorders/psychology ; },
abstract = {Shorter telomeres mark cellular aging and are linked to chronic stress exposure as well as negative physical and psychological outcomes. However, it is unclear whether telomere length mediates associations between early stress exposure and later externalizing problems, or whether boys and girls differ in pathways to these concerns. We therefore examined associations between telomere length, early stress via negative caregiving, and children's externalizing symptom development over time in 409 three-year-old children and their parents. Telomere length mediated the association between early parental intrusiveness and later rule-breaking behavior; however, this association was moderated by children's biological sex such that parent intrusiveness was related only to boys' rule-breaking. Findings support the notion that children's telomere length may mark individual differences in responses to negative early caregiving, and highlight a potential mechanism contributing to the development of rule-breaking problems in boys.},
}
@article {pmid34725903,
year = {2022},
author = {Pal, J and Rajput, Y and Shrivastava, S and Gahine, R and Mungutwar, V and Barardiya, T and Chandrakar, A and Ramakrishna, PP and Mishra, SS and Banjara, H and Choudhary, V and Patra, PK and Shammas, MA},
title = {A standalone approach to utilize telomere length measurement as a surveillance tool in oral leukoplakia.},
journal = {Molecular oncology},
volume = {16},
number = {8},
pages = {1650-1660},
pmid = {34725903},
issn = {1878-0261},
support = {I01 BX001584/BX/BLRD VA/United States ; P50 CA100707/CA/NCI NIH HHS/United States ; },
mesh = {*Carcinoma, Squamous Cell/diagnosis/genetics/metabolism ; Female ; *Head and Neck Neoplasms ; Humans ; Leukocytes, Mononuclear/metabolism ; Leukoplakia, Oral/diagnosis/genetics/metabolism ; Male ; *Mouth Neoplasms/genetics ; Telomere/metabolism/pathology ; },
abstract = {Oral squamous cell carcinoma (OSCC) is often preceded by a white patch on a surface of the mouth, called oral leukoplakia (OL). As accelerated telomere length (TL) shortening in dividing epithelial cells may lead to oncogenic transformation, telomere length measurement could serve as a predictive biomarker in OL. However, due to high variability and lack of a universal reference, there has been a limited translational application. Here, we describe an approach of evaluating TL using paired peripheral blood mononuclear cells (PBMC) as an internal reference and demonstrate its translational relevance. Oral brush biopsy and paired venous blood were collected from 50 male OL patients and 44 male healthy controls (HC). Relative TL was measured by quantitative PCR. TL of each OL or healthy sample was normalized to the paired PBMC sample (TL ratio). In OL patients, the mean TL ratio was significantly smaller not only in the patch but also in distal normal oral tissue, relative to healthy controls without a high-risk oral habit. Dysplasia was frequently associated with a subgroup that showed a normal TL ratio at the patch but significantly smaller TL ratio at a paired normal distal site. Our data suggest that evaluation of TL attrition using a paired PBMC sample eliminates the requirement of external reference DNA, makes data universally comparable and provides a useful marker to define high-risk OL groups for follow-up programs. Larger studies will further validate the approach and its broader application in other premalignant conditions.},
}
@article {pmid34725692,
year = {2021},
author = {Ghadaouia, S and Olivier, MA and Martinez, A and Kientega, T and Qin, J and Lambert-Lanteigne, P and Cardin, GB and Autexier, C and Malaquin, N and Rodier, F},
title = {Homologous recombination-mediated irreversible genome damage underlies telomere-induced senescence.},
journal = {Nucleic acids research},
volume = {49},
number = {20},
pages = {11690-11707},
pmid = {34725692},
issn = {1362-4962},
support = {MOP114962//CIHR/Canada ; },
mesh = {Cells, Cultured ; DNA Damage ; DNA End-Joining Repair ; *Genomic Instability ; *Homologous Recombination ; Humans ; Rad51 Recombinase/metabolism ; Telomere Shortening/*genetics ; },
abstract = {Loss of telomeric DNA leads to telomere uncapping, which triggers a persistent, p53-centric DNA damage response that sustains a stable senescence-associated proliferation arrest. Here, we show that in normal cells telomere uncapping triggers a focal telomeric DNA damage response accompanied by a transient cell cycle arrest. Subsequent cell division with dysfunctional telomeres resulted in sporadic telomeric sister chromatid fusions that gave rise to next-mitosis genome instability, including non-telomeric DNA lesions responsible for a stable, p53-mediated, senescence-associated proliferation arrest. Unexpectedly, the blocking of Rad51/RPA-mediated homologous recombination, but not non-homologous end joining (NHEJ), prevented senescence despite multiple dysfunctional telomeres. When cells approached natural replicative senescence, interphase senescent cells displayed genome instability, whereas near-senescent cells that underwent mitosis despite the presence of uncapped telomeres did not. This suggests that these near-senescent cells had not yet acquired irreversible telomeric fusions. We propose a new model for telomere-initiated senescence where tolerance of telomere uncapping eventually results in irreversible non-telomeric DNA lesions leading to stable senescence. Paradoxically, our work reveals that senescence-associated tumor suppression from telomere shortening requires irreversible genome instability at the single-cell level, which suggests that interventions to repair telomeres in the pre-senescent state could prevent senescence and genome instability.},
}
@article {pmid34725130,
year = {2021},
author = {Lazzerini Denchi, E and Celli, G and de Lange, T},
title = {Corrigendum: Hepatocytes with extensive telomere deprotection and fusion remain viable and regenerate liver mass through endoreduplication.},
journal = {Genes &amp; development},
volume = {35},
number = {21-22},
pages = {1548-1549},
doi = {10.1101/gad.349030.121},
pmid = {34725130},
issn = {1549-5477},
}
@article {pmid34718547,
year = {2021},
author = {Holland, CL and Sanderson, BA and Titus, JK and Weis, MF and Riojas, AM and Malczewskyj, E and Wasko, BM and Lewis, LK},
title = {Suppression of telomere capping defects of Saccharomyces cerevisiae yku70 and yku80 mutants by telomerase.},
journal = {G3 (Bethesda, Md.)},
volume = {11},
number = {12},
pages = {},
pmid = {34718547},
issn = {2160-1836},
support = {R25 GM102783/GM/NIGMS NIH HHS/United States ; R15 GM139093/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA-Binding Proteins/genetics/metabolism ; Repressor Proteins ; Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; Telomere-Binding Proteins/genetics ; },
abstract = {The Ku complex performs multiple functions inside eukaryotic cells, including protection of chromosomal DNA ends from degradation and fusion events, recruitment of telomerase, and repair of double-strand breaks (DSBs). Inactivation of Ku complex genes YKU70 or YKU80 in cells of the yeast Saccharomyces cerevisiae gives rise to mutants that exhibit shortened telomeres and temperature-sensitive growth. In this study, we have investigated the mechanism by which overexpression of telomerase suppresses the temperature sensitivity of yku mutants. Viability of yku cells was restored by overexpression of the Est2 reverse transcriptase and TLC1 RNA template subunits of telomerase, but not the Est1 or Est3 proteins. Overexpression of other telomerase- and telomere-associated proteins (Cdc13, Stn1, Ten1, Rif1, Rif2, Sir3, and Sir4) did not suppress the growth defects of yku70 cells. Mechanistic features of suppression were assessed using several TLC1 RNA deletion derivatives and Est2 enzyme mutants. Supraphysiological levels of three catalytically inactive reverse transcriptase mutants (Est2-D530A, Est2-D670A, and Est2-D671A) suppressed the loss of viability as efficiently as the wild-type Est2 protein, without inducing cell senescence. Roles of proteins regulating telomere length were also determined. The results support a model in which chromosomes in yku mutants are stabilized via a replication-independent mechanism involving structural reinforcement of protective telomere cap structures.},
}
@article {pmid34717997,
year = {2022},
author = {He, J and Ge, X and Cheng, H and Bao, Y and Feng, X and Zan, G and Wang, F and Zou, Y and Yang, X},
title = {Sex-specific associations of exposure to metal mixtures with telomere length change: Results from an 8-year longitudinal study.},
journal = {The Science of the total environment},
volume = {811},
number = {},
pages = {151327},
doi = {10.1016/j.scitotenv.2021.151327},
pmid = {34717997},
issn = {1879-1026},
mesh = {Bayes Theorem ; *Cadmium ; Female ; Humans ; Longitudinal Studies ; Male ; *Metals/toxicity ; Telomere ; },
abstract = {Studies on the relationships between exposure to metal mixtures and telomere length (TL) are limited, particularly longitudinal studies. Few studies are available on the potential sex-specific associations between metal exposures and TL change. We examined blood metal concentrations and TL at baseline (August 2012) and follow-up (June 2020) among 316 participants in a ferro-manganese refinery. The least absolute shrinkage and selection operator (LASSO) followed by the generalized linear model (GLM) was applied to evaluate the associations between multiple-metal exposures and TL change (TL in 2012 minus TL in 2020). Bayesian kernel machine regression (BKMR) was applied to cope with metal mixtures and evaluate their joint effects on TL change. Among men, three statistical methods consistently showed rubidium was negatively associated with TL change (β [95% CI] = -2.755 [-5.119, -0.391] in the GLM) and dominated the negative overall effects of 10 metal mixtures (magnesium, manganese, iron, cobalt, copper, zinc, selenium, rubidium, cadmium, and lead) on TL change (posterior inclusion probabilities = 0.816). Among women, the GLM (β [95% CI] = 4.463 [0.943, 7.983]) and LASSO (β = 4.289) showed rubidium was positively associated with TL change. Interestingly, no significant association was observed between exposure to metal mixtures and TL change in overall participants (P > 0.05). Furthermore, stratified analysis showed significant relationships between rubidium and TL change in men (β = -2.744), women (β = 3.624), and current smokers (β = -3.266) (both P interaction <0.05). In summary, our findings underlined the steady and negative association between rubidium and TL change among men with potential sex-dependent heterogeneities. Further experimental studies are required to expound the underlying mechanisms.},
}
@article {pmid34715000,
year = {2022},
author = {Pippal, N and Halder, S and Srivastava, S and Kar, R and Gupta, R and Anthonio, AE},
title = {Correlation between telomere length and efficacy of oral and long-acting injectable antipsychotics on severity and cognitive impairment of schizophrenia.},
journal = {International journal of psychiatry in clinical practice},
volume = {26},
number = {2},
pages = {157-164},
doi = {10.1080/13651501.2021.1994613},
pmid = {34715000},
issn = {1471-1788},
mesh = {*Antipsychotic Agents ; *Cognitive Dysfunction ; Delayed-Action Preparations ; Humans ; *Schizophrenia ; Telomere ; },
abstract = {OBJECTIVE: To study the correlation between telomere length (TL) and long-acting injectable (LAI) and oral atypical antipsychotic (OAA) efficacy on schizophrenia (SCZ) severity and cognitive impairment.<br><br>METHODS: Sixty Schizophrenia patients of 18-50&#x2009;years and of either sex were included in a 12-week study. Thirty patients were recruited in each group, LAI and OAA. Positive and Negative Syndrome Scale (PANSS) and National Institute of Mental Health and Neuro-Sciences (NIMHANS) neuropsychological battery tests were evaluated at baseline and 12&#x2009;weeks. TL was estimated at baseline.<br><br>RESULTS: Both groups showed a significant improvement in PANSS and NIMHANS battery test scores after treatment (p&#x2009;<&#x2009;0.001) within the group, though not between the groups. Mean TL at baseline was 407.58&#x2009;&#xb1;&#x2009;143.93 and 443.40&#x2009;&#xb1;&#x2009;178.46 in LAI and OAA groups respectively. A significant negative correlation (r = -0.28, p&#x2009;=&#x2009;0.03) of TL was seen with the mean change in negative PANSS score after treatment.<br><br>CONCLUSIONS: LAI antipsychotics are similar to OAA in decreasing the disorder severity and improving the cognitive impairment in schizophrenia. Also, patients who have shorter TL show greater improvement in the negative PANSS score. Hence, TL holds the potential of predicting antipsychotic drug response in schizophrenia patients.KEY POINTSLong-acting injectable antipsychotic was comparable to oral atypical antipsychotics in bringing out improvement in disorder severity, cognitive functions over 12 weeks.Shorter telomere length has been found to be associated with a greater response in negative symptoms of schizophrenia.},
}
@article {pmid34714693,
year = {2022},
author = {Bai, L and Rohrer, C and Liu, Y},
title = {Liver Histology in Short Telomere Syndrome: A Case Report and Review of the Literature.},
journal = {International journal of surgical pathology},
volume = {30},
number = {3},
pages = {350-355},
doi = {10.1177/10668969211054102},
pmid = {34714693},
issn = {1940-2465},
mesh = {Adult ; *Dyskeratosis Congenita/diagnosis/genetics/pathology ; Growth Disorders ; Humans ; Hypercalcemia ; Inflammation ; *Liver Diseases/diagnosis/genetics ; Male ; Metabolic Diseases ; Middle Aged ; Mutation ; Nephrocalcinosis ; Telomere/genetics/pathology ; },
abstract = {Short telomere syndrome (STS) encompasses a broad family of genetically inherited conditions caused by various mutations in telomerase and other telomere maintenance genes, resulting in premature telomere shortening. STS involves a variety of clinical manifestations, including dyskeratosis congenita, premature achromotrichia, bone marrow failure, immunodeficiency, pulmonary fibrosis and liver disease. Liver histopathologic features in STS patients have not been well characterized. We report a 46-year-old male patient who presented for dyspnea. The patient had a complicated medical history significant for immune thrombocytopenic purpura and splenectomy, recurrent respiratory tract infections, pneumonia, primary immunodeficiency, and severe hepatopulmonary syndrome. He and his brother both developed gray hair by their late 20s. He had a long history of intermittently elevated liver enzymes starting at age 33. These clinical manifestations prompted an evaluation for a possible telomere biology disorder, which revealed the telomere length was critically short and fell at or below the first percentile for age, supporting the diagnosis. The liver biopsy showed marked portal inflammation with interface hepatitis, ductular reaction and frequent foci of lobular inflammation with focal hepatocyte dropout. Hepatocytes around the portal tracts demonstrated ballooning degeneration and occasional Mallory-Denk bodies. A trichrome stain highlighted bridging fibrosis. A literature review shows liver histology is available in only a small number of STS patients, demonstrating a variety of morphologic features. Our case and others suggest liver disease associated with STS exhibits a spectrum of histopathology. Being aware of these features is important for establishing the correct diagnosis of STS which is under recognized.},
}
@article {pmid34708049,
year = {2021},
author = {Panner Selvam, MK and Baskaran, S and Sikka, SC},
title = {Telomere Signaling and Maintenance Pathways in Spermatozoa of Infertile Men Treated With Antioxidants: An in silico Approach Using Bioinformatic Analysis.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {768510},
pmid = {34708049},
issn = {2296-634X},
abstract = {Telomere shortening is considered as a marker of cellular senescence and it is regulated by various signaling pathways. Sperm telomere appears to play important role in its longevity and function. Antioxidant intake has been known to prevent the shortening of telomere. In the management of male infertility, antioxidants are commonly used to counterbalance the seminal oxidative stress. It is important to understand how antioxidants treatment may modulate telomere signaling in sperm. In the current study, we have identified 377 sperm proteins regulated by antioxidants based on data mining of published literature. Bioinformatic analysis revealed involvement of 399 upstream regulators and 806 master regulators associated with differentially expressed sperm proteins. Furthermore, upstream regulator analysis indicated activation of kinases (EGFR and MAPK3) and transcription factors (CCNE1, H2AX, MYC, RB1, and TP53). Hence, it is evident that antioxidant supplementation activates molecules associated with telomere function in sperm. The outcome of this in silico study suggests that antioxidant therapy has beneficial effects on certain transcription factors and kinases associated with sperm telomere maintenance and associated signaling pathways that may play an important role in the management of male factor infertility.},
}
@article {pmid34706411,
year = {2021},
author = {Birkenæs, V and Elvsåshagen, T and Westlye, LT and Høegh, MC and Haram, M and Werner, MCF and Quintana, DS and Lunding, SH and Martin-Ruiz, C and Agartz, I and Djurovic, S and Steen, NE and Andreassen, OA and Aas, M},
title = {Telomeres are shorter and associated with number of suicide attempts in affective disorders.},
journal = {Journal of affective disorders},
volume = {295},
number = {},
pages = {1032-1039},
doi = {10.1016/j.jad.2021.08.135},
pmid = {34706411},
issn = {1573-2517},
mesh = {*Depressive Disorder, Major/epidemiology/genetics ; Humans ; Mood Disorders/epidemiology/genetics ; Suicide, Attempted ; *Telomere/genetics ; Telomere Shortening/genetics ; },
abstract = {BACKGROUND: Shorter telomere length is a putative biomarker of accelerated aging and has been associated with affective disorders and mortality. Psychological factors and behaviors associated with telomere shortening are yet to be clarified. Here, we investigate the association between history of suicide attempts and telomere length in patients with affective disorders.<br><br>METHODS: Leucocyte telomere length was determined by quantitative real-time Polymerase Chain Reaction (qPCR) in patients with affective disorders (n&#xa0;=&#xa0;248) including bipolar disorders type I (n&#xa0;=&#xa0;159), type II (n&#xa0;=&#xa0;67), major depressive disorder (n&#xa0;=&#xa0;22), and healthy controls (n&#xa0;=&#xa0;401). Diagnosis, duration of illness, and age at onset were assessed using the Structural Clinical Interview for DSM-IV (SCID-I). Number of lifetime suicide attempts were based on self-reports. Effect size was calculated using Cohen's d.<br><br>RESULTS: Telomere length was reduced in patients with affective disorders relative to healthy controls (d&#xa0;=&#xa0;0.18, F&#xa0;=&#xa0;5.26, p&#xa0;=&#xa0;0.02). Among patients, a higher number of suicide attempts was associated with shorter telomere length (&#x3b2;&#xa0;=&#xa0;-0.24, t&#xa0;=&#xa0;-3.83, CI&#xa0;=&#xa0;-0.44 to -0.14, p&#xa0;<&#xa0;0.001), also when controlling for duration of illness and age at onset (&#x3b2;&#xa0;=&#xa0;-.23, CI&#xa0;=&#xa0;-.42 to -.12, p&#xa0;=&#xa0;0.001). Multiple suicide attempts were associated with telomere length reduction comparable to eight years lifespan, adjusted for demographic and clinical characteristics.<br><br>CONCLUSIONS: While longitudinal data are needed to clarify the temporal course, previous suicide attempts and related distress may accelerate telomere shortening and aging in patients with affective disorders.},
}
@article {pmid34703795,
year = {2021},
author = {Heidari, HR and Fathi, E and Montazersaheb, S and Mamandi, A and Farahzadi, R and Zalavi, S and Nozad Charoudeh, H},
title = {Mesenchymal Stem Cells cause Telomere Length Reduction of Molt-4 Cells via Caspase-3, BAD and P53 Apoptotic Pathway.},
journal = {International journal of molecular and cellular medicine},
volume = {10},
number = {2},
pages = {113-122},
pmid = {34703795},
issn = {2251-9637},
abstract = {Mesenchymal stem cells (MSCs) as undifferentiated cells are specially considered in cell-based cancer therapy due to unique features such as multi-potency, pluripotency, and self-renewal. A multitude of cytokines secreted from MSCs are known to give such multifunctional attributes, but details of their role are yet to be unknown. In the present study, MSCs were cultured, characterized and co-cultured with Molt-4 cells as acute lymphoblastic leukemia cell line in a trans-well plate. Then, cultured Molt-4 alone and Molt-4 co-cultured with MSCs (10:1) were collected on day 7 and subjected to real time-PCR and Western blotting for gene and protein expression assessment, respectively. Ki-67/caspase-3 as well as telomere length were investigated by flow cytometry and real time-PCR, respectively. The results showed that MSCs caused significant decrease in telomere length as well as hTERT gene expression of Molt-4 cells. Also, gene and protein expression of BAD and P53 were significantly increased. Furthermore, the flow cytometry analysis indicated the decrease and increase of the Ki-67 and caspaspase-3 expression, respectively. It was concluded that MSCs co-cultured with Molt-4 cells could be involved in the promotion of Molt-4 cell apoptosis via caspase-3, BAD, and P53 expression. In addition, the decrease of telomere length is another effect of MSCs on Molt-4 leukemic cells.},
}
@article {pmid34702734,
year = {2022},
author = {Sholes, SL and Karimian, K and Gershman, A and Kelly, TJ and Timp, W and Greider, CW},
title = {Chromosome-specific telomere lengths and the minimal functional telomere revealed by nanopore sequencing.},
journal = {Genome research},
volume = {32},
number = {4},
pages = {616-628},
pmid = {34702734},
issn = {1549-5469},
support = {R35 CA209974/CA/NCI NIH HHS/United States ; T32 GM007445/GM/NIGMS NIH HHS/United States ; U01 CA253481/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; P01 CA013106/CA/NCI NIH HHS/United States ; },
mesh = {Intracellular Signaling Peptides and Proteins/genetics ; *Nanopore Sequencing ; Protein Serine-Threonine Kinases ; Repressor Proteins/genetics ; Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {We developed a method to tag telomeres and measure telomere length by nanopore sequencing in the yeast S. cerevisiae Nanopore allows long-read sequencing through the telomere, through the subtelomere, and into unique chromosomal sequence, enabling assignment of telomere length to a specific chromosome end. We observed chromosome end-specific telomere lengths that were stable over 120 cell divisions. These stable chromosome-specific telomere lengths may be explained by slow clonal variation or may represent a new biological mechanism that maintains equilibrium unique to each chromosome end. We examined the role of RIF1 and TEL1 in telomere length regulation and found that TEL1 is epistatic to RIF1 at most telomeres, consistent with the literature. However, at telomeres that lack subtelomeric Y' sequences, tel1Δ rif1Δ double mutants had a very small, but significant, increase in telomere length compared with the tel1Δ single mutant, suggesting an influence of Y' elements on telomere length regulation. We sequenced telomeres in a telomerase-null mutant (est2Δ) and found the minimal telomere length to be ∼75 bp. In these est2Δ mutants, there were apparent telomere recombination events at individual telomeres before the generation of survivors, and these events were significantly reduced in est2Δ rad52Δ double mutants. The rate of telomere shortening in the absence of telomerase was similar across all chromosome ends at ∼5 bp per generation. This new method gives quantitative, high-resolution telomere length measurement at each individual chromosome end and suggests possible new biological mechanisms regulating telomere length.},
}
@article {pmid34700072,
year = {2022},
author = {Wani, NA and Praveen Kumar, K and Hong, S and Umer, MA},
title = {Telomere length in dromedary camels (Camelus dromedarius) produced by somatic cell nuclear transfer (SCNT) and their age-matched naturally produced counterparts.},
journal = {Theriogenology},
volume = {177},
number = {},
pages = {151-156},
doi = {10.1016/j.theriogenology.2021.10.012},
pmid = {34700072},
issn = {1879-3231},
mesh = {Animals ; *Camelus ; *Cloning, Organism/veterinary ; Embryo Transfer/veterinary ; Nuclear Transfer Techniques/veterinary ; Telomere/genetics ; },
abstract = {There are controversial reports on the restoration of eroded telomere length in offspring produced by somatic cell nuclear transfer (SCNT) in different animal species. To the best of our knowledge, no earlier studies report the telomere length in naturally produced or cloned animals in any of the camelid species. Therefore, the present study was conducted to estimate the telomere length in dromedary camels produced by SCNT, the donor cells, and their age-matched naturally produced counterparts by Terminal Restriction Fragment (TRF) length analysis and real-time Q PCR T/S ratio methods. Genomic DNA was extracted from venous blood collected from 6 cloned animals and their age-matched counterparts. Using the southern blot technique, digested DNA was blotted onto a positively charged nylon membrane, and its hybridization was carried out using telomere (TTAGGG)n specific, DIG-labeled hybridization probe (Roche Diagnostics, Germany) at 42 °C for 4 h. Stringent washes were carried out at the same temperature, followed by a chemiluminescence reaction. The signals were captured using the Azure Biosystems C600 gel documentation system. A TeloTool program from MATLAB software with a built-in probe intensity correction algorithm was used for TRF analysis. The experiment was replicated three times, and the data, presented as mean ± SEM, were analyzed using a two-sample t-test (MINITAB statistical software, Minitab ltd, CV3 2 TE, UK). No difference was found in the mean telomere length of cloned camels when compared to their naturally produced age-matched counterparts. However, the telomere length was more (P < 0.05) than that of the somatic cells used for producing the SCNT embryos. A moderate positive Pearson correlation coefficient (r = 0.6446) was observed between the telomere lengths estimated by TRF and Q PCR T/S ratio method. In conclusion, this is the first study wherein we are reporting telomere length in naturally produced and cloned dromedary camels produced by somatic cell nuclear transfer. We found that telomere lengths in cloned camels were similar to their age-matched naturally produced counterparts, suggesting that the camel cytoplast reprograms the somatic cell nucleus and restores the telomere length to its totipotency stage.},
}
@article {pmid34697054,
year = {2022},
author = {Zhang, X and Wolff, MS and Shen, J and Parada, H and Santella, RM and Neugut, AI and Chen, J and Teitelbaum, SL},
title = {Phthalates and Phenols, Leukocyte Telomere Length, and Breast Cancer Risk and Mortality in the Long Island Breast Cancer Study Project.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {31},
number = {1},
pages = {117-123},
pmid = {34697054},
issn = {1538-7755},
support = {UG3 OD023320/OD/NIH HHS/United States ; K01 ES012645/ES/NIEHS NIH HHS/United States ; U01 CA066572/CA/NCI NIH HHS/United States ; P30 ES023515/ES/NIEHS NIH HHS/United States ; U01 ES019459/ES/NIEHS NIH HHS/United States ; U54 CA132379/CA/NCI NIH HHS/United States ; K01 CA234317/CA/NCI NIH HHS/United States ; UH3 OD023337/OD/NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; P30 AG059299/AG/NIA NIH HHS/United States ; U54 CA132384/CA/NCI NIH HHS/United States ; },
mesh = {Biomarkers, Tumor/*analysis ; Breast Neoplasms/*chemically induced/*genetics/mortality ; Case-Control Studies ; Environmental Exposure/*adverse effects ; Female ; Humans ; Leukocytes ; Middle Aged ; New York ; Phenols/urine ; Phthalic Acids/urine ; Risk Factors ; Telomere/*genetics ; },
abstract = {BACKGROUND: Phthalates and phenols from the environment have been inconsistently associated with breast cancer risk or mortality. Studies on the potential modifying role of leukocyte telomere length (LTL), a biomarker of biological aging, on these associations are lacking.<br><br>METHODS: We included 1,268 women from the Long Island Breast Cancer Study Project with available data on phthalate and phenol analytes and LTL measurements. Twenty-two phthalate and phenol analytes were measured in spot urines and LTL was measured in blood. The modifying effect of LTL on the associations of individual analyte with breast cancer risk as well as mortalities was estimated using interaction terms between LTL and urinary concentrations of analyte in logistic regression and Cox regression models, respectively. ORs, HRs, and corresponding 95% confidence intervals for a one-unit (ln &#x3bc;g/g creatinine) increase of urinary phthalate/phenol level were estimated at 10th, 50th, and 90th percentiles of LTL.<br><br>RESULTS: LTL significantly (P < 0.05) modified associations between 11 of 22 of urinary phthalate/phenols analytes and breast cancer risk. An inverse association between phthalate/phenols analytes and breast cancer risk at shorter LTL and a positive association at longer LTL was generally suggested. No modifying effect was found for LTL on the association between these phthalate/phenols analytes and breast cancer mortalities.<br><br>CONCLUSIONS: LTL may modify the associations between phthalate and phenol exposures and breast cancer risk.<br><br>IMPACT: This study is the first study that determined the modifying effect of biological aging in the association between environmental chemical exposure and breast cancer risk.},
}
@article {pmid34695574,
year = {2021},
author = {Giaccherini, M and Gentiluomo, M and Fornili, M and Lucenteforte, E and Baglietto, L and Campa, D},
title = {Association between telomere length and mitochondrial copy number and cancer risk in humans: A meta-analysis on more than 300,000 individuals.},
journal = {Critical reviews in oncology/hematology},
volume = {167},
number = {},
pages = {103510},
doi = {10.1016/j.critrevonc.2021.103510},
pmid = {34695574},
issn = {1879-0461},
mesh = {DNA Copy Number Variations ; DNA, Mitochondrial/genetics ; Humans ; Leukocytes/metabolism ; Mitochondria/genetics ; *Neoplasms/epidemiology/genetics/metabolism ; *Telomere/genetics ; },
abstract = {In the last decades the association of leukocyte telomere length (LTL) and mitochondrial copy number (mtDNAcn) with cancer risk has been the focus of many reports, however the relation is not yet completely understood. A meta-analysis of 112 studies including 64,184 cancer cases and 278,641 controls that analysed LTL and mtDNAcn in relation to cancer risk has been conducted to further our understanding of the topic. Stratified analyses for tumor type were also performed. Overall, no association was observed for all cancer combined neither for LTL nor mtDNAcn. Significant associations were detected for these biomarkers and specific cancer type; however, a large degree of heterogeneity was present, even within the same tumor type. Alternatives approaches based on polymorphic variants, such as polygenic risk scores and mendelian randomization, could be adopted to unravel the causal correlation of telomere length and mitochondrial copy number with cancer risk.},
}
@article {pmid34688387,
year = {2021},
author = {Kronenberg, F},
title = {Telomere length and chronic kidney disease: cause or consequence?.},
journal = {Kidney international},
volume = {100},
number = {5},
pages = {980-983},
doi = {10.1016/j.kint.2021.08.013},
pmid = {34688387},
issn = {1523-1755},
mesh = {Aging/genetics ; Humans ; Mendelian Randomization Analysis ; *Renal Insufficiency, Chronic/genetics ; *Telomere/genetics ; Telomere Shortening ; },
abstract = {Telomere length is considered as a clock mirroring aging and is influenced by oxidative stress and inflammation. Both conditions are highly prevalent in patients with chronic kidney disease and other degenerative disorders, such as cardiovascular disease. However, it is discussed controversially whether short telomeres are causally associated with chronic kidney disease or whether chronic kidney disease is contributing to an attrition of telomere length. Park et al., in this issue of Kidney International, use an extended 2-sample Mendelian randomization analysis with large data sets to shed new light on this research question.},
}
@article {pmid34687577,
year = {2022},
author = {Spießberger, M and Hoelzl, F and Smith, S and Vetter, S and Ruf, T and Nowack, J},
title = {The tarnished silver spoon? Trade-off between prenatal growth and telomere length in wild boar.},
journal = {Journal of evolutionary biology},
volume = {35},
number = {1},
pages = {81-90},
pmid = {34687577},
issn = {1420-9101},
mesh = {Animals ; *Silver ; Sus scrofa/genetics ; Swine ; Telomere ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Life-history theory predicts a trade-off between growth rates and lifespan, which is reflected by telomere length, a biomarker of somatic state. We investigated the correlation between telomere length and early-life growth of wild boar piglets, Sus scrofa, kept under semi-natural conditions with high food availability to examine our hypothesis that increased pre- and postnatal growth will lead to telomere length attrition, but that a high supply of nutrient may provide the possibility to compensate telomere loss via telomere repair mechanisms. As predicted, our data showed a clear negative correlation between birth body mass and initial telomere length: heavier neonates had shorter telomeres at birth, and we did not find an influence of the mother on initial telomere length. Body mass at birth correlated with body mass later in life and postnatal growth rate did not affect telomere length. We observed an increase in telomere length during postnatal development, suggesting that high food availability allowed piglets to invest into both, growth and telomere restoration. The increase in telomere length over the duration of the study was not accompanied by telomerase activity; thus, telomere elongation was caused either by alternative mechanisms or by short pulses of telomerase activity that we missed. Taken together, this study suggests a trade-off between investment into growth and telomere maintenance even before birth and the possibility to compensate telomere attrition during growth under high amounts of available energy.},
}
@article {pmid34687313,
year = {2022},
author = {Gao, X and Li, S and Dong, S and Li, J and Yan, Y and Zhang, T and Chen, W},
title = {Response to Letter to the Editor from Bin Zhou et al: "Association Between Body Weight and Telomere Length Is Predominantly Mediated Through C-reactive Protein".},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {107},
number = {3},
pages = {e1329-e1330},
doi = {10.1210/clinem/dgab765},
pmid = {34687313},
issn = {1945-7197},
mesh = {Body Weight ; *C-Reactive Protein ; Humans ; *Telomere/genetics ; },
}
@article {pmid34687310,
year = {2022},
author = {Lahav, Y and Avidor, S and Levy, D and Ohry, A and Zeilig, G and Lahav, M and Golander, H and Guber, AC and Uziel, O and Defrin, R},
title = {Shorter Telomeres Among Individuals With Physical Disability: The Moderating Role of Perceived Stress.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {77},
number = {8},
pages = {1384-1393},
doi = {10.1093/geronb/gbab200},
pmid = {34687310},
issn = {1758-5368},
mesh = {Aged ; Cellular Senescence ; Humans ; Male ; Stress, Psychological/psychology ; Surveys and Questionnaires ; *Telomere ; *Telomere Shortening ; },
abstract = {OBJECTIVES: Evidence suggests that individuals with physical disability may suffer from psychological distress and accelerated cellular aging, manifested by shortened telomere length (TL), compared with healthy individuals. Studies indicate that high levels of perceived stress and depression may increase the physiological susceptibility and, thus, may contribute to a short TL. However, the moderating role of perceived stress and depression within the relationship between physical disability and TL remains unknown.<br><br>METHOD: The participants consisted of 119 male subjects (mean age 54.36 years, range 35-70). Of them, 30 were able-bodied and 89 had a physical disability: 34 were due to poliomyelitis (polio) and 55 were due to spinal cord injury. Blood samples for TL analysis were collected; the participants completed questionnaires and underwent disability evaluation.<br><br>RESULTS: Participants with disability had a shorter TL as well as elevated levels of perceived stress and depression compared with able-bodied controls. Both the perceived stress and depression were correlated with a shorter TL. Nonetheless, perceived stress, rather than depression, moderated the relationship between disability and TL; among participants with higher perceived stress levels, in particular, individuals with physical disability had a shorter TL than the able-bodied controls.<br><br>DISCUSSION: The present findings suggest that individuals with physical disability and who exhibit high levels of perceived stress may be particularly vulnerable for accelerated cellular aging, suggesting that perceived stress can be used as a valuable target for intervention.},
}
@article {pmid34687297,
year = {2022},
author = {Zhou, B and Sun, X and Yu, N and Zhang, S},
title = {Letter to the Editor From Zhou et al.: "Association Between Body Weight and Telomere Length Is Predominantly Mediated Through C-Reactive Protein".},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {107},
number = {3},
pages = {e1319-e1320},
doi = {10.1210/clinem/dgab764},
pmid = {34687297},
issn = {1945-7197},
mesh = {Body Weight ; *C-Reactive Protein ; Humans ; *Telomere/genetics ; },
}
@article {pmid34686653,
year = {2021},
author = {Mangaonkar, AA and Ferrer, A and Vairo, FPE and Hammel, CW and Prochnow, C and Gangat, N and Hogan, WJ and Litzow, MR and Peters, SG and Scott, JP and Utz, JP and Baqir, M and Carmona-Porquera, EM and Kalra, S and Sekiguchi, H and Khan, SP and Simonetto, DA and Klee, EW and Kamath, PS and Roden, AC and Joshi, AY and Kennedy, CC and Wylam, ME and Patnaik, MM},
title = {Clinical and molecular correlates from a predominantly adult cohort of patients with short telomere lengths.},
journal = {Blood cancer journal},
volume = {11},
number = {10},
pages = {170},
pmid = {34686653},
issn = {2044-5385},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Child, Preschool ; Female ; Humans ; Male ; Middle Aged ; RNA/*genetics ; Retrospective Studies ; Telomerase/*genetics ; Telomere/*genetics ; *Telomere Homeostasis ; },
}
@article {pmid34685641,
year = {2021},
author = {Kordowitzki, P and Merle, R and Hass, PK and Plendl, J and Rieger, J and Kaessmeyer, S},
title = {Influence of Age and Breed on Bovine Ovarian Capillary Blood Supply, Ovarian Mitochondria and Telomere Length.},
journal = {Cells},
volume = {10},
number = {10},
pages = {},
pmid = {34685641},
issn = {2073-4409},
mesh = {Aging/*physiology ; Animals ; *Breeding ; Capillaries/*physiology ; Cattle ; Female ; Leukocytes, Mononuclear/metabolism ; Mitochondria/*metabolism/ultrastructure ; Organ Size ; Ovarian Follicle/blood supply/ultrastructure ; Ovary/*blood supply/ultrastructure ; *Telomere Homeostasis ; },
abstract = {Worldwide, dairy cows of the type of high-producing cattle (HPC) suffer from health and fertility problems at a young age and therefore lose productivity after an average of only three lactations. It is still contentious whether these problems are primarily due to genetics, management, feeding or other factors. Vascularization plays a fundamental role in the cyclic processes of reproductive organs, as well as in the regeneration of tissues. In a previous study, HPC were shown to have a greater ovarian corpus luteum vascularization compared to dual-purpose breeds. We hypothesize that this activated angiogenesis could likely lead to an early exhaustion of HPC's regenerative capacity and thus to premature reproductive senescence. The objective of this study was to investigate if a HPC breed (Holstein-Friesian, HF) exhibits higher ovarian angiogenesis than a dual-purpose breed (Polish Red cow, PR) and if this is related to early ovarian aging and finally reproductive failure. For this purpose, we assessed the degree of vascularization by means of ovarian blood vessel characterization using light microscopy. As indicators for aging, we measured ovarian mitochondrial size and telomere length in peripheral leukocytes. We report in this study that in both breeds the distance between capillaries became smaller with increasing age and that the mean telomere length decreased with increasing age. The only difference between the two breeds was that PR developed larger capillaries than HF. Neither a relationship between telomere length, nor the morphology of the mitochondrial apparatus and nor angiogenesis in HF was proven. Although the data trends indicated that the proportion of shortened telomeres in HF was higher than in the PR, no significant difference between the two breeds was detected.},
}
@article {pmid34685603,
year = {2021},
author = {Zeid, D and Mooney-Leber, S and Seemiller, LR and Goldberg, LR and Gould, TJ},
title = {Terc Gene Cluster Variants Predict Liver Telomere Length in Mice.},
journal = {Cells},
volume = {10},
number = {10},
pages = {},
pmid = {34685603},
issn = {2073-4409},
support = {1U01DA041632/DA/NIDA NIH HHS/United States ; 1F31DA049395/DA/NIDA NIH HHS/United States ; T32 GM108563/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Genetic Variation ; Genotype ; Liver/*metabolism ; Male ; Mice, Inbred C57BL ; *Multigene Family ; RNA/*genetics/metabolism ; Telomerase/*genetics/metabolism ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Mice ; },
abstract = {Variants in a gene cluster upstream-adjacent to TERC on human chromosome 3, which includes genes APRM, LRRC31, LRRC34 and MYNN, have been associated with telomere length in several human populations. Currently, the mechanism by which variants in the TERC gene cluster influence telomere length in humans is unknown. Given the proximity between the TERC gene cluster and TERC (~0.05 Mb) in humans, it is speculated that cluster variants are in linkage disequilibrium with a TERC causal variant. In mice, the Terc gene/Terc gene cluster are also located on chromosome 3; however, the Terc gene cluster is located distantly downstream of Terc (~60 Mb). Here, we initially aim to investigate the interactions between genotype and nicotine exposure on absolute liver telomere length (aTL) in a panel of eight inbred mouse strains. Although we found no significant impact of nicotine on liver aTL, this first experiment identified candidate single nucleotide polymorphisms (SNPs) in the murine Terc gene cluster (within genes Lrrc31, Lrriq4 and Mynn) co-varying with aTL in our panel. In a second experiment, we tested the association of these Terc gene cluster variants with liver aTL in an independent panel of eight inbred mice selected based on candidate SNP genotype. This supported our initial finding that Terc gene cluster polymorphisms impact aTL in mice, consistent with data in human populations. This provides support for mice as a model for telomere dynamics, especially for studying mechanisms underlying the association between Terc cluster variants and telomere length. Finally, these data suggest that mechanisms independent of linkage disequilibrium between the Terc/TERC gene cluster and the Terc/TERC gene mediate the cluster's regulation of telomere length.},
}
@article {pmid34681758,
year = {2021},
author = {Sung, JY and Cheong, JH},
title = {Pan-Cancer Analysis of Clinical Relevance via Telomere Maintenance Mechanism.},
journal = {International journal of molecular sciences},
volume = {22},
number = {20},
pages = {},
pmid = {34681758},
issn = {1422-0067},
mesh = {Gene Expression Regulation, Neoplastic ; Glioblastoma/genetics/mortality ; Head and Neck Neoplasms/genetics/metabolism ; Humans ; Neoplasms/*genetics/*mortality/pathology ; Pancreatic Neoplasms/genetics/mortality ; Prognosis ; Squamous Cell Carcinoma of Head and Neck/genetics/mortality ; Telomere/genetics/*physiology ; Telomere Homeostasis/physiology ; },
abstract = {Understanding the telomere maintenance mechanism (TMM) in immortal cancer cells is vital for TMM-targeted therapies in clinical settings. In this study, we classified four telomere maintenance mechanisms into telomerase, ALT, telomerase + ALT, and non-defined telomere maintenance mechanism (NDTMM) across 31 cancer types using 10,704 transcriptomic datasets from The Cancer Genome Atlas. Our results demonstrated that approximately 50% of the total cohort displayed ALT activity with high telomerase activity in most cancer types. We confirmed significant patient prognoses according to distinct TMMs in six cancer types: adrenocortical carcinoma (ACC), PAAD, HNSC, SARC, GBM, and metastatic cancer. Patients with metastasis had a poor prognosis in the ALT group (p < 0.006) subjected to RAS protein signal transduction. Glioblastoma patients had poor prognosis in NDTMM (p < 0.0043) and showed high levels of myeloid leukocyte activation. Pancreatic adenocarcinoma (p < 0.04) and head and neck squamous cell carcinoma (p < 0.046) patients had a good prognosis in the ALT group with high immune cell activation. Furthermore, we showed that master transcriptional regulators might affect the selection of the TMM pathway and explained why different telomere maintenance mechanisms exist. Furthermore, they can be used to segregate patients and predict responders to different TMM-targeted therapeutics.},
}
@article {pmid34680452,
year = {2021},
author = {Gruber, HJ and Semeraro, MD and Renner, W and Herrmann, M},
title = {Telomeres and Age-Related Diseases.},
journal = {Biomedicines},
volume = {9},
number = {10},
pages = {},
pmid = {34680452},
issn = {2227-9059},
abstract = {Telomeres are at the non-coding ends of linear chromosomes. Through a complex 3-dimensional structure, they protect the coding DNA and ensure appropriate separation of chromosomes. Aging is characterized by a progressive shortening of telomeres, which compromises their structure and function. Because of their protective function for genomic DNA, telomeres appear to play an important role in the development and progression of many age-related diseases, such as cardiovascular disease (CVD), malignancies, dementia, and osteoporosis. Despite substantial evidence that links telomere length with these conditions, the nature of these observations remains insufficiently understood. Therefore, future studies should address the question of causality. Furthermore, analytical methods should be further improved with the aim to provide informative and comparable results. This review summarize the actual knowledge of telomere biology and the possible implications of telomere dysfunction for the development and progression of age-related diseases. Furthermore, we provide an overview of analytical techniques for the measurement of telomere length and telomerase activity.},
}
@article {pmid34680268,
year = {2021},
author = {Forsyth, RG and Krenács, T and Athanasou, N and Hogendoorn, PCW},
title = {Cell Biology of Giant Cell Tumour of Bone: Crosstalk between m/wt Nucleosome H3.3, Telomeres and Osteoclastogenesis.},
journal = {Cancers},
volume = {13},
number = {20},
pages = {},
pmid = {34680268},
issn = {2072-6694},
abstract = {Giant cell tumour of bone (GCTB) is a rare and intriguing primary bone neoplasm. Worrisome clinical features are its local destructive behaviour, its high tendency to recur after surgical therapy and its ability to create so-called benign lung metastases (lung 'plugs'). GCTB displays a complex and difficult-to-understand cell biological behaviour because of its heterogenous morphology. Recently, a driver mutation in histone H3.3 was found. This mutation is highly conserved in GCTB but can also be detected in glioblastoma. Denosumab was recently introduced as an extra option of medical treatment next to traditional surgical and in rare cases, radiotherapy. Despite these new insights, many 'old' questions about the key features of GCTB remain unanswered, such as the presence of telomeric associations (TAs), the reactivation of hTERT, and its slight genomic instability. This review summarises the recent relevant literature of histone H3.3 in relation to the GCTB-specific G34W mutation and pays specific attention to the G34W mutation in relation to the development of TAs, genomic instability, and the characteristic morphology of GCTB. As pieces of an etiogenetic puzzle, this review tries fitting all these molecular features and the unique H3.3 G34W mutation together in GCTB.},
}
@article {pmid34680143,
year = {2021},
author = {Hecker, M and Bühring, J and Fitzner, B and Rommer, PS and Zettl, UK},
title = {Genetic, Environmental and Lifestyle Determinants of Accelerated Telomere Attrition as Contributors to Risk and Severity of Multiple Sclerosis.},
journal = {Biomolecules},
volume = {11},
number = {10},
pages = {},
pmid = {34680143},
issn = {2218-273X},
mesh = {Aging/*genetics ; Cellular Senescence/genetics ; Chromosomes/genetics ; Humans ; Inflammation/*genetics/pathology ; Life Style ; Multiple Sclerosis/*genetics/pathology ; Oxidative Stress/genetics ; Telomere/genetics ; Telomere Shortening/*genetics ; },
abstract = {Telomeres are protective structures at the ends of linear chromosomes. Shortened telomere lengths (TL) are an indicator of premature biological aging and have been associated with a wide spectrum of disorders, including multiple sclerosis (MS). MS is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system. The exact cause of MS is still unclear. Here, we provide an overview of genetic, environmental and lifestyle factors that have been described to influence TL and to contribute to susceptibility to MS and possibly disease severity. We show that several early-life factors are linked to both reduced TL and higher risk of MS, e.g., adolescent obesity, lack of physical activity, smoking and vitamin D deficiency. This suggests that the mechanisms underlying the disease are connected to cellular aging and senescence promoted by increased inflammation and oxidative stress. Additional prospective research is needed to clearly define the extent to which lifestyle changes can slow down disease progression and prevent accelerated telomere loss in individual patients. It is also important to further elucidate the interactions between shared determinants of TL and MS. In future, cell type-specific studies and advanced TL measurement methods could help to better understand how telomeres may be causally involved in disease processes and to uncover novel opportunities for improved biomarkers and therapeutic interventions in MS.},
}
@article {pmid34679783,
year = {2021},
author = {Badmus, KA and Idrus, Z and Meng, GY and Sazili, AQ and Mamat-Hamidi, K},
title = {Telomere Length and Regulatory Genes as Novel Stress Biomarkers and Their Diversities in Broiler Chickens (Gallus gallus domesticus) Subjected to Corticosterone Feeding.},
journal = {Animals : an open access journal from MDPI},
volume = {11},
number = {10},
pages = {},
pmid = {34679783},
issn = {2076-2615},
support = {9629100//Universiti Putra Malaysia/ ; },
abstract = {This study was designed to characterize telomere length and its regulatory genes and to evaluate their potential as well-being biomarkers. Chickens were fed a diet containing corticosterone (CORT) for 4 weeks and performances, organ weight, plasma CORT levels, telomere lengths and regulatory genes were measured and recorded. Body weights of CORT-fed chickens were significantly suppressed (p < 0.05), and organ weights and circulating CORT plasma levels (p < 0.05) were altered. Interaction effect of CORT and duration was significant (p < 0.05) on heart and liver telomere length. CORT significantly (p < 0.05) shortened the telomere length of the whole blood, muscle, liver and heart. The TRF1, chTERT, TELO2 and HSF1 were significantly (p < 0.05) upregulated in the liver and heart at week 4 although these genes and TERRA were downregulated in the muscles at weeks 2 and 4. Therefore, telomere lengths and their regulators are associated and diverse, so they can be used as novel biomarkers of stress in broiler chickens fed with CORT.},
}
@article {pmid34679731,
year = {2021},
author = {Fernández de la Puente, M and Hernández-Alonso, P and Canudas, S and Marti, A and Fitó, M and Razquin, C and Salas-Salvadó, J},
title = {Modulation of Telomere Length by Mediterranean Diet, Caloric Restriction, and Exercise: Results from PREDIMED-Plus Study.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {10},
number = {10},
pages = {},
pmid = {34679731},
issn = {2076-3921},
support = {021/CB07/03/2004//Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition/ ; },
abstract = {Telomere length (TL) has been associated with aging and is determined by lifestyle. However, the mechanisms by which a dietary pattern such as the Mediterranean diet (MedDiet) affects TL homeostasis are still unknown. Our aim was to analyse the effect of an energy-restricted MedDiet with physical activity promotion (intervention group) versus an unrestricted-caloric MedDiet with no weight-loss advice (control group) on TL and 8-hydroxydeoxyguanosine (8-OHdG) plasma levels. In total, 80 non-diabetic participants with metabolic syndrome were randomly selected from the PREDIMED (PREvención con DIeta MEDiterránea)-Plus-Reus study. TL was measured by a hybridisation method and 8-OHdG levels by ELISA at baseline and after one year of intervention. Linear mixed models (LMM)-raw and after adjusting for potential confounders-were used to examine the associations between TL or 8-OHdG plasma levels by intervention group and/or time. A total of 69 subjects with available DNA samples were included in the analyses. A significant β-coefficient was found for time towards increasing values through the year of follow-up for TL (unadjusted β of 0.740 (95% CI: 0.529 to 0.951), and multivariable model β of 0.700 (95% CI: 0.477 to 0.922)). No significant βs were found, neither for the intervention group nor for the interaction between the intervention group and time. Regarding 8-OHdG plasma levels, no significant βs were found for the intervention group, time, and its interaction. Our results suggest that MedDiet could have an important role in preventing telomere shortening, but calorie restriction and exercise promotion did not provide an additional advantage concerning telomere length after one year of MedDiet intervention.},
}
@article {pmid34675961,
year = {2021},
author = {Yang, J and Xu, H and Cai, B and Wei, J and Sun, L and Li, Y and Wang, T and Li, Y},
title = {Genetically Predicted Longer Telomere Length May Reduce Risk of Hip Osteoarthritis.},
journal = {Frontiers in genetics},
volume = {12},
number = {},
pages = {718890},
pmid = {34675961},
issn = {1664-8021},
abstract = {Objective: This two-sample Mendelian randomization (MR) study aimed to examine the potential causal association of telomere length (TL) with the risk of osteoarthritis (OA). Method: The summary-level data for OA was derived from the United Kingdom Biobank cohort, including 50,508 individuals of European descent. Eighteen single nucleotide polymorphisms associated with TL were identified as instrumental variables from the most up-to-date TL genome-wide association study (GWAS) involving over 78,592 individuals of European descent. Based on the GWASs data, MR was performed using established statistical analysis methods including the inverse variance weighted, weighted median, MR-Egger, and MR pleiotropy residual sum and outlier. Results: Genetically determined TL was not associated with the risk of total OA (IVW odds ratio [OR] = 1.00, 95% confidence interval [CI] = 0.83, 1.21). In subgroup analyses stratified by OA site, no evidence in favor of association between genetically determined TL and knee OA was found (IVW OR = 1.18, 95% CI = 0.89, 1.58). However, using WM method, we observed a limited protective effect of longer TL on the risk of hip OA (OR = 0.60, 95% CI = 0.36-0.99), whereas the results of the IVW (p = 0.931) and MR-PRESSO (p = 0.932) showed that TL had no effect on hip OA. Conclusions: This study does not support a causal association between TL and total OA. A potential protective association between longer TL and hip OA, though possible, remains less certain.},
}
@article {pmid34674335,
year = {2022},
author = {Wolf, SE and Sanders, TL and Beltran, SE and Rosvall, KA},
title = {The telomere regulatory gene POT1 responds to stress and predicts performance in nature: Implications for telomeres and life history evolution.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6155-6171},
doi = {10.1111/mec.16237},
pmid = {34674335},
issn = {1365-294X},
support = {T32HD049336/NH/NIH HHS/United States ; },
mesh = {Female ; Genes, Regulator ; Shelterin Complex ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; *Telomere-Binding Proteins/genetics/metabolism ; *Swallows/genetics ; Animals ; },
abstract = {Telomeres are emerging as correlates of fitness-related traits and may be important mediators of ecologically relevant variation in life history strategies. Growing evidence suggests that telomere dynamics can be more predictive of performance than length itself, but very little work considers how telomere regulatory mechanisms respond to environmental challenges or influence performance in nature. Here, we combine observational and experimental data sets from free-living tree swallows (Tachycineta bicolor) to assess how performance is predicted by the telomere regulatory gene POT1, which encodes a shelterin protein that sterically blocks telomerase from repairing the telomere. First, we show that lower POT1 gene expression in the blood was associated with higher female quality, that is, earlier breeding and heavier body mass. We next challenged mothers with an immune stressor (lipopolysaccharide injection) that led to "sickness" in mothers and 24 h of food restriction in their offspring. While POT1 did not respond to maternal injection, females with lower constitutive POT1 gene expression were better able to maintain feeding rates following treatment. Maternal injection also generated a 1-day stressor for chicks, which responded with lower POT1 gene expression and elongated telomeres. Other putatively stress-responsive mechanisms (i.e., glucocorticoids, antioxidants) showed marginal responses in stress-exposed chicks. Model comparisons indicated that POT1 mRNA abundance was a largely better predictor of performance than telomere dynamics, indicating that telomere regulators may be powerful modulators of variation in life history strategies.},
}
@article {pmid34673443,
year = {2021},
author = {Martinez-Verbo, L and Estrada, N and Cabezón, M and Palomo, L and García, O and Arnan, M and Coll, R and Xicoy, B and Zamora, L},
title = {Mutational profile and relative telomere length in Chronic Myelomonocytic Leukemia subgroups according to the 2016 World Health Organization classification.},
journal = {Leukemia research},
volume = {111},
number = {},
pages = {106726},
doi = {10.1016/j.leukres.2021.106726},
pmid = {34673443},
issn = {1873-5835},
mesh = {Aged ; Aged, 80 and over ; Biomarkers, Tumor/*genetics ; Case-Control Studies ; Female ; Follow-Up Studies ; Humans ; Leukemia, Myelomonocytic, Chronic/classification/genetics/*pathology ; Male ; Middle Aged ; *Mutation ; Prognosis ; Retrospective Studies ; *Telomere Homeostasis ; World Health Organization ; },
}
@article {pmid34672915,
year = {2021},
author = {Mizuno, Y and Konishi, S and Imai, H and Fujimori, E and Kojima, N and Kajiwara, C and Yoshinaga, J},
title = {Telomere length and urinary 8-hydroxy-2'-deoxyguanosine and essential trace element concentrations in female Japanese university students.},
journal = {Journal of environmental science and health. Part A, Toxic/hazardous substances &amp; environmental engineering},
volume = {56},
number = {12},
pages = {1328-1334},
doi = {10.1080/10934529.2021.1991741},
pmid = {34672915},
issn = {1532-4117},
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Adolescent ; Adult ; Biomarkers ; Deoxyguanosine ; Female ; Humans ; Japan ; Oxidative Stress ; Students ; Telomere ; *Trace Elements ; Universities ; Young Adult ; },
abstract = {Telomere length is thought to be a biomarker of biological aging. This study examined whether telomere length was associated with urinary concentrations of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative stress, and antioxidative trace elements in 73 female Japanese university students (age: 19.2 ± 0.7 years). We quantified 8-OHdG and selenium in urine by liquid chromatography-mass spectrometry and inductively coupled plasma-mass spectrometry, respectively. Telomere length and urinary concentrations of other essential trace elements (molybdenum, cobalt, and chromium) that were previously measured in the same study participants, were used in this study. We used multiple linear regression analysis to examine the associations of telomere length with urinary 8-OHdG and essential trace element concentrations (covariates: urinary cotinine concentration, age, BMI, and drinking status). The geometric means (geometric standard deviation) of 8-OHdG and selenium were 3.4 (1.5) and 31 (1.3) µg/g creatinine, respectively. Telomere length was not associated with urinary 8-OHdG concentration, but was negatively associated with urinary selenium concentration. In conclusion, telomere length was not associated with urinary 8-OHdG concentration in the young women in this study. Longitudinal studies should be conducted to clarify the association between telomere shortening rate and oxidative stress level.},
}
@article {pmid34671387,
year = {2021},
author = {Čapková Frydrychová, R and Mason, JM and Peska, V},
title = {Editorial: Telomere Flexibility and Versatility: A Role of Telomeres in Adaptive Potential.},
journal = {Frontiers in genetics},
volume = {12},
number = {},
pages = {771938},
pmid = {34671387},
issn = {1664-8021},
}
@article {pmid34671377,
year = {2021},
author = {Yin, X and Zhang, Y and Chen, Y and Wang, J and Wang, RR and Fan, C and Hu, Z},
title = {Precise Characterization and Tracking of Stably Inherited Artificial Minichromosomes Made by Telomere-Mediated Chromosome Truncation in Brassica napus.},
journal = {Frontiers in plant science},
volume = {12},
number = {},
pages = {743792},
pmid = {34671377},
issn = {1664-462X},
abstract = {Plant artificial minichromosomes are the next-generation technology for plant genetic engineering and represent an independent platform for expressing foreign genes and the tools for studying the structure and function of chromosomes. Minichromosomes have been successfully produced by telomere-mediated chromosome truncation in several plants. However, previous studies have primarily focused on the construction and rough characterization of minichromosomes, while the development of stably inherited minichromosomes and their precise characterization and tracking over different generations have rarely been demonstrated. In this study, a 0.35-kb direct repeat of the Arabidopsis telomeric sequence was transformed into Brassica napus to produce artificial minichromosomes, which were analyzed by multifluorescence in situ hybridization (multi-FISH), Southern hybridization, and primer extension telomere rapid amplification (PETRA). The stably inherited minichromosomes C2 and C4 were developed by crossing transgenic plants with wild-type plants and then selfing the hybrids. Notably, two truncation sites on chromosomes C2 and C4, respectively, were identified by resequencing; thus, the artificial minichromosomes were tracked over different generations with insertion site-specific PCR. This study provided two stably inherited minichromosomes in oilseed rape and describes approaches to precisely characterize the truncation position and track the minichromosomes in offspring through multi-FISH, genome resequencing, and insertion site-specific PCR.},
}
@article {pmid34669125,
year = {2021},
author = {Navarro, PA and Wang, F and Pimentel, R and Robinson, LG and Berteli, TS and Keefe, DL},
title = {Zidovudine inhibits telomere elongation, increases the transposable element LINE-1 copy number and compromises mouse embryo development.},
journal = {Molecular biology reports},
volume = {48},
number = {12},
pages = {7767-7773},
pmid = {34669125},
issn = {1573-4978},
support = {Process 2015/21907-0//FAPESP/ ; process n. 88887.371487/2019-00//CAPES/ ; },
mesh = {Animals ; Anti-HIV Agents/pharmacology ; Blastocyst/drug effects ; DNA Transposable Elements/genetics ; Embryonic Development/drug effects ; Female ; HIV Infections/drug therapy/genetics ; Long Interspersed Nucleotide Elements/genetics/physiology ; Mice/embryology ; Models, Animal ; Oocytes/drug effects ; Pregnancy ; RNA-Binding Proteins/*genetics/metabolism ; Reverse Transcriptase Inhibitors/pharmacology ; Telomere/drug effects/*metabolism ; Zidovudine/adverse effects/metabolism/*pharmacology ; Zygote/drug effects ; },
abstract = {PURPOSE: Millions of pregnant, HIV-infected women take reverse transcriptase inhibitors, such as zidovudine (azidothymidine or AZT), during pregnancy. Reverse transcription plays important roles in early development, including regulation of telomere length (TL) and activity of transposable elements (TE). So we evaluated the effects of AZT on embryo development, TL, and copy number of an active TE, Long Interspersed Nuclear Element 1 (LINE-1), during early development in a murine model.<br><br>DESIGN: Experimental study.<br><br>METHODS: In vivo fertilized mouse zygotes from B6C3F1/B6D2F1 mice were cultured for 48&#xa0;h in KSOM with no AZT (n&#x2009;=&#x2009;45), AZT 1&#xa0;&#x3bc;M (n&#x2009;=&#x2009;46) or AZT 10&#xa0;&#x3bc;M (n&#x2009;=&#x2009;48). TL was measured by single-cell quantitative PCR (SC-pqPCR) and LINE-1 copy number by qPCR. The percentage of morulas at 48&#xa0;h, TL and LINE-1 copy number were compared among groups.<br><br>RESULTS: Exposure to AZT 1&#xa0;&#x3bc;M or 10&#xa0;&#x3bc;M significantly impairs early embryo development. TL elongates from oocyte to control embryos. TL in AZT 1&#xa0;&#x3bc;M embryos is shorter than in control embryos. LINE-1 copy number is significantly lower in oocytes than control embryos. AZT 1&#xa0;&#x3bc;M increases LINE-1 copy number compared to oocytes controls, and AZT 10&#xa0;&#x3bc;M embryos.<br><br>CONCLUSION: AZT at concentrations approaching those used to prevent perinatal HIV transmission compromises mouse embryo development, prevents telomere elongation and increases LINE-1 copy number after 48&#xa0;h treatment. The impact of these effects on the trajectory of aging of children exposed to AZT early during development deserves further investigation.},
}
@article {pmid34665991,
year = {2021},
author = {Brown, AM and Wood, EM and Capilla-Lasheras, P and Harrison, XA and Young, AJ},
title = {Longitudinal evidence that older parents produce offspring with longer telomeres in a wild social bird.},
journal = {Biology letters},
volume = {17},
number = {10},
pages = {20210409},
pmid = {34665991},
issn = {1744-957X},
support = {BB/H022716/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/M009122/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/J014400/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Animals, Wild ; Longevity ; *Sparrows ; *Telomere/genetics ; Telomere Shortening ; },
abstract = {As telomere length (TL) often predicts survival and lifespan, there is considerable interest in the origins of inter-individual variation in TL. Cross-generational effects of parental age on offspring TL are thought to be a key source of variation, but the rarity of longitudinal studies that examine the telomeres of successive offspring born throughout the lives of parents leaves such effects poorly understood. Here, we exploit TL measures of successive offspring produced throughout the long breeding tenures of parents in wild white-browed sparrow weaver (Plocepasser mahali) societies, to isolate the effects of within-parent changes in age on offspring TLs. Our analyses reveal the first evidence to date of a positive within-parent effect of advancing age on offspring TL: as individual parents age, they produce offspring with longer telomeres (a modest effect that persists into offspring adulthood). We consider the potential for pre- and post-natal mechanisms to explain our findings. As telomere attrition predicts offspring survival to adulthood in this species, this positive parental age effect could impact parent and offspring fitness if it arose via differential telomere attrition during offspring development. Our findings support the view that cross-generational effects of parental age can be a source of inter-individual variation in TL.},
}
@article {pmid34661551,
year = {2021},
author = {Gorenjak, V and Petrelis, AM and Stathopoulou, MG and Toupance, S and Kumar, S and Labat, C and Masson, C and Murray, H and Lamont, J and Fitzgerald, P and Benetos, A and Visvikis-Siest, S and , },
title = {A genetic determinant of VEGF-A levels is associated with telomere attrition.},
journal = {Aging},
volume = {13},
number = {20},
pages = {23517-23526},
pmid = {34661551},
issn = {1945-4589},
mesh = {Hematopoiesis/genetics ; Humans ; Polymorphism, Single Nucleotide/genetics ; Telomere/*genetics ; Telomere Shortening/*genetics ; Vascular Endothelial Growth Factor A/*genetics ; },
abstract = {Telomere length (TL) is a hallmark of cellular aging and is associated with chronic diseases development. The vascular endothelial growth factor A (VEGF-A), a potent angiogenesis factor, is implicated in the pathophysiology of many chronic diseases. The aim of the present study was to investigate the associations between VEGF-A and TL. TL in leukocytes (LTL) and skeletal muscle (MTL) were measured, 10 VEGF-related polymorphisms genotyped, and VEGF-A plasma concentrations determined in 402 individuals from the TELARTA cohort. LTL/MTL ratio was calculated as an estimate of lifelong TL attrition. Associations between VEGF-A variants and levels, and TL parameters were investigated. We identified one significant association between the minor allele (T) of rs6993770 variant and LTL/MTL ratio (P=0.001143, β=0.0148, SE=0.004516). The rs6993770 is an intronic variant of the ZFPM2 gene, which is involved in haematopoiesis and the identified association with increased telomere attrition could be due to increased haematopoiesis. No significant epistatic interaction was identified, and no association was found between levels of VEGF-A and any of assessed phenotypes. We identified a potential common genetic regulation between VEGF-A and telomere length attrition that could be explained by mechanisms of increased hematopoiesis and production of platelets. VEGF-A and TL could play an important role in personalized medicine of chronic diseases and identification of molecular links between them can promote the understanding of their complex implications.},
}
@article {pmid34661200,
year = {2021},
author = {Chakravarti, D and DePinho, RA},
title = {Telomere Dysfunction as an Initiator of Inflammation: Clues to an Age-Old Mystery.},
journal = {Journal of inflammatory bowel diseases &amp; disorders},
volume = {6},
number = {2},
pages = {},
pmid = {34661200},
support = {R01 CA084628/CA/NCI NIH HHS/United States ; },
abstract = {Inflammatory Bowel Disease (IBD) is a challenging medical condition that is driven by various genetic and environmental factors. Therapeutic opportunities for this disease remain limited due to the lack of in-depth understanding of the pathogenetic mechanisms and actionable targets driving the disease. Analysis of telomere dysfunctional mice and patients with genetic defects in telomere maintenance unexpectedly revealed phenotypes mirroring those observed in IBD. Molecular characterization of this model identified a pathway driven by telomere DNA damage-mediated activation of the ATM/cABL/YAP1 pathway, which directly regulates genes central to IBD pathogenesis and amenable to therapeutic intervention. This review summarizes the evidence correlating telomere dysfunction with IBD and colitis-associated cancer and proposes therapeutic opportunities for such inflammatory conditions targeting this newly identified pathway.},
}
@article {pmid34661101,
year = {2021},
author = {Luttermann, T and Rückert, C and Wibberg, D and Busche, T and Schwarzhans, JP and Friehs, K and Kalinowski, J},
title = {Establishment of a near-contiguous genome sequence of the citric acid producing yeast Yarrowia lipolytica DSM 3286 with resolution of rDNA clusters and telomeres.},
journal = {NAR genomics and bioinformatics},
volume = {3},
number = {4},
pages = {lqab085},
pmid = {34661101},
issn = {2631-9268},
abstract = {Yarrowia lipolytica is an oleaginous yeast that is particularly suitable for the sustainable production of secondary metabolites. The genome of this yeast is characterized by its relatively large size and its high number of different rDNA clusters located in its telomeric regions. However, due to the presence of long repetitive elements in the sub-telomeric regions, rDNA clusters and telomeres are missing in current genome assemblies of Y. lipolytica. Here, we present the near-contiguous genome sequence of the biotechnologically relevant strain DSM 3286. We employed a hybrid assembly strategy combining Illumina and nanopore sequencing reads to integrate all six rDNA clusters as well as telomeric repeats into the genome sequence. By fine-tuning of DNA isolation and library preparation protocols, we were able to create ultra-long reads that not only contained multiples of mitochondrial genomes but also shed light on the inter- and intra-chromosomal diversity of rDNA cluster types. We show that there are ten different rDNA units present in this strain that additionally appear in a predefined order in a cluster. Based on single reads, we also demonstrate that the number of rDNA repeats in a specific cluster varies from cell to cell within a population.},
}
@article {pmid34659314,
year = {2021},
author = {Barakate, A and Arrieta, M and Macaulay, M and Vivera, S and Davidson, D and Stephens, J and Orr, J and Schreiber, M and Ramsay, L and Halpin, C and Waugh, R},
title = {Downregulation of Barley Regulator of Telomere Elongation Helicase 1 Alters the Distribution of Meiotic Crossovers.},
journal = {Frontiers in plant science},
volume = {12},
number = {},
pages = {745070},
pmid = {34659314},
issn = {1664-462X},
support = {BB/F020872/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
abstract = {Programmed meiotic DNA double-strand breaks (DSBs), necessary for proper chromosomal segregation and viable gamete formation, are repaired by homologous recombination (HR) as crossovers (COs) or non-crossovers (NCOs). The mechanisms regulating the number and distribution of COs are still poorly understood. The regulator of telomere elongation helicase 1 (RTEL1) DNA helicase was previously shown to enforce the number of meiotic COs in Caenorhabditis elegans but its function in plants has been studied only in the vegetative phase. Here, we characterised barley RTEL1 gene structure and expression using RNA-seq data previously obtained from vegetative and reproductive organs and tissues. Using RNAi, we downregulated RTEL1 expression specifically in reproductive tissues and analysed its impact on recombination using a barley 50k iSelect SNP Array. Unlike in C. elegans, in a population segregating for RTEL1 downregulated by RNAi, high resolution genome-wide genetic analysis revealed a significant increase of COs at distal chromosomal regions of barley without a change in their total number. Our data reveal the important role of RTEL1 helicase in plant meiosis and control of recombination.},
}
@article {pmid34656614,
year = {2022},
author = {Ingold, N and Dusingize, JC and Neale, RE and Olsen, CM and Whiteman, DC and Duffy, DL and MacGregor, S and Law, MH},
title = {Examining Evidence for a Causal Association between Telomere Length and Nevus Count.},
journal = {The Journal of investigative dermatology},
volume = {142},
number = {5},
pages = {1502-1505.e6},
doi = {10.1016/j.jid.2021.09.021},
pmid = {34656614},
issn = {1523-1747},
mesh = {Humans ; *Nevus/genetics ; *Nevus, Pigmented ; *Skin Neoplasms/genetics ; Telomere/genetics ; },
}
@article {pmid34654043,
year = {2022},
author = {Fu, J and Ji, X and Liu, J and Chen, X and Shang, H},
title = {Meta-analysis of the Connection Between Alzheimer Disease and Telomeres.},
journal = {Alzheimer disease and associated disorders},
volume = {36},
number = {1},
pages = {73-79},
doi = {10.1097/WAD.0000000000000468},
pmid = {34654043},
issn = {1546-4156},
mesh = {*Alzheimer Disease/genetics ; China ; Humans ; *Neurodegenerative Diseases ; Telomere ; },
abstract = {BACKGROUND: Alzheimer disease (AD) is the most common neurodegenerative disease of the central nervous system. The stability of the telomere-telomerase system is closely related to AD. A previous meta-analysis indicated that AD patients had shorter telomere length (TL) than control subjects. However, there are no consistent telomerase activity findings in AD patients, and the published telomerase studies were not meta-analyzed yet.<br><br>METHODS: We searched all the related studies that probed into TL and/or telomerase activity in AD patients based on PubMed and Embase database from the establishment to September 2020. The Chinese National Knowledge Infrastructure, Wanfang and China Science and Technology Journal Database were also utilized. The quality of the included studies was evaluated by using Newcastle-Ottawa Scale. All the statistical analyses of this meta-analysis were performed using Stata version 15.0.<br><br>RESULTS: Analyzing 30 TL data from 2248 AD patients and 4865 controls, AD patients had a significantly shorter TL than the controls, with a standardized mean difference of -0.70 (confidence interval: -0.95 to -0.46; P<0.05). The meta-analysis included 3 primary studies and did not find a significant difference in the telomerase activity between 233 AD patients and 132 controls, but AD patients had a trend of increased telomerase activity compared with controls (standardized mean difference: 0.47; confidence interval: -0.29 to 1.23; P>0.05).<br><br>CONCLUSION: Our results showed that compared with the control group, the AD group had a shorter TL and may have higher telomerase activity.},
}
@article {pmid34646443,
year = {2021},
author = {Criscuolo, F and Dobson, FS and Schull, Q},
title = {The influence of phylogeny and life history on telomere lengths and telomere rate of change among bird species: A meta-analysis.},
journal = {Ecology and evolution},
volume = {11},
number = {19},
pages = {12908-12922},
pmid = {34646443},
issn = {2045-7758},
abstract = {Longevity is highly variable among animal species and has coevolved with other life-history traits, such as body size and rates of reproduction. Telomeres, through their erosion over time, are one of the cell mechanisms that produce senescence at the cell level and might even have an influence on the rate of aging in whole organisms. However, uneroded telomeres are also risk factors of cell immortalization. The associations of telomere lengths, their rate of change, and life-history traits independent of body size are largely underexplored for birds. To test associations of life-history traits and telomere dynamics, we conducted a phylogenetic meta-analysis using studies of 53 species of birds. We restricted analyses to studies that applied the telomere restriction fragment length (TRF) method, and examined relationships between mean telomere length at the chick (Chick TL) and adult (Adult TL) stages, the mean rate of change in telomere length during life (TROC), and life-history traits. We examined 3 principal components of 12 life-history variables that represented: body size (PC1), the slow-fast continuum of pace of life (PC2), and postfledging parental care (PC3). Phylogeny had at best a small-to-medium influence on Adult and Chick TL (r [2] = .190 and .138, respectively), but a substantial influence on TROC (r [2] = .688). Phylogeny strongly influenced life histories: PC1 (r [2] = .828), PC2 (.838), and PC3 (.613). Adult TL and Chick TL were poorly associated with the life-history variables. TROC, however, was negatively and moderate-to-strongly associated with PC2 (unadjusted r = -.340; with phylogenetic correction, r = -.490). Independent of body size, long-lived species with smaller clutches, and slower embryonic rate of growth may exhibit less change in telomere length over their lifetimes. We suggest that telomere lengths may have diverged, even among closely avian-related species, yet telomere dynamics are strongly linked to the pace of life.},
}
@article {pmid34638246,
year = {2021},
author = {Monteagudo, M and Martínez, P and Leandro-García, LJ and Martínez-Montes, &#xc1;M and Calsina, B and Pulgarín-Alfaro, M and Díaz-Talavera, A and Mellid, S and Letón, R and Gil, E and Pérez-Martínez, M and Megías, D and Torres-Ruiz, R and Rodriguez-Perales, S and González, P and Caleiras, E and Jiménez-Villa, S and Roncador, G and Álvarez-Escolá, C and Regojo, RM and Calatayud, M and Guadalix, S and Currás-Freixes, M and Rapizzi, E and Canu, L and Nölting, S and Remde, H and Fassnacht, M and Bechmann, N and Eisenhofer, G and Mannelli, M and Beuschlein, F and Quinkler, M and Rodríguez-Antona, C and Cascón, A and Blasco, MA and Montero-Conde, C and Robledo, M},
title = {Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma.},
journal = {Cancers},
volume = {13},
number = {19},
pages = {},
pmid = {34638246},
issn = {2072-6694},
support = {LCF/BQ/PI20/11760011//"la Caixa" Foundation/ ; 16-1177/AICR_/Worldwide Cancer Research/United Kingdom ; no grant number applicable to M.R.//Pheipas Association/ ; S2017/BMD-3724; TIRONET2-CM//Comunidad de Madrid/ ; ERC-AvG Shelterines GA882385/ERC_/European Research Council/International ; no grant number applicable//Centro de Investigacion Biom&#xe9;dica en Red de Enfermedades Raras/ ; no grant number applicable//Immuno-TargET project under the umbrella of University Medicine Zurich/ ; Becas de Excelencia Rafael del Pino 2017//Fundaci&#xf3;n Rafael del Pino/ ; 205/1//Deutsche Forschungsgemeinschaft (DFG) within the CRC/Transregio/ ; AIO15152858 MONT//Fundaci&#xf3;n Cient&#xed;fica Asociaci&#xf3;n Espa&#xf1;ola Contra el C&#xe1;ncer/ ; no grant number applicable//Fundaci&#xf3;n Bot&#xed;n/ ; PI17/01796//Instituto de Salud Carlos III/ ; no grant number applicable to M.R.//Paradifference Foundation/ ; SAF2017-82623-R, SAF2015-72455-EXP//Spanish State Research Agency (AEI), Ministry of Science and Innovation, cofounded by the European Regional Development Fund (ERDF)/ ; S2017/BMD-3770//Comunidad de Madrid/ ; FPU18/00064//Spanish Ministry of Science, Innovation and Universities/ ; PI17/01796, PI20/01169//Instituto de Salud Carlos III (ISCIII), Acci&#xf3;n Estrat&#xe9;gica en Salud, cofinanciado a trav&#xe9;s del Fondo Europeo de Desarrollo Regional (FEDER)/ ; },
abstract = {One of the main problems we face with PPGL is the lack of molecular markers capable of predicting the development of metastases in patients. Telomere-related genes, such as TERT and ATRX, have been recently described in PPGL, supporting the association between the activation of immortalization mechanisms and disease progression. However, the contribution of other genes involving telomere preservation machinery has not been previously investigated. In this work, we aimed to analyze the prognostic value of a comprehensive set of genes involved in telomere maintenance. For this study, we collected 165 PPGL samples (97 non-metastatic/63 metastatic), genetically characterized, in which the expression of 29 genes of interest was studied by NGS. Three of the 29 genes studied, TERT, ATRX and NOP10, showed differential expression between metastatic and non-metastatic cases, and alterations in these genes were associated with a shorter time to progression, independent of SDHB-status. We studied telomere length by Q-FISH in patient samples and in an in vitro model. NOP10 overexpressing tumors displayed an intermediate-length telomere phenotype without ALT, and in vitro results suggest that NOP10 has a role in telomerase-dependent telomere maintenance. We also propose the implementation of NOP10 IHC to better stratify PPGL patients.},
}
@article {pmid34637637,
year = {2021},
author = {Velando, A and Noguera, JC and Aira, M and Domínguez, J},
title = {Gut microbiome and telomere length in gull hatchlings.},
journal = {Biology letters},
volume = {17},
number = {10},
pages = {20210398},
pmid = {34637637},
issn = {1744-957X},
mesh = {Animals ; *Charadriiformes ; Corticosterone ; *Gastrointestinal Microbiome ; Telomere ; Telomere Shortening ; },
abstract = {In many animals, recent evidence indicates that the gut microbiome may be acquired during early development, with possible consequences on newborns' health. Thus, it has been hypothesized that a healthy microbiome protects telomeres and genomic integrity against cellular stress. However, the link between the early acquired microbiome and telomere dynamics has not hitherto been investigated. In birds, this link may also be potentially modulated by the transfer of maternal glucocorticoids, since these substances dysregulate microbiome composition during postnatal development. Here, we examined the effect of the interplay between the microbiome and stress hormones on the telomere length of yellow-legged gull hatchlings by using a field experiment in which we manipulated the corticosterone content in eggs. We found that the hatchling telomere length was related to microbiome composition, but this relationship was not affected by the corticosterone treatment. Hatchlings with a microbiome dominated by potential commensal bacteria (i.e. Catellicoccus and Cetobacterium) had larger telomeres, suggesting that an early establishment of the species-specific microbiome during development may have important consequences on offspring health and survival.},
}
@article {pmid34636058,
year = {2022},
author = {Stainczyk, SA and Westermann, F},
title = {Neuroblastoma-Telomere maintenance, deregulated signaling transduction and beyond.},
journal = {International journal of cancer},
volume = {150},
number = {6},
pages = {903-915},
doi = {10.1002/ijc.33839},
pmid = {34636058},
issn = {1097-0215},
mesh = {Anaplastic Lymphoma Kinase/antagonists &amp; inhibitors/genetics ; Animals ; Aurora Kinase A/antagonists &amp; inhibitors ; Chromosome Aberrations ; Genes, p53 ; Genes, ras ; Humans ; Mutation ; Neuroblastoma/drug therapy/*genetics ; Signal Transduction ; Telomere Homeostasis/drug effects/*physiology ; },
abstract = {The childhood malignancy neuroblastoma belongs to the group of embryonal tumors and originates from progenitor cells of the sympathoadrenal lineage. Treatment options for children with high-risk and relapsed disease are still very limited. In recent years, an ever-growing molecular diversity was identified using (epi)-genetic profiling of neuroblastoma tumors, indicating that molecularly targeted therapies could be a promising therapeutic option. In this review article, we summarize the various molecular subtypes and genetic events associated with neuroblastoma and describe recent advances in targeted therapies. We lay a strong emphasis on the importance of telomere maintenance mechanisms for understanding tumor progression and risk classification of neuroblastoma.},
}
@article {pmid34631753,
year = {2021},
author = {van Batenburg, AA and van Oosterhout, MFM and Knoppert, SN and Kazemier, KM and van der Vis, JJ and Grutters, JC and Goldschmeding, R and van Moorsel, CHM},
title = {The Extent of Inflammatory Cell Infiltrate and Fibrosis in Lungs of Telomere- and Surfactant-Related Familial Pulmonary Fibrosis.},
journal = {Frontiers in medicine},
volume = {8},
number = {},
pages = {736485},
pmid = {34631753},
issn = {2296-858X},
abstract = {Familial pulmonary fibrosis (FPF) is a monogenic disease most commonly involving telomere- (TERT) or surfactant- (SFTP) related mutations. These mutations have been shown to alter lymphocytic inflammatory responses, and FPF biopsies with histological lymphocytic infiltrates have been reported. Recently, a model of a surfactant mutation in mice showed that the disease initially started with an inflammatory response followed by fibrogenesis. Since inflammation and fibrogenesis are targeted by different drugs, we investigated whether the degree of these two features co-localize or occur independently in different entities of FPF, and whether they influence survival. We quantified the number of lymphocyte aggregates per surface area, the extent of diffuse lymphocyte cell infiltrate, the number of fibroblast foci per surface area, and the percentage of fibrotic lung surface area in digitally scanned hematoxylin and eosin (H&amp;E) sections of diagnostic surgical biopsies of patients with TERT-related FPF (TERT-PF; n = 17), SFTP-related FPF (SFTP-PF; n = 7), and sporadic idiopathic pulmonary fibrosis (sIPF; n = 10). For comparison, we included biopsies of patients with cellular non-specific interstitial pneumonia (cNSIP; n = 10), an inflammatory interstitial lung disease with high lymphocyte influx and usually responsive to immunosuppressive therapy. The degree of inflammatory cell infiltrate and fibrosis in TERT-PF and SFTP-PF was not significantly different from that in sIPF. In comparison with cNSIP, the extent of lymphocyte infiltrates was significantly lower in sIPF and TERT-PF, but not in SFTP-PF. However, in contrast with cNSIP, in sIPF, TERT-PF, and SFTP-PF, diffuse lymphocyte cell infiltrates were predominantly present and lymphocyte aggregates were only present in fibrotic areas (p < 0.0001). Furthermore, fibroblast foci and percentage of fibrotic lung surface were associated with survival (p = 0.022 and p = 0.018, respectively), while this association was not observed for lymphocyte aggregates or diffuse lymphocytic infiltration. Inflammatory cells in diagnostic lung biopsies of TERT-PF, SFTP-PF, and sIPF were largely confined to fibrotic areas. However, based on inflammation and fibrosis, no differences were found between FPF and sIPF, substantiating the histological similarities between monogenic familial and sporadic disease. Furthermore, the degree of fibrosis, rather than inflammation, correlates with survival, supporting that fibrogenesis is the key feature for therapeutic targeting of FPF.},
}
@article {pmid34630527,
year = {2021},
author = {Buddhachat, K and Brown, JL and Kaewkool, M and Poommouang, A and Kaewmong, P and Kittiwattanawong, K and Nganvongpanit, K},
title = {Life Expectancy in Marine Mammals Is Unrelated to Telomere Length but Is Associated With Body Size.},
journal = {Frontiers in genetics},
volume = {12},
number = {},
pages = {737860},
pmid = {34630527},
issn = {1664-8021},
abstract = {Marine mammals vary greatly in size and lifespan across species. This study determined whether measures of adult body weight, length and relative telomere length were related to lifespan. Skin tissue samples (n = 338) were obtained from 23 marine mammal species, including four Mysticeti, 19 Odontoceti and one dugong species, and the DNA extracted to measure relative telomere length using real-time PCR. Life span, adult body weight, and adult body length of each species were retrieved from existing databases. The phylogenetic signal analysis revealed that body length might be a significant factor for shaping evolutionary processes of cetacean species through time, especially for genus Balaenoptera that have an enormous size. Further, our study found correlations between lifespan and adult body weight (R [2] = 0.6465, p < 0.001) and adult body length (R [2] = 0.6142, p ≤0.001), but no correlations with relative telomere length (R [2] = -0.0476, p = 0.9826). While data support our hypothesis that larger marine mammals live longer, relative telomere length is not a good predictor of species longevity.},
}
@article {pmid34628468,
year = {2021},
author = {Lin, YF and Chen, PY and Liu, HC and Chen, YL and Chou, WH and Huang, MC},
title = {Shortened leukocyte telomere length in young adults who use methamphetamine.},
journal = {Translational psychiatry},
volume = {11},
number = {1},
pages = {519},
pmid = {34628468},
issn = {2158-3188},
mesh = {Adult ; Aging ; Humans ; Leukocytes ; *Methamphetamine/adverse effects ; *Telomere/genetics ; Telomere Shortening ; Young Adult ; },
abstract = {Methamphetamine (METH) use, most prevalent in young adults, has been associated with high rates of morbidity and mortality. The relationship between METH use and accelerated biological aging, which can be measured using leukocyte telomere length (LTL), remains unclear. We examined whether young adult METH users have shorter LTL and explored the relationship between characteristics of METH use and LTL by using Mendelian randomization (MR) analysis. We compared the LTL for 187 METH users and 159 healthy individuals aged between 25 and 34 years and examined the relationship of LTL with METH use variables (onset age, duration, and maximum frequency of METH use) by using regression analyses. In addition, 2-stage-least-squares (2SLS) MR was also performed to possibly avoid uncontrolled confounding between characteristics of METH use and LTL. We found METH users had significantly shorter LTL compared to controls. Multivariate regression analysis showed METH use was negatively associated with LTL (β = -0.36, P < .001). Among METH users, duration of METH use was negatively associated with LTL after adjustment (β = -0.002, P = .01). We identified a single nucleotide polymorphism (SNP) rs6585206 genome-wide associated with duration of METH use. This SNP was used as an instrumental variable to avoid uncontrolled confounding for the relationship between the use duration and LTL shortening. In conclusion, we show that young adult METH users may have shorter LTL compared with controls and longer duration of METH use was significantly associated with telomere shortening. These observations suggest that METH use may accelerate biological senescence.},
}
@article {pmid34627377,
year = {2021},
author = {Martin, H and Doumic, M and Teixeira, MT and Xu, Z},
title = {Telomere shortening causes distinct cell division regimes during replicative senescence in Saccharomyces cerevisiae.},
journal = {Cell &amp; bioscience},
volume = {11},
number = {1},
pages = {180},
pmid = {34627377},
issn = {2045-3701},
support = {ANR-17-CE20-0002-01//agence nationale de la recherche/ ; LabEx Dynamo ANR-11-LABX-0011-01//agence nationale de la recherche/ ; ANR-16-CE12-0026//agence nationale de la recherche/ ; Programme &#xc9;mergence(s)//ville de paris/ ; &#xc9;quipe FRM EQU202003010428//fondation pour la recherche m&#xe9;dicale/ ; INCa_15192//institut national du cancer/ ; },
abstract = {BACKGROUND: Telomerase-negative cells have limited proliferation potential. In these cells, telomeres shorten until they reach a critical length and induce a permanently arrested state. This process called replicative senescence is associated with genomic instability and participates in tissue and organismal ageing. Experimental data using single-cell approaches in the budding yeast model organism show that telomerase-negative cells often experience abnormally long cell cycles, which can be followed by cell cycles of normal duration, before reaching the terminal senescent state. These series of non-terminal cell cycle arrests contribute to the heterogeneity of senescence and likely magnify its genomic instability. Due to their apparent stochastic nature, investigating the dynamics and the molecular origins of these arrests has been difficult. In particular, whether the non-terminal arrests series stem from a mechanism similar to the one that triggers terminal senescence is not known.<br><br>RESULTS: Here, we provide a mathematical description of sequences of non-terminal arrests to understand how they appear. We take advantage of an experimental data set of cell cycle duration measurements performed in individual telomerase-negative yeast cells that keep track of the number of generations since telomerase inactivation. Using numerical simulations, we show that the occurrence of non-terminal arrests is a generation-dependent process that can be explained by the shortest telomere reaching a probabilistic threshold length. While the onset of senescence is also triggered by telomere shortening, we highlight differences in the laws that describe the number of consecutive arrests in non-terminal arrests compared to senescence arrests, suggesting distinct underlying mechanisms and cellular states.<br><br>CONCLUSIONS: Replicative senescence is a complex process that affects cell divisions earlier than anticipated, as exemplified by the frequent occurrence of non-terminal arrests early after telomerase inactivation. The present work unravels two kinetically and mechanistically distinct generation-dependent processes underlying non-terminal and terminal senescence arrests. We suggest that these two processes are responsible for two consequences of senescence at the population level, the increase of genome instability on the one hand, and the limitation of proliferation capacity on the other hand.},
}
@article {pmid34627342,
year = {2021},
author = {Ide, S and Sasaki, A and Kawamoto, Y and Bando, T and Sugiyama, H and Maeshima, K},
title = {Telomere-specific chromatin capture using a pyrrole-imidazole polyamide probe for the identification of proteins and non-coding RNAs.},
journal = {Epigenetics &amp; chromatin},
volume = {14},
number = {1},
pages = {46},
pmid = {34627342},
issn = {1756-8935},
mesh = {Animals ; *Chromatin ; Imidazoles ; Mice ; *Nylons ; Pyrroles ; Telomere ; },
abstract = {BACKGROUND: Knowing chromatin components at a DNA regulatory element at any given time is essential for understanding how the element works during cellular proliferation, differentiation and development. A region-specific chromatin purification is an invaluable approach to dissecting the comprehensive chromatin composition at a particular region. Several methods (e.g., PICh, enChIP, CAPTURE and CLASP) have been developed for isolating and analyzing chromatin components. However, all of them have some shortcomings in identifying non-coding RNA associated with DNA regulatory elements.<br><br>RESULTS: We have developed a new approach for affinity purification of specific chromatin segments employing an N-methyl pyrrole (P)-N-methylimidazole (I) (PI) polyamide probe, which binds to a specific sequence in double-stranded DNA via Watson-Crick base pairing as a minor groove binder. This new technique is called proteomics and RNA-omics of isolated chromatin segments (PI-PRICh). Using PI-PRICh to isolate mouse and human telomeric components, we found enrichments of shelterin proteins, the well-known telomerase RNA component (TERC) and telomeric repeat-containing RNA (TERRA). When PI-PRICh was performed for alternative lengthening of telomere (ALT) cells with highly recombinogenic telomeres, in addition to the conventional telomeric chromatin, we obtained chromatin regions containing telomeric repeat insertions scattered in the genome and their associated RNAs.<br><br>CONCLUSION: PI-PRICh reproducibly identified both the protein and RNA components of telomeric chromatin when targeting telomere repeats. PI polyamide is a promising alternative to simultaneously isolate associated proteins and RNAs of sequence-specific chromatin regions under native conditions, allowing better understanding of chromatin organization and functions within the cell.},
}
@article {pmid34624827,
year = {2021},
author = {Cavalcante, SG and Pereira, BJA and Lerario, AM and Sola, PR and Oba-Shinjo, SM and Marie, SKN},
title = {The chromatin remodeler complex ATRX-DAXX-H3.3 and telomere length in meningiomas.},
journal = {Clinical neurology and neurosurgery},
volume = {210},
number = {},
pages = {106962},
doi = {10.1016/j.clineuro.2021.106962},
pmid = {34624827},
issn = {1872-6968},
mesh = {Adult ; Aged ; Aged, 80 and over ; Co-Repressor Proteins/genetics/*metabolism ; Female ; Histones/genetics/*metabolism ; Humans ; Male ; Meningeal Neoplasms/genetics/*metabolism/pathology ; Meningioma/genetics/*metabolism/pathology ; Middle Aged ; Molecular Chaperones/genetics/*metabolism ; Telomere/genetics/*metabolism ; X-linked Nuclear Protein/genetics/*metabolism ; },
abstract = {ATRX-DAXX-H3.3 chromatin remodeler complex is a well known epigenetic factor responsible for the heterochromatin maintenance and control. ATRX is an important nucleosome controller, especially in tandem repeat regions, and DAXX is a multi-function protein with particular role in histone H3.3 deposition due to its chaperone characteristic. Abnormalities in this complex have been associated with telomere dysfunction and consequently with activation of alternative lengthening of telomeres mechanism, genomic instability, and tumor progression in different types of cancer. However, the characterization of this complex is still incomplete in meningioma. We analyzed ATRX, DAXX and H3.3 expressions and the telomere length in a cohort of meningioma of different malignant grades. We observed ATRX upregulation at gene and protein levels in grade II/III meningiomas. A low variability of telomere length was observed in meningiomas across different ages and malignant grades, in contrast to the shortening of telomere length with aging in normal controls.},
}
@article {pmid34624021,
year = {2021},
author = {Morgunova, V and Kordyukova, M and Mikhaleva, EA and Butenko, I and Pobeguts, OV and Kalmykova, A},
title = {Loss of telomere silencing is accompanied by dysfunction of Polo kinase and centrosomes during Drosophila oogenesis and early development.},
journal = {PloS one},
volume = {16},
number = {10},
pages = {e0258156},
pmid = {34624021},
issn = {1932-6203},
mesh = {Animals ; Cell Death ; Centrioles/metabolism ; Centrosome/*metabolism ; Drosophila Proteins/*metabolism ; Drosophila melanogaster/*embryology/*metabolism ; Embryo, Nonmammalian/metabolism ; *Embryonic Development ; Mitosis ; *Oogenesis ; Protein Binding ; Protein Serine-Threonine Kinases/*metabolism ; RNA/metabolism ; Retroelements/genetics ; Ribonucleoproteins/metabolism ; Telomere/*metabolism ; Zygote/metabolism ; },
abstract = {Telomeres are nucleoprotein complexes that protect the ends of eukaryotic linear chromosomes from degradation and fusions. Telomere dysfunction leads to cell growth arrest, oncogenesis, and premature aging. Telomeric RNAs have been found in all studied species; however, their functions and biogenesis are not clearly understood. We studied the mechanisms of development disorders observed upon overexpression of telomeric repeats in Drosophila. In somatic cells, overexpression of telomeric retrotransposon HeT-A is cytotoxic and leads to the accumulation of HeT-A Gag near centrosomes. We found that RNA and RNA-binding protein Gag encoded by the telomeric retrotransposon HeT-A interact with Polo and Cdk1 mitotic kinases, which are conserved regulators of centrosome biogenesis and cell cycle. The depletion of proteins Spindle E, Ccr4 or Ars2 resulting in HeT-A overexpression in the germline was accompanied by mislocalization of Polo as well as its abnormal stabilization during oogenesis and severe deregulation of centrosome biogenesis leading to maternal-effect embryonic lethality. These data suggest a mechanistic link between telomeric HeT-A ribonucleoproteins and cell cycle regulators that ensures the cell response to telomere dysfunction.},
}
@article {pmid34618297,
year = {2021},
author = {Wang, F and Chamani, IJ and Luo, D and Chan, K and Navarro, PA and Keefe, DL},
title = {Inhibition of LINE-1 retrotransposition represses telomere reprogramming during mouse 2-cell embryo development.},
journal = {Journal of assisted reproduction and genetics},
volume = {38},
number = {12},
pages = {3145-3153},
pmid = {34618297},
issn = {1573-7330},
support = {6-FY14-432//march of dimes foundation/ ; Stanley H. Kaplan Endowment//nyu langone medical center/ ; },
mesh = {Animals ; Cell Differentiation/genetics/physiology ; Embryo, Mammalian/*physiology ; Embryonic Development/*genetics/physiology ; Mice ; Mouse Embryonic Stem Cells/physiology ; RNA-Binding Proteins/*genetics ; Telomere/*genetics ; Zygote/physiology ; },
abstract = {PURPOSE: To investigate whether inhibition of LINE-1 affects telomere reprogramming during 2-cell embryo development.<br><br>METHODS: Mouse zygotes were cultured with or without 1&#xa0;&#xb5;M azidothymidine (AZT) for up to 15&#xa0;h (early 2-cell, G1/S) or 24&#xa0;h (late 2-cell, S/G2). Gene expression and DNA copy number were determined by RT-qPCR and qPCR respectively. Immunostaining and telomeric PNA-FISH were performed for co-localization between telomeres and ZSCAN4 or LINE-1-Orf1p.<br><br>RESULTS: LINE-1 copy number was remarkably reduced in later 2-cell embryos by exposure to 1&#xa0;&#xb5;M AZT, and telomere lengths in late 2-cell embryos with AZT were significantly shorter compared to control embryos (P&#x2009;=&#x2009;0.0002). Additionally, in the absence of LINE-1 inhibition, Dux, Zscan4, and LINE-1 were highly transcribed in early 2-cell embryos, as compared to late 2-cell embryos (P&#x2009;<&#x2009;0.0001), suggesting that these 2-cell genes are activated at the early 2-cell stage. However, in early 2-cell embryos with AZT treatment, mRNA levels of Dux, Zscan4, and LINE-1 were significantly decreased. Furthermore, both Zscan4 and LINE-1 encoded proteins localized to telomere regions in 2-cell embryos, but this co-localization was dramatically reduced after AZT treatment (P&#x2009;<&#x2009;0.001).<br><br>CONCLUSIONS: Upon inhibition of LINE-1 retrotransposition in mouse 2-cell embryos, Dux, Zscan4, and LINE-1 were significantly downregulated, and telomere elongation was blocked. ZSCAN4 foci and their co-localization with telomeres were also significantly decreased, indicating that ZSCAN4 is an essential component of the telomere reprogramming that occurs in mice at the 2-cell stage. Our findings also suggest that LINE-1 may directly contribute to telomere reprogramming in addition to regulating gene expression.},
}
@article {pmid34617352,
year = {2021},
author = {Borie, R and Renzoni, E},
title = {Pulmonary fibrosis associated with telomere-related gene mutations: A complex inheritance.},
journal = {Respirology (Carlton, Vic.)},
volume = {26},
number = {12},
pages = {1098-1100},
doi = {10.1111/resp.14168},
pmid = {34617352},
issn = {1440-1843},
mesh = {Humans ; Multifactorial Inheritance ; Mutation ; *Pulmonary Fibrosis/genetics ; Telomere/genetics ; Telomere Shortening ; },
}
@article {pmid34616503,
year = {2021},
author = {Tung, KTS and Hung, CMW and Chan, KL and Wong, RS and Tsang, HW and Wong, WHS and Lo, CKM and Tso, WWY and Chua, GT and Yee, BK and Wong, ICK and Leung, WC and Ip, P},
title = {Influence of Maternal Infection and Pregnancy Complications on Cord Blood Telomere Length.},
journal = {Oxidative medicine and cellular longevity},
volume = {2021},
number = {},
pages = {3339456},
pmid = {34616503},
issn = {1942-0994},
mesh = {Adult ; Anemia/*epidemiology ; Female ; Fetal Blood/*cytology ; Gestational Age ; Hong Kong/epidemiology ; Humans ; Hypertension, Pregnancy-Induced/*epidemiology ; Infant, Newborn ; Longitudinal Studies ; Male ; Pregnancy ; Pregnancy Complications, Infectious/*epidemiology ; Quality of Life ; *Telomere ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {BACKGROUND: Exposure to suboptimal intrauterine environment might induce structural and functional changes that can affect neonatal health. Telomere length as an important indicator of cellular health has been associated with increased risk for disease development.<br><br>OBJECTIVES: This study was aimed to examine the independent and combined effects of maternal, obstetric, and foetal factors on cord blood telomere length (TL).<br><br>METHODS: Pregnant women at the gestational age of 20[th] to 24[th] week who attended the antenatal clinic of a major local hospital in Hong Kong were recruited. Participants were asked to complete a questionnaire on demographics, health-related quality of life, and history of risk behaviors. Medical history including pregnancy complications and neonatal outcomes was obtained from electronic medical records of both mother and neonate. Umbilical cord blood was collected at delivery for TL determination.<br><br>RESULTS: A total of 753 pregnant women (average age: 32.18 &#xb1; 4.51 years) were recruited. The prevalence of maternal infection, anaemia, and hypertension during pregnancy was 30.8%, 30.0%, and 6.0%, respectively. The adjusted regression model displayed that maternal infection was negatively associated with cord blood TL (&#x3b2; = -0.18, p = 0.026). This association became even stronger in the presence of antenatal anaemia, hypertension, delivery complications, or neonatal jaundice (&#x3b2; = -0.25 to -0.45).<br><br>CONCLUSIONS: This study consolidates evidence on the impact of adverse intrauterine environment at the cellular level. Maternal infection was significantly associated with shorter cord blood TL in a unique manner such that its presence may critically determine the susceptibility of telomere to other factors.},
}
@article {pmid34611362,
year = {2021},
author = {Codd, V and Wang, Q and Allara, E and Musicha, C and Kaptoge, S and Stoma, S and Jiang, T and Hamby, SE and Braund, PS and Bountziouka, V and Budgeon, CA and Denniff, M and Swinfield, C and Papakonstantinou, M and Sheth, S and Nanus, DE and Warner, SC and Wang, M and Khera, AV and Eales, J and Ouwehand, WH and Thompson, JR and Di Angelantonio, E and Wood, AM and Butterworth, AS and Danesh, JN and Nelson, CP and Samani, NJ},
title = {Polygenic basis and biomedical consequences of telomere length variation.},
journal = {Nature genetics},
volume = {53},
number = {10},
pages = {1425-1433},
pmid = {34611362},
issn = {1546-1718},
support = {MR/L003120/1/MRC_/Medical Research Council/United Kingdom ; MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom ; MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; CH/12/2/29428/BHF_/British Heart Foundation/United Kingdom ; R/L003120/1/MRC_/Medical Research Council/United Kingdom ; RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom ; SP/16/4/32697/BHF_/British Heart Foundation/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; K08 HG010155/HG/NHGRI NIH HHS/United States ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Genome, Human ; Genome-Wide Association Study ; Humans ; Mendelian Randomization Analysis ; Multifactorial Inheritance/*genetics ; Quantitative Trait Loci ; Telomere Homeostasis/*genetics ; },
abstract = {Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community.},
}
@article {pmid34611226,
year = {2021},
author = {Zhao, H and Shen, J and Chang, D and Ye, Y and Wu, X and Chow, WH and Zhang, K},
title = {Land use mix and leukocyte telomere length in Mexican Americans.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {19742},
pmid = {34611226},
issn = {2045-2322},
mesh = {Adult ; Aging ; Biomarkers ; *Built Environment ; Female ; Humans ; *Leukocytes ; Male ; Mexican Americans/*genetics ; Middle Aged ; *Models, Theoretical ; Telomere/*genetics ; Telomere Homeostasis ; Young Adult ; },
abstract = {It has been well-known that built environment features influence the risk of chronic diseases. However, the existing data of its relationship with telomere length, a biomarker of biological aging, is still limited, with no study available for Mexican Americans. This study investigates the relationship between several factors of the built environment with leukocyte telomere length among 5508 Mexican American adults enrolled in Mano-A-Mano, the Mexican American Cohort Study (MACS). Based on the quartile levels of telomere length, the study population was categorized into four groups, from the lowest (1st quartile) to the highest telomere length group (4th quartile). For individual built environment factors, their levels did not differ significantly across four groups. However, in the multinominal logistic regression analysis, increased Rundle's land use mixture (LUM) and Frank's LUM were found statistically significantly associated with increased odds of having high levels of telomere length (Rundle's LUM: 2nd quartile: Odds ratio (OR) 1.26, 95% Confidence interval (CI) 1.07, 1.48; 3rd quartile: OR 1.25, 95% CI 1.06, 1.46; 4th quartile: OR 1.19, 95% CI 1.01, 1.41; Frank's LUM: 2nd quartile: OR 1.34, 95% CI 1.02, 2.63; 3rd quartile: OR 1.55, 95% CI 1.04, 2.91; 4th quartile: OR 1.36, 95% CI 1.05, 2.72, respectively). The associations for Rundle's LUM remained significant after further adjusting other non-redundant built environment factors. Finally, in stratified analysis, we found the association between Rundle's LUM and telomere length was more evident among younger individuals (< 38 years old), women, and those with obesity, born in Mexico, having low levels of physical activity, and having low levels of acculturation than their relative counterparts. In summary, our results indicate that land use mixture may impact telomere length in leukocytes in Mexican Americans.},
}
@article {pmid34605011,
year = {2022},
author = {Barade, A and Aboobacker, F and Korula, A and Lakshmi, K and Devasia, A and Abraham, A and Mathews, V and Edison, E and George, B},
title = {Impact of donor telomere length on survival in patients undergoing matched sibling donor transplantation for aplastic anaemia.},
journal = {British journal of haematology},
volume = {196},
number = {3},
pages = {724-734},
doi = {10.1111/bjh.17880},
pmid = {34605011},
issn = {1365-2141},
mesh = {Adolescent ; Adult ; Age Factors ; Anemia, Aplastic/*mortality/*therapy ; Child ; Child, Preschool ; Female ; Graft Rejection ; Graft Survival ; *Hematopoietic Stem Cell Transplantation/methods/mortality ; Humans ; Male ; Middle Aged ; Prognosis ; *Siblings ; Telomere/*genetics ; *Telomere Homeostasis ; *Tissue Donors ; Transplantation Conditioning/methods ; Treatment Outcome ; Young Adult ; },
abstract = {Although telomere shortening is seen frequently in patients with aplastic anaemia (AA), there are no data on its association in matched sibling donor (MSD) transplants. We evaluated the effect of pre-transplant telomere length of patients and donors, measured by quantitative real-time polymerase chain reaction in 163 recipients undergoing MSD transplants. The median age of patients and donors was 24 and 26 years, respectively. Fludarabine and cyclophosphamide was the main conditioning regimen used and all received peripheral blood stem cell grafts. Engraftment occurred in 89% with graft failure (primary and secondary) in 6%. Acute and chronic graft-versus-host disease (GVHD) occurred in 28% and 24%, respectively. At a median follow-up of 37 months, 117 patients (72%) were alive. All patients and donors were divided into short and long telomere length based on their median and quartile values. Patient telomere length was not associated with severity of AA, neutrophil recovery, graft failure, acute GVHD or chronic GVHD. Longer donor telomere length was associated with better overall survival [hazard ratio (HR) = 0·2, P = 0·006] but did not influence neutrophil recovery, graft failure, acute or chronic GVHD. The five-year overall survival was significantly better (94·9 ± 3·5% vs 65·4 ± 4·3%, P = 0·002) for donors with long (highest quartile, DTL-HQ) versus short (lower three quartiles, DTL-LQ) telomeres, respectively. On multivariate analysis, longer donor telomere length, recipient age and acute GVHD continued to remain significant. This is the first study demonstrating an association of donor telomere length on overall survival following MSD transplant for AA but it needs to be confirmed in larger studies.},
}
@article {pmid34604243,
year = {2021},
author = {Jeon, HJ and Oh, JS},
title = {TRF1 Depletion Reveals Mutual Regulation Between Telomeres, Kinetochores, and Inner Centromeres in Mouse Oocytes.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {749116},
pmid = {34604243},
issn = {2296-634X},
abstract = {In eukaryotic chromosomes, the centromere and telomere are two specialized structures that are essential for chromosome stability and segregation. Although centromeres and telomeres often are located in close proximity to form telocentric chromosomes in mice, it remained unclear whether these two structures influence each other. Here we show that TRF1 is required for inner centromere and kinetochore assembly in addition to its role in telomere protection in mouse oocytes. TRF1 depletion caused premature chromosome segregation by abrogating the spindle assembly checkpoint (SAC) and impairing kinetochore-microtubule (kMT) attachment, which increased the incidence of aneuploidy. Notably, TRF1 depletion disturbed the localization of Survivin and Ndc80/Hec1 at inner centromeres and kinetochores, respectively. Moreover, SMC3 and SMC4 levels significantly decreased after TRF1 depletion, suggesting that TRF1 is involved in chromosome cohesion and condensation. Importantly, inhibition of inner centromere or kinetochore function led to a significant decrease in TRF1 level and telomere shortening. Therefore, our results suggest that telomere integrity is required to preserve inner centromere and kinetochore architectures, and vice versa, suggesting mutual regulation between telomeres and centromeres.},
}
@article {pmid34603596,
year = {2021},
author = {Hao, L and Chen, Q and Chen, X and Zhou, Q},
title = {Association of Serum Total Bilirubin Concentration with Telomere Length: The National Health and Nutrition Examination Survey.},
journal = {Oxidative medicine and cellular longevity},
volume = {2021},
number = {},
pages = {4688900},
pmid = {34603596},
issn = {1942-0994},
mesh = {Adult ; Aged ; Bilirubin/*blood ; Female ; Humans ; Linear Models ; Male ; Middle Aged ; Nutrition Surveys ; Regression Analysis ; Telomere/*metabolism ; Telomere Shortening ; United States ; },
abstract = {INTRODUCTION: Mildly increased bilirubin concentration has a protective effect on oxidative stress-related diseases. However, it remains unknown whether elevated circulating bilirubin is associated with longer telomere length. The aim of this cross-sectional study was to examine the association between total bilirubin concentration and telomere length.<br><br>METHODS: We used the data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. The multivariable linear regression model was used to examine the association between total bilirubin concentration and telomere length. The nonlinear relationship was analyzed using a generalized additive model with the smoothing plot.<br><br>RESULTS: A total of 7818 participants with a mean age of 49.20 &#xb1; 18.82 years were included. Compared with the lowest concentration of total bilirubin (Q1), the highest quartile of total bilirubin concentration was associated with longer telomere length in male (&#x3b2; = 0.04, 95 CI%: 0.00, 0.07, P = 0.024) and female (&#x3b2; = 0.04, 95 CI%: 0.02, 0.04, P = 0.002). Furthermore, an inverted U-shaped relationship between total bilirubin and telomere length was found. On the left of turning points (total&#x2009;bilirubin < 0.5&#x2009;mg/dL), total bilirubin concentration was positively associated with telomere length (&#x3b2; = 0.23, 95 CI%: 0.14, 0.32, P < 0.001). However, the association between total bilirubin concentration and telomere length was not significant (&#x3b2; = 0.01, 95% CI: -0.01, 0.04, P = 0.346) above the turning point.<br><br>CONCLUSION: This is the first evidence based on a nationally representative survey demonstrating a positive and nonlinear association between total bilirubin concentration and telomere length. Future large-scale prospective studies are warranted to confirm our findings.},
}
@article {pmid34603389,
year = {2021},
author = {Hastings, WJ and Eisenberg, DTA and Shalev, I},
title = {Impact of Amplification Efficiency Approaches on Telomere Length Measurement via Quantitative-Polymerase Chain Reaction.},
journal = {Frontiers in genetics},
volume = {12},
number = {},
pages = {728603},
pmid = {34603389},
issn = {1664-8021},
support = {T32 AG049676/AG/NIA NIH HHS/United States ; U01 ES030949/ES/NIEHS NIH HHS/United States ; },
abstract = {Background: Precise determination of amplification efficiency is critical for reliable conversion of within-sample changes in fluorescence occurring on a logarithmic scale to between-sample differences in DNA content occurring on a linear scale. This endeavor is especially challenging for the telomere length (TL) quantitative-PCR (qPCR) assay, where amplification efficiency can vary between reactions targeting telomeric repeats (T) and those targeting a single-copy gene (S) to calculate TL as the T/S ratio. Methods: We compared seven different approaches toward estimating amplification efficiency, including the standard-curve method utilized by the qPCR instrument software, and alternative approaches which estimate efficiency on a reaction-by-reaction basis using the stand-alone program LinRegPCR. After calculating T/S ratios using efficiency estimates from each approach (N = 363), we tested their relative performance on metrics of assay precision and correlates of external validity including chronological age (age range = 1-72 years), across tissues within-person (leukocyte-buccal), and between parents and offspring. Results: Estimated amplification efficiency for telomere reactions was significantly lower than estimates for single-copy gene reactions. Efficiency estimates for both reaction sets were significantly higher when estimated with the standard-curve method utilized by the qPCR instrument relative to estimates reconstructed during the log-linear phase with LinRegPCR. While estimates of single-copy gene efficiency reconstructed using LinRegPCR measured within 90% of perfect exponential doubling (E = 1.92), estimates generated using the standard-curve method were inflated beyond 100% (E = 2.10-2.12), indicating poor fidelity. Despite differences in raw value, TL measurements calculated with LinRegPCR efficiency estimates exhibited similar relationships with external validity correlates to measurements generated using the qPCR instrument software. Conclusion: Since methods to estimate amplification efficiency can vary across qPCR instruments, we suggest that future analyses empirically consider external methods of efficiency calculations such as LinRegPCR, and that already generated data be re-analyzed to glean possible improvements.},
}
@article {pmid34602328,
year = {2021},
author = {Bosquet Enlow, M and Kane-Grade, F and De Vivo, I and Petty, CR and Nelson, CA},
title = {Corrigendum to "Patterns of change in telomere length over the first three years of life in healthy children" [Psychoneuroendocrinology 115 (2020) 104602].},
journal = {Psychoneuroendocrinology},
volume = {133},
number = {},
pages = {105419},
doi = {10.1016/j.psyneuen.2021.105419},
pmid = {34602328},
issn = {1873-3360},
}
@article {pmid34597314,
year = {2021},
author = {Zane, L and Ensminger, DC and Vázquez-Medina, JP},
title = {Short-term elevations in glucocorticoids do not alter telomere lengths: A systematic review and meta-analysis of non-primate vertebrate studies.},
journal = {PloS one},
volume = {16},
number = {10},
pages = {e0257370},
pmid = {34597314},
issn = {1932-6203},
mesh = {Animals ; Glucocorticoids/*blood ; Hypothalamo-Hypophyseal System/*physiology ; Pituitary-Adrenal System/*physiology ; *Telomere Shortening ; Vertebrates ; },
abstract = {BACKGROUND: The neuroendocrine stress response allows vertebrates to cope with stressors via the activation of the Hypothalamic-Pituitary-Adrenal (HPA) axis, which ultimately results in the secretion of glucocorticoids (GCs). Glucocorticoids have pleiotropic effects on behavior and physiology, and might influence telomere length dynamics. During a stress event, GCs mobilize energy towards survival mechanisms rather than to telomere maintenance. Additionally, reactive oxygen species produced in response to increased GC levels can damage telomeres, also leading to telomere shortening. In our systematic review and meta-analysis, we tested whether GC levels impact telomere length and if this relationship differs among time frame, life history stage, or stressor type. We hypothesized that elevated GC levels are linked to a decrease in telomere length.<br><br>METHODS: We conducted a literature search for studies investigating the relationship between telomere length and GCs in non-human vertebrates using four search engines: Web of Science, Google Scholar, Pubmed and Scopus, last searched on September 27th, 2020. This review identified 31 studies examining the relationship between GCs and telomere length. We pooled the data using Fisher's Z for 15 of these studies. All quantitative studies underwent a risk of bias assessment. This systematic review study was registered in the Open Science Framework Registry (https://osf.io/rqve6).<br><br>RESULTS: The pooled effect size from fifteen studies and 1066 study organisms shows no relationship between GCs and telomere length (Fisher's Z = 0.1042, 95% CI = 0.0235; 0.1836). Our meta-analysis synthesizes results from 15 different taxa from the mammalian, avian, amphibian groups. While these results support some previous findings, other studies have found a direct relationship between GCs and telomere dynamics, suggesting underlying mechanisms or concepts that were not taken into account in our analysis. The risk of bias assessment revealed an overall low risk of bias with occasional instances of bias from missing outcome data or bias in the reported result.<br><br>CONCLUSION: We highlight the need for more targeted experiments to understand how conditions, such as experimental timeframes, stressor(s), and stressor magnitudes can drive a relationship between the neuroendocrine stress response and telomere length.},
}
@article {pmid34597213,
year = {2020},
author = {Gaydosh, L and Mitchell, C and Notterman, D and Schneper, L and Brooks-Gunn, J and Wagner, B and Koss, K and McLanahan, S},
title = {Demographic and developmental patterns in telomere length across adolescence.},
journal = {Biodemography and social biology},
volume = {66},
number = {3-4},
pages = {208-219},
pmid = {34597213},
issn = {1948-5573},
support = {P2C HD042849/HD/NICHD NIH HHS/United States ; R01 HD076592/HD/NICHD NIH HHS/United States ; R01 MD011716/MD/NIMHD NIH HHS/United States ; R24 AG037898/AG/NIA NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Biomarkers ; *Cellular Senescence ; Child ; Demography ; Humans ; *Telomere/genetics ; Telomere Shortening ; },
abstract = {Telomere length is often used in studies of adults as a biomarker of cellular aging and an indicator of stress exposure. However, we know little about how telomeres change over time, particularly over the course of the important developmental period of adolescence. We use data on telomere length collected at two points in time spanning adolescence (Years 9 and 15) from the Fragile Families and Child Wellbeing Study to examine longitudinal patterns (n = 1,654) in telomere length. We find a quantitatively small but significant average lengthening in telomere length across adolescence and little evidence of associations between telomere length and pubertal development.},
}
@article {pmid34591601,
year = {2021},
author = {Peng, Q and Zhou, M and Zuo, S and Liu, Y and Li, X and Yang, Y and He, Q and Yu, X and Zhou, J and He, Z and He, Q},
title = {Nuclear Factor Related to KappaB Binding Protein (NFRKB) Is a Telomere-Associated Protein and Involved in Liver Cancer Development.},
journal = {DNA and cell biology},
volume = {40},
number = {10},
pages = {1298-1307},
doi = {10.1089/dna.2021.0486},
pmid = {34591601},
issn = {1557-7430},
mesh = {Biomarkers, Tumor/genetics/*metabolism ; Carcinogenesis/genetics/metabolism ; Carcinoma, Hepatocellular/genetics/*metabolism/pathology ; DNA-Binding Proteins/genetics/*metabolism ; HEK293 Cells ; HeLa Cells ; Hep G2 Cells ; Hepatocytes/metabolism ; Humans ; K562 Cells ; Liver Neoplasms/genetics/*metabolism/pathology ; MCF-7 Cells ; Protein Binding ; Telomere/metabolism ; },
abstract = {Alternative lengthening of telomeres (ALT) is a homologous recombination-based telomere maintenance mechanism activated in 10-15% of human cancers. Although significant progress has been made, the key regulators of the ALT pathway and its role in cancer development remain elusive. Bioinformatics methods were used to predict novel telomere-associated proteins (TAPs) by analysis of large-scale ChIP-Seq data. Immunostaining and fluorescence in situ hybridization experiments were applied to detect the subcellular location of target genes and telomeres. Western blot and reverse transcription-polymerase chain reaction (RT-PCR) were used to examine the expression of targeting genes. Overall survival (OS) analyses were used to evaluate the relationship between gene expression and survival time; immunohistochemistry was used to detect the distribution of target genes in liver cancer tissues. We found that nuclear factor related to kappaB binding protein (NFRKB), a metazoan-specific subunit of the INO80 complex, can associate with telomeres in human ALT cells. Loss of NFRKB induces dysfunction of telomeres and less PML bodies in U2OS cells. In addition, NFRKB is low/moderately expressed in cytoplasm of normal hepatocytes but heavily accumulating in the nucleus of liver cancer cells. Finally, the high expression of NFRKB is associated with short OS time and poor prognosis. NFRKB is a TAP and protects telomeres from DNA damage in ALT cells. It is highly expressed in hepatocellular carcinoma (HCC) cells and predicts a poor prognosis. NFRKB may be a promising prognostic biomarker for the treatment of HCC in the future.},
}
@article {pmid34589726,
year = {2021},
author = {Fritz, MM and Walsh, LC and Cole, SW and Epel, E and Lyubomirsky, S},
title = {Kindness and cellular aging: A pre-registered experiment testing the effects of prosocial behavior on telomere length and well-being.},
journal = {Brain, behavior, &amp; immunity - health},
volume = {11},
number = {},
pages = {100187},
pmid = {34589726},
issn = {2666-3546},
abstract = {OBJECTIVE: Prosocial behavior can improve psychological well-being and physical health. However, the underlying biological mechanisms that mediate the relationship between prosociality and health remain unclear. In this pre-registered experiment, we tested whether a 4-week kindness intervention could slow leukocyte telomere shortening and increase well-being.<br><br>METHODS: Community adults (N&#xa0;&#x200b;=&#xa0;&#x200b;230) were randomly assigned to complete 1 of 3 activities, each week for 4 weeks: to perform 3 kind acts for other people, to perform 3 kind acts for themselves, or to list daily activities. At baseline and post-intervention, participants came to the lab to provide a small dried blood spot (DBS) sample via finger prick for analysis of telomere length. Participants completed psychological measures (e.g., loneliness, life satisfaction) at baseline, post-intervention, and at the 2-week follow up.<br><br>RESULTS: Participants who performed kind acts for others did not demonstrate hypothesized changes in well-being, nor in telomere length, relative to controls. Exploratory analyses revealed that, relative to controls, participants who did kind acts for others showed reductions in loneliness through the 2-week follow up.<br><br>CONCLUSIONS: The salubrious effects of prosocial behavior in the short term are not likely due to the inhibition of cellular aging (at least as indexed by telomere length). However, extending kindness to others holds promise as a future research direction for interventions to alleviate loneliness.},
}
@article {pmid34588995,
year = {2021},
author = {Wang, DX and Zhu, XD and Ma, XR and Wang, LB and Dong, ZJ and Lin, RR and Cao, YN and Zhao, JW},
title = {Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity.},
journal = {Frontiers in physiology},
volume = {12},
number = {},
pages = {726345},
pmid = {34588995},
issn = {1664-042X},
abstract = {Maintenance of telomere length is essential to delay replicative cellular senescence. It is controversial on whether growth differentiation factor 11 (GDF11) can reverse cellular senescence, and this work aims to establish the causality between GDF11 and the telomere maintenance unequivocally. Using CRISPR/Cas9 technique and a long-term in vitro culture model of cellular senescence, we show here that in vitro genetic deletion of GDF11 causes shortening of telomere length, downregulation of telomeric reverse transcriptase (TERT) and telomeric RNA component (TERC), the key enzyme and the RNA component for extension of the telomere, and reduction of telomerase activity. In contrast, both recombinant and overexpressed GDF11 restore the transcription of TERT in GDF11[KO] cells to the wild-type level. Furthermore, loss of GDF11-induced telomere shortening is likely caused by enhancing the nuclear entry of SMAD2 which inhibits the transcription of TERT and TERC. Our results provide the first proof-of-cause-and-effect evidence that endogenous GDF11 plays a causal role for proliferative cells to maintain telomere length, paving the way for potential rejuvenation of the proliferative cells, tissues, and organs.},
}
@article {pmid34587336,
year = {2022},
author = {Rouan, A and Pousse, M and Tambutté, E and Djerbi, N and Zozaya, W and Capasso, L and Zoccola, D and Tambutté, S and Gilson, E},
title = {Telomere dysfunction is associated with dark-induced bleaching in the reef coral Stylophora pistillata.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6087-6099},
doi = {10.1111/mec.16199},
pmid = {34587336},
issn = {1365-294X},
mesh = {Animals ; *Anthozoa/genetics ; Ecosystem ; Phylogeny ; Coral Reefs ; Symbiosis/genetics ; },
abstract = {Telomere DNA length is a complex trait controlled by both multiple loci and environmental factors. A growing number of studies are focusing on the impact of stress and stress accumulation on telomere length and the link with survival and fitness in ecological contexts. Here, we investigated the telomere changes occurring in a symbiotic coral, Stylophora pistillata, that has experienced continuous darkness over 6 months. This stress condition led to the loss of its symbionts in a similar manner to that observed during large-scale bleaching events due to climate changes and anthropogenic activities, threatening reef ecosystems worldwide. We found that continuous darkness was associated with telomere length shortening. This result, together with a phylogenetic analysis of the telomere coral proteins and a transcriptome survey of the continuous darkness condition, paves the way for future studies on the role of telomeres in the coral stress response and the importance of environmentally induced telomere shortening in endangered coral species.},
}
@article {pmid34586731,
year = {2021},
author = {Sung, JY and Cheong, JH},
title = {Alternative lengthening of telomeres is mechanistically linked to potential therapeutic vulnerability in the stem-like subtype of gastric cancer.},
journal = {Clinical and translational medicine},
volume = {11},
number = {9},
pages = {e561},
pmid = {34586731},
issn = {2001-1326},
support = {HI14C1324//Ministry of Health and Welfare, Republic of Korea/ ; HI14C1324//Korea Health Industry Development Institute/ ; 2018R1A5A2025079//National Research Foundation (NRF), Ministry of Science and ICT, KOREA/ ; },
mesh = {Drug Resistance, Neoplasm/genetics ; Energy Metabolism/genetics ; Epithelial-Mesenchymal Transition/genetics ; Humans ; Protein Interaction Maps/genetics ; *Stomach Neoplasms/genetics/pathology ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
}
@article {pmid34585887,
year = {2021},
author = {Chandru, S and Prabhu, P and Balasubramanyam, M and Subhashini, R and Tiwaskar, M and Pramodkumar, TA and Pradeepa, R and Anjana, RM and Mohan, V},
title = {Beneficial Primary Outcomes of Metabolic Surgery with Changes in Telomere Length and Mitochondrial DNA in Obese Asian Indians with Dysglycemia.},
journal = {The Journal of the Association of Physicians of India},
volume = {69},
number = {9},
pages = {11-12},
pmid = {34585887},
issn = {0004-5772},
mesh = {*Bariatric Surgery ; DNA, Mitochondrial/genetics ; *Diabetes Mellitus, Type 2/complications/genetics ; Follow-Up Studies ; Humans ; Obesity/complications/genetics ; Prospective Studies ; Telomere/genetics ; },
abstract = {INTRODUCTION: Although metabolic surgery has been shown to offer beneficial primary outcome results in obese individuals / obese Type 2 diabetes mellitus (T2DM) patients, there is paucity of information on the underlying mechanisms. In the recent years, estimations of non-invasive molecular parameters viz., telomere length and mtDNA copy number (mtDNAcn) assume significance as robust biomarkers. However, there is lack of evidence about this especially, in the Indian context. To assess the changes in the telomere length and mtDNAcn levels after metabolic surgery in obese Asian Indians with dysglycemia along with routine measurements of anthropometry, glycemic/lipidimic parameters and inflammatory markers.<br><br>METHODS: This study is a prospective one-year follow-up study of 16 obese individuals with dysglycemia who underwent metabolic surgery at a tertiary diabetes centre in South India. Telomere length, mtDNAcn, serum adiponectin, glycated haemoglobin and high- sensitivity C-reactive protein (hs-CRP) levels were analysed before surgery and at 6 and 12 months after surgery.<br><br>RESULTS: There was a significant reduction in weight (p<0.001), BMI (p<0.001), waist circumference (p<0.001), fasting and postprandial glucose (p<0.05), HbA1c (p<0.001), triglycerides (p<0.05), hs CRP (p<0.05) and increase in serum adiponectin (p<0.05) at 6 and 12 months post-surgery compared to the preoperative status. There was a significant reduction in mtDNAcn (p<0.001) and a significant increase in telomere length (p<0.001) at 6 and 12 months post metabolic surgery.<br><br>CONCLUSION: We report an increase in telomere length and decrease in circulatory mtDNA copy number levels at 6 and 12 months post metabolic surgery in obese individuals with T2DM in India.},
}
@article {pmid34585163,
year = {2021},
author = {Tichy, ED and Mourkioti, F},
title = {Telomere length assessments of muscle stem cells in rodent and human skeletal muscle sections.},
journal = {STAR protocols},
volume = {2},
number = {4},
pages = {100830},
pmid = {34585163},
issn = {2666-1667},
support = {R01 AR075914/AR/NIAMS NIH HHS/United States ; R01 HL146662/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Humans ; Muscle Fibers, Skeletal ; Muscle, Skeletal ; *Myoblasts ; *Rodentia ; Telomere/genetics ; },
abstract = {Measurements of telomere length in skeletal muscle stem cells (MuSCs), a rare cell population within muscles, provide insights into cellular dysfunction in diseased conditions. Here, we describe a protocol (cryosection muscle quantitative fluorescent in situhybridization) using skeletal muscle cryosections for assessments of telomere length in MuSCs, in their native environment. Using a free software, telomere length measurements are assessed on a single-cell level. We also provide methodology to perform data analyses in several ways. For complete details on the use and execution of this protocol, please refer to Tichy et al. (2021).},
}
@article {pmid34583600,
year = {2020},
author = {Cuevas, AG and Greatorex-Voith, S and Abuelezam, N and Eckert, N and Assari, S},
title = {Educational mobility and telomere length in middle-aged and older adults: testing three alternative hypotheses.},
journal = {Biodemography and social biology},
volume = {66},
number = {3-4},
pages = {220-235},
doi = {10.1080/19485565.2021.1983760},
pmid = {34583600},
issn = {1948-5573},
mesh = {Aged ; Cross-Sectional Studies ; Educational Status ; Humans ; Middle Aged ; *Social Class ; *Sociodemographic Factors ; Telomere/genetics ; Telomere Shortening ; },
abstract = {Critical period, social mobility, and social accumulation are three hypotheses that may explain how educational mobility impacts health. Thus far, there is little evidence on how these processes are associated with biological aging as measured by telomere length. Using cross-sectional data from the 2008 Health and Retirement Study, we examined the association between educational mobility (parental education and contemporaneous education) and telomere length. The final model is adjusted for sociodemographic factors and socioeconomic status, childhood adversity, and health behaviors/risk factors, as well as depressive symptoms. A total of 1,894 participants were included in the main analyses. High parental education was associated with longer telomere length in a fully adjusted model (B = 0.03, CI [0.002,0.07]). Downwardly mobile individuals (high parental education and low contemporaneous education) had longer telomere length compared to stably low individuals in a fully adjusted model (B = 0.05, CI [0.004,0.09]). There was support for the critical period hypothesis and partial support for the change hypothesis. There was no evidence to support the social accumulation hypothesis. Prospective studies are needed to understand the mechanism that can help further explain the association between educational mobility and telomere length.},
}
@article {pmid34580961,
year = {2021},
author = {van der Vis, JJ and van der Smagt, JJ and van Batenburg, AA and Goldschmeding, R and van Es, HW and Grutters, JC and van Moorsel, CHM},
title = {Pulmonary fibrosis in non-mutation carriers of families with short telomere syndrome gene mutations.},
journal = {Respirology (Carlton, Vic.)},
volume = {26},
number = {12},
pages = {1160-1170},
doi = {10.1111/resp.14145},
pmid = {34580961},
issn = {1440-1843},
mesh = {Humans ; Mutation ; *Pulmonary Fibrosis/genetics ; *Telomerase/genetics ; Telomere/genetics ; Telomere Shortening ; },
abstract = {BACKGROUND AND OBJECTIVE: Diagnostic and predictive genetic testing for disease cause and risk estimation is common in many countries. For genetic diseases, predictive test results are commonly straightforward: presence of the mutation involves increased risk for disease and absence of the mutation involves no inherit risk for disease. Germline mutations in telomere-related genes (TRGs) can lead to telomere shortening and are associated with short telomere syndrome (STS). Telomere length is heritable, and in families with STS due to a TRG mutation, progeny with and without the TRG mutation is known to have shorter than average telomeres. We hypothesize that progeny of TRG mutation carriers who did not inherit the TRG mutation may still develop pulmonary fibrosis.<br><br>METHODS: A genetic screen of 99 unrelated families with familial pulmonary fibrosis revealed five patients with features of pulmonary fibrosis but without carrying the familial disease-causing TRG mutation.<br><br>RESULTS: Features of STS were present in each family, including short telomeres in blood and tissue of the non-mutation carrying patients. Additional genetic, clinical or environmental risk factors for pulmonary fibrosis were present in each non-mutation carrying patient.<br><br>CONCLUSION: Our study shows that non-mutation carrying first-degree relatives in families with STS are at increased risk for pulmonary fibrosis. Disease development may be triggered by inherited short telomeres and additional risk factors for disease. This observation has profound consequences for genetic counselling. Unlike any other genetic syndrome, absence of the mutation does not imply absence of disease risk. Therefore, clinical follow-up is still urged for non-mutation carrying first-degree family members.},
}
@article {pmid34576030,
year = {2021},
author = {Huang, YC and Wang, CY},
title = {Telomere Attrition and Clonal Hematopoiesis of Indeterminate Potential in Cardiovascular Disease.},
journal = {International journal of molecular sciences},
volume = {22},
number = {18},
pages = {},
pmid = {34576030},
issn = {1422-0067},
support = {NHRIEX106-10617SI, NHRI-110A1-CSCO-17212418//National Health Research Institutes/ ; 105-2628-B-182-009-MY4 and 109-2314-B-182-070-MY3//National Science Council/ ; CMRPG3H0133, CMRPG3I0322, CMRPG3H0843, and CORPG3K0011//Chang Gung Memorial Hospital/ ; },
mesh = {Aging/genetics/pathology ; Atherosclerosis/*genetics/pathology ; Cardiovascular Diseases/*genetics/pathology ; Clonal Evolution/genetics ; Clonal Hematopoiesis/genetics ; DNA (Cytosine-5-)-Methyltransferases/*genetics ; DNA Methyltransferase 3A ; DNA-Binding Proteins/*genetics ; Dioxygenases/*genetics ; Humans ; Mutation/genetics ; Repressor Proteins/*genetics ; Telomere/genetics ; },
abstract = {Clinical evidence suggests that conventional cardiovascular disease (CVD) risk factors cannot explain all CVD incidences. Recent studies have shown that telomere attrition, clonal hematopoiesis of indeterminate potential (CHIP), and atherosclerosis (telomere-CHIP-atherosclerosis, TCA) evolve to play a crucial role in CVD. Telomere dynamics and telomerase have an important relationship with age-related CVD. Telomere attrition is associated with CHIP. CHIP is commonly observed in elderly patients. It is characterized by an increase in blood cell clones with somatic mutations, resulting in an increased risk of hematological cancer and atherosclerotic CVD. The most common gene mutations are DNA methyltransferase 3 alpha (DNMT3A), Tet methylcytosine dioxygenase 2 (TET2), and additional sex combs-like 1 (ASXL1). Telomeres, CHIP, and atherosclerosis increase chronic inflammation and proinflammatory cytokine expression. Currently, their epidemiology and detailed mechanisms related to the TCA axis remain incompletely understood. In this article, we reviewed recent research results regarding the development of telomeres and CHIP and their relationship with atherosclerotic CVD.},
}
@article {pmid34572228,
year = {2021},
author = {Monnin, A and Vizeneux, A and Nagot, N and Eymard-Duvernay, S and Meda, N and Singata-Madliki, M and Ndeezi, G and Tumwine, JK and Kankasa, C and Goga, A and Tylleskär, T and Van de Perre, P and Molès, JP},
title = {Longitudinal Follow-Up of Blood Telomere Length in HIV-Exposed Uninfected Children Having Received One Year of Lopinavir/Ritonavir or Lamivudine as Prophylaxis.},
journal = {Children (Basel, Switzerland)},
volume = {8},
number = {9},
pages = {},
pmid = {34572228},
issn = {2227-9067},
support = {ANRS#12274//Agence Nationale de Recherches sur le Sida et les H&#xe9;patites Virales/ ; ANRS12174-B90//Agence Nationale de Recherches sur le Sida et les H&#xe9;patites Virales/ ; #CT.2006.33020.004//European and Developing Countries Clinical Trials Partnership/ ; GlobVac grant # 183600//Royal council of Norway/ ; AP-FPB-2013-2/09//Pierre Berg&#xe9; fundation/ ; },
abstract = {Telomere shortening can be enhanced upon human immunodeficiency virus (HIV) infection and by antiretroviral (ARV) exposures. The aim of this study was to evaluate the acute and long-term effect on telomere shortening of two ARV prophylaxes, lopinavir/ritonavir (LPV/r) and lamivudine (3TC), administered to children who are HIV-exposed uninfected (CHEU) to prevent HIV acquisition through breastfeeding during the first year of life, and to investigate the relationship between telomere shortening and health outcomes at six years of age. We included 198 CHEU and measured telomere length at seven days of life, at week-50 and at six years (year-6) using quantitative polymerase chain reaction. At week-50, telomere shortening was observed among 44.3% of CHEU, irrespective of the prophylactic treatment. Furthermore, this telomere shortening was neither associated with poor growth indicators nor neuropsychological outcomes at year-6, except for motor abilities (MABC test n = 127, β = -3.61, 95%CI: -7.08, -0.14; p = 0.04). Safety data on telomere shortening for infant HIV prophylaxis are scarce. Its association with reduced motor abilities deserves further attention among CHEU but also HIV-infected children receiving ARV treatment.},
}
@article {pmid34565437,
year = {2021},
author = {Tometten, M and Kirschner, M and Isfort, S and Berres, ML and Brümmendorf, TH and Beier, F},
title = {Transient elastography in adult patients with cryptic dyskeratosis congenita reveals subclinical liver fibrosis: a retrospective analysis of the Aachen telomere biology disease registry.},
journal = {Orphanet journal of rare diseases},
volume = {16},
number = {1},
pages = {395},
pmid = {34565437},
issn = {1750-1172},
mesh = {Adult ; Biology ; *Dyskeratosis Congenita/genetics ; *Elasticity Imaging Techniques ; Humans ; Liver/diagnostic imaging ; Liver Cirrhosis/diagnostic imaging/genetics ; Registries ; Retrospective Studies ; Telomere/genetics ; },
abstract = {BACKGROUND: Telomere biology disorders (TBD) such as dyskeratosis congenita (DKC) lead to progressive multi-organ failure as impaired telomere maintenance disturbs cellular proliferative capacity. A wide range of hepatic manifestations from asymptomatic liver enzyme elevation to overt liver fibrosis/cirrhosis can be observed in TBD patients. However, the incidence of hepatic involvement remains unknown. Non-invasive transient elastography (TE) predicts early fibrosis by measuring liver stiffness and may uncover subclinical liver damage in TBD patients.<br><br>METHODS: Liver screening procedures of nine TBD patients from the Aachen TBD Registry are being presented retrospectively. Following clinical suspicion, TBD was diagnosed using flow-FISH with telomere length (TL) below the 1% percentile and confirmed by next-generation sequencing (NGS) detecting pathogenic mutations in telomere maintenance genes TERC or TERT.<br><br>RESULTS: In all patients, TBD was first diagnosed in adulthood. Patients showed normal to slightly elevated liver function test parameters. Hepatic ultrasound revealed inhomogeneous parenchyma in seven (77.7%) and increased liver echogenicity in four patients (44.4%). Median liver stiffness was 10.7 kilopascal (kPa) (interquartile range 8.4, 15.7&#xa0;kPa). Using 7.1&#xa0;kPa as cut-off, 88.8% of patients were classified as moderate fibrosis to cirrhosis.<br><br>CONCLUSION: Subclinical chronic liver involvement is frequent in patients with adult-onset TBD. TE could have a valuable role in the routine work-up of patients with telomere disorders including DKC for early detection of patients at risk for liver function impairment.},
}
@article {pmid34564066,
year = {2022},
author = {Nickels, M and Mastana, S and Codd, V and Denniff, M and Akam, E},
title = {Comparison of Telomere Length in Young and Master Endurance Runners and Sprinters.},
journal = {Journal of aging and physical activity},
volume = {30},
number = {3},
pages = {510-516},
doi = {10.1123/japa.2021-0236},
pmid = {34564066},
issn = {1543-267X},
mesh = {Athletes ; Humans ; Middle Aged ; Nutritional Status ; Physical Endurance/genetics ; *Running ; Telomere ; },
abstract = {It is unclear how running modality influences telomere length (TL). This single laboratory visit study compared the TL of master sprinters and endurance runners with their young counterparts. The correlation between leukocyte and buccal cell TL in athletes was also explored. Participants consisted of 11 young controls, 11 young sprinters, 12 young endurance runners, 12 middle-aged controls, 11 master sprinters, and 12 master endurance runners. Blood and buccal samples were collected and randomized for analysis of TL by quantitative polymerase chain reaction. Young endurance runners displayed longer telomeres than master athletes (p < .05); however, these differences were not significant when controlled for covariates (p > .05). A positive correlation existed between leukocyte and buccal cell TL in athletes (r = .567, p < .001). In conclusion, young endurance runners possess longer telomeres than master endurance runners and sprinters, a consequence of lower body mass index and visceral fat.},
}
@article {pmid34562085,
year = {2022},
author = {Lyu, L and Yu, J and Liu, Y and He, S and Zhao, Y and Qi, M and Ping, F and Xu, L and Li, W and Zhang, H and Li, Y},
title = {High Hemoglobin Glycation Index Is Associated With Telomere Attrition Independent of HbA1c, Mediated by TNFα.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {107},
number = {2},
pages = {462-473},
doi = {10.1210/clinem/dgab703},
pmid = {34562085},
issn = {1945-7197},
mesh = {Adult ; Cross-Sectional Studies ; DNA Copy Number Variations ; DNA, Mitochondrial/genetics ; Female ; Glycated Hemoglobin/analysis/*metabolism ; Glycosylation ; Humans ; Male ; Middle Aged ; Oxidative Stress/genetics ; Telomere/metabolism ; *Telomere Shortening ; Tumor Necrosis Factor-alpha/*metabolism ; },
abstract = {CONTEXT: The hemoglobin glycation index (HGI) is correlated with metabolic diseases and inflammation. Whether the HGI is associated with the aging process and how inflammation and oxidative stress affect the relationship remain unclear.<br><br>OBJECTIVE: We aimed to analyze links between the HGI and aging biomarkers, and to explore a potential role of inflammation and oxidative stress in the correlations.<br><br>METHODS: A cross-sectional study of 434 subjects with different glucose intolerances in a rural community was enrolled. The HGI was calculated as the difference between the measured and predicted hemoglobin A1c (HbA1c). The population was categorized into tertiles of the HGI. Telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) determined by polymerase chain reaction assay. Tumor necrosis factor (TNF) &#x3b1; and interleukin (IL) 6, 8-oxo-2'-deoxyguanosine (8-oxo-dG), superoxide dismutase (SOD) activities, and glutathione reductase (GR) were measured.<br><br>RESULTS: Participants in the high HGI group were older and reported a shorter LTL, higher levels of TNF&#x3b1;, SOD activities, and HbA1c. Correlation analyses demonstrated that HGI was correlated with LTL (r = -0.25, P < .001) and TNF&#x3b1; (r = 0.19, P < .001) regardless of HbA1c levels. No relationship was found between HGI and mtDNAcn. HGI (&#x3b2; = -0.238, 95% CI -0.430, -0.046, P = .015) and TNF&#x3b1; (&#x3b2; = -0.02, 95% CI -0.030, -0.014, P < .001) were proved to be correlated with LTL independently, using multiple linear regression analysis. Ordinal logistic regression models showed that compared with subjects the high HGI group, the possibilities of a higher-level LTL was 5.29-fold in the low HGI group (OR 5.29, 95% CI (2.45, 11.41), P < .001), 2.41-fold in the moderate HGI group (OR 2.41, 95% CI 1.35, 4.30, P = .003) after controlling for confounding variables. Mediation analyses indicated that TNF&#x3b1; accounted for 30.39% of the effects of the HGI on LTL.<br><br>CONCLUSION: HGI was negatively related to telomere attrition, independent of HbA1c. TNF&#x3b1; acted as a mediator of the relationship between HGI and LTL.},
}
@article {pmid34559557,
year = {2021},
author = {Lee, L and Perez Oliva, AB and Martinez-Balsalobre, E and Churikov, D and Peter, J and Rahmouni, D and Audoly, G and Azzoni, V and Audebert, S and Camoin, L and Mulero, V and Cayuela, ML and Kulathu, Y and Geli, V and Lachaud, C},
title = {UFMylation of MRE11 is essential for telomere length maintenance and hematopoietic stem cell survival.},
journal = {Science advances},
volume = {7},
number = {39},
pages = {eabc7371},
pmid = {34559557},
issn = {2375-2548},
abstract = {Ubiquitin-fold modifier 1 (UFM1) is involved in neural and erythroid development, yet its biological roles in these processes are unknown. Here, we generated zebrafish models deficient in Ufm1 and Ufl1 that exhibited telomere shortening associated with developmental delay, impaired hematopoiesis and premature aging. We further report that HeLa cells lacking UFL1 have instability of telomeres replicated by leading-strand synthesis. We uncover that MRE11 UFMylation is necessary for the recruitment of the phosphatase PP1-α leading to dephosphorylation of NBS1. In the absence of UFMylation, NBS1 remains phosphorylated, thereby reducing MRN recruitment to telomeres. The absence of MRN at telomeres favors the formation of the TRF2-Apollo/SNM1 complex consistent with the loss of leading telomeres. These results suggest that MRE11-UFMylation may serve as module to recruit PP1-α. Last, zebrafish expressing Mre11 that cannot be UFMylated phenocopy Ufm1-deficient zebrafish, demonstrating that UFMylation of MRE11 is a previously undescribed evolutionarily conserved mechanisms regulating telomere length.},
}
@article {pmid34559348,
year = {2022},
author = {Aida, J and Takubo, K and Vieth, M and Neuhaus, H and Fujiwara, M and Arai, T and Ishiwata, T},
title = {Telomere lengths in Barrett's esophagus as a precancerous lesion.},
journal = {Esophagus : official journal of the Japan Esophageal Society},
volume = {19},
number = {2},
pages = {287-293},
pmid = {34559348},
issn = {1612-9067},
mesh = {*Barrett Esophagus/genetics/pathology ; Humans ; Intestines/pathology ; Mucous Membrane/pathology ; *Precancerous Conditions/genetics/pathology ; Telomere/genetics/pathology ; },
abstract = {BACKGROUND: We have reported that precancerous conditions and lesions invariably have shorter telomeres and associated chromosomal instability relative to normal tissue.<br><br>METHODS: Using the Q-FISH method and our original software, Tissue Telo, we estimated telomere lengths in cardiac- and intestinal-type mucosae in 48 cases of Barrett's esophagus (short-segment (SS) n&#x2009;=&#x2009;18; long-segment (LS) n&#x2009;=&#x2009;30).<br><br>RESULTS: There were no significant differences in telomere length between the cardiac and intestinal types in any of the 48 cases, suggesting that the presence or absence of goblet cells in the columnar segments is unrelated to telomere-dependent chromosomal instability in Barrett's esophagus. In LS Barrett's esophagus, telomeres were shorter in cardiac-type than in intestinal-type mucosa, suggesting that the former may play a more important role than the latter as a precancerous lesion in LS. Telomeres in cardiac-type mucosa were longer in SS than in LS, supporting the possibility that cardiac-type LS may pose a higher risk as a precancerous lesion than cardiac-type SS.<br><br>CONCLUSIONS: Although it has been considered that Barrett's carcinoma arises only from intestinal-type mucosa, our present findings support previous histogenetic studies suggesting that cardiac-type mucosa is more important as a precancerous condition in Barrett's esophagus than anticipated.},
}
@article {pmid34558851,
year = {2022},
author = {Rattan, P and Penrice, DD and Ahn, JC and Ferrer, A and Patnaik, M and Shah, VH and Kamath, PS and Mangaonkar, AA and Simonetto, DA},
title = {Inverse Association of Telomere Length With Liver Disease and Mortality in the US Population.},
journal = {Hepatology communications},
volume = {6},
number = {2},
pages = {399-410},
pmid = {34558851},
issn = {2471-254X},
support = {U01 AA026886/AA/NIAAA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Cause of Death ; Disease Progression ; Female ; Humans ; Leukocytes/cytology ; Linear Models ; Liver Diseases/*genetics/*mortality ; Male ; Middle Aged ; Nutrition Surveys ; Proportional Hazards Models ; *Telomere Shortening ; United States/epidemiology ; Young Adult ; },
abstract = {Physiologic aging leads to attrition of telomeres and replicative senescence. An acceleration of this process has been hypothesized in the progression of chronic liver disease. We sought to examine the association of telomere length (TL) with liver disease and its impact on mortality risk. A cohort of 7,072 adults with leukocyte TL measurements from the National Health and Nutrition Examination Survey 1999-2002 with mortality follow-up through 2015 was analyzed. Liver disease was defined by aminotransferase levels and classified into etiology-based and advanced fibrosis categories. Multivariable-adjusted linear regression models estimated effect sizes, with 95% confidence intervals (CIs), of the presence of liver disease on TL. Cox regression models evaluated associations between TL and all-cause mortality risk using adjusted hazard ratios (HRs). The cohort was representative of the US population with mean age 46.1 years and mean TL 5.79 kilobase pairs. No overall association between TL and liver disease was found; however, there was a significant negative association of TL and advanced liver fibrosis in individuals aged 65 and above. The liver disease cohort (HR 1.22, 95% CI 0.99-1.51) and those with metabolic syndrome (HR 1.26, 95% CI 0.96-1.67) had increased mortality risk with shorter TL. The relationship between TL and all-cause mortality was stronger in women (HR 1.51, 95% CI 1.02-2.23) and in non-Hispanic Whites (HR 1.37, 95% CI 1.02-1.84). Conclusion: Shortened leukocyte TL is independently associated with advanced liver disease at older ages, and with a higher risk of all-cause mortality in those with liver disease. These associations reaffirm the need to better understand the role of telomeres in the progression of liver disease.},
}
@article {pmid34558545,
year = {2022},
author = {Polho, GB and Cardillo, GM and Kerr, DS and Chile, T and Gattaz, WF and Forlenza, OV and Brentani, HP and De-Paula, VJ},
title = {Antipsychotics preserve telomere length in peripheral blood mononuclear cells after acute oxidative stress injury.},
journal = {Neural regeneration research},
volume = {17},
number = {5},
pages = {1156-1160},
pmid = {34558545},
issn = {1673-5374},
abstract = {Antipsychotics may prolong or retain telomere length, affect mitochondrial function, and then affect the metabolism of nerve cells. To validate the hypothesis that antipsychotics can prolong telomere length after oxidative stress injury, leukocytes from healthy volunteers were extracted using Ficoll-Histopaque density gradient. The mononuclear cells layer was resuspended in cell culture medium. Oxidative stress was induced with hydrogen peroxide in cultured leukocytes. Four days later, leukocytes were treated with aripiprazole, haloperidol or clozapine for 7 days. Real-time PCR revealed that treatments with aripiprazole and haloperidol increased the telomere length by 23% and 20% in peripheral blood mononuclear cells after acute oxidative stress injury. These results suggest that haloperidol and aripiprazole can reduce the damage to telomeres induced by oxidative stress. The experiment procedure was approved by the Ethics Committee of Faculty of Medicine of the University of São Paulo (FMUSP/CAAE approval No. 52622616.8.0000.0065).},
}
@article {pmid34556550,
year = {2021},
author = {Garus, A and Autexier, C},
title = {Dyskerin: an essential pseudouridine synthase with multifaceted roles in ribosome biogenesis, splicing, and telomere maintenance.},
journal = {RNA (New York, N.Y.)},
volume = {27},
number = {12},
pages = {1441-1458},
pmid = {34556550},
issn = {1469-9001},
support = {PJT-166130//CIHR/Canada ; },
mesh = {*Alternative Splicing ; Cell Cycle Proteins/genetics/*metabolism ; Dyskeratosis Congenita ; Humans ; Intramolecular Transferases/genetics/*metabolism ; *Mutation ; Nuclear Proteins/genetics/*metabolism ; *RNA Processing, Post-Transcriptional ; Ribosomes/*metabolism ; Telomere/*physiology ; },
abstract = {Dyskerin and its homologs are ancient and conserved enzymes that catalyze the most common post-transcriptional modification found in cells, pseudouridylation. The resulting pseudouridines provide stability to RNA molecules and regulate ribosome biogenesis and splicing events. Dyskerin does not act independently-it is the core component of a protein heterotetramer, which associates with RNAs that contain the H/ACA motif. The variety of H/ACA RNAs that guide the function of this ribonucleoprotein (RNP) complex highlights the diversity of cellular processes in which dyskerin participates. When associated with small nucleolar (sno) RNAs, it regulates ribosomal (r) RNAs and ribosome biogenesis. By interacting with small Cajal body (sca) RNAs, it targets small nuclear (sn) RNAs to regulate pre-mRNA splicing. As a component of the telomerase holoenzyme, dyskerin binds to the telomerase RNA to modulate telomere maintenance. In a disease context, dyskerin malfunction can result in multiple detrimental phenotypes. Mutations in DKC1, the gene that encodes dyskerin, cause the premature aging syndrome X-linked dyskeratosis congenita (X-DC), a still incurable disorder that typically leads to bone marrow failure. In this review, we present the classical and most recent findings on this essential protein, discussing the evolutionary, structural, and functional aspects of dyskerin and the H/ACA RNP. The latest research underscores the role that dyskerin plays in the regulation of gene expression, translation efficiency, and telomere maintenance, along with the impacts that defective dyskerin has on aging, cell proliferation, haematopoietic potential, and cancer.},
}
@article {pmid34553645,
year = {2023},
author = {Güneşliol, BE and Karaca, E and Ağagündüz, D and Acar, ZA},
title = {Association of physical activity and nutrition with telomere length, a marker of cellular aging: A comprehensive review.},
journal = {Critical reviews in food science and nutrition},
volume = {63},
number = {5},
pages = {674-692},
doi = {10.1080/10408398.2021.1952402},
pmid = {34553645},
issn = {1549-7852},
mesh = {*Nutritional Status ; *Telomere Shortening ; Telomere ; Exercise ; },
abstract = {The aging of the population has great social and economic effects because it is characterized by a gradual loss in physiological integrity, resulting in functional decline, thereby loss of ability to move independently. Telomeres, the hallmarks of biological aging, play a protective role in both cell death and aging. Critically short telomeres give rise to a metabolically active cell that is unable to repair damage or divide, thereby leading to aging. Lifestyle factors such as physical activity (PA) and nutrition could be associated with telomere length (TL). Indeed, regular PA and healthy nutrition as integral parts of our lifestyle can slow down telomere shortening, thereby delaying aging. In this context, the present comprehensive review summarizes the data from recent literature on the association of PA and nutrition with TL.},
}
@article {pmid34551154,
year = {2022},
author = {Sheldon, EL and Ton, R and Boner, W and Monaghan, P and Raveh, S and Schrey, AW and Griffith, SC},
title = {Associations between DNA methylation and telomere length during early life: Insight from wild zebra finches (Taeniopygia guttata).},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6261-6272},
doi = {10.1111/mec.16187},
pmid = {34551154},
issn = {1365-294X},
mesh = {Animals ; *Finches/genetics ; DNA Methylation/genetics ; Australia ; Aging/genetics ; Telomere/genetics ; },
abstract = {Telomere length and DNA methylation (DNAm) are two promising biomarkers of biological age. Environmental factors and life history traits are known to affect variation in both these biomarkers, especially during early life, yet surprisingly little is known about their reciprocal association, especially in natural populations. Here, we explore how variation in DNAm, growth rate, and early-life conditions are associated with telomere length changes during development. We tested these associations by collecting data from wild, nestling zebra finches in the Australian desert. We found that increases in the level of DNAm were negatively correlated with telomere length changes across early life. We also confirm previously documented effects of post hatch growth rate and clutch size on telomere length in a natural ecological context for a species that has been extensively studied in the laboratory. However, we did not detect any effect of ambient temperature during developmental on telomere length dynamics. We also found that the absolute telomere length of wild zebra finches, measured using the in-gel TRF method, was similar to that of captive birds. Our findings highlight exciting new opportunities to link and disentangle potential relationships between DNA based biomarkers of ageing, and of physiological reactions to environmental change.},
}
@article {pmid34549596,
year = {2021},
author = {Nolte, J},
title = {Lrrc34 Interacts with Oct4 and Has an Impact on Telomere Length in Mouse Embryonic Stem Cells.},
journal = {Stem cells and development},
volume = {30},
number = {22},
pages = {1093-1102},
doi = {10.1089/scd.2021.0113},
pmid = {34549596},
issn = {1557-8534},
mesh = {Animals ; Cellular Reprogramming ; *Induced Pluripotent Stem Cells/metabolism ; Mice ; Mouse Embryonic Stem Cells/metabolism ; *Octamer Transcription Factor-3/metabolism ; *Repressor Proteins/metabolism ; *Telomerase/genetics/metabolism ; Telomere/genetics ; Telomere Homeostasis ; },
abstract = {Telomere length maintenance in pluripotent stem cells (PSCs) is a main characteristic and a major premise for their undifferentiated long-term survival. However, little is known about the factors that control telomere length and elongation in these cells. Here, I describe Lrrc34 (leucine-rich repeat 34) as a novel telomere length regulating gene in murine embryonic stem cells. Downregulation of Lrrc34 results in significant reduction of telomerase activity and telomere length over time while also influencing the expression of known telomere length-associated genes. Generating induced PSCs (iPSCs) with Lrrc34 as a fifth factor in classical Yamanaka reprogramming increases the efficiency but did not have an impact on telomere length in the resulting iPSCs. Moreover, Lrrc34 was found to interact with Oct4, connecting the pluripotency network to telomere length regulation.},
}
@article {pmid34547897,
year = {2021},
author = {Bazaz, MR and Balasubramanian, R and Monroy-Jaramillo, N and Dandekar, MP},
title = {Linking the Triad of Telomere Length, Inflammation, and Gut Dysbiosis in the Manifestation of Depression.},
journal = {ACS chemical neuroscience},
volume = {12},
number = {19},
pages = {3516-3526},
doi = {10.1021/acschemneuro.1c00457},
pmid = {34547897},
issn = {1948-7193},
mesh = {Depression ; *Dysbiosis ; *Gastrointestinal Microbiome ; Humans ; Inflammation ; Telomere ; },
abstract = {Telomere length is an indispensable marker for cellular and biological aging, and it also represents an individual's physical and mental health status. Telomere shortening has been observed in chronic inflammatory conditions, which in turn accelerates aging and risk for psychiatric disorders, including depression. Considering the influence of inflammation and telomere shortening on the gut-brain axis, herein we describe a plausible interplay between telomere attrition, inflammation, and gut dysbiosis in the neurobiology of depression. Telomere shortening and hyperinflammation are well reported in depression. A negative impact of augmented inflammation has been noted on the intestinal permeability and microbial consortia and their byproducts in depressive patients. Moreover, gut dysbiosis provokes host-immune responses. As the gut microbiome is gaining importance in the manifestation and management of depression, herein we discuss whether telomere attrition is connected with the perturbation of commensal microflora. We also describe a pathological connection of cortisol with hyperinflammation, telomere shortening, and gut dysbiosis occurring in depression. This review summarizes how the triad of telomere attrition, inflammation, and gut dysbiosis is interconnected and modulates the risk for depression by regulating the systemic cortisol levels.},
}
@article {pmid34545641,
year = {2021},
author = {Peña, E and León-Mengíbar, J and Powell, TR and Caixàs, A and Cardoner, N and Rosa, A},
title = {Telomere length in patients with obesity submitted to bariatric surgery: A systematic review.},
journal = {European eating disorders review : the journal of the Eating Disorders Association},
volume = {29},
number = {6},
pages = {842-853},
doi = {10.1002/erv.2865},
pmid = {34545641},
issn = {1099-0968},
support = {MR/N014863/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; *Bariatric Surgery ; Humans ; Obesity/genetics/surgery ; Prospective Studies ; *Telomere ; Telomere Shortening ; },
abstract = {BACKGROUND: Patients with obesity show evidence of increased levels of inflammation, oxidative stress and premature ageing. Telomere length (TL) is a key marker of cellular ageing, and patients with obesity often present shorter TL. Bariatric surgery (BS) is currently the most effective treatment for severe obesity. The aim of this systematic review was to explore whether the beneficial health effects observed after surgery in obese patients correspond to a restoration in TL or slower rates of shortening. As a secondary aim, we evaluated, at baseline and post-surgery, the relationship between TL and different factors that could play a role in TL changes along time.<br><br>METHODS: Searches for relevant articles were performed in MEDLINE, Web of Knowledge and SCOPUS. Prospective longitudinal studies that evaluated leukocyte TL in adult patients who had undergone BS were included. Data were extracted and evaluated by two independent researchers. The protocol was registered in PROSPERO with the number CRD42020197711.<br><br>RESULTS: Seven studies based on independent samples that fulfilled our inclusion criteria were included. Obese patients showed shorter telomeres compared to healthy individuals. Long-term studies (>2&#xa0;years) seem to suggest an improvement in TL after surgery presumably due to the improvement of the inflammatory and oxidative levels of the patients induced by weight loss.<br><br>CONCLUSION: Studies seem to point towards a beneficial long-term effect of BS on TL recovery. However, the scarce number of studies and the heterogeneity in the variables analysed in the different cohorts make it difficult to draw a firm conclusion. More studies are needed to evaluate long-term changes to TL following BS.},
}
@article {pmid34535663,
year = {2021},
author = {Gu, P and Jia, S and Takasugi, T and Tesmer, VM and Nandakumar, J and Chen, Y and Chang, S},
title = {Distinct functions of POT1 proteins contribute to the regulation of telomerase recruitment to telomeres.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {5514},
pmid = {34535663},
issn = {2041-1723},
support = {R01 GM141350/GM/NIGMS NIH HHS/United States ; R01 AG050509/AG/NIA NIH HHS/United States ; R01 GM120094/GM/NIGMS NIH HHS/United States ; R01 CA202816/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; CRISPR-Cas Systems/genetics ; DNA Mutational Analysis ; DNA-Binding Proteins/*metabolism ; Mice ; Protein Binding ; Rad51 Recombinase/metabolism ; Sarcoma/pathology ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Human shelterin components POT1 and TPP1 form a stable heterodimer that protects telomere ends from ATR-dependent DNA damage responses and regulates telomerase-dependent telomere extension. Mice possess two functionally distinct POT1 proteins. POT1a represses ATR/CHK1 DNA damage responses and the alternative non-homologous end-joining DNA repair pathway while POT1b regulates C-strand resection and recruits the CTC1-STN1-TEN1 (CST) complex to telomeres to mediate C-strand fill-in synthesis. Whether POT1a and POT1b are involved in regulating the length of the telomeric G-strand is unclear. Here we demonstrate that POT1b, independent of its CST function, enhances recruitment of telomerase to telomeres through three amino acids in its TPP1 interacting C-terminus. POT1b thus coordinates the synthesis of both telomeric G- and C-strands. In contrast, POT1a negatively regulates telomere length by inhibiting telomerase recruitment to telomeres. The identification of unique amino acids between POT1a and POT1b helps us understand mechanistically how human POT1 switches between end protective functions and promoting telomerase recruitment.},
}
@article {pmid34534358,
year = {2021},
author = {Pignolo, RJ and Johnson, FB},
title = {Do the telomere ends justify the physical means?.},
journal = {Journal of the American Geriatrics Society},
volume = {69},
number = {11},
pages = {3071-3073},
pmid = {34534358},
issn = {1532-5415},
support = {P01 AG062413/AG/NIA NIH HHS/United States ; P01 AG062413/NH/NIH HHS/United States ; },
mesh = {Humans ; *Telomere ; },
}
@article {pmid34534325,
year = {2021},
author = {Xiong, F and Frasch, WD},
title = {ΩqPCR measures telomere length from single-cells in base pair units.},
journal = {Nucleic acids research},
volume = {49},
number = {20},
pages = {e120},
pmid = {34534325},
issn = {1362-4962},
mesh = {Cell Line ; Humans ; Limit of Detection ; Polymerase Chain Reaction/*methods/standards ; Single-Cell Analysis/*methods/standards ; Telomere/*chemistry/genetics ; *Telomere Homeostasis ; },
abstract = {ΩqPCR determines absolute telomere length in kb units from single cells. Accuracy and precision of ΩqPCR were assessed using 800 bp and 1600 bp synthetic telomeres inserted into plasmids, which were measured to be 819 ± 19.6 and 1590 ± 42.3 bp, respectively. This is the first telomere length measuring method verified in this way. The approach uses Ω-probes, a DNA strand containing sequence information that enables: (i) hybridization with the telomere via the 3' and 5' ends that become opposed; (ii) ligation of the hybridized probes to circularize the Ω-probes and (iii) circularized-dependent qPCR due to sequence information for a forward primer, and for a reverse primer binding site, and qPCR hydrolysis probe binding. Read through of the polymerase during qPCR occurs only in circularized Ω-probes, which quantifies their number that is directly proportional to telomere length. When used in concert with information about the cell cycle stage from a single-copy gene, and ploidy, the MTL of single cells measured by ΩqPCR was consistent with that obtained from large sample sizes by TRF.},
}
@article {pmid34532917,
year = {2022},
author = {Bauch, C and Boonekamp, JJ and Korsten, P and Mulder, E and Verhulst, S},
title = {High heritability of telomere length and low heritability of telomere shortening in wild birds.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6308-6323},
pmid = {34532917},
issn = {1365-294X},
mesh = {Animals ; *Telomere Shortening/genetics ; Animals, Wild/genetics ; Birds/genetics ; Biological Evolution ; Telomere/genetics ; *Crows/genetics ; },
abstract = {Telomere length and telomere shortening predict survival in many organisms. This raises the question of the contribution of genetic and environmental effects to variation in these traits, which is still poorly known, particularly for telomere shortening. We used experimental (cross-fostering) and statistical (quantitative genetic "animal models") means to disentangle and estimate genetic and environmental contributions to telomere length variation in pedigreed free-living jackdaws (Corvus monedula). Telomere length was measured twice in nestlings, at ages 4 (n = 715) and 29 days (n = 474), using telomere restriction fragment (TRF) analysis, adapted to exclude interstitial telomeric sequences. Telomere length shortened significantly over the nestling period (10.4 ± 0.3 bp day[-1]) and was highly phenotypically (rP = 0.95 ± 0.01) and genetically (rG > 0.99 ± 0.01) correlated within individuals. Additive genetic effects explained a major part of telomere length variation among individuals, with its heritability estimated at h[2] = 0.74 on average. We note that TRF-based studies reported higher heritabilities than qPCR-based studies, and we discuss possible explanations. Parent-offspring regressions yielded similar heritability estimates for mothers and fathers when accounting for changes in paternal telomere length over life. Year effects explained a small but significant part of telomere length variation. Heritable variation for telomere shortening was low (h[2] = 0.09 ± 0.11). The difference in heritability between telomere length (high) and telomere shortening (low) agrees with evolutionary theory, in that telomere shortening has stronger fitness consequences in this population. Despite the high heritability of telomere length, its evolvability, which scales the additive genetic variance by mean telomere length, was on average 0.48%. Hence, evolutionary change of telomere length due to selection is likely to be slow.},
}
@article {pmid34532611,
year = {2021},
author = {Nassour, J and Schmidt, TT and Karlseder, J},
title = {Telomeres and Cancer: Resolving the Paradox.},
journal = {Annual review of cancer biology},
volume = {5},
number = {1},
pages = {59-77},
pmid = {34532611},
issn = {2472-3428},
support = {R01 CA227934/CA/NCI NIH HHS/United States ; R01 CA234047/CA/NCI NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; R01 CA228211/CA/NCI NIH HHS/United States ; K99 CA252447/CA/NCI NIH HHS/United States ; },
abstract = {Decades of study on cell cycle regulation have provided great insight into human cellular life span barriers, as well as their dysregulation during tumorigenesis. Telomeres, the extremities of linear chromosomes, perform an essential role in implementing these proliferative boundaries and preventing the propagation of potentially cancerous cells. The tumor-suppressive function of telomeres relies on their ability to initiate DNA damage signaling pathways and downstream cellular events, ranging from cell cycle perturbation to inflammation and cell death. While the tumor-suppressor role of telomeres is undoubtable, recent advances have pointed to telomeres as a major source of many of the genomic aberrations found in both early- and late-stage cancers, including the most recently discovered mutational phenomenon of chromothripsis. Telomere shortening appears as a double-edged sword that can function in opposing directions in carcinogenesis. This review focuses on the current knowledge of the dual role of telomeres in cancer and suggests a new perspective to reconcile the paradox of telomeres and their implications in cancer etiology.},
}
@article {pmid34531540,
year = {2022},
author = {Wang, L and Song, L and Liu, B and Zhang, L and Wu, M and Liu, Y and Bi, J and Yang, S and Cao, Z and Xia, W and Li, Y and Tian, Y and Zhang, B and Xu, S and Zhou, A and Wang, Y},
title = {Association between maternal urinary selenium during pregnancy and newborn telomere length: results from a birth cohort study.},
journal = {European journal of clinical nutrition},
volume = {76},
number = {5},
pages = {716-721},
pmid = {34531540},
issn = {1476-5640},
mesh = {Birth Cohort ; Child ; Cohort Studies ; Creatinine ; Female ; Humans ; Infant, Newborn ; *Maternal Exposure ; Mothers ; Pregnancy ; *Selenium ; Telomere ; },
abstract = {BACKGROUND: Newborn telomere length is considered as an effective predictor of lifespan and health outcomes in later life. Selenium is an essential trace element for human health, and its antioxidation is of great significance for the prevention of telomere erosion.<br><br>METHODS: We recruited 746 mother-newborn pairs in Wuhan Children's Hospital between 2013 and 2015. Urine samples were repeatedly collected at three time points during pregnancy, and umbilical cord blood samples were collected right after parturition. Urinary selenium concentration was detected using inductively coupled plasma mass spectrometry, and newborn telomere length was measured using quantitative real-time polymerase chain reaction. We applied general estimating equations to examine the trimester-specific association between maternal urinary selenium during pregnancy and newborn telomere length.<br><br>RESULTS: The median of creatinine-corrected selenium concentrations during pregnancy were 16.29, 18.08, and 18.35&#x2009;&#x3bc;g/g&#xb7;creatinine in the first, second, and third trimesters, respectively. Selenium concentrations in all the three trimesters were significantly associated with newborn telomere length. Per doubling of maternal urinary selenium concentrations was associated with 6.44% (95% CI: 0.92, 12.25), 6.54% (95% CI: 0.17, 13.31), and 6.02% (95% CI: 0.29, 12.09) longer newborn telomere length in the first, second, and third trimesters, respectively, after adjusting for potential confounders.<br><br>CONCLUSIONS: This is the first study to provide evidence for the effect of maternal selenium levels on fetal telomere erosion. Findings from our study suggested that maternal urinary selenium was positively associated with newborn telomere length, indicating that intrauterine selenium exposure might have effect on initial setting of human telomere length.},
}
@article {pmid34525499,
year = {2021},
author = {García-García, C and Shin, C and Baik, I},
title = {Association between body temperature and leukocyte telomere length in Korean middle-aged and older adults.},
journal = {Epidemiology and health},
volume = {43},
number = {},
pages = {e2021063},
pmid = {34525499},
issn = {2092-7193},
support = {2019R1A2C2084000)//National Research Foundation of Korea/ ; 2011-E71004-00//Korea Centers for Disease Control and Prevention/Republic of Korea ; 2012-E71005-00//Korea Centers for Disease Control and Prevention/Republic of Korea ; },
mesh = {Aged ; *Body Temperature ; Female ; Humans ; Leukocytes ; Longitudinal Studies ; Male ; Middle Aged ; Republic of Korea ; *Telomere/genetics ; Temperature ; },
abstract = {OBJECTIVES: Data on associations between body temperature (BT) and leukocyte telomere length (LTL), which has been widely used as a biomarker of cellular senescence in recent epidemiological studies, are limited. Therefore, this study aimed to explore the associations between a normal BT range (35.0-37.5°C) and LTL via 6-year longitudinal observations of 2,004 male and female adults aged 50 or older.<br><br>METHODS: BT was obtained by measuring the tympanic temperature, and relative LTL was determined by real-time polymerase chain reaction. Robust regression analysis was used to evaluate the association between the baseline and follow-up LTL values and their differences.<br><br>RESULTS: A significant inverse association was found between BT and LTL at baseline. The regression coefficient estimate was -0.03 (95% confidence interval, -0.07 to -0.001; p<0.05). This association was stronger in participants with a body mass index >25 kg/m2 and males (p<0.01). However, there were no associations between BT and LTL at follow-up or BT and 6-year longitudinal differences in LTL.<br><br>CONCLUSIONS: These findings suggest that having a high BT between 35&#xb0;C and 37.5&#xb0;C (95&#xb0;F and 99&#xb0;F) may be detrimental for obese individuals in terms of biological aging.},
}
@article {pmid34522616,
year = {2021},
author = {Roake, CM and Juntilla, M and Agarwal-Hashmi, R and Artandi, S and Kuo, CS},
title = {Tissue-specific telomere shortening and degenerative changes in a patient with TINF2 mutation and dyskeratosis congenita.},
journal = {Human pathology (New York)},
volume = {25},
number = {},
pages = {},
pmid = {34522616},
issn = {2214-3300},
support = {P30 CA124435/CA/NCI NIH HHS/United States ; R01 AG056575/AG/NIA NIH HHS/United States ; T32 GM007365/GM/NIGMS NIH HHS/United States ; },
abstract = {Dyskeratosis congenita is a disease of impaired tissue maintenance downstream of telomere dysfunction. Characteristically, patients present with the clinical triad of nail dystrophy, oral leukoplakia, and skin pigmentation defects, but the disease involves degenerative changes in multiple organs. Mutations in telomere-binding proteins such as TINF2 (TRF1-interacting nuclear factor 2) or in telomerase, the enzyme that counteracts age related telomere shortening, are causative in dyskeratosis congenita. We present a patient who presented with severe hypoxemia at age 13. The patient had a history of myelodysplastic syndrome treated with bone marrow transplant at the age of 5. At age 18 she was hospitalized for an acute pneumonia progressing to respiratory failure, developed renal failure and ultimately, she and her family opted to withdraw support as she was not a candidate for a lung transplant. Sequencing of the patient's TINF2 locus revealed a heterozygous mutation (c.844C > T, Arg282Cys) which has previously been reported in a subset of dyskeratosis congenita patients. Tissue sections from multiple organs showed degenerative changes including disorganized bone remodeling, diffuse alveolar damage and small vessel proliferation in the lung, and hyperkeratosis with hyperpigmentation of the skin. Autopsy samples revealed a bimodal distribution of telomere length, with telomeres from donor hematopoietic tissues being an age-appropriate length and those from patient tissues showing pathogenic shortening, with the shortest telomeres in lung, liver, and kidney. We report for the first time a survey of degenerative changes and telomere lengths in multiple organs in a patient with dyskeratosis congenita.},
}
@article {pmid34514660,
year = {2022},
author = {Ravindran, S and Froy, H and Underwood, SL and Dorrens, J and Seeker, LA and Watt, K and Wilbourn, RV and Pilkington, JG and Harrington, L and Pemberton, JM and Nussey, DH},
title = {The association between female reproductive performance and leukocyte telomere length in wild Soay sheep.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6184-6196},
doi = {10.1111/mec.16175},
pmid = {34514660},
issn = {1365-294X},
support = {BB/L020769/1 and University of Edinburgh Wellcome Trust PhD programme grant//Biotechnology and Biological Sciences Research Council/United Kingdom ; 108905/Z/15/Z//Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Sheep/genetics ; Female ; *Longevity ; *Reproduction/genetics ; Telomere Shortening ; Leukocytes ; Telomere/genetics ; },
abstract = {Telomere length (TL), typically measured across a sample of blood cells, has emerged as an exciting potential marker of physiological state and of the costs of investment in growth and reproduction within evolutionary ecology. While there is mounting evidence from studies of wild vertebrates that short TL predicts raised subsequent mortality risk, the relationship between reproductive investment and TL is less clear cut, and previous studies report both negative and positive associations. In this study, we examined the relationship between TL and different aspects of maternal reproductive performance in a free-living population of Soay sheep. We find evidence for shorter TL in females that bred, and thus paid any costs of gestation, compared to females that did not breed. However, we found no evidence for any association between TL and litter size. Furthermore, females that invested in gestation and lactation actually had longer TL than females who only invested in gestation because their offspring died shortly after birth. We used multivariate models to decompose these associations into among- and within-individual effects, and discovered that within-individual effects were driving both the negative association between TL and gestation, and the positive association between TL and lactation. This suggests that telomere dynamics may reflect recent physiologically costly investment or variation in physiological condition, depending on the aspect of reproduction being investigated. Our results highlight the physiological complexity of vertebrate reproduction, and the need to better understand how and why different aspects of physiological variation underpinning life histories impact blood cell TL.},
}
@article {pmid34508574,
year = {2022},
author = {Dhillon, VS and Deo, P and Chua, A and Thomas, P and Fenech, M},
title = {Sleep Duration, Health Promotion Index, sRAGE, and ApoE-ε4 Genotype Are Associated With Telomere Length in Healthy Australians.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {77},
number = {2},
pages = {243-249},
doi = {10.1093/gerona/glab264},
pmid = {34508574},
issn = {1758-535X},
mesh = {*Apolipoprotein E4/genetics ; *Apolipoproteins E/genetics ; Australia ; Female ; Genotype ; Health Promotion ; Humans ; Male ; Middle Aged ; Receptor for Advanced Glycation End Products/genetics ; Sleep/genetics ; Telomere/genetics ; },
abstract = {Significant alterations in sleep duration and/or quality of sleep become more pronounced as people get older. Poor sleep in elderly people is associated with adverse health outcomes and cellular aging. We examined the relationship between telomere length (TL) and sleep duration, Health Promotion Index (HPI), and tested whether the presence of Apolipoprotein-E4 (ApoE-ε4) allele affects both sleep and TL. The present study was carried out in 174 healthy participants (21% male; mean age 53.79 years) from South Australia. Lymphocyte TL was measured by real-time quantitative PCR (qPCR) and ApoE genotype was determined by TaqMan assay. HPI was calculated from a questionnaire regarding 8 lifestyle habits, including sleeping hours. Multivariate regression analysis was used to establish these associations adjusted for specified confounders. TL was found to be inversely associated with age (r = -0.199; p = .008) and body mass index (r = -0.121; p = .11), and was significantly shorter in participants who slept for less than 7 hours (p = .001) relative to those sleeping ≥7 hours. TL was positively correlated with HPI (r = 0.195; p = .009). ApoE-ε4 allele carriers who slept for less than 7 hours had shortest TL (p = .01) compared to noncarriers. Plasma soluble receptor for advanced glycation end product (sRAGE) level was significantly (p = .001) lower in individuals who sleep less than 7 hours and ApoE-ε4 carriers. Our results suggest that inadequate sleep duration or poor HPI is associated with shorter TL in cognitively normal people and that carriage of APOE-ε4 genotype may influence the extent of these effects.},
}
@article {pmid34504179,
year = {2021},
author = {Shin, HK and Park, JH and Yu, JH and Jin, YJ and Suh, YJ and Lee, JW and Kim, W and , },
title = {Association between telomere length and hepatic fibrosis in non-alcoholic fatty liver disease.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {18004},
pmid = {34504179},
issn = {2045-2322},
mesh = {Adult ; Age Factors ; Aged ; Alanine Transaminase/blood ; Alkaline Phosphatase/blood ; Aspartate Aminotransferases/blood ; Cholesterol, HDL/blood ; Cross-Sectional Studies ; Female ; Humans ; Liver/metabolism/pathology ; Liver Cirrhosis/blood/diagnosis/*genetics/pathology ; Logistic Models ; Male ; Middle Aged ; Non-alcoholic Fatty Liver Disease/blood/diagnosis/*genetics/pathology ; Odds Ratio ; Severity of Illness Index ; Telomere/*chemistry ; *Telomere Homeostasis ; gamma-Glutamyltransferase/blood ; },
abstract = {Telomere length has been linked to the prevalence and progression of metabolic disease. However, clinical implications of telomere length in biopsy-proven non-alcoholic fatty liver disease (NAFLD) patients remain unclear. Therefore, this study aimed to investigate the association of telomere length with the histological severity of NAFLD. The cross-sectional data derived from the prospectively enrolled Boramae NAFLD registry (n = 91) were analyzed. The liver tissues and clinical information were obtained from both NAFLD patients and non-NAFLD subjects. Binary logistic regression was performed to identify the independent association between telomere length and the histological severity of NAFLD. A total of 83 subjects with or without biopsy-proven NAFLD were included for analysis: non-NAFLD in 23 (27.7%), non-alcoholic fatty liver in 15 (18.1%), and non-alcoholic steatohepatitis (NASH) in 45 (54.2%). Telomere length measured from liver tissues showed a strong negative correlation (p < 0.001) with age, regardless of NAFLD status. Therefore, telomere length was corrected for age. Age-adjusted telomere length than decreased gradually with an increasing severity of fibrosis in patients with NAFLD (p < 0.028). In multivariate analysis, age-adjusted telomere length (odds ratio [OR] 0.59; 95% CI 0.37-0.92; p = 0.019) and high-density lipoprotein cholesterol (OR 0.94; 95% CI 0.80-0.99; p = 0.039) were independently associated with significant fibrosis. The age-adjusted telomere length tends to decrease along with the fibrosis stage of NAFLD. In particular, among the histological components of NAFLD, fibrosis severity seems to be related to telomere length in the liver.},
}
@article {pmid34494545,
year = {2021},
author = {Lin, A and Mertens, AN and Arnold, BF and Tan, S and Lin, J and Stewart, CP and Hubbard, AE and Ali, S and Benjamin-Chung, J and Shoab, AK and Rahman, MZ and Famida, SL and Hossen, MS and Mutsuddi, P and Akther, S and Rahman, M and Unicomb, L and Naved, RT and Mamun, MMA and Parvin, K and Dhabhar, FS and Kariger, P and Fernald, LC and Luby, SP and Colford, JM},
title = {Telomere length is associated with growth in children in rural Bangladesh.},
journal = {eLife},
volume = {10},
number = {},
pages = {},
pmid = {34494545},
issn = {2050-084X},
support = {K01 AI136885/AI/NIAID NIH HHS/United States ; },
mesh = {Bangladesh ; *Child Development ; Child, Preschool ; Cross-Sectional Studies ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Rural Population ; Telomere/*chemistry/metabolism ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Previously, we demonstrated that a water, sanitation, handwashing, and nutritional intervention improved linear growth and was unexpectedly associated with shortened childhood telomere length (TL) (Lin et al., 2017). Here, we assessed the association between TL and growth.<br><br>METHODS: We measured relative TL in whole blood from 713 children. We reported differences between the 10th percentile and 90th percentile of TL or change in TL distribution using generalized additive models, adjusted for potential confounders.<br><br>RESULTS: In cross-sectional analyses, long TL was associated with a higher length-for-age Z score at age 1 year (0.23 SD adjusted difference in length-for-age Z score [95% CI 0.05, 0.42; FDR-corrected p-value = 0.01]). TL was not associated with other outcomes.<br><br>CONCLUSIONS: Consistent with the metabolic telomere attrition hypothesis, our previous trial findings support an adaptive role for telomere attrition, whereby active TL regulation is employed as a strategy to address 'emergency states' with increased energy requirements such as rapid growth during the first year of life. Although short periods of active telomere attrition may be essential to promote growth, this study suggests that a longer overall initial TL setting in the first 2 years of life could signal increased resilience against future telomere erosion events and healthy growth trajectories.<br><br>FUNDING: Funded by the Bill and Melinda Gates Foundation.<br><br>CLINICAL TRIAL NUMBER: NCT01590095.},
}
@article {pmid34493830,
year = {2021},
author = {Belser, C and Baurens, FC and Noel, B and Martin, G and Cruaud, C and Istace, B and Yahiaoui, N and Labadie, K and Hřibová, E and Doležel, J and Lemainque, A and Wincker, P and D'Hont, A and Aury, JM},
title = {Telomere-to-telomere gapless chromosomes of banana using nanopore sequencing.},
journal = {Communications biology},
volume = {4},
number = {1},
pages = {1047},
pmid = {34493830},
issn = {2399-3642},
support = {ANR-10-LABX-0001-01//Agence Nationale de la Recherche (French National Research Agency)/ ; ANR-10-INBS-09-08//Agence Nationale de la Recherche (French National Research Agency)/ ; },
mesh = {Chromosomes, Plant/*genetics ; *Genome, Plant ; Musa/*genetics ; Nanopore Sequencing ; Nanopores ; *Telomere ; },
abstract = {Long-read technologies hold the promise to obtain more complete genome assemblies and to make them easier. Coupled with long-range technologies, they can reveal the architecture of complex regions, like centromeres or rDNA clusters. These technologies also make it possible to know the complete organization of chromosomes, which remained complicated before even when using genetic maps. However, generating a gapless and telomere-to-telomere assembly is still not trivial, and requires a combination of several technologies and the choice of suitable software. Here, we report a chromosome-scale assembly of a banana genome (Musa acuminata) generated using Oxford Nanopore long-reads. We generated a genome coverage of 177X from a single PromethION flowcell with near 17X with reads longer than 75 kbp. From the 11 chromosomes, 5 were entirely reconstructed in a single contig from telomere to telomere, revealing for the first time the content of complex regions like centromeres or clusters of paralogous genes.},
}
@article {pmid34493579,
year = {2021},
author = {Shi, S and Zhou, Y and Lu, Y and Sun, H and Xue, J and Wu, Z and Lei, M},
title = {Ccq1-Raf2 interaction mediates CLRC recruitment to establish heterochromatin at telomeres.},
journal = {Life science alliance},
volume = {4},
number = {11},
pages = {},
pmid = {34493579},
issn = {2575-1077},
mesh = {Cell Cycle Proteins/genetics/metabolism ; Chromatin Assembly and Disassembly/*genetics/physiology ; Heterochromatin/metabolism ; Histone-Lysine N-Methyltransferase/genetics/metabolism ; Methylation ; Schizosaccharomyces/genetics/metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Shelterin Complex/metabolism/physiology ; Telomere/metabolism ; },
abstract = {Telomeres, highly ordered DNA-protein complexes at eukaryotic linear chromosome ends, are specialized heterochromatin loci conserved among eukaryotes. In Schizosaccharomyces pombe, the shelterin complex is important for subtelomeric heterochromatin establishment. Despite shelterin has been demonstrated to mediate the recruitment of the Snf2/histone deacetylase-containing repressor complex (SHREC) and the Clr4 methyltransferase complex (CLRC) to telomeres, the mechanism involved in telomeric heterochromatin assembly remains elusive due to the multiple functions of the shelterin complex. Here, we found that CLRC plays a dominant role in heterochromatin establishment at telomeres. In addition, we identified a series of amino acids in the shelterin subunit Ccq1 that are important for the specific interaction between Ccq1 and the CLRC subunit Raf2. Finally, we demonstrated that the Ccq1-Raf2 interaction is essential for the recruitment of CLRC to telomeres, that contributes to histone H3 lysine 9 methylation, nucleosome stability and the shelterin-chromatin association, promoting a positive feedback mechanism for the nucleation and spreading of heterochromatin at subtelomeres. Together, our findings provide a mechanistic understanding of subtelomeric heterochromatin assembly by shelterin-dependent CLRC recruitment to chromosomal ends.},
}
@article {pmid34490122,
year = {2021},
author = {Rolles, B and Gorgulho, J and Tometten, M and Roderburg, C and Vieri, M and Abels, A and Vucur, M and Heymann, F and Tacke, F and Brümmendorf, TH and Luedde, T and Beier, F and Loosen, SH},
title = {Telomere Shortening in Peripheral Leukocytes Is Associated With Poor Survival in Cancer Patients Treated With Immune Checkpoint Inhibitor Therapy.},
journal = {Frontiers in oncology},
volume = {11},
number = {},
pages = {729207},
pmid = {34490122},
issn = {2234-943X},
abstract = {BACKGROUND: Immune checkpoint inhibitor (ICI) therapy represents a new standard of care for an increasing number of malignancies. Nevertheless, response rates and outcome of ICI treatment vary between individuals and the identification of predictive markers or hints towards immune cell exhaustion during therapy has remained a major challenge. Leukocyte telomere length is an established predictive biomarker of replicative aging and cellular proliferative potential in various hematological diseases. However, its relevance in the context of ICI therapy has not been investigated to date. Here, we analyze the age-adapted delta telomere length (ΔTL) of peripheral leukocytes as a potential predictive and prognostic marker in patients undergoing ICI therapy.<br><br>METHODS: Age-adapted delta telomere length (&#x394;TL) of 84 patients treated with ICIs for solid malignancies was measured via quantitative real-time PCR. &#x394;TL was correlated with outcome and clinical data.<br><br>RESULTS: &#x394;TL was not significantly altered between patients with different tumor entities or tumor stages and did not predict tumor response to ICI therapy. However, &#x394;TLs at initiation of treatment were a prognostic marker for overall survival (OS). When using a calculated ideal cut-off value, the median OS in patients with shorter &#x394;TL was 5.7 months compared to 18.0 months in patients showing longer &#x394;TL. The prognostic role of age-adapted &#x394;TL was further confirmed by uni- and multivariate Cox-regression analyses.<br><br>CONCLUSION: In the present study, we demonstrate that shorter telomere lengths in peripheral blood leukocytes are associated with a significantly impaired outcome in patients receiving ICI therapy across different malignancies. We explain our findings by hypothesizing an older replicative age in peripheral leukocytes of patients with an impaired overall survival, reflected by a premature TL shortening. Whether this association is ICI-specific remains unknown. Further follow-up studies are needed to provide insights about the exact mechanism of how shortened telomeres eventually affect OS and could help guiding therapeutic decisions in future.},
}
@article {pmid34488828,
year = {2021},
author = {Yang, L and Wang, B and Jiao, X and Zhou, C and Chen, S and Gao, X and Sun, W and Song, S and Li, J and Liu, J and Wang, Y and Liu, P},
title = {TAZ maintains telomere length in TNBC cells by mediating Rad51C expression.},
journal = {Breast cancer research : BCR},
volume = {23},
number = {1},
pages = {89},
pmid = {34488828},
issn = {1465-542X},
mesh = {Cell Line, Tumor ; Cell Proliferation/genetics ; Cellular Senescence/genetics ; DNA Damage/genetics ; DNA-Binding Proteins/*genetics ; Gene Expression Regulation, Neoplastic ; Humans ; Shelterin Complex/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/metabolism/pathology ; Telomere Homeostasis/*genetics ; Telomere Shortening/genetics ; Transcription Factors/genetics ; Transcriptional Coactivator with PDZ-Binding Motif Proteins/genetics/*metabolism ; Triple Negative Breast Neoplasms/*genetics/pathology ; },
abstract = {BACKGROUND: Telomere maintenance is crucial for the unlimited proliferation of cancer cells and essential for the "stemness" of multiple cancer cells. TAZ is more extensively expressed in triple negative breast cancers (TNBC) than in other types of breast cancers, and promotes proliferation, transformation and EMT of cancer cells. It was reported that TAZ renders breast cancer cells with cancer stem cell features. However, whether TAZ regulates telomeres is still unclear. In this study, we explored the roles of TAZ in the regulation of telomere maintenance in TNBC cells.<br><br>METHODS: siRNA and shRNA was used to generate TAZ-depleted TNBC cell lines. qPCR and Southern analysis of terminal restriction fragments techniques were used to test telomere length. Co-immunoprecipitation, Western blotting, immunofluorescence, Luciferase reporter assay and Chromatin-IP were conducted to investigate the underlying mechanism.<br><br>RESULTS: By knocking down the expression of TAZ in TNBC cells, we found, for the first time, that TAZ is essential for the maintenance of telomeres in TNBC cells. Moreover, loss of TAZ causes senescence phenotype of TNBC cells. The observed extremely shortened telomeres in late passages of TAZ knocked down cells correlate with an elevated hTERT expression, reductions of shelterin proteins, and an activated DNA damage response pathway. Our data also showed that depletion of TAZ results in overexpression of TERRAs, which are a group of telomeric repeat-containing RNAs and regulate telomere length and integrity. Furthermore, we discovered that TAZ maintains telomere length of TNBC cells likely by facilitating the expression of Rad51C, a crucial element of homologous recombination pathway that promotes telomere replication.<br><br>CONCLUSIONS: This study supports the notion that TAZ is an oncogenic factor in TNBC, and further reveals a novel telomere-related pathway that is employed by TAZ to regulate TNBC.},
}
@article {pmid34486664,
year = {2021},
author = {Dogan, F and Forsyth, NR},
title = {Epigenetic features in regulation of telomeres and telomerase in stem cells.},
journal = {Emerging topics in life sciences},
volume = {5},
number = {4},
pages = {497-505},
doi = {10.1042/ETLS20200344},
pmid = {34486664},
issn = {2397-8554},
mesh = {Cellular Senescence ; Epigenesis, Genetic ; *Pluripotent Stem Cells/metabolism ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {The epigenetic nature of telomeres is still controversial and different human cell lines might show diverse histone marks at telomeres. Epigenetic modifications regulate telomere length and telomerase activity that influence telomere structure and maintenance. Telomerase is responsible for telomere elongation and maintenance and is minimally composed of the catalytic protein component, telomerase reverse transcriptase (TERT) and template forming RNA component, telomerase RNA (TERC). TERT promoter mutations may underpin some telomerase activation but regulation of the gene is not completely understood due to the complex interplay of epigenetic, transcriptional, and posttranscriptional modifications. Pluripotent stem cells (PSCs) can maintain an indefinite, immortal, proliferation potential through their endogenous telomerase activity, maintenance of telomere length, and a bypass of replicative senescence in vitro. Differentiation of PSCs results in silencing of the TERT gene and an overall reversion to a mortal, somatic cell phenotype. The precise mechanisms for this controlled transcriptional silencing are complex. Promoter methylation has been suggested to be associated with epigenetic control of telomerase regulation which presents an important prospect for understanding cancer and stem cell biology. Control of down-regulation of telomerase during differentiation of PSCs provides a convenient model for the study of its endogenous regulation. Telomerase reactivation has the potential to reverse tissue degeneration, drive repair, and form a component of future tissue engineering strategies. Taken together it becomes clear that PSCs provide a unique system to understand telomerase regulation fully and drive this knowledge forward into aging and therapeutic application.},
}
@article {pmid34486523,
year = {2021},
author = {Hu, K and Ghandi, M and Huang, FW},
title = {Integrated evaluation of telomerase activation and telomere maintenance across cancer cell lines.},
journal = {eLife},
volume = {10},
number = {},
pages = {},
pmid = {34486523},
issn = {2050-084X},
mesh = {Cell Line, Tumor ; Epigenesis, Genetic ; Humans ; Neoplasms/genetics ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {In cancer, telomere maintenance is critical for the development of replicative immortality. Using genome sequences from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer Project, we calculated telomere content across 1299 cancer cell lines. We find that telomerase reverse transcriptase (TERT) expression correlates with telomere content in lung, central nervous system, and leukemia cell lines. Using CRISPR/Cas9 screening data, we show that lower telomeric content is associated with dependency of CST telomere maintenance genes. Increased dependencies of shelterin members are associated with wild-type TP53 status. Investigating the epigenetic regulation of TERT, we find widespread allele-specific expression in promoter-wildtype contexts. TERT promoter-mutant cell lines exhibit hypomethylation at PRC2-repressed regions, suggesting a cooperative global epigenetic state in the reactivation of telomerase. By incorporating telomere content with genomic features across comprehensively characterized cell lines, we provide further insights into the role of telomere regulation in cancer immortality.},
}
@article {pmid34484375,
year = {2021},
author = {Peng, X and Huang, J and Xia, S and Yang, Y and Dong, K},
title = {Association of leukocyte telomere length with metabolic syndrome in type 2 diabetes mellitus.},
journal = {Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences},
volume = {26},
number = {},
pages = {43},
pmid = {34484375},
issn = {1735-1995},
abstract = {BACKGROUND: Leukocyte telomere length (LTL) has been revealed to be associated with aging-related diseases such as metabolic syndrome (MetS) and Type 2 diabetes mellitus (T2DM). We aimed to investigate the correlation of LTL with MetS and its components in T2DM patients in this cross-sectional study.<br><br>MATERIALS AND METHODS: A total of 344 T2DM patients were enrolled into this study. LTL was measured by Southern blot-based terminal restriction fragment length analysis. MetS was clinically defined by 2007 Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults.<br><br>RESULTS: Of 344 T2DM patients, 53% had MetS. T2DM patients with MetS had significantly longer LTL than those without MetS (6451.95 &#xb1; 51.10 base pairs vs. 6076.13 &#xb1; 55.13 base pairs, P < 0.001), especially when T2DM patients had poor glycemic control (hemoglobin A1c &#x2265;7%). Meanwhile, the trend of longer LTL was associated with the increased components of MetS in T2DM patient. Finally, LTL had a significant association with MetS (odds ratio [OR]: 2.096, 95% confidence interval [CI] 1.337-3.285, P = 0.001), low levels of high-density lipoprotein-cholesterol (HDL-C) (OR: 2.412, 95% CI 1.350-4.308, P = 0.003) in T2DM patients.<br><br>CONCLUSION: T2DM patients with MetS had a significantly longer LTL than those without MetS. The longer LTL was especially evident in T2DM patients with poor glycemic control. Longer LTL was positively associated with MetS, particularly low levels of HDL-C in T2DM patients.},
}
@article {pmid34482039,
year = {2021},
author = {Darvishi, FZ and Saadat, M},
title = {Morphine treatment is associated with diminished telomere length together with down-regulated TERT and TERF2 mRNA levels.},
journal = {Drug and alcohol dependence},
volume = {227},
number = {},
pages = {108982},
doi = {10.1016/j.drugalcdep.2021.108982},
pmid = {34482039},
issn = {1879-0046},
mesh = {Down-Regulation ; Humans ; Morphine/pharmacology ; RNA, Messenger/genetics ; *Telomerase/genetics/metabolism ; *Telomere/genetics/metabolism ; Telomeric Repeat Binding Protein 2 ; },
abstract = {BACKGROUND: Drug dependence promotes accelerated aging and higher mortality compare with the general population. Telomere length is a biomarker of determination of cellular aging. Telomere attrition has been reported in heroin dependent patients. To investigate whether telomere length is affected by morphine or not, the expressions of hTERT and TERF2 in morphine treated human SH-SY5Y cells were determined and compared with untreated cells.<br><br>METHODS: The SH-SY5Y cells were treated with 1 and 5&#x2009;&#x3bc;M concentrations of morphine for different exposure times (1d, 2d, 3d, 7d and 60 days). The mRNA levels of hTERT and TERF2 were determined using quantitative real-time RCR. The relative telomere length was measured as the ratio of telomere/36B4.<br><br>RESULTS: The hTERT and TERF2 mRNA levels were down regulated in morphine treated cells as a function of exposure duration. These alterations were reversible if morphine was removed from the culture medium. No reduction in the relative expression of hTERT and TERF2 in the cells exposed to N-acetyl cysteine (NAC) plus morphine was observed. In the SH-SY5Y cells treated by 5&#x2009;&#x3bc;M morphine for 60 consecutive days, the hTERT and TERF2 mRNA levels and relative telomere lengths remarkably decreased.<br><br>CONCLUSIONS: Reversible alteration of mRNA levels by removing morphine from culture medium, and effect of NAC in co-treatment of morphine plus NAC, emphasize the role of reactive oxygen species in down-regulation of the expression of hTERT and TERF2 by morphine. Telomere attrition in morphine treated cells is a consequence of down-regulation of the expression of hTERT and TERF2.},
}
@article {pmid34478576,
year = {2022},
author = {Atema, E and van Noordwijk, AJ and Verhulst, S},
title = {Telomere dynamics in relation to experimentally increased locomotion costs and fitness in great tits.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6208-6215},
pmid = {34478576},
issn = {1365-294X},
mesh = {Animals ; Male ; *Aging ; Ecology ; *Passeriformes ; *Telomere/genetics ; Telomere Shortening/genetics ; },
abstract = {Evidence that telomere length (TL) and dynamics can be interpreted as proxy for 'life stress' experienced by individuals stems largely from correlational studies. We tested for effects of an experimental increase of workload on telomere dynamics by equipping male great tits (Parus major) with a 0.9 g backpack for a full year. In addition, we analysed associations between natural life-history variation, TL and TL dynamics. Carrying 5% extra weight for a year did not significantly accelerate telomere attrition. This agrees with our earlier finding that this experiment did not affect survival or future reproduction. Apparently, great tit males were able to compensate behaviourally or physiologically for the increase in locomotion costs we imposed. We found no cross-sectional association between reproductive success and TL, but individuals with higher reproductive success (number of recruits) lost fewer telomere base pairs in the subsequent year. We used the TRF method to measure TL, which method yields a TL distribution for each sample, and the association between reproductive success and telomere loss was more pronounced in the higher percentiles of the telomere distribution, in agreement with the higher impact of ageing on longer telomeres within individuals. Individuals with longer telomeres and less telomere shortening were more likely to survive to the next breeding season, but these patterns did not reach statistical significance. Whether successful individuals are characterized by losing fewer or more base pairs from their telomeres varies between species, and we discuss aspects of ecology and social organisation that may explain this variation.},
}
@article {pmid34477880,
year = {2022},
author = {Saunders, CN and Kinnersley, B and Culliford, R and Cornish, AJ and Law, PJ and Houlston, RS},
title = {Relationship between genetically determined telomere length and glioma risk.},
journal = {Neuro-oncology},
volume = {24},
number = {2},
pages = {171-181},
pmid = {34477880},
issn = {1523-5866},
support = {C1298/A8362//Cancer Research UK/United Kingdom ; },
mesh = {*Genome-Wide Association Study ; *Glioma/genetics/metabolism ; Humans ; Leukocytes/metabolism ; Polymorphism, Single Nucleotide ; Risk Factors ; Telomere/genetics ; Telomere Homeostasis/genetics ; },
abstract = {BACKGROUND: Telomere maintenance is increasingly recognized as being fundamental to glioma oncogenesis with longer leukocyte telomere length (LTL) reported to increase risk of glioma. To gain further insight into the relationship between telomere genetics and risk of glioma, we conducted several complementary analyses, using genome-wide association studies data on LTL (78 592 individuals) and glioma (12 488 cases and 18 169 controls).<br><br>METHODS: We performed both classical and summary Mendelian randomization (SMR), coupled with heterogeneity in dependent instruments tests, at genome-wide significant LTL loci to examine if an association was mediated by the same causal variant in glioma. To prioritize genes underscoring glioma-LTL associations, we analyzed gene expression and DNA methylation data.<br><br>RESULTS: Genetically increased LTL was significantly associated with increased glioma risk, random-effects inverse variance weighted ORs per 1 SD unit increase in the putative risk factor (odds ratio [OR]SD) 4.79 (95% confidence interval: 2.11-10.85; P = 1.76 &#xd7; 10-4). SMR confirmed the previously reported LTL associations at 3q26.2 (TERC; PSMR = 1.33 &#xd7; 10-5), 5p15.33 (TERT; PSMR = 9.80 &#xd7; 10-27), 10q24.33 (STN1 alias OBFC1; PSMR = 4.31 &#xd7; 10-5), and 20q13.3 (STMN3/RTEL1; PSMR = 2.47 &#xd7; 10-4) glioma risk loci. Our analysis implicates variation at 1q42.12 (PSMR = 1.55 &#xd7; 10-2), 6p21.3 (PSMR = 9.76 &#xd7; 10-3), 6p22.2 (PSMR = 5.45 &#xd7; 10-3), 7q31.33 (PSMR = 6.52 &#xd7; 10-3), and 11q22.3 (PSMR = 8.89 &#xd7; 10-4) as risk factors for glioma risk. While complicated by patterns of linkage disequilibrium, genetic variation involving PARP1, PRRC2A, CARMIL1, POT1, and ATM-NPAT1 was implicated in the etiology of glioma.<br><br>CONCLUSIONS: These observations extend the role of telomere-related genes in the development of glioma.},
}
@article {pmid34477845,
year = {2021},
author = {Purdue-Smithe, AC and Kim, K and Andriessen, VC and Pollack, AZ and Sjaarda, LA and Silver, RM and Schisterman, EF and Mumford, SL},
title = {Preconception leukocyte telomere length and pregnancy outcomes among women with demonstrated fecundity.},
journal = {Human reproduction (Oxford, England)},
volume = {36},
number = {12},
pages = {3122-3130},
pmid = {34477845},
issn = {1460-2350},
mesh = {Adolescent ; Adult ; Aged ; Cross-Sectional Studies ; Female ; *Fertility ; Humans ; Leukocytes ; Pregnancy ; *Pregnancy Outcome ; Prospective Studies ; Telomere ; Young Adult ; },
abstract = {STUDY QUESTION: Is preconception leukocyte telomere length associated with fecundability, pregnancy loss and live birth among women attempting natural conception with a history of 1-2 prior pregnancy losses?<br><br>SUMMARY ANSWER: Preconception leukocyte telomere length is not associated with fecundability, pregnancy loss or live birth.<br><br>WHAT IS KNOWN ALREADY: As women increasingly delay childbearing, accessible preconception biomarkers to predict pregnancy outcomes among women seeking natural conception could improve preconception counseling. Findings of small case-control or cross-sectional studies suggest that telomere attrition is associated with adverse pregnancy outcomes among women undergoing fertility treatment, but prospective studies in non-clinical populations are lacking.<br><br>STUDY DESIGN, SIZE, DURATION: Participants included 1228 women aged 18-40&#x2009;years with a history of 1-2 prior pregnancy losses who were recruited at four university medical centers (2006-2012).<br><br>Preconception leukocyte telomere length was measured at baseline using PCR and reported as a ratio (T/S) in relation to population-specific standard reference DNA. Women were followed for up to six cycles while attempting to conceive. Associations of telomere length with fecundability, live birth and pregnancy loss were estimated using discrete Cox proportional hazards models and log-binomial models.<br><br>After adjustment for age, BMI, smoking and other factors, preconception telomere length was not associated with fecundability (Q4 vs Q1 FOR = 1.00; 95% CI = 0.79, 1.27), live birth (Q4 vs Q1 RR = 1.00; 95% CI = 0.85, 1.19), or pregnancy loss (Q4 vs Q1 RR = 1.12; 95% CI = 0.78, 1.62).<br><br>Telomere length was measured in leukocytes, which is an accessible tissue in women attempting natural conception but may not reflect telomere length in oocytes. Most women were younger than 35&#x2009;years, limiting our ability to evaluate associations among older women. Participants had a history of 1-2 prior pregnancy losses; therefore, our findings may not be widely generalizable.<br><br>Despite prior research suggesting that telomere length may be associated with pregnancy outcomes among women seeking fertility treatment, our findings suggest that leukocyte telomere length is not a suitable biomarker of pregnancy establishment or maintenance among women attempting natural conception.<br><br>This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (National Institutes of Health, Bethesda, MD, USA; contract numbers HHSN267200603423, HHSN267200603424 and HHSN267200603426). The authors have no conflicts of interest to disclose.<br><br>TRIAL REGISTRATION NUMBER: The trial was registered with ClinicalTrials.gov, number NCT00467363.},
}
@article {pmid34469544,
year = {2021},
author = {Pennarun, G and Picotto, J and Etourneaud, L and Redavid, AR and Certain, A and Gauthier, LR and Fontanilla-Ramirez, P and Busso, D and Chabance-Okumura, C and Thézé, B and Boussin, FD and Bertrand, P},
title = {Increase in lamin B1 promotes telomere instability by disrupting the shelterin complex in human cells.},
journal = {Nucleic acids research},
volume = {49},
number = {17},
pages = {9886-9905},
pmid = {34469544},
issn = {1362-4962},
mesh = {Cells, Cultured ; Humans ; Lamin Type B/chemistry/*metabolism ; Shelterin Complex/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 2/chemistry/*metabolism ; },
abstract = {Telomere maintenance is essential to preserve genomic stability and involves telomere-specific proteins, DNA replication and repair proteins. Lamins are key components of the nuclear envelope and play numerous roles, including maintenance of the nuclear integrity, regulation of transcription, and DNA replication. Elevated levels of lamin B1, one of the major lamins, have been observed in some human pathologies and several cancers. Yet, the effect of lamin B1 dysregulation on telomere maintenance remains unknown. Here, we unveil that lamin B1 overexpression drives telomere instability through the disruption of the shelterin complex. Indeed, lamin B1 dysregulation leads to an increase in telomere dysfunction-induced foci, telomeric fusions and telomere losses in human cells. Telomere aberrations were preceded by mislocalizations of TRF2 and its binding partner RAP1. Interestingly, we identified new interactions between lamin B1 and these shelterin proteins, which are strongly enhanced at the nuclear periphery upon lamin B1 overexpression. Importantly, chromosomal fusions induced by lamin B1 in excess were rescued by TRF2 overexpression. These data indicated that lamin B1 overexpression triggers telomere instability through a mislocalization of TRF2. Altogether our results point to lamin B1 as a new interacting partner of TRF2, that is involved in telomere stability.},
}
@article {pmid34468230,
year = {2023},
author = {Zadeh, FA and Bokov, DO and Yasin, G and Vahdat, S and Abbasalizad-Farhangi, M},
title = {Central obesity accelerates leukocyte telomere length (LTL) shortening in apparently healthy adults: A systematic review and meta-analysis.},
journal = {Critical reviews in food science and nutrition},
volume = {63},
number = {14},
pages = {2119-2128},
doi = {10.1080/10408398.2021.1971155},
pmid = {34468230},
issn = {1549-7852},
mesh = {Humans ; Adult ; *Obesity, Abdominal ; Risk Factors ; Body Mass Index ; *Obesity ; Leukocytes ; Telomere ; },
abstract = {Shorter telomere length is associated with numerous comorbidities; central obesity might trigger leukocyte telomere shortening; in the current meta-analysis we evaluated the association of central obesity with leukocyte telomere length among adults. A systematic search from Scopus, PubMed, Embase and Proquest electronic databases up to May 2021 was done. The final screening, provided five articles to be included in final meta-analysis. Those in the highest category of telomere length had 3.72 cm lower waist circumference (WC) compared with those in the lowest category (WMD=-3.718; CI=-7.180, -0.257 P = 0.035; I[2] = 95.4%). Also, those in the highest LTL category had 0.02 lower waist to hip ratio (WHR) compared with those in the lowest category, although this association was not significant (WMD: -0.02; CI=-0.04, 0.01; P = 0.19; I[2]= 90.7%). In quality assessment of included studies, all of the studies had moderate or high quality score and there was no study with poor quality. Higher leukocyte telomere length was accompanied with lower WC among adults. This association was not significant for difference in WHR. Because of the high heterogeneity values and also because of the observational design of included studies, the inference of causality of these associations needs further investigations.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021.1971155 .},
}
@article {pmid34458916,
year = {2021},
author = {Hailu, EM and Lewis, TT and Needham, BL and Lin, J and Seeman, TE and Mujahid, MS},
title = {Longitudinal Associations Between Discrimination, Neighborhood Social Cohesion, and Telomere Length: The Multi-Ethnic Study of Atherosclerosis.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glab193},
pmid = {34458916},
issn = {1758-535X},
support = {T32 HD101364/HD/NICHD NIH HHS/United States ; R01HL101161/NH/NIH HHS/United States ; N01-HC-95159/HL/NHLBI NIH HHS/United States ; },
abstract = {BACKGROUND: We aimed to examine if neighborhood social cohesion moderated longitudinal associations between baseline reports of discrimination and 10-year changes in leukocyte telomere length (LTL).<br><br>METHODS: Data are from the Multi-Ethnic Study of Atherosclerosis (N = 1064; age range 45-84 years). Baseline discrimination was measured using the Major Experiences of Discrimination Scale (MDS; none, 1 domain, &#x2265;2 domains) and the Experiences of Discrimination Scale (EDS; none, moderate, high). Neighborhood social cohesion at baseline was assessed via a community survey within census tract-defined neighborhoods. 10-year change in LTL was defined as regression to the mean-corrected 10-year difference in the ratio of telomeric DNA to a single-copy gene (T/S).<br><br>RESULTS: In linear mixed-effects models, we found that neighborhood social cohesion modified the effect of baseline reports of MDS on 10-year changes in LTL, independent of sociodemographic characteristics, health behaviors, and health conditions (p(&#x3c7;&#x200a;2) = .01). Among those residing in neighborhoods with low social cohesion, experiencing major discrimination in &#x2265;2 domains was associated with faster LTL attrition over 10 years, compared to reporting no discrimination (&#x3b2; = -0.03; 95% confidence interval: -0.06, -0.003). We found no main associations for either discrimination measure and no interaction between EDS and neighborhood social cohesion.<br><br>CONCLUSIONS: Results indicate that neighborhood social cohesion is an important dimension of the neighborhood context that may moderate the impact of major experiences of discrimination on telomere length attrition. These findings help advance our understanding of the integral role that neighborhood environments play in attenuating the effect of discrimination on accelerated cell aging.},
}
@article {pmid34455645,
year = {2022},
author = {Kärkkäinen, T and Briga, M and Laaksonen, T and Stier, A},
title = {Within-individual repeatability in telomere length: A meta-analysis in nonmammalian vertebrates.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6339-6359},
doi = {10.1111/mec.16155},
pmid = {34455645},
issn = {1365-294X},
mesh = {Animals ; Phylogeny ; *Telomere/genetics ; *Vertebrates/genetics ; Biomarkers ; Telomere Shortening ; },
abstract = {Telomere length is increasingly used as a biomarker of long-term somatic state and future survival prospects. While most studies have overlooked this aspect, biological interpretations based on a given telomere length will benefit from considering the level of within-individual repeatability of telomere length through time. Therefore, we conducted a meta-analysis on 74 longitudinal studies in nonmammalian vertebrates, with the aim to establish the current pattern of within-individual repeatability in telomere length and to identify the methodological (e.g., qPCR/TRF) and biological factors (e.g., age class, phylogeny) that may affect it. While the median within-individual repeatability of telomere length was moderate to high (R = 0.55; 95% CI: 0.05-0.95; N = 82), marked heterogeneity between studies was evident. Measurement method affected the repeatability estimate strongly, with TRF-based studies exhibiting high repeatability (R = 0.80; 95% CI: 0.34-0.96; N = 25), while repeatability of qPCR-based studies was markedly lower and more variable (R = 0.46; 95% CI: 0.04-0.82; N = 57). While phylogeny explained some variance in repeatability, phylogenetic signal was not significant (λ = 0.32; 95% CI: 0.00-0.83). None of the biological factors investigated here significantly explained variation in the repeatability of telomere length, being potentially obscured by methodological differences. Our meta-analysis highlights the high variability in within-individual repeatability estimates between studies and the need to put more effort into separating technical and biological explanations. This is important to better understand to what extent biological factors can affect the repeatability of telomere length and thus the interpretation of telomere length data.},
}
@article {pmid34454696,
year = {2021},
author = {Bolzán, AD},
title = {Mutagen-induced telomere instability in human cells.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {868-869},
number = {},
pages = {503387},
doi = {10.1016/j.mrgentox.2021.503387},
pmid = {34454696},
issn = {1879-3592},
mesh = {Animals ; Cellular Senescence/drug effects/genetics ; Chromosomal Instability/*drug effects/genetics ; DNA/genetics ; DNA Breaks, Double-Stranded/drug effects ; Genomic Instability/*drug effects/genetics ; Humans ; Mutagens/*toxicity ; Telomere/*drug effects/genetics ; },
abstract = {Telomere instability is one of the main sources of genome instability and may result from chromosome end loss (due to chromosome breakage at one or both ends) or, more frequently, telomere dysfunction. Dysfunctional telomeres arise when they lose their end-capping function or become critically short, which causes chromosomal termini to behave like a DNA double-strand break. Telomere instability may occur at the chromosomal or at the molecular level, giving rise, respectively, to telomere-related chromosomal aberrations or the loss or modification of any of the components of the telomere (telomere DNA, telomere-associated proteins, or telomere RNA). Since telomeres play a fundamental role in maintaining genome stability, the study of telomere instability in cells exposed to mutagens is of great importance to understand the telomere-driven genomic instability present in those cells. In the present review, we will focus on the current knowledge about telomere instability induced by physical, chemical, and biological mutagens in human cells.},
}
@article {pmid34454691,
year = {2021},
author = {Bull, C and Mayrhofer, G and Fenech, M},
title = {Exposure to hypomethylating 5-aza-2'-deoxycytidine (decitabine) causes rapid, severe DNA damage, telomere elongation and mitotic dysfunction in human WIL2-NS cells.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {868-869},
number = {},
pages = {503385},
doi = {10.1016/j.mrgentox.2021.503385},
pmid = {34454691},
issn = {1879-3592},
mesh = {Biomarkers/metabolism ; Cell Line ; Chromosomal Instability/drug effects ; Cytokinesis/drug effects ; DNA Damage/*drug effects ; DNA Methylation/*drug effects ; Decitabine/*pharmacology ; Humans ; Lymphocytes/drug effects ; Micronucleus Tests/methods ; Mitosis/drug effects ; Telomere/*drug effects ; },
abstract = {BACKGROUND: 5-aza-2'-deoxycytidine (5azadC, decitabine) is a DNA hypomethylating agent used in the treatment of myelodysplastic syndromes. Due to cytotoxic side effects dose optimization is essential. The aim of this study was to define and quantify the effects of 5azadC on biomarkers of chromosomal stability, and telomere length, in human lymphoblastoid cell line, WIL2-NS, at clinically relevant dosages.<br><br>METHODS: Human WIL2-NS cells were maintained in complete medium containing 0, 0.2 or 1.0 &#x3bc;M 5azadC for four days, and analysed daily for telomere length (flow cytometry), chromosomal stability (cytokinesis-block micronucleus cytome (CBMN-cyt) assay), and global methylation (%5me-C).<br><br>RESULTS: DNA methylation decreased significantly in 1.0 &#x3bc;M 5azadC, relative to control (p < 0.0001). Exposure to 1.0 &#x3bc;M 5azadC resulted in 1.7-fold increase in telomere length (p < 0.0001), in parallel with rapid increase in biomarkers of DNA damage; (micronuclei (MN, 6-fold increase), nucleoplasmic bridges (NPB, a 12-fold increase), and nuclear buds (NBud, a 13-fold increase) (all p < 0.0001). Fused nuclei (FUS), indicative of mitotic dysfunction, showed a 5- and 13-fold increase in the 0.2 &#x3bc;M and 1.0 &#x3bc;M conditions, respectively (p = 0.001) after 4 days.<br><br>CONCLUSIONS: These data show that (i) clinically relevant concentrations of 5azadC are highly genotoxic; (ii) hypomethylation was associated with increased TL and DNA damage; and (iii) longer TL was associated with chromosomal instability. These findings suggest that lower doses of 5azdC may be effective as a hypomethylating agent, while potentially reducing DNA damage and risk for secondary disease.},
}
@article {pmid34454526,
year = {2021},
author = {Clarity, C and Trowbridge, J and Gerona, R and Ona, K and McMaster, M and Bessonneau, V and Rudel, R and Buren, H and Morello-Frosch, R},
title = {Associations between polyfluoroalkyl substance and organophosphate flame retardant exposures and telomere length in a cohort of women firefighters and office workers in San Francisco.},
journal = {Environmental health : a global access science source},
volume = {20},
number = {1},
pages = {97},
pmid = {34454526},
issn = {1476-069X},
support = {R01 ES027051/ES/NIEHS NIH HHS/United States ; T42 OH008429/OH/NIOSH CDC HHS/United States ; },
mesh = {Adult ; Biological Monitoring ; Cohort Studies ; Fatty Acids/*blood ; Female ; *Firefighters ; Flame Retardants/*analysis ; Fluorocarbons/*blood ; Humans ; Leukocytes/metabolism ; Middle Aged ; Occupational Exposure/analysis ; Organophosphates/*urine ; San Francisco ; Sulfonic Acids/*blood ; *Telomere ; },
abstract = {BACKGROUND: Environmental chemical exposures can affect telomere length, which in turn has been associated with adverse health outcomes including cancer. Firefighters are occupationally exposed to many hazardous chemicals and have higher rates of certain cancers. As a potential biomarker of effect, we assessed associations between chemical exposures and telomere length in women firefighters and office workers from San Francisco, CA.<br><br>METHODS: We measured serum concentrations of polyfluoroalkyl substances (PFAS), urinary metabolites of flame retardants, including organophosphate flame retardants (OPFRs), and telomere length in peripheral blood leukocytes in women firefighters (N&#xa0;=&#x2009;84) and office workers (N&#xa0;=&#x2009;79) who participated in the 2014-15 Women Workers Biomonitoring Collaborative. Multiple linear regression models were used to assess associations between chemical exposures and telomere length.<br><br>RESULTS: Regression results revealed significant positive associations between perfluorooctanoic acid (PFOA) and telomere length and perfluorooctanesulfonic acid (PFOS) and telomere length among the whole cohort. Models stratified by occupation showed stronger and more significant associations among firefighters as compared to office workers. Among firefighters in models adjusted for age, we found positive associations between telomere length and log-transformed PFOA (&#x3b2; (95%CI)&#x2009;=&#x2009;0.57(0.12, 1.02)), PFOS (0.44 (0.05, 0.83)), and perfluorodecanoic acid (PFDA) (0.43 (0.02, 0.84)). Modeling PFAS as categories of exposure showed significant associations between perfluorononanoic acid (PFNA) and telomere length among firefighters. Significant associations between OPFR metabolites and telomere length were seen for bis (1,3-dichloro-2-propyl) phosphate (BDCPP) and telomere length among office workers (0.21(0.03, 0.40)) and bis (2-chloroethyl) phosphate (BCEP) and telomere length among firefighters (-&#x2009;0.14(-&#x2009;0.28, -&#x2009;0.01)). For OPFRs, the difference in the direction of effect by occupational group may be due to the disparate detection frequencies and concentrations of exposure between the two groups and/or potential unmeasured confounding.<br><br>CONCLUSION: Our findings suggest positive associations between PFAS and telomere length in women workers, with larger effects seen among firefighters as compared to office workers. The OPFR metabolites BDCPP and BCEP are also associated with telomere length in firefighters and office workers. Associations between chemical exposures and telomere length reported here and by others suggest mechanisms by which these chemicals may affect carcinogenesis and other adverse health outcomes.},
}
@article {pmid34451431,
year = {2021},
author = {Li, B and Zhao, Y},
title = {Regulation of Antigenic Variation by Trypanosoma brucei Telomere Proteins Depends on Their Unique DNA Binding Activities.},
journal = {Pathogens (Basel, Switzerland)},
volume = {10},
number = {8},
pages = {},
pmid = {34451431},
issn = {2076-0817},
support = {R01 AI066095/AI/NIAID NIH HHS/United States ; AI066095//National Institute of Allergy and Infectious Diseases/ ; JCYJ20170818104619974//Shenzhen Fundamental Research Program/ ; PolyU 151062/18M//Research Grants Council Hong Kong/ ; },
abstract = {Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen, Variant Surface Glycoprotein (VSG), to evade the host immune response. Such antigenic variation is a key pathogenesis mechanism that enables T. brucei to establish long-term infections. VSG is expressed exclusively from subtelomere loci in a strictly monoallelic manner, and DNA recombination is an important VSG switching pathway. The integrity of telomere and subtelomere structure, maintained by multiple telomere proteins, is essential for T. brucei viability and for regulating the monoallelic VSG expression and VSG switching. Here we will focus on T. brucei TRF and RAP1, two telomere proteins with unique nucleic acid binding activities, and summarize their functions in telomere integrity and stability, VSG switching, and monoallelic VSG expression. Targeting the unique features of TbTRF and TbRAP1's nucleic acid binding activities to perturb the integrity of telomere structure and disrupt VSG monoallelic expression may serve as potential therapeutic strategy against T. brucei.},
}
@article {pmid34449264,
year = {2022},
author = {Gleason, JL and Thoma, ME and Zukerman Willinger, N and Shenassa, ED},
title = {Endometriosis and Uterine Fibroids and Their Associations with Elevated C-Reactive Protein and Leukocyte Telomere Length Among a Representative Sample of U.S. Women: Data from the National Health and Nutrition Examination Survey, 1999-2002.},
journal = {Journal of women's health (2002)},
volume = {31},
number = {7},
pages = {1020-1028},
doi = {10.1089/jwh.2021.0044},
pmid = {34449264},
issn = {1931-843X},
mesh = {Biomarkers ; C-Reactive Protein/metabolism ; Chronic Disease ; *Endometriosis ; Female ; Humans ; Inflammation ; *Leiomyoma/epidemiology ; Leukocytes/metabolism ; Nutrition Surveys ; Telomere/metabolism ; },
abstract = {Background: Recent studies have suggested a link between reproductive health and later-life chronic conditions, yet the mechanism remains unclear. One proposed mechanism is through chronic inflammation. The objective of this study was to examine the association between endometriosis and uterine fibroids and biomarkers of inflammation and cellular aging. Materials and Methods: We used data from the National Health and Nutrition Examination Survey (N = 2342; 1999-2002). Adjusted logistic and linear regression were used to examine the association between these two reproductive conditions and elevated C-reactive protein (CRP; >3.0 mg/L) and leukocyte telomere length (T/S ratio), respectively. Given that a greater length of time spent with a condition may represent persistence of an inflammatory process, we further examined the association between time since disease diagnosis on telomere length among the subset of women with diagnosed endometriosis and fibroids. Results: Women with endometriosis had greater odds of having elevated CRP than those without endometriosis (OR = 1.60; 95% CI: 1.05 to 2.45). Women with endometriosis had a shorter telomere length than women without endometriosis (-3.4, 95% CI: -7.3 to -0.3 in age-adjusted models and -2.9, 95% CI: -8.8 to 3.5 in fully adjusted models). Telomeres were 1% (95% CI: -1.2 to -0.6) shorter for every elapsed year since endometriosis diagnosis. No substantive patterns emerged between uterine fibroids and CRP or telomere length. Conclusions: Women with endometriosis (or a longer duration of time spent with endometriosis) had higher inflammatory markers and shorter mean telomere length. These results provide further insights into potential mechanisms linking endometriosis to chronic disease and later-life health.},
}
@article {pmid34448287,
year = {2022},
author = {Friesen, CR and Wapstra, E and Olsson, M},
title = {Of telomeres and temperature: Measuring thermal effects on telomeres in ectothermic animals.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6069-6086},
doi = {10.1111/mec.16154},
pmid = {34448287},
issn = {1365-294X},
mesh = {Animals ; Temperature ; *Vertebrates ; *Biological Evolution ; Reproduction ; Telomere/genetics ; },
abstract = {Ectotherms are classic models for understanding life-history tradeoffs, including the reproduction-somatic maintenance tradeoffs that may be reflected in telomere length and their dynamics. Importantly, life-history traits of ectotherms are tightly linked to their thermal environment, with diverse or synergistic mechanistic explanations underpinning the variation. Telomere dynamics potentially provide a mechanistic link that can be used to monitor thermal effects on individuals in response to climatic perturbations. Growth rate, age and developmental stage are all affected by temperature, which interacts with telomere dynamics in complex and intriguing ways. The physiological processes underpinning telomere dynamics can be visualized and understood using thermal performance curves (TPCs). TPCs reflect the evolutionary history and the thermal environment during an individual's ontogeny. Telomere maintenance should be enhanced at or near the thermal performance optimum of a species, population and individual. The thermal sensitivity of telomere dynamics should reflect the interacting TPCs of the processes underlying them. The key processes directly underpinning telomere dynamics are mitochondrial function (reactive oxygen production), antioxidant activity, telomerase activity and telomere endcap protein status. We argue that identifying TPCs for these processes will significantly help design robust, repeatable experiments and field studies of telomere dynamics in ectotherms. Conceptually, TPCs are a valuable framework to predict and interpret taxon- and population-specific telomere dynamics across thermal regimes. The literature of thermal effects on telomeres in ectotherms is sparse and mostly limited to vertebrates, but our conclusions and recommendations are relevant across ectothermic animals.},
}
@article {pmid34448238,
year = {2021},
author = {},
title = {Retraction statement: Wang Z, Li J, Liu J, Wang L, Lu Y, Liu J-P. Molecular insight into the selective binding between human telomere G-quadruplex, a negatively charged stabilizer. Clin Exp Pharmacol Physiol. 2020;47:892-902. https://doi.org/10.1111/1440-1681.13249.},
journal = {Clinical and experimental pharmacology &amp; physiology},
volume = {48},
number = {9},
pages = {1300},
doi = {10.1111/1440-1681.13558},
pmid = {34448238},
issn = {1440-1681},
}
@article {pmid34448146,
year = {2021},
author = {Womersley, JS and Spies, G and Tromp, G and Seedat, S and Hemmings, SMJ},
title = {Longitudinal telomere length profile does not reflect HIV and childhood trauma impacts on cognitive function in South African women.},
journal = {Journal of neurovirology},
volume = {27},
number = {5},
pages = {735-749},
pmid = {34448146},
issn = {1538-2443},
support = {P30 AI036214/AI/NIAID NIH HHS/United States ; UL1 TR001442/TR/NCATS NIH HHS/United States ; },
mesh = {*Adverse Childhood Experiences ; Cognition ; Cross-Sectional Studies ; Female ; *HIV Infections/complications/genetics ; Humans ; Longitudinal Studies ; Telomere/genetics ; },
abstract = {HIV-associated neurocognitive disorders (HAND) present a challenge in South Africa where the burden of HIV infection is the highest. Identification of biological correlates of HAND is required to improve diagnosis and inform interventions. Telomeres maintain genomic integrity and their shortening is a marker of biological aging sensitive to environmental influences. This study examined relative telomere length (rTL) as a predictor of cognitive function in the context of HIV and childhood trauma (CT), a risk factor for HAND. Two hundred and eighty-six women completed a neurocognitive assessment battery and the Childhood Trauma Questionnaire-Short Form (CTQ). Quantitative polymerase chain reaction for amplification of telomeric repeats and the reference gene human beta-globin was used to calculate rTL. Neurocognitive and rTL assessments were repeated at 1 year in 110 participants. Cross-sectional and longitudinal data were assessed using linear and mixed models, respectively. Participants with HIV (n = 135 in cross-sectional and n = 62 in longitudinal study groups) reported more severe CT and had shorter baseline rTL compared to seronegative controls. Participants without HIV had a greater 1-year decline in rTL. Global cognitive and attention/working memory scores declined in participants with HIV. Our data indicate that baseline rTL in the context of CT and HIV did not predict decline in cognitive scores. HIV-associated pathophysiological processes driving cognitive decline may also engage mechanisms that protect against telomere shortening. The results highlight the importance of examining biological correlates in longitudinal studies.},
}
@article {pmid34446526,
year = {2021},
author = {Salehian, S and Semple, T and Pabary, R},
title = {Childhood interstitial lung disease: short lessons from telomeres.},
journal = {Thorax},
volume = {76},
number = {12},
pages = {1250-1252},
doi = {10.1136/thoraxjnl-2021-217479},
pmid = {34446526},
issn = {1468-3296},
mesh = {Child ; Humans ; *Lung Diseases, Interstitial/genetics ; Telomere/genetics ; },
}
@article {pmid34444842,
year = {2021},
author = {Paltoglou, G and Raftopoulou, C and Nicolaides, NC and Genitsaridi, SM and Karampatsou, SI and Papadopoulou, M and Kassari, P and Charmandari, E},
title = {A Comprehensive, Multidisciplinary, Personalized, Lifestyle Intervention Program Is Associated with Increased Leukocyte Telomere Length in Children and Adolescents with Overweight and Obesity.},
journal = {Nutrients},
volume = {13},
number = {8},
pages = {},
pmid = {34444842},
issn = {2072-6643},
support = {(project code: T1EDK-01386, MIS: 5030543, Acronym: PEDOBESITY).//This research has been co-financed by the European Regional Development Fund of the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call RESEARCH - CREATE - INNOVATE/ ; },
mesh = {Adolescent ; Aging/*genetics ; Behavior Therapy/methods ; Body Composition ; Body Mass Index ; Child ; Exercise/physiology ; Female ; Humans ; Leukocytes/*pathology ; Life Style ; Male ; Pediatric Obesity/blood/*genetics/therapy ; Program Evaluation ; Prospective Studies ; Telomere/*pathology ; Treatment Outcome ; Waist Circumference ; Weight Reduction Programs/*methods ; },
abstract = {Leucocyte telomere length (LTL) is a robust marker of biological aging and is associated with obesity and cardiometabolic risk factors in childhood and adolescence. We investigated the effect of a structured, comprehensive, multidisciplinary, personalized, lifestyle intervention program of healthy diet and physical exercise on LTL in 508 children and adolescents (239 males, 269 females; 282 prepubertal, 226 pubertal), aged 10.14 ± 0.13 years. Participants were classified as obese (n = 267, 52.6%), overweight (n = 174, 34.2%), or of normal BMI (n = 67, 13.2%) according to the International Obesity Task Force (IOTF) cutoff points and were studied prospectively for one year. We demonstrated that LTL increased significantly after 1 year of the lifestyle interventions, irrespective of gender, pubertal status, or body mass index (BMI). Waist circumference was the best negative predictor of LTL at initial assessment. The implementation of the lifestyle interventions also resulted in a significant improvement in clinical (BMI, BMI z-score and waist to height ratio) and body composition indices of obesity, inflammatory markers, hepatic enzymes, glycated hemoglobin (HbA1C), quantitative insulin sensitivity check index (QUICKI), and lipid profile in all participants. These findings indicate that the increased LTL may be associated with a more favorable metabolic profile and decreased morbidity later in life.},
}
@article {pmid34444746,
year = {2021},
author = {Ruiz-Narváez, EA and Baylin, A and Azofeifa, J and Leal, A and Rosero-Bixby, L},
title = {Diet and Leukocyte Telomere Length in a Population with Extended Longevity: The Costa Rican Longevity and Healthy Aging Study (CRELES).},
journal = {Nutrients},
volume = {13},
number = {8},
pages = {},
pmid = {34444746},
issn = {2072-6643},
support = {072406/Z/03/Z/WT_/Wellcome Trust/United Kingdom ; P30 AG012839/AG/NIA NIH HHS/United States ; R01 AG031716/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging ; Costa Rica ; *Diet ; Fabaceae ; Female ; Food ; Healthy Aging ; Humans ; *Leukocytes ; *Longevity ; Male ; *Telomere ; },
abstract = {Elderly Costa Ricans have lower mortality rates compared to their counterparts from developed countries. Reasons for this survival advantage are not completely known. In the present study, we aimed to identify dietary factors associated with leukocyte telomere length (LTL), a marker of biologic aging, in the elderly population of Costa Rica. We conducted prospective analysis in 909 participants aged 60+ years from the Costa Rican Longevity and Healthy Aging Study (CRELES). We used a food frequency questionnaire to assess usual diet. We calculated dietary patterns using Principal Component Analysis (PCA). We used generalized linear models to examine the association of dietary patterns and food groups with leukocyte telomere length. We found two major dietary patterns explaining 9.15% and 7.18% of the total variation of food intake, respectively. The first dietary pattern, which represents a traditional Costa Rican rice and beans pattern, was more frequent in rural parts of the country and was positively associated with baseline LTL: β (95% CI) = 42.0 base-pairs (bp) (9.9 bp, 74.1 bp) per one-unit increase of the traditional dietary pattern. In analysis of individual food groups, intake of grains was positively associated with baseline LTL: β (95% CI) = 43.6 bp (13.9 bp, 73.3 bp) per one-serving/day increase of consumption of grains. Our results suggest that dietary factors, in particular a traditional food pattern, are associated with telomere length and may contribute to the extended longevity of elderly Costa Ricans.},
}
@article {pmid34441997,
year = {2021},
author = {Pavanello, S and Campisi, M and Grassi, A and Mastrangelo, G and Durante, E and Veronesi, A and Gallucci, M},
title = {Longer Leukocytes Telomere Length Predicts a Significant Survival Advantage in the Elderly TRELONG Cohort, with Short Physical Performance Battery Score and Years of Education as Main Determinants for Telomere Elongation.},
journal = {Journal of clinical medicine},
volume = {10},
number = {16},
pages = {},
pmid = {34441997},
issn = {2077-0383},
support = {175721//Universit&#xe0; degli Studi di Padova/ ; },
abstract = {Leukocyte telomere length (LTL) represents a key integrating component of the cumulative effects of environmental, lifestyle, and genetic factors. A question, however, remains on whether LTL can be considered predictive for a longer and healthier life. Within the elderly prospective TRELONG cohort (n = 612), we aimed to investigate LTL as a predictor of longevity and identify the main determinants of LTL among many different factors (physiological and lifestyle characteristics, physical performance and frailty measures, chronic diseases, biochemical measurements and apolipoprotein E genotyping). We found an ever-increasing relationship between LTL quartiles and survival. Hazard ratio analysis showed that for each unit increase in LTL and Short Physical Performance Battery (SPPB) scores, the mortality risk was reduced by 22.41% and 8.78%, respectively. Conversely, male gender, Charlson Comorbidity Index, and age threatened survival, with mortality risk growing by 74.99%, 16.57% and 8.5%, respectively. Determinants of LTL elongation were SPPB scores (OR = 1.1542; p = 0.0066) and years of education (OR = 1.0958; p = 0.0065), while male gender (OR = 0.4388; p = 0.0143) and increased Disease Count Index (OR = 0.6912; p = 0.0066) were determinants of LTL attrition. Longer LTL predicts a significant survival advantage in elderly people. By identifying determinants of LTL elongation, we provided additional knowledge that could offer a potential translation into prevention strategies.},
}
@article {pmid34440635,
year = {2021},
author = {Kordowitzki, P},
title = {Oxidative Stress Induces Telomere Dysfunction and Shortening in Human Oocytes of Advanced Age Donors.},
journal = {Cells},
volume = {10},
number = {8},
pages = {},
pmid = {34440635},
issn = {2073-4409},
mesh = {Adult ; Age Factors ; DNA Damage ; Female ; Humans ; Maternal Age ; *Oocyte Donation/adverse effects ; Oocytes/*metabolism/pathology ; *Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Risk Assessment ; Risk Factors ; Telomere/*metabolism/pathology ; *Telomere Shortening ; *Tissue Donors ; },
abstract = {Research from the past decades provided strong evidence that in humans the pool of oocytes starts to decline already before the birth of a female individual, and from menarche to menopause the oocyte is exposed to different environmental stimuli. Since more and more women of the 21st century in developed countries wish to postpone the first pregnancy to their thirties, higher rates of miscarriage and chromosomal non-disjunction might occur. In oocytes of advanced maternal age, meaning above 35 years of age, characteristics such as chromosomal instabilities/abnormalities, spindle defects, decreased mitochondrial function and telomere shortening become more prevalent than in younger counterparts. Telomere attrition belongs to the so-called "hallmarks of aging" which are also relevant for the female germ-line cells. In oocytes, telomeres shorten with advancing maternal age due to the effects of reactive oxygen species and not upon replicative senescence, similar to how it is common in dividing cells.},
}
@article {pmid34440552,
year = {2021},
author = {Carugno, M and Borroni, E and Fedrizzi, L and Hoxha, M and Vigna, L and Consonni, D and Bollati, V and Pesatori, AC},
title = {Long- and Short-Term Exposures to PM10 Can Shorten Telomere Length in Individuals Affected by Overweight and Obesity.},
journal = {Life (Basel, Switzerland)},
volume = {11},
number = {8},
pages = {},
pmid = {34440552},
issn = {2075-1729},
support = {ERC-2011-StG 282413/ERC_/European Research Council/International ; },
abstract = {Reduced telomere length (TL) has been associated with increased risk of age-related diseases, most likely through oxidative stress and inflammation, which have also been claimed as mechanisms underlying health effects of air pollution exposure. We aimed to verify whether exposure to particulate matter with diameter ≤10 µm (PM10) affects TL. We recruited 1792 participants with overweight/obesity in Milan (Italy) in 2010-2015 who completed a structured questionnaire on sociodemographic data, gave a blood sample for TL measurement by real-time PCR, and were assigned air pollution and meteorological data of their residential address. In multivariate mixed-effects linear models (with a random intercept on PCR plate), we observed a -0.51% change in TL (95% confidence interval (CI): -0.98; -0.05)) per 10 µg/m[3] increase in PM10 at the day of recruitment. A similar decreasing trend in TL was observed up to two weeks before withdrawal, with percentage changes as low as -1.53% (average exposure of the 12 days before recruitment). Mean annual exposure to PM10 was associated with -2.57% TL reduction (95%CI: -5.06; -0.08). By showing consistent associations between short- and long-term PM10 exposures and reduced TL, our findings shed light on the potential mechanisms responsible for the excess of age-related diseases associated with air pollution exposure.},
}
@article {pmid34439779,
year = {2021},
author = {Akter, J and Kamijo, T},
title = {How Do Telomere Abnormalities Regulate the Biology of Neuroblastoma?.},
journal = {Biomolecules},
volume = {11},
number = {8},
pages = {},
pmid = {34439779},
issn = {2218-273X},
mesh = {Antineoplastic Agents/therapeutic use ; Child ; Gene Expression Regulation, Neoplastic ; *Genome, Human ; Genomic Instability ; Humans ; Mutation ; N-Myc Proto-Oncogene Protein/*genetics/metabolism ; Neoplasm Metastasis ; Nervous System Neoplasms/drug therapy/*genetics/mortality/pathology ; Neuroblastoma/drug therapy/*genetics/mortality/pathology ; Risk Factors ; Signal Transduction ; Survival Analysis ; Telomerase/*genetics/metabolism ; Telomere/*chemistry/drug effects/pathology ; Telomere Homeostasis ; X-linked Nuclear Protein/*genetics/metabolism ; },
abstract = {Telomere maintenance plays important roles in genome stability and cell proliferation. Tumor cells acquire replicative immortality by activating a telomere-maintenance mechanism (TMM), either telomerase, a reverse transcriptase, or the alternative lengthening of telomeres (ALT) mechanism. Recent advances in the genetic and molecular characterization of TMM revealed that telomerase activation and ALT define distinct neuroblastoma (NB) subgroups with adverse outcomes, and represent promising therapeutic targets in high-risk neuroblastoma (HRNB), an aggressive childhood solid tumor that accounts for 15% of all pediatric-cancer deaths. Patients with HRNB frequently present with widely metastatic disease, with tumors harboring recurrent genetic aberrations (MYCN amplification, TERT rearrangements, and ATRX mutations), which are mutually exclusive and capable of promoting TMM. This review provides recent insights into our understanding of TMM in NB tumors, and highlights emerging therapeutic strategies as potential treatments for telomerase- and ALT-positive tumors.},
}
@article {pmid34437736,
year = {2022},
author = {Remot, F and Ronget, V and Froy, H and Rey, B and Gaillard, JM and Nussey, DH and Lemaitre, JF},
title = {Decline in telomere length with increasing age across nonhuman vertebrates: A meta-analysis.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {5917-5932},
doi = {10.1111/mec.16145},
pmid = {34437736},
issn = {1365-294X},
support = {P51 RR000165/RR/NCRR NIH HHS/United States ; P51 RR013986/RR/NCRR NIH HHS/United States ; },
mesh = {Adult ; Humans ; Animals ; *Aging/genetics ; *Vertebrates/genetics ; Telomere/genetics ; Telomere Shortening/genetics ; },
abstract = {The prediction that telomere length (TL) shortens with increasing age is a major element in considering the role of telomeres as a key player in evolution. While telomere attrition is found in humans both in vitro and in vivo, the increasing number of studies reporting diverse age-specific patterns of TL challenges the hypothesis of a universal decline of TL with increasing age. Here, we performed a meta-analysis to estimate the relationship between TL and age across 175 estimates encompassing 98 species of vertebrates. We found that, on average, TL does decline with increasing age during adulthood. However, this decline was weak and variable across vertebrate classes, and we also found evidence for a publication bias that might weaken our current evidence of decreasing TL with increasing age. We found no evidence for a faster decline in TL with increasing age when considering the juvenile stage (from birth to age at first reproduction) compared to the adult stage. Heterogeneity in TL ageing rates was explained by the method used to measure telomeres: detectable TL declines with increasing age were found only among studies using TRF with in-gel hybridisation and qFISH methods, but not in studies using qPCR and Southern blot-based TRF methods. While we confirmed that TL declines with increasing age in most adult vertebrates, our results identify an influence of telomere measurement methodology, which highlights the need to examine more thoroughly the effect of the method of measurement on TL estimates.},
}
@article {pmid34436787,
year = {2021},
author = {Glousker, G and Lingner, J},
title = {Challenging endings: How telomeres prevent fragility.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {43},
number = {10},
pages = {e2100157},
doi = {10.1002/bies.202100157},
pmid = {34436787},
issn = {1521-1878},
mesh = {Chromatin/genetics ; DNA Repair/genetics ; *DNA Replication/genetics ; Homologous Recombination ; *Telomere/genetics ; },
abstract = {It has become apparent that difficulties to replicate telomeres concern not only the very ends of eukaryotic chromosomes. The challenges already start when the replication fork enters the telomeric repeats. The obstacles encountered consist mainly of noncanonical nucleic acid structures that interfere with replication if not resolved. Replication stress at telomeres promotes the formation of so-called fragile telomeres displaying an abnormal appearance in metaphase chromosomes though their exact molecular nature remains to be elucidated. A substantial number of factors is required to counteract fragility. In this review we promote the hypothesis that telomere fragility is not caused directly by an initial insult during replication but it results as a secondary consequence of DNA repair of damaged replication forks by the homologous DNA recombination machinery. Incomplete DNA synthesis at repair sites or partial chromatin condensation may become apparent as telomere fragility. Fragility and DNA repair during telomere replication emerges as a common phenomenon which exacerbates in multiple disease conditions.},
}
@article {pmid34435398,
year = {2022},
author = {Metcalfe, NB and Olsson, M},
title = {How telomere dynamics are influenced by the balance between mitochondrial efficiency, reactive oxygen species production and DNA damage.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6040-6052},
doi = {10.1111/mec.16150},
pmid = {34435398},
issn = {1365-294X},
mesh = {Humans ; Reactive Oxygen Species/metabolism ; *DNA Damage ; *Oxidative Stress/genetics ; Mitochondria/genetics/metabolism ; Telomere/genetics ; Adenosine Triphosphate/metabolism ; },
abstract = {It is well known that oxidative stress is a major cause of DNA damage and telomere attrition. Most endogenous reactive oxygen species (ROS) are produced in the mitochondria, producing a link between mitochondrial function, DNA integrity and telomere dynamics. In this review we will describe how ROS production, rates of damage to telomeric DNA and DNA repair are dynamic processes. The rate of ROS production depends on mitochondrial features such as the level of inner membrane uncoupling and the proportion of time that ATP is actively being produced. However, the efficiency of ATP production (the ATP/O ratio) is positively related to the rate of ROS production, so leading to a trade-off between the body's energy requirements and its need to prevent oxidative stress. Telomeric DNA is especially vulnerable to oxidative damage due to features such as its high guanine content; while repair to damaged telomere regions is possible through a range of mechanisms, these can result in more rapid telomere shortening. There is increasing evidence that mitochondrial efficiency varies over time and with environmental context, as do rates of DNA repair. We argue that telomere dynamics can only be understood by appreciating that the optimal solution to the trade-off between energetic efficiency and telomere protection will differ between individuals and will change over time, depending on resource availability, energetic demands and life history strategy.},
}
@article {pmid34434216,
year = {2021},
author = {Rahnama, M and Wang, B and Dostart, J and Novikova, O and Yackzan, D and Yackzan, A and Bruss, H and Baker, M and Jacob, H and Zhang, X and Lamb, A and Stewart, A and Heist, M and Hoover, J and Calie, P and Chen, L and Liu, J and Farman, ML},
title = {Telomere Roles in Fungal Genome Evolution and Adaptation.},
journal = {Frontiers in genetics},
volume = {12},
number = {},
pages = {676751},
pmid = {34434216},
issn = {1664-8021},
support = {P30 CA177558/CA/NCI NIH HHS/United States ; },
abstract = {Telomeres form the ends of linear chromosomes and usually comprise protein complexes that bind to simple repeated sequence motifs that are added to the 3' ends of DNA by the telomerase reverse transcriptase (TERT). One of the primary functions attributed to telomeres is to solve the "end-replication problem" which, if left unaddressed, would cause gradual, inexorable attrition of sequences from the chromosome ends and, eventually, loss of viability. Telomere-binding proteins also protect the chromosome from 5' to 3' exonuclease action, and disguise the chromosome ends from the double-strand break repair machinery whose illegitimate action potentially generates catastrophic chromosome aberrations. Telomeres are of special interest in the blast fungus, Pyricularia, because the adjacent regions are enriched in genes controlling interactions with host plants, and the chromosome ends show enhanced polymorphism and genetic instability. Previously, we showed that telomere instability in some P. oryzae strains is caused by novel retrotransposons (MoTeRs) that insert in telomere repeats, generating interstitial telomere sequences that drive frequent, break-induced rearrangements. Here, we sought to gain further insight on telomeric involvement in shaping Pyricularia genome architecture by characterizing sequence polymorphisms at chromosome ends, and surrounding internalized MoTeR loci (relics) and interstitial telomere repeats. This provided evidence that telomere dynamics have played historical, and likely ongoing, roles in shaping the Pyricularia genome. We further demonstrate that even telomeres lacking MoTeR insertions are poorly preserved, such that the telomere-adjacent sequences exhibit frequent presence/absence polymorphism, as well as exchanges with the genome interior. Using TERT knockout experiments, we characterized chromosomal responses to failed telomere maintenance which suggested that much of the MoTeR relic-/interstitial telomere-associated polymorphism could be driven by compromised telomere function. Finally, we describe three possible examples of a phenomenon known as "Adaptive Telomere Failure," where spontaneous losses of telomere maintenance drive rapid accumulation of sequence polymorphism with possible adaptive advantages. Together, our data suggest that telomere maintenance is frequently compromised in Pyricularia but the chromosome alterations resulting from telomere failure are not as catastrophic as prior research would predict, and may, in fact, be potent drivers of adaptive polymorphism.},
}
@article {pmid34430678,
year = {2021},
author = {Kotah, JM and Hoeijmakers, L and Nutma, E and Lucassen, PJ and Korosi, A},
title = {Early-life stress does not alter spatial memory performance, hippocampal neurogenesis, neuroinflammation, or telomere length in 20-month-old male mice.},
journal = {Neurobiology of stress},
volume = {15},
number = {},
pages = {100379},
pmid = {34430678},
issn = {2352-2895},
abstract = {Early-life stress (ES) increases the risk for psychopathology and cognitive decline later in life. Because the neurobiological substrates affected by ES (i.e., cognition, neuroplasticity, and neuroinflammation) are also altered in aging, we set out to investigate if and how ES in the first week of life affects these domains at an advanced age, and how ES modulates the aging trajectory per se. We subjected C57BL/6j mice to an established ES mouse model from postnatal days 2-9. Mice underwent behavioral testing at 19 months of age and were sacrificed at 20 months to investigate their physiology, hippocampal neuroplasticity, neuroinflammation, and telomere length. ES mice, as a group, did not perform differently from controls in the open field or Morris water maze (MWM). Hippocampal neurogenesis and synaptic marker gene expression were not different in ES mice at this age. While we find aging-associated alterations to neuroinflammatory gene expression and telomere length, these were unaffected by ES. When integrating the current data with those from our previously reported 4- and 10-month-old cohorts, we conclude that ES leads to a 'premature' shift in the aging trajectory, consisting of early changes that do not further worsen at the advanced age of 20 months. This could be explained e.g. by a 'floor' effect in ES-induced impairments, and/or age-induced impairments in control mice. Future studies should help understand how exactly ES affects the overall aging trajectory.},
}
@article {pmid34428605,
year = {2021},
author = {Niu, Z and Wen, X and Buka, SL and Wang, M and Tian, L and Loucks, EB and Kubzansky, LD and Mu, L},
title = {Associations of telomere length at birth with predicted atherosclerotic lesions and cardiovascular disease risk factors in midlife: A 40-year longitudinal study.},
journal = {Atherosclerosis},
volume = {333},
number = {},
pages = {67-74},
doi = {10.1016/j.atherosclerosis.2021.08.013},
pmid = {34428605},
issn = {1879-1484},
support = {R21 HD091515/HD/NICHD NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; *Atherosclerosis/diagnosis/epidemiology/genetics ; *Cardiovascular Diseases/diagnosis/epidemiology/genetics ; Female ; Humans ; Longitudinal Studies ; Middle Aged ; Pregnancy ; Risk Factors ; Telomere ; },
abstract = {BACKGROUND AND AIMS: Adult telomere length (TL) is substantially determined by birth TL, but associations of birth TL with cardiovascular disease (CVD) are unknown.<br><br>METHODS: We included 144 adult offspring born in 1959-1966 from the Collaborative Perinatal Project, a US birth cohort. Birth TL was measured from banked cord blood with quantitative polymerase chain reaction. Atherosclerotic lesions were predicted by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) score that was based on blood pressure, lipids, hemoglobin A1c, and body weight at the midlife follow-up in 2003-2008 (average age: 42 years). Information on midlife CVD risk factors including the age at first diagnoses of hypertension, hypercholesterolemia, and diabetes was also collected. We used linear and logistic regression models to analyze associations of birth TL with the continuous PDAY score and categorical CVD risk factors, respectively, adjusting for prenatal confounders.<br><br>RESULTS: At midlife follow-up, 31.2% and 18.7% of participants had ever been diagnosed with hypercholesterolemia and hypertension, respectively, and 8.3% met the criteria for metabolic syndrome. Short birth TL (Quartile 1, Q1) was associated with a higher PDAY score (adjusted &#x3b2;: 1.78, 95% CI: 0.31, 3.25), increased odds of hypercholesterolemia (adjusted odds ratio [OR]: 3.23, 95% CI: 1.28, 8.18) and the presence of any cardiometabolic abnormalities (adjusted OR: 2.54, 95% CI: 1.00, 6.48) as compared to longer birth TL (Q2-Q4) after adjusting for prenatal confounders.<br><br>CONCLUSIONS: People born with short TL may be at increased risk of predicted midlife atherosclerotic lesions and hypercholesterolemia. Future studies with larger sample sizes and CVD morbidities are warranted to replicate our findings.},
}
@article {pmid34421981,
year = {2021},
author = {Sellami, M and Bragazzi, N and Prince, MS and Denham, J and Elrayess, M},
title = {Regular, Intense Exercise Training as a Healthy Aging Lifestyle Strategy: Preventing DNA Damage, Telomere Shortening and Adverse DNA Methylation Changes Over a Lifetime.},
journal = {Frontiers in genetics},
volume = {12},
number = {},
pages = {652497},
pmid = {34421981},
issn = {1664-8021},
abstract = {Exercise training is one of the few therapeutic interventions that improves health span by delaying the onset of age-related diseases and preventing early death. The length of telomeres, the 5'-TTAGGG [n] -3' tandem repeats at the ends of mammalian chromosomes, is one of the main indicators of biological age. Telomeres undergo shortening with each cellular division. This subsequently leads to alterations in the expression of several genes that encode vital proteins with critical functions in many tissues throughout the body, and ultimately impacts cardiovascular, immune and muscle physiology. The sub-telomeric DNA is comprised of heavily methylated, heterochromatin. Methylation and histone acetylation are two of the most well-studied examples of the epigenetic modifications that occur on histone proteins. DNA methylation is the type of epigenetic modification that alters gene expression without modifying gene sequence. Although diet, genetic predisposition and a healthy lifestyle seem to alter DNA methylation and telomere length (TL), recent evidence suggests that training status or physical fitness are some of the major factors that control DNA structural modifications. In fact, TL is positively associated with cardiorespiratory fitness, physical activity level (sedentary, active, moderately trained, or elite) and training intensity, but is shorter in over-trained athletes. Similarly, somatic cells are vulnerable to exercise-induced epigenetic modification, including DNA methylation. Exercise-training load, however, depends on intensity and volume (duration and frequency). Training load-dependent responses in genomic profiles could underpin the discordant physiological and physical responses to exercise. In the current review, we will discuss the role of various forms of exercise training in the regulation of DNA damage, TL and DNA methylation status in humans, to provide an update on the influence exercise training has on biological aging.},
}
@article {pmid34408079,
year = {2021},
author = {Koneru, B and Farooqi, A and Nguyen, TH and Chen, WH and Hindle, A and Eslinger, C and Makena, MR and Burrow, TA and Wilson, J and Smith, A and Pilla Reddy, V and Cadogan, E and Durant, ST and Reynolds, CP},
title = {ALT neuroblastoma chemoresistance due to telomere dysfunction-induced ATM activation is reversible with ATM inhibitor AZD0156.},
journal = {Science translational medicine},
volume = {13},
number = {607},
pages = {},
pmid = {34408079},
issn = {1946-6242},
support = {R01 CA217251/CA/NCI NIH HHS/United States ; R01 CA221957/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; *Ataxia Telangiectasia ; Ataxia Telangiectasia Mutated Proteins ; Drug Resistance, Neoplasm ; Humans ; Mice ; Neoplasm Recurrence, Local ; *Neuroblastoma/drug therapy ; Pyridines ; Quinolines ; Telomere ; Telomere Homeostasis ; },
abstract = {Cancers overcome replicative immortality by activating either telomerase or an alternative lengthening of telomeres (ALT) mechanism. ALT occurs in ~25% of high-risk neuroblastomas, and progression in patients with ALT neuroblastoma during or after front-line therapy is frequent and often fatal. Temozolomide + irinotecan is commonly used as salvage therapy for neuroblastoma. Patient-derived cell lines and xenografts established from patients with relapsed ALT neuroblastoma demonstrated de novo resistance to temozolomide + irinotecan [SN-38 in vitro, P < 0.05; in vivo mouse event-free survival (EFS), P < 0.0001] vs. telomerase-positive neuroblastomas. We observed that ALT neuroblastoma cells manifested constitutive ataxia-telangiectasia mutated (ATM) activation due to spontaneous telomere dysfunction which was not observed in telomerase-positive neuroblastoma cells. We demonstrated that induction of telomere dysfunction resulted in ATM activation that, in turn, conferred resistance to temozolomide + SN-38 (4.2-fold change in IC50, P < 0.001). ATM knockdown (shRNA) or inhibition using a clinical-stage small-molecule inhibitor (AZD0156) reversed resistance to temozolomide + irinotecan in ALT neuroblastoma cell lines in vitro (P < 0.001) and in four ALT xenografts in vivo (EFS, P < 0.0001). AZD0156 showed modest to no enhancement of temozolomide + irinotecan activity in telomerase-positive neuroblastoma cell lines and xenografts. Ataxia telangiectasia and Rad3 related (ATR) inhibition using AZD6738 did not enhance temozolomide + SN-38 activity in ALT neuroblastoma cells. Thus, ALT neuroblastoma chemotherapy resistance occurs via ATM activation and is reversible with ATM inhibitor AZD0156. Combining AZD0156 with temozolomide + irinotecan warrants clinical testing for neuroblastoma.},
}
@article {pmid34407217,
year = {2022},
author = {Jeon, HJ and Kang, M and Kim, JS and Oh, JS},
title = {TCTP overexpression reverses age-associated telomere attrition by upregulating telomerase activity in mouse oocytes.},
journal = {Journal of cellular physiology},
volume = {237},
number = {1},
pages = {833-845},
doi = {10.1002/jcp.30557},
pmid = {34407217},
issn = {1097-4652},
mesh = {Animals ; Female ; Mice ; Oocytes/metabolism ; Oogenesis ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; Telomere Shortening ; Tumor Protein, Translationally-Controlled 1/*metabolism ; },
abstract = {A prolonged time span between ovulation and fertilization can cause postovulatory aging of oocytes, which impairs oocyte quality and subsequent embryo development. Telomere attrition has long been considered as the primary hallmark of aging or the cause of age-associated diseases. However, the status of telomere and its regulation during postovulatory oocyte aging are poorly understood. Here we found that oocytes experience telomere shortening during postovulatory aging, although they have the capacity to maintain telomere length. However, translationally controlled tumor protein (TCTP) overexpression could reverse age-associated telomere shortening by upregulating telomerase activity in mouse oocytes. Telomere length in mature oocytes gradually decreased with postovulatory aging, which was associated with a marked reduction in TRF1 expression, decreased telomerase activity, and decreased homologous combination (HR)-based alternative lengthening of telomeres (ALT) with a concomitant increase in oxidative stress. Surprisingly, however, overexpression of TCTP led to a remarkable increase in telomere length during postovulatory aging. Notably, neither TRF1 nor BRCA1 level was altered by TCTP overexpression. Moreover, TCTP-mediated telomere lengthening was not blocked by HR inhibition. In striking contrast, telomerase activity, as well as TERT and TERC levels, increased after TCTP overexpression. Importantly, unlike the chromosome-wide distribution of endogenous TCTP, overexpressed TCTP was ectopically localized at telomeres, implying that TCTP overexpression is required to increase telomerase activity. Collectively, our results demonstrate that TCTP prevents telomere attrition during postovulatory aging by upregulating telomerase activity in mouse oocytes.},
}
@article {pmid34407110,
year = {2021},
author = {Geronimus, AT and Bound, J and Mitchell, C and Martinez-Cardoso, A and Evans, L and Hughes, L and Schneper, L and Notterman, DA},
title = {Coming up short: Comparing venous blood, dried blood spots &amp; saliva samples for measuring telomere length in health equity research.},
journal = {PloS one},
volume = {16},
number = {8},
pages = {e0255237},
pmid = {34407110},
issn = {1932-6203},
support = {T32 AG000221/AG/NIA NIH HHS/United States ; T32 HD007339/HD/NICHD NIH HHS/United States ; P30 AG012846/AG/NIA NIH HHS/United States ; R01 MD011716/MD/NIMHD NIH HHS/United States ; P2C HD041028/HD/NICHD NIH HHS/United States ; R01 AG047167/AG/NIA NIH HHS/United States ; R01 HD076592/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Dried Blood Spot Testing/*methods ; *Health Equity ; Humans ; Leukocytes, Mononuclear/metabolism ; Michigan ; Middle Aged ; *Research ; Saliva/*metabolism ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Telomere length (TL) in peripheral blood mononuclear cells (PBMC) from fresh venous blood is increasingly used to estimate molecular impacts of accumulated social adversity on population health. Sometimes, TL extracted from saliva or dried blood spots (DBS) are substituted as less invasive and more scalable specimen collection methods; yet, are they interchangeable with fresh blood? Studies find TL is correlated across tissues, but have not addressed the critical question for social epidemiological applications: Do different specimen types show the same association between TL and social constructs?<br><br>METHODS: We integrate expertise in social epidemiology, molecular biology, and the statistical impact of measurement error on parameter estimates. Recruiting a diverse sample of 132 Metro-Detroit women, we measure TL for each woman from fresh blood PBMC, DBS, and saliva. Using regression methods, we estimate associations between social characteristics and TL, comparing estimates across specimen types for each woman.<br><br>RESULTS: Associations between TL and social characteristics vary by specimen type collected from the same woman, sometimes qualitatively altering estimates of the magnitude or direction of a theorized relationship. Being Black is associated with shorter TL in PBMC, but longer TL in saliva or DBS. Education is positively associated with TL in fresh blood, but negatively associated with TL using DBS.<br><br>CONCLUSION: Findings raise concerns about the use of TL measures derived from different tissues in social epidemiological research. Investigators need to consider the possibility that associations between social variables and TL may be systematically related to specimen type, rather than be valid indicators of socially-patterned biopsychosocial processes.},
}
@article {pmid34406239,
year = {2021},
author = {Teixeira, MZ},
title = {Telomere length: biological marker of cellular vitality, aging, and health-disease process.},
journal = {Revista da Associacao Medica Brasileira (1992)},
volume = {67},
number = {2},
pages = {173-177},
doi = {10.1590/1806-9282.67.02.20200655},
pmid = {34406239},
issn = {1806-9282},
mesh = {Aging/genetics ; Biomarkers ; *COVID-19 ; Humans ; Pandemics ; SARS-CoV-2 ; *Telomere/genetics ; },
abstract = {The aging process occurs due to the decline of vital physiological functions and adaptability of the body, being influenced by genetics and lifestyle. With advances in genetics, biological aging can be calculated by telomere length. Telomeres are regions at the ends of chromosomes that play a role in the maintenance and integrity of DNA. With biological aging, telomere shortening occurs, causing cellular senescence. Several studies show that shorter telomeres are associated with acute and chronic diseases, stress, addictions, and intoxications. Even in the current COVID-19 pandemic, telomere shortening is proposed as a marker of severity in individuals infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On the other hand, healthy lifestyle habits increase telomere length and balance of various cellular functions, preventing diseases.},
}
@article {pmid34401283,
year = {2021},
author = {Singh, M and Merwat, SK and Fair, JH and Duarte, AG},
title = {Liver transplant recipient with respiratory failure due to pulmonary fibrosis related to telomere disease requiring lung transplantation.},
journal = {Respiratory medicine case reports},
volume = {33},
number = {},
pages = {101443},
pmid = {34401283},
issn = {2213-0071},
abstract = {Short telomere syndrome (STS) is characterized as multiorgan dysfunction presenting with unexplained cytopenias, cryptogenic cirrhosis and pulmonary fibrosis. We present a liver transplant recipient that gradually developed hypoxic respiratory failure attributed to idiopathic pulmonary fibrosis associated telomere disease that culminated in a successful single lung transplantation.},
}
@article {pmid34395476,
year = {2021},
author = {Planas-Cerezales, L and Arias-Salgado, EG and Berastegui, C and Montes-Worboys, A and González-Montelongo, R and Lorenzo-Salazar, JM and Vicens-Zygmunt, V and Garcia-Moyano, M and Dorca, J and Flores, C and Perona, R and Román, A and Molina-Molina, M},
title = {Lung Transplant Improves Survival and Quality of Life Regardless of Telomere Dysfunction.},
journal = {Frontiers in medicine},
volume = {8},
number = {},
pages = {695919},
pmid = {34395476},
issn = {2296-858X},
abstract = {Introduction: Fibrotic interstitial lung diseases (ILDs) are the first indication for lung transplantation (LT). Telomere dysfunction has been associated with poor post-transplant outcomes. The aim of the study was to evaluate the morbi-mortality and quality of life in fibrotic ILDs after lung transplant depending on telomere biology. Methods: Fibrotic ILD patients that underwent lung transplant were allocated to two arms; with or without telomere dysfunction at diagnosis based on the telomere length and telomerase related gene mutations revealed by whole-exome sequencing. Post-transplant evaluation included: (1) short and long-term mortality and complications and (2) quality of life. Results: Fifty-five percent of patients that underwent LT carried rare coding mutations in telomerase-related genes. Patients with telomere shortening more frequently needed extracorporeal circulation and presented a higher rate of early post-transplant hematological complications, longer stay in the intensive care unit (ICU), and a higher number of long-term hospital admissions. However, post-transplant 1-year survival was higher than 80% regardless of telomere dysfunction, with improvement in the quality of life and oxygen therapy withdrawal. Conclusions: Post-transplant morbidity is higher in patients with telomere dysfunction and differs according to elapsed time from transplantation. However, lung transplant improves survival and quality of life and the associated complications are manageable.},
}
@article {pmid34395152,
year = {2021},
author = {Adibkia, K and Ehsani, A and Jodaei, A and Fathi, E and Farahzadi, R and Barzegar-Jalali, M},
title = {Silver nanoparticles induce the cardiomyogenic differentiation of bone marrow derived mesenchymal stem cells via telomere length extension.},
journal = {Beilstein journal of nanotechnology},
volume = {12},
number = {},
pages = {786-797},
pmid = {34395152},
issn = {2190-4286},
abstract = {Finding new strategies for the treatment of heart failures using stem cells has attracted a lot of attention. Meanwhile, nanotechnology-based approaches to regenerative medicine hypothesize a possible combination of stem cells and nanotechnology in the treatment of diseases. This study aims to investigate the in vitro effect of silver nanoparticles (Ag-NPs) on the cardiomyogenic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs) through detection of cardiac markers. For this purpose, MSCs were isolated from bone marrow resident and differentiated to the cardiac cells using a dedicated medium with Ag-NPs. Also, the cardiomyogenic differentiation of BM-MSCs was confirmed using immunocytochemistry. Then, real-time PCR and western blotting assay were used for measuring absolute telomere length (TL) measurement, and gene and protein assessment of the cells, respectively. It was found that 2.5 µg/mL Ag-NPs caused elongation of the telomeres and altered VEGF, C-TnI, VWF, SMA, GATA-4, TERT, and cyclin D protein and gene expression in the cardiomyogenically differentiated BM-MSCs. Also, there was a significant increase in the protein and gene expression of Wnt3 and β-catenin as main components of pathways. We concluded that Ag-NPs could change the in vitro expression of cardiac markers of BM-MSCs via the Wnt3/β-catenin signaling pathway.},
}
@article {pmid34393992,
year = {2021},
author = {Zhang, Y and Xu, Z and Yang, Y and Cao, S and Lyu, S and Duan, W},
title = {Association Between Weight Change and Leukocyte Telomere Length in U.S. Adults.},
journal = {Frontiers in endocrinology},
volume = {12},
number = {},
pages = {650988},
pmid = {34393992},
issn = {1664-2392},
mesh = {Adult ; Aged ; *Aging ; Body Mass Index ; *Body Weight ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/*cytology/metabolism ; Linear Models ; Male ; Middle Aged ; Multivariate Analysis ; Nutrition Surveys ; Obesity/complications/genetics ; Overweight ; Telomere/*ultrastructure ; Telomere Shortening ; United States ; *Weight Gain ; },
abstract = {OBJECTIVE: To investigate the association of dynamic weight change in adulthood with leukocyte telomere length among U.S. adults.<br><br>METHODS: This study included 3,886 subjects aged 36-75 years from the National Health and Nutrition Examination Survey (NHANES) 1999-2002 cycle. Survey-weighted multivariable linear regression with adjustments for potential confounders was utilized.<br><br>RESULTS: 3,386 individuals were finally included. People with stable obesity had a 0.130 kbp (95% CI: 0.061-0.198, P=1.97E-04) shorter leukocyte telomere length than those with stable normal weight (reference group) during the 10-year period, corresponding to approximately 8.7 years of aging. Weight gain from non-obesity to obesity shortened the leukocyte telomere length by 0.094 kbp (95% CI: 0.012-0.177, P=0.026), while normal weight to overweight or remaining overweight shortened the leukocyte telomere length by 0.074 kbp (95% CI: 0.014-0.134, P=0.016). The leukocyte telomere length has 0.003 kbp attrition on average for every 1&#xa0;kg increase in weight from a mean age of 41 years to 51 years. Further stratified analysis showed that the associations generally varied across sex and race/ethnicity.<br><br>CONCLUSIONS: This study found that weight changes during a 10-year period was associated with leukocyte telomere length and supports the theory that weight gain promotes aging across adulthood.},
}
@article {pmid34390428,
year = {2021},
author = {Page, RL and Han, G and Akinlotan, M and Patron, MP and Gandhi, H and Kochan, KJ},
title = {Telomere Length and Preterm Birth in Pregnant Mexican-Origin Women.},
journal = {Maternal and child health journal},
volume = {25},
number = {11},
pages = {1798-1805},
pmid = {34390428},
issn = {1573-6628},
mesh = {Female ; Humans ; Infant, Newborn ; Pilot Projects ; Pregnancy ; Pregnant Women ; *Premature Birth/epidemiology ; Prospective Studies ; Telomere ; Telomere Shortening ; },
abstract = {OBJECTIVES: Despite the obstacles of limited education and employment opportunities-and the stress associated with immigration and pregnancy-Mexican immigrant women have low rates of preterm birth (PTB) compared to the US national average for all races and ethnicities. Stressors during pregnancy, and stressors associated with acculturation, may accelerate cellular aging manifested by shortened telomere length (TL) in pregnant women. Our objectives were to: (1) determine whether women with PTBs had shorter telomere lengths compared to women who had full term births; (2) assess the association of acculturation with TL and PTB.<br><br>METHODS: This prospective pilot study collected data from 100 self-identified Mexican-origin pregnant women. Survey data included self-administered sociodemographic and acculturation measures and was collected from participants via paper and pen, while biologic data was collected via a single blood draw during a regularly scheduled prenatal visit between 26 and 36&#xa0;weeks gestation. PTB data was collected from the participant's medical record after delivery.<br><br>RESULTS: TL was significantly associated with PTB; the median TL of the women with PTB was less than the median TL for the full sample (p&#x2009;=&#x2009;0.02). Based on regression analysis for PTB vs acculturation, we found no significant associations between acculturation and PTB or TL.<br><br>CONCLUSIONS FOR PRACTICE: This study provides important evidence of the association between shortened maternal TL and adverse birth outcomes. By linking social, clinical and biologic data, we can enhance our understanding of social determinants that may affect racial and ethnic disparities in preterm birth.},
}
@article {pmid34390055,
year = {2021},
author = {Shan, W and Kubová, M and Mandáková, T and Lysak, MA},
title = {Nuclear organization in crucifer genomes: nucleolus-associated telomere clustering is not a universal interphase configuration in Brassicaceae.},
journal = {The Plant journal : for cell and molecular biology},
volume = {108},
number = {2},
pages = {528-540},
doi = {10.1111/tpj.15459},
pmid = {34390055},
issn = {1365-313X},
mesh = {Arabidopsis/genetics ; Arabis/genetics ; Brassicaceae/*genetics ; Cell Nucleolus/*genetics ; Centromere/genetics ; Chromatin/genetics ; DNA, Ribosomal/genetics ; Genome Size ; *Genome, Plant ; Heterochromatin/genetics ; In Situ Hybridization, Fluorescence ; Interphase ; Phylogeny ; Telomere/*genetics ; },
abstract = {Arabidopsis thaliana has become a major plant research model, where interphase nuclear organization exhibits unique features, including nucleolus-associated telomere clustering. The chromocenter (CC)-loop model, or rosette-like configuration, describes intranuclear chromatin organization in Arabidopsis as megabase-long loops anchored in, and emanating from, peripherally positioned CCs, with those containing telomeres associating with the nucleolus. To investigate whether the CC-loop organization is universal across the mustard family (crucifers), the nuclear distributions of centromeres, telomeres and nucleoli were analyzed by fluorescence in situ hybridization in seven diploid species (2n = 10-16) representing major crucifer clades with an up to 26-fold variation in genome size (160-4260 Mb). Nucleolus-associated telomere clustering was confirmed in Arabidopsis (157 Mb) and was newly identified as the major nuclear phenotype in other species with a small genome (215-381 Mb). In large-genome species (2611-4264 Mb), centromeres and telomeres adopted a Rabl-like configuration or dispersed distribution in the nuclear interior; telomeres only rarely associated with the nucleolus. In Arabis cypria (381 Mb) and Bunias orientalis (2611 Mb), tissue-specific patterns deviating from the major nuclear phenotypes were observed in anther and stem tissues, respectively. The rosette-like configuration, including nucleolus-associated telomere clustering in small-genome species from different infrafamiliar clades, suggests that genomic properties rather than phylogenetic position determine the interphase nuclear organization. Our data suggest that nuclear genome size, average chromosome size and degree of longitudinal chromosome compartmentalization affect interphase chromosome organization in crucifer genomes.},
}
@article {pmid34388352,
year = {2021},
author = {Degradi, L and Tava, V and Kunova, A and Cortesi, P and Saracchi, M and Pasquali, M},
title = {Telomere to Telomere Genome Assembly of Fusarium musae F31, Causal Agent of Crown Rot Disease of Banana.},
journal = {Molecular plant-microbe interactions : MPMI},
volume = {34},
number = {12},
pages = {1455-1457},
doi = {10.1094/MPMI-05-21-0127-A},
pmid = {34388352},
issn = {0894-0282},
mesh = {*Fusarium/genetics ; *Musa ; Plant Diseases ; Telomere ; },
abstract = {Fusarium musae causes crown rot of banana and it is also associated to clinical fusariosis. A chromosome-level genome assembly of F. musae F31 obtained combining Nanopore long reads and Illumina paired-end reads resulted in 12 chromosomes plus one contig with overall N50 of 4.36 Mb, and is presented together with its mitochondrial genome (58,072 bp). The F31 genome includes telomeric regions for 11 of the 12 chromosomes representing one of the most complete genomes available in the Fusarium fujikuroi species complex. The high-quality assembly of the F31 genome will be a valuable resource for studying the pathogenic interactions occurring between F. musae and banana. Moreover, it represents an important resource for understanding the genome evolution in the F. fujikuroi species complex.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.},
}
@article {pmid34388328,
year = {2022},
author = {Schroder, JD and de Araújo, JB and de Oliveira, T and de Moura, AB and Fries, GR and Quevedo, J and Réus, GZ and Ignácio, ZM},
title = {Telomeres: the role of shortening and senescence in major depressive disorder and its therapeutic implications.},
journal = {Reviews in the neurosciences},
volume = {33},
number = {3},
pages = {227-255},
doi = {10.1515/revneuro-2021-0070},
pmid = {34388328},
issn = {2191-0200},
mesh = {Aging/genetics ; Animals ; *Depressive Disorder, Major/genetics/therapy ; Humans ; Pituitary-Adrenal System/metabolism ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {Major depressive disorder (MDD) is one of the most prevalent and debilitating psychiatric disorders, with a large number of patients not showing an effective therapeutic response to available treatments. Several biopsychosocial factors, such as stress in childhood and throughout life, and factors related to biological aging, may increase the susceptibility to MDD development. Included in critical biological processes related to aging and underlying biological mechanisms associated with MDD is the shortening of telomeres and changes in telomerase activity. This comprehensive review discusses studies that assessed the length of telomeres or telomerase activity and function in peripheral blood cells and brain tissues of MDD individuals. Also, results from in vitro protocols and animal models of stress and depressive-like behaviors were included. We also expand our discussion to include the role of telomere biology as it relates to other relevant biological mechanisms, such as the hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, inflammation, genetics, and epigenetic changes. In the text and the discussion, conflicting results in the literature were observed, especially considering the size of telomeres in the central nervous system, on which there are different protocols with divergent results in the literature. Finally, the context of this review is considering cell signaling, transcription factors, and neurotransmission, which are involved in MDD and can be underlying to senescence, telomere shortening, and telomerase functions.},
}
@article {pmid34387012,
year = {2022},
author = {Power, ML and Foley, NM and Jones, G and Teeling, EC},
title = {Taking flight: An ecological, evolutionary and genomic perspective on bat telomeres.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6053-6068},
doi = {10.1111/mec.16117},
pmid = {34387012},
issn = {1365-294X},
mesh = {Animals ; *Chiroptera/genetics ; *Telomerase/genetics ; Biological Evolution ; Mammals/genetics ; Genomics ; Telomere/genetics ; },
abstract = {Over 20% of all living mammals are bats (order Chiroptera). Bats possess extraordinary adaptations including powered flight, laryngeal echolocation and a unique immune system that enables them to tolerate a diversity of viral infections without presenting clinical disease symptoms. They occupy multiple trophic niches and environments globally. Significant physiological and ecological diversity occurs across the order. Bats also exhibit extreme longevity given their body size with many species showing few signs of ageing. The molecular basis of this extended longevity has recently attracted attention. Telomere maintenance potentially underpins bats' extended healthspan, although functional studies are still required to validate the causative mechanisms. In this review, we detail the current knowledge on bat telomeres, telomerase expression, and how these relate to ecology, longevity and life-history strategies. Patterns of telomere shortening and telomerase expression vary across species, and comparative genomic analyses suggest that alternative telomere maintenance mechanisms evolved in the longest-lived bats. We discuss the unique challenges faced when working with populations of wild bats and highlight ways to advance the field including expanding long-term monitoring across species that display contrasting life-histories and occupy different environmental niches. We further review how new high quality, chromosome-level genome assemblies can enable us to uncover the molecular mechanisms governing telomere dynamics and how phylogenomic analyses can reveal the adaptive significance of telomere maintenance and variation in bats.},
}
@article {pmid34385579,
year = {2021},
author = {Sonnenberg, ASM and Sedaghat-Telgerd, N and Lavrijssen, B and Ohm, RA and Hendrickx, PM and Scholtmeijer, K and Baars, JJP and van Peer, A},
title = {Author Correction: Telomere-to-telomere assembled and centromere annotated genomes of the two main subspecies of the button mushroom Agaricus bisporus reveal especially polymorphic chromosome ends.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {16734},
doi = {10.1038/s41598-021-96123-y},
pmid = {34385579},
issn = {2045-2322},
}
@article {pmid34383056,
year = {2021},
author = {},
title = {Erratum to: Correlation Between Telomere Attrition of Zona Fasciculata and Adrenal Weight Reduction in Older Men.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {106},
number = {12},
pages = {e5283},
doi = {10.1210/clinem/dgab534},
pmid = {34383056},
issn = {1945-7197},
support = {//Daiwa Securities Health Foundation/ ; },
}
@article {pmid34375555,
year = {2021},
author = {Salmón, P and Millet, C and Selman, C and Monaghan, P},
title = {Growth acceleration results in faster telomere shortening later in life.},
journal = {Proceedings. Biological sciences},
volume = {288},
number = {1956},
pages = {20211118},
pmid = {34375555},
issn = {1471-2954},
mesh = {Acceleration ; Animals ; Longevity ; *Songbirds ; Telomere/genetics ; *Telomere Shortening ; },
abstract = {There is a wealth of evidence for a lifespan penalty when environmental conditions influence an individual's growth trajectory, such that growth rate is accelerated to attain a target size within a limited time period. Given this empirically demonstrated relationship between accelerated growth and lifespan, and the links between lifespan and telomere dynamics, increased telomere loss could underpin this growth-lifespan trade. We experimentally modified the growth trajectory of nestling zebra finches (Taeniopygia guttata), inducing a group of nestlings to accelerate their growth between 7 and 15 days of age, the main phase of body growth. We then sequentially measured their telomere length in red blood cells at various time points from 7 days to full adulthood (120 days). Accelerated growth between 7 and 15 days was not associated with a detectable increase in telomere shortening during this period compared with controls. However, only in the treatment group induced to show growth acceleration was the rate of growth during the experimental period positively related to the amount of telomere shortening between 15 and 120 days. Our findings provide evidence of a long-term influence of growth rate on later-life telomere shortening, but only when individuals have accelerated growth in response to environmental circumstances.},
}
@article {pmid34371369,
year = {2021},
author = {Miner, AE and Graves, JS},
title = {What telomeres teach us about MS.},
journal = {Multiple sclerosis and related disorders},
volume = {54},
number = {},
pages = {103084},
doi = {10.1016/j.msard.2021.103084},
pmid = {34371369},
issn = {2211-0356},
mesh = {Age Factors ; *Aging/genetics ; Female ; Humans ; Leukocytes ; Phenotype ; *Telomere ; },
abstract = {While the precise mechanisms driving progressive forms of MS are not fully understood, patient age has clear impact on disease phenotype. The very young with MS have high relapse rates and virtually no progressive disease, whereas older patients tend to experience more rapid disability accumulation with few relapses. Defining a patient's biological age may offer more precision in determining the role of aging processes in MS phenotype and pathophysiology than just working with an individual's birthdate. The most well recognized measurement of an individual's "biological clock" is telomere length (TL). While TL may differ across tissue types in an individual, most cells TL correlate well with leukocyte TL (LTL), which is the most common biomarker used for aging. LTL has been associated with risk for aging related diseases and most recently with higher levels of disability and brain atrophy in people living with MS. LTL explains 15% of the overall association of chronological age with MS disability level. While LTL may be used just as a biomarker of overall somatic aging processes, triggering of the DNA damage response by telomere attrition leads to senescence pathways that are likely highly relevant to a chronic autoimmune disease. Considering reproductive aging factors, particularly ovarian aging in women, which correlates with LTL and oocyte telomere length, may complement measurements of somatic aging in understanding MS progression. The key to stopping non-relapse related progression in MS might lie in targeting pathways related to biological aging effects on the immune and nervous systems.},
}
@article {pmid34369610,
year = {2021},
author = {Amirzadegan, M and Sadeghi, N and Tavalaee, M and Nasr-Esfahani, MH},
title = {Analysis of leukocyte and sperm telomere length in oligozoospermic men.},
journal = {Andrologia},
volume = {53},
number = {10},
pages = {e14204},
doi = {10.1111/and.14204},
pmid = {34369610},
issn = {1439-0272},
mesh = {Humans ; *Infertility, Male/genetics ; Leukocytes ; Male ; Sperm Count ; Spermatozoa ; *Telomere/genetics ; },
abstract = {Telomere length is considered one of the most relevant biological markers of genomic stability since it protects DNA from impairment and also ensures chromosome alignment during DNA replication. The negative impact of telomere shortening on sperm quality has been suggested as an important indicator of male infertility. Therefore, we aimed to assess leucocyte and sperm telomere length (LTL&amp;STL), as well as sperm parameters, DNA damage and protamine deficiency in men with oligozoospermia as compared to fertile men. Our results demonstrated a significant reduction in sperm parameters (concentration, motility, morphology), LTL &amp; STL and a significant increase in sperm DNA damage and protamine deficiency in oligozoospermic men compared with fertile individuals. These outcomes revealed that low sperm concentration in men is possibly a sign of impaired meiotic and/or meiotic division during the spermatogenesis process. It is not only associated with proper chromatin packaging but also with telomere length as a key player in the process of mitosis and meiosis, assisting in chromosomal alignment, pairing, synapsis and crossing over during spermatogenesis.},
}
@article {pmid34369336,
year = {2021},
author = {Ferensztajn-Rochowiak, E and Kurczewska, E and Rubiś, B and Lulkiewicz, M and Hołysz, H and Rybakowski, F and Rybakowski, JK},
title = {Decreased leucocyte telomere length in male patients with chronic bipolar disorder: lack of effect of long-term lithium treatment.},
journal = {Acta neuropsychiatrica},
volume = {33},
number = {6},
pages = {299-306},
doi = {10.1017/neu.2021.20},
pmid = {34369336},
issn = {1601-5215},
mesh = {*Bipolar Disorder/drug therapy/genetics ; Female ; Humans ; Leukocytes ; Lithium ; Male ; Telomere/genetics ; Telomere Shortening ; },
abstract = {OBJECTIVES: Bipolar disorder (BD) may be connected with accelerated aging, the marker of this can be shorter telomere length (TL). Some data suggest that lithium may exert a protective effect against telomere shortening. The study aimed to compare the TL between patients with BD and control subjects. The effect of long-term lithium treatment was also assessed.<br><br>METHODS: The study group comprised 41 patients with BD, including 29 patients treated longitudinally with lithium (mean 16.5 years) and 20 healthy people. TL was assessed by the quantitative polymerase chain reaction (qPCR).<br><br>RESULTS: In the control group, the TL was significantly longer in males than in females. Male bipolar patients had significantly shorter TL compared with the control male group. In bipolar patients, there was no correlation between TL and duration of treatment. The TL was negatively correlated with age in male bipolar patients.<br><br>CONCLUSIONS: The study did not confirm the lithium effect on TL in bipolar patients. TL showed gender differences, being shorter in BD males, compared to control males, and longer in healthy males, compared to control females.},
}
@article {pmid34368190,
year = {2021},
author = {Campisi, M and Liviero, F and Maestrelli, P and Guarnieri, G and Pavanello, S},
title = {DNA Methylation-Based Age Prediction and Telomere Length Reveal an Accelerated Aging in Induced Sputum Cells Compared to Blood Leukocytes: A Pilot Study in COPD Patients.},
journal = {Frontiers in medicine},
volume = {8},
number = {},
pages = {690312},
pmid = {34368190},
issn = {2296-858X},
abstract = {Aging is the predominant risk factor for most degenerative diseases, including chronic obstructive pulmonary disease (COPD). This process is however very heterogeneous. Defining the biological aging of individual tissues may contribute to better assess this risky process. In this study, we examined the biological age of induced sputum (IS) cells, and peripheral blood leukocytes in the same subject, and compared these to assess whether biological aging of blood leukocytes mirrors that of IS cells. Biological aging was assessed in 18 COPD patients (72.4 ± 7.7 years; 50% males). We explored mitotic and non-mitotic aging pathways, using telomere length (TL) and DNA methylation-based age prediction (DNAmAge) and age acceleration (AgeAcc) (i.e., difference between DNAmAge and chronological age). Data on demographics, life style and occupational exposure, lung function, and clinical and blood parameters were collected. DNAmAge (67.4 ± 5.80 vs. 61.6 ± 5.40 years; p = 0.0003), AgeAcc (-4.5 ± 5.02 vs. -10.8 ± 3.50 years; p = 0.0003), and TL attrition (1.05 ± 0.35 vs. 1.48 ± 0.21 T/S; p = 0.0341) are higher in IS cells than in blood leukocytes in the same patients. Blood leukocytes DNAmAge (r = 0.927245; p = 0.0026) and AgeAcc (r = 0.916445; p = 0.0037), but not TL, highly correlate with that of IS cells. Multiple regression analysis shows that both blood leukocytes DNAmAge and AgeAcc decrease (i.e., younger) in patients with FEV1% enhancement (p = 0.0254 and p = 0.0296) and combined inhaled corticosteroid (ICS) therapy (p = 0.0494 and p = 0.0553). In conclusion, new findings from our work reveal a differential aging in the context of COPD, by a direct quantitative comparison of cell aging in the airway with that in the more accessible peripheral blood leukocytes, providing additional knowledge which could offer a potential translation into the disease management.},
}
@article {pmid34362683,
year = {2021},
author = {Sun, J and Liu, W and Guo, Y and Zhang, H and Jiang, D and Luo, Y and Liu, R and Chen, C},
title = {Characterization of tree shrew telomeres and telomerase.},
journal = {Journal of genetics and genomics = Yi chuan xue bao},
volume = {48},
number = {7},
pages = {631-639},
doi = {10.1016/j.jgg.2021.06.004},
pmid = {34362683},
issn = {1673-8527},
mesh = {*Telomerase ; },
abstract = {The use of tree shrews as experimental animals for biomedical research is a new practice. Several recent studies suggest that tree shrews are suitable for studying cancers, including breast cancer, glioblastoma, lung cancer, and hepatocellular carcinoma. However, the telomeres and the telomerase of tree shrews have not been studied to date. Here, we characterize telomeres and telomerase in tree shrews. The telomere length of tree shrews is approximately 23 kb, which is longer than that of primates and shorter than that of mice, and it is extended in breast tumor tissues according to Southern blot and flow-fluorescence in situ hybridization (FISH) analyses. Tree shrew spleen, bone marrow, testis, ovary, and uterus show high telomerase activities, which are increased in breast tumor tissues by telomeric repeat amplification protocol assays. The telomere length becomes shorter, and telomerase activity decreases with age. The tree shrew TERT and TERC are more highly similar to primates than to rodents. These findings lay a solid foundation for using tree shrews to study aging and cancers.},
}
@article {pmid34359923,
year = {2021},
author = {Ghilain, C and Gilson, E and Giraud-Panis, MJ},
title = {Multifunctionality of the Telomere-Capping Shelterin Complex Explained by Variations in Its Protein Composition.},
journal = {Cells},
volume = {10},
number = {7},
pages = {},
pmid = {34359923},
issn = {2073-4409},
support = {TELOCHROM//Agence Nationale de la Recherche/ ; Programme//Fondation ARC pour la Recherche sur le Cancer/ ; AGEMED//Institut National de la Sant&#xe9; et de la Recherche M&#xe9;dicale/ ; },
mesh = {Animals ; DNA/metabolism ; DNA Replication ; Humans ; Models, Molecular ; Protein Structure, Quaternary ; Telomere/*metabolism ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {Protecting telomere from the DNA damage response is essential to avoid the entry into cellular senescence and organismal aging. The progressive telomere DNA shortening in dividing somatic cells, programmed during development, leads to critically short telomeres that trigger replicative senescence and thereby contribute to aging. In several organisms, including mammals, telomeres are protected by a protein complex named Shelterin that counteract at various levels the DNA damage response at chromosome ends through the specific function of each of its subunits. The changes in Shelterin structure and function during development and aging is thus an intense area of research. Here, we review our knowledge on the existence of several Shelterin subcomplexes and the functional independence between them. This leads us to discuss the possibility that the multifunctionality of the Shelterin complex is determined by the formation of different subcomplexes whose composition may change during aging.},
}
@article {pmid34359743,
year = {2021},
author = {Li, Y and Sundquist, K and Wang, X and Zhang, N and Hedelius, A and Sundquist, J and Memon, AA},
title = {Association of Mitochondrial DNA Copy Number and Telomere Length with Prevalent and Incident Cancer and Cancer Mortality in Women: A Prospective Swedish Population-Based Study.},
journal = {Cancers},
volume = {13},
number = {15},
pages = {},
pmid = {34359743},
issn = {2072-6694},
abstract = {Changes in mitochondrial DNA copy number (mtDNA-CN) and telomere length have, separately, been proposed as risk factors for various cancer types. However, those results are conflicting. Here, mtDNA-CN and relative telomere length were measured in 3225 middle-aged women included in a large population-based prospective cohort. The baseline mtDNA-CN in patients with prevalent breast cancer was significantly higher (12.39 copies/µL) than cancer-free individuals. During an average of 15.2 years of follow-up, 520 patients were diagnosed with cancer. Lower mtDNA-CN was associated with decreased risk of genital organ cancer (hazard ratio (HR), 0.84), and shorter telomere length was associated with increased risk of urinary system cancer (HR, 1.79). Furthermore, mtDNA-CN was inversely associated with all-cause (HR, 1.20) and cancer-specific mortality (HR, 1.21) when considering all cancer types. Surprisingly, shorter telomere length was associated with decreased risk of cancer-specific mortality when considering all cancer types (HR, 0.85). Finally, lower mtDNA-CN and shorter telomere length were associated with increased risk of both all-cause and cancer-specific mortality in genital organ cancer patients. In this study population, we found that mtDNA-CN and telomere length were significantly associated with prevalent and incident cancer and cancer mortality. However, these associations were cancer type specific and need further investigation.},
}
@article {pmid34359672,
year = {2021},
author = {Zheng, X and Wezel, F and Azoitei, A and Meessen, S and Wang, W and Najjar, G and Wang, X and Kraus, JM and Kestler, HA and John, A and Zengerling, F and Bolenz, C and Günes, C},
title = {Shorter Leukocyte Telomere Length Is Associated with Worse Survival of Patients with Bladder Cancer and Renal Cell Carcinoma.},
journal = {Cancers},
volume = {13},
number = {15},
pages = {},
pmid = {34359672},
issn = {2072-6694},
abstract = {BACKGROUND: Telomeres are protein-DNA complexes at the tips of linear chromosomes. They protect the DNA from end-to-end fusion and exonucleolytic degradation. Shortening of telomeric DNA during aging can generate dysfunctional telomeres, promoting tumorigenesis. More recent data indicate that both short and long telomeres of peripheral blood leukocyte (PBL) cells can serve as prognostic biomarkers for cancer risk and may be associated with survival of patients with solid cancers. Telomere length in PBL cells could also be a potential prognostic biomarker for survival in bladder cancer (BC) or renal cell carcinoma (RCC).<br><br>METHODS: The relative telomere length (RTL) of PBL cells was assessed in patients with BC (n = 144) and RCC (n = 144) by using qPCR. A control population of patients without malignant disease (NC, n = 73) was included for comparison. The correlation and association of RTL with histopathological parameters and overall survival (OS) were evaluated.<br><br>RESULTS: Patients with BC and RCC had significantly shorter telomeres compared to patients without malignant disease. Within the cancer cohorts, multivariate analysis revealed that short RTL is an independent predictor of worse survival in BC (p = 0.039) and RCC (p = 0.041).<br><br>CONCLUSION: Patients with BC and RCC had significantly shorter telomeres compared to the normal population. Shorter RTL in BC and RCC was an independent predictor of reduced survival.},
}
@article {pmid34358137,
year = {2021},
author = {Hsiao, CB and Bedi, H and Gomez, R and Khan, A and Meciszewski, T and Aalinkeel, R and Khoo, TC and Sharikova, AV and Khmaladze, A and Mahajan, SD},
title = {Telomere Length Shortening in Microglia: Implication for Accelerated Senescence and Neurocognitive Deficits in HIV.},
journal = {Vaccines},
volume = {9},
number = {7},
pages = {},
pmid = {34358137},
issn = {2076-393X},
abstract = {The widespread use of combination antiretroviral therapy (cART) has led to the accelerated aging of the HIV-infected population, and these patients continue to have a range of mild to moderate HIV-associated neurocognitive disorders (HAND). Infection results in altered mitochondrial function. The HIV-1 viral protein Tat significantly alters mtDNA content and enhances oxidative stress in immune cells. Microglia are the immune cells of the central nervous system (CNS) that exhibit a significant mitotic potential and are thus susceptible to telomere shortening. HIV disrupts the normal interplay between microglia and neurons, thereby inducing neurodegeneration. HIV cART contributes to the inhibition of telomerase activity and premature telomere shortening in activated peripheral blood mononuclear cells (PBMC). However, limited information is available on the effect of cART on telomere length (TL) in microglia. Although it is well established that telomere shortening induces cell senescence and contributes to the development of age-related neuro-pathologies, the effect of HIV-Tat on telomere length in human microglial cells and its potential contribution to HAND are not well understood. It is speculated that in HAND intrinsic molecular mechanisms that control energy production underlie microglia-mediated neuronal injury. TL, telomerase and mtDNA expression were quantified in microglial cells using real time PCR. Cellular energetics were measured using the Seahorse assay. The changes in mitochondrial function were examined by Raman Spectroscopy. We have also examined TL in the PBMC obtained from HIV-1 infected rapid progressors (RP) on cART and those who were cART naïve, and observed a significant decrease in telomere length in RP on cART as compared to RP's who were cART naïve. We observed a significant decrease in telomerase activity, telomere length and mitochondrial function, and an increase in oxidative stress in human microglial cells treated with HIV Tat. Neurocognitive impairment in HIV disease may in part be due to accelerated neuro-pathogenesis in microglial cells, which is attributable to increased oxidative stress and mitochondrial dysfunction.},
}
@article {pmid34357912,
year = {2021},
author = {Kaali, S and Jack, D and Opoku-Mensah, J and Bloomquist, T and Aanaro, J and Quinn, A and Boamah-Kaali, EA and Kinney, P and Mujtaba, MN and Agyei, O and Yawson, AK and Osei-Owusu, S and Delimini, R and Wylie, B and Ae-Ngibise, KA and Baccarelli, A and Owusu-Agyei, S and Chillrud, SN and Asante, KP and Lee, A},
title = {Prenatal Household Air Pollution Exposure, Cord Blood Mononuclear Cell Telomere Length and Age Four Blood Pressure: Evidence from a Ghanaian Pregnancy Cohort.},
journal = {Toxics},
volume = {9},
number = {7},
pages = {},
pmid = {34357912},
issn = {2305-6304},
support = {ES019547/NH/NIH HHS/United States ; R21 TW010957/TW/FIC NIH HHS/United States ; TW010957/TW/FIC NIH HHS/United States ; ES026991/NH/NIH HHS/United States ; R01 ES026991/ES/NIEHS NIH HHS/United States ; K23 HL135349/HL/NHLBI NIH HHS/United States ; ES009089/NH/NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; },
abstract = {Associations between prenatal household air pollution exposure (HAP), newborn telomere length and early childhood blood pressure are unknown. Methods: Pregnant women were randomized to liquefied petroleum gas (LPG) stove, improved biomass stove or control (traditional, open fire cook stove). HAP was measured by personal carbon monoxide (CO) (n = 97) and fine particulate matter (PM2.5) (n = 60). At birth, cord blood mononuclear cells (CBMCs) were collected for telomere length (TL) analyses. At child age four years, we measured resting blood pressure (BP) (n = 97). We employed multivariable linear regression to determine associations between prenatal HAP and cookstove arm and assessed CBMC relative to TL separately. We then examined associations between CBMC TL and resting BP. Results: Higher prenatal PM2.5 exposure was associated with reduced TL (β = -4.9% (95% CI -8.6, -0.4), p = 0.03, per 10 ug/m[3] increase in PM2.5). Infants born to mothers randomized to the LPG cookstove had longer TL (β = 55.3% (95% CI 16.2, 109.6), p < 0.01)) compared with control. In all children, shorter TL was associated with higher systolic BP (SBP) (β = 0.35 mmHg (95% CI 0.001, 0.71), p = 0.05, per 10% decrease in TL). Increased prenatal HAP exposure is associated with shorter TL at birth. Shorter TL at birth is associated with higher age four BP, suggesting that TL at birth may be a biomarker of HAP-associated disease risk.},
}
@article {pmid34354128,
year = {2021},
author = {Guillén, R and Otero, F and Mosquera, A and Vázquez-Mosquera, M and Rego-Pérez, I and Blanco, FJ and Fernández, JL},
title = {Association of accelerated dynamics of telomere sequence loss in peripheral blood leukocytes with incident knee osteoarthritis in Osteoarthritis Initiative cohort.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {15914},
pmid = {34354128},
issn = {2045-2322},
mesh = {Aging ; Cohort Studies ; Follow-Up Studies ; Humans ; Incidence ; Knee Joint/pathology ; Leukocytes/pathology ; Leukocytes, Mononuclear/pathology ; Osteoarthritis/genetics/metabolism/pathology ; Osteoarthritis, Knee/*genetics/metabolism/pathology ; Prospective Studies ; Risk Factors ; Telomere/metabolism/*pathology/physiology ; Telomere Homeostasis/genetics/*physiology ; },
abstract = {Osteoarthritis (OA) is a chronic degenerative joint disease, being the main cause of laboral inability. Decreased telomere size in peripheral blood leukocytes (PBL) has been correlated with age-related pathologies, like knee OA. In a dynamic approach, telomere-qPCR was performed to evaluate the relative percentage of PBL telomere loss after a 6-year follow-up, in 281 subjects from the prospective osteoarthritis initiative (OAI) cohort. A radiological Kellgren-Lawrence (KL) grade ≥ 2 was indicative of knee OA. Individuals with knee OA at recruitment (n = 144) showed a higher PBL telomere loss after 6 years than those without knee OA at baseline (n = 137; p = 0.018). Moreover, individuals that developed knee OA during the follow-up (n = 39) exhibited a higher telomere loss compared to those that remained without OA (n = 98; p < 0.001). Logistic regression analysis showed that PBLs telomere loss was not significantly associated with knee OA at recruitment, but behaves as an independent risk factor associated with incidence after follow-up (OR: 1.043; p = 0.041), together with maximum KL grade (OR: 3.627; p = 0.011), body mass index-BMI (OR: 1.252; p < 0.001) and WOMAC-index (OR: 1.247; p = 0.021), at recruitment. The telomere decay in PBLs is faster in individuals with incident knee OA, possibly reflecting a systemic-global accelerated aging that enhances the cartilage degeneration.},
}
@article {pmid34353674,
year = {2021},
author = {Tian, XP and Qian, D and He, LR and Huang, H and Mai, SJ and Li, CP and Huang, XX and Cai, MY and Liao, YJ and Kung, HF and Zeng, YX and Xie, D},
title = {Corrigendum to "The telomere/telomerase binding factor PinX1 regulates paclitaxel sensitivity depending on spindle assembly checkpoint in human cervical squamous cell carcinomas" [Canc. Lett. 353 (2014) 104-114].},
journal = {Cancer letters},
volume = {519},
number = {},
pages = {345},
doi = {10.1016/j.canlet.2021.07.043},
pmid = {34353674},
issn = {1872-7980},
}
@article {pmid34348341,
year = {2022},
author = {Ban, X and Mo, S and Lu, Z and Jia, C and Shao, H and Yan, J and Chang, X and Mao, X and Wu, Y and Zhang, Y and Fan, X and Yu, S and Chen, J},
title = {Alternative Lengthening of Telomeres Phenotype Predicts Progression Risk in Noninsulinomas in a Chinese Cohort.},
journal = {Neuroendocrinology},
volume = {112},
number = {5},
pages = {510-522},
doi = {10.1159/000518413},
pmid = {34348341},
issn = {1423-0194},
mesh = {Adaptor Proteins, Signal Transducing/metabolism ; China ; Co-Repressor Proteins/genetics/metabolism ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Molecular Chaperones/genetics/metabolism ; *Neuroendocrine Tumors/pathology ; *Pancreatic Neoplasms/pathology ; Phenotype ; Telomere/genetics/metabolism/pathology ; Telomere Homeostasis/genetics ; X-linked Nuclear Protein/genetics/metabolism ; },
abstract = {INTRODUCTION: Recent studies have suggested that alternative lengthening of telomeres (ALT) is associated with metastasis and poor survival in pancreatic neuroendocrine tumors (PanNETs). This study evaluated whether this association is applicable to Chinese patients as well as the potential somatic mutations associated with ALT.<br><br>METHODS: We assessed the prevalence of ALT by performing telomere-specific fluorescence in situ hybridization and analyzed DAXX/ATRX expression using immunohistochemistry in 112 Chinese patients with PanNETs to evaluate the association between ALT and clinical outcomes. A subset of the noninsulinoma samples (28/60) was subjected to Sanger sequencing and targeted sequencing.<br><br>RESULTS: The ALT-positive phenotype was identified in 23.2% (26/112) of the samples. The clinicopathologic factors significantly associated with progression in the noninsulinoma (n = 60) cohort were the female sex (p = 0.006), Ki-67 index (p < 0.001), World Health Organization grade (p = 0.031), and ALT positivity (p = 0.013). Patients with ALT-positive PanNETs had significantly shorter progression-free survival than those with ALT-negative PanNETs in the entire cohort (p < 0.001), noninsulinoma subgroup (p = 0.01), and G2 subgroup (p = 0.001). ALT-positive samples frequently harbored somatic mutations in DAXX, ATRX, MEN1, SETBP1, PRKDC, and GNAS.<br><br>CONCLUSIONS: We confirmed that ALT positivity is an effective risk predictor, especially in the noninsulinoma and G2 subgroups. ALT is also related to somatic mutations in MEN1, SETBP1, PRKDC, and GNAS, in addition to DAXX and ATRX.},
}
@article {pmid34347924,
year = {2021},
author = {Sun, G and Cao, H and Bai, Y and Wang, J and Zhou, Y and Li, K and Xiao, JH},
title = {A novel multiplex qPCR method for assessing the comparative lengths of telomeres.},
journal = {Journal of clinical laboratory analysis},
volume = {35},
number = {9},
pages = {e23929},
pmid = {34347924},
issn = {1098-2825},
support = {2017SHZDZX01//Shanghai Municipal Science and Technology Major Project/ ; },
mesh = {DNA/analysis/*genetics ; HEK293 Cells ; HeLa Cells ; Humans ; Real-Time Polymerase Chain Reaction/*methods ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: The comparative length of telomeres is considered to be related to diseases such as cancer, aging, and cardiovascular diseases. qPCR is currently one of the main methods for detecting telomere length. However, due to the unique sequence of telomeres (highly repetitive six-base sequence), it is difficult to design primers and probes to expand and detect telomere and to put internal reference gene and telomere into the same tube for detection to reduce the possible inter-pore errors and improve amplification efficiency. Besides, the stability and accuracy of the test results are greatly affected by the difference between reference genes and telomere copy number.<br><br>METHODS: In this study, the single-copy genes were replaced with high-copy genes (300 copies) as the internal control to reduce the copy number difference of the internal genes and telomere. In addition, a multiplex qPCR system was constructed to detect the telomeres and an internal reference gene product. We also detected the lengths of telomeres in the genomic DNA in immortalized cells (293T and Hela) from different generations of cells.<br><br>RESULTS: We detected the comparative telomere lengths of 1500 random Chinese volunteers of different ages with the multiplex qPCR method; the result shows that the comparative length of telomeres is negatively related to age. In addition, we compared our qPCR detection method with a terminal restriction fragmentation (TRF) method. Both of them were highly consistent, indicating that the qPCR method was reliable.<br><br>CONCLUSIONS: In conclusion, we developed a stable, convenient, and accurate comparative telomere length detection method.},
}
@article {pmid34343614,
year = {2021},
author = {Kodali, HP and Borrell, LN},
title = {Telomere length and mortality risk among adults in the United States: The role of age and race and ethnicity.},
journal = {Annals of epidemiology},
volume = {63},
number = {},
pages = {68-74},
doi = {10.1016/j.annepidem.2021.07.013},
pmid = {34343614},
issn = {1873-2585},
mesh = {Adult ; *Cardiovascular Diseases/genetics ; *Ethnicity ; Humans ; Nutrition Surveys ; Retrospective Studies ; Telomere ; United States/epidemiology ; },
abstract = {PURPOSE: To examine whether there was an association of leucocyte telomere length (LTL) with all-cause, cardiovascular (CVD)- and cancer-specific mortality risks among U.S. adults; and whether these associations vary with race and ethnicity and age.<br><br>METHODS: We conducted a retrospective cohort using data from the National Health and Nutrition Examination Survey, 1999 to 2002 and the 2015 Linked Mortality File on adults 25 years or older (n&#xa0;=&#xa0;6,526 and 1,753 deaths). Cox proportional hazards regression was used to quantify the association of LTL with each outcome adjusting for baseline sociodemographic and health-related characteristics. We tested a three-way interaction for LTL, race and ethnicity, and age groups.<br><br>RESULTS: After adjustment, the rate of dying for all-cause and CVD-specific mortality was at least 24% lower for a 1 kilobase increase in LTL. When compared with adults with the shortest telomere, the rates of dying were at least 17% lower for all-cause and CVD-specific mortality for those with longer telomere. For all-cause mortality, increase LTL was associated with lower rate of dying among non-Hispanic Blacks 45 years or older, and non-Hispanic Whites 65 years or older.<br><br>CONCLUSIONS: We found that increase telomere length was associated with lower all-cause and CVD-specific mortality rates among U.S. adults. For all-cause mortality, this association varies within racial and ethnic groups across age groups.},
}
@article {pmid34343137,
year = {2021},
author = {Schratz, KE and Gaysinskaya, V and Cosner, ZL and DeBoy, EA and Xiang, Z and Kasch-Semenza, L and Florea, L and Shah, PD and Armanios, M},
title = {Somatic reversion impacts myelodysplastic syndromes and acute myeloid leukemia evolution in the short telomere disorders.},
journal = {The Journal of clinical investigation},
volume = {131},
number = {18},
pages = {},
pmid = {34343137},
issn = {1558-8238},
support = {F32 HL142207/HL/NHLBI NIH HHS/United States ; R01 HL119476/HL/NHLBI NIH HHS/United States ; T32 GM007309/GM/NIGMS NIH HHS/United States ; T32 GM136577/GM/NIGMS NIH HHS/United States ; T32 HL007525/HL/NHLBI NIH HHS/United States ; R01 CA225027/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Case-Control Studies ; Child ; Female ; Germ-Line Mutation ; High-Throughput Nucleotide Sequencing ; Humans ; Leukemia, Myeloid, Acute/*genetics ; Male ; Middle Aged ; Mutation ; Myelodysplastic Syndromes/*genetics ; Promoter Regions, Genetic ; RNA/genetics ; Shelterin Complex ; Telomerase/genetics ; Telomere/*genetics ; Telomere Shortening/genetics ; Telomere-Binding Proteins/genetics ; Young Adult ; },
abstract = {BACKGROUNDGermline mutations in telomerase and other telomere maintenance genes manifest in the premature aging short telomere syndromes. Myelodysplastic syndromes and acute myeloid leukemia (MDS/AML) account for 75% of associated malignancies, but how these cancers overcome the inherited telomere defect is unknown.METHODSWe used ultra-deep targeted sequencing to detect somatic reversion mutations in 17 candidate telomere lengthening genes among controls and patients with short telomere syndromes with and without MDS/AML, and we tested the functional significance of these mutations.RESULTSWhile no controls carried somatic mutations in telomere maintenance genes, 29% (16 of 56) of adults with germline telomere maintenance defects carried at least 1 (P < 0.001), and 13% (7 of 56) had 2 or more. In addition to TERT promoter mutations, which were present in 19%, another 13% of patients carried a mutation in POT1 or TERF2IP. POT1 mutations impaired telomere binding in vitro and some mutations were identical to ones seen in familial melanoma associated with longer telomere length. Exclusively in patients with germline defects in telomerase RNA (TR), we identified somatic mutations in nuclear RNA exosome genes RBM7, SKIV2L2, and DIS3, where loss-of-function upregulates mature TR levels. Somatic reversion events in 6 telomere-related genes were more prevalent in patients who were MDS/AML-free (P = 0.02, RR 4.4, 95% CI 1.2-16.7), and no patient with MDS/AML had more than 1 reversion mutation.CONCLUSIONOur data indicate that diverse adaptive somatic mutations arise in the short telomere syndromes. Their presence may alleviate the telomere crisis that promotes transformation to MDS/AML.FUNDINGThis work was supported by the NIH, the Commonwealth Foundation, the S&amp;R Foundation Kuno Award, the Williams Foundation, the Vera and Joseph Dresner Foundation, the MacMillan Pathway to Independence Award, the American Society of Hematology Scholar Award, the Johns Hopkins Research Program for Medical Students, and the Turock Scholars Fund.},
}
@article {pmid34341708,
year = {2021},
author = {Bühring, J and Hecker, M and Fitzner, B and Zettl, UK},
title = {Systematic Review of Studies on Telomere Length in Patients with Multiple Sclerosis.},
journal = {Aging and disease},
volume = {12},
number = {5},
pages = {1272-1286},
pmid = {34341708},
issn = {2152-5250},
abstract = {Telomeres are protective cap structures at the end of chromosomes that are essential for maintaining genomic stability. Accelerated telomere shortening is related to premature cellular senescence. Shortened telomere lengths (TL) have been implicated in the pathogenesis of various chronic immune-mediated and neurological diseases. We aimed to systematically review the current literature on the association of TL as a measure of biological age and multiple sclerosis (MS). A comprehensive literature search was conducted to identify original studies that presented data on TL in samples from persons with MS. Quantitative and qualitative information was extracted from the articles to summarize and compare the studies. A total of 51 articles were screened, and 7 of them were included in this review. In 6 studies, average TL were analyzed in peripheral blood cells, whereas in one study, bone marrow-derived cells were used. Four of the studies reported significantly shorter leukocyte TL in at least one MS subtype in comparison to healthy controls (p=0.003 in meta-analysis). Shorter telomeres in patients with MS were found to be associated, independently of age, with greater disability, lower brain volume, increased relapse rate and more rapid conversion from relapsing to progressive MS. However, it remains unclear how telomere attrition in MS may be linked to oxidative stress, inflammation and age-related disease processes. Despite few studies in this field, there is substantial evidence on the association of TL and MS. Variability in TL appears to reflect heterogeneity in clinical presentation and course. Further investigations in large and well-characterized cohorts are warranted. More detailed studies on TL of individual chromosomes in specific cell types may help to gain new insights into the pathomechanisms of MS.},
}
@article {pmid34339747,
year = {2021},
author = {Park, S and Lee, S and Kim, Y and Cho, S and Kim, K and Kim, YC and Han, SS and Lee, H and Lee, JP and Joo, KW and Lim, CS and Kim, YS and Kim, DK},
title = {A Mendelian randomization study found causal linkage between telomere attrition and chronic kidney disease.},
journal = {Kidney international},
volume = {100},
number = {5},
pages = {1063-1070},
doi = {10.1016/j.kint.2021.06.041},
pmid = {34339747},
issn = {1523-1755},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aged ; Genome-Wide Association Study ; Glomerular Filtration Rate/genetics ; Humans ; *Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; *Renal Insufficiency, Chronic/epidemiology/genetics ; Telomere/genetics ; },
abstract = {Chronic kidney disease (CKD) is highly prevalent in the elderly population. However, it is rarely investigated whether kidney function is causally linked to biological aging itself. In this Mendelian randomization study, genetic instruments for telomere attrition were applied to a CKDGen genome wide association study results for 41,395 cases of CKD among 480,698 individuals as summary-level Mendelian randomization. A replicative analysis was performed by polygenic score analysis using independent United Kingdom Biobank data for 8,118 cases of CKD among 321,024 white individuals of British ancestry. Reverse-direction Mendelian randomization analysis was performed utilizing genetic instruments for log-estimated glomerular filtration rate change with Z-standardized telomere length outcome data for 326,075 participants in the UK Biobank. Genetic predisposition toward telomere attrition (one Z score decrease in length) was found to be a causative factor for a higher CKD risk [Odds Ratio 1.20 (95% confidence interval 1.08‒1.33)], as supported by pleiotropy-robust Mendelian randomization sensitivity analyses implemented using the CKDGen data. Based on United Kingdom Biobank data, the polygenic score for telomere attrition was significantly associated with a higher risk of CKD [1.20 (1.04‒1.39)]. In reverse-direction Mendelian randomization, the genetically predicted kidney function decrease was significantly associated with a higher degree of telomere attrition [beta 0.039 (0.009‒0.069)]. Thus, our study supports the causal linkage between telomere attrition and kidney function impairment.},
}
@article {pmid34337078,
year = {2021},
author = {Qi, YY and Liu, XR and He, YX and Zhou, M and Ning, XH and Zhai, YL and Zhang, XX and Wang, XY and Zhao, YF and Cui, Y and Zhao, ZZ},
title = {Association of the PINX1 Variant rs6984094, Which Lengthens Telomeres, with Systemic Lupus Erythematosus Susceptibility in Chinese Populations.},
journal = {Journal of immunology research},
volume = {2021},
number = {},
pages = {7079359},
pmid = {34337078},
issn = {2314-7156},
mesh = {Adolescent ; Adult ; Asian People/genetics ; Case-Control Studies ; Cell Cycle Proteins/*genetics/metabolism ; China/epidemiology ; Female ; *Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Lupus Erythematosus, Systemic/blood/epidemiology/*genetics ; Male ; Polymorphism, Single Nucleotide ; Telomere Homeostasis/genetics ; Tumor Suppressor Proteins/*genetics/metabolism ; Young Adult ; },
abstract = {A recent genome-wide association study (GWAS) of Asian ancestry reported that single nucleotide polymorphism (SNP) in TERT (telomerase reverse transcriptase) was associated with systemic lupus erythematosus (SLE). TERT has a critical role in maintaining the chromosomal stability and the length of telomere. Given that only a small portion of the genetic heritability of SLE has been explained so far, we aimed to identify novel loci in telomere-related genes responsible for SLE susceptibility in Chinese populations. We performed a comprehensive genetic association analysis of SLE with telomere-related genes. To identify functional significance, we analyzed the publicly available HaploReg v4.1 and RegulomeDB databases. Differential gene expression analysis was also performed using ArrayExpress. A novel signal of PINX1 rs6984094 was identified (P discovery = 4.13 × 10[-2], OR = 0.58, 95% CI 0.35-0.98) and successfully replicated (P replication = 5.73 × 10[-3], OR = 0.45, 95% CI 0.26-0.81). Multiple layers of functional analysis suggested that the PINX1 rs6984094 risk T allele exhibited increased nuclear protein binding. We also observed an increased expression of PINX1 mRNA in peripheral blood mononuclear cells from SLE patients compared with healthy controls. Overall, we observed a novel genetic association between PINX1 (encodes the PinX1 protein, an inhibitory telomerase enzyme that lengthens telomeres) and SLE susceptibility in Chinese populations.},
}
@article {pmid34335309,
year = {2021},
author = {Marques, A and Peralta, M and Marconcin, P and Henriques-Neto, D and Gouveia, &#xc9;R and Ferrari, G and Martins, J and Sarmento, H and Ihle, A},
title = {A Systematic Review of the Association Between Muscular Fitness and Telomere Length Across the Adult Lifespan.},
journal = {Frontiers in physiology},
volume = {12},
number = {},
pages = {706189},
pmid = {34335309},
issn = {1664-042X},
abstract = {This study aimed to systematically review the association between telomere length (TL) and muscular fitness. In October 2020, an articles search was applied to PubMed, Scopus, and Web of Science. Eligibility criteria included: cross-sectional, prospective, and experimental study design; outcomes included TL; results expressed the relationship between muscular fitness and TL; studies published in English, Portuguese, or Spanish. Nine studies were included in the review. Results from the four prospective studies are mixed. In one study, the changes in TL were associated with grip strength. Another study concluded that longer mid-life TL was associated with increased grip strength later in life. However, in the other two studies, the association between TL and sarcopenia was not strong. Nevertheless, longer TL was associated with a slower decline in grip strength in older people. From the four cross-sectional studies, three indicated that TL was associated with muscular fitness. On the other hand, in a study with powerlifters, TL remained within the range of values found in subjects with no history of regular strength training, supporting the notion that muscular fitness was not associated with TL. The cross-sectional and prospective studies showed that the relationship between TL and muscular fitness is not conclusive. It seems that there is a positive association between TL and muscular fitness in middle-aged and older adults. However, among younger adults, this relationship was not observed.},
}
@article {pmid34333383,
year = {2021},
author = {Duan, X and Wang, H and Yang, Y and Wang, P and Zhang, H and Liu, B and Wei, W and Yao, W and Zhou, X and Zhao, J and Wang, W},
title = {Genetic variants in telomerase-associated protein 1 are associated with telomere damage in PAH-exposed workers.},
journal = {Ecotoxicology and environmental safety},
volume = {223},
number = {},
pages = {112558},
doi = {10.1016/j.ecoenv.2021.112558},
pmid = {34333383},
issn = {1090-2414},
mesh = {*Environmental Pollutants ; Humans ; *Polycyclic Aromatic Hydrocarbons/analysis/toxicity ; *Telomerase/genetics ; Telomere/genetics ; Telomere Shortening ; },
abstract = {Telomeres are functional complexes at the ends of linear chromosomes, and telomerase aids in their maintenance and replication. Additionally, accumulating evidence suggests that telomerase-associated protein 1 (TEP1) is a component of the telomerase ribonucleoprotein complex and is responsible for catalyzing the addition of new synthetic telomere sequences to chromosome ends. In our previous study, we found that genetic variants of the TERT gene participated in the regulation of telomere length. Exposure to particulate matter, environmental pollutants, oxidative stress, and pesticides is associated with shortening of telomere length. However, it is unknown whether genetic variants in the TEP1 gene may affect telomere length (TL) in polycyclic aromatic hydrocarbon (PAH)-exposed workers. Therefore, we measured the peripheral leukocyte TL and genotyped the polymorphism loci in the TEP1 gene among 544 PAH-exposed workers and 238 healthy controls. Covariance analysis showed that the individuals carrying TEP1 rs1760903 CC and TEP1 rs1760904 TT had longer TL in the control group (P < 0.05). In the generalized linear model, we found that rs1760903 CC was a protective factor against TL shortening, and PAH exposure could promote telomere shortening (P < 0.05). Thus, this study reinforces the roles of environmental factors and genetic variations in telomere damage, and provides a theoretical foundation for the early detection of susceptible populations and the establishment of occupational standards.},
}
@article {pmid34333235,
year = {2021},
author = {Aviv, A},
title = {Short telomeres and severe COVID-19: The connection conundrum.},
journal = {EBioMedicine},
volume = {70},
number = {},
pages = {103513},
pmid = {34333235},
issn = {2352-3964},
support = {R01 HL134840/HL/NHLBI NIH HHS/United States ; U01 AG066529/AG/NIA NIH HHS/United States ; },
mesh = {*COVID-19 ; Humans ; SARS-CoV-2 ; *Telomere ; Telomere Shortening ; },
}
@article {pmid34332790,
year = {2021},
author = {Lyons, LA},
title = {Cats - telomere to telomere and nose to tail.},
journal = {Trends in genetics : TIG},
volume = {37},
number = {10},
pages = {865-867},
doi = {10.1016/j.tig.2021.06.001},
pmid = {34332790},
issn = {0168-9525},
mesh = {Animals ; Cat Diseases/*genetics ; Cats ; Chromosomes, Mammalian/genetics ; Evolution, Molecular ; Gene Expression Regulation ; Genetic Speciation ; Genetic Variation ; Genome/*genetics ; *Genomic Medicine ; *Genomics ; Humans ; Pets/*genetics ; Telomere/*genetics ; *Veterinary Medicine ; },
abstract = {Feline genomic medicine can decode human variants of uncertain significance (VUSs). Telomere-to-telomere genome assemblies are feasible for all felid species, supporting genetic evolution and speciation studies. Their highly conserved genomic organization compared to humans suggests cats may also decipher the intergenic variation affecting the 3D chromosome structures influencing gene regulation.},
}
@article {pmid34331967,
year = {2022},
author = {Penrice, DD and Havlichek, D and Kamath, PS and Simonetto, DA},
title = {Outcomes following liver transplant in adults with telomere biology disorders.},
journal = {Journal of hepatology},
volume = {76},
number = {1},
pages = {214-216},
doi = {10.1016/j.jhep.2021.07.022},
pmid = {34331967},
issn = {1600-0641},
mesh = {Adult ; Aged ; Humans ; Liver Transplantation/methods/*standards/trends ; Male ; Middle Aged ; Telomere Shortening/immunology/*physiology ; Treatment Outcome ; },
}
@article {pmid34330985,
year = {2021},
author = {Kosebent, EG and Ozturk, S},
title = {Telomere associated gene expression as well as TERT protein level and telomerase activity are altered in the ovarian follicles of aged mice.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {15569},
pmid = {34330985},
issn = {2045-2322},
mesh = {Animals ; Female ; Mice ; Ovarian Follicle/metabolism ; RNA/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism/pathology ; },
abstract = {Telomeres cap the ends of eukaryotic chromosomes to maintain genomic stability and integrity during an organism's lifespan. The length of telomeres inevitably shortens due to DNA replication, genotoxic agents, and biological aging. A limited number of cell types, e.g., stem cells, germline cells, and early embryos can elongate shortened telomeres via the enzymatic action of telomerase, which is composed of telomerase reverse transcriptase (TERT) and telomerase RNA component (Terc). Additionally, telomere-associated proteins including telomeric repeat binding factor 1 (TRF1) and 2 (TRF2), as well as protection of telomeres 1a (POT1a), bind to telomeres to maintain their structural integrity and length. During ovarian aging in mammals, telomeres progressively shorten, accompanied by fertility loss; however, the molecular mechanism underlying this attrition during follicle development remains unclear. In this study, the primary, secondary, preantral, and antral follicles were obtained either from 6-week-old adult (n = 19) or 52-week-old aged (n = 12) mice. We revealed that the Tert, Terc, Trf1, Trf2, and Pot1a gene expression (P < 0.001) and TERT protein (P < 0.01) levels significantly decreased in certain ovarian follicles of the aged group when compared to those of the adult group. Also, telomerase activity exhibited remarkable changes in the follicles of both groups. Consequently, altered telomere-associated gene expression and reduced TERT protein levels in the follicles of aged mice may be a determinant of telomere shortening during ovarian aging, and infertility appearing in the later decades of reproductive lifespan. Further investigations are required to determine the molecular mechanisms underlying these alterations in the follicles during ovarian aging.},
}
@article {pmid34330324,
year = {2021},
author = {Wang, C and Songyang, Z and Huang, Y},
title = {TRIM28 inhibits alternative lengthening of telomere phenotypes by protecting SETDB1 from degradation.},
journal = {Cell &amp; bioscience},
volume = {11},
number = {1},
pages = {149},
pmid = {34330324},
issn = {2045-3701},
support = {81871109//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: About 10-15% of tumor cells extend telomeres through the alternative lengthening of telomeres (ALT) mechanism, which is a recombination-dependent replication pathway. It is generally believed that ALT cells are related to the chromatin modification of telomeres. However, the mechanism of ALT needs to be further explored.<br><br>RESULTS: Here we found that TRIM28/KAP1 is preferentially located on the telomeres of ALT cells and interacts with telomeric shelterin/telosome complex. Knocking down TRIM28 in ALT cells delayed cell growth, decreased the level of C-circle which is one kind of extrachromosomal circular telomeric DNA, increased the frequency of ALT-associated promyelocytic leukemia bodies (APBs), led to telomere prolongation and increased the telomere sister chromatid exchange in ALT cells. Mechanistically, TRIM28 protects telomere histone methyltransferase SETDB1 from degradation, thus maintaining the H3K9me3 heterochromatin state of telomere DNA.<br><br>CONCLUSIONS: Our work provides a model that TRIM28 inhibits alternative lengthening of telomere phenotypes by protecting SETDB1 from degradation. In general, our results reveal the mechanism of telomere heterochromatin maintenance and its effect on ALT, and TRIM28 may serve as a target for the treatment of ALT tumor cells.},
}
@article {pmid34329803,
year = {2021},
author = {Parolini, M and De Felice, B and Mondellini, S and Caprioli, M and Possenti, CD and Rubolini, D},
title = {Prenatal exposure to triclosan induced brain telomere shortening in a wild bird species.},
journal = {Environmental toxicology and pharmacology},
volume = {87},
number = {},
pages = {103718},
doi = {10.1016/j.etap.2021.103718},
pmid = {34329803},
issn = {1872-7077},
mesh = {Animals ; Anti-Infective Agents/*toxicity ; Brain/*drug effects/embryology/metabolism ; Charadriiformes/*embryology/*genetics ; DNA Damage ; Embryo, Nonmammalian/drug effects/metabolism ; Female ; Male ; Oxidative Stress/drug effects ; Telomere Shortening/*drug effects ; Triclosan/*toxicity ; },
abstract = {Exposure to the antimicrobial agent Triclosan (TCS) induces oxidative stress in diverse organisms, including birds. However, whether TCS-induced oxidative stress effectively translates into detrimental effects is still unclear. The present study examined whether prenatal TCS exposure induces oxidative stress and telomere shortening in the brain and the liver of near-term embryos of the yellow-legged gull (Larus michahellis). Prenatal TCS exposure caused a significant overproduction of reactive oxygen species (ROS) in the brain, but no oxidative damage occurred. Telomeres of TCS-exposed embryos had brain telomeres 30 % shorter compared to controls, probably because the relatively modest antioxidant defenses of this organ during prenatal development cannot counteract the impact of the TCS-induced ROS. No telomere shortening was observed in the liver. Our results demonstrated that prenatal exposure to TCS in wild bird species can modulate the oxidative status and induce telomere shortening in the brain of the yellow-legged gull embryos.},
}
@article {pmid34324695,
year = {2021},
author = {Kohlrausch, FB and Wang, F and Chamani, I and Keefe, DL},
title = {Telomere Shortening and Fusions: A Link to Aneuploidy in Early Human Embryo Development.},
journal = {Obstetrical &amp; gynecological survey},
volume = {76},
number = {7},
pages = {429-436},
doi = {10.1097/OGX.0000000000000907},
pmid = {34324695},
issn = {1533-9866},
mesh = {Aged ; Aneuploidy ; Animals ; Cattle ; *Embryonic Development/genetics ; Female ; Humans ; Mice ; Oocytes ; Pregnancy ; Telomere/genetics ; *Telomere Shortening ; },
abstract = {IMPORTANCE: It is known that oocytes undergo aging that is caused by exposure to an aged ovarian microenvironment. Telomere length in mouse and bovine oocytes declines with age, and age-associated telomere shortening in oocytes is considered a sign of poor development competency. Women with advanced age undergoing assisted reproductive technologies have poor outcomes because of increasing aneuploidy rates with age. Research has shown that aneuploidy is associated with DNA damage, reactive oxygen species, and telomere dysfunction.<br><br>OBJECTIVE: In this review, we focus on the possible relationship between telomere dysfunction and aneuploidy in human early embryo development and several reproductive and perinatal outcomes, discussing the mechanism of aneuploidy caused by telomere shortening and fusion in human embryos.<br><br>EVIDENCE ACQUISITION: We reviewed the current literature evidence concerning telomere dysfunction and aneuploidy in early human embryo development.<br><br>RESULTS: Shorter telomeres in oocytes, leukocytes, and granulosa cells, related to aging in women, were associated with recurrent miscarriage, trisomy 21, ovarian insufficiency, and decreasing chance of in vitro fertilization success. Telomere length and telomerase activity in embryos have been related to the common genomic instability at the cleavage stage of human development. Complications of assisted reproductive technology pregnancies, such as miscarriage, birth defects, preterm births, and intrauterine growth restriction, also might result from telomere shortening as observed in oocytes, polar body, granulosa cells, and embryos.<br><br>CONCLUSIONS AND RELEVANCE: Telomere length clearly plays an important role in the development of the embryo and fetus, and the abnormal shortening of telomeres is likely involved in embryo loss during early human development. However, telomere fusion studies have yet to be performed in early human development.},
}
@article {pmid34321211,
year = {2021},
author = {Lee, JH and Hong, J and Zhang, Z and de la Peña Avalos, B and Proietti, CJ and Deamicis, AR and Guzmán G, P and Lam, HM and Garcia, J and Roudier, MP and Sisk, AE and De La Rosa, R and Vu, K and Yang, M and Liao, Y and Scheirer, J and Pechacek, D and Yadav, P and Rao, MK and Zheng, S and Johnson-Pais, TL and Leach, RJ and Elizalde, PV and Dray, E and Xu, K},
title = {Regulation of telomere homeostasis and genomic stability in cancer by N [6]-adenosine methylation (m[6]A).},
journal = {Science advances},
volume = {7},
number = {31},
pages = {},
pmid = {34321211},
issn = {2375-2548},
support = {P30 CA054174/CA/NCI NIH HHS/United States ; },
abstract = {The role of RNA methylation on N [6]-adenosine (m[6]A) in cancer has been acknowledged, but the underlying mechanisms remain obscure. Here, we identified homeobox containing 1 (HMBOX1) as an authentic target mRNA of m[6]A machinery, which is highly methylated in malignant cells compared to the normal counterparts and subject to expedited degradation upon the modification. m[6]A-mediated down-regulation of HMBOX1 causes telomere dysfunction and inactivation of p53 signaling, which leads to chromosome abnormalities and aggressive phenotypes. CRISPR-based, m[6]A-editing tools further prove that the methyl groups on HMBOX1 per se contribute to the generation of altered cancer genome. In multiple types of human cancers, expression of the RNA methyltransferase METTL3 is negatively correlated with the telomere length but favorably with fractions of altered cancer genome, whereas HMBOX1 mRNA levels show the opposite patterns. Our work suggests that the cancer-driving genomic alterations may potentially be fixed by rectifying particular epitranscriptomic program.},
}
@article {pmid34319984,
year = {2021},
author = {Rosin, LF and Gil, J and Drinnenberg, IA and Lei, EP},
title = {Oligopaint DNA FISH reveals telomere-based meiotic pairing dynamics in the silkworm, Bombyx mori.},
journal = {PLoS genetics},
volume = {17},
number = {7},
pages = {e1009700},
pmid = {34319984},
issn = {1553-7404},
mesh = {Animals ; Bombyx/*genetics ; Cell Cycle Proteins/genetics ; Centromere/metabolism ; Chromosomal Proteins, Non-Histone/genetics ; Chromosome Pairing/*genetics ; Chromosome Segregation/genetics ; Chromosomes/genetics ; DNA/genetics ; Female ; Male ; Meiosis/genetics ; Microtubules/metabolism ; Synaptonemal Complex/metabolism ; Telomere/*genetics ; },
abstract = {Accurate chromosome segregation during meiosis is essential for reproductive success. Yet, many fundamental aspects of meiosis remain unclear, including the mechanisms regulating homolog pairing across species. This gap is partially due to our inability to visualize individual chromosomes during meiosis. Here, we employ Oligopaint FISH to investigate homolog pairing and compaction of meiotic chromosomes and resurrect a classical model system, the silkworm Bombyx mori. Our Oligopaint design combines multiplexed barcoding with secondary oligo labeling for high flexibility and low cost. These studies illustrate that Oligopaints are highly specific in whole-mount gonads and on meiotic squashes. We show that meiotic pairing is robust in both males and females and that pairing can occur through numerous partially paired intermediate structures. We also show that pairing in male meiosis occurs asynchronously and seemingly in a transcription-biased manner. Further, we reveal that meiotic bivalent formation in B. mori males is highly similar to bivalent formation in C. elegans, with both of these pathways ultimately resulting in the pairing of chromosome ends with non-paired ends facing the spindle pole. Additionally, microtubule recruitment in both C. elegans and B. mori is likely dependent on kinetochore proteins but independent of the centromere-specifying histone CENP-A. Finally, using super-resolution microscopy in the female germline, we show that homologous chromosomes remain associated at telomere domains in the absence of chiasma and after breakdown and modification to the synaptonemal complex in pachytene. These studies reveal novel insights into mechanisms of meiotic homolog pairing both with or without recombination.},
}
@article {pmid34319229,
year = {2022},
author = {Ren, CY and Liu, PP and Li, J and Li, YQ and Zhang, LJ and Chen, GH and Dong, FY and Hu, D and Zhang, M},
title = {Changes in telomere length and serum neurofilament light chain levels in female patients with chronic insomnia disorder.},
journal = {Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine},
volume = {18},
number = {2},
pages = {383-392},
pmid = {34319229},
issn = {1550-9397},
mesh = {Biomarkers ; *Cognitive Dysfunction ; Female ; Humans ; Intermediate Filaments ; Sleep ; *Sleep Initiation and Maintenance Disorders ; Telomere ; },
abstract = {STUDY OBJECTIVES: The aims of this study were to explore changes in the telomere length (relative telomere repeat copy/single-copy gene [T/S ratio]) and serum neurofilament light chain (sNfL) levels in female patients with chronic insomnia disorder (CID), examine their relationships with emotional abnormalities and cognitive impairment, and determine whether these 2 indicators were independently associated with sleep quality.<br><br>METHODS: The CID group contained 80 patients diagnosed with CID, and 51 individuals constituted a healthy control group. Participants completed sleep, emotion, and cognition assessments. Telomere length was detected through quantitative real-time polymerase chain reaction. Enzyme-linked immunosorbent assay was used to determine sNfL concentrations.<br><br>RESULTS: Relative to the healthy control group, the CID group had elevated Pittsburgh Sleep Quality Index, Hamilton Anxiety Scale-14, and Hamilton Depression Rating Scale-17 scores and reduced Montreal Cognitive Assessment scale scores, a decreased T/S ratio, and an increased sNfL concentration. Subgroup analysis according to various CID-associated sleep factors showed that poor sleep performance corresponded to a lower T/S ratio. Higher anxiety levels and more cognitive dysfunction correlated with shorter telomere lengths. The T/S ratio negatively correlated with age, whereas the sNfL concentration positively correlated with age in the CID group. The Pittsburgh Sleep Quality Index score negatively correlated with the T/S ratio but did not correlate with sNfL levels. Multiple linear regression analysis showed that the T/S ratio had a negative and independent effect on Pittsburgh Sleep Quality Index scores.<br><br>CONCLUSIONS: The CID group had shorter telomeres and higher sNfL concentrations, and reduced telomere length independently affected sleep quality.<br><br>CITATION: Ren C-Y, Liu P-P, Li J, et&#xa0;al. Changes in telomere length and serum neurofilament light chain levels in female patients with chronic insomnia disorder. J Clin Sleep Med. 2022;18(2):383-392.},
}
@article {pmid34316718,
year = {2021},
author = {Yang, SY and Chang, EYC and Lim, J and Kwan, HH and Monchaud, D and Yip, S and Stirling, PC and Wong, JMY},
title = {G-quadruplexes mark alternative lengthening of telomeres.},
journal = {NAR cancer},
volume = {3},
number = {3},
pages = {zcab031},
pmid = {34316718},
issn = {2632-8674},
abstract = {About 10-15% of all human cancer cells employ a telomerase-independent recombination-based telomere maintenance method, known as alternative lengthening of telomere (ALT), of which the full mechanism remains incompletely understood. While implicated in previous studies as the initiating signals for ALT telomere repair, the prevalence of non-canonical nucleic acid structures in ALT cancers remains unclear. Extending earlier reports, we observe higher levels of DNA/RNA hybrids (R-loops) in ALT-positive (ALT+) compared to telomerase-positive (TERT+) cells. Strikingly, we observe even more pronounced differences for an associated four-stranded nucleic acid structure, G-quadruplex (G4). G4 signals are found at the telomere and are broadly associated with telomere length and accompanied by DNA damage markers. We establish an interdependent relationship between ALT-associated G4s and R-loops and confirm that these two structures can be spatially linked into unique structures, G-loops, at the telomere. Additionally, stabilization of G4s and R-loops cooperatively enhances ALT-activity. However, co-stabilization at higher doses resulted in cytotoxicity in a synergistic manner. Nuclear G4 signals are significantly and reproducibly different between ALT+ and TERT+ low-grade glioma tumours. Together, we present G4 as a novel hallmark of ALT cancers with potential future applications as a convenient biomarker for identifying ALT+ tumours and as therapeutic targets.},
}
@article {pmid34316326,
year = {2021},
author = {Petrov, N and Lee, HS and Liskovykh, M and Teulade-Fichou, MP and Masumoto, H and Earnshaw, WC and Pommier, Y and Larionov, V and Kouprina, N},
title = {Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells.},
journal = {Oncotarget},
volume = {12},
number = {15},
pages = {1444-1456},
pmid = {34316326},
issn = {1949-2553},
abstract = {Telomerase/telomere-targeting therapy is a potentially promising approach for cancer treatment because even transient telomere dysfunction can induce chromosomal instability (CIN) and may be a barrier to tumor growth. We recently developed a dual-HAC (Human Artificial Chromosome) assay that enables identification and ranking of compounds that induce CIN as a result of telomere dysfunction. This assay is based on the use of two isogenic HT1080 cell lines, one carrying a linear HAC (containing telomeres) and the other carrying a circular HAC (lacking telomeres). Disruption of telomeres in response to drug treatment results in specific destabilization of the linear HAC. Results: In this study, we used the dual-HAC assay for the analysis of the platinum-derived G4 ligand Pt-tpy and five of its derivatives: Pt-cpym, Pt-vpym, Pt-ttpy, Pt(PA)-tpy, and Pt-BisQ. Our analysis revealed four compounds, Pt-tpy, Pt-ttpy, Pt-vpym and Pt-cpym, that induce a specific loss of a linear but not a circular HAC. Increased CIN after treatment by these compounds correlates with the induction of double-stranded breaks (DSBs) predominantly localized at telomeres and reflecting telomere-associated DNA damage. Analysis of the mitotic phenotypes induced by these drugs revealed an elevated rate of chromatin bridges (CBs) in late mitosis and cytokinesis. These terpyridine platinum-derived G4 ligands are promising compounds for cancer treatment.},
}
@article {pmid34313963,
year = {2022},
author = {Xie, H and Ma, Y and Shao, M and Kong, J and Zhou, T and Wang, F and Cai, G and Xu, S and Pan, F},
title = {Telomere length in patients with osteoarthritis: a systematic review and meta-analysis.},
journal = {Aging clinical and experimental research},
volume = {34},
number = {3},
pages = {495-503},
pmid = {34313963},
issn = {1720-8319},
support = {81773514//National Natural Science Foundation of China/ ; 82073655//National Natural Science Foundation of China/ ; },
mesh = {Aging ; Biomarkers ; Humans ; *Osteoarthritis/genetics ; Publication Bias ; Telomere ; },
abstract = {BACKGROUND: Telomere length (TL) as a biomarker of aging was associated with many age-related diseases. The relationship between TL and osteoarthritis (OA), the most common form of joint diseases, had been investigated in a number of studies, but with the result inconsistent.<br><br>AIMS: The purpose of this study was to systematically evaluate the relationship between TL and OA.<br><br>METHODS: Until January 1, 2021, PubMed, Web of Science and Cochrane Library were comprehensively retrieved for relevant literatures. Quality of included literature was assessed using the Newcastle-Ottawa Scale (NOS) assessment scale. The pooled standard mean difference (SMD) with 95% confidence interval (CI) of Leukocytes TL was calculated using random-effect model. Subgroup analysis and meta-regression were used to investigate the potential source of heterogeneity.<br><br>RESULTS: Six original studies containing 678 OA patients and 1457 healthy controls were included in this meta-analysis. All six included studies were case-control designed. Pooled results showed that patients with OA had a shorter TL in peripheral blood leukocytes (PBLs) compared with healthy controls, (SMD&#x2009;=&#x2009;-&#xa0;0.32, 95% CI -&#xa0;0.57 to -&#xa0;0.06, Z&#x2009;=&#x2009;-&#xa0;2.45, P&#x2009;=&#x2009;0.014). Subgroup and meta-regression analysis showed that sex ratio and body mass index (BMI) were possible sources of heterogeneity. Publication bias was not observed.<br><br>CONCLUSION: The TL of PBLs in patients with OA was shorter than that of healthy controls, suggesting that PBLs TL may be closely associated with the pathogenesis and progression of OA.},
}
@article {pmid34312982,
year = {2021},
author = {Loh, NY and Noordam, R and Christodoulides, C},
title = {Telomere length and metabolic syndrome traits: A Mendelian randomisation study.},
journal = {Aging cell},
volume = {20},
number = {8},
pages = {e13445},
pmid = {34312982},
issn = {1474-9726},
support = {FS/16/45/32359/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Humans ; Mendelian Randomization Analysis/*methods ; Metabolic Syndrome/*genetics ; Telomere/*genetics ; },
abstract = {Observational studies have revealed associations between short leucocyte telomere length (LTL), a TL marker in somatic tissues and multiple Metabolic Syndrome (MetS) traits. Animal studies have supported these findings by showing that increased telomere attrition leads to adipose tissue dysfunction and insulin resistance. We investigated the associations between genetically instrumented LTL and MetS traits using Mendelian Randomisation (MR). Fifty-two independent variants identified at FDR<0.05 from a genome-wide association study (GWAS) including 78,592 Europeans and collectively accounting for 2.93% of LTL variance were selected as genetic instruments for LTL. Summary-level data for MetS traits and for the MetS as a binary phenotype were obtained from the largest publicly available GWAS and two-sample MR analyses were used to estimate the associations of LTL with these traits. The combined effect of the genetic instruments was modelled using inverse variance weighted regression and sensitivity analyses with MR-Egger, weighted-median and MR-PRESSO were performed to test for and correct horizonal pleiotropy. Genetically instrumented longer LTL was associated with higher waist-to-hip ratio adjusted for body mass index (β = 0.045 SD, SE = 0.018, p = 0.01), raised systolic (β = 1.529 mmHg, SE = 0.332, p = 4x10[-6]) and diastolic (β = 0.633 mmHg, SE = 0.222, p = 0.004) blood pressure, and increased MetS risk (OR = 1.133, 95% CI 1.057-1.215). Consistent results were obtained in sensitivity analyses, which provided no evidence of unbalanced horizontal pleiotropy. Telomere shortening might not be a major driver of cellular senescence and dysfunction in human adipose tissue. Future experimental studies should examine the mechanistic bases for the links between longer LTL and increased upper-body fat distribution and raised blood pressure.},
}
@article {pmid34311139,
year = {2021},
author = {Kim, EJ and Koh, SH and Ha, J and Na, DL and Seo, SW and Kim, HJ and Park, KW and Lee, JH and Roh, JH and Kwon, JC and Yoon, SJ and Jung, NY and Jeong, JH and Jang, JW and Kim, HJ and Park, KH and Choi, SH and Kim, S and Park, YH and Kim, BC and Kim, YE and Kwon, HS and Park, HH and Jin, JH},
title = {Increased telomere length in patients with frontotemporal dementia syndrome.},
journal = {Journal of the neurological sciences},
volume = {428},
number = {},
pages = {117565},
doi = {10.1016/j.jns.2021.117565},
pmid = {34311139},
issn = {1878-5883},
mesh = {*Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; *Frontotemporal Dementia/genetics ; Humans ; Syndrome ; Telomere/genetics ; },
abstract = {BACKGROUND: Telomeres are repetitive DNA sequences of TTAGGG at the ends of chromosomes. Many studies have shown that telomere shortening is associated with aging-related diseases, such as cardiovascular diseases, hypertension, diabetes, cancer, and various neurodegenerative diseases, including Alzheimer's disease, vascular dementia, Parkinson's disease, and dementia with Lewy bodies. However, changes in telomere length (TL) in patients with frontotemporal dementia (FTD) syndrome are unclear. Accordingly, in this study, we assessed TL in blood samples from patients with FTD syndrome.<br><br>METHODS: Absolute TL was measured in peripheral blood leukocytes from 53 patients with FTD syndromes (25 with behavioral variant FTD, 19 with semantic variant primary progressive aphasia [PPA], six with nonfluent/agrammatic variant PPA, and three with amyotrophic lateral sclerosis [ALS] plus) and 28 cognitively unimpaired (CU) controls using terminal restriction fragment analysis.<br><br>RESULTS: TL was significantly longer in the FTD group than in the CU group. All FTD subtypes had significantly longer TL than controls. There were no significant differences in TL among FTD syndromes. No significant correlations were found between TL and demographic factors in the FTD group.<br><br>CONCLUSIONS: Longer telomeres were associated with FTD syndrome, consistent with a recent report demonstrating that longer telomeres are related to ALS. Therefore, our results may support a shared biology between FTD and ALS. More studies with larger sample sizes are needed.},
}
@article {pmid34310343,
year = {2021},
author = {Alcaraz, MJ and Alcaraz, A and Teruel-Montoya, R and Campillo, JA and de la Torre, A and Muñoz, &#xc1; and Tomás, C and Puche, G and Báguena, C and Cano, A and Minguela, A and Bernal, E},
title = {Subclinical atherosclerosis and immune activation in young HIV-infected patients with telomere shortening.},
journal = {Aging},
volume = {13},
number = {14},
pages = {18094-18105},
pmid = {34310343},
issn = {1945-4589},
mesh = {Adult ; *Aging, Premature ; Anti-Retroviral Agents/therapeutic use ; Atherosclerosis/diagnostic imaging/*immunology/virology ; Biomarkers ; CD8-Positive T-Lymphocytes/immunology ; Carotid Arteries/diagnostic imaging ; *Carotid Intima-Media Thickness ; Cross-Sectional Studies ; Female ; HIV Infections/drug therapy/*immunology ; Humans ; Logistic Models ; Lymphocyte Activation ; Male ; Middle Aged ; *Telomere Shortening ; },
abstract = {BACKGROUND: To date, available data on premature aging in young HIV-infected adults are scarce and no reports offer comprehensive assessment of telomere shortening (TS) in relation to subclinical atherosclerosis (SCA). In this study, we investigate if telomere shortening and immune activation markers are associated with SCA, which is one of the main degenerative diseases in young HIV-infected adults.<br><br>METHODS: A descriptive cross-sectional study was carried out in 149 HIV-infected patients on stable antiretroviral regimen (ART). Carotid intima-media thickness (cIMT) was estimated by carotid ultrasound. Quantitative singleplex PCR was performed to evaluate TS. The expression of activation/senescence markers was evaluated by multiparametric flow cytometry.<br><br>RESULTS: TS was observed in 73 patients (49%). Higher cIMT was observed in patients with TS than those without it (0.86 vs. 0.80 mm; p=0.041). Patients under the age of 50 (defined as young adults) with TS showed higher absolute numbers of activated lymphocyte T cells CD8+CD38+ (3.94 vs. 2.34 cell/&#x3bc;l; p=0.07) and lymphocyte B cells CD19+CD38+ (3.07 vs. 2.10 cell/&#x3bc;l; p=0.004) compared to those without TS. In the multivariate analysis, the only factor independently associated with TS was the absolute number of lymphocyte T cells CD8+CD38+ T cells (OR = 1.18; 95%-CI = 1.00-1.39; p = 0.05).<br><br>CONCLUSION: Young HIV-infected adults show premature biological aging with accentuated immune activation. Chronic inflammation with excessive T-cells activation could be associated to TS, premature aging, and SCA in young HIV-infected adults.},
}
@article {pmid34307383,
year = {2021},
author = {Novo, CL},
title = {A Tale of Two States: Pluripotency Regulation of Telomeres.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {703466},
pmid = {34307383},
issn = {2296-634X},
support = {/WT_/Wellcome Trust/United Kingdom ; },
abstract = {Inside the nucleus, chromatin is functionally organized and maintained as a complex three-dimensional network of structures with different accessibility such as compartments, lamina associated domains, and membraneless bodies. Chromatin is epigenetically and transcriptionally regulated by an intricate and dynamic interplay of molecular processes to ensure genome stability. Phase separation, a process that involves the spontaneous organization of a solution into separate phases, has been proposed as a mechanism for the timely coordination of several cellular processes, including replication, transcription and DNA repair. Telomeres, the repetitive structures at the end of chromosomes, are epigenetically maintained in a repressed heterochromatic state that prevents their recognition as double-strand breaks (DSB), avoiding DNA damage repair and ensuring cell proliferation. In pluripotent embryonic stem cells, telomeres adopt a non-canonical, relaxed epigenetic state, which is characterized by a low density of histone methylation and expression of telomere non-coding transcripts (TERRA). Intriguingly, this telomere non-canonical conformation is usually associated with chromosome instability and aneuploidy in somatic cells, raising the question of how genome stability is maintained in a pluripotent background. In this review, we will explore how emerging technological and conceptual developments in 3D genome architecture can provide novel mechanistic perspectives for the pluripotent epigenetic paradox at telomeres. In particular, as RNA drives the formation of LLPS, we will consider how pluripotency-associated high levels of TERRA could drive and coordinate phase separation of several nuclear processes to ensure genome stability. These conceptual advances will provide a better understanding of telomere regulation and genome stability within the highly dynamic pluripotent background.},
}
@article {pmid34304048,
year = {2021},
author = {Wang, Q and Codd, V and Raisi-Estabragh, Z and Musicha, C and Bountziouka, V and Kaptoge, S and Allara, E and Angelantonio, ED and Butterworth, AS and Wood, AM and Thompson, JR and Petersen, SE and Harvey, NC and Danesh, JN and Samani, NJ and Nelson, CP},
title = {Shorter leukocyte telomere length is associated with adverse COVID-19 outcomes: A cohort study in UK Biobank.},
journal = {EBioMedicine},
volume = {70},
number = {},
pages = {103485},
pmid = {34304048},
issn = {2352-3964},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; MR/L003120/1/MRC_/Medical Research Council/United Kingdom ; RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom ; MC_PC_21003/MRC_/Medical Research Council/United Kingdom ; FS/17/81/33318/BHF_/British Heart Foundation/United Kingdom ; RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom ; MC_PC_21001/MRC_/Medical Research Council/United Kingdom ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; CH/12/2/29428/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Aged ; Biological Specimen Banks ; COVID-19/pathology/*virology ; Cohort Studies ; Female ; Humans ; Leukocytes/*pathology ; Male ; Mendelian Randomization Analysis ; Middle Aged ; Risk Factors ; SARS-CoV-2/*genetics ; Telomere/*genetics ; United Kingdom ; },
abstract = {Background Older age is the most powerful risk factor for adverse coronavirus disease-19 (COVID-19) outcomes. It is uncertain whether leucocyte telomere length (LTL), previously proposed as a marker of biological age, is also associated with COVID-19 outcomes. Methods We associated LTL values obtained from participants recruited into UK Biobank (UKB) during 2006-2010 with adverse COVID-19 outcomes recorded by 30 November 2020, defined as a composite of any of the following: hospital admission, need for critical care, respiratory support, or mortality. Using information on 130 LTL-associated genetic variants, we conducted exploratory Mendelian randomisation (MR) analyses in UKB to evaluate whether observational associations might reflect cause-and-effect relationships. Findings Of 6775 participants in UKB who tested positive for infection with SARS-CoV-2 in the community, there were 914 (13.5%) with adverse COVID-19 outcomes. The odds ratio (OR) for adverse COVID-19 outcomes was 1·17 (95% CI 1·05-1·30; P = 0·004) per 1-SD shorter usual LTL, after adjustment for age, sex and ethnicity. Similar ORs were observed in analyses that: adjusted for additional risk factors; disaggregated the composite outcome and reduced the scope for selection or collider bias. In MR analyses, the OR for adverse COVID-19 outcomes was directionally concordant but non-significant. Interpretation Shorter LTL is associated with higher risk of adverse COVID-19 outcomes, independent of several major risk factors for COVID-19 including age. Further data are needed to determine whether this association reflects causality. Funding UK Medical Research Council, Biotechnology and Biological Sciences Research Council and British Heart Foundation.},
}
@article {pmid34299219,
year = {2021},
author = {Turner, KJ and Watson, EM and Skinner, BM and Griffin, DK},
title = {Telomere Distribution in Human Sperm Heads and Its Relation to Sperm Nuclear Morphology: A New Marker for Male Factor Infertility?.},
journal = {International journal of molecular sciences},
volume = {22},
number = {14},
pages = {},
pmid = {34299219},
issn = {1422-0067},
support = {TBC/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Biomarkers/metabolism ; Case-Control Studies ; Cell Nucleus/genetics/metabolism/pathology ; Cohort Studies ; *DNA Damage ; Humans ; Infertility, Male/genetics/*metabolism/*pathology ; Male ; Sperm Head/metabolism/*pathology ; Telomere/genetics/*metabolism ; },
abstract = {Infertility is a problem affecting an increasing number of couples worldwide. Currently, marker tests for male factor infertility are complex, highly technical and relatively subjective. Up to 40% of cases of male factor infertility are currently diagnosed as idiopathic therefore, there is a clear need for further research into better ways of diagnosing it. Changes in sperm telomere length have been associated with infertility and closely linked to DNA damage and fragmentation, which are also known to be related to infertility. However, telomere distribution is a parameter thus far underexplored as an infertility marker. Here, we assessed morphological parameters of sperm nuclei in fertile control and male factor infertile cohorts. In addition, we used 2D and 3D fluorescence in situ hybridization (FISH) to compare telomere distribution between these two groups. Our findings indicate that the infertile cohort sperm nuclei were, on average, 2.9% larger in area and showed subtle differences in sperm head height and width. Telomeres were mainly distributed towards the periphery of the nuclei in the control cohort, with diminishing telomere signals towards the center of the nuclei. Sperm nuclei of infertile males, however, had more telomere signals towards the center of the nuclei, a finding supported by 3D imaging. We conclude that, with further development, both morphology and telomere distribution may prove useful investigative tools in the fertility clinic.},
}
@article {pmid34299077,
year = {2021},
author = {Garcia-Martin, I and Penketh, RJA and Garay, SM and Jones, RE and Grimstead, JW and Baird, DM and John, RM},
title = {Symptoms of Prenatal Depression Associated with Shorter Telomeres in Female Placenta.},
journal = {International journal of molecular sciences},
volume = {22},
number = {14},
pages = {},
pmid = {34299077},
issn = {1422-0067},
support = {29202/CRUK_/Cancer Research UK/United Kingdom ; MR/M013960/1/MRC_/Medical Research Council/United Kingdom ; C17199/A18246/A29202/CRUK_/Cancer Research UK/United Kingdom ; MR/N013794/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Anxiety Disorders/*complications/psychology ; Depression/*complications/psychology ; Female ; Gestational Age ; Humans ; Infant ; Male ; Maternal Age ; Placenta/metabolism/*pathology ; Pregnancy ; Sex Factors ; *Telomere Shortening ; },
abstract = {BACKGROUND: Depression is a common mood disorder during pregnancy impacting one in every seven women. Children exposed to prenatal depression are more likely to be born at a low birth weight and develop chronic diseases later in life. A proposed hypothesis for this relationship between early exposure to adversity and poor outcomes is accelerated aging. Telomere length has been used as a biomarker of cellular aging. We used high-resolution telomere length analysis to examine the relationship between placental telomere length distributions and maternal mood symptoms in pregnancy.<br><br>METHODS: This study utilised samples from the longitudinal Grown in Wales (GiW) study. Women participating in this study were recruited at their presurgical appointment prior to a term elective caesarean section (ELCS). Women completed the Edinburgh Postnatal Depression Scale (EPDS) and trait subscale of the State-Trait Anxiety Inventory (STAI). Telomere length distributions were generated using single telomere length analysis (STELA) in 109 term placenta (37-42 weeks). Multiple linear regression was performed to examine the relationship between maternally reported symptoms of depression and anxiety at term and mean placental telomere length.<br><br>RESULTS: Prenatal depression symptoms were significantly negatively associated with XpYp telomere length in female placenta (B = -0.098, p = 0.026, 95% CI -0.184, -0.012). There was no association between maternal depression symptoms and telomere length in male placenta (B = 0.022, p = 0.586, 95% CI -0.059, 0.103). There was no association with anxiety symptoms and telomere length for either sex.<br><br>CONCLUSION: Maternal prenatal depression is associated with sex-specific differences in term placental telomeres. Telomere shortening in female placenta may indicate accelerated placental aging.},
}
@article {pmid34294626,
year = {2021},
author = {Joo, EJ and Ahn, YM and Park, M and Kim, SA},
title = {Significant Shortening of Leukocyte Telomere Length in Korean Patients with Bipolar Disorder 1.},
journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology},
volume = {19},
number = {3},
pages = {559-563},
pmid = {34294626},
issn = {1738-1088},
abstract = {OBJECTIVE: Telomere shortening has been seen in major psychiatric disorders, including major depressive disorder. However, only a few small studies have examined this in bipolar disorder (BD). We compared the telomere length in patients with BD1 or BD2 with that in matched healthy controls.<br><br>METHODS: We included 215 patients with BD (128 BD1, 87 BD2) and 204 age- and sex-matched healthy controls. Relative telomere length was determined by quantitative polymerase chain reaction. The patients and controls were compared separately for age groups, sex, and BD subgroups (BD1 and BD2).<br><br>RESULTS: We found significant telomere shortening in patients with BD1 (p < 0.001), but not in patients with BD2. In male patients with BD1, the 30-39 year age group had significant shortening of telomere length than controls (p = 0.01). Female patients with BD1 in the 19-29-year age group had significantly shortened telomeres compared to the controls (p < 0.01).<br><br>CONCLUSION: Our results suggest a significant reduction in telomere length in BD1. Telomere shortening would be a potential biomarker for BD.},
}
@article {pmid34291629,
year = {2021},
author = {Kang, JI and Park, CI and Lin, J and Kim, ST and Kim, HW and Kim, SJ},
title = {Alterations of cellular aging markers in obsessive- compulsive disorder: mitochondrial DNA copy number and telomere length.},
journal = {Journal of psychiatry &amp; neuroscience : JPN},
volume = {46},
number = {4},
pages = {E451-E458},
pmid = {34291629},
issn = {1488-2434},
mesh = {Adult ; Biomarkers ; Cellular Senescence/*genetics ; Cross-Sectional Studies ; DNA Copy Number Variations/*genetics ; DNA, Mitochondrial/*genetics ; Female ; Humans ; Male ; Middle Aged ; Obsessive-Compulsive Disorder/*genetics ; Telomere/*genetics ; Telomere Shortening/genetics ; Young Adult ; },
abstract = {BACKGROUND: The present study examined whether mitochondrial DNA copy number (mtDNAcn) and telomere length - key markers of cellular aging - were altered in male and female participants with obsessive-compulsive disorder (OCD) compared to healthy controls. We also tested for associations between these alterations and OCD-related clinical features and inflammatory index.<br><br>METHODS: A total of 235 patients with OCD (38.7% female) and 234 healthy controls (41.5% female) were included. We quantified whole-blood mtDNAcn and leukocyte telomere length using quantitative polymerase chain reaction. We also calculated the neutrophil-to-lymphocyte ratio from complete blood cell counts.<br><br>RESULTS: Multivariate analysis of covariance showed that OCD status had a significant overall effect on cellular aging markers in men (Wilks &#x3bb; = 0.889, F2,275 = 17.13, p < 0.001) and women (Wilks &#x3bb; = 0.742, F2,182 = 31.61, p < 0.001) after controlling for age, body mass index and childhood trauma. In post-hoc comparisons, men with OCD had lower mtDNAcn than controls (p < 0.001), but we found no between-group difference for telomere length (p = 0.55). Women with OCD had a significantly lower mtDNAcn (p < 0.001) and shortened telomere length (p = 0.023) compared to controls. Moreover, the lower mtDNAcn shown in the OCD group was significantly correlated with an increase in systemic inflammation for both sexes, as measured by neutrophil-to-lymphocyte ratio.<br><br>LIMITATIONS: The present cross-sectional design did not allow us to infer a causal relationship between OCD disease status and cellular aging markers.<br><br>CONCLUSION: The present study is, to our knowledge, the first to demonstrate alterations in mtDNAcn and telomere shortening in OCD. These results suggest that aging-associated molecular mechanisms may be important in the pathophysiology of OCD.},
}
@article {pmid34291053,
year = {2021},
author = {Li, B},
title = {Keeping Balance Between Genetic Stability and Plasticity at the Telomere and Subtelomere of Trypanosoma brucei.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {699639},
pmid = {34291053},
issn = {2296-634X},
support = {R01 AI066095/AI/NIAID NIH HHS/United States ; },
abstract = {Telomeres, the nucleoprotein complexes at chromosome ends, are well-known for their essential roles in genome integrity and chromosome stability. Yet, telomeres and subtelomeres are frequently less stable than chromosome internal regions. Many subtelomeric genes are important for responding to environmental cues, and subtelomeric instability can facilitate organismal adaptation to extracellular changes, which is a common theme in a number of microbial pathogens. In this review, I will focus on the delicate and important balance between stability and plasticity at telomeres and subtelomeres of a kinetoplastid parasite, Trypanosoma brucei, which causes human African trypanosomiasis and undergoes antigenic variation to evade the host immune response. I will summarize the current understanding about T. brucei telomere protein complex, the telomeric transcript, and telomeric R-loops, focusing on their roles in maintaining telomere and subtelomere stability and integrity. The similarities and differences in functions and underlying mechanisms of T. brucei telomere factors will be compared with those in human and yeast cells.},
}
@article {pmid34288423,
year = {2021},
author = {Gu, R and Cao, J and Wei, S and Gong, X and Wang, Y and Mi, Y and Zhang, J and Qiu, S and Rao, Q and Wang, M and Wei, H and Wang, J},
title = {Evaluation of pretreatment telomere length as a prognostic marker in intermediate-risk acute myeloid leukemia.},
journal = {International journal of laboratory hematology},
volume = {43},
number = {6},
pages = {1510-1515},
doi = {10.1111/ijlh.13665},
pmid = {34288423},
issn = {1751-553X},
support = {81830005//State Key Program of National Natural Science of China/ ; 82000131//National Natural Science Foundation of China/ ; 81770181//National Natural Science Foundation of China/ ; 81800173//National Natural Science Foundation of China/ ; 2019YFC0840605//National Key Research and Development Program of China/ ; 18JCZDJC45000//Tianjin Natural Science Foundation/ ; 2020-I2M-C&amp;T-B-084//CAMS Innovation Fund for Medical Sciences/ ; },
mesh = {Adult ; *Biomarkers, Tumor ; Disease Progression ; Humans ; Leukemia, Myeloid, Acute/diagnosis/*genetics/*mortality/therapy ; Multivariate Analysis ; Prognosis ; Proportional Hazards Models ; Recurrence ; Telomere/*genetics ; Telomere Shortening ; Treatment Outcome ; },
abstract = {INTRODUCTION: The current framework for risk stratification is still insufficient for highly heterogeneous intermediate-risk acute myeloid leukemia (IRC-AML), which lacks specific genomic abnormalities.<br><br>METHODS: In order to incorporate novel biomarkers to refine current risk stratification strategies for patients with this subtype, we investigated pretreatment telomere length (TL), which is essential for maintaining genomic stability, in 204 adults with de novo AML (non-acute promyelocytic leukemia).<br><br>RESULTS: We found that TL measured at diagnosis did not decrease with advancing age in 204 patients with AML (R[2] &#xa0;=&#xa0;0.001, P&#xa0;=&#xa0;.695). A multivariate analysis demonstrated that short TL was independently associated with an inferior relapse-free survival (hazard ratio [HR] 3.08, 95% confidence interval [CI] 1.48-6.41, P&#xa0;=&#xa0;.003); event-free survival (HR 2.14, 95% CI 1.12-4.08, P&#xa0;=&#xa0;.021); and overall survival (HR 2.26, 95% CI 1.09-4.67, P&#xa0;=&#xa0;.028) in IRC-AML patients. In addition, IRC-AML patients with short TL also exhibited an increased cumulative incidence of hematologic relapse (HR 2.32, 95% CI 1.08-5.26, P&#xa0;=&#xa0;.032).<br><br>CONCLUSION: Short TL is an independent prognostic factor for poor prognosis in patients with IRC-AML and may represent a novel mechanism that links genomic stability and disease progression.},
}
@article {pmid34285374,
year = {2021},
author = {Seimiya, H and Nagasawa, K and Shin-Ya, K},
title = {Chemical targeting of G-quadruplexes in telomeres and beyond for molecular cancer therapeutics.},
journal = {The Journal of antibiotics},
volume = {74},
number = {10},
pages = {617-628},
pmid = {34285374},
issn = {1881-1469},
mesh = {Animals ; Antineoplastic Agents/chemistry/*pharmacology ; *Drug Delivery Systems ; *G-Quadruplexes ; Humans ; Neoplasms/*drug therapy ; *Telomere ; },
abstract = {G-quadruplexes (G4s) are higher-order structures formed by guanine-rich sequences of nucleic acids, such as the telomeric 5'-TTAGGG-3'/5'-UUAGGG-3' repeats and those in gene regulatory regions. G4s regulate various biological events, including replication, transcription, and translation. Imbalanced G4 dynamics is associated with diseases, such as cancer and neurodegenerative diseases. Telomestatin is a natural macrocyclic compound derived from Streptomyces anulatus 3533-SV4. It interacts with the guanine quartet via π-π stacking and potently stabilizes G4. Because G4 stabilization at the telomeric repeat inhibits the telomere-synthesizing enzyme telomerase, telomestatin was originally identified as a telomerase inhibitor. Whereas non-toxic doses of telomestatin induce gradual shortening of telomeres and eventual crisis in human cancer cells, higher doses trigger prompt replication stress and DNA damage responses, resulting in acute cell death. Suppression of the transcription and translation of G4-containing genes is also implicated in the anticancer effects of telomestatin. Because telomestatin is rare, labile, and insoluble, synthetic oxazole telomestatin derivatives have been developed and verified for their therapeutic efficacies in preclinical cancer models. Furthermore, a variety of G4-stabilizing compounds have been reported as promising seeds for molecular cancer therapeutics. To improve the design of future clinical studies, it will be important to identify predictive biomarkers of drug efficacy.},
}
@article {pmid34282826,
year = {2021},
author = {Hailu, EM and Lewis, TT and Needham, BL and Lin, J and Seeman, TE and Mujahid, MS},
title = {Longitudinal Associations between Discrimination, Neighborhood Social Cohesion, and Telomere Length: The Multi-Ethnic Study of Atherosclerosis (MESA).},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glab193},
pmid = {34282826},
issn = {1758-535X},
abstract = {BACKGROUND: We aimed to examine if neighborhood social cohesion moderated longitudinal associations between baseline reports of discrimination and 10-year changes in Leukocyte Telomere Length (LTL).<br><br>METHODS: Data are from the Multi-Ethnic Study of Atherosclerosis (MESA; N=1,064; age range 45-84 years). Baseline discrimination was measured using the Major Experiences of Discrimination Scale (MDS; none, 1 domain, &#x2265;2 domains) and the Experiences of Discrimination Scale (EDS; none, moderate, high). Neighborhood social cohesion at baseline was assessed via a community survey within census tract defined neighborhoods. 10-year change in LTL was defined as Regression to the Mean corrected 10-year difference in the ratio of telomeric DNA to a single copy gene (T/S).<br><br>RESULTS: In linear mixed effects models, we found that neighborhood social cohesion modified the effect of baseline reports of MDS on 10-year changes in LTL, independent of sociodemographic characteristics, health behaviors, and health conditions (p(&#x3c7; 2)=0.01). Among those residing in neighborhoods with low social cohesion, experiencing major discrimination in &#x2265;2 domains was associated with faster LTL attrition over 10-years, compared to reporting no discrimination (&#x3b2;=-0.03; 95% CI: -0.06, -0.003). We found no main associations for either discrimination measure and no interaction between EDS and neighborhood social cohesion.<br><br>CONCLUSIONS: Results indicate that neighborhood social cohesion is an important dimension of the neighborhood context that may moderate the impact of major experiences of discrimination on telomere length attrition. These findings help advance our understanding of the integral role that neighborhood environments play in attenuating the effect of discrimination on accelerated cell aging.},
}
@article {pmid34282343,
year = {2021},
author = {Lakota, K and Varga, J},
title = {Linking autoimmunity, short telomeres and lung fibrosis in SSc.},
journal = {Nature reviews. Rheumatology},
volume = {17},
number = {9},
pages = {511-512},
pmid = {34282343},
issn = {1759-4804},
mesh = {*Autoimmunity/genetics ; Fibrosis ; Humans ; *Pulmonary Fibrosis/genetics ; Telomere/genetics ; },
}
@article {pmid34278498,
year = {2021},
author = {Wang, Z and Wu, X},
title = {Abnormal function of telomere protein TRF2 induces cell mutation and the effects of environmental tumor‑promoting factors (Review).},
journal = {Oncology reports},
volume = {46},
number = {2},
pages = {},
pmid = {34278498},
issn = {1791-2431},
mesh = {Cell Cycle ; Gene Expression Regulation, Neoplastic ; Humans ; Mutation ; Neoplasm Proteins/*genetics ; Neoplasms/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {Recent studies have found that somatic gene mutations and environmental tumor‑promoting factors are both indispensable for tumor formation. Telomeric repeat‑binding factor (TRF)2 is the core component of the telomere shelterin complex, which plays an important role in chromosome stability and the maintenance of normal cell physiological states. In recent years, TRF2 and its role in tumor formation have gradually become a research hot topic, which has promoted in‑depth discussions into tumorigenesis and treatment strategies, and has achieved promising results. Some cells bypass elimination, due to either aging, apoptosis via mutations or abnormal prolongation of the mitotic cycle, and enter the telomere crisis period, where large‑scale DNA reorganization occurs repeatedly, which manifests as the precancerous cell cycle. Finally, at the end of the crisis cycle, the mutation activates either the expression level of telomerase or activates the alternative lengthening of telomere mechanism to extend the local telomeres. Under the protection of TRF2, chromosomes are gradually stabilized, immortal cells are formed and the stagewise mutation‑driven transformation of normal cells to cancer cells is completed. In addition, TRF2 also shares the characteristics of environmental tumor‑promoting factors. It acts on multiple signal transduction pathway‑related proteins associated with cell proliferation, and affects peripheral angiogenesis, inhibits the immune recognition and killing ability of the microenvironment, and maintains the stemness characteristics of tumor cells. TRF2 levels are abnormally elevated by a variety of tumor control proteins, which are more conducive to the protection of telomeres and the survival of tumor cells. In brief, the various regulatory mechanisms which tumor cells rely on to survive are organically integrated around TRF2, forming a regulatory network, which is conducive to the optimization of the survival direction of heterogeneous tumor cells, and promotes their survival and adaptability. In terms of clinical application, TRF2 is expected to become a new type of cancer prognostic marker and a new tumor treatment target. Inhibition of TRF2 overexpression could effectively cut off the core network regulating tumor cell survival, reduce drug resistance, or bypass the mutation under the pressure of tumor treatment selection, which may represent a promising therapeutic strategy for the complete eradication of tumors in the clinical setting. Based on recent research, the aim of the present review was to systematically elaborate on the basic structure and functional characteristics of TRF2 and its role in tumor formation, and to analyze the findings indicating that TRF2 deficiency or overexpression could cause severe damage to telomere function and telomere shortening, and induce DNA damage response and chromosomal instability.},
}
@article {pmid34277003,
year = {2021},
author = {García-Martínez, S and González-Gamo, D and Fernández-Marcelo, T and Tesolato, S and De La Serna, S and Domínguez-Serrano, I and Cano-Valderrama, O and Barabash, A and De Juan, C and Torres-García, A and Iniesta, P},
title = {Obesity and telomere status in the prognosis of patients with colorectal cancer submitted to curative intention surgical treatment.},
journal = {Molecular and clinical oncology},
volume = {15},
number = {3},
pages = {184},
pmid = {34277003},
issn = {2049-9469},
abstract = {The risk of colorectal cancer (CRC) development has been associated with telomere dysfunction and obesity. However, clinical relevance of these parameters in CRC prognosis is not clear. Therefore, the aim of the present study was to evaluate the impact of obesity and telomere status in the prognosis of patients affected by CRC and submitted to curative surgical treatment. According to published data, this is the first work in which obesity and telomere status are jointly considered in relation to CRC prognosis. A prospective study including 162 patients with CRC submitted to curative surgical treatment was performed. Subjects were classified according to their BMI. Telomere status was established through telomere length and telomerase activity evaluation. Statistical analyses were performed using the SPSS software package version 22. Telomere shortening was inversely associated with BMI in patients with CRC. Notably, among patients with CRC, subjects with obesity exhibited less shortening of tumor telomeres than non-obese patients (P=0.047). Patients with shorter telomeres, both in the tumor (median telomere length <6.5 kb) and their non-tumor paired tissues (median telomere length <7.1 kb), had the best clinical evolution, regardless of the Dukes' stage of cancers (P=0.025, for tumor samples; P=0.003, for non-tumor samples). Additionally, subjects with a BMI >31.85 kg/m[2] showed the worse clinical outcomes compared with subjects with other BMI values. Interestingly, the impact of BMI showed sex dependence, since only the group of men displayed significant differences in CRC prognosis in relation to obesity status (P=0.037). From the results of the present study, based on a multivariate prediction model to establish prognosis, it was concluded that telomere length is a useful biomarker to predict prognosis in patients with CRC. Regardless of BMI values, the improved clinical evolution was associated with shorter telomeres. The impact of BMI seems to be associated with other factors, such as sex.},
}
@article {pmid34273872,
year = {2021},
author = {Farzan, SF and Shahriar, M and Kibriya, MG and Jasmine, F and Sarwar, G and Slavkovic, V and Graziano, JH and Ahsan, H and Argos, M},
title = {Urinary arsenic and relative telomere length in 5-7 year old children in Bangladesh.},
journal = {Environment international},
volume = {156},
number = {},
pages = {106765},
pmid = {34273872},
issn = {1873-6750},
support = {K99 ES024144/ES/NIEHS NIH HHS/United States ; R00 ES024144/ES/NIEHS NIH HHS/United States ; R01 ES024423/ES/NIEHS NIH HHS/United States ; },
mesh = {*Arsenic/toxicity ; Bangladesh ; Child ; Child, Preschool ; Humans ; Telomere ; Telomere Homeostasis ; Telomere Shortening ; },
abstract = {BACKGROUND: Telomere length has been associated with the occurrence and progression of common chronic and age-related diseases, and in younger populations, may represent a biomarker of disease susceptibility. Early childhood is a critical period for telomere biology as this period is characterized by a rapid decline in telomere length due to a large turnover of highly proliferative cells and may represent a period of unique sensitivity to environmental insults. Arsenic (As) exposure has been associated with both telomere lengthening and shortening in adults and children and some evidence suggests the effects may differ by level and timing of exposure.<br><br>OBJECTIVES: Given the lack of clarity across studies, we investigated the association between urinary As and leukocyte telomere length among 476 five- to seven-year-old children enrolled in the Bangladesh Environmental Research in Children's Health (BiRCH) cohort.<br><br>METHODS: In a series of multivariable models, adjusted for key covariates, we examined associations between urinary As and relative telomere length (RTL) of whole blood DNA.<br><br>RESULTS: We observed small but consistent, negative associations between urinary As and RTL, such that a doubling of urinary As was associated with a -0.017 (95% CI: -0.030, -0.005; p&#xa0;=&#xa0;0.0056) decrease in RTL, in fully adjusted models. We also observed a somewhat stronger inverse relationship between urinary As concentration and RTL among children born to fathers&#xa0;&#x2265;&#xa0;30&#xa0;years of age at the time of birth, than those&#xa0;<&#xa0;30&#xa0;years; however, we did not observe a statistically significant interaction.<br><br>DISCUSSION: Our study suggests that As influences RTL, with detectable associations in early to mid-childhood. Further studies are needed to confirm our findings and investigate the potential long-term impacts of telomere shortening in childhood on later life health outcomes. Additional studies exploring how dose and timing of exposure may relate to RTL are critical to understanding As's relationship to telomere length.},
}
@article {pmid34272332,
year = {2021},
author = {Liu, S and Chung, MP and Ley, B and French, S and Elicker, BM and Fiorentino, DF and Chung, LS and Boin, F and Wolters, PJ},
title = {Peripheral blood leucocyte telomere length is associated with progression of interstitial lung disease in systemic sclerosis.},
journal = {Thorax},
volume = {76},
number = {12},
pages = {1186-1192},
pmid = {34272332},
issn = {1468-3296},
support = {R01 HL139897/HL/NHLBI NIH HHS/United States ; T32 AR050942/AR/NIAMS NIH HHS/United States ; },
mesh = {Humans ; *Idiopathic Pulmonary Fibrosis ; Lung ; *Lung Diseases, Interstitial/genetics ; Retrospective Studies ; *Scleroderma, Systemic/complications/genetics ; Telomere ; },
abstract = {BACKGROUND: Peripheral blood leucocyte telomere length (PBL-TL) is associated with outcomes in patients with idiopathic pulmonary fibrosis. Whether PBL-TL is associated with progression of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is unknown.<br><br>METHODS: A retrospective observational cohort study was performed using prospectively collected data from 213 patients with SSc followed at the University of California San Francisco (UCSF) Scleroderma Center. PBL-TL was measured by quantitative PCR of DNA isolated from peripheral blood. Associations between PBL-TL and pulmonary function test trends in patients with SSc-ILD were assessed by longitudinal analysis using Generalised Linear Mixed Models. Findings were validated in a cohort of 61 patients with SSc-ILD enrolled in the Stanford University Scleroderma Center database.<br><br>RESULTS: Patients with UCSF SSc with ILD were found to have shorter PBL-TL compared with those without ILD (6554&#xb1;671&#x2009;base pairs (bp) vs 6782&#xb1;698&#x2009;bp, p=0.01). Shorter PBL-TL was associated with the presence of ILD (adjusted OR 2.1 per 1000&#x2009;bp TL decrease, 95%&#x2009;CI [1.25 to 3.70], p=0.006). PBL-TL was shorter in patients with SSc-ILD lacking SSc-specific autoantibodies compared with seropositive subjects (6237&#xb1;647&#x2009;bp vs 6651&#xb1;653&#x2009;bp, p=0.004). Shorter PBL-TL was associated with increased risk for lung function deterioration with an average of 67&#x2009;mL greater loss in per year for every 1000&#x2009;bp decrease in PBL-TL in the combined SSc-ILD cohorts (longitudinal analysis, adjusted model: 95%&#x2009;CI -104 mL to -33&#x2009;mL, p<0.001).<br><br>CONCLUSIONS: These findings suggest that telomere dysfunction may be associated with SSc-ILD progression and that PBL-TL measurement may be useful for stratifying risk for SSc-ILD progression.},
}
@article {pmid34270368,
year = {2022},
author = {Bailey, SM and Luxton, JJ and McKenna, MJ and Taylor, LE and George, KA and Jhavar, SG and Swanson, GP},
title = {Ad Astra - telomeres in space!.},
journal = {International journal of radiation biology},
volume = {98},
number = {3},
pages = {395-403},
doi = {10.1080/09553002.2021.1956010},
pmid = {34270368},
issn = {1362-3095},
mesh = {*Aging ; Female ; Humans ; Laboratories ; Male ; Middle Aged ; *Space Flight ; Telomere ; },
abstract = {PURPOSE: My journey to the stars began as I - along with the whole world - stood still and watched Neil Armstrong take those first small steps on the Moon. Fast forward 50 years and NASA astronauts Scott Kelly and Christina Koch each spend nearly a year in space aboard the International Space Station (ISS), a remarkable multinational collaborative project and floating U.S. National Laboratory that has supported continuous human presence in low Earth orbit for the past 20 years. Marking a new era of human space exploration, the first commercial rocket, SpaceX Falcon 9, recently launched NASA astronauts Doug Hurley and Bob Behnken in the Crew Dragon spacecraft Endeavor to the ISS and returned safely to Earth. NASA and its commercial partners are rapidly advancing innovative space technologies, and with the recently announced Artemis team of astronauts, plans to send the first woman and next man back to the moon and establish sustainable exploration by the end of the decade. Humankind will then be poised to take the next giant leap - pioneering human exploration of Mars.<br><br>CONCLUSIONS: Historically, fewer than 600 individuals have participated in spaceflight, the vast majority of whom have been middle aged males (35-55&#x2009;years) on short duration missions (less than 20&#x2009;days). Thus, as the number and diversity of space travelers increase, a better understanding of how long-duration spaceflight affects human health is essential to maintaining individual astronaut performance during, and improving disease and aging trajectories following, future exploration missions. Here, I review findings from our NASA Twins Study and Telomeres investigations, highlighting potential mechanistic roles of chronic space radiation exposure in changes in telomere length and persistent DNA damage responses associated with long-duration spaceflight. Importantly, similar trends were observed in prostate cancer patients undergoing intensity-modulated radiation therapy (IMRT), additional support specifically for the role of radiation exposure. Individual differences in response were also observed in both cohorts, underscoring the importance of developing personalized approaches for evaluating human health effects and long-term outcomes associated with radiation exposures, whether on Earth or living in the extreme environment of space.},
}
@article {pmid34269919,
year = {2021},
author = {Luchini, C and Lawlor, RT and Bersani, S and Vicentini, C and Paolino, G and Mattiolo, P and Pea, A and Cingarlini, S and Milella, M and Scarpa, A},
title = {Alternative Lengthening of Telomeres (ALT) in Pancreatic Neuroendocrine Tumors: Ready for Prime-Time in Clinical Practice?.},
journal = {Current oncology reports},
volume = {23},
number = {9},
pages = {106},
pmid = {34269919},
issn = {1534-6269},
support = {203885/2017//Fondazione Cariverona/ ; J38D19000690001//Fondazione italiana Malattie Pancreas/ ; 12182//Associazione Italiana per la Ricerca sul Cancro/ ; },
mesh = {Biomarkers, Tumor/genetics/metabolism ; Co-Repressor Proteins/genetics ; Genetic Predisposition to Disease/*genetics ; Humans ; In Situ Hybridization, Fluorescence/methods ; Molecular Chaperones/genetics ; *Mutation ; Neuroendocrine Tumors/*genetics/metabolism/pathology ; Pancreatic Neoplasms/*genetics/metabolism/pathology ; Telomere/*genetics ; *Telomere Homeostasis ; X-linked Nuclear Protein/genetics/metabolism ; },
abstract = {PURPOSE OF REVIEW: Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism used by some types of malignancies, including pancreatic neuroendocrine tumors, to overcome the issue of telomere shortening, thus supporting tumor growth and cell proliferation. This review is focused on the most important achievements and opportunities deriving from ALT assessment in PanNET onco-pathology, highlighting the most promising fields in which such biomarker could be implemented in clinical practice.<br><br>RECENT FINDINGS: In pancreatic neuroendocrine tumors (PanNET), ALT is strongly correlated with the mutational status of two chromatin remodeling genes, DAXX and ATRX. Recent advances in tumor biology permitted to uncover important roles of ALT in the landscape of PanNET, potentially relevant for introducing this biomarker into clinical practice. Indeed, ALT emerged as a reliable indicator of worse prognosis for PanNET, helping in clinical stratification and identification of "high-risk" patients. Furthermore, it is a very specific marker supporting the pancreatic origin of neuroendocrine neoplasms and can be used for improving the diagnostic workflow of patients presenting with neuroendocrine metastasis from unknown primary. The activation of this process can be determined by specific FISH analysis. ALT should be introduced in clinical practice for identifying "high-risk" PanNET patients and improving their clinical management, and as a marker of pancreatic origin among neuroendocrine tumors.},
}
@article {pmid34268523,
year = {2021},
author = {Anderson, JJ and Susser, E and Arbeev, KG and Yashin, AI and Levy, D and Verhulst, S and Aviv, A},
title = {Short Telomeres and a T-Cell Shortfall in COVID-19: The Aging Effect.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {34268523},
support = {R01 HL134840/HL/NHLBI NIH HHS/United States ; RF1 AG046860/AG/NIA NIH HHS/United States ; U01 AG066529/AG/NIA NIH HHS/United States ; U24 AG066528/AG/NIA NIH HHS/United States ; },
abstract = {UNLABELLED: The slow pace of global vaccination and the rapid emergence of SARS-CoV-2 variants suggest recurrent waves of COVID-19 in coming years. Therefore, understanding why deaths from COVID-19 are highly concentrated among older adults is essential for global health. Severe COVID-19 T-cell lymphopenia is more common among older adults, and it entails poor prognosis. Much about the primary etiology of this form of lymphopenia remains unknown, but regardless of its causes, offsetting the decline in T-cell count during SARS-CoV-2 infection demands fast and massive T-cell clonal expansion, which is telomere length (TL)-dependent. We have built a model that captures the effect of age-dependent TL shortening in hematopoietic cells and its effect on T-cell clonal expansion capacity. The model shows that an individual with average hematopoietic cell TL (HCTL) at age twenty years maintains maximal T-cell clonal expansion capacity until the 6th decade of life when this capacity plummets by more than 90% over the next ten years. The collapse coincides with the steep increase in COVID-19 mortality with age. HCTL metrics may thus explain the vulnerability of older adults to COVID-19. That said, the wide inter-individual variation in HCTL across the general population means that some younger adults with inherently short HCTL might be at risk of severe COVID-19 lymphopenia and mortality from the disease.<br><br>SIGNIFICANCE STATEMENT: Declining immunity with advancing age is a general explanation for the increased mortality from COVID-19 among older adults. This mortality far exceeds that from viral illnesses such as the seasonal influenza, and it thus requires specific explanations. One of these might be diminished ability with age to offset the development of severe T-cell lymphopenia (a low T-cell count in the blood) that often complicates COVID-19. We constructed a model showing that age-dependent shortening of telomeres might constrain the ability of T-cells of some older COVID-19 patients to undertake the massive proliferation required to clear the virus that causes the infection. The model predicts that individuals with short telomeres, principally seniors, might be at a higher risk of death from COVID-19.},
}
@article {pmid34267850,
year = {2021},
author = {Harrigan, AM and MacDonald, S and Crooks, B and Dyack, S and Trottier, AM},
title = {A Case Series of TERC Variant Telomere Biology Disorders in Unrelated Families From Atlantic Canada.},
journal = {Journal of hematology},
volume = {10},
number = {3},
pages = {130-135},
pmid = {34267850},
issn = {1927-1220},
abstract = {TERC variant telomere biology disorders (TBDs) are a rare, heterogenous group of disorders that arise from germline variants in TERC, a gene that encodes for the RNA component of telomerase. Variants in TERC lead to accelerated telomere attrition and can manifest as many different phenotypes. In this case series, we aimed to add to the literature describing TERC variant TBDs by reporting cases from two unrelated families from Atlantic Canada. The first case, a previously described germline TERC variant, n.107G>T (NR_001566.1), was identified in a young woman with myelodysplastic syndrome (MDS) and found to segregate with cytopenias in the family. This case represents a unique phenotypic presentation: this variant has not previously been described in patients with MDS and adds important segregation data to the literature. The second case, a novel TERC n.437T>G variant, was identified in a patient with both aplastic anemia and pulmonary fibrosis manifesting in his early 30s. We report these novel cases of germline TERC variants in order to help clinicians recognize TBDs, as well as to add important supporting information for the pathogenicity of these variants.},
}
@article {pmid34266503,
year = {2021},
author = {Hackenhaar, FS and Josefsson, M and Adolfsson, AN and Landfors, M and Kauppi, K and Hultdin, M and Adolfsson, R and Degerman, S and Pudas, S},
title = {Short leukocyte telomeres predict 25-year Alzheimer's disease incidence in non-APOE ε4-carriers.},
journal = {Alzheimer's research &amp; therapy},
volume = {13},
number = {1},
pages = {130},
pmid = {34266503},
issn = {1758-9193},
mesh = {*Alzheimer Disease/epidemiology/genetics ; *Apolipoprotein E4/genetics ; Apolipoproteins E/genetics ; Genotype ; Humans ; Incidence ; Leukocytes ; Risk Factors ; Telomere ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) has been shown to predict Alzheimer's disease (AD), albeit inconsistently. Failing to account for the competing risks between AD, other dementia types, and mortality, can be an explanation for the inconsistent findings in previous time-to-event analyses. Furthermore, previous studies indicate that the association between LTL and AD is non-linear and may differ depending on apolipoprotein E (APOE) ε4 allele carriage, the strongest genetic AD predictor.<br><br>METHODS: We analyzed whether baseline LTL in interaction with APOE &#x3b5;4 predicts AD, by following 1306 initially non-demented subjects for 25 years. Gender- and age-residualized LTL (rLTL) was categorized into tertiles of short, medium, and long rLTLs. Two complementary time-to-event models that account for competing risks were used; the Fine-Gray model to estimate the association between the rLTL tertiles and the cumulative incidence of AD, and the cause-specific hazard model to assess whether the cause-specific risk of AD differed between the rLTL groups. Vascular dementia and death were considered competing risk events. Models were adjusted for baseline lifestyle-related risk factors, gender, age, and non-proportional hazards.<br><br>RESULTS: After follow-up, 149 were diagnosed with AD, 96 were diagnosed with vascular dementia, 465 died without dementia, and 596 remained healthy. Baseline rLTL and other covariates were assessed on average 8 years before AD onset (range 1-24). APOE &#x3b5;4-carriers had significantly increased incidence of AD, as well as increased cause-specific AD risk. A significant rLTL-APOE interaction indicated that short rLTL at baseline was significantly associated with an increased incidence of AD among non-APOE &#x3b5;4-carriers (subdistribution hazard ratio = 3.24, CI 1.404-7.462, P = 0.005), as well as borderline associated with increased cause-specific risk of AD (cause-specific hazard ratio = 1.67, CI 0.947-2.964, P = 0.07). Among APOE &#x3b5;4-carriers, short or long rLTLs were not significantly associated with AD incidence, nor with the cause-specific risk of AD.<br><br>CONCLUSIONS: Our findings from two complementary competing risk time-to-event models indicate that short rLTL may be a valuable predictor of the AD incidence in non-APOE &#x3b5;4-carriers, on average 8 years before AD onset. More generally, the findings highlight the importance of accounting for competing risks, as well as the APOE status of participants in AD biomarker research.},
}
@article {pmid34265700,
year = {2021},
author = {Heba, AC and Toupance, S and Arnone, D and Peyrin-Biroulet, L and Benetos, A and Ndiaye, NC},
title = {Telomeres: New players in immune-mediated inflammatory diseases?.},
journal = {Journal of autoimmunity},
volume = {123},
number = {},
pages = {102699},
doi = {10.1016/j.jaut.2021.102699},
pmid = {34265700},
issn = {1095-9157},
mesh = {Arthritis, Rheumatoid/etiology ; Humans ; Inflammation/*etiology/immunology ; Inflammatory Bowel Diseases/etiology ; Psoriasis/etiology ; Spondylarthritis/etiology ; Telomere/*physiology ; Uveitis/etiology ; },
abstract = {Telomeres are repetitive DNA sequences located at the ends of linear chromosomes that preserve the integrity and stability of the genome. Telomere dysfunctions due to short telomeres or altered telomere structures can ultimately lead to replicative cellular senescence and chromosomal instability, both mechanisms being hallmarks of ageing. Chronic inflammation, oxidative stress and finally telomere length (TL) dynamics have been shown to be involved in various age-related non-communicable diseases (NCDs). Immune-mediated inflammatory diseases (IMIDs), including affections such as inflammatory bowel disease, psoriasis, rheumatoid arthritis, spondyloarthritis and uveitis belong to this group of age-related NCDs. Although in recent years, we have witnessed the emergence of studies in the literature linking these IMIDs to TL dynamics, the causality between these diseases and telomere attrition is still unclear and controversial. In this review, we provide an overview of available studies on telomere dynamics and discuss the utility of TL measurements in immune-mediated inflammatory diseases.},
}
@article {pmid34265046,
year = {2021},
author = {Lee, RS and Zandi, PP and Santos, A and Aulinas, A and Carey, JL and Webb, SM and McCaul, ME and Resmini, E and Wand, GS},
title = {Cross-species Association Between Telomere Length and Glucocorticoid Exposure.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {106},
number = {12},
pages = {e5124-e5135},
pmid = {34265046},
issn = {1945-7197},
support = {U01 AA020890/AA/NIAAA NIH HHS/United States ; NIAAA U01 AA020890/NH/NIH HHS/United States ; },
mesh = {Adult ; *Aging ; Animals ; Case-Control Studies ; Cushing Syndrome/etiology/metabolism/*pathology ; *Disease Models, Animal ; Female ; Follow-Up Studies ; Glucocorticoids/*adverse effects ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Rats ; Rats, Sprague-Dawley ; Species Specificity ; *Stress, Physiological ; *Telomere Shortening ; },
abstract = {CONTEXT: Chronic exposure to glucocorticoids (GCs) or stress increases the risk of medical disorders, including cardiovascular and neuropsychiatric disorders. GCs contribute to accelerated aging; however, while the link between chronic GC exposure and disease onset is well established, the underpinning mechanisms are not clear.<br><br>OBJECTIVE: We explored the potential nexus between GCs or stress exposure and telomere length.<br><br>METHODS: In addition to rats exposed to 3 weeks of chronic stress, an iatrogenic mouse model of Cushing syndrome (CS), and a mouse neuronal cell line, we studied 32 patients with CS and age-matched controls and another cohort of 75 healthy humans.<br><br>RESULTS: (1) Exposure to stress in rats was associated with a 54.5% (P&#x2005;=&#x2005;0.036) reduction in telomere length in T cells. Genomic DNA (gDNA) extracted from the dentate gyrus of stressed and unstressed rats showed 43.2% reduction in telomere length (P&#x2005;=&#x2005;0.006). (2) Mice exposed to corticosterone had a 61.4% reduction in telomere length in blood gDNA (P&#x2005;=&#x2005;5.75&#x2005;&#xd7;&#x2005;10-5) and 58.8% reduction in telomere length in the dentate gyrus (P&#x2005;= 0.002). (3) We observed a 40.8% reduction in the telomere length in patients with active CS compared to healthy controls (P&#x2005;=&#x2005;0.006). There was a 17.8% reduction in telomere length in cured CS patients, which was not different from that of healthy controls (P&#x2005;=&#x2005;0.08). For both cured and active CS, telomere length correlated significantly with duration of hypercortisolism (R2&#x2005;=&#x2005;0.22, P&#x2005;=&#x2005;0.007). (4) There was a 27.6% reduction in telomere length between low and high tertiles in bedtime cortisol levels of healthy participants (P&#x2005;=&#x2005;0.019).<br><br>CONCLUSION: Our findings demonstrate that exposure to stress and/or GCs is associated with shortened telomeres, which may be partially reversible.},
}
@article {pmid34256387,
year = {2022},
author = {Aguiar, SS and Rosa, TS and Neves, RVP and Leite, PLA and Maciel, LA and Gutierrez, SD and Rosa, EC and Andrade, RV and Degens, H and Korhonen, MT and Lewis, JE and Simões, HG},
title = {Telomere Length, SIRT1, and Insulin in Male Master Athletes: The Path to Healthy Longevity?.},
journal = {International journal of sports medicine},
volume = {43},
number = {1},
pages = {29-33},
doi = {10.1055/a-1510-9259},
pmid = {34256387},
issn = {1439-3964},
support = {Funda&#xe7;&#xe3;o de Apoio &#xe0; Pesquisa do Distrito Federal (FAP/DF)//0193.001762/2017/ ; },
mesh = {Adult ; Aging ; *Athletes ; Cross-Sectional Studies ; Humans ; Insulin/*blood ; Leukocytes ; *Longevity ; Male ; Middle Aged ; *Sirtuin 1/genetics ; Telomere/*ultrastructure ; },
abstract = {Lower SIRT1 and insulin resistance are associated with accelerated telomere shortening. This study investigated whether the lifestyle of master athletes can attenuate these age-related changes and thereby slow aging. We compared insulin, SIRT1, and telomere length in highly trained male master athletes (n=52; aged 49.9±7.2 yrs) and age-matched non-athletes (n=19; aged 47.3±8.9 yrs). This is a cross-sectional study, in which all data were collected in one visit. Overnight fasted SIRT1 and insulin levels in whole blood were assessed using commercial kits. Relative telomere length was determined in leukocytes through qPCR analyses. Master athletes had higher SIRT1, lower insulin, and longer telomere length than age-matched non-athletes (p<0.05 for all). Insulin was inversely associated with SIRT1 (r=-0.38; p=0.001). Telomere length correlated positively with SIRT1 (r=0.65; p=0.001), whereas telomere length and insulin were not correlated (r=0.03; p=0.87). In conclusion, master athletes have higher SIRT1, lower insulin, and longer telomeres than age-matched non-athletes. Furthermore, SIRT1 was negatively associated with insulin and positively associated with telomere length. These findings suggest that in this sample of middle-aged participants reduced insulin, increased SIRT1 activity, and attenuation of biological aging are connected.},
}
@article {pmid34255844,
year = {2021},
author = {Liu, J and Hu, X and Bao, K and Kim, JK and Zhang, C and Jia, S and Qiao, F},
title = {The cooperative assembly of shelterin bridge provides a kinetic gateway that controls telomere length homeostasis.},
journal = {Nucleic acids research},
volume = {49},
number = {14},
pages = {8110-8119},
pmid = {34255844},
issn = {1362-4962},
support = {R01 GM098943/GM/NIGMS NIH HHS/United States ; R35 GM126910/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes/genetics ; DNA/genetics ; DNA, Single-Stranded/genetics ; DNA-Binding Proteins/*genetics ; Humans ; Kinetics ; Multiprotein Complexes/genetics/ultrastructure ; Mutation ; Schizosaccharomyces/genetics ; Schizosaccharomyces pombe Proteins/*genetics ; Shelterin Complex ; Telomere/genetics ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/*genetics/ultrastructure ; },
abstract = {Shelterin is a six-protein complex that coats chromosome ends to ensure their proper protection and maintenance. Similar to the human shelterin, fission yeast shelterin is composed of telomeric double- and single-stranded DNA-binding proteins, Taz1 and Pot1, respectively, bridged by Rap1, Poz1 and Tpz1. The assembly of the proteinaceous Tpz1-Poz1-Rap1 complex occurs cooperatively and disruption of this shelterin bridge leads to unregulated telomere elongation. However, how this biophysical property of bridge assembly is integrated into shelterin function is not known. Here, utilizing synthetic bridges with a range of binding properties, we find that synthetic shelterin bridge lacking cooperativity requires a linker pair that matches the native bridge in complex lifespan but has dramatically higher affinity. We find that cooperative assembly confers kinetic properties on the shelterin bridge allowing disassembly to function as a molecular timer, regulating the duration of the telomere open state, and consequently telomere lengthening to achieve a defined species-specific length range.},
}
@article {pmid34253611,
year = {2021},
author = {Chakravarti, D and Lee, R and Multani, AS and Santoni, A and Keith, Z and Hsu, WH and Chang, K and Reyes, L and Rashid, A and Wu, CJ and Li, J and Zhang, J and Shim, HS and Chandra, K and Deng, P and Spring, DJ and Nielsen, OH and Riis, LB and Mayigegowda, KK and Blutt, SE and Zhang, J and Younes, M and DuPont, A and Thirumurthi, S and Vilar, E and Estes, MK and Colla, S and Shroyer, NF and DePinho, RA},
title = {Telomere dysfunction instigates inflammation in inflammatory bowel disease.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {118},
number = {29},
pages = {},
pmid = {34253611},
issn = {1091-6490},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; R01 DK118904/DK/NIDDK NIH HHS/United States ; P30 DK056338/DK/NIDDK NIH HHS/United States ; R01 CA084628/CA/NCI NIH HHS/United States ; T32 CA186892/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins/genetics/immunology ; Humans ; Inflammatory Bowel Diseases/genetics/*immunology ; Interleukin-18/genetics/immunology ; Intestinal Mucosa/immunology ; Mice ; Telomerase/genetics/immunology ; Telomere/genetics/*immunology ; YAP-Signaling Proteins/genetics/immunology ; },
abstract = {Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway. In organoid models from ulcerative colitis and Crohn's disease patients, pharmacological interventions of telomerase reactivation, suppression of DNA damage signaling, or YAP1 inhibition reduced pro-IL-18 production. Together, these findings support a model wherein telomere dysfunction in the intestinal epithelium can initiate the inflammatory process in IBD, pointing to therapeutic interventions for this disease.},
}
@article {pmid34253240,
year = {2021},
author = {Xue, L and Gao, Y and Wu, M and Tian, T and Fan, H and Huang, Y and Huang, Z and Li, D and Xu, L},
title = {Telomere-to-telomere assembly of a fish Y chromosome reveals the origin of a young sex chromosome pair.},
journal = {Genome biology},
volume = {22},
number = {1},
pages = {203},
pmid = {34253240},
issn = {1474-760X},
support = {J 4477/FWF_/Austrian Science Fund FWF/Austria ; },
mesh = {Animals ; Centromere ; Eels/*genetics ; Fish Proteins/genetics/metabolism ; Gene Expression ; *Genome ; HMGN Proteins/*genetics/metabolism ; Heterochromatin/chemistry ; Karyotype ; Male ; *Sex Determination Processes ; *Telomere ; Testis/growth &amp; development/metabolism ; X Chromosome ; Y Chromosome/*chemistry ; },
abstract = {BACKGROUND: The origin of sex chromosomes requires the establishment of recombination suppression between the proto-sex chromosomes. In many fish species, the sex chromosome pair is homomorphic with a recent origin, providing species for studying how and why recombination suppression evolved in the initial stages of sex chromosome differentiation, but this requires accurate sequence assembly of the X and Y (or Z and W) chromosomes, which may be difficult if they are recently diverged.<br><br>RESULTS: Here we produce a haplotype-resolved genome assembly of zig-zag eel (Mastacembelus armatus), an aquaculture fish, at the chromosomal scale. The diploid assembly is nearly gap-free, and in most chromosomes, we resolve the centromeric and subtelomeric heterochromatic sequences. In particular, the Y chromosome, including its highly repetitive short arm, has zero gaps. Using resequencing data, we identify a ~7 Mb fully sex-linked region (SLR), spanning the sex chromosome centromere and almost entirely embedded in the pericentromeric heterochromatin. The SLRs on the X and Y chromosomes are almost identical in sequence and gene content, but both are repetitive and heterochromatic, consistent with zero or low recombination. We further identify an HMG-domain containing gene HMGN6 in the SLR as a candidate sex-determining gene that is expressed at the onset of testis development.<br><br>CONCLUSIONS: Our study supports the idea that preexisting regions of low recombination, such as pericentromeric regions, can give rise to SLR in the absence of structural variations between the proto-sex chromosomes.},
}
@article {pmid34245740,
year = {2021},
author = {Chico-Sordo, L and Córdova-Oriz, I and Polonio, AM and S-Mellado, LS and Medrano, M and García-Velasco, JA and Varela, E},
title = {Reproductive aging and telomeres: Are women and men equally affected?.},
journal = {Mechanisms of ageing and development},
volume = {198},
number = {},
pages = {111541},
doi = {10.1016/j.mad.2021.111541},
pmid = {34245740},
issn = {1872-6216},
mesh = {*Aging/pathology/physiology ; Cellular Senescence/*physiology ; Female ; *Genitalia/metabolism/physiopathology ; Gonadal Steroid Hormones/*metabolism ; Humans ; *Infertility/etiology/physiopathology ; Male ; Oocytes/*physiology ; Reproduction/physiology ; Spermatozoa/*physiology ; Telomere Homeostasis/*physiology ; },
abstract = {Successful reproduction is very important for individuals and for society. Currently, the human health span and lifespan are the object of intense and productive investigation with great achievements, compared to the last century. However, reproduction span does not progress concomitantly with lifespan. Reproductive organs age, decreasing the levels of sexual hormones, which are protectors of health through their action on several organs of the body. Thus, this is the starting point of the organismal decay and infertility. This starting point is easily detected in women. In men, it goes under the surface, undetected, but it goes, nevertheless. Regarding fertility, aging alters the hormonal equilibrium, decreases the potential of reproductive organs, diminishes the quality of the gametes and worsen the reproductive outcomes. All these events happen at a different pace and affecting different organs in women and men. The question is what molecular pathways are involved in reproductive aging and if there is a possible halting or even reversion of the aging events. Answers to all these points will be explained in the present review.},
}
@article {pmid34244792,
year = {2021},
author = {Apte, MS and Masuda, H and Wheeler, DL and Cooper, JP},
title = {RNAi and Ino80 complex control rate limiting translocation step that moves rDNA to eroding telomeres.},
journal = {Nucleic acids research},
volume = {49},
number = {14},
pages = {8161-8176},
pmid = {34244792},
issn = {1362-4962},
mesh = {Chromosomes/genetics ; DNA, Ribosomal/*genetics ; Multiprotein Complexes/genetics ; RNA Interference ; Schizosaccharomyces/genetics ; Schizosaccharomyces pombe Proteins/*genetics ; Telomerase/genetics ; Telomere/*genetics ; Transcription Factors/*genetics ; Translocation, Genetic/*genetics ; },
abstract = {The discovery of HAATIrDNA, a telomerase-negative survival mode in which canonical telomeres are replaced with ribosomal DNA (rDNA) repeats that acquire chromosome end-protection capability, raised crucial questions as to how rDNA tracts 'jump' to eroding chromosome ends. Here, we show that HAATIrDNA formation is initiated and limited by a single translocation that juxtaposes rDNA from Chromosome (Chr) III onto subtelomeric elements (STE) on Chr I or II; this rare reaction requires RNAi and the Ino80 nucleosome remodeling complex (Ino80C), thus defining an unforeseen relationship between these two machineries. The unique STE-rDNA junction created by this initial translocation is efficiently copied to the remaining STE chromosome ends, independently of RNAi or Ino80C. Intriguingly, both RNAi and Ino80C machineries contain a component that plays dual roles in HAATI subtype choice. Dcr1 of the RNAi pathway and Iec1 of Ino80C both promote HAATIrDNA formation as part of their respective canonical machineries, but both also inhibit formation of the exceedingly rare HAATISTE (where STE sequences mobilize throughout the genome and assume chromosome end protection capacity) in non-canonical, pathway-independent manners. This work provides a glimpse into a previously unrecognized crosstalk between RNAi and Ino80C in controlling unusual translocation reactions that establish telomere-free linear chromosome ends.},
}
@article {pmid34237641,
year = {2021},
author = {Chang-Chien, J and Huang, JL and Tsai, HJ and Wang, SL and Kuo, ML and Yao, TC},
title = {Particulate matter causes telomere shortening and increase in cellular senescence markers in human lung epithelial cells.},
journal = {Ecotoxicology and environmental safety},
volume = {222},
number = {},
pages = {112484},
doi = {10.1016/j.ecoenv.2021.112484},
pmid = {34237641},
issn = {1090-2414},
mesh = {Cellular Senescence ; Epithelial Cells/metabolism ; Humans ; Lung/metabolism ; *Particulate Matter/toxicity ; Telomere ; *Telomere Shortening ; Tumor Suppressor Protein p53/genetics ; },
abstract = {Exposure to particulate matter (PM) has been associated with DNA damage, but the relationships between PM, telomere length and cellular senescence remain unclear. This study aimed to investigate the effects and potential mechanisms of PM on telomere length and cellular senescence in human lung epithelial cells. Human lung epithelial A549 cells were exposed to PM for 24 h. Cell viability and cytotoxicity were measured by the WST-1 assay and the lactate dehydrogenase release, respectively. Cellular uptake of PM was observed using transmission electron microscopy. Telomere length was measured using qPCR and expressed as T/S ratio. Cell cycle progression was analyzed by flow cytometry. Expression of human telomerase reverse transcriptase (hTERT) and cell cycle regulators was measured using mRNA by qPCR and protein levels by Western blot. Cellular senescence was determined by the expression of senescence-associated β-galactosidase (SA-β-Gal) with fluorescent microscopy and flow cytometry. Exposed to PM at the concentration of 200 μg/ml decreased cell viability and increased LDH levels in culture medium. Remarkably increased uptake of PM, shortening of telomere length, induction of G0/G1 phase arrest, and increased expression of senescence hallmarks were observed after exposure to PM in A549 cells. PM exposure induced upregulation of p21 and downregulation of proliferating cell nuclear antigen (PCNA) and hTERT expression, but no significant change in p53 expression, in A549 cells. Overall, exposure to PM may downregulate hTERT and PCNA through p53-independent induction of p21 expression, leading to telomere shortening, G0/G1 arrest and the onset of cellular senescence in human lung epithelial cells.},
}
@article {pmid34235373,
year = {2021},
author = {Wojcicki, JM and Lustig, RH and Jacobs, LM and Mason, AE and Hartman, A and Leung, C and Stanhope, K and Lin, J and Schmidt, LA and Epel, ES},
title = {Longer Leukocyte Telomere Length Predicts Stronger Response to a Workplace Sugar-Sweetened Beverage Sales Ban: An Exploratory Study.},
journal = {Current developments in nutrition},
volume = {5},
number = {7},
pages = {nzab084},
pmid = {34235373},
issn = {2475-2991},
support = {P30 DK092926/DK/NIDDK NIH HHS/United States ; P30 DK098722/DK/NIDDK NIH HHS/United States ; },
abstract = {BACKGROUND: Shorter leukocyte telomere length (LTL) is associated with increased risk of a number of metabolic diseases including insulin resistance and the development of type 2 diabetes mellitus. Shorter LTL is also associated with stress reactivity suggestive of a possible role for LTL to predict response to behavioral interventions. However, few studies have evaluated how interventions, such as weight loss or dietary changes, are associated with LTL changes or whether LTL can predict behavioral responses to interventions.<br><br>OBJECTIVES: We evaluated metabolic changes in relation to LTL changes and LTL at baseline in a cohort of at-risk adults in response to a 10-mo workplace-based sugar-sweetened beverage (SSB) intervention.<br><br>METHODS: At baseline, metabolic health and LTL measurements were assessed through standard blood draws on 212 participants. Multivariable linear regression models were used to assess changes in anthropometrics, SSB consumption, and 13 blood-based metabolic risk factors, in relation to LTL at baseline and changes in LTL.<br><br>RESULTS: Longer LTL at baseline was associated with decreases in SSB consumption over the 6-mo follow-up period (B = -29.67; P&#xa0;=&#xa0;0.04). Slower LTL attrition rates were associated with decreases in waist circumference (B = -0.27; P&#xa0;&#xa0;=&#xa0;0.03), HDL cholesterol (B = -0.20; P&#xa0;&#xa0;=&#xa0;0.05), and apoA1 (B = -0.09; P&#xa0;=&#xa0;0.01).<br><br>CONCLUSIONS: Longer LTL at baseline predicted a favorable overall response to a behavioral intervention: decreases in SSB consumption. Abdominal adiposity losses paralleled slower declines in LTL suggestive of overall health benefits, but we found differences in the relations between metabolic changes and LTL at baseline compared with LTL attrition rates. Longer LTL may be a proxy marker of a positive behavioral response.This trial was registered at clinicaltrials.gov as NCT02585336.},
}
@article {pmid34228441,
year = {2021},
author = {Jin, M and Li, J and Chen, Y and Zhao, J and Zhang, J and Zhang, Z and Du, P and Zhang, L and Lu, X},
title = {Near-Infrared Small Molecule as a Specific Fluorescent Probe for Ultrasensitive Recognition of Antiparallel Human Telomere G-Quadruplexes.},
journal = {ACS applied materials &amp; interfaces},
volume = {13},
number = {28},
pages = {32743-32752},
doi = {10.1021/acsami.1c07101},
pmid = {34228441},
issn = {1944-8252},
mesh = {DNA/*analysis/genetics ; Fluorescent Dyes/chemical synthesis/*chemistry ; *G-Quadruplexes ; HeLa Cells ; Humans ; Limit of Detection ; Microscopy, Fluorescence ; Quinolines/chemical synthesis/*chemistry ; Quinolizines/chemical synthesis/*chemistry ; RNA/analysis/genetics ; Telomere/*chemistry ; },
abstract = {In the past 10 years, many fluorescent probes have been developed to recognize G-quadruplexes (G4s) since G4s play an important role in biological systems. However, the selectivity and sensitivity of existing probes for G4s limit their further applications. Herein, we design and synthesize a new probe (TOVJ) by introducing 9-vinyljulolidine into TO. The new probe exhibits almost no fluorescence in an aqueous solution. Upon interacting with G4s, especially the antiparallel G4s, the fluorescence intensity was greatly enhanced (maximum 2742-fold) with a large Stokes shift of 198 nm and the maximum emission peak at 694 nm (near-infrared region). TOVJ showed high sensitivity and selectivity to G4s over other DNA topologies (ssDNA/dsDNA), especially to antiparallel G4s. For antiparallel human telomere G4 detection, the limits of detection of Hum24 and 22AG Na[+] were as low as 164 and 231 pM, respectively. This indicates that TOVJ is a highly sensitive fluorescence sensor that can be effectively used for antiparallel human telomere G4 detection. The result of live-cell imaging showed that TOVJ could enter live cells and locate in the mitochondria.},
}
@article {pmid34225037,
year = {2021},
author = {Needham, BL and Straight, B and Hilton, CE and Olungah, CO and Lin, J},
title = {Family socioeconomic status and child telomere length among the Samburu of Kenya.},
journal = {Social science &amp; medicine (1982)},
volume = {283},
number = {},
pages = {114182},
doi = {10.1016/j.socscimed.2021.114182},
pmid = {34225037},
issn = {1873-5347},
mesh = {Animals ; Cattle ; Child ; Educational Status ; Family ; Female ; Humans ; Kenya ; Sheep ; *Social Class ; Socioeconomic Factors ; *Telomere ; },
abstract = {Previous research in high-income countries suggests that children from families with lower socioeconomic status (SES) tend to have shorter telomere length - a biomarker of stress and cell aging - than children from families with greater social and economic resources. However, little is known about predictors of child telomere length in low-income settings. Data for the current study are from a sample of 214 Samburu children aged 1-9 years. The Samburu are semi-nomadic pastoralists who live in the Rift Valley of north-central Kenya. Samburu livelihood is based primarily on livestock, and polygynous marriage is common. Drawing on prior ethnographic research, we measured 14 culturally relevant indicators of family SES, including mother's education, head of household's education, whether the child is currently attending school, household spending, mother's employment history, head of household's employment history, mother's perceived wealth, whether the child lives in a modern house, livestock holdings (total, cows, sheep/goats, and camels), mother's wife number, and whether the child lives in a polygynous household. Telomere length was measured in salivary DNA by the quantitative polymerase chain reaction (qPCR) method. Using latent class analysis, we identified four groups of children that are similar based on the 14 indicators of family SES: Lower SES; Middle SES, Traditional; Middle SES, Modern; and Higher SES. SES classes were not significantly associated with child telomere length. In models examining individual indicators of SES, we found that telomere length was 0.57 standard deviations greater for children who lived in families in the lowest quartile of total livestock holdings compared to those in the highest quartile (b = 0.57, p = 0.03). While additional research is needed to identify the mechanisms underlying this counterintuitive finding, the current study highlights the importance of cultural context in shaping the social gradient in health.},
}
@article {pmid34223882,
year = {2022},
author = {Li, Z and Zhou, D and Zhang, D and Zhao, J and Li, W and Sun, Y and Chen, Y and Liu, H and Wilson, JX and Qian, Z and Huang, G},
title = {Folic Acid Inhibits Aging-Induced Telomere Attrition and Apoptosis in Astrocytes In Vivo and In Vitro.},
journal = {Cerebral cortex (New York, N.Y. : 1991)},
volume = {32},
number = {2},
pages = {286-297},
doi = {10.1093/cercor/bhab208},
pmid = {34223882},
issn = {1460-2199},
mesh = {Aging ; Animals ; Apoptosis ; *Astrocytes ; *Folic Acid/pharmacology ; Mice ; Telomere ; },
abstract = {Folic acid (FA) has been reported to inhibit astrocyte apoptosis and improve aging-induced disorders; however, its role in telomere attrition remains unclear. In present study, 4-month-old senescence-accelerated mouse prone 8 (SAMP8) mice were assigned to four treatment groups for the in vivo experiment: FA-deficient diet (FA-D) group, FA-normal diet (FA-N) group, low FA-supplemented diet (FA-L) group, and high FA-supplemented diet (FA-H) group. These mice were euthanized when 10 months old. There was also a young SAMP8 (4 months old) control group (Con-Y) fed with FA-normal diet. In in vitro study, primary cultures of astrocytes from hippocampus and cerebral cortex were incubated for five generations with various concentrations of FA (0-40 μM) and were assigned to five groups: FA 0 μM (generation 5), FA 10 μM (generation 5), FA 20 μM (generation 5), FA 40 μM (generation 5), and FA 10 μM (generation 1). The results showed that FA supplementation inhibited aging-induced astrocytosis, astrocyte apoptosis, neurodegeneration, and prevented telomere attrition in hippocampus and cortex of SAMP8 mice. FA supplementation also decreased apoptosis and telomere attrition, and increased telomerase activity, in primary cultures of astrocytes. These results showed that it may be one of the mechanisms that FA inhibiting aging-induced apoptosis of astrocyte by alleviating telomere attrition.},
}
@article {pmid34221339,
year = {2021},
author = {Piplani, S and Prabhu, M and Alemao, NN and Akash, C and Ram, P and Ambar, S and Kumbar, V and Chugh, Y and Raychauduri, SP and Chugh, SK},
title = {Conventional Risk Factors, Telomere Length, and Ischemic Heart disease: Insights into the Mediation Analysis.},
journal = {Genome integrity},
volume = {12},
number = {},
pages = {1},
pmid = {34221339},
issn = {2041-9414},
abstract = {Telomere length is regarded as a potential biomarker of biological ageing and is associated with various age-related diseases, such as ischemic heart disease (IHD), myocardial infarction, peripheral vascular disease, and cancer. As there is a paucity of study that deals with this influence, this study aimed to assess how the cardiovascular risk factors influence the risk of IHD by performing mediation analysis. A total of 407 males were included in the study. IHD was diagnosed through echocardiography and coronary angiography by determining the number of coronary vessels involved. Demographic data, clinical history, and laboratory investigations such as random blood sugar (RBS), fasting lipid profile, serum creatinine, and serum urea levels of all the subjects were measured and recorded. Serum uric acid and blood urea nitrogen (BUN) levels were significantly higher in IHD subjects compared to non-IHD subjects (P < 0.05). Body mass index (BMI), glycosylated hemoglobin (HbA1c), RBS, serum uric acid, serum creatinine, BUN, total cholesterol, triglycerides, and telomere length significantly differed between subjects with and without IHD (P < 0.05). Further, telomere length (P < 0.001), BMI (P < 0.001), and total cholesterol level (P < 0.001) were risk factors that significantly affected the incidence of IHD, as proved by logistic regression. It indicates that shorter telomeres contribute to increased risk of IHD, influenced by BMI, HbA1c, BUN, total cholesterol levels, and RBS (P < 0.001). The study established a link between telomere shortening, conventional risk factors, and IHD; moreover, the study takes care in the role of mediation analysis which is a novel idea as little is done in this area of biostatistics with telomere length. Overall, this further establishes that telomeres length might serve as the promising biomarkers in predicting the risk of IHD.},
}
@article {pmid34219315,
year = {2022},
author = {Brown, TJ and Spurgin, LG and Dugdale, HL and Komdeur, J and Burke, T and Richardson, DS},
title = {Causes and consequences of telomere lengthening in a wild vertebrate population.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {5933-5945},
doi = {10.1111/mec.16059},
pmid = {34219315},
issn = {1365-294X},
support = {BB/M011216/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Humans ; Animals ; Male ; Adult ; Female ; *Telomere Homeostasis ; *Vertebrates ; Telomere Shortening/genetics ; Biological Evolution ; Telomere/genetics ; },
abstract = {Telomeres have been advocated to be important markers of biological age in evolutionary and ecological studies. Telomeres usually shorten with age and shortening is frequently associated with environmental stressors and increased subsequent mortality. Telomere lengthening - an apparent increase in telomere length between repeated samples from the same individual - also occurs. However, the exact circumstances, and consequences, of telomere lengthening are poorly understood. Using longitudinal data from the Seychelles warbler (Acrocephalus sechellensis), we tested whether telomere lengthening - which occurs in adults of this species - is associated with specific stressors (reproductive effort, food availability, malarial infection and cooperative breeding) and predicts subsequent survival. In females, telomere shortening was observed under greater stress (i.e., low food availability, malaria infection), while telomere lengthening was observed in females experiencing lower stress (i.e., high food availability, assisted by helpers, without malaria). The telomere dynamics of males were not associated with the key stressors tested. These results indicate that, at least for females, telomere lengthening occurs in circumstances more conducive to self-maintenance. Importantly, both females and males with lengthened telomeres had improved subsequent survival relative to individuals that displayed unchanged, or shortened, telomeres - indicating that telomere lengthening is associated with individual fitness. These results demonstrate that telomere dynamics are bidirectionally responsive to the level of stress that an individual faces, but may poorly reflect the accumulation of stress over an individuals lifetime.},
}
@article {pmid34214617,
year = {2021},
author = {Hu, X and Gao, S and Wang, P and Zhou, Y and Chen, K and Chen, Q and Wang, B and Hu, W and Cheng, P and Eid, R and Giraud-Panis, MJ and Wang, L and Gilson, E and Ye, J and Lu, Y},
title = {The knockdown efficiency of telomere associated genes with specific methodology in a zebrafish cell line.},
journal = {Biochimie},
volume = {190},
number = {},
pages = {12-19},
doi = {10.1016/j.biochi.2021.06.013},
pmid = {34214617},
issn = {1638-6183},
mesh = {Animals ; Cell Line ; DNA-Binding Proteins/genetics/metabolism ; Gene Knockdown Techniques/*methods ; Gene Silencing/drug effects ; Monomeric GTP-Binding Proteins/genetics ; Morpholinos/pharmacology ; Shelterin Complex/genetics ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/genetics ; Telomeric Repeat Binding Protein 1/genetics ; Transfection/methods ; Zebrafish ; Zebrafish Proteins/genetics/metabolism ; },
abstract = {Zebrafish is broadly used as a model organism in gene loss-of-function studies in vivo, but its employment in vitro is greatly limited by the lack of efficient gene knockdown approaches in zebrafish cell lines such as ZF4. In this article, we attempted to induce silencing of telomere associated genes in ZF4 by applying the frequently-used siRNA transfection technology and a novel moiety-linked morpholino (vivo-MO). By proceeding with integrated optimization of siRNAs transfection and vivo-MOs treatment, we compared five transfection reagents and vivo-MOs simultaneously to evaluate the efficiency of terfa silencing in ZF4. 48 h after siRNAs transfection, Lipofectamine™ 3000 and X-tremeGENE™ HP leaded to knockdown in 35% and 43% of terfa transcription, respectively, while vivo-MO-terfa modulated 58% down-expression of zfTRF2 in contrast to vivo-MO-ctrl 72 h after treatment. Further siRNAs transfection targeting telomere associated genes by X-tremeGENE™ HP showed silencing in 40-68% of these genes without significant cytotoxicity and off-target effect. Our results confirmed the feasibility of gene loss-of-function studies in a zebrafish cell line, offered a systematic optimizing strategy to employ gene silencing experiments, and presented Lipofectamine™ 3000, X-tremeGENE™ HP and vivo-morpholinos as candidate gene silencing approaches for zebrafish in vitro gene loss-of-function studies. Successfully knockdown of shelterin genes further opened a new field for telomeric study in zebrafish.},
}
@article {pmid34214172,
year = {2021},
author = {Chatain, J and Blond, A and Phan, AT and Saintomé, C and Alberti, P},
title = {GGGCTA repeats can fold into hairpins poorly unfolded by replication protein A: a possible origin of the length-dependent instability of GGGCTA variant repeats in human telomeres.},
journal = {Nucleic acids research},
volume = {49},
number = {13},
pages = {7588-7601},
pmid = {34214172},
issn = {1362-4962},
mesh = {DNA/chemistry ; G-Quadruplexes ; Humans ; Nucleic Acid Conformation ; Nucleotide Motifs ; Oligonucleotides/chemistry ; Repetitive Sequences, Nucleic Acid ; Replication Protein A/*metabolism ; Shelterin Complex ; Telomere/*chemistry/metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Human telomeres are composed of GGGTTA repeats and interspersed with variant repeats. The GGGCTA variant motif was identified in the proximal regions of human telomeres about 10 years ago and was shown to display a length-dependent instability. In parallel, a structural study showed that four GGGCTA repeats folded into a non-canonical G-quadruplex (G4) comprising a Watson-Crick GCGC tetrad. It was proposed that this non-canonical G4 might be an additional obstacle for telomere replication. In the present study, we demonstrate that longer GGGCTA arrays fold into G4 and into hairpins. We also demonstrate that replication protein A (RPA) efficiently binds to GGGCTA repeats structured into G4 but poorly binds to GGGCTA repeats structured into hairpins. Our results (along with results obtained with a more stable variant motif) suggest that GGGCTA hairpins are at the origin of GGGCTA length-dependent instability. They also suggest, as working hypothesis, that failure of efficient binding of RPA to GGGCTA structured into hairpins might be involved in the mechanism of GGGCTA array instability. On the basis of our present and past studies about telomeric G4 and their interaction with RPA, we propose an original point of view about telomeric G4 and the evolution of telomeric motifs.},
}
@article {pmid34208129,
year = {2021},
author = {Daneels, L and Martens, DS and Arredouani, S and Billen, J and Koppen, G and Devlieger, R and Nawrot, TS and Ghosh, M and Godderis, L and Pauwels, S},
title = {Maternal Vitamin D and Newborn Telomere Length.},
journal = {Nutrients},
volume = {13},
number = {6},
pages = {},
pmid = {34208129},
issn = {2072-6643},
support = {12W8618N//Fonds Wetenschappelijk Onderzoek/ ; },
mesh = {Dietary Supplements ; Female ; Humans ; *Infant, Newborn ; Male ; Nutritional Status ; Pregnancy ; Pregnancy Trimesters ; *Prenatal Nutritional Physiological Phenomena ; *Telomere ; Vitamin D/*administration &amp; dosage/analogs &amp; derivatives/blood ; Vitamins/*administration &amp; dosage ; },
abstract = {Nutrition is important during pregnancy for offspring health. Gestational vitamin D intake may prevent several adverse outcomes and might have an influence on offspring telomere length (TL). In this study, we want to assess the association between maternal vitamin D intake during pregnancy and newborn TL, as reflected by cord blood TL. We studied mother-child pairs enrolled in the Maternal Nutrition and Offspring's Epigenome (MANOE) cohort, Leuven, Belgium. To calculate the dietary vitamin D intake, 108 women were asked to keep track of their diet using the seven-day estimated diet record (EDR) method. TL was assessed in 108 cord blood using a quantitative real-time PCR method. In each trimester of pregnancy, maternal serum 25-hydroxyvitamin D (25-OHD) concentration was measured. We observed a positive association (β = 0.009, p-value = 0.036) between newborn average relative TL and maternal vitamin D intake (diet + supplement) during the first trimester. In contrast, we found no association between average relative TL of the newborn and mean maternal serum 25-OHD concentrations during pregnancy. To conclude, vitamin D intake (diet + supplements), specifically during the first trimester of pregnancy, is an important factor associated with TL at birth.},
}
@article {pmid34206297,
year = {2021},
author = {Karow, A and Haubitz, M and Oppliger Leibundgut, E and Helsen, I and Preising, N and Steiner, D and Dantonello, TM and Ammann, RA and Roessler, J and Kartal-Kaess, M and Röth, A and Baerlocher, GM},
title = {Targeting Telomere Biology in Acute Lymphoblastic Leukemia.},
journal = {International journal of molecular sciences},
volume = {22},
number = {13},
pages = {},
pmid = {34206297},
issn = {1422-0067},
support = {no grant number//Geron Corporation/ ; },
mesh = {Adolescent ; Antineoplastic Agents/pharmacology/therapeutic use ; Apoptosis ; Biomarkers, Tumor/analysis ; Child ; Child, Preschool ; Female ; Humans ; Male ; Oligonucleotides/*pharmacology/therapeutic use ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy/genetics/metabolism/physiopathology ; Prognosis ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Increased cell proliferation is a hallmark of acute lymphoblastic leukemia (ALL), and genetic alterations driving clonal proliferation have been identified as prognostic factors. To evaluate replicative history and its potential prognostic value, we determined telomere length (TL) in lymphoblasts, B-, and T-lymphocytes, and measured telomerase activity (TA) in leukocytes of patients with ALL. In addition, we evaluated the potential to suppress the in vitro growth of B-ALL cells by the telomerase inhibitor imetelstat. We found a significantly lower TL in lymphoblasts (4.3 kb in pediatric and 2.3 kb in adult patients with ALL) compared to B- and T-lymphocytes (8.0 kb and 8.2 kb in pediatric, and 6.4 kb and 5.5 kb in adult patients with ALL). TA in leukocytes was 3.2 TA/C for pediatric and 0.7 TA/C for adult patients. Notably, patients with high-risk pediatric ALL had a significantly higher TA of 6.6 TA/C compared to non-high-risk patients with 2.2 TA/C. The inhibition of telomerase with imetelstat ex vivo led to significant dose-dependent apoptosis of B-ALL cells. These results suggest that TL reflects clonal expansion and indicate that elevated TA correlates with high-risk pediatric ALL. In addition, telomerase inhibition induces apoptosis of B-ALL cells cultured in vitro. TL and TA might complement established markers for the identification of patients with high-risk ALL. Moreover, TA seems to be an effective therapeutic target; hence, telomerase inhibitors, such as imetelstat, may augment standard ALL treatment.},
}
@article {pmid34205622,
year = {2021},
author = {Krapivin, MI and Tikhonov, AV and Efimova, OA and Pendina, AA and Smirnova, AA and Chiryaeva, OG and Talantova, OE and Petrova, LI and Dudkina, VS and Baranov, VS},
title = {Telomere Length in Chromosomally Normal and Abnormal Miscarriages and Ongoing Pregnancies and Its Association with 5-hydroxymethylcytosine Patterns.},
journal = {International journal of molecular sciences},
volume = {22},
number = {12},
pages = {},
pmid = {34205622},
issn = {1422-0067},
support = {19-75-00023//Russian Science Foundation/ ; AAAA-A19-119021290033-1//Ministry of Science and Higher Education of the Russian Federation/ ; },
mesh = {5-Methylcytosine/analogs &amp; derivatives/metabolism ; Abortion, Spontaneous/*pathology ; Case-Control Studies ; Chorion/pathology ; DNA Methylation ; Female ; Humans ; Lymphocytes/pathology ; Pregnancy ; Pregnancy Trimester, First ; Telomere/*pathology ; *Telomere Homeostasis ; Trophoblasts/*pathology ; },
abstract = {The present study investigates telomere length (TL) in dividing chorionic cytotrophoblast cells from karyotypically normal and abnormal first trimester miscarriages and ongoing pregnancies. Using Q-FISH, we measured relative TLs in the metaphase chromosomes of 61 chorionic villous samples. Relative TLs did not differ between karyotypically normal samples from miscarriages and those from ongoing pregnancies (p = 0.3739). However, among the karyotypically abnormal samples, relative TLs were significantly higher in ongoing pregnancies than in miscarriages (p < 0.0001). Relative TLs were also significantly higher in chorion samples from karyotypically abnormal ongoing pregnancies than in those from karyotypically normal ones (p = 0.0018) in contrast to miscarriages, where relative TL values were higher in the karyotypically normal samples (p = 0.002). In the karyotypically abnormal chorionic cytotrophoblast, the TL variance was significantly lower than in any other group (p < 0.05). Assessed by TL ratios between sister chromatids, interchromatid TL asymmetry demonstrated similar patterns across all of the chorion samples (p = 0.22) but significantly exceeded that in PHA-stimulated lymphocytes (p < 0.0001, p = 0.0003). The longer telomere was predominantly present in the hydroxymethylated sister chromatid in chromosomes featuring hemihydroxymethylation (containing 5-hydroxymethylcytosine in only one sister chromatid)-a typical sign of chorionic cytotrophoblast cells. Our results suggest that the phenomena of interchromatid TL asymmetry and its association to 5hmC patterns in chorionic cytotrophoblast, which are potentially linked to telomere lengthening through recombination, are inherent to the development programme. The TL differences in chorionic cytotrophoblast that are associated with karyotype and embryo viability seem to be determined by heredity rather than telomere elongation mechanisms. The inheritance of long telomeres by a karyotypically abnormal embryo promotes his development, whereas TL in karyotypically normal first-trimester embryos does not seem to have a considerable impact on developmental capacity.},
}
@article {pmid34205609,
year = {2021},
author = {Azcona-Sanjulian, MC},
title = {Telomere Length and Pediatric Obesity: A Review.},
journal = {Genes},
volume = {12},
number = {6},
pages = {},
pmid = {34205609},
issn = {2073-4425},
mesh = {Adolescent ; Child ; Humans ; Pediatric Obesity/*genetics ; *Telomere Homeostasis ; },
abstract = {Obesity is a chronic disease, which needs to be early detected early and treated in order prevent its complications. Changes in telomere length (TL) have been associated with obesity and its complications, such as diabetes mellitus and metabolic syndrome. Therefore, we conducted a systematic review to summarize results of studies that have measured TL in children and adolescents with obesity. Fourteen studies aiming to assess TL in pediatric patients with either obesity or who were overweight were included in this review. In conclusion, obesity and adiposity parameters are negatively associated with TL. Shorter telomeres are observed in children with obesity compared with their lean counterparts. Factors involved in obesity etiology, such as diet and physical activity, may contribute to maintenance of TL integrity. In the long term, TL change could be used as a biomarker to predict response to obesity treatment.},
}
@article {pmid34205454,
year = {2021},
author = {Rassoulzadegan, M and Sharifi-Zarchi, A and Kianmehr, L},
title = {DNA-RNA Hybrid (R-Loop): From a Unified Picture of the Mammalian Telomere to the Genome-Wide Profile.},
journal = {Cells},
volume = {10},
number = {6},
pages = {},
pmid = {34205454},
issn = {2073-4409},
support = {2019-2020 Minoo Rassoulzadegan//La Fondation Nestl&#xe9; France/ ; },
mesh = {Animals ; *DNA/genetics/metabolism ; Genome-Wide Association Study ; Male ; Mice ; *R-Loop Structures ; *RNA, Long Noncoding/genetics/metabolism ; *Telomere/genetics/metabolism ; },
abstract = {Local three-stranded DNA/RNA hybrid regions of genomes (R-loops) have been detected either by binding of a monoclonal antibody (DRIP assay) or by enzymatic recognition by RNaseH. Such a structure has been postulated for mouse and human telomeres, clearly suggested by the identification of the complementary RNA Telomeric repeat-containing RNA "TERRA". However, the tremendous disparity in the information obtained with antibody-based technology drove us to investigate a new strategy. Based on the observation that DNA/RNA hybrids in a triplex complex genome co-purify with the double-stranded chromosomal DNA fraction, we developed a direct preparative approach from total protein-free cellular extract without antibody that allows their physical isolation and determination of their RNA nucleotide sequence. We then define in the normal mouse and human sperm genomes the notion of stable DNA associated RNA terminal R-loop complexes, including TERRA molecules synthesized from local promoters of every chromosome. Furthermore, the first strong evidence of all telomeric structures, applied additionally to the whole murine sperm genome compared to the testes, showed reproducible R-loop complexes of the whole genome and suggesting a defined profile in the sperm genome for the next generation.},
}
@article {pmid34204343,
year = {2021},
author = {Chronowski, C and Akhanov, V and Chan, D and Catic, A and Finegold, M and Sahin, E},
title = {Fructose Causes Liver Damage, Polyploidy, and Dysplasia in the Setting of Short Telomeres and p53 Loss.},
journal = {Metabolites},
volume = {11},
number = {6},
pages = {},
pmid = {34204343},
issn = {2218-1989},
support = {R01 AG047924/AG/NIA NIH HHS/United States ; R01 DK115454/DK/NIDDK NIH HHS/United States ; R01AG047924/GF/NIH HHS/United States ; },
abstract = {Studies in humans and model systems have established an important role of short telomeres in predisposing to liver fibrosis through pathways that are incompletely understood. Recent studies have shown that telomere dysfunction impairs cellular metabolism, but whether and how these metabolic alterations contribute to liver fibrosis is not well understood. Here, we investigated whether short telomeres change the hepatic response to metabolic stress induced by fructose, a sugar that is highly implicated in non-alcoholic fatty liver disease. We find that telomere shortening in telomerase knockout mice (TKO) imparts a pronounced susceptibility to fructose as reflected in the activation of p53, increased apoptosis, and senescence, despite lower hepatic fat accumulation in TKO mice compared to wild type mice with long telomeres. The decreased fat accumulation in TKO is mediated by p53 and deletion of p53 normalizes hepatic fat content but also causes polyploidy, polynuclearization, dysplasia, cell death, and liver damage. Together, these studies suggest that liver tissue with short telomers are highly susceptible to fructose and respond with p53 activation and liver damage that is further exacerbated when p53 is lost resulting in dysplastic changes.},
}
@article {pmid34203694,
year = {2021},
author = {Jacczak, B and Rubiś, B and Totoń, E},
title = {Potential of Naturally Derived Compounds in Telomerase and Telomere Modulation in Skin Senescence and Aging.},
journal = {International journal of molecular sciences},
volume = {22},
number = {12},
pages = {},
pmid = {34203694},
issn = {1422-0067},
support = {502-20-33184320//Poznan University of Medical Sciences/ ; 2016/21/B/NZ7/01079//Narodowe Centrum Nauki/ ; },
mesh = {Aging/*metabolism ; Animals ; Biological Products/*pharmacology ; Humans ; Skin/drug effects/*pathology ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Proper functioning of cells-their ability to divide, differentiate, and regenerate-is dictated by genomic stability. The main factors contributing to this stability are the telomeric ends that cap chromosomes. Telomere biology and telomerase activity have been of interest to scientists in various medical science fields for years, including the study of both cancer and of senescence and aging. All these processes are accompanied by telomere-length modulation. Maintaining the key levels of telomerase component (hTERT) expression and telomerase activity that provide optimal telomere length as well as some nontelomeric functions represents a promising step in advanced anti-aging strategies, especially in dermocosmetics. Some known naturally derived compounds contribute significantly to telomere and telomerase metabolism. However, before they can be safely used, it is necessary to assess their mechanisms of action and potential side effects. This paper focuses on the metabolic potential of natural compounds to modulate telomerase and telomere biology and thus prevent senescence and skin aging.},
}
@article {pmid34203235,
year = {2021},
author = {Sellami, M and Al-Muraikhy, S and Al-Jaber, H and Al-Amri, H and Al-Mansoori, L and Mazloum, NA and Donati, F and Botre, F and Elrayess, MA},
title = {Age and Sport Intensity-Dependent Changes in Cytokines and Telomere Length in Elite Athletes.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {10},
number = {7},
pages = {},
pmid = {34203235},
issn = {2076-3921},
support = {UREP26-043-3-018//Qatar National Research Fund/ ; },
abstract = {BACKGROUND: Exercise-associated immune response plays a crucial role in the aging process. The aim of this study is to investigate the effect of sport intensity on cytokine levels, oxidative stress markers and telomere length in aging elite athletes.<br><br>METHODS: In this study, 80 blood samples from consenting elite athletes were collected for anti-doping analysis at an anti-doping laboratory in Italy (FMSI). Participants were divided into three groups according to their sport intensity: low-intensity skills and power sports (LI, n = 18); moderate-intensity mixed soccer players (MI, n = 31); and high-intensity endurance sports (HI, n = 31). Participants were also divided into two age groups: less than 25 (n = 45) and above 25 years old (n = 35). Serum levels of 10 pro and anti-inflammatory cytokines and two antioxidant enzymes were compared in age and sport intensity groups and telomere lengths were measured in their respective blood samples.<br><br>RESULTS: Tumor necrosis factor-alpha (TNF-&#x3b1;) was the only cytokine showing significantly higher concentration in older athletes, regardless of sport intensity. Interleukin (IL)-10 increased significantly in HI regardless of age group, whereas IL-6 concentration was higher in the older HI athletes. IL-8 showed a significant interaction with sport intensity in different age groups. Overall, significant positive correlations among levels of IL-6, IL-10, IL-8 and TNF-&#x3b1; were identified. The antioxidant catalase activity was positively correlated with levels of TNF-&#x3b1;. Telomere length increased significantly with sport intensity, especially in the younger group.<br><br>CONCLUSION: HI had longer telomeres and higher levels of pro- and anti-inflammatory cytokines, suggesting less aging in HI compared to low and moderate counterparts in association with heightened immune response. Investigation of the functional significance of these associations on the health and performance of elite athletes is warranted.},
}
@article {pmid34202278,
year = {2021},
author = {Maestri, E and Duszka, K and Kuznetsov, VA},
title = {Immunity Depletion, Telomere Imbalance, and Cancer-Associated Metabolism Pathway Aberrations in Intestinal Mucosa upon Short-Term Caloric Restriction.},
journal = {Cancers},
volume = {13},
number = {13},
pages = {},
pmid = {34202278},
issn = {2072-6694},
support = {The EMPIRE innovative program//State University of New York/ ; },
abstract = {Systems cancer biology analysis of calorie restriction (CR) mechanisms and pathways has not been carried out, leaving therapeutic benefits unclear. Using metadata analysis, we studied gene expression changes in normal mouse duodenum mucosa (DM) response to short-term (2-weeks) 25% CR as a biological model. Our results indicate cancer-associated genes consist of 26% of 467 CR responding differential expressed genes (DEGs). The DEGs were enriched with over-expressed cell cycle, oncogenes, and metabolic reprogramming pathways that determine tissue-specific tumorigenesis, cancer, and stem cell activation; tumor suppressors and apoptosis genes were under-expressed. DEG enrichments suggest telomeric maintenance misbalance and metabolic pathway activation playing dual (anti-cancer and pro-oncogenic) roles. The aberrant DEG profile of DM epithelial cells is found within CR-induced overexpression of Paneth cells and is coordinated significantly across GI tract tissues mucosa. Immune system genes (ISGs) consist of 37% of the total DEGs; the majority of ISGs are suppressed, including cell-autonomous immunity and tumor-immune surveillance. CR induces metabolic reprogramming, suppressing immune mechanics and activating oncogenic pathways. We introduce and argue for our network pro-oncogenic model of the mucosa multicellular tissue response to CR leading to aberrant transcription and pre-malignant states. These findings change the paradigm regarding CR's anti-cancer role, initiating specific treatment target development. This will aid future work to define critical oncogenic pathways preceding intestinal lesion development and biomarkers for earlier adenoma and colorectal cancer detection.},
}
@article {pmid34200513,
year = {2021},
author = {Pousa, PA and Souza, RM and Melo, PHM and Correa, BHM and Mendonça, TSC and Simões-E-Silva, AC and Miranda, DM},
title = {Telomere Shortening and Psychiatric Disorders: A Systematic Review.},
journal = {Cells},
volume = {10},
number = {6},
pages = {},
pmid = {34200513},
issn = {2073-4409},
mesh = {Humans ; Mental Disorders/genetics/*metabolism ; Mitochondria/genetics/*metabolism ; *Oxidative Stress ; Telomere/genetics/*metabolism ; *Telomere Shortening ; },
abstract = {Telomeres are aging biomarkers, as they shorten while cells undergo mitosis. The aim of this study was to evaluate whether psychiatric disorders marked by psychological distress lead to alterations to telomere length (TL), corroborating the hypothesis that mental disorders might have a deeper impact on our physiology and aging than it was previously thought. A systematic search of the literature using MeSH descriptors of psychological distress ("Traumatic Stress Disorder" or "Anxiety Disorder" or "depression") and telomere length ("cellular senescence", "oxidative stress" and "telomere") was conducted on PubMed, Cochrane Library and ScienceDirect databases. A total of 56 studies (113,699 patients) measured the TL from individuals diagnosed with anxiety, depression and posttraumatic disorders and compared them with those from healthy subjects. Overall, TL negatively associates with distress-related mental disorders. The possible underlying molecular mechanisms that underly psychiatric diseases to telomere shortening include oxidative stress, inflammation and mitochondrial dysfunction linking. It is still unclear whether psychological distress is either a cause or a consequence of telomere shortening.},
}
@article {pmid34200325,
year = {2021},
author = {Mongelli, A and Barbi, V and Gottardi Zamperla, M and Atlante, S and Forleo, L and Nesta, M and Massetti, M and Pontecorvi, A and Nanni, S and Farsetti, A and Catalano, O and Bussotti, M and Dalla Vecchia, LA and Bachetti, T and Martelli, F and La Rovere, MT and Gaetano, C},
title = {Evidence for Biological Age Acceleration and Telomere Shortening in COVID-19 Survivors.},
journal = {International journal of molecular sciences},
volume = {22},
number = {11},
pages = {},
pmid = {34200325},
issn = {1422-0067},
support = {PRIN2017S55RXB//Ministero dell'Educazione, Universit&#xe0; e ricerca/ ; PRIN2015HPMLFY//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; RF 2010-2318330//Ministero della Salute/ ; "RicercaCorrente" and "Progetto di Rete Cardiovascolare IRCCS: CardioCovid"//Ministero della Salute/ ; 446 GGP19035A//Fondazione Telethon/ ; 23054//Fondazione Telethon/ ; 101016072//Horizon 2020/ ; 22858//Associazione Italiana per la Ricerca sul Cancro/ ; },
mesh = {Adult ; Aged ; Aging/*genetics ; Angiotensin-Converting Enzyme 2/blood ; Biomarkers ; COVID-19/complications/etiology/*genetics/*physiopathology ; *CpG Islands ; DNA Methylation ; Dipeptidyl Peptidase 4/blood ; Epigenomics ; Female ; High-Throughput Nucleotide Sequencing ; Host Microbial Interactions ; Humans ; Male ; Middle Aged ; Risk Factors ; Survivors ; Telomere/*metabolism ; *Telomere Shortening ; Post-Acute COVID-19 Syndrome ; },
abstract = {The SARS-CoV-2 infection determines the COVID-19 syndrome characterized, in the worst cases, by severe respiratory distress, pulmonary and cardiac fibrosis, inflammatory cytokine release, and immunosuppression. This condition has led to the death of about 2.15% of the total infected world population so far. Among survivors, the presence of the so-called persistent post-COVID-19 syndrome (PPCS) is a common finding. In COVID-19 survivors, PPCS presents one or more symptoms: fatigue, dyspnea, memory loss, sleep disorders, and difficulty concentrating. In this study, a cohort of 117 COVID-19 survivors (post-COVID-19) and 144 non-infected volunteers (COVID-19-free) was analyzed using pyrosequencing of defined CpG islands previously identified as suitable for biological age determination. The results show a consistent biological age increase in the post-COVID-19 population, determining a DeltaAge acceleration of 10.45 ± 7.29 years (+5.25 years above the range of normality) compared with 3.68 ± 8.17 years for the COVID-19-free population (p < 0.0001). A significant telomere shortening parallels this finding in the post-COVID-19 cohort compared with COVID-19-free subjects (p < 0.0001). Additionally, ACE2 expression was decreased in post-COVID-19 patients, compared with the COVID-19-free population, while DPP-4 did not change. In light of these observations, we hypothesize that some epigenetic alterations are associated with the post-COVID-19 condition, particularly in younger patients (< 60 years).},
}
@article {pmid34197088,
year = {2021},
author = {Gao, K and Zhou, Y and Lu, Q and Lu, J and Su, L and Su, R and Zhang, M and Tian, Y and Wu, L and Yan, X},
title = {High-Throughput Human Telomere Length Analysis at the Single-Chromosome Level by FISH Coupled with Nano-Flow Cytometry.},
journal = {Analytical chemistry},
volume = {93},
number = {27},
pages = {9531-9540},
doi = {10.1021/acs.analchem.1c01544},
pmid = {34197088},
issn = {1520-6882},
mesh = {Flow Cytometry ; Humans ; In Situ Hybridization, Fluorescence ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics ; *Telomere/genetics ; },
abstract = {Telomere length (TL) is a highly relevant biomarker for age-associated diseases and cancer, yet its clinical applications have been hindered by the inability of existing methods to rapidly measure the TL distribution and the percentage of chromosomes with critically short telomeres (CSTs, < 3 kb). Herein, we report the development of a high-throughput method to measure TL at the single-chromosome level. Metaphase chromosomes are isolated, hybridized with the Alexa Fluor 488-labeled telomeric peptide nucleic acid probe, and analyzed using a laboratory-built ultrasensitive nano-flow cytometer. The fluorescence intensity of individual chromosomes is converted to TL in kilobases upon external calibration. With an analysis rate of several thousand chromosomes per minute, a statistically robust TL distribution histogram is acquired in minutes, and the percentage of chromosomes with CSTs can be quickly assessed. By analyzing peripheral blood lymphocytes of 158 healthy donors, TL is found to shorten with age at a rate of 64 ± 3 bp/year and the percentage of chromosomes with CSTs increases with age at a rate of 0.32 ± 0.02%/year. Moreover, the data of 28 patients with chronic myeloid leukemia (CML) indicate that telomeres are significantly shorter at the time of diagnosis and the clinical phases of CML are closely associated with TL and the percentage of chromosomes with CSTs. This powerful tool could greatly deepen our understanding of telomere biology and improve the clinical utility of telomere biomarkers.},
}
@article {pmid34196896,
year = {2021},
author = {Dweck, A and Maitra, R},
title = {The advancement of telomere quantification methods.},
journal = {Molecular biology reports},
volume = {48},
number = {7},
pages = {5621-5627},
pmid = {34196896},
issn = {1573-4978},
mesh = {Chromosomal Instability ; DNA Replication ; Genetic Testing/*methods/standards ; Humans ; In Situ Hybridization, Fluorescence ; Real-Time Polymerase Chain Reaction ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; Telomere Shortening/genetics ; },
abstract = {Telomeres, guanine rich DNA sequences, which are found at both ends of human chromosomes, play a vital role in genome protection. These repetitive nucleotide sequences protect the genome from nucleolytic degradation, unnecessary recombination, and interchromosomal fusion. Though, as somatic cells go through replication cycles, their telomeres shrink until they reach a critical length called the Hayflick limit. At this limit, cellular senescence, an irreversible cell cycle arrest, is prompted. For all the above reasons, telomere length is a hopeful biomarker for age-associated diseases and cancer. While there are numerous methods for telomere measurement and quantification, there are still challenges for routine analysis in clinics as these methods are not simple and rapid. Recently, a new method has been developed that measures absolute length and absolute quantities of single telomere molecules. This method, single telomere absolute-length rapid (STAR) assay, which promises to measure telomere length rapidly and accurately, is also expected to be scalable. This review will discuss different telomere length measurement methods, including STAR assay, and will highlight each of their advantages and drawbacks. It will culminate in determining if STAR assay has the potential to be the superior method for telomere measurement.},
}
@article {pmid34195674,
year = {2021},
author = {Wang, L and Wang, Z and Liu, JP},
title = {Identification of peptidomimetic telomere dysfunction inhibitor (TELODIN) through telomere dysfunction-induced foci (TIF) assay.},
journal = {STAR protocols},
volume = {2},
number = {3},
pages = {100620},
pmid = {34195674},
issn = {2666-1667},
mesh = {Cells, Cultured ; Humans ; *Peptidomimetics ; Telomere/*drug effects ; },
abstract = {Telomere dysfunction-induced focus (TIF) assay allows efficient profiling of telomere dysfunctions in cells and tissues. Here, we describe the use of the TIF assay to screen synthetic peptides from E3 ubiquitin ligase FBW7, a tumor suppressor gene product, to prevent TIFs caused by environmental radiation stress. We demonstrate peptidomimetic telomere dysfunction inhibitor as a potentially intervening therapeutic drug candidate in aging-related diseases. This work demonstrates a novel utility of the TIF assay protocol in identifying telomere dysfunction inhibitors. For complete details on the use and execution of this protocol, please refer to Wang et al (2020).},
}
@article {pmid34193151,
year = {2021},
author = {Eick, SM and Goin, DE and Cushing, L and DeMicco, E and Park, JS and Wang, Y and Smith, S and Padula, AM and Woodruff, TJ and Morello-Frosch, R},
title = {Mixture effects of prenatal exposure to per- and polyfluoroalkyl substances and polybrominated diphenyl ethers on maternal and newborn telomere length.},
journal = {Environmental health : a global access science source},
volume = {20},
number = {1},
pages = {76},
pmid = {34193151},
issn = {1476-069X},
support = {U24 AG066528/AG/NIA NIH HHS/United States ; UH3 OD023272/OD/NIH HHS/United States ; UG3 OD023272/OD/NIH HHS/United States ; P30 ES030284/ES/NIEHS NIH HHS/United States ; P01 ES022841/ES/NIEHS NIH HHS/United States ; P20 ES018135/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; Biological Monitoring ; Environmental Pollutants/analysis/*toxicity ; Fatty Acids/analysis/toxicity ; Female ; Flame Retardants/analysis/*toxicity ; Fluorocarbons/analysis/*toxicity ; Halogenated Diphenyl Ethers/analysis/*toxicity ; Humans ; Infant, Newborn ; Male ; Maternal Exposure ; Maternal-Fetal Exchange ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Sulfonic Acids/analysis/toxicity ; Telomere/*drug effects ; },
abstract = {BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) and polybrominated diphenyl ethers (PBDEs) are endocrine disrupting chemicals with widespread exposures across the U.S. given their abundance in consumer products. PFAS and PBDEs are associated with reproductive toxicity and adverse health outcomes, including certain cancers. PFAS and PBDEs may affect health through alternations in telomere length. In this study, we examined joint associations between prenatal exposure to PFAS, PBDEs, and maternal and newborn telomere length using mixture analyses, to characterize effects of cumulative environmental chemical exposures.<br><br>METHODS: Study participants were enrolled in the Chemicals in Our Bodies (CIOB) study, a demographically diverse cohort of pregnant people and children in San Francisco, CA. Seven PFAS (ng/mL) and four PBDEs (ng/g lipid) were measured in second trimester maternal serum&#xa0;samples. Telomere length (T/S ratio) was measured in delivery cord blood of 292 newborns and 110&#xa0;second trimester maternal whole blood samples. Quantile g-computation was used to assess the joint associations between groups of PFAS and PBDEs and newborn and maternal telomere length. Groups considered were: (1) all PFAS and PBDEs combined, (2) PFAS, and (3) PBDEs. Maternal and newborn telomere length were modeled as separate outcomes.<br><br>RESULTS: T/S ratios in newborn cord and maternal whole blood were moderately correlated (Spearman &#x3c1;&#x2009;=&#x2009;0.31). In mixtures analyses, a simultaneous one quartile increase in all PFAS and PBDEs was associated with a small increase in newborn (mean change per quartile increase&#x2009;=&#x2009;0.03, 95% confidence interval [CI]&#x2009;=&#x2009;-0.03, 0.08) and maternal telomere length (mean change per quartile increase&#x2009;=&#x2009;0.03 (95% CI&#x2009;=&#x2009;-0.03, 0.09). When restricted to maternal-fetal paired samples (N&#x2009;=&#x2009;76), increasing all PFAS and PBDEs combined was associated with a strong, positive increase in newborn telomere length (mean change per quartile increase&#x2009;=&#x2009;0.16, 95% CI&#x2009;=&#x2009;0.03, 0.28). These associations were primarily driven by PFAS (mean change per quartile increase&#x2009;=&#x2009;0.11 [95% CI&#x2009;=&#x2009;0.01, 0.22]). No associations were observed with maternal telomere length among paired samples.<br><br>CONCLUSIONS: Our findings suggest that PFAS and PBDEs may be positively associated with newborn telomere length.},
}
@article {pmid34192361,
year = {2021},
author = {Marasco, V and Boner, W and Griffiths, K and Heidinger, B and Monaghan, P},
title = {Repeated exposure to challenging environmental conditions influences telomere dynamics across adult life as predicted by changes in mortality risk.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {35},
number = {8},
pages = {e21743},
doi = {10.1096/fj.202100556R},
pmid = {34192361},
issn = {1530-6860},
support = {268926/ERC_/European Research Council/International ; M 2520/FWF_/Austrian Science Fund FWF/Austria ; },
mesh = {Aging/*genetics/*physiology ; Animals ; Environment ; Female ; Finches/blood/*genetics/*physiology ; Longevity/*genetics/*physiology ; Risk Factors ; Stress, Physiological/genetics ; Telomere Homeostasis/*genetics/*physiology ; Telomere Shortening/genetics/physiology ; },
abstract = {The effects of stress exposure are likely to vary depending on life-stage and stressor. While it has been postulated that mild stress exposure may have beneficial effects, the duration of such effects and the underlying mechanisms are unclear. While the long-term effects of early-life stress are relatively well studied, we know much less about the effects of exposure in adulthood since the early- and adult-life environments are often similar. We previously reported that repeated experimental exposure to a relatively mild stressor in female zebra finches, first experienced in young adulthood, initially had no effect on mortality risk, reduced mortality in middle age, but the apparently beneficial effects disappeared in old age. We show here that this is underpinned by differences between the control and stress-exposed group in the pattern of telomere change, with stress-exposed birds showing reduced telomere loss in middle adulthood. We thereby provide novel experimental evidence that telomere dynamics play a key role linking stress resilience and aging.},
}
@article {pmid34187905,
year = {2021},
author = {Robinson, NJ and Miyagi, M and Scarborough, JA and Scott, JG and Taylor, DJ and Schiemann, WP},
title = {SLX4IP promotes RAP1 SUMOylation by PIAS1 to coordinate telomere maintenance through NF-κB and Notch signaling.},
journal = {Science signaling},
volume = {14},
number = {689},
pages = {},
pmid = {34187905},
issn = {1937-9145},
support = {S10 RR031537/RR/NCRR NIH HHS/United States ; UL1 TR002548/TR/NCATS NIH HHS/United States ; TL1 TR002549/TR/NCATS NIH HHS/United States ; R01 CA236273/CA/NCI NIH HHS/United States ; S10 OD016164/OD/NIH HHS/United States ; F30 CA213892/CA/NCI NIH HHS/United States ; T32 GM007250/GM/NIGMS NIH HHS/United States ; R01 GM133841/GM/NIGMS NIH HHS/United States ; R01 CA240993/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Carrier Proteins/*genetics ; Cell Line, Tumor ; Mice ; NF-kappa B/genetics ; Protein Inhibitors of Activated STAT/*metabolism ; Receptors, Notch ; Signal Transduction ; *Sumoylation ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; Ubiquitin-Protein Ligases/metabolism ; rap1 GTP-Binding Proteins/*metabolism ; },
abstract = {The maintenance of telomere length supports repetitive cell division and therefore plays a central role in cancer development and progression. Telomeres are extended by either the enzyme telomerase or the alternative lengthening of telomeres (ALT) pathway. Here, we found that the telomere-associated protein SLX4IP dictates telomere proteome composition by recruiting and activating the E3 SUMO ligase PIAS1 to the SLX4 complex. PIAS1 SUMOylated the telomere-binding protein RAP1, which disrupted its interaction with the telomere-binding protein TRF2 and facilitated its nucleocytoplasmic shuttling. In the cytosol, RAP1 bound to IκB kinase (IKK), resulting in activation of the transcription factor NF-κB and its induction of Jagged-1 expression, which promoted Notch signaling and the institution of ALT. This axis could be targeted therapeutically in ALT-driven cancers and in tumor cells that develop resistance to antitelomerase therapies. Our results illuminate the mechanisms underlying SLX4IP-dependent telomere plasticity and demonstrate the role of telomere proteins in directly coordinating intracellular signaling and telomere maintenance dynamics.},
}
@article {pmid34184077,
year = {2021},
author = {Oh, BK and Choi, Y and Choi, JS},
title = {Telomere shortening and expression of TRF1 and TRF2 in uterine leiomyoma.},
journal = {Molecular medicine reports},
volume = {24},
number = {2},
pages = {},
doi = {10.3892/mmr.2021.12243},
pmid = {34184077},
issn = {1791-3004},
mesh = {Adult ; Cell Cycle Proteins/genetics/metabolism ; Cell Transformation, Neoplastic/genetics ; Correlation of Data ; Female ; Humans ; Leiomyoma/*genetics/*metabolism ; Middle Aged ; Myometrium/metabolism ; Telomere/chemistry/metabolism ; Telomere Shortening/*genetics ; Telomeric Repeat Binding Protein 1/*genetics/*metabolism ; Telomeric Repeat Binding Protein 2/*genetics/*metabolism ; Tumor Suppressor Proteins/genetics/metabolism ; },
abstract = {Uterine leiomyoma is a benign smooth muscle tumor of the uterus that can exhibit histopathological traits that mimic malignancy. Telomere shortening is an early event in tumorigenesis and telomerase activation facilitates tumor progression later in the course of carcinogenesis. Telomeric repeat‑binding factor (TRF)1 and TRF2 protect telomeres, and their gene expression levels are dysregulated in various cancer types. However, the roles of telomeres and telomere protection proteins in uterine leiomyoma remain largely unknown. In this study, telomere length and the mRNA levels of various telomere‑related genes in normal tissues and leiomyoma were determined, and their relationships were evaluated. Uterine leiomyoma and normal myometrium were surgically obtained from 18 and 13 patients, respectively. Telomere length and gene expression were determined by Southern blot analysis and reverse transcription‑quantitative PCR, respectively. In matched samples, telomeres were consistently shorter in leiomyoma tissue than in adjacent normal tissue. TRF1, TRF2, PIN2‑interacting telomerase inhibitor 1 (PINX1), and telomerase RNA component were expressed at comparable levels in both leiomyoma and normal tissues. None of these genes were associated with telomere length in leiomyoma. All tested tissues were negative for telomerase reverse transcriptase, which encodes the catalytic component of telomerase, indicating that cells in uterine leiomyoma were not immortalized. In summary, telomere erosion, which reflects active proliferation during tumor evolution, was evident in uterine leiomyoma. Steady‑state expression of TRF1, TRF2 and PINX1 may be important for maintenance of telomere integrity in leiomyoma, where telomere length is shortened.},
}
@article {pmid34182850,
year = {2021},
author = {Moore, S and Patel, R and Stewart, J and McLain, AC and Heiney, S},
title = {Social inequalities in accelerated aging among southern U.S. women: an analysis of the biosocial and behavioral pathways linking social determinants to telomere length.},
journal = {Biodemography and social biology},
volume = {66},
number = {2},
pages = {118-131},
doi = {10.1080/19485565.2020.1869918},
pmid = {34182850},
issn = {1948-5573},
mesh = {Aging/genetics ; Female ; Humans ; Social Class ; *Social Determinants of Health ; Socioeconomic Factors ; *Telomere/genetics ; },
abstract = {Few studies have examined the biosocial pathways linking socioeconomic status (SES) to accelerated aging in a population-based sample of southern US women. Even fewer have examined the importance of chronic compared to perceived stress in linking SES to women's salivary telomere length (STL). Using data from a probability-based sample of 156 US women and structural equation modeling, we examined three pathways - chronic stress exposure, stress appraisal, and coping behavior - linking SES to STL. SES was positively associated with STL (βTE = 0.16, p < .05). Everyday discrimination was negatively associated with STL (βDE = -0.21, p < .05), but perceived stress was positively associated with STL (βDE = 0.20, p < .05). Current smoking decreased STL (βDE = -0.19, p < .01). Perceived stress acted to suppress the negative relationship of chronic stress exposure on STL. Given the dearth of STL studies that include measures of both perceived and chronic stress, our study supports the importance of disentangling stress measures and a biosocial approach to the study of accelerated aging.},
}
@article {pmid34180971,
year = {2022},
author = {Watanabe, S and Hibiya, S and Katsukura, N and Kitagawa, S and Sato, A and Okamoto, R and Watanabe, M and Tsuchiya, K},
title = {Importance of Telomere Shortening in the Pathogenesis of Ulcerative Colitis: A New Treatment From the Aspect of Telomeres in Intestinal Epithelial Cells.},
journal = {Journal of Crohn's &amp; colitis},
volume = {16},
number = {1},
pages = {109-121},
doi = {10.1093/ecco-jcc/jjab115},
pmid = {34180971},
issn = {1876-4479},
support = {17H06654//Japanese Ministry of Education, Culture, Sports, Science and Technology/ ; 18bm03041h0006//Japan Agency for Medical Research and Development/ ; //Naoki Tsuchida Research/ ; },
mesh = {Animals ; Biopsy ; Cell Proliferation ; Clustered Regularly Interspaced Short Palindromic Repeats ; Colitis, Ulcerative/*pathology ; Colonoscopy ; Epithelial Cells/*pathology ; Humans ; Intestinal Mucosa/*cytology ; Mice ; Organoids/metabolism/pathology/transplantation ; Reactive Oxygen Species/metabolism ; Telomerase/metabolism ; *Telomere Shortening ; Transplantation, Heterologous ; },
abstract = {BACKGROUND AND AIMS: Ulcerative colitis [UC] is a chronic inflammatory disease of the colon with frequent relapses. Telomere shortening in intestinal epithelial cells has been reported in severe or longstanding cases. However, its influence on UC pathogenesis remains unelucidated. To this end, we evaluated telomere shortening using a long-term organoid inflammation model that we had originally established.<br><br>METHODS: A UC model using human colon organoids was established to assess telomere changes chronologically. MST-312 was used for the telomerase inhibition assay. The potential of telomerase activators as a novel UC treatment was evaluated with an in vitro model, including microarray analysis, and histological changes were assessed using xenotransplantation into mouse colonic mucosa.<br><br>RESULTS: Our UC model reproduced telomere shortening in vitro, which was induced by the continuous suppression of telomerase activity via P53. MST-312-based analysis revealed that telomere shortening was involved in the pathogenesis of UC. Madecassoside [MD] improved the telomere length of the UC model and UC patient-derived organoids, which further promoted cell proliferation in vitro and improved the graft take-rate of xenotransplantation. Moreover, histological analysis revealed that MD induced normal crypt structure with abundant goblet cells.<br><br>CONCLUSIONS: This study is the first to reveal the mechanism and importance of telomere shortening in the pathogenesis of UC. MD could be a novel candidate for UC treatment beyond endoscopic mucosal healing.},
}
@article {pmid34173371,
year = {2021},
author = {Casavant, SG and Li, H and Reese, B and Chen, MH and Cong, XS},
title = {Pilot Study of Absolute Telomere Lengths in Preterm Infants.},
journal = {Nursing research},
volume = {70},
number = {6},
pages = {481-486},
pmid = {34173371},
issn = {1538-9847},
support = {F32 NR018591/NR/NINR NIH HHS/United States ; R01 NR016928/NR/NINR NIH HHS/United States ; },
mesh = {*Feeding Behavior ; Female ; Growth and Development/*genetics ; Humans ; Infant, Newborn ; Infant, Premature/*growth &amp; development ; Male ; Neurodevelopmental Disorders/*diagnosis/*genetics ; Pain/*genetics ; Pilot Projects ; Telomere/*genetics ; },
abstract = {BACKGROUND: Annually, approximately 15 million babies are born preterm (<37 weeks gestational age) globally. In the neonatal intensive care unit (NICU) environment, infants are exposed to repeated stressful or painful procedures as part of routine lifesaving care. These procedures have been associated with epigenetic alterations that may lead to an increased risk of neurodevelopmental disorders. Telomere length has been negatively associated with adverse life experiences in studies of adults.<br><br>OBJECTIVES: This pilot study aimed to describe telomere length in a sample of preterm infants at NICU discharge and examine any associations with pain, feeding method, and neurodevelopment.<br><br>METHODS: This descriptive pilot study sample includes baseline absolute telomere length (aTL) of 36 preterm infants immediately prior to discharge. Quantitative polymerase chain reaction was used to determine aTL. Infant demographics, pain/stress, type of feeding, antibiotic use, neurodevelopment, and buccal swab data were collected. Descriptive data analysis was used to describe the telomere length using graphs.<br><br>RESULTS: Among our preterm infant samples, the mean aTL was far greater than the average adult telomere length. Although no significant associations were found between aTL and pain, feeding method, and neurodevelopment, a trend between sex was noted where male telomere lengths were shorter than females as they aged.<br><br>DISCUSSION: This is one of few studies to evaluate preterm infant telomere length. Although other researchers have used relative telomere length, we used the more accurate aTL. We found nonsignificant shorter telomere lengths among males. Additional large-scale, longitudinal studies are needed to better identify the predictors of telomere length at the time of discharge from NICU.},
}
@article {pmid34162976,
year = {2021},
author = {Kychygina, A and Dall'Osto, M and Allen, JAM and Cadoret, JC and Piras, V and Pickett, HA and Crabbe, L},
title = {Progerin impairs 3D genome organization and induces fragile telomeres by limiting the dNTP pools.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {13195},
pmid = {34162976},
issn = {2045-2322},
mesh = {Adult ; Animals ; Cells, Cultured ; Cellular Senescence/genetics ; Chromatin/*ultrastructure ; DNA Damage ; DNA Replication ; Deoxyribonucleotides/*metabolism ; Fibroblasts ; Genes, Reporter ; Green Fluorescent Proteins ; Histone Code ; Humans ; Infant, Newborn ; Lamin Type A/analysis/deficiency/genetics/*physiology ; Lamin Type B/analysis ; Mice ; Mice, Knockout ; Nuclear Lamina/*pathology ; Progeria/*genetics/pathology ; Recombinant Fusion Proteins/metabolism ; Skin/pathology ; Telomere/*pathology ; Telomere Homeostasis/*genetics ; },
abstract = {Chromatin organization within the nuclear volume is essential to regulate many aspects of its function and to safeguard its integrity. A key player in this spatial scattering of chromosomes is the nuclear envelope (NE). The NE tethers large chromatin domains through interaction with the nuclear lamina and other associated proteins. This organization is perturbed in cells from Hutchinson-Gilford progeria syndrome (HGPS), a genetic disorder characterized by premature aging features. Here, we show that HGPS-related lamina defects trigger an altered 3D telomere organization with increased contact sites between telomeres and the nuclear lamina, and an altered telomeric chromatin state. The genome-wide replication timing signature of these cells is perturbed, with a shift to earlier replication for regions that normally replicate late. As a consequence, we detected a higher density of replication forks traveling simultaneously on DNA fibers, which relies on limiting cellular dNTP pools to support processive DNA synthesis. Remarkably, increasing dNTP levels in HGPS cells rescued fragile telomeres, and improved the replicative capacity of the cells. Our work highlights a functional connection between NE dysfunction and telomere homeostasis in the context of premature aging.},
}
@article {pmid34162698,
year = {2021},
author = {Grigorev, K and Foox, J and Bezdan, D and Butler, D and Luxton, JJ and Reed, J and McKenna, MJ and Taylor, L and George, KA and Meydan, C and Bailey, SM and Mason, CE},
title = {Haplotype diversity and sequence heterogeneity of human telomeres.},
journal = {Genome research},
volume = {31},
number = {7},
pages = {1269-1279},
pmid = {34162698},
issn = {1549-5469},
support = {R01 CA249054/CA/NCI NIH HHS/United States ; R01 MH117406/MH/NIMH NIH HHS/United States ; R01 AI151059/AI/NIAID NIH HHS/United States ; P01 HD067244/HD/NICHD NIH HHS/United States ; P01 CA214274/CA/NCI NIH HHS/United States ; R01 NS076465/NS/NINDS NIH HHS/United States ; },
abstract = {Telomeres are regions of repetitive nucleotide sequences capping the ends of eukaryotic chromosomes that protect against deterioration, and whose lengths can be correlated with age and adverse health risk factors. Yet, given their length and repetitive nature, telomeric regions are not easily reconstructed from short-read sequencing, thus making telomere sequencing, mapping, and variant resolution challenging problems. Recently, long-read sequencing, with read lengths measuring in hundreds of kilobase pairs, has made it possible to routinely read into telomeric regions and inspect their sequence structure. Here, we describe a framework for extracting telomeric reads from whole-genome single-molecule sequencing experiments, including de novo identification of telomere repeat motifs and repeat types, and also describe their sequence variation. We find that long, complex telomeric stretches and repeats can be accurately captured with long-read sequencing, observe extensive sequence heterogeneity of human telomeres, discover and localize noncanonical telomere sequence motifs (both previously reported, as well as novel), and validate them in short-read sequence data. These data reveal extensive intra- and inter-population diversity of repeats in telomeric haplotypes, reveal higher paternal inheritance of telomeric variants, and represent the first motif composition maps of multi-kilobase-pair human telomeric haplotypes across three distinct ancestries (Ashkenazi, Chinese, and Utah), which can aid in future studies of genetic variation, aging, and genome biology.},
}
@article {pmid34161613,
year = {2021},
author = {Valente, C and Andrade, R and Alvarez, L and Rebelo-Marques, A and Stamatakis, E and Espregueira-Mendes, J},
title = {Effect of physical activity and exercise on telomere length: Systematic review with meta-analysis.},
journal = {Journal of the American Geriatrics Society},
volume = {69},
number = {11},
pages = {3285-3300},
doi = {10.1111/jgs.17334},
pmid = {34161613},
issn = {1532-5415},
mesh = {Bias ; Exercise/*physiology ; Humans ; *Sedentary Behavior ; Telomere/*physiology ; },
abstract = {PURPOSE: To compare a physically active lifestyle or structured exercise program to physically inactive lifestyle or control groups on telomere length (TL).<br><br>METHOD: We searched PubMed, EMBASE, Cochrane Library, and Open Gray databases up to March 31, 2020. We calculated standardized mean differences (SMD) with 95% confidence intervals (CI) of TL comparing physically active to physically inactive individuals and exercise intervention to control groups. Risk of bias was judged using the Risk of Bias Assessment tool for Non-randomized Studies (RoBANS) for physical activity (PA) studies and the Cochrane risk-of-bias (RoB2) for exercise intervention studies. Certainty of evidence was judged using Grading of Recommendations Assessment, Development and Evaluation (GRADE).<br><br>RESULTS: We included 30 studies (24 assessing the effects of PA and 6 assessing the effects of exercise interventions) comprising 7418 individuals. Physically active individuals had longer telomeres (SMD&#xa0;=&#xa0;0.70, 95% CI 0.12-1.28, very-low certainty), especially in middle-aged individuals (SMD&#xa0;=&#xa0;0.90, 95% CI 0.08-1.72, very-low certainty) and when considering only athletes (SMD&#xa0;=&#xa0;0.54, 95% CI 0.18-0.90, very-low certainty). Trim-and-fill analyses revealed that most of the pooled effects were overestimated. Exercise interventions did not yield any significant effect on TL.<br><br>CONCLUSION: There is very-low certainty that physically active individuals have longer telomeres with a moderate effect, but this effect is probably overestimated.},
}
@article {pmid34158470,
year = {2021},
author = {Khayat, F and Cannavo, E and Alshmery, M and Foster, WR and Chahwan, C and Maddalena, M and Smith, C and Oliver, AW and Watson, AT and Carr, AM and Cejka, P and Bianchi, A},
title = {Inhibition of MRN activity by a telomere protein motif.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {3856},
pmid = {34158470},
issn = {2041-1723},
support = {/WT_/Wellcome Trust/United Kingdom ; 110047/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; C28567/A12720/CRUK_/Cancer Research UK/United Kingdom ; G0701428/MRC_/Medical Research Council/United Kingdom ; },
mesh = {*Amino Acid Motifs ; Amino Acid Sequence ; DNA Breaks, Double-Stranded ; DNA End-Joining Repair ; DNA Helicases/genetics/*metabolism ; DNA, Fungal/genetics/metabolism ; Endodeoxyribonucleases/genetics/*metabolism ; Exodeoxyribonucleases/genetics/*metabolism ; Genomic Instability ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Origin Recognition Complex/genetics/metabolism ; Protein Serine-Threonine Kinases/genetics/metabolism ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Sequence Homology, Amino Acid ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {The MRN complex (MRX in Saccharomyces cerevisiae, made of Mre11, Rad50 and Nbs1/Xrs2) initiates double-stranded DNA break repair and activates the Tel1/ATM kinase in the DNA damage response. Telomeres counter both outcomes at chromosome ends, partly by keeping MRN-ATM in check. We show that MRX is disabled by telomeric protein Rif2 through an N-terminal motif (MIN, MRN/X-inhibitory motif). MIN executes suppression of Tel1, DNA end-resection and non-homologous end joining by binding the Rad50 N-terminal region. Our data suggest that MIN promotes a transition within MRX that is not conductive for endonuclease activity, DNA-end tethering or Tel1 kinase activation, highlighting an Achilles' heel in MRN, which we propose is also exploited by the RIF2 paralog ORC4 (Origin Recognition Complex 4) in Kluyveromyces lactis and the Schizosaccharomyces pombe telomeric factor Taz1, which is evolutionarily unrelated to Orc4/Rif2. This raises the possibility that analogous mechanisms might be deployed in other eukaryotes as well.},
}
@article {pmid34153093,
year = {2021},
author = {Gao, X and Li, S and Dong, S and Li, J and Yan, Y and Zhang, T and Chen, W},
title = {Association Between Body Weight and Telomere Length Is Predominantly Mediated Through C-Reactive Protein.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {106},
number = {11},
pages = {e4634-e4640},
doi = {10.1210/clinem/dgab455},
pmid = {34153093},
issn = {1945-7197},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging ; Biomarkers/*metabolism ; Body Mass Index ; *Body Weight ; C-Reactive Protein/*metabolism ; Cohort Studies ; Cross-Sectional Studies ; Female ; Follow-Up Studies ; Humans ; Inflammation/*epidemiology/metabolism/pathology ; Leukocytes/metabolism/pathology ; Male ; Middle Aged ; Nutrition Surveys ; Obesity/*complications ; Prognosis ; Telomere/genetics/*metabolism ; United States/epidemiology ; Young Adult ; },
abstract = {CONTEXT: Both obesity and inflammation are related to accelerated aging. It is not yet known whether inflammation mediates the effects of obesity on aging.<br><br>OBJECTIVE: This work aims to dissect the direct effect of body mass index (BMI) and its indirect effect through C-reactive protein (CRP) on leukocyte telomere length (LTL) to determine the mediation effect of CRP on the BMI-LTL association.<br><br>METHODS: The study cohort included 5451 adults (1404 Mexican American, 3114 White, and 933 Black individuals; 53.5% male; mean age&#x2005;=&#x2005;49.2 years) from the 1999 to 2002 National Health and Nutrition Examination Survey. General mediation models were used to examine the mediation effect of CRP on the BMI-LTL association.<br><br>RESULTS: After adjusting for age, race, sex, physical activity, alcohol use, and serum cotinine, the total effect of BMI on LTL was significant (standardized regression coefficient, &#x3b2;&#x2005;=&#x2005;-.054, P&#x2005;<&#x2005;.001) without CRP included in the model. With inclusion of CRP in the model, the indirect effect of BMI on LTL through CRP was estimated at &#x3b2; equal to -.023 (P&#x2005;<&#x2005;.001), and the direct effect of BMI on LTL in its absolute value decreased to &#x3b2; equal to -.031 (P&#x2005;=&#x2005;.025). The mediation effect of CRP was estimated at 42.6%. The mediation model parameters did not differ significantly between race and sex groups.<br><br>CONCLUSION: These results suggest that the inverse BMI-LTL association is partly mediated by obesity-induced inflammation. The significant direct effect of BMI on LTL with removal of the mediation effect through CRP indicates that obesity is associated with LTL attrition also through other noninflammatory mechanisms.},
}
@article {pmid34152657,
year = {2021},
author = {Manoli, F and Doria, F and Colombo, G and Zambelli, B and Freccero, M and Manet, I},
title = {The Binding Pocket at the Interface of Multimeric Telomere G-quadruplexes: Myth or Reality?.},
journal = {Chemistry (Weinheim an der Bergstrasse, Germany)},
volume = {27},
number = {45},
pages = {11707-11720},
pmid = {34152657},
issn = {1521-3765},
support = {IG 14708//Associazione Italiana per la Ricerca sul Cancro/ ; },
mesh = {Circular Dichroism ; DNA ; *G-Quadruplexes ; Humans ; Ligands ; Telomere ; },
abstract = {Human telomeric DNA with hundreds of repeats of the 5'-TTAGGG-3' motif plays a crucial role in several biological processes. It folds into G-quadruplex (G4) structures and features a pocket at the interface of two contiguous G4 blocks. Up to now no structural NMR and crystallographic data are available for ligands interacting with contiguous G4s. Naphthalene diimide monomers and dyads were investigated as ligands of a dimeric G4 of human telomeric DNA comparing the results with those of the model monomeric G4. Time-resolved fluorescence, circular dichroism, isothermal titration calorimetry and molecular modeling were used to elucidate binding features. Ligand fluorescence lifetime and induced circular dichroism unveiled occupancy of the binding site at the interface. Thermodynamic parameters confirmed the hypothesis as they remarkably change for the dyad complexes of the monomeric and dimeric telomeric G4. The bi-functional ligand structure of the dyads is a fundamental requisite for binding at the G4 interface as only the dyads engage in complexes with 1 : 1 stoichiometry, lodging in the pocket at the interface and establishing multiple interactions with the DNA skeleton. In the absence of NMR and crystallographic data, our study affords important proofs of binding at the interface pocket and clues on the role played by the ligand structure.},
}
@article {pmid34152095,
year = {2021},
author = {Mendes-Silva, AP and Vieira, ELM and Xavier, G and Barroso, LSS and Bertola, L and Martins, EAR and Brietzke, EM and Belangero, SIN and Diniz, BS},
title = {Telomere shortening in late-life depression: A potential marker of depression severity.},
journal = {Brain and behavior},
volume = {11},
number = {8},
pages = {e2255},
pmid = {34152095},
issn = {2162-3279},
mesh = {Aged ; Depression/genetics ; *Depressive Disorder, Major/genetics ; Humans ; Leukocytes ; Telomere/genetics ; *Telomere Shortening ; },
abstract = {OBJECTIVES: Telomeres are structures at the extremity of chromosomes that prevents genomic instability, and its shortening seems to be a hallmark of cellular aging. Past studies have shown contradictory results of telomere length (TL) in major depression, and are a few studies in late-life depression (LLD). This explores the association between TL as a molecular marker of aging and diagnosis of LLD, the severity of depressive symptoms, and cognitive performance in older adults.<br><br>METHODS/DESIGN: We included 78 older adults (45 with LLD and 33 nondepressed controls, according to DSM-V criteria), aged 60-90 years. TL was measured in leukocytes by a quantitative polymerase chain reaction, determining the relative ratio (T/S) between the telomere region copy number (T) and a single copy gene (S), using a relative standard curve.<br><br>RESULTS: TL was significantly shorter in the LLD compared with control participants (p&#xa0;=&#xa0;.039). Comparing groups through the severity of depressive symptoms, we found a negative correlation with the severity of depressive symptoms (Hamilton Depression Rating Scale-21, r&#xa0;=&#xa0;-0.325, p&#xa0;=&#xa0;.004) and medical burden (r&#xa0;=&#xa0;-0.271, p&#xa0;=&#xa0;.038). There was no significant correlation between TL and cognitive performance (Mattis Dementia Rating Scale, r&#xa0;=&#xa0;0.152, p&#xa0;=&#xa0;.21).<br><br>CONCLUSIONS: We found that older adults with LLD have shorter telomere than healthy controls, especially those with a more severe depressive episode. Our findings suggest that shorter TL can be a marker of the severity of depressive episodes in older adults and indicate that these individuals may be at higher risk of age-associated adverse outcomes linked to depression.},
}
@article {pmid34151032,
year = {2021},
author = {Dos Santos, GA and Pimenta, R and Viana, NI and Guimarães, VR and Romão, P and Candido, P and de Camargo, JA and Hatanaka, DM and Queiroz, PG and Teruya, A and Leite, KRM and Srougi, V and Srougi, M and Reis, ST},
title = {Shorter leukocyte telomere length is associated with severity of COVID-19 infection.},
journal = {Biochemistry and biophysics reports},
volume = {27},
number = {},
pages = {101056},
pmid = {34151032},
issn = {2405-5808},
support = {CH/12/2/29428/BHF_/British Heart Foundation/United Kingdom ; RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom ; RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom ; },
abstract = {The infection by COVID-19 is a serious global public health problem. An efficient way to improve this disease's clinical management would be to characterize patients at higher risk of progressing to critically severe infection using prognostic biomarkers. The telomere length could be used for this purpose. Telomeres are responsible for controlling the number of maximum cell divisions. The telomere length is a biomarker of aging and several diseases. We aimed to compare leukocyte telomere length (LTL) between patients without COVID-19 and patients with different clinical severity of the infection. Were included 53 patients who underwent SARS-CoV-2 PCR divided in four groups. The first group was composed by patients with a negative diagnosis for COVID-19 (n = 12). The other three groups consisted of patients with a confirmed diagnosis of COVID-19 divided according to the severity of the disease: mild (n = 15), moderate (n = 17) and severe (n = 9). The LTL was determined by Q-PCR. The severe group had the shortest LTL, followed by the moderate group. The negative and mild groups showed no differences. There is an increase of patients with hypertension (p = 0.0099) and diabetes (p = 0.0067) in moderate and severe groups. Severe group was composed by older patients in comparison with the other three groups (p = 0.0083). Regarding sex, there was no significant difference between groups (p = 0.6279). In an ordinal regression model, only LTL and diabetes were significantly associated with disease severity. Shorter telomere length was significantly associated with the severity of COVID-19 infection, which can be useful as a biomarker or to better understand the SARS-CoV-2 pathophysiology.},
}
@article {pmid34149773,
year = {2021},
author = {Aguilar, M and Prieto, P},
title = {Telomeres and Subtelomeres Dynamics in the Context of Early Chromosome Interactions During Meiosis and Their Implications in Plant Breeding.},
journal = {Frontiers in plant science},
volume = {12},
number = {},
pages = {672489},
pmid = {34149773},
issn = {1664-462X},
abstract = {Genomic architecture facilitates chromosome recognition, pairing, and recombination. Telomeres and subtelomeres play an important role at the beginning of meiosis in specific chromosome recognition and pairing, which are critical processes that allow chromosome recombination between homologs (equivalent chromosomes in the same genome) in later stages. In plant polyploids, these terminal regions are even more important in terms of homologous chromosome recognition, due to the presence of homoeologs (equivalent chromosomes from related genomes). Although telomeres interaction seems to assist homologous pairing and consequently, the progression of meiosis, other chromosome regions, such as subtelomeres, need to be considered, because the DNA sequence of telomeres is not chromosome-specific. In addition, recombination operates at subtelomeres and, as it happens in rye and wheat, homologous recognition and pairing is more often correlated with recombining regions than with crossover-poor regions. In a plant breeding context, the knowledge of how homologous chromosomes initiate pairing at the beginning of meiosis can contribute to chromosome manipulation in hybrids or interspecific genetic crosses. Thus, recombination in interspecific chromosome associations could be promoted with the aim of transferring desirable agronomic traits from related genetic donor species into crops. In this review, we summarize the importance of telomeres and subtelomeres on chromatin dynamics during early meiosis stages and their implications in recombination in a plant breeding framework.},
}
@article {pmid34148055,
year = {2022},
author = {Pepper, AGS and Zucchetto, A and Norris, K and Tissino, E and Polesel, J and Soe, Z and Allsup, D and Hockaday, A and Ow, PL and Hillmen, P and Rawstron, A and Catovsky, D and Bulian, P and Bomben, R and Baird, DM and Fegan, CD and Gattei, V and Pepper, C},
title = {Combined analysis of IGHV mutations, telomere length and CD49d identifies long-term progression-free survivors in TP53 wild-type CLL treated with FCR-based therapies.},
journal = {Leukemia},
volume = {36},
number = {1},
pages = {271-274},
pmid = {34148055},
issn = {1476-5551},
support = {25447/CRUK_/Cancer Research UK/United Kingdom ; 29202/CRUK_/Cancer Research UK/United Kingdom ; MR/V009095/1/MRC_/Medical Research Council/United Kingdom ; /DH_/Department of Health/United Kingdom ; },
mesh = {Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Biomarkers, Tumor/analysis ; Cyclophosphamide/administration &amp; dosage ; Follow-Up Studies ; Humans ; Immunoglobulin Heavy Chains/*genetics ; Immunoglobulin Variable Region/*genetics ; Integrin alpha4/genetics/*metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/genetics/*mortality/pathology ; *Mutation ; Neoplasm Recurrence, Local/drug therapy/genetics/mortality/pathology ; Prognosis ; Rituximab/administration &amp; dosage ; Survival Rate ; *Telomere Homeostasis ; Tumor Suppressor Protein p53/*genetics ; Vidarabine/administration &amp; dosage/analogs &amp; derivatives ; },
}
@article {pmid34148053,
year = {2022},
author = {Boyle, EM and Williams, L and Blaney, P and Ashby, C and Bauer, M and Walker, BA and Ghamlouch, H and Choi, J and Perrial, E and Wang, Y and Caro, J and Stoeckle, JH and Arbini, A and Kaminetzky, D and Braunstein, M and Bruno, B and Razzo, B and Diamond, B and Maclachlan, K and Maura, F and Landgren, O and Litke, R and Fegan, CD and Keats, J and Auclair, D and Davies, FE and Morgan, GJ},
title = {Improving prognostic assignment in older adults with multiple myeloma using acquired genetic features, clonal hemopoiesis and telomere length.},
journal = {Leukemia},
volume = {36},
number = {1},
pages = {221-224},
pmid = {34148053},
issn = {1476-5551},
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/*genetics ; *Clonal Hematopoiesis ; Combined Modality Therapy ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Multiple Myeloma/genetics/*pathology/therapy ; Prognosis ; RNA-Seq ; Survival Rate ; *Telomere Homeostasis ; },
}
@article {pmid34146858,
year = {2021},
author = {Akcha, F and Cahuc, C and Rouxel, J and Munschy, C and Aminot, Y and Chouvelon, T and Mahe, K and Budzinski, H and Mauffret, A},
title = {Development in the European flounder (Platichthys flesus) of a q-PCR assay for the measurement of telomere length, a potential biomarker of pollutant effects for biomonitoring studies.},
journal = {Marine pollution bulletin},
volume = {170},
number = {},
pages = {112610},
doi = {10.1016/j.marpolbul.2021.112610},
pmid = {34146858},
issn = {1879-3363},
mesh = {Animals ; Biological Monitoring ; Biomarkers ; Child, Preschool ; Environmental Monitoring ; *Environmental Pollutants ; *Flounder/genetics ; Humans ; Liver/chemistry ; Polymerase Chain Reaction ; Telomere/chemistry ; *Water Pollutants, Chemical/analysis/toxicity ; },
abstract = {Telomeres protect the coding sequence of chromosome ends and Telomere Length (TL) has been proposed as a biomarker of cellular aging, cumulative stress exposure and life-span in humans. With the aim to propose new biomarkers, a q-PCR protocol was adapted for the measurement of TL in the European flounder Platichthys flesus. The protocol was then applied in 2-year-old flounders from the Seine Estuary. The absolute TL in the flounder is 54 ± 13 kbp per genome (mean ± standard error). Considering relative or absolute TL, no correlation was observed with DNA damage and any of the measured contaminant concentrations (trace elements, metabolites of polycyclic aromatic hydrocarbons, polychlorobiphenyls, organochlorinated pesticides, polybrominated diphenyl ethers, perfluoroalkyl substances). Because sampling was limited, further investigations are required to state a possible impact of chemical pollution on flatfish telomeres. This is motivated by correlations observed with organochlorinated compounds when decreasing statistical significance (p ≤ 0.10).},
}
@article {pmid34145295,
year = {2021},
author = {Silva, B and Arora, R and Bione, S and Azzalin, CM},
title = {TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {3760},
pmid = {34145295},
issn = {2041-1723},
mesh = {Cell Line, Tumor ; Chromosome Breakage ; DNA Damage/genetics ; DNA Replication/genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Neoplasms/genetics ; RNA, Long Noncoding/*genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Transcription, Genetic/*genetics ; },
abstract = {Alternative Lengthening of Telomeres (ALT) is a Break-Induced Replication (BIR)-based mechanism elongating telomeres in a subset of human cancer cells. While the notion that spontaneous DNA damage at telomeres is required to initiate ALT, the molecular triggers of this physiological telomere instability are largely unknown. We previously proposed that the telomeric long noncoding RNA TERRA may represent one such trigger; however, given the lack of tools to suppress TERRA transcription in cells, our hypothesis remained speculative. We have developed Transcription Activator-Like Effectors able to rapidly inhibit TERRA transcription from multiple chromosome ends in an ALT cell line. TERRA transcription inhibition decreases marks of DNA replication stress and DNA damage at telomeres and impairs ALT activity and telomere length maintenance. We conclude that TERRA transcription actively destabilizes telomere integrity in ALT cells, thereby triggering BIR and promoting telomere elongation. Our data point to TERRA transcription manipulation as a potentially useful target for therapy.},
}
@article {pmid34142138,
year = {2021},
author = {Noguera, JC and Velando, A},
title = {Telomerase activity can mediate the effects of growth on telomeres during post-natal development in a wild bird.},
journal = {The Journal of experimental biology},
volume = {224},
number = {12},
pages = {},
doi = {10.1242/jeb.242465},
pmid = {34142138},
issn = {1477-9145},
mesh = {Animals ; Animals, Wild ; Charadriiformes/*growth &amp; development ; *Telomerase/genetics ; *Telomere/genetics ; Telomere Shortening ; },
abstract = {In wild animals, telomere attrition during early development has been linked with several fitness disadvantages throughout life. Telomerase enzyme can elongate telomeres, but it is generally assumed that its activity is suppressed in most somatic tissues upon birth. However, recent evidence suggests that this may not be the case for long-lived bird species. We have therefore investigated whether telomerase activity is maintained during the postnatal growth period in a wild yellow-legged gull (Larus michahellis) population. Our results indicate that telomerase activity is not negligible in the blood cells, but activity levels sharply decline from hatching to fledging following a similar pattern to the reduction observed in telomere length. Our results further suggest that the observed variation in telomere length may be the result of a negative effect of fast growth on telomerase activity, thus providing a new mechanism through which growth rates may affect telomere dynamics and potentially life-history trajectories.},
}
@article {pmid34141465,
year = {2021},
author = {Delgado, M and Buffington, CAT and Bain, M and Smith, DL and Vernau, K},
title = {Early maternal separation is not associated with changes in telomere length in domestic kittens (Felis catus).},
journal = {PeerJ},
volume = {9},
number = {},
pages = {e11394},
pmid = {34141465},
issn = {2167-8359},
abstract = {OBJECTIVE: Studies of multiple species have found that adverse early life experiences, including childhood trauma and maternal separation, can result in accelerated telomere shortening. The objective of this study was to determine if premature separation from the mother affected telomere length in domestic kittens (Felis catus). Subjects were 42 orphaned kittens and 10 mother-reared kittens from local animal rescue groups and shelters. DNA was extracted from whole blood collected from kittens at approximately 1 week and 2 months of age. Telomere length was assessed by qPCR (quantitative polymerase chain reaction) from a total of 86 samples and expressed as a ratio of telomere PCR relative to a single copy gene PCR (T/S).<br><br>RESULTS: A generalized linear mixed model found there were no detectable differences in telomere length based on survival (F 1, 76.2 = 3.35, p = 0.07), orphan status (F 1, 56.5 = 0.44, p = 0.51), time point (F 1, 43.5 = 0.19, p = 0.67), or the interaction between orphan status and time (F 1, 43.5 = 0.86, p = 0.36). Although in other species telomere shortening is commonly associated with aging, even early in life, we did not find evidence for telomere shortening by two months of age. Our results suggest that the experience of early maternal separation in domestic cats who are subsequently hand-reared by humans does not accelerate telomere shortening compared to mother-reared kittens, at least in the first few months of life.},
}
@article {pmid34140564,
year = {2021},
author = {Peska, V and Fajkus, P and Bubeník, M and Brázda, V and Bohálová, N and Dvořáček, V and Fajkus, J and Garcia, S},
title = {Extraordinary diversity of telomeres, telomerase RNAs and their template regions in Saccharomycetaceae.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {12784},
pmid = {34140564},
issn = {2045-2322},
mesh = {Base Sequence ; Benzothiazoles/metabolism ; Fluorescence ; G-Quadruplexes ; *Genetic Variation ; RNA/*genetics ; Reproducibility of Results ; Saccharomycetales/*genetics ; Telomerase/*genetics ; Telomere/*genetics ; *Templates, Genetic ; },
abstract = {Telomerase RNA (TR) carries the template for synthesis of telomere DNA and provides a scaffold for telomerase assembly. Fungal TRs are long and have been compared to higher eukaryotes, where they show considerable diversity within phylogenetically close groups. TRs of several Saccharomycetaceae were recently identified, however, many of these remained uncharacterised in the template region. Here we show that this is mainly due to high variability in telomere sequence. We predicted the telomere sequences using Tandem Repeats Finder and then we identified corresponding putative template regions in TR candidates. Remarkably long telomere units and the corresponding putative TRs were found in Tetrapisispora species. Notably, variable lengths of the annealing sequence of the template region (1-10 nt) were found. Consequently, species with the same telomere sequence may not harbour identical TR templates. Thus, TR sequence alone can be used to predict a template region and telomere sequence, but not to determine these exactly. A conserved feature of telomere sequences, tracts of adjacent Gs, led us to test the propensity of individual telomere sequences to form G4. The results show highly diverse values of G4-propensity, indicating the lack of ubiquitous conservation of this feature across Saccharomycetaceae.},
}
@article {pmid34136834,
year = {2021},
author = {Idilli, AI and Segura-Bayona, S and Lippert, TP and Boulton, SJ},
title = {A C-circle assay for detection of alternative lengthening of telomere activity in FFPE tissue.},
journal = {STAR protocols},
volume = {2},
number = {2},
pages = {100569},
pmid = {34136834},
issn = {2666-1667},
support = {FC0010048/CRUK_/Cancer Research UK/United Kingdom ; FC0010048/MRC_/Medical Research Council/United Kingdom ; FC0010048/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Humans ; In Situ Hybridization, Fluorescence/methods ; *Telomere ; *Telomere Homeostasis ; },
abstract = {Alternative lengthening of telomeres (ALT) is a telomerase-independent, recombination-based telomere maintenance mechanism that allows cancer cells to acquire unlimited proliferative capacity. The C-circle assay (CCA) has emerged as the gold standard for quantitative measurement of ALT activity. Here, we present a modified CCA protocol to examine ALT activity in formalin-fixed paraffin-embedded specimens. We optimized several aspects of the procedure including genomic DNA isolation and hybridization steps, which allows for sensitive and robust quantitation of ALT activity in patient biopsies. For complete details on the use and execution of this protocol, please refer to Lippert et al. (2021).},
}
@article {pmid34133663,
year = {2021},
author = {Santos, GAD and Reis, ST and Leite, KRM and Srougi, M},
title = {Telomere Attrition and p53 Response 1 (TAPR1): a new player in cancer biology?.},
journal = {Clinics (Sao Paulo, Brazil)},
volume = {76},
number = {},
pages = {e2997},
pmid = {34133663},
issn = {1980-5322},
mesh = {Humans ; *Neoplasms/genetics ; Proteins/*genetics ; },
}
@article {pmid34125900,
year = {2021},
author = {Pobiega, S and Alibert, O and Marcand, S},
title = {A new assay capturing chromosome fusions shows a protection trade-off at telomeres and NHEJ vulnerability to low-density ionizing radiation.},
journal = {Nucleic acids research},
volume = {49},
number = {12},
pages = {6817-6831},
pmid = {34125900},
issn = {1362-4962},
mesh = {Centromere ; *Chromosome Aberrations ; DNA End-Joining Repair/*radiation effects ; Genetic Techniques ; Radiation, Ionizing ; Saccharomyces cerevisiae/genetics ; *Telomere/metabolism ; Telomere Homeostasis ; },
abstract = {Chromosome fusions threaten genome integrity and promote cancer by engaging catastrophic mutational processes, namely chromosome breakage-fusion-bridge cycles and chromothripsis. Chromosome fusions are frequent in cells incurring telomere dysfunctions or those exposed to DNA breakage. Their occurrence and therefore their contribution to genome instability in unchallenged cells is unknown. To address this issue, we constructed a genetic assay able to capture and quantify rare chromosome fusions in budding yeast. This chromosome fusion capture (CFC) assay relies on the controlled inactivation of one centromere to rescue unstable dicentric chromosome fusions. It is sensitive enough to quantify the basal rate of end-to-end chromosome fusions occurring in wild-type cells. These fusions depend on canonical nonhomologous end joining (NHEJ). Our results show that chromosome end protection results from a trade-off at telomeres between positive effectors (Rif2, Sir4, telomerase) and a negative effector partially antagonizing them (Rif1). The CFC assay also captures NHEJ-dependent chromosome fusions induced by ionizing radiation. It provides evidence for chromosomal rearrangements stemming from a single photon-matter interaction.},
}
@article {pmid34119568,
year = {2023},
author = {Xu, Y and Xie, CB and Yang, J and Xing, YJ and Xia, WP and Liu, Y and Xi, WB and Li, ZJ and Tu, WF and Zhang, JL},
title = {Association between telomere length in the DNA of peripheral blood leukocytes and the propofol dose in anesthesia induction: an observational study.},
journal = {Brazilian journal of anesthesiology (Elsevier)},
volume = {73},
number = {6},
pages = {764-768},
pmid = {34119568},
issn = {2352-2291},
mesh = {Humans ; Aged ; *Propofol/pharmacology ; Anesthetics, Intravenous/pharmacology ; Anesthesia, General ; DNA ; Leukocytes ; Body Weight ; Telomere ; Electroencephalography ; },
abstract = {INTRODUCTION: Propofol is a widely used anesthetic and its dose is closely related to aging. Telomere length (TL) is a unique heritable trait, and emerging as a biomarker of aging, health and disease. Telomerase RNA component (TERC) plays an important role in maintaining TL. We proposed a hypothesis that propofol dose in general anesthesia can be predicted by measuring TL before operation, which greatly reduced the risk of anesthesia, especially the elderly.<br><br>METHODS: The association between the propofol dose in anesthesia induction and: TL in the DNA of peripheral blood leukocytes; body weight; sex; difference of the Bispectral Index (BIS) before and after anesthesia induction in patients was evaluated by multivariable linear regression analyses. The mutation at the 5'end or 3'end of TERC was detected. We recruited 100 patients of elective surgery.<br><br>RESULTS: We found that propofol dose in anesthesia induction was clearly correlated significantly with TL (r = 0.78, p < 0.001), body weight (r = 0.84, p = 0.004), sex (r = 0.83, p= 0.84, p = 0.004), sex (r = 0.83, p = 0.004), and difference of BIS before and after anesthesia induction (r = 0.85, p = 0.029). By comparing the absolute values of standardized regression coefficients (0.58, 0.21, 0.19, and 0.12) of the four variables, it can be seen that TL contributes the most to the propofol dose in anesthesia induction. However, the mutation at the 5' end or 3' end of TERC was not found.<br><br>CONCLUSIONS: These findings provide preliminary evidence that the propofol dose in anesthesia induction was clearly correlated with genetically determined TL. TL may be a promising predictor of the propofol dose, which is beneficial to improve the safety of anesthesia and reduce perioperative complications.},
}
@article {pmid34117333,
year = {2021},
author = {Bijnens, EM and Derom, C and Thiery, E and Martens, DS and Loos, RJF and Weyers, S and Nawrot, TS},
title = {Serum gamma-glutamyl transferase, a marker of alcohol intake, is associated with telomere length and cardiometabolic risk in young adulthood.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {12407},
pmid = {34117333},
issn = {2045-2322},
mesh = {Adolescent ; Adult ; Alcohol Drinking/*blood ; Female ; Humans ; Male ; Metabolic Syndrome/*epidemiology ; Risk Factors ; *Telomere ; Young Adult ; gamma-Glutamyltransferase/*blood ; },
abstract = {Studies based on self-reported alcohol consumption and telomere length show inconsistent results. Therefore, we studied the association between gamma-glutamyl transferase (GGT), a widely used biomarker of alcohol intake, and telomere length. The possible health relevance in young adulthood was explored by investigating cardiometabolic risk factors. Mixed modelling was performed to examine GGT and alcohol consumption in association with telomere length in buccal cells of 211 adults between 18 and 30 years old of the East Flanders Prospective Twin Survey. In addition, we investigated the association between GGT and cardiometabolic risk factors; waist circumference, systolic blood pressure, fasting glucose, HDL cholesterol, and triglycerides. Although we did not observe an association between self-reported alcohol consumption and telomere length, our results show that a doubling in serum GGT is associated with 7.80% (95% CI - 13.9 to - 1.2%; p = 0.02) shorter buccal telomeres, independently from sex, chronological age, educational level, zygosity and chorionicity, waist-to-hip ratio and smoking. The association between GGT was significant for all five cardiometabolic risk factors, while adjusting for age. We show that GGT, a widely used biomarker of alcohol consumption, is associated with telomere length and with risk factors of cardiometabolic syndrome, despite the young age of this study population.},
}
@article {pmid34114988,
year = {2021},
author = {Wang, S and Gao, Y and Zhao, L and Hu, R and Yang, X and Liu, Y},
title = {Shortened leukocyte telomere length as a potential biomarker for predicting the progression of atrial fibrillation from paroxysm to persistence in the short-term.},
journal = {Medicine},
volume = {100},
number = {23},
pages = {e26020},
pmid = {34114988},
issn = {1536-5964},
support = {81700295//National Natural Science Foundation of China/ ; 81670214//National Natural Science Foundation of China/ ; },
mesh = {*Atrial Fibrillation/diagnosis/epidemiology/genetics ; China/epidemiology ; Cross-Sectional Studies ; *Disease Progression ; Female ; Genetic Markers/physiology ; Humans ; Leukocytes/*physiology ; Male ; Middle Aged ; Risk Factors ; Telomere Homeostasis ; Telomere Shortening/*physiology ; },
abstract = {This study aimed to assess the role of leukocyte telomere length (LTL) in the development of atrial fibrillation (AF) among Chinese patients.This is a cross-sectional study. A total of 350 patients from June 2016 to December 2017 were retrospectively analyzed. These included 219 AF patients and 131 with sinus rhythm in the control group. Quantitative real-time PCR was used to measure relative LTL.The relative LTLs of all subjects (n = 350) ranged from 0.4 to 2.41 (0.98 ± 0.29), showing a significant negative correlation (P < .001) with age. The AF-group had significantly shorter LTLs (0.93 ± 0.26 vs 1.07 ± 0.33, P < .001) and were older (61.50 ± 6.49 vs 59.95 ± 6.17, P = .028) than controls. LTLs among patients with persistent AF (PsAF), paroxysmal AF (PAF), and controls were significantly different (P < .001), with LTLs of PsAF patients being the shortest and controls being the longest. After adjusting for possible confounding factors, the PsAF group still showed significantly shorter LTLs than the PAF and control groups (P = .013 and P = .001, respectively). After an 18-month follow-up, 20 out of 119 PAF patients had progressed into PsAF and a relative LTL of ≤0.73 was an independent predictor for progression of PAF into PsAF.LTL was found to be shorter in patients with AF than in age-matched individuals with sinus rhythm and positively correlated with severity of AF. LTL shortening could be an independent risk factor for progression from paroxysmal AF to persistent AF in the short term.},
}
@article {pmid34113796,
year = {2021},
author = {AlDehaini, DMB and Al-Bustan, SA and Malalla, ZHA and Ali, ME and Sater, M and Giha, HA},
title = {Analogous telomeres shortening and different metabolic profile: hypertension versus hypertension/type 2 diabetes mellitus comorbidity.},
journal = {Cardiovascular endocrinology &amp; metabolism},
volume = {10},
number = {2},
pages = {106-112},
pmid = {34113796},
issn = {2574-0954},
abstract = {BACKGROUND: Eukaryotes chromosomal ends are capped and protected by telomeres, which are noncoding DNA repeats synthesized by telomerase enzyme. The telomerase enzyme is a nucleoprotein encoded by TERC and TERT genes. Naturally, the length of the telomeres shortens with each cell cycle but the shortening is fastened in certain age-related diseases like hypertension (HTN) and type 2 diabetes mellitus (T2DM).<br><br>MATERIALS AND METHODS: Blood samples (n&#x2009;=&#x2009;171) were obtained from Kuwaiti subjects with HTN, and HTN/T2DM comorbidity (HTN-DM) and healthy subjects. The leukocyte telomere length (LTL) was measured by SYBR green quantitative rtPCR, and plasma telomerase enzyme was measured by ELISA, in addition, three single nucleotide polymorphisms (SNPs) in telomere-related genes; TERC rs12696304GC, TERT rs2736100CA, and ACYP2 rs6713088GC were genotyped by real-time PCR.<br><br>RESULTS: Marked LTL shortening in subjects with HTN and HTN-DM compared to healthy subjects, P&#x2009;=&#x2009;0.043 and P&#x2009;<&#x2009;0.001, respectively, was noticed. On the contrary, the plasma telomerase enzyme levels and minor allele frequencies and genotypes of the tested SNPs were comparable between the study groups, except for TERT (CA) genotype which was over-represented in HTN (P&#x2009;=&#x2009;0.037). Furthermore, the comparisons between HTN and HTN-DM revealed significantly higher total cholesterol (P&#x2009;=&#x2009;0.015) and LDL-C (P&#x2009;=&#x2009;0.008) in HTN, while higher insulin levels (P&#x2009;<&#x2009;001), HOMA-IR (P&#x2009;<&#x2009;001), and BMI (P&#x2009;=&#x2009;0.004) were observed in HTN-DM.<br><br>CONCLUSION: This study showed comparable LTL shortening in HTN and HTN-DM, irrespective of plasma telomerase enzyme levels or tested TERC, TERT, and ACYP2 gene polymorphisms, although HTN and HTN-DM differed in several metabolic markers. More studies are required to affirm these observations.},
}
@article {pmid34103668,
year = {2021},
author = {Brosnan-Cashman, JA and Davis, CM and Diplas, BH and Meeker, AK and Rodriguez, FJ and Heaphy, CM},
title = {SMARCAL1 loss and alternative lengthening of telomeres (ALT) are enriched in giant cell glioblastoma.},
journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},
volume = {34},
number = {10},
pages = {1810-1819},
pmid = {34103668},
issn = {1530-0285},
support = {T32 CA009110/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Biopsy ; Brain Neoplasms/genetics/*metabolism/pathology ; Child, Preschool ; DNA Helicases/genetics/*metabolism ; Female ; Glioblastoma/genetics/*metabolism/pathology ; Humans ; Isocitrate Dehydrogenase/genetics/metabolism ; Male ; Middle Aged ; Mutation ; Telomere Homeostasis/*genetics ; X-linked Nuclear Protein/genetics/metabolism ; Young Adult ; },
abstract = {Subsets of high-grade gliomas, including glioblastoma (GBM), are known to utilize the alternative lengthening of telomeres (ALT) pathway for telomere length maintenance. However, the telomere maintenance profile of one subtype of GBM-giant cell GBM-has not been extensively studied. Here, we investigated the prevalence of ALT, as well as ATRX and SMARCAL1 protein loss, in a cohort of classic giant cell GBM and GBM with giant cell features. To determine the presence of ALT, a telomere-specific fluorescence in situ hybridization assay was performed on 15 cases of classic giant cell GBM, 28 additional GBMs found to have giant cell features, and 1 anaplastic astrocytoma with giant cell features. ATRX, SMARCAL1, and IDH1 protein status were assessed in a proportion of cases by immunohistochemistry and were compared to clinical-pathologic and molecular characteristics. In the overall cohort of 44 cases, 19 (43%) showed evidence of ALT. Intriguingly, of the ALT-positive cases, only 9 (47.4%) displayed loss of the ALT suppressor ATRX by immunohistochemistry. Since inactivating mutations in SMARCAL1 have been identified in ATRX wild-type ALT-positive gliomas, we developed an immunohistochemistry assay for SMARCAL1 protein expression using genetically validated controls. Of the 19 ALT-positive cases, 6 (31.5%) showed loss or mis-localization of SMARCAL1 by immunohistochemistry. Of these cases, four retained ATRX protein expression, while two cases also displayed ATRX loss. Additionally, we assessed five cases from which multiple temporal samples were available and ALT status was concordant between both tumor biopsies. In summary, we have identified a subset of giant cell GBM that utilize the ALT telomere maintenance mechanism. Importantly, in addition to ATRX loss, ALT-positive tumors harboring SMARCAL1 alterations are prevalent in giant cell GBM.},
}
@article {pmid34101921,
year = {2022},
author = {Bae, J and Bertucci, EM and Bock, SL and Hale, MD and Moore, J and Wilkinson, PM and Rainwater, TR and Bowden, JA and Koal, T and PhamTuan, H and Parrott, BB},
title = {Intrinsic and extrinsic factors interact during development to influence telomere length in a long-lived reptile.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6114-6127},
doi = {10.1111/mec.16017},
pmid = {34101921},
issn = {1365-294X},
mesh = {Animals ; *Glucocorticoids ; *Alligators and Crocodiles ; Aging ; Telomere/genetics ; },
abstract = {The mechanisms connecting environmental conditions to plasticity in biological aging trajectories are fundamental to understanding individual variation in functional traits and life history. Recent findings suggest that telomere biology is especially dynamic during early life stages and has long-term consequences for subsequent reproduction and survival. However, our current understanding is mostly derived from studies investigating ecological and anthropogenic factors separately, leaving the effects of complex environmental interactions unresolved. American alligators (Alligator mississippiensis) are long-lived apex predators that rely on incubation temperature during a discrete period during development and endocrine cues to determine sex, making them especially vulnerable to current climatic variability and exposure to anthropogenic contaminants interfering with hormone function. Here, we combine field studies with a factorial design to understand how the developmental environment, along with intrinsic biological variation contribute to persistent telomere variation. We found that exposure to a common endocrine disrupting contaminant, DDE, affects telomere length, but that the directionality is highly dependent upon incubation temperature. Variation in hatchling growth, underlies a strong clutch effect. We also assess concentrations of a panel of glucocorticoid hormones and find that contaminant exposure elicits an increase in circulating glucocorticoids. Consistent with emerging evidence linking stress and aging trajectories, GC levels also appear to trend with shorter telomere length. Thus, we add support for a mechanistic link between contaminants and glucocorticoid signalling, which interacts with ecological aspects of the developmental environment to alter telomere dynamics.},
}
@article {pmid34101279,
year = {2022},
author = {van Lieshout, SHJ and Badás, EP and Bright Ross, JG and Bretman, A and Newman, C and Buesching, CD and Burke, T and Macdonald, DW and Dugdale, HL},
title = {Early-life seasonal, weather and social effects on telomere length in a wild mammal.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {5993-6007},
doi = {10.1111/mec.16014},
pmid = {34101279},
issn = {1365-294X},
mesh = {Animals ; Seasons ; *Weather ; Longevity/genetics ; Telomere Shortening/genetics ; *Mustelidae/genetics ; Telomere/genetics ; },
abstract = {Early-life environmental conditions can provide a source of individual variation in life-history strategies and senescence patterns. Conditions experienced in early life can be quantified by measuring telomere length, which can act as a biomarker of survival probability in some species. Here, we investigate whether seasonal changes, weather conditions and group size are associated with early-life and/or early-adulthood telomere length in a wild population of European badgers (Meles meles). We found substantial intra-annual changes in telomere length during the first 3 years of life, where within-individual effects showed shorter telomere lengths in the winter following the first spring and a trend for longer telomere lengths in the second spring compared to the first winter. In terms of weather conditions, cubs born in warmer, wetter springs with low rainfall variability had longer early-life (3-12 months old) telomeres. Additionally, cubs born in groups with more cubs had marginally longer early-life telomeres, providing no evidence of resource constraint from cub competition. We also found that the positive association between early-life telomere length and cub survival probability remained when social and weather variables were included. Finally, after sexual maturity, in early adulthood (i.e., 12-36 months) we found no significant association between same-sex adult group size and telomere length (i.e., no effect of intrasexual competition). Overall, we show that controlling for seasonal effects, which are linked to food availability, is important in telomere length analyses, and that variation in telomere length in badgers reflects early-life conditions and also predicts first year cub survival.},
}
@article {pmid34101251,
year = {2021},
author = {Lin, L and Qin, K and Chen, D and Lu, C and Chen, W and Guo, VY},
title = {Systematic review and meta-analysis of the association between paediatric obesity and telomere length.},
journal = {Acta paediatrica (Oslo, Norway : 1992)},
volume = {110},
number = {10},
pages = {2695-2703},
doi = {10.1111/apa.15971},
pmid = {34101251},
issn = {1651-2227},
support = {51000-18841211//The Start-up Fund from Sun Yat-sen University/ ; 2021qntd42//The Fundamental Research Funds for the Central Universities/ ; },
mesh = {Child ; Female ; Humans ; Male ; Overweight/genetics ; *Pediatric Obesity/genetics ; Research Design ; Telomere/genetics ; Telomere Shortening ; },
abstract = {AIM: This systematic review and meta-analysis aimed to assess the association between paediatric obesity and telomere length.<br><br>METHODS: We conducted a comprehensive literature search for original studies assessing the associations between obesity and telomere length in children. Fixed or random effects with inverse-variance meta-analysis were used to estimate the standardised mean difference (SMD) and its 95% confidence interval (95% CI) between overweight or obese and normal-weight children. Heterogeneity was assessed using the I[2] statistic, and meta-regression analyses were used to evaluate the potential source of heterogeneity. Subgroup analysis was further conducted by sex.<br><br>RESULTS: A total of 11 studies were included. The meta-analysis showed that children who were overweight or obese had shorter telomere length than normal-weight children (SMD: -0.85; 95% CI: -1.42 to -0.28; p&#xa0;<&#xa0;0.01). However, significant heterogeneity was present (I[2] &#xa0;=&#xa0;97%; p&#xa0;<&#xa0;0.01). Study design, methods used for measuring telomere length, tissue types, mean age, and percentage of boys were not the source of heterogeneity revealed by meta-regression analysis. The inverse trend was significant only in boys, but not in girls.<br><br>CONCLUSION: There was a negative association between paediatric obesity and telomere length. Weight control in children might have beneficial effect on telomere length.},
}
@article {pmid34091434,
year = {2021},
author = {Tian, XP and Qian, D and He, LR and Huang, H and Mai, SJ and Li, CP and Huang, XX and Cai, MY and Liao, YJ and Kung, HF and Zeng, YX and Xie, D},
title = {Corrigendum to ‟The telomere/telomerase binding factor PinX1 regulates paclitaxel sensitivity depending on spindle assembly checkpoint in human cervical squamous cell carcinomas" [Canc. Lett. 353 (2014) 104-114].},
journal = {Cancer letters},
volume = {516},
number = {},
pages = {61-63},
doi = {10.1016/j.canlet.2021.05.023},
pmid = {34091434},
issn = {1872-7980},
}
@article {pmid34086604,
year = {2021},
author = {Wang, C and Nawrot, TS and Van Der Stukken, C and Tylus, D and Sleurs, H and Peusens, M and Alfano, R and Langie, SAS and Plusquin, M and Martens, DS},
title = {Different epigenetic signatures of newborn telomere length and telomere attrition rate in early life.},
journal = {Aging},
volume = {13},
number = {11},
pages = {14630-14650},
pmid = {34086604},
issn = {1945-4589},
mesh = {Child, Preschool ; CpG Islands/genetics ; DNA Methylation/genetics ; *Epigenesis, Genetic ; Female ; *Gene Expression Profiling ; Genome-Wide Association Study ; Humans ; Infant, Newborn ; Male ; Models, Genetic ; Telomere Homeostasis/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Telomere length (TL) and telomere shortening are biological indicators of aging, and epigenetic associates have been found for TL in adults. However, the role of epigenetic signatures in setting newborn TL and early life telomere dynamics is unknown. In the present study, based on 247 participating newborns from the ENVIRONAGE birth cohort, whole-genome DNA methylation, profiled on the Illumina MethylationEPIC BeadChip microarray, and TL were measured in cord blood. In a follow-up visit at a mean age of 4.58 years, leukocyte TL was evaluated. We combined an epigenome-wide association study and a statistical learning method with re-sampling to select CpGs and their two-way interactions to model baseline (cord blood) TL and early-life telomere attrition rate, where distinct epigenetic signatures were identified for the two outcomes. In addition, a stronger epigenetic regulation was suggested in setting newborn TL than that of telomere dynamics in early life: 47 CpGs and 7 between-CpG interactions explained 76% of the variance in baseline TLs, while 72% of the total variance in telomere attrition rate was explained by 31 CpGs and 5 interactions. Functional enrichment analysis based on the selected CpGs in the two models revealed GLUT4 translocation and immune cell signaling pathways, respectively. These CpGs and interactions, as well as the cellular pathways, are potential novel targets of further investigation of telomere biology and aging.},
}
@article {pmid34084786,
year = {2021},
author = {van Batenburg, AA and Kazemier, KM and van Oosterhout, MFM and van der Vis, JJ and Grutters, JC and Goldschmeding, R and van Moorsel, CHM},
title = {Telomere shortening and DNA damage in culprit cells of different types of progressive fibrosing interstitial lung disease.},
journal = {ERJ open research},
volume = {7},
number = {2},
pages = {},
pmid = {34084786},
issn = {2312-0541},
abstract = {Pulmonary fibrosis is strongly associated with telomere shortening and increased DNA damage. Key cells in the pathogenesis involve alveolar type 2 (AT2) cells, club cells and myofibroblasts; however, to what extent these cells are affected by telomere shortening and DNA damage is not yet known. We sought to determine the degree of, and correlation between, telomere shortening and DNA damage in different cell types involved in the pathogenesis of progressive fibrosing interstitial lung disease. Telomere length and DNA damage were quantified, using combined fluorescence in situ hybridisation and immunofluorescence staining techniques, in AT2 cells, club cells and myofibroblasts of controls and patients with pulmonary fibrosis and a telomerase reverse transcriptase mutation (TERT-PF), idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (fHP). In IPF and TERT-PF lungs, AT2 cells contained shorter telomeres and expressed higher DNA damage signals than club cells and myofibroblasts. In fHP lungs, club cells contained highly elevated levels of DNA damage, while telomeres were not obviously short. In vitro, we found significantly shorter telomeres and higher DNA damage levels only in AT2 surrogate cell lines treated with telomerase inhibitor BIBR1532. Our study demonstrated that in IPF and TERT-PF lungs, telomere shortening and accumulation of DNA damage primarily affects AT2 cells, further supporting the importance of AT2 cells in these diseases, while in fHP the particularly high telomere-independent DNA damage signals in club cells underscores its bronchiolocentric pathogenesis. These findings suggest that cell type-specific telomere shortening and DNA damage may help to discriminate between different drivers of fibrogenesis.},
}
@article {pmid34083495,
year = {2021},
author = {Pearce, EE and Horvath, S and Katta, S and Dagnall, C and Aubert, G and Hicks, BD and Spellman, SR and Katki, H and Savage, SA and Alsaggaf, R and Gadalla, SM},
title = {DNA-methylation-based telomere length estimator: comparisons with measurements from flow FISH and qPCR.},
journal = {Aging},
volume = {13},
number = {11},
pages = {14675-14686},
pmid = {34083495},
issn = {1945-4589},
support = {U01 AG060908/AG/NIA NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; DNA Methylation/*genetics ; Female ; Humans ; *In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; *Real-Time Polymerase Chain Reaction ; Reproducibility of Results ; Telomere Homeostasis/*genetics ; Young Adult ; },
abstract = {Telomere length (TL) is a marker of biological aging associated with several health outcomes. High throughput reproducible TL measurements are needed for large epidemiological studies. We compared the novel DNA methylation-based estimator (DNAmTL) with the high-throughput quantitative PCR (qPCR) and the highly accurate flow cytometry with fluorescent in situ hybridization (flow FISH) methods using blood samples from healthy adults. We used Pearson's correlation coefficient, Bland Altman plots and linear regression models for statistical analysis. Shorter DNAmTL was associated with older age, male sex, white race, and cytomegalovirus seropositivity (p<0.01 for all). DNAmTL was moderately correlated with qPCR TL (N=635, r=0.41, p < 0.0001) and flow FISH total lymphocyte TL (N=144, r=0.56, p < 0.0001). The agreements between flow FISH TL and DNAmTL or qPCR were acceptable but with wide limits of agreement. DNAmTL correctly classified >70% of TL categorized above or below the median, but the accuracy dropped with increasing TL categories. The ability of DNAmTL to detect associations with age and other TL-related factors in the absence of strong correlation with measured TL may indicate its capture of aspects of telomere maintenance mechanisms and not necessarily TL. The inaccuracy of DNAmTL prediction should be considered during data interpretation and across-study comparisons.},
}
@article {pmid34072630,
year = {2021},
author = {Steele, SL and Hsieh, AYY and Gadawski, I and Kroeun, H and Barr, SI and Devlin, AM and Côté, HCF and Karakochuk, CD},
title = {Daily Oral Supplementation with 60 mg of Elemental Iron for 12 Weeks Alters Blood Mitochondrial DNA Content, but Not Leukocyte Telomere Length in Cambodian Women.},
journal = {Nutrients},
volume = {13},
number = {6},
pages = {},
pmid = {34072630},
issn = {2072-6643},
support = {N/A//International Life Sciences Institute/ ; N/A/CAPMC/CIHR/Canada ; N/A//Micronutrient Initiative/ ; N/A//Sight and Life Foundation/ ; Scholar Award//Michael Smith Foundation for Health Research/ ; },
mesh = {Adult ; Antioxidants/administration &amp; dosage/pharmacology ; Cambodia ; *DNA, Mitochondrial/blood/drug effects ; *Dietary Supplements ; Female ; Humans ; *Iron/administration &amp; dosage/pharmacology ; Leukocytes/*drug effects ; Oxidative Stress/drug effects ; Telomere/*drug effects ; Young Adult ; },
abstract = {There is limited evidence regarding the potential risk of untargeted iron supplementation, especially among individuals who are iron-replete or have genetic hemoglobinopathies. Excess iron exposure can increase the production of reactive oxygen species, which can lead to cellular damage. We evaluated the effect of daily oral supplementation on relative leukocyte telomere length (rLTL) and blood mitochondrial DNA (mtDNA) content in non-pregnant Cambodian women (18-45 years) who received 60 mg of elemental iron as ferrous sulfate (n = 190) or a placebo (n = 186) for 12 weeks. Buffy coat rLTL and mtDNA content were quantified by monochrome multiplex quantitative polymerase chain reaction. Generalized linear mixed-effects models were used to predict the absolute and percent change in rLTL and mtDNA content after 12 weeks. Iron supplementation was not associated with an absolute or percent change in rLTL after 12 weeks compared with placebo (ß-coefficient: -0.04 [95% CI: -0.16, 0.08]; p = 0.50 and ß-coefficient: -0.96 [95% CI: -2.69, 0.77]; p = 0.28, respectively). However, iron supplementation was associated with a smaller absolute and percent increase in mtDNA content after 12 weeks compared with placebo (ß-coefficient: -11 [95% CI: -20, -2]; p = 0.02 and ß-coefficient: -11 [95% CI: -20, -1]; p= 0.02, respectively). Thus, daily oral iron supplementation for 12 weeks was associated with altered mitochondrial homeostasis in our study sample. More research is needed to understand the risk of iron exposure and the biological consequences of altered mitochondrial homeostasis in order to inform the safety of the current global supplementation policy.},
}
@article {pmid34071160,
year = {2021},
author = {Glover, LM and Cené, CW and Reiner, A and Gebreab, S and Williams, DR and North, KE and Sims, M},
title = {Discrimination and Leukocyte Telomere Length by Depressive Symptomatology: The Jackson Heart Study.},
journal = {Healthcare (Basel, Switzerland)},
volume = {9},
number = {6},
pages = {},
pmid = {34071160},
issn = {2227-9032},
support = {HHSN268201800012C/HL/NHLBI NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; T32 HL129982/HL/NHLBI NIH HHS/United States ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; },
abstract = {BACKGROUND: Psychosocial stressors, such as perceived discrimination and depressive symptoms, may shorten telomeres and exacerbate aging-related illnesses.<br><br>METHODS: Participants from the Jackson Heart Study at visit 1 (2000-2004) with LTL data and Center for Epidemiological Studies-Depression (CES-D) scores (n = 580 men, n = 910 women) were utilized. The dimensions of discrimination scores (everyday, lifetime, burden of lifetime, and stress from lifetime discrimination) were standardized and categorized as low, moderate, and high. Coping responses to everyday and lifetime discrimination were categorized as passive and active coping. Multivariable linear regression analyses were performed to estimate the mean difference (standard errors-SEs) in LTL by dimensions of discrimination and coping responses stratified by CES-D scores < 16 (low) and &#x2265; 16 (high) and sex. Covariates were age, education, waist circumference, smoking and CVD status.<br><br>RESULTS: Neither everyday nor lifetime discrimination was associated with mean differences in LTL for men or women by levels of depressive symptoms. Burden of lifetime discrimination was marginally associated with LTL among women who reported low depressive symptoms after full adjustment (b = 0.11, SE = 0.06, p = 0.08). Passive coping with lifetime discrimination was associated with longer LTL among men who reported low depressive symptoms after full adjustment (b = 0.18, SE = 0.09, p < 0.05); and active coping with lifetime discrimination was associated with longer LTL among men who reported high depressive symptoms after full adjustment (b = 1.18, SE = 0.35, p < 0.05).<br><br>CONCLUSIONS: The intersection of perceived discrimination and depressive symptomatology may be related to LTL, and the effects may vary by sex.},
}
@article {pmid34070406,
year = {2021},
author = {Pendina, AA and Krapivin, MI and Efimova, OA and Tikhonov, AV and Mekina, ID and Komarova, EM and Koltsova, AS and Gzgzyan, AM and Kogan, IY and Chiryaeva, OG and Baranov, VS},
title = {Telomere Length in Metaphase Chromosomes of Human Triploid Zygotes.},
journal = {International journal of molecular sciences},
volume = {22},
number = {11},
pages = {},
pmid = {34070406},
issn = {1422-0067},
support = {18-75-10046//Russian Science Foundation/ ; },
mesh = {Chromosomes, Human/*metabolism ; Fertilization in Vitro ; Humans ; *Metaphase ; Telomere/*metabolism/pathology ; *Telomere Homeostasis ; *Triploidy ; Zygote/*metabolism/pathology ; },
abstract = {The human lifespan is strongly influenced by telomere length (TL) which is defined in a zygote-when two highly specialised haploid cells form a new diploid organism. Although TL is a variable parameter, it fluctuates in a limited range. We aimed to establish the determining factors of TL in chromosomes of maternal and paternal origin in human triploid zygotes. Using Q-FISH, we examined TL in the metaphase chromosomes of 28 human triploid zygotes obtained from 22 couples. The chromosomes' parental origin was identified immunocytochemically through weak DNA methylation and strong hydroxymethylation in the sperm-derived (paternal) chromosomes versus strong DNA methylation and weak hydroxymethylation in the oocyte-derived (maternal) ones. In 24 zygotes, one maternal and two paternal chromosome sets were identified, while the four remaining zygotes contained one paternal and two maternal sets. For each zygote, we compared mean relative TLs between parental chromosomes, identifying a significant difference in favour of the paternal chromosomes, which attests to a certain "imprinting" of these regions. Mean relative TLs in paternal or maternal chromosomes did not correlate with the respective parent's age. Similarly, no correlation was observed between the mean relative TL and sperm quality parameters: concentration, progressive motility and normal morphology. Based on the comparison of TLs in chromosomes inherited from a single individual's gametes with those in chromosomes inherited from different individuals' gametes, we compared intraindividual (intercellular) and interindividual variability, obtaining significance in favour of the latter and thus validating the role of heredity in determining TL in zygotes. A comparison of the interchromatid TL differences across the chromosomes from sets of different parental origin with those from PHA-stimulated lymphocytes showed an absence of a significant difference between the maternal and paternal sets but a significant excess over the lymphocytes. Therefore, interchromatid TL differences are more pronounced in zygotes than in lymphocytes. To summarise, TL in human zygotes is determined both by heredity and parental origin; the input of other factors is possible within the individual's reaction norm.},
}
@article {pmid34069972,
year = {2021},
author = {Tung, KTS and Wong, RS and Tsang, HW and Chua, GT and Chan, D and Chan, KC and Wong, WHS and Yam, JC and Ho, M and Tham, CC and Wong, ICK and Chan, GCF and Ip, P},
title = {Impact of Snoring on Telomere Shortening in Adolescents with Atopic Diseases.},
journal = {Genes},
volume = {12},
number = {5},
pages = {},
pmid = {34069972},
issn = {2073-4425},
mesh = {Adolescent ; Aging/genetics ; Asthma/genetics ; Female ; Food Hypersensitivity/genetics ; Humans ; Male ; Oxidative Stress/genetics ; Snoring/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Atopic diseases can impose a significant burden on children and adolescents. Telomere length is a cellular marker of aging reflecting the impact of cumulative stress exposure on individual health. Since elevated oxidative stress and inflammation burden induced by chronic atopy and snoring may impact telomere length, this study aimed to investigate whether snoring would moderate the relationship between atopic diseases and telomere length in early adolescence. We surveyed 354 adolescents and their parents. Parents reported the adolescents' history of atopic diseases, recent snoring history as well as other family sociodemographic characteristics. Buccal swab samples were also collected from the adolescents for telomere length determination. Independent and combined effects of atopic diseases and snoring on telomere length were examined. Among the surveyed adolescents, 174 were reported by parents to have atopic diseases (20 had asthma, 145 had allergic rhinitis, 53 had eczema, and 25 had food allergy). Shorter TL was found in participants with a history of snoring and atopic diseases (β = -0.34, p = 0.002) particularly for asthma (β = -0.21, p = 0.007) and allergic rhinitis (β = -0.22, p = 0.023). Our findings suggest that snoring in atopic patients has important implications for accelerated telomere shortening. Proper management of atopic symptoms at an early age is important for the alleviation of long-term health consequences at the cellular level.},
}
@article {pmid34068820,
year = {2021},
author = {Maugeri, A and Barchitta, M and Magnano San Lio, R and La Rosa, MC and La Mastra, C and Favara, G and Ferlito, M and Giunta, G and Panella, M and Cianci, A and Agodi, A},
title = {The Effect of Alcohol on Telomere Length: A Systematic Review of Epidemiological Evidence and a Pilot Study during Pregnancy.},
journal = {International journal of environmental research and public health},
volume = {18},
number = {9},
pages = {},
pmid = {34068820},
issn = {1660-4601},
mesh = {Cohort Studies ; *Ethanol ; Female ; Humans ; Infant, Newborn ; Leukocytes ; Pilot Projects ; Pregnancy ; *Telomere/genetics ; },
abstract = {Several studies-albeit with still inconclusive and limited findings-began to focus on the effect of drinking alcohol on telomere length (TL). Here, we present results from a systematic review of these epidemiological studies to investigate the potential association between alcohol consumption, alcohol-related disorders, and TL. The analysis of fourteen studies-selected from PubMed, Medline, and Web of Science databases-showed that people with alcohol-related disorders exhibited shorter TL, but also that alcohol consumption per se did not appear to affect TL in the absence of alcohol abuse or dependence. Our work also revealed a lack of studies in the periconceptional period, raising the need for evaluating this potential relationship during pregnancy. To fill this gap, we conducted a pilot study using data and samples form the Mamma &amp; Bambino cohort. We compared five non-smoking but drinking women with ten non-smoking and non-drinking women, matched for maternal age, gestational age at recruitment, pregestational body mass index, and fetal sex. Interestingly, we detected a significant difference when analyzing relative TL of leukocyte DNA of cord blood samples from newborns. In particular, newborns from drinking women exhibited shorter relative TL than those born from non-drinking women (p = 0.024). Although these findings appeared promising, further research should be encouraged to test any dose-response relationship, to adjust for the effect of other exposures, and to understand the molecular mechanisms involved.},
}
@article {pmid34054718,
year = {2021},
author = {Velazquez, ME and Millan, AL and Rojo, M and Abruzzese, GA and Cocucci, SE and Iglesias Molli, AE and Frechtel, GD and Motta, AB and Cerrone, GE},
title = {Telomere Length Differently Associated to Obesity and Hyperandrogenism in Women With Polycystic Ovary Syndrome.},
journal = {Frontiers in endocrinology},
volume = {12},
number = {},
pages = {604215},
pmid = {34054718},
issn = {1664-2392},
mesh = {Adult ; Argentina/epidemiology ; Body Mass Index ; Case-Control Studies ; Female ; Humans ; Hyperandrogenism/complications/epidemiology/*genetics ; Obesity/complications/epidemiology/*genetics ; Polycystic Ovary Syndrome/complications/epidemiology/*genetics ; Retrospective Studies ; Telomere/chemistry/*metabolism ; Telomere Homeostasis/physiology ; Testosterone/blood ; },
abstract = {BACKGROUND: Polycystic Ovary Syndrome (PCOS) often present metabolic disorders and hyperandrogenism (HA), facts that may influence the telomere length (TL).<br><br>AIMS: To compare the absolute TL (aTL) between women with PCOS and control women, and their association with the presence of obesity and HA parameters.<br><br>MATERIALS AND METHODS: The PCOS group included 170 unrelated women outpatients and the control group, 64 unrelated donor women. Anthropometric, biochemical-clinical parameters and androgen profile were determined. The PCOS patients were divided accordingly to the presence of obesity and androgenic condition. The aTL was determined from peripheral blood leukocytes by Real Time quantitative PCR.<br><br>RESULTS: Women with PCOS exhibited a significantly longer aTL than controls after age adjustment (p=0.001). A stepwise multivariate linear regression in PCOS women, showed that WC (waist circumference) contributed negatively (b=-0.17) while testosterone levels contributed positively (b=7.24) to aTL. The non-Obese PCOS (noOB-PCOS) presented the longest aTL when compared to controls (p=0.001). Meanwhile, the aTL was significantly higher in the hyperandrogenic PCOS phenotype (HA-PCOS) than in the controls (p=0.001) and non hyperandrogenic PCOS phenotype (NHA-PCOS) (p=0.04). Interestingly, when considering obesity and HA parameters in PCOS, HA exerts the major effect over the aTL as non-obese HA exhibited the lengthiest aTL (23.9 &#xb1; 13.13 Kbp). Conversely, the obese NHA patients showed the shortest aTL (16.5 &#xb1; 10.59 Kbp).<br><br>CONCLUSIONS: Whilst a shorter aTL could be related to the presence of obesity, a longer aTL would be associated with HA phenotype. These findings suggest a balance between the effect produced by the different metabolic and hormonal components, in PCOS women.},
}
@article {pmid34051657,
year = {2021},
author = {Ämmälä, AJ and Suvisaari, J and Kananen, L and Lönnqvist, J and Ripatti, S and Pirkola, S and Paunio, T and Hovatta, I},
title = {Childhood adversities are associated with shorter leukocyte telomere length at adult age in a population-based study.},
journal = {Psychoneuroendocrinology},
volume = {130},
number = {},
pages = {105276},
doi = {10.1016/j.psyneuen.2021.105276},
pmid = {34051657},
issn = {1873-3360},
mesh = {Child ; Humans ; Leukocytes ; *Sleep Wake Disorders ; *Sociodemographic Factors ; Telomere/genetics ; Telomere Shortening ; },
abstract = {Telomeres are repeat sequences and an associated protein complex located at the end of the chromosomes. They shorten with every cell division and are regarded markers for cellular aging. Shorter leukocyte telomere length (LTL) has been observed in many complex diseases, including psychiatric disorders. However, analyses focusing on psychiatric disorders are mainly based on clinical samples and the significance of shorter LTL on the population level remains uncertain. We addressed this question in a population-based sample from Finland (N = 7142). The survey was performed and the blood samples were collected in 2000-2001 to assess major public health problems and their determinants. DSM-IV diagnoses of major psychiatric illnesses were obtained by interview using the Composite International Diagnostic Interview. Information regarding their risk factors, including the number of self-reported childhood adversities, recent psychological distress, and sleep difficulties was collected by questionnaires. LTL was measured by qPCR. None of the studied psychiatric illnesses, sleep difficulties, or recent psychological distress associated with LTL. However, individuals with three or more childhood adversities had shorter LTL at adult age (β = -0.006, P = 0.005). Also, current occupational status was associated with LTL (β = -0.03, P = 0.04). These effects remained significant after adjusting for known LTL-associated lifestyle or sociodemographic factors. In conclusion, relatively common childhood adversities were associated with shorter LTL at adult age in a nationally representative population-based cohort, implying that childhood adversities may cause accelerated telomere shortening. Our finding has potentially important implications as it supports the view that childhood adversities have an impact on psychological and somatic well-being later in life.},
}
@article {pmid34050178,
year = {2021},
author = {Kam, MLW and Nguyen, TTT and Ngeow, JYY},
title = {Telomere biology disorders.},
journal = {NPJ genomic medicine},
volume = {6},
number = {1},
pages = {36},
pmid = {34050178},
issn = {2056-7944},
abstract = {Telomere biology disorders (TBD) are a heterogeneous group of diseases arising from germline mutations affecting genes involved in telomere maintenance. Telomeres are DNA-protein structures at chromosome ends that maintain chromosome stability; their length affects cell replicative potential and senescence. A constellation of bone marrow failure, pulmonary fibrosis, liver cirrhosis and premature greying is suggestive, however incomplete penetrance results in highly variable manifestations, with idiopathic pulmonary fibrosis as the most common presentation. Currently, the true extent of TBD burden is unknown as there is no established diagnostic criteria and the disorder often is unrecognised and underdiagnosed. There is no gold standard for measuring telomere length and not all TBD-related mutations have been identified. There is no specific cure and the only treatment is organ transplantation, which has poor outcomes. This review summarises the current literature and discusses gaps in understanding and areas of need in managing TBD.},
}
@article {pmid34049038,
year = {2021},
author = {Tempaku, PF and D'Almeida, V and da Silva, SMA and Andersen, ML and Belangero, SI and Tufik, S},
title = {Klotho genetic variants mediate the association between obstructive sleep apnea and short telomere length.},
journal = {Sleep medicine},
volume = {83},
number = {},
pages = {210-213},
doi = {10.1016/j.sleep.2021.01.015},
pmid = {34049038},
issn = {1878-5506},
mesh = {Glucuronidase/genetics ; Humans ; Klotho Proteins ; Polysomnography ; *Sleep Apnea, Obstructive/genetics ; *Telomere/genetics ; },
abstract = {The core features of obstructive sleep apnea (OSA) can potentially contribute to the acceleration of telomere shortening mechanisms. Other factor associated with telomeres is Klotho gene as it can negatively regulates telomerase activity. Noteworthy, KLOTHO protein level has recently been associated with OSA. In this sense, it was plausible to hypothesize that OSA would be associated with short telomere length and those with OSA plus risk single nucleotide polymorphisms (SNPs) in Klotho gene would present even shorter telomere length. As part of the EPISONO cohort, 1042 individuals answered questionnaires, underwent polysomnography and had blood collected for DNA extraction. OSA was defined according to AHI≥ 15 events/hour. Leukocyte telomere length (LTL) was measured through real-time polymerase chain reaction (qPCR) and Klotho SNPs were genotyped by array. Mediation analyses considered the presence of SNPs in Klotho gene and how this interaction can affect OSA and its consequence in telomere length. All the analyses were corrected for multiple comparisons. LTL was significantly shorter in OSA compared to controls in a severity-dependent manner (B = 0.055; CI = 0.007-0.102; p = 0.02). Among the 43 Klotho SNPs analyzed, we observed that 4 SNPs (rs525014, rs7982726, rs685417 and rs9563124) significantly mediated the association between OSA and short LTL. Klotho gene opens a new venue in OSA research since it can contribute in the increase of knowledge of the mechanisms involved in the consequences of short telomeres in individuals with OSA.},
}
@article {pmid34047997,
year = {2022},
author = {Niño, MD},
title = {Poverty, Material Hardship, and Telomere Length Among Latina/o Children.},
journal = {Journal of racial and ethnic health disparities},
volume = {9},
number = {4},
pages = {1315-1324},
pmid = {34047997},
issn = {2196-8837},
mesh = {Adolescent ; Child ; *Hispanic or Latino ; Humans ; Parents ; *Poverty ; Telomere ; },
abstract = {BACKGROUND: Despite increased attention on the links between poverty and the health and wellbeing of youth, few have attempted to understand the physiological consequences associated with different forms of economic disadvantage among Latina/o children. The present study begins to address this gap by (1) examining whether different forms of economic disadvantage were related to telomere length for Latina/o children and (2) determining whether parents' nativity shapes economic disadvantage-telomere length relationships.<br><br>METHODS: Data were drawn from the Fragile Families and Child Wellbeing Study, a longitudinal, stratified multistage probability sample of couples and children in 20 large US cities. The sample consisted of 417 Latina/o children and their parents that were followed from birth to age 9. Ordinary least squares regressions were used to examine relationships between economic disadvantage and telomere length.<br><br>RESULTS: Findings revealed that poverty status was not significantly related to telomere length, whereas some forms of material hardship were shown to play a role in the risk of premature cellular aging. More specifically, medical hardship and difficulty paying bills were associated with shorter telomere length at age 9. Results also provide minimal evidence economic disadvantage-telomere length patterns varied by parents' nativity. Only medical hardship was related to shorter telomere length at age 9 for children with at least one foreign-born parent.<br><br>CONCLUSION: Overall, results indicate that the risk of premature cellular aging depends on the measure of economic disadvantage under investigation. Findings from this study can inform targeted strategies designed to reduce the deleterious consequences associated with economic deprivation.},
}
@article {pmid34045188,
year = {2021},
author = {Zhao, Z and Gad, H and Benitez-Buelga, C and Sanjiv, K and Xiangwei, H and Kang, H and Feng, M and Zhao, Z and Berglund, UW and Xia, Q and Helleday, T},
title = {NEIL3 Prevents Senescence in Hepatocellular Carcinoma by Repairing Oxidative Lesions at Telomeres during Mitosis.},
journal = {Cancer research},
volume = {81},
number = {15},
pages = {4079-4093},
pmid = {34045188},
issn = {1538-7445},
mesh = {Carcinoma, Hepatocellular/*genetics ; Humans ; Liver Neoplasms/*genetics ; Mitosis/*genetics ; N-Glycosyl Hydrolases/*metabolism ; Oxidation-Reduction ; Telomere/*metabolism ; Transfection ; },
abstract = {Patients with hepatocellular carcinoma (HCC) suffer from few treatment options and poor survival rates. Here we report that endonuclease VIII-like protein 3 (NEIL3) is overexpressed in HCC and correlates with poor survival. All six HCC cell lines investigated were dependent on NEIL3 catalytic activity for survival and prevention of senescence, while NEIL3 was dispensable for nontransformed cells. NEIL3-depleted HCC cell lines accumulated oxidative DNA lesions specifically at telomeres, resulting in telomere dysfunctional foci and 53BP1 foci formation. Following oxidative DNA damage during mitosis, NEIL3 relocated to telomeres and recruited apurinic endonuclease 1 (APE1), indicating activation of base excision repair. META-FISH revealed that NEIL3, but not NEIL1 or NEIL2, is required to initiate APE1 and polymerase beta (POLB)-dependent base excision repair at oxidized telomeres. Repeated exposure of NEIL3-depleted cells to oxidizing damage induced chromatin bridges and damaged telomeres. These results demonstrate a novel function for NEIL3 in repair of oxidative DNA damage at telomeres in mitosis, which is important to prevent senescence of HCC cells. Furthermore, these data suggest that NEIL3 could be a target for therapeutic intervention for HCC. SIGNIFICANCE: This study describes compartmentalization of base excision repair during mitosis that is dependent on NEIL3, APE1, and POLB to repair oxidative damage accumulating at telomeres in hepatocellular carcinoma.},
}
@article {pmid34043865,
year = {2021},
author = {Oseini, AM and Hamilton, JP and Hammami, MB and Kim, A and Oshima, K and Woreta, T and Rizkalla, N and Pustavoitau, A and Merlo, C and Nguyen, MC and King, EA and Wesson, RN and Garonzik-Wang, J and Ottmann, S and Philosophe, B and Cameron, AM and Armanios, M and Gurakar, A},
title = {Liver Transplantation in Short Telomere-Mediated Hepatopulmonary Syndrome Following Bone Marrow Transplantation Using HCV Positive Allografts: A Case Series.},
journal = {Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society},
volume = {27},
number = {12},
pages = {1844-1848},
pmid = {34043865},
issn = {1527-6473},
support = {R01 CA225027/CA/NCI NIH HHS/United States ; },
mesh = {Allografts ; Bone Marrow Transplantation/adverse effects ; *Hepatitis C/complications ; *Hepatopulmonary Syndrome/etiology/surgery ; Humans ; *Liver Transplantation/adverse effects ; Telomere ; },
}
@article {pmid34040069,
year = {2021},
author = {Yetim, E and Topcuoglu, MA and Yurur Kutlay, N and Tukun, A and Oguz, KK and Arsava, EM},
title = {The association between telomere length and ischemic stroke risk and phenotype.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {10967},
pmid = {34040069},
issn = {2045-2322},
mesh = {Age of Onset ; Aged ; Aging/genetics ; Brain Ischemia/epidemiology/*genetics/pathology ; Case-Control Studies ; Chromosomes, Human/ultrastructure ; Comorbidity ; Female ; Genetic Predisposition to Disease ; Humans ; Leukocytes/ultrastructure ; Male ; Middle Aged ; Phenotype ; Prospective Studies ; Risk ; Risk Factors ; Smoking/epidemiology ; *Telomere Shortening ; Turkey/epidemiology ; },
abstract = {The chronological age of a person is a key determinant of etiology and prognosis in the setting of ischemic stroke. Telomere length, an indicator of biological aging, progressively shortens with every cell cycle. Herein, we determined telomere length from peripheral blood leukocytes by Southern blot analyses in a prospective cohort of ischemic stroke patients (n = 163) and equal number of non-stroke controls and evaluated its association with various ischemic stroke features including etiology, severity, and outcome. A shorter telomere length (i.e. lowest quartile; ≤ 5.5 kb) was significantly associated with ischemic stroke (OR 2.95, 95% CI 1.70-5.13). This significant relationship persisted for all stroke etiologies, except for other rare causes of stroke. No significant association was present between admission lesion volume and telomere length; however, patients with shorter telomeres had higher admission National Institutes of Health Stroke Scale scores when adjusted for chronological age, risk factors, etiology, and infarct volume (p = 0.046). On the other hand, chronological age, but not telomere length, was associated with unfavorable outcome (modified Rankin scale > 2) and mortality at 90 days follow-up. The association between shorter telomere length and more severe clinical phenotype at the time of admission, might reflect reduced resilience of cerebral tissue to ischemia as part of biological aging.},
}
@article {pmid34034513,
year = {2021},
author = {Fitzpatrick, LJ and Olsson, M and Pauliny, A and While, GM and Wapstra, E},
title = {Individual telomere dynamics and their links to life history in a viviparous lizard.},
journal = {Proceedings. Biological sciences},
volume = {288},
number = {1951},
pages = {20210271},
pmid = {34034513},
issn = {1471-2954},
mesh = {Adult ; Animals ; Humans ; Infant, Newborn ; *Lizards/genetics ; Reproduction ; *Telomere/genetics ; Telomere Homeostasis ; Telomere Shortening ; },
abstract = {Emerging patterns suggest telomere dynamics and life history are fundamentally linked in endotherms through life-history traits that mediate the processes underlying telomere attrition. Unlike endotherms, ectotherms maintain the ability to lengthen somatic telomeres throughout life and the link between life-history strategies and ectotherm telomere dynamics is unknown. In a well-characterized model system (Niveoscincus ocellatus), we used long-term longitudinal data to study telomere dynamics across climatically divergent populations. We found longer telomeres in individuals from the cool highlands than those from the warm lowlands at birth and as adults. The key determinant of adult telomere length across populations was telomere length at birth, with population-specific effects of age and growth on adult telomere length. The reproductive effort had no proximate effect on telomere length in either population. Maternal factors influenced telomere length at birth in the warm lowlands but not the cool highlands. Our results demonstrate that life-history traits can have pervasive and context-dependent effects on telomere dynamics in ectotherms both within and between populations. We argue that these telomere dynamics may reflect the populations' different life histories, with the slow-growing cool highland population investing more into telomere lengthening compared to the earlier-maturing warm lowland population.},
}
@article {pmid34034512,
year = {2021},
author = {Heidinger, BJ and Kucera, AC and Kittilson, JD and Westneat, DF},
title = {Longer telomeres during early life predict higher lifetime reproductive success in females but not males.},
journal = {Proceedings. Biological sciences},
volume = {288},
number = {1951},
pages = {20210560},
pmid = {34034512},
issn = {1471-2954},
mesh = {Animals ; Female ; Longevity ; Male ; Reproduction ; *Sparrows/genetics ; *Telomere/genetics ; Telomere Shortening ; },
abstract = {The mechanisms that contribute to variation in lifetime reproductive success are not well understood. One possibility is that telomeres, conserved DNA sequences at chromosome ends that often shorten with age and stress exposures, may reflect differences in vital processes or influence fitness. Telomere length often predicts longevity, but longevity is only one component of fitness and little is known about how lifetime reproductive success is related to telomere dynamics in wild populations. We examined the relationships between telomere length beginning in early life, telomere loss into adulthood and lifetime reproductive success in free-living house sparrows (Passer domesticus). We found that females, but not males, with longer telomeres during early life had higher lifetime reproductive success, owing to associations with longevity and not reproduction per year or attempt. Telomeres decreased with age in both sexes, but telomere loss was not associated with lifetime reproductive success. In this species, telomeres may reflect differences in quality or condition rather than the pace of life, but only in females. Sexually discordant selection on telomeres is expected to influence the stability and maintenance of within population variation in telomere dynamics and suggests that any role telomeres play in mediating life-history trade-offs may be sex specific.},
}
@article {pmid34031828,
year = {2023},
author = {Liang, J and Shao, Y and Huang, D and Yang, C and Liu, T and Zeng, X and Li, C and Tang, Z and Juan, JTH and Song, Y and Liu, S and Qiu, X},
title = {Effects of prenatal exposure to bisphenols on newborn leucocyte telomere length: a prospective birth cohort study in China.},
journal = {Environmental science and pollution research international},
volume = {30},
number = {10},
pages = {25013-25023},
doi = {10.1007/s11356-021-14496-z},
pmid = {34031828},
issn = {1614-7499},
support = {81860587//National Natural Science Foundation of China/ ; 81460517//National Natural Science Foundation of China/ ; AB17195012//Guangxi Key Research Program/ ; },
mesh = {Infant ; Humans ; Infant, Newborn ; Pregnancy ; Female ; Adult ; Cohort Studies ; *Prenatal Exposure Delayed Effects ; Prospective Studies ; Maternal Exposure ; China ; Benzhydryl Compounds/toxicity ; Telomere ; },
abstract = {Telomere length (TL) at birth is related to diseases that may arise in the future and long-term health. Bisphenols exhibit toxic effects and can cross the placenta barrier. However, the effects of prenatal exposure to bisphenols on newborn TL remain unknown. We aimed to explore the effects of prenatal exposure to bisphenols (i.e., bisphenol A [BPA], bisphenol B [BPB], bisphenol F [BPF], bisphenol S [BPS] and tetrabromobisphenol A [TBBPA]) on relative TL in newborns. A total of 801 mother-infant pairs were extracted from the Guangxi Zhuang Birth Cohort. The relationship between bisphenol levels in maternal serum and relative TL in cord blood was examined by generalized linear models and restricted cubic spline (RCS) models. After adjusting for confounders, we observed a 3.19% (95% CI: -6.08%, -0.21%; P = 0.037) reduction in relative cord blood TL among mothers ≥ 28 years old, with each onefold increase in BPS. However, in each onefold increase of TBBPA, we observed a 3.31% (95% CI: 0.67%, 6.01%; P = 0.014) increase in relative cord blood TL among mothers < 28 years old. The adjusted RCS models revealed similar results (P overall < 0.05, P non-linear > 0.05). This study was the first to establish a positive association between serum TBBPA levels and relative TL in newborns born to young mothers. However, BPS levels were inversely correlated with TL in fetus born to old mothers. The results suggested that the fetus of old pregnant women may be more sensitive to BPS exposure. Moreover, BPS exposure early in life may accelerate aging or increase the risk of developing BPS-related diseases in later life.},
}
@article {pmid34025845,
year = {2021},
author = {Mazidi, M and Shekoohi, N and Katsiki, N and Rakowski, M and Mikhailidis, DP and Banach, M},
title = {Serum anti-inflammatory and inflammatory markers have no causal impact on telomere length: a Mendelian randomization study.},
journal = {Archives of medical science : AMS},
volume = {17},
number = {3},
pages = {739-751},
pmid = {34025845},
issn = {1734-1922},
abstract = {INTRODUCTION: The relationship between inflammatory and anti-inflammatory markers and telomere length (TL), a biological index of aging, is still poorly understood. By applying a 2-sample Mendelian randomization (MR), we investigated the causal associations between adiponectin, bilirubin, C-reactive protein (CRP), leptin, and serum uric acid (SUA) with TL.<br><br>MATERIAL AND METHODS: MR was implemented by using summary-level data from the largest ever genome-wide association studies (GWAS) conducted on our interested exposure and TL. Inverse variance weighted method (IVW), weighted median (WM)-based method, MR-Egger, MR-Robust Adjusted Profile Score (RAPS), and MR-Pleiotropy RESidual Sum and Outlier (PRESSO) were applied. Sensitivity analysis was conducted using the leave-one-out method.<br><br>RESULTS: With regard to adiponectin, CRP, leptin, and SUA levels, we found no effect on TL for all 4 types of tests (all p > 0.108). Results of the MR-Egger (p = 0.892) and IVW (p = 0.124) showed that bilirubin had no effect on telomere maintenance, whereas the results of the WM (p = 0.030) and RAPS (p = 0.022) were negative, with higher bilirubin concentrations linked to shorter TL. There was a low likelihood of heterogeneity for all the estimations, except for bilirubin (IVW p = 0.026, MR Egger p = 0.018). MR-PRESSO highlighted no outlier. For all the estimations, we observed negligible intercepts that were indicative of low likelihood of the pleiotropy (all p > 0.161). The results of leave-one-out method demonstrated that the links are not driven because of single nucleotide polymorphisms (SNPs).<br><br>CONCLUSIONS: Our results highlight that neither the anti-inflammatory nor pro-inflammatory markers tested have any significant causal effect on TL. The casual role of bilirubin on TL still needs to be investigated.},
}
@article {pmid34021581,
year = {2021},
author = {Ali, S and Lombardi, EP and Ghosh, D and Jia, T and Vitry, G and Saker, L and Poupon, J and Teulade-Fichou, MP and Nicolas, A and Londono-Vallejo, A and Bombard, S},
title = {Pt-ttpy, a G-quadruplex binding platinum complex, induces telomere dysfunction and G-rich regions DNA damage.},
journal = {Metallomics : integrated biometal science},
volume = {13},
number = {6},
pages = {},
doi = {10.1093/mtomcs/mfab029},
pmid = {34021581},
issn = {1756-591X},
mesh = {Antineoplastic Agents/pharmacology ; Apoptosis ; Cell Proliferation ; Cisplatin/*pharmacology ; *DNA Damage ; Female ; *G-Quadruplexes ; Humans ; Organoplatinum Compounds/chemistry/*pharmacology ; Ovarian Neoplasms/drug therapy/genetics/*pathology ; Telomere/*drug effects ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; Tumor Cells, Cultured ; },
abstract = {Pt-ttpy (tolyl terpyridin-Pt complex) covalently binds to G-quadruplex (G4) structures in vitro and to telomeres in cellulo via its Pt moiety. Here, we identified its targets in the human genome, in comparison to Pt-tpy, its derivative without G4 affinity, and cisplatin. Pt-ttpy, but not Pt-tpy, induces the release of the shelterin protein TRF2 from telomeres concomitantly to the formation of DNA damage foci at telomeres but also at other chromosomal locations. γ-H2AX chromatin immunoprecipitation (ChIP-seq) after treatment with Pt-ttpy or cisplatin revealed accumulation in G- and A-rich tandemly repeated sequences, but not particularly in potential G4 forming sequences. Collectively, Pt-ttpy presents dual targeting efficiency on DNA, by inducing telomere dysfunction and genomic DNA damage at specific loci.},
}
@article {pmid34021256,
year = {2021},
author = {Uryga, AK and Grootaert, MOJ and Garrido, AM and Oc, S and Foote, K and Chappell, J and Finigan, A and Rossiello, F and d'Adda di Fagagna, F and Aravani, D and Jorgensen, HF and Bennett, MR},
title = {Telomere damage promotes vascular smooth muscle cell senescence and immune cell recruitment after vessel injury.},
journal = {Communications biology},
volume = {4},
number = {1},
pages = {611},
pmid = {34021256},
issn = {2399-3642},
support = {PG/19/6/34153/BHF_/British Heart Foundation/United Kingdom ; RG71070/BHF_/British Heart Foundation/United Kingdom ; PG/13/25/30014/BHF_/British Heart Foundation/United Kingdom ; RG/20/2/34763/BHF_/British Heart Foundation/United Kingdom ; CH/2000003/12800/BHF_/British Heart Foundation/United Kingdom ; RG/13/14/30314/BHF_/British Heart Foundation/United Kingdom ; RG/08/009/25841/BHF_/British Heart Foundation/United Kingdom ; PG/16/24/32090/BHF_/British Heart Foundation/United Kingdom ; PG/16/11/32021/BHF_/British Heart Foundation/United Kingdom ; RG84554/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Animals ; Atherosclerosis/etiology/metabolism/*pathology ; Cell Proliferation ; Cells, Cultured ; *Cellular Senescence ; DNA Damage ; Disease Models, Animal ; Humans ; Inflammation/etiology/metabolism/*pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microfilament Proteins/physiology ; Muscle Proteins/physiology ; Muscle, Smooth, Vascular/immunology/metabolism/*pathology ; Myocytes, Smooth Muscle/immunology/metabolism/*pathology ; Neointima/etiology/metabolism/*pathology ; Telomere/genetics/*pathology ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Accumulation of vascular smooth muscle cells (VSMCs) is a hallmark of multiple vascular pathologies, including following neointimal formation after injury and atherosclerosis. However, human VSMCs in advanced atherosclerotic lesions show reduced cell proliferation, extensive and persistent DNA damage, and features of premature cell senescence. Here, we report that stress-induced premature senescence (SIPS) and stable expression of a telomeric repeat-binding factor 2 protein mutant (TRF2[T188A]) induce senescence of human VSMCs, associated with persistent telomeric DNA damage. VSMC senescence is associated with formation of micronuclei, activation of cGAS-STING cytoplasmic sensing, and induction of multiple pro-inflammatory cytokines. VSMC-specific TRF2[T188A] expression in a multicolor clonal VSMC-tracking mouse model shows no change in VSMC clonal patches after injury, but an increase in neointima formation, outward remodeling, senescence and immune/inflammatory cell infiltration or retention. We suggest that persistent telomere damage in VSMCs inducing cell senescence has a major role in driving persistent inflammation in vascular disease.},
}
@article {pmid34020720,
year = {2021},
author = {Dasanayaka, NN and Sirisena, ND and Samaranayake, N},
title = {The effects of meditation on length of telomeres in healthy individuals: a systematic review.},
journal = {Systematic reviews},
volume = {10},
number = {1},
pages = {151},
pmid = {34020720},
issn = {2046-4053},
mesh = {Adult ; Bias ; Female ; Health Status ; Humans ; Male ; *Meditation ; Middle Aged ; *Telomere ; },
abstract = {BACKGROUND: Meditation-based practices have been suggested to result in many biological benefits which include reduction of attrition of telomeres, the protective nucleotide-protein complexes at termini of eukaryotic chromosomes. This systematic review evaluated the effects of meditation on telomere length (TL) in healthy adults.<br><br>METHODS: Randomized controlled trials (RCTs) and observational studies conducted to determine the effects of meditation on TL in healthy individuals, published up to July 2020 were retrieved by searching seven electronic databases (PubMed, Scopus, PsycINFO, EMBASE, Cochrane Library, CINAHL and Google Scholar). The methodological quality of RCTs and observational studies was assessed using the Cochrane Collaboration Risk of Bias Tool and Joanna Briggs Institute critical appraisal checklist, respectively. The data was synthesized narratively and the effect estimates of TL in the RCTs were synthesized using alternative methods as a meta-analysis was not conducted. The certainty of evidence was classified according to the GRADE system.<br><br>RESULTS: A total of 1740 articles were screened. Five studies comprising two RCTs and three case-control studies (CCS) were included in the final review based on the inclusion and exclusion criteria. The combined sample consisted of 615 participants with 41.7% males. Average age of participants was 47.7 years. One CCS and one RCT reported significant beneficial effects of meditation on TL while the two remaining CCS and the RCT showed positive effects of meditation on TL which were not significant. For all CCS and one RCT, the methodological quality was high while the remaining RCT was of moderate quality. The quality of evidence for the primary outcome was moderate in RCTs.<br><br>CONCLUSION: The effect of meditation on TL per se is still unclear. Strictly designed and well-reported RCTs with larger sample sizes are required to provide evidence of higher quality.<br><br>The protocol of this review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) database (registration number: CRD42020153977).},
}
@article {pmid34020264,
year = {2021},
author = {Cowell, W and Tang, D and Yu, J and Guo, J and Wang, S and Baccarelli, AA and Perera, F and Herbstman, JB},
title = {Telomere dynamics across the early life course: Findings from a longitudinal study in children.},
journal = {Psychoneuroendocrinology},
volume = {129},
number = {},
pages = {105270},
pmid = {34020264},
issn = {1873-3360},
support = {R03 ES026416/ES/NIEHS NIH HHS/United States ; T32 ES007322/ES/NIEHS NIH HHS/United States ; T32 ES023772/ES/NIEHS NIH HHS/United States ; P50 ES009600/ES/NIEHS NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; },
mesh = {Child ; Child, Preschool ; Female ; Humans ; Longitudinal Studies ; Male ; *Telomere/genetics ; },
abstract = {Telomeres are protective caps on chromosome ends that shorten with each cell division. Telomere length (TL) predicts the onset of cellular senescence and correlates with longevity and age-related disease risk. Previous research suggests that adults display fixed ranking and tracking of TL by age 20 years, supporting the importance of TL at birth and attrition during childhood. However, longitudinal research examining telomere dynamics during early life is sparse. Here, we used monochrome multiplex quantitative polymerase chain reaction to measure relative TL in leukocytes isolated from cord blood and child blood collected at ages 3, 5, 7, and 9 years among 224 minority children enrolled in a New York City-based birth cohort. We also measured maternal TL at delivery in a subset of 197 participants with a biobanked blood sample. TL decreased most rapidly in the first years of life (birth to 3 years), followed by a period of maintenance into the pre-puberty period. Mothers with longer telomeres gave birth to newborns with longer telomeres that remained longer across childhood, suggesting that the fixed ranking and tracking of TL observed among adults may extend to early childhood or even the prenatal period with a potential transgenerational basis. We did not find significant sex differences in the pattern of child TL change across development. These findings emphasize the need to understand factors and mechanisms that determine TL during early childhood.},
}
@article {pmid34019816,
year = {2021},
author = {Chang, ACY and Pardon, G and Chang, ACH and Wu, H and Ong, SG and Eguchi, A and Ancel, S and Holbrook, C and Ramunas, J and Ribeiro, AJS and LaGory, EL and Wang, H and Koleckar, K and Giaccia, A and Mack, DL and Childers, MK and Denning, C and Day, JW and Wu, JC and Pruitt, BL and Blau, HM},
title = {Increased tissue stiffness triggers contractile dysfunction and telomere shortening in dystrophic cardiomyocytes.},
journal = {Stem cell reports},
volume = {16},
number = {9},
pages = {2169-2181},
pmid = {34019816},
issn = {2213-6711},
support = {SP/15/9/31605/BHF_/British Heart Foundation/United Kingdom ; G0801098/MRC_/Medical Research Council/United Kingdom ; R21 AG044815/AG/NIA NIH HHS/United States ; MR/M017354/1/MRC_/Medical Research Council/United Kingdom ; PG/14/59/ 31000/BHF_/British Heart Foundation/United Kingdom ; 201411MFE-338745-169197//CIHR/Canada ; R01 AR063963/AR/NIAMS NIH HHS/United States ; RG/14/1/30588/BHF_/British Heart Foundation/United Kingdom ; R35 CA197713/CA/NCI NIH HHS/United States ; RG/15/6/31436/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Biomarkers ; Cardiomyopathies/etiology/pathology/physiopathology ; Cell Differentiation ; Cells, Cultured ; Cellular Microenvironment/drug effects ; Culture Media, Conditioned/metabolism/pharmacology ; Fibrosis ; Fluorescent Antibody Technique ; Gene Expression ; Humans ; Immunophenotyping ; Induced Pluripotent Stem Cells/cytology/metabolism ; Mechanical Phenomena ; Muscular Dystrophies/*genetics/pathology/*physiopathology ; Muscular Dystrophy, Duchenne/etiology/pathology/physiopathology ; Myocardial Contraction/drug effects/*genetics ; Myocytes, Cardiac/*metabolism ; Telomere Shortening/*genetics ; },
abstract = {Duchenne muscular dystrophy (DMD) is a rare X-linked recessive disease that is associated with severe progressive muscle degeneration culminating in death due to cardiorespiratory failure. We previously observed an unexpected proliferation-independent telomere shortening in cardiomyocytes of a DMD mouse model. Here, we provide mechanistic insights using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using traction force microscopy, we show that DMD hiPSC-CMs exhibit deficits in force generation on fibrotic-like bioengineered hydrogels, aberrant calcium handling, and increased reactive oxygen species levels. Furthermore, we observed a progressive post-mitotic telomere shortening in DMD hiPSC-CMs coincident with downregulation of shelterin complex, telomere capping proteins, and activation of the p53 DNA damage response. This telomere shortening is blocked by blebbistatin, which inhibits contraction in DMD cardiomyocytes. Our studies underscore the role of fibrotic stiffening in the etiology of DMD cardiomyopathy. In addition, our data indicate that telomere shortening is progressive, contraction dependent, and mechanosensitive, and suggest points of therapeutic intervention.},
}
@article {pmid34019708,
year = {2021},
author = {Giri, N and Alter, BP and Savage, SA and Stratton, P},
title = {Gynaecological and reproductive health of women with telomere biology disorders.},
journal = {British journal of haematology},
volume = {193},
number = {6},
pages = {1238-1246},
pmid = {34019708},
issn = {1365-2141},
support = {N02CP11019/CP/NCI NIH HHS/United States ; ZIA CP010190/ImNIH/Intramural NIH HHS/United States ; HHSN261200655001C//Westat, Inc/ ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; *Dyskeratosis Congenita/epidemiology/genetics ; Female ; *Fertility ; Humans ; Middle Aged ; *Pre-Eclampsia/epidemiology/genetics ; Pregnancy ; *Premature Birth/epidemiology/genetics ; *Reproductive Health ; *Uterine Diseases/epidemiology/genetics ; },
abstract = {Reproductive health may be adversely impacted in women with dyskeratosis congenita (DC) and related telomere biology disorders (TBD). We evaluated gynaecological problems, fertility, and pregnancy outcomes in 39 females aged 10-81 years who were followed longitudinally in our DC/TBD cohort. Twenty-six had bone marrow failure and 12 underwent haematopoietic cell transplantation. All attained menarche at a normal age. Thirteen women reported menorrhagia; ten used hormonal contraception to reduce bleeding. Nine experienced natural normal-aged menopause. Gynaecological problems (endometriosis = 3, pelvic varicosities = 1, cervical intraepithelial neoplasia = 1, and uterine prolapse = 2) resulted in surgical menopause in seven. Twenty-five of 26 women attempting fertility carried 80 pregnancies with 49 (61%) resulting in livebirths. Ten (38%) women experienced 28 (35%) miscarriages, notably recurrent pregnancy loss in five (19%). Preeclampsia (n = 6, 24%) and progressive cytopenias (n = 10, 40%) resulted in maternal-fetal compromise, including preterm (n = 5) and caesarean deliveries (n = 18, 37%). Gynaecological/reproductive problems were noted mainly in women with autosomal-dominant inheritance; others were still young or died early. Although women with TBDs had normal menarche, fertility, and menopause, gynaecological problems and pregnancy complications leading to caesarean section, preterm delivery, or transfusion support were frequent. Women with TBDs will benefit from multidisciplinary, coordinated care by haematology, gynaecology and maternal-fetal medicine.},
}
@article {pmid34018656,
year = {2021},
author = {Dong, X and Sun, S and Zhang, L and Kim, S and Tu, Z and Montagna, C and Maslov, AY and Suh, Y and Wang, T and Campisi, J and Vijg, J},
title = {Age-related telomere attrition causes aberrant gene expression in sub-telomeric regions.},
journal = {Aging cell},
volume = {20},
number = {6},
pages = {e13357},
pmid = {34018656},
issn = {1474-9726},
support = {P01 AG047200/AG/NIA NIH HHS/United States ; K99 AG056656/AG/NIA NIH HHS/United States ; U19 AG056278/AG/NIA NIH HHS/United States ; R01 AG055501/AG/NIA NIH HHS/United States ; R00 AG056656/AG/NIA NIH HHS/United States ; P30 AG038072/AG/NIA NIH HHS/United States ; P01 AG017242/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging ; Cellular Senescence/*genetics ; Female ; Gene Expression/*genetics ; Humans ; Male ; Middle Aged ; Telomere/*genetics ; Young Adult ; },
abstract = {Telomere attrition has been proposed as a biomarker and causal factor in aging. In addition to causing cellular senescence and apoptosis, telomere shortening has been found to affect gene expression in subtelomeric regions. Here, we analyzed the distribution of age-related differentially expressed genes from the GTEx RNA sequencing database of 54 tissue types from 979 human subjects and found significantly more upregulated than downregulated genes in subtelomeric regions as compared to the genome-wide average. Our data demonstrate spatial relationships between telomeres and gene expression in aging.},
}
@article {pmid34009632,
year = {2021},
author = {da Silva Neto Trajano, LA and da Silva Sergio, LP and de Oliveira, DSL and Trajano, ETL and Dos Santos Silva, MA and de Paoli, F and Mencalha, AL and de Souza da Fonseca, A},
title = {Low-power infrared laser modulates telomere length in heart tissue from an experimental model of acute lung injury.},
journal = {Photochemical &amp; photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology},
volume = {20},
number = {5},
pages = {653-661},
pmid = {34009632},
issn = {1474-9092},
mesh = {Acute Lung Injury/chemically induced/*genetics/pathology ; Animals ; *Heart ; *Lasers ; Lipopolysaccharides ; RNA, Messenger/genetics ; Sepsis/chemically induced/*genetics/pathology ; Telomere/*genetics ; },
abstract = {Acute lung injury and acute respiratory distress syndrome can occur as a result of sepsis. Cardiac dysfunction is a serious component of multi-organ failure caused by severe sepsis. Telomere shortening is related to several heart diseases. Telomeres are associated with the shelterin protein complex, which contributes to the maintenance of telomere length. Low-power infrared lasers modulate mRNA levels of shelterin complex genes. This study aimed to evaluate effects of a low-power infrared laser on mRNA relative levels of genes involved in telomere stabilization and telomere length in heart tissue of an experimental model of acute lung injury caused by sepsis. Animals were divided into six groups, treated with intraperitoneal saline solution, saline solution and exposed to a low-power infrared laser at 10 J cm[-2] and 20 J cm[-2], lipopolysaccharide (LPS), and LPS and, after 4 h, exposed to a low-power infrared laser at 10 J cm[-2] and 20 J cm[-2]. The laser exposure was performed only once. Analysis of mRNA relative levels and telomere length by RT-qPCR was performed. Telomere shortening and reduction in mRNA relative levels of TRF1 mRNA in heart tissues of LPS-induced ALI animals were observed. In addition, laser exposure increased the telomere length at 10 J cm[-2] and modulated the TRF1 mRNA relative levels of at 20 J cm[-2] in healthy animals. Although the telomeres were shortened and mRNA levels of TRF1 gene were increased in nontreated controls, the low-power infrared laser irradiation increased the telomere length at 10 J cm[-2] in cardiac tissue of animals affected by LPS-induced acute lung injury, which suggests that telomere maintenance is a part of the photobiomodulation effect induced by infrared radiation.},
}
@article {pmid34008434,
year = {2021},
author = {Whitlock, B},
title = {Telomere Length and Arsenic: Improving Animal Models of Toxicity by Choosing Mice With Shorter Telomeres.},
journal = {International journal of toxicology},
volume = {40},
number = {3},
pages = {211-217},
doi = {10.1177/10915818211009844},
pmid = {34008434},
issn = {1092-874X},
mesh = {Animals ; Arsenic/*toxicity ; Carcinogens/*toxicity ; Disease Models, Animal ; Environmental Exposure/*adverse effects ; Humans ; Male ; Mice ; Telomere/*drug effects ; },
abstract = {Arsenic is both a chemotherapeutic drug and an environmental toxicant that affects hundreds of millions of people each year. Arsenic exposure in drinking water has been called the worst poisoning in human history. How arsenic is handled in the body is frequently studied using rodent models to investigate how arsenic both causes and treats disease. These models, used in a variety of arsenic-related testing, from tumor formation to drug toxicity monitoring, have virtually always been developed from animals with telomeres that are unnaturally long, likely because of accidental artificial selective pressures. Mice that have been bred in captivity in laboratory conditions, often for over 100 years, are the standard in creating animal models for this research. Using these mice introduces challenges to any work that can be affected by the length of telomeres and the related capacities for tissue repair and cancer resistance. However, arsenic research is particularly susceptible to the misuse of such animal models due to the multiple and various interactions between arsenic and telomeres. Researchers in the field commonly find mouse models and humans behaving very differently upon exposure to acute and chronic arsenic, including drug therapies which seem safe in mice but are toxic in humans. Here, some complexities and apparent contradictions of the arsenic carcinogenicity and toxicity research are reconciled by an explanatory model that involves telomere length explained by the evolutionary pressures in laboratory mice. A low-risk hypothesis is proposed which has the power to determine whether researchers can easily develop more powerful and accurate mouse models by simply avoiding mouse lineages that are very old and have strangely long telomeres. Swapping in newer mouse lineages for the older, long-telomere mice may vastly improve our ability to research arsenic toxicity with virtually no increase in cost or difficulty of research.},
}
@article {pmid34000743,
year = {2021},
author = {Teixeira, MZ},
title = {Telomere and Telomerase: Biological Markers of Organic Vital Force State and Homeopathic Treatment Effectiveness.},
journal = {Homeopathy : the journal of the Faculty of Homeopathy},
volume = {110},
number = {4},
pages = {283-291},
pmid = {34000743},
issn = {1476-4245},
mesh = {Biomarkers ; *Homeopathy ; *Telomerase/genetics/metabolism ; Telomere/metabolism ; Treatment Outcome ; },
abstract = {BACKGROUND: Philosophical-scientific correlations described in previous studies suggest that the genome can be the biological representation of the vital force, whilst the disease-promoting epigenetic alterations would be the biological representation of the chronic miasmas. In this study, we expand the functional correlation between vital force and chromosomes, describing the mechanism of action of the telomere-telomerase complex in the context of physiological balance.<br><br>AIMS: &#x2003;The aim of the work is to study the role of the telomere-telomerase complex in cell vitality, biological aging, and the health-disease process, with the goal of proposing the use of telomere length as a biomarker of the vital force state and the effectiveness of homeopathic treatment.<br><br>RESULTS: &#x2003;Similar to the vital force, telomere length and telomerase enzyme activity play an important role in maintaining cellular vitality, biological longevity, and physiological homeostasis. Telomere shortening functions as a biomarker of vital imbalance and is associated with numerous diseases and health disorders. On the other hand, health-promotion practices neutralize the pathological shortening of the telomeres, acting therapeutically in diseases or age-dependent health disorders.<br><br>CONCLUSIONS: &#x2003;As a hypothetical biomarker of the vital force state, an intra-individual analysis of the mean leukocyte telomere length before, during, and after homeopathic treatment can be used as a biomarker of therapeutic effectiveness.},
}
@article {pmid34000259,
year = {2021},
author = {Fernandes, JR and Pinto, TNC and Piemonte, LL and Arruda, LB and Marques da Silva, CCB and F Carvalho, CR and Pinto, RMC and S Duarte, AJ and Benard, G},
title = {Long-term tobacco exposure and immunosenescence: Paradoxical effects on T-cells telomere length and telomerase activity.},
journal = {Mechanisms of ageing and development},
volume = {197},
number = {},
pages = {111501},
doi = {10.1016/j.mad.2021.111501},
pmid = {34000259},
issn = {1872-6216},
mesh = {Aged ; Aging/*immunology ; CD4-Positive T-Lymphocytes/*immunology ; CD8-Positive T-Lymphocytes/*immunology ; Female ; Humans ; *Immunosenescence ; Longitudinal Studies ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/*immunology ; Smoking/adverse effects/*immunology ; Telomerase/*immunology ; Telomere Shortening/*immunology ; },
abstract = {Immunosenescence are alterations on immune system that occurs throughout an individual life. The main characteristic of this process is replicative senescence, evaluated by telomere shortening. Several factors implicate on telomere shortening, such as smoking. In this study, we evaluated the influence of smoking and Chronic Obstructive Pulmonary Disease (COPD) on cytokines, telomere length and telomerase activity. Blood samples were collected from subjects aged over 60 years old: Healthy (never smokers), Smokers (smoking for over 30 years) and COPDs (ex-smokers for ≥15 years). A young group was included as control. PBMCs were cultured for assessment of telomerase activity using RT-PCR, and cytokines secretion flow cytometry. CD4+ and CD8+ purified lymphocytes were used to assess telomere length using FlowFISH. We observed that COPD patients have accelerated telomere shortening. Paradoxically, smokers without lung damage showed preserved telomere length, suggesting that tobacco smoking may affect regulatory mechanisms, such as telomerase. Telomerase activity showed diminished activity in COPDs, while Smokers showed increased activity compared to COPDs and Healthy groups. Extracellular environment reflected this unbalance, indicated by an anti-inflammatory profile in Smokers, while COPDs showed an inflammatory prone profile. Further studies focusing on telomeric maintenance may unveil mechanisms that are associated with cancer under long-term smoking.},
}
@article {pmid33994338,
year = {2022},
author = {Alonso-Pedrero, L and Ojeda-Rodríguez, A and Zalba, G and Razquin, C and Martínez-González, M&#xc1; and Bes-Rastrollo, M and Marti, A},
title = {Association between ideal cardiovascular health and telomere length in participants older than 55 years old from the SUN cohort.},
journal = {Revista espanola de cardiologia (English ed.)},
volume = {75},
number = {4},
pages = {308-315},
doi = {10.1016/j.rec.2021.04.002},
pmid = {33994338},
issn = {1885-5857},
mesh = {American Heart Association ; Blood Pressure/physiology ; Body Mass Index ; *Cardiovascular Diseases/epidemiology/genetics ; *Exercise ; Female ; Humans ; Male ; Middle Aged ; Risk Factors ; Telomere/genetics ; United States ; },
abstract = {INTRODUCTION AND OBJECTIVES: Telomeres are noncoding regions located at the end of chromosomes and their shortening has been associated with risk factors and cardiovascular disease. The aim of this study was to evaluate the association between ideal cardiovascular health (Life's simple 7) and the odds of having short telomeres in a subsample of participants older than 55 years from the Seguimiento Universidad de Navarra (SUN) study.<br><br>METHODS: We included 886 participants older than 55 years (645 men and 241 women). Telomere length was measured using a real-time quantitative polymerase chain reaction. Cardiovascular health score was defined by the American Heart Association as a composite score of 7 key risk factors (smoking status, physical activity, diet, body mass index, blood pressure, total cholesterol, and fasting blood glucose) with 0 to 2 points for each factor. We categorized this score in tertiles as poor (0-9 points), intermediate (10-11 points) and ideal (12-14 points). The odds of having short telomeres was defined as telomere length below the 20th percentile.<br><br>RESULTS: Individuals with higher ideal cardiovascular health had a lower prevalence of having short telomeres (adjusted OR, 0.60; 95%CI, 0.34-1.05; P trend=.052). This association was statistically significant in men (adjusted OR, 0.37; 95%CI, 0.17-0.83; P trend=.025) but not in women.<br><br>CONCLUSIONS: An inverse association between cardiovascular health score and short telomeres was found especially for men older than 55 years in the SUN population. The SUN project was registered at ClinicalTrials.gov (Identifier: NCT02669602).},
}
@article {pmid33986331,
year = {2021},
author = {Choudhury, A and Mohammad, T and Samarth, N and Hussain, A and Rehman, MT and Islam, A and Alajmi, MF and Singh, S and Hassan, MI},
title = {Structural genomics approach to investigate deleterious impact of nsSNPs in conserved telomere maintenance component 1.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {10202},
pmid = {33986331},
issn = {2045-2322},
mesh = {Computational Biology/methods ; DNA/genetics ; Databases, Genetic ; Genomics/methods ; Humans ; Mutation ; Polymorphism, Single Nucleotide ; Structure-Activity Relationship ; Telomere/*genetics ; Telomere Homeostasis ; Telomere-Binding Proteins/*genetics ; },
abstract = {Conserved telomere maintenance component 1 (CTC1) is an important component of the CST (CTC1-STN1-TEN1) complex, involved in maintaining the stability of telomeric DNA. Several non-synonymous single-nucleotide polymorphisms (nsSNPs) in CTC1 have been reported to cause Coats plus syndrome and Dyskeratosis congenital diseases. Here, we have performed sequence and structure analyses of nsSNPs of CTC1 using state-of-the-art computational methods. The structure-based study focuses on the C-terminal OB-fold region of CTC1. There are 11 pathogenic mutations identified, and detailed structural analyses were performed. These mutations cause a significant disruption of noncovalent interactions, which may be a possible reason for CTC1 instability and consequent diseases. To see the impact of such mutations on the protein conformation, all-atom molecular dynamics (MD) simulations of CTC1-wild-type (WT) and two of the selected mutations, R806C and R806L for 200 ns, were carried out. A significant conformational change in the structure of the R806C mutant was observed. This study provides a valuable direction to understand the molecular basis of CTC1 dysfunction in disease progression, including Coats plus syndrome.},
}
@article {pmid33981033,
year = {2021},
author = {He, Y and Wang, Y and Liu, B and Helmling, C and Sušac, L and Cheng, R and Zhou, ZH and Feigon, J},
title = {Structures of telomerase at several steps of telomere repeat synthesis.},
journal = {Nature},
volume = {593},
number = {7859},
pages = {454-459},
pmid = {33981033},
issn = {1476-4687},
support = {U24 GM129541/GM/NIGMS NIH HHS/United States ; R35 GM131901/GM/NIGMS NIH HHS/United States ; S10 OD018111/OD/NIH HHS/United States ; U24 GM129539/GM/NIGMS NIH HHS/United States ; S10 RR023057/RR/NCRR NIH HHS/United States ; U24 GM116792/GM/NIGMS NIH HHS/United States ; R01 GM071940/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Motifs ; Binding Sites ; *Cryoelectron Microscopy ; DNA/chemistry/metabolism/ultrastructure ; Humans ; Models, Molecular ; Nucleotides ; Protein Binding ; RNA/chemistry/metabolism/ultrastructure ; Ribonucleoproteins/chemistry/metabolism/ultrastructure ; Shelterin Complex/chemistry/metabolism ; Telomerase/*chemistry/*metabolism/ultrastructure ; Telomere/genetics/*metabolism/ultrastructure ; Telomere-Binding Proteins/chemistry/metabolism ; Templates, Genetic ; Tetrahymena thermophila/*enzymology/ultrastructure ; },
abstract = {Telomerase is unique among the reverse transcriptases in containing a noncoding RNA (known as telomerase RNA (TER)) that includes a short template that is used for the processive synthesis of G-rich telomeric DNA repeats at the 3' ends of most eukaryotic chromosomes[1]. Telomerase maintains genomic integrity, and its activity or dysregulation are critical determinants of human longevity, stem cell renewal and cancer progression[2,3]. Previous cryo-electron microscopy structures have established the general architecture, protein components and stoichiometries of Tetrahymena and human telomerase, but our understandings of the details of DNA-protein and RNA-protein interactions and of the mechanisms and recruitment involved remain limited[4-6]. Here we report cryo-electron microscopy structures of active Tetrahymena telomerase with telomeric DNA at different steps of nucleotide addition. Interactions between telomerase reverse transcriptase (TERT), TER and DNA reveal the structural basis of the determination of the 5' and 3' template boundaries, handling of the template-DNA duplex and separation of the product strand during nucleotide addition. The structure and binding interface between TERT and telomerase protein p50 (a homologue of human TPP1[7,8]) define conserved interactions that are required for telomerase activation and recruitment to telomeres. Telomerase La-related protein p65 remodels several regions of TER, bridging the 5' and 3' ends and the conserved pseudoknot to facilitate assembly of the TERT-TER catalytic core.},
}
@article {pmid33980827,
year = {2021},
author = {Roisné-Hamelin, F and Pobiega, S and Jézéquel, K and Miron, S and Dépagne, J and Veaute, X and Busso, D and Du, ML and Callebaut, I and Charbonnier, JB and Cuniasse, P and Zinn-Justin, S and Marcand, S},
title = {Mechanism of MRX inhibition by Rif2 at telomeres.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {2763},
pmid = {33980827},
issn = {2041-1723},
mesh = {Amino Acid Motifs ; Chromosomes, Fungal/metabolism ; DNA Breaks, Double-Stranded ; DNA End-Joining Repair ; DNA, Fungal/metabolism ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Endodeoxyribonucleases/chemistry/*metabolism ; Exodeoxyribonucleases/chemistry/*metabolism ; Models, Molecular ; Multiprotein Complexes ; Mutation ; Protein Binding ; Protein Domains ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/chemistry/genetics/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {Specific proteins present at telomeres ensure chromosome end stability, in large part through unknown mechanisms. In this work, we address how the Saccharomyces cerevisiae ORC-related Rif2 protein protects telomere. We show that the small N-terminal Rif2 BAT motif (Blocks Addition of Telomeres) previously known to limit telomere elongation and Tel1 activity is also sufficient to block NHEJ and 5' end resection. The BAT motif inhibits the ability of the Mre11-Rad50-Xrs2 complex (MRX) to capture DNA ends. It acts through a direct contact with Rad50 ATP-binding Head domains. Through genetic approaches guided by structural predictions, we identify residues at the surface of Rad50 that are essential for the interaction with Rif2 and its inhibition. Finally, a docking model predicts how BAT binding could specifically destabilise the DNA-bound state of the MRX complex. From these results, we propose that when an MRX complex approaches a telomere, the Rif2 BAT motif binds MRX Head in its ATP-bound resting state. This antagonises MRX transition to its DNA-bound state, and favours a rapid return to the ATP-bound state. Unable to stably capture the telomere end, the MRX complex cannot proceed with the subsequent steps of NHEJ, Tel1-activation and 5' resection.},
}
@article {pmid33979985,
year = {2021},
author = {Moon, DH and Kim, J and Lim, MN and Bak, SH and Kim, WJ},
title = {Correlation between Telomere Length and Chronic Obstructive Pulmonary Disease-Related Phenotypes: Results from the Chronic Obstructive Pulmonary Disease in Dusty Areas (CODA) Cohort.},
journal = {Tuberculosis and respiratory diseases},
volume = {84},
number = {3},
pages = {188-199},
pmid = {33979985},
issn = {1738-3536},
abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease with increased prevalence in the elderly. Telomeres are repetitive DNA sequences found at the end of the chromosome, which progressively shorten as cells divide. Telomere length is known to be a molecular marker of aging. This study aimed to assess the relationship between telomere length and the risk of COPD, lung function, respiratory symptoms, and emphysema index in Chronic Obstructive Pulmonary Disease in Dusty Areas (CODA) cohort.<br><br>METHODS: We extracted DNA from the peripheral blood samples of 446 participants, including 285 COPD patients and 161 control participants. We measured absolute telomere length using quantitative real-time polymerase chain reaction. All participants underwent spirometry and quantitative computed tomography scan. Questionnaires assessing respiratory symptoms and the COPD Assessment Test was filled by all the participants.<br><br>RESULTS: The mean age of participants at the baseline visit was 72.5&#xb1;7.1 years. Males accounted for 72% (321 participants) of the all participants. The mean telomere length was lower in the COPD group compared to the non-COPD group (COPD, 16.81&#xb1;13.90 kb; non-COPD, 21.97&#xb1;14.43 kb). In COPD patients, 112 (75.7%) were distributed as tertile 1 (shortest), 91 (61.1%) as tertile 2 and 82 (55%) as tertile 3 (longest). We did not find significant associations between telomere length and lung function, exacerbation, airway wall thickness, and emphysema index after adjusting for sex, age, and smoking status.<br><br>CONCLUSION: In this study, the relationship between various COPD phenotypes and telomere length was analyzed, but no significant statistical associations were shown.},
}
@article {pmid33979621,
year = {2021},
author = {Tichy, ED and Ma, N and Sidibe, D and Loro, E and Kocan, J and Chen, DZ and Khurana, TS and Hasty, P and Mourkioti, F},
title = {Persistent NF-κB activation in muscle stem cells induces proliferation-independent telomere shortening.},
journal = {Cell reports},
volume = {35},
number = {6},
pages = {109098},
pmid = {33979621},
issn = {2211-1247},
support = {P30 AR069619/AR/NIAMS NIH HHS/United States ; R01 AR075914/AR/NIAMS NIH HHS/United States ; R01 HL146662/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Cell Proliferation ; Disease Models, Animal ; Humans ; Mice ; NF-kappa B/*metabolism ; Stem Cells/*metabolism ; Telomere Shortening/*genetics ; },
abstract = {During the repeated cycles of damage and repair in many muscle disorders, including Duchenne muscular dystrophy (DMD), the muscle stem cell (MuSC) pool becomes less efficient at responding to and repairing damage. The underlying mechanism of such stem cell dysfunction is not fully known. Here, we demonstrate that the distinct early telomere shortening of diseased MuSCs in both mice and young DMD patients is associated with aberrant NF-κB activation. We find that prolonged NF-κB activation in MuSCs in chronic injuries leads to shortened telomeres and Ku80 dysregulation and results in severe skeletal muscle defects. Our studies provide evidence of a role for NF-κB in regulating stem-cell-specific telomere length, independently of cell replication, and could be a congruent mechanism that is applicable to additional tissues and/or diseases characterized by systemic chronic inflammation.},
}
@article {pmid33973299,
year = {2022},
author = {McLennan, D and Auer, SK and McKelvey, S and McKelvey, L and Anderson, G and Boner, W and Duprez, JS and Metcalfe, NB},
title = {Habitat restoration weakens negative environmental effects on telomere dynamics.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6100-6113},
pmid = {33973299},
issn = {1365-294X},
mesh = {Animals ; Climate ; *Ecosystem ; Invertebrates ; *Salmo salar/genetics ; Telomere/genetics ; },
abstract = {Habitat quality can have far-reaching effects on organismal fitness, an issue of concern given the current scale of habitat degradation. Many temperate upland streams have reduced nutrient levels due to human activity. Nutrient restoration confers benefits in terms of invertebrate food availability and subsequent fish growth rates. Here we test whether these mitigation measures also affect the rate of cellular ageing of the fish, measured in terms of the telomeres that cap the ends of eukaryotic chromosomes. We equally distributed Atlantic salmon eggs from the same 30 focal families into 10 human-impacted oligotrophic streams in northern Scotland. Nutrient levels in five of the streams were restored by simulating the deposition of a small number of adult Atlantic salmon Salmo salar carcasses at the end of the spawning period, while five reference streams were left as controls. Telomere lengths and expression of the telomerase reverse transcriptase (TERT) gene that may act to lengthen telomeres were then measured in the young fish when 15 months old. While TERT expression was unrelated to any of the measured variables, telomere lengths were shorter in salmon living at higher densities and in areas with a lower availability of the preferred substrate (cobbles and boulders). However, the adverse effects of these habitat features were much reduced in the streams receiving nutrients. These results suggest that adverse environmental pressures are weakened when nutrients are restored, presumably because the resulting increase in food supply reduces levels of both competition and stress.},
}
@article {pmid33971995,
year = {2022},
author = {Ward, SJ and Hill, AM and Buckley, JD and Banks, S and Dhillon, VS and Holman, SL and Morrison, JL and Coates, AM},
title = {Minimal changes in telomere length after a 12-week dietary intervention with almonds in mid-age to older, overweight and obese Australians: results of a randomised clinical trial.},
journal = {The British journal of nutrition},
volume = {127},
number = {6},
pages = {872-884},
doi = {10.1017/S0007114521001549},
pmid = {33971995},
issn = {1475-2662},
mesh = {Adult ; Australia ; Humans ; Obesity ; *Overweight ; *Prunus dulcis ; Telomere ; },
abstract = {Diet is a modifiable risk factor for chronic disease and a potential modulator of telomere length (TL). The study aim was to investigate associations between diet quality and TL in Australian adults after a 12-week dietary intervention with an almond-enriched diet (AED). Participants (overweight/obese, 50-80 years) were randomised to an AED (n 62) or isoenergetic nut-free diet (NFD, n 62) for 12 weeks. Diet quality was assessed using a Dietary Guideline Index (DGI), applied to weighed food records, that consists of ten components reflecting adequacy, variety and quality of core food components and discretionary choices within the diet. TL was measured by quantitative PCR in samples of lymphocytes, neutrophils, and whole blood. There were no significant associations between DGI scores and TL at baseline. Diet quality improved with AED and decreased with NFD after 12 weeks (change from baseline AED + 9·8 %, NFD - 14·3 %; P < 0·001). TL increased in neutrophils (+9·6 bp, P = 0·009) and decreased in whole blood, to a trivial extent (-12·1 bp, P = 0·001), and was unchanged in lymphocytes. Changes did not differ between intervention groups. There were no significant relationships between changes in diet quality scores and changes in lymphocyte, neutrophil or whole blood TL. The inclusion of almonds in the diet improved diet quality scores but had no impact on TL mid-age to older Australian adults. Future studies should investigate the impact of more substantial dietary changes over longer periods of time.},
}
@article {pmid33963974,
year = {2021},
author = {Ospanov, O and Akilzhanova, A and Buchwald, JN and Fursov, A and Bekmurzinova, F and Rakhimova, S and Yeleuov, G and Kozhamkulov, U and Abdina, Z and Fursov, R and Jumayeva, L},
title = {Stapleless vs Stapled Gastric Bypass vs Hypocaloric Diet: a Three-Arm Randomized Controlled Trial of Body Mass Evolution with Secondary Outcomes for Telomere Length and Metabolic Syndrome Changes.},
journal = {Obesity surgery},
volume = {31},
number = {7},
pages = {3165-3176},
pmid = {33963974},
issn = {1708-0428},
mesh = {Diet ; *Gastric Bypass ; Humans ; *Metabolic Syndrome/genetics ; *Obesity, Morbid/surgery ; Telomere ; Treatment Outcome ; },
abstract = {BACKGROUND: Obesity and metabolic syndrome (MetS) reduce life expectancy and are challenging to resolve. This randomized controlled trial (RCT) of patients with obesity and MetS undergoing surgical vs nonsurgical treatment compared changes in BMI, and secondarily, telomere length (as a biomarker of life expectancy) and changes in MetS components (insulin resistance, dyslipidemia, hypertension).<br><br>METHODS: Study design was a single-center, prospective, three-arm RCT. Group 1 patients underwent novel unstapled laparoscopic one anastomosis gastric bypass with an obstructive stapleless pouch and anastomosis (LOAGB-OSPAN); Group 2, stapled laparoscopic mini-gastric bypass-one anastomosis gastric bypass (LMGB-OAGB); and Group 3, nonsurgical weight loss therapy via a hypocaloric diet with energy restriction (HDER). The primary outcome measure was change in BMI; secondary outcome measures included change in leukocyte telomere length and other MetS components.<br><br>RESULTS: Of 96 participants screened, 60 were randomly allocated to 3 groups: LOAGB-OSPAN group (n = 20), LMGB-OAGB group (n = 20), and HDER group (n = 20). At post-treatment month 12, respective BMI changes: BMI -12.13 (-8.34, -15.93); -16.04 (-11.7, 20.37); -2,76 (-3.84, -9.36) (p < 0.01). The two surgical groups experienced significant change in telomere length: LOAGB-OSPAN 2.02 (1.61, 2.41), p = 0.001; LMGB-OAGB 2.07 (1.72, 2.43), p = 0.001; and HDER 0.28 (0.22, 0.78), p = 0.26. The surgical groups were also more effective in treating MetS components. There were no deaths. Adverse events: LOAGB-OSPAN (n = 2) (Clavien-Dindo grade II); LMGB-OAGB (n = 8) (grade I (n = 6) and grade II (n = 2).<br><br>CONCLUSIONS: Compared with hypocaloric diet therapy, both bariatric procedures resulted in greater BMI loss, and secondarily, a significant increase in telomere length, and greater MetS resolution.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov , NCT03667469, registered on 11 September 2018.},
}
@article {pmid33959889,
year = {2021},
author = {Inandiklioğlu, N and Demir, V and Ercan, M},
title = {Telomere Length and Oxidative Stress in Patients with ST-Segment Elevation and Non-ST-Segment Elevation Myocardial Infarction.},
journal = {Advances in experimental medicine and biology},
volume = {1347},
number = {},
pages = {183-195},
pmid = {33959889},
issn = {0065-2598},
mesh = {Humans ; *Myocardial Infarction/genetics ; *Non-ST Elevated Myocardial Infarction ; Oxidative Stress ; Risk Factors ; *ST Elevation Myocardial Infarction/genetics ; Telomere/genetics ; Treatment Outcome ; },
abstract = {PURPOSE: The telomere length is shown to act as a biomarker, especially for biological aging and cardiovascular diseases, and it is also suggested that with this correlation, increased exposure to the oxidative stress accelerates the vascular aging process. Therefore, this study aims to understand the correlation between the plasma oxidative stress index (OSI) status and leukocyte telomere length (LTL) and cardiologic parameters between the ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) groups.<br><br>METHOD: One hundred one newly diagnosed patients with STEMI (n&#xa0;=&#xa0;55) and NSTEMI (n&#xa0;=&#xa0;46) were included in the study, along with 100 healthy controls who matched the patients in terms of age and gender. Plasma total antioxidant status (TAS), total oxidant status (TOS), and LTL were measured.<br><br>RESULTS: When LTL, TAS, TOS, and OSI values were evaluated between the patient and control group, OSI (p&#xa0;=&#xa0;0.000) and LTL (p&#xa0;=&#xa0;0.05) values were statistically significant in the patient group compared to the control group. Evaluation was conducted to understand whether there is a difference between the STEMI and NSTEMI groups. The plasma OSI (p&#xa0;=&#xa0;0.007) and LTL (p&#xa0;=&#xa0;0.05) were found to be significantly lower in STEMI patients. However, LTL and OSI results were not statistically significant in NSTEMI patients.<br><br>CONCLUSION: This is the first study evaluating telomere length and oxidative stress in STEMI and NSTEMI patients in Turkey. Our results support the existence of short telomere length in STEMI patients. Future studies on telomere length and oxidative stress will support the importance of our findings.},
}
@article {pmid33955230,
year = {2021},
author = {Toupance, S and Simonici, S and Labat, C and Dumoulin, C and Lai, TP and Lakomy, C and Regnault, V and Lacolley, P and Dignat George, F and Sabatier, F and Aviv, A and Benetos, A and , },
title = {Number and Replating Capacity of Endothelial Colony-Forming Cells are Telomere Length Dependent: Implication for Human Atherogenesis.},
journal = {Journal of the American Heart Association},
volume = {10},
number = {10},
pages = {e020606},
pmid = {33955230},
issn = {2047-9980},
support = {R01 HD071180/HD/NICHD NIH HHS/United States ; R01 HL116446/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/metabolism/*pathology ; Atherosclerosis/metabolism/*pathology ; Cell Proliferation ; Cells, Cultured ; Endothelial Progenitor Cells/metabolism/*pathology ; Female ; Humans ; Male ; Middle Aged ; Neovascularization, Physiologic/*physiology ; Retrospective Studies ; Telomere/metabolism/*pathology ; Telomere Homeostasis/*physiology ; Young Adult ; },
abstract = {Background Short leukocyte telomere length (TL) is associated with atherosclerotic cardiovascular disease. Endothelial repair plays a key role in the development of atherosclerosis. The objective was to examine associations between TL and proliferative dynamics of endothelial colony-forming cells (ECFCs), which behave as progenitor cells displaying endothelial repair activity. Methods and Results To isolate ECFCs, we performed a clonogenic assay on blood samples from 116 participants (aged 24-94 years) in the TELARTA (Telomere in Arterial Aging) cohort study. We detected no ECFC clones in 29 (group 1), clones with no replating capacity in other 29 (group 2), and clones with replating capacity in the additional 58 (group 3). Leukocyte TL was measured by Southern blotting and ECFCs (ECFC-TL). Age- and sex-adjusted leukocyte TL (mean±SEM) was the shortest in group 1 (6.51±0.13 kb), longer in group 2 (6.69±0.13 kb), and the longest in group 3 (6.78±0.09 kb) (P<0.05). In group 3, ECFC-TL was associated with the number of detected clones (P<0.01). ECFC-TL (7.98±0.13 kb) was longer than leukocyte TL (6.74±0.012 kb) (P<0.0001) and both parameters were strongly correlated (r=0.82; P<0.0001). Conclusions Individuals with longer telomeres display a higher number of self-renewing ECFCs. Our results also indicate that leukocyte TL, as a proxy of TL dynamics in ECFCs, could be used as a surrogate marker of endothelial repair capacity in clinical and laboratory practice because of easy accessibility of leukocytes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02176941.},
}
@article {pmid33952676,
year = {2021},
author = {Mukherjee, J and Pandita, A and Kamalakar, C and Johannessen, TC and Ohba, S and Tang, Y and Dalle-Ore, CL and Bjerkvig, R and Pieper, RO},
title = {RETRACTED: A subset of PARP inhibitors induces lethal telomere fusion in ALT-dependent tumor cells.},
journal = {Science translational medicine},
volume = {13},
number = {592},
pages = {},
doi = {10.1126/scitranslmed.abc7211},
pmid = {33952676},
issn = {1946-6242},
support = {R01 NS105087/NS/NINDS NIH HHS/United States ; },
mesh = {DNA ; DNA Damage ; Humans ; *Neoplasms ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; *Telomere/genetics ; },
abstract = {About 10% of all tumors, including most lower-grade astrocytoma, rely on the alternative lengthening of telomere (ALT) mechanism to resolve telomeric shortening and avoid limitations on their growth. Here, we found that dependence on the ALT mechanism made cells hypersensitive to a subset of poly(ADP-ribose) polymerase inhibitors (PARPi). We found that this hypersensitivity was not associated with PARPi-created genomic DNA damage as in most PARPi-sensitive populations but rather with PARPi-induced telomere fusion. Mechanistically, we determined that PARP1 was recruited to the telomeres of ALT-dependent cells as part of a DNA damage response. By recruiting MRE11 and BRCC3 to stabilize TRF2 at the ends of telomeres, PARP1 blocked chromosomal fusion. Exposure of ALT-dependent tumor cells to a subset of PARPi induced a conformational change in PARP1 that limited binding to MRE11 and BRCC3 and delayed release of the TRF2-mediated block on lethal telomeric fusion. These results therefore provide a basis for PARPi treatment of ALT-dependent tumors, as well as establish chromosome fusion as a biomarker of their activity.},
}
@article {pmid33951396,
year = {2021},
author = {Badran, M and Abuyassin, B and Ayas, N and Sin, DD and Laher, I},
title = {Vascular and renal telomere shortening in mice exposed to chronic intermittent hypoxia.},
journal = {Canadian journal of physiology and pharmacology},
volume = {99},
number = {10},
pages = {1112-1113},
doi = {10.1139/cjpp-2021-0143},
pmid = {33951396},
issn = {1205-7541},
mesh = {Animals ; Aorta/metabolism/*pathology ; Disease Models, Animal ; Hypoxia/*physiopathology ; Kidney/metabolism/*pathology ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress ; *Telomere Shortening ; },
abstract = {Obstructive sleep apnea (OSA) is a chronic condition characterized by chronic intermittent hypoxia (IH) and is associated with cardiovascular (CVD) and chronic kidney diseases (CKD). Patients with OSA have increased biomarkers of aging such as telomere shortening. We used PCR to report shortened telomere lengths in aortic and renal tissues from mice exposed to 8 weeks of IH. Our data indicate that IH, a hallmark of OSA, accelerates vascular and renal aging that may contribute to OSA-induced CVD and CKD.},
}
@article {pmid33948907,
year = {2022},
author = {Khan, RJ and Needham, BL and Advani, S and Brown, K and Dagnall, C and Xu, R and Gibbons, GH and Davis, SK},
title = {Association of Childhood Socioeconomic Status with Leukocyte Telomere Length Among African Americans and the Mediating Role of Behavioral and Psychosocial Factors: Results from the GENE-FORECAST Study.},
journal = {Journal of racial and ethnic health disparities},
volume = {9},
number = {3},
pages = {1012-1023},
pmid = {33948907},
issn = {2196-8837},
mesh = {Adult ; *Black or African American ; Educational Status ; Humans ; Leukocytes ; *Social Class ; Telomere ; },
abstract = {PURPOSE: We examined if childhood socioeconomic status (SES) was related to adult leucocyte telomere length (TL) using the data of 361 African American (AA) participants from the GENE-FORECAST Study. We also assessed the mediating role of behavioral and psychosocial factors in the association between childhood SES and adult TL.<br><br>METHODS: Childhood SES was assessed individually by using participant's mother's education and occupation, father's education and occupation, parental home ownership, and family structure. TL was assessed using the quantitative polymerase chain reaction method. Information on potential confounders and mediators were collected. The associations of childhood SES with TL were assessed using multivariable linear regression models. We used path analysis to quantify and test the share of these associations that was statistically explained by each of the mediators (participant's educational attainment, smoking status, physical activity, dietary habit, perceived stress, and depressive symptoms).<br><br>RESULTS: Mother's education was associated with longer average TL (&#x3b2;: 0.021; 95% CI: 0.001, 0.04, p=0.038) in confounder adjusted models. Once mediators were introduced in the model, the estimates were reduced and remained marginally significant (&#x3b2;: 0.017; 95% CI: -0.003, 0.038, p=0.061). According to path model, approximately 19% of the effect of mother's education on TL (&#x3b2;: 0.004; 95% CI: -0.001, 0.01, p < 0.10) was mediated through participant's own education level. No significant mediation effect was observed for any other mediators.<br><br>CONCLUSIONS: These data provide evidence that participant's mother's education was positively linked to adult TL in AA population. Participant's own educational level partially explained this association.},
}
@article {pmid33946181,
year = {2021},
author = {Jang, JW and Kim, JS and Kim, HS and Tak, KY and Lee, SK and Nam, HC and Sung, PS and Kim, CM and Park, JY and Bae, SH and Choi, JY and Yoon, SK},
title = {Significance of TERT Genetic Alterations and Telomere Length in Hepatocellular Carcinoma.},
journal = {Cancers},
volume = {13},
number = {9},
pages = {},
pmid = {33946181},
issn = {2072-6694},
support = {NRF-2019R1A2C1009439//Ministry of Science, ICT and Future Planning/ ; KASLKLF2018-02//Korean Association for the Study of the Liver/ ; },
abstract = {Telomerase reverse transcriptase (TERT) mutations are reportedly the most frequent somatic genetic alterations in hepatocellular carcinoma (HCC). An integrative analysis of TERT-telomere signaling during hepatocarcinogenesis is lacking. This study aimed to investigate the clinicopathological association and prognostic value of TERT gene alterations and telomere length in HCC patients undergoing hepatectomy as well as transarterial chemotherapy (TACE). TERT promoter mutation, expression, and telomere length were analyzed by Sanger sequencing and real-time PCR in 305 tissue samples. Protein-protein interaction (PPI) analysis was performed to identify a set of genes that physically interact with TERT. The PPI analysis identified eight key TERT-interacting genes, namely CCT5, TUBA1B, mTOR, RPS6KB1, AKT1, WHAZ, YWHAQ, and TERT. Among these, TERT was the most strongly differentially expressed gene. TERT promoter mutations were more frequent, TERT expression was significantly higher, and telomere length was longer in tumors versus non-tumors. TERT promoter mutations were most frequent in HCV-related HCCs and less frequent in HBV-related HCCs. TERT promoter mutations were associated with higher TERT levels and longer telomere length and were an independent predictor of worse overall survival after hepatectomy. TERT expression was positively correlated with tumor differentiation and stage progression, and independently predicted shorter time to progression after TACE. The TERT-telomere network may have a crucial role in the development and progression of HCC. TERT-telomere abnormalities might serve as useful biomarkers for HCC, but the prognostic values may differ with tumor characteristics and treatment.},
}
@article {pmid33945962,
year = {2021},
author = {Schürhoff, F and Corfdir, C and Pignon, B and Lajnef, M and Richard, JR and Marcos, E and Pelissolo, A and Leboyer, M and Adnot, S and Jamain, S and Szöke, A},
title = {No alteration of leukocyte telomere length in first episode psychosis.},
journal = {Psychiatry research},
volume = {301},
number = {},
pages = {113941},
doi = {10.1016/j.psychres.2021.113941},
pmid = {33945962},
issn = {1872-7123},
mesh = {Humans ; Leukocytes ; *Psychotic Disorders/genetics ; *Schizophrenia/genetics ; Telomere/genetics ; Telomere Shortening ; },
abstract = {Both shorter telomeres and schizophrenia have been associated with a decrease in life expectancy. Furthermore, several studies found a shorter telomere length (TL) in schizophrenia. Understanding whether or not telomere shortening is directly related to pathophysiology of schizophrenia or is a consequence of a cumulative exposure to chronic stress is of major importance. Comparing the TL of subjects at the very beginning of the disease (FEP) and control subjects could help to decide between these two hypotheses. The aim of the present study was to compare TL between FEP subjects (N=91) and controls (N=137). After accounting for multiple potential confounders, no significant association was observed between FEP and TL. Our result is consistent with the hypothesis that psycho-social stress / adversities and stressful situations in people with schizophrenia affect TL rather than that telomere erosion contributes to the development of this disorder.},
}
@article {pmid33945829,
year = {2021},
author = {Sadhukhan, R and Ghosh, U},
title = {PARP1 modulates telomere sister chromatid exchange and telomere length homeostasis by regulating telomere localization of SLX4 in U2OS cells.},
journal = {Life sciences},
volume = {277},
number = {},
pages = {119556},
doi = {10.1016/j.lfs.2021.119556},
pmid = {33945829},
issn = {1879-0631},
mesh = {Cell Line, Tumor ; Chromatids/metabolism/physiology ; DNA Repair ; Homeostasis ; Humans ; Poly (ADP-Ribose) Polymerase-1/*metabolism/physiology ; Poly(ADP-ribose) Polymerases/genetics ; Recombinases/genetics/*metabolism/physiology ; Sister Chromatid Exchange/*physiology ; Telomerase/metabolism ; Telomere/physiology ; Telomere Homeostasis/physiology ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {OBJECTIVE: Poly(ADP-ribose) polymerase1 (PARP1) interacts and poly(ADP-ribosyl)ates telomere repeat binding factor 2 (TRF2), which acts as a platform to recruit a large number of proteins at the telomere. Since the discovery of TRF2-SLX4 interaction, SLX4 is becoming the key player in telomere length (TL) maintenance and repair by telomere sister chromatid exchange (T-SCE). Defective TL maintenance pathway results in a spectrum of diseases called telomeropathies like dyskeratosis congenita, aplastic anemia, fanconi anemia, cancer. We aimed to study the role of SLX4 and PARP1 on each other's telomere localization, T-SCE, and TL maintenance in human telomerase-negative osteosarcoma U2OS cells to understand some of the molecular mechanisms of telomere homeostasis.<br><br>MATERIALS AND METHODS: We checked the role of SLX4 and PARP1 on each other's telomere localization by telomere immunofluorescence. We have cloned full-length wild-type and catalytically inactive mutant PARP1 to understand the role of poly(ADP-ribosyl)ation reaction by PARP1 in telomere length homeostasis. TL of U2OS cells was measured by Q-FISH. T-SCE was measured by Telomere-FISH.<br><br>KEY FINDINGS: We observed that SLX4 has no role in the telomere localization of PARP1. However, reduced localization of SLX4 at undamaged and damaged telomere upon PARP1 depletion was reversed by overexpression of exogenous wild-type PARP1 but not by overexpression of catalytically inactive mutant PARP1. PARP1 depletion synergized SLX4 depletion-mediated reduction of T-SCE. Furthermore, SLX4 depletion elongated TL, and combined insufficiency of SLX4 with PARP1 further elongated TL.<br><br>CONCLUSION: So, PARP1 controls SLX4 recruitment at telomere by poly(ADP-ribosyl)ation reaction, thereby regulating SLX4-mediated T-SCE and TL homeostasis.},
}
@article {pmid33942458,
year = {2021},
author = {Piñeiro-Hermida, S and Martínez, P and Blasco, MA},
title = {Short and dysfunctional telomeres protect from allergen-induced airway inflammation.},
journal = {Aging cell},
volume = {20},
number = {5},
pages = {e13352},
pmid = {33942458},
issn = {1474-9726},
mesh = {Allergens/immunology ; Animals ; Asthma/*genetics/immunology/pathology ; Cell Differentiation/drug effects ; Deoxyguanosine/analogs &amp; derivatives/pharmacology ; Goblet Cells/drug effects/pathology ; Hyperplasia ; Lung/pathology ; Mice ; Pyroglyphidae/immunology ; Telomerase/genetics ; Telomere/drug effects ; *Telomere Shortening ; Thionucleosides/pharmacology ; },
abstract = {Asthma is a chronic inflammatory disease affecting 300 million people worldwide. As telomere shortening is a well-established hallmark of aging and that asthma incidence decreases with age, here we aimed to study the role of short telomeres in asthma pathobiology. To this end, wild-type and telomerase-deficient mice with short telomeres (third-generation (G3 Tert[-/-] mice)) were challenged with intranasal house dust mite (HDM) extract. We also challenged with HDM wild-type mice in which we induced a telomere dysfunction by the administration of 6-thio-2´-deoxyguanosine (6-thio-dG). Following HDM exposure, G3 Tert[-/-] and 6-thio-dG treated mice exhibited attenuated eosinophil counts and presence of hematopoietic stem cells in the bone marrow, as well as lower levels of IgE and circulating eosinophils. Accordingly, both G3 Tert[-/-] and 6-thio-dG treated wild-type mice displayed reduced airway hyperresponsiveness (AHR), as indicated by decreased airway remodeling and allergic airway inflammation markers in the lung. Furthermore, G3 Tert[-/-] and 6-thio-dG treated mice showed lower differentiation of Club cells, attenuating goblet cell hyperplasia. Club cells of G3 Tert[-/-] and 6-thio-dG treated mice displayed increased DNA damage and senescence and reduced proliferation. Thus, short/dysfunctional telomeres play a protective role in murine asthma by impeding both AHR and mucus secretion after HDM exposure. Therefore, our findings imply that telomeres play a relevant role in allergen-induced airway inflammation.},
}
@article {pmid33941849,
year = {2021},
author = {Chang, X and Gurung, RL and Wang, L and Jin, A and Li, Z and Wang, R and Beckman, KB and Adams-Haduch, J and Meah, WY and Sim, KS and Lim, WK and Davila, S and Tan, P and Teo, JX and Yeo, KK and M, Y and Liu, S and Lim, SC and Liu, J and van Dam, RM and Friedlander, Y and Koh, WP and Yuan, JM and Khor, CC and Heng, CK and Dorajoo, R},
title = {Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population.},
journal = {Communications biology},
volume = {4},
number = {1},
pages = {519},
pmid = {33941849},
issn = {2399-3642},
mesh = {Adult ; Aged ; Aged, 80 and over ; Asian People/genetics ; Chronic Disease ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/metabolism/*pathology ; Male ; Middle Aged ; Neoplasms/*epidemiology/genetics/pathology ; *Polymorphism, Single Nucleotide ; Prospective Studies ; Shelterin Complex ; Singapore/epidemiology ; *Telomere Homeostasis ; Telomere-Binding Proteins/*genetics ; Young Adult ; },
abstract = {The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. Here we evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese samples. Three East Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with LTL (Meta-analysis P 2.49×10[-14]-6.94×10[-10]). Rs79314063, a missense variant (p.Asp410His) at POT1, shows effect 5.3 fold higher and independent of a previous common index SNP. TERF1 (rs79617270) and STN1 (rs139620151) are linked to LTL-associated common index SNPs at these loci. Rs79617270 is associated with cancer mortality [HR95%CI = 1.544 (1.173, 2.032), PAdj = 0.018] and 4.76% of the association between the rs79617270 and colon cancer is mediated through LTL. Overall, genetically determined LTL is particularly associated with lung adenocarcinoma [HR95%CI = 1.123 (1.051, 1.201), Padj = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers.},
}
@article {pmid33938706,
year = {2021},
author = {Jogi, R and Tager, MJ and Perez, D and Tsapekos, M},
title = {Bovine Colostrum, Telomeres, and Skin Aging.},
journal = {Journal of drugs in dermatology : JDD},
volume = {20},
number = {5},
pages = {538-545},
doi = {10.36849/JDD.5851},
pmid = {33938706},
issn = {1545-9616},
mesh = {Animals ; Cattle ; Cell Proliferation/drug effects/genetics ; Cells, Cultured ; Colostrum/*chemistry ; Culture Media/chemistry/pharmacology ; Female ; Fibroblasts ; Hydrogen Peroxide/metabolism ; Liposomes ; Oxidative Stress/drug effects/genetics ; Pregnancy ; Primary Cell Culture ; *Rejuvenation ; Skin/cytology ; Skin Aging/*drug effects/genetics ; Telomere/metabolism ; Telomere Shortening/drug effects ; },
abstract = {BACKGROUND: Applied topically, growth factors, cytokines, and other components in bovine colostrum are known to affect collagen biosynthesis, thus offering promise as a therapeutic modality in wound healing, delay in skin aging, and skin rejuvenation.<br><br>OBJECTIVE: To demonstrate the protective effect that liposomal bovine colostrum exerts on skin aging using telomere length as an aging biomarker.<br><br>METHODS: Human fibroblasts were cultured for 8 weeks with colostrum at three concentrations (0.125%, 0.25%, 0.50%). Cells were cultured and assayed both under standard conditions, as well as with H2O2 added as an agent of oxidative stress. Alterations in proliferation rates, telomere lengths, and telomere shortening rates (TSRs) were determined in each treatment group and compared.<br><br>RESULTS: Colostrum increased the proliferation rate of the fibroblast control cells and the addition of H2O2(without colostrum) decreased the proliferation rates of the fibroblast control cells. Under standard culture conditions, telomeres shortened progressively over 8 weeks and the addition of colostrum reduced the rate of telomere shortening. Under oxidative stress conditions (H2O2 &amp;ndash; induced) the TSR increased; however, treatment with colostrum appeared to attenuate this increase.<br><br>CONCLUSIONS: Under normal culture conditions and after both 4 weeks and 8 weeks of treatment, liposomal bovine colostrum appears to exert a protective effect on telomere length erosion. Under culture conditions of oxidative stress and after 8 weeks of treatment, colostrum appears to exert a protective effect on telomere length erosion. These results suggest that topical treatment of the liposomal bovine colostrum formulation would enhance skin health as the skin ages. J Drugs Dermatol. 20(5):538-545. doi:10.36849/JDD.5851.},
}
@article {pmid33937245,
year = {2021},
author = {Liu, Y and Zhao, X and Wang, B and Liu, Z and Zhang, M and Wang, J and Xu, C and Wang, Y and Du, L and Wang, F and Wang, Q and Liu, Q},
title = {miR-376a Provokes Rectum Adenocarcinoma Via CTC1 Depletion-Induced Telomere Dysfunction.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {649328},
pmid = {33937245},
issn = {2296-634X},
abstract = {CTC1 is a component of the mammalian CST (CTC1-STN1-TEN1) complex which plays essential roles in resolving replication problems to facilitate telomeric DNA and genomic DNA replication. We previously reported that the depletion of CTC1 leads to stalled replication fork restart defects. Moreover, the mutation in CTC1 caused cancer-prone diseases including Coats plus (CP) or dyskeratosis congenita (DC). To better understand the CTC1 regulatory axis, the microRNAs (miRNAs) targeting to CTC1 were predicted by a bioinformatics tool, and the selected candidates were further confirmed by a dual-luciferase reporter assay. Here, our current results revealed that miR-376a significantly reduced CTC1 expression at the transcription level by recognizing CTC1 3'-UTR. In addition, the overexpression of miR-376a induced telomere replication defection and resulted in direct replicative telomere damage, which could be rescued by adding back CTC1. Telomere shortening was also observed upon miR-376a treatment. Furthermore, for the clinical patient samples, the high expression of miR-376a was associated with the deregulation of CTC1 and a poor outcome for the rectum adenocarcinoma patients. Together, our results uncovered a novel role of miR-376a in stimulating rectum adenocarcinoma progression via CTC1 downregulating induced telomere dysfunction.},
}
@article {pmid33936089,
year = {2021},
author = {Mackintosh, JA and Yerkovich, ST and Tan, ME and Samson, L and Hopkins, PM and Chambers, DC},
title = {Airway Telomere Length in Lung Transplant Recipients.},
journal = {Frontiers in immunology},
volume = {12},
number = {},
pages = {658062},
pmid = {33936089},
issn = {1664-3224},
mesh = {Adult ; Age Factors ; Allografts ; Female ; Humans ; *Lung Transplantation/adverse effects/methods ; Male ; Middle Aged ; Polymerase Chain Reaction ; Prognosis ; Prospective Studies ; Respiratory Mucosa ; Risk Factors ; Telomere/*genetics ; *Telomere Homeostasis ; *Transplant Recipients ; Treatment Outcome ; },
abstract = {INTRODUCTION: Chronic lung allograft dysfunction (CLAD) represents the major impediment to long term survival following lung transplantation. Donor and recipient telomere length have been shown to associate with lung transplant outcomes, including CLAD. In this study we aimed to measure the telomere lengths of bronchial and bronchiolar airway cells in lung allografts early after transplantation and to investigate associations with CLAD and all-cause mortality.<br><br>METHODS: This prospective, longitudinal study was performed at The Prince Charles Hospital, Australia. Airway cells were collected via bronchial and bronchiolar airway brushings at post-transplant bronchoscopies. The relative telomere length in airway cells was determined by quantitative PCR based on the T/S ratio. All patients were censored for CLAD and all-cause mortality in August 2020.<br><br>RESULTS: In total 231 bronchoscopies incorporating transbronchial brush and bronchial brush were performed in 120 patients. At the time of censoring, 43% and 35% of patients, respectively, had developed CLAD and had died. Airway bronchiolar and bronchial telomere lengths were strongly correlated (r=0.78, p<0.001), confirming conservation of telomere length with airway branch generation. Both the bronchiolar (r = -0.34, p<0.001) and bronchial (r = -0.31, p<0.001) telomere length decreased with age. Shorter airway telomere length was associated with older donor age and higher donor pack-year smoking history. Neither the bronchiolar nor the bronchial airway telomere length were associated with the development of CLAD (HR 0.39 (0.06-2.3), p=0.30; HR 0.66 (0.2-1.7), p=0.39, respectively) or all-cause mortality (HR 0.92 (0.2-4.5), p=0.92; HR 0.47 (0.1-1.9), p=0.28, respectively).<br><br>CONCLUSIONS: In this cohort, airway telomere length was associated with donor age and smoking history but was not associated with the future development of CLAD or all-cause mortality.},
}
@article {pmid33935155,
year = {2021},
author = {Cecchini, MJ and Tarmey, T and Ferreira, A and Mangaonkar, AA and Ferrer, A and Patnaik, MM and Wylam, ME and Jenkins, SM and Spears, GM and Yi, ES and Hartman, TE and Scott, JP and Roden, AC},
title = {Pathology, Radiology, and Genetics of Interstitial Lung Disease in Patients With Shortened Telomeres.},
journal = {The American journal of surgical pathology},
volume = {45},
number = {7},
pages = {871-884},
doi = {10.1097/PAS.0000000000001725},
pmid = {33935155},
issn = {1532-0979},
mesh = {Adult ; Aged ; Biomarkers/analysis ; Biopsy ; Cyclin-Dependent Kinase Inhibitor p16/analysis ; Diagnosis, Differential ; Female ; Fibroblasts/chemistry/pathology ; Humans ; Immunohistochemistry ; *Lung/chemistry/diagnostic imaging/pathology ; *Lung Diseases, Interstitial/diagnostic imaging/genetics/pathology ; Male ; Middle Aged ; *Molecular Diagnostic Techniques ; Predictive Value of Tests ; Retrospective Studies ; Telomere/genetics/*pathology ; *Telomere Shortening ; *Tomography, X-Ray Computed ; },
abstract = {Interstitial lung diseases (ILDs) in patients with shortened telomeres have not been well characterized. We describe demographic, radiologic, histopathologic, and molecular features, and p16 expression in patients with telomeres ≤10th percentile (shortened telomeres) and compare them to patients with telomere length >10th percentile. Lung explants, wedge biopsies, and autopsy specimens of patients with telomere testing were reviewed independently by 3 pathologists using defined parameters. High-resolution computed tomography scans were reviewed by 3 radiologists. p16-positive fibroblast foci were quantified. A multidisciplinary diagnosis was recorded. Patients with shortened telomeres (N=26) were morphologically diagnosed as usual interstitial pneumonia (UIP) (N=11, 42.3%), chronic hypersensitivity pneumonitis (N=6, 23.1%), pleuroparenchymal fibroelastosis, fibrotic nonspecific interstitial pneumonia, desquamative interstitial pneumonia (N=1, 3.8%, each), and fibrotic interstitial lung disease (fILD), not otherwise specified (N=6, 23.1%). Patients with telomeres >10th percentile (N=18) showed morphologic features of UIP (N=9, 50%), chronic hypersensitivity pneumonitis (N=3, 16.7%), fibrotic nonspecific interstitial pneumonia (N=2, 11.1%), or fILD, not otherwise specified (N=4, 22.2%). Patients with shortened telomeres had more p16-positive foci (P=0.04). The number of p16-positive foci correlated with outcome (P=0.0067). Thirty-nine percent of patients with shortened telomeres harbored telomere-related gene variants. Among 17 patients with shortened telomeres and high-resolution computed tomography features consistent with or probable UIP, 8 (47.1%) patients showed morphologic features compatible with UIP; multidisciplinary diagnosis most commonly was idiopathic pulmonary fibrosis (N=7, 41.2%) and familial pulmonary fibrosis (N=5, 29%) in these patients. In conclusion, patients with shortened telomeres have a spectrum of fILDs. They often demonstrate atypical and discordant features on pathology and radiology leading to diagnostic challenges.},
}
@article {pmid33934394,
year = {2021},
author = {Kim, WT and Hennick, K and Johnson, J and Finnerty, B and Choo, S and Short, SB and Drubin, C and Forster, R and McMaster, ML and Hockemeyer, D},
title = {Cancer-associated POT1 mutations lead to telomere elongation without induction of a DNA damage response.},
journal = {The EMBO journal},
volume = {40},
number = {12},
pages = {e107346},
pmid = {33934394},
issn = {1460-2075},
support = {R01 CA196884/CA/NCI NIH HHS/United States ; U54 DK106829/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; DNA Damage ; Female ; Humans ; K562 Cells ; Male ; Mice ; Mutation ; Neoplasms/*genetics ; Shelterin Complex ; Stem Cells ; *Telomere ; Telomere-Binding Proteins/*genetics ; },
abstract = {Mutations in the shelterin protein POT1 are associated with chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, angiosarcoma, melanoma, and other cancers. These cancer-associated POT1 (caPOT1) mutations are generally heterozygous, missense, or nonsense mutations occurring throughout the POT1 reading frame. Cancers with caPOT1 mutations have elongated telomeres and show increased genomic instability, but which of the two phenotypes promotes tumorigenesis is unclear. We tested the effects of CAS9-engineered caPOT1 mutations in human embryonic and hematopoietic stem cells (hESCs and HSCs, respectively). HSCs with caPOT1 mutations did not show overt telomere damage. In vitro and in vivo competition experiments showed the caPOT1 mutations did not confer a selective disadvantage. Since DNA damage signaling is known to affect the fitness of HSCs, the data argue that caPOT1 mutations do not cause significant telomere damage. Furthermore, hESC lines with caPOT1 mutations showed no detectable telomere damage response while showing consistent telomere elongation. Thus, caPOT1 mutations are likely selected for during cancer progression because of their ability to elongate telomeres and extend the proliferative capacity of the incipient cancer cells.},
}
@article {pmid33933630,
year = {2021},
author = {Ensminger, DC and Siegel, SR and Owen, DAS and Sheriff, MJ and Langkilde, T},
title = {Elevated glucocorticoids during gestation suggest sex-specific effects on offspring telomere lengths in a wild lizard.},
journal = {Comparative biochemistry and physiology. Part A, Molecular &amp; integrative physiology},
volume = {257},
number = {},
pages = {110971},
doi = {10.1016/j.cbpa.2021.110971},
pmid = {33933630},
issn = {1531-4332},
mesh = {Adrenal Cortex Hormones/pharmacology ; Animals ; Cellular Senescence ; Corticosterone/metabolism ; DNA/analysis/metabolism ; Female ; Glucocorticoids/*metabolism ; Lizards/*physiology ; Phenotype ; Pregnancy ; *Pregnancy, Animal ; Prenatal Exposure Delayed Effects ; Real-Time Polymerase Chain Reaction ; Stress, Physiological ; Telomere/ultrastructure ; },
abstract = {The effects of maternal glucocorticoids (e.g. corticosterone, CORT) on offspring interest biologists due to increasing environmental perturbations. While little is known about the impact of maternal CORT on offspring fitness, it may modulate telomere length and compromise offspring health. Here, we use a modified real-time quantitative PCR assay to assess telomere length using small DNA quantities (<60 ng). We tested the hypothesis that increased maternal CORT during gestation decreases offspring telomere length. While CORT-driven telomere shortening is well established within individuals, cross-generational effects remain unclear. We treated wild-caught gravid female eastern fence lizards (Sceloporus undulatus) with daily transdermal applications of CORT, at ecologically relevant levels, from capture to laying. Maternal CORT treatment did not alter maternal telomere length, although baseline maternal CORT concentrations had a weak, negative correlation with maternal telomere length. There was no relation between mother and offspring telomere length. There was a trend for maternal CORT treatment to shorten telomeres of sons but not daughters. Our treatment replicated exposure to a single stressor per day, likely underestimating effects seen in the wild where stressors may be more frequent. Future research should further explore fitness consequences of maternal CORT effects.},
}
@article {pmid33931781,
year = {2021},
author = {Wang, M},
title = {Telomere shortening promotes kidney fibrosis.},
journal = {Nature reviews. Nephrology},
volume = {17},
number = {6},
pages = {368},
pmid = {33931781},
issn = {1759-507X},
}
@article {pmid33927016,
year = {2021},
author = {McGroder, CF and Zhang, D and Choudhury, MA and Salvatore, MM and D'Souza, BM and Hoffman, EA and Wei, Y and Baldwin, MR and Garcia, CK},
title = {Pulmonary fibrosis 4 months after COVID-19 is associated with severity of illness and blood leucocyte telomere length.},
journal = {Thorax},
volume = {76},
number = {12},
pages = {1242-1245},
pmid = {33927016},
issn = {1468-3296},
support = {T32 HL105323/HL/NHLBI NIH HHS/United States ; P30 ES005605/ES/NIEHS NIH HHS/United States ; R01 HL093096/HL/NHLBI NIH HHS/United States ; R01 HL103676/HL/NHLBI NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; },
mesh = {*COVID-19/complications ; Dyspnea ; Fibrosis ; Humans ; *Pulmonary Fibrosis/diagnostic imaging/genetics/virology ; *Telomere/genetics ; Post-Acute COVID-19 Syndrome ; },
abstract = {The risk factors for development of fibrotic-like radiographic abnormalities after severe COVID-19 are incompletely described and the extent to which CT findings correlate with symptoms and physical function after hospitalisation remains unclear. At 4 months after hospitalisation, fibrotic-like patterns were more common in those who underwent mechanical ventilation (72%) than in those who did not (20%). We demonstrate that severity of initial illness, duration of mechanical ventilation, lactate dehydrogenase on admission and leucocyte telomere length are independent risk factors for fibrotic-like radiographic abnormalities. These fibrotic-like changes correlate with lung function, cough and measures of frailty, but not with dyspnoea.},
}
@article {pmid33925940,
year = {2021},
author = {Litwin, I and Mucha, S and Pilarczyk, E and Wysocki, R and Maciaszczyk-Dziubinska, E},
title = {Complex Mechanisms of Antimony Genotoxicity in Budding Yeast Involves Replication and Topoisomerase I-Associated DNA Lesions, Telomere Dysfunction and Inhibition of DNA Repair.},
journal = {International journal of molecular sciences},
volume = {22},
number = {9},
pages = {},
pmid = {33925940},
issn = {1422-0067},
support = {2016/21/B/NZ2/01751//National Science Centre, Poland/ ; },
mesh = {Antimony/*toxicity ; DNA/metabolism ; DNA Breaks, Double-Stranded/drug effects ; DNA Damage/*drug effects/genetics ; DNA Repair/drug effects ; DNA Replication/*drug effects ; DNA Topoisomerases, Type I/metabolism ; Oxidative Stress/genetics ; Recombination, Genetic/drug effects/genetics ; Recombinational DNA Repair/drug effects/genetics ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Saccharomycetales/genetics/metabolism ; Telomere/metabolism ; },
abstract = {Antimony is a toxic metalloid with poorly understood mechanisms of toxicity and uncertain carcinogenic properties. By using a combination of genetic, biochemical and DNA damage assays, we investigated the genotoxic potential of trivalent antimony in the model organism Saccharomyces cerevisiae. We found that low doses of Sb(III) generate various forms of DNA damage including replication and topoisomerase I-dependent DNA lesions as well as oxidative stress and replication-independent DNA breaks accompanied by activation of DNA damage checkpoints and formation of recombination repair centers. At higher concentrations of Sb(III), moderately increased oxidative DNA damage is also observed. Consistently, base excision, DNA damage tolerance and homologous recombination repair pathways contribute to Sb(III) tolerance. In addition, we provided evidence suggesting that Sb(III) causes telomere dysfunction. Finally, we showed that Sb(III) negatively effects repair of double-strand DNA breaks and distorts actin and microtubule cytoskeleton. In sum, our results indicate that Sb(III) exhibits a significant genotoxic activity in budding yeast.},
}
@article {pmid33922436,
year = {2021},
author = {Tucker, LA},
title = {Fruit and Vegetable Intake and Telomere Length in a Random Sample of 5448 U.S. Adults.},
journal = {Nutrients},
volume = {13},
number = {5},
pages = {},
pmid = {33922436},
issn = {2072-6643},
mesh = {Adult ; Age Factors ; Female ; *Fruit ; Humans ; Male ; Middle Aged ; Telomere/metabolism ; *Telomere Homeostasis ; *Vegetables ; },
abstract = {The relationship between fruit and vegetable intake and telomere length was examined using a cross-sectional design and an NHANES random sample of 5448 U.S. adults. Fruit and vegetable (F&amp;V) consumption was assessed using a 24 h recall, and telomere length, an index of cellular aging, was measured using the quantitative polymerase chain reaction method. Telomere length was linearly related to F&amp;V intake when combined (F = 22.7, p < 0.0001) and also when separated as fruit (F = 7.2, p < 0.0121) or vegetables (F = 15.4, p < 0.0005), after adjusting for covariates. Specifically, telomeres were 27.8 base pairs longer for each 100 g (3.5 ounces) of F&amp;V consumed. Because each additional year of chronological age was associated with telomeres that were 14.9 base pairs shorter, when women and men were analyzed together, results indicated that a 100 g (3.5 oz) per day increment in F&amp;V corresponded with 1.9 years less biological aging. When the 75th percentile of F&amp;V intake was compared to the 25th, the difference was 4.4 years of cellular aging. When separated by sex, fruits and vegetables were both related to telomere length in women, but only vegetable intake was predictive of telomere length in men. In conclusion, evidence based on a random sample of U.S. adults indicates that the more the servings of F&amp;V, the longer telomeres tend to be.},
}
@article {pmid33921898,
year = {2021},
author = {Rangel-Pozzo, A and Yu, PLI and LaL, S and Asbaghi, Y and Sisdelli, L and Tammur, P and Tamm, A and Punab, M and Klewes, L and Louis, S and Knecht, H and Olujohungbe, A and Mai, S},
title = {Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma.},
journal = {Cancers},
volume = {13},
number = {8},
pages = {},
pmid = {33921898},
issn = {2072-6694},
support = {1111//Myeloma Canada/ ; 1111//Cancer Research Society/ ; },
abstract = {The prognosis of multiple myeloma (MM), an incurable B-cell malignancy, has significantly improved through the introduction of novel therapeutic modalities. Myeloma prognosis is essentially determined by cytogenetics, both at diagnosis and at disease progression. However, for a large cohort of patients, cytogenetic analysis is not always available. In addition, myeloma patients with favorable cytogenetics can display an aggressive clinical course. Therefore, it is necessary to develop additional prognostic and predictive markers for this disease to allow for patient risk stratification and personalized clinical decision-making. Genomic instability is a prominent characteristic in MM, and we have previously shown that the three-dimensional (3D) nuclear organization of telomeres is a marker of both genomic instability and genetic heterogeneity in myeloma. In this study, we compared in a longitudinal prospective study blindly the 3D telomeric profiles from bone marrow samples of 214 initially treatment-naïve patients with either monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or MM, with a minimum follow-up of 5 years. Here, we report distinctive 3D telomeric profiles correlating with disease aggressiveness and patient response to treatment in MM patients, and also distinctive 3D telomeric profiles for disease progression in smoldering multiple myeloma patients. In particular, lower average intensity (telomere length, below 13,500 arbitrary units) and increased number of telomere aggregates are associated with shorter survival and could be used as a prognostic factor to identify high-risk SMM and MM patients.},
}
@article {pmid33921485,
year = {2021},
author = {Berby, B and Bichara, C and Rives-Feraille, A and Jumeau, F and Pizio, PD and Sétif, V and Sibert, L and Dumont, L and Rondanino, C and Rives, N},
title = {Oxidative Stress Is Associated with Telomere Interaction Impairment and Chromatin Condensation Defects in Spermatozoa of Infertile Males.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {10},
number = {4},
pages = {},
pmid = {33921485},
issn = {2076-3921},
abstract = {Telomere length can be influenced by reactive oxygen species (ROS) generated by lifestyle factors or environmental exposure. We sought to determine whether oxidative stress has an impact on sperm nuclear alterations, especially on chromatin organization and telomere interactions in the spermatozoa of infertile males. We performed an observational and prospective study including fifty-two males, allocated in the "case group" (30 infertile males presenting conventional semen parameter alterations) and the "control group" (22 males with normal conventional semen parameters). ROS detection was determined on spermatozoa using CellROX[©] probes. Sperm nuclear damage was assessed using quantitative fluorescence in situ hybridization (Q-FISH) for relative telomere length and telomere number, aniline blue staining for chromatin condensation, terminal deoxynucleotidyl transferase dUTP nick-end labeling for DNA fragmentation, and FISH for aneuploidy and 8-hydroxy-2'-deoxyguanosine immunostaining for oxidative DNA damages. Infertile males had significantly increased levels of cytoplasmic ROS and chromatin condensation defects as well as a higher mean number of telomere signals per spermatozoon in comparison with controls. In addition, the mean number of sperm telomere signals were positively correlated with the percentage of spermatozoa with chromatin condensation defect. In infertile males with conventional semen parameter alterations, oxidative stress is associated with telomere interaction impairment and chromatin condensation defects.},
}
@article {pmid33921254,
year = {2021},
author = {Gentiluomo, M and Luddi, A and Cingolani, A and Fornili, M and Governini, L and Lucenteforte, E and Baglietto, L and Piomboni, P and Campa, D},
title = {Telomere Length and Male Fertility.},
journal = {International journal of molecular sciences},
volume = {22},
number = {8},
pages = {},
pmid = {33921254},
issn = {1422-0067},
support = {Internal funds//Universit&#xe0; degli Studi di Siena/ ; Internal funds//Universit&#xe0; di Pisa/ ; },
mesh = {Acid Anhydride Hydrolases/*genetics ; Acrosome/metabolism/pathology ; Adult ; Female ; Genetic Association Studies ; Humans ; Infertility, Male/*genetics/pathology ; Intracellular Signaling Peptides and Proteins/*genetics ; Leukocytes/metabolism/pathology ; Male ; Nerve Tissue Proteins/*genetics ; Polymorphism, Single Nucleotide/genetics ; Protein Serine-Threonine Kinases/*genetics ; Ribonucleoproteins/*genetics ; Spermatogenesis/genetics ; Spermatozoa/metabolism/pathology ; Telomere/*genetics ; Telomere Homeostasis/genetics ; },
abstract = {Over the past decade, telomeres have attracted increasing attention due to the role they play in human fertility. However, conflicting results have been reported on the possible association between sperm telomere length (STL) and leukocyte telomere length (LTL) and the quality of the sperm parameters. The aim of this study was to run a comprehensive study to investigate the role of STL and LTL in male spermatogenesis and infertility. Moreover, the association between the sperm parameters and 11 candidate single nucleotide polymorphisms (SNPs), identified in the literature for their association with telomere length (TL), was investigated. We observed no associations between sperm parameters and STL nor LTL. For the individual SNPs, we observed five statistically significant associations with sperm parameters: considering a p < 0.05. Namely, ACYP2-rs11125529 and decreased sperm motility (p = 0.03); PXK-rs6772228 with a lower sperm count (p = 0.02); NAF1-rs7675998 with increased probability of having abnormal acrosomes (p = 0.03) and abnormal flagellum (p = 0.04); ZNF208-rs8105767 and reduction of sperms with normal heads (p = 0.009). This study suggests a moderate involvement of telomere length in male fertility; however, in our analyses four SNPs were weakly associated with sperm variables, suggesting the SNPs to be pleiotropic and involved in other regulatory mechanisms independent of telomere homeostasis, but involved in the spermatogenic process.},
}
@article {pmid33918710,
year = {2021},
author = {Imran, SAM and Yazid, MD and Idrus, RBH and Maarof, M and Nordin, A and Razali, RA and Lokanathan, Y},
title = {Is There an Interconnection between Epithelial-Mesenchymal Transition (EMT) and Telomere Shortening in Aging?.},
journal = {International journal of molecular sciences},
volume = {22},
number = {8},
pages = {},
pmid = {33918710},
issn = {1422-0067},
support = {GP-2019-K005900, GP-2020-K005900, FF-2020-386/1, FPR-1//Universiti Kebangsaan Malaysia/ ; },
mesh = {Aging/*genetics ; Animals ; Biomarkers ; Disease Susceptibility ; Epithelial-Mesenchymal Transition/*genetics ; Extracellular Matrix ; Gene Expression Regulation ; Humans ; Signal Transduction ; Telomere/genetics/metabolism ; *Telomere Shortening ; },
abstract = {Epithelial-Mesenchymal Transition (EMT) was first discovered during the transition of cells from the primitive streak during embryogenesis in chicks. It was later discovered that EMT holds greater potential in areas other than the early development of cells and tissues since it also plays a vital role in wound healing and cancer development. EMT can be classified into three types based on physiological functions. EMT type 3, which involves neoplastic development and metastasis, has been the most thoroughly explored. As EMT is often found in cancer stem cells, most research has focused on its association with other factors involving cancer progression, including telomeres. However, as telomeres are also mainly involved in aging, any possible interaction between the two would be worth noting, especially as telomere dysfunction also contributes to cancer and other age-related diseases. Ascertaining the balance between degeneration and cancer development is crucial in cell biology, in which telomeres function as a key regulator between the two extremes. The essential roles that EMT and telomere protection have in aging reveal a potential mutual interaction that has not yet been explored, and which could be used in disease therapy. In this review, the known functions of EMT and telomeres in aging are discussed and their potential interaction in age-related diseases is highlighted.},
}
@article {pmid33915984,
year = {2021},
author = {Liu, J and Hong, X and Wang, L and Liang, CY and Liu, JP},
title = {Sir4 Deficiency Reverses Cell Senescence by Sub-Telomere Recombination.},
journal = {Cells},
volume = {10},
number = {4},
pages = {},
pmid = {33915984},
issn = {2073-4409},
support = {31501110//National Natural Science Foundation of China/ ; 81530039//National Natural Science Foundation of China/ ; 2018YFC2000100//National Key Research and Development Program of China/ ; 2018QDL010//Start-up Research Program of Hangzhou Normal University/ ; 2014M551470//China Postdoctoral Science Foundation/ ; 2014KIP305//Postdoctoral Research Program of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/ ; },
mesh = {*Cellular Senescence ; Gene Deletion ; Models, Biological ; Recombination, Genetic/*genetics ; Saccharomyces cerevisiae/*cytology/*metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/deficiency/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Telomere shortening results in cellular senescence and the regulatory mechanisms remain unclear. Here, we report that the sub-telomere regions facilitate telomere lengthening by homologous recombination, thereby attenuating senescence in yeast Saccharomyces cerevisiae. The telomere protein complex Sir3/4 represses, whereas Rif1 promotes, the sub-telomere Y' element recombination. Genetic disruption of SIR4 increases Y' element abundance and rescues telomere-shortening-induced senescence in a Rad51-dependent manner, indicating a sub-telomere regulatory switch in regulating organismal senescence by DNA recombination. Inhibition of the sub-telomere recombination requires Sir4 binding to perinuclear protein Mps3 for telomere perinuclear localization and transcriptional repression of the telomeric repeat-containing RNA TERRA. Furthermore, Sir4 repression of Y' element recombination is negatively regulated by Rif1 that mediates senescence-evasion induced by Sir4 deficiency. Thus, our results demonstrate a dual opposing control mechanism of sub-telomeric Y' element recombination by Sir3/4 and Rif1 in the regulation of telomere shortening and cell senescence.},
}
@article {pmid33915805,
year = {2021},
author = {Pericuesta, E and Gutiérrez-Arroyo, JL and Sánchez-Calabuig, MJ and Gutiérrez-Adán, A},
title = {Postnatal Catch-Up Growth Programs Telomere Dynamics and Glucose Intolerance in Low Birth Weight Mice.},
journal = {International journal of molecular sciences},
volume = {22},
number = {7},
pages = {},
pmid = {33915805},
issn = {1422-0067},
support = {RTI2018-093548-B100//Ministerio de Ciencia e Innovaci&#xf3;n/ ; },
mesh = {Animals ; *Body Weight ; Brain/metabolism ; Disease Models, Animal ; Female ; Fetal Growth Retardation/*metabolism/physiopathology ; Gene Expression Regulation, Developmental ; Glucose Intolerance/*etiology ; Intercellular Signaling Peptides and Proteins/*metabolism ; Liver/metabolism ; Male ; Mice ; Muscles/metabolism ; *Telomere Homeostasis ; },
abstract = {Low birth weight and rapid postnatal weight gain are independent predictors of obesity and diabetes in adult life, yet the molecular events involved in this process remain unknown. In inbred and outbred mice, this study examines natural intrauterine growth restriction (IUGR) in relation to body weight, telomere length (TL), glucose tolerance, and growth factor gene (Igf1, Igf2, Insr, Igf1r, and Igf2r) mRNA expression levels in the brain, liver, and muscle at 2- and 10 days of age and then at 3- and 9 months of age. At birth, ~15% of the animals showed IUGR, but by 3 and 9 months, half of these animals had regained the same weight as controls without IUGR (recuperated group). At 10 days, there was no difference in TL between animals undergoing IUGR and controls. However, by 3 and 9 months of age, the recuperated animals had shorter TL than the control and IUGR-non recuperated animals and also showed glucose intolerance. Further, compared to controls, Igf1 and Igf2 growth factor mRNA expression was lower in Day 2-IUGR mice, while Igf2r and Insr mRNA expression was higher in D10-IUGR animals. Moreover, at 3 months of age, only in the recuperated group were brain and liver Igf1, Igf2, Insr, and Igf2r expression levels higher than in the control and IUGR-non-recuperated groups. These data indicate that catch-up growth but not IUGR per se affects TL and glucose tolerance, and suggest a role in this latter process of insulin/insulin-like growth signaling pathway gene expression during early development.},
}
@article {pmid33900288,
year = {2021},
author = {Zhao, R and Chenoweth, DM and Zhang, H},
title = {Chemical Dimerization-Induced Protein Condensates on Telomeres.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {170},
pages = {},
pmid = {33900288},
issn = {1940-087X},
support = {K22 CA237632/CA/NCI NIH HHS/United States ; },
mesh = {Escherichia coli/*enzymology ; Escherichia coli Proteins/chemistry/*metabolism ; Humans ; Ligands ; Protein Binding ; *Protein Multimerization ; Telomere/*metabolism ; Tetrahydrofolate Dehydrogenase/chemistry/*metabolism ; Trimethoprim/chemistry/*metabolism ; },
abstract = {Chromatin-associated condensates are implicated in many nuclear processes, but the underlying mechanisms remain elusive. This protocol describes a chemically-induced protein dimerization system to create condensates on telomeres. The chemical dimerizer consists of two linked ligands that can each bind to a protein: Halo ligand to Halo-enzyme and trimethoprim (TMP) to E. coli dihydrofolate reductase (eDHFR), respectively. Fusion of Halo enzyme to a telomere protein anchors dimerizers to telomeres through covalent Halo ligand-enzyme binding. Binding of TMP to eDHFR recruits eDHFR-fused phase separating proteins to telomeres and induces condensate formation. Because TMP-eDHFR interaction is non-covalent, condensation can be reversed by using excess free TMP to compete with the dimerizer for eDHFR binding. An example of inducing promyelocytic leukemia (PML) nuclear body formation on telomeres and determining condensate growth, dissolution, localization and composition is shown. This method can be easily adapted to induce condensates at other genomic locations by fusing Halo to a protein that directly binds to the local chromatin or to dCas9 that is targeted to the genomic locus with a guide RNA. By offering the temporal resolution required for single cell live imaging while maintaining phase separation in a population of cells for biochemical assays, this method is suitable for probing both the formation and function of chromatin-associated condensates.},
}
@article {pmid33899660,
year = {2021},
author = {Wils, RS and Jacobsen, NR and Di Ianni, E and Roursgaard, M and Møller, P},
title = {Reactive oxygen species production, genotoxicity and telomere length in FE1-Muta™Mouse lung epithelial cells exposed to carbon nanotubes.},
journal = {Nanotoxicology},
volume = {15},
number = {5},
pages = {661-672},
doi = {10.1080/17435390.2021.1910359},
pmid = {33899660},
issn = {1743-5404},
mesh = {*DNA Damage ; Epithelial Cells ; Humans ; Lung/drug effects ; *Nanotubes, Carbon/toxicity ; Reactive Oxygen Species ; *Telomere ; },
abstract = {Carbon nanotubes (CNTs) are fiber-like nanomaterials, which are used in various applications with possible exposure to humans. The genotoxicity and carcinogenic potential of CNTs remain to be fully understood. This study assessed the genotoxicity of three different multi-walled carbon nanotubes (MWCNTs) (MWCNT-7, NM-401 and NM-403) and one single-walled carbon nanotube (SWCNT) (NM-411) in FE1-Muta™Mouse lung epithelial (MML) cells using the alkaline comet assay. With the 2',7'-dichlorodihydrofluorescein diacetate fluorescent probe, we assessed the effect of CNT-exposure on the intracellular production of reactive oxygen species (ROS). We measured the effect of a 10-week CNT exposure on telomere length using quantitative PCR. Two of the included MWCNTs (NM-401 and MWCNT-7) and the SWCNT (NM-411) caused a significant increase in the level of DNA damage at concentrations up to 40 µg/ml (all concentrations pooled, p < 0.05), but no concentration-response relationships were found. All of the CNTs caused an increase in intracellular ROS production compared to unexposed cells (ptrend < 0.05). Results from the long-term exposure showed longer telomere length in cells exposed to MWCNTs compared to unexposed cells (p < 0.01). In conclusion, our results indicated that the included CNTs cause ROS production and DNA strand breaks in FE1-MML cells. Moreover, the MWCNTs, but not the SWCNT, had an impact on telomere length in a long-term exposure scenario.},
}
@article {pmid33898197,
year = {2021},
author = {Wang, H and Gong, P and Chen, T and Gao, S and Wu, Z and Wang, X and Li, J and Marjani, SL and Costa, J and Weissman, SM and Qi, F and Pan, X and Liu, L},
title = {Colorectal Cancer Stem Cell States Uncovered by Simultaneous Single-Cell Analysis of Transcriptome and Telomeres.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {8},
number = {8},
pages = {2004320},
pmid = {33898197},
issn = {2198-3844},
mesh = {Cell Line, Tumor ; Colorectal Neoplasms/*genetics/pathology ; Humans ; Neoplastic Stem Cells/*pathology ; Single-Cell Analysis/*methods ; Telomere/*genetics/pathology ; Transcriptome/*genetics ; },
abstract = {Cancer stem cells (CSCs) presumably contribute to tumor progression and drug resistance, yet their definitive features have remained elusive. Here, simultaneous measurement of telomere length and transcriptome in the same cells enables systematic assessment of CSCs in primary colorectal cancer (CRC). The in-depth transcriptome profiled by SMART-seq2 is independently validated by high-throughput scRNA-seq using 10 × Genomics. It is found that rare CSCs exist in dormant state and display plasticity toward cancer epithelial cells (EPCs) that essentially are presumptive tumor-initiating cells (TICs), while both retaining the prominent signaling pathways including WNT, TGF-β, and HIPPO/YAP. Moreover, CSCs exhibit chromosome copy number variation (CNV) pattern resembling cancer EPCs but distinct from normal stem cells, suggesting the phylogenetic relationship between CSCs and cancer EPCs. Notably, CSCs maintain shorter telomeres and possess minimal telomerase activity consistent with their nonproliferative nature, unlike cancer EPCs. Additionally, the specific signature of CSCs particularly NOTUM, SMOC2, BAMBI, PHLDA1, and TNFRSF19 correlates with the prognosis of CRC. These findings characterize the heterogeneity of CSCs and their linkage to cancer EPCs/TICs, some of which are conventionally regarded as CSCs.},
}
@article {pmid33897985,
year = {2021},
author = {Wang, G and Wang, S and Chai, X and Zhang, J and Yang, W and Jiang, C and Chen, K and Miao, W and Xiong, J},
title = {A strategy for complete telomere-to-telomere assembly of ciliate macronuclear genome using ultra-high coverage Nanopore data.},
journal = {Computational and structural biotechnology journal},
volume = {19},
number = {},
pages = {1928-1932},
pmid = {33897985},
issn = {2001-0370},
abstract = {Ciliates contain two kinds of nuclei: the germline micronucleus (MIC) and the somatic macronucleus (MAC) in a single cell. The MAC usually have fragmented chromosomes. These fragmented chromosomes, capped with telomeres at both ends, could be gene size to several megabases in length among different ciliate species. So far, no telomere-to-telomere assembly of entire MAC genome in ciliate species has been finished. Development of the third generation sequencing technologies allows to generate sequencing reads up to megabases in length that could possibly span an entire MAC chromosome. Taking advantage of the ultra-long Nanopore reads, we established a simple strategy for the complete assembly of ciliate MAC genomes. Using this strategy, we assembled the complete MAC genomes of two ciliate species Tetrahymena thermophila and Tetrahymena shanghaiensis, composed of 181 and 214 chromosomes telomere-to-telomere respectively. The established strategy as well as the high-quality genome data will provide a useful approach for ciliate genome assembly, and a valuable community resource for further biological, evolutionary and population genomic studies.},
}
@article {pmid33897770,
year = {2021},
author = {Nersisyan, L and Simonyan, A and Binder, H and Arakelyan, A},
title = {Telomere Maintenance Pathway Activity Analysis Enables Tissue- and Gene-Level Inferences.},
journal = {Frontiers in genetics},
volume = {12},
number = {},
pages = {662464},
pmid = {33897770},
issn = {1664-8021},
abstract = {Telomere maintenance is one of the mechanisms ensuring indefinite divisions of cancer and stem cells. Good understanding of telomere maintenance mechanisms (TMM) is important for studying cancers and designing therapies. However, molecular factors triggering selective activation of either the telomerase dependent (TEL) or the alternative lengthening of telomeres (ALT) pathway are poorly understood. In addition, more accurate and easy-to-use methodologies are required for TMM phenotyping. In this study, we have performed literature based reconstruction of signaling pathways for the ALT and TEL TMMs. Gene expression data were used for computational assessment of TMM pathway activities and compared with experimental assays for TEL and ALT. Explicit consideration of pathway topology makes bioinformatics analysis more informative compared to computational methods based on simple summary measures of gene expression. Application to healthy human tissues showed high ALT and TEL pathway activities in testis, and identified genes and pathways that may trigger TMM activation. Our approach offers a novel option for systematic investigation of TMM activation patterns across cancers and healthy tissues for dissecting pathway-based molecular markers with diagnostic impact.},
}
@article {pmid33896973,
year = {2020},
author = {Abou-Elela, DH and El-Edel, RH and Shalaby, AS and Fouaad, MA and Sonbol, AA},
title = {Telomere length and 8-hydroxy-2-deoxyguanosine as markers for early prediction of Alzheimer disease.},
journal = {Indian journal of psychiatry},
volume = {62},
number = {6},
pages = {678-683},
pmid = {33896973},
issn = {0019-5545},
abstract = {BACKGROUND: Becoming shorter by each cell division, telomere length (TL) is regarded as a marker of cellular aging. Relative TL (T/S) depends on the quantitation of telomere hexamer repeat copy number normalized to autosomal single-copy gene copy number. TL is influenced by several factors, including oxidative stress (OS) and inflammation. This study aimed to investigate the possible role of TL and OS as markers for Alzheimer's disease (AD).<br><br>MATERIALS AND METHODS: One hundred and eighty participants were categorized into three groups. Group 1: Included 60 patients with AD. Group II: included 60 age-matched nondemented subjects. Group III (pregeriatric group): included 60 healthy controls with their ages ranging between 30 and 60 years. TL was determined by the quantitative Real time-PCR method, plasma levels of 8-OHdG by enzyme-linked immunosorbent assay, and total antioxidant capacity (TAC) by colorimetery.<br><br>RESULTS: In comparison to the other two groups, patients with AD showed shortened TL, increased plasma 8-OHdG concentration, and decreased TAC. The sensitivity of T/S ratio to predict AD was 86.67%, whereas the specificity was 96.67%. The sensitivity of 8-OHdG to predict AD was 96.67%, whereas the specificity was 86.67%.<br><br>CONCLUSION: AD is associated with shortened TL and increased OS as manifested by decreased TAC and increased serum 8-OHdG. T/S and 8-OHdG could be used as early predictors for AD.},
}
@article {pmid33882640,
year = {2021},
author = {Miwata, S and Narita, A and Okuno, Y and Suzuki, K and Hamada, M and Yoshida, T and Imaya, M and Yamamori, A and Wakamatsu, M and Narita, K and Kitazawa, H and Ichikawa, D and Taniguchi, R and Kawashima, N and Nishikawa, E and Nishio, N and Kojima, S and Muramatsu, H and Takahashi, Y},
title = {Clinical diagnostic value of telomere length measurement in inherited bone marrow failure syndromes.},
journal = {Haematologica},
volume = {106},
number = {9},
pages = {2511-2515},
pmid = {33882640},
issn = {1592-8721},
mesh = {*Anemia, Aplastic/diagnosis/genetics ; *Bone Marrow Diseases/diagnosis/genetics ; Bone Marrow Failure Disorders ; Congenital Bone Marrow Failure Syndromes ; Humans ; Telomere/genetics ; },
}
@article {pmid33879171,
year = {2021},
author = {Kan, G and Wang, Z and Sheng, C and Yao, C and Mao, Y and Chen, S},
title = {Inhibition of DKC1 induces telomere-related senescence and apoptosis in lung adenocarcinoma.},
journal = {Journal of translational medicine},
volume = {19},
number = {1},
pages = {161},
pmid = {33879171},
issn = {1479-5876},
mesh = {*Adenocarcinoma of Lung/genetics ; Apoptosis/genetics ; Cell Cycle Proteins ; Gene Expression Regulation, Neoplastic ; Humans ; *Lung Neoplasms/genetics ; Nuclear Proteins ; Telomere/genetics ; },
abstract = {BACKGROUND: Lung cancer is one of the most widely spread cancers in the world and half of the non-small cell lung cancers are lung adenocarcinoma (LUAD). Although there were several drugs been approved for LUAD therapy, a large portion of LUAD still cannot be effectively treated due to lack of available therapeutic targets. Here, we investigated the oncogenic roles of DKC1 in LUAD and its potential mechanism and explored the possibility of targeting DKC1 for LUAD therapy.<br><br>METHODS: The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas Program (TCGA) databases were used to examine the DKC1 transcript levels. Gene expression with clinical information from tissue microarray of LUAD were analyzed for associations between DKC1 expression and LUAD prognosis. In addition, loss- and gain-of-function assays were used for oncogenic function of DKC1 both in vitro and in vivo.<br><br>RESULTS: DKC1 is overexpressed in LUAD compared with adjacent normal tissues. High expression of DKC1 predicts the poor overall survival. DKC1 knockdown in LUAD cell lines induced G1 phase arrest and inhibited cell proliferation. Ectopic expression of DKC1 could rescue the growth of LUAD cell lines. In addition, the abundance of DKC1 is positively correlated with telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT) levels in LUAD. DKC1 downregulation resulted in decreased TERC expression, reduced telomerase activity and shorten telomere, and thus eventually led to cell senescence and apoptosis.<br><br>CONCLUSIONS: Our results show that high DKC1 expression indicates poor prognosis of LUAD and DKC1 downregulation could induce telomere-related cell senescence and apoptosis. This study suggests that DKC1 could serve as a candidate diagnostic biomarker and therapeutic target for LUAD.},
}
@article {pmid33876756,
year = {2021},
author = {Froy, H and Underwood, SL and Dorrens, J and Seeker, LA and Watt, K and Wilbourn, RV and Pilkington, JG and Harrington, L and Pemberton, JM and Nussey, DH},
title = {Heritable variation in telomere length predicts mortality in Soay sheep.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {118},
number = {15},
pages = {},
pmid = {33876756},
issn = {1091-6490},
support = {BB/L020769/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; *Genetic Variation ; *Longevity ; Sheep/*genetics/growth &amp; development/physiology ; *Telomere Homeostasis ; },
abstract = {Telomere length (TL) is considered an important biomarker of whole-organism health and aging. Across humans and other vertebrates, short telomeres are associated with increased subsequent mortality risk, but the processes responsible for this correlation remain uncertain. A key unanswered question is whether TL-mortality associations arise due to positive effects of genes or early-life environment on both an individual's average lifetime TL and their longevity, or due to more immediate effects of environmental stressors on within-individual TL loss and increased mortality risk. Addressing this question requires longitudinal TL and life history data across the entire lifetimes of many individuals, which are difficult to obtain for long-lived species like humans. Using longitudinal data and samples collected over nearly two decades, as part of a long-term study of wild Soay sheep, we dissected an observed positive association between TL and subsequent survival using multivariate quantitative genetic models. We found no evidence that telomere attrition was associated with increased mortality risk, suggesting that TL is not an important marker of biological aging or exposure to environmental stress in our study system. Instead, we find that among-individual differences in average TL are associated with increased lifespan. Our analyses suggest that this correlation between an individual's average TL and lifespan has a genetic basis. This demonstrates that TL has the potential to evolve under natural conditions, and suggests an important role of genetics underlying the widespread observation that short telomeres predict mortality.},
}
@article {pmid33869233,
year = {2021},
author = {Bonnell, E and Pasquier, E and Wellinger, RJ},
title = {Telomere Replication: Solving Multiple End Replication Problems.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {668171},
pmid = {33869233},
issn = {2296-634X},
abstract = {Eukaryotic genomes are highly complex and divided into linear chromosomes that require end protection from unwarranted fusions, recombination, and degradation in order to maintain genomic stability. This is accomplished through the conserved specialized nucleoprotein structure of telomeres. Due to the repetitive nature of telomeric DNA, and the unusual terminal structure, namely a protruding single stranded 3' DNA end, completing telomeric DNA replication in a timely and efficient manner is a challenge. For example, the end replication problem causes a progressive shortening of telomeric DNA at each round of DNA replication, thus telomeres eventually lose their protective capacity. This phenomenon is counteracted by the recruitment and the activation at telomeres of the specialized reverse transcriptase telomerase. Despite the importance of telomerase in providing a mechanism for complete replication of telomeric ends, the majority of telomere replication is in fact carried out by the conventional DNA replication machinery. There is significant evidence demonstrating that progression of replication forks is hampered at chromosomal ends due to telomeric sequences prone to form secondary structures, tightly DNA-bound proteins, and the heterochromatic nature of telomeres. The telomeric loop (t-loop) formed by invasion of the 3'-end into telomeric duplex sequences may also impede the passage of replication fork. Replication fork stalling can lead to fork collapse and DNA breaks, a major cause of genomic instability triggered notably by unwanted repair events. Moreover, at chromosomal ends, unreplicated DNA distal to a stalled fork cannot be rescued by a fork coming from the opposite direction. This highlights the importance of the multiple mechanisms involved in overcoming fork progression obstacles at telomeres. Consequently, numerous factors participate in efficient telomeric DNA duplication by preventing replication fork stalling or promoting the restart of a stalled replication fork at telomeres. In this review, we will discuss difficulties associated with the passage of the replication fork through telomeres in both fission and budding yeasts as well as mammals, highlighting conserved mechanisms implicated in maintaining telomere integrity during replication, thus preserving a stable genome.},
}
@article {pmid33867793,
year = {2021},
author = {Afshar, H and Abedini, A and Nadji, SA and Sadr, M and Kiani, A and Alizadeh, N and Javadi, A},
title = {Telomere length assessment in blood leukocytes of patients with sarcoidosis.},
journal = {Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG},
volume = {38},
number = {1},
pages = {e2021009},
pmid = {33867793},
issn = {2532-179X},
abstract = {BACKGROUND: Accelerated aging and telomere shortening have been studied in many chronic diseases such as interstitial pulmonary fibrosis and chronic obstructive pulmonary disease. Different studies have shown that patients with these diseases have shorter telomere lengths than controls; this can be a marker of the progression and outcome of the disease. So far, a few studies have been evaluated the telomere length in sarcoidosis. In this study we determine the telomere length in patients with sarcoidosis and compare it with control subjects.<br><br>OBJECTIVE: Our aim is to compare telomere length in patients with sarcoidosis and normal population. Methods: We select 58 patients with sarcoidosis who were visited in the sarcoidosis clinic of Masih Daneshvari Hospital. 58 sex and age-matched (with&#xb1;2 years) healthy control subjects were selected. Telomere length was measured by quantitative real time PCR as described by Cawthon on peripheral blood sample. The telomere repeat copy number (T) to single-gene copy number(S) ratio was calculated using the comparative Ct method. Results: The mean and standard deviation of telomere length in the patient and control group was 0.65 &#xb1; 0.05 and 0.72 &#xb1; 0.07 respectively. There was a statistically significant difference between the two groups. (P = 0.031). Conclusion: Sarcoidosis is an inflammatory disease that can involve many organs. Like other chronic diseases, aging phenomenon occurs in that; which led to decrease cellular and tissue telomere length. This article demonstrates shorter telomere length in Iranian sarcoidosis patients compared to normal population.},
}
@article {pmid33867038,
year = {2021},
author = {Yu, P and Yang, T and Zhang, D and Xu, L and Cheng, X and Ding, S and Cheng, W},
title = {An all-in-one telomerase assay based on CRISPR-Cas12a trans-cleavage while telomere synthesis.},
journal = {Analytica chimica acta},
volume = {1159},
number = {},
pages = {338404},
doi = {10.1016/j.aca.2021.338404},
pmid = {33867038},
issn = {1873-4324},
mesh = {CRISPR-Cas Systems ; *Clustered Regularly Interspaced Short Palindromic Repeats ; HeLa Cells ; Humans ; *Telomerase/genetics ; Telomere/genetics ; },
abstract = {As one of the crucial factors associated with human life span and cancer progression, telomerase is regarded as an emerging biomarker for cancer diagnosis. Therefore, a facile, rapid and sensitive approach for telomerase activity detection with point-of-care (POC) diagnosis potential is in great demands. Herein, an all-in-one telomerase activity detection assay was established based on the telomere synthesis activated CRISPR-Cas12a system. A telomerase extension reaction generated telomere repeats sequences (TTAGGG)n, which was recognized by a customized CRISPR-guided RNA (crRNA) simultaneously, and finally activated a typical trans-cleavage based CRISPR-Cas12a detection assay. With the inherent sensitivity of CRISPR-Cas12a, this approach achieved a great linear regression ranging from 100 to 2000 HeLa cells and a limitation of detection down to 26 HeLa cells. Moreover, by using the proposed method, telomerase can be detected in one pot under isothermal condition (37 °C) by a simple and fast workflow (one step within 1 h). Due to its excellent performance, this all-in-one method shows great potential in POC detection of the telomerase activity.},
}
@article {pmid33864121,
year = {2021},
author = {Quque, M and Paquet, M and Zahn, S and Théron, F and Faivre, B and Sueur, C and Criscuolo, F and Doutrelant, C and Covas, R},
title = {Contrasting associations between nestling telomere length and pre and postnatal helpers' presence in a cooperatively breeding bird.},
journal = {Oecologia},
volume = {196},
number = {1},
pages = {37-51},
pmid = {33864121},
issn = {1432-1939},
support = {318994//FP7 People: Marie-Curie Actions/ ; 0007//FCT/ ; ANR-15-CE32-0012-02//ANR/ ; },
mesh = {Animals ; Longevity ; Reproduction ; *Sparrows ; *Telomere ; },
abstract = {Studies on cooperative breeders have addressed the effects of non-breeding 'helpers' on reproduction and parental care, but the consequences for offspring physiology and long-term survival are less understood. Helpers are expected to benefit offspring, but their presence can also lead to decreased pre- or post-natal parental reproductive effort. To examine whether prenatal and postnatal helpers influence offspring condition, we conducted a whole-clutch cross-fostering experiment in sociable weavers (Philetairus socius) that altered the nestlings' social environment (presence/absence of helpers). We tested whether relative telomere length (rTL), an indicator of somatic maintenance, was influenced by prenatal and/or postnatal presence of helpers 9 and 17 days after hatching, and whether rTL predicted long-term survival. Nine days after hatching, we found an overall positive effect of postnatal helpers on rTL: for nestlings with prenatal helpers, a reduction in the number of helpers post-hatch was associated with shorter telomeres, while nestlings swapped from nests without helpers to nests with helpers had a larger rTL. However, when prenatal helpers were present, an increased number of helpers after hatching led to shorter telomeres. Nine-day old chicks with longer rTL tended to be more likely to survive over the 5 years following hatching. However, close to fledging, there was no detectable effect of the experiment on rTL and no link between rTL and survival. This experimental study of a wild cooperative breeder, therefore, presents partial support for the importance of the presence of helpers for offspring rTL and the link between early-life telomere length and long-term survival.},
}
@article {pmid33863507,
year = {2021},
author = {Corfdir, C and Pignon, B and Szöke, A and Schürhoff, F},
title = {[Accelerated telomere erosion in schizophrenia: A literature review].},
journal = {L'Encephale},
volume = {47},
number = {4},
pages = {369-375},
doi = {10.1016/j.encep.2020.12.001},
pmid = {33863507},
issn = {0013-7006},
mesh = {Humans ; *Psychotic Disorders ; Reproducibility of Results ; *Schizophrenia/genetics ; Telomere/genetics ; Telomere Shortening ; },
abstract = {Schizophrenia is associated with a weighted average of 14.5 years of potential life lost according to a recent meta-analysis. This is partly explained by high rates of suicide and a high prevalence of non-psychiatric comorbidity (cardiovascular diseases, diabetes, cancers…). However, all these causes could not fully explain the loss of life expectancy in people suffering from schizophrenia. Life expectancy has been strongly correlated with telomere length (TL). Telomeres are noncoding structures consisting of DNA TTAGGG tandem repeats and associated proteins located at the end of the chromosomes. Their role is to help preserve genome stability by protecting chromosomal ends from the loss of genetic material. The progressive loss of telomeric material during cell divisions has led researchers to consider telomeres as molecular clocks that measure the number of divisions left until cellular death. The fact that both shorter telomeres and schizophrenia have been associated with a decrease in life expectancy has fueled the interest in the study of TL in schizophrenia. In this article, after a detailed review of the literature on the relationships between telomere length and schizophrenia, we discuss the different pathophysiological mechanisms which might explain this association. Based on this analysis, in the last part of the article we discuss potential research, therapeutic and prevention prospects. To date, the majority of the studies and meta-analyses found a decrease in TL in subjects with schizophrenia compared to control subjects. Conversely, all the studies exploring the TL in subjects suffering from first episode psychosis (FEP) have shown no significant difference from TL in control subjects. This suggests that excessive shortening of telomeres occurs during the course of the disease, thus it seems more probable that schizophrenia (or processes associated with it) affects TL rather than telomere erosion being a cause of the disorder. Several pathophysiological, non-mutually exclusive mechanisms have been proposed to explain the observed data. A first hypothesis to explain the acceleration of the physiological process of telomere erosion in schizophrenia is the activation of inflammation processes and oxidative stress as a consequence of schizophrenia per se. However, it seems more probable that reduced TL may be a result of cumulative exposure to chronic stress related to schizophrenia. Indeed, in healthy individuals a growing body of evidence has linked chronic stress to accelerated shortening of TL. This might explain why telomere erosion is too small to be detected in FEP patients who are younger and have a shorter duration of illness than subjects with schizophrenia. Based on these both explanations, telomere alterations may be considered as a biomarker of illness progression and might be useful for illness staging. Identifying processes associated with TL reduction might improve our understanding of the increased mortality and morbidity in schizophrenia, improve reliability of diagnosis, and hopefully suggest means for prevention and/or treatment. Treatments that prevent exposure and/or vulnerability to stressful life events that ameliorate schizophrenia may also prevent or decelerate telomere erosion. In this perspective, engaging subjects suffering from schizophrenia in a healthy diet and regular activity could be both promising strategies to protect telomere maintenance and improve health span at old age. In addition, the inflammatory process and oxidative stress involved in the physiopathology in at least a subgroup of subjects with schizophrenia could also be responsible for telomere erosion. Thus, an efficient anti-inflammatory therapeutic approach that targets these specific pathways could be of interest in this subgroup to limit telomere erosion. Mindfulness-based stress reduction (MBSR) therapies have been shown to reduce telomere erosion by increasing telomerase activity, although these psychological therapies should be used carefully in psychosis. Finally, advancing our understanding of the relationship between stress, inflammation and TL is of great interest for psychiatric research and for understanding stress effects in this population.},
}
@article {pmid33854038,
year = {2021},
author = {Giaccherini, M and Macauda, A and Orciuolo, E and Rymko, M and Gruenpeter, K and Dumontet, C and Raźny, M and Moreno, V and Buda, G and Beider, K and Varkonyi, J and Avet-Loiseau, H and Martinez-Lopez, J and Marques, H and Watek, M and Sarasquete, ME and Andersen, V and Karlin, L and Suska, A and Kruszewski, M and Abildgaard, N and Dudziński, M and Butrym, A and Nagler, A and Vangsted, AJ and Kadar, K and Waldemar, T and Jamroziak, K and Jacobsen, SEH and Ebbesen, LH and Taszner, M and Mazur, G and Lesueur, F and Pelosini, M and Garcia-Sanz, R and Jurczyszyn, A and Demangel, D and Reis, RM and Iskierka-Jażdżewska, E and Markiewicz, M and Gemignani, F and Subocz, E and Zawirska, D and Druzd-Sitek, A and Stępień, A and Alonso, MH and Sainz, J and Canzian, F and Campa, D},
title = {Genetically determined telomere length and multiple myeloma risk and outcome.},
journal = {Blood cancer journal},
volume = {11},
number = {4},
pages = {74},
pmid = {33854038},
issn = {2044-5385},
mesh = {Adult ; Aged ; Female ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Male ; Middle Aged ; Multiple Myeloma/diagnosis/*genetics ; Polymorphism, Single Nucleotide ; Prognosis ; Prospective Studies ; Retrospective Studies ; Telomere/genetics ; *Telomere Homeostasis ; },
abstract = {Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 × 10[-6] for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.},
}
@article {pmid33851958,
year = {2021},
author = {Vessoni, AT and Zhang, T and Quinet, A and Jeong, HC and Munroe, M and Wood, M and Tedone, E and Vindigni, A and Shay, JW and Greenberg, RA and Batista, LFZ},
title = {Telomere erosion in human pluripotent stem cells leads to ATR-mediated mitotic catastrophe.},
journal = {The Journal of cell biology},
volume = {220},
number = {6},
pages = {},
pmid = {33851958},
issn = {1540-8140},
support = {R01 CA174904/CA/NCI NIH HHS/United States ; R01 GM101149/GM/NIGMS NIH HHS/United States ; T32 HL007088/HL/NHLBI NIH HHS/United States ; R01 HL137793/HL/NHLBI NIH HHS/United States ; R01 CA237263/CA/NCI NIH HHS/United States ; },
mesh = {Aneuploidy ; Ataxia Telangiectasia Mutated Proteins/genetics/*metabolism ; *Cell Cycle ; Cell Cycle Proteins/genetics/*metabolism ; DNA Damage ; Humans ; *Mitosis ; Pluripotent Stem Cells/metabolism/*pathology ; Telomere/*physiology ; Tumor Suppressor Protein p53/genetics/*metabolism ; },
abstract = {It is well established that short telomeres activate an ATM-driven DNA damage response that leads to senescence in terminally differentiated cells. However, technical limitations have hampered our understanding of how telomere shortening is signaled in human stem cells. Here, we show that telomere attrition induces ssDNA accumulation (G-strand) at telomeres in human pluripotent stem cells (hPSCs), but not in their differentiated progeny. This led to a unique role for ATR in the response of hPSCs to telomere shortening that culminated in an extended S/G2 cell cycle phase and a longer period of mitosis, which was associated with aneuploidy and mitotic catastrophe. Loss of p53 increased resistance to death, at the expense of increased mitotic abnormalities in hPSCs. Taken together, our data reveal an unexpected dominant role of ATR in hPSCs, combined with unique cell cycle abnormalities and, ultimately, consequences distinct from those observed in their isogenic differentiated counterparts.},
}
@article {pmid33849943,
year = {2022},
author = {Hackeng, WM and Brosens, LAA and Kim, JY and O'Sullivan, R and Sung, YN and Liu, TC and Cao, D and Heayn, M and Brosnan-Cashman, J and An, S and Morsink, FHM and Heidsma, CM and Valk, GD and Vriens, MR and Nieveen van Dijkum, E and Offerhaus, GJA and Dreijerink, KMA and Zeh, H and Zureikat, AH and Hogg, M and Lee, K and Geller, D and Marsh, JW and Paniccia, A and Ongchin, M and Pingpank, JF and Bahary, N and Aijazi, M and Brand, R and Chennat, J and Das, R and Fasanella, KE and Khalid, A and McGrath, K and Sarkaria, S and Singh, H and Slivka, A and Nalesnik, M and Han, X and Nikiforova, MN and Lawlor, RT and Mafficini, A and Rusev, B and Corbo, V and Luchini, C and Bersani, S and Pea, A and Cingarlini, S and Landoni, L and Salvia, R and Milione, M and Milella, M and Scarpa, A and Hong, SM and Heaphy, CM and Singhi, AD},
title = {Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size.},
journal = {Gut},
volume = {71},
number = {5},
pages = {961-973},
pmid = {33849943},
issn = {1468-3288},
support = {P30 CA047904/CA/NCI NIH HHS/United States ; P30 DK120531/DK/NIDDK NIH HHS/United States ; R01 CA207209/CA/NCI NIH HHS/United States ; R37 CA263622/CA/NCI NIH HHS/United States ; },
mesh = {Co-Repressor Proteins/genetics ; Genes, Homeobox ; Homeodomain Proteins ; Humans ; *Intellectual Disability/genetics ; Molecular Chaperones/genetics ; Neoplasm Recurrence, Local/genetics ; *Neuroendocrine Tumors/genetics ; Nuclear Proteins/genetics ; *Pancreatic Neoplasms/pathology ; Telomere/genetics/pathology ; Transcription Factors/genetics ; X-linked Nuclear Protein/genetics ; *alpha-Thalassemia/genetics ; },
abstract = {OBJECTIVE: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown.<br><br>DESIGN: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS).<br><br>RESULTS: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001&#x2009;and p<0.001). Shorter 5-year RFS rates for &#x2264;2.0&#x2009;cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%).<br><br>CONCLUSIONS: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including &#x2264;2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.},
}
@article {pmid33847963,
year = {2021},
author = {Cicconi, A and Micheli, E and Raffa, GD and Cacchione, S},
title = {Atomic Force Microscopy Reveals that the Drosophila Telomere-Capping Protein Verrocchio Is a Single-Stranded DNA-Binding Protein.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2281},
number = {},
pages = {241-263},
pmid = {33847963},
issn = {1940-6029},
mesh = {Animals ; DNA, Single-Stranded/chemistry/*metabolism ; Drosophila Proteins/*metabolism ; Drosophila melanogaster/genetics/*metabolism ; Microscopy, Atomic Force ; Protein Binding ; Single Molecule Imaging ; Telomere/genetics/metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Atomic force microscopy (AFM) is a scanning probe technique that allows visualization of biological samples with a nanometric resolution. Determination of the physical properties of biological molecules at a single-molecule level is achieved through topographic analysis of the sample adsorbed on a flat and smooth surface. AFM has been widely used for the structural analysis of nucleic acid-protein interactions, providing insights on binding specificity and stoichiometry of proteins forming complexes with DNA substrates. Analysis of single-stranded DNA-binding proteins by AFM requires specific single-stranded/double-stranded hybrid DNA molecules as substrates for protein binding. In this chapter we describe the protocol for AFM characterization of binding properties of Drosophila telomeric protein Ver using DNA constructs that mimic the structure of chromosome ends. We provide details on the methodology used, including the procedures for the generation of DNA substrates, the preparation of samples for AFM visualization, and the data analysis of AFM images. The presented procedure can be adapted for the structural studies of any single-stranded DNA-binding protein.},
}
@article {pmid33847961,
year = {2021},
author = {de Oliveira Vitarelli, M and Elias, MC},
title = {Quantifying the Affinity of Trypanosoma cruzi RPA-1 to the Single-Stranded DNA Overhang of the Telomere Using Surface Plasmon Resonance.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2281},
number = {},
pages = {217-228},
pmid = {33847961},
issn = {1940-6029},
mesh = {Biosensing Techniques/instrumentation ; DNA, Protozoan/metabolism ; DNA, Single-Stranded/*metabolism ; Kinetics ; Protein Binding ; Protozoan Proteins/metabolism ; Replication Protein A/*metabolism ; Surface Plasmon Resonance ; Telomere/genetics ; Trypanosoma cruzi/genetics/*metabolism ; },
abstract = {Surface plasmon resonance (SPR) biosensors provide real-time binding affinity measurements between a pair of biomolecules, characterizing its interaction dynamics. An example of Trypanosoma cruzi's RPA-1 and a single-stranded DNA telomere sequence is presented with detailed guidelines and fundamentals for SPR technology.},
}
@article {pmid33836691,
year = {2021},
author = {Wei, B and Shao, Y and Liang, J and Tang, P and Mo, M and Liu, B and Huang, H and Tan, HJJ and Huang, D and Liu, S and Qiu, X},
title = {Maternal overweight but not paternal overweight before pregnancy is associated with shorter newborn telomere length: evidence from Guangxi Zhuang birth cohort in China.},
journal = {BMC pregnancy and childbirth},
volume = {21},
number = {1},
pages = {283},
pmid = {33836691},
issn = {1471-2393},
support = {81460517//Natural Science Foundation of China/ ; 81860587//Natural Science Foundation of China (CN)/ ; AB17195012//Guangxi Key Research Program/ ; },
mesh = {Adult ; Body Mass Index ; China/epidemiology ; Cohort Studies ; Fathers/statistics &amp; numerical data ; Female ; Fetal Blood ; Humans ; Infant, Newborn ; Male ; *Maternal Inheritance ; Mothers/statistics &amp; numerical data ; Overweight/diagnosis/*epidemiology/genetics ; Paternal Inheritance ; Pregnancy ; Risk Factors ; Telomere/*genetics ; Telomere Homeostasis/genetics ; Young Adult ; },
abstract = {BACKGROUND: Telomere length (TL) is variable at birth and is inversely associated with body mass index (BMI) in adulthood. A growing number of evidences suggested that a higher maternal pre-pregnancy BMI results in adverse offspring health outcomes, especially shorter newborn TL. However, a newborn's genetic endowment is equally derived from both parents, the association between parental pre-pregnancy BMI and newborn TL has been rarely discussed. We aimed to determine the association between parental pre-pregnancy BMI and newborn TL.<br><br>METHODS: A total of 1082 parent-newborn pairs were recruited from the Guangxi Zhuang Birth Cohort (GZBC). TL in cord blood was measured using quantitative real-time polymerase chain reaction (qPCR) and expressed as the ratio of telomere copy number to single-copy gene number (T/S). A series of linear regressions were performed to assess the associations between parental pre-pregnancy BMI and newborn TL.<br><br>RESULTS: Mothers who were overweight before pregnancy had significantly shorter cord blood telomere length in their newborns than those who were normal weight before pregnancy [percentage change: -&#x2009;7.96% (95% CI: -&#x2009;14.49 to -&#x2009;0.69%; P&#xa0;=&#x2009;0.032)]. Further analysis of the combined effects of parental weight status on newborn TL showed that TL was significantly shortened among newborns whose mothers were overweight and fathers were of healthy weight when compared with those whose mothers and fathers were both of normal weight [percentage change: -&#x2009;8.38% (95% CI: -&#x2009;15.47 to -&#x2009;0.92%; P&#xa0;=&#x2009;0.028)]. Subgroup analysis indicated these effects were more pronounced among male newborns and those whose paternal age&#x2009;<&#x2009;31&#x2009;years or maternal age&#xa0;&#x2265;&#x2009;28&#x2009;years at delivery.<br><br>CONCLUSIONS: Maternal pre-pregnancy overweight, but not paternal pre-pregnancy overweight is associated with shorter newborn TL. Weight control in reproductive women and effective healthy weight management before pregnancy may be of particular benefit for improving longevity and life quality of offspring.},
}
@article {pmid33833304,
year = {2021},
author = {Cerveira de Baumont, A and Hoffmann, MS and Bortoluzzi, A and Fries, GR and Lavandoski, P and Grun, LK and Guimarães, LSP and Guma, FTCR and Salum, GA and Barbé-Tuana, FM and Manfro, GG},
title = {Telomere length and epigenetic age acceleration in adolescents with anxiety disorders.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {7716},
pmid = {33833304},
issn = {2045-2322},
support = {KL2 TR003168/TR/NCATS NIH HHS/United States ; R01 MH120482/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Aging/genetics ; Anxiety Disorders/*genetics ; Case-Control Studies ; DNA Methylation ; *Epigenesis, Genetic ; Female ; Humans ; Male ; Real-Time Polymerase Chain Reaction ; *Telomere ; },
abstract = {Evidence on the relationship between genetics and mental health are flourishing. However, few studies are evaluating early biomarkers that might link genes, environment, and psychopathology. We aimed to study telomere length (TL) and epigenetic age acceleration (AA) in a cohort of adolescents with and without anxiety disorders (N = 234). We evaluated a representative subsample of participants at baseline and after 5 years (n = 76) and categorized them according to their anxiety disorder diagnosis at both time points: (1) control group (no anxiety disorder, n = 18), (2) variable group (anxiety disorder in one evaluation, n = 38), and (3) persistent group (anxiety disorder at both time points, n = 20). We assessed relative mean TL by real-time quantitative PCR and DNA methylation by Infinium HumanMethylation450 BeadChip. We calculated AA using the Horvath age estimation algorithm and analyzed differences among groups using generalized linear mixed models. The persistent group of anxiety disorder did not change TL over time (p = 0.495). The variable group had higher baseline TL (p = 0.003) but no accelerated TL erosion in comparison to the non-anxiety control group (p = 0.053). Furthermore, there were no differences in AA among groups over time. Our findings suggest that adolescents with chronic anxiety did not change telomere length over time, which could be related to a delay in neuronal development in this period of life.},
}
@article {pmid33831300,
year = {2021},
author = {Lin, YY and Li, MH and Chang, YC and Fu, PY and Ohniwa, RL and Li, HW and Lin, JJ},
title = {Dynamic DNA Shortening by Telomere-Binding Protein Cdc13.},
journal = {Journal of the American Chemical Society},
volume = {143},
number = {15},
pages = {5815-5825},
doi = {10.1021/jacs.1c00820},
pmid = {33831300},
issn = {1520-5126},
mesh = {DNA Helicases/chemistry/genetics/metabolism ; DNA, Single-Stranded/chemistry/*metabolism ; Dimerization ; Microscopy, Atomic Force ; Mutagenesis, Site-Directed ; Protein Binding ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/chemistry/genetics/*metabolism ; Telomere/chemistry/metabolism ; Telomere Shortening ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {Telomeres are essential for chromosome maintenance. Cdc13 is a single-stranded telomeric DNA binding protein that caps telomeres and regulates telomerase function in yeast. Although specific binding of Cdc13 to telomeric DNA is critical for telomere protection, the detail mechanism how Cdc13-DNA complex protects telomere is unclear. Using two single-molecule methods, tethered particle motion and atomic force microscopy, we demonstrate that specific binding of Cdc13 on single-stranded telomeric DNA shortens duplex DNA into distinct states differed by ∼70-80 base pairs. DNA shortening by Cdc13 is dynamic and independent of duplex DNA sequences or length. Significantly, we found that Pif1 helicase is incapable of removing Cdc13 from the shortened DNA-Cdc13 complex, suggesting that Cdc13 forms structurally stable complex by shortening of the bound DNA. Together our data identified shortening of DNA by Cdc13 and provided an indication for efficient protection of telomere ends by the shortened DNA-Cdc13 complex.},
}
@article {pmid33831179,
year = {2021},
author = {Pathak, GA and Wendt, FR and Levey, DF and Mecca, AP and van Dyck, CH and Gelernter, J and Polimanti, R},
title = {Pleiotropic effects of telomere length loci with brain morphology and brain tissue expression.},
journal = {Human molecular genetics},
volume = {30},
number = {14},
pages = {1360-1370},
pmid = {33831179},
issn = {1460-2083},
support = {R21 DC018098/DC/NIDCD NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; F32 MH122058/MH/NIMH NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; R21 DA047527/DA/NIDA NIH HHS/United States ; },
mesh = {Brain ; *Genome-Wide Association Study ; Leukocytes/metabolism ; Polymorphism, Single Nucleotide/genetics ; *Telomere/genetics ; Telomere Homeostasis/genetics ; },
abstract = {Several studies have reported association between leukocyte telomere length (LTL) and neuropsychiatric disorders. Although telomere length is affected by environmental factors, genetic variants in certain loci are strongly associated with LTL. Thus, we aimed to identify the genomic relationship between genetic variants of LTL with brain-based regulatory changes and brain volume. We tested genetic colocalization of seven and nine LTL loci in two ancestry groups, European (EUR) and East-Asian (EAS), respectively, with brain morphology measures for 101 T1-magnetic resonance imaging-based region of interests (n = 21 821). The posterior probability (>90%) was observed for 'fourth ventricle', 'gray matter' and 'cerebellar vermal lobules I-IV' volumes. We then tested causal relationship using LTL loci for gene and methylation expression. We found causal pleiotropy for gene (EAS = four genes; EUR = five genes) and methylation expression (EUR = 17 probes; EAS = 4 probes) of brain tissues (P ≤ 2.47 × 10-6). Integrating chromatin profiles with LTL-single nucleotide polymorphisms identified 45 genes (EUR) and 79 genes (EAS) (P ≤ 9.78×10-7). We found additional 38 LTL-genes using chromatin-based gene mapping for EUR ancestry population. Gene variants in three LTL-genes-GPR37, OBFC1 and RTEL1/RTEL1-TNFRSF6B-show convergent evidence of pleiotropy with brain morphology, gene and methylation expression and chromatin association. Mapping gene functions to drug-gene interactions, we identified process 'transmission across chemical synapses' (P < 2.78 × 10-4). This study provides evidence that genetic variants of LTL have pleiotropic roles with brain-based effects that could explain the phenotypic association of LTL with several neuropsychiatric traits.},
}
@article {pmid33828097,
year = {2021},
author = {Dewhurst, SM and Yao, X and Rosiene, J and Tian, H and Behr, J and Bosco, N and Takai, KK and de Lange, T and Imieliński, M},
title = {Structural variant evolution after telomere crisis.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {2093},
pmid = {33828097},
issn = {2041-1723},
support = {R01 AG016642/AG/NIA NIH HHS/United States ; R35 CA210036/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line ; Chromosomal Instability ; *Chromothripsis ; Fibroblasts ; Genome ; Genomic Instability ; Humans ; Lung ; Metaphase ; Models, Biological ; Neoplasms/*genetics ; Telomere/*chemistry/ultrastructure ; },
abstract = {Telomere crisis contributes to cancer genome evolution, yet only a subset of cancers display breakage-fusion-bridge (BFB) cycles and chromothripsis, hallmarks of experimental telomere crisis identified in previous studies. We examine the spectrum of structural variants (SVs) instigated by natural telomere crisis. Eight spontaneous post-crisis clones did not show prominent patterns of BFB cycles or chromothripsis. Their crisis-induced genome rearrangements varied from infrequent simple SVs to more frequent and complex SVs. In contrast, BFB cycles and chromothripsis occurred in MRC5 fibroblast clones that escaped telomere crisis after CRISPR-controlled telomerase activation. This system revealed convergent evolutionary lineages altering one allele of chromosome 12p, where a short telomere likely predisposed to fusion. Remarkably, the 12p chromothripsis and BFB events were stabilized by independent fusions to chromosome 21. The data establish that telomere crisis can generate a wide spectrum of SVs implying that a lack of BFB patterns and chromothripsis in cancer genomes does not indicate absence of past telomere crisis.},
}
@article {pmid33824452,
year = {2022},
author = {Suliman, ME and Ansari, MGA and Rayis, MA and Hamza, MA and Saeed, AA and Mohammed, AK and Al-Daghri, NM},
title = {Telomere length and telomere repeat-binding protein in children with sickle cell disease.},
journal = {Pediatric research},
volume = {91},
number = {3},
pages = {539-544},
pmid = {33824452},
issn = {1530-0447},
mesh = {*Anemia, Sickle Cell/drug therapy/genetics ; Biomarkers ; Child ; Humans ; *Hydroxyurea/therapeutic use ; Leukocytes ; Telomere-Binding Proteins ; },
abstract = {BACKGROUND: This study aimed to assess the telomere length and plasma telomere repeat-binding factor 2 (TRF2) levels in addition to other inflammatory markers in children with sickle cell disease (SCD).<br><br>METHODS: We enrolled 106 children (90 SCD and 26 controls) aged 1-15 years from the Hematology unit of King Fahad Medical City (KFMC), Saudi Arabia. Genomic DNA extracted from blood and leukocyte TL was determined using quantitative reverse transcription PCR, whereas TRF2, C-reactive protein, interleukin-6, and DNA oxidative damage were determined by using respective commercially available assays.<br><br>RESULTS: Leukocyte TL was inversely correlated with age in the SCD patients (r&#x2009;=&#x2009;-0.24, P&#x2009;=&#x2009;0.02) and the controls (r&#x2009;=&#x2009;-0.68, P&#x2009;<&#x2009;0.0001). In addition, SCD patients had significantly shorter TL (7.74&#x2009;&#xb1;&#x2009;0.81&#x2009;kb) (P&#x2009;=&#x2009;0.003) than controls (8.28&#x2009;&#xb1;&#x2009;0.73&#x2009;kb). In contrast, no significant difference in TL among the SCD genotypes (HbSS and HbS&#x3b2;0) has been observed. A modest, positive correlation was seen between TL and reticulocyte % (r&#x2009;=&#x2009;0.21; P&#x2009;=&#x2009;0.06). There were no significant differences in the TL and TRF2 concentrations between subjects with HbSS and HbS&#x3b2;[0] genotypes.<br><br>CONCLUSIONS: Short leukocyte TL was significantly associated with SCD. An inverse association was observed between TL and hemoglobin. Hydroxyurea treatment revealed no impact on TL.<br><br>IMPACT: This study explored the TL and plasma TRF2 in Saudi children with SCD. This is the first documentation that SCD children have shorter TL than their healthy counterparts, and no association between TL and TRF2 has been observed. Hydroxyurea treatment showed no impact on TL in children with SCD. This study is the first of its kind in children with SCD. It will pave the way for another study with a larger sample size in a diverse population to scrutinize these findings better.},
}
@article {pmid33822976,
year = {2021},
author = {Raffenberg, M and Engel, T and Schoepf, IC and Kootstra, NA and Reiss, P and Braun, DL and Thorball, CW and Fellay, J and Kouyos, RD and Ledergerber, B and Günthard, HF and Tarr, PE and , and , },
title = {Impact of Delaying Antiretroviral Treatment During Primary Human Immunodeficiency Virus Infection on Telomere Length.},
journal = {The Journal of infectious diseases},
volume = {224},
number = {10},
pages = {1775-1784},
doi = {10.1093/infdis/jiab186},
pmid = {33822976},
issn = {1537-6613},
mesh = {Adult ; Anti-Retroviral Agents/therapeutic use ; Female ; *HIV Infections/drug therapy ; Humans ; Leukocytes, Mononuclear ; Male ; Telomere ; Telomere Shortening ; },
abstract = {BACKGROUND: Telomere length (TL) shortens during aging, HIV seroconversion, and untreated chronic HIV infection. It is unknown whether early antiretroviral therapy (ART) start is associated with less TL shortening during primary HIV infection (PHI).<br><br>METHODS: We measured TL in peripheral blood mononuclear cells by quantitative polymerase chain reaction in participants of the Zurich PHI Study with samples available for &#x2265;6 years. We obtained univariable/multivariable estimates from mixed-effects models and evaluated the association of delaying ART start or interrupting ART with baseline and longitudinal TL.<br><br>RESULTS: In 105 participants with PHI (median age 36 years, 9% women), median ART delay was 25, 42, and 60 days, respectively, in the first (shortest), second, and third (longest) ART delay tertile. First ART delay tertile was associated with longer baseline TL (P for trend&#x2005;=&#x2005;.034), and longer TL over 6 years, but only with continuous ART (P&#x2005;<&#x2005;.001), not if ART was interrupted &#x2265;12 months (P&#x2005;=&#x2005;.408). In multivariable analysis, participants in the second and third ART delay tertile had 17.6% (5.4%-29.7%; P&#x2005;=&#x2005;.004) and 21.5% (9.4%-33.5%; P&#x2005;<&#x2005;.001) shorter TL, after adjustment for age, with limited effect modification by clinical variables.<br><br>CONCLUSIONS: In PHI, delaying ART start for even a matter of weeks was associated with significant and sustained TL shortening.},
}
@article {pmid33821432,
year = {2022},
author = {Kliewer, W and Robins, JL},
title = {Adverse Childhood Experiences Are Associated with Cardiometabolic Risk Indicators and Telomere Length in Low-Income African-American Adolescents.},
journal = {International journal of behavioral medicine},
volume = {29},
number = {1},
pages = {131-135},
pmid = {33821432},
issn = {1532-7558},
mesh = {Adolescent ; *Adverse Childhood Experiences ; Black or African American/genetics ; *Cardiovascular Diseases/epidemiology/genetics ; Child ; Female ; Humans ; Male ; Telomere/genetics ; Telomere Shortening ; },
abstract = {BACKGROUND: Adverse childhood experiences (ACEs) have been linked to increased risk for cardiovascular disease later in life, and to shortened telomere length in children and adolescents, but few studies have examined associations between ACEs and cardiometabolic risk in adolescence or potential associations between ACEs, cardiometabolic risk indicators, and telomere length in this population. The present study examined competing models of associations between adolescent ACEs (as reported by mothers); cardiovascular, inflammatory, and metabolic indicators of health risk; and leukocyte telomere length in youth.<br><br>METHOD: Data was collected from 108 low-income African-American adolescents (42.6% male; Mage&#x2009;=&#x2009;14.27&#xa0;years, SD&#x2009;=&#x2009;1.17) living in the southeastern USA. Waist circumference was measured during a home interview, and measures of C-reactive protein, insulin resistance, and leukocyte telomere length were obtained from blood following overnight fasting.<br><br>RESULTS: Path analysis supported a main effects model, whereby ACEs were significantly associated with shortened leukocyte telomere length, higher levels of C-reactive protein, and larger waist circumferences, controlling for maternal education and adolescent sex. Exploratory analyses examining whether cardiometabolic risk mediated associations between ACEs and telomere length, or whether telomere length mediated associations between ACEs and cardiometabolic risk, were not supported.<br><br>CONCLUSIONS: ACEs are associated with risk of future cardiometabolic disorders and shortened leukocyte telomere length. Because cytogenetic changes are potentially modifiable, interventions to decrease family ACEs or alter responses to ACEs may lessen chronic disease risk in the African-American population. Targeted interventions to improve health are discussed.},
}
@article {pmid33816507,
year = {2021},
author = {Hoerr, RE and Ngo, K and Friedman, KL},
title = {When the Ends Justify the Means: Regulation of Telomere Addition at Double-Strand Breaks in Yeast.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {655377},
pmid = {33816507},
issn = {2296-634X},
support = {R01 GM123292/GM/NIGMS NIH HHS/United States ; T32 GM008554/GM/NIGMS NIH HHS/United States ; T32 GM137793/GM/NIGMS NIH HHS/United States ; },
abstract = {Telomeres, repetitive sequences located at the ends of most eukaryotic chromosomes, provide a mechanism to replenish terminal sequences lost during DNA replication, limit nucleolytic resection, and protect chromosome ends from engaging in double-strand break (DSB) repair. The ribonucleoprotein telomerase contains an RNA subunit that serves as the template for the synthesis of telomeric DNA. While telomere elongation is typically primed by a 3' overhang at existing chromosome ends, telomerase can act upon internal non-telomeric sequences. Such de novo telomere addition can be programmed (for example, during chromosome fragmentation in ciliated protozoa) or can occur spontaneously in response to a chromosome break. Telomerase action at a DSB can interfere with conservative mechanisms of DNA repair and results in loss of distal sequences but may prevent additional nucleolytic resection and/or chromosome rearrangement through formation of a functional telomere (termed "chromosome healing"). Here, we review studies of spontaneous and induced DSBs in the yeast Saccharomyces cerevisiae that shed light on mechanisms that negatively regulate de novo telomere addition, in particular how the cell prevents telomerase action at DSBs while facilitating elongation of critically short telomeres. Much of our understanding comes from the use of perfect artificial telomeric tracts to "seed" de novo telomere addition. However, endogenous sequences that are enriched in thymine and guanine nucleotides on one strand (TG-rich) but do not perfectly match the telomere consensus sequence can also stimulate unusually high frequencies of telomere formation following a DSB. These observations suggest that some internal sites may fully or partially escape mechanisms that normally negatively regulate de novo telomere addition.},
}
@article {pmid33810393,
year = {2021},
author = {Toubiana, S and Tzur-Gilat, A and Selig, S},
title = {Epigenetic Characteristics of Human Subtelomeres Vary in Cells Utilizing the Alternative Lengthening of Telomeres (ALT) Pathway.},
journal = {Life (Basel, Switzerland)},
volume = {11},
number = {4},
pages = {},
pmid = {33810393},
issn = {2075-1729},
support = {1362/17//Israel Science Foundation/ ; },
abstract = {Most human cancers circumvent senescence by activating a telomere length maintenance mechanism, most commonly involving telomerase activation. A minority of cancers utilize the recombination-based alternative lengthening of telomeres (ALT) pathway. The exact requirements for unleashing normally repressed recombination at telomeres are yet unclear. Epigenetic modifications at telomeric regions were suggested to be pivotal for activating ALT; however, conflicting data exist regarding their exact nature and necessity. To uncover common ALT-positive epigenetic characteristics, we performed a comprehensive analysis of subtelomeric DNA methylation, histone modifications, and TERRA expression in several ALT-positive and ALT-negative cell lines. We found that subtelomeric DNA methylation does not differentiate between the ALT-positive and ALT-negative groups, and most of the analyzed subtelomeres within each group do not share common DNA methylation patterns. Additionally, similar TERRA levels were measured in the ALT-positive and ALT-negative groups, and TERRA levels varied significantly among the members of the ALT-positive group. Subtelomeric H3K4 and H3K9 trimethylation also differed significantly between samples in the ALT-positive group. Our findings do not support a common route by which epigenetic modifications activate telomeric recombination in ALT-positive cells, and thus, different therapeutic approaches will be necessary to overcome ALT-dependent cellular immortalization.},
}
@article {pmid33808277,
year = {2021},
author = {Stock, CJW and Renzoni, EA},
title = {Telomeres in Interstitial Lung Disease.},
journal = {Journal of clinical medicine},
volume = {10},
number = {7},
pages = {},
pmid = {33808277},
issn = {2077-0383},
support = {20719/VAC_/Versus Arthritis/United Kingdom ; },
abstract = {Interstitial lung diseases (ILD) encompass a group of conditions involving fibrosis and/or inflammation of the pulmonary parenchyma. Telomeres are repetitive DNA sequences at chromosome ends which protect against genome instability. At each cell division, telomeres shorten, but the telomerase complex partially counteracts progressive loss of telomeres by catalysing the synthesis of telomeric repeats. Once critical telomere shortening is reached, cell cycle arrest or apoptosis are triggered. Telomeres progressively shorten with age. A number of rare genetic mutations have been identified in genes encoding for components of the telomerase complex, including telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), in familial and, less frequently, in sporadic fibrotic ILDs. Defects in telomerase result in extremely short telomeres. More rapidly progressive disease is observed in fibrotic ILD patients with telomere gene mutations, regardless of underlying diagnosis. Associations with common single nucleotide polymorphisms in telomere related genes have also been demonstrated for various ILDs. Shorter peripheral blood telomere lengths compared to age-matched healthy individuals are found in a proportion of patients with fibrotic ILDs, and in idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (HP) have been linked to worse survival, independently of disease severity. Greater susceptibility to immunosuppressant-induced side effects in patients with short telomeres has been described in patients with IPF and with fibrotic HP. Here, we discuss recent evidence for the involvement of telomere length and genetic variations in the development, progression, and treatment of fibrotic ILDs.},
}
@article {pmid33804854,
year = {2021},
author = {Travina, AO and Ilicheva, NV and Mittenberg, AG and Shabelnikov, SV and Kotova, AV and Podgornaya, OI},
title = {The Long Linker Region of Telomere-Binding Protein TRF2 Is Responsible for Interactions with Lamins.},
journal = {International journal of molecular sciences},
volume = {22},
number = {7},
pages = {},
pmid = {33804854},
issn = {1422-0067},
support = {19-34-80032//Russian Foundation for Basic Research/ ; 20-34-90067//Russian Foundation for Basic Research/ ; 19-74-20102//Russian Science Support Foundation/ ; },
mesh = {Binding Sites ; Cells, Cultured ; Humans ; Lamins/*metabolism ; Protein Binding ; Telomeric Repeat Binding Protein 2/chemistry/*metabolism ; },
abstract = {Telomere-binding factor 2 (TRF2) is part of the shelterin protein complex found at chromosome ends. Lamin A/C interacts with TRF2 and influences telomere position. TRF2 has an intrinsically disordered region between the ordered dimerization and DNA-binding domains. This domain is referred to as the long linker region of TRF2, or udTRF2. We suggest that udTRF2 might be involved in the interaction between TRF2 and lamins. The recombinant protein corresponding to the udTRF2 region along with polyclonal antibodies against this region were used in co-immunoprecipitation with purified lamina and nuclear extracts. Co-immunoprecipitation followed by Western blots and mass spectrometry indicated that udTRF2 interacts with lamins, preferably lamins A/C. The interaction did not involve any lamin-associated proteins, was not dependent on the post-translation modification of lamins, nor did it require their higher-order assembly. Besides lamins, a number of other udTRF2-interacting proteins were identified by mass spectrometry, including several heterogeneous nuclear ribonucleoproteins (hnRNP A2/B1, hnRNPA1, hnRNP A3, hnRNP K, hnRNP L, hnRNP M), splicing factors (SFPQ, NONO, SRSF1, and others), helicases (DDX5, DHX9, and Eif4a3l1), topoisomerase I, and heat shock protein 71, amongst others. Some of the identified interactors are known to be involved in telomere biology; the roles of the others remain to be investigated. Thus, the long linker region of TRF2 (udTRF2) is a regulatory domain responsible for the association between TRF2 and lamins and is involved in interactions with other proteins.},
}
@article {pmid33804844,
year = {2021},
author = {Gavia-García, G and Rosado-Pérez, J and Arista-Ugalde, TL and Aguiñiga-Sánchez, I and Santiago-Osorio, E and Mendoza-Núñez, VM},
title = {Telomere Length and Oxidative Stress and Its Relation with Metabolic Syndrome Components in the Aging.},
journal = {Biology},
volume = {10},
number = {4},
pages = {},
pmid = {33804844},
issn = {2079-7737},
abstract = {A great amount of scientific evidence supports that Oxidative Stress (OxS) can contribute to telomeric attrition and also plays an important role in the development of certain age-related diseases, among them the metabolic syndrome (MetS), which is characterised by clinical and biochemical alterations such as obesity, dyslipidaemia, arterial hypertension, hyperglycaemia, and insulin resistance, all of which are considered as risk factors for type 2 diabetes mellitus (T2DM) and cardiovascular diseases, which are associated in turn with an increase of OxS. In this sense, we review scientific evidence that supports the association between OxS with telomere length (TL) dynamics and the relationship with MetS components in aging. It was analysed whether each MetS component affects the telomere length separately or if they all affect it together. Likewise, this review provides a summary of the structure and function of telomeres and telomerase, the mechanisms of telomeric DNA repair, how telomere length may influence the fate of cells or be linked to inflammation and the development of age-related diseases, and finally, how the lifestyles can affect telomere length.},
}
@article {pmid33804786,
year = {2021},
author = {Pilbauerova, N and Soukup, T and Suchankova Kleplova, T and Schmidt, J and Suchanek, J},
title = {The Effect of Cultivation Passaging on the Relative Telomere Length and Proliferation Capacity of Dental Pulp Stem Cells.},
journal = {Biomolecules},
volume = {11},
number = {3},
pages = {},
pmid = {33804786},
issn = {2218-273X},
support = {Q40/13 and Q40/06//Charles University's program PROGRES/ ; },
mesh = {Cell Proliferation/genetics/*physiology ; Dental Pulp/*cytology ; Flow Cytometry ; Humans ; Immunohistochemistry ; Phenotype ; Polymerase Chain Reaction ; Stem Cells/*cytology/*metabolism ; Telomerase/metabolism ; Telomere/*genetics ; },
abstract = {Telomeres are repetitive nucleoprotein DNA sequences that shorten with each cell division. The stem cells activate telomerase to compensate for the telomere loss. This study aimed to evaluate the effect of cultivation passaging on the relative telomere length and proliferation capacity of dental pulp stem cells. We used ten dental pulp stem cell (DPSC) lineages stored for 12 months using uncontrolled-rate freezing to reach the study's goal. We analyzed their proliferation rate, phenotype using flow cytometry, multipotency, and relative telomere length using a qPCR analysis. We determined the relative telomere length in the added study by performing analysis after one, two, and three weeks of cultivation with no passaging. We documented the telomere attrition with increasing passaging. The shorter the relative telomere length, the lower reached population doublings, and longer population doubling time were observed at the end of the cultivation. We observed the telomere prolongation in DPSCs cultivated for two weeks with no passaging in the added subsequent study. We concluded that excessive proliferation demands on DPSCs during in vitro cultivation result in telomere attrition. We opened the theory that the telomerase might be more efficient during cell cultivation with no passaging. This observation could help in preserving the telomere length during ex vivo DPSC expansion.},
}
@article {pmid33803567,
year = {2021},
author = {Samiec, M and Skrzyszowska, M},
title = {Extranuclear Inheritance of Mitochondrial Genome and Epigenetic Reprogrammability of Chromosomal Telomeres in Somatic Cell Cloning of Mammals.},
journal = {International journal of molecular sciences},
volume = {22},
number = {6},
pages = {},
pmid = {33803567},
issn = {1422-0067},
support = {04-19-05-00//Ministry of Science and Higher Education in Poland/ ; },
mesh = {Animals ; Chromosomes, Mammalian/*genetics ; *Epigenesis, Genetic ; Extrachromosomal Inheritance/*genetics ; *Genome, Mitochondrial ; Mammals/*genetics ; *Nuclear Transfer Techniques ; Telomere/*genetics ; },
abstract = {The effectiveness of somatic cell nuclear transfer (SCNT) in mammals seems to be still characterized by the disappointingly low rates of cloned embryos, fetuses, and progeny generated. These rates are measured in relation to the numbers of nuclear-transferred oocytes and can vary depending on the technique applied to the reconstruction of enucleated oocytes. The SCNT efficiency is also largely affected by the capability of donor nuclei to be epigenetically reprogrammed in a cytoplasm of reconstructed oocytes. The epigenetic reprogrammability of donor nuclei in SCNT-derived embryos appears to be biased, to a great extent, by the extranuclear (cytoplasmic) inheritance of mitochondrial DNA (mtDNA) fractions originating from donor cells. A high frequency of mtDNA heteroplasmy occurrence can lead to disturbances in the intergenomic crosstalk between mitochondrial and nuclear compartments during the early embryogenesis of SCNT-derived embryos. These disturbances can give rise to incorrect and incomplete epigenetic reprogramming of donor nuclei in mammalian cloned embryos. The dwindling reprogrammability of donor nuclei in the blastomeres of SCNT-derived embryos can also be impacted by impaired epigenetic rearrangements within terminal ends of donor cell-descended chromosomes (i.e., telomeres). Therefore, dysfunctions in epigenetic reprogramming of donor nuclei can contribute to the enhanced attrition of telomeres. This accelerates the processes of epigenomic aging and replicative senescence in the cells forming various tissues and organs of cloned fetuses and progeny. For all the above-mentioned reasons, the current paper aims to overview the state of the art in not only molecular mechanisms underlying intergenomic communication between nuclear and mtDNA molecules in cloned embryos but also intrinsic determinants affecting unfaithful epigenetic reprogrammability of telomeres. The latter is related to their abrasion within somatic cell-inherited chromosomes.},
}
@article {pmid33801762,
year = {2021},
author = {Eladl, A and Yamaoki, Y and Hoshina, S and Horinouchi, H and Kondo, K and Waga, S and Nagata, T and Katahira, M},
title = {Investigation of the Interaction of Human Origin Recognition Complex Subunit 1 with G-Quadruplex DNAs of Human c-myc Promoter and Telomere Regions.},
journal = {International journal of molecular sciences},
volume = {22},
number = {7},
pages = {},
pmid = {33801762},
issn = {1422-0067},
support = {20H03192//Ministry of Education, Culture, Sports, Science and Technology/ ; 20K21477//Ministry of Education, Culture, Sports, Science and Technology/ ; 20K06524//Ministry of Education, Culture, Sports, Science and Technology/ ; 19K16054//Ministry of Education, Culture, Sports, Science and Technology/ ; ZE2020A-39//The Joint Usage/Joint Research Center for Zero Emission Energy Research, Institute of Advanced Energy, Kyoto University/ ; },
mesh = {Binding Sites ; DNA/*genetics ; DNA Replication ; Fluorescence Polarization ; *G-Quadruplexes ; Humans ; Magnetic Resonance Spectroscopy ; Open Reading Frames ; *Origin Recognition Complex/genetics ; *Promoter Regions, Genetic ; Protein Binding ; Proto-Oncogene Proteins c-myc/*genetics ; Replication Origin ; Telomere/*ultrastructure ; },
abstract = {Origin recognition complex (ORC) binds to replication origins in eukaryotic DNAs and plays an important role in replication. Although yeast ORC is known to sequence-specifically bind to a replication origin, how human ORC recognizes a replication origin remains unknown. Previous genome-wide studies revealed that guanine (G)-rich sequences, potentially forming G-quadruplex (G4) structures, are present in most replication origins in human cells. We previously suggested that the region comprising residues 413-511 of human ORC subunit 1, hORC1[413-511], binds preferentially to G-rich DNAs, which form a G4 structure in the absence of hORC1[413-511]. Here, we investigated the interaction of hORC1[413-511] with various G-rich DNAs derived from human c-myc promoter and telomere regions. Fluorescence anisotropy revealed that hORC1[413-511] binds preferentially to DNAs that have G4 structures over ones having double-stranded structures. Importantly, circular dichroism (CD) and nuclear magnetic resonance (NMR) showed that those G-rich DNAs retain the G4 structures even after binding with hORC1[413-511]. NMR chemical shift perturbation analyses revealed that the external G-tetrad planes of the G4 structures are the primary binding sites for hORC1[413-511]. The present study suggests that human ORC1 may recognize replication origins through the G4 structure.},
}
@article {pmid33801585,
year = {2021},
author = {Sharma, S and Sengupta, A and Chowdhury, S},
title = {Emerging Molecular Connections between NM23 Proteins, Telomeres and Telomere-Associated Factors: Implications in Cancer Metastasis and Ageing.},
journal = {International journal of molecular sciences},
volume = {22},
number = {7},
pages = {},
pmid = {33801585},
issn = {1422-0067},
support = {IA/S/18/2/504021/WTDBT_/DBT-Wellcome Trust India Alliance/India ; },
mesh = {*Aging ; Animals ; Cell Differentiation ; Cell Movement ; Cell Proliferation ; Cytoskeleton/metabolism ; DNA/chemistry ; G-Quadruplexes ; *Gene Expression Regulation, Neoplastic ; Humans ; Lymphocyte Activation ; Mitochondria/metabolism ; NM23 Nucleoside Diphosphate Kinases/*metabolism ; *Neoplasm Metastasis ; Neoplasms/*genetics/*metabolism ; Nucleoside Diphosphate Kinase D/chemistry ; Protein Binding ; Proto-Oncogene Proteins c-myc/metabolism ; Signal Transduction ; T-Lymphocytes/cytology ; Telomere/*metabolism/ultrastructure ; Transcription Factors/metabolism ; },
abstract = {The metastasis suppressor function of NM23 proteins is widely understood. Multiple enzymatic activities of NM23 proteins have also been identified. However, relatively less known interesting aspects are being revealed from recent developments that corroborate the telomeric interactions of NM23 proteins. Telomeres are known to regulate essential physiological events such as metastasis, ageing, and cellular differentiation via inter-connected signalling pathways. Here, we review the literature on the association of NM23 proteins with telomeres or telomere-related factors, and discuss the potential implications of emerging telomeric functions of NM23 proteins. Further understanding of these aspects might be instrumental in better understanding the metastasis suppressor functions of NM23 proteins.},
}
@article {pmid33800260,
year = {2021},
author = {Luxton, JJ and McKenna, MJ and Lewis, AM and Taylor, LE and Jhavar, SG and Swanson, GP and Bailey, SM},
title = {Telomere Length Dynamics and Chromosomal Instability for Predicting Individual Radiosensitivity and Risk via Machine Learning.},
journal = {Journal of personalized medicine},
volume = {11},
number = {3},
pages = {},
pmid = {33800260},
issn = {2075-4426},
support = {Advanced Industry (AI) Bioscience Proof of Concept (POC) award//Colorado Office of Economic Development and International Trade (OEDIT)/ ; },
abstract = {The ability to predict a cancer patient's response to radiotherapy and risk of developing adverse late health effects would greatly improve personalized treatment regimens and individual outcomes. Telomeres represent a compelling biomarker of individual radiosensitivity and risk, as exposure can result in dysfunctional telomere pathologies that coincidentally overlap with many radiation-induced late effects, ranging from degenerative conditions like fibrosis and cardiovascular disease to proliferative pathologies like cancer. Here, telomere length was longitudinally assessed in a cohort of fifteen prostate cancer patients undergoing Intensity Modulated Radiation Therapy (IMRT) utilizing Telomere Fluorescence in situ Hybridization (Telo-FISH). To evaluate genome instability and enhance predictions for individual patient risk of secondary malignancy, chromosome aberrations were assessed utilizing directional Genomic Hybridization (dGH) for high-resolution inversion detection. We present the first implementation of individual telomere length data in a machine learning model, XGBoost, trained on pre-radiotherapy (baseline) and in vitro exposed (4 Gy γ-rays) telomere length measurements, to predict post radiotherapy telomeric outcomes, which together with chromosomal instability provide insight into individual radiosensitivity and risk for radiation-induced late effects.},
}
@article {pmid33799157,
year = {2021},
author = {Arantes Dos Santos, G and Viana, NI and Pimenta, R and Reis, ST and Ramos Moreira Leite, K and Srougi, M},
title = {Hypothesis: The triad androgen receptor, zinc finger proteins and telomeres modulates the global gene expression pattern during prostate cancer progression.},
journal = {Medical hypotheses},
volume = {150},
number = {},
pages = {110566},
doi = {10.1016/j.mehy.2021.110566},
pmid = {33799157},
issn = {1532-2777},
mesh = {Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; *Prostatic Neoplasms/genetics ; *Receptors, Androgen/genetics/metabolism ; Telomere/genetics/metabolism ; Zinc Fingers ; },
abstract = {Currently, the biggest challenge for prostate cancer (PCa) is to understand the mechanism by which the disease acquires the castration-resistant phenotype and progresses to a fatal disease. PCa has a high genetic heterogeneity, and cannot be separated into well-defined molecular subtypes. Despite this, there is consensus about the role of the androgen receptor (AR) in all stages of the disease, including the transition to the castration-resistant phenotype. Since AR is a transcription factor, we investigated the possibility of PCa presenting a pattern of global gene expression during disease progression. By analyzing the TCGA and CCLE datasets, we were able to find a pattern of waves of genes being expressed during each stage of disease progression. This phenomenon suggests the existence of a mechanism that globally regulates gene expression, being AR, telomeres, and zinc finger proteins (ZNF), three important players. The AR modulates the telomere biology, and its transcription is regulated by ZNF. Recently, a study suggested that the telomere length might influence the expression of ZNF. Thus, we hypothesized that changes in the triad AR, telomeres, and ZNF control gene expression during the progression of PCa.},
}
@article {pmid33798832,
year = {2021},
author = {Panjawatanan, P and Charoenkwan, P and Tantiworawit, A and Strogatz, D and Perry, KE and Tuntiwechapikul, W},
title = {Telomere shortening correlates with disease severity in hemoglobin H disease patients.},
journal = {Blood cells, molecules &amp; diseases},
volume = {89},
number = {},
pages = {102563},
doi = {10.1016/j.bcmd.2021.102563},
pmid = {33798832},
issn = {1096-0961},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Blood Transfusion ; Child ; Female ; Ferritins/blood ; Gene Deletion ; Hemoglobin H/*genetics ; Humans ; Male ; Middle Aged ; Severity of Illness Index ; *Telomere Shortening ; Young Adult ; alpha-Thalassemia/blood/diagnosis/*genetics/therapy ; beta-Globins/*genetics ; },
abstract = {Hemoglobin H (Hb H) disease is the most significant health problem of the α-thalassemia syndromes. The Hb disease patients are categorized based on their genotype to deletional and nondeletional, with the latter genotype presents the more severe clinical symptoms. Since telomere length is an indicator of biological aging and health, we hypothesized that telomere length could reflect Hb H disease's severity. In this study, we recruited 48 deletional and 47 nondeletional Hb H disease patients, along with 109 normal controls, for telomere length assessment. The leukocyte telomere length was assessed by monochromatic multiplex real-time PCR and reported as the telomere to single-copy gene (T/S) ratio. When telomere length was adjusted for age, the analysis of covariance between the control and the two Hb H disease groups revealed no significant difference. However, the telomere shortening rate was more rapid in the nondeletional Hb H disease group than those of the control and deletional Hb H disease groups. Gender analysis found that male patients have a significantly lower T/S ratio than females in the nondeletional group but not in the control and deletional groups. In the two disease groups, the T/S ratio was not influenced by ferritin level or transfusion burden but was positively correlated with the absolute reticulocyte count.},
}
@article {pmid33793114,
year = {2021},
author = {Galtseva, IV and Filipenko, ML and Davydova, YO and Luchkin, AV and Kapranov, NM and Kondratieva, YA and Subbotin, SV and Khrapov, EA and Nikiforova, KA and Fidarova, ZT and Gaponova, TV and Mendeleeva, LP and Mikhailova, EA and Parovichnikova, EN and Savchenko, VG},
title = {Comparison of polymerase chain reaction and flow cytometry for measuring telomere length of human leukocytes.},
journal = {Klinicheskaia laboratornaia diagnostika},
volume = {66},
number = {3},
pages = {154-159},
doi = {10.51620/0869-2084-2021-66-3-154-159},
pmid = {33793114},
issn = {0869-2084},
mesh = {DNA ; Flow Cytometry ; Humans ; In Situ Hybridization, Fluorescence ; *Leukocytes ; *Telomere/genetics ; },
abstract = {Telomere length can be measured by polymerase chain reaction (PCR), allowing to obtain the absolute length of telomeres (ALT) in base pair, and by flow cytometry, which can only estimate the relative telomere length. The aim of the study was to compare the results of the two methods and to develop an accurate and reliable way of converting the relative telomere length to absolute. The peripheral blood from 21 donors was analyzed. Measurement of leukocyte telomere length by flow cytometry was carried out using a commercial Telomere PNA Kit / FITC (Dako, Denmark) with two CytoFLEX flow cytometers (Beckman Coulter, China) and BD FACSCanto II (Becton Dickinson, USA), obtaining the molecular equivalent of fluorescence (MEF). To measure telomere length by real-time PCR, calibrators with a known number of telomeric repeats were prepared. Two quantitative PCRs were carried out: one for telomeric repeats, the other for determining the number of genome-equivalents of DNA, three times for each sample, which made it possible to calculate ALT. A strong direct relationship was found between the MEF obtained with BD FACSCanto II and CytoFLEX (r = 0.97). Analysis of PCR and flow cytometry results showed a significant correlation between ALT and MEF. We calculated the regression equations of ALT and MEF for CytoFLEX - y = 0.0043x (r = 0.84) and for BD FACSCanto II - y = 0.0051x (r = 0.82). Correlation analysis showed a high comparability of telomere lengths measured by two methods. The obtained regression equations allow converting the results of flow cytometry into absolute values, allowing the comparison of the results of different research groups and the use of this method in clinical trials.},
}
@article {pmid33789973,
year = {2022},
author = {Romaine, SPR and Denniff, M and Codd, V and Nath, M and Koekemoer, A and Anker, SD and Cleland, JG and Filippatos, G and Levin, D and Metra, M and Mordi, IR and Ouwerkerk, W and Ter Maaten, JM and van Veldhuisen, DJ and Zannad, F and Ng, LL and van der Harst, P and Lang, CC and Voors, AA and Nelson, CP and Samani, NJ},
title = {Telomere length is independently associated with all-cause mortality in chronic heart failure.},
journal = {Heart (British Cardiac Society)},
volume = {108},
number = {2},
pages = {124-129},
doi = {10.1136/heartjnl-2020-318654},
pmid = {33789973},
issn = {1468-201X},
support = {MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; SP/16/4/32697/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Chronic Disease ; Cohort Studies ; *Heart Failure/diagnosis/genetics ; Humans ; Leukocytes ; Risk Factors ; *Telomere/genetics ; },
abstract = {OBJECTIVE: Patients with heart failure have shorter mean leucocyte telomere length (LTL), a marker of biological age, compared with healthy subjects, but it is unclear whether this is of prognostic significance. We therefore sought to determine whether LTL is associated with outcomes in patients with heart failure.<br><br>METHODS: We measured LTL in patients with heart failure from the BIOSTAT-CHF Index (n=2260) and BIOSTAT-CHF Tayside (n=1413) cohorts. Cox proportional hazards analyses were performed individually in each cohort and the estimates combined using meta-analysis. Our co-primary endpoints were all-cause mortality and heart failure hospitalisation.<br><br>RESULTS: In age-adjusted and sex-adjusted analyses, shorter LTL was associated with higher all-cause mortality in both cohorts individually and when combined (meta-analysis HR (per SD decrease in LTL)=1.16 (95% CI 1.08 to 1.24); p=2.66&#xd7;10[-5]), an effect equivalent to that of being four&#x2009;years older. The association remained significant after adjustment for the BIOSTAT-CHF clinical risk score to account for known prognostic factors (HR=1.12 (95% CI 1.05 to 1.20); p=1.04&#xd7;10[-3]). Shorter LTL was associated with both cardiovascular (HR=1.09 (95% CI 1.00 to 1.19); p=0.047) and non-cardiovascular deaths (HR=1.18 (95% CI 1.05 to 1.32); p=4.80&#xd7;10[-3]). There was no association between LTL and heart failure hospitalisation (HR=0.99 (95% CI 0.92 to 1.07); p=0.855).<br><br>CONCLUSION: In patients with heart failure, shorter mean LTL is independently associated with all-cause mortality.},
}
@article {pmid33788432,
year = {2021},
author = {Wang, Y and Yang, JH and Zhao, CJ},
title = {[Effect of moxibustion on acupoints at "opening" time on telomere length and expression of liver cell cycle regulators in aging rats].},
journal = {Zhen ci yan jiu = Acupuncture research},
volume = {46},
number = {2},
pages = {117-122},
doi = {10.13702/j.1000-0607.200222},
pmid = {33788432},
issn = {1000-0607},
mesh = {Acupuncture Points ; Aging/genetics ; Animals ; Cell Cycle ; Liver ; Male ; *Moxibustion ; Rats ; Rats, Sprague-Dawley ; Telomere/genetics ; },
abstract = {OBJECTIVE: To observe the effects of "lingguibafa" moxibustion performing at the appropriate acupoints at their "opening" time on telomere length，expressions of p53 of tumor supressor genes and retinoblastoma gene(Rb)in the liver of aging rats，so as to explore its mechanisms underlying delaying senescence.<br><br>METHODS: Forty male SD rats were randomly divi-ded into normal, model, prevention and treatment groups, with 10 rats in each group. The rat model was established by intrape-ritoneally injection of D-galactose (200 mg/kg) once a day for 42 days. The rats in the prevention group were given "lingguibafa" moxibustion during modeling, while those in the treatment group were given "lingguibafa" moxibustion after modeling. Quantitative real-time PCR was used to detect the telomere length and the mRNA expressions of p53 and Rb&#xff0c;ELISA was used to detect the protein contents of p53 and Rb in the liver tissues.<br><br>RESULTS: Compared with the normal group, the relative telomere length of the model group was significantly shortened (P<0.01), the mRNA expressions and protein contents of p53 and Rb were significantly increased (P<0.01). After intervention and in comparison with the model group, the relative telomere length of the prevention group and the treatments group were significantly increased (P<0.01), and the expressions of p53 and Rb mRNA and protein contents were significantly reduced (P<0.01, P<0.05). There were no significant difference between the prevention and the treatment groups in the abovementioned indexes (P>0.05).<br><br>CONCLUSION: Moxibustion on acupoints at "opening" time can inhibit the shortening of telomere length and the down-regulation of the expressions of p53 and Rb in aging rats, which may contribute to its function in delaying the process of cell senescence.},
}
@article {pmid33785504,
year = {2021},
author = {Friesen, CR and Wilson, M and Rollings, N and Sudyka, J and Giraudeau, M and Whittington, CM and Olsson, M},
title = {Exercise training has morph-specific effects on telomere, body condition and growth dynamics in a color-polymorphic lizard.},
journal = {The Journal of experimental biology},
volume = {224},
number = {9},
pages = {},
doi = {10.1242/jeb.242164},
pmid = {33785504},
issn = {1477-9145},
mesh = {Animals ; Australia ; *Lizards/genetics ; Male ; Reproduction ; Sexual Behavior, Animal ; Telomere ; },
abstract = {Alternative reproductive tactics (ARTs) are correlated suites of sexually selected traits that are likely to impose differential physiological costs on different individuals. While moderate activity might be beneficial, animals living in the wild often work at the margins of their resources and performance limits. Individuals using ARTs may have divergent capacities for activity. When pushed beyond their respective capacities, they may experience condition loss, oxidative stress, and molecular damage that must be repaired with limited resources. We used the Australian painted dragon lizard that exhibits color polymorphism as a model to experimentally test the effect of exercise on body condition, growth, reactive oxygen species (ROS) and telomere dynamics - a potential marker of stress and aging and a correlate of longevity. For most males, ROS levels tended to be lower with greater exercise; however, males with yellow throat patches - or bibs - had higher ROS levels than non-bibbed males. At the highest level of exercise, bibbed males exhibited telomere loss, while non-bibbed males gained telomere length; the opposite pattern was observed in the no-exercise controls. Growth was positively related to food intake but negatively correlated with telomere length at the end of the experiment. Body condition was not related to food intake but was positively correlated with increases in telomere length. These results, along with our previous work, suggest that aggressive - territory holding - bibbed males suffer physiological costs that may reduce longevity compared with non-bibbed males with superior postcopulatory traits.},
}
@article {pmid33783830,
year = {2021},
author = {Sosnowski, DW and Kliewer, W and Valrie, CR and Winter, MA and Serpell, Z and Amstadter, AB},
title = {The Association Between Adverse Childhood Experiences and Child Telomere Length: Examining Self-Regulation as a Behavioral Mediator.},
journal = {Child development},
volume = {92},
number = {2},
pages = {746-759},
doi = {10.1111/cdev.13441},
pmid = {33783830},
issn = {1467-8624},
mesh = {Adolescent ; Adverse Childhood Experiences/*psychology/trends ; Child ; Child Behavior/*physiology/*psychology ; Child, Preschool ; Female ; Humans ; Infant ; Longitudinal Studies ; Male ; Parents/psychology ; Self-Control/*psychology ; Telomere Homeostasis/*physiology ; Telomere Shortening/*physiology ; },
abstract = {Childhood adversity is linked to shortened telomere length (TL), but behavioral indicators of telomere attrition remain unclear. This study examined the association between adverse childhood experiences (ACEs) and child TL, and if ACEs were indirectly associated with TL through children's self-regulatory abilities (i.e., effortful control and self-control). Hypotheses were tested using national data from teachers, parents, and their children (N = 2,527; Mage = 9.35, SD = .36 years). More ACEs were uniquely associated with short TL, and low self-control mediated the association between more ACEs and short TL. While longitudinal studies are needed to strengthen claims of causation, this study identifies a pathway from ACEs to TL that should be explored further.},
}
@article {pmid33781200,
year = {2021},
author = {Bliznina, A and Masunaga, A and Mansfield, MJ and Tan, Y and Liu, AW and West, C and Rustagi, T and Chien, HC and Kumar, S and Pichon, J and Plessy, C and Luscombe, NM},
title = {Telomere-to-telomere assembly of the genome of an individual Oikopleura dioica from Okinawa using Nanopore-based sequencing.},
journal = {BMC genomics},
volume = {22},
number = {1},
pages = {222},
pmid = {33781200},
issn = {1471-2164},
mesh = {Animals ; Genome ; Male ; *Nanopore Sequencing ; *Nanopores ; Telomere/genetics ; *Urochordata/genetics ; },
abstract = {BACKGROUND: The larvacean Oikopleura dioica is an abundant tunicate plankton with the smallest (65-70 Mbp) non-parasitic, non-extremophile animal genome identified to date. Currently, there are two genomes available for the Bergen (OdB3) and Osaka (OSKA2016) O. dioica laboratory strains. Both assemblies have full genome coverage and high sequence accuracy. However, a chromosome-scale assembly has not yet been achieved.<br><br>RESULTS: Here, we present a chromosome-scale genome assembly (OKI2018_I69) of the Okinawan O. dioica produced using long-read Nanopore and short-read Illumina sequencing data from a single male, combined with Hi-C chromosomal conformation capture data for scaffolding. The OKI2018_I69 assembly has a total length of 64.3 Mbp distributed among 19 scaffolds. 99% of the assembly is contained within five megabase-scale scaffolds. We found telomeres on both ends of the two largest scaffolds, which represent assemblies of two fully contiguous autosomal chromosomes. Each of the other three large scaffolds have telomeres at one end only and we propose that they correspond to sex chromosomes split into a pseudo-autosomal region and X-specific or Y-specific regions. Indeed, these five scaffolds mostly correspond to equivalent linkage groups in OdB3, suggesting overall agreement in chromosomal organization between the two populations. At a more detailed level, the OKI2018_I69 assembly possesses similar genomic features in gene content and repetitive elements reported for OdB3. The Hi-C map suggests few reciprocal interactions between chromosome arms. At the sequence level, multiple genomic features such as GC content and repetitive elements are distributed differently along the short and long arms of the same chromosome.<br><br>CONCLUSIONS: We show that a hybrid approach of integrating multiple sequencing technologies with chromosome conformation information results in an accurate de novo chromosome-scale assembly of O. dioica's highly polymorphic genome. This genome assembly opens up the possibility of cross-genome comparison between O. dioica populations, as well as of studies of chromosomal evolution in this lineage.},
}
@article {pmid33780718,
year = {2021},
author = {Lyu, X and Sang, PB and Chai, W},
title = {CST in maintaining genome stability: Beyond telomeres.},
journal = {DNA repair},
volume = {102},
number = {},
pages = {103104},
pmid = {33780718},
issn = {1568-7856},
support = {R01 CA234266/CA/NCI NIH HHS/United States ; R01 GM112864/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Checkpoint Kinase 1/metabolism ; DNA/metabolism ; DNA Breaks, Double-Stranded ; DNA Repair ; DNA Replication ; *Genomic Instability ; Humans ; Signal Transduction ; Telomere-Binding Proteins/*metabolism ; },
abstract = {The human CST (CTC1-STN1-TEN1) complex is an RPA-like single-stranded DNA binding protein complex. While its telomeric functions have been well investigated, numerous studies have revealed that hCST also plays important roles in maintaining genome stability beyond telomeres. Here, we review and discuss recent discoveries on CST in various global genome maintenance pathways, including findings on the CST supercomplex structure, its functions in unperturbed DNA replication, stalled replication, double-strand break repair, and the ATR-CHK1 activation pathway. By summarizing these recent discoveries, we hope to offer new insights into genome maintenance mechanisms and the pathogenesis of CST mutation-associated diseases.},
}
@article {pmid33780109,
year = {2021},
author = {Gan, P and Hiroyama, R and Tsushima, A and Masuda, S and Shibata, A and Ueno, A and Kumakura, N and Narusaka, M and Hoat, TX and Narusaka, Y and Takano, Y and Shirasu, K},
title = {Telomeres and a repeat-rich chromosome encode effector gene clusters in plant pathogenic Colletotrichum fungi.},
journal = {Environmental microbiology},
volume = {23},
number = {10},
pages = {6004-6018},
doi = {10.1111/1462-2920.15490},
pmid = {33780109},
issn = {1462-2920},
mesh = {*Colletotrichum/genetics ; DNA Copy Number Variations ; Multigene Family ; Phylogeny ; Plant Diseases ; Telomere/genetics ; },
abstract = {Members of the Colletotrichum gloeosporioides species complex are causal agents of anthracnose in many commercially important plants. Closely related strains have different levels of pathogenicity on hosts despite their close phylogenetic relationship. To gain insight into the genetics underlying these differences, we generated and annotated whole-genome assemblies of multiple isolates of C. fructicola (Cf) and C. siamense (Cs), as well as three previously unsequenced species, C. aenigma (Ca), C. tropicale and C. viniferum with different pathogenicity on strawberry. Based on comparative genomics, we identified accessory regions with a high degree of conservation in strawberry-pathogenic Cf, Cs and Ca strains. These regions encode homologs of pathogenicity-related genes known as effectors, organized in syntenic gene clusters, with copy number variations in different strains of Cf, Cs and Ca. Analysis of highly contiguous assemblies of Cf, Cs and Ca revealed the association of related accessory effector gene clusters with telomeres and repeat-rich chromosomes and provided evidence of exchange between these two genomic compartments. In addition, expression analysis indicated that orthologues in syntenic gene clusters showed a tendency for correlated gene expression during infection. These data provide insight into mechanisms by which Colletotrichum genomes evolve, acquire and organize effectors.},
}
@article {pmid33777932,
year = {2021},
author = {Saraieva, I and Benetos, A and Labat, C and Franco-Cereceda, A and Bäck, M and Toupance, S},
title = {Telomere Length in Valve Tissue Is Shorter in Individuals With Aortic Stenosis and in Calcified Valve Areas.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {618335},
pmid = {33777932},
issn = {2296-634X},
abstract = {BACKGROUND: Short telomere length (TL) is associated with age-related diseases, in particular cardiovascular diseases. However, whether the onset and course of aortic stenosis (AS) is linked to TL in aortic valves remains unknown.<br><br>OBJECTIVES: To assess telomere dynamics (TL and telomerase activity) in aortic valves and the possible implication of TL in onset and course of AS.<br><br>METHODS: DNA was extracted from aortic valves obtained from 55 patients (78.2% men; age, 37-79 years), who had undergone replacement surgery due to AS (AS group, n = 32), aortic valve regurgitation and aortic dilation (Non-AS group, n = 23). TL was measured by telomere restriction fragment analysis (TRF) in calcified and non-calcified aortic valve areas. Telomerase activity was evaluated using telomerase repeat amplification protocol (TRAP) in protein extracts from non-calcified and calcified areas of valves obtained from 4 additional patients (50% men; age, 27-70 years).<br><br>RESULTS: TL was shorter in calcified aortic valve areas in comparison to non-calcified areas (n = 31, 8.58 &#xb1; 0.73 kb vs. 8.12 &#xb1; 0.75 kb, p < 0.0001), whereas telomerase activity was not detected in any of those areas. Moreover, patients from AS group displayed shorter telomeres in non-calcified areas than those from the Non-AS group (8.40 &#xb1; 0.64 kb vs. 8.85 &#xb1; 0.65, p = 0.01).<br><br>CONCLUSIONS: Short telomeres in aortic valves may participate in the development of AS, while concurrently the calcification process seems to promote further local decrease of TL in calcified areas of valves.},
}
@article {pmid33774188,
year = {2021},
author = {Erdem, HB and Bahsi, T and Ergün, MA},
title = {Function of telomere in aging and age related diseases.},
journal = {Environmental toxicology and pharmacology},
volume = {85},
number = {},
pages = {103641},
doi = {10.1016/j.etap.2021.103641},
pmid = {33774188},
issn = {1872-7077},
mesh = {*Aging ; Animals ; Humans ; Telomerase ; *Telomere ; },
abstract = {Telomeres consist of specialized non-coding DNA repeat sequences. They are essential for preserving the integrity of the genome during cancer development, senescence. Mammalian telomeres might have 1-50 kb of telomeric DNA, which becomes 40-200 base pairs shorter after per cell cycle, and becomes 5-8 kilobase shorter during senescence. There are many studies on the correlation of telomere length and aging rate. However, as the differences in the methods used in the studies and the scarcity of prospective studies, factors affecting telomere length are not really well understood. Some of the age related diseases may develop due to telomere dysfunction and telomere shortness. The short telomere structure detected in both peripheral blood leukocytes and cells of the disease-related tissue has the feature of being a predictive marker for many age-related diseases. It is expected that with future research, telomere length analysis is expected to enter clinical practice.},
}
@article {pmid33772917,
year = {2022},
author = {Sepp, T and Meitern, R and Heidinger, B and Noreikiene, K and Rattiste, K and Hõrak, P and Saks, L and Kittilson, J and Urvik, J and Giraudeau, M},
title = {Parental age does not influence offspring telomeres during early life in common gulls (Larus canus).},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6197-6207},
doi = {10.1111/mec.15905},
pmid = {33772917},
issn = {1365-294X},
mesh = {Animals ; *Charadriiformes/genetics ; Telomere Shortening/genetics ; Telomere/genetics ; },
abstract = {Parental age can affect offspring telomere length through heritable and epigenetic-like effects, but at what stage during development these effects are established is not well known. To address this, we conducted a cross-fostering experiment in common gulls (Larus canus) that enabled us distinguish between pre- and post-natal parental age effects on offspring telomere length. Whole clutches were exchanged after clutch completion within and between parental age classes (young and old) and blood samples were collected from chicks at hatching and during the fastest growth phase (11 days later) to measure telomeres. Neither the ages of the natal nor the foster parents predicted the telomere length or the change in telomere lengths of their chicks. Telomere length (TL) was repeatable within chicks, but increased across development (repeatability = 0.55, intraclass correlation coefficient within sampling events 0.934). Telomere length and the change in telomere length were not predicted by post-natal growth rate. Taken together, these findings suggest that in common gulls, telomere length during early life is not influenced by parental age or growth rate, which may indicate that protective mechanisms buffer telomeres from external conditions during development in this relatively long-lived species.},
}
@article {pmid33772576,
year = {2021},
author = {Shubin, CB and Mayangsari, R and Swett, AD and Greider, CW},
title = {Rif1 regulates telomere length through conserved HEAT repeats.},
journal = {Nucleic acids research},
volume = {49},
number = {7},
pages = {3967-3980},
pmid = {33772576},
issn = {1362-4962},
support = {T32 GM007445/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites ; Protein Binding ; Protein Domains ; Repressor Proteins/*physiology ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/*physiology ; Telomere/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/*physiology ; },
abstract = {In budding yeast, Rif1 negatively regulates telomere length, but the mechanism of this regulation has remained elusive. Previous work identified several functional domains of Rif1, but none of these has been shown to mediate telomere length. To define Rif1 domains responsible for telomere regulation, we localized truncations of Rif1 to a single specific telomere and measured telomere length of that telomere compared to bulk telomeres. We found that a domain in the N-terminus containing HEAT repeats, Rif1177-996, was sufficient for length regulation when tethered to the telomere. Charged residues in this region were previously proposed to mediate DNA binding. We found that mutation of these residues disrupted telomere length regulation even when Rif1 was tethered to the telomere. Mutation of other conserved residues in this region, which were not predicted to interact with DNA, also disrupted telomere length maintenance, while mutation of conserved residues distal to this region did not. Our data suggest that conserved amino acids in the region from 436 to 577 play a functional role in telomere length regulation, which is separate from their proposed DNA binding function. We propose that the Rif1 HEAT repeats region represents a protein-protein binding interface that mediates telomere length regulation.},
}
@article {pmid33769480,
year = {2021},
author = {Galli, M and Frigerio, C and Longhese, MP and Clerici, M},
title = {The regulation of the DNA damage response at telomeres: focus on kinases.},
journal = {Biochemical Society transactions},
volume = {49},
number = {2},
pages = {933-943},
doi = {10.1042/BST20200856},
pmid = {33769480},
issn = {1470-8752},
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins/metabolism ; DNA/genetics/metabolism ; DNA Breaks, Double-Stranded ; *DNA Damage ; DNA Repair/*genetics ; Humans ; Models, Genetic ; Protein Kinases/*metabolism ; Proto-Oncogene Proteins c-ets/metabolism ; Repressor Proteins/metabolism ; Telomerase/metabolism ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/*metabolism ; ETS Translocation Variant 6 Protein ; },
abstract = {The natural ends of linear chromosomes resemble those of accidental double-strand breaks (DSBs). DSBs induce a multifaceted cellular response that promotes the repair of lesions and slows down cell cycle progression. This response is not elicited at chromosome ends, which are organized in nucleoprotein structures called telomeres. Besides counteracting DSB response through specialized telomere-binding proteins, telomeres also prevent chromosome shortening. Despite of the different fate of telomeres and DSBs, many proteins involved in the DSB response also localize at telomeres and participate in telomere homeostasis. In particular, the DSB master regulators Tel1/ATM and Mec1/ATR contribute to telomere length maintenance and arrest cell cycle progression when chromosome ends shorten, thus promoting a tumor-suppressive process known as replicative senescence. During senescence, the actions of both these apical kinases and telomere-binding proteins allow checkpoint activation while bulk DNA repair activities at telomeres are still inhibited. Checkpoint-mediated cell cycle arrest also prevents further telomere erosion and deprotection that would favor chromosome rearrangements, which are known to increase cancer-associated genome instability. This review summarizes recent insights into functions and regulation of Tel1/ATM and Mec1/ATR at telomeres both in the presence and in the absence of telomerase, focusing mainly on discoveries in budding yeast.},
}
@article {pmid33764576,
year = {2021},
author = {Lagnado, A and Leslie, J and Ruchaud-Sparagano, MH and Victorelli, S and Hirsova, P and Ogrodnik, M and Collins, AL and Vizioli, MG and Habiballa, L and Saretzki, G and Evans, SA and Salmonowicz, H and Hruby, A and Geh, D and Pavelko, KD and Dolan, D and Reeves, HL and Grellscheid, S and Wilson, CH and Pandanaboyana, S and Doolittle, M and von Zglinicki, T and Oakley, F and Gallage, S and Wilson, CL and Birch, J and Carroll, B and Chapman, J and Heikenwalder, M and Neretti, N and Khosla, S and Masuda, CA and Tchkonia, T and Kirkland, JL and Jurk, D and Mann, DA and Passos, JF},
title = {Neutrophils induce paracrine telomere dysfunction and senescence in ROS-dependent manner.},
journal = {The EMBO journal},
volume = {40},
number = {9},
pages = {e106048},
pmid = {33764576},
issn = {1460-2075},
support = {MR/K001949/1/MRC_/Medical Research Council/United Kingdom ; G0900535/MRC_/Medical Research Council/United Kingdom ; R01 AG050582/AG/NIA NIH HHS/United States ; R37 AG013925/AG/NIA NIH HHS/United States ; BB/K017314/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MR/K0019494/1/MRC_/Medical Research Council/United Kingdom ; 26813/CRUK_/Cancer Research UK/United Kingdom ; T32 AG049672/AG/NIA NIH HHS/United States ; BB/L502066/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; P01 AG062413/AG/NIA NIH HHS/United States ; 23390/CRUK_/Cancer Research UK/United Kingdom ; R01 AG068182/AG/NIA NIH HHS/United States ; NC/K000748/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; C18342/A23390/CRUK_/Cancer Research UK/United Kingdom ; MR/R023026/1/MRC_/Medical Research Council/United Kingdom ; R01 AG068048/AG/NIA NIH HHS/United States ; P30 DK084567/DK/NIDDK NIH HHS/United States ; },
mesh = {Acute Lung Injury/chemically induced/*immunology/metabolism ; Animals ; Carbon Tetrachloride/*adverse effects ; Cell Line ; Cellular Senescence ; Coculture Techniques ; Disease Models, Animal ; Female ; Fibroblasts/cytology/metabolism ; Humans ; Male ; Mice ; Neutrophils/*cytology/metabolism ; Oxidative Stress ; Paracrine Communication ; Reactive Oxygen Species/*metabolism ; *Telomere Shortening ; },
abstract = {Cellular senescence is characterized by an irreversible cell cycle arrest as well as a pro-inflammatory phenotype, thought to contribute to aging and age-related diseases. Neutrophils have essential roles in inflammatory responses; however, in certain contexts their abundance is associated with a number of age-related diseases, including liver disease. The relationship between neutrophils and cellular senescence is not well understood. Here, we show that telomeres in non-immune cells are highly susceptible to oxidative damage caused by neighboring neutrophils. Neutrophils cause telomere dysfunction both in vitro and ex vivo in a ROS-dependent manner. In a mouse model of acute liver injury, depletion of neutrophils reduces telomere dysfunction and senescence. Finally, we show that senescent cells mediate the recruitment of neutrophils to the aged liver and propose that this may be a mechanism by which senescence spreads to surrounding cells. Our results suggest that interventions that counteract neutrophil-induced senescence may be beneficial during aging and age-related disease.},
}
@article {pmid33763035,
year = {2021},
author = {Li, Y and Cheang, I and Zhang, Z and Yao, W and Zhou, Y and Zhang, H and Liu, Y and Zuo, X and Li, X and Cao, Q},
title = {Prognostic Association of TERC, TERT Gene Polymorphism, and Leukocyte Telomere Length in Acute Heart Failure: A Prospective Study.},
journal = {Frontiers in endocrinology},
volume = {12},
number = {},
pages = {650922},
pmid = {33763035},
issn = {1664-2392},
mesh = {Acute Disease ; Aged ; Alleles ; Female ; Gene Frequency ; Genotype ; Haplotypes ; Heart Failure/*diagnosis/*genetics ; Homozygote ; Humans ; Leukocytes/*cytology ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; Prognosis ; Proportional Hazards Models ; Prospective Studies ; RNA/*genetics ; Risk Factors ; Telomerase/*genetics ; Telomere/*ultrastructure ; Treatment Outcome ; },
abstract = {BACKGROUND: Telomere length and telomerase are associated in development of cardiovascular diseases. Study aims to investigate the associations of TERC and TERT gene polymorphism and leukocyte telomere length (LTL) in the prognosis of acute heart failure (AHF).<br><br>METHODS: Total 322 patients with AHF were enrolled and divided into death and survival group according to all-cause mortality within 18 months. Seven single nucleotide polymorphisms (SNPs) of TERC and TERT were selected. Baseline characteristics, genotype distribution and polymorphic allele frequency, and genetic model were initially analyzed. Genotypes and the LTL were determined for further analysis.<br><br>RESULTS: Compared to carrying homozygous wild genotype, the risk of death in patients with mutated alleles of four SNPs- rs12696304(G>C), rs10936599(T>C), rs1317082(G>A), and rs10936601(T>C) of TERC were significantly higher. The dominant models of above were independently associated with mortality. In recessive models, rs10936599 and rs1317082 of TERC, rs7726159 of TERT were independently associated with long-term mortality. Further analysis showed, in haplotype consisting with TERC - rs12696304, rs10936599, rs1317082, and rs10936601, mutant alleles CCAC and wild alleles GTGT were significant difference between groups (P<0.05). CCAC is a risk factor and GTGT is a protective factor for AHF patients. Relative LTL decreased over age, but showed no difference between groups and genotypes.<br><br>CONCLUSIONS: The SNPs of TERC and TERT are associated with the prognosis of AHF, and are the independent risk factors for predicting 18-month mortality in AHF.},
}
@article {pmid33758594,
year = {2021},
author = {Yamada, S and Misawa, K and Mima, M and Imai, A and Mochizuki, D and Yamada, T and Shinmura, D and Kita, J and Ishikawa, R and Yamaguchi, Y and Misawa, Y and Kawasaki, H and Mineta, H},
title = {Telomere shortening in head and neck cancer: association between DNA demethylation and survival.},
journal = {Journal of Cancer},
volume = {12},
number = {8},
pages = {2165-2172},
pmid = {33758594},
issn = {1837-9664},
abstract = {A growing body of evidence indicates that telomere dysfunction is a biological marker of progression in several types of cancer. However, the association between head and neck squamous cell carcinoma (HNSCC) and telomere length (TL) remains unknown. We measured the absolute TL levels in a well-characterised dataset of 211 tumoral vs normal tissues obtained from the same patients by quantitative polymerase chain reaction assay. Normalised TL levels were significantly lower in tumour samples than in normal tissue (P < 0.001) and there was a positive correlation between tumour tissue and normal mucosal tissue (R[2] = 0.176, P < 0.001). We were able to distinguish two classes, one with a tumour/normal TL ratio ≤ 0.3 (38.4%), which showed clear telomere erosion, and the other with a tumour/normal TL ratio > 0.3 (61.6%), in which the TL was slightly shorter or longer than that in normal tissue. Notably, the tumour/normal TL ratio was correlated with the likelihood of disease recurrence (P = 0.002), the 5-hydroxymethylcytosine level (P = 0.043), and expression of the ten-eleven translocation (TET) gene (P = 0.043). Our findings show that TL shortening and subsequent low levels of 5-hydroxymethylcytosine and TET expression may contribute to development of HNSCC.},
}
@article {pmid33754023,
year = {2021},
author = {Cai, Y and Liu, H and Song, E and Wang, L and Xu, J and He, Y and Zhang, D and Zhang, L and Cheng, KK and Jin, L and Wu, M and Liu, S and Qi, D and Zhang, L and Lopaschuk, GD and Wang, S and Xu, A and Xia, Z},
title = {Deficiency of telomere-associated repressor activator protein 1 precipitates cardiac aging in mice via p53/PPARα signaling.},
journal = {Theranostics},
volume = {11},
number = {10},
pages = {4710-4727},
pmid = {33754023},
issn = {1838-7640},
mesh = {Aging/*genetics ; Animals ; Benzothiazoles/pharmacology ; Cardiomegaly/diagnostic imaging/*genetics/physiopathology ; Cellular Senescence/*genetics ; DNA Damage ; Echocardiography ; Fatty Acids/metabolism ; Heart Diseases/diagnostic imaging/genetics/physiopathology ; Histones/metabolism ; Mice ; Mice, Knockout ; Mitochondria, Heart/metabolism/ultrastructure ; Myocytes, Cardiac/*metabolism ; Open Field Test ; PPAR alpha/*genetics/metabolism ; Peroxisome Proliferators/pharmacology ; Pyrimidines/pharmacology ; Shelterin Complex ; Signal Transduction ; Telomere/metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/*genetics/metabolism ; Toluene/analogs &amp; derivatives/pharmacology ; Tumor Suppressor Protein p53/antagonists &amp; inhibitors/*genetics/metabolism ; },
abstract = {Background: Telomere shortening and dysfunction may cause metabolic disorders, tissue damage and age-dependent pathologies. However, little is known about the association of telomere-associated protein Rap1 with mitochondrial energy metabolism and cardiac aging. Methods: Echocardiography was performed to detect cardiac structure and function in Rap1[+/+] and Rap1[-/-] mice at different ages (3 months, 12 months and 20 months). Telomere length, DNA damage, cardiac senescence and cardiomyocyte size were analyzed using the real-time PCR, Western blotting, senescence associated β-galactosidase assay and wheat germ agglutinin staining, respectively. Western blotting was also used to determine the level of cardiac fatty acid metabolism related key enzymes in mouse and human myocardium. Chromatin immunoprecipitation assay was used to verify the direct link between p53 and PPARα. The p53 inhibitor, Pifithrin-α and PPARα activator WY14643 were utilized to identify the effects of Rap1/p53/PPARα signaling pathway. Results: Telomere was shortened concomitant with extensive DNA damage in aged Rap1[-/-] mouse hearts, evidenced by reduced T/S ratios and increased nuclear γH2AX. Meanwhile, the aging-associated phenotypes were pronounced as reflected by altered mitochondrial ultrastructure, enhanced senescence, cardiac hypertrophy and dysfunction. Mechanistically, acetylated p53 and nuclear p53 was enhanced in the Rap1[-/-] mouse hearts, concomitant with reduced PPARα. Importantly, p53 directly binds to the promoter of PPARα in mouse hearts and suppresses the transcription of PPARα. In addition, aged Rap1[-/-] mice exhibited reduced cardiac fatty acid metabolism. Pifithrin-α alleviated cardiac aging and enhanced fatty acid metabolism in the aged Rap1[-/-] mice. Activating PPARα with WY14643 in primarily cultured Rap1[-/-] cardiomyocytes restored maximal oxygen consumption rates. Reduced Rap1 expression and impaired p53/PPARα signaling also presented in aged human myocardium. Conclusion: In summary, Rap1 may link telomere biology to fatty acid metabolism and aging-related cardiac pathologies via modulating the p53/PPARα signaling pathway, which could represent a therapeutic target in preventing/attenuating cardiac aging.},
}
@article {pmid33752601,
year = {2021},
author = {Lyčka, M and Peska, V and Demko, M and Spyroglou, I and Kilar, A and Fajkus, J and Fojtová, M},
title = {WALTER: an easy way to online evaluate telomere lengths from terminal restriction fragment analysis.},
journal = {BMC bioinformatics},
volume = {22},
number = {1},
pages = {145},
pmid = {33752601},
issn = {1471-2105},
support = {18-07027S//Grantov&#xe1; Agentura &#x10c;esk&#xe9; Republiky/ ; CZ.02.1.01/0.0 /0.0/15_003/0000477//European Regional and Development Fund/ ; },
mesh = {*Software ; *Telomere/genetics ; },
abstract = {BACKGROUND: Telomeres, nucleoprotein structures comprising short tandem repeats and delimiting the ends of linear eukaryotic chromosomes, play an important role in the maintenance of genome stability. Therefore, the determination of the length of telomeres is of high importance for many studies. Over the last years, new methods for the analysis of the length of telomeres have been developed, including those based on PCR or analysis of NGS data. Despite that, terminal restriction fragment (TRF) method remains the gold standard to this day. However, this method lacks universally accepted and precise tool capable to analyse and statistically evaluate TRF results.<br><br>RESULTS: To standardize the processing of TRF results, we have developed WALTER, an online toolset allowing rapid, reproducible, and user-friendly analysis including statistical evaluation of the data. Given its web-based nature, it provides an easily accessible way to analyse TRF data without any need to install additional software.<br><br>CONCLUSIONS: WALTER represents a major upgrade from currently available tools for the image processing of TRF scans. This toolset enables a rapid, highly reproducible, and user-friendly evaluation of almost any TRF scan including in-house statistical evaluation of the data. WALTER platform together with user manual describing the evaluation of TRF scans in detail and presenting tips and troubleshooting, as well as test data to demo the software are available at https://www.ceitec.eu/chromatin-molecular-complexes-jiri-fajkus/rg51/tab?tabId=125#WALTER and the source code at https://github.com/mlyc93/WALTER .},
}
@article {pmid33750872,
year = {2021},
author = {Young, RC and Kitaysky, AS and Drummond, HM},
title = {Telomere lengths correlate with fitness but assortative mating by telomeres confers no benefit to fledgling recruitment.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {5463},
pmid = {33750872},
issn = {2045-2322},
mesh = {Animals ; Birds/*physiology ; Breeding ; Female ; Longevity ; Male ; Reproduction ; *Telomere Homeostasis ; },
abstract = {Assortative mating by telomere lengths has been observed in several bird species, and in some cases may increase fitness of individuals. Here we examined the relationship between telomere lengths of Blue-footed Booby (Sula nebouxii) mates, long-lived colonial seabirds with high annual divorce rates. We tested the hypothesis that interactions between maternal and paternal telomere lengths affect offspring and parental survival. We found that relative telomere lengths (RTL) were strongly positively correlated between members of a breeding pair. In addition, RTL of both parents interacted to predict fledgling recruitment, although fledglings with two very long-RTL parents performed only averagely. Telomere lengths also predicted adult survival: birds with long telomeres were more likely to survive, but birds whose mate had long telomeres were less likely to survive. Thus, having long telomeres benefits survival, while choosing a mate with long telomeres benefits reproductive output while penalizing survival. These patterns demonstrate that while a breeder's RTL predicts offspring quality, assortative mating by RTL does not enhance fitness, and a trade-off between different components of fitness may govern patterns of assortative mating by telomere length. They also illustrate how testing the adaptive value of only one parent's telomere length on either survival or reproductive success alone may provide equivocal results.},
}
@article {pmid33749670,
year = {2021},
author = {Godwin, LS and Bridger, JM and Foster, HA},
title = {Fluorescence In Situ Hybridization on DNA Halo Preparations to Reveal Whole Chromosomes, Telomeres and Gene Loci.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {169},
pages = {},
doi = {10.3791/62017},
pmid = {33749670},
issn = {1940-087X},
mesh = {Cell Nucleus/metabolism ; Cells, Cultured ; Chromosomes/*metabolism ; Chromosomes, Artificial, Bacterial/metabolism ; DNA/*metabolism ; Dermis/cytology ; Fibroblasts/metabolism ; *Genetic Loci ; Humans ; Image Processing, Computer-Assisted ; *In Situ Hybridization, Fluorescence ; Telomere/*metabolism ; },
abstract = {The genome is associated with several structures inside cell nuclei, in order to regulate its activity and anchor it in specific locations. These structures are collectively known as the nucleoskeleton and include the nuclear lamina, the nucleoli, and nuclear bodies. Although many variants of fluorescence in situ hybridization (FISH) exist to study the genome and its organization, these are often limited by resolution and provide insufficient information on the genome's association with nuclear structures. The DNA halo method uses high salt concentrations and nonionic detergents to generate DNA loops that remain anchored to structures within nuclei through attachment regions within the genome. Here, soluble nuclear proteins, such as histones, lipids, and DNA not tightly bound to the nuclear matrix, are extracted. This leads to the formation of a halo of unattached DNA surrounding a residual nucleus which itself contains DNA closely associated with internal nuclear structures and extraction-resistant proteins. These extended DNA strands enable increased resolution and can facilitate physical mapping. In combination with FISH, this method has the added advantage of studying genomic interactions with all the structures that the genome is anchored by. This technique, termed HALO-FISH, is highly versatile whereby DNA halos can be coupled with nucleic acid probes to reveal gene loci, whole chromosomes, alpha satellite, telomeres and even RNA. This technique provides an insight into nuclear organization and function in normal cells and in disease progression such as with cancer.},
}
@article {pmid33749133,
year = {2021},
author = {Ismail, H and Helby, J and Hölmich, LR and H Chakera, A and Bastholt, L and Klyver, H and Sjøgren, P and Schmidt, H and Schöllhammer, L and Nordestgaard, BG and Bojesen, SE},
title = {Genetic predisposition to long telomeres is associated with increased mortality after melanoma: A study of 2101 melanoma patients from hospital clinics and the general population.},
journal = {Pigment cell &amp; melanoma research},
volume = {34},
number = {5},
pages = {946-954},
doi = {10.1111/pcmr.12971},
pmid = {33749133},
issn = {1755-148X},
mesh = {Adult ; Aged ; Alleles ; Disease-Free Survival ; Female ; *Genetic Predisposition to Disease ; Humans ; Male ; Melanoma/*genetics/metabolism/*mortality ; Middle Aged ; Neoplasm Proteins/*genetics/metabolism ; *Polymorphism, Single Nucleotide ; Survival Rate ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Whether there is an association between measured and genetically predicted telomere length and melanoma mortality is unclear. We tested the hypothesis that measured and genetically predicted telomere length is associated with mortality after a melanoma diagnosis. We followed 2,101 patients with melanoma from hospital clinics and the general population for risk of death for up to 26 years. All had telomere length measured in DNA from leukocytes, and 2052 of these were genotyped for the three single nucleotide polymorphisms rs7726159 (TERT), rs1317082 (TERC), and rs2487999 (OBFC1); all three genotypes are associated with telomere length and combined into an allele count from 0 to 6. For each telomere-lengthening allele, the hazard ratios (HRs) for mortality in the age-adjusted and multivariable-adjusted Cox analysis were 1.12 (95% confidence interval: 1.02-1.23) and 1.11 (1.01-1.23). However, for each standard deviation increase in measured telomere length, HR for mortality was 0.97 (0.88-1.08). In conclusion, in more than 2000 melanoma patients from hospital clinics and from the general population, genetically predicted long telomeres were associated with increased mortality, but measured leukocyte telomere length was not.},
}
@article {pmid33744488,
year = {2021},
author = {Adam, N and Beattie, TL and Riabowol, K},
title = {Fluorescence microscopy methods for examining telomeres during cell aging.},
journal = {Ageing research reviews},
volume = {68},
number = {},
pages = {101320},
doi = {10.1016/j.arr.2021.101320},
pmid = {33744488},
issn = {1872-9649},
support = {MOP-133646//CIHR/Canada ; },
mesh = {Aging/genetics ; *Cellular Senescence ; Genomic Instability ; Humans ; Microscopy, Fluorescence ; *Telomere ; },
abstract = {Telomeres are protective structures, composed of nucleic acids and a complex protein mixture, located at the end of the chromosomes. They play an important role in preventing genomic instability and ensuring cell health. Defects in telomere integrity result in cell dysfunction and the development of diseases, including neurodegenerative disorders, cancer and premature aging syndromes, among others. Loss of telomere integrity during normal cell aging also initiates DNA damage signals that culminate in the senescence phenotype. Fluorescence microscopy has allowed researchers to study the dynamics, shape, localization, and co-distribution of telomeres with proteins of interest. The microscopy tools to investigate these structures have evolved, making it possible to understand in greater detail the molecular mechanisms affecting telomeres that contribute to cell aging and the development of age-related diseases. Using human fibroblasts as an example, we will highlight several characteristics of telomeres that can be investigated using three different microscopy systems, including wide-field microscopy, and the two super-resolution techniques called 3D Structured Illumination Microscopy (3D-SIM) and direct Stochastic Optical Reconstruction Microscopy (dSTORM). In this review, we will also discuss their limitations and highlight their importance in answering telomere-related scientific questions.},
}
@article {pmid33740104,
year = {2021},
author = {Beier, F and Esser, A and Vankann, L and Abels, A and Schettgen, T and Kraus, T and Brümmendorf, TH and Ziegler, P},
title = {Longitudinal changes in telomere length in PCB-exposed individuals: interaction with CMV infection.},
journal = {Archives of toxicology},
volume = {95},
number = {4},
pages = {1517-1520},
pmid = {33740104},
issn = {1432-0738},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*immunology ; Cohort Studies ; Cytomegalovirus Infections/*complications/immunology ; Follow-Up Studies ; Humans ; Longitudinal Studies ; Lymphocytes/immunology ; Middle Aged ; Polychlorinated Biphenyls/*toxicity ; Telomere/drug effects/*immunology/virology ; Telomere Shortening/immunology ; Time Factors ; Young Adult ; },
abstract = {We recently demonstrated a significant shortening of age-adapted telomere length (TL) in lymphocytes of polychlorinated biphenyls (PCB)-exposed individuals. Here, we analyzed TL in individuals of the same PCB-exposed cohort during a 6-year follow-up period, investigating the change in TL between the first and second measurement as a function of time, concentration of PCBs and cytomegalovirus (CMV) infection. The age-adjusted TL of lymphocytes within the cohort of PCB-exposed individuals recovered from a first assessment in 2011 to a second assessment in 2017. Remarkably, if the concentration of lower chlorinated PCBs (LC PCBs) in 2011 was high (≥ 0.055 µg/L), the TL of CMV seropositive individuals remained significantly shortened both compared to age-adjusted controls as well as intra individually. This was confirmed by analysis of covariance as well as by multivariate linear mixed effects models. Since telomeres are responsive to various stress response pathways, including viral infection, we conclude that PCBs could contribute to immune senescence-like phenotypes associated with CMV infections and exacerbate negative aspects associated with the aging of the immune system.},
}
@article {pmid33737296,
year = {2021},
author = {Brown, DW and Lan, Q and Rothman, N and Pluta, J and Almstrup, K and Dalgaard, MD and Greene, MH and Grotmol, T and Loveday, C and Schwartz, SM and Turnbull, C and Wiklund, F and Kanetsky, PA and Nathanson, KL and McGlynn, KA and Machiela, MJ and , },
title = {Genetically Inferred Telomere Length and Testicular Germ Cell Tumor Risk.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {30},
number = {6},
pages = {1275-1278},
pmid = {33737296},
issn = {1538-7755},
support = {R01 CA114478/CA/NCI NIH HHS/United States ; U01 CA164947/CA/NCI NIH HHS/United States ; R01 CA085914/CA/NCI NIH HHS/United States ; P30 ES013508/ES/NIEHS NIH HHS/United States ; N01PC35142/CA/NCI NIH HHS/United States ; P30 CA016520/CA/NCI NIH HHS/United States ; N01 CN067009/CN/NCI NIH HHS/United States ; ZIA CP010126/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Case-Control Studies ; Genetic Predisposition to Disease ; Humans ; Male ; Mendelian Randomization Analysis ; Neoplasms, Germ Cell and Embryonal/*epidemiology/genetics ; Risk Assessment/statistics &amp; numerical data ; Risk Factors ; Telomere/*metabolism ; Telomere Homeostasis/*genetics ; Testicular Neoplasms/*epidemiology/genetics ; },
abstract = {BACKGROUND: Studies evaluating the association between peripheral blood leukocyte telomere length (LTL) and testicular germ cell tumor (TGCT) risk have produced conflicting results.<br><br>METHODS: Using available genotype data from the Testicular Cancer Consortium (TECAC), polygenic risk score and Mendelian randomization analyses of genetic variants previously associated with LTL were used to assess potential etiologic associations between telomere length and TGCT risk.<br><br>RESULTS: Genetically inferred telomere length was not associated with TGCT risk among 2,049 cases and 6,921 controls with individual-level genotype data (OR, 1.02; 95% confidence interval, 0.97-1.07). Mendelian randomization analyses using summary statistic data further indicated no evidence for an association between telomere length and TGCT risk among all available TECAC participants (3,558 cases and 13,971 controls).<br><br>CONCLUSIONS: Our analyses in the largest molecular genetic testicular cancer study to date provide no evidence for an association between genetically inferred peripheral blood LTL and TGCT risk.<br><br>IMPACT: The lack of evidence for an overall association indicates that peripheral blood LTL is likely not a strong biomarker for TGCT risk.},
}
@article {pmid33735395,
year = {2021},
author = {Welendorf, CR and Nicoletti, CF and Noronha, NY and Ferreira, FC and Wolf, LS and de Souza Pinhel, MA and Pinhanelli, VC and de Oliveira, CC and de Oliveira, BAP and Dos Santos Martins, L and Junior, WS and Nonino, CB},
title = {The Impact of Gastric Bypass on Telomere Length and Shelterin Complex Gene Expression: 6 Months Prospective Study.},
journal = {Obesity surgery},
volume = {31},
number = {6},
pages = {2599-2606},
pmid = {33735395},
issn = {1708-0428},
mesh = {Female ; *Gastric Bypass ; Gene Expression ; Humans ; *Obesity, Morbid/surgery ; Prospective Studies ; Telomere/genetics ; },
abstract = {BACKGROUND: Telomeres are structures located at the ends of chromosomes associated with a protein complex, known as the shelterin complex. In individuals with obesity, excess adipose tissue plays a key role in inducing a chronic and systemic inflammatory state, which can cause TL shortening. In this context, bariatric surgery is one of the most effective treatment modalities in improving metabolic control.<br><br>AIM: Therefore, the present study aimed to evaluate how a short postoperative period of gastric bypass affects TL and expression of POT1, TRF1 and TRF2 genes.<br><br>METHODS: Forty-eight women submitted to RYGB were evaluated before and after 6 months of the surgical procedure. Anthropometric measures of body weight and height (BMI), abdominal circumference (AC), body composition, food intake and blood collection for biochemical evaluation, TL analysis (DNA), and gene expression (RNA) were collected at each moment.<br><br>RESULTS: There was a reduction of weight, BMI, AC, FM and FFM as well as of glycemia, total cholesterol, LDL-cholesterol, and triglycerides after gastric bypass. No difference in energy intake and macronutrients consumption was observed. There was no significant change in TL, but there was a significant increase of POT1 and TRF1 gene expression after surgery, while TRF2 expression did not change.<br><br>CONCLUSIONS: Despite bariatric surgery is not capable of increasing telomere length in a short-term period, no reduction is observed; additionally, we found a correlation between serum triglycerides concentration and TL. The increase of POT1 and TRF1 gene expression may explain the maintenance of the TL after 6 months postoperative period.},
}
@article {pmid33732625,
year = {2021},
author = {Doroschuk, NA and Postnov, AY and Doroschuk, AD and Ryzhkova, AI and Sinyov, VV and Sazonova, MD and Khotina, VA and Orekhov, AN and Sobenin, IA and Sazonova, MA},
title = {An original biomarker for the risk of developing cardiovascular diseases and their complications: Telomere length.},
journal = {Toxicology reports},
volume = {8},
number = {},
pages = {499-504},
pmid = {33732625},
issn = {2214-7500},
abstract = {AIM: The aim of this work was to study the effect of telomere length in the chromosomes of nuclear blood cells in individuals with coronary heart disease (CHD) on the development of cardiovascular complications (CVC).<br><br>MATERIALS AND METHODS: DNA was isolated from nuclear blood cells of 498 study participants. The telomere length was determined by real-time polymerase chain reaction. The investigation of each sample was repeated three times. Five years after the end of this study, a telephone survey of 119 patients with CHD was conducted in order to obtain data on the presence of CVC.<br><br>RESULTS: According to the results obtained, a decrease in telomere length in patients with coronary heart disease increases the risk of subsequent development of cardiovascular complications.<br><br>CONCLUSION: Patients with coronary heart disease with shorter telomeres compared with conventionally healthy study participants had an increased risk of cardiovascular complications within 5 years after telomere analysis.},
}
@article {pmid33732317,
year = {2021},
author = {Sibert, NT and Ventura Ferreira, MS and Wagner, W and Eipel, M and Dreschers, S and Brümmendorf, TH and Orlikowsky, T and Beier, F},
title = {Cord blood telomere shortening associates with increased gestational age and birth weight in preterm neonates.},
journal = {Experimental and therapeutic medicine},
volume = {21},
number = {4},
pages = {344},
pmid = {33732317},
issn = {1792-0981},
abstract = {Preterm birth is considered to be associated with premature cellular aging. To address this question, two hallmarks of aging were analyzed in cord blood cells, namely telomere length and age-associated DNA methylation. Cord blood samples from 35 preterm and 11 full-term neonates were enrolled in the present study. Furthermore, quantitative telomere fluorescence in situ hybridization and flow cytometry (flow-FISH) were applied to demonstrate that telomere shortening was strongly associated with advanced gestational age and increased birth weight (R[2]=0.267 for granulocytes and R[2]=0.307 for lymphocytes). The estimated rate of telomere attrition in newborns during gestation ranged from 126 base pairs (bp)/week and 186 bp/week for granulocytes and lymphocytes, respectively. In addition, neonates with longer telomeres at birth were characterized by increased weight gain during the first year of their life compared with that noted to neonates with shorter telomeres. By contrast, the epigenetic aging signature (EAS) revealed a negative correlation between epigenetic age and premature birth of unclear basis (R[2]=0.26). Pending prospective validation in a larger patient cohort, the present study suggested that telomere length may be a novel biomarker alone or in combination with traditional indicators for the prediction of weight development in preterm neonates.},
}
@article {pmid33728719,
year = {2022},
author = {Boonekamp, J and Rodríguez-Muñoz, R and Hopwood, P and Zuidersma, E and Mulder, E and Wilson, A and Verhulst, S and Tregenza, T},
title = {Telomere length is highly heritable and independent of growth rate manipulated by temperature in field crickets.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6128-6140},
doi = {10.1111/mec.15888},
pmid = {33728719},
issn = {1365-294X},
mesh = {Animals ; Infant ; Humans ; *Gryllidae/genetics ; Temperature ; Telomere Homeostasis ; Longevity ; Telomere/genetics ; },
abstract = {Many organisms are capable of growing faster than they do. Restrained growth rate has functionally been explained by negative effects on lifespan of accelerated growth. However, the underlying mechanisms remain elusive. Telomere attrition has been proposed as a causal agent and has been mostly studied in endothermic vertebrates. We established that telomeres exist as chromosomal-ends in a model insect, the field cricket Gryllus campestris, using terminal restriction fragment and Bal 31 methods. Telomeres comprised TTAGGn repeats of 38 kb on average, more than four times longer than the telomeres of human infants. Bal 31 assays confirmed that telomeric repeats were located at the chromosome-ends. We tested whether rapid growth between day 1, day 65, day 85, and day 125 is achieved at the expense of telomere length by comparing nymphs reared at 23°C with their siblings reared at 28°C, which grew three times faster in the initial 65 days. Surprisingly, neither temperature treatment nor age affected average telomere length. Concomitantly, the broad sense heritability of telomere length was remarkably high at ~100%. Despite high heritability, the evolvability (a mean-standardized measure of genetic variance) was low relative to that of body mass. We discuss our findings in the context of telomere evolution. Some important features of vertebrate telomere biology are evident in an insect species dating back to the Triassic. The apparent lack of an effect of growth rate on telomere length is puzzling, suggesting strong telomere length maintenance during the growth phase. Whether such maintenance of telomere length is adaptive remains elusive and requires further study investigating the links with fitness in the wild.},
}
@article {pmid33726560,
year = {2021},
author = {Espigares, F and Abad-Tortosa, D and Varela, SAM and Ferreira, MG and Oliveira, RF},
title = {Short telomeres drive pessimistic judgement bias in zebrafish.},
journal = {Biology letters},
volume = {17},
number = {3},
pages = {20200745},
pmid = {33726560},
issn = {1744-957X},
mesh = {Animals ; *Pessimism ; *Telomerase/genetics/metabolism ; Telomere/genetics ; Telomere Shortening ; Zebrafish/genetics ; },
abstract = {The role of telomerase reverse transcriptase has been widely investigated in the contexts of ageing and age-related diseases. Interestingly, decreased telomerase activities (and accelerated telomere shortening) have also been reported in patients with emotion-related disorders, opening the possibility for subjective appraisal of stressful stimuli playing a key role in stress-driven telomere shortening. In fact, patients showing a pessimistic judgement bias have shorter telomeres. However, in humans the evidence for this is correlational and the causal directionality between pessimism and telomere shortening has not been established experimentally yet. We have developed and validated a judgement bias experimental paradigm to measure subjective evaluations of ambiguous stimuli in zebrafish. This behavioural assay allows classification of individuals in an optimistic-pessimistic dimension (i.e. from individuals that consistently evaluate ambiguous stimuli as negative to others that perceive them as positive). Using this behavioural paradigm we found that telomerase-deficient zebrafish (tert[-][/-]) were more pessimistic in response to ambiguous stimuli than wild-type zebrafish. The fact that individuals with constitutive shorter telomeres have pessimistic behaviours demonstrates for the first time in a vertebrate model a genetic basis of judgement bias.},
}
@article {pmid33724410,
year = {2021},
author = {McGurk, MP and Dion-Côté, AM and Barbash, DA},
title = {Rapid evolution at the Drosophila telomere: transposable element dynamics at an intrinsically unstable locus.},
journal = {Genetics},
volume = {217},
number = {2},
pages = {},
pmid = {33724410},
issn = {1943-2631},
support = {R01 GM074737/GM/NIGMS NIH HHS/United States ; R01 GM119125/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *DNA Transposable Elements ; Drosophila melanogaster ; *Evolution, Molecular ; Genomic Instability ; Polymorphism, Genetic ; Recombination, Genetic ; Telomere/*genetics ; },
abstract = {Drosophila telomeres have been maintained by three families of active transposable elements (TEs), HeT-A, TAHRE, and TART, collectively referred to as HTTs, for tens of millions of years, which contrasts with an unusually high degree of HTT interspecific variation. While the impacts of conflict and domestication are often invoked to explain HTT variation, the telomeres are unstable structures such that neutral mutational processes and evolutionary tradeoffs may also drive HTT evolution. We leveraged population genomic data to analyze nearly 10,000 HTT insertions in 85 Drosophila melanogaster genomes and compared their variation to other more typical TE families. We observe that occasional large-scale copy number expansions of both HTTs and other TE families occur, highlighting that the HTTs are, like their feral cousins, typically repressed but primed to take over given the opportunity. However, large expansions of HTTs are not caused by the runaway activity of any particular HTT subfamilies or even associated with telomere-specific TE activity, as might be expected if HTTs are in strong genetic conflict with their hosts. Rather than conflict, we instead suggest that distinctive aspects of HTT copy number variation and sequence diversity largely reflect telomere instability, with HTT insertions being lost at much higher rates than other TEs elsewhere in the genome. We extend previous observations that telomere deletions occur at a high rate, and surprisingly discover that more than one-third do not appear to have been healed with an HTT insertion. We also report that some HTT families may be preferentially activated by the erosion of whole telomeres, implying the existence of HTT-specific host control mechanisms. We further suggest that the persistent telomere localization of HTTs may reflect a highly successful evolutionary strategy that trades away a stable insertion site in order to have reduced impact on the host genome. We propose that HTT evolution is driven by multiple processes, with niche specialization and telomere instability being previously underappreciated and likely predominant.},
}
@article {pmid33722350,
year = {2021},
author = {Cherdyntseva, V and Gagos, S},
title = {Corrigendum to: "Chromosome extremities under the microscopy lens: molecular cytogenetics in telomere research". [Curr Opin Genet Dev. 2020; 60:69-76].},
journal = {Current opinion in genetics &amp; development},
volume = {66},
number = {},
pages = {110-111},
doi = {10.1016/j.gde.2021.02.002},
pmid = {33722350},
issn = {1879-0380},
}
@article {pmid33720621,
year = {2021},
author = {Doroshchuk, NA and Lankin, VZ and Tikhaze, AK and Kheimets, GI and Doroshсhuk, AD and Smirnova, MD and Chazova, IE},
title = {[Telomere length as a biomarker of the risk of cardiovascular complications in patients with coronary heart disease].},
journal = {Terapevticheskii arkhiv},
volume = {93},
number = {1},
pages = {20-24},
doi = {10.26442/00403660.2021.01.200588},
pmid = {33720621},
issn = {0040-3660},
mesh = {Biomarkers ; *Coronary Disease/diagnosis/epidemiology/genetics ; Humans ; Leukocytes ; Lipoproteins, LDL ; *Telomere/genetics ; },
abstract = {AIM: To study the effect of oxidative stress and telomere length in the chromosomes of blood leukocytes in patients with coronary heart disease (CHD) on the development of cardiovascular complications.<br><br>MATERIALS AND METHODS: In 119 patients with CHD, the level of oxidatively modified low-density lipoproteins (ox-LDL) in blood plasma and the length of telomeres in nuclear blood cells were determined during the examination. After 5 years, a telephone survey of patients (or their relatives) was conducted to obtain data on the presence of cardiovascular complications. Telomere length was determined using quantitative real-time PCR, and the level of ox-LDL was determined by immunochemical method.<br><br>RESULTS: It was found that reducing the length of telomeres in patients with CHD increases the risk of subsequent development of cardiovascular complications. A strong negative correlation was found between the level of ox-LDL and telomere length in the group of examined CHD patients who had cardiovascular complications after 5 years.<br><br>CONCLUSION: CHD patients with short telomere length and high levels of ox-LDL have an increased risk of cardiovascular complications during 5 years.},
}
@article {pmid33720476,
year = {2022},
author = {Garfein, J and Flannagan, KS and Rittman, D and Ramirez-Zea, M and Villamor, E and , },
title = {Leukocyte telomere length is inversely associated with a metabolic risk score in Mesoamerican children.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {34},
number = {1},
pages = {e23596},
doi = {10.1002/ajhb.23596},
pmid = {33720476},
issn = {1520-6300},
support = {HHSN268200900028C/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Blood Glucose ; Body Mass Index ; Child ; Cross-Sectional Studies ; Humans ; Leukocytes ; *Metabolic Syndrome/epidemiology ; Risk Factors ; Telomere ; Triglycerides ; Waist Circumference ; },
abstract = {OBJECTIVE: Leukocyte telomere length (LTL) may be involved in the etiology of the metabolic syndrome (MetS). We examined the associations of LTL with MetS and its components among Mesoamerican children and their adult parents, in a region where MetS prevalence is high.<br><br>METHODS: We conducted a cross-sectional study of 151 children aged 7-12&#x2009;years and 346 parents from the capitals of Belize, Honduras, Nicaragua, Costa Rica, Panama, and Chiapas State, Mexico. We quantified LTL by qPCR on DNA extracted from whole blood. In children, we created an age- and sex-standardized metabolic risk score using waist circumference (WC), the homeostasis model of insulin resistance (HOMA-IR), blood pressure, serum high-density lipoprotein (HDL) cholesterol, and serum triglycerides. In adults, MetS was defined according to the National Cholesterol Education Program's Adult Treatment Panel III definition. We estimated mean differences in metabolic risk score and prevalence ratios of MetS across quartiles of LTL using multivariable-adjusted linear and Poisson regression models, respectively.<br><br>RESULTS: In children, every 1 LTL z-score was related to an adjusted 0.05&#x2009;units lower (95% CI: -0.09, -0.02, P&#xa0;=&#x2009;0.005) MetS risk score, through WC, HOMA-IR, and HDL. Among adults, LTL was not associated with MetS prevalence; however, every 1 LTL z-score was associated with an adjusted 34% lower prevalence of high fasting glucose (95% CI: 3%, 55%, p&#xa0;=&#xa0;.03).<br><br>CONCLUSIONS: Among Mesoamerican children, LTL is associated with an improved metabolic profile; among adults, LTL is inversely associated with the prevalence of high fasting glucose.},
}
@article {pmid33719348,
year = {2021},
author = {Lue, NF},
title = {Duplex Telomere-Binding Proteins in Fungi With Canonical Telomere Repeats: New Lessons in the Rapid Evolution of Telomere Proteins.},
journal = {Frontiers in genetics},
volume = {12},
number = {},
pages = {638790},
pmid = {33719348},
issn = {1664-8021},
support = {R01 GM107287/GM/NIGMS NIH HHS/United States ; },
abstract = {The telomere protein assemblies in different fungal lineages manifest quite profound structural and functional divergence, implying a high degree of flexibility and adaptability. Previous comparative analyses of fungal telomeres have focused on the role of telomere sequence alterations in promoting the evolution of corresponding proteins, particularly in budding and fission yeast. However, emerging evidence suggests that even in fungi with the canonical 6-bp telomere repeat unit, there are significant remodeling of the telomere assembly. Indeed, a new protein family can be recruited to serve dedicated telomere functions, and then experience subsequent loss in sub-branches of the clade. An especially interesting example is the Tay1 family of proteins, which emerged in fungi prior to the divergence of basidiomycetes from ascomycetes. This relatively recent protein family appears to have acquired its telomere DNA-binding activity through the modification of another Myb-containing protein. Members of the Tay1 family evidently underwent rather dramatic functional diversification, serving, e.g., as transcription factors in fission yeast while acting to promote telomere maintenance in basidiomycetes and some hemi-ascomycetes. Remarkably, despite its distinct structural organization and evolutionary origin, a basidiomycete Tay1 appears to promote telomere replication using the same mechanism as mammalian TRF1, i.e., by recruiting and regulating Blm helicase activity. This apparent example of convergent evolution at the molecular level highlight the ability of telomere proteins to acquire new interaction targets. The remarkable evolutionary history of Tay1 illustrates the power of protein modularity and the facile acquisition of nucleic acid/protein-binding activity to promote telomere flexibility.},
}
@article {pmid33712616,
year = {2021},
author = {Baxley, RM and Leung, W and Schmit, MM and Matson, JP and Yin, L and Oram, MK and Wang, L and Taylor, J and Hedberg, J and Rogers, CB and Harvey, AJ and Basu, D and Taylor, JC and Pagnamenta, AT and Dreau, H and Craft, J and Ormondroyd, E and Watkins, H and Hendrickson, EA and Mace, EM and Orange, JS and Aihara, H and Stewart, GS and Blair, E and Cook, JG and Bielinsky, AK},
title = {Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {1626},
pmid = {33712616},
issn = {2041-1723},
support = {R01 GM134681/GM/NIGMS NIH HHS/United States ; R01 GM083024/GM/NIGMS NIH HHS/United States ; P30 CA077598/CA/NCI NIH HHS/United States ; UL1 TR002494/TR/NCATS NIH HHS/United States ; R01 GM074917/GM/NIGMS NIH HHS/United States ; T32 CA009138/CA/NCI NIH HHS/United States ; R25 GM055336/GM/NIGMS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 GM102413/GM/NIGMS NIH HHS/United States ; WT 100127/WT_/Wellcome Trust/United Kingdom ; R01 AI120989/AI/NIAID NIH HHS/United States ; /DH_/Department of Health/United Kingdom ; P30 CA016086/CA/NCI NIH HHS/United States ; R35 GM118047/GM/NIGMS NIH HHS/United States ; R01 CA190492/CA/NCI NIH HHS/United States ; },
mesh = {*Alleles ; Cardiomyopathies/*genetics ; Cell Cycle Proteins/metabolism ; Cell Line ; DNA Replication ; DNA-Binding Proteins/genetics/metabolism ; Endonucleases/genetics/metabolism ; Humans ; Killer Cells, Natural ; Minichromosome Maintenance Proteins/*genetics/*immunology ; *Telomere Shortening ; },
abstract = {Minichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus. To understand the mechanism of MCM10-associated disease, we modeled these variants in human cell lines. MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion. Our data suggest that loss of MCM10 function constrains telomerase activity by accumulating abnormal replication fork structures enriched with single-stranded DNA. Terminally-arrested replication forks in MCM10-deficient cells require endonucleolytic processing by MUS81, as MCM10:MUS81 double mutants display decreased viability and accelerated telomere shortening. We propose that these bi-allelic variants in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes observed in both NKD and RCM patients.},
}
@article {pmid33712600,
year = {2021},
author = {Shiromoto, Y and Sakurai, M and Minakuchi, M and Ariyoshi, K and Nishikura, K},
title = {ADAR1 RNA editing enzyme regulates R-loop formation and genome stability at telomeres in cancer cells.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {1654},
pmid = {33712600},
issn = {2041-1723},
support = {P30 CA010815/CA/NCI NIH HHS/United States ; R01 CA175058/CA/NCI NIH HHS/United States ; R01 GM040536/GM/NIGMS NIH HHS/United States ; R01 GM130716/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenosine Deaminase/genetics/*metabolism ; Animals ; Cell Line, Tumor ; DNA ; DNA Damage ; *Genomic Instability ; Genomics ; HEK293 Cells ; HeLa Cells ; Humans ; Mice ; Neoplasms/genetics/*metabolism ; *R-Loop Structures ; *RNA Editing ; RNA-Binding Proteins/genetics/*metabolism ; Telomere/*metabolism ; Transcriptome ; },
abstract = {ADAR1 is involved in adenosine-to-inosine RNA editing. The cytoplasmic ADAR1p150 edits 3'UTR double-stranded RNAs and thereby suppresses induction of interferons. Loss of this ADAR1p150 function underlies the embryonic lethality of Adar1 null mice, pathogenesis of the severe autoimmune disease Aicardi-Goutières syndrome, and the resistance developed in cancers to immune checkpoint blockade. In contrast, the biological functions of the nuclear-localized ADAR1p110 remain largely unknown. Here, we report that ADAR1p110 regulates R-loop formation and genome stability at telomeres in cancer cells carrying non-canonical variants of telomeric repeats. ADAR1p110 edits the A-C mismatches within RNA:DNA hybrids formed between canonical and non-canonical variant repeats. Editing of A-C mismatches to I:C matched pairs facilitates resolution of telomeric R-loops by RNase H2. This ADAR1p110-dependent control of telomeric R-loops is required for continued proliferation of telomerase-reactivated cancer cells, revealing the pro-oncogenic nature of ADAR1p110 and identifying ADAR1 as a promising therapeutic target of telomerase positive cancers.},
}
@article {pmid33711516,
year = {2021},
author = {Fernandes, SG and Dsouza, R and Khattar, E},
title = {External environmental agents influence telomere length and telomerase activity by modulating internal cellular processes: Implications in human aging.},
journal = {Environmental toxicology and pharmacology},
volume = {85},
number = {},
pages = {103633},
doi = {10.1016/j.etap.2021.103633},
pmid = {33711516},
issn = {1872-7077},
mesh = {Aging/metabolism ; Animals ; Cell Physiological Phenomena/drug effects ; Environmental Pollutants/*toxicity ; Humans ; Telomerase/*metabolism ; Telomere/*drug effects ; },
abstract = {External environment affects cellular physiological processes and impact the stability of our genome. The most important structural components of our linear chromosomes which endure the impact by these agents, are the chromosomal ends called telomeres. Telomeres preserve the integrity of our genome by preventing end to end fusions and telomeric loss through by inhibiting DNA damage response (DDR) activation. This is accomplished by the presence of a six membered shelterin complex at telomeres. Further, telomeres cannot be replicated by normal DNA polymerase and require a special enzyme called telomerase which is expressed only in stem cells, few immune cells and germ cells. Telomeres are rich in guanine content and thus become extremely prone to damage arising due to physiological processes like oxidative stress and inflammation. External environmental factors which includes various physical, biological and chemical agents also affect telomere homeostasis by increasing oxidative stress and inflammation. In the present review, we highlight the effect of these external factors on telomerase activity and telomere length. We also discuss how the external agents affect the physiological processes, thus modulating telomere stability. Further, we describe its implication in the development of aging and its related pathologies.},
}
@article {pmid33711214,
year = {2021},
author = {Lesmana, A and Tian, P and Karlaftis, V and Hearps, S and Monagle, P and Ignjatovic, V and Elwood, N and , },
title = {Continuous reference intervals for leukocyte telomere length in children: the method matters.},
journal = {Clinical chemistry and laboratory medicine},
volume = {59},
number = {7},
pages = {1279-1288},
doi = {10.1515/cclm-2021-0059},
pmid = {33711214},
issn = {1437-4331},
mesh = {Child ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes ; Reference Values ; *Telomere/genetics ; *Telomere Shortening ; },
abstract = {OBJECTIVES: Children with very short telomeres commonly develop bone marrow failure and other severe diseases. Identifying the individuals with short telomeres can improve outcome of bone marrow transplantation, with accurate diagnosis requiring the use of age-matched reference intervals (RIs). This study aimed to establish RIs for telomere length (TL) in children using three commonly used methods for TL measurement.<br><br>METHODS: Healthy children aged 30&#xa0;days to 18 years were recruited for assessment using age as a continuous variable. Venous blood samples were collected and leukocyte&#xa0;TL was measured using terminal restriction fragment (TRF) analysis, quantitative PCR (QPCR) and flow cytometry with fluorescence in situ hybridization (Flow-FISH). Fractional polynomial model and quantile regression were performed&#xa0;to generate continuous RIs. Factors that might contribute to variation in TL, such as gender, were also examined.<br><br>RESULTS: A total of 212 samples were analyzed. Continuous RIs are presented as functions of age. TRF analysis and QPCR showed significant negative correlation between TL and age (r=-0.28 and r=-0.38, p<0.001). In contrast, Flow-FISH showed no change in TL with age (r=-0.08, p=0.23). Gender did not have significant influence on TL in children.<br><br>CONCLUSIONS: This study provides three options to assess TL in children by establishing method-specific continuous RIs. Choosing which method to use will depend on several factors such as amount and type of sample available and required sensitivity to age-related change.},
}
@article {pmid33711210,
year = {2021},
author = {Mizuno, T and Hirabayashi, K and Miyazawa, S and Kobayashi, Y and Shoji, K and Kobayashi, M and Hanaoka, F and Imamoto, N and Torigoe, H},
title = {The intrinsically disordered N-terminal region of mouse DNA polymerase alpha mediates its interaction with POT1a/b at telomeres.},
journal = {Genes to cells : devoted to molecular &amp; cellular mechanisms},
volume = {26},
number = {6},
pages = {360-380},
doi = {10.1111/gtc.12845},
pmid = {33711210},
issn = {1365-2443},
support = {25440097//Japan Society for the Promotion of Science/ ; FY2017//RIKEN/ ; FY2016//RIKEN/ ; },
mesh = {Amino Acid Sequence ; Aminopeptidases/metabolism ; Animals ; Antibody Specificity/immunology ; Cell Cycle ; DNA Polymerase I/*chemistry/*metabolism ; DNA-Binding Proteins/*metabolism ; Databases, Genetic ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism ; Genome ; Humans ; Intrinsically Disordered Proteins/*metabolism ; Mice ; Models, Biological ; NIH 3T3 Cells ; Protein Binding ; Sequence Homology, Amino Acid ; Serine Proteases/metabolism ; Shelterin Complex ; Structure-Activity Relationship ; Subcellular Fractions/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Mouse telomerase and the DNA polymerase alpha-primase complex elongate the leading and lagging strands of telomeres, respectively. To elucidate the molecular mechanism of lagging strand synthesis, we investigated the interaction between DNA polymerase alpha and two paralogs of the mouse POT1 telomere-binding protein (POT1a and POT1b). Yeast two-hybrid analysis and a glutathione S-transferase pull-down assay indicated that the C-terminal region of POT1a/b binds to the intrinsically disordered N-terminal region of p180, the catalytic subunit of mouse DNA polymerase alpha. Subcellular distribution analyses showed that although POT1a, POT1b, and TPP1 were localized to the cytoplasm, POT1a-TPP1 and POT1b-TPP1 coexpressed with TIN2 localized to the nucleus in a TIN2 dose-dependent manner. Coimmunoprecipitation and cell cycle synchronization experiments indicated that POT1b-TPP1-TIN2 was more strongly associated with p180 than POT1a-TPP1-TIN2, and this complex accumulated during the S phase. Fluorescence in situ hybridization and proximity ligation assays showed that POT1a and POT1b interacted with p180 and TIN2 on telomeric chromatin. Based on the present study and a previous study, we propose a model in which POT1a/b-TPP1-TIN2 translocates into the nucleus in a TIN2 dose-dependent manner to target the telomere, where POT1a/b interacts with DNA polymerase alpha for recruitment at the telomere for lagging strand synthesis.},
}
@article {pmid33709208,
year = {2021},
author = {Norris, K and Walne, AJ and Ponsford, MJ and Cleal, K and Grimstead, JW and Ellison, A and Alnajar, J and Dokal, I and Vulliamy, T and Baird, DM},
title = {High-throughput STELA provides a rapid test for the diagnosis of telomere biology disorders.},
journal = {Human genetics},
volume = {140},
number = {6},
pages = {945-955},
pmid = {33709208},
issn = {1432-1203},
support = {WCRC/HCRW/HCRW_/United Kingdom ; 14032/LLR_/Blood Cancer UK/United Kingdom ; 29202/CRUK_/Cancer Research UK/United Kingdom ; A18246/A29202/CRUK_/Cancer Research UK/United Kingdom ; MR/P018440/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Asymptomatic Diseases ; Bone Marrow Failure Disorders/*diagnosis/genetics/pathology ; Case-Control Studies ; Child ; Child, Preschool ; Dyskeratosis Congenita/*diagnosis/genetics/pathology ; Female ; Fetal Growth Retardation/*diagnosis/genetics/pathology ; Genetic Carrier Screening/*methods ; Heterozygote ; Humans ; Infant ; Intellectual Disability/*diagnosis/genetics/pathology ; Male ; Microcephaly/*diagnosis/genetics/pathology ; Middle Aged ; Severity of Illness Index ; Survival Analysis ; Telomere/metabolism/*pathology ; Telomere Homeostasis ; },
abstract = {Telomere biology disorders are complex clinical conditions that arise due to mutations in genes required for telomere maintenance. Telomere length has been utilised as part of the diagnostic work-up of patients with these diseases; here, we have tested the utility of high-throughput STELA (HT-STELA) for this purpose. HT-STELA was applied to a cohort of unaffected individuals (n = 171) and a retrospective cohort of mutation carriers (n = 172). HT-STELA displayed a low measurement error with inter- and intra-assay coefficient of variance of 2.3% and 1.8%, respectively. Whilst telomere length in unaffected individuals declined as a function of age, telomere length in mutation carriers appeared to increase due to a preponderance of shorter telomeres detected in younger individuals (< 20 years of age). These individuals were more severely affected, and age-adjusted telomere length differentials could be used to stratify the cohort for overall survival (Hazard Ratio = 5.6 (1.5-20.5); p < 0.0001). Telomere lengths of asymptomatic mutation carriers were shorter than controls (p < 0.0001), but longer than symptomatic mutation carriers (p < 0.0001) and telomere length heterogeneity was dependent on the diagnosis and mutational status. Our data show that the ability of HT-STELA to detect short telomere lengths, that are not readily detected with other methods, means it can provide powerful diagnostic discrimination and prognostic information. The rapid format, with a low measurement error, demonstrates that HT-STELA is a new high-quality laboratory test for the clinical diagnosis of an underlying telomeropathy.},
}
@article {pmid33704499,
year = {2021},
author = {},
title = {Corrigendum for Vahter et al. Placental and Cord Blood Telomere Length in Relation to Maternal Nutritional Status. J Nutr 2020;150(10):2646-55, https://doi.org/10.1093/jn/nxaa198.},
journal = {The Journal of nutrition},
volume = {151},
number = {3},
pages = {742},
doi = {10.1093/jn/nxaa378},
pmid = {33704499},
issn = {1541-6100},
}
@article {pmid33693934,
year = {2021},
author = {Mustafa, G and Shiekh, S and Gc, K and Abeysirigunawardena, S and Balci, H},
title = {Interrogating accessibility of telomeric sequences with FRET-PAINT: evidence for length-dependent telomere compaction.},
journal = {Nucleic acids research},
volume = {49},
number = {6},
pages = {3371-3380},
pmid = {33693934},
issn = {1362-4962},
support = {R15 GM109386/GM/NIGMS NIH HHS/United States ; R15 GM123443/GM/NIGMS NIH HHS/United States ; },
mesh = {Fluorescence Resonance Energy Transfer ; Humans ; Peptide Nucleic Acids/metabolism ; Telomere/*chemistry/metabolism ; },
abstract = {Single-stranded telomeric overhangs are ∼200 nucleotides long and can form tandem G-quadruplex (GQ) structures, which reduce their accessibility to nucleases and proteins that activate DNA damage response. Whether these tandem GQs further stack to form compact superstructures, which may provide better protection for longer telomeres, is not known. We report single-molecule measurements where the accessibility of 24-144 nucleotide long human telomeric DNA molecules is interrogated by a short PNA molecule that is complementary to a single GGGTTA repeat, as implemented in the FRET-PAINT method. Binding of the PNA strand to available GGGTTA sequences results in discrete FRET bursts which were analyzed in terms of their dwell times, binding frequencies, and topographic distributions. The binding frequencies were greater for binding to intermediate regions of telomeric DNA compared to 3'- or 5'-ends, suggesting these regions are more accessible. Significantly, the binding frequency per telomeric repeat monotonically decreased with increasing telomere length. These results are consistent with telomeres forming more compact structures at longer lengths, reducing accessibility of these critical genomic sites.},
}
@article {pmid33693840,
year = {2021},
author = {Kim, E and Kim, J and Kim, C and Lee, J},
title = {Long-read sequencing and de novo genome assemblies reveal complex chromosome end structures caused by telomere dysfunction at the single nucleotide level.},
journal = {Nucleic acids research},
volume = {49},
number = {6},
pages = {3338-3353},
pmid = {33693840},
issn = {1362-4962},
mesh = {Animals ; Caenorhabditis elegans/genetics ; *Chromosome Aberrations ; Chromosome Breakage ; Chromosomes ; DNA Damage ; DNA Repair ; Genomic Instability ; Genomics ; INDEL Mutation ; Nucleotides ; Sequence Analysis, DNA ; Sequence Deletion ; *Telomere/chemistry ; *Telomere Homeostasis ; Translocation, Genetic ; },
abstract = {Karyotype change and subsequent evolution is triggered by chromosome fusion and rearrangement events, which often occur when telomeres become dysfunctional. Telomeres protect linear chromosome ends from DNA damage responses (DDRs), and telomere dysfunction may result in genome instability. However, the complex chromosome end structures and the other possible consequences of telomere dysfunction have rarely been resolved at the nucleotide level due to the lack of the high-throughput methods needed to analyse these highly repetitive regions. Here we applied long-read sequencing technology to Caenorhabditis elegans survivor lines that emerged after telomere dysfunction. The survivors have preserved traces of DDRs in their genomes and our data revealed that variants generated by telomere dysfunction are accumulated along all chromosomes. The reconstruction of the chromosome end structures through de novo genome assemblies revealed diverse types of telomere damage processing at the nucleotide level. When telomeric repeats were totally eroded by telomere dysfunction, DDRs were mostly terminated by chromosome fusion events. We also partially reconstructed the most complex end structure and its DDR signatures, which would have been accumulated via multiple cell divisions. These finely resolved chromosome end structures suggest possible mechanisms regarding the repair processes after telomere dysfunction, providing insights into chromosome evolution in nature.},
}
@article {pmid33692400,
year = {2021},
author = {Seeker, LA and Underwood, SL and Wilbourn, RV and Dorrens, J and Froy, H and Holland, R and Ilska, JJ and Psifidi, A and Bagnall, A and Whitelaw, B and Coffey, M and Banos, G and Nussey, DH},
title = {Telomere attrition rates are associated with weather conditions and predict productive lifespan in dairy cattle.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {5589},
pmid = {33692400},
issn = {2045-2322},
support = {BB/L007312/1//BBSRC/ ; },
mesh = {Animals ; Cattle ; Female ; Leukocytes/*metabolism ; *Longevity ; Telomere/*metabolism ; *Telomere Shortening ; *Weather ; },
abstract = {Telomere length is predictive of adult health and survival across vertebrate species. However, we currently do not know whether such associations result from among-individual differences in telomere length determined genetically or by early-life environmental conditions, or from differences in the rate of telomere attrition over the course of life that might be affected by environmental conditions. Here, we measured relative leukocyte telomere length (RLTL) multiple times across the entire lifespan of dairy cattle in a research population that is closely monitored for health and milk production and where individuals are predominantly culled in response to health issues. Animals varied in their change in RLTL between subsequent measurements and RLTL shortened more during early life and following hotter summers which are known to cause heat stress in dairy cows. The average amount of telomere attrition calculated over multiple repeat samples of individuals predicted a shorter productive lifespan, suggesting a link between telomere loss and health. TL attrition was a better predictor of when an animal was culled than their average TL or the previously for this population reported significant TL at the age of 1 year. Our present results support the hypothesis that TL is a flexible trait that is affected by environmental factors and that telomere attrition is linked to animal health and survival traits. Change in telomere length may represent a useful biomarker in animal welfare studies.},
}
@article {pmid33692348,
year = {2021},
author = {Feuerbach, L},
title = {Formal reply to "Alternative lengthening of telomeres is not synonymous with mutations in ATRX/DAXX".},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {1551},
pmid = {33692348},
issn = {2041-1723},
mesh = {Co-Repressor Proteins ; Genomics ; Humans ; Molecular Chaperones ; Mutation ; *Neoplasms ; *Telomere/genetics ; Telomere Homeostasis ; X-linked Nuclear Protein/genetics ; },
}
@article {pmid33692341,
year = {2021},
author = {de Nonneville, A and Reddel, RR},
title = {Alternative lengthening of telomeres is not synonymous with mutations in ATRX/DAXX.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {1552},
pmid = {33692341},
issn = {2041-1723},
mesh = {Co-Repressor Proteins ; Genomics ; Humans ; Molecular Chaperones ; Mutation ; *Neoplasms ; *Telomere/genetics ; Telomere Homeostasis/genetics ; X-linked Nuclear Protein/genetics ; },
}
@article {pmid33690611,
year = {2021},
author = {Sánchez-Vázquez, R and Martínez, P and Blasco, MA},
title = {AKT-dependent signaling of extracellular cues through telomeres impact on tumorigenesis.},
journal = {PLoS genetics},
volume = {17},
number = {3},
pages = {e1009410},
pmid = {33690611},
issn = {1553-7404},
mesh = {Animals ; Cell Transformation, Neoplastic/*genetics/*metabolism ; DNA Damage ; Genomic Instability ; Humans ; Mice ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis ; Proto-Oncogene Proteins c-akt/*metabolism ; *Signal Transduction ; Telomere/*genetics/*metabolism ; Telomere Shortening ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; },
abstract = {The telomere-bound shelterin complex is essential for chromosome-end protection and genomic stability. Little is known on the regulation of shelterin components by extracellular signals including developmental and environmental cues. Here, we show that human TRF1 is subjected to AKT-dependent regulation. To study the importance of this modification in vivo, we generate knock-in human cell lines carrying non-phosphorylatable mutants of the AKT-dependent TRF1 phosphorylation sites by CRISPR-Cas9. We find that TRF1 mutant cells show decreased TRF1 binding to telomeres and increased global and telomeric DNA damage. Human cells carrying non-phosphorylatable mutant TRF1 alleles show accelerated telomere shortening, demonstrating that AKT-dependent TRF1 phosphorylation regulates telomere maintenance in vivo. TRF1 mutant cells show an impaired response to proliferative extracellular signals as well as a decreased tumorigenesis potential. These findings indicate that telomere protection and telomere length can be regulated by extracellular signals upstream of PI3K/AKT activation, such as growth factors, nutrients or immune regulators, and this has an impact on tumorigenesis potential.},
}
@article {pmid33679878,
year = {2021},
author = {Yu, G and Lu, L and Ma, Z and Wu, S},
title = {Genetically Predicted Telomere Length and Its Relationship With Alzheimer's Disease.},
journal = {Frontiers in genetics},
volume = {12},
number = {},
pages = {595864},
pmid = {33679878},
issn = {1664-8021},
abstract = {Are shorter telomeres causal risk factors for Alzheimer's disease (AD)? This study aimed to examine if shorter telomeres were causally associated with a higher risk of AD using Mendelian randomization (MR) analysis. Two-sample MR methods were applied to the summary effect sizes and standard errors from a genome-wide association study for AD. Twenty single nucleotide polymorphisms of genome-wide significance were selected as instrumental variables for leukocyte telomere length. The main analyses were performed primarily using the random-effects inverse-variance weighted method and complemented with the other three methods: weighted median approaches, MR-Egger regression, and weighted mode approach. The intercept of MR-Egger regression was used to assess horizontal pleiotropy. We found that longer telomeres were associated with lower risks of AD (odds ratio = 0.79, 95% confidence interval: 0.67, 0.93, P = 0.004). Comparable results were obtained using weighted median approaches, MR-Egger regression, and weighted mode approaches. The intercept of the MR-Egger regression was close to zero. This may show that there was not suggestive of horizontal pleiotropy. Our findings provided additional evidence regarding the putative causal association between shorter telomere length and the higher risk of AD.},
}
@article {pmid33677456,
year = {2021},
author = {Tarry-Adkins, JL and Aiken, CE and Dearden, L and Fernandez-Twinn, DS and Ozanne, S},
title = {Exploring Telomere Dynamics in Aging Male Rat Tissues: Can Tissue-Specific Differences Contribute to Age-Associated Pathologies?.},
journal = {Gerontology},
volume = {67},
number = {2},
pages = {233-242},
doi = {10.1159/000511608},
pmid = {33677456},
issn = {1423-0003},
support = {RG/17/12/33167/BHF_/British Heart Foundation/United Kingdom ; MC_UU_00014/4/MRC_/Medical Research Council/United Kingdom ; MC_UU_12012/4/MRC_/Medical Research Council/United Kingdom ; 106026/Z/14/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Aging/genetics ; Animals ; Longevity ; Male ; Rats ; Rats, Wistar ; *Telomere/genetics ; *Telomere Shortening ; },
abstract = {INTRODUCTION: Due to increasing lifespan, global aging rates are rising rapidly and age-associated diseases are increasing. To ensure that health span is concomitant with life span, a greater understanding of cellular mechanisms of aging is important.<br><br>METHODS: Telomere length analysis from a wide range of tissues from weaning, young adult, and middle-aged (3, 12 and 52 week) male Wistar rats were conducted using Southern blotting. Telomere lengths were compared between tissues and ages using regression models based on the ratios of longest-to-shortest telomere fragments.<br><br>RESULTS: Robust linear age-dependent telomere attrition was observed in the liver; 3 versus 12 weeks, 3 versus 52 weeks (p < 0.01), 12 versus 52 weeks (p < 0.05) and the heart; 3 versus 12 weeks (p < 0.05) and 3 versus 52 weeks (p < 0.001). More subtle shortening was observed in aorta and epididymal fat; 3 and 12 versus 52 weeks (p < 0.001) and in skeletal muscle; 3 versus 52 weeks (p < 0.05), 12 versus 52 weeks (p < 0.01). Young thymus telomeres increased in length (3 vs. 12 weeks) and then shortened between 12 and 52 weeks (p < 0.001). We also reported disparity in telomere shortening within tissues: telomeres in aging brain cortex significantly shortened; 3 versus 52 weeks (p < 0.05), 12 versus 52 weeks (p < 0.01). This was not seen in the hypothalamic region. A robust stepwise shortening was observed in the renal cortex; 3 versus 12 weeks, 12 versus 52 weeks (p < 0.05), and 3 versus 52 weeks (p < 0.001), which was not as apparent in the renal medulla; 3 versus 12 weeks (p < 0.01) and 3 versus 52 weeks (p < 0.01). The vastus lateralis skeletal muscle demonstrated the shortest telomere length at weaning and underwent robust age-associated attrition; 3 versus 52 weeks (p < 0.05), 12 versus 52 weeks (p < 0.01). We demonstrated that specific tissues exhibit unique telomere attrition profiles which may partially explain why certain diseases are more prevalent in aged individuals.<br><br>DISCUSSION/CONCLUSION: We show wide variations between tissues in vulnerability to the aging process. In the future, this may help target potential interventions to improve health span.},
}
@article {pmid33673424,
year = {2021},
author = {Mentegari, E and Bertoletti, F and Kissova, M and Zucca, E and Galli, S and Tagliavini, G and Garbelli, A and Maffia, A and Bione, S and Ferrari, E and Fagagna, FDD and Francia, S and Sabbioneda, S and Chen, LY and Lingner, J and Bergoglio, V and Hoffmann, JS and Hübscher, U and Crespan, E and Maga, G},
title = {A Role for Human DNA Polymerase λ in Alternative Lengthening of Telomeres.},
journal = {International journal of molecular sciences},
volume = {22},
number = {5},
pages = {},
pmid = {33673424},
issn = {1422-0067},
support = {IG20762//Associazione Italiana per la Ricerca sul Cancro/ ; MFAG2016 18811//Associazione Italiana per la Ricerca sul Cancro/ ; 24263//Fondazione Italiana per la Ricerca sul Cancro/ ; Start-up Grant 12710//Associazione Italiana per la Ricerca sul Cancro/ ; },
mesh = {Aminopeptidases/*metabolism ; Cell Line, Tumor ; DNA Polymerase beta/*metabolism ; *G-Quadruplexes ; Humans ; Multiprotein Complexes ; Replication Protein A/metabolism ; Serine Proteases/*metabolism ; Shelterin Complex ; Telomere/chemistry/metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomerase negative cancer cell types use the Alternative Lengthening of Telomeres (ALT) pathway to elongate telomeres ends. Here, we show that silencing human DNA polymerase (Pol λ) in ALT cells represses ALT activity and induces telomeric stress. In addition, replication stress in the absence of Pol λ, strongly affects the survival of ALT cells. In vitro, Pol λ can promote annealing of even a single G-rich telomeric repeat to its complementary strand and use it to prime DNA synthesis. The noncoding telomeric repeat containing RNA TERRA and replication protein A negatively regulate this activity, while the Protection of Telomeres protein 1 (POT1)/TPP1 heterodimer stimulates Pol λ. Pol λ associates with telomeres and colocalizes with TPP1 in cells. In summary, our data suggest a role of Pol λ in the maintenance of telomeres by the ALT mechanism.},
}
@article {pmid33672393,
year = {2021},
author = {Aronen, T and Virta, S and Varis, S},
title = {Telomere Length in Norway Spruce during Somatic Embryogenesis and Cryopreservation.},
journal = {Plants (Basel, Switzerland)},
volume = {10},
number = {2},
pages = {},
pmid = {33672393},
issn = {2223-7747},
abstract = {Telomeres i.e., termini of the eukaryotic chromosomes protect chromosomes during DNA replication. Shortening of telomeres, either due to stress or ageing is related to replicative cellular senescence. There is little information on the effect of biotechnological methods, such as tissue culture via somatic embryogenesis (SE) or cryopreservation on plant telomeres, even if these techniques are widely applied. The aim of the present study was to examine telomeres of Norway spruce (Picea abies (L.) Karst.) during SE initiation, proliferation, embryo maturation, and cryopreservation to reveal potential ageing or stress-related effects that could explain variation observed at SE process. Altogether, 33 genotypes from 25 families were studied. SE initiation containing several stress factors cause telomere shortening in Norway spruce. Following initiation, the telomere length of the embryogenic tissues (ETs) and embryos produced remains unchanged up to one year of culture, with remarkable genotypic variation. Being prolonged in vitro culture can, however, shorten the telomeres and should be avoided. This is achieved by successful cryopreservation treatment preserving telomere length. Somatic embryo production capacity of the ETs was observed to vary a lot not only among the genotypes, but also from one timepoint to another. No connection between embryo production and telomere length was found, so this variation remains unexplained.},
}
@article {pmid33671887,
year = {2021},
author = {Yegorov, YE and Poznyak, AV and Nikiforov, NG and Starodubova, AV and Orekhov, AN},
title = {Role of Telomeres Shortening in Atherogenesis: An Overview.},
journal = {Cells},
volume = {10},
number = {2},
pages = {},
pmid = {33671887},
issn = {2073-4409},
mesh = {Atherosclerosis/*genetics ; Endothelial Cells/metabolism ; Endothelium, Vascular/metabolism ; Humans ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Shortening/*genetics ; },
abstract = {It is known that the shortening of the telomeres leads to cell senescence, accompanied by acquiring of pro-inflammatory phenotype. The expression of telomerase can elongate telomeres and resist the onset of senescence. The initiation of atherosclerosis is believed to be associated with local senescence of the endothelial cells of the arteries in places with either low or multidirectional oscillatory wall shear stress. The process of regeneration of the artery surface that has begun does not lead to success for several reasons. Atherosclerotic plaques are formed, which, when developed, lead to fatal consequences, which are the leading causes of death in the modern world. The pronounced age dependence of the manifestations of atherosclerosis pushes scientists to try to link the development of atherosclerosis with telomere length. The study of the role of telomere shortening in atherosclerosis is mainly limited to measuring the telomeres of blood cells, and only in rare cases (surgery or post-mortem examination) are the telomeres of local cells available for measurement. The review discusses the basic issues of cellular aging and the interpretation of telomere measurement data in atherosclerosis, as well as the prospects for the prevention and possible treatment of atherosclerosis.},
}
@article {pmid33670145,
year = {2021},
author = {Howard, JT and Janak, JC and Santos-Lozada, AR and McEvilla, S and Ansley, SD and Walker, LE and Spiro, A and Stewart, IJ},
title = {Telomere Shortening and Accelerated Aging in US Military Veterans.},
journal = {International journal of environmental research and public health},
volume = {18},
number = {4},
pages = {},
pmid = {33670145},
issn = {1660-4601},
mesh = {Aging ; Cellular Senescence ; Female ; Humans ; Leukocytes ; Male ; Nutrition Surveys ; Telomere Shortening ; *Veterans ; },
abstract = {A growing body of literature on military personnel and veterans' health suggests that prior military service may be associated with exposures that increase the risk of cardiovascular disease (CVD), which may differ by race/ethnicity. This study examined the hypothesis that differential telomere shortening, a measure of cellular aging, by race/ethnicity may explain prior findings of differential CVD risk in racial/ethnic groups with military service. Data from the first two continuous waves of the National Health and Nutrition Examination Survey (NHANES), administered from 1999-2002 were analyzed. Mean telomere length in base pairs was analyzed with multivariable adjusted linear regression with complex sample design, stratified by sex. The unadjusted mean telomere length was 225.8 base shorter for individuals with prior military service. The mean telomere length for men was 47.2 (95% CI: -92.9, -1.5; p < 0.05) base pairs shorter for men with military service after adjustment for demographic, socioeconomic, and behavioral variables, but did not differ significantly in women with and without prior military service. The interaction between military service and race/ethnicity was not significant for men or women. The results suggest that military service may contribute to accelerated aging as a result of health damaging exposures, such as combat, injury, and environmental contaminants, though other unmeasured confounders could also potentially explain the results.},
}
@article {pmid33664422,
year = {2021},
author = {Lai, TP and Simpson, M and Patel, K and Verhulst, S and Noh, J and Roche, N and Heller, D and Guirguis, G and Shay, JW and Herbig, U and Aviv, A},
title = {Telomeres and replicative cellular aging of the human placenta and chorioamniotic membranes.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {5115},
pmid = {33664422},
issn = {2045-2322},
support = {R01 CA136533/CA/NCI NIH HHS/United States ; R01 HL116446/HL/NHLBI NIH HHS/United States ; R01 CA184572/CA/NCI NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; R21 AG067368/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aging/genetics ; Cellular Senescence/*genetics ; Chorioallantoic Membrane/growth &amp; development/*metabolism ; DNA Damage/genetics ; DNA Replication/genetics ; Female ; Gestational Age ; Humans ; In Situ Hybridization, Fluorescence ; Infant, Newborn ; Placenta/metabolism/*physiology ; Placentation ; Pregnancy ; Premature Birth/genetics/pathology ; Telomere/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Recent hypotheses propose that the human placenta and chorioamniotic membranes (CAMs) experience telomere length (TL)-mediated senescence. These hypotheses are based on mean TL (mTL) measurements, but replicative senescence is triggered by short and dysfunctional telomeres, not mTL. We measured short telomeres by a vanguard method, the Telomere shortest length assay, and telomere-dysfunction-induced DNA damage foci (TIF) in placentas and CAMs between 18-week gestation and at full-term. Both the placenta and CAMs showed a buildup of short telomeres and TIFs, but not shortening of mTL from 18-weeks to full-term. In the placenta, TIFs correlated with short telomeres but not mTL. CAMs of preterm birth pregnancies with intra-amniotic infection showed shorter mTL and increased proportions of short telomeres. We conclude that the placenta and probably the CAMs undergo TL-mediated replicative aging. Further research is warranted whether TL-mediated replicative aging plays a role in all preterm births.},
}
@article {pmid33663806,
year = {2021},
author = {Juríková, K and De Wulf, P and Cusanelli, E},
title = {Nuclear Periphery and Telomere Maintenance: TERRA Joins the Stage.},
journal = {Trends in genetics : TIG},
volume = {37},
number = {7},
pages = {608-611},
doi = {10.1016/j.tig.2021.02.003},
pmid = {33663806},
issn = {0168-9525},
mesh = {DNA-Binding Proteins/genetics ; Humans ; Nuclear Envelope/*genetics ; RNA, Long Noncoding/*genetics ; Saccharomyces cerevisiae/genetics ; Telomerase/genetics ; Telomere/genetics ; Telomere Homeostasis/*genetics ; *Transcription, Genetic ; },
abstract = {Long noncoding (lnc)RNAs derived from telomeres, the ends of linear eukaryotic chromosomes, help to maintain telomere length and stability by multiple means, including regulation of telomerase activity and recombination-based telomere maintenance. New findings in yeast promote a model in which telomere attachment to the nuclear envelope regulates telomere transcription and maintenance.},
}
@article {pmid33662151,
year = {2022},
author = {Pepke, ML and Eisenberg, DTA},
title = {On the comparative biology of mammalian telomeres: Telomere length co-evolves with body mass, lifespan and cancer risk.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6286-6296},
doi = {10.1111/mec.15870},
pmid = {33662151},
issn = {1365-294X},
mesh = {Animals ; Longevity/genetics ; *Telomerase/genetics/metabolism ; Phylogeny ; Mammals/genetics ; *Neoplasms/genetics ; Telomere/genetics/metabolism ; Biology ; Cellular Senescence/genetics ; },
abstract = {Telomeres, the short repetitive DNA sequences that cap the ends of linear chromosomes, shorten during cell division and are implicated in senescence in most species. Telomerase can rebuild telomeres but is repressed in many mammals that exhibit replicative senescence, presumably as a tumour suppression mechanism. It is therefore important to understand the co-evolution of telomere biology and life-history traits that has shaped the diversity of senescence patterns across species. Gomes et al. previously produced a large data set on telomere length (TL), telomerase activity, body mass and lifespan among 57 mammal species. We re-analysed their data using the same phylogenetic multiple regressions and with several additional analyses to test the robustness of the findings. We found substantial inconsistencies in our results compared to Gomes et al.'s. Consistent with Gomes et al. we found an inverse association between TL and lifespan. Contrary to the analyses in Gomes et al., we found a generally robust inverse association between TL and mass, and only weak nonrobust evidence for an association between telomerase activity and mass. These results suggest that shorter TL may have been selected for in larger and longer lived species, probably as a mechanism to suppress cancer. We support this hypothesis by showing that longer telomeres predict higher cancer risk across 22 species. Furthermore, we find that domesticated species have longer telomeres. Our results call into question past interpretations of the co-evolution of telomere biology and life-history traits and stress the need for careful attention to model construction.},
}
@article {pmid33659892,
year = {2021},
author = {Katipoglu, B and Naharci, MI},
title = {Comment on: Non-esterified fatty acids and telomere length in older adults.},
journal = {Metabolism open},
volume = {9},
number = {},
pages = {100084},
pmid = {33659892},
issn = {2589-9368},
}
@article {pmid33657651,
year = {2022},
author = {Wood, EM and Capilla-Lasheras, P and Cram, DL and Walker, LA and York, JE and Lange, A and Hamilton, PB and Tyler, CR and Young, AJ},
title = {Social dominance and rainfall predict telomere dynamics in a cooperative arid-zone bird.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6141-6154},
doi = {10.1111/mec.15868},
pmid = {33657651},
issn = {1365-294X},
support = {BB/H022716/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/J0144004/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/M009122/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Animals, Wild ; Reproduction/genetics ; *Social Dominance ; *Sparrows/physiology ; Telomere/genetics ; },
abstract = {In many vertebrate societies dominant individuals breed at substantially higher rates than subordinates, but whether this hastens ageing remains poorly understood. While frequent reproduction may trade off against somatic maintenance, the extraordinary fecundity and longevity of some social insect queens highlight that breeders need not always suffer more rapid somatic deterioration than their nonbreeding subordinates. Here, we used extensive longitudinal assessments of telomere dynamics to investigate the impact of dominance status on within-individual age-related changes in somatic integrity in a wild social bird, the white-browed sparrow-weaver (Plocepasser mahali). Dominant birds, who monopolise reproduction, had neither shorter telomeres nor faster telomere attrition rates over the long-term (1-5 years) than their subordinates. However, over shorter (half-year) time intervals dominants with shorter telomeres showed lower rates of telomere attrition (and evidence suggestive of telomere lengthening), while the same was not true among subordinates. Dominants may therefore invest more heavily in telomere length regulation (and/or somatic maintenance more broadly); a strategy that could mitigate the long-term costs of reproductive effort, leaving their long-term telomere dynamics comparable to those of subordinates. Consistent with the expectation that reproduction entails short-term costs to somatic integrity, telomere attrition rates were most severe for all birds during the breeding seasons of wetter years (rainfall is the key driver of reproductive activity in this arid-zone species). Our findings suggest that, even in vertebrate societies in which dominants monopolise reproduction, dominants may experience long-term somatic integrity trajectories indistinguishable from those of their nonreproductive subordinates.},
}
@article {pmid33651921,
year = {2021},
author = {Vangorder-Braid, JT and Sirman, AE and Kucera, AC and Kittilson, JD and Kibble, TM and Heidinger, BJ},
title = {TA-65 does not increase telomere length during post-natal development in house sparrow chicks (Passer domesticus).},
journal = {Journal of experimental zoology. Part A, Ecological and integrative physiology},
volume = {335},
number = {3},
pages = {359-366},
doi = {10.1002/jez.2449},
pmid = {33651921},
issn = {2471-5646},
support = {//North Dakota State University/ ; 1656194//National Science Foundation/ ; },
mesh = {Animals ; Drugs, Chinese Herbal/*pharmacology ; Sparrows/*growth &amp; development ; Telomere Homeostasis/*drug effects ; },
abstract = {Telomeres, protective caps at the end of chromosomes, are often positively related to lifespan and are thought to be an important mechanism of organismal aging. To better understand the casual relationships between telomere length and longevity, it is essential to be able to experimentally manipulate telomere dynamics (length and loss rate). Previous studies suggest that exposure to TA-65, an extract from the Chinese root Astragalus membranaceus, activates telomerase, lengthens telomeres, increases the growth of keratin-based structures, and boosts the immune system in adults. However, telomere loss is expected to be greatest during early life but whether TA-65 has similar effects during this life stage is currently unknown. Here, we experimentally exposed free-living house sparrow (Passer domesticus) chicks to TA-65 during post-natal development and examined the effects on telomere length and loss, growth of keratin-based structures, and a measure of cellular immunity. Contrary to expectation, the growth of keratin-based structures was reduced in TA-65 chicks and in the second year of the study, chicks exposed to TA-65 experienced more telomere loss than controls. Thus, the effects of TA-65 on telomeres and keratin-based structures differ across life stages and future research will be necessary to determine the mechanisms underlying these age-specific effects.},
}
@article {pmid33649061,
year = {2021},
author = {Fajardo, RG and Fariña, FO and Rey, AM and Rego-Pérez, I and Blanco, FJ and García, JLF},
title = {Relationship Between the Dynamics of Telomere Loss in Peripheral Blood Leukocytes From Knee Osteoarthritis Patients and Mitochondrial DNA Haplogroups.},
journal = {The Journal of rheumatology},
volume = {48},
number = {10},
pages = {1603-1607},
doi = {10.3899/jrheum.201316},
pmid = {33649061},
issn = {1499-2752},
mesh = {DNA, Mitochondrial/genetics ; Haplotypes ; Humans ; Leukocytes ; Mitochondria ; *Osteoarthritis, Knee/diagnostic imaging/genetics ; Telomere/genetics ; },
abstract = {OBJECTIVE: To evaluate the evolution of telomere length from peripheral blood leukocytes (PBLs) in subjects from the Osteoarthritis Initiative (OAI) cohort in relation to the incidence of osteoarthritis (OA), and to explore its possible interactive influence with the mitochondrial DNA (mtDNA) haplogroup.<br><br>METHODS: Dynamics of telomere sequence loss were quantified in PBLs from initially healthy individuals (without symptoms or radiological signs), 78 carrying the mtDNA cluster HV, and 47 with cluster JT, from the OAI, during a 72-month follow-up period. The incidence of knee OA during this period (n = 39) was radiographically established when Kellgren-Lawrence (KL) score increased from < 2 at recruitment, to &#x2265; 2 at the end of 72 months of follow-up. Multivariate analysis using binary logistic regression was performed to assess PBL telomere loss and mtDNA haplogroups as associated risk factors of incidence of knee OA.<br><br>RESULTS: Carriers of cluster HV showed knee OA incidence twice that of the JT carriers (n = 30 vs 9). The rate of PBL telomere loss was higher in cluster HV carriers and in individuals with incident knee OA. Multivariate analysis showed that the dynamics of PBL telomere shortening can be a consistent risk marker of knee OA incidence. Subjects with nonincident knee OA showed a slower telomere loss than those with incident knee OA; the difference was more significant in carriers of cluster JT than in HV.<br><br>CONCLUSION: An increased rate of telomere loss in PBLs may reflect a systemic accelerated senescence phenotype that could be potentiated by the mitochondrial function, increasing the susceptibility of developing knee OA.},
}
@article {pmid33644714,
year = {2021},
author = {Reed, J and Kirkman, LA and Kafsack, BF and Mason, CE and Deitsch, KW},
title = {Telomere length dynamics in response to DNA damage in malaria parasites.},
journal = {iScience},
volume = {24},
number = {2},
pages = {102082},
pmid = {33644714},
issn = {2589-0042},
support = {R01 AI052390/AI/NIAID NIH HHS/United States ; R01 AI099327/AI/NIAID NIH HHS/United States ; R01 AI146153/AI/NIAID NIH HHS/United States ; },
abstract = {Malaria remains a major cause of morbidity and mortality in the developing world. Recent work has implicated chromosome end stability and the repair of DNA breaks through telomere healing as potent drivers of variant antigen diversification, thus associating basic mechanisms for maintaining genome integrity with aspects of host-parasite interactions. Here we applied long-read sequencing technology to precisely examine the dynamics of telomere addition and chromosome end stabilization in response to double-strand breaks within subtelomeric regions. We observed that the process of telomere healing induces the initial synthesis of telomere repeats well in excess of the minimal number required for end stability. However, once stabilized, these newly created telomeres appear to function normally, eventually returning to a length nearing that of intact chromosome ends. These results parallel recent observations in humans, suggesting an evolutionarily conserved mechanism for chromosome end repair.},
}
@article {pmid33639094,
year = {2021},
author = {Kockler, ZW and Comeron, JM and Malkova, A},
title = {A unified alternative telomere-lengthening pathway in yeast survivor cells.},
journal = {Molecular cell},
volume = {81},
number = {8},
pages = {1816-1829.e5},
pmid = {33639094},
issn = {1097-4164},
support = {P30 CA086862/CA/NCI NIH HHS/United States ; R21 ES030307/ES/NIEHS NIH HHS/United States ; R35 GM127006/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA/genetics ; Rad51 Recombinase/genetics ; Recombination, Genetic/genetics ; Saccharomyces cerevisiae/*genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Alternative lengthening of telomeres (ALT) is a recombination process that maintains telomeres in the absence of telomerase and helps cancer cells to survive. Yeast has been used as a robust model of ALT; however, the inability to determine the frequency and structure of ALT survivors hinders understanding of the ALT mechanism. Here, using population and molecular genetics approaches, we overcome these problems and demonstrate that contrary to the current view, both RAD51-dependent and RAD51-independent mechanisms are required for a unified ALT survivor pathway. This conclusion is based on the calculation of ALT frequencies, as well as on ultra-long sequencing of ALT products that revealed hybrid sequences containing features attributed to both recombination pathways. Sequencing of ALT intermediates demonstrates that recombination begins with Rad51-mediated strand invasion to form DNA substrates that are matured by a Rad51-independent ssDNA annealing pathway. A similar unified ALT pathway may operate in other organisms, including humans.},
}
@article {pmid33634147,
year = {2021},
author = {Sullivan, DI and Jiang, M and Hinchie, AM and Roth, MG and Bahudhanapati, H and Nouraie, M and Liu, J and McDyer, JF and Mallampalli, RK and Zhang, Y and Kass, DJ and Finkel, T and Alder, JK},
title = {Transcriptional and Proteomic Characterization of Telomere-Induced Senescence in a Human Alveolar Epithelial Cell Line.},
journal = {Frontiers in medicine},
volume = {8},
number = {},
pages = {600626},
pmid = {33634147},
issn = {2296-858X},
support = {F32 HL152503/HL/NHLBI NIH HHS/United States ; R01 HL096376/HL/NHLBI NIH HHS/United States ; R01 HL135062/HL/NHLBI NIH HHS/United States ; T32 HL007563/HL/NHLBI NIH HHS/United States ; },
abstract = {Cellular senescence due to telomere dysfunction has been hypothesized to play a role in age-associated diseases including idiopathic pulmonary fibrosis (IPF). It has been postulated that paracrine mediators originating from senescent alveolar epithelia signal to surrounding mesenchymal cells and contribute to disease pathogenesis. However, murine models of telomere-induced alveolar epithelial senescence fail to display the canonical senescence-associated secretory phenotype (SASP) that is observed in senescent human cells. In an effort to understand human-specific responses to telomere dysfunction, we modeled telomere dysfunction-induced senescence in a human alveolar epithelial cell line. We hypothesized that this system would enable us to probe for differences in transcriptional and proteomic senescence pathways in vitro and to identify novel secreted protein (secretome) changes that potentially contribute to the pathogenesis of IPF. Following induction of telomere dysfunction, a robust senescence phenotype was observed. RNA-seq analysis of the senescent cells revealed the SASP and comparisons to previous murine data highlighted differences in response to telomere dysfunction. We conducted a proteomic analysis of the senescent cells using a novel biotin ligase capable of labeling secreted proteins. Candidate biomarkers selected from our transcriptional and secretome data were then evaluated in IPF and control patient plasma. Four novel proteins were found to be differentially expressed between the patient groups: stanniocalcin-1, contactin-1, tenascin C, and total inhibin. Our data show that human telomere-induced, alveolar epithelial senescence results in a transcriptional SASP that is distinct from that seen in analogous murine cells. Our findings suggest that studies in animal models should be carefully validated given the possibility of species-specific responses to telomere dysfunction. We also describe a pragmatic approach for the study of the consequences of telomere-induced alveolar epithelial cell senescence in humans.},
}
@article {pmid33628118,
year = {2021},
author = {Lin, Z and Gao, H and Wang, B and Wang, Y},
title = {Cytomegalovirus Infection and Its Relationship with Leukocyte Telomere Length: A Cross-Sectional Study.},
journal = {Mediators of inflammation},
volume = {2021},
number = {},
pages = {6675353},
pmid = {33628118},
issn = {1466-1861},
mesh = {Adult ; Antibodies, Viral/metabolism ; Body Mass Index ; C-Reactive Protein/metabolism ; Cross-Sectional Studies ; Cytomegalovirus Infections/immunology/*metabolism ; Female ; Humans ; Leukocytes/metabolism ; Male ; Telomere/genetics/*metabolism ; },
abstract = {BACKGROUND: Telomeres undergo shortening with each cell division, which could be accelerated by infection. The association between virus infection and telomere length is poorly understood. In the present study, we investigated the putative associations between leukocyte telomere length (TL), cytomegalovirus (CMV) infection, and C-reactive protein (CRP) in a national representative sample of noninstitutionalized population.<br><br>METHODS: We analyzed data that was collected in a cross-sectional setting, where 3,987 participants were enrolled with available data on telomere length. The association between telomere length with previous CMV infection and CRP was analyzed using multivariable linear regression models. We further tested if obesity, measured by body mass index (BMI), and smoking could modify this relationship.<br><br>RESULTS: In total, around 46% percent of the study population were men and 54% were women. Average ages were 35.1 years for men and 35.0 years for women. One unit increase of CMV antibody IgG titer was associated with -0.07 (95% confidence interval: -0.12, -0.01) unit decrease of leukocyte TL when sex was adjusted for. After additionally adjusting for BMI and smoking status, the magnitude of the association was only slightly decreased to -0.06 (95% confidence interval: -0.11, -0.01). The effect sizes were comparable after additionally adjusting for CRP. These analyses imply that previous CMV infection affects leukocyte TL through pathways other than CRP.<br><br>CONCLUSIONS: Previous CMV infection was associated with shorter leukocyte TL. This association was independent of CRP.},
}
@article {pmid33627664,
year = {2021},
author = {Hartlieb, SA and Sieverling, L and Nadler-Holly, M and Ziehm, M and Toprak, UH and Herrmann, C and Ishaque, N and Okonechnikov, K and Gartlgruber, M and Park, YG and Wecht, EM and Savelyeva, L and Henrich, KO and Rosswog, C and Fischer, M and Hero, B and Jones, DTW and Pfaff, E and Witt, O and Pfister, SM and Volckmann, R and Koster, J and Kiesel, K and Rippe, K and Taschner-Mandl, S and Ambros, P and Brors, B and Selbach, M and Feuerbach, L and Westermann, F},
title = {Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {1269},
pmid = {33627664},
issn = {2041-1723},
mesh = {Blotting, Western ; Exons/genetics ; Flow Cytometry ; Humans ; Proteome/metabolism ; Retrospective Studies ; Sequence Analysis, RNA/methods ; Telomere/genetics/metabolism ; Telomere Homeostasis/genetics ; Whole Genome Sequencing/*methods ; X-linked Nuclear Protein/genetics ; },
abstract = {Telomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas (n = 760) and characterize its features using multi-omics profiling. ALT-positive tumors are molecularly distinct from other neuroblastoma subtypes and enriched in a population-based clinical sequencing study cohort for relapsed cases. They display reduced ATRX/DAXX complex abundance, due to either ATRX mutations (55%) or low protein expression. The heterochromatic histone mark H3K9me3 recognized by ATRX is enriched at the telomeres of ALT-positive tumors. Notably, we find a high frequency of telomeric repeat loci with a neuroblastoma ALT-specific hotspot on chr1q42.2 and loss of the adjacent chromosomal segment forming a neo-telomere. ALT-positive neuroblastomas proliferate slowly, which is reflected by a protracted clinical course of disease. Nevertheless, children with an ALT-positive neuroblastoma have dismal outcome.},
}
@article {pmid33624913,
year = {2021},
author = {Li, X and Zhang, J and Yang, Y and Wu, Q and Ning, H},
title = {MicroRNA-340-5p increases telomere length by targeting telomere protein POT1 to improve Alzheimer's disease in mice.},
journal = {Cell biology international},
volume = {45},
number = {6},
pages = {1306-1315},
doi = {10.1002/cbin.11576},
pmid = {33624913},
issn = {1095-8355},
support = {SB201901052//Henan Provincial Health Commission, a joint project between the province and the ministry to study the mechanism of telomeres in the early diagnosis of Alzheimer's disease/ ; },
mesh = {Alzheimer Disease/*metabolism ; Animals ; Cellular Senescence ; Female ; HEK293 Cells ; HT29 Cells ; Humans ; Male ; Mice ; MicroRNAs/*physiology ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism/physiology ; },
abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disorder which is the primary cause of dementia in the elderly. Telomere attrition has been proposed as a hallmark of aging. Our study aimed to explore the mechanism of the protection of telomere 1 (POT1) in regulating telomere length and affecting cellular senescence in AD. The AD mouse model was established by d-galactose and aluminum chloride, and the water maze test and dark avoidance test were used to detect the behaviors of mice and confirm the success of AD mouse model. AD cell model was established with HT22 cells induced by Aβ42 oligomers. POT1 expression in the AD model was detected by quantitative real-time polymerase chain reaction. Cellular telomere length in hippocampal tissue was analyzed by telomere restriction fragment. Localization of intracellular POT1, telomerase, and telomeres was analyzed by immunofluorescence and fluorescence in situ hybridization. Dual-luciferase assay was used to validate the targeted binding relationship between microRNA-340-5p (miR-340-5p) and POT1. After inhibiting POT1 expression, the symptoms of AD in mice were improved. Aβ1-42 deposition was reduced, whereas telomere length and telomerase activity was increased. Dual-luciferase assay verified the binding relationship between miR-340-5p and POT1. An increase in miR-340-5p expression could alleviate cellular senescence and AD symptoms. miR-340-5p increased cellular telomere length and delayed cell senescence by inhibiting POT1 expression to improve AD symptoms. This study made a conclusion that miR-340-5p increased cellular telomere length and delayed cell senescence by inhibiting POT1 expression to improve AD symptoms in mice.},
}
@article {pmid33624078,
year = {2022},
author = {Banach, M and Penson, PE},
title = {Cellular senescence, telomeres, and cardiovascular risk in familial hypercholesterolaemia.},
journal = {European journal of preventive cardiology},
volume = {29},
number = {5},
pages = {718-720},
doi = {10.1093/eurjpc/zwaa145},
pmid = {33624078},
issn = {2047-4881},
mesh = {*Cardiovascular Diseases/diagnosis/epidemiology/genetics ; Cellular Senescence ; Heart Disease Risk Factors ; Humans ; *Hypercholesterolemia ; *Hyperlipidemias ; *Hyperlipoproteinemia Type II/complications/diagnosis/genetics ; Risk Factors ; Telomere/genetics ; },
}
@article {pmid33624064,
year = {2022},
author = {Baragetti, A and Bonacina, F and Da Dalt, L and Moregola, A and Zampoleri, V and Pellegatta, F and Grigore, L and Pirillo, A and Spina, R and Cefalù, AB and Averna, M and Norata, GD and Catapano, AL},
title = {Genetically determined hypercholesterolaemia results into premature leucocyte telomere length shortening and reduced haematopoietic precursors.},
journal = {European journal of preventive cardiology},
volume = {29},
number = {5},
pages = {721-729},
doi = {10.1093/eurjpc/zwaa115},
pmid = {33624064},
issn = {2047-4881},
mesh = {Animals ; Cholesterol, LDL ; Humans ; *Hypercholesterolemia/genetics ; *Hyperlipoproteinemia Type II/diagnosis/genetics ; Leukocytes ; Mice ; Telomere/genetics ; },
abstract = {AIMS: Leucocyte telomere length (LTL) shortening is a marker of cellular senescence and associates with increased risk of cardiovascular disease (CVD). A number of cardiovascular risk factors affect LTL, but the correlation between elevated LDL cholesterol (LDL-C) and shorter LTL is debated: in small cohorts including subjects with a clinical diagnosis of familial hypercholesterolaemia (FH). We assessed the relationship between LDL-C and LTL in subjects with genetic familial hypercholesterolaemia (HeFH) compared to those with clinically diagnosed, but not genetically confirmed FH (CD-FH), and normocholesterolaemic subjects.<br><br>METHODS AND RESULTS: LTL was measured in mononuclear cells-derived genomic DNA from 206 hypercholesterolaemic subjects (135 HeFH and 71 CD-FH) and 272 controls. HeFH presented shorter LTL vs. controls (1.27&#x2009;&#xb1;&#x2009;0.07 vs. 1.59&#x2009;&#xb1;&#x2009;0.04, P&#x2009;=&#x2009;0.045). In particular, we found shorter LTL in young HeFH as compared to young controls (<35&#x2009;y) (1.34&#x2009;&#xb1;&#x2009;0.08 vs. 1.64&#x2009;&#xb1;&#x2009;0.08, P&#x2009;=&#x2009;0.019); moreover, LTL was shorter in statin-na&#xef;ve HeFH subjects as compared to controls (1.23&#x2009;&#xb1;&#x2009;0.08 vs. 1.58&#x2009;&#xb1;&#x2009;0.04, P&#x2009;=&#x2009;0.001). HeFH subjects presented shorter LTL compared to LDL-C matched CD-FH (1.33&#x2009;&#xb1;&#x2009;0.05 vs. 1.55&#x2009;&#xb1;&#x2009;0.08, P&#x2009;=&#x2009;0.029). Shorter LTL was confirmed in leucocytes of LDLR-KO vs. wild-type mice and associated with lower abundance of long-term haematopoietic stem and progenitor cells (LT-HSPCs) in the bone marrow. Accordingly, HeFH subjects presented lower circulating haematopoietic precursors (CD34 + CD45dim cells) vs. CD-FH and controls.<br><br>CONCLUSIONS: We found (i) shorter LTL in genetically determined hypercholesterolaemia, (ii) lower circulating haematopoietic precursors in HeFH subjects, and reduced bone marrow resident LT-HSPCs in LDLR-KO mice. We support early cellular senescence and haematopoietic alterations in subjects with FH.},
}
@article {pmid33624047,
year = {2022},
author = {Michels, N and van Aart, CJC and Martens, DS and De Henauw, S and Nawrot, TS},
title = {Telomere length and cardiovascular disease precursors: a 7-year follow-up from childhood to early adolescence.},
journal = {European journal of preventive cardiology},
volume = {29},
number = {1},
pages = {e22-e24},
doi = {10.1093/eurjpc/zwaa123},
pmid = {33624047},
issn = {2047-4881},
mesh = {Adolescent ; *Cardiovascular Diseases/diagnosis/epidemiology/genetics ; Child ; Follow-Up Studies ; Humans ; Telomere/genetics ; },
}
@article {pmid33621803,
year = {2021},
author = {Mehta, SR and Iudicello, JE and Lin, J and Ellis, RJ and Morgan, E and Okwuegbuna, O and Cookson, D and Karris, M and Saloner, R and Heaton, R and Grant, I and Letendre, S and , },
title = {Telomere length is associated with HIV infection, methamphetamine use, inflammation, and comorbid disease risk.},
journal = {Drug and alcohol dependence},
volume = {221},
number = {},
pages = {108639},
pmid = {33621803},
issn = {1879-0046},
support = {K24 MH097673/MH/NIMH NIH HHS/United States ; P50 DA026306/DA/NIDA NIH HHS/United States ; UL1 TR001442/TR/NCATS NIH HHS/United States ; R01 DA047879/DA/NIDA NIH HHS/United States ; P30 MH062512/MH/NIMH NIH HHS/United States ; F31 AG064989/AG/NIA NIH HHS/United States ; P30 AI036214/AI/NIAID NIH HHS/United States ; K23 DA037793/DA/NIDA NIH HHS/United States ; },
mesh = {Adult ; Aging/*blood ; Amphetamine-Related Disorders/*blood/epidemiology/psychology ; Biomarkers/blood ; Cohort Studies ; Comorbidity ; Cross-Sectional Studies ; Female ; HIV Infections/*blood/epidemiology/psychology ; Humans ; Inflammation Mediators/*blood ; Male ; Methamphetamine/*adverse effects ; Middle Aged ; Risk Factors ; Telomere/*physiology ; },
abstract = {BACKGROUND: HIV infection and methamphetamine dependence (METH) are each associated with inflammation and premature aging, but their impact on biological aging is difficult to measure. Here we examined the impact of HIV and METH on leukocyte telomere lengths (LTL), and the correlations between LTL and other aging biomarkers.<br><br>METHODS: The study was a cross-sectional analysis of 161 individuals categorized by HIV and methamphetamine (METH) dependence status into four groups: HIV-METH- (n = 50), HIV-METH+ (n = 29), HIV + METH- (n = 40), and HIV + METH+ (n = 42). We analyzed the relationships of leukocyte telomere length (telomere to single copy gene [T/S] ratio) with demographic and clinical data as well as a panel of biomarkers of inflammation and endothelial activation measured in blood and cerebrospinal fluid (CSF).<br><br>RESULTS: HIV and METH were independently associated with shorter T/S ratio, even after adjusting for demographics and leukocyte count (R[2] = 0&#xb7;59, p < 0&#xb7;0001). Higher plasma C-reactive protein (p = 0&#xb7;0036) and CSF VCAM-1 (p = 0&#xb7;0080) were also associated with shorter T/S ratio. A shorter T/S ratio was associated with higher risk for cardiovascular disease (p < 0&#xb7;0001) and stroke (p < 0&#xb7;0001), worse motor functioning (p = 0&#xb7;037) and processing speed (p = 0&#xb7;023), more depressive symptoms (p = 0&#xb7;013), and higher CSF neurofilament-light (p = 0&#xb7;003).<br><br>CONCLUSIONS: HIV and METH dependence were each associated with shorter telomeres. After adjusting for demographics, HIV, and METH, T/S ratio remained associated with aging-related outcomes including neurocognitive impairment, neurodegeneration, risks of cardiovascular disease and stroke. While not establishing causality, this study supports using the T/S ratio as a biomarker for estimating the impact of HIV and comorbidities on long-term health.},
}
@article {pmid33612129,
year = {2021},
author = {Poláková, E and Záhonová, K and Albanaz, ATS and Butenko, A and Lukeš, J and Yurchenko, V},
title = {Diverse telomeres in trypanosomatids.},
journal = {Parasitology},
volume = {148},
number = {10},
pages = {1254-1270},
pmid = {33612129},
issn = {1469-8161},
mesh = {Leishmania mexicana/*genetics ; Telomere/*metabolism ; Trypanosomatina/*genetics/metabolism ; },
abstract = {Telomeres are the ends of linear eukaryotic chromosomes facilitating the resolution of the ‘end replication and protection’ problems, associated with linearity. At the nucleotide level, telomeres typically represent stretches of tandemly arranged telomeric repeats, which vary in length and sequence among different groups of organisms. Recently, a composition of the telomere-associated protein complex has been scrutinized in Trypanosoma brucei. In this work, we subjected proteins from that list to a more detailed bioinformatic analysis and delineated a core set of 20 conserved proteins putatively associated with telomeres in trypanosomatids. Out of these, two proteins (Ku70 and Ku80) are conspicuously missing in representatives of the genus Blastocrithidia, yet telomeres in these species do not appear to be affected. In this work, based on the analysis of a large set of trypanosomatids widely different in their phylogenetic position and life strategies, we demonstrated that telomeres of trypanosomatids are diverse in length, even within groups of closely related species. Our analysis showed that the expression of two proteins predicted to be associated with telomeres (those encoding telomerase and telomere-associated hypothetical protein orthologous to Tb927.6.4330) may directly affect and account for the differences in telomere length within the species of the Leishmania mexicana complex.},
}
@article {pmid33609998,
year = {2021},
author = {Bi, J and Wu, M and Liu, Y and Song, L and Wang, L and Liu, Q and Chen, K and Xiong, C and Li, Y and Xia, W and Xu, S and Zhou, A and Wang, Y},
title = {Association between maternal urinary manganese concentrations and newborn telomere length: Results from a birth cohort study.},
journal = {Ecotoxicology and environmental safety},
volume = {213},
number = {},
pages = {112037},
doi = {10.1016/j.ecoenv.2021.112037},
pmid = {33609998},
issn = {1090-2414},
mesh = {Adult ; Aging ; China ; Cohort Studies ; Environmental Pollutants/*urine ; Female ; Fetal Blood/chemistry ; Humans ; Infant ; Infant, Newborn ; Male ; Manganese/analysis/*urine ; Maternal Exposure/statistics &amp; numerical data ; Pregnancy ; Pregnancy Trimesters ; Real-Time Polymerase Chain Reaction ; Telomere/*drug effects ; Telomere Shortening ; },
abstract = {OBJECTIVE: Telomere length (TL) is a biomarker for biological aging, and the initial setting of TL at birth is a determinant factor of TL in later life. Newborn TL is sensitive to maternal metals concentrations, while study about the association between maternal manganese (Mn) concentrations and newborn TL was not found. Our study aimed to investigate whether newborn TL is related to maternal Mn concentrations.<br><br>METHODS: Data were collected from a birth cohort study of 762 mother-newborn pairs conducted from November 2013 to March 2015 in Wuhan, China. We measured the Mn concentrations in spot urine samples collected during three trimesters by inductively coupled plasma mass spectrometry (ICP-MS) and relative cord blood TL by quantitative real-time polymerase chain reaction (qPCR). We applied multiple informant models to investigate the associations between maternal Mn concentrations and cord blood TL.<br><br>RESULTS: The geometric mean of creatinine-corrected urinary Mn concentrations were 1.58&#xa0;&#x3bc;g/g creatinine, 2.53&#xa0;&#x3bc;g/g creatinine, and 2.62&#xa0;&#x3bc;g/g creatinine in the first, second, and third trimester, respectively. After adjusting for potential confounders, a doubling of maternal urinary Mn concentration during the second trimester was related to a 2.10% (95% CI: 0.25%, 3.99%) increase in cord blood TL. Mothers with the highest tertile of urinary Mn concentrations during the second trimester had a 9.67% (95% CI: 2.13%, 17.78%) longer cord blood TL than those with the lowest tertile. This association was more evident in male infants. No relationship was found between maternal urinary Mn concentrations and cord blood TL during the first and third trimesters in our study.<br><br>CONCLUSIONS: Our findings suggested that maternal Mn concentration during the second trimester was positively associated with newborn TL. These results might provide an epidemiology evidence on the protective role of maternal Mn for newborn TL and offer clues for the early prevention of telomere shortening related diseases.},
}
@article {pmid33608692,
year = {2021},
author = {Lim, CJ and Cech, TR},
title = {Publisher Correction: Shaping human telomeres: from shelterin and CST complexes to telomeric chromatin organization.},
journal = {Nature reviews. Molecular cell biology},
volume = {22},
number = {4},
pages = {299},
doi = {10.1038/s41580-021-00353-x},
pmid = {33608692},
issn = {1471-0080},
support = {R00 GM131023/GM/NIGMS NIH HHS/United States ; },
}
@article {pmid33608273,
year = {2021},
author = {Augereau, A and Mariotti, M and Pousse, M and Filipponi, D and Libert, F and Beck, B and Gorbunova, V and Gilson, E and Gladyshev, VN},
title = {Naked mole rat TRF1 safeguards glycolytic capacity and telomere replication under low oxygen.},
journal = {Science advances},
volume = {7},
number = {8},
pages = {},
pmid = {33608273},
issn = {2375-2548},
support = {P01 AG047200/AG/NIA NIH HHS/United States ; R01 AG027237/AG/NIA NIH HHS/United States ; R01 AG064223/AG/NIA NIH HHS/United States ; },
abstract = {The naked mole rat (NMR), a long-lived and cancer-resistant rodent, is highly resistant to hypoxia. Here, using robust cellular models wherein the mouse telomeric protein TRF1 is substituted by NMR TRF1 or its mutant forms, we show that TRF1 supports maximal glycolytic capacity under low oxygen, shows increased nuclear localization and association with telomeres, and protects telomeres from replicative stress. We pinpoint this evolutionary gain of metabolic function to specific amino acid changes in the homodimerization domain of this protein. We further find that NMR TRF1 accelerates telomere shortening. These findings reveal an evolutionary strategy to adapt telomere biology for metabolic control under an extreme environment.},
}
@article {pmid33608013,
year = {2021},
author = {Córdoba-Lanús, E and Cazorla-Rivero, S and García-Bello, MA and Mayato, D and Gonzalvo, F and Ayra-Plasencia, J and Celli, B and Casanova, C},
title = {Telomere length dynamics over 10-years and related outcomes in patients with COPD.},
journal = {Respiratory research},
volume = {22},
number = {1},
pages = {56},
pmid = {33608013},
issn = {1465-993X},
support = {12/00355//Instituto de Salud Carlos III/ ; 13/007//Sociedad Espa&#xf1;ola de Neumolog&#xed;a y Cirug&#xed;a Tor&#xe1;cica/ ; },
mesh = {Adult ; Aged ; Aging/*genetics ; Case-Control Studies ; Cross-Sectional Studies ; Disease Progression ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Prospective Studies ; Pulmonary Disease, Chronic Obstructive/*genetics ; Smoking/adverse effects ; Telomere/genetics/*metabolism ; Telomere Shortening/*genetics ; Time Factors ; },
abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) has been proposed as a disease of accelerated aging. Several cross-sectional studies have related a shorter telomere length (TL), a marker of biological aging, with COPD outcomes. Whether accelerated telomere shortening over time relates to worse outcomes in COPD patients, is not known.<br><br>METHODS: Relative telomere length (T/S) was determined by qPCR in DNA samples from peripheral blood in 263 patients at baseline and up to 10&#xa0;years post enrolment. Yearly clinical and lung function data of 134 patients with at least two-time measures of T/S over this time were included in the analysis.<br><br>RESULTS: At baseline, T/S inversely correlated with age (r&#x2009;=&#x2009;-&#x2009;0.236; p&#x2009;<&#x2009;0.001), but there was no relationship between T/S and clinical and lung function variables (p&#x2009;>&#x2009;0.05). Over 10&#xa0;years of observation, there was a median shortening of TL of 183&#xa0;bp/year for COPD patients. After adjusting for age, gender, active smoking and mean T/S, patients that shortened their telomeres the most over time, had worse gas exchange, more lung hyperinflation and extrapulmonary affection during the follow-up, (PaO2 p&#x2009;<&#x2009;0.0001; KCO p&#x2009;=&#x2009;0.042; IC/TLC p&#x2009;<&#x2009;0.0001; 6MWD p&#x2009;=&#x2009;0.004 and BODE index p&#x2009;=&#x2009;0.009). Patients in the lowest tertile of T/S through the follow-up period had an increased risk of death [HR&#x2009;=&#x2009;5.48, (1.23-24.42) p&#x2009;=&#x2009;0.026].<br><br>CONCLUSIONS: This prospective study shows an association between accelerated telomere shortening and progressive worsening of pulmonary gas exchange, lung hyperinflation and extrapulmonary affection in COPD patients. Moreover, persistently shorter telomeres over this observation time increase the risk for all-cause mortality.},
}
@article {pmid33607270,
year = {2021},
author = {Puttabyatappa, M and Ciarelli, JN and Chatoff, AG and Padmanabhan, V},
title = {Developmental programming: Metabolic tissue-specific changes in endoplasmic reticulum stress, mitochondrial oxidative and telomere length status induced by prenatal testosterone excess in the female sheep.},
journal = {Molecular and cellular endocrinology},
volume = {526},
number = {},
pages = {111207},
pmid = {33607270},
issn = {1872-8057},
support = {P01 HD044232/HD/NICHD NIH HHS/United States ; P30 DK020572/DK/NIDDK NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; R01 HD099096/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Biomarkers/metabolism ; Collagen/metabolism ; Electron Transport ; *Endoplasmic Reticulum Stress/genetics ; Female ; Fibrosis ; Gene Dosage ; Gene Expression Regulation ; Liver/pathology ; Mitochondria/*metabolism ; Muscles/pathology ; *Organ Specificity ; Oxidation-Reduction ; Oxidative Phosphorylation ; Pregnancy ; Prenatal Exposure Delayed Effects/genetics/*pathology ; RNA, Messenger/genetics/metabolism ; Sheep ; Telomere/*metabolism ; Testosterone/*metabolism ; },
abstract = {Prenatal testosterone (T) excess-induced metabolic dysfunctions involve tissue specific changes in insulin sensitivity with insulin resistant, oxidative and lipotoxic state in liver/muscle and insulin sensitive but inflammatory and oxidative state in visceral adipose tissues (VAT). We hypothesized that mitochondrial dysfunction, endoplasmic reticulum (ER) stress and premature cellular senescence are contributors to the tissue-specific changes in insulin sensitivity. Markers of mitochondrial number, function, and oxidative phosphorylation (OxPhos), ER stress and cellular senescence (telomere length) were assessed in liver, muscle and 4 adipose (VAT, subcutaneous [SAT], epicardiac [ECAT] and perirenal [PRAT]) depots collected from control and prenatal T-treated female sheep at 21 months of age. Prenatal T treatment led to: (a) reduction in mitochondrial number and OxPhos complexes and increase in ER stress markers in muscle; (b) increase in fibrosis with trend towards increase in short telomere fragments in liver (c) depot-specific mitochondrial changes with OxPhos complexes namely increase in SAT and reduction in PRAT and increase in mitochondrial number in ECAT; (d) depot-specific ER stress marker changes with increase in VAT, reduction in SAT, contrasting changes in ECAT and no changes in PRAT; and (d) reduced shorter telomere fragments in SAT, ECAT and PRAT. These changes indicate insulin resistance may be driven by mitochondrial and ER dysfunction in muscle, fibrosis and premature senescence in liver, and depot-specific changes in mitochondrial function and ER stress without involving cellular senescence in adipose tissue. These findings provide mechanistic insights into pathophysiology of metabolic dysfunction among female offspring from hyperandrogenic pregnancies.},
}
@article {pmid33599797,
year = {2021},
author = {Akincilar, SC and Chan, CHT and Ng, QF and Fidan, K and Tergaonkar, V},
title = {Non-canonical roles of canonical telomere binding proteins in cancers.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {78},
number = {9},
pages = {4235-4257},
pmid = {33599797},
issn = {1420-9071},
support = {OFYIRG/18MAY-0008//National Medical Research Council (SG)/ ; },
mesh = {Cell Cycle Proteins/genetics/metabolism ; Dyskeratosis Congenita/genetics/pathology ; Humans ; Neoplasms/metabolism/*pathology ; Nuclear Proteins/genetics/metabolism ; Promoter Regions, Genetic ; Ribonucleoproteins, Small Nucleolar/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/metabolism ; Telomere-Binding Proteins/chemistry/*metabolism ; rap1 GTP-Binding Proteins/genetics/metabolism ; },
abstract = {Reactivation of telomerase is a major hallmark observed in 90% of all cancers. Yet paradoxically, enhanced telomerase activity does not correlate with telomere length and cancers often possess short telomeres; suggestive of supplementary non-canonical roles that telomerase might play in the development of cancer. Moreover, studies have shown that aberrant expression of shelterin proteins coupled with their release from shortening telomeres can further promote cancer by mechanisms independent of their telomeric role. While targeting telomerase activity appears to be an attractive therapeutic option, this approach has failed in clinical trials due to undesirable cytotoxic effects on stem cells. To circumvent this concern, an alternative strategy could be to target the molecules involved in the non-canonical functions of telomeric proteins. In this review, we will focus on emerging evidence that has demonstrated the non-canonical roles of telomeric proteins and their impact on tumorigenesis. Furthermore, we aim to address current knowledge gaps in telomeric protein functions and propose future research approaches that can be undertaken to achieve this.},
}
@article {pmid33597559,
year = {2021},
author = {Katoto, PDMC and Kayembe-Kitenge, T and Pollitt, KJG and Martens, DS and Ghosh, M and Nachega, JB and Nemery, B and Nawrot, TS},
title = {Telomere length and outcome of treatment for pulmonary tuberculosis in a gold mining community.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {4031},
pmid = {33597559},
issn = {2045-2322},
support = {R25 TW011217/TW/FIC NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; D43 TW010937/TW/FIC NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Biomarkers, Pharmacological/blood ; Child ; Child, Preschool ; DNA, Mitochondrial/analysis/drug effects/genetics ; Democratic Republic of the Congo/epidemiology ; Female ; Gold ; Humans ; Male ; Middle Aged ; Miners ; Mining ; Occupational Diseases/etiology ; Proportional Hazards Models ; Prospective Studies ; Telomere/genetics/*metabolism ; Telomere Homeostasis/drug effects/genetics/*physiology ; Tuberculosis, Pulmonary/*genetics/therapy ; },
abstract = {Telomere length (TL) is a marker of ageing and mitochondrial DNA (mtDNA) is an early marker of inflammation caused by oxidative stress. We determined TL and mtDNA content among active pulmonary tuberculosis (PTB) patients to assess if these cellular biomarkers differed between artisanal miners and non-miners, and to assess if they were predictive of treatment outcome. We conducted a prospective cohort study from August 2018 to May 2019 involving newly diagnosed PTB patients at three outpatient TB clinics in a rural Democratic Republic of Congo. We measured relative TL and mtDNA content in peripheral blood leukocytes (at inclusion) via qPCR and assessed their association with PTB treatment outcome. We included 129 patients (85 miners and 44 non-miners) with PTB (median age 40 years; range 5-71 years, 22% HIV-coinfected). For each increase in year and HIV-coinfection, TL shortened by - 0.85% (- 0.19 to - 0.52) (p ≤ 0.0001) and - 14% (- 28.22 to - 1.79) (p = 0.02) respectively. Independent of these covariates, patients with longer TL were more likely to have successful TB treatment [adjusted hazard ratio; 95% CI 1.27 for a doubling of leucocyte telomere length at baseline; 1.05-1.44] than patients with a shorter TL. Blood mtDNA content was not predictive for PTB outcome. For a given chronological age, PTB patients with longer telomeres at time of diagnosis were more likely to have successful PTB treatment outcome.},
}
@article {pmid33597549,
year = {2021},
author = {Kim, C and Sung, S and Kim, JS and Lee, H and Jung, Y and Shin, S and Kim, E and Seo, JJ and Kim, J and Kim, D and Niida, H and Kim, VN and Park, D and Lee, J},
title = {Telomeres reforged with non-telomeric sequences in mouse embryonic stem cells.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {1097},
pmid = {33597549},
issn = {2041-1723},
mesh = {Animals ; DNA-Binding Proteins/genetics ; Epigenomics/methods ; HEK293 Cells ; Humans ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mouse Embryonic Stem Cells/cytology/*metabolism ; Proteomics/methods ; Repetitive Sequences, Nucleic Acid/*genetics ; Sequence Analysis, RNA/methods ; Single-Cell Analysis/methods ; Telomerase/*genetics/metabolism ; Telomere/enzymology/*genetics ; Telomere Homeostasis/*genetics ; Transcription Factors/genetics ; },
abstract = {Telomeres are part of a highly refined system for maintaining the stability of linear chromosomes. Most telomeres rely on simple repetitive sequences and telomerase enzymes to protect chromosomal ends; however, in some species or telomerase-defective situations, an alternative lengthening of telomeres (ALT) mechanism is used. ALT mainly utilises recombination-based replication mechanisms and the constituents of ALT-based telomeres vary depending on models. Here we show that mouse telomeres can exploit non-telomeric, unique sequences in addition to telomeric repeats. We establish that a specific subtelomeric element, the mouse template for ALT (mTALT), is used for repairing telomeric DNA damage as well as for composing portions of telomeres in ALT-dependent mouse embryonic stem cells. Epigenomic and proteomic analyses before and after ALT activation reveal a high level of non-coding mTALT transcripts despite the heterochromatic nature of mTALT-based telomeres. After ALT activation, the increased HMGN1, a non-histone chromosomal protein, contributes to the maintenance of telomere stability by regulating telomeric transcription. These findings provide a molecular basis to study the evolution of new structures in telomeres.},
}
@article {pmid33595114,
year = {2021},
author = {Raghunandan, M and Geelen, D and Majerova, E and Decottignies, A},
title = {NHP2 downregulation counteracts hTR-mediated activation of the DNA damage response at ALT telomeres.},
journal = {The EMBO journal},
volume = {40},
number = {6},
pages = {e106336},
pmid = {33595114},
issn = {1460-2075},
mesh = {DNA Damage/genetics ; DNA Repair/genetics ; DNA-Activated Protein Kinase/metabolism ; Down-Regulation ; Heterogeneous Nuclear Ribonucleoprotein A1/metabolism ; Humans ; Neoplasms/genetics ; Nuclear Proteins/*biosynthesis ; RNA/*genetics ; Rad51 Recombinase/metabolism ; Ribonucleoproteins, Small Nuclear/*biosynthesis ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Homeostasis/*physiology ; },
abstract = {About 10% of cancer cells employ the "alternative lengthening of telomeres" (ALT) pathway instead of re-activating the hTERT subunit of human telomerase. The hTR RNA subunit is also abnormally silenced in some ALT[+] cells not expressing hTERT, suggesting a possible negative non-canonical impact of hTR on ALT. Indeed, we show that ectopically expressed hTR reduces phosphorylation of ssDNA-binding protein RPA (p-RPA[S33]) at ALT telomeres by promoting the hnRNPA1- and DNA-PK-dependent depletion of RPA. The resulting defective ATR checkpoint signaling at telomeres impairs recruitment of the homologous recombination protein, RAD51. This induces ALT telomere fragility, increases POLD3-dependent C-circle production, and promotes the recruitment of the DNA damage marker 53BP1. In ALT[+] cells that naturally retain hTR expression, NHP2 H/ACA ribonucleoprotein levels are downregulated, likely in order to restrain DNA damage response (DDR) activation at telomeres through reduced 53BP1 recruitment. This unexpected role of NHP2 is independent from hTR's non-canonical function in modulating telomeric p-RPA[S33] . Collectively, our study shines new light on the interference between telomerase- and ALT-dependent pathways and unravels a crucial role for hTR and NHP2 in DDR regulation at ALT telomeres.},
}
@article {pmid33593713,
year = {2022},
author = {Gutierrez-Rodrigues, F and Alves-Paiva, RM and Scatena, NF and Martinez, EZ and Scheucher, PS and Calado, RT},
title = {Association between leukocyte telomere length and sex by quantile regression analysis.},
journal = {Hematology, transfusion and cell therapy},
volume = {44},
number = {3},
pages = {346-351},
pmid = {33593713},
issn = {2531-1387},
abstract = {INTRODUCTION: Telomere length (TL) is a biomarker of cellular proliferative history. In healthy individuals, leukocyte TL shortens with age and associates with the lifespan of men and women. However, most of studies had used linear regression models to address the association of the TL attrition, aging and sex.<br><br>METHODS: We evaluated the association between the TL, aging and sex in a cohort of 180 healthy subjects by quantile regression. The TL of nucleated blood cells was measured by fluorescent in situ hypridization (flow-FISH) in a cohort of 89 men, 81 women, and 10 umbilical cord samples. The results were validated by quantitative polymerase chain reaction (qPCR) and compared to a linear regression analysis.<br><br>RESULTS: By quantile regression, telomere dynamics slightly differed between sexes with aging: women had longer telomeres at birth and slower attrition rate than men until the sixth decade of life; after that, TL eroded faster and became shorter than that in men. These differences were not observed by linear regression analysis, as the overall telomere attrition rates in women and men were similar (42 pb per year, p&#x202f;<&#x202f;0.0001 vs. 45 pb kb per year, p&#x202f;<&#x202f;0.0001). Also, qPCR did not recapitulate flow-FISH findings, as the telomere dynamics by qPCR followed a linear model.<br><br>CONCLUSION: The quantile regression analysis accurately reproduced a third-order polynomial TL attrition rate in both women and men, but it depended on the technique applied to measure TL. The Flow-FISH reproduced the expected telomere dynamics through life and, differently from the qPCR, was able to detect the subtle TL variations associated with sex and aging.},
}
@article {pmid33586226,
year = {2022},
author = {Sparks, AM and Spurgin, LG and van der Velde, M and Fairfield, EA and Komdeur, J and Burke, T and Richardson, DS and Dugdale, HL},
title = {Telomere heritability and parental age at conception effects in a wild avian population.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6324-6338},
doi = {10.1111/mec.15804},
pmid = {33586226},
issn = {1365-294X},
mesh = {Animals ; Female ; Humans ; Cross-Sectional Studies ; *Fertilization ; *Passeriformes/genetics ; Telomere/genetics ; Parents ; },
abstract = {Individual variation in telomere length is predictive of health and mortality risk across a range of species. However, the relative influence of environmental and genetic variation on individual telomere length in wild populations remains poorly understood. Heritability of telomere length has primarily been calculated using parent-offspring regression which can be confounded by shared environments. To control for confounding variables, quantitative genetic "animal models" can be used, but few studies have applied animal models in wild populations. Furthermore, parental age at conception may also influence offspring telomere length, but most studies have been cross-sectional. We investigated within- and between-parental age at conception effects and heritability of telomere length in the Seychelles warbler using measures from birds caught over 20 years and a multigenerational pedigree. We found a weak negative within-paternal age at conception effect (as fathers aged, their offspring had shorter telomeres) and a weak positive between-maternal age at conception effect (females that survived to older ages had offspring with longer telomeres). Animal models provided evidence that heritability and evolvability of telomere length were low in this population, and that variation in telomere length was not driven by early-life effects of hatch period or parental identities. Quantitative polymerase chain reaction plate had a large influence on telomere length variation and not accounting for it in the models would have underestimated heritability. Our study illustrates the need to include and account for technical variation in order to accurately estimate heritability, as well as other environmental effects, on telomere length in natural populations.},
}
@article {pmid33581499,
year = {2021},
author = {Shen, M and Young, A and Autexier, C},
title = {PCNA, a focus on replication stress and the alternative lengthening of telomeres pathway.},
journal = {DNA repair},
volume = {100},
number = {},
pages = {103055},
doi = {10.1016/j.dnarep.2021.103055},
pmid = {33581499},
issn = {1568-7856},
mesh = {DNA/metabolism ; DNA Replication ; Eukaryota/genetics/metabolism ; Humans ; Neoplasms/genetics/metabolism ; Proliferating Cell Nuclear Antigen/*metabolism ; *Recombinational DNA Repair ; *Telomere Homeostasis ; },
abstract = {The maintenance of telomeres, which are specialized stretches of DNA found at the ends of linear chromosomes, is a crucial step for the immortalization of cancer cells. Approximately 10-15 % of cancer cells use a homologous recombination-based mechanism known as the Alternative Lengthening of Telomeres (ALT) pathway to maintain their telomeres. Telomeres in general pose a challenge to DNA replication owing to their repetitive nature and potential for forming secondary structures. Telomeres in ALT[+] cells especially are subject to elevated levels of replication stress compared to telomeres that are maintained by the enzyme telomerase, in part due to the incorporation of telomeric variant repeats at ALT+ telomeres, their on average longer lengths, and their modified chromatin states. Many DNA metabolic strategies exist to counter replication stress and to protect stalled replication forks. The role of proliferating cell nuclear antigen (PCNA) as a platform for recruiting protein partners that participate in several of these DNA replication and repair pathways has been well-documented. We propose that many of these pathways may be active at ALT[+] telomeres, either to facilitate DNA replication, to manage replication stress, or during telomere extension. Here, we summarize recent evidence detailing the role of PCNA in pathways including DNA secondary structure resolution, DNA damage bypass, replication fork restart, and DNA damage synthesis. We propose that an examination of PCNA and its post-translational modifications (PTMs) may offer a unique lens by which we might gain insight into the DNA metabolic landscape that is distinctively present at ALT[+] telomeres.},
}
@article {pmid33580702,
year = {2021},
author = {Choi, JY and Abdulkina, LR and Yin, J and Chastukhina, IB and Lovell, JT and Agabekian, IA and Young, PG and Razzaque, S and Shippen, DE and Juenger, TE and Shakirov, EV and Purugganan, MD},
title = {Natural variation in plant telomere length is associated with flowering time.},
journal = {The Plant cell},
volume = {33},
number = {4},
pages = {1118-1134},
pmid = {33580702},
issn = {1532-298X},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; R01 GM127402/GM/NIGMS NIH HHS/United States ; },
mesh = {Arabidopsis/genetics ; Flowers/*physiology ; *Genetic Variation ; Genome Size ; Genome, Plant ; Genome-Wide Association Study ; Oryza/genetics ; Plant Physiological Phenomena/*genetics ; Selection, Genetic ; Tandem Repeat Sequences ; Telomerase/genetics ; Telomere/*genetics ; Time Factors ; Zea mays/genetics ; },
abstract = {Telomeres are highly repetitive DNA sequences found at the ends of chromosomes that protect the chromosomes from deterioration duringcell division. Here, using whole-genome re-sequencing and terminal restriction fragment assays, we found substantial natural intraspecific variation in telomere length in Arabidopsis thaliana, rice (Oryza sativa), and maize (Zea mays). Genome-wide association study (GWAS) mapping in A. thaliana identified 13 regions with GWAS-significant associations underlying telomere length variation, including a region that harbors the telomerase reverse transcriptase (TERT) gene. Population genomic analysis provided evidence for a selective sweep at the TERT region associated with longer telomeres. We found that telomere length is negatively correlated with flowering time variation not only in A. thaliana, but also in maize and rice, indicating a link between life-history traits and chromosome integrity. Our results point to several possible reasons for this correlation, including the possibility that longer telomeres may be more adaptive in plants that have faster developmental rates (and therefore flower earlier). Our work suggests that chromosomal structure itself might be an adaptive trait associated with plant life-history strategies.},
}
@article {pmid33579245,
year = {2021},
author = {Lee, SW and Lim, KH and Lee, KJ and Heo, YR and Lee, JH},
title = {No association between telomere length and osteonecrosis of the femoral head.},
journal = {BMC musculoskeletal disorders},
volume = {22},
number = {1},
pages = {176},
pmid = {33579245},
issn = {1471-2474},
mesh = {*Femoral Neck Fractures ; Femur Head/diagnostic imaging ; *Femur Head Necrosis/diagnostic imaging/genetics ; Humans ; Real-Time Polymerase Chain Reaction ; Telomere ; },
abstract = {BACKGROUND: Telemore length (TL) shortening has been found in many diseases. However, clinical characteristics of TL shortening in osteonecrosis of the femoral head (ONFH) has not been investigated. Therefore, we studied whether TL changes have clinicopathological values in ONFH.<br><br>METHODS: The TL in the synovial tissues of 36 ONFH and 127 control patients (femoral neck fracture) was examined by quantitative real-time PCR as relative length, &#x394; Ct value. In addition, the correlation between TL and clinical features of ONFH and controls was analyzed.<br><br>RESULTS: The average TL in the femoral tissues was 1.46&#x2009;&#xb1;&#x2009;3.12 (standard deviation). The average TL in the ONFH and control tissues was 1.92&#x2009;&#xb1;&#x2009;4.11 and 1.34&#x2009;&#xb1;&#x2009;2.78, respectively, however, the difference was absent (p&#x2009;=&#x2009;0.324). Furthermore, a shorter TL was tended to be associated with erythrocyte sedimentation rate (100% vs. 61.5%, p&#x2009;=&#x2009;0.073); however, the association was not statistically significant.<br><br>CONCLUSIONS: In this study, we demonstrated that there is no association between the TL and clinicopathologic characteristics of ONFH patients. However, further studies considering the genetic factors are needed to be performed.},
}
@article {pmid33578394,
year = {2021},
author = {Blagosklonny, MV},
title = {DNA- and telomere-damage does not limit lifespan: evidence from rapamycin.},
journal = {Aging},
volume = {13},
number = {3},
pages = {3167-3175},
pmid = {33578394},
issn = {1945-4589},
mesh = {Animals ; *DNA Damage/drug effects/genetics ; *Longevity/drug effects/genetics ; Mice ; Mice, Knockout ; Sirolimus/*pharmacology ; *Telomere/drug effects/genetics ; },
abstract = {Failure of rapamycin to extend lifespan in DNA repair mutant and telomerase-knockout mice, while extending lifespan in normal mice, indicates that neither DNA damage nor telomere shortening limits normal lifespan or causes normal aging.},
}
@article {pmid33578128,
year = {2021},
author = {Quintana-Sosa, M and León-Mejía, G and Luna-Carrascal, J and De Moya, YS and Rodríguez, IL and Acosta-Hoyos, A and Anaya-Romero, M and Trindade, C and Narváez, DM and Restrepo, HG and Dias, J and Niekraszewicz, L and Garcia, ALH and Rohr, P and da Silva, J and Henriques, JAP},
title = {Cytokinesis-block micronucleus cytome (CBMN-CYT) assay biomarkers and telomere length analysis in relation to inorganic elements in individuals exposed to welding fumes.},
journal = {Ecotoxicology and environmental safety},
volume = {212},
number = {},
pages = {111935},
doi = {10.1016/j.ecoenv.2021.111935},
pmid = {33578128},
issn = {1090-2414},
mesh = {Air Pollutants, Occupational/*analysis ; *Biological Assay ; Biomarkers/analysis ; Cytokinesis ; DNA Damage ; Humans ; Lymphocytes ; Micronucleus Tests/*methods ; Occupational Exposure/*analysis ; Oxidative Stress ; *Telomere ; Welding ; },
abstract = {During the welding activities many compounds are released, several of these cause oxidative stress and inflammation and some are considered carcinogenic, in fact the International Agency for Research on Cancer established that welding fumes are carcinogenic to humans. The aim of the present study was to analyze the cytotoxic and genotoxic potential of exposure to welding fumes and to determine concentrations of metals in blood and urine of occupationally exposed workers. We included 98 welders and 100 non-exposed individuals. Our results show significant increase in the frequency of micronuclei (MN), nucleoplasmic bridges (NPB), nuclear buds (NBUD) and necrotic cells (NECR) in cytokinesis-block micronucleus cytome (CBMN-Cyt) assay, as well as in the telomere length (TL) of the exposed individuals with respect to the non-exposed group. In the analysis of the concentrations of inorganic elements using PIXE method, were found higher concentrations of Cr, Fe and Cu in the urine, and Cr, Fe, Mg, Al, S, and Mn in the blood in the exposed group compared to the non-exposed group. A significant correlation was observed between MN and age and between NPB and years of exposure. Additionally, we found a significant correlation for TL in relation to MN, NPB, age and years of exposure in the exposed group. Interestingly, a significant correlation between MN and the increase in the concentration of Mg, S, Fe and Cu in blood samples of the exposed group, and between MN and Cr, Fe, Ni and Cu in urine. Thus, our findings may be associated with oxidative and inflammatory damage processes generated by the components contained in welding fumes, suggesting a high occupational risk in welding workers.},
}
@article {pmid33568707,
year = {2021},
author = {Baquero, JM and Benítez-Buelga, C and Rajagopal, V and Zhenjun, Z and Torres-Ruiz, R and Müller, S and Hanna, BMF and Loseva, O and Wallner, O and Michel, M and Rodríguez-Perales, S and Gad, H and Visnes, T and Helleday, T and Benítez, J and Osorio, A},
title = {Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {3490},
pmid = {33568707},
issn = {2045-2322},
mesh = {Antimetabolites, Antineoplastic/*pharmacology ; Benzimidazoles/*pharmacology ; Cell Cycle ; Cell Line, Tumor ; DNA Glycosylases/*antagonists &amp; inhibitors/metabolism ; DNA Repair/*drug effects ; Drug Synergism ; Enzyme Inhibitors/pharmacology ; Genomic Instability ; Humans ; Methotrexate/*pharmacology ; Oxidation-Reduction ; *Oxidative Stress ; Piperidines/*pharmacology ; Reactive Oxygen Species/metabolism ; Telomere/*metabolism ; },
abstract = {The most common oxidative DNA lesion is 8-oxoguanine which is mainly recognized and excised by the 8-oxoG DNA glycosylase 1 (OGG1), initiating the base excision repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress (OS) which disrupts telomere homeostasis triggering genome instability. In the present study, we have investigated the effects of inactivating BER in OS conditions, by using a specific inhibitor of OGG1 (TH5487). We have found that in OS conditions, TH5487 blocks BER initiation at telomeres causing an accumulation of oxidized bases, that is correlated with telomere losses, micronuclei formation and mild proliferation defects. Moreover, the antimetabolite methotrexate synergizes with TH5487 through induction of intracellular reactive oxygen species (ROS) formation, which potentiates TH5487-mediated telomere and genome instability. Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to induce oxidative DNA damage at telomeres, with the potential for developing new combination therapies for cancer treatment.},
}
@article {pmid33568696,
year = {2021},
author = {Mei, Y and Deng, Z and Vladimirova, O and Gulve, N and Johnson, FB and Drosopoulos, WC and Schildkraut, CL and Lieberman, PM},
title = {TERRA G-quadruplex RNA interaction with TRF2 GAR domain is required for telomere integrity.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {3509},
pmid = {33568696},
issn = {2045-2322},
support = {P30 CA010815/CA/NCI NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; R01 GM045751/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Damage/*genetics ; DNA-Binding Proteins/genetics ; G-Quadruplexes/drug effects ; Humans ; Protein Binding/genetics ; RNA/*genetics/metabolism ; RNA, Long Noncoding/genetics ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/*genetics/metabolism ; Transcription Factors/genetics ; },
abstract = {Telomere dysfunction causes chromosomal instability which is associated with many cancers and age-related diseases. The non-coding telomeric repeat-containing RNA (TERRA) forms a structural and regulatory component of the telomere that is implicated in telomere maintenance and chromosomal end protection. The basic N-terminal Gly/Arg-rich (GAR) domain of telomeric repeat-binding factor 2 (TRF2) can bind TERRA but the structural basis and significance of this interaction remains poorly understood. Here, we show that TRF2 GAR recognizes G-quadruplex features of TERRA. We show that small molecules that disrupt the TERRA-TRF2 GAR complex, such as N-methyl mesoporphyrin IX (NMM) or genetic deletion of TRF2 GAR domain, result in the loss of TERRA, and the induction of γH2AX-associated telomeric DNA damage associated with decreased telomere length, and increased telomere aberrations, including telomere fragility. Taken together, our data indicates that the G-quadruplex structure of TERRA is an important recognition element for TRF2 GAR domain and this interaction between TRF2 GAR and TERRA is essential to maintain telomere stability.},
}
@article {pmid33565341,
year = {2021},
author = {Banevicius, M and Gedvilaite, G and Vilkeviciute, A and Kriauciuniene, L and Zemaitiene, R and Liutkeviciene, R},
title = {Association of relative leukocyte telomere length and genetic variants in telomere-related genes (TERT, TERT-CLPTM1, TRF1, TNKS2, TRF2) with atrophic age-related macular degeneration.},
journal = {Ophthalmic genetics},
volume = {42},
number = {2},
pages = {189-194},
doi = {10.1080/13816810.2021.1881976},
pmid = {33565341},
issn = {1744-5094},
mesh = {Aged ; Case-Control Studies ; Female ; Geographic Atrophy/genetics/*pathology ; Humans ; Leukocytes/metabolism/*physiology ; Macular Degeneration/genetics/*pathology ; Male ; Membrane Proteins/genetics ; Middle Aged ; *Polymorphism, Single Nucleotide ; Prognosis ; Tankyrases/genetics ; Telomerase/genetics ; *Telomere ; Telomere-Binding Proteins/*genetics ; Telomeric Repeat Binding Protein 1/genetics ; Telomeric Repeat Binding Protein 2/genetics ; },
abstract = {Background: In an experimental model, telomere shortening inhibits neovascularization. It is thus possible that telomere shortening might have a role in the pathogenesis of geographic atrophy in case of age-related macular degeneration (AMD). This is why we aimed to find any associated differences of telomere length and genetic variants in telomere-related genes (TERT, TERT-CLPTM1, TRF1, TNKS2, and TRF2) in patients with atrophic AMD compared to healthy controls.Methods: The study enrolled patients with atrophic AMD (n = 56) and healthy (n = 73) controls. Samples of DNA from peripheral blood leukocytes were extracted by DNA salting-out method. The genotyping of TERT rs2736098, rs401681 in TERT-CLPTM1 locus, TRF1 rs1545827, rs10107605, TNKS2 rs10509637, rs10509639, and TRF2 rs251796 and relative leukocyte telomere length (T/S) measurement were carried out using a real-time polymerase chain reaction method. The results were assessed using the statistical analysis method of "IBM SPSS Statistics 20.0".Results: We found statistically significantly higher T/S in atrophic AMD patients than in healthy controls (T/S, median (IQR): 1.638 (1.110) vs. 0.764 (0.801), p < .001). Also, statistically significant differences were found in TRF1 rs10107605 allele (A and C) distributions between the atrophic AMD and control groups (88.36% and 11.64% vs. 95.54% and 4.46%, respectively, p = .041), as well as between the short telomere and long telomere groups (86.92% and 13.08% vs. 96.09% and 3.91%, respectively, p = .008).Conclusions: Our research revealed the leukocyte telomere length having a role in atrophic AMD development, also the association between TRF1 rs10107605 and the telomere length.},
}
@article {pmid33564874,
year = {2021},
author = {Nettle, D and Gadalla, SM and Lai, TP and Susser, E and Bateson, M and Aviv, A},
title = {Measurement of Telomere Length for Longitudinal Analysis: Implications of Assay Precision.},
journal = {American journal of epidemiology},
volume = {190},
number = {7},
pages = {1406-1413},
pmid = {33564874},
issn = {1476-6256},
support = {75N910D00024/CA/NCI NIH HHS/United States ; U01 AG066529/AG/NIA NIH HHS/United States ; R01 HL134840/HL/NHLBI NIH HHS/United States ; },
mesh = {Blotting, Southern/*statistics &amp; numerical data ; *Correlation of Data ; Cross-Sectional Studies ; Humans ; Leukocytes/*ultrastructure ; Longitudinal Studies ; Real-Time Polymerase Chain Reaction/*statistics &amp; numerical data ; Reproducibility of Results ; Research Design ; *Telomere ; },
abstract = {Researchers increasingly wish to test hypotheses concerning the impact of environmental or disease exposures on telomere length (TL), and they use longitudinal study designs to do so. In population studies, TL is usually measured with a quantitative polymerase chain reaction (qPCR)-based method. This method has been validated by calculating its correlation with a gold standard method such as Southern blotting (SB) in cross-sectional data sets. However, in a cross-section, the range of true variation in TL is large, and measurement error is introduced only once. In a longitudinal study, the target variation of interest is small, and measurement error is introduced at both baseline and follow-up. In this paper, we present results from a small data set (n = 20) in which leukocyte TL was measured twice 6.6 years apart by means of both qPCR and SB. The cross-sectional correlations between qPCR and SB were high at both baseline (r = 0.90) and follow-up (r = 0.85), yet their correlation for TL change was poor (r = 0.48). Moreover, the qPCR data but not the SB data showed strong signatures of measurement error. Through simulation, we show that the statistical power gain from performing a longitudinal analysis is much greater for SB than for qPCR. We discuss implications for optimal study design and analysis.},
}
@article {pmid33564645,
year = {2021},
author = {Bevelacqua, JJ and Welsh, J and Mortazavi, SAR and Keshavarz, M and Mortazavi, SMJ},
title = {Space Medicine: Why Do Recently Published Papers about Telomere Length Alterations Increase our Uncertainty Rather than Reduce it?.},
journal = {Journal of biomedical physics &amp; engineering},
volume = {11},
number = {1},
pages = {103-108},
pmid = {33564645},
issn = {2251-7200},
abstract = {There is a growing interest in examining alterations in telomere length as a reliable biomarker of general health, as well as a marker for predicting later morbidity and mortality. Substantial evidence shows that telomere length is associated with aging; telomere shortening acts as a "counting mechanism" that drives replicative senescence by limiting the mitotic potential of normal (but not malignant) cells. In this Correspondence, we attempt to answer the question of why recently published papers about telomere length alterations increase our uncertainty rather than reduce it. This discussion includes three major research areas regarding telomere length: environmental stressors, aging, and life span. Our review suggests that activation of telomerase activity due to stressors in space might be a double-edged sword with both favorable and unfavorable consequences. The selection of an effect's consequence must clearly elucidate the experimental conditions as well as associated stressors. In this Correspondence, we attempt to answer the question of why recently published papers about telomere length alterations increase our uncertainty rather than reduce it. The selection of an effect's consequence must clearly elucidate the experimental conditions as well as associated stressors. Both positive and negative consequences must be clearly addressed in order to bolster the conclusions, as well as identify future research directions.},
}
@article {pmid33564154,
year = {2021},
author = {Lim, CJ and Cech, TR},
title = {Shaping human telomeres: from shelterin and CST complexes to telomeric chromatin organization.},
journal = {Nature reviews. Molecular cell biology},
volume = {22},
number = {4},
pages = {283-298},
pmid = {33564154},
issn = {1471-0080},
support = {R00 GM131023/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Animals ; Chromatin/*metabolism ; Chromosomes/metabolism ; DNA/metabolism ; Humans ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {The regulation of telomere length in mammals is crucial for chromosome end-capping and thus for maintaining genome stability and cellular lifespan. This process requires coordination between telomeric protein complexes and the ribonucleoprotein telomerase, which extends the telomeric DNA. Telomeric proteins modulate telomere architecture, recruit telomerase to accessible telomeres and orchestrate the conversion of the newly synthesized telomeric single-stranded DNA tail into double-stranded DNA. Dysfunctional telomere maintenance leads to telomere shortening, which causes human diseases including bone marrow failure, premature ageing and cancer. Recent studies provide new insights into telomerase-related interactions (the 'telomere replisome') and reveal new challenges for future telomere structural biology endeavours owing to the dynamic nature of telomere architecture and the great number of structures that telomeres form. In this Review, we discuss recently determined structures of the shelterin and CTC1-STN1-TEN1 (CST) complexes, how they may participate in the regulation of telomere replication and chromosome end-capping, and how disease-causing mutations in their encoding genes may affect specific functions. Major outstanding questions in the field include how all of the telomere components assemble relative to each other and how the switching between different telomere structures is achieved.},
}
@article {pmid33561231,
year = {2021},
author = {Gonzalez de la Rosa, PM and Thomson, M and Trivedi, U and Tracey, A and Tandonnet, S and Blaxter, M},
title = {A telomere-to-telomere assembly of Oscheius tipulae and the evolution of rhabditid nematode chromosomes.},
journal = {G3 (Bethesda, Md.)},
volume = {11},
number = {1},
pages = {},
pmid = {33561231},
issn = {2160-1836},
mesh = {Animals ; Centromere ; Chromosomes ; Karyotype ; *Nematoda/genetics ; Phylogeny ; *Telomere ; },
abstract = {Eukaryotic chromosomes have phylogenetic persistence. In many taxa, each chromosome has a single functional centromere with essential roles in spindle attachment and segregation. Fusion and fission can generate chromosomes with no or multiple centromeres, leading to genome instability. Groups with holocentric chromosomes (where centromeric function is distributed along each chromosome) might be expected to show karyotypic instability. This is generally not the case, and in Caenorhabditis elegans, it has been proposed that the role of maintenance of a stable karyotype has been transferred to the meiotic pairing centers, which are found at one end of each chromosome. Here, we explore the phylogenetic stability of nematode chromosomes using a new telomere-to-telomere assembly of the rhabditine nematode Oscheius tipulae generated from nanopore long reads. The 60-Mb O. tipulae genome is resolved into six chromosomal molecules. We find the evidence of specific chromatin diminution at all telomeres. Comparing this chromosomal O. tipulae assembly with chromosomal assemblies of diverse rhabditid nematodes, we identify seven ancestral chromosomal elements (Nigon elements) and present a model for the evolution of nematode chromosomes through rearrangement and fusion of these elements. We identify frequent fusion events involving NigonX, the element associated with the rhabditid X chromosome, and thus sex chromosome-associated gene sets differ markedly between species. Despite the karyotypic stability, gene order within chromosomes defined by Nigon elements is not conserved. Our model for nematode chromosome evolution provides a platform for investigation of the tensions between local genome rearrangement and karyotypic evolution in generating extant genome architectures.},
}
@article {pmid33557298,
year = {2021},
author = {Glapa-Nowak, A and Mutt, SJ and Lisowska, A and Sapiejka, E and Goździk-Spychalska, J and Wieczorek-Filipiak, M and Drzymała-Czyż, S and Nowak, JK and Thalmann, O and Herzig, KH and Walkowiak, J},
title = {Leukocyte Telomere Length Is Not Reduced in Children and Adults with Cystic Fibrosis but Associates with Clinical Characteristics-A Cross-Sectional Study.},
journal = {Journal of clinical medicine},
volume = {10},
number = {4},
pages = {},
pmid = {33557298},
issn = {2077-0383},
support = {2017/25/N/NZ5/02126//Narodowe Centrum Nauki/ ; },
abstract = {We hypothezied that telomere length is considerably altered in cystic fibrosis (CF) patients compared to healthy subjects (HS), and that leukocyte telomere length variation reflects the severity of CF. Relative telomere length (RTL) was assessed by qPCR in 70 children aged 5-10 (34 CF; 36 HS) and 114 adults aged 18-45 (53 CF; 61 HS). Telomere length was similar in CF and HS (median (interquartile range): 0.799 (0.686-0.950) vs. 0.831 (0.707-0.986); p = 0.5283) both in children and adults. In adults, women had longer telomeres than men (0.805 (0.715-0.931) vs. 0.703 (0.574-0.790); p = 0.0002). Patients treated with inhaled corticosteroids had a shorter RTL compared to those without steroid therapy (0.765 (0.664-0.910) vs. 0.943 (0.813-1.191); p = 0.0007) and this finding remained significant after adjusting for gender, age, BMI, and child/adult status (p = 0.0003). Shorter telomeres were independently associated with the presence of comorbidities (0.763 (0.643-0.905) vs. 0.950 (0.783-1.130); p = 0.0006) and antibiotic treatment at the moment of blood sampling (0.762 (0.648-0.908) vs. 0.832 (0.748-1.129); p = 0.0172). RTL correlated with number of multiple-day hospitalizations (rho = -0.251; p = 0.0239), as well as number of hospitalization days (rho = -0.279; p = 0.0113). Leukocyte RTL in children and adults with CF was not shorter than in healthy controls, and did not seem to have any potential as a predictor of CF survival. However, it inversely associated with the investigated clinical characteristics.},
}
@article {pmid33556205,
year = {2021},
author = {On, K and Crevel, G and Cotterill, S and Itoh, M and Kato, Y},
title = {Drosophila telomere capping protein HOAP interacts with DSB sensor proteins Mre11 and Nbs.},
journal = {Genes to cells : devoted to molecular &amp; cellular mechanisms},
volume = {26},
number = {4},
pages = {219-229},
doi = {10.1111/gtc.12836},
pmid = {33556205},
issn = {1365-2443},
support = {S2802//The Japan Society for the Promotion of Science (JSPS) Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers/ ; },
mesh = {Amino Acid Sequence ; Animals ; Carrier Proteins/*metabolism ; Cell Nucleus/metabolism ; Chromosomal Proteins, Non-Histone/chemistry/*metabolism ; *DNA Breaks, Double-Stranded ; Drosophila Proteins/chemistry/*metabolism ; Drosophila melanogaster/*metabolism ; Endodeoxyribonucleases/*metabolism ; Protein Binding ; Protein Transport ; Telomere/*metabolism ; },
abstract = {In eukaryotes, specific DNA-protein structures called telomeres exist at linear chromosome ends. Telomere stability is maintained by a specific capping protein complex. This capping complex is essential for the inhibition of the DNA damage response (DDR) at telomeres and contributes to genome integrity. In Drosophila, the central factors of telomere capping complex are HOAP and HipHop. Furthermore, a DDR protein complex Mre11-Rad50-Nbs (MRN) is known to be important for the telomere association of HOAP and HipHop. However, whether MRN interacts with HOAP and HipHop, and the telomere recognition mechanisms of HOAP and HipHop are poorly understood. Here, we show that Nbs interacts with Mre11 and transports the Mre11-Rad50 complex from the cytoplasm to the nucleus. In addition, we report that HOAP interacts with both Mre11 and Nbs. The N-terminal region of HOAP is essential for its co-localization with HipHop. Finally, we reveal that Nbs interacts with the N-terminal region of HOAP.},
}
@article {pmid33555479,
year = {2021},
author = {Zhang, N and Li, Y and Lai, TP and Shay, JW and Danuser, G},
title = {Imaging assay to probe the role of telomere length shortening on telomere-gene interactions in single cells.},
journal = {Chromosoma},
volume = {130},
number = {1},
pages = {61-73},
pmid = {33555479},
issn = {1432-0886},
support = {R01 GM067230/GM/NIGMS NIH HHS/United States ; R35 GM136428/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; Cytokines/genetics/metabolism ; Fibroblasts/cytology/metabolism ; *Gene Expression Regulation ; *Image Processing, Computer-Assisted/methods ; *Molecular Imaging/methods ; *Single-Cell Analysis/methods ; Telomerase/genetics/metabolism ; *Telomere ; *Telomere Shortening ; Ubiquitins/genetics/metabolism ; },
abstract = {Telomeres are repetitive non-coding nucleotide sequences (TTAGGGn) capping the ends of chromosomes. Progressive telomere shortening with increasing age has been associated with shifts in gene expression through models such as the telomere position effect (TPE), which suggests reduced interference of the telomere with transcriptional activity of increasingly more distant genes. A modification of the TPE model, referred to as Telomere Position Effects over Long Distance (TPE-OLD), explains why some genes 1-10 MB from a telomere are still affected by TPE, but genes closer to the telomere are not. Here, we describe an imaging approach to systematically examine the occurrence of TPE-OLD at the single cell level. Compared to existing methods, the pipeline allows rapid analysis of hundreds to thousands of cells, which is necessary to establish TPE-OLD as an acceptable mechanism of gene expression regulation. We examined two human genes, ISG15 and TERT, for which TPE-OLD has been described before. For both genes, we found less interaction with the telomere on the same chromosome in old cells compared to young cells; and experimentally elongated telomeres in old cells rescued the level of telomere interaction for both genes. However, the dependency of the interactions on the age progression from young to old cells varied. One model for the differences between ISG15 and TERT may relate to the markedly distinct interstitial telomeric sequence arrangement in the two genes. Overall, this provides a strong rationale for the role of telomere length shortening in the regulation of gene expression.},
}
@article {pmid33553179,
year = {2021},
author = {Ge, J and Li, C and Sun, H and Xin, Y and Zhu, S and Liu, Y and Tang, S and Han, L and Huang, Z and Wang, Q},
title = {Telomere Dysfunction in Oocytes and Embryos From Obese Mice.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {617225},
pmid = {33553179},
issn = {2296-634X},
abstract = {Maternal obesity impairs oocyte quality and embryo development. However, the potential molecular pathways remain to be explored. In the present study, we examined the effects of obesity on telomere status in oocytes and embryos obtained from mice fed with high-fat diet (HFD). Of note, telomere shortening was observed in both oocytes and early embryos from obese mice, as evidenced by the reduced expression of telomerase reverse transcriptase and activity of telomerase. Moreover, quantitative analysis of telomere dysfunction-induced foci (TIFs) revealed that maternal obesity induces the defective telomeres in oocytes and embryos. Meanwhile, the high frequency of aneuploidy was detected in HFD oocytes and embryos as compared to controls, accompanying with the increased incidence of apoptotic blastocysts. In conclusion, these results indicate that telomere dysfunction might be a molecular pathway mediating the effects of maternal obesity on oocyte quality and embryo development.},
}
@article {pmid33552142,
year = {2020},
author = {Vaiserman, A and Krasnienkov, D},
title = {Telomere Length as a Marker of Biological Age: State-of-the-Art, Open Issues, and Future Perspectives.},
journal = {Frontiers in genetics},
volume = {11},
number = {},
pages = {630186},
pmid = {33552142},
issn = {1664-8021},
abstract = {Telomere shortening is a well-known hallmark of both cellular senescence and organismal aging. An accelerated rate of telomere attrition is also a common feature of age-related diseases. Therefore, telomere length (TL) has been recognized for a long time as one of the best biomarkers of aging. Recent research findings, however, indicate that TL per se can only allow a rough estimate of aging rate and can hardly be regarded as a clinically important risk marker for age-related pathologies and mortality. Evidence is obtained that other indicators such as certain immune parameters, indices of epigenetic age, etc., could be stronger predictors of the health status and the risk of chronic disease. However, despite these issues and limitations, TL remains to be very informative marker in accessing the biological age when used along with other markers such as indices of homeostatic dysregulation, frailty index, epigenetic clock, etc. This review article is aimed at describing the current state of the art in the field and at discussing recent research findings and divergent viewpoints regarding the usefulness of leukocyte TL for estimating the human biological age.},
}
@article {pmid33549587,
year = {2021},
author = {Xu, M and Axhemi, A and Malgowska, M and Chen, Y and Leonard, D and Srinivasan, S and Jankowsky, E and Taylor, DJ},
title = {Active and Passive Destabilization of G-Quadruplex DNA by the Telomere POT1-TPP1 Complex.},
journal = {Journal of molecular biology},
volume = {433},
number = {7},
pages = {166846},
pmid = {33549587},
issn = {1089-8638},
support = {R01 CA240993/CA/NCI NIH HHS/United States ; R01 GM133841/GM/NIGMS NIH HHS/United States ; R35 GM118088/GM/NIGMS NIH HHS/United States ; T32 GM007250/GM/NIGMS NIH HHS/United States ; },
mesh = {Aminopeptidases/*genetics ; *G-Quadruplexes ; Humans ; Multiprotein Complexes/genetics/ultrastructure ; Mutation/genetics ; Protein Binding/genetics ; Protein Conformation ; Protein Structure, Secondary/genetics ; Serine Proteases/*genetics ; Shelterin Complex ; Telomerase/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {Chromosome ends are protected by guanosine-rich telomere DNA that forms stable G-quadruplex (G4) structures. The heterodimeric POT1-TPP1 complex interacts specifically with telomere DNA to shield it from illicit DNA damage repair and to resolve secondary structure that impedes telomere extension. The mechanism by which POT1-TPP1 accomplishes these tasks is poorly understood. Here, we establish the kinetic framework for POT1-TPP1 binding and unfolding of telomere G4 DNA. Our data identify two modes of POT1-TPP1 destabilization of G4 DNA that are governed by protein concentration. At low concentrations, POT1-TPP1 passively captures transiently unfolded G4s. At higher concentrations, POT1-TPP1 proteins bind to G4s to actively destabilize the DNA structures. Cancer-associated POT1-TPP1 mutations impair multiple reaction steps in this process, resulting in less efficient destabilization of G4 structures. The mechanistic insight highlights the importance of cell cycle dependent expression and localization of the POT1-TPP1 complex and distinguishes diverse functions of this complex in telomere maintenance.},
}
@article {pmid33547621,
year = {2021},
author = {Hecker, M and Fitzner, B and Jäger, K and Bühring, J and Schwartz, M and Hartmann, A and Walter, M and Zettl, UK},
title = {Leukocyte Telomere Length in Patients with Multiple Sclerosis and Its Association with Clinical Phenotypes.},
journal = {Molecular neurobiology},
volume = {58},
number = {6},
pages = {2886-2896},
pmid = {33547621},
issn = {1559-1182},
mesh = {Adolescent ; Adult ; Aged ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Multiple Sclerosis/*genetics/*pathology ; Phenotype ; Telomere/metabolism ; *Telomere Homeostasis ; Young Adult ; },
abstract = {Aging is a significant factor influencing the course of multiple sclerosis (MS). Accelerated telomere attrition is an indicator of premature biological aging and a potential contributor to various chronic diseases, including neurological disorders. However, there is currently a lack of studies focusing on telomere lengths in patients with MS. We measured the average leukocyte telomere length (LTL) in biobanked DNA samples of 40 relapsing-remitting MS patients (RRMS), 20 primary progressive MS patients (PPMS), and 60 healthy controls using a multiplex quantitative polymerase chain reaction method. Changes in LTL over a period of >10 years were evaluated in a subset of 10 patients. Association analyses of baseline LTL with the long-term clinical profiles of the patients were performed using inferential statistical tests and regression models adjusted for age and sex. The cross-sectional analysis revealed that the RRMS group was characterized by a significantly shorter relative LTL, on average, as compared to the PPMS group and controls. Shorter telomeres at baseline were also associated with a higher conversion rate from RRMS to secondary progressive MS (SPMS) in the 10-year follow-up. The LTL decrease over time was similar in RRMS patients and PPMS patients in the longitudinal analysis. Our data suggest a possible contributory role of accelerated telomere shortening in the pathobiology of MS. The interplay between disease-related immune system alterations, immunosenescence, and telomere dynamics deserves further investigation. New insights into the mechanisms of disease might be obtained, e.g., by exploring the distribution of telomere lengths in specific blood cell populations.},
}
@article {pmid33544428,
year = {2021},
author = {Kosebent, EG and Ozturk, S},
title = {The spatiotemporal expression of TERT and telomere repeat binding proteins in the postnatal mouse testes.},
journal = {Andrologia},
volume = {53},
number = {3},
pages = {e13976},
doi = {10.1111/and.13976},
pmid = {33544428},
issn = {1439-0272},
mesh = {Animals ; DNA ; Male ; Mice ; Telomerase/*genetics ; Telomere/genetics ; Telomere Shortening ; Telomere-Binding Proteins/metabolism ; *Testis/metabolism ; },
abstract = {Telomeres consist of repetitive DNA sequences and telomere-associated proteins. Telomeres located at the ends of eukaryotic chromosomes undergo shortening due to DNA replication, genotoxic factors and reactive oxygen species. The short telomeres are elongated by the enzyme telomerase expressed in the germ line, embryonic and stem cells. Telomerase is in the structure of ribonucleoprotein composed of telomerase reverse transcriptase (TERT), telomerase RNA component (Terc) and other components. Among telomere-associated proteins, telomeric repeat binding factor 1 (TRF1) and 2 (TRF2) exclusively bind to the double-stranded telomeric DNA to regulate its length. However, protection of telomeres 1 (POT1) interacts with the single-stranded telomeric DNA to protect from DNA damage response. Herein, we characterised the spatial and temporal expression of the TERT, TRF1, TRF2 and POT1 proteins in the postnatal mouse testes at the ages of 6, 8, 16, 20, 29, 32 and 88 days by using immunohistochemistry. Significant differences in the spatiotemporal expression patterns and levels of these proteins were determined in the postnatal testes (p < .05). These findings indicate that TERT and telomere repeat binding proteins seem to be required for maintaining the length and structural integrity of telomeres in the spermatogenic cells from newborn to adult terms.},
}
@article {pmid33543592,
year = {2021},
author = {Meshkani, SE and Kooshki, A and Alahabadi, A and Lari Najafi, M and Rad, A and Riahimanesh, F and Miri, M},
title = {Dietary pattern and telomere length in preschool children in a middle-income country.},
journal = {Maternal &amp; child nutrition},
volume = {17},
number = {3},
pages = {e13146},
pmid = {33543592},
issn = {1740-8709},
mesh = {Child, Preschool ; Cross-Sectional Studies ; *Diet ; Feeding Behavior ; Fruit ; Humans ; Iran ; Leukocytes ; *Telomere ; Vegetables ; },
abstract = {Telomere length (TL) has been associated with lifestyle and dietary pattern. However, the available evidence on this association in children is scarce, especially in low- and middle-income countries (LMICs). Therefore, this study aimed to evaluate the association of dietary pattern and leukocyte TL (LTL) in preschool children, Sabzevar, Iran (2017). This cross-sectional study was based on 187 preschool children (aged 5 to 7) recruited from 27 kindergartens. Nutrition information including amounts of consumed dairy products, meat and processed meat products, nuts and seeds, white bread and refined grains, fruits, vegetables, simple sugars, fats and drinks was obtained through a questionnaire. Linear mixed-effects models were fitted with polymerase chain reaction (PCR) plate ID and kindergartens as random effects to estimate the association of each food group consumption with LTL, controlled for relevant covariates. Higher consumption of dairy products and sugar was associated with shorter LTL (β = -0.180, 95% confidence interval [CI]: -0.276, -0.085, P value <0.001 and β = -0.139, 95% CI: -0.193, -0.086, P value <0.001, respectively). An increase in consumption of fish, nuts and seeds, coloured fruits, green leafy vegetables, cruciferous vegetables and olive was significantly associated with the increase in relative LTL. The associations for the consumption of legumes, other fruits, yellow and orange vegetables, red meat, egg, white bread and refined grains, solid and liquid fats, processed meats, potato chips, carbonated drinks, tea (black) and soft drinks groups were not statistically significant. Our findings showed that there was an association between the consumption of certain food groups with LTL.},
}
@article {pmid33542458,
year = {2021},
author = {Lister-Shimauchi, EH and Dinh, M and Maddox, P and Ahmed, S},
title = {Gametes deficient for Pot1 telomere binding proteins alter levels of telomeric foci for multiple generations.},
journal = {Communications biology},
volume = {4},
number = {1},
pages = {158},
pmid = {33542458},
issn = {2399-3642},
support = {R01 GM135470/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Animals, Genetically Modified ; Caenorhabditis elegans/embryology/genetics/*metabolism ; Caenorhabditis elegans Proteins/genetics/metabolism ; DNA-Binding Proteins/*deficiency/genetics ; Epigenesis, Genetic ; Female ; *Gametogenesis ; Gene Expression Regulation, Developmental ; Germ Cells/*metabolism ; Heredity ; Histone Methyltransferases/genetics/metabolism ; Histone-Lysine N-Methyltransferase/genetics/metabolism ; Male ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Deficiency for telomerase results in transgenerational shortening of telomeres. However, telomeres have no known role in transgenerational epigenetic inheritance. C. elegans Protection Of Telomeres 1 (Pot1) proteins form foci at the telomeres of germ cells that disappear at fertilization and gradually accumulate during development. We find that gametes from mutants deficient for Pot1 proteins alter levels of telomeric foci for multiple generations. Gametes from pot-2 mutants give rise to progeny with abundant POT-1::mCherry and mNeonGreen::POT-2 foci throughout development, which persists for six generations. In contrast, gametes from pot-1 mutants or pot-1; pot-2 double mutants induce diminished Pot1 foci for several generations. Deficiency for MET-2, SET-25, or SET-32 methyltransferases, which promote heterochromatin formation, results in gametes that induce diminished Pot1 foci for several generations. We propose that C. elegans POT-1 may interact with H3K9 methyltransferases during pot-2 mutant gametogenesis to induce a persistent form of transgenerational epigenetic inheritance that causes constitutively high levels of heterochromatic Pot1 foci.},
}
@article {pmid33539370,
year = {2021},
author = {McGrath, SL and Huang, SH and Kobryn, K},
title = {Single stranded DNA annealing is a conserved activity of telomere resolvases.},
journal = {PloS one},
volume = {16},
number = {2},
pages = {e0246212},
pmid = {33539370},
issn = {1932-6203},
mesh = {Agrobacterium tumefaciens/*enzymology/genetics ; Bacterial Proteins/genetics/metabolism ; Borrelia/enzymology/genetics ; Cloning, Molecular ; DNA, Bacterial/genetics ; DNA, Single-Stranded/*genetics ; Endodeoxyribonucleases/genetics/metabolism ; Recombinases/genetics/*metabolism ; Telomere/genetics ; },
abstract = {Bacterial species of the genera Agrobacterium and Borrelia possess chromosomes terminated by hairpin telomeres. Replication produces dimeric replication intermediates fused via replicated telomere junctions. A specialized class of enzymes, referred to as telomere resolvases, promotes the resolution of the replicated intermediate into linear monomers terminated by hairpin telomeres. Telomere resolution is catalyzed via DNA cleavage and rejoining events mechanistically similar to those promoted by topoisomerase-IB and tyrosine recombinase enzymes. Examination of the borrelial telomere resolvase, ResT, revealed unanticipated multifunctionality; aside from its expected telomere resolution activity ResT possessed a singled-stranded DNA (ssDNA) annealing activity that extended to both naked ssDNA and ssDNA complexed with its cognate single-stranded DNA binding protein (SSB). At present, the role this DNA annealing activity plays in vivo remains unknown. We have demonstrated here that single-stranded DNA annealing is also a conserved property of the agrobacterial telomere resolvase, TelA. This activity in TelA similarly extends to both naked ssDNA and ssDNA bound by its cognate SSB. TelA's annealing activity was shown to stem from the N-terminal domain; removal of this domain abolished annealing without affecting telomere resolution. Further, independent expression of the N-terminal domain of TelA produced a functional annealing protein. We suggest that the apparent conservation of annealing activity in two telomere resolvases, from distantly related bacterial species, implies a role for this activity in hairpin telomere metabolism. Our demonstration of the separation of the telomere resolution and annealing activities of TelA provides a platform for future experiments aimed at identifying the role DNA annealing performs in vivo.},
}
@article {pmid33539012,
year = {2021},
author = {Engin, AB and Engin, A},
title = {The Connection Between Cell Fate and Telomere.},
journal = {Advances in experimental medicine and biology},
volume = {1275},
number = {},
pages = {71-100},
pmid = {33539012},
issn = {0065-2598},
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; DNA Damage ; DNA End-Joining Repair ; *Telomere/genetics/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; *Telomeric Repeat Binding Protein 2/genetics/metabolism ; },
abstract = {Abolition of telomerase activity results in telomere shortening, a process that eventually destabilizes the ends of chromosomes, leading to genomic instability and cell growth arrest or death. Telomere shortening leads to the attainment of the "Hayflick limit", and the transition of cells to state of senescence. If senescence is bypassed, cells undergo crisis through loss of checkpoints. This process causes massive cell death concomitant with further telomere shortening and spontaneous telomere fusions. In functional telomere of mammalian cells, DNA contains double-stranded tandem repeats of TTAGGG. The Shelterin complex, which is composed of six different proteins, is required for the regulation of telomere length and stability in cells. Telomere protection by telomeric repeat binding protein 2 (TRF2) is dependent on DNA damage response (DDR) inhibition via formation of T-loop structures. Many protein kinases contribute to the DDR activated cell cycle checkpoint pathways, and prevent DNA replication until damaged DNA is repaired. Thereby, the connection between cell fate and telomere length-associated telomerase activity is regulated by multiple protein kinase activities. Contrarily, inactivation of DNA damage checkpoint protein kinases in senescent cells can restore cell-cycle progression into S phase. Therefore, telomere-initiated senescence is a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres. In this review, in addition to the above mentioned, the choice of main repair pathways, which comprise non-homologous end joining and homologous recombination in telomere uncapping telomere dysfunctions, are discussed.},
}
@article {pmid33537752,
year = {2021},
author = {Červenák, F and Sepšiová, R and Nosek, J and Tomáška, &#x13d;},
title = {Step-by-Step Evolution of Telomeres: Lessons from Yeasts.},
journal = {Genome biology and evolution},
volume = {13},
number = {2},
pages = {},
pmid = {33537752},
issn = {1759-6653},
mesh = {Ascomycota/classification/*genetics ; DNA, Fungal/chemistry ; *Evolution, Molecular ; Genetic Variation ; RNA, Untranslated/physiology ; Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; },
abstract = {In virtually every eukaryotic species, the ends of nuclear chromosomes are protected by telomeres, nucleoprotein structures counteracting the end-replication problem and suppressing recombination and undue DNA repair. Although in most cases, the primary structure of telomeric DNA is conserved, there are several exceptions to this rule. One is represented by the telomeric repeats of ascomycetous yeasts, which encompass a great variety of sequences, whose evolutionary origin has been puzzling for several decades. At present, the key questions concerning the driving force behind their rapid evolution and the means of co-evolution of telomeric repeats and telomere-binding proteins remain largely unanswered. Previously published studies addressed mostly the general concepts of the evolutionary origin of telomeres, key properties of telomeric proteins as well as the molecular mechanisms of telomere maintenance; however, the evolutionary process itself has not been analyzed thoroughly. Here, we aimed to inspect the evolution of telomeres in ascomycetous yeasts from the subphyla Saccharomycotina and Taphrinomycotina, with special focus on the evolutionary origin of species-specific telomeric repeats. We analyzed the sequences of telomeric repeats from 204 yeast species classified into 20 families and as a result, we propose a step-by-step model, which integrates the diversity of telomeric repeats, telomerase RNAs, telomere-binding protein complexes and explains a propensity of certain species to generate the repeat heterogeneity within a single telomeric array.},
}
@article {pmid33530115,
year = {2021},
author = {Onat, T and Çaltekin, MD and Inandiklioglu, N and Baser, E and Kirmizi, DA and Kara, M and Ercan, F and Yalvac, ES},
title = {Telomere Length in Idiopathic Recurrent Pregnancy Loss.},
journal = {Zeitschrift fur Geburtshilfe und Neonatologie},
volume = {225},
number = {2},
pages = {119-124},
doi = {10.1055/a-1345-9821},
pmid = {33530115},
issn = {1439-1651},
support = {Yozgat Bozok University Project Coordination Application and Research Center//6602a-TF/18-202/ ; },
mesh = {*Abortion, Habitual/diagnosis/genetics ; Female ; Humans ; Pregnancy ; Telomere/genetics ; *Telomere Shortening/genetics ; },
abstract = {OBJECTIVE: Telomere length is used as an indicator of biological aging. It is well known that one of the most remarkable risk factors of recurrent pregnancy losses is advanced maternal age. The objective of this study was to investigate the correlation between idiopathic recurrent pregnancy loss and telomere length.<br><br>METHOD: The study group included 40 women, while the control group consisted of 41 healthy women whose age and body mass index were matched. A venous blood sample was taken from all participants into EDTA tubes in the early follicular phase, and telomere length was measured through the qPCR technique.<br><br>RESULTS: When the mean TL of the groups was compared, it was determined that TL was significantly shorter among the iRPL group (7763.89&#xb1;924.58 base pair) compared to the control group (8398.84&#xb1;1102.95 base pair) (p<0.006). Whereas FSH and E2 were higher in the iRPL group, TAFC was lower (p<0.001). When the correlation between telomere length and endocrine parameters was statistically tested in the iRPL group, a negative correlation was found between FSH and telomere length (r=-0.437; p<0.001).<br><br>CONCLUSION: Shortened telomere length might play a role in the etiology of iRPL. We are of the opinion that patients with RPL should be screened for the presence of cardiovascular diseases and other chronic diseases, as is the case for POF.},
}
@article {pmid33529748,
year = {2021},
author = {Dragović, G and Andjić, M and Toljić, B and Jevtović, D and Lukić, R and de Luka, S and Trbovich, A and Milašin, J},
title = {Correlation between metabolic syndrome and relative telomere length shortening in HIV/AIDS patients on combined antiretroviral therapy.},
journal = {Experimental gerontology},
volume = {147},
number = {},
pages = {111269},
doi = {10.1016/j.exger.2021.111269},
pmid = {33529748},
issn = {1873-6815},
mesh = {Aging ; *HIV Infections/drug therapy ; Humans ; Male ; *Metabolic Syndrome/genetics ; Telomere ; Telomere Shortening ; },
abstract = {BACKGROUND: Components of the metabolic syndrome (MetS) play an important role in the accelerated aging process. Relative telomere length (RTL) is a marker of biological aging. The aim of our study was to determine RTL and its possible association with MetS and the components of MetS in HIV-infected patients treated with cART.<br><br>METHODS: We included 24 HIV-infected men, all Caucasians, with successful cART (<50 HIV-RNA copies/mL) and on stable cART for at least 24&#xa0;months. The presence of MetS and its components was determined by the criteria prescribed by the International Diabetes Federation. RTL was determined by Real-Time PCR and &#x394;&#x394;Ct method. We performed a multiple linear regression modeling on log-transformed RTL (dependant variable) to evaluate which components of the metabolic syndrome as well as cART duration and cART type, had an impact on RTL.<br><br>RESULTS: Eleven (45.8%) patients had and 13 (54.2%) had not MetS. All patients, had an undetectable viral RNA and a relatively good immune status. The mean RTL was 0.62&#xa0;&#xb1;&#xa0;0.15 and 0.95&#xa0;&#xb1;&#xa0;0.36 in patients with and without MetS, respectively (p&#xa0;=&#xa0;0.01). Multiple linear regression model showed no significant association between duration of cART, cART type and RTL (p&#xa0;=&#xa0;0.2165, p&#xa0;=&#xa0;0.8628, respectively). The same analysis showed that an increase in number of MetS components was associated with shorter telomere length (&#x3b2;&#xa0;=&#xa0;-0.4982, p&#xa0;=&#xa0;0.042).<br><br>CONCLUSIONS: We showed for the first time association between RTL shortening in HIV-infected men with metabolic syndrome. Furthermore, our study also indicated that an increment of metabolic syndrome components is strongly associated with shorter telomere length.},
}
@article {pmid33529269,
year = {2021},
author = {de Fluiter, KS and Codd, V and Denniff, M and Kerkhof, GF and van Beijsterveldt, IALP and Breij, LM and Samani, NJ and Abrahamse-Berkeveld, M and Hokken-Koelega, ACS},
title = {Longitudinal telomere length and body composition in healthy term-born infants during the first two years of life.},
journal = {PloS one},
volume = {16},
number = {2},
pages = {e0246400},
pmid = {33529269},
issn = {1932-6203},
support = {MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Abdominal Fat/metabolism ; Adiposity ; Body Composition ; *Body Fat Distribution ; Female ; Humans ; Infant ; Intra-Abdominal Fat/metabolism ; Leukocytes/metabolism ; Longitudinal Studies ; Male ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {OBJECTIVE: Leukocyte telomere length (LTL) is one of the markers of biological aging as shortening occurs over time. Shorter LTL has been associated with adiposity and a higher risk of cardiovascular diseases. The objective was to assess LTL and LTL shortening during the first 2 years of life in healthy, term-born infants and to associate LTL shortening with potential stressors and body composition.<br><br>STUDY DESIGN: In 145 healthy, term-born infants (85 boys), we measured LTL in blood, expressed as telomere to single-gene copy ratio (T/S ratio), at 3 months and 2 years by quantitative PCR technique. Fat mass (FM) was assessed longitudinally by PEAPOD, DXA, and abdominal FM by ultrasound.<br><br>RESULTS: LTL decreased by 8.5% from 3 months to 2 years (T/S ratio 4.10 vs 3.75, p<0.001). LTL shortening from 3 months to 2 years associated with FM%(R = 0.254), FM index(R = 0.243) and visceral FM(R = 0.287) at 2 years. LTL shortening tended to associate with gain in FM% from 3 to 6 months (R = 0.155, p = 0.11), in the critical window for adiposity programming. There was a trend to a shorter LTL in boys at 2 years(p = 0.056). LTL shortening from 3 months to 2 years was not different between sexes.<br><br>CONCLUSION: We present longitudinal LTL values and show that LTL shortens considerably (8.5%) during the first 2 years of life. LTL shortening during first 2 years of life was associated with FM%, FMI and visceral FM at age 2 years, suggesting that adverse adiposity programming in early life could contribute to more LTL shortening.},
}
@article {pmid33528568,
year = {2021},
author = {Benetos, A and Lai, TP and Toupance, S and Labat, C and Verhulst, S and Gautier, S and Ungeheuer, MN and Perret-Guillaume, C and Levy, D and Susser, E and Aviv, A},
title = {The Nexus Between Telomere Length and Lymphocyte Count in Seniors Hospitalized With COVID-19.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {76},
number = {8},
pages = {e97-e101},
pmid = {33528568},
issn = {1758-535X},
support = {U01 AG066529/AG/NIA NIH HHS/United States ; R01HL134840/NH/NIH HHS/United States ; },
mesh = {Aged, 80 and over ; COVID-19/*physiopathology ; Cellular Senescence ; *Hospitalization ; Humans ; *Lymphocyte Count ; *Lymphopenia/etiology/pathology ; SARS-CoV-2/pathogenicity ; T-Lymphocytes/immunology ; Telomere Shortening/*physiology ; },
abstract = {Profound T-cell lymphopenia is the hallmark of severe coronavirus disease 2019 (COVID-19). T-cell proliferation is telomere length (TL) dependent and telomeres shorten with age. Older COVID-19 patients, we hypothesize, are, therefore, at a higher risk of having TL-dependent lymphopenia. We measured TL by the novel Telomere Shortest Length Assay (TeSLA), and by Southern blotting (SB) of the terminal restriction fragments in peripheral blood mononuclear cells of 17 COVID-19 and 21 non-COVID-19 patients, aged 87 ± 8 (mean ± SD) and 87 ± 9 years, respectively. TeSLA tallies and measures single telomeres, including short telomeres undetected by SB. Such telomeres are relevant to TL-mediated biological processes, including cell viability and senescence. TeSLA yields 2 key metrics: the proportions of telomeres with different lengths (expressed in %) and their mean (TeSLA mTL), (expressed in kb). Lymphocyte count (109/L) was 0.91 ± 0.42 in COVID-19 patients and 1.50 ± 0.50 in non-COVID-19 patients (p < .001). In COVID-19 patients, but not in non-COVID-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kb (p = .005) and positively correlated with TeSLA mTL (p = .03). Lymphocyte count was not significantly correlated with SB mTL in either COVID-19 or non-COVID-19 patients. We propose that compromised TL-dependent T-cell proliferative response, driven by short telomere in the TL distribution, contributes to COVID-19 lymphopenia among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons. Clinical Trials Registration Number: NCT04325646.},
}
@article {pmid33520723,
year = {2020},
author = {Jebaraj, BMC and Stilgenbauer, S},
title = {Telomere Dysfunction in Chronic Lymphocytic Leukemia.},
journal = {Frontiers in oncology},
volume = {10},
number = {},
pages = {612665},
pmid = {33520723},
issn = {2234-943X},
abstract = {Telomeres are nucleprotein structures that cap the chromosomal ends, conferring genomic stability. Alterations in telomere maintenance and function are associated with tumorigenesis. In chronic lymphocytic leukemia (CLL), telomere length is an independent prognostic factor and short telomeres are associated with adverse outcome. Though telomere length associations have been suggested to be only a passive reflection of the cell's replication history, here, based on published findings, we suggest a more dynamic role of telomere dysfunction in shaping the disease course. Different members of the shelterin complex, which form the telomere structure have deregulated expression and POT1 is recurrently mutated in about 3.5% of CLL. In addition, cases with short telomeres have higher telomerase (TERT) expression and activity. TERT activation and shelterin deregulation thus may be pivotal in maintaining the minimal telomere length necessary to sustain survival and proliferation of CLL cells. On the other hand, activation of DNA damage response and repair signaling at dysfunctional telomeres coupled with checkpoint deregulation, leads to terminal fusions and genomic complexity. In summary, multiple components of the telomere system are affected and they play an important role in CLL pathogenesis, progression, and clonal evolution. However, processes leading to shelterin deregulation as well as cell intrinsic and microenvironmental factors underlying TERT activation are poorly understood. The present review comprehensively summarizes the complex interplay of telomere dysfunction in CLL and underline the mechanisms that are yet to be deciphered.},
}
@article {pmid33517527,
year = {2021},
author = {Wirth, A and Wolf, B and Huang, CK and Glage, S and Hofer, SJ and Bankstahl, M and Bär, C and Thum, T and Kahl, KG and Sigrist, SJ and Madeo, F and Bankstahl, JP and Ponimaskin, E},
title = {Novel aspects of age-protection by spermidine supplementation are associated with preserved telomere length.},
journal = {GeroScience},
volume = {43},
number = {2},
pages = {673-690},
pmid = {33517527},
issn = {2509-2723},
mesh = {Aging ; Animals ; Autophagy ; Dietary Supplements ; Mice ; *Spermidine/pharmacology ; *Telomere ; },
abstract = {Ageing provokes a plethora of molecular, cellular and physiological deteriorations, including heart failure, neurodegeneration, metabolic maladaptation, telomere attrition and hair loss. Interestingly, on the molecular level, the capacity to induce autophagy, a cellular recycling and cleaning process, declines with age across a large spectrum of model organisms and is thought to be responsible for a subset of age-induced changes. Here, we show that a 6-month administration of the natural autophagy inducer spermidine in the drinking water to aged mice is sufficient to significantly attenuate distinct age-associated phenotypes. These include modulation of brain glucose metabolism, suppression of distinct cardiac inflammation parameters, decreased number of pathological sights in kidney and liver and decrease of age-induced hair loss. Interestingly, spermidine-mediated age protection was associated with decreased telomere attrition, arguing in favour of a novel cellular mechanism behind the anti-ageing effects of spermidine administration.},
}
@article {pmid33513745,
year = {2021},
author = {Vodicka, P and Andera, L and Opattova, A and Vodickova, L},
title = {The Interactions of DNA Repair, Telomere Homeostasis, and p53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction.},
journal = {Cancers},
volume = {13},
number = {3},
pages = {},
pmid = {33513745},
issn = {2072-6694},
support = {18-09709S//Grantov&#xe1; Agentura &#x10c;esk&#xe9; Republiky/ ; 19-10543S//Grantov&#xe1; Agentura &#x10c;esk&#xe9; Republiky/ ; NV18-00199//Agentura Pro Zdravotnick&#xfd; V&#xfd;zkum &#x10c;esk&#xe9; Republiky/ ; PROGRES Q 28//Grantov&#xe1; Agentura, Univerzita Karlova/ ; UNCE/MED/006//Grantov&#xe1; Agentura, Univerzita Karlova/ ; CZ.02.1.01/0.0./0.0/16_019/0000787//Ministerstvo &#x160;kolstv&#xed;, Ml&#xe1;de&#x17e;e a T&#x11b;lov&#xfd;chovy/ ; },
abstract = {The disruption of genomic integrity due to the accumulation of various kinds of DNA damage, deficient DNA repair capacity, and telomere shortening constitute the hallmarks of malignant diseases. DNA damage response (DDR) is a signaling network to process DNA damage with importance for both cancer development and chemotherapy outcome. DDR represents the complex events that detect DNA lesions and activate signaling networks (cell cycle checkpoint induction, DNA repair, and induction of cell death). TP53, the guardian of the genome, governs the cell response, resulting in cell cycle arrest, DNA damage repair, apoptosis, and senescence. The mutational status of TP53 has an impact on DDR, and somatic mutations in this gene represent one of the critical events in human carcinogenesis. Telomere dysfunction in cells that lack p53-mediated surveillance of genomic integrity along with the involvement of DNA repair in telomeric DNA regions leads to genomic instability. While the role of individual players (DDR, telomere homeostasis, and TP53) in human cancers has attracted attention for some time, there is insufficient understanding of the interactions between these pathways. Since solid cancer is a complex and multifactorial disease with considerable inter- and intra-tumor heterogeneity, we mainly dedicated this review to the interactions of DNA repair, telomere homeostasis, and TP53 mutational status, in relation to (a) cancer risk, (b) cancer progression, and (c) cancer therapy.},
}
@article {pmid33510409,
year = {2021},
author = {Sperka, T and Song, Z and Morita, Y and Nalapareddy, K and Guachalla, LM and Lechel, A and Begus-Nahrmann, Y and Burkhalter, MD and Mach, M and Schlaudraff, F and Liss, B and Ju, Z and Speicher, MR and Rudolph, KL},
title = {Author Correction: Puma and p21 represent cooperating checkpoints limiting self-renewal and chromosomal instability of somatic stem cells in response to telomere dysfunction.},
journal = {Nature cell biology},
volume = {23},
number = {3},
pages = {292},
doi = {10.1038/s41556-021-00633-w},
pmid = {33510409},
issn = {1476-4679},
}
@article {pmid33509633,
year = {2021},
author = {Stone, RC and Aviv, A and Paus, R},
title = {Telomere Dynamics and Telomerase in the Biology of Hair Follicles and their Stem Cells as a Model for Aging Research.},
journal = {The Journal of investigative dermatology},
volume = {141},
number = {4S},
pages = {1031-1040},
doi = {10.1016/j.jid.2020.12.006},
pmid = {33509633},
issn = {1523-1747},
support = {R01 HL134840/HL/NHLBI NIH HHS/United States ; U01 AG066529/AG/NIA NIH HHS/United States ; U01 DK119085/DK/NIDDK NIH HHS/United States ; },
mesh = {Aging/drug effects/*genetics/pathology ; Animals ; Hair Diseases/drug therapy/genetics/pathology ; Hair Follicle/cytology/enzymology/*pathology ; Humans ; Mice ; Mice, Transgenic ; Pigmentation Disorders/drug therapy/genetics/pathology ; Stem Cells/enzymology/*pathology ; Telomerase/antagonists &amp; inhibitors/genetics/*metabolism ; Telomere Shortening/drug effects/*genetics ; },
abstract = {In this review, we propose that telomere length dynamics play an important but underinvestigated role in the biology of the hair follicle (HF), a prototypic, cyclically remodeled miniorgan that shows an intriguing aging pattern in humans. Whereas the HF pigmentary unit ages quickly, its epithelial stem cell (ESC) component and regenerative capacity are surprisingly aging resistant. Telomerase-deficient mice with short telomeres display an aging phenotype of hair graying and hair loss that is attributed to impaired HF ESC mobilization. Yet, it remains unclear whether the function of telomerase and telomeres in murine HF biology translate to the human system. Therefore, we propose new directions for future telomere research of the human HF. Such research may guide the development of novel treatments for selected disorders of human hair growth or pigmentation (e.g., chemotherapy-induced alopecia, telogen effluvium, androgenetic alopecia, cicatricial alopecia, graying). It might also increase the understanding of the global role of telomeres in aging-related human disease.},
}
@article {pmid33509090,
year = {2021},
author = {Saud, Z and Kortsinoglou, AM and Kouvelis, VN and Butt, TM},
title = {Telomere length de novo assembly of all 7 chromosomes and mitogenome sequencing of the model entomopathogenic fungus, Metarhizium brunneum, by means of a novel assembly pipeline.},
journal = {BMC genomics},
volume = {22},
number = {1},
pages = {87},
pmid = {33509090},
issn = {1471-2164},
mesh = {*Genome, Mitochondrial ; High-Throughput Nucleotide Sequencing ; *Metarhizium/genetics ; Sequence Analysis, DNA ; Telomere/genetics ; },
abstract = {BACKGROUND: More accurate and complete reference genomes have improved understanding of gene function, biology, and evolutionary mechanisms. Hybrid genome assembly approaches leverage benefits of both long, relatively error-prone reads from third-generation sequencing technologies and short, accurate reads from second-generation sequencing technologies, to produce more accurate and contiguous de novo genome assemblies in comparison to using either technology independently. In this study, we present a novel hybrid assembly pipeline that allowed for both mitogenome de novo assembly and telomere length de novo assembly of all 7 chromosomes of the model entomopathogenic fungus, Metarhizium brunneum.<br><br>RESULTS: The improved assembly allowed for better ab initio gene prediction and a more BUSCO complete proteome set has been generated in comparison to the eight current NCBI reference Metarhizium spp. genomes. Remarkably, we note that including the mitogenome in ab initio gene prediction training improved overall gene prediction. The assembly was further validated by comparing contig assembly agreement across various assemblers, assessing the assembly performance of each tool. Genomic synteny and orthologous protein clusters were compared between Metarhizium brunneum and three other Hypocreales species with complete genomes, identifying core proteins, and listing orthologous protein clusters shared uniquely between the two entomopathogenic fungal species, so as to further facilitate the understanding of molecular mechanisms underpinning fungal-insect pathogenesis.<br><br>CONCLUSIONS: The novel assembly pipeline may be used for other haploid fungal species, facilitating the need to produce high-quality reference fungal genomes, leading to better understanding of fungal genomic evolution, chromosome structuring and gene regulation.},
}
@article {pmid33507936,
year = {2021},
author = {Han, X and Kubota, R and Tanaka, KI and Hayashi, H and Seki, M and Sakai, N and Kawaguchi-Ihara, N and Arakawa, K and Murohashi, I},
title = {The correlation of salivary telomere length and single nucleotide polymorphisms of the ADIPOQ, SIRT1 and FOXO3A genes with lifestyle-related diseases in a Japanese population.},
journal = {PloS one},
volume = {16},
number = {1},
pages = {e0243745},
pmid = {33507936},
issn = {1932-6203},
mesh = {Adiponectin/*genetics ; Adult ; Aged ; Aged, 80 and over ; Female ; Forkhead Box Protein O3/*genetics ; Humans ; Hypertension/epidemiology/*genetics ; Japan/epidemiology ; Male ; Middle Aged ; *Neoplasms/epidemiology/genetics ; *Polymorphism, Single Nucleotide ; Saliva ; Sirtuin 1/*genetics ; Telomere/*metabolism ; },
abstract = {BACKGROUND: It has been reported that genetic factors are associated with risk factors and onset of lifestyle-related diseases, but this finding is still the subject of much debate.<br><br>OBJECTIVE: The aim of the present study was to investigate the correlation of genetic factors, including salivary telomere length and three single nucleotide polymorphisms (SNPs) that may influence lifestyle-related diseases, with lifestyle-related diseases themselves.<br><br>METHODS: In one year at a single facility, relative telomere length and SNPs were determined by using monochrome multiplex quantitative polymerase chain reaction and TaqMan SNP Genotyping Assays, respectively, and were compared with lifestyle-related diseases in 120 Japanese individuals near our university.<br><br>RESULTS: In men and all participants, age was inversely correlated with relative telomere length with respective p values of 0.049 and 0.034. In men, the frequency of hypertension was significantly higher in the short relative telomere length group than in the long group with unadjusted p value of 0.039, and the difference in the frequency of hypertension between the two groups was of borderline statistical significance after adjustment for age (p = 0.057). Furthermore, in men and all participants, the sum of the number of affected lifestyle-related diseases, including hypertension, was significantly higher in the short relative telomere length group than in the long group, with p values of 0.004 and 0.029, respectively. For ADIPOQ rs1501299, men's ankle brachial index was higher in the T/T genotype than in the G/G and G/T genotypes, with p values of 0.001 and 0.000, respectively. For SIRT1 rs7895833, men's body mass index and waist circumference and all participants' brachial-ankle pulse wave velocity were higher in the A/G genotype than in the G/G genotype, with respective p values of 0.048, 0.032 and 0.035. For FOXO3A rs2802292, women's body temperature and all participants' saturation of peripheral oxygen were lower in the G/T genotype than in the T/T genotype, with respective p values of 0.039 and 0.032. However, relative telomere length was not associated with physiological or anthropometric measurements except for height in men (p = 0.016). ADIPOQ rs1501299 in men, but not the other two SNPs, was significantly associated with the sum of the number of affected lifestyle-related diseases (p = 0.013), by genotype. For each SNPs, there was no significant difference in the frequency of hypertension or relative telomere length by genotype.<br><br>CONCLUSION: Relative telomere length and the three types of SNPs determined using saliva have been shown to be differentially associated with onset of and measured risk factors for lifestyle-related diseases consisting mainly of cardiovascular diseases and cancer.},
}
@article {pmid35754453,
year = {2021},
author = {Aguayo, L and Ogolsky, B and Teran-Garcia, M and Pineros-Leano, M and Wiley, A and Lin, J and Aguirre-Pereyra, R and Schwingel, A},
title = {From culture to chromosomes: A mother-child dyadic study of acculturation, telomere lengths and body fat.},
journal = {Comprehensive psychoneuroendocrinology},
volume = {5},
number = {},
pages = {100029},
pmid = {35754453},
issn = {2666-4976},
abstract = {Studies suggest that telomere lengths, a biomarker of aging, could also capture the physiological weathering attributable to poor health behaviors and adverse experiences, particularly those experienced in early life. For these reasons, we propose that telomere lengths may be a pivotal biomarker for measuring the heightened susceptibility to illness resulting from the cumulative exposure to acculturation to the US culture. This binational study used an Actor-Partner Interdependence Model to test if maternal acculturation to the US moderates the cross-sectional associations of telomere lengths with percentage of body fat (PBF) among Mexican women, among their children, and the intergenerational associations of mother and children telomere lengths with each other's PBF. Low income Mexican child-mother dyads (n = 108 dyads) were recruited to participate in this cross-sectional study in Mexico and the US. The pooled dataset included measurements of maternal acculturation to the US, mother and children's salivary telomere lengths, PBF measured through bioelectrical impedance, and demographic characteristics. Results showed that the influences of maternal acculturation in the associations of telomere lengths with PBF were different for mothers and their children: Among mothers with higher maternal acculturation to the US, longer salivary telomere lengths were associated with lower PBF. In contrast, among mothers with lower maternal acculturation to the US, salivary telomere lengths were not associated with PBF. There were no significant associations between children's salivary telomere lengths and PBF, and the null associations did not vary across different levels of maternal acculturation to the US. Future longitudinal studies are needed to determine whether acculturation to the US (experienced through immigration or remotely) influences the association of telomere length attrition with obesity risks among immigrant and non-immigrant Mexican children and adults.},
}
@article {pmid35515777,
year = {2020},
author = {Wang, S and Liang, L and Tang, J and Cai, Y and Zhao, C and Fang, S and Wang, H and Weng, T and Wang, L and Wang, D},
title = {Label-free single-molecule identification of telomere G-quadruplexes with a solid-state nanopore sensor.},
journal = {RSC advances},
volume = {10},
number = {45},
pages = {27215-27224},
pmid = {35515777},
issn = {2046-2069},
abstract = {Telomere sequences can spontaneously form G-quadruplexes (G4) in the presence of some cations. In view of their relevance to genetic processes and potential as therapeutic-targets, hitherto, a wealth of conventional techniques have been reported for interrogation of G4 conformation diversity and corresponding folding kinetics, most of which are limited in precision and sensitivity. This work introduces a label-free solid-state nanopore (SSN) approach for the determination of inter-, intra- and tandem molecular G4 with distinct base permutation in various cation buffers with a tailored aperture and meanwhile captures the single-molecule G4 folding process. SSN translocation properties elucidated that both inter- and intramolecular G4 generated higher current blockage with longer duration than flexible homopolymer nucleotide, and intramolecular G4 are structurally more stable with higher event frequency and longer blockage time than intermolecular ones; base arrangement played weak role in translocation behaviors; the same sequences with one, two and three G4 skeletons displayed an increase in current blockage and a gradual extension in dwell time with the increase of molecule size recorded in the same nanopore. We observed the conformation change of single-molecule G4 which indicated the existence of folding/unfolding equilibration in nanopore, and real-time test suggested a gradual formation of G4 with time. Our results could provide a continued and improved understanding of the underlying relevance of structural stability and G4 folding process by utilizing SSN platform which exhibits strategic potential advances over the other methods with high spatial and temporal resolution.},
}
@article {pmid33718773,
year = {2020},
author = {Hastings, WJ and Eisenberg, DTA and Shalev, I},
title = {Uninterruptible Power Supply Improves Precision and External Validity of Telomere Length Measurement via qPCR.},
journal = {Experimental results},
volume = {1},
number = {},
pages = {},
pmid = {33718773},
issn = {2516-712X},
support = {U01 ES030949/ES/NIEHS NIH HHS/United States ; },
abstract = {Technical challenges associated with telomere length (TL) measurements have prompted concerns regarding their utility as a biomarker of aging. Several factors influence TL assessment via qPCR, the most common measurement method in epidemiological studies, including storage conditions and DNA extraction method. Here, we tested the impact of power supply during the qPCR assay. Momentary fluctuations in power can affect the functioning of high-performance electronics, including real-time thermocyclers. We investigated if mitigating these fluctuations by using an uninterruptible power supply (UPS) influenced TL assessment via qPCR. Samples run with a UPS had significantly lower standard deviation (p < 0.001) and coefficient of variation (p < 0.001) across technical replicates than those run without a UPS. UPS usage also improved exponential amplification efficiency at the replicate, sample, and plate levels. Together these improvements translated to increased performance across metrics of external validity including correlation with age, within-person correlation across tissues, and correlation between parents and offspring.},
}
@article {pmid33868775,
year = {2019},
author = {Adam, E and Islam, T and Ranjan, D and Riethman, H},
title = {Nanopore Guided Assembly of Segmental Duplications near Telomeres.},
journal = {Proceedings. IEEE International Symposium on Bioinformatics and Bioengineering},
volume = {2019},
number = {},
pages = {},
pmid = {33868775},
issn = {2159-5410},
support = {R21 CA177395/CA/NCI NIH HHS/United States ; },
abstract = {Human subtelomere regions are highly enriched in large segmental duplications and structural variants, leading to many gaps and misassemblies in these regions. We develop a novel method, NPGREAT (NanoPore Guided REgional Assembly Tool), which combines Nanopore ultralong read datasets and short-read assemblies derived from 10x linked-reads to efficiently assemble these subtelomere regions into a single continuous sequence. We show that with the use of ultralong Nanopore reads as a guide, the highly accurate shorter linked-read sequence contigs are correctly oriented, ordered, spaced and extended. In the rare cases where a linked-read sequence contig contains inaccurately assembled segments, the use of Nanopore reads allows for detection and correction of this error. We tested NPGREAT on four representative subtelomeres of the NA12878 human genome (10p, 16p, 19q and 20p). The results demonstrate that the final computed assembly of each subtelomere is accurate and complete.},
}
@article {pmid34025848,
year = {2021},
author = {Albarrán-Tamayo, F and Murillo-Ortiz, B and González Amaro, R and López Briones, S},
title = {Both in vitro T cell proliferation and telomere length are decreased, but CD25 expression and IL-2 production are not affected in aged men.},
journal = {Archives of medical science : AMS},
volume = {17},
number = {3},
pages = {775-784},
pmid = {34025848},
issn = {1734-1922},
abstract = {INTRODUCTION: Aging is a natural process involving dysfunction of multiple organs and is characterized by increased susceptibility to infections, cancer and autoimmune diseases. The functionality of the immune system depends on the capacity of lymphocytes to proliferate in response to antigenic challenges, and telomere length has an important role regulating the number of cell divisions. The aim of this study was to determine the possible relationship between telomere length, interleukin 2 (IL-2) production, CD25 expression and proliferation of peripheral blood mononuclear cells (PBMCs) in aged men.<br><br>MATERIAL AND METHODS: Telomere length was measured by RT-PCR in PBMCs from young and aged men. IL-2 production and CD25 expression were determined by ELISA and flow cytometry, respectively. Cell proliferation was measured by CFSE dilution assays upon in vitro stimulation with concanavalin A (Con A).<br><br>RESULTS: PBMCs from aged men showed a shorter telomere length and a reduced capacity to proliferate in vitro, compared to young men. In contrast, no significant differences in the level of CD25 expression on T lymphocytes, and in vitro production of IL-2 were detected in both groups. In addition, no significant correlation was detected between levels of CD25 expression, IL-2 production, cell proliferation, and telomere length in aged men.<br><br>CONCLUSIONS: In aged men the telomere length shortening and the reduced T cell proliferation are not related to the capacity of IL-2 production and CD25 expression on T lymphocytes.},
}
@article {pmid35117117,
year = {2019},
author = {Park, JY and Luu, HN and Park, HY and Lin, HY and Radlein, S and Di Pietro, G and Yeo, CD and Kim, SJ and Kang, N and Antwi, S and Sexton, WJ and Spiess, PE and Dickinson, S and Parker, A},
title = {Telomere length in peripheral blood leukocytes and risk of renal cell carcinoma.},
journal = {Translational cancer research},
volume = {8},
number = {Suppl 4},
pages = {S397-S403},
pmid = {35117117},
issn = {2219-6803},
abstract = {BACKGROUND: Telomeres are essential for chromosomal stability and may play a key role in carcinogenesis. Telomere length is suggested as a tentative biomarker of risk for renal cell carcinoma (RCC). However, results of previous association studies between telomere length and risk for RCC are inconsistent.<br><br>METHODS: We evaluated RCC risk in relation to peripheral blood leukocyte telomere length using a hospital-based case-control study of 169 RCC cases and 189 controls. Cases were histologically-confirmed RCC patients who were treated at the Moffitt Cancer Center (Tampa, FL). Controls with no history of cancer underwent a screening exam at the Lifetime Cancer Screening Center at Moffitt Cancer Center to rule out the presence of cancer. Relative telomere length (RTL) was measured by quantitative real-time polymerase chain reaction (PCR) using peripheral blood leukocyte DNA. Logistic regression was used to determine the association between RTL and RCC risk.<br><br>RESULTS: As expected, increasing age was inversely correlated with RTL (Pearson r=-0.213, P=0.003) among controls but not cases. Average RTL was significantly shorter in cases as compared with controls [mean &#xb1; standard deviation (SD): 3.18&#xb1;1.50 and 4.39&#xb1;1.99, respectively, P<0.001]. In contrast, average RTL was not significantly different by gender, race, smoking status among controls or by clinical stages among RCC cases. In regression analysis, we observed that shorter RTL is significantly associated with RCC risk [odds ratio (OR) =1.48; 95% confidence interval (CI): 1.27-1.71] after adjustment for covariates.<br><br>CONCLUSIONS: We found that shorter RTL is associated with an increased risk for RCC. Our findings suggest that telomere length may be involved in the development of RCC.},
}
@article {pmid33778338,
year = {2019},
author = {Alexeeff, SE and Schaefer, CA and Kvale, MN and Shan, J and Blackburn, EH and Risch, N and Ranatunga, DK and Jorgenson, E and Hoffmann, TJ and Sakoda, LC and Quesenberry, CP and Van Den Eeden, SK},
title = {Telomere length and socioeconomic status at neighborhood and individual levels among 80,000 adults in the Genetic Epidemiology Research on Adult Health and Aging cohort.},
journal = {Environmental epidemiology (Philadelphia, Pa.)},
volume = {3},
number = {3},
pages = {e049},
pmid = {33778338},
issn = {2474-7882},
abstract = {BACKGROUND: Telomere length (TL) may serve as a biologic marker of aging. We examined neighborhood and individual-level socioeconomic status (SES) in relation to TL.<br><br>METHODS: The study included 84,996 non-Hispanic white subjects from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, part of the Research Program on Genes, Environment and Health. Relative TL (T/S) was log2 transformed to improve normality and standardized to have mean 0 and variance 1. Neighborhood SES was measured using the Neighborhood Deprivation Index (NDI), and individual SES was measured by self-reported education level. We fit linear regression models of TL on age, sex, smoking, body mass index, comorbidities, NDI, and education level. We tested for differences in the associations by sex and nonlinearity in the association of NDI with TL.<br><br>RESULTS: Each SD increase in NDI was associated with a decrease of 0.0192 in standardized TL, 95% confidence interval (CI) = -0.0306, -0.0078. There was no evidence of nonlinearity in the association of NDI with TL. We further found that less than high school education was associated with a decrease of 0.1371 in standardized TL, 95% CI = -0.1919, -0.0823 as compared to a college education. There were no differences in the associations by sex.<br><br>CONCLUSIONS: We found evidence that both lower neighborhood SES and lower individual-level SES are associated with shorter TL among non-Hispanic whites. Our findings suggest that socioeconomic factors may influence aging by contributing to shorter TL.},
}
@article {pmid34522248,
year = {2021},
author = {Melicher, D and Illés, A and Littvay, L and Tárnoki, &#xc1;D and Tárnoki, DL and Bikov, A and Kunos, L and Csabán, D and Buzás, EI and Molnár, MJ and Falus, A},
title = {Positive association and future perspectives of mitochondrial DNA copy number and telomere length - a pilot twin study.},
journal = {Archives of medical science : AMS},
volume = {17},
number = {5},
pages = {1191-1199},
pmid = {34522248},
issn = {1734-1922},
abstract = {INTRODUCTION: Recent experimental and population studies have highlighted the existence of telomere-mitochondria interplay. Besides studies revealing the molecular mechanisms underlying the associations of telomere defects and mitochondrial functions, investigations of mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) in healthy and disease phenotypes have likewise begun, with the aim of gaining more insights about their relationship in humans.<br><br>MATERIAL AND METHODS: A total of 142 asymptomatic adult twins, comprising 96 monozygotic (MZ) and 46 dizygotic (DZ) twins (mean age: 50.54 &#xb1;15.43 years), members of the Hungarian Twin Registry, were included in the analysis. Applying the qPCR standard curve method, we investigated the relationship of mtDNA copy number, telomere length and clinical data, besides assessing co-twin similarities of MZ and DZ twins for their mtDNAcn and TL measures.<br><br>RESULTS: We found that twins were similar in their intraclass correlation coefficients irrespective of zygosity, suggesting a possibly more important role of common (shared) environmental factors compared to non-shared (unique) environmental and to a smaller degree also individual genetic influences. We confirmed a significant positive association between mtDNAcn and TL (r = 0.28, p < 0.01) in age- and sex-corrected analysis. Following bivariate estimates and correction with significant predictors, the independent positive associations were further verified.<br><br>CONCLUSIONS: Our results extend the until now modest number of studies investigating mtDNAcn and TL simultaneously in humans. In addition, we are the first to examine the relationship between mtDNAcn and telomere length in MZ and DZ twin subjects.},
}
@article {pmid33636955,
year = {2017},
author = {Blauwkamp, MN and Fasching, CL and Lin, J and Guegler, K and Hytopoulos, E and Watson, D and Harley, CB},
title = {Analytical Validation of Relative Average Telomere Length Measurement in a Clinical Laboratory Environment.},
journal = {The journal of applied laboratory medicine},
volume = {2},
number = {1},
pages = {4-16},
doi = {10.1373/jalm.2016.022137},
pmid = {33636955},
issn = {2576-9456},
abstract = {BACKGROUND: Average telomere length in whole blood has become a biomarker of aging, disease, and mortality risk across a broad range of clinical conditions. The most common method of telomere length measurement for large patient sample sets is based on quantitative PCR (qPCR). For laboratory-developed tests to be performed on clinical samples, they must undergo a rigorous analytical validation, currently regulated under CLIA.<br><br>METHODS: Whole blood samples from 40 donors were used in the analytical validation of methods for relative average telomere length (rATL) measurement. Three technical replicate DNA samples were extracted from each whole blood sample and placed in three independent wells on a sample plate. Each of these sample plates was assayed 12 times during the validation process. The study was conducted over a 20-day period, once in the morning and once in the evening, using 3 different operators.<br><br>RESULTS: Our process of rATL measurement beginning with DNA extraction followed by qPCR-based assay resulted in repeatability and reproducibility CV of <5% and amplification efficiencies near 100%. The validated assay was used to establish a reference interval derived from 2 cohorts of individuals: (a) San Francisco Bay area (n = 504) and (b) a US cross-sectional, demographic population (n = 357).<br><br>CONCLUSIONS: We present advances in the establishment of a highly reproducible analytically validated process for determining rATLs in a CLIA laboratory environment.},
}
@article {pmid33503312,
year = {2022},
author = {Heidinger, BJ and Slowinski, SP and Sirman, AE and Kittilson, J and Gerlach, NM and Ketterson, ED},
title = {Experimentally elevated testosterone shortens telomeres across years in a free-living songbird.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6216-6223},
doi = {10.1111/mec.15819},
pmid = {33503312},
issn = {1365-294X},
support = {2 T32 HD049336-11A1//National Institute of Health Common Themes in Reproductive Diversity Pre-doctoral Fellowship/ ; },
mesh = {Animals ; Male ; *Songbirds/genetics ; Longitudinal Studies ; Reproduction/physiology ; *Passeriformes ; Testosterone ; Telomere/genetics ; },
abstract = {Reproductive investment often comes at a cost to longevity, but the mechanisms that underlie these long-term effects are not well understood. In male vertebrates, elevated testosterone has been shown to increase reproductive success, but simultaneously to decrease survival. One factor that may contribute to or serve as a biomarker of these long-term effects of testosterone on longevity is telomeres, which are often positively related to lifespan and have been shown to shorten in response to reproduction. In this longitudinal study, we measured the effects of experimentally elevated testosterone on telomere shortening in free-living, male dark-eyed juncos (Junco hyemalis carolinensis), a system in which the experimental elevation of testosterone has previously been shown to increase reproductive success and reduce survival. We found a small, significant effect of testosterone treatment on telomeres, with testosterone-treated males exhibiting significantly greater telomere shortening with age than controls. These results are consistent with the hypothesis that increased telomere shortening may be a long-term cost of elevated testosterone exposure. As both testosterone and telomeres are conserved physiological mechanisms, our results suggest that their interaction may apply broadly to the long-term costs of reproduction in male vertebrates.},
}
@article {pmid33501739,
year = {2021},
author = {Ooi, DSQ and Dorajoo, R and Gurung, RL and Dehghan, R and Lim, YY and Ho, CWL and Tay, V and Karuppiah, V and Loke, KY and Lim, SC and Liu, JJ and Sng, AA and Lee, YS},
title = {Association of leukocyte telomere length with obesity-related traits in Asian children with early-onset obesity.},
journal = {Pediatric obesity},
volume = {16},
number = {8},
pages = {e12771},
doi = {10.1111/ijpo.12771},
pmid = {33501739},
issn = {2047-6310},
mesh = {Age of Onset ; Asia/epidemiology ; Child ; Humans ; *Leukocytes ; *Pediatric Obesity/epidemiology/genetics ; *Telomere ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) is associated with obesity and obesity-related traits, and there are ethnic-specific determinants of LTL.<br><br>OBJECTIVE: To evaluate LTL associations with obesity and metabolic parameters in Asian children with early-onset obesity.<br><br>METHODS: Genomic DNA was extracted from peripheral blood leukocytes of a cohort of children with (N = 371) and without obesity (N = 23), and LTL was measured using quantitative PCR (qPCR). Blood plasma was used for metabolic phenotyping. Statistical analysis was performed using SPSS and STATA.<br><br>RESULTS: Children with obesity had shorter LTL (coefficient = -0.683, PAdj = 1.24&#x2009;&#xd7;&#x2009;10[-3]) as compared to children who were lean. LTL was found to be associated with waist circumference (coefficient = -0.326, PAdj = 0.044) and skin-fold measures (coefficient between 0.267 and 0.301, PAdj between 4.27&#x2009;&#xd7;&#x2009;10[-4] and 7.06&#x2009;&#xd7;&#x2009;10[-7]) in children with obesity. However, no significant associations were observed between LTL and metabolic parameters, and between LTL and inflammatory cytokines. LTL also did not significantly mediate the risk of non-alcoholic fatty liver disease (NAFLD) in children with obesity.<br><br>CONCLUSIONS: We showed for the first time that Asian children with severe obesity had shorter LTL, and the shortening of LTL was associated with other adiposity measures including waist circumference and skin-fold measurements.},
}
@article {pmid33500500,
year = {2021},
author = {Kim, B and Ryu, KJ and Lee, S and Kim, T},
title = {Changes in telomere length and senescence markers during human ovarian tissue cryopreservation.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {2238},
pmid = {33500500},
issn = {2045-2322},
mesh = {Adolescent ; Adult ; Cryopreservation/*methods ; Female ; Fertility Preservation/*methods ; Humans ; Immunohistochemistry ; In Situ Nick-End Labeling ; Ovarian Follicle/metabolism ; Ovary/metabolism ; Telomere/*genetics ; Young Adult ; },
abstract = {Ovarian tissue cryopreservation is considered as a useful option to preserve fertility for cancer patients. This study purposed to evaluate the change of telomere length and senescence markers during human ovarian tissue cryopreservation. Ovarian tissues were obtained from women who underwent benign ovarian surgery in the gynecology research unit of a university hospital with prior consent and IRB approval. DNA was extracted from the ovarian tissues using a DNeasy tissue kit and telomere lengths in the DNA samples were determined by real time PCR before and after cryopreservation. All tissues were stained with hematoxylin-eosin and subjected to immunohistochemistry and TUNEL assays. Other senescence markers, including p53, p16, p21, and phospho-pRb proteins, were evaluated using western blot analysis. Ovarian tissues were collected from ten patients and prepared for slow freezing with the same size of diameter 4 mm and 1 mm thickness. Mean age of patients was 26.7 ± 6.2 years (range, 16-34 years), and ovarian tissues were cryopreserved and thawed 4 weeks after cryopreservation. The mean telomere length was significantly decreased after cryopreservation (9.57 ± 1.47 bp vs. 8.34 ± 1.83 bp, p = 0.001). Western blot analysis revealed that p53, p16, and p21 proteins increased and phospho-pRb protein expression decreased after ovarian tissue cryopreservation. Ovarian tissue cryopreservation and transplantation is regarded as one of promising options for fertility preservation. However, clinicians and researchers should be aware of possible irreversible DNA changes such as shortening of telomere length and alterations of other senescence markers in human ovarian tissues.},
}
@article {pmid33500413,
year = {2021},
author = {Zhang, S and Yu, X and Zhang, Y and Xue, X and Yu, Q and Zha, Z and Gogol, M and Workman, JL and Li, S},
title = {Metabolic regulation of telomere silencing by SESAME complex-catalyzed H3T11 phosphorylation.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {594},
pmid = {33500413},
issn = {2041-1723},
support = {R35 GM118068/GM/NIGMS NIH HHS/United States ; },
mesh = {Autophagy ; *Chromosomal Instability ; Gene Expression Regulation, Fungal ; Heterochromatin/metabolism ; Histones/*metabolism ; Multienzyme Complexes/*metabolism ; Phosphorylation ; Proteolysis ; Pyruvate Kinase/metabolism ; Saccharomyces cerevisiae/enzymology/*genetics ; Serine/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/metabolism ; Sirtuin 2/metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are organized into a heterochromatin structure and maintenance of silent heterochromatin is required for chromosome stability. How telomere heterochromatin is dynamically regulated in response to stimuli remains unknown. Pyruvate kinase Pyk1 forms a complex named SESAME (Serine-responsive SAM-containing Metabolic Enzyme complex) to regulate gene expression by phosphorylating histone H3T11 (H3pT11). Here, we identify a function of SESAME in regulating telomere heterochromatin structure. SESAME phosphorylates H3T11 at telomeres, which maintains SIR (silent information regulator) complex occupancy at telomeres and protects Sir2 from degradation by autophagy. Moreover, SESAME-catalyzed H3pT11 directly represses autophagy-related gene expression to further prevent autophagy-mediated Sir2 degradation. By promoting H3pT11, serine increases Sir2 protein levels and enhances telomere silencing. Loss of H3pT11 leads to reduced Sir2 and compromised telomere silencing during chronological aging. Together, our study provides insights into dynamic regulation of silent heterochromatin by histone modifications and autophagy in response to cell metabolism and aging.},
}
@article {pmid33499376,
year = {2021},
author = {Pitkänen, N and Pahkala, K and Rovio, SP and Saijonmaa, OJ and Nyman, AE and Jula, A and Lagström, H and Viikari, JSA and Rönnemaa, T and Niinikoski, H and Simell, O and Fyhrquist, F and Raitakari, OT},
title = {Effects of Randomized Controlled Infancy-Onset Dietary Intervention on Leukocyte Telomere Length-The Special Turku Coronary Risk Factor Intervention Project (STRIP).},
journal = {Nutrients},
volume = {13},
number = {2},
pages = {},
pmid = {33499376},
issn = {2072-6643},
support = {206374, 294834, 251360, 275595, 307996, 322112//Academy of Finland/ ; NA//Juho Vainion S&#xe4;&#xe4;ti&#xf6;/ ; NA//Syd&#xe4;ntutkimuss&#xe4;&#xe4;ti&#xf6;/ ; NA//Opetus- ja Kulttuuriministeri&#xf6;/ ; NA//Suomen Kulttuurirahasto/ ; NA//Sigrid Jus&#xe9;liuksen S&#xe4;&#xe4;ti&#xf6;/ ; NA//Yrj&#xf6; Jahnssonin S&#xe4;&#xe4;ti&#xf6;/ ; NA//Suomen L&#xe4;&#xe4;ketieteen S&#xe4;&#xe4;ti&#xf6;/ ; NA//Special Governmental grants for Health Sciences Research (Turku University Hospital)/ ; NA//Turku University Foundation/ ; },
mesh = {Adolescent ; Blood Pressure ; Cardiometabolic Risk Factors ; Child ; Child, Preschool ; Diet, Fat-Restricted/*methods ; Dietary Fats ; Exercise ; Female ; Finland ; Humans ; Infant ; Insulin/metabolism ; Life Style ; Male ; Prospective Studies ; Smoking ; Telomere/*metabolism/*ultrastructure ; Young Adult ; },
abstract = {Reduced telomere length (TL) is a biological marker of aging. A high inter-individual variation in TL exists already in childhood, which is partly explained by genetics, but also by lifestyle factors. We examined the influence of a 20-year dietary/lifestyle intervention on TL attrition from childhood to early adulthood. The study comprised participants of the longitudinal randomized Special Turku Coronary Risk Factor Intervention Project (STRIP) conducted between 1990 and 2011. Healthy 7-month-old children were randomized to the intervention group (n = 540) receiving dietary counseling mainly focused on dietary fat quality and to the control group (n = 522). Leukocyte TL was measured using the Southern blot method from whole blood samples collected twice: at a mean age of 7.5 and 19.8 years (n = 232; intervention n = 108, control n = 124). Yearly TL attrition rate was calculated. The participants of the intervention group had slower yearly TL attrition rate compared to the controls (intervention: mean = -7.5 bp/year, SD = 24.4 vs. control: mean = -15.0 bp/year, SD = 30.3; age, sex and baseline TL adjusted β = 0.007, SE = 0.004, p = 0.040). The result became stronger after additional adjustments for dietary fat quality and fiber intake, serum lipid and insulin concentrations, systolic blood pressure, physical activity and smoking (β = 0.013, SE = 0.005, p = 0.009). A long-term intervention focused mainly on dietary fat quality may affect the yearly TL attrition rate in healthy children/adolescents.},
}
@article {pmid33498968,
year = {2021},
author = {Henckel, E and James, A and Konradsen, JR and Nordlund, B and Kjellberg, M and Berggren-Broström, E and Hedlin, G and Degerman, S and Bohlin, K},
title = {A Novel Association between YKL-40, a Marker of Structural Lung Disease, and Short Telomere Length in 10-Year-Old Children with Bronchopulmonary Dysplasia.},
journal = {Children (Basel, Switzerland)},
volume = {8},
number = {2},
pages = {},
pmid = {33498968},
issn = {2227-9067},
abstract = {Extremely preterm infants are born with immature lungs and are exposed to an inflammatory environment as a result of oxidative stress. This may lead to airway remodeling, cellular aging and the development of bronchopulmonary dysplasia (BPD). Reliable markers that predict the long-term consequences of BPD in infancy are still lacking. We analyzed two biomarkers of cellular aging and lung function, telomere length and YKL-40, respectively, at 10 years of age in children born preterm with a history of BPD (n = 29). For comparison, these markers were also evaluated in sex-and-age-matched children born at term with childhood asthma (n = 28). Relative telomere length (RTL) was measured in whole blood with qPCR and serum YKL-40 with ELISA, and both were studied in relation to gas exchange and the regional ventilation/perfusion ratio using three-dimensional V/Q-scintigraphy (single photon emission computer tomography, SPECT) in children with BPD. Higher levels of YKL-40 were associated with shorter leukocyte RTL (Pearson's correlation: -0.55, p = 0.002), but were not associated with a lower degree of matching between ventilation and perfusion within the lung. Serum YKL-40 levels were significantly higher in children with BPD compared to children with asthma (17.7 vs. 13.2 ng/mL, p < 0.01). High levels of YKL-40 and short RTLs were associated to the need for ventilatory support more than 1 month in the neonatal period (p < 0.01). The link between enhanced telomere shortening in childhood and structural remodeling of the lung, as observed in children with former BPD but not in children with asthma at the age of 10 years, suggests altered lung development related to prematurity and early life inflammatory exposure. In conclusion, relative telomere length and YKL-40 may serve as biomarkers of altered lung development as a result of early-life inflammation in children with a history of prematurity.},
}
@article {pmid33498228,
year = {2021},
author = {D'Amico-Willman, KM and Anderson, ES and Gradziel, TM and Fresnedo-Ramírez, J},
title = {Relative Telomere Length and Telomerase Reverse Transcriptase (TERT) Expression Are Associated with Age in Almond (Prunus dulcis [Mill.] D.A.Webb).},
journal = {Plants (Basel, Switzerland)},
volume = {10},
number = {2},
pages = {},
pmid = {33498228},
issn = {2223-7747},
support = {2018113//College of Food, Agricultural, and Environmental Sciences, Ohio State University/ ; Fellowship//Center for Applied Plant Sciences, Ohio State University/ ; 2019-67011-29558//National Institute of Food and Agriculture/ ; },
abstract = {While all organisms age, our understanding of how aging occurs varies among species. The aging process in perennial plants is not well-defined, yet can have implications on production and yield of valuable fruit and nut crops. Almond exhibits an age-related disorder known as non-infectious bud failure (BF) that affects vegetative bud development, indirectly affecting kernel yield. This species and disorder present an opportunity to address aging in a commercially relevant and vegetatively propagated perennial crop. The hypothesis tested in this study was that relative telomere length and/or telomerase reverse transcriptase (TERT) expression can serve as biomarkers of aging in almond. Relative telomere lengths and expression of TERT, a subunit of the enzyme telomerase, were measured via qPCR methods using bud and leaf samples collected from distinct age cohorts over a two-year period. Results from this work show a marginal but significant association between both relative telomere length and TERT expression, and age, suggesting that as almonds age, telomeres shorten and TERT expression decreases. This work provides information on potential biomarkers of perennial plant aging, contributing to our knowledge of this process. In addition, these results provide opportunities to address BF in almond breeding and nursery propagation.},
}
@article {pmid33495397,
year = {2021},
author = {Caslini, C and Connelly, JA and Serna, A and Broccoli, D and Hess, JL},
title = {Erratum for Caslini et al., "MLL Associates with Telomeres and Regulates Telomeric Repeat-Containing RNA Transcription".},
journal = {Molecular and cellular biology},
volume = {41},
number = {2},
pages = {},
doi = {10.1128/MCB.00566-20},
pmid = {33495397},
issn = {1098-5549},
support = {R01 CA092251/CA/NCI NIH HHS/United States ; },
}
@article {pmid33495152,
year = {2021},
author = {Adler, BL and Boin, F and Wolters, PJ and Bingham, CO and Shah, AA and Greider, C and Casciola-Rosen, L and Rosen, A},
title = {Autoantibodies targeting telomere-associated proteins in systemic sclerosis.},
journal = {Annals of the rheumatic diseases},
volume = {80},
number = {7},
pages = {912-919},
pmid = {33495152},
issn = {1468-2060},
support = {P30 AR053503/AR/NIAMS NIH HHS/United States ; P30 AR070254/AR/NIAMS NIH HHS/United States ; R01 HL139897/HL/NHLBI NIH HHS/United States ; T32 AR048522/AR/NIAMS NIH HHS/United States ; },
mesh = {Adult ; Aged ; Autoantibodies/blood/*immunology ; Autoantigens/immunology ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/blood/immunology ; Male ; Middle Aged ; Scleroderma, Systemic/blood/*immunology ; Shelterin Complex ; Telomere/pathology ; Telomere-Binding Proteins/*immunology ; },
abstract = {OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune fibrotic disease affecting multiple tissues including the lung. A subset of patients with SSc with lung disease exhibit short telomeres in circulating lymphocytes, but the mechanisms underlying this observation are unclear.<br><br>METHODS: Sera from the Johns Hopkins and University of California, San Francisco (UCSF) Scleroderma Centers were screened for autoantibodies targeting telomerase and the shelterin proteins using immunoprecipitation and ELISA. We determined the relationship between autoantibodies targeting the shelterin protein TERF1 and telomere length in peripheral leucocytes measured by qPCR and flow cytometry and fluorescent in situ hybridisation (Flow-FISH). We also explored clinical associations of these autoantibodies.<br><br>RESULTS: In a subset of patients with SSc, we identified autoantibodies targeting telomerase and the shelterin proteins that were rarely present in rheumatoid arthritis, myositis and healthy controls. TERF1 autoantibodies were present in 40/442 (9.0%) patients with SSc and were associated with severe lung disease (OR 2.4, p=0.04, Fisher's exact test) and short lymphocyte telomere length. 6/6 (100%) patients with TERF1 autoantibodies in the Hopkins cohort and 14/18 (78%) patients in the UCSF cohort had a shorter telomere length in lymphocytes or leukocytes, respectively, relative to the expected age-adjusted telomere length. TERF1 autoantibodies were present in 11/152 (7.2%) patients with idiopathic pulmonary fibrosis (IPF), a fibrotic lung disease believed to be mediated by telomere dysfunction.<br><br>CONCLUSIONS: Autoantibodies targeting telomere-associated proteins in a subset of patients with SSc are associated with short lymphocyte telomere length and lung disease. The specificity of these autoantibodies for SSc and IPF suggests that telomere dysfunction may have a distinct role in the pathogenesis of SSc and pulmonary fibrosis.},
}
@article {pmid33493798,
year = {2021},
author = {Needham, BL},
title = {Newborn telomere length and the early life origins of age-related disease.},
journal = {EBioMedicine},
volume = {64},
number = {},
pages = {103214},
pmid = {33493798},
issn = {2352-3964},
support = {R01 MD011721/MD/NIMHD NIH HHS/United States ; R21 MD012683/MD/NIMHD NIH HHS/United States ; },
mesh = {Aging/*genetics ; *Disease Susceptibility ; Female ; Humans ; Infant, Newborn ; Male ; Telomere/*genetics ; *Telomere Homeostasis ; },
}
@article {pmid33493537,
year = {2021},
author = {Adli, A and Hosseini, SM and Lari Najafi, M and Behmanesh, M and Ghezi, E and Rasti, M and Kazemi, AA and Rad, A and Falanji, F and Mohammadzadeh, M and Miri, M and Dadvand, P},
title = {Polycyclic aromatic hydrocarbons exposures and telomere length: A cross-sectional study on preschool children.},
journal = {Environmental research},
volume = {195},
number = {},
pages = {110757},
doi = {10.1016/j.envres.2021.110757},
pmid = {33493537},
issn = {1096-0953},
mesh = {Child, Preschool ; Cross-Sectional Studies ; Environmental Exposure/analysis ; Female ; Humans ; Iran ; Male ; *Polycyclic Aromatic Hydrocarbons/analysis ; Telomere ; },
abstract = {Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with shorter telomere length (TL), a marker of ageing at cellular level. However, the available evidence on this association among children is still scarce. We therefore aimed to assess, the relationship between urinary 1-hydroxipayrene (1-OHP), a marker of exposure to PAHs, and relative leukocyte TL (LTL) in children at preschool age. Our study was based on 200 children enrolled from 27 randomly-selected kindergartens in the city of Sabzevar, Iran (2017). 1-OHP levels in the participants' urine samples were measured using solid phase extraction (SPE) method and high-performance liquid chromatography (HPLC). Moreover, real-time PCR was used to measure the LTL in the participants' blood samples. Linear mixed effects models, controlled for relevant covariates, were applied to investigate the association of 1-OHP concentration and LTL. The median (interquartile range (IQR)) of relative LTL and urinary 1-OHP were 0.83 (0.7) and 257 (375.5) ng/L, respectively. In the fully adjusted model, an IQR increase in urinary 1-OHP was related to -0.05 (95% confidence interval (CI): 0.09, -0.01, P-value = 0.02) decrease in relative LTL. This association was similar among boys and girls; however, we observed indications for a stronger association for those children whose parents had university education. Our study suggested an inverse relationship between urinary 1-OHP and LTL in children at preschool age. However, further longitudinal research with repeated measures of PAHs and LTL are needed to confirm these findings.},
}
@article {pmid33482595,
year = {2021},
author = {Grill, S and Nandakumar, J},
title = {Molecular mechanisms of telomere biology disorders.},
journal = {The Journal of biological chemistry},
volume = {296},
number = {},
pages = {100064},
pmid = {33482595},
issn = {1083-351X},
support = {R01 AG050509/AG/NIA NIH HHS/United States ; R01 GM120094/GM/NIGMS NIH HHS/United States ; T32 GM007544/GM/NIGMS NIH HHS/United States ; },
mesh = {Anemia, Aplastic/genetics ; Dyskeratosis Congenita/genetics ; Humans ; Mutation ; Shelterin Complex ; Telomerase/genetics/metabolism ; *Telomere ; Telomere Shortening ; Telomere-Binding Proteins ; },
abstract = {Genetic mutations that affect telomerase function or telomere maintenance result in a variety of diseases collectively called telomeropathies. This wide spectrum of disorders, which include dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia, is characterized by severely short telomeres, often resulting in hematopoietic stem cell failure in the most severe cases. Recent work has focused on understanding the molecular basis of these diseases. Mutations in the catalytic TERT and TR subunits of telomerase compromise activity, while others, such as those found in the telomeric protein TPP1, reduce the recruitment of telomerase to the telomere. Mutant telomerase-associated proteins TCAB1 and dyskerin and the telomerase RNA maturation component poly(A)-specific ribonuclease affect the maturation and stability of telomerase. In contrast, disease-associated mutations in either CTC1 or RTEL1 are more broadly associated with telomere replication defects. Yet even with the recent surge in studies decoding the mechanisms underlying these diseases, a significant proportion of dyskeratosis congenita mutations remain uncharacterized or poorly understood. Here we review the current understanding of the molecular basis of telomeropathies and highlight experimental data that illustrate how genetic mutations drive telomere shortening and dysfunction in these patients. This review connects insights from both clinical and molecular studies to create a comprehensive view of the underlying mechanisms that drive these diseases. Through this, we emphasize recent advances in therapeutics and pinpoint disease-associated variants that remain poorly defined in their mechanism of action. Finally, we suggest future avenues of research that will deepen our understanding of telomere biology and telomere-related disease.},
}
@article {pmid33480989,
year = {2021},
author = {Subecz, C and Sun, JS and Roger, L},
title = {Effect of DNA repair inhibitor AsiDNA on the incidence of telomere fusion in crisis.},
journal = {Human molecular genetics},
volume = {30},
number = {3-4},
pages = {172-181},
pmid = {33480989},
issn = {1460-2083},
mesh = {DNA Repair/*drug effects ; HCT116 Cells ; Humans ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {Telomere fusions lead to a state of genomic instability, and are thought to drive clonal evolution and tumorigenesis. Telomere fusions occur via both Classical and Alternative Non-Homologous End Joining repair pathways. AsiDNA is a DNA repair inhibitor that acts by mimicking a DNA double strand break (DSB) and hijacking the recruitment of proteins involved in various DNA repair pathways. In this study, we investigated whether the inhibition of DSB-repair pathways by AsiDNA could prevent telomere fusions during crisis. The present study showed that AsiDNA decreased the frequency of telomere fusions without affecting the rate of telomere erosion. Further, it indicated that AsiDNA does not impact the choice of the repair pathway used for the fusion of short dysfunctional telomeres. AsiDNA is thought to prevent short telomeres from fusing by inhibiting DNA repair. An alternative, non-mutually exclusive possibility is that cells harbouring fusions preferentially die in the presence of AsiDNA, thus resulting in a reduction in fusion frequency. This important work could open the way for investigating the use of AsiDNA in the treatment of tumours that have short dysfunctional telomeres and/or are experiencing genomic instability.},
}
@article {pmid33479235,
year = {2021},
author = {Lippert, TP and Marzec, P and Idilli, AI and Sarek, G and Vancevska, A and Bower, M and Farrell, PJ and Ojala, PM and Feldhahn, N and Boulton, SJ},
title = {Oncogenic herpesvirus KSHV triggers hallmarks of alternative lengthening of telomeres.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {512},
pmid = {33479235},
issn = {2041-1723},
support = {FC0010048/MRC_/Medical Research Council/United Kingdom ; /DH_/Department of Health/United Kingdom ; MR/S022597/1/MRC_/Medical Research Council/United Kingdom ; FC0010048/CRUK_/Cancer Research UK/United Kingdom ; 13016/LLR_/Blood Cancer UK/United Kingdom ; FC0010048/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Carcinogenesis ; Cell Line ; Cell Line, Tumor ; DNA Damage ; DNA Replication/genetics ; HeLa Cells ; Herpesvirus 8, Human/physiology ; Host-Pathogen Interactions ; Humans ; In Situ Hybridization, Fluorescence ; Neoplasms/*genetics/pathology/virology ; Proteome/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere Shortening/*genetics ; },
abstract = {To achieve replicative immortality, cancer cells must activate telomere maintenance mechanisms to prevent telomere shortening. ~85% of cancers circumvent telomeric attrition by re-expressing telomerase, while the remaining ~15% of cancers induce alternative lengthening of telomeres (ALT), which relies on break-induced replication (BIR) and telomere recombination. Although ALT tumours were first reported over 20 years ago, the mechanism of ALT induction remains unclear and no study to date has described a cell-based model that permits the induction of ALT. Here, we demonstrate that infection with Kaposi's sarcoma herpesvirus (KSHV) induces sustained acquisition of ALT-like features in previously non-ALT cell lines. KSHV-infected cells acquire hallmarks of ALT activity that are also observed in KSHV-associated tumour biopsies. Down-regulating BIR impairs KSHV latency, suggesting that KSHV co-opts ALT for viral functionality. This study uncovers KSHV infection as a means to study telomere maintenance by ALT and reveals features of ALT in KSHV-associated tumours.},
}
@article {pmid33478187,
year = {2021},
author = {Han, S and Ma, X and Fang, J},
title = {[Clinical Application and Challenges of Telomere and Telomerase Research in Lung Cancer].},
journal = {Zhongguo fei ai za zhi = Chinese journal of lung cancer},
volume = {24},
number = {1},
pages = {25-30},
pmid = {33478187},
issn = {1999-6187},
mesh = {Animals ; Enzyme Inhibitors/administration &amp; dosage ; Humans ; Lung Neoplasms/drug therapy/enzymology/genetics/*metabolism ; Telomerase/antagonists &amp; inhibitors/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Lung cancer is one of the malignant tumors with high incidence rate and high mortality worldwide. Telomere and telomerase are closely related to the occurrence and development of lung cancer. Although telomerase may not be the direct cause of carcinogenesis, it plays a key role in maintaining telomere length and tumor growth. The length of most tumors, including lung cancer, is shortened. The change of telomere length is related to the risk of lung cancer, and may become the therapeutic target and predictive index. Target drugs for telomere and telomerase signaling pathway are constantly being explored, and drugs represented by telomerase inhibitors are expected to be used in clinical treatment of lung cancer in the future. However, the research on telomere and telomerase is far from enough. The bypass mechanism of telomere length maintenance may be the direction of further research. .},
}
@article {pmid33478114,
year = {2021},
author = {Levstek, T and Redenšek, S and Trošt, M and Dolžan, V and Podkrajšek, KT},
title = {Assessment of the Telomere Length and Its Effect on the Symptomatology of Parkinson's Disease.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {10},
number = {1},
pages = {},
pmid = {33478114},
issn = {2076-3921},
support = {P1-0170//Javna Agencija za Raziskovalno Dejavnost RS/ ; },
abstract = {Telomeres, which are repetitive sequences that cap the end of the chromosomes, shorten with each cell division. Besides cellular aging, there are several other factors that influence telomere length (TL), in particular, oxidative stress and inflammation, which play an important role in the pathogenesis of neurodegenerative brain diseases including Parkinson's disease (PD). So far, the majority of studies have not demonstrated a significant difference in TL between PD patients and healthy individuals. However, studies investigating the effect of TL on the symptomatology and disease progression of PD are scarce, and thus, warranted. We analyzed TL of peripheral blood cells in a sample of 204 PD patients without concomitant autoimmune diseases and analyzed its association with several PD related phenotypes. Monochrome multiplex quantitative PCR (mmqPCR) was used to determine relative TL given as a ratio of the amount of DNA between the telomere and albumin as the housekeeping gene. We found a significant difference in the relative TL between PD patients with and without dementia, where shorter TL presented higher risk for dementia (p = 0.024). However, the correlation was not significant after adjustment for clinical factors (p = 0.509). We found no correlations between TLs and the dose of dopaminergic therapy when the analysis was adjusted for genetic variability in inflammatory or oxidative factors. In addition, TL influenced time to onset of motor complications after levodopa treatment initiation (p = 0.0134), but the association did not remain significant after adjustment for age at inclusion and disease duration (p = 0.0781). Based on the results of our study we conclude that TL contributes to certain PD-related phenotypes, although it may not have a major role in directing the course of the disease. Nevertheless, this expends currently limited knowledge regarding the association of the telomere attrition and the disease severity or motor complications in Parkinson's disease.},
}
@article {pmid33471860,
year = {2021},
author = {Lindrose, AR and McLester-Davis, LWY and Tristano, RI and Kataria, L and Gadalla, SM and Eisenberg, DTA and Verhulst, S and Drury, S},
title = {Method comparison studies of telomere length measurement using qPCR approaches: A critical appraisal of the literature.},
journal = {PloS one},
volume = {16},
number = {1},
pages = {e0245582},
pmid = {33471860},
issn = {1932-6203},
support = {U24 AG066528/AG/NIA NIH HHS/United States ; },
mesh = {Guidelines as Topic ; Polymerase Chain Reaction/*methods/standards ; Reference Standards ; Reproducibility of Results ; Research Design ; Telomere/*genetics ; },
abstract = {Use of telomere length (TL) as a biomarker for various environmental exposures and diseases has increased in recent years. Various methods have been developed to measure telomere length. Polymerase chain reaction (PCR)-based methods remain wide-spread for population-based studies due to the high-throughput capability. While several studies have evaluated the repeatability and reproducibility of different TL measurement methods, the results have been variable. We conducted a literature review of TL measurement cross-method comparison studies that included a PCR-based method published between January 1, 2002 and May 25, 2020. A total of 25 articles were found that matched the inclusion criteria. Papers were reviewed for quality of methodologic reporting of sample and DNA quality, PCR assay characteristics, sample blinding, and analytic approaches to determine final TL. Overall, methodologic reporting was low as assessed by two different reporting guidelines for qPCR-based TL measurement. There was a wide range in the reported correlation between methods (as assessed by Pearson's r) and few studies utilized the recommended intra-class correlation coefficient (ICC) for assessment of assay repeatability and methodologic comparisons. The sample size for nearly all studies was less than 100, raising concerns about statistical power. Overall, this review found that the current literature on the relation between TL measurement methods is lacking in validity and scientific rigor. In light of these findings, we present reporting guidelines for PCR-based TL measurement methods and results of analyses of the effect of assay repeatability (ICC) on statistical power of cross-sectional and longitudinal studies. Additional cross-laboratory studies with rigorous methodologic and statistical reporting, adequate sample size, and blinding are essential to accurately determine assay repeatability and replicability as well as the relation between TL measurement methods.},
}
@article {pmid33471805,
year = {2021},
author = {Belfort, MB and Qureshi, F and Litt, J and Enlow, MB and De Vivo, I and Gregory, K and Tiemeier, H},
title = {Telomere length shortening in hospitalized preterm infants: A pilot study.},
journal = {PloS one},
volume = {16},
number = {1},
pages = {e0243468},
pmid = {33471805},
issn = {1932-6203},
support = {T32 CA009001/CA/NCI NIH HHS/United States ; T32 HL098048/HL/NHLBI NIH HHS/United States ; },
mesh = {Age Factors ; Female ; *Hospitalization ; Humans ; Infant, Newborn ; Infant, Premature/*metabolism ; Intensive Care Units, Neonatal ; Male ; Patient Discharge ; Pilot Projects ; *Telomere Shortening ; },
abstract = {Leukocyte telomere length is a biomarker of aging-related health risks. Hospitalized preterm infants frequently experience elevated oxidative stress and inflammation, both of which contribute to telomere shortening. Our aim was to examine changes in telomere length during neonatal intensive care unit (NICU) hospitalization in a cohort of preterm infants <32 weeks' gestation. We conducted a longitudinal study of 10 infants (mean gestational age 27 weeks, range 23.5 to 29, at birth). We isolated DNA from dried blood spots and used Real Time Quantitative PCR to measure relative leukocyte telomere length in triplicate at three time points for each participant. From birth to discharge, infants experienced an average decline in relative telomere length of 0.021 units per week (95% CI -0.040, -0.0020; p = 0.03), after adjustment for gestational age at birth. Our results suggest a measurable decline in telomere length during NICU hospitalization. We speculate that telomere length change may convey information about NICU exposures that carry short- and long-term health risks.},
}
@article {pmid33471779,
year = {2021},
author = {Barbé-Tuana, FM and Grun, LK and Pierdoná, V and Parisi, MM and Friedrich, F and Guma, FTCR and Pinto, LA and Stein, RT and Pitrez, PMC and Jones, MH},
title = {Shorter telomeres in children with severe asthma, an indicative of accelerated aging.},
journal = {Aging},
volume = {13},
number = {2},
pages = {1686-1691},
pmid = {33471779},
issn = {1945-4589},
mesh = {Adolescent ; Aging/blood/*genetics ; Asthma/blood/*genetics ; Case-Control Studies ; Chemokine CCL11/blood ; Child ; Female ; Humans ; Male ; Telomere Shortening/*physiology ; },
abstract = {Severe therapy-resistant asthma (STRA) is closely associated with distinct clinical and inflammatory pheno-endotypes, which may contribute to the development of age-related comorbidities. Evidence has demonstrated a contribution of accelerated telomere shortening on the poor prognosis of respiratory diseases in adults. Eotaxin-1 (CCL11) is an important chemokine for eosinophilic recruitment and the progression of asthma. In the last years has also been proposed as an age-promoting factor. This study aimed to investigate the association of relative telomere length (rTL) and eotaxin-1 in asthmatic children. Children aged 8-14 years (n=267) were classified as healthy control (HC, n=126), mild asthma (MA, n=124) or severe therapy-resistant asthma (STRA, n=17). rTL was performed by qPCR from peripheral blood. Eotaxin-1 was quantified by ELISA from fresh-frozen plasma. STRA had shorter telomeres compared to HC (p=0.02) and MA (p=0.006). Eotaxin-1 levels were up-regulated in STRA [median; IQR25-75)] [(1,190 pg/mL; 108-2,510)] compared to MA [(638 pg/mL; 134-1,460)] (p=0.03) or HC [(627 pg/mL; 108-1,750)] (p<0.01). Additionally, shorter telomeres were inversely correlated with eotaxin-1 levels in STRA (r=-0.6, p=0.013). Our results suggest that short telomeres and up-regulated eotaxin-1, features of accelerated aging, could prematurely contribute to a senescent phenotype increasing the risk for early development of age-related diseases in asthma.},
}
@article {pmid33469834,
year = {2021},
author = {Huang, Z and Liu, C and Ruan, Y and Guo, Y and Sun, S and Shi, Y and Wu, F},
title = {Dynamics of leukocyte telomere length in adults aged 50 and older: a longitudinal population-based cohort study.},
journal = {GeroScience},
volume = {43},
number = {2},
pages = {645-654},
pmid = {33469834},
issn = {2509-2723},
support = {R01 AG034479/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; China ; Cohort Studies ; Cross-Sectional Studies ; Female ; Humans ; *Leukocytes ; Male ; Middle Aged ; *Telomere/genetics ; },
abstract = {It is well established from previous cross-sectional studies that telomeres shorten with age. However, due to a considerable inter-individual variation in telomere length (TL), its relationship with biological aging is difficult to unpick. Longitudinal repeated assessments of TL changes within individuals should augment our understanding of TL dynamics in aging. This study disentangles within- and inter-individual effects of age on leukocyte telomere length (LTL) dynamics in a large population-based cohort of older adults. A total of 4053 subjects aged 50 and older from the WHO Study on global AGEing and adult health (SAGE) in Shanghai were studied. Relative LTL (T/S ratio) was measured at baseline (2009-2010) and follow-up (2017-2018) by quantitative real-time polymerase chain reaction. We used linear random slope models to analyze LTL dynamics in relation to age and sex and within-subject centering method to distinguish within- versus between-subject effects. We observed LTL shortening in 66.32%, maintenance in 11.23%, and elongation in 22.45% of the study participants. LTL declined significantly with age both cross-sectionally and longitudinally. More importantly, the longitudinal decline in LTL was much greater than the cross-sectional decline (- 0.017 (p < 0.001) versus - 0.002 (p < 0.001) per year). Furthermore, women had a lower within-subject LTL shortening rate than men (- 0.014 versus - 0.020 per year, p < 0.001). The within-individual longitudinal decline in LTL was much greater than the inter-individual cross-sectional decline, indicating that chronological age might impose a greater impact on LTL shortening than other influencing factors combined. Moreover, women showed a lower within-individual LTL shortening rate than men.},
}
@article {pmid33469644,
year = {2021},
author = {Monsen, RC and Chakravarthy, S and Dean, WL and Chaires, JB and Trent, JO},
title = {The solution structures of higher-order human telomere G-quadruplex multimers.},
journal = {Nucleic acids research},
volume = {49},
number = {3},
pages = {1749-1768},
pmid = {33469644},
issn = {1362-4962},
support = {P41 GM103311/GM/NIGMS NIH HHS/United States ; P41 GM103622/GM/NIGMS NIH HHS/United States ; R01 GM077422/GM/NIGMS NIH HHS/United States ; S10 OD018090/OD/NIH HHS/United States ; },
mesh = {Circular Dichroism ; *G-Quadruplexes ; Humans ; Models, Molecular ; Molecular Dynamics Simulation ; Scattering, Small Angle ; Telomere/*chemistry ; X-Ray Diffraction ; },
abstract = {Human telomeres contain the repeat DNA sequence 5'-d(TTAGGG), with duplex regions that are several kilobases long terminating in a 3' single-stranded overhang. The structure of the single-stranded overhang is not known with certainty, with disparate models proposed in the literature. We report here the results of an integrated structural biology approach that combines small-angle X-ray scattering, circular dichroism (CD), analytical ultracentrifugation, size-exclusion column chromatography and molecular dynamics simulations that provide the most detailed characterization to date of the structure of the telomeric overhang. We find that the single-stranded sequences 5'-d(TTAGGG)n, with n = 8, 12 and 16, fold into multimeric structures containing the maximal number (2, 3 and 4, respectively) of contiguous G4 units with no long gaps between units. The G4 units are a mixture of hybrid-1 and hybrid-2 conformers. In the multimeric structures, G4 units interact, at least transiently, at the interfaces between units to produce distinctive CD signatures. Global fitting of our hydrodynamic and scattering data to a worm-like chain (WLC) model indicates that these multimeric G4 structures are semi-flexible, with a persistence length of ∼34 Å. Investigations of its flexibility using MD simulations reveal stacking, unstacking, and coiling movements, which yield unique sites for drug targeting.},
}
@article {pmid33466545,
year = {2021},
author = {Konečná, K and Sováková, PP and Anteková, K and Fajkus, J and Fojtová, M},
title = {Distinct Responses of Arabidopsis Telomeres and Transposable Elements to Zebularine Exposure.},
journal = {International journal of molecular sciences},
volume = {22},
number = {1},
pages = {},
pmid = {33466545},
issn = {1422-0067},
support = {CZ.02.1.01/0.0/0.0/16_026/0008446//European Regional Development Fund/ ; INTER-COST LTC20003//Ministerstvo &#x160;kolstv&#xed;, Ml&#xe1;de&#x17e;e a T&#x11b;lov&#xfd;chovy/ ; },
mesh = {Arabidopsis/*genetics/metabolism ; Cytidine/*analogs &amp; derivatives/genetics ; Cytosine/metabolism ; DNA Methylation/genetics ; DNA Transposable Elements/*genetics ; Epigenesis, Genetic/genetics ; Plant Cells/metabolism ; Telomere/*genetics ; Telomere Homeostasis/genetics ; Telomere Shortening/genetics ; Transcriptional Activation/genetics ; },
abstract = {Involvement of epigenetic mechanisms in the regulation of telomeres and transposable elements (TEs), genomic regions with the protective and potentially detrimental function, respectively, has been frequently studied. Here, we analyzed telomere lengths in Arabidopsis thaliana plants of Columbia, Landsberg erecta and Wassilevskija ecotypes exposed repeatedly to the hypomethylation drug zebularine during germination. Shorter telomeres were detected in plants growing from seedlings germinated in the presence of zebularine with a progression in telomeric phenotype across generations, relatively high inter-individual variability, and diverse responses among ecotypes. Interestingly, the extent of telomere shortening in zebularine Columbia and Wassilevskija plants corresponded to the transcriptional activation of TEs, suggesting a correlated response of these genomic elements to the zebularine treatment. Changes in lengths of telomeres and levels of TE transcripts in leaves were not always correlated with a hypomethylation of cytosines located in these regions, indicating a cytosine methylation-independent level of their regulation. These observations, including differences among ecotypes together with distinct dynamics of the reversal of the disruption of telomere homeostasis and TEs transcriptional activation, reflect a complex involvement of epigenetic processes in the regulation of crucial genomic regions. Our results further demonstrate the ability of plant cells to cope with these changes without a critical loss of the genome stability.},
}
@article {pmid33465329,
year = {2021},
author = {Molbert, N and Angelier, F and Alliot, F and Ribout, C and Goutte, A},
title = {Fish from urban rivers and with high pollutant levels have shorter telomeres.},
journal = {Biology letters},
volume = {17},
number = {1},
pages = {20200819},
pmid = {33465329},
issn = {1744-957X},
mesh = {Animals ; Environmental Monitoring ; *Environmental Pollutants ; France ; Rivers ; Telomere/genetics ; *Water Pollutants, Chemical/toxicity ; },
abstract = {Environmental pressures, such as urbanization and exposure to pollutants may jeopardize survival of free-living animals. Yet, much remains to be known about physiological and ecological responses to currently-released pollutants, especially in wild vertebrate ectotherms. We tested the effect of urbanization and pollution (phthalates, organochlorine and pyrethroid pesticides, polychlorobiphenyls, polybromodiphenylethers, polycyclic aromatic hydrocarbons, and some of their metabolites) on telomere length, a suggested biomarker of life expectancy, in the European chub, Squalius cephalus, from urban and agricultural rivers of the Marne hydrographic network, France. We showed that telomere length was reduced in chub from urban rivers. Moreover, among the wide range of anthropogenic contaminants investigated, high levels of phthalate metabolites in liver were associated with shorter telomeres. This study suggests that urbanization and chemical pollution may compromise survival of wild fish, by accelerating telomere attrition.},
}
@article {pmid33460462,
year = {2022},
author = {Vedder, O and Moiron, M and Bichet, C and Bauch, C and Verhulst, S and Becker, PH and Bouwhuis, S},
title = {Telomere length is heritable and genetically correlated with lifespan in a wild bird.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6297-6307},
doi = {10.1111/mec.15807},
pmid = {33460462},
issn = {1365-294X},
mesh = {Animals ; *Longevity/genetics ; Animals, Wild/genetics ; Birds/genetics ; Telomere Shortening/genetics ; *Charadriiformes/genetics ; Telomere/genetics ; },
abstract = {Telomeres are protective caps at the end of eukaryotic chromosomes that shorten with age and in response to stressful or resource-demanding conditions. Their length predicts individual health and lifespan across a wide range of animals, but whether the observed positive association between telomere length and lifespan is environmentally induced, or set at conception due to a shared genetic basis, has not been tested in wild animals. We applied quantitative genetic "animal models" to longitudinal telomere measurements collected over a 10-year period from individuals of a wild seabird (common tern; Sterna hirundo) with known pedigree. We found no variation in telomere shortening with age among individuals at the phenotypic and genetic level, and only a small permanent environmental effect on adult telomere length. Instead, we found telomere length to be highly heritable and strongly positively genetically correlated with lifespan. Such heritable differences between individuals that are set at conception may present a hitherto underappreciated component of variation in somatic state.},
}
@article {pmid33459354,
year = {2021},
author = {Samavat, H and Luu, HN and Beckman, KB and Jin, A and Wang, R and Koh, WP and Yuan, JM},
title = {Leukocyte telomere length, cancer incidence and all-cause mortality among Chinese adults: Singapore Chinese Health Study.},
journal = {International journal of cancer},
volume = {148},
number = {2},
pages = {352-362},
pmid = {33459354},
issn = {1097-0215},
support = {R01 CA144034/CA/NCI NIH HHS/United States ; T32 CA186873/CA/NCI NIH HHS/United States ; UM1 CA182876/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Asian People ; China/ethnology ; Cohort Studies ; DNA/blood/genetics ; Female ; Humans ; Incidence ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Neoplasms/blood/epidemiology/genetics/*mortality ; Prospective Studies ; Singapore/epidemiology ; Telomere/*genetics ; },
abstract = {Telomeres play a key role in chromosomal maintenance and stability. To date, few studies have investigated the association of leukocyte telomere length with risk of cancer incidence and all-cause mortality in a large prospective cohort, particularly of the Asian population. Relative telomere lengths in genomic DNA from peripheral blood samples were quantified using a validated quantitative real-time PCR among 26 540 middle-aged or older Chinese adults. Hazard ratios (HRs) and 95% confidence intervals (CIs) of cancer and deaths by quintiles of telomere length were calculated using the Cox proportional hazards regression method with adjustment for age, sex and other potential confounders. After baseline blood collection, 4353 persons developed cancer and 7609 died. Participants with the longest decile of telomeres had a 26% (95% CI: 11%-44%) higher risk of total cancer incidence compared to the shortest decile after controlling for age, sex and other potential founders (Ptrend < .0001). In contrast, longer telomeres were associated with lower risk of all-cause mortality (HR = 0.93; 95% CI: 0.84-1.03), noncancer death (HR = 0.81; 95% CI: 0.71-0.92), specifically, death from chronic obstructive pulmonary disease and pneumonia (HR = 0.79, 95% CI: 0.70-0.89) and digestive diseases (HR = 0.60, 95% CI: 0.42-0.88). Our findings demonstrated that longer telomeres are associated with increased risk of cancer development overall and several common cancer types including breast, rectal, prostate, pancreatic cancer and lung adenocarcinoma. Our study also confirmed that longer telomeres are associated with a reduced risk of noncancer related death.},
}
@article {pmid33453166,
year = {2021},
author = {Zhang, JM and Genois, MM and Ouyang, J and Lan, L and Zou, L},
title = {Alternative lengthening of telomeres is a self-perpetuating process in ALT-associated PML bodies.},
journal = {Molecular cell},
volume = {81},
number = {5},
pages = {1027-1042.e4},
pmid = {33453166},
issn = {1097-4164},
support = {R01 CA197779/CA/NCI NIH HHS/United States ; R01 CA218856/CA/NCI NIH HHS/United States ; R01 CA248526/CA/NCI NIH HHS/United States ; R01 GM118833/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line ; Cell Line, Tumor ; DNA Polymerase III/genetics/metabolism ; Epithelial Cells/cytology/metabolism ; Fanconi Anemia Complementation Group Proteins/antagonists &amp; inhibitors/*genetics/metabolism ; *Feedback, Physiological ; Fibroblasts/cytology/metabolism ; Gene Expression Regulation ; Gene Knockdown Techniques ; Humans ; Intranuclear Inclusion Bodies/genetics/metabolism ; Poly-ADP-Ribose Binding Proteins/antagonists &amp; inhibitors/*genetics/metabolism ; Protein Inhibitors of Activated STAT/antagonists &amp; inhibitors/*genetics/metabolism ; RNA Helicases/antagonists &amp; inhibitors/*genetics/metabolism ; RNA, Small Interfering/genetics/metabolism ; Rad52 DNA Repair and Recombination Protein/genetics/metabolism ; RecQ Helicases/genetics/metabolism ; Signal Transduction ; Sumoylation ; Telomere/*chemistry/metabolism ; *Telomere Homeostasis ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; },
abstract = {Alternative lengthening of telomeres (ALT) is mediated by break-induced replication (BIR), but how BIR is regulated at telomeres is poorly understood. Here, we show that telomeric BIR is a self-perpetuating process. By tethering PML-IV to telomeres, we induced telomere clustering in ALT-associated PML bodies (APBs) and a POLD3-dependent ATR response at telomeres, showing that BIR generates replication stress. Ablation of BLM helicase activity in APBs abolishes telomere synthesis but causes multiple chromosome bridges between telomeres, revealing a function of BLM in processing inter-telomere BIR intermediates. Interestingly, the accumulation of BLM in APBs requires its own helicase activity and POLD3, suggesting that BIR triggers a feedforward loop to further recruit BLM. Enhancing BIR induces PIAS4-mediated TRF2 SUMOylation, and PIAS4 loss deprives APBs of repair proteins and compromises ALT telomere synthesis. Thus, a BLM-driven and PIAS4-mediated feedforward loop operates in APBs to perpetuate BIR, providing a critical mechanism to extend ALT telomeres.},
}
@article {pmid33450878,
year = {2021},
author = {Samad, MA and Saiman, MZ and Abdul Majid, N and Karsani, SA and Yaacob, JS},
title = {Berberine Inhibits Telomerase Activity and Induces Cell Cycle Arrest and Telomere Erosion in Colorectal Cancer Cell Line, HCT 116.},
journal = {Molecules (Basel, Switzerland)},
volume = {26},
number = {2},
pages = {},
pmid = {33450878},
issn = {1420-3049},
support = {RP030C-15AFR//Universiti Malaya/ ; RU004C-2020//Universiti Malaya/ ; CEBAR RU006-2018//Universiti Malaya/ ; },
mesh = {Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology ; Berberine/chemistry/*pharmacology ; Cell Cycle Checkpoints/drug effects ; Cell Proliferation/drug effects ; Colorectal Neoplasms/*drug therapy/metabolism/pathology ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors/chemical synthesis/chemistry/*pharmacology ; Humans ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/drug effects/metabolism ; Tumor Cells, Cultured ; },
abstract = {Colorectal cancer (CRC) is the most common cancer among males and females, which is associated with the increment of telomerase level and activity. Some plant-derived compounds are telomerase inhibitors that have the potential to decrease telomerase activity and/or level in various cancer cell lines. Unfortunately, a deeper understanding of the effects of telomerase inhibitor compound(s) on CRC cells is still lacking. Therefore, in this study, the aspects of telomerase inhibitors on a CRC cell line (HCT 116) were investigated. Screening on HCT 116 at 48 h showed that berberine (10.30 ± 0.89 µg/mL) is the most effective (lowest IC50 value) telomerase inhibitor compared to boldine (37.87 ± 3.12 µg/mL) and silymarin (>200 µg/mL). Further analyses exhibited that berberine treatment caused G0/G1 phase arrest at 48 h due to high cyclin D1 (CCND1) and low cyclin-dependent kinase 4 (CDK4) protein and mRNA levels, simultaneous downregulation of human telomerase reverse transcriptase (TERT) mRNA and human telomerase RNA component (TERC) levels, as well as a decrease in the TERT protein level and telomerase activity. The effect of berberine treatment on the cell cycle was time dependent as it resulted in a delayed cell cycle and doubling time by 2.18-fold. Telomerase activity and level was significantly decreased, and telomere erosion followed suit. In summary, our findings suggested that berberine could decrease telomerase activity and level of HCT 116, which in turn inhibits the proliferative ability of the cells.},
}
@article {pmid33450357,
year = {2021},
author = {Gala, K and Khattar, E},
title = {Long non-coding RNAs at work on telomeres: Functions and implications in cancer therapy.},
journal = {Cancer letters},
volume = {502},
number = {},
pages = {120-132},
doi = {10.1016/j.canlet.2020.12.036},
pmid = {33450357},
issn = {1872-7980},
mesh = {Humans ; Neoplasms/*genetics/metabolism ; Precision Medicine ; RNA/*genetics ; RNA, Long Noncoding/*genetics ; Telomerase/*genetics/metabolism ; Telomere/*metabolism ; },
abstract = {Long non-coding RNAs (lncRNAs) are known to regulate various biological processes including cancer. Cancer cells possess limitless replicative potential which is attained by telomere length maintenance while normal somatic cells have a limited lifespan because their telomeres shorten with every cell division ultimately triggering replicative senescence. Two lncRNAs have been observed to play a key role in telomere length maintenance. First is the lncRNA TERC (telomerase RNA component) which functions as a template for telomeric DNA synthesis in association with telomerase reverse transcriptase (TERT) which serves as the catalytic component. Together they constitute the telomerase complex which functions as a reverse transcriptase to elongate telomeres. Second lncRNA that helps in regulating telomere length is the telomeric repeat-containing RNA (TERRA) which is transcribed from the subtelomeric region and extends to the telomeric region. TERC and TERRA exhibit important functions in cancer with implications in precision oncology. In this review, we discuss various aspects of these important lncRNAs in humans and their role in cancer along with recent advancements in their anticancer therapeutic application.},
}
@article {pmid33450206,
year = {2021},
author = {Chakravarti, D and LaBella, KA and DePinho, RA},
title = {Telomeres: history, health, and hallmarks of aging.},
journal = {Cell},
volume = {184},
number = {2},
pages = {306-322},
pmid = {33450206},
issn = {1097-4172},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; R01 CA084628/CA/NCI NIH HHS/United States ; TL1 TR003169/TR/NCATS NIH HHS/United States ; UL1 TR003167/TR/NCATS NIH HHS/United States ; },
mesh = {Aging/*genetics ; Animals ; Cellular Senescence/genetics ; Genomic Instability ; *Health ; Humans ; Telomerase/metabolism ; Telomere/*genetics ; },
abstract = {The escalating social and economic burden of an aging world population has placed aging research at center stage. The hallmarks of aging comprise diverse molecular mechanisms and cellular systems that are interrelated and act in concert to drive the aging process. Here, through the lens of telomere biology, we examine how telomere dysfunction may amplify or drive molecular biological processes underlying each hallmark of aging and contribute to development of age-related diseases such as neurodegeneration and cancer. The intimate link of telomeres to aging hallmarks informs preventive and therapeutic interventions designed to attenuate aging itself and reduce the incidence of age-associated diseases.},
}
@article {pmid33447828,
year = {2021},
author = {Liddiard, K and Grimstead, JW and Cleal, K and Evans, A and Baird, DM},
title = {Tracking telomere fusions through crisis reveals conflict between DNA transcription and the DNA damage response.},
journal = {NAR cancer},
volume = {3},
number = {1},
pages = {zcaa044},
pmid = {33447828},
issn = {2632-8674},
support = {18246/CRUK_/Cancer Research UK/United Kingdom ; 29202/CRUK_/Cancer Research UK/United Kingdom ; },
abstract = {Identifying attributes that distinguish pre-malignant from senescent cells provides opportunities for targeted disease eradication and revival of anti-tumour immunity. We modelled a telomere-driven crisis in four human fibroblast lines, sampling at multiple time points to delineate genomic rearrangements and transcriptome developments that characterize the transition from dynamic proliferation into replicative crisis. Progression through crisis was associated with abundant intra-chromosomal telomere fusions with increasing asymmetry and reduced microhomology usage, suggesting shifts in DNA repair capacity. Eroded telomeres also fused with genomic loci actively engaged in transcription, with particular enrichment in long genes. Both gross copy number alterations and transcriptional responses to crisis likely underpin the elevated frequencies of telomere fusion with chromosomes 9, 16, 17, 19 and most exceptionally, chromosome 12. Juxtaposition of crisis-regulated genes with loci undergoing de novo recombination exposes the collusive contributions of cellular stress responses to the evolving cancer genome.},
}
@article {pmid33446513,
year = {2021},
author = {Henslee, G and Williams, CL and Liu, P and Bertuch, AA},
title = {Identification and characterization of novel ACD variants: modulation of TPP1 protein level offsets the impact of germline loss-of-function variants on telomere length.},
journal = {Cold Spring Harbor molecular case studies},
volume = {7},
number = {1},
pages = {},
pmid = {33446513},
issn = {2373-2873},
support = {R01 HL131744/HL/NHLBI NIH HHS/United States ; T32 GM008231/GM/NIGMS NIH HHS/United States ; },
mesh = {B-Lymphocytes ; Cell Line ; Child, Preschool ; Female ; Gene Deletion ; Germ Cells/*metabolism ; Humans ; Leukoplakia, Oral/genetics ; Microcephaly/genetics ; Nails ; Pedigree ; Receptor, EphB2 ; Sequence Analysis, DNA ; Serine Proteases/*genetics ; Shelterin Complex ; Skin Pigmentation ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*genetics/*isolation &amp; purification ; },
abstract = {Telomere biology disorders, largely characterized by telomere lengths below the first centile for age, are caused by variants in genes associated with telomere replication, structure, or function. One of these genes, ACD, which encodes the shelterin protein TPP1, is associated with both autosomal dominantly and autosomal recessively inherited telomere biology disorders. TPP1 recruits telomerase to telomeres and stimulates telomerase processivity. Several studies probing the effect of various synthetic or patient-derived variants have mapped specific residues and regions of TPP1 that are important for interaction with TERT, the catalytic component of telomerase. However, these studies have come to differing conclusions regarding ACD haploinsufficiency. Here, we report a proband with compound heterozygous novel variants in ACD (NM_001082486.1)-c.505_507delGAG, p.(Glu169del); and c.619delG, p.(Asp207Thrfs*22)-and a second proband with a heterozygous chromosomal deletion encompassing ACD: arr[hg19] 16q22.1(67,628,846-67,813,408)x1. Clinical data, including symptoms and telomere length within the pedigrees, suggested that loss of one ACD allele was insufficient to induce telomere shortening or confer clinical features. Further analyses of lymphoblastoid cell lines showed decreased nascent ACD RNA and steady-state mRNA, but normal TPP1 protein levels, in cells containing heterozygous ACD c.619delG, p.(Asp207Thrfs*22), or the ACD-encompassing chromosomal deletion compared to controls. Based on our results, we conclude that cells are able to compensate for loss of one ACD allele by activating a mechanism to maintain TPP1 protein levels, thus maintaining normal telomere length.},
}
@article {pmid33440881,
year = {2021},
author = {Lejawa, M and Osadnik, K and Osadnik, T and Pawlas, N},
title = {Association of Metabolically Healthy and Unhealthy Obesity Phenotypes with Oxidative Stress Parameters and Telomere Length in Healthy Young Adult Men. Analysis of the MAGNETIC Study.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {10},
number = {1},
pages = {},
pmid = {33440881},
issn = {2076-3921},
support = {UMO-2014113IBINZ5/03166//Narodowe Centrum Nauki/ ; KNW-1-039/N/8/K//&#x15a;l&#x105;ski Uniwersytet Medyczny/ ; },
abstract = {Obesity is a significant factor related to metabolic disturbances that can lead to metabolic syndrome (MetS). Metabolic dysregulation causes oxidative stress, which affects telomere structure. The current study aimed to evaluate the relationships between telomere length, oxidative stress and the metabolically healthy and unhealthy phenotypes in healthy young men. Ninety-eight participants were included in the study (49 healthy slim and 49 obese patients). Study participants were divided into three subgroups according to body mass index and metabolic health. Selected oxidative stress markers were measured in serum. Relative telomere length (rTL) was measured using quantitative polymerase chain reaction. The analysis showed associations between laboratory markers, oxidative stress markers and rTL in metabolically healthy and unhealthy participants. Total oxidation status (TOS), total antioxidant capacity (TAC) and rTL were significantly connected with metabolically unhealthy obesity. TAC was associated with metabolically healthy obesity. Telomeres shorten in patients with metabolic dysregulation related to oxidative stress and obesity linked to MetS. Further studies among young metabolically healthy and unhealthy individuals are needed to determine the pathways related to metabolic disturbances that cause oxidative stress that leads to MetS.},
}
@article {pmid33435578,
year = {2021},
author = {Sławińska, N and Krupa, R},
title = {Molecular Aspects of Senescence and Organismal Ageing-DNA Damage Response, Telomeres, Inflammation and Chromatin.},
journal = {International journal of molecular sciences},
volume = {22},
number = {2},
pages = {},
pmid = {33435578},
issn = {1422-0067},
mesh = {Aging/*genetics ; Animals ; Cellular Senescence/*genetics ; Chromatin/*genetics/metabolism ; *DNA Damage ; Heterochromatin/genetics/metabolism ; Humans ; Inflammation/*genetics/metabolism ; Telomere/*genetics/metabolism ; Telomere Shortening/genetics ; },
abstract = {Cells can become senescent in response to stress. Senescence is a process characterised by a stable proliferative arrest. Sometimes it can be beneficial-for example, it can suppress tumour development or take part in tissue repair. On the other hand, studies show that it is also involved in the ageing process. DNA damage response (DDR) is triggered by DNA damage or telomere shortening during cell division. When left unresolved, it may lead to the activation of senescence. Senescent cells secrete certain proteins in larger quantities. This phenomenon is referred to as senescence-associated secretory phenotype (SASP). SASP can induce senescence in other cells; evidence suggests that overabundance of senescent cells contributes to ageing. SASP proteins include proinflammatory cytokines and metalloproteinases, which degrade the extracellular matrix. Shortening of telomeres is another feature associated with organismal ageing. Older organisms have shorter telomeres. Restoring telomerase activity in mice not only slowed but also partially reversed the symptoms of ageing. Changes in chromatin structure during senescence include heterochromatin formation or decondensation and loss of H1 histones. During organismal ageing, cells can experience heterochromatin loss, DNA demethylation and global histone loss. Cellular and organismal ageing are both complex processes with many aspects that are often related. The purpose of this review is to bring some of these aspects forward and provide details regarding them.},
}
@article {pmid33435482,
year = {2021},
author = {Selvaraju, V and Phillips, M and Fouty, A and Babu, JR and Geetha, T},
title = {Telomere Length as a Biomarker for Race-Related Health Disparities.},
journal = {Genes},
volume = {12},
number = {1},
pages = {},
pmid = {33435482},
issn = {2073-4425},
mesh = {Black or African American/genetics/statistics &amp; numerical data ; Blood Pressure/genetics ; Blood Pressure Determination/statistics &amp; numerical data ; Child ; Female ; *Health Status Disparities ; Heart Rate/genetics ; Humans ; Male ; Pediatric Obesity/epidemiology/*genetics ; Telomere/*metabolism ; Telomere Homeostasis/*genetics ; White People/genetics/statistics &amp; numerical data ; },
abstract = {Disparities between the races have been well documented in health and disease in the USA. Recent studies show that telomere length, a marker of aging, is associated with obesity and obesity-related diseases, such as heart disease and diabetes. The current study aimed to evaluate the connection between telomere length ratio, blood pressure, and childhood obesity. The telomere length ratio was measured in 127 children from both European American (EA) and African American (AA) children, aged 6-10 years old. AA children had a significantly high relative telomere to the single copy gene (T/S) ratio compared to EA children. There was no significant difference in the T/S ratio between normal weight (NW) and overweight/obese (OW/OB) groups of either race. Blood pressure was significantly elevated in AA children with respect to EA children. Hierarchical regression analysis adjusted for race, gender, and age expressed a significant relationship between the T/S ratio and diastolic pressure. Low T/S ratio participants showed a significant increase in systolic pressure, while a high T/S ratio group showed an increase in diastolic pressure and heart rate of AA children. In conclusion, our findings show that AA children have high T/S ratio compared to EA children. The high T/S ratio is negatively associated with diastolic pressure.},
}
@article {pmid33434830,
year = {2021},
author = {Lee, HH and Okuzono, SS and Kim, ES and De Vivo, I and Raffield, LM and Glover, L and Sims, M and Grodstein, F and Kubzansky, LD},
title = {Optimism and telomere length among African American adults in the Jackson Heart Study.},
journal = {Psychoneuroendocrinology},
volume = {125},
number = {},
pages = {105124},
pmid = {33434830},
issn = {1873-3360},
support = {R01 AG053273/AG/NIA NIH HHS/United States ; T32 HL129982/HL/NHLBI NIH HHS/United States ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; },
mesh = {Adult ; *Black or African American/genetics ; Aged ; Aged, 80 and over ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes ; Longitudinal Studies ; Male ; Middle Aged ; *Telomere/genetics ; Telomere Shortening ; Young Adult ; },
abstract = {BACKGROUND: Optimism is linked with greater longevity in both White and African American populations. Optimism may enhance longevity by slowing cellular aging, for which leukocyte telomere shortening is a biomarker. However, limited studies have examined the association of optimism with leukocyte telomere length among African Americans.<br><br>METHODS: Data are from 723 men and 1244 women participating in the Jackson Heart Study (age&#xa0;=&#xa0;21-93 years). We used multivariable linear regression models to conduct cross-sectional analyses examining whether higher optimism was associated with longer mean absolute leukocyte telomere length (assayed with Southern blot analysis). Models adjusted for sociodemographic characteristics, depressive symptomatology, health conditions, and health behavior-related factors. We also considered potential effect modification by key factors.<br><br>RESULTS: In the age-adjusted model, optimism, measured as a continuous variable, was not associated with leukocyte telomere length (&#x3b2;&#xa0;=&#xa0;0.01, 95%CI: -0.02, 0.04). This association remained null in the fully-adjusted model (&#x3b2;&#xa0;=&#xa0;0.02, 95%CI: -0.02, 0.05) and was also null when considering optimism as a binary measure (higher vs. lower optimism). We found no evidence of effect modification by sex, age, body mass index, income, or chronic conditions.<br><br>CONCLUSIONS: Optimism was not associated with leukocyte telomere length among African American adults. Future studies should investigate alternate biological and behavioral mechanisms that may explain the optimism-health association.},
}
@article {pmid33434042,
year = {2021},
author = {Eaton, MJ and Gauthier, NA and Vaillancourt, LJ},
title = {Use of Telomere Fingerprinting to Identify Clonal Lineages of Colletotrichum fioriniae in Kentucky Mixed-Fruit Orchards.},
journal = {Plant disease},
volume = {105},
number = {8},
pages = {2050-2055},
doi = {10.1094/PDIS-08-20-1713-SC},
pmid = {33434042},
issn = {0191-2917},
mesh = {*Colletotrichum/genetics ; Fruit ; Kentucky ; Plant Diseases ; Telomere ; },
abstract = {Multiple species in the fungal genus Colletotrichum cause anthracnose fruit rot diseases that are responsible for major yield losses of as much as 100%. Individual species of Colletotrichum typically have broad host ranges and can infect multiple fruit species. Colletotrichum fioriniae causes anthracnose fruit rots of apples, blueberries, and strawberries in Kentucky orchards where these fruits grow in close proximity. This raises the possibility of cross-infection, which may have significant management implications. The potential occurrence of cross-infection was investigated by using telomere fingerprinting to identify C. fioriniae clones in several mixed-fruit orchards. Telomere fingerprints were highly polymorphic among a test group of C. fioriniae strains and effectively defined clonal lineages. Fingerprints were compared among apple, blueberry, and strawberry isolates of C. fioriniae from three different orchards and similarity matrices were calculated to build phylograms for each orchard group. Multiple clonal lineages of C. fioriniae were identified within each orchard on the same fruit host. Related lineages were found among isolates from different hosts, but the results did not provide direct evidence for cross-infection of different fruit species by the same clones. Recovery of the same clonal lineages within orchards across multiple years suggested that local dispersal was important in pathogen population structure and that C. fioriniae strains persisted within orchards over time. Isolates from blueberry were less diverse than isolates from apple, perhaps related to more intensive anthracnose management protocols on apple versus blueberry. Telomere fingerprinting is a valuable tool for understanding population dynamics of Colletotrichum fruit rot fungi.},
}
@article {pmid33432658,
year = {2021},
author = {Lee, JS and La, J and Aziz, S and Dobrinskikh, E and Brownell, R and Jones, KD and Achtar-Zadeh, N and Green, G and Elicker, BM and Golden, JA and Matthay, MA and Kukreja, J and Schwartz, DA and Wolters, PJ},
title = {Molecular markers of telomere dysfunction and senescence are common findings in the usual interstitial pneumonia pattern of lung fibrosis.},
journal = {Histopathology},
volume = {79},
number = {1},
pages = {67-76},
pmid = {33432658},
issn = {1365-2559},
support = {KL2 TR000143/TR/NCATS NIH HHS/United States ; HL108794/HL/NHLBI NIH HHS/United States ; HL138131/HL/NHLBI NIH HHS/United States ; P30 NS048154/NS/NINDS NIH HHS/United States ; K23 HL138131/HL/NHLBI NIH HHS/United States ; UCSF-CTI KL2TR000143/TR/NCATS NIH HHS/United States ; P01 HL108794/HL/NHLBI NIH HHS/United States ; T32 HL007085/HL/NHLBI NIH HHS/United States ; UG3 HL151865/HL/NHLBI NIH HHS/United States ; R01 HL149836/HL/NHLBI NIH HHS/United States ; HL139897/HL/NHLBI NIH HHS/United States ; UH3 HL151865/HL/NHLBI NIH HHS/United States ; R01 NS086839/NS/NINDS NIH HHS/United States ; R01 HL139897/HL/NHLBI NIH HHS/United States ; I01 BX005295/BX/BLRD VA/United States ; },
mesh = {Aged ; Biomarkers/*analysis ; Cellular Senescence/*physiology ; Cohort Studies ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/*pathology ; Male ; Middle Aged ; Telomere/*pathology ; },
abstract = {AIMS: Idiopathic pulmonary fibrosis (IPF) is a genetically mediated, age-associated, progressive form of pulmonary fibrosis characterised pathologically by a usual interstitial pneumonia (UIP) pattern of fibrosis. The UIP pattern is also found in pulmonary fibrosis attributable to clinical diagnoses other than IPF (non-IPF UIP), whose clinical course is similarly poor, suggesting common molecular drivers. This study investigates whether IPF and non-IPF UIP lungs similarly express markers of telomere dysfunction and senescence.<br><br>METHODS AND RESULTS: To test whether patients with IPF and non-IPF UIP share molecular drivers, lung tissues from 169 IPF patients and 57 non-IPF UIP patients were histopathologically and molecularly compared. Histopathological changes in both IPF and non-IPF UIP patients included temporal heterogeneity, microscopic honeycombing, fibroblast foci, and dense collagen fibrosis. Non-IPF UIP lungs were more likely to have lymphocytic infiltration, non-caseating granulomas, airway-centred inflammation, or small airways disease. Telomeres were shorter in alveolar type II (AECII) cells of both IPF and non-IPF UIP lungs than in those of age-similar, unused donor, controls. Levels of molecular markers of senescence (p16 and p21) were elevated in lysates of IPF and non-IPF UIP lungs. Immunostaining localised expression of these proteins to AECII cells. The mucin 5B (MUC5B) gene promoter variant minor allele frequency was similar between IPF and non-IPF UIP patients, and MUC5B expression was similar in IPF and non-IPF UIP lungs.<br><br>CONCLUSIONS: Molecular markers of telomere dysfunction and senescence are pathologically expressed in both IPF and non-IPF UIP lungs. These findings suggest that common molecular drivers may contribute to the pathogenesis of UIP-associated pulmonary fibrosis, regardless of the clinical diagnosis.},
}
@article {pmid33431974,
year = {2021},
author = {Evans, JR and Torres-Pérez, JV and Miletto Petrazzini, ME and Riley, R and Brennan, CH},
title = {Stress reactivity elicits a tissue-specific reduction in telomere length in aging zebrafish (Danio rerio).},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {339},
pmid = {33431974},
issn = {2045-2322},
support = {BB/M007863/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Aging/*genetics/*physiology ; Animals ; Male ; Stress, Psychological/*genetics ; Telomere/*genetics ; Telomere Shortening ; *Zebrafish ; },
abstract = {Individual differences in personality are associated with variation in healthy aging. Health behaviours are often cited as the likely explanation for this association; however, an underlying biological mechanism may also exist. Accelerated leukocyte telomere shortening is implicated in multiple age-related diseases and is associated with chronic activation of the hypothalamus-pituitary-adrenal (HPA) axis, providing a link between stress-related personality differences and adverse health outcomes. However, the effects of the HPA axis are tissue specific. Thus, leukocyte telomere length may not accurately reflect telomere length in disease-relevant tissues. Here, we examined the correlation between stress reactivity and telomere length in heart and brain tissue in young (6-9 month) and aging (18 month) zebrafish. Stress reactivity was assessed by tank diving and through gene expression. Telomere length was assessed using quantitative PCR. We show that aging zebrafish have shorter telomeres in both heart and brain. Telomere length was inversely related to stress reactivity in heart but not brain of aging individuals. These data support the hypotheses that an anxious predisposition contributes to accelerated telomere shortening in heart tissue, which may have important implications for our understanding of age-related heart disease, and that stress reactivity contributes to age-related telomere shortening in a tissue-specific manner.},
}
@article {pmid33431711,
year = {2021},
author = {Crocco, P and De Rango, F and Dato, S and Rose, G and Passarino, G},
title = {Telomere length as a function of age at population level parallels human survival curves.},
journal = {Aging},
volume = {13},
number = {1},
pages = {204-218},
pmid = {33431711},
issn = {1945-4589},
mesh = {Aged ; Aged, 80 and over ; *Aging ; Female ; Humans ; Italy ; Leukocytes ; *Longevity ; Male ; *Telomere Shortening ; },
abstract = {Telomeres are subject to age related shortening which can be accelerated by oxidative stress and inflammation. Many studies have reported an inverse correlation between telomere length and survival, but such inverse correlation has not been always confirmed in different populations. We analyzed the trend of Leukocyte Telomere Length (LTL) as a function of age in a cohort of 516 subjects aged 65-106 years from Southern Italy. The trend of LTL obtained was quite similar to demographic survival curves reported with data of western societies. We observed a decrease of LTL after 70 years of age and then an increase after 92 years, in agreement with the sharp decrease of survival after 70 years of age and its increase after 90 years, due to the deceleration of mortality at old ages. Our data suggest that a generalized LTL attrition after 70 years of age, associated to organismal decline, affects most of the population. Such generalized attrition may exacerbate senescence in these subjects, predisposing them to high mortality risk. Conversely, the subjects with better physical conditions, experience a lower attrition and, consequently, a delayed senescence, contributing to the deceleration of mortality which has been observed among very old subjects in modern societies.},
}
@article {pmid33428591,
year = {2021},
author = {Sanchez-Vazquez, R and Guío-Carrión, A and Zapatero-Gaviria, A and Martínez, P and Blasco, MA},
title = {Shorter telomere lengths in patients with severe COVID-19 disease.},
journal = {Aging},
volume = {13},
number = {1},
pages = {1-15},
pmid = {33428591},
issn = {1945-4589},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Aging/*genetics ; COVID-19/diagnosis/*genetics ; Female ; Humans ; Male ; Middle Aged ; Risk Assessment ; Risk Factors ; Severity of Illness Index ; Telomere/*genetics ; *Telomere Shortening ; COVID-19 Drug Treatment ; },
abstract = {The incidence of severe manifestations of COVID-19 increases with age with older patients showing the highest mortality, suggesting that molecular pathways underlying aging contribute to the severity of COVID-19. One mechanism of aging is the progressive shortening of telomeres, which are protective structures at chromosome ends. Critically short telomeres impair the regenerative capacity of tissues and trigger loss of tissue homeostasis and disease. The SARS-CoV-2 virus infects many different cell types, forcing cell turn-over and regeneration to maintain tissue homeostasis. We hypothesize that presence of short telomeres in older patients limits the tissue response to SARS-CoV-2 infection. We measure telomere length in peripheral blood lymphocytes COVID-19 patients with ages between 29 and 85 years-old. We find that shorter telomeres are associated to increased severity of the disease. Individuals within the lower percentiles of telomere length and higher percentiles of short telomeres have higher risk of developing severe COVID-19 pathologies.},
}
@article {pmid33422989,
year = {2021},
author = {Martens, DS and Van Der Stukken, C and Derom, C and Thiery, E and Bijnens, EM and Nawrot, TS},
title = {Newborn telomere length predicts later life telomere length: Tracking telomere length from birth to child- and adulthood.},
journal = {EBioMedicine},
volume = {63},
number = {},
pages = {103164},
pmid = {33422989},
issn = {2352-3964},
mesh = {Adolescent ; Age Factors ; Aging/genetics ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Infant, Newborn ; Longevity/*genetics ; Male ; Pregnancy ; Prognosis ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Young Adult ; },
abstract = {BACKGROUND: Telomere length (TL) is considered a biological marker of aging and may indicate age-related disease susceptibility. Adults and children show a fixed ranking and tracking of TL over time. However, the contribution of an individual's initial birth TL to their later life TL is unknown. We evaluated change and tracking of TL from birth to child- and adulthood.<br><br>METHODS: Telomere length at birth was measured using qPCR in two independent prospective birth cohorts. After a median follow-up period of 4 years in ENVIRONAGE (n&#xa0;=&#xa0;273) we assessed leukocyte telomere length (LTL) and after 23 years in EFPTS (n&#xa0;=&#xa0;164) buccal TL was assessed. Correlations and multivariable regression models were applied to study telomere tracking and determinants of TL change from birth onwards.<br><br>FINDINGS: In children, LTL at the age of 4 correlates with TL at the start of life both in cord blood (r&#xa0;=&#xa0;0.71, P&#xa0;<&#xa0;0.0001;) and placenta (r&#xa0;=&#xa0;0.60, P&#xa0;<&#xa0;0.0001) and was -11.2% and -33.1% shorter, respectively. In adulthood, buccal TL at the age of 23 correlates with placental TL (r&#xa0;=&#xa0;0.46, P&#xa0;<&#xa0;0.0001) and was -35.9% shorter. TL attrition was higher in individuals with longer birth TL. However, based on TL ranking, individuals do not tend to change dramatically from TL rank after 4 or 23 years of follow-up. Finally, longer maternal TL associates with lower telomere attrition in the next generation.<br><br>INTERPRETATION: The high prediction of newborn TL for later life TL, and stable TL ranking from birth onwards underscores the importance of understanding the initial setting of newborn TL and its significance for later life.<br><br>FUNDING: European Research Council (ERC-StG310898) and Flemish Scientific Fund (12X9620N).},
}
@article {pmid33422583,
year = {2021},
author = {Cheng, F and Luk, AO and Wu, H and Lim, CKP and Carroll, L and Tam, CHT and Fan, B and Yang, A and Lau, ESH and Ng, ACW and Lee, HM and Chow, E and Kong, APS and Keech, AC and Joglekar, MV and So, WY and Jenkins, AJ and Chan, JCN and Hardikar, AA and Ma, RCW},
title = {Shortened relative leukocyte telomere length is associated with all-cause mortality in type 2 diabetes- analysis from the Hong Kong Diabetes Register.},
journal = {Diabetes research and clinical practice},
volume = {173},
number = {},
pages = {108649},
doi = {10.1016/j.diabres.2021.108649},
pmid = {33422583},
issn = {1872-8227},
mesh = {Diabetes Mellitus, Type 2/*genetics/mortality ; Female ; Hong Kong ; Humans ; Male ; Middle Aged ; Prospective Studies ; Registries ; Risk Factors ; Survival Analysis ; Telomere Shortening/*genetics ; },
abstract = {AIMS: Few studies have investigated the relationship between rLTL and mortality in patients with type 2 diabetes in a large prospective study, particularly in the Asian population. This study investigates the relationship between rLTL and the risk of death in Chinese patients with type 2 diabetes.<br><br>METHODS: Consecutive Chinese patients with type 2 diabetes (N&#xa0;=&#xa0;5349) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied. rLTL was measured using a quantitative polymerase chain reaction. Mortality and clinical outcomes were obtained based on ICD-9 codes.<br><br>RESULTS: The mean (SD) age of the subjects was 57.5 (13.3) years and mean (SD) follow-up duration was 13.4 (5.5) years. Baseline rLTL was significantly shorter in the 1925 subjects who subsequently died compared with the remaining subjects (4.3&#xa0;&#xb1;&#xa0;1.2 vs. 4.7&#xa0;&#xb1;&#xa0;1.2, P&#xa0;<&#xa0;0.001). Shorter rLTL was associated with a higher risk of mortality (HR: 1.19 (1.14-1.23), P&#xa0;<&#xa0;0.001), which remained significant after adjusting for traditional risk factors.<br><br>CONCLUSIONS: Shorter rLTL was significantly associated with an increased risk of all-cause and CVD mortality in patients with type 2 diabetes, independent of established risk factors. Telomere length may be a useful biomarker for mortality risk in patients with type 2 diabetes.},
}
@article {pmid33413962,
year = {2021},
author = {Sethuram, R and Bazzi, AA and Salih, SM and Puscheck, EE},
title = {Peripheral lymphocyte telomere dysfunction: a valid surrogate marker for female fertility?.},
journal = {Fertility and sterility},
volume = {115},
number = {1},
pages = {85-86},
doi = {10.1016/j.fertnstert.2020.10.063},
pmid = {33413962},
issn = {1556-5653},
mesh = {Biomarkers ; Female ; Fertility ; Humans ; *Infertility ; Lymphocytes ; *Telomere/genetics ; },
}
@article {pmid33413203,
year = {2021},
author = {Liu, X and Liu, X and Shi, Q and Fan, X and Qi, K},
title = {Association of telomere length and telomerase methylation with n-3 fatty acids in preschool children with obesity.},
journal = {BMC pediatrics},
volume = {21},
number = {1},
pages = {24},
pmid = {33413203},
issn = {1471-2431},
support = {2020-bjsekyjs//the Research Funds of Profession Quota Budget from Beijing Municipal Science and Technology Commission/ ; },
mesh = {Child, Preschool ; DNA Methylation ; *Fatty Acids, Omega-3 ; Humans ; *Pediatric Obesity/genetics ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {BACKGROUND: Telomeres play a crucial role in cellular survival and its length is a predictor for onset of chronic non-communicable diseases. Studies on association between telomeres and obesity in children have brought discrepant results and the underlying mechanisms and influential factors are to be elucidated. This study aimed to investigate changes in telomere length and telomerase reverse transcriptase (TERT) DNA methylation, and further to determine their correlation with n-3 polyunsaturated fatty acids (PUFAs) in preschool children with obesity.<br><br>METHODS: Forty-six preschool children with obesity aged 3 to 4&#x2009;years were included in the study, with equal numbers of age- and gender-matched children with normal weight as control. Leukocyte telomere length was determined by the ratio of telomeric product and single copy gene obtained using real-time qPCR. DNA methylation of TERT promoter was analyzed by bisulfite sequencing. Fatty acids in erythrocytes were measured by gas chromatography with a total of 15 fatty acids analyzed. The total saturated fatty acids (SFAs), total n-6 PUFAs, total n-3 PUFAs, and the ratio of arachidonic acid (AA) to docosahexaenoic acid (DHA) were calculated. Then the correlation between leukocyte telomere length, TERT promoter methylation and fatty acids was determined.<br><br>RESULTS: In preschool children with obesity, leukocyte telomeres were shortened and had a negative association with the body mass index. The methylated fractions in 13 of 25 CpG sites in the TERT promoter were increased by approximately 3 to 35% in the children with obesity compared to the normal weight children. Erythrocyte lauric acid and total SFAs, lenoleic acid and total n-6 PUFAs were higher, and DHA was lower in the children with obesity than those in the children with normal weight. Correlative analysis showed that leukocyte telomere length had a positive association with total SFAs and DHA, and a negative association with the AA/DHA ratio. However, no association between erythrocyte DHA and the TERT promoter methylation was found.<br><br>CONCLUSION: These data indicate that the reduced body DHA content and increased AA/DHA ratio may be associated with shortened leukocyte telomeres in child obesity, which is probably not involved in the TERT promoter methylation.},
}
@article {pmid33407441,
year = {2021},
author = {Kalungi, A and Kinyanda, E and Womersley, JS and Joloba, ML and Ssembajjwe, W and Nsubuga, RN and Kaleebu, P and Levin, J and Kidd, M and Seedat, S and Hemmings, SMJ},
title = {TERT rs2736100 and TERC rs16847897 genotypes moderate the association between internalizing mental disorders and accelerated telomere length attrition among HIV+ children and adolescents in Uganda.},
journal = {BMC medical genomics},
volume = {14},
number = {1},
pages = {15},
pmid = {33407441},
issn = {1755-8794},
support = {UL1 TR001442/TR/NCATS NIH HHS/United States ; MR/L004623/1/MRC_/Medical Research Council/United Kingdom ; MC_UP_1204/10/MRC_/Medical Research Council/United Kingdom ; 205069/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; P30 AI036214/AI/NIAID NIH HHS/United States ; MC_UU_00027/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adolescent ; Child ; Genotype ; Humans ; Male ; Middle Aged ; RNA/*genetics ; Telomerase/*genetics ; *Telomere ; Uganda ; },
abstract = {BACKGROUND: Internalizing mental disorders (IMDs) (depression, anxiety and post-traumatic stress disorder) have been associated with accelerated telomere length (TL) attrition; however, this association has not been investigated in the context of genetic variation that has been found to influence TL. We have previously reported an association between IMDs and accelerated TL attrition among Ugandan HIV+ children and adolescents. This study investigated the moderating effects of selected single nucleotide polymorphisms in the telomerase reverse transcriptase gene (TERT) (rs2736100, rs7726159, rs10069690 and rs2853669) and the telomerase RNA component gene (TERC) (rs12696304, rs16847897 and rs10936599) on the association between IMDs and TL, among Ugandan HIV+ children (aged 5-11 years) and adolescents (aged 12-17 years).<br><br>RESULTS: We found no significant interaction between IMDs as a group and any of the selected SNPs on TL at baseline. We observed significant interactions of IMDs with TERT rs2736100 (p&#x2009;=&#x2009;0.007) and TERC rs16847897 (p&#x2009;=&#x2009;0.012), respectively, on TL at 12&#xa0;months.<br><br>CONCLUSIONS: TERT rs2736100 and TERC rs16847897 moderate the association between IMDs and TL among Ugandan HIV+ children and adolescents at 12&#xa0;months. Understanding the nature of this association may shed light on the pathophysiological mechanisms underlying advanced cellular aging in IMDs.},
}
@article {pmid33406938,
year = {2021},
author = {Godhamgaonkar, AA and Sundrani, DP and Joshi, SR},
title = {Role of maternal nutrition and oxidative stress in placental telomere attrition in women with preeclampsia.},
journal = {Hypertension in pregnancy},
volume = {40},
number = {1},
pages = {63-74},
doi = {10.1080/10641955.2020.1869248},
pmid = {33406938},
issn = {1525-6065},
mesh = {Adult ; Cellular Senescence ; Female ; Humans ; *Nutritional Status ; *Oxidative Stress ; *Pre-Eclampsia ; Pregnancy ; Telomere/*pathology ; },
abstract = {Background:Maternal nutrition influences the growth and development of the fetus and influences pregnancy outcome. We have earlier demonstrated altered maternal nutrition and increased oxidative stress in women with preeclampsia. Oxidative stress is known to be associated with reduced telomere length and short telomere aggregates. Increased telomere attrition leads to increased cellular senescence and tissue ageing. Methods:The present review focuses on the role of maternal nutrition and oxidative stress in telomere attrition in preeclampsia. Results and Conclusion:Future studies need to examine the association between maternal nutritional status in early pregnancy, oxidative stress and telomere attrition in preeclampsia.},
}
@article {pmid33406566,
year = {2020},
author = {Fan, YL and Ye, Q},
title = {[A concise review of telomere and telomerase-related genetic markers in fibrotic lung diseases].},
journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases},
volume = {38},
number = {12},
pages = {952-956},
doi = {10.3760/cma.j.cn121094-20200305-00104},
pmid = {33406566},
issn = {1001-9391},
support = {81970061//National Natural Science Foundation of China/ ; 2015ZX09J15104//National Major Scientific and Technological Special Project for Significant New Drugs Development/ ; },
mesh = {Aged ; Genetic Markers ; Humans ; *Idiopathic Pulmonary Fibrosis/genetics ; *Telomerase/genetics ; Telomere/genetics ; Telomere Shortening ; },
abstract = {Fibrotic lung diseases are a heterogeneous group of diffuse parenchymal lung diseases caused by various factors. Pulmonary fibrosis is one of the common pathological changes of advanced fibrotic lung diseases. Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disorder with unknown etiology. IPF mainly affects the elderly that is considered as an aging related disease. Telomeres are specialized structures at the ends of chromosomes. Telomere shortening results in cellular senescence or apoptosis. Telomerase is a ribonucleoprotein complex that maintains telomere length and genome stability. The telomere shortening and mutations in telomere-related genes are associated with incidence and prognosis of pulmonary fibrosis. Here, a concise review of telomere and telomerase-related genomic markers in IPF and other fibrotic lung diseases is written.},
}
@article {pmid33401959,
year = {2021},
author = {Elmadawy, MA and Abdullah, OA and El Gazzar, WB and Ahmad, ES and Ameen, SG and Abdelkader, A},
title = {Telomere length and signal joint T-cell receptor rearrangement excision circles as biomarkers for chronological age estimation.},
journal = {Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals},
volume = {26},
number = {2},
pages = {168-173},
doi = {10.1080/1354750X.2020.1871412},
pmid = {33401959},
issn = {1366-5804},
mesh = {Adolescent ; Adult ; Aged ; Aging/*genetics ; *Biological Assay ; Biomarkers/metabolism ; Child ; Child, Preschool ; DNA/*genetics ; Female ; Forensic Medicine/*methods ; Healthy Volunteers ; Humans ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Mouth Mucosa/chemistry ; Polymorphism, Restriction Fragment Length ; Receptors, Antigen, T-Cell/*genetics ; Regression Analysis ; T-Lymphocytes/metabolism ; *Telomere ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Chronological age estimation is a challenging marker in the field of forensic medicine. The current study aimed to investigate the accuracy of signal joint T-cell receptor rearrangement excision circles (sjTRECs) quantification and telomere length measurement as methods for estimating chronological age.<br><br>METHODS: Telomere length was estimated in the DNA derived from the buccal cells through estimating the telomeric restriction fragment (TRF) length using TeloTTAGGG Telomere Length Assay while the sjTRECs quantification was carried out on DNA isolated from the blood samples using qPCR.<br><br>RESULTS: The TRF length was shortened with increased age (r = -0.722, p&#x2009;<&#x2009;0.001). The sjTRECs were also decreased with increased age (r = -0.831, p&#x2009;<&#x2009;0.001). Stronger coefficient and lower standard error of the estimate was obtained when multiple regression analysis for age prediction based on the values of both methods was applied (r = -0.876, p&#x2009;<&#x2009;0.001).},
}
@article {pmid33397920,
year = {2021},
author = {Viswanath, P and Batsios, G and Mukherjee, J and Gillespie, AM and Larson, PEZ and Luchman, HA and Phillips, JJ and Costello, JF and Pieper, RO and Ronen, SM},
title = {Non-invasive assessment of telomere maintenance mechanisms in brain tumors.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {92},
pmid = {33397920},
issn = {2041-1723},
support = {P01 CA118816/CA/NCI NIH HHS/United States ; R01 CA172845/CA/NCI NIH HHS/United States ; P50 CA097257/CA/NCI NIH HHS/United States ; R01 NS105087/NS/NINDS NIH HHS/United States ; P41 EB013598/EB/NIBIB NIH HHS/United States ; R01 CA239288/CA/NCI NIH HHS/United States ; R01 CA197254/CA/NCI NIH HHS/United States ; },
mesh = {Alanine/metabolism ; Animals ; Biomarkers, Tumor/metabolism ; Brain Neoplasms/*genetics/metabolism/pathology ; Carbon Isotopes/metabolism ; Cell Line, Tumor ; Genetic Engineering ; Glioma/genetics/metabolism/pathology ; Lactic Acid/metabolism ; Male ; Metabolome ; Models, Biological ; Neoplasm Grading ; Neoplasm Proteins/metabolism ; Proton Magnetic Resonance Spectroscopy ; Pyruvic Acid/metabolism ; RNA, Messenger/genetics/metabolism ; Rats, Nude ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; Xenograft Model Antitumor Assays ; Rats ; },
abstract = {Telomere maintenance is a universal hallmark of cancer. Most tumors including low-grade oligodendrogliomas use telomerase reverse transcriptase (TERT) expression for telomere maintenance while astrocytomas use the alternative lengthening of telomeres (ALT) pathway. Although TERT and ALT are hallmarks of tumor proliferation and attractive therapeutic targets, translational methods of imaging TERT and ALT are lacking. Here we show that TERT and ALT are associated with unique [1]H-magnetic resonance spectroscopy (MRS)-detectable metabolic signatures in genetically-engineered and patient-derived glioma models and patient biopsies. Importantly, we have leveraged this information to mechanistically validate hyperpolarized [1-[13]C]-alanine flux to pyruvate as an imaging biomarker of ALT status and hyperpolarized [1-[13]C]-alanine flux to lactate as an imaging biomarker of TERT status in low-grade gliomas. Collectively, we have identified metabolic biomarkers of TERT and ALT status that provide a way of integrating critical oncogenic information into non-invasive imaging modalities that can improve tumor diagnosis and treatment response monitoring.},
}
@article {pmid33397445,
year = {2021},
author = {Starnino, L and Dupuis, G and Busque, L and Bourgoin, V and Dubé, MP and Busseuil, D and D'Antono, B},
title = {The associations of hostility and defensiveness with telomere length are influenced by sex and health status.},
journal = {Biology of sex differences},
volume = {12},
number = {1},
pages = {2},
pmid = {33397445},
issn = {2042-6410},
support = {#111015//CIHR/Canada ; },
mesh = {Aged ; Coronary Artery Disease/genetics ; *Emotions ; Female ; Health Status ; Hostility ; Humans ; Male ; Middle Aged ; Risk Factors ; *Sex Characteristics ; Telomere ; },
abstract = {BACKGROUND: Shorter telomere length (TL) may indicate premature cellular aging and increased risk for disease. While there is substantial evidence for shorter TL in individuals suffering from psychiatric disorders, data is scarce on maladaptive personality traits related to coronary artery disease (CAD). The purpose of this study was to evaluate the association of TL with hostility and defensiveness in individuals with CAD or other non-cardiovascular illnesses and whether associations were moderated by CAD status and sex.<br><br>METHODS: One thousand thirty-six individuals (Mage = 65.40 &#xb1; 6.73&#x2009;years) with and without CAD completed the Marlowe-Crowne Social Desirability Scale and the Cook-Medley Hostility Scale. Relative TL was measured via quantitative polymerase chain reaction of total genomic DNA samples. Analyses involved hierarchical regressions on TL, performed separately for hostility and defensiveness, controlling for pertinent sociodemographic, behavioural, and medical risk factors. Separate analyses were performed on 25 healthy participants.<br><br>RESULTS: A hostility by sex interaction emerged (&#x3b2; = -&#x2009;.08, p = .006) in the patient groups, where greater hostility was associated with shorter TL in women only (p < .01). A Defensiveness by CAD status interaction (&#x3b2; = -&#x2009;.06, p = .049) revealed longer TL in more defensive CAD patients only (p = .06). In healthy men, shorter TL was observed in those with greater defensiveness (&#x3b2; = .52, p = .006) but lower hostility (&#x3b2; = -&#x2009;.43, p = .049).<br><br>CONCLUSION: Hostility and defensiveness are differentially associated with TL as a function of sex and health status. The implication of these results for health remains to be determined, but propose an additional pathway through which the effect of maladaptive personality traits may contribute to CV and other disease.},
}
@article {pmid33395949,
year = {2021},
author = {Li, X and Liu, J and Zhou, G and Sang, Y and Zhang, Y and Jing, L and Shi, Z and Zhou, X and Sun, Z},
title = {BDE-209 and DBDPE induce male reproductive toxicity through telomere-related cell senescence and apoptosis in SD rat.},
journal = {Environment international},
volume = {146},
number = {},
pages = {106307},
doi = {10.1016/j.envint.2020.106307},
pmid = {33395949},
issn = {1873-6750},
mesh = {Animals ; Apoptosis ; *Bromobenzenes ; Cellular Senescence ; *Flame Retardants/toxicity ; Halogenated Diphenyl Ethers/toxicity ; Humans ; Male ; Rats ; Rats, Sprague-Dawley ; Reproduction ; Telomere ; },
abstract = {Decabrominated diphenyl ether (BDE-209) and decabromodiphenyl ethane (DBDPE) are common flame retardants utilized in many kinds of electronic and textile products. Due to their persistence and bioaccumulation, BDE-209 and DBDPE extensively exist in the surrounding environment and wild animals. Previous studies have indicated that BDE-209 could induce male reproductive toxicity, whereas those of DBDPE remains relatively rare. In this study, we investigated the effects of both BDE-209 and DBDPE on reproductive system in male SD rats, and explored the potential mechanisms under the reproductive toxicity of BDE-209 and DBDPE. Male rats were orally administered with BDE-209 and DBDPE (0, 5, 50 and 500 mg/kg/day) for a 28-day exposure experiment. The current results showed that BDE-209 and DBDPE led to testicular damage in physiological structure, decreased the sperm number and motility, and increased the sperm malformation rates in rat. Moreover, BDE-209 and DBDPE could damage the telomeric function by shortening telomere length and reducing telomerase activity, which consequently caused cell senescence and apoptosis in testis of rat. This could contribute to the decline of sperm quality and quantity. In conclusion, BDE-209 and DBDPE led to reproductive toxicity by inducing telomere dysfunction and the related cell senescence and apoptosis in testis of SD rat. Comparatively, BDE-209 had more severe effects on male reproduction. Our findings may provide new insight into the potential deleterious effects of BFRs on male reproductive health.},
}
@article {pmid33394227,
year = {2021},
author = {Shah, A and George, M and Dhangar, S and Rajendran, A and Mohan, S and Vundinti, BR},
title = {Severe telomere shortening in Fanconi anemia complementation group L.},
journal = {Molecular biology reports},
volume = {48},
number = {1},
pages = {585-593},
pmid = {33394227},
issn = {1573-4978},
support = {EEQ/2016/000510;B.R.V.//Department of Science and Technology, Government of India(IN)/ ; },
mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; Chromosome Breakage ; DNA-Binding Proteins/genetics ; Fanconi Anemia/*genetics/pathology ; Fanconi Anemia Complementation Group A Protein/*genetics ; Fanconi Anemia Complementation Group G Protein/*genetics ; Fanconi Anemia Complementation Group L Protein/*genetics ; Female ; Gene Expression Regulation/genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; Telomere/genetics ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {Fanconi Anemia (FA) is a rare genetic disease with the incidence of 1 in 360,000 and is characterised by bone marrow failure, physical abnormalities, pancytopenia, and high frequency of chromosomal breakage and increased risk of evolving into malignancy. Telomere plays an important role in genomic stability, ageing process and cancers. Telomere shortening has been reported in FA. We studied telomere length in FA subjects and compared with complementation groups. Chromosomal breakage analysis from PHA stimulated, MMC induced peripheral blood culture was carried out in 37 clinically diagnosed FA. Molecular study of FANCA, G, and L was done through Sanger sequencing and next generation sequencing. Telomere length was estimated using real time quantitative polymerase chain reaction (qPCR) method. Student t-test was applied to test the significance. A high frequency of chromosomal breakage was observed in all the patients compared to healthy controls. We found significantly shorter telomere length in all the three complementation groups compare to age matched healthy controls. Among all complementation groups, FANCL showed severe telomere shortening (P value 0.0001). A negative correlation was observed between telomere length and chromosomal breakage frequency (R = -0.3116). Telomere shortening is not uncommon in FA subjects. However the telomere length shortening is different in complementation groups as FANCL showed severe telomere shortening in FA subjects. Though BM transplantation is essential for the management of the FA subjects, the telomere length can be considered as biological marker to understand the prognosis of the disease as FA subjects primarily treated with androgens.},
}
@article {pmid33393836,
year = {2021},
author = {Mizuno, Y and Konishi, S and Goto, C and Yoshinaga, J and Hidaka, M and Imai, H},
title = {Association between nutrient intake and telomere length in Japanese female university students.},
journal = {Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals},
volume = {26},
number = {2},
pages = {138-145},
doi = {10.1080/1354750X.2020.1871409},
pmid = {33393836},
issn = {1366-5804},
mesh = {Age Factors ; Dietary Carbohydrates/administration &amp; dosage ; Dietary Fats/administration &amp; dosage ; Dietary Fiber/administration &amp; dosage ; Dietary Proteins/administration &amp; dosage ; Eating/*physiology ; Energy Intake/*physiology ; Female ; Humans ; Japan ; Students ; Surveys and Questionnaires ; Telomere/*drug effects ; Telomere Homeostasis/*drug effects ; Trace Elements/administration &amp; dosage ; Universities ; Vitamins/administration &amp; dosage ; Young Adult ; },
abstract = {OBJECTIVE: Telomere length can be a biomarker of cumulative oxidative stress and inflammation indicating biological aging. Previous studies examined association of nutrient intake with telomere length targeting middle-aged and elderly individuals. This study examined whether dietary macro- and micronutrient intake was associated with telomere length in young females.<br><br>METHODS: Seventy-four Japanese young females (median (interquartile range) age was 19 (19&#x2009;-&#x2009;20) years) participated. We estimated their intake of nutrients (energy, protein, fat, carbohydrate, essential elements, vitamins, fatty acids, and dietary fibre) using a semi-quantitative food frequency questionnaire and measured telomere length (T/S ratio, the ratio of telomere repeat copy number (T) to single-copy gene number (S)) of DNA extracted from blood by qPCR. The association between telomere length and tertiles of nutrient intake were analysed.<br><br>RESULTS: The median (interquartile range) of telomere length was 0.70 (0.52&#x2009;-&#x2009;0.98). Vitamin A intake was positively associated with telomere length (tertile 1 vs. 2, coefficient [95% confidence interval]&#x2009;=&#x2009;0.42 [0.12, 0.71]; tertile 1 vs. 3, coefficient [95% confidence interval]&#x2009;=&#x2009;0.33 [0.04, 0.62]) after adjusting for covariates (age, BMI, passive smoking, and drinking).<br><br>CONCLUSIONS: Our findings suggest that variation in vitamin A intake might influence telomere attrition in healthy individuals.},
}
@article {pmid33393513,
year = {2021},
author = {Begus-Nahrmann, Y and Hartmann, D and Kraus, J and Eshraghi, P and Scheffold, A and Grieb, M and Rasche, V and Schirmacher, P and Lee, HW and Kestler, HA and Lechel, A and Rudolph, KL},
title = {Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis.},
journal = {The Journal of clinical investigation},
volume = {131},
number = {1},
pages = {},
doi = {10.1172/JCI145852},
pmid = {33393513},
issn = {1558-8238},
}
@article {pmid33391781,
year = {2020},
author = {Remot, F and Ronget, V and Froy, H and Rey, B and Gaillard, JM and Nussey, DH and Lemaître, JF},
title = {No sex differences in adult telomere length across vertebrates: a meta-analysis.},
journal = {Royal Society open science},
volume = {7},
number = {11},
pages = {200548},
pmid = {33391781},
issn = {2054-5703},
abstract = {In many mammalian species, females live on average longer than males. In humans, women have consistently longer telomeres than men, and this has led to speculation that sex differences in telomere length (TL) could play a role in sex differences in longevity. To address the generality and drivers of patterns of sex differences in TL across vertebrates, we performed meta-analyses across 51 species. We tested two main evolutionary hypotheses proposed to explain sex differences in TL, namely the heterogametic sex disadvantage and the sexual selection hypotheses. We found no support for consistent sex differences in TL between males and females among mammal, bird, fish and reptile species. This absence of sex differences in TL across different classes of vertebrates does not support the heterogametic sex disadvantage hypothesis. Likewise, the absence of any negative effect of sexual size dimorphism on male TL suggests that sexual selection is not likely to mediate the magnitude of sex differences in TL across vertebrates. Finally, the comparative analyses we conducted did not detect any association between sex differences in TL and sex differences in longevity, which does not support the idea that sex differences in TL could explain the observed sex differences in longevity.},
}
@article {pmid33389530,
year = {2021},
author = {Goswami, A and Huda, N and Yasmin, T and Hosen, MI and Hasan, AKMM and Nabi, AHMN},
title = {Association study of leukocyte telomere length and genetic polymorphism within hTERT promoter with type 2 diabetes in Bangladeshi population.},
journal = {Molecular biology reports},
volume = {48},
number = {1},
pages = {285-295},
pmid = {33389530},
issn = {1573-4978},
support = {15-167 RG/BIO/AS_G - FR3240287016//The World Academy of Sciences/ ; },
mesh = {Adult ; Aged ; Bangladesh/epidemiology ; Diabetes Mellitus, Type 2/epidemiology/*genetics/pathology ; Female ; *Genetic Association Studies ; *Genetic Predisposition to Disease ; Genotype ; Humans ; Leukocytes/metabolism/pathology ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/genetics ; Promoter Regions, Genetic/genetics ; Telomerase/*genetics ; Telomere/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Telomeres are protective cap on the ends of DNA of non-coding tandem repeats of TTAGGG. Human telomerase reverse transcriptase (hTERT) is a catalytic subunit of telomerase that maintains the structure of telomeres. Type 2 diabetes (T2D) affects multi-organ and telomere length by altering telomerase activity. We aimed to evaluate the relative telomere length (RTL) and risk association of rs2853669 with T2D in Bangladeshi population. RTL was measured in 408 unrelated Bangladeshi (224 T2D and 184 healthy) using primers for target gene and reference gene albumin. Genotypic frequencies for rs2853669 were determined using TaqMan® probes. The mean level of age adjusted RTL (AARTL) varied significantly between the healthy and individuals with T2D for all the genotypes with respect to rs2853669. Moreover, healthy individuals had significantly higher AARTL than T2D. Similar findings were observed when study participants were stratified based on their gender. Association studies revealed that under codominant model of inheritance, TC genotype showed protective role against development of type 2 diabetes. This study suggests a possible role of telomere biology in T2DM, but their association needs to be evaluated further with a larger series and matched healthy controls.},
}
@article {pmid33388564,
year = {2021},
author = {Hautekiet, P and Nawrot, TS and Janssen, BG and Martens, DS and De Clercq, EM and Dadvand, P and Plusquin, M and Bijnens, EM and Saenen, ND},
title = {Child buccal telomere length and mitochondrial DNA content as biomolecular markers of ageing in association with air pollution.},
journal = {Environment international},
volume = {147},
number = {},
pages = {106332},
doi = {10.1016/j.envint.2020.106332},
pmid = {33388564},
issn = {1873-6750},
mesh = {*Air Pollutants/analysis/toxicity ; *Air Pollution/adverse effects/analysis ; Child ; DNA, Mitochondrial/genetics ; Environmental Exposure/analysis ; Humans ; Particulate Matter/analysis/toxicity ; Telomere ; },
abstract = {BACKGROUND: Pro-inflammatory conditions such as air pollution might induce biological ageing. However, the available evidence on such an impact in children is still very scarce. We studied in primary schoolchildren the association of ambient residential air pollution exposure with telomere length (TL) and mitochondrial DNA content (mtDNAc), two important targets of the core axis of ageing.<br><br>METHODS: Between 2012 and 2014, buccal TL and mtDNAc were repeatedly assessed using qPCR in 197 Belgian primary schoolchildren (mean age 10.3&#x202f;years) as part of the COGNAC study. At the child's residence, recent (week), sub-chronic (month) and chronic (year) exposure to nitrogen dioxide (NO2), particulate matter&#x202f;&#x2264;&#x202f;2.5&#x202f;&#xb5;m (PM2.5) and black carbon (BC) were estimated using a high resolution spatiotemporal model. A mixed-effects model with school and subject as random effect was used while adjusting for a priori chosen covariates.<br><br>RESULTS: An interquartile range (IQR) increment (1.9&#x202f;&#xb5;g/m[3]) in chronic PM2.5 exposure was associated with a 8.9% (95% CI: -15.4 to -1.9%) shorter TL. In contrast to PM2.5, chronic exposure to BC and NO2 was not associated with TL but recent exposure to BC and NO2 showed significant inverse associations with TL: an IQR increment in recent exposure to BC (0.9&#x202f;&#xb5;g/m[3]) and NO2 (10.2&#x202f;&#xb5;g/m[3]) was associated with a 6.2% (95% CI: -10.6 to -1.6%) and 6.4% (95% CI: -11.8 to -0.7%) shorter TL, respectively. Finally, an IQR increment in chronic PM2.5 exposure was associated with a 12.7% (95% CI: -21.7 to -2.6%) lower mtDNAc. However, no significant associations were seen for NO2 and BC or for other exposure windows.<br><br>CONCLUSION: Chronic exposure to PM2.5 below the EU threshold was associated with child's shorter buccal TL and lower mtDNAc, while traffic-related pollutants (BC and NO2) showed recent effects on telomere biology. Our data add to the literature on air pollution-induced effects of TL and mtDNAc, two measures part of the core axis of cellular ageing, from early life onwards.},
}
@article {pmid33387607,
year = {2021},
author = {Aguiar, SS and Sousa, CV and Santos, PA and Barbosa, LP and Maciel, LA and Coelho-Júnior, HJ and Motta-Santos, D and Rosa, TS and Degens, H and Simões, HG},
title = {Master athletes have longer telomeres than age-matched non-athletes. A systematic review, meta-analysis and discussion of possible mechanisms.},
journal = {Experimental gerontology},
volume = {146},
number = {},
pages = {111212},
doi = {10.1016/j.exger.2020.111212},
pmid = {33387607},
issn = {1873-6815},
mesh = {Aged ; *Aging ; Athletes ; Humans ; Oxidative Stress ; *Telomere ; },
abstract = {The aim of this systematic review and meta-analysis was 1) to assess whether master athletes have longer telomeres than age-matched non-athletes and 2) discuss possible underlying mechanisms underlying telomere length preservation in master athletes. A literature search was performed in PubMed, Web of Science, Scopus and SPORTDiscus up to August 2020. Only original articles published in peer-reviewed journals that compared telomere length between master athletes and aged-matched non-athletes were included. Eleven studies fulfilled eligibility criteria and were included in the final analysis. Overall, 240 master athletes (51.9±7.5 years) and 209 age-matched non-athletes (50.1±9.1 years) were analyzed. Master athletes had been participating in high-level competitions for approximately 16.6 years. Pooled analyses revealed that master athletes had longer telomeres than aged-matched non-athletes (SMD=0.89; 95% CI=0.45 to 1.33; p<0.001). Master athletes showed lower pro-oxidant damage (SMD=0.59; 95% CI=0.26 to 0.91; p<0.001) and higher antioxidant capacity (SMD=-0.46; 95% CI=-0.89 to -0.03; p=0.04) than age-matched non-athletes. Further, greater telomere length in master athletes is associated with lower oxidative stress and chronic inflammation, and enhanced shelterin protein expression and telomerase activity. In conclusion, 1) master athletes have longer telomeres than age-matched non-athletes, which may be the result of 2) lower levels of oxidative stress and chronic inflammation, and elevated shelterin expression and telomerase activity.},
}
@article {pmid33384420,
year = {2020},
author = {Fransson, S and Martinez-Monleon, A and Johansson, M and Sjöberg, RM and Björklund, C and Ljungman, G and Ek, T and Kogner, P and Martinsson, T},
title = {Whole-genome sequencing of recurrent neuroblastoma reveals somatic mutations that affect key players in cancer progression and telomere maintenance.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {22432},
pmid = {33384420},
issn = {2045-2322},
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; DNA Copy Number Variations ; Disease Progression ; Female ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks ; Humans ; Male ; Middle Aged ; *Mutation ; Neoplasm Recurrence, Local ; Neuroblastoma/*genetics/metabolism/*pathology ; Prognosis ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; *Whole Genome Sequencing ; },
abstract = {Neuroblastoma is the most common and deadly childhood tumor. Relapsed or refractory neuroblastoma has a very poor prognosis despite recent treatment advances. To investigate genomic alterations associated with relapse and therapy resistance, whole-genome sequencing was performed on diagnostic and relapsed lesions together with constitutional DNA from seven children. Sequencing of relapsed tumors indicates somatic alterations in diverse genes, including those involved in RAS-MAPK signaling, promoting cell cycle progression or function in telomere maintenance and immortalization. Among recurrent alterations, CCND1-gain, TERT-rearrangements, and point mutations in POLR2A, CDK5RAP, and MUC16 were shown in ≥ 2 individuals. Our cohort contained examples of converging genomic alterations in primary-relapse tumor pairs, indicating dependencies related to specific genetic lesions. We also detected rare genetic germline variants in DNA repair genes (e.g., BARD1, BRCA2, CHEK2, and WRN) that might cooperate with somatically acquired variants in these patients with highly aggressive recurrent neuroblastoma. Our data indicate the importance of monitoring recurrent neuroblastoma through sequential genomic characterization and that new therapeutic approaches combining the targeting of MAPK signaling, cell cycle progression, and telomere activity are required for this challenging patient group.},
}
@article {pmid33377991,
year = {2021},
author = {Salas-Huetos, A and Tüttelmann, F and Wyrwoll, MJ and Kliesch, S and Lopes, AM and Gonçalves, J and Boyden, SE and Wöste, M and Hotaling, JM and , and Nagirnaja, L and Conrad, DF and Carrell, DT and Aston, KI},
title = {Correction to: Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermia.},
journal = {Human genetics},
volume = {140},
number = {1},
pages = {229},
doi = {10.1007/s00439-020-02244-1},
pmid = {33377991},
issn = {1432-1203},
}
@article {pmid33371776,
year = {2021},
author = {Yu, YL and Liu, H},
title = {Marital Quality and Salivary Telomere Length Among Older Men and Women in the United States.},
journal = {Journal of aging and health},
volume = {33},
number = {5-6},
pages = {300-309},
pmid = {33371776},
issn = {1552-6887},
support = {R01 AG061118/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; *Aging ; Cellular Senescence ; Female ; Humans ; Interpersonal Relations ; Male ; Retirement ; *Telomere ; United States ; },
abstract = {Objective: The link between marital quality and cellular aging remains underexplored. This study examined how both positive and negative marital quality were associated with salivary telomere length among partnered adults in the United States over the age of 50°years. Methods: Data were from the 2008 Health and Retirement Study (N = 3203). Ordinary least squares regression was used to estimate the link between marital quality and telomere length. Results: While neither positive nor negative marital quality was significantly associated with telomere length among older women, positive and negative marital quality had an interacting effect on telomere length among men. Specifically, when negative marital quality was low, higher positive marital quality was associated with shorter telomere length, whereas when negative marital quality was high, higher positive marital quality was associated with longer telomere length. Discussion: The findings speak to the complex nature of intimate partnerships and the implications of these partnerships for cellular aging processes.},
}
@article {pmid33371195,
year = {2020},
author = {Perona, R},
title = {The Different Roads to Maintain Telomeres in Cancer Cells.},
journal = {Genes},
volume = {11},
number = {12},
pages = {},
pmid = {33371195},
issn = {2073-4425},
abstract = {Telomeres are the protective structures at the ends of linear chromosomes that progressively shorten each time that a cell divides, which is in part caused by the end-replication problem [...].},
}
@article {pmid33370275,
year = {2020},
author = {Wagner, T and Pérez-Martínez, L and Schellhaas, R and Barrientos-Moreno, M and Öztürk, M and Prado, F and Butter, F and Luke, B},
title = {Chromatin modifiers and recombination factors promote a telomere fold-back structure, that is lost during replicative senescence.},
journal = {PLoS genetics},
volume = {16},
number = {12},
pages = {e1008603},
pmid = {33370275},
issn = {1553-7404},
mesh = {*DNA Replication ; Histone Deacetylases/genetics/*metabolism ; Methyltransferases/genetics/*metabolism ; Rad51 Recombinase/genetics/metabolism ; Rad52 DNA Repair and Recombination Protein/genetics/metabolism ; Repressor Proteins/genetics/*metabolism ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/*metabolism ; Sirtuin 2/genetics/*metabolism ; Telomere/chemistry/*genetics ; Telomere Homeostasis ; },
abstract = {Telomeres have the ability to adopt a lariat conformation and hence, engage in long and short distance intra-chromosome interactions. Budding yeast telomeres were proposed to fold back into subtelomeric regions, but a robust assay to quantitatively characterize this structure has been lacking. Therefore, it is not well understood how the interactions between telomeres and non-telomeric regions are established and regulated. We employ a telomere chromosome conformation capture (Telo-3C) approach to directly analyze telomere folding and its maintenance in S. cerevisiae. We identify the histone modifiers Sir2, Sin3 and Set2 as critical regulators for telomere folding, which suggests that a distinct telomeric chromatin environment is a major requirement for the folding of yeast telomeres. We demonstrate that telomeres are not folded when cells enter replicative senescence, which occurs independently of short telomere length. Indeed, Sir2, Sin3 and Set2 protein levels are decreased during senescence and their absence may thereby prevent telomere folding. Additionally, we show that the homologous recombination machinery, including the Rad51 and Rad52 proteins, as well as the checkpoint component Rad53 are essential for establishing the telomere fold-back structure. This study outlines a method to interrogate telomere-subtelomere interactions at a single unmodified yeast telomere. Using this method, we provide insights into how the spatial arrangement of the chromosome end structure is established and demonstrate that telomere folding is compromised throughout replicative senescence.},
}
@article {pmid33367858,
year = {2020},
author = {Kroupa, M and Rachakonda, S and Vymetalkova, V and Tomasova, K and Liska, V and Vodenkova, S and Cumova, A and Rossnerova, A and Vodickova, L and Hemminki, K and Soucek, P and Kumar, R and Vodicka, P},
title = {Telomere length in peripheral blood lymphocytes related to genetic variation in telomerase, prognosis and clinicopathological features in breast cancer patients.},
journal = {Mutagenesis},
volume = {35},
number = {6},
pages = {491-497},
doi = {10.1093/mutage/geaa030},
pmid = {33367858},
issn = {1464-3804},
mesh = {Adult ; Aged ; Aged, 80 and over ; Alleles ; Biomarkers, Tumor/genetics ; Breast Neoplasms/blood/*genetics/pathology ; Female ; Genetic Predisposition to Disease/genetics ; Genetic Variation/genetics ; Genome-Wide Association Study ; Genotype ; Humans ; Leukocytes/pathology ; Leukocytes, Mononuclear ; Lymphatic Metastasis/genetics/pathology ; Middle Aged ; Neoplasm Staging ; Polymorphism, Single Nucleotide/genetics ; RNA/*genetics ; Telomerase/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Disruption of telomere length (TL) homeostasis in peripheral blood lymphocytes has been previously assessed as a potential biomarker of breast cancer (BC) risk. The present study addressed the relationship between lymphocyte TL (LTL), prognosis and clinicopathological features in the BC patients since these associations are insufficiently explored at present. LTL was measured in 611 BC patients and 154 healthy controls using the monochrome multiplex quantitative Polymerase Chain Reaction assay. In addition, we genotyped nine TL-associated single-nucleotide polymorphisms that had been identified through genome-wide association studies. Our results showed that the patients had significantly (P = 0.001, Mann-Whitney U-test) longer LTL [median (interquartile range); 1.48 (1.22-1.78)] than the healthy controls [1.27 (0.97-1.82)]. Patients homozygous (CC) for the common allele of hTERT rs2736108 or the variant allele (CC) of hTERC rs16847897 had longer LTL. The latter association remained statistically significant in the recessive genetic model after the Bonferroni correction (P = 0.004, Wilcoxon two-sample test). We observed no association between LTL and overall survival or relapse-free survival of the patients. LTL did not correlate with cancer staging based on Union for International Cancer Control (UICC), The tumor node metastasis (TNM) staging system classification, tumour grade or molecular BC subtypes. Overall, we observed an association between long LTL and BC disease and an association of the hTERC rs16847897 CC genotype with increased LTL. However, no association between LTL, clinicopathological features and survival of the patients was found.},
}
@article {pmid33367599,
year = {2021},
author = {Pudas, S and Josefsson, M and Nordin Adolfsson, A and Landfors, M and Kauppi, K and Veng-Taasti, LM and Hultdin, M and Adolfsson, R and Degerman, S},
title = {Short Leukocyte Telomeres, But Not Telomere Attrition Rates, Predict Memory Decline in the 20-Year Longitudinal Betula Study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {76},
number = {6},
pages = {955-963},
pmid = {33367599},
issn = {1758-535X},
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers ; Cognitive Dysfunction/genetics/*metabolism ; Female ; Humans ; Leukocytes/*metabolism ; Longitudinal Studies ; Male ; Middle Aged ; Neuropsychological Tests ; Telomere/metabolism ; *Telomere Shortening ; },
abstract = {Leukocyte telomere length (LTL) is a proposed biomarker for aging-related disorders, including cognitive decline and dementia. Long-term longitudinal studies measuring intra-individual changes in both LTL and cognitive outcomes are scarce, precluding strong conclusions about a potential aging-related relationship between LTL shortening and cognitive decline. This study investigated associations between baseline levels and longitudinal changes in LTL and memory performance across an up to 20-year follow-up in 880 dementia-free participants from a population-based study (mean baseline age: 56.8 years, range: 40-80; 52% female). Shorter baseline LTL significantly predicted subsequent memory decline (r = .34, 95% confidence interval: 0.06, 0.82), controlling for age, sex, and other relevant covariates. No significant associations were however observed between intra-individual changes in LTL and memory, neither concurrently nor with a 5-year time-lag between LTL shortening and memory decline. These results support the notion of short LTL as a predictive factor for aging-related memory decline, but suggest that LTL dynamics in adulthood and older age may be less informative of cognitive outcomes in aging. Furthermore, the results highlight the importance of long-term longitudinal evaluation of outcomes in biomarker research.},
}
@article {pmid33367550,
year = {2020},
author = {Gadalla, SM},
title = {Telomere length in hematopoietic cell transplant.},
journal = {Blood},
volume = {136},
number = {26},
pages = {2972-2973},
pmid = {33367550},
issn = {1528-0020},
mesh = {*Hematopoietic Stem Cell Transplantation ; Humans ; *Myelodysplastic Syndromes ; Stem Cell Transplantation ; Telomere/genetics ; Transplantation, Homologous ; },
abstract = {In this issue of Blood, Myllymäki et al evaluated the role of pretransplant leukocyte telomere length (LTL) on survival outcomes in patients with myelodysplastic syndrome (MDS). The authors found associations between recipient short LTL and poor overall survival and high risk of nonrelapse mortality (NRM) after unrelated donor hematopoietic cell transplant (HCT).},
}
@article {pmid33367544,
year = {2020},
author = {Myllymäki, M and Redd, R and Reilly, CR and Saber, W and Spellman, SR and Gibson, CJ and Hu, ZH and Wang, T and Orr, EH and Grenier, JG and Chen, MM and Steensma, DP and Cutler, C and De Vivo, I and Antin, JH and Neuberg, D and Agarwal, S and Lindsley, RC},
title = {Short telomere length predicts nonrelapse mortality after stem cell transplantation for myelodysplastic syndrome.},
journal = {Blood},
volume = {136},
number = {26},
pages = {3070-3081},
pmid = {33367544},
issn = {1528-0020},
support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; K08 CA204734/CA/NCI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; T32 HL116324/HL/NHLBI NIH HHS/United States ; P30 CA006516/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Allografts ; Disease-Free Survival ; Female ; Humans ; Male ; Melphalan/administration &amp; dosage ; Middle Aged ; *Myelodysplastic Syndromes/genetics/metabolism/mortality/therapy ; Predictive Value of Tests ; *Stem Cell Transplantation ; Survival Rate ; *Telomere/genetics/metabolism ; *Telomere Homeostasis ; *Transplantation Conditioning ; },
abstract = {Allogeneic hematopoietic stem cell transplantation is the only potentially curative treatment for patients with myelodysplastic syndrome (MDS), but long-term survival is limited by the risk of transplant-related complications. Short telomere length, mediated by inherited or acquired factors, impairs cellular response to genotoxic and replicative stress and could identify patients at higher risk for toxicity after transplantation. We measured relative telomere length in pretransplant recipient blood samples in 1514 MDS patients and evaluated the association of telomere length with MDS disease characteristics and transplantation outcomes. Shorter telomere length was significantly associated with older age, male sex, somatic mutations that impair the DNA damage response, and more severe pretransplant cytopenias, but not with bone marrow blast count, MDS treatment history, or history of prior cancer therapy. Among 1267 patients ≥40 years old, telomere length in the shortest quartile was associated with inferior survival (P < .001) because of a high risk of nonrelapse mortality (NRM; P = .001) after adjusting for significant clinical and genetic variables. The adverse impact of shorter telomeres on NRM was independent of recipient comorbidities and was observed selectively among patients receiving more intensive conditioning, including myeloablative regimens and higher dose melphalan-based reduced-intensity regimens. The effect of shorter telomeres on NRM was prominent among patients who developed severe acute graft-versus-host disease, suggesting that short telomere length may limit regenerative potential of mucosal tissues after acute injury. MDS patients with shorter telomere length, who have inferior survival driven by excess toxicity, could be considered for strategies focused on minimizing toxic effects of transplantation.},
}
@article {pmid33358512,
year = {2022},
author = {Tomos, I and Karakatsani, A and Manali, ED and Kottaridi, C and Spathis, A and Argentos, S and Papiris, SA},
title = {Telomere length across different UIP fibrotic-Interstitial Lung Diseases: a prospective Greek case-control study.},
journal = {Pulmonology},
volume = {28},
number = {4},
pages = {254-261},
doi = {10.1016/j.pulmoe.2020.11.005},
pmid = {33358512},
issn = {2531-0437},
mesh = {Aged ; Case-Control Studies ; Greece/epidemiology ; Humans ; *Idiopathic Pulmonary Fibrosis/genetics ; *Lung Diseases, Interstitial/genetics ; Prospective Studies ; Retrospective Studies ; Telomere/genetics ; },
abstract = {INTRODUCTION: Short telomeres are recognized as risk factor for idiopathic pulmonary fibrosis (IPF). We aimed to assess the role of telomere length (TL) in fibrotic-Interstitial Lung Diseases (f-ILDs) associated with a usual interstitial pneumonia (UIP) pattern as well as in IPF acute exacerbation (IPF-AE).<br><br>AIM AND METHODS: TL was measured from peripheral white blood cells using a multiplex quantitative polymerase chain reaction in consecutive patients with f-ILDs, all presenting UIP pattern in the high-resolution chest-computed-tomography and compared to age-matched healthy controls.<br><br>RESULTS: Seventy-nine individuals were included (mean age 69.77&#x202f;&#xb1;&#x202f;0.72 years); 24 stable IPF, 18 IPF-AE, 10 combined pulmonary fibrosis and emphysema, 7 Rheumatoid arthritis-UIP-ILDs and 20 controls. TL in all patients was significantly shorter compared to controls [mean T/S ratio (SE) 0.77 (&#xb1;0.05) vs 2.26 (&#xb1;0.36), p&#x202f;<&#x202f;0.001] as well as separately in each one of f-ILD subgroups. IPF-AE patients presented significantly shorter TL compared to stable IPF (p&#x202f;=&#x202f;0.029). Patients with IPF and shorter than the median TL (0-0.72) showed reduced overall survival (p&#x202f;=&#x202f;0.004). T/S&#x202f;<&#x202f;0.72 was associated with increased risk for IPF-AE (OR&#x202f;=&#x202f;30.787, 95% CI: 2.153, 440.183, p&#x202f;=&#x202f;0.012) independent of age, gender, smoking and lung function impairment. A protective effect of TL was observed, as it was inversely associated with risk of death both in UIP-f-ILDs (HR&#x202f;=&#x202f;0.174, 95%CI: 0.036, 0.846, p&#x202f;=&#x202f;0.030) and IPF patients (HR&#x202f;=&#x202f;0.096, 95%CI: 0.011, 0.849, p&#x202f;=&#x202f;0.035).<br><br>CONCLUSIONS: Shorter TL characterizes different UIP f-ILDs. Although no difference was observed in TL among diverse UIP subgroups, IPF-AE presented shorter TL compared to stable IPF. Reduced overall survival and higher hazard ratio of death are associated with shorter TL in IPF.},
}
@article {pmid33357657,
year = {2020},
author = {Gupta, MD and Miglani, M and Bansal, A and Jain, V and Arora, S and Kumar, S and Virani, SS and Kalra, A and Yadav, R and Pasha, Q and Yusuf, J and Mukhopadhyay, S and Tyagi, S and Girish, MP},
title = {Telomere length in young patients with acute myocardial infarction without conventional risk factors: A pilot study from a South Asian population.},
journal = {Indian heart journal},
volume = {72},
number = {6},
pages = {619-622},
pmid = {33357657},
issn = {2213-3763},
mesh = {Adolescent ; Adult ; Biomarkers/metabolism ; Case-Control Studies ; DNA/*genetics ; Female ; Humans ; Incidence ; India/epidemiology ; Male ; Middle Aged ; Myocardial Infarction/epidemiology/*genetics/metabolism ; Pilot Projects ; Risk Factors ; Telomere/*genetics ; Young Adult ; },
abstract = {BACKGROUND: There is need to identify novel markers that lead to an early occurrence of myocardial infarction (MI) in young South Asian population. This population has different risk profile as compared with others. Telomere length is known to be a marker of aging, and shorter telomeres have been reported in cardiovascular diseases (CVDs). We aimed to identify the association of telomere length in young nonsmokers and non-diabetic MI patients.<br><br>METHODS: In a case-control study of 154 subjects (n&#xa0;=&#xa0;77 cases (ages 18-45 years, non-diabetic, non-smoker patients with MI) and n&#xa0;=&#xa0;77, age and sex matched healthy controls), DNA extraction from peripheral blood leukocytes was carried out and the relative telomere length was estimated by quantitative PCR. The results were adjusted with various demographic parameters like age, gender and body mass index (BMI). The correlation studies were carried out between telomere length, sex and type of MI.<br><br>RESULTS: The relative telomere length was significantly shorter in young MI patients (31-45 years) compared with matched healthy controls (p&#xa0;<&#xa0;0.0001). Interestingly, in a gender-based comparison, the female patients had shorter telomere length (p&#xa0;<&#xa0;0.01).<br><br>CONCLUSION: In this pilot study, we found that the telomere length was shorter among young, non-diabetic, non-smoker MI patients as compared with similar young controls without MI in a South Asian cohort. Thus, telomere length may be a potential screening tool for young patients who don't have conventional risk factors. Larger studies are needed to confirm these findings.},
}
@article {pmid33357405,
year = {2021},
author = {Le, R and Huang, Y and Zhang, Y and Wang, H and Lin, J and Dong, Y and Li, Z and Guo, M and Kou, X and Zhao, Y and Chen, M and Zhu, Q and Zhao, A and Yin, J and Sun, J and Su, Z and Shi, K and Gao, Y and Chen, J and Liu, W and Kang, L and Wang, Y and Li, C and Liu, X and Gao, R and Wang, H and Ju, Z and Gao, S},
title = {Dcaf11 activates Zscan4-mediated alternative telomere lengthening in early embryos and embryonic stem cells.},
journal = {Cell stem cell},
volume = {28},
number = {4},
pages = {732-747.e9},
doi = {10.1016/j.stem.2020.11.018},
pmid = {33357405},
issn = {1875-9777},
mesh = {Animals ; Embryonic Stem Cells ; Mice ; *Telomere ; *Telomere Homeostasis ; },
abstract = {Telomeres play vital roles in ensuring chromosome stability and are thus closely linked with the onset of aging and human disease. Telomeres undergo extensive lengthening during early embryogenesis. However, the detailed molecular mechanism of telomere resetting in early embryos remains unknown. Here, we show that Dcaf11 (Ddb1- and Cul4-associated factor 11) participates in telomere elongation in early embryos and 2-cell-like embryonic stem cells (ESCs). The deletion of Dcaf11 in embryos and ESCs leads to reduced telomere sister-chromatid exchange (T-SCE) and impairs telomere lengthening. Importantly, Dcaf11-deficient mice exhibit gradual telomere erosion with successive generations, and hematopoietic stem cell (HSC) activity is also greatly compromised. Mechanistically, Dcaf11 targets Kap1 (KRAB-associated protein 1) for ubiquitination-mediated degradation, leading to the activation of Zscan4 downstream enhancer and the removal of heterochromatic H3K9me3 at telomere/subtelomere regions. Our study therefore demonstrates that Dcaf11 plays important roles in telomere elongation in early embryos and ESCs through activating Zscan4.},
}
@article {pmid33355657,
year = {2021},
author = {Allsopp, R},
title = {Take a Ride on the Telomere-Aging Train.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {76},
number = {1},
pages = {1-2},
doi = {10.1093/gerona/glaa245},
pmid = {33355657},
issn = {1758-535X},
mesh = {Aging/*genetics ; Humans ; *Telomere/ultrastructure ; },
}
@article {pmid33355185,
year = {2021},
author = {Joshu, CE and Heaphy, CM and Barber, JR and Lu, J and Zarinshenas, R and Davis, C and Han, M and Lotan, TL and Sfanos, KS and De Marzo, AM and Meeker, AK and Platz, EA},
title = {Obesity is Associated with Shorter Telomere Length in Prostate Stromal Cells in Men with Aggressive Prostate Cancer.},
journal = {Cancer prevention research (Philadelphia, Pa.)},
volume = {14},
number = {4},
pages = {463-470},
pmid = {33355185},
issn = {1940-6215},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; P50 CA058236/CA/NCI NIH HHS/United States ; },
mesh = {*Body Mass Index ; Cross-Sectional Studies ; Humans ; *Life Style ; Male ; Middle Aged ; Obesity/*complications ; Overweight/*complications ; Prostatic Neoplasms/etiology/genetics/*pathology ; Risk Factors ; Stromal Cells/metabolism/*pathology ; *Telomere Shortening ; },
abstract = {In our prior studies, obesity was associated with shorter telomeres in prostate cancer-associated stromal (CAS) cells, and shorter CAS telomeres were associated with an increased risk of prostate cancer death. To determine whether the association between obesity and shorter CAS telomeres is replicable, we conducted a pooled analysis of 790 men who were surgically treated for prostate cancer, whose tissue samples were arrayed on five tissue microarray (TMA) sets. Telomere signal was measured using a quantitative telomere-specific FISH assay and normalized to 4',6-diamidino-2-phenylindole for 351 CAS cells (mean) per man; men were assigned their median value. Weight and height at surgery, collected via questionnaire or medical record, were used to calculate body mass index (BMI; kg/m[2]) and categorize men as normal (<25), overweight (25 ≤ BMI < 30), or obese (≥30). Analyses were stratified by grade and stage. Men were divided into tertiles of TMA- (overall) or TMA- and disease aggressiveness- (stratified) specific distributions; short CAS telomere status was defined by the bottom two tertiles. We used generalized linear mixed models to estimate the association between obesity and short CAS telomeres, adjusting for age, race, TMA set, pathologic stage, and grade. Obesity was not associated with short CAS telomeres overall, or among men with nonaggressive disease. Among men with aggressive disease (Gleason≥4+3 and stage>T2), obese men had a 3-fold increased odds of short CAS telomeres (OR: 3.06; 95% confidence interval: 1.07-8.75; P trend = 0.045) when compared with normal weight men. Telomere shortening in prostate stromal cells may be one mechanism through which lifestyle influences lethal prostate carcinogenesis. PREVENTION RELEVANCE: This study investigates a potential mechanism underlying the association between obesity and prostate cancer death. Among men with aggressive prostate cancer, obesity was associated with shorter telomeres prostate cancer associated stromal cells, and shorter CAS telomeres have been associated with an increased risk of prostate cancer death.},
}
@article {pmid33354567,
year = {2020},
author = {Yu, SN and Chen, SQ and Fan, GQ and Pan, WZ and Jia, J and Wang, Q and Ma, L and Li, B and Qiang, M and Qiu, YL and Wang, T},
title = {Relative Telomere Length in Peripheral Blood Cells and Hypertension Risk among Mine Workers: A Case-Control Study in Chinese Coal Miners.},
journal = {BioMed research international},
volume = {2020},
number = {},
pages = {5681096},
pmid = {33354567},
issn = {2314-6141},
mesh = {Adult ; Case-Control Studies ; China ; *Coal Mining ; Essential Hypertension/*blood/diagnosis/*genetics ; Female ; Humans ; Hypertension ; Male ; Middle Aged ; *Miners ; *Occupational Exposure ; Real-Time Polymerase Chain Reaction ; Regression Analysis ; Retrospective Studies ; Risk Factors ; Surveys and Questionnaires ; Telomere/*ultrastructure ; },
abstract = {Hypertension is a common chronic disease in middle-aged and elderly people and is an important risk factor for many cardiovascular diseases. Its pathogenesis remains unclear. Epidemiological studies have found that the loss of telomere length in peripheral blood cells can increase the risk of coronary heart disease, myocardial infarction, and other diseases. However, a correlation between loss of telomere length and hypertension has not been established. In this study, we aimed to explore the association between telomere length and the risk of essential hypertension (EH) in Chinese coal miners. A case-control study was performed with 215 EH patients and 222 healthy controls in a large coal mining group located in North China. Face-to-face interviews were conducted by trained staff with the necessary medical knowledge. Relative telomere length (RTL) was measured by a quantitative real-time PCR assay using DNA extracted from peripheral blood. In the control group, the age-adjusted RTL was statistically significantly lower in miners performing hard physical labour compared with nonphysical labour (P = 0.043). A significantly shorter age-adjusted RTL was found in the control group of participants who consumed alcohol regularly compared with those who do not consume alcohol (P = 0.024). Age-adjusted RTL was negatively correlated with body mass index (BMI) and alcohol consumption. Hypertension was also found to be significantly correlated with factors such as age, BMI, alcohol consumption, smoking, and tea consumption. Our results suggest that RTL is associated with hypertension in coal miners.},
}
@article {pmid33353140,
year = {2020},
author = {Minamoto, T and Nakayama, K and Ishibashi, T and Ishikawa, M and Nakamura, K and Yamashita, H and Shanta, K and Mahmud, HM and Razia, S and Iida, K and Sakashita, G and Nakamura, T and Kanda, H and Kyo, S},
title = {Pregnancy by Assisted Reproductive Technology Is Associated with Shorter Telomere Length in Neonates.},
journal = {International journal of molecular sciences},
volume = {21},
number = {24},
pages = {},
pmid = {33353140},
issn = {1422-0067},
mesh = {Adolescent ; Adult ; Female ; *Gestational Age ; Humans ; Infant, Newborn ; Male ; *Maternal Age ; Pregnancy ; Reproductive Techniques, Assisted/*statistics &amp; numerical data ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {Telomere length (TL) influences the development of lifestyle-related diseases, and neonatal TL may influence their prevalence. Various factors have been reported to affect neonatal TL. Although the fetus is exposed to multiple conditions in utero, the main factors affecting the shortening of neonatal TL are still not known. In this study, we sought to identify factors that influence fetal TL. A total of 578 mother-newborn pairs were included for TL analysis. TL was measured in genomic DNA extracted from cord blood samples using quantitative PCR. The clinical factors examined at enrollment included the following intrauterine environmental factors: maternal age, assisted reproductive technology (ART) used, body mass index (BMI), gestational diabetes mellitus (GDM), maternal stress, smoking, alcohol consumption, preterm delivery, small-for-gestational-age, neonatal sex, and placental weight. Univariate and multivariate regression analyses were used to verify the relationship between neonatal TL and these clinical factors. The median neonatal TL to single-copy gene ratio was 1.0. Pregnancy with ART was among the 11 factors associated with shorter neonatal TL. From multiple regression analysis, we determined that neonatal TL was significantly shorter for pregnancies in the ART group than in the other groups. We conclude that pregnancy with ART is associated with shorter neonatal TL.},
}
@article {pmid33351357,
year = {2020},
author = {Dudinskaya, EN and Tkacheva, ON and Brailova, NV and Strazhesko, ID and Shestakova, MV},
title = {[Telomere biology and metabolic disorders: the role of insulin resistance and type 2 diabetes].},
journal = {Problemy endokrinologii},
volume = {66},
number = {4},
pages = {35-44},
doi = {10.14341/probl12510},
pmid = {33351357},
issn = {2308-1430},
mesh = {Adult ; Biology ; *Diabetes Mellitus, Type 2/genetics ; Humans ; *Insulin Resistance/genetics ; Middle Aged ; Telomere/genetics ; Telomere Shortening ; },
abstract = {BACKGROUND: Insulin resistance accelerates the aging process, but its speed depends on the individual characteristics of the metabolism. One of the reasons for the different aging rates in individuals with insulin resistance is the initially different "genetic protection" of cells, which many scientists associate with replicative cellular aging.<br><br>AIMS: to study the relationship between the state of carbohydrate metabolism and markers of replicative cell aging in individuals with different sensitivity to insulin.<br><br>MATERIALS AND METHODS: The observation study included 305 patients. The parameters of glucose metabolism and telomere biology were studied.<br><br>RESULTS: The mean age of the patients was 51.5&#xb1;13.3 years. Patients were divided into three groups depending on presence of insulin resistance: healthy, with insulin resistance and with type 2 diabetes. The mean age of healthy patients was 48.82&#xb1;13.87 years, in insulin resistance group - 53.04&#xb1;12.8, in 2 diabetes mellitus - 58.4&#xb1;7.90. The median telomere length was 9.76. The median telomerase activity was 0.48. Both telomere length and telomerase activity progressively decrease as insulin resistance increases. In patients with diabetes, short telomere lengths and low telomerase activity predominated. The insulin resistance index has the greatest impact on the risk of detecting "short" telomeres. In patients with insulin resistance, an increase in glycated hemoglobin increases the likelihood of detecting short telomeres by 2.4 times, and in diabetes mellitus by 4.26 times, an increase in fasting plasma glucose by 90%, and an increase in HOMA-IR by 35%. An increase in insulin resistance increases the risk of detecting &#xab;low&#xbb; telomerase activity by 53% and the risk of detecting &#xab;very low&#xbb; telomerase activity by 92%. A decrease in synsulin resistance increases the chance of increasing telomerase activity to &#xab;very high&#xbb; by 51%.<br><br>CONCLUSION: Shorter telomeres are associated with more pronounced disorders of carbohydrate metabolism and a higher degree of insulin resistance. Further studies of metabolic status are necessary to personalize their lifestyle and treatment goals.},
}
@article {pmid33350936,
year = {2020},
author = {Saint-Leandre, B and Christopher, C and Levine, MT},
title = {Adaptive evolution of an essential telomere protein restricts telomeric retrotransposons.},
journal = {eLife},
volume = {9},
number = {},
pages = {},
pmid = {33350936},
issn = {2050-084X},
support = {R00 GM107351/GM/NIGMS NIH HHS/United States ; R35 GM124684/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Biological Evolution ; Chromosomal Proteins, Non-Histone/*genetics ; Drosophila ; Drosophila Proteins/*genetics ; Retroelements/*genetics ; Telomere/*genetics ; },
abstract = {Essential, conserved cellular processes depend not only on essential, strictly conserved proteins but also on essential proteins that evolve rapidly. To probe this poorly understood paradox, we exploited the rapidly evolving Drosophila telomere-binding protein, cav/HOAP, which protects chromosomes from lethal end-to-end fusions. We replaced the D. melanogaster HOAP with a highly diverged version from its close relative, D. yakuba. The D. yakuba HOAP ('HOAP[yak]') localizes to D. melanogaster telomeres and protects D. melanogaster chromosomes from fusions. However, HOAP[yak] fails to rescue a previously uncharacterized HOAP function: silencing of the specialized telomeric retrotransposons that, instead of telomerase, maintain chromosome length in Drosophila. Whole genome sequencing and cytogenetics of experimentally evolved populations revealed that HOAP[yak] triggers telomeric retrotransposon proliferation, resulting in aberrantly long telomeres. This evolution-generated, separation-of-function allele resolves the paradoxical observation that a fast-evolving essential gene directs an essential, strictly conserved function: telomeric retrotransposon containment, not end-protection, requires evolutionary innovation at HOAP.},
}
@article {pmid33347580,
year = {2021},
author = {Li, X and Wang, M and Zheng, W and Huang, W and Wang, Z and Jin, K and Liu, L and Yu, Z},
title = {Dynamics of TRF1 organizing a single human telomere.},
journal = {Nucleic acids research},
volume = {49},
number = {2},
pages = {760-775},
pmid = {33347580},
issn = {1362-4962},
mesh = {Biotinylation ; Digoxigenin ; Humans ; Inverted Repeat Sequences ; K562 Cells ; Magnets ; Micromanipulation/*methods ; Shelterin Complex ; Single Molecule Imaging ; Telomere/chemistry/*ultrastructure ; Telomere-Binding Proteins/chemistry/physiology ; Telomeric Repeat Binding Protein 1/*metabolism ; },
abstract = {Chromosome stability is primarily determined by telomere length. TRF1 is the core subunit of shelterin that plays a critical role in telomere organization and replication. However, the dynamics of TRF1 in scenarios of telomere-processing activities remain elusive. Using single-molecule magnetic tweezers, we here investigated the dynamics of TRF1 upon organizing a human telomere and the protein-DNA interactions at a moving telomeric fork. We first developed a method to obtain telomeres from human cells for directly measuring the telomere length by single-molecule force spectroscopy. Next, we examined the compaction and decompaction of a telomere by TRF1 dimers. TRF1 dissociates from a compacted telomere with heterogenous loops in ∼20 s. We also found a negative correlation between the number of telomeric loops and loop sizes. We further characterized the dynamics of TRF1 at a telomeric DNA fork. With binding energies of 11 kBT, TRF1 can modulate the forward and backward steps of DNA fork movements by 2-9 s at a critical force of F1/2, temporarily maintaining the telomeric fork open. Our results shed light on the mechanisms of how TRF1 organizes human telomeres and facilitates the efficient replication of telomeric DNA. Our work will help future research on the chemical biology of telomeres and shelterin-targeted drug discovery.},
}
@article {pmid33347069,
year = {2021},
author = {Luxton, JJ and Bailey, SM},
title = {Twins, Telomeres, and Aging-in Space!.},
journal = {Plastic and reconstructive surgery},
volume = {147},
number = {1S-2},
pages = {7S-14S},
doi = {10.1097/PRS.0000000000007616},
pmid = {33347069},
issn = {1529-4242},
mesh = {Aging/*genetics/radiation effects ; Cosmic Radiation/adverse effects ; Genomic Instability/radiation effects ; Humans ; Longitudinal Studies ; Male ; *Space Flight ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere Shortening/*physiology/radiation effects ; Time Factors ; Twins, Monozygotic/*genetics ; },
abstract = {BACKGROUND: The landmark National Aeronautics and Space Administration Twins Study represented an integrated effort to launch human space life science research into the modern age of molecular- and "omics"-based studies. As part of the first One-Year Mission aboard the International Space Station, identical twin astronauts Scott and Mark Kelly were the subjects of this "out of this world" research opportunity. Telomeres, the natural ends of chromosomes that shorten with cell division and a host of lifestyle factors and stresses, are key molecular determinants of aging and aging trajectories.<br><br>METHODS: We proposed that telomere length dynamics (changes over time) represent a particularly relevant and integrative biomarker for astronauts, as they reflect the combined experiences and environmental exposures encountered during spaceflight. Telomere length (quantitative polymerase chain reaction and telomere fluorescence in situ hybridization) and telomerase activity (quantitative polymerase chain reaction -telomere repeat amplification protocol) were longitudinally assessed in the space- and earth-bound twins. Chromosome aberrations (directional genomic hybridization), signatures of radiation exposure, were also evaluated.<br><br>RESULTS: The twins had relatively similar telomere lengths before spaceflight, and the earth-bound twins' telomeres remained relatively stable over the course of the study. Surprisingly, the space twins' telomeres were longer during spaceflight, and upon return to Earth shortened rapidly, resulting in many more short telomeres after spaceflight than before. Chromosomal signatures of space radiation exposure were also elevated during spaceflight, and increased inversion frequencies persisted after spaceflight, suggestive of ongoing genome instability.<br><br>CONCLUSION: Although the definitive mechanisms underlying such dramatic spaceflight-associated shifts in telomere length remain unclear, improved maintenance of telomere length has important implications for aging science and improving healthspan for those on Earth, as well.},
}
@article {pmid33345078,
year = {2020},
author = {Simões, HG and Rosa, TS and Sousa, CV and Aguiar, SDS and Motta-Santos, D and Degens, H and Korhonen, MT and Campbell, CSG},
title = {Does Longer Leukocyte Telomere Length and Higher Physical Fitness Protect Master Athletes From Consequences of Coronavirus (SARS-CoV-2) Infection?.},
journal = {Frontiers in sports and active living},
volume = {2},
number = {},
pages = {87},
pmid = {33345078},
issn = {2624-9367},
}
@article {pmid33344901,
year = {2020},
author = {Goncalves, T and Zoumpoulidou, G and Alvarez-Mendoza, C and Mancusi, C and Collopy, LC and Strauss, SJ and Mittnacht, S and Tomita, K},
title = {Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by Ataxia Telangiectasia and Rad3-Related Inhibitors.},
journal = {ACS pharmacology &amp; translational science},
volume = {3},
number = {6},
pages = {1253-1264},
pmid = {33344901},
issn = {2575-9108},
support = {12097/CRUK_/Cancer Research UK/United Kingdom ; },
abstract = {To avoid replicative senescence or telomere-induced apoptosis, cancers employ telomere maintenance mechanisms (TMMs) involving either the upregulation of telomerase or the acquisition of recombination-based alternative telomere lengthening (ALT). The choice of TMM may differentially influence cancer evolution and be exploitable in targeted therapies. Here, we examine TMMs in a panel of 17 osteosarcoma-derived cell lines, defining three separate groups according to TMM and the length of telomeres maintained. Eight were ALT-positive, including the previously uncharacterized lines, KPD and LM7. While ALT-positive lines all showed excessive telomere length, ALT-negative cell lines fell into two groups according to their telomere length: HOS-MNNG, OHSN, SJSA-1, HAL, 143b, and HOS displayed subnormally short telomere length, while MG-63, MHM, and HuO-3N1 displayed long telomeres. Hence, we further subcategorized ALT-negative TMM into long-telomere (LT) and short-telomere (ST) maintenance groups. Importantly, subnormally short telomeres were significantly associated with hypersensitivity to three different therapeutics targeting the protein kinase ataxia telangiectasia and Rad3-related (ATR) (AZD-6738/Ceralasertib, VE-822/Berzoserib, and BAY-1895344) compared to long telomeres maintained via ALT or telomerase. Within 24 h of ATR inhibition, cells with short but not long telomeres displayed chromosome bridges and underwent cell death, indicating a selective dependency on ATR for chromosome stability. Collectively, our work provides a resource to identify links between the mode of telomere maintenance and drug sensitivity in osteosarcoma and indicates that telomere length predicts ATR inhibitor sensitivity in cancer.},
}
@article {pmid33338512,
year = {2021},
author = {Ningarhari, M and Caruso, S and Hirsch, TZ and Bayard, Q and Franconi, A and Védie, AL and Noblet, B and Blanc, JF and Amaddeo, G and Ganne, N and Ziol, M and Paradis, V and Guettier, C and Calderaro, J and Morcrette, G and Kim, Y and MacLeod, AR and Nault, JC and Rebouissou, S and Zucman-Rossi, J},
title = {Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target.},
journal = {Journal of hepatology},
volume = {74},
number = {5},
pages = {1155-1166},
doi = {10.1016/j.jhep.2020.11.052},
pmid = {33338512},
issn = {1600-0641},
mesh = {Aging/*physiology ; Carcinogenesis/*genetics ; *Carcinoma, Hepatocellular/genetics/metabolism/pathology/therapy ; Cell Line, Tumor ; Drug Discovery ; Ethanol/metabolism ; Humans ; Liver Cirrhosis/etiology/metabolism ; *Liver Neoplasms/genetics/metabolism/pathology ; Oligonucleotides, Antisense/*pharmacology ; Oncogene Addiction ; Sex Factors ; Telomerase/genetics/*metabolism ; *Telomere Homeostasis/drug effects/physiology ; },
abstract = {BACKGROUND &amp; AIMS: Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. Thus, we aimed to elucidate the role of telomere length maintenance during liver carcinogenesis.<br><br>METHODS: Telomere length was measured in the tumor and non-tumor liver tissues of 1,502 patients (978 with HCC) and integrated with TERT alterations and expression, as well as clinical and molecular (analyzed by genome, exome, targeted and/or RNA-sequencing) features of HCC. The preclinical efficacy of anti-TERT antisense oligonucleotides (ASO) was assessed in vitro in 26 cell lines and in vivo in a xenograft mouse model.<br><br>RESULTS: Aging, liver fibrosis, male sex and excessive alcohol consumption were independent determinants of liver telomere attrition. HCC that developed in livers with long telomeres frequently had wild-type TERT with progenitor features and BAP1 mutations. In contrast, HCC that developed on livers with short telomeres were enriched in the non-proliferative HCC class and frequently had somatic TERT promoter mutations. In HCCs, telomere length is stabilized in a narrow biological range around 5.7 kb, similar to non-tumor livers, by various mechanisms that activate TERT expression. Long telomeres are characteristic of very aggressive HCCs, associated with the G3 transcriptomic subclass, TP53 alterations and poor prognosis. In HCC cell lines, TERT silencing with ASO was efficient in highly proliferative and poorly differentiated cells. Treatment for 3 to 16 weeks induced cell proliferation arrest in 12 cell lines through telomere shortening, DNA damage and activation of apoptosis. The therapeutic effect was also obtained in a xenograft mouse model.<br><br>CONCLUSIONS: Telomere maintenance in HCC carcinogenesis is diverse, and is associated with tumor progression and aggressiveness. The efficacy of anti-TERT ASO treatment in cell lines revealed the oncogenic addiction to TERT in HCC, providing a preclinical rationale for anti-TERT ASO treatment in HCC clinical trials.<br><br>LAY SUMMARY: Telomeres are repeated DNA sequences that protect chromosomes and naturally shorten in most adult cells because of the inactivation of the TERT gene, coding for the telomerase enzyme. Here we show that telomere attrition in the liver, modulated by aging, sex, fibrosis and alcohol, associates with specific clinical and molecular features of hepatocellular carcinoma, the most frequent primary liver cancer. We also show that liver cancer is dependent on TERT reactivation and telomere maintenance, which could be targeted through a novel therapeutic approach called antisense oligonucleotides.},
}
@article {pmid33335933,
year = {2020},
author = {Iyengar, S and Cȏté, HCF and Fitch, KV and Torriani, M and Feldpausch, M and Srinivasa, S},
title = {Relationship of Telomere Length to Fat Redistribution in HIV.},
journal = {Open forum infectious diseases},
volume = {7},
number = {12},
pages = {ofaa523},
pmid = {33335933},
issn = {2328-8957},
support = {P30 DK040561/DK/NIDDK NIH HHS/United States ; UL1 TR002541/TR/NCATS NIH HHS/United States ; },
abstract = {Persons with HIV demonstrate increased risk for aging-associated complications and have reduced telomere length (TL) compared with age-matched persons without HIV. Our data show that greater visceral fat is related to reduced TL in HIV, independent of age and smoking. Fat redistribution may be a relevant mediator of TL attrition in HIV.},
}
@article {pmid33335813,
year = {2020},
author = {Leonida, SRL and Bennett, NC and Leitch, AR and Faulkes, CG},
title = {Patterns of telomere length with age in African mole-rats: New insights from quantitative fluorescence in situ hybridisation (qFISH).},
journal = {PeerJ},
volume = {8},
number = {},
pages = {e10498},
pmid = {33335813},
issn = {2167-8359},
abstract = {Naked mole-rats Heterocephalus glaber (NMRs) are the longest-lived rodent and also resist the normal signs of senescence. In a number of species, cellular ageing has been correlated with a reduction in telomere length, yet relatively little is known about telomeres and their age-related dynamics in NMRs and other African mole-rats. Here, we apply fluorescence in situ hybridisation (FISH) to quantify telomeric repeat sequences in the NMR, the Damaraland mole-rat, Fukomys damarensis (DMR) and the Mahali mole-rat, Cryptomys hottentotus mahali (MMR). Both terminal and non-terminal telomeric sequences were identified in chromosomes of the NMR and DMR, whilst the MMR displayed only terminal telomeric repeats. Measurements of tooth wear and eruption patterns in wild caught DMRs and MMRs, and known ages in captive bred NMRs, were used to place individuals into relative age classes and compared with a quantitative measure of telomeric fluorescence (as a proxy for telomere size). While NMRs and MMRs failed to show an age-related decline in telomeric fluorescence, the DMR had a significant decrease in fluorescence with age, suggesting a decrease in telomere size in older animals. Our results suggest that among African mole-rats there is variation between species with respect to the role of telomere shortening in ageing, and the replicative theory of cellular senescence.},
}
@article {pmid33331615,
year = {2021},
author = {Zarei, M and Zarezadeh, M and Hamedi Kalajahi, F and Javanbakht, MH},
title = {The Relationship Between Vitamin D and Telomere/Telomerase: A Comprehensive Review.},
journal = {The Journal of frailty &amp; aging},
volume = {10},
number = {1},
pages = {2-9},
doi = {10.14283/jfa.2020.33},
pmid = {33331615},
issn = {2260-1341},
mesh = {Aging/blood/genetics/metabolism/pathology ; Cellular Senescence/*physiology ; Humans ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Vitamin D/*blood/*metabolism ; },
abstract = {Telomeres are repetitive nucleotide sequences that together with the associated sheltrin complex protect the ends of chromosomes and maintain genomic stability. Evidences from various organisms suggests that several factors influence telomere length regulation, such as telomere binding proteins, telomere capping proteins, telomerase, and DNA replication enzymes. Recent studies suggest that micronutrients, such as vitamin D, folate and vitamin B12, are involved in telomere biology and cellular aging. In particular, vitamin D is important for a range of vital cellular processes including cellular differentiation, proliferation and apoptosis. As a result of the multiple functions of vitamin D it has been speculated that vitamin D might play a role in telomere biology and genomic stability. In this study, our main goal is investigating the relationship between telomerase enzyme and vitamin D. Findings of this study suggest that higher vitamin D concentrations, which are easily modifiable through nutritional supplementation, are associated with longer LTL, which underscores the potentially beneficial effects of this hormone on aging and age-related diseases. Vitamin D may reduce telomere shortening through anti-inflammatory and anti-cell proliferation mechanisms. Significant Low levels of telomerase activity create short telomeres, which in turn signal exit from the cell cycle resulting in cell senescence and apoptosis. In follow-up examination, the patients who remained vitamin D deficient tended to have shorter telomeres than those patients whose 25-hydroxyvitamin D levels were depleted. Increasing 25-hydroxyvitamin D levels in patients with SLE may be beneficial in maintaining telomere length and preventing cellular aging. Moreover, anti-telomere antibody levels may be a promising biomarker of SLE status and disease activity.},
}
@article {pmid33329978,
year = {2020},
author = {Gutlapalli, SD and Kondapaneni, V and Toulassi, IA and Poudel, S and Zeb, M and Choudhari, J and Cancarevic, I},
title = {The Effects of Resveratrol on Telomeres and Post Myocardial Infarction Remodeling.},
journal = {Cureus},
volume = {12},
number = {11},
pages = {e11482},
pmid = {33329978},
issn = {2168-8184},
abstract = {Post myocardial infarction (MI) remodeling is the term used to define the changes in cardiac musculature after sustaining an ischemic injury. These changes decrease myocardial function and ultimately lead to heart failure. We review the contributing factors to post-MI remodeling, its association with telomere biology, as well as a myriad of other factors affecting aging and telomere length in relation to cardiovascular health. The main focus is on the effects of resveratrol in the cardiovascular system and its potential for therapeutic use in preventing long-term cardiovascular morbidity and mortality. We tried to answer important questions regarding the potential for resveratrol as a therapeutic drug to prevent adverse post-MI remodeling. In our search, we gathered 62 studies and narrowed our data down to 44 studies. The database used was PubMed, and the keywords used are "Resveratrol", "Telomere", "Post Myocardial Infarction". All the studies were carefully screened for relevant articles regarding our topic manually, Articles related to a positive association between resveratrol and its anti-aging, cardioprotective effects have been included in our study, as we could not find any articles in our search which showed a negative correlation. Our review concluded that resveratrol had pro-telomerase effects which could counter the development of adverse post-MI remodeling. Therefore resveratrol could be a useful therapeutic add-on drug to prevent cardiovascular disease. It is essential that further research including observational and large-scale clinical trials should be conducted to increase our understanding of the efficacy and viability of these novel therapeutic interventions.},
}
@article {pmid33328546,
year = {2020},
author = {Yu, EY and Zahid, SS and Ganduri, S and Sutherland, JH and Hsu, M and Holloman, WK and Lue, NF},
title = {Structurally distinct telomere-binding proteins in Ustilago maydis execute non-overlapping functions in telomere replication, recombination, and protection.},
journal = {Communications biology},
volume = {3},
number = {1},
pages = {777},
pmid = {33328546},
issn = {2399-3642},
support = {R01 GM107287/GM/NIGMS NIH HHS/United States ; GM107287/GM/NIGMS NIH HHS/United States ; },
mesh = {Basidiomycota/*genetics/*metabolism ; Binding Sites ; *DNA Replication ; Evolution, Molecular ; Humans ; Models, Molecular ; Protein Conformation ; Proto-Oncogene Proteins c-myb/genetics ; *Recombination, Genetic ; Repetitive Sequences, Nucleic Acid ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {Duplex telomere binding proteins exhibit considerable structural and functional diversity in fungi. Herein we interrogate the activities and functions of two Myb-containing, duplex telomere repeat-binding factors in Ustilago maydis, a basidiomycete that is evolutionarily distant from the standard fungi. These two telomere-binding proteins, UmTay1 and UmTrf2, despite having distinct domain structures, exhibit comparable affinities and sequence specificity for the canonical telomere repeats. UmTay1 specializes in promoting telomere replication and an ALT-like pathway, most likely by modulating the helicase activity of Blm. UmTrf2, in contrast, is critical for telomere protection; transcriptional repression of Umtrf2 leads to severe growth defects and profound telomere aberrations. Comparative analysis of UmTay1 homologs in different phyla reveals broad functional diversity for this protein family and provides a case study for how DNA-binding proteins can acquire and lose functions at various chromosomal locations. Our findings also point to stimulatory effect of telomere protein on ALT in Ustilago maydis that may be conserved in other systems.},
}
@article {pmid33325602,
year = {2021},
author = {Oskouei, Z and Mehri, S and Kalalinia, F and Hosseinzadeh, H},
title = {Evaluation of the effect of thymoquinone in d-galactose-induced memory impairments in rats: Role of MAPK, oxidative stress, and neuroinflammation pathways and telomere length.},
journal = {Phytotherapy research : PTR},
volume = {35},
number = {4},
pages = {2252-2266},
doi = {10.1002/ptr.6982},
pmid = {33325602},
issn = {1099-1573},
support = {940993//the Vice-Chancellor of Research, Mashhad University of Medical Sciences, Mashhad/ ; },
mesh = {Animals ; Benzoquinones/*chemistry ; Galactose/*adverse effects ; Male ; Memory Disorders/*chemically induced/*drug therapy ; Mitogen-Activated Protein Kinase Kinases/*metabolism ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Telomere Homeostasis ; },
abstract = {D-galactose (d-gal) induces aging and memory impairment via oxidative stress and neuroinflammation pathways. This study evaluated the neuroprotective activity of thymoquinone (TQ) against d-gal. d-gal (400 mg/kg, SC), d-gal plus TQ (2.5, 5, 10 mg/kg, i.p.), and TQ alone (2.5 and 10 mg/kg) for 8 weeks were administered to rats. The effect of TQ on learning and memory were studied using the Morris water maze test. Malondialdehyde (MDA) and glutathione (GSH) levels were determined in the hippocampus. The levels of MAPKs (p-ERK/ERK, p-P38/P38), cAMP response elements binding (p-CREB/CREB), advanced glycation end products (AGEs), inflammatory markers (TNFα, IL-1β), glial fibrillary acidic protein (GFAP), and brain-derived neurotrophic factor (BDNF) were analyzed by western blotting. Telomere length was evaluated using real-time PCR. Memory and learning impairment, MDA enhancement, GSH reduction, and neuroinflammation via increasing the TNFα, IL-1β, and GFAP contents were observed in d-gal group. TQ with d-gal, improved memory impairment, reduced oxidative stress, and alleviated neuroinflammation. The elevated level of AGEs decreased by TQ compared to d-gal. No changes were observed in the levels of p-ERK/ERK, p-CREB/CREB, p-P38/P38, BDNF, and telomere length following administration of d-gal or TQ plus d-gal. TQ improved memory deficits of d-gal through anti-oxidative and anti-inflammatory mechanisms.},
}
@article {pmid33324010,
year = {2020},
author = {Gao, Z and Daquinag, AC and Fussell, C and Zhao, Z and Dai, Y and Rivera, A and Snyder, BE and Eckel-Mahan, KL and Kolonin, MG},
title = {Age-associated telomere attrition in adipocyte progenitors predisposes to metabolic disease.},
journal = {Nature metabolism},
volume = {2},
number = {12},
pages = {1482-1497},
pmid = {33324010},
issn = {2522-5812},
support = {R01 LM012806/LM/NLM NIH HHS/United States ; },
mesh = {Adipocytes/*pathology ; Adipocytes, Beige/metabolism ; Adipocytes, White/metabolism ; Aging/*pathology ; Animals ; Cell Differentiation ; Cell Lineage/genetics ; Cell Proliferation ; Diet, High-Fat ; Female ; Humans ; Insulin Resistance/genetics ; Intra-Abdominal Fat ; Male ; Metabolic Diseases/metabolism/*pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Receptor, Platelet-Derived Growth Factor alpha/genetics/metabolism ; Stem Cells/*pathology ; Subcutaneous Fat/metabolism/pathology ; Telomerase/genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {White and beige adipocytes in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) are maintained by proliferation and differentiation of adipose progenitor cells (APCs). Here we use mice with tissue-specific telomerase reverse transcriptase (TERT) gene knockout (KO), which undergo premature telomere shortening and proliferative senescence in APCs, to investigate the effect of over-nutrition on APC exhaustion and metabolic dysfunction. We find that TERT KO in the Pdgfra[+] cell lineage results in adipocyte hypertrophy, inflammation and fibrosis in SAT, while TERT KO in the Pdgfrb[+] lineage leads to adipocyte hypertrophy in both SAT and VAT. Systemic insulin resistance is observed in both KO models and is aggravated by a high-fat diet. Analysis of human biopsies demonstrates that telomere shortening in SAT is associated with metabolic disease progression after bariatric surgery. Our data indicate that over-nutrition can promote APC senescence and provide a mechanistic link between ageing, obesity and diabetes.},
}
@article {pmid33323554,
year = {2020},
author = {Lee, EH and Han, MH and Ha, J and Park, HH and Koh, SH and Choi, SH and Lee, JH},
title = {Relationship between telomere shortening and age in Korean individuals with mild cognitive impairment and Alzheimer's disease compared to that in healthy controls.},
journal = {Aging},
volume = {13},
number = {2},
pages = {2089-2100},
pmid = {33323554},
issn = {1945-4589},
mesh = {Age Factors ; Aged ; Aged, 80 and over ; Aging/*genetics/metabolism ; Alzheimer Disease/*genetics ; Case-Control Studies ; Cognitive Dysfunction/*genetics ; Female ; Humans ; Leukocytes/metabolism ; Linear Models ; Male ; Middle Aged ; Multivariate Analysis ; Republic of Korea ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {Although telomere length (TL) is highly variable, a shorter TL indicate increased biological age. This multicenter study was conducted to identify the overall correlation between age and TL in Koreans and investigate the associations between age and TL in healthy individuals and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). TL was measured in peripheral leukocyte DNA. MCI and AD were diagnosed based on clinical examinations and amyloid deposition on positron emission tomography. This study enrolled 437 individuals. Multivariable linear analysis showed an overall approximate TL decrease of 37 bp per 1-year increase in age in all individuals (B=-0.037; P=0.002). There was no significant difference in the mean TL between healthy individuals and individuals with AD. Multivariable linear regression analysis showed that the mean rate of telomere shortening was 60 bp per year in individuals with AD (B=-0.060; P=0.006). There was a negative association between age and TL in our study. Our study results showed more significant telomere shortening per year in women than that in men. In addition, individuals with AD had greater telomere shortening every year than healthy individuals and individuals with MCI.},
}
@article {pmid33323545,
year = {2020},
author = {Wu, F and Huang, Y and Hu, J and Shao, Z},
title = {Mendelian randomization study of telomere length and bone mineral density.},
journal = {Aging},
volume = {13},
number = {2},
pages = {2015-2030},
pmid = {33323545},
issn = {1945-4589},
mesh = {Bone Density/*genetics ; Causality ; Humans ; Leukocytes/*metabolism ; Mendelian Randomization Analysis ; Osteoporosis/*epidemiology/genetics ; Polymorphism, Single Nucleotide ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {PURPOSE: Some epidemiological studies and animal studies have reported a relationship between leukocyte telomere length (LTL) and bone mineral density (BMD). However, the causality underlying the purported relationship has not been determined. Here we performed a two-sample MR analysis to test the causal link between telomere length and BMD.<br><br>RESULTS: Our research suggested no causal link of LTL and BMD using IVW method. The weighted median, MR-Egger regression and MR.RAPS method yielded a similar pattern of effects. MR-Egger intercept test demonstrated our results were not influenced by pleiotropy. Heterogeneities among the genetic variants on heel estimated BMD and TB-BMD vanished after excluding rs6028466. "Leave-one-out" sensitivity analysis confirmed the stability of our results.<br><br>CONCLUSION: Our MR analysis did not support causal effect of telomere length on BMD.<br><br>METHODS: We utilized 5 independent SNPs robustly associated with LTL as instrument variables. The outcome results were obtained from GWAS summary data of BMD. The two-sample MR analysis was conducted using IVW, weighted median, MR-Egger regression and MR.RAPS method. MR-Egger intercept test, Cochran's Q test and I[2] statistics and "leave-one-out" sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities and stability of these genetic variants on BMD.},
}
@article {pmid33323453,
year = {2020},
author = {Fan, Y and Zheng, C and Wu, N and Li, Y and Huang, X and Ye, Q},
title = {Telomerase gene variants and telomere shortening in patients with silicosis or asbestosis.},
journal = {Occupational and environmental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1136/oemed-2020-107046},
pmid = {33323453},
issn = {1470-7926},
abstract = {OBJECTIVES: Telomerase gene variants that lead to accelerated telomere shortening are linked to progressive-fibrosing interstitial lung diseases. However, little is known about their relationships with pneumoconiosis. This study aimed to identify TERT/TERC variants and leucocyte telomere lengths (LTL) in patients with silicosis or asbestosis.<br><br>METHODS: In the present study, Sanger sequencing of TERT/TERC variants was performed in 193 Chinese Han patients with pneumoconiosis, including 109 with silicosis and 84 with asbestosis. Quantitative PCR was used to measure LTL in peripheral blood of the patients and 200 age and sex-matched healthy controls.<br><br>RESULTS: In total, 7.3% patients with pneumoconiosis had 17 TERT/TERC variants. Among which 8.3% of patients with silicosis and 3.6% of patients with asbestosis had TERT variants, respectively. No TERC variants were detected in silicosis, whereas 3.6% of patients with asbestosis had TERC variants. Telomeres were significantly shorter in the patients with pneumoconiosis compared with healthy controls (p<0.001). No significant differences in LTL were found between TERT/TERC variant carriers and non-carriers. Exposure to silica dust was associated with the severity of pneumoconiosis after adjusting for covariates (OR 4.92, p=0.002). However, TERT/TERC variants and short telomeres were not associated with the severity of pneumoconiosis.<br><br>CONCLUSION: Telomerase gene variants and short telomeres may be identified in the patients with silicosis and asbestosis in response to the exposure to silica or asbestos dust but are not related to disease severity.},
}
@article {pmid33321495,
year = {2021},
author = {Huang, J and Peng, X and Dong, K and Tao, J and Yang, Y},
title = {The Association between Antidiabetic Agents and Leukocyte Telomere Length in the Novel Classification of Type 2 Diabetes Mellitus.},
journal = {Gerontology},
volume = {67},
number = {1},
pages = {60-68},
doi = {10.1159/000511362},
pmid = {33321495},
issn = {1423-0003},
mesh = {Acarbose/*therapeutic use ; Aged ; Cellular Senescence/drug effects ; Cluster Analysis ; *Diabetes Mellitus, Type 2/blood/classification/drug therapy ; Female ; Humans ; Hypoglycemic Agents/*therapeutic use ; *Leukocytes ; Male ; Metformin/*therapeutic use ; Telomere Homeostasis/drug effects ; Telomere Shortening/*drug effects ; Treatment Outcome ; },
abstract = {AIMS: This study aimed to explore the new role of telomere length (TL) in the novel classification of type 2 diabetes mellitus (T2DM) patients driven by cluster analysis.<br><br>MATERIALS AND METHODS: A total of 541 T2DM patients were divided into 4 subgroups by k-means analysis: mild obesity-related diabetes (MOD), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), and mild age-related diabetes (MARD). After patients with insufficient data were excluded, further analysis was conducted on 246 T2DM patients. The TL was detected using telomere restriction fragment, and the related diabetic indexes were also measured by clinical standard procedures.<br><br>RESULTS: The MARD group had significantly shorter TLs than the MOD and SIDD groups. Then, we subdivided all T2DM patients into the MARD and NONMARD groups, which included the MOD, SIDD, and SIRD groups. The TLs of the MARD group, associated with age, were discovered to be significantly shorter than those of the NONMARD group (p = 0.0012), and this difference in TL disappeared after metformin (p = 0.880) and acarbose treatment (p = 0.058). The linear analysis showed that metformin can more obviously reduce telomere shortening in the MARD group (r = 0.030, 95% CI 0.010-0.051, p = 0.004), and acarbose can more apparently promote telomere attrition in the SIRD group (r = -0.069, 95% CI -0.100 to -0.039, p< 0.001) compared with other T2DM patients after adjusting for age and gender.<br><br>CONCLUSIONS: The MARD group was found to have shorter TLs and benefit more from the antiaging effect of metformin than other T2DM. Shorter TLs were observed in the SIRD group after acarbose use.},
}
@article {pmid33321417,
year = {2021},
author = {Solek, P and Shemedyuk, N and Shemedyuk, A and Dudzinska, E and Koziorowski, M},
title = {Risk of wild fungi treatment failure: Phallus impudicus-induced telomere damage triggers p21/p53 and p16-dependent cell cycle arrest and may contribute to male fertility reduction in vitro.},
journal = {Ecotoxicology and environmental safety},
volume = {209},
number = {},
pages = {111782},
doi = {10.1016/j.ecoenv.2020.111782},
pmid = {33321417},
issn = {1090-2414},
mesh = {Agaricales/metabolism ; Apoptosis ; *Basidiomycota ; Cell Cycle ; Cell Cycle Checkpoints/drug effects ; DNA Damage ; Fertility/*drug effects ; Humans ; Male ; Mycotoxins/*toxicity ; Telomere ; Treatment Failure ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {The multifunctional characteristics of Phallus impudicus extract encourage to conduct research for its potential use in medical applications. Well, science is constantly seeking new evidence for the biological activity of extracts of natural origin. Drugs of natural origin should not cause any side effects on the physiological functions of the human body; however, this is not always successful. In this study, we used in vitro approach to evaluate the toxicity of alcohol Phallus impudicus extract on spermatogenic cells. We show, for the first time, cytotoxic properties of Phallus impudicus treatment associated with a decrease in cellular metabolic activity, dysregulation of redox homeostasis and impairment of selected antioxidant cell protection systems. As a consequence, p53/p21- and p16-mediated cell cycle arrest followed by p27 activation is initiated. The observed changes were associated with telomere shortening and numerous DNA damage at the chromosome ends (altered expression pattern of TRF1 and TRF2 proteins), as well as upregulation of cleaved caspase-3 with a decrease in Bcl-2 expression, suggesting induction of apoptotic death. Therefore, these results provide molecular evidence for mechanistic pathways and novel adverse outcomes linked to the Phallus impudicus treatment towards men's health and fertility reduction.},
}
@article {pmid33318425,
year = {2021},
author = {Corbo, RM and Businaro, R and Scarabino, D},
title = {Leukocyte telomere length and plasma interleukin-1β and interleukin-18 levels in mild cognitive impairment and Alzheimer's disease: new biomarkers for diagnosis and disease progression?.},
journal = {Neural regeneration research},
volume = {16},
number = {7},
pages = {1397-1398},
pmid = {33318425},
issn = {1673-5374},
}
@article {pmid33317189,
year = {2020},
author = {Alnafakh, R and Choi, F and Bradfield, A and Adishesh, M and Saretzki, G and Hapangama, DK},
title = {Endometriosis Is Associated with a Significant Increase in hTERC and Altered Telomere/Telomerase Associated Genes in the Eutopic Endometrium, an Ex-Vivo and In Silico Study.},
journal = {Biomedicines},
volume = {8},
number = {12},
pages = {},
pmid = {33317189},
issn = {2227-9059},
support = {RG2137//Wellbeing of Women/ ; RA thesis//Higher Committee for Education Development in Iraq/ ; Mres projects//North West Cancer Research Fund/ ; },
abstract = {Telomeres protect chromosomal ends and they are maintained by the specialised enzyme, telomerase. Endometriosis is a common gynaecological disease and high telomerase activity and higher hTERT levels associated with longer endometrial telomere lengths are characteristics of eutopic secretory endometrial aberrations of women with endometriosis. Our ex-vivo study examined the levels of hTERC and DKC1 RNA and dyskerin protein levels in the endometrium from healthy women and those with endometriosis (n = 117). The in silico study examined endometriosis-specific telomere- and telomerase-associated gene (TTAG) transcriptional aberrations of secretory phase eutopic endometrium utilising publicly available microarray datasets. Eutopic secretory endometrial hTERC levels were significantly increased in women with endometriosis compared to healthy endometrium, yet dyskerin mRNA and protein levels were unperturbed. Our in silico study identified 10 TTAGs (CDKN2A, PML, ZNHIT2, UBE3A, MCCC2, HSPC159, FGFR2, PIK3C2A, RALGAPA1, and HNRNPA2B1) to be altered in mid-secretory endometrium of women with endometriosis. High levels of hTERC and the identified other TTAGs might be part of the established alteration in the eutopic endometrial telomerase biology in women with endometriosis in the secretory phase of the endometrium and our data informs future research to unravel the fundamental involvement of telomerase in the pathogenesis of endometriosis.},
}
@article {pmid33310362,
year = {2021},
author = {Zhang, B and Liu, L and Guo, L and Guo, S and Zhao, X and Liu, G and Li, Q and Jiang, L and Pan, B and Nie, J and Yang, J},
title = {Telomere length mediates the association between polycyclic aromatic hydrocarbons exposure and abnormal glucose level among Chinese coke oven plant workers.},
journal = {Chemosphere},
volume = {266},
number = {},
pages = {129111},
doi = {10.1016/j.chemosphere.2020.129111},
pmid = {33310362},
issn = {1879-1298},
mesh = {Asian People ; *Coke/analysis ; Cross-Sectional Studies ; Glucose ; Humans ; *Occupational Exposure/analysis ; *Polycyclic Aromatic Hydrocarbons/analysis/toxicity ; Pyrenes ; Telomere ; },
abstract = {INTRODUCTION: Diabetes is a chronic and complex disease determined by environmental and genetic factors. This study aimed to investigate the association between polycyclic aromatic hydrocarbons (PAHs) exposure and fasting blood glucose levels and telomere length among coke-oven plant workers, to explore potential role of telomere length (TL) in the association between PAHs exposure and abnormal glucose level.<br><br>METHODS: The cross-sectional survey was conducted in 2017. The high-performance liquid chromatography mass spectrometry (HPLC-MS) was used to detect 11 urine biomarkers of PAHs exposure. TL was measured using the Real-time quantitative polymerase chain reaction (RT-qPCR) method. Logistic regression model, the modified Poisson regression models, and mediation analysis were used to evaluate the associations between PAHs exposure, TL, and abnormal glucose.<br><br>RESULTS: The results showed that the urinary 1-hydroxypyrene (1-PYR) was positively related to abnormal glucose in a dose-dependent manner (Ptrend&#xa0;=&#xa0;0.007), the prevalence ratio of abnormal glucose was 8% (95% CI: 1.01-1.16) higher in 3rd tertile of urinary 1-PYR levels. Urinary 1-PYR in the 2nd tertile and 3rd tertile were associated with a 53% (OR&#xa0;=&#xa0;0.47, 95% CI: 0.28-0.79) and 59% (OR&#xa0;=&#xa0;0.41, 95% CI: 0.23-0.76) higher risk of shortening TL. And there was a negatively association between 1-PYR and TL in a dose-dependent manner (Ptrend&#xa0;=&#xa0;0.045). We observed that the association between 1-PYR and abnormal glucose was more significantly positive among participants with median TL level (Ptrend&#xa0;=&#xa0;0.006). In addition, mediation analysis showed the TL could explain 11.7% of the effect of abnormal glucose related to PAHs exposure.<br><br>CONCLUSIONS: Our findings suggested the effect of abnormal glucose related to PAHs exposure was mediated by telomere length in coke oven plant workers.},
}
@article {pmid33310082,
year = {2021},
author = {Uppuluri, L and Varapula, D and Young, E and Riethman, H and Xiao, M},
title = {Single-molecule telomere length characterization by optical mapping in nano-channel array: Perspective and review on telomere length measurement.},
journal = {Environmental toxicology and pharmacology},
volume = {82},
number = {},
pages = {103562},
pmid = {33310082},
issn = {1872-7077},
support = {R01 HG005946/HG/NHGRI NIH HHS/United States ; R21 CA177395/CA/NCI NIH HHS/United States ; },
mesh = {*High-Throughput Screening Assays ; Humans ; Nanotechnology ; *Telomere ; },
abstract = {In humans, the telomere consists of tandem 5'TTAGGG3' DNA repeats on both ends of all 46 chromosomes. Telomere shortening has been linked to aging and age-related diseases. Similarly, telomere length changes have been associated with chemical exposure, molecular-level DNA damage, and tumor development. Telomere elongation has been associated to tumor development, caused due to chemical exposure and molecular-level DNA damage. The methods used to study these effects mostly rely on average telomere length as a biomarker. The mechanisms regulating subtelomere-specific and haplotype-specific telomere lengths in humans remain understudied and poorly understood, primarily because of technical limitations in obtaining these data for all chromosomes. Recent studies have shown that it is the short telomeres that are crucial in preserving chromosome stability. The identity and frequency of specific critically short telomeres potentially is a useful biomarker for studying aging, age-related diseases, and cancer. Here, we will briefly review the role of telomere length, its measurement, and our recent single-molecule telomere length measurement assay. With this assay, one can measure individual telomere lengths as well as identify their physically linked subtelomeric DNA. This assay can also positively detect telomere loss, characterize novel subtelomeric variants, haplotypes, and previously uncharacterized recombined subtelomeres. We will also discuss its applications in aging cells and cancer cells, highlighting the utility of the single molecule telomere length assay.},
}
@article {pmid33309414,
year = {2021},
author = {Chen, L and Shivappa, N and Dong, X and Ming, J and Zhao, Q and Xu, H and Liang, P and Cheng, M and Liu, J and Sun, P and Ban, B},
title = {Association between appendicular skeletal muscle index and leukocyte telomere length in adults: A study from National Health and Nutrition Examination Survey (NHANES) 1999-2002.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {40},
number = {5},
pages = {3470-3478},
doi = {10.1016/j.clnu.2020.11.031},
pmid = {33309414},
issn = {1532-1983},
mesh = {Adult ; Aging/physiology ; Body Composition/*physiology ; Body Mass Index ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/*cytology ; Male ; Middle Aged ; Muscle, Skeletal/*physiology ; Nutrition Surveys ; Telomere/*genetics ; },
abstract = {BACKGROUND: A higher body mass index (BMI) is associated with shorter telomeres. The loss of muscle mass with aging is associated with adverse outcomes. The appendicular skeletal muscle index (ASMI) is currently used to quantify muscle mass.<br><br>OBJECTIVE: We investigated the association of the ASMI with leukocyte telomere length in adult Americans.<br><br>METHODS: This cross-sectional study used the National Health and Nutrition Examination Survey (NHANES) 1999-2002 dataset. Body composition was measured by dual-energy X-ray absorptiometry. Low muscle mass was defined using sex-specific thresholds of the appendicular skeletal muscle mass index (ASMI). The telomere-to-single-copy gene ratio (T/S ratio) was converted to base pairs. Generalized linear models were performed to evaluate the association of ASMI with telomere length.<br><br>RESULTS: In multivariable adjustment regression models, higher ASMI was associated with longer telomeres in US adults (&#x3b2;&#xa0;=&#xa0;70.2, P&#xa0;<&#xa0;0.001, P trend<0.001). In participants with preserved muscle mass, the ASMI was related to longer telomere length (&#x3b2;&#xa0;=&#xa0;75.1, P&#xa0;<&#xa0;0.001), but not significantly in low muscle mass participants (&#x3b2;&#xa0;=&#xa0;68.7, P&#xa0;=&#xa0;0.30). Further subgroup analysis by a combination of age groups and muscle mass status showed positive association with young-preserved muscle mass (&#x3b2;&#xa0;=&#xa0;82.6, P&#xa0;<&#xa0;0.001), old-preserved muscle mass (&#x3b2;&#xa0;=&#xa0;44.4, P&#xa0;=&#xa0;0.12), young-low muscle mass (&#x3b2;&#xa0;=&#xa0;135.4, P&#xa0;=&#xa0;0.20), and old-low muscle mass (&#x3b2;&#xa0;=&#xa0;52.7, P&#xa0;=&#xa0;0.55). Because each additional year of chronological age was associated with telomeres that were 15.3 base pairs shorter, on average, this would equate to 5.4 fewer years of biological aging (82.6&#xa0;&#xf7;&#xa0;15.3) in the young-preserved muscle mass participants.<br><br>CONCLUSIONS: A higher ASMI is associated with longer telomeres. The prevention of skeletal muscle loss has the potential to delay telomere shortening and account for less biological aging.},
}
@article {pmid33301453,
year = {2020},
author = {Izano, MA and Cushing, LJ and Lin, J and Eick, SM and Goin, DE and Epel, E and Woodruff, TJ and Morello-Frosch, R},
title = {The association of maternal psychosocial stress with newborn telomere length.},
journal = {PloS one},
volume = {15},
number = {12},
pages = {e0242064},
pmid = {33301453},
issn = {1932-6203},
support = {UH3 OD023272/OD/NIH HHS/United States ; UG3 OD023272/OD/NIH HHS/United States ; P30 ES030284/ES/NIEHS NIH HHS/United States ; P01 ES022841/ES/NIEHS NIH HHS/United States ; P20 ES018135/ES/NIEHS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Female ; Fetal Blood/cytology ; Humans ; Infant, Newborn ; Leukocytes/metabolism ; Male ; Maternal Health/*statistics &amp; numerical data ; Pregnancy ; Pregnant Women/*psychology ; Prenatal Exposure Delayed Effects/*genetics ; Stress, Psychological/complications/*epidemiology/genetics/physiopathology ; Telomere/metabolism ; Telomere Homeostasis/physiology ; *Telomere Shortening ; Young Adult ; },
abstract = {BACKGROUND: Telomere length in early life predicts later length, and shortened telomere length among adults and children has been linked to increased risk of chronic disease and mortality. Maternal stress during pregnancy may impact telomere length of the newborn.<br><br>METHODS: In a diverse cohort of 355 pregnant women receiving prenatal and delivery care services at two hospitals in San Francisco, California, we investigated the relationship between self-reported maternal psychosocial stressors during the 2nd trimester of pregnancy and telomere length (T/S ratio) in newborn umbilical cord blood leukocytes. We examined financial strain, food insecurity, high job strain, poor neighborhood quality, low standing in one's community, experience of stressful/traumatic life events, caregiving for a dependent family member, perceived stress, and unplanned pregnancy. We used linear regression and Targeted Minimum Loss-Based Estimation (TMLE) to evaluate the change in the T/S ratio associated with exposure to each stressor controlling for maternal age, education, parity, race/ethnicity, and delivery hospital.<br><br>RESULTS: In TMLE analyses, low community standing (-0.09; 95% confidence interval [CI]-0.19 to 0.00) and perceived stress (-0.07; 95% CI -0.15 to 0.021 was marginally associated with shorter newborn telomere length, but the associations were not significant after adjusting for multiple comparisons. All linear regression estimates were not statistically significant. Our results also suggest that the association between some maternal stressors and newborn telomere length varies by race/ethnicity and infant sex.<br><br>CONCLUSIONS: This study is the first to examine the joint effect of multiple stressors during pregnancy on newborn TL using a flexible modeling approach.},
}
@article {pmid33300081,
year = {2021},
author = {Li, H and Wang, B and Li, D and Li, J and Luo, Y and Dan, J},
title = {Roles of telomeres and telomerase in age‑related renal diseases (Review).},
journal = {Molecular medicine reports},
volume = {23},
number = {2},
pages = {},
pmid = {33300081},
issn = {1791-3004},
mesh = {Aging/genetics/*metabolism/pathology ; Humans ; Kidney Diseases/genetics/*metabolism/pathology/therapy ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism/pathology ; *Telomere Homeostasis ; },
abstract = {Age‑related renal diseases, which account for various progressive renal disorders associated with cellular and organismal senescence, are becoming a substantial public health burden. However, their aetiologies are complicated and their pathogeneses remain poorly understood. Telomeres and telomerase are known to be essential for maintaining the integrity and stability of eukaryotic genomes and serve crucial roles in numerous related signalling pathways that activate renal functions, such as repair and regeneration. Previous studies have reported that telomere dysfunction served a role in various types of age‑related kidney disease through various different molecular pathways. The present review aimed to summarise the current knowledge of the association between telomeres and ageing‑related kidney diseases and explored the contribution of dysfunctional telomeres to these diseases. The findings may help to provide novel strategies for treating patients with renal disease.},
}
@article {pmid33296627,
year = {2020},
author = {Cherfils-Vicini, J and Gilson, &#xc9;},
title = {[Longevity clocks: The promoting role of telomeres?].},
journal = {Medecine sciences : M/S},
volume = {36},
number = {12},
pages = {1113-1117},
doi = {10.1051/medsci/2020242},
pmid = {33296627},
issn = {1958-5381},
mesh = {Aging/genetics/physiology ; Animals ; Cellular Senescence/genetics ; Circadian Clocks/genetics/*physiology ; Humans ; Longevity/*genetics ; Telomere/*physiology ; },
abstract = {Aging is an alteration of our physiological capacities that is accompanied by an increased susceptibility to develop a wide range of diseases and which determines in large part our longevity. Despite intensive research on the origin of aging, its etiology is still poorly understood. We discuss here the hypothesis that the telomere shortening, programmed to start at the end of embryogenesis in numerous tissues, couples development with aging by a time-dependent regulation of a set of interconnected processes essential for the somatic maintenance of genome, epigenome, metabolism, circadian clock and immunity.},
}
@article {pmid33293233,
year = {2021},
author = {Lee, JJ and Lee, J and Lee, H},
title = {Alternative paths to telomere elongation.},
journal = {Seminars in cell &amp; developmental biology},
volume = {113},
number = {},
pages = {88-96},
doi = {10.1016/j.semcdb.2020.11.003},
pmid = {33293233},
issn = {1096-3634},
mesh = {Cellular Senescence/*genetics ; Humans ; Recombination, Genetic/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Overcoming cellular senescence that is induced by telomere shortening is critical in tumorigenesis. A majority of cancers achieve telomere maintenance through telomerase expression. However, a subset of cancers takes an alternate route for elongating telomeres: recombination-based alternative lengthening of telomeres (ALT). Current evidence suggests that break-induced replication (BIR), independent of RAD51, underlies ALT telomere synthesis. However, RAD51-dependent homologous recombination is required for homology search and inter-chromosomal telomere recombination in human ALT cancer cell maintenance. Accumulating evidence suggests that the breakdown of stalled replication forks, the replication stress, induces BIR at telomeres. Nevertheless, ALT research is still in its early stage and a comprehensive view is still unclear. Here, we review the current findings regarding the genesis of ALT, how this recombinant pathway is chosen, the epigenetic regulation of telomeres in ALT, and perspectives for clinical applications with the hope that this overview will generate new questions.},
}
@article {pmid33292353,
year = {2020},
author = {Noppert, GA and Feinstein, L and Dowd, JB and Stebbins, RC and Zang, E and Needham, BL and Meier, HCS and Simanek, A and Aiello, AE},
title = {Pathogen burden and leukocyte telomere length in the United States.},
journal = {Immunity &amp; ageing : I &amp; A},
volume = {17},
number = {1},
pages = {36},
pmid = {33292353},
issn = {1742-4933},
support = {P30 AG021342/AG/NIA NIH HHS/United States ; K99AG062749-01A1/AG/NIA NIH HHS/United States ; AG000029-41/AG/NIA NIH HHS/United States ; T32 HD007168/HD/NICHD NIH HHS/United States ; R01AG033592/AG/NIA NIH HHS/United States ; T32 HD091058/HD/NICHD NIH HHS/United States ; T32 AG000029/AG/NIA NIH HHS/United States ; P2C HD050924/HD/NICHD NIH HHS/United States ; },
abstract = {BACKGROUND: Prior studies in humans have suggested that telomere shortening may be accelerated by infection, but research on multiple pathogens and use of large population-based study samples has been limited. We estimated cross-sectional associations between seropositivity to five persistent pathogens (Herpes Simplex Virus Type-1 (HSV-1), Herpes Simplex Virus Type-2 (HSV-2), cytomegalovirus (CMV), Helicobacter pylori (H.pylori), and Hepatitis B) as well as total pathogen burden and leukocyte telomere length. Data were derived from the National Health and Nutrition Examination Survey (1999-2000) for individuals 20-49 years of age, N = 1708. We analyzed the influence of each pathogen separately, a pathogen count score and a latent class model of pathogen burden on log telomere length using linear regression models, adjusted for covariates.<br><br>RESULTS: Individuals in a latent&#xa0;pathogen burden class characterized by high probabilities of infection with HSV-1, CMV, and H. pylori, had significantly decreased log telomere length (-&#x2009;0.30 [95% CI: -&#x2009;0.36, -&#x2009;0.24]) compared to those in a latent class characterized by low probabilities of all five infections. There were limited significant associations using other pathogen measures.<br><br>CONCLUSIONS: These results suggest that infection with specific combinations of pathogens may be one mechanism contributing to accelerated cellular senescence with possible origins early in the life course.},
}
@article {pmid33289498,
year = {2021},
author = {Thomas, MD and Sohail, S and Mendez, RM and Márquez-Magaña, L and Allen, AM},
title = {Racial Discrimination and Telomere Length in Midlife African American Women: Interactions of Educational Attainment and Employment Status.},
journal = {Annals of behavioral medicine : a publication of the Society of Behavioral Medicine},
volume = {55},
number = {7},
pages = {601-611},
pmid = {33289498},
issn = {1532-4796},
support = {P60 MD006902/MD/NIMHD NIH HHS/United States ; UL1 GM118985/GM/NIGMS NIH HHS/United States ; },
mesh = {Adult ; Black or African American/*ethnology/statistics &amp; numerical data ; Aging/ethnology ; Cellular Senescence/*physiology ; *Educational Status ; *Employment ; Female ; Humans ; Middle Aged ; Racism/*ethnology/statistics &amp; numerical data ; San Francisco/epidemiology ; *Social Class ; Telomere Shortening/*physiology ; Women's Health/ethnology ; },
abstract = {BACKGROUND: Over the life course, African American (AA) women have faster telomere attrition, a biological indicator of accelerated aging, than White women. Race, sex, age, and composite socioeconomic status (SES) modify associations of institutional racial discrimination and telomere length. However, interactions with everyday racial discrimination have not been detected in AA women, nor have interactions with individual socioeconomic predictors.<br><br>PURPOSE: We estimated statistical interaction of institutional and everyday racial discrimination with age, education, employment, poverty, and composite SES on telomere length among midlife AA women.<br><br>METHODS: Data are from a cross-section of 140 AA women aged 30-50 years residing in the San Francisco Bay Area. Participants completed questionnaires, computer-assisted self-interviews, physical examinations, and blood draws. Adjusted linear regression estimated bootstrapped racial discrimination-relative telomere length associations with interaction terms.<br><br>RESULTS: Racial discrimination did not interact with age, poverty, or composite SES measures to modify associations with telomere length. Interactions between independent SES variables were nonsignificant for everyday discrimination whereas institutional discrimination interacted with educational attainment and employment status to modify telomere length. After adjusting for covariates, we found that higher institutional discrimination was associated with shorter telomeres among employed women with lower education (&#x3b2; = -0.020; 95% confidence interval = -0.036, -0.003). Among unemployed women with higher education, higher institutional discrimination was associated with longer telomeres (&#x3b2; = 0.017; 95% confidence interval = 0.003, 0.032). Factors related to having a post-high school education may be protective against the negative effects of institutional racism on cellular aging for AA women.},
}
@article {pmid33287595,
year = {2022},
author = {Samuel, P and Tsapekos, M and de Pedro, N and Liu, AG and Casey Lippmeier, J and Chen, S},
title = {Ergothioneine Mitigates Telomere Shortening under Oxidative Stress Conditions.},
journal = {Journal of dietary supplements},
volume = {19},
number = {2},
pages = {212-225},
doi = {10.1080/19390211.2020.1854919},
pmid = {33287595},
issn = {1939-022X},
mesh = {*Ergothioneine/metabolism ; Humans ; Hydrogen Peroxide ; In Situ Hybridization, Fluorescence ; Oxidative Stress ; Telomere/metabolism ; *Telomere Shortening ; },
abstract = {Shortened telomeres are associated with aging and age-related diseases. Oxidative stress is thought to be a major contributor to telomere shortening, and antioxidants may be able to mitigate these effects. Ergothioneine is a naturally occurring amino acid with potent antioxidant properties. In order to investigate ergothioneine's effects on telomere length, we cultured primary human fibroblasts under standard and oxidative (10 µM H2O2) conditions and treated cells with 0.04, 0.1, 0.3, or 1.0 mg/ml ergothioneine for 8 weeks. Telomere length measurements were performed using high-throughput quantitative fluorescent in situ hybridization (HT Q-FISH). Treatment with ergothioneine transiently increased relative telomerase activity after 24 h (p < 0.05 for all concentrations). Under oxidative conditions, ergothioneine treatment resulted in significantly longer median telomere length and 20[th] percentile telomere length, and significantly reduced the percentage of short telomeres (<3 kilobase pairs) for all treatment concentrations after 8 weeks. Telomere shortening rate was also reduced. Overall, ergothioneine demonstrated beneficial effects by decreasing the rate of telomere shortening and preserving telomere length under oxidative stress conditions. Our data support a potential role for ergothioneine in oxidative stress-related conditions and healthy aging.},
}
@article {pmid33285115,
year = {2021},
author = {Nayis, A and Liebl, K and Frost, CV and Zacharias, M},
title = {Targeting Telomeres: Molecular Dynamics and Free Energy Simulation of Gold-Carbene Binding to DNA.},
journal = {Biophysical journal},
volume = {120},
number = {1},
pages = {101-108},
pmid = {33285115},
issn = {1542-0086},
mesh = {DNA ; *G-Quadruplexes ; Gold ; Ligands ; Methane/analogs &amp; derivatives ; *Molecular Dynamics Simulation ; Telomere ; },
abstract = {DNA sequences in regulatory regions and in telomers at the ends of chromosomes frequently contain tandem repeats of guanine nucleotides that can form stacked structures stabilized by Hoogsten pairing and centrally bound monovalent cations. The replication and elongation of telomeres requires the disruption of these G-quadruplex structures. Hence, drug molecules such as gold (Au)-carbene that stabilize G-quadruplexes may also interfere with the elongation of telomeres and, in turn, could be used to control cell replication and growth. To better understand the molecular mechanism of Au-carbene binding to G-quadruplexes, we employed molecular dynamics simulations and free energy simulations. Whereas very restricted mobility of two Au-carbene ligands was found upon binding as a doublet to one side of the G-quadruplex, much larger translational and orientational mobility was observed for a single Au-carbene binding at the second G-quadruplex surface. Comparative simulations on duplex DNA in the presence of Au-carbene ligands indicates a preference for the minor groove and weaker unspecific and more salt-dependent binding than to the G-quadruplex surface. Analysis of energetic contributions reveals a dominance of nonpolar and van der Waals interactions to drive binding. The simulations can also be helpful for proposing possible modifications that could improve Au-carbene affinity and specificity for G-quadruplex binding.},
}
@article {pmid33280738,
year = {2020},
author = {van Moorsel, CHM},
title = {Putting Genetics Into Practice: Challenges Associated With the Genetics of Short Telomere Syndromes.},
journal = {Chest},
volume = {158},
number = {6},
pages = {2249-2250},
doi = {10.1016/j.chest.2020.09.071},
pmid = {33280738},
issn = {1931-3543},
mesh = {Cell Cycle Proteins ; Humans ; Nuclear Proteins ; *Pulmonary Fibrosis ; RNA ; Silent Mutation ; Syndrome ; *Telomerase/genetics ; Telomere/genetics ; },
}
@article {pmid33276807,
year = {2020},
author = {Alhareeri, AA and Archer, KJ and Fu, H and Lyon, DE and Elswick, RK and Kelly, DL and Starkweather, AR and Elmore, LW and Bokhari, YA and Jackson-Cook, CK},
title = {Telomere lengths in women treated for breast cancer show associations with chemotherapy, pain symptoms, and cognitive domain measures: a longitudinal study.},
journal = {Breast cancer research : BCR},
volume = {22},
number = {1},
pages = {137},
pmid = {33276807},
issn = {1465-542X},
support = {R01 NR012667/NR/NINR NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Aged ; Aging/genetics ; Antineoplastic Combined Chemotherapy Protocols/*adverse effects ; Breast Neoplasms/diagnosis/*drug therapy ; Cancer Survivors/psychology/statistics &amp; numerical data ; Cognitive Dysfunction/diagnosis/epidemiology/*genetics ; Female ; Humans ; Karyotyping ; Longitudinal Studies ; Middle Aged ; Pain/diagnosis/epidemiology/*genetics ; Pain Measurement ; Quality of Life ; Telomere/metabolism ; Telomere Homeostasis/*drug effects ; Time Factors ; Young Adult ; },
abstract = {BACKGROUND: Survival rates for breast cancer (BC) have improved, but quality of life post-diagnosis/treatment can be adversely affected, with survivors reporting a constellation of psychoneurological symptoms (PNS) including stress, anxiety, depression, pain, fatigue, sleep disturbance, and cognitive dysfunction.<br><br>METHODS: To assess a potential relationship between telomere length (TL) and the development/persistence of PNS, we longitudinally studied 70 women (ages 23-71) with early stage BC (I-IIIA) at 5 time-points: prior to treatment (baseline), the mid-point of their chemotherapy cycle, 6&#x2009;months, 1&#x2009;year, and 2&#x2009;years following the initiation of chemotherapy. Measures quantified included assessments of each of the PNS noted above and TL [using both a multiplex qPCR assay and a chromosome-specific fluorescence in situ hybridization (FISH) assay].<br><br>RESULTS: Variables associated with qPCR mean TLs were age (p&#x2009;=&#x2009;0.004) and race (T/S ratios higher in Blacks than Whites; p&#x2009;=&#x2009;0.019). Significant differences (mostly decreases) in chromosome-specific TLs were identified for 32 of the 46 chromosomal arms at the mid-chemo time-point (p&#x2009;=&#x2009;0.004 to 0.049). Unexpectedly, the sequential administration of doxorubicin [Adriamycin], cyclophosphamide [Cytoxan], and docetaxel [Taxotere] (TAC regimen) was consistently associated with higher TLs, when compared to TLs in women receiving a docetaxel [Taxotere], Carboplatin [Paraplatin], and trastuzumab [Herceptin] [TCH] chemotherapy regimen [association was shown with both the qPCR and FISH assays (p&#x2009;=&#x2009;0.036)]. Of the PNS, pain was significantly negatively associated with TL (higher pain; shorter telomeres) for a subset of chromosomal arms (5q, 8p, 13p, 20p, 22p, Xp, Xq) (p&#x2009;=&#x2009;0.014-0.047). Chromosomal TLs were also associated with 7 of the 8 cognitive domains evaluated, with the strongest relationship being noted for chromosome 17 and the visual memory domain (shorter telomeres; lower scores).<br><br>CONCLUSIONS: We showed that race and age were significantly associated with telomere length in women treated for early stage BC and that acquired telomere alterations differed based on the woman's treatment regimen. Our study also demonstrated that pain and cognitive domain measures were significantly related to telomere values in this study cohort. Expanding upon the knowledge gained from this longitudinal study could provide insight about the biological cascade of events that contribute to PNS related to BC and/or its treatment.},
}
@article {pmid33276262,
year = {2021},
author = {Brown, R and Hailu, EM and Needham, BL and Roux, AD and Seeman, TE and Lin, J and Mujahid, MS},
title = {Neighborhood social environment and changes in leukocyte telomere length: The Multi-Ethnic Study of Atherosclerosis (MESA).},
journal = {Health &amp; place},
volume = {67},
number = {},
pages = {102488},
doi = {10.1016/j.healthplace.2020.102488},
pmid = {33276262},
issn = {1873-2054},
support = {N01HC95169/HL/NHLBI NIH HHS/United States ; R01 HL076831/HL/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; R01 HL101161/HL/NHLBI NIH HHS/United States ; },
mesh = {*Atherosclerosis/genetics ; Humans ; Leukocytes ; Longitudinal Studies ; Middle Aged ; Residence Characteristics ; Social Environment ; Socioeconomic Factors ; *Telomere ; },
abstract = {Given limited research on the impact of neighborhood environments on accelerated biological aging, we examined whether changes in neighborhood socioeconomic and social conditions were associated with change in leukocyte telomere length using 10 years of longitudinal data from the Multi-Ethnic Study of Atherosclerosis (years 2000-2011; N = 1031; mean age = 61, SD = 9.4). Leukocyte telomere length change was corrected for regression to the mean and neighborhood was defined as census tract. Neighborhood socioeconomic indicators (factor-based score of income, education, occupation, and wealth of neighborhood) and neighborhood social environment indicators (aesthetic quality, social cohesion, safety) were obtained from the U.S Census/American Community Survey and via study questionnaire, respectively. Results of linear mixed-effects models showed that independent of individual sociodemographic characteristics, each unit of improvement in neighborhood socioeconomic status was associated with slower telomere length attrition over 10-years (β = 0.002; 95% Confidence Interval (CI): 0.0001, 0.004); whereas each unit of increase in safety (β = -0.043; 95% CI: -0.069, -0.016) and overall neighborhood social environment score (β = -0.005; 95% CI: -0.009, -0.0004) were associated with more pronounced telomere attrition, after additionally adjusting for neighborhood socioeconomic status. This study provides support for considerations of the broader social and socioeconomic contexts in relation to biological aging. Future research should explore potential psychosocial mechanisms underlying these associations using longitudinal study designs with repeated observations.},
}
@article {pmid33275732,
year = {2020},
author = {Schratz, KE},
title = {Extrahematopoietic manifestations of the short telomere syndromes.},
journal = {Hematology. American Society of Hematology. Education Program},
volume = {2020},
number = {1},
pages = {115-122},
pmid = {33275732},
issn = {1520-4383},
support = {R01 CA225027/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Female ; *Growth Disorders/diagnosis/genetics/metabolism/pathology ; Humans ; *Hypercalcemia/diagnosis/genetics/metabolism/pathology ; *Metabolic Diseases/diagnosis/genetics/metabolism/pathology ; Mice ; Middle Aged ; *Nephrocalcinosis/diagnosis/genetics/metabolism/pathology ; *Telomere/genetics/metabolism/pathology ; },
abstract = {The short telomere syndromes encompass a spectrum of clinical manifestations that present from infancy to late adulthood. They are caused by mutations in telomerase and other telomere maintenance genes and have a predominantly degenerative phenotype characterized by organ failure across multiple systems. They are collectively one of the most common inherited bone marrow failure syndromes; however, their most prevalent presentations are extrahematopoietic. This review focuses on these common nonhematologic complications, including pulmonary fibrosis, liver pathology, and immunodeficiency. The short telomere syndrome diagnosis informs clinical care, especially in guiding diagnostic evaluations as well as in the solid organ transplant setting. Early recognition allows an individualized approach to screening and management. This review illustrates a myriad of extrahematopoietic presentations of short telomere syndromes and how they impact clinical decisions.},
}
@article {pmid33272640,
year = {2021},
author = {Hanson, BM and Tao, X and Zhan, Y and Kim, JG and Klimczak, AM and Herlihy, NS and Scott, RT and Seli, E},
title = {Shorter telomere length of white blood cells is associated with higher rates of aneuploidy among infertile women undergoing in vitro fertilization.},
journal = {Fertility and sterility},
volume = {115},
number = {4},
pages = {957-965},
doi = {10.1016/j.fertnstert.2020.09.164},
pmid = {33272640},
issn = {1556-5653},
mesh = {Adult ; *Aneuploidy ; Cohort Studies ; Female ; Fertilization in Vitro/methods/*trends ; Humans ; Infertility, Female/diagnosis/*genetics/*therapy ; Leukocytes/*physiology ; Ovulation Induction/methods/trends ; Prospective Studies ; Sperm Injections, Intracytoplasmic/methods/trends ; Telomere Homeostasis/*physiology ; },
abstract = {OBJECTIVE: To evaluate whether the telomere length of white blood cells (WBC) and cumulus cells (CC) in an infertile population is associated with ovarian and embryonic performance.<br><br>DESIGN: Prospective cohort study.<br><br>SETTING: Academic-affiliated private practice.<br><br>PATIENTS: A total of 175 infertile women undergoing in&#xa0;vitro fertilization (IVF) at a single center between July 2017 and December&#xa0;2018.<br><br>INTERVENTIONS: On the day of oocyte retrieval, genomic DNA was isolated from WBC and CC samples. Telomere length assessment was performed for both tissue types using quantitative real-time polymerase chain reaction. Telomere lengths were normalized using an AluYa5 sequence as an endogenous control, and linear regressions were applied.<br><br>MAIN OUTCOME MEASURES: This study assessed the relationship between relative telomere length of WBC and CC samples and measures of ovarian and embryonic performance. Specifically, patient age, antim&#xfc;llerian hormone (AMH) level, peak estradiol (E2) level, number of oocytes retrieved, number of mature (MII) oocytes retrieved, blastulation rate, and aneuploidy rate were assessed.<br><br>RESULTS: There was a statistically significant relationship between WBC relative telomere length and patient age as well as rates of embryonic aneuploidy, with shorter WBC relative telomere length associated with increasing patient age (P<.01) and higher rates of aneuploidy (P=.01). No statistically significant relationships were observed between WBC relative telomere length and the other outcome measures. No significant associations were noted between CC relative telomere length and any outcomes assessed in this study.<br><br>CONCLUSION: The relationship between WBC relative telomere length and aneuploidy warrants further investigation, particularly because significant overlap exists between increasing maternal age and rates of embryonic aneuploidy.},
}
@article {pmid33272625,
year = {2021},
author = {M'kacher, R and Colicchio, B and Marquet, V and Borie, C and Najar, W and Hempel, WM and Heidingsfelder, L and Oudrhiri, N and Al Jawhari, M and Wilhelm-Murer, N and Miguet, M and Dieterlen, A and Deschênes, G and Tabet, AC and Junker, S and Grynberg, M and Fenech, M and Bennaceur-Griscelli, A and Voisin, P and Carde, P and Jeandidier, E and Yardin, C},
title = {Telomere aberrations, including telomere loss, doublets, and extreme shortening, are increased in patients with infertility.},
journal = {Fertility and sterility},
volume = {115},
number = {1},
pages = {164-173},
doi = {10.1016/j.fertnstert.2020.07.005},
pmid = {33272625},
issn = {1556-5653},
mesh = {Adult ; Case-Control Studies ; Chromosomal Instability/physiology ; *Chromosome Aberrations/statistics &amp; numerical data ; Chromosome Duplication/physiology ; Cytogenetic Analysis/methods ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Infertility/epidemiology/etiology/*genetics ; Male ; Middle Aged ; Retrospective Studies ; Telomere/*genetics ; Telomere Shortening/genetics/*physiology ; Young Adult ; },
abstract = {OBJECTIVE: To test the hypothesis that telomere shortening and/or loss are risk factors for infertility.<br><br>DESIGN: Retrospective analysis of the telomere status in patients with infertility using conventional cytogenetic data collected prospectively.<br><br>SETTING: Academic centers.<br><br>PATIENT(S): Cytogenetic slides with cultured peripheral lymphocytes from 50 patients undergoing fertility treatment and 150 healthy donors, including 100 donors matched for age.<br><br>INTERVENTION(S): Cytogenetic slides were used to detect chromosomal and telomere aberrations.<br><br>MAIN OUTCOME MEASURE(S): Telomere length and telomere aberrations were analyzed after telomere and centromere staining.<br><br>RESULT(S): The mean telomere length of patients consulting for infertility was significantly less than that of healthy donors of similar age. Moreover, patients with infertility showed significantly more extreme telomere loss and telomere doublet formation than healthy controls. Telomere shortening and/or telomere aberrations were more pronounced in patients with structural chromosomal aberrations. Dicentric chromosomes were identified in 6/13 patients, with constitutional chromosomal aberrations leading to chromosomal instability that correlated with chromosomal end-to-end fusions.<br><br>CONCLUSION(S): Our findings demonstrate the feasibility of analyzing telomere aberrations in addition to chromosomal aberrations, using cytogenetic slides. Telomere attrition and/or dysfunction represent the main common cytogenetic characteristic of patients with infertility, leading to potential implications for fertility assessment. Pending further studies, these techniques that correlate the outcome of assisted reproduction and telomere integrity status may represent a novel and useful diagnostic and/or prognostic tool for medical care in this field.},
}
@article {pmid33270890,
year = {2020},
author = {Liu, JC and Li, QJ and He, MH and Hu, C and Dai, P and Meng, FL and Zhou, BO and Zhou, JQ},
title = {Swc4 positively regulates telomere length independently of its roles in NuA4 and SWR1 complexes.},
journal = {Nucleic acids research},
volume = {48},
number = {22},
pages = {12792-12803},
pmid = {33270890},
issn = {1362-4962},
mesh = {Adenosine Triphosphatases/*genetics ; Chromatin/genetics ; DNA-Binding Proteins/genetics ; Gene Expression Regulation, Fungal/genetics ; Histone Acetyltransferases/*genetics ; Histones/genetics ; Humans ; Multiprotein Complexes/genetics ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/*genetics ; Telomerase/genetics ; Telomere/genetics ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/genetics ; },
abstract = {Telomeres at the ends of eukaryotic chromosomes are essential for genome integrality and stability. In order to identify genes that sustain telomere maintenance independently of telomerase recruitment, we have exploited the phenotype of over-long telomeres in the cells that express Cdc13-Est2 fusion protein, and examined 195 strains, in which individual non-essential gene deletion causes telomere shortening. We have identified 24 genes whose deletion results in dramatic failure of Cdc13-Est2 function, including those encoding components of telomerase, Yku, KEOPS and NMD complexes, as well as quite a few whose functions are not obvious in telomerase activity regulation. We have characterized Swc4, a shared subunit of histone acetyltransferase NuA4 and chromatin remodeling SWR1 (SWR1-C) complexes, in telomere length regulation. Deletion of SWC4, but not other non-essential subunits of either NuA4 or SWR1-C, causes significant telomere shortening. Consistently, simultaneous disassembly of NuA4 and SWR1-C does not affect telomere length. Interestingly, inactivation of Swc4 in telomerase null cells accelerates both telomere shortening and senescence rates. Swc4 associates with telomeric DNA in vivo, suggesting a direct role of Swc4 at telomeres. Taken together, our work reveals a distinct role of Swc4 in telomere length regulation, separable from its canonical roles in both NuA4 and SWR1-C.},
}
@article {pmid33269665,
year = {2020},
author = {Ackerson, SM and Gable, CI and Stewart, JA},
title = {Human CTC1 promotes TopBP1 stability and CHK1 phosphorylation in response to telomere dysfunction and global replication stress.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {19},
number = {24},
pages = {3491-3507},
pmid = {33269665},
issn = {1551-4005},
support = {P20 GM109091/GM/NIGMS NIH HHS/United States ; R00 GM104409/GM/NIGMS NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins/metabolism ; Carrier Proteins/*chemistry/genetics/*metabolism ; Cell Proliferation/genetics ; Checkpoint Kinase 1/*metabolism ; DNA Damage/genetics ; DNA Replication/*genetics ; DNA, Single-Stranded/*metabolism ; DNA-Binding Proteins/*chemistry/genetics/*metabolism ; G2 Phase Cell Cycle Checkpoints/genetics ; Gene Knockout Techniques ; HCT116 Cells ; Humans ; Nuclear Proteins/*chemistry/genetics/*metabolism ; Phosphorylation ; Protein Stability ; Replication Protein A/metabolism ; Signal Transduction/*genetics ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Transfection ; },
abstract = {CST (CTC1-STN1-TEN1) is a heterotrimeric, RPA-like complex that binds to single-stranded DNA (ssDNA) and functions in the replication of telomeric and non-telomeric DNA. Previous studies demonstrated that deletion of CTC1 results in decreased cell proliferation and telomere DNA damage signaling. However, a detailed analysis of the consequences of conditional CTC1 knockout (KO) has not been fully elucidated. Here, we investigated the effects of CTC1 KO on cell cycle progression, genome-wide replication and activation of the DNA damage response. Consistent with previous findings, we demonstrate that CTC1 KO results in decreased cell proliferation, G2 arrest and RPA-bound telomeric ssDNA. However, despite the increased levels of telomeric RPA-ssDNA, global ATR-dependent CHK1 and p53 phosphorylation was not detected in CTC1 KO cells. Nevertheless, we show that RPA-ssDNA does activate ATR, leading to the phosphorylation of RPA and autophosphorylation of ATR. Further analysis determined that inactivation of ATR, but not CHK1 or ATM, suppressed the accumulation of G2 arrested cells and phosphorylated RPA following CTC1 removal. These results suggest that ATR is localized and active at telomeres but is unable to elicit a global checkpoint response through CHK1. Furthermore, CTC1 KO inhibited CHK1 phosphorylation following hydroxyurea-induced replication stress. Additional studies revealed that this suppression of CHK1 phosphorylation, following replication stress, is caused by decreased levels of the ATR activator TopBP1. Overall, our results identify CST as a novel regulator of the ATR-CHK1 pathway.},
}
@article {pmid33264397,
year = {2020},
author = {Stivison, EA and Young, KJ and Symington, LS},
title = {Interstitial telomere sequences disrupt break-induced replication and drive formation of ectopic telomeres.},
journal = {Nucleic acids research},
volume = {48},
number = {22},
pages = {12697-12710},
pmid = {33264397},
issn = {1362-4962},
support = {R35 GM126997/GM/NIGMS NIH HHS/United States ; },
mesh = {DEAD-box RNA Helicases/*genetics ; DNA Breaks, Double-Stranded ; DNA Damage/genetics ; DNA Helicases/genetics ; DNA Polymerase III/genetics ; DNA Repair/genetics ; DNA Replication/*genetics ; *Recombination, Genetic ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/*genetics ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {Break-induced replication (BIR) is a mechanism used to heal one-ended DNA double-strand breaks, such as those formed at collapsed replication forks or eroded telomeres. Instead of utilizing a canonical replication fork, BIR is driven by a migrating D-loop and is associated with a high frequency of mutagenesis. Here we show that when BIR encounters an interstitial telomere sequence (ITS), the machinery frequently terminates, resulting in the formation of an ectopic telomere. The primary mechanism to convert the ITS to a functional telomere is by telomerase-catalyzed addition of telomeric repeats with homology-directed repair serving as a back-up mechanism. Termination of BIR and creation of an ectopic telomere is promoted by Mph1/FANCM helicase, which has the capacity to disassemble D-loops. Other sequences that have the potential to seed new telomeres but lack the unique features of a natural telomere sequence, do not terminate BIR at a significant frequency in wild-type cells. However, these sequences can form ectopic telomeres if BIR is made less processive. Our results support a model in which features of the ITS itself, such as the propensity to form secondary structures and telomeric protein binding, pose a challenge to BIR and increase the vulnerability of the D-loop to dissociation by helicases, thereby promoting ectopic telomere formation.},
}
@article {pmid33264196,
year = {2020},
author = {Wei, H and Zhang, C and Silveyra, P},
title = {The Relationships Between Prenatal Smoking Exposure and Telomere Lengths in Fetuses, Infants, and Children: A Systematic Literature Review.},
journal = {Journal of addictions nursing},
volume = {31},
number = {4},
pages = {243-252},
doi = {10.1097/JAN.0000000000000364},
pmid = {33264196},
issn = {1548-7148},
mesh = {Child ; Cross-Sectional Studies ; Female ; Fetus ; Humans ; Infant ; Infant, Newborn ; Maternal Exposure/*adverse effects ; Pregnancy ; Smoking/*adverse effects ; Telomere/*drug effects ; },
abstract = {OBJECTIVE: The aim of this study was to evaluate the relationships between prenatal smoking exposure and telomere lengths (TLs) in fetuses, infants, and children.<br><br>METHODS: This is a systematic review guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Databases searched were Biomedical Reference Collection, MEDLINE via PubMed, CINAHL, PsycINFO, and Google Scholar. The latest search was on October 18, 2019.<br><br>RESULTS: Seven studies met the inclusion criteria and thus were reviewed. Five of the studies showed significant inverse relationships between prenatal tobacco exposure and TLs in fetuses, infants, and children. One study showed a modification effect of the postconceptual age, indicating that older fetuses with prenatal smoking exposure had shorter TLs than their counterparts. This effect was more prominent after 93 days of postconception. Another study reported a finding that was contrary to the above results, showing that the telomeres of newborns with prenatal smoking exposure were longer than those of their counterparts.<br><br>CONCLUSION/RECOMMENDATIONS: This review shows that the impact of prenatal smoking on the health of unborn fetuses, infants, and children is an understudied area. Because of the inconsistent findings and cross-sectional study designs, more research is required, especially longitudinally studies. Nonetheless, the findings of the review provide partial evidence that prenatal smoking can potentially impact the genetic biomarker, TLs, and, thus, health of fetuses, infants, and children. The evidence confirms the current practice that pregnant women should be encouraged to stop smoking as soon as they become pregnant.},
}
@article {pmid33261558,
year = {2020},
author = {Eckhardt, F and Pauliny, A and Rollings, N and Mutschmann, F and Olsson, M and Kraus, C and Kappeler, PM},
title = {Stress-related changes in leukocyte profiles and telomere shortening in the shortest-lived tetrapod, Furcifer labordi.},
journal = {BMC evolutionary biology},
volume = {20},
number = {1},
pages = {160},
pmid = {33261558},
issn = {1471-2148},
mesh = {Animals ; Leukocytes/*metabolism ; Lizards/*genetics ; *Longevity/genetics ; Madagascar ; Stress, Physiological/*genetics ; *Telomere/genetics ; *Telomere Shortening/genetics ; },
abstract = {BACKGROUND: Life history theory predicts that during the lifespan of an organism, resources are allocated to either growth, somatic maintenance or reproduction. Resource allocation trade-offs determine the evolution and ecology of different life history strategies and define an organisms' position along a fast-slow continuum in interspecific comparisons. Labord's chameleon (Furcifer labordi) from the seasonal dry forests of Madagascar is the tetrapod species with the shortest reported lifespan (4-9 months). Previous investigations revealed that their lifespan is to some degree dependent on environmental factors, such as the amount of rainfall and the length of the vegetation period. However, the intrinsic mechanisms shaping such a fast life history remain unknown. Environmental stressors are known to increase the secretion of glucocorticoids in other vertebrates, which, in turn, can shorten telomeres via oxidative stress. To investigate to what extent age-related changes in these molecular and cellular mechanisms contribute to the relatively short lifetime of F. labordi, we assessed the effects of stressors indirectly via leukocyte profiles (H/L ratio) and quantified relative telomere length from blood samples in a wild population in Kirindy Forest. We compared our findings with the sympatric, but longer-lived sister species F. cf. nicosiai, which exhibit the same annual timing of reproductive events, and with wild-caught F. labordi that were singly housed under ambient conditions.<br><br>RESULTS: We found that H/L ratios were consistently higher in wild F. labordi compared to F. cf. nicosiai. Moreover, F. labordi already exhibited relatively short telomeres during the mating season when they were 3-4&#xa0;months old, and telomeres further shortened during their post-reproductive lives. At the beginning of their active season, telomere length was relatively longer in F. cf. nicosiai, but undergoing rapid shortening towards the southern winter, when both species gradually die off. Captive F. labordi showed comparatively longer lifespans and lower H/L ratios than their wild counterparts.<br><br>CONCLUSION: We suggest that environmental stress and the corresponding accelerated telomere attrition have profound effects on the lifespan of F. labordi in the wild, and identify physiological mechanisms potentially driving their relatively early senescence and mortality.},
}
@article {pmid33261163,
year = {2020},
author = {Zannas, AS and Kosyk, O and Leung, CS},
title = {Prolonged Glucocorticoid Exposure Does Not Accelerate Telomere Shortening in Cultured Human Fibroblasts.},
journal = {Genes},
volume = {11},
number = {12},
pages = {},
pmid = {33261163},
issn = {2073-4425},
support = {T32 MH093315/MH/NIMH NIH HHS/United States ; },
mesh = {Cell Line ; Cellular Senescence/drug effects ; Dexamethasone/*pharmacology ; Fibroblasts/*drug effects/ultrastructure ; Humans ; Hydrocortisone/*pharmacology ; RNA, Messenger/biosynthesis/genetics ; Stress, Psychological ; Tacrolimus Binding Proteins/biosynthesis/genetics ; Telomere/drug effects/ultrastructure ; Telomere Shortening/*drug effects ; Up-Regulation/drug effects ; },
abstract = {Psychosocial stress, especially when chronic or excessive, can increase disease risk and accelerate biological aging. Although the underlying mechanisms are unclear, in vivo studies have associated exposure to stress and glucocorticoid stress hormones with shorter telomere length. However, the extent to which prolonged glucocorticoid exposure can shorten telomeres in controlled experimental settings remains unknown. Using a well-characterized cell line of human fibroblasts that undergo gradual telomere shortening during serial passaging in culture, we show that prolonged exposure (up to 51 days) to either naturalistic levels of the human endogenous glucocorticoid cortisol or the more potent synthetic glucocorticoid dexamethasone is not sufficient to accelerate telomere shortening. While our findings await extension in other cell types and biological contexts, they indicate that the in vivo association of psychosocial stress with telomere shortening is unlikely to be mediated by a direct and universal glucocorticoid effect on telomere length.},
}
@article {pmid33258446,
year = {2020},
author = {Schmutz, I and Mensenkamp, AR and Takai, KK and Haadsma, M and Spruijt, L and de Voer, RM and Choo, SS and Lorbeer, FK and van Grinsven, EJ and Hockemeyer, D and Jongmans, MC and de Lange, T},
title = {TINF2 is a haploinsufficient tumor suppressor that limits telomere length.},
journal = {eLife},
volume = {9},
number = {},
pages = {},
pmid = {33258446},
issn = {2050-084X},
support = {W81XWH-19-1-0586//U.S. Department of Defense/International ; R35 CA210036/CA/NCI NIH HHS/United States ; R01 CA196884/CA/NCI NIH HHS/United States ; 577521/MRA/Melanoma Research Alliance/United States ; 133396-RSG-19-029-01-DMC//American Cancer Society/International ; },
mesh = {Cell Line ; Female ; *Genes, Tumor Suppressor ; HEK293 Cells ; Heterozygote ; Humans ; Loss of Function Mutation ; Male ; Neoplasms/genetics ; Telomere/*genetics/pathology ; Telomere Shortening/*genetics ; Telomere-Binding Proteins/genetics/*physiology ; Telomeric Repeat Binding Protein 1/metabolism ; Tumor Suppressor Proteins ; },
abstract = {Telomere shortening is a presumed tumor suppressor pathway that imposes a proliferative barrier (the Hayflick limit) during tumorigenesis. This model predicts that excessively long somatic telomeres predispose to cancer. Here, we describe cancer-prone families with two unique TINF2 mutations that truncate TIN2, a shelterin subunit that controls telomere length. Patient lymphocyte telomeres were unusually long. We show that the truncated TIN2 proteins do not localize to telomeres, suggesting that the mutations create loss-of-function alleles. Heterozygous knock-in of the mutations or deletion of one copy of TINF2 resulted in excessive telomere elongation in clonal lines, indicating that TINF2 is haploinsufficient for telomere length control. In contrast, telomere protection and genome stability were maintained in all heterozygous clones. The data establish that the TINF2 truncations predispose to a tumor syndrome. We conclude that TINF2 acts as a haploinsufficient tumor suppressor that limits telomere length to ensure a timely Hayflick limit.},
}
@article {pmid33257117,
year = {2021},
author = {Zhou, L and Li, L and Hao, G and Li, B and Yang, S and Wang, N and Liang, J and Sun, H and Ma, S and Yan, L and Zhao, C and Wei, Y and Niu, Y and Zhang, R},
title = {Sperm mtDNA copy number, telomere length, and seminal spermatogenic cells in relation to ambient air pollution: Results of a cross-sectional study in Jing-Jin-Ji region of China.},
journal = {Journal of hazardous materials},
volume = {406},
number = {},
pages = {124308},
doi = {10.1016/j.jhazmat.2020.124308},
pmid = {33257117},
issn = {1873-3336},
mesh = {*Air Pollutants/analysis/toxicity ; *Air Pollution/adverse effects/analysis ; China ; Cross-Sectional Studies ; DNA Copy Number Variations ; DNA, Mitochondrial/pharmacology ; Humans ; Male ; Particulate Matter/analysis/toxicity ; Semen Analysis ; Sperm Count ; Spermatozoa ; Telomere/chemistry/genetics ; },
abstract = {Evidences on the association of air pollutants and semen quality were limited and mechanism-based biomarkers were sparse. We enrolled 423 men at a fertility clinic in Shijiazhuang, China to evaluate associations between air pollutants and semen quality parameters including the conventional ones, sperm mitochondrial DNA copy number (mtDNAcn), sperm telomere length (STL) and seminal spermatogenic cells. PM2.5, PM10, CO, SO2, NO2 and O3 exposure during lag0-90, lag0-9, lag10-14 and lag70-90 days were evaluated with ordinary Kringing model. The exposure-response correlations were analyzed with multiple linear regression models. CO, PM2.5 and PM10 were adversely associated with conventional semen parameters including sperm count, motility and morphology. Besides, CO was positively associated with seminal primary spermatocyte (lag70-90, 0.49; 0.14, 0.85) and mtDNAcn (lag0-90, 0.37; 0.12, 0.62, lag10-14, 0.31; 0.12, 0.49), negatively associated with STL (lag0-9, -0.30; -0.57, -0.03). PM2.5 was positively associated with mtDNAcn (0.50; 0.24, 0.75 and 0.38; 0.02, 0.75 for lag0-90 and lag70-90) while negatively associated with STL (lag70-90, -0.49; -0.96, -0.01). PM10 and NO2 were positively associated with mtDNAcn. Our findings indicate CO and PM might impair semen quality testicularly and post-testicularly while seminal spermatogenic cell, STL and mtDNAcn change indicate necessity for more attention on these mechanisms.},
}
@article {pmid33257049,
year = {2021},
author = {Wu, M and Wang, L and Song, L and Liu, B and Liu, Y and Bi, J and Liu, Q and Chen, K and Li, Y and Xia, W and Xu, S and Cao, Z and Zhou, A and Tian, Y and Wang, Y},
title = {The association between prenatal exposure to thallium and shortened telomere length of newborns.},
journal = {Chemosphere},
volume = {265},
number = {},
pages = {129025},
doi = {10.1016/j.chemosphere.2020.129025},
pmid = {33257049},
issn = {1879-1298},
mesh = {Child ; China ; Cohort Studies ; Female ; Humans ; Infant, Newborn ; Maternal Exposure/adverse effects ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Telomere ; Telomere Shortening ; *Thallium/toxicity ; },
abstract = {BACKGROUND: Thallium is a widely known toxic heavy metal that has been reported have embryo toxicity.<br><br>OBJECTIVE: We aimed to investigate the relationship of prenatal thallium exposure with neonatal telomere length.<br><br>METHODS: A total of 746 mother-newborn pairs were recruited from Wuhan Children Hospital between November 2013 and March 2015 in Wuhan City, China. Maternal thallium exposure levels were measured in spot urine samples collected during the three trimesters and during hospital delivery using inductively coupled plasma mass spectrometry. Neonatal relative telomere length (rTL) was measured by a real-time quantitative polymerase chain reaction assay in cord blood. Multiple informant models were used to evaluate the association of maternal thallium exposure with neonatal rTL.<br><br>RESULTS: After adjustment for multiple potential confounders, each 25% incremental increase of maternal thallium exposure, measured in urine samples collected during hospital delivery, was associated with a 1.85% shortened neonatal rTL (95% CI:&#xa0;-3.62%,&#xa0;-0.05%; P&#xa0;=&#xa0;0.044). Similarly, mothers in the highest quartile of urinary thallium exposure had a 11.74% (95% CI:&#xa0;-21.57%,&#xa0;-0.68%; P&#xa0;=&#xa0;0.038) shorter cord blood leukocyte rTL than those in the lowest quartile. However, no significant association was found between neonatal rTL and maternal thallium exposure measured in urine samples collected during the three trimesters of pregnancy.<br><br>CONCLUSIONS: This study reveals that prenatal thallium exposure was related to shortened neonatal telomere length in Chinese population, pointing to the important role of thallium exposure in accelerating biological aging.},
}
@article {pmid33256968,
year = {2021},
author = {Mergny, JL and Guittat, L and Ségal-Bendirdjian, &#xc9;},
title = {[Are telomeres and telomerase still relevant targets in oncology?].},
journal = {Bulletin du cancer},
volume = {108},
number = {1},
pages = {30-38},
doi = {10.1016/j.bulcan.2020.10.007},
pmid = {33256968},
issn = {1769-6917},
mesh = {Enzyme Inhibitors/*pharmacology ; Humans ; Immunotherapy/methods ; Neoplasms/*enzymology/immunology/therapy ; Nucleic Acids/chemistry ; Oncolytic Virotherapy ; Oncolytic Viruses/immunology ; RNA/*physiology ; Telomerase/antagonists &amp; inhibitors/*physiology ; Telomere/*physiology ; },
}
@article {pmid33250812,
year = {2020},
author = {Mehrsafar, AH and Serrano Rosa, MA and Moghadam Zadeh, A and Gazerani, P},
title = {Stress, Professional Lifestyle, and Telomere Biology in Elite Athletes: A Growing Trend in Psychophysiology of Sport.},
journal = {Frontiers in psychology},
volume = {11},
number = {},
pages = {567214},
pmid = {33250812},
issn = {1664-1078},
abstract = {Professional lifestyle and championship period often put a great deal of pressure on athletes, who usually experience highly stressful periods during training for competitions. Recently, biomarkers of cellular aging, telomere length (TL) and telomerase activity (TA), have been considered to investigate the effects of stress and lifestyle factors. Studies in non-athletic populations have shown that stress and poor lifestyle decrease TL and TA. On the other hand, it has been shown that in general, exercise increases TL and its activity, although the underlying mechanisms remained largely unexplored. TL and TA outcomes in elite athletes remain inconclusive and mainly affected by confounding factors, such as age. Elite athletes, therefore, might offer a unique target group for studying exercise-telomere hypothesis for further investigation of the roles of stressors on telomere-related biomarkers. In this perspective, we highlight the potentials for studying these psychophysiological markers in elite athletes in order to understand stress-aging relationship and potential underlying mechanisms. Moreover, we present important methodological aspects that could help in the development of future experimental designs.},
}
@article {pmid33249778,
year = {2021},
author = {Opstad, TB and Berg, TJ and Holte, KB and Arnesen, H and Solheim, S and Seljeflot, I},
title = {Reduced leukocyte telomere lengths and sirtuin 1 gene expression in long-term survivors of type 1 diabetes: A Dialong substudy.},
journal = {Journal of diabetes investigation},
volume = {12},
number = {7},
pages = {1183-1192},
pmid = {33249778},
issn = {2040-1124},
support = {//Oslo Diabetes Research Centre/ ; //Stein Erik Hagen Foundation for Clinical Heart Research, Oslo Norway/ ; //The Norwegian Council for Cardiovascular Diseases/ ; //Norwegian Diabetics' Centre/ ; },
mesh = {Aged ; Aging/genetics ; Bone Morphogenetic Proteins/blood ; Case-Control Studies ; Coronary Artery Disease/blood/etiology/*genetics ; Cross-Sectional Studies ; Diabetes Mellitus, Type 1/blood/complications/*genetics ; Female ; Gene Expression/*genetics ; Genetic Markers/genetics ; Growth Differentiation Factors/blood ; Humans ; Leukocytes/physiology ; Male ; Middle Aged ; Sirtuin 1/*blood ; Survivors ; Telomere Shortening/*genetics ; Time Factors ; },
abstract = {AIMS/INTRODUCTION: The shortening of leukocyte telomere length with age has been associated with coronary disease, whereas the association with type 1 diabetes is unclear. We aimed to explore telomere lengths in diabetes patients with regard to coronary artery disease, compared with healthy controls. The longevity factors sirtuin 1 and growth-differentiating factor 11 were investigated accordingly.<br><br>MATERIALS AND METHODS: We carried out a cross-sectional study of 102 participants with long-term type&#xa0;1 diabetes and 75 controls (mean age 62 and 63&#xa0;years, respectively), where 88 cases and 60 controls without diagnosed coronary artery disease completed computed tomography coronary angiography. Telomere lengths and gene expression of sirtuin&#xa0;1 and growth-differentiating factor&#xa0;11 were quantified in leukocytes.<br><br>RESULTS: Telomere lengths and sirtuin&#xa0;1 were reduced in diabetes patients versus controls, medians (25th to 75th percentiles): 0.97 (0.82-1.15) versus 1.08 (0.85-1.29) and 0.88 (0.65-1.14) vs 1.01 (0.78-1.36), respectively, adjusted P&#xa0;<&#xa0;0.05, both. Previous coronary artery disease in diabetes patients (n&#xa0;=&#xa0;15) was associated with lower sirtuin&#xa0;1 and growth-differentiating factor&#xa0;11 messenger ribonucleic acid expression (adjusted P&#xa0;<&#xa0;0.03, both). In the combined diabetes and control group, previous artery coronary disease (n&#xa0;=&#xa0;18) presented with significantly shorter telomeres (adjusted P&#xa0;=&#xa0;0.038). Newly diagnosed obstructive coronary artery disease, defined as >50% stenosis, was not associated with the investigated variables.<br><br>CONCLUSIONS: Long-term type&#xa0;1 diabetes presented with reduced telomeres and sirtuin&#xa0;1 expression, with additional reduction in diabetes patients with previous coronary artery disease, showing their importance for cardiovascular disease development with potential as novel biomarkers in diabetes and coronary artery disease.},
}
@article {pmid33248477,
year = {2021},
author = {Cheng, F and Carroll, L and Joglekar, MV and Januszewski, AS and Wong, KK and Hardikar, AA and Jenkins, AJ and Ma, RCW},
title = {Diabetes, metabolic disease, and telomere length.},
journal = {The lancet. Diabetes &amp; endocrinology},
volume = {9},
number = {2},
pages = {117-126},
doi = {10.1016/S2213-8587(20)30365-X},
pmid = {33248477},
issn = {2213-8595},
mesh = {Diabetes Complications/*genetics ; Diabetes Mellitus/*genetics ; Humans ; Metabolic Diseases/*genetics ; Risk Factors ; Telomere/*genetics ; },
abstract = {Telomeres are regions of repetitive nucleotide sequences at the ends of chromosomes. Telomere length is a marker of DNA damage, which is often considered a biomarker for biological ageing, and has also been linked with cardiovascular disease, diabetes, and cancer. Emerging studies have highlighted the role of genetic and environmental factors, and explored the effect of modulating telomere length. We provide an overview of studies to date on diabetes and telomere length, and compare different methods and assays for evaluating telomere length and telomerase activity. We highlight the limitations of current studies and areas that warrant further research to unravel the link between diabetes and telomere length. The value of adding telomere length to clinical risk factors to improve risk prediction of diabetes and related complications also merits further investigation.},
}
@article {pmid33244044,
year = {2020},
author = {Alhendi, ASN and Royle, NJ},
title = {The absence of (TCAGGG)n repeats in some telomeres, combined with variable responses to NR2F2 depletion, suggest that this nuclear receptor plays an indirect role in the alternative lengthening of telomeres.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {20597},
pmid = {33244044},
issn = {2045-2322},
support = {G0500336/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Base Sequence ; COUP Transcription Factor II/*genetics ; Cell Line, Tumor ; Cells, Cultured ; DNA Damage ; Humans ; Male ; Middle Aged ; Repetitive Sequences, Nucleic Acid ; Sequence Deletion ; Telomere/*genetics ; *Telomere Homeostasis ; Transcriptome ; },
abstract = {The alternative lengthening of telomeres (ALT) facilitates telomere lengthening by a DNA strand invasion and copying mechanism. The nuclear receptors (NRs), NR2F2 and NR2C2, can bind to (TCAGGG)n variant repeats within telomeres and it has been proposed that this facilitates telomere interactions in ALT+ cells. Here we show that the frequency of cells with detectable NR2F2 and NR2C2 nuclear foci varies considerably between ALT+ cell lines and does not correlate with the level of protein expression. In addition, four of five ALT+ cell lines lack (TCAGGG)n repeats in some telomeres, indicating that direct NR binding does not play a role in ALT at these telomeres. NR2F2-depletion altered the abundance of C-circles and APBs but the direction of the response was inconsistent between three ALT+ cell lines. Moreover, transcriptome analysis following NR2F2-depletion in the ALT+ cell lines revealed different very responses. For example, NR2F2-depletion down-regulated many genes in U2OS cells, consistent with the cell cycle arrest and changes to ALT markers, but these features were not shared by the other two ALT+ cell lines. Among 86 ALT-associated genes, only MND1 showed consistent down-regulation across three NR2F2-depleted ALT+ cell lines. Altogether our data suggest that NR2F2 does not play a direct role in ALT and we speculate about an alternative role for this NR in a DNA damage response at telomeres.},
}
@article {pmid33243459,
year = {2021},
author = {Moazzam, M and Yim, T and Kumaresan, V and Henderson, DC and Farrer, LA and Zhang, H},
title = {Analysis of telomere length variation and Shelterin complex subunit gene expression changes in ethanol-exposed human embryonic stem cells.},
journal = {Journal of psychiatric research},
volume = {143},
number = {},
pages = {543-549},
pmid = {33243459},
issn = {1879-1379},
support = {R01 AA025080/AA/NIAAA NIH HHS/United States ; },
mesh = {Ethanol/toxicity ; Gene Expression ; *Human Embryonic Stem Cells ; Humans ; Shelterin Complex ; *Telomere/genetics ; Telomere-Binding Proteins/genetics ; Telomeric Repeat Binding Protein 2/genetics ; },
abstract = {Telomeres protect chromosome ends from degradation. Telomere length (TL) can be altered by aging and environmental stress. Shortened TL has been observed in peripheral blood leukocytes of alcohol dependent subjects and ethanol-exposed somatic cells. To understand the impact of ethanol on telomeres in pluripotent stem cells, we investigated the influence of ethanol on TL and the expression of six Shelterin complex subunit or telomere-regulating genes (POT1, RAP1, TIN2, TPP1, TRF1, and TRF2) in human embryonic stem cells (hESCs), which were exposed to 0, 25, 50, or 100 mM of ethanol for 3, 7, or 14 days. Ethanol-induced TL and Shelterin complex subunit gene expression changes were examined by quantitative polymerase chain reactions. Two-way ANOVA tests indicated that TL variation and expression changes of four associated Shelterin complex subunit genes (POT1, TPP1, TIN2, and TRF2) were mainly dependent on the length of ethanol exposure, while TRF1 and RAP1expression was influenced by ethanol concentration, exposure time, and the interaction of ethanol concentration and exposure time. Tukey's multiple comparison tests showed that TL and the expression of POT1, RAP1, TIN2, TPP1, and TRF1 were decreased after a 7-day (versus a 3-day) ethanol exposure. However, the decreased expression of all six Shelterin complex subunit genes was recovered and TL was not further shortened after a 14-day (versus a 7-day) ethanol exposure, likely due to the adaptation of hESCs to ethanol-induced stress. Our study provided further evidence that TL is regulated and maintained by telomere-regulating genes in stem cells under ethanol stress.},
}
@article {pmid33243026,
year = {2019},
author = {Needham, BL and Salerno, S and Roberts, E and Boss, J and Allgood, KL and Mukherjee, B},
title = {Do black/white differences in telomere length depend on socioeconomic status?.},
journal = {Biodemography and social biology},
volume = {65},
number = {4},
pages = {287-312},
pmid = {33243026},
issn = {1948-5573},
support = {R01 AG033592/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Black People/*classification/psychology/statistics &amp; numerical data ; Female ; Health Status Disparities ; Humans ; Male ; Middle Aged ; *Social Class ; Telomere/*classification ; United States ; Weights and Measures/instrumentation ; White People/*classification/psychology/statistics &amp; numerical data ; },
abstract = {Social and economic disadvantage are hypothesized to increase the risk of disease and death via accelerated biological aging. Given that US blacks are socially and economically disadvantaged relative to whites, health disparities scholars expected that blacks would have shorter telomere length-a biomarker of cell aging-than whites. Yet the majority of studies have found that blacks have longer telomere length than whites. Using data from the National Health and Nutrition Examination Survey (n = 3,761; 28.3% non-Hispanic black, 71.7% non-Hispanic white), we found that leukocyte telomere length was 4.00% (95% CI: 1.12%, 6.87%) longer among blacks compared to whites in the full sample, but differences were greatest among those with lower SES (5.66%; 95% CI: 0.10%, 10.32%), intermediate among those with middle SES (4.14%; 95% CI: 0.05%, 8.24%), and smallest among those with higher SES (2.33%; 95% CI: -3.02%, 7.67%). These results challenge purely genetic explanations for race differences in telomere length and point to a potential social-environmental cause of longer telomere length in US blacks.},
}
@article {pmid33242471,
year = {2021},
author = {Baskind, MJ and Hawkins, J and Heyman, MB and Wojcicki, JM},
title = {Obesity at Age 6 Months Is Associated with Shorter Preschool Leukocyte Telomere Length Independent of Parental Telomere Length.},
journal = {The Journal of pediatrics},
volume = {233},
number = {},
pages = {141-149},
pmid = {33242471},
issn = {1097-6833},
support = {P30 DK063720/DK/NIDDK NIH HHS/United States ; M01 RR001271/RR/NCRR NIH HHS/United States ; K01 DK080825/DK/NIDDK NIH HHS/United States ; R03 DK097458/DK/NIDDK NIH HHS/United States ; P30 DK098722/DK/NIDDK NIH HHS/United States ; },
mesh = {Breast Feeding ; Child, Preschool ; Cohort Studies ; Female ; *Hispanic or Latino ; Humans ; Infant ; Leukocytes/physiology ; Linear Models ; Male ; Pediatric Obesity/epidemiology/*genetics ; San Francisco/epidemiology ; Sugar-Sweetened Beverages ; *Telomere Shortening ; },
abstract = {OBJECTIVE: To assess whether early modifiable dietary factors and obesity measures are associated with leukocyte telomere length at 3-5 years of age after controlling for the heritability of leukocyte telomere length in a prospective cohort of low-income Latina mothers and their children in San Francisco.<br><br>STUDY DESIGN: We analyzed data from the Latinx, Eating and Diabetes cohort, a prospective study of 97 woman-infant dyads. We used linear regression models to evaluate associations between early dietary factors and obesity measures and child leukocyte telomere length at 3-5&#xa0;years of age. Multivariable models included child age at the time of telomere collection, breastfeeding at 6&#xa0;months (yes/no), obesity at 6&#xa0;months, maternal education, child sex, and maternal and paternal leukocyte telomere length.<br><br>RESULTS: Data for 73 of the 97 children at 3-5&#xa0;years of age were analyzed. Any breastfeeding at 6&#xa0;months was positively associated (&#x3b2;&#xa0;=&#xa0;0.14; P&#xa0;=&#xa0;.02) and obesity at 6&#xa0;months was negatively associated (&#x3b2;&#xa0;=&#xa0;-0.21; P&#xa0;<&#xa0;.001) with leukocyte telomere length in bivariate analyses. In multivariable models including parental leukocyte telomere length, obesity at 6&#xa0;months was associated with a shorter leukocyte telomere length at 3-5&#xa0;years of age (&#x3b2;&#xa0;=&#xa0;-0.15; P&#xa0;=&#xa0;.02). Analyses of dietary factors showed high flavored milk consumption at 3&#xa0;years of age was associated with shorter leukocyte telomere length after adjustment for possible confounders.<br><br>CONCLUSIONS: In a low-income Latinx population, obesity at 6&#xa0;months of age is negatively associated with cellular health at 3-5&#xa0;years of age after controlling for genetic factors (parental leukocyte telomere length) associated with leukocyte telomere length. Early life obesity may be more deleterious for cellular health than obesity later in childhood.},
}
@article {pmid33242411,
year = {2020},
author = {Luxton, JJ and McKenna, MJ and Taylor, LE and George, KA and Zwart, SR and Crucian, BE and Drel, VR and Garrett-Bakelman, FE and Mackay, MJ and Butler, D and Foox, J and Grigorev, K and Bezdan, D and Meydan, C and Smith, SM and Sharma, K and Mason, CE and Bailey, SM},
title = {Temporal Telomere and DNA Damage Responses in the Space Radiation Environment.},
journal = {Cell reports},
volume = {33},
number = {10},
pages = {108435},
doi = {10.1016/j.celrep.2020.108435},
pmid = {33242411},
issn = {2211-1247},
support = {UH3 DK114920/DK/NIDDK NIH HHS/United States ; },
mesh = {Adult ; Astronauts ; DNA/genetics/radiation effects ; DNA Breaks, Double-Stranded ; DNA Damage/*genetics/radiation effects ; DNA Repair/genetics/*physiology/radiation effects ; Dose-Response Relationship, Radiation ; Extraterrestrial Environment ; Female ; Humans ; Male ; Space Flight ; Telomere/*genetics/metabolism/radiation effects ; Time Factors ; Weightlessness/adverse effects ; },
abstract = {Telomeres, repetitive terminal features of chromosomes essential for maintaining genome integrity, shorten with cell division, lifestyle factors and stresses, and environmental exposures, and so they provide a robust biomarker of health, aging, and age-related diseases. We assessed telomere length dynamics (changes over time) in three unrelated astronauts before, during, and after 1-year or 6-month missions aboard the International Space Station (ISS). Similar to our results for National Aeronautics and Space Administration's (NASA's) One-Year Mission twin astronaut (Garrett-Bakelman et al., 2019), significantly longer telomeres were observed during spaceflight for two 6-month mission astronauts. Furthermore, telomere length shortened rapidly after return to Earth for all three crewmembers and, overall, telomere length tended to be shorter after spaceflight than before spaceflight. Consistent with chronic exposure to the space radiation environment, signatures of persistent DNA damage responses were also detected, including mitochondrial and oxidative stress, inflammation, and telomeric and chromosomal aberrations, which together provide potential mechanistic insight into spaceflight-specific telomere elongation.},
}
@article {pmid33242406,
year = {2020},
author = {Luxton, JJ and McKenna, MJ and Lewis, A and Taylor, LE and George, KA and Dixit, SM and Moniz, M and Benegas, W and Mackay, MJ and Mozsary, C and Butler, D and Bezdan, D and Meydan, C and Crucian, BE and Zwart, SR and Smith, SM and Mason, CE and Bailey, SM},
title = {Telomere Length Dynamics and DNA Damage Responses Associated with Long-Duration Spaceflight.},
journal = {Cell reports},
volume = {33},
number = {10},
pages = {108457},
doi = {10.1016/j.celrep.2020.108457},
pmid = {33242406},
issn = {2211-1247},
mesh = {Adult ; Astronauts ; DNA/chemistry/radiation effects ; DNA Damage/physiology ; DNA Repair/*physiology/radiation effects ; Female ; Humans ; Male ; Middle Aged ; Oxidative Stress/physiology ; Space Flight ; Telomerase/metabolism ; Telomere/metabolism/physiology ; Telomere Homeostasis/*physiology/radiation effects ; Time Factors ; Weightlessness/*adverse effects ; },
abstract = {Telomere length dynamics and DNA damage responses were assessed before, during, and after one-year or shorter duration missions aboard the International Space Station (ISS) in a comparatively large cohort of astronauts (n = 11). Although generally healthy individuals, astronauts tended to have significantly shorter telomeres and lower telomerase activity than age- and sex-matched ground controls before and after spaceflight. Although telomeres were longer during spaceflight irrespective of mission duration, telomere length shortened rapidly upon return to Earth, and overall astronauts had shorter telomeres after spaceflight than they did before; inter-individual differences were identified. During spaceflight, all crewmembers experienced oxidative stress, which positively correlated with telomere length dynamics. Significantly increased frequencies of chromosomal inversions were observed during and after spaceflight; changes in cell populations were also detected. We propose a telomeric adaptive response to chronic oxidative damage in extreme environments, whereby the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway is transiently activated in normal somatic cells.},
}
@article {pmid33241110,
year = {2020},
author = {Chartrand, P and Sfeir, A},
title = {A single-molecule view of telomerase regulation at telomeres.},
journal = {Molecular &amp; cellular oncology},
volume = {7},
number = {6},
pages = {1818537},
pmid = {33241110},
issn = {2372-3556},
abstract = {Telomerase plays a key role in the immortalization of cancer cells by maintaining telomeres length. Using single-molecule imaging of telomerase RNA molecules in cancer cells, we recently reported novel insights into the role of Cajal bodies in telomerase biogenesis and the regulation of telomerase recruitment to telomeres.},
}
@article {pmid33240643,
year = {2020},
author = {Cherdsukjai, P and Buddhachat, K and Brown, J and Kaewkool, M and Poommouang, A and Kaewmong, P and Kittiwattanawong, K and Nganvongpanit, K},
title = {Age relationships with telomere length, body weight and body length in wild dugong (Dugong dugon).},
journal = {PeerJ},
volume = {8},
number = {},
pages = {e10319},
pmid = {33240643},
issn = {2167-8359},
abstract = {The ability to estimate age and determine the growth status of free-ranging dugongs (Dugong dugon) is vital to providing insight into the basic biology of this endangered species. Currently, age estimation in dugong carcasses relies on counting dentin growth layer groups (GLGs) in tusks, but a disadvantage is they need to be intact. We explored whether measures of telomere length could be used as an alternative approach to age estimation in dugongs given that in other species, telomere length and age are inversely related. In this study, relative telomere length (rTL) was measured by qPCR in skin samples from 24 dugongs of varying ages determined by counts of GLGs. In addition, relationships between age by GLG counts and body weight and length and were examined. Our findings indicate that age estimated by GLGs was negatively correlated with telomere length using the logistic formula with a rate of telomere attrition of approximately 0.036 rTL/year between the ages of 5-20 years. By comparison, both body weight and length were positively correlated with GLG-based age, with growth rates of ~8.8 kg/year for weight and ~3.58 cm/year for length, respectively. After that, growth rates slowed substantially and then plateaued. The results suggest that physical maturity in dugongs occurs at 20 years of age and that measures of rTL might serve as a tool for age estimation in dugongs, living and deceased.},
}
@article {pmid33239785,
year = {2021},
author = {Markiewicz-Potoczny, M and Lobanova, A and Loeb, AM and Kirak, O and Olbrich, T and Ruiz, S and Lazzerini Denchi, E},
title = {TRF2-mediated telomere protection is dispensable in pluripotent stem cells.},
journal = {Nature},
volume = {589},
number = {7840},
pages = {110-115},
pmid = {33239785},
issn = {1476-4687},
support = {ZIA BC012015/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Animals ; Cell Proliferation ; Cell Survival ; DNA Damage ; DNA-Binding Proteins/metabolism ; Female ; Gene Expression Regulation, Developmental ; Mice ; Mouse Embryonic Stem Cells/cytology/metabolism ; Pluripotent Stem Cells/cytology/*metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/*deficiency/genetics/*metabolism ; Totipotent Stem Cells/cytology/metabolism ; Transcription Factors/metabolism ; Transcription, Genetic ; Tumor Suppressor p53-Binding Protein 1/metabolism ; },
abstract = {In mammals, telomere protection is mediated by the essential protein TRF2, which binds chromosome ends and ensures genome integrity[1,2]. TRF2 depletion results in end-to-end chromosome fusions in all cell types that have been tested so far. Here we find that TRF2 is dispensable for the proliferation and survival of mouse embryonic stem (ES) cells. Trf2[-/-] (also known as Terf2) ES cells do not exhibit telomere fusions and can be expanded indefinitely. In response to the deletion of TRF2, ES cells exhibit a muted DNA damage response that is characterized by the recruitment of γH2AX-but not 53BP1-to telomeres. To define the mechanisms that control this unique DNA damage response in ES cells, we performed a CRISPR-Cas9-knockout screen. We found a strong dependency of TRF2-null ES cells on the telomere-associated protein POT1B and on the chromatin remodelling factor BRD2. Co-depletion of POT1B or BRD2 with TRF2 restores a canonical DNA damage response at telomeres, resulting in frequent telomere fusions. We found that TRF2 depletion in ES cells activates a totipotent-like two-cell-stage transcriptional program that includes high levels of ZSCAN4. We show that the upregulation of ZSCAN4 contributes to telomere protection in the absence of TRF2. Together, our results uncover a unique response to telomere deprotection during early development.},
}
@article {pmid33234683,
year = {2021},
author = {Kärkkäinen, T and Teerikorpi, P and Schuett, W and Stier, A and Laaksonen, T},
title = {Interplays between pre- and post-natal environments affect early-life mortality, body mass and telomere dynamics in the wild.},
journal = {The Journal of experimental biology},
volume = {224},
number = {Pt 1},
pages = {},
doi = {10.1242/jeb.231290},
pmid = {33234683},
issn = {1477-9145},
mesh = {Animals ; Eggs ; Phenotype ; *Songbirds ; *Telomere/genetics ; },
abstract = {Early-life conditions are crucial determinants of phenotype and fitness. The effects of pre- and post-natal conditions on fitness prospects have been widely studied but their interactive effects have received less attention. In birds, asynchronous hatching creates challenging developmental conditions for the last-hatched chicks, but differential allocation in last-laid eggs might help to compensate this initial handicap. The relative importance and potential interaction between pre- and post-hatching developmental conditions for different fitness components remains mostly unknown. We manipulated hatching order in wild pied flycatchers (Ficedula hypoleuca), creating three groups: natural asynchrony (last-laid eggs hatching last), reversed asynchrony (last-laid eggs hatching first) and hatching synchrony (all eggs hatching at once). We examined the effects of these manipulations on early-life survival, growth and telomere length, a potential cellular biomarker of fitness prospects. Mortality was mostly affected by hatching order, with last-hatched chicks being more likely to die. Early-life telomere dynamics and growth were influenced by the interplays between laying and hatching order. Last-laid but first-hatched chicks were heavier but had shorter telomeres 5 days after hatching than their siblings, indicating rapid early growth with potential adverse consequences on telomere length. Synchronous chicks did not suffer any apparent cost of hatching synchronously. Impaired phenotypes only occurred when reversing the natural hatching order (i.e. developmental mismatch), suggesting that maternal investment in last-laid eggs might indeed counterbalance the initial handicap of last-hatched chicks. Our experimental study thus highlights that potential interplays between pre- and post-natal environments are likely to shape fitness prospects in the wild.},
}
@article {pmid33230966,
year = {2020},
author = {Gurung, RL and M, Y and Moh, AMC and Dorajoo, R and Liu, S and Liu, JJ and Shabbir, A and So, JBY and Tan, CH and Cheng, AKS and Lim, SC},
title = {Correlation of Telomere Length in Adipose Tissue and Leukocytes and its Association with Postsurgical Weight Loss.},
journal = {Obesity (Silver Spring, Md.)},
volume = {28},
number = {12},
pages = {2424-2430},
doi = {10.1002/oby.23017},
pmid = {33230966},
issn = {1930-739X},
mesh = {Adult ; Bariatric Surgery/*methods ; Female ; Humans ; Intra-Abdominal Fat/*physiopathology ; Leukocytes/*metabolism ; Male ; Obesity, Morbid/*surgery ; Telomere/*physiology ; Weight Loss/*physiology ; },
abstract = {OBJECTIVE: The aim of this study was to determine the relationship between telomere length (TL) in subcutaneous adipose tissue (SAT), visceral adipose tissues (VAT), and leukocytes, as well as to examine the associations of TL in these tissues with postsurgical weight loss in Asians with severe obesity.<br><br>METHODS: Presurgery TL was measured in leukocytes, SAT, and VAT of 91 patients who underwent weight loss surgery. Correlation between TL in multiple tissues was assessed using Pearson correlation. The association of presurgery TL and postsurgical weight loss at 6 or 12 months, expressed as a percentage of weight loss, was determined using linear regression in 70 patients.<br><br>RESULTS: Telomeres were longer in VAT compared with those in leukocytes and SAT (P < 0.001) but were highly correlated between tissues. The strongest correlation was observed between TL in VAT and leukocytes (r&#x2009;=&#x2009;0.739, P&#x2009;=&#x2009;6.22&#x2009;&#xd7;&#x2009;10[-17]). Compared with individuals in the highest tertile, those in the lowest tertile of VAT TL showed greater weight loss (&#x3b2;&#x2009;=&#x2009;6.23, SE&#x2009;=&#x2009;3.10, P&#x2009;=&#x2009;0.044) independent of age, sex, ethnicity, types of surgery, diabetes condition, preoperative BMI, and follow-up period.<br><br>CONCLUSIONS: Among patients with severe obesity, TL in leukocytes and adipose tissue was highly correlated. However, there was variability in the association of TL in these tissues with weight loss after surgery.},
}
@article {pmid33229517,
year = {2020},
author = {Wight, DJ and Aimola, G and Aswad, A and Jill Lai, CY and Bahamon, C and Hong, K and Hill, JA and Kaufer, BB},
title = {Unbiased optical mapping of telomere-integrated endogenous human herpesvirus 6.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {117},
number = {49},
pages = {31410-31416},
pmid = {33229517},
issn = {1091-6490},
mesh = {Chromosomes, Human/genetics ; Genome, Viral ; Herpesvirus 6, Human/genetics/*physiology ; Host-Pathogen Interactions ; Humans ; *Optical Imaging ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Next-generation sequencing technologies allowed sequencing of thousands of genomes. However, there are genomic regions that remain difficult to characterize, including telomeres, centromeres, and other low-complexity regions, as well as transposable elements and endogenous viruses. Human herpesvirus 6A and 6B (HHV-6A and HHV-6B) are closely related viruses that infect most humans and can integrate their genomes into the telomeres of infected cells. Integration also occurs in germ cells, meaning that the virus can be inherited and result in individuals harboring the virus in every cell of their body. The integrated virus can reactivate and cause disease in humans. While it is well established that the virus resides in the telomere region, the integration locus is poorly defined due to the low sequence complexity (TTAGGG)n of telomeres that cannot be easily resolved through sequencing. We therefore employed genome imaging of the integrated HHV-6A and HHV-6B genomes using whole-genome optical site mapping technology. Using this technology, we identified which chromosome arm harbors the virus genome and obtained a high-resolution map of the integration loci of multiple patients. Surprisingly, this revealed long telomere sequences at the virus-subtelomere junction that were previously missed using PCR-based approaches. Contrary to what was previously thought, our technique revealed that the telomere lengths of chromosomes harboring the integrated virus genome were comparable to the other chromosomes. Taken together, our data shed light on the genetic structure of the HHV-6A and HHV-6B integration locus, demonstrating the utility of optical mapping for the analysis of genomic regions that are difficult to sequence.},
}
@article {pmid33226680,
year = {2021},
author = {Tschirren, B and Romero-Haro, A&#xc1; and Zahn, S and Criscuolo, F},
title = {Sex-specific effects of experimental ectoparasite infestation on telomere length in great tit nestlings.},
journal = {Journal of evolutionary biology},
volume = {34},
number = {3},
pages = {584-589},
doi = {10.1111/jeb.13744},
pmid = {33226680},
issn = {1420-9101},
mesh = {Animals ; Female ; *Host-Parasite Interactions ; Male ; *Sex Characteristics ; Siphonaptera/*physiology ; Songbirds/genetics/*parasitology ; *Telomere Homeostasis ; },
abstract = {Telomere length is a biomarker of biological ageing and lifespan in various vertebrate taxa. Evidence is accumulating that telomeres shorten more rapidly when an individual is exposed to environmental stressors. Parasites are potent selective agents that can cause physiological stress directly or indirectly through the activation of the host's immune system. Yet to date, empirical evidence for a role of parasites in telomere dynamics in natural populations is limited. Here, we show experimentally that exposure to ectoparasitic hen fleas (Ceratophyllus gallinae) during growth results in shorter telomeres in female, but not male, great tit (Parus major) nestlings. Females had longer telomeres than males when growing up in experimentally deparasitized nests but, likely because of the sex-specific effects of ectoparasitism on telomere length, this sexual dimorphism was absent in birds growing up in experimentally infested nests. Our results provide the first experimental evidence for a role of ectoparasitism in telomere dynamics in a natural vertebrate population, and suggest that the costs of infection manifest in sex-specific ways.},
}
@article {pmid33221306,
year = {2021},
author = {Isaevska, E and Moccia, C and Asta, F and Cibella, F and Gagliardi, L and Ronfani, L and Rusconi, F and Stazi, MA and Richiardi, L},
title = {Exposure to ambient air pollution in the first 1000 days of life and alterations in the DNA methylome and telomere length in children: A systematic review.},
journal = {Environmental research},
volume = {193},
number = {},
pages = {110504},
doi = {10.1016/j.envres.2020.110504},
pmid = {33221306},
issn = {1096-0953},
mesh = {*Air Pollutants/analysis/toxicity ; *Air Pollution/adverse effects/analysis ; Child ; Epigenome ; Female ; Humans ; Infant, Newborn ; Maternal Exposure/adverse effects ; Particulate Matter/analysis ; Pregnancy ; Telomere/genetics ; },
abstract = {BACKGROUND: Exposure to air pollution during the first 1000 days of life (from conception to the 2nd year of life) might be of particular relevance for long-term child health. Changes in molecular markers such as DNA methylation and telomere length could underlie the association between air pollution exposure and pollution-related diseases as well as serve as biomarkers for past exposure. The objective of this systematic review was to assess the association between air pollution exposure during pregnancy and the first two years of life and changes in DNA methylation or telomere length in children.<br><br>METHODS: PubMed was searched in October 2020 by using terms relative to ambient air pollution exposure, DNA methylation, telomere length and the population of interest: mother/child dyads and children. Screening and selection of the articles was completed independently by two reviewers. Thirty-two articles matched our criteria. The majority of the articles focused on gestational air pollution exposure and measured DNA methylation/telomere length in newborn cord blood or placental tissue, to study global, candidate-gene or epigenome-wide methylation patterns and/or telomere length. The number of studies in children was limited.<br><br>RESULTS: Ambient air pollution exposure during pregnancy was associated with global loss of methylation in newborn cord blood and placenta, indicating the beginning of the pregnancy as a potential period of susceptibility. Candidate gene and epigenome-wide association studies provided evidence that gestational exposure to air pollutants can lead to locus-specific changes in methylation, in newborn cord blood and placenta, particularly in genes involved in cellular responses to oxidative stress, mitochondrial function, inflammation, growth and early life development. Telomere length shortening in newborns and children was seen in relation to gestational pollutant exposure.<br><br>CONCLUSIONS: Ambient air pollution during pregnancy is associated with changes in both global and locus-specific DNA methylation and with telomere length shortening. Future studies need to test the robustness of the association across different populations, to explore potential windows of vulnerability and assess the role of the methylation and telomere length as mediators in the association between early exposure to ambient air pollutants and specific childhood health outcomes.},
}
@article {pmid33221021,
year = {2021},
author = {Takahashi, S and Arima, H and Nakano, M and Ohki, T and Morita, J and Tabata, K and Takayama, Y and Tanno, K and Yamamoto, T},
title = {Telomere shortening as a stress-related biomarker in children exposed to maternal chronic stress in utero measured 7 years after the Great East Japan Earthquake.},
journal = {Psychiatry research},
volume = {295},
number = {},
pages = {113565},
doi = {10.1016/j.psychres.2020.113565},
pmid = {33221021},
issn = {1872-7123},
mesh = {Adult ; Biomarkers ; Child ; Child, Preschool ; *Earthquakes ; Environmental Exposure/*adverse effects ; Female ; Humans ; Japan ; Male ; Maternal Exposure/*adverse effects ; Middle Aged ; Natural Disasters ; Polymerase Chain Reaction ; Pregnancy ; Prenatal Exposure Delayed Effects/*genetics ; Saliva/chemistry ; Stress, Psychological/*genetics/metabolism ; Telomere Shortening/*genetics/radiation effects ; Time Factors ; },
abstract = {Seven years after the Great East Japan Earthquake, we investigated telomeres as a potential biomarker of maternal chronic stress in children according to the timing of exposure to the disaster. The subjects were children aged 5-9 years living in Rikuzentakata, Japan. Relative telomere length (rTL) was measured with PCR in saliva samples. The partial regression coefficient of the rTL was significantly shorter in the group of children conceived after the disaster than in the children who were in utero on the day of the disaster. Telomere length should be investigated as a biomarker for assessing disaster-related trauma in future studies.},
}
@article {pmid33219062,
year = {2020},
author = {Baltrus, PT and Li, C and H Gaglioti, A},
title = {Having a Usual Source of Care Is Associated with Longer Telomere Length in a National Sample of Older Adults.},
journal = {Journal of the American Board of Family Medicine : JABFM},
volume = {33},
number = {6},
pages = {832-841},
pmid = {33219062},
issn = {1558-7118},
support = {P30 AG031054/AG/NIA NIH HHS/United States ; U54 MD007588/MD/NIMHD NIH HHS/United States ; },
mesh = {Aged ; Cross-Sectional Studies ; Humans ; *Leukocytes ; Nutrition Surveys ; *Telomere ; },
abstract = {OBJECTIVE: To provide a potential biological, mechanistic link for the well-established association between primary care access and reduced mortality, this study sought to measure the impact of having a usual source of health care on leukocyte telomere length (LTL).<br><br>DATA SOURCES: Our study population included 3202 participants aged 50 to 84&#x2009;years from National Health and Nutrition Examination Survey 1999 to 2001.<br><br>STUDY DESIGN: Cross-sectional Study. LTLs between people with and without a usual source of care were compared using unadjusted and adjusted linear regression models. Fully adjusted models accounted for demographic characteristics, health conditions, and health behaviors.<br><br>PRINCIPAL FINDINGS: After controlling for individual factors, health conditions, and health behaviors, people who had a usual source of health care had significantly longer LTL (&#x3b2;&#x2009;=&#x2009;89.8 base pairs, P-value&#x2009;=&#x2009;.005) compared with those without a usual source of care; corresponding to approximately 7&#x2009;years of life.<br><br>CONCLUSIONS: Having a usual source of health care is associated with longer LTL among older adults. This study provides a potential biologic link for the noted association between primary care access and reduced mortality that has been observed at the individual and population level.},
}
@article {pmid33219058,
year = {2020},
author = {Seehusen, DA and Bowman, MA},
title = {Must-Read Family Medicine Research-Glucosamine/Chondroitin Supplements and Mortality, Telomere Length and the Doctor-Patient Relationship, Reducing Opioid Use, and More.},
journal = {Journal of the American Board of Family Medicine : JABFM},
volume = {33},
number = {6},
pages = {823-826},
doi = {10.3122/jabfm.2020.06.200513},
pmid = {33219058},
issn = {1558-7118},
mesh = {*Analgesics, Opioid ; Chondroitin ; Dietary Supplements ; Family Practice ; Glucosamine ; Humans ; *Physician-Patient Relations ; Telomere ; },
abstract = {This issue of the Journal contains some exceptional research articles. A few are truly "must-reads," including a fascinating look at the relationship between having a usual source of care and telomere length. Glucosamine/chrondroitin supplementation seems to be helpful for more than just arthritis pain. There is a very practical advice on keeping patients discharged from the emergency department out of the hospital and on reducing patient requests for inappropriate antibiotics. This issue also features 5 articles addressing how family physicians can combat the opioid epidemic. Three articles highlight research on diabetes and another 3 on breast cancer. Payment reform, dermoscopy, and telemedicine are among many other topics covered.},
}
@article {pmid33218817,
year = {2021},
author = {Li, R and Li, S and Pan, M and Chen, H and Liu, X and Chen, G and Chen, R and Mao, Z and Huo, W and Wang, X and Yu, S and Duan, Y and Guo, Y and Hou, J and Wang, C},
title = {Physical activity attenuated the association of air pollutants with telomere length in rural Chinese adults.},
journal = {The Science of the total environment},
volume = {759},
number = {},
pages = {143491},
doi = {10.1016/j.scitotenv.2020.143491},
pmid = {33218817},
issn = {1879-1026},
mesh = {Adolescent ; Adult ; Aged ; *Air Pollutants/analysis ; *Air Pollution/analysis ; Asian People ; China ; Cohort Studies ; *Diabetes Mellitus, Type 2 ; Environmental Exposure/analysis ; Exercise ; Humans ; Middle Aged ; Nitrogen Dioxide/analysis ; Particulate Matter/analysis ; Telomere ; Young Adult ; },
abstract = {BACKGROUND: Exposure to air pollutants (nitrogen dioxide (NO2) and particulate matters (PMs)) or physical inactivity is linked to telomere length (TL) shortening. However, there is a lack of research on combined effects of either NO2 or PMs and physical activity (PA) on TL. This study aimed to explore the joint associations of air pollutants (NO2 or PMs) and PA with relative TL in rural Chinese adults.<br><br>METHODS: This study was conducted among 2704 participants aged 18-79&#xa0;years in rural China. Concentrations of NO2 and PMs (PM with an aerodynamics diameter&#xa0;&#x2264;&#xa0;1.0&#xa0;&#x3bc;m (PM1), &#x2264;2.5&#xa0;&#x3bc;m (PM2.5) or &#x2264;10&#xa0;&#x3bc;m (PM10)) were estimated using random forest models incorporated with satellites data, meteorological data, and land use information. Relative TL of each participant was measured by a quantitative real-time polymerase chain reaction. Linear regression models were applied to examine the independent associations between PA, NO2 or PMs and relative TL. Interaction plots were used to depict the altered associations between NO2, PM1, PM2.5, or PM10 and relative TL along with increasing PA levels.<br><br>RESULTS: Each 1&#xa0;&#x3bc;g/m[3] increment in NO2, PM1, PM2.5, or PM10 was associated with a 0.038 (95% confidence intervals (CI): -0.044, -0.033), 0.036 (95% CI: -0.041, -0.031), 0.052 (95% CI: -0.059, -0.045), or 0.022 (95% CI: -0.025, -0.019) decrease in relative TL among all participants; similar findings were observed among normal glucose tolerance or impaired fasting glucose (IFG) participants as well as type 2 diabetes mellitus (T2DM) patients. PA at certain levels counteracted the association of air pollutants (NO2, PM1, PM2.5, and PM10) with relative TL among IFG participants or T2DM patients.<br><br>CONCLUSIONS: Long-term exposure to NO2 and PMs was associated with relative TL shortening and these effects may be counteracted by PA at certain levels in IFG participants or T2DM patients.},
}
@article {pmid33216348,
year = {2021},
author = {Nathan, V and Johansson, PA and Palmer, JM and Hamilton, HR and Howlie, M and Brooks, KM and Hayward, NK and Pritchard, AL},
title = {A rare missense variant in protection of telomeres 1 (POT1) predisposes to a range of haematological malignancies.},
journal = {British journal of haematology},
volume = {192},
number = {2},
pages = {e57-e60},
doi = {10.1111/bjh.17218},
pmid = {33216348},
issn = {1365-2141},
support = {9353763//Highlands and Islands Enterprise/ ; 1093017//National Health and Medical Research Council/ ; 1117663//National Health and Medical Research Council/ ; //Cure Cancer Australia Foundation/ ; },
mesh = {Female ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Hematologic Neoplasms/*genetics ; Humans ; Male ; *Mutation, Missense ; Pedigree ; Shelterin Complex ; Telomere-Binding Proteins/*genetics ; },
}
@article {pmid33216232,
year = {2020},
author = {Lee, KH and Kimmel, M},
title = {Stationary Distribution of Telomere Lengths in Cells with Telomere Length Maintenance and its Parametric Inference.},
journal = {Bulletin of mathematical biology},
volume = {82},
number = {12},
pages = {150},
doi = {10.1007/s11538-020-00811-1},
pmid = {33216232},
issn = {1522-9602},
support = {5 R01 HL128173/NH/NIH HHS/United States ; },
mesh = {Bayes Theorem ; *Cell Physiological Phenomena ; Cellular Senescence/genetics ; *Models, Biological ; *Telomere/genetics ; *Telomere Homeostasis/genetics ; },
abstract = {Telomeres are nucleotide caps located at the ends of each eukaryotic chromosome. Under normal physiological conditions as well as in culture, they shorten during each DNA replication round. Short telomeres initiate a proliferative arrest of cells termed 'replicative senescence'. However, cancer cells possessing limitless replication potential can avoid senescence by the telomere maintenance mechanism, which offsets telomeric loss. Therefore, cancer cells have sufficiently long telomeres even though their lengths are significantly shorter than their normal counterparts. This implies that the attrition and elongation rates play crucial roles in deciding whether and when cells ultimately become carcinogenic. In this research, we propose a concise mathematical model that shows the shortest telomere length at each cell division and prove mathematical conditions related to the attrition and elongation rates, which are necessary and sufficient for the existence of stationary distribution of telomere lengths. Moreover, we estimate the parameters of the telomere length maintenance process based on frequentist and Bayesian approaches. This study expands our knowledge of the mathematical relationship between the telomere attrition and elongation rates in cancer cells, which is important because the telomere length dynamics is a useful biomarker of cancer diagnosis and prognosis.},
}
@article {pmid33214205,
year = {2021},
author = {Justet, A and Klay, D and Porcher, R and Cottin, V and Ahmad, K and Molina Molina, M and Nunes, H and Reynaud-Gaubert, M and Naccache, JM and Manali, E and Froidure, A and Jouneau, S and Wemeau, L and Andrejak, C and Gondouin, A and Hirschi, S and Blanchard, E and Bondue, B and Bonniaud, P and Tromeur, C and Prévot, G and Marchand-Adam, S and Funke-Chambour, M and Gamez, AS and Ba, I and Papiris, S and Grutters, J and Crestani, B and van Moorsel, C and Kannengiesser, C and Borie, R and , },
title = {Safety and efficacy of pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis and carrying a telomere-related gene mutation.},
journal = {The European respiratory journal},
volume = {57},
number = {2},
pages = {},
doi = {10.1183/13993003.03198-2020},
pmid = {33214205},
issn = {1399-3003},
mesh = {Humans ; *Idiopathic Pulmonary Fibrosis/drug therapy/genetics ; Indoles ; Mutation ; Pyridones/therapeutic use ; *Telomere ; Treatment Outcome ; },
}
@article {pmid33211388,
year = {2021},
author = {Bicanova, L and Kreilmeier-Berger, T and Reifinger, M and Holzmann, K and Kleiter, M},
title = {Prevalence and potentially prognostic value of C-circles associated with alternative lengthening of telomeres in canine appendicular osteosarcoma.},
journal = {Veterinary and comparative oncology},
volume = {19},
number = {2},
pages = {222-231},
pmid = {33211388},
issn = {1476-5829},
mesh = {Animals ; *Bone Neoplasms/veterinary ; *Dog Diseases ; Dogs ; Humans ; Male ; *Osteosarcoma/veterinary ; Prevalence ; Prognosis ; Retrospective Studies ; *Telomerase/metabolism ; Telomere/metabolism ; },
abstract = {Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism (TMM) with high prevalence in human osteosarcomas but remains unknown in canine osteosarcomas. The aim of this study was to evaluate the prevalence of ALT by detection of extra-chromosomal circles of telomeric DNA and to assess clinical outcome in canine patients with spontaneous occurring appendicular osteosarcoma. Fifty dogs with histopathological confirmed osteosarcomas were included into this study. Medical records were retrospectively analysed for patient characteristics, oncologic therapy and survival. DNA was isolated from archived FFPE tumour tissue specimens and applied for C- and G-circle assay (CCA and GCA) and for telomeric content (TC) measurement with radiolabeled probes. ALT activity was detected for 10 of 50 (20%) cases by CCA. Four CCA positive cases were detected even with input DNA below 1 ng and demonstrated the high sensitivity of CCA for canine tumours. G-circles and TC were not suitable to distinguish CCA positive and negative cases. CCA-status showed an association with male gender and Rottweiler breed. Dogs with CCA positive osteosarcomas had shorter overall survival times than patients with CCA-tumours and CCA-status was a significant prognostic factor besides treatment in the Cox proportional hazard model. These findings make canine osteosarcomas an interesting model for comparative TMM research, but future studies are warranted to investigate if CCA-status can serve as novel prognostic marker.},
}
@article {pmid33211200,
year = {2021},
author = {Salas-Huetos, A and Tüttelmann, F and Wyrwoll, MJ and Kliesch, S and Lopes, AM and Goncalves, J and Boyden, SE and Wöste, M and Hotaling, JM and , and Nagirnaja, L and Conrad, DF and Carrell, DT and Aston, KI},
title = {Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermia.},
journal = {Human genetics},
volume = {140},
number = {1},
pages = {217-227},
pmid = {33211200},
issn = {1432-1203},
support = {P50 HD096723/HD/NICHD NIH HHS/United States ; R01 HD078641/HD/NICHD NIH HHS/United States ; DFG CRU326//German Research Foundation/ ; R01HD078641//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; },
mesh = {Adult ; Aged ; Azoospermia/*genetics ; Cell Cycle Proteins/*genetics ; DNA-Binding Proteins/*genetics ; Exome/genetics ; Heterozygote ; Homozygote ; Humans ; Male ; Meiosis/*genetics ; Membrane Proteins/*genetics ; Mutation, Missense/genetics ; Phenotype ; Spermatogenesis/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics ; Testis/pathology ; Exome Sequencing/methods ; },
abstract = {Non-obstructive azoospermia (NOA), the lack of spermatozoa in semen due to impaired spermatogenesis affects nearly 1% of men. In about half of cases, an underlying cause for NOA cannot be identified. This study aimed to identify novel variants associated with idiopathic NOA. We identified a nonconsanguineous family in which multiple sons displayed the NOA phenotype. We performed whole-exome sequencing in three affected brothers with NOA, their two unaffected brothers and their father, and identified compound heterozygous frameshift variants (one novel and one extremely rare) in Telomere Repeat Binding Bouquet Formation Protein 2 (TERB2) that segregated perfectly with NOA. TERB2 interacts with TERB1 and Membrane Anchored Junction Protein (MAJIN) to form the tripartite meiotic telomere complex (MTC), which has been shown in mouse models to be necessary for the completion of meiosis and both male and female fertility. Given our novel findings of TERB2 variants in NOA men, along with the integral role of the three MTC proteins in spermatogenesis, we subsequently explored exome sequence data from 1495 NOA men to investigate the role of MTC gene variants in spermatogenic impairment. Remarkably, we identified two NOA patients with likely damaging rare homozygous stop and missense variants in TERB1 and one NOA patient with a rare homozygous missense variant in MAJIN. Available testis histology data from three of the NOA patients indicate germ cell maturation arrest, consistent with mouse phenotypes. These findings suggest that variants in MTC genes may be an important cause of NOA in both consanguineous and outbred populations.},
}
@article {pmid33206065,
year = {2021},
author = {Tang, J and Wu, J and Zhu, R and Wang, Z and Zhao, C and Tang, P and Xie, W and Wang, D and Liang, L},
title = {Reversible photo-regulation on the folding/unfolding of telomere G-quadruplexes with solid-state nanopores.},
journal = {The Analyst},
volume = {146},
number = {2},
pages = {655-663},
doi = {10.1039/d0an01930e},
pmid = {33206065},
issn = {1364-5528},
mesh = {Azo Compounds/chemistry ; *G-Quadruplexes ; *Nanopores ; Nanotechnology/*methods ; Telomere/*chemistry ; },
abstract = {The formation of G-quadruplexes (G4) in human telomere and other important biological regions inhibits the replication and transcription of DNA, thereby influencing further cell proliferation. The investigation of G4 formation and unfolding is vital for understanding their modulation in biological processes and life science. Photo regulation is a facile and sensitive approach for monitoring the structures of biomacromolecules and material surface properties. The nanopore-based technique is also prevalent for label-free single-molecule characterization with high accuracy. This study provides a combination of solid-state nanopore technology with light-switch as a platform for the modulation of human telomere G4 formation and splitting under switchable light exposure. The introduction of molecular switch, namely azobenzene moiety at different positions of the DNA sequence influences the formation and stability of G4. Three azobenzenes immobilized on each of the G-quartet plane (hTelo-3azo-p) or four azobenzenes on the same plane (hTelo-4azo-4p) of the human telomere G4 sequence realized the reversible control of G4 folding/unfolding at the temporal scale upon photo regulation, and the formation and splitting of G4 with hTelo-4azo-4p is slower and not thorough compared to that with hTelo-3azo-p due to the coplanar steric hindrance. Moreover, the G4 formation recorded with the combined nanopore and photo-responsive approach was also characterized with fluorescence, and the variation in the fluorescence intensity of the NMM and G4 complex exhibited a different tendency under reverse light irradiation due to the distinct interactions of NMM with the azobenzene-modified G4. Our study demonstrated a controllable and sensitive way for the manipulation of G4 structures, which will be inspiring for the intervention of G4-related cell senescence, cancer diagnosis and drug exploration.},
}
@article {pmid33206062,
year = {2020},
author = {Hachmo, Y and Hadanny, A and Abu Hamed, R and Daniel-Kotovsky, M and Catalogna, M and Fishlev, G and Lang, E and Polak, N and Doenyas, K and Friedman, M and Zemel, Y and Bechor, Y and Efrati, S},
title = {Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells: a prospective trial.},
journal = {Aging},
volume = {12},
number = {22},
pages = {22445-22456},
pmid = {33206062},
issn = {1945-4589},
mesh = {Age Factors ; Aged ; Aged, 80 and over ; *Aging/genetics/immunology/metabolism ; Female ; Healthy Volunteers ; Humans ; *Hyperbaric Oxygenation ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; *Immunosenescence ; Israel ; Lymphocyte Subsets/*immunology/metabolism ; Male ; Middle Aged ; Prospective Studies ; *Telomere Homeostasis ; *Telomere Shortening ; Time Factors ; Treatment Outcome ; },
abstract = {INTRODUCTION: Aging is characterized by the progressive loss of physiological capacity. At the cellular level, two key hallmarks of the aging process include telomere length (TL) shortening and cellular senescence. Repeated intermittent hyperoxic exposures, using certain hyperbaric oxygen therapy (HBOT) protocols, can induce regenerative effects which normally occur during hypoxia. The aim of the current study was to evaluate whether HBOT affects TL and senescent cell concentrations in a normal, non-pathological, aging adult population.<br><br>METHODS: Thirty-five healthy independently living adults, aged 64 and older, were enrolled to receive 60 daily HBOT exposures. Whole blood samples were collected at baseline, at the 30[th] and 60[th] session, and 1-2 weeks following the last HBOT session. Peripheral blood mononuclear cells (PBMCs) telomeres length and senescence were assessed.<br><br>RESULTS: Telomeres length of T helper, T cytotoxic, natural killer and B cells increased significantly by over 20% following HBOT. The most significant change was noticed in B cells which increased at the 30[th] session, 60[th] session and post HBOT by 25.68%&#xb1;40.42 (p=0.007), 29.39%&#xb1;23.39 (p=0.0001) and 37.63%&#xb1;52.73 (p=0.007), respectively. There was a significant decrease in the number of senescent T helpers by -37.30%&#xb1;33.04 post-HBOT (P<0.0001). T-cytotoxic senescent cell percentages decreased significantly by -10.96%&#xb1;12.59 (p=0.0004) post-HBOT. In conclusion, the study indicates that HBOT may induce significant senolytic effects including significantly increasing telomere length and clearance of senescent cells in the aging populations.},
}
@article {pmid33203878,
year = {2020},
author = {Cicconi, A and Rai, R and Xiong, X and Broton, C and Al-Hiyasat, A and Hu, C and Dong, S and Sun, W and Garbarino, J and Bindra, RS and Schildkraut, C and Chen, Y and Chang, S},
title = {Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {5861},
pmid = {33203878},
issn = {2041-1723},
support = {R01 GM045751/GM/NIGMS NIH HHS/United States ; T32 CA193200/CA/NCI NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; },
mesh = {Aminopeptidases/genetics/metabolism ; Animals ; Binding Sites ; Calorimetry ; Cell Cycle Proteins/chemistry/genetics/*metabolism ; Cytoskeletal Proteins/chemistry/genetics/*metabolism ; DNA Damage ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics/metabolism ; Fibroblasts ; HeLa Cells ; Histones/genetics/metabolism ; Humans ; Mice ; Microcephaly/*genetics ; Mutation ; Protein Interaction Domains and Motifs ; Serine Proteases/genetics/metabolism ; Shelterin Complex ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Telomeric Repeat Binding Protein 2/chemistry/genetics/*metabolism ; },
abstract = {Telomeres protect chromosome ends from inappropriately activating the DNA damage and repair responses. Primary microcephaly is a key clinical feature of several human telomere disorder syndromes, but how microcephaly is linked to dysfunctional telomeres is not known. Here, we show that the microcephalin 1/BRCT-repeats inhibitor of hTERT (MCPH1/BRIT1) protein, mutated in primary microcephaly, specifically interacts with the TRFH domain of the telomere binding protein TRF2. The crystal structure of the MCPH1-TRF2 complex reveals that this interaction is mediated by the MCPH1 330YRLSP334 motif. TRF2-dependent recruitment of MCPH1 promotes localization of DNA damage factors and homology directed repair of dysfunctional telomeres lacking POT1-TPP1. Additionally, MCPH1 is involved in the replication stress response, promoting telomere replication fork progression and restart of stalled telomere replication forks. Our work uncovers a previously unrecognized role for MCPH1 in promoting telomere replication, providing evidence that telomere replication defects may contribute to the onset of microcephaly.},
}
@article {pmid33203829,
year = {2020},
author = {Ferrer, A and Mangaonkar, AA and Stroik, S and Zimmermann, MT and Sigafoos, AN and Kamath, PS and Simonetto, DA and Wylam, ME and Carmona, EM and Lazaridis, KN and Peters, S and Stewart, K and Klee, EW and Hendrickson, EA and Patnaik, MM},
title = {Functional validation of TERT and TERC variants of uncertain significance in patients with short telomere syndromes.},
journal = {Blood cancer journal},
volume = {10},
number = {11},
pages = {120},
pmid = {33203829},
issn = {2044-5385},
support = {R01 CA190492/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; RNA/*metabolism ; Syndrome ; Telomerase/*metabolism ; *Telomere Shortening ; },
}
@article {pmid33201323,
year = {2020},
author = {Criscuolo, F and Pillay, N and Zahn, S and Schradin, C},
title = {Seasonal variation in telomere dynamics in African striped mice.},
journal = {Oecologia},
volume = {194},
number = {4},
pages = {609-620},
pmid = {33201323},
issn = {1432-1939},
mesh = {Aging ; Animals ; Food ; Humans ; Male ; Mice ; *Murinae/genetics ; Seasons ; *Telomere ; Telomere Shortening ; },
abstract = {Telomere shortening has been used as an indicator of aging and is believed to accelerate under harsh environmental conditions. This can be attributed to the fact that telomere shortening has often been regarded as non-reversible and negatively impacting fitness. However, studies of laboratory mice indicate that they may be able to repair telomere loss to recover from environmental harshness, as indicated by recent studies in hibernating rodents. We studied seasonal variation in telomere dynamics in African striped mice (Rhabdomys pumilio) living in a highly seasonal environment. In our annual species, individuals born in the moist spring (high food availability) need to survive the harsh dry summer (low food availability) to be able to reproduce in the following spring. We studied the effect of the harsh dry vs. the benign moist season on telomere dynamics. We also tested if telomere length or the rate of change in telomere length over the dry season predicted the probablity of dissapearance from the population at the same time. Male, but not female, stripped mice showed age-related telomere erosion. Telomeres were longer at the beginning of the dry season compared to the rest of the year. Telomeres increased significantly in length during the moist season. Neither telomere length at the onset of the dry season nor telomere loss over the dry season predicted whether or not individuals disappeared. In conclusion, our data suggest that seasonal attrition and restoring of telomeres also occurs in non-hibernating wild rodents living in hot food restricted environments.},
}
@article {pmid33198936,
year = {2020},
author = {Gaikwad, AS and Mahmood, R and B, R and Kondhalkar, S},
title = {Evaluation of telomere length and genotoxicity among asphalt associated workers.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {858-860},
number = {},
pages = {503255},
doi = {10.1016/j.mrgentox.2020.503255},
pmid = {33198936},
issn = {1879-3592},
mesh = {8-Hydroxy-2'-Deoxyguanosine/urine ; Adult ; Case-Control Studies ; Environmental Monitoring/methods ; Environmental Pollutants/*poisoning ; Female ; Humans ; Hydrocarbons/*poisoning ; India ; Male ; Micronucleus Tests/methods ; Mutagenicity Tests/*methods ; Occupational Exposure/*analysis ; Particulate Matter ; Telomere/*drug effects/genetics ; Telomere Homeostasis/*drug effects/genetics ; Young Adult ; },
abstract = {There are contradictory reports about bitumen exposure and malignancy risk worldwide. Also, the evidence for genotoxicity risk among workers occupationally exposed to asphalt is insufficient. The study intended to evaluate particulate matter 10 (PM10) at the workplace and biomarkers of genotoxicity effects among a group of asphalt workers in and around Bangalore, India. This study involved a total of 107 participants (54 exposed group and 53 unexposed control group). To evaluate the genotoxicity, the urinary 8-OHdG and relative telomere length as oxidative damage while micronucleus (MN) assay for cytogenetic damage was carried out during the study. The majority of workers have reported health complaints and 57.4% of them were not using any personal protective equipments (PPE's). The level of PM10 detected was 104 ± 9.5 μg/m[3] and 619 ± 22.7 μg/m[3] in the road paving and asphalt mixing sites respectively. The biomonitoring study observed a highly significant (p = <0.001) increase in the level of 8-hydroxy-2-deoxyguanosine (8-OHdG) in the exposed group (23.17 ± 8.65 ng/mg creatinine) compared to the control (13.6 ± 7.12 ng/mg creatinine), revealed age significant associated and non-smoking borderline significant associated for oxidative stress. The relative telomere length (TL) analysis revealed its highly significant (p = 0.004) reduction in the exposed group, adjusted mean 0.95 (95% CI 0.83-1.07) compared to the control 1.06 (95% CI 0.91-1.26). The job category (p = 0.028), non-smoking (p = 0.026), and tobacco chewing (p = 0.013) were associated with reduced relative TL in the asphalt exposed group. In cytogenotoxicity analysis, the mean micronucleus (MN) frequency per 100 cells in the exposed group (26.46 ± 19.8) was significantly (p = <0.001) increased over the control group (8.56 ± 7.18). Neither smoking habit nor age appeared to influence the MN frequencies in either group. In the present study, we have demonstrated genetic damage in workers occupationally exposed to asphalt and particulate matter, raising concern for an increased risk of malignancy in these workers.},
}
@article {pmid33198931,
year = {2020},
author = {Xue, Y and Guo, X and Huang, X and Zhu, Z and Chen, M and Chu, J and Yang, G and Wang, Q and Kong, X},
title = {Shortened telomere length in peripheral blood leukocytes of patients with lung cancer, chronic obstructive pulmonary disease in a high indoor air pollution region in China.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {858-860},
number = {},
pages = {503250},
doi = {10.1016/j.mrgentox.2020.503250},
pmid = {33198931},
issn = {1879-3592},
mesh = {Aged ; Air Pollution, Indoor/adverse effects/*analysis ; China/epidemiology ; Coal ; Female ; Humans ; Incidence ; Leukocytes/*metabolism ; Lung Neoplasms/epidemiology/etiology/*genetics ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/epidemiology/etiology/*genetics ; Risk Assessment/methods/statistics &amp; numerical data ; Risk Factors ; Smoke ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Lung cancer and chronic obstructive pulmonary disease (COPD) are closely linked diseases. In Xuanwei, China, the extremely high incidence and mortality rates of lung cancer and COPD are associated with exposure to household smoky coal burning. Previous studies found that telomere length was related to lung disease. The objective of this study is to investigate the relationship of peripheral blood leukocyte telomere length to both lung cancer and COPD, as well as indoor coal smoke exposure in Xuanwei. We measured telomere length using quantitative polymerase chain reaction (qPCR) in peripheral blood leukocytes of 216 lung cancer patients, 296 COPD patients, and 426 healthy controls from Xuanwei. The telomere length ratios (mean ± SD) in patients with lung cancer (0.76 ± 0.35) and COPD (0.81 ± 0.35) were significantly shorter than in that of controls (0.95 ± 0.39). Individuals with the shortest tertile telomere length had 3.90- and 4.54-fold increased risks of lung cancer and COPD, respectively, compared with individuals with the longest tertile telomere length. No correlation was found between telomere length and pack-years of smoking. In healthy subjects, coal smoke exposure level affected telomere length. Lung function was positively and negatively associated with telomere length and environmental exposure, respectively, when combination the control and COPD groups. The result suggests that shortened telomere length in peripheral blood leukocytes was associated with lung cancer and COPD and might be affected by coal smoke exposure level in Xuanwei. Whether variation in telomere length caused by environmental exposure has a role in lung cancer and COPD development and exacerbation needs further research.},
}
@article {pmid33198352,
year = {2020},
author = {Gadji, M and Mathur, S and Bélanger, B and Jangamreddy, JR and Lamoureux, J and Tsanaclis, AMC and Fortin, D and Drouin, R and Mai, S},
title = {Three-Dimensional Nuclear Telomere Profiling as a Biomarker for Recurrence in Oligodendrogliomas: A Pilot Study.},
journal = {International journal of molecular sciences},
volume = {21},
number = {22},
pages = {},
pmid = {33198352},
issn = {1422-0067},
support = {763110142//Leukemia and Lymphoma Society of Canada/ ; },
mesh = {Adult ; Aged ; Biomarkers, Tumor/*metabolism ; Biopsy ; Brain Neoplasms/*diagnosis/genetics/pathology ; Cell Nucleus/*metabolism ; Chromosomes, Human, Pair 1 ; Chromosomes, Human, Pair 19 ; Disease Progression ; Female ; Genomics ; Humans ; Imaging, Three-Dimensional ; In Situ Hybridization, Fluorescence ; Kaplan-Meier Estimate ; Male ; Middle Aged ; *Neoplasm Recurrence, Local ; Oligodendroglioma/*diagnosis/genetics/pathology ; Pilot Projects ; Prospective Studies ; Quality of Life ; Telomere/*metabolism/ultrastructure ; Treatment Outcome ; },
abstract = {Mechanisms of recurrence in oligodendrogliomas are poorly understood. Recurrence might be driven by telomere dysfunction-mediated genomic instability. In a pilot study, we investigated ten patients with oligodendrogliomas at the time of diagnosis (first surgery) and after recurrence (second surgery) using three-dimensional nuclear telomere analysis performed with quantitative software TeloView[®] (Telo Genomics Corp, Toronto, Ontario, Canada). 1p/19q deletion status of each patient was determined by fluorescent in situ hybridization on touch preparation slides. We found that a very specific 3D telomeric profile was associated with two pathways of recurrence in oligodendrogliomas independent of their 1p/19q status: a first group of 8 patients displayed significantly different 3D telomere profiles between both surgeries (p < 0.0001). Their recurrence happened at a mean of 231.375 ± 117.42 days and a median time to progression (TTP) of 239 days, a period defined as short-term recurrence; and a second group of three patients displayed identical 3D telomere profiles between both surgery samples (p > 0.05). Their recurrence happened at a mean of 960.666 ± 86.19 days and a median TTP of 930 days, a period defined as long-term recurrence. Our results suggest a potential link between nuclear telomere architecture and telomere dysfunction with time to recurrence in oligodendrogliomas, independently of the 1p/19q status.},
}
@article {pmid33197388,
year = {2021},
author = {Duckworth, A and Gibbons, MA and Allen, RJ and Almond, H and Beaumont, RN and Wood, AR and Lunnon, K and Lindsay, MA and Wain, LV and Tyrrell, J and Scotton, CJ},
title = {Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study.},
journal = {The Lancet. Respiratory medicine},
volume = {9},
number = {3},
pages = {285-294},
doi = {10.1016/S2213-2600(20)30364-7},
pmid = {33197388},
issn = {2213-2619},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; //British Heart Foundation/United Kingdom ; //Department of Health/United Kingdom ; //Wellcome Trust/United Kingdom ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aged ; Case-Control Studies ; Causality ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/epidemiology/*genetics ; Male ; Mendelian Randomization Analysis ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/epidemiology/*genetics ; Risk Factors ; Telomere Shortening/*genetics ; },
abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease accounting for 1% of UK deaths. In the familial form of pulmonary fibrosis, causal genes have been identified in about 30% of cases, and a majority of these causal genes are associated with telomere maintenance. Prematurely shortened leukocyte telomere length is associated with IPF and chronic obstructive pulmonary disease (COPD), a disease with similar demographics and shared risk factors. Using mendelian randomisation, we investigated evidence supporting a causal role for short telomeres in IPF and COPD.<br><br>METHODS: Mendelian randomisation inference of telomere length causality was done for IPF (up to 1369 cases) and COPD (13&#x2008;538 cases) against 435&#x2008;866 controls of European ancestry in UK Biobank. Polygenic risk scores were calculated and two-sample mendelian randomisation analyses were done using seven genetic variants previously associated with telomere length, with replication analysis in an IPF cohort (2668 cases vs 8591 controls) and COPD cohort (15&#x2008;256 cases vs 47&#x2008;936 controls).<br><br>FINDINGS: In the UK Biobank, a genetically instrumented one-SD shorter telomere length was associated with higher odds of IPF (odds ratio [OR] 4&#xb7;19, 95% CI 2&#xb7;33-7&#xb7;55; p=0&#xb7;0031) but not COPD (1&#xb7;07, 0&#xb7;88-1&#xb7;30; p=0&#xb7;51). Similarly, an association was found in the IPF replication cohort (12&#xb7;3, 5&#xb7;05-30&#xb7;1; p=0&#xb7;0015) and not in the COPD replication cohort (1&#xb7;04, 0&#xb7;71-1&#xb7;53; p=0&#xb7;83). Meta-analysis of the two-sample mendelian randomisation results provided evidence inferring that shorter telomeres cause IPF (5&#xb7;81 higher odds of IPF, 95% CI 3&#xb7;56-9&#xb7;50; p=2&#xb7;19&#x2008;&#xd7;&#x2008;10[-12]). There was no evidence to infer that telomere length caused COPD (OR 1&#xb7;07, 95% CI 0&#xb7;90-1&#xb7;27; p=0&#xb7;46).<br><br>INTERPRETATION: Cellular senescence is hypothesised as a major driving force in IPF and COPD; telomere shortening might be a contributory factor in IPF, suggesting divergent mechanisms in COPD. Defining a key role for telomere shortening enables greater focus in telomere-related diagnostics, treatments, and the search for a cure in IPF. Investigation of therapies that improve telomere length is warranted.<br><br>FUNDING: Medical Research Council.},
}
@article {pmid33193711,
year = {2020},
author = {Gao, Y and Wei, Y and Zhou, X and Huang, S and Zhao, H and Zeng, P},
title = {Assessing the Relationship Between Leukocyte Telomere Length and Cancer Risk/Mortality in UK Biobank and TCGA Datasets With the Genetic Risk Score and Mendelian Randomization Approaches.},
journal = {Frontiers in genetics},
volume = {11},
number = {},
pages = {583106},
pmid = {33193711},
issn = {1664-8021},
support = {/WT_/Wellcome Trust/United Kingdom ; MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; },
abstract = {BACKGROUND: Telomere length is an important indicator of tumor progression and survival for cancer patients. Previous work investigated the associations between genetically predicted telomere length and cancers; however, the types of cancers investigated in those studies were relatively limited or the telomere length-associated genetic variants employed often came from genome-wide association studies (GWASs) with small sample sizes.<br><br>METHODS: We constructed the genetic risk score (GRS) for leukocyte telomere length based on 17 associated genetic variants available from the largest telomere length GWAS up to 78,592 individuals. Then, a comprehensive analysis was undertaken to evaluate the association between the constructed GRS and the risk or mortality of a wide range of cancers [i.e., 37 cancers in the UK Biobank and 33 cancers in The Cancer Genome Atlas (TCGA)]. We further applied the two-sample Mendelian randomization (MR) to estimate the causal effect of leukocyte telomere length on UK Biobank cancers via summary statistics.<br><br>RESULTS: In the UK Biobank dataset, we found that the GRS of leukocyte telomere length was associated with a decreased risk of nine types of cancer (i.e., significant association with multiple myeloma, chronic lymphocytic leukemia, kidney/renal cell cancer, bladder cancer, malignant melanoma, basal cell carcinoma, and prostate cancer and suggestive association with sarcoma/fibrosarcoma and Hodgkin's lymphoma/Hodgkin's disease). In addition, we found that the GRS was suggestively associated with an increased risk of leukemia. In the TCGA dataset, we observed suggestive evidence that the GRS was associated with a high death hazard of rectum adenocarcinoma (READ), sarcoma (SARC), and skin cutaneous melanoma (SKCM), while the GRS was associated with a low death hazard of kidney renal papillary cell carcinoma (KIRP). The results of MR further supported the association for leukocyte telomere length on the risk of malignant melanoma, Hodgkin's lymphoma/Hodgkin's disease, chronic lymphocytic leukemia and multiple myeloma.<br><br>CONCLUSION: Our study reveals that telomere played diverse roles in different types of cancers. However, further validations in large-scale prospective studies and deeper investigations of the biologic mechanisms are warranted.},
}
@article {pmid33192450,
year = {2020},
author = {Linghui, D and Shi, Q and Chi, C and Xiaolei, L and Lixing, Z and Zhiliang, Z and Birong, D},
title = {The Association Between Leukocyte Telomere Length and Cognitive Performance Among the American Elderly.},
journal = {Frontiers in aging neuroscience},
volume = {12},
number = {},
pages = {527658},
pmid = {33192450},
issn = {1663-4365},
abstract = {BACKGROUND: Age-related cognitive decline begins in middle age and persists with age. Leukocyte telomere length (LTL) decreases with age and is enhanced by inflammation and oxidative stress. However, whether shorter LTL correlates with cognitive decline remains controversial.<br><br>AIMS: We aimed to investigate the relationship between LTL and cognitive decline in the American elderly.<br><br>METHODS: We used data from the 1999 to 2002 U.S. National Health and Nutrition Examination Survey (NHANES). We included participants aged 65-80 with available data on LTL and cognitive assessments. The cognitive function assessment used the digit symbol substitution test (DSST). We applied multivariate modeling to estimate the association between LTL and cognitive performance. Additionally, to ensure robust data analysis, we converted LTL into categorical variables through quartile and then calculated the P for trend.<br><br>RESULTS: After adjusting for age, cardiovascular disease (CAD) score, gender, race, body mass index (BMI), and educational level, LTL showed a positive correlation with DSST score (odds ratio [OR] 3.47 [0.14, 6.79], P = 0.04). Additionally, to further quantify the LTL-DSST interaction, we found a similar trend when LTL was regarded as a categorical variable (quartile) (P for trend = 0.03).<br><br>CONCLUSION: LTL was associated with cognitive capabilities among the elderly, implying that LTL might be a biomarker of cognitive aging.},
}
@article {pmid33190211,
year = {2021},
author = {El Assar, M and Angulo, J and Carnicero, JA and Walter, S and García-García, FJ and Rodríguez-Artalejo, F and Rodríguez-Mañas, L},
title = {Association between telomere length, frailty and death in older adults.},
journal = {GeroScience},
volume = {43},
number = {2},
pages = {1015-1027},
pmid = {33190211},
issn = {2509-2723},
mesh = {Aged ; Aging/genetics ; Biomarkers ; *Frailty/genetics ; Humans ; Independent Living ; Telomere/genetics ; },
abstract = {Frailty is considered a clinical marker of functional ageing. Telomere length (TL) has been proposed as a biomarker of biological age but its role in human ageing is controversial. The main aim of the study was to evaluate the longitudinal association of TL with incident frailty and mortality in two cohorts of Spanish community-dwelling older adults. TL was determined at baseline in blood samples from older adults included in Toledo Study for Healthy Aging and ENRICA cohorts while frailty was determined by frailty phenotype (FP) at baseline and at follow-up (3.5 years). Deaths occurring during follow-up were also recorded. Associations of TL with frailty and mortality were analysed by logistic regression with progressive adjustment. Data were separately analysed in the two cohorts and in all subjects by performing a meta-analysis. TL was not different between frail and non-frail subjects. Longer telomeres were not associated with lower risk of prevalent frailty. Similarly, TL at baseline failed to predict incident frailty (OR: 1.04 [0.88-1.23]) or even the development of a new FP criterion (OR: 0.97 [0.90-1.05]) at follow-up. Lack of association was also observed when analysing the development of specific FP criteria. Finally, while frailty at baseline was significantly associated with higher risk of death at follow-up (OR: 4.08 [1.97-8.43], p < 0.001), TL did not significantly change the mortality risk (OR: 1.05 [0.94-1.16]). Results show that TL does not predict incident frailty or mortality in older adults. This suggests that TL is not a reliable biomarker of functional age.},
}
@article {pmid33188147,
year = {2021},
author = {Mangosh, TL and Awadallah, WN and Grabowska, MM and Taylor, DJ},
title = {SLX4IP Promotes Telomere Maintenance in Androgen Receptor-Independent Castration-Resistant Prostate Cancer through ALT-like Telomeric PML Localization.},
journal = {Molecular cancer research : MCR},
volume = {19},
number = {2},
pages = {301-316},
pmid = {33188147},
issn = {1557-3125},
support = {R01 CA240993/CA/NCI NIH HHS/United States ; R01 GM133841/GM/NIGMS NIH HHS/United States ; T32 GM008056/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Carrier Proteins/*metabolism ; Humans ; Male ; Mice ; Mice, Nude ; Prostatic Neoplasms, Castration-Resistant/*genetics/pathology ; Receptors, Androgen/*metabolism ; Signal Transduction ; Telomere/*metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {In advanced prostate cancer, resistance to androgen deprivation therapy is achieved through numerous mechanisms, including loss of the androgen receptor (AR) allowing for AR-independent growth. Therapeutic options are limited for AR-independent castration-resistant prostate cancer (CRPC), and defining mechanisms critical for survival is of utmost importance for targeting this lethal disease. Our studies focus on identifying telomere maintenance mechanism (TMM) hallmarks adopted by CRPC to promote survival. TMMs are responsible for telomere elongation to instill replicative immortality and prevent senescence, with the two TMM pathways available being telomerase and alternative lengthening of telomeres (ALT). Here, we show that AR-independent CRPC demonstrates an atypical ALT-like phenotype with variable telomerase expression and activity, whereas AR-dependent models lack discernible ALT hallmarks. In addition, AR-independent CRPC cells exhibited elevated levels of SLX4IP, a protein implicated in promoting ALT. SLX4IP overexpression in AR-dependent C4-2B cells promoted an ALT-like phenotype and telomere maintenance. SLX4IP knockdown in AR-independent DU145 and PC-3 cells led to ALT-like hallmark reduction, telomere shortening, and induction of senescence. In PC-3 xenografts, this effect translated to reduced tumor volume. Using an in vitro model of AR-independent progression, loss of AR in AR-dependent C4-2B cells promoted an atypical ALT-like phenotype in an SLX4IP-dependent manner. Insufficient SLX4IP expression diminished ALT-like hallmarks and resulted in accelerated telomere loss and senescence. IMPLICATIONS: This study demonstrates a unique reliance of AR-independent CRPC on SLX4IP-mediated ALT-like hallmarks and loss of these hallmarks induces telomere shortening and senescence, thereby impairing replicative immortality.},
}
@article {pmid33187969,
year = {2021},
author = {Antwi, SO and Bamlet, WR and Cawthon, RM and Rabe, KG and Druliner, BR and Sicotte, H and Jatoi, A and Mahipal, A and Boardman, LA and Oberg, AL and Petersen, GM},
title = {Shorter Treatment-Naïve Leukocyte Telomere Length is Associated with Poorer Overall Survival of Patients with Pancreatic Ductal Adenocarcinoma.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {30},
number = {1},
pages = {210-216},
pmid = {33187969},
issn = {1538-7755},
support = {KL2 TR002379/TR/NCATS NIH HHS/United States ; P50 CA102701/CA/NCI NIH HHS/United States ; K01 CA237875/CA/NCI NIH HHS/United States ; R01 CA204013/CA/NCI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/blood ; Carcinoma, Pancreatic Ductal/blood/*mortality ; Female ; Humans ; Male ; Middle Aged ; Pancreatic Neoplasms/blood/*mortality ; Proportional Hazards Models ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; Risk Assessment ; *Telomere Shortening ; },
abstract = {BACKGROUND: Critically shortened telomeres contribute to chromosomal instability and neoplastic transformation and are associated with early death of patients with certain cancer types. Shorter leukocyte telomere length (LTL) has been associated with higher risk for pancreatic ductal adenocarcinoma (PDAC) and might be associated also with survival of patients with PDAC. We investigated the association between treatment-naïve LTL and overall survival of patients with incident PDAC.<br><br>METHODS: The study included 642 consecutively enrolled PDAC patients in the Mayo Clinic Biospecimen Resource for Pancreas Research. Blood samples were obtained at the time of diagnosis, before the start of cancer treatment, from which LTL was assayed by qRT-PCR. LTL was first modeled as a continuous variable (per-interquartile range decrease in LTL) and then as a categorized variable (short, medium, long). Multivariable-adjusted HRs and 95% confidence intervals (CI) were calculated for overall mortality using Cox proportional hazard models.<br><br>RESULTS: Shorter treatment-na&#xef;ve LTL was associated with higher mortality among patients with PDAC (HRcontinuous = 1.13, 95% CI: 1.01-1.28, P = 0.03; HRshortest vs. longest LTL = 1.29, 95% CI: 1.05-1.59, P trend = 0.01). There was a difference in the association between LTL and overall mortality by tumor stage at diagnosis; resectable tumors (HRcontinuous = 0.91; 95% CI: 0.73-1.12), locally advanced tumors (HRcontinuous = 1.29; 95% CI: 1.07-1.56), and metastatic tumors (HRcontinuous = 1.17; 95% CI: 0.96-1.42), P interaction = 0.04.<br><br>CONCLUSION: Shorter treatment-na&#xef;ve LTL is associated with poorer overall survival of patients with incident PDAC.<br><br>IMPACT: Peripheral blood LTL might be a prognostic marker for PDAC.},
}
@article {pmid33187486,
year = {2020},
author = {Nsereko, E and Uwase, A and Muvunyi, CM and Rulisa, S and Ntirushwa, D and Moreland, P and Corwin, EJ and Santos, N and Lin, J and Chen, JL and Nzayirambaho, M and Wojcicki, JM},
title = {Association between micronutrients and maternal leukocyte telomere length in early pregnancy in Rwanda.},
journal = {BMC pregnancy and childbirth},
volume = {20},
number = {1},
pages = {692},
pmid = {33187486},
issn = {1471-2393},
support = {M01 RR001271/RR/NCRR NIH HHS/United States ; P30 DK098722/DK/NIDDK NIH HHS/United States ; Investment ID: OPP1107312//Bill and Melinda Gates Foundation/ ; },
mesh = {Adolescent ; Adult ; Female ; Gestational Age ; Humans ; Leukocytes/*pathology ; Linear Models ; Longitudinal Studies ; Male ; Maternal Age ; *Maternal Nutritional Physiological Phenomena ; Micronutrients/*blood ; Middle Aged ; Pregnancy ; Prospective Studies ; Rwanda ; Telomere/*pathology ; Young Adult ; },
abstract = {BACKGROUND: Exposure to environmental stressors can lead to shorter leukocyte telomere length and increase the risk of chronic diseases. Preservation of leukocyte telomere length by reducing oxidative stress exposure and reinforcing immunity may be a mechanism by which nutritional factors delay or prevent chronic disease development.<br><br>METHODS: Healthy pregnant women (aged 18-45&#x2009;years) at 9-15&#x2009;weeks of gestation living in Gasabo District, Kigali, Rwanda, were recruited from 10 health centers for a prospective, longitudinal study from September to October 2017 to determine possible associations between nutrition health, infectious disease and leukocyte telomere length. Anthropometric and laboratory measurements were performed using standard procedures; sociodemographic parameters and health histories were assessed via surveys, and leukocyte telomere length was assessed using quantitative PCR expressed as the ratio of a telomeric product to a single-copy gene product (T/S).<br><br>RESULTS: Mean gestational age of participants (n&#x2009;=&#x2009;297) at enrollment was 13.04&#x2009;&#xb1;&#x2009;3.50&#x2009;weeks, age was 28.16&#x2009;&#xb1;&#x2009;6.10&#x2009;years and leukocyte telomere length was 1.16&#x2009;&#xb1;&#x2009;0.22 (T/S). Younger age; no schooling vs. primary schooling; and lower levels of ferritin, soluble transferrin receptors and retinol-binding protein were independent predictors of longer telomere length in multivariable models.<br><br>CONCLUSIONS: Leukocyte telomere length is an indicator of biological aging in pregnant Rwandan women. Maternal micronutrient status, specifically lower ferritin, soluble transferrin receptor levels, and retinol-binding protein levels were associated with longer maternal telomere length in contrast with some studies from North America and Europe. There were no associations between inflammation and infectious disease status and maternal leukocyte telomere length. Further studies are needed to enhance our understanding of the interplay between maternal nutritional status and infectious disease in relation to leukocyte telomere length in developing countries.},
}
@article {pmid33176222,
year = {2021},
author = {Bosquet Enlow, M and Petty, CR and Hacker, MR and Burris, HH},
title = {Maternal psychosocial functioning, obstetric health history, and newborn telomere length.},
journal = {Psychoneuroendocrinology},
volume = {123},
number = {},
pages = {105043},
pmid = {33176222},
issn = {1873-3360},
support = {K23 ES022242/ES/NIEHS NIH HHS/United States ; UL1 TR001102/TR/NCATS NIH HHS/United States ; },
mesh = {Female ; Humans ; Infant, Newborn ; Male ; *Mothers/psychology ; Prospective Studies ; *Psychosocial Functioning ; *Reproductive History ; *Telomere Shortening ; },
abstract = {There is growing interest in elucidating the determinants of newborn telomere length, given its potential as a biomarker of lifetime disease risk affected by prenatal exposures. There is limited evidence that increased maternal stress during pregnancy predicts shorter newborn telomere length. However, the few studies published to date have been conducted primarily with small samples utilizing inconsistent definitions of maternal stress. Moreover, the potential influence of fetal sex as a moderator of maternal stress effects on newborn telomere length has been largely ignored despite compelling evidence of likely impact. In a prospective cohort study of pregnant women seeking routine prenatal care, we tested whether a range of maternal measures of stressor exposures, subjective feelings of stress, and mental health (depression, anxiety) were associated with newborn telomere length assessed from cord blood among 146 pregnant women and their newborn infants. We further examined whether the pattern of associations differed by infant sex. Sociodemographic and maternal and newborn health indicators were considered as potential covariates. When examined within the whole sample, none of the maternal psychosocial measures were associated with newborn telomere length. Among potential covariates, maternal history of smoking and preeclampsia in a previous pregnancy were negatively associated with newborn telomere length. In adjusted linear regression analyses that considered potential sex-specific effects, maternal depression, general anxiety, and pregnancy-specific anxiety symptoms were positively associated with newborn telomere length among males. Overall, the findings provide some evidence for an association between maternal psychosocial wellbeing in pregnancy and newborn telomere length in males, although in the opposite direction than previously reported. Maternal smoking and obstetric history prior to conception may be associated with shorter offspring telomere length.},
}
@article {pmid33176178,
year = {2021},
author = {Shoeb, M and Meier, HCS and Antonini, JM},
title = {Telomeres in toxicology: Occupational health.},
journal = {Pharmacology &amp; therapeutics},
volume = {220},
number = {},
pages = {107742},
pmid = {33176178},
issn = {1879-016X},
support = {CC999999/ImCDC/Intramural CDC HHS/United States ; },
mesh = {DNA ; Humans ; *Occupational Health ; Shelterin Complex ; *Telomere/genetics/metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins ; *Toxicology ; },
abstract = {The ends of chromosomes shorten at each round of cell division, and this process is thought to be affected by occupational exposures. Occupational hazards may alter telomere length homeostasis resulting in DNA damage, chromosome aberration, mutations, epigenetic alterations and inflammation. Therefore, for the protection of genetic material, nature has provided a unique nucleoprotein structure known as a telomere. Telomeres provide protection by averting an inappropriate activation of the DNA damage response (DDR) at chromosomal ends and preventing recognition of single and double strand DNA (ssDNA and dsDNA) breaks or chromosomal end-to-end fusion. Telomeres and their interacting six shelterin complex proteins in coordination act as inhibitors of DNA damage machinery by blocking DDR activation at chromosomes, thereby preventing the occurrence of genome instability, perturbed cell cycle, cellular senescence and apoptosis. However, inappropriate DNA repair may result in the inadequate distribution of genetic material during cell division, resulting in the eventual development of tumorigenesis and other pathologies. This article reviews the current literature on the association of changes in telomere length and its interacting proteins with different occupational exposures and the potential application of telomere length or changes in the regulatory proteins as potential biomarkers for exposure and health response, including recent findings and future perspectives.},
}
@article {pmid33176153,
year = {2020},
author = {Drosopoulos, WC and Deng, Z and Twayana, S and Kosiyatrakul, ST and Vladimirova, O and Lieberman, PM and Schildkraut, CL},
title = {TRF2 Mediates Replication Initiation within Human Telomeres to Prevent Telomere Dysfunction.},
journal = {Cell reports},
volume = {33},
number = {6},
pages = {108379},
pmid = {33176153},
issn = {2211-1247},
support = {R01 CA085344/CA/NCI NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; R01 GM045751/GM/NIGMS NIH HHS/United States ; T32 AG023475/AG/NIA NIH HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; },
mesh = {DNA Replication/*genetics ; Genomic Instability ; Humans ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {The telomeric shelterin protein telomeric repeat-binding factor 2 (TRF2) recruits origin recognition complex (ORC) proteins, the foundational building blocks of DNA replication origins, to telomeres. We seek to determine whether TRF2-recruited ORC proteins give rise to functional origins in telomere repeat tracts. We find that reduction of telomeric recruitment of ORC2 by expression of an ORC interaction-defective TRF2 mutant significantly reduces telomeric initiation events in human cells. This reduction in initiation events is accompanied by telomere repeat loss, telomere aberrations and dysfunction. We demonstrate that telomeric origins are activated by induced replication stress to provide a key rescue mechanism for completing compromised telomere replication. Importantly, our studies also indicate that the chromatin remodeler SNF2H promotes telomeric initiation events by providing access for ORC2. Collectively, our findings reveal that active recruitment of ORC by TRF2 leads to formation of functional origins, providing an important mechanism for avoiding telomere dysfunction and rescuing challenged telomere replication.},
}
@article {pmid33175128,
year = {2021},
author = {Sindi, S and Solomon, A and Kåreholt, I and Hovatta, I and Antikainen, R and Hänninen, T and Levälahti, E and Laatikainen, T and Lehtisalo, J and Lindström, J and Paajanen, T and Peltonen, M and Singh Khalsa, D and Wolozin, B and Strandberg, T and Tuomilehto, J and Soininen, H and Ngandu, T and Kivipelto, M and , },
title = {Telomere Length Change in a Multidomain Lifestyle Intervention to Prevent Cognitive Decline: A Randomized Clinical Trial.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {76},
number = {3},
pages = {491-498},
pmid = {33175128},
issn = {1758-535X},
mesh = {Aged ; Cognitive Dysfunction/diagnosis/etiology/*prevention &amp; control ; Exercise ; Female ; Finland ; Health Behavior ; Humans ; Leukocytes/*physiology ; *Life Style ; Male ; Middle Aged ; Neuropsychological Tests ; Patient Education as Topic ; Telomere Homeostasis/*physiology ; },
abstract = {BACKGROUND: Shorter leukocyte telomere length (LTL) is associated with aging and dementia. Impact of lifestyle changes on LTL, and relation to cognition and genetic susceptibility for dementia, has not been investigated in randomized controlled trials (RCTs).<br><br>METHODS: Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability is a 2-year RCT enrolling 1260 participants at risk for dementia from the general population, aged 60-77 years, randomly assigned (1:1) to multidomain lifestyle intervention or control group. The primary outcome was cognitive change (Neuropsychological Test Battery z-score). Relative LTL was measured using quantitative real-time polymerase chain reaction (trial registration: NCT01041989).<br><br>RESULTS: This exploratory LTL substudy included 756 participants (377 intervention, 379 control) with baseline and 24-month LTL measurements. The mean annual LTL change (SD) was -0.016 (0.19) in the intervention group and -0.023 (0.17) in the control group. Between-group difference was nonsignificant (unstandardized &#x3b2;-coefficient 0.007, 95% CI -0.015 to 0.030). Interaction analyses indicated better LTL maintenance among apolipoprotein E (APOE)-&#x3b5;4 carriers versus noncarriers: 0.054 (95% CI 0.007 to 0.102); younger versus older participants: -0.005 (95% CI -0.010 to -0.001); and those with more versus less healthy lifestyle changes: 0.047 (95% CI 0.005 to 0.089). Cognitive intervention benefits were more pronounced among participants with better LTL maintenance for executive functioning (0.227, 95% CI 0.057 to 0.396) and long-term memory (0.257, 95% CI 0.024 to 0.489), with a similar trend for Neuropsychological Test Battery total score (0.127, 95% CI -0.011 to 0.264).<br><br>CONCLUSIONS: This is the first large RCT showing that a multidomain lifestyle intervention facilitated LTL maintenance among subgroups of older people at risk for dementia, including APOE-&#x3b5;4 carriers. LTL maintenance was associated with more pronounced cognitive intervention benefits.<br><br>NCT01041989.},
}
@article {pmid33174947,
year = {2020},
author = {Bastos, MF and Matias, MST and Alonso, AC and Silva, LCR and de Araújo, AL and Silva, PR and Benard, G and Bocalini, DS and Steven Baker, J and Leme, LEG},
title = {Moderate levels of physical fitness maintain telomere length in non-senescent T CD8+ cells of aged men.},
journal = {Clinics (Sao Paulo, Brazil)},
volume = {75},
number = {},
pages = {e1628},
pmid = {33174947},
issn = {1980-5322},
mesh = {Aged ; Aged, 80 and over ; CD8-Positive T-Lymphocytes ; Flow Cytometry ; Humans ; Male ; Physical Fitness ; *Quality of Life ; *Telomere ; },
abstract = {OBJECTIVES: Immunosenescence is an age-associated change characterized by a decreased immune response. Although physical activity has been described as fundamental for maintaining the quality of life, few studies have evaluated the effects of different levels of exercise on telomere length in aged populations. The present study aimed to analyze the effects of different levels of physical activity, classified by the Maximal oxygen consumption (VO2 max) values, on the telomere length of memory Cluster of differentiation (CD) CD4+(CD45ROneg and CD45RO+), effector CD8+CD28neg, and CD8+CD28+ T cells in aged individuals.<br><br>METHODS: Fifty-three healthy elderly men (aged 65-85 years) were included in this study. Their fitness level was classified according to the American College of Sports Medicine (ACSM) for VO2 max (mL/kg/min). Blood samples were obtained from all participants to analyze the percentage of CD3, CD4, CD8, CD28+, na&#xef;ve, and subpopulations of memory T cells by using flow cytometry. Furthermore, using the Flow-FISH methodology, the CD4+CD45RO+, CD4+CD45ROneg, CD8+CD28+, and CD8+CD28negT cell telomere lengths were measured.<br><br>RESULTS: There was a greater proportion of effector memory T CD4+ cells and longer telomeres in CD8+CD28+ T cells in the moderate physical fitness group than in the other groups. There was a higher proportion of terminally differentiated memory effector T cells in the low physical fitness group.<br><br>CONCLUSION: A moderate physical activity may positively influence the telomere shortening of CD28+CD8+T cells. However, additional studies are necessary to evaluate the importance of this finding with regard to immune function responses in older men.},
}
@article {pmid33173912,
year = {2020},
author = {Clarity, C and Trowbridge, J and Gerona, R and Ona, K and McMaster, M and Bessonneau, V and Rudel, R and Buren, H and Morello-Frosch, R},
title = {Associations between polyfluoroalkyl substance and organophosphate flame retardant exposures and telomere length in a cohort of women firefighters and office workers in San Francisco.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2020.11.05.20226183},
pmid = {33173912},
abstract = {BACKGROUND: Environmental chemical exposures can affect telomere length, which in turn has been associated with adverse health outcomes including cancer. Firefighters are occupationally exposed to many hazardous chemicals and have higher rates of certain cancers. As a potential marker of effect, we assessed associations between chemical exposures and telomere length in women firefighters and office workers from San Francisco, CA.<br><br>METHODS: We measured serum levels of polyfluoroalkyl substances (PFAS), urinary metabolites of flame retardants, including organophosphate flame retardants (OPFRs), and telomere length in peripheral blood leukocytes in women firefighters and office workers who participated in the 2014-15 Women Workers Biomonitoring Collaborative. Multiple linear regression models were used to assess associations between chemical exposures and telomere length.<br><br>RESULTS: Regression results revealed significant positive associations between perfluorooctanoic acid (PFOA) and telomere length and perfluorooctanesulfonic acid (PFOS) and telomere length among the whole cohort. Models stratified by occupation showed stronger and more significant associations among firefighters as compared to office workers. Among firefighters in models adjusted for age, we found positive associations between telomere length and log-transformed PFOA (&#x3b2; (95%CI) = 0.57(0.12, 1.02)), PFOS (0.44 (0.05, 0.83)), and perfluorodecanoic acid (PFDA) (0.43 (0.02, 0.84)). Modeling PFAS as categories of exposure showed significant associations between perfluorononanoic acid (PFNA) and telomere length among firefighters. Significant associations between OPFR metabolites and telomere length were seen for bis(1,3-dichloro-2-propyl) phosphate (BDCPP) and telomere length among office workers (0.21(0.03, 0.40)) and bis(2-chloroethyl) phosphate (BCEP) and telomere length among firefighters (-0.14(-0.28, -0.01)). For OPFRs, the difference in the direction of effect by occupational group may be due to the disparate detection frequencies and levels of exposure between the two groups and/or potential unmeasured confounding.<br><br>CONCLUSION: Our findings suggest positive associations between PFAS and telomere length in women workers, with larger effects seen among firefighters as compared to office workers. The OPFR metabolites BDCPP and BCEP are also associated with telomere length in firefighters and office workers. Associations between chemical exposures and telomere length reported here and by others suggest mechanisms by which these chemicals may affect carcinogenesis and other adverse health outcomes.},
}
@article {pmid33171154,
year = {2020},
author = {Boniewska-Bernacka, E and Pańczyszyn, A and Klinger, M},
title = {Telomeres and telomerase in risk assessment of cardiovascular diseases.},
journal = {Experimental cell research},
volume = {397},
number = {2},
pages = {112361},
doi = {10.1016/j.yexcr.2020.112361},
pmid = {33171154},
issn = {1090-2422},
mesh = {Animals ; Cardiovascular Diseases/etiology/metabolism/*pathology ; *Cellular Senescence ; *DNA Damage ; Humans ; Telomerase/genetics/*metabolism ; *Telomere Shortening ; },
abstract = {Telomeres are repetitive nucleoprotein structures located at the ends of chromosomes. Reduction in the number of repetitions causes cell senescence. Cells with high proliferative potential age with each replication cycle. Post-mitotic cells (e.g. cardiovascular cells) have a different aging mechanism. During the aging of cardiovascular system cells, permanent DNA damage occurs in the telomeric regions caused by mitochondrial dysfunction, which is a phenomenon independent of cell proliferation and telomere length. Mitochondrial dysfunction is accompanied by increased production of reactive oxygen species and development of inflammation. This phenomenon in the cells of blood vessels can lead to atherosclerosis development. Telomere damage in cardiomyocytes leads to the activation of the DNA damage response system, histone H2A.X phosphorylation, p53 activation and p21 and p16 protein synthesis, resulting in the SASP phenotype (senescence-associated secretory phenotype), increased inflammation and cardiac dysfunction. Cardiovascular cells show the activity of the TERT subunit of telomerase, an enzyme that prevents telomere shortening. It turns out that disrupting the activity of this enzyme can also contribute to the formation of cardiovascular diseases. Measurements of telomere length according to the "blood-muscle" model may help in the future to assess the risk of cardiovascular complications in people undergoing cardiological procedures, as well as to assess the effectiveness of some drugs.},
}
@article {pmid33171077,
year = {2020},
author = {Stier, A and Hsu, BY and Marciau, C and Doligez, B and Gustafsson, L and Bize, P and Ruuskanen, S},
title = {Born to be young? Prenatal thyroid hormones increase early-life telomere length in wild collared flycatchers.},
journal = {Biology letters},
volume = {16},
number = {11},
pages = {20200364},
pmid = {33171077},
issn = {1744-957X},
mesh = {Animals ; Cross-Sectional Studies ; Female ; Humans ; Longevity ; Male ; Pregnancy ; *Songbirds ; *Telomere/genetics ; Telomere Shortening ; Thyroid Hormones ; },
abstract = {The underlying mechanisms of the lifelong consequences of prenatal environmental condition on health and ageing remain little understood. Thyroid hormones (THs) are important regulators of embryogenesis, transferred from the mother to the embryo. Since prenatal THs can accelerate early-life development, we hypothesized that this might occur at the expense of resource allocation in somatic maintenance processes, leading to premature ageing. Therefore, we investigated the consequences of prenatal TH supplementation on potential hallmarks of ageing in a free-living avian model in which we previously demonstrated that experimentally elevated prenatal TH exposure accelerates early-life growth. Using cross-sectional sampling, we first report that mitochondrial DNA (mtDNA) copy number and telomere length significantly decrease from early-life to late adulthood, thus suggesting that these two molecular markers could be hallmarks of ageing in our wild bird model. Elevated prenatal THs had no effect on mtDNA copy number but counterintuitively increased telomere length both soon after birth and at the end of the growth period (equivalent to offsetting ca 4 years of post-growth telomere shortening). These findings suggest that prenatal THs might have a role in setting the 'biological' age at birth, but raise questions about the nature of the evolutionary costs of prenatal exposure to high TH levels.},
}
@article {pmid33164936,
year = {2020},
author = {Yang, T and Wang, H and Xiong, Y and Chen, C and Duan, K and Jia, J and Ma, F},
title = {Vitamin D Supplementation Improves Cognitive Function Through Reducing Oxidative Stress Regulated by Telomere Length in Older Adults with Mild Cognitive Impairment: A 12-Month Randomized Controlled Trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {78},
number = {4},
pages = {1509-1518},
doi = {10.3233/JAD-200926},
pmid = {33164936},
issn = {1875-8908},
mesh = {8-Hydroxy-2'-Deoxyguanosine/metabolism ; Aged ; Calcifediol/metabolism ; Calcitriol/metabolism ; Cholecalciferol/*therapeutic use ; *Cognition ; Cognitive Dysfunction/*drug therapy/metabolism/physiopathology ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; DNA Glycosylases/genetics ; Dietary Supplements ; Double-Blind Method ; Female ; Humans ; Intelligence Tests ; Male ; Middle Aged ; *Oxidative Stress ; Telomere/*metabolism ; Vitamins/*therapeutic use ; },
abstract = {BACKGROUND: Cognitive decline in older adults is a serious public health problem today. Association between vitamin D supplementation and cognition remains controversial.<br><br>OBJECTIVE: To determine whether a 12-month vitamin D supplementation improves cognitive function in elderly subjects with mild cognitive impairment (MCI), and whether it is mediated through the mechanism in which telomere length (TL) regulate oxidative stress.<br><br>METHODS: This was a double-blind, randomized, placebo-controlled trial in Tianjin, China. Participants were all native Chinese speakers aged 65 years and older with MCI. 183 subjects were randomized to an intervention group (vitamin D 800 IU/day, n&#x200a;=&#x200a;93) or a placebo group (the matching starch granules, n&#x200a;=&#x200a;90), and followed up for 12 months. Tests of cognitive function and mechanism-related biomarkers were evaluated at baseline, 6 months, and 12 months.<br><br>RESULTS: Repeated-measures ANOVA showed substantial improvements in the full scale intelligence quotient (FSIQ), information, digit span, vocabulary, block design, and picture arrangement scores in the vitamin D group over the placebo group (p&#x200a;<&#x200a;0.001). Leukocyte TL was significantly higher, while serum 8-OXO-dG, OGG1mRNA, and P16INK4amRNA revealed greater decreases in the vitamin D group over the placebo group (p&#x200a;<&#x200a;0.001). According to mixed-model repeated-measures ANOVA analysis, vitamin D group showed a significant enhancement in the FSIQ score for 12 months compared with the control (estimate value&#x200a;=&#x200a;5.132, p&#x200a;<&#x200a;0.001).<br><br>CONCLUSION: Vitamin D supplementation for 12 months appears to improve cognitive function through reducing oxidative stress regulated by increased TL in order adults with MCI. Vitamin D may be a promising public health strategy to prevent cognitive decline.},
}
@article {pmid33163366,
year = {2020},
author = {Alam, MR and Kim, DK},
title = {Alterations in telomere length and mitochondrial DNA copy number in human lymphocytes on short-term exposure to moderate hypoxia.},
journal = {Toxicology reports},
volume = {7},
number = {},
pages = {1443-1447},
pmid = {33163366},
issn = {2214-7500},
abstract = {Hypoxia is related to a variety of diseases, such as cardiovascular and inflammatory diseases and various cancers. Telomere length (TL) may vary according to the hypoxia level and cell types. To the best of our knowledge, no study has investigated the effect of moderate hypoxia on TL and mitochondrial DNA copy number (mtDNAcn) in human lymphocytes. Therefore, in this study, we analyzed the effect of moderate hypoxia on TL in correlation with mtDNAcn. This study included 32 healthy male nonsmoker's subjects; in this cohort, we had previously studied sister chromatid exchange and microsatellite instability. Blood samples from each subject were divided into three groups: a control group and two experimental groups exposed to moderate hypoxia for 12 or 24 h. Relative TL and mtDNAcn were measured by a quantitative real-time polymerase chain reaction. The TL in the control group did not significantly differ from that in the experimental group subjected to hypoxia for 12 h; however, the TL in the 24 h hypoxia-treated experimental group was significantly higher than that in the control group. The correlation between TL and mtDNAcn was not statistically significant in the two hypoxic states. The increase in TL was observed on exposure to hypoxia for 24 h and not for 12 h; thus, the findings suggest that telomere elongation is related to hypoxia exposure duration. The mtDNAcn in the two experimental groups did not significantly differ from that in the control group. These observations suggest that mtDNAcn alterations show more genetic stability than TL alterations. To the best of our knowledge, this is the first in vitro study on human lymphocytes reporting an increase in TL and no alteration in mtDNAcn after short-time exposure to moderate hypoxia.},
}
@article {pmid33163281,
year = {2020},
author = {Chen, M and Tsai, CW and Chang, WS and Xu, J and Xu, Y and Bau, DT and Gu, J},
title = {Prognostic value of leukocyte telomere length in renal cell carcinoma patients.},
journal = {American journal of cancer research},
volume = {10},
number = {10},
pages = {3428-3439},
pmid = {33163281},
issn = {2156-6976},
abstract = {Telomeres play important roles in cancer initiation and progression. Leukocyte telomere length (LTL) can modulate cancer risk and outcome. We hypothesize that genetically predicted short LTL is associated with worse prognosis in renal cell carcinoma (RCC). A total of 1,086 histologically confirmed RCC patients were included in this study. A weighted genetic risk score (GRS) predictive of LTL was constructed using 10 confirmed LTL-associated single nucleotide polymorphisms (SNPs). The associations of individual SNPs and GRS with recurrence and survival were determined by multivariate Cox proportional hazards analysis. In individual SNP analysis, long LTL-associated allele of rs7675998 in NAF1 gene at chromosome 4 was significantly associated with a reduced risk of recurrence (HR=0.85, 95% CI, 0.73-0.99, P=0.043), while the long LTL-associated allele of rs10936599 in TERC at chromosome 3 conferred a reduced risk of death (HR=0.85, 95% CI, 0.73-1.00, P=0.047). More importantly, genetically predicted LTL was associated with both recurrence and survival. Dichotomized at the median value of GRS, patients with low GRS (indicating short LTL) exhibited significantly increased risks of recurrence (HR=1.26, 95% CI, 1.03-1.54, P=0.025) and death (HR=1.23, 95% CI, 1.00-1.50, P=0.045). Hence, we concluded that genetically predicted short LTL is associated with worse prognosis in RCC patients.},
}
@article {pmid33161111,
year = {2021},
author = {Zhou, X and Li, X and Wei, W and Duan, X and Zhang, H and Ding, M and Yao, W and Wang, Q and Wang, W and Yang, Y},
title = {Association between genetic polymorphisms of telomere pathway genes and hydrogen peroxide level in omethoate exposure workers.},
journal = {Environmental toxicology and pharmacology},
volume = {82},
number = {},
pages = {103541},
doi = {10.1016/j.etap.2020.103541},
pmid = {33161111},
issn = {1872-7077},
mesh = {Adult ; Dimethoate/*analogs &amp; derivatives/toxicity ; Female ; Genotype ; Humans ; Hydrogen Peroxide/*blood ; Insecticides/*toxicity ; Male ; Middle Aged ; Occupational Exposure/*adverse effects ; Polymorphism, Genetic ; Shelterin Complex ; Telomerase/genetics ; Telomere/genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {OBJECTIVE: The aim of this study was to explore the association between genetic variations in telomere pathway genes and the level of hydrogen peroxide (H2O2) in omethoate exposure workers.<br><br>METHODS: A total of 180 omethoate exposure workers and 115 healthy controls were recruited. The level of H2O2 in plasma was determined with molybdenic acid colorimetry. Polymerase chain reaction and restriction fragment length was used to detect polymorphisms in POT1 rs1034794, POT1 rs10250202, TERF1 rs3863242, and TERT rs2736098.<br><br>RESULTS: The level of H2O2 in exposure group (4.26&#x2009;&#xb1;&#x2009;0.71) was significantly higher than that in control group (3.29&#x2009;&#xb1;&#x2009;0.46). Generalized linear models indicated that risk factors for the increase H2O2 level were exposure [&#x3b2;(95 % CI)&#x2009;=&#x2009;0.951 (0.806, 1.096), P&#x2009;<&#x2009;0.001] and AA&#x2009;+&#x2009;AT genotype in POT1 rs034794 [&#x3b2;(95 % CI)&#x2009;=&#x2009;0.397 (0.049, 0.745), P&#x2009;=&#x2009;0.025].<br><br>CONCLUSION: The increase H2O2 level was associated with omethoate exposure and AA&#x2009;+&#x2009;AT genotypes in POT1 gene rs1034794. It provided a new idea that polymorphisms in telomere pathway genes may indirectly regulate telomere length by influencing oxidative stress.},
}
@article {pmid33157092,
year = {2021},
author = {McKnight, I and Hart, C and Park, IH and Shim, JW},
title = {Genes causing congenital hydrocephalus: Their chromosomal characteristics of telomere proximity and DNA compositions.},
journal = {Experimental neurology},
volume = {335},
number = {},
pages = {113523},
pmid = {33157092},
issn = {1090-2430},
support = {P20 GM103434/GM/NIGMS NIH HHS/United States ; P20 GM121299/GM/NIGMS NIH HHS/United States ; U54 GM104942/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenine ; Alzheimer Disease/genetics ; Animals ; Carrier Proteins/genetics ; Chromosome Mapping ; Chromosomes/*genetics ; DNA/*chemistry/*genetics ; Databases, Genetic ; Humans ; Hydrocephalus/*genetics ; Membrane Proteins/genetics ; Mice ; Mice, Knockout ; Mutation/genetics ; Neural Tube Defects/genetics ; Nuclear Proteins/genetics ; Parkinson Disease/genetics ; Telomere/*ultrastructure ; Thymine ; },
abstract = {Congenital hydrocephalus (CH) is caused by genetic mutations, but whether factors impacting human genetic mutations are disease-specific remains elusive. Given two factors associated with high mutation rates, we reviewed how many disease-susceptible genes match with (i) proximity to telomeres or (ii) high adenine and thymine (A + T) content in human CH as compared to other disorders of the central nervous system (CNS). We extracted genomic information using a genome data viewer. Importantly, 98 of 108 genes causing CH satisfied (i) or (ii), resulting in >90% matching rate. However, such a high accordance no longer sustained as we checked two factors in Alzheimer's disease (AD) and/or familial Parkinson's disease (fPD), resulting in 84% and 59% matching, respectively. A disease-specific matching of telomere proximity or high A + T content predicts causative genes of CH much better than neurodegenerative diseases and other CNS conditions, likely due to sufficient number of known causative genes (n = 108) and precise determination and classification of the genotype and phenotype. Our analysis suggests a need for identifying genetic basis of both factors before human clinical studies, to prioritize putative genes found in preclinical models into the likely (meeting at least one) and more likely candidate (meeting both), which predisposes human genes to mutations.},
}
@article {pmid33156376,
year = {2021},
author = {Kabaha, MM and Tzfati, Y},
title = {Telomerase, the recombination machinery and Rap1 play redundant roles in yeast telomere protection.},
journal = {Current genetics},
volume = {67},
number = {1},
pages = {153-163},
pmid = {33156376},
issn = {1432-0983},
support = {2005088//United States - Israel Binational Science Foundation/ ; 2009204//United States - Israel Binational Science Foundation/ ; I-849-253.13/2004//German-Israeli Foundation for Scientific Research and Development/ ; 3-5363/2008-2009//Ministry of Science and Technology, Israel/ ; },
mesh = {DNA End-Joining Repair/genetics ; Humans ; Kluyveromyces/genetics ; Mutation/genetics ; RNA/genetics ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/*genetics ; Shelterin Complex ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Homeostasis/genetics ; Telomere-Binding Proteins/*genetics ; Transcription Factors/*genetics ; },
abstract = {Telomeres are specialized nucleoprotein complexes that protect the ends of eukaryotic chromosomes and distinguish them from broken DNA ends. Disruption of telomere protection may cause aging-associated pathologies and cancer. Here, we examined what makes telomere protection durable and resistant to perturbations using a budding yeast model organism. The protein Rap1 binds the telomeric repeats, negatively regulates telomere length, and protects telomeres by repressing homologous recombination and non-homologous end joining (NHEJ). A single-nucleotide mutation in the Kluyveromyces lactis telomerase RNA (TER1) template, ter1-16T, is incorporated into the telomeric repeats, disrupting the binding of Rap1 and causing dramatic telomere elongation. However, cell viability is not significantly affected, suggesting the existence of additional mechanism(s) for telomere protection. To examine this hypothesis, we explored the contribution of the recombination factor Rad52 and telomerase to telomere protection in the background of ter1-16T. To disrupt the function of telomerase, we exploited small mutations in a stem-loop domain of TER1 (Reg2), which result in short but stable telomeres. We generated K. lactis strains with combinations of three different mutations: ter1-16T, RAD52 deletion, and a two-nucleotide substitution in Reg2. Our results show that upon Rap1 depletion from telomeres, telomerase and the recombination machinery compensate for the loss of Rap1 protection and play redundant but critical roles in preventing NHEJ and maintaining telomere integrity and cell viability. These results demonstrate how redundant pathways make the essential role of telomeres-protecting our genome integrity and preventing cancer-more robust and resistant to assaults and perturbations.},
}
@article {pmid33154635,
year = {2020},
author = {Cagsin, H and Uzan, A and Tosun, O and Rasmussen, F and Serakinci, N},
title = {Tissue-Specific Ultra-Short Telomeres in Chronic Obstructive Pulmonary Disease.},
journal = {International journal of chronic obstructive pulmonary disease},
volume = {15},
number = {},
pages = {2751-2757},
pmid = {33154635},
issn = {1178-2005},
mesh = {Forced Expiratory Volume ; Humans ; Lung ; *Pulmonary Disease, Chronic Obstructive/diagnosis/genetics ; Smoking/adverse effects ; Telomere/genetics ; },
abstract = {PURPOSE: Telomere biology, especially tissue-specific ultra-short telomeres, might provide a strong contribution to our current knowledge in COPD development as well as a predictive marker for prognosis. To test this hypothesis, we investigated telomere lengths in lung tissue and leukocytes in patients diagnosed with COPD.<br><br>PATIENTS AND METHODS: Thirty-two patients were included in the current study. All patients showed a post-bronchodilator ratio of less than 70% post-bronchodilator predicted value of forced expiratory volume in second (FEV1%), mean 56%; range [19% to 86%]. To be able to investigate ultra-short telomeres, universal single telomere length analysis (U-STELA) was used.<br><br>RESULTS: Our results showed a higher level of the ultra-short telomere presence in bronchoalveolar lavage (BAL) cells when compared to leukocytes with statistical significance t(62)=5.771, p<0.00001. The FEV1% was lower in subjects with ultra-short telomeres in BAL (50.6% vs 81.6%: p<0.001) and in ultra-short telomeres in blood leukocytes (37.3% vs 58.5%: p=0.051) when compared to subjects without ultra-short telomeres in leukocytes. Furthermore, the patients who had ultra-short telomeres in BAL samples were significantly older (p=0.014) than patients who did not have ultra-short telomeres. Ultra-short telomeres in BAL (p=0.05) but not in leukocytes (p=0.33) were associated with FEV1% in a regressions model adjusting for age (p<0.0001), ever smoking (p<0.0001) and sex (p=0.71). The patients with ultra-short telomeres were graded higher in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification (p=0.006).<br><br>CONCLUSION: This study emphasizes the need to investigate the correct tissue to get a representative evaluation of the stage or advancedness of COPD. To our knowledge, this is the first study to show that there is a correlation between the presence of ultra-short telomeres in lung tissue and COPD severity. Our results suggest that ultra-short telomeres are involved in the molecular pathogenesis of COPD and might be used as a tissue-specific predictive biomarker.},
}
@article {pmid33144412,
year = {2020},
author = {Nogueira, BMD and Machado, CB and Montenegro, RC and DE Moraes, MEA and Moreira-Nunes, CA},
title = {Telomere Length and Hematological Disorders: A Review.},
journal = {In vivo (Athens, Greece)},
volume = {34},
number = {6},
pages = {3093-3101},
pmid = {33144412},
issn = {1791-7549},
mesh = {*Hematologic Diseases/genetics ; *Hematologic Neoplasms/genetics ; Humans ; *Neoplasms ; *Telomerase/genetics ; Telomere/genetics/metabolism ; },
abstract = {Telomeres compose the end portions of human chromosomes, and their main function is to protect the genome. In hematological disorders, telomeres are shortened, predisposing to genetic instability that may cause DNA damage and chromosomal rearrangements, inducing a poor clinical outcome. Studies from 2010 to 2019 were compiled and experimental studies using samples of patients diagnosed with hematological malignancies that reported the size of the telomeres were described. Abnormal telomere shortening is described in cancer, but in hematological neoplasms, telomeres are still shortened even after telomerase reactivation. In this study, we compared the sizes of telomeres in leukemias, myelodysplastic syndrome and lymphomas, identifying that the smallest telomeres are present in patients at relapse. In conclusion, the experimental and clinical data analyzed in this review demonstrate that excessive telomere shortening is present in major hematological malignancies and its analysis and measurement is a crucial step in determining patient prognosis, predicting disease risk and assisting in the decision for targeted therapeutic strategies.},
}
@article {pmid33144154,
year = {2021},
author = {Lemaître, JF and Carbillet, J and Rey, B and Palme, R and Froy, H and Wilbourn, RV and Underwood, SL and Cheynel, L and Gaillard, JM and Hewison, AJM and Verheyden, H and Débias, F and Duhayer, J and Régis, C and Pardonnet, S and Pellerin, M and Nussey, DH and Gilot-Fromont, E},
title = {Short-term telomere dynamics is associated with glucocorticoid levels in wild populations of roe deer.},
journal = {Comparative biochemistry and physiology. Part A, Molecular &amp; integrative physiology},
volume = {252},
number = {},
pages = {110836},
doi = {10.1016/j.cbpa.2020.110836},
pmid = {33144154},
issn = {1531-4332},
support = {BB/L020769/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Deer/*metabolism ; Female ; Glucocorticoids/*metabolism ; Male ; *Telomere ; },
abstract = {While evidence that telomere length is associated with health and mortality in humans and birds is accumulating, a large body of research is currently seeking to identify factors that modulate telomere dynamics. We tested the hypothesis that high levels of glucocorticoids in individuals under environmental stress should accelerate telomere shortening in two wild populations of roe deer (Capreolus capreolus) living in different ecological contexts. From two consecutive annual sampling sessions, we found that individuals with faster rates of telomere shortening had higher concentrations of fecal glucocorticoid metabolites, suggesting a functional link between glucocorticoid levels and telomere attrition rate. This relationship was consistent for both sexes and populations. This finding paves the way for further studies of the fitness consequences of exposure to environmental stressors in wild vertebrates.},
}
@article {pmid33143762,
year = {2021},
author = {Ojeda-Rodríguez, A and Zazpe, I and Alonso-Pedrero, L and Zalba, G and Martínez-González, MA and Marti, A},
title = {Higher adherence to an empirically derived Mediterranean dietary pattern is positively associated with telomere length: the Seguimiento Universidad de Navarra (SUN) project.},
journal = {The British journal of nutrition},
volume = {126},
number = {4},
pages = {531-540},
doi = {10.1017/S0007114520004274},
pmid = {33143762},
issn = {1475-2662},
mesh = {Aged ; *Diet, Mediterranean ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; Spain ; Surveys and Questionnaires ; Telomere/*ultrastructure ; Telomere Homeostasis ; },
abstract = {Telomere integrity is influenced by oxidative stress. Also, inflammation-related factors, including nutritional factors, could modulate telomere integrity. The relationship between a posteriori-derived dietary patterns and telomere length (TL) has been scarcely investigated. Thus, our objective was to examine the association between empirically derived dietary patterns ascertained through principal component analysis (PCA) and TL in an older adult Spanish population. A total of 886 older adults (>55 years old; 645 males and 241 females) from the Seguimiento Universidad de Navarra (SUN) cohort were included in the study. TL was measured by monochrome multiplex real-time quantitative PCR. Age-adjusted TL was used for all analyses. Dietary patterns were identified by PCA based on thirty predefined candidate food groups collected from a validated 136-food items frequency questionnaire. Generalised linear models were fitted to obtain β-coefficients and their 95 % CI evaluating differences in TL between each of the four upper quintiles of adherence to dietary patterns and the lowest quintile. Sensitivity analyses by rerunning all multiple linear models under different stratifications were performed to evaluate the robustness of our results. Two major dietary patterns were empirically identified, Western dietary pattern (WDP) and Mediterranean dietary pattern (MDP). After adjustment for potential confounders, longer TL was found among subjects in the highest quintile of MDP (β = 0·064; 95 % CI 0·004, 0·123). The WDP showed no significant association with TL. In conclusion, higher adherence to a posteriori-derived MDP was independently associated with longer telomeres in an older adult Spanish population of the SUN project.},
}
@article {pmid33142697,
year = {2020},
author = {Garrido-Navas, MC and Tippins, F and Barwell, J and Hoffman, J and Codd, V and Royle, NJ},
title = {Telomere Instability in Lynch Syndrome Families Leads to Some Shorter Telomeres in MSH2+/- Carriers.},
journal = {Life (Basel, Switzerland)},
volume = {10},
number = {11},
pages = {},
pmid = {33142697},
issn = {2075-1729},
support = {G0500336/MRC_/Medical Research Council/United Kingdom ; PhD studentship//Univeristy of Leicester/ ; Development Funding//Cancer Research UK Leicester Centre/ ; },
abstract = {Lynch syndrome (LS) is an inherited predisposition to early onset of various cancers, caused by mutation in a DNA mismatch repair (MMR) gene. In heterozygous MMR[+/-] carriers, somatic mutation, loss or silencing of the wild type allele increases the mutation rate, facilitating the initiation of MMR-defective cancers. These cancers are characterized by instability at short tandem repeats (STRs) and in telomeric DNA. We have investigated telomere length in saliva DNA from LS and control families, using single telomere analysis at XpYp and 12q and by qPCR to measure total telomeric DNA. Single telomere analysis showed a trend for shorter XpYp telomeres in MSH2[+/-] carriers compared to MLH1[+/][-] carriers or controls, but this was masked in the comparative analysis of total telomeric DNA. Comparison of age-adjusted telomere length within families showed that neither MSH2[+/-] or MLH1[+/-] children had consistently shorter or longer telomeres than their MMR[+/-] parent, indicating the absence of an inter-generational effect on telomere length. Unexpectedly however, wildtype children in families with MSH2 mutations, had significantly longer XpYp telomeres than their MMR[+/-] parent. Altogether our data suggest that MMR insufficiency, particularly in MSH2[+/-] carriers, increases telomere instability and somatic cell turnover during the lifetime of LS mutation carriers but has minimal consequences for telomere length in the germline.},
}
@article {pmid33140570,
year = {2021},
author = {Yu, QQ and Gao, JJ and Lang, XX and Li, HY and Wang, MQ},
title = {Microenvironment-Sensitive Fluorescent Ligand Binds Ascaris Telomere Antiparallel G-Quadruplex DNA with Blue-Shift and Enhanced Emission.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {22},
number = {6},
pages = {1042-1048},
doi = {10.1002/cbic.202000671},
pmid = {33140570},
issn = {1439-7633},
support = {21907042//National Natural Science Foundation of China/ ; BK20180857//Natural Science Foundation of Jiangsu Province/ ; },
mesh = {Animals ; Ascaris/*genetics ; Binding Sites ; Carbazoles/chemistry ; Circular Dichroism ; Fluorescent Dyes/*chemistry ; *G-Quadruplexes ; HeLa Cells ; Humans ; Hydrogen-Ion Concentration ; Ligands ; Metals/chemistry ; Molecular Docking Simulation ; Nucleic Acid Conformation ; Spectrometry, Fluorescence ; Telomere/*chemistry ; },
abstract = {The development of small molecules that can selectively target G-quadruplex (G4) DNAs has drawn considerable attention due to their unique physiological and pathological functions. However, only a few molecules have been found to selectively bind a particular G4 DNA structure. We have developed a fluorescence ligand Q1, a molecular scaffold with a carbazole-pyridine core bridged by a phenylboronic acid side chain, that acts as a selective ascaris telomere antiparallel G4 DNA ASC20 ligand with about 18 nm blue-shifted and enhanced fluorescence intensity. Photophysical properties revealed that Q1 was sensitive to the microenvironment and gave the best selectivity to ASC20 with an equilibrium binding constant Ka =6.04×10[5] M[-1] . Time-resolved fluorescence studies also demonstrated that Q1 showed a longer fluorescence lifetime in the presence of ASC20. The binding characteristics of Q1 with ASC20 were shown in detail in a fluorescent intercalator displacement (FID) assay, a 2-Ap titration experiment and by molecular docking. Ligand Q1 could adopt an appropriate pose at terminal G-quartets of ASC20 through multiple interactions including π-π stacking between aromatic rings; this led to strong fluorescence enhancement. In addition, a co-staining image showed that Q1 is mainly distributed in the cytoplasm. Accordingly, this work provides insights for the development of ligands that selectively targeting a specific G4 DNA structure.},
}
@article {pmid33140537,
year = {2021},
author = {Navarro-Mateu, F and Husky, M and Cayuela-Fuentes, P and Álvarez, FJ and Roca-Vega, A and Rubio-Aparicio, M and Chirlaque, MD and Cayuela, ML and Martínez, S and Sánchez-Meca, J},
title = {The association of telomere length with substance use disorders: a systematic review and meta-analysis of observational studies.},
journal = {Addiction (Abingdon, England)},
volume = {116},
number = {8},
pages = {1954-1972},
doi = {10.1111/add.15312},
pmid = {33140537},
issn = {1360-0443},
mesh = {Humans ; Observational Studies as Topic ; Research Design ; *Substance-Related Disorders/genetics ; *Telomere/genetics ; },
abstract = {BACKGROUND AND AIMS: Several recent studies have investigated the relationship between telomere length and substance use disorders with inconsistent results. We aimed to assess this association and to identify moderators of the relationship.<br><br>METHODS: Systematic review and meta-analysis. Selection criteria were observational studies reporting telomere length in people with a substance use disorder compared with a control group. Studies focused solely on nicotine addiction, employing other study designs, and non-human studies were excluded. Study selection and data extraction were independently conducted by two researchers following a standardized protocol and included studies until December 2019. Standardized mean differences were used as the effect size index [d; 95% confidence interval (CI)] and random-effects models were used for the meta-analysis. Cochran's Q-statistic, I[2] index, visual inspection of the forest plot and a 95% prediction interval were applied to verify study heterogeneity. Subgroup analyses and meta-regressions were conducted to explore heterogeneity. Small study effects were examined using the 'funnel plot', the Egger test, Duval &amp; Tweedie's trim-and-fill method and the precision-effect test-precision-effect estimate with standard error (PET-PEESE) method. The risk of bias and the quality of evidence were assessed.<br><br>RESULTS: Ten studies (12 analysis units with 2671 cases and 4532 controls) met the selection criteria. An overall effect size of moderate magnitude was found (d+ &#xa0;=&#xa0;-0.63; 95% CI&#xa0;=&#xa0;-1.00 and -0.26; P&#xa0;=&#xa0;0.0008). A potential small study effect was detected, as well as large heterogeneity between studies (Q-statistic P&#xa0;<&#xa0;0.001, I[2] &#xa0;=&#xa0;97.3%). Selection of controls, reporting laboratory quality control procedures and total sample size significantly affected the effect size. The quality of the evidence was very low, based on risk of bias analysis and the grading of recommendations assessment, development and evaluation (GRADE) system.<br><br>CONCLUSIONS: People with substance use disorders appear to have shorter telomere length than controls; however, this finding should be interpreted with caution due to the poor quality of the evidence.},
}
@article {pmid33139395,
year = {2020},
author = {Criscuolo, F and Torres, R and Zahn, S and Williams, TD},
title = {Telomere dynamics from hatching to sexual maturity and maternal effects in the 'multivariate egg'.},
journal = {The Journal of experimental biology},
volume = {223},
number = {Pt 23},
pages = {},
doi = {10.1242/jeb.232496},
pmid = {33139395},
issn = {1477-9145},
mesh = {Animals ; Egg Yolk ; Female ; Male ; Maternal Inheritance ; *Songbirds ; *Telomere ; Testosterone ; },
abstract = {Avian eggs contain a large number of molecules deposited by the mother that provide the embryo with energy but also potentially influence its development via the effects of maternally derived hormones and antibodies: the avian egg is thus 'multivariate'. Multivariate effects on offspring phenotype were evaluated in a study on captive zebra finches, by simultaneously manipulating maternally derived antibodies (MAb) by lipopolysaccharide (LPS) treatment of mothers and injection of testosterone into the egg yolk. LPS treatment had a positive effect on body mass growth at 30 days after hatching and immune response at sexual maturity, while egg testosterone treatment positively influenced immune response at fledging and courtship behaviour in sexually mature male offspring. Maternal effects are known to modulate offspring telomere length (TL). However, the multivariate effects of egg-derived maternal components on offspring telomere dynamics from hatching to sexual maturity are undefined. Here, we tested: (1) the effects of LPS and testosterone treatments on TL from hatching to sexual maturity (day 82); (2) how LPS treatment modulated TL over reproduction in adult females; and (3) the relationship between maternal and offspring TL. We predicted that TL would be shorter in LPS fledglings (as a cost of faster growth) and that TL would be longer in sexually mature adults after yolk testosterone treatment (as a proxy of individual quality). In adult females, there was an overall negative relationship between laying and rearing investments and TL, this relationship was weaker in LPS-treated females. In chicks, there was an overall negative effect of LPS treatment on TL measured at fledging and sexual maturity (day 25-82). In addition, at fledging, there was a Sex×LPS×Testosterone interaction, suggesting the existence of antagonistic effects of our treatments. Our data partially support the hypothesis that telomeres are proxies of individual quality and that individual differences in TL are established very early in life.},
}
@article {pmid33132941,
year = {2020},
author = {Lundberg, M and Millischer, V and Backlund, L and Martinsson, L and Stenvinkel, P and Sellgren, CM and Lavebratt, C and Schalling, M},
title = {Lithium and the Interplay Between Telomeres and Mitochondria in Bipolar Disorder.},
journal = {Frontiers in psychiatry},
volume = {11},
number = {},
pages = {586083},
pmid = {33132941},
issn = {1664-0640},
abstract = {Bipolar disorder is a severe psychiatric disorder which affects more than 1% of the world's population and is a leading cause of disability among young people. For the past 50 years, lithium has been the drug of choice for maintenance treatment of bipolar disorder due to its potent ability to prevent both manic and depressive episodes as well as suicide. However, though lithium has been associated with a multitude of effects within different cellular pathways and biological systems, its specific mechanism of action in stabilizing mood remains largely elusive. Mitochondrial dysfunction and telomere shortening have been implicated in both the pathophysiology of bipolar disorder and as targets of lithium treatment. Interestingly, it has in recent years become clear that these phenomena are intimately linked, partly through reactive oxygen species signaling and the subcellular translocation and non-canonical actions of telomerase reverse transcriptase. In this review, we integrate the current understanding of mitochondrial dysfunction, oxidative stress and telomere shortening in bipolar disorder with documented effects of lithium. Moreover, we propose that lithium's mechanism of action is intimately connected with the interdependent regulation of mitochondrial bioenergetics and telomere maintenance.},
}
@article {pmid33128602,
year = {2021},
author = {Minasi, S and Baldi, C and Gianno, F and Antonelli, M and Buccoliero, AM and Pietsch, T and Massimino, M and Buttarelli, FR},
title = {Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma.},
journal = {Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery},
volume = {37},
number = {3},
pages = {809-818},
pmid = {33128602},
issn = {1433-0350},
mesh = {*Brain Neoplasms/genetics ; Child ; *Glioma/genetics ; Humans ; Mutation/genetics ; Telomere/genetics ; Telomere Homeostasis/genetics ; X-linked Nuclear Protein/genetics ; },
abstract = {PURPOSE: The maintenance of telomere length prevents cancer cell senescence and occurs via two mutually exclusive mechanisms: (a) reactivation of telomerase expression and (b) activation of alternative lengthening of telomeres (ALT). ALT is frequently related to alterations on ATRX, a chromatin-remodelling protein. Recent data have identified different molecular subgroups of paediatric high-grade glioma (pHGG) with mutations of H3F3A, TERTp and ATRX; however, differences in telomere length among these molecular subgroups were not thoroughly examined.<br><br>METHODS: We investigated which genetic alterations trigger the ALT mechanism in 52 IDH-wildtype, 1p/19q-wildtype pHGG. Samples were analysed for telomere length using Tel-FISH. ATRX nuclear loss of expression was assessed by IHC, H3F3A and TERTp mutations by DNA sequencing, and TERTp methylation by MS-PCR.<br><br>RESULTS: Mutant H3.3 was found in 21 cases (40.3%): 19.2% with K27M mutation and 21.1% with G34R mutation. All H3.3G34R-mutated cases showed the ALT phenotype (100%); on the opposite, only 40% of the H3.3K27M-mutated showed ALT activation. ATRX nuclear loss was seen in 16 cases (30.7%), associated sometimes with the G34R mutation, and never with the K27M mutation. ATRX nuclear loss was always related to telomere elongation. TERTp C250T mutations were rare (5.4%) and were not associated with high intensity Tel-FISH signals, as TERTp hyper-methylation detected in 21% of the cases. H3.3/ATRX/TERTp-wildtype pHGG revealed all basal levels of telomere length.<br><br>CONCLUSION: Our results show a strong association between H3.3 mutations and ALT, and highlight the different telomeric profiles in histone-defined subgroups: H3.3-G34R mutants always trigger ALT to maintain telomere length, irrespective of ATRX status, whereas only some H3.3-K27M tumours activate ALT. These findings suggest that acquiring the gly34 mutation on H3.3 might suffice to trigger the ALT mechanism.},
}
@article {pmid33128102,
year = {2020},
author = {Smith, LE and Jones, ME and Hamede, R and Risques, R and Patton, AH and Carter, PA and Storfer, A},
title = {Telomere Length is a Susceptibility Marker for Tasmanian Devil Facial Tumor Disease.},
journal = {EcoHealth},
volume = {17},
number = {3},
pages = {280-291},
pmid = {33128102},
issn = {1612-9210},
support = {R01 GM126563/GM/NIGMS NIH HHS/United States ; 1316549//Division of Environmental Biology/International ; },
mesh = {Animals ; *Biomarkers ; DNA/analysis ; Facial Neoplasms/epidemiology/*genetics ; *Marsupialia ; Tasmania ; Telomere/*physiology ; },
abstract = {Telomeres protect chromosomes from degradation during cellular replication. In humans, it is well-documented that excessive telomere degradation is one mechanism by which cells can become cancerous. Increasing evidence from wildlife studies suggests that telomere length is positively correlated with survival and health and negatively correlated with disease infection intensity. The recently emerged devil facial tumor disease (DFTD) has led to dramatic and rapid population declines of the Tasmanian devil throughout its geographic range. Here, we tested the hypothesis that susceptibility to DFTD is negatively correlated with telomere length in devils across three populations with different infection histories. Our findings suggest telomere length is correlated with DFTD resistance in three ways. First, devils from a population with the slowest recorded increase in DFTD prevalence (West Pencil Pine) have significantly longer telomeres than those from two populations with rapid and exponential increases in prevalence (Freycinet and Narawantapu). Second, using extensive mark-recapture data obtained from a long-term demographic study, we found that individuals with relatively long telomeres tend to be infected at a significantly later age than those with shorter telomeres. Third, a hazard model showed devils with longer telomeres tended to become infected at a lower rate than those with shorter telomeres. This research provides a rare study of telomere length variation and its association with disease in a wildlife population. Our results suggest that telomere length may be a reliable marker of susceptibility to DFTD and assist with future management of this endangered species.},
}
@article {pmid33126880,
year = {2020},
author = {Chang, X and Dorajoo, R and Sun, Y and Wang, L and Ong, CN and Liu, J and Khor, CC and Yuan, JM and Koh, WP and Friedlander, Y and Heng, CK},
title = {Effect of plasma polyunsaturated fatty acid levels on leukocyte telomere lengths in the Singaporean Chinese population.},
journal = {Nutrition journal},
volume = {19},
number = {1},
pages = {119},
pmid = {33126880},
issn = {1475-2891},
support = {R01 CA144034/CA/NCI NIH HHS/United States ; UM1 CA182876/CA/NCI NIH HHS/United States ; },
mesh = {Case-Control Studies ; China ; Fatty Acids, Unsaturated ; Humans ; *Leukocytes ; *Telomere/genetics ; },
abstract = {BACKGROUND: Shorter telomere length (TL) has been associated with poor health behaviors, increased risks of chronic diseases and early mortality. Excessive shortening of telomere is a marker of accelerated aging and can be influenced by oxidative stress and nutritional deficiency. Plasma n6:n3 polyunsaturated fatty acid (PUFA) ratio may impact cell aging. Increased dietary intake of marine n-3 PUFA is associated with reduced telomere attrition. However, the effect of plasma PUFA on leukocyte telomere length (LTL) and its interaction with genetic variants are not well established.<br><br>METHODS: A nested coronary artery disease (CAD) case-control study comprising 711 cases and 638 controls was conducted within the Singapore Chinese Health Study (SCHS). Samples genotyped with the Illumina ZhongHua-8 array. Plasma n-3 and n-6 PUFA were quantified using mass spectrometry (MS). LTL was measured with quantitative PCR method. Linear regression was used to test the association between PUFA and LTL. The interaction between plasma PUFAs and genetic variants was assessed by introducing an additional term (PUFA&#xd7;genetic variant) in the regression model. Analysis was carried out in cases and controls separately and subsequently meta-analyzed using the inverse-variance weighted method. We further assessed the association of PUFA and LTL with CAD risk by Cox Proportional-Hazards model and whether the effect of PUFA on CAD was mediated through LTL by using structural equation modeling.<br><br>RESULTS: Higher n6:n3 ratio was significantly associated with shorter LTL (p&#x2009;=&#x2009;0.018) and increased CAD risk (p&#x2009;=&#x2009;0.005). These associations were mainly driven by elevated plasma total n-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (p&#x2009;<&#x2009;0.05). There was a statistically significant interaction for an intergenic single nucleotide polymorphism (SNP) rs529143 with plasma total n-3 PUFA and DHA on LTL beyond the genome-wide threshold (p&#x2009;<&#x2009;5&#x2009;&#xd7;&#x2009;&#xa0;10[-&#x2009;8]). Mediation analysis showed that PUFA and LTL affected CAD risk independently.<br><br>CONCLUSIONS: Higher plasma n6:n3 PUFA ratio, and lower EPA and DHA n-3 PUFAs were associated with shorter LTL and increased CAD risk in this Chinese population. Furthermore, genetic variants may modify the effect of PUFAs on LTL. PUFA and LTL had independent effect on CAD risk in our study population.},
}
@article {pmid33126043,
year = {2020},
author = {Grandin, N and Gallego, ME and White, CI and Charbonneau, M},
title = {Inhibition of the alternative lengthening of telomeres pathway by subtelomeric sequences in Saccharomyces cerevisiae.},
journal = {DNA repair},
volume = {96},
number = {},
pages = {102996},
doi = {10.1016/j.dnarep.2020.102996},
pmid = {33126043},
issn = {1568-7856},
mesh = {*Cellular Senescence ; Rad51 Recombinase/metabolism ; Rad52 DNA Repair and Recombination Protein/metabolism ; *Recombination, Genetic ; *Regulatory Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*genetics/physiology ; Saccharomyces cerevisiae Proteins/metabolism ; Telomerase ; Telomere/metabolism ; *Telomere Homeostasis ; },
abstract = {In the budding yeast Saccharomyces cerevisiae, telomerase is constitutively active and is essential for chromosome end protection and illimited proliferation of cell populations. However, upon inactivation of telomerase, alternative mechanims of telomere maintenance allow proliferation of only extremely rare survivors. S. cerevisiae type I and type II survivors differ by the nature of the donor sequences used for repair by homologous recombination of the uncapped terminal TG1-3 telomeric sequences. Type I amplifies the subtelomeric Y' sequences and is more efficient than type II, which amplifies the terminal TG1-3 repeats. However, type II survivors grow faster than type I survivors and can easily outgrow them in liquid cultures. The mechanistic interest of studying S. cerevisiae telomeric recombination is reinforced by the fact that type II recombination is the equivalent of the alternative lengthening of telomeres (ALT) pathway that is used by 5-15 % of cancer types as an alternative to telomerase reactivation. In budding yeast, only around half of the 32 telomeres harbor Y' subtelomeric elements. We report here that in strains harboring Y' elements on all telomeres, type II survivors are not observed, most likely due to an increase in the efficiency of type I recombination. However, in a temperature-sensitive cdc13-1 mutant grown at semi-permissive temperature, the increased amount of telomeric TG1-3 repeats could overcome type II inhibition by the subtelomeric Y' sequences. Strikingly, in the 100 % Y' strain the replicative senescence crisis normally provoked by inactivation of telomerase completely disappeared and the severity of the crisis was proportional to the percentage of chromosome-ends lacking Y' subtelomeric sequences. The present study highlights the fact that the nature of subtelomeric elements can influence the selection of the pathway of telomere maintenance by recombination, as well as the response of the cell to telomeric damage caused by telomerase inactivation.},
}
@article {pmid33125425,
year = {2020},
author = {Warner, ET and Zhang, Y and Gu, Y and Taporoski, TP and Pereira, A and DeVivo, I and Spence, ND and Cozier, Y and Palmer, JR and Kanaya, AM and Kandula, NR and Cole, SA and Tworoger, S and Shields, A},
title = {Physical and sexual abuse in childhood and adolescence and leukocyte telomere length: A pooled analysis of the study on psychosocial stress, spirituality, and health.},
journal = {PloS one},
volume = {15},
number = {10},
pages = {e0241363},
pmid = {33125425},
issn = {1932-6203},
support = {U01 HL041654/HL/NHLBI NIH HHS/United States ; 75N92019D00028/HL/NHLBI NIH HHS/United States ; R01 HL093009/HL/NHLBI NIH HHS/United States ; K01 CA188075/CA/NCI NIH HHS/United States ; U01 HL065521/HL/NHLBI NIH HHS/United States ; R01 HL109282/HL/NHLBI NIH HHS/United States ; 75N92019D00030/HL/NHLBI NIH HHS/United States ; P30 DK098722/DK/NIDDK NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; U01 HL041642/HL/NHLBI NIH HHS/United States ; R01 CA163451/CA/NCI NIH HHS/United States ; U01 CA164974/CA/NCI NIH HHS/United States ; UL1 TR001872/TR/NCATS NIH HHS/United States ; R01 HL109319/HL/NHLBI NIH HHS/United States ; 75N92019D00029/HL/NHLBI NIH HHS/United States ; U01 CA176726/CA/NCI NIH HHS/United States ; R01 HL109315/HL/NHLBI NIH HHS/United States ; R01 CA058420/CA/NCI NIH HHS/United States ; R01 HL120725/HL/NHLBI NIH HHS/United States ; K24 HL112827/HL/NHLBI NIH HHS/United States ; R01 HL109284/HL/NHLBI NIH HHS/United States ; R01 CA067262/CA/NCI NIH HHS/United States ; U01 HL041652/HL/NHLBI NIH HHS/United States ; 75N92019D00027/HL/NHLBI NIH HHS/United States ; R01 CA098663/CA/NCI NIH HHS/United States ; U01 HL065520/HL/NHLBI NIH HHS/United States ; R01 HL109301/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Child ; Humans ; Leukocytes/*metabolism ; Physical Abuse ; Telomere/*genetics ; },
abstract = {INTRODUCTION: We examined whether abuse in childhood and/or adolescence was associated with shorter telomere length in a pooled analysis of 3,232 participants from five diverse cohorts. We also assessed whether religion or spirituality (R/S) could buffer deleterious effects of abuse.<br><br>METHODS: Physical and sexual abuse in childhood (age <12) and adolescence (age 12-18) was assessed using the Revised Conflict Tactics Scale and questions from a 1995 Gallup survey. We measured relative leukocyte telomere lengths (RTL) using quantitative real time polymerase chain reaction. We used generalized estimating equations to assess associations of physical and sexual abuse with log-transformed RTL z-scores. Analyses were conducted in each cohort, overall, and stratified by extent of religiosity or spirituality and religious coping in adulthood. We pooled study-specific estimates using random-effects models and assessed between-study heterogeneity.<br><br>RESULTS: Compared to no abuse, severe sexual abuse was associated with lower RTL z-scores, in childhood: -15.6%, 95% CI: -25.9, -4.9; p-trend = 0.04; p-heterogeneity = 0.58 and in adolescence: -16.5%, 95% CI: -28.1, -3.0; p-trend = 0.08; p-heterogeneity = 0.68. Sexual abuse experienced in both childhood and adolescence was associated with 11.3% lower RTL z-scores after adjustment for childhood and demographic covariates (95% CI: -20.5%, -2.0%; p-trend = 0.03; p-heterogeneity = 0.62). There was no evidence of effect modification by R/S. Physical abuse was not associated with telomere length.<br><br>CONCLUSIONS: Sexual abuse in childhood or adolescence was associated with a marker of accelerated biological aging, decreased telomere length. The lack of moderation by R/S may be due to inability to capture the appropriate time period for those beliefs and practices.},
}
@article {pmid33123024,
year = {2020},
author = {Polettini, J and da Silva, MG},
title = {Telomere-Related Disorders in Fetal Membranes Associated With Birth and Adverse Pregnancy Outcomes.},
journal = {Frontiers in physiology},
volume = {11},
number = {},
pages = {561771},
pmid = {33123024},
issn = {1664-042X},
abstract = {Telomere disorders have been associated with aging-related diseases, including diabetes, vascular, and neurodegenerative diseases. The main consequence of altered telomere is the induction of the state of irreversible cell cycle arrest. Though several mechanisms responsible for the activation of senescence have been identified, it is still unclear how a cell is indeed induced to become irreversibly arrested. Most tissues in the body will experience senescence throughout its lifespan, but intrinsic and extrinsic stressors, such as chemicals, pollution, oxidative stress (OS), and inflammation accelerate the process. Pregnancy is a state of OS, as the higher metabolic demand of the growing fetus results in increased reactive oxygen species production. As a temporary organ in the mother, senescence in fetal membranes and placenta is expected and linked to term parturition (>37 weeks of gestation). However, a persistent, overwhelming, or premature OS affects placental antioxidant capacity, with consequent accumulation of OS causing damage to lipids, proteins, and DNA in the placental tissues. Therefore, senescence and its main inducer, telomere length (TL) reduction, have been associated with pregnancy complications, including stillbirth, preeclampsia, intrauterine growth restriction, and prematurity. Fetal membranes have a notable role in preterm births, which continue to be a major health issue associated with increased risk of neo and perinatal adverse outcomes and/or predisposition to disease in later life; however, the ability to mediate a delay in parturition during such cases is limited, because the pathophysiology of preterm births and physiological mechanisms of term births are not yet fully elucidated. Here, we review the current knowledge regarding the regulation of telomere-related senescence mechanisms in fetal membranes, highlighting the role of inflammation, methylation, and telomerase activity. Moreover, we present the evidences of TL reduction and senescence in gestational tissues by the time of term parturition. In conclusion, we verified that telomere regulation in fetal membranes requires a more complete understanding, in order to support the development of successful effective interventions of the molecular mechanisms that triggers parturition, including telomere signals, which may vary throughout placental tissues.},
}
@article {pmid33122450,
year = {2020},
author = {Wu, Y and Pei, Y and Yang, Z and Li, K and Lou, X and Cui, W},
title = {Accelerated telomere shortening independent of LRRK2 variants in Chinese patients with Parkinson's disease.},
journal = {Aging},
volume = {12},
number = {20},
pages = {20483-20492},
pmid = {33122450},
issn = {1945-4589},
mesh = {Aged ; Asian People/genetics ; Case-Control Studies ; Female ; *Genetic Variation ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/*genetics ; Male ; Middle Aged ; Parkinson Disease/*genetics ; Telomere Shortening/*genetics ; Time Factors ; },
abstract = {Oxidative stress and inflammation play vital roles in Parkinson's disease (PD) development. Thus, telomere length is expected to be shortened in this disease, but current data are inconclusive. We performed a case-control study of 261 patients with PD and 270 sex and age-matched healthy controls treated at the Peking Union Medical College Hospital. We found leucocyte telomere length (LTL) was significantly shortened in PD as compared with controls [1.02 (0.84-1.39) vs. 1.48 (1.08-1.94), P<0.001] and shorter LTL was associated with a dramatically increased risk of PD (lowest vs. highest quartile odds ratio (OR) =9.54, 95% CI: 5.33-17.06, P<0.001). We also investigated the roles of six LRRK2 variants in the susceptibility to PD. R1441C/G/H, G2019S, and I2020T variations were not detected in our study. No significant differences were found in the presence of variants R1398H (15.4% vs. 17.0%, P=0.619) and R1628P (2.3% vs. 0.7%, P=0.159) in PD and controls, while the G2385R variant was found to be a risk factor associated with increased PD susceptibility (OR=2.14, 95% CI: 1.12-4.10, P=0.021). No significant association was found between different LRRK2 variants and telomere length. These findings suggest that shorter LTL might be associated with PD in a manner independent of LRRK2 variants.},
}
@article {pmid33122338,
year = {2021},
author = {Adegunsoye, A and Morisset, J and Newton, CA and Oldham, JM and Vittinghoff, E and Linderholm, AL and Strek, ME and Noth, I and Garcia, CK and Wolters, PJ and Ley, B},
title = {Leukocyte telomere length and mycophenolate therapy in chronic hypersensitivity pneumonitis.},
journal = {The European respiratory journal},
volume = {57},
number = {3},
pages = {},
pmid = {33122338},
issn = {1399-3003},
support = {KL2 TR001870/TR/NCATS NIH HHS/United States ; K23 HL146942/HL/NHLBI NIH HHS/United States ; R01 HL093096/HL/NHLBI NIH HHS/United States ; R01 HL130796/HL/NHLBI NIH HHS/United States ; R01 HL139897/HL/NHLBI NIH HHS/United States ; K23 HL148498/HL/NHLBI NIH HHS/United States ; K23 HL138190/HL/NHLBI NIH HHS/United States ; },
mesh = {*Alveolitis, Extrinsic Allergic/drug therapy ; Humans ; Leukocytes ; *Telomere ; },
}
@article {pmid33122293,
year = {2020},
author = {Pinzaru, AM and Kareh, M and Lamm, N and Lazzerini-Denchi, E and Cesare, AJ and Sfeir, A},
title = {Replication stress conferred by POT1 dysfunction promotes telomere relocalization to the nuclear pore.},
journal = {Genes &amp; development},
volume = {34},
number = {23-24},
pages = {1619-1636},
pmid = {33122293},
issn = {1549-5477},
support = {P30 CA016087/CA/NCI NIH HHS/United States ; U01 CA231019/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; DNA Damage/genetics ; DNA Replication/*genetics ; Humans ; Mitosis/genetics ; Mutation ; Neoplasms/genetics/physiopathology ; Nuclear Pore/*pathology ; Shelterin Complex ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {Mutations in the telomere-binding protein POT1 are associated with solid tumors and leukemias. POT1 alterations cause rapid telomere elongation, ATR kinase activation, telomere fragility, and accelerated tumor development. Here, we define the impact of mutant POT1 alleles through complementary genetic and proteomic approaches based on CRISPR interference and biotin-based proximity labeling, respectively. These screens reveal that replication stress is a major vulnerability in cells expressing mutant POT1, which manifests as increased telomere mitotic DNA synthesis at telomeres. Our study also unveils a role for the nuclear pore complex in resolving replication defects at telomeres. Depletion of nuclear pore complex subunits in the context of POT1 dysfunction increases DNA damage signaling, telomere fragility and sister chromatid exchanges. Furthermore, we observed telomere repositioning to the nuclear periphery driven by nuclear F-actin polymerization in cells with POT1 mutations. In conclusion, our study establishes that relocalization of dysfunctional telomeres to the nuclear periphery is critical to preserve telomere repeat integrity.},
}
@article {pmid33121962,
year = {2021},
author = {Michniacki, TF and Weyand, AC},
title = {Gastrointestinal Bleeding: Expanding the Shortened Telomere Disorder Phenotype.},
journal = {The Journal of pediatrics},
volume = {230},
number = {},
pages = {12-14},
doi = {10.1016/j.jpeds.2020.10.057},
pmid = {33121962},
issn = {1097-6833},
mesh = {Biology ; Gastrointestinal Hemorrhage/etiology/genetics ; Humans ; Phenotype ; *Telomere/genetics ; *Telomere Shortening ; },
}
@article {pmid33120877,
year = {2020},
author = {Torrance, JB and Goldband, S},
title = {Mathematical Connection between Short Telomere Induced Senescence Calculation and Mortality Rate Data.},
journal = {International journal of molecular sciences},
volume = {21},
number = {21},
pages = {},
pmid = {33120877},
issn = {1422-0067},
mesh = {Aging/*genetics ; Canada/epidemiology ; Cellular Senescence ; Female ; Humans ; Longevity ; Male ; Models, Theoretical ; Mortality ; Sex Characteristics ; Telomere/*genetics ; Telomere Shortening ; },
abstract = {The last 20 years have seen a surge in scientific activity and promising results in the study of aging and longevity. Many researchers have focused on telomeres, which are composed of a series of TTAGGG repeat nucleotide sequences at the ends of each chromosome. Measurements of the length of these telomere strands show that they decrease in length with increasing age, leading many authors to propose that when the length of these telomere strands decreases sufficiently, the cells enter into a state of replicative senescence, eventually leading to disease and death. These ideas are supported by evidence that short telomere length is correlated with increased mortality. In this paper, we extend this idea to make an actual calculation of the predicted mortality rate caused by short telomere length induced senescence (STLIS). We derive a simple equation for the mathematical relationship between telomere length and mortality rate. Using only three parameters based on telomere length measurement data of Canadians, we have calculated both the magnitude and the age dependence of the mortality rate for both men and women. We show that these calculated data are in good quantitative agreement with the actual number of Canadians that die. This agreement demonstrates the quantitative correlation between the mortality calculated by the STLIS model and the mortality of the major diseases of aging (e.g., cardiovascular disease, many cancers and diabetes mellitus), which dominate human mortality. This result represents significant progress in our understanding of the factors behind the cause of aging.},
}
@article {pmid33120230,
year = {2021},
author = {Harnung Scholten, R and Møller, P and Jovanovic Andersen, Z and Dehlendorff, C and Khan, J and Brandt, J and Ketzel, M and Knudsen, LE and Mathiesen, L},
title = {Telomere length in newborns is associated with exposure to low levels of air pollution during pregnancy.},
journal = {Environment international},
volume = {146},
number = {},
pages = {106202},
doi = {10.1016/j.envint.2020.106202},
pmid = {33120230},
issn = {1873-6750},
mesh = {*Air Pollutants/analysis/toxicity ; *Air Pollution/adverse effects/analysis ; Child ; Female ; Fetal Blood/chemistry ; Humans ; Infant, Newborn ; Maternal Exposure/adverse effects ; Particulate Matter/analysis/toxicity ; Pregnancy ; Telomere ; },
abstract = {Telomere length (TL) is a biomarker of biological aging that may be affected by prenatal exposure to air pollution. The aim of this study was to assess the association between prenatal exposure to air pollution and TL in maternal blood cells (leukocytes), placenta and umbilical cord blood cells, sampled immediately after birth in 296 Danish mother-child pairs from a birth cohort. Exposure data was obtained using the high-resolution and spatial-temporal air pollution modeling system DEHM-UBM-AirGIS for PM2.5, PM10, SO2, NH4[+], black carbon (BC), organic carbon (OC), CO, O3, NO2, and NOx at residential and occupational addresses of the participating women for the full duration of the pregnancy. The association between prenatal exposure to air pollutants and TL was investigated using distributed lag models. There were significant and positive associations between TL in umbilical cord blood cells and prenatal exposure to BC, OC, NO2, NOx, CO, and O3 during the second trimester. TL in umbilical cord blood was significantly and inversely associated with prenatal exposure to PM2.5, BC, OC, SO2, NH4[+], CO and NO2 during the third trimester. There were similar inverse associations between TL from umbilical cord blood cells and air pollution exposure at the residential and occupational addresses. There were weaker or no associations between air pollution exposure and TL in placenta tissue and maternal blood cells. In conclusion, both the second and third trimesters of pregnancy are shown to be sensitive windows of exposure to air pollution affecting fetal TL.},
}
@article {pmid33115534,
year = {2020},
author = {Zhang, C and Ostrom, QT and Semmes, EC and Ramaswamy, V and Hansen, HM and Morimoto, L and de Smith, AJ and Pekmezci, M and Vaksman, Z and Hakonarson, H and Diskin, SJ and Metayer, C and , and Taylor, MD and Wiemels, JL and Bondy, ML and Walsh, KM},
title = {Genetic predisposition to longer telomere length and risk of childhood, adolescent and adult-onset ependymoma.},
journal = {Acta neuropathologica communications},
volume = {8},
number = {1},
pages = {173},
pmid = {33115534},
issn = {2051-5960},
support = {CA139020/CA/NCI NIH HHS/United States ; T32 CA151022/CA/NCI NIH HHS/United States ; CA190991/CA/NCI NIH HHS/United States ; CA52689/CA/NCI NIH HHS/United States ; R01 CA194189/CA/NCI NIH HHS/United States ; T32 GM007171/GM/NIGMS NIH HHS/United States ; },
mesh = {Acid Anhydride Hydrolases/genetics ; Adolescent ; Adult ; Age of Onset ; Brain Neoplasms/epidemiology/*genetics ; Case-Control Studies ; Child ; DNA Helicases/genetics ; Ependymoma/epidemiology/*genetics ; Female ; Genetic Predisposition to Disease ; Humans ; Infratentorial Neoplasms/epidemiology/genetics ; Male ; Mendelian Randomization Analysis ; RNA/genetics ; Ribonucleoproteins/genetics ; Telomerase/genetics ; Telomere/*metabolism ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/genetics ; Young Adult ; },
abstract = {Ependymoma is the third most common brain tumor in children, with well-described molecular characterization but poorly understood underlying germline risk factors. To investigate whether genetic predisposition to longer telomere length influences ependymoma risk, we utilized case-control data from three studies: a population-based pediatric and adolescent ependymoma case-control sample from California (153 cases, 696 controls), a hospital-based pediatric posterior fossa type A (EPN-PF-A) ependymoma case-control study from Toronto's Hospital for Sick Children and the Children's Hospital of Philadelphia (83 cases, 332 controls), and a multicenter adult-onset ependymoma case-control dataset nested within the Glioma International Case-Control Consortium (GICC) (103 cases, 3287 controls). In the California case-control sample, a polygenic score for longer telomere length was significantly associated with increased risk of ependymoma diagnosed at ages 12-19 (P = 4.0 × 10[-3]), but not with ependymoma in children under 12 years of age (P = 0.94). Mendelian randomization supported this observation, identifying a significant association between genetic predisposition to longer telomere length and increased risk of adolescent-onset ependymoma (ORPRS = 1.67; 95% CI 1.18-2.37; P = 3.97 × 10[-3]) and adult-onset ependymoma (PMR-Egger = 0.042), but not with risk of ependymoma diagnosed before age 12 (OR = 1.12; 95% CI 0.94-1.34; P = 0.21), nor with EPN-PF-A (PMR-Egger = 0.59). These findings complement emerging literature suggesting that augmented telomere maintenance is important in ependymoma pathogenesis and progression, and that longer telomere length is a risk factor for diverse nervous system malignancies.},
}
@article {pmid33113831,
year = {2020},
author = {Rampazzo, E and Cecchin, E and Del Bianco, P and Menin, C and Spolverato, G and Giunco, S and Lonardi, S and Malacrida, S and De Paoli, A and Toffoli, G and Pucciarelli, S and De Rossi, A},
title = {Genetic Variants of the TERT Gene, Telomere Length, and Circulating TERT as Prognostic Markers in Rectal Cancer Patients.},
journal = {Cancers},
volume = {12},
number = {11},
pages = {},
pmid = {33113831},
issn = {2072-6694},
support = {Grant n. RF-2011-02349645//Ministero della Salute/ ; Grant 5 x1000//Istituto Oncologico Veneto/ ; },
abstract = {Single-nucleotide polymorphisms (SNPs) in the TERT gene can affect telomere length and TERT expression and have been associated with risk and/or outcome for several tumors, but very few data are available about their impact on rectal cancer. Eight SNPs (rs2736108, rs2735940, rs2736098, rs2736100, rs35241335, rs11742908, rs2736122 and rs2853690), mapping in regulatory and coding regions of the TERT gene, were studied in 194 rectal cancer patients to evaluate their association with constitutive telomere length, circulating TERT mRNA levels, response to neoadjuvant chemoradiotherapy (CRT) and disease outcome. At diagnosis, the rs2736100CC genotype was associated with longer telomeres measured pre-CRT, while the rs2736100CC, rs2736108TT and rs2735940AA were associated with greater telomere erosion evaluated post-CRT. The rs2736108CC and rs2853690AA/GG genotypes, respectively associated with lower telomere erosion and lower levels of circulating TERT post-CRT, were also independently associated with a better response to therapy [OR 4.6(1.1-19.1) and 3.0(1.3-6.9)]. Overall, post-CRT, low levels (≤ median value) of circulating TERT and its stable/decreasing levels compared to those pre-CRT, were independently associated with a better response to therapy [OR 5.8(1.9-17.8) and 5.3(1.4-19.4), respectively]. Furthermore, post-CRT, patients with long telomeres (>median value) and low levels of circulating TERT had a significantly lower risk of disease progression [HR 0.4(0.1-0.9) and 0.3(0.1-0.8), respectively]. These findings suggest that TERT SNPs could be a useful tool for improving the selection of patients who could benefit from CRT and support the role of telomere length and circulating TERT mRNA levels as useful markers for monitoring the response to therapy and disease outcome in rectal cancer patients.},
}
@article {pmid33113164,
year = {2021},
author = {van Lieshout, SHJ and Sparks, AM and Bretman, A and Newman, C and Buesching, CD and Burke, T and Macdonald, DW and Dugdale, HL},
title = {Estimation of environmental, genetic and parental age at conception effects on telomere length in a wild mammal.},
journal = {Journal of evolutionary biology},
volume = {34},
number = {2},
pages = {296-308},
doi = {10.1111/jeb.13728},
pmid = {33113164},
issn = {1420-9101},
mesh = {Animals ; Female ; Male ; *Maternal Age ; Mustelidae/*physiology ; *Paternal Age ; Quantitative Trait, Heritable ; *Telomere Homeostasis ; },
abstract = {Understanding individual variation in fitness-related traits requires separating the environmental and genetic determinants. Telomeres are protective caps at the ends of chromosomes that are thought to be a biomarker of senescence as their length predicts mortality risk and reflect the physiological consequences of environmental conditions. The relative contribution of genetic and environmental factors to individual variation in telomere length is, however, unclear, yet important for understanding its evolutionary dynamics. In particular, the evidence for transgenerational effects, in terms of parental age at conception, on telomere length is mixed. Here, we investigate the heritability of telomere length, using the 'animal model', and parental age at conception effects on offspring telomere length in a wild population of European badgers (Meles meles). Although we found no heritability of telomere length and low evolvability (<0.001), our power to detect heritability was low and a repeatability of 2% across individual lifetimes provides a low upper limit to ordinary narrow-sense heritability. However, year (32%) and cohort (3%) explained greater proportions of the phenotypic variance in telomere length, excluding qPCR plate and row variances. There was no support for cross-sectional or within-individual parental age at conception effects on offspring telomere length. Our results indicate a lack of transgenerational effects through parental age at conception and a low potential for evolutionary change in telomere length in this population. Instead, we provide evidence that individual variation in telomere length is largely driven by environmental variation in this wild mammal.},
}
@article {pmid33110040,
year = {2020},
author = {Latour, CD and O'Connell, K and Romano, ME and Kantor, ED and Du, M},
title = {Maternal age at last birth and leukocyte telomere length in a nationally representative population of perimenopausal and postmenopausal women.},
journal = {Menopause (New York, N.Y.)},
volume = {27},
number = {11},
pages = {1242-1250},
pmid = {33110040},
issn = {1530-0374},
support = {P20 GM104416/GM/NIGMS NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; P30 CA023108/CA/NCI NIH HHS/United States ; R25 CA214255/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Child ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes ; Maternal Age ; Nutrition Surveys ; *Perimenopause ; Postmenopause ; Pregnancy ; *Telomere ; },
abstract = {OBJECTIVE: The primary aim of this study was to evaluate if maternal age at birth of last child is associated with leukocyte telomere length in a nationally representative population of perimenopausal and postmenopausal women.<br><br>METHODS: We conducted a cross-sectional analysis of 1,232 women from the National Health and Nutrition Examination Survey to examine maternal age at last birth and telomere length, surveyed between 1999 and 2002. We included perimenopausal and postmenopausal women age 40 years and older. Maternal age at last live birth was self-reported, and leukocyte telomere length was measured using quantitative polymerase chain reaction. We calculated least-squares geometric mean telomere length across categories of maternal age adjusted for age, race/ethnicity, number of live births, survey cycle, and history of hysterectomy or oophorectomy. P trend < 0.05 was considered statistically significant. For hypothesis-generation, we explored modification by reproductive and sociodemographic factors.<br><br>RESULTS: Maternal age at last birth was positively associated with telomere length: the multivariable-adjusted least-squares geometric mean leukocyte telomere length across categories of age at last birth (<25, 25-29, 30-34, 35-39, &#x2265;40 y) was 0.90, 0.93, 0.93, 0.95, and 0.96, respectively (P trend&#x200a;=&#x200a;0.04). There was suggestive evidence this association may be restricted to those women with one or two live births or women who reported ever using oral contraceptives (P interaction <0.10 for both).<br><br>CONCLUSIONS: Later maternal age was associated with longer telomere length in a nationally representative population of women. These data provide new insight into the biological relationship between reproductive history and long-term health. : Video Summary:http://links.lww.com/MENO/A662.},
}
@article {pmid33104521,
year = {2020},
author = {Froidure, A and Mahieu, M and Hoton, D and Laterre, PF and Yombi, JC and Koenig, S and Ghaye, B and Defour, JP and Decottignies, A},
title = {Short telomeres increase the risk of severe COVID-19.},
journal = {Aging},
volume = {12},
number = {20},
pages = {19911-19922},
pmid = {33104521},
issn = {1945-4589},
mesh = {Adult ; Aged ; Aged, 80 and over ; COVID-19 ; Cellular Senescence ; *Coronavirus Infections ; Female ; Humans ; Lung/pathology ; Male ; Middle Aged ; *Pandemics ; *Pneumonia, Viral ; Prospective Studies ; *Telomere ; *Telomere Homeostasis ; },
abstract = {Telomeres are non-coding DNA sequences that protect chromosome ends and shorten with age. Short telomere length (TL) is associated with chronic diseases and immunosenescence. The main risk factor for mortality of coronavirus disease 2019 (COVID-19) is older age, but outcome is very heterogeneous among individuals of the same age group. Therefore, we hypothesized that TL influences COVID-19-related outcomes. In a prospective study, we measured TL by Flow-FISH in 70 hospitalized COVID-19 patients and compared TL distribution with our reference cohort of 491 healthy volunteers. We also correlated TL with baseline clinical and biological parameters. We stained autopsy lung tissue from six non-survivor COVID-19 patients to detect senescence-associated β-galactosidase activity, a marker of cellular aging. We found a significantly higher proportion of patients with short telomeres (<10[th] percentile) in the COVID-19 patients as compared to the reference cohort (P<0.001). Short telomeres were associated with a higher risk of critical disease, defined as admission to intensive care unit (ICU) or death without ICU. TL was negatively correlated with C-reactive protein and neutrophil-to-lymphocyte ratio. Finally, lung tissue from patients with very short telomeres exhibit signs of senescence in structural and immune cells. Our results suggest that TL influences the severity of the disease.},
}
@article {pmid33093047,
year = {2020},
author = {Sun, S and Shinya, R and Dayi, M and Yoshida, A and Sternberg, PW and Kikuchi, T},
title = {Telomere-to-Telomere Genome Assembly of Bursaphelenchus okinawaensis Strain SH1.},
journal = {Microbiology resource announcements},
volume = {9},
number = {43},
pages = {},
pmid = {33093047},
issn = {2576-098X},
abstract = {Bursaphelenchus okinawaensis is a self-fertilizing, hermaphroditic, fungus-feeding nematode used as a laboratory model for the genus Bursaphelenchus, which includes the important pathogen Bursaphelenchus xylophilus Here, we report the nearly complete genome sequence of B. okinawaensis The 70-Mbp assembly contained six scaffolds (>11 Mbp each) with telomere repeats on their ends, indicating complete chromosomes.},
}
@article {pmid33091002,
year = {2020},
author = {Mukherjee, AK and Sharma, S and Sengupta, S and Saha, D and Kumar, P and Hussain, T and Srivastava, V and Roy, SD and Shay, JW and Chowdhury, S},
title = {Correction: Telomere length-dependent transcription and epigenetic modifications in promoters remote from telomere ends.},
journal = {PLoS genetics},
volume = {16},
number = {10},
pages = {e1009152},
pmid = {33091002},
issn = {1553-7404},
abstract = {[This corrects the article DOI: 10.1371/journal.pgen.1007782.].},
}
@article {pmid33090998,
year = {2020},
author = {Brown, DW and Lin, SH and Loh, PR and Chanock, SJ and Savage, SA and Machiela, MJ},
title = {Genetically predicted telomere length is associated with clonal somatic copy number alterations in peripheral leukocytes.},
journal = {PLoS genetics},
volume = {16},
number = {10},
pages = {e1009078},
pmid = {33090998},
issn = {1553-7404},
support = {/WT_/Wellcome Trust/United Kingdom ; DP2 ES030554/ES/NIEHS NIH HHS/United States ; /BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Adult ; Aged ; Cell Division/genetics ; Clonal Evolution/*genetics ; DNA Copy Number Variations/genetics ; Female ; Genetics, Population ; Humans ; Leukocytes/metabolism/pathology ; Male ; Middle Aged ; Neoplasms/*blood/epidemiology/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; United Kingdom/epidemiology ; },
abstract = {Telomeres are DNA-protein structures at the ends of chromosomes essential in maintaining chromosomal stability. Observational studies have identified associations between telomeres and elevated cancer risk, including hematologic malignancies; but biologic mechanisms relating telomere length to cancer etiology remain unclear. Our study sought to better understand the relationship between telomere length and cancer risk by evaluating genetically-predicted telomere length (gTL) in relation to the presence of clonal somatic copy number alterations (SCNAs) in peripheral blood leukocytes. Genotyping array data were acquired from 431,507 participants in the UK Biobank and used to detect SCNAs from intensity information and infer telomere length using a polygenic risk score (PRS) of variants previously associated with leukocyte telomere length. In total, 15,236 (3.5%) of individuals had a detectable clonal SCNA on an autosomal chromosome. Overall, higher gTL value was positively associated with the presence of an autosomal SCNA (OR = 1.07, 95% CI = 1.05-1.09, P = 1.61×10-15). There was high consistency in effect estimates across strata of chromosomal event location (e.g., telomeric ends, interstitial or whole chromosome event; Phet = 0.37) and strata of copy number state (e.g., gain, loss, or neutral events; Phet = 0.05). Higher gTL value was associated with a greater cellular fraction of clones carrying autosomal SCNAs (β = 0.004, 95% CI = 0.002-0.007, P = 6.61×10-4). Our population-based examination of gTL and SCNAs suggests inherited components of telomere length do not preferentially impact autosomal SCNA event location or copy number status, but rather likely influence cellular replicative potential.},
}
@article {pmid33090930,
year = {2020},
author = {Arabadjiev, B and Pankov, R and Vassileva, I and Petrov, LS and Buchvarov, I},
title = {Photobiomodulation with 590 nm Wavelength Delays the Telomere Shortening and Replicative Senescence of Human Dermal Fibroblasts In Vitro.},
journal = {Photobiomodulation, photomedicine, and laser surgery},
volume = {38},
number = {11},
pages = {656-660},
doi = {10.1089/photob.2020.4822},
pmid = {33090930},
issn = {2578-5478},
mesh = {Cellular Senescence ; Fibroblasts/metabolism ; Humans ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; *Telomere Shortening ; },
abstract = {Background: Cellular senescence is one of the major factors contributing to the aging process. Photobiomodulation (PBM) is known to trigger an array of cellular responses, but there are no data on how it affects the process of cellular senescence. In this study, we analyze the effect of PBM on the cellular senescence and telomere dynamics. Methods: Human dermal fibroblasts were irradiated by a panel of light-emitting diodes with 590 nm and dose 30 J/cm[2] accumulated over 1200 sec repeated in 4-day cycle within 40 days. After the last cycle of PBM treatment, the difference in number of senescent cells between PBM treated groups end nontreated control groups was measured by senescent sensitive β-galactosidase assay, and the difference in average telomere length between the experimental end control groups was analyzed using relative human telomere length quantitative Polymerase Chain Reaction (qPCR) assay. Results: After 10 cycles of irradiation, the percentage of senescent cells in PBM-treated cultures was 19.7% ± 4.5%, p < 0.05 smaller than the percentage of senescent cells in the control group, and their relative telomere length was 1.19 ± 0.09-fold, p < 0.05 greater than nontreated controls. Conclusions: Our study demonstrates for the first time that PBM with appropriate parameters can delay the attrition of the telomeres and the entry of cells into senescence, suggesting a potential involvement of telomerase reactivation. A hypothetical mechanism for this light-induced antiaging effect is discussed.},
}
@article {pmid33086033,
year = {2020},
author = {Wang, L and Chen, R and Li, G and Wang, Z and Liu, J and Liang, Y and Liu, JP},
title = {FBW7 Mediates Senescence and Pulmonary Fibrosis through Telomere Uncapping.},
journal = {Cell metabolism},
volume = {32},
number = {5},
pages = {860-877.e9},
doi = {10.1016/j.cmet.2020.10.004},
pmid = {33086033},
issn = {1932-7420},
mesh = {Aging/*metabolism ; Aminopeptidases/metabolism ; Animals ; Cell Line ; *Cellular Senescence ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism ; F-Box-WD Repeat-Containing Protein 7/*metabolism ; Humans ; Mice ; *Oxidative Stress ; Serine Proteases/metabolism ; Shelterin Complex ; Stem Cells ; Telomere/*metabolism ; Telomere Shortening ; Telomere-Binding Proteins ; },
abstract = {Tissue stem cells undergo premature senescence under stress, promoting age-related diseases; however, the associated mechanisms remain unclear. Here, we report that in response to radiation, oxidative stress, or bleomycin, the E3 ubiquitin ligase FBW7 mediates cell senescence and tissue fibrosis through telomere uncapping. FBW7 binding to telomere protection protein 1 (TPP1) facilitates TPP1 multisite polyubiquitination and accelerates degradation, triggering telomere uncapping and DNA damage response. Overexpressing TPP1 or inhibiting FBW7 by genetic ablation, epigenetic interference, or peptidomimetic telomere dysfunction inhibitor (TELODIN) reduces telomere uncapping and shortening, expanding the pulmonary alveolar AEC2 stem cell population in mice. TELODIN, synthesized from the seventh β strand blade of FBW7 WD40 propeller domain, increases TPP1 stability, lung respiratory function, and resistance to senescence and fibrosis in animals chronically exposed to environmental stress. Our findings elucidate a pivotal mechanism underlying stress-induced pulmonary epithelial stem cell senescence and fibrosis, providing a framework for aging-related disorder interventions.},
}
@article {pmid33082515,
year = {2021},
author = {Nie, X and Xiao, D and Ge, Y and Xie, Y and Zhou, H and Zheng, T and Li, X and Liu, H and Huang, H and Zhao, Y},
title = {TRF2 recruits nucleolar protein TCOF1 to coordinate telomere transcription and replication.},
journal = {Cell death and differentiation},
volume = {28},
number = {3},
pages = {1062-1075},
pmid = {33082515},
issn = {1476-5403},
support = {81771506, 31571410, 31570827, 31701196//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
mesh = {Cell Line ; DNA Damage ; DNA Replication ; DNA-Binding Proteins/metabolism ; Humans ; Nuclear Proteins/*genetics ; Phosphoproteins/*genetics ; Ribonuclease H/*metabolism ; Telomere/chemistry/*metabolism ; Telomeric Repeat Binding Protein 2/*genetics ; Transcription Factors/metabolism ; },
abstract = {Telomeres are transcribed into telomeric RNA termed as TERRA. However, the transcription itself and excessive TERRA may interfere with telomere replication during S phase. The mechanism that coordinates telomere transcription and replication is unknown. Here, we report that TCOF1 leaves the nucleolus and is recruited to telomeres specifically during S phase by interacting with TRF2. Therein, TCOF1 acts to suppress telomere transcription by binding and inhibiting Pol II. Thus, TERRA is limited to low levels in S phase. Depletion of TCOF1 leads to abnormally elevated TERRA and formation of DNA/RNA hybrids (R-loops) at telomeres, which induces replication fork stalling and fragile telomeres. Importantly, telomere replication defect induced by TCOF1 deficiency can be rescued by either masking TERRA or expressing an R-loop eraser RNase H1, demonstrating a critical role of TCOF1 in coordinating telomere transcription and replication. These findings link nucleolus to telomeres and uncover a novel function of TCOF1 on ensuring telomere integrity.},
}
@article {pmid33082350,
year = {2020},
author = {Mazzucco, G and Huda, A and Galli, M and Piccini, D and Giannattasio, M and Pessina, F and Doksani, Y},
title = {Telomere damage induces internal loops that generate telomeric circles.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {5297},
pmid = {33082350},
issn = {2041-1723},
mesh = {Animals ; DNA, Single-Stranded/chemistry/genetics/metabolism ; Humans ; Mice ; Telomere/*chemistry/genetics/*metabolism ; Telomere Homeostasis ; },
abstract = {Extrachromosomal telomeric circles are commonly invoked as important players in telomere maintenance, but their origin has remained elusive. Using electron microscopy analysis on purified telomeres we show that, apart from known structures, telomeric repeats accumulate internal loops (i-loops) that occur in the proximity of nicks and single-stranded DNA gaps. I-loops are induced by single-stranded damage at normal telomeres and represent the majority of telomeric structures detected in ALT (Alternative Lengthening of Telomeres) tumor cells. Our data indicate that i-loops form as a consequence of the exposure of single-stranded DNA at telomeric repeats. Finally, we show that these damage-induced i-loops can be excised to generate extrachromosomal telomeric circles resulting in loss of telomeric repeats. Our results identify damage-induced i-loops as a new intermediate in telomere metabolism and reveal a simple mechanism that links telomere damage to the accumulation of extrachromosomal telomeric circles and to telomere erosion.},
}
@article {pmid33078399,
year = {2021},
author = {Weyburne, E and Bosco, G},
title = {Cancer-associated mutations in the condensin II subunit CAPH2 cause genomic instability through telomere dysfunction and anaphase chromosome bridges.},
journal = {Journal of cellular physiology},
volume = {236},
number = {5},
pages = {3579-3598},
pmid = {33078399},
issn = {1097-4652},
support = {P20 GM113132/GM/NIGMS NIH HHS/United States ; P30 CA023108/CA/NCI NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases/chemistry/*genetics/metabolism ; Amino Acid Sequence ; *Anaphase ; Cell Cycle Proteins/chemistry/genetics/*metabolism ; Chromatin/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes, Human/*metabolism ; DNA Damage ; DNA-Binding Proteins/chemistry/*genetics/metabolism ; *Genomic Instability ; Humans ; Micronucleus, Germline/metabolism ; Multiprotein Complexes/chemistry/*genetics/metabolism ; Mutant Proteins/metabolism ; Mutation/*genetics ; Neoplasms/*genetics/pathology ; Nuclear Proteins/chemistry/genetics/*metabolism ; Protein Binding ; Protein Stability ; Protein Subunits/chemistry/genetics/metabolism ; S Phase ; Telomere/metabolism/*pathology ; },
abstract = {Genome instability in cancer drives tumor heterogeneity, undermines the success of therapies, and leads to metastasis and recurrence. Condensins are conserved chromatin-binding proteins that promote genomic stability, mainly by ensuring proper condensation of chromatin and mitotic chromosome segregation. Condensin mutations are found in human tumors, but it is not known how or even if such mutations promote cancer progression. In this study, we focus on condensin II subunit CAPH2 and specific CAPH2 mutations reported to be enriched in human cancer patients, and we test how CAPH2 cancer-specific mutations may lead to condensin II complex dysfunction and contribute to genome instability. We find that R551P, R551S, and S556F mutations in CAPH2 cause genomic instability by causing DNA damage, anaphase defects, micronuclei, and chromosomal instability. DNA damage and anaphase defects are caused primarily by ataxia telangiectasia and Rad3-related-dependent telomere dysfunction, as anaphase bridges are enriched for telomeric repeat sequences. We also show that these mutations decrease the binding of CAPH2 to the ATPase subunit SMC4 as well as the rest of the condensin II complex, and decrease the amount of CAPH2 protein bound to chromatin. Thus, in vivo the R551P, R551S, and S556F cancer-specific CAPH2 mutant proteins are likely to impair condensin II complex formation, impede condensin II activity during mitosis and interphase, and promote genetic heterogeneity in cell populations that can lead to clonal outgrowth of cancer cells with highly diverse genotypes.},
}
@article {pmid33073402,
year = {2020},
author = {Glousker, G and Briod, AS and Quadroni, M and Lingner, J},
title = {Human shelterin protein POT1 prevents severe telomere instability induced by homology-directed DNA repair.},
journal = {The EMBO journal},
volume = {39},
number = {23},
pages = {e104500},
pmid = {33073402},
issn = {1460-2075},
support = {KLS-3824-02-2016//Swiss Cancer League/ ; 182880//NCCR RNA &amp; disease network of the SNSF/ ; 812829//Initial Training Network (ITN) grant (aDDRess) from the European Commission's Seventh Framework Programme/ ; 310030_184718/SNSF_/Swiss National Science Foundation/Switzerland ; },
mesh = {Cell Cycle/physiology ; DNA/metabolism ; DNA, Single-Stranded ; Gene Knockout Techniques ; HEK293 Cells ; HeLa Cells ; Humans ; Phenotype ; Proteome ; Recombinational DNA Repair/*genetics/*physiology ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/*genetics/*metabolism ; Transcriptome ; },
abstract = {The evolutionarily conserved POT1 protein binds single-stranded G-rich telomeric DNA and has been implicated in contributing to telomeric DNA maintenance and the suppression of DNA damage checkpoint signaling. Here, we explore human POT1 function through genetics and proteomics, discovering that a complete absence of POT1 leads to severe telomere maintenance defects that had not been anticipated from previous depletion studies in human cells. Conditional deletion of POT1 in HEK293E cells gives rise to rapid telomere elongation and length heterogeneity, branched telomeric DNA structures, telomeric R-loops, and telomere fragility. We determine the telomeric proteome upon POT1-loss, implementing an improved telomeric chromatin isolation protocol. We identify a large set of proteins involved in nucleic acid metabolism that engage with telomeres upon POT1-loss. Inactivation of the homology-directed repair machinery suppresses POT1-loss-mediated telomeric DNA defects. Our results unravel as major function of human POT1 the suppression of telomere instability induced by homology-directed repair.},
}
@article {pmid33068677,
year = {2021},
author = {Nickels, M and Mastana, S and Denniff, M and Codd, V and Akam, E},
title = {Elite swimmers possess shorter telomeres than recreationally active controls.},
journal = {Gene},
volume = {769},
number = {},
pages = {145242},
doi = {10.1016/j.gene.2020.145242},
pmid = {33068677},
issn = {1879-0038},
mesh = {Adolescent ; *Athletic Performance ; Case-Control Studies ; Female ; Genotype ; Humans ; INDEL Mutation ; Male ; Peptidyl-Dipeptidase A/*genetics ; *Swimming ; *Telomere ; Young Adult ; },
abstract = {PURPOSE: Elite athletes are reported to possess longer telomeres than their less active counterparts. ACE gene (Insertion/Deletion) polymorphism has been previously associated with elite athletic performance, with the deletion (D) variant appearing more frequently in short distance swimmers. Additionally, the D allele has been reported to have a negative effect on telomere length. The aim of this study was to investigate the telomere length of elite swimmers and its potential association with ACE genotype.<br><br>METHODS: Telomere length was measured by real-time quantitative PCR and ACE I/D genotypes analysed by standard PCR and electrophoresis in 51 young elite swimmers and 56 controls.<br><br>RESULTS: Elite swimmers displayed shorter telomeres than controls (1.043 &#xb1; 0.127 vs 1.128 &#xb1; 0.177, p = 0.006). When split by sex, only elite female swimmers showed significantly shorter telomeres than their recreationally active counterparts (p = 0.019). ACE genotype distribution and allelic frequency did not differ between elite swimmers and controls, or by event distance among elite swimmers only. No association was observed between telomere length and ACE genotype in the whole cohort.<br><br>CONCLUSIONS: Elite swimmers possessed shorter telomeres than recreationally active controls. Our findings suggesting a negative effect of high-level swimming competition and/or training on telomere length and subsequent biological aging, particularly in females. However, this significant difference in telomere length does not appear to be attributed to the D allele as we report a lack of association between telomere length and ACE genotype frequency in elite swimmers and controls.},
}
@article {pmid33065771,
year = {2022},
author = {Noguera, JC and da Silva, A and Velando, A},
title = {Egg corticosterone can stimulate telomerase activity and promote longer telomeres during embryo development.},
journal = {Molecular ecology},
volume = {31},
number = {23},
pages = {6252-6260},
doi = {10.1111/mec.15694},
pmid = {33065771},
issn = {1365-294X},
mesh = {Animals ; Corticosterone/pharmacology ; *Telomerase ; *Charadriiformes ; Telomere/genetics ; Embryonic Development/genetics ; },
abstract = {It is often assumed that the transfer of maternal glucocorticoids (GCs; e.g., corticosterone or cortisol) to offspring is an inevitable cost associated with adverse or stressful conditions experienced by mothers. However, recent evidence indicates that maternal GCs may adaptively programme particular physiological and molecular pathways during development to enhance offspring fitness. In this context, an important mechanism through which maternal GCs may lastingly affect offspring phenotypic quality and survival is via effects on embryo telomerase activity and so on offspring postnatal telomere length. Here, using a field experimental design for which we manipulated the corticosterone content in yellow-legged gull (Larus michahellis) eggs, we show that embryos from corticosterone-injected eggs not only had a higher telomerase activity but also longer telomeres just after hatching. A complementary analysis further revealed that gull hatchlings with longer telomeres had a higher survival probability during the period when most of the chick mortality occurs. Given the important role that telomere length and its restoring mechanisms have on ageing trajectories and disease risk, our findings provide a new mechanistic link by which mothers may presumably shape offspring life-history trajectories and phenotype.},
}
@article {pmid33057192,
year = {2020},
author = {Feretzaki, M and Pospisilova, M and Valador Fernandes, R and Lunardi, T and Krejci, L and Lingner, J},
title = {RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops.},
journal = {Nature},
volume = {587},
number = {7833},
pages = {303-308},
pmid = {33057192},
issn = {1476-4687},
support = {//Wellcome Trust/United Kingdom ; 166675/SNSF_/Swiss National Science Foundation/Switzerland ; 206292//Wellcome Trust/United Kingdom ; 206292/E/17/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Base Sequence ; Biocatalysis ; Genes, Reporter ; HeLa Cells ; Humans ; *R-Loop Structures ; RNA, Long Noncoding/*chemistry/genetics ; Rad51 Recombinase/*metabolism ; Ribonuclease H/metabolism ; Telomere/*chemistry/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; },
abstract = {Telomeres-repeated, noncoding nucleotide motifs and associated proteins that are found at the ends of eukaryotic chromosomes-mediate genome stability and determine cellular lifespan[1]. Telomeric-repeat-containing RNA (TERRA) is a class of long noncoding RNAs (lncRNAs) that are transcribed from chromosome ends[2,3]; these RNAs in turn regulate telomeric chromatin structure and telomere maintenance through the telomere-extending enzyme telomerase[4-6] and homology-directed DNA repair[7,8]. The mechanisms by which TERRA is recruited to chromosome ends remain poorly defined. Here we develop a reporter system with which to dissect the underlying mechanisms, and show that the UUAGGG repeats of TERRA are both necessary and sufficient to target TERRA to chromosome ends. TERRA preferentially associates with short telomeres through the formation of telomeric DNA-RNA hybrid (R-loop) structures that can form in trans. Telomere association and R-loop formation trigger telomere fragility and are promoted by the recombinase RAD51 and its interacting partner BRCA2, but counteracted by the RNA-surveillance factors RNaseH1 and TRF1. RAD51 physically interacts with TERRA and catalyses R-loop formation with TERRA in vitro, suggesting a direct involvement of this DNA recombinase in the recruitment of TERRA by strand invasion. Together, our findings reveal a RAD51-dependent pathway that governs TERRA-mediated R-loop formation after transcription, providing a mechanism for the recruitment of lncRNAs to new loci in trans.},
}
@article {pmid33053112,
year = {2020},
author = {Normando, P and Bezerra, FF and Santana, BA and Calado, RT and Santos-Rebouças, CB and Epel, ES and Faerstein, E},
title = {Association between socioeconomic markers and adult telomere length differs according to sex: Pro-Saúde study.},
journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas},
volume = {53},
number = {11},
pages = {e10223},
pmid = {33053112},
issn = {1414-431X},
mesh = {Adult ; Aging ; Brazil ; Cross-Sectional Studies ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; *Telomere ; },
abstract = {Understanding the social determinants of telomere length is critical to evaluate the risk of early biological aging. We investigated sex differences on the association between socioeconomic status (SES) and demographic markers and leukocyte telomere length (LTL) in Brazilian adults. This cross-sectional study was conducted in a subsample (women=228; men=200) nested within the Pro-Saúde study, a prospective cohort study of university civil servants in Rio de Janeiro, Brazil (2012-2013). Adjusted multivariate models were used to test the relationship between SES markers (marital status, educational attainment, father's educational attainment, race/skin color, household income, and childhood experience of food deprivation) and LTL. After adjusting for age and potential health-related confounders, lower educational attainment was associated with shorter LTL among men (β=-0.05, 95% confidence interval (CI)=95%CI: -0.10, 0.00, P=0.03). In women, LTL was inversely associated with unmarried status (β=-0.05, 95%CI: -0.09, 0.00, P=0.03), lower father's educational attainment (β=-0.05, 95%CI: -0.13, 0.00, P=0.04), and childhood experience of food deprivation (β=-0.07, 95%CI: -0.13, 0.00, P=0.04). Our findings suggested that the association between SES markers and LTL differs according to sex. SES markers able to induce lifelong stress, reflected in LTL, appeared to be more related to individual factors in men, whereas in women they were family-related.},
}
@article {pmid33051039,
year = {2020},
author = {Keng, SL and Looi, PS and Tan, ELY and Yim, OS and Lai, PS and Chew, SH and Ebstein, RP},
title = {Effects of Mindfulness-Based Stress Reduction on Psychological Symptoms and Telomere Length: A Randomized Active-Controlled Trial.},
journal = {Behavior therapy},
volume = {51},
number = {6},
pages = {984-996},
doi = {10.1016/j.beth.2020.01.005},
pmid = {33051039},
issn = {1878-1888},
mesh = {Adult ; Anxiety ; *Anxiety Disorders/genetics/therapy ; Humans ; *Mindfulness ; *Stress, Psychological/genetics/therapy ; *Telomere ; Treatment Outcome ; },
abstract = {Much research has demonstrated the beneficial effects of mindfulness-based stress reduction (MBSR) on psychological and physical health, but it is not known whether MBSR may impact cellular aging in healthy populations. Further, little research has evaluated MBSR against an active control condition, which precludes strong conclusions regarding the unique effects of mindfulness on psychological functioning. The present study examined the effects of MBSR versus music therapy-based stress reduction (MTSR) on trait mindfulness, self-compassion, and several psychological health outcomes, as well as leukocyte telomere length (LTL). One hundred and fifty eight Singaporean Chinese adults were recruited and randomly assigned to an eight-week MBSR or MTSR course. Participants provided blood samples and completed a battery of self-report measures pre- and post-intervention. Analyses showed that participants in the MBSR condition demonstrated significantly greater improvements in depressive symptoms, trait mindfulness, and self-compassion compared to the control condition. Treatment condition did not predict changes in LTL, anxiety, stress, or happiness, though there was a trend for duration of home mindfulness practice to predict increases in LTL. Overall, the study demonstrated MBSR's unique effects in reducing depressive symptoms. Improvements in trait mindfulness and self-compassion correspond with theorized mechanisms of change underlying mindfulness training. The lack of intervention effect with regards to LTL suggests that a more intensive intervention may be required for mindfulness to exert noticeable impact on aging at the cellular level, or that the effect may only emerge over a longer term.},
}
@article {pmid33049239,
year = {2021},
author = {Cleber Gama de Barcellos Filho, P and Campos Zanelatto, L and Amélia Aparecida Santana, B and Calado, RT and Rodrigues Franci, C},
title = {Effects chronic administration of corticosterone and estrogen on HPA axis activity and telomere length in brain areas of female rats.},
journal = {Brain research},
volume = {1750},
number = {},
pages = {147152},
doi = {10.1016/j.brainres.2020.147152},
pmid = {33049239},
issn = {1872-6240},
mesh = {Adrenocorticotropic Hormone/metabolism ; Amygdala/drug effects ; Animals ; Brain/drug effects/metabolism ; Corticosterone/metabolism/*pharmacology ; Corticotropin-Releasing Hormone/metabolism ; Estrogens/metabolism/*pharmacology ; Female ; Hippocampus/drug effects ; Hypothalamo-Hypophyseal System/metabolism ; Paraventricular Hypothalamic Nucleus/drug effects ; Pituitary-Adrenal System/metabolism ; Rats ; Stress, Physiological ; Telomere/drug effects/metabolism/physiology ; Telomere Homeostasis/drug effects/*physiology ; },
abstract = {Chronic stress is related to the acceleration of telomere shortening. Recent work showed a correlation between chronic psychosocial stress and reduced telomere length in certain cells. The exposure of T lymphocytes to cortisol promoted a significant reduction in telomerase activity. Although stress can promote changes in telomere length, whether increased glucocorticoid concentrations alter telomere length in brain tissue cells is unclear. In addition to modulating the activity of the stress system, estrogen also influences telomere length. The objective of this study was to verify whether chronic exposure to glucocorticoids promotes changes in the telomere length of encephalic areas involved in the control of HPA axis activity and whether estrogen affects these changes. Wistar rats were ovariectomized and treated with estradiol cypionate [(50 or 100 μg/kg, subcutaneously)] or oil and 20 mg/kg corticosterone or vehicle (isotonic saline with 2% Tween 80, subcutaneously) for 28 days. On the day after the end of the hormonal treatment, the animals were euthanized for collection of blood, brain and pituitary gland samples. Estrogen modulated the activity of the HPA axis. CRH, AVP and POMC mRNA levels were reduced by estrogen. At least in doses and treatment time used, there was no correlation between effects of exposure to glucocorticoids and estrogen on telomere length in the brain areas of female rats. However, estrogen treatment reduced the telomere length in the central amygdala and dorsal hippocampus, but not in the PVN, indicating a variation of reaction of telomeres for estrogen in different brain areas.},
}
@article {pmid33049101,
year = {2021},
author = {Power, ML and Power, S and Bertelsen, MF and Jones, G and Teeling, EC},
title = {Wing: A suitable nonlethal tissue type for repeatable and rapid telomere length estimates in bats.},
journal = {Molecular ecology resources},
volume = {21},
number = {2},
pages = {421-432},
doi = {10.1111/1755-0998.13276},
pmid = {33049101},
issn = {1755-0998},
support = {//Royal Irish Academy/ ; //Irish Research Council/ ; },
mesh = {Animals ; *Chiroptera/genetics ; DNA ; Specimen Handling ; *Telomere/genetics ; *Wings, Animal ; },
abstract = {Telomeres are used increasingly in ecology and evolution as biomarkers for ageing and environmental stress, and are typically measured from DNA extracted from nonlethally sampled blood. However, obtaining blood is not always possible in field conditions and only limited amounts can be taken from small mammals, such as bats, which moreover lack nucleated red blood cells and hence yield relatively low amounts of DNA. As telomere length can vary within species according to age and tissue, it is important to determine which tissues serve best as a representation of the organism as a whole. Here, we investigated whether wing tissue biopsies, a rapid and relatively noninvasive tissue collection method, could serve as a proxy for other tissues when measuring relative telomere length (rTL) in the Egyptian fruit bat (Rousettus aegyptiacus). Telomeres were measured from blood, brain, heart, kidney, liver lung, muscle and wing, and multiple wing biopsies were taken from the same individuals to determine intra-individual repeatability of rTL measured by using qPCR. Wing rTL correlated with rTL estimates from most tissues apart from blood. Blood rTL was not significantly correlated with rTL from any other tissue. Blood and muscle rTLs were significantly longer compared with other tissues, while lung displayed the shortest rTLs. Individual repeatability of rTL measures from wing tissue was high (>70%). Here we show the relationships between tissue telomere dynamics for the first time in a bat, and our results provide support for the use of wing tissue for rTL measurements.},
}
@article {pmid33046137,
year = {2020},
author = {Cao, W and Zheng, D and Zhang, J and Wang, A and Liu, D and Zhang, J and Singh, M and Maranga, IE and Cao, M and Wu, L and Song, M and Wang, W and Wang, Y},
title = {Association between telomere length in peripheral blood leukocytes and risk of ischemic stroke in a Han Chinese population: a linear and non-linear Mendelian randomization analysis.},
journal = {Journal of translational medicine},
volume = {18},
number = {1},
pages = {385},
pmid = {33046137},
issn = {1479-5876},
mesh = {*Brain Ischemia/genetics ; China ; Humans ; *Ischemic Stroke ; Leukocytes ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide/genetics ; *Stroke/genetics ; Telomere/genetics ; },
abstract = {BACKGROUND: Many contradictory conclusions pertaining to the telomere length in peripheral leukocyte chromosomes as a potential biomarker for ischemic stroke (IS) risk have been reported by the various observational studies in previous years. This study aims to investigate whether the leukocyte telomere length is associated with an increased IS risk or not, based on the Mendelian randomization (MR) approach.<br><br>METHODS: Based on the NHGRI-EBI GWAS Catalog database, the Chinese online genetic database as well as the previous published studies, twelve single nucleotide polymorphisms (SNPs) with minor allele frequency&#x2009;&#x2265;&#x2009;0.05 were selected and the leukocyte telomere length was measured in 431 first-ever IS patients and 304 healthy controls (quantitative polymerase chain reaction). To explore linear and non-linear effect of telomere length on the IS risk, we preformed the linear MR analysis (the inverse-variance weighted method, the maximum likelihood method, and the mode-based estimation method), and the non-linear MR analysis (semiparametric method with three tests for non-linearity, including the quadratic test, Cochran's Q test, and the fractional polynomial test).<br><br>RESULTS: Two verified SNPs (rs11125529 and rs412658) were chosen as instrumental variables. In linear MR analysis, the adjusted odds ratios and 95% confidence intervals of IS for genetically predicted telomere lengths, based on the two SNPs, were 1.312 (0.979 to 1.759), 1.326 (0.932 to 1.888) and 1.226 (0.844 to 1.781) for the inverse-variance weighted method, the maximum likelihood method, and the mode-based estimation method, respectively. Three tests for nonlinearity failed to reject the null exactly, indicating that the relationship between telomere length and IS risk is unlikely to be non-linear.<br><br>CONCLUSION: This MR study based on individual data does not provide strong evidence for a positive linear or non-linear effect of telomere length on the IS risk.},
}
@article {pmid33045076,
year = {2021},
author = {Chang, X and Chua, KY and Wang, L and Liu, J and Yuan, JM and Khor, CC and Heng, CK and Koh, WP and Dorajoo, R},
title = {Midlife Leukocyte Telomere Length as an Indicator for Handgrip Strength in Late Life.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {76},
number = {1},
pages = {172-175},
pmid = {33045076},
issn = {1758-535X},
support = {UM1 CA182876/CA/NCI NIH HHS/United States ; R01 CA144034/CA/NCI NIH HHS/United States ; },
mesh = {Age Factors ; Female ; *Hand Strength ; Humans ; *Leukocytes/ultrastructure ; Male ; Middle Aged ; Prospective Studies ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Telomere attrition has been proposed as a hallmark of aging. We previously reported on the association between blood leukocyte telomere length (LTL) at midlife and risk of chronic diseases and mortality.<br><br>METHODS: In this study, we investigated the effect of midlife LTL and genetic proxies on 5 markers of aging outcomes, namely handgrip strength, timed up-and-go (TUG), Singapore-modified Mini-Mental State Examination (SM-MMSE) scores, anxiety, and depression indices, measured after a median 20-year follow-up in the Singapore Chinese Health Study (N = 9581).<br><br>RESULTS: We observed a significant association between midlife LTL and handgrip strength later in life (p = .004, padjust = .020), as well as a nominal significant association between midlife LTL and TUG later in life (p = .036, padjust = .180). The weighted Genetic Risk Score (wGRS) comprising 15 previously reported LTL reducing loci in East Asians was not significantly associated with handgrip strength. However, results from Structural Equation Modeling showed that the effect of this wGRS on handgrip strength was mediated through LTL (proportion of wGRS effect on handgrip strength mediated through LTL = 33.3%, p = .010).<br><br>CONCLUSIONS: Longer midlife LTL was associated with increased handgrip strength later in life.},
}
@article {pmid33038659,
year = {2020},
author = {Osum, M and Serakinci, N},
title = {Impact of circadian disruption on health; SIRT1 and Telomeres.},
journal = {DNA repair},
volume = {96},
number = {},
pages = {102993},
doi = {10.1016/j.dnarep.2020.102993},
pmid = {33038659},
issn = {1568-7856},
mesh = {Aging ; Animals ; Cellular Senescence ; *Circadian Rhythm ; Humans ; Sirtuin 1/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Circadian clock is a biochemical oscillator in organisms that regulates the circadian rhythm of numerous genes over 24 h. The circadian clock is involved in telomere homeostasis by regulating the diurnal rhythms of telomerase activity, TERT mRNA level, TERRA expression, and telomeric heterochromatin formation. Particularly, CLOCK and BMAL1 deficiency contribute to telomere shortening by preventing rhythmic telomerase activity and TERRA expression, respectively. Telomere shortening increases the number of senescent cells with impaired circadian rhythms. In return, telomerase reconstitution improves impaired circadian rhythms of senescent cells. SIRT1 that is an NAD+-dependent deacetylase positively regulates circadian clock and telomere homeostasis. SIRT1 contributes to the circadian clock by mediating CLOCK/BMAL1 complex formation, BMAL1 transcription and PER2 disruption. On the other hand, SIRT1 ensures telomere homeostasis by inducing telomerase and shelterin protein expression and regulating telomere heterochromatin formation. SIRT1 inhibition leads to both circadian clock and telomeres dysfunction that inhibit its activity. In light of this current evidence, we could suggest that the BMAL1/CLOCK complex regulates the telomere homeostasis in SIRT1 dependent manner, and also telomere dysfunction inhibits circadian clock function by suppressing SIRT1 activity to induce age-related diseases. We consider that increasing SIRT1 activity can prevent age-related diseases and help healthy aging by protecting telomere integrity and circadian clock function for individuals subjected to circadian rhythm disruption such as shift works, individuals with sleep disorders, and in the elderly population.},
}
@article {pmid33035329,
year = {2020},
author = {Feurstein, S and Adegunsoye, A and Mojsilovic, D and Vij, R and West DePersia, AH and Rajagopal, PS and Osman, A and Collins, RH and Kim, RH and Gore, SD and Greenberg, P and Godley, LA and Li, Z and Del Gaudio, D and Subramanian, HP and Das, S and Walsh, T and Gulsuner, S and Segal, JP and Husain, AN and Gurbuxani, S and King, MC and Strek, ME and Churpek, JE},
title = {Telomere biology disorder prevalence and phenotypes in adults with familial hematologic and/or pulmonary presentations.},
journal = {Blood advances},
volume = {4},
number = {19},
pages = {4873-4886},
pmid = {33035329},
issn = {2473-9537},
support = {R01 MH083989/MH/NIMH NIH HHS/United States ; R03 HL145253/HL/NHLBI NIH HHS/United States ; R35 CA197458/CA/NCI NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; },
mesh = {Biology ; *Hematology ; In Situ Hybridization, Fluorescence ; Mutation ; Phenotype ; Prevalence ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {Telomere biology disorders (TBDs) present heterogeneously, ranging from infantile bone marrow failure associated with very short telomeres to adult-onset interstitial lung disease (ILD) with normal telomere length. Yield of genetic testing and phenotypic spectra for TBDs caused by the expanding list of telomere genes in adults remain understudied. Thus, we screened adults aged ≥18 years with a personal and/or family history clustering hematologic disorders and/or ILD enrolled on The University of Chicago Inherited Hematologic Disorders Registry for causative variants in 13 TBD genes. Sixteen (10%) of 153 probands carried causative variants distributed among TERT (n = 6), TERC (n = 4), PARN (n = 5), or RTEL1 (n = 1), of which 19% were copy number variants. The highest yield (9 of 22 [41%]) was in families with mixed hematologic and ILD presentations, suggesting that ILD in hematology populations and hematologic abnormalities in ILD populations warrant TBD genetic testing. Four (3%) of 117 familial hematologic disorder families without ILD carried TBD variants, making TBD second to only DDX41 in frequency for genetic diagnoses in this population. Phenotypes of 17 carriers with heterozygous PARN variants included 4 (24%) with hematologic abnormalities, 67% with lymphocyte telomere lengths measured by flow cytometry and fluorescence in situ hybridization at or above the 10th percentile, and a high penetrance for ILD. Alternative etiologies for cytopenias and/or ILD such as autoimmune features were noted in multiple TBD families, emphasizing the need to maintain clinical suspicion for a TBD despite the presence of alternative explanations.},
}
@article {pmid33033864,
year = {2021},
author = {Zhan, Y and Hägg, S},
title = {Association between genetically predicted telomere length and facial skin aging in the UK Biobank: a Mendelian randomization study.},
journal = {GeroScience},
volume = {43},
number = {3},
pages = {1519-1525},
pmid = {33033864},
issn = {2509-2723},
mesh = {Biological Specimen Banks ; Genome-Wide Association Study ; Humans ; Mendelian Randomization Analysis ; *Skin Aging/genetics ; *Telomere/genetics ; United Kingdom ; },
abstract = {Are shorter telomeres causal risk factors for facial aging on a large population level? To examine if longer, genetically predicted telomeres were causally associated with less facial aging using Mendelian randomization analysis. Two-sample Mendelian randomization methods were applied to the summary statistics of a genome-wide association study (GWAS) for self-reported facial aging from 417, 772 participants of the UK Biobank data. Twenty single-nucleotide polymorphisms (SNPs) that were of genome-wide significance were selected as instrumental variables for leukocyte telomere length. The main analyses were performed primarily using the random-effects inverse-variance weighted method and were complemented with the MR-Egger regression, weighted median, and weighted mode approaches. The intercept of MR-Egger regression was used to assess horizontal pleiotropy. Longer genetically predicted telomeres were associated with a lower likelihood of facial aging (β = - 0.02, 95% confidence interval: - 0.04, - 0.002). Comparable results were obtained using MR-Egger regression, weighted median, and weighted mode approaches. The intercept of MR-Egger regression was close to zero (0.002) that was not suggestive of horizontal pleiotropy. Our findings provided evidence to support a potential causal relationship between longer genetically predicted telomeres and less facial aging.},
}
@article {pmid33031470,
year = {2020},
author = {Protsenko, E and Rehkopf, D and Prather, AA and Epel, E and Lin, J},
title = {Are long telomeres better than short? Relative contributions of genetically predicted telomere length to neoplastic and non-neoplastic disease risk and population health burden.},
journal = {PloS one},
volume = {15},
number = {10},
pages = {e0240185},
pmid = {33031470},
issn = {1932-6203},
mesh = {Cardiovascular Diseases/epidemiology/*genetics ; Genetic Predisposition to Disease ; Humans ; Mendelian Randomization Analysis/methods ; Neoplasms/epidemiology/*genetics ; Neurodegenerative Diseases/epidemiology/*genetics ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Mendelian Randomization (MR) studies exploiting single nucleotide polymorphisms (SNPs) predictive of leukocyte telomere length (LTL) have suggested that shorter genetically determined telomere length (gTL) is associated with increased risks of degenerative diseases, including cardiovascular and Alzheimer's diseases, while longer gTL is associated with increased cancer risks. These varying directions of disease risk have long begged the question: when it comes to telomeres, is it better to be long or short? We propose to operationalize and answer this question by considering the relative impact of long gTL vs. short gTL on disease incidence and burden in a population.<br><br>METHODS AND FINDINGS: We used odds ratios (OR) of disease associated with gTL from a recently published MR meta-analysis to approximate the relative contributions of gTL to the incidence and burden of neoplastic and non-neoplastic disease in a European population. We obtained incidence data of the 9 cancers associated with long gTL and 4 non-neoplastic diseases associated with short gTL from the Institute of Health Metrics (IHME). Incidence rates of individual cancers from SEER, a database of United States cancer records, were used to weight the ORs in order to align with the available IHME data. These data were used to estimate the excess incidences due to long vs. short gTL, expressed as per 100,000 persons per standard deviation (SD) change in gTL. To estimate the population disease burden, we used the Disability Adjusted Life Years (DALY) metric from the IHME, a measure of overall disease burden that accounts for both mortality and morbidity, and similarly calculated the excess DALY associated with long vs. short gTL.<br><br>RESULTS: Our analysis shows that, despite the markedly larger ORs of neoplastic disease, the large incidence of degenerative diseases causes the excess incidence attributable to gTL to balance that of neoplastic diseases. Long gTL is associated with an excess incidence of 94.04 cases/100,000 persons/SD (45.49-168.84, 95%CI) from the 9 cancer, while short gTL is associated with an excess incidence of 121.49 cases/100,000 persons/SD (48.40-228.58, 95%CI) from the 4 non-neoplastic diseases. When considering disease burden using the DALY metric, long gTL is associated with an excess 1255.25 DALYs/100,000 persons/SD (662.71-2163.83, 95%CI) due to the 9 cancers, while short gTL is associated with an excess 1007.75 DALYs/100,000 persons/SD (411.63-1847.34, 95%CI) due to 4 non-neoplastic diseases.<br><br>CONCLUSIONS: Our results show that genetically determined long and short telomere length are associated with disease risk and burden of approximately equal magnitude. These results provide quantitative estimates of the relative impact of genetically-predicted short vs. long TL in a human population, and provide evidence in support of the cancer-aging paradox, wherein human telomere length is balanced by opposing evolutionary forces acting to minimize both neoplastic and non-neoplastic diseases. Importantly, our results indicate that odds ratios alone can be misleading in different clinical scenarios, and disease risk should be assessed from both an individual and population level in order to draw appropriate conclusions about the risk factor's role in human health.},
}
@article {pmid33026063,
year = {2020},
author = {Martín, M and Millan, A and Ferraro, F and Tetzlaff, WF and Lozano, CE and Botta, E and Castro, M and Boero, L and Rey, J and Daruich, J and Frechtel, G and Meroño, T and Cerrone, G and Brites, F},
title = {Leukocyte telomere length is associated with iron overload in male adults with hereditary hemochromatosis.},
journal = {Bioscience reports},
volume = {40},
number = {10},
pages = {},
pmid = {33026063},
issn = {1573-4935},
mesh = {Adult ; Aged ; Aging/immunology ; Cross-Sectional Studies ; Ferritins/blood ; Hemochromatosis/blood/diagnosis/genetics/*immunology ; Hemochromatosis Protein/genetics ; Humans ; Iron/blood/*metabolism ; Leukocytes/*immunology/metabolism ; Male ; Middle Aged ; Mutation ; Oxidative Stress/immunology ; Telomere/*metabolism ; Telomere Homeostasis/*immunology ; },
abstract = {BACKGROUND: Hereditary hemochromatosis (HH) is a primary iron overload (IO) condition. Absolute telomere length (ATL) is a marker of cellular aging and DNA damage associated with chronic diseases and mortality.<br><br>AIM: To evaluate the relationship between ATL and IO in patients with HH.<br><br>METHODS: Cross-sectional study including 25 patients with HH: 8 with IO and 17 without IO (ferritin < 300 ng/ml) and 25 healthy controls. Inclusion criteria were: age > 18 years, male sex and HH diagnosis. Patients with diabetes or other endocrine and autoimmune diseases were excluded. ATL was measured by real-time PCR.<br><br>RESULTS: HH patients with IO were older (P<0.001) and showed higher ferritin concentration (P<0.001). Patients with HH, disregarding the iron status, showed higher glucose and body mass index (BMI) than controls (both P<0.01). ATL was shorter in patients with IO than controls [with IO: 8 (6-14), without IO: 13 (9-20), and controls: 19 (15-25) kilobase pairs, P<0.01]; with a linear trend within groups (P for trend <0.01). Differences in ATL remained statistically significant after adjusting by age, BMI and glucose (P<0.05).<br><br>DISCUSSION: Patients with IO featured shorter ATL while patients without IO showed only mild alterations vs. controls. Screening for IO is encouraged to prevent iron-associated cellular damage and early telomere attrition.},
}
@article {pmid33024983,
year = {2020},
author = {Benetos, A and Lai, TP and Toupance, S and Labat, C and Verhulst, S and Perret-Guillaume, C and Gautier, S and Ungeheuer, MN and Levy, D and Susser, E and Aviv, A},
title = {A Mechanism for Severity of Disease in Older Patients with COVID-19: The Nexus between Telomere Length and Lymphopenia.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2020.10.01.20205393},
pmid = {33024983},
abstract = {BACKGROUND: Lymphopenia due to a plummeting T-cell count is a major feature of severe COVID-19. T-cell proliferation is telomere length (TL)-dependent and TL shortens with age. Older persons are disproportionally affected by severe COVID-19, and we hypothesized that those with short TL have less capacity to mount an adequate T-cell proliferative response to SARS-CoV-2. This hypothesis predicts that among older patients with COVID-19, shorter telomeres of peripheral blood mononuclear cells (PBMCs) will be associated with a lower lymphocyte count.<br><br>METHODS: Our sample comprised 17 COVID-19 and 21 non-COVID-19 patients, aged 87(8) (mean(SD)) and 87 (9) years, respectively. We measured TL by the Telomere Shortest Length Assay, a novel method that measures and tallies the short telomeres directly relevant to telomere-mediated biological processes. The primary analysis quantified TL as the proportion of telomeres shorter than 2 kilobases. For comparison, we also quantified TL by Southern blotting, which measures the mean length of telomeres.<br><br>RESULTS: Lymphocyte count (109/L) was 0.91 (0.42) in COVID-19 patients and 1.50(0.50) in non-COVID-19 patients (P < 0.001). In COVID-19 patients, but not in non-COVID-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kilobases (P = 0.005) and positively correlated with the mean of telomeres measured by TeSLA (P = 0.03). Lymphocyte counts showed no statistically significant correlations with Southern blotting results in COVID-19 or non-COVID-19 patients.<br><br>CONCLUSIONS: These results support the hypothesis that a compromised TL-dependent T-cell proliferative response contributes to lymphopenia and the resulting disproportionate severity of COVID-19 among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons.},
}
@article {pmid33024526,
year = {2020},
author = {Menshawy, NE and Ashwah, SE and Ebrahim, MA},
title = {Short Dysfunctional Telomere Is Highly Predictive of Dismal Outcome in MDS but Not in AML Patients.},
journal = {International journal of hematology-oncology and stem cell research},
volume = {14},
number = {3},
pages = {188-199},
pmid = {33024526},
issn = {2008-3009},
abstract = {Background: A trigger for initiation the clonal hematopoietic stem cells disorders could be short telomere length probably due to chromosomal instability. The relationship between relative telomere length (RTL) and the two linked hematological stem cell disorders, myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) is still unclear. Materials and Methods: We evaluated the role of RTL in MDS (n=96) and AML (n=130) at the time of diagnosis using a real time quantitative polymerase chain reaction (RT-PCR) technique. The median value of RTL (1) was set as the cutoff for statistical comparison. Overall survival (OS) is defined as the time from diagnosis to death or last follow-up. Results: RTL was significantly longer in both MDS and AML cases versus control (p<0.0001) and was significantly longer in MDS versus AML cases (p =0.03). RTL correlated negatively with age in MDS (p <0.0001) but not in AML cases. RTL was also significantly shorter in MDS cases with pancytopenia and poor risk cytogenetics (p < 0.0001 for each) and short RTL was significantly associated with inferior survival (p = 0.007), while RTL showed no significant impact on OS in AML cases. Moreover, short RTL retained independent prognostic value in multivariate analysis (HR= 3.42 [95% CI, 8.97-19.35], p = 0.004). Conclusion: RTL showed an association with both AML and MDS; however, short RTL was an independent poor prognostic factor in MDS patients only.},
}
@article {pmid33022284,
year = {2020},
author = {VanEtten, SL and Bonner, MR and Ren, X and Birnbaum, LS and Kostyniak, PJ and Wang, J and Olson, JR},
title = {Telomeres as targets for the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) in rats.},
journal = {Toxicology and applied pharmacology},
volume = {408},
number = {},
pages = {115264},
doi = {10.1016/j.taap.2020.115264},
pmid = {33022284},
issn = {1096-0333},
mesh = {Animals ; Carcinogens/*toxicity ; Female ; Gene Expression Regulation/drug effects ; Liver/drug effects/metabolism ; Lung/drug effects/metabolism ; Polychlorinated Biphenyls/*toxicity ; Polychlorinated Dibenzodioxins/*toxicity ; Rats, Sprague-Dawley ; Telomere/*drug effects ; },
abstract = {Telomere length (TL) can be affected by various factors, including age and oxidative stress. Changes in TL have been associated with chronic disease, including a higher risk for several types of cancer. Environmental exposure of humans to PCBs and dioxins has been associated with longer or shorter leukocyte TL. Relative telomere length (RTL) may serve as a biomarker associated with neoplastic and/or non-neoplastic responses observed with chronic exposures to TCDD and PCBs. RTL was measured in DNA isolated from archived frozen liver and lung tissues from the National Toxicology Program (NTP) studies conducted in female Harlan Sprague Dawley rats exposed for 13, 30, and 52 weeks to TCDD, dioxin-like (DL) PCB 126, non-DL PCB 153, and a mixture of PCB 126 and PCB 153. RTL was assessed by quantitative polymerase chain reaction (qPCR). Consistent with literature, decreased liver and lung RTL was seen with aging. Relative to time-matched vehicle controls, RTL was increased in both the liver and lung tissues of rats exposed to TCDD, PCB 126, PCB 153, and the mixture of PCB 126 and PCB 153, which is consistent with most epidemiological studies that found PCB exposures were associated with increased leukocyte RTL. Increased RTL was observed at doses and/or time points where little to no pathology was observed. In addition to serving as a biomarker of exposure to these compounds in rats and humans, increases in RTL may be an early indicator of neoplastic and non-neoplastic responses that occur following chronic exposure to TCDD and PCBs.},
}
@article {pmid33015044,
year = {2020},
author = {Wang, G and Wu, X and Zhou, L and Gao, S and Yun, D and Liang, A and Sun, F},
title = {Tethering of Telomeres to the Nuclear Envelope Is Mediated by SUN1-MAJIN and Possibly Promoted by SPDYA-CDK2 During Meiosis.},
journal = {Frontiers in cell and developmental biology},
volume = {8},
number = {},
pages = {845},
pmid = {33015044},
issn = {2296-634X},
abstract = {During meiosis, telomeres attach to the nuclear envelope (NE) to promote homologous chromosome moving, pairing, synapsis, and recombination. The telomere-NE attachment is mediated by SUN1, TERB1-TERB2-MAJIN (TTM complex), and TRF1. The interaction of the TTM complex with shelterin is mediated by TERB1 and TRF1, but how SUN1 interacts with the TTM complex is not yet fully understood. In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. The binding sites of MAJIN and SPDYA at SUN1 were mapped, and both MAJIN and SPDYA bound to the N-terminal domain of SUN1 and the two binding sites were close to each other. Furthermore, SPDYA bound to SUN1 via the Ringo domain and recruited CDK2 to SUN1. Then, we found that the interaction of SUN1 with MAJIN was decreased by the CDK2 inhibitors. Taken together, our results provide the possible mechanism of SUN1, MAJIN, and SPDYA-CDK2 in promoting the telomere-NE attachment during meiosis.},
}
@article {pmid33015032,
year = {2020},
author = {Burgess, A and Caldon, CE},
title = {Editorial: Proceedings From ACCM19: Cell Cycle, DNA Damage Response and Telomeres.},
journal = {Frontiers in cell and developmental biology},
volume = {8},
number = {},
pages = {805},
pmid = {33015032},
issn = {2296-634X},
}
@article {pmid33013423,
year = {2020},
author = {Maremanda, KP and Sundar, IK and Li, D and Rahman, I},
title = {Age-Dependent Assessment of Genes Involved in Cellular Senescence, Telomere, and Mitochondrial Pathways in Human Lung Tissue of Smokers, COPD, and IPF: Associations With SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 Axis.},
journal = {Frontiers in pharmacology},
volume = {11},
number = {},
pages = {584637},
pmid = {33013423},
issn = {1663-9812},
abstract = {BACKGROUND: Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Here, we determined how aging contributes to the altered gene expression related to mitochondrial function, cellular senescence, and telomeric length processes that play an important role in the progression of COPD and idiopathic pulmonary fibrosis (IPF).<br><br>METHODS: Total RNA from the human lung tissues of non-smokers, smokers, and patients with COPD and IPF were processed and analyzed using a Nanostring platform based on their ages (younger: <55 years and older: >55 years).<br><br>RESULTS: Several genes were differentially expressed in younger and older smokers, and patients with COPD and IPF compared to non-smokers which were part of the mitochondrial biogenesis/function (HSPD1, FEN1, COX18, COX10, UCP2 &amp; 3), cellular senescence (PCNA, PTEN, KLOTHO, CDKN1C, TNKS2, NFATC1 &amp; 2, GADD45A), and telomere replication/maintenance (PARP1, SIRT6, NBN, TERT, RAD17, SLX4, HAT1) target genes. Interestingly, NOX4 and TNKS2 were increased in the young IPF as compared to the young COPD patients. Genes in the mitochondrial dynamics and quality control mechanisms like FIS1 and RHOT2 were decreased in young IPF compared to their age matched COPD subjects. ERCC1 and GADD45B were higher in young COPD as compared to IPF. Aging plays an important role in various infectious diseases including the SARS-CoV-2 infection. Lung immunoblot analysis of smokers, COPD and IPF subjects revealed increased abundance of proteases and receptor/spike protein like TMPRSS2, furin, and DPP4 in association with a slight increase in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor ACE2 levels.<br><br>CONCLUSIONS: Overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition in the pathobiology of lung aging in COPD and IPF is associated with alterations in SARS-CoV-2 ACE2-TMPRSS2-Furin-DPP4 axis as pharmacological targets for COVID-19.},
}
@article {pmid33012014,
year = {2022},
author = {Thomas, N and Hudaib, AR and Romano-Silva, M and Bozaoglu, K and H X Thomas, E and Rossell, S and Kulkarni, J and Gurvich, C},
title = {Influence of cortisol awakening response on telomere length: Trends for males and females.},
journal = {The European journal of neuroscience},
volume = {55},
number = {9-10},
pages = {2794-2803},
doi = {10.1111/ejn.14996},
pmid = {33012014},
issn = {1460-9568},
mesh = {Female ; Humans ; *Hydrocortisone ; Longevity ; Male ; Saliva ; Sex Characteristics ; *Telomere ; },
abstract = {Although telomere attrition is associated with the process of normal ageing, shorter telomere length (TL) has been associated with acute and chronic stressors. A neurobiological factor hypothesised to be responsible for this accelerated attrition is the dysregulation of the cortisol stress response, which can induce DNA damage affecting DNA telomeric caps. Marked sex differences are reported in both the cortisol stress response and telomere dynamics, yet no explicit investigation of sex specificity on the relationship between cortisol and TL exists. This study used mathematical equation modelling to describe the relationship between diurnal cortisol levels and telomere length within the context of sex, in a healthy population. Cortisol awakening responses (CAR) were measured via ELISA methodology in fifty-one healthy participants (28 males, 23 females). qPCRs determined TL from genomic DNA extracted from saliva. To assess the effect of free cortisol on relative TL ratio, a semi-log regression plot of the two variables trended for sex were fitted using spline curves. Results demonstrated significant differences between males and females in the relationship defining CAR and TL association (p = 0.03). These results suggest the relationship is not linear and can be represented as a complex arcsin function, and that the patterns are opposite in males and females. Males demonstrate a positive correlation, with higher levels of CAR being associated with longer telomere sequences. Females demonstrated a negative correlation. Future studies must carefully take into consideration moderating factors such as sex, and sex hormones across the lifespan when investigating telomere length.},
}
@article {pmid33007378,
year = {2021},
author = {Sethi, I and Bhat, GR and Kumar, R and Rai, E and Sharma, S},
title = {Dual labeled fluorescence probe based qPCR assay to measure the telomere length.},
journal = {Gene},
volume = {767},
number = {},
pages = {145178},
doi = {10.1016/j.gene.2020.145178},
pmid = {33007378},
issn = {1879-0038},
mesh = {Benzothiazoles ; DNA/genetics ; Diamines ; Fluorescence ; Fluorescent Dyes/chemistry/metabolism ; Humans ; In Situ Hybridization, Fluorescence/methods ; Organic Chemicals/chemistry ; Polymerase Chain Reaction/*methods ; Quinolines ; Repetitive Sequences, Nucleic Acid/genetics ; Telomere/*genetics/*metabolism ; Telomere Homeostasis/genetics ; },
abstract = {Telomeres are highly repetitive regions capping the chromosomes and composed of multiple units of hexa-nucleotides, TTAGGG, making their quantification difficult. Most of the methods developed to estimate telomeres are extensively cumbersome or expensive. The quantitative polymerase chain reaction (qPCR) based assay is relatively easy and cheaper method that applies SyBr Green dye chemistry to measure telomere length. SyBr Green dye fluoresces after intercalation into the double stranded DNA (dsDNA), thus detection of unspecific products has been a limitation as it may affect quantitation of telomeres. To overcome this limitation of SyBr Green dye, we developed a dual labeled fluorescence probe based quantitative polymerase chain reaction (qPCR) to measure the telomere length. This highly efficient, yet cost effective and easy method, utilizes a probe that targets primarily the telomeric DNA and this increases accuracy of an existing qPCR method.},
}
@article {pmid33006015,
year = {2020},
author = {Yildirim, H and Yildiz, P and Coskunpinar, E},
title = {Investigation of telomere related gene mutations in idiopathic pulmonary fibrosis.},
journal = {Molecular biology reports},
volume = {47},
number = {10},
pages = {7851-7860},
doi = {10.1007/s11033-020-05861-1},
pmid = {33006015},
issn = {1573-4978},
support = {2018/039//University of Health Sciences, Scientific Research Project Unit/ ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/*genetics/metabolism/pathology ; Male ; Middle Aged ; *Mutation ; RNA/*genetics/metabolism ; Telomerase/*genetics/metabolism ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Idiopathic Pulmonary Fibrosis (IPF) is the most common type of Idiopathic Interstitial Pneumonias (IIP). The aim of this study is to determine the mutation of variants in four telomere-related genes and to determine the possible relationship between these mutations and telomere shortening in order to contribute to the understanding of the pathophysiology of IPF. For this study, 34 individuals with IPF, 32 individuals with non-IPF ILD (Interstitial Lung Disease), and 31 healthy controls between the ages of 40 and 85 were included. The mutation analysis and telomere measurements were examined for the volunteers. According to the mutation screening results, no significant difference was found between the patients with IPF, non-IPF ILD groups and healthy individuals in terms of genotyping analysis. However, in terms of the allele distribution for two genes, statistically significant difference was found in IPF and non-IPF ILD patients (TERT; p = 0.002 and TERC; p = 0.001). According to the telomere length measurement, the telomeres of the patients were shorter than of the control group (p = 0.0001). In compliance with the results of our analysis, it is thought that genes that have allelic significance from the point of gene mutations as well as telomere shortening may be risk factors for the disease.},
}
@article {pmid33005120,
year = {2020},
author = {Polonio, AM and Chico-Sordo, L and Córdova-Oriz, I and Medrano, M and García-Velasco, JA and Varela, E},
title = {Impact of Ovarian Aging in Reproduction: From Telomeres and Mice Models to Ovarian Rejuvenation.},
journal = {The Yale journal of biology and medicine},
volume = {93},
number = {4},
pages = {561-569},
pmid = {33005120},
issn = {1551-4056},
mesh = {Aging/genetics ; Animals ; Female ; Humans ; Mice ; *Ovary ; Pregnancy ; Rejuvenation ; Reproduction ; *Telomere/genetics ; },
abstract = {The trend in our society to delay procreation increases the difficulty to conceive spontaneously. Thus, there is a growing need to use assisted reproduction technologies (ART) to form a family. With advanced maternal age, ovaries not only produce a lower number of oocytes after ovarian stimulation but also a lower quality-mainly aneuploidies-requiring further complex analysis to avoid complications during implantation and pregnancy. Although there are different options to have a child at advanced maternal age (like donor eggs), this is not the preferred choice for most patients. Unless women had cryopreserved their eggs at a younger age, reproductive medicine should try to optimize their opportunities to become pregnant with their own oocytes, when chances of success are reasonable. Aging has many causes, but telomere attrition is ultimately one of the main pathways involved in this process. Several reports link telomere biology and reproduction, but the molecular reasons for the rapid loss of ovarian function at middle age are still elusive. This review will focus on the knowledge acquired during the last years about ovarian aging and disease, both in mouse models of reproductive senescence and in humans with ovarian failure, and the implication of telomeres in this process. In addition, the review will discuss recent results on ovarian rejuvenation, achieved with stem cell therapies that are currently under study, or ovarian reactivation by tissue fragmentation and the attempts to generate oocytes in vitro.},
}
@article {pmid33002310,
year = {2020},
author = {Huang, JW and Xie, C and Niu, Z and He, LJ and Li, JJ},
title = {The relation between Helicobacter pylori immunoglobulin G seropositivity and leukocyte telomere length in US adults from NHANES 1999-2000.},
journal = {Helicobacter},
volume = {25},
number = {6},
pages = {e12760},
doi = {10.1111/hel.12760},
pmid = {33002310},
issn = {1523-5378},
mesh = {Adult ; Aged ; Helicobacter Infections/*immunology ; *Helicobacter pylori ; Humans ; Immunoglobulin G/*blood ; *Leukocytes ; Middle Aged ; Nutrition Surveys ; *Telomere ; United States ; },
abstract = {BACKGROUND: Helicobacter pylori (H pylori) immunoglobulin G (IgG) seropositivity is prevalent but its relation with leukocyte telomere length (LTL), a cellular aging biomarker, is unclear.<br><br>METHODS: Among 3,472 participants from the National Health and Nutrition Examination Survey (NHANES) cycle 1999-2000, LTL was measured with the quantitative polymerase chain reaction. H&#xa0;pylori IgG was measured by enzyme-linked immunosorbent assays and defined as seropositivity with an immune status ratio score&#xa0;>&#xa0;0.9. We used linear regression models to examine the relation of H&#xa0;pylori IgG seropositivity with continuous LTL and logistic regression for the relation with short LTL (<10th percentile of the population distribution) adjusting for potential confounders. We stratified the analyses by a priori selected variables.<br><br>RESULTS: Population prevalence of H&#xa0;pylori IgG seropositivity was 31.5% in the overall population with higher prevalence found in those with older age, other races than non-Hispanic whites, lower education, and being born out of the United States. Continuous LTL was non-significantly shorter in those with H&#xa0;Pylori IgG seropositivity versus seronegativity (mean difference&#xa0;=&#xa0;-40.3&#xa0;bp, 95% CI: -112.4, 31.9). This difference was not significant after adjusting for potential confounders nor stratifying by potential effect modifiers. H&#xa0;Pylori IgG seropositivity was significantly associated with short LTL among the elderly (55-75&#xa0;years, adjusted OR: 3.06, 95% CI: 1.17, 7.99), but not in the overall population (OR: 1.28, 95% CI: 0.81-2.02).<br><br>CONCLUSION: H Pylori IgG seropositivity was not associated with continuous LTL in the general population but may be associated with an excessively short LTL in the elderly.},
}
@article {pmid33001148,
year = {2021},
author = {Vyas, CM and Ogata, S and Reynolds, CF and Mischoulon, D and Chang, G and Cook, NR and Manson, JE and Crous-Bou, M and De Vivo, I and Okereke, OI},
title = {Telomere length and its relationships with lifestyle and behavioural factors: variations by sex and race/ethnicity.},
journal = {Age and ageing},
volume = {50},
number = {3},
pages = {838-846},
pmid = {33001148},
issn = {1468-2834},
support = {R01 DK088762/DK/NIDDK NIH HHS/United States ; P30 MH090333/MH/NIMH NIH HHS/United States ; R01 CA138962/CA/NCI NIH HHS/United States ; R01 HL102122/HL/NHLBI NIH HHS/United States ; R01 AG036755/AG/NIA NIH HHS/United States ; R01 MH091448/MH/NIMH NIH HHS/United States ; R01 AR060574/AR/NIAMS NIH HHS/United States ; },
mesh = {Aged ; Aging/genetics ; *Ethnicity ; Female ; Hispanic or Latino ; Humans ; Life Style ; Male ; *Telomere ; },
abstract = {BACKGROUND: Adherence to healthy lifestyles/behaviours promotes healthy ageing. However, little is known about whether age, sex and/or race/ethnicity moderate associations of lifestyle/behavioural factors with relative telomere length (RTL), a potential biomarker of ageing.<br><br>METHODS: We included 749 midlife to older non-Hispanic White (n&#x2009;=&#x2009;254), Black (n&#x2009;=&#x2009;248) and Hispanic (n&#x2009;=&#x2009;247) US participants [mean (standard deviation) age&#x2009;=&#x2009;69.3 (7.2) years; women: 50.5%]. We extracted genomic DNA from peripheral leucocytes. RTL was assayed using real-time quantitative polymerase chain reaction. Multivariable regression was used to examine associations between lifestyle/behavioural exposures (i.e. physical activity, alcohol consumption, smoking and depression) with RTL.<br><br>RESULTS: Increasing chronological age was associated with shorter RTL (P&#x2009;<&#x2009;0.01). Higher physical activity was associated with longer RTL (P-trend&#x2009;=&#x2009;0.03); daily versus never/rare alcohol consumption and 30+ versus <5 smoking pack-year were associated with shorter RTLs (P-trend&#x2009;=&#x2009;0.02). Associations varied significantly by sex and race/ethnicity. The association between physical activity and longer RTL appeared strongest among non-Hispanic Whites (P-interaction&#x2009;=&#x2009;0.01). Compared to men, women had stronger associations between heavy smoking and shorter RTLs (P-interaction&#x2009;=&#x2009;0.03). Light/moderate alcohol consumption (monthly/weekly) was associated with longer RTL among non-Hispanic Whites, while daily consumption was related to shorter RTLs among Blacks and Hispanics (P-interactions < 0.01). Associations of daily alcohol and heavy smoking with shorter RTLs were particularly apparent among Black women.<br><br>CONCLUSION: We observed novel variations by sex and race/ethnicity in associations between lifestyle/behavioural factors and RTL. Further work is needed to replicate these findings and to address potential public health implications for modifying strategies by sex or across racial/ethnic groups to optimise lifestyles/behaviours for healthy ageing.},
}
@article {pmid33000239,
year = {2020},
author = {Vodenkova, S and Kroupa, M and Polivkova, Z and Musak, L and Ambrus, M and Schneiderova, M and Kozevnikovova, R and Vodickova, L and Rachakonda, S and Hemminki, K and Kumar, R and Vodicka, P},
title = {Chromosomal damage and telomere length in peripheral blood lymphocytes of cancer patients.},
journal = {Oncology reports},
volume = {44},
number = {5},
pages = {2219-2230},
doi = {10.3892/or.2020.7774},
pmid = {33000239},
issn = {1791-2431},
mesh = {Aged ; Case-Control Studies ; *Chromosome Aberrations ; Disease-Free Survival ; Female ; Follow-Up Studies ; Genomic Instability ; Humans ; Lymphocytes/*metabolism ; Male ; Middle Aged ; Neoplasm Recurrence, Local/*epidemiology/genetics ; Neoplasms/blood/*genetics/mortality ; Prognosis ; Telomerase ; Telomere/*metabolism ; Telomere Shortening ; },
abstract = {Accumulation of non‑specific structural chromosomal aberrations (CAs) and telomere shortening contribute to genome instability, which constitutes as one of the hallmarks of cancer. CAs arise due to direct DNA damage or telomere shortening. CAs in peripheral blood lymphocytes (PBL), which are considered to be markers of exposure, have been previously reported to serve a role in the pathophysiology and progression of cancer through mechanisms that are poorly understood. In addition, the prognostic relevance of telomere length (TL) in patients with cancer remains to be elucidated. In the present study, CAs and TL in PBL isolated from patients with newly diagnosed cancer (151 breast, 96 colorectal, 90 lung) and 335 cancer‑free control individuals were investigated. These results were then correlated with clinicopathological factors and follow‑up data. The accumulation of CAs in PBL was observed with increased susceptibility to breast and lung cancer (P<0.0001), while individuals with longer TL were found to be at a higher risk of breast cancer (P<0.0001). Increased chromatid‑type aberrations were also revealed to be associated with lower overall survival of patients with breast and colorectal cancers using a multivariate model. Compared with control individuals, no association was observed between TL and CAs or age in patients with cancer. In conclusion, the present study demonstrates the association between CAs/TL in PBL and the susceptibility, prognosis and survival of patients with breast, colorectal and lung cancer.},
}
@article {pmid32998948,
year = {2021},
author = {Chen, M and Xu, Y and Xu, J and Chancoco, H and Gu, J},
title = {Leukocyte Telomere Length and Bladder Cancer Risk: A Large Case-Control Study and Mendelian Randomization Analysis.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {30},
number = {1},
pages = {203-209},
doi = {10.1158/1055-9965.EPI-20-0351},
pmid = {32998948},
issn = {1538-7755},
mesh = {Aged ; Case-Control Studies ; Female ; Genetic Predisposition to Disease ; Humans ; Leukocytes/metabolism ; Male ; Mendelian Randomization Analysis ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Risk Assessment ; Telomere Shortening/*genetics ; Urinary Bladder Neoplasms/*genetics ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) has been associated with risk of several cancers. The association between LTL and bladder cancer is still inconsistent.<br><br>METHODS: In this large case-control study consisting of 2,011 patients with bladder cancer and 2,259 healthy controls of European ancestry, we investigated the associations of real-time qPCR-measured LTL (a retrospective case-control study) and genetically predicted LTL [a Mendelian randomization (MR) study] with bladder cancer risk. Genotypes from 10 LTL-associated SNPs were used as instrumental variables to predict LTL. We used an individual level data-based weighted genetic risk score (GRS) and a summary statistics-based inverse-variance weighting (IVW) method in MR analyses.<br><br>RESULTS: The qPCR-measured LTL was shorter in cases with muscle-invasive bladder cancer (MIBC) than those with non-muscle-invasive bladder cancer [NMIBC; ratio of telomere repeats copy number to single gene copy number (T/S): 1.19 &#xb1; 0.34 vs. 1.23 &#xb1; 0.36, P = 0.081]. Multivariable logistic regression analyses showed long qPCR-measured LTL was associated with a reduced risk of MIBC. In MR analyses, genetically predicted LTL was weakly associated with bladder cancer risk in both the GRS analysis [OR = 1.13, per SD increase; 95% confidence interval (CI), 0.73-1.75; P = 0.595] and the IVW analysis (OR = 1.14 per SD increase; 95% CI, 0.75-1.74; P = 0.543).<br><br>CONCLUSIONS: There was no strong evidence supporting an association between LTL and bladder cancer risk in European Americans.<br><br>IMPACT: This is the largest study of LTL and bladder cancer risk. The study showed that LTL does not play an important role in bladder cancer etiology.},
}
@article {pmid32998016,
year = {2020},
author = {Luo, M and Luo, H and Li, H and Liu, D and Lu, H},
title = {Single-stranded DNA-binding proteins in plant telomeres.},
journal = {International journal of biological macromolecules},
volume = {165},
number = {Pt A},
pages = {1463-1467},
doi = {10.1016/j.ijbiomac.2020.09.211},
pmid = {32998016},
issn = {1879-0003},
mesh = {DNA, Single-Stranded/*genetics ; DNA-Binding Proteins/*genetics ; Plants/genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {Telomere single-stranded DNA-binding proteins bind to the terminal single-stranded DNA of telomeres, maintaining and protecting the chromosomal end in eukaryotes. This paper focuses on the protective mechanism of single-stranded DNA-binding proteins in plant telomeres. This review summarizes the roles of plant single-stranded DNA-binding proteins and their influence on telomere length and telomerase. This review provides insights into the mechanism and development of single-stranded DNA-binding proteins in plants.},
}
@article {pmid32996594,
year = {2021},
author = {Song, W and Yang, J and Niu, Z},
title = {Association of periodontitis with leukocyte telomere length in US adults: A cross-sectional analysis of NHANES 1999 to 2002.},
journal = {Journal of periodontology},
volume = {92},
number = {6},
pages = {833-843},
doi = {10.1002/JPER.20-0269},
pmid = {32996594},
issn = {1943-3670},
mesh = {Adult ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes ; Male ; Nutrition Surveys ; *Periodontitis/epidemiology/genetics ; *Telomere/genetics ; },
abstract = {BACKGROUND: This study examines the association of periodontitis with telomere length (TL) and effect modification by population characteristics.<br><br>METHODS: We analyzed data from 3,478 participants from the 1999 to 2002 National Health and Nutrition Examination Survey. Probing depth, attachment loss, and bleed on probing (BOP, available for 1,973 participants only) were examined on the distal, mesial, or mid-facial site of each tooth in two randomly selected quadrants. We defined periodontitis severity according to the Centers for Disease Control/American Academy of Periodontology guideline. TL from leukocytes was measured with qPCR. We used linear and logistic regression to examine the adjusted association of different severity of periodontitis and BOP with continuous TL (bp) and dichotomized short TL (<median), respectively. To assess effect modification, we stratified the analyses by a priori selected population characteristics including sex, age, body weight status, smoking, and cardiometabolic comorbidity.<br><br>RESULTS: Moderate BOP (<10% bleeding sites) was significantly associated with a shorter continuous TL (&#x3b2; = -89.0, SE = 37.8). Moderate to severe periodontitis was significantly associated with 47% (95% confidence interval [IL], 1.04 to 2.09) higher odds of shorter TL, compared with those with mild or no periodontitis. The association was stronger in those who were female (adjusted OR, 1.76; 95% CI, 1.10 to 2.83), overweight or obese (adjusted OR, 1.64; 95% CI, 1.12 to 2.41), or had cardiometabolic comorbidities (adjusted OR, 2.13; 95% CI, 1.38 to 3.29).<br><br>CONCLUSIONS: Periodontitis was associated with TL, a biomarker of cellular aging. The association was stronger in females, overweight or obese, or those with cardiometabolic diseases. Treatment on periodontitis could potentially protect individuals from aging-related diseases.},
}
@article {pmid32995737,
year = {2020},
author = {Ahiawodzi, P and Fitzpatrick, AL and Djousse, L and Ix, JH and Kizer, JR and Mukamal, KJ},
title = {Non-esterified fatty acids and telomere length in older adults: The Cardiovascular Health Study.},
journal = {Metabolism open},
volume = {8},
number = {},
pages = {100058},
pmid = {32995737},
issn = {2589-9368},
support = {U01 HL130114/HL/NHLBI NIH HHS/United States ; },
abstract = {BACKGROUND: Telomeres shorten as organisms age, placing limits on cell proliferation and serving as a marker of biological aging. Non-esterified fatty acids (NEFAs) are a key mediator of age-related metabolic abnormalities. We aimed to determine if NEFAs are associated with telomere length in community-living older adults.<br><br>MATERIAL AND METHODS: We cross-sectionally studied 1648 participants of the Cardiovascular Health Study (CHS) who underwent concomitant telomere length measurement from a sample of 4715 participants who underwent measurement of circulating total fasting NEFAs in stored specimens from their 1992-3 clinic visit. We used linear regression and inverse probability weighting to model telomere length as a function of NEFAs with adjustment for age, gender, race, clinic, BMI, marital status, smoking status, alcohol intake, diabetes status, years of education, hypertension status, prevalent cardiovascular disease, C-reactive protein, total adiponectin, albumin, fetuin-A, fasting insulin, eGFR, total cholesterol, HDL-cholesterol, triglycerides, and general health status.<br><br>RESULTS: Higher NEFAs were significantly associated with shorter telomere length, after adjusting for age, gender, race, and clinic site (&#x3b2;&#xa0;=&#xa0;-0.034; SE&#xa0;=&#xa0;0.015; P&#xa0;=&#xa0;0.02). Estimates remained similar in fully adjusted models where each SD of NEFA increment was associated with 0.042 kilobase (kb) pairs shorter telomere length (standard error&#xa0;=&#xa0;0.016; P&#xa0;=&#xa0;0.007); for comparison the coefficient for a single year of age in the same model was&#xa0;-0.017. These results were similar in strata of sex, and waist circumference although they tended to be strongest among participants in the youngest tertile of age (&#x3b2;&#xa0;=&#xa0;-0.079; SE&#xa0;=&#xa0;0.029; P&#xa0;=&#xa0;0.01).<br><br>CONCLUSIONS: In this population-based cohort of community-living elders, we observed a significant inverse association between NEFAs and telomere length. If confirmed, NEFAs may represent a promising target for interventions to slow biological aging.},
}
@article {pmid32991882,
year = {2020},
author = {Wang, Y and Liu, Z and Huang, C and Zhao, L and Jiang, X and Liu, Y and Liu, Y and Wan, Y and Chou, Y and Li, X},
title = {Analysis of lens epithelium telomere length in age-related cataract.},
journal = {Experimental eye research},
volume = {201},
number = {},
pages = {108279},
doi = {10.1016/j.exer.2020.108279},
pmid = {32991882},
issn = {1096-0007},
mesh = {Aged ; *Aging ; Cataract/*genetics/pathology ; Epithelium/*pathology ; Female ; Humans ; Lens Nucleus, Crystalline/*pathology ; Male ; Prospective Studies ; Telomere/*pathology ; *Visual Acuity ; },
abstract = {We aimed to investigate the associations among lens epithelium telomere length (LETL), cataract types, and systemic pro-senescence factors in patients with age-related cataract. In this prospective study, the general demographic factors, body mass index, smoking history, depression, hypertension, diabetes, various psychological measures, and uncorrected distant visual acuity of patients with age-related cataract were recorded. Lens Opacities Classification System III (LOCS III) scores and lens density measured by Scheimpflug imaging were used to evaluate the cataracts. LETL was measured by real-time polymerase chain reaction. Correlations among these parameters were analyzed. The LOCS III nuclear opalescence (NO) score was associated with age (β = 0.053, P < 0.001) and Patient Health Questionnaire-9 score (β = -0.042, P = 0.004). Smoking was identified as a risk factor affecting LOCS III NO score (odds ratio = 1.546, 95% confidence interval, 1.128-2.119), but not the LOCS III cortical or posterior subcapsular scores. LETLs showed a weak association with systemic factors and LOCS III scores, and a significantly moderate correlation with the average objective lens densities of different regions measured by Scheimpflug imaging (r values ranged from -0.278 to -0.523, P < 0.05). However, there was no correlation between the LETLs and the maximum lens densities. The groups with a relatively low lens density had longer LETLs. In Conclusion, being an age-related disease, cortical cataract was also associated with "aging of the lens epithelium." Notably, lens epithelium activity rarely showed systemic effects. Thus, future studies should emphasize the importance of the telomeric system in cataractous process and aging.},
}
@article {pmid32991318,
year = {2020},
author = {Tan, J and Wang, X and Hwang, BJ and Gonzales, R and Konen, O and Lan, L and Lu, AL},
title = {An ordered assembly of MYH glycosylase, SIRT6 protein deacetylase, and Rad9-Rad1-Hus1 checkpoint clamp at oxidatively damaged telomeres.},
journal = {Aging},
volume = {12},
number = {18},
pages = {17761-17785},
pmid = {32991318},
issn = {1945-4589},
support = {R01 GM118837/GM/NIGMS NIH HHS/United States ; },
abstract = {In the base excision repair pathway, MYH/MUTYH DNA glycosylase prevents mutations by removing adenine mispaired with 8-oxoG, a frequent oxidative lesion. MYH glycosylase activity is enhanced by Rad9-Rad1-Hus1 (9-1-1) checkpoint clamp and SIRT6 histone/protein deacetylase. Here, we show that MYH, SIRT6, and 9-1-1 are recruited to confined oxidatively damaged regions on telomeres in mammalian cells. Using different knockout cells, we show that SIRT6 responds to damaged telomeres very early, and then recruits MYH and Hus1 following oxidative stress. However, the recruitment of Hus1 to damaged telomeres is partially dependent on SIRT6. The catalytic activities of SIRT6 are not important for SIRT6 response but are essential for MYH recruitment to damaged telomeres. Compared to wild-type MYH, the recruitment of hMYH[V315A] mutant (defective in both SIRT6 and Hus1 interactions), but not hMYH[Q324H] mutant (defective in Hus1 interaction only), to damaged telomeres is severely reduced. The formation of MYH/SIRT6/9-1-1 complex is of biological significance as interrupting their interactions can increase cell's sensitivity to H2O2 and/or elevate cellular 8-oxoG levels after H2O2 treatment. Our results establish that SIRT6 acts as an early sensor of BER enzymes and both SIRT6 and 9-1-1 serve critical roles in DNA repair to maintain telomere integrity.},
}
@article {pmid32984752,
year = {2019},
author = {Niehoff, NM and Gammon, MD and Keil, AP and Nichols, HB and Engel, LS and Taylor, JA and White, AJ and Sandler, DP},
title = {Hazardous air pollutants and telomere length in the Sister Study.},
journal = {Environmental epidemiology (Philadelphia, Pa.)},
volume = {3},
number = {4},
pages = {},
pmid = {32984752},
issn = {2474-7882},
support = {T32 CA057726/CA/NCI NIH HHS/United States ; T32 ES007018/ES/NIEHS NIH HHS/United States ; Z01 ES044005/ImNIH/Intramural NIH HHS/United States ; },
abstract = {BACKGROUND: Telomeres are vital for genomic integrity and telomere length has been linked to many adverse health outcomes. Some hazardous air pollutants, or air toxics, increase oxidative stress and inflammation, two possible determinants of shortened telomere length. No studies have examined air toxic-telomere length associations in a non-occupational setting.<br><br>METHODS: This study included 731 Sister Study participants (enrolled 2003-2007) who were randomly selected to assess telomere length in baseline blood samples. Multiplex qPCR was used to determine telomere to single copy gene (T/S) ratios. Census tract concentration estimates of 29 air toxics from the 2005 National Air Toxics Assessment were linked to baseline residential addresses. Air toxics were classified into tertile-based categories of the exposure. Multivariable linear regression was used to estimate &#x3b2; coefficients and 95% confidence intervals (CI) in single pollutant models. Multipollutant groups were identified with regression trees.<br><br>RESULTS: The average T/S ratio was 1.24. Benzidine (T3vsT1 &#x3b2;= -0.08; 95% CI: -0.14, -0.01) and 1,4-dioxane (T3vsT1 &#x3b2;= -0.06; 95% CI: -0.13, 0.00) in particular, as well as carbon tetrachloride, chloroprene, ethylene dibromide, and propylene dichloride, were associated with shorter relative telomere length. Benzidine (p=0.02) and 1,4-dioxane (p=0.06) demonstrated some evidence of a monotonic trend. The regression tree identified age, BMI, physical activity, ethylene oxide, acrylonitrile, ethylidene dichloride, propylene dichloride, and styrene in multipollutant groups related to telomere length.<br><br>CONCLUSIONS: In this first study of air toxics and telomere length in a non-occupational setting, several air toxics, particularly 1,4-dioxane and benzidine, were associated with shorter relative telomere length.},
}
@article {pmid32984050,
year = {2020},
author = {Yuan, G and Song, J and Li, N and Song, Q and Li, Y and Du, Y and Wang, X and Jiao, Y and Wu, L},
title = {Telomere Maintenance Associated Mutations in the Genetic Landscape of Gynecological Mucosal Melanoma.},
journal = {Frontiers in oncology},
volume = {10},
number = {},
pages = {1707},
pmid = {32984050},
issn = {2234-943X},
abstract = {PURPOSE: Gynecological melanomas (GMs) are rare tumors with a poor prognosis. Here, we performed exome sequencing to generate the mutational landscape of GMs.<br><br>METHODS: Next-generation sequencing was carried out on mucosal melanoma samples (n = 35) obtained from gynecological sites. The alternative telomere lengthening (ALT) phenotype was verified by fluorescence in situ hybridization and the C-circle assay. Immunohistochemistry was performed to detect ATRX protein. Copy number variations in TERT were detected by droplet digital polymerase chain reaction.<br><br>RESULTS: In the 58 formalin-fixed paraffin-embedded samples, we identified 33 (56.9%) ALT-positive cases, with 23 showing loss of ATRX protein. TERT promoter mutation was not detected in GMs (n = 40), but copy number variations in the TERT region were observed in 20% (7/35) of the samples. TERT amplification was mutually exclusive with ALT (P < 0.05). Kaplan-Meier revealed that ALT relative to TERT amplification was associated with longer overall survival in GM patients without metastasis.<br><br>CONCLUSION: These findings indicate that telomere maintenance mechanisms play a critical role in the tumorigenesis of GMs and may aid in the prediction of clinical prognosis and the development of targeted therapy for the treatment of GM.},
}
@article {pmid32980685,
year = {2020},
author = {Iannuzzi, A and Della Valle, G and Russo, M and Longobardi, V and Albero, G and De Canditiis, C and Kosior, MA and Pistucci, R and Gasparrini, B},
title = {Evaluation of bovine sperm telomere length and association with semen quality.},
journal = {Theriogenology},
volume = {158},
number = {},
pages = {227-232},
doi = {10.1016/j.theriogenology.2020.09.019},
pmid = {32980685},
issn = {1879-3231},
mesh = {Animals ; Cattle/genetics ; Male ; Semen ; *Semen Analysis/veterinary ; *Semen Preservation/veterinary ; Sperm Motility ; Spermatozoa ; Telomere/genetics ; },
abstract = {The study aimed to evaluate if the sperm telomere length can be considered as a new biomarker for sperm quality in bulls. Sperm Telomere Length was evaluated by Monochrome Multiplex Quantitative PCR in group A (n = 8) and group B (n = 8) bulls, classified according to standard semen analysis. Also, this parameter was measured before and after Percoll gradient separation within bulls that produced semen of satisfactory quality. Sperm telomere length, measured as T/S ratio (average ratio of telomere repeats copy number to a single copy gene), was higher in group A than in group B bulls (0.77 ± 0.03 vs 0.43 ± 0.06; P < 0.01). Sperm telomere length was positively correlated with motility, viability and membrane integrity, and it was negatively correlated with sperm anomalies. Furthermore, Percoll gradient selected sperms with higher T/S ratio than unselected sperms (1.19 ± 0.02 vs 0.67 ± 0.03). These results suggest that sperm telomere length can be used as a new marker of bovine semen quality.},
}
@article {pmid32978426,
year = {2020},
author = {Tran, HTT and Herz, C and Lamy, E},
title = {Long-term exposure to "low-dose" bisphenol A decreases mitochondrial DNA copy number, and accelerates telomere shortening in human CD8 + T cells.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {15786},
pmid = {32978426},
issn = {2045-2322},
mesh = {Adult ; Benzhydryl Compounds/*pharmacology ; CD8-Positive T-Lymphocytes/drug effects/*metabolism ; Cell Proliferation ; Cells, Cultured ; *DNA Copy Number Variations ; DNA, Mitochondrial/*genetics ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology ; Humans ; Leukocytes, Mononuclear/drug effects/*metabolism ; Male ; Phenols/*pharmacology ; Signal Transduction ; Telomere/*genetics ; Telomere Shortening/*drug effects ; Time Factors ; Young Adult ; },
abstract = {Exposure to the endocrine disruptor bisphenol A (BPA) has been linked with immune disorders and increased tumour risk. Our previous work in activated human peripheral blood mononuclear cells demonstrated that exposure to "low-dose" BPA diminished telomerase activity via an ER/GPR30-ERK signalling pathway. Leukocyte telomerase activity and telomere maintenance are crucial for normal immune function and homeostasis. We thus here further studied the effects of BPA on human T cell subpopulations. Exposure to 0.3-3 nM BPA, i. e. at doses in the realm of human exposure, notably reduced telomerase activity in activated CD8 + T but not CD4 + T cells in a non-monotonic response pattern as determined by the TRAP-ELISA assay. Under long-term BPA exposure, significant telomere length shortening, reduction in mitochondrial DNA copy number, cell proliferation and IFN-γ as well as hTERT protein suppression could be observed in CD8 + lymphocytes, as analysed by qRT-PCR, flow cytometry and western blot analysis. This study extends our previous in vitro findings that "low-dose" BPA has potential negative effects on healthy human cytotoxic T cell response. These results might merit some special attention to further investigate chronic BPA exposure in the context of adaptive immune response dysfunction and early onset of cancer in man.},
}
@article {pmid32973827,
year = {2020},
author = {Khosravi, S and Schindele, P and Gladilin, E and Dunemann, F and Rutten, T and Puchta, H and Houben, A},
title = {Application of Aptamers Improves CRISPR-Based Live Imaging of Plant Telomeres.},
journal = {Frontiers in plant science},
volume = {11},
number = {},
pages = {1254},
pmid = {32973827},
issn = {1664-462X},
abstract = {Development of live imaging techniques for providing information how chromatin is organized in living cells is pivotal to decipher the regulation of biological processes. Here, we demonstrate the improvement of a live imaging technique based on CRISPR/Cas9. In this approach, the sgRNA scaffold is fused to RNA aptamers including MS2 and PP7. When the dead Cas9 (dCas9) is co-expressed with chimeric sgRNA, the fluorescent coat protein-tagged for MS2 and PP7 aptamers (tdMCP-FP and tdPCP-FP) are recruited to the targeted sequence. Compared to previous work with dCas9:GFP, we show that the quality of telomere labeling was improved in transiently transformed Nicotiana benthamiana using aptamer-based CRISPR-imaging constructs. Labeling is influenced by the copy number of aptamers and less by the promoter types. The same constructs were not applicable for labeling of repeats in stably transformed plants and roots. The constant interaction of the RNP complex with its target DNA might interfere with cellular processes.},
}
@article {pmid32971146,
year = {2021},
author = {Himes, RW and Chiou, EH and Queliza, K and Shouval, DS and Somech, R and Agarwal, S and Jajoo, K and Ziegler, DS and Kratz, CP and Huang, J and Lucas, TL and Myers, KC and Nelson, AS and DiNardo, CD and Alter, BP and Giri, N and Khincha, PP and McReynolds, LJ and Dufour, C and Pierri, F and Goldman, FD and Sherif, Y and Savage, SA and Miloh, T and Bertuch, AA},
title = {Gastrointestinal Hemorrhage: A Manifestation of the Telomere Biology Disorders.},
journal = {The Journal of pediatrics},
volume = {230},
number = {},
pages = {55-61.e4},
doi = {10.1016/j.jpeds.2020.09.038},
pmid = {32971146},
issn = {1097-6833},
mesh = {Adolescent ; Adult ; Ataxia/complications/genetics ; Bone Diseases, Metabolic/complications/genetics ; Bone Marrow/abnormalities ; Brain Neoplasms/complications/genetics ; Calcinosis/complications/genetics ; Central Nervous System Cysts/complications/genetics ; Child ; Child, Preschool ; Dyskeratosis Congenita/complications/genetics ; Female ; Fetal Growth Retardation/genetics ; Gastrointestinal Hemorrhage/*etiology/genetics ; Humans ; Intellectual Disability/complications/genetics ; Leukoencephalopathies/complications/genetics ; Male ; Microcephaly/complications/genetics ; Muscle Spasticity/complications/genetics ; Mutation ; Retina ; Retinal Diseases/complications/genetics ; Seizures/complications/genetics ; Telomere/*genetics/metabolism/pathology ; Young Adult ; },
abstract = {OBJECTIVE: To describe the clinical features, therapeutic interventions, and patient outcomes of gastrointestinal (GI) hemorrhage in individuals with a telomere biology disorder, including dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome, Revesz syndrome, and Coats plus.<br><br>STUDY DESIGN: Clinical Care Consortium for Telomere Associated Ailments members were invited to contribute data on individuals with telomere biology disorders at their institutions who experienced GI bleeding. Patient demographic, laboratory, imaging, procedural, and treatment information and outcomes were extracted from the medical record.<br><br>RESULTS: Sixteen patients who experienced GI hemorrhage were identified at 11 centers. Among 14 patients who underwent genetic testing, 8 had mutations in TINF2, 4 had mutations in CTC1 or STN1, and 1 patient each had a mutation in TERC and RTEL1. Ten patients had a history of hematopoietic cell transplantation. The patients with Coats plus and those without Coats plus had similar clinical features and courses. Angiodysplasia of the stomach and/or small bowel was described in 8 of the 12 patients who underwent endoscopy; only 4 had esophageal varices. Various medical interventions were trialed. No single intervention was uniformly associated with cessation of bleeding, although 1 patient had a sustained response to treatment with bevacizumab. Recurrence was common, and the overall long-term outcome for affected patients was poor.<br><br>CONCLUSIONS: GI bleeding in patients with telomere biology disorders is associated with significant morbidity and with vascular ectasias rather than varices.},
}
@article {pmid32971118,
year = {2020},
author = {Dratwa, M and Wysoczanska, B and Turlej, E and Anisiewicz, A and Maciejewska, M and Wietrzyk, J and Bogunia-Kubik, K},
title = {Heterogeneity of telomerase reverse transcriptase mutation and expression, telomerase activity and telomere length across human cancer cell lines cultured in vitro.},
journal = {Experimental cell research},
volume = {396},
number = {1},
pages = {112298},
doi = {10.1016/j.yexcr.2020.112298},
pmid = {32971118},
issn = {1090-2422},
mesh = {A549 Cells ; Cell Line ; Cell Line, Tumor ; Gene Expression ; HL-60 Cells ; HT29 Cells ; Humans ; K562 Cells ; MCF-7 Cells ; *Mutation ; Organ Specificity ; Promoter Regions, Genetic ; THP-1 Cells ; Telomerase/*genetics/metabolism ; Telomere/*chemistry/metabolism ; *Telomere Homeostasis ; },
abstract = {Promoter region of the telomerase reverse transcriptase gene (TERTp) constitutes a regulatory element capable to affect TERT expression (TE), telomerase activity (TA) and telomere length (TL). TERTp mutation status, TL, TA and TE were assessed in 27 in vitro cultured human cell lines, including 11 solid tumour, 13 haematological and 3 normal cell lines. C228T and C250T TERTp mutations were detected in 5 solid tumour and none of haematological cell lines (p = 0.0100). As compared to other solid tumour cell lines, those with the presence of somatic mutations were characterized by: shorter TL, lower TA and TE. Furthermore, cell lines carrying TERTp mutations showed a linear correlation between TE and TA (R = 0.9708, p = 0.0021). Moreover, haematological cell lines exhibited higher TE compared to solid tumour cell lines (p = 0.0007). TL and TA were correlated in both solid tumour (R = 0.4875, p = 0.0169) and haematological (R = 0.4719, p = 0.0095) cell lines. Our results based on the in vitro model suggest that oncogenic processes may differ between solid tumours and haematological malignancies with regard to their TERT gene regulation mechanisms.},
}
@article {pmid32970185,
year = {2021},
author = {Vinchure, OS and Whittemore, K and Kushwah, D and Blasco, MA and Kulshreshtha, R},
title = {miR-490 suppresses telomere maintenance program and associated hallmarks in glioblastoma.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {78},
number = {5},
pages = {2299-2314},
pmid = {32970185},
issn = {1420-9071},
mesh = {3' Untranslated Regions/genetics ; Brain Neoplasms/*genetics/metabolism/pathology ; Cell Line, Tumor ; *Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Glioblastoma/*genetics/metabolism/pathology ; Humans ; MicroRNAs/*genetics ; Protein Serine-Threonine Kinases/genetics/metabolism ; SOXB1 Transcription Factors/genetics/metabolism ; SOXC Transcription Factors/genetics/metabolism ; Tankyrases/genetics/metabolism ; Telomere Homeostasis/*genetics ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; },
abstract = {Glioblastoma (GBM) is the most aggressive cancer of central nervous system with worst patient outcome. Telomere maintenance is a crucial mechanism governing GBM initiation and progression making it an attractive target. microRNAs (miRNAs) have shown therapeutic potential in GBM. Earlier, we showed miR-490 is downregulated in GBM patients and plays a tumor suppressive role. Here, we show that miR-490 regulates telomere maintenance program in GBM by directly targeting Telomeric Repeat-binding Factor 2 (TERF2) of the shelterin complex, Tankyrase 2 (TNKS2) and Serine/Threonine-protein kinase, SMG1. Overexpression of miR-490 resulted in effects characteristic to hampered telomere maintenance via TERF2 inhibition. These include induction of telomere dysfunction-induced foci and global DNA damage (53BP1 foci), along with an increase in p-γH2AX levels. Further, it led to inhibition of telomere maintenance hallmarks via reduced stemness (SOX2 and SOX4 downregulation) and induction of senescence (H3K9me3 marks gain and SIRT1 downregulation). It also initiated downstream DNA damage response (DDR) leading to p53 pathway activation. Moreover, microarray data analysis highlighted an overlap between miR-490 expression and REST-inhibition responses in GBM. Thus, miR-490-mediated targeting of telomere maintenance could be therapeutically important in GBM.},
}
@article {pmid32969697,
year = {2020},
author = {Zerach, G and Shevlin, M and Solomon, Z},
title = {Associations between hardiness, C-reactive protein, and telomere length among former prisoners of war.},
journal = {Health psychology : official journal of the Division of Health Psychology, American Psychological Association},
volume = {39},
number = {11},
pages = {1007-1012},
doi = {10.1037/hea0001030},
pmid = {32969697},
issn = {1930-7810},
mesh = {C-Reactive Protein/*metabolism ; Humans ; Longitudinal Studies ; Male ; Prisoners of War/*psychology ; Prospective Studies ; Stress Disorders, Post-Traumatic/*psychology ; Telomere/*physiology ; },
abstract = {BACKGROUND: War captivity and posttraumatic stress disorder (PTSD) are known to be associated with several poor health outcomes of an accelerated aging process. However, the contribution of personality protective factors to this phenomenon are rarely studied. The present 24-year prospective study examined associations between psychological hardiness and three health outcomes: C-reactive protein (CRP) levels, metabolic syndrome (MetS), and telomere length (TL).<br><br>METHOD: Eighty-eight Israeli former prisoners of war (ex-POWs) were assessed 18 (T1) and 42 (T2) years after repatriation. Data on hardiness was collected at T1 while leukocyte TL, CRP, and MetS data was collected 42 years after the war.<br><br>RESULTS: While adjusting for age, body mass index (BMI), self-rated health, depressive and PTSD symptoms at T2, higher levels of hardiness at T1 predicted decreased CRP and longer TL at T2.<br><br>CONCLUSIONS: Long-term health vulnerabilities of traumatized ex-POWs are manifested in an accelerated aging process and cellular senescence. Raising awareness of the importance of protective factors such as veterans' hardiness might be associated with improving their longevity and well-being. (PsycInfo Database Record (c) 2020 APA, all rights reserved).},
}
@article {pmid32968801,
year = {2021},
author = {Habibi, N and Bianco-Miotto, T and Phoi, YY and Jankovic-Karasoulos, T and Roberts, CT and Grieger, JA},
title = {Maternal diet and offspring telomere length: a systematic review.},
journal = {Nutrition reviews},
volume = {79},
number = {2},
pages = {148-159},
doi = {10.1093/nutrit/nuaa097},
pmid = {32968801},
issn = {1753-4887},
mesh = {Adult ; Caffeine/metabolism ; Calcifediol/blood ; Child ; Child, Preschool ; Diet ; Eating ; Fatty Acids, Omega-3/metabolism ; Female ; Fetal Blood ; Folic Acid/blood/metabolism ; Humans ; Leukocytes, Mononuclear/*metabolism ; *Maternal Nutritional Physiological Phenomena ; *Nutritional Status ; Pregnancy ; Telomere/metabolism ; *Telomere Homeostasis ; Vitamins/metabolism ; Young Adult ; },
abstract = {CONTEXT: Many studies assert a negative influence of inappropriate maternal diet and nutritional status during pregnancy on offspring, not only in utero but throughout life, because of the role in the programing of noncommunicable diseases. Telomere length is a biomarker of aging, and shorter telomeres are associated with chronic disease later in life. Maternal nutrition and nutritional status may be an important determinant of offspring telomere length.<br><br>OBJECTIVE: A systematic review was conducted to determine the effect of maternal nutrition and nutritional status in pregnancy on offspring telomere length.<br><br>DATA SOURCES: This systematic review was conducted according to PRISMA guidelines. Database searches of PubMed, CINAHL, Scopus, Medline, and Web of Science were performed.<br><br>STUDY SELECTION: Included studies assessed the association between maternal nutrition (dietary intake and nutritional status) during pregnancy and offspring telomere length measured in cord blood, serum, plasma, and peripheral blood mononuclear cells.<br><br>DATA EXTRACTION: Three authors screened and determined the quality of the articles; disagreements were resolved by a fourth author. All authors compared the compiled data.<br><br>RESULTS: Seven studies were extracted and evaluated. Studies comprised a double-blind placebo-controlled trial (n&#x2009;=&#x2009;1), prospective cohort studies (n&#x2009;=&#x2009;5), and a cross-sectional study (n&#x2009;=&#x2009;1). Higher circulating maternal folate and 25-hydroxyvitamin D3 concentrations, along with higher maternal dietary caffeine intakes, were associated with longer offspring telomere length, whereas higher dietary intake of carbohydrate, folate, n-3 polyunsaturated fatty acids, vitamin&#x2009;C, or sodium was not.<br><br>CONCLUSION: The limited but suggestive evidence highlights the need for further research to be conducted in this area, particularly longitudinal studies involving larger cohorts of pregnant women.<br><br>PROSPERO registration no. CRD42019136506.},
}
@article {pmid32967926,
year = {2020},
author = {Fan, J and Jin, H and Koch, BA and Yu, HG},
title = {Mps2 links Csm4 and Mps3 to form a telomere-associated LINC complex in budding yeast.},
journal = {Life science alliance},
volume = {3},
number = {12},
pages = {},
pmid = {32967926},
issn = {2575-1077},
support = {R01 GM117102/GM/NIGMS NIH HHS/United States ; R01 GM138838/GM/NIGMS NIH HHS/United States ; T32 HL007843/HL/NHLBI NIH HHS/United States ; MCB1951313//National Science Foundation/International ; },
mesh = {Cell Cycle Proteins/genetics ; Chromosome Segregation ; Cytoskeleton/metabolism ; Homologous Recombination ; Meiosis ; Membrane Proteins/*metabolism/physiology ; Microtubules/metabolism ; Nuclear Envelope/metabolism ; Nuclear Matrix/metabolism ; Nuclear Proteins/genetics/*metabolism/physiology ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/*metabolism/physiology ; Saccharomycetales/metabolism ; Telomere/metabolism ; },
abstract = {The linker of the nucleoskeleton and cytoskeleton (LINC) complex is composed of two transmembrane proteins: the KASH domain protein localized to the outer nuclear membrane and the SUN domain protein to the inner nuclear membrane. In budding yeast, the sole SUN domain protein, Mps3, is thought to pair with either Csm4 or Mps2, two KASH-like proteins, to form two separate LINC complexes. Here, we show that Mps2 mediates the interaction between Csm4 and Mps3 to form a heterotrimeric telomere-associated LINC (t-LINC) complex in budding yeast meiosis. Mps2 binds to Csm4 and Mps3, and all three are localized to the telomere. Telomeric localization of Csm4 depends on both Mps2 and Mps3; in contrast, Mps2's localization depends on Mps3 but not Csm4. Mps2-mediated t-LINC complex regulates telomere movement and meiotic recombination. By ectopically expressing CSM4 in vegetative yeast cells, we reconstitute the heterotrimeric t-LINC complex and demonstrate its ability to tether telomeres. Our findings therefore reveal the heterotrimeric composition of the t-LINC complex in budding yeast and have implications for understanding variant LINC complex formation.},
}
@article {pmid32959123,
year = {2020},
author = {Bose, S and Suescún, AV and Song, J and Castillo-González, C and Aklilu, BB and Branham, E and Lynch, R and Shippen, DE},
title = {tRNA ADENOSINE DEAMINASE 3 is required for telomere maintenance in Arabidopsis thaliana.},
journal = {Plant cell reports},
volume = {39},
number = {12},
pages = {1669-1685},
pmid = {32959123},
issn = {1432-203X},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; MCB151787//National Science Foundation/ ; R01 GM065383/NH/NIH HHS/United States ; },
mesh = {3' Untranslated Regions ; Adenosine Deaminase/*genetics/metabolism ; Apoptosis/genetics ; Arabidopsis/*genetics/metabolism ; Arabidopsis Proteins/*genetics/metabolism ; DNA Damage ; Gene Expression Regulation, Plant ; Mutation ; Nuclear Proteins/genetics/metabolism ; RNA, Long Noncoding/genetics ; RNA, Plant/*genetics ; Sequence Analysis, RNA ; Telomerase/genetics/metabolism ; Telomere/*genetics ; Telomere Homeostasis/genetics/physiology ; },
abstract = {KEY MESSAGE: tRNA Adenosine Deaminase 3 helps to sustain telomere tracts in a telomerase-independent fashion, likely through regulating cellular metabolism. Telomere length maintenance is influenced by a complex web of chromatin and metabolism-related factors. We previously reported that a lncRNA termed AtTER2 regulates telomerase activity in Arabidopsis thaliana in response to DNA damage. AtTER2 was initially shown to partially overlap with the 5' UTR of the tRNA ADENOSINE DEAMINASE 3 (TAD3) gene. However, updated genome annotation showed that AtTER2 was completely embedded in TAD3, raising the possibility that phenotypes ascribed to AtTER2 could be derived from TAD3. Here we show through strand-specific RNA-Seq, strand-specific qRT-PCR and bioinformatic analyses that AtTER2 does not encode a stable lncRNA. Further examination of the original tad3 (ter2-1/tad3-1) mutant revealed expression of an antisense transcript driven by a cryptic promoter in the T-DNA. Hence, a new hypomorphic allele of TAD3 (tad3-2) was examined. tad3-2 mutants showed hypersensitivity to DNA damage, but no deregulation of telomerase, suggesting that the telomerase phenotype of tad3-1 mutants reflects an off-target effect. Unexpectedly, however, tad3-2 plants displayed progressive loss of telomeric DNA over successive generations that was not accompanied by alteration of terminal architecture or end protection. The phenotype was exacerbated in plants lacking the telomerase processivity factor POT1a, indicating that TAD3 promotes telomere maintenance through a non-canonical, telomerase-independent pathway. The transcriptome of tad3-2 mutants revealed significant dysregulation of genes involved in auxin signaling and glucosinolate biosynthesis, pathways that intersect the stress response, cell cycle regulation and DNA metabolism. These findings indicate that the TAD3 locus indirectly contributes to telomere length homeostasis by altering the metabolic profile in Arabidopsis.},
}
@article {pmid32958778,
year = {2020},
author = {Chakravarti, D and Hu, B and Mao, X and Rashid, A and Li, J and Li, J and Liao, WT and Whitley, EM and Dey, P and Hou, P and LaBella, KA and Chang, A and Wang, G and Spring, DJ and Deng, P and Zhao, D and Liang, X and Lan, Z and Lin, Y and Sarkar, S and Terranova, C and Deribe, YL and Blutt, SE and Okhuysen, P and Zhang, J and Vilar, E and Nielsen, OH and Dupont, A and Younes, M and Patel, KR and Shroyer, NF and Rai, K and Estes, MK and Wang, YA and Bertuch, AA and DePinho, RA},
title = {Telomere dysfunction activates YAP1 to drive tissue inflammation.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {4766},
pmid = {32958778},
issn = {2041-1723},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; R00 CA194289/CA/NCI NIH HHS/United States ; R01 DK118904/DK/NIDDK NIH HHS/United States ; P30 DK056338/DK/NIDDK NIH HHS/United States ; K99 CA218891/CA/NCI NIH HHS/United States ; R01 CA084628/CA/NCI NIH HHS/United States ; P50 CA140388/CA/NCI NIH HHS/United States ; TL1 TR003169/TR/NCATS NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing/antagonists &amp; inhibitors/genetics/*metabolism ; Animals ; Anti-Bacterial Agents/therapeutic use ; Ataxia Telangiectasia Mutated Proteins/antagonists &amp; inhibitors/metabolism ; Caspase 1/metabolism ; Cell Cycle Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Child ; Colon/metabolism/microbiology/pathology ; Gastrointestinal Diseases/pathology ; Gastrointestinal Microbiome/drug effects/physiology ; Humans ; Inflammation/drug therapy/metabolism/microbiology/*pathology ; Interleukin-18/genetics/metabolism ; Intestinal Mucosa/metabolism/pathology ; Mice ; Mice, Mutant Strains ; Phosphorylation ; Protein Precursors/genetics/metabolism ; Signal Transduction ; Telomerase/genetics/metabolism ; Telomere/*pathology ; YAP-Signaling Proteins ; },
abstract = {Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation.},
}
@article {pmid32955878,
year = {2020},
author = {Tsubono, Y and Kawamoto, Y and Hidaka, T and Pandian, GN and Hashiya, K and Bando, T and Sugiyama, H},
title = {A Near-Infrared Fluorogenic Pyrrole-Imidazole Polyamide Probe for Live-Cell Imaging of Telomeres.},
journal = {Journal of the American Chemical Society},
volume = {142},
number = {41},
pages = {17356-17363},
pmid = {32955878},
issn = {1520-5126},
support = {R01 CA236350/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; DNA/*analysis ; Fluorescent Dyes/*chemistry ; Humans ; Imidazoles/*chemistry ; Intercalating Agents/chemistry ; Mitosis ; Nylons/*chemistry ; Optical Imaging ; Pyrroles/*chemistry ; Rhodamines/chemistry ; Silicon/chemistry ; Spectroscopy, Near-Infrared ; Telomere/*chemistry ; },
abstract = {Telomeres are closely associated with cellular senescence and cancer. Although some techniques have been developed to label telomeres in living cells for study of telomere dynamics, few biocompatible near-infrared probes based on synthetic molecules have been reported. In this study, we developed a near-infrared fluorogenic pyrrole-imidazole polyamide probe (SiR-TTet59B) to visualize telomeres by conjugating a silicon-rhodamine (SiR) fluorophore with a tandem tetramer pyrrole-imidazole polyamide targeting 24 bp in the telomeric double-stranded (ds) DNA. SiR-TTet59B was almost nonfluorescent in water but increased its fluorescence dramatically on binding to telomeric dsDNA. Using a peptide-based delivery reagent, we demonstrated the specific and effective visualization of telomeres in living U2OS cells. Moreover, SiR-TTet59B could be used to observe the dynamic movements of telomeres during interphase and mitosis. This simple imaging method using a synthetic near-infrared probe could be a powerful tool for studies of telomeres and for diagnosis.},
}
@article {pmid32953227,
year = {2020},
author = {Truta, B and Wohler, E and Sobreira, N and Datta, LW and Brant, SR},
title = {Role of telomere shortening in anticipation of inflammatory bowel disease.},
journal = {World journal of gastrointestinal pharmacology and therapeutics},
volume = {11},
number = {4},
pages = {69-78},
pmid = {32953227},
issn = {2150-5349},
abstract = {BACKGROUND: The existence of genetic anticipation has been long disputed in inflammatory bowel disease (IBD) in the absence of the explanatory mechanism.<br><br>AIM: To determine whether it was predictive of genetic anticipation, we evaluated telomere length in IBD. We hypothesized that multiplex IBD families exhibit a genetic defect impacting telomere maintenance mechanisms.<br><br>METHODS: We studied three IBD families with multiple affected members in three successive generations. We determined telomere length (TL) in lymphocytes and granulocytes from peripheral blood of the affected members using flow cytometry and fluorescence in-situ hybridization (flow FISH). We also performed whole exome sequencing in the blood of all available family members and used PhenoDB to identify potential candidate gene variants with recessive or dominant modes of inheritance.<br><br>RESULTS: Out of twenty-four patients of European descent selected to participate in the study, eleven patients, eight parent-child pairs affected by IBD, were included in the genetic anticipation analysis. Median difference in age at diagnosis between two successive generations was 16.5 years, with earlier age at onset in the younger generations. In most of the affected members, the disease harbored similar gastrointestinal and extraintestinal involvement but was more aggressive among the younger generations. TL was not associated with earlier age at onset or more severe disease in members of successive generations affected by IBD. NOD2 gene mutations were present in the Crohn's disease patients of one family. However, no gene variants were identified as potential candidates for inheritance.<br><br>CONCLUSION: Telomere shortening appears unlikely to be involved in mechanisms of possible genetic anticipation in IBD. Further studies using a larger sample size are required to confirm or refute our findings.},
}
@article {pmid32952122,
year = {2020},
author = {Cao, L and Li, ZQ and Shi, YY and Liu, Y},
title = {Telomere length and type 2 diabetes: Mendelian randomization study and polygenic risk score analysis.},
journal = {Yi chuan = Hereditas},
volume = {42},
number = {9},
pages = {882-888},
doi = {10.16288/j.yczz.20-077},
pmid = {32952122},
issn = {0253-9772},
mesh = {*Diabetes Mellitus, Type 2 ; *Genome-Wide Association Study ; Humans ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; Telomere ; },
abstract = {Recent epidemiological studies suggest an association between shorter telomere length and higher risk for type 2 diabetes (T2D). However, results from observational studies are susceptible to confounding and reverse causation, and it is not clear whether there is a causal association between telomere length and T2D. Using Mendelian randomization (MR) and polygenic risk score (PRS) approaches, we had evaluated the causal effect of telomere length on T2D in the Chinese Han population. Using 8 telomere-length associated genetic variants as instrumental variables, an analysis of genetically predicted telomere length and T2D risk was performed in the MR study based on data from a T2D genome-wide association study (GWAS) in 2632 individuals (1318 cases and 1314 controls). We also applied a PRS approach to investigate the causal relationship using Chinese GWAS data. The inverse-variance weighted, MR-Egger regression, simple median, and weighted median methods yielded no evidence of association between genetically predicted longer telomere length and risk of T2D (OR = 0.78, 95% CI: 0.36 ~ 1.68, P = 0.522; OR = 0.23, 95% CI: 0.01 ~ 7.64, P = 0.412; OR = 0.60, 95% CI: 0.28 ~ 1.28, P = 0.185; OR = 0.64, 95% CI: 0.31 ~ 1.33,P = 0.233; respectively). Further, PRS analysis did not produce consistent genetic overlap between telomere length and T2D. Accordingly, this study found no evidence supporting a causal association between telomere length and T2D. Further studies with larger cohorts could yield more reliable results and conclusions.},
}
@article {pmid32950787,
year = {2020},
author = {Wang, T and Tu, Y and Zhang, G and Gong, S and Wang, K and Zhang, Y and Meng, Y and Wang, T and Li, A and Christiani, DC and Au, W and Zhu, Y and Xia, ZL},
title = {Development of a benchmark dose for lead-exposure based on its induction of micronuclei, telomere length changes and hematological toxicity.},
journal = {Environment international},
volume = {145},
number = {},
pages = {106129},
doi = {10.1016/j.envint.2020.106129},
pmid = {32950787},
issn = {1873-6750},
mesh = {*Benchmarking ; China ; Female ; Humans ; *Lead/toxicity ; Male ; Risk Assessment ; Telomere ; },
abstract = {BACKGROUND: Excessive lead exposure is associated with adverse health effects. However, there is a lack of systematic investigation using large populations to ascertain acceptable exposure limits.<br><br>OBJECTIVES: Our study was aimed to identify human exposure-response relationships between lead exposure and health-related outcomes, and to determine a benchmark dose (BMD).<br><br>METHODS: A total of 1896 participants from a lead-acid battery plant were recruited. Blood lead levels (BLLs) were detected for all participants. Hematological parameters (n&#xa0;=&#xa0;1896), micronuclei (MN) frequencies (n&#xa0;=&#xa0;934), and relative telomere length (rTL) (n&#xa0;=&#xa0;757) were also determined. Multivariate linear/Poisson regression analyses were performed to examine associations between BLLs and these health outcomes. Restricted cubic splines were used to identify dose-response relationships. Three BMD approaches were used to calculate BMD and its 95% lower confidence limit (BMDL).<br><br>RESULTS: Among all participants, BLLs show a right-skewed distribution (median, 185.40&#xa0;&#x3bc;g/L; 25th - 75th percentile, 104.63-271.70&#xa0;&#x3bc;g/L). There existed significant differences for red blood cell (RBC), hemoglobin (Hb), MN and rTL among different BLL dose groups. After adjusting for possible confounders, all indicators were significantly associated with BLLs. Restricted cubic splines show that there were linear dose-response relationships for RBC and Hb with BLLs, while non-linear for MN and rTL. Results from the three BMD approaches indicate that the dichotomous models were better than continuous models to calculate BMD and BMDL of BLLs. The conservative BMDL obtained from RBC data was 135 for total, 104 for male and 175&#xa0;&#x3bc;g/L for female. The corresponding BMDL obtained from Hb data was 105 for total, 116 for male and 70&#xa0;&#x3bc;g/L for female. As for MN data, the BMDL estimate was 66 for total, 69 for male and 64&#xa0;&#x3bc;g/L for female. Finally, the BMDL from rTL data was 35 for total, 32 for male and 43&#xa0;&#x3bc;g/L for female.<br><br>CONCLUSIONS: Our data show significant dose-response relationships between lead exposure and expressions of hematological toxicity and genotoxicity. The new BMDLs of 135 and 105&#xa0;&#x3bc;g/L based on RBC and Hb, and even more strict level of 66 and 35&#xa0;&#x3bc;g/L based on MN and rTL are lower than current exposure limits in China. Therefore, the four values can be considered as novel exposure limits. In addition, sex effect should be taken into account when setting occupational health standard. Considering that different biomarkers have different sensitivities, better understanding their relationships will certainly improve the current emphasis on precision health risk assessment.},
}
@article {pmid32948591,
year = {2020},
author = {Afrin, M and Gaurav, AK and Yang, X and Pan, X and Zhao, Y and Li, B},
title = {TbRAP1 has an unusual duplex DNA binding activity required for its telomere localization and VSG silencing.},
journal = {Science advances},
volume = {6},
number = {38},
pages = {},
pmid = {32948591},
issn = {2375-2548},
support = {R01 AI066095/AI/NIAID NIH HHS/United States ; S10 OD025252/OD/NIH HHS/United States ; },
mesh = {DNA/genetics ; Humans ; *Membrane Glycoproteins/genetics ; Protozoan Proteins/chemistry ; Telomere/genetics/metabolism ; *Variant Surface Glycoproteins, Trypanosoma/genetics/metabolism ; },
abstract = {Localization of Repressor Activator Protein 1 (RAP1) to the telomere is essential for its telomeric functions. RAP1 homologs either directly bind the duplex telomere DNA or interact with telomere-binding proteins. We find that Trypanosoma brucei RAP1 relies on a unique double-stranded DNA (dsDNA) binding activity to achieve this goal. T. brucei causes human sleeping sickness and regularly switches its major surface antigen, variant surface glycoprotein (VSG), to evade the host immune response. VSGs are monoallelically expressed from subtelomeres, and TbRAP1 is essential for VSG regulation. We identify dsDNA and single-stranded DNA binding activities in TbRAP1, which require positively charged 737RKRRR741 residues that overlap with TbRAP1's nuclear localization signal in the MybLike domain. Both DNA binding activities are electrostatics-based and sequence nonspecific. The dsDNA binding activity can be substantially diminished by phosphorylation of two 737RKRRR741-adjacent S residues and is essential for TbRAP1's telomere localization, VSG silencing, telomere integrity, and cell proliferation.},
}
@article {pmid32939537,
year = {2020},
author = {Cheng, WH},
title = {Placental Telomere Length: Linking Maternal Nutrition to Transgenerational Healthy Aging?.},
journal = {The Journal of nutrition},
volume = {150},
number = {10},
pages = {2619-2620},
doi = {10.1093/jn/nxaa277},
pmid = {32939537},
issn = {1541-6100},
mesh = {Female ; *Healthy Aging ; Humans ; Placenta/*physiology ; Pregnancy ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; },
}
@article {pmid32937369,
year = {2020},
author = {Luo, Y and Viswanathan, R and Hande, MP and Loh, AHP and Cheow, LF},
title = {Massively parallel single-molecule telomere length measurement with digital real-time PCR.},
journal = {Science advances},
volume = {6},
number = {34},
pages = {},
pmid = {32937369},
issn = {2375-2548},
abstract = {Telomere length is a promising biomarker for age-associated diseases and cancer, but there are still substantial challenges to routine telomere analysis in clinics because of the lack of a simple and rapid yet scalable method for measurement. We developed the single telomere absolute-length rapid (STAR) assay, a novel high-throughput digital real-time PCR approach for rapidly measuring the absolute lengths and quantities of individual telomere molecules. We show that this technique provides the accuracy and sensitivity to uncover associations between telomere length distribution and telomere maintenance mechanisms in cancer cell lines and primary tumors. The results indicate that the STAR assay is a powerful tool to enable the use of telomere length distribution as a biomarker in disease and population-wide studies.},
}
@article {pmid32937289,
year = {2020},
author = {Pańczyszyn, A and Boniewska-Bernacka, E and Goc, A},
title = {The role of telomeres and telomerase in the senescence of postmitotic cells.},
journal = {DNA repair},
volume = {95},
number = {},
pages = {102956},
doi = {10.1016/j.dnarep.2020.102956},
pmid = {32937289},
issn = {1568-7856},
mesh = {Animals ; Cellular Senescence/*genetics ; Humans ; *Mitosis ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {Senescence is a process related to the stopping of divisions and changes leading the cell to the SASP phenotype. Permanent senescence of many SASP cells contributes to faster aging of the body and development of age-related diseases due to the release of pro-inflammatory factors. Both mitotically active and non-dividing cells can undergo senescence as a result of activation of different molecular pathways. Telomeres, referred to as the molecular clock, direct the dividing cell into the aging pathway when reaching a critical length. In turn, the senescence of postmitotic cells depends not on the length of telomeres, but their functionality. Dysfunctional telomeres are responsible for triggering the signaling of DNA damage response (DDR). Telomerase subunits in post-mitotic cells translocate between the nucleus, cytoplasm and mitochondria, participating in the regulation of their activity. Among other things, they contribute to the reduction of reactive oxygen species generation, which leads to telomere dysfunction and, consequently, senescence. Some proteins of the shelterin complex also play a protective role by inhibiting senescence-initiating kinases and limiting ROS production by mitochondria.},
}
@article {pmid32937184,
year = {2021},
author = {AlDehaini, DMB and Al-Bustan, SA and Malalla, ZHA and Ali, ME and Sater, M and Giha, HA},
title = {The influence of TERC, TERT and ACYP2 genes polymorphisms on plasma telomerase concentration, telomeres length and T2DM.},
journal = {Gene},
volume = {766},
number = {},
pages = {145127},
doi = {10.1016/j.gene.2020.145127},
pmid = {32937184},
issn = {1879-0038},
mesh = {Acid Anhydride Hydrolases/*genetics ; Adult ; Aged ; Aged, 80 and over ; Alleles ; Diabetes Mellitus, Type 2/*genetics ; Female ; Genetic Predisposition to Disease/genetics ; Genotype ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/*genetics ; RNA/*genetics ; Telomerase/blood/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Telomeres are duplex tandem repeats of DNA sequence 5'-TTAGGG-3' at chromosomal ends synthesized by telomerase enzyme (TE). Telomeres length (TL) shortening is associated with age and age-related disorders. Recently, we demonstrated marked leukocytes TL (LTL) shortening in T2DM. To set the relationship between the TE, LTL and T2DM, we analyzed samples from 212 Kuwaiti subjects, 112 patients withT2DM and 100 non-diabetic subjects. The plasma TE and fasting insulin were measured by ELISA, the LTL was estimated by qPCR and three SNPs of genes related to TL; TERC rs12696304 (C/G), TERT rs2736100 (C/A) and ACYP2 rs6713088 (C/G) were genotyped by rtPCR. Results revealed comparable TE levels and alleles/genotypes between the cases and controls with no influence of either on the LTL. Interestingly, although the plasma concentration of the TE was generally low, it was significantly influenced by the TERT and ACYP2 but not TERC polymorphisms. The CC genotype carriers of rs2736100 (C/A) had significantly higher plasma TE levels compared to CA and AA carriers, p 0.009 and p 0.047, respectively, and the A-allele was associated with low TE, p 0.018. Similarly, significantly higher TE levels were detected in CC carriers of ACYP2 rs6713088 (C/G) compared with GC carriers, p 0.002, and the G-allele was associated with low TE, p 0.009. Finally, the TERT and ACYP2 polymorphisms had an influence on blood glucose levels. In conclusion, the telomeres shortening in T2DM was not due to TE deficiency or gene polymorphisms, while the TE levels were significantly associated with the TERT and ACYP2 but not TERC polymorphisms.},
}
@article {pmid32935380,
year = {2020},
author = {Sun, C and Wang, K and Stock, AJ and Gong, Y and Demarest, TG and Yang, B and Giri, N and Harrington, L and Alter, BP and Savage, SA and Bohr, VA and Liu, Y},
title = {Re-equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction.},
journal = {The EMBO journal},
volume = {39},
number = {21},
pages = {e103420},
pmid = {32935380},
issn = {1460-2075},
support = {//HHS | NIH | National Institute on Aging (NIA)/ ; //HHS | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (DCEG)/ ; },
mesh = {ADP-ribosyl Cyclase 1/genetics ; Animals ; Brain/pathology ; Cell Line ; Cellular Senescence ; Dyskeratosis Congenita/*genetics/*metabolism/pathology ; Female ; Fibroblasts/*metabolism ; Homeostasis ; Humans ; Membrane Glycoproteins/genetics ; Mice ; Mice, Knockout ; Mitochondria/metabolism ; NAD/*metabolism ; Niacinamide/analogs &amp; derivatives/metabolism ; Phenotype ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Pyridinium Compounds/metabolism ; Telomerase/*genetics/metabolism ; Telomere/*metabolism ; },
abstract = {Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced poly(ADP-ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and CD38 inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere-driven diseases.},
}
@article {pmid32927181,
year = {2020},
author = {Carroll, JE and Mahrer, NE and Shalowitz, M and Ramey, S and Dunkel Schetter, C},
title = {Prenatal maternal stress prospectively relates to shorter child buccal cell telomere length.},
journal = {Psychoneuroendocrinology},
volume = {121},
number = {},
pages = {104841},
pmid = {32927181},
issn = {1873-3360},
support = {U01 NR008929/NR/NINR NIH HHS/United States ; U01 HD044207/HD/NICHD NIH HHS/United States ; R03 HD059584/HD/NICHD NIH HHS/United States ; R01 HD072021/HD/NICHD NIH HHS/United States ; U01 HD054791/HD/NICHD NIH HHS/United States ; U01 HD044245/HD/NICHD NIH HHS/United States ; U01 HD044253/HD/NICHD NIH HHS/United States ; R01 AG052655/AG/NIA NIH HHS/United States ; U01 HD044219/HD/NICHD NIH HHS/United States ; K01 AG044462/AG/NIA NIH HHS/United States ; U01 HD044226/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Cellular Senescence/physiology ; Cheek/physiology ; Child, Preschool ; Cohort Studies ; Female ; Humans ; Male ; Maternal Exposure ; Maternal-Fetal Exchange/physiology ; Mothers ; Pregnancy ; Pregnancy Trimester, Third/physiology ; Prenatal Exposure Delayed Effects/*physiopathology ; Stress, Psychological/metabolism/*physiopathology ; Telomere/genetics/*metabolism ; Telomere Shortening/physiology ; },
abstract = {Prenatal exposure to stress increases risk for suboptimal child and adult mental and physical health outcomes, hypothesized to occur via fetal exposure to maternal stress hormones that alter growth and development. One proposed pathway through which stress exposure in utero could affect the offspring is by accelerating cellular aging in the form of telomere attrition. We tested this hypothesis in a cohort of 111 mother-child dyads, where mothers were assessed over 6 or more years, beginning prior to conception, and later during pregnancy, postpartum, and when the children were 3-5 years old. Adjusting for child age and concurrent maternal stress, we found that higher maternal perceived stress in the 3rd trimesters of pregnancy was predictive of shorter child buccal telomere length (bTL) (β = -0.24, p < .05), while maternal preconception and postpartum maternal stress were not associated with bTL (all p's > 0.42). These findings suggest a vulnerable time period in pregnancy when maternal stress influences offspring telomere length, suggesting the early embedding of adult disease might occur through biological aging pathways.},
}
@article {pmid32922609,
year = {2020},
author = {Cheng, G and Dai, M and Xin, Q and Wang, L and Kong, F and Xu, D},
title = {Patients with benign prostatic hyperplasia show shorter leukocyte telomere length but no association with telomerase gene polymorphisms in Han Chinese males.},
journal = {International journal of clinical and experimental pathology},
volume = {13},
number = {8},
pages = {2123-2129},
pmid = {32922609},
issn = {1936-2625},
abstract = {OBJECTIVE: Benign prostatic hyperplasia (BPH) is an age-related disease, occurring in >70% of men of age >60. Because telomeres and telomerase play a key role in aging and age-related diseases, and certain telomerase gene single nucleotide polymorphisms (SNPs) are shown to be associated with the susceptibility to age-related diseases, we wanted to determine the relationship between BPH and leukocyte telomere length (LTL) and telomere length-related single nucleotide polymorphisms (SNPs) of the telomerase holoenzyme genes.<br><br>METHODS: Peripheral blood was collected from both BPH patients and age-matched healthy male controls and genomic DNA was extracted. rs2736100 and rs2736098 at the TERT and rs12696304 at the TERC locus were analysed using pre-designed TaqMan SNP genotyping assay kits. LTL was determined using qPCR.<br><br>RESULTS: Patients with BPH had significantly shorter LTL (1.231 &#xb1; 0.532 vs 0.899 &#xb1; 0.322, P < 0.001). The genotyping results show similar frequencies in rs2736100, rs2736098 and rs12696304 between healthy and BPH individuals.<br><br>CONCLUSIONS: Shorter telomeres but not telomerase SNPs at the TERT and TERC loci, are associated with BPH. Short telomeres may promote senescence of a fraction of prostatic epithelial cells, while senescent cells in turn facilitate epithelial and stromal cell proliferation by the senescence-associated secretory phenotype mechanism, thereby eventually leading to BPH development.},
}
@article {pmid32922179,
year = {2020},
author = {Cheng, G and Wang, L and Dai, M and Wei, F and Xu, D},
title = {Shorter Leukocyte Telomere Length coupled with lower expression of Telomerase Genes in patients with Essential Hypertension.},
journal = {International journal of medical sciences},
volume = {17},
number = {14},
pages = {2180-2186},
pmid = {32922179},
issn = {1449-1907},
mesh = {Aged ; Alleles ; Antihypertensive Agents/pharmacology/therapeutic use ; Blood Pressure Determination ; Case-Control Studies ; Enzyme Activators/pharmacology/therapeutic use ; Essential Hypertension/diagnosis/drug therapy/*genetics ; Female ; Gene Expression Profiling ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; RNA/*genetics/metabolism ; Telomerase/*genetics/metabolism ; Telomere/*metabolism ; Telomere Homeostasis/drug effects/*genetics ; },
abstract = {Background: The essential hypertension (EH) pathophysiology remains poorly understood. Many studies indicate that reduced leukocyte telomere length (LTL) is involved in the EH pathogenesis, however, the direct analysis of arterial telomere length (ATL) from EH patients and normotensive individuals did not show a difference. To address these discrepant observations between LTL and ATL, we performed comprehensive analyses of LTL, telomerase gene expression and their genetic variants in healthy normotensive controls and EH patients. Methods: Sex-matched 206 EH patients and equal numbers of healthy controls were recruited. LTL, and the expression of two key telomerase components, telomerase reverse transcriptase (TERT) and internal RNA template (TERC) were determined using qPCR. Genetic variants of rs2736100 at the TERT and rs12696304 at the TERC loci were determined using TaqMan genotyping kits. Results: LTL was significantly shorter in EH patients than in their normotensive controls (0.96 ± 0.52 vs 1.19 ± 0.58, P = 0.001). Moreover, TERT and TERC expression in patients' leukocytes were substantially lower compare to that in healthy controls (TERT, 0.98 ± 0.98 vs 1.76 ± 1.75, P = 0.003; TERC, 1.26 ± 1.62 vs 4.69 ± 3.61, P < 0.001). However, there were no differences in the genetic variants of rs2736100 and rs12696304 between patient and control groups. Conclusions: EH patients have significantly shorter LTL, which may result from defective TERT and TERC expression in leukocytes. Collectively, lower telomerase expression contributes to shorter LTL observed in EH patients, and telomerase activators may be considered for EH therapy.},
}
@article {pmid32920596,
year = {2020},
author = {Palmos, AB and Duarte, RRR and Smeeth, DM and Hedges, EC and Nixon, DF and Thuret, S and Powell, TR},
title = {Telomere length and human hippocampal neurogenesis.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {45},
number = {13},
pages = {2239-2247},
pmid = {32920596},
issn = {1740-634X},
support = {MR/N030087/1/MRC_/Medical Research Council/United Kingdom ; MR/N014863/1/MRC_/Medical Research Council/United Kingdom ; /DH_/Department of Health/United Kingdom ; MR/R006237/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; *Bipolar Disorder ; Cellular Senescence ; Hippocampus ; Humans ; Neurogenesis ; *Telomere ; Telomere Shortening ; },
abstract = {Short telomere length is a risk factor for age-related disease, but it is also associated with reduced hippocampal volumes, age-related cognitive decline and psychiatric disorder risk. The current study explored whether telomere shortening might have an influence on cognitive function and psychiatric disorder pathophysiology, via its hypothesised effects on adult hippocampal neurogenesis. We modelled telomere shortening in human hippocampal progenitor cells in vitro using a serial passaging protocol that mimics the end-replication problem. Serially passaged progenitors demonstrated shorter telomeres (P ≤ 0.05), and reduced rates of cell proliferation (P ≤ 0.001), with no changes in the ability of cells to differentiate into neurons or glia. RNA-sequencing and gene-set enrichment analyses revealed an effect of cell ageing on gene networks related to neurogenesis, telomere maintenance, cell senescence and cytokine production. Downregulated transcripts in our model showed a significant overlap with genes regulating cognitive function (P ≤ 1 × 10[-5]), and risk for schizophrenia (P ≤ 1 × 10[-10]) and bipolar disorder (P ≤ 0.005). Collectively, our results suggest that telomere shortening could represent a mechanism that moderates the proliferative capacity of human hippocampal progenitors, which may subsequently impact on human cognitive function and psychiatric disorder pathophysiology.},
}
@article {pmid32919410,
year = {2020},
author = {Squassina, A and Manchia, M and Pisanu, C and Ardau, R and Arzedi, C and Bocchetta, A and Caria, P and Cocco, C and Congiu, D and Cossu, E and Dettori, T and Frau, DV and Garzilli, M and Manca, E and Meloni, A and Montis, MA and Mura, A and Nieddu, M and Noli, B and Paribello, P and Pinna, F and Robledo, R and Severino, G and Sogos, V and Del Zompo, M and Ferri, GL and Chillotti, C and Vanni, R and Carpiniello, B},
title = {Telomere attrition and inflammatory load in severe psychiatric disorders and in response to psychotropic medications.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {45},
number = {13},
pages = {2229-2238},
pmid = {32919410},
issn = {1740-634X},
mesh = {*Bipolar Disorder/drug therapy ; Case-Control Studies ; *Depressive Disorder, Major/drug therapy ; Humans ; In Situ Hybridization, Fluorescence ; Telomere ; },
abstract = {Individuals with severe psychiatric disorders have a reduced life expectancy compared to the general population. At the biological level, patients with these disorders present features that suggest the involvement of accelerated aging, such as increased circulating inflammatory markers and shorter telomere length (TL). To date, the role of the interplay between inflammation and telomere dynamics in the pathophysiology of severe psychiatric disorders has been scarcely investigated. In this study we measured T-lymphocytes TL with quantitative fluorescent in situ hybridization (Q-FISH) and plasma levels of inflammatory markers in a cohort comprised of 40 patients with bipolar disorder (BD), 41 with schizophrenia (SZ), 37 with major depressive disorder (MDD), and 36 non-psychiatric controls (NPC). TL was shorter in SZ and in MDD compared to NPC, while it was longer in BD (model F6, 137 = 20.128, p = 8.73 × 10[-17], effect of diagnosis, F3 = 31.870; p = 1.08 × 10[-15]). There was no effect of the different classes of psychotropic medications, while duration of treatment with mood stabilizers was associated with longer TL (Partial correlation controlled for age and BMI: correlation coefficient = 0.451; p = 0.001). Levels of high-sensitivity C-Reactive Protein (hsCRP) were higher in SZ compared to NPC (adjusted p = 0.027), and inversely correlated with TL in the whole sample (r = -0.180; p = 0.042). Compared to NPC, patients with treatment resistant (TR) SZ had shorter TL (p = 0.001), while patients with TR MDD had higher levels of tumor necrosis factor-α (TNFα) compared to NPC (p = 0.028) and to non-TR (p = 0.039). Comorbidity with cardio-metabolic disorders did not influence the observed differences in TL, hsCRP, and TNFα among the diagnostic groups. Our study suggests that patients with severe psychiatric disorders present reduced TL and increased inflammation.},
}
@article {pmid32919107,
year = {2020},
author = {Yu, J and Kanchi, MM and Rawtaer, I and Feng, L and Kumar, AP and Kua, EH and Mahendran, R},
title = {The functional and structural connectomes of telomere length and their association with cognition in mild cognitive impairment.},
journal = {Cortex; a journal devoted to the study of the nervous system and behavior},
volume = {132},
number = {},
pages = {29-40},
doi = {10.1016/j.cortex.2020.08.006},
pmid = {32919107},
issn = {1973-8102},
mesh = {Aged ; Brain/diagnostic imaging ; Cognition ; *Cognitive Dysfunction/diagnostic imaging/genetics ; *Connectome ; Humans ; Magnetic Resonance Imaging ; Telomere/genetics ; },
abstract = {Previous findings on the relationship between telomere length and cognition have inconclusive, despite the relatively consistent telomere-shortening associated atrophy in the subcortical regions. Perhaps, there could be other more important telomere-associated factors in the brain, such as functional connectivity (FC) and structural connectivity (SC) that modulate cognition. The current study examined the relationship between telomere length, connectivity, and cognition. Telomere length measurements, neurocognitive scores, diffusion tensor and resting-state functional magnetic resonance imaging scans were collected from 82 older adults with mild cognitive impairment. SC and FC matrices were derived from these scans and, in various combinations, entered into connectome-based predictive models to predict telomere length. The telomere-associated features were then used to predict memory and executive functions. Leave-one-out cross-validation was performed. Predictive accuracy was assessed via the correlation between predicted and observed scores (rpredicted-observed). Correlation analyses were carried out between cognition and telomere length. Telomere length was significantly and negatively correlated with executive functions (EF), after controlling for demographical confounds. Telomere length was best predicted by negative SC and positive FC features (rpredicted-observed = .57; p < .001). The telomere-associated negative SC features significantly predicted EF scores (rpredicted-observed = -.26; p = .015). Telomere-shortening was associated with better EF and alterations in both FC and SC. This enhanced EF can be partly attributed to the telomere-associated changes in SC. Given that telomere is known to be a nonspecific marker of health, our findings illustrated a potential clinical use of telomere length to predict individualized health-related information from FC and SC features.},
}
@article {pmid32916703,
year = {2020},
author = {Miglani, M and Rain, M and Pasha, Q and Raj, VS and Thinlas, T and Mohammad, G and Gupta, A and Pandey, RP and Vibhuti, A},
title = {Shorter telomere length, higher telomerase activity in association with tankyrase gene polymorphism contribute to high-altitude pulmonary edema.},
journal = {Human molecular genetics},
volume = {29},
number = {18},
pages = {3094-3106},
doi = {10.1093/hmg/ddaa205},
pmid = {32916703},
issn = {1460-2083},
mesh = {Adult ; Aged ; Alleles ; Altitude ; Altitude Sickness/*genetics/physiopathology ; DNA Damage/genetics ; DNA Repair/genetics ; Female ; Genetic Association Studies ; *Genetic Predisposition to Disease ; Genotype ; Healthy Volunteers ; Humans ; Hypertension, Pulmonary/*genetics/physiopathology ; Hypoxia/genetics/physiopathology ; Male ; Middle Aged ; Polymorphism, Restriction Fragment Length/genetics ; Tankyrases/*genetics ; Telomerase/*genetics ; Telomere/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {High-altitude pulmonary edema (HAPE) is a noncardiogenic form of pulmonary edema, which is induced upon exposure to hypobaric hypoxia at high altitude (HA). Hypobaric hypoxia generates reactive oxygen species that may damage telomeres and disturb normal physiological processes. Telomere complex comprises of multiple proteins, of which, tankyrase (TNKS) is actively involved in DNA damage repairs. We hence investigated the association of TNKS and telomeres with HAPE to delineate their potential role at HA. The study was performed in three groups, High-altitude pulmonary edema patients (HAPE-p, n = 200), HAPE-resistant sojourners (HAPE-r, n = 200) and highland permanent healthy residents (HLs, n = 200). Variants of TNKS were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Plasma TNKS level was estimated using enzyme-linked immunosorbent assay, expression of TNKS and relative telomere length were assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and telomerase activity was assessed by the telomere repeat amplification protocol assay. TNKS poly-ADP ribosylates the telomere-repeat factor (TRF), which is a negative regulator of telomere length. Consequently, TRF expression was also measured by RT-qPCR. The TNKS heterozygotes rs7015700GA were prevalent in HLs compared to the HAPE-p and HAPE-r. The plasma TNKS was significantly decreased in HAPE-p than HAPE-r (P = 0.006). TNKS was upregulated 9.27 folds in HAPE-p (P = 1.01E-06) and downregulated in HLs by 3.3 folds (P = 0.02). The telomere length was shorter in HAPE-p compared to HAPE-r (P = 0.03) and HLs (P = 4.25E-4). The telomerase activity was significantly higher in HAPE-p compared to both HAPE-r (P = 0.01) and HLs (P = 0.001). HAPE-p had the lowest TNKS levels (0.186 ± 0.031 ng/μl) and the highest telomerase activity (0.0268 amoles/μl). The findings of the study indicate the association of TNKS and telomeres with HA adaptation/maladaptation.},
}
@article {pmid32913074,
year = {2020},
author = {Demanelis, K and Jasmine, F and Chen, LS and Chernoff, M and Tong, L and Delgado, D and Zhang, C and Shinkle, J and Sabarinathan, M and Lin, H and Ramirez, E and Oliva, M and Kim-Hellmuth, S and Stranger, BE and Lai, TP and Aviv, A and Ardlie, KG and Aguet, F and Ahsan, H and , and Doherty, JA and Kibriya, MG and Pierce, BL},
title = {Determinants of telomere length across human tissues.},
journal = {Science (New York, N.Y.)},
volume = {369},
number = {6509},
pages = {},
pmid = {32913074},
issn = {1095-9203},
support = {R01 CA229618/CA/NCI NIH HHS/United States ; U01 MH104393/MH/NIMH NIH HHS/United States ; R01 MH109905/MH/NIMH NIH HHS/United States ; R01 MH106842/MH/NIMH NIH HHS/United States ; T32 GM007281/GM/NIGMS NIH HHS/United States ; K99 HG009916/HG/NHGRI NIH HHS/United States ; R01 HL142028/HL/NHLBI NIH HHS/United States ; R01 CA107431/CA/NCI NIH HHS/United States ; R01 MH090951/MH/NIMH NIH HHS/United States ; UL1 TR002550/TR/NCATS NIH HHS/United States ; U01 AG066529/AG/NIA NIH HHS/United States ; R01 HL134840/HL/NHLBI NIH HHS/United States ; R01 HG010480/HG/NHGRI NIH HHS/United States ; R01 DA006227/DA/NIDA NIH HHS/United States ; U41 HG002371/HG/NHGRI NIH HHS/United States ; R01 HG008150/HG/NHGRI NIH HHS/United States ; R01 MH107666/MH/NIMH NIH HHS/United States ; T32 AG051146/AG/NIA NIH HHS/United States ; UM1 HG008901/HG/NHGRI NIH HHS/United States ; U01 HG007593/HG/NHGRI NIH HHS/United States ; R01 GM124486/GM/NIGMS NIH HHS/United States ; R01 MH090936/MH/NIMH NIH HHS/United States ; U01 HG007598/HG/NHGRI NIH HHS/United States ; R25 GM109439/GM/NIGMS NIH HHS/United States ; R01 ES020506/ES/NIEHS NIH HHS/United States ; T32 DK110919/DK/NIDDK NIH HHS/United States ; R01 HG002585/HG/NHGRI NIH HHS/United States ; U01 HG007601/HG/NHGRI NIH HHS/United States ; R01 HG006855/HG/NHGRI NIH HHS/United States ; T32 HG000044/HG/NHGRI NIH HHS/United States ; P30 ES027792/ES/NIEHS NIH HHS/United States ; F32 HG009987/HG/NHGRI NIH HHS/United States ; R01 HG010067/HG/NHGRI NIH HHS/United States ; R01 MH090941/MH/NIMH NIH HHS/United States ; R01 GM122924/GM/NIGMS NIH HHS/United States ; U41 HG009494/HG/NHGRI NIH HHS/United States ; R01 MH101822/MH/NIMH NIH HHS/United States ; R35 ES028379/ES/NIEHS NIH HHS/United States ; HHSN261200800001C/RC/CCR NIH HHS/United States ; R01 MH090937/MH/NIMH NIH HHS/United States ; HHSN268201000029C/HL/NHLBI NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; R01 MH101814/MH/NIMH NIH HHS/United States ; R35 HG010718/HG/NHGRI NIH HHS/United States ; P30 DK020595/DK/NIDDK NIH HHS/United States ; R01 GM108711/GM/NIGMS NIH HHS/United States ; T32 AG000243/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*genetics ; Genetic Markers ; Genetic Variation ; Humans ; Organ Specificity ; Telomere/*physiology ; Telomere Homeostasis/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in nonblood, disease-relevant tissue types. Here, we characterize variability in TLs from 6391 tissue samples, representing >20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation affects TL in multiple tissue types and that TL may mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health.},
}
@article {pmid32911996,
year = {2021},
author = {Verner, G and Epel, E and Lahti-Pulkkinen, M and Kajantie, E and Buss, C and Lin, J and Blackburn, E and Räikkönen, K and Wadhwa, PD and Entringer, S},
title = {Maternal Psychological Resilience During Pregnancy and Newborn Telomere Length: A Prospective Study.},
journal = {The American journal of psychiatry},
volume = {178},
number = {2},
pages = {183-192},
pmid = {32911996},
issn = {1535-7228},
support = {P30 DK063720/DK/NIDDK NIH HHS/United States ; P30 DK098722/DK/NIDDK NIH HHS/United States ; R01 AG050455/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Cohort Studies ; Female ; Fetal Blood ; Humans ; Infant, Newborn ; Maternal Health ; Pregnancy ; Pregnancy Complications/*psychology ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; *Resilience, Psychological ; *Telomere Homeostasis ; },
abstract = {OBJECTIVE: In the context of the importance of elucidating the determinants of the initial, newborn setting of telomere length (TL), it is increasingly evident that maternal stress and stress-related processes during pregnancy play a major role. Although psychological resilience may function as a buffer, research in this area has not yet examined its potential role vis-à-vis that of stress. The authors examined the relationship between maternal psychological resilience during pregnancy and newborn TL.<br><br>METHODS: In a sample of 656 mother-child dyads from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction cohort, multiple serial assessments were conducted over the course of pregnancy to quantify maternal stress, negative and positive emotional responses to pregnancy events, positive affect, and perceived social support. Principal component analysis identified two latent factors: stress and positivity. A measure of resilience was computed by regressing the positivity factor on the stress factor, in order to quantify positivity after accounting for stress. TL was measured using quantitative polymerase chain reaction in leukocytes extracted from cord blood shortly after birth. Linear regression was used to predict newborn TL from maternal resilience during pregnancy, adjusting for other potential determinants.<br><br>RESULTS: Maternal stress significantly predicted shorter newborn TL (&#x3b2;=-0.079), and positivity significantly predicted longer TL (&#x3b2;=0.135). Maternal resilience (positivity accounting for stress) was significantly and positively associated with newborn TL (&#x3b2;=0.114, 95% CI=0.035, 0.189), with each standard deviation increase in resilience predicting 12% longer newborn TL.<br><br>CONCLUSIONS: The results indicate that maternal psychological resilience may exert a salubrious effect on offspring telomere biology and highlight the importance of enhancing maternal mental health and well-being during pregnancy.},
}
@article {pmid32907975,
year = {2020},
author = {Khanal, S and Tang, Q and Cao, D and Zhao, J and Nguyen, LN and Oyedeji, OS and Dang, X and Nguyen, LNT and Schank, M and Thakuri, BKC and Ogbu, C and Morrison, ZD and Wu, XY and Zhang, Z and He, Q and El Gazzar, M and Li, Z and Ning, S and Wang, L and Moorman, JP and Yao, ZQ},
title = {Telomere and ATM Dynamics in CD4 T-Cell Depletion in Active and Virus-Suppressed HIV Infections.},
journal = {Journal of virology},
volume = {94},
number = {22},
pages = {},
pmid = {32907975},
issn = {1098-5514},
support = {I01 BX002670/BX/BLRD VA/United States ; I01 BX004281/BX/BLRD VA/United States ; R01 AI114748/AI/NIAID NIH HHS/United States ; R21 AI138598/AI/NIAID NIH HHS/United States ; },
mesh = {Apoptosis ; Ataxia Telangiectasia/*genetics ; Ataxia Telangiectasia Mutated Proteins/genetics/metabolism ; CD4-Positive T-Lymphocytes/*metabolism ; Cell Line ; Cellular Senescence ; DNA Damage ; HEK293 Cells ; HIV Infections/*immunology ; HIV-1/genetics ; Humans ; Telomere/*metabolism ; Virus Replication ; },
abstract = {CD4 T-cell depletion is a hallmark of HIV/AIDS, but the underlying mechanism is still unclear. We have recently shown that ataxia-telangiectasia-mutated (ATM) deficiency in CD4 T cells accelerates DNA damage, telomere erosion, and cell apoptosis in HIV-infected individuals on antiretroviral therapy (ART). Whether these alterations in ART-treated HIV subjects occur in vitro in HIV-infected CD4 T cells remains unknown. In this study, we employed a cellular model of HIV infection to characterize the mechanisms underlying CD4 T-cell destruction by analyzing the telomeric DNA damage response (DDR) and cellular apoptosis in highly permissive SupT1 cells, followed by the validation of our observations in primary CD4 T cells with active or drug-suppressed HIV infection. Specifically, we established an in vitro HIV T-cell culture system with viral replication and raltegravir (RAL; an integrase inhibitor) suppression, mimicking active and ART-controlled HIV infection in vivo We demonstrated that HIV-induced, telomeric DDR plays a pivotal role in triggering telomere erosion, premature T-cell aging, and CD4 T-cell apoptosis or depletion via dysregulation of the PI3K/ATM pathways. This in vitro model provides a new tool to investigate HIV pathogenesis, and our results shed new light on the molecular mechanisms of telomeric DDR and CD4 T-cell homeostasis during HIV infection.IMPORTANCE The hallmark of HIV infection is a gradual depletion of CD4 T cells, with a progressive decline of host immunity. How CD4 T cells are depleted in individuals with active and virus-suppressed HIV infection remains unclear. In this study, we employed a cellular model of HIV infection to characterize the mechanisms underlying CD4 T-cell destruction by analyzing the chromosome end (telomere) DNA damage response (DDR) and cellular apoptosis in a T-cell line (highly permissive SupT1 cells), as well as in primary CD4 T cells with active or drug-suppressed HIV infection. We demonstrated that HIV-induced telomeric DDR plays a critical role in inducing telomere loss, premature cell aging, and CD4 T-cell apoptosis or depletion via dysregulation of the PI3K/ATM pathways. This study sheds new light on the molecular mechanisms of telomeric DDR and its role in CD4 T-cell homeostasis during HIV infection.},
}
@article {pmid32906638,
year = {2020},
author = {Muresanu, C and Somasundaram, SG and Vissarionov, SV and Torres Solis, LF and Solís Herrera, A and Kirkland, CE and Aliev, G},
title = {Updated Understanding of Cancer as a Metabolic and Telomere-Driven Disease, and Proposal for Complex Personalized Treatment, a Hypothesis.},
journal = {International journal of molecular sciences},
volume = {21},
number = {18},
pages = {},
pmid = {32906638},
issn = {1422-0067},
support = {5-100//I.M. Sechenov First Moscow State Medical University/ ; Research Center//GALLY International Research Institute/ ; },
mesh = {Cell Division ; Cellular Senescence/genetics ; DNA Damage/genetics/physiology ; DNA, Mitochondrial/genetics ; Holistic Health ; Humans ; Mitochondria/metabolism ; Neoplasms/genetics/*metabolism/therapy ; Oxidative Stress ; Precision Medicine/methods ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; Telomere Homeostasis/genetics/*physiology ; },
abstract = {In this review, we propose a holistic approach to understanding cancer as a metabolic disease. Our search for relevant studies in medical databases concludes that cancer cells do not evolve directly from normal healthy cells. We hypothesize that aberrant DNA damage accumulates over time-avoiding the natural DNA controls that otherwise repair or replace the rapidly replicating cells. DNA damage starts to accumulate in non-replicating cells, leading to senescence and aging. DNA damage is linked with genetic and epigenetic factors, but the development of cancer is favored by telomerase activity. Evidence indicates that telomere length is affected by chronic inflammations, alterations of mitochondrial DNA, and various environmental factors. Emotional stress also influences telomere length. Chronic inflammation can cause oxidative DNA damage. Oxidative stress, in turn, can trigger mitochondrial changes, which ultimately alter nuclear gene expression. This vicious cycle has led several scientists to view cancer as a metabolic disease. We have proposed complex personalized treatments that seek to correct multiple changes simultaneously using a psychological approach to reduce chronic stress, immune checkpoint therapy with reduced doses of chemo and radiotherapy, minimal surgical intervention, if any, and mitochondrial metabolic reprogramming protocols supplemented by intermittent fasting and personalized dietary plans without interfering with the other therapies.},
}
@article {pmid32903138,
year = {2020},
author = {Boyle, JM and Hennick, KM and Regalado, SG and Vogan, JM and Zhang, X and Collins, K and Hockemeyer, D},
title = {Telomere length set point regulation in human pluripotent stem cells critically depends on the shelterin protein TPP1.},
journal = {Molecular biology of the cell},
volume = {31},
number = {23},
pages = {2583-2596},
pmid = {32903138},
issn = {1939-4586},
support = {R01 CA196884/CA/NCI NIH HHS/United States ; R01 HL079585/HL/NHLBI NIH HHS/United States ; R35 GM130315/GM/NIGMS NIH HHS/United States ; },
mesh = {HeLa Cells ; Humans ; Mutation ; Pluripotent Stem Cells/*metabolism ; Protein Isoforms ; Shelterin Complex ; Telomerase/metabolism ; Telomere/genetics/metabolism ; Telomere Homeostasis/genetics/*physiology ; Telomere-Binding Proteins/*metabolism/physiology ; },
abstract = {Telomere maintenance is essential for the long-term proliferation of human pluripotent stem cells, while their telomere length set point determines the proliferative capacity of their differentiated progeny. The shelterin protein TPP1 is required for telomere stability and elongation, but its role in establishing a telomere length set point remains elusive. Here, we characterize the contribution of the shorter isoform of TPP1 (TPP1S) and the amino acid L104 outside the TEL patch, TPP1's telomerase interaction domain, to telomere length control. We demonstrate that cells deficient for TPP1S (TPP1S knockout [KO]), as well as the complete TPP1 KO cell lines, undergo telomere shortening. However, TPP1S KO cells are able to stabilize short telomeres, while TPP1 KO cells die. We compare these phenotypes with those of TPP1[L104A/L104A] mutant cells, which have short and stable telomeres similar to the TPP1S KO. In contrast to TPP1S KO cells, TPP1[L104A/L104A] cells respond to increased telomerase levels and maintain protected telomeres. However, TPP1[L104A/L104A] shows altered sensitivity to expression changes of shelterin proteins suggesting the mutation causes a defect in telomere length feedback regulation. Together this highlights TPP1[L104A/L104A] as the first shelterin mutant engineered at the endogenous locus of human stem cells with an altered telomere length set point.},
}
@article {pmid32900359,
year = {2020},
author = {Lee, KH and Kimmel, M},
title = {Analysis of two mechanisms of telomere maintenance based on the theory of g-Networks and stochastic automata networks.},
journal = {BMC genomics},
volume = {21},
number = {Suppl 9},
pages = {587},
pmid = {32900359},
issn = {1471-2164},
mesh = {Cell Division ; Cellular Senescence ; Homeostasis ; *Telomerase/genetics ; *Telomere/genetics ; Telomere Homeostasis/genetics ; },
abstract = {*: Background Telomeres, which are composed of repetitive nucleotide sequences at the end of chromosomes, behave as a division clock that measures replicative senescence. Under the normal physiological condition, telomeres shorten with each cell division, and cells use the telomere lengths to sense the number of divisions. Replicative senescence has been shown to occur at approximately 50-70 cell divisions, which is termed the Hayflick's limit. However, in cancer cells telomere lengths are stabilized, thereby allowing continual cell replication by two known mechanisms: activation of telomerase and Alternative Lengthening of Telomeres (ALT). The connections between the two mechanisms are complicated and still poorly understood. *: Results In this research, we propose that two different approaches, G-Networks and Stochastic Automata Networks, which are stochastic models motivated by queueing theory, are useful to identify a set of genes that play an important role in the state of interest and to infer their previously unknown correlation by obtaining both stationary and joint transient distributions of the given system. Our analysis using G-Network detects five statistically significant genes (CEBPA, FOXM1, E2F1, c-MYC, hTERT) with either mechanism, contrasted to normal cells. A new algorithm is introduced to show how the correlation between two genes of interest varies in the transient state according not only to each mechanism but also to each cell condition. *: Conclusions This study expands our existing knowledge of genes associated with mechanisms of telomere maintenance and provides a platform to understand similarities and differences between telomerase and ALT in terms of the correlation between two genes in the system. This is particularly important because telomere dynamics plays a major role in many physiological and disease processes, including hematopoiesis.},
}
@article {pmid32899298,
year = {2020},
author = {Bradfield, A and Button, L and Drury, J and Green, DC and Hill, CJ and Hapangama, DK},
title = {Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer.},
journal = {Methods and protocols},
volume = {3},
number = {3},
pages = {},
pmid = {32899298},
issn = {2409-9279},
support = {MR/P020941/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Endometrial cancer (EC) is the commonest gynaecological malignancy. Current prognostic markers are inadequate to accurately predict patient survival, necessitating novel prognostic markers, to improve treatment strategies. Telomerase has a unique role within the endometrium, whilst aberrant telomerase activity is a hallmark of many cancers. The aim of the current in silico study is to investigate the role of telomere and telomerase associated genes and proteins (TTAGPs) in EC to identify potential prognostic markers and therapeutic targets. Analysis of RNA-seq data from The Cancer Genome Atlas identified differentially expressed genes (DEGs) in EC (568 TTAGPs out of 3467) and ascertained DEGs associated with histological subtypes, higher grade endometrioid tumours and late stage EC. Functional analysis demonstrated that DEGs were predominantly involved in cell cycle regulation, while the survival analysis identified 69 DEGs associated with prognosis. The protein-protein interaction network constructed facilitated the identification of hub genes, enriched transcription factor binding sites and drugs that may target the network. Thus, our in silico methods distinguished many critical genes associated with telomere maintenance that were previously unknown to contribute to EC carcinogenesis and prognosis, including NOP56, WFS1, ANAPC4 and TUBB4A. Probing the prognostic and therapeutic utility of these novel TTAGP markers will form an exciting basis for future research.},
}
@article {pmid32894749,
year = {2021},
author = {Dhillon, VS and Deo, P and Chua, A and Thomas, P and Fenech, M},
title = {Telomere Length in Healthy Adults Is Positively Associated With Polyunsaturated Fatty Acids, Including Arachidonic Acid, and Negatively With Saturated Fatty Acids.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {76},
number = {1},
pages = {3-6},
doi = {10.1093/gerona/glaa213},
pmid = {32894749},
issn = {1758-535X},
mesh = {Arachidonic Acid/*metabolism ; Cohort Studies ; Erythrocytes/*metabolism ; Fatty Acids/*metabolism ; Fatty Acids, Unsaturated/*metabolism ; Female ; Humans ; *Lymphocytes/ultrastructure ; Male ; Middle Aged ; Telomere/*ultrastructure ; },
abstract = {Lymphocyte telomere length (LTL) is a biomarker of aging that may be modified by dietary factors including fat. Red blood cell fatty acid status is a well-validated indicator of long-term dietary intake of fat from various sources. Recent findings from epidemiological studies of LTL in relation to fatty acids in red blood cells are not conclusive. The present study was carried out to investigate if red blood cell fatty acid status in 174 healthy older South Australians is associated with LTL. Lymphocyte telomere length was measured by real-time qPCR and fatty acid content in red blood cells was measured by gas chromatography. Our results indicate that the majority of saturated fatty acids and monounsaturated fatty acids are negatively associated with LTL, whereas polyunsaturated fatty acids are positively associated with LTL. Multiple regression analysis revealed that arachidonic acid (C20:4n-6) is significantly, independently, positively correlated with LTL (β = 0.262; p = .000). The significant association of fatty acids, particularly C20:4n-6, with telomere length warrants further research.},
}
@article {pmid32890403,
year = {2020},
author = {Leal, AZ and Schwebs, M and Briggs, E and Weisert, N and Reis, H and Lemgruber, L and Luko, K and Wilkes, J and Butter, F and McCulloch, R and Janzen, CJ},
title = {Genome maintenance functions of a putative Trypanosoma brucei translesion DNA polymerase include telomere association and a role in antigenic variation.},
journal = {Nucleic acids research},
volume = {48},
number = {17},
pages = {9660-9680},
pmid = {32890403},
issn = {1362-4962},
support = {104111/WT_/Wellcome Trust/United Kingdom ; G0401553/MRC_/Medical Research Council/United Kingdom ; },
mesh = {*Antigenic Variation ; Cell Line ; Cell Nucleus/enzymology/genetics ; Chromosome Segregation ; DNA Replication ; DNA-Directed DNA Polymerase/genetics/*metabolism ; Gene Expression Regulation ; Genome, Protozoan ; Humans ; Protozoan Proteins/genetics/metabolism ; RNA Interference ; Telomere/*genetics/metabolism ; Trypanosoma brucei brucei/*genetics/metabolism/pathogenicity ; Variant Surface Glycoproteins, Trypanosoma/genetics ; DNA Polymerase theta ; },
abstract = {Maintenance of genome integrity is critical to guarantee transfer of an intact genome from parent to offspring during cell division. DNA polymerases (Pols) provide roles in both replication of the genome and the repair of a wide range of lesions. Amongst replicative DNA Pols, translesion DNA Pols play a particular role: replication to bypass DNA damage. All cells express a range of translesion Pols, but little work has examined their function in parasites, including whether the enzymes might contribute to host-parasite interactions. Here, we describe a dual function of one putative translesion Pol in African trypanosomes, which we now name TbPolIE. Previously, we demonstrated that TbPolIE is associated with telomeric sequences and here we show that RNAi-mediated depletion of TbPolIE transcripts results in slowed growth, altered DNA content, changes in cell morphology, and increased sensitivity to DNA damaging agents. We also show that TbPolIE displays pronounced localization at the nuclear periphery, and that its depletion leads to chromosome segregation defects and increased levels of endogenous DNA damage. Finally, we demonstrate that TbPolIE depletion leads to deregulation of telomeric variant surface glycoprotein genes, linking the function of this putative translesion DNA polymerase to host immune evasion by antigenic variation.},
}
@article {pmid32887908,
year = {2020},
author = {Sonnenberg, ASM and Sedaghat-Telgerd, N and Lavrijssen, B and Ohm, RA and Hendrickx, PM and Scholtmeijer, K and Baars, JJP and van Peer, A},
title = {Telomere-to-telomere assembled and centromere annotated genomes of the two main subspecies of the button mushroom Agaricus bisporus reveal especially polymorphic chromosome ends.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {14653},
pmid = {32887908},
issn = {2045-2322},
mesh = {Agaricus/*genetics ; Base Sequence ; Centromere/*genetics ; *Chromosomes, Fungal ; Computational Biology/methods ; DNA Transposable Elements/genetics ; DNA, Fungal/genetics ; *Genes, Fungal ; Meiosis/genetics ; Molecular Sequence Annotation ; *Polymorphism, Single Nucleotide ; Telomere/*genetics ; },
abstract = {Agaricus bisporus, the most cultivated edible mushroom worldwide, is represented mainly by the subspecies var. bisporus and var. burnettii. var. bisporus has a secondarily homothallic life cycle with recombination restricted to chromosome ends, while var. burnettii is heterothallic with recombination seemingly equally distributed over the chromosomes. To better understand the relationship between genomic make-up and different lifestyles, we have de novo sequenced a burnettii homokaryon and synchronised gene annotations with updated versions of the published genomes of var. bisporus. The genomes were assembled into telomere-to-telomere chromosomes and a consistent set of gene predictions was generated. The genomes of both subspecies were largely co-linear, and especially the chromosome ends differed in gene model content between the two subspecies. A single large cluster of repeats was found on each chromosome at the same respective position in all strains, harbouring nearly 50% of all repeats and likely representing centromeres. Repeats were all heavily methylated. Finally, a mapping population of var. burnettii confirmed an even distribution of crossovers in meiosis, contrasting the recombination landscape of var. bisporus. The new findings using the exceptionally complete and well annotated genomes of this basidiomycete demonstrate the importance for unravelling genetic components underlying the different life cycles.},
}
@article {pmid32883756,
year = {2020},
author = {Compton, A and Liang, J and Chen, C and Lukyanchikova, V and Qi, Y and Potters, M and Settlage, R and Miller, D and Deschamps, S and Mao, C and Llaca, V and Sharakhov, IV and Tu, Z},
title = {The Beginning of the End: A Chromosomal Assembly of the New World Malaria Mosquito Ends with a Novel Telomere.},
journal = {G3 (Bethesda, Md.)},
volume = {10},
number = {10},
pages = {3811-3819},
pmid = {32883756},
issn = {2160-1836},
support = {R21 AI133571/AI/NIAID NIH HHS/United States ; R21 AI135298/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; *Anopheles/genetics ; Female ; High-Throughput Nucleotide Sequencing ; *Malaria/genetics ; Repetitive Sequences, Nucleic Acid ; Telomere/genetics ; },
abstract = {Chromosome level assemblies are accumulating in various taxonomic groups including mosquitoes. However, even in the few reference-quality mosquito assemblies, a significant portion of the heterochromatic regions including telomeres remain unresolved. Here we produce a de novo assembly of the New World malaria mosquito, Anopheles albimanus by integrating Oxford Nanopore sequencing, Illumina, Hi-C and optical mapping. This 172.6 Mbps female assembly, which we call AalbS3, is obtained by scaffolding polished large contigs (contig N50 = 13.7 Mbps) into three chromosomes. All chromosome arms end with telomeric repeats, which is the first in mosquito assemblies and represents a significant step toward the completion of a genome assembly. These telomeres consist of tandem repeats of a novel 30-32 bp Telomeric Repeat Unit (TRU) and are confirmed by analyzing the termini of long reads and through both chromosomal in situ hybridization and a Bal31 sensitivity assay. The AalbS3 assembly included previously uncharacterized centromeric and rDNA clusters and more than doubled the content of transposable elements and other repetitive sequences. This telomere-to-telomere assembly, although still containing gaps, represents a significant step toward resolving biologically important but previously hidden genomic components. The comparison of different scaffolding methods will also inform future efforts to obtain reference-quality genomes for other mosquito species.},
}
@article {pmid32883681,
year = {2020},
author = {Yang, Z and Takai, KK and Lovejoy, CA and de Lange, T},
title = {Break-induced replication promotes fragile telomere formation.},
journal = {Genes &amp; development},
volume = {34},
number = {19-20},
pages = {1392-1405},
pmid = {32883681},
issn = {1549-5477},
support = {R01 AG016642/AG/NIA NIH HHS/United States ; R56 AG016642/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; Cells, Cultured ; Chromosome Fragile Sites/*genetics ; *DNA Breaks, Double-Stranded ; DNA Repair ; *DNA Replication ; Endodeoxyribonucleases/genetics/metabolism ; Fibroblasts ; Humans ; Mice ; RecQ Helicases/*genetics/*metabolism ; Recombinases/genetics/metabolism ; Telomere/*pathology ; },
abstract = {TRF1 facilitates the replication of telomeric DNA in part by recruiting the BLM helicase, which can resolve G-quadruplexes on the lagging-strand template. Lagging-strand telomeres lacking TRF1 or BLM form fragile telomeres-structures that resemble common fragile sites (CFSs)-but how they are formed is not known. We report that analogous to CFSs, fragile telomeres in BLM-deficient cells involved double-strand break (DSB) formation, in this case by the SLX4/SLX1 nuclease. The DSBs were repaired by POLD3/POLD4-dependent break-induced replication (BIR), resulting in fragile telomeres containing conservatively replicated DNA. BIR also promoted fragile telomere formation in cells with FokI-induced telomeric DSBs and in alternative lengthening of telomeres (ALT) cells, which have spontaneous telomeric damage. BIR of telomeric DSBs competed with PARP1-, LIG3-, and XPF-dependent alternative nonhomologous end joining (alt-NHEJ), which did not generate fragile telomeres. Collectively, these findings indicate that fragile telomeres can arise from BIR-mediated repair of telomeric DSBs.},
}
@article {pmid32881625,
year = {2020},
author = {Hernando, B and Gil-Barrachina, M and Tomás-Bort, E and Martinez-Navarro, I and Collado-Boira, E and Hernando, C},
title = {The effect of long-term ultra-endurance exercise and SOD2 genotype on telomere shortening with age.},
journal = {Journal of applied physiology (Bethesda, Md. : 1985)},
volume = {129},
number = {4},
pages = {873-879},
doi = {10.1152/japplphysiol.00570.2020},
pmid = {32881625},
issn = {1522-1601},
mesh = {Aged ; Aging/genetics ; Female ; Genotype ; Humans ; Middle Aged ; Oxidative Stress/genetics ; *Superoxide Dismutase/genetics ; Telomere/genetics ; *Telomere Shortening ; },
abstract = {Telomere shortening, a well-known biomarker of aging, is a complex process influenced by several intrinsic and lifestyle factors. Although habitual exercise may promote telomere length maintenance, extreme endurance exercise has been also associated with increased oxidative stress-presumed to be the major cause of telomere shortening. Therefore, the pace of telomere shortening with age may also depend on antioxidant system efficiency, which is, in part, genetically determined. In this study, we aimed to evaluate the impact of ultra-endurance exercise and oxidative stress susceptibility (determined by the rs4880 polymorphism in the superoxide dismutase 2 (SOD2) gene) on telomere length. Genomic DNA was obtained from 53 sedentary individuals (34 females, 19-67 yr) and 96 ultra-trail runners (31 females, 23-58 yr). Indeed, blood samples before and after finishing a 107-km-trail race were collected from 69 runners to measure c-reactive protein (CRP) levels and, thus, analyze whether acute inflammation response is modulated by the SOD2 rs4880 polymorphism. Our results revealed that telomere length was better preserved in ultra-trail runners compared with controls, especially in elderly runners who have been regularly training for many years. Carrying the SOD2 rs4880*A allele was significantly associated with having shorter telomeres, as well as with having increased CRP levels after the ultra-trail race. In conclusion, habitual ultra-endurance exercise had a beneficial effect on telomere length maintenance, especially at older ages. This study also suggested that the SOD2 rs4880 polymorphism may also have an impact on acute and chronic oxidative-related damage (inflammatory response and telomere length) after an ultra-trail race.NEW &amp; NOTEWORTHY Habitual ultra-endurance exercise seems to promote telomere length maintenance, especially at older ages. In addition, the beneficial effect of ultra-endurance training on biological aging is higher in ultra-trail runners who have been engaged to ultra-endurance training during many years. Finally, and for the first time, this study shows that the SOD2 rs4880 polymorphism has a significant impact on telomere length, as well as on acute inflammatory response to a 107-km trail race.},
}
@article {pmid32880939,
year = {2020},
author = {Tsilingiris, D and Tentolouris, A and Eleftheriadou, I and Tentolouris, N},
title = {Telomere length, epidemiology and pathogenesis of severe COVID-19.},
journal = {European journal of clinical investigation},
volume = {50},
number = {10},
pages = {e13376},
pmid = {32880939},
issn = {1365-2362},
mesh = {Apoptosis/immunology ; Betacoronavirus ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; COVID-19 ; Cellular Senescence/immunology ; Coronavirus Infections/*immunology/metabolism/physiopathology ; Humans ; Lymphocytes/*immunology/metabolism ; Lymphopenia/*immunology ; Mitochondria/metabolism ; NAD/metabolism ; Pandemics ; Pneumonia, Viral/*immunology/metabolism/physiopathology ; Risk Factors ; SARS-CoV-2 ; Severity of Illness Index ; Sirtuins/metabolism ; T-Lymphocytes/immunology ; Telomere/*metabolism ; Telomere Homeostasis ; Telomere Shortening/*immunology ; },
}
@article {pmid32876842,
year = {2020},
author = {Lulkiewicz, M and Bajsert, J and Kopczynski, P and Barczak, W and Rubis, B},
title = {Telomere length: how the length makes a difference.},
journal = {Molecular biology reports},
volume = {47},
number = {9},
pages = {7181-7188},
pmid = {32876842},
issn = {1573-4978},
support = {2016/21/B/NZ7/01079//Narodowym Centrum Nauki (PL)/ ; },
mesh = {*Cell Division ; Humans ; *Longevity ; Telomerase ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Telomerase is perceived as an immortality enzyme that might provide longevity to cells and whole organisms. Importantly, it is generally inactive in most somatic cells of healthy, adult men. Consequently, its substrates, i.e. telomeres, get shorter in most human cells with time. Noteworthy, cell life limitation due to telomere attrition during cell divisions, may not be as bad as it looks since longer cell life means longer exposition to harmful factors. Consequently, telomere length (attrition rate) becomes a factor that is responsible for inducing the signaling that leads to the elimination of cells that lived long enough to acquire severe damage. It seems that telomere length that depends on many different factors (including telomerase activity but also genetic factors, a hormonal profile that reflects sex, etc.) might become a useful marker of aging and exposition to stress. Thus in the current paper, we review the factors that affect telomere length in human cells focusing on sex that all together with different environmental and hormonal regulations as well as parental aspect affect telomere attrition rate. We also raise some limitations in the assessment of telomere length that hinders a trustworthy meta-analysis that might lead to acknowledgment of the real value of this parameter.},
}
@article {pmid32873778,
year = {2020},
author = {Giaccherini, M and Macauda, A and Sgherza, N and Sainz, J and Gemignani, F and Maldonado, JMS and Jurado, M and Tavano, F and Mazur, G and Jerez, A and Góra-Tybor, J and Gołos, A and Mohedo, FH and Lopez, JM and Várkonyi, J and Spadano, R and Butrym, A and Canzian, F and Campa, D},
title = {Genetic polymorphisms associated with telomere length and risk of developing myeloproliferative neoplasms.},
journal = {Blood cancer journal},
volume = {10},
number = {8},
pages = {89},
pmid = {32873778},
issn = {2044-5385},
mesh = {Aged ; Female ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Myeloproliferative Disorders/etiology/*genetics ; *Polymorphism, Single Nucleotide ; Risk Factors ; *Telomere Homeostasis ; },
abstract = {Telomere length measured in leukocyte (LTL) has been found to be associated with the risk of developing several cancer types, including myeloproliferative neoplasms (MPNs). LTL is genetically determined by, at least, 11 SNPs previously shown to influence LTL. Their combination in a score has been used as a genetic instrument to measure LTL and evaluate the causative association between LTL and the risk of several cancer types. We tested, for the first time, the "teloscore" in 480 MPN patients and 909 healthy controls in a European multi-center case-control study. We found an increased risk to develop MPNs with longer genetically determined telomeres (OR = 1.82, 95% CI 1.24-2.68, P = 2.21 × 10[-3], comparing the highest with the lowest quintile of the teloscore distribution). Analyzing the SNPs individually we confirm the association between TERT-rs2736100-C allele and increased risk of developing MPNs and we report a novel association of the OBFC1-rs9420907-C variant with higher MPN risk (ORallelic = 1.43; 95% CI 1.15-1.77; P = 1.35 × 10[-3]). Consistently with the results obtained with the teloscore, both risk alleles are also associated with longer LTL. In conclusion, our results suggest that genetically determined longer telomeres could be a risk marker for MPN development.},
}
@article {pmid32871095,
year = {2021},
author = {Ojeda-Rodríguez, A and Morell-Azanza, L and Martín-Calvo, N and Zalba, G and Chueca, M and Azcona-Sanjulian, MC and Marti, A},
title = {Association between favourable changes in objectively measured physical activity and telomere length after a lifestyle intervention in pediatric patients with abdominal obesity.},
journal = {Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme},
volume = {46},
number = {3},
pages = {205-212},
doi = {10.1139/apnm-2020-0297},
pmid = {32871095},
issn = {1715-5320},
mesh = {Accelerometry ; Adolescent ; Child ; Diet, Mediterranean ; *Exercise ; Female ; Humans ; *Life Style ; Male ; Obesity, Abdominal/*therapy ; Pediatric Obesity/*therapy ; Sedentary Behavior ; Spain ; Telomere/*ultrastructure ; },
abstract = {The purpose of this study was to assess the effect of physical activity (PA) changes, measured by accelerometry, on telomere length (TL) in pediatric patients with abdominal obesity after a lifestyle intervention. One hundred and twenty-one children (7-16 years old) with abdominal obesity were randomized to the intervention (a moderately hypocaloric Mediterranean diet) or the usual care group (standard pediatric recommendations) for 22 months (a 2 month intensive phase and a subsequent 20 month follow-up). Both groups were encouraged to accumulate an extra 200 min/week of PA. TL was measured by MMqPCR. Data were analyzed in 102 subjects after 2 months and 64 subjects at the first 10 months of follow-up. Light PA level decreased in both groups after 12 months of intervention. At month 2, moderate to vigorous PA (MVPA) increased in the intervention group (+5.4 min/day, p = 0.035) and so did sedentary time in the usual care group (+49.7 min/day, p = 0.010). TL changes were positively associated (p < 0.050) with metabolic equivalents (METs), MVPA level, and number of steps, and were inversely associated with sedentary and light PA levels in the intervention group after the intensive phase. In conclusion, favourable changes in PA levels in the intensive phase of a lifestyle intervention could contribute to TL maintenance in a pediatric population with abdominal obesity. Novelty Changes in physical activity levels had a direct effect on telomere length, a biomarker of cellular aging and oxidative stress. PA advice based on The American College of Sports Medicine included in this intervention is easy to implement in primary care.},
}
@article {pmid32861877,
year = {2020},
author = {Fathi, E and Farahzadi, R and Javanmardi, S and Vietor, I},
title = {L-carnitine Extends the Telomere Length of the Cardiac Differentiated CD117[+]- Expressing Stem Cells.},
journal = {Tissue &amp; cell},
volume = {67},
number = {},
pages = {101429},
doi = {10.1016/j.tice.2020.101429},
pmid = {32861877},
issn = {1532-3072},
mesh = {Animals ; Bone Marrow Cells/cytology/drug effects/metabolism ; Carnitine/*pharmacology ; *Cell Differentiation/drug effects/genetics ; Cell Proliferation/drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Gene Expression Regulation/drug effects ; Myocardium/*cytology ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-kit/metabolism ; RNA, Messenger/genetics/metabolism ; Rats ; Stem Cells/*cytology/drug effects/metabolism ; Telomerase/metabolism ; *Telomere Homeostasis/drug effects ; Wnt3 Protein/metabolism ; beta Catenin/metabolism ; },
abstract = {Stem cell-based therapy has emerged as an attractive method for regenerating and repairing the lost heart organ. On other hand, poor survival and maintenance of the cells transferred into the damaged heart tissue are broadly accepted as serious barriers to enhance the efficacy of the regenerative therapy. For this reason, external factors, such as antioxidants are used as a favorite strategy by the investigators to improve the cell survival and retention properties. Therefore, the present study was conducted to investigate the In -vitro effect of L-carnitine (LC) on the telomere length and human telomerase reverse transcriptase (hTERT) gene expression in the cardiac differentiated bone marrow resident CD117[+] stem cells through Wnt3/β-catenin and ERK1/2 pathways. To do this, bone marrow resident CD117[+] stem cells were enriched by the magnetic-activated cell sorting (MACS) method, and were differentiated to the cardiac cells in the absence (-LC) and presence of the LC (+LC). Also, characterization of the enriched c-kit[+] cells was performed using the flow cytometry and immunocytochemistry. At the end of the treatment period, the cells were subjected to the real-time PCR technique along with western blotting assay for measurement of the telomere length and assessment of mRNA and protein, respectively. The results showed that 0.2 mM LC caused the elongation of the telomere length and increased the hTERT gene expression in the cardiac differentiated CD117[+] stem cells. In addition, a significant increase was observed in the mRNA and protein expression of Wnt3, β-catenin and ERK1/2 as key components of these pathways. It can be concluded that the LC can increase the telomere length as an effective factor in increasing the cell survival and maintenance of the cardiac differentiated bone marrow resident CD117[+] stem cells via Wnt3/β-catenin and ERK1/2 signaling pathway components.},
}
@article {pmid32856217,
year = {2021},
author = {Uysal, F and Kosebent, EG and Toru, HS and Ozturk, S},
title = {Decreased expression of TERT and telomeric proteins as human ovaries age may cause telomere shortening.},
journal = {Journal of assisted reproduction and genetics},
volume = {38},
number = {2},
pages = {429-441},
pmid = {32856217},
issn = {1573-7330},
support = {TUBITAK; Grant no. 117S258//The Scientific and Technological Research Council of Turkey/ ; },
mesh = {Aging/*genetics/pathology ; Female ; Gene Expression Regulation, Developmental/genetics ; Gene Expression Regulation, Enzymologic/genetics ; Humans ; In Situ Hybridization, Fluorescence ; Ovary/*growth &amp; development/metabolism ; Protein Binding/genetics ; Telomerase/*genetics ; Telomere/genetics/metabolism ; Telomere Shortening/*genetics ; },
abstract = {OBJECTIVE: Telomeres are repetitive sequences localized at the ends of eukaryotic chromosomes comprising noncoding DNA and telomere-binding proteins. TRF1 and TRF2 both bind to the double-stranded telomeric DNA to regulate its length throughout the lifespan of eukaryotic cells. POT1 interacts with single-stranded telomeric DNA and contributes to protecting genomic integrity. Previous studies have shown that telomeres gradually shorten as ovaries age, coinciding with fertility loss. However, the molecular background of telomere shortening with ovarian aging is not fully understood.<br><br>METHODS: The present study aimed to determine the spatial and temporal expression levels of the TERT, TRF1, TRF2, and POT1 proteins in different groups of human ovaries: fetal (n = 11), early postnatal (n = 10), premenopausal (n = 12), and postmenopausal (n = 14). Also, the relative telomere signal intensity of each group was measured using the Q-FISH method.<br><br>RESULTS: We found that the telomere signal intensities decreased evenly and significantly from fetal to postmenopausal groups (P < 0.05). The TERT, TRF1, TRF2, and POT1 proteins were localized in the cytoplasmic and nuclear regions of the oocytes, granulosa and stromal cells. Furthermore, the expression levels of these proteins reduced significantly from fetal to postmenopausal groups (P < 0.05).<br><br>CONCLUSION: These findings suggest that decreased TERT and telomere-binding protein expression may underlie the telomere shortening of ovaries with age, which may be associated with female fertility loss. Further investigations are required to elicit the molecular mechanisms regulating the gradual decrease in the expression of TERT and telomere-binding proteins in human oocytes and granulosa cells during ovarian aging.},
}
@article {pmid32856116,
year = {2020},
author = {Hussien, MT and Shaban, S and Temerik, DF and Helal, SR and Mosad, E and Elgammal, S and Mostafa, A and Hassan, E and Ibrahim, A},
title = {Impact of DAXX and ATRX expression on telomere length and prognosis of breast cancer patients.},
journal = {Journal of the Egyptian National Cancer Institute},
volume = {32},
number = {1},
pages = {34},
doi = {10.1186/s43046-020-00045-1},
pmid = {32856116},
issn = {2589-0409},
mesh = {Adaptor Proteins, Signal Transducing/genetics ; *Breast Neoplasms ; *Co-Repressor Proteins/metabolism ; Female ; Humans ; *Molecular Chaperones/metabolism ; Nuclear Proteins/genetics ; *Pancreatic Neoplasms ; Prognosis ; Telomere ; *X-linked Nuclear Protein/metabolism ; },
abstract = {BACKGROUND: Telomere stability is one of the hallmarks of cancer that promotes cellular longevity, the accumulation of genetic alterations, and tumorigenesis. The loss of death domain-associated protein (DAXX) and α-thalassemia/mental retardation X-linked protein (ATRX) plays a role in telomere lengthening and stability. This study aims to evaluate the prognostic significance of telomere length (TL) and its association with DAXX and ATRX proteins in breast cancer (BC). Our study used the FISH technique to detect peptide nucleic acid (PNA) in the peripheral blood cells of a cohort of BC patients (n = 220) and a control group of apparently healthy individuals (n = 100). Expression of DAXX and ATRX proteins was evaluated using immunohistochemistry (IHC) in all BC tissues.<br><br>RESULTS: Patients with a shorter TL had worse disease-free survival (DFS) and overall survival (OS). There were significant associations between shorter TL and advanced disease stages, lymph node metastasis, and positive HER2/neu expression. DAXX protein expression was significantly correlated with TL. Lower DAXX expression was significantly with shorter DFS.<br><br>CONCLUSION: Assessing TL can be used as a worthy prognostic indicator in BC patients. Specifically, short TL had a poor impact on the prognosis of BC patients. Low DAXX expression is associated with poor outcomes in BC. Further mechanistic studies are warranted to reveal the underlying mechanisms of these associations.},
}
@article {pmid32853653,
year = {2020},
author = {Maleki, M and Khelghati, N and Alemi, F and Bazdar, M and Asemi, Z and Majidinia, M and Sadeghpoor, A and Mahmoodpoor, A and Jadidi-Niaragh, F and Targhazeh, N and Yousefi, B},
title = {Stabilization of telomere by the antioxidant property of polyphenols: Anti-aging potential.},
journal = {Life sciences},
volume = {259},
number = {},
pages = {118341},
doi = {10.1016/j.lfs.2020.118341},
pmid = {32853653},
issn = {1879-0631},
mesh = {Animals ; Antioxidants/*pharmacology ; Drug Combinations ; Humans ; Plantago/*drug effects ; Polyphenols/*pharmacology ; Senna Extract ; Telomere/*drug effects ; Telomere Shortening/drug effects ; },
abstract = {Aging is a form of a gradual loss of physiological integrity that results in impaired cellular function and ultimately increased vulnerability to disease and death. This process is a significant risk factor for critical age-related disorders such as cancer, diabetes, cardiovascular disease, and neurological conditions. Several mechanisms contribute to aging, most notably progressive telomeres shortening, which can be counteracted by telomerase enzyme activity and increasing in this enzyme activity associated with partly delaying the onset of aging. Individual behaviors and environmental factors such as nutrition affect the life-span by impact the telomerase activity rate. Healthy eating habits, including antioxidant intakes, such as polyphenols, can have a positive effect on telomere length by this mechanism. In this review, after studying the underlying mechanisms of aging and understanding the relationships between telomeres, telomerase, and aging, it has been attempted to explain the effect of polyphenols on reversing the oxidative stress and aging process.},
}
@article {pmid32842933,
year = {2020},
author = {Stier, A and Metcalfe, NB and Monaghan, P},
title = {Pace and stability of embryonic development affect telomere dynamics: an experimental study in a precocial bird model.},
journal = {Proceedings. Biological sciences},
volume = {287},
number = {1933},
pages = {20201378},
pmid = {32842933},
issn = {1471-2954},
mesh = {Adult ; Animals ; *Coturnix ; *Embryonic Development ; Female ; Glucocorticoids ; Humans ; Pregnancy ; *Telomere ; Telomere Shortening ; Temperature ; },
abstract = {Prenatal effects on telomere length are increasingly recognized as a potential contributor to the developmental origin of health and adult disease. While it is becoming clear that telomere length is influenced by prenatal conditions, the factors affecting telomere dynamics during embryogenesis remain poorly understood. We manipulated both the pace and stability of embryonic development through varying incubation temperature and its stability in Japanese quail. We investigated the impact on telomere dynamics from embryogenesis to adulthood, together with three potential drivers of telomere shortening, growth rate, oxidative damage and prenatal glucocorticoid levels. Telomere length was not affected by our prenatal manipulation for the first 75% of embryogenesis, but was reduced at hatching in groups experiencing faster (i.e. high temperature) or less stable embryonic development. These early life differences in telomere length persisted until adulthood. The effect of developmental instability on telomere length at hatching was potentially mediated by an increased secretion of glucocorticoid hormones during development. Both the pace and the stability of embryo development appear to be key factors determining telomere length and dynamics into adulthood, with fast and less stable development leading to shorter telomeres, with the potential for adverse associated outcomes in terms of reduced longevity.},
}
@article {pmid32841635,
year = {2020},
author = {Colicino, E and Cowell, W and Bozack, A and Foppa Pedretti, N and Joshi, A and Niedzwiecki, MM and Bollati, V and Berin, C and Wright, RO and Wright, RJ},
title = {Association between prenatal immune phenotyping and cord blood leukocyte telomere length in the PRISM pregnancy cohort.},
journal = {Environmental research},
volume = {191},
number = {},
pages = {110113},
pmid = {32841635},
issn = {1096-0953},
support = {UG3 OD023337/OD/NIH HHS/United States ; P30 ES023515/ES/NIEHS NIH HHS/United States ; UH3 OD023337/OD/NIH HHS/United States ; R01 HL095606/HL/NHLBI NIH HHS/United States ; R01 HL114396/HL/NHLBI NIH HHS/United States ; R01 ES030302/ES/NIEHS NIH HHS/United States ; T32 HD049311/HD/NICHD NIH HHS/United States ; },
mesh = {*Air Pollutants ; Bayes Theorem ; Child ; Female ; *Fetal Blood ; Humans ; Infant, Newborn ; Leukocytes ; Pregnancy ; Telomere/genetics ; },
abstract = {BACKGROUND: Environmental exposures including air pollutants, toxic metals, and psychosocial stress have been associated with shorter telomere length (TL) in newborns. These exposures have in turn been linked to an enhanced inflammatory immune response. Increased inflammation during pregnancy may be a central biological pathway linking environmental factors with reduced TL at birth. Approaches that more comprehensively characterize the prenatal inflammatory milieu rather than targeting specific individual cytokines in relation to newborn TL may better elucidate inflammatory mechanisms.<br><br>METHODS: Analyses included 129 mother-child dyads enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort. We measured 92 inflammation related proteins during pregnancy in maternal serum using the Olink protein array and quantified cord blood relative leukocyte TL (rLTL) via qPCR. We leveraged a tree-based machine learning algorithm to select the most important inflammatory related proteins jointly associated with rLTL. We then evaluated the combined association between the selected proteins with rLTL using Bayesian Weighted Quantile Sum (BWQS) Regression. Analyses were adjusted for gestational week of serum collection, maternal race/ethnicity, age, and education, and fetal sex. We evaluated major biological function of the identified proteins by using the UniProtKB, a centralized repository of curated functional information.<br><br>RESULTS: Three proteins were negatively and linearly associated with rLTL (CASP8 &#x3b2;: -0.22 p&#xa0;=&#xa0;0.008, BNGF &#x3b2;: -0.43 p&#xa0;=&#xa0;0.033, TRANCE &#x3b2;: 0.38 p&#xa0;=&#xa0;0.004). Results from BWQS regression showed a significant overall decrease in rLTL (&#x3b2;: -0.26 95%CrI: -0.43, -0.07) per quartile increase of the mixture, with CASP8 contributing the greatest weight (CASP8 50%; BNGF 27%, and TRANCE 23%). The identified proteins were involved in the regulation of apoptotic processes and cell proliferation.<br><br>CONCLUSIONS: This proteomics approach identifies novel maternal prenatal inflammatory protein biomarkers associated with shortened rLTL in newborns.},
}
@article {pmid32840794,
year = {2021},
author = {Simon, MN and Churikov, D and Géli, V},
title = {Analysis of Recombination at Yeast Telomeres.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2153},
number = {},
pages = {395-402},
doi = {10.1007/978-1-0716-0644-5_27},
pmid = {32840794},
issn = {1940-6029},
mesh = {Blotting, Southern ; DNA Replication ; Homologous Recombination ; Saccharomyces cerevisiae/genetics/*growth &amp; development/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Telomerase/*genetics ; Telomere/*metabolism ; },
abstract = {Upon telomerase inactivation telomeres are getting shorter at each round of DNA replication and progressively lose capping functions and hence protection against homologous recombination. In addition, telomerase-minus cells undergo a round of stochastic DNA damage before the bulk of telomeres become critically short because telomeres are difficult regions to replicate. Although most of the cells will enter finally replicative senescence, those that unleash recombination can eventually recover functional telomeres and growth capacity. Formation of these survivors in yeast depends on various recombination mechanisms. Here, we present assays that we developed to analyze and quantify recombination at telomeres.},
}
@article {pmid32829966,
year = {2021},
author = {Chen, R and Zhan, Y},
title = {Association between telomere length and Parkinson's disease: a Mendelian randomization study.},
journal = {Neurobiology of aging},
volume = {97},
number = {},
pages = {144.e9-144.e11},
doi = {10.1016/j.neurobiolaging.2020.07.019},
pmid = {32829966},
issn = {1558-1497},
mesh = {Female ; *Genome-Wide Association Study ; Humans ; Male ; *Mendelian Randomization Analysis ; Parkinson Disease/*genetics ; Risk Factors ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {In this study, we examined the potential association of telomere length with Parkinson's disease (PD) using the publicly available genome-wide association study summary statistics from the International Parkinson's Disease Genomics Consortium involving up to 37,688 patients with PD and 449,056 controls in Mendelian randomization framework. The Mendelian randomization approach has the potential to investigate a causal relationship between a risk factor and a disease, avoiding confounding and reverse causation that often present in conventional epidemiological studies. We did not find that longer telomeres were associated with higher risks of PD (odds ratio: 1.18, 95% confidence interval: 0.94, 1.48, p = 0.15). Our study, therefore, did not provide evidence to support a potential causal relationship between telomere length and PD.},
}
@article {pmid32825843,
year = {2020},
author = {Fattet, AJ and Toupance, S and Thornton, SN and Monnin, N and Guéant, JL and Benetos, A and Koscinski, I},
title = {Telomere length in granulosa cells and leukocytes: a potential marker of female fertility? A systematic review of the literature.},
journal = {Journal of ovarian research},
volume = {13},
number = {1},
pages = {96},
pmid = {32825843},
issn = {1757-2215},
support = {ANR-15-IDEX-04-LUE//Agence Nationale de la Recherche/ ; },
mesh = {Biomarkers/metabolism ; Female ; Granulosa Cells/*metabolism ; Humans ; Leukocytes/*metabolism ; Primary Ovarian Insufficiency/blood/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {In the context of a continuously increased delay of motherhood and of an increase of the incidence of premature ovarian failure, it is of the greatest interest to dispose of a predictive marker of the duration of the fertility window. Unfortunately, current available markers of women's fertility (hormonal rates or echography count of small follicles) have a poor predictive value of premature ovarian failure. In the last ten years, some studies have suggested that telomere length may be correlated with premature ovarian failure, but the results of these studies are contradictory.In accordance with guidelines from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), this systematic review of the literature selected studies evaluating telomere length or telomerase activity in granulosa cells and/or in leukocytes as a premature ovarian failure marker.Five publications (252 premature ovarian failure patients) were included in this review of experimental evidence. Two of them studied telomere length and/or telomerase activity in granulosa cells and 4 in leukocytes in women with premature ovarian failure. For each study, authors determined if there was a positive or a negative correlation between telomeric parameters and premature ovarian failure.3 studies (178 premature ovarian failure patients) found shorter telomere length in granulosa cells and/or leukocytes and/or lower telomerase activity in premature ovarian failure patients. 2 studies (74 premature ovarian failure patients) presented contradictory results about the correlation of leucocyte telomere length with premature ovarian failure.Shorter telomeres and diminished telomerase activity in granulosa cells appear to be associated with ovarian insufficiency. However, the number of studies and of subjects within are low and the methodology questionable. The confirmation of these results is essential with more subjects, better defined populations and more adapted methodology, in order to consider telomere length in granulosa cells and/or in leucocytes as an early and reliable marker for the decline of ovarian function.},
}
@article {pmid32824789,
year = {2020},
author = {Bernabeu-Wittel, M and Gómez-Díaz, R and González-Molina, &#xc1; and Vidal-Serrano, S and Díez-Manglano, J and Salgado, F and Soto-Martín, M and Ollero-Baturone, M and On Behalf Of The Proteo Researchers, },
title = {Oxidative Stress, Telomere Shortening, and Apoptosis Associated to Sarcopenia and Frailty in Patients with Multimorbidity.},
journal = {Journal of clinical medicine},
volume = {9},
number = {8},
pages = {},
pmid = {32824789},
issn = {2077-0383},
abstract = {BACKGROUND: The presence of oxidative stress, telomere shortening, and apoptosis in polypathological patients (PP) with sarcopenia and frailty remains unknown.<br><br>METHODS: Multicentric prospective observational study in order to assess oxidative stress markers (catalase, glutathione reductase (GR), total antioxidant capacity to reactive oxygen species (TAC-ROS), and superoxide dismutase (SOD)), absolute telomere length (aTL), and apoptosis (DNA fragmentation) in peripheral blood samples of a hospital-based population of PP. Associations of these biomarkers to sarcopenia, frailty, functional status, and 12-month mortality were analyzed.<br><br>RESULTS: Of the 444 recruited patients, 97 (21.8%), 278 (62.6%), and 80 (18%) were sarcopenic, frail, or both, respectively. Oxidative stress markers (lower TAC-ROS and higher SOD) were significantly enhanced and aTL significantly shortened in patients with sarcopenia, frailty or both syndromes. No evidence of apoptosis was detected in blood leukocytes of any of the patients. Both oxidative stress markers (GR, p = 0.04) and telomere shortening (p = 0.001) were associated to death risk and to less survival days.<br><br>CONCLUSIONS: Oxidative stress markers and telomere length were enhanced and shortened, respectively, in blood samples of polypathological patients with sarcopenia and/or frailty. Both were associated to decreased survival. They could be useful in the clinical practice to assess vulnerable populations with multimorbidity and of potential interest as therapeutic targets.},
}
@article {pmid32823549,
year = {2020},
author = {Bryan, TM},
title = {G-Quadruplexes at Telomeres: Friend or Foe?.},
journal = {Molecules (Basel, Switzerland)},
volume = {25},
number = {16},
pages = {},
pmid = {32823549},
issn = {1420-3049},
mesh = {DNA, Single-Stranded/chemistry/genetics ; *G-Quadruplexes ; Humans ; Telomere/*chemistry/*genetics ; },
abstract = {Telomeres are DNA-protein complexes that cap and protect the ends of linear chromosomes. In almost all species, telomeric DNA has a G/C strand bias, and the short tandem repeats of the G-rich strand have the capacity to form into secondary structures in vitro, such as four-stranded G-quadruplexes. This has long prompted speculation that G-quadruplexes play a positive role in telomere biology, resulting in selection for G-rich tandem telomere repeats during evolution. There is some evidence that G-quadruplexes at telomeres may play a protective capping role, at least in yeast, and that they may positively affect telomere maintenance by either the enzyme telomerase or by recombination-based mechanisms. On the other hand, G-quadruplex formation in telomeric DNA, as elsewhere in the genome, can form an impediment to DNA replication and a source of genome instability. This review summarizes recent evidence for the in vivo existence of G-quadruplexes at telomeres, with a focus on human telomeres, and highlights some of the many unanswered questions regarding the location, form, and functions of these structures.},
}
@article {pmid32821950,
year = {2020},
author = {Hunt, SC and Hansen, MEB and Verhulst, S and McQuillan, MA and Beggs, W and Lai, TP and Mokone, GG and Mpoloka, SW and Meskel, DW and Belay, G and Nyambo, TB and Abnet, CC and Yeager, M and Chanock, SJ and Province, MA and Williams, SM and Aviv, A and Tishkoff, SA},
title = {Genetics and geography of leukocyte telomere length in sub-Saharan Africans.},
journal = {Human molecular genetics},
volume = {29},
number = {18},
pages = {3014-3020},
pmid = {32821950},
issn = {1460-2083},
support = {R01 HL138402/HL/NHLBI NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; R01 HL116446/HL/NHLBI NIH HHS/United States ; P30 ES013508/ES/NIEHS NIH HHS/United States ; R01 DK104339/DK/NIDDK NIH HHS/United States ; T32 ES019851/ES/NIEHS NIH HHS/United States ; R35 GM134957/GM/NIGMS NIH HHS/United States ; },
mesh = {Adult ; Africa South of the Sahara/epidemiology ; Black or African American/genetics ; Black People/genetics ; Cardiovascular Diseases/blood/epidemiology/*genetics ; Female ; Humans ; Leukocytes/pathology ; Male ; Middle Aged ; Neoplasms/blood/epidemiology/*genetics ; Phylogeography ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; White People/genetics ; },
abstract = {Leukocyte telomere length (LTL) might be causal in cardiovascular disease and major cancers. To elucidate the roles of genetics and geography in LTL variability across humans, we compared LTL measured in 1295 sub-Saharan Africans (SSAs) with 559 African-Americans (AAms) and 2464 European-Americans (EAms). LTL differed significantly across SSAs (P = 0.003), with the San from Botswana (with the oldest genomic ancestry) having the longest LTL and populations from Ethiopia having the shortest LTL. SSAs had significantly longer LTL than AAms [P = 6.5(e-16)] whose LTL was significantly longer than EAms [P = 2.5(e-7)]. Genetic variation in SSAs explained 52% of LTL variance versus 27% in AAms and 34% in EAms. Adjustment for genetic variation removed the LTL differences among SSAs. LTL genetic variation among SSAs, with the longest LTL in the San, supports the hypothesis that longer LTL was ancestral in humans. Identifying factors driving LTL variation in Africa may have important ramifications for LTL-associated diseases.},
}
@article {pmid32814800,
year = {2020},
author = {Ämmälä, AJ and Vitikainen, EIK and Hovatta, I and Paavonen, J and Saarenpää-Heikkilä, O and Kylliäinen, A and Pölkki, P and Porkka-Heiskanen, T and Paunio, T},
title = {Maternal stress or sleep during pregnancy are not reflected on telomere length of newborns.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {13986},
pmid = {32814800},
issn = {2045-2322},
mesh = {Female ; Humans ; Infant, Newborn ; Linear Models ; Male ; Pregnancy ; Pregnancy Complications/*physiopathology ; Prenatal Exposure Delayed Effects/*diagnosis/genetics/physiopathology ; Self Report ; Sleep Wake Disorders/*physiopathology ; Stress, Psychological/*physiopathology ; Surveys and Questionnaires ; Telomere/genetics/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Telomeres play an important role in maintaining chromosomal integrity. With each cell division, telomeres are shortened and leukocyte telomere length (LTL) has therefore been considered a marker for biological age. LTL is associated with various lifetime stressors and health-related outcomes. Transgenerational effects have been implicated in newborns, with maternal stress, depression, and anxiety predicting shorter telomere length at birth, possibly reflecting the intrauterine growth environment. Previous studies, with relatively small sample sizes, have reported an effect of maternal stress, BMI, and depression during pregnancy on the LTL of newborns. Here, we attempted to replicate previous findings on prenatal stress and newborn LTL in a sample of 1405 infants using a qPCR-based method. In addition, previous research has been expanded by studying the relationship between maternal sleep quality and LTL. Maternal prenatal stress, anxiety, depression, BMI, and self-reported sleep quality were evaluated with self-reported questionnaires. Despite sufficient power to detect similar or even considerably smaller effects than those previously reported in the literature, we were unable to replicate the previous correlation between maternal stress, anxiety, depression, or sleep with LTL. We discuss several possible reasons for the discrepancies between our findings and those previously described.},
}
@article {pmid32807581,
year = {2021},
author = {Öngel, ME and Yıldız, C and Akpınaroğlu, C and Yilmaz, B and Özilgen, M},
title = {Why women may live longer than men do? A telomere-length regulated and diet-based entropic assessment.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {40},
number = {3},
pages = {1186-1191},
doi = {10.1016/j.clnu.2020.07.030},
pmid = {32807581},
issn = {1532-1983},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Diet/*adverse effects ; Diet, Ketogenic ; Diet, Mediterranean ; Diet, Vegan ; Diet, Western ; Energy Intake/genetics ; Entropy ; Female ; Humans ; Longevity/*genetics ; Male ; Middle Aged ; *Sex Factors ; Telomere/*genetics ; Telomere Shortening/genetics ; Young Adult ; },
abstract = {BACKGROUND &amp; AIMS: Empirical analyses of the data available around the word concluded that women have longer life span now, when compared to the men. Available literature unfortunately could not offer full answers to this observation. The "entropic age" concept suggests that ageing related changes in the body, such as loss of molecular functions and overwhelming of the maintenance systems, may be explained in terms of entropy generation.<br><br>METHODS: Telomere-length regulated entropic assessment based on metabolic activity with four different diets carried out.<br><br>RESULTS: Estimates of the life expectancy of the women on all of these diets is longer than those of the men. Faster shortening of the telomere lengths in men was the major reason of the shorter life expectancy. The highest and the lowest life expectancy for women were estimated with Mediterranean and the vegetarian diets, respectively; men were estimated to have the longest life span with the vegetarian diet and the shortest life span with the ketogenic diet.<br><br>CONCLUSIONS: A higher rate of metabolism causes higher entropy generation and hints correlations that can be helpful in future ageing research. Faster shortening of the telomere lengths in men was the major reason of the estimation of the shorter life span for men.},
}
@article {pmid32807015,
year = {2020},
author = {Piekna-Przybylska, D and Bambara, RA and Maggirwar, SB and Dewhurst, S},
title = {G-quadruplex ligands targeting telomeres do not inhibit HIV promoter activity and cooperate with latency reversing agents in killing latently infected cells.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {19},
number = {18},
pages = {2298-2313},
pmid = {32807015},
issn = {1551-4005},
support = {R01 NS066801/NS/NINDS NIH HHS/United States ; R21 AI131961/AI/NIAID NIH HHS/United States ; },
mesh = {Acridines/pharmacology ; Anti-HIV Agents/*pharmacology ; Apoptosis/drug effects ; Bryostatins/pharmacology ; CD4-Positive T-Lymphocytes/*drug effects/metabolism/pathology/virology ; DNA Damage ; DNA Mismatch Repair ; DNA Repair ; Drug Synergism ; Drug Therapy, Combination ; *G-Quadruplexes ; HIV Infections/*drug therapy/metabolism/pathology/virology ; HIV-1/*drug effects/genetics/metabolism/pathogenicity ; Host-Pathogen Interactions ; Humans ; Jurkat Cells ; Ligands ; Porphyrins/pharmacology ; Promoter Regions, Genetic/*drug effects ; Telomere/*drug effects/genetics/metabolism ; Telomere Homeostasis/*drug effects ; Virus Activation/drug effects ; Virus Latency/drug effects ; Vorinostat/pharmacology ; },
abstract = {Altered telomere maintenance mechanism (TMM) is linked to increased DNA damage at telomeres and telomere uncapping. We previously showed that HIV-1 latent cells have altered TMM and are susceptible to ligands that target G-quadruplexes (G4) at telomeres. Susceptibility of latent cells to telomere targeting could potentially be used to support approaches to eradicate HIV reservoirs. However, G4 ligands also target G-quadruplexes in promoters blocking gene transcription. Since HIV promoter sequence can form G-quadruplexes, we investigated whether G4 ligands interfere with HIV-1 promoter activity and virus reactivation from latency, and whether telomere targeting could be combined with latency reversing agents (LRAs) to promote elimination of HIV reservoirs. Our results indicate that Sp1 binding region in HIV-1 promoter can adopt G4 structures in duplex DNA, and that in vitro binding of Sp1 to G-quadruplex is blocked by G4 ligand, suggesting that agents targeting telomeres interfere with virus reactivation. However, our studies show that G4 agents do not affect HIV-1 promoter activity in cell culture, and do not interfere with latency reversal. Importantly, primary memory CD4 + T cells infected with latent HIV-1 are more susceptible to combined treatment with LRAs and G4 ligands, indicating that drugs targeting TMM may enhance killing of HIV reservoirs. Using a cell-based DNA repair assay, we also found that HIV-1 infected cells have reduced efficiency of DNA mismatch repair (MMR), and base excision repair (BER), suggesting that altered TMM in latently infected cells could be associated with accumulation of DNA damage at telomeres and changes in telomeric caps.},
}
@article {pmid32804988,
year = {2020},
author = {Leisen, T and Bietz, F and Werner, J and Wegner, A and Schaffrath, U and Scheuring, D and Willmund, F and Mosbach, A and Scalliet, G and Hahn, M},
title = {CRISPR/Cas with ribonucleoprotein complexes and transiently selected telomere vectors allows highly efficient marker-free and multiple genome editing in Botrytis cinerea.},
journal = {PLoS pathogens},
volume = {16},
number = {8},
pages = {e1008326},
pmid = {32804988},
issn = {1553-7374},
mesh = {Botrytis/*physiology ; *CRISPR-Cas Systems ; *Gene Editing ; Genetic Vectors/administration &amp; dosage/genetics ; Oryza/genetics/*microbiology ; Plant Diseases/genetics/*microbiology ; Ribonucleoproteins/*antagonists &amp; inhibitors/genetics ; Telomere/*genetics ; },
abstract = {CRISPR/Cas has become the state-of-the-art technology for genetic manipulation in diverse organisms, enabling targeted genetic changes to be performed with unprecedented efficiency. Here we report on the first establishment of robust CRISPR/Cas editing in the important necrotrophic plant pathogen Botrytis cinerea based on the introduction of optimized Cas9-sgRNA ribonucleoprotein complexes (RNPs) into protoplasts. Editing yields were further improved by development of a novel strategy that combines RNP delivery with cotransformation of transiently stable vectors containing telomeres, which allowed temporary selection and convenient screening for marker-free editing events. We demonstrate that this approach provides superior editing rates compared to existing CRISPR/Cas-based methods in filamentous fungi, including the model plant pathogen Magnaporthe oryzae. Genome sequencing of edited strains revealed very few additional mutations and no evidence for RNP-mediated off-targeting. The high performance of telomere vector-mediated editing was demonstrated by random mutagenesis of codon 272 of the sdhB gene, a major determinant of resistance to succinate dehydrogenase inhibitor (SDHI) fungicides by in bulk replacement of the codon 272 with codons encoding all 20 amino acids. All exchanges were found at similar frequencies in the absence of selection but SDHI selection allowed the identification of novel amino acid substitutions which conferred differential resistance levels towards different SDHI fungicides. The increased efficiency and easy handling of RNP-based cotransformation is expected to accelerate molecular research in B. cinerea and other fungi.},
}
@article {pmid32804179,
year = {2020},
author = {Yamaguchi, I and Ooe, R and Wang, A},
title = {Water-soluble oligofluorenes bearing N1-alkylcytosine side chains as turn-on and turn-off materials in telomere DNA length sensing.},
journal = {Chemical communications (Cambridge, England)},
volume = {56},
number = {74},
pages = {10914-10917},
doi = {10.1039/d0cc05153e},
pmid = {32804179},
issn = {1364-548X},
mesh = {Cytosine/analogs &amp; derivatives/*chemistry ; DNA/*chemistry ; Fluorenes/chemical synthesis/*chemistry ; Molecular Structure ; Solubility ; Telomere/*chemistry ; Water/chemistry ; },
abstract = {Water-soluble cationic and anionic oligofluorenes bearing N1-alkylcytosine side chains, namely OF-1 and OF-2, were synthesized. The photoluminescence (PL) intensity of an aqueous solution of OF-1 decreased on the addition of (TTAGGG)m as telomere DNA models. In contrast, the PL intensity of OF-2 increased on the addition of DNA.},
}
@article {pmid32799224,
year = {2020},
author = {Koroleva, AG and Evtushenko, EV and Vershinin, AV and Zaytseva, EP and Timoshkin, OA and Kirilchik, SV},
title = {[Age Dynamics of Telomere Length in Endemic Baikal Planarians].},
journal = {Molekuliarnaia biologiia},
volume = {54},
number = {4},
pages = {616-625},
doi = {10.31857/S0026898420040072},
pmid = {32799224},
issn = {0026-8984},
mesh = {Animals ; Lakes ; Phylogeny ; *Planarians/genetics/physiology ; Russia ; Species Specificity ; *Telomerase/metabolism ; Telomere/*physiology ; Telomere Shortening ; },
abstract = {Age-related changes in telomere length (TL) in somatic tissues are not limited only to shortening. It is known that many organisms show different TL dynamics. Such species specificity indicates the complexity of the mechanisms involved in the regulation of TL. Owing to their morphological, physiological, and ecological features, Baikal planarians are an interesting model for studying the TL dynamics and the factors influencing it in comparison with species living outside Baikal. In this work, we investigated telomerase activity and age-related changes in TL in three endemic species of planarians from the Dendrocoelidae family. Two species are giant deep-water species (7-12 cm long, Sorocelis hepatizon and Rimacephalus arecepta), and one is a coastal shallow species (1 cm long, Baikalobia guttata). In addition, we investigated the telomere biology in another small Siberian species from the Planariidae family (2 cm in length, Phagocata sibirica), which is not found in Baikal. TL and telomerase activity were determined using real-time PCR and the TRAP method. Three types of age-related TL dynamics were detected with active telomerase: (1) TL shortening at the juvenile stage of development and subsequent maintenance (R. arecepta, Ph. sibirica), (2) gradual TL shortening during ontogeny (S. hepatizon) and (3) cyclic dynamics of TL (B. guttata). Thus, the changes of TL in the studied planarians does not have an obvious connection with body size, habitat depth, phylogenetic relationship and is probably a consequence of species features in the regulation of telomerase activity.},
}
@article {pmid32792056,
year = {2020},
author = {Huang, Z and Zhao, X and Zhang, H and Liang, G and Qi, H and He, X and Zhu, C and Ge, S and Zhang, J},
title = {The association between mitochondrial DNA copy number, telomere length, and tubal pregnancy.},
journal = {Placenta},
volume = {97},
number = {},
pages = {108-114},
doi = {10.1016/j.placenta.2020.06.017},
pmid = {32792056},
issn = {1532-3102},
mesh = {Adult ; *DNA Copy Number Variations ; DNA, Mitochondrial/genetics/*metabolism ; Female ; Humans ; Pregnancy ; Pregnancy, Tubal/genetics/*metabolism ; Retrospective Studies ; *Telomere ; *Telomere Shortening ; },
abstract = {Growing evidence has demonstrated association between the occurrence of tubal ectopic pregnancy (TP) and oxidative stress (OS) status, in which mitochondria and telomeres play important roles. However, little is known about the underlying correlation between TP and the mitochondrial DNA copy number (mtDNAcn) or telomere length (TL) abnormalities. In this study, we found OS level was elevated in TP patients. We hierarchically detected the relative mtDNAcn and TL of villi from normal pregnancy (NP) and TP samples according to different gestational age, fetal sex, maternal age, and BMI. The results revealed that the relative mtDNAcn was significantly lower in the villi in the TP group compared with the NP cohort, which was negatively correlated with OS status. In the NP group, the mtDNAcn in the female subgroup was apparently lower than that in the male subgroup, while no statistical difference was found in the mtDNAcn in the TP group between the female and male subgroups. Moreover, the relative TL in the TP group was at a similar level to the NP group, and no statistical correlation was observed between relative TL and OS level. In summary, our findings indicate that the abnormal level of mtDNAcn rather than TL is correlated with TP, which provides new insights into the mechanism of TP.},
}
@article {pmid32792055,
year = {2020},
author = {Kohlrausch, FB and Keefe, DL},
title = {Telomere erosion as a placental clock: From placental pathologies to adverse pregnancy outcomes.},
journal = {Placenta},
volume = {97},
number = {},
pages = {101-107},
doi = {10.1016/j.placenta.2020.06.022},
pmid = {32792055},
issn = {1532-3102},
mesh = {Female ; Fetal Growth Retardation/genetics/metabolism/pathology ; Humans ; Infant, Small for Gestational Age ; Placenta/metabolism/*pathology ; Pregnancy ; Pregnancy Outcome ; Telomere/*genetics/metabolism ; *Telomere Shortening ; Trophoblasts/metabolism ; },
abstract = {The placenta provides nutritional and gas exchange between fetus and mother. Early in pregnancy, placental trophoblasts proliferate rapidly and invade aggressively. As pregnancy progresses, placental cells begin to age. Indeed, pregnancy itself has a tightly regulated duration, determined in large part by placental lifespan. Late in pregnancy, placental cells reach a senescent apoptotic state, activated by a number of intrinsic and extrinsic factors, including oxidative stress (OS), and DNA damage. Pregnancy complications, stillbirths and neonatal deaths have been related to OS and abnormal placental aging. Telomeres, the protective nucleoprotein structures at the ends of linear chromosomes, shorten both from cell replication and from exposure to OS. When telomeres become critically short they trigger cell cycle arrest and eventually cell death. Telomere attrition thus provide an intrinsic mechanism to explain tissue senescence and aging. Mounting evidence suggests that senescence of placental and fetal membrane cells results from telomere attrition. We review the studies that have addressed the role of telomere length (TL) in placentas from normal and complicated pregnancies, including pre-eclampsia, intrauterine growth restriction, gestational diabetes, and stillbirth. To date studies have uncovered associations between TL and a number of obstetrical complications. Future research is needed to determine whether these associations are causative, i.e. whether these clinical conditions result from telomere dysfunction, and whether particular features of telomeres, e.g. mean or shortest length, etc. could serve as clinically useful biomarkers of placental health.},
}
@article {pmid32784588,
year = {2020},
author = {Sung, JY and Lim, HW and Joung, JG and Park, WY},
title = {Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity.},
journal = {Cancers},
volume = {12},
number = {8},
pages = {},
pmid = {32784588},
issn = {2072-6694},
support = {NRF-2018R1D1A1B07048531//Ministry of Science and ICT, South Korea/ ; },
abstract = {Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism that extends telomeres in cancer cells. It influences tumorigenesis and patient survival. Despite the clinical significance of ALT in tumors, the manner in which ALT is activated and influences prognostic outcomes in distinct cancer types is unclear. In this work, we profiled distinct telomere maintenance mechanisms (TMMs) using 8953 transcriptomes of 31 different cancer types from The Cancer Genome Atlas (TCGA). Our results demonstrated that approximately 29% of cancer types display high ALT activity with low telomerase activity in the telomere-lengthening group. Among the distinct ALT mechanisms, homologous recombination was frequently observed in sarcoma, adrenocortical carcinoma, and kidney chromophobe. Five cancer types showed a significant difference in survival in the presence of high ALT activity. Sarcoma patients with elevated ALT had unfavorable risks (p < 0.038) coupled with a high expression of TOP2A, suggesting this as a potential drug target. On the contrary, glioblastoma patients had favorable risks (p < 0.02), and showed low levels of antigen-presenting cells. Together, our analyses highlight cancer type-dependent TMM activities and ALT-associated genes as potential therapeutic targets.},
}
@article {pmid32781627,
year = {2020},
author = {Sharma, R and Martins, N},
title = {Telomeres, DNA Damage and Ageing: Potential Leads from Ayurvedic Rasayana (Anti-Ageing) Drugs.},
journal = {Journal of clinical medicine},
volume = {9},
number = {8},
pages = {},
pmid = {32781627},
issn = {2077-0383},
abstract = {Ageing, while a relentless, unidirectional and pleiotropic phenomenon of life, is a key trigger for several age-related disorders, such as cancer, cataract, osteoporosis, hypertension, cardiovascular (CV), metabolic and even neurodegenerative ailments, including Alzheimer's (AD) and Parkinson's (PD) disease [1] [...].},
}
@article {pmid32781553,
year = {2020},
author = {Herrmann, W and Herrmann, M},
title = {The Importance of Telomere Shortening for Atherosclerosis and Mortality.},
journal = {Journal of cardiovascular development and disease},
volume = {7},
number = {3},
pages = {},
pmid = {32781553},
issn = {2308-3425},
abstract = {Telomeres are the protective end caps of chromosomes and shorten with every cell division. Short telomeres are associated with older age and adverse lifestyle factors. Leucocyte telomere length (LTL) has been proposed as a biomarker of biological age. The shortening of LTL with age is the result of the end-replication problem, environmental, and lifestyle-related factors. Epidemiologic studies have shown that LTL predicts cardiovascular disease, all-cause mortality, and death from vascular causes. Age appears to be an important co-variate that explains a substantial fraction of this effect. Although it has been proposed that short telomeres promote atherosclerosis and impair the repair of vascular lesions, existing results are inconsistent. Oxidative stress and chronic inflammation can both accelerate telomere shortening. Multiple factors, including homocysteine (HCY), vitamin B6, and vitamin B12 modulate oxidative stress and inflammation through direct and indirect mechanisms. This review provides a compact overview of telomere physiology and the utility of LTL measurements in atherosclerosis and cardiovascular disease. In addition, it summarizes existing knowledge regarding the impact of oxidative stress, inflammation, HCY, and B-vitamins on telomere function.},
}
@article {pmid32777275,
year = {2020},
author = {Cowell, W and Colicino, E and Tanner, E and Amarasiriwardena, C and Andra, SS and Bollati, V and Kannan, S and Ganguri, H and Gennings, C and Wright, RO and Wright, RJ},
title = {Prenatal toxic metal mixture exposure and newborn telomere length: Modification by maternal antioxidant intake.},
journal = {Environmental research},
volume = {190},
number = {},
pages = {110009},
pmid = {32777275},
issn = {1096-0953},
support = {R01 HD082078/HD/NICHD NIH HHS/United States ; R01 HL095606/HL/NHLBI NIH HHS/United States ; R21 ES021318/ES/NIEHS NIH HHS/United States ; UG3 OD023337/OD/NIH HHS/United States ; P30 ES023515/ES/NIEHS NIH HHS/United States ; UH3 OD023337/OD/NIH HHS/United States ; R01 ES030302/ES/NIEHS NIH HHS/United States ; T32 HD049311/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; *Antioxidants ; Boston ; Female ; Humans ; Infant, Newborn ; Maternal Exposure/adverse effects ; New York City ; Pregnancy ; *Telomere ; },
abstract = {BACKGROUND: Telomere length (TL) predicts the onset of cellular senescence and correlates with longevity and age-related disease risk. While telomeres erode throughout life, adults display fixed ranking and tracking of TL, supporting the importance of the early environment in determining inter-individual variability across the life course. Given their guanine-rich structure, telomeres are highly susceptible to oxidative stress (OS). We examined maternal metal exposure, which can induce OS, in relation to newborn TL. We also considered the modifying role of maternal antioxidant intake.<br><br>METHODS: Analyses included 100 mother-newborn pairs enrolled in the Boston and New York City-based PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort. We measured As, Ba, Cd, Ni, and Pb in maternal late-pregnancy urine by ICP-MS and quantified relative leukocyte TL (rLTL) in cord blood using qPCR. We used Weighted Quantile Sum (WQS) regression to estimate the metal mixture - rLTL association and conducted repeated holdout validation to improve the stability of estimates across data partitions. We examined models stratified by high (>median) versus low (&#x2264;median) maternal antioxidant intake, estimated from Block98 Food Frequency Questionnaires. We considered urinary creatinine, week of urine collection, maternal age, and race/ethnicity as covariates.<br><br>RESULTS: In adjusted models, urinary metals were inversely associated with newborn rLTL (&#x3b2;WQS&#xa0;=&#xa0;-0.50, 95% CI: -0.78, -0.21). The top metals contributing to the negative association included Ba (weight: 35.4%), Cd (24.5%) and Pb (26.9%). In models stratified by antioxidant intake, the significant inverse association between metals and rLTL remained only among mothers with low antioxidant intake (low: &#x3b2;WQS&#xa0;=&#xa0;-0.92, 95% CI: -1.53, -0.30; high: &#x3b2;WQS&#xa0;=&#xa0;-0.03, 95% CI: -0.58, 0.52). Results were similar in unadjusted models.<br><br>CONCLUSIONS: Relative LTL was shorter among newborns of mothers with higher exposure to metals during pregnancy. Higher maternal antioxidant intake may mitigate the negative influence of metals on newborn rLTL.},
}
@article {pmid32776370,
year = {2020},
author = {Liu, J and Hong, X and Liang, CY and Liu, JP},
title = {Simultaneous visualisation of the complete sets of telomeres from the MmeI generated terminal restriction fragments in yeasts.},
journal = {Yeast (Chichester, England)},
volume = {37},
number = {11},
pages = {585-595},
doi = {10.1002/yea.3517},
pmid = {32776370},
issn = {1097-0061},
mesh = {Deoxyribonucleases, Type II Site-Specific/*metabolism ; Repressor Proteins/genetics/metabolism ; Saccharomyces cerevisiae/enzymology/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere Shortening ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Telomere length is measured using Southern blotting of the chromosomal terminal restriction fragments (TRFs) released by endonuclease digestion in cells from yeast to human. In the budding yeast Saccharomyces cerevisiae, XhoI or PstI is applied to cut the subtelomere Y' element and release TRFs from the 17 subtelomeres. However, telomeres from other 15 X-element-only subtelomeres are omitted from analysis. Here, we report a method for measuring all 32 telomeres in S. cerevisiae using the endonuclease MmeI. Based on analyses of the endonuclease cleavage sites, we found that the TRFs generated by MmeI displayed two distinguishable bands in the sizes of ~500 and ~700 bp comprising telomeres (300 bp) and subtelomeres (200-400 bp). The modified MmeI-restricted TRF (mTRF) method recapitulated telomere shortening and lengthening caused by deficiencies of YKu and Rif1 respectively in S. cerevisiae. Furthermore, we found that mTRF was also applicable to telomere length analysis in S. paradoxus strains. These results demonstrate a useful tool for simultaneous detection of telomeres from all chromosomal ends with both X-element-only and Y'-element subtelomeres in S. cerevisiae species.},
}
@article {pmid32774788,
year = {2020},
author = {Aramburu, T and Plucinsky, S and Skordalakes, E},
title = {POT1-TPP1 telomere length regulation and disease.},
journal = {Computational and structural biotechnology journal},
volume = {18},
number = {},
pages = {1939-1946},
pmid = {32774788},
issn = {2001-0370},
support = {P30 CA010815/CA/NCI NIH HHS/United States ; },
abstract = {Telomeres are DNA repeats at the ends of linear chromosomes and are replicated by telomerase, a ribonucleoprotein reverse transcriptase. Telomere length regulation and chromosome end capping are essential for genome stability and are mediated primarily by the shelterin and CST complexes. POT1-TPP1, a subunit of shelterin, binds the telomeric overhang, suppresses ATR-dependent DNA damage response, and recruits telomerase to telomeres for DNA replication. POT1 localization to telomeres and chromosome end protection requires its interaction with TPP1. Therefore, the POT1-TPP1 complex is critical to telomere maintenance and full telomerase processivity. The aim of this mini-review is to summarize recent POT1-TPP1 structural studies and discuss how the complex contributes to telomere length regulation. In addition, we review how disruption of POT1-TPP1 function leads to human disease.},
}
@article {pmid32768567,
year = {2020},
author = {Utyro, O and Perła-Kaján, J and Kubalska, J and Graban, A and Jakubowski, H},
title = {Telomere length and mtDNA copy number in human cystathionine β-synthase deficiency.},
journal = {Free radical biology &amp; medicine},
volume = {160},
number = {},
pages = {219-226},
doi = {10.1016/j.freeradbiomed.2020.07.036},
pmid = {32768567},
issn = {1873-4596},
mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; *Cystathionine beta-Synthase/deficiency/genetics ; DNA Copy Number Variations ; *DNA, Mitochondrial/genetics ; Female ; Homocysteine ; *Homocystinuria ; Humans ; *Hyperhomocysteinemia ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Telomere/genetics ; *Telomere Shortening ; Young Adult ; },
abstract = {Telomere shortening and mitochondrial DNA (mtDNA) copy number are associated with human disease and a reduced life span. Cystathionine β-synthase (CBS) is a housekeeping enzyme that catalyzes the first step in metabolic conversion of homocysteine (Hcy) to cysteine. Mutations in the CBS gene cause CBS deficiency, a rare recessive metabolic disease, manifested by severe hyperhomocysteinemia (HHcy) and thromboembolism, which ultimately reduces the life span. However, it was not known whether telomere shortening or mtDNA is involved in the pathology of human CBS deficiency. We quantified leukocyte telomere length (TL), mtDNA copy number, and plasma Hcy levels in CBS[-/][-] patients (n = 23) and in sex- and age-matched unaffected CBS[+/+] control individuals (n = 28) 0.08-57 years old. We found that TL was significantly increased in severely HHcy CBS[-/][-] female patients but unaffected in severely HHcy CBS[-/][-] male patients, relative to the corresponding CBS[+/+] controls who had normal plasma Hcy levels. In multiple regression analysis TL was associated with CBS genotype in women but not in men. MtDNA copy number was not significantly affected by the CBS[-/][-] genotype. Taken together, these findings identify the CBS gene as a new locus in human DNA that affects TL in women and illustrate a concept that a housekeeping metabolic gene can be involved in telomere biology. Our findings suggest that neither telomere shortening nor reduced mtDNA copy number contribute to the reduced life span in CBS[-/][-] patients.},
}
@article {pmid32767207,
year = {2020},
author = {Lopes, AC and Oliveira, PF and Pinto, S and Almeida, C and Pinho, MJ and Sá, R and Rocha, E and Barros, A and Sousa, M},
title = {Discordance between human sperm quality and telomere length following differential gradient separation/swim-up.},
journal = {Journal of assisted reproduction and genetics},
volume = {37},
number = {10},
pages = {2581-2603},
pmid = {32767207},
issn = {1573-7330},
mesh = {Adult ; Centrifugation, Density Gradient ; Humans ; Male ; Middle Aged ; *Reproductive Techniques, Assisted ; Sperm Count ; Sperm Motility/genetics ; Spermatozoa/*cytology/growth &amp; development ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: Strong evidence has suggested an important role of telomeres in meiosis, fertilization, and embryo development.<br><br>PURPOSE: To determine if sperm telomere length (STL) in sperm purified by differential gradient centrifugation followed by swim-up (selected STL) is correlated with sperm quality and clinical outcomes.<br><br>METHODS: Relative selected STL was assessed by quantitative polymerase chain reaction (Q-PCR) in 78 consecutive assisted reproductive technology (ART) treatments during 2017. Statistical analyses were performed in the totality of patients, and in normozoospermic and non-normozoospermic patients. These included correlations between selected STL and sperm quality parameters, embryological parameters (multivariable linear regression), and clinical parameters (multivariable logistic regression).<br><br>RESULTS: No significant correlations were found between selected STL and sperm quality in the total population. However, selected STL was significantly correlated with total sperm count (r&#x2009;=&#x2009;0.361; P&#x2009;=&#x2009;0.039) and sperm DNA fragmentation-post-acrosomal region pattern (r&#x2009;=&#x2009;-&#x2009;0.464; P&#x2009;=&#x2009;0.030) in normozoospermic patients. No relation was observed between selected STL and clinical outcomes in any clinical group.<br><br>CONCLUSIONS: As the correlations observed in normozoospermic patients were not representative of the whole heterogeneous population, differences in the sperm characteristics of the study population may lead to discrepant results when evaluating the association of STL with sperm quality. Since the total population selected STL was not related with sperm quality and with clinical outcomes, results do not support the use of selected STL measurement to evaluate the reproductive potential of the male patient or to predict the success rates of ART treatments.},
}
@article {pmid32766884,
year = {2021},
author = {Ajaykumar, A and Wong, GC and Yindom, LM and McHugh, G and Dauya, E and Majonga, E and Mujuru, H and Ferrand, RA and Rowland-Jones, SL and Côté, HCF},
title = {Shorter Granulocyte Telomeres Among Children and Adolescents With Perinatally Acquired Human Immunodeficiency Virus Infection and Chronic Lung Disease in Zimbabwe.},
journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America},
volume = {73},
number = {7},
pages = {e2043-e2051},
pmid = {32766884},
issn = {1537-6591},
support = {206316/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Adolescent ; Aged ; Child ; Granulocytes ; *HIV Infections/drug therapy/epidemiology ; Humans ; *Lung Diseases ; Telomere ; Zimbabwe/epidemiology ; },
abstract = {BACKGROUND: Chronic lung disease (CLD) has been reported among African children with perinatally acquired human immunodeficiency virus (HIV) infection (C-PHIV), despite combination antiretroviral therapy (cART). In adults, shorter telomere length (TL) has been reported in association with both CLD and HIV. As little is known in children, our objective was to compare TL in HIV-positive (cART-naive or -treated) and HIV-negative children with and without CLD.<br><br>METHODS: Participants included Zimbabwean C-PHIV, aged 6-16, who were either newly diagnosed and cART-naive, or on cART for >6 months, and HIV-negative controls of similar age and sex. Packed blood cell (granulocyte) TLs from 621 children were compared cross-sectionally between groups. For a subset of newly diagnosed C-PHIV, changes in TL following cART initiation were evaluated.<br><br>RESULTS: C-PHIV had shorter granulocyte TL compared with uninfected peers, regardless of cART. Among 255 C-PHIV without CLD, TL was shorter in cART-naive participants. In multivariable analyses adjusted for age, sex, CLD, and HIV/cART status, shorter TL was independently associated with older age, being HIV positive, and having reduced forced vital capacity (FVC). Last, cART initiation increased TL.<br><br>CONCLUSIONS: In this cohort, C-PHIV and those with reduced FVC have shorter granulocyte TL, possibly the result of increased immune activation and cellular turnover due to longstanding HIV infection with delayed cART initiation.},
}
@article {pmid32765866,
year = {2020},
author = {Manoy, P and Yuktanandana, P and Tanavalee, A and Tanpowpong, T and Ittipanichpong, T and Honsawek, S},
title = {Telomere shortening is associated with poor physical performance in knee osteoarthritis.},
journal = {Biomedical reports},
volume = {13},
number = {4},
pages = {27},
pmid = {32765866},
issn = {2049-9434},
abstract = {Telomere length is a hallmark characteristic of ageing and age-related diseases. Osteoarthritis (OA) is the most common cause of joint pain and physical disability in the elderly. Previous studies have revealed the role of telomere shortening in OA; however, the relationship between telomere length, muscle strength and physical performance in knee OA patients remains unknown. The aim of the present study was to investigate the association of telomere length and physical performance in patients with knee OA. A total of 202 patients with knee OA and 60 healthy controls were enrolled in the study. The quality of life was assessed using Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and Short Form Health Survey. The skeletal muscle mass was examined using bioelectrical impedance analysis, while the muscle strength was analyzed using hand grip force and isometric knee extension force. The physical performance of patients with knee OA was also investigated using gait speed, Timed up and go test (TUGT), Sit to stand test and 6-min walk test (6MWT). Blood leukocyte relative telomere length (RTL) was assessed using real time quantitative PCR. The mean blood leukocyte RTL in knee OA subjects was significantly lower compared with healthy controls (P<0.001). Knee OA patients with RTL values in the lowest quartile had a slow gait speed (P=0.006) and prolonged TUGT time (P=0.03). Multivariate regression analyses and multiple logistic regression analyses adjusted for age, sex, waist circumference, body mass index, fat mass, skeletal muscle index and the total WOMAC demonstrated that gait speed, TUGT and 6MWT were associated with longer RTL (P-trend<0.05). These findings suggested that poorer physical performance was associated with shorter RTL. Therefore, leukocyte telomere length and physical performance tests, especially gait speed, TUGT and 6MWT, could predict the health status and quality of life in patients with knee OA.},
}
@article {pmid32763773,
year = {2020},
author = {Miri, M and de Prado-Bert, P and Alahabadi, A and Najafi, ML and Rad, A and Moslem, A and Aval, HE and Ehrampoush, MH and Bustamante, M and Zare Sakhvidi, MJ and Nawrot, T and Sunyer, J and Dadvand, P},
title = {Association of greenspace exposure with telomere length in preschool children.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {266},
number = {Pt 1},
pages = {115228},
doi = {10.1016/j.envpol.2020.115228},
pmid = {32763773},
issn = {1873-6424},
mesh = {Aging ; Child ; Child, Preschool ; *Environment ; Humans ; Iran ; Leukocytes ; *Telomere ; },
abstract = {Exposure to greenspace has been associated with a wide range of health benefits; however, the available evidence on the association of this exposure with telomere length (TL), an early marker of ageing, is still scarce. We investigated the association of greenspace exposure with TL in a sample of 200 preschool children (aged 5-7 years) residing in Sabzevar, Iran (2017). We comprehensively characterized different aspects of greenspace exposure encompassing residential, kindergarten, and total (including both residential and kindergarten) surrounding greenspace (using satellite-derived Normalized Difference Vegetation Index), residential and kindergarten distance to green spaces, time spent in private gardens and public green spaces, and the number of plant pots at home. Relative leukocyte TL (LTL) in blood samples of the study participants was measured using quantitative polymerase chain reaction (qPCR). We applied mixed effects linear regression models with kindergarten and qPCR plate as random effects, to estimate the association of indicators of greenspace exposure (one at a time) with LTL, controlled for relevant covariates. We observed an inverse association between distance from home and kindergarten to green spaces larger than 5000 m[2] and LTL. Moreover, higher total surrounding greenspace at 300m and 500m buffers and higher surrounding greenspace at 300m buffer around kindergarten and home were associated with longer LTL. Furthermore, longer time spent (h/week) in the public green spaces was associated with longer LTL. Our findings for residential and kindergarten distance to any green space (regardless of the size), residential surrounding greenspace at 100m and 500m buffers, kindergarten surrounding greenspace at 100m buffer, time spent in private gardens (h/week) and the number of plant pots at home were not conclusive. Our findings were generally suggestive for a positive association between greenspace exposure and LTL in preschool children. More studies are needed to confirm these findings in other settings with different climates and populations.},
}
@article {pmid32762107,
year = {2021},
author = {Hudon, SF and Palencia Hurtado, E and Beck, JD and Burden, SJ and Bendixsen, DP and Callery, KR and Sorensen Forbey, J and Waits, LP and Miller, RA and Nielsen, &#xd3;K and Heath, JA and Hayden, EJ},
title = {Primers to highly conserved elements optimized for qPCR-based telomere length measurement in vertebrates.},
journal = {Molecular ecology resources},
volume = {21},
number = {1},
pages = {59-67},
doi = {10.1111/1755-0998.13238},
pmid = {32762107},
issn = {1755-0998},
support = {2018-SB-2842//Semiconductor Research Corporation/ ; 1145552//National Science Foundation/ ; 1263167//National Science Foundation/ ; 1807809//National Science Foundation/ ; 1826801//National Science Foundation/ ; 80NSSC17K0738/NASA/NASA/United States ; 80NSSC17K0738/NASA/NASA/United States ; },
mesh = {Animals ; DNA Primers/*genetics ; Real-Time Polymerase Chain Reaction ; Reproducibility of Results ; *Telomere/genetics ; *Vertebrates/genetics ; },
abstract = {Telomere length dynamics are an established biomarker of health and ageing in animals. The study of telomeres in numerous species has been facilitated by methods to measure telomere length by real-time quantitative PCR (qPCR). In this method, telomere length is determined by quantifying the amount of telomeric DNA repeats in a sample and normalizing this to the total amount of genomic DNA. This normalization requires the development of genomic reference primers suitable for qPCR, which remains challenging in nonmodel organism with genomes that have not been sequenced. Here we report reference primers that can be used in qPCR to measure telomere lengths in any vertebrate species. We designed primer pairs to amplify genetic elements that are highly conserved between evolutionarily distant taxa and tested them in species that span the vertebrate tree of life. We report five primer pairs that meet the specificity and reproducibility standards of qPCR. In addition, we demonstrate an approach to choose the best primers for a given species by testing the primers on multiple individuals within a species and then applying an established computational tool. These reference primers can facilitate qPCR-based telomere length measurements in any vertebrate species of ecological or economic interest.},
}
@article {pmid32761187,
year = {2021},
author = {Yeap, BB and Hui, J and Knuiman, MW and Flicker, L and Divitini, ML and Arscott, GM and Twigg, SM and Almeida, OP and Hankey, GJ and Golledge, J and Norman, PE and Beilby, JP},
title = {U-Shaped Relationship of Leukocyte Telomere Length With All-Cause and Cancer-Related Mortality in Older Men.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {76},
number = {1},
pages = {164-171},
doi = {10.1093/gerona/glaa190},
pmid = {32761187},
issn = {1758-535X},
mesh = {Aged ; Aged, 80 and over ; Cardiovascular Diseases/*genetics/*mortality ; Cause of Death ; Cohort Studies ; Humans ; *Leukocytes/ultrastructure ; Male ; Neoplasms/*genetics/*mortality ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Telomeres are essential DNA-protein complexes whose attrition results in cellular dysfunction and senescence. Leukocyte telomere length (LTL) correlates with tissue telomere length, representing a biomarker for biological age. However, its predictive value for mortality risk, and for cardiovascular versus cancer deaths, in older adults remains uncertain.<br><br>METHOD: We studied 3608 community-dwelling men aged 77.0 &#xb1; 3.6 years. Leukocyte telomere length was measured using multiplex quantitative PCR, expressed as amount of telomeric DNA relative to single-copy control gene (T/S ratio). Deaths from any cause, cardiovascular disease (CVD), and cancer were ascertained using data linkage. Curve fitting used restricted cubic splines and Cox regression analyses adjusted for age, cardiometabolic risk factors, and prevalent disease.<br><br>RESULTS: There was a U-shaped association of LTL with all-cause mortality. Men with T/S ratio in the middle quartiles had lower mortality (quartiles, Q2 vs Q1, hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.77-0.97, p = .012; Q3 vs Q1 HR = 0.88, CI 0.79-0.99, p = .032). There was no association of LTL with CVD mortality. There was a U-shaped association of LTL with cancer mortality. Men with LTL in the middle quartiles had lower risk of cancer death (Q2 vs Q1, HR = 0.73, CI 0.59-0.90, p = .004; Q3 vs Q1, HR = 0.75, CI 0.61-0.92, p = .007).<br><br>CONCLUSIONS: In older men, both shorter and longer LTL are associated with all-cause mortality. A similar U-shaped association was seen with cancer deaths, with no association found for cardiovascular deaths. Further research is warranted to explore the prognostic utility of LTL in ageing.},
}
@article {pmid32760251,
year = {2020},
author = {Levstek, T and Kozjek, E and Dolžan, V and Trebušak Podkrajšek, K},
title = {Telomere Attrition in Neurodegenerative Disorders.},
journal = {Frontiers in cellular neuroscience},
volume = {14},
number = {},
pages = {219},
pmid = {32760251},
issn = {1662-5102},
abstract = {Telomere attrition is increased in various disorders and is therefore a potential biomarker for diagnosis and/or prognosis of these disorders. The contribution of telomere attrition in the pathogenesis of neurodegenerative disorders is yet to be fully elucidated. We are reviewing the current knowledge regarding the telomere biology in two common neurodegenerative disorders, Alzheimer's disease (AD), and Parkinson's disease (PD). Furthermore, we are discussing future prospective of telomere research in these disorders. The majority of studies reported consistent evidence of the accelerated telomere attrition in AD patients, possibly in association with elevated oxidative stress levels. On the other hand in PD, various studies reported contradictory evidence regarding telomere attrition. Consequently, due to the low specificity and sensitivity, the clinical benefit of telomere length as a biomarker of neurodegenerative disease development and progression is not yet recognized. Nevertheless, longitudinal studies in large carefully selected cohorts might provide further elucidation of the complex involvement of the telomeres in the pathogenesis of neurodegenerative diseases. Telomere length maintenance is a complex process characterized by environmental, genetic, and epigenetic determinants. Thus, in addition to the selection of the study cohort, also the selection of analytical methods and types of biological samples for evaluation of the telomere attrition is of utmost importance.},
}
@article {pmid32755577,
year = {2020},
author = {Segura-Bayona, S and Villamor-Payà, M and Attolini, CS and Koenig, LM and Sanchiz-Calvo, M and Boulton, SJ and Stracker, TH},
title = {Tousled-Like Kinases Suppress Innate Immune Signaling Triggered by Alternative Lengthening of Telomeres.},
journal = {Cell reports},
volume = {32},
number = {5},
pages = {107983},
pmid = {32755577},
issn = {2211-1247},
support = {/WT_/Wellcome Trust/United Kingdom ; FC0010048/CRUK_/Cancer Research UK/United Kingdom ; FC0010048/MRC_/Medical Research Council/United Kingdom ; FC0010048/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Cell Line, Tumor ; Heterochromatin/metabolism ; Humans ; *Immunity, Innate ; Membrane Proteins/metabolism ; Neoplasms/enzymology/immunology ; Nucleotidyltransferases/metabolism ; Protein Kinases/*metabolism ; Protein Serine-Threonine Kinases/*metabolism ; Recombination, Genetic/genetics ; *Signal Transduction ; Telomere/metabolism ; *Telomere Homeostasis ; },
abstract = {The Tousled-like kinases 1 and 2 (TLK1/2) control histone deposition through the ASF1 histone chaperone and influence cell cycle progression and genome maintenance, yet the mechanisms underlying TLK-mediated genome stability remain uncertain. Here, we show that TLK loss results in severe chromatin decompaction and altered genome accessibility, particularly affecting heterochromatic regions. Failure to maintain heterochromatin increases spurious transcription of repetitive elements and induces features of alternative lengthening of telomeres (ALT). TLK depletion culminates in a cGAS-STING-TBK1-mediated innate immune response that is independent of replication-stress signaling and attenuated by the depletion of factors required to produce extra-telomeric DNA. Analysis of human cancers reveals that chromosomal instability correlates with high TLK2 and low STING levels in many cohorts. Based on these findings, we propose that high TLK levels contribute to immune evasion in chromosomally unstable and ALT+ cancers.},
}
@article {pmid32748415,
year = {2021},
author = {Fang, B and Yan, E and Tung, K and Liu, Z and Ip, P},
title = {Association between elder abuse and telomere shortening in older adults: A 2-year prospective study.},
journal = {International journal of geriatric psychiatry},
volume = {36},
number = {1},
pages = {54-63},
doi = {10.1002/gps.5390},
pmid = {32748415},
issn = {1099-1166},
mesh = {Aged ; China/epidemiology ; *Elder Abuse ; Humans ; Prospective Studies ; Telomere/genetics ; *Telomere Shortening ; },
abstract = {BACKGROUNDS: Elder abuse is a public health issue associated with increased morbidity and mortality. Its impact on victims' health at the cellular level, however, remains unknown. This study assessed the association between abuse exposure and shortening of telomere length (TL), a promising molecular marker for biological aging, in older victims.<br><br>SETTING: The geriatric departments of three Grade-A hospitals in the People's Republic of China (PRC).<br><br>PARTICIPANTS: Six hundred Chinese older adults, including 300 abused victims and 300 non-abused controls were randomly drawn respectively from a larger sample of 467 abused and 518 non-abused older adults recruited at baseline. Participants were assessed for physical and psychological abuse exposure at baseline between September 2015 and February 2016 and assessed for TL 2&#x2009;years after the abuse assessment.<br><br>MEASUREMENTS: TL was quantified using a quantitative PCR method and expressed as T/S ratio (the ratio of telomere repeat copy numbers to single-copy gene numbers). Physical and psychological abuse was measured using the Revised Conflicts Tactics Scale.<br><br>RESULTS: Adjusting for demographic, medical, and behavioral confounders, physical and psychological abuse exposure at baseline were independently associated with shorter TL at follow-up. The association was the most significant between multiple forms of abuse (physical and psychological) exposure and shorter TL.<br><br>CONCLUSION: This study provides the first evidence on the relationship between abuse and shortened TL in older victims, implying the potential effect of elder abuse on accelerated cellular aging. The findings suggest the importance of routinely assessing and intervening abuse in older adults by healthcare professionals, to promote and maintain physical health in older adults.},
}
@article {pmid32745307,
year = {2020},
author = {Seeker, LA},
title = {Telomere shortening correlates with harsh weather conditions in the bat species Myotis myotis.},
journal = {Molecular ecology},
volume = {29},
number = {16},
pages = {2951-2953},
doi = {10.1111/mec.15580},
pmid = {32745307},
issn = {1365-294X},
mesh = {Animals ; Cellular Senescence ; *Chiroptera/genetics ; Humans ; Telomere/genetics ; *Telomere Shortening ; Weather ; },
abstract = {The relationship of telomere shortening and cellular ageing in cultured cells such as fibroblasts is straightforward: telomeres shorten with an increasing number of cell divisions until they trigger replicative senescence which prevents further mitotic cycles. But studies investigating the relationship between telomere shortening and ageing in whole organisms show contrasting results: while there is a clear decline in telomere length (TL) with chronological age in some species such as humans, no such decline is observed in others. In this issue of Molecular Ecology, Foley et al. (2020) show that experiencing harsh weather conditions correlates with longitudinal telomere shortening in the bat species Myotis myotis, whereas chronological age does not (Foley et al., 2020). Further, the authors investigated whether genetics influence TL and find a low heritability (h[2] = 0.01-0.06) again suggesting that environmental effects are the dominant drivers of variation in TL in this species. These are important findings as there is disagreement in the literature about the relative magnitude of genetic and environmental effects contributing to TL variation in different species. This paper investigating the impact of environmental effects makes a novel and important contribution to the literature on TL in free-living mammals.},
}
@article {pmid32744739,
year = {2021},
author = {Kirschner, M and Vieri, M and Kricheldorf, K and Ferreira, MSV and Wlodarski, MW and Schwarz, M and Balabanov, S and Rolles, B and Isfort, S and Koschmieder, S and Höchsmann, B and Panse, J and Brümmendorf, TH and Beier, F},
title = {Androgen derivatives improve blood counts and elongate telomere length in adult cryptic dyskeratosis congenita.},
journal = {British journal of haematology},
volume = {193},
number = {3},
pages = {669-673},
doi = {10.1111/bjh.16997},
pmid = {32744739},
issn = {1365-2141},
mesh = {Adult ; Androgens/*pharmacology ; Blood Cell Count ; Dyskeratosis Congenita/*blood/drug therapy/genetics ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Mutation ; Myelodysplastic Syndromes/chemically induced/genetics/metabolism ; RNA/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomere Homeostasis/*drug effects ; },
abstract = {Dyskeratosis Congenita (DKC) is a systemic disorder caused by mutations resulting in impaired telomere maintenance. Clinical features include bone marrow failure and an increased risk of developing hematological malignancies. There are conflicting data whether androgen derivatives (AD) can elongate telomeres in vivo and whether AD treatment enhances the risk of gaining myelodysplastic syndrome-related mutations. Seven TERC or TERT-mutated DKC patients underwent AD treatment. All patients revealed hematological response. Telomere length of lymphocytes and granulocytes increased significantly and no MDS-related mutations were detected. Pending longer follow-up, treatment with AD seems to represent an efficient and safe therapy for DKC patients.},
}
@article {pmid32742684,
year = {2020},
author = {Olsson, M and Geraghty, NJ and Wapstra, E and Wilson, M},
title = {Telomere length varies substantially between blood cell types in a reptile.},
journal = {Royal Society open science},
volume = {7},
number = {6},
pages = {192136},
pmid = {32742684},
issn = {2054-5703},
abstract = {Telomeres are repeat sequences of non-coding DNA-protein molecules that cap or intersperse metazoan chromosomes. Interest in telomeres has increased exponentially in recent years, to now include their ongoing dynamics and evolution within natural populations where individuals vary in telomere attributes. Phylogenetic analyses show profound differences in telomere length across non-model taxa. However, telomeres may also differ in length within individuals and between tissues. The latter becomes a potential source of error when researchers use different tissues for extracting DNA for telomere analysis and scientific inference. A commonly used tissue type for assessing telomere length is blood, a tissue that itself varies in terms of nuclear content among taxa, in particular to what degree their thrombocytes and red blood cells (RBCs) contain nuclei or not. Specifically, when RBCs lack nuclei, leucocytes become the main source of telomeric DNA. RBCs and leucocytes differ in lifespan and how long they have been exposed to 'senescence' and erosion effects. We report on a study in which cells in whole blood from individual Australian painted dragon lizards (Ctenophorus pictus) were identified using flow cytometry and their telomere length simultaneously measured. Lymphocyte telomeres were on average 270% longer than RBC telomeres, and in azurophils (a reptilian monocyte), telomeres were more than 388% longer than those in RBCs. If this variation in telomere length among different blood cell types is a widespread phenomenon, and DNA for comparative telomere analyses are sourced from whole blood, evolutionary inference of telomere traits among taxa may be seriously complicated by the blood cell type comprising the main source of DNA.},
}
@article {pmid32742450,
year = {2020},
author = {Li, Z and Song, Y and Xu, Y and Shen, Y and Zhang, N and Yang, M and Yu, D},
title = {Identification of Leukocyte telomere length-related genetic variants contributing to predisposition of Esophageal Squamous Cell Carcinoma.},
journal = {Journal of Cancer},
volume = {11},
number = {17},
pages = {5025-5031},
pmid = {32742450},
issn = {1837-9664},
abstract = {Background: Cancers may arise from cells with dysregulated telomeric functions due to shorten telomere length. We and others previously found that short leukocyte telomere length was associated with markedly evaluated risk of esophageal squamous cell carcinoma (ESCC). Hence, we hypothesized that single nucleotide polymorphisms (SNPs) associated with shorter telomere length may contribute to ESCC predisposition. Methods: We systematically evaluated association between seven candidate seven SNPs (CXCR4 rs6430612, TERT rs13172201, TERT rs10069690, TERT rs2853676, TERT rs451360, OBFC1 rs4387287, and VPS34 rs2162440) and ESCC risk in two case-control sets consisting of 1588 ESCC cases and 1600 controls. Logistic regression models were utilized to estimate associations between SNPs and ESCC susceptibility and odds ratios (ORs) and their 95% confidence intervals (95% CIs) were computed. Results: We firstly identified three SNPs (rs6430612, rs13172201 and rs4387287) which are significantly associated with telomere length in Chinese populations (all P<0.05). Importantly, CXCR4 rs6430612 and OBFC1 rs4387287 polymorphisms significantly confer reduced risk of ESCC (P=1.7×10[-7] and P=3.9×10[-5]). On the contrary, we observed an evidently increased risk for ESCC development associated with TERT rs13172201 genetic variant (P=2.2×10[-4]). Conclusions: In summary, rs6430612, rs13172201 and rs4387287 might be key genetic components in complicated regulation of telomere length and contributing to ESCC predisposition. Our results elucidate the prevalent involvement of genetic variants in telomere biology and further provide pathogenic insights into the role of telomeres in cancer development.},
}
@article {pmid32742149,
year = {2020},
author = {Davis, SK and Xu, R and Khan, RJ and Gaye, A},
title = {Adiposity and Leukocyte Telomere Length in US Adults by Sex-Specific Race/Ethnicity: National Health and Nutrition Examination Survey.},
journal = {Ethnicity &amp; disease},
volume = {30},
number = {3},
pages = {441-450},
pmid = {32742149},
issn = {1945-0826},
mesh = {Adiposity/*ethnology ; Adult ; Body Mass Index ; Cross-Sectional Studies ; *Ethnicity/genetics/statistics &amp; numerical data ; Female ; Humans ; Leukocytes/*physiology ; Male ; Nutrition Surveys ; *Obesity/diagnosis/ethnology/genetics ; Sex Factors ; Telomere Homeostasis/*physiology ; United States/epidemiology ; Waist Circumference/ethnology ; },
abstract = {OBJECTIVE: Little is known about the relationship between adiposity and telomere length in the United States population. The objective of our research was to examine this relationship in a representative, socioeconomically and sex-specific, diverse racial/ethnic population in the United States.<br><br>METHODS: Body mass index (BMI), % total body fat (TBF) and waist circumference (WC) with leukocyte telomere length (LTL) were examined according to sex-specific race/ethnicity using separate adjusted multivariate linear regressions on a sample of 4,919 respondents aged 20-84 years from the National Health and Nutrition Examination Survey's 1999-2002 data.<br><br>RESULTS: LTL was shortened .41%, .44%, and .16% in African American (AA) women and was associated with increasing BMI, %TBF, and WC, (&#x3b2;:-.0041, 95%CI: -.0070, -.0012; P=.007; &#x3b2;:-.0044, 95% CI: -.0081, -.0007; P=.02; &#x3b2;:-.0016, 95%CI: -.0031, -.0001; P=.04, respectively). LTL was shortened .29% in White women and was associated with increasing %TBF (&#x3b2;:-.0029, 95%CI: -.0048, -.0009; P=.006). There were no associations among AA men, White men or Mexican American men and women.<br><br>CONCLUSIONS: LTL is associated with an obesity phenotype in AA women. Tailored intervention is needed to ameliorate the burden of excess adiposity and subsequent cellular aging.},
}
@article {pmid32741725,
year = {2020},
author = {Peña, E and Powell, TR and Arenas, C and Cardoner, N and Rebasa, P and Luna, A and Caixàs, A and Rosa, A},
title = {Longitudinal changes in telomere length in a cohort of obese patients submitted to bariatric surgery: a 2-year follow-up.},
journal = {Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery},
volume = {16},
number = {11},
pages = {1794-1801},
doi = {10.1016/j.soard.2020.06.027},
pmid = {32741725},
issn = {1878-7533},
support = {MR/N014863/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {*Bariatric Surgery ; *Diabetes Mellitus, Type 2 ; Follow-Up Studies ; Humans ; Obesity/genetics/surgery ; Spain ; Telomere/genetics ; Telomere Shortening ; },
abstract = {BACKGROUND: Telomere length (TL) is one biomarker of cell aging used to explore the effects of the environment on age-related pathologies. Obesity and high body mass index have been identified as a risk factors for shortened TL.<br><br>OBJECTIVE: To evaluate TL in different subtypes of obese patients, and to examine changes in TL in relation to weight loss after bariatric surgery.<br><br>SETTING: University Hospital in Spain.<br><br>METHODS: A cohort of 94 patients submitted to bariatric surgery were followed-up during 24 months (t24m: lost to follow-up = 0%). All patients were evaluated before surgery (t0) and during the postoperative period (t6m, t12m, and t24m) for body mass index and metabolic variables. We assessed TL at each timepoint using quantitative polymerase chain reactions and the telomere sequence to single-copy gene sequence ratio method.<br><br>RESULTS: Patients with class III obesity showed significantly shorter TL at baseline than those patients with class II obesity (P = .027). No differences in TL were found between patients with or without type 2 diabetes or metabolic syndrome. Longitudinal analysis did not show an effect of time, type of surgery, age, or sex on TL. However, a generalized estimating equation model showed that TL was&#xa0;shorter amongst class III obesity patients across the time course (P = .008). Comparison between patients with obesity class II and class III showed differences in TL at t6m (adjusted P = .024), whereby class II patients had longer TL. However, no difference was observed at the other evaluated times.<br><br>CONCLUSION: Obesity severity may have negative effects on TL independently of type 2 diabetes or metabolic syndrome. Although TL is significantly longer in class II obesity patients relative to class III 6 months after bariatric surgery. This difference is not apparent after 24 months.},
}
@article {pmid32734707,
year = {2020},
author = {Heidinger, BJ and Young, RC},
title = {Cross-Generational Effects of Parental Age on Offspring Longevity: Are Telomeres an Important Underlying Mechanism?.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {42},
number = {9},
pages = {e1900227},
doi = {10.1002/bies.201900227},
pmid = {32734707},
issn = {1521-1878},
support = {1656194//National Science Foundation/International ; },
mesh = {Humans ; *Longevity/genetics ; Parents ; *Telomere/genetics ; Telomere Shortening ; },
abstract = {Parental age at offspring conception often influences offspring longevity, but the mechanisms underlying this link are poorly understood. One mechanism that may be important is telomeres, highly conserved, repetitive sections of non-coding DNA that form protective caps at chromosome ends and are often positively associated with longevity. Here, the potential pathways by which the age of the parents at the time of conception may impact offspring telomeres are described first, including direct effects on parental gamete telomeres and indirect effects on offspring telomere loss during pre- or post-natal development. Then a surge of recent studies demonstrating the effects of parental age on offspring telomeres in diverse taxa are reviewed. In doing so, important areas for future research and experimental approaches that will enhance the understanding of how and when these effects likely occur are highlighted. It is concluded by considering the potential evolutionary consequences of parental age on offspring telomeres.},
}
@article {pmid32733650,
year = {2020},
author = {Achrem, M and Szućko, I and Kalinka, A},
title = {The epigenetic regulation of centromeres and telomeres in plants and animals.},
journal = {Comparative cytogenetics},
volume = {14},
number = {2},
pages = {265-311},
pmid = {32733650},
issn = {1993-0771},
abstract = {The centromere is a chromosomal region where the kinetochore is formed, which is the attachment point of spindle fibers. Thus, it is responsible for the correct chromosome segregation during cell division. Telomeres protect chromosome ends against enzymatic degradation and fusions, and localize chromosomes in the cell nucleus. For this reason, centromeres and telomeres are parts of each linear chromosome that are necessary for their proper functioning. More and more research results show that the identity and functions of these chromosomal regions are epigenetically determined. Telomeres and centromeres are both usually described as highly condensed heterochromatin regions. However, the epigenetic nature of centromeres and telomeres is unique, as epigenetic modifications characteristic of both eu- and heterochromatin have been found in these areas. This specificity allows for the proper functioning of both regions, thereby affecting chromosome homeostasis. This review focuses on demonstrating the role of epigenetic mechanisms in the functioning of centromeres and telomeres in plants and animals.},
}
@article {pmid32733163,
year = {2020},
author = {Yu, J and Liu, H and He, S and Li, P and Ma, C and Ma, M and Liu, Y and Lv, L and Ping, F and Zhang, H and Li, W and Sun, Q and Xu, L and Li, Y},
title = {Corrigendum to "Dietary Magnesium Intake and Leukocyte Telomere Attrition in Adults: The Regulatory Role of Serum Tumor Necrosis Factor α".},
journal = {Mediators of inflammation},
volume = {2020},
number = {},
pages = {2594730},
pmid = {32733163},
issn = {1466-1861},
abstract = {[This corrects the article DOI: 10.1155/2020/7610436.].},
}
@article {pmid32731419,
year = {2020},
author = {Molina-Carrión, S and Brochado-Kith, &#xd3; and González-García, J and Berenguer, J and Díez, C and Llop, E and Hontañón, V and Ibañez-Samaniego, L and Montes, ML and Resino, S and Fernández-Rodríguez, A and Jiménez-Sousa, M&#xc1;},
title = {Telomere Length Increase in HIV/HCV-Coinfected Patients with Cirrhosis after HCV Eradication with Direct-Acting Antivirals.},
journal = {Journal of clinical medicine},
volume = {9},
number = {8},
pages = {},
pmid = {32731419},
issn = {2077-0383},
support = {1.010.932//Universidad Alfonso X el Sabio/ ; CP17CIII/00007//Instituto de Salud Carlos III/ ; PI18CIII/00028//Instituto de Salud Carlos III/ ; PI18CIII/00020//Instituto de Salud Carlos III/ ; PI15CIII/00031//Instituto de Salud Carlos III/ ; PI14/01094//Instituto de Salud Carlos III/ ; PI17/00657//Instituto de Salud Carlos III/ ; PI17/00903//Instituto de Salud Carlos III/ ; PI14CIII/00011//Instituto de Salud Carlos III/ ; PI17CIII/00003//Instituto de Salud Carlos III/ ; },
abstract = {INTRODUCTION: Human immunodeficiency virus (HIV) infection and cirrhosis are associated with a senescent phenotype that decreases telomere length. We evaluated the impact of hepatitis C virus (HCV) elimination on telomere length in patients with advanced HCV-related cirrhosis after sustained virological response (SVR), with all-oral direct-acting antiviral agents (DAAs).<br><br>METHODS: Prospective study of 60 HIV/HCV-coinfected and 30 HCV-monoinfected patients with advanced HCV cirrhosis (liver decompensation or liver stiffness measurement (LSM) &#x2265; 25 kPa, hepatic liver pressure gradient (HVPG) &#x2265; 10 mmHg, or Child-Pugh-Turcotte (CPT) &#x2265; 7). The relative telomere length (RTL) was quantified by real-time multiplex PCR (MMqPCR) on peripheral blood mononuclear cells at baseline and 48 weeks after HCV treatment. Generalized linear models (GLMs) adjusted for the most relevant clinical and epidemiological variables and mixed GLMs were used.<br><br>RESULTS: In comparison with HCV-monoinfected patients, HIV/HCV-coinfected patients were younger (p < 0.001), had lower body mass index (BMI) (p = 0.002), and had been exposed less frequently to interferons (p = 0.011). In addition, they were more frequently men (p = 0.011), smokers (p = 0.005), prior intravenous drug users (IVDUs) (p < 0.001), and alcohol abusers (p = 0.005). RTL was significantly lower in HIV/HCV-coinfected patients than in HCV-monoinfected patients, both at baseline (p < 0.001), and at the end of follow-up (p = 0.032). A significant RTL increase over time was found only for HIV/HCV-coinfected patients (p < 0.001), especially in those patients with compensated cirrhosis (p < 0.001).<br><br>CONCLUSION: HCV eradication with all-oral DAAs was associated with an increase in telomere length in HIV/HCV-coinfected patients with advanced cirrhosis, particularly in compensated patients. This finding suggests that HCV clearance may have implications in age-related conditions in this population group.},
}
@article {pmid32730558,
year = {2020},
author = {Canudas, S and Becerra-Tomás, N and Hernández-Alonso, P and Galié, S and Leung, C and Crous-Bou, M and De Vivo, I and Gao, Y and Gu, Y and Meinilä, J and Milte, C and García-Calzón, S and Marti, A and Boccardi, V and Ventura-Marra, M and Salas-Salvadó, J},
title = {Mediterranean Diet and Telomere Length: A Systematic Review and Meta-Analysis.},
journal = {Advances in nutrition (Bethesda, Md.)},
volume = {11},
number = {6},
pages = {1544-1554},
pmid = {32730558},
issn = {2156-5376},
support = {P30 DK092926/DK/NIDDK NIH HHS/United States ; R01 AG059013/AG/NIA NIH HHS/United States ; },
mesh = {Cross-Sectional Studies ; *Diet, Mediterranean ; Humans ; Prospective Studies ; Telomere ; Telomere Shortening ; },
abstract = {Accelerated telomere shortening has been associated with several age-related diseases and/or decreased lifespan in humans. The Mediterranean diet (MedDiet) is considered to be 1 of the most recognized diets for disease prevention and healthy aging, partially due to its demonstrated anti-inflammatory and antioxidative properties which may impact on telomere length (TL). The aim of this meta-analysis was to determine the associations between MedDiet adherence and TL maintenance. MEDLINE-PubMed and Cochrane databases were searched up to December 2018 for studies evaluating the association between MedDiet adherence and TL in blood cells. Two reviewers, working independently, screened all titles and abstracts to identify studies that met the inclusion criteria [cross-sectional, case-control, and prospective cohort studies and randomized clinical trials (RCTs) published in English and excluded nonoriginal articles]. Data were pooled by the generic inverse variance method using the random effects model and expressed as standardized mean difference (SMD). Heterogeneity was identified using the Cochran Q test and quantified by the I2 statistic. A total of 8 original cross-sectional studies were included for the quantitative meta-analysis, comprising a total of 13,733 participants from 5 countries. A positive association between adherence to the MedDiet and TL was observed in all meta-analyses, with the exception of those conducted only in men: SMD (95% CI) of 0.130 (0.029; 0.231) for all subjects, 0.078 (0.005; 0.152) for women, and 0.095 (-0.005; 0.195) for men. Only 1 prospective cohort study and 1 RCT were identified, therefore, we could not undertake a meta-analysis for these study designs. The present meta-analysis of cross-sectional studies demonstrates that higher MedDiet adherence is associated with longer TL. At the same time, larger and high-quality prospective studies and clinical trials are warranted to confirm this association.},
}
@article {pmid32728890,
year = {2020},
author = {McAninch, D and Bianco-Miotto, T and Gatford, KL and Leemaqz, SY and Andraweera, PH and Garrett, A and Plummer, MD and Dekker, GA and Roberts, CT and Smithers, LG and Grieger, JA},
title = {The metabolic syndrome in pregnancy and its association with child telomere length.},
journal = {Diabetologia},
volume = {63},
number = {10},
pages = {2140-2149},
doi = {10.1007/s00125-020-05242-0},
pmid = {32728890},
issn = {1432-0428},
support = {GNT1174971//National Health and Medical Research Council/International ; GNT1090778//National Health and Medical Research Council, Peter Doherty Early Career Fellowship/International ; GNT 161305//Channel 7 Children's Research Foundation/International ; },
mesh = {Adult ; Australia/epidemiology ; Body Mass Index ; Child ; Cohort Studies ; Female ; Humans ; Ireland/epidemiology ; Male ; Metabolic Syndrome/*epidemiology ; New Zealand/epidemiology ; Pregnancy ; Pregnancy Complications/*epidemiology ; Prenatal Exposure Delayed Effects/*epidemiology/metabolism ; Prospective Studies ; Telomere/*metabolism ; *Telomere Shortening ; United Kingdom/epidemiology ; Young Adult ; },
abstract = {AIMS/HYPOTHESIS: The aim of this study was to determine whether presence of the metabolic syndrome in pregnancy associates with child telomere length or child anthropometry (weight, BMI) and BP, measured at 10 years of age.<br><br>METHODS: The Screening for Pregnancy Endpoints study (SCOPE) was a multicentre, international prospective cohort of nulliparous pregnant women recruited from Australia, New Zealand, Ireland and the UK (N&#x2009;=&#x2009;5628). The current analysis is a 10&#xa0;year follow-up of SCOPE pregnant women and their children, from the Australian cohort. Clinical data collected at 14-16&#xa0;weeks' gestation during the SCOPE study were used to diagnose the metabolic syndrome using IDF criteria. Telomere length, a biomarker of ageing, was assessed by quantitative PCR from children's saliva collected at 10&#xa0;years of age.<br><br>RESULTS: In women who completed follow-up (n&#x2009;=&#x2009;255), 20% had the metabolic syndrome in pregnancy. After adjusting for a range of confounders, children of mothers who had the metabolic syndrome in pregnancy had 14% shorter telomeres than children of mothers without the metabolic syndrome in pregnancy (mean difference -0.36 [95% CI -0.74, 0.01]). Height- and weight-for-age, and BMI z scores were similar in children of mothers who did and did not have the metabolic syndrome during pregnancy.<br><br>CONCLUSIONS/INTERPRETATION: Children of mothers who had the metabolic syndrome in pregnancy have shorter telomeres, a biomarker of accelerated ageing. These findings warrant further studies in larger cohorts of children, as well as investigations into whether telomere length measured in cord blood associates with telomere length in childhood.},
}
@article {pmid32725240,
year = {2021},
author = {Engel, T and Raffenberg, M and Schoepf, IC and Kootstra, NA and Reiss, P and Thorball, CW and Hasse, B and Hirzel, C and Wissel, K and Roth, JA and Bernasconi, E and Darling, KEA and Calmy, A and Fellay, J and Kouyos, RD and Günthard, HF and Ledergerber, B and Tarr, PE and , },
title = {Telomere Length, Traditional Risk Factors, Factors Related to Human Immunodeficiency Virus (HIV) and Coronary Artery Disease Events in Swiss Persons Living With HIV.},
journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America},
volume = {73},
number = {7},
pages = {e2070-e2076},
doi = {10.1093/cid/ciaa1034},
pmid = {32725240},
issn = {1537-6591},
support = {177499/SNSF_/Swiss National Science Foundation/Switzerland ; 177499//Swiss HIV Cohort Study/ ; },
mesh = {Cohort Studies ; *Coronary Artery Disease/epidemiology/genetics ; Female ; HIV ; *HIV Infections/complications/epidemiology ; Humans ; Male ; Middle Aged ; Risk Factors ; Switzerland/epidemiology ; Telomere/genetics ; },
abstract = {BACKGROUND: Leukocyte telomere length (TL) shortens with age and is associated with coronary artery disease (CAD) events in the general population. Persons living with human immunodeficiency virus (HIV; PLWH) may have accelerated atherosclerosis and shorter TL than the general population. It is unknown whether TL is associated with CAD in PLWH.<br><br>METHODS: We measured TL by quantitative polymerase chain reaction (PCR) in white Swiss HIV Cohort Study participants. Cases had a first CAD event during 1 January 2000 to 31 December 2017. We matched 1-3 PLWH controls without CAD events on sex, age, and observation time. We obtained univariable and multivariable odds ratios (OR) for CAD from conditional logistic regression analyses.<br><br>RESULTS: We included 333 cases (median age 54 years; 14% women; 83% with suppressed HIV RNA) and 745 controls. Median time (interquartile range) of TL measurement was 9.4 (5.9-13.8) years prior to CAD event. Compared to the 1st (shortest) TL quintile, participants in the 5th (longest) TL quintile had univariable and multivariable CAD event OR&#x2005;=&#x2005;0.56 (95% confidence interval [CI], .35-.91) and OR&#x2005;=&#x2005;0.54 (95% CI, .31-.96). Multivariable OR for current smoking was 1.93 (95% CI, 1.27-2.92), dyslipidemia OR&#x2005;=&#x2005;1.92 (95% CI, 1.41-2.63), and for recent abacavir, cumulative lopinavir, indinavir, and darunavir exposure was OR&#x2005;=&#x2005;1.82 (95% CI, 1.27-2.59), OR&#x2005;=&#x2005;2.02 (95% CI, 1.34-3.04), OR&#x2005;=&#x2005;3.42 (95% CI, 2.14-5.45), and OR&#x2005;=&#x2005;1.66 (95% CI, 1.00-2.74), respectively. The TL-CAD association remained significant when adjusting only for Framingham risk score, when excluding TL outliers, and when adjusting for CMV-seropositivity, HCV-seropositivity, time spent with detectable HIV viremia, and injection drug use.<br><br>CONCLUSIONS: In PLWH, TL measured >9 years before, is independently associated with CAD events after adjusting for multiple traditional and HIV-related factors.},
}
@article {pmid32724340,
year = {2020},
author = {Trybek, T and Kowalik, A and Góźdź, S and Kowalska, A},
title = {Telomeres and telomerase in oncogenesis.},
journal = {Oncology letters},
volume = {20},
number = {2},
pages = {1015-1027},
pmid = {32724340},
issn = {1792-1074},
abstract = {Telomeres are located at the ends of chromosomes and protect them from degradation. Suppressing the activity of telomerase, a telomere-synthesizing enzyme, and maintaining short telomeres is a protective mechanism against cancer in humans. In most human somatic cells, the expression of telomerase reverse transcriptase (TERT) is repressed and telomerase activity is inhibited. This leads to the progressive shortening of telomeres and inhibition of cell growth in a process called replicative senescence. Most types of primary cancer exhibit telomerase activation, which allows uncontrolled cell proliferation. Previous research indicates that TERT activation also affects cancer development through activities other than the canonical function of mediating telomere elongation. Recent studies have improved the understanding of the structure and function of telomeres and telomerase as well as key mechanisms underlying the activation of TERT and its role in oncogenesis. These advances led to a search for drugs that inhibit telomerase as a target for cancer therapy. The present review article summarizes the organization and function of telomeres, their role in carcinogenesis, and advances in telomerase-targeted therapy.},
}
@article {pmid32722302,
year = {2020},
author = {In der Stroth, L and Tharehalli, U and Günes, C and Lechel, A},
title = {Telomeres and Telomerase in the Development of Liver Cancer.},
journal = {Cancers},
volume = {12},
number = {8},
pages = {},
pmid = {32722302},
issn = {2072-6694},
support = {GRK2254/C3 - HEIST//Deutsche Forschungsgemeinschaft/ ; GU 569/6-1//Deutsche Forschungsgemeinschaft/ ; },
abstract = {Liver cancer is one of the most common cancer types worldwide and the fourth leading cause of cancer-related death. Liver carcinoma is distinguished by a high heterogeneity in pathogenesis, histopathology and biological behavior. Dysregulated signaling pathways and various gene mutations are frequent in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which represent the two most common types of liver tumors. Both tumor types are characterized by telomere shortening and reactivation of telomerase during carcinogenesis. Continuous cell proliferation, e.g., by oncogenic mutations, can cause extensive telomere shortening in the absence of sufficient telomerase activity, leading to dysfunctional telomeres and genome instability by breakage-fusion-bridge cycles, which induce senescence or apoptosis as a tumor suppressor mechanism. Telomerase reactivation is required to stabilize telomere functionality and for tumor cell survival, representing a genetic risk factor for the development of liver cirrhosis and liver carcinoma. Therefore, telomeres and telomerase could be useful targets in hepatocarcinogenesis. Here, we review similarities and differences between HCC and iCCA in telomere biology.},
}
@article {pmid32719516,
year = {2020},
author = {Maciejowski, J and Chatzipli, A and Dananberg, A and Chu, K and Toufektchan, E and Klimczak, LJ and Gordenin, DA and Campbell, PJ and de Lange, T},
title = {APOBEC3-dependent kataegis and TREX1-driven chromothripsis during telomere crisis.},
journal = {Nature genetics},
volume = {52},
number = {9},
pages = {884-890},
pmid = {32719516},
issn = {1546-1718},
support = {R35 CA210036/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; ZIA ES103266/ImNIH/Intramural NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R00 CA212290/CA/NCI NIH HHS/United States ; },
mesh = {APOBEC Deaminases ; Cell Line, Tumor ; Chromothripsis ; Cytidine Deaminase/*genetics ; Cytosine Deaminase/genetics ; Exodeoxyribonucleases/*genetics ; Genomic Instability/genetics ; Humans ; Mutation/genetics ; Neoplasms/genetics ; Phosphoproteins/*genetics ; Telomere/*genetics ; U937 Cells ; },
abstract = {Chromothripsis and kataegis are frequently observed in cancer and may arise from telomere crisis, a period of genome instability during tumorigenesis when depletion of the telomere reserve generates unstable dicentric chromosomes[1-5]. Here we examine the mechanism underlying chromothripsis and kataegis by using an in vitro telomere crisis model. We show that the cytoplasmic exonuclease TREX1, which promotes the resolution of dicentric chromosomes[4], plays a prominent role in chromothriptic fragmentation. In the absence of TREX1, the genome alterations induced by telomere crisis primarily involve breakage-fusion-bridge cycles and simple genome rearrangements rather than chromothripsis. Furthermore, we show that the kataegis observed at chromothriptic breakpoints is the consequence of cytosine deamination by APOBEC3B. These data reveal that chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B.},
}
@article {pmid32710419,
year = {2020},
author = {Khosravi, S and Dreissig, S and Schindele, P and Wolter, F and Rutten, T and Puchta, H and Houben, A},
title = {Live-Cell CRISPR Imaging in Plant Cells with a Telomere-Specific Guide RNA.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2166},
number = {},
pages = {343-356},
doi = {10.1007/978-1-0716-0712-1_20},
pmid = {32710419},
issn = {1940-6029},
mesh = {CRISPR-Associated Protein 9/genetics ; CRISPR-Cas Systems/*genetics ; Chromatin/genetics/metabolism ; Clustered Regularly Interspaced Short Palindromic Repeats/*genetics ; Genetic Loci ; Green Fluorescent Proteins/genetics ; Microscopy, Confocal/methods ; Plant Cells/*metabolism ; Plant Leaves/*cytology ; RNA, Guide, CRISPR-Cas Systems/*genetics ; Staphylococcus aureus/genetics ; Streptococcus pyogenes/genetics ; Telomere/*genetics/metabolism ; Nicotiana/*cytology ; },
abstract = {Chromatin organization is highly dynamic in living cells. Therefore, it might have a regulatory role over biological mechanisms like transcription, replication, and DNA repair. To elucidate how these mechanisms are regulated, it is required to establish imaging methods to visualize the chromatin dynamic in living cells. Here, we provide a protocol for a live plant cell imaging technique based on application of two orthologs of the bacterial clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) from Streptococcus pyogenes and Staphylococcus aureus. This technique uses the inactive variants of Cas9 combined with different fluorescent proteins (GFP and mRuby) and telomere-specific guide RNA to target telomeric repeats in Nicotiana benthamiana. Our immuno-FISH data revealed that signals arising from the CRISPR/dCas9 method are specifically belonging to telomeric regions.},
}
@article {pmid32709557,
year = {2020},
author = {Wilson, SH},
title = {Telomeres come to life thanks to an exciting review article in this issue.},
journal = {DNA repair},
volume = {94},
number = {},
pages = {102904},
doi = {10.1016/j.dnarep.2020.102904},
pmid = {32709557},
issn = {1568-7856},
mesh = {Cellular Senescence ; Molecular Biology ; *Telomerase/genetics/metabolism ; *Telomere/genetics/metabolism ; },
}
@article {pmid32708340,
year = {2020},
author = {Armendáriz-Castillo, I and López-Cortés, A and García-Cárdenas, J and Guevara-Ramírez, P and Leone, PE and Pérez-Villa, A and Yumiceba, V and Zambrano, AK and Guerrero, S and Paz-Y-Miño, C},
title = {TCGA Pan-Cancer Genomic Analysis of Alternative Lengthening of Telomeres (ALT) Related Genes.},
journal = {Genes},
volume = {11},
number = {7},
pages = {},
pmid = {32708340},
issn = {2073-4425},
mesh = {Genetic Predisposition to Disease ; Humans ; Neoplasms/*genetics/metabolism ; Protein Interaction Maps ; *Telomere Homeostasis ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Telomere maintenance mechanisms (TMM) are used by cancer cells to avoid apoptosis, 85-90% reactivate telomerase, while 10-15% use the alternative lengthening of telomeres (ALT). Due to anti-telomerase-based treatments, some tumors switch from a telomerase-dependent mechanism to ALT; in fact, the co-existence between both mechanisms has been observed in some cancers. Although different elements in the ALT pathway are uncovered, some molecular mechanisms are still poorly understood. Therefore, with the aim to identify potential molecular markers for the study of ALT, we combined in silico approaches in a 411 telomere maintenance gene set. As a consequence, we conducted a genomic analysis of these genes in 31 Pan-Cancer Atlas studies from The Cancer Genome Atlas and found 325,936 genomic alterations; from which, we identified 20 genes highly mutated in the cancer studies. Finally, we made a protein-protein interaction network and enrichment analysis to observe the main pathways of these genes and discuss their role in ALT-related processes, like homologous recombination and homology directed repair. Overall, due to the lack of understanding of the molecular mechanisms of ALT cancers, we proposed a group of genes, which after ex vivo validations, could represent new potential therapeutic markers in the study of ALT.},
}
@article {pmid32705188,
year = {2020},
author = {Razgonova, MP and Zakharenko, AM and Golokhvast, KS and Thanasoula, M and Sarandi, E and Nikolouzakis, K and Fragkiadaki, P and Tsoukalas, D and Spandidos, DA and Tsatsakis, A},
title = {Telomerase and telomeres in aging theory and chronographic aging theory (Review).},
journal = {Molecular medicine reports},
volume = {22},
number = {3},
pages = {1679-1694},
pmid = {32705188},
issn = {1791-3004},
mesh = {Aging/*metabolism ; Humans ; Mitochondria/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Shortening ; },
abstract = {The current review focuses on the connection of telomerase and telomeres with aging. In this review, we describe the changes in telomerase and telomere length (TEL) during development, their role in carcinogenesis processes, and the consequences of reduced telomerase activity. More specifically, the connection of TEL in peripheral blood cells with the development of aging‑associated diseases is discussed. The review provides systematic data on the role of telomerase in mitochondria, the biology of telomeres in stem cells, as well as the consequences of the forced expression of telomerase (telomerization) in human cells. Additionally, it presents the effects of chronic stress exposure on telomerase activity, the effect of TEL on fertility, and the effect of nutraceutical supplements on TEL. Finally, a comparative review of the chronographic theory of aging, presented by Olovnikov is provided based on currently available scientific research on telomere, telomerase activity, and the nature of aging by multicellular organisms.},
}
@article {pmid32703912,
year = {2020},
author = {Hsieh, AYY and Kimmel, E and Pick, N and Sauvé, L and Brophy, J and Kakkar, F and Bitnun, A and Murray, MCM and Côté, HCF},
title = {Inverse relationship between leukocyte telomere length attrition and blood mitochondrial DNA content loss over time.},
journal = {Aging},
volume = {12},
number = {15},
pages = {15196-15221},
pmid = {32703912},
issn = {1945-4589},
support = {//CIHR/Canada ; },
mesh = {Adolescent ; Adult ; Aged ; Aging/blood/genetics ; Biomarkers/blood ; Cross-Sectional Studies ; DNA, Mitochondrial/*blood ; Female ; HIV Infections/*blood/*genetics ; Humans ; *Leukocytes ; Longitudinal Studies ; Middle Aged ; *Telomere Shortening ; Time Factors ; Young Adult ; },
abstract = {Leukocyte telomere length (LTL) and whole blood mitochondrial DNA (WB mtDNA) content are aging markers impacted by chronic diseases such as human immunodeficiency virus (HIV) infection. We characterized the relationship between these two markers in 312 women ≥12 years of age living with HIV and 300 HIV-negative controls. We found no relationship between the two markers cross-sectionally. In multivariable models, age, ethnicity, HIV, and tobacco smoking were independently associated with shorter LTL, and the former three with lower WB mtDNA. Longitudinally, among a subgroup of 228 HIV participants and 68 HIV-negative controls with ≥2 biospecimens ≥1 year apart, an inverted pattern was observed between the rates of change in LTL and WB mtDNA content per year, whereby faster decline of one was associated with the preservation of the other. Furthermore, if HIV viral control was not maintained between visits, increased rates of both LTL attrition and WB mtDNA loss were observed. We describe a novel relationship between two established aging markers, whereby rates of change in LTL and WB mtDNA are inversely related. Our findings highlight the importance of maintaining HIV viral control, the complementary longitudinal relationship between the two markers, and the need to consider both in aging studies.},
}
@article {pmid32702724,
year = {2020},
author = {Maremanda, KP and Sundar, IK and Li, D and Rahman, I},
title = {Age-dependent assessment of genes involved in cellular senescence, telomere and mitochondrial pathways in human lung tissue of smokers, COPD and IPF: Associations with SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 axis.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {32702724},
support = {R01 ES029177/ES/NIEHS NIH HHS/United States ; R01 HL135613/HL/NHLBI NIH HHS/United States ; R01 HL137738/HL/NHLBI NIH HHS/United States ; UL1 TR002001/TR/NCATS NIH HHS/United States ; },
abstract = {Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Cigarette smoke is a major etiological risk factor that has been shown to alter cellular processes involving mitochondrial function, cellular senescence and telomeric length. Here we determined how aging contribute to the alteration in the gene expression of above mentioned cellular processes that play an important role in the progression of COPD and IPF. We hypothesized that aging may differentially alter the expression of mitochondrial, cellular senescence and telomere genes in smokers and patients with COPD and IPF compared to non-smokers. Total RNA from human lung tissues from non-smokers, smokers, and patients with COPD and IPF were processed and analyzed based on their ages (younger: <55 yrs and older: >55 yrs). NanoString nCounter panel was used to analyze the gene expression profiles using a custom designed codeset containing 112 genes including 6 housekeeping controls (mitochondrial biogenesis and function, cellular senescence, telomere replication and maintenance). mRNA counts were normalized, log2 transformed for differential expression analysis using linear models in the limma package (R/Bioconductor). Data from non-smokers, smokers and patients with COPD and IPF were analyzed based on the age groups (pairwise comparisons between younger vs. older groups). Several genes were differentially expressed in younger and older smokers, and patients with COPD and IPF compared to non-smokers which were part of the mitochondrial biogenesis/function (HSPD1, FEN1, COX18, COX10, UCP2 &amp; 3), cellular senescence (PCNA, PTEN, KLOTHO, CDKN1C, TNKS2, NFATC1 &amp; 2, GADD45A) and telomere replication/maintenance (PARP1, SIRT6, NBN, TERT, RAD17, SLX4, HAT1) target genes. Interestingly, NOX4 and TNKS2 were increased in the young IPF as compared to the young COPD patients. Genes in the mitochondrial dynamics and other quality control mechanisms like FIS1 and RHOT2 were decreased in young IPF compared to their age matched COPD subjects. ERCC1 (Excision Repair Cross-Complementation Group 1) and GADD45B were higher in young COPD as compared to IPF. Aging plays an important role in various infectious diseases. Elderly patients with chronic lung disease and smokers were found to have high incidence and mortality rates in the current pandemic of SARS-CoV-2 infection. Immunoblot analysis in the lung homogenates of smokers, COPD and IPF subjects revealed increased protein abundance of important proteases and spike proteins like TMPRSS2, furin and DPP4 in association with a slight increase in SARS-CoV-2 receptor ACE2 levels. This may further strengthen the observation that smokers, COPD and IPF subjects are more prone to COVID-19 infection. Overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition add to the pathobiology of lung aging in COPD and IPF and other smoking-related chronic lung disease in associated with alterations in SARS-CoV-2 ACE2-TMPRSS2-Furin-DPP4 axis for COVID-19 infection.},
}
@article {pmid32699404,
year = {2020},
author = {Gao, Y and Wang, T and Yu, X and , and Zhao, H and Zeng, P},
title = {Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {12184},
pmid = {32699404},
issn = {2045-2322},
support = {MR/L501542/1/MRC_/Medical Research Council/United Kingdom ; G-0907/PUK_/Parkinson's UK/United Kingdom ; MC_U123160651/MRC_/Medical Research Council/United Kingdom ; G0701075/MRC_/Medical Research Council/United Kingdom ; MC_UU_00024/1/MRC_/Medical Research Council/United Kingdom ; G0900652/MRC_/Medical Research Council/United Kingdom ; P30 AG062422/AG/NIA NIH HHS/United States ; G0301152/MRC_/Medical Research Council/United Kingdom ; G0400074/MRC_/Medical Research Council/United Kingdom ; R01 MH120794/MH/NIMH NIH HHS/United States ; R01 AG062268/AG/NIA NIH HHS/United States ; MR/N026004/1/MRC_/Medical Research Council/United Kingdom ; G0901254/MRC_/Medical Research Council/United Kingdom ; P30 AG066462/AG/NIA NIH HHS/United States ; G0502157/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Asian People/genetics ; Cholesterol/blood ; *Frontotemporal Dementia/genetics/pathology ; Genome-Wide Association Study ; Humans ; Leukocytes/cytology/*metabolism ; Lipoproteins, LDL/blood ; *Mendelian Randomization Analysis ; Odds Ratio ; Polymorphism, Single Nucleotide ; Proportional Hazards Models ; Telomerase/genetics ; Telomere/*physiology ; Telomere Shortening ; White People/genetics ; },
abstract = {We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93-1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53-1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.},
}
@article {pmid32699327,
year = {2020},
author = {Adams, CD and Boutwell, BB},
title = {A Mendelian randomization study of telomere length and blood-cell traits.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {12223},
pmid = {32699327},
issn = {2045-2322},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Blood Cells/*metabolism ; Female ; Genome-Wide Association Study/methods ; Germ-Line Mutation/genetics ; Humans ; Male ; Mendelian Randomization Analysis ; Middle Aged ; Phenotype ; Polymorphism, Single Nucleotide/*genetics ; Risk Factors ; Telomere/*genetics/*metabolism ; Telomere Homeostasis/genetics ; Young Adult ; },
abstract = {Whether telomere attrition reducing proliferative reserve in blood-cell progenitors is causal has important public-health implications. Mendelian randomization (MR) is an analytic technique using germline genetic variants as instrumental variables. If certain assumptions are met, estimates from MR should be free from most environmental sources of confounding and reverse causation. Here, two-sample MR is performed to test whether longer telomeres cause changes to hematological traits. Summary statistics for genetic variants strongly associated with telomere length were extracted from a genome-wide association (GWA) study for telomere length in individuals of European ancestry (n = 9190) and from GWA studies of blood-cell traits, also in those of European ancestry (n ~ 173,000 participants). A standard deviation increase in genetically influenced telomere length increased red blood cell and white blood cell counts, decreased mean corpuscular hemoglobinand mean cell volume, and had no observable impact on mean corpuscular hemoglobin concentration, red cell distribution width, hematocrit, or hemoglobin. Sensitivity tests for pleiotropic distortion were mostly inconsistent with glaring violations to the MR assumptions. Similar to germline mutations in telomere biology genes leading to bone-marrow failure, these data provide evidence that genetically influenced common variation in telomere length impacts hematologic traits in the population.},
}
@article {pmid32697083,
year = {2020},
author = {Wang, CX and Zhang, ZL and Yin, QK and Tu, JL and Wang, JE and Xu, YH and Rao, Y and Ou, TM and Huang, SL and Li, D and Wang, HG and Li, QJ and Tan, JH and Chen, SB and Huang, ZS},
title = {Design, Synthesis, and Evaluation of New Quinazolinone Derivatives that Inhibit Bloom Syndrome Protein (BLM) Helicase, Trigger DNA Damage at the Telomere Region, and Synergize with PARP Inhibitors.},
journal = {Journal of medicinal chemistry},
volume = {63},
number = {17},
pages = {9752-9772},
doi = {10.1021/acs.jmedchem.0c00917},
pmid = {32697083},
issn = {1520-4804},
mesh = {Apoptosis/drug effects ; Cell Proliferation/drug effects ; Chemistry Techniques, Synthetic ; *DNA Damage ; *Drug Design ; Drug Synergism ; HCT116 Cells ; Humans ; Models, Molecular ; Poly(ADP-ribose) Polymerase Inhibitors/*pharmacology ; Protein Conformation ; Quinazolinones/*chemical synthesis/chemistry/*pharmacology ; RecQ Helicases/*antagonists &amp; inhibitors/chemistry ; Structure-Activity Relationship ; Telomere/*genetics ; },
abstract = {DNA damage response (DDR) pathways are crucial for the survival of cancer cells and are attractive targets for cancer therapy. Bloom syndrome protein (BLM) is a DNA helicase that performs important roles in DDR pathways. Our previous study discovered an effective new BLM inhibitor with a quinazolinone scaffold by a screening assay. Herein, to better understand the structure-activity relationship (SAR) and biological roles of the BLM inhibitor, a series of new derivatives were designed, synthesized, and evaluated based on this scaffold. Among them, compound 9h exhibited nanomolar inhibitory activity and binding affinity for BLM. 9h could effectively disrupt BLM recruitment to DNA in cells. Furthermore, 9h inhibited the proliferation of the colorectal cell line HCT116 by significantly triggering DNA damage in the telomere region and inducing apoptosis, especially in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor. This result suggested a synthetic lethal effect between the BLM and PARP inhibitors in DDR pathways.},
}
@article {pmid32696640,
year = {2020},
author = {Sebastiano, M and Angelier, F and Blévin, P and Ribout, C and Sagerup, K and Descamps, S and Herzke, D and Moe, B and Barbraud, C and Bustnes, JO and Gabrielsen, GW and Chastel, O},
title = {Exposure to PFAS is Associated with Telomere Length Dynamics and Demographic Responses of an Arctic Top Predator.},
journal = {Environmental science &amp; technology},
volume = {54},
number = {16},
pages = {10217-10226},
doi = {10.1021/acs.est.0c03099},
pmid = {32696640},
issn = {1520-5851},
mesh = {Animals ; Arctic Regions ; Cross-Sectional Studies ; Demography ; *Environmental Pollutants/analysis/toxicity ; Female ; *Fluorocarbons/analysis/toxicity ; Male ; Svalbard ; Telomere/chemistry ; },
abstract = {Environmental factors that can influence telomeres are diverse, but the association between telomeres and exposure to environmental contaminants is yet to be elucidated. To date, prior studies have focused on legacy persistent chlorinated pollutants (POPs), while the effects of poly- and perfluoroalkyl substances (PFAS) have been poorly documented. Here, we investigated the associations among PFAS congeners, absolute telomere length (cross-sectional approach), and telomere dynamics (rate of telomere length change over time, longitudinal approach) in one of the most contaminated arctic top predators, the glaucous gull Larus hyperboreus from Svalbard. We further estimated the effect of PFAS on apparent survival rates and re-sighting probabilities using a 10-year capture/recapture dataset (2010-2019). We found that birds exposed to higher concentrations of perfluorononadecanoate (PFNA) (median of 1565 pg/mL of ww in males and 1370 pg/mL of ww in females) and perfluorotetradecanoate (PFTeDA) (median of 370 pg/mL of ww in males and 210 pg/mL of ww in females) showed the slowest rate of telomere shortening. We also found that high blood concentrations of perfluorooctanoate (PFOA) (median of 120 pg/mL of ww in males and 150 pg/mL of ww in females) and perfluorohexanesulfonate (PFHxS) (median of 495 pg/mL of ww in males and 395 pg/mL of ww in females) were positively associated with higher re-sighting probabilities and apparent survival in males but not in females. Our work is the first to report an association between single PFAS compounds and telomeres, and the first to link PFAS exposure with survival probabilities, suggesting that the effect of PFAS exposure might be more tied to the type of compound rather than the total concentration of PFAS.},
}
@article {pmid32688270,
year = {2020},
author = {Miranda, DM and Rosa, DV and Costa, BS and Nicolau, NF and Magno, LAV and de Paula, JJ and Romano-Silva, MA},
title = {Telomere shortening in patients with drug-resistant epilepsy.},
journal = {Epilepsy research},
volume = {166},
number = {},
pages = {106427},
doi = {10.1016/j.eplepsyres.2020.106427},
pmid = {32688270},
issn = {1872-6844},
mesh = {Adolescent ; Adult ; Case-Control Studies ; Drug Resistant Epilepsy/*diagnosis/genetics/*physiopathology ; Female ; Humans ; Male ; Middle Aged ; Telomere Shortening/*physiology ; Young Adult ; },
abstract = {Epilepsy affects about 1 % of the world population. Mesial temporal lobe epilepsy (mTLE) presents with seizures initiated in hippocampus and is the most frequent form of epilepsy. About 30 % of individuals with mTLE do not respond to conventional medications maintaining seizures and consequently new lesions on a daily basis. Treatment-resistant epilepsy has a huge social and individual burden due to impaired quality of life and increased mortality rate. There are many reasons for telomere shortening in individuals with mTLE, such as a chronic mitochondrial oxidative stress and increased levels of pro-inflammatory mediators. In the past 10 years, there was a boom of studies establishing association between telomere length and chronic/complex disorders. Telomeres are essential for the maintenance of genomic integrity. Telomere length has been assumed as a biological marker for stress and cellular ageing. Here we hypothesized that individuals affected with treatment-resistant mTLE would course with a shorter telomere than controls. So, we measured leucocytes telomere length in a sample of 89 individuals, 48 treatment-resistant mTLE compared to 41 healthy controls. As expected, we observed a significant shorter telomere in the peripheral cell leukocytes of treatment-resitant mTLE group. Telomere length was not associated with sex, side of hippocampal sclerosis, family history, etiology of seizures, duration of disease or the Engel score. Our results points towards the need of further investigation to shed light on the relation of telomeres shortening and the outcomes and impacts of epilepsy.},
}
@article {pmid32687724,
year = {2021},
author = {Maeda, T and Horiuchi, T and Makino, N},
title = {Telomere shortening velocity of patients administered with hypnotics is accelerated in a gender-differential manner.},
journal = {Canadian journal of physiology and pharmacology},
volume = {99},
number = {3},
pages = {278-283},
doi = {10.1139/cjpp-2020-0291},
pmid = {32687724},
issn = {1205-7541},
mesh = {Aged ; Aged, 80 and over ; Aging/drug effects ; Female ; Humans ; Hypnotics and Sedatives/*pharmacology ; Leukocytes/drug effects/ultrastructure ; Life Style ; Male ; Middle Aged ; Sex Characteristics ; Telomere Shortening/*drug effects ; },
abstract = {The telomere length and its distribution were compared between patients administered with and without hypnotics to see if regular administration of hypnotics is associated with their aging-related somatic telomere shortening. Male patients presented significant shortening of telomere length of circulating leukocytes in association with age (-41.9 bp/year, p = 0.045) in contrast with controls (-18.3 kb/year, p = 0.155). On the other hand, female patients presented no significant shortening of telomere length with aging (-16.4 bp/year, p = 0.372) in contrast with controls (-55.9 bp/year, p = 0.00005). These results suggested that regular administration of hypnotics is associated with aging progression in a gender-related manner. The administration of hypnotics could be an indicator as the somatic aging status and for the screening of background lifestyle-associated diseases promoting biological aging.},
}
@article {pmid32687062,
year = {2020},
author = {Li, T and Luo, Z and Lin, S and Li, C and Dai, S and Wang, H and Huang, J and Ma, W and Songyang, Z and Huang, Y},
title = {MiR-185 targets POT1 to induce telomere dysfunction and cellular senescence.},
journal = {Aging},
volume = {12},
number = {14},
pages = {14791-14807},
pmid = {32687062},
issn = {1945-4589},
mesh = {3' Untranslated Regions/genetics ; Aging/genetics ; Ataxia Telangiectasia Mutated Proteins/genetics ; Biomarkers, Tumor ; Cell Line, Tumor ; Cellular Senescence/*genetics ; Computational Biology ; Gene Knockdown Techniques ; Humans ; MicroRNAs/*genetics ; Shelterin Complex ; Signal Transduction/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {Protection of telomere 1 (POT1), the telomeric single-stranded DNA (ssDNA)-binding protein in the shelterin complex, has been implicated in the DNA damage response, tumorigenesis and aging. Telomere dysfunction induced by telomere deprotection could accelerate cellular senescence in primary human cells. While previous work demonstrated the biological mechanism of POT1 in aging and cancer, how POT1 is posttranscriptionally regulated remains largely unknown. To better understand the POT1 regulatory axis, we performed bioinformatic prediction, and selected candidates were further confirmed by dual-luciferase reporter assay. Collectively, our results revealed that miR-185 can significantly reduce POT1 mRNA and protein levels by directly targeting the POT1 3'-untranslated region (3'-UTR). Overexpression of miR-185 increased telomere dysfunction-induced foci (TIF) signals in both cancer cells and primary human fibroblasts. Elevated miR-185 led to telomere elongation in the telomerase-positive cell line HTC75, which was phenotypically consistent with POT1 knocking down. Moreover, miR-185 accelerated the replicative senescence process in primary human fibroblasts in a POT1-dependent manner. Interestingly, increased serum miR-185 could represent a potential aging-related biomarker. Taken together, our findings reveal miR-185 as a novel aging-related miRNA that targets POT1 and provide insight into the telomere and senescence regulatory network at both the intracellular and extracellular levels.},
}
@article {pmid32681489,
year = {2020},
author = {Schořová, &#x160; and Fajkus, J and Schrumpfová, PP},
title = {Optimized Detection of Protein-Protein and Protein-DNA Interactions, with Particular Application to Plant Telomeres.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2175},
number = {},
pages = {139-167},
doi = {10.1007/978-1-0716-0763-3_11},
pmid = {32681489},
issn = {1940-6029},
mesh = {Arabidopsis/genetics/*metabolism ; Arabidopsis Proteins/genetics/metabolism ; Cell Nucleus/metabolism ; Chromatin/metabolism ; Chromatin Immunoprecipitation/methods ; DNA, Plant/metabolism ; DNA-Binding Proteins/isolation &amp; purification/*metabolism ; Immunoprecipitation/methods ; Optical Imaging/*methods ; Protein Binding ; Protein Interaction Mapping/*methods ; Telomerase/*metabolism ; Telomere/*metabolism ; Two-Hybrid System Techniques ; },
abstract = {Characterization of protein-protein and protein-DNA interactions is critical to understand mechanisms governing the biology of cells. Here we describe optimized methods and their mutual combinations for this purpose: bimolecular fluorescence complementation (BiFC), co-immunoprecipitation (Co-IP), yeast two-hybrid systems (Y2H), and chromatin immunoprecipitation (ChIP). These improved protocols detect trimeric complexes in which two proteins of interest interact indirectly via a protein sandwiched between them. They also allow isolation of low-abundance chromatin proteins and confirmation that proteins of interest are associated with specific DNA sequences, for example telomeric tracts. Here we describe these methods and their application to map interactions of several telomere- and telomerase-associated proteins and to purify a sufficient amount of chromatin from Arabidopsis thaliana for further investigations (e.g., next-generation sequencing, hybridization).},
}
@article {pmid32679078,
year = {2020},
author = {Barroso-González, J and García-Expósito, L and Hoang, SM and Lynskey, ML and Roncaioli, JL and Ghosh, A and Wallace, CT and de Vitis, M and Modesti, M and Bernstein, KA and Sarkar, SN and Watkins, SC and O'Sullivan, RJ},
title = {RAD51AP1 Is an Essential Mediator of Alternative Lengthening of Telomeres.},
journal = {Molecular cell},
volume = {79},
number = {2},
pages = {359},
doi = {10.1016/j.molcel.2020.06.026},
pmid = {32679078},
issn = {1097-4164},
support = {R01 CA207209/CA/NCI NIH HHS/United States ; },
}
@article {pmid32678440,
year = {2020},
author = {Vahter, M and Broberg, K and Harari, F},
title = {Placental and Cord Blood Telomere Length in Relation to Maternal Nutritional Status.},
journal = {The Journal of nutrition},
volume = {150},
number = {10},
pages = {2646-2655},
pmid = {32678440},
issn = {1541-6100},
mesh = {Body Composition ; Body Mass Index ; Female ; *Fetal Blood ; Humans ; Maternal Nutritional Physiological Phenomena ; Nutritional Status ; Placenta/*metabolism ; Pregnancy ; *Telomere ; *Telomere Homeostasis ; Vitamin B 12/blood ; },
abstract = {BACKGROUND: The uterine environment may be important for the chromosomal telomere length (TL) at birth, which, in turn, influences disease susceptibility throughout life. However, little is known about the importance of specific nutritional factors.<br><br>OBJECTIVES: We assessed the impact of multiple maternal nutritional factors on TL in placenta and cord blood.<br><br>METHODS: In a population-based mother-child cohort in northwestern Argentina, we measured maternal weight, BMI, body fat percentage (BFP), and several nutrients [selenium, magnesium, calcium, zinc, manganese, iodine, vitamin B-12, folate, 25-hydroxycholecalciferol (25(OH)D3)], hemoglobin, and homocysteine in maternal whole blood, serum, plasma, or urine during pregnancy (mean gestational week 27). We measured the relative TL (rTL) in placenta (n&#xa0;=&#xa0;99) and cord blood (n&#xa0;=&#xa0;98) at delivery by real-time PCR. Associations were evaluated by multivariable-adjusted linear regression.<br><br>RESULTS: The women's prepregnancy BMI (kg/m2; mean&#xa0;&#xb1;&#xa0;SD: 23.7&#xa0;&#xb1;&#xa0;4.1), body weight (55.4&#xa0;&#xb1;&#xa0;9.9&#xa0;kg), and BFP (29.9&#xa0;&#xb1;&#xa0;5.5%), but not height (153&#xa0;&#xb1;&#xa0;5.3&#xa0;cm), were inversely associated with placental rTL (P&#xa0;<&#xa0;0.01 for all), with &#x223c;0.5 SD shorter rTL for an IQR increase in prepregnancy body weight, BMI, or BFP. Also, impedance-based BFP, but not lean body mass, in the third trimester was associated with shorter placental rTL. In addition, serum vitamin B-12 (232&#xa0;&#xb1;&#xa0;96&#xa0;pmol/L) in pregnancy (P&#xa0;=&#xa0;0.038), but not folate or homocysteine, was associated with shorter placental rTL (0.2 SD for an IQR increase). In contrast, plasma 25(OH)D3 (46&#xa0;&#xb1;&#xa0;15&#xa0;nmol/L) was positively associated with placental rTL (P&#xa0;<&#xa0;0.01), which increased by 0.4 SD for an IQR increase in 25(OH)D3. No clear associations of the studied maternal nutritional factors were found with cord blood rTL.<br><br>CONCLUSIONS: Maternal BMI, BFP, and vitamin B-12 were inversely associated, whereas 25(OH)D3 was positively associated, with placental TL. No association was observed with cord blood TL. Future studies should elucidate the role of placental TL for child health.},
}
@article {pmid32674474,
year = {2020},
author = {Fernandes, SG and Dsouza, R and Pandya, G and Kirtonia, A and Tergaonkar, V and Lee, SY and Garg, M and Khattar, E},
title = {Role of Telomeres and Telomeric Proteins in Human Malignancies and Their Therapeutic Potential.},
journal = {Cancers},
volume = {12},
number = {7},
pages = {},
pmid = {32674474},
issn = {2072-6694},
support = {(No. BT/RLF/Re-entry/06/2015//Department of Biotechnology, Ministry of Science and Technology, India/ ; (ECR/2018/002117//Science and Engineering Research Board/ ; BT/RLF/Re-entry/24/2014//Department of Biotechnology, Ministry of Science and Technology, India/ ; ECR/2016/001519//Science and Engineering Research Board/ ; },
abstract = {Telomeres are the ends of linear chromosomes comprised of repetitive nucleotide sequences in humans. Telomeres preserve chromosomal stability and genomic integrity. Telomere length shortens with every cell division in somatic cells, eventually resulting in replicative senescence once telomere length becomes critically short. Telomere shortening can be overcome by telomerase enzyme activity that is undetectable in somatic cells, while being active in germline cells, stem cells, and immune cells. Telomeres are bound by a shelterin complex that regulates telomere lengthening as well as protects them from being identified as DNA damage sites. Telomeres are transcribed by RNA polymerase II, and generate a long noncoding RNA called telomeric repeat-containing RNA (TERRA), which plays a key role in regulating subtelomeric gene expression. Replicative immortality and genome instability are hallmarks of cancer and to attain them cancer cells exploit telomere maintenance and telomere protection mechanisms. Thus, understanding the role of telomeres and their associated proteins in cancer initiation, progression and treatment is very important. The present review highlights the critical role of various telomeric components with recently established functions in cancer. Further, current strategies to target various telomeric components including human telomerase reverse transcriptase (hTERT) as a therapeutic approach in human malignancies are discussed.},
}
@article {pmid32673712,
year = {2020},
author = {Wang, J and Liu, Y and Xia, Q and Xia, Q and Wang, B and Yang, C and Liang, J and Liu, X},
title = {Potential roles of telomeres and telomerase in neurodegenerative diseases.},
journal = {International journal of biological macromolecules},
volume = {163},
number = {},
pages = {1060-1078},
doi = {10.1016/j.ijbiomac.2020.07.046},
pmid = {32673712},
issn = {1879-0003},
mesh = {Aging/metabolism ; Animals ; Cell Proliferation/physiology ; Cell Survival/physiology ; DNA Replication/physiology ; Humans ; Neurodegenerative Diseases/*metabolism ; Neurons/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres, protective DNA-protein complexes at the end of eukaryotic linear chromosomes, play pivotal roles in the maintenance of genomic stability during cell division. When telomeres are severely shortened, cells stop dividing and die, consequently leading to tissues degeneration. Concretely, replicative senescence and genomic damage are generally accompanied with telomere shortening, which may be a potential contributor in the pathogenesis of neurological disorders. Regardless of occasional negative findings, accelerated telomere erosion is routinely found in neurodegenerative diseases and has been believed to be positively correlated with the severity of neurodegenerative diseases. As considerable knowledge of telomeres and telomerase continues to accumulate, telomerase is increasingly being recognized as a promising therapeutic target for neurodegenerative disease. Until now, strong evidence has accumulated that activated telomerase is responsible for telomere elongation that may be sufficient to prevent "mother cells" from replicative aging, and besides, telomerase activators exhibit remarkable neuroprotective effects through the prolongation of telomere length and the promotion of neuronal survival as well as proliferation. Therefore, a consensus is emerging that the activation of telomerase, promoted by peptides, natural herbal extracts, small molecules compounds and others, represents a novel promising treatment strategy for neurodegenerative diseases.},
}
@article {pmid32673551,
year = {2020},
author = {Sánchez-Montes, G and Martínez-Solano, &#xcd; and Díaz-Paniagua, C and Vilches, A and Ariño, AH and Gomez-Mestre, I},
title = {Telomere attrition with age in a wild amphibian population.},
journal = {Biology letters},
volume = {16},
number = {7},
pages = {20200168},
pmid = {32673551},
issn = {1744-957X},
mesh = {Animals ; Bufonidae ; Cross-Sectional Studies ; Male ; *Telomere/genetics ; *Telomere Shortening ; },
abstract = {Telomere shortening with age has been documented in many organisms, but few studies have reported telomere length measurements in amphibians, and no information is available for growth after metamorphosis, nor in wild populations. We provide both cross-sectional and longitudinal evidence of net telomere attrition with age in a wild amphibian population of natterjack toads (Epidalea calamita). Based on age-estimation by skeletochronology and qPCR telomere length measurements in the framework of an individual-based monitoring programme, we confirmed telomere attrition in recaptured males. Our results support that toads experience telomere attrition throughout their ontogeny, and that most attrition occurs during the first 1-2 years. We did not find associations between telomere length and inbreeding or body condition. Our results on telomere length dynamics under natural conditions confirm telomere shortening with age in amphibians and provide quantification of wide telomere length variation within and among age-classes in a wild breeding population.},
}
@article {pmid32669102,
year = {2020},
author = {Abid, HZ and McCaffrey, J and Raseley, K and Young, E and Lassahn, K and Varapula, D and Riethman, H and Xiao, M},
title = {Single-molecule analysis of subtelomeres and telomeres in Alternative Lengthening of Telomeres (ALT) cells.},
journal = {BMC genomics},
volume = {21},
number = {1},
pages = {485},
pmid = {32669102},
issn = {1471-2164},
support = {R01 HG005946/HG/NHGRI NIH HHS/United States ; R21HG007205 and R21CA177395/NH/NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; DNA/chemistry ; Humans ; Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Telomeric DNA is typically comprised of G-rich tandem repeat motifs and maintained by telomerase (Greider CW, Blackburn EH; Cell 51:887-898; 1987). In eukaryotes lacking telomerase, a variety of DNA repair and DNA recombination based pathways for telomere maintenance have evolved in organisms normally dependent upon telomerase for telomere elongation (Webb CJ, Wu Y, Zakian VA; Cold Spring Harb Perspect Biol 5:a012666; 2013); collectively called Alternative Lengthening of Telomeres (ALT) pathways. By measuring (TTAGGG) n tract lengths from the same large DNA molecules that were optically mapped, we simultaneously analyzed telomere length dynamics and subtelomere-linked structural changes at a large number of specific subtelomeric loci in the ALT-positive cell lines U2OS, SK-MEL-2 and Saos-2.<br><br>RESULTS: Our results revealed loci-specific ALT telomere features. For example, while each subtelomere included examples of single molecules with terminal (TTAGGG) n tracts as well as examples of recombinant telomeric single molecules, the ratio of these molecules was subtelomere-specific, ranging from 33:1 (19p) to 1:25 (19q) in U2OS. The Saos-2 cell line shows a similar percentage of recombinant telomeres. The frequency of recombinant subtelomeres of SK-MEL-2 (11%) is about half that of U2OS and Saos-2 (24 and 19% respectively). Terminal (TTAGGG) n tract lengths and heterogeneity levels, the frequencies of telomere signal-free ends, and the frequency and size of retained internal telomere-like sequences (ITSs) at recombinant telomere fusion junctions all varied according to the specific subtelomere involved in a particular cell line. Very large linear extrachromosomal telomere repeat (ECTR) DNA molecules were found in all three cell lines; these are in principle capable of templating synthesis of new long telomere tracts via break-induced repair (BIR) long-tract DNA synthesis mechanisms and contributing to the very long telomere tract length and heterogeneity characteristic of ALT cells. Many of longest telomere tracts (both end-telomeres and linear ECTRs) displayed punctate CRISPR/Cas9-dependent (TTAGGG) n labeling patterns indicative of interspersion of stretches of non-canonical telomere repeats.<br><br>CONCLUSION: Identifying individual subtelomeres and characterizing linked telomere (TTAGGG) n tract lengths and structural changes using our new single-molecule methodologies reveals the structural consequences of telomere damage, repair and recombination mechanisms in human ALT cells in unprecedented molecular detail and significant differences in different ALT-positive cell lines.},
}
@article {pmid32668770,
year = {2020},
author = {Panasiak, L and Dobosz, S and Ocalewicz, K},
title = {Telomere Dynamics in the Diploid and Triploid Rainbow Trout (Oncorhynchus mykiss) Assessed by Q-FISH Analysis.},
journal = {Genes},
volume = {11},
number = {7},
pages = {},
pmid = {32668770},
issn = {2073-4425},
mesh = {Animals ; *Diploidy ; Female ; Gametogenesis/genetics ; Male ; Oncorhynchus mykiss/*genetics ; Ovary/growth &amp; development/metabolism ; Sexual Maturation/genetics ; Telomere/*genetics ; *Triploidy ; },
abstract = {Changes of telomere length with age were assessed in diploid and triploid rainbow trout (Oncorhynchus mykiss) females in the cross-sectional study using Q-FISH technique. Triploid trout as sterile do not invest an energy in gametogenesis and continue to grow, whereas fertile diploid individuals suffer from declines in growth and survival during sexual maturation. However, triploid and diploid specimens exhibited similar patterns of telomere dynamics. Telomere length in the embryos, larvae and one-year-old juveniles did not change significantly. In the second year after hatching, subadults exhibited substantially shortened telomeres, while significant increase of the telomere length was reported in the three-year-old adults. On the other hand, correlation between telomere length and body size was observed in the triploid, but not in the diploid rainbow trout. Telomere shortening observed in two-year-old subadults may have been associated with the premature period of the fast growth in rainbow trout. Similar pattern of the telomere dynamics reported in the fertile diploids and sterile triploids indicated processes related to reproduction did not affect telomere dynamics in this species. Unexpected increase of the telomere length reported during the third year of life confirmed that in rainbow trout telomeric DNA shortens and lengthens, depending on the developmental stage.},
}
@article {pmid32666074,
year = {2021},
author = {Frati, G and Versaci, F and Sciarretta, S},
title = {A novel signalling mechanism regulating telomere length in cardiomyocytes.},
journal = {Cardiovascular research},
volume = {117},
number = {1},
pages = {13-14},
doi = {10.1093/cvr/cvaa210},
pmid = {32666074},
issn = {1755-3245},
mesh = {Animals ; Cellular Senescence ; Mice ; *Myocytes, Cardiac ; Signal Transduction ; *Telomere/genetics ; Transforming Growth Factor beta ; },
}
@article {pmid32666011,
year = {2020},
author = {Tatsi, C and Flippo, C and Faucz, FR and Sinaii, N and Stratakis, CA},
title = {Telomere Length Changes in Children With Cushing Disease: A Pilot Study.},
journal = {Journal of the Endocrine Society},
volume = {4},
number = {7},
pages = {bvaa067},
pmid = {32666011},
issn = {2472-1972},
abstract = {CONTEXT: Changes in telomere length (TL) have been linked to certain diseases. Studies on the effect of cortisol on TL have not led to conclusive results.<br><br>OBJECTIVE: To determine whether TL is affected in pediatric patients with Cushing disease (CD) through an exploratory study.<br><br>DESIGN: We studied 10 pediatric patients [mean age: 13.3 (2.6) years, 7 females], diagnosed and treated successfully for CD. TL was measured before and approximately 1 year after treatment. TL was compared with controls adjusting for age, and associations with disease characteristics were assessed.<br><br>RESULTS: Adjusting for age, total lymphocyte TL of patients did not differ from controls during active disease (P = 0.13) but was shorter than controls at follow-up (P = 0.031). Total lymphocyte TL during active CD and at follow-up did not correlate with markers of hypercortisolemia. There was strong inverse correlation between TL during active disease and at follow-up with triglyceride levels at active disease (adjusted [Adj] R[2] = 0.64; P = 0.02 and Adj R[2] = 0.5; P = 0.036, respectively), suggesting that the higher the triglycerides, the shorter the TL in patients with CD. The change of TL between active disease and follow-up was positively correlated with systolic blood pressure (Adj R[2] = 0.76; P = 0.006).<br><br>CONCLUSIONS: In this pilot study, TL is shorter in children with hypercortisolemia, a difference that becomes detectable only after cure of CD. Triglycerides and blood pressure appear to be factors that are associated with TL in these patients. Further studies are required to confirm these results.},
}
@article {pmid32663838,
year = {2020},
author = {Miga, KH and Koren, S and Rhie, A and Vollger, MR and Gershman, A and Bzikadze, A and Brooks, S and Howe, E and Porubsky, D and Logsdon, GA and Schneider, VA and Potapova, T and Wood, J and Chow, W and Armstrong, J and Fredrickson, J and Pak, E and Tigyi, K and Kremitzki, M and Markovic, C and Maduro, V and Dutra, A and Bouffard, GG and Chang, AM and Hansen, NF and Wilfert, AB and Thibaud-Nissen, F and Schmitt, AD and Belton, JM and Selvaraj, S and Dennis, MY and Soto, DC and Sahasrabudhe, R and Kaya, G and Quick, J and Loman, NJ and Holmes, N and Loose, M and Surti, U and Risques, RA and Graves Lindsay, TA and Fulton, R and Hall, I and Paten, B and Howe, K and Timp, W and Young, A and Mullikin, JC and Pevzner, PA and Gerton, JL and Sullivan, BA and Eichler, EE and Phillippy, AM},
title = {Telomere-to-telomere assembly of a complete human X chromosome.},
journal = {Nature},
volume = {585},
number = {7823},
pages = {79-84},
pmid = {32663838},
issn = {1476-4687},
support = {2U41HG007234/HG/NHGRI NIH HHS/United States ; T32 GM007445/GM/NIGMS NIH HHS/United States ; MR/S035362/1/MRC_/Medical Research Council/United Kingdom ; R21 HG010548/HG/NHGRI NIH HHS/United States ; R21 CA238758/CA/NCI NIH HHS/United States ; HG002385/NH/NIH HHS/United States ; P30 CA014236/CA/NCI NIH HHS/United States ; R01 HG009190/HG/NHGRI NIH HHS/United States ; R01 HG002385/HG/NHGRI NIH HHS/United States ; MR/M501621/1/MRC_/Medical Research Council/United Kingdom ; MR/J014370/1/MRC_/Medical Research Council/United Kingdom ; HG010169/NH/NIH HHS/United States ; R01 GM124041/GM/NIGMS NIH HHS/United States ; U01 1U01HG010971/NH/NIH HHS/United States ; U01 HL137183/HL/NHLBI NIH HHS/United States ; DP2 MH119424/MH/NIMH NIH HHS/United States ; U54 1U54HG007990/NH/NIH HHS/United States ; T32 LM012419/LM/NLM NIH HHS/United States ; U01 1U01HL137183/HL/NHLBI NIH HHS/United States ; 1F32GM134558-01/NH/NIH HHS/United States ; 212965/Z/18/Z/WT_/Wellcome Trust/United Kingdom ; /HHMI/Howard Hughes Medical Institute/United States ; F32 GM134558/GM/NIGMS NIH HHS/United States ; R01 HG010169/HG/NHGRI NIH HHS/United States ; R01 GM129263/GM/NIGMS NIH HHS/United States ; U41 HG007234/HG/NHGRI NIH HHS/United States ; R01 CA181308/CA/NCI NIH HHS/United States ; U01 HG010971/HG/NHGRI NIH HHS/United States ; U54 HG007990/HG/NHGRI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R44 HG008118/HG/NHGRI NIH HHS/United States ; },
mesh = {Centromere/genetics ; Chromosomes, Human, X/*genetics ; CpG Islands/genetics ; DNA Methylation ; DNA, Satellite/genetics ; Female ; Genome, Human/*genetics ; Humans ; Hydatidiform Mole/genetics ; Male ; Pregnancy ; Reproducibility of Results ; Telomere/*genetics ; Testis/metabolism ; },
abstract = {After two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no single chromosome has been finished end to end, and hundreds of unresolved gaps persist[1,2]. Here we present a human genome assembly that surpasses the continuity of GRCh38[2], along with a gapless, telomere-to-telomere assembly of a human chromosome. This was enabled by high-coverage, ultra-long-read nanopore sequencing of the complete hydatidiform mole CHM13 genome, combined with complementary technologies for quality improvement and validation. Focusing our efforts on the human X chromosome[3], we reconstructed the centromeric satellite DNA array (approximately 3.1 Mb) and closed the 29 remaining gaps in the current reference, including new sequences from the human pseudoautosomal regions and from cancer-testis ampliconic gene families (CT-X and GAGE). These sequences will be integrated into future human reference genome releases. In addition, the complete chromosome X, combined with the ultra-long nanopore data, allowed us to map methylation patterns across complex tandem repeats and satellite arrays. Our results demonstrate that finishing the entire human genome is now within reach, and the data presented here will facilitate ongoing efforts to complete the other human chromosomes.},
}
@article {pmid32661422,
year = {2020},
author = {Ge, Y and Wu, Z and Chen, H and Zhong, Q and Shi, S and Li, G and Wu, J and Lei, M},
title = {Structural insights into telomere protection and homeostasis regulation by yeast CST complex.},
journal = {Nature structural &amp; molecular biology},
volume = {27},
number = {8},
pages = {752-762},
pmid = {32661422},
issn = {1545-9985},
mesh = {Crystallography, X-Ray ; DNA, Fungal/chemistry/metabolism ; Fungal Proteins/chemistry/*metabolism ; Kluyveromyces/chemistry/*metabolism ; Models, Molecular ; Protein Conformation ; Protein Multimerization ; Telomere/chemistry/*metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {Budding yeast Cdc13-Stn1-Ten1 (CST) complex plays an essential role in telomere protection and maintenance. Despite extensive studies, only structural information of individual domains of CST is available; the architecture of CST still remains unclear. Here, we report crystal structures of Kluyveromyces lactis Cdc13-telomeric-DNA, Cdc13-Stn1 and Stn1-Ten1 complexes and propose an integrated model depicting how CST assembles and plays its roles at telomeres. Surprisingly, two oligonucleotide/oligosaccharide-binding (OB) folds of Cdc13 (OB2 and OB4), previously believed to mediate Cdc13 homodimerization, actually form a stable intramolecular interaction. This OB2-OB4 module of Cdc13 is required for the Cdc13-Stn1 interaction that assembles CST into an architecture with a central ring-like core and multiple peripheral modules in a 2:2:2 stoichiometry. Functional analyses indicate that this unique CST architecture is essential for both telomere capping and homeostasis regulation. Overall, our results provide fundamentally valuable structural information regarding the CST complex and its roles in telomere biology.},
}
@article {pmid32661111,
year = {2020},
author = {Cheng, F and Luk, AO and Tam, CHT and Fan, B and Wu, H and Yang, A and Lau, ESH and Ng, ACW and Lim, CKP and Lee, HM and Chow, E and Kong, AP and Keech, AC and Joglekar, MV and So, WY and Jenkins, AJ and Chan, JCN and Hardikar, AA and Ma, RCW},
title = {Shortened Relative Leukocyte Telomere Length Is Associated With Prevalent and Incident Cardiovascular Complications in Type 2 Diabetes: Analysis From the Hong Kong Diabetes Register.},
journal = {Diabetes care},
volume = {43},
number = {9},
pages = {2257-2265},
doi = {10.2337/dc20-0028},
pmid = {32661111},
issn = {1935-5548},
mesh = {Adult ; Aged ; Biomarkers/blood ; Cardiovascular Diseases/blood/diagnosis/epidemiology/etiology ; Diabetes Mellitus, Type 2/blood/complications/diagnosis/*epidemiology ; Diabetic Angiopathies/blood/diagnosis/*epidemiology/etiology ; Female ; Follow-Up Studies ; Hong Kong/epidemiology ; Humans ; Incidence ; Leukocytes/*metabolism/pathology ; Male ; Middle Aged ; Prevalence ; Registries ; Risk Factors ; Telomere/metabolism/*physiology ; Telomere Shortening/*physiology ; },
abstract = {OBJECTIVE: Several studies support potential links between relative leukocyte telomere length (rLTL), a biomarker of biological aging, and type 2 diabetes. This study investigates relationships between rLTL and incident cardiovascular disease (CVD) in patients with type 2 diabetes.<br><br>RESEARCH DESIGN AND METHODS: Consecutive Chinese patients with type 2 diabetes (N = 5,349) from the Hong Kong Diabetes Register for whom DNA obtained at baseline was stored and follow-up data were available were studied. rLTL was measured by using quantitative PCR. CVD was diagnosed on the basis of ICD-9 code.<br><br>RESULTS: Mean follow-up was 13.4 years (SD 5.5 years). rLTL was correlated inversely with age, diabetes duration, blood pressure, HbA1c, and urine albumin-to-creatinine ratio (ACR), and positively with estimated glomerular filtration rate (eGFR) (all P < 0.001). Subjects with CVD at baseline had a shorter rLTL (4.3 &#xb1; 1.2 &#x394;&#x394;Ct) than did subjects without CVD (4.6 &#xb1; 1.2 &#x394;&#x394;Ct) (P < 0.001). Of the 4,541 CVD-free subjects at baseline, the 1,140 who developed CVD during follow-up had a shorter rLTL (4.3 &#xb1; 1.2 &#x394;&#x394;Ct) than those who remained CVD-free after adjusting for age, sex, smoking, and albuminuria status (4.7 &#xb1; 1.2 &#x394;&#x394;Ct) (P < 0.001). In Cox regression models, shorter rLTL was associated with higher risk of incident CVD (for each unit decrease, hazard ratio 1.252 [95% CI 1.195-1.311], P < 0.001), which remained significant after adjusting for age, sex, BMI, systolic blood pressure, LDL cholesterol, HbA1c, eGFR, and ACR (hazard ratio 1.141 [95% CI 1.084-1.200], P < 0.001).<br><br>CONCLUSIONS: rLTL is significantly shorter in patients with type 2 diabetes and CVD, is associated with cardiometabolic risk factors, and is independently associated with incident CVD. Telomere length may be a useful biomarker for CVD risk in patients with type 2 diabetes.},
}
@article {pmid32660821,
year = {2020},
author = {Hu, X and Guo, X and Ni, J and Wang, H and Cao, N and Liang, Z and Wang, X},
title = {High homocysteine promotes telomere dysfunction and chromosomal instability in human neuroblastoma SH-SY5Y cells.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {854-855},
number = {},
pages = {503197},
doi = {10.1016/j.mrgentox.2020.503197},
pmid = {32660821},
issn = {1879-3592},
mesh = {Apoptosis/genetics ; Cell Death/genetics ; Cell Division/genetics ; Cell Line, Tumor ; Chromosomal Instability/*genetics ; Cytokinesis/genetics ; DNA Damage/genetics ; Homocysteine/*genetics ; Humans ; Micronuclei, Chromosome-Defective ; Micronucleus Tests/methods ; Necrosis/genetics ; Neuroblastoma/*genetics ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {Telomeres, specialized structures at the ends of linear chromosomes, protect chromosome ends from degradation, recombination, and mis-repair. Critically short telomere length (TL) may result in chromosome instability (CIN), causing tumor promotion and, at higher levels, cell death and tumor suppression. Homocysteine (Hcy) is a sulfur-containing amino acid involved in one-carbon metabolism. Elevated plasma Hcy is a cancer risk factor. Human SH-SY5Y neuroblastoma cells were treated with pathophysiological concentrations of Hcy (15-120 μM) for 14 and 28 days. The cytokinesis-block micronucleus cytome assay was used to determine cytostasis (nuclear division index, NDI), cell death (apoptosis and necrosis), and CIN (micronuclei, nucleoplasmic bridges, and nuclear buds in binucleated cells). Quantitative PCR was used to measure TL and the expression of hTERT, the gene encoding the catalytic subunit of telomerase for TL elongation. The results showed that Hcy induced elongation of TL and fluctuating changes in expression of hTERT. TL elongation was associated with increased CIN. Hcy decreased the NDI and increased cell death. This study shows that there is cross-talk between Hcy and TL in tumor cells and supports the concept that high Hcy inhibits cell division and promotes the death of tumor cells by abnormal elongation of TL and elevation of CIN.},
}
@article {pmid32658923,
year = {2020},
author = {Collin, V and Gravel, A and Kaufer, BB and Flamand, L},
title = {The Promyelocytic Leukemia Protein facilitates human herpesvirus 6B chromosomal integration, immediate-early 1 protein multiSUMOylation and its localization at telomeres.},
journal = {PLoS pathogens},
volume = {16},
number = {7},
pages = {e1008683},
pmid = {32658923},
issn = {1553-7374},
support = {MOP_123214//CIHR/Canada ; PJT_156118//CIHR/Canada ; },
mesh = {Cell Line ; Herpesvirus 6, Human/genetics/*metabolism ; Humans ; Immediate-Early Proteins/*metabolism ; Phosphoproteins/*metabolism ; Promyelocytic Leukemia Protein/*metabolism ; Roseolovirus Infections/genetics/*metabolism ; Sumoylation ; Telomere/*virology ; Virus Latency/genetics ; },
abstract = {Human herpesvirus 6B (HHV-6B) is a betaherpesvirus capable of integrating its genome into the telomeres of host chromosomes. Until now, the cellular and/or viral proteins facilitating HHV-6B integration have remained elusive. Here we show that a cellular protein, the promyelocytic leukemia protein (PML) that forms nuclear bodies (PML-NBs), associates with the HHV-6B immediate early 1 (IE1) protein at telomeres. We report enhanced levels of SUMOylated IE1 in the presence of PML and have identified a putative SUMO Interacting Motif (SIM) within IE1, essential for its nuclear distribution, overall SUMOylation and association with PML to nuclear bodies. Furthermore, using PML knockout cell lines we made the original observation that PML is required for efficient HHV-6B integration into host chromosomes. Taken together, we could demonstrate that PML-NBs are important for IE1 multiSUMOylation and that PML plays an important role in HHV-6B integration into chromosomes, a strategy developed by this virus to maintain its genome in its host over long periods of time.},
}
@article {pmid32650286,
year = {2020},
author = {Stroik, S and Hendrickson, EA},
title = {Telomere replication-When the going gets tough.},
journal = {DNA repair},
volume = {94},
number = {},
pages = {102875},
doi = {10.1016/j.dnarep.2020.102875},
pmid = {32650286},
issn = {1568-7856},
mesh = {Animals ; *DNA Replication ; Eukaryota/genetics/metabolism ; Genomic Instability ; Humans ; Telomere/*genetics ; },
abstract = {Telomeres consist of repetitive tracts of DNA that shield a chromosome's contents from erosion and replicative attrition. However, telomeres are also late-replicating regions of the genome in which a myriad of replicative obstructions reside. The obstacles contained within telomeres, as well as their genomic location, drive replicative stalling and subsequent fork collapse in these regions. Consequently, large scale deletions, under-replicated DNA, translocations, and fusion events arise following telomere replication failure. Further, under-replicated DNA and telomere fusions that are permitted to enter mitosis will produce mitotic DNA bridges - known drivers of genetic loss and chromothripsis. Thus, aberrant telomere replication promotes genomic instability, which, in turn leads either to cellular death, senescence or oncogenic transformation. The importance of these issues for organismal well-being necessitates a need for resolute telomere maintenance. Here, we describe recent advances in identifying and understanding the molecular mechanisms that are in place in human cells to escort the replisome through the telomere's unwieldy structures and repetitive sequences. Finally, we review the pathways that combat the deleterious outcomes that occur when telomeric replication forks do collapse.},
}
@article {pmid32641227,
year = {2020},
author = {Fazzini, F and Lamina, C and Raschenberger, J and Schultheiss, UT and Kotsis, F and Schönherr, S and Weissensteiner, H and Forer, L and Steinbrenner, I and Meiselbach, H and Bärthlein, B and Wanner, C and Eckardt, KU and Köttgen, A and Kronenberg, F and , },
title = {Results from the German Chronic Kidney Disease (GCKD) study support association of relative telomere length with mortality in a large cohort of patients with moderate chronic kidney disease.},
journal = {Kidney international},
volume = {98},
number = {2},
pages = {488-497},
doi = {10.1016/j.kint.2020.02.034},
pmid = {32641227},
issn = {1523-1755},
mesh = {*Cardiovascular Diseases/genetics ; Cohort Studies ; Humans ; Prospective Studies ; *Renal Insufficiency, Chronic/diagnosis/genetics ; Risk Factors ; Telomere/genetics ; },
abstract = {Telomere length is known to be inversely associated with aging and has been proposed as a marker for aging-related diseases. Telomere attrition can be accelerated by oxidative stress and inflammation, both commonly present in patients with chronic kidney disease. Here, we investigated whether relative telomere length is associated with mortality in a large cohort of patients with chronic kidney disease stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. Relative telomere length was quantified in peripheral blood by a quantitative PCR method in 4,955 patients from the GCKD study, an ongoing prospective observational cohort. Complete four-year follow-up was available from 4,926 patients in whom we recorded 354 deaths. Relative telomere length was a strong and independent predictor of all-cause mortality. Each decrease of 0.1 relative telomere length unit was highly associated with a 14% increased risk of death (hazard ratio1.14 [95% confidence interval 1.06-1.22]) in a model adjusted for age, sex, baseline eGFR, urine albumin/creatinine ratio, diabetes mellitus, prevalent cardiovascular disease, LDL-cholesterol, HDL-cholesterol, smoking, body mass index, systolic and diastolic blood pressure, C-reactive protein and serum albumin. This translated to a 75% higher risk for those in the lowest compared to the highest quartile of relative telomere length. The association was mainly driven by 117 cardiovascular deaths (1.20 [1.05-1.35]) as well as 67 deaths due to infections (1.27 [1.07-1.50]). Thus, our findings support an association of shorter telomere length with all-cause mortality, cardiovascular mortality and death due to infections in patients with moderate chronic kidney disease.},
}
@article {pmid32637486,
year = {2020},
author = {Ren, JC and Liu, H and Zhang, GH and Wang, T and Li, J and Dong, T and Wu, H and Xia, ZL},
title = {Dataset on the effect of Benzene exposure on genetic damage, hematotoxicity, telomere length and polymorphisms in metabolic and DNA repair genes.},
journal = {Data in brief},
volume = {31},
number = {},
pages = {105869},
pmid = {32637486},
issn = {2352-3409},
abstract = {In this paper, we present an occupational dataset to evaluate benzene exposure on the effective biomarkers of genetic damage, indicated as cytokinesis-block micronucleus (MN) frequency, hematotoxicity, indicated as white blood cells (WBC) counts, and molecular marker of telomere length (TL). And we further to eliminate the mechanism of benzene induced damage. Then evaluate the effects of sites polymorphism in environmental response genes, including 18 sites in metabolic and DNA repair genes, and the interaction between gene polymorphism and benzene exposure. This dataset is supplementary to the submitted research by [1] focused on the biomarkers TL, and a detailed description of the subjects sampling, biomarkers detection, data analysis and discussion are discussed in detail.},
}
@article {pmid32632978,
year = {2020},
author = {Antkowiak, M and Green, RM},
title = {Telomeres, p53, Hepatocyte Nuclear Factor 4α, and Liver Disease.},
journal = {Hepatology (Baltimore, Md.)},
volume = {72},
number = {4},
pages = {1166-1168},
doi = {10.1002/hep.31454},
pmid = {32632978},
issn = {1527-3350},
mesh = {Hepatocyte Nuclear Factor 4/metabolism ; Hepatocyte Nuclear Factors ; Hepatocytes/metabolism ; Humans ; *Liver Diseases/genetics ; Telomere/genetics/metabolism ; *Tumor Suppressor Protein p53 ; },
}
@article {pmid32620872,
year = {2020},
author = {Azarm, K and Bhardwaj, A and Kim, E and Smith, S},
title = {Persistent telomere cohesion protects aged cells from premature senescence.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {3321},
pmid = {32620872},
issn = {2041-1723},
support = {R01 CA200751/CA/NCI NIH HHS/United States ; F31 CA221162/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; Cell Line ; Cell Line, Tumor ; Cellular Senescence/genetics ; DNA Damage ; HEK293 Cells ; Heterochromatin/genetics/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Mutation ; RNA Interference ; Tankyrases/metabolism ; Telomere/*genetics/metabolism ; Telomere Shortening/*genetics ; Telomeric Repeat Binding Protein 1/deficiency/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/deficiency/*genetics/metabolism ; },
abstract = {Human telomeres are bound by the telomere repeat binding proteins TRF1 and TRF2. Telomere shortening in human cells leads to a DNA damage response that signals replicative senescence. While insufficient loading of TRF2 at shortened telomeres contributes to the DNA damage response in senescence, the contribution of TRF1 to senescence induction has not been determined. Here we show that counter to TRF2 deficiency-mediated induction of DNA damage, TRF1 deficiency serves a protective role to limit induction of DNA damage induced by subtelomere recombination. Shortened telomeres recruit insufficient TRF1 and as a consequence inadequate tankyrase 1 to resolve sister telomere cohesion. Our findings suggest that the persistent cohesion protects short telomeres from inappropriate recombination. Ultimately, in the final division, telomeres are no longer able to maintain cohesion and subtelomere copying ensues. Thus, the gradual loss of TRF1 and concomitant persistent cohesion that occurs with telomere shortening ensures a measured approach to replicative senescence.},
}
@article {pmid32619407,
year = {2020},
author = {Mender, I and Zhang, A and Ren, Z and Han, C and Deng, Y and Siteni, S and Li, H and Zhu, J and Vemula, A and Shay, JW and Fu, YX},
title = {Telomere Stress Potentiates STING-Dependent Anti-tumor Immunity.},
journal = {Cancer cell},
volume = {38},
number = {3},
pages = {400-411.e6},
pmid = {32619407},
issn = {1878-3686},
support = {C06 RR030414/RR/NCRR NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; },
mesh = {Adaptive Immunity/drug effects ; Animals ; CD8-Positive T-Lymphocytes/drug effects/immunology/metabolism ; Cell Line, Tumor ; Deoxyguanosine/*analogs &amp; derivatives/pharmacology/therapeutic use ; HCT116 Cells ; Humans ; Immunity, Innate/drug effects ; Membrane Proteins/genetics/*immunology/metabolism ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Neoplasms/*drug therapy/genetics/immunology ; Neoplasms, Experimental/drug therapy/genetics/immunology ; Signal Transduction/drug effects/genetics/immunology ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/enzymology/*genetics ; Thionucleosides/*pharmacology/therapeutic use ; Tumor Burden/drug effects/genetics/immunology ; },
abstract = {Telomerase is an attractive target for anti-tumor therapy as it is almost universally expressed in cancer cells. Here, we show that treatment with a telomere-targeting drug, 6-thio-2'-deoxyguanosine (6-thio-dG), leads to tumor regression through innate and adaptive immune-dependent responses in syngeneic and humanized mouse models of telomerase-expressing cancers. 6-thio-dG treatment causes telomere-associated DNA damages that are sensed by dendritic cells (DCs) and activates the host cytosolic DNA sensing STING/interferon I pathway, resulting in enhanced cross-priming capacity of DCs and tumor-specific CD8[+] T cell activation. Moreover, 6-thio-dG overcomes resistance to checkpoint blockade in advanced cancer models. Our results unveil how telomere stress increases innate sensing and adaptive anti-tumor immunity and provide strong rationales for combining telomere-targeting therapy with immunotherapy.},
}
@article {pmid32618906,
year = {2020},
author = {},
title = {The Association Between Psychiatric Disorders and Telomere Length: A Meta-Analysis Involving 14,827 Persons: Erratum.},
journal = {Psychosomatic medicine},
volume = {82},
number = {6},
pages = {631},
doi = {10.1097/PSY.0000000000000831},
pmid = {32618906},
issn = {1534-7796},
}
@article {pmid32617831,
year = {2020},
author = {Vahidi, S and Norollahi, SE and Agah, S and Samadani, AA},
title = {DNA Methylation Profiling of hTERT Gene Alongside with the Telomere Performance in Gastric Adenocarcinoma.},
journal = {Journal of gastrointestinal cancer},
volume = {51},
number = {3},
pages = {788-799},
doi = {10.1007/s12029-020-00427-7},
pmid = {32617831},
issn = {1941-6636},
mesh = {Adenocarcinoma/*genetics ; Carcinogenesis/genetics ; DNA Methylation ; Epigenesis, Genetic ; Epigenomics ; *Gene Expression Regulation, Neoplastic ; Histone Code/genetics ; Histones/metabolism ; Humans ; Promoter Regions, Genetic/genetics ; RNA, Long Noncoding/metabolism ; Stomach Neoplasms/*genetics ; Telomerase/*genetics/metabolism ; Telomere/*metabolism ; Telomere Homeostasis/genetics ; },
abstract = {PURPOSE: Epigenetic modification including of DNA methylation, histone acetylation, histone methylation, histon phosphorylation and non-coding RNA can impress the gene expression and genomic stability and cause different types of malignancies and also main human disorder. Conspicuously, the epigenetic alteration special DNA methylation controls telomere length, telomerase activity and also function of different genes particularly hTERT expression. Telomeres are important in increasing the lifespan, health, aging, and the development and progression of some diseases like cancer.<br><br>METHODS: This review provides an assessment of the epigenetic alterations of telomeres, telomerase and repression of its catalytic subunit, hTERT and function of long non-coding RNAs such as telomeric-repeat containing RNA (TERRA) in carcinogenesis and tumorgenesis of gastric cancer.<br><br>RESULTS: hTERT expression is essential and indispensable in telomerase activation through immortality and malignancies and also plays an important role in maintaining telomere length. Telomeres and telomerase have been implicated in regulating epigenetic factors influencing certain gene expression. Correspondingly, these changes in the sub telomere and telomere regions are affected by the shortening of telomere length and increased telomerase activity and hTERT gene expression have been observed in many cancers, remarkably in gastric cancer.<br><br>CONCLUSION: Epigenetic alteration and regulation of hTERT gene expression are critical in controlling telomerase activity and its expression. Graphical Abstract.},
}
@article {pmid32614411,
year = {2020},
author = {Tsai, CW and Chang, WS and Xu, J and Xu, Y and Huang, M and Pettaway, C and Bau, DT and Gu, J},
title = {Leukocyte telomere length is associated with aggressive prostate cancer in localized African American prostate cancer patients.},
journal = {Carcinogenesis},
volume = {41},
number = {9},
pages = {1213-1218},
doi = {10.1093/carcin/bgaa070},
pmid = {32614411},
issn = {1460-2180},
mesh = {Black or African American/*genetics/statistics &amp; numerical data ; Aged ; Follow-Up Studies ; Genetic Predisposition to Disease ; Humans ; Leukocytes/metabolism/*pathology ; Male ; Middle Aged ; Neoplasm Grading ; Prostatectomy ; Prostatic Neoplasms/ethnology/genetics/*pathology/surgery ; *Telomere Homeostasis ; },
abstract = {Telomeres play important roles in cancer initiation and progression. Leukocyte telomere length (LTL) has been associated with the risk and prognosis of several cancers, but its association with prostate cancer (PCa) prognosis in African Americans (AAs) has not been reported. In this study, we measured relative LTL from 317 AA PCa patients and assessed its associations with aggressive disease characteristics at diagnosis and biochemical recurrence (BCR) after radical prostatectomy and radiotherapy. LTL was shorter in patients with higher Gleason scores (GS) at diagnosis. Dichotomized into short and long LTL groups, patients with short LTL exhibited a 1.91-fold (95% confidence interval, CI, 1.14-3.20, P = 0.013) increased risk of being diagnosed with high-risk disease (GS =7 [4 + 3] and GS ≥8) than those with long LTL in multivariable logistic regression analysis. Moreover, shorter LTL was significantly associated with an increased risk of BCR (hazard ratio = 1.68, 95% CI, 1.18-11.44, P = 0.024) compared with longer LTL in localized patients receiving prostatectomy or radiotherapy in multivariable Cox analysis. Kaplan-Meier survival analysis showed patients with short LTL had significantly shorter BCR-free survival time than patients with long LTL (Log rank P = 0.011). In conclusion, our results showed for the first time that LTL was shorter in PCa patients with higher GS and short LTL was associated with worse prognosis in AA PCa patients receiving prostatectomy or radiotherapy.},
}
@article {pmid32613841,
year = {2020},
author = {Sun, Y and Wang, W and Jiao, YR and Ren, J and Gao, L and Li, Y and Hu, P and Ren, TY and Han, QF and Chen, C and Yao, HC},
title = {Leukocyte telomere length: a potential biomarker for the prognosis of coronary artery disease.},
journal = {Biomarkers in medicine},
volume = {14},
number = {11},
pages = {933-941},
doi = {10.2217/bmm-2020-0171},
pmid = {32613841},
issn = {1752-0371},
mesh = {Aged ; Biomarkers/metabolism ; Coronary Artery Disease/*diagnosis/*genetics ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Prognosis ; Risk Factors ; Telomere/*genetics ; },
abstract = {Aim: This study aimed to explore the prognostic value of leukocyte telomere length (LTL) in patients with coronary artery disease (CAD). Materials &amp; methods: We enrolled 366 CAD patients and 76 healthy subjects in this study. LTL was measured. All subjects were followed up for 6 months for further analysis regarding major adverse cardiac events (MACEs). Results: CAD patients had a significantly shortened LTL compared with healthy subjects (p < 0.05). The area under the curve for LTL prediction of MACEs was 0.769 (p < 0.001), with a shorter LTL being an independent predictor of MACEs (Cox proportional hazards regression, hazard ratio: 2.866; p < 0.001). Conclusion: LTL could be considered as an independent predictor of short-term MACEs in CAD.},
}
@article {pmid32612998,
year = {2020},
author = {Kahl, VFS and Allen, JAM and Nelson, CB and Sobinoff, AP and Lee, M and Kilo, T and Vasireddy, RS and Pickett, HA},
title = {Telomere Length Measurement by Molecular Combing.},
journal = {Frontiers in cell and developmental biology},
volume = {8},
number = {},
pages = {493},
pmid = {32612998},
issn = {2296-634X},
abstract = {Telomeres are repetitive regions of DNA bound by specialized proteins at the termini of linear chromosomes that prevent the natural chromosome ends from being recognized as DNA double strand breaks. Telomeric DNA is gradually eroded with each round of cell division, resulting in the accumulation of critically short or dysfunctional telomeres that eventually trigger cellular senescence. Consequently, telomere length is indicative of the proliferative capacity of a cell. Multiple methods exist to measure telomere length and telomere content, but a simple and reliable technique to accurately measure individual telomere lengths is currently lacking. We have developed the Telomere length Combing Assay (TCA) to measure telomere length on stretched DNA fibers. We used TCA to measure telomere erosion in primary human fibroblasts, and to detect telomere lengthening in response to activation of telomere maintenance pathways. TCA was also used to accurately measure telomere length in healthy individuals, and to identify critically short telomeres in patients with telomere biology disorders. TCA is performed on isolated DNA, negating the need for cycling cells. TCA is amenable to semi-automated image analysis, and can be fully automated using the Genomic Vision molecular combing platform. This not only precludes sampling bias, but also provides the potential for high-throughput applications and clinical development. TCA is a simple and versatile technique to measure the distribution of individual telomere lengths in a cell population, offering improved accuracy, and more detailed biological insight for telomere length measurement applications.},
}
@article {pmid32606142,
year = {2020},
author = {Jumatovaite, Z and Kriauciunas, A and Vilkeviciute, A and Gedvilaite, G and Liutkevicius, V and Uloza, V and Smalinskiene, A and Liutkeviciene, R},
title = {Association of Leukocyte Telomere Length and Genes Involved in its Regulation With Oral Carcinoma.},
journal = {In vivo (Athens, Greece)},
volume = {34},
number = {4},
pages = {1739-1747},
pmid = {32606142},
issn = {1791-7549},
mesh = {*Carcinoma, Squamous Cell/genetics ; Genetic Predisposition to Disease ; Genotype ; *Head and Neck Neoplasms ; Humans ; Leukocytes ; *Mouth Neoplasms/genetics ; Polymorphism, Single Nucleotide ; *Tankyrases ; Telomere/genetics ; },
abstract = {BACKGROUND/AIM: This study aimed to determine the relationship between the relative leukocyte telomere length (RLTL) and gene polymorphisms involved in its regulation with the occurrence of oral squamous cell carcinoma (OSCC).<br><br>PATIENTS AND METHODS: Patients with OSCC and healthy subjects were examined. Genotyping and RLTL measurement were carried out using rPCR.<br><br>RESULTS: The OSCC group had longer telomeres than controls (p=0.001). Minor allele T at TERF1rs1545827 may increase RLTL shortening (p=0.047). TNKS2rs10509639 A/G and A/G+G/G genotypes were associated with a 2.6-fold increased odd (p=0.012) and a 2.4-fold increased odd (p=0.019) of RLTL elongation compared to A/A genotype. The A/G genotype was associated with a 2.6-fold increased odd (p=0.011) compared to the A/A+G/G genotypes. Each G allele was associated with a 2.1-fold increased odd of longer RLTL (p=0.036).<br><br>CONCLUSION: Longer telomeres were found in patients with OSCC than in controls. The TERF1 rs1545827 and the TNKS2 rs10509639 polymorphisms were associated with an increase in RLTL.},
}
@article {pmid32604805,
year = {2020},
author = {Valera-Gran, D and Prieto-Botella, D and Peral-Gómez, P and Hurtado-Pomares, M and Sánchez-Pérez, A and Navarrete-Muñoz, EM},
title = {Bibliometric Analysis of Research on Telomere Length in Children: A Review of Scientific Literature.},
journal = {International journal of environmental research and public health},
volume = {17},
number = {12},
pages = {},
pmid = {32604805},
issn = {1660-4601},
mesh = {Asia ; *Bibliometrics ; Child ; Europe ; Humans ; Publications ; *Telomere ; *Telomere Homeostasis ; *Telomere Shortening ; United States ; },
abstract = {Telomere length in early life has been recently associated with biological aging and development of negative consequences in later adult life. A relevant area of research has emerged to understand the factors that impact telomere length in children. We conducted a bibliometric analysis to track research output and identify global trends and gaps in the knowledge of telomere length in children. Bibliographic data were retrieved from the Web of Science database and then analyzed by using Bibliometrix R package. A total of 840 publications were yielded from 1991 to 2019. The references were prominently published in journals, with 20 high ranked journals contributing to 30% of literature on telomere length in children. The USA was the most productive country (35.7%), followed by Europe (12.1%), and Asia (11.9%). A knowledge map of telomere length in children through keyword analyses revealed that there were two potential main lines of research based on two different approaches: genomic research and epidemiological research. This study shows that telomere length in children is a topic of research that has gained significant relevance in the last decade. This bibliometric study may be helpful in identifying research trends and finding research hot spots and gaps in this research field.},
}
@article {pmid32603955,
year = {2020},
author = {Coimbra, BM and Carvalho, CM and Ota, VK and Vieira-Fonseca, T and Bugiga, A and Mello, AF and Mello, MF and Belangero, SI},
title = {A systematic review on the effects of social discrimination on telomere length.},
journal = {Psychoneuroendocrinology},
volume = {120},
number = {},
pages = {104766},
doi = {10.1016/j.psyneuen.2020.104766},
pmid = {32603955},
issn = {1873-3360},
mesh = {Cellular Senescence/physiology ; Female ; Humans ; Male ; Racism/psychology ; Risk Factors ; Social Class ; Social Discrimination/*psychology/trends ; Stress, Psychological/metabolism ; Telomere/*metabolism/physiology ; Telomere Homeostasis/*physiology ; Telomere Shortening/physiology ; },
abstract = {Discrimination is unfair treatment against a certain group based on race, age, gender, sexual orientation, or other social identities. Discrimination is pervasive in society, elevates psychosocial stress, and is associated with negative mental and physical health outcomes. However, more research is needed to understand the biological mechanisms underlying discrimination-related health disparities. Telomere science may contribute to elucidate some of these aspects. Telomeres are protein-DNA complexes that shorten after cell division and are valuable markers of cellular aging. Short telomeres have been associated with the onset of age-related diseases. Evidence shows that chronic psychological stress may accelerate telomere shortening. Since discrimination can lead to psychological strain with cumulative impact on general health, we hypothesized that groups that report more discrimination show reduced telomere length (TL) as a consequence of psychosocial stress elevation. Through a systematic review of the literature we found 12 articles that met our criteria. Eligible studies measured racial, gender, unfair policing, and multiple forms of discrimination in association with TL. Our review showed mixed results, suggesting that there is weak evidence of a main association between discrimination and TL. However, discrimination may interact with several variables (such as depressive symptoms, acculturation, higher socioeconomic status, internalization of negative racial bias, and not discussing discrimination experiences with others) and contribute to shorten telomeres. Discrimination is a complex social construct composed of a vast sum of experiences, impressions, and contexts that in combination with other sources of stress may have an impact on TL. Telomeres may be a plausible pathway to investigate health discrepancies in discriminated groups in society, but more evidence is needed to investigate the potential harm of discrimination on cells.},
}
@article {pmid32599751,
year = {2020},
author = {Ogłuszka, M and Te Pas, MFW and Poławska, E and Nawrocka, A and Stepanow, K and Pierzchała, M},
title = {Omega-3 Alpha-Linolenic Fatty Acid Affects the Level of Telomere Binding Protein TRF1 in Porcine Skeletal Muscle.},
journal = {Animals : an open access journal from MDPI},
volume = {10},
number = {6},
pages = {},
pmid = {32599751},
issn = {2076-2615},
support = {RG 2/2016//NUTRICIA Foundation/ ; 2015/17/N/NZ9/01105//National Science Centre/ ; },
abstract = {Omega-3 fatty acids are health-promoting nutrients that contribute to the amelioration of age-related diseases. Recent studies have reported the role of these fatty acids in the aging process, explicitly impacting telomere biology. The shelterin protein complex, located at the extremities of chromosomes, ensures telomere protection and length regulation. Here, we analyzed the impact of dietary omega-3 alpha-linolenic fatty acid from linseed oil on skeletal muscle telomere biology using an animal model of female pigs. Fifteen animals were supplemented with linseed oil for nine weeks and an equal number of individuals were fed with a control diet. Linseed-oil-supplemented animals showed an increased level of alpha-linolenic acid in skeletal muscles compared to control animals. There was no difference between groups in the telomere length measured in leukocytes and muscles. However, muscles of the linseed-oil-supplemented pigs showed lower levels of the shelterin TRF1 protein compared to the control group. Our results suggest that omega-3 linolenic acid counteracts the elevation of TRF1 levels, which increase with age and due to the presence of reactive oxygen species in muscle. The observed effect may be due to attenuation of oxidative stress.},
}
@article {pmid32597753,
year = {2020},
author = {Shubin, CB and Greider, CW},
title = {The role of Rif1 in telomere length regulation is separable from its role in origin firing.},
journal = {eLife},
volume = {9},
number = {},
pages = {},
pmid = {32597753},
issn = {2050-084X},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; T32 GM007445/GM/NIGMS NIH HHS/United States ; DGE-1746891//National Science Foundation/International ; },
mesh = {Cell Cycle ; Cell Cycle Proteins/genetics/*metabolism ; DNA Replication ; DNA-Binding Proteins/genetics ; Gene Dosage ; Genome, Fungal ; Mutation ; Protein Phosphatase 1/metabolism ; Protein Serine-Threonine Kinases/*metabolism ; *Replication Origin ; Repressor Proteins/*metabolism ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/*ultrastructure ; Telomere Homeostasis ; Telomere-Binding Proteins/*metabolism ; },
abstract = {To examine the established link between DNA replication and telomere length, we tested whether firing of telomeric origins would cause telomere lengthening. We found that RIF1 mutants that block Protein Phosphatase 1 (PP1) binding activated telomeric origins but did not elongate telomeres. In a second approach, we found overexpression of ∆N-Dbf4 and Cdc7 increased DDK activity and activated telomeric origins, yet telomere length was unchanged. We tested a third mechanism to activate origins using the sld3-A mcm5-bob1 mutant that de-regulates the pre-replication complex, and again saw no change in telomere length. Finally, we tested whether mutations in RIF1 that cause telomere elongation would affect origin firing. We found that neither rif1-∆1322 nor rif1HOOK affected firing of telomeric origins. We conclude that telomeric origin firing does not cause telomere elongation, and the role of Rif1 in regulating origin firing is separable from its role in regulating telomere length.},
}
@article {pmid32594585,
year = {2020},
author = {Martínez-González, K and Islas-Hernández, A and Martínez-Ezquerro, JD and Bermúdez-Rattoni, F and Garcia-delaTorre, P},
title = {Telomere length and oxidative stress variations in a murine model of Alzheimer's disease progression.},
journal = {The European journal of neuroscience},
volume = {52},
number = {12},
pages = {4863-4874},
doi = {10.1111/ejn.14877},
pmid = {32594585},
issn = {1460-9568},
support = {179594//Consejo Nacional de Ciencia y Tecnolog&#xed;a/ ; },
mesh = {*Alzheimer Disease/genetics ; Animals ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Oxidative Stress ; Telomere/genetics ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, and ageing is its major risk factor. Changes in telomere length have been associated with ageing and some degenerative diseases. Our aim was to explore some of the molecular changes caused by the progression of AD in a transgenic murine model (3xTg-AD; B6; 129-Psen1 <tm1Mpm> Tg (APPSwe, tauP301L) 1Lfa). Telomere length was assessed by qPCR in both brain tissue and peripheral blood cells and compared between three age groups: 5, 9 and 13 months. In addition, a possible effect of oxidative stress on telomere length and AD progression was explored. Shorter telomeres were found in blood cells of older transgenic mice compared to younger and wild-type mice but no changes in telomere length in the hippocampus. An increase in oxidative stress with age was found for all strains, but no correlation was found between oxidative stress and shorter telomere length for transgenic mice. Telomere length and oxidative stress are affected by AD progression in the 3xTg-AD murine model. Changes in blood cells are more noticeable than changes in brain tissue, suggesting that systemic changes can be detected early in the disease in this murine model.},
}
@article {pmid32589715,
year = {2020},
author = {Peska, V and Mátl, M and Mandáková, T and Vitales, D and Fajkus, P and Fajkus, J and Garcia, S},
title = {Human-like telomeres in Zostera marina reveal a mode of transition from the plant to the human telomeric sequences.},
journal = {Journal of experimental botany},
volume = {71},
number = {19},
pages = {5786-5793},
doi = {10.1093/jxb/eraa293},
pmid = {32589715},
issn = {1460-2431},
mesh = {Base Sequence ; Genome, Plant ; Humans ; In Situ Hybridization, Fluorescence ; *Telomere/genetics ; *Zosteraceae ; },
abstract = {A previous study describing the genome of Zostera marina, the most widespread seagrass in the Northern hemisphere, revealed some genomic signatures of adaptation to the aquatic environment such as the loss of stomatal genes, while other functions such as an algal-like cell wall composition were acquired. Beyond these, the genome structure and organization were comparable with those of the majority of plant genomes sequenced, except for one striking feature that went unnoticed at that time: the presence of human-like instead of the expected plant-type telomeric sequences. By using different experimental approaches including fluorescence in situ hybridization (FISH), genome skimming by next-generation sequencing (NGS), and analysis of non-coding transcriptome, we have confirmed its telomeric location in the chromosomes of Z. marina. We have also identified its telomerase RNA (TR) subunit, confirming the presence of the human-type telomeric sequence in the template region. Remarkably, this region was found to be very variable even in clades with a highly conserved telomeric sequence across their species. Based on this observation, we propose that alternative annealing preferences in the template borders can explain the transition between the plant and human telomeric sequences. The further identification of paralogues of TR in several plant genomes led us to the hypothesis that plants may retain an increased ability to change their telomeric sequence. We discuss the implications of this occurrence in the evolution of telomeres while introducing a mechanistic model for the transition from the plant to the human telomeric sequences.},
}
@article {pmid32588935,
year = {2021},
author = {Millan, AL and Trobo, SI and de Dios, A and Cerrato García, M and Pérez, MS and Cerrone, GE and Frechtel, GD and López, AP},
title = {MODY patients exhibit shorter telomere length than non-diabetic subjects.},
journal = {Diabetes/metabolism research and reviews},
volume = {37},
number = {2},
pages = {e3374},
doi = {10.1002/dmrr.3374},
pmid = {32588935},
issn = {1520-7560},
support = {2018//Sociedad Argentina de Diabetes/ ; 20720170200027BA//Universidad de Buenos Aires/ ; },
mesh = {*Diabetes Mellitus, Type 2/genetics ; Humans ; *Telomere/genetics ; },
abstract = {BACKGROUND: Given the increasing evidence supporting the association between telomere shortening and diabetes, the aim of the present work was to establish whether MODY patients suffer a reduction in telomere lenght (TL) due to oxidative stress produced by chronic hyperglycemia, despite not presenting insulin resistance or inflammation.<br><br>METHODS: We analysed clinical and biochemical parameters in 35 MODY2 and 12 MODY3 patients compared with 48 control subjects. The absolute telomere length (aTL) of peripheral blood leukocytes was measured using the quantitative polymerase chain reaction (qPCR).<br><br>RESULTS: A significant negative correlation was observed between aTL and age in the whole population, among MODY patients and in each subtype studied, MODY2 and MODY3, which allowed us to validate the method. We found, for the first time, that MODY patients have shorter aTL with respect to non-diabetic controls (6.49&#x2009;&#xb1;&#x2009;3.31 kbp vs 11.13&#x2009;&#xb1;&#x2009;7.82 kbp, p = .006). However, no differences were found between MODY2 and MODY3. In addition, aTL showed a negative correlation with duration of the disease and fasting plasma glucose (FPG) levels in MODY patients in general and also with HbA1c in MODY2 patients in particular.<br><br>CONCLUSIONS: Both MODY2 and MODY3 types present telomere shortening, which, at least partly, responds to HbA1c and FPG levels. These findings suggest comparable mechanisms underlying the attrition of TL. Taken together, our results on aTL in MODY patients may provide a parameter relatively easy and inexpensive to quantify in order to measure the impact of high glucose levels and potentially carry out antidiabetic treatment with stricter targets.},
}
@article {pmid32588833,
year = {2020},
author = {Vysotskaya, OV and Glukhov, AI and Semochkina, YP and Gordeev, SA and Moskaleva, EY},
title = {[Telomerase activity, mTert gene expression and the telomere length in mouse mesenchymal stem cells in the late period after γ- and γ,n-irradiation and in the tumors developed from these cells].},
journal = {Biomeditsinskaia khimiia},
volume = {66},
number = {3},
pages = {265-273},
doi = {10.18097/PBMC20206603265},
pmid = {32588833},
issn = {2310-6972},
mesh = {Animals ; Cell Line ; Fibrosarcoma/pathology ; *Gamma Rays ; *Mesenchymal Stem Cells ; Mice ; *Telomerase/genetics/metabolism ; *Telomere/genetics ; },
abstract = {In proliferating normal and tumor cells, the telomere length (TL) is maintained by high telomerase activity (TA). In the absence of TA the TL maintenance involves a mechanism of alternative lengthening of telomeres (ALT). The aim of this study was to investigate the level of TA, the mTert expression and TL in cultured normal and transformed by γ- and γ,n-irradiation mesenchymal stem cells (MSCs) from mouse bone marrow, in sarcomas that developed after the transplantation of these cells into syngeneic mice, and in fibrosarcoma cell lines obtained from these tumors to find out the role of AT or ALT in maintaining TL in these cells. During prolonged cultivation of normal and transformed under the influence of γ- (1 Gy and 6 Gy) and γ,n-irradiation (0.05 Gy, 0.5 Gy, and 2 Gy) MSCs from mouse bone marrow, a decrease in TA was detected in irradiated cells. Even deeper decrease in TA was found in sarcomas developed after administration of transformed MSCs to syngeneic mice and in fibrosarcoma cell lines isolated from these tumors in which TA was either absent or was found to be at a very low level. TL in three of the four lines obtained was halved compared to the initial MSCs. With absent or low TA and reduced TL, the cells of all the obtained fibrosarcoma lines successfully proliferated without signs of a change in survival. The mechanism of telomere maintainance in fibrosarcoma cell lines in the absence of TA needs further investigation and it can be assumed that it is associated with the use of the ALT. The detected decrease or absence of TA in transformed under the action of irradiation MSCs with the preservation or even an increase in the telomerase gene expression may be associated with the formation of inactive splicing variants, and requires further study. The obtained lines of transformed MSCs and fibrosarcomas with TA and without the activity of this enzyme can be a useful model for studying the efficacy of TA and ALT inhibitors in vitro and in vivo.},
}
@article {pmid32587985,
year = {2020},
author = {Maremanda, KP and Sundar, IK and Li, D and Rahman, I},
title = {Age-dependent assessment of genes involved in cellular senescence, telomere and mitochondrial pathways in human lung tissue of smokers, COPD and IPF: Associations with SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 axis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2020.06.14.20129957},
pmid = {32587985},
abstract = {Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Cigarette smoke is a major etiological risk factor that has been shown to alter cellular processes involving mitochondrial function, cellular senescence and telomeric length. Here we determined how aging contribute to the alteration in the gene expression of above mentioned cellular processes that play an important role in the progression of COPD and IPF. We hypothesized that aging may differentially alter the expression of mitochondrial, cellular senescence and telomere genes in smokers and patients with COPD and IPF compared to non-smokers. Total RNA from human lung tissues from non-smokers, smokers, and patients with COPD and IPF were processed and analyzed based on their ages (younger: <55 yrs and older: >55 yrs). NanoString nCounter panel was used to analyze the gene expression profiles using a custom designed codeset containing 112 genes including 6 housekeeping controls (mitochondrial biogenesis and function, cellular senescence, telomere replication and maintenance). mRNA counts were normalized, log2 transformed for differential expression analysis using linear models in the limma package (R/Bioconductor). Data from non-smokers, smokers and patients with COPD and IPF were analyzed based on the age groups (pairwise comparisons between younger vs. older groups). Several genes were differentially expressed in younger and older smokers, and patients with COPD and IPF compared to non-smokers which were part of the mitochondrial biogenesis/function (HSPD1, FEN1, COX18, COX10, UCP2 &amp; 3), cellular senescence (PCNA, PTEN, KLOTHO, CDKN1C, TNKS2, NFATC1 &amp; 2, GADD45A) and telomere replication/maintenance (PARP1, SIRT6, NBN, TERT, RAD17, SLX4, HAT1) target genes. Interestingly, NOX4 and TNKS2 were increased in the young IPF as compared to the young COPD patients. Genes in the mitochondrial dynamics and other quality control mechanisms like FIS1 and RHOT2 were decreased in young IPF compared to their age matched COPD subjects. ERCC1 (Excision Repair Cross-Complementation Group 1) and GADD45B were higher in young COPD as compared to IPF. Aging plays an important role in various infectious diseases. Elderly patients with chronic lung disease and smokers were found to have high incidence and mortality rates in the current pandemic of SARS-CoV-2 infection. Immunoblot analysis in the lung homogenates of smokers, COPD and IPF subjects revealed increased protein abundance of important proteases and spike proteins like TMPRSS2, furin and DPP4 in association with a slight increase in SARS-CoV-2 receptor ACE2 levels. This may further strengthen the observation that smokers, COPD and IPF subjects are more prone to COVID-19 infection. Overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition add to the pathobiology of lung aging in COPD and IPF and other smoking-related chronic lung disease in associated with alterations in SARS-CoV-2 ACE2-TMPRSS2-Furin-DPP4 axis for COVID-19 infection.},
}
@article {pmid32586834,
year = {2020},
author = {Yin, H and Hardikar, S and Lindstroem, S and Hsu, L and Anderson, KE and Banbury, BL and Berndt, SI and Chan, AT and Giovanucci, EL and Harrison, TA and Joshi, AD and Nan, H and Potter, JD and Sakoda, LC and Slattery, ML and Schoen, RE and White, E and Peters, U and Newcomb, PA},
title = {Telomere Maintenance Variants and Survival after Colorectal Cancer: Smoking- and Sex-Specific Associations.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {29},
number = {9},
pages = {1817-1824},
pmid = {32586834},
issn = {1538-7755},
support = {U01 HG004438/HG/NHGRI NIH HHS/United States ; U01 HG004446/HG/NHGRI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; U01 CA164930/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; HHSN271201100004C/AG/NIA NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA042182/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; K05 CA152715/CA/NCI NIH HHS/United States ; HHSN268201100003I/HL/NHLBI NIH HHS/United States ; HHSN268201100002I/HL/NHLBI NIH HHS/United States ; P50 CA127003/CA/NCI NIH HHS/United States ; HHSN268201100004C/WH/WHI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; HHSN268201100001I/HL/NHLBI NIH HHS/United States ; R01 CA076366/CA/NCI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; HHSN268201100004I/HL/NHLBI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; R01 CA048998/CA/NCI NIH HHS/United States ; HHSN268201100003C/WH/WHI NIH HHS/United States ; Z01 CP010200/ImNIH/Intramural NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; HHSN268201100002C/WH/WHI NIH HHS/United States ; K07 CA222060/CA/NCI NIH HHS/United States ; K07 CA190673/CA/NCI NIH HHS/United States ; HHSN268201100001C/WH/WHI NIH HHS/United States ; },
mesh = {Aged ; Colorectal Neoplasms/*genetics/mortality/pathology ; Female ; Humans ; Male ; Prognosis ; Sex Factors ; Smoking/*adverse effects ; Survival Analysis ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Telomeres play an important role in colorectal cancer prognosis. Variation in telomere maintenance genes may be associated with survival after colorectal cancer diagnosis, but evidence is limited. In addition, possible interactions between telomere maintenance genes and prognostic factors, such as smoking and sex, also remain to be investigated.<br><br>METHODS: We conducted gene-wide analyses of colorectal cancer prognosis in 4,896 invasive colorectal cancer cases from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO); 1,871 common variants within 13 telomere maintenance genes were included. Cox models were fit to estimate associations of these variants individually with overall and colorectal cancer-specific survival. Likelihood ratio tests were used to test for interaction by smoking and sex. P values were adjusted using Bonferroni correction.<br><br>RESULTS: The association between minor allele of rs7200950 (ACD) with colorectal cancer-specific survival varied significantly by smoking pack-years (corrected P = 0.049), but no significant trend was observed. By sex, minor alleles for rs2975843 (TERF1), rs75676021 (POT1), and rs74429678 (POT1) were associated with decreased overall and/or colorectal cancer-specific survival in women but not in men.<br><br>CONCLUSIONS: Our study reported a gene-wide statistically significant interaction with sex (TERF1, POT1). Although significant interaction by smoking pack-years (ACD) was observed, there was no evidence of a dose response. Validation of these findings in other large studies and further functional annotation on these SNPs are warranted.<br><br>IMPACT: Our study found a gene-smoking and gene-sex interaction on survival after colorectal cancer diagnosis, providing new insights into the role of genetic polymorphisms in telomere maintenance on colorectal cancer prognosis.},
}
@article {pmid32586523,
year = {2020},
author = {Koss, KJ and Schneper, LM and Brooks-Gunn, J and McLanahan, S and Mitchell, C and Notterman, DA},
title = {Early Puberty and Telomere Length in Preadolescent Girls and Mothers.},
journal = {The Journal of pediatrics},
volume = {222},
number = {},
pages = {193-199.e5},
pmid = {32586523},
issn = {1097-6833},
support = {R01 HD036916/HD/NICHD NIH HHS/United States ; R01 HD076592/HD/NICHD NIH HHS/United States ; R01 MD011716/MD/NIMHD NIH HHS/United States ; R25 HD074544/HD/NICHD NIH HHS/United States ; },
mesh = {Adolescent ; Child ; *Child Development ; Female ; Humans ; Menarche/*genetics ; *Mothers ; Puberty/*genetics ; Retrospective Studies ; Telomere/*genetics ; Telomere Homeostasis/*physiology ; Young Adult ; },
abstract = {OBJECTIVE: To test the association between early puberty and telomere length in preadolescent girls and mothers from a large representative sample of US females.<br><br>STUDY DESIGN: We analyzed data from 1194 preadolescent girls and 2421 mothers from the Fragile Families and Child Wellbeing Study. Participants were from a population-based birth cohort (1998-2000) born in large US cities. Telomere length was assessed by quantitative polymerase chain reaction from saliva samples provided by preadolescent girls and mothers of preadolescent youth. Mothers completed a questionnaire about their child's pubertal development to determine concurrent Tanner stages and provided self-reports of her own age at menarche. Linear regression models were used to estimate the association between pubertal development (status and timing) and telomere length.<br><br>RESULTS: Early pubertal timing but not pubertal status was associated with shorter telomere length in preadolescent girls (P&#xa0;<&#xa0;.01). Early age at menarche was associated with shorter telomere length in a sample of mothers of preadolescent youth (P&#xa0;<&#xa0;.05).<br><br>CONCLUSIONS: Results provide evidence for the association between early puberty and shorter telomeres evidenced by associations in both preadolescent girls and mothers. Future research should address the limitations of this study by using longitudinal measurements of pubertal development assessed through medical examinations and repeated assessments of telomere length to capture telomere attrition.},
}
@article {pmid32583791,
year = {2020},
author = {Vakili, SA and George, A and Ayatollahi, SA and Martorell, M and Ostrander, EA and Salehi, B and Martins, N and Sharifi-Rad, J},
title = {Phenolic compounds, saponins and alkaloids on cancer progression: emphasis on p53 expression and telomere length.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {66},
number = {4},
pages = {110-119},
pmid = {32583791},
issn = {1165-158X},
mesh = {Alkaloids/*pharmacology ; Animals ; *Disease Progression ; Humans ; Neoplasms/*pathology ; Phenols/*pharmacology ; Saponins/*pharmacology ; Telomere Homeostasis/*drug effects ; Tumor Suppressor Protein p53/*metabolism ; },
abstract = {Telomere length is correlated with cell proliferation, and cancer cells are characterized by an uncontrolled cell cycle. Being apoptosis one of the checks and balances incorporated into cells cycle, due to its characteristics, cancer cells are able to overcome this process. In particular, the tumour suppressor protein p53 loss or inactivation can lead to activation of telomerase enzyme, which can make cells unable to detect DNA damages that spurs apoptosis. Some bioactive compounds, in particular phenolic compounds, saponins and alkaloids have revealed good abilities to affect p53 expression and indirectly control the telomere length. In this sense, this review gives a key emphasis to the ability of these compounds in blocking cancer progression by acting on p53 expression and controlling telomere length. As main findings, phenolic compounds, saponins and alkaloids interfere with cancer progression by stimulating p53 expression, which can cause pro-apoptotic onset and restrict the anti-apoptotic activity, in addition to preventing telomerase enzyme activity.},
}
@article {pmid32583532,
year = {2020},
author = {Fang, C and Huang, H and Zhang, Q and Wang, N and Jing, X and Guo, J and Ferianc, M and Xu, Z},
title = {Relation between sex hormones and leucocyte telomere length in men with idiopathic pulmonary fibrosis.},
journal = {Respirology (Carlton, Vic.)},
volume = {25},
number = {12},
pages = {1265-1273},
pmid = {32583532},
issn = {1440-1843},
mesh = {Aging/*physiology ; *Androgens/blood/genetics/metabolism ; Case-Control Studies ; Correlation of Data ; Humans ; *Idiopathic Pulmonary Fibrosis/blood/genetics/metabolism ; Leukocytes/*physiology ; Male ; Middle Aged ; Mutation ; Telomerase/*genetics ; Telomere Shortening/physiology ; *Testosterone/blood/genetics ; Exome Sequencing/methods ; },
abstract = {BACKGROUND AND OBJECTIVE: IPF is an ageing-related lung disorder featuring progressive lung scarring. IPF patients are frequently identified with short telomeres but coding mutations in telomerase can only explain a minority of cases. Sex hormones regulate telomerase activity in vitro and levels of sex hormones are related to LTL. The objective of this study was to explore whether sex hormones were associated with LTL, whether they interacted with genetic variants in telomerase and whether polymorphisms in the exon of androgen metabolism genes were associated with plasma testosterone concentrations in male IPF patients.<br><br>METHODS: A case-control study was performed on 101 male IPF subjects and 51 age-matched healthy controls. Early morning plasma sex hormones were quantified, and whole-exome sequencing was used to identify rare protein-altering variants of telomerase and SNP in the exon of androgen metabolism genes. LTL was analysed by PCR and expressed as a T/S ratio.<br><br>RESULTS: LTL, testosterone and DHT were decreased significantly in the IPF group. After adjustments for age and variant status in telomerase-related genes, only testosterone was positively associated with LTL (P = 0.001). No significant interaction (P = 0.661) was observed between rare protein-altering variants of telomerase and testosterone. No coding SNP in androgen metabolism genes were significantly associated with testosterone concentrations.<br><br>CONCLUSION: Plasma testosterone is associated with LTL independent of age or rare protein-altering variants of telomerase. No genetic variations of androgen-related pathway genes are associated with androgen concentrations. Further studies are warranted to examine whether hormonal interventions might retard telomere loss in male IPF patients.},
}
@article {pmid32581523,
year = {2020},
author = {Mir, SM and Samavarchi Tehrani, S and Goodarzi, G and Jamalpoor, Z and Asadi, J and Khelghati, N and Qujeq, D and Maniati, M},
title = {Shelterin Complex at Telomeres: Implications in Ageing.},
journal = {Clinical interventions in aging},
volume = {15},
number = {},
pages = {827-839},
pmid = {32581523},
issn = {1178-1998},
mesh = {Aging/genetics/*metabolism ; DNA Replication ; Humans ; *Oxidative Stress ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Different factors influence the development‎ and control of ageing. It is well known that progressive telomere shorting is one of the molecular mechanisms underlying ageing. The shelterin complex consists of six telomere-specific proteins which are involved in the protection of chromosome ends. More particularly, this vital complex protects the telomeres from degradation, prevents from activation of unwanted repair systems, regulates the activity of telomerase, and has a crucial role in cellular senescent and ageing-related pathologies. This review explores the organization and function of telomeric DNA along with the mechanism of telomeres during ageing, followed by a discussion of the critical role of shelterin components and their changes during ageing.},
}
@article {pmid32581228,
year = {2020},
author = {Zhang, Y and Zhou, Q and Yang, R and Hu, C and Huang, Z and Zheng, C and Liang, Q and Gong, R and Zhu, X and Gong, H and Yuan, H and Chen, C and Li, X and Zhang, N and Yang, Z and Sun, L},
title = {Serum branched-chain amino acids are associated with leukocyte telomere length and frailty based on residents from Guangxi longevity county.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {10252},
pmid = {32581228},
issn = {2045-2322},
mesh = {Adult ; Aged ; Aged, 80 and over ; Amino Acids, Branched-Chain/*blood ; China ; Chromatography, Liquid ; Cross-Sectional Studies ; Female ; Frailty/*blood/metabolism ; Humans ; Leukocytes/*chemistry ; Male ; Middle Aged ; Tandem Mass Spectrometry ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Branched-chain amino acids (BCAAs) and telomere length are biologically associated with healthy aging. However, the association between them and their interaction on frailty remain unclear in humans. Here, a cross-sectional study based on residents from Guangxi longevity county was conducted to investigate the association of serum BCAAs, peripheral leukocyte telomere length (LTL) and frailty. A total of 1,034 subjects aged 20 to 110 years were recruited in the study. The real-time qPCR method and a targeted metabolomics approach based on isotope dilution liquid chromatography tandem mass spectrometry (LC/MS/MS) method were used for measurement of LTL and BCAAs, respectively. A frailty score defined as the proportion of accumulated deficits based on 24 aging-related items was used assess the health status of elderly subjects. First, we found that a higher concentration of BCAAs was significantly associated with longer LTL only in middle-aged subjects, independent of age and BMI (P < 0.05). In the oldest-old subjects, we identified a significantly inverse association between BCAAs and frailty score (P < 0.001), even after adjustment for age and BMI (P < 0.05). Additionally, we recognized a statistically significant synergetic interaction between BCAAs and LTL on frailty score in the oldest-old subjects by the general linear model (P = 0.042), although we did not find any significant association between LTL and frailty score. In summary, our findings suggest a potentially protective effect of circulating BCAAs on LTL and frailty based on the subjects from longevity county in East Asia and indicate a potential synergetic interaction between BCAAs and LTL in healthy aging.},
}
@article {pmid32579791,
year = {2020},
author = {Seimiya, H},
title = {Crossroads of telomere biology and anticancer drug discovery.},
journal = {Cancer science},
volume = {111},
number = {9},
pages = {3089-3099},
pmid = {32579791},
issn = {1349-7006},
support = {N/A//Nippon Foundation/ ; 19H03523//Japan Society for the Promotion of Science/ ; 20H04789//Japan Society for the Promotion of Science/ ; 20ck0106476h0002 and N/A//Japan Agency for Medical Research and Development/ ; },
mesh = {Animals ; Antineoplastic Agents/*pharmacology/therapeutic use ; Cell Transformation, Neoplastic/genetics ; *Drug Discovery ; G-Quadruplexes/drug effects ; Genetic Therapy ; Humans ; Ligands ; Neoplasms/drug therapy/genetics/pathology ; Oncolytic Virotherapy ; Promoter Regions, Genetic ; RNA, Untranslated/genetics ; Telomerase/genetics/metabolism ; Telomere/*drug effects/genetics ; Telomere Shortening/drug effects ; },
abstract = {The telomere is the specialized nucleoprotein complex at the end of the chromosome. Its highly conserved 5'-TTAGGG-3' repeats and shelterin protein complexes form a protective loop structure to maintain the integrity and stability of linear chromosomes. Although human somatic cells gradually shorten telomeres to undergo senescence or crisis, cancer cells activate telomerase, or the recombination-based mechanism to maintain telomeres and exhibit immortality. As the most frequent non-coding mutations in cancer, gain-of-function mutations in the promoter region of the telomerase catalytic subunit, TERT, trigger telomerase activation. Promoter methylation and copy number gain are also associated with the enhanced TERT expression. Although telomerase inhibitors were pioneered from telomere-directed therapeutics, their efficacies are limited to cancer with short telomeres and some hematological malignancies. Other therapeutic approaches include a nucleoside analog incorporated to telomeres and TERT promoter-driven oncolytic adenoviruses. Tankyrase poly(ADP-ribose) polymerase, a positive regulator of telomerase, has been rediscovered as a target for Wnt-driven cancer. Meanwhile, telomeric nucleic acids form a higher-order structure called a G-quadruplex (G4). G4s are formed genome-wide and their dynamics affect various events, including replication, transcription, and translation. G4-stabilizing compounds (G4 ligands) exert anticancer effects and are in clinical investigations. Collectively, telomere biology has provided clues for deeper understanding of cancer, which expands opportunities to discover innovative anticancer drugs.},
}
@article {pmid32579423,
year = {2020},
author = {Zhang, H and Zhao, R and Tones, J and Liu, M and Dilley, RL and Chenoweth, DM and Greenberg, RA and Lampson, MA},
title = {Nuclear body phase separation drives telomere clustering in ALT cancer cells.},
journal = {Molecular biology of the cell},
volume = {31},
number = {18},
pages = {2048-2056},
pmid = {32579423},
issn = {1939-4586},
support = {K22 CA237632/CA/NCI NIH HHS/United States ; R01 CA174904/CA/NCI NIH HHS/United States ; R01 GM101149/GM/NIGMS NIH HHS/United States ; U54 CA193417/CA/NCI NIH HHS/United States ; R35 GM122475/GM/NIGMS NIH HHS/United States ; R01 GM118510/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line ; DNA Damage ; DNA Repair ; Humans ; Leukemia, Promyelocytic, Acute/genetics/metabolism ; Nuclear Proteins/metabolism ; Promyelocytic Leukemia Protein/genetics/*metabolism ; Telomerase/genetics ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; Telomeric Repeat Binding Protein 1/metabolism ; Transcription Factors/metabolism ; },
abstract = {Telomerase-free cancer cells employ a recombination-based alternative lengthening of telomeres (ALT) pathway that depends on ALT-associated promyelocytic leukemia nuclear bodies (APBs), whose function is unclear. We find that APBs behave as liquid condensates in response to telomere DNA damage, suggesting two potential functions: condensation to enrich DNA repair factors and coalescence to cluster telomeres. To test these models, we developed a chemically induced dimerization approach to induce de novo APB condensation in live cells without DNA damage. We show that telomere-binding protein sumoylation nucleates APB condensation via interactions between small ubiquitin-like modifier (SUMO) and SUMO interaction motif (SIM), and that APB coalescence drives telomere clustering. The induced APBs lack DNA repair factors, indicating that APB functions in promoting telomere clustering can be uncoupled from enriching DNA repair factors. Indeed, telomere clustering relies only on liquid properties of the condensate, as an alternative condensation chemistry also induces clustering independent of sumoylation. Our findings introduce a chemical dimerization approach to manipulate phase separation and demonstrate how the material properties and chemical composition of APBs independently contribute to ALT, suggesting a general framework for how chromatin condensates promote cellular functions.},
}
@article {pmid32578161,
year = {2020},
author = {Sasamoto, N and Yland, J and Vitonis, AF and Cramer, DW and Titus, LJ and De Vivo, I and Missmer, SA and Terry, KL},
title = {Peripheral Blood Leukocyte Telomere Length and Endometriosis.},
journal = {Reproductive sciences (Thousand Oaks, Calif.)},
volume = {27},
number = {10},
pages = {1951-1959},
pmid = {32578161},
issn = {1933-7205},
support = {R01 HD094842/HD/NICHD NIH HHS/United States ; Trainee Award//Boston Center for Endometriosis (US)/International ; Liz Tilberis Award//Ovarian Cancer Research Fund (US)/International ; },
mesh = {Adult ; Algorithms ; Case-Control Studies ; Endometriosis/*metabolism ; Female ; Humans ; Leukocytes, Mononuclear/*metabolism ; Middle Aged ; Nutrition Surveys ; *Telomere ; },
abstract = {Endometriosis is a common gynecologic disease defined by the presence of endometrial-like tissue outside the uterine cavity. While its etiology is largely unknown, accumulating evidence suggests that inflammation plays a major role. Our objective was to investigate the association between peripheral blood leukocyte telomere length (LTL) and endometriosis using data from two large population-based studies, the New England Case-Control Study (NEC; n = 877) and the National Health and Nutrition Examination Survey (NHANES; n = 2268). NEC control participants were identified through a combination of random digit dialing, drivers' license lists, and town resident lists. In NHANES, selection algorithms were used to identify a nationally representative sample. Blood samples and demographic, reproductive, and health-related information were available from both data sources. Endometriosis was defined as self-reported of physician-diagnosed endometriosis. LTL was measured using quantitative polymerase chain reaction. Multivariable logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the association between LTL and endometriosis. Shorter LTL was associated with greater odds of history of endometriosis. In NEC, women with the shortest LTL tertile compared with the longest had a 2.5-fold greater odds of endometriosis (ORT3/T1 = 2.56, 95% CI = 1.16-5.63; p value, test for linear trend = 0.02). The association was stronger among women who usually experienced moderate or severe menstrual pain (OR T3/T1 = 3.50, 95% CI = 1.12-10.97). In NHANES, the data suggested a similar but attenuated association (ORT3/T1 = 1.29, 95% CI = 0.85-1.96). The observed associations in NEC suggest that shorter LTL may be associated with greater odds of endometriosis. A better understanding of how LTL influences endometriosis risk could elucidate novel disease pathophysiology.},
}
@article {pmid32577419,
year = {2020},
author = {Courtwright, AM and Lamattina, AM and Takahashi, M and Trindade, AJ and Hunninghake, GM and Rosas, IO and Agarwal, S and Raby, BA and Goldberg, HJ and El-Chemaly, S},
title = {Shorter telomere length following lung transplantation is associated with clinically significant leukopenia and decreased chronic lung allograft dysfunction-free survival.},
journal = {ERJ open research},
volume = {6},
number = {2},
pages = {},
pmid = {32577419},
issn = {2312-0541},
support = {R01 HL111024/HL/NHLBI NIH HHS/United States ; R01 HL130974/HL/NHLBI NIH HHS/United States ; R01 HL135142/HL/NHLBI NIH HHS/United States ; },
abstract = {Patients with short telomeres and interstitial lung disease may have decreased chronic lung allograft dysfunction (CLAD)-free survival following lung transplantation. The relationship between post-transplant telomere length and outcomes following lung transplantation has not been characterised among all recipients, regardless of native lung disease. This was a single-centre prospective cohort study. Consenting transplant recipients had their telomere length measured using quantitative real-time PCR assays on peripheral blood collected at the time of surveillance bronchoscopy. We assessed the association between early post-transplant telomere length (as measured in the first 100 days) and CLAD-free survival, time to clinically significant leukopenia, cytomegalovirus (CMV) viraemia, chronic kidney disease, and acute cellular rejection. We also assessed the association between rate of telomere shortening and CLAD-free survival. Telomere lengths were available for 98 out of 215 (45.6%) recipients who underwent lung transplant during the study period (median measurement per patient=2 (interquartile range, 1-3)). Shorter telomere length was associated with decreased CLAD-free survival (hazard ratio (HR)=1.24; 95% CI=1.03-1.48; p=0.02), leukopenia requiring granulocyte colony-stimulating factor (HR=1.17, 95% CI=1.01-1.35, p=0.03), and CMV viraemia among CMV-mismatch recipients (HR=4.04, 95% CI=1.05-15.5, p=0.04). Telomere length was not associated with acute cellular rejection or chronic kidney disease. Recipients with more rapid loss in telomere length (defined as the highest tertile of telomere shortening) did not have worse subsequent CLAD-free survival than those without rapid loss (HR=1.38, 95% CI=0.27-7.01, p=0.70). Shorter early post-transplant telomere length is associated with decreased CLAD-free survival and clinically significant leukopenia in lung transplant recipients, regardless of native lung disease.},
}
@article {pmid32577134,
year = {2020},
author = {Huang, P and Li, R and Shen, L and He, W and Chen, S and Dong, Y and Ma, J and Chen, X and Xu, M},
title = {Single nucleotide polymorphisms in telomere length-related genes are associated with hepatocellular carcinoma risk in the Chinese Han population.},
journal = {Therapeutic advances in medical oncology},
volume = {12},
number = {},
pages = {1758835920933029},
pmid = {32577134},
issn = {1758-8340},
abstract = {BACKGROUND: Single nucleotide polymorphisms (SNPs) in telomere-related genes are associated with a high risk of hepatocellular carcinoma (HCC). In this study, we investigated the SNPs of telomere length-related genes and their correlation with HCC risk in the Chinese Han population.<br><br>MATERIALS AND METHODS: A total of 473 HCC patients and 564 healthy volunteers were recruited. Overall, 42 SNPs distributed in telomere-related genes were selected and identified. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.<br><br>RESULTS: We found rs6713088 (OR&#x2009;=&#x2009;1.27, 95% CI&#x2009;=&#x2009;1.07-1.52, p&#x2009;=&#x2009;0.007), rs843711 (OR&#x2009;=&#x2009;1.29, 95% CI&#x2009;=&#x2009;1.09-1.54, p&#x2009;=&#x2009;0.004) and rs843706 (OR&#x2009;=&#x2009;1.30, 95% CI&#x2009;=&#x2009;1.09-1.55, p&#x2009;=&#x2009;0.003) in the ACYP2 gene, rs10936599 (OR&#x2009;=&#x2009;1.21, 95% CI&#x2009;=&#x2009;1.02-1.44, p&#x2009;=&#x2009;0.032) in the TERC gene and rs7708392 (OR&#x2009;=&#x2009;1.24, 95% CI&#x2009;=&#x2009;1.00-1.52, p&#x2009;=&#x2009;0.042) in the TNIP1 gene were associated with high HCC risk (OR&#x2009;>&#x2009;1). In contrast, rs1682111 (OR&#x2009;=&#x2009;0.77, 95% CI&#x2009;=&#x2009;0.64-0.94, p&#x2009;=&#x2009;0.008) in the ACYP2 gene, rs2320615 (OR&#x2009;=&#x2009;0.79, 95% CI&#x2009;=&#x2009;0.64-0.99, p&#x2009;=&#x2009;0.038) in the NAF1 gene, rs10069690 (OR&#x2009;=&#x2009;0.75, 95% CI&#x2009;=&#x2009;0.59-0.96, p&#x2009;=&#x2009;0.021) and rs2242652 (OR&#x2009;=&#x2009;0.70, 95% CI&#x2009;=&#x2009;0.55-0.90, p&#x2009;=&#x2009;0.004) in the TERT gene were associated with low HCC risk (OR&#x2009;<&#x2009;1). Based on genotype frequency distributions, rs6713088, rs843645, rs843711 and rs843706 located in the ACYP2 gene as well as rs10936599 in the TERC gene were associated with a high incidence of HCC (p&#x2009;<&#x2009;0.05). In addition, SNPs in these genes could form a linkage imbalance haplotype. Specifically, the haploid 'GC' formed by rs10069690 and rs2242652 within the TERT gene increased the risk of HCC (p&#x2009;<&#x2009;0.05).<br><br>CONCLUSION: SNPs in ACYP2, TERC, TERT and other genes were correlated with HCC risk in the Chinese Han population. These data may provide new insights into early diagnosis and screening of HCC.},
}
@article {pmid32576588,
year = {2020},
author = {Vaiciulis, P and Liutkeviciene, R and Liutkevicius, V and Vilkeviciute, A and Gedvilaite, G and Uloza, V},
title = {Association of Relative Leucocyte Telomere Length and Gene Single Nucleotide Polymorphisms (TERT, TRF1, TNKS2) in Laryngeal Squamous Cell Carcinoma.},
journal = {Cancer genomics &amp; proteomics},
volume = {17},
number = {4},
pages = {431-439},
pmid = {32576588},
issn = {1790-6245},
mesh = {Biomarkers, Tumor/*genetics ; Case-Control Studies ; Female ; Follow-Up Studies ; Genetic Predisposition to Disease ; Head and Neck Neoplasms/genetics/pathology ; Humans ; Leukocytes/metabolism/pathology ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; Prognosis ; Shelterin Complex ; Squamous Cell Carcinoma of Head and Neck/genetics/*pathology ; Tankyrases/*genetics ; Telomerase/*genetics ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {BACKGROUND/AIM: The study aimed to evaluate associations of relative leukocyte telomere length (LTL) and polymorphisms of telomere length-associated genes TERT (rs2736098), TERT-CLPTM1L (rs401681), TRF1 (rs1545827, rs10107605) and TNKS2 (rs10509637, rs10509639) in patients with laryngeal squamous cell carcinoma (LSCC).<br><br>MATERIALS AND METHODS: The study consisted of 300 patients with LSCC and 369 healthy control subjects. Genotyping and relative LTL measuring were carried out using qPCR.<br><br>RESULTS: Relative LTL was statistically significantly shorter in the G3 (tumor differentiation grade) subgroup of patients with LSCC compared to the G1 and G2 subgroups. Significant differences were found in genotype distributions of TERT rs401681 and TNKS2 rs10509639 between the study groups. TERT rs401681 C/T and T/T genotypes were associated with approximately 30% decreased odds of LSCC development.<br><br>CONCLUSION: LTL was shorter in the G3 subgroup compared to the G2 and G1 subgroups of LSCC patients. TERT rs401681 and its C/T and T/T genotypes were associated with decreased odds of overall LSCC development.},
}
@article {pmid32575418,
year = {2020},
author = {Posch, A and Hofer-Zeni, S and Klieser, E and Primavesi, F and Naderlinger, E and Brandstetter, A and Filipits, M and Urbas, R and Swiercynski, S and Jäger, T and Winkelmann, P and Kiesslich, T and Lu, L and Neureiter, D and Stättner, S and Holzmann, K},
title = {Hot Spot TERT Promoter Mutations Are Rare in Sporadic Pancreatic Neuroendocrine Neoplasms and Associated with Telomere Length and Epigenetic Expression Patterns.},
journal = {Cancers},
volume = {12},
number = {6},
pages = {},
pmid = {32575418},
issn = {2072-6694},
support = {UL1 TR001863/TR/NCATS NIH HHS/United States ; },
abstract = {Cancer cells activate a telomere maintenance mechanism like telomerase in order to proliferate indefinitely. Telomerase can be reactivated by gain-of-function Telomerase Reverse Transcriptase (TERT) promoter mutations (TPMs) that occur in several cancer subtypes with high incidence and association with diagnosis, prognosis and epigenetics. However, such information about TPMs in sporadic pancreatic neuroendocrine neoplasms (pNENs) including tumor (pNET) and carcinoma (pNEC) is less well defined. We have studied two hot spot TPMs and telomere length (TL) in pNEN and compared the results with clinicopathological information and proliferation-associated miRNA/HDAC expression profiles. DNA was isolated from formalin-fixed paraffin-embedded (FFPE) tissue of 58 sporadic pNEN patients. T allele frequency of C250T and C228T TPM was analyzed by pyrosequencing, relative TL as telomeric content by qPCR. In total, five pNEN cases (9%) including four pNETs and one pNEC were identified with TPMs, four cases with exclusive C250T as predominant TPM and one case with both C250T and C228T. T allele frequencies of DNA isolated from adjacent high tumor cell content FFPE tissue varied considerably, which may indicate TPM tumor heterogeneity. Overall and disease-free survival was not associated with TPM versus wild-type pNEN cases. Binary category analyses indicated a marginally significant relationship between TPM status and longer telomeres (p = 0.086), and changes in expression of miR449a (p = 0.157), HDAC4 (p = 0.146) and HDAC9 (p = 0.149). Future studies with larger patient cohorts are needed to assess the true clinical value of these rare mutations in pNEN.},
}
@article {pmid32575077,
year = {2020},
author = {Semeraro, MD and Smith, C and Kaiser, M and Levinger, I and Duque, G and Gruber, HJ and Herrmann, M},
title = {Physical activity, a modulator of aging through effects on telomere biology.},
journal = {Aging},
volume = {12},
number = {13},
pages = {13803-13823},
pmid = {32575077},
issn = {1945-4589},
mesh = {Aging/*genetics ; Cardiovascular Diseases/genetics/mortality/*prevention &amp; control ; DNA/metabolism ; Exercise/*physiology ; Humans ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/physiology ; },
abstract = {Aging is a complex process that is not well understood but involves finite changes at the genetic and epigenetic level. Physical activity is a well-documented modulator of the physiological process of aging. It has been suggested that the beneficial health effects of regular exercise are at least partly mediated through its effects on telomeres and associated regulatory pathways. Telomeres, the region of repetitive nucleotide sequences functioning as a "cap" at the chromosomal ends, play an important role to protect genomic DNA from degradation. Telomeres of dividing cells progressively shorten with age. Leucocyte telomere length (TL) has been associated with age-related diseases. Epidemiologic evidence indicates a strong relationship between physical activity and TL. In addition, TL has also been shown to predict all-cause and cardiovascular mortality. Experimental studies support a functional link between aerobic exercise and telomere preservation through activation of telomerase, an enzyme that adds nucleotides to the telomeric ends. However, unresolved questions regarding exercise modalities, pathomechanistic aspects and analytical issues limit the interpretability of available data. This review provides an overview about the current knowledge in the area of telomere biology, aging and physical activity. Finally, the capabilities and limitations of available analytical methods are addressed.},
}
@article {pmid32575070,
year = {2020},
author = {Honkonen, M and Vääräniemi, K and Saijonmaa, O and Nyman, A and Tikkakoski, AJ and Koskela, J and Lehtimäki, T and Kähönen, M and Mustonen, J and Fyhrquist, F and Pörsti, I},
title = {Leukocyte telomere length is inversely associated with arterial wave reflection in 566 normotensive and never-treated hypertensive subjects.},
journal = {Aging},
volume = {12},
number = {12},
pages = {12376-12392},
pmid = {32575070},
issn = {1945-4589},
mesh = {Adult ; Aged ; Aging/*genetics ; Blood Pressure/*genetics ; Cardiography, Impedance ; Female ; Humans ; Hypertension/blood/*genetics ; Leukocytes/metabolism ; Male ; Middle Aged ; Prospective Studies ; Pulse Wave Analysis ; Telomere Homeostasis/*physiology ; Vascular Resistance/*genetics ; Young Adult ; },
abstract = {Telomeres are short segments in chromosome ends, the length of which is reduced during cell lifecycles. We examined the association of mean leukocyte telomere length (LTL) and short telomere proportion (STP) with hemodynamic variables in normotensive and never-treated hypertensive volunteers (n=566, 19-72 years). STP and mean LTL were determined using Southern blotting, and supine hemodynamics recorded using continuous tonometric pulse wave analysis and whole-body impedance cardiography. The analyses were adjusted for age, body mass index (BMI), alcohol use, smoking, plasma chemistry, and estimated glomerular filtration rate (eGFR). In univariate analyses, mean LTL and STP both correlated with age, BMI, eGFR, aortic blood pressure, augmentation index, and pulse wave velocity (p<0.05 for all). Mean LTL also correlated with systemic vascular resistance (p<0.05). In linear regression analyses of all hemodynamic variables, mean LTL was only an independent explanatory factor for augmentation index (Beta -0.006, p=0.032), while STP was not an explanatory factor for any of the hemodynamic variables, in contrast to age, BMI and several cardiovascular risk factors. To conclude, augmentation index was predominantly related with chronological aging, but also with mean LTL, suggesting that this variable of central wave reflection is a modest marker of vascular biological aging.},
}
@article {pmid32571415,
year = {2020},
author = {Keng, SL and Yim, OS and Lai, PS and Chew, SH and Ebstein, RP},
title = {Correction to: Association among dispositional mindfulness, self-compassion, and leukocyte telomere length in Chinese adults.},
journal = {BMC psychology},
volume = {8},
number = {1},
pages = {65},
pmid = {32571415},
issn = {2050-7283},
abstract = {An amendment to this paper has been published and can be accessed via the original article.},
}
@article {pmid32565730,
year = {2020},
author = {Yu, J and Liu, H and He, S and Li, P and Ma, C and Ma, M and Liu, Y and Lv, L and Ping, F and Zhang, H and Li, W and Sun, Q and Xu, L and Li, Y},
title = {Dietary Magnesium Intake and Leukocyte Telomere Attrition in Adults: The Regulatory Role of Serum Tumor Necrosis Factor α.},
journal = {Mediators of inflammation},
volume = {2020},
number = {},
pages = {7610436},
pmid = {32565730},
issn = {1466-1861},
mesh = {Adult ; Aged ; Anthropometry ; Blood Glucose/metabolism ; Cross-Sectional Studies ; Diabetes Mellitus, Type 2/blood ; Diet ; Female ; Glycated Hemoglobin/metabolism ; Humans ; Inflammation ; Leukocytes/*metabolism ; Magnesium/*metabolism ; Male ; Middle Aged ; Odds Ratio ; Oxidative Stress ; Real-Time Polymerase Chain Reaction ; Regression Analysis ; Telomere/*metabolism ; Tumor Necrosis Factor-alpha/*blood ; },
abstract = {OBJECTIVES: In this study, we assessed the effects of dietary magnesium on leukocyte telomere length (LTL).<br><br>DESIGNS: The current cross-sectional analysis was based on data collected within a type 2 diabetes project. Settings. Dietary magnesium intake is associated with peripheral blood leukocyte telomere length (LTL). However, few epidemiological studies have evaluated the effects of magnesium on LTL in the clinical setting. Participants. This cross-sectional analysis included 467 participants (34.8% men). Measurements. Serum blood lipid profile, HbA1c, oxidative stress, and proinflammatory mediator levels were measured. Detailed dietary data were obtained using a 24&#x2009;h food recall. LTL was assessed using a real-time PCR assay. Regression models and simple regulatory models were used for data analysis.<br><br>RESULTS: There was an inverse relationship between dietary magnesium and LTL (P < 0.001), with a between-extreme-quarter difference of -0.55. Conversely, there was a positive relationship between dietary magnesium and serum tumor necrosis factor (TNF) &#x3b1;, with an interquarter difference of 3.79&#x2009;pmol/mL (P&#x2009;for&#x2009;trend = 0.006). Multivariate regression analysis revealed that the odds ratios (ORs) for shorter LTL and higher serum TNF&#x3b1; increased with magnesium intake, and the ORs of the differences between extreme quartiles were 2.60 (95% confidence interval (CI): 1.31-5.36; P = 0.003) and 1.98 (95% CI: 1.09-3.59; P = 0.008). There was a direct negative effect of dietary magnesium intake on LTL (B = -0.002; P = 0.001), which appeared to be indirectly influenced by TNF&#x3b1; (-0.002 to -0.0005).<br><br>CONCLUSIONS: Dietary magnesium intake may be a critical component of the cellular aging process, and its effect could be partly mediated by TNF&#x3b1;.},
}
@article {pmid32565330,
year = {2020},
author = {Aguado, J and d'Adda di Fagagna, F and Wolvetang, E},
title = {Telomere transcription in ageing.},
journal = {Ageing research reviews},
volume = {62},
number = {},
pages = {101115},
doi = {10.1016/j.arr.2020.101115},
pmid = {32565330},
issn = {1872-9649},
mesh = {Aging/genetics ; Cellular Senescence/genetics ; Genomic Instability ; Humans ; RNA, Untranslated/genetics ; *Telomere/genetics ; },
abstract = {Telomeres, the ends of eukaryotic chromosomes, play a central role in the control of cellular senescence and organismal ageing and need to be protected in order to avoid being recognised as damaged DNA and activate DNA damage response pathways. Dysfunctional telomeres arise from critically short telomeres or altered telomere structures, which ultimately lead to replicative cellular senescence and chromosome instability: both hallmarks of ageing. The observation that telomeres are transcribed led to the discovery that telomeric transcripts play important roles in chromosome end protection and genome stability maintenance. Recent evidence indicates that particular long non-coding (nc)RNAs transcribed at telomeres, namely TElomeric Repeat-containing RNA (TERRA) and telomeric damage-induced long ncRNAs (tdilncRNA), play key roles in age-related pathways by actively orchestrating the mechanisms known to regulate telomere length, chromosome end protection and DNA damage signalling. Here, we provide a comprehensive overview of the telomere transcriptome, outlining how it functions as a regulatory platform with essential functions in safeguarding telomere integrity and stability. We next review emerging antisense oligonucleotides therapeutic strategies that target telomeric ncRNAs and discuss their potential for ameliorating ageing and age-related diseases. Altogether, this review provides insights on the biological relevance of telomere transcription mechanisms in human ageing physiology and pathology.},
}
@article {pmid32564008,
year = {2020},
author = {Habib, R and Kim, R and Neitzel, H and Demuth, I and Chrzanowska, K and Seemanova, E and Faber, R and Digweed, M and Voss, R and Jäger, K and Sperling, K and Walter, M},
title = {Telomere attrition and dysfunction: a potential trigger of the progeroid phenotype in nijmegen breakage syndrome.},
journal = {Aging},
volume = {12},
number = {12},
pages = {12342-12375},
pmid = {32564008},
issn = {1945-4589},
mesh = {Adolescent ; Animals ; Cell Cycle Proteins/*genetics ; Cell Line, Tumor ; Child ; Child, Preschool ; Disease Models, Animal ; Female ; Heterozygote ; Homozygote ; Humans ; Infant ; Karyotyping ; Male ; Mice ; Mice, Transgenic ; Nijmegen Breakage Syndrome/*complications/genetics/pathology ; Nuclear Proteins/*genetics ; Progeria/*genetics/pathology ; Telomerase/metabolism ; Telomere/*pathology ; Telomere Homeostasis/*genetics ; Young Adult ; },
abstract = {BACKGROUND: Nibrin, as part of the NBN/MRE11/RAD50 complex, is mutated in Nijmegen breakage syndrome (NBS), which leads to impaired DNA damage response and lymphoid malignancy.<br><br>RESULTS: Telomere length (TL) was markedly reduced in homozygous patients (and comparably so in all chromosomes) by ~40% (qPCR) and was slightly reduced in NBS heterozygotes older than 30 years (~25% in qPCR), in accordance with the respective cancer rates. Humanized cancer-free NBS mice had normal TL. Telomere elongation was inducible by telomerase and/or alternative telomere lengthening but was associated with abnormal expression of telomeric genes involved in aging and/or cell growth. Lymphoblastoid cells from NBS patients with long survival times (>12 years) displayed the shortest telomeres and low caspase 7 activity.<br><br>CONCLUSIONS: NBS is a secondary telomeropathy. The two-edged sword of telomere attrition enhances the cancer-prone situation in NBS but can also lead to a relatively stable cellular phenotype in tumor survivors. Results suggest a modular model for progeroid syndromes with abnormal expression of telomeric genes as a molecular basis.<br><br>METHODS: We studied TL and function in 38 homozygous individuals, 27 heterozygotes, one homozygous fetus, six NBS lymphoblastoid cell lines, and humanized NBS mice, all with the same founder NBN mutation: c.657_661del5.},
}
@article {pmid32560940,
year = {2020},
author = {Liu, Z and Han, R and Zhu, W and Xiu, J and Shen, Y and Xu, Q},
title = {Inverse changes in telomere length between the blood and brain in depressive-like mice.},
journal = {Journal of affective disorders},
volume = {273},
number = {},
pages = {453-461},
doi = {10.1016/j.jad.2020.01.089},
pmid = {32560940},
issn = {1573-2517},
mesh = {Animals ; Brain/metabolism ; *Depressive Disorder, Major/genetics ; Humans ; Mice ; *Telomerase/genetics ; Telomere/genetics/metabolism ; Telomere Homeostasis/genetics ; },
abstract = {BACKGROUND: Telomeres are nucleoprotein complexes located at the end of chromosomes. Previous studies have confirmed that telomere length is reduced in the peripheral blood of depression patients. However, studies regarding whether telomere length is altered in brain regions associated with depression are limited. It remains unclear whether the peripheral blood telomere length indicates telomere variation in the brain.<br><br>METHODS: Using quantitative PCR, we measured telomere length in five brain regions (prefrontal cortex, amygdala, nucleus accumbens, paraventricular nucleus, and hippocampus) from depressive-like mice and in peripheral blood from depressive-like mice and major depressive disorder (MDD) patients. We also examined the expression of telomerase- and alternative lengthening of telomere (ALT)-related genes in the prefrontal cortex and amygdala of depressive-like mice.<br><br>RESULTS: Telomeres were shortened in the peripheral blood of depressive-like mice and MDD patients, but were elongated in the prefrontal cortex and amygdala compared with healthy controls. We also observed that the expression of ALT-related genes increased in the prefrontal cortex and amygdala.<br><br>LIMITATIONS: The amount of human sample was limited. The mechanism of telomere lengthening in the brain of depressive-like mice was not well explained. Mice and humans have inherently different telomere and telomere maintenance systems.<br><br>CONCLUSION: These findings illustrate that the telomere length in the peripheral blood may not indicate the dynamics of telomere length in the brain. They offer a new perspective on variable telomere length in different brain regions affected in depression and provide a new basis for understanding the relationship between variable telomere length and MDD.},
}
@article {pmid32558886,
year = {2020},
author = {Rahnama, M and Novikova, O and Starnes, JH and Zhang, S and Chen, L and Farman, ML},
title = {Transposon-mediated telomere destabilization: a driver of genome evolution in the blast fungus.},
journal = {Nucleic acids research},
volume = {48},
number = {13},
pages = {7197-7217},
pmid = {32558886},
issn = {1362-4962},
mesh = {Evolution, Molecular ; Magnaporthe/*genetics ; Plant Diseases/*microbiology ; Retroelements/*genetics ; Telomere/*genetics ; },
abstract = {The fungus Magnaporthe oryzae causes devastating diseases of crops, including rice and wheat, and in various grasses. Strains from ryegrasses have highly unstable chromosome ends that undergo frequent rearrangements, and this has been associated with the presence of retrotransposons (Magnaporthe oryzae Telomeric Retrotransposons-MoTeRs) inserted in the telomeres. The objective of the present study was to determine the mechanisms by which MoTeRs promote telomere instability. Targeted cloning, mapping, and sequencing of parental and novel telomeric restriction fragments (TRFs), along with MinION sequencing of genomic DNA allowed us to document the precise molecular alterations underlying 109 newly-formed TRFs. These included truncations of subterminal rDNA sequences; acquisition of MoTeR insertions by 'plain' telomeres; insertion of the MAGGY retrotransposons into MoTeR arrays; MoTeR-independent expansion and contraction of subtelomeric tandem repeats; and a variety of rearrangements initiated through breaks in interstitial telomere tracts that are generated during MoTeR integration. Overall, we estimate that alterations occurred in approximately sixty percent of chromosomes (one in three telomeres) analyzed. Most importantly, we describe an entirely new mechanism by which transposons can promote genomic alterations at exceptionally high frequencies, and in a manner that can promote genome evolution while minimizing collateral damage to overall chromosome architecture and function.},
}
@article {pmid32558330,
year = {2020},
author = {Ojeda-Rodríguez, A and Morell-Azanza, L and Zalba, G and Zazpe, I and Azcona-Sanjulian, MC and Marti, A},
title = {Associations of telomere length with two dietary quality indices after a lifestyle intervention in children with abdominal obesity: a randomized controlled trial.},
journal = {Pediatric obesity},
volume = {15},
number = {11},
pages = {e12661},
doi = {10.1111/ijpo.12661},
pmid = {32558330},
issn = {2047-6310},
mesh = {Adiposity ; Adolescent ; Body Composition ; Body Mass Index ; Child ; *Diet, Healthy ; Diet, Mediterranean ; Female ; *Healthy Lifestyle ; Humans ; Male ; Obesity, Abdominal/*genetics ; Spain ; Telomere Homeostasis/*physiology ; },
abstract = {BACKGROUND: Dietary factors seem to influence telomere length. Moreover, associations between changes in adiposity indices and telomere length (TL) have been found in intervention studies.<br><br>OBJECTIVE: We evaluated changes in two diet quality indices and their association with TL in children with abdominal obesity in a 12-month lifestyle intervention.<br><br>METHODS: Eighty-seven participants (7-16&#x2009;years old) were assigned to the intervention (moderate hypocaloric Mediterranean diet) or usual care group (standard paediatric recommendations) for a 2-month intensive phase and a subsequent 10-month follow-up. Diet quality was assessed using the Diet Quality Index for Adolescents (DQI-A) and the Healthy Lifestyle Diet Index (HLD-I). TL was measured by monochrome multiplex real-time quantitative PCR. The intra-class correlation coefficient for TL was 0.793 (95% CI 0.707, 0.857).<br><br>RESULTS: After a 12-month lifestyle intervention, a significant reduction in BMI-SDS (-0.57 and -0.49 for the intervention and usual care groups, respectively) and fat mass was observed in all subjects without differences between groups. Changes in DQI-A (+12.36% vs +5.53%, P = .005) and HLD-I (+4.43 vs +1.09, P&#x2009;<&#x2009;.001) were higher in the intervention subjects compared with usual care subjects after 2 months. Interestingly, we observed a positive change in TL between 2 and 12&#x2009;months (P = .025), which was associated with higher scores on the DQI-A (&#x3b2; = 0.008, R[2] = 0.088, P = .010) and HLD-I (&#x3b2; = 0.022, R[2] = 0.198, P = .015), in the intervention group after the 2-month intensive phase.<br><br>CONCLUSION: Favourable changes in diet quality indices could contribute to telomere integrity in children with abdominal obesity enrolled in an intensive lifestyle intervention.},
}
@article {pmid32554492,
year = {2020},
author = {Lex, K and Maia Gil, M and Lopes-Bastos, B and Figueira, M and Marzullo, M and Giannetti, K and Carvalho, T and Ferreira, MG},
title = {Telomere shortening produces an inflammatory environment that increases tumor incidence in zebrafish.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {117},
number = {26},
pages = {15066-15074},
pmid = {32554492},
issn = {1091-6490},
support = {/HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Animals ; Disease Models, Animal ; Humans ; Melanoma/genetics/immunology/*metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomere Shortening ; Tumor Necrosis Factor-alpha/genetics/immunology ; Zebrafish/genetics/immunology/*metabolism ; Zebrafish Proteins/genetics/metabolism ; },
abstract = {Cancer incidence increases exponentially with age when human telomeres are shorter. Similarly, telomerase reverse transcriptase (tert) mutant zebrafish have premature short telomeres and anticipate cancer incidence to younger ages. However, because short telomeres constitute a road block to cell proliferation, telomere shortening is currently viewed as a tumor suppressor mechanism and should protect from cancer. This conundrum is not fully understood. In our current study, we report that telomere shortening promotes cancer in a noncell autonomous manner. Using zebrafish chimeras, we show increased incidence of invasive melanoma when wild-type (WT) tumors are generated in tert mutant zebrafish. Tissues adjacent to melanoma lesions (skin) and distant organs (intestine) in tert mutants exhibited higher levels of senescence and inflammation. In addition, we transferred second generation (G2) tert blastula cells into WT to produce embryo chimeras. Cells with very short telomeres induced increased tumor necrosis factor1-α (TNF1-α) expression and senescence in larval tissues in a noncell autonomous manner, creating an inflammatory environment. Considering that inflammation is protumorigenic, we transplanted melanoma-derived cells into G2 tert zebrafish embryos and observed that tissue environment with short telomeres leads to increased tumor development. To test if inflammation was necessary for this effect, we treated melanoma transplants with nonsteroid anti-inflammatory drugs and show that higher melanoma dissemination can be averted. Thus, apart from the cell autonomous role of short telomeres in contributing to genome instability, we propose that telomere shortening with age causes systemic chronic inflammation leading to increased tumor incidence.},
}
@article {pmid32551854,
year = {2020},
author = {Naikawadi, RP and Green, G and Jones, KD and Achtar-Zadeh, N and Mieleszko, JE and Arnould, I and Kukreja, J and Greenland, JR and Wolters, PJ},
title = {Airway Epithelial Telomere Dysfunction Drives Remodeling Similar to Chronic Lung Allograft Dysfunction.},
journal = {American journal of respiratory cell and molecular biology},
volume = {63},
number = {4},
pages = {490-501},
pmid = {32551854},
issn = {1535-4989},
support = {I01 CX002011/CX/CSRD VA/United States ; IK2 CX001034/CX/CSRD VA/United States ; R01 HL139897/HL/NHLBI NIH HHS/United States ; R01 HL151552/HL/NHLBI NIH HHS/United States ; },
mesh = {Allografts/metabolism/*pathology ; Alveolar Epithelial Cells/metabolism/*pathology ; Animals ; Biomarkers/metabolism ; Cellular Senescence/genetics ; Humans ; Lung/metabolism/*physiology ; Lung Transplantation/methods ; Mice ; Pulmonary Fibrosis/genetics/metabolism/pathology ; Telomere/*genetics ; Uteroglobin/genetics/metabolism ; },
abstract = {Telomere dysfunction is associated with multiple fibrotic lung processes, including chronic lung allograft dysfunction (CLAD)-the major limitation to long-term survival following lung transplantation. Although shorter donor telomere lengths are associated with an increased risk of CLAD, it is unknown whether short telomeres are a cause or consequence of CLAD pathology. Our objective was to test whether telomere dysfunction contributes to the pathologic changes observed in CLAD. Histopathologic and molecular analysis of human CLAD lungs demonstrated shortened telomeres in lung epithelial cells quantified by teloFISH, increased numbers of surfactant protein C immunoreactive type II alveolar epithelial cells, and increased expression of senescence markers (β-galactosidase, p16, p53, and p21) in lung epithelial cells. TRF1[F/F] (telomere repeat binding factor 1 flox/flox) mice were crossed with tamoxifen-inducible SCGB1a1-cre mice to generate SCGB1a1-creTRF1[F/F] mice. Following 9 months of tamoxifen-induced deletion of TRF1 in club cells, mice developed mixed obstructive and restrictive lung physiology, small airway obliteration on microcomputed tomography, a fourfold decrease in telomere length in airway epithelial cells, collagen deposition around bronchioles and adjacent lung parenchyma, increased type II aveolar epithelial cell numbers, expression of senescence-associated β-galactosidase in epithelial cells, and decreased SCGB1a1 expression in airway epithelial cells. These findings demonstrate that telomere dysfunction isolated to airway epithelial cells leads to airway-centric lung remodeling and fibrosis similar to that observed in patients with CLAD and suggest that lung epithelial cell telomere dysfunction may be a molecular driver of CLAD.},
}
@article {pmid32551387,
year = {2020},
author = {Nickels, M and Mastana, S and Hunter, D and Denniff, M and Codd, V and Akam, E},
title = {The effect of a 12-week resistance training intervention on leukocyte telomere length.},
journal = {Heliyon},
volume = {6},
number = {6},
pages = {e04151},
pmid = {32551387},
issn = {2405-8440},
abstract = {Telomere dynamics are an active biological process and positive lifestyle factors such as exercise are proposed to potentiate their length. The aim of this study was to investigate the effect of a low-resistance, high-repetition resistance training intervention on leukocyte telomere length (LTL) and associated health parameters. 23 sedentary middle-aged adults volunteered for this study (16 female/7 male; age = 51.5 ± 4.9 years) and performed two one-hour sessions of Les Mills BODYPUMP™ per week for 12 weeks. Outcome measures were taken at baseline, after the training intervention and at 12-month follow-up. LTL remained unchanged following the training intervention (pre 0.819 ± 0.121 vs post 0.812 ± 0.114, p = 0.420), despite a borderline significant increase in hTERT expression (p = 0.050). Circulating levels of tumour necrosis factor alpha were reduced after the intervention (p = 0.001). At 12-month follow-up, subjects who returned to a sedentary lifestyle (n = 10) displayed shorter telomeres compared to their pre (p = 0.036) values. In conclusion, no changes were observed in LTL following the 12-week training intervention, despite improvements in molecular parameters associated with telomere dynamics. It appears continued long-term exercise (>12 months) is necessary to preserve LTL in previously sedentary individuals.},
}
@article {pmid32547557,
year = {2020},
author = {Trindade, AJ and Thaniyavarn, T and Townsend, K and Klasek, R and Tsveybel, KP and Kennedy, JC and Goldberg, HJ and El-Chemaly, S},
title = {Alemtuzumab as a Therapy for Chronic Lung Allograft Dysfunction in Lung Transplant Recipients With Short Telomeres.},
journal = {Frontiers in immunology},
volume = {11},
number = {},
pages = {1063},
pmid = {32547557},
issn = {1664-3224},
support = {R01 HL130275/HL/NHLBI NIH HHS/United States ; },
mesh = {Alemtuzumab/adverse effects/*therapeutic use ; Allografts ; CD52 Antigen/antagonists &amp; inhibitors ; Female ; Graft Rejection/genetics/immunology/*therapy ; Hematologic Diseases/etiology ; Humans ; Immunosuppressive Agents/adverse effects/therapeutic use ; Lung Transplantation/*adverse effects ; Male ; Middle Aged ; Retrospective Studies ; Safety ; *Telomere Shortening/immunology ; Treatment Outcome ; },
abstract = {Alemtuzumab, a monoclonal antibody targeting CD52 that causes lymphocyte apoptosis, is a form of advanced immunosuppression that is currently used as a therapy for refractory acute cellular rejection and chronic lung allograft dysfunction in lung transplant recipients (1-3). Side effects of alemtuzumab include bone marrow suppression, infection, and malignancy. Whether alemtuzumab can be safely used in allograft recipients that have an increased propensity for bone marrow suppression due to telomeropathies is unknown. In a retrospective case series, we report outcomes associated with alemtuzumab in three lung allograft recipients with short telomere lengths, comparing endpoints such as leukopenia, transfusion needs, infection, hospitalization and survival to those of 17 patients without known telomeropathies that received alemtuzumab. We show that the use of alemtuzumab in lung transplant recipients with short telomeres is safe, though is associated with an increased incidence of neutropenia, thrombocytopenia and anemia requiring packed red blood cell transfusions. Alemtuzumab appears to be an acceptable advanced immunosuppressive therapy in patients with telomeropathies, though given the design and scope of this study, the actual clinical effect needs further evaluation in larger trials.},
}
@article {pmid32541825,
year = {2020},
author = {Maasen, K and James, PT and Prentice, AM and Moore, SE and Fall, CH and Chandak, GR and Betts, M and Silver, MJ and Buxton, JL},
title = {Periconceptional environment predicts leukocyte telomere length in a cross-sectional study of 7-9 year old rural Gambian children.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {9675},
pmid = {32541825},
issn = {2045-2322},
support = {MC_PC_MR/R020183/1/MRC_/Medical Research Council/United Kingdom ; MC_U123292701/MRC_/Medical Research Council/United Kingdom ; G0400519/MRC_/Medical Research Council/United Kingdom ; MC_U123292700/MRC_/Medical Research Council/United Kingdom ; MC_UP_1005/1/MRC_/Medical Research Council/United Kingdom ; MR/N006208/1/MRC_/Medical Research Council/United Kingdom ; MC_UP_A620_1016/MRC_/Medical Research Council/United Kingdom ; MR/P012019/1/MRC_/Medical Research Council/United Kingdom ; MC-A760- 5QX00/MRC_/Medical Research Council/United Kingdom ; MC_UU_12011/3/MRC_/Medical Research Council/United Kingdom ; MC_UU_00026/3/MRC_/Medical Research Council/United Kingdom ; MC_EX_MR/M01424X/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Child ; Child, Preschool ; Cross-Sectional Studies ; Female ; Fertilization ; Gambia ; Humans ; Leukocytes/*metabolism ; Male ; Regression Analysis ; Seasons ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {Early life exposures are important predictors of adult disease risk. Although the underlying mechanisms are largely unknown, telomere maintenance may be involved. This study investigated the relationship between seasonal differences in parental exposures at time of conception and leukocyte telomere length (LTL) in their offspring. LTL was measured in two cohorts of children aged 2 yrs (N = 487) and 7-9 yrs (N = 218). The association between date of conception and LTL was examined using Fourier regression models, adjusted for age, sex, leukocyte cell composition, and other potential confounders. We observed an effect of season in the older children in all models [likelihood ratio test (LRT) χ[2]2 = 7.1, p = 0.03; fully adjusted model]. LTL was greatest in children conceived in September (in the rainy season), and smallest in those conceived in March (in the dry season), with an effect size (LTL peak-nadir) of 0.60 z-scores. No effect of season was evident in the younger children (LRT χ[2]2 = 0.87, p = 0.65). The different results obtained for the two cohorts may reflect a delayed effect of season of conception on postnatal telomere maintenance. Alternatively, they may be explained by unmeasured differences in early life exposures, or the increased telomere attrition rate during infancy.},
}
@article {pmid32540968,
year = {2020},
author = {Abdisalaam, S and Bhattacharya, S and Mukherjee, S and Sinha, D and Srinivasan, K and Zhu, M and Akbay, EA and Sadek, HA and Shay, JW and Asaithamby, A},
title = {Dysfunctional telomeres trigger cellular senescence mediated by cyclic GMP-AMP synthase.},
journal = {The Journal of biological chemistry},
volume = {295},
number = {32},
pages = {11144-11160},
pmid = {32540968},
issn = {1083-351X},
support = {R01 HL115275/HL/NHLBI NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; C06 RR030414/RR/NCRR NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; R01 AG053341/AG/NIA NIH HHS/United States ; },
mesh = {Cell Cycle ; Cellular Senescence/*genetics ; DNA Breaks, Double-Stranded ; Humans ; Ligases/*metabolism ; Nucleotides, Cyclic/*metabolism ; Signal Transduction ; *Telomere ; },
abstract = {Defective DNA damage response (DDR) signaling is a common mechanism that initiates and maintains the cellular senescence phenotype. Dysfunctional telomeres activate DDR signaling, genomic instability, and cellular senescence, but the links among these events remains unclear. Here, using an array of biochemical and imaging techniques, including a highly regulatable CRISPR/Cas9 strategy to induce DNA double strand breaks specifically in the telomeres, ChIP, telomere immunofluorescence, fluorescence in situ hybridization (FISH), micronuclei imaging, and the telomere shortest length assay (TeSLA), we show that chromosome mis-segregation due to imperfect DDR signaling in response to dysfunctional telomeres creates a preponderance of chromatin fragments in the cytosol, which leads to a premature senescence phenotype. We found that this phenomenon is caused not by telomere shortening, but by cyclic GMP-AMP synthase (cGAS) recognizing cytosolic chromatin fragments and then activating the stimulator of interferon genes (STING) cytosolic DNA-sensing pathway and downstream interferon signaling. Significantly, genetic and pharmacological manipulation of cGAS not only attenuated immune signaling, but also prevented premature cellular senescence in response to dysfunctional telomeres. The findings of our study uncover a cellular intrinsic mechanism involving the cGAS-mediated cytosolic self-DNA-sensing pathway that initiates premature senescence independently of telomere shortening.},
}
@article {pmid32533363,
year = {2020},
author = {Albizua, I and Chopra, P and Allen, EG and He, W and Amin, AS and Sherman, SL},
title = {Study of telomere length in men who carry a fragile X premutation or full mutation allele.},
journal = {Human genetics},
volume = {139},
number = {12},
pages = {1531-1539},
pmid = {32533363},
issn = {1432-1203},
support = {U54 NS091859/NS/NINDS NIH HHS/United States ; NS091859//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; },
mesh = {5' Untranslated Regions/genetics ; Adult ; Aged ; Alleles ; Ataxia/*genetics/pathology ; Fragile X Mental Retardation Protein/*genetics ; Fragile X Syndrome/*genetics/pathology ; Humans ; Male ; Middle Aged ; Mutation/genetics ; Telomere/*genetics/pathology/ultrastructure ; Telomere Homeostasis/genetics ; Tremor/*genetics/pathology ; Trinucleotide Repeat Expansion/genetics ; Young Adult ; },
abstract = {The fragile X premutation is defined by the expansion of the CGG trinucleotide repeat at the 5' UTR of the FMR1 gene to between 55 and 200 repeats, while repeat tracks longer than 200 are defined as full mutations. Men carrying a premutation are at increased risk for fragile X-associated tremor/ataxia syndrome (FXTAS); those with > 200 repeats have fragile X syndrome, a common genetic form of intellectual disabilities. In our study, we tested the hypothesis that men carrying a fragile X premutation or full mutation are "biologically older", as suggested by the associated age-related disorder in the presence of the fragile X premutation or the altered cellular pathology that affects both the fragile X premutation and full mutation carriers. Thus, we predicted that both groups would have shorter telomeres than men carrying the normal size repeat allele. Using linear regression models, we found that, on average, premutation carriers had shorter telomeres compared with non-carriers (n = 69 vs n = 36; p = 0.02) and that there was no difference in telomere length between full mutation carriers and non-carriers (n = 37 vs n = 29; p > 0.10). Among premutation carriers only, we also asked whether telomere length was shorter among men with vs without symptoms of FXTAS (n = 28 vs n = 38 and n = 27 vs n = 41, depending on criteria) and found no evidence for a difference (p > 0.10). Previous studies have shown that the premutation is transcribed whereas the full mutation is not, and the expanded repeat track in FMR1 transcript is thought to lead to the risk for premutation-associated disorders. Thus, our data suggest that the observed premutation-only telomere shortening may be a consequence of the toxic effect of the premutation transcript and suggest that premutation carriers are "biologically older" than men carrying the normal size allele in the same age group.},
}
@article {pmid32532864,
year = {2020},
author = {Casagrande, S and Stier, A and Monaghan, P and Loveland, JL and Boner, W and Lupi, S and Trevisi, R and Hau, M},
title = {Increased glucocorticoid concentrations in early life cause mitochondrial inefficiency and short telomeres.},
journal = {The Journal of experimental biology},
volume = {223},
number = {Pt 15},
pages = {},
doi = {10.1242/jeb.222513},
pmid = {32532864},
issn = {1477-9145},
mesh = {Glucocorticoids ; Mitochondria ; Oxidative Stress ; *Telomere ; *Telomere Shortening ; },
abstract = {Telomeres are DNA structures that protect chromosome ends. However, telomeres shorten during cell replication and at critically low lengths can reduce cell replicative potential, induce cell senescence and decrease fitness. Stress exposure, which elevates glucocorticoid hormone concentrations, can exacerbate telomere attrition. This phenomenon has been attributed to increased oxidative stress generated by glucocorticoids ('oxidative stress hypothesis'). We recently suggested that glucocorticoids could increase telomere attrition during stressful periods by reducing the resources available for telomere maintenance through changes in the metabolic machinery ('metabolic telomere attrition hypothesis'). Here, we tested whether experimental increases in glucocorticoid levels affected telomere length and mitochondrial function in wild great tit (Parus major) nestlings during the energy-demanding early growth period. We monitored resulting corticosterone (Cort) concentrations in plasma and red blood cells, telomere lengths and mitochondrial metabolism (metabolic rate, proton leak, oxidative phosphorylation, maximal mitochondrial capacity and mitochondrial inefficiency). We assessed oxidative damage caused by reactive oxygen species (ROS) metabolites as well as the total non-enzymatic antioxidant protection in plasma. Compared with control nestlings, Cort-nestlings had higher baseline corticosterone, shorter telomeres and higher mitochondrial metabolic rate. Importantly, Cort-nestlings showed increased mitochondrial proton leak, leading to a decreased ATP production efficiency. Treatment groups did not differ in oxidative damage or antioxidants. Hence, glucocorticoid-induced telomere attrition is associated with changes in mitochondrial metabolism, but not with ROS production. These findings support the hypothesis that shortening of telomere length during stressful periods is mediated by glucocorticoids through metabolic rearrangements.},
}
@article {pmid32532801,
year = {2020},
author = {Aklilu, BB and Peurois, F and Saintomé, C and Culligan, KM and Kobbe, D and Leasure, C and Chung, M and Cattoor, M and Lynch, R and Sampson, L and Fatora, J and Shippen, DE},
title = {Functional Diversification of Replication Protein A Paralogs and Telomere Length Maintenance in Arabidopsis.},
journal = {Genetics},
volume = {215},
number = {4},
pages = {989-1002},
pmid = {32532801},
issn = {1943-2631},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; },
mesh = {Arabidopsis/genetics/growth &amp; development/*metabolism ; Arabidopsis Proteins/genetics/*metabolism ; *Homologous Recombination ; Meiosis ; *Phenotype ; Replication Protein A/genetics/*metabolism ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Replication protein A (RPA) is essential for many facets of DNA metabolism. The RPA gene family expanded in Arabidopsis thaliana with five phylogenetically distinct RPA1 subunits (RPA1A-E), two RPA2 (RPA2A and B), and two RPA3 (RPA3A and B). RPA1 paralogs exhibit partial redundancy and functional specialization in DNA replication (RPA1B and RPA1D), repair (RPA1C and RPA1E), and meiotic recombination (RPA1A and RPA1C). Here, we show that RPA subunits also differentially impact telomere length set point. Loss of RPA1 resets bulk telomeres at a shorter length, with a functional hierarchy for replication group over repair and meiosis group RPA1 subunits. Plants lacking RPA2A, but not RPA2B, harbor short telomeres similar to the replication group. Telomere shortening does not correlate with decreased telomerase activity or deprotection of chromosome ends in rpa mutants. However, in vitro assays show that RPA[1B2A3B] unfolds telomeric G-quadruplexes known to inhibit replications fork progression. We also found that ATR deficiency can partially rescue short telomeres in rpa2a mutants, although plants exhibit defects in growth and development. Unexpectedly, the telomere shortening phenotype of rpa2a mutants is completely abolished in plants lacking the RTEL1 helicase. RTEL1 has been implicated in a variety of nucleic acid transactions, including suppression of homologous recombination. Thus, the lack of telomere shortening in rpa2a mutants upon RTEL1 deletion suggests that telomere replication defects incurred by loss of RPA may be bypassed by homologous recombination. Taken together, these findings provide new insight into how RPA cooperates with replication and recombination machinery to sustain telomeric DNA.},
}
@article {pmid32531916,
year = {2020},
author = {Slusher, AL and Kim, JJ and Ludlow, AT},
title = {The Role of Alternative RNA Splicing in the Regulation of hTERT, Telomerase, and Telomeres: Implications for Cancer Therapeutics.},
journal = {Cancers},
volume = {12},
number = {6},
pages = {},
pmid = {32531916},
issn = {2072-6694},
support = {R00 CA197672/CA/NCI NIH HHS/United States ; CA197672-01A1//National Institutes of Health/ National Cancer Institute/ ; },
abstract = {Alternative RNA splicing impacts the majority (>90%) of eukaryotic multi-exon genes, expanding the coding capacity and regulating the abundance of gene isoforms. Telomerase (hTERT) is a key example of a gene that is alternatively spliced during human fetal development and becomes dysregulated in nearly all cancers. Approximately 90% of human tumors use telomerase to synthesize de novo telomere repeats and obtain telomere-dependent cellular immortality. Paradigm shifting data indicates that hTERT alternative splicing, in addition to transcription, plays an important role in the regulation of active telomerase in cells. Our group and others are pursuing the basic science studies to progress this emerging area of telomerase biology. Recent evidence demonstrates that switching splicing of hTERT from the telomerase activity producing full-length hTERT isoform to alternatively spliced, non-coding isoforms may be a novel telomerase inhibition strategy to prevent cancer growth and survival. Thus, the goals of this review are to detail the general roles of telomerase in cancer development, explore the emerging regulatory mechanisms of alternative RNA splicing of the hTERT gene in various somatic and cancer cell types, define the known and potential roles of hTERT splice isoforms in cancer cell biology, and provide insight into new treatment strategies targeting hTERT in telomerase-positive cancers.},
}
@article {pmid32531572,
year = {2020},
author = {Louzon, M and Zahn, S and Capelli, N and Massemin, S and Coeurdassier, M and Pauget, B and Gimbert, F and de Vaufleury, A},
title = {Impact of ageing and soil contaminants on telomere length in the land snail.},
journal = {Ecotoxicology and environmental safety},
volume = {201},
number = {},
pages = {110766},
doi = {10.1016/j.ecoenv.2020.110766},
pmid = {32531572},
issn = {1090-2414},
mesh = {Animals ; Environmental Pollution ; Helix, Snails ; Mercury ; Polycyclic Aromatic Hydrocarbons/analysis/toxicity ; Snails/drug effects/*physiology ; Soil ; Soil Pollutants/analysis/*toxicity ; Telomere/*drug effects ; },
abstract = {Telomeres (TLs) are non-coding DNA sequences that are usually shortened with ageing and/or chemical exposure. Bioindicators such as the land snail can be used to assess the environmental risk of contaminated soils. As for most invertebrates, the evolution of TLs with ageing or exposure to contaminants is unknown in this mollusc. The aims of this study were to explore the relationships between ageing, contaminant exposure, sublethal effects and TL length in the terrestrial gastropod Cantareus aspersus. TL length was investigated in haemocytes from five age classes of C. aspersus. The impact of contaminants on sub-adult snails exposed to Cd, Hg or a mixture of polycyclic aromatic hydrocarbons (PAHs) in soils for one or two months was studied. Bioaccumulation, growth, sexual maturity and TLs were measured. TL attrition was significant for the juvenile and sub-adult stages, but not later. Exposure to Cd increased the mortality (around 30%). Exposure to polluted soils inhibited growth (19-40%) and sexual maturity (6-100%). Although the health of the snails exposed to Cd, Hg and PAHs was altered, TL length in haemocytes was not disturbed, suggesting a high capacity of this snail species to maintain its TLs in haemocytes under chemical stress. These results first address TL length in snails and reveal that the relationship commonly proposed for vertebrates between TL shortening and ageing or exposure to contaminants cannot be generalized.},
}
@article {pmid32526789,
year = {2020},
author = {Penrice, DD and Simonetto, DA},
title = {Short Telomeres: Cause and Consequence in Liver Disease.},
journal = {Seminars in liver disease},
volume = {40},
number = {4},
pages = {385-391},
doi = {10.1055/s-0040-1713007},
pmid = {32526789},
issn = {1098-8971},
mesh = {Humans ; *Liver Diseases/diagnosis/genetics/therapy ; *Metabolic Diseases ; Syndrome ; Telomere/genetics ; Telomere Shortening ; },
abstract = {Short telomere syndrome is a genetically inherited syndrome resulting in premature telomere shortening. This premature shortening of telomeres can result in hematologic, pulmonary, vascular, gastrointestinal, and hepatic manifestations of disease. Identifying patients with short telomere syndrome can be a clinical challenge due to the multitude of potential manifestations and lack of widely available diagnostic tests. In this review, we will highlight hepatic manifestations of short telomere syndrome with a focus on diagnosis, testing, and potential treatments.},
}
@article {pmid32522626,
year = {2020},
author = {Burraco, P and Comas, M and Reguera, S and Zamora-Camacho, FJ and Moreno-Rueda, G},
title = {Telomere length mirrors age structure along a 2200-m altitudinal gradient in a Mediterranean lizard.},
journal = {Comparative biochemistry and physiology. Part A, Molecular &amp; integrative physiology},
volume = {247},
number = {},
pages = {110741},
doi = {10.1016/j.cbpa.2020.110741},
pmid = {32522626},
issn = {1531-4332},
mesh = {Age Factors ; Altitude ; Animals ; Body Temperature Regulation/physiology ; Lizards/metabolism/*physiology ; Mediterranean Region ; Telomerase/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {The timing of organisms' senescence is developmentally programmed but also shaped by the interaction between environmental inputs and life-history traits. In ectotherms, ageing dynamics are still poorly understood even though their body temperature, metabolism, or growth trajectory are very sensitive to environmental changes. Here, we investigated the role of life-history traits such as age, sex, body size, body condition, and tail autotomy (i.e self-amputation) in shaping telomere length in six populations of the Algerian sand lizard (Psammodromus algirus) distributed along an elevational gradient from 300 to 2500 m above the sea level. Additionally, we compiled the available information on reptiles' telomere length in a review table. Our cross-sectional study shows that older lizards have longer telomeres, which might be mostly linked to the selective disappearance of individuals with shorter telomeres or, alternatively, mediated by a higher expression of telomerase across their life. In fact, variation in telomere length across elevation was explained by age structure of lizards; thus, in contrast to our predictions, altitude had no effect on telomere length in this study system. Telomere length was unaffected by tail regeneration and was sex-independent, but positively correlated with body condition, which might be linked to high somatic investment. Hence, our results suggest that life-history traits such as age or body condition can be major drivers of telomere dynamics for this species, whereas environmental conditions apparently had scarce or no effects on lizard telomeres. Our findings emphasize the relevance of understanding species' life histories for fully disentangling the causes and consequences of differences in ageing in ectotherms.},
}
@article {pmid32516515,
year = {2020},
author = {Munroe, M and Niero, EL and Fok, WC and Vessoni, AT and Jeong, HC and Brenner, KA and Batista, LFZ},
title = {Telomere Dysfunction Activates p53 and Represses HNF4α Expression Leading to Impaired Human Hepatocyte Development and Function.},
journal = {Hepatology (Baltimore, Md.)},
volume = {72},
number = {4},
pages = {1412-1429},
pmid = {32516515},
issn = {1527-3350},
support = {1R01HL137793/HL/NHLBI NIH HHS/United States ; T32 HL007088/HL/NHLBI NIH HHS/United States ; R01 HL137793/HL/NHLBI NIH HHS/United States ; P30 DK052574/DK/NIDDK NIH HHS/United States ; HL007088/HL/NHLBI NIH HHS/United States ; },
mesh = {Cell Differentiation ; Cells, Cultured ; Embryonic Stem Cells ; Hepatocyte Nuclear Factor 4/*physiology ; Hepatocytes/cytology/*physiology ; Humans ; Telomerase/genetics ; Telomere/*physiology ; Tumor Suppressor Protein p53/*physiology ; },
abstract = {BACKGROUND AND AIMS: Telomere attrition is a major risk factor for end-stage liver disease. Due to a lack of adequate models and intrinsic difficulties in studying telomerase in physiologically relevant cells, the molecular mechanisms responsible for liver disease in patients with telomere syndromes remain elusive. To circumvent that, we used genome editing to generate isogenic human embryonic stem cells (hESCs) harboring clinically relevant mutations in telomerase and subjected them to an in vitro, stage-specific hepatocyte differentiation protocol that resembles hepatocyte development in vivo.<br><br>APPROACH AND RESULTS: Using this platform, we observed that while telomerase is highly expressed in hESCs, it is quickly silenced, specifically due to telomerase reverse transcriptase component (TERT) down-regulation, immediately after endoderm differentiation and completely absent in in vitro-derived hepatocytes, similar to what is observed in human primary hepatocytes. While endoderm derivation is not impacted by telomere shortening, progressive telomere dysfunction impaired hepatic endoderm formation. Consequently, hepatocyte derivation, as measured by expression of specific hepatic markers as well by albumin expression and secretion, is severely compromised in telomerase mutant cells with short telomeres. Interestingly, this phenotype was not caused by cell death induction or senescence. Rather, telomere shortening prevents the up-regulation and activation of human hepatocyte nuclear factor 4 alpha (HNF4&#x3b1;) in a p53-dependent manner. Both reactivation of telomerase and silencing of p53 rescued hepatocyte formation in telomerase mutants. Likewise, the conditional expression (doxycycline-controlled) of HNF4&#x3b1;, even in cells that retained short telomeres, accrued DNA damage, and exhibited p53 stabilization, successfully restored hepatocyte formation from hESCS.<br><br>CONCLUSIONS: Our data show that telomere dysfunction acts as a major regulator of HNF4&#x3b1; during hepatocyte development, pointing to a target in the treatment of liver disease in telomere-syndrome patients.},
}
@article {pmid32515222,
year = {2020},
author = {Khalangot, M and Krasnienkov, D and Vaiserman, A},
title = {Telomere length in different metabolic categories: Clinical associations and modification potential.},
journal = {Experimental biology and medicine (Maywood, N.J.)},
volume = {245},
number = {13},
pages = {1115-1121},
pmid = {32515222},
issn = {1535-3699},
mesh = {Animals ; Blood Glucose/metabolism ; Fasting/physiology ; Humans ; Leukocytes/metabolism ; Metabolic Syndrome/*metabolism ; Telomere/*metabolism ; },
abstract = {Metabolic disorders are known to be associated with accelerated telomere attrition. Their pathophysiological heterogeneity suggests the importance of multiple tests in examining these associations. However, oral glucose tolerance test (OGTT) has rarely been performed in such studies to date. There are few studies aimed at determining leukocyte telomere length (LTL) in different categories of impaired glucose tolerance (IGT), and those that do exist do not take into account the impaired fasting glucose (IFG)/IGT categorization. Therefore, we believe our study, when the OGTT was used, is important to the field. This testing made it possible to determine whether LTLs are associated with glucose levels in different hyperglycemic categories. Our data indicate that relationships between LTLs and IFG/IGT levels are not the same. This distinction can potentially be used in categorization of metabolic disorders and in determining the effectiveness of interventions aimed at treating diabetes and other metabolic abnormalities.},
}
@article {pmid32512904,
year = {2020},
author = {Shanta, K and Nakayama, K and Ishikawa, M and Ishibashi, T and Yamashita, H and Sato, S and Sasamori, H and Sawada, K and Kurose, S and Mahmud, HM and Razia, S and Iida, K and Ishikawa, N and Kyo, S},
title = {Prognostic Value of Peripheral Blood Lymphocyte Telomere Length in Gynecologic Malignant Tumors.},
journal = {Cancers},
volume = {12},
number = {6},
pages = {},
pmid = {32512904},
issn = {2072-6694},
support = {18K09229 and 18K09291//JSPS KAKENHI/ ; },
abstract = {Background: Lymphocyte telomere length is strongly correlated with patient prognosis in several malignant tumor types and is thought to be related to tumor immunity. However, this correlation has not been studied in gynecological cancers. We determined the prognostic significance of peripheral blood lymphocyte telomere length in gynecologic cancers. Methods: Telomere length of lymphocytes from patients with gynecological malignant tumors (ovarian cancer (OC), N = 72; cervical cancer (CC), N = 63; endometrial cancer (EC), N = 87) was examined by quantitative reverse-transcription PCR of isolated mononuclear cells. Kaplan-Meier and Cox proportional hazard analyses were used to determine the association between lymphocyte telomere length and clinicopathological factors. Results: The overall survival (OS) and progression-free survival (PFS) of patients were based on the dichotomized lymphocyte telomere length using the median as a threshold (OC: 0.75, CC: 1.94, and EC: 1.09). A short telomere length was significantly correlated with residual tumors (≥1 cm) in OC and with advanced stage (III and IV) of CC. In OC and CC, patients with shorter relative lymphocyte telomere length (RLT) had significantly poorer OS and PFS than patients with longer RLT (p = 0.002, p = 0.003, and p = 0.001, p = 0.001, respectively). However, in EC, RLT was not significantly associated with OS or PFS (p = 0.567 and p = 0.304, log-rank test). Multivariate analysis showed that shorter RLT was a significant independent prognostic factor of PFS and OS for OC (p = 0.03 and p = 0.04, respectively) and CC (p = 0.02 and p = 0.03, respectively). Conclusions: Patients with OC and CC with shorter lymphocyte telomeres have significantly reduced survival; therefore, the peripheral blood lymphocyte telomere length is a prognostic biomarker in OC and CC.},
}
@article {pmid32512652,
year = {2020},
author = {Bloom, SI and Tuluca, A and Ives, SJ and Reynolds, TH},
title = {High-fat diet induced obesity and age influence the telomere shelterin complex and telomerase gene expression in mouse adipose tissue.},
journal = {Physiological reports},
volume = {8},
number = {11},
pages = {e14461},
pmid = {32512652},
issn = {2051-817X},
support = {R15 AG053790/AG/NIA NIH HHS/United States ; T32 5T32HL139451-02/NH/NIH HHS/United States ; R15 AG053790-01/AG/NIA NIH HHS/United States ; },
mesh = {Adipose Tissue/*metabolism ; Age Factors ; Animals ; Cellular Senescence ; DNA-Binding Proteins/genetics ; *Diet, High-Fat ; *Gene Expression ; Inflammation/genetics ; Male ; Mice, Inbred C57BL ; Obesity/etiology/*genetics ; RNA, Messenger ; Telomerase/*genetics ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/*genetics ; },
abstract = {Obesity and aging are linked to inflammation and increased risk of chronic disease. Telomeres are the endcaps of chromosomes that are regulated by telomerase, the enzyme that elongates telomeres, as well as a protein complex known as shelterin. Telomere dysfunction is associated with inflammation, aging, and disease. However, the effect of high-fat diet (HFD) induced obesity and advancing age on the shelterin complex and telomerase in adipose tissue is unknown. The present study investigated the effects of obesity and aging on C57BL/6J mice adipose tissue mRNA expression of shelterin complex genes. Young (YG) mice (3 mo) were randomly assigned to be fed either a high-fat diet (YG + HFD; 60% kcal from fat) or a low-fat diet (YG + LFD; 10% kcal from fat). A subset of mice were aged until 16 months. Body weight and epididymal white adipose tissue (EWAT) weight increased with age or a HFD. There was a trend for increased Terf2 expression, as expression was increased in HFD + YG by ~47% and aged mice by ~80%. Pot1b expression was increased in aged mice by ~35%-60% compared to YG, independent of diet. mTert, the gene that codes for the catalytic subunit of telomerase, was significantly elevated in aged mice. Changes in telomere associated gene expression was accompanied by changes in expression of inflammatory markers Mcp1 and Tnfα. These findings suggest obesity and age impact expression of shelterin complex and telomerase related genes in adipose, perhaps altering telomere function in adipose tissue thereby increasing inflammation and risk of chronic disease.},
}
@article {pmid32512281,
year = {2020},
author = {Guan, X and Fu, W and Wei, W and Li, G and Wu, X and Bai, Y and Feng, Y and Meng, H and Li, H and Li, M and Fu, M and Zhang, X and He, M and Guo, H},
title = {Mediation of the association between polycyclic aromatic hydrocarbons exposure and telomere attrition by oxidative stress: A prospective cohort study.},
journal = {Journal of hazardous materials},
volume = {399},
number = {},
pages = {123058},
doi = {10.1016/j.jhazmat.2020.123058},
pmid = {32512281},
issn = {1873-3336},
mesh = {Biomarkers ; Cohort Studies ; *Coke/analysis ; Humans ; *Occupational Exposure/adverse effects/analysis ; Oxidative Stress ; *Polycyclic Aromatic Hydrocarbons/analysis/toxicity ; Prospective Studies ; Telomere/chemistry ; },
abstract = {Previous studies have reported associations between polycyclic aromatic hydrocarbons (PAHs) exposure and telomere attrition, but the underlying mechanisms remain to be elucidated. This study aimed to explore the mediation role of oxidative stress on the effects of PAHs exposure on telomere attrition in a cohort study of 1180 coke-oven workers. We determined baseline urinary concentrations of ten urinary PAH metabolites, two oxidative stress biomarkers [8-hydroxydeoxyguanosine (8-OHdG) and 8-iso-prostaglandin-F2α (8-isoPGF2α)] and peripheral leukocytes telomere length (TL) in both baseline and follow-up visits. Mediation analysis was applied to assess effects of oxidative stress biomarkers on the PAHs-TL attrition associations. The baseline 8-OHdG had a significant dose-response relationship with TL decline [β(95 %CI) = 0.07(0.03-0.12), P = 0.001] and TL ratio [β(95 %CI)]=0.07 (0.02-0.12), P = 0.003]. Mediation analyses indicated that 8-OHdG mediated a separate 39.1 %, 47.0 %, 43.3 %, and 58.0 % of the associations between 1-hydroxynaphthalene (1-OHNa), 2-OHNa, ΣOHNa, 1-hydroxypyrene (1-OHP) and TL decline (P = 0.016, 0.008, 0.012, and 0.014, respectively). Additionally, 8-OHdG mediated a separate 44.8 %, 49.4 %, 49.2 %, and 35.5 % of the associations between 1-OHNa, 2-OHNa, ΣOHNa, 1-OHP and TL ratio (P = 0.012, 0.008, 0.012, and 0.046, respectively). Our study proposed the positive association of 8-OHdG with TL attrition and revealed the mediation roles of 8-OHdG in PAHs-TL attrition associations.},
}
@article {pmid32511191,
year = {2020},
author = {Wysocki, K and Seibert, D},
title = {Genomics of aging: Genes, adducts, and telomeres.},
journal = {Journal of the American Association of Nurse Practitioners},
volume = {32},
number = {6},
pages = {419-422},
pmid = {32511191},
issn = {2327-6924},
mesh = {Aging/*genetics ; DNA Adducts/*genetics ; Humans ; Telomere/genetics/physiology ; },
abstract = {Genomics influences the aging process in many different ways. This 10-part series of articles describes what is known about genetics and aging, including genes, adducts, and telomeres, decreased immune defenses, oxidation and inefficient mitochondria, toxins and radiation, glycosylation, caloric intake and sirtuin production, neurotransmitter imbalance, hormone mechanisms, reduced nitric oxide, and stem cell slowdown. This first article explores gene adducts as an epigenetic "sludge," the influence of telomeres and other mutations that contribute to DNA dysfunction, cell stress, and premature aging. Factors that contribute to adduct formation and reduced telomere length are presented along with some changes in behavior, environmental exposure, food/supplement use, weight, sleep, and exercise that have been found to reduce damage, potentially increasing longevity. Adherence to a Mediterranean diet that contains fruits and whole grains along with fiber, antioxidants (e.g., beta-carotene, vitamins C and E), omega-3 fatty acids, and soy protein may reduce DNA adducts and protect telomeres. So providers may want to recommend these simple but key clinical and individual changes to enhance DNA health, wellness, and longevity.},
}
@article {pmid32504677,
year = {2020},
author = {Miga, KH},
title = {Centromere studies in the era of 'telomere-to-telomere' genomics.},
journal = {Experimental cell research},
volume = {394},
number = {2},
pages = {112127},
pmid = {32504677},
issn = {1090-2422},
support = {R01 HG011274/HG/NHGRI NIH HHS/United States ; R21 HG010548/HG/NHGRI NIH HHS/United States ; U01 HG010971/HG/NHGRI NIH HHS/United States ; },
mesh = {Centromere/*metabolism ; DNA, Satellite/genetics ; *Genomics ; Humans ; Reproducibility of Results ; Tandem Repeat Sequences/genetics ; Telomere/*metabolism ; },
abstract = {We are entering into an exciting era of genomics where truly complete, high-quality assemblies of human chromosomes are available end-to-end, or from 'telomere-to-telomere' (T2T). This technological advance offers a new opportunity to include endogenous human centromeric regions in high-resolution, sequence-based studies. These emerging reference maps are expected to reveal a new functional landscape in the human genome, where centromere proteins, transcriptional regulation, and spatial organization can be examined with base-level resolution across different stages of development and disease. Such studies will depend on innovative assembly methods of extremely long tandem repeats (ETRs), or satellite DNAs, paired with the development of new, orthogonal validation methods to ensure accuracy and completeness. This review reflects the progress in centromere genomics, credited by recent advancements in long-read sequencing and assembly methods. In doing so, I will discuss the challenges that remain and the promise for a new period of scientific discovery for satellite DNA biology and centromere function.},
}
@article {pmid32502401,
year = {2020},
author = {Reddel, RR and MacKenzie, KL and Bryan, TM},
title = {End Products of Telomere Research.},
journal = {Cell stem cell},
volume = {26},
number = {6},
pages = {804-805},
doi = {10.1016/j.stem.2020.05.006},
pmid = {32502401},
issn = {1875-9777},
mesh = {Humans ; Stem Cells/metabolism ; *Telomerase/metabolism ; *Telomere/genetics/metabolism ; Telomere Shortening ; },
abstract = {Most rare inherited telomere biology disorders and some common aging-related diseases are associated with shortened telomeres. In this issue of Cell Stem Cell, insights into one of the rarest genetic causes of these disorders led to the discovery (Nagpal et al., 2020) of small molecules that lengthen telomeres.},
}
@article {pmid32502208,
year = {2020},
author = {Wu, S and Ge, Y and Li, X and Yang, Y and Zhou, H and Lin, K and Zhang, Z and Zhao, Y},
title = {BRM-SWI/SNF chromatin remodeling complex enables functional telomeres by promoting co-expression of TRF2 and TRF1.},
journal = {PLoS genetics},
volume = {16},
number = {6},
pages = {e1008799},
pmid = {32502208},
issn = {1553-7404},
mesh = {Chromosomal Proteins, Non-Histone/*metabolism ; Genomic Instability ; HEK293 Cells ; HeLa Cells ; Hep G2 Cells ; Heterochromatin/metabolism ; Humans ; Promoter Regions, Genetic ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/*genetics/metabolism ; Transcription Factors/genetics/*metabolism ; },
abstract = {TRF2 and TRF1 are a key component in shelterin complex that associates with telomeric DNA and protects chromosome ends. BRM is a core ATPase subunit of SWI/SNF chromatin remodeling complex. Whether and how BRM-SWI/SNF complex is engaged in chromatin end protection by telomeres is unknown. Here, we report that depletion of BRM does not affect heterochromatin state of telomeres, but results in telomere dysfunctional phenomena including telomere uncapping and replication defect. Mechanistically, expression of TRF2 and TRF1 is jointly regulated by BRM-SWI/SNF complex, which is localized to promoter region of both genes and facilitates their transcription. BRM-deficient cells bear increased TRF2-free or TRF1-free telomeres due to insufficient expression. Importantly, BRM depletion-induced telomere uncapping or replication defect can be rescued by compensatory expression of exogenous TRF2 or TRF1, respectively. Together, these results identify a new function of BRM-SWI/SNF complex in enabling functional telomeres for maintaining genome stability.},
}
@article {pmid32502020,
year = {2020},
author = {Lili, M and Yuxiang, F and Zhongcheng, H and Ying, S and Ru, C and Rong, X and Jiang, L},
title = {Genetic variations associated with telomere length affect the risk of gastric carcinoma.},
journal = {Medicine},
volume = {99},
number = {23},
pages = {e20551},
pmid = {32502020},
issn = {1536-5964},
mesh = {Case-Control Studies ; China/epidemiology ; DNA-Binding Proteins/*genetics ; Female ; *Genetic Predisposition to Disease ; Haplotypes ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Real-Time Polymerase Chain Reaction ; Stomach Neoplasms/*genetics ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Homeostasis ; },
abstract = {This study aimed to further understand the role of relative telomere length (RTL) in susceptibility to gastric carcinoma (GC) and investigate the association between genetic polymorphisms in the telomere length related genes and GC risk.RTL was measured using the real-time quantitative polymerase chain reaction from 1000 patients and 1100 healthy controls. Genotyping was performed using the Agena MassARRAY platform. The statistical analysis was performed using the chi-square/ Welch T tests, Mann-Whitney U test, and logistic regression analysis.The association analysis of telomere length and GC showed that the RTL in the case group was shorter than in the controls, and the shorter RTL was associated with an increased risk of GC. The association analysis between telomere length related genes polymorphisms and genetic susceptibility to GC indicated that: In the allele models and genetic models, TERT (rs10069690, rs2242652 and rs2853676) and TN1F1 (rs7708392 and rs10036748) were significantly associated with an increased risk of GC. In addition, the haplotype 'Grs10069690Crs2242652" of TERT and the haplotype 'Grs7708392Trs10036748" of TNIP1 were associated with an increased risk of GCOur results suggested that shorter RTL was associated with an increased risk of GC; The association analysis have identified that the TERT (rs10069690, rs2242652 and rs2853676) and TN1P1 (rs7708392 and rs10036748) were associated with GC risk.},
}
@article {pmid32500358,
year = {2020},
author = {AlDehaini, DMB and Al-Bustan, SA and Ali, ME and Malalla, ZHA and Sater, M and Giha, HA},
title = {Shortening of the leucocytes' telomeres length in T2DM independent of age and telomerase activity.},
journal = {Acta diabetologica},
volume = {57},
number = {11},
pages = {1287-1295},
pmid = {32500358},
issn = {1432-5233},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Blood Glucose/metabolism ; Body Mass Index ; Cross-Sectional Studies ; Diabetes Mellitus, Type 2/genetics/*metabolism/physiopathology ; Female ; Humans ; Insulin Resistance ; Leukocytes/*metabolism ; Male ; Middle Aged ; Risk Factors ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Shortening ; },
abstract = {AIMS: This study aimed to examine the role of plasma telomerase (TE), plasma insulin, patient's age and disease duration in determination of the leucocytes' telomeres length (LTL) in T2DM.<br><br>METHODS: Blood samples from Kuwaiti patients with T2DM (110) and non-diabetic subjects (94) were analyzed by SYBR Green Quantitative PCR for estimation of the Absolute Human Telomere Length and by ELISA for estimation of the TE activity and insulin level. The body mass index (BMI) and HOMA-IR were calculated.<br><br>RESULTS: The results revealed marked shortening of the LTL in T2DM compared with the non-diabetic subjects (6.068, 2.276-11.652 vs. 10.979, 6.495-23.402&#xa0;kb), p&#x2009;<&#x2009;0.001, while the TE concentration was comparable between the two groups (3.16, 0.00-6.02 vs. 4.16, 1.38-7.94 U/L, respectively), p 0.100. Importantly, in T2DM the LTL did not vary significantly with the disease duration (1&#xa0;month to 40&#xa0;years), p 0.959, and did not correlate with age, BMI, insulin-resistance, or glycemic parameters. Interestingly, there was a positive correlation between the LTL and insulin levels in T2DM (CC 0.211, p 0.0419). Finally, in non-diabetic subjects, HbA1c&#x2009;&#x2265;&#x2009;6% was associated significantly with shorter LTL, this observation together with the lack of association of the LTL with the disease duration, suggests a causal role of short telomeres in T2DM development.<br><br>CONCLUSIONS: This study confirmed the LTL shortening in T2DM in Kuwaiti Arabs, and showed that the LTL was independent of age and TE activity but positively influenced by insulin levels. Furthermore, the study suggested that telomeres shortening could be a risk factor for T2DM.},
}
@article {pmid32499315,
year = {2020},
author = {Lambing, C and Kuo, PC and Tock, AJ and Topp, SD and Henderson, IR},
title = {ASY1 acts as a dosage-dependent antagonist of telomere-led recombination and mediates crossover interference in Arabidopsis.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {117},
number = {24},
pages = {13647-13658},
pmid = {32499315},
issn = {1091-6490},
support = {681987/ERC_/European Research Council/International ; BB/M004937/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Arabidopsis/*genetics/metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Cell Cycle Proteins/genetics/metabolism ; *Crossing Over, Genetic ; DNA-Binding Proteins/genetics/*metabolism ; *Recombination, Genetic ; Telomere/*genetics/metabolism ; },
abstract = {During meiosis, interhomolog recombination produces crossovers and noncrossovers to create genetic diversity. Meiotic recombination frequency varies at multiple scales, with high subtelomeric recombination and suppressed centromeric recombination typical in many eukaryotes. During recombination, sister chromatids are tethered as loops to a polymerized chromosome axis, which, in plants, includes the ASY1 HORMA domain protein and REC8-cohesin complexes. Using chromatin immunoprecipitation, we show an ascending telomere-to-centromere gradient of ASY1 enrichment, which correlates strongly with REC8-cohesin ChIP-seq data. We mapped crossovers genome-wide in the absence of ASY1 and observe that telomere-led recombination becomes dominant. Surprisingly, asy1/+ heterozygotes also remodel crossovers toward subtelomeric regions at the expense of the pericentromeres. Telomeric recombination increases in asy1/+ occur in distal regions where ASY1 and REC8 ChIP enrichment are lowest in wild type. In wild type, the majority of crossovers show interference, meaning that they are more widely spaced along the chromosomes than expected by chance. To measure interference, we analyzed double crossover distances, MLH1 foci, and fluorescent pollen tetrads. Interestingly, while crossover interference is normal in asy1/+, it is undetectable in asy1 mutants, indicating that ASY1 is required to mediate crossover interference. Together, this is consistent with ASY1 antagonizing telomere-led recombination and promoting spaced crossover formation along the chromosomes via interference. These findings provide insight into the role of the meiotic axis in patterning recombination frequency within plant genomes.},
}
@article {pmid32497584,
year = {2020},
author = {Hagman, M and Werner, C and Kamp, K and Fristrup, B and Hornstrup, T and Meyer, T and Böhm, M and Laufs, U and Krustrup, P},
title = {Reduced telomere shortening in lifelong trained male football players compared to age-matched inactive controls.},
journal = {Progress in cardiovascular diseases},
volume = {63},
number = {6},
pages = {738-749},
doi = {10.1016/j.pcad.2020.05.009},
pmid = {32497584},
issn = {1873-1740},
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; *Athletes ; Case-Control Studies ; *Cellular Senescence ; Cross-Sectional Studies ; Humans ; Male ; *Physical Fitness ; *Soccer ; Telomere/*genetics ; *Telomere Shortening ; Young Adult ; },
abstract = {AIMS: Current evidence points to cellular anti-ageing effects of regular endurance training which may differ from other sport modalities. Effects of football training on markers of cell senescence have not been tested.<br><br>METHODS: One hundred and forty healthy, non-smoking men participated in the study, including young elite football players aged 18-30&#x202f;years (YF, n&#x202f;=&#x202f;35, 21.6&#x202f;&#xb1;&#x202f;0.5&#x202f;yrs), elderly football players aged 65-80&#x202f;years (EF, n&#x202f;=&#x202f;35, 71.9&#x202f;&#xb1;&#x202f;0.5&#x202f;yrs), untrained young controls (YC, n&#x202f;=&#x202f;35, 24.3&#x202f;&#xb1;&#x202f;0.6&#x202f;yrs) and elderly controls (EC, n&#x202f;=&#x202f;35, 70.1&#x202f;&#xb1;&#x202f;0.7&#x202f;yrs). Besides body composition (DXA scan), resting heart rate (RHR), blood pressure (BP) and selected fasting blood variables, mononuclear cells (MNC) were isolated. MNC telomere length was determined by flow-fluorescence in-situ hybridization (FISH) and polymerase chain reaction (PCR). Telomerase activity was quantified using telomerase repeat amplification protocol (TRAP) assay. mRNA expression of anti- and pro-senescent factors was measured with real-time PCR.<br><br>RESULTS: EF showed 2.5% higher (p&#x202f;=&#x202f;0.047) granulocyte telomere length and 1.3% higher (p&#x202f;=&#x202f;0.009) lymphocyte telomere length compared to EC. EF had 37% lower (p&#x202f;=&#x202f;0.025) mRNA expression of the pro-senescent factor p16 compared to EC. No significant between-group differences (p&#x202f;>&#x202f;0.050) were observed in telomerase activity or anti-senescent factors (TRF2, Ku70 and POT1a) for EF vs EC. YF had higher telomerase activity (4.2-fold, p&#x202f;=&#x202f;0.001), telomere repeat binding factor (TRF) 2 mRNA expression (3.2-fold, p&#x202f;=&#x202f;0.003), Ku70 mRNA expression (2.3-fold, p&#x202f;<&#x202f;0.001) and POT1a mRNA expression (2.2-fold, p&#x202f;=&#x202f;0.002) compared to YC, but there was no significant between-group difference in telomere length.<br><br>CONCLUSION: This study is the first cross-sectional, controlled trial showing effects of lifelong football participation on telomere shortening and senescence markers in circulating cells, suggesting that football induces cellular anti-senescence mechanisms implying positive long-term cardiovascular health effects.},
}
@article {pmid32497497,
year = {2020},
author = {Laprade, H and Querido, E and Smith, MJ and Guérit, D and Crimmins, H and Conomos, D and Pourret, E and Chartrand, P and Sfeir, A},
title = {Single-Molecule Imaging of Telomerase RNA Reveals a Recruitment-Retention Model for Telomere Elongation.},
journal = {Molecular cell},
volume = {79},
number = {1},
pages = {115-126.e6},
doi = {10.1016/j.molcel.2020.05.005},
pmid = {32497497},
issn = {1097-4164},
support = {PJT-162156//CIHR/Canada ; },
mesh = {Clustered Regularly Interspaced Short Palindromic Repeats ; Coiled Bodies/*metabolism ; DNA, Single-Stranded/genetics/*metabolism ; Gene Editing ; HeLa Cells ; Humans ; Mutation ; RNA/genetics/*metabolism ; Shelterin Complex ; Single Molecule Imaging/*methods ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Extension of telomeres is a critical step in the immortalization of cancer cells. This complex reaction requires proper spatiotemporal coordination of telomerase and telomeres and remains poorly understood at the cellular level. To understand how cancer cells execute this process, we combine CRISPR genome editing and MS2 RNA tagging to image single molecules of telomerase RNA (hTR). Real-time dynamics and photoactivation experiments of hTR in Cajal bodies (CBs) reveal that hTERT controls the exit of hTR from CBs. Single-molecule tracking of hTR at telomeres shows that TPP1-mediated recruitment results in short telomere-telomerase scanning interactions, and then base pairing between hTR and telomere ssDNA promotes long interactions required for stable telomerase retention. Interestingly, POT1 OB-fold mutations that result in abnormally long telomeres in cancers act by enhancing this retention step. In summary, single-molecule imaging unveils the life cycle of telomerase RNA and provides a framework to reveal how cancer-associated mutations mechanistically drive defects in telomere homeostasis.},
}
@article {pmid32496827,
year = {2020},
author = {Furtado, CLM and Iannetta, R and Ferriani, RA and Rosa E Silva, ACJS and Martinelli, CE and Calado, RT and Dos Reis, RM},
title = {Telomere length is not altered in girls with idiopathic central precocious puberty treated with a GnRH analog - leuprolide acetate.},
journal = {Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology},
volume = {36},
number = {12},
pages = {1119-1123},
doi = {10.1080/09513590.2020.1770212},
pmid = {32496827},
issn = {1473-0766},
mesh = {Adolescent ; Age Factors ; Body Composition ; Body Mass Index ; Body Weight ; Case-Control Studies ; Child ; Electric Impedance ; Female ; Gonadotropin-Releasing Hormone/*analogs &amp; derivatives ; Humans ; Insulin/blood ; Insulin Resistance ; Leuprolide/*therapeutic use ; Puberty, Precocious/drug therapy/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; Young Adult ; },
abstract = {BACKGROUND: Idiopathic central precocious puberty (iCPP) presents a disproportionate advancement of bone age and maturation, as well as metabolic and endocrinological changes that may be related to effects on telomere biology.<br><br>OBJECTIVE: To investigate the telomere length in iCPP girls treated with GnRHa.<br><br>STUDY DESIGN: Observational case-control study with 85 girls, including 45 iCPP treated with GnRHa and 40 controls. It was analyzed age, height, weight and body mass index (BMI), insulin, triglycerides, testosterone, insulin resistance by HOMA, and telomere length by real-time PCR. Statistical analyses were determined by Wilcoxon test and Spearman correlation was carried out.<br><br>RESULTS: Weight, BMI, insulin level and HOMA index were higher in the iCPP than in the control group (p&#x2009;<&#x2009;.01); without difference between mean ages. The telomere length did not differ between iCPP and control group. However, a negative correlation was observed between the telomere length and age in iCPP (p&#x2009;=&#x2009;.0009) and control group (p&#x2009;=&#x2009;.014), and weight in the iCPP (p&#x2009;=&#x2009;.017).<br><br>CONCLUSIONS: We did not observe any difference in the telomere length in the iCPP and control group. Even though, some characteristics of the disease, such as increased weight and body fat, negatively influence the telomere biology.},
}
@article {pmid32489697,
year = {2020},
author = {Zhang, S and Li, R and Yang, Y and Chen, Y and Yang, S and Li, J and Wu, C and Kong, T and Liu, T and Cai, J and Fu, L and Zhao, Y and Hui, R and Zhang, W},
title = {Longitudinal Association of Telomere Attrition with the Effects of Antihypertensive Treatment and Blood Pressure Lowering.},
journal = {Aging and disease},
volume = {11},
number = {3},
pages = {494-508},
pmid = {32489697},
issn = {2152-5250},
abstract = {Leukocytes telomere length has been associated with hypertension, but, whether longitudinal telomeres change could serve as a useful predictive tool in hypertension remains uncertain. This study aimed to examine the longitudinal trajectory of leukocytes telomere length in a population-based prospective study of 1,108 individuals with hypertension. Leukocytes telomere length were measured at baseline and again after a median 2.2 (range 1.5-2.4) years of follow-up. Age as an independent predictor was inversely associated with baseline telomeres and follow-up telomeres. Annual telomere attrition rate was calculated as (follow-up telomeres-baseline telomeres)/follow-up years, and participants were categorized into the shorten and the lengthen groups. Results showed that telomere lengthening was significantly correlated with decreased systolic blood pressure (SBP) (β=-3.28; P=0.02) and pulse pressure (PP) (β=-2.53; P=0.02), and the differences were respectively -3.3 mmHg (95%CI, -6.2 to -0.3; P=0.03) in ∆SBP and -2.4 mmHg (95%CI, -4.9 to -0.1; P=0.04) in ∆PP between two groups after adjustment for vascular risk factors and baseline blood pressures. When stratified by age and gender, the correlations were observed in women and patients ≤60 years. Furthermore, among patients using calcium channel blocker (CCB) and angiotensin receptor blocker (ARB), those with telomeres lengthening showed a significantly lower level of ∆SBP and ∆PP. There was no correlation between telomere attrition and incidence of cardiovascular events. Our data indicated that increased telomere length of leukocytes was associated with decreased SBP and PP, particularly for patients who received CCB and ARB, supporting that telomere attrition may provide new sight in clinical intervention for hypertension.},
}
@article {pmid32488018,
year = {2020},
author = {Nichuguti, N and Fujiwara, H},
title = {Essential factors involved in the precise targeting and insertion of telomere-specific non-LTR retrotransposon, SART1Bm.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {8963},
pmid = {32488018},
issn = {2045-2322},
mesh = {3' Untranslated Regions ; Animals ; Base Sequence ; Bombyx/genetics ; Cloning, Molecular/*methods ; Repetitive Sequences, Nucleic Acid ; Retroelements/*genetics/physiology ; Telomere/metabolism ; Telomere Homeostasis/*genetics/physiology ; Terminal Repeat Sequences/genetics/physiology ; },
abstract = {Telomere length maintenance is essential for most eukaryotes to ensure genome stability and integrity. A non-long terminal repeat (LTR) retrotransposon, SART1Bm, targets telomeric repeats (TTAGG)n of the silkworm Bombyx mori and is presumably involved in telomere length maintenance. However, how many telomeric repeats are required for its retrotransposition and how reverse transcription is initiated at the target site are not well understood. Here, using an ex vivo and trans-in vivo recombinant baculovirus retrotransposition system, we demonstrated that SART1Bm requires at least three (TTAGG) telomeric repeats and a longer poly(A) tail for its accurate retrotransposition. We found that SART1Bm retrotransposed only in the third (TTAGG) tract of three repeats and that the A residue of the (TTAGG) unit was essential for its retrotransposition. Interestingly, SART1Bm also retrotransposed into telomeric repeats of other species, such as human (TTAGGG)n repeats, albeit with low retrotransposition efficiency. We further showed that the reverse transcription of SART1Bm occurred inaccurately at the internal site of the 3' untranslated region (UTR) when using a short poly(A) tail but at the accurate site when using a longer poly(A) tail. These findings promote our understanding of the general mechanisms of site-specific retrotransposition and aid the development of a site-specific gene knock-in tool.},
}
@article {pmid32487251,
year = {2020},
author = {Nanthatanti, N and Tantiworawit, A and Piriyakhuntorn, P and Rattanathammethee, T and Hantrakool, S and Chai-Adisaksopha, C and Rattarittamrong, E and Norasetthada, L and Tuntiwechapikul, W and Fanhchaksai, K and Charoenkwan, P and Kumfu, S and Chattipakorn, N},
title = {Leukocyte telomere length in patients with transfusion-dependent thalassemia.},
journal = {BMC medical genomics},
volume = {13},
number = {1},
pages = {73},
pmid = {32487251},
issn = {1755-8794},
support = {FUND-2559-03967//Chiang Mai University/International ; },
mesh = {Adolescent ; Adult ; Blood Transfusion/*methods ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/metabolism/*pathology ; Male ; Middle Aged ; *Telomere Shortening ; Thalassemia/*genetics/*pathology/therapy ; Young Adult ; },
abstract = {BACKGROUND: Thalassemia is a hereditary hemolytic anemia with a severity ranging from mild, non-transfusion dependent to severe chronic anemia requiring lifelong transfusion. Transfusional iron overload is a major complication in patients with transfusion-dependent thalassemia (TDT). Telomeres are sequences of nucleotides forming the end caps of chromosomes that act as a DNA repair system. Iron overload in thalassemia can cause increased oxidative stress which leads to cellular damage and senescence. This may result in telomere length shortening. The degree of telomere length shortening may reflect the severity of thalassemia.<br><br>METHODS: This research aimed to study the leukocyte telomere length in patients with TDT in comparison to non-thalassemic individuals and to identify the clinical and laboratory parameters that are associated with telomere length. We conducted a cross-sectional study in patients with TDT aged &#x2265;18&#x2009;years. Leukocyte telomere length was measured by real-time quantitative PCR.<br><br>RESULTS: Sixty-five patients with TDT were enrolled onto the study. There were 37 female patients (54.4%). The median age was 27 (18-57) years, and mean pre-transfusion hemoglobin level was 7.1 (&#xb1; 1.07) g/dL. The mean telomere to single copy gene (T/S) ratios of patients with TDT and the controls were 0.72&#x2009;&#xb1;&#x2009;0.18 and 0.99&#x2009;&#xb1;&#x2009;0.25, respectively (p&#x2009;<&#x2009;0.0001). There was a significant correlation between the T/S ratio and age (p&#x2009;=&#x2009;0.0002), and hemoglobin level (p&#x2009;=&#x2009;0.044). There was no correlation between telomere length and other factors.<br><br>CONCLUSIONS: Our study showed that TDT patients had shorter leukocyte telomere length compared with controls. Leukocyte telomere shortening in TDT was an aging-dependent process and associated with lower hemoglobin level.},
}
@article {pmid32486379,
year = {2020},
author = {Toupance, S and Stathopoulou, MG and Petrelis, AM and Gorenjak, V and Labat, C and Lai, TP and Visvikis-Siest, S and Benetos, A},
title = {TERC Variants Associated with Short Leukocyte Telomeres: Implication of Higher Early Life Leukocyte Telomere Attrition as Assessed by the Blood-and-Muscle Model.},
journal = {Cells},
volume = {9},
number = {6},
pages = {},
pmid = {32486379},
issn = {2073-4409},
mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; *Genetic Variation ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Muscles/*metabolism ; Polymorphism, Single Nucleotide/genetics ; RNA/*genetics ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Homeostasis ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {Short leukocyte telomere length (LTL) is associated with atherosclerotic cardiovascular disease (ASCVD). Mendelian randomisation studies, using single nucleotide polymorphisms (SNPs) associated with short LTL, infer a causal role of LTL in ASCVD. Recent results, using the blood-and-muscle model, indicate that higher early life LTL attrition, as estimated by the ratio between LTL and skeletal muscle telomere length (MTL), rather than short LTL at conception, as estimated by MTL, should be responsible of the ASCVD-LTL connection. We combined LTL and MTL measurements and SNPs profiling in 402 individuals to determine if 15 SNPs classically described as associated with short LTL at adult age were rather responsible for higher LTL attrition during early life than for shorter LTL at birth. Two of these SNPs (rs12696304 and rs10936599) were associated with LTL in our cohort (p = 0.027 and p = 0.025, respectively). These SNPs, both located on the TERC gene, were associated with the LTL/MTL ratio (p = 0.007 and p = 0.037, respectively), but not with MTL (p = 0.78 and p = 0.32 respectively). These results suggest that SNPs located on genes coding for telomere maintenance proteins may contribute to a higher LTL attrition during the highly replicative first years of life and have an impact later on the development of ASCVD.},
}
@article {pmid32482456,
year = {2020},
author = {Brenner, KA and Nandakumar, J},
title = {Small Molecules Restore Telomeres in Patient Stem Cells.},
journal = {Trends in pharmacological sciences},
volume = {41},
number = {8},
pages = {506-508},
pmid = {32482456},
issn = {1873-3735},
support = {R01 AG050509/AG/NIA NIH HHS/United States ; R01 GM120094/GM/NIGMS NIH HHS/United States ; },
mesh = {*Dyskeratosis Congenita ; Humans ; RNA ; Stem Cells/metabolism ; *Telomerase/genetics/metabolism ; Telomere/metabolism ; },
abstract = {Genetic defects in telomere maintenance result in stem cell exhaustion and a spectrum of telomere biology diseases. Systemic treatments beyond organ transplantation are lacking for these diseases. Nagpal and colleagues identified small molecules that restore telomere maintenance in patient-derived stem cells, offering a promising therapy for telomere biology diseases.},
}
@article {pmid32479352,
year = {2020},
author = {Thierry, AD},
title = {Association between telomere length and neighborhood characteristics by race and region in US midlife and older adults.},
journal = {Health &amp; place},
volume = {62},
number = {},
pages = {102272},
pmid = {32479352},
issn = {1873-2054},
support = {P60 AG011268/AG/NIA NIH HHS/United States ; T32 AG000029/AG/NIA NIH HHS/United States ; },
mesh = {Black or African American/statistics &amp; numerical data ; Aged ; Aged, 80 and over ; Aging/*physiology ; Cooperative Behavior ; Female ; *Health Status Disparities ; Health Surveys ; Humans ; Male ; Middle Aged ; Racial Groups/*statistics &amp; numerical data ; Residence Characteristics/*statistics &amp; numerical data ; Telomere/*physiology ; United States ; White People/statistics &amp; numerical data ; },
abstract = {Disadvantaged neighborhoods are correlated with worse health outcomes, particularly among US Blacks. However, less is known about the link between neighborhood characteristics and biomarkers of cellular age, such as telomere length (TL), which may be implicated in racial health inequities. Moreover, this relationship may vary across US region given patterns of racial segregation across the US. Therefore, this study analyzed 2008 Health and Retirement Study data on 3,869 US-born white and Black adults >50 years old to examine race differences in the relationship between salivary TL and (1) neighborhood safety, cleanliness, and social cohesion and (2) interactions between neighborhood characteristics and US region. Neighborhood characteristics were not associated with TL in whites. However, significant associations were found among Blacks with variation by region. Blacks living in less clean neighborhoods in the Northeast (b = -0.03, SE = 0.01, p < 0.05), Midwest (b = -0.04, SE = 0.01, p < 0.01), and South (b = -0.05, SE = 0.01, p < 0.01) as well as those reporting less neighborhood safety and social cohesion in the Midwest (b = -0.03, SE = 0.02, p < 0.05 and b = -0.03, SE = 0.01, p < 0.05) and South (b = -0.03, SE = 0.01, p < 0.05 for both characteristics) had shorter TL than Blacks in the West. Therefore, exposure to neighborhood level historical discrimination and neglect may be detrimental to TL in Blacks. Future research should further examine how neighborhoods contribute to aging disparities.},
}
@article {pmid32474316,
year = {2020},
author = {Lee, AG and Cowell, W and Kannan, S and Ganguri, HB and Nentin, F and Wilson, A and Coull, BA and Wright, RO and Baccarelli, A and Bollati, V and Wright, RJ},
title = {Prenatal particulate air pollution and newborn telomere length: Effect modification by maternal antioxidant intakes and infant sex.},
journal = {Environmental research},
volume = {187},
number = {},
pages = {109707},
pmid = {32474316},
issn = {1096-0953},
support = {R21 ES021318/ES/NIEHS NIH HHS/United States ; UG3 OD023337/OD/NIH HHS/United States ; P30 ES023515/ES/NIEHS NIH HHS/United States ; T32 HD049311/HD/NICHD NIH HHS/United States ; K23 HL135349/HL/NHLBI NIH HHS/United States ; UH3 OD023337/OD/NIH HHS/United States ; R01 HL095606/HL/NHLBI NIH HHS/United States ; R01 HL114396/HL/NHLBI NIH HHS/United States ; },
mesh = {*Air Pollutants/analysis ; *Air Pollution/analysis ; Antioxidants ; Bayes Theorem ; Child ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Maternal Exposure/adverse effects ; Particulate Matter/analysis ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Telomere ; },
abstract = {BACKGROUND: Evidence links gestational exposure to particulate matter with an aerodynamic diameter of less than 2.5 μm (PM2.5) with changes in leukocyte telomere length in cord blood with some studies showing sex-specific effects. PM2.5 exposure in utero increases oxidative stress, which can impact telomere biology. Thus, maternal antioxidant intakes may also modify the particulate air pollution effects.<br><br>METHODS: We examined associations among prenatal PM2.5 exposure and newborn relative leukocyte telomere length (rLTL), and the modifying effects of maternal antioxidant intake and infant sex. We estimated daily PM2.5 exposures over gestation using a validated spatiotemporally resolved satellite-based model. Maternal dietary and supplemental antioxidant intakes over the prior three months were ascertained during the second trimester using the modified Block98 food frequency questionnaire; high and low antioxidant intakes were categorized based on a median split. We employed Bayesian distributed lag interaction models (BDLIMs) to identify both sensitive windows of exposure and cumulative effect estimates for prenatal PM2.5 exposure on newborn rLTL, and to examine effect modification by maternal antioxidant intakes. A 3-way interaction between PM2.5, maternal antioxidant intake and infant sex was also explored.<br><br>RESULTS: For the main effect of PM2.5, BDLIMs identified a sensitive window at 12-20 weeks gestation for the association between increased prenatal PM2.5 exposure and shorter newborn rLTL and a cumulative effect of PM2.5 over gestation on newborn telomere length [cumulative effect estimate (CEE)&#xa0;=&#xa0;-0.29 (95% CI -0.49 to -0.10) per 1&#x3bc;g/m[3] increase in PM2.5]. In models examining maternal antioxidant intake effects, BDLIMs found that children born to mothers reporting low antioxidant intakes were most vulnerable [CEE of low maternal antioxidant intake&#xa0;=&#xa0;-0.31 (95% CI -0.55 to -0.06) vs high maternal antioxidant intake&#xa0;=&#xa0;-0.07 (95% CI -0.34 to 0.17) per 1&#x3bc;g/m[3] increase in PM2.5]. In exploratory models examining effect modification by both maternal antioxidant intakes and infant sex, the cumulative effect remained significant only in boys whose mothers reported low antioxidant intakes [CEE&#xa0;=&#xa0;-0.38 (95% CI -0.80 to -0.004)]; no sensitive windows were identified in any group.<br><br>CONCLUSIONS: Prenatal PM2.5 exposure in mid-gestation was associated with reduced infant telomere length. Higher maternal antioxidant intakes mitigated these effects.},
}
@article {pmid32472076,
year = {2020},
author = {de Krijger, I and van der Torre, J and Peuscher, MH and Eder, M and Jacobs, JJL},
title = {H3K36 dimethylation by MMSET promotes classical non-homologous end-joining at unprotected telomeres.},
journal = {Oncogene},
volume = {39},
number = {25},
pages = {4814-4827},
pmid = {32472076},
issn = {1476-5594},
mesh = {Animals ; Cells, Cultured ; DNA Breaks, Double-Stranded ; *DNA End-Joining Repair ; Embryo, Mammalian/cytology ; Fibroblasts/cytology/metabolism ; HEK293 Cells ; Histone-Lysine N-Methyltransferase/genetics/*metabolism ; Histones/*metabolism ; Humans ; Lysine/*metabolism ; Methylation ; Mice, Knockout ; RNA Interference ; Repressor Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {The epigenetic environment plays an important role in DNA damage recognition and repair, both at DNA double-strand breaks and at deprotected telomeres. To increase understanding on how DNA damage responses (DDR) at deprotected telomeres are regulated by modification and remodeling of telomeric chromatin we screened 38 methyltransferases for their ability to promote telomere dysfunction-induced genomic instability. As top hit we identified MMSET, a histone methyltransferase (HMT) causally linked to multiple myeloma and Wolf-Hirschhorn syndrome. We show that MMSET promotes non-homologous end-joining (NHEJ) at deprotected telomeres through Ligase4-dependent classical NHEJ, and does not contribute to Ligase3-dependent alternative NHEJ. Moreover, we show that this is dependent on the catalytic activity of MMSET, enabled by its SET-domain. Indeed, in absence of MMSET H3K36-dimethylation (H3K36me2) decreases, both globally and at subtelomeric regions. Interestingly, the level of MMSET-dependent H3K36me2 directly correlates with NHEJ-efficiency. We show that MMSET depletion does not impact on recognition of deprotected telomeres by the DDR-machinery or on subsequent recruitment of DDR-factors acting upstream or at the level of DNA repair pathway choice. Our data are most consistent with an important role for H3K36me2 in more downstream steps of the DNA repair process. Moreover, we find additional H3K36me2-specific HMTs to contribute to NHEJ at deprotected telomeres, further emphasizing the importance of H3K36me2 in DNA repair.},
}
@article {pmid32469808,
year = {2020},
author = {He, S and Li, J and Wang, Z and Wang, L and Liu, L and Sun, X and Shohaib, SA and Koenig, HG},
title = {Early-life exposure to famine and late-life depression: Does leukocyte telomere length mediate the association?.},
journal = {Journal of affective disorders},
volume = {274},
number = {},
pages = {223-228},
doi = {10.1016/j.jad.2020.05.082},
pmid = {32469808},
issn = {1573-2517},
mesh = {Adult ; China/epidemiology ; Cross-Sectional Studies ; Depression/epidemiology ; Famine ; Female ; Humans ; Leukocytes ; Middle Aged ; Pregnancy ; *Prenatal Exposure Delayed Effects ; *Starvation ; Telomere ; },
abstract = {BACKGROUND: A positive association between early-life famine exposure and depression has been demonstrated. However, the mechanisms by which famine exposure in early life leads to late-life depression remains unclear. The present study examines the impact of leukocyte telomere length (LTL) and/or religiosity on the relationship between early-life famine exposure and late-life depression in a Chinese minority sample.<br><br>METHODS: A cross-sectional study of community-dwelling adults aged 55 or older was conducted in the Ningxia province of western China from 2013 to 2016. Multivariate ordinal logistic regression was used to examine the association between famine exposure and depression status, and a series mediation model was constructed to identify the mediation role of LTL and religiosity.<br><br>RESULTS: Compared with famine exposure during adulthood, fetal famine exposure was associated with a higher risk of late-life depression (adjusted odds ratio of 3.17, 95% CI: 1.36-7.38). A cumulative effect of fetal famine exposure on the risk of late-life depression was observed. Participants born in 1961 (the third year of the famine) had the strongest association with late-life depression. LTL played a mediating role in the association between famine exposure and depression which accounted for 21% of the total effect.<br><br>LIMITATIONS: The cross-sectional design prevents causal inferences regarding the relationships between famine and depression.<br><br>CONCLUSIONS: Fetal famine exposure was associated with an increased risk of late-life depression in a Chinese minority community-dwelling population. Telomere shortening partially mediated this association.},
}
@article {pmid32468974,
year = {2021},
author = {Savoy, CD and Schmidt, LA and McGowan, PO and Saigal, S and Van Lieshout, RJ},
title = {Extremely low birth weight influences the relationship between stress and telomere length in adulthood.},
journal = {Journal of developmental origins of health and disease},
volume = {12},
number = {2},
pages = {328-334},
doi = {10.1017/S2040174420000409},
pmid = {32468974},
issn = {2040-1752},
support = {TMH-103145//CIHR/Canada ; },
mesh = {Adult ; Female ; Humans ; Hydrocortisone/*metabolism ; Infant, Extremely Low Birth Weight/*physiology ; Infant, Newborn ; Longitudinal Studies ; Male ; Saliva/*metabolism ; *Stress, Physiological ; *Telomere Homeostasis ; Young Adult ; },
abstract = {This study examined the link between two biological markers of stress vulnerability at 22-26 years of age and telomere length at 30-35 among extremely low birth weight (ELBW; <1000 g) survivors and normal birth weight (NBW; >2500 g) control participants. Sixteen ELBW and 22 NBW participants provided baseline afternoon salivary cortisol samples and resting frontal electroencephalogram (EEG) alpha asymmetry data at 22-26 years. Buccal cells were assayed for telomere length at 30-35 years. Analyses controlled for sex, postnatal steroid exposure, childhood socioeconomic status, time of cortisol sample collection, and body mass index at 22-26 years. Salivary cortisol and frontal asymmetry at age 22-26 independently predicted telomere length at age 30-35, such that relatively higher cortisol and greater relative right frontal asymmetry at rest predicted telomere shortening among NBW controls, but not among ELBW survivors. However, similar associations were not noted in ELBW survivors, suggesting that ELBW survivors may have different mechanisms of stress coping as a result of their early-life exposures. These findings offer preliminary evidence in support of the role of stress in the genesis of cellular senescence at least among those born at NBW, but that these links may differ in those born preterm.},
}
@article {pmid32468620,
year = {2020},
author = {Park, MK and Lee, JC and Lee, JW and Kang, S and Kim, J and Park, MH and Hwang, SJ and Lee, M},
title = {Effects of fermented rice bran on DEN-induced oxidative stress in mice: GSTP1, LINE-1 methylation, and telomere length ratio.},
journal = {Journal of food biochemistry},
volume = {44},
number = {7},
pages = {e13274},
doi = {10.1111/jfbc.13274},
pmid = {32468620},
issn = {1745-4514},
mesh = {Animals ; *Glutathione Transferase/metabolism ; Methylation ; Mice ; *Oryza ; Oxidative Stress ; Telomere/metabolism ; },
abstract = {N-diethylnitrosamine (DEN), a well-known carcinogen, not only induces excessive reactive oxygen species but also suppresses DNA methylation. This study investigated the effect of fermented rice bran (FRB) treatment on DEN-induced oxidative stress through DNA methylation and telomere length analysis. To evaluate the potential protective role of FRB in oxidative stress, two different doses of FRB, DEN, and their combination were administered to mice that were preadapted or not to FRB. Glutathione-S-transferase P1 (GSTP1) methylation levels significantly decreased at 2 and 24 hr after FRB and DEN co-administration in mice with and without pre-adaptation. Moreover, GSTP1 mRNA was upregulated under DEN-induced oxidative stress. Furthermore, changes in long interspersed nuclear element-1 methylation were observed from the viewpoint of genomic instability. In addition, FRB preadapted mice displayed a lower telomere length ratio than the non-adapted mice, suggesting that FRB adaptation offers advantages over the non-adapted conditions in terms of inflammation suppression. PRACTICAL APPLICATIONS: DEN induces excessive ROS, which is associated with oxidative stress on DNA and other cellular components, resulting in inflammation. This study shows that FRB may alleviate DEN-triggered oxidative stress, based on changes in GSTP1, LINE-1 methylation, and telomere length ratios, thereby, revealing the potential of dietary intervention during inflammation. Furthermore, this study furthers the current understanding of DNA methylation mechanisms underlying the antioxidant and anti-inflammatory effects of functional food components. These results indicate that dietary inclusion of FRB may help decrease oxidative DNA damage and its associated inflammation at early stages of a disease.},
}
@article {pmid32467172,
year = {2020},
author = {Wu, J and Crowe, DL},
title = {Telomere DNA Damage Signaling Regulates Prostate Cancer Tumorigenesis.},
journal = {Molecular cancer research : MCR},
volume = {18},
number = {9},
pages = {1326-1339},
doi = {10.1158/1541-7786.MCR-19-1129},
pmid = {32467172},
issn = {1557-3125},
mesh = {Animals ; Carcinogenesis ; DNA Damage/*genetics ; Disease Models, Animal ; Humans ; Male ; Mice ; Signal Transduction ; Telomere/*metabolism ; },
abstract = {Telomere shortening has been demonstrated in benign prostatic hypertrophy (BPH), which is associated with prostate epithelial cell senescence. Telomere shortening is the most frequently observed genetic alteration in prostatic intraepithelial neoplasia, and is associated with poor clinical outcomes in prostate cancer. Gene expression database analysis revealed decreased TRF2 expression during malignant progression of the prostate gland. We reasoned that reduced TRF2 expression in prostate epithelium, by activating the telomere DNA damage response, would allow us to model both benign and malignant prostate disease. Prostate glands with reduced epithelial TRF2 expression developed age- and p53-dependent hypertrophy, senescence, ductal dilation, and smooth muscle hyperplasia similar to human BPH. Prostate tumors with reduced TRF2 expression were classified as high-grade androgen receptor-negative adenocarcinomas, which exhibited decreased latency, increased proliferation, and distant metastases. Prostate cancer stem cells with reduced TRF2 expression were highly tumorigenic and maintained telomeres both by telomerase and alternative lengthening (ALT). Telomerase inhibition in prostate glands with reduced TRF2 expression produced significant reduction in prostate tumor incidence by halting progression at intraepithelial neoplasia (PIN). These lesions were highly differentiated, exhibited low proliferation index, and high apoptotic cell fraction. Prostate tumors with reduced TRF2 expression and telomerase inhibition failed to metastasize and did not exhibit ALT. IMPLICATIONS: Our results demonstrate that the telomere DNA damage response regulates BPH, PIN, and prostate cancer and may be therapeutically manipulated to prevent prostate cancer progression.},
}
@article {pmid32464172,
year = {2020},
author = {Kosebent, EG and Uysal, F and Ozturk, S},
title = {The altered expression of telomerase components and telomere-linked proteins may associate with ovarian aging in mouse.},
journal = {Experimental gerontology},
volume = {138},
number = {},
pages = {110975},
doi = {10.1016/j.exger.2020.110975},
pmid = {32464172},
issn = {1873-6815},
mesh = {Aging/genetics ; Animals ; Female ; Mice ; Ovary ; *Telomerase/genetics/metabolism ; *Telomere/genetics/metabolism ; Telomere Shortening ; },
abstract = {Telomeres are repetitive DNA sequences localized at the ends of eukaryotic chromosomes, and shorten during ovarian aging. The molecular background of telomere shortening during ovarian aging is not fully understood. As the telomerase components (TERT and Terc) and telomere-associated proteins (TRF1, TRF2, and POT1a) play key roles in the elongation and maintenance of telomeres, we aimed to determine their spatial and temporal expression and cellular localization in the mouse ovaries at the different ages of postnatal life. For this purpose, five groups were generated based on the ovarian histological changes in the postnatal mouse ovaries as follows: young (1- and 2-week-old; n = 3 from each week), prepubertal (3- and 4-week-old; n = 3 from each week), pubertal (5- and 6-week-old; n = 3 from each week), postpubertal (16- and 18-week-old; n = 3 from each week) and aged (52-, 60- and 72-week-old, n = 3 from each week). We found significant changes for the Tert, Terc, Trf1, Trf2, and Pot1a genes expression in the postnatal ovary groups from young to aged (P < 0.05) as well as in the follicles from primordial to antral stages and their oocytes and granulosa cells. Also, we have detected gradually decreasing telomere length from young to aged groups (P < 0.001). In conclusion, the altered Tert, Terc, Trf2, and Pot1a genes expression compatible with telomere shortening may be associated with ovarian aging.},
}
@article {pmid32462419,
year = {2020},
author = {Benati, M and Montagnana, M and Danese, E and Mazzon, M and Paviati, E and Garzon, S and Laganà, AS and Casarin, J and Giudici, S and Raffaelli, R and Ghezzi, F and Franchi, M and Lippi, G},
title = {Aberrant Telomere Length in Circulating Cell-Free DNA as Possible Blood Biomarker with High Diagnostic Performance in Endometrial Cancer.},
journal = {Pathology oncology research : POR},
volume = {26},
number = {4},
pages = {2281-2289},
pmid = {32462419},
issn = {1532-2807},
mesh = {Aged ; Biomarkers, Tumor/blood/*genetics ; Case-Control Studies ; Cell-Free Nucleic Acids/blood/*genetics ; Combined Modality Therapy ; DNA, Neoplasm/blood/*genetics ; Endometrial Neoplasms/*diagnosis/genetics/therapy ; Female ; Follow-Up Studies ; Gene Dosage ; Humans ; Middle Aged ; Prognosis ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {To investigate the diagnostic performance of relative telomere length (RTL) in cell-free DNA (cfDNA) for endometrioid endometrial cancer (EC). We measured RTL in cfDNA of 40 EC patients (65 ± 12 years) and 31 healthy controls (HC) (63 ± 13 years), excluding in both groups other oncologic and severe non-oncologic diseases to limit confounders. Circulating cfDNA was extracted from serum using the QIAamp DNA Blood Mini kit (Qiagen, Hilden, Germany). After the quantitative real-time polymerase chain reaction, telomere repeat copy number to single-gene copy number ratio was calculated. RTL in cfDNA was found to be significantly lower in EC patients than in HC (p < 0.0001). The diagnostic performance of cfDNA RTL was estimated with receiver operating characteristics (ROC) curve analysis, which showed a diagnostic accuracy for EC of 0.87 (95% CI: 0.79-0.95, p < 0.0001). The cutoff cfDNA RTL value of 2.505 (T/S copy ratio) reported a sensitivity of 80.0% (95% CI: 64.35-90.95) and a specificity of 80.65% (95% CI: 62.53-92.55). Significant differences of RTL among EC stages or grades (p = 0.85 and p = 0.89, respectively) were not observed. Our results suggest that cfDNA RTL analysis may be a diagnostic tool for EC detection since the early stage, whilst its diagnostic performance seems unsatisfactory for cancer progression, staging, and grading. However, further studies are needed to confirm these preliminary findings. In particular, future investigations should focus on high-risk patients (such as those with atypical endometrial hyperplasia) that may benefit from this tool, because TL shortening is not specific for EC and is influenced by other oncologic and non-oncologic diseases.},
}
@article {pmid32458497,
year = {2020},
author = {Viblanc, VA and Schull, Q and Stier, A and Durand, L and Lefol, E and Robin, JP and Zahn, S and Bize, P and Criscuolo, F},
title = {Foster rather than biological parental telomere length predicts offspring survival and telomere length in king penguins.},
journal = {Molecular ecology},
volume = {29},
number = {16},
pages = {3155-3167},
doi = {10.1111/mec.15485},
pmid = {32458497},
issn = {1365-294X},
mesh = {Animals ; Chickens ; Female ; Humans ; Mothers ; Reproduction/genetics ; *Spheniscidae/genetics ; *Telomere/genetics ; },
abstract = {Because telomere length and dynamics relate to individual growth, reproductive investment and survival, telomeres have emerged as possible markers of individual quality. Here, we tested the hypothesis that, in species with parental care, parental telomere length can be a marker of parental quality that predicts offspring phenotype and survival. In king penguins (Aptenodytes patagonicus), we experimentally swapped the single egg of 66 breeding pairs just after egg laying to disentangle the contribution of prelaying parental quality (e.g., genetics, investment in the egg) and/or postlaying parental quality (e.g., incubation, postnatal feeding rate) on offspring growth, telomere length and survival. Parental quality was estimated through the joint effects of biological and foster parent telomere length on offspring traits, both soon after hatching (day 10) and at the end of the prewinter growth period (day 105). We expected that offspring traits would be mostly related to the telomere lengths (i.e., quality) of biological parents at day 10 and to the telomere lengths of foster parents at day 105. Results show that chick survival up to 10 days was negatively related to biological fathers' telomere length, whereas survival up to 105 days was positively related to foster fathers' telomere lengths. Chick growth was not related to either biological or foster parents' telomere length. Chick telomere length was positively related to foster mothers' telomere length at both 10 and 105 days. Overall, our study shows that, in a species with biparental care, parents' telomere length is foremost a proxy of postlaying parental care quality, supporting the "telomere - parental quality hypothesis."},
}
@article {pmid32454945,
year = {2020},
author = {Lyu, L and He, S and Zhang, H and Li, W and Zeng, J and Ping, F and Li, YX},
title = {TNFα Mediates the Interaction of Telomeres and Mitochondria Induced by Hyperglycemia: A Rural Community-Based Cross-Sectional Study.},
journal = {Oxidative medicine and cellular longevity},
volume = {2020},
number = {},
pages = {8235873},
pmid = {32454945},
issn = {1942-0994},
mesh = {Biomarkers/metabolism ; Blood Glucose/metabolism ; Cross-Sectional Studies ; DNA, Mitochondrial/genetics ; Fasting/blood ; Female ; Glucose Tolerance Test ; Glycated Hemoglobin/metabolism ; Humans ; Hyperglycemia/blood/*metabolism ; Inflammation Mediators/metabolism ; Interleukin-6/metabolism ; Leukocytes/metabolism ; Male ; Middle Aged ; Mitochondria/*metabolism ; *Rural Population ; Superoxide Dismutase/metabolism ; Telomere/*metabolism ; Telomere Shortening ; Tumor Necrosis Factor-alpha/*metabolism ; },
abstract = {This study is aimed at evaluating the relationship between leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) in a noninterventional rural community of China with different glucose tolerance statuses. In addition, we investigate whether the indicators of oxidative stress and inflammation were involved and identify mediators among them. A total of 450 subjects in rural China were included and divided into two groups according to a 75 g oral glucose tolerance test (OGTT): the abnormal glucose metabolism (AGM, n = 257, 57.1%) group and the normal glucose tolerance (NGT, n = 193, 42.9%) group. Indicators of oxidative stress (superoxide dismutase (SOD) and glutathione reductase (GR)) and inflammatory indices (tumor necrosis factor α (TNFα) and interleukin-6 (IL-6)) were all determined by ELISA. LTL and mtDNAcn were measured using a real-time PCR assay. Linear regressions were used to adjust for covariates that might affect the relationship between LTL and mtDNAcn. Mediation analyses were utilized to evaluate the mediators. In the AGM, LTL was correlated with mtDNAcn (r = 0.214, p = 0.001), but no correlation was found in the NGT. The association between LTL and mtDNAcn was weakened after adjusting for inflammatory factors in the AGM (p = 0.087). LTL and mtDNAcn were both inversely related to HbA1c, IL-6, TNFα, and SOD activity. Mediation analysis demonstrated that TNFα was a significant mediator in the telomere-mitochondrial interactome in the AGM. This result suggests that inflammation and oxidative stress may play a vital role in telomere shortening as well as mitochondrial dysfunction. In the subjects with hyperglycemia, a significant positive correlation is observed between LTL and mtDNAcn, which is probably mediated by TNFα. TNFα may be considered a potential therapeutic target against aging-related disease in hyperglycemia.},
}
@article {pmid32447915,
year = {2020},
author = {Gao, YY and Guo, JY and Zhang, Z and Han, ZC and Lei, LJ and Sun, CM and Huang, JJ and Wang, T},
title = {[Relationship of telomere length, mitochondrial DNA copy number of peripheral blood with hypertension in coal miners].},
journal = {Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi},
volume = {41},
number = {5},
pages = {727-732},
doi = {10.3760/cma.j.cn112338-20190930-00714},
pmid = {32447915},
issn = {0254-6450},
support = {81872701//National Natural Science Foundation of China/ ; 2016JD24//Shanxi Provincial Foundation For Talent Training in Joint Postgraduate Training Base/ ; },
mesh = {Case-Control Studies ; Coal ; DNA Copy Number Variations ; *DNA, Mitochondrial ; Humans ; *Hypertension/genetics ; Telomere ; },
abstract = {Objective: To explore the relationship of telomere length, mitochondrial DNA copy number of peripheral blood with hypertension and the interaction between telomere length and mtDNA-CN on hypertension in coal miners. Methods: A case control study was conducted in a coal mine of Shanxi province from July to December of 2013, in which 325 healthy workers were selected as the control group and 378 workers with hypertension as the case group. The information about general demographic characteristics and life behavior habits of the subjects were collected through questionnaire. Levels of telomere length and mtDNA-CN in peripheral blood were detected by real-time PCR. Unconditional logistic regression was used to examine the association between hypertension and telomere length, mtDNA-CN. The interaction test between telomere length and mtDNA-CN on hypertension was performed by adding the interaction term in the corresponding model. Results: The mean telomere length of the workers in the case group was (1.50±0.55) kb, and that of the control group was (2.01±0.62) kb, the difference between two groups was significant (t=11.68, P<0.001). The correlation analysis showed that telomere length was positively correlated with mtDNA-CN (r=0.157, P=0.002) in the case group. Multivariate analysis showed that telomere length (OR=4.408, 95%CI: 3.012-6.452), age (OR=0.417, 95%CI: 0.284-0.613), BMI (OR=1.357, 95%CI: 1.162-1.584), monthly household income level (OR=0.656, 95%CI: 0.553-0.778) and work duration (OR=1.249, 95%CI: 1.100-1.417) were influencing factors of hypertension. The multiply interaction between telomere length and mtDNA-CN was significant on hypertension (OR=1.267, 95%CI: 1.094-1.468). Conclusions: The results suggest shorter telomere length is a risk factor of hypertension. There is a multiply interaction between telomere length and mtDNA-CN on hypertension. However, the association between mtDNA-CN and hypertension was not found.},
}
@article {pmid32447718,
year = {2020},
author = {Vita, GL and Aguennouz, M and Sframeli, M and Sanarica, F and Mantuano, P and Oteri, R and Polito, F and Licata, N and Romeo, S and Distefano, MG and La Rosa, M and Bonanno, C and Nicocia, G and Vita, G and De Luca, A and Messina, S},
title = {Effect of exercise on telomere length and telomere proteins expression in mdx mice.},
journal = {Molecular and cellular biochemistry},
volume = {470},
number = {1-2},
pages = {189-197},
doi = {10.1007/s11010-020-03761-3},
pmid = {32447718},
issn = {1573-4919},
support = {MIUR PRIN 2015 to ADL [n. 2015MJBEM2_005].//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; },
mesh = {Animals ; Disease Models, Animal ; Genotype ; Mice ; Mice, Inbred mdx ; Muscle, Skeletal/metabolism ; Muscular Dystrophy, Duchenne/*metabolism ; *Physical Conditioning, Animal ; Poly (ADP-Ribose) Polymerase-1/*genetics ; Signal Transduction ; Telomerase/*genetics ; Telomere/*metabolism ; Telomere Shortening ; Telomeric Repeat Binding Protein 1/*genetics ; },
abstract = {In Duchenne muscular dystrophy (DMD), telomere shortening has been postulated to contribute to the failure of regenerative activity promoting the premature senescence of satellite cells. The aim of the present study was to investigate the telomere length and the expression of telomeric repeat-binding factor-1 (TRF1), poly (ADP-ribose) polymerase-1 (PARP1) and mouse telomerase reverse transcriptase (MTERT) in gastrocnemius, tibialis anterior and diaphragm muscles of the murine model of DMD, the mdx mouse and whether a chronic protocol of forced exercise impacts on them. Our results confirmed a telomere shortening in mdx muscles, more evident in the diaphragm, in which exercise induced a greater shortening than in wild-type mice. Moreover, we showed for the first time in mdx an increased TRF1 and PARP1 expression and an augmented activity of MTERT, further enhanced by exercise. These results reinforce the hypothesis that a deregulation of mechanisms involved in telomere length occurs and may pave the way for the test of compounds targeting proteins modulating telomere maintenance as a novel strategy to treat dystrophinopathies.},
}
@article {pmid32444498,
year = {2020},
author = {Vinayagamurthy, S and Ganguly, A and Chowdhury, S},
title = {Extra-telomeric impact of telomeres: Emerging molecular connections in pluripotency or stemness.},
journal = {The Journal of biological chemistry},
volume = {295},
number = {30},
pages = {10245-10254},
pmid = {32444498},
issn = {1083-351X},
mesh = {Aging/genetics/*metabolism/pathology ; *Cell Differentiation ; DNA Damage ; Humans ; Myocytes, Cardiac/metabolism/pathology ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; Pluripotent Stem Cells/*metabolism/pathology ; Telomere/genetics/*metabolism/pathology ; Telomere Homeostasis ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Telomeres comprise specialized nucleic acid-protein complexes that help protect chromosome ends from DNA damage. Moreover, telomeres associate with subtelomeric regions through looping. This results in altered expression of subtelomeric genes. Recent observations further reveal telomere length-dependent gene regulation and epigenetic modifications at sites spread across the genome and distant from telomeres. This regulation is mediated through the telomere-binding protein telomeric repeat-binding factor 2 (TRF2). These observations suggest a role of telomeres in extra-telomeric functions. Most notably, telomeres have a broad impact on pluripotency and differentiation. For example, cardiomyocytes differentiate with higher efficacy from induced pluripotent stem cells having long telomeres, and differentiated cells obtained from human embryonic stem cells with relatively long telomeres have a longer lifespan. Here, we first highlight reports on these two seemingly distinct research areas: the extra-telomeric role of telomere-binding factors and the role of telomeres in pluripotency/stemness. On the basis of the observations reported in these studies, we draw attention to potential molecular connections between extra-telomeric biology and pluripotency. Finally, in the context of the nonlocal influence of telomeres on pluripotency and stemness, we discuss major opportunities for progress in molecular understanding of aging-related disorders and neurodegenerative diseases.},
}
@article {pmid32443982,
year = {2020},
author = {Pasquier, E and Wellinger, RJ},
title = {In vivo chromatin organization on native yeast telomeric regions is independent of a cis-telomere loopback conformation.},
journal = {Epigenetics &amp; chromatin},
volume = {13},
number = {1},
pages = {23},
pmid = {32443982},
issn = {1756-8935},
support = {FDN 154315//CIHR/Canada ; Telomere Biology//Canada Research Chairs/International ; },
mesh = {Chromatin/*chemistry/genetics ; Chromosomes, Fungal/*chemistry/genetics ; Saccharomyces cerevisiae ; Telomere/*chemistry/genetics ; },
abstract = {BACKGROUND: DNA packaging into chromatin regulates all DNA-related processes and at chromosomal ends could affect both essential functions of telomeres: protection against DNA damage response and telomere replication. Despite this primordial role of chromatin, little is known about chromatin organization, and in particular about nucleosome positioning on unmodified subtelomere-telomere junctions in Saccharomyces cerevisiae.<br><br>RESULTS: By ChEC experiments and indirect end-labeling, we characterized nucleosome positioning as well as specialized protein-DNA associations on most subtelomere-telomere junctions present in budding yeast. The results show that there is a relatively large nucleosome-free region at chromosome ends. Despite the absence of sequence homologies between the two major classes of subtelomere-telomere junctions (i.e.: Y'-telomeres and X-telomeres), all analyzed subtelomere-telomere junctions show a terminal nucleosome-free region just distally from the known Rap1-covered telomeric repeats. Moreover, previous evidence suggested a telomeric chromatin fold-back structure onto subtelomeric areas that supposedly was implicated in chromosome end protection. The in vivo ChEC method used herein in conjunction with several proteins in a natural context revealed no evidence for such structures in bulk chromatin.<br><br>CONCLUSIONS: Our study allows a structural definition of the chromatin found at chromosome ends in budding yeast. This definition, derived with direct in vivo approaches, includes a terminal area that is free of nucleosomes, certain positioned nucleosomes and conserved DNA-bound protein complexes. This organization of subtelomeric and telomeric areas however does not include a telomeric cis-loopback conformation. We propose that the observations on such fold-back structures may report rare and/or transient associations and not stable or constitutive structures.},
}
@article {pmid32439486,
year = {2020},
author = {Davis, SK and Xu, R and Khan, RJ and Gaye, A},
title = {Modifiable mediators associated with the relationship between adiposity and leukocyte telomere length in US adults: The National Health and Nutrition Examination Survey.},
journal = {Preventive medicine},
volume = {138},
number = {},
pages = {106133},
pmid = {32439486},
issn = {1096-0260},
support = {ZIA HG200393/ImNIH/Intramural NIH HHS/United States ; ZIA HG200404/ImNIH/Intramural NIH HHS/United States ; },
mesh = {*Adiposity ; Adult ; Cross-Sectional Studies ; Humans ; Leukocytes ; Nutrition Surveys ; Obesity/genetics ; *Telomere ; Telomere Shortening ; },
abstract = {Obesity is associated with age-related health conditions and telomere attrition - a marker of cellular aging. Obesity is attributable to adverse modifiable lifestyle factors. Little is known about the mediation effect of lifestyle factors associated with the relationship between obesity and telomere length. Our objective was to examine this association in the US. Pack years smoked, drinking level per day, physical activity (PA) per week and diet based on Healthy Eating Index (HEI) were assessed as mediators associated with the relationship between adiposity measures and leukocyte telomere length (LTL); adiposity measures included body mass index (BMI), % total body fat (TBF) and waist circumference (WC). Separate adjusted linear regressions and mediation analysis were conducted on a total of 4919 respondents aged 20-84 years using cross-sectional 1999-2002 data from the US National Health and Nutrition Examination Survey. Inadequate PA correlated with 1.28% shorter LTL and was a factor accounting for 35% of the relationship between BMI and LTL (β = -0.0128, 95% CI = 0.0259, 0.0004, p = .05). Smoking 30-≥59 pack years correlated with 4% shorter LTL and accounted for 21% of the relationship between %TBF and LTL (β = -0.0386, 95% CI = -0.0742, -0.0030, p = .03). Improvement in diet correlated with 0.11% longer LTL and contributed 25% of the association between %TBF and LTL (β = 0.0011, 95%CI =0.0004, 0.0018, p = .01). Diet correlated with 0.11% longer LTL and correspond to 28% of the relationship between WC and LTL (β = 0.0011, 95%CI = 0.0004, 0.0018, p = .03). Interventions to improve modifiable behaviors may ameliorate cellular aging and aging related health conditions due to obesity among US adults.},
}
@article {pmid32439402,
year = {2020},
author = {Kang, JI and Mueller, SG and Wu, GWY and Lin, J and Ng, P and Yehuda, R and Flory, JD and Abu-Amara, D and Reus, VI and Gautam, A and , and Hammamieh, R and Doyle, FJ and Jett, M and Marmar, CR and Mellon, SH and Wolkowitz, OM},
title = {Effect of Combat Exposure and Posttraumatic Stress Disorder on Telomere Length and Amygdala Volume.},
journal = {Biological psychiatry. Cognitive neuroscience and neuroimaging},
volume = {5},
number = {7},
pages = {678-687},
doi = {10.1016/j.bpsc.2020.03.007},
pmid = {32439402},
issn = {2451-9030},
mesh = {Amygdala ; *Combat Disorders ; Humans ; Male ; *Stress Disorders, Post-Traumatic ; Telomere ; Veterans ; },
abstract = {BACKGROUND: Traumatic stress can adversely affect physical and mental health through neurobiological stress response systems. We examined the effects of trauma exposure and posttraumatic stress disorder (PTSD) on telomere length, a biomarker of cellular aging, and volume of the amygdala, a key structure of stress regulation, in combat-exposed veterans. In addition, the relationships of psychopathological symptoms and autonomic function with telomere length and amygdala volume were examined.<br><br>METHODS: Male combat veterans were categorized as having PTSD diagnosis (n&#xa0;= 102) or no lifetime PTSD diagnosis (n&#xa0;= 111) based on the Clinician-Administered PTSD Scale. Subjects were assessed for stress-related psychopathology, trauma severity, autonomic function, and amygdala volumes by magnetic resonance imaging.<br><br>RESULTS: A significant interaction was found between trauma severity and PTSD status for telomere length and amygdala volume after adjusting for multiple confounders. Subjects with PTSD showed shorter telomere length and larger amygdala volume than those without PTSD among veterans exposed to high trauma, while there was no significant group difference in these parameters among those exposed to low trauma. Among veterans exposed to high trauma, greater telomere shortening was significantly correlated with greater norepinephrine, and larger amygdala volume was correlated with more severe psychological symptoms and higher heart rates.<br><br>CONCLUSIONS: These data suggest that the intensity of the index trauma event plays an important role in interacting with PTSD symptomatology and autonomic activity in predicting telomere length and amygdala volume. These results highlight the importance of trauma severity and PTSD status in predicting certain biological outcomes.},
}
@article {pmid32433826,
year = {2020},
author = {Li, Y and Gu, J and Ding, Y and Gao, H and Li, Y and Sun, Y and He, M and Zhang, W and Yin, J and Bai, C and Gao, Y},
title = {A small molecule compound IX inhibits telomere and attenuates oncogenesis of drug-resistant leukemia cells.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {34},
number = {7},
pages = {8843-8857},
doi = {10.1096/fj.201902651RR},
pmid = {32433826},
issn = {1530-6860},
mesh = {Apoptosis ; Carcinogenesis/*drug effects/metabolism/pathology ; Cell Cycle ; Cell Movement ; Cell Proliferation ; *Drug Resistance, Neoplasm ; Humans ; Leukemia, Experimental/*drug therapy/metabolism/pathology ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy/metabolism/pathology ; Leukemia, Myeloid, Acute/*drug therapy/metabolism/pathology ; Neoplastic Stem Cells/drug effects/metabolism/pathology ; Pharmaceutical Preparations/administration &amp; dosage ; Small Molecule Libraries/*pharmacology ; Telomere/*drug effects/metabolism ; Tumor Cells, Cultured ; },
abstract = {Drug resistance is a common obstacle in leukemia treatment and failing to eradicate leukemia stem cells is the main cause of leukemia relapse. Previous studies have demonstrated that telomerase activity is associated with deregulated self-renewal of leukemia stem cells (LSCs). Here, we identified a novel compound IX, an imatinib derivative with a replacement fragment of a telomerase inhibitor, which can effectively eradicate LSCs but had no influence on normal hematopoietic stem cells (HSCs) survival. We showed that compound IX can decrease the viability of drug-resistant K562/G cells and blast crisis CML primary patient cells. Besides, IX can affect LSC survival, inhibit the colony-forming ability, and reduce LSC frequency. In vivo results showed that IX can relieve the tumor burden in patient-derived xenograft (PDX) model and prolong the lifespan. We observed that compound IX can not only decrease telomerase activity, but also affect the alternative lengthening of telomeres. In addition, IX can inhibit both the canonical and non-canonical Wnt pathways. Our data suggested this novel compound IX as a promising candidate for drug-resistant leukemia therapy.},
}
@article {pmid32430098,
year = {2020},
author = {Vecoli, C and Borghini, A and Andreassi, MG},
title = {The molecular biomarkers of vascular aging and atherosclerosis: telomere length and mitochondrial DNA[4977] common deletion.},
journal = {Mutation research. Reviews in mutation research},
volume = {784},
number = {},
pages = {108309},
doi = {10.1016/j.mrrev.2020.108309},
pmid = {32430098},
issn = {1388-2139},
mesh = {Aging/genetics/metabolism/*pathology ; Animals ; Atherosclerosis/*diagnosis/genetics/metabolism ; Biomarkers/*analysis ; DNA, Mitochondrial/*genetics ; *Gene Deletion ; Humans ; Mitochondria/genetics/*pathology ; Risk Factors ; Telomere Shortening/*genetics ; },
abstract = {Age is the dominant risk factor for the most prevalent atherosclerotic vascular diseases, including coronary artery disease, myocardial infarction, cerebrovascular disease and stroke. In human, telomere erosion and mitochondrial DNA (mtDNA) damage play a central role in the mechanisms leading to cellular aging decline. This review summarizes the most relevant findings on the role of telomere shortening and the common mtDNA[4977] deletion in the progression and evolution of atherosclerosis by combining insight from experimental models and human clinical studies. The current evidence shows a link between telomere erosion and compromised mitochondrial function and provides a new perspective regarding their potential role as clinical biomarkers and therapeutic targets.},
}
@article {pmid32429809,
year = {2020},
author = {Noguera, JC and Velando, A},
title = {Gull chicks grow faster but lose telomeres when prenatal cues mismatch the real presence of sibling competitors.},
journal = {Proceedings. Biological sciences},
volume = {287},
number = {1927},
pages = {20200242},
pmid = {32429809},
issn = {1471-2954},
mesh = {Animals ; Charadriiformes/*physiology ; Clutch Size ; Cues ; Siblings ; Social Environment ; *Telomere ; },
abstract = {During embryonic life, individuals should adjust their phenotype to the conditions that they will encounter after birth, including the social environment, if they have access to (social) cues that allow them to forecast future conditions. In birds, evidence indicates that embryos are sensitive to cues from clutch mates, but whether embryos adjust their development to cope with the expected level of sibling competition has not hitherto been investigated. To tackle this question, we performed a 'match versus mismatch' experimental design where we manipulated the presence of clutch mates (i.e. clutch size manipulation) and the real (postnatal) level of sibling competition (i.e. brood size manipulation) in the yellow-legged gull (Larus michahellis). We provide evidence that the prenatal cues of sibling presence induced developmental changes (such as epigenetic profiles) that had programming effects on chick begging behaviour and growth trajectories after hatching. While receiving mismatching information favoured chick begging and growth, this came at the cost of reduced antioxidant defences and a premature loss of telomeres. Our findings highlight the role of the prenatal social environment in developmental plasticity and suggest that telomere attrition may be an important physiological cost of phenotype-environment mismatch.},
}
@article {pmid32427758,
year = {2020},
author = {Gerritsen, L and Hägg, S and Reynolds, CA and Pedersen, NL},
title = {The Association of Individual Changes in Stressful Life Events and Telomere Length Over Time in Twins 50 Years and Older.},
journal = {Psychosomatic medicine},
volume = {82},
number = {6},
pages = {614-622},
doi = {10.1097/PSY.0000000000000826},
pmid = {32427758},
issn = {1534-7796},
mesh = {Aged ; Aging/*genetics ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Stress, Psychological/*genetics ; Sweden ; Telomere Shortening/*genetics ; Twins, Dizygotic ; Twins, Monozygotic ; },
abstract = {OBJECTIVE: Exposure to adverse stressors has been associated with shortening of leukocyte telomere length (LTL). The present longitudinal study investigates the time course of exposure to life events and LTL to determine whether increases in exposure to life events are related to subsequent accelerated LTL shortening.<br><br>METHODS: In the Swedish Adoption/Twin Study of Aging, we assessed late-life stressful events and LTL in 543 individual participants (mean age = 68.4 years, 40% men, including 48 complete monozygotic twin pairs and 167 complete dizygotic twin pairs) in up to five separate measurements over a period of 25 years. LTL was measured using quantitative polymerase chain reaction. Longitudinal analyses were conducted using time-varying mixed modeling, corrected for life-style factors and depressive symptoms.<br><br>RESULTS: When adjusting for differences in genetic makeup by looking only in monozygotic twins, we found that an increase in life stressors within an individual was related to decreased LTL over time (B = -0.02; 95% confidence interval = -0.04 to 0.01; p = .002). None of the findings were significant when only looking at dizygotic twins (all, p > .05).<br><br>CONCLUSIONS: Our findings in an older population show a causal relation between increase in life stress and accelerated LTL shortening by using intraindividual time-varying analysis.},
}
@article {pmid32427393,
year = {2020},
author = {Aviv, A},
title = {Telomeres and COVID-19.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {34},
number = {6},
pages = {7247-7252},
pmid = {32427393},
issn = {1530-6860},
support = {R01 HL134840/HL/NHLBI NIH HHS/United States ; U01 AG066529/AG/NIA NIH HHS/United States ; ES562296//Norwegian Research Council/International ; U01AG066529//HHS | NIH | National Institute on Aging (NIA)/International ; },
mesh = {*Betacoronavirus ; Biomarkers ; Bone Marrow/pathology ; COVID-19 ; Cell Division ; Coronavirus Infections/genetics/immunology/mortality/*pathology ; Disease Progression ; Hematopoietic Stem Cells/pathology ; Humans ; Lymphocyte Activation ; Lymphocyte Count ; Lymphopenia/*etiology/pathology ; Lymphopoiesis ; *Models, Biological ; Pandemics ; Pneumonia, Viral/genetics/immunology/mortality/*pathology ; Prognosis ; Risk ; SARS-CoV-2 ; T-Lymphocyte Subsets/*ultrastructure ; Telomere/*ultrastructure ; *Telomere Shortening ; },
abstract = {The medical, public health, and scientific communities are grappling with monumental imperatives to contain COVID-19, develop effective vaccines, identify efficacious treatments for the infection and its complications, and find biomarkers that detect patients at risk of severe disease. The focus of this communication is on a potential biomarker, short telomere length (TL), that might serve to identify patients more likely to die from the SARS-CoV-2 infection, regardless of age. The common thread linking these patients is lymphopenia, which largely reflects a decline in the numbers of CD4/CD8 T cells but not B cells. These findings are consistent with data that lymphocyte TL dynamics impose a limit on T-cell proliferation. They suggest that T-cell lymphopoiesis might stall in individuals with short TL who are infected with SARS-CoV-2.},
}
@article {pmid32427102,
year = {2020},
author = {El Maï, M and Marzullo, M and de Castro, IP and Ferreira, MG},
title = {Opposing p53 and mTOR/AKT promote an in vivo switch from apoptosis to senescence upon telomere shortening in zebrafish.},
journal = {eLife},
volume = {9},
number = {},
pages = {},
pmid = {32427102},
issn = {2050-084X},
support = {PTDC/SAU-ORG/116826/2010//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/International ; PJA 20161205137//Fondation ARC pour la Recherche sur le Cancer/International ; Installation Grant: Action 2 - 2019//Universit&#xe9; C&#xf4;te d'Azur - Acad&#xe9;mie 4/International ; IECS/HHMI/Howard Hughes Medical Institute/United States ; Postdoctoral fellowship//Ville de Nice/International ; },
mesh = {Aging ; Animals ; Apoptosis/*genetics ; Cell Proliferation ; Cellular Senescence/*genetics ; DNA Damage ; Female ; Male ; Mitochondria ; Mutation ; Phosphorylation ; Proto-Oncogene Proteins c-akt/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/genetics/*metabolism ; Telomerase/genetics/metabolism ; Telomere/metabolism ; Telomere Shortening/*genetics ; Tumor Suppressor Protein p53/genetics/*metabolism ; Zebrafish/*genetics/physiology ; },
abstract = {Progressive telomere shortening during lifespan is associated with restriction of cell proliferation, genome instability and aging. Apoptosis and senescence are the two major outcomes upon irreversible cellular damage. Here, we show a transition of these two cell fates during aging of telomerase deficient zebrafish. In young telomerase mutants, proliferative tissues exhibit DNA damage and p53-dependent apoptosis, but no senescence. However, these tissues in older animals display loss of cellularity and senescence becomes predominant. Tissue alterations are accompanied by a pro-proliferative stimulus mediated by AKT signaling. Upon AKT activation, FoxO transcription factors are phosphorylated and translocated out of the nucleus. This results in reduced SOD2 expression causing an increase of ROS and mitochondrial dysfunction. These alterations induce p15/16 growth arrest and senescence. We propose that, upon telomere shortening, early apoptosis leads to cell depletion and insufficient compensatory proliferation. Following tissue damage, the mTOR/AKT is activated causing mitochondrial dysfunction and p15/16-dependent senescence.},
}
@article {pmid32425970,
year = {2020},
author = {van der Spek, A and Warner, SC and Broer, L and Nelson, CP and Vojinovic, D and Ahmad, S and Arp, PP and Brouwer, RWW and Denniff, M and van den Hout, MCGN and van Rooij, JGJ and Kraaij, R and van IJcken, WFJ and Samani, NJ and Ikram, MA and Uitterlinden, AG and Codd, V and Amin, N and van Duijn, CM},
title = {Exome Sequencing Analysis Identifies Rare Variants in ATM and RPL8 That Are Associated With Shorter Telomere Length.},
journal = {Frontiers in genetics},
volume = {11},
number = {},
pages = {337},
pmid = {32425970},
issn = {1664-8021},
support = {SP/16/4/32697/BHF_/British Heart Foundation/United Kingdom ; U54 HG003067/HG/NHGRI NIH HHS/United States ; },
abstract = {Telomeres are important for maintaining genomic stability. Telomere length has been associated with aging, disease, and mortality and is highly heritable (∼82%). In this study, we aimed to identify rare genetic variants associated with telomere length using whole-exome sequence data. We studied 1,303 participants of the Erasmus Rucphen Family (ERF) study, 1,259 of the Rotterdam Study (RS), and 674 of the British Heart Foundation Family Heart Study (BHF-FHS). We conducted two analyses, first we analyzed the family-based ERF study and used the RS and BHF-FHS for replication. Second, we combined the summary data of the three studies in a meta-analysis. Telomere length was measured by quantitative polymerase chain reaction in blood. We identified nine rare variants significantly associated with telomere length (p-value < 1.42 × 10[-7], minor allele frequency of 0.2-0.5%) in the ERF study. Eight of these variants (in C11orf65, ACAT1, NPAT, ATM, KDELC2, and EXPH5) were located on chromosome 11q22.3 that contains ATM, a gene involved in telomere maintenance. Although we were unable to replicate the variants in the RS and BHF-FHS (p-value ≥ 0.21), segregation analysis showed that all variants segregate with shorter telomere length in a family. In the meta-analysis of all studies, a nominally significant association with LTL was observed with a rare variant in RPL8 (p-value = 1.48 × 10[-6]), which has previously been associated with age. Additionally, a novel rare variant in the known RTEL1 locus showed suggestive evidence for association (p-value = 1.18 × 10[-4]) with LTL. To conclude, we identified novel rare variants associated with telomere length. Larger samples size are needed to confirm these findings and to identify additional variants.},
}
@article {pmid32422075,
year = {2020},
author = {Morais, M and Dias, F and Resende, T and Nogueira, I and Oliveira, J and Maurício, J and Teixeira, AL and Medeiros, R},
title = {Leukocyte telomere length and hTERT genetic polymorphism rs2735940 influence the renal cell carcinoma clinical outcome.},
journal = {Future oncology (London, England)},
volume = {16},
number = {18},
pages = {1245-1255},
doi = {10.2217/fon-2019-0795},
pmid = {32422075},
issn = {1744-8301},
mesh = {Adult ; Aged ; Biomarkers, Tumor ; Carcinoma, Renal Cell/*genetics/*mortality/pathology ; Case-Control Studies ; Female ; Genetic Predisposition to Disease ; Humans ; Kidney Neoplasms/*genetics/*mortality/pathology ; Leukocytes/*metabolism ; Male ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; *Polymorphism, Single Nucleotide ; Prognosis ; Proportional Hazards Models ; Telomerase/*genetics ; Telomere Homeostasis ; },
abstract = {Aim: Analysis of the genetic hTERT-1327 C>T (rs2735940) influence on leukocyte telomere length (LTL) and tumor development, progression and overall survival in renal cell carcinoma (RCC) patients. Materials &amp; methods: Using leukocyte DNA of RCC patients and healthy individuals, LTL measurement and allelic discrimination of rs2735940 was performed by real-time PCR. Results: RCC patients showed shorter LTL than healthy individuals and LTL increased with clinical stage. CC+TC genotypes healthy carriers' presented shorter LTL. However, no statistical association between the different genotypes and RCC risk. Nevertheless, CC homozygous presented a reduced time to disease progression and a lower overall survival. The use of hTERT-1327 single nucleotide polymorphism information increased the capacity to predict risk for RCC progression. Conclusion: In fact, in healthy individuals, hTERT-1327 CC+TC genotypes were associated with shorter LTL, and this single nucleotide polymorphism was associated with time to disease progression, being a promising potential prognosis biomarker to be used in the future.},
}
@article {pmid32417614,
year = {2020},
author = {Wang, C and Wolters, PJ and Calfee, CS and Liu, S and Balmes, JR and Zhao, Z and Koyama, T and Ware, LB},
title = {Long-term ozone exposure is positively associated with telomere length in critically ill patients.},
journal = {Environment international},
volume = {141},
number = {},
pages = {105780},
pmid = {32417614},
issn = {1873-6750},
support = {K24 HL103836/HL/NHLBI NIH HHS/United States ; R01 HL135849/HL/NHLBI NIH HHS/United States ; R01 HL139897/HL/NHLBI NIH HHS/United States ; R35 HL140026/HL/NHLBI NIH HHS/United States ; },
mesh = {*Air Pollutants/analysis/toxicity ; *Air Pollution/analysis ; Critical Illness ; Environmental Exposure/adverse effects/analysis ; Humans ; *Ozone/analysis/toxicity ; Particulate Matter/analysis ; Telomere ; },
abstract = {RATIONALE: Chronic air pollutant exposure has been associated with development of Acute Respiratory Distress Syndrome (ARDS) in patients at risk, particularly from severe trauma. We recently reported that shorter peripheral blood leukocyte (PBL) telomere length (TL) was associated with worse outcomes and higher severity of ARDS in critically ill patients. Since most major air pollutants are potent oxidants that can induce cellular oxidative stress, and oxidative stress can accelerate telomere shortening, we hypothesized that higher levels of chronic air pollutant exposure would be associated with shorter telomere length in critically ill patients including patients with ARDS.<br><br>METHODS: PBL-TL was measured in genomic DNA collected on the morning of ICU day 2 in 772 critically ill patients enrolled in a prospective observational study. Exposures to air pollutants including ozone (warm-season only), particulate matter&#xa0;<&#xa0;2.5&#xa0;&#xb5;m (PM2.5), particulate matter&#xa0;<&#xa0;10&#xa0;&#xb5;m (PM10), CO, NO2 and SO2, were estimated by weighted average of daily levels from all monitors within 50&#xa0;km of each patient's residential address for the 3&#xa0;years prior to admission. Associations of each air pollutant exposure and PBL-TL were investigated by multivariable linear regression models adjusting for age, ethnicity, sex, smoking history, alcohol abuse, insurance status, median household income, history of malignancy and APACHE II.<br><br>RESULTS: Contrary to our hypothesis, TL increased across exposure quartiles in both ozone and PM2.5 analyses (p&#xa0;<&#xa0;0.05). In a regression model controlling for potential confounders, long term ozone exposure was significantly associated with an increase in TL in the entire cohort (0.31&#xa0;kb per 10&#xa0;ppb), as well as in subgroups with sepsis, trauma and ARDS (all p&#xa0;<&#xa0;0.05). In multivariable models, entire-year exposure to PM2.5, PM10, CO, NO2 and SO2 was not associated with TL after adjustment for potential confounders. In an analysis restricted to warm-season levels to assess the effect of seasonality, higher warm-season PM2.5 and CO exposures were independently associated with longer TL.<br><br>CONCLUSIONS: Long-term exposure to ozone is associated with longer peripheral blood TL in critically ill patients. Further studies are needed to investigate the potential underlying mechanisms for this unexpected positive association between telomere length and air pollution exposure in critical illness.},
}
@article {pmid32416388,
year = {2020},
author = {Ren, JC and Liu, H and Zhang, GH and Wang, T and Li, J and Dong, T and Wu, H and Xia, ZL},
title = {Interaction effects of environmental response gene polymorphisms and benzene exposure on telomere length in shoe-making workers.},
journal = {Chemosphere},
volume = {255},
number = {},
pages = {126841},
doi = {10.1016/j.chemosphere.2020.126841},
pmid = {32416388},
issn = {1879-1298},
mesh = {Adult ; Air Pollutants, Occupational/*analysis/toxicity ; Benzene/*analysis/toxicity ; China ; Cytochrome P-450 CYP2E1/genetics ; Female ; Genotype ; Humans ; Male ; Occupational Exposure/*analysis ; Polymorphism, Genetic ; Shoes ; *Telomere ; },
abstract = {Benzene is a globally occurring environmental and occupational pollutant that causes leukemia. To better understand telomere length (TL) as a function of benzene toxicity, we recruited 294 shoe-making workers and 102 controls from Wenzhou, China in 2011. Biomarkers of TL, cytokinesis-block micronucleus (MN) frequency, and white blood cells (WBC) were measured. In total, 18 polymorphic sites in environmental response genes, including metabolic and DNA repair genes, were analyzed. Results indicate that benzene exposure led to a longer TL at a threshold of 32 mg/m[3]-year of cumulative exposure dose (CED). Furthermore, the TL was longer in members of the damaged group, when evaluated for MN frequency (P < 0.001) and reduced WBC (P < 0.001), than in those of the normal group. Workers carrying genotype TT (β = 0.32, P = 0.042) in rs3212986 of ERCC1 and genotype TC (β = 0.24, P = 0.082) in rs1051740 of mEH exon3 were associated with a longer TL as compared to the wild-type group. TA (β = -0.53, P < 0.001) in rs6413432 of CYP2E1 was associated with a shorter TL. Benzene exposure interacted with the TA type in rs6413432 (β = 0.003, 95% CI: 0, 0.006, P = 0.042) and the CC type in rs1051740 (β = 0.007, 95% CI: 0.001, 0.013, P = 0.015) after adjusting for confounding factors. Our results indicate that benzene induces an increase in TL at a threshold of CED ≥32mg/m[3]-year. Rs1051740, rs3212986, and rs6413432 were found to be involved in benzene-induced telomere growth; in particular, rs1051740 and rs6413432 interacted with the benzene exposure, resulting in an extended TL.},
}
@article {pmid32412326,
year = {2020},
author = {Lee, CY and Bisig, CG and Conrad, MN and Ditamo, Y and Previato de Almeida, L and Dresser, ME and Pezza, RJ},
title = {Telomere-led meiotic chromosome movements: recent update in structure and function.},
journal = {Nucleus (Austin, Tex.)},
volume = {11},
number = {9},
pages = {111-116},
pmid = {32412326},
issn = {1949-1042},
support = {R01 GM125803/GM/NIGMS NIH HHS/United States ; R21 HD103562/HD/NICHD NIH HHS/United States ; },
mesh = {Actin Cytoskeleton/metabolism ; Chromosome Structures ; *Chromosomes, Fungal/genetics/metabolism ; *Meiosis/genetics ; Models, Molecular ; Saccharomyces cerevisiae/cytology/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {In S. cerevisiae prophase meiotic chromosomes move by forces generated in the cytoplasm and transduced to the telomere via a protein complex located in the nuclear membrane. We know that chromosome movements require actin cytoskeleton [13,31] and the proteins Ndj1, Mps3, and Csm4. Until recently, the identity of the protein connecting Ndj1-Mps3 with the cytoskeleton components was missing. It was also not known the identity of a cytoplasmic motor responsible for interacting with the actin cytoskeleton and a protein at the outer nuclear envelope. Our recent work [36] identified Mps2 as the protein connecting Ndj1-Mps3 with cytoskeleton components; Myo2 as the cytoplasmic motor that interacts with Mps2; and Cms4 as a regulator of Mps2 and Myo2 interaction and activities (Figure 1). Below we present a model for how Mps2, Csm4, and Myo2 promote chromosome movements by providing the primary connections joining telomeres to the actin cytoskeleton through the LINC complex.},
}
@article {pmid32411758,
year = {2020},
author = {Huang, YQ and Liu, L and Lo, K and Huang, JY and Zhang, B and Feng, YQ},
title = {The relationship between mean telomere length and blood pressure: results from the National Health and Nutrition Examination Surveys.},
journal = {Annals of translational medicine},
volume = {8},
number = {8},
pages = {535},
pmid = {32411758},
issn = {2305-5839},
abstract = {BACKGROUND: Recent studies have shown that telomere length has significantly relationship with different age-related diseases. However, the relationship between mean telomere length (MTL) and elevated blood pressure (BP) has been unclear. Therefore, the aim of the recent study was tried to explore the association of MLT with BP.<br><br>METHODS: There were 5,981 subjects from the National Health and Nutrition Examination Surveys (NHANES, 1999-2002) was included in analysis. The MTL was measured using the quantitative polymerase chain reaction (PCR) method and expressed in telomere-to-single copy gene (T/S) ratio and grouped into quartiles. Multivariate linear [expressed in beta and 95% confidence interval (CI)], logistic regression [odds ratios (ORs) and 95% CI] analyses and smooth curve fitting were performed to evaluate the relationship between MTL, BPs and the likelihood of hypertension.<br><br>RESULTS: The mean age of the participants was 45.2&#xb1;17.3 years, including 2,923 (48.9%) males. After adjusting for potential confounders, MLT was significantly related to the prevalence of hypertension (OR: 0.12, 95% CI: 0.02, 0.94; P=0.04). Smooth curve fitting found a non-linear relationship between MTL, the levels of systolic and diastolic blood pressure (SBP/DBP) and the prevalence of hypertension. The inflection points for the smooth curve of MLT were at 0.86, 1.02 and 0.80 (T/S ratio) respectively. The betas (95% CIs) for SBP [-12.58 (-20.07, -5.09), P<0.01 and 2.25 (0.07, 4.43), P=0.04] and DBP [4.88 (1.29, 8.47), P<0.01 and -3.30 (-5.54, -1.06), P<0.01], and ORs (95% CIs) for the prevalence of hypertension [0.02 (0.001, 9.71), P=0.15 and 0.26 (0.026, 2.60), P=0.25] on the left and right of the inflection point, respectively.<br><br>CONCLUSIONS: Our findings revealed that MTL was related with SBP, DBP and the odds of hypertension in a non-linear manner.},
}
@article {pmid32410007,
year = {2020},
author = {Oko, Y and Ito, N and Sakamoto, T},
title = {The mechanisms and significance of the positional control of centromeres and telomeres in plants.},
journal = {Journal of plant research},
volume = {133},
number = {4},
pages = {471-478},
pmid = {32410007},
issn = {1618-0860},
support = {19K06748//Japan Society for the Promotion of Science/ ; },
mesh = {Animals ; *Centromere/genetics/physiology ; Interphase ; *Plants/genetics ; *Telomere/genetics ; },
abstract = {The centromere and telomere are universal heterochromatic domains; however, the proper positioning of those domains in nuclear space during the mitotic interphase differs among eukaryotes. Consequently, the question arises how and why this difference occurs. Studies over the past 2 decades have identified several nuclear membrane proteins, nucleolar proteins, and the structural maintenance of a chromosome complex as factors involved in the positional control of centromeres and/or telomeres during the mitotic interphase in yeasts, animals, and plants. In this review, with a primary focus on plants, the roles of those factors are summarized, and the biological significance of proper centromere and telomere positionings during the mitotic interphase is discussed in an effort to provide guidance for this question.},
}
@article {pmid32408858,
year = {2020},
author = {da Cruz, I and Brochier-Armanet, C and Benavente, R},
title = {The TERB1-TERB2-MAJIN complex of mouse meiotic telomeres dates back to the common ancestor of metazoans.},
journal = {BMC evolutionary biology},
volume = {20},
number = {1},
pages = {55},
pmid = {32408858},
issn = {1471-2148},
support = {Be1168/8-1//DFG/International ; },
mesh = {Amino Acid Sequence ; Animals ; Carrier Proteins/chemistry/*genetics ; Cell Cycle Proteins/chemistry/*genetics ; Female ; Gene Expression Regulation ; Germ Cells/metabolism ; Gonads/metabolism ; Male ; Meiosis/*genetics ; Membrane Proteins/chemistry/*genetics ; Mice ; *Phylogeny ; Protein Domains ; Telomere/*genetics ; Telomere-Binding Proteins/chemistry/*genetics/metabolism ; },
abstract = {BACKGROUND: Meiosis is essential for sexual reproduction and generates genetically diverse haploid gametes from a diploid germ cell. Reduction of ploidy depends on active chromosome movements during early meiotic prophase I. Chromosome movements require telomere attachment to the nuclear envelope. This attachment is mediated by telomere adaptor proteins. Telomere adaptor proteins have to date been identified in fission yeast and mice. In the mouse, they form a complex composed of the meiotic proteins TERB1, TERB2, and MAJIN. No sequence similarity was observed between these three mouse proteins and the adaptor proteins of fission yeast, raising the question of the evolutionary history and significance of this specific protein complex.<br><br>RESULT: Here, we show the TERB1, TERB2, and MAJIN proteins are found throughout the Metazoa and even in early-branching non-bilateral phyla such as Cnidaria, Placozoa and Porifera. Metazoan TERB1, TERB2, and MAJIN showed comparable domain architecture across all clades. Furthermore, the protein domains involved in the formation of the complex as well as those involved for the interaction with the telomere shelterin protein and the LINC complexes revealed high sequence similarity. Finally, gene expression in the cnidarian Hydra vulgaris provided evidence that the TERB1-TERB2-MAJIN complex is selectively expressed in the germ line.<br><br>CONCLUSION: Our results indicate that the TERB1-TERB2-MAJIN complex has an ancient origin in metazoans, suggesting conservation of meiotic functions.},
}
@article {pmid32399105,
year = {2020},
author = {Ustaoglu, M and Bektas, A and Bedir, A and Bakir, T and Duzgun, A and Nar, R and Ecemis, O and Aslan, R},
title = {The telomere length of gastric mucosal samples and peripheral blood lymphocytes in patients who have undergone Billroth II distal gastrectomy.},
journal = {Archives of medical science : AMS},
volume = {16},
number = {3},
pages = {577-583},
pmid = {32399105},
issn = {1734-1922},
abstract = {INTRODUCTION: Telomeres play an important role in maintaining chromosomal integrity. Functional loss of telomeres increases the risk of cancer by causing genomic instability. Telomere length abnormalities have been reported in several precancerous lesions. There is no study that evaluates telomere length in Billroth II distal gastrectomy, which is known as a risk factor for gastric stump carcinogenesis, in the literature. The aim of this study was to assess the relationship between the telomere length of residual gastric mucosal samples, peripheral blood lymphocytes, and other clinicopathological parameters of patients who had undergone Billroth II distal gastrectomy.<br><br>MATERIAL AND METHODS: There were two groups: a control group (n = 15) and a patient group (n = 15). In all cases, upper gastrointestinal endoscopy was performed, and biopsies were taken during endoscopy. Telomere lengths were measured by qRT-PCR.<br><br>RESULTS: It was observed that the lengths of the telomeres were shortened as the time of postoperative period increased in the patient group (r = -0.126) (p > 0.05). Also, the lengths of the telomeres were shortened in chronic inflammation, neutrophil activity, glandular atrophy, and intestinal metaplasia.<br><br>CONCLUSIONS: The telomere length was shortened as the time of postoperative period increased in the patient group. The telomeres were also shorter in chronic inflammation, neutrophil activity, intestinal metaplasia, and glandular atrophy, in all of the study groups. Telomere length abnormalities in gastric stump carcinogenesis process may be a guide for early diagnosis and treatment.},
}
@article {pmid32390193,
year = {2020},
author = {Braz, MG and Silva, MAP and Figueiredo, DBS and Aun, AG and Marques, LSK and Lara, JR and Braz, LG},
title = {Genetic instability assessed by telomere length and micronucleus in physicians exposed to anesthetics.},
journal = {Environmental and molecular mutagenesis},
volume = {61},
number = {8},
pages = {843-847},
doi = {10.1002/em.22380},
pmid = {32390193},
issn = {1098-2280},
support = {167481/2019-3//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/International ; 304107/2018-2//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/International ; 471604/2013-5//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/International ; 472453/2013-0//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/International ; 2013/05084-8//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/International ; 2013/21130-0//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/International ; 2016/15559-1//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/International ; 03/2015-PROPG//Universidade Estadual Paulista/International ; },
mesh = {Adult ; Anesthetics/*toxicity ; Female ; *Genomic Instability ; Humans ; Male ; *Micronucleus Tests ; Middle Aged ; *Occupational Exposure ; *Physicians ; *Telomere ; Young Adult ; },
abstract = {This study evaluated both telomere length (TL) and micronucleus (MN) as indicators of genome instability in 40 anesthesiologists occupationally exposed to anesthetics and in 40 physicians without occupational exposure to anesthetics who were matched by age, sex, and lifestyle. Blood and buccal samples were collected from both groups at the same period. Anesthetic exposure assessment was performed. The studied groups were assessed regarding relative TL by quantitative polymerase chain reaction and MN by buccal MN assay. Mean trace concentrations of anesthetics were below two parts per million. No significant differences between groups were found for both biomarkers. However, MN frequency was slightly increased (1.9-fold; p = .094) in the exposed group compared to the control group and in the exposed males (2.4-fold; p = .090) compared to unexposed males. TL and age showed a significant negative correlation. Anesthetic occupational exposure below recommended levels is not associated with changes in TL and MN in anesthesiologists.},
}
@article {pmid32389660,
year = {2020},
author = {Heaphy, CM and Haffner, MC and Graham, MK and Lim, D and Davis, C and Corey, E and Epstein, JI and Eisenberger, MA and Wang, H and De Marzo, AM and Meeker, AK and Lotan, TL},
title = {Telomere lengths differ significantly between small-cell neuroendocrine prostate carcinoma and adenocarcinoma of the prostate.},
journal = {Human pathology},
volume = {101},
number = {},
pages = {70-79},
pmid = {32389660},
issn = {1532-8392},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; P50 CA058236/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma/genetics/*pathology ; Carcinoma, Neuroendocrine/genetics/pathology ; Carcinoma, Small Cell/genetics/*pathology ; Humans ; Male ; Middle Aged ; Prostatic Neoplasms/genetics/*pathology ; Telomere/*pathology ; },
abstract = {Small-cell neuroendocrine carcinoma (SCNC) of the prostate is an aggressive subtype with frequent TP53 mutation and RB1 inactivation; however, the molecular phenotype remains an area of investigation. Here, we compared telomere lengths in prostatic SCNC and usual-type prostatic adenocarcinoma (AdCa). We studied 32 cases of prostatic SCNC (including 11 cases with concurrent AdCa) and 347 cases of usual-type AdCa on tissue microarrays. Telomere lengths in tumor cells were qualitatively compared with those in normal cells using a telomere-specific fluorescence in situ hybridization assay. ERG, PTEN, and TP53 status were assessed in a proportion of cases using genetically validated immunohistochemistry protocols. Clinicopathological and molecular characteristics of cases were compared between the telomere groups using the chi-square test.A significantly higher proportion of prostatic SCNC cases (50%, 16/32) showed normal/long telomeres compared with AdCa cases (11%, 39/347; P < 0.0001). In 82% (9/11) of cases with concurrent SCNC and AdCa, the paired components were concordant for telomere length status. Among AdCa cases, the proportion of cases with normal/long telomeres significantly increased with increasing tumor grade group (P = 0.01) and pathologic stage (P = 0.02). Cases with normal/long telomeres were more likely to be ERG positive (P = 0.04) and to have TP53 missense mutation (P = 0.01) than cases with short telomeres.Normal or long telomere lengths are significantly more common in prostatic SCNC than in AdCa and are similar between concurrent SCNC and AdCa tumors, supporting a common origin. Among AdCa cases, longer telomere lengths are significantly associated with high-risk pathologic and molecular features.},
}
@article {pmid32389293,
year = {2020},
author = {Harari, Y and Gershon, L and Alonso-Perez, E and Klein, S and Berneman, Y and Choudhari, K and Singh, P and Sau, S and Liefshitz, B and Kupiec, M},
title = {Telomeres and stress in yeast cells: When genes and environment interact.},
journal = {Fungal biology},
volume = {124},
number = {5},
pages = {311-315},
doi = {10.1016/j.funbio.2019.09.003},
pmid = {32389293},
issn = {1878-6146},
mesh = {*Environment ; Humans ; Mutation ; *Saccharomyces cerevisiae/genetics ; *Stress, Physiological/genetics ; *Telomere/genetics ; Telomere Homeostasis/genetics ; },
abstract = {Telomeres are structures composed of simple DNA repeats and specific proteins that protect the eukaryotic chromosomal ends from degradation, and facilitate the replication of the genome. They are central to the maintenance of the genome integrity, and play important roles in the development of cancer and in the process of aging in humans. The yeast Saccharomyces cerevisiae has greatly contributed to our understanding of basic telomere biology. Our laboratory has carried out systematic screen for mutants that affect telomere length, and identified ∼500 genes that, when mutated, affect telomere length. Remarkably, all ∼500 TLM (Telomere Length Maintenance) genes participate in a very tight homeostatic process, and it is enough to mutate one of them to change the steady-state telomere length. Despite this complex network of balances, it is also possible to change telomere length in yeast by applying several types of external stresses. We summarize our insights about the molecular mechanisms by which genes and environment interact to affect telomere length.},
}
@article {pmid32388964,
year = {2020},
author = {Chen, XX and Sun, Y},
title = {[A review and update of the potential impact of early life adversity on telomere length].},
journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]},
volume = {54},
number = {5},
pages = {581-585},
doi = {10.3760/cma.j.cn112150-20190624-00503},
pmid = {32388964},
issn = {0253-9624},
support = {81872638//National Natural Science Foundation of China/ ; 1908085J26//Natural Science Fund for Distinguished Young Scholars of Anhui Province/ ; },
mesh = {*Adverse Childhood Experiences ; Humans ; Risk Factors ; *Telomere ; *Telomere Shortening ; },
abstract = {Early life adversity is a risk factor for many diseases, but the related mechanism is not clear. Some research clues suggest that early life adversity is related to biological aging, and at present, the more recognized biological aging index is telomere length. Therefore, exploring the relationship between early life adversity and telomere length is of great significance to reveal the related mechanism of adversity. Through a review of previous literature, this paper discusses the possible effects of different adversity types, exposure time and research design on the relationship between early life adversity and telomere length, so as to provide a basis for the intervention of early life adversity.},
}
@article {pmid32387852,
year = {2020},
author = {Li, Z and Liu, H and Qian, Y and Li, X and Guo, C and Wang, Z and Wei, Y},
title = {Influence of metals from e-waste dismantling on telomerelength and mitochondrial DNA copy number in people living near recycling sites.},
journal = {Environment international},
volume = {140},
number = {},
pages = {105769},
doi = {10.1016/j.envint.2020.105769},
pmid = {32387852},
issn = {1873-6750},
mesh = {China ; DNA Copy Number Variations ; DNA, Mitochondrial ; *Electronic Waste ; Humans ; *Metals, Heavy/analysis ; Recycling ; },
abstract = {Metals are the primary toxicants released by electronic waste (e-waste) recycling, but their adverse effects on people working in e-waste recycling or living near e-waste sites have not been studied well. Taizhou is one of the three largest e-waste recycling locations in China. Atpresent, to prevent the environmental problems stem from e-waste dismantling, the local government has shut down all the industries in 2015. In this study, we collected blood samples of residents living near e-waste dismantling factories, and in matched reference areas in Taizhou, in December 2017, after the factories have been shut down for two years. Seventeen metals were quantified in all blood samples. Among them, the concentrations of arsenic (As), nickel (Ni), silver (Ag), lanthanum (La), and Cerium (Ce) were statistically significant higher in individuals in e-waste recycling locations than those in reference location. Length of telomere (LOT) and mitochondrialDNA copy number (MCN) were measured in blood as a marker of human health. In the e-waste dismantling location, the level LOT and MCN were elevated in resident living near e-waste sites (RE) and former working in e-waste recycling (OE) than residents living in the reference area (RF). Furthermore, Pearson correlation and multiple linear regression analysis between the changed metals and LOT, MCN in blood were performed. In RE and OE, the concentration of Ni significantly positively correlated with MCN; in OE, the Ni level significantly positively correlated with MCN and LOT. Considering that the high level of Ni, TL and mtDNA were correlated with the risk of cancer, we speculated that e-waste exposure elevate the risk of cancer, and Ni that has long been present in the body was the potential hazardous element causing cancer.},
}
@article {pmid32385108,
year = {2020},
author = {Jurikova, K and Gajarsky, M and Hajikazemi, M and Nosek, J and Prochazkova, K and Paeschke, K and Trantirek, L and Tomaska, L},
title = {Role of folding kinetics of secondary structures in telomeric G-overhangs in the regulation of telomere maintenance in Saccharomyces cerevisiae.},
journal = {The Journal of biological chemistry},
volume = {295},
number = {27},
pages = {8958-8971},
pmid = {32385108},
issn = {1083-351X},
mesh = {DNA/metabolism ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/metabolism ; Electrophoretic Mobility Shift Assay ; G-Quadruplexes ; Kinetics ; Nucleic Acid Conformation ; Oligonucleotides/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Telomerase/genetics ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; Telomere-Binding Proteins/metabolism ; },
abstract = {The ends of eukaryotic chromosomes typically contain a 3' ssDNA G-rich protrusion (G-overhang). This overhang must be protected against detrimental activities of nucleases and of the DNA damage response machinery and participates in the regulation of telomerase, a ribonucleoprotein complex that maintains telomere integrity. These functions are mediated by DNA-binding proteins, such as Cdc13 in Saccharomyces cerevisiae, and the propensity of G-rich sequences to form various non-B DNA structures. Using CD and NMR spectroscopies, we show here that G-overhangs of S. cerevisiae form distinct Hoogsteen pairing-based secondary structures, depending on their length. Whereas short telomeric oligonucleotides form a G-hairpin, their longer counterparts form parallel and/or antiparallel G-quadruplexes (G4s). Regardless of their topologies, non-B DNA structures exhibited impaired binding to Cdc13 in vitro as demonstrated by electrophoretic mobility shift assays. Importantly, whereas G4 structures formed relatively quickly, G-hairpins folded extremely slowly, indicating that short G-overhangs, which are typical for most of the cell cycle, are present predominantly as single-stranded oligonucleotides and are suitable substrates for Cdc13. Using ChIP, we show that the occurrence of G4 structures peaks at the late S phase, thus correlating with the accumulation of long G-overhangs. We present a model of how time- and length-dependent formation of non-B DNA structures at chromosomal termini participates in telomere maintenance.},
}
@article {pmid32383700,
year = {2020},
author = {Cherska, M and Krasnienkov, D and Tronko, N and Kondratiuk, V and Guryanov, V and Kukharskyy, V},
title = {TELOMERE LENGTH, TELOMERASE ACTIVITY, HEART RATE VARIABILITY, OR OXIDATIVE STRESS: WHICH ONE IS MOST ASSOCIATED WITH THE ATHEROTHROMBOTIC STROKE IN THE ELDERLY?.},
journal = {Georgian medical news},
volume = {},
number = {300},
pages = {43-48},
pmid = {32383700},
issn = {1512-0112},
mesh = {Aged ; *Diabetes Mellitus, Type 2 ; Heart Rate ; Humans ; Longitudinal Studies ; Middle Aged ; Oxidative Stress ; Prospective Studies ; *Stroke ; *Telomerase ; Telomere ; },
abstract = {The objective of this study - to evaluate the impact of the markers of oxidative stress and HRV to stroke. The comprehensive clinical and instrumental study involved 84 patients with the diagnosis "Cerebral Atherosclerosis" (CA). Study design: simple, prospective, non-randomized, with sequential inclusion of patients. All patients underwent generally accepted clinical, laboratory and instrumental examination. All patients received antihypertensive drugs and metformin if they had DM and didn't receive any statins. Patients were divided into the 2 groups: I - those who underwent ischemic stroke (IS), II - with CA of 1-2 degrees. Mean age was 65.5±10.2 and 66.0±9.3 years, respectively. The number of patients with type 2 diabetes and the average fasting glucose was comparable in both groups. The LF/HF indicator reflects the state of the sympatho-parasympathetic balance of the ANS. Large values of this indicator indicate the predominance of the tone of the sympathetic ANS, which was observed (p <0.05) in patients of the 2nd group, while HF, LF and VLF were also higher (p>0.05) in the group of patients with cerebral atherosclerosis of 1-2 stages and above normal international values. Both groups were comparable in terms of telomere length and telomerase activity, as well as markers of oxidative stress, with the exception of GSH, which was higher in post-stroke patients (p>0.05). Our findings show that markers of oxidative stress together with HRV indices are useful for the atherothrombotic stroke risk assessment in the elderly. Future longitudinal study with bigger sample size and, probably wide panel of markers required for clarifying links between oxidative stress, HRV and stroke.},
}
@article {pmid32380304,
year = {2020},
author = {Bai, Y and Fu, W and Guan, X and Wu, X and Li, G and Wei, W and Feng, Y and Meng, H and Li, H and Li, M and Fu, M and Jie, J and Wang, C and Zhang, X and He, M and Guo, H},
title = {Co-exposure to multiple metals, TERT-CLPTM1L variants, and their joint influence on leukocyte telomere length.},
journal = {Environment international},
volume = {140},
number = {},
pages = {105762},
doi = {10.1016/j.envint.2020.105762},
pmid = {32380304},
issn = {1873-6750},
mesh = {*Coke ; Genotype ; Humans ; Leukocytes ; Membrane Proteins/genetics ; Neoplasm Proteins/genetics ; *Telomerase/genetics ; Telomere/genetics ; },
abstract = {OBJECTIVE: Telomere is required for maintaining chromosome stability and genome integrity, while telomere length is sensitive to environmental stressors. We aimed to identify the effects of multiple metals co-exposure as well as their joint effects with TERT-CLPTM1L variants on leukocyte telomere length (LTL).<br><br>METHODS: This study included 842 workers from a coke-oven plant, of whom plasma concentrations of 23 metals and LTL were determined. Genetic variations in TERT-CLPTM1L were genotyped by using the Global Screening Array. Multipollutant-based statistical methods, including the Bonferroni-correction, backward elimination procedure, and LASSO penalized regression analysis, were used to select the LTL-associated metals. Generalized linear regression models were used to evaluate the joint effects of TERT-CLPTM1L variants with positive metal on LTL.<br><br>RESULTS: Each 1% increase in plasma concentration of manganese (Mn) was significantly associated with a 0.153% increase in LTL [&#x3b2;(95%CI)&#xa0;=&#xa0;0.153(0.075, 0.230), P&#xa0;<&#xa0;0.001] in single-metal models after Bonferroni-correction. The multiple-metal models and the LASSO penalized regression analysis both indicated Mn as the sole significant predictor for LTL. Furthermore, 5 tagSNPs (rs33954691, rs6554759, rs465498, rs2455393, and rs31489) in TERT-CLPTM1L with high plasma Mn (>4.21&#xa0;&#x3bc;g/L) showed joint effects on increasing LTL.<br><br>CONCLUSIONS: Our study revealed the independent and positive association between plasma Mn and LTL when accounting for co-exposure to other metals. This effect can be further enhanced by TERT-CLPTM1L variants. These results may advance our understanding of the complex interplay between genetic and environmental factors on telomere length. Further experimental studies are warranted to elucidate the underlying mechanisms.},
}
@article {pmid32380018,
year = {2020},
author = {Jacome Burbano, MS and Gilson, E},
title = {Long-lived post-mitotic cell aging: is a telomere clock at play?.},
journal = {Mechanisms of ageing and development},
volume = {189},
number = {},
pages = {111256},
doi = {10.1016/j.mad.2020.111256},
pmid = {32380018},
issn = {1872-6216},
mesh = {Animals ; *Cellular Senescence ; Humans ; *Mitosis ; Reactive Oxygen Species/*metabolism ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {Senescence is a cellular response to stress for both dividing and post-mitotic cells. Noteworthy, long-lived post-mitotic cells (collectively named LLPMCs), which can live for decades in the organism, can exhibit a distinct type of cellular aging characterized by a progressive functional decline not associated to an overt senescence phenotype. The age-related drivers of senescence and aging in LLPMCs remain largely unknown. There is evidence that an increased production of reactive oxygen species (ROS) due to dysfunctional mitochondria, coupled with an inherent inability of cellular-degradation mechanisms to remove damaged molecules, is responsible for senescence and aging in LLPMC. Although telomeric DNA shortening, by nature linked to cell division, is generally not considered as a driver of LLPMC aging and senescence, we discuss recent reports revealing the existence of age-related telomere changes in LLPMC. These findings reveal unexpected roles for telomeres in LLPMC function and invite us to consider the hypothesis of a complex telomere clock involved in both dividing and non-dividing cell aging.},
}
@article {pmid32379321,
year = {2020},
author = {Shi, G and Hu, Y and Zhu, X and Jiang, Y and Pang, J and Wang, C and Huang, W and Zhao, Y and Ma, W and Liu, D and Huang, J and Songyang, Z},
title = {A critical role of telomere chromatin compaction in ALT tumor cell growth.},
journal = {Nucleic acids research},
volume = {48},
number = {11},
pages = {6019-6031},
pmid = {32379321},
issn = {1362-4962},
mesh = {Cell Line, Tumor ; *Cell Proliferation ; *Chromatin Assembly and Disassembly ; DNA Damage ; DNA-Binding Proteins ; Euchromatin/genetics/metabolism ; Gene Knockdown Techniques ; Heterochromatin/genetics/*metabolism ; Histone Code ; Histones/chemistry/*metabolism ; Humans ; Methylation ; Nuclear Proteins/antagonists &amp; inhibitors/deficiency/metabolism ; Protein Multimerization ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {ALT tumor cells often contain abundant DNA damage foci at telomeres and rely on the alternative lengthening of telomeres (ALT) mechanism to maintain their telomeres. How the telomere chromatin is regulated and maintained in these cells remains largely unknown. In this study, we present evidence that heterochromatin protein 1 binding protein 3 (HP1BP3) can localize to telomeres and is particularly enriched on telomeres in ALT cells. HP1BP3 inhibition led to preferential growth inhibition of ALT cells, which was accompanied by telomere chromatin decompaction, increased presence of C-circles, more pronounced ALT-associated phenotypes and elongated telomeres. Furthermore, HP1BP3 appeared to participate in regulating telomere histone H3K9me3 epigenetic marks. Taken together, our data suggest that HP1BP3 functions on telomeres to maintain telomere chromatin and represents a novel target for inhibiting ALT cancer cells.},
}
@article {pmid32375866,
year = {2020},
author = {George, SL and Parmar, V and Lorenzi, F and Marshall, LV and Jamin, Y and Poon, E and Angelini, P and Chesler, L},
title = {Novel therapeutic strategies targeting telomere maintenance mechanisms in high-risk neuroblastoma.},
journal = {Journal of experimental &amp; clinical cancer research : CR},
volume = {39},
number = {1},
pages = {78},
pmid = {32375866},
issn = {1756-9966},
support = {14610/CRUK_/Cancer Research UK/United Kingdom ; MC_PC_18051/MRC_/Medical Research Council/United Kingdom ; 28278/CRUK_/Cancer Research UK/United Kingdom ; A18339/CRUK_/Cancer Research UK/United Kingdom ; MC_PC_16047/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Cell Line, Tumor ; Child, Preschool ; Female ; Humans ; Infant ; Male ; Neuroblastoma/drug therapy/genetics/*therapy ; Telomere/drug effects/genetics/metabolism/*physiology ; },
abstract = {The majority of high-risk neuroblastomas can be divided into three distinct molecular subgroups defined by the presence of MYCN amplification, upstream TERT rearrangements or alternative lengthening of telomeres (ALT). The common defining feature of all three subgroups is altered telomere maintenance; MYCN amplification and upstream TERT rearrangements drive high levels of telomerase expression whereas ALT is a telomerase independent telomere maintenance mechanism. As all three telomere maintenance mechanisms are independently associated with poor outcomes, the development of strategies to selectively target either telomerase expressing or ALT cells holds great promise as a therapeutic approach that is applicable to the majority of children with aggressive disease.Here we summarise the biology of telomere maintenance and the molecular drivers of aggressive neuroblastoma before describing the most promising therapeutic strategies to target both telomerase expressing and ALT cancers. For telomerase-expressing neuroblastoma the most promising targeted agent to date is 6-thio-2'-deoxyguanosine, however clinical development of this agent is required. In osteosarcoma cell lines with ALT, selective sensitivity to ATR inhibition has been reported. However, we present data showing that in fact ALT neuroblastoma cells are more resistant to the clinical ATR inhibitor AZD6738 compared to other neuroblastoma subtypes. More recently a number of additional candidate compounds have been shown to show selectivity for ALT cancers, such as Tetra-Pt (bpy), a compound targeting the telomeric G-quadruplex and pifithrin-α, a putative p53 inhibitor. Further pre-clinical evaluation of these compounds in neuroblastoma models is warranted.In summary, telomere maintenance targeting strategies offer a significant opportunity to develop effective new therapies, applicable to a large proportion of children with high-risk neuroblastoma. In parallel to clinical development, more pre-clinical research specifically for neuroblastoma is urgently needed, if we are to improve survival for this common poor outcome tumour of childhood.},
}
@article {pmid32372689,
year = {2020},
author = {Pisanu, C and Congiu, D and Manchia, M and Caria, P and Cocco, C and Dettori, T and Frau, DV and Manca, E and Meloni, A and Nieddu, M and Noli, B and Pinna, F and Robledo, R and Sogos, V and Ferri, GL and Carpiniello, B and Vanni, R and Bocchetta, A and Severino, G and Ardau, R and Chillotti, C and Zompo, MD and Squassina, A},
title = {Differences in telomere length between patients with bipolar disorder and controls are influenced by lithium treatment.},
journal = {Pharmacogenomics},
volume = {21},
number = {8},
pages = {533-540},
doi = {10.2217/pgs-2020-0028},
pmid = {32372689},
issn = {1744-8042},
mesh = {Adult ; Antidepressive Agents/pharmacology/*therapeutic use ; Bipolar Disorder/diagnosis/*drug therapy/*genetics ; Female ; Genome-Wide Association Study/*methods ; Humans ; Leukocytes/drug effects/physiology ; Lithium Compounds/pharmacology/*therapeutic use ; Longitudinal Studies ; Male ; Middle Aged ; Telomere/drug effects/physiology ; Telomere Shortening/*drug effects/physiology ; Treatment Outcome ; },
abstract = {Aim: To assess the role of lithium treatment in the relationship between bipolar disorder (BD) and leukocyte telomere length (LTL). Materials &amp; methods: We compared LTL between 131 patients with BD, with or without a history of lithium treatment, and 336 controls. We tested the association between genetically determined LTL and BD in two large genome-wide association datasets. Results: Patients with BD with a history lithium treatment showed longer LTL compared with never-treated patients (p = 0.015), and similar LTL compared with controls. Patients never treated with lithium showed shorter LTL compared with controls (p = 0.029). Mendelian randomization analysis showed no association between BD and genetically determined LTL. Conclusion: Our data support previous findings showing that long-term lithium treatment might protect against telomere shortening.},
}
@article {pmid32367011,
year = {2021},
author = {Rubio Galisteo, JM and Fernández, L and Gómez Gómez, E and de Pedro, N and Cano Castiñeira, R and Pedregosa, AB and Guler, I and Carrasco Valiente, J and Esteban, L and González, S and Castelló, N and Otero, L and García, J and Segovia, E and Requena Tapia, MJ and Najarro, P},
title = {Telomere-based risk models for the early diagnosis of clinically significant prostate cancer.},
journal = {Prostate cancer and prostatic diseases},
volume = {24},
number = {1},
pages = {88-95},
pmid = {32367011},
issn = {1476-5608},
mesh = {Aged ; Biomarkers, Tumor/blood ; *Early Diagnosis ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Neoplasm Grading ; *Neoplasm Staging ; Prospective Studies ; Prostate-Specific Antigen/blood ; Prostatic Neoplasms/blood/*diagnosis/genetics ; ROC Curve ; Risk Assessment/*methods ; Risk Factors ; Telomere/*genetics ; },
abstract = {BACKGROUND: The objective of this study was to explore telomere-associated variables (TAV) as complementary biomarkers in the early diagnosis of prostate cancer (PCa), analyzing their application in risk models for significant PCa (Gleason score > 6).<br><br>METHODS: As part of a larger prospective longitudinal study of patients with suspicion of PCa undergoing prostate biopsy according to clinical practice, a subgroup of patients (n&#x2009;=&#x2009;401) with PSA 3-10&#x2009;ng/ml and&#xa0;no prior biopsies was used to evaluate the contribution of TAV to discern non-significant PCa from significant PCa. The cohort was randomly split for training (2/3) and validation (1/3) of the models. High-throughput quantitative fluorescence in-situ hybridization was used to evaluate TAV in peripheral blood mononucleated cells. Models were generated following principal component analysis and random forest and their utility as risk predictors was evaluated by analyzing their predictive capacity and accuracy, summarized by ROC curves, and their clinical benefit with decision curves analysis.<br><br>RESULTS: The median age of the patients was 63 years, with a median PSA of 5&#x2009;ng/ml and a percentage of PCa diagnosis of 40.6% and significant PCa of 19.2%. Two TAV-based risk models were selected (TAV models 1 and 2) with an AUC&#x2009;&#x2265;&#x2009;0.83 in the full study cohort, and AUC&#x2009;>&#x2009;0.76 in the internal validation cohort. Both models showed an improvement in decision capacity when compared to the application of the PCPT-RC in the low-risk probabilities range. In the validation cohort, with TAV models 1 and 2, 33% /48% of biopsies would have been avoided losing 0/10.3% of significant PCa, respectively. The models were also tested and validated on an independent, retrospective, non contemporary cohort.<br><br>CONCLUSIONS: Telomere analysis through TAV should be considered as a new risk-score biomarker with potential to increase the prediction capacity of significant PCa in patients with PSA between 3-10&#x2009;ng/ml.},
}
@article {pmid32366852,
year = {2020},
author = {Laroche-Clary, A and Chaire, V and Verbeke, S and Algéo, MP and Malykh, A and Le Loarer, F and Italiano, A},
title = {ATR Inhibition Broadly Sensitizes Soft-Tissue Sarcoma Cells to Chemotherapy Independent of Alternative Lengthening Telomere (ALT) Status.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {7488},
pmid = {32366852},
issn = {2045-2322},
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins/*antagonists &amp; inhibitors/metabolism ; Cell Line, Tumor ; DNA Damage ; Female ; Humans ; Isoxazoles/*pharmacology ; Mice ; Mice, Knockout ; Neoplasm Proteins/*antagonists &amp; inhibitors/metabolism ; Pyrazines/*pharmacology ; S Phase Cell Cycle Checkpoints/*drug effects ; *Sarcoma/drug therapy/metabolism/pathology ; Telomere Homeostasis/*drug effects ; Xenograft Model Antitumor Assays ; },
abstract = {Only few drugs have shown activity in patients with advanced soft-tissue and the median overall survival is only 18 months. Alterations of genes involved in the DNA damage repair pathway have been associated with sarcoma risk and prognosis. ATR plays a crucial role in maintaining genomic integrity by responding to a large spectrum of DNA damage, including double strand breaks (DSBs) that interfere with replication. The objective of this study is to evaluate the pre-clinical activity of ATR inhibition in soft tissue sarcomas (STS). We explored the ability of the ATR inhibitor, VE-822, to prevent chemotherapy-induced intra-S-phase checkpoint activation and evaluated the antitumor potential of this combination in vitro and in vivo in STS cell lines and in a patient-derived xenograft model. The combination of VE-822 and gemcitabine in vitro was synergistic, inhibited cell proliferation, induced apoptosis, and accumulated in the S phase of the cell cycle with higher efficacy than either single agent alone. The combination also resulted in enhanced γH2AX intranuclear accumulation as a result of DNA damage induction. These effects were unrelated to the alternative lengthening of telomeres pathway. In vivo, the combination of VE-822 and gemcitabine significantly enhanced tumor growth inhibition and progression-free survival in an aggressive model of undifferentiated pleomorphic sarcoma. The combination of ATR inhibitor and chemotherapy is beneficial in pre-clinical models of soft-tissue sarcoma and deserves further exploration in the clinical setting.},
}
@article {pmid32366311,
year = {2020},
author = {Sun, Q and Liu, J and Cheng, G and Dai, M and Liu, J and Qi, Z and Zhao, J and Li, W and Kong, F and Liu, G and Björkholm, M and Xu, D},
title = {The telomerase gene polymorphisms, but not telomere length, increase susceptibility to primary glomerulonephritis/end stage renal diseases in females.},
journal = {Journal of translational medicine},
volume = {18},
number = {1},
pages = {184},
pmid = {32366311},
issn = {1479-5876},
mesh = {Case-Control Studies ; Female ; Genetic Predisposition to Disease ; Genotype ; *Glomerulonephritis/genetics ; Humans ; *Kidney Failure, Chronic/genetics ; Leukocytes ; Polymorphism, Single Nucleotide/genetics ; *Telomerase/genetics ; Telomere/genetics ; },
abstract = {BACKGROUND: Primary glomerulonephritis (GN) is the leading cause of chronic kidney disease (CKD) and frequently progresses into end stage renal diseases (ESRDs). Shorter leukocyte telomere length (LTL) has been implicated in the CKD susceptibility and diminished kidney function, however, it is unclear whether the variants in telomerase genes contribute to risk to GN/CKD/ESRD. Here we address this issue by determining their association with the genetic variants of rs12696304 at the telomerase RNA component (TERC) and rs2736100 at the telomerase reverse transcriptase (TERT) loci.<br><br>METHODS: The study includes 769 patients (243 primary GN-derived CKD and 526 ESRD cases) and sex-/age-matched healthy controls. Genomic DNA was extracted from peripheral blood of both controls and patients. Genotyping of rs12696304 and rs2736100 variants was carried out using PCR-based assays. Leukocyte telomere length (LTL) was determined using quantitative PCR (qPCR).<br><br>RESULTS: A significantly higher frequency of TERC rs12696304 G allele was observed in patients and associated with increased disease risk (C vs G: OR&#x2009;=&#x2009;1.334, 95% CI 1.112-1.586, P&#x2009;=&#x2009;0.001; CC&#x2009;+&#x2009;GC vs GG: OR&#x2009;=&#x2009;1.334, 95% CI 1.122-1.586, P&#x2009;=&#x2009;0.001). Further analyses showed that such significant differences were only present between female controls and patients (C vs G: OR&#x2009;=&#x2009;1.483, 95% CI 1.140-1.929, P&#x2009;=&#x2009;0.003; CC&#x2009;+&#x2009;GC vs CC: OR&#x2009;=&#x2009;1.692, 95% CI 1.202-2.383, P&#x2009;=&#x2009;0.003), but not males. There were no differences in rs2736100 variants between controls and patients, but female ESRD patients carried significantly higher C allele frequencies than did female controls (A vs C: OR&#x2009;=&#x2009;1.306, 95% CI 1.005-1.698, P&#x2009;=&#x2009;0.046; AA vs CC: OR&#x2009;=&#x2009;1.781, 95% CI 1.033-3.070, P&#x2009;=&#x2009;0.037). There was no difference in LTL between controls and patients.<br><br>CONCLUSIONS: Our results reveal that the TERC rs12696304 and TERT rs2736100 polymorphisms, but not LTL per se, contribute to GN/CDK/ESRD risk.},
}
@article {pmid32364595,
year = {2020},
author = {Martens, DS and Janssen, BG and Bijnens, EM and Clemente, DBP and Vineis, P and Plusquin, M and Nawrot, TS},
title = {Association of Parental Socioeconomic Status and Newborn Telomere Length.},
journal = {JAMA network open},
volume = {3},
number = {5},
pages = {e204057},
pmid = {32364595},
issn = {2574-3805},
support = {MR/S019669/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Aging/*genetics ; Cohort Studies ; *Fathers ; Female ; Humans ; Infant, Newborn ; Male ; *Mothers ; Netherlands ; Pregnancy ; Prospective Studies ; Social Class ; Surveys and Questionnaires ; Telomere ; White People/genetics ; },
abstract = {IMPORTANCE: Low socioeconomic status is associated with higher all-cause mortality and risks for aging-related diseases. Biological aging is a potential process underlying health conditions related to social disadvantages, which may be present from birth onward.<br><br>OBJECTIVE: To evaluate the association of parental socioeconomic status with telomere length (TL) at birth, a marker of biological aging.<br><br>This prospective birth cohort study was conducted among 1504 mother-newborn pairs in Belgium recruited between February 1, 2010, and July 1, 2017.<br><br>EXPOSURES: Parental socioeconomic measures, including maternal educational level, occupation, paternal educational level, and neighborhood income based on median annual household income.<br><br>MAIN OUTCOMES AND MEASURES: Mean relative TL was measured in cord blood and placental tissue. By constructing a principal component, an integrative socioeconomic measure was derived that integrates parental socioeconomic status and neighborhood income. Multivariable adjusted regression analyses were performed to associate the integrative socioeconomic measure and TL at birth.<br><br>RESULTS: In 1026 newborns (517 boys; mean [SD] gestational age, 39.2 [1.4] weeks), a higher socioeconomic status was associated with longer cord blood TL and placental TL. Each unit increment in the integrative socioeconomic status measure was associated with 2.1% (95% CI, 0.9%-3.4%; P&#x2009;<&#x2009;.001) longer cord blood TL in boys, while no association was observed for girls (0.5% longer cord blood TL; 95% CI, -0.9% to 1.8%; P&#x2009;=&#x2009;.50). The sex-specific socioeconomic status interaction revealed a stronger association in boys compared with newborn girls (1.6%; 95% CI, 0.02%-3.3%; P&#x2009;=&#x2009;.047 for interaction). In placental tissue, higher socioeconomic status was associated with 1.8% (95% CI, 0.3%-3.3%; P&#x2009;=&#x2009;.02) longer TL in newborn boys but not in girls (0.4% longer TL; 95% CI, -1.2% to 2.0%; P&#x2009;=&#x2009;.63). For placental tissue, no sex and socioeconomic status interaction on TL was observed (1.4%; 95% CI, -0.5% to 3.4%; P&#x2009;=&#x2009;.16 for interaction).<br><br>CONCLUSIONS AND RELEVANCE: This study suggests that parental socioeconomic status is associated with newborn TL, especially in boys. The results indicate that familial social economic factors are associated with the potential cellular longevity of the next generation, with a potential higher transgenerational vulnerability for newborn boys.},
}
@article {pmid32364591,
year = {2020},
author = {Notterman, DA and Schneper, L},
title = {Telomere Time-Why We Should Treat Biological Age Cautiously.},
journal = {JAMA network open},
volume = {3},
number = {5},
pages = {e204352},
doi = {10.1001/jamanetworkopen.2020.4352},
pmid = {32364591},
issn = {2574-3805},
support = {R01 HD076592/HD/NICHD NIH HHS/United States ; },
mesh = {Age Factors ; *Aging ; Humans ; Infant, Newborn ; Parents ; Social Class ; *Telomere ; },
}
@article {pmid32359029,
year = {2020},
author = {Aoulad Fares, D and Schalekamp-Timmermans, S and Nawrot, TS and Steegers-Theunissen, RPM},
title = {Preconception telomere length as a novel maternal biomarker to assess the risk of spina bifida in the offspring.},
journal = {Birth defects research},
volume = {112},
number = {9},
pages = {645-651},
pmid = {32359029},
issn = {2472-1727},
support = {//The Bo Hjelt Foundation for Spina Bifida in memory of Madeleine Hjelt./International ; },
mesh = {Animals ; Biomarkers ; Female ; Mice ; *Neural Tube Defects/genetics ; Pregnancy ; Risk Factors ; *Spinal Dysraphism/genetics ; Telomere/genetics ; },
abstract = {BACKGROUND: Periconception interactions between maternal conditions and environmental and genetic factors are involved in the pathogenesis and prevention of neural tube defects (NTD), such as spina bifida. These factors have in common that they can impair the oxidative pathway, resulting in excessive (chronic) oxidative stress and inflammation.<br><br>METHODS: Review of the literature concerning underlying mechanisms and biomarkers of aging particularly during reproduction. A number of molecular markers for biological aging have been identified, including telomere length (TL). Excessive telomere shortening is an index of senescence, causes genomic instability and is associated with a higher risk of age-related diseases. Furthermore, TL shortening is associated with the similar environmental and lifestyle exposures associated with NTD risk.<br><br>RESULTS: Embryonic mice deficient in the telomerase gene show shorter TL and failure of closure of the neural tube as the main defect, suggesting that this developmental process is among the most sensitive to telomere loss and chromosomal instability.<br><br>CONCLUSIONS: From this background, we hypothesize that preconceptional long term exposure to harmful environmental and lifestyle risk factors accelerates a woman's aging process, which can be measured by TL, and thereby her underlying risk of NTD offspring. Alternatively, it might be that women with an increased NTD risk already exhibit a more advanced biological age before the onset of pregnancy compared to women of identical calendar age.},
}
@article {pmid32357278,
year = {2020},
author = {Cao, H and Zhai, Y and Ji, X and Wang, Y and Zhao, J and Xing, J and An, J and Ren, T},
title = {Noncoding telomeric repeat-containing RNA inhibits the progression of hepatocellular carcinoma by regulating telomerase-mediated telomere length.},
journal = {Cancer science},
volume = {111},
number = {8},
pages = {2789-2802},
pmid = {32357278},
issn = {1349-7006},
support = {81802772//National Natural Science Foundation of China/ ; 81872302//National Natural Science Foundation of China/ ; 81372606 81773177 81802345//National Natural Science Foundation of China/ ; 2017SF-188//Natural Science Foundation of Shanxi Province/ ; },
mesh = {Animals ; Carcinoma, Hepatocellular/*genetics/mortality/pathology ; Cell Line, Tumor ; Disease ; Disease Progression ; Down-Regulation ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Humans ; Liver/pathology ; Liver Neoplasms/*genetics/mortality/pathology ; Male ; Mice ; RNA, Long Noncoding/*metabolism ; Shelterin Complex ; Telomerase/*genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Up-Regulation ; Xenograft Model Antitumor Assays ; },
abstract = {Telomeric repeat-containing RNA (TERRA) is closely involved in the regulation of telomere length, which plays critical roles in tumorigenesis. However, the biological significance of TERRA in hepatocellular carcinoma (HCC) remains largely unknown. In this study, we found that HCC cells show a frequent downregulation of TERRA and its positive regulator TTAGGG repeat binding factor-1 (TRF1), whereas the negative regulator TTAGGG repeat binding factor-1 (TRF2) was upregulated. We found that TERRA, TRF1, and TRF2 contributed to poor prognosis of HCC patients. Importantly, we found that the downregulation of TERRA significantly promoted HCC cell growth and metastasis in vitro and in vivo, whereas the upregulation of TERRA showed an opposite effect. Mechanistically, downregulation of TERRA significantly increased telomerase activity and promoted telomere elongation. Moreover, the inhibitory effects of TERRA overexpression on the growth and metastasis of HCC cells were reversed by treatment with TA-65 that activates telomerase activity. In contrast, the protumor effect of TERRA downregulation was reversed by treatment with TMPyP4 that inhibits telomerase activity. Our findings reveal that TERRA plays a critical role in HCC cell growth and metastasis, indicating that TERRA is a potential therapeutic target for HCC.},
}
@article {pmid32355801,
year = {2020},
author = {Lu, Y and Jiang, H and Li, B and Cao, L and Shen, Q and Yi, W and Ju, Z and Chen, L and Han, F and Appelgren, D and Segelmark, M and de Buhr, N and von Köckritz-Blickwede, M and Chen, J},
title = {Telomere dysfunction promotes small vessel vasculitis via the LL37-NETs-dependent mechanism.},
journal = {Annals of translational medicine},
volume = {8},
number = {6},
pages = {357},
pmid = {32355801},
issn = {2305-5839},
abstract = {BACKGROUND: Small vessel vasculitis (SVV) is a group of systemic autoimmune diseases that are mediated by neutrophil extracellular traps (NETs) in response to cathelicidin LL37, an aging molecular marker, which could be induced by telomere dysfunction. Therefore, in this study, we evaluated the hypothesis that telomere dysfunction in neutrophils may promote SVV via an LL37-NETs-dependent mechanism.<br><br>METHODS: We contrasted the release of neutrophil NETs from mice with telomere dysfunction, mice with DNA damage and wide-type mice. Neutrophil telomere length, the expression of LL37, and the formation of NETs were measured in SVV patients and healthy controls (HCs). The co-expression of &#x3b3;H2AX, LL37, and NETs were detected in SVV patients to evaluate the association of the immune aging of neutrophils and pro-inflammatory conditions. LL37 inhibitor was used to verify its key role in NETs release in SVV patients and DNA damage mice.<br><br>RESULTS: We found that NETs were over-induced by telomere dysfunction and DNA damage in mice, which may be associated with a marked increase in LL37. For patients with SVV, telomeres in neutrophils were significantly shortened, which was also associated with higher levels of LL37 and NETs. Inhibition of LL37 reduced the NETs released from neutrophils.<br><br>CONCLUSIONS: Taken together, the results of these studies suggest that dysfunction of telomeres may promote SVV through the mechanism of LL37-dependent NETs. Thus, targeting the LL37-NETs may be a novel therapy for SVV.},
}
@article {pmid32355752,
year = {2020},
author = {Dong, K and Zhang, Y and Huang, JJ and Xia, SS and Yang, Y},
title = {Shorter leucocyte telomere length as a potential biomarker for nonalcoholic fatty liver disease-related advanced fibrosis in T2DM patients.},
journal = {Annals of translational medicine},
volume = {8},
number = {6},
pages = {308},
pmid = {32355752},
issn = {2305-5839},
abstract = {BACKGROUND: Telomere length has been linked to hepatic fibrosis. Type 2 diabetes mellitus (T2DM) is considered as a particular risk for the development of hepatic fibrosis. This study is to explore the association of leucocyte telomere length (LTL) and nonalcoholic fatty liver disease (NAFLD)-related advanced fibrosis in T2DM patients.<br><br>METHODS: A total of 442 patients with T2DM were enrolled from Tongji Hospital, Wuhan, China. Clinical features were collected and LTL was measured by Southern blot-based terminal restriction fragment length. Hepatic advanced fibrosis was determined by both the NAFLD fibrosis score (NFS) and fibrosis-4 score (FIB-4). Explanatory factors for advanced fibrosis in T2DM patients were identified using multiple logistic regressions.<br><br>RESULTS: T2DM patients with advanced fibrosis had significant shorter LTL than the no-advanced group. Additionally, LTL, age, male and aminotransferase (ALT) were significantly associated with advanced fibrosis status in T2DM patients. Longer diabetes duration was found to have a strong association with advanced fibrosis in elder T2DM patients.<br><br>CONCLUSIONS: Shorter LTL was significantly associated with advanced fibrosis in T2DM patients. Longer diabetes duration was an independent risk factor for advanced fibrosis in old T2DM patients. Shorter LTL may be used as a biomarker for advanced fibrosis in T2DM patients.},
}
@article {pmid32355231,
year = {2020},
author = {Choudhury, AR and Ju, Z and Djojosubroto, MW and Schienke, A and Lechel, A and Schaetzlein, S and Jiang, H and Stepczynska, A and Wang, C and Buer, J and Lee, HW and von Zglinicki, T and Ganser, A and Schirmacher, P and Nakauchi, H and Rudolph, KL},
title = {Author Correction: Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation.},
journal = {Nature genetics},
volume = {52},
number = {5},
pages = {548},
doi = {10.1038/s41588-020-0593-6},
pmid = {32355231},
issn = {1546-1718},
abstract = {An amendment to this paper has been published and can be accessed via a link at the top of the paper.},
}
@article {pmid32354058,
year = {2020},
author = {Ingles, ED and Deakin, JE},
title = {Comparative Cytogenetic Mapping and Telomere Analysis Provide Evolutionary Predictions for Devil Facial Tumour 2.},
journal = {Genes},
volume = {11},
number = {5},
pages = {},
pmid = {32354058},
issn = {2073-4425},
mesh = {Animals ; Facial Neoplasms/*genetics/pathology ; Humans ; In Situ Hybridization, Fluorescence/methods ; Karyotype ; Karyotyping ; Marsupialia/*genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {The emergence of a second transmissible tumour in the Tasmanian devil population, devil facial tumour 2 (DFT2), has prompted questions on the origin and evolution of these transmissible tumours. We used a combination of cytogenetic mapping and telomere length measurements to predict the evolutionary trajectory of chromosome rearrangements in DFT2. Gene mapping by fluorescence in situ hybridization (FISH) provided insight into the chromosome rearrangements in DFT2 and identified the evolution of two distinct DFT2 lineages. A comparison of devil facial tumour 1 (DFT1) and DFT2 chromosome rearrangements indicated that both started with the fusion of a chromosome, with potentially critically short telomeres, to chromosome 1 to form dicentric chromosomes. In DFT1, the dicentric chromosome resulted in breakage-fusion-bridge cycles leading to highly rearranged chromosomes. In contrast, the silencing of a centromere on the dicentric chromosome in DFT2 stabilized the chromosome, resulting in a less rearranged karyotype than DFT1. DFT2 retains a bimodal distribution of telomere length dimorphism observed on Tasmanian devil chromosomes, a feature lost in DFT1. Using long term cell culture, we observed homogenization of telomere length over time. We predict a similar homogenization of telomere lengths occurred in DFT1, and that DFT2 is unlikely to undergo further substantial rearrangements due to maintained telomere length.},
}
@article {pmid32353828,
year = {2020},
author = {De Vusser, K and Winckelmans, E and Martens, D and Lerut, E and Kuypers, D and Nawrot, T and Naesens, M},
title = {Intrarenal arteriosclerosis and telomere attrition associate with dysregulation of the cholesterol pathway.},
journal = {Aging},
volume = {12},
number = {9},
pages = {7830-7847},
pmid = {32353828},
issn = {1945-4589},
mesh = {Aging/*physiology ; Arteriosclerosis/*metabolism/pathology ; Cholesterol/*metabolism ; Female ; Humans ; Male ; Middle Aged ; Renal Artery/*pathology ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Recently, we demonstrated that arteriosclerosis in the smaller intrarenal arteries is associated with shorter telomere length, independently of history of cardiovascular events and calendar age. This suggests that intrarenal arteriosclerosis reflects replicative senescence, although the underlying molecular alterations remain unclear.<br><br>RESULTS: Shorter intrarenal telomere length associated significantly with the presence of renal arteriosclerosis (T/S ratio 0.91&#xb1;0.15 vs. 1.20&#xb1;0.23 with vs. without arteriosclerosis, p=0.007, test cohort; T/S ratio 0.98 &#xb1;0.26 vs. 1.03 &#xb1;0.18 with vs. without arteriosclerosis, p=0.02, validation cohort). The presence versus absence of intrarenal arteriosclerosis was associated with differential expression of 1472 transcripts. Pathway analysis revealed enrichment of molecules involved in the superpathway of cholesterol biosynthesis as the most significant. The differential expression of these genes was confirmed in the independent validation cohort. Furthermore, the specific mRNA expression of the molecules in the superpathway of cholesterol biosynthesis associated significantly with intrarenal telomere length, and with history of cardiovascular events.<br><br>INTERPRETATION: Our study illustrates that the superpathway of cholesterol biosynthesis interacts with the previously published association between shorter telomere length and arteriosclerosis.<br><br>METHODS: This study included a test cohort of 40 consecutive kidney donors (calendar age 48.0 &#xb1; 15), with biopsies obtained prior to transplantation. Intrarenal leucocyte telomere length content was assessed using quantitative RT-PCR. Whole genome microarray mRNA expression analysis was performed using Affymetrix Gene 2.0 ST arrays. We investigated the associations between mRNA gene expression, telomere length as marker of replicative senescence, and intrarenal arteriosclerosis (Banff "cv" score = vascular fibrous intimal thickening = intimal hyperplasia) using adjusted multiple regression models. For biological interpretation and pathway overrepresentation analysis, we used Ingenuity Pathway Analysis. The significant pathways and genes were validated in an independent validation cohort of 173 kidney biopsies obtained prior to transplantation.},
}
@article {pmid32349350,
year = {2020},
author = {M'kacher, R and Colicchio, B and Borie, C and Junker, S and Marquet, V and Heidingsfelder, L and Soehnlen, K and Najar, W and Hempel, WM and Oudrhiri, N and Wilhelm-Murer, N and Miguet, M and Arnoux, M and Ferrapie, C and Kerbrat, W and Plesch, A and Dieterlen, A and Girinsky, T and Voisin, P and Deschenes, G and Tabet, AC and Yardin, C and Bennaceur-Griscelli, A and Fenech, M and Carde, P and Jeandidier, E},
title = {Telomere and Centromere Staining Followed by M-FISH Improves Diagnosis of Chromosomal Instability and Its Clinical Utility.},
journal = {Genes},
volume = {11},
number = {5},
pages = {},
pmid = {32349350},
issn = {2073-4425},
mesh = {Centromere/*genetics ; Chromosomal Instability/*genetics ; Chromosome Aberrations ; Cytogenetic Analysis/methods ; Female ; Humans ; In Situ Hybridization, Fluorescence/methods ; Lymphocytes/pathology ; Male ; Metaphase/genetics ; Middle Aged ; Neoplasms/classification/*diagnosis/genetics/pathology ; Telomere/*genetics ; },
abstract = {Dicentric chromosomes are a relevant marker of chromosomal instability. Their appearance is associated with telomere dysfunction, leading to cancer progression and a poor clinical outcome. Here, we present Telomere and Centromere staining followed by M-FISH (TC+M-FISH) for improved detection of telomere dysfunction and the identification of dicentric chromosomes in cancer patients and various genetic syndromes. Significant telomere length shortening and significantly higher frequencies of telomere loss and deletion were found in the peripheral lymphocytes of patients with cancer and genetic syndromes relative to similar age-matched healthy donors. We assessed our technique against conventional cytogenetics for the detection of dicentric chromosomes by subjecting metaphase preparations to both approaches. We identified dicentric chromosomes in 28/50 cancer patients and 21/44 genetic syndrome patients using our approach, but only 7/50 and 12/44, respectively, using standard cytogenetics. We ascribe this discrepancy to the identification of the unique configuration of dicentric chromosomes. We observed significantly higher frequencies of telomere loss and deletion in patients with dicentric chromosomes (p < 10[-4]). TC+M-FISH analysis is superior to classical cytogenetics for the detection of chromosomal instability. Our approach is a relatively simple but useful tool for documenting telomere dysfunction and chromosomal instability with the potential to become a standard additional diagnostic tool in medical genetics and the clinic.},
}
@article {pmid32344376,
year = {2020},
author = {Hsu, RYC and Lin, YC and Redon, C and Sun, Q and Singh, DK and Wang, Y and Aggarwal, V and Mitra, J and Matur, A and Moriarity, B and Ha, T and Aladjem, MI and Prasanth, KV and Prasanth, SG},
title = {ORCA/LRWD1 Regulates Homologous Recombination at ALT-Telomeres by Modulating Heterochromatin Organization.},
journal = {iScience},
volume = {23},
number = {5},
pages = {101038},
pmid = {32344376},
issn = {2589-0042},
support = {R01 GM099669/GM/NIGMS NIH HHS/United States ; ZIA BC010419/ImNIH/Intramural NIH HHS/United States ; R01 GM125196/GM/NIGMS NIH HHS/United States ; R21 AG065748/AG/NIA NIH HHS/United States ; R01 GM088252/GM/NIGMS NIH HHS/United States ; },
abstract = {Telomeres are maintained by telomerase or in a subset of cancer cells by a homologous recombination (HR)-based mechanism, Alternative Lengthening of Telomeres (ALT). The mechanisms regulating telomere-homeostasis in ALT cells remain unclear. We report that a replication initiator protein, Origin Recognition Complex-Associated (ORCA/LRWD1), by localizing at the ALT-telomeres, modulates HR activity. ORCA's localization to the ALT-telomeres is facilitated by its interaction to SUMOylated shelterin components. The loss of ORCA in ALT-positive cells elevates the levels of two mediators of HR, RPA and RAD51, and consistent with this, we observe increased ALT-associated promyelocytic leukemia body formation and telomere sister chromatid exchange. ORCA binds to RPA and modulates the association of RPA to telomeres. Finally, the loss of ORCA causes global chromatin decondensation, including at the telomeres. Our results demonstrate that ORCA acts as an inhibitor of HR by modulating RPA binding to ssDNA and inducing chromatin compaction.},
}
@article {pmid32342830,
year = {2020},
author = {Ashrafi, A and Cosentino, S and Kang, MS and Lee, JH and Schupf, N and Andersen, SL and Christensen, K and Province, MA and Thyagarajan, B and Zmuda, JM and Honig, LS},
title = {Leukocyte Telomere Length Is Unrelated to Cognitive Performance Among Non-Demented and Demented Persons: An Examination of Long Life Family Study Participants.},
journal = {Journal of the International Neuropsychological Society : JINS},
volume = {26},
number = {9},
pages = {906-917},
pmid = {32342830},
issn = {1469-7661},
support = {P30 AG066462/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; U01 AG023749/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging ; Biomarkers ; Cognition/*physiology ; Cognitive Aging/physiology ; Cohort Studies ; Dementia/*physiopathology ; Family ; Female ; Humans ; Leukocytes/*physiology ; Longevity/*physiology ; Male ; Neuropsychological Tests ; Telomere/*physiology ; },
abstract = {OBJECTIVE: Leukocyte telomere length (LTL) is a widely hypothesized biomarker of biological aging. Persons with shorter LTL may have a greater likelihood of developing dementia. We investigate whether LTL is associated with cognitive function, differently for individuals without cognitive impairment versus individuals with dementia or incipient dementia.<br><br>METHOD: Enrolled subjects belong to the Long Life Family Study (LLFS), a multi-generational cohort study, where enrollment was predicated upon exceptional family longevity. Included subjects had valid cognitive and telomere data at baseline. Exclusion criteria were age &#x2264; 60 years, outlying LTL, and missing sociodemographic/clinical information. Analyses were performed using linear regression with generalized estimating equations, adjusting for sex, age, education, country, generation, and lymphocyte percentage.<br><br>RESULTS: Older age and male gender were associated with shorter LTL, and LTL was significantly longer in family members than spouse controls (p < 0.005). LTL was not associated with working or episodic memory, semantic processing, and information processing speed for 1613 cognitively unimpaired individuals as well as 597 individuals with dementia or incipient dementia (p < 0.005), who scored significantly lower on all cognitive domains (p < 0.005).<br><br>CONCLUSIONS: Within this unique LLFS cohort, a group of families assembled on the basis of exceptional survival, LTL is unrelated to cognitive ability for individuals with and without cognitive impairment. LTL does not change in the context of degenerative disease for these individuals who are biologically younger than the general population.},
}
@article {pmid32341108,
year = {2020},
author = {Ley, B and Liu, S and Elicker, BM and Henry, TS and Vittinghoff, E and Golden, JA and Jones, KD and Wolters, PJ},
title = {Telomere length in patients with unclassifiable interstitial lung disease: a cohort study.},
journal = {The European respiratory journal},
volume = {56},
number = {2},
pages = {},
doi = {10.1183/13993003.00268-2020},
pmid = {32341108},
issn = {1399-3003},
mesh = {Cohort Studies ; Humans ; *Idiopathic Pulmonary Fibrosis ; Lung ; *Lung Diseases, Interstitial/genetics ; Telomere/genetics ; },
}
@article {pmid32339571,
year = {2020},
author = {Liao, TC and Ma, TZ and Chen, SB and Cilibrizzi, A and Zhang, MJ and Li, JH and Zhou, CQ},
title = {Human telomere double G-quadruplex recognition by berberine-bisquinolinium imaging conjugates in vitro and cells.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ijbiomac.2020.04.171},
pmid = {32339571},
issn = {1879-0003},
abstract = {Molecular tools of double or multimeric G-quadruplexes have been given higher requirements on detection sensitivity, thermal stabilization and cell imaging to establish functions of these G-quadruplex aggregates and biological mechanisms as anticancer reagents. Here, two smart berberine-bisquinolinium conjugates (Ber-360A and Ber-PDS) by linking the berberine fluorophore ligand and an established G-quadruplex binder (i.e. bisquinolinium scaffold), have been designed and evaluated their activities and mechanisms for G-quadruplex aggregation. Two conjugates, especially Ber-PDS, are two highly selective, sensitive and fluorescent sensors which can distinguish human telomere double G-quadruplexes from other type G-quadruplexes and ds DNA. These two ligands could be the first example to stack two adjacent G-quadruplex units and fluorescently recognize human telomere double G-quadruplexes. Furthermore, conjugate Ber-PDS could enter the nucleoli and target G-quadruplex DNA through microscopy experiments, and also display strong telomerase inhibition and antitumor activities.},
}
@article {pmid32339158,
year = {2020},
author = {Kordowitzki, P and Hamdi, M and Derevyanko, A and Rizos, D and Blasco, M},
title = {The effect of rapamycin on bovine oocyte maturation success and metaphase telomere length maintenance.},
journal = {Aging},
volume = {12},
number = {8},
pages = {7576-7584},
pmid = {32339158},
issn = {1945-4589},
mesh = {Animals ; Cattle ; Disease Models, Animal ; Embryonic Development ; Female ; In Vitro Oocyte Maturation Techniques/*methods ; Infertility, Female/metabolism/*therapy ; Metaphase ; Oocytes/*drug effects/metabolism ; Ovarian Follicle/cytology/*drug effects/metabolism ; Pregnancy ; *Pregnancy, Animal ; Sirolimus/*pharmacology ; Telomere Homeostasis/*drug effects ; },
abstract = {Maternal aging-associated reduction of oocyte viability is a common feature in mammals, but more research is needed to counteract this process. In women, the first aging phenotype appears with a decline in reproductive function, and the follicle number gradually decreases from menarche to menopause. Cows can be used as a model of early human embryonic development and reproductive aging because both species share a very high degree of similarity during follicle selection, cleavage, and blastocyst formation. Recently, it has been proposed that the main driver of aging is the mammalian target of rapamycin (mTOR) signaling rather than reactive oxygen species. Based on these observations, the study aimed to investigate for the first time the possible role of rapamycin on oocyte maturation, embryonic development, and telomere length in the bovine species, as a target for future strategies for female infertility caused by advanced maternal age. The 1nm rapamycin in vitro treatment showed the best results for maturation rates (95.21±4.18%) of oocytes and was considered for further experiments. In conclusion, rapamycin influenced maturation rates of oocytes in a concentration-dependent manner. Our results also suggest a possible link between mTOR, telomere maintenance, and bovine blastocyst formation.},
}
@article {pmid32337843,
year = {2020},
author = {Mason-Osann, E and Terranova, K and Lupo, N and Lock, YJ and Carson, LM and Flynn, RL},
title = {RAD54 promotes alternative lengthening of telomeres by mediating branch migration.},
journal = {EMBO reports},
volume = {21},
number = {6},
pages = {e49495},
pmid = {32337843},
issn = {1469-3178},
support = {R01 CA201446/CA/NCI NIH HHS/United States ; //Edward Mallinckrodt, Jr. Foundation (EMF)/International ; T32 GM008541/GM/NIGMS NIH HHS/United States ; //Pharmaceutical Research and Manufacturers of America Foundation (PhRMA Foundation)/International ; //Peter Paul Professorship/International ; },
mesh = {DNA Polymerase III/genetics ; DNA Repair ; DNA Replication ; *Telomere/genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {Cancer cells can activate the alternative lengthening of telomeres (ALT) pathway to promote replicative immortality. The ALT pathway promotes telomere elongation through a homologous recombination pathway known as break-induced replication (BIR), which is often engaged to repair single-ended double-stranded breaks (DSBs). Single-ended DSBs are resected to promote strand invasion and facilitate the formation of a local displacement loop (D-loop), which can trigger DNA synthesis, and ultimately promote telomere elongation. However, the exact proteins involved in the maturation, migration, and resolution of D-loops at ALT telomeres are unclear. In vitro, the DNA translocase RAD54 both binds D-loops and promotes branch migration suggesting that RAD54 may function to promote ALT activity. Here, we demonstrate that RAD54 is enriched at ALT telomeres and promotes telomeric DNA synthesis through its ATPase-dependent branch migration activity. Loss of RAD54 leads to the formation of unresolved recombination intermediates at telomeres that form ultra-fine anaphase bridges in mitosis. These data demonstrate an important role for RAD54 in promoting ALT-mediated telomere synthesis.},
}
@article {pmid32333143,
year = {2020},
author = {Zencir, S and Hsieh, MH and Hsu, JS and Ergun, Y and Chou, GL and Li, TK and Teng, SC and Topcu, Z},
title = {Selected ellipticine derivatives, known to target topoisomerase II, suppress the alternative lengthening of telomere (ALT) pathway in telomerase-negative cells.},
journal = {Journal of cancer research and clinical oncology},
volume = {146},
number = {7},
pages = {1671-1676},
pmid = {32333143},
issn = {1432-1335},
mesh = {Antineoplastic Agents/chemistry/*pharmacology ; Cell Line ; Ellipticines/chemistry/*pharmacology ; Fluorescent Antibody Technique ; Humans ; In Situ Hybridization, Fluorescence ; Telomerase/*genetics ; Telomere Homeostasis/*drug effects ; Topoisomerase II Inhibitors/*pharmacology ; },
abstract = {BACKGROUND: DNA topoisomerase and telomerase enzymes are popular targets of several anti-tumor drugs. Smooth proceeding of telomeric recombination requires Topoisomerase II (Top2), which is involved in telomere-telomere recombination through functioning in relaxation of positive supercoils among the cells adopting telomerase-independent Alternative lengthening of telomere (ALT) pathway. Most of the inhibitors reported so far have been designed to targetsolely telomerase-positive cells, which can potentially lead to therapeutic failure because tumor cells treated with telomerase inhibitors can activate the ALT pathway for telomere maintenance. Knowing that ALT cells are more sensitive against a Top2 inhibitor, ICRF-93 agent, compared to telomerase-positive cells, we analyzed two selected ellipticine derivatives that we recently reported as TopII-targeting compounds, to assess their effects on the formation of DNA breaks and suppression of ALT pathway.<br><br>METHODS: Cell viability, Comet, C-Circle assays, dot blot, immunofluorescence staining, and telomere fluorescence in situ hybridization (FISH) staining were used for determining the effect of the compounds on ALT status of tumor cells.<br><br>RESULTS AND CONCLUSIONS: Treatment of ALT cells with ellipticine derivatives resulted in the formation of DNA breaks and suppression of ALT-associated phenotypes in vitro. Our results will contribute to the development of therapeutic strategies combining telomerase and ALT pathway inhibitors.},
}
@article {pmid32330232,
year = {2020},
author = {Alonso-Pedrero, L and Ojeda-Rodríguez, A and Martínez-González, MA and Zalba, G and Bes-Rastrollo, M and Marti, A},
title = {Ultra-processed food consumption and the risk of short telomeres in an elderly population of the Seguimiento Universidad de Navarra (SUN) Project.},
journal = {The American journal of clinical nutrition},
volume = {111},
number = {6},
pages = {1259-1266},
doi = {10.1093/ajcn/nqaa075},
pmid = {32330232},
issn = {1938-3207},
mesh = {Aged ; Aged, 80 and over ; Aging/*metabolism ; Cross-Sectional Studies ; Fast Foods/*adverse effects ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Prospective Studies ; Spain ; Telomere/genetics/*metabolism ; Telomere Shortening ; },
abstract = {BACKGROUND: Telomere length (TL) is a marker of biological age that may be affected by dietary factors through oxidation and inflammation mechanisms. In addition, ultra-processed food (UPF) consumption has increased worldwide and it has been associated with the risk of developing several diseases.<br><br>OBJECTIVES: We aimed to evaluate the association between UPF consumption and the risk of having short telomeres in an elderly population of the Seguimiento Universidad de Navarra (SUN) Project.<br><br>METHODS: This is a cross-sectional study of 886 participants (645 men and 241 women) aged 57-91 y recruited from the SUN Project (Spain, 1999-2018). TL was measured from saliva samples by real-time qPCR at baseline and UPF consumption was collected using a validated 136-item FFQ and classified according to the NOVA system. We evaluated the association between consumption of energy-adjusted UPF categorized into quartiles (low, medium-low, medium-high, and high consumption) and the risk of having short telomeres (<20th percentile) using logistic regression models.<br><br>RESULTS: Those participants with the highest UPF consumption had almost twice the odds of having short telomeres compared with those with the lowest consumption (adjusted OR: 1.82; 95% CI: 1.05, 3.22; P-trend&#xa0;=&#xa0;0.03).<br><br>CONCLUSIONS: A higher consumption of UPF (>3 servings/d) was associated with higher risk of having shorter telomeres in an elderly Spanish population of the SUN Project.This trial was registered at clinicaltrials.gov as NCT02669602.},
}
@article {pmid32324874,
year = {2020},
author = {Vetter, VM and Spira, D and Banszerus, VL and Demuth, I},
title = {Epigenetic Clock and Leukocyte Telomere Length Are Associated with Vitamin D Status but not with Functional Assessments and Frailty in the Berlin Aging Study II.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {75},
number = {11},
pages = {2056-2063},
doi = {10.1093/gerona/glaa101},
pmid = {32324874},
issn = {1758-535X},
mesh = {Aged ; Aged, 80 and over ; Aging/*genetics ; Cross-Sectional Studies ; DNA Methylation ; *Epigenomics ; Female ; Frailty/*genetics ; Humans ; *Leukocytes ; Male ; Middle Aged ; Telomere Shortening/*genetics ; Vitamin D Deficiency/*genetics ; },
abstract = {DNA methylation (DNAm) age acceleration, a parameter derived via the epigenetic clock, has recently been suggested as a biomarker of aging. We hypothesized that accelerated biological aging, measured by both this new and the established biomarker of aging, relative leukocyte telomere length (rLTL), are associated with vitamin D deficiency. Moreover, we tested for an association between rLTL/DNAm age acceleration and different clinical assessments for functional capacity, including the Fried frailty score. Cross-sectional data of 1,649 participants of the Berlin Aging Study II was available (~50% female, age: 22-37 and 60-84 years). A seven cytosine-phosphate-guanine clock was estimated to calculate the DNAm age acceleration. rLTL was measured by quantitative real-time polymerase chain reaction (PCR). 25-hydroxyvitamin D (25(OH)D) serum levels <25 nmol/L was defined as vitamin D deficiency and <50 nmol/L as vitamin D insufficiency. Vitamin D-sufficient individuals had a 1.4 years lower mean DNAm age acceleration (p < .05, analysis of variance [ANOVA]) and a 0.11 longer rLTL (p < .001, ANOVA) than vitamin D-deficient participants. Likewise, vitamin D-sufficient participants had lower DNAm age acceleration (β = 1.060, p = .001) and longer rLTL (β = -0.070; p < .001) than vitamin D nonsufficient subjects in covariate-adjusted analysis. Neither DNAm age acceleration nor rLTL were significantly associated with the Fried frailty score or the functional assessments. Only the clock drawing test was associated with DNAm age acceleration (subgroup of older men: β = 1.898, p = .002). Whether the analyzed biomarkers of aging can be used to predict an individual's functional capacity or will be associated with frailty in the advanced course of aging, will be clarified by future longitudinal analyses.},
}
@article {pmid32323911,
year = {2020},
author = {Lewis, CR and Taguinod, F and Jepsen, WM and Cohen, J and Agrawal, K and Huentelman, MJ and Smith, CJ and Ringenbach, SDR and Braden, BB},
title = {Telomere Length and Autism Spectrum Disorder Within the Family: Relationships With Cognition and Sensory Symptoms.},
journal = {Autism research : official journal of the International Society for Autism Research},
volume = {13},
number = {7},
pages = {1094-1101},
doi = {10.1002/aur.2307},
pmid = {32323911},
issn = {1939-3806},
mesh = {Adolescent ; *Autism Spectrum Disorder/complications/genetics ; Child ; Child, Preschool ; Cognition ; Humans ; Infant ; Male ; Parents ; Siblings ; *Telomere/genetics ; },
abstract = {Telomeres are repetitive noncoding deoxynucleotide sequences that cap chromosomes to protect DNA. Telomere length (TL) is affected by both genetic and environmental factors, and shortening of telomeres is associated with multiple neuropsychiatric disorders, early life stress, and age-related cognitive dysfunction. Two previous studies associated shorter TL with autism spectrum disorder (ASD). We aimed to replicate this finding, describe TL in unaffected siblings, and explore novel relationships with symptoms and cognitive function in families with ASD. Participants were 212 male children and adolescents ages 1-17 years (86 with ASD, 57 unaffected siblings, and 69 typically developing [TD]) and 64 parents. TL was measured from blood leukocytes with quantitative real-time polymerase chain reaction and results are expressed by relative ratios with a single copy gene. We replicated that children and adolescents with ASD have shorter TL, compared to TD, and show that unaffected siblings have TL in between those of TD and ASD. We present novel associations between TL and sensory symptoms in ASD. Finally, we demonstrate cognitive functions, but not autistic traits, are related to TL in parents of children with ASD. Cognitive function and TL were not related in children and adolescents. As the third replication, our results elicit confidence in the finding that ASD is associated with shorter TL. Our novel sensory investigation suggests that shortened TL may be a biological mechanism of sensory symptoms in ASD. Furthermore, results highlight the need to better understand relationships between cognition, aging, and TL in families with ASD. Autism Res 2020, 13: 1094-1101. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Telomeres cap chromosomes to protect DNA. They progressively shorten as people age and are related to health outcomes. We replicated previous findings that children and adolescents with autism spectrum disorder (ASD) have shorter telomeres, compared to typically developing (TD), and show that unaffected siblings have telomere length (TL) in between those of TD and ASD. We find shortened TL is related to more severe sensory symptoms. This may mean families with ASD, especially those with elevated sensory symptoms, are at risk for worse age-related health outcomes.},
}
@article {pmid32322021,
year = {2020},
author = {Mangge, H and Herrmann, M and Almer, G and Zelzer, S and Moeller, R and Horejsi, R and Renner, W},
title = {Telomere shortening associates with elevated insulin and nuchal fat accumulation.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {6863},
pmid = {32322021},
issn = {2045-2322},
mesh = {Adolescent ; Adult ; Aged ; Biomarkers/blood ; *Body Mass Index ; *Carotid Intima-Media Thickness ; Child ; Female ; Humans ; Insulin/*blood ; *Lipogenesis ; Male ; Middle Aged ; *Nuchal Translucency Measurement ; *Obesity/blood/diagnostic imaging ; *Telomere Shortening ; },
abstract = {Obesity and relative leucocyte telomere length (RTL) are both linked to accelerated aging and premature mortality. We examined if nuchal subcutaneous adipose tissue (SAT) thickness, a surrogate marker of central trunk-weighted obesity, is an independent predictor of RTL that provides information beyond BMI, metabolic and inflammatory markers. RTL and nuchal SAT thickness were determined in 362 participants of the STYJOBS/EDECTA study (STYrian Juvenile Obesity Study, Early DEteCTion of atherosclerosis), which included overweight individuals and matched eutrophic controls. Fasting plasma samples were used for the measurement of leptin, resistin, adiponectin, glucose, insulin, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), liver enzymes, creatinine, cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, oxidized LDL, triglycerides, homocysteine and uric acid. Furthermore, all participants underwent carotid artery ultrasound. Obese individuals had markedly higher body mass index (BMI), nuchal SAT thickness, hip and waist circumferences and carotid intima media thickness (IMT) than eutrophic controls. In addition, they showed typical biochemical abnormalities related to energy metabolism, systemic inflammation and liver function. RTL was inversely correlated with nuchal SAT thickness, IMT, hs-CRP, alkaline phosphatase, insulin, resistin, and leptin. Positive correlations were seen with homocysteine and creatinine. Stepwise linear regression analyses identified nuchal SAT thickness and insulin as the only significant predictors of RTL. In conclusion, nuchal SAT thickness is a robust predictor of RTL that provides information beyond traditional obesity-related metabolic and inflammatory biomarkers. This suggests an important role of fat depots at the neck for accelerated telomere shortening.},
}
@article {pmid32319517,
year = {2020},
author = {Deo, P and Dhillon, VS and Lim, WM and Jaunay, EL and Donnellan, L and Peake, B and McCullough, C and Fenech, M},
title = {Advanced glycation end-products accelerate telomere attrition and increase pro-inflammatory mediators in human WIL2-NS cells.},
journal = {Mutagenesis},
volume = {35},
number = {3},
pages = {291-297},
doi = {10.1093/mutage/geaa012},
pmid = {32319517},
issn = {1464-3804},
mesh = {Cell Line ; Chromatography, Liquid ; Fructose/pharmacology ; Glucose/pharmacology ; Glycation End Products, Advanced/*pharmacology ; Humans ; Inflammation Mediators/*metabolism ; Nitric Oxide/metabolism ; Serum Albumin, Bovine/*pharmacology ; Tandem Mass Spectrometry ; Telomere/*drug effects/genetics/*metabolism ; Tumor Necrosis Factor-alpha/metabolism ; },
abstract = {This study investigated the effect of dietary sugars and advanced glycation end-products (AGE) on telomere dynamics in WIL2-NS cells. Dietary sugars [glucose (Glu) and fructose (Fru); 0.1 M each] were incubated with bovine serum albumin (BSA) (10 mg/ml) at 60 ± 1°C for 6 weeks to generate AGE-BSA. Liquid chromatography-mass spectrometry (LC-MS/MS) analysis showed total AGE levels as 87.74 ± 4.46 nmol/mg and 84.94 ± 4.28 nmol/mg respectively in Glu-BSA and Fru-BSA model. Cell treatment studies using WIL2-NS cells were based on either glucose, fructose (each 2.5-40 mM) or AGE-BSA (200-600 µg/ml) in a dose-dependent manner for 9 days. Telomere length (TL) was measured using qPCR. Nitric oxide (NO) production and tumour necrosis factor-α (TNF-α) levels were measured in WIL2-NS culture medium. An increasing trend for TNF-α and NO production was observed with higher concentration of glucose (R2 = 0.358; P = 0.019; R2 = 0.307; P = 0.027) and fructose (R2 = 0.669; P = 0.001; R2 = 0.339; P = 0.006). A decreasing trend for TL (R2 = 0.828; P = 0.000), and an increasing trend for NO production (R2 = 0.352; P = 0.031) were observed with increasing Glu-BSA concentrations. Fru-BSA treatment did not show significant trend on TL (R2 = 0.135; P = 0.352) with increasing concentration, however, a significant reduction was observed at 600 µg/ml (P < 0.01) when compared to BSA treatment. No trends for TNF-α levels and a decreasing trend on NO production (R2 = 0.5201; P = 0.019) was observed with increasing Fru-BSA treatment. In conclusion, this study demonstrates a potential relationship between dietary sugars, AGEs and telomere attrition. AGEs may also exert telomere shortening through the production of pro-inflammatory metabolites, which ultimately increase the risk of diabetes complications and age-related disease throughout lifespan.},
}
@article {pmid32316332,
year = {2020},
author = {Salmina, K and Bojko, A and Inashkina, I and Staniak, K and Dudkowska, M and Podlesniy, P and Rumnieks, F and Vainshelbaum, NM and Pjanova, D and Sikora, E and Erenpreisa, J},
title = {"Mitotic Slippage" and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres.},
journal = {International journal of molecular sciences},
volume = {21},
number = {8},
pages = {},
pmid = {32316332},
issn = {1422-0067},
support = {1.1.1.2/VIAA/3/19/463//European Regional Development Fund/ ; UMO-2015/17/B/NZ3/03531//Polska Akademia Nauk/ ; SAF2017-89791-R//Ministerio de Ciencia e Innovaci&#xf3;n/ ; PhD Student Scholarship//Latvijas Universit&#x101;tes Fonds/ ; },
mesh = {Antibiotics, Antineoplastic/pharmacology ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cellular Senescence/drug effects ; DNA/*metabolism ; DNA Damage/drug effects ; Doxorubicin/pharmacology ; Drug Resistance, Neoplasm/*genetics ; Humans ; Mitosis/drug effects ; Neoplasms/drug therapy/genetics ; Recombinational DNA Repair ; Sequestosome-1 Protein/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere Shortening ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Mitotic slippage (MS), the incomplete mitosis that results in a doubled genome in interphase, is a typical response of TP53-mutant tumors resistant to genotoxic therapy. These polyploidized cells display premature senescence and sort the damaged DNA into the cytoplasm. In this study, we explored MS in the MDA-MB-231 cell line treated with doxorubicin (DOX). We found selective release into the cytoplasm of telomere fragments enriched in telomerase reverse transcriptase (hTERT), telomere capping protein TRF2, and DNA double-strand breaks marked by γH2AX, in association with ubiquitin-binding protein SQSTM1/p62. This occurs along with the alternative lengthening of telomeres (ALT) and DNA repair by homologous recombination (HR) in the nuclear promyelocytic leukemia (PML) bodies. The cells in repeated MS cycles activate meiotic genes and display holocentric chromosomes characteristic for inverted meiosis (IM). These giant cells acquire an amoeboid phenotype and finally bud the depolyploidized progeny, restarting the mitotic cycling. We suggest the reversible conversion of the telomerase-driven telomere maintenance into ALT coupled with IM at the sub-telomere breakage sites introduced by meiotic nuclease SPO11. All three MS mechanisms converging at telomeres recapitulate the amoeba-like agamic life-cycle, decreasing the mutagenic load and enabling the recovery of recombined, reduced progeny for return into the mitotic cycle.},
}
@article {pmid32312758,
year = {2020},
author = {Antwi, SO and Bamlet, WR and Rabe, KG and Cawthon, RM and Umudi, I and Druliner, BR and Sicotte, H and Oberg, AL and Jatoi, A and Boardman, LA and Petersen, GM},
title = {Leukocyte Telomere Length and Its Interaction with Germline Variation in Telomere-Related Genes in Relation to Pancreatic Adenocarcinoma Risk.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {29},
number = {7},
pages = {1492-1500},
pmid = {32312758},
issn = {1538-7755},
support = {K01 CA237875/CA/NCI NIH HHS/United States ; P50 CA102701/CA/NCI NIH HHS/United States ; R01 CA204013/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma/*genetics/mortality ; Case-Control Studies ; Female ; Genetic Variation/*genetics ; Germ Cells ; Humans ; Leukocytes/*metabolism ; Male ; Pancreatic Neoplasms/*genetics/mortality ; Risk Factors ; Telomere/*genetics ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) has been associated with risk of multiple cancers, but its association with pancreatic ductal adenocarcinoma (PDAC) is unclear. We therefore investigated the association between peripheral blood LTL and PDAC risk, and examined effect modification by candidate SNPs previously reported to be associated with variation in LTL.<br><br>METHODS: A case-control study of 1,460 PDAC cases and 1,459 frequency-matched controls was performed using biospecimens and data from the Mayo Clinic Biospecimen Resource for Pancreas Research. Quantitative PCR was used to measure LTL and categorized into tertiles based on sex-specific control distribution. Eleven telomere-related SNPs also were genotyped. Logistic regression was used to calculate ORs and 95% confidence intervals (CI).<br><br>RESULTS: Shorter peripheral blood LTL was associated with a higher risk of PDAC (ORT1vsT3 = 1.26, 95% CI = 1.03-1.54, P trend = 0.02; ORcontinuous = 1.14, 95% CI = 1.02-1.28), but the association was restricted to cases with treatment-na&#xef;ve blood samples (ORT1vsT3 = 1.51, 95% CI = 1.16-1.96, P trend = 0.002; ORcontinuous = 1.25, 95% CI = 1.08-1.45) and not cases whose blood samples were collected after initiation of cancer therapy (ORT1vsT3 = 1.10, 95% CI = 0.87-1.39, P trend = 0.42; ORcontinuous = 1.08, 95% CI = 0.94-1.23). Three SNPs (TERC-rs10936599, ACYP2-rs11125529, and TERC-rs1317082) were each associated with interindividual variation in LTL among controls, but there was no evidence of effect modification by these SNPs.<br><br>CONCLUSIONS: Treatment-na&#xef;ve short LTL is associated with a higher risk of PDAC, and the association does not differ by germline variation in the candidate telomere-related SNPs examined.<br><br>IMPACT: Peripheral blood LTL might serve as a molecular marker for risk modeling to identify persons at high risk of PDAC.},
}
@article {pmid32310030,
year = {2020},
author = {Diala, I and Shiohama, Y and Fujita, T and Kotake, Y and Demonacos, C and Krstic-Demonacos, M and Leva, GD and Fujii, M},
title = {Telomerase inhibition, telomere attrition and proliferation arrest of cancer cells induced by phosphorothioate ASO-NLS conjugates targeting hTERC and siRNAs targeting hTERT.},
journal = {Nucleosides, nucleotides &amp; nucleic acids},
volume = {39},
number = {1-3},
pages = {407-425},
doi = {10.1080/15257770.2020.1713357},
pmid = {32310030},
issn = {1532-2335},
mesh = {Cell Cycle Checkpoints/*drug effects ; Cell Proliferation/drug effects ; Enzyme Activation ; Enzyme Inhibitors/*chemistry/*pharmacology ; HeLa Cells ; Humans ; Nuclear Localization Signals/*chemistry ; *Oligonucleotides, Antisense ; Peptides/chemistry ; Phosphates/*chemistry ; RNA, Messenger/genetics ; RNA, Small Interfering/genetics ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Telomerase/*antagonists &amp; inhibitors/chemistry ; Telomere/*chemistry ; Tumor Cells, Cultured ; },
abstract = {Telomerase activity has been regarded as a critical step in cellular immortalization and carcinogenesis and because of this, regulation of telomerase represents an attractive target for anti-tumor specific therapeutics. Recently, one avenue of cancer research focuses on antisense strategy to target the oncogenes or cancer driver genes, in a sequence specific fashion to down-regulate the expression of the target gene. The protein catalytic subunit, human telomerase reverse transcriptase (hTERT) and the template RNA component (hTERC) are essential for telomerase function, thus theoretically, inhibition of telomerase activity can be achieved by interfering with either the gene expression of hTERT or the hTERC of the telomerase enzymatic complex. The present study showed that phosphorothioate antisense oligonucleotide (sASO)-nuclear localization signal (NLS) peptide conjugates targeting hTERC could inhibit telomerase activity very efficiently at 5 μM concentration but less efficiently at 1 μM concentration. On the other hand, siRNA targeting hTERT mRNA could strongly suppress hTERT expression at 200 nM concentration. It was also revealed that siRNA targeting hTERT could induce telomere attrition and then irreversible arrest of proliferation of cancer cells.},
}
@article {pmid32308926,
year = {2020},
author = {Liu, Y and Liu, Z and Wei, Y and Wang, Y and Shuang, J and Peng, R},
title = {Cloning and preliminary verification of telomere-associated sequences in upland cotton.},
journal = {Comparative cytogenetics},
volume = {14},
number = {2},
pages = {183-195},
pmid = {32308926},
issn = {1993-0771},
abstract = {Telomeres are structures enriched in repetitive sequences at the end of chromosomes. In this study, using the telomere primer AA(CCCTAAA)3CCC for the single primer PCR, two DNA sequences were obtained from Gossypium hirsutum (Linnaeus, 1753) accession (acc.) TM-1. Sequence analysis showed that the two obtained sequences were all rich in A/T base, which was consistent with the characteristic of the telomere-associated sequence (TAS). They were designated as GhTAS1 and GhTAS2 respectively. GhTAS1 is 489 bp long, with 57.6% of A/T, and GhTAS2 is 539 bp long, with 63.9% of A/T. Fluorescence in situ hybridization results showed that both of the cloned TASs were located at the ends of the partial chromosomes of G. hirsutum, with the strong signals, which further confirmed that GhTAS1 and GhTAS2 were telomere-associated sequences including highly tandemly repetitive sequences. Results of blast against the assembled genome of G. hirsutum showed that GhTAS sequences may be missed on some assembled chromosomes. The results provide important evidence for the evaluation of the integrity of assembled chromosome end sequences, and will also contribute to the further perfection of the draft genomes of cotton.},
}
@article {pmid32303682,
year = {2020},
author = {Bergstrand, S and Böhm, S and Malmgren, H and Norberg, A and Sundin, M and Nordgren, A and Farnebo, M},
title = {Biallelic mutations in WRAP53 result in dysfunctional telomeres, Cajal bodies and DNA repair, thereby causing Hoyeraal-Hreidarsson syndrome.},
journal = {Cell death &amp; disease},
volume = {11},
number = {4},
pages = {238},
pmid = {32303682},
issn = {2041-4889},
mesh = {Child, Preschool ; Coiled Bodies/*metabolism ; DNA Repair/*genetics ; Dyskeratosis Congenita/*genetics ; Fetal Growth Retardation/*genetics ; Humans ; Intellectual Disability/*genetics ; Male ; Microcephaly/*genetics ; Molecular Chaperones/*metabolism ; Mutation ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Approximately half of all cases of Hoyeraal-Hreidarsson syndrome (HHS), a multisystem disorder characterized by bone marrow failure, developmental defects and very short telomeres, are caused by germline mutations in genes related to telomere biology. However, the varying symptoms and severity of the disease indicate that additional mechanisms are involved. Here, a 3-year-old boy with HHS was found to carry biallelic germline mutations in WRAP53 (WD40 encoding RNA antisense to p53), that altered two highly conserved amino acids (L283F and R398W) in the WD40 scaffold domain of the protein encoded. WRAP53β (also known as TCAB1 or WDR79) is involved in intracellular trafficking of telomerase, Cajal body functions and DNA repair. We found that both mutations cause destabilization, mislocalization and faulty interactions of WRAP53β, defects linked to misfolding by the TRiC chaperonin complex. Consequently, WRAP53β HHS mutants cannot elongate telomeres, maintain Cajal bodies or repair DNA double-strand breaks. These findings provide a molecular explanation for the pathogenesis underlying WRAP53β-associated HHS and highlight the potential contribution of DNA damage and/or defects in Cajal bodies to the early onset and/or severity of this disease.},
}
@article {pmid32301432,
year = {2020},
author = {Natalini, JG and George, MD and Kawut, SM and Johnson, CR},
title = {Association between antinuclear antibody seropositivity and telomere length: a nationwide population-based study.},
journal = {Clinical and experimental rheumatology},
volume = {38},
number = {5},
pages = {989-992},
pmid = {32301432},
issn = {0392-856X},
support = {K01 HL135459/HL/NHLBI NIH HHS/United States ; K23 AR073931/AR/NIAMS NIH HHS/United States ; K24 HL103844/HL/NHLBI NIH HHS/United States ; T32 HL007891/HL/NHLBI NIH HHS/United States ; },
mesh = {Aging ; *Antibodies, Antinuclear ; Cross-Sectional Studies ; Female ; Humans ; Male ; Nutrition Surveys ; *Telomere/genetics ; },
abstract = {OBJECTIVES: Telomere shortening is a well-established marker of biological aging. Whether telomere erosion coincides with age-related increases in antinuclear antibody (ANA) seropositivity remains unknown. Our study aimed to determine the association between ANA seropositivity and shortened telomeres among 1999-2002 National Health and Nutrition Examination Survey (NHANES) subjects.<br><br>METHODS: We performed a cross-sectional analysis of 2,188 NHANES study participants with available ANA and telomere length data. ANA testing was performed using indirect immunofluorescence. Telomere lengths were measured via quantitative polymerase chain reaction methods. Applying appropriate sample weighting techniques, we used univariate and multivariate logistic regression methods to assess the association between shortened telomeres (i.e. lowest decile of the cohort) and ANA seropositivity.<br><br>RESULTS: ANAs were positive in 322 out of 2,188 (14.7%, 95% CI 13.3-16.3%) individuals. Subjects with shortened telomeres were more likely to be older (p<0.001), male (p=0.005), and have a cancer history (p<0.001). A higher proportion of non-Hispanic white participants (61.6% vs. 49.3%) and a lower proportion of non-Hispanic black participants (7.8% vs. 17.9%) had shortened telomeres (p<0.001). Shortened telomeres were not independently associated with ANA seropositivity (OR 1.48, 95% CI 0.87-2.52, p=0.14). However, female sex (OR 1.91, 95% CI 1.23-2.96, p=0.006), age &#x2265;80 years (OR 2.06, 95% CI 1.08-3.92, p=0.03), and African American race (OR 1.58, 95% CI 1.00-2.51, p=0.05) were independent risk factors for ANA seropositivity. Neither sex nor race modified the relationship between ANA seropositivity and telomere length.<br><br>CONCLUSIONS: Telomere erosion does not appear to be responsible for age-related increases in the prevalence of ANA seropositivity.},
}
@article {pmid32300848,
year = {2020},
author = {Karimi, B and Nabizadeh, R and Yunesian, M},
title = {Association Between Leukocyte Telomere Length and Serum Concentrations of PCBs and Organochlorine Pesticides.},
journal = {Archives of environmental contamination and toxicology},
volume = {79},
number = {1},
pages = {122-130},
doi = {10.1007/s00244-020-00732-z},
pmid = {32300848},
issn = {1432-0703},
mesh = {Adult ; Age Factors ; Humans ; Hydrocarbons, Chlorinated/*blood/toxicity ; Iran ; Leukocytes/*drug effects/pathology ; Lipids/blood ; Male ; Pesticides/*blood/toxicity ; Polychlorinated Biphenyls/*blood/toxicity ; Random Allocation ; Surveys and Questionnaires ; Telomere/*drug effects ; Telomere Homeostasis/*drug effects ; },
abstract = {Exposure to polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) through food, water, and air occurred during the life, which may change telomere length (TL) in peripheral blood leukocytes. The present study was designed to investigate the association between TL and serum levels of PCBs and OCPs in Tehran male's population. Whole blood samples were randomly taken from 300 adult males, aged between 25 and 40 years. TL was determined by real-time PCR to measure the number of the telomere (T) repeats to the number of a single-copy gene (S). We applied the multivariate linear regression model to compare the effect of each lipid adjusted serum levels of PCBs and OCPs congener on the TL, with adjustment for age, body mass index, education, smoking, and food patterns. Each doubling of the nondioxin-like PCBs, dioxin-like PCBs, and OCPs levels were associated with 1.9% [95% confidence interval (CI) - 0.70 to 5.40%], 2.5% (95% CI 0.30-8.3%), and - 2.4% (95% CI - 0.70 to - 6.2%) variation in the TL, respectively. The percent difference in the TL with exposure to nondioxin-like PCBs, dioxin-like PCBs, and OCPs for participants with older than age 37 years were 6.45% (95% CI 2.81-16.50%), 4.52% (95% CI 1.60-10.54%), and - 7.44% (95% CI - 1.55 to - 15.51%), respectively. Exposures to nondioxin-like PCBs (except for PCB 28 and 52) with high chlorine in structure and dioxin-like PCBs were related to longer TLs. Conversely, serum levels of OCPs can be associated with oxidative stress and systemic inflammation that lead to telomere shortening.},
}
@article {pmid32300648,
year = {2020},
author = {Toufektchan, E and Lejour, V and Durand, R and Giri, N and Draskovic, I and Bardot, B and Laplante, P and Jaber, S and Alter, BP and Londono-Vallejo, JA and Savage, SA and Toledo, F},
title = {Germline mutation of MDM4, a major p53 regulator, in a familial syndrome of defective telomere maintenance.},
journal = {Science advances},
volume = {6},
number = {15},
pages = {eaay3511},
pmid = {32300648},
issn = {2375-2548},
mesh = {Alleles ; Amino Acid Substitution ; Animals ; Bone Marrow/pathology ; Cell Cycle Proteins/*genetics/metabolism ; Disease Models, Animal ; Family ; Female ; Genetic Association Studies ; *Genetic Predisposition to Disease ; *Germ-Line Mutation ; Humans ; Male ; Mice ; Mice, Knockout ; Pedigree ; Phenotype ; Proto-Oncogene Proteins/*genetics/metabolism ; Signal Transduction ; Syndrome ; Telomere/*genetics/*metabolism ; Telomere Homeostasis/*genetics ; Telomere Shortening ; Tumor Suppressor Protein p53/*metabolism ; },
abstract = {Dyskeratosis congenita is a cancer-prone inherited bone marrow failure syndrome caused by telomere dysfunction. A mouse model recently suggested that p53 regulates telomere metabolism, but the clinical relevance of this finding remained uncertain. Here, a germline missense mutation of MDM4, a negative regulator of p53, was found in a family with features suggestive of dyskeratosis congenita, e.g., bone marrow hypocellularity, short telomeres, tongue squamous cell carcinoma, and acute myeloid leukemia. Using a mouse model, we show that this mutation (p.T454M) leads to increased p53 activity, decreased telomere length, and bone marrow failure. Variations in p53 activity markedly altered the phenotype of Mdm4 mutant mice, suggesting an explanation for the variable expressivity of disease symptoms in the family. Our data indicate that a germline activation of the p53 pathway may cause telomere dysfunction and point to polymorphisms affecting this pathway as potential genetic modifiers of telomere biology and bone marrow function.},
}
@article {pmid32297856,
year = {2020},
author = {Criqui, M and Qamra, A and Chu, TW and Sharma, M and Tsao, J and Henry, DA and Barsyte-Lovejoy, D and Arrowsmith, CH and Winegarden, N and Lupien, M and Harrington, L},
title = {Telomere dysfunction cooperates with epigenetic alterations to impair murine embryonic stem cell fate commitment.},
journal = {eLife},
volume = {9},
number = {},
pages = {},
pmid = {32297856},
issn = {2050-084X},
support = {084637//Wellcome/ ; OGI-055//Ontario Genomics Institute/ ; 367427//CIHR/Canada ; /WT_/Wellcome Trust/United Kingdom ; 133573//CIHR/Canada ; },
mesh = {Animals ; Cell Differentiation/*genetics ; Cellular Senescence/genetics/physiology ; Embryonic Stem Cells/*metabolism ; Epigenesis, Genetic/*physiology ; Histones/*genetics/metabolism ; Mice ; Telomere/metabolism/*pathology ; },
abstract = {The precise relationship between epigenetic alterations and telomere dysfunction is still an extant question. Previously, we showed that eroded telomeres lead to differentiation instability in murine embryonic stem cells (mESCs) via DNA hypomethylation at pluripotency-factor promoters. Here, we uncovered that telomerase reverse transcriptase null (Tert[-/-]) mESCs exhibit genome-wide alterations in chromatin accessibility and gene expression during differentiation. These changes were accompanied by an increase of H3K27me3 globally, an altered chromatin landscape at the Pou5f1/Oct4 promoter, and a refractory response to differentiation cues. Inhibition of the Polycomb Repressive Complex 2 (PRC2), an H3K27 tri-methyltransferase, exacerbated the impairment in differentiation and pluripotency gene repression in Tert[-/-] mESCs but not wild-type mESCs, whereas inhibition of H3K27me3 demethylation led to a partial rescue of the Tert[-/-] phenotype. These data reveal a new interdependent relationship between H3K27me3 and telomere integrity in stem cell lineage commitment that may have implications in aging and cancer.},
}
@article {pmid32297771,
year = {2020},
author = {Li, X and Jiang, Y and Qiao, S and Gu, H and Zhao, J},
title = {Effects of parental HIV on telomere length among children in rural China.},
journal = {Health psychology : official journal of the Division of Health Psychology, American Psychological Association},
volume = {39},
number = {7},
pages = {617-621},
doi = {10.1037/hea0000872},
pmid = {32297771},
issn = {1930-7810},
support = {/NH/NIH HHS/United States ; //National Social Science Foundation of China/ ; //Henan University; Philosophy and Social Science Innovation Team/ ; //National Institutes of Health/ ; },
mesh = {Adolescent ; Child ; Child of Impaired Parents/*psychology ; China ; Female ; HIV Infections/*complications/*genetics ; Humans ; Male ; Telomere/*physiology ; },
abstract = {OBJECTIVE: Cumulative evidence has shown the adverse effects of HIV-related death and illness on children's psychosocial well-being. However, few studies have examined whether these factors can "get under the skin" to affect children's health. This study, therefore, examined the effects of HIV-related parental death on telomere length, a biomarker of cellular aging. This study further explored whether the results on telomere length were consistent with results based on self-report health outcomes, namely depressive symptoms.<br><br>METHOD: A total of 117 children (10-17 years of age) affected by parental HIV (27 children living with HIV-positive parents and 90 AIDS orphans) from Henan China provided blood samples for telomere length assay and completed a survey for depressive symptoms and demographic information.<br><br>RESULTS: Results showed that AIDS orphans had a shorter telomere length than children living with HIV-positive parents and that such differences in telomere length were more evident than were differences in depressive symptoms. There were no significant differences in telomere length or depressive symptoms between children who lost one parent and those who lost both.<br><br>CONCLUSIONS: The results suggest that HIV-related parental death may contribute to accelerated telomere shortening and highlight that telomere length may be a novel and useful biomarker for health needs assessment in pediatric AIDS care. (PsycInfo Database Record (c) 2020 APA, all rights reserved).},
}
@article {pmid32297568,
year = {2020},
author = {de Oliveira, DM},
title = {Telomere Based Approach for Cancer Therapy.},
journal = {Current topics in medicinal chemistry},
volume = {20},
number = {6},
pages = {409},
doi = {10.2174/156802662006200305112748},
pmid = {32297568},
issn = {1873-4294},
mesh = {Antineoplastic Agents/*pharmacology ; Cell Proliferation/drug effects ; Humans ; Neoplasms/*drug therapy/metabolism/pathology ; Telomere/*drug effects/metabolism ; },
}
@article {pmid32296102,
year = {2020},
author = {Sethi, I and Sharma, V and Sharma, I and Singh, G and Bhat, GR and Bhanwer, AJS and Sharma, S and Rai, E},
title = {Telomere Maintenance Genes are associated with Type 2 Diabetes Susceptibility in Northwest Indian Population Group.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {6444},
pmid = {32296102},
issn = {2045-2322},
mesh = {Aged ; Case-Control Studies ; Computational Biology ; Diabetes Mellitus, Type 2/epidemiology/*genetics ; Female ; *Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; India/epidemiology ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Telomere/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {Telomere length attrition has been implicated in various complex disorders including Type 2 Diabetes (T2D). However, very few candidate gene association studies have been carried out worldwide targeting telomere maintenance genes. In the present study, variants in various critical telomere maintenance pathway genes for T2D susceptibility in Northwest Indian population were explored. With case-control candidate gene association study design, twelve variants from seven telomere maintenance genes were evaluated. Amongst these five variants, rs9419958 (OBFC1), rs4783704 (TERF2), rs16847897 (TERC/LRRC31), rs10936599 (TERC/MYNN), and rs74019828 (CSNK2A2) showed significant association with T2D (at p-value ≤ 0.003, threshold set after Bonferroni correction) in the studied population. In silico analyses of these variants indicated interesting functional roles that warrant experimental validations. Findings showed that variants in telomere maintenance genes are associated with pathogenesis of T2D in Northwest Indian population. We anticipate further, such candidate gene association studies in other Indian populations and worldwide would contribute in understanding the missing heritability of T2D.},
}
@article {pmid32294415,
year = {2020},
author = {Cleal, K and Baird, DM},
title = {Catastrophic Endgames: Emerging Mechanisms of Telomere-Driven Genomic Instability.},
journal = {Trends in genetics : TIG},
volume = {36},
number = {5},
pages = {347-359},
doi = {10.1016/j.tig.2020.02.001},
pmid = {32294415},
issn = {0168-9525},
support = {18246/CRUK_/Cancer Research UK/United Kingdom ; 29202/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Chromosome Disorders/*genetics/pathology ; Chromothripsis ; DNA Replication/genetics ; Genomic Instability/*genetics ; Genomics ; Humans ; Mutation ; Neoplasms/*genetics/pathology ; Telomere/*genetics ; },
abstract = {When cells progress to malignancy, they must overcome a final telomere-mediated proliferative lifespan barrier called replicative crisis. Crisis is characterized by extensive telomere fusion that drives widespread genomic instability, mitotic arrest, hyperactivation of autophagy, and cell death. Recently, it has become apparent that that the resolution of dicentric chromosomes, which arise from telomere fusions during crisis, can initiate a sequence of events that leads to chromothripsis, a form of extreme genomic catastrophe. Chromothripsis is characterized by localized genomic regions containing tens to thousands of rearrangements and it is becoming increasingly apparent that chromothripsis occurs widely across tumor types and has a clinical impact. Here we discuss how telomere dysfunction can initiate genomic complexity and the emerging mechanisms of chromothripsis.},
}
@article {pmid32294263,
year = {2020},
author = {Johnson, SM and McGinty, KA and Hayashi, PH and Sasatomi, E},
title = {Large Cell Change in a Small Liver: A Histological Clue to Short Telomere Syndromes?.},
journal = {Hepatology (Baltimore, Md.)},
volume = {72},
number = {6},
pages = {2231-2234},
pmid = {32294263},
issn = {1527-3350},
mesh = {Adult ; Anemia, Aplastic/diagnosis/*genetics ; Biopsy ; DNA Mutational Analysis ; Humans ; Liver/cytology/diagnostic imaging/*pathology ; Liver Cirrhosis/diagnosis/*genetics/pathology ; Male ; Mutation, Missense ; Syndrome ; Telomerase/*genetics/metabolism ; Telomere/metabolism ; *Telomere Shortening ; Tomography, X-Ray Computed ; },
}
@article {pmid32291317,
year = {2020},
author = {Koneru, B and Lopez, G and Farooqi, A and Conkrite, KL and Nguyen, TH and Macha, SJ and Modi, A and Rokita, JL and Urias, E and Hindle, A and Davidson, H and Mccoy, K and Nance, J and Yazdani, V and Irwin, MS and Yang, S and Wheeler, DA and Maris, JM and Diskin, SJ and Reynolds, CP},
title = {Telomere Maintenance Mechanisms Define Clinical Outcome in High-Risk Neuroblastoma.},
journal = {Cancer research},
volume = {80},
number = {12},
pages = {2663-2675},
pmid = {32291317},
issn = {1538-7445},
support = {R35 CA220500/CA/NCI NIH HHS/United States ; R01 CA204974/CA/NCI NIH HHS/United States ; R01 CA217251/CA/NCI NIH HHS/United States ; R01 CA221957/CA/NCI NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; RC1 MD004418/MD/NIMHD NIH HHS/United States ; U10 CA098413/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Child ; Child, Preschool ; Disease-Free Survival ; Female ; Follow-Up Studies ; *Gene Expression Regulation, Neoplastic ; Humans ; Infant ; Male ; Neoplasm Recurrence, Local ; Neuroblastoma/*genetics/mortality/pathology ; RNA, Messenger/isolation &amp; purification/metabolism ; RNA-Seq ; Telomerase/genetics/isolation &amp; purification/*metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; Whole Genome Sequencing ; X-linked Nuclear Protein/genetics ; Xenograft Model Antitumor Assays ; },
abstract = {Neuroblastoma is a childhood cancer with heterogeneous clinical outcomes. To comprehensively assess the impact of telomere maintenance mechanism (TMM) on clinical outcomes in high-risk neuroblastoma, we integrated the C-circle assay [a marker for alternative lengthening of telomeres (ALT)], TERT mRNA expression by RNA-sequencing, whole-genome/exome sequencing, and clinical covariates in 134 neuroblastoma patient samples at diagnosis. In addition, we assessed TMM in neuroblastoma cell lines (n = 104) and patient-derived xenografts (n = 28). ALT was identified in 23.4% of high-risk neuroblastoma tumors and genomic alterations in ATRX were detected in 60% of ALT tumors; 40% of ALT tumors lacked genomic alterations in known ALT-associated genes. Patients with high-risk neuroblastoma were classified into three subgroups (TERT-high, ALT[+], and TERT-low/non-ALT) based on presence of C-circles and TERT mRNA expression (above or below median TERT expression). Event-free survival was similar among TERT-high, ALT[+], or TERT-low/non-ALT patients. However, overall survival (OS) for TERT-low/non-ALT patients was significantly higher relative to TERT-high or ALT patients (log-rank test; P < 0.01) independent of current clinical and molecular prognostic markers. Consistent with the observed higher OS in patients with TERT-low/non-ALT tumors, continuous shortening of telomeres and decreasing viability occurred in low TERT-expressing, non-ALT patient-derived high-risk neuroblastoma cell lines. These findings demonstrate that assaying TMM with TERT mRNA expression and C-circles provides precise stratification of high-risk neuroblastoma into three subgroups with substantially different OS: a previously undescribed TERT-low/non-ALT cohort with superior OS (even after relapse) and two cohorts of patients with poor survival that have distinct molecular therapeutic targets. SIGNIFICANCE: These findings assess telomere maintenance mechanisms with TERT mRNA and the ALT DNA biomarker C-circles to stratify neuroblastoma into three groups, with distinct overall survival independent of currently used clinical risk classifiers.},
}
@article {pmid32290440,
year = {2020},
author = {Recagni, M and Bidzinska, J and Zaffaroni, N and Folini, M},
title = {The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications.},
journal = {Cancers},
volume = {12},
number = {4},
pages = {},
pmid = {32290440},
issn = {2072-6694},
support = {22933//Fondazione AIRC per la Ricerca sul Cancro/ ; 15194//Fondazione AIRC per la ricerca sul Cancro/ ; },
abstract = {Telomere maintenance mechanisms (i.e., telomerase activity (TA) and the alternative lengthening of telomere (ALT) mechanism) contribute to tumorigenesis by providing unlimited proliferative capacity to cancer cells. Although the role of either telomere maintenance mechanisms seems to be equivalent in providing a limitless proliferative ability to tumor cells, the contribution of TA and ALT to the clinical outcome of patients may differ prominently. In addition, several strategies have been developed to interfere with TA in cancer, including Imetelstat that has been the first telomerase inhibitor tested in clinical trials. Conversely, the limited information available on the molecular underpinnings of ALT has hindered thus far the development of genuine ALT-targeting agents. Moreover, whether anti-telomerase therapies may be hampered or not by possible adaptive responses is still debatable. Nonetheless, it is plausible hypothesizing that treatment with telomerase inhibitors may exert selective pressure for the emergence of cancer cells that become resistant to treatment by activating the ALT mechanism. This notion, together with the evidence that both telomere maintenance mechanisms may coexist within the same tumor and may distinctly impinge on patients' outcomes, suggests that ALT may exert an unexpected role in tumor biology that still needs to be fully elucidated.},
}
@article {pmid32289486,
year = {2020},
author = {Scarabino, D and Peconi, M and Broggio, E and Gambina, G and Maggi, E and Armeli, F and Mantuano, E and Morello, M and Corbo, RM and Businaro, R},
title = {Relationship between proinflammatory cytokines (Il-1beta, Il-18) and leukocyte telomere length in mild cognitive impairment and Alzheimer's disease.},
journal = {Experimental gerontology},
volume = {136},
number = {},
pages = {110945},
doi = {10.1016/j.exger.2020.110945},
pmid = {32289486},
issn = {1873-6815},
mesh = {*Alzheimer Disease/genetics ; Biomarkers ; *Cognitive Dysfunction/diagnosis/genetics ; Cytokines ; Humans ; Interleukin-18 ; Leukocytes ; Telomere ; },
abstract = {Inflammation plays a crucial role in Alzheimer's disease (AD). AD neurodegeneration and concurrent involvement of the peripheral immune system may promote leukocyte division and telomere shortening. We examined genotypes and plasma levels of two proinflammatory cytokines, IL-1beta and IL-18, and leukocyte telomere length (LTL) in patients with mild cognitive impairment (MCI) and AD. We wanted to determine whether changes in plasma IL-1beta and IL-18 levels, together with LTL shortening, could be diagnostic for disease progression from MCI to AD. Median plasma IL-1beta levels were in the order MCI patients (2.2 pg/ml) < AD patients (4.0 pg/ml), both of which differed significantly from the controls (0.0 pg/ml). In the AD patients, the lowest IL-1beta levels were associated with the presence of the C allele of IL-1beta rs16944 SNP. Median plasma IL-18 levels were in the order MCI patients (116.3 pg/ml) > AD patients (85.8 pg/ml), both of which were significantly higher than in the controls (17.6 pg/ml). Analysis of LTL showed a progressive reduction in the order controls > MCI > AD patients (p < 0.0001). Overall LTL reduction was correlated with increased plasma IL-1beta levels, substantiating the hypothesis that inflammatory processes secondary to neuroinflammation may trigger telomere attrition. Changes in plasma IL-1beta and Il-18 levels, and LTL seem to reflect shifts in AD stage; they may have potential use as blood biomarkers to monitor disease onset and progression from MCI to AD.},
}
@article {pmid32287268,
year = {2020},
author = {Langston, RE and Palazzola, D and Bonnell, E and Wellinger, RJ and Weinert, T},
title = {Loss of Cdc13 causes genome instability by a deficiency in replication-dependent telomere capping.},
journal = {PLoS genetics},
volume = {16},
number = {4},
pages = {e1008733},
pmid = {32287268},
issn = {1553-7404},
support = {FDN154315//CIHR/Canada ; },
mesh = {Chromosomes, Fungal/genetics ; DNA Breaks, Double-Stranded ; DNA Replication ; Exodeoxyribonucleases/genetics/metabolism ; *Genomic Instability ; Recombination, Genetic ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {In budding yeast, Cdc13, Stn1, and Ten1 form the telomere-binding heterotrimer CST complex. Here we investigate the role of Cdc13/CST in maintaining genome stability by using a Chr VII disome system that can generate recombinants, chromosome loss, and enigmatic unstable chromosomes. In cells expressing a temperature sensitive CDC13 allele, cdc13F684S, unstable chromosomes frequently arise from problems in or near a telomere. We found that, when Cdc13 is defective, passage through S phase causes Exo1-dependent ssDNA and unstable chromosomes that are then the source for additional chromosome instability events (e.g. recombinants, chromosome truncations, dicentrics, and/or chromosome loss). We observed that genome instability arises from a defect in Cdc13's function during DNA replication, not Cdc13's putative post-replication telomere capping function. The molecular nature of the initial unstable chromosomes formed by a Cdc13-defect involves ssDNA and does not involve homologous recombination nor non-homologous end joining; we speculate the original unstable chromosome may be a one-ended double strand break. This system defines a link between Cdc13's function during DNA replication and genome stability in the form of unstable chromosomes, that then progress to form other chromosome changes.},
}
@article {pmid32285610,
year = {2020},
author = {Viera, A and Berenguer, I and Ruiz-Torres, M and Gómez, R and Guajardo, A and Barbero, JL and Losada, A and Suja, JA},
title = {PDS5 proteins regulate the length of axial elements and telomere integrity during male mouse meiosis.},
journal = {EMBO reports},
volume = {21},
number = {6},
pages = {e49273},
pmid = {32285610},
issn = {1469-3178},
support = {BFU2014-53681-P//Ministerio de Econom&#xed;a y Competitividad (MEC)/International ; BFU2016-79841-R//Ministerio de Econom&#xed;a y Competitividad (MEC)/International ; BFU2017-89408-R//Ministerio de Econom&#xed;a y Competitividad (MEC)/International ; //FEDER/International ; },
mesh = {Animals ; Cell Cycle Proteins/genetics ; Male ; *Meiosis/genetics ; Mice ; Mitosis ; Spermatocytes ; Synaptonemal Complex ; *Telomere/genetics ; },
abstract = {Cohesin cofactors regulate the loading, maintenance, and release of cohesin complexes from chromosomes during mitosis but little is known on their role during vertebrate meiosis. One such cofactor is PDS5, which exists as two paralogs in somatic and germline cells, PDS5A and PDS5B, with unclear functions. Here, we have analyzed their distribution and functions in mouse spermatocytes. We show that simultaneous excision of Pds5A and Pds5B results in severe defects during early prophase I while their individual depletion does not, suggesting their functional redundancy. Shortened axial/lateral elements and a reduction of early recombination nodules are observed after the strong depletion of PDS5A/B proteins. Moreover, telomere integrity and their association to the nuclear envelope are severely compromised. As these defects occur without detectable reduction in chromosome-bound cohesin, we propose that the dynamic behavior of the complex, mediated by PDS5 proteins, is key for successful completion of meiotic prophase I.},
}
@article {pmid32284029,
year = {2020},
author = {Marques, A and Gouveira, &#xc9;R and Peralta, M and Martins, J and Venturini, J and Henriques-Neto, D and Sarmento, H},
title = {Cardiorespiratory fitness and telomere length: a systematic review.},
journal = {Journal of sports sciences},
volume = {38},
number = {14},
pages = {1690-1697},
doi = {10.1080/02640414.2020.1754739},
pmid = {32284029},
issn = {1466-447X},
mesh = {Aging/physiology ; Cardiorespiratory Fitness/*physiology ; Exercise/*physiology ; Humans ; Physical Conditioning, Human/physiology ; Physical Endurance/physiology ; Telomere/*physiology ; Telomere Shortening/physiology ; },
abstract = {This study aimed to systematically review the association between cardiorespiratory fitness and telomere length (TL). Studies were identified from searches in Cochrane Central, PubMed, Scopus, Sportdiscus, and Web of Science databases through July 2019. Eligibility criteria included: cross-sectional, prospective, and experimental study design; outcomes included TL; results expressed the relationship between cardiorespiratory fitness and TL; studies published in English, Portuguese, or Spanish. A total of 20 articles met the inclusion criteria. Sixteen studies (80%) reported a significant relationship between cardiorespiratory fitness, or training load, and TL. Better cardiorespiratory fitness or a large cardiorespiratory training load are associated with an increase in TL. Although, TL was related to regular moderate-to-vigorous aerobic exercise and cardiorespiratory fitness in older healthy humans, it was not related to cardiorespiratory fitness among young subjects. There seems to be a positive and significant relationship between cardiorespiratory fitness and TL, mainly among middle age and older people, which emphasizes the importance of cardiorespiratory fitness for healthy ageing. Therefore, endurance exercise and better cardiorespiratory fitness may regulate the TL in middle age and older adults, slowing the cellular ageing process.},
}
@article {pmid32277935,
year = {2020},
author = {Rossi, M and Gorospe, M},
title = {Noncoding RNAs Controlling Telomere Homeostasis in Senescence and Aging.},
journal = {Trends in molecular medicine},
volume = {26},
number = {4},
pages = {422-433},
pmid = {32277935},
issn = {1471-499X},
support = {Z01 AG000511-11/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Aging/*genetics ; Animals ; Cellular Senescence/*genetics ; Homeostasis/*genetics ; Humans ; RNA, Untranslated/*genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Aging is a universal and time-dependent biological decline associated with progressive deterioration of cells, tissues, and organs. Age-related decay can eventually lead to pathology such as cardiovascular and neurodegenerative diseases, cancer, and diabetes. A prominent molecular process underlying aging is the progressive shortening of telomeres, the structures that protect the ends of chromosomes, eventually triggering cellular senescence. Noncoding (nc)RNAs are emerging as major regulators of telomere length homeostasis. In this review, we describe the impact of ncRNAs on telomere function and discuss their implications in senescence and age-related diseases. We discuss emerging therapeutic strategies targeting telomere-regulatory ncRNAs in aging pathology.},
}
@article {pmid32276199,
year = {2020},
author = {Schratz, KE and Armanios, M},
title = {Cancer and myeloid clonal evolution in the short telomere syndromes.},
journal = {Current opinion in genetics &amp; development},
volume = {60},
number = {},
pages = {112-118},
pmid = {32276199},
issn = {1879-0380},
support = {R01 CA225027/CA/NCI NIH HHS/United States ; R01 HL119476/HL/NHLBI NIH HHS/United States ; T32 HL007525/HL/NHLBI NIH HHS/United States ; },
mesh = {Cell Transformation, Neoplastic/genetics/*pathology ; *Clonal Evolution ; *Genomic Instability ; Humans ; Leukemia, Myeloid, Acute/enzymology/genetics/*pathology ; Mutation ; Myelodysplastic Syndromes/enzymology/genetics/*pathology ; Telomerase/genetics/*metabolism ; *Telomere ; },
abstract = {The short telomere syndromes are considered the most common premature aging disorders. Although studies in genetically modified cells and animal models have suggested telomere dysfunction may promote genome instability, only a minority of humans with inherited loss-of-function mutations in telomerase and related genes develop cancer. Solid tumors are overall rare, and the vast majority of cancers are bone marrow-derived with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) comprising three-quarter of cases. In contrast to young short telomere syndrome patients who develop aplastic anemia, MDS and AML are usually diagnosed in adults who have milder short telomere defects. Here, we dissect the mechanisms by which these two bone marrow failure states, aplastic anemia and MDS-AML, evolve in the setting of varying degrees of telomere shortening. We discuss the implications of these observations for patient care as well as for understanding the genetics and biology of age-related myeloid clonal evolution.},
}
@article {pmid32267847,
year = {2020},
author = {Chalouni, M and Rodriguez-Centeno, J and Samri, A and Blanco, J and Stella-Ascariz, N and Wallet, C and Knobel, H and Zucman, D and Alejos Ferreras, B and Autran, B and Thiebaut, R and Raffi, F and Arribas, JR and , },
title = {Correlation between blood telomere length and CD4+ CD8+ T-cell subsets changes 96 weeks after initiation of antiretroviral therapy in HIV-1-positive individuals.},
journal = {PloS one},
volume = {15},
number = {4},
pages = {e0230772},
pmid = {32267847},
issn = {1932-6203},
mesh = {ADP-ribosyl Cyclase 1/immunology ; Adult ; Anti-Retroviral Agents/*immunology/therapeutic use ; Antiretroviral Therapy, Highly Active/methods ; CD4 Lymphocyte Count/methods ; CD4-Positive T-Lymphocytes/*immunology ; CD8-Positive T-Lymphocytes/*immunology ; Female ; HIV Infections/drug therapy/*immunology ; HIV Seropositivity/immunology ; HIV-1/drug effects/immunology ; Humans ; Immunologic Memory/immunology ; Immunophenotyping/methods ; Lymphocyte Activation/immunology ; Male ; Middle Aged ; T-Lymphocyte Subsets/*immunology ; Telomere/*immunology ; Viral Load/immunology ; },
abstract = {In 31 participants who started first-line antiretroviral therapy in the NEAT 001/ANRS 143 clinical trial, we found after 96 weeks a statistically significant increase in blood telomere length (TL) of 0.04 (T/S Ratio) (p = 0.03). This increase was positively correlated with both the change in the percentage of CD4+ T-cells and with the decrease of CD38+ molecules on Central Memory CD8+ and negatively correlated with the change in the percentage of CD4+ Effector Memory cells. Increase in TL could be an expression of immune reconstitution and the associated decrease in immune activation. We acknowledge for the low statistical power due to the small sample size and the potential for false positive results due to multiple testing. Hence, further studies are needed to confirm these observations.},
}
@article {pmid32260476,
year = {2020},
author = {Utyro, O and Perła-Kaján, J and Jakubowski, H},
title = {The Cbs Locus Affects the Expression of Senescence Markers and mtDNA Copy Number, but not Telomere Dynamics in Mice.},
journal = {International journal of molecular sciences},
volume = {21},
number = {7},
pages = {},
pmid = {32260476},
issn = {1422-0067},
support = {2019/33/B/NZ4/01760//Narodowe Centrum Nauki/ ; 2018/29/B/NZ4/0071//Narodowe Centrum Nauki/ ; 2016/23/B/NZ5/00573//Narodowe Centrum Nauki/ ; 2015/17/N/NZ3/03626//Narodowe Centrum Nauki/ ; 17GRNT32910002//American Heart Association/ ; },
mesh = {Animals ; Brain/growth &amp; development/metabolism ; Cystathionine beta-Synthase/*genetics ; DNA, Mitochondrial/*genetics ; Female ; *Gene Dosage ; Genetic Loci ; Kidney/growth &amp; development/metabolism ; Liver/growth &amp; development/metabolism ; Longevity/*genetics ; Male ; Mice ; Mice, Inbred C57BL ; Telomerase/genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {Cystathionine β-synthase (CBS) is a housekeeping enzyme that catalyzes the first step of the homocysteine to cysteine transsulfuration pathway. Homozygous deletion of the Cbs gene in mice causes severe hyperhomocysteinemia and reduces life span. Here, we examined a possible involvement of senescence, mitochondrial DNA, and telomeres in the reduced life span of Cbs[-/-] mice. We found that senescence-related p21, Pai-1, Mcp1, and Il-6 mRNAs were significantly upregulated (2-10-fold) in liver, while p21 was upregulated in the brain of Cbs[-/-] mice (n = 20) compared with control Cbs[+/-] siblings (n = 20) in a sex- and age-dependent manner. Telomere length in blood (n = 80), liver (n = 40), and brain (n = 40) was not affected by the Cbs[-/-] genotype, but varied with sex and/or age. Levels of mitochondrial DNA tended to be reduced in livers, but not brains and blood, of Cbs[-/-] females (n = 20-40). The Cbs[-/-] genotype significantly reduced Tert mRNA expression in brain, but not liver, in a sex- and age-dependent manner. Multiple regression analysis showed that the senescence-related liver (but not brain) mRNAs and liver (but not brain or blood) mitochondrial DNA were associated with the Cbs genotype. In contrast, telomere length in blood, brain, and liver was not associated with the Cbs genotype or hyperhomocysteinemia, but was associated with sex (in brain and liver) and age (in brain and blood). Taken together, these findings suggest that the changes in senescence marker expression and mtDNA levels, but not telomere shortening, could account for the reduced life span of Cbs[-/-] mice.},
}
@article {pmid32260112,
year = {2020},
author = {Joglekar, MV and Satoor, SN and Wong, WKM and Cheng, F and Ma, RCW and Hardikar, AA},
title = {An Optimised Step-by-Step Protocol for Measuring Relative Telomere Length.},
journal = {Methods and protocols},
volume = {3},
number = {2},
pages = {},
pmid = {32260112},
issn = {2409-9279},
abstract = {Telomeres represent the nucleotide repeat sequences at the ends of chromosomes and are essential for chromosome stability. They can shorten at each round of DNA replication mainly because of incomplete DNA synthesis of the lagging strand. Reduced relative telomere length is associated with aging and a range of disease states. Different methods such as terminal restriction fragment analysis, real-time quantitative PCR (qPCR) and fluorescence in situ hybridization are available to measure telomere length; however, the qPCR-based method is commonly used for large population-based studies. There are multiple variations across qPCR-based methods, including the choice of the single-copy gene, primer sequences, reagents, and data analysis methods in the different reported studies so far. Here, we provide a detailed step-by-step protocol that we have optimized and successfully tested in the hands of other users. This protocol will help researchers interested in measuring relative telomere lengths in cells or across larger clinical cohort/study samples to determine associations of telomere length with health and disease.},
}
@article {pmid32257105,
year = {2020},
author = {Tan, J and Lan, L},
title = {The DNA secondary structures at telomeres and genome instability.},
journal = {Cell &amp; bioscience},
volume = {10},
number = {},
pages = {47},
pmid = {32257105},
issn = {2045-3701},
abstract = {Telomeric DNA are TTAGGG tandem repeats, which are susceptible for oxidative DNA damage and hotspot regions for formation of DNA secondary structures such as t-loop, D-loop, G-quadruplexes (G4), and R-loop. In the past two decades, unique DNA or RNA secondary structures at telomeres or some specific regions of genome have become promising therapeutic targets. G-quadruplex and R-loops at telomeres or transcribed regions of genome have been considered as the potential targets for cancer therapy. Here we discuss the potentials to target the secondary structures (G4s and R-loops) in genome as therapy approaches.},
}
@article {pmid32249523,
year = {2020},
author = {Koi, Y and Tsutani, Y and Nishiyama, Y and Kanda, M and Shiroma, Y and Yamamoto, Y and Sasada, S and Akita, T and Masumoto, N and Kadoya, T and Takahashi, RU and Tanaka, J and Okada, M and Tahara, H},
title = {Diagnostic performance of peripheral leukocyte telomere G-tail length for detecting breast cancer.},
journal = {Cancer science},
volume = {111},
number = {5},
pages = {1856-1861},
pmid = {32249523},
issn = {1349-7006},
support = {JP26310106//Japan Society for the Promotion of Science/ ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/metabolism ; Breast Neoplasms/blood/*diagnosis/ultrastructure ; Early Detection of Cancer ; Female ; Humans ; Leukocytes/*ultrastructure ; Middle Aged ; Telomere/*metabolism ; Telomere Shortening ; },
abstract = {The telomere G-tail (G-tail) plays an essential role in maintaining chromosome stability. In this study, we assessed the leukocyte G-tail length of breast cancer (BC) patients and cancer-free individuals and evaluated the association between the G-tail length and the presence of BC. A significant shortening of the median G-tail length was observed in BC patients compared with cancer-free individuals and was found in the early phase of BC. Our study indicated that the leukocyte G-tail length might be a potential biomarker for BC detection.},
}
@article {pmid32247554,
year = {2020},
author = {Zaguia, N and Laplagne, E and Colicchio, B and Cariou, O and Al Jawhari, M and Heidingsfelder, L and Hempel, WM and Jrad, BBH and Jeandidier, E and Dieterlen, A and Carde, P and Voisin, P and M'kacher, R},
title = {A new tool for genotoxic risk assessment: Reevaluation of the cytokinesis-block micronucleus assay using semi-automated scoring following telomere and centromere staining.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {850-851},
number = {},
pages = {503143},
doi = {10.1016/j.mrgentox.2020.503143},
pmid = {32247554},
issn = {1879-3592},
mesh = {Aneugens/pharmacology ; Centromere/*drug effects/genetics ; Cytokinesis/drug effects/genetics ; DNA Damage/*drug effects/genetics ; Humans ; Lymphocytes/drug effects ; Micronuclei, Chromosome-Defective/drug effects ; Micronucleus Tests ; *Mutagenicity Tests ; Mutagens/toxicity ; Risk Assessment ; Telomere/*drug effects/genetics ; },
abstract = {BACKGROUND: The cytokinesis-block micronucleus (CBMN) assay is an internationally recognized method for measuring DNA damage after exposure to genotoxic agents, as well as a biomarker for DNA repair and chromosomal instability. The high baseline level of micronuclei (MN) in the healthy population has limited the sensitivity and application of the CBMN assay for the follow-up of exposed populations. We reevaluated the sensitivity of the CBNM assay using semi-automated MN scoring following telomere and centromere (TC) staining after in vitro exposure to genotoxic agents (mitomycin or radiation) or aneugenic agents (vinblastine).<br><br>MATERIALS AND METHODS: Blood samples from 12 healthy donors were exposed to [137]Cs at seven doses from 0.1-4 Gy and cultured for 72 h. Cytochalasin B was added at 46 h of culture. The exposure of chemical agents (mitomycin or vinblastine) was performed after 48 h of culture for 3 h. Cytochalasin B was added after treatment and slides were prepared 24 h after. MN was semi-automatically scored following TC staining. Nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) were assessed in a human cell line after TC staining.<br><br>RESULTS: The introduction TC staining to the scoring of MN not only renders MN scoring more efficient and robust, but also permits discrimination between exposure to clastogenic (MN with only telomere signals) and aneugenic agents (MN with both TC signals). The resulting improvement of MN detection led to an increase in the sensitivity of the CBMN assay following low-dose radiation exposure (0.3 versus 0.1 Gy). Hyperradiosensitivity phenomenon was observed after low dose exposure. A dose-response curve was obtained for up to 4 Gy. In addition, TC staining permits assessment of the nature of NPBs and NBUDs as biomarkers for genotoxicity and chromosomal instability.<br><br>CONCLUSION: These approaches can be potentially used to follow-up populations exposed to genotoxic agents and assess cancer risk.},
}
@article {pmid32240902,
year = {2020},
author = {Ghosh, M and Janssen, L and Martens, DS and Öner, D and Vlaanderen, J and Pronk, A and Kuijpers, E and Vermeulen, R and Nawrot, TS and Godderis, L and Hoet, PH},
title = {Increased telomere length and mtDNA copy number induced by multi-walled carbon nanotube exposure in the workplace.},
journal = {Journal of hazardous materials},
volume = {394},
number = {},
pages = {122569},
doi = {10.1016/j.jhazmat.2020.122569},
pmid = {32240902},
issn = {1873-3336},
mesh = {DNA Copy Number Variations ; *DNA, Mitochondrial/genetics ; Humans ; *Nanotubes, Carbon/toxicity ; *Telomere/genetics ; *Workplace ; },
abstract = {Carbon nanotubes (CNTs) except MWCNT-7 have been classified as Group 3 ["Not classifiable as to its carcinogenicity to humans"] by the IARC. Despite considerable mechanistic evidence in vitro/in vivo, the classification highlights a general lack of data, especially among humans. In our previous study, we reported epigenetic changes in the MWCNT exposed workers. Here, we evaluated whether MWCNT can also cause alterations in aging related features including relative telomere length (TL) and/or mitochondrial copy number (mtDNAcn). Relative TL and mtDNAcn were measured on extracted DNA from peripheral blood from MWCNT exposed workers (N = 24) and non-exposed controls (N = 43) using a qPCR method. A higher mtDNAcn and longer TL were observed in MWCNT exposed workers when compared to controls. Independent of age, sex, smoking behavior, alcohol consumption and BMI, MWCNT-exposure was associated with an 18.30 % increase in blood TL (95 % CI: 7.15-30.62 %; p = 0.001) and 35.21 % increase in mtDNAcn (95 % CI: 19.12-53.46 %). Our results suggest that exposure to MWCNT can induce an increase in the mtDNAcn and TL; however, the mechanistic basis or consequence of such change requires further experimental studies.},
}
@article {pmid32236965,
year = {2020},
author = {Kim, C and Sung, S and Kim, J and Lee, J},
title = {Repair and Reconstruction of Telomeric and Subtelomeric Regions and Genesis of New Telomeres: Implications for Chromosome Evolution.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {42},
number = {6},
pages = {e1900177},
doi = {10.1002/bies.201900177},
pmid = {32236965},
issn = {1521-1878},
support = {IBS-R008-D1//Institute for Basic Science/International ; IBS-R008-D1//Samsung Science and Technology Foundation/International ; },
mesh = {DNA Damage ; *DNA Repair/genetics ; Genomic Instability/genetics ; Humans ; *Telomere/genetics ; },
abstract = {DNA damage repair within telomeres are suppressed to maintain the integrity of linear chromosomes, but the accidental activation of repairs can lead to genome instability. This review develops the concept that mechanisms to repair DNA damage in telomeres contribute to genetic variability and karyotype evolution, rather than catastrophe. Spontaneous breaks in telomeres can be repaired by telomerase, but in some cases DNA repair pathways are activated, and can cause chromosomal rearrangements or fusions. The resultant changes can also affect subtelomeric regions that are adjacent to telomeres. Subtelomeres are actively involved in such chromosomal changes, and are therefore the most variable regions in the genome. The case of Caenorhabditis elegans in the context of changes of subtelomeric structures revealed by long-read sequencing is also discussed. Theoretical and methodological issues covered in this review will help to explore the mechanism of chromosome evolution by reconstruction of chromosomal ends in nature.},
}
@article {pmid32231287,
year = {2020},
author = {Mendez-Bermudez, A and Giraud-Panis, MJ and Ye, J and Gilson, E},
title = {Heterochromatin replication goes hand in hand with telomere protection.},
journal = {Nature structural &amp; molecular biology},
volume = {27},
number = {4},
pages = {313-318},
pmid = {32231287},
issn = {1545-9985},
mesh = {Chromatin/*genetics/ultrastructure ; DNA Replication/genetics ; Heterochromatin/*genetics/ultrastructure ; Humans ; Proteins/chemistry/*genetics/ultrastructure ; Telomere/*genetics/ultrastructure ; },
abstract = {Telomeres arose from the need to stabilize natural chromosome ends, resulting in terminal chromatin structures with specific protective functions. Their constituent proteins also execute general functions within heterochromatin, mediating late replication and facilitating fork progression. Emerging insights into the mechanisms governing heterochromatin replication suggest telomeres and heterochromatin act in concert during development and aging. They also suggest a common evolutionary origin for these two chromosome regions that arose during eukaryogenesis.},
}
@article {pmid32229187,
year = {2020},
author = {Iloabuchi, C and Innes, KE and Sambamoorthi, U},
title = {Association of sleep quality with telomere length, a marker of cellular aging: A retrospective cohort study of older adults in the United States.},
journal = {Sleep health},
volume = {6},
number = {4},
pages = {513-521},
pmid = {32229187},
issn = {2352-7226},
support = {R15 AT008606/AT/NCCIH NIH HHS/United States ; U01 AG009740/AG/NIA NIH HHS/United States ; U54 GM104942/GM/NIGMS NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Biomarkers ; *Cellular Senescence ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; *Sleep ; *Telomere ; United States ; },
abstract = {BACKGROUND: Sleep quality is a risk factor for age-related diseases, and although the underlying mechanisms remain unclear, the effects of poor sleep quality on telomere length (TL) may play a role.<br><br>OBJECTIVE: The objective of the study was to evaluate the independent association between sleep quality and salivary TL in a large sample of older adults.<br><br>DESIGN: We adopted a retrospective cohort design, and participants comprised 5,268 adults drawn from the Health and Retirement Study. We used the 2006 (baseline) and 2008 (follow-up) waves. Baseline sleep quality was assessed using 4 Likert scale questions (trouble falling asleep, waking up during the night, waking up too early and not being able to fall sleep again, and feeling well rested in the morning). The TL was assessed using the T/S ratio, a continuous variable. The associations between sleep quality and T/S were assessed using multivariable ordinary least squares regressions. All analyses were adjusted for demographics, lifestyle characteristics, psychosocial, and other factors.<br><br>RESULTS: Overall, 16% reported never feeling well rested in the morning; 25.7% of respondents always had trouble waking during the night; and 12.8% always had trouble waking up too early in the morning. Respondents who never felt rested in the morning had significantly shorter TL than those who always felt rested in the morning (adjusted beta&#xa0;= -0.08, standard error&#xa0;= 0.03, P < .01). The composite sleep measure was not significantly associated with shorter TL.<br><br>CONCLUSIONS: In this cohort of older adults, not feeling well rested in the morning was significantly and inversely associated with TL; however, the composite measure of sleep quality was not significantly associated with TL. These findings suggest a potential connection between one of the measures of impaired sleep and reduction in TL, a marker of cellular aging that has been linked to multiple chronic conditions.},
}
@article {pmid32226245,
year = {2020},
author = {Prasad, R and Pal, D and Mohammad, W},
title = {Therapeutic Targets in Telomerase and Telomere Biology of Cancers.},
journal = {Indian journal of clinical biochemistry : IJCB},
volume = {35},
number = {2},
pages = {135-146},
pmid = {32226245},
issn = {0970-1915},
abstract = {Telomeres play an important role to conserve genomic integrity by protecting the ends of chromosomes in normal cells. Since, their progressive shortening during successive cell division which lead to chromosomal instability. Notably, telomere length is perpetuated by telomerase in large majority of cancers, thereby ensure indefinite cell proliferation-a hallmark of cancer-and this unique feature has provided telomerase as the preferred target for drug development in cancer therapeutics. Cancer cells have acquired the potential to have telomere length maintenance by telomerase activation- up-regulation of hTERT gene expression in tumor cells is synchronized by multiple genetic and epigenetic modification mechanisms viz hTERT structural variants, hTERT promoter mutation and epigenetic modifications through hTERT promoter methylation which have been implicated in various cancers initiation and progression. In view of these facts, strategies have been made to target the underlining molecular mechanisms involved in telomerase reactivation as well as of telomere structure with special reference to distortion of sheltrin proteins. This review is focussed on extensive understanding of telomere and telomerase biology. which will provide indispensable informations for enhancing the efficiency of rational anticancer drug design. However, there is also an urgent need for better understanding of cell signalling pathways for alternative lengthening of telomere which is present in telomerase negative cancer for therapeutic targets.},
}
@article {pmid32223329,
year = {2022},
author = {Aghaee, S and Allen, A and Ramirez, J and Shariff-Marco, S and Allen, L and DeRouen, M and Elmofty, M and Marquez-Magana, L and Gomez, SL},
title = {Everyday discrimination and telomere length in a multiethnic cohort of breast cancer survivors.},
journal = {Ethnicity &amp; health},
volume = {27},
number = {3},
pages = {542-553},
doi = {10.1080/13557858.2020.1739231},
pmid = {32223329},
issn = {1465-3419},
support = {P30 AG015272/AG/NIA NIH HHS/United States ; },
mesh = {*Breast Neoplasms ; *Cancer Survivors ; Ethnicity ; Female ; Humans ; Minority Groups ; Pilot Projects ; Telomere ; },
abstract = {Objectives: Racial/ethnic minority women have disproportionately lower breast cancer survival rates compared to white women. As minorities in the US are exposed to higher levels of discrimination, and exposure to discrimination has been associated with shorter telomere lengths (TLs), we investigated the association between perceived everyday discrimination and TL in a multiethnic sample of breast cancer survivors.Design: We examined a cohort of 58 breast cancer survivors who participated in a pilot study to investigate biological stress. Participants were drawn from the Equality in Breast Cancer Care (EBCC) study and were asked to provide saliva samples for DNA extraction. Ordinary least squares linear regression was used to derive regression coefficients (β) and 95% confidence intervals (CI).Results: Higher levels of everyday discrimination were associated with longer TLs (e[β] = 1.04, CI: 1.01-1.07), adjusting for age, race/ethnicity, breast cancer stage, and breast cancer subtype. Luminal B subtypes were associated with longer telomeres relative to luminal A, while African Americans were less likely than Whites to have longer telomeres.Conclusions: Further research, particularly longitudinal studies, is needed to understand how discrimination, and other social stressors, impact biological stress and health outcomes.},
}
@article {pmid32222548,
year = {2020},
author = {Fernandes, CAH and Morea, EGO and Dos Santos, GA and da Silva, VL and Vieira, MR and Viviescas, MA and Chatain, J and Vadel, A and Saintomé, C and Fontes, MRM and Cano, MIN},
title = {A multi-approach analysis highlights the relevance of RPA-1 as a telomere end-binding protein (TEBP) in Leishmania amazonensis.},
journal = {Biochimica et biophysica acta. General subjects},
volume = {1864},
number = {7},
pages = {129607},
doi = {10.1016/j.bbagen.2020.129607},
pmid = {32222548},
issn = {1872-8006},
mesh = {DNA ; *Leishmania/genetics ; Molecular Docking Simulation ; Replication Protein A/chemistry/genetics/metabolism ; Telomere/genetics/metabolism ; *Telomere-Binding Proteins/chemistry/genetics ; },
abstract = {BACKGROUND: Telomeres are chromosome end structures important in the maintenance of genome homeostasis. They are replenished by the action of telomerase and associated proteins, such as the OB (oligonucleotide/oligosaccharide-binding)-fold containing telomere-end binding proteins (TEBP) which plays an essential role in telomere maintenance and protection. The nature of TEBPs is well known in higher and some primitive eukaryotes, but it remains undetermined in trypanosomatids. Previous in silico searches have shown that there are no homologs of the classical TEPBs in trypanosomatids, including Leishmania sp. However, Replication Protein A subunit 1 (RPA-1), an OB-fold containing DNA-binding protein, was found co-localized with trypanosomatids telomeres and showed a high preference for the telomeric G-rich strand.<br><br>METHODS AND RESULTS: We predicted the absence of structural homologs of OB-fold containing TEBPs in the Leishmania sp. genome using structural comparisons. We demonstrated by molecular docking that the ssDNA binding mode of LaRPA-1 shares features with the higher eukaryotes POT1 and RPA-1 crystal structures ssDNA binding mode. Using fluorescence spectroscopy, protein-DNA interaction assays, and FRET, we respectively show that LaRPA-1 shares some telomeric functions with the classical TEBPs since it can bind at least one telomeric repeat, protect the telomeric G-rich DNA from 3'-5' Exonuclease I digestion, and unfold telomeric G-quadruplex.<br><br>CONCLUSIONS: Our results suggest that RPA-1 emerges as a TEBP in trypanosomatids, and in this context, we present two possible evolutionary landscapes of trypanosomatids RPA-1 that could reflect upon the evolution of OB-fold containing TEBPs from all eukaryotes.},
}
@article {pmid32221362,
year = {2020},
author = {Udomsinprasert, W and Chanhom, N and Suvichapanich, S and Wattanapokayakit, S and Mahasirimongkol, S and Chantratita, W and Jittikoon, J},
title = {Leukocyte telomere length as a diagnostic biomarker for anti-tuberculosis drug-induced liver injury.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {5628},
pmid = {32221362},
issn = {2045-2322},
mesh = {Antitubercular Agents/*adverse effects/pharmacology ; Biomarkers/*metabolism ; Case-Control Studies ; Chemical and Drug Induced Liver Injury/*diagnosis/*metabolism ; Female ; Humans ; Kaplan-Meier Estimate ; Leukocytes/*metabolism ; Male ; Middle Aged ; Risk Factors ; Telomere/*metabolism ; Transaminases/metabolism ; Tuberculosis/drug therapy/*metabolism ; },
abstract = {Despite being relatively rare, anti-tuberculosis drug-induced liver injury (ATDILI) is a leading cause of acute liver failure and a major reason for treatment discontinuation, because of no specific and selective markers for ATDILI. Herein, this study aimed to investigate whether telomere length, a biological indicator of age-related diseases, is associated with ATDILI outcomes and could serve as an early ATDILI biomarker. Relative telomere length (RTL) in blood leukocyte of 100 age- and gender-matched healthy controls, 49 tuberculosis patients with ATDILI, and 53 tuberculosis patients with non-ATDILI was quantified using real-time polymerase chain reaction. Both tuberculosis patients with and without ATDILI had significantly shorter RTL than healthy controls. Compared with tuberculosis patients with non-ATDILI, RTL in those with ATDILI was significantly increased. Longer RTL was found to be significantly associated with increased susceptibility to ATDILI. Multivariate linear regression analysis showed that an increment in RTL was independently correlated with elevated values of aspartate aminotransferase and alanine aminotransferase assessed within 60 days after anti-tuberculosis treatment. Kaplan-Meier curve analysis demonstrated that longer RTL was associated with elevated rates of hepatotoxicity in tuberculosis patients. Receiver-operating characteristic curve analysis unveiled a diagnostic accuracy of RTL as a novel indicator for ATDILI progression (AUC = 0.73), which yielded more sensitive and specific values than traditional liver biomarkers including serum enzyme activities of aminotransferases measured within 7 days after treatment with anti-tuberculosis regimens. Collectively, aberrant RTL in blood leukocyte would reflect hepatotoxicity induced by anti-tuberculosis agents and might have a potential biomarker for early ATDILI progression.},
}
@article {pmid32220800,
year = {2020},
author = {Pepper, C and Norris, K and Fegan, C},
title = {Clinical utility of telomere length measurements in cancer.},
journal = {Current opinion in genetics &amp; development},
volume = {60},
number = {},
pages = {107-111},
doi = {10.1016/j.gde.2020.02.012},
pmid = {32220800},
issn = {1879-0380},
mesh = {Cell Transformation, Neoplastic/genetics/*pathology ; Humans ; Neoplasms/*genetics/*pathology ; *Telomere ; *Telomere Homeostasis ; },
abstract = {Cancer remains one of the leading causes of death in the developed world and despite impressive advances in therapeutic modalities, only a small subset of patients are currently cured. The underlying genetic heterogeneity of cancers clearly plays a crucial role in determining both the clinical course of individual pathologies and their responses to standard treatments. Although every tumour is to some extent distinct, there are recurrent features of cancers that can be exploited as therapeutic targets and as prognostic and predictive biomarkers; one such attribute is telomere length. Here we discuss the utility of telomere length evaluation in cancer and describe some of the promise and challenges of bringing this into clinical practice.},
}
@article {pmid32217664,
year = {2020},
author = {Loe, TK and Li, JSZ and Zhang, Y and Azeroglu, B and Boddy, MN and Denchi, EL},
title = {Telomere length heterogeneity in ALT cells is maintained by PML-dependent localization of the BTR complex to telomeres.},
journal = {Genes &amp; development},
volume = {34},
number = {9-10},
pages = {650-662},
pmid = {32217664},
issn = {1549-5477},
support = {R01 GM068608/GM/NIGMS NIH HHS/United States ; R01 GM122987/GM/NIGMS NIH HHS/United States ; R35 GM136273/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; DNA Topoisomerases, Type I/*metabolism ; DNA-Binding Proteins/*metabolism ; HeLa Cells ; Humans ; Protein Transport ; RecQ Helicases/*metabolism ; Telomere/*genetics/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {Telomeres consist of TTAGGG repeats bound by protein complexes that serve to protect the natural end of linear chromosomes. Most cells maintain telomere repeat lengths by using the enzyme telomerase, although there are some cancer cells that use a telomerase-independent mechanism of telomere extension, termed alternative lengthening of telomeres (ALT). Cells that use ALT are characterized, in part, by the presence of specialized PML nuclear bodies called ALT-associated PML bodies (APBs). APBs localize to and cluster telomeric ends together with telomeric and DNA damage factors, which led to the proposal that these bodies act as a platform on which ALT can occur. However, the necessity of APBs and their function in the ALT pathway has remained unclear. Here, we used CRISPR/Cas9 to delete PML and APB components from ALT-positive cells to cleanly define the function of APBs in ALT. We found that PML is required for the ALT mechanism, and that this necessity stems from APBs' role in localizing the BLM-TOP3A-RMI (BTR) complex to ALT telomere ends. Strikingly, recruitment of the BTR complex to telomeres in a PML-independent manner bypasses the need for PML in the ALT pathway, suggesting that BTR localization to telomeres is sufficient to sustain ALT activity.},
}
@article {pmid32215181,
year = {2020},
author = {Liu, Y and Ma, C and Li, P and Ma, C and He, S and Ping, F and Zhang, H and Li, W and Xu, L and Li, Y},
title = {Leukocyte Telomere Length Independently Predicts 3-Year Diabetes Risk in a Longitudinal Study of Chinese Population.},
journal = {Oxidative medicine and cellular longevity},
volume = {2020},
number = {},
pages = {9256107},
pmid = {32215181},
issn = {1942-0994},
mesh = {Asian People ; Biomarkers/blood ; Cellular Senescence ; DNA, Mitochondrial/blood ; Diabetes Mellitus/*blood/epidemiology ; Female ; Healthy Volunteers ; Humans ; Inflammation ; Leukocytes/*pathology ; Longitudinal Studies ; Male ; Middle Aged ; Oxidative Stress ; Risk ; Telomere/*pathology ; *Telomere Shortening ; },
abstract = {Cellular aging markers, including telomere length and mitochondrial function, as well as oxidative stress and inflammation markers influence each other and form a complex network, which is affected in diabetes. However, it remains unknown whether these markers could independently predict future diabetes after adjustment for their mutual effects. We conducted a 3-year longitudinal study in a Chinese cohort that comprised 108 nondiabetic individuals at baseline. The 2-hour 75 g oral glucose tolerance tests were performed at baseline and at 3-year follow-up. At baseline, leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) in leukocytes were determined using the polymerase chain reaction method. Tumor necrosis factor (TNF-α), interleukin-6, 8-hydroxy-2-deoxyguanosine levels, and superoxide dismutase (SOD) activity were measured by the enzyme-linked immunosorbent assay. Participants who developed diabetes at the 3-year follow-up (n = 28) had shorter LTL and higher levels of TNF-α and SOD activity at baseline. Baseline LTL was found to be independently associated with the development of diabetes at the 3-year follow-up after the adjustment for mtDNAcn, markers of oxidative stress and inflammation, and conventional diabetes risk factors. Our findings suggest that LTL is an independent predictor for 3-year diabetes risk, which might inform timely prevention and treatment of diabetes. Telomere shortening might be involved in the pathogenesis of diabetes independently of conventional diabetes risk factors, mtDNAcn, or oxidative stress and inflammation pathways.},
}
@article {pmid32214202,
year = {2020},
author = {Yang, ZY and Kao, TW and Peng, TC and Chen, YY and Yang, HF and Wu, CJ and Chen, WL},
title = {Examining the association between serum phosphate levels and leukocyte telomere length.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {5438},
pmid = {32214202},
issn = {2045-2322},
mesh = {Adult ; Aged ; Diet ; Female ; Humans ; Leukocytes/*cytology ; Male ; Middle Aged ; Minerals ; Nutrients/pharmacology ; Nutrition Surveys ; Phosphates/*blood ; Regression Analysis ; Social Class ; Telomere/*genetics/*pathology ; Telomere Homeostasis/drug effects ; United States ; Vitamins ; },
abstract = {Accelerated telomere attrition is related to various diseases, and multiple factors have been reported to influence telomere length. However, little attention has focused on the relationship between serum phosphate levels and mean telomere length. The purpose of this study was to explore the relationship between serum phosphate levels and mean telomere length in the US general population. A total of 7,817 participants from the 1999-2002 NHANES were included. The association between serum phosphate levels and mean telomere length was investigated using regression models. A remarkably positive relationship between serum phosphate levels and mean telomere length emerged after adjustments were made for covariates. The adjusted β coefficient of serum phosphate levels for mean telomere length was 0.038 (95% confidence intervals (CIs), 0.022 to 0.095, p = 0.002). A longer telomere length was observed in participants with serum phosphate levels in the highest quartiles, and a dose-dependent association was observed. Our study demonstrated that higher quartiles of phosphate had a remarkable correlation with longer telomere length.},
}
@article {pmid32213432,
year = {2020},
author = {Moslem, A and Rad, A and de Prado Bert, P and Alahabadi, A and Ebrahimi Aval, H and Miri, M and Gholizadeh, A and Ehrampoush, MH and Sunyer, J and Nawrot, TS and Miri, M and Dadvand, P},
title = {Association of exposure to air pollution and telomere length in preschool children.},
journal = {The Science of the total environment},
volume = {722},
number = {},
pages = {137933},
doi = {10.1016/j.scitotenv.2020.137933},
pmid = {32213432},
issn = {1879-1026},
mesh = {Air Pollutants ; *Air Pollution ; Child ; Child, Preschool ; Cross-Sectional Studies ; Environmental Exposure ; Humans ; Iran ; Leukocytes ; Particulate Matter ; Telomere ; },
abstract = {Exposure to air pollution is associated with adverse health effects; however, the available evidence of its association with telomere length (TL), an early marker of ageing, in children is still scarce with no study available for preschool children. This study aimed to investigate the association of exposure to air pollution and traffic indicators at home and kindergarten with relative leukocyte TL (LTL) in preschool children. This cross-sectional study included 200 preschool children (5-7 years old) recruited from 27 kindergartens in Sabzevar, Iran (2017). Outdoor annual average levels PM1, PM2.5, and PM10 at residential address and kindergartens were estimated applying land use regression (LUR) models. Moreover, indoor levels of PMs at kindergartens were measured for four days in each season resulting in a total of 16 days of measurements for each kindergarten. Total streets length in different buffers and distance to major road were calculated as traffic indicators at residential address and kindergartens. We applied quantitative real-time polymerase chain reaction (qRT-PCR) to measure relative LTL in blood samples obtained from children. Mixed linear regression models were developed with qPCR plate and kindergarten as random effects, to estimate association of each pollutant and traffic indicator with LTL, controlled for relevant covariates. Higher concentrations of outdoor PM1, PM2.5, and PM10, at home and kindergartens were associated with shorter relative LTL. Similarly, increase in indoor PM2.5 concentrations at kindergartens was associated with shorter relative LTL (β = -0.18, 95% CI: -0.36, -0.01, P-value < 0.01). Moreover, higher total street length in 100 m buffer around residence and lower residential distance to major roads were associated with shorter relative LTL (β = -0.25, 95% CI: -0.37, -0.13, P-value < 0.01, and 0.32, 95% CI: 0.20, 0.44, P-value < 0.01, respectively). Overall, our study suggested that higher exposure to air pollution and traffic at kindergarten and residential home were associated with shorter relative LTL in preschool children.},
}
@article {pmid32212792,
year = {2020},
author = {Arimura-Omori, M and Kiyohara, C and Yanagihara, T and Yamamoto, Y and Ogata-Suetsugu, S and Harada, E and Hamada, N and Tsuda, T and Takata, S and Shimabukuro, I and Nagata, N and Yatera, K and Torii, R and Okamoto, M and Fujita, M and Nakanishi, Y},
title = {Association between Telomere-Related Polymorphisms and the Risk of IPF and COPD as a Precursor Lesion of Lung Cancer: Findings from the Fukuoka Tobacco-Related Lung Disease (FOLD) Registry.},
journal = {Asian Pacific journal of cancer prevention : APJCP},
volume = {21},
number = {3},
pages = {667-673},
pmid = {32212792},
issn = {2476-762X},
mesh = {Female ; Humans ; Idiopathic Pulmonary Fibrosis/*genetics ; Lung Neoplasms/*genetics ; Male ; *Polymorphism, Single Nucleotide ; Pulmonary Disease, Chronic Obstructive/*genetics ; Registries ; Risk Factors ; Telomerase/*genetics ; Nicotiana/adverse effects ; },
abstract = {BACKGROUND: Lung cancer coexisting with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) can lead to poor prognosis. Telomere-related polymorphisms may be implicated in the pathogenesis of these three lung diseases. As to elucidate the mechanism of lung cancer via IPF or COPD may enable early detection and early treatment of the disease, we firstly examined the association between telomere-related polymorphisms and the risk of IPF and COPD in a case-control study.<br><br>MATERIALS AND METHODS: A total of 572 patients with IPF (n = 155) or COPD (n = 417), who were derived from our on-going cohort study, and controls (n = 379), who were derived from our previous case-control study, were included in this study.&#xa0; Telomerase reverse transcriptase (TERT) rs2736100, telomere RNA component (TERC) rs1881984, and oligonucleotide/oligosaccharide-binding fold containing1 (OBFC1) rs11191865 were genotyped with real-time PCR using TaqMan fluorescent probes. Unconditional logistic regression was used to assess the adjusted odds ratios and 95% confidence intervals.<br><br>RESULTS: TERT rs2736100 was significantly associated with the risk of IPF; increases in the number of this risk allele increased the risk of IPF (Ptrend = 0.008).&#xa0; Similarly, TERT rs2736100 was associated with the risk of COPD.&#xa0; In regard to the combined action of the three loci, increasing numbers of "at-risk" genotypes increased the risk of IPF in a dose-dependent manner (P trend=0.003).<br><br>CONCLUSIONS: TERT rs2736100 was associated with the risks of both IPF and COPD in a Japanese population. A combination of the "at-risk" genotypes might be important to identify the population at risk for IPF more clearly.},
}
@article {pmid32211971,
year = {2020},
author = {Wang, L and Song, L and Liu, B and Zhang, L and Wu, M and Xia, W and Li, Y and Xiong, C and Cao, Z and Xu, S and Zhang, B and Tian, Y and Wang, Y},
title = {Earlier maternal menarche is associated with shorter newborn telomere length.},
journal = {European journal of pediatrics},
volume = {179},
number = {10},
pages = {1507-1513},
pmid = {32211971},
issn = {1432-1076},
support = {81273083//National Natural Science Foundation of China/ ; 91643207//National Natural Science Foundation of China/ ; WJ2017Z001//Hubei Province Health &amp; Family Planning Scientific Research Project/ ; },
mesh = {Child ; China ; Female ; Fetal Blood ; Humans ; Infant, Newborn ; *Menarche/genetics ; Mothers ; *Telomere/genetics ; },
abstract = {The aim of our study was to investigate the relationship between maternal age at menarche and newborn telomere length which has been linked to lifespan and many age-related diseases. There were 734 mother-newborn pairs recruited from Wuhan Children's Hospital Wuhan, Hubei Province, China. Age at menarche was self-reported and categorized into three groups (≤ 12 years, 13 years, and ≥ 14 years). Telomere length in cord blood was measured using quantitative real-time polymerase chain reaction and expressed as the ratio of telomere copy number to single-copy gene number (T/S). The mean age at menarche of 734 mothers was 13.1 (± 1.1) years and the adjusted geometric means in the T/S of newborn telomeres in the three groups were 0.693, 0.721, and 0.748 respectively. Earlier age at menarche (≤ 12 years), compared with later age at menarche ≥ 14 years, was significantly associated with 7.32% (95% CI - 13.70%, - 0.23%) shorter telomere length in offspring after adjusting for potential confounders.Conclusion: Mothers with earlier age at menarche were more likely to give birth newborn with shorter telomere length. Our study provides evidences for the effect of earlier menarche on fetal telomere programming in offspring. What is Known: • Newborn telomere length is considered an indicator of lifespan and health outcomes in later life. • The adverse effects of earlier menarche age to their offspring have been found, but its relationship with newborn telomere length has not been assessed before. What is New: • This is the first study to explore the relationship of maternal menarche age with newborn telomere length. • We provided primary evidence that earlier maternal age at menarche was associated with shorter newborn telomere length.},
}
@article {pmid32203094,
year = {2020},
author = {Heaphy, CM and Bi, WL and Coy, S and Davis, C and Gallia, GL and Santagata, S and Rodriguez, FJ},
title = {Telomere length alterations and ATRX/DAXX loss in pituitary adenomas.},
journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},
volume = {33},
number = {8},
pages = {1475-1481},
pmid = {32203094},
issn = {1530-0285},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; T32 GM007748/GM/NIGMS NIH HHS/United States ; W81XWH-18-1-0496//Department of Defense/International ; },
mesh = {Adenoma/*genetics/pathology ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Co-Repressor Proteins/*biosynthesis ; Female ; Humans ; Male ; Middle Aged ; Molecular Chaperones/*biosynthesis ; Pituitary Neoplasms/*genetics/pathology ; Telomere/*metabolism ; Telomere Homeostasis/physiology ; X-linked Nuclear Protein/*biosynthesis ; Young Adult ; },
abstract = {Telomeres are nucleoprotein complexes located at the termini of eukaryotic chromosomes that prevent exonucleolytic degradation and end-to-end chromosomal fusions. Cancers often have critically shortened, dysfunctional telomeres contributing to genomic instability. Telomere shortening has been reported in a wide range of precancerous lesions and invasive carcinomas. However, the role of telomere alterations, including the presence of alternative lengthening of telomeres (ALT), has not been studied in pituitary adenomas. Telomere length and the presence of ALT were assessed directly at the single cell level using a telomere-specific fluorescence in situ hybridization assay in tissue microarrays. Tumors were characterized as either ALT-positive or having short, normal, or long telomere lengths and then these categories were compared with clinicopathological characteristics. ATRX and DAXX expression was studied through immunohistochemistry. We characterized a discovery set of 106 pituitary adenomas including both functional and nonfunctional subsets (88 primary, 18 recurrent). Telomere lengths were estimated and we observed 64 (59.4%) cases with short, 39 (36.8%) cases with normal, and 0 (0%) cases with long telomeres. We did not observe significant differences in the clinicopathological characteristics of the group with abnormally shortened telomeres compared to the group with normal telomeres. However, three pituitary adenomas were identified as ALT-positive of which two were recurrent tumors. Two of these three ALT-positive cases had alterations in either of the chromatin remodeling proteins, ATRX and DAXX, which are routinely altered in other ALT-positive tumor subtypes. In a second cohort of 32 recurrent pituitary adenomas from 22 patients, we found that the tumors from 36% of patients (n = 8) were ALT-positive. This study demonstrates that short telomere lengths are prevalent in pituitary adenomas and that ALT-positive pituitary adenomas are enriched in recurrent disease.},
}
@article {pmid32199234,
year = {2020},
author = {Henninger, E and Teixeira, MT},
title = {Telomere-driven mutational processes in yeast.},
journal = {Current opinion in genetics &amp; development},
volume = {60},
number = {},
pages = {99-106},
doi = {10.1016/j.gde.2020.02.018},
pmid = {32199234},
issn = {1879-0380},
mesh = {*Chromosomes, Fungal ; Evolution, Molecular ; *Gene Expression Regulation, Fungal ; *Genome, Fungal ; *Mutation ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; *Telomere ; },
abstract = {Telomeres are part of the system that guards genome integrity in eukaryotes, protecting linear chromosomes from fusions and degradations. The protective functions of telomeres are put at risk in physiological situations where telomeres shorten and trigger replicative senescence. Current models suggest that when telomeres shorten, combined actions of the DNA damage signalling network, DNA repair pathways, and the mechanics of mitosis result in translocations, gene losses, and aneuploidy. In yeasts, many of these processes (signalling, repair, mitosis) can be molecularly dissected because telomerase can be experimentally removed to enable detection of early and rare events. Here we review recent findings on telomere-driven mutational processes in yeast models and discuss how telomere dynamics may contribute to genome evolution.},
}
@article {pmid32199233,
year = {2020},
author = {Herate, C and Sabatier, L},
title = {Telomere instability initiates and then boosts carcinogenesis by the butterfly effect.},
journal = {Current opinion in genetics &amp; development},
volume = {60},
number = {},
pages = {92-98},
doi = {10.1016/j.gde.2020.01.005},
pmid = {32199233},
issn = {1879-0380},
mesh = {Cell Transformation, Neoplastic/genetics/*pathology ; *Chromosomal Instability ; Humans ; Neoplasms/*genetics/*pathology ; *Telomere ; *Telomere Homeostasis ; },
abstract = {Telomeres are composed of DNA repeat sequences at the ends of chromosomes that recruit a multitude of proteins to form a complex loop structure at each extremity. The integrity of this structure is critical and correct conformation of the loop is essential for the protection of chromosome ends from DDR signaling. The properties of telomere composition and synthesis result in telomere shortening at each cell division, programming cellular lifespan by driving aged cells towards death. Indeed, many external factors, such as cellular stress, trigger cell-cycle dysfunction and, in some cases, enable the survival of cells with dysfunctionally short telomeres. Destabilized loops at chromosome ends can then lead to dramatic consequences, via a butterfly effect such as multiple chromosomal fusions and rearrangements causing large chromosomal deletions, XXL-LOH (loss of heterozygoty due to very large chromosome deletions, up to whole chromosome arm), the expression of recessive mutations, and potential cell transformation.},
}
@article {pmid32198150,
year = {2020},
author = {Walsh, KM},
title = {Telomere Attrition in Childhood Cancer Survivors.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {26},
number = {10},
pages = {2281-2283},
doi = {10.1158/1078-0432.CCR-20-0380},
pmid = {32198150},
issn = {1557-3265},
mesh = {Adult ; *Cancer Survivors ; Child ; Humans ; Leukocytes ; *Neoplasms/genetics/therapy ; Prevalence ; Survivors ; Telomere/genetics ; },
abstract = {Childhood cancer survivors experience substantial treatment-related morbidity and biomarkers of long-term survivor health are needed. Leukocyte telomere length is shortened in childhood cancer survivors and associates with the occurrence of numerous chronic health conditions. Healthy lifestyle factors can attenuate telomere attrition in young-adult survivors, implicating critical windows for intervention.See related article by Song et al., p. 2362.},
}
@article {pmid32193147,
year = {2020},
author = {Cherdyntseva, V and Gagos, S},
title = {Chromosome extremities under the microscopy lens: molecular cytogenetics in telomere research.},
journal = {Current opinion in genetics &amp; development},
volume = {60},
number = {},
pages = {69-76},
doi = {10.1016/j.gde.2020.02.011},
pmid = {32193147},
issn = {1879-0380},
mesh = {Cytogenetic Analysis ; *DNA Damage ; *DNA Repair ; DNA Replication ; *Genomic Instability ; Humans ; Microscopy/*methods ; Neoplasms/*genetics/*pathology ; *Telomere ; },
abstract = {At the crossroads of DNA damage repair and genomic instability, telomere research significantly expands our knowledge on fundamental mechanisms involved in cancer initiation and progression, pledging novel tools for targeted and universal onco-therapies. Molecular cytogenetics through the application of a battery of fluorescent hybridization technologies plays an important role toward understanding telomere homeostasis. Herein, we review distinct molecular cytogenetic phenotypes associated with telomere repair, functionality, and elongation. We discuss the underlying mechanisms responsible for their formation or repair, focusing on Break-induced-Replication (BIR)-mediated conservative telomeric neo-synthesis, recently shown to drive the enigmatic Alternative Lengthening of Telomeres in neoplasia.},
}
@article {pmid32189404,
year = {2021},
author = {Rej, PH and Bondy, MH and Lin, J and Prather, AA and Kohrt, BA and Worthman, CM and Eisenberg, DTA},
title = {Telomere length analysis from minimally-invasively collected samples: Methods development and meta-analysis of the validity of different sampling techniques: American Journal of Human Biology.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {33},
number = {1},
pages = {e23410},
pmid = {32189404},
issn = {1520-6300},
support = {P2C HD042828/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Dried Blood Spot Testing/instrumentation/*methods ; Humans ; Middle Aged ; Specimen Handling/instrumentation/*methods ; Telomere/*physiology ; Young Adult ; },
abstract = {OBJECTIVES: Telomeres are the protective caps of chromosomes. They shorten with cell replication, age, and possibly environmental stimuli (eg, infection and stress). Short telomere length (TL) predicts subsequent worse health. Although venous whole blood (VWB) is most commonly used for TL measurement, other, more minimally invasive, sampling techniques are becoming increasingly common due to their field-friendliness, allowing for feasible measurement in low-resource contexts. We conducted statistical validation work for measuring TL in dried blood spots (DBS) and incorporated our results into a meta-analysis evaluating minimally invasive sampling techniques to measure TL.<br><br>METHODS: We isolated DNA extracts from DBS using a modified extraction protocol and tested how they endured different shipping conditions and long-term cryostorage. We then included our in-house DBS TL validation statistics (correlation values with VWB TL and age) in a series of meta-analyses of results from 24 other studies that published similar associations for values between TL measured in DBS, saliva, and buccal cells.<br><br>RESULTS: Our modified DBS extraction technique produced DNA yields that were roughly twice as large as previously recorded. Partially extracted DBS DNA was stable for 7&#x2009;days at room temperature, and still provided reliable TL measurements, as determined by external validation statistics. In our meta-analysis, DBS TL had the highest external validity, followed by saliva, and then buccal cells-possibly reflecting similarities/differences in cellular composition vs VWB.<br><br>CONCLUSIONS: DBS DNA is the best proxy for VWB from the three minimally-invasively specimen types evaluated and can be used to expand TL research to diverse settings and populations.},
}
@article {pmid32189393,
year = {2020},
author = {Darmishonnejad, Z and Zarei-Kheirabadi, F and Tavalaee, M and Zarei-Kheirabadi, M and Zohrabi, D and Nasr-Esfahani, MH},
title = {Relationship between sperm telomere length and sperm quality in infertile men.},
journal = {Andrologia},
volume = {52},
number = {5},
pages = {e13546},
doi = {10.1111/and.13546},
pmid = {32189393},
issn = {1439-0272},
support = {Grant No: 965463//National Institute for Medical Research Development/ ; },
mesh = {Adult ; Case-Control Studies ; Chromatin/*metabolism ; DNA Fragmentation ; Humans ; Infertility, Male/*genetics/pathology ; Lipid Peroxidation/genetics ; Male ; Middle Aged ; Oxidative Stress/genetics ; Protamines/analysis/metabolism ; Sperm Count ; Sperm Motility ; Spermatozoa/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; Young Adult ; },
abstract = {Telomeres, noncoding and repetitive DNA sequences play a significant function in chromatin integrity. Telomere length is age-dependent in somatic cells, while it increases in sperm cell with age. Therefore, we aimed to assess sperm chromatin, leucocyte and sperm telomere length (LTL, STL) in spermatozoon of 38 infertile and 19 fertile men aged between 20 and 50 years. Protamine deficiency (chromomycin A3 test), DNA fragmentation (TUNEL assay), lipid peroxidation (Bodipy probe) and telomere length (quantitative real-time PCR) were assessed. A significant decrease in mean of sperm concentration and motility and a significant increase in means of sperm abnormal morphology, DNA fragmentation, lipid peroxidation and protamine deficiency were observed in infertile compared with fertile men. In addition, the mean of LTL and STL were significantly shorter in infertile men compared with fertile individuals. We observed significant associations between telomere length with sperm concentration, DNA fragmentation and lipid peroxidation. We hypothesised that increased oxidative stress in spermatozoa of infertile men can result in abnormal packaging of chromatin, damage of DNA and shorter sperm telomere length. Together, these anomalies may account for fertility failure in these individuals.},
}
@article {pmid32186410,
year = {2020},
author = {Schmidt, CW},
title = {Telomere Length and Air Pollution: Observations in Women Who Use Biomass Cookstoves.},
journal = {Environmental health perspectives},
volume = {128},
number = {3},
pages = {34005},
pmid = {32186410},
issn = {1552-9924},
mesh = {*Air Pollution ; *Air Pollution, Indoor ; Biomass ; Female ; Humans ; Telomere ; },
}
@article {pmid32184670,
year = {2020},
author = {Morais, M and Dias, F and Teixeira, AL and Medeiros, R},
title = {Telomere Length in Renal Cell Carcinoma: The Jekyll and Hyde Biomarker of Ageing of the Kidney.},
journal = {Cancer management and research},
volume = {12},
number = {},
pages = {1669-1679},
pmid = {32184670},
issn = {1179-1322},
abstract = {Renal cell carcinoma (RCC) is a heterogeneous group of cancers where the clear cell (ccRCC) is the most common and the most lethal. The absence of accurate diagnostic and follow-up biomarkers along with the time-limited response to therapies may explain the lethality and shows the necessity of new sensitive and specific biomarkers. One of the most studied molecules are the telomeres: specialized ribonucleoprotein structures that keep the structural integrity of the genome. Among other features, telomere length (TL) has been widely studied in several tumor models regarding its biomarker potential, due to the easy detection and quantification. The scope of this review was to analyze all the information about this parameter in RCC. There was some disparity in the results of the studies, since some pointed to an association between short TL and risk or poor outcome of RCC; others between long TL and RCC outcome and some did not find any association. We propose some epidemiological and biological explanations to these differences. The telomeres may play a dual role during RCC carcinogenesis in the early stages, short telomeres may increase RCC risk and in late carcinogenesis, long telomeres seem to be associated with tumor prognosis. However, the controversy of the results along with the lack of specificity are some problems that need to be clarified for the usage of TL as a prognostic biomarker.},
}
@article {pmid32183210,
year = {2020},
author = {Zhang, H and Wang, D and Ma, H and Li, C and Wang, S and Wang, Y and Yang, L and Xu, L},
title = {Association between Leucocyte Telomere Length and Risk of Hearing Loss in the General Population: A Case-Control Study in Zhejiang Province, China.},
journal = {International journal of environmental research and public health},
volume = {17},
number = {6},
pages = {},
pmid = {32183210},
issn = {1660-4601},
mesh = {Case-Control Studies ; China/epidemiology ; Female ; *Hearing Loss/epidemiology/genetics ; Humans ; Male ; Middle Aged ; Risk Factors ; *Telomere ; },
abstract = {Limited studies have assessed the relation between telomere length and risk of hearing loss; moreover, they have reported equivocal associations. In the first case-control study, the subjects were chosen from the general population of Zhejiang province in order to assess the association between leucocyte telomere length and risk of hearing loss from 2016 to 2018. A total of 817 cases (55.93 ± 8.99 years) and 817 age-, sex- and residential city-matched controls (55.91 ± 9.03 years) were included for analysis. In the multivariable models, individuals in the top quartile of relative telomere length (RTL) had an odds ratio (OR) for hearing loss of 0.53 (95% confidence intervals [CI], 0.38-0.74) compared to those in the bottom quartile, and specifically, the OR was 0.45 (95% CI, 0.28-0.73) in females. In females, the risk of hearing loss decreased by 46% as RTL doubling increased; the standard deviation of RTL was associated with a 29% decrease in hearing loss risk. Additional analysis showed significant difference between participants in the female mild hearing loss group and corresponding controls. These results suggest that telomere length is associated with hearing loss in the general population, particularly in females with mild hearing loss. Telomere length might be a potential predictive biomarker of hearing loss at early stage.},
}
@article {pmid32182214,
year = {2020},
author = {Dolcini, J and Wu, H and Nwanaji-Enwerem, JC and Kiomourtozlogu, MA and Cayir, A and Sanchez-Guerra, M and Vokonas, P and Schwarz, J and Baccarelli, AA},
title = {Correction for: Mitochondria and aging in older individuals: an analysis of DNA methylation age metrics, leukocyte telomere length, and mitochondrial DNA copy number in the VA normative aging study.},
journal = {Aging},
volume = {12},
number = {6},
pages = {5585-5586},
doi = {10.18632/aging.102962},
pmid = {32182214},
issn = {1945-4589},
}
@article {pmid32181726,
year = {2020},
author = {},
title = {Correction to: Impact of Mothers' Age on Telomere Length and Human Telomerase Reverse Transcriptase Expression in Human Fetal Membrane-Derived Mesenchymal Stem Cells by Alrefaei GI, Alkarim SA, and Abduljabbar HS. Stem Cells Dev 2019;28;24;1632-1645 DOI:10.1089/scd.2019-0144.},
journal = {Stem cells and development},
volume = {29},
number = {6},
pages = {380-381},
doi = {10.1089/scd.2019.0144.correx},
pmid = {32181726},
issn = {1557-8534},
}
@article {pmid32180739,
year = {2020},
author = {Gampawar, P and Schmidt, R and Schmidt, H},
title = {Leukocyte Telomere Length Is Related to Brain Parenchymal Fraction and Attention/Speed in the Elderly: Results of the Austrian Stroke Prevention Study.},
journal = {Frontiers in psychiatry},
volume = {11},
number = {},
pages = {100},
pmid = {32180739},
issn = {1664-0640},
abstract = {There are controversial results if leukocyte telomere length (LTL) is related to structural brain changes and cognitive decline in aging. Here, we investigated the association between LTL and 1) global MRI correlates of brain aging such as brain parenchymal fraction (BPF) and white matter hyperintensities (WMH) load and Fazekas score as well as 2) global (g-factor) and domain-specific cognition such as attention/speed, conceptualization, memory, and visuopractical skills. In total, 909 participants of the Austrian Stroke Prevention Study with LTL, MRI, and cognitive tests were included. There were 388 (42.7%) men, and the mean age was 65.9 years. Longer LTL was significantly associated with larger BPF (β = 0.43, p < 0.001), larger WMH load (β = 0.03, p = 0.04), and score (β = 0.05, p = 0.04) after adjusting for age, sex, vascular risk factors, and ApoE4 carrier status. The effect on BPF was more significant in the subgroups of women (β = 0.51, p = 0.001), age >65 years (β = 0.58, p = 0.002), BMI ≥ 25 (β = 0.40, p = 0.004), education ≤10 years (β = 0.42, p = 0.002), hypertensives (β = 0.51, p = 0.001), cardiovascular disease (CVD) (β = 0.58, p = 0.005), non-diabetics (β = 0.42, p < 0.001), and Apoe4 non-carriers (β = 0.49, p < 0.001). The effect on WMH was significant within the hypertensives (load: β = 0.04, p = 0.02), non-diabetics (load:β = 0.03, p = 0.01; score: β = 0.06, p = 0.02), in those with education ≤10 years (load: β = 0.03, p = 0.04; score: β = 0.07, p = 0.02), in ApoE4 non-carriers (load: β = 0.03, p = 0.02; score: β = 0.07, p = 0.01) and in subjects without CVD (score: β = 0.06, p = 0.05). We only observed a significant association between LTL and the cognitive domain of attention/speed, which was confined to the subgroups of BMI ≥ 25 (β = 0.04, p = 0.05) and education ≤10 years (β = 0.04, p = 0.05). The effect of LTL on attention/speed was partly mediated in both subgroups by BPF (β = 0.02, 95% CI = 0.01:0.03) when tested by bootstrapping. Our results support a strong protective role of longer LTL on global brain volume which in turn may contribute to better cognitive functions, especially in the attention/speed domain in the elderly.},
}
@article {pmid32176281,
year = {2021},
author = {Ebeid, DE and Khalafalla, FG and Broughton, KM and Monsanto, MM and Esquer, CY and Sacchi, V and Hariharan, N and Korski, KI and Moshref, M and Emathinger, J and Cottage, CT and Quijada, PJ and Nguyen, JH and Alvarez, R and Völkers, M and Konstandin, MH and Wang, BJ and Firouzi, F and Navarrete, JM and Gude, NA and Goumans, MJ and Sussman, MA},
title = {Pim1 maintains telomere length in mouse cardiomyocytes by inhibiting TGFβ signalling.},
journal = {Cardiovascular research},
volume = {117},
number = {1},
pages = {201-211},
pmid = {32176281},
issn = {1755-3245},
support = {R01 HL105759/HL/NHLBI NIH HHS/United States ; R37 HL091102/HL/NHLBI NIH HHS/United States ; R01 HL113647/HL/NHLBI NIH HHS/United States ; R01 HL067245/HL/NHLBI NIH HHS/United States ; P01 HL085577/HL/NHLBI NIH HHS/United States ; R01 HL117163/HL/NHLBI NIH HHS/United States ; 18PRE33990268/AHA/American Heart Association-American Stroke Association/United States ; },
mesh = {A549 Cells ; Animals ; Cellular Senescence/*drug effects ; Humans ; Male ; Mice, Knockout ; Myocytes, Cardiac/*drug effects/enzymology ; Phosphorylation ; Proto-Oncogene Proteins c-pim-1/genetics/*metabolism ; Receptors, Transforming Growth Factor beta/metabolism ; Signal Transduction ; Smad2 Protein/metabolism ; Smad3 Protein/metabolism ; Telomerase/metabolism ; Telomere Homeostasis/*drug effects ; Transforming Growth Factor beta1/*pharmacology ; Mice ; },
abstract = {AIMS: Telomere attrition in cardiomyocytes is associated with decreased contractility, cellular senescence, and up-regulation of proapoptotic transcription factors. Pim1 is a cardioprotective kinase that antagonizes the aging phenotype of cardiomyocytes and delays cellular senescence by maintaining telomere length, but the mechanism remains unknown. Another pathway responsible for regulating telomere length is the transforming growth factor beta (TGFβ) signalling pathway where inhibiting TGFβ signalling maintains telomere length. The relationship between Pim1 and TGFβ has not been explored. This study delineates the mechanism of telomere length regulation by the interplay between Pim1 and components of TGFβ signalling pathways in proliferating A549 cells and post-mitotic cardiomyocytes.<br><br>METHODS AND RESULTS: Telomere length was maintained by lentiviral-mediated overexpression of PIM1 and inhibition of TGF&#x3b2; signalling in A549 cells. Telomere length maintenance was further demonstrated in isolated cardiomyocytes from mice with cardiac-specific overexpression of PIM1 and by pharmacological inhibition of TGF&#x3b2; signalling. Mechanistically, Pim1 inhibited phosphorylation of Smad2, preventing its translocation into the nucleus and repressing expression of TGF&#x3b2; pathway genes.<br><br>CONCLUSION: Pim1 maintains telomere lengths in cardiomyocytes by inhibiting phosphorylation of the TGF&#x3b2; pathway downstream effectors Smad2 and Smad3, which prevents repression of telomerase reverse transcriptase. Findings from this study demonstrate a novel mechanism of telomere length maintenance and provide a potential target for preserving cardiac function.},
}
@article {pmid32175820,
year = {2020},
author = {Tucker, LA},
title = {Walking and biologic ageing: Evidence based on NHANES telomere data.},
journal = {Journal of sports sciences},
volume = {38},
number = {9},
pages = {1026-1035},
doi = {10.1080/02640414.2020.1739896},
pmid = {32175820},
issn = {1466-447X},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*physiology ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes ; Male ; Middle Aged ; Nutrition Surveys ; Telomere Shortening/*physiology ; Walking/*physiology ; Young Adult ; },
abstract = {The length of telomeres is an objective measure of biologic ageing. This study evaluated the extent minutes of walking per week are associated with leukocyte telomere length (LTL) in a random sample of 5,823 U.S. adults. The investigation was cross-sectional and data were obtained from the National Health and Nutrition Examination Survey (NHANES). LTL was measured by the quantitative polymerase chain reaction method. Walking minutes was calculated from walking frequency and duration measures. Results showed that for each year of chronological age, telomeres were 15.6 base pairs shorter (P < 0.0001). With walking minutes and LTL treated as continuous variables, the relationship was quadratic, not linear (F = 11.2, P = 0.0023). With walking time divided into three categories, adults who performed ≥ 150 minutes of walking per week had longer telomeres than those who did no regular walking, and those who did some, but less than the recommendation (F = 5.0, P = 0.0137). Regular walkers were estimated to have a biologic ageing advantage associated with 6.5-7.6 years less biologic ageing compared to non-walkers, after adjusting for covariates. Additional investigations designed to study causality and the mechanisms associated with the walking and LTL relationship are needed.},
}
@article {pmid32175073,
year = {2020},
author = {Zhang, JM and Zou, L},
title = {Alternative lengthening of telomeres: from molecular mechanisms to therapeutic outlooks.},
journal = {Cell &amp; bioscience},
volume = {10},
number = {},
pages = {30},
pmid = {32175073},
issn = {2045-3701},
abstract = {To escape replicative senescence, cancer cells have to overcome telomere attrition during DNA replication. Most of cancers rely on telomerase to extend and maintain telomeres, but 4-11% of cancers use a homologous recombination-based pathway called alternative lengthening of telomeres (ALT). ALT is prevalent in cancers from the mesenchymal origin and usually associates with poor clinical outcome. Given its critical role in protecting telomeres and genomic integrity in tumor cells, ALT is an Achilles heel of tumors and an attractive target for cancer therapy. Here, we review the recent progress in the mechanistic studies of ALT, and discuss the emerging therapeutic strategies to target ALT-positive cancers.},
}
@article {pmid32171975,
year = {2020},
author = {Stroik, S and Hendrickson, EA},
title = {Telomere fusions and translocations: a bridge too far?.},
journal = {Current opinion in genetics &amp; development},
volume = {60},
number = {},
pages = {85-91},
pmid = {32171975},
issn = {1879-0380},
support = {R01 CA190492/CA/NCI NIH HHS/United States ; R01 GM088351/GM/NIGMS NIH HHS/United States ; },
mesh = {*Genomic Instability ; Humans ; *Mitosis ; Neoplasms/*genetics/*pathology ; *Telomere ; *Telomere Homeostasis ; *Translocation, Genetic ; },
abstract = {Telomere fusions inevitably arise as a cell's last-ditch effort to protect exposed chromosomal ends when telomeres are lost due to aging-associated erosion, breakage, failed replication, or a plethora of other cellular mistakes. Fusion of an exposed chromosomal end to another telomere presumably presents a superficially attractive option to the cell as opposed to the alternative of the impending degradation of the unprotected chromosomal terminus. However, when allowed to progress to mitosis these fusion events subsequently foster non-disjunction or bridge:breakage events - both of which drive highly pathogenic genomic instability and additional chromosomal translocations. Thus, the question becomes how and when telomere fusion events arise and, most importantly, is there a mechanism available to resolve these telomere bridges such that proper repair, and not genomic instability, results? Recent evidence suggests that the formation, and then the resolution of, ultrafine bridges may facilitate this process.},
}
@article {pmid32171974,
year = {2020},
author = {Cicconi, A and Chang, S},
title = {Shelterin and the replisome: at the intersection of telomere repair and replication.},
journal = {Current opinion in genetics &amp; development},
volume = {60},
number = {},
pages = {77-84},
doi = {10.1016/j.gde.2020.02.016},
pmid = {32171974},
issn = {1879-0380},
mesh = {*DNA Damage ; *DNA Repair ; *DNA Replication ; Genomic Instability ; Humans ; Neoplasms/enzymology/*genetics/*pathology ; Shelterin Complex ; *Telomere ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Telomeres are G-rich repetitive sequences that are difficult to replicate, resulting in increased replication stress that can threaten genome stability. Shelterin protects telomeres from engaging in aberrant DNA repair and dictates the choice of DNA repair pathway at dysfunctional telomeres. Recently, shelterin has been shown to participate in telomere replication. Here we review the most recent discoveries documenting the mechanisms by which shelterin represses DNA repair pathways at telomeres while assisting its replication. The interplay between shelterin and the replisome complex highlights a novel connection between telomere maintenance and repair.},
}
@article {pmid32171108,
year = {2020},
author = {Nelson, CP and Codd, V},
title = {Genetic determinants of telomere length and cancer risk.},
journal = {Current opinion in genetics &amp; development},
volume = {60},
number = {},
pages = {63-68},
doi = {10.1016/j.gde.2020.02.007},
pmid = {32171108},
issn = {1879-0380},
mesh = {Biomarkers, Tumor/*genetics ; *Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Neoplasms/*genetics/*pathology ; *Polymorphism, Single Nucleotide ; Risk Factors ; *Telomere ; *Telomere Homeostasis ; },
abstract = {The relationship of telomere length with cancer risk has been the source of much debate within epidemiological studies, which have produced inconsistent finding both between and within different cancer types. Over recent years, genome-wide association studies of increasing size have identified variants that determine human telomere length. These variants have subsequently been utilised as instrumental variables in Mendelian randomisation based studies, allowing the investigation of potential causal relationships between telomere length and cancer. Here we discuss recent advances in both genomic discovery, studies that give increasing evidence towards a causal role for telomere length in cancer risk and considerations for future studies.},
}
@article {pmid32168019,
year = {2020},
author = {Kresovich, JK and Parks, CG and Sandler, DP and Weinberg, CR and Taylor, JA},
title = {The Role of Blood Cell Composition in Epidemiologic Studies of Telomeres.},
journal = {Epidemiology (Cambridge, Mass.)},
volume = {31},
number = {4},
pages = {e34-e36},
pmid = {32168019},
issn = {1531-5487},
support = {ZIA ES044005/ImNIH/Intramural NIH HHS/United States ; ZIA ES049033/ImNIH/Intramural NIH HHS/United States ; },
mesh = {*Blood Cells ; *Epidemiologic Studies ; Humans ; *Telomere ; },
}
@article {pmid32166868,
year = {2020},
author = {Del Brío Castillo, R and Bleesing, J and McCormick, T and Squires, JE and Mazariegos, GV and Squires, J and McKiernan, PJ},
title = {Successful liver transplantation in short telomere syndromes without bone marrow failure due to DKC1 mutation.},
journal = {Pediatric transplantation},
volume = {24},
number = {3},
pages = {e13695},
doi = {10.1111/petr.13695},
pmid = {32166868},
issn = {1399-3046},
mesh = {Bone Marrow Failure Disorders ; Cell Cycle Proteins/*genetics ; Child ; Genetic Markers ; Hepatopulmonary Syndrome/etiology/surgery ; Humans ; Kidney Failure, Chronic/etiology/*surgery ; Liver Cirrhosis/etiology/surgery ; *Liver Transplantation ; Male ; *Mutation ; Nuclear Proteins/*genetics ; Syndrome ; Telomere Shortening/*genetics ; },
abstract = {Short telomere syndromes are a heterogenous spectrum of disorders leading to premature cellular aging. These may involve bone marrow failure, adult-onset idiopathic pulmonary fibrosis, and liver disease, and classical entities such as dyskeratosis congenita. We report a patient who presented with common variable immunodeficiency at 3 years of age and autoimmune cytopenias at 8 years of age. He was found to have short telomeres, and genetic testing confirmed a hemizygous mutation NM_001363.4: c.-142C > G in DKC1 gene. He subsequently developed cirrhosis with severe portal hypertension and hepatopulmonary syndrome, prompting liver transplantation at 11 years of age. He remains well 10 years after transplant with no progression of bone marrow failure or progressive lung disease. In conclusion, short telomere syndromes should be considered as a potential cause of pediatric liver disease of unknown etiology, and in severe cases, isolated liver transplantation may be both appropriate and successful.},
}
@article {pmid32165663,
year = {2020},
author = {Mendioroz, M and Puebla-Guedea, M and Montero-Marín, J and Urdánoz-Casado, A and Blanco-Luquin, I and Roldán, M and Labarga, A and García-Campayo, J},
title = {Telomere length correlates with subtelomeric DNA methylation in long-term mindfulness practitioners.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {4564},
pmid = {32165663},
issn = {2045-2322},
mesh = {Adult ; Case-Control Studies ; Cross-Sectional Studies ; *DNA Methylation ; Epigenesis, Genetic ; Female ; Gene Expression Regulation ; Humans ; Male ; Middle Aged ; Mindfulness/*methods ; Oligonucleotide Array Sequence Analysis ; Receptors, G-Protein-Coupled/*genetics ; Serpins/*genetics ; Telomere/*metabolism ; },
abstract = {Mindfulness and meditation techniques have proven successful for the reduction of stress and improvement in general health. In addition, meditation is linked to longevity and longer telomere length, a proposed biomarker of human aging. Interestingly, DNA methylation changes have been described at specific subtelomeric regions in long-term meditators compared to controls. However, the molecular basis underlying these beneficial effects of meditation on human health still remains unclear. Here we show that DNA methylation levels, measured by the Infinium HumanMethylation450 BeadChip (Illumina) array, at specific subtelomeric regions containing GPR31 and SERPINB9 genes were associated with telomere length in long-term meditators with a strong statistical trend when correcting for multiple testing. Notably, age showed no association with telomere length in the group of long-term meditators. These results may suggest that long-term meditation could be related to epigenetic mechanisms, in particular gene-specific DNA methylation changes at distinct subtelomeric regions.},
}
@article {pmid32163830,
year = {2020},
author = {Lorbeer, FK and Hockemeyer, D},
title = {TERT promoter mutations and telomeres during tumorigenesis.},
journal = {Current opinion in genetics &amp; development},
volume = {60},
number = {},
pages = {56-62},
doi = {10.1016/j.gde.2020.02.001},
pmid = {32163830},
issn = {1879-0380},
support = {R01 CA196884/CA/NCI NIH HHS/United States ; },
mesh = {Carcinogenesis/genetics/metabolism/*pathology ; *DNA Methylation ; Gene Expression Regulation, Neoplastic ; Humans ; Neoplasms/enzymology/genetics/*pathology ; *Promoter Regions, Genetic ; Telomerase/*genetics ; *Telomere ; *Telomere Homeostasis ; },
abstract = {Telomerase regulation and telomere shortening act as a strong tumor suppressor mechanism in human somatic cells. Point mutations in the promoter of telomerase reverse transcriptase (TERT) are the most frequent non-coding mutation in cancer. These TERT promoter mutations (TPMs) create de novo ETS factor binding sites upstream of the start codon of the gene, which can be bound by different ETS factors. TPMs can occur early during tumorigenesis and are thought to be among the first mutations in melanoma, glioblastoma and hepatocellular carcinoma. Despite their association with increased TERT levels, TPMs do not prohibit telomere shortening and TPM-harboring cancers present with short telomeres. Their short telomere length combined with their high prevalence and specificity for cancer makes TPMs an attractive target for future therapeutic exploitation of telomerase inhibition and telomere deprotection-induced cell death.},
}
@article {pmid32160539,
year = {2020},
author = {Matmati, S and Lambert, S and Géli, V and Coulon, S},
title = {Telomerase Repairs Collapsed Replication Forks at Telomeres.},
journal = {Cell reports},
volume = {30},
number = {10},
pages = {3312-3322.e3},
doi = {10.1016/j.celrep.2020.02.065},
pmid = {32160539},
issn = {2211-1247},
mesh = {Biocatalysis ; Cell Survival ; *DNA Repair ; *DNA Replication ; DNA, Fungal/metabolism ; Mutation/genetics ; Schizosaccharomyces/cytology/metabolism ; Schizosaccharomyces pombe Proteins/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are difficult-to-replicate sites whereby replication itself may threaten telomere integrity. We investigate, in fission yeast, telomere replication dynamics in telomerase-negative cells to unmask problems associated with telomere replication. Two-dimensional gel analysis reveals that replication of telomeres is severely impaired and correlates with an accumulation of replication intermediates that arises from stalled and collapsed forks. In the absence of telomerase, Rad51, Mre11-Rad50-Nbs1 (MRN) complex, and its co-factor CtIP[Ctp1] become critical to maintain telomeres, indicating that homologous recombination processes these intermediates to facilitate fork restart. We further show that a catalytically dead mutant of telomerase prevents Ku recruitment to telomeres, suggesting that telomerase and Ku both compete for the binding of telomeric-free DNA ends that are likely to originate from a reversed fork. We infer that Ku removal at collapsed telomeric forks allows telomerase to repair broken telomeres, thereby shielding telomeres from homologous recombination.},
}
@article {pmid32156247,
year = {2020},
author = {Wong, SK and Ima-Nirwana, S and Chin, KY},
title = {Can telomere length predict bone health? A review of current evidence.},
journal = {Bosnian journal of basic medical sciences},
volume = {20},
number = {4},
pages = {423-429},
pmid = {32156247},
issn = {1840-4812},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging ; Bone Density ; Bone and Bones/*pathology ; DNA/analysis ; Female ; Humans ; Male ; Middle Aged ; Osteoblasts/metabolism ; Osteoclasts/metabolism ; Osteoporosis/*diagnosis ; Telomerase/chemistry ; Telomere/*ultrastructure ; *Telomere Shortening ; Young Adult ; },
abstract = {Telomeres are repetitive DNA sequences located at the end of chromosomes that serve as a protective barrier against chromosomal deterioration during cell division. Approximately 50-200 base pairs of nucleotides are lost per cell division, and new repetitive nucleotides are added by the enzyme telomerase, allowing telomere maintenance. Telomere shortening has been proposed as an indicator for biological aging, but its relationship with age-related osteoporosis is ambiguous. We summarize the current evidence on the relationship between telomere length and bone health in experimental and epidemiological studies, which serve as a scientific reference for the development of novel diagnostic markers of osteoporosis or novel therapeutics targeting telomere and telomerase of bone cells to treat osteoporosis.},
}
@article {pmid32155570,
year = {2020},
author = {Gong, Y and Stock, AJ and Liu, Y},
title = {The enigma of excessively long telomeres in cancer: lessons learned from rare human POT1 variants.},
journal = {Current opinion in genetics &amp; development},
volume = {60},
number = {},
pages = {48-55},
pmid = {32155570},
issn = {1879-0380},
support = {Z99 AG999999/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Cell Transformation, Neoplastic/genetics/*pathology ; *Germ-Line Mutation ; Humans ; Neoplasms/*genetics/*pathology ; Shelterin Complex ; *Telomere ; *Telomere Homeostasis ; Telomere-Binding Proteins/*genetics ; },
abstract = {The discovery that rare POT1 variants are associated with extremely long telomeres and increased cancer predisposition has provided a framework to revisit the relationship between telomere length and cancer development. Telomere shortening is linked with increased risk for cancer. However, over the past decade, there is increasing evidence to show that extremely long telomeres caused by mutations in shelterin components (POT1, TPP1, and RAP1) also display an increased risk of cancer. Here, we will review current knowledge on germline mutations of POT1 identified from cancer-prone families. In particular, we will discuss some common features presented by the mutations through structure-function studies. We will further provide an overview of how POT1 mutations affect telomere length regulation and tumorigenesis.},
}
@article {pmid32155445,
year = {2020},
author = {Saint-Leandre, B and Levine, MT},
title = {The Telomere Paradox: Stable Genome Preservation with Rapidly Evolving Proteins.},
journal = {Trends in genetics : TIG},
volume = {36},
number = {4},
pages = {232-242},
pmid = {32155445},
issn = {0168-9525},
support = {R35 GM124684/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Diptera/genetics ; *Evolution, Molecular ; Humans ; Plants/genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {Telomeres ensure chromosome length homeostasis and protection from catastrophic end-to-end chromosome fusions. All eukaryotes require this essential, strictly conserved telomere-dependent genome preservation. However, recent evolutionary analyses of mammals, plants, and flies report pervasive rapid evolution of telomere proteins. The causes of this paradoxical observation - that unconserved machinery underlies an essential, conserved function - remain enigmatic. Indeed, these fast-evolving telomere proteins bind, extend, and protect telomeric DNA, which itself evolves slowly in most systems. We hypothesize that the universally fast-evolving subtelomere - the telomere-adjacent, repetitive sequence - is a primary driver of the 'telomere paradox'. Under this model, radical sequence changes in the subtelomere perturb subtelomere-dependent, telomere functions. Compromised telomere function then spurs adaptation of telomere proteins to maintain telomere length homeostasis and protection. We propose an experimental framework that leverages both protein divergence and subtelomeric sequence divergence to test the hypothesis that subtelomere sequence evolution shapes recurrent innovation of telomere machinery.},
}
@article {pmid32153618,
year = {2020},
author = {Peska, V and Garcia, S},
title = {Origin, Diversity, and Evolution of Telomere Sequences in Plants.},
journal = {Frontiers in plant science},
volume = {11},
number = {},
pages = {117},
pmid = {32153618},
issn = {1664-462X},
abstract = {Telomeres are basic structures of eukaryote genomes. They distinguish natural chromosome ends from double-stranded breaks in DNA and protect chromosome ends from degradation or end-to-end fusion with other chromosomes. Telomere sequences are usually tandemly arranged minisatellites, typically following the formula (TxAyGz)n. Although they are well conserved across large groups of organisms, recent findings in plants imply that their diversity has been underestimated. Changes in telomeres are of enormous evolutionary importance as they can affect whole-genome stability. Even a small change in the telomere motif of each repeat unit represents an important interference in the system of sequence-specific telomere binding proteins. Here, we provide an overview of telomere sequences, considering the latest phylogenomic evolutionary framework of plants in the broad sense (Archaeplastida), in which new telomeric sequences have recently been found in diverse and economically important families such as Solanaceae and Amaryllidaceae. In the family Lentibulariaceae and in many groups of green algae, deviations from the typical plant telomeric sequence have also been detected recently. Ancestry and possible homoplasy in telomeric motifs, as well as extant gaps in knowledge are discussed. With the increasing availability of genomic approaches, it is likely that more telomeric diversity will be uncovered in the future. We also discuss basic methods used for telomere identification and we explain the implications of the recent discovery of plant telomerase RNA on further research about the role of telomerase in eukaryogenesis or on the molecular causes and consequences of telomere variability.},
}
@article {pmid32151946,
year = {2020},
author = {Dewhurst, SM},
title = {Chromothripsis and telomere crisis: engines of genome instability.},
journal = {Current opinion in genetics &amp; development},
volume = {60},
number = {},
pages = {41-47},
pmid = {32151946},
issn = {1879-0380},
support = {R35 CA210036/CA/NCI NIH HHS/United States ; },
mesh = {Cell Transformation, Neoplastic/genetics/*pathology ; *Chromothripsis ; Genome, Human ; *Genomic Instability ; Humans ; Neoplasms/*genetics/*pathology ; *Telomere ; *Telomere Homeostasis ; },
abstract = {In the early stages of carcinogenesis cells confront two key suppressive checkpoints; senescence and telomere crisis. Telomere crisis is characterized by massive chromosomal instability and cell death. The genetic instability initiated during crisis leaves detectable scars on cancer genomes, the full scope of which is only just beginning to be appreciated. In particular, the dramatic genome reshuffling phenomenon chromothripsis has been mechanistically linked to the resolution of DNA bridges formed by dicentric chromosomes, and by the shattering of DNA inside micronuclei. Furthermore, an intriguing connection to innate immune signaling has begun to position telomere crisis as a crucial stage not only in the evolution of the cancer genome, but also in the interaction between the genome and the immune system.},
}
@article {pmid32150919,
year = {2020},
author = {Xu, Y and Xu, J and Chancoco, H and Huang, M and Torres, KE and Gu, J},
title = {Long Leukocyte Telomere Length Is Associated with Increased Risks of Soft Tissue Sarcoma: A Mendelian Randomization Study.},
journal = {Cancers},
volume = {12},
number = {3},
pages = {},
pmid = {32150919},
issn = {2072-6694},
abstract = {BACKGROUND: Leukocyte telomere length (LTL) has been associated with the risks of several cancers in observational studies. Mendelian randomization (MR) studies, using genetic variants as instrumental variables, have also shown associations of genetically predicted LTL with cancer risks. In this study, we performed the first MR analysis on soft tissue sarcoma (STS) to investigate the causal relationship between LTL and the risk of STS.<br><br>METHODS: Genotypes from eleven LTL-associated single nucleotide polymorphisms (SNPs) in 821 STS cases and 851 cancer-free controls were aggregated into a weighted genetic risk score (GRS) to predict LTL. Multivariate logistic regression was used to assess the association of STS risk with individual SNPs and aggregated GRS.<br><br>RESULTS: Four SNPs displayed evidence for an individual association between long LTL-conferring allele and increased STS risk: rs7675998 (odds ratio (OR) = 1.21, 95% confidence interval (CI) = 1.02-1.43), rs9420907 (OR = 1.31, 95% CI = 1.08-1.59), rs8105767 (OR = 1.18, 95% CI = 1.02-1.37), and rs412658 (OR = 1.18, 95% CI = 1.02-1.36). Moreover, longer genetically predicted LTL, calculated as GRS, was strongly associated with an increased risk of STS (OR = 1.44, 95% CI = 1.18-1.75, p < 0.001), and there was a significant dose-response association (p for trend <0.001 in tertile and quartile analyses). The association of longer LTL with higher STS risk was more evident in women than in men. In stratified analyses by major STS subtypes, longer LTL was significantly associated with higher risks of leiomyosarcoma and gastrointestinal stromal tumors.<br><br>CONCLUSIONS: Longer LTL is associated with increased risks of STS.},
}
@article {pmid32145504,
year = {2020},
author = {Bhargava, R and Fischer, M and O'Sullivan, RJ},
title = {Genome rearrangements associated with aberrant telomere maintenance.},
journal = {Current opinion in genetics &amp; development},
volume = {60},
number = {},
pages = {31-40},
pmid = {32145504},
issn = {1879-0380},
support = {R01 CA207209/CA/NCI NIH HHS/United States ; P30 CA047904/CA/NCI NIH HHS/United States ; },
mesh = {Cell Proliferation ; Cell Transformation, Neoplastic/genetics/*pathology ; *Genome, Human ; *Genomic Instability ; Humans ; Neoplasms/*genetics/*pathology ; *Telomere ; *Telomere Homeostasis ; },
abstract = {There is unequivocal evidence that telomeres are crucial for cellular homeostasis and that telomere dysfunction can elicit genome instability and potentially initiate events that culminate in cancer. Mounting evidence points to telomeres having a crucial role in driving local and systemic structural rearrangements that drive cancer. These include the classical 'breakage-fusion-bridge' (BFB) cycles and more recently identified genome re-shaping events like kataegis and chromothripsis. In this brief review, we outline the established and most recent advances describing the roles that telomere dysfunction has in the origin of these catastrophic genome rearrangements. We discuss how local and systemic structural rearrangements enable telomere length maintenance, by either telomerase or the alternative lengthening of telomeres, that is essential to sustain cancer cell proliferation.},
}
@article {pmid32142223,
year = {2020},
author = {Ropio, J and Chebly, A and Ferrer, J and Prochazkova-Carlotti, M and Idrissi, Y and Azzi-Martin, L and Cappellen, D and Pham-Ledard, A and Soares, P and Merlio, JP and Chevret, E},
title = {Reliable blood cancer cells' telomere length evaluation by qPCR.},
journal = {Cancer medicine},
volume = {9},
number = {9},
pages = {3153-3162},
pmid = {32142223},
issn = {2045-7634},
mesh = {Aged ; Aged, 80 and over ; Apoptosis ; Case-Control Studies ; Cell Proliferation ; Humans ; Leukocytes, Mononuclear/metabolism/*pathology ; Lymphoma, Large-Cell, Anaplastic/*diagnosis/genetics ; Middle Aged ; Real-Time Polymerase Chain Reaction/*methods ; Schizophrenia/blood/*diagnosis/genetics ; Skin Neoplasms/*diagnosis/genetics ; Telomere Homeostasis/*genetics ; Tumor Cells, Cultured ; },
abstract = {BACKGROUND: Telomere shortening is linked to a range of different human diseases, hence reliable measurement methods are needed to uncover such associations. Among the plethora of telomere length measurement methods, qPCR is reported as easy to conduct and a cost-effective approach to study samples with low DNA amounts.<br><br>METHODS: Cancer cells' telomere length was evaluated by relative and absolute qPCR methods.<br><br>RESULTS: Robust and reproducible telomere length measurements were optimized taking into account a careful reference gene selection and by knowing the cancer cells ploidy. qPCR data were compared to "gold standard" measurement from terminal restriction fragment (TRF).<br><br>CONCLUSIONS: Our study provides guidance and recommendations for accurate telomere length measurement by qPCR in cancer cells, taking advantage of our expertise in telomere homeostasis investigation in primary cutaneous T-cell lymphomas. Furthermore, our data emphasize the requirement of samples with both, high DNA quality and high tumor cells representation.},
}
@article {pmid32141666,
year = {2020},
author = {Bauch, C and Gatt, MC and Granadeiro, JP and Verhulst, S and Catry, P},
title = {Sex-specific telomere length and dynamics in relation to age and reproductive success in Cory's shearwaters.},
journal = {Molecular ecology},
volume = {29},
number = {7},
pages = {1344-1357},
pmid = {32141666},
issn = {1365-294X},
mesh = {Age Factors ; Animals ; Charadriiformes/*genetics ; Female ; Genetic Fitness ; Linear Models ; Male ; Portugal ; *Reproduction ; *Sex Characteristics ; Telomere/*ultrastructure ; Telomere Shortening ; },
abstract = {Individuals in free-living animal populations generally differ substantially in reproductive success, lifespan and other fitness-related traits, but the molecular mechanisms underlying this variation are poorly understood. Telomere length and dynamics are candidate traits explaining this variation, as long telomeres predict a higher survival probability and telomere loss has been shown to reflect experienced "life stress." However, telomere dynamics among very long-lived species are unresolved. Additionally, it is generally not well understood how telomeres relate to reproductive success or sex. We measured telomere length and dynamics in erythrocytes to assess their relationship to age, sex and reproduction in Cory's shearwaters (Calonectris borealis), a long-lived seabird, in the context of a long-term study. Adult males had on average 231 bp longer telomeres than females, independent of age. In females, telomere length changed relatively little with age, whereas male telomere length declined significantly. Telomere shortening within males from one year to the next was three times higher than the interannual shortening rate based on cross-sectional data of males. Past long-term reproductive success was sex-specifically reflected in age-corrected telomere length: males with on average high fledgling production were characterized by shorter telomeres, whereas successful females had longer telomeres, and we discuss hypotheses that may explain this contrast. In conclusion, telomere length and dynamics in relation to age and reproduction are sex-dependent in Cory's shearwaters and these findings contribute to our understanding of what characterises individual variation in fitness.},
}
@article {pmid32140970,
year = {2020},
author = {Yuzurihara, H and Aizawa, Y and Saotome, M and Ichikawa, Y and Yokoyama, H and Chikashige, Y and Haraguchi, T and Hiraoka, Y and Kurumizaka, H and Kagawa, W},
title = {Improved Methods for Preparing the Telomere Tethering Complex Bqt1-Bqt2 for Structural Studies.},
journal = {The protein journal},
volume = {39},
number = {2},
pages = {174-181},
pmid = {32140970},
issn = {1875-8355},
mesh = {Bacterial Proteins/*metabolism ; Caldicellulosiruptor ; Firmicutes/*metabolism ; Maltose-Binding Proteins/*metabolism ; Meiosis ; Recombinant Fusion Proteins/metabolism ; Telomere/metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {In eukaryotes, chromosome ends (telomeres) are tethered to the inner nuclear membrane. During the early stages of meiosis, telomeres move along the nuclear membrane and gather near the spindle-pole body, resulting in a bouquet-like arrangement of chromosomes. This chromosomal configuration appears to be widely conserved among eukaryotes, and is assumed to play an important role in the normal progression of meiosis, by mediating the proper pairing of homologous chromosomes. In fission yeast, the Bqt1-Bqt2 protein complex plays a key role in tethering the telomere to the inner nuclear membrane. However, the structural details of the complex required to clarify how telomeres are gathered near the spindle-pole body remain enigmatic. Previously, we devised a preparation procedure for the Schizosaccharomyces japonicus Bqt1-Bqt2 complex, in which a SUMO tag was fused to the N-terminus of the Bqt1 protein. This allowed us to purify the Bqt1-Bqt2 complex from the soluble fraction. In the present study, we found that a maltose-binding protein homolog, Athe_0614, served as a better fusion partner than the SUMO protein, resulting in the marked increase in the solubility of the Bqt1-Bqt2 complex. The Athe_0614 fusion partner may open up new avenues for X-ray crystallographic analyses of the structure of the Bqt1-Bqt2 complex.},
}
@article {pmid32134704,
year = {2020},
author = {Bevelacqua, JJ and Welsh, J and Mortazavi, SMJ},
title = {Comments on "Association of telomere length with chronic exposure to ionizing radiation among inhabitants of natural high background radiation areas of Ramsar, Iran".},
journal = {International journal of radiation biology},
volume = {96},
number = {6},
pages = {707-708},
doi = {10.1080/09553002.2020.1739770},
pmid = {32134704},
issn = {1362-3095},
mesh = {*Background Radiation ; Iran ; Radiation, Ionizing ; *Telomere ; },
}
@article {pmid32133978,
year = {2019},
author = {M'kacher, R and Breton, L and Colicchio, B and Puget, H and Hempel, WM and Al Jawhari, M and Jeandidier, E and Frey, M},
title = {Benefit of an association of an antioxidative substrate and a traditional chinese medicine on telomere elongation.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {65},
number = {8},
pages = {54-58},
pmid = {32133978},
issn = {1165-158X},
mesh = {Adolescent ; Adult ; Aged ; Antioxidants/*administration &amp; dosage ; Astragalus Plant/metabolism ; Child ; Child, Preschool ; *Dietary Supplements ; Humans ; Lymphocytes/metabolism ; *Medicine, Chinese Traditional ; Middle Aged ; Polysaccharides/administration &amp; dosage/chemistry ; S-Adenosylmethionine/administration &amp; dosage/chemistry ; Telomere/*metabolism ; Telomere Shortening ; Young Adult ; },
abstract = {Telomere shortening is involved in age-related disorders, such as cancer and cardiovascular diseases. Recently, telomerase re-activation strategies have been proposed to counteract telomere shortening and its consequences. Here, we investigated the benefit of dietary supplementation with a mix of S-adenosyl-methionine (SAMe) and a polysaccharide extract of Astragalus (APS) on telomere length of circulating lymphocytes of healthy volunteers. Blood lymphocytes of a cohort of 26 healthy volunteers who were administrated the mix of SAMe and APS in a food supplement for one year were collected. In vitro treatment of blood lymphocytes of healthy volunteers with the mix was also performed. A cohort of 150 healthy volunteers was used as a control. Telomere length was measured by Q-FISH. The micronucleus assay was performed to detect genotoxicity of the mix. The telomeres of circulating lymphocytes of the cohort of 26 donors supplemented with the mix were significantly longer than those of matched controls (p < 10-4). This elongation was essentially observed in the lymphocytes of older donors. Similarly, in vitro treatment of circulating lymphocytes with the mix significantly increased telomere length and decrease the proportion of cells with short telomeres. Here, we observed an increase in telomere length after in vivo and in vitro administration of a mix with SAMe and APS. The benefit of dietary supplementation with this mix opens a new horizon for the battle against aging and could be used in the treatment of chronic age-related disorders.},
}
@article {pmid32133733,
year = {2020},
author = {Morinha, F and Magalhães, P and Blanco, G},
title = {Standard guidelines for the publication of telomere qPCR results in evolutionary ecology.},
journal = {Molecular ecology resources},
volume = {20},
number = {3},
pages = {},
doi = {10.1111/1755-0998.13152},
pmid = {32133733},
issn = {1755-0998},
support = {FJCI-2017-32055//Ministerio de Ciencia e Innovaci&#xf3;n/ ; },
mesh = {Animals ; DNA/genetics ; DNA Primers/genetics ; Ecology/*standards ; Humans ; Real-Time Polymerase Chain Reaction/*standards ; Reproducibility of Results ; Telomere/*genetics ; },
abstract = {Telomere length has been used as a proxy of fitness, aging and lifespan in vertebrates. In the last decade, dozens of articles reporting on telomere dynamics in the fields of ecology and evolution have been published for a wide range of taxa. With this growing interest, it is necessary to ensure the accuracy and reproducibility of telomere length measurement techniques. Real-time quantitative PCR (qPCR) is routinely applied to measure relative telomere length. However, this technique is highly sensitive to several methodological variables and the optimization of qPCR telomere assays remains highly variable between studies. Therefore, standardized guidelines are required to enable the optimization of robust protocols, and to help in judging the validity of the presented results. This review provides an overview of preanalytical and analytical factors that can lead to qPCR inconsistencies and biases, including: (a) sample type, collection and storage; (b) DNA extraction, storage and quality; (c) qPCR primers, laboratory reagents, and assay conditions; and (d) data analysis. We propose a minimum level of information for publication of qPCR telomere assays in evolutionary ecology considering the methodological pitfalls and sources of error. This review highlights the complexity of the optimization and validation of qPCR for telomere measurement per se, demonstrating the importance of transparency and clarity of reporting methodological details required for reliable, reproducible and comparable qPCR telomere assays. We encourage efforts to implement standardized protocols that ensure the rigour and quality of telomere dynamics studies.},
}
@article {pmid32128135,
year = {2020},
author = {Monteforte, S and Cattelan, S and Morosinotto, C and Pilastro, A and Grapputo, A},
title = {Maternal predator-exposure affects offspring size at birth but not telomere length in a live-bearing fish.},
journal = {Ecology and evolution},
volume = {10},
number = {4},
pages = {2030-2039},
pmid = {32128135},
issn = {2045-7758},
abstract = {The perception of predation risk could affect prey phenotype both within and between generations (via parental effects). The response to predation risk could involve modifications in physiology, morphology, and behavior and can ultimately affect long-term fitness. Among the possible modifications mediated by the exposure to predation risk, telomere length could be a proxy for investigating the response to predation risk both within and between generations, as telomeres can be significantly affected by environmental stress. Maternal exposure to the perception of predation risk can affect a variety of offspring traits but the effect on offspring telomere length has never been experimentally tested. Using a live-bearing fish, the guppy (Poecilia reticulata), we tested if the perceived risk of predation could affect the telomere length of adult females directly and that of their offspring with a balanced experimental setup that allowed us to control for both maternal and paternal contribution. We exposed female guppies to the perception of predation risk during gestation using a combination of both visual and chemical cues and we then measured female telomere length after the exposure period. Maternal effects mediated by the exposure to predation risk were measured on offspring telomere length and body size at birth. Contrary to our predictions, we did not find a significant effect of predation-exposure neither on female nor on offspring telomere length, but females exposed to predation risk produced smaller offspring at birth. We discuss the possible explanations for our findings and advocate for further research on telomere dynamics in ectotherms.},
}
@article {pmid32127537,
year = {2020},
author = {Ferrara-Romeo, I and Martinez, P and Saraswati, S and Whittemore, K and Graña-Castro, O and Thelma Poluha, L and Serrano, R and Hernandez-Encinas, E and Blanco-Aparicio, C and Maria Flores, J and Blasco, MA},
title = {The mTOR pathway is necessary for survival of mice with short telomeres.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {1168},
pmid = {32127537},
issn = {2041-1723},
mesh = {Aging/drug effects/*genetics ; Animals ; DNA Damage/drug effects ; Female ; Longevity/drug effects/genetics ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Neoplasms/genetics ; Phosphorylation ; RNA/*genetics ; Ribosomal Protein S6 Kinases, 90-kDa/genetics ; Sirolimus/pharmacology ; Survival Rate ; TOR Serine-Threonine Kinases/genetics/*metabolism ; Telomerase/*genetics ; Telomere/drug effects/*genetics/metabolism ; },
abstract = {Telomerase deficiency leads to age-related diseases and shorter lifespans. Inhibition of the mechanistic target of rapamycin (mTOR) delays aging and age-related pathologies. Here, we show that telomerase deficient mice with short telomeres (G2-Terc[-/-]) have an hyper-activated mTOR pathway with increased levels of phosphorylated ribosomal S6 protein in liver, skeletal muscle and heart, a target of mTORC1. Transcriptional profiling confirms mTOR activation in G2-Terc[-/-] livers. Treatment of G2-Terc[-/-] mice with rapamycin, an inhibitor of mTORC1, decreases survival, in contrast to lifespan extension in wild-type controls. Deletion of mTORC1 downstream S6 kinase 1 in G3-Terc[-/-] mice also decreases longevity, in contrast to lifespan extension in single S6K1[-/-] female mice. These findings demonstrate that mTOR is important for survival in the context of short telomeres, and that its inhibition is deleterious in this setting. These results are of clinical interest in the case of human syndromes characterized by critically short telomeres.},
}
@article {pmid32126022,
year = {2020},
author = {Koh, SH and Choi, SH and Jeong, JH and Jang, JW and Park, KW and Kim, EJ and Kim, HJ and Hong, JY and Yoon, SJ and Yoon, B and Kang, JH and Lee, JM and Park, HH and Ha, J and Suh, YJ and Kang, S},
title = {Telomere shortening reflecting physical aging is associated with cognitive decline and dementia conversion in mild cognitive impairment due to Alzheimer's disease.},
journal = {Aging},
volume = {12},
number = {5},
pages = {4407-4423},
pmid = {32126022},
issn = {1945-4589},
mesh = {Activities of Daily Living ; Aged ; Aged, 80 and over ; Aging/*genetics/psychology ; Alzheimer Disease/*genetics/metabolism/psychology ; Amyloid beta-Peptides/metabolism ; Cognitive Dysfunction/*genetics/metabolism/psychology ; Dementia/*genetics/metabolism/psychology ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Neuropsychological Tests ; Telomere Shortening/*physiology ; tau Proteins/metabolism ; },
abstract = {We investigated whether telomere length (TL) reflecting physical rather than chronological aging is associated with disease progression in the different cognitive stages of Alzheimer's disease (AD). Study participants included 89 subjects with amyloid pathology (A+), determined through amyloid PET or cerebrospinal fluid analysis, including 26 cognitively unimpaired (CU A+) individuals, 28 subjects with mild cognitive impairment (MCI A+), and 35 subjects with AD dementia (ADD A+). As controls, 104 CU A- individuals were selected. The participants were evaluated annually over two years from baseline. Compared to the highest TL quartile group of MCI A+ participants, the lowest TL quartile group yielded 2-year differences of -9.438 (95% confidence interval [CI] = -14.567 ~ -4.309), -26.708 (-41.576 ~ -11.839), 3.198 (1.323 ~ 5.056), and 2.549 (0.527 ~ 4.571) on the Mini-Mental State Examination, Consortium to Establish a Registry for AD, Clinical Dementia Rating-Sum of Boxes, and Blessed Dementia Scale-Activities of Daily Living, respectively. With this group, the lowest TL quartile group had a significantly greater probability of progressing to ADD than the highest TL quartile group (hazard ratio = 13.16, 95% CI = 1.11 ~ 156.61). Telomere shortening may be associated with rapid cognitive decline and conversion to dementia in MCI A+.},
}
@article {pmid32125944,
year = {2020},
author = {Deng, S and Liu, S and Xu, S and He, Y and Zhou, X and Ni, G},
title = {Shorter Telomere Length in Peripheral Blood Leukocytes Is Associated with Post-Traumatic Chronic Osteomyelitis.},
journal = {Surgical infections},
volume = {21},
number = {9},
pages = {773-777},
doi = {10.1089/sur.2019.326},
pmid = {32125944},
issn = {1557-8674},
mesh = {C-Reactive Protein ; Humans ; Leukocyte Count ; Leukocytes/*pathology ; Osteomyelitis/*genetics/*pathology ; Telomere/*genetics ; },
abstract = {Background: This study investigated the association between post-traumatic chronic osteomyelitis (COM) and peripheral leukocyte telomere length (PLTL) and explored factors associated with PLTL in COM. Methods: A total of 56 patients with post-traumatic COM of the extremity and 62 healthy control subjects were recruited. The PLTL was measured by real-time PCR. Binary logistic regression analysis was used to identify factors in correlation with telomere length. Sex, age, white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and infection duration were included as independent variables in the logistic regression model. Results: Post-traumatic COM patients had significantly shorter PLTLs (5.39 ± 0.40) than healthy control subjects (5.69 ± 0.46; p < 0.001). Binary logistic regression analysis showed that PLTL had a statistically significant association with age (B = -0.072; p = 0.013) and CRP (B = -0.061; p = 0.033). The logistic regression model was statistically significant and explained 31.4% (Nagelkerke R[2]) of the change in telomere length and correctly classified 69.6% of the cases. Conclusions: Patients with post-traumatic COM have shorter PLTLs than healthy subjects. The PLTL erosion of post-traumatic COM was partially explained by age and CRP.},
}
@article {pmid32123624,
year = {2020},
author = {Griffin, I and Ibrahimou, B and Navejar, N and Aggarwal, A and Myers, K and Mauck, D and Yusuf, KK and Wudil, UJ and Aliyu, MH and Salihu, HM},
title = {Maternal Caffeine Consumption and Racial Disparities in Fetal Telomere Length.},
journal = {International journal of MCH and AIDS},
volume = {9},
number = {1},
pages = {14-21},
pmid = {32123624},
issn = {2161-8674},
abstract = {BACKGROUND AND OBJECTIVES: The identification of risk factors for shorter telomere length, especially during fetal development, would be important towards caffeine consumption recommendations for pregnant women on a global scale. The purpose of this study was to evaluate the association between caffeine intake and fetal telomere length as well as racial/ethnic differences in telomere length regardless of maternal caffeine consumption status.<br><br>METHODS: Caffeine intake was measured using a food frequency questionnaire (FFQ). Three generalized linear models (GLM) were compared based on binary categorical variables of caffeine levels using data mean value of 117.3 mg as cut-off; the World Health Organization (WHO) recommendations of 300 mg; and the American College of Obstetricians and Gynecologists (ACOG) recommendations of 200 mg. The association between caffeine consumption and telomere length (telomere to single-copy [T/S] ratio) was then assessed.<br><br>RESULTS: Among 57 maternal-fetal dyads, 77.2% reported less than 200 mg of caffeine (ACOG) and 89.5% less than 300 mg (WHO). Both WHO and ACOG models found that caffeine intake was significantly and positively associated with longer telomere length (p<0.05); and sodium (p<0.05). Other" race (p<0.001) and "white" race (p<0.001) were also significantly and positively associated with longer telomere length in the same models. Increasing maternal age shortened telomere length significantly in all models (p<0.001).<br><br>Caffeine intake, maternal age, and race may be associated with alterations in fetal telomere length. This indicates that caffeine consumption during pregnancy may have long-term implications for fetal development. The racial/ethnic differences in telomere length found in this study warrant larger studies to further confirm these associations.},
}
@article {pmid32121056,
year = {2020},
author = {Srinivas, N and Rachakonda, S and Kumar, R},
title = {Telomeres and Telomere Length: A General Overview.},
journal = {Cancers},
volume = {12},
number = {3},
pages = {},
pmid = {32121056},
issn = {2072-6694},
support = {01KT15511//Bundesministerium f&#xfc;r Bildung und Forschung/ ; },
abstract = {Telomeres are highly conserved tandem nucleotide repeats that include proximal double-stranded and distal single-stranded regions that in complex with shelterin proteins afford protection at chromosomal ends to maintain genomic integrity. Due to the inherent limitations of DNA replication and telomerase suppression in most somatic cells, telomeres undergo age-dependent incremental attrition. Short or dysfunctional telomeres are recognized as DNA double-stranded breaks, triggering cells to undergo replicative senescence. Telomere shortening, therefore, acts as a counting mechanism that drives replicative senescence by limiting the mitotic potential of cells. Telomere length, a complex hereditary trait, is associated with aging and age-related diseases. Epidemiological data, in general, support an association with varying magnitudes between constitutive telomere length and several disorders, including cancers. Telomere attrition is also influenced by oxidative damage and replicative stress caused by genetic, epigenetic, and environmental factors. Several single nucleotide polymorphisms at different loci, identified through genome-wide association studies, influence inter-individual variation in telomere length. In addition to genetic factors, environmental factors also influence telomere length during growth and development. Telomeres hold potential as biomarkers that reflect the genetic predisposition together with the impact of environmental conditions and as targets for anti-cancer therapies.},
}
@article {pmid32120019,
year = {2020},
author = {Bosquet Enlow, M and Kane-Grade, F and De Vivo, I and Petty, CR and Nelson, CA},
title = {Patterns of change in telomere length over the first three years of life in healthy children.},
journal = {Psychoneuroendocrinology},
volume = {115},
number = {},
pages = {104602},
pmid = {32120019},
issn = {1873-3360},
support = {R01 MH078829/MH/NIMH NIH HHS/United States ; },
mesh = {Child Development/*physiology ; Child, Preschool ; Female ; Humans ; Infant ; Longitudinal Studies ; Male ; Parents ; Sex Factors ; Social Class ; Telomere/*metabolism ; Telomere Shortening/physiology ; },
abstract = {There is growing interest in the use of telomere length as a biomarker of health and a predictor of later morbidity and mortality. However, little is known about developmentally expected telomere erosion over the first years of life. This gap hinders our ability to interpret the meaning of relative telomere length and rate of attrition in relation to risk factors and health outcomes. The overall goal of this study was to examine the rate of relative telomere length attrition in a large, normative sample of healthy children (N = 630) followed from infancy to three years of age. A secondary goal was to explore associations between sociodemographic characteristics and telomere erosion over this time period. Relative telomere length was assessed from DNA in saliva samples collected in infancy (M = 8.6 months), age 2 years (M = 25.2 months), and age 3 years (M = 38.3 months). In the sample as a whole, relative telomere length decreased from infancy to 2 years but remained stable from 2 years to 3 years. Notably, increases in relative telomere length were observed in 29 % of children between infancy and 2 years of age and in 46 % of children between 2 and 3 years of age; 62 % of children showed both increases and decreases in relative telomere length across the study period. Females showed longer relative telomere length than males, regardless of timepoint. There was some evidence that parental age and family finances were associated with changes in child relative telomere length across time. Overall, the findings suggest that telomere length attrition is not uniform across the early years of life, with the most rapid attrition occurring during the first two years, and that increases as well as decreases in telomere length during this period are commonly observed.},
}
@article {pmid32119936,
year = {2020},
author = {Sobinoff, AP and Pickett, HA},
title = {Mechanisms that drive telomere maintenance and recombination in human cancers.},
journal = {Current opinion in genetics &amp; development},
volume = {60},
number = {},
pages = {25-30},
doi = {10.1016/j.gde.2020.02.006},
pmid = {32119936},
issn = {1879-0380},
mesh = {Cell Transformation, Neoplastic/genetics/*pathology ; *DNA Replication ; Humans ; Neoplasms/*genetics/*pathology ; *Recombination, Genetic ; *Telomere ; *Telomere Homeostasis ; },
abstract = {Telomere maintenance is essential for the continued proliferation of mitotically active cells. Alternative Lengthening of Telomeres (ALT) is a recombination-dependent pathway of telomere maintenance analogous to break-induced replication (BIR) [1] that becomes activated in approximately 10-15% of human cancers. ALT is prevalent in tumours of mesenchymal or neuroepithelial origin, and typically confers a poor prognosis. The aggressiveness and lack of effective strategies to treat these cancers make the ALT pathway a compelling potential therapeutic target to prevent tumour formation and/or the appearance of secondary malignancies after conventional chemotherapy [2]. While the precise initiator of ALT during tumourigenesis remains elusive, substantial progress has been made in interrogating the underlying homology-directed repair mechanisms that converge at telomeres to enable telomere length maintenance. Here, we describe recent advances in our understanding of the ALT mechanism and highlight potential therapeutic targets that may offer future promise in the treatment of ALT cancers.},
}
@article {pmid32114293,
year = {2020},
author = {Claude, E and Decottignies, A},
title = {Telomere maintenance mechanisms in cancer: telomerase, ALT or lack thereof.},
journal = {Current opinion in genetics &amp; development},
volume = {60},
number = {},
pages = {1-8},
doi = {10.1016/j.gde.2020.01.002},
pmid = {32114293},
issn = {1879-0380},
mesh = {Cell Transformation, Neoplastic/genetics/*pathology ; Humans ; Neoplasms/enzymology/*genetics/*pathology ; Telomerase/genetics/*metabolism ; *Telomere ; *Telomere Homeostasis ; },
abstract = {Cancer cells acquire replicative immortality by activating a telomere maintenance mechanism (TMM), either the telomerase or the Alternative Lengthening of Telomeres (ALT) mechanism. ALT is frequently activated in tumors derived from mesenchymal cells, which are more frequent in childhood cancers. Recent studies showed that, occasionally, cancer cells can arise without any TMM activation. Here, we discuss the challenge in assessing which TMM is activated in tumors. We also evaluate the prevalence of ALT mechanism in pediatric cancers and review the associated survival prognosis in different tumor types. Finally, we discuss about possible anti-TMM therapies for new emerging cancer treatments.},
}
@article {pmid32112636,
year = {2020},
author = {Ghorbani-Sini, R and Izadi, T and Tavalaee, M and Azadi, L and Hajian, M and Rahimi Zamani, M and Nasr-Esfahani, MH},
title = {Comparison of Sperm Telomere Length between Two Sperm Selection Procedures: Density Gradient Centrifugation and Zeta Potential.},
journal = {International journal of fertility &amp; sterility},
volume = {14},
number = {1},
pages = {51-56},
pmid = {32112636},
issn = {2008-076X},
abstract = {BACKGROUND: Telomeres are particular sequences of DNA located at the end of the eukaryotic chromosomes that are essential for genome integrity. Telomere length in spermatozoa differs among males, as well as spermatozoa. Also, decreased telomere length in spermatozoa of infertile men is associated with the reduction of fertility potential and embryo quality. Density gradient centrifugation (DGC) and swim-up are useful techniques for separation of spermatozoa with longer telomeres. Also, the selection of sperm based on surface negative electric charge or "Zeta potential", can separate high percentage of spermatozoa with intact chromatin compared to DGC alone, and also the combination of DGC-Zeta can improve clinical outcomes of infertile men candidate for intracytoplasmic sperm injection (ICSI). Therefore, we compared sperm telomere length and DNA fragmentation between two sperm preparation procedures, namely DGC and zeta potential.<br><br>MATERIALS AND METHODS: In this experimental study, we assessed sperm telomere length and DNA fragmentation by quantitative real-time polymerase chain reaction (PCR) and TUNEL assay methods, respectively. The spermatozoa were obtained from infertile men with normozoospermia between September 2017 and December 2017 and prepared either by DGC or zeta potential methods. Sperm telomere length was expressed as relative and absolute units.<br><br>RESULTS: Compared with washed semen samples or control, no significant (P>0.05) difference was observed in the mean relative or absolute sperm telomere length when the two methods DGC or zeta potential were compared. However, the mean percentage of DNA fragmentation was significantly (P<0.05) lower in spermatozoa prepared by DGC or zeta potential methods than spermatozoa obtained from control samples.<br><br>CONCLUSION: This is the first study that compared the effect of DGC and zeta potential as the sperm preparation methods on sperm telomere length. It seems that both methods can select sperm population with high DNA integrity and the same sperm telomeres length.},
}
@article {pmid32109830,
year = {2020},
author = {Toubiana, S and Selig, S},
title = {Human subtelomeric DNA methylation: regulation and roles in telomere function.},
journal = {Current opinion in genetics &amp; development},
volume = {60},
number = {},
pages = {9-16},
doi = {10.1016/j.gde.2020.02.004},
pmid = {32109830},
issn = {1879-0380},
mesh = {*DNA Methylation ; *Gene Expression Regulation, Neoplastic ; Humans ; Neoplasms/*genetics/*pathology ; Promoter Regions, Genetic ; *Telomere ; *Telomere Homeostasis ; },
abstract = {Subtelomeres are the regions at chromosome ends, immediately adjacent to the terminal telomeric repeats. The majority of human subtelomeres are CpG-rich in their distal two kilobases, and are methylated during early embryonic development by the de novo DNA methyltransferase DNMT3B. The biological relevance of subtelomeric DNA methylation is highlighted by the presence of promoters for the long non-coding TERRA transcripts in these CpG-rich regions. Indeed, deviant subtelomeric methylation has been linked with abnormal telomeric phenotypes, as most strikingly found in ICF syndrome. Here we review recent studies that explore new aspects of subtelomeric methylation regulation and demonstrate the significance of maintaining proper DNA methylation at the extreme distal human subtelomeric regions.},
}
@article {pmid32109421,
year = {2020},
author = {Li, C and Stoma, S and Lotta, LA and Warner, S and Albrecht, E and Allione, A and Arp, PP and Broer, L and Buxton, JL and Da Silva Couto Alves, A and Deelen, J and Fedko, IO and Gordon, SD and Jiang, T and Karlsson, R and Kerrison, N and Loe, TK and Mangino, M and Milaneschi, Y and Miraglio, B and Pervjakova, N and Russo, A and Surakka, I and van der Spek, A and Verhoeven, JE and Amin, N and Beekman, M and Blakemore, AI and Canzian, F and Hamby, SE and Hottenga, JJ and Jones, PD and Jousilahti, P and Mägi, R and Medland, SE and Montgomery, GW and Nyholt, DR and Perola, M and Pietiläinen, KH and Salomaa, V and Sillanpää, E and Suchiman, HE and van Heemst, D and Willemsen, G and Agudo, A and Boeing, H and Boomsma, DI and Chirlaque, MD and Fagherazzi, G and Ferrari, P and Franks, P and Gieger, C and Eriksson, JG and Gunter, M and Hägg, S and Hovatta, I and Imaz, L and Kaprio, J and Kaaks, R and Key, T and Krogh, V and Martin, NG and Melander, O and Metspalu, A and Moreno, C and Onland-Moret, NC and Nilsson, P and Ong, KK and Overvad, K and Palli, D and Panico, S and Pedersen, NL and Penninx, BWJH and Quirós, JR and Jarvelin, MR and Rodríguez-Barranco, M and Scott, RA and Severi, G and Slagboom, PE and Spector, TD and Tjonneland, A and Trichopoulou, A and Tumino, R and Uitterlinden, AG and van der Schouw, YT and van Duijn, CM and Weiderpass, E and Denchi, EL and Matullo, G and Butterworth, AS and Danesh, J and Samani, NJ and Wareham, NJ and Nelson, CP and Langenberg, C and Codd, V},
title = {Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.},
journal = {American journal of human genetics},
volume = {106},
number = {3},
pages = {389-404},
pmid = {32109421},
issn = {1537-6605},
support = {MR/L003120/1/MRC_/Medical Research Council/United Kingdom ; RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom ; 29017/CRUK_/Cancer Research UK/United Kingdom ; MC_UU_00006/2/MRC_/Medical Research Council/United Kingdom ; MC_UU_12015/2/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; MR/S019669/1/MRC_/Medical Research Council/United Kingdom ; RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom ; MC_UU_12015/1/MRC_/Medical Research Council/United Kingdom ; 19170/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {*Genome-Wide Association Study ; Humans ; Leukocytes/*ultrastructure ; Nucleotides/*metabolism ; *Telomere ; },
abstract = {Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.},
}
@article {pmid32105386,
year = {2020},
author = {Foley, NM and Petit, EJ and Brazier, T and Finarelli, JA and Hughes, GM and Touzalin, F and Puechmaille, SJ and Teeling, EC},
title = {Drivers of longitudinal telomere dynamics in a long-lived bat species, Myotis myotis.},
journal = {Molecular ecology},
volume = {29},
number = {16},
pages = {2963-2977},
doi = {10.1111/mec.15395},
pmid = {32105386},
issn = {1365-294X},
mesh = {Animals ; Bayes Theorem ; Child ; Child, Preschool ; *Chiroptera/genetics ; Cross-Sectional Studies ; France ; Humans ; Infant ; Infant, Newborn ; Telomere/genetics ; Telomere Shortening/genetics ; },
abstract = {Age-related telomere shortening is considered a hallmark of the ageing process. However, a recent cross-sectional ageing study of relative telomere length (rTL) in bats failed to detect a relationship between rTL and age in the long-lived genus Myotis (M. myotis and M. bechsteinii), suggesting some other factors are responsible for driving telomere dynamics in these species. Here, we test if longitudinal rTL data show signatures of age-associated telomere attrition in M. myotis and differentiate which intrinsic or extrinsic factors are likely to drive telomere length dynamics. Using quantitative polymerase chain reaction, rTL was measured in 504 samples from a marked population, from Brittany, France, captured between 2013 and 2016. These represent 174 individuals with an age range of 0 to 7+ years. We find no significant relationship between rTL and age (p = .762), but demonstrate that within-individual rTL is highly variable from year to year. To investigate the heritability of rTL, a population pedigree (n = 1744) was constructed from genotype data generated from a 16-microsatellite multiplex, designed from an initial, low-coverage, Illumina genome for M. myotis. Heritability was estimated in a Bayesian, mixed model framework, and showed that little of the observed variance in rTL is heritable (h[2] = 0.01-0.06). Rather, correlations of first differences, correlating yearly changes in telomere length and weather variables, demonstrate that, during the spring transition, average temperature, minimum temperature, rainfall and windspeed correlate with changes in longitudinal telomere dynamics. As such, rTL may represent a useful biomarker to quantify the physiological impact of various environmental stressors in bats.},
}
@article {pmid32104213,
year = {2020},
author = {Fragkiadaki, P and Nikitovic, D and Kalliantasi, K and Sarandi, E and Thanasoula, M and Stivaktakis, PD and Nepka, C and Spandidos, DA and Tosounidis, T and Tsatsakis, A},
title = {Telomere length and telomerase activity in osteoporosis and osteoarthritis.},
journal = {Experimental and therapeutic medicine},
volume = {19},
number = {3},
pages = {1626-1632},
pmid = {32104213},
issn = {1792-0981},
abstract = {Osteoarthritis (OA) and osteoporosis (OP) are associated skeletal pathologies and have as a distinct feature the abnormal reconstruction of the subchondral bone. OA and OP have been characterized as age-related diseases and have been associated with telomere shortening and altered telomerase activity (TA). This review discusses the role of telomeres and telomerase in OA and OP pathologies and focuses on the usability of telomere length (TL) and the rate of telomere shortening as potential disease biomarkers. A number of studies have demonstrated that telomere shortening may contribute to OA and OP as an epigenetic factor. Therefore, it has been claimed that the measurement of TL of chondrocytes and/or peripheral blood cells may be an appropriate marker for the evaluation of the progression of these diseases. However, there is a need to be perform further studies with larger cohorts, with the aim of obtaining objective results and a better understanding of the association between TL, inflammation and aging, in order to provide further insight into the pathophysiology of degenerative joint diseases.},
}
@article {pmid32103672,
year = {2020},
author = {Qiao, S and Jiang, Y and Li, X},
title = {The Impact of Health Promotion Interventions on Telomere Length: A Systematic Review.},
journal = {American journal of health promotion : AJHP},
volume = {34},
number = {6},
pages = {633-647},
doi = {10.1177/0890117120906958},
pmid = {32103672},
issn = {2168-6602},
support = {R21 AI122919/AI/NIAID NIH HHS/United States ; R01 HD074221/HD/NICHD NIH HHS/United States ; },
mesh = {Exercise ; *Health Promotion ; Humans ; Life Style ; *Telomere ; Weight Loss ; },
abstract = {OBJECTIVES: The aim of this study was to evaluate the effectiveness of health promotion interventions in delaying telomere shortening (a biomarker for aging).<br><br>DATA SOURCE: PubMed, PsychINFO, EMBASE, CINAHL, and Cochrane Library databases.<br><br>Inclusion criteria: (1) empirical studies involving human subjects; (2) health promotion intervention studies including both randomized control trials (RCTs) and non-RCTs.; (3) measured telomere length as an intervention outcome; and (4) were written in English. Exclusion criteria: (1) observational studies without any health promotion intervention practices and (2) did not report intervention effects.<br><br>DATA EXTRACTION: Data extraction was performed by two reviewers following the preferred reporting items for systematic reviews and meta-analysis guidelines.<br><br>DATA SYNTHESIS: Substantial heterogeneity in intervention type and study design in the included studies precluded a meta-analysis. We conducted a narrative synthesis instead.<br><br>RESULTS: Thirty studies were included in the review, of which 16 were RCTs. One-third of the included studies reported significant intervention impacts in delaying telomere shortening, with relatively consistent significant results emerged from weight-loss interventions and interventions involving multiple lifestyle modification components (eg, diet and exercise). Most of supplement intervention studies observed null effects in telomere length.<br><br>CONCLUSIONS: Weight-loss and comprehensive lifestyle intervention strategies show encouraging impacts in delaying telomere shortening. More rigorous studies targeting populations at different age stages through life span are needed.},
}
@article {pmid32103422,
year = {2020},
author = {Hackeng, WM and Schelhaas, W and Morsink, FHM and Heidsma, CM and van Eeden, S and Valk, GD and Vriens, MR and Heaphy, CM and Nieveen van Dijkum, EJM and Offerhaus, GJA and Dreijerink, KMA and Brosens, LAA},
title = {Alternative Lengthening of Telomeres and Differential Expression of Endocrine Transcription Factors Distinguish Metastatic and Non-metastatic Insulinomas.},
journal = {Endocrine pathology},
volume = {31},
number = {2},
pages = {108-118},
pmid = {32103422},
issn = {1559-0097},
support = {CDG 14-020//Maag Lever Darm Stichting/ ; },
mesh = {Adult ; Aged ; Biomarkers, Tumor/analysis ; Female ; Homeodomain Proteins/*metabolism ; Humans ; Insulinoma/diagnosis/*pathology ; Male ; Middle Aged ; Pancreatic Neoplasms/diagnosis/*pathology ; Telomere Homeostasis/physiology ; Trans-Activators/*metabolism ; Transcription Factors/*metabolism ; },
abstract = {Insulin-producing pancreatic neuroendocrine tumors (PanNETs)/insulinomas are generally considered to be indolent tumors with an excellent prognosis after complete resection. However, some insulinomas have a poor prognosis due to relapses and metastatic disease. Recently, studies in non-functional PanNETs indicated that behavior can be stratified according to alpha- and beta-cell differentiation, as defined by expression of the transcription factors ARX and PDX1, respectively. It is unknown whether similar mechanisms play a role in insulinomas. Therefore, we determined ARX and PDX1 expression in a cohort of 35 sporadic primary insulinomas and two liver metastases of inoperable primary insulinomas. In addition, WHO grade and loss of ATRX or DAXX were determined by immunohistochemistry, and alternative lengthening of telomeres (ALT) and CDKN2A status by fluorescence in situ hybridization. These findings were correlated with tumor characteristics and clinical follow-up data. In total, five out of 37 insulinoma patients developed metastatic disease. Metastatic insulinomas were all larger than 3 cm, whereas the indolent insulinomas were smaller (p value < 0.05). All three primary insulinomas that metastasized showed ARX expression, 2/3 showed ALT, and 1/3 had a homozygous deletion of CDKN2A as opposed to absence of ARX expression, ALT, or CDKN2A deletions in the 32 non-metastatic cases. The two liver metastases also showed ARX expression and ALT (2/2). The presence of ARX expression, which is usually absent in beta-cells, and genetic alterations not seen in indolent insulinomas strongly suggest a distinct tumorigenic mechanism in malignant insulinomas, with similarities to non-functional PanNETs. These observations may inform future follow-up strategies after insulinoma surgery.},
}
@article {pmid32101727,
year = {2020},
author = {Hoang, SM and O'Sullivan, RJ},
title = {Alternative Lengthening of Telomeres: Building Bridges To Connect Chromosome Ends.},
journal = {Trends in cancer},
volume = {6},
number = {3},
pages = {247-260},
pmid = {32101727},
issn = {2405-8025},
support = {R01 CA207209/CA/NCI NIH HHS/United States ; },
mesh = {Chromatin/ultrastructure ; Clonal Evolution ; Co-Repressor Proteins/antagonists &amp; inhibitors/physiology ; DNA Damage ; DNA Repair ; DNA Replication ; DNA, Neoplasm/metabolism/ultrastructure ; Histones/physiology ; Homologous Recombination ; Humans ; Models, Genetic ; Molecular Chaperones/antagonists &amp; inhibitors/physiology ; Mutation ; Neoplasm Proteins/antagonists &amp; inhibitors/genetics/physiology ; Neoplasms/*genetics/ultrastructure ; Nucleic Acid Conformation ; Telomerase/genetics/physiology ; *Telomere Homeostasis ; X-linked Nuclear Protein/antagonists &amp; inhibitors/physiology ; },
abstract = {Alternative lengthening of telomeres (ALT) is a mechanism of telomere maintenance that is observed in many of the most recalcitrant cancer subtypes. Telomeres in ALT cancer cells exhibit a distinctive nucleoprotein architecture shaped by the mismanagement of chromatin that fosters cycles of DNA damage and replicative stress that activate homology-directed repair (HDR). Mutations in specific chromatin-remodeling factors appear to be key determinants of the emergence and survival of ALT cancer cells. However, these may represent vulnerabilities for the targeted elimination of ALT cancer cells that infiltrate tissues and organs to become devastating tumors. In this review we examine recent findings that provide new insights into the factors and mechanisms that mediate telomere length maintenance and survival of ALT cancer cells.},
}
@article {pmid32101485,
year = {2020},
author = {Berthezene, J and Reyes, C and Li, T and Coulon, S and Bernard, P and Gachet, Y and Tournier, S},
title = {Aurora B and condensin are dispensable for chromosome arm and telomere separation during meiosis II.},
journal = {Molecular biology of the cell},
volume = {31},
number = {9},
pages = {889-905},
pmid = {32101485},
issn = {1939-4586},
mesh = {Adenosine Triphosphatases/*metabolism ; Aurora Kinases/*metabolism ; *Chromosome Segregation ; DNA-Binding Proteins/*metabolism ; Kinetochores ; *Meiosis ; Microtubules ; Multiprotein Complexes/*metabolism ; Schizosaccharomyces/enzymology/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/*metabolism ; *Telomere ; },
abstract = {In mitosis, while the importance of kinetochore (KT)-microtubule (MT) attachment has been known for many years, increasing evidence suggests that telomere dysfunctions also perturb chromosome segregation by contributing to the formation of chromatin bridges at anaphase. Recent evidence suggests that Aurora B kinase ensures proper chromosome segregation during mitosis not only by controlling KT-MT attachment but also by regulating telomere and chromosome arm separation. However, whether and how Aurora B governs telomere separation during meiosis has remained unknown. Here, we show that fission yeast Aurora B localizes at telomeres during meiosis I and promotes telomere separation independently of the meiotic cohesin Rec8. In meiosis II, Aurora B controls KT-MT attachment but appears dispensable for telomere and chromosome arm separation. Likewise, condensin activity is nonessential in meiosis II for telomere and chromosome arm separation. Thus, in meiosis, the requirements for Aurora B are distinct at centromeres and telomeres, illustrating the critical differences in the control of chromosome segregation between mitosis and meiosis II.},
}
@article {pmid32101305,
year = {2020},
author = {Arbeev, KG and Verhulst, S and Steenstrup, T and Kark, JD and Bagley, O and Kooperberg, C and Reiner, AP and Hwang, SJ and Levy, D and Fitzpatrick, AL and Christensen, K and Yashin, AI and Aviv, A},
title = {Association of Leukocyte Telomere Length With Mortality Among Adult Participants in 3 Longitudinal Studies.},
journal = {JAMA network open},
volume = {3},
number = {2},
pages = {e200023},
pmid = {32101305},
issn = {2574-3805},
support = {HHSN268201600001C/HL/NHLBI NIH HHS/United States ; R03 HD050374/HD/NICHD NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; U01 HL130114/HL/NHLBI NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; N01HC85082/HL/NHLBI NIH HHS/United States ; P30 AG034424/AG/NIA NIH HHS/United States ; N01HC55222/HL/NHLBI NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; N01HC85086/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; P01 AG043352/AG/NIA NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; N01HC85081/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; N01HC85080/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; R01 HL116446/HL/NHLBI NIH HHS/United States ; N01HC85079/HL/NHLBI NIH HHS/United States ; N01HC85083/HL/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Cardiovascular Diseases/mortality ; Female ; Humans ; Leukocytes/*physiology ; *Life Expectancy ; Longitudinal Studies ; Male ; Middle Aged ; Neoplasms/mortality ; Telomere/*genetics ; },
abstract = {IMPORTANCE: Leukocyte telomere length (LTL) is a trait associated with risk of cardiovascular disease and cancer, the 2 major disease categories that largely define longevity in the United States. However, it remains unclear whether LTL is associated with the human life span.<br><br>OBJECTIVE: To examine whether LTL is associated with the life span of contemporary humans.<br><br>This cohort study included 3259 adults of European ancestry from the Cardiovascular Health Study (CHS), Framingham Heart Study (FHS), and Women's Health Initiative (WHI). Leukocyte telomere length was measured in 1992 and 1997 in the CHS, from 1995 to 1998 in the FHS, and from 1993 to 1998 in the WHI. Data analysis was conducted from February 2017 to December 2019.<br><br>MAIN OUTCOMES AND MEASURES: Death and LTL, measured by Southern blots of the terminal restriction fragments, were the main outcomes. Cause of death was adjudicated by end point committees.<br><br>RESULTS: The analyzed sample included 3259 participants (2342 [71.9%] women), with a median (range) age of 69.0 (50.0-98.0) years at blood collection. The median (range) follow-up until death was 10.9 (0.2-23.0) years in CHS, 19.7 (3.4-23.0) years in FHS, and 16.6 (0.5-20.0) years in WHI. During follow-up, there were 1525 deaths (482 [31.6%] of cardiovascular disease; 373 [24.5%] of cancer, and 670 [43.9%] of other or unknown causes). Short LTL, expressed in residual LTL, was associated with increased mortality risk. Overall, the hazard ratio for all-cause mortality for a 1-kilobase decrease in LTL was 1.34 (95% CI, 1.21-1.47). This association was stronger for noncancer causes of death (cardiovascular death: hazard ratio, 1.28; 95% CI, 1.08-1.52; cancer: hazard ratio, 1.13; 95% CI, 0.93-1.36; and other causes: hazard ratio, 1.53; 95% CI, 1.32-1.77).<br><br>CONCLUSIONS AND RELEVANCE: The results of this study indicate that LTL is associated with a natural life span limit in contemporary humans.},
}
@article {pmid32098394,
year = {2020},
author = {Nalobin, D and Alipkina, S and Gaidamaka, A and Glukhov, A and Khuchua, Z},
title = {Telomeres and Telomerase in Heart Ontogenesis, Aging and Regeneration.},
journal = {Cells},
volume = {9},
number = {2},
pages = {},
pmid = {32098394},
issn = {2073-4409},
mesh = {Adult ; Aging/*metabolism ; Animals ; Animals, Newborn ; Cell Proliferation/physiology ; Humans ; Myocytes, Cardiac/*metabolism ; Organogenesis/*physiology ; Regeneration/*physiology ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {The main purpose of the review article is to assess the contributions of telomere length and telomerase activity to the cardiac function at different stages of development and clarify their role in cardiac disorders. It has been shown that the telomerase complex and telomeres are of great importance in many periods of ontogenesis due to the regulation of the proliferative capacity of heart cells. The review article also discusses the problems of heart regeneration and the identification of possible causes of dysfunction of telomeres and telomerase.},
}
@article {pmid32097601,
year = {2020},
author = {Dupoué, A and Angelier, F and Ribout, C and Meylan, S and Rozen-Rechels, D and Decencière, B and Agostini, S and Le Galliard, JF},
title = {Chronic water restriction triggers sex-specific oxidative stress and telomere shortening in lizards.},
journal = {Biology letters},
volume = {16},
number = {2},
pages = {20190889},
pmid = {32097601},
issn = {1744-957X},
mesh = {Animals ; Antioxidants ; Female ; Horses ; *Lizards ; Male ; Oxidative Stress ; Telomere ; *Telomere Shortening ; Water ; },
abstract = {Animals use a variety of strategies to avoid acute dehydration and death. Yet, how chronic exposure to sub-lethal dehydration may entail physiological and fitness costs remains elusive. In this study, we experimentally tested if water restriction causes increased oxidative stress (OS) and telomere length (TL) shortening, two well-described mediators of environment-fitness relationships. We exposed 100 yearling female and male common lizards (Zootoca vivipara) either to a 51-day period of water restriction or to water ad libitum, followed by 45 days in common garden outdoor conditions. We measured the kinetic changes in OS and TL and found that water-restricted males had enhanced antioxidant defences and decreased oxidative damage at day 36, whereas females did not immediately respond. A month and a half after water restriction, both sexes experienced a drop in antioxidant capacity but only males exhibited significant TL shortening. In the following 3 years, we found that lizards with longer initial TL and those who maintained stronger antioxidant defences experienced higher longevity, irrespective of sex and water restriction. Together, these results unravelled sex-specific responses to water restriction, with potential applications in better understanding the physiological costs of increasing summer droughts as a result of global climate change.},
}
@article {pmid32096305,
year = {2020},
author = {Lototska, L and Yue, JX and Li, J and Giraud-Panis, MJ and Songyang, Z and Royle, NJ and Liti, G and Ye, J and Gilson, E and Mendez-Bermudez, A},
title = {Human RAP1 specifically protects telomeres of senescent cells from DNA damage.},
journal = {EMBO reports},
volume = {21},
number = {4},
pages = {e49076},
pmid = {32096305},
issn = {1469-3178},
support = {81522017//National Natural Science Foundation of China/International ; ANR-19-CE12-0020-01//Agence Nationale de la Recherche (ANR) (program TELOCHROM)/International ; 19XD1422500//Shanghai Municipal Science and Technology Commission/International ; G0500336/MRC_/Medical Research Council/United Kingdom ; //Institut Nationale du Cancer (INCa) (program REPLITOP)/International ; 81971312//National Natural Science Foundation of China/International ; FDT20170437327//Fondation pour la Recherche M&#xe9;dicale FRM/International ; 91749126//National Natural Science Foundation of China/International ; 15ZH4005//Foundation of Shanghai Jiaotong University School of Medicine for Translational Medicine Innovation Project/International ; ANR-11-LABX-0028-01//LABEX SIGNALIFE/International ; //Fondation ARC ("Programme Labellis&#xe9;")/International ; },
mesh = {Animals ; Cellular Senescence/genetics ; DNA Damage ; HeLa Cells ; Humans ; *Telomere/genetics ; Telomere-Binding Proteins/genetics ; *Transcription Factor AP-1 ; },
abstract = {Repressor/activator protein 1 (RAP1) is a highly evolutionarily conserved protein found at telomeres. Although yeast Rap1 is a key telomere capping protein preventing non-homologous end joining (NHEJ) and consequently telomere fusions, its role at mammalian telomeres in vivo is still controversial. Here, we demonstrate that RAP1 is required to protect telomeres in replicative senescent human cells. Downregulation of RAP1 in these cells, but not in young or dividing pre-senescent cells, leads to telomere uncapping and fusions. The anti-fusion effect of RAP1 was further explored in a HeLa cell line where RAP1 expression was depleted through an inducible CRISPR/Cas9 strategy. Depletion of RAP1 in these cells gives rise to telomere fusions only when telomerase is inhibited. We further show that the fusions triggered by RAP1 loss are dependent upon DNA ligase IV. We conclude that human RAP1 is specifically involved in protecting critically short telomeres. This has important implications for the functions of telomeres in senescent cells.},
}
@article {pmid32093292,
year = {2020},
author = {Pejenaute, &#xc1; and Cortés, A and Marqués, J and Montero, L and Beloqui, &#xd3; and Fortuño, A and Martí, A and Orbe, J and Zalba, G},
title = {NADPH Oxidase Overactivity Underlies Telomere Shortening in Human Atherosclerosis.},
journal = {International journal of molecular sciences},
volume = {21},
number = {4},
pages = {},
pmid = {32093292},
issn = {1422-0067},
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Atherosclerosis/*blood/diagnostic imaging ; Biomarkers/blood ; Carotid Intima-Media Thickness ; Female ; Humans ; Male ; Middle Aged ; NADPH Oxidases/*blood ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Telomere shortening and oxidative stress are involved in the pathogenesis of atherosclerosis. Different studies have shown that phagocytic NADPH oxidase is associated with this disease. This study aimed to investigate the association between phagocytic NADPH oxidase and telomere shortening in human atherosclerosis. To assess this potential association, telomere length and phagocytic NADPH oxidase activity were determined by PCR and chemiluminescence, respectively, in a population of asymptomatic subjects free of overt clinical atherosclerosis. We also measured serum 8-hydroxy-2-deoxyguanosine (8-OHdG) levels (an index of oxidative stress) and carotid intima-media thickness (IMT), a surrogate marker of atherosclerosis. After adjusting them for age and sex, telomere length inversely correlated (p < 0.05) with NADPH oxidase-mediated superoxide production, with 8-OHdG values, and with carotid IMT. Interestingly, the asymptomatic subjects with plaques have a lower telomere length (p < 0.05), and higher values of plasma 8-OHdG and superoxide production (p < 0.05). These data were confirmed in a second population in which patients with coronary artery disease showed lower telomere length and higher 8-OHdG and superoxide production than the asymptomatic subjects. In both studies, NADPH oxidase-dependent superoxide production in phagocytic cells was only due to the specific expression of the Nox2 isoform. In conclusion, these findings suggest that phagocytic NADPH oxidase may be involved in oxidative stress-mediated telomere shortening, and that this axis may be critically involved in human atherosclerosis.},
}
@article {pmid32088715,
year = {2020},
author = {Jantunen, H and Wasenius, NS and Guzzardi, MA and Iozzo, P and Kajantie, E and Kautiainen, H and Salonen, MK and Eriksson, JG},
title = {Physical Activity and Telomeres in Old Age: A Longitudinal 10-Year Follow-Up Study.},
journal = {Gerontology},
volume = {66},
number = {4},
pages = {315-322},
doi = {10.1159/000505603},
pmid = {32088715},
issn = {1423-0003},
support = {/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Aged ; Cohort Studies ; Exercise/*physiology ; Female ; Finland ; Follow-Up Studies ; Healthy Aging/*physiology ; Humans ; Leisure Activities ; Leukocytes/physiology ; Longitudinal Studies ; Male ; Middle Aged ; Prospective Studies ; Surveys and Questionnaires ; Telomere/*physiology ; Telomere Shortening/*physiology ; },
abstract = {BACKGROUND: Telomeres are crucial parts of chromosomes that protect the genome. They shorten every time the cell replicates, and shorter telomeres have been associated with increasing age and with many health behaviours. There is inconclusive evidence on the association between physical activity (PA) and telomere length.<br><br>OBJECTIVES: To examine how leisure-time PA (LTPA) is associated with telomere length and telomere attrition during 10 years of follow-up in elderly people.<br><br>DESIGN: This study is a 10-year prospective follow-up study.<br><br>METHOD: For this prospective study, we examined 1,014 subjects (mean age at baseline 60.8 years) from the Helsinki Birth Cohort Study (HBCS). Relative leukocyte telomere length (LTL) was measured with a quantitative real-time PCR and LTPA with a validated questionnaire. Multiple linear regression analyses were used to assess the association between sex-specific LTPA quartiles and LTL at baseline and change in LTL over 10 years. The analyses were adjusted for age, educational attainment, smoking, body fat percentage, oestrogen exposure in women and for follow-up time when applicable.<br><br>RESULTS: At baseline, volume of LTPA was not associated with LTL in men (p = 0.66) or in women (p = 0.33). Among women, however, higher volume of LTPA at baseline was associated with greater shortening of LTL (p for linearity 0.040) during the 10-year follow-up. No association was found among men (p for linearity 0.75).<br><br>CONCLUSIONS: Our findings suggest that PA has a sex-specific role in regulation of telomere length in the aging process as in our study a high volume of LTPA in elderly women, but not in men, was associated with more rapid telomere attrition.},
}
@article {pmid32084415,
year = {2020},
author = {Lalonde, M and Chartrand, P},
title = {TERRA, a Multifaceted Regulator of Telomerase Activity at Telomeres.},
journal = {Journal of molecular biology},
volume = {432},
number = {15},
pages = {4232-4243},
doi = {10.1016/j.jmb.2020.02.004},
pmid = {32084415},
issn = {1089-8638},
support = {MOP-89768//CIHR/Canada ; PJT-162156//CIHR/Canada ; },
mesh = {Animals ; Gene Expression Regulation, Enzymologic ; Humans ; R-Loop Structures ; RNA, Long Noncoding/chemistry/*genetics ; Telomerase/*metabolism ; Telomere/chemistry/*metabolism ; },
abstract = {In eukaryotes, telomeres are repetitive sequences at the end of chromosomes, which are maintained in a constitutive heterochromatin state. It is now known that telomeres can be actively transcribed, leading to the production of a telomeric repeat-containing noncoding RNA called TERRA. Due to its sequence complementarity to the telomerase template, it was suggested early on that TERRA could be an inhibitor of telomerase. Since then, TERRA has been shown to be involved in heterochromatin formation at telomeres, to invade telomeric dsDNA and form R-loops, and even to promote telomerase recruitment at short telomeres. All these functions depend on the diverse capacities of this lncRNA to bind various cofactors, act as a scaffold, and promote higher-order complexes in cells. In this review, it will be highlighted as to how these properties of TERRA work together to regulate telomerase activity at telomeres.},
}
@article {pmid32083302,
year = {2020},
author = {Tomasova, K and Kroupa, M and Forsti, A and Vodicka, P and Vodickova, L},
title = {Telomere maintenance in interplay with DNA repair in pathogenesis and treatment of colorectal cancer.},
journal = {Mutagenesis},
volume = {35},
number = {3},
pages = {261-271},
doi = {10.1093/mutage/geaa005},
pmid = {32083302},
issn = {1464-3804},
mesh = {Cell Cycle Checkpoints/genetics ; Cell Transformation, Neoplastic/*genetics/metabolism ; Cellular Senescence/genetics ; Chromosomal Instability ; Colorectal Neoplasms/drug therapy/genetics/*metabolism/pathology ; DNA Repair/*genetics ; Humans ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Colorectal cancer (CRC) continues to be one of the leading malignancies and causes of tumour-related deaths worldwide. Both impaired DNA repair mechanisms and disrupted telomere length homeostasis represent key culprits in CRC initiation, progression and prognosis. Mechanistically, altered DNA repair results in the accumulation of mutations in the genome and, ultimately, in genomic instability. DNA repair also determines the response to chemotherapeutics in CRC treatment, suggesting its utilisation in the prediction of therapy response and individual approach to patients. Telomere attrition resulting in replicative senescence, simultaneously by-passing cell cycle checkpoints, is a hallmark of malignant transformation of the cell. Telomerase is almost ubiquitous in advanced solid cancers, including CRC, and its expression is fundamental to cell immortalisation. Therefore, there is a persistent effort to develop therapeutics, which are telomerase-specific and gentle to non-malignant tissues. However, in practice, we are still at the level of clinical trials. The current state of knowledge and the route, which the research takes, gives us a positive perspective that the problem of molecular models of telomerase activation and telomere length stabilisation will finally be solved. We summarise the current literature herein, by pointing out the crosstalk between proteins involved in DNA repair and telomere length homeostasis in relation to CRC.},
}
@article {pmid32080954,
year = {2020},
author = {Moschouri, E and Vionnet, J and Giostra, E and Daccord, C and Lazor, R and Sciarra, A and Letovanec, I and Sempoux, C and Gonzalez, M and Unger, S and Fodstad, H and Haubitz, M and Baerlocher, GM and Voruz, S and Naveiras, O and Jacquemin, E and Moradpour, D and Fraga, M},
title = {Combined Lung and Liver Transplantation for Short Telomere Syndrome.},
journal = {Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society},
volume = {26},
number = {6},
pages = {840-844},
doi = {10.1002/lt.25734},
pmid = {32080954},
issn = {1527-6473},
mesh = {Growth Disorders ; Humans ; *Liver Transplantation ; Lung/surgery ; *Lung Transplantation/adverse effects ; *Nephrocalcinosis ; Telomere/genetics ; },
}
@article {pmid32080884,
year = {2020},
author = {Vančevska, A and Ahmed, W and Pfeiffer, V and Feretzaki, M and Boulton, SJ and Lingner, J},
title = {SMCHD1 promotes ATM-dependent DNA damage signaling and repair of uncapped telomeres.},
journal = {The EMBO journal},
volume = {39},
number = {7},
pages = {e102668},
pmid = {32080884},
issn = {1460-2075},
support = {310030_184718//Schweizerischer Nationalfonds zur F&#xf6;rderung der Wissenschaftlichen Forschung (SNF)/International ; KLS-3824-02-2016//Krebsforschung Schweiz (Swiss Cancer Research)/International ; 182880//NCCR RNA &amp; Disease/International ; },
mesh = {Ataxia Telangiectasia Mutated Proteins/*metabolism ; Chromosomal Proteins, Non-Histone/*genetics/*metabolism ; DNA Damage ; DNA End-Joining Repair ; Epistasis, Genetic ; Gene Knockout Techniques ; HeLa Cells ; Humans ; Phosphorylation ; Shelterin Complex/genetics/metabolism ; Signal Transduction ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Telomeric Repeat Binding Protein 2/*genetics ; Tumor Suppressor p53-Binding Protein 1/metabolism ; },
abstract = {Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1) has been implicated in X-chromosome inactivation, imprinting, and DNA damage repair, and mutations in SMCHD1 can cause facioscapulohumeral muscular dystrophy. More recently, SMCHD1 has also been identified as a component of telomeric chromatin. Here, we report that SMCHD1 is required for DNA damage signaling and non-homologous end joining (NHEJ) at unprotected telomeres. Co-depletion of SMCHD1 and the shelterin subunit TRF2 reduced telomeric 3'-overhang removal in time-course experiments, as well as the number of chromosome end fusions. SMCHD1-deficient cells displayed reduced ATM S1981 phosphorylation and diminished formation of γH2AX foci and of 53BP1-containing telomere dysfunction-induced foci (TIFs), indicating defects in DNA damage checkpoint signaling. Removal of TPP1 and subsequent activation of ATR signaling rescued telomere fusion events in TRF2-depleted SMCHD1 knockout cells. Together, these data indicate that SMCHD1 depletion reduces telomere fusions in TRF2-depleted cells due to defects in ATM-dependent checkpoint signaling and that SMCHD1 mediates DNA damage response activation upstream of ATM phosphorylation at uncapped telomeres.},
}
@article {pmid32077865,
year = {2020},
author = {Testori, A},
title = {Short telomere syndromes, premature ageing syndromes, and biological ageing.},
journal = {Hong Kong medical journal = Xianggang yi xue za zhi},
volume = {26},
number = {1},
pages = {76-77},
doi = {10.12809/hkmj187782},
pmid = {32077865},
issn = {1024-2708},
mesh = {Aging/*genetics ; Humans ; Syndrome ; Telomere Shortening/*genetics ; Werner Syndrome/*genetics ; },
}
@article {pmid32077369,
year = {2020},
author = {Zhou, X and Wei, W and Duan, X and Zhang, H and Feng, X and Wang, T and Wang, P and Ding, M and Liu, S and Li, L and Yao, W and Wang, Q and Acquaye, RM and Liang, H and Wang, W and Yang, Y},
title = {Effect of TRF1 rs3863242 polymorphism on telomere length in omethoate-exposed workers.},
journal = {Journal of environmental science and health. Part. B, Pesticides, food contaminants, and agricultural wastes},
volume = {55},
number = {6},
pages = {525-529},
doi = {10.1080/03601234.2020.1728167},
pmid = {32077369},
issn = {1532-4109},
mesh = {Adult ; Asian People ; Case-Control Studies ; Dimethoate/*analogs &amp; derivatives/toxicity ; Female ; Genotype ; Humans ; Male ; Middle Aged ; *Occupational Exposure/adverse effects ; Polymerase Chain Reaction/methods ; Polymorphism, Restriction Fragment Length ; *Polymorphism, Single Nucleotide ; Shelterin Complex ; Telomere/*drug effects ; Telomere-Binding Proteins/genetics ; Telomeric Repeat Binding Protein 1/*genetics ; Telomeric Repeat Binding Protein 2/genetics ; },
abstract = {Telomere length was found to be associated with omethoate exposure and polymorphisms in certain genes among occupational workers. However, whether the polymorphisms in telomere-binding protein genes influence telomere length remains unclear. To explore the correlation between telomere length and polymorphisms in telomere-binding protein genes, telomere length in peripheral blood leukocytes was determined by real-time quantitative polymerase chain reaction in 180 omethoate-exposed workers and 115 healthy controls. Polymorphisms in 10 pairs of alleles were detected using flight mass spectrometry or polymerase chain reaction-restriction fragment length polymorphism technique. The results showed that individuals with GG genotype in TRF1 rs3863242 had longer telomere lengths than those with AG + AA genotype in the control group (p = 0.005). The multiple regression analysis suggested that both omethoate exposure (b = 0.526, p < 0.001) and TRF1 rs3863242 GG (b = 0.220, p = 0.002) were related to a longer telomere length. In conclusion, GG genotype in TRF1 rs3863242 is linked to prolongation of telomere length, and individuals with GG genotype are recommended to strengthen health protection in a Chinese occupational omethoate-exposed population.},
}
@article {pmid32076714,
year = {2020},
author = {Schratz, KE and Haley, L and Danoff, SK and Blackford, AL and DeZern, AE and Gocke, CD and Duffield, AS and Armanios, M},
title = {Cancer spectrum and outcomes in the Mendelian short telomere syndromes.},
journal = {Blood},
volume = {135},
number = {22},
pages = {1946-1956},
pmid = {32076714},
issn = {1528-0020},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; R01 CA225027/CA/NCI NIH HHS/United States ; R01 HL119476/HL/NHLBI NIH HHS/United States ; T32 HL007525/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Cell Cycle Proteins/genetics ; Child ; Female ; *Germ-Line Mutation ; Hematopoiesis/genetics ; Humans ; Leukemia, Myeloid, Acute/diagnosis/genetics/therapy ; Male ; Middle Aged ; Myelodysplastic Syndromes/diagnosis/genetics/therapy ; Neoplasms/diagnosis/*genetics/therapy ; Nuclear Proteins/genetics ; Prognosis ; Registries ; Risk Factors ; Syndrome ; Telomere/*genetics ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {Short telomeres have been linked to cancer risk, yet other evidence supports them being tumor suppressive. Here, we report cancer outcomes in individuals with germline mutations in telomerase and other telomere-maintenance genes. Among 180 individuals evaluated in a hospital-based setting, 12.8% had cancer. Solid tumors were rare (2.8%); nearly all were young male DKC1 mutation carriers, and they were generally resectable with good short-term outcomes. Myelodysplastic syndrome (MDS) was most common, followed by acute myeloid leukemia (AML); they accounted for 75% of cancers. Age over 50 years was the biggest risk factor, and MDS/AML usually manifested with marrow hypoplasia and monosomy 7, but the somatic mutation landscape was indistinct from unselected patients. One- and 2-year survival were 61% and 39%, respectively, and two-thirds of MDS/AML patients died of pulmonary fibrosis and/or hepatopulmonary syndrome. In one-half of the cases, MDS/AML patients showed a recurrent peripheral blood pattern of acquired, granulocyte-specific telomere shortening. This attrition was absent in age-matched mutation carriers who did not have MDS/AML. We tested whether adult short telomere patients without MDS/AML also had evidence of clonal hematopoiesis of indeterminate potential-related mutations and found that 30% were affected. These patients also primarily suffered morbidity from pulmonary fibrosis during follow-up. Our data show that the Mendelian short telomere syndromes are associated with a relatively narrow cancer spectrum, primarily MDS and AML. They suggest that short telomere length is sufficient to drive premature age-related clonal hematopoiesis in these inherited disorders.},
}
@article {pmid32073638,
year = {2020},
author = {Zhou, Y and Hambly, BD and Simmons, D and McLachlan, CS},
title = {Sex-specific educational attainment is associated with telomere length in an Australian rural population.},
journal = {QJM : monthly journal of the Association of Physicians},
volume = {113},
number = {7},
pages = {469-473},
doi = {10.1093/qjmed/hcaa031},
pmid = {32073638},
issn = {1460-2393},
mesh = {Australia ; Cross-Sectional Studies ; Educational Status ; Female ; Humans ; Linear Models ; Male ; Middle Aged ; Rural Population ; *Sex Characteristics ; *Social Class ; *Telomere Shortening ; },
abstract = {BACKGROUND: There is limited understanding on whether and how socioeconomic status (SES), particularly educational attainment and household income, impacts on telomere length in an Australian rural context. Additionally, it is unknown whether access to health services via the Australian public or private health system influences telomere length.<br><br>AIM: This study investigates whether there is a relationship between telomere length and SES indicators (income, education) as well as health insurance status in a rural Australian population.<br><br>METHODS: Samples were drawn from the Australian Rural Victoria cross-sectional Crossroads Study. Leucocyte telomere length (LTL) was measured using a multiplex quantitative polymerase chain reaction method.<br><br>RESULTS: Among 1424 participants, we did not find a significant main effect association with LTL across education, income level and health insurance. An exploratory finding was sex may influence the relationship between educational attainment and LTL (P&#x2009;=&#x2009;0.021). In males, but not females, higher education was associated with longer LTL by 0.033 [95% confidence interval (CI) 0.002-0.063, P&#x2009;=&#x2009;0.035]; in those with low education attainment, male participants had shorter LTL by 0.058 (95% CI -0.086 to -0.029) than female participants (P&#x2009;<&#x2009;0.0001).<br><br>CONCLUSION: Being male and having lower education attainment was associated with shorter telomere length in our rural population. Evidence from our study supports the importance of education on LTL in males in rural Australia. Our studies also support previous findings that LTL in later life may not be closely associated with indicators of SES.},
}
@article {pmid32071280,
year = {2020},
author = {Robinson, NJ and Morrison-Smith, CD and Gooding, AJ and Schiemann, BJ and Jackson, MW and Taylor, DJ and Schiemann, WP},
title = {SLX4IP and telomere dynamics dictate breast cancer metastasis and therapeutic responsiveness.},
journal = {Life science alliance},
volume = {3},
number = {4},
pages = {},
pmid = {32071280},
issn = {2575-1077},
support = {R01 CA177069/CA/NCI NIH HHS/United States ; TL1 TR002549/TR/NCATS NIH HHS/United States ; R01 CA236273/CA/NCI NIH HHS/United States ; S10 OD016164/OD/NIH HHS/United States ; P30 CA043703/CA/NCI NIH HHS/United States ; R01 GM133841/GM/NIGMS NIH HHS/United States ; F30 CA213892/CA/NCI NIH HHS/United States ; T32 GM007250/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Biomarkers, Pharmacological ; Breast Neoplasms/*genetics/metabolism/physiopathology ; Carrier Proteins/*genetics/metabolism ; Cell Line, Tumor ; Female ; HEK293 Cells ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Metastasis/*genetics ; Neoplasm Recurrence, Local/genetics ; Telomerase/genetics ; Telomere/metabolism ; Telomere Homeostasis/genetics ; Xenograft Model Antitumor Assays/methods ; },
abstract = {Metastasis is the leading cause of breast cancer-related death and poses a substantial clinical burden owing to a paucity of targeted treatment options. The clinical manifestations of metastasis occur years-to-decades after initial diagnosis and treatment because disseminated tumor cells readily evade detection and resist therapy, ultimately giving rise to recurrent disease. Using an unbiased genetic screen, we identified SLX4-interacting protein (SLX4IP) as a regulator of metastatic recurrence and established its relationship in governing telomere maintenance mechanisms (TMMs). Inactivation of SLX4IP suppressed alternative lengthening of telomeres (ALT), coinciding with activation of telomerase. Importantly, TMM selection dramatically influenced metastatic progression and survival of patients with genetically distinct breast cancer subtypes. Notably, pharmacologic and genetic modulation of TMMs elicited telomere-dependent cell death and prevented disease recurrence by disseminated tumor cells. This study illuminates SLX4IP as a potential predictive biomarker for breast cancer progression and metastatic relapse. SLX4IP expression correlates with TMM identity, which also carries prognostic value and informs treatment selection, thereby revealing new inroads into combating metastatic breast cancers.},
}
@article {pmid32071117,
year = {2020},
author = {Santa-Maria, CA and Coughlin, JW and Sharma, D and Armanios, M and Blackford, AL and Schreyer, C and Dalcin, A and Carpenter, A and Jerome, GJ and Armstrong, DK and Chaudhry, M and Cohen, GI and Connolly, RM and Fetting, J and Miller, RS and Smith, KL and Snyder, C and Wolfe, A and Wolff, AC and Huang, CY and Appel, LJ and Stearns, V},
title = {The Effects of a Remote-based Weight Loss Program on Adipocytokines, Metabolic Markers, and Telomere Length in Breast Cancer Survivors: the POWER-Remote Trial.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {26},
number = {12},
pages = {3024-3034},
pmid = {32071117},
issn = {1557-3265},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; },
mesh = {Adipokines/*blood ; Adult ; Aged ; Biomarkers/*blood ; Body Mass Index ; Breast Neoplasms/metabolism/*rehabilitation/therapy ; C-Reactive Protein/analysis ; Cancer Survivors/*statistics &amp; numerical data ; Case-Control Studies ; *Exercise ; Female ; Follow-Up Studies ; Humans ; Leukocytes, Mononuclear/metabolism ; Middle Aged ; Prognosis ; Quality of Life ; Survival Rate ; Telerehabilitation/methods ; *Telomere ; *Weight Loss ; },
abstract = {PURPOSE: We initiated a clinical trial to determine the proportion of breast cancer survivors achieving ≥5% weight loss using a remotely delivered weight loss intervention (POWER-remote) or a self-directed approach, and to determine the effects of the intervention on biomarkers of cancer risk including metabolism, inflammation, and telomere length.<br><br>EXPERIMENTAL DESIGN: Women with stage 0-III breast cancer, who completed local therapy and chemotherapy, with a body mass index &#x2265;25 kg/m[2] were randomized to a 12-month intervention (POWER-remote) versus a self-directed approach. The primary objective was to determine the number of women who achieved at least 5% weight loss at 6 months. We assessed baseline and 6-month change in a panel of adipocytokines (adiponectin, leptin, resistin, HGF, NGF, PAI1, TNF&#x3b1;, MCP1, IL1&#x3b2;, IL6, and IL8), metabolic factors (insulin, glucose, lipids, hs-CRP), and telomere length in peripheral blood mononuclear cells.<br><br>RESULTS: From 2013 to 2015, 96 women were enrolled, and 87 were evaluable for the primary analysis; 45 to POWER-remote and 42 to self-directed. At 6 months, 51% of women randomized to POWER-remote lost &#x2265;5% of their baseline body weight, compared with 12% in the self-directed arm [OR, 7.9; 95% confidence interval (CI), 2.6-23.9; P = 0.0003]; proportion were similar at 12 months (51% vs 17%, respectively, P = 0.003). Weight loss correlated with significant decreases in leptin, and favorable modulation of inflammatory cytokines and lipid profiles. There was no significant change in telomere length at 6 months.<br><br>CONCLUSIONS: A remotely delivered weight loss intervention resulted in significant weight loss in breast cancer survivors, and favorable effects on several biomarkers.},
}
@article {pmid32070634,
year = {2020},
author = {Hailu, EM and Needham, BL and Lewis, TT and Lin, J and Seeman, TE and Roux, AD and Mujahid, MS},
title = {Discrimination, social support, and telomere length: the Multi-Ethnic Study of Atherosclerosis (MESA).},
journal = {Annals of epidemiology},
volume = {42},
number = {},
pages = {58-63.e2},
doi = {10.1016/j.annepidem.2019.12.009},
pmid = {32070634},
issn = {1873-2585},
support = {P2C HD041022/HD/NICHD NIH HHS/United States ; R01 HL101161/HL/NHLBI NIH HHS/United States ; T32 HD101364/HD/NICHD NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Atherosclerosis/*ethnology/genetics/psychology ; *Discrimination, Psychological ; Ethnicity/*psychology/statistics &amp; numerical data ; Female ; Humans ; Male ; Middle Aged ; *Social Support ; Stress, Psychological ; *Telomere ; },
abstract = {PURPOSE: We sought to assess the association of reports of discrimination with leukocyte telomere length (LTL) and effect measure modification by social support.<br><br>METHODS: This study used data from the Multi-Ethnic Study of Atherosclerosis Stress Ancillary Study (n&#xa0;=&#xa0;1153). Discrimination was measured using the everyday discrimination and the major experiences of discrimination scales. LTL was defined as the ratio of telomeric DNA to single-copy control gene (mean&#xa0;=&#xa0;0.916, SD&#xa0;=&#xa0;0.205). Linear regression models were used to examine the relationship between discrimination and LTL.<br><br>RESULTS: We found no association between either measure of discrimination and LTL, but there was evidence of effect modification by social support (P (&#x3c7;[2])&#xa0;=&#xa0;0.001) for everyday discrimination only. Among those with low social support, reporting moderate and high everyday discrimination was associated with a 0.35 (95% CI:&#xa0;-0.54 to&#xa0;-0.16) and a 0.17 (95% CI:&#xa0;-0.34 to&#xa0;-0.01) shorter telomere length, respectively, compared to reporting no discrimination, after adjusting for demographic factors, health behaviors, and health conditions. There were no associations between discrimination and LTL among those reporting moderate or high social support.<br><br>CONCLUSIONS: These findings underscore the importance of continued investigation of the potential health consequences of chronic unfair treatment in the absence of supportive resources.},
}
@article {pmid32068123,
year = {2020},
author = {Bonafè, M and Sabbatinelli, J and Olivieri, F},
title = {Exploiting the telomere machinery to put the brakes on inflamm-aging.},
journal = {Ageing research reviews},
volume = {59},
number = {},
pages = {101027},
doi = {10.1016/j.arr.2020.101027},
pmid = {32068123},
issn = {1872-9649},
mesh = {Aging/*genetics ; Animals ; Cellular Senescence/*genetics ; Gene Expression Regulation ; Humans ; Longevity/genetics ; Mice ; Telomerase/*genetics ; Telomere/*chemistry ; Telomere Shortening/*genetics ; },
abstract = {Telomere shortening accompanies mammalian aging in vivo, and the burden of senescent cells with short telomeres and a senescence-associated secretory phenotype (SASP) increases with aging. The release into the cytoplasm and the extracellular vesicle-mediated intercellular exchange of telomeric TTAGGG repeats could exert an anti-inflammatory activity by preventing the activation of the misplaced nucleic acid-sensing pathway. Many pharmacological and genetic strategies have been developed to prevent telomere shortening or to achieve telomere elongation. Recently, it was demonstrated that telomere elongation can be obtained - without genetic manipulation - by culturing mice embryonic stem cells into appropriate media. Based on this observation, we hypothesize that environmental factors could affect the initial length of telomeres by modulating the activity of telomerase during the early stages of pregnancy. Therefore, organisms with longer telomeres could exploit the anti-inflammatory activity of telomeric sequences over an extended time span, eventually delaying the development and progression of age-related diseases.},
}
@article {pmid32065062,
year = {2020},
author = {Victorelli, S and Passos, JF},
title = {Telomeres: beacons of autocrine and paracrine DNA damage during skin aging.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {19},
number = {5},
pages = {532-540},
pmid = {32065062},
issn = {1551-4005},
support = {BB/H022384/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/L502066/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; *Autocrine Communication ; Bystander Effect ; *Cellular Senescence/genetics ; *DNA Damage/genetics ; Humans ; Melanocytes/*pathology ; *Paracrine Communication ; Skin Aging/genetics/*pathology ; Stress, Physiological ; Telomere/*pathology ; },
abstract = {Cellular senescence is an irreversible cell cycle arrest, which can be triggered by a number of stressors, including telomere damage. Among many other phenotypic changes, senescence is accompanied by increased secretion of pro-inflammatory molecules, also known as the senescence-associated secretory phenotype (SASP). It is thought that accumulation of senescent cells contributes to age-associated tissue dysfunction partly by inducing senescence in neighboring cells through mechanisms involving SASP factors. Here, we will review evidence suggesting that telomeres can become dysfunctional irrespectively of shortening, and that this may be a mechanism-driving senescence in post-mitotic or slow dividing cells. Furthermore, we review recent evidence that supports that senescent melanocytes induce paracrine telomere damage during skin aging, which may be the mechanism responsible for propagation of senescent cells. We propose that telomeres are sensors of imbalances in the cellular milieu and act as beacons of stress, contributing to autocrine and paracrine senescence.},
}
@article {pmid32064679,
year = {2020},
author = {Licea-Cejudo, RC and Arenas-Sandoval, LK and Salazar-León, J and Martínez-Martínez, MV and Carreón-Rodríguez, A and Pedraza-Alva, G and Pérez-Martínez, L},
title = {A dysfunctional family environment and a high body fat percentage negatively affect telomere length in Mexican boys aged 8-10 years.},
journal = {Acta paediatrica (Oslo, Norway : 1992)},
volume = {109},
number = {10},
pages = {2091-2098},
doi = {10.1111/apa.15234},
pmid = {32064679},
issn = {1651-2227},
mesh = {*Adipose Tissue ; Body Mass Index ; Child ; Cross-Sectional Studies ; Female ; Humans ; Male ; Mexico ; *Telomere/genetics ; },
abstract = {AIM: The aim of this study was to determine whether a direct relationship existed between absolute telomere length (aTL), obesity and familial functionality in a group of Mexican children.<br><br>METHODS: We recruited 134 children (52% boys) aged 8-10&#xa0;years during regular primary care check-ups in 2016 and evaluated physical activity (PA), feeding practices, anthropometrics, body fat percentage (BF%) and family dysfunction. Optimised quantitative PCR determined aTL from genomic deoxyribonucleic acid isolated from saliva samples.<br><br>RESULTS: Boys with a healthy BF% showed a higher aTL than their high BF% counterparts (P&#xa0;<&#xa0;.01). aTL was higher in children who performed PA than their sedentary counterparts (P&#xa0;<&#xa0;.05). Alarmingly, 90% of the children belonged to dysfunctional families and a dysfunctional family was correlated with a higher BF% (r&#xa0;=&#xa0;-.57). Negative correlations between the BF% and aTL (r&#xa0;=&#xa0;-.1765) and the BF% and time dedicated to PA (r&#xa0;=&#xa0;-.031) were observed in boys. On the contrary, we found a positive correlation between the aTL and weekly PA (r&#xa0;=&#xa0;.1938). These correlations were not observed in girls.<br><br>CONCLUSION: Telomere shortening was associated with a high BF% in boys, but not girls. Dysfunctional families were also a key factor. School PA programmes should be mandatory.},
}
@article {pmid32063089,
year = {2020},
author = {Oaks, BM and Adu-Afarwuah, S and Kumordzie, S and Laudenslager, ML and Smith, DL and Lin, J and Young, RR and Arnold, CD and Bentil, H and Okronipa, H and Ocansey, M and Dewey, KG},
title = {Impact of a nutritional supplement during gestation and early childhood on child salivary cortisol, hair cortisol, and telomere length at 4-6 years of age: a follow-up of a randomized controlled trial.},
journal = {Stress (Amsterdam, Netherlands)},
volume = {23},
number = {5},
pages = {597-606},
pmid = {32063089},
issn = {1607-8888},
mesh = {Adolescent ; Child ; Child, Preschool ; Dietary Supplements ; Female ; Follow-Up Studies ; Ghana ; Humans ; *Hydrocortisone ; Infant ; Micronutrients ; Pregnancy ; Stress, Psychological ; *Telomere ; },
abstract = {Dysregulation of the stress response can occur early in life and may be affected by nutrition. Our objective was to evaluate the long-term effect of nutritional supplementation during gestation and early childhood on child cortisol and buccal telomere length (a marker of cellular aging) at 4-6 years of age. We conducted a follow-up study of children born to women who participated in a nutritional supplementation trial in Ghana. In one group, a lipid-based nutrient supplement (LNS) was provided to women during gestation and the first 6 months postpartum and to their infants from age 6 to 18 months. The control groups received either iron and folic acid (IFA) during gestation or multiple micronutrients during gestation and the first 6 months postpartum, with no infant supplementation. At age 4-6 years, we measured hair cortisol, buccal telomere length, and salivary cortisol before and after a stressor. Salivary cortisol was available for 364 children across all three trial arms and hair cortisol and telomere length were available for a subset of children (n = 275 and 278, respectively) from the LNS and IFA groups. Telomere length, salivary cortisol, and hair cortisol did not differ by supplementation group. Overall, these findings suggest that nutritional supplementation given during gestation and early childhood does not have an effect on child stress response or chronic stress in children at 4-6 years. Trial registration: ClinicalTrials.gov Identifier NCT00970866.Lay SummaryThis study addressed a research gap about whether improved nutrition during pregnancy and early childhood impacts telomere length and cortisol in preschool children. There was no difference in child telomere length or cortisol between two trial arms of a nutritional supplementation trial that began during pregnancy. The research outcomes indicate lipid-based nutrient supplements, a relatively new form of supplementation, do not have an effect on markers of stress or cellular aging measured in later childhood.},
}
@article {pmid32061930,
year = {2020},
author = {Coulon, S and Vaurs, M},
title = {Telomeric Transcription and Telomere Rearrangements in Quiescent Cells.},
journal = {Journal of molecular biology},
volume = {432},
number = {15},
pages = {4220-4231},
doi = {10.1016/j.jmb.2020.01.034},
pmid = {32061930},
issn = {1089-8638},
mesh = {Humans ; RNA, Untranslated/*genetics ; Telomere/*genetics ; Telomere Homeostasis ; *Transcription, Genetic ; Yeasts/genetics ; },
abstract = {Despite the condensed nature of terminal sequences, the telomeres are transcribed into a group of noncoding RNAs, including the TElomeric Repeat-containing RNA (TERRA). Since the discovery of TERRA, its evolutionary conserved function has been confirmed, and its involvement in telomere length regulation, heterochromatin establishment, and telomere recombination has been demonstrated. We previously reported that TERRA is upregulated in quiescent fission yeast cells, although the global transcription is highly reduced. Elevated telomeric transcription was also detected when telomeres detach from the nuclear periphery. These intriguing observations unveil unexpected facets of telomeric transcription in arrested cells. In this review, we present the different aspects of TERRA transcription during quiescence and discuss their implications for telomere maintenance and cell fate.},
}
@article {pmid32061901,
year = {2020},
author = {Erusalimsky, JD},
title = {Oxidative stress, telomeres and cellular senescence: What non-drug interventions might break the link?.},
journal = {Free radical biology &amp; medicine},
volume = {150},
number = {},
pages = {87-95},
doi = {10.1016/j.freeradbiomed.2020.02.008},
pmid = {32061901},
issn = {1873-4596},
mesh = {Aging/genetics ; *Cellular Senescence ; Humans ; Oxidative Stress ; *Telomere/genetics ; Telomere Shortening ; },
abstract = {Telomeres are higher order structures that cap and protect chromosome ends. Telomeric DNA naturally shortens during somatic cell division and as a result of oxidative stress. Excessive shortening disrupts the integrity of the telomere, causing cellular senescence, one of the hallmarks of organismal ageing. The accumulation of senescent cells with ageing contributes to the loss of tissue homeostasis and the development of age-related pathologies. Hence, counteracting telomere shortening may be one relevant approach to develop strategies for healthier ageing. In this review I present the case for the existence of a link between oxidative stress, accelerated telomere shortening and cellular senescence. I also examine findings from human observational studies exploring associations between telomere length and oxidative stress-related parameters. Finally, I discuss results from randomised control trials testing the impact of non-pharmacological lifestyle interventions on the maintenance of telomere length, considering the potential mechanisms that might be involved.},
}
@article {pmid32059353,
year = {2020},
author = {Guinobert, I and Blondeau, C and Colicchio, B and Oudrhiri, N and Dieterlen, A and Jeandidier, E and Deschenes, G and Bardot, V and Cotte, C and Ripoche, I and Carde, P and Berthomier, L and M'Kacher, R},
title = {The Use of Natural Agents to Counteract Telomere Shortening: Effects of a Multi-Component Extract of Astragalus mongholicus Bunge and Danazol.},
journal = {Biomedicines},
volume = {8},
number = {2},
pages = {},
pmid = {32059353},
issn = {2227-9059},
abstract = {A link between telomere shortening and oxidative stress was found in aging people and patients with cancer or inflammatory diseases. Extracts of Astragalus spp. are known to stimulate telomerase activity, thereby compensating telomere shortening. We characterized a multi-component hydroethanolic root extract (HRE) of Astragalus mongholicus Bunge and assessed its effects on telomeres compared to those of danazol. Astragalosides I to IV, flavonoids, amino acids and sugars were detected in the HRE. Samples of peripheral blood lymphocytes with short telomeres from 18 healthy donors (mean age 63.5 years; range 3286 years) were exposed to a single dose of 1 µg/mL HRE or danazol for three days. Telomere length and telomerase expression were then measured. Significant elongation of telomeres associated to a less toxicity was observed in lymphocytes from 13/18 donors following HRE treatment (0.54 kb (0.15-2.06 kb)) and in those from 9/18 donors after danazol treatment (0.95 kb (0.06-2.06 kb)). The rate of cells with short telomeres (<3 kb) decreased in lymphocytes from all donors after exposure to either HRE or danazol, telomere elongation being telomerase-dependent. These findings suggest that the HRE could be used for the management of age-related diseases.},
}
@article {pmid32057534,
year = {2020},
author = {Shu, Y and Wu, M and Yang, S and Wang, Y and Li, H},
title = {Association of dietary selenium intake with telomere length in middle-aged and older adults.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {39},
number = {10},
pages = {3086-3091},
doi = {10.1016/j.clnu.2020.01.014},
pmid = {32057534},
issn = {1532-1983},
mesh = {Age Factors ; Aged ; Aging/genetics/*metabolism ; Cross-Sectional Studies ; *Diet ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Nutrition Surveys ; Selenium/*administration &amp; dosage/metabolism ; Sex Factors ; Telomere/*metabolism ; *Telomere Homeostasis ; United States ; },
abstract = {BACKGROUND: Growing evidence suggested that lifestyle factors including dietary habits may influence the telomere length which is a reliable marker of biological aging and predictor for chronic diseases. However, the role of dietary selenium intake in telomere length maintenance is rarely examined.<br><br>OBJECTIVE: We aimed to test the relationship between dietary selenium intake and telomere length among middle-aged and older adults in America.<br><br>METHODS: A total of 3194 United States adults older than 45 years old were extracted from the National Health and Nutrition Examination Survey (NHANES) in 1999-2000 and 2001-2002. Leukocyte telomere length was measured using the quantitative real-time polymerase chain reaction (qPCR). Dietary selenium intake was assessed by a trained interviewer using 24-h dietary recall method. Generalized linear models were performed to evaluate the association of dietary selenium intake with telomere length. The restricted cubic spline analysis was used to further explore the nonlinear dose-response relationship between dietary selenium intake and telomere length.<br><br>RESULTS: After adjusting potential confounders, every 20&#xa0;&#x3bc;g increase in dietary selenium intake was associated with 0.42% (95% CI: 0.02%, 0.82%) longer telomere length in all participants. In the subgroup analyses, dietary selenium intake was related to longer telomere length in females (Percentage change: 0.87%; 95% CI: 0.26%, 1.49%) and non-obese participants (Percentage change: 0.53%; 95% CI: 0.04%, 1.02%), but not in males (Percentage change: 0.04%; 95% CI:&#xa0;-0.49%, 0.57%) and obese participants (Percentage change: 0.21%; 95% CI:&#xa0;-0.47%, 0.91%). The restricted cubic spline analysis showed a linear association between dietary selenium intake and telomere length.<br><br>CONCLUSIONS: This study indicated that the increased dietary selenium intake was associated with longer telomere length among middle-aged and older adults in America. These findings require further corroboration from future prospective studies.},
}
@article {pmid32050150,
year = {2020},
author = {Habib, R and Ocklenburg, S and Hoffjan, S and Haghikia, A and Epplen, JT and Arning, L},
title = {Association between shorter leukocyte telomeres and multiple sclerosis.},
journal = {Journal of neuroimmunology},
volume = {341},
number = {},
pages = {577187},
doi = {10.1016/j.jneuroim.2020.577187},
pmid = {32050150},
issn = {1872-8421},
mesh = {Adult ; Aged ; Aging/genetics ; Case-Control Studies ; Female ; Humans ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Multiple Sclerosis/*genetics ; Severity of Illness Index ; Sex Characteristics ; *Telomere Shortening ; },
abstract = {Relative telomere length (TL) is regarded as a biomarker of biological age. Accelerated immune aging, as represented by TL reduction, has been demonstrated in autoimmune diseases, including multiple sclerosis (MS). However, it is still unresolved whether telomere shortening is the cause or the consequence of the pathogenic events underlying autoimmunity. Assessing TL in whole blood DNA samples in 138 MS patients and 120 healthy controls showed reduced TL in patients as compared with controls There seems to be a prelude of accelerated telomere shortening, which may increase the risk for development of MS.},
}
@article {pmid32046456,
year = {2020},
author = {Pedroso, DCC and Santana, VP and Donaires, FS and Picinato, MC and Giorgenon, RC and Santana, BA and Pimentel, RN and Keefe, DL and Calado, RT and Ferriani, RA and Furtado, CLM and Reis, RM},
title = {Telomere Length and Telomerase Activity in Immature Oocytes and Cumulus Cells of Women with Polycystic Ovary Syndrome.},
journal = {Reproductive sciences (Thousand Oaks, Calif.)},
volume = {27},
number = {6},
pages = {1293-1303},
doi = {10.1007/s43032-019-00120-6},
pmid = {32046456},
issn = {1933-7205},
mesh = {Adult ; Androstenedione/blood ; Body Mass Index ; Case-Control Studies ; Cumulus Cells/*metabolism ; Estradiol/blood ; Female ; Follicle Stimulating Hormone/blood ; Humans ; Insulin/blood ; Oocytes/*metabolism ; Oogenesis/physiology ; Polycystic Ovary Syndrome/*metabolism ; Prospective Studies ; Telomerase/*metabolism ; Telomere/*metabolism ; Testosterone/blood ; },
abstract = {Metaphase II oocytes (MII) from polycystic ovary syndrome (PCOS) frequently have impaired oocyte competence. Since telomere maintenance is important for folliculogenesis, oocyte maturation, and early embryonic development, we sought to verify the implications of PCOS on telomere length and telomerase activity in immature oocytes and cumulus cells. 43 PCOS and 67 control women were included, and anthropometric, biochemical, and hormonal characteristics were evaluated. The telomere length in germinal vesicle stage (GV) and in metaphase I (MI) oocytes, as well as in the cumulus cells of immature (CCI) and mature oocytes (CCM), and in leukocytes was measured by qPCR. The telomerase activity in reproductive cells was evaluated by the TRAPeze® XL Kit. The body mass index (p = 0.001), LH (p = 0.015), estradiol (p = 0.004), insulin (p = 0.002), testosterone (p < 0.0001), androstenedione (p = 0.001), free androgen index (p < 0.0001), and c-reactive protein (p = 0.003) were greater, while the FSH (p = 0.0002) was lower in the PCOS group. The telomere length in the CCI (p = 0.649) and CCM (p = 0.378) did not differ between the PCOS and the control groups. On the other hand, telomerase activity in the CCI (p = 0.003) and CCM (p = 0.022) was higher in the PCOS group. In the leukocyte's cells, the telomere length was reduced in the PCOS group (p = 0.025). In the GV and MI oocytes, no differences were observed in telomere length and telomerase activity between the groups. We showed that telomere length is not altered in reproductive cells from PCOS. However, higher telomerase activity in the CCI and CCM may be required for telomere length maintenance.},
}
@article {pmid32046424,
year = {2020},
author = {Colatto, BN and de Souza, IF and Schinke, LAA and Noda-Nicolau, NM and da Silva, MG and Morceli, G and Menon, R and Polettini, J},
title = {Telomere Length and Telomerase Activity in Foetal Membranes from Term and Spontaneous Preterm Births.},
journal = {Reproductive sciences (Thousand Oaks, Calif.)},
volume = {27},
number = {1},
pages = {411-417},
doi = {10.1007/s43032-019-00054-z},
pmid = {32046424},
issn = {1933-7205},
mesh = {Adolescent ; Adult ; Extraembryonic Membranes/*metabolism ; Female ; Fetal Membranes, Premature Rupture/metabolism ; Humans ; Obstetric Labor, Premature/metabolism ; Pregnancy ; Premature Birth/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; Term Birth/*metabolism ; Young Adult ; },
abstract = {The reduction of telomere length, the protective cap structures of chromosomes, is one of the biomarkers of senescence (a mechanism of ageing), and ageing of foetal gestational tissues is associated with both term and preterm parturition. A mechanism regulating telomere length is the activity of telomerase, an enzyme that adds telomere fragments during DNA replication and cell division; however, its role in regulating telomere length is not well studied in gestational tissues. The objective of this study is to correlate telomere length and telomerase activity in foetal membranes from term and spontaneous preterm births. Foetal membrane samples were collected from pregnant women experiencing term labour (TL), term not in labour (TNL), preterm premature rupture of membranes (pPROM) and spontaneous preterm labour (PTL) with intact membranes (n = 20/group). Telomere length and telomerase activity were analyzed by relative quantification (T/S), real-time PCR and PCR-based fluorometric detection, respectively. Data were analyzed by ANOVA or the Kruskal-Wallis test. Demographic variables were not statistically different among the groups. Foetal membranes from the TL group showed telomere length reduction compared with those from the others (p < 0.0002). Telomerase activity did not change in foetal membranes irrespective of pregnancy outcome. Telomere shortening in foetal membranes is suggestive of senescence associated with triggering of labour at term; however, this is likely independent of telomerase activity, while prematurity may be associated with senescence, but due to other mechanisms than telomere length reduction in foetal membranes.},
}
@article {pmid32045948,
year = {2020},
author = {Sousa, CV and Silva Aguiar, S and Deus, LA and Barbosa, LP and Dos Santos, PA and Neves, RVP and Maciel, LA and Moraes, MR and Moreira, SR and Grubert Campbell, CS and Andrade, RV and Dos Santos Rosa, T and Simoes, HG},
title = {Faster and Healthier: Relationship between Telomere and Performance in Master Athletes.},
journal = {International journal of sports medicine},
volume = {41},
number = {5},
pages = {339-344},
doi = {10.1055/a-1088-5279},
pmid = {32045948},
issn = {1439-3964},
mesh = {Adiposity/physiology ; Adult ; Aged ; Aging/*physiology ; Athletic Performance/*physiology ; *Healthy Lifestyle ; Humans ; Inflammation/physiopathology ; Male ; Middle Aged ; Oxidative Stress/physiology ; Physical Conditioning, Human/methods ; Physical Endurance/physiology ; Telomere Shortening/*physiology ; },
abstract = {Aging is associated with increased oxidative stress, chronic inflammation, and decreased telomere length (TL). However, the lifestyle of master athletes can lead to a reduced risk of these conditions, and thus attenuates aging and performance deterioration. We aimed to analyze the relationships between TL and relative performance (RP), and their relation to adiposity, oxidative stress, and inflammation in endurance (END) and sprint/power (SPW) master athletes (MAs). Twenty-two world-class MAs visited the laboratory for anamnesis, anthropometrics, and blood sampling. Inflammatory and oxidative stress parameters were assessed using commercial kits. Relative TL was determined in leukocytes through qPCR analyses. A positive association was observed between RP and TL in both groups (SPW: r=0.641; END: r=0.685) and the whole sample (r=0.594). The IL6/IL10 ratio presented an inverse correlation with RP in the whole sample (r=-0.580). Body mass index also demonstrated a negative correlation with TL for the END group (r=-0.690) and the whole sample analysis (r=-0.455). Moreover, the IL6/IL10 ratio was negatively associated with strength/power training hours (r=-0.464), whereas the CAT/TBARS ratio was negatively associated with aerobic training hours (r=-0.482). In conclusion, TL of MAs was associated with RP regardless of the training model (endurance or sprint/power), and inflammation and adiposity were associated with shorter telomeres.},
}
@article {pmid32045728,
year = {2020},
author = {Wai, KM and Umezaki, M and Umemura, M and Mar, O and Watanabe, C},
title = {Protective role of selenium in the shortening of telomere length in newborns induced by in utero heavy metal exposure.},
journal = {Environmental research},
volume = {183},
number = {},
pages = {109202},
doi = {10.1016/j.envres.2020.109202},
pmid = {32045728},
issn = {1096-0953},
mesh = {Cohort Studies ; Female ; Humans ; Infant, Newborn ; *Metals, Heavy/toxicity ; Myanmar ; Pregnancy ; *Selenium/pharmacology ; Telomere ; *Telomere Shortening ; },
abstract = {The effects of toxic heavy metals, such as arsenic (As), cadmium (Cd), and lead (Pb), on telomere length (TL) have been reported previously. Although selenium (Se) is considered as an anti-oxidant which may detoxify the effects, there are no data on whether Se could protect against the TL-shortening effects of heavy metals. Thus, the aim of this study was to evaluate the protective role of Se against heavy metal-induced TL shortening. A birth cohort study was conducted in Myanmar in 2016, including 408 mother-infant pairs. First, pregnant women in the third trimester were interviewed concerning their socioeconomic, and pregnancy and birth characteristics using a pre-validated questionnaire. Maternal spot urine samples were collected after the interview. During the follow-up period (1-3 months), blood samples were collected from the umbilical cord at birth by local health workers. Metal concentrations were measured using inductively coupled plasma mass spectrometry (ICP-MS). TL was measured by quantitative real-time polymerase chain reaction (PCR). Relative TL was calculated as the ratio of telomere genes to single-copy genes. To evaluate the effect of Se on TL shortening, molar ratios were calculated. Linear regression analyses were performed to examine the associations between heavy metals and TL, individually and after adjustment for Se level. The effects of As, Cd, and Pb exposure on TL were smaller after adjustment for the Se level, especially for Pb (unadjusted β = -0.10; 95% CI: 0.18, -0.01; adjusted β = -0.03; 95% CI: 0.13, 0.05). On stratifying the data by Se concentration, there was no significant association between Cd or Pb exposure and TL in the high-Se group. Our study indicated a protective effect of Se against the TL shortening induced by heavy metal exposure, where the effect sizes were smaller after adjusting for the Se level, compared to individual metal exposure.},
}
@article {pmid32043210,
year = {2020},
author = {Ng, TK and Chen, CB and Xu, C and Xu, Y and Yao, X and Huang, L and Liang, JJ and Cheung, HS and Pang, CP and Huang, Y},
title = {Attenuated regenerative properties in human periodontal ligament-derived stem cells of older donor ages with shorter telomere length and lower SSEA4 expression.},
journal = {Cell and tissue research},
volume = {381},
number = {1},
pages = {71-81},
pmid = {32043210},
issn = {1432-0878},
support = {180918154960752//Special Fund for the Innovative Science and Technology Strategy of Guangdong Province/ ; 2016A030313063//Natural Science Foundation of Guangdong Province/ ; 18-001//Internal grant from the Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong/ ; },
mesh = {Adult ; *Age Factors ; Cell Proliferation ; Cells, Cultured ; Chronic Periodontitis/*therapy ; Female ; Guided Tissue Regeneration, Periodontal ; Humans ; Interleukin-6/metabolism ; Interleukin-8/metabolism ; Male ; Osteogenesis ; Periodontal Ligament/*cytology ; Stage-Specific Embryonic Antigens/*metabolism ; Stem Cells/*cytology ; Telomere/*ultrastructure ; Young Adult ; },
abstract = {Periodontal ligament (PDL) stem cell properties are critical in the periodontal tissue regeneration for periodontitis. Previously, we have demonstrated that cigarette smoking attenuates PDL-derived stem cell (PDLSC) regenerative properties. Here, we report the findings on the regenerative properties of human PDLSCs with different donor ages and the underlying mechanisms. Human PDLSCs from 18 independent donors were divided into different age groups (≤ 20, 20-40, and > 40 years old). The proliferation of PDLSCs with donor age of ≤ 20 years old was significantly higher than that of the 20-40- and > 40-years-old groups, whereas the migration of PDLSCs with donor age of ≤ 20 and 20-40 years old was significantly higher than that of the > 40-years-old group. Moreover, the mesodermal lineage differentiation capabilities of PDLSCs were also higher in the donor age group of ≤ 20 years old than the donor age of > 40 years old. In addition, shorter telomere length and lower expression of SSEA4 were found in PDLSCs with donor age of > 40 years old, compared with those with donor age of ≤ 20-years-old group. Besides, PDLSCs with donor age of 20-40 and > 40 years old had higher IL6 and CXCL8 gene expressions. In summary, results from this study revealed the attenuated proliferation, migration, and mesodermal lineage differentiation properties in human PDLSCs with older donor ages. Donor age of PDLSCs should be considered as the selection criteria for the periodontal tissue regeneration treatment.},
}
@article {pmid32041072,
year = {2020},
author = {Karimi, B and Nabizadeh Nodehi, R and Yunesian, M},
title = {Serum level of PCBs and OCPs and leukocyte telomere length among adults in Tehran, Iran.},
journal = {Chemosphere},
volume = {248},
number = {},
pages = {126092},
doi = {10.1016/j.chemosphere.2020.126092},
pmid = {32041072},
issn = {1879-1298},
mesh = {Adult ; Cross-Sectional Studies ; Female ; Humans ; Hydrocarbons, Chlorinated/*blood ; Iran ; Leukocytes/*drug effects/ultrastructure ; Male ; Pesticides/*blood ; Polychlorinated Biphenyls/*blood ; Random Allocation ; Telomere/*drug effects/ultrastructure ; Telomere Shortening/*drug effects ; Young Adult ; },
abstract = {Exposure to polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) may change leukocyte telomere length (TL) at the end of the DNA sequence. The purpose of this study was to investigate the association between PCBs and OCPs exposure with TL in Tehran adult males. Whole-blood samples were randomly taken from three hundred adult males in population-based cross-section study from October 2016 to November 2017. We studied the serum levels of PCBs, OCPs as well as socio-demographic characteristics of individuals. The quantitative PCR was used to investigate the number of the telomere (T) repeats to the number of a single copy gene. We measured the effect of each PCBs and OCPs congeners on TL using linear regressions adjusted for age, BMI, smoking, and dietary patterns. The median level of the six non-dioxin-likes, five dioxin-likes PCBs three OCPs and TL in the study population were 344.5, 306.0, 45.0 ng/g lipid and 5377.7 ± 573.4 base pairs, respectively. In the adjusted model, the percent difference in the TLs with exposure to Σnon-dioxin-like PCBs, Σdioxin-like PCBs, and OCPs were 1.93 (-0.70 to 5.4), 3.4 (1.8-8.3) and -2.4 (-0.80 to -6.2), respectively. In the fourth quartile compared to the first quartile, the percent difference in the TLs due to Σnon-dioxin-like PCBs, Σdioxin-like PCBs, and OCP exposure were 0.01 (-0.01 to 0.05), 10.3 (2.9-18.1) and -0.20 (-0.10 to -4.5), respectively. Exposures to ndl-PCBs and dl-PCBs (except for PCB28) were related to longer TLs, but OCPs exposure can be related to telomere shortening.},
}
@article {pmid32039800,
year = {2020},
author = {Pańczyszyn, A and Boniewska-Bernacka, E and Głąb, G},
title = {Telomere length in leukocytes and cervical smears of women with high-risk human papillomavirus (HR HPV) infection.},
journal = {Taiwanese journal of obstetrics &amp; gynecology},
volume = {59},
number = {1},
pages = {51-55},
doi = {10.1016/j.tjog.2019.11.007},
pmid = {32039800},
issn = {1875-6263},
mesh = {Adult ; Case-Control Studies ; Cervix Uteri/virology ; Early Detection of Cancer/methods ; Female ; Humans ; Leukocytes/*virology ; Papanicolaou Test ; Papillomaviridae/*genetics ; Papillomavirus Infections/blood/complications/*virology ; Risk Assessment ; Telomere/*pathology ; Uterine Cervical Neoplasms/virology ; *Vaginal Smears ; },
abstract = {OBJECTIVE: Persistent high-risk HPV (HR HPV) infection leads to the development of squamous intraepithelial lesions, which in turn may progress to cervical cancer. Telomere elongation or shortening may indicate a carcinogenesis process. In the present study, we analyzed telomere length from blood and cervical smears of women without and with high-risk HPV infection.<br><br>MATERIALS AND METHODS: Telomere length was quantified by real-time PCR in blood and cervical smears from 48 women with high-risk HPV infection and HGSIL or LGSIL, 29 women HR-HPV positive without SIL, and 11 HPV-negative women.<br><br>RESULTS: No correlation was found between age and telomere length in blood and cervical smears. Women with high-risk HPV infection had shorter telomeres in cervical smears, but not in blood compared to the control group.<br><br>CONCLUSION: These findings suggest that telomere shortening occurs in cervical cells of women with HR HPV infection both with LGSIL and HGSIL and may indicate the onset of carcinogenesis. In turn, there is no correlation between leukocyte telomere length and cervical cancer risk in women with HR HPV infection.},
}
@article {pmid32039009,
year = {2019},
author = {Kent, T and Gracias, D and Shepherd, S and Clynes, D},
title = {Alternative Lengthening of Telomeres in Pediatric Cancer: Mechanisms to Therapies.},
journal = {Frontiers in oncology},
volume = {9},
number = {},
pages = {1518},
pmid = {32039009},
issn = {2234-943X},
abstract = {Achieving replicative immortality is a crucial step in tumorigenesis and requires both bypassing cell cycle checkpoints and the extension of telomeres, sequences that protect the distal ends of chromosomes during replication. In the majority of cancers this is achieved through the enzyme telomerase, however a subset of cancers instead utilize a telomerase-independent mechanism of telomere elongation-the Alternative Lengthening of Telomeres (ALT) pathway. Recent work has aimed to decipher the exact mechanism that underlies this pathway. To this end, this pathway has now been shown to extend telomeres through exploitation of DNA repair machinery in a unique process that may present a number of druggable targets. The identification of such targets, and the subsequent development or repurposing of therapies to these targets may be crucial to improving the prognosis for many ALT-positive cancers, wherein mean survival is lower than non-ALT counterparts and the cancers themselves are particularly unresponsive to standard of care therapies. In this review we summarize the recent identification of many aspects of the ALT pathway, and the therapies that may be employed to exploit these new targets.},
}
@article {pmid32034293,
year = {2020},
author = {Dai, W and Wu, J and Wang, D and Wang, J},
title = {Cancer gene therapy by NF-κB-activated cancer cell-specific expression of CRISPR/Cas9 targeting telomeres.},
journal = {Gene therapy},
volume = {27},
number = {6},
pages = {266-280},
pmid = {32034293},
issn = {1476-5462},
mesh = {Animals ; *CRISPR-Cas Systems/genetics ; Genes, Neoplasm ; Humans ; Mice ; NF-kappa B/genetics/metabolism ; *Neoplasms/genetics/therapy ; Telomere/metabolism ; },
abstract = {The transcription factor NF-κB is an attractive target for cancer therapy due to its over-activation in all tumours; however, NF-κB inhibitors developed in the past decades rarely became drugs due to undesirable side effects. In this study, we developed a gene therapy strategy named NF-κB-activated gene expression (Nage), which could induce the death of cancer cells in vitro and in vivo by utilising NF-κB over-activity in cancer cells, but had no effects on normal cells. Nage was consisted of an NF-κB-specific promoter formed by fusing an NF-κB decoy sequence with a minimal promoter, which could be bound by the intracellular over-activated NF-κB and thus activated the expression of downstream effector genes in an NF-κB-specific manner. In this study, we first confirmed the cancer cell-specific over-activation of NF-κB and then tested the cancer cell specificity of the Nage vector by expressing the reporter gene ZsGreen in various in vitro cultivated cells. We next demonstrated that the Nage vector could be used to express CRISPR/Cas9 protein only in cancer cells. The Cas9 protein was then guided by a sgRNA targeting telomeric DNA and induced cancer cell death. The Nage vector expressing Cas9/sgRNA could be packaged into adeno-associated virus (AAV) and intravenously injected to inhibit tumour growth in mice without visible side effects and toxicity.},
}
@article {pmid32033737,
year = {2020},
author = {Barlow, DH},
title = {Telomere length and its assessment for female reproduction.},
journal = {Fertility and sterility},
volume = {113},
number = {1},
pages = {91-92},
doi = {10.1016/j.fertnstert.2019.10.021},
pmid = {32033737},
issn = {1556-5653},
mesh = {*Cumulus Cells ; Female ; Humans ; Leukocytes ; Reproduction ; *Telomere ; Telomere Homeostasis ; },
}
@article {pmid32033110,
year = {2020},
author = {Amir, M and Khan, P and Queen, A and Dohare, R and Alajmi, MF and Hussain, A and Islam, A and Ahmad, F and Hassan, I},
title = {Structural Features of Nucleoprotein CST/Shelterin Complex Involved in the Telomere Maintenance and Its Association with Disease Mutations.},
journal = {Cells},
volume = {9},
number = {2},
pages = {},
pmid = {32033110},
issn = {2073-4409},
mesh = {Animals ; Disease/*genetics ; Humans ; Models, Biological ; Mutation/*genetics ; Nucleoproteins/*chemistry ; Shelterin Complex ; *Telomere Homeostasis ; Telomere-Binding Proteins/*chemistry ; },
abstract = {Telomere comprises the ends of eukaryotic linear chromosomes and is composed of G-rich (TTAGGG) tandem repeats which play an important role in maintaining genome stability, premature aging and onsets of many diseases. Majority of the telomere are replicated by conventional DNA replication, and only the last bit of the lagging strand is synthesized by telomerase (a reverse transcriptase). In addition to replication, telomere maintenance is principally carried out by two key complexes known as shelterin (TRF1, TRF2, TIN2, RAP1, POT1, and TPP1) and CST (CDC13/CTC1, STN1, and TEN1). Shelterin protects the telomere from DNA damage response (DDR) and regulates telomere length by telomerase; while, CST govern the extension of telomere by telomerase and C strand fill-in synthesis. We have investigated both structural and biochemical features of shelterin and CST complexes to get a clear understanding of their importance in the telomere maintenance. Further, we have analyzed ~115 clinically important mutations in both of the complexes. Association of such mutations with specific cellular fault unveils the importance of shelterin and CST complexes in the maintenance of genome stability. A possibility of targeting shelterin and CST by small molecule inhibitors is further investigated towards the therapeutic management of associated diseases. Overall, this review provides a possible direction to understand the mechanisms of telomere borne diseases, and their therapeutic intervention.},
}
@article {pmid32026548,
year = {2020},
author = {Pérez-Martínez, L and Öztürk, M and Butter, F and Luke, B},
title = {Npl3 stabilizes R-loops at telomeres to prevent accelerated replicative senescence.},
journal = {EMBO reports},
volume = {21},
number = {3},
pages = {e49087},
pmid = {32026548},
issn = {1469-3178},
support = {Bu2996/1-2//Deutsche Forschungsgemeinschaft (DFG)/International ; LU1709/2-1//Deutsche Forschungsgemeinschaft (DFG)/International ; //Impulse Fonds of the state of Rheinland Palatinate/International ; },
mesh = {Cellular Senescence/genetics ; Proteomics ; *R-Loop Structures ; *Telomere/genetics ; Telomere Shortening ; },
abstract = {Telomere shortening rates must be regulated to prevent premature replicative senescence. TERRA R-loops become stabilized at critically short telomeres to promote their elongation through homology-directed repair (HDR), thereby counteracting senescence onset. Using a non-bias proteomic approach to detect telomere binding factors, we identified Npl3, an RNA-binding protein previously implicated in multiple RNA biogenesis processes. Using chromatin immunoprecipitation and RNA immunoprecipitation, we demonstrate that Npl3 interacts with TERRA and telomeres. Furthermore, we show that Npl3 associates with telomeres in an R-loop-dependent manner, as changes in R-loop levels, for example, at short telomeres, modulate the recruitment of Npl3 to chromosome ends. Through a series of genetic and biochemical approaches, we reveal that Npl3 binds to TERRA and stabilizes R-loops at short telomeres, which in turn promotes HDR and prevents premature replicative senescence onset. This may have implications for diseases associated with excessive telomere shortening.},
}
@article {pmid32025863,
year = {2020},
author = {Prabu, P and Poongothai, S and Shanthirani, CS and Anjana, RM and Mohan, V and Balasubramanyam, M},
title = {Altered circulatory levels of miR-128, BDNF, cortisol and shortened telomeres in patients with type 2 diabetes and depression.},
journal = {Acta diabetologica},
volume = {57},
number = {7},
pages = {799-807},
pmid = {32025863},
issn = {1432-5233},
support = {Extramural Research Grant//Indian Council of Medical Research (IN)/ ; },
mesh = {Adult ; Biomarkers/blood ; Brain-Derived Neurotrophic Factor/*blood ; Cardiovascular System/physiopathology ; Case-Control Studies ; Depression/*blood/complications ; Diabetes Mellitus, Type 2/*blood/complications/psychology ; Female ; Humans ; Hydrocortisone/*blood ; India ; Insulin Resistance ; Male ; MicroRNAs/*blood ; Middle Aged ; Telomere Shortening/*physiology ; },
abstract = {AIMS: Several studies have reported the role of biomarkers either in diabetes or depression. The present study is aimed at profiling the circulating levels of miR-128, brain-derived neurotrophic factor (BDNF), cortisol and telomere length in patients with type 2 diabetes with and without depression compared to individuals with normal glucose tolerance.<br><br>METHODS: Study subjects (n&#x2009;=&#x2009;160) were recruited from an ongoing epidemiological study in southern India. Non-diabetic and diabetic individuals were diagnosed as per the World Health Organization criteria. Depression score was derived using PHQ-12 questionnaire. Real-time quantitative PCR and ELISA methodologies were used to quantify the biomarkers.<br><br>RESULTS: Circulatory levels of miR-128 and cortisol were significantly (p&#x2009;<&#x2009;0.05) increased with decreased BDNF levels and shortened telomeres in T2DM patients with or without depression compared to NGT individuals. T2DM patients with depression had the highest levels of miR-128 and cortisol and lowest levels of BDNF and telomere length compared to other groups. Pearson correlation analysis showed miR-128 levels were negatively associated with BDNF, telomere length and HDL cholesterol and positively correlated with cortisol, depression score, poor glycemic control and insulin resistance. Regression analysis confirmed that miR-128 was significantly associated with depression score even after adjusted for several confounding factors. However, this association was lost when adjusted for cortisol or telomere length.<br><br>CONCLUSIONS: Patients with type 2 diabetes and depression exhibited increased circulatory levels of miR-128 and serum cortisol and decreased levels of BDNF and shortened telomeres. These neuroendocrine signatures were more markedly altered in those with combined diabetes and depression.},
}
@article {pmid32024817,
year = {2020},
author = {Sieverling, L and Hong, C and Koser, SD and Ginsbach, P and Kleinheinz, K and Hutter, B and Braun, DM and Cortés-Ciriano, I and Xi, R and Kabbe, R and Park, PJ and Eils, R and Schlesner, M and , and Brors, B and Rippe, K and Jones, DTW and Feuerbach, L and , },
title = {Genomic footprints of activated telomere maintenance mechanisms in cancer.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {733},
pmid = {32024817},
issn = {2041-1723},
support = {R01 CA095175/CA/NCI NIH HHS/United States ; R01 CA218112/CA/NCI NIH HHS/United States ; R01 CA217991/CA/NCI NIH HHS/United States ; R35 GM127029/GM/NIGMS NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; },
mesh = {Case-Control Studies ; Co-Repressor Proteins/genetics ; Genome, Human ; Humans ; Molecular Chaperones/genetics ; *Mutation ; Neoplasms/*genetics ; RNA, Long Noncoding ; Repetitive Sequences, Nucleic Acid ; Telomerase/genetics ; Telomere/*genetics ; Whole Genome Sequencing ; X-linked Nuclear Protein/genetics ; },
abstract = {Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXX[trunc]) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXX[trunc] tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer.},
}
@article {pmid32023455,
year = {2020},
author = {Chen, L and Roake, CM and Galati, A and Bavasso, F and Micheli, E and Saggio, I and Schoeftner, S and Cacchione, S and Gatti, M and Artandi, SE and Raffa, GD},
title = {Loss of Human TGS1 Hypermethylase Promotes Increased Telomerase RNA and Telomere Elongation.},
journal = {Cell reports},
volume = {30},
number = {5},
pages = {1358-1372.e5},
pmid = {32023455},
issn = {2211-1247},
support = {R01 AG056575/AG/NIA NIH HHS/United States ; R35 CA197563/CA/NCI NIH HHS/United States ; T32 GM007365/GM/NIGMS NIH HHS/United States ; },
mesh = {Biocatalysis ; Coiled Bodies/metabolism ; Guanosine/metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Methylation ; Methyltransferases/*deficiency/genetics ; Models, Biological ; Mutation/genetics ; Polyadenylation ; RNA/*metabolism ; RNA Caps/metabolism ; Subcellular Fractions/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Biogenesis of the human telomerase RNA (hTR) involves a complex series of posttranscriptional modifications, including hypermethylation of the 5' mono-methylguanosine cap to a tri-methylguanosine cap (TMG). How the TMG cap affects hTR maturation is unknown. Here, we show that depletion of trimethylguanosine synthase 1 (TGS1), the enzyme responsible for cap hypermethylation, increases levels of hTR and telomerase. Diminished trimethylation increases hTR association with the cap-binding complex (CBC) and with Sm chaperone proteins. Loss of TGS1 causes an increase in accumulation of mature hTR in both the nucleus and the cytoplasm compared with controls. In TGS1 mutant cells, increased hTR assembles with telomerase reverse transcriptase (TERT) protein to yield elevated active telomerase complexes and increased telomerase activity, resulting in telomere elongation in cultured human cells. Our results show that TGS1-mediated hypermethylation of the hTR cap inhibits hTR accumulation, restrains levels of assembled telomerase, and limits telomere elongation.},
}
@article {pmid32012161,
year = {2020},
author = {Epum, EA and Mohan, MJ and Ruppe, NP and Friedman, KL},
title = {Interaction of yeast Rad51 and Rad52 relieves Rad52-mediated inhibition of de novo telomere addition.},
journal = {PLoS genetics},
volume = {16},
number = {2},
pages = {e1008608},
pmid = {32012161},
issn = {1553-7404},
support = {R01 GM123292/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Breaks, Double-Stranded ; Gene Knockout Techniques ; Mutation ; Protein Binding/genetics ; Rad51 Recombinase/genetics/*metabolism ; Rad52 DNA Repair and Recombination Protein/genetics/*metabolism ; *Recombinational DNA Repair ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {DNA double-strand breaks (DSBs) are toxic forms of DNA damage that must be repaired to maintain genome integrity. Telomerase can act upon a DSB to create a de novo telomere, a process that interferes with normal repair and creates terminal deletions. We previously identified sequences in Saccharomyces cerevisiae (SiRTAs; Sites of Repair-associated Telomere Addition) that undergo unusually high frequencies of de novo telomere addition, even when the original chromosome break is several kilobases distal to the eventual site of telomerase action. Association of the single-stranded telomere binding protein Cdc13 with a SiRTA is required to stimulate de novo telomere addition. Because extensive resection must occur prior to Cdc13 binding, we utilized these sites to monitor the effect of proteins involved in homologous recombination. We find that telomere addition is significantly reduced in the absence of the Rad51 recombinase, while loss of Rad52, required for Rad51 nucleoprotein filament formation, has no effect. Deletion of RAD52 suppresses the defect of the rad51Δ strain, suggesting that Rad52 inhibits de novo telomere addition in the absence of Rad51. The ability of Rad51 to counteract this effect of Rad52 does not require DNA binding by Rad51, but does require interaction between the two proteins, while the inhibitory effect of Rad52 depends on its interaction with Replication Protein A (RPA). Intriguingly, the genetic interactions we report between RAD51 and RAD52 are similar to those previously observed in the context of checkpoint adaptation. Forced recruitment of Cdc13 fully restores telomere addition in the absence of Rad51, suggesting that Rad52, through its interaction with RPA-coated single-stranded DNA, inhibits the ability of Cdc13 to bind and stimulate telomere addition. Loss of the Rad51-Rad52 interaction also stimulates a subset of Rad52-dependent microhomology-mediated repair (MHMR) events, consistent with the known ability of Rad51 to prevent single-strand annealing.},
}
@article {pmid32009007,
year = {2020},
author = {Dolcini, J and Wu, H and Nwanaji-Enwerem, JC and Kiomourtozlogu, MA and Cayir, A and Sanchez-Guerra, M and Vokonas, P and Schwarz, J and Baccarelli, AA},
title = {Mitochondria and aging in older individuals: an analysis of DNA methylation age metrics, leukocyte telomere length, and mitochondrial DNA copy number in the VA normative aging study.},
journal = {Aging},
volume = {12},
number = {3},
pages = {2070-2083},
pmid = {32009007},
issn = {1945-4589},
support = {P30 ES009089/ES/NIEHS NIH HHS/United States ; R01 ES021733/ES/NIEHS NIH HHS/United States ; R01 ES025225/ES/NIEHS NIH HHS/United States ; R01 ES027747/ES/NIEHS NIH HHS/United States ; },
mesh = {Aged ; Aging/*genetics/metabolism ; Alcohol Drinking ; Body Mass Index ; Coronary Disease ; *DNA Methylation ; DNA, Mitochondrial/*metabolism ; Diabetes Mellitus ; Genome, Mitochondrial ; Humans ; Hypertension ; Leukocytes/metabolism ; Male ; Overweight ; Smoking ; Telomere/*metabolism ; United States ; Veterans ; },
abstract = {Population aging is a looming global health challenge. New biological aging metrics based on DNA methylation levels have been developed in addition to traditional aging biomarkers. The prospective relationships of aging biomarkers with mitochondrial changes are still not well understood. Here, we examined the prospective associations of mitochondrial copy number (mtDNAcn) with several aging biomarkers - DNAm-Age, DNAm-PhenoAge, DNAm-GrimAge, and leukocyte telomere length. We analyzed 812 individuals from Veteran Affairs Normative Aging Study (NAS) with available blood samples from 1999-2013. Whole blood mtDNAcn and relative leukocyte telomere length were measured via qPCR. DNA methylation was assessed and used to calculate DNAm-Age, DNAm-GrimAge, and DNAm-PhenoAge. Linear mixed models were used to quantify the associations of mtDNAcn with DNAm-Age, DNAm-GrimAge, DNAm-PhenoAge, and leukocyte telomere length. In multivariable cross-sectional analyses, mtDNAcn is negatively associated with DNAm-Age PhenoAge and DNAm-PhenoAge. In contrast, mtDNAcn is associated with prospective measures of higher DNAm-PhenoAge and shorter leukocyte telomere length. Our study shows that higher mtDNAcn is associated with prospective measures of greater DNAm-PhenoAge and shorter leukocyte telomere length independent of chronological age. This indicates a role for mitochondrial in aging-related disease and mortality, but not the departure of biological age from chronological age.},
}
@article {pmid32007334,
year = {2020},
author = {Morell-Azanza, L and Ojeda-Rodríguez, A and Azcona-SanJulián, MC and Zalba, G and Marti, A},
title = {Associations of telomere length with anthropometric and glucose changes after a lifestyle intervention in abdominal obese children.},
journal = {Nutrition, metabolism, and cardiovascular diseases : NMCD},
volume = {30},
number = {4},
pages = {694-700},
doi = {10.1016/j.numecd.2019.12.002},
pmid = {32007334},
issn = {1590-3729},
mesh = {*Adiposity ; Adolescent ; Age Factors ; Biomarkers/blood ; Blood Glucose/*metabolism ; Body Mass Index ; Caloric Restriction ; Child ; Diet, Healthy ; Diet, Mediterranean ; Exercise ; Female ; *Healthy Lifestyle ; Humans ; Male ; Obesity, Abdominal/blood/genetics/physiopathology/*therapy ; Pediatric Obesity/blood/genetics/physiopathology/*therapy ; *Risk Reduction Behavior ; Spain ; *Telomere Homeostasis ; *Telomere Shortening ; Time Factors ; Treatment Outcome ; Waist Circumference ; Weight Loss ; },
abstract = {BACKGROUND AND AIMS: In lifestyle intervention studies, we demonstrated that changes in telomere length (TL) were associated with changes in anthropometric indices. Therefore, our new hypothesis is that TL could be a predictor of changes in anthropometric or metabolic measures in children with abdominal obesity. The aim of the study was to evaluate the association between anthropometric and biochemical measurements with TL before and after an 8-week lifestyle intervention in children with abdominal obesity (7-16 years old).<br><br>METHODS AND RESULTS: We assessed anthropometric and biochemical outcomes at baseline and after 8-week lifestyle intervention in 106 children with abdominal obesity (11.30&#xa0;&#xb1;&#xa0;2.49 years old, 63% girls). TL was measured by monochrome multiplex real-time quantitative PCR. After the lifestyle intervention, anthropometric parameters and glucose metabolism indicators significantly improved in the participants. TL did not change after the intervention in participants. Significant negative correlations between baseline TL and anthropometric measures (BMI, body weight and waist circumference) were observed. Furthermore, baseline TL was a predictor for changes in blood glucose levels after the lifestyle intervention.<br><br>CONCLUSIONS: An inverse correlation between TL and obesity traits was observed in children with abdominal obesity. Interestingly, we found that baseline TL could predict changes in blood glucose levels.<br><br>CLINICAL TRIAL: NCT03147261. Registered 10 May 2017.},
}
@article {pmid32006886,
year = {2020},
author = {Grunst, ML and Grunst, AS and Pinxten, R and Eens, M},
title = {Anthropogenic noise is associated with telomere length and carotenoid-based coloration in free-living nestling songbirds.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {260},
number = {},
pages = {114032},
doi = {10.1016/j.envpol.2020.114032},
pmid = {32006886},
issn = {1873-6424},
mesh = {Animals ; Carotenoids ; Humans ; *Noise ; *Passeriformes ; *Songbirds ; Telomere ; },
abstract = {Growing evidence suggests that anthropogenic noise has deleterious effects on the behavior and physiology of free-living animals. These effects may be particularly pronounced early in life, when developmental trajectories are sensitive to stressors, yet studies investigating developmental effects of noise exposure in free-living populations remain scarce. To elucidate the effects of noise exposure during development, we examined whether noise exposure is associated with shorter telomeres, duller carotenoid-based coloration and reduced body mass in nestlings of a common urban bird, the great tit (Parus major). We also assessed how the noise environment is related to reproductive success. We obtained long-term measurements of the noise environment, over a ∼24-h period, and characterized both the amplitude (measured by LAeq, LA90, LA10, LAmax) and variance in noise levels, since more stochastic, as well as louder, noise regimes might be more likely to induce stress. In our urban population, noise levels varied substantially, with louder, but less variable, noise characteristic of areas adjacent to a highway. Noise levels were also highly repeatable, suggesting that individuals experience consistent differences in noise exposure. The amplitude of noise near nest boxes was associated with shorter telomeres among smaller, but not larger, brood members. In addition, carotenoid chroma and hue were positively associated with variance in average and maximum noise levels, and average reflectance was negatively associated with variance in background noise. Independent of noise, hue was positively related to telomere length. Nestling mass and reproductive success were unaffected by noise exposure. Results indicate that multiple dimensions of the noise environment, or factors associated with the noise environment, could affect the phenotype of developing organisms, that noise exposure, or correlated variables, might have the strongest effects on sensitive groups of individuals, and that carotenoid hue could serve as a signal of early-life telomere length.},
}
@article {pmid32004962,
year = {2020},
author = {Duan, X and Yang, Y and Wang, S and Feng, X and Wang, T and Wang, P and Ding, M and Zhang, H and Liu, B and Wei, W and Yao, W and Cui, L and Zhou, X and Wang, W},
title = {Dose-related telomere damage associated with the genetic polymorphisms of cGAS/STING signaling pathway in the workers exposed by PAHs.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {260},
number = {},
pages = {113995},
doi = {10.1016/j.envpol.2020.113995},
pmid = {32004962},
issn = {1873-6424},
mesh = {Coke ; DNA Damage ; Humans ; Nucleotidyltransferases ; *Occupational Exposure ; *Polycyclic Aromatic Hydrocarbons ; Polymorphism, Genetic ; Pyrenes ; Signal Transduction ; Telomere/drug effects ; },
abstract = {Telomeres are located at the end of eukaryotic chromosomes and vulnerable to exogenous chemical compounds. Exposure to coke oven emissions (COEs) leads to a dose-related telomere damage, and such chromosomal damage might trigger the cGAS/STING signaling pathway which plays an important role in immune surveillance. However, the relationship between the genetic variations in the cGAS/STING signaling pathway and telomere damage in the COEs-exposure workers has not been investigated. Therefore, we recruited 544 coke oven workers and 238 healthy control participants, and determined the level of COEs exposure, concentration of urinary 1-hydroxypyrene (1-OHPYR), genetic polymorphisms and telomere length. The results showed that the telomere length significantly decreased from the control-to high-exposure groups as defined by the external exposure level (P < 0.05). The results also indicated that STING rs7447927 CC, cGAS rs34413328 AA, and cGAS rs610913 AA could inhibit telomere shortening in the exposure group (P < 0.05), and cGAS rs34413328, urine 1-OHPYR and cumulative exposure dose (CED) had a significant association with telomere length by generalized linear model. In conclusion, telomere shortening was a combined consequence of short-term exposure, long-term exposure, and genetic variations among the COEs-exposure workers.},
}
@article {pmid32000334,
year = {2020},
author = {Osorio-Yáñez, C and Clemente, DBP and Maitre, L and Vives-Usano, M and Bustamante, M and Martinez, D and Casas, M and Alexander, J and Thomsen, C and Chatzi, L and Gützkow, KB and Grazuleviciene, R and Martens, DS and Plusquin, M and Slama, R and McEachan, RC and Wright, J and Yang, TC and Urquiza, J and Tamayo, I and Sunyer, J and Vafeiadi, M and Nawrot, TS and Vrijheid, M},
title = {Early life tobacco exposure and children's telomere length: The HELIX project.},
journal = {The Science of the total environment},
volume = {711},
number = {},
pages = {135028},
doi = {10.1016/j.scitotenv.2019.135028},
pmid = {32000334},
issn = {1879-1026},
support = {MR/N024397/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Child ; Child, Preschool ; Cohort Studies ; Cotinine ; Female ; Humans ; Pregnancy ; Telomere ; *Nicotiana ; Tobacco Smoke Pollution ; },
abstract = {Telomere length and mitochondrial DNA content are considered biomarkers of cellular aging, oxidative stress, and inflammation, but there is almost no information on their association with tobacco smoke exposure in fetal and early life. The aim of this study was to assess whether prenatal and childhood tobacco exposure were associated with leukocyte telomere length (LTL) and mitochondrial DNA (mtDNA) content in children. As part of a multi-centre European birth cohort study HELIX (Human Early-Life Exposome) (n = 1396) we assessed maternal smoking status during pregnancy through questionnaires, and through urinary cotinine levels that were then used to classify women as not exposed to smoking (<10 µg/L), exposed to secondhand smoke (SHS) (10-50 µg/L) and active smokers (>50 µg/L). When the children were around 8 years of age (range: 5.4-12.0 years), childhood SHS tobacco smoke exposure was assessed through an extensive questionnaire and through measurements of urinary cotinine (<3.03 µg/L non-detected, >3.03 µg/L detected). Leukocyte mtDNA content and LTL were measured in the children at 8 years employing real time polymerase chain reaction (qPCR). Effect estimates were calculated using multivariate linear regression models for prenatal and childhood exposures adjusted for potential confounders. Maternal cotinine levels indicative of SHS exposure during pregnancy were associated with a decrease of 3.90% in LTL in children (95% CI: -6.68, -0.91), compared with non-smoking, whereas the association for maternal cotinine levels indicative of active smoking did not reach statistical significance (-3.24%; 95% CI: -6.59, 0.21). Childhood SHS tobacco exposure was not associated with LTL in children. Global SHS exposure during childhood was associated with an increase of 3.51% (95% CI: 0.78, 6.27) in mtDNA content. Our findings suggest that tobacco smoke exposure during pregnancy, even at SHS levels, may accelerate telomere shortening in children and thus induce biological aging from an early age.},
}
@article {pmid32000015,
year = {2020},
author = {Lorke, M and Willen, M and Lucas, K and Schille, JT and Lüder Ripoli, F and Willenbrock, S and Beyerbach, M and Wefstaedt, P and Murua Escobar, H and Nolte, I},
title = {Effect of antioxidants, mitochondrial cofactors and omega-3 fatty acids on telomere length and kinematic joint mobility in young and old shepherd dogs - A randomized, blinded and placebo-controlled study.},
journal = {Research in veterinary science},
volume = {129},
number = {},
pages = {137-153},
doi = {10.1016/j.rvsc.2020.01.008},
pmid = {32000015},
issn = {1532-2661},
mesh = {Aging/*physiology ; Animals ; Antioxidants/*pharmacology ; Diet/veterinary ; Dietary Supplements ; Dogs ; Double-Blind Method ; Fatty Acids, Omega-3/*pharmacology ; Mitochondria/*metabolism ; Oxidative Stress ; Shoulder Joint/*physiology ; Stifle ; Telomere/drug effects ; Telomere Homeostasis/*drug effects ; Telomere Shortening ; },
abstract = {In dogs, decreasing telomere length is a biomarker for cellular aging. On a systemic level, aging affects the locomotor system in particular, leading to restricted joint mobility. As aging is thought to be related to oxidative stress, it may be counteracted by a diet enriched with antioxidants, mitochondrial cofactors and omega-3 fatty acids. This randomized, blinded and placebo-controlled study examined the influence of an accordingly enriched diet compared to a control diet on 36 young and 38 old shepherd dogs. At the outset, after 3 and after 6 months, mean and minimum telomere lengths were measured. Furthermore, minimum and maximum joint angles and range of motion of the shoulder, elbow, carpal, hip, stifle and tarsal joints were measured by computer-assisted gait analysis. A positive influence of the enriched diet on old dogs could be verified for minimum telomere length and all three parameters of the shoulder joint on the side with the higher vertical ground reaction force after 6 months. In the other joints there were less significant differences; in some cases they indicated a contrary influence of the enriched diet on young dogs, probably due to its reduced protein content. The greater effect of the enriched diet on minimum than on mean telomere length may be due to the higher preference of telomerase for short telomeres. The greater effect on shoulder joint mobility is explained by the greater influence of musculature and connective tissue in this joint. For elderly dogs it is advisable to feed these nutritional supplements.},
}
@article {pmid31998853,
year = {2019},
author = {Yeh, JK and Lin, MH and Wang, CY},
title = {Telomeres as Therapeutic Targets in Heart Disease.},
journal = {JACC. Basic to translational science},
volume = {4},
number = {7},
pages = {855-865},
pmid = {31998853},
issn = {2452-302X},
abstract = {Telomeres are double-stranded repeats of G-rich tandem DNA sequences that gradually shorten with each cell division. Aging, inflammation, and oxidative stress accelerate the process of telomere shortening. Telomerase counteracts this process by maintaining and elongating the telomere length. Patients with atherosclerotic diseases and cardiovascular risk factors (e.g., smoking, obesity, sedentary lifestyle, and hypertension) have shorter leukocyte telomere length. Following myocardial infarction, telomerase expression and activity in cardiomyocytes and endothelial cells increase significantly, implying that telomerase plays a role in regulating tissue repairs in heart diseases. Although previous studies have focused on the changes of telomeres in heart diseases and the telomere length as a marker for aging cardiovascular systems, recent studies have explored the potential of telomeres and telomerase in the treatment of cardiovascular diseases. This review discusses the significant advancements of telomere therapeutics in gene therapy, atherosclerosis, anti-inflammation, and immune modulation in patients with cardiovascular diseases.},
}
@article {pmid31998659,
year = {2019},
author = {Ramirez, JL},
title = {An Evolutionary View of Trypanosoma Cruzi Telomeres.},
journal = {Frontiers in cellular and infection microbiology},
volume = {9},
number = {},
pages = {439},
pmid = {31998659},
issn = {2235-2988},
mesh = {Animals ; Base Sequence ; DNA, Protozoan ; *Evolution, Molecular ; Genes, Protozoan/genetics ; Genome, Protozoan ; Glycoproteins ; Humans ; Multigene Family ; Neuraminidase ; Protozoan Proteins/genetics ; Retroelements ; Telomere/*genetics ; Trypanosoma brucei brucei/genetics ; Trypanosoma cruzi/*genetics ; },
abstract = {Like in most eukaryotes, the linear chromosomes of Trypanosoma cruzi end in a nucleoprotein structure called the telomere, which is preceded by regions of variable length called subtelomeres. Together telomeres and subtelomeres are dynamic sites where DNA sequence rearrangements can occur without compromising essential interstitial genes or chromosomal synteny. Good examples of subtelomeres involvement are the expansion of human olfactory receptors genes, variant surface antigens in Trypanosoma brucei, and Saccharomyces cerevisiae mating types. T. cruzi telomeres are made of long stretches of the hexameric repeat 5'-TTAGGG-OH-3', and its subtelomeres are enriched in genes and pseudogenes from the large gene families RHS, TS and DGF1, DEAD/H-RNA helicase and N-acetyltransferase, intermingled with sequences of retrotransposons elements. In particular, members of the Trans-sialidase type II family appear to have played a role in shaping the current T. cruzi telomere structure. Although the structure and function of T. cruzi telomeric and subtelomeric regions have been documented, recent experiments are providing new insights into T. cruzi's telomere-subtelomere dynamics. In this review, I discuss the co-evolution of telomere, subtelomeres and the TS gene family, and the role that these regions may have played in shaping T. cruzi's genome.},
}
@article {pmid31993494,
year = {2020},
author = {Kumar, N and Qian, W and Van Houten, B},
title = {Sick mitochondria cause telomere damage: implications for disease.},
journal = {Molecular &amp; cellular oncology},
volume = {7},
number = {1},
pages = {1678362},
pmid = {31993494},
issn = {2372-3556},
support = {R33 ES025606/ES/NIEHS NIH HHS/United States ; },
abstract = {Dysfunctional mitochondria have been implicated in a variety of human pathophysiological conditions such as cancer, neurodegeneration, and aging. However, the precise role of mitochondrial-generated reactive oxygen species (ROS) in these maladies is unclear. Using a light-activated mitochondrially targeted approach, we recently reported direct evidence that damaged mitochondria produce a wave of secondary ROS, causing rapid and preferential telomere dysfunction but not gross nuclear DNA damage (Fig 1).},
}
@article {pmid31992162,
year = {2020},
author = {Pereira, FSM and Thomasini, RL and Lustosa, LP and Pereira, DS and Pereira, LSM and Kassab, GBI and Silva, TJ and Guerra, RO and Parentoni, AN},
title = {Is the Leukocyte Telomere Length Associated with Decreased Physical Functional Capacity in the Elderly?.},
journal = {Rejuvenation research},
volume = {23},
number = {5},
pages = {387-393},
doi = {10.1089/rej.2019.2264},
pmid = {31992162},
issn = {1557-8577},
mesh = {Aged ; Aging ; Brazil ; Cross-Sectional Studies ; Female ; *Geriatric Assessment ; Humans ; Leukocytes ; Male ; *Telomere ; *Telomere Shortening ; },
abstract = {Leukocyte telomere length in the elderly has been positively associated with healthy living and physical activity. Factors that interfere with telomere shortening are similar to those that may be associated with decreasing functional capacity. To investigate the relationship between mean leukocyte telomere length and functional capacity in community-dwelling elderly individuals, this is an observational, cross sectional, multicentric study conducted with elderly Brazilian patients. Sample characterization was performed using a sociodemographic clinical questionnaire. Telomere length was evaluated by quantitative polymerase chain reaction, and functional capacity was evaluated by the Short Physical Performance Battery (SPPB). A total of 113 elderly individuals (age 70 ± 5.4 years; 75 women and 38 men) were enrolled in this study. Unexpectedly, it was found that lower relative telomere length was associated with better physical capacity in the global SPPB score. Although telomere shortening is observed with increasing age, it is not associated with decreased functional capacity. Functionality is broad and multidimensional, involving the connection of biopsychosocial and cultural factors. While functionality may not be considered a marker of functional aging in an elderly cohort, it can still play an important role in longitudinal studies, which attempt to elucidate process theories. Future studies should use different techniques to measure telomere lengths in subpopulations of cells.},
}
@article {pmid31990469,
year = {2019},
author = {Bhattacharya, M and Bhaumik, P and Kumar-Dey, S},
title = {Telomere length comparison between oral cells and blood cells among neonates.},
journal = {The Turkish journal of pediatrics},
volume = {61},
number = {4},
pages = {520-524},
doi = {10.24953/turkjped.2019.04.008},
pmid = {31990469},
issn = {2791-6421},
mesh = {*Blood Cells ; Blotting, Southern ; Cheek ; Female ; Humans ; Infant, Newborn ; Male ; Mouth Mucosa/*cytology ; *Telomere ; },
abstract = {Bhattacharya M, Bhaumik P, Kumar-Dey S. Telomere length comparison between oral cells and blood cells among neonates. Turk J Pediatr 2019; 61: 520-524. Telomere length, measured from blood cells, is commonly used as the standard telomere length of the whole body. The relationship between blood telomere length and oral telomere length is still unclear, especially among neonates. In this study, we measured blood telomere length as well as cheek cells telomere length to find out the overall telomere synchronization in neonates. Children aged 1 month or younger were included in this study. Blood and cheek cells were collected by heel stick method and nylon brush accordingly. Telomere length was measured by Southern blotting. A strong telomere length correlation (0.77, p < 0.001) existed between oral and blood cells which showing telomere length synchronization among different tissue types. Mean telomere length and length variability were significantly higher (t=3.73, p=0.0004) in oral cells. Longer telomere among oral cells can be justified by progenitor cell pool theory. The cause of high telomere length variability in the oral source is not clear although the presence of leukocytes among cheek cells cannot be excluded. Therefore, for telomere length measurement purpose blood should be given preference over the oral source.},
}
@article {pmid31989559,
year = {2020},
author = {Fouquerel, E and Opresko, P},
title = {Analysis of Telomere Length and Aberrations by Quantitative FISH.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2102},
number = {},
pages = {237-249},
doi = {10.1007/978-1-0716-0223-2_13},
pmid = {31989559},
issn = {1940-6029},
support = {R01 ES028242/ES/NIEHS NIH HHS/United States ; R00 ES027028/ES/NIEHS NIH HHS/United States ; R35 ES030396/ES/NIEHS NIH HHS/United States ; R01 ES022944/ES/NIEHS NIH HHS/United States ; R01 CA207342/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Metaphase ; Microscopy, Fluorescence ; Nucleic Acid Probes ; Peptide Nucleic Acids/chemistry/genetics ; Telomere/*genetics ; Telomere Homeostasis ; Workflow ; },
abstract = {A key component of sustained cellular proliferation is the preservation of telomere integrity. Telomeres are nucleoprotein structures that cap and protect linear chromosomes. Their linearity and repetitive sequence represent a challenge for the replication machinery and cause telomere shortening, fragility, and losses. Here we describe the common technique of quantitative fluorescent in situ hybridization that allows for the scoring of telomere aberrations and measurement of telomere length directly on metaphase chromosomes through the use of highly specific peptide nucleic acid probes.},
}
@article {pmid31988640,
year = {2020},
author = {Sui, J and Zhang, S and Chen, BPC},
title = {DNA-dependent protein kinase in telomere maintenance and protection.},
journal = {Cellular &amp; molecular biology letters},
volume = {25},
number = {},
pages = {2},
pmid = {31988640},
issn = {1689-1392},
support = {R01 CA233594/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; DNA End-Joining Repair/genetics ; DNA Topoisomerases, Type II/metabolism ; DNA-Activated Protein Kinase/chemistry/genetics/*metabolism ; Heterogeneous Nuclear Ribonucleoprotein A1/*metabolism ; Humans ; Ku Autoantigen/metabolism ; Shelterin Complex ; Telomerase/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {This review focuses on DNA-dependent protein kinase (DNA-PK), which is the key regulator of canonical non-homologous end-joining (NHEJ), the predominant mechanism of DNA double-strand break (DSB) repair in mammals. DNA-PK consists of the DNA-binding Ku70/80 heterodimer and the catalytic subunit DNA-PKcs. They assemble at DNA ends, forming the active DNA-PK complex, which initiates NHEJ-mediated DSB repair. Paradoxically, both Ku and DNA-PKcs are associated with telomeres, and they play crucial roles in protecting the telomere against fusions. Herein, we discuss possible mechanisms and contributions of Ku and DNA-PKcs in telomere regulation.},
}
@article {pmid31988227,
year = {2020},
author = {Manchia, M and Paribello, P and Arzedi, C and Bocchetta, A and Caria, P and Cocco, C and Congiu, D and Cossu, E and Dettori, T and Frau, DV and Garzilli, M and Manca, E and Meloni, A and Montis, MA and Mura, A and Nieddu, M and Noli, B and Pinna, F and Pisanu, C and Robledo, R and Severino, G and Sogos, V and Chillotti, C and Carpiniello, B and Del Zompo, M and Ferri, GL and Vanni, R and Squassina, A},
title = {A multidisciplinary approach to mental illness: do inflammation, telomere length and microbiota form a loop? A protocol for a cross-sectional study on the complex relationship between inflammation, telomere length, gut microbiota and psychiatric disorders.},
journal = {BMJ open},
volume = {10},
number = {1},
pages = {e032513},
pmid = {31988227},
issn = {2044-6055},
mesh = {Adolescent ; Adult ; Aged ; Aging/*physiology ; Aging, Premature/*etiology ; Bipolar Disorder/complications ; Case-Control Studies ; Comorbidity ; Cross-Sectional Studies ; Depressive Disorder, Major/complications ; Female ; *Gastrointestinal Microbiome ; Humans ; Inflammation/*complications ; Italy ; Life Expectancy ; Male ; Mental Disorders/*complications ; Middle Aged ; Research Design ; Schizophrenia/complications ; *Telomere ; *Telomere Shortening ; Young Adult ; },
abstract = {INTRODUCTION: Severe psychiatric disorders are typically associated with a significant reduction in life expectancy compared with the general population. Among the different hypotheses formulated to explain this observation, accelerated ageing has been increasingly recognised as the main culprit. At the same time, telomere shortening is becoming widely accepted as a proxy molecular marker of ageing. The present study aims to fill a gap in the literature by better defining the complex interaction/s between inflammation, age-related comorbidities, telomere shortening and gut microbiota in psychiatric disorders.<br><br>METHODS AND ANALYSIS: A cross-sectional study is proposed, recruiting 40 patients for each of three different diagnostic categories (bipolar disorder, schizophrenia and major depressive disorder) treated at the Section of Psychiatry and at the Unit of Clinical Pharmacology of the University Hospital Agency of Cagliari (Italy), compared with 40 age-matched and sex-matched non-psychiatric controls. Each group includes individuals suffering, or not, from age-related comorbidities, to account for the impact of these medical conditions on the biological make-up of recruited patients. The inflammatory state, microbiota composition and telomere length (TL) are assessed.<br><br>ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of the University Hospital Agency of Cagliari (PG/2018/11693, 5 September 2018). The study is conducted in accordance with the principles of good clinical practice and the Declaration of Helsinki, and in compliance with the relevant Italian national legislation. Written, informed consent is obtained from all participants. Participation in the study is on a voluntary basis only. Patients will be part of the dissemination phase of the study results, during which a local conference will be organised and families of patients will also be involved. Moreover, findings will be published in one or more research papers and presented at national and international conferences, in posters or oral communications.},
}
@article {pmid31988064,
year = {2020},
author = {Sanchez, M and Hoang, S and Kannengiesser, C and Potier, L and Hadjadj, S and Marre, M and Roussel, R and Velho, G and Mohammedi, K},
title = {Leukocyte Telomere Length, DNA Oxidation, and Risk of Lower-Extremity Amputation in Patients With Long-standing Type 1 Diabetes.},
journal = {Diabetes care},
volume = {43},
number = {4},
pages = {828-834},
doi = {10.2337/dc19-0973},
pmid = {31988064},
issn = {1935-5548},
mesh = {Adult ; Amputation, Surgical/*statistics &amp; numerical data ; Cohort Studies ; DNA/*metabolism ; *Diabetes Mellitus, Type 1/complications/epidemiology/metabolism/surgery ; Diabetic Foot/epidemiology/etiology/metabolism/surgery ; Disease Progression ; Female ; Humans ; Incidence ; Leukocytes/*metabolism ; Lower Extremity/pathology/surgery ; Male ; Middle Aged ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; Risk Factors ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; Time Factors ; },
abstract = {OBJECTIVE: Telomere shortening and DNA oxidation are associated with premature vascular aging, which may be involved in lower-extremity amputation (LEA). We sought to investigate whether leukocyte telomere length (LTL) and plasma 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of DNA oxidation, were associated with LEA in subjects with type 1 diabetes at high vascular risk.<br><br>RESEARCH DESIGN AND METHODS: LTL (quantitative PCR) and plasma 8-OHdG concentrations (immunoassay method) were assessed at baseline in the GENEDIAB (G&#xe9;n&#xe9;tique de la N&#xe9;phropathie Diab&#xe9;tique) type 1 diabetes cohort. Logistic and Cox proportional hazards regression models were fitted to estimate odds ratio (OR) (at baseline) and hazard ratio (HR) (during follow-up), with related 95% CI, by increasing biomarker tertiles (T1, T2, T3).<br><br>RESULTS: Among 478 participants (56% male, mean &#xb1; SD age 45 &#xb1; 12 years and diabetes duration 29 &#xb1; 10 years), 84 patients had LEA at baseline. Baseline history of LEA was associated with shorter LTL (OR for T2 vs. T1 0.62 [95% CI 0.32-1.22] and for T3 vs. T1 0.41 [0.20-0.84]) but not with plasma 8-OHdG (1.16 [0.56-2.39] and 1.24 [0.61-2.55], respectively). New cases of LEA occurred in 34 (12.3%) participants during the 10-year follow-up. LTL were shorter (HR T2 vs. T1 0.25 [95% CI 0.08-0.67] and T3 vs. T1 0.29 [0.10-0.77]) and plasma 8-OHdG higher (2.20 [0.76-7.35] and 3.11 [1.07-10.32]) in participants who developed LEA during follow-up compared with others. No significant interaction was observed between biomarkers on their association with LEA.<br><br>CONCLUSIONS: We report the first independent association between LTL shortening and excess risk of LEA in type 1 diabetes. High plasma 8-OHdG was also associated with incident LEA but partly dependent on cofounding variables.},
}
@article {pmid31984849,
year = {2020},
author = {Sun, Y and Zhao, JQ and Jiao, YR and Ren, J and Zhou, YH and Li, L and Yao, HC},
title = {Predictive value of leukocyte telomere length for the severity of coronary artery disease.},
journal = {Personalized medicine},
volume = {17},
number = {3},
pages = {175-183},
doi = {10.2217/pme-2019-0152},
pmid = {31984849},
issn = {1744-828X},
mesh = {Aged ; Coronary Angiography/methods ; Coronary Artery Disease/genetics/*physiopathology ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; ROC Curve ; Risk Factors ; Severity of Illness Index ; Telomere/genetics/metabolism ; Telomere Homeostasis/*genetics/physiology ; },
abstract = {Aim: This study aimed to explore leukocyte telomere length (LTL) in the prediction of the severity of coronary artery disease (CAD). Materials &amp; methods: A total of 359 CAD patients who underwent coronary angiography were enrolled in this study. Severity of coronary artery was assessed by Gensini score (GS). Results: LTL is negatively correlated with GS (Spearman's rank correlation coefficient = -0.335; p < 0.001). Multivariate logistic regression results showed that LTL was an independent predictor of high GS (p = 0.001). Area under the curve value of LTL for predicting high GS was 0.659 (p < 0.001). Conclusion: LTL could be considered as a potential predictor of the severity of coronary artery in patients with CAD.},
}
@article {pmid31981976,
year = {2020},
author = {Xu, J and Chang, WS and Tsai, CW and Bau, DT and Xu, Y and Davis, JW and Thompson, TC and Logothetis, CJ and Gu, J},
title = {Leukocyte telomere length is associated with aggressive prostate cancer in localized prostate cancer patients.},
journal = {EBioMedicine},
volume = {52},
number = {},
pages = {102616},
pmid = {31981976},
issn = {2352-3964},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; P50 CA140388/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Biomarkers, Tumor ; Combined Modality Therapy ; Disease Progression ; Genetic Predisposition to Disease ; Humans ; Kaplan-Meier Estimate ; Leukocytes/*metabolism ; Male ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; Prognosis ; Prostatic Neoplasms/*genetics/mortality/*pathology/therapy ; Risk Factors ; Telomere/*genetics ; Telomere Homeostasis ; Treatment Outcome ; },
abstract = {BACKGROUND: Telomeres play important roles in cancer initiation and progression. The aim of this study is to investigate whether leukocyte telomere length (LTL) is associated with aggressive prostate cancer (PCa).<br><br>METHODS: We measured relative LTL in a cohort of 1,889 white PCa patients who were treated and followed up at the University of Texas MD Anderson Cancer Center and assessed its associations with aggressive disease characteristics at diagnosis and biochemical recurrence (BCR) after active treatments (radical prostatectomy and radiotherapy). We further used a Mendelian randomization (MR) approach to compute a weighted genetic risk score (GRS) predictive of LTL using 10 established LTL-associated genetic variants and determined whether this GRS is associated with aggressive PCa.<br><br>FINDINGS: LTL was significantly shorter in patients with higher Gleason scores at diagnosis. Dichotomized at the median value of LTL, patients with short LTL exhibited a 2.74-fold (95% confidence interval, 1.79-4.18, P&#xa0;=&#xa0;3.11&#xa0;&#xd7;&#xa0;10[-6]) increased risk of presenting with GS&#x2265;8 disease than those with long LTL in multivariate logistic regression analysis. Moreover, shorter LTL was significantly associated with an increased risk of BCR (hazard ratio&#xa0;=&#xa0;1.53, 95% confidence interval, 1.01-2.34) compared to longer LTL in localized patients receiving prostatectomy or radiotherapy with a significant dose-response association (P for trend&#xa0;=&#xa0;0.017) in multivariate Cox proportional hazards regression analysis. In MR analysis, genetically predicted short LTL was also associated with an increased risk of BCR (HR=1.73, 95% CI, 1.08-2.78).<br><br>INTERPRETATION: Our results showed for the first time that LTL was shorter in PCa patients with high Gleason scores and that short LTL and genetically predicted short LTL are associated with worse prognosis in PCa patients receiving prostatectomy or radiotherapy.<br><br>FUNDING: Cancer Prevention and Research Institute of Texas (CPRIT) grant (RP140556), National Cancer Institute Specialized Program of Research Excellence (SPORE) grant (CA140388), and MD Anderson Cancer Center start-up fund.},
}
@article {pmid31980821,
year = {2020},
author = {Maestroni, L and Reyes, C and Vaurs, M and Gachet, Y and Tournier, S and Géli, V and Coulon, S},
title = {Nuclear envelope attachment of telomeres limits TERRA and telomeric rearrangements in quiescent fission yeast cells.},
journal = {Nucleic acids research},
volume = {48},
number = {6},
pages = {3029-3041},
pmid = {31980821},
issn = {1362-4962},
mesh = {Cell Division/genetics ; DNA-Binding Proteins/*genetics ; Membrane Proteins/*genetics ; Nuclear Envelope/*genetics ; Nuclear Proteins/*genetics ; Recombination, Genetic ; Schizosaccharomyces/genetics ; Schizosaccharomyces pombe Proteins/*genetics ; Shelterin Complex ; Telomere/genetics ; Telomere Shortening/*genetics ; Telomere-Binding Proteins/*genetics ; Transcription, Genetic ; },
abstract = {Telomere anchoring to nuclear envelope (NE) is a key feature of nuclear genome architecture. Peripheral localization of telomeres is important for chromatin silencing, telomere replication and for the control of inappropriate recombination. Here, we report that fission yeast quiescent cells harbor predominantly a single telomeric cluster anchored to the NE. Telomere cluster association to the NE relies on Rap1-Bqt4 interaction, which is impacted by the length of telomeric sequences. In quiescent cells, reducing telomere length or deleting bqt4, both result in an increase in transcription of the telomeric repeat-containing RNA (TERRA). In the absence of Bqt4, telomere shortening leads to deep increase in TERRA level and the concomitant formation of subtelomeric rearrangements (STEEx) that accumulate massively in quiescent cells. Taken together, our data demonstrate that Rap1-Bqt4-dependent telomere association to NE preserves telomere integrity in post-mitotic cells, preventing telomeric transcription and recombination. This defines the nuclear periphery as an area where recombination is restricted, creating a safe zone for telomeres of post-mitotic cells.},
}
@article {pmid31980517,
year = {2020},
author = {Udroiu, I},
title = {On the correlation between telomere shortening rate and life span.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {117},
number = {5},
pages = {2248-2249},
pmid = {31980517},
issn = {1091-6490},
mesh = {Cellular Senescence ; *Longevity ; Telomere ; *Telomere Shortening ; },
}
@article {pmid31980516,
year = {2020},
author = {Whittemore, K and Blasco, MA},
title = {Reply to Udroiu: Interesting mathematical analysis of telomere shortening rate and life span.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {117},
number = {5},
pages = {2250},
pmid = {31980516},
issn = {1091-6490},
mesh = {Cellular Senescence ; *Longevity ; Telomere ; *Telomere Shortening ; },
}
@article {pmid31975049,
year = {2020},
author = {Mormile, R},
title = {Leukocyte Telomere Length and Pancreatic Cancer Survival: a Consequence of Activation of IL-6 Signaling Pathway in the Carcinogenic Process?.},
journal = {Journal of gastrointestinal cancer},
volume = {51},
number = {2},
pages = {720-721},
doi = {10.1007/s12029-020-00364-5},
pmid = {31975049},
issn = {1941-6636},
mesh = {Biomarkers, Tumor/*analysis ; Humans ; Interleukin-6/*metabolism ; Leukocytes/metabolism/*pathology ; Pancreatic Neoplasms/genetics/metabolism/*mortality/pathology ; Prognosis ; Signal Transduction ; Survival Rate ; Telomere/*genetics ; },
}
@article {pmid31974116,
year = {2020},
author = {Feng, E and Batenburg, NL and Walker, JR and Ho, A and Mitchell, TRH and Qin, J and Zhu, XD},
title = {CSB cooperates with SMARCAL1 to maintain telomere stability in ALT cells.},
journal = {Journal of cell science},
volume = {133},
number = {4},
pages = {},
doi = {10.1242/jcs.234914},
pmid = {31974116},
issn = {1477-9137},
support = {PJT159793//CIHR/Canada ; },
mesh = {DNA Repair ; Endonucleases/metabolism ; Homologous Recombination ; *Telomere/genetics/metabolism ; *Telomere Homeostasis/genetics ; },
abstract = {Elevated replication stress is evident at telomeres of about 10-15% of cancer cells, which maintain their telomeres via a homologous recombination (HR)-based mechanism, referred to as alternative lengthening of telomeres (ALT). How ALT cells resolve replication stress to support their growth remains incompletely characterized. Here, we report that CSB (also known as ERCC6) promotes recruitment of HR repair proteins (MRN, BRCA1, BLM and RPA32) and POLD3 to ALT telomeres, a process that requires the ATPase activity of CSB and is controlled by ATM- and CDK2-dependent phosphorylation. Loss of CSB stimulates telomeric recruitment of MUS81 and SLX4, components of the structure-specific MUS81-EME1-SLX1-SLX4 (MUS-SLX) endonuclease complex, suggesting that CSB restricts MUS-SLX-mediated processing of stalled forks at ALT telomeres. Loss of CSB coupled with depletion of SMARCAL1, a chromatin remodeler implicated in catalyzing regression of stalled forks, synergistically promotes not only telomeric recruitment of MUS81 but also the formation of fragile telomeres, the latter of which is reported to arise from fork stalling. These results altogether suggest that CSB-mediated HR repair and SMARCAL1-mediated fork regression cooperate to prevent stalled forks from being processed into fragile telomeres in ALT cells.},
}
@article {pmid31969337,
year = {2020},
author = {Song, N and Li, Z and Qin, N and Howell, CR and Wilson, CL and Easton, J and Mulder, HL and Edmonson, MN and Rusch, MC and Zhang, J and Hudson, MM and Yasui, Y and Robison, LL and Ness, KK and Wang, Z},
title = {Shortened Leukocyte Telomere Length Associates with an Increased Prevalence of Chronic Health Conditions among Survivors of Childhood Cancer: A Report from the St. Jude Lifetime Cohort.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {26},
number = {10},
pages = {2362-2371},
pmid = {31969337},
issn = {1557-3265},
support = {P30 CA021765/CA/NCI NIH HHS/United States ; R01 CA174851/CA/NCI NIH HHS/United States ; U01 CA195547/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; *Cancer Survivors ; Child ; Cohort Studies ; Humans ; Leukocytes ; *Neoplasms/epidemiology/genetics ; Prevalence ; Prospective Studies ; Retrospective Studies ; Survivors ; Telomere/genetics ; Young Adult ; },
abstract = {PURPOSE: We aimed to analyze and compare leukocyte telomere length (LTL) and age-dependent LTL attrition between childhood cancer survivors and noncancer controls, and to evaluate the associations of LTL with treatment exposures, chronic health conditions (CHC), and health behaviors among survivors.<br><br>EXPERIMENTAL DESIGN: We included 2,427 survivors and 293 noncancer controls of European ancestry, drawn from the participants in St. Jude Lifetime Cohort Study (SJLIFE), a retrospective hospital-based study with prospective follow-up (2007-2016). Common nonneoplastic CHCs (59 types) and subsequent malignant neoplasms (5 types) were clinically assessed. LTL was measured with whole-genome sequencing data.<br><br>RESULTS: After adjusting for age at DNA sampling, gender, genetic risk score based on 9 SNPs known to be associated with telomere length, and eigenvectors, LTL among survivors was significantly shorter both overall [adjusted mean (AM) = 6.20 kb; SE = 0.03 kb] and across diagnoses than controls (AM = 6.69 kb; SE = 0.07 kb). Among survivors, specific treatment exposures associated with shorter LTL included chest or abdominal irradiation, glucocorticoid, and vincristine chemotherapies. Significant negative associations of LTL with 14 different CHCs, and a positive association with subsequent thyroid cancer occurring out of irradiation field were identified. Health behaviors were significantly associated with LTL among survivors aged 18 to 35 years (P trend = 0.03).<br><br>CONCLUSIONS: LTL is significantly shorter among childhood cancer survivors than noncancer controls, and is associated with CHCs and health behaviors, suggesting LTL as an aging biomarker may be a potential mechanistic target for future intervention studies designed to prevent or delay onset of CHCs in childhood cancer survivors.See related commentary by Walsh, p. 2281.},
}
@article {pmid31966066,
year = {2020},
author = {Antoun, S and Atallah, D and Tahtouh, R and Assaf, MD and Moubarak, M and Ayoub, EN and Chahine, G and Hilal, G},
title = {Glucose restriction combined with chemotherapy decreases telomere length and cancer antigen-125 secretion in ovarian carcinoma.},
journal = {Oncology letters},
volume = {19},
number = {2},
pages = {1338-1350},
pmid = {31966066},
issn = {1792-1074},
abstract = {Although chemotherapy is the standard treatment for ovarian cancer (OC), recent studies have focused on its coupling with hypoglycemic drugs to decrease glucose availability. Similarly to cancer antigen 125 (Ca-125), telomerase, the key protein for telomere lengthening, is overexpressed in 90% of OC cases. The aim of the present study was to investigate the effect of the combination of glucose restriction and chemotherapy on telomere length and Ca-125 secretion in OC cells. SKOV-3, OVCAR-3 and Igrov-1 cells were treated with 20 µM cisplatin and 100 nM paclitaxel for 48 h in three different glucose concentrations: i) 4.5 g/l, ii) 1 g/l and iii) 0.5 g/l. The same treatment was repeated once per week for 6 consecutive weeks. The surviving cells were considered platinum-taxane escape (PTES) cells. The expression levels of telomerase and Ca-125 in treated and PTES cells were quantified by qPCR, and Ca-125 secretion by ELISA. Telomere length was evaluated by qPCR according to the Cawthon method. The modulation of Ca-125 by telomerase was assessed using inhibitors, small interfering RNA and transfection with human telomerase reverse transcriptase (hTERT) vectors. The implication of phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR) in Ca-125 modulation was investigated using specific inhibitors. An increase in hTERT and Ca-125 expression levels (range, 1.5-3 fold) was observed in short-term treated cells. However, an opposite effect was detected in PTES cells, where the rate of decrease in the expression levels of hTERT and Ca-125 reached 60% after treatment in 0.5 g/l glucose. Moreover, telomere length was decreased by 30% in cells treated with 0.5 g/l glucose. Inhibition of hTERT expression significantly decreased Ca-125 secretion, suggesting a potential modulation of Ca-125 by hTERT. The inhibition of the PI3K/Akt/mTOR pathway also decreased Ca-125 secretion; however, the effect of this treatment was not enhanced when coupled with telomerase inhibitors. In conclusion, the combination of chemotherapy and glucose restriction was observed to decrease Ca-125 secretion and telomerase expression leading to shortening in telomere length. Thus, decreasing glucose availability for OC cells during treatment may lead to a better clinical outcome and potentially improve the prognosis of patients with OC.},
}
@article {pmid31965837,
year = {2019},
author = {Lew, LC and Hor, YY and Jaafar, MH and Lau, ASY and Ong, JS and Chuah, LO and Yap, KP and Azzam, G and Azlan, A and Liong, MT},
title = {Lactobacilli modulated AMPK activity and prevented telomere shortening in ageing rats.},
journal = {Beneficial microbes},
volume = {10},
number = {8},
pages = {883-892},
doi = {10.3920/BM2019.0058},
pmid = {31965837},
issn = {1876-2891},
mesh = {AMP-Activated Protein Kinases/*genetics ; Aging, Premature/chemically induced/*metabolism/pathology ; Animals ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Galactose/administration &amp; dosage/adverse effects ; Gene Expression/drug effects ; Lactobacillus/*physiology ; Lipid Peroxidation/drug effects ; Male ; Physical Endurance/drug effects ; Probiotics/administration &amp; dosage/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Telomere Shortening/*drug effects ; },
abstract = {This study aimed to evaluate the anti-ageing effects of different strains of lactobacilli putative probiotics on an ageing rat model as induced by D-galactose and a high fat diet. Male Sprague-Dawley rats were fed with high fat diet (54% kcal fat) and injected with D-galactose daily for 12 weeks to induce ageing. The effects of putative probiotic strains on age-related impairment such as telomere length, plasma lipid peroxidation, hepatic 5'adenosine monophosphate-activated protein kinase (AMPK) expression, as well as endurance performance were evaluated. Administration of statin, Lactobacillus plantarum DR7 (LP-DR7), Lactobacillus fermentum DR9 (LF-DR9), and Lactobacillus reuteri 8513d (LR-8513d) significantly reduced the shortening of telomere and increased the expression of AMPK subunit-α1 (P<0.05). Plasma lipid peroxidation was lower (P<0.05) in groups administered with statin and LF-DR9 as compared to the control. AMPK subunit-α2 was elevated in rats administered with LP-DR7 as compared to the control (P<0.05). Using an in vivo ageing rat model, the current study has illustrated the potentials of lactobacilli putative probiotics in alleviation of age-related impairment in a strain-dependent manner.},
}
@article {pmid31961192,
year = {2020},
author = {Beijers, R and Hartman, S and Shalev, I and Hastings, W and Mattern, BC and de Weerth, C and Belsky, J},
title = {Testing three hypotheses about effects of sensitive-insensitive parenting on telomeres.},
journal = {Developmental psychology},
volume = {56},
number = {2},
pages = {237-250},
pmid = {31961192},
issn = {1939-0599},
support = {T32 AG049676/AG/NIA NIH HHS/United States ; //Netherlands Organization for Scientific Research/ ; //Royal Netherlands Academy of Arts and Sciences/ ; //Jacobs Foundation/ ; },
mesh = {Child ; Child, Preschool ; Female ; Humans ; Longitudinal Studies ; Male ; *Parent-Child Relations ; *Parenting ; Pregnancy ; Prenatal Exposure Delayed Effects/*metabolism ; Stress, Psychological/*metabolism ; Telomere/*metabolism ; *Telomere Shortening/genetics ; },
abstract = {Telomeres are the protective DNA-protein sequences appearing at the ends of chromosomes; they shorten with each cell division and are considered a biomarker of aging. Shorter telomere length and greater erosion have been associated with compromised physical and mental health and are hypothesized to be affected by early life stress. In the latter case, most work has relied on retrospective measures of early life stressors. The Dutch research (n = 193) presented herein tested 3 hypotheses prospectively regarding effects of sensitive-insensitive parenting during the first 2.5 years on telomere length at age 6, when first measured, and change over the following 4 years. It was predicted that (1) less sensitive parenting would predict shorter telomeres and greater erosion and that such effects would be most pronounced in children (2) exposed to prenatal stress and/or (3) who were highly negatively emotional as infants. Results revealed, only, that prenatal stress amplified parenting effects on telomere change-in a differential-susceptibility-related manner: Prenatally stressed children displayed more erosion when they experienced insensitive parenting and less erosion when they experienced sensitive parenting. Mechanisms that might initiate greater postnatal plasticity as a result of prenatal stress are highlighted and future work outlined. (PsycINFO Database Record (c) 2020 APA, all rights reserved).},
}
@article {pmid31960234,
year = {2020},
author = {Ferreira, MSV and Sørensen, MD and Pusch, S and Beier, D and Bouillon, AS and Kristensen, BW and Brümmendorf, TH and Beier, CP and Beier, F},
title = {Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation.},
journal = {Journal of neuro-oncology},
volume = {147},
number = {1},
pages = {1-14},
pmid = {31960234},
issn = {1573-7373},
support = {17/18517//Region of Southern Denmark/ ; },
mesh = {Adolescent ; Adult ; Aged ; Astrocytoma/*genetics ; Brain Neoplasms/*genetics ; Child ; Child, Preschool ; Female ; Humans ; Isocitrate Dehydrogenase/*genetics/metabolism ; Male ; Middle Aged ; Mutation ; Single-Cell Analysis ; Telomerase/*genetics ; Telomere Homeostasis/*genetics ; Tumor Cells, Cultured ; X-linked Nuclear Protein/*genetics ; Young Adult ; },
abstract = {PURPOSE: Isocitrate dehydrogenase 1 (IDH1) mutations are associated with improved survival in gliomas. Depending on the IDH1 status, TERT promoter mutations affect prognosis. IDH1 mutations are associated with alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutations and alternative lengthening of telomeres (ALT), suggesting an interaction between IDH1 and telomeres. However, little is known how IDH1 mutations affect telomere maintenance.<br><br>METHODS: We analyzed cell-specific telomere length (CS-TL) on a single cell level in 46 astrocytoma samples (WHO II-IV) by modified immune-quantitative fluorescence in situ hybridization, using endothelial cells as internal reference. In the same samples, we determined IDH1/TERT promoter mutation status and ATRX expression. The interaction of IDH1[R132H] mutation and CS-TL was studied in vitro using an IDH1[R132H] doxycycline-inducible glioma cell line system.<br><br>RESULTS: Virtually all ALT[positive] astrocytomas had normal TERT promoter and lacked ATRX expression. Further, all ALT[positive] samples had IDH1[R132H] mutations, resulting in a significantly longer CS-TL of IDH1[R132H] gliomas, when compared to their wildtype counterparts. Conversely, TERT promotor mutations were associated with IDH[wildtype], ATRX expression, lack of ALT and short CS-TL. ALT, TERT promoter mutations, and CS-TL remained without prognostic significance, when correcting for IDH1 status. In vitro, overexpression of IDH[R132H] in the glioma cell line LN319 resulted in downregulation of ATRX and rapid TERT-independent telomere lengthening consistent with ALT.<br><br>CONCLUSION: ALT is the major telomere maintenance mechanism in IDH[R132H] mutated astrocytomas, while TERT promoter mutations were associated with IDH[wildtype] glioma. IDH1[R132H] downregulates ATRX expression in vitro resulting in ALT, which may contribute to the strong association of IDH1[R132H] mutations, ATRX loss, and ALT.},
}
@article {pmid31960186,
year = {2020},
author = {Boscolo-Rizzo, P and Giunco, S and Rampazzo, E and Brutti, M and Spinato, G and Menegaldo, A and Stellin, M and Mantovani, M and Bandolin, L and Rossi, M and Del Mistro, A and Tirelli, G and Dei Tos, AP and Guerriero, A and Niero, M and Da Mosto, MC and Polesel, J and De Rossi, A},
title = {TERT promoter hotspot mutations and their relationship with TERT levels and telomere erosion in patients with head and neck squamous cell carcinoma.},
journal = {Journal of cancer research and clinical oncology},
volume = {146},
number = {2},
pages = {381-389},
pmid = {31960186},
issn = {1432-1335},
mesh = {Adult ; Aged ; Aged, 80 and over ; Cohort Studies ; Female ; Head and Neck Neoplasms/*genetics/metabolism/pathology ; Humans ; Male ; Middle Aged ; *Mutation ; Promoter Regions, Genetic ; Prospective Studies ; Squamous Cell Carcinoma of Head and Neck/*genetics/metabolism/pathology ; Survival Analysis ; Telomerase/*genetics/metabolism ; Telomere/genetics/*metabolism/pathology ; },
abstract = {PURPOSE: To evaluate the prevalence of two recurrent somatic mutations (-124 C>T and -146 C>T) within the promoter of the gene encoding telomerase reverse transcriptase (TERT) as well as their relationship with TERT level, telomeres length, and outcome in patients with head and neck squamous cell carcinomas (HNSCCs).<br><br>METHODS: We evaluate the prevalence of TERT promoter mutations, TERT levels, and telomere length in paired cancer tissue and adjacent mucosa (AM) in a series of HNSCCs.<br><br>RESULTS: Cancer tissue and AM specimens from 105 patients were analyzed. Telomere length and TERT mRNA levels were estimated using real-time polymerase chain reaction. TERT promoter mutations were assessed using Sanger sequencing. Out of 105 cases, 101 were considered suitable for the analysis. TERT promoter harbored mutations in 12 tumors (11.9%), with -124 C>T and -146 C>T accounting for 83.3% and 16.7% of the alterations, respectively. No mutations were detected in AM samples. The prevalence of TERT promoter mutations was significantly higher in oral cavity SCCs (10 out of 27 tumors; 37%), and telomere length in AM was shorter in patients with tumors carrying TERT promoter mutations than in patients with unmutated TERT promoter cancers (p&#x2009;=&#x2009;0.023). TERT levels in tumor did not significantly differ according to the mutational status of TERT promoter. No significant association was found between TERT promoter status and overall survival.<br><br>CONCLUSION: TERT promoter mutations are most likely a late event in tumor development, occurring in a context of critically short telomeres, mostly in patients with oral cavity SCC. TERT levels, but not TERT promoter mutational status impact clinical outcome.},
}
@article {pmid31957893,
year = {2020},
author = {Jimbo, K and Konuma, T and Mizukami, M and Nagai, E and Oiwa-Monna, M and Isobe, M and Kato, S and Takahashi, S and Tojo, A},
title = {Telomere length in CD4[+] and CD8[+] T cells among long-term survivors of adults after single cord blood transplantation.},
journal = {European journal of haematology},
volume = {104},
number = {5},
pages = {509-511},
doi = {10.1111/ejh.13385},
pmid = {31957893},
issn = {1600-0609},
support = {//Takeda Science Foundation/ ; //Japanese Society for the Promotion of Science/ ; },
mesh = {CD4-Positive T-Lymphocytes/*metabolism ; CD8-Positive T-Lymphocytes/*metabolism ; Cord Blood Stem Cell Transplantation ; Humans ; *Survivors ; *Telomere ; *Telomere Homeostasis ; },
}
@article {pmid31956916,
year = {2021},
author = {Kemp, BR and Ferraro, KF},
title = {Are Biological Consequences of Childhood Exposures Detectable in Telomere Length Decades Later?.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {76},
number = {1},
pages = {7-14},
pmid = {31956916},
issn = {1758-535X},
support = {R01 AG043544/AG/NIA NIH HHS/United States ; RF1 AG043544/AG/NIA NIH HHS/United States ; U01 AG009740/AG/NIA NIH HHS/United States ; },
mesh = {*Adverse Childhood Experiences ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Risk Assessment ; Telomere/*ultrastructure ; Telomere Shortening ; Time Factors ; },
abstract = {Negative early-life exposures have been linked to a host of poor adult health outcomes, but are such early exposures associated with cellular senescence decades later? This study uses data from the Health and Retirement Study to examine the association between six childhood exposure domains (eg, socioeconomic disadvantage, risky parental behavior) and a biomarker of aging, telomere length, among 4,935 respondents. Telomere length is obtained from DNA of cells found in saliva and is measured as the telomere repeat copy number to single gene copy number ratio (T/S). Men who as children were exposed to risky parental behaviors or who reported risky adolescent behaviors have shorter telomeres (b = -0.031, p = .052; b = -0.041, p = .045, respectively); however, these relationships are attenuated after adjusting for adult risks and resources. Among women, parental substance abuse is associated with shorter telomeres even after adjusting for adult risks and resources (b = -0.041, p = .005). In addition, men and women whose mother lived at least until the age of 85 have longer telomeres than those without a long-lived mother (b = 0.021, p = .045; b = 0.032, p = .005, respectively). Taken together, the ways in which early-life exposures are associated with adult telomeres vary for men and women.},
}
@article {pmid31956299,
year = {2020},
author = {de Pedro, N and Díez, M and García, I and García, J and Otero, L and Fernández, L and García, B and González, R and Rincón, S and Pérez, D and Rodríguez, E and Segovia, E and Najarro, P},
title = {Analytical Validation of Telomere Analysis Technology® for the High-Throughput Analysis of Multiple Telomere-Associated Variables.},
journal = {Biological procedures online},
volume = {22},
number = {},
pages = {2},
pmid = {31956299},
issn = {1480-9222},
abstract = {BACKGROUND: A large number of studies have suggested a correlation between the status of telomeres and disease risk. High-throughput quantitative fluorescence in situ hybridization (HT Q-FISH) is a highly accurate telomere measurement technique that can be applied to the study of large cell populations. Here we describe the analytical performance testing and validation of Telomere Analysis Technology (TAT®), a laboratory-developed HT Q-FISH-based methodology that includes HT imaging and software workflows that provide a highly detailed view of telomere populations.<br><br>METHODS: TAT was developed for the analysis of telomeres in peripheral blood mononuclear cells (PBMCs). TAT was compared with Terminal Restriction Fragment (TRF) length analysis, and tested for accuracy, precision, limits of detection (LOD) and specificity, reportable range and reference range.<br><br>RESULTS: Using 6 different lymphocyte cell lines, we found a high correlation between TAT and TRF for telomere length (R[2]&#xa0;&#x2265;&#x2009;0.99). The standard variation (assay error) of TAT was 454 base pairs, and the limit of detection of 800 base pairs. A standard curve was constructed to cover human median reportable range values and defined its lower limit at 4700&#x2009;bp and upper limits at 14,400&#x2009;bp. Using TAT, up to 223 telomere associated variables (TAVs) can be obtained from a single sample. A pilot, population study, of telomere analysis using TAT revealed high accuracy and reliability of the methodology.<br><br>CONCLUSIONS: Analytical validation of TAT shows that is a robust and reliable technique for the characterization of a detailed telomere profile in large cell populations. The combination of high-throughput imaging and software workflows allows for the collection of a large number of telomere-associated variables from each sample, which can then be used in epidemiological and clinical studies.},
}
@article {pmid31952540,
year = {2020},
author = {Zhao, Y and Wang, B and Wang, G and Huang, L and Yin, T and Li, X and Liu, X and Wang, Q and Jing, J and Yang, J and Zhang, Y},
title = {Functional interaction between plasma phospholipid fatty acids and insulin resistance in leucocyte telomere length maintenance.},
journal = {Lipids in health and disease},
volume = {19},
number = {1},
pages = {11},
pmid = {31952540},
issn = {1476-511X},
support = {81160358//National Natural Science Foundation of China/ ; XY201621//Ningxia medical university scientific research project/ ; NXYLXK2017A08//Top Discipline of Public Health and Prevent Medicine/ ; },
mesh = {Adult ; Aged ; Cross-Sectional Studies ; Fatty Acids, Monounsaturated/blood ; Fatty Acids, Omega-6/blood ; Female ; Humans ; Insulin Resistance/*physiology ; Leukocytes/*metabolism ; Linear Models ; Male ; Middle Aged ; Phospholipids/*blood ; Telomere/genetics/*metabolism ; Telomere Homeostasis/genetics/physiology ; },
abstract = {BACKGROUND: Previous evidence suggests that plasma phospholipid fatty acids (PPFAs) and HOMA insulin resistance (HOMA-IR) are independently related to leukocyte telomere length (LTL). However, there is limited evidence of regarding the effect of their interaction on relative LTL (RLTL). Therefore, here, we aimed to determine the effect of the interaction between PPFAs and HOMA-IR on RLTL.<br><br>METHODS: We conducted a cross-sectional study, involving a total of 1246 subjects aged 25-74&#x2009;years. PPFAs and RLTL were measured, and HOMA-IR was calculated. The effect of the interaction between PPFAs and HOMA-IR on RLTL was assessed by univariate analysis, adjusting for potential confounders.<br><br>RESULTS: In age-adjusted analyses, multivariate linear regression revealed a significant association of the levels of elaidic acid, HOMA-IR, monounsaturated fatty acids (MUFA) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) with RLTL. After adjustment of age and gender, race, smoking, drinking, tea, and exercise, elaidic acid, and omega-3 (n-3) PUFA were negatively associated with RLTL, and HOMA-IR and n-6 PUFA were positively associated with RLTL. These associations were not significantly altered upon further adjustment for anthropometric and biochemical indicators. Meanwhile, the effect of the interaction of elaidic acid and HOMA-IR on RLTL was significant, and remained unchanged even after adjusting for the aforementioned potential confounders. Interestingly, individuals who had the lowest HOMA-IR and the highest elaidic acid levels presented the shortest RLTL.<br><br>CONCLUSIONS: Our findings indicated that shorter RLTL was associated with lower HOMA-IR and higher elaidic acid level. These findings might open a new avenue for exploring the potential role of the interaction between elaidic acid and HOMA-IR in maintaining RLTL.},
}
@article {pmid31950310,
year = {2020},
author = {Brandao, CFC and Nonino, CB and de Carvalho, FG and Nicoletti, CF and Noronha, NY and San Martin, R and de Freitas, EC and Junqueira-Franco, MVM and Marchini, JS},
title = {The effects of short-term combined exercise training on telomere length in obese women: a prospective, interventional study.},
journal = {Sports medicine - open},
volume = {6},
number = {1},
pages = {5},
pmid = {31950310},
issn = {2199-1170},
support = {303563/2018-4//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 420753/2018-4//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 154169/2018-8//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 2017/10080-2//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo (BR)/ ; },
abstract = {BACKGROUND: Telomere length is inversely associated with the senescence and aging process. Parallelly, obesity can promote telomere shortening. Evidence suggests that physical activity may promote telomere elongation.<br><br>OBJECTIVE: This study's objective is to evaluate the effects of combined exercise training on telomere length in obese women.<br><br>DESIGN AND METHODS: Twenty pre-menopausal women (BMI 30-40&#x2009;kg/m[2], 20-40&#x2009;years) submitted to combined training (strength and aerobic exercises), but only 13 finished the protocol. Each exercise session lasted 55&#x2009;min/day, three times a week, throughout 8 weeks. Anthropometric data, body composition, physical performance (Vo2max), and 8-h fasting blood samples were taken before and after 8 weeks of training. Leukocyte DNA was extracted for telomere length by RT-qPCR reaction, using the 2[-&#x394;&#x394;Ct] methodology.<br><br>RESULTS: After the&#xa0;training intervention, significant differences (p < 0.05) were observed in telomere length (respectively before and after, 1.03 &#xb1; 0.04 to 1.07 &#xb1; 0.04&#x2009;T/S ratio), fat-free mass (46 &#xb1; 7 to 48 &#xb1; 5&#x2009;kg), Vo2max (35 &#xb1; 3 to 38 &#xb1; 3&#x2009;ml/kg/min), and waist circumference (96 &#xb1; 8 to 90 &#xb1; 6&#x2009;cm). In addition, an inverse correlation between waist circumference and telomere length was found, before (r = -&#x2009;0.536, p = 0.017) and after (r = -&#x2009;0.655, p = 0.015) exercise training.<br><br>CONCLUSION: Combined exercise promoted leukocyte telomere elongation in obese women. Besides, the data suggested that greater waist circumference may predict shorter telomere length.<br><br>CLINICAL TRIAL REGISTRATION: ClinicalTrails.gov, NCT03119350. Retrospectively registered on 18 April 2017.},
}
@article {pmid31949878,
year = {2019},
author = {Zhang, X and Wang, Y and Zhao, R and Hu, X and Zhang, B and Lv, X and Guo, Z and Zhang, Z and Yuan, J and Chu, X and Wang, F and Li, G and Geng, X and Liu, Y and Sui, L and Wang, F},
title = {Folic Acid Supplementation Suppresses Sleep Deprivation-Induced Telomere Dysfunction and Senescence-Associated Secretory Phenotype (SASP).},
journal = {Oxidative medicine and cellular longevity},
volume = {2019},
number = {},
pages = {4569614},
pmid = {31949878},
issn = {1942-0994},
mesh = {Adult ; Aged ; Aged, 80 and over ; Animals ; Cellular Senescence/*drug effects ; Cytokines ; *DNA Damage ; *Dietary Supplements ; Female ; Folic Acid/*administration &amp; dosage ; Humans ; Inflammation/drug therapy/physiopathology ; Male ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Oxidative Stress/*drug effects ; Phenotype ; Sleep Deprivation/*drug therapy/physiopathology ; Telomere/*drug effects/genetics ; },
abstract = {Sleep deprivation is reported to cause oxidative stress and is hypothesized to induce subsequent aging-related diseases including chronic inflammation, Alzheimer's disease, and cardiovascular disease. However, how sleep deprivation contributes to the pathogenesis of sleep deficiency disorder remains incompletely defined. Accordingly, more effective treatment methods for sleep deficiency disorder are needed. Thus, to better understand the detailed mechanism of sleep deficiency disorder, a sleep deprivation mouse model was established by the multiple platform method in our study. The accumulation of free radicals and senescence-associated secretory phenotype (SASP) was observed in the sleep-deprived mice. Moreover, our mouse and human population-based study both demonstrated that telomere shortening and the formation of telomere-specific DNA damage are dramatically increased in individuals suffering from sleeplessness. To our surprise, the secretion of senescence-associated cytokines and telomere damage are greatly improved by folic acid supplementation in mice. Individuals with high serum baseline folic acid levels have increased resistance to telomere shortening, which is induced by insomnia. Thus, we conclude that folic acid supplementation could be used to effectively counteract sleep deprivation-induced telomere dysfunction and the associated aging phenotype, which may potentially improve the prognosis of sleeplessness disorder patients.},
}
@article {pmid31949102,
year = {2020},
author = {Mayr, FB and Yende, S},
title = {Size matters! Peripheral blood leukocyte telomere length and survival after critical illness.},
journal = {The European respiratory journal},
volume = {55},
number = {1},
pages = {},
pmid = {31949102},
issn = {1399-3003},
support = {K23 GM132688/GM/NIGMS NIH HHS/United States ; },
mesh = {Critical Illness ; Humans ; Leukocytes ; *Sepsis ; *Telomere ; },
}
@article {pmid31948608,
year = {2019},
author = {Denham, J},
title = {The association between sperm telomere length, cardiorespiratory fitness and exercise training in humans.},
journal = {Biomedical journal},
volume = {42},
number = {6},
pages = {430-433},
pmid = {31948608},
issn = {2320-2890},
mesh = {Adult ; Cardiorespiratory Fitness/*physiology ; Exercise/*physiology ; Female ; Humans ; Male ; Middle Aged ; Semen Analysis/methods ; Spermatozoa/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; Young Adult ; },
abstract = {Telomeres protect genomic integrity and shorten in somatic cells due to the end replication problem. Sperm telomeres are, however, longer in older individuals and linked to semen quality. Exercise training may attenuate age-related telomere shortening in somatic cells, but the influence of exercise on sperm telomeres is unknown. Mature sperm from 34 healthy men were isolated by density gradient centrifugation and telomere length was assessed by qPCR. No significant correlations were observed between telomere length, fitness or exercise performance. Inter-individual variation in sperm telomere length responses to a 6-wk vigorous exercise training intervention (ΔT/S ratio range: -0.49 to 0.87) and a strong correlation between improvements in fitness and sperm telomere lengthening were revealed (r = 0.87, p < 0.001). These preliminary data suggest exercise training may regulate sperm telomere length and should encourage larger studies to explore the implications this may have on the health of the next generation.},
}
@article {pmid31948316,
year = {2020},
author = {Kite, E and Forer, A},
title = {The role of phosphorylation in the elasticity of the tethers that connect telomeres of separating anaphase chromosomes.},
journal = {Nucleus (Austin, Tex.)},
volume = {11},
number = {1},
pages = {19-31},
pmid = {31948316},
issn = {1949-1042},
mesh = {Anaphase/drug effects/genetics/*physiology ; Animals ; Chromosomes/drug effects/genetics/*metabolism ; Diptera/cytology/drug effects/*genetics ; *Elasticity/drug effects ; Enzyme Inhibitors/pharmacology ; Marine Toxins/pharmacology ; Oxazoles/pharmacology ; Phosphorylation/drug effects/genetics ; Telomere/drug effects/genetics/*metabolism ; },
abstract = {Elastic tethers, connecting telomeres of all separating anaphase chromosome pairs, lose elasticity when they lengthen during anaphase. Treatment with phosphatase inhibitor CalyculinA causes anaphase chromosomes to move backwards after they reach the poles, suggesting that dephosphorylation causes loss of tether elasticity. We added 50nM CalyculinA to living anaphase crane-fly spermatocytes with different length tethers. When tethers were short, almost all partner chromosomes moved backwards after nearing the poles. When tethers were longer, fewer chromosomes moved backwards. With yet longer tethers none moved backward. This is consistent with tether elasticity being lost by dephosphorylation. 50nM CalyculinA blocks both PP1 and PP2A. To distinguish between PP1 and PP2A we treated cells with short tethers with 50nM okadaic acid which blocks solely PP2A, or with 1µM okadaic acid which blocks both PP1 and PP2A. Only 1µM okadaic acid caused chromosomes to move backward. Thus, tether elasticity is lost because of dephosphorylation by PP1.},
}
@article {pmid31942041,
year = {2020},
author = {Monroe, DM and Goldstein, RL and Teylan, MA and Hart, JE and DeVivo, I and Orr, EH and Garshick, E},
title = {Correction: Clinical associations with telomere length in chronic spinal cord injury.},
journal = {Spinal cord},
volume = {58},
number = {4},
pages = {514},
doi = {10.1038/s41393-020-0417-7},
pmid = {31942041},
issn = {1476-5624},
abstract = {An amendment to this paper has been published and can be accessed via a link at the top of the paper.},
}
@article {pmid31937223,
year = {2020},
author = {Pineda-Pampliega, J and Herrera-Dueñas, A and Mulder, E and Aguirre, JI and Höfle, U and Verhulst, S},
title = {Antioxidant supplementation slows telomere shortening in free-living white stork chicks.},
journal = {Proceedings. Biological sciences},
volume = {287},
number = {1918},
pages = {20191917},
pmid = {31937223},
issn = {1471-2954},
mesh = {Animals ; Antioxidants/*metabolism ; Birds/*physiology ; *Dietary Supplements ; Telomere Shortening/*physiology ; },
abstract = {Telomere length (TL) and shortening is increasingly shown to predict variation in survival and lifespan, raising the question of what causes variation in these traits. Oxidative stress is well known to accelerate telomere attrition in vitro, but its importance in vivo is largely hypothetical. We tested this hypothesis experimentally by supplementing white stork (Ciconia ciconia) chicks with antioxidants. Individuals received either a control treatment, or a supply of tocopherol (vitamin E) and selenium, which both have antioxidant properties. The antioxidant treatment increased the concentration of tocopherol for up to two weeks after treatment but did not affect growth. Using the telomere restriction fragment technique, we evaluated erythrocyte TL and its dynamics. Telomeres shortened significantly over the 21 days between the baseline and final sample, independent of sex, mass, size and hatching order. The antioxidant treatment significantly mitigated shortening rate of average TL (-31% in shorter telomeres; percentiles 10th, 20th and 30th). Thus, our results support the hypothesis that oxidative stress shortens telomeres in vivo.},
}
@article {pmid31935457,
year = {2020},
author = {Praveen, G and Shalini, T and Sivaprasad, M and Reddy, GB},
title = {Relative telomere length and mitochondrial DNA copy number variation with age: Association with plasma folate and vitamin B12.},
journal = {Mitochondrion},
volume = {51},
number = {},
pages = {79-87},
doi = {10.1016/j.mito.2020.01.007},
pmid = {31935457},
issn = {1872-8278},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging ; Biomarkers/blood ; Cross-Sectional Studies ; DNA Copy Number Variations/*genetics ; DNA, Mitochondrial/*genetics ; Female ; Folic Acid/*blood ; Humans ; India ; Longevity/genetics ; Male ; Middle Aged ; Mitochondria/genetics ; Telomere/physiology ; Telomere Homeostasis/*genetics ; Vitamin B 12/*blood ; Young Adult ; },
abstract = {Telomere attrition and mitochondrial DNA variations are implicated in the biological aging process and genomic stability can be influenced by nutritional factors. This study aims to analyze the relative telomere length (rTL) and mitochondrial DNA copy number (mtCN) in aged individuals and their association with plasma folate and vitamin B12 levels. This community-based cross-sectional study involves 428 subjects (<60 years: 242 &amp; ≥60 years: 186). Quantitative real-time PCR was used to measure rTL and mtCN variation, and radioimmunoassay to measure plasma folate and vitamin B12 levels. The subjects in the ≥60 years age group have significantly shorter telomeres and lower mtCN compared to the <60 years age group. A significant positive correlation was observed between the rTL and mtCN, and both of them were positively associated with plasma folate and vitamin B12 levels. In the ≥60 age group; folate and vitamin B12 positively correlated with rTL and vitamin B12 with mtCN. The study revealed a decline of rTL and mtCN with age in the Indian population and their association suggests that they may co-regulate each other with age. In conclusion, folate and vitamin B12 may delay aging by preventing the reduction in rTL length and mtCN.},
}
@article {pmid31934863,
year = {2020},
author = {Porreca, RM and Herrera-Moyano, E and Skourti, E and Law, PP and Gonzalez Franco, R and Montoya, A and Faull, P and Kramer, H and Vannier, JB},
title = {TRF1 averts chromatin remodelling, recombination and replication dependent-break induced replication at mouse telomeres.},
journal = {eLife},
volume = {9},
number = {},
pages = {},
pmid = {31934863},
issn = {2050-084X},
support = {MC_UP_1102/14/MRC_/Medical Research Council/United Kingdom ; MRC Career Development Award/MRC_/Medical Research Council/United Kingdom ; Telomere Replication and Stability/MRC_/Medical Research Council/United Kingdom ; 637798 MetDNASecStr//European Commission/ ; },
mesh = {Animals ; Cell Cycle Proteins/metabolism ; Cell Line ; Chromatin/metabolism ; *Chromatin Assembly and Disassembly ; DNA/biosynthesis ; *DNA Breaks ; DNA Polymerase III/metabolism ; DNA Replication/*genetics ; Gene Deletion ; Humans ; Inclusion Bodies/metabolism ; Mice ; Mitosis ; Recombination, Genetic/*genetics ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; Up-Regulation/genetics ; },
abstract = {Telomeres are a significant challenge to DNA replication and are prone to replication stress and telomere fragility. The shelterin component TRF1 facilitates telomere replication but the molecular mechanism remains uncertain. By interrogating the proteomic composition of telomeres, we show that mouse telomeres lacking TRF1 undergo protein composition reorganisation associated with the recruitment of DNA damage response and chromatin remodellers. Surprisingly, mTRF1 suppresses the accumulation of promyelocytic leukemia (PML) protein, BRCA1 and the SMC5/6 complex at telomeres, which is associated with increased Homologous Recombination (HR) and TERRA transcription. We uncovered a previously unappreciated role for mTRF1 in the suppression of telomere recombination, dependent on SMC5 and also POLD3 dependent Break Induced Replication at telomeres. We propose that TRF1 facilitates S-phase telomeric DNA synthesis to prevent illegitimate mitotic DNA recombination and chromatin rearrangement.},
}
@article {pmid31932620,
year = {2020},
author = {Axelsson, J and Wapstra, E and Miller, E and Rollings, N and Olsson, M},
title = {Contrasting seasonal patterns of telomere dynamics in response to environmental conditions in the ectothermic sand lizard, Lacerta agilis.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {182},
pmid = {31932620},
issn = {2045-2322},
mesh = {Animals ; *Body Temperature Regulation ; Lizards/*genetics ; Reactive Oxygen Species/*metabolism ; *Seasons ; Telomere/*genetics ; *Telomere Shortening ; Temperature ; },
abstract = {Telomeres, the protective, terminal parts of the chromosomes erode during cell division and as a result of oxidative damage by reactive oxygen species (ROS). Ectotherms rely on the ambient temperature for maintaining temperature-dependent metabolic rate, regulated through behavioural thermoregulation. Their temperature-dependant metabolism, hence also the ROS production, is indirectly regulated through thermoregulation. Consequently, a potential causal chain affecting telomere length and attrition is: temperature (in particular, its deviation from a species-specific optimum) - metabolism - ROS production - anti-oxidation - telomere erosion. We measured telomere length in sand lizards (Lacerta agilis) using qPCR on blood samples from 1998-2006. Effects of climatological parameters (mean temperature and average sunshine hours) in the summer and winter preceding telomere sampling were used as predictors of telomere length in mixed model analysis. During the lizards' active period (summer), there was a largely negative effect of mean temperature and sun on telomere length, whereas a combined measure of age and size (head length) was positively related to telomere length. During the inactive period of lizards (winter), the results were largely the opposite with a positive relationship between temperature and sunshine hours and telomere length. In all four cases, thermal and age effects on telomere length appeared to be non-linear in the two sexes and seasons, with complex response surface effects on telomere length from combined age and thermal effects.},
}
@article {pmid31932509,
year = {2020},
author = {Barg-Wojas, A and Muraszko, J and Kramarz, K and Schirmeisen, K and Baranowska, G and Carr, AM and Dziadkowiec, D},
title = {Schizosaccharomyces pombe DNA translocases Rrp1 and Rrp2 have distinct roles at centromeres and telomeres that ensure genome stability.},
journal = {Journal of cell science},
volume = {133},
number = {3},
pages = {},
doi = {10.1242/jcs.230193},
pmid = {31932509},
issn = {1477-9137},
mesh = {Centromere/genetics ; Chromosomal Proteins, Non-Histone/genetics ; DNA ; Genomic Instability/genetics ; Humans ; *Schizosaccharomyces/genetics ; *Schizosaccharomyces pombe Proteins/genetics ; Telomere/genetics ; },
abstract = {The regulation of telomere and centromere structure and function is essential for maintaining genome integrity. Schizosaccharomyces pombe Rrp1 and Rrp2 are orthologues of Saccharomyces cerevisiae Uls1, a SWI2/SNF2 DNA translocase and SUMO-targeted ubiquitin ligase. Here, we show that Rrp1 or Rrp2 overproduction leads to chromosome instability and growth defects, a reduction in global histone levels and mislocalisation of centromere-specific histone Cnp1. These phenotypes depend on putative DNA translocase activities of Rrp1 and Rrp2, suggesting that Rrp1 and Rrp2 may be involved in modulating nucleosome dynamics. Furthermore, we confirm that Rrp2, but not Rrp1, acts at telomeres, reflecting a previously described interaction between Rrp2 and Top2. In conclusion, we identify roles for Rrp1 and Rrp2 in maintaining centromere function by modulating histone dynamics, contributing to the preservation of genome stability during vegetative cell growth.},
}
@article {pmid31928178,
year = {2020},
author = {He, H and Li, W and Comiskey, DF and Liyanarachchi, S and Nieminen, TT and Wang, Y and DeLap, KE and Brock, P and de la Chapelle, A},
title = {A Truncating Germline Mutation of TINF2 in Individuals with Thyroid Cancer or Melanoma Results in Longer Telomeres.},
journal = {Thyroid : official journal of the American Thyroid Association},
volume = {30},
number = {2},
pages = {204-213},
pmid = {31928178},
issn = {1557-9077},
mesh = {Adenocarcinoma, Follicular/*genetics ; Adult ; Aged, 80 and over ; Female ; Genetic Predisposition to Disease ; *Germ-Line Mutation ; Humans ; Male ; Melanoma/*genetics ; Middle Aged ; *Telomere ; Telomere-Binding Proteins/*genetics ; Thyroid Cancer, Papillary/*genetics ; Thyroid Neoplasms/*genetics ; },
abstract = {Background: Our genome sequencing analysis revealed a frameshift mutation in the shelterin gene TINF2 in a large family with individuals affected with papillary thyroid carcinoma (PTC) and melanoma. Here, we further characterized the mutation and screened for coding variants in the 6 shelterin genes in 24 families. Methods: Sanger sequencing was performed to screen for the TINF2 mutation in the key family. Quantitative reverse transcription-polymerase chain reaction (PCR) was used for TINF2 gene expression analysis. Exogenous expression and co-immunoprecipitation techniques were used for assessing TINF2 binding to TERF1. Relative telomere length (RTL) was quantified in DNAs from lymphocytes by using quantitative real-time PCR. Whole exome sequencing (WES) was performed in seven families with individuals affected with PTC and other cancer types. Screening for DNA variants in shelterin genes was performed by using whole genome sequencing data from 17 families and WES data from 7 further families. Results: The TINF2 mutation (TINF2 p.Trp198fs) showed complete co-segregation with PTC and melanoma in the key family. The mutation is not reported in databases and not identified in 23 other families we screened. The expression of TINF2 was borderline reduced in individuals with the mutation. The truncated TINF2 protein showed abolished binding to TERF1. The RTL in the individuals with the mutation was significantly longer when compared with those without the mutation from the same family as well as compared with 62 healthy controls. Among the 24 families, we identified 3 missense and 1 synonymous variant(s) in 2 shelterin genes (TINF2 and ACD). Conclusions: The rare frameshift mutation in the TINF2 gene and the associated longer telomere length suggest that dysregulated telomeres could be a mechanism predisposing to PTC and melanoma. DNA coding variants in shelterin genes are rare. Further studies are required to evaluate the roles of variants in shelterin genes in thyroid cancer and melanoma.},
}
@article {pmid31928029,
year = {2020},
author = {Chae, DH and Wang, Y and Martz, CD and Slopen, N and Yip, T and Adler, NE and Fuller-Rowell, TE and Lin, J and Matthews, KA and Brody, GH and Spears, EC and Puterman, E and Epel, ES},
title = {Racial discrimination and telomere shortening among African Americans: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.},
journal = {Health psychology : official journal of the Division of Health Psychology, American Psychological Association},
volume = {39},
number = {3},
pages = {209-219},
pmid = {31928029},
issn = {1930-7810},
support = {/HL/NHLBI NIH HHS/United States ; F31 AR076234/AR/NIAMS NIH HHS/United States ; K01 AG041787/AG/NIA NIH HHS/United States ; //National Institutes of Health; National Institute on Aging/ ; //MacArthur Foundation; SES and Health Network/ ; //Intramural Research Program of the NIA/ ; },
mesh = {Adolescent ; Adult ; Black or African American/*genetics ; Coronary Artery Disease/*etiology ; Female ; Humans ; Male ; Racism/*psychology ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {OBJECTIVE: Telomeres are protective sequences of DNA capping the ends of chromosomes that shorten over time. Leukocyte telomere length (LTL) is posited to reflect the replicative history of cells and general systemic aging of the organism. Chronic stress exposure leads to accelerated LTL shortening, which has been linked to increased susceptibility to and faster progression of aging-related diseases. This study examined longitudinal associations between LTL and experiences of racial discrimination, a qualitatively unique source of minority psychosocial stress, among African Americans.<br><br>METHOD: Data are from 391 African Americans in the Coronary Artery Risk Development in Young Adults (CARDIA) Telomere Ancillary Study. We examined the number of domains in which racial discrimination was experienced in relation to LTL collected in Years 15 and 25 (Y15: 2000/2001; Y25: 2010/2011). Multivariable linear regression examined if racial discrimination was associated with LTL. Latent change score analysis (LCS) examined changes in racial discrimination and LTL in relation to one another.<br><br>RESULTS: Controlling for racial discrimination at Y15, multivariable linear regression analyses indicated that racial discrimination at Y25 was significantly associated with LTL at Y25. This relationship remained robust after adjusting for LTL at Y15 (b = -.019, p = .015). Consistent with this finding, LCS revealed that increases in experiences of racial discrimination were associated with faster 10-year LTL shortening (b = -.019, p = .015).<br><br>CONCLUSIONS: This study adds to evidence that racial discrimination contributes to accelerated physiologic weathering and health declines among African Americans through its impact on biological systems, including via its effects on telomere attrition. (PsycINFO Database Record (c) 2020 APA, all rights reserved).},
}
@article {pmid31926882,
year = {2020},
author = {Wieczór, M and Czub, J},
title = {Telomere uncapping by common oxidative guanine lesions: Insights from atomistic models.},
journal = {Free radical biology &amp; medicine},
volume = {148},
number = {},
pages = {162-169},
doi = {10.1016/j.freeradbiomed.2020.01.006},
pmid = {31926882},
issn = {1873-4596},
mesh = {DNA Damage ; *Guanine ; Oxidation-Reduction ; Oxidative Stress ; *Telomere/genetics ; },
abstract = {Oxidative damage to DNA is widely known to contribute to aging and disease. This relationship has been extensively studied for telomeres - structures that cap chromosome ends - due to their role in cell proliferation and senescence, and exceptional susceptibility to oxidation. Indeed, the repetitive telomeric DNA sequence contains the 5'-GGG-3' motif that has the lowest ionization potential of all trinucleotides. Accordingly, experiments consistently show that telomeric oxidative lesions are more abundant and persistent than elsewhere in the genome. This led to a hypothesis that telomeres act as sensors of prolonged oxidative stress and prevent carcinogenesis, as disruption of telomeric integrity triggers senescence or apoptosis. Here, we use atomistic alchemical Molecular Dynamics simulations to perform a combinatorial assessment of changes in DNA binding affinity of telomeric proteins induced by oxidative guanine lesions. We rank lesions by their effect on telomere integrity, as well as telomeric proteins by their sensitivity to DNA oxidation. While the binding of most proteins is abolished by DNA oxidation, HOT1 emerges as a notable exception, suggesting its potential role in sensing of oxidative damage. Through statistical analysis and free energy decomposition, we also identify common trends in structural responses of protein-DNA complexes that contribute to decreased binding affinity.},
}
@article {pmid31924155,
year = {2020},
author = {da Silva, GG and Morais, KS and Arcanjo, DS and de Oliveira, DM},
title = {Clinical Relevance of Alternative Lengthening of Telomeres in Cancer.},
journal = {Current topics in medicinal chemistry},
volume = {20},
number = {6},
pages = {485-497},
doi = {10.2174/1568026620666200110112854},
pmid = {31924155},
issn = {1873-4294},
mesh = {Humans ; Neoplasms/*genetics ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {The alternative lengthening of telomere (ALT) is a pathway responsible for cell immortalization in some kinds of tumors. Since the first description of ALT is relatively recent in the oncology field, its mechanism remains elusive, but recent works address ALT-related proteins or cellular structures as potential druggable targets for more specific and efficient antitumor therapies. Moreover, some new generation compounds for antitelomerase therapy in cancer were able to provoke acquisition of ALT phenotype in treated tumors, enhancing the importance of studies on this alternative lengthening of the telomere. However, ALT has been implicated in different - sometimes opposite - outcomes, according to the tumor type studied. Then, in order to design and develop new drugs for ALT+ cancer in an effective way, it is crucial to understand its clinical implications. In this review, we gathered works published in the last two decades to highlight the clinical relevance of ALT on oncology.},
}
@article {pmid31923847,
year = {2020},
author = {Michels, KB and De Vivo, I and Calafat, AM and Binder, AM},
title = {In utero exposure to endocrine-disrupting chemicals and telomere length at birth.},
journal = {Environmental research},
volume = {182},
number = {},
pages = {109053},
pmid = {31923847},
issn = {1096-0953},
support = {R03 ES025348/ES/NIEHS NIH HHS/United States ; },
mesh = {*Endocrine Disruptors/toxicity ; *Environmental Pollutants ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; *Maternal Exposure ; Phenols ; *Phthalic Acids ; Pregnancy ; Sex Factors ; Telomere ; *Telomere Homeostasis/drug effects ; *Telomere Shortening/drug effects ; *Triclosan ; },
abstract = {Telomere length correlates with morbidity and mortality. While telomere length appears to be influenced by hormone levels, the potential impact of exposure to endocrine-disrupting chemicals (EDCs) has not been studied. We examined the association between maternal gestational concentrations of biomarkers of EDC exposure and telomere length at birth in the Harvard Epigenetic Birth Cohort. EDC (phenols and phthalates) biomarker concentrations were measured in maternal spot urine samples during the first trimester and telomere length in maternal and cord blood collected at delivery among 181 mother-newborn singleton dyads. Maternal and newborn telomere length exhibited a positive correlation (Spearman ρ = 0.20 (p-value< 0.01). Infant telomere length was associated with maternal biomarker concentrations of specific EDCs, and most of these associations were observed to be infant sex-specific. Prenatal exposure to triclosan, a non-paraben phenol with antimicrobial properties, was one of the most strongly associated EDCs with telomere length; telomere length was 20% (95% CI 5%-33%) shorter among boys in the highest quartile of maternal biomarker concentrations compared to the lowest quartile. In contrast, we observed longer telomere length associated with increased gestational concentrations of mono-isobutyl phthalate, and among boys, with increased concentrations of mono-2-ethylhexyl phthalate. In this birth cohort, we observed associations between maternal gestational exposure to select EDC biomarkers and telomere length, most of which were sex-specific. These findings need to be confirmed in future studies.},
}
@article {pmid31923465,
year = {2020},
author = {Ma, Y and Bellini, N and Scholten, RH and Andersen, MHG and Vogel, U and Saber, AT and Loft, S and Møller, P and Roursgaard, M},
title = {Effect of combustion-derived particles on genotoxicity and telomere length: A study on human cells and exposed populations.},
journal = {Toxicology letters},
volume = {322},
number = {},
pages = {20-31},
doi = {10.1016/j.toxlet.2020.01.002},
pmid = {31923465},
issn = {1879-3169},
mesh = {A549 Cells ; Air Pollutants, Occupational/toxicity ; Cell Survival/drug effects ; *DNA Damage ; Firefighters ; Humans ; Inhalation Exposure/*adverse effects/analysis ; Leukocytes, Mononuclear/drug effects/pathology ; Occupational Exposure/adverse effects/analysis ; Oxidative Stress/drug effects/genetics ; Particle Size ; Particulate Matter/*toxicity ; Smoke/*adverse effects ; Telomere Homeostasis/*drug effects/genetics ; Vehicle Emissions/*toxicity ; },
abstract = {Particulate matter (PM) from combustion processes has been associated with oxidative stress to DNA, whereas effects related to telomere dysfunction are less investigated. We collected air-borne PM from a passenger cabin of a diesel-propelled train and at a training facility for smoke diving exercises. Effects on oxidative stress biomarkers, genotoxicity measured by the comet assay and telomere length in PM-exposed A549 cells were compared with the genotoxicity and telomere length in peripheral blood mononuclear cells (PBMCs) from human volunteers exposed to the same aerosol source. Although elevated levels of DNA strand breaks and oxidatively damaged DNA in terms of Fpg-sensitive sites were observed in PBMCs from exposed humans, the PM collected at same locations did not cause genotoxicity in the comet assay in A549 cells. Nevertheless, A549 cells displayed telomere length shortening after four weeks exposure to PM. This is in line with slightly shorter telomere length in PBMCs from exposed humans, although it was not statistically significant. In conclusion, the results indicate that genotoxic potency measured by the comet assay of PM in A549 cells may not predict genotoxicity in exposed humans, whereas telomere length measurements may be a novel indicator of genotoxic stress in cell cultures and humans.},
}
@article {pmid31923255,
year = {2020},
author = {Chan, D and Martin-Ruiz, C and Saretzki, G and Neely, D and Qiu, W and Kunadian, V},
title = {The association of telomere length and telomerase activity with adverse outcomes in older patients with non-ST-elevation acute coronary syndrome.},
journal = {PloS one},
volume = {15},
number = {1},
pages = {e0227616},
pmid = {31923255},
issn = {1932-6203},
support = {/DH_/Department of Health/United Kingdom ; CS/15/7/31679/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Acute Coronary Syndrome/blood/genetics/metabolism ; Aged ; Aged, 80 and over ; Coronary Angiography ; Female ; Hemorrhage/complications ; Humans ; Incidence ; Leukocytes, Mononuclear/metabolism ; Male ; Middle Aged ; Myocardial Infarction/complications ; Non-ST Elevated Myocardial Infarction/blood/*genetics/metabolism ; Prognosis ; Proportional Hazards Models ; Risk Factors ; Stroke/complications ; Telomerase/genetics ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics/physiology ; Treatment Outcome ; },
abstract = {BACKGROUND: Non-ST elevation acute coronary syndrome (NSTEACS) occurs more frequently in older patients with an increased occurrence of recurrent cardiac events following the index presentation. Telomeres are structures consisting of repeated DNA sequences as associated shelterin proteins at the ends of chromosomes. We aim to determine whether telomere length (TL) and telomerase activity (TA) predicted poor outcomes in older patients presenting with NSTEACS undergoing invasive care.<br><br>METHOD: Older patients undergoing invasive management for NSTEACS were recruited to the ICON-1 biomarker study (NCT01933581). Peripheral blood mononuclear cells (PBMC) were recovered on 153 patients. DNA was isolated and mean TL was measured by quantitative PCR expressed as relative T (telomere repeat copy number) to S (single copy gene number) ratio (T/S ratio), and a telomere repeat amplification assay was used to assess TA during index presentation with NSTEACS. Primary clinical outcomes consisted of death, myocardial infarction (MI), unplanned revascularisation, stroke and significant bleeding recorded at 1 year. TL and TA were divided into tertile groups for analysis. Cox proportional hazards regression was performed. Ordinal regression was performed to evaluate the relationship between TL and TA and traditional cardiovascular risk factors at baseline.<br><br>RESULTS: 298 patients were recruited in the ICON-1 study of which 153 had PBMC recovered. The mean age was 81.0 &#xb1; 4.0 years (64% male). Mean telomere length T/S ratio was 0.47 &#xb1; 0.25 and mean TA was 1.52 &#xb1; 0.61 units. The primary composite outcome occurred in 44 (28.8%) patients. There was no association between short TL or low TA and incidence of the primary composite outcome (Hazard Ratio [HR] 1.50, 95% Confidence Interval [CI] 0.68-3.34, p = 0.32 and HR 1.33, 95% CI 0.52-3.36, p = 0.51 respectively).<br><br>CONCLUSION: TL and TA are not found to be associated with the incidence of adverse outcomes in older patients presenting with NSTEACS undergoing invasive care.<br><br>CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov Unique identifier: NCT01933581.},
}
@article {pmid31922164,
year = {2020},
author = {Ma, TZ and Zhang, MJ and Liao, TC and Li, JH and Zou, M and Wang, ZM and Zhou, CQ},
title = {Dimers formed with the mixed-type G-quadruplex binder pyridostatin specifically recognize human telomere G-quadruplex dimers.},
journal = {Organic &amp; biomolecular chemistry},
volume = {18},
number = {5},
pages = {920-930},
doi = {10.1039/c9ob02470k},
pmid = {31922164},
issn = {1477-0539},
mesh = {Aminoquinolines/chemical synthesis/*chemistry ; Calorimetry ; Circular Dichroism ; *Dimerization ; Enzyme Inhibitors/pharmacology ; *G-Quadruplexes ; Humans ; Kinetics ; Picolinic Acids/chemical synthesis/*chemistry ; Telomerase/antagonists &amp; inhibitors ; Telomere/*metabolism ; Thermodynamics ; },
abstract = {By choosing pyridostatin (PDS) with high thermal stabilization towards mixed-type G-quadruplexes as the monomer in dimers, three novel polyether-tethered PDS dimers (1a-c) were first synthesized and their interaction with human telomere G-quadruplex dimers (G2T1) was studied. Through the regulation of the linker length in PDS dimers, the dimer with a medium-length polyether linker (1b) showed higher binding selectivity and thermal stabilization (ΔTm = 29.5 °C) towards antiparallel G2T1 over G-quadruplex monomers (G1). Furthermore, the dimer with the longest-length polyether linker (1c) showed higher binding selectivity and thermal stabilization towards mixed-type G2T1 over mixed-type G1, c-kit 1, c-kit 2, c-myc and ds DNA. This work provides new insights into the development of G2T1 binders, especially mixed-type G2T1 binders, which could be promoted by a polymer formed with a mixed-type G-quadruplex binder. In addition, dimer 1c exhibited stronger telomerase inhibition than dimers 1a and 1b.},
}
@article {pmid31921685,
year = {2019},
author = {Shi, Y and Zhang, Y and Zhang, L and Ma, JL and Zhou, T and Li, ZX and Liu, WD and Li, WQ and Deng, DJ and You, WC and Pan, KF},
title = {Telomere Length of Circulating Cell-Free DNA and Gastric Cancer in a Chinese Population at High-Risk.},
journal = {Frontiers in oncology},
volume = {9},
number = {},
pages = {1434},
pmid = {31921685},
issn = {2234-943X},
abstract = {Background: Telomeres have long been found to be involved in cancer development, while little was known about the dynamic changes of telomere length in carcinogenesis process. Methods: The present study longitudinally investigated telomere alterations of cell-free DNA (cfDNA) in 86 gastric cancer (GC) subjects recruited through a 16-year prospective cohort with 2-4 serums collected before each GC-diagnosis from baseline and three follow-up time-points (a total of 276 samples). As the control, 86 individual-matched cancer-free subjects were enrolled with 276 serums from the matched calendar year. Results: In the 73 pairs of baseline serums from GC and control subjects, shortened telomeres showed increased subsequent GC risk [odds ratio (OR) = 9.17, 95% CI: 2.72-31.25 for 1 unit shortening]. In each baseline gastric lesion category, higher risks of GC progression were also found with shortened cfDNA telomeres; ORs per 1 unit shortening were 6.99 (95% CI: 1.63-30.30) for mild gastric lesions, 6.06 (95% CI: 1.89-19.61) for intestinal metaplasia and 15.63 (95% CI: 1.91-125.00) for dysplasia. With all measurements from baseline and follow-up time-points, shortened telomeres also showed significant association with GC risk (OR = 7.37, 95% CI: 2.06-26.32 for 1 unit shortening). In temporal trend analysis, shortened telomeres were found in GC subjects compared to corresponding controls more than 3 years ahead of GC-diagnosis (most P < 0.05), while no significant difference was found between two groups within 3 years approaching to GC-diagnosis. Conclusion: Our findings suggest that telomere shortening may be associated with gastric carcinogenesis, which supports further etiological study and potential biomarker for risk stratification.},
}
@article {pmid31919463,
year = {2020},
author = {Xu, C and Wang, Z and Su, X and Da, M and Yang, Z and Duan, W and Mo, X},
title = {Association between leucocyte telomere length and cardiovascular disease in a large general population in the United States.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {80},
pmid = {31919463},
issn = {2045-2322},
mesh = {Aged ; Cardiovascular Diseases/epidemiology/*genetics/*pathology ; Female ; Humans ; Leukocytes/metabolism/*pathology ; Male ; Telomere/*genetics ; *Telomere Homeostasis ; United States/epidemiology ; },
abstract = {Leucocyte telomere length (LTL) has been reported to be linked to ageing, cancer and cardiovascular disease (CVD). This study aimed to explore the association between LTL and CVD risk in a nationally representative sample of U.S. adults. Complex associations, including nonlinearity and interaction, were also examined. A total of 7,378 subjects from the National Health and Nutrition Examination Survey (NHANES) 1999-2002 were collected. Telomere length was detected from DNA samples and expressed as the mean T/S ratio (telomere repeats per single-copy gene). We performed multiple logistic regression models and interactive analysis to explore the associations between LTL and CVD risk by adjusting for potential confounders. We also performed a sensitivity analysis to investigate the robustness of our results. Among all participants, LTL was associated with the risk of CVD (OR = 0.79, 95% CI: 0.63~0.98, P = 0.033) in a linear manner rather than in a nonlinear manner (P = 0.874). Interaction effects of LTL with both education (P = 0.017) and hypertension (P = 0.007) were observed. Furthermore, using subgroup analyses, protective effects of LTL on CVD risk were found in females and in individuals who were college graduates or above, had serum cotinine >10 ng/ml, did not have hypertension, or had normal white blood cell levels. LTL is linearly inversely associated with CVD risk in the general population of the United States.},
}
@article {pmid31916516,
year = {2020},
author = {Berei, J and Eckburg, A and Miliavski, E and Anderson, AD and Miller, RJ and Dein, J and Giuffre, AM and Tang, D and Deb, S and Racherla, KS and Patel, M and Vela, MS and Puri, N},
title = {Potential Telomere-Related Pharmacological Targets.},
journal = {Current topics in medicinal chemistry},
volume = {20},
number = {6},
pages = {458-484},
doi = {10.2174/1568026620666200109114339},
pmid = {31916516},
issn = {1873-4294},
mesh = {Antineoplastic Agents/chemistry/*pharmacology ; Biological Availability ; Humans ; Neoplasms/*drug therapy/genetics/metabolism ; Telomerase/antagonists &amp; inhibitors/genetics/metabolism ; Telomere/*drug effects/genetics/metabolism ; },
abstract = {Telomeres function as protective caps at the terminal portion of chromosomes, containing non-coding nucleotide sequence repeats. As part of their protective function, telomeres preserve genomic integrity and minimize chromosomal exposure, thus limiting DNA damage responses. With continued mitotic divisions in normal cells, telomeres progressively shorten until they reach a threshold at a point where they activate senescence or cell death pathways. However, the presence of the enzyme telomerase can provide functional immortality to the cells that have reached or progressed past senescence. In senescent cells that amass several oncogenic mutations, cancer formation can occur due to genomic instability and the induction of telomerase activity. Telomerase has been found to be expressed in over 85% of human tumors and is labeled as a near-universal marker for cancer. Due to this feature being present in a majority of tumors but absent in most somatic cells, telomerase and telomeres have become promising targets for the development of new and effective anticancer therapeutics. In this review, we evaluate novel anticancer targets in development which aim to alter telomerase or telomere function. Additionally, we analyze the progress that has been made, including preclinical studies and clinical trials, with therapeutics directed at telomere-related targets. Furthermore, we review the potential telomere-related therapeutics that are used in combination therapy with more traditional cancer treatments. Throughout the review, topics related to medicinal chemistry are discussed, including drug bioavailability and delivery, chemical structure-activity relationships of select therapies, and the development of a unique telomere assay to analyze compounds affecting telomere elongation.},
}
@article {pmid31916507,
year = {2022},
author = {Lara-Cerrillo, S and Gual-Frau, J and Benet, J and Abad, C and Prats, J and Amengual, MJ and Ribas-Maynou, J and García-Peiró, A},
title = {Microsurgical varicocelectomy effect on sperm telomere length, DNA fragmentation and seminal parameters.},
journal = {Human fertility (Cambridge, England)},
volume = {25},
number = {1},
pages = {135-141},
doi = {10.1080/14647273.2019.1711204},
pmid = {31916507},
issn = {1742-8149},
mesh = {DNA Fragmentation ; Humans ; *Infertility, Male/genetics/surgery ; Male ; Sperm Motility ; Spermatozoa ; Telomere ; *Varicocele/genetics/surgery ; },
abstract = {Varicocele is one of the main causes of male infertility and microsurgical varicocelectomy (MV) seems to be the best procedure for its repair and to reduce testicular oxidative stress (ROS). As ROS causes guanine modifications, we postulated that DNA damage could be more intense in telomeres due to their G-rich nature. We studied the effect of MV on sperm telomere length (TL), single- and double-strand DNA fragmentation (ssSDF and dsSDF) and seminal parameters. Sperm telomeres from 12 fertile donors and 20 varicocele patients before and nine months after MV were labelled using FITC-PNA qFISH (a new method to obtain absolute TL from relative fluorescence intensity using FITC-fluorescent spheres). Both ssSDF and dsSDF were analysed using the alkaline and neutral Comet assays, respectively. The results showed that varicocele and MV had no effect on TL. Seminal parameters, ssSDF and dsSDF of varicocele patients were altered. Although these parameters improved after MV, values did not reach those seen in fertile donors. A good estimation of absolute TL was developed based on FITC-fluorescent spheres. The results showed that TL is not affected by varicocele or surgery. However, MV is able to partially reduce altered seminal parameters, ssSDF and dsSDF values in varicocele patients.},
}
@article {pmid31915143,
year = {2020},
author = {Heaphy, CM and Joshu, CE and Barber, JR and Davis, C and Zarinshenas, R and De Marzo, AM and Lotan, TL and Sfanos, KS and Meeker, AK and Platz, EA},
title = {Racial Difference in Prostate Cancer Cell Telomere Lengths in Men with Higher Grade Prostate Cancer: A Clue to the Racial Disparity in Prostate Cancer Outcomes.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {29},
number = {3},
pages = {676-680},
pmid = {31915143},
issn = {1538-7755},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; P50 CA058236/CA/NCI NIH HHS/United States ; },
mesh = {Black or African American/genetics/statistics &amp; numerical data ; Aged ; *Health Status Disparities ; Humans ; Male ; Middle Aged ; Neoplasm Grading ; Prognosis ; Prostate/*pathology/surgery ; Prostatectomy ; Prostatic Neoplasms/diagnosis/genetics/*mortality/pathology ; *Telomere Homeostasis ; White People/genetics/statistics &amp; numerical data ; },
abstract = {BACKGROUND: Black men have worse prostate cancer outcomes following treatment than White men even when accounting for prognostic factors. However, biological explanations for this racial disparity have not been fully identified. We previously showed that more variable telomere lengths among cancer cells and shorter telomere lengths in cancer-associated stromal (CAS) cells individually and together ("telomere biomarker") are associated with prostate cancer-related death in surgically treated men independent of currently used prognostic indicators. Here, we hypothesize that Black-White differences in the telomere biomarker and/or in its components may help explain the racial disparity in prostate cancer outcomes.<br><br>METHODS: Black [higher grade (Gleason &#x2265;4+3) = 34 and lower grade = 93] and White (higher grade = 34 and lower grade = 89) surgically treated men were frequency matched on age, pathologic stage, and grade. We measured telomere lengths in cancer and CAS cells using a robust telomere-specific FISH assay. Tissue microarray and grade-specific distributional cutoff points without regard to race were evaluated.<br><br>RESULTS: Among men with higher grade disease, the proportion of Black men (47.1%) with more variable cancer cell telomere lengths was 2.3-times higher (P = 0.02) than that in White men (20.6%). In contrast, among men with lower grade disease, cancer cell telomere length variability did not differ by race. The proportion of men with shorter CAS cell telomeres did not differ by race for either higher or lower grade disease.<br><br>CONCLUSIONS: A greater proportion of Black men with higher grade disease have an adverse prostate cancer cell telomere phenotype than White men with higher grade disease.<br><br>IMPACT: Our findings suggest a possible explanation for the racial disparity in prostate cancer outcomes.},
}
@article {pmid31914653,
year = {2020},
author = {Peters-Hall, JR and Min, J and Tedone, E and Sho, S and Siteni, S and Mender, I and Shay, JW},
title = {Proliferation of adult human bronchial epithelial cells without a telomere maintenance mechanism for over 200 population doublings.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {34},
number = {1},
pages = {386-398},
pmid = {31914653},
issn = {1530-6860},
support = {P50 CA070907/CA/NCI NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; CA142543//HHS | NIH | National Cancer Institute (NCI)/International ; },
mesh = {Adult ; Bronchi/*cytology/physiology ; Cell Culture Techniques/*methods ; Cell Division ; *Cell Proliferation ; Cells, Cultured ; *Cellular Senescence ; Epithelial Cells/*cytology/physiology ; Fibroblasts/*cytology/physiology ; Humans ; Telomerase/metabolism ; Telomere/*physiology ; Telomere Shortening ; },
abstract = {To date, there is no direct evidence of telomerase activity in adult lung epithelial cells, but typical culture conditions only support cell proliferation for 30-40 population doublings (PD), a point at which telomeres remain relatively long. Here we report that in in vitro low stress culture conditions consisting of a fibroblast feeder layer, rho-associated coiled coil protein kinase inhibitor (ROCKi), and low oxygen (2%), normal human bronchial epithelial basal progenitor cells (HBECs) divide for over 200 PD without engaging a telomere maintenance mechanism (almost four times the "Hayflick limit"). HBECs exhibit critically short telomeres at 200 PD and the population of cells start to undergo replicative senescence. Subcloning these late passage cells to clonal density, to mimic lung injury in vivo, selects for rare subsets of HBECs that activate low levels of telomerase activity to maintain short telomeres. CRISPR/Cas9 knockout of human telomerase reverse transcriptase or treatment with the telomerase-mediated telomere targeting agent 6-thio-2'deoxyguanosine abrogates colony growth in these late passage cultures (>200 PD) but not in early passage cultures (<200 PD). To our knowledge, this is the first study to report such long-term growth of HBECs without a telomere maintenance mechanism. This report also provides direct evidence of telomerase activation in HBECs near senescence when telomeres are critically short. This novel cell culture system provides an experimental model to understand how telomerase is regulated in normal adult tissues.},
}
@article {pmid31914160,
year = {2020},
author = {Steiner, B and Ferrucci, LM and Mirabello, L and Lan, Q and Hu, W and Liao, LM and Savage, SA and De Vivo, I and Hayes, RB and Rajaraman, P and Huang, WY and Freedman, ND and Loftfield, E},
title = {Association between coffee drinking and telomere length in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.},
journal = {PloS one},
volume = {15},
number = {1},
pages = {e0226972},
pmid = {31914160},
issn = {1932-6203},
support = {UL1 TR001863/TR/NCATS NIH HHS/United States ; },
mesh = {Aged ; Caffeine/*pharmacology ; *Coffee/metabolism ; Colorectal Neoplasms/prevention &amp; control ; Cross-Sectional Studies ; Female ; Humans ; Lung Neoplasms/prevention &amp; control ; Male ; Middle Aged ; Ovarian Neoplasms/prevention &amp; control ; Prostatic Neoplasms/prevention &amp; control ; Telomere Homeostasis/*drug effects ; },
abstract = {Mounting evidence indicates that coffee, a commonly consumed beverage worldwide, is inversely associated with various chronic diseases and overall mortality. Few studies have evaluated the effect of coffee drinking on telomere length, a biomarker of chromosomal integrity, and results have been inconsistent. Understanding this association may provide mechanistic insight into associations of coffee with health. The aim of our study was to test the hypothesis that heavier coffee intake is associated with greater likelihood of having above-median telomere length. We evaluated the cross-sectional association between coffee intake and relative telomere length using data from 1,638 controls from four previously conducted case-control studies nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Coffee intake was assessed using a food frequency questionnaire, and relative telomere length was measured from buffy-coat, blood, or buccal cells. We used unconditional logistic regression models to generate multivariable-adjusted, study-specific odds ratios for the association between coffee intake and relative telomere length. We then conducted a random-effects meta-analysis to determine summary odds ratios. We found that neither summary continuous (OR = 1.01, 95% CI = 0.99-1.03) nor categorical (OR <3 cups/day vs. none = 1.37, 95% CI = 0.71-2.65; OR ≥3 cups/day vs. none = 1.47, 95% CI = 0.81-2.66) odds ratio estimates of coffee drinking and relative telomere length were statistically significant. However, in the largest of the four contributing studies, moderate (<3 cups/day) and heavy coffee drinkers (≥3 cups/day) were 2.10 times (95% CI = 1.25, 3.54) and 1.93 times as likely (95% CI = 1.17, 3.18) as nondrinkers to have above-median telomere length, respectively. In conclusion, we found no evidence that coffee drinking is associated with telomere length. Thus, it is unlikely that telomere length plays a role in potential coffee-disease associations.},
}
@article {pmid31910222,
year = {2020},
author = {van Batenburg, AA and Kazemier, KM and van Oosterhout, MFM and van der Vis, JJ and van Es, HW and Grutters, JC and Goldschmeding, R and van Moorsel, CHM},
title = {From organ to cell: Multi-level telomere length assessment in patients with idiopathic pulmonary fibrosis.},
journal = {PloS one},
volume = {15},
number = {1},
pages = {e0226785},
pmid = {31910222},
issn = {1932-6203},
mesh = {Adult ; Aged ; Alveolar Epithelial Cells/cytology/*metabolism ; Biomarkers/*analysis ; Case-Control Studies ; Cohort Studies ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/genetics/*pathology ; Male ; Middle Aged ; Telomerase/genetics/*metabolism ; Telomere/*genetics ; Telomere Shortening/*genetics ; Exome Sequencing ; },
abstract = {RATIONALE: A subset of patients with idiopathic pulmonary fibrosis (IPF) contains short leukocyte telomeres or telomere related mutations. We previously showed that alveolar type 2 cells have short telomeres in fibrotic lesions. Our objectives were to better understand how telomere shortening associates with fibrosis in IPF lung and identify a subset of patients with telomere-related disease.<br><br>METHODS: Average telomere length was determined in multiple organs, basal and apical lung, and diagnostic and end-stage fibrotic lung biopsies. Alveolar type 2 cells telomere length was determined in different areas of IPF lungs.<br><br>RESULTS: In IPF but not in controls, telomere length in lung was shorter than in other organs, providing rationale to focus on telomere length in lung. Telomere length did not correlate with age and no difference in telomere length was found between diagnostic and explant lung or between basal and apical lung, irrespective of the presence of a radiological apicobasal gradient or fibrosis. Fifteen out of 28 IPF patients had average lung telomere length in the range of patients with a telomerase (TERT) mutation, and formed the IPFshort group. Only in this IPFshort and TERT group telomeres of alveolar type 2 cells were extremely short in fibrotic areas. Additionally, whole exome sequencing of IPF patients revealed two genetic variations in RTEL1 and one in PARN in the IPFshort group.<br><br>CONCLUSIONS: Average lung tissue telomere shortening does not associated with fibrotic patterns in IPF, however, approximately half of IPF patients show excessive lung telomere shortening that is associated with pulmonary fibrosis driven by telomere attrition.},
}
@article {pmid31905921,
year = {2019},
author = {Udroiu, I and Sgura, A},
title = {Alternative Lengthening of Telomeres and Chromatin Status.},
journal = {Genes},
volume = {11},
number = {1},
pages = {},
pmid = {31905921},
issn = {2073-4425},
mesh = {Animals ; Chromatin/*genetics ; *Epigenesis, Genetic ; Homologous Recombination ; Humans ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Telomere length is maintained by either telomerase, a reverse transcriptase, or alternative lengthening of telomeres (ALT), a mechanism that utilizes homologous recombination (HR) proteins. Since access to DNA for HR enzymes is regulated by the chromatin status, it is expected that telomere elongation is linked to epigenetic modifications. The aim of this review is to elucidate the epigenetic features of ALT-positive cells. In order to do this, it is first necessary to understand the telomeric chromatin peculiarities. So far, the epigenetic nature of telomeres is still controversial: some authors describe them as heterochromatic, while for others, they are euchromatic. Similarly, ALT activity should be characterized by the loss (according to most researchers) or formation (as claimed by a minority) of heterochromatin in telomeres. Besides reviewing the main works in this field and the most recent findings, some hypotheses involving the role of telomere non-canonical sequences and the possible spatial heterogeneity of telomeres are given.},
}
@article {pmid31905589,
year = {2020},
author = {Ock, J and Kim, J and Choi, YH},
title = {Organophosphate insecticide exposure and telomere length in U.S. adults.},
journal = {The Science of the total environment},
volume = {709},
number = {},
pages = {135990},
doi = {10.1016/j.scitotenv.2019.135990},
pmid = {31905589},
issn = {1879-1026},
mesh = {Environmental Exposure ; Humans ; Insecticides ; Nutrition Surveys ; Organophosphates ; Organophosphorus Compounds ; *Telomere ; Young Adult ; },
abstract = {BACKGROUND: Organophosphate insecticides have been widely used for >30 years, and are reported to be associated with various age-related chronic diseases. While shortening of telomere length has been considered as a marker of cellular aging, only a few small studies have been conducted to examine any difference of telomere length in workers exposed to organophosphates versus controls. Epidemiologic studies of the dose-response associations between environmental organophosphate exposure and telomere length in the general population are few.<br><br>OBJECTIVE: This study aimed to evaluate the association between levels of organophosphate insecticide exposure and telomere length in the general population.<br><br>METHODS: We analyzed data for 1724 participants aged 20&#xa0;years or more from the National Health and Nutrition Examination Survey 1999-2002. Organophosphate insecticide exposure was estimated using measures of urinary concentrations for 3,5,6-trichloro-2-pyridinol (TCPY) and six non-specific dialkyl phosphate metabolites, e.g., diethyl thiophosphate (DETP). Multiple linear regression was conducted to assess the association between organophosphate exposure and telomere length.<br><br>RESULTS: After controlling for sociodemographic and physical factors and urinary creatinine, participants in the second quartile for urinary TCPY had 0.06 (95% CI: 0.02-0.10) T/S ratio shorter telomere length than those in the lowest quartile. By contrast, participants in the second and third tertiles of urinary DETP had 0.08 (95% CI: 0.02-0.14) and 0.06 (95% CI, 0.01-0.11) T/S ratio longer telomere length than those in the lowest tertile. For other five metabolites, there was no association with telomere length.<br><br>CONCLUSIONS: Levels of environmental exposures to certain organophosphate insecticides may be linked to altered telomere length in adults in the general population. Although our findings may need to be replicated, we provide the first evidence that environmental exposure to organophosphates may contribute to the alteration of telomere length, which is potentially related to biological aging and to the development of various chronic diseases.},
}
@article {pmid31903880,
year = {2020},
author = {Yuan, X and Dai, M and Xu, D},
title = {Telomere-related Markers for Cancer.},
journal = {Current topics in medicinal chemistry},
volume = {20},
number = {6},
pages = {410-432},
pmid = {31903880},
issn = {1873-4294},
mesh = {Antineoplastic Agents/pharmacology ; Biomarkers, Tumor/genetics/*metabolism ; Humans ; Neoplasms/drug therapy/genetics/*metabolism/pathology ; Telomere/drug effects/genetics/*metabolism ; Telomere Homeostasis/drug effects ; },
abstract = {Telomeres are structurally nucleoprotein complexes at termini of linear chromosomes and essential to chromosome stability/integrity. In normal human cells, telomere length erodes progressively with each round of cell divisions, which serves as an important barrier to uncontrolled proliferation and malignant transformation. In sharp contrast, telomere maintenance is a key feature of human malignant cells and required for their infinite proliferation and maintenance of other cancer hallmarks as well. Thus, a telomere-based anti-cancer strategy has long been suggested. However, clinically efficient and specific drugs targeting cancer telomere-maintenance have still been in their infancy thus far. To achieve this goal, it is highly necessary to elucidate how exactly cancer cells maintain functional telomeres. In the last two decades, numerous studies have provided profound mechanistic insights, and the identified mechanisms include the aberrant activation of telomerase or the alternative lengthening of telomere pathway responsible for telomere elongation, dysregulation and mutation of telomereassociated factors, and other telomere homeostasis-related signaling nodes. In the present review, these various strategies employed by malignant cells to regulate their telomere length, structure and function have been summarized, and potential implications of these findings in the rational development of telomere- based cancer therapy and other clinical applications for precision oncology have been discussed.},
}
@article {pmid31903785,
year = {2020},
author = {Schutte, NS and Malouff, JM and Keng, SL},
title = {Meditation and telomere length: a meta-analysis.},
journal = {Psychology &amp; health},
volume = {35},
number = {8},
pages = {901-915},
doi = {10.1080/08870446.2019.1707827},
pmid = {31903785},
issn = {1476-8321},
mesh = {Female ; Humans ; Male ; *Meditation ; *Mindfulness ; Telomere/*physiology ; },
abstract = {Objective: Telomeres are the caps at the end of chromosomes. Short telomeres are a biomarker for worsening health and early death.Design: The present study consolidated research on meditation and telomere length through a meta-analysis of results of studies examining the effect of meditation on telomere length by comparing the telomere length of meditating participants with participants in control conditions.Results: A search of the literature identified 11 studies reporting 12 comparisons of meditating individuals with individuals in control conditions. An overall significant weighted effect size of g =.40 indicated that the individuals in meditation conditions had longer telomeres. When an outlier effect size was trimmed from the analysis, the effect size was smaller, g =.16. Across studies, a greater number of hours of meditation among participants in meditation conditions was associated with larger effect sizes.Conclusion: These findings provide tentative support for the hypothesis that participants in meditation conditions have longer telomeres than participants in comparison conditions, and that a greater number of hours of meditation is associated with a greater impact on telomere biology. The results of the meta-analysis have potential clinical significance in that they suggest that meditation-based interventions may prevent telomere attrition or increase telomere length.},
}
@article {pmid31902602,
year = {2020},
author = {Mazidi, M and Mikhailidis, DP and Banach, M and Dehghan, A},
title = {Impact of serum 25-hydroxyvitamin D 25(OH) on telomere attrition: A Mendelian Randomization study.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {39},
number = {9},
pages = {2730-2733},
doi = {10.1016/j.clnu.2019.12.008},
pmid = {31902602},
issn = {1532-1983},
mesh = {Genome-Wide Association Study ; Humans ; Mendelian Randomization Analysis/*methods ; Polymorphism, Single Nucleotide ; Telomere Homeostasis/genetics/physiology ; Telomere Shortening/genetics/*physiology ; Vitamin D/*analogs &amp; derivatives/blood ; },
abstract = {BACKGROUND: Conventional observational studies have suggested that 25-hydroxyvitamin D (25(OH)D) is inversely associated with telomere shortening. We aimed to apply two-sample Mendelian randomization (MR) to assess the causal association between serum 25(OH) D and telomere length (TL).<br><br>METHODS: MR was implemented by using summary-level data from the largest genome-wide association studies (GWAS) on vitamin D (n&#xa0;=&#xa0;73&#xa0;699) and TL (n&#xa0;=&#xa0;37&#xa0;684). Inverse variance weighted method (IVW) was used to estimate the causal estimates. Weighted median (WM)-based method, and MR-Egger, leave-one-out were applied as sensitivity analysis.<br><br>RESULTS: The results of MR demonstrated no effect of 25(OH)D on TL (IVW&#xa0;=&#xa0;&#x3b2;:-0.104, p&#xa0;=&#xa0;0.219, WM&#xa0;=&#xa0;&#x3b2;:-0.109, p&#xa0;=&#xa0;0.188; MR Egger&#xa0;=&#xa0;&#x3b2;:-0.127, p&#xa0;=&#xa0;0.506). None of the 25(OH)D-related single nucleotide polymorphisms (SNPs) were significantly associated with TL. Heterogeneity tests did not detect heterogeneity. Furthermore, MR pleiotropy residual sum and outlier (MR-PRESSO) did not highlight any outliers (p&#xa0;=&#xa0;0.424). Results of leave-one-out method demonstrated that the links are not driven because of the single SNPs.<br><br>CONCLUSIONS: Our study does not support any causal effect of 25(OH) D on TL.},
}
@article {pmid31901896,
year = {2020},
author = {Hiam, D and Smith, C and Voisin, S and Denham, J and Yan, X and Landen, S and Jacques, M and Alvarez-Romero, J and Garnham, A and Woessner, MN and Herrmann, M and Duque, G and Levinger, I and Eynon, N},
title = {Aerobic capacity and telomere length in human skeletal muscle and leukocytes across the lifespan.},
journal = {Aging},
volume = {12},
number = {1},
pages = {359-369},
pmid = {31901896},
issn = {1945-4589},
mesh = {Adult ; Aerobiosis/*genetics ; Aging/*genetics ; Female ; Humans ; Leukocytes/*metabolism ; Longevity/genetics ; Male ; Muscle, Skeletal/*metabolism ; Physical Fitness ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {A reduction in aerobic capacity and the shortening of telomeres are hallmarks of the ageing process. We examined whether a lower aerobic capacity is associated with shorter TL in skeletal muscle and/or leukocytes, across a wide age range of individuals. We also tested whether TL in human skeletal muscle (MTL) correlates with TL in leukocytes (LTL). Eighty-two recreationally active, healthy men from the Gene SMART cohort (31.4±8.2 years; body mass index (BMI)=25.3±3.3kg/m[2]), and 11 community dwelling older men (74.2±7.5years-old; BMI=28.7±2.8kg/m[2]) participated in the study. Leukocytes and skeletal muscle samples were collected at rest. Relative telomere length (T/S ratio) was measured by RT-PCR. Associations between TL, aerobic capacity (VO2 peak and peak power) and age were assessed with robust linear models. Older age was associated with shorter LTL (45% variance explained, P<0.001), but not MTL (P= 0.7). Aerobic capacity was not associated with MTL (P=0.5), nor LTL (P=0.3). MTL and LTL were correlated across the lifespan (rs=0.26, P=0.03). In healthy individuals, age explain most of the variability of LTL and this appears to be independent of individual aerobic capacity. Individuals with longer LTL also have a longer MTL, suggesting that there might be a shared molecular mechanism regulating telomere length.},
}
@article {pmid31900099,
year = {2020},
author = {Rentscher, KE and Carroll, JE and Mitchell, C},
title = {Psychosocial Stressors and Telomere Length: A Current Review of the Science.},
journal = {Annual review of public health},
volume = {41},
number = {},
pages = {223-245},
doi = {10.1146/annurev-publhealth-040119-094239},
pmid = {31900099},
issn = {1545-2093},
mesh = {Adolescent ; Adult ; *Adult Survivors of Child Abuse ; Aged ; Aged, 80 and over ; Aging/*genetics/*physiology ; Child ; *Child Abuse ; Child, Preschool ; Female ; Humans ; *Life Change Events ; Male ; Middle Aged ; Stress, Psychological/*genetics/physiopathology ; Telomere Shortening/*genetics/physiology ; Young Adult ; },
abstract = {A growing literature suggests that exposure to adverse social conditions may accelerate biological aging, offering one mechanism through which adversity may increase risk for age-related disease. As one of the most extensively studied biological markers of aging, telomere length (TL) provides a valuable tool to understand potential influences of social adversity on the aging process. Indeed, a sizeable literature now links a wide range of stressors to TL across the life span. The aim of this article is to review and evaluate this extant literature with a focus on studies that investigate psychosocial stress exposures and experiences in early life and adulthood. We conclude by outlining potential biological and behavioral mechanisms through which psychosocial stress may influence TL, and we discuss directions for future research in this area.},
}
@article {pmid31897670,
year = {2020},
author = {Márquez-Ruiz, AB and González-Herrera, L and Luna, JD and Valenzuela, A},
title = {DNA methylation levels and telomere length in human teeth: usefulness for age estimation.},
journal = {International journal of legal medicine},
volume = {134},
number = {2},
pages = {451-459},
pmid = {31897670},
issn = {1437-1596},
support = {Contrato 3193-00//Andalusian Centre of Excellence for Forensic Research (CEIFA)/ ; },
mesh = {Adolescent ; Adult ; *Age Determination by Teeth ; Aged ; Aged, 80 and over ; Amidohydrolases/*genetics ; Biomarkers ; CpG Islands ; Cyclic Nucleotide Phosphodiesterases, Type 4/*genetics ; *DNA Methylation ; Fatty Acid Elongases/*genetics ; Female ; Forensic Dentistry ; Forensic Genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; Middle Aged ; Models, Statistical ; Regression Analysis ; *Telomere ; },
abstract = {In the last decade, increasing knowledge of epigenetics has led to the development of DNA methylation-based models to predict age, which have shown high predictive accuracy. However, despite the value of teeth as forensic samples, few studies have focused on this source of DNA. This study used bisulfite pyrosequencing to measure the methylation levels of specific CpG sites located in the ELOVL2, ASPA, and PDE4C genes, with the aim of selecting the most age-informative genes and determining their associations with age, in 65 tooth samples from individuals 15 to 85 years old. As a second aim, methylation data and measurements of relative telomere length in the same set of samples were used to develop preliminary age prediction models to evaluate the accuracy of both biomarkers together and separately in estimating age from teeth for forensic purposes. In our sample, several CpG sites from ELOVL2 and PDE4C genes, as well as telomere length, were significantly associated with chronological age. We developed age prediction quantile regression models based on DNA methylation levels, with and without telomere length as an additional variable, and adjusted for type of tooth and sex. Our results suggest that telomere length may have limited usefulness as a supplementary marker for DNA methylation-based age estimation in tooth samples, given that it contributed little improvement in the prediction errors of the models. In addition, even at older ages, DNA methylation appeared to be more informative in predicting age than telomere length when both biomarkers were evaluated separately.},
}
@article {pmid31897598,
year = {2020},
author = {Chan, R and Leung, J and Tang, N and Woo, J},
title = {Dietary patterns and telomere length in community-dwelling Chinese older men and women: a cross-sectional analysis.},
journal = {European journal of nutrition},
volume = {59},
number = {7},
pages = {3303-3311},
pmid = {31897598},
issn = {1436-6215},
support = {CUHK 4101/02M//Research Grants Council of Hong Kong/ ; Not applicable//The Hong Kong Jockey Club Charities Trust/ ; Not applicable//The Centre for Nutritional Studies, The Chinese University of Hong Kong/ ; },
mesh = {Aged ; Asian People/*statistics &amp; numerical data ; Cross-Sectional Studies ; Diet/*statistics &amp; numerical data ; *Feeding Behavior ; Female ; Hong Kong/epidemiology ; Humans ; Independent Living/*statistics &amp; numerical data ; Male ; *Telomere ; },
abstract = {PURPOSE: Environmental and lifestyle factors that affect oxidative stress and inflammation may influence telomere length (TL). There are limited data to relate dietary patterns with TL. This study examined the association of various dietary patterns with TL in Chinese older adults.<br><br>METHODS: We conducted a cross-sectional analysis and performed multivariate linear regression analyses using available data from 1981 (965 men, 1016 women) community-dwelling Chinese adults aged 65&#xa0;years and over in Hong Kong. The interviewer administered questionnaires that covered dietary intake estimation and dietary pattern generation from the food frequency questionnaire, demographic and lifestyle factors, and self-reported medical history. TL was measured by quantitative real-time polymerase chain reaction.<br><br>RESULTS: None of the dietary pattern scores including the Diet Quality Index-International (DQI-I) score, the Dietary Approaches to Stop Hypertension (DASH) score, the Mediterranean-DASH Intervention for Neurodegenerative Delay Diet (MIND) score, the Mediterranean Diet Score (MDS), the Okinawan diet score, as well as the "vegetables-fruits" pattern score, the "snacks-drinks-milk" pattern score, and the "meat-fish" pattern score were associated with TL in the age- and sex-adjusted model and the multivariate adjusted model.<br><br>CONCLUSION: Our findings suggest a minimal role of dietary patterns in telomere length in community-dwelling Chinese older adults.},
}
@article {pmid31896063,
year = {2020},
author = {Todendi, PF and Martínez, JA and Reuter, CP and Matos, WL and Franke, SIR and Razquin, C and Milagro, FI and Kahl, VFS and Fiegenbaum, M and Valim, ARM},
title = {Biochemical profile, eating habits, and telomere length among Brazilian children and adolescents.},
journal = {Nutrition (Burbank, Los Angeles County, Calif.)},
volume = {71},
number = {},
pages = {110645},
doi = {10.1016/j.nut.2019.110645},
pmid = {31896063},
issn = {1873-1244},
mesh = {Adiposity/genetics ; Adolescent ; Anthropometry ; Brazil ; Child ; Cross-Sectional Studies ; Diet/adverse effects ; Ethnicity/*genetics ; Feeding Behavior/ethnology/*physiology ; Female ; Humans ; Male ; Pediatric Obesity/*ethnology/*genetics ; Telomere ; Telomere Homeostasis/*genetics ; },
abstract = {OBJECTIVES: Lifestyle, obesity, and eating habits are emerging as determinants for the instability of telomeres. The increase in childhood and adolescent obesity and the association of biochemical profiles and dietary components with telomere length (TL) makes it an important issue in nutritional research. The aim of the present study was to investigate TL and its association with ethnic background, adiposity, clinical and biochemical parameters, and dietary patterns among Brazilian children and adolescents.<br><br>METHODS: A cross-sectional study encompassing 981 children and adolescents between 7 and 17 y of age was performed. Dietary intake habits, anthropometry, and clinical data were collected. TL analysis was performed by quantitative polymerase chain reaction.<br><br>RESULTS: Children presented significantly longer TL than adolescents (P&#xa0;=&#xa0;0.046). Participants who self-declared as black, mulatto, or brown (P < 0.001) also showed longer TL than those who were white. Regarding biochemical parameters, individuals with altered glucose levels had shorter TL than normoglycemic participants in the total sample (P&#xa0;=&#xa0;0.014). Such difference remained statistically significant in adolescents (P&#xa0;=&#xa0;0.019). Participants who reported eating fruits and vegetables regularly had longer TL than those who did not (P < 0.001).<br><br>CONCLUSION: The results suggested that both biochemical parameters and the intake of antioxidant-rich food, such as fruits and vegetables, are associated with the stability of telomere biology among young Brazilians.},
}
@article {pmid31894867,
year = {2020},
author = {Wang, Z and Li, J and Liu, J and Wang, L and Lu, Y and Liu, JP},
title = {Molecular insight into the selective binding between human telomere G-quadruplex and a negatively charged stabilizer.},
journal = {Clinical and experimental pharmacology &amp; physiology},
volume = {47},
number = {5},
pages = {892-902},
doi = {10.1111/1440-1681.13249},
pmid = {31894867},
issn = {1440-1681},
mesh = {Binding Sites ; *G-Quadruplexes ; Humans ; Indoles/*metabolism/pharmacology ; Isoindoles ; Ligands ; *Molecular Docking Simulation ; *Molecular Dynamics Simulation ; Nucleic Acid Conformation ; Telomere/genetics/*metabolism ; },
abstract = {The single-strand human telomere overhang forms intramolecular high-order structures named G-quadruplex (G4) under physiological conditions. Telomere G4 stabilization prevents telomere lengthening by telomerase in cancer cells representing a promising strategy in cancer therapy. Using molecular docking and molecular dynamics (MD) simulations, specific binding of the anionic phthalocyanine 3,4',4'',4'''-tetrasulfonic acid (APC) to the human hybrid (3 + 1) G4s was investigated at the atomic level. We found that APC preferred the end-stacking binding with the telomere hybrid type II (hybrid-II) G4 as compared to the groove binding with the hybrid type I (hybrid-I) G4 remarkable stabilizing effect and more favourable binding free energies. Analysis of non-covalent interaction and decomposition of the binding free energy revealed that van der Waals interaction played a leading role in the binding of APC and telomere hybrid G4s. These findings provide evidence for the first time to shed light on the designs of selective telomere G4 stabilizers.},
}
@article {pmid31892296,
year = {2020},
author = {Epel, ES},
title = {Can Childhood Adversity Affect Telomeres of the Next Generation? Possible Mechanisms, Implications, and Next-Generation Research.},
journal = {The American journal of psychiatry},
volume = {177},
number = {1},
pages = {7-9},
doi = {10.1176/appi.ajp.2019.19111161},
pmid = {31892296},
issn = {1535-7228},
mesh = {*Adverse Childhood Experiences ; *Biomedical Research ; Humans ; Mental Disorders/*genetics/*physiopathology ; Telomere/genetics/*physiology ; Telomere Shortening/genetics/*physiology ; },
}
@article {pmid31890852,
year = {2019},
author = {Mahoney, ER and Dumitrescu, L and Seto, M and Nudelman, KNH and Buckley, RF and Gifford, KA and Saykin, AJ and Jefferson, AJ and Hohman, TJ},
title = {Telomere length associations with cognition depend on Alzheimer's disease biomarkers.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {5},
number = {},
pages = {883-890},
pmid = {31890852},
issn = {2352-8737},
support = {U01 AG024904/AG/NIA NIH HHS/United States ; R21 AG059941/AG/NIA NIH HHS/United States ; R01 AG059716/AG/NIA NIH HHS/United States ; S10 OD023680/OD/NIH HHS/United States ; K01 AG049164/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: While telomere shortening, a marker of cellular aging, may impact the progression of age-related neurodegenerative diseases, its association with cognition is unclear, particularly in the context of Alzheimer's disease (AD) pathology.<br><br>METHODS: Telomere, cognitive, and CSF data from 482 participants in the AD Neuroimaging Initiative (148 cognitively normal, 283 mild cognitive impairment, 51 AD) was leveraged to assess telomere length associations with cognition (measured by memory and executive function) and interactions with CSF amyloid-&#x3b2;, tau, and APOE -&#x3b5;4. Secondary analyses assessed brain volume and thickness outcomes.<br><br>RESULTS: Longer telomeres at baseline were associated with faster executive function decline. Amyloid-&#x3b2; and tau interacted with telomere length on cognition, with longer telomeres related to faster decline among biomarker-positive individuals.<br><br>DISCUSSION: Telomere associations with cognition shift with AD progression, with longer telomeres related to worse outcomes as pathology increases, highlighting the need for further investigation of telomere length along the AD neuropathological cascade.},
}
@article {pmid31886808,
year = {2020},
author = {Gu, D and Li, J and Little, J and Li, H and Zhang, X},
title = {Associations between Serum Sex Hormone Concentrations and Telomere Length among U.S. Adults, 1999-2002.},
journal = {The journal of nutrition, health &amp; aging},
volume = {24},
number = {1},
pages = {48-54},
pmid = {31886808},
issn = {1760-4788},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/blood ; Female ; Gonadal Steroid Hormones/*analysis ; Humans ; Leukocytes/physiology ; Male ; Middle Aged ; Nutrition Surveys ; Pregnancy ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; Sedentary Behavior ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; Telomere Shortening/*physiology ; United States ; Young Adult ; },
abstract = {BACKGROUND AND OBJECTIVES: Sex hormone concentrations and telomere length are age related responses of human body, while whether there is a direct relation between sex hormone and telomere length is uncertain. Therefore, we used the data of National Health and Nutrition Examination Survey (NHANES) to quantify their direct association.<br><br>RESEARCH DESIGN AND METHODS: A total of 710 women aged 35-60 years and 539 men aged 20-85 years were included from two cycles of the NHANES (1999-2002). Telomere length relative to standard reference DNA (T/S ratio) was measured using quantitative polymerase chain reaction method. Seven hormones in serum (5 in men and 2 in women) were assayed. Logistic regressions were used to calculate the odds ratios to evaluate the telomere length-sex hormones association.<br><br>RESULTS: Men with vigorous physical activity (71.1%) and without history of cardiovascular diseases, diabetes, and lipid-lowering drugs using tended to have a longer telomere length (all P-values < 0.05); while women with longer sedentary time, smaller pregnant or live birth, and with older ages of firth/last birth were likely with longer telomere length (all P-values < 0.05). After adjusted for potential confounders, only anti-Mullerian hormone was positively and stably associated with short leukocytes telomere length in men (OR: 1.098; 95% CI: 1.034, 1.165). We did not detect any significant association of short telomere length with sex hormones in men and women. Discussion and Implications: Serum anti-Mullerian hormone in men was positively and stably associated with telomere length. More large-scaled and well-designed prospective studies are warranted to reconfirm our conclusions.},
}
@article {pmid31886802,
year = {2020},
author = {Shen, G and Huang, JY and Huang, YQ and Feng, YQ},
title = {The Relationship between Telomere Length and Cancer Mortality: Data from the 1999-2002 National Healthy and Nutrition Examination Survey (NHANES).},
journal = {The journal of nutrition, health &amp; aging},
volume = {24},
number = {1},
pages = {9-15},
pmid = {31886802},
issn = {1760-4788},
mesh = {Adult ; Aged ; Alcohol Drinking ; Blood Pressure/physiology ; Body Mass Index ; C-Reactive Protein/metabolism ; Cardiovascular Diseases/mortality ; Female ; Health Status ; Humans ; Male ; Middle Aged ; Neoplasms/*mortality/pathology ; Nutrition Surveys/*statistics &amp; numerical data ; Prospective Studies ; Telomere/*physiology ; Telomere Shortening/*physiology ; United States ; },
abstract = {OBJECTIVES: The association between telomeres length (TL) and cancer mortality is uncertain. We tested the hypotheses that long TL are associated with reduced cancer mortality.<br><br>DESIGN: Prospective cohort study.<br><br>SETTING: the National Health and Nutrition Survey (NHANES, 1999-2002).<br><br>PARTICIPANTS: The analytic sample included adults (n = 7183) who had TL measurements.<br><br>MEASUREMENTS: DNA was obtained via blood samples. Telomere length was assessed using the quantitative polymerase chain reaction method.<br><br>RESULTS: During follow-up (0.08-12.7 person-years, median = 9.5 years), we observed 195 participants had cancer as causes of death. TL was negatively corelated with age, body mass index (BMI), systolic blood pressure (SBP), C-reactive protein (CRP), race, diabetes, hypertension, cardiovascular diseases (CVD) and cancer mortality, conversely, positively corelated with alcohol use, but not related to diastolic blood pressure (DBP) and smoking. Kaplan-Meier analysis revealed that TL was significantly associated with cancer mortality (log-rank, P <0.001).<br><br>CONCLUSIONS: Our study expands upon previous evidence of a relationship between TL and cancer mortality. TL may be a useful tool for evaluating risk of cancer mortality in American adults.},
}
@article {pmid31882992,
year = {2020},
author = {Li, M and Liu, K},
title = {Protection of the shelterin complex is key for tethering telomeres to the nuclear envelope during meiotic prophase I†.},
journal = {Biology of reproduction},
volume = {102},
number = {4},
pages = {771-772},
doi = {10.1093/biolre/ioz231},
pmid = {31882992},
issn = {1529-7268},
mesh = {Meiosis ; Meiotic Prophase I ; *Nuclear Envelope ; Prophase ; *Telomere/genetics ; },
}
@article {pmid31881852,
year = {2019},
author = {Kalstad, AA and Tveit, S and Myhre, PL and Laake, K and Opstad, TB and Tveit, A and Schmidt, EB and Solheim, S and Arnesen, H and Seljeflot, I},
title = {Leukocyte telomere length and serum polyunsaturated fatty acids, dietary habits, cardiovascular risk factors and features of myocardial infarction in elderly patients.},
journal = {BMC geriatrics},
volume = {19},
number = {1},
pages = {376},
pmid = {31881852},
issn = {1471-2318},
mesh = {Aged ; Aged, 80 and over ; Aging/blood/physiology ; Biomarkers/blood ; Cardiovascular Diseases/blood/epidemiology/genetics ; Cross-Sectional Studies ; Fatty Acids, Omega-3/administration &amp; dosage/*blood ; Fatty Acids, Unsaturated/*blood ; Feeding Behavior/*physiology ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Myocardial Infarction/*blood/epidemiology/genetics ; Risk Factors ; Telomere/*metabolism ; Telomere Shortening/physiology ; },
abstract = {BACKGROUND: Telomeres are non-coding sequences at the end of eukaryote chromosomes, which in complex with associated proteins serve to protect subtelomeric DNA. Telomeres shorten with each cell division, are regarded as a biomarker for aging and have also been suggested to play a role in atherosclerosis and cardiovascular disease (CVD). The aim of the present study was to explore the associations between leukocyte telomere length and serum polyunsaturated fatty acids, diet, cardiovascular risk factors and features of myocardial infarction (MI) in elderly patients.<br><br>METHODS: The material is based upon the first 299 included patients in the OMEMI trial, where patients aged 70-82&#x2009;years of age are randomized to receive omega-3 supplements or corn oil (placebo) after MI. Patients were included 2-8&#x2009;weeks after the index MI. DNA was extracted from whole blood, and leukocyte telomere length (LTL) was analyzed by qPCR and reported as a number relative to a reference gene. Serum long chain polyunsaturated fatty acid (LCPUFA) content was analyzed by gas chromatography. Diet was evaluated with the validated SmartDiet food frequency questionnaire. Medical records, patient interviews and clinical examination provided previous medical history and anthropometric data. Non-parametric statistical tests were used.<br><br>RESULTS: Median (25, 75 percentile) LTL was 0.55 (0.42, 0.72). Patients had a median age of 75&#x2009;years, 70.2% were male and 45.2% used omega-3 supplements. There was a weak, but significant correlation between LTL and linoleic acid (r&#xa0;=&#x2009;0.139, p&#xa0;=&#x2009;0.017), but not with other LCPUFAs. There was a trend towards longer telomeres with a healthier diet, but this did not reach statistical significance (p&#xa0;=&#x2009;0.073). No associations were found between LTL and CVD risk factors or features of MI.<br><br>CONCLUSIONS: In our population of elderly with a recent myocardial infarction LTL was associated with linoleic acid concentrations, but not with other LCPUFAs. Patients with a healthy diet tended to have longer telomeres. The limited associations may be due to age and the narrow age-span in our population. Further studies, designed to detect longitudinal changes should be performed to explore the role of telomeres in cardiovascular aging.<br><br>TRIAL REGISTRATION: Clinical trials no. NCT01841944, registration date April 29, 2013.},
}
@article {pmid31881507,
year = {2020},
author = {Normando, P and Santos-Rebouças, C and Leung, C and Epel, E and da Fonseca, AC and Zembrzuski, V and Faerstein, E and Bezerra, FF},
title = {Variants in gene encoding for vitamin D binding protein were associated with leukocyte telomere length: The Pró-Saúde Study.},
journal = {Nutrition (Burbank, Los Angeles County, Calif.)},
volume = {71},
number = {},
pages = {110618},
doi = {10.1016/j.nut.2019.110618},
pmid = {31881507},
issn = {1873-1244},
mesh = {Adult ; Aged ; Brazil ; Cross-Sectional Studies ; Female ; Genotype ; Humans ; Leukocytes/*physiology ; Linear Models ; Male ; Middle Aged ; Nutritional Status/*genetics ; Polymorphism, Single Nucleotide/*genetics ; Telomere/*genetics ; Telomere Homeostasis ; Vitamin D/analogs &amp; derivatives ; Vitamin D-Binding Protein/*genetics ; },
abstract = {OBJECTIVE: The aim of this study was to investigate the association between single-nucleotide polymorphisms (SNPs) in vitamin D metabolic pathway genes, serum 25-hydroxyvitamin D [25(OH)D] concentrations, and leukocyte telomere length (LTL) in Brazilian adults.<br><br>METHODS: The study population comprised 461 participants (33-79 y of age; 51% women) from the Pr&#xf3;-Sa&#xfa;de Study, a cohort of civil servants at a university campus in Rio de Janeiro, Brazil. LTL, genotypes of vitamin D-related SNPs (rs12785878, rs10741657, rs6013897, and rs2282679), and serum 25(OH)D concentrations were determined cross-sectionally. Differences in age- and sex-adjusted LTL means by categories of genotypes and 25(OH)D serum concentrations were evaluated. LTL associations with genotypes and 25(OH)D were investigated using multiple linear regression models adjusted for sociodemographic characteristics and markers of health behavior.<br><br>RESULTS: Participants with CC genotype (rs2282679) had shorter age- and sex-adjusted mean LTL than those with AC and AA genotypes (mean &#xb1; SE: 0.51 &#xb1; 0.03, 0.58 &#xb1; 0.01 and 0.5 &#xb1; 0.01, respectively, P < 0.05). In adjusted analyses, the CC genotype (rs2282679) was inversely associated with LTL (&#x3b2;&#x202f;=&#x202f;-0.061; 95% confidence interval, -0.120 to -0.001). Other vitamin D-related SNPs and serum 25(OH)D concentrations were not associated with LTL.<br><br>CONCLUSIONS: Genetic variations in the gene encoding vitamin D binding protein (GC - rs2282679) were associated with LTL, suggesting an influence of vitamin D status on telomere length that may start early in life.},
}
@article {pmid31879780,
year = {2020},
author = {Bonetti, D and Rinaldi, C and Vertemara, J and Notaro, M and Pizzul, P and Tisi, R and Zampella, G and Longhese, MP},
title = {DNA binding modes influence Rap1 activity in the regulation of telomere length and MRX functions at DNA ends.},
journal = {Nucleic acids research},
volume = {48},
number = {5},
pages = {2424-2441},
pmid = {31879780},
issn = {1362-4962},
mesh = {Alleles ; DNA Breaks, Double-Stranded ; DNA Damage ; DNA, Fungal/*metabolism ; Models, Biological ; Multiprotein Complexes/*metabolism ; Mutation/genetics ; Protein Binding ; Saccharomyces cerevisiae/cytology/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Shelterin Complex ; Telomere/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/*metabolism ; Transcription Factors/*metabolism ; Transcription, Genetic ; },
abstract = {The cellular response to DNA double-strand breaks (DSBs) is initiated by the Mre11-Rad50-Xrs2 (MRX) complex that has structural and catalytic functions. MRX association at DSBs is counteracted by Rif2, which is known to interact with Rap1 that binds telomeric DNA through two tandem Myb-like domains. Whether and how Rap1 acts at DSBs is unknown. Here we show that Rif2 inhibits MRX association to DSBs in a manner dependent on Rap1, which binds to DSBs and promotes Rif2 association to them. Rap1 in turn can negatively regulate MRX function at DNA ends also independently of Rif2. In fact, a characterization of Rap1 mutant variants shows that Rap1 binding to DNA through both Myb-like domains results in formation of Rap1-DNA complexes that control MRX functions at both DSBs and telomeres primarily through Rif2. By contrast, Rap1 binding to DNA through a single Myb-like domain results in formation of high stoichiometry complexes that act at DNA ends mostly in a Rif2-independent manner. Altogether these findings indicate that the DNA binding modes of Rap1 influence its functional properties, thus highlighting the structural plasticity of this protein.},
}
@article {pmid31879376,
year = {2019},
author = {Guachalla, LM and Ju, Z and Koziel, R and von Figura, G and Song, Z and Fusser, M and Epe, B and Jansen-Dürr, P and Rudolph, KL},
title = {Correction for: Sod2 haploinsufficiency does not accelerate aging of telomere dysfunctional mice.},
journal = {Aging},
volume = {11},
number = {23},
pages = {11793-11794},
doi = {10.18632/aging.102602},
pmid = {31879376},
issn = {1945-4589},
}
@article {pmid31872047,
year = {2019},
author = {Bhala, S and Best, AF and Giri, N and Alter, BP and Pao, M and Gropman, A and Baker, EH and Savage, SA},
title = {CNS manifestations in patients with telomere biology disorders.},
journal = {Neurology. Genetics},
volume = {5},
number = {6},
pages = {370},
pmid = {31872047},
issn = {2376-7839},
abstract = {OBJECTIVE: We systematically evaluated CNS manifestations in patients with inherited telomere biology disorders (TBDs) to better understand the clinical and biological consequences of germline aberrations in telomere biology.<br><br>METHODS: Forty-four participants with TBDs (31 dyskeratosis congenita, 12 Hoyeraal-Hreidarsson syndrome, and 1 Revesz syndrome) enrolled in an institutional review board-approved longitudinal cohort study underwent detailed clinical assessments, brain MRI, and genetic testing. Lymphocyte telomere length Z-scores were calculated to adjust for age.<br><br>RESULTS: In this cohort, 25/44 (57%) patients with a TBD had at least 1 structural brain abnormality or variant, most commonly cerebellar hypoplasia (39%). Twenty-one patients (48%) had neurodevelopmental disorder or psychomotor abnormality. Twelve had psychiatric diagnoses, including depression and/or anxiety disorders. Other findings such as hypomyelination, prominent cisterna magna, and cavum septum pellucidum were more frequent than in the general population (p < 0.001). Shorter lymphocyte telomere length was associated with an increased number of MRI findings (p = 0.02) and neurodevelopmental abnormalities (p < 0.001). Patients with autosomal recessive or X-linked TBDs had more neurologic findings than those with autosomal dominant disease.<br><br>CONCLUSIONS: Structural brain abnormalities and variants are common in TBDs, as are neurologic and psychiatric symptoms. The connection between neurodevelopment and telomere biology warrants future study.},
}
@article {pmid31872036,
year = {2020},
author = {Powell-Wiley, TM and Gebreab, SY and Claudel, SE and Ayers, C and Andrews, MR and Adu-Brimpong, J and Berrigan, D and Davis, SK},
title = {The relationship between neighborhood socioeconomic deprivation and telomere length: The 1999-2002 National Health and Nutrition Examination Survey.},
journal = {SSM - population health},
volume = {10},
number = {},
pages = {100517},
pmid = {31872036},
issn = {2352-8273},
abstract = {Socioeconomically disadvantaged neighborhoods have been associated with poor health outcomes. Little is known about the biological mechanism by which deprived neighborhood conditions exert negative influences on health. Data from the 1999-2002 National Health and Nutrition Examination Surveys (NHANES) were used to assess the relationship between neighborhood deprivation index (NDI) and log-transformed leukocyte telomere length (LTL) via multilevel modeling to control for census tract level clustering. Models were constructed using tertiles of NDI (ref = low NDI). NDI was calculated using census tract level socioeconomic indicators from the 2000 U.S. Census. The sample (n = 5,106 adults) was 49.8% female and consisted of 82.9% non-Hispanic whites, 9.4% non-Hispanic blacks, and 7.6% Mexican Americans. Mean age was 45.8 years. Residents of neighborhoods with high NDI were younger, non-white, had lower educational attainment, and had a lower poverty to income ratio (all p < 0.0001). Neighborhood deprivation was inversely associated with LTL among individuals living in neighborhoods with medium NDI (β = -0.043, SE = 0.012, p = 0.0005) and high NDI (β = -0.039, SE = 0.013, p = 0.003). Among men, both medium (β = -0.042, SE = 0.015, p = 0.006) and high (β = -0.047, SE = 0.015, p = 0.001) NDI were associated with shorter LTL. Among women, only medium NDI (β = -0.020, SE = 0.016, p = 0.009) was associated with shorter LTL. After controlling for individual characteristics, including individual-level socioeconomic status, increasing neighborhood socioeconomic deprivation is associated with shorter LTL among a nationally representative sample of US adults. This suggests that telomere shortening may be a mechanism through which neighborhood deprivation results in poor health outcomes.},
}
@article {pmid31867825,
year = {2020},
author = {Rej, PH and , and Gravlee, CC and Mulligan, CJ},
title = {Shortened telomere length is associated with unfair treatment attributed to race in African Americans living in Tallahassee, Florida.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {32},
number = {3},
pages = {e23375},
doi = {10.1002/ajhb.23375},
pmid = {31867825},
issn = {1520-6300},
mesh = {Adult ; Black or African American/*statistics &amp; numerical data ; Female ; Florida ; Humans ; Male ; Middle Aged ; Racism/psychology/*statistics &amp; numerical data ; Risk Factors ; Self Report ; Stress, Psychological/*etiology ; *Telomere Shortening ; },
abstract = {OBJECTIVES: Experiences of interpersonal discrimination are pervasive stressors in the lives of African Americans. Increased discrimination stress may cause premature aging. Telomere length (TL) is a plastic genetic trait that is an emerging indicator of cellular health and aging. Short TL is a risk factor for the earlier onset of disease. TL shortens with age, a process that may be accelerated by psychosocial stress. Our study explores the relationship between TL and experiences of discrimination in the form of self-reported unfair treatment (UT).<br><br>METHODS: Using a qPCR-based method, we measured TL in DNA from saliva samples provided by 135 African American adults from Tallahassee, FL. We developed discrimination measures using a modified survey that explores nine social domains of self-reported unfair treatment experienced both directly and indirectly. We used multiple regression to examine associations between UT and TL.<br><br>RESULTS: We found that racial discrimination in the form of self-reported unfair treatment attributed to race (UT-Race-Self) is inversely associated with TL.<br><br>CONCLUSIONS: The significant association between increased UT-Race-Self and shorter telomeres supports the hypothesis that psychosocial stress stemming from racial discrimination may affect TL. The potential impact of discrimination on TL may contribute to premature biological aging and racial health inequalities seen in African Americans.},
}
@article {pmid31861819,
year = {2019},
author = {Li, W and Ma, Y and Li, Z and Lv, X and Wang, X and Zhou, D and Luo, S and Wilson, JX and Huang, G},
title = {Folic Acid Decreases Astrocyte Apoptosis by Preventing Oxidative Stress-Induced Telomere Attrition.},
journal = {International journal of molecular sciences},
volume = {21},
number = {1},
pages = {},
pmid = {31861819},
issn = {1422-0067},
support = {81730091//National Natural Science Foundation of China/ ; 81602849//National Natural Science Foundation of China/ ; 19JCQNJC11700//Natural Science Foundation of Tianjin City/ ; 2017QNRC001//young elite scientist's sponsorship program by CAST/ ; },
mesh = {Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Astrocytes/cytology/*drug effects/metabolism ; Cells, Cultured ; Folic Acid/*pharmacology ; Oxidative Stress/*drug effects ; Rats, Sprague-Dawley ; Telomere/drug effects/metabolism ; Vitamin B Complex/*pharmacology ; },
abstract = {Astrocytes are the most widely distributed cells in the brain, and astrocyte apoptosis may play an important role in the pathogenesis of neurodegenerative diseases. Folate is required for the normal development of the nervous system, but its effect on astrocyte apoptosis is unclear. In this study, we hypothesized that folic acid (the therapeutic form of folate) decreases astrocyte apoptosis by preventing oxidative stress-induced telomere attrition. Primary cultures of astrocytes were incubated for 12 days with various concentrations of folic acid (0-40 μmol/L), then cell proliferation, apoptosis, intracellular folate concentration, intracellular homocysteine (Hcy) concentration, intracellular reactive oxygen species (ROS) levels, telomeric DNA oxidative damage, and telomere length were determined. The results showed that folic acid deficiency decreased intracellular folate, cell proliferation, and telomere length, whereas it increased Hcy concentration, ROS levels, telomeric DNA oxidative damage, and apoptosis. In contrast, folic acid dose-dependently increased intracellular folate, cell proliferation, and telomere length but it decreased Hcy concentration, ROS levels, telomeric DNA oxidative damage, and apoptosis. In conclusion, folic acid inhibited apoptosis in astrocytes. The underlying mechanism for this protective effect may be that folic acid decreased oxidative stress and thereby prevented telomeric DNA oxidative damage and telomere attrition.},
}
@article {pmid31860719,
year = {2020},
author = {Luo, M and Teng, X and Wang, B and Zhang, J and Liu, Y and Liu, D and Li, H and Lu, H},
title = {Protection of telomeres 1 (POT1) of Pinus tabuliformis bound the telomere ssDNA.},
journal = {Tree physiology},
volume = {40},
number = {1},
pages = {119-127},
doi = {10.1093/treephys/tpz125},
pmid = {31860719},
issn = {1758-4469},
mesh = {Animals ; DNA, Single-Stranded ; Humans ; Pinus/*genetics ; Protein Binding ; Shelterin Complex ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; },
abstract = {Protection of telomeres 1 (POT1) is a telomeric protein that binds to the telomere single-stranded (ss) region. It plays an essential role in maintaining genomic stability in both plants and animals. In this study, we investigated the properties of POT1 in Pinus tabuliformis Carr. (PtPOT1) through electrophoretic mobility shift assay. PtPOT1 harbored affinity for telomeric ssDNA and could bind plant- and mammalian-type ssDNA sequences. Notably, there were two oligonucleotide/oligosaccharide binding (OB) folds, and OB1 or OB2 alone, or both together, could bind ssDNA, which is significantly different from human POT1. Based on our data, we hypothesized that the two OB folds of PtPOT1 bound the same ssDNA. This model not only provides new insight into the ssDNA binding of PtPOT1 but also sheds light on the functional divergence of POT1 proteins in gymnosperms and humans.},
}
@article {pmid31858822,
year = {2020},
author = {Groer, M and Louis-Jacques, A and Szalacha, L and Redwine, L and Dracxler, R and Keefe, D},
title = {Relationship of Anxiety, Inflammation, and Telomere Length in Postpartum Women: A Pilot Study.},
journal = {Biological research for nursing},
volume = {22},
number = {2},
pages = {256-262},
pmid = {31858822},
issn = {1552-4175},
support = {R01 NR005000/NR/NINR NIH HHS/United States ; },
mesh = {Adult ; Anxiety Disorders/*blood ; Cross-Sectional Studies ; Cytokines/*blood ; Depressive Disorder, Major/*blood ; Female ; Humans ; Inflammation/*blood ; Iodide Peroxidase/*blood ; Leukocytes, Mononuclear/*physiology ; Middle Aged ; Pilot Projects ; Postpartum Period/*psychology ; *Telomere ; Young Adult ; },
abstract = {BACKGROUND: The postpartum period can be a vulnerable time during which many women are prone to mood disturbances. Since telomere length (TL) is known to be associated with dysphoric moods, inflammation, and stress in many populations, this study's objective was to assess the relationships among TL, dysphoric moods, stress, and inflammation during the postpartum period.<br><br>METHOD: This cross-sectional pilot study is a secondary analysis of data collected in a larger parent study of anti-thyroid peroxidase (TPO) enzyme antibody positive versus negative women. The parent study followed selected mothers every month for 6 postpartum months. From this parent study, a random sample of preserved peripheral blood mononuclear cells from 97 participants collected at 2-4 months postpartum were measured for TL. Data were available on the production of interleukin-6 (IL-6), an inflammatory cytokine, in stimulated ex vivo cultures for 59 of these women. Dysphoric moods and stress were measured. Pearson correlations and linear regressions were performed, controlling for postpartum thyroiditis status and age.<br><br>RESULTS: There were no statistically significant relationships between TL and demographic factors, stress, depression, or TPO status. There were significant negative correlations between TL and anxiety and a trend for a relationship between TL and IL-6 levels. IL-6 levels were significantly, positively associated with negative moods.<br><br>CONCLUSIONS: Higher anxiety scores and inflammation were associated with shorter TL. Inflammation was related to anxiety and other dysphoric moods and was marginally associated with shorter TLs.},
}
@article {pmid31851867,
year = {2020},
author = {Peker Eyüboğlu, &#x130; and Yenmiş, G and Bingöl, EN and Yüksel, &#x15e; and Tokat, F and Özbek, P and Güllü Amuran, G and Yakıcıer, C and Akkiprik, M},
title = {Next-Generation Sequencing Identifies BRCA1 and/or BRCA2 Mutations in Women at High Hereditary Risk for Breast Cancer with Shorter Telomere Length.},
journal = {Omics : a journal of integrative biology},
volume = {24},
number = {1},
pages = {5-15},
doi = {10.1089/omi.2019.0103},
pmid = {31851867},
issn = {1557-8100},
mesh = {Alleles ; BRCA1 Protein/chemistry/*genetics ; BRCA2 Protein/chemistry/*genetics ; Breast Neoplasms/*genetics ; Female ; *Genetic Predisposition to Disease ; Genotype ; High-Throughput Nucleotide Sequencing ; Humans ; Models, Molecular ; *Mutation ; Protein Conformation ; Real-Time Polymerase Chain Reaction ; Risk Assessment ; Risk Factors ; Structure-Activity Relationship ; *Telomere Shortening ; },
abstract = {Telomeres, and telomere length in particular, have broad significance for genome biology and thus are prime research targets for complex diseases such as cancers. In this context, BRCA1 and BRCA2 gene mutations have been implicated in relationship to telomere length, and breast cancer susceptibility. Yet, the linkages among human genetic variation and telomere length in persons with high hereditary cancer risk are inadequately mapped. We report here original findings in 113 unrelated women at high hereditary risk for breast cancer, who were characterized for the BRCA1 and BRCA2 mutations using next-generation sequencing. Thirty-one BRCA2 and 21 BRCA1 mutations were identified in 47 subjects (41.6%). The women with a mutation in BRCA1 and/or BRCA2 genes had, on average, 12% shorter telomere compared to women with no BRCA1 or BRCA2 mutation (p = 0.0139). Moreover, the association between telomere length and BRCA mutation status held up upon stratified analysis in those with or without a breast cancer diagnosis. We also indentified two rare mutations, c.536_537insT and c.10078A>G, and a novel mutation c.8680C>G in BRCA2 that was studied further by homology modeling of the DNA binding tower domain of BRCA2 and the structure of the protein. These data collectively lend evidence to the idea that BRCA1 and BRCA2 mutations play a role in telomere length in women at high hereditary risk for breast cancer. Further clinical and diagnostics discovery research on BRCA1 and BRCA2 variation, telomere length, and breast cancer mechanistic linkages are called for in larger study samples.},
}
@article {pmid31847782,
year = {2021},
author = {Amir, M and Ahamad, S and Mohammad, T and Jairajpuri, DS and Hasan, GM and Dohare, R and Islam, A and Ahmad, F and Hassan, MI},
title = {Investigation of conformational dynamics of Tyr89Cys mutation in protection of telomeres 1 gene associated with familial melanoma.},
journal = {Journal of biomolecular structure &amp; dynamics},
volume = {39},
number = {1},
pages = {35-44},
doi = {10.1080/07391102.2019.1705186},
pmid = {31847782},
issn = {1538-0254},
mesh = {Humans ; *Melanoma/genetics ; Mutation ; Shelterin Complex ; *Skin Neoplasms ; Telomere/genetics ; Telomere-Binding Proteins/genetics ; },
abstract = {Protection of telomeres 1 (POT1) is a component of the shelterin complex which is crucial for the regulation of telomere length and maintenance. Many naturally occurring mutations in the POT1 gene have been found to be associated with cardiac angiosarcoma, glioma, familial melanoma, and chronic lymphocytic leukemia. In particular, Y89C is a naturally occurring mutation of POT1, responsible for familial melanoma, and the molecular basis of this mutation is unexplored. In this study, we have extensively analyzed the structure of WT and Y89C mutant of POT1 to see the change in the conformational dynamics, free energy landscape, molecular motions and configurational frustration using molecular dynamics (MD) and other bioinformatics approaches. Y89C mutation shows a significant change in the backbone orientation, compactness, residual fluctuation, solvent accessibility, and hydrogen bonding, suggesting an overall destabilization of the protein structure. Besides, essential dynamics, conformation, magnitude, direction of motion and frustration analysis further suggesting the structural loss in POT1 due to Y89C mutation. Free energy landscape analysis also indicates the presence of a single well-defined free-energy minima in case of WT compared to multiple wells defined free energy minima observed in Y89C, clearly suggesting that this mutation leads to reduce the stability of POT1. This study possibly provides a valuable path to understand the molecular basis of Y89C-mediated development of familial melanoma.Communicated by Ramaswamy H. Sarma.},
}
@article {pmid31846834,
year = {2020},
author = {Aschacher, T and Wolf, B and Aschacher, O and Enzmann, F and Laszlo, V and Messner, B and Türkcan, A and Weis, S and Spiegl-Kreinecker, S and Holzmann, K and Laufer, G and Ehrlich, M and Bergmann, M},
title = {Long interspersed element-1 ribonucleoprotein particles protect telomeric ends in alternative lengthening of telomeres dependent cells.},
journal = {Neoplasia (New York, N.Y.)},
volume = {22},
number = {2},
pages = {61-75},
pmid = {31846834},
issn = {1476-5586},
mesh = {Cell Line, Tumor ; DNA Damage/genetics ; DNA Topoisomerases, Type I/*genetics ; DNA-Binding Proteins/*genetics ; Glioma/*genetics/pathology ; Humans ; Long Interspersed Nucleotide Elements/genetics ; Ribonucleoproteins/genetics ; Telomere/*genetics ; Telomere Homeostasis/genetics ; Transcription Factors/*genetics ; },
abstract = {Malignant cells ensure telomere maintenance by the alternative lengthening of telomeres (ALT) in the absence of telomerase activity (TA). The retrotransposons "long interspersed nuclear element-1" (LINE-1, L1) are expressed in malignant cells and are primarily known to contribute to complex karyotypes. Here we demonstrate that LINE-1 ribonucleoprotein particles (L1-RNPs) expression is significantly higher in ALT[+]- versus in TA[+]-human glioma. Analyzing a role of L1-RNP in ALT, we show that L1-RNPs bind to telomeric repeat containing RNA (TERRA), which is critical for telomere stabilization and which is overexpressed in ALT[+] cells. In turn, L1-RNP knockdown (KD) abrogated the nuclear retention of TERRA, resulted in increased telomeric DNA damage, decreased cell growth and reduced expression of ALT characteristics such as c-circles and PML-bodies. L1-RNP KD also decreased the expression of Shelterin- and the ALT-regulating protein Topoisomerase IIIα (TopoIIIα) indicating a more general role of L1-RNPs in supporting telomeric integrity in ALT. Our findings suggest an impact of L1-RNP on telomere stability in ALT[+] dependent tumor cells. As L1-RNPs are rarely expressed in normal adult human tissue those elements might serve as a novel target for tumor ablative therapy.},
}
@article {pmid31845317,
year = {2020},
author = {Eisenberg, DTA and Rej, PH and Duazo, P and Carba, D and Hayes, MG and Kuzawa, CW},
title = {Testing for paternal influences on offspring telomere length in a human cohort in the Philippines.},
journal = {American journal of physical anthropology},
volume = {171},
number = {3},
pages = {520-528},
pmid = {31845317},
issn = {1096-8644},
support = {P30 ES010126/ES/NIEHS NIH HHS/United States ; P2C HD042828/HD/NICHD NIH HHS/United States ; P30 DK056350/DK/NIDDK NIH HHS/United States ; R01 DK078150/DK/NIDDK NIH HHS/United States ; P20 RR020649/RR/NCRR NIH HHS/United States ; R01 TW005596/TW/FIC NIH HHS/United States ; },
mesh = {Adult ; *Body Height ; Female ; Humans ; Longitudinal Studies ; Male ; *Paternal Inheritance ; Philippines ; Smoking/*adverse effects ; Stress, Psychological/*psychology ; Telomere Homeostasis/*genetics ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {OBJECTIVES: Telomeres, emerging biomarkers of aging, are comprised of DNA repeats located at chromosomal ends that shorten with cellular replication and age in most human tissues. In contrast, spermatocyte telomeres lengthen with age. These changes in telomere length (TL) appear to be heritable, as older paternal ages of conception (PAC) predict longer offspring TL. Mouse-model studies raise questions about the potential for effects of paternal experiences on human offspring TL, as they suggest that smoking, inflammation, DNA damage, and stressors all shorten sperm TL. Here, we examined whether factors from the paternal environment predict offspring TL as well as interact with PAC to predict offspring TL.<br><br>MATERIALS AND METHODS: Using data from the Philippines, we tested if smoking, psychosocial stressors, or shorter knee height (a measure of early life adversity) predict shorter offspring TL. We also tested if these interacted with PAC in predicting offspring TL.<br><br>RESULTS: While we did not find the predicted associations, we observed a trend toward fathers with shorter knee height having offspring with longer TL. In addition, we found that knee height interacted with PAC to predict offspring TL. Specifically, fathers with shorter knee heights showed a stronger positive effect of PAC on offspring TL.<br><br>DISCUSSION: While the reasons for these associations remain uncertain, shorter knee height is characteristic of earlier puberty. Since spermatocyte TL increases with the production of sperm, we speculate that individuals with earlier puberty, and its concomitant commencement of production of sperm, had more time to accumulate longer sperm telomeres.},
}
@article {pmid31841853,
year = {2020},
author = {Powolny, T and Bassin, N and Crini, N and Fourel, I and Morin, C and Pottinger, TG and Massemin, S and Zahn, S and Coeurdassier, M},
title = {Corticosterone mediates telomere length in raptor chicks exposed to chemical mixture.},
journal = {The Science of the total environment},
volume = {706},
number = {},
pages = {135083},
doi = {10.1016/j.scitotenv.2019.135083},
pmid = {31841853},
issn = {1879-1026},
mesh = {Animals ; Corticosterone ; *Raptors ; Stress, Physiological ; Telomere ; Telomere Shortening ; },
abstract = {Stressors experience early in life by animals may have carry over impacts on life-traits over the life cycle. Accelerated telomere attrition induced by stress during development and growth could play a role in such delayed effects. Among stressors, exposure to chemicals may modify telomere dynamic but, to date, the trends evidenced between exposure and telomere shortening remains inconsistent. Moreover, the role of corticosterone as a possible mediator of chemical impact on telomere is not yet clearly established. Here, we investigated in wild populations of Red kite whether nestling exposure to metals and pesticides was related to corticosterone concentrations in feathers and telomere length measured in 47 individuals. Lead and mercury concentrations in blood ranged from 2.3 to 59.0 µg L[-1] and to 1.4 to 115.7 µg L[-1], respectively, and were below the toxicity thresholds proposed for wildlife. Rodenticides were detected in 30% of the chicks. Corticosterone increased with mercury and lead in interaction, showing a synergistic effect of these 2 non-essential metals on this stress hormone. Telomere length was not linked to metals and/or rodenticide exposure while it was related negatively to corticosterone. The relationship between telomere and corticosterone was modulated by nestling's age, which suggests that the rate of telomere shortening is higher when corticosterone increases. Our findings propose an effect of low exposure of Red Kite nestlings to mercury and lead mixture to raise baseline corticosterone in feathers. The relationships established suggest the hypothesis that telomere attrition could be an indirect consequence of metal exposure mediated by corticosterone.},
}
@article {pmid31841491,
year = {2019},
author = {Shvaiko, LI and Bazyka, KD and Sushko, VO and Ilienko, IM and Bazyka, DA},
title = {LUNG FUNCTION AND TELOMERE RELATIVE LENGTH IN CLEAN-UP WORKERS OF CHORNOBYL NPP ACCIDENT IN A REMOTE POST-ACCIDENT PERIOD.},
journal = {Problemy radiatsiinoi medytsyny ta radiobiolohii},
volume = {24},
number = {},
pages = {503-515},
doi = {10.33145/2304-8336-2019-24-503-515},
pmid = {31841491},
issn = {2313-4607},
mesh = {Aged ; *Chernobyl Nuclear Accident ; Dose-Response Relationship, Radiation ; *Emergency Responders ; Humans ; Lung/pathology/radiation effects ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/etiology/genetics/*physiopathology ; Radiation Dosage ; Radiation Exposure/*adverse effects ; Radiation Injuries/etiology/genetics/*physiopathology ; Respiratory Function Tests ; Survivors ; Telomere/*ultrastructure ; Telomere Shortening ; Time Factors ; Ukraine ; },
abstract = {OBJECTIVE: The objective was to study the relationship between functional status of bronchopulmonary system and telomere length in clean-up workers of Chornobyl NPP accident in a remote post-accident period.<br><br>MATERIALS AND METHODS: A study was performed in 113 clean-up workers of Chornobyl NPP accident. Individual do- cumented doses of irradiation in clean-up workers ranged from 1,0 to 880 mSv (330.4 &#xb1; 317.7 (M &#xb1; SD)). The aver- age age of the Chornobyl NPP participants was (62.21 &#xb1; 6.99) years. A complex of functional pulmonary tests (spirometry, body plethysmography, examination of lung diffusion capacity) was performed. Relative telomere length (RTL) was analysed by flow-FISH.<br><br>RESULTS: There was a tendency to decrease the relative telomere length in clean-up workers with COPD I-II stage and COPD III-IV, compared with patients with the absence of bronchopulmonary diseases (RTL 15,2 &#xb1; 2,7). Significantly shorter telomeres were observed in patients with COPD who were exposed to radiation at a dose of more than 500 mSv (13.6 &#xb1; 2.5) compared with COPD patients who were exposed at a dose <10 mSv (RTL 15.3 &#xb1; 2.3). When analyzing the correlation relationships of the studied indicators, no significant associations were found with the relative telomere length. At this stage of the study no association of relative telomere length with age, body mass index, and functional criteria (FEV1 (l), intrathoracic pressure (ITGV), total lung capacity (TLC), diffusion lung capac- ity (DLCO)) was detected.<br><br>CONCLUSIONS: The analyzed telomere length relationship from liquidators of the Chernobyl found no direct associa- tion with indicators of lung function tests, however, showed a trend towards reducing the relative telomere length in clean-up workers who suffer from COPD and exposed to doses from 100 to 500 mSv and above 500 mSv.},
}
@article {pmid31841253,
year = {2020},
author = {Bichet, C and Bouwhuis, S and Bauch, C and Verhulst, S and Becker, PH and Vedder, O},
title = {Telomere length is repeatable, shortens with age and reproductive success, and predicts remaining lifespan in a long-lived seabird.},
journal = {Molecular ecology},
volume = {29},
number = {2},
pages = {429-441},
doi = {10.1111/mec.15331},
pmid = {31841253},
issn = {1365-294X},
mesh = {Aging/genetics/physiology ; Animals ; Humans ; Reproduction/genetics/physiology ; Telomere/*genetics/physiology ; Telomere Shortening/*genetics/physiology ; },
abstract = {Telomeres are protective caps at the end of chromosomes, and their length is positively correlated with individual health and lifespan across taxa. Longitudinal studies have provided mixed results regarding the within-individual repeatability of telomere length. While some studies suggest telomere length to be highly dynamic and sensitive to resource-demanding or stressful conditions, others suggest that between-individual differences are mostly present from birth and relatively little affected by the later environment. This dichotomy could arise from differences between species, but also from methodological issues. In our study, we used the highly reliable Terminal Restriction Fragment analysis method to measure telomeres over a 10-year period in adults of a long-lived seabird, the common tern (Sterna hirundo). Telomeres shortened with age within individuals. The individual repeatability of age-dependent telomere length was high (>0.53), and independent of the measurement interval (i.e., one vs. six years). A small (R[2] = .01), but significant part of the between-individual variation in telomere length was, however, explained by the number of fledglings produced in the previous year, while reproduction in years prior to the previous year had no effect. We confirmed that age-dependent telomere length predicted an individual's remaining lifespan. Overall, our study suggests that the majority of between-individual variation in adult telomere length is consistent across adult life, and that a smaller part of the variation can be explained by dynamic factors, such as reproduction.},
}
@article {pmid31839608,
year = {2020},
author = {Fani, L and Hilal, S and Sedaghat, S and Broer, L and Licher, S and Arp, PP and van Meurs, JBJ and Ikram, MK and Ikram, MA},
title = {Telomere Length and the Risk of Alzheimer's Disease: The Rotterdam Study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {73},
number = {2},
pages = {707-714},
pmid = {31839608},
issn = {1875-8908},
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*epidemiology/*genetics ; Apolipoproteins E/genetics ; Female ; Follow-Up Studies ; Genotype ; Humans ; Incidence ; Leukocytes/ultrastructure ; Male ; Middle Aged ; Netherlands/epidemiology ; Predictive Value of Tests ; Prospective Studies ; Risk Assessment ; Telomere/*genetics ; },
abstract = {There is a wide interest in biomarkers that capture the burden of detrimental factors as these accumulate with the passage of time, i.e., increasing age. Telomere length has received considerable attention as such a marker, because it is easily quantified and it may aid in disentangling the etiology of dementia or serve as predictive marker. We determined the association of telomere length with risk of Alzheimer's disease and all-cause dementia in a population-based setting. Within the Rotterdam Study, we performed quantitative PCR to measure mean leukocyte telomere length in blood. We determined the association of telomere length with risk of Alzheimer's disease until 2016, using Cox regression models. Of 1,961 participants (mean age 71.4±9.3 years, 57.1% women) with a median follow-up of 8.3 years, 237 individuals were diagnosed with Alzheimer's disease. We found a U-shaped association between telomere length and risk of Alzheimer's disease: compared to the middle tertile the adjusted hazard ratio was 1.59 (95% confidence interval (CI), 1.13-2.23) for the lowest tertile and 1.47 (1.03-2.10) for the highest tertile. Results were similarly U-shaped but slightly attenuated for all-cause dementia. In conclusion, shorter and longer telomere length are both associated with an increased risk of Alzheimer's disease in the general population.},
}
@article {pmid31837846,
year = {2020},
author = {Bhattacharjee, P and Das, A and Giri, AK and Bhattacharjee, P},
title = {Epigenetic regulations in alternative telomere lengthening: Understanding the mechanistic insight in arsenic-induced skin cancer patients.},
journal = {The Science of the total environment},
volume = {704},
number = {},
pages = {135388},
doi = {10.1016/j.scitotenv.2019.135388},
pmid = {31837846},
issn = {1879-1026},
mesh = {Arsenic/*toxicity ; Carcinogenesis ; Cell Transformation, Neoplastic ; DNA Methylation ; *Epigenesis, Genetic ; Humans ; Skin Neoplasms/*chemically induced ; Telomerase ; Telomere ; *Telomere Homeostasis ; },
abstract = {Telomere integrity is considered to be one of the primary mechanisms during malignant transformation. Arsenic, a group 1 carcinogenic metalloid, has been reported to cause telomere lengthening in a telomerase-independent manner. Recent studies suggest a significant role for epigenetic modifications in regulating telomeric length and integrity. Here, we have explored the role of epigenetic deregulation in alternative lengthening of telomeres (ALT) in arsenic-exposed skin cancer tissues and corresponding non-tumor tissues. The relative telomere length (RTL) was analyzed by qRT-PCR using 2[-ΔΔCt] method. The subtelomeric methylation pattern of the four chromosomes (7q, 18p, 21q and XpYp) were analysed by Methylation Specific PCR (MSP) in 40 pairs of arsenic exposed skin cancer tissues and its corresponding control. The role of constitutive heterochromatin histone marks in the regulation of telomere length (TL) was analyzed by targeted ELISA. A 2-fold increase of relative telomere length in 85% of the arsenic-induced skin cancer tissues was observed. Among the four chromosomes, subtelomere of XpYp was found to be hypermethylated (p < 0.001) whereas 18p was hypomethylated (p < 0.01). Additionally, the level of H4K20me3, a heterochromatic mark was found to be significantly down-regulated (p < 0.0003), and inversely correlated with telomere length indicating loss of heterochromatinization of telomeric DNA. These observations highlight the novel role of epigenetic regulation in the maintenance of constitutive heterochromatin structure at telomere. Alteration in subtelomeric DNA methylation patterns and depletion of H4K20me3 might lead to loss of heterochromatinization resulting in arsenic-induced telomeric elongation. We provide novel data indicating possible alternative determinants of telomere elongation through epigenetic modifications during arsenic-induced skin carcinogenesis which could be used as early 'epimarkers' in the near future. The findings provide new insights about the mechanism of arsenic-induced carcinogenesis.},
}
@article {pmid31837325,
year = {2020},
author = {Storti, CB and de Oliveira, RA and de Carvalho, M and Hasimoto, EN and Cataneo, DC and Cataneo, AJM and De Faveri, J and Vasconcelos, EJR and Dos Reis, PP and Cano, MIN},
title = {Telomere-associated genes and telomeric lncRNAs are biomarker candidates in lung squamous cell carcinoma (LUSC).},
journal = {Experimental and molecular pathology},
volume = {112},
number = {},
pages = {104354},
doi = {10.1016/j.yexmp.2019.104354},
pmid = {31837325},
issn = {1096-0945},
mesh = {Adenocarcinoma/classification/*genetics/pathology ; Biomarkers, Tumor/genetics ; Brazil ; Carcinoma, Non-Small-Cell Lung/classification/*genetics/pathology ; Cell Cycle Proteins/genetics ; Cell Proliferation/genetics ; DNA-Binding Proteins/genetics ; Gene Expression Regulation, Neoplastic/genetics ; Humans ; Neoplasms, Squamous Cell/classification/*genetics/pathology ; Nuclear Proteins/genetics ; RNA/genetics ; RNA, Long Noncoding/genetics ; Shelterin Complex ; Telomerase/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; Transcription Factors/genetics ; Transcriptome/genetics ; },
abstract = {In the past decade, research efforts were made to identify molecular biomarkers useful as therapeutic targets in Non-Small Cell Lung Cancer (NSCLC), the most frequent type of lung carcinoma. NSCLC presents different histological subtypes being the most prevalent LUSC (Lung Squamous Cell Cancer) and LUAD (Lung Adenocarcinoma), and only a subset of LUAD patients' present tumors expressing known targetable genetic alterations. Telomeres and its components, including telomerase, the enzyme that replenishes telomeres, have been considered potential cancer biomarkers due to their crucial role in cell proliferation and genome stability. Our study aims to quantify expression changes affecting telomere-associated genes and ncRNAs associated with telomere regulation and maintenance in NSCLC. We first assessed the transcriptome (RNA-Seq) data of NSCLC patients from The Cancer Genome Atlas (TCGA) and then we tested the expression of telomere-associated genes and telomeric ncRNAs (TERC, telomerase RNA component, and TERRA, telomere repeat-containing RNA) in Brazilian NCSLC patient samples by quantitative RT-PCR, using matched normal adjacent tissue samples as the control. We also estimated the mean size of terminal restriction fragments (TRF) of some Brazilian NSCLC patients using telomeric Southern blot. The TCGA analysis identified alterations in the expression profile of TERT and telomere damage repair genes, mainly in the LUSC subtype. The study of Brazilian NSCLC samples by RT-qPCR showed that LUSC and LUAD express high amounts of TERT and that although the mean TRF size of tumor samples was shorter compared to normal cells, telomeres in NSCLC are probably maintained by telomerase. Also, the expression analysis of Brazilian NSCLC samples identified statistically significant alterations in the expression of genes involved with telomere damage repair, as well as in TERC and TERRA, mainly in the LUSC subtype. We, therefore, concluded that telomere maintenance genes are significantly deregulated in NSCLC, representing potential biomarkers in the LUSC subtype.},
}
@article {pmid31836759,
year = {2019},
author = {Pan, X and Chen, Y and Biju, B and Ahmed, N and Kong, J and Goldenberg, M and Huang, J and Mohan, N and Klosek, S and Parsa, K and Guh, CY and Lu, R and Pickett, HA and Chu, HP and Zhang, D},
title = {FANCM suppresses DNA replication stress at ALT telomeres by disrupting TERRA R-loops.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {19110},
pmid = {31836759},
issn = {2045-2322},
mesh = {BRCA2 Protein/metabolism ; Biomarkers, Tumor/metabolism ; Cell Line, Tumor ; DNA Damage ; DNA Helicases/*metabolism ; DNA Polymerase III/metabolism ; DNA Repair ; *DNA Replication ; DNA, Single-Stranded ; Fanconi Anemia Complementation Group D2 Protein/metabolism ; Fanconi Anemia Complementation Group N Protein/metabolism ; *Gene Expression Regulation, Neoplastic ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Phenotype ; *R-Loop Structures ; Rad51 Recombinase/metabolism ; Telomere/*physiology ; *Telomere Homeostasis ; },
abstract = {Cancer cells maintain their telomeres by either re-activating telomerase or adopting the homologous recombination (HR)-based Alternative Lengthening of Telomere (ALT) pathway. Among the many prominent features of ALT cells, C-circles (CC) formation is considered to be the most specific and quantifiable biomarker of ALT. However, the molecular mechanism behind the initiation and maintenance of CC formation in ALT cells is still largely unknown. We reported previously that depletion of the FANCM complex (FANCM-FAAP24-MHF1&amp;2) in ALT cells induced pronounced replication stress, which primarily takes place at their telomeres. Here, we characterized the changes in ALT associated phenotypes in cells deficient of the FANCM complex. We found that depletion of FAAP24 or FANCM, but not MHF1&amp;2, induces a dramatic increase of CC formation. Most importantly, we identified multiple DNA damage response (DDR) and DNA repair pathways that stimulate the dramatic increase of CC formation in FANCM deficient cells, including the dissolvase complex (BLM-TOP3A-RMI1/2, or BTR), DNA damage checkpoint kinases (ATR and Chk1), HR proteins (BRCA2, PALB2, and Rad51), as well as proteins involved in Break-Induced Replication (BIR) (POLD1 and POLD3). In addition, FANCD2, another Fanconi Anemia (FA) protein, is also required for CC formation, likely through promoting the recruitment of BLM to the replication stressed ALT telomeres. Finally, we demonstrated that TERRA R-loops accumulate at telomeres in FANCM deficient ALT cells and downregulation of which attenuates the ALT-associated PML bodies (APBs), replication stress and CC formation. Taken together, our data suggest that FANCM prevents replisomes from stalling/collapsing at ALT telomeres by disrupting TERRA R-loops.},
}
@article {pmid31835618,
year = {2019},
author = {Zhao, S and Wang, F and Liu, L},
title = {Alternative Lengthening of Telomeres (ALT) in Tumors and Pluripotent Stem Cells.},
journal = {Genes},
volume = {10},
number = {12},
pages = {},
pmid = {31835618},
issn = {2073-4425},
mesh = {Animals ; Cell Line ; Cellular Senescence ; DNA/genetics ; Genome/genetics ; Genomic Instability/genetics ; Humans ; Neoplasms/genetics/metabolism ; Neoplastic Stem Cells/metabolism ; Pluripotent Stem Cells/metabolism/physiology ; Repetitive Sequences, Nucleic Acid/genetics ; Telomerase/genetics ; Telomere/*genetics/metabolism/physiology ; Telomere Homeostasis/*genetics/physiology ; Telomere Shortening/*genetics/physiology ; },
abstract = {A telomere consists of repeated DNA sequences (TTAGGG)n as part of a nucleoprotein structure at the end of the linear chromosome, and their progressive shortening induces DNA damage response (DDR) that triggers cellular senescence. The telomere can be maintained by telomerase activity (TA) in the majority of cancer cells (particularly cancer stem cells) and pluripotent stem cells (PSCs), which exhibit unlimited self-proliferation. However, some cells, such as telomerase-deficient cancer cells, can add telomeric repeats by an alternative lengthening of the telomeres (ALT) pathway, showing telomere length heterogeneity. In this review, we focus on the mechanisms of the ALT pathway and potential clinical implications. We also discuss the characteristics of telomeres in PSCs, thereby shedding light on the therapeutic significance of telomere length regulation in age-related diseases and regenerative medicine.},
}
@article {pmid31834959,
year = {2020},
author = {Adamusová, K and Khosravi, S and Fujimoto, S and Houben, A and Matsunaga, S and Fajkus, J and Fojtová, M},
title = {Two combinatorial patterns of telomere histone marks in plants with canonical and non-canonical telomere repeats.},
journal = {The Plant journal : for cell and molecular biology},
volume = {102},
number = {4},
pages = {678-687},
doi = {10.1111/tpj.14653},
pmid = {31834959},
issn = {1365-313X},
mesh = {Arabidopsis/genetics ; Chromatin/genetics ; *Epigenomics ; Histone Code/*genetics ; Phylogeny ; Plants/*genetics ; Telomere/*genetics ; Nicotiana/genetics ; },
abstract = {Telomeres, nucleoprotein structures at the ends of linear eukaryotic chromosomes, are crucial for the maintenance of genome integrity. In most plants, telomeres consist of conserved tandem repeat units comprising the TTTAGGG motif. Recently, non-canonical telomeres were described in several plants and plant taxons, including the carnivorous plant Genlisea hispidula (TTCAGG/TTTCAGG), the genus Cestrum (Solanaceae; TTTTTTAGGG), and plants from the Asparagales order with either a vertebrate-type telomere repeat TTAGGG or Allium genus-specific CTCGGTTATGGG repeat. We analyzed epigenetic modifications of telomeric histones in plants with canonical and non-canonical telomeres, and further in telomeric chromatin captured from leaves of Nicotiana benthamiana transiently transformed by telomere CRISPR-dCas9-eGFP, and of Arabidopsis thaliana stably transformed with TALE_telo C-3×GFP. Two combinatorial patterns of telomeric histone modifications were identified: (i) an Arabidopsis-like pattern (A. thaliana, G. hispidula, Genlisea nigrocaulis, Allium cepa, Narcissus pseudonarcissus, Petunia hybrida, Solanum tuberosum, Solanum lycopersicum) with telomeric histones decorated predominantly by H3K9me2; (ii) a tobacco-like pattern (Nicotiana tabacum, N. benthamiana, C. elegans) with a strong H3K27me3 signal. Our data suggest that epigenetic modifications of plant telomere-associated histones are related neither to the sequence of the telomere motif nor to the lengths of the telomeres. Nor the phylogenetic position of the species plays the role; representatives of the Solanaceae family are included in both groups. As both patterns of histone marks are compatible with fully functional telomeres in respective plants, we conclude that the described specific differences in histone marks are not critical for telomere functions.},
}
@article {pmid31831784,
year = {2019},
author = {Karere, GM and Mahaney, MC and Newman, DE and Riojas, AM and Christensen, C and Birnbaum, S and VandeBerg, JL and Cox, L},
title = {Diet-induced leukocyte telomere shortening in a baboon model for early stage atherosclerosis.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {19001},
pmid = {31831784},
issn = {2045-2322},
support = {P01 HL028972/HL/NHLBI NIH HHS/United States ; P51 RR013986/RR/NCRR NIH HHS/United States ; P51 OD011133/OD/NIH HHS/United States ; C06 RR013556/RR/NCRR NIH HHS/United States ; C06 RR017515/RR/NCRR NIH HHS/United States ; },
mesh = {Aging/physiology ; Animals ; Atherosclerosis/*pathology ; Biomarkers/metabolism ; *Diet ; Disease Models, Animal ; Female ; Leukocytes/*metabolism ; Male ; Papio ; Pedigree ; Risk Factors ; *Telomere Shortening ; },
abstract = {Reported associations between leukocyte telomere length (LTL) attrition, diet and cardiovascular disease (CVD) are inconsistent. This study explores effects of prolonged exposure to a high cholesterol high fat (HCHF) diet on LTL in a baboon model of atherosclerosis. We measured LTL by qPCR in pedigreed baboons fed a chow (n = 105) or HCHF (n = 106) diet for 2 years, tested for effects of diet on LTL, and association between CVD risk factors and atherosclerotic lesions with LTL. Though not different at baseline, after 2 years median LTL is shorter in HCHF fed baboons (P < 0.0001). Diet predicts sex- and age-adjusted LTL and LTL attrition (P = 0.0009 and 0.0156, respectively). Serum concentrations of CVD biomarkers are associated with LTL at the 2-year endpoint and LTL accounts approximately 6% of the variance in aortic lesions (P = 0.04). Although heritable at baseline (h[2] = 0.27, P = 0.027) and after 2 years (h[2] = 0.46, P = 0.0038), baseline LTL does not predict lesion extent after 2 years. Atherogenic diet influences LTL, and LTL is a potential biomarker for early atherosclerosis. Prolonged exposure to an atherogenic diet decreases LTL and increases LTL attrition, and shortened LTL is associated with early-stage atherosclerosis in pedigreed baboons.},
}
@article {pmid31830692,
year = {2020},
author = {Everson, F and Martens, DS and Nawrot, TS and Goswami, N and Mthethwa, M and Webster, I and Mashele, N and Charania, S and Kamau, F and De Boever, P and Strijdom, H},
title = {Personal exposure to NO2 and benzene in the Cape Town region of South Africa is associated with shorter leukocyte telomere length in women.},
journal = {Environmental research},
volume = {182},
number = {},
pages = {108993},
doi = {10.1016/j.envres.2019.108993},
pmid = {31830692},
issn = {1096-0953},
mesh = {Adult ; *Air Pollutants ; *Benzene/analysis/toxicity ; Benzene Derivatives ; Cities ; Environmental Exposure ; Environmental Monitoring ; Female ; Humans ; Leukocytes ; Middle Aged ; *Nitrogen Dioxide/analysis/toxicity ; South Africa ; Telomere ; *Telomere Shortening/drug effects ; },
abstract = {Air pollution exposure is a major global health concern and has been associated with molecular aging. Unfortunately, the situation has not received much attention in the African region. The aim of this study was to investigate whether current personal ambient NO2 and benzene, toluene, ethyl-benzene and xylenes (ortho (o)-, meta (m)- and para (p)-xylene (BTEX) exposure is associated with leukocyte telomere length (LTL), a marker of molecular ageing, in apparently healthy women (mean ± SD age: 42.5 ± 13.4 years) residing in the Cape Town region of South Africa. The repeated measures study collected data from 61 women. Seven-day median (interquartile range (IQR)) personal NO2 and BTEX exposure levels were determined via compact passive diffusion samplers carried on the person prior to baseline (NO2: 14.2 (9.4-17.2) μg/m[3]; Benzene: 3.1 (2.1-5.3) μg/m[3]) and 6-month follow-up (NO2: 10.6 (6.6-13.6) μg/m[3]; Benzene: 2.2 (1.3-4.9) μg/m[3]) visits. LTL was measured at baseline and follow-up using a real-time PCR method. Multiple linear mixed model analyses (adjusting for age, body mass index, smoking, employment status, level of education and assessment visit) showed that each IQR increment increase in NO2 (7.0 μg/m[3]) and benzene (3.3 μg/m[3]) was associated with -7.30% (95% CI: -10.98 to -3.46%; p < 0.001) and -6.78% (95% CI: -11.88 to -1.39%; p = 0.015) difference in LTL, respectively. The magnitude of these effects of NO2 and benzene corresponds to the effect of an increase of 10.3- and 6.0-year in chronological age on LTL. Our study shows that personal exposures to NO2 and benzene are associated with molecular ageing as indicated by LTL in healthy women residing in the Cape Town region.},
}
@article {pmid31828313,
year = {2020},
author = {Davé, A and Pai, CC and Durley, SC and Hulme, L and Sarkar, S and Wee, BY and Prudden, J and Tinline-Purvis, H and Cullen, JK and Walker, C and Watson, A and Carr, AM and Murray, JM and Humphrey, TC},
title = {Homologous recombination repair intermediates promote efficient de novo telomere addition at DNA double-strand breaks.},
journal = {Nucleic acids research},
volume = {48},
number = {3},
pages = {1271-1284},
pmid = {31828313},
issn = {1362-4962},
support = {BB/C510291/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MC_PC_12003/MRC_/Medical Research Council/United Kingdom ; MC_U142784382/MRC_/Medical Research Council/United Kingdom ; MC_UU_00001/4/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Chromosomes, Fungal/genetics ; DNA Breaks, Double-Stranded ; DNA Helicases/*genetics ; DNA-Binding Proteins/*genetics ; Exodeoxyribonucleases/genetics ; Gene Expression Regulation, Fungal/genetics ; Genome, Fungal/genetics ; Genomic Instability/genetics ; Loss of Heterozygosity/genetics ; Rad51 Recombinase/genetics ; Recombinational DNA Repair/*genetics ; Schizosaccharomyces/genetics ; Schizosaccharomyces pombe Proteins/*genetics ; Telomere/*genetics ; },
abstract = {The healing of broken chromosomes by de novo telomere addition, while a normal developmental process in some organisms, has the potential to cause extensive loss of heterozygosity, genetic disease, or cell death. However, it is unclear how de novo telomere addition (dnTA) is regulated at DNA double-strand breaks (DSBs). Here, using a non-essential minichromosome in fission yeast, we identify roles for the HR factors Rqh1 helicase, in concert with Rad55, in suppressing dnTA at or near a DSB. We find the frequency of dnTA in rqh1Δ rad55Δ cells is reduced following loss of Exo1, Swi5 or Rad51. Strikingly, in the absence of the distal homologous chromosome arm dnTA is further increased, with nearly half of the breaks being healed in rqh1Δ rad55Δ or rqh1Δ exo1Δ cells. These findings provide new insights into the genetic context of highly efficient dnTA within HR intermediates, and how such events are normally suppressed to maintain genome stability.},
}
@article {pmid31825846,
year = {2019},
author = {Rai, R and Gu, P and Broton, C and Kumar-Sinha, C and Chen, Y and Chang, S},
title = {The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function.},
journal = {Cell reports},
volume = {29},
number = {11},
pages = {3708-3725.e5},
pmid = {31825846},
issn = {2211-1247},
support = {R01 CA129037/CA/NCI NIH HHS/United States ; R01 CA202816/CA/NCI NIH HHS/United States ; R03 CA223612/CA/NCI NIH HHS/United States ; R03 CA252689/CA/NCI NIH HHS/United States ; },
mesh = {Acid Anhydride Hydrolases/metabolism ; Adaptor Proteins, Signal Transducing/metabolism ; Aminopeptidases/deficiency/metabolism ; Animals ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cells, Cultured ; Checkpoint Kinase 1/metabolism ; *DNA End-Joining Repair ; DNA Repair Enzymes/metabolism ; DNA-Binding Proteins/metabolism ; DNA-Directed DNA Polymerase/genetics/*metabolism ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/deficiency/metabolism ; Exodeoxyribonucleases/metabolism ; HEK293 Cells ; Humans ; MRE11 Homologue Protein/metabolism ; Mice ; Multienzyme Complexes/genetics/*metabolism ; Proliferating Cell Nuclear Antigen/metabolism ; Serine Proteases/deficiency/metabolism ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/deficiency/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Telomeres use shelterin to protect chromosome ends from activating the DNA damage sensor MRE11-RAD50-NBS1 (MRN), repressing ataxia-telangiectasia, mutated (ATM) and ATM and Rad3-related (ATR) dependent DNA damage checkpoint responses. The MRE11 nuclease is thought to be essential for the resection of the 5' C-strand to generate the microhomologies necessary for alternative non-homologous end joining (A-NHEJ) repair. In the present study, we uncover DNA damage signaling and repair pathways engaged by components of the replisome complex to repair dysfunctional telomeres. In cells lacking MRN, single-stranded telomeric overhangs devoid of POT1-TPP1 do not recruit replication protein A (RPA), ATR-interacting protein (ATRIP), and RAD 51. Rather, components of the replisome complex, including Claspin, Proliferating cell nuclear antigen (PCNA), and Downstream neighbor of SON (DONSON), initiate DNA-PKcs-mediated p-CHK1 activation and A-NHEJ repair. In addition, Claspin directly interacts with TRF2 and recruits EXO1 to newly replicated telomeres to promote 5' end resection. Our data indicate that MRN is dispensable for the repair of dysfunctional telomeres lacking POT1-TPP1 and highlight the contributions of the replisome in telomere repair.},
}
@article {pmid31825239,
year = {2020},
author = {Lincz, LF and Scorgie, FE and Garg, MB and Gilbert, J and Sakoff, JA},
title = {A simplified method to calculate telomere length from Southern blot images of terminal restriction fragment lengths.},
journal = {BioTechniques},
volume = {68},
number = {1},
pages = {28-34},
doi = {10.2144/btn-2019-0082},
pmid = {31825239},
issn = {1940-9818},
mesh = {Adult ; Aged ; Blotting, Southern/*methods ; Cell Line, Tumor ; Female ; Healthy Volunteers ; Humans ; Image Processing, Computer-Assisted/*methods ; Male ; Middle Aged ; *Software ; *Telomere ; },
abstract = {Southern blotting of DNA terminal restriction fragment lengths is the gold standard for measuring mean telomere length. Analysis of the final image is a crucial step in this process, however, current techniques are cumbersome and prone to error. Here we present a simple and accurate method for analyzing telomere smears. Basic 2D gel imaging software was used to automatically subtract background, generate standard curves and calculate net intensity and MW at each position (i) along the telomere smear. Our method required no statistical software or major data manipulation and correctly classified >80% of 18 samples as having short, medium or long telomeres compared with 33-72% using other methods.},
}
@article {pmid31824705,
year = {2019},
author = {Bateson, M and Eisenberg, DTA and Nettle, D},
title = {Controlling for baseline telomere length biases estimates of the rate of telomere attrition.},
journal = {Royal Society open science},
volume = {6},
number = {10},
pages = {190937},
pmid = {31824705},
issn = {2054-5703},
support = {NC/K000802/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; },
abstract = {Longitudinal studies have sought to establish whether environmental exposures such as smoking accelerate the attrition of individuals' telomeres over time. These studies typically control for baseline telomere length (TL) by including it as a covariate in statistical models. However, baseline TL also differs between smokers and non-smokers, and telomere attrition is spuriously linked to baseline TL via measurement error and regression to the mean. Using simulated datasets, we show that controlling for baseline TL overestimates the true effect of smoking on telomere attrition. This bias increases with increasing telomere measurement error and increasing difference in baseline TL between smokers and non-smokers. Using a meta-analysis of longitudinal datasets, we show that as predicted, the estimated difference in telomere attrition between smokers and non-smokers is greater when statistical models control for baseline TL than when they do not, and the size of the discrepancy is positively correlated with measurement error. The bias we describe is not specific to smoking and also applies to other exposures. We conclude that to avoid invalid inference, models of telomere attrition should not control for baseline TL by including it as a covariate. Many claims of accelerated telomere attrition in individuals exposed to adversity need to be re-assessed.},
}
@article {pmid31823970,
year = {2019},
author = {Martínez-Ezquerro, JD and Rodríguez-Castañeda, A and Ortiz-Ramírez, M and Sánchez-García, S and Rosas-Vargas, H and Sánchez-Arenas, R and García-de la Torre, P},
title = {OXIDATIVE STRESS, TELOMERE LENGTH, AND FRAILTY IN AN OLD AGE POPULATION.},
journal = {Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion},
volume = {71},
number = {6},
pages = {393-401},
doi = {10.24875/RIC.19003116},
pmid = {31823970},
issn = {0034-8376},
mesh = {Age Factors ; Aged ; Aged, 80 and over ; Aging ; Biomarkers/metabolism ; Cohort Studies ; Cross-Sectional Studies ; Female ; *Frail Elderly ; Frailty/*epidemiology/physiopathology ; Humans ; Male ; Middle Aged ; Oxidative Stress/*physiology ; Reactive Oxygen Species/metabolism ; Risk Factors ; Telomere/*physiology ; },
abstract = {BACKGROUND: A global aging population requires focusing on the risk factors for unhealthy aging, preventive medicine, and chronic disease management. The identification of adverse health outcomes in older adults has been addressed by the characterization of frailty as a biological syndrome. In this field, oxidative stress and telomere length have been suggested as biomarkers of aging.<br><br>OBJECTIVE: The objective of the study was to study the association of oxidative stress, telomere length, and frailty in an old age population.<br><br>METHODS: We conducted a cross-sectional study based on 2015 data from 202 members of a cohort of older adults (n = 202; F/M gender ratio: 133/69; mean age: 69.89 &#xb1; 7.39 years). Reactive oxygen species were measured by dichlorofluorescein diacetate and lipid peroxidation by malondialdehyde. Telomere length was determined using quantitative polymerase chain reaction with SYBR Green Master Mix.<br><br>RESULTS: Statistical analysis showed an association between telomere length and frailty but no association between oxidative stress and telomere length or frailty.<br><br>CONCLUSIONS: Telomere length could eventually be used as a marker to differentiate between healthy and unhealthy aging as expressed by frailty phenotype; oxidative stress seemed merely a biological process of aging.},
}
@article {pmid31822763,
year = {2019},
author = {Clemente, DBP and Maitre, L and Bustamante, M and Chatzi, L and Roumeliotaki, T and Fossati, S and Grazuleviciene, R and Gützkow, KB and Lepeule, J and Martens, DS and McEachan, RRC and Meltzer, HM and Petraviciene, I and Slama, R and Tamayo-Uria, I and Urquiza, J and Vafeiadi, M and Wright, J and Nawrot, TS and Vrijheid, M},
title = {Obesity is associated with shorter telomeres in 8 year-old children.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {18739},
pmid = {31822763},
issn = {2045-2322},
support = {MR/N024397/1/MRC_/Medical Research Council/United Kingdom ; P30 ES007048/ES/NIEHS NIH HHS/United States ; R21 ES029681/ES/NIEHS NIH HHS/United States ; },
mesh = {Adiposity ; Adult ; Aging/*genetics/physiology ; Biomarkers ; Body Mass Index ; Child ; Cohort Studies ; Female ; Humans ; Male ; Obesity/*genetics ; Pregnancy ; Retrospective Studies ; Risk Factors ; Skinfold Thickness ; Telomere/*genetics/metabolism ; Telomere Shortening/genetics/physiology ; Waist Circumference ; },
abstract = {Telomere length is considered a biomarker of biological aging. Shorter telomeres and obesity have both been associated with age-related diseases. To evaluate the association between various indices of obesity with leukocyte telomere length (LTL) in childhood, data from 1,396 mother-child pairs of the multi-centre European birth cohort study HELIX were used. Maternal pre-pregnancy body mass index (BMI) and 4 adiposity markers in children at age 8 (6-11) years were assessed: BMI, fat mass, waist circumference, and skinfold thickness. Relative LTL was obtained. Associations of LTL with each adiposity marker were calculated using linear mixed models with a random cohort effect. For each 1 kg/m[2] increment in maternal pre-pregnancy BMI, the child's LTL was 0.23% shorter (95%CI: 0.01,0.46%). Each unit increase in child BMI z-score was associated with 1.21% (95%CI: 0.30,2.11%) shorter LTL. Inverse associations were observed between waist circumference and LTL (-0.96% per z-score unit; 95%CI: -2.06,0.16%), and skinfold thickness and LTL (-0.10% per z-score unit; 95%CI: -0.23,0.02%). In conclusion, this large multicentric study suggests that higher child adiposity indicators are associated with short telomeres in children, and that associations are stronger for child BMI than for maternal pre-pregnancy BMI.},
}
@article {pmid31822713,
year = {2019},
author = {Nersisyan, L and Nikoghosyan, M and , and Arakelyan, A},
title = {WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {18758},
pmid = {31822713},
issn = {2045-2322},
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Child ; Datasets as Topic ; Female ; Genome-Wide Association Study ; Humans ; Linear Models ; Male ; Maternal Age ; *Maternal Inheritance ; Middle Aged ; *Models, Genetic ; Netherlands ; Paternal Age ; Polymorphism, Single Nucleotide ; Ribonucleoside Diphosphate Reductase/*genetics/metabolism ; Sex Factors ; Telomere/*metabolism ; Telomere Homeostasis/*genetics ; Whole Genome Sequencing ; Young Adult ; },
abstract = {Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother's, and, to a lesser extent, with father's TL having the strongest influence on the offspring. In this cohort, mother's, but not father's age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait.},
}
@article {pmid31822618,
year = {2019},
author = {Tesmer, VM and Smith, EM and Danciu, O and Padmanaban, S and Nandakumar, J},
title = {Combining conservation and species-specific differences to determine how human telomerase binds telomeres.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {116},
number = {52},
pages = {26505-26515},
pmid = {31822618},
issn = {1091-6490},
support = {R01 AG050509/AG/NIA NIH HHS/United States ; R01 GM120094/GM/NIGMS NIH HHS/United States ; },
abstract = {Telomerase catalyzes telomeric DNA synthesis at chromosome ends to allow for continued cell division. The telomeric protein TPP1 is essential for enhancing the processivity of telomerase and recruiting the enzyme to telomeres. The telomerase interaction surface on human TPP1 has been mapped to 2 regions of the N-terminal oligosaccharide/oligonucleotide-binding (OB) domain, namely the TPP1 glutamate (E) and leucine (L)-rich (TEL) patch and the N terminus of TPP1-oligosaccharide/oligonucleotide-binding (NOB) region. To map the telomerase side of the interface, we exploited the predicted structural similarities for human and Tetrahymena thermophila telomerase as well as the species specificity of human and mouse telomerase for their cognate TPP1 partners. We show that swapping in the telomerase essential N-terminal (TEN) and insertions in fingers domain (IFD)-TRAP regions of the human telomerase catalytic protein subunit TERT into the mouse TERT backbone is sufficient to bias the species specificity toward human TPP1. Employing a structural homology-based mutagenesis screen focused on surface residues of the TEN and IFD regions, we identified TERT residues that are critical for contacting TPP1 but dispensable for other aspects of telomerase structure or function. We present a functionally validated structural model for how human telomerase engages TPP1 at telomeres, setting the stage for a high-resolution structure of this interface.},
}
@article {pmid31815300,
year = {2020},
author = {Markova, DN and Christensen, SM and Betrán, E},
title = {Telomere-Specialized Retroelements in Drosophila: Adaptive Symbionts of the Genome, Neutral, or in Conflict?.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {42},
number = {1},
pages = {e1900154},
doi = {10.1002/bies.201900154},
pmid = {31815300},
issn = {1521-1878},
mesh = {Animals ; Drosophila/*genetics ; *Genome, Insect ; Long Interspersed Nucleotide Elements ; Retroelements/*genetics ; Symbiosis ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Linear chromosomes shorten in every round of replication. In Drosophila, telomere-specialized long interspersed retrotransposable elements (LINEs) belonging to the jockey clade offset this shortening by forming head-to-tail arrays at Drosophila telomere ends. As such, these telomeric LINEs have been considered adaptive symbionts of the genome, protecting it from premature decay, particularly as Drosophila lacks a conventional telomerase holoenzyme. However, as reviewed here, recent work reveals a high degree of variation and turnover in the telomere-specialized LINE lineages across Drosophila. There appears to be no absolute requirement for LINE activity to maintain telomeres in flies, hence the suggestion that the telomere-specialized LINEs may instead be neutral or in conflict with the host, rather than adaptive.},
}
@article {pmid31815205,
year = {2019},
author = {Adam, N and Degelman, E and Briggs, S and Wazen, RM and Colarusso, P and Riabowol, K and Beattie, T},
title = {Telomere analysis using 3D fluorescence microscopy suggests mammalian telomere clustering in hTERT-immortalized Hs68 fibroblasts.},
journal = {Communications biology},
volume = {2},
number = {},
pages = {451},
pmid = {31815205},
issn = {2399-3642},
support = {//CIHR/Canada ; },
mesh = {Animals ; Fibroblasts/*metabolism ; Humans ; Image Processing, Computer-Assisted ; Imaging, Three-Dimensional ; In Situ Hybridization, Fluorescence ; *Microscopy, Fluorescence/methods ; Reproducibility of Results ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Homeostasis ; },
abstract = {Telomere length and dynamics are central to understanding cell aging, genomic instability and cancer. Currently, there are limited guidelines for analyzing telomeric features in 3D using different cellular models. Image processing for telomere analysis is of increasing interest in many fields, however a lack of standardization can make comparisons and reproducibility an issue. Here we provide a user's guide for quantitative immunofluorescence microscopy of telomeres in interphase cells that covers image acquisition, processing and analysis. Strategies for determining telomere size and number are identified using normal human diploid Hs68 fibroblasts. We demonstrate how to accurately determine telomere number, length, volume, and degree of clustering using quantitative immunofluorescence. Using this workflow, we make the unexpected observation that hTERT-immortalized Hs68 cells with longer telomeres have fewer resolvable telomeres in interphase. Rigorous quantification indicates that this is due to telomeric clustering, leading to systematic underestimation of telomere number and overestimation of telomere size.},
}
@article {pmid31815007,
year = {2019},
author = {Li, Y and Li, X and Cao, M and Jiang, Y and Yan, J and Liu, Z and Yang, R and Chen, X and Sun, P and Xiang, R and Wang, L and Shi, Y},
title = {Seryl tRNA synthetase cooperates with POT1 to regulate telomere length and cellular senescence.},
journal = {Signal transduction and targeted therapy},
volume = {4},
number = {},
pages = {50},
pmid = {31815007},
issn = {2059-3635},
abstract = {Deregulated telomere length is a causative factor in many physiological and pathological processes, including aging and cancer. Many studies focusing on telomeres have revealed important roles for cooperation between the Shelterin protein complex and telomerase in maintaining telomere length. However, it remains largely unknown whether and how aging-related stresses, such as deregulated protein homeostasis, impact telomere length. Here, we explored the possible roles of aminoacyl tRNA synthetases (AARSs), key enzymes catalyzing the first reactions in protein synthesis, in regulating telomere length and aging. We selected seryl tRNA synthetase (SerRS) since our previous studies discovered expanded functions of SerRS in the nucleus in addition to its canonical cytoplasmic role in protein synthesis. In this study, we revealed that overexpression of SerRS promoted cellular senescence and inhibited the growth of cervical tumor xenografts in mice by triggering the senescence of tumor cells. In the nucleus, SerRS directly bound to telomeric DNA repeats and tethered more POT1 proteins to telomeres through a direct interaction between the UNE-S domain of SerRS and the OB1 domain of POT1. We further demonstrated that SerRS-induced enrichment of POT1 prevented the recruitment of telomerase to telomeres, resulting in progressive telomere shortening. Our data suggested a possible molecular link between protein synthesis and telomere length control, the deregulation of which may be associated with aging and cancer.},
}
@article {pmid31814184,
year = {2020},
author = {Aref, S and Al Saeed, A and El Menshawy, N and Abdalla, D and El Ashery, M},
title = {Prognostic relevance of telomere length and telomerase reverse transcriptase variant (rs2242652) on the multiple myeloma patients.},
journal = {Journal of clinical laboratory analysis},
volume = {34},
number = {4},
pages = {e23133},
pmid = {31814184},
issn = {1098-2825},
mesh = {Adult ; Aged ; Case-Control Studies ; Female ; *Genetic Predisposition to Disease ; Humans ; Kaplan-Meier Estimate ; Logistic Models ; Male ; Middle Aged ; Multiple Myeloma/*enzymology/*genetics ; Neoplasm Staging ; Polymorphism, Single Nucleotide/*genetics ; Prognosis ; Remission Induction ; Telomerase/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: The search for enhancement of multiple myeloma prognostic tools is an area of current research. This study aimed to assess the clinicopathological impact of telomere length and telomerase reverse transcriptase (TERT) polymorphic variant, rs2242652, on multiple myeloma (MM) patients.<br><br>METHODS: Fifty MM patients and 50 healthy controls were included. Relative telomere length (RTL) and rs2242652 genotype polymorphic variants of TERT were analyzed using real-time polymerase chain reaction (PCR). The MM patients' group was categorized into stage I (n&#xa0;=&#xa0;16); stage II (n&#xa0;=&#xa0;12), and stage III (n&#xa0;=&#xa0;22).<br><br>RESULTS: The median telomere length was significantly longer in MM patients' group (0.78) as compared to controls (0.43) (P&#xa0;=&#xa0;.001). Multivariate regression analysis revealed that MM patients with RTL&#xa0;<&#xa0;0.5 had significant poor response for induction remission therapy with odds ratio 26.45. On the other hand, TERT genotyping analysis of rs2242652 revealed insignificant difference between cases and controls (P&#xa0;=&#xa0;.234), regarding to induction remission response. Survival analysis using Kaplan-Meier curve revealed that patients with shorter telomere length and those with TERT genotype GA had shorter overall survival.<br><br>CONCLUSION: Telomere length and TERT rs2242652 genotype polymorphism could be used for refining risk stratification of MM patients.},
}
@article {pmid31809318,
year = {2019},
author = {Zhang, M and Hu, ML and Huang, JJ and Xia, SS and Yang, Y and Dong, K},
title = {Association of leukocyte telomere length with non-alcoholic fatty liver disease in patients with type 2 diabetes.},
journal = {Chinese medical journal},
volume = {132},
number = {24},
pages = {2927-2933},
pmid = {31809318},
issn = {2542-5641},
mesh = {Adult ; Aged ; Cross-Sectional Studies ; Diabetes Mellitus, Type 2/*genetics ; Female ; Humans ; Leukocytes/*metabolism ; Logistic Models ; Male ; Middle Aged ; Non-alcoholic Fatty Liver Disease/*genetics ; *Telomere ; },
abstract = {BACKGROUND: Leukocyte telomere has been shown to be related to insulin resistance-related diseases, such as type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). This cross-sectional study investigated the association of leukocyte telomere length (LTL) with NAFLD in T2DM patients.<br><br>METHODS: Clinical features were collected and LTL was measured by Southern blot-based terminal restriction fragment length analysis in 120 T2DM patients without NAFLD and 120 age-matched T2DM patients with NAFLD. NAFLD was clinically defined by manifestations of ultrasonography. The correlation between LTL and clinical and biochemical parameters were analyzed by Pearson correlation or Spearman correlation analysis. Factors for NAFLD in T2DM patients were identified using multiple logistic regressions.<br><br>RESULTS: LTL in T2DM patients with NAFLD were significantly longer than those without NAFLD (6400.2&#x200a;&#xb1;&#x200a;71.8 base pairs [bp] vs. 6023.7&#x200a;&#xb1;&#x200a;49.5 bp, P&#x200a;<&#x200a;0.001), especially when diabetes duration was less than 2 years. Meanwhile, the trend of shorter LTL was associated with the increased diabetes duration in T2DM patient with NAFLD, but not in T2DM patients without NAFLD. Finally, LTL (odds ratio [OR]: 1.001, 95% confidence interval [CI]: 1.000-1.002, P&#x200a;=&#x200a;0.001), as well as body mass index (OR: 1.314, 95% CI: 1.169-1.477, P&#x200a;<&#x200a;0.001) and triglycerides (OR: 1.984, 95% CI: 1.432-2.747, P&#x200a;<&#x200a;0.001), had a significant association with NAFLD status in T2DM patients.<br><br>CONCLUSIONS: T2DM patients with NAFLD had a significantly longer LTL than those without NAFLD. The longer LTL was especially evident in the early stage of T2DM, indicating that longer LTL may be used as a biomarker for NAFLD in T2DM patients.},
}
@article {pmid31808320,
year = {2020},
author = {Wang, Y and Best, A and Fernández-Torrón, R and Alsaggaf, R and Garcia-Puga, M and Dagnall, CL and Hicks, B and Thompson, M and Matheu Fernandez, A and Zulaica Ijurco, M and Greene, MH and Lopez de Munain, A and Gadalla, SM},
title = {Leukocyte telomere length in patients with myotonic dystrophy type I: a pilot study.},
journal = {Annals of clinical and translational neurology},
volume = {7},
number = {1},
pages = {126-131},
pmid = {31808320},
issn = {2328-9503},
support = {//Intramural Research Program of the Division of Cancer Epidemiology and Genetics/International ; /CA/NCI NIH HHS/United States ; /NH/NIH HHS/United States ; /CA/NCI NIH HHS/United States ; /NH/NIH HHS/United States ; },
mesh = {Adult ; Female ; Humans ; *Leukocytes ; Male ; Middle Aged ; Myotonic Dystrophy/*genetics ; Pilot Projects ; Telomere Shortening/*genetics ; },
abstract = {Myotonic dystrophy type I (DM1) is an autosomal dominant disease of which clinical manifestations resemble premature aging. We evaluated the contribution of telomere length in pathogenesis in 361 DM1 patients (12 with serial measurements) and 223 unaffected relative controls using qPCR assay. While no differences in baseline leukocyte relative telomere length (RTL) was noted, the data suggested an accelerated RTL attrition in DM1 (discovery cohort: T/S change/year = -0.013 in DM1 vs. -0.005 in controls, P = 0.04); similar trend was noted in validation cohort. Further investigations are needed to examine the role of TL in the pathophysiology of DM1.},
}
@article {pmid31805818,
year = {2020},
author = {Opstad, TB and Kalstad, AA and Holte, KB and Berg, TJ and Solheim, S and Arnesen, H and Seljeflot, I},
title = {Shorter Leukocyte Telomere Lengths in Healthy Relatives of Patients with Coronary Heart Disease.},
journal = {Rejuvenation research},
volume = {23},
number = {4},
pages = {324-332},
doi = {10.1089/rej.2019.2258},
pmid = {31805818},
issn = {1557-8577},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; *Aging ; Bone Morphogenetic Proteins/genetics/*metabolism ; Coronary Disease/*physiopathology ; Family ; Female ; Growth Differentiation Factors/genetics/*metabolism ; Healthy Volunteers ; Humans ; Inflammation Mediators/metabolism ; Leukocytes/*metabolism ; Male ; Middle Aged ; Sirtuin 1/genetics/*metabolism ; *Telomere Homeostasis ; Young Adult ; },
abstract = {Telomere length (TL), sirtuin (SIRT) 1, growth differentiation factor (GDF) 11, as well as inflammaging have been related to age-related diseases. In healthy subjects, we aimed to investigate whether leukocyte TL (LTL) associated with family history of coronary heart disease (CHD), age, sex, and lifestyle, and further potential covariations between LTL, GDF11, SIRT1 and selected proinflammatory markers. In 118 healthy subjects (18-81 years, 58% females), whole blood was collected for DNA and RNA isolation and polymerase chain reaction relative quantification of LTLs and gene-expression of SIRT1, GDF11, interleukin (IL)-18, and interferon (IFN)ƴ, respectively, and serum SIRT1 and IL-18 analyses. Shorter LTLs were associated with a seven-fold higher frequency of hereditary CHD in subjects with LTLs in quartile (Q)1 compared with Q2-4 (odds ratio = 7.5, 95% confidence interval: 2.5-21.6, p < 0.001, adjusted). We also observed that LTLs in Q4 compared with Q1-3 associated with higher leukocyte expression of SIRT1 and GDF11 (p = 0.052 and p = 0.058), lower IFNƴ expression (p = 0.009), and lower circulating IL-18 levels (p = 0.027). SIRT1 and GDF11 expression were strongly intercorrelated (Spearman's rho = 0.85, p < 0.001). Overall, smoking, snus, and alcohol consumption were not associated with LTLs. The observed shorter LTLs in association with elevated expression of SIRT1 and GDF11 and dampened inflammation in hereditary CHD subjects, suggest impending risk of disease. More research are warranted to shed light on early lifestyle interventions targeting these mechanisms, to promote healthier aging in individuals with hereditary burden. Graphical Abstract [Figure: see text].},
}
@article {pmid31803085,
year = {2019},
author = {Gao, K and Wei, C and Zhu, J and Wang, X and Chen, G and Luo, Y and Zhang, D and Yue, W and Yu, H},
title = {Exploring the Causal Pathway From Telomere Length to Alzheimer's Disease: An Update Mendelian Randomization Study.},
journal = {Frontiers in psychiatry},
volume = {10},
number = {},
pages = {843},
pmid = {31803085},
issn = {1664-0640},
abstract = {Increasing evidence shows that telomere length shortening is associated with the risk for Alzheimer's disease (AD), pointing to a potential modifiable target for prevention. However, the causality of this association is still not clear. To investigate the causal relationship between telomere length and AD, we use two-sample Mendelian randomization (MR) to assess potential causal inference. We used summary-level data for telomere length (9,190 participants) and AD (71,880 cases and 383,378 controls). We performed two-sample MR analysis with single nucleotide polymorphisms previously identified to be associated with telomere length. The MR analyses were conducted using the inverse-variance-weighted method and complemented with the maximum likelihood, weighted median, weighted mode approaches. MR evidence suggested that shorter telomere length was causally associated with a higher risk for AD (inverse-variance weighted estimate of odds ratio (OR): 1.03 per SD decrease of telomere length, P=1.21×10[-2]). The maximum likelihood, weighted median, weighted mode yielded a similar pattern of effects. The results were similar in sensitivity analyses. Using genetic instruments identified from large-scale genome-wide association study, robust evidence supports a causal role of telomere length shortening with increased risk of AD.},
}
@article {pmid31796605,
year = {2020},
author = {Dantzer, B and van Kesteren, F and Westrick, SE and Boutin, S and McAdam, AG and Lane, JE and Gillespie, R and Majer, A and Haussmann, MF and Monaghan, P},
title = {Maternal glucocorticoids promote offspring growth without inducing oxidative stress or shortening telomeres in wild red squirrels.},
journal = {The Journal of experimental biology},
volume = {223},
number = {Pt 1},
pages = {},
pmid = {31796605},
issn = {1477-9145},
support = {R15 HD083870/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Female ; Glucocorticoids/*metabolism ; Male ; *Oxidative Stress ; Sciuridae/growth &amp; development/*physiology ; *Telomere Shortening ; },
abstract = {Elevations in glucocorticoid (GC) levels in breeding females may induce adaptive shifts in offspring life histories. Offspring produced by mothers with elevated GCs may be better prepared to face harsh environments, where a faster pace of life is beneficial. We examined how experimentally elevated GCs in pregnant or lactating North American red squirrels (Tamiasciurus hudsonicus) affected offspring postnatal growth, structural size and oxidative stress levels (two antioxidants and oxidative protein damage) in three different tissues (blood, heart and liver) and liver telomere lengths. We predicted that offspring from mothers treated with GCs would grow faster but would also have higher levels of oxidative stress and shorter telomeres, which may predict reduced longevity. Offspring from mothers treated with GCs during pregnancy were 8.3% lighter around birth but grew (in body mass) 17.0% faster than those from controls, whereas offspring from mothers treated with GCs during lactation grew 34.8% slower than those from controls and did not differ in body mass around birth. Treating mothers with GCs during pregnancy or lactation did not alter the oxidative stress levels or telomere lengths of their offspring. Fast-growing offspring from any of the treatment groups did not have higher oxidative stress levels or shorter telomere lengths, indicating that offspring that grew faster early in life did not exhibit oxidative costs after this period of growth. Our results indicate that elevations in maternal GCs may induce plasticity in offspring growth without long-term oxidative costs to the offspring that might result in a shortened lifespan.},
}
@article {pmid31796604,
year = {2019},
author = {Noguera, JC and Velando, A},
title = {Reduced telomere length in embryos exposed to predator cues.},
journal = {The Journal of experimental biology},
volume = {222},
number = {Pt 24},
pages = {},
doi = {10.1242/jeb.216176},
pmid = {31796604},
issn = {1477-9145},
mesh = {Animals ; Charadriiformes/growth &amp; development/*physiology ; *Cues ; Food Chain ; *Predatory Behavior ; *Telomere Shortening ; },
abstract = {It is often assumed that embryos are isolated from external influences, but recent studies indicate that environmental stressors during prenatal stages can exert long-term negative effects on fitness. A potential mechanism by which predation risk may lastingly shape life-history traits and phenotypes is via effects on telomeres. However, whether prenatal exposure to environmental stressors, such as cues of predator presence, affects postnatal telomere length has not hitherto been investigated. Using an experimental design in which we modified the exposure of yellow-legged gull (Larus michahellis) embryos to social cues of predator presence (i.e. alarm calls), we show that prenatally exposed chicks had shorter telomeres after hatching. As young birds with shorter telomere lengths have reduced fledging success, reproductive success and lifespan, the reduced telomere length in the exposed chicks is likely to have long-term fitness consequences. Moreover, our results provide a mechanistic link through which predators may negatively affect population dynamics.},
}
@article {pmid31792215,
year = {2019},
author = {Abdulkina, LR and Kobayashi, C and Lovell, JT and Chastukhina, IB and Aklilu, BB and Agabekian, IA and Suescún, AV and Valeeva, LR and Nyamsuren, C and Aglyamova, GV and Sharipova, MR and Shippen, DE and Juenger, TE and Shakirov, EV},
title = {Components of the ribosome biogenesis pathway underlie establishment of telomere length set point in Arabidopsis.},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {5479},
pmid = {31792215},
issn = {2041-1723},
support = {R01 GM127402/GM/NIGMS NIH HHS/United States ; },
mesh = {Arabidopsis/*genetics/metabolism ; Arabidopsis Proteins/genetics/metabolism ; Chromosome Mapping ; Polymorphism, Genetic ; Quantitative Trait Loci ; Ribosomes/*genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres cap the physical ends of eukaryotic chromosomes to ensure complete DNA replication and genome stability. Heritable natural variation in telomere length exists in yeast, mice, plants and humans at birth; however, major effect loci underlying such polymorphism remain elusive. Here, we employ quantitative trait locus (QTL) mapping and transgenic manipulations to identify genes controlling telomere length set point in a multi-parent Arabidopsis thaliana mapping population. We detect several QTL explaining 63.7% of the total telomere length variation in the Arabidopsis MAGIC population. Loss-of-function mutants of the NOP2A candidate gene located inside the largest effect QTL and of two other ribosomal genes RPL5A and RPL5B establish a shorter telomere length set point than wild type. These findings indicate that evolutionarily conserved components of ribosome biogenesis and cell proliferation pathways promote telomere elongation.},
}
@article {pmid31787382,
year = {2020},
author = {de Souza, MR and Rohr, P and Kahl, VFS and Kvitko, K and Cappetta, M and Lopes, WM and Simon, D and da Silva, J},
title = {The influence of polymorphisms of xenobiotic-metabolizing and DNA repair genes in DNA damage, telomere length and global DNA methylation evaluated in open-cast coal mining workers.},
journal = {Ecotoxicology and environmental safety},
volume = {189},
number = {},
pages = {109975},
doi = {10.1016/j.ecoenv.2019.109975},
pmid = {31787382},
issn = {1090-2414},
mesh = {Adolescent ; Adult ; Aged ; Coal/*toxicity ; *Coal Mining ; Cytochrome P-450 CYP1A1/genetics ; *DNA Damage ; *DNA Methylation ; DNA Repair ; DNA-Binding Proteins/genetics ; Female ; Genotype ; Glutathione S-Transferase pi/genetics ; Glutathione Transferase/genetics ; Humans ; Male ; Middle Aged ; *Occupational Exposure ; *Polymorphism, Genetic ; *Telomere Homeostasis ; X-ray Repair Cross Complementing Protein 1/genetics ; Xenobiotics/metabolism ; Young Adult ; },
abstract = {Coal plants represent one of the main sources of environmental pollution due to the combustion process of this mineral and the consequent release of gases and particles which, in significant quantities, can lead to a potential risk to health and the environment. The susceptibility of individuals to the genotoxic effects of coal mining can be modulated by genetic variations in the xenobiotic detoxification and DNA repair processes. The aim of this study was to evaluate if xenobiotic metabolism polymorphism, base excision repair polymorphisms and non-homologous end joining repair polymorphism, could modify individual susceptibility to genomic instability and epigenetic alterations induced in workers by occupational exposure to coal. In this study, polymerase chain reaction was used to examine the polymorphic sites. The sample population comprising 70 coal mine workers and 71 workers non-exposed to coal. Our results demonstrated the effect of individual genotypes on different biomarkers evaluated. Significant decrease in % of global DNA methylation were observed in CYP1A1 Val/- exposed individuals compared to CYP1A1 Ile/Ile individuals. Coal workers who carried the XRCC4 Ile/Ile genotype showed decrease NBUD frequencies, while the XRCC4 Thr/- genotype was associated with decrease in Buccal micronucleus cells for the group not exposed. No influence of GSTM1 null, GSTT1 null, GSTP1 Ile105Val, hOGG1 Ser326Cys, XRCC1 Arg194Trp polymorphisms was observed. Thus, the current study reinforces the importance of considering the effect of metabolizing and repair variant genotypes on the individual susceptibility to incorporate DNA damage, as these processes act in a coordinated manner to determine the final response to coal exposure.},
}
@article {pmid31787100,
year = {2019},
author = {Navarro-Mateu, F and Rubio-Aparicio, M and Cayuela, P and Álvarez, FJ and Roca-Vega, A and Chirlaque, MD and Cayuela, ML and Husky, M and Martínez, S and Sánchez-Meca, J},
title = {The association of telomere length with substance use disorders: systematic review and meta-analysis protocol.},
journal = {Systematic reviews},
volume = {8},
number = {1},
pages = {298},
pmid = {31787100},
issn = {2046-4053},
mesh = {Humans ; *Meta-Analysis as Topic ; *Research Design ; Substance-Related Disorders/*genetics ; *Systematic Reviews as Topic ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: The present protocol was designed for a systematic review and meta-analysis aimed at determining the association of telomere length with substance use disorders with the exclusion of nicotine addiction, and to identify potential moderators of the effect of telomere length. Such methodological information may provide guidance to improve the quality of future research on this important topic.<br><br>METHODS: Potential studies will be identified through electronic databases (PubMed/MEDLINE, EMBASE, PsycINFO, and Web of Science) up from inception onwards. The inclusion criteria will include published or unpublished observational studies (cohort, case-control, and cross-sectional studies) reporting telomere length in adult patients with substance use disorder compared with a control group. Non-human studies or other study designs such as reviews, case-only, family-based, and/or population studies with only healthy participants will be excluded, as well as those focused solely on nicotine addiction. The main outcome will be telomere length in adults with substance use disorder (primary) and, specifically, in those with alcohol use disorder (secondary). Two investigators will independently evaluate the preselected studies for possible inclusion and will extract data following a standardized protocol. Disagreements will be resolved by consensus. The risk of bias of all included studies will be assessed using the Newcastle-Ottawa Quality Assessment Scale for non-randomized studies. Data will be converted into standardized mean differences as effect size index, and random-effects models will be used for the meta-analysis. Cochran's Q statistic, I[2] index, and visual inspection of the forest plot will be used to verify study heterogeneity. Subgroup analyses and meta-regressions will be conducted to ascertain heterogeneity. Several sensitivity analyses will be conducted to address the influence of potential confounding factors. Publication bias will be examined using the "funnel plot" method with Duval and Tweedie's trim-and-fill method and Egger test.<br><br>DISCUSSION: This systematic review will assess the association of telomere length with substance use disorders aside from nicotine addiction.<br><br>PROSPERO registration number CRD42019119785.},
}
@article {pmid31785500,
year = {2020},
author = {Shahane, AD and LeRoy, AS and Denny, BT and Fagundes, CP},
title = {Connecting cognition, cardiology, and chromosomes: Cognitive reappraisal impacts the relationship between heart rate variability and telomere length in CD8[+]CD28[-] cells.},
journal = {Psychoneuroendocrinology},
volume = {112},
number = {},
pages = {104517},
pmid = {31785500},
issn = {1873-3360},
support = {UL1 TR000005/TR/NCATS NIH HHS/United States ; UL1 RR024153/RR/NCRR NIH HHS/United States ; F32 HL146064/HL/NHLBI NIH HHS/United States ; R01 AI066367/AI/NIAID NIH HHS/United States ; RC1 AT005799/AT/NCCIH NIH HHS/United States ; F31 HL147394/HL/NHLBI NIH HHS/United States ; R01 HL127260/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Autonomic Nervous System/*physiology ; *CD28 Antigens ; *CD8-Positive T-Lymphocytes/metabolism ; Emotional Regulation/*physiology ; Female ; Health Surveys ; Heart Rate/*physiology ; Humans ; Judgment/*physiology ; Male ; Middle Aged ; Telomere/*physiology ; Telomere Shortening/*physiology ; Young Adult ; },
abstract = {Individuals who poorly regulate emotion exhibit premature aging and worse general health. Telomere shortening, a prognostic biomarker of physical health, is related to aging, poor immunocompetence and autonomic nervous system functioning. Cognitive reappraisal is one type of emotion regulation strategy, which involves changing one's appraisal of an aversive situation to modify its emotional impact. Heart rate variability (HRV; i.e., oscillations in heart rate) relates to emotion regulatory processes, such that higher HRV typically reflects greater regulatory capacity. Previous research has identified a positive association between HRV and telomere length. Importantly, the association between HRV and telomere length may change depending on how often an individual uses cognitive reappraisal. One hundred and thirty-seven healthy participants completed measures of cognitive reappraisal frequency, HRV, and underwent blood draws to measure telomere length (computed with the relative ratio of telomere repeat copy number to single copy gene number) in the T cell effector population, CD8[+]CD28[-]. Cognitive reappraisal moderated the relationship between telomere length and HRV such that individuals with high cognitive reappraisal frequency had a significant positive association between HRV and telomere length, while individuals with average and less than average frequency did not exhibit this relationship. The results suggest that frequent usage of cognitive reappraisal enhances the already positive influence of HRV on chromosomal integrity in CD8[+]CD28[-] T lymphocytes. Although future research is needed to test these effects causally, these findings suggest that regularly using emotion regulation techniques may buffer the relationship between autonomic nervous system functioning and chromosomal integrity in immune cells.},
}
@article {pmid31784133,
year = {2020},
author = {Hou, J and Yin, W and Li, P and Hu, C and Xu, T and Cheng, J and Li, T and Wang, L and Yu, Z and Yuan, J},
title = {Joint effect of polycyclic aromatic hydrocarbons and phthalates exposure on telomere length and lung function.},
journal = {Journal of hazardous materials},
volume = {386},
number = {},
pages = {121663},
doi = {10.1016/j.jhazmat.2019.121663},
pmid = {31784133},
issn = {1873-3336},
mesh = {Adolescent ; Adult ; China ; Complex Mixtures/toxicity ; Female ; Humans ; Lung/*drug effects/physiology ; Male ; Middle Aged ; Phthalic Acids/*toxicity ; Polycyclic Aromatic Hydrocarbons/*toxicity ; *Respiratory Function Tests ; Telomere/*drug effects ; Young Adult ; },
abstract = {Exposure to polycyclic aromatic hydrocarbons and phthalates are linked to lung function decline and altered relative telomere length (RTL) accompanying with oxidative stress and inflammatory events in human body. However, limited data are available about impacts of co-exposure of PAHs and phthalates on lung function and RTL. We conducted a pilot study with repeated measures during the winter of 2014 and summer of 2015 in Wuhan city, China. Participants took part in the measures of lung function, RTL, urinary monohydroxylated-PAHs (OH-PAHs) and phthalate metabolites over three consecutive days in each season. Linear mixed-effect (LME) models and Bayesian kernel machine regression (BKMR) were used to analyze the relations of OH-PAHs or phthalate metabolites with lung function or RTL. LME models showed the negative associations of 3-day average of hydroxyphenanthrene (2 + 3-, 4-OHPhe) or 1-hydroxypyrene with FEV1, 3-day average of 2 + 3-OHPhe with FVC. BKMR models revealed the negative relation of eight OH-PAHs with FEV1, FVC or RTL; nine phthalate metabolites may counteract an overall effect of eight OH-PAHs on FEV1, FVC or RTL. The findings indicated that urinary phthalate metabolites may counteract the negative association of urinary OH-PAHs on FEV1 or FVC, which may be partially linked to shorter RTL regarding biological aging.},
}
@article {pmid31783399,
year = {2020},
author = {Kim, JH and Nam, CM and Lee, D and Bang, H and Ko, JH and Lim, I and Kim, GJ and Koes, BW and Lee, DC},
title = {Heritability of telomere length across three generations of Korean families.},
journal = {Pediatric research},
volume = {87},
number = {6},
pages = {1060-1065},
pmid = {31783399},
issn = {1530-0447},
support = {R01 EB015611/EB/NIBIB NIH HHS/United States ; },
mesh = {Asian People/*genetics ; Environment ; *Family/ethnology ; Female ; Heredity ; Humans ; Infant, Newborn ; *Inheritance Patterns ; Male ; Marriage/ethnology ; Pedigree ; Seoul ; Sex Factors ; Telomere/*genetics ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL), an indicator of aging, is influenced by both genetic and environmental factors; however, its heritability is unknown. We determined heritability and inheritance patterns of telomere length across three generations of families.<br><br>METHODS: We analyzed 287 individuals from three generations of 41 Korean families, including newborns, parents, and grandparents. LTL (the ratio of telomere repeat copy number to single gene copy number) was measured by quantitative real-time PCR. We estimated heritability using the SOLAR software maximum-likelihood variance component methods and a pedigree dataset. With adjustment for age and length of marriage, Pearson's partial correlation was performed for spousal pairs.<br><br>RESULTS: Heritability of LTL was high in all participants (h[2]&#x2009;=&#x2009;0.64). There were no significant differences in correlation coefficients of telomere length between paternal and maternal lines. There was a positive LTL correlation in grandfather-grandmother pairs (r&#x2009;=&#x2009;0.25, p&#x2009;=&#x2009;0.03) but not in father-mother pairs. After adjusting for age and length of marriage, the relationship between telomere lengths in grandfathers and grandmothers disappeared. There were inverse correlations between spousal rank differences of telomere length and length of marriage.<br><br>CONCLUSIONS: LTL is highly heritable without a sex-specific inheritance pattern and may be influenced by a shared environment.},
}
@article {pmid31781563,
year = {2019},
author = {Zheng, Q and Huang, J and Wang, G},
title = {Mitochondria, Telomeres and Telomerase Subunits.},
journal = {Frontiers in cell and developmental biology},
volume = {7},
number = {},
pages = {274},
pmid = {31781563},
issn = {2296-634X},
abstract = {Mitochondrial functions and telomere functions have mostly been studied independently. In recent years, it, however, has become clear that there are intimate links between mitochondria, telomeres, and telomerase subunits. Mitochondrial dysfunctions cause telomere attrition, while telomere damage leads to reprogramming of mitochondrial biosynthesis and mitochondrial dysfunctions, which has important implications in aging and diseases. In addition, evidence has accumulated that telomere-independent functions of telomerase also exist and that the protein component of telomerase TERT shuttles between the nucleus and mitochondria under oxidative stress. Our previously published data show that the RNA component of telomerase TERC is also imported into mitochondria, processed, and exported back to the cytosol. These data show a complex regulation network where telomeres, nuclear genome, and mitochondria are co-regulated by multi-localization and multi-function proteins and RNAs. This review summarizes the connections between mitochondria and telomeres, the mitochondrion-related functions of telomerase subunits, and how they play a role in crosstalk between mitochondria and the nucleus.},
}
@article {pmid31781094,
year = {2019},
author = {Zhao, J and Nguyen, LNT and Nguyen, LN and Dang, X and Cao, D and Khanal, S and Schank, M and Thakuri, BKC and Ogbu, SC and Morrison, ZD and Wu, XY and Li, Z and Zou, Y and El Gazzar, M and Ning, S and Wang, L and Moorman, JP and Yao, ZQ},
title = {ATM Deficiency Accelerates DNA Damage, Telomere Erosion, and Premature T Cell Aging in HIV-Infected Individuals on Antiretroviral Therapy.},
journal = {Frontiers in immunology},
volume = {10},
number = {},
pages = {2531},
pmid = {31781094},
issn = {1664-3224},
support = {R01 CA219342/CA/NCI NIH HHS/United States ; R15 AI143377/AI/NIAID NIH HHS/United States ; S10 OD021572/OD/NIH HHS/United States ; },
mesh = {Anti-Retroviral Agents/therapeutic use ; Ataxia Telangiectasia Mutated Proteins/*deficiency/immunology ; Cellular Senescence ; *DNA Damage ; HIV Infections/drug therapy/genetics/*immunology ; Humans ; T-Lymphocytes/*immunology ; Telomere ; },
abstract = {HIV infection leads to a phenomenon of inflammaging, in which chronic inflammation induces an immune aged phenotype, even in individuals on combined antiretroviral therapy (cART) with undetectable viremia. In this study, we investigated T cell homeostasis and telomeric DNA damage and repair machineries in cART-controlled HIV patients at risk for inflammaging. We found a significant depletion of CD4 T cells, which was inversely correlated with the cell apoptosis in virus-suppressed HIV subjects compared to age-matched healthy subjects (HS). In addition, HIV CD4 T cells were prone to DNA damage that extended to chromosome ends-telomeres, leading to accelerated telomere erosion-a hallmark of cell senescence. Mechanistically, the DNA double-strand break (DSB) sensors MRE11, RAD50, and NBS1 (MRN complex) remained intact, but both expression and activity of the DNA damage checkpoint kinase ataxia-telangiectasia mutated (ATM) and its downstream checkpoint kinase 2 (CHK2) were significantly suppressed in HIV CD4 T cells. Consistently, ATM/CHK2 activation, DNA repair, and cellular functions were also impaired in healthy CD4 T cells following ATM knockdown or exposure to the ATM inhibitor KU60019 in vitro, recapitulating the biological effects observed in HIV-derived CD4 T cells in vivo. Importantly, ectopic expression of ATM was essential and sufficient to reduce the DNA damage, apoptosis, and cellular dysfunction in HIV-derived CD4 T cells. These results demonstrate that failure of DSB repair due to ATM deficiency leads to increased DNA damage and renders CD4 T cells prone to senescence and apoptotic death, contributing to CD4 T cell depletion or dysfunction in cART-controlled, latent HIV infection.},
}
@article {pmid31773847,
year = {2020},
author = {Chatelain, M and Drobniak, SM and Szulkin, M},
title = {The association between stressors and telomeres in non-human vertebrates: a meta-analysis.},
journal = {Ecology letters},
volume = {23},
number = {2},
pages = {381-398},
doi = {10.1111/ele.13426},
pmid = {31773847},
issn = {1461-0248},
support = {2015/19/P/NZ8/02992//National Science Centre, Poland/ ; 2014/14/E/NZ8/00386//National Science Centre, Poland/ ; 2015/18/E/NZ8/00505//National Science Centre, Poland/ ; DE180100202//Australian Research Council/ ; },
mesh = {Animals ; Cellular Senescence ; Phylogeny ; *Telomere ; *Telomere Shortening ; Vertebrates ; },
abstract = {Animal response to stressors such as harsh environmental conditions and demanding biological processes requires energy generated through increased mitochondrial activity. This results in the production of reactive oxygen species (ROS). In vitro and some in vivo studies suggest that oxidative damage of DNA caused by ROS is responsible for telomere shortening. Since telomere length is correlated with survival in many vertebrates, telomere loss is hypothesised to trigger cellular ageing and/ or to reflect the harshness of the environment an individual has experienced. To improve our understanding of stress-induced telomere dynamics in non-human vertebrates, we analysed 109 relevant studies in a meta-analytical framework. Overall, the exposure to possible stressors was associated with shorter telomeres or higher telomere shortening rate (average effect size = -0.16 ± 0.03). This relationship was consistent for all phylogenetic classes and for all a priori-selected stressor categories. It was stronger in the case of pathogen infection, competition, reproductive effort and high activity level, which emphasises their importance in explaining intraspecific telomere length variability and, potentially, lifespan variability. Interestingly, the association between stressor exposure and telomeres in one hand, and oxidative stress in the other hand, covaried, suggesting the implication of oxidative stress in telomere dynamics.},
}
@article {pmid31772698,
year = {2019},
author = {Tucker, LA},
title = {Milk Fat Intake and Telomere Length in U.S. Women and Men: The Role of the Milk Fat Fraction.},
journal = {Oxidative medicine and cellular longevity},
volume = {2019},
number = {},
pages = {1574021},
pmid = {31772698},
issn = {1942-0994},
mesh = {Animals ; Energy Intake/*physiology ; Female ; Humans ; Male ; Middle Aged ; Milk/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; United States ; },
abstract = {The associations between milk intake frequency and milk fat consumption and telomere length, an index of biological aging, were studied using an NHANES sample of 5,834 U.S. adults and a cross-sectional design. The milk consumption variables were assessed with the NHANES Diet Behavior and Nutrition questionnaire. The quantitative polymerase chain reaction method was used to measure leukocyte telomere length. Results showed that milk consumption frequency was not related to telomere length; however, there was a strong association between milk fat intake and telomere length. With the sample delimited to milk drinkers only, milk fat intake was linearly and inversely related to telomere length, after adjusting for the covariates (F = 8.6, P = 0.0066). For each 1 percentage point increase in milk fat consumed (e.g., 1% to 2%), adults had more than 4 years of additional biological aging. With milk fat intake divided into 5 categories (i.e., milk abstainers, nonfat, 1%, 2%, and full-fat milk), mean telomere lengths differed across the categories (F = 4.1, P = 0.0093). The mean telomere difference between the extremes of milk fat intake (nonfat vs. full-fat) was 145 base pairs, representing years of additional biological aging for full-fat milk consumers. Effect modification testing indicated that the milk fat and cellular aging association may be partly due to saturated fat intake differences across the milk fat groups. When the sample was delimited to adults reporting only high total saturated fat intake (tertile 3), the milk fat and telomere relationship was strong. However, when the sample was restricted to adults reporting only low saturated fat consumption (tertile 1), there was no relationship between milk fat intake and telomere length. Overall, the findings highlight an association of increased biological aging in U.S. adults who consumed high-fat milk. The results support the latest Dietary Guidelines for Americans (2015-2020), which recommend consumption of low-fat milk, but not high-fat milk, as part of a healthy diet.},
}
@article {pmid31772219,
year = {2019},
author = {Boscolo-Rizzo, P and Rampazzo, E and Polesel, J and Giunco, S and Menegaldo, A and Mantovani, M and Stellin, M and Bandolin, L and Spinato, G and Del Mistro, A and Borsetto, D and Fussey, J and Tirelli, G and Da Mosto, MC and De Rossi, A},
title = {Predictive and prognostic significance of telomerase levels/telomere length in tissues and peripheral blood in head and neck squamous cell carcinoma.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {17572},
pmid = {31772219},
issn = {2045-2322},
mesh = {Adult ; Aged ; Aged, 80 and over ; Carcinoma, Squamous Cell/blood/chemistry/*diagnosis/mortality ; Female ; Head and Neck Neoplasms/blood/chemistry/*diagnosis/mortality ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Prognosis ; Survival Analysis ; Telomerase/*analysis/blood/chemistry/metabolism ; Telomere/*metabolism ; },
abstract = {A growing body of evidence indicates that the expression of TERT, the catalytic subunit of telomerase, is a biological marker of progression in several cancers. We investigated the predictive and prognostic role of TERT levels and telomere length in tissues and peripheral blood in patients with head and neck squamous cell carcinoma (HNSCC). High TERT levels in cancer tissues were independently associated with worse response to therapy (odds ratio [OR]:6.26), regional failure (hazard ratio [HR]:5.75), progression (HR:2.12), and death (HR:3.53). Longer telomeres in the mucosa surrounding the tumor (SM) were independently associated with a lower risk of mucosal failure (HR:0.39). While telomere length in peripheral blood mononuclear cells (PBMC) significantly decreased with age, no correlation was found between age and telomere length in SM. No associations were found between TERT levels in plasma and telomere length in PBMC and the prognostic variables. High levels of TERT transcripts in cancer cells represent a reliable prognostic marker for identifying HNSCC patients with risk of progression. The altered relationship of telomere length to age in SM compared with PBMC suggests that in a subset of cases the phenotypically normal SM constitutes an acquired telomere-shortened epithelial field prone to genetic instability.},
}
@article {pmid31769603,
year = {2020},
author = {Berneau, SC and Shackleton, J and Nevin, C and Altakroni, B and Papadopoulos, G and Horne, G and Brison, DR and Murgatroyd, C and Povey, AC and Carroll, M},
title = {Associations of sperm telomere length with semen parameters, clinical outcomes and lifestyle factors in human normozoospermic samples.},
journal = {Andrology},
volume = {8},
number = {3},
pages = {583-593},
doi = {10.1111/andr.12734},
pmid = {31769603},
issn = {2047-2927},
mesh = {Adult ; *Fertility ; Fertilization in Vitro ; Humans ; *Life Style ; Male ; Semen ; *Spermatozoa ; *Telomere ; },
abstract = {BACKGROUND: Many studies have demonstrated that lifestyle factors can affect sperm quality and fertility. Sperm telomere length (STL) has been reported as potential biomarker or sperm quality. However, no studies have investigated how lifestyle factors can affect STL and associated clinical outcomes.<br><br>OBJECTIVES: The purpose of this manuscript is to investigate any association between STL with lifestyle factors, semen parameters and clinical outcomes.<br><br>MATERIALS AND METHODS: Sperm telomere length was measured using real-time PCR in normozoospermic male partners (n&#xa0;=&#xa0;66) of couples undergoing ART treatment. Each participant also completed a detailed questionnaire about general lifestyle. Linear regression univariate analysis and ANCOVA were performed to respectively determine correlations between STL and study parameters or identify statistically significant differences in STL while controlling for age, BMI and other factors.<br><br>RESULTS: Using a linear regression model, STL is positively correlated with in vitro fertilization success (n&#xa0;=&#xa0;65, r = 0.37, P = .004) but not with embryo cleavage rates and post-implantation clinical outcomes including gestational age-adjusted birth weight. No associations were observed between STL and sperm count, concentration or progressive motility. We further found that STL did not associate age, BMI, health or lifestyle factors.<br><br>DISCUSSION: In somatic cells, the rate of telomere shortening is influenced by a number of lifestyle factors such as smoking, diet and occupation. However, little is known about how lifestyle factors affect STL and subsequently reproductive outcome. Out data suggest that STL might have an important role mechanistically for fertilization rate regardless of sperm parameters and lifestyle factors.<br><br>CONCLUSION: The results of this study demonstrate that STL is associated with in vitro fertilization rates, but not with semen parameters nor lifestyle factors. Further investigations are warranted to identify the potential variation of STL overtime to clarify its significance as a potential biomarker in ART.},
}
@article {pmid31767308,
year = {2020},
author = {Duan, X and Zhang, D and Wang, S and Feng, X and Wang, T and Wang, P and Ding, M and Zhang, H and Liu, B and Wei, W and Acquaye, RM and Yao, W and Cui, L and Zhou, X and Wang, W and Yang, Y},
title = {Effects of polycyclic aromatic hydrocarbon exposure and miRNA variations on peripheral blood leukocyte DNA telomere length: A cross-sectional study in Henan Province, China.},
journal = {The Science of the total environment},
volume = {703},
number = {},
pages = {135600},
doi = {10.1016/j.scitotenv.2019.135600},
pmid = {31767308},
issn = {1879-1026},
mesh = {Adult ; Air Pollutants, Occupational/analysis/*toxicity ; China ; Coke/analysis ; Cross-Sectional Studies ; DNA ; Environmental Exposure/*statistics &amp; numerical data ; Humans ; MicroRNAs ; Polycyclic Aromatic Hydrocarbons/analysis/*toxicity ; Telomere/*drug effects ; },
abstract = {Telomeres play a major role in human aging and disease, especially in most cancers. Telomere length was shortened in workers exposed to polycyclic aromatic hydrocarbons (PAHs) and influenced by individual genetic variations in telomere-binding proteins. MicroRNAs (miRNAs) can affect the progress of messenger RNA (mRNA) transcription; however, whether polymorphisms in miRNA can act on the telomere length is still unknown. Therefore, we aimed to explore the relationships between telomere damage and genetic polymorphisms in miRNA or environmental exposure. A total of 544 coke oven workers and 238 healthy controls were recruited. After collecting peripheral blood and extracting the genomic DNA of the study subjects, the telomere length (TL) in their leucocytes was detected by a real-time quantitative polymerase chain reaction (PCR), and polymorphisms in miRNAs were genotyped using the flight mass spectrometry technique. The concentrations of the four urine OH-PAHs were determined by high performance liquid chromatography (HPLC), and the Soxhlet extraction method was used to detect the concentration of coke oven emissions (COEs) in the air. We found that the peripheral blood leucocyte DNA TL was significantly shorter in the exposure group (0.75; 0.51, 1.08) than that in the control group (1.05; 0.76, 1.44) (Z = 7.692, P < 0.001). The total cumulative exposure dose (CED), 1-hydroxypyrene, 2-hydroxynaphthalene, and 3-hydroxyphenanthrene were significantly negatively correlated with TL (r = -0.307, P < 0.001; r = -0.212, P < 0.001; r = -0.110, P = 0.025; r = -0.251, P < 0.001, respectively). MiR-145 rs353291 GG, miR-30a rs2222722 CT/CC, and miR-197 rs1889470 AA could protect the telomere end in the exposed workers (P < 0.05). The interaction between miR-197 rs1889470 and the CED had an effect on TL (β = 0.066, P = 0.034). This is the first study to evaluate gene-environmental interactions for miRNA polymorphisms and PAH exposure in coke oven workers.},
}
@article {pmid31767135,
year = {2020},
author = {Ojeda-Rodríguez, A and Zazpe, I and Alonso-Pedrero, L and Zalba, G and Guillen-Grima, F and Martinez-Gonzalez, MA and Marti, A},
title = {Association between diet quality indexes and the risk of short telomeres in an elderly population of the SUN project.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {39},
number = {8},
pages = {2487-2494},
doi = {10.1016/j.clnu.2019.11.003},
pmid = {31767135},
issn = {1532-1983},
mesh = {Aged ; Diet Surveys ; Diet, Healthy/*statistics &amp; numerical data ; Eating/*genetics ; Female ; Geriatric Assessment ; Humans ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Risk Assessment ; Risk Factors ; Saliva/*chemistry ; Surveys and Questionnaires ; Telomere/*metabolism ; Telomere Shortening/*genetics ; },
abstract = {BACKGROUND: Shorter telomeres are associated with several age-related diseases, and lifestyle factors could influence this relationship. The aim of this study was to examine associations between salivary telomere length (TL) and diet quality using 5 evidence-based dietary indexes in an elderly (>55 years old) Spanish population of the SUN project (n = 886).<br><br>METHOD: TL was measured using the quantitative real-time polymerase chain reaction. Age-adjusted TL variable through residuals methods was used for all analysis. Diet quality was assessed by the Prime Diet Quality Score (PDQS), Fat Quality Index (FQI), Mediterranean Diet Adherence Screener (MEDAS), Dietary Approaches to Stop Hypertension (DASH) index and the Alternative Healthy Eating Index (AHEI-2010).<br><br>RESULTS: TL did differ according to sex, smoking status, and dyslipidemia in elderly subjects of the SUN study. In addition, subjects with dyslipidemia (compared to absence of dyslipidemia) had a significantly higher risk (27% vs. 18%, p&#xa0;=&#xa0;0.015) of short telomeres (<percentile 20th). Interestingly, a lower risk of having short telomeres was observed among participants in the top tertiles of the following diet quality score PDQS, MEDAS and DASH compared to the bottom tertiles in crude and adjusted models. Moreover, FQI and AHEI-2010 scores showed an inverse association with the risk of having short telomeres after adjustment for potential confounders (model adjusted for dyslipidemia interaction, p for trend&#xa0;=&#xa0;0.025 and 0.021, respectively; and model additionally adjusted for sex and smoking status, p for trend&#xa0;=&#xa0;0.033 and 0.029, respectively).<br><br>CONCLUSION: Adherence to high quality diet is associated to longer salivary TL in our elderly Spanish population of the SUN study.},
}
@article {pmid31763768,
year = {2019},
author = {Ravindranathan, A and Diolaiti, ME and Cimini, BA and Stohr, BA},
title = {In Situ Visualization of Telomere Length, Telomere Elongation, and TERT Expression in Single Cells.},
journal = {Current protocols in cell biology},
volume = {85},
number = {1},
pages = {e97},
doi = {10.1002/cpcb.97},
pmid = {31763768},
issn = {1934-2616},
mesh = {Gene Expression ; Genetic Vectors/genetics ; Humans ; Lentivirus/genetics ; RNA/analysis ; Single-Cell Analysis ; Telomerase/genetics/*metabolism ; Telomere/*physiology ; Telomere Homeostasis ; },
abstract = {Telomerase plays a critical role in cancer and aging by adding hexa-nucleotide repeats to the ends of telomeres and extending the cellular proliferative lifespan. The very low level of telomerase expression in most cell populations and the difficulty of detecting telomere elongation in single cells have limited the study of telomerase expression and function in individual cells of a heterogeneous population. The method described in this article combines single-molecule detection (RNAscope) of telomerase reverse transcriptase (TERT) with our previously described TSQ1 assay for in situ monitoring of telomere extension, thereby enabling detection of TERT expression, telomere length, and telomere elongation in single cells and providing a unique approach for studying the factors that regulate telomere elongation by telomerase. © 2019 by John Wiley &amp; Sons, Inc. Basic Protocol 1: TSQ1 lentivirus production Basic Protocol 2: TSQ1 lentiviral infection and plating Basic Protocol 3: RNAscope analysis Basic Protocol 4: TSQ1 PNA-FISH detection.},
}
@article {pmid31762827,
year = {2019},
author = {Gu, CY and Jin, SM and Qin, XJ and Zhu, Y and Bo, D and Lin, GW and Shi, GH and Ye, DW},
title = {Genetic variants in RTEL1 influencing telomere length are associated with prostate cancer risk.},
journal = {Journal of Cancer},
volume = {10},
number = {24},
pages = {6170-6174},
pmid = {31762827},
issn = {1837-9664},
abstract = {Telomere length measured in lymphocytes has been evaluated as a potential biomarker for prostate cancer (PCa) risk. Identifying genetic variants that affect telomere length and testing their association with disease could clarify any causal role. We therefore investigated associations between genetic variants in three telomere length-related genes and PCa risk in a case-control study. The influence of these variants on the leukocyte telomere lengths was then appraised by real-time PCR. RTEL1 rs2297441 [odds ratio (OR): 1.23; 95% confidence interval (CI): 1.03-1.46, P = 0.021] and rs3208008 (OR: 1.23; 95% CI: 1.03-1.46) were associated with PCa risk. These two risk single nucleotide polymorphisms (SNPs) (OR: 0.59; 95% CI: 0.39-0.89, P = 0.012 and OR: 0.58; 95% CI: 0.38-0.87, P = 0.009, respectively) and another SNP PARP1 rs1136410 (OR: 1.53; 95% CI: 1.01-2.31, P = 0.043) were also associated with leukocyte telomere length. These findings support that genetic determinants of telomere length may influence PCa risk.},
}
@article {pmid31762528,
year = {2019},
author = {McLennan, D and Recknagel, H and Elmer, KR and Monaghan, P},
title = {Distinct telomere differences within a reproductively bimodal common lizard population.},
journal = {Functional ecology},
volume = {33},
number = {10},
pages = {1917-1927},
pmid = {31762528},
issn = {0269-8463},
abstract = {Different strategies of reproductive mode, either oviparity (egg-laying) or viviparity (live-bearing), will be associated with a range of other life-history differences that are expected to affect patterns of ageing and longevity. It is usually difficult to compare the effects of alternative reproductive modes because of evolutionary and ecological divergence. However, the very rare exemplars of reproductive bimodality, in which different modes exist within a single species, offer an opportunity for robust and controlled comparisons.One trait of interest that could be associated with life history, ageing and longevity is the length of the telomeres, which form protective caps at the chromosome ends and are generally considered a good indicator of cellular health. The shortening of these telomeres has been linked to stressful conditions; therefore, it is possible that differing reproductive costs will influence patterns of telomere loss. This is important because a number of studies have linked a shorter telomere length to reduced survival.Here, we have studied maternal and offspring telomere dynamics in the common lizard (Zootoca vivipara). Our study has focused on a population where oviparous and viviparous individuals co-occur in the same habitat and occasionally interbreed to form admixed individuals.While viviparity confers many advantages for offspring, it might also incur substantial costs for the mother, for example require more energy. Therefore, we predicted that viviparous mothers would have relatively shorter telomeres than oviparous mothers, with admixed mothers having intermediate telomere lengths. There is thought to be a heritable component to telomere length; therefore, we also hypothesized that offspring would follow the same pattern as the mothers.Contrary to our predictions, the viviparous mothers and offspring had the longest telomeres, and the oviparous mothers and offspring had the shortest telomeres. The differing telomere lengths may have evolved as an effect of the life-history divergence between the reproductive modes, for example due to the increased growth rate that viviparous individuals may undergo to reach a similar size at reproduction. A free http://onlinelibrary.wiley.com/doi/10.1111/1365-2435.13408/suppinfo can be found within the Supporting Information of this article.},
}
@article {pmid31761987,
year = {2019},
author = {Khavinson, VK and Pendina, AA and Efimova, OA and Tikhonov, AV and Koltsova, AS and Krapivin, MI and Petrovskaia-Kaminskaia, AV and Petrova, LI and Lin'kova, NS and Baranov, VS},
title = {Effect of Peptide AEDG on Telomere Length and Mitotic Index of PHA-Stimulated Human Blood Lymphocytes.},
journal = {Bulletin of experimental biology and medicine},
volume = {168},
number = {1},
pages = {141-144},
doi = {10.1007/s10517-019-04664-0},
pmid = {31761987},
issn = {1573-8221},
mesh = {Adolescent ; Adult ; Humans ; In Situ Hybridization, Fluorescence ; Lymphocyte Activation/drug effects ; Lymphocytes/*drug effects/*metabolism ; Middle Aged ; Mitotic Index ; Phytohemagglutinins/*pharmacology ; Telomere/*drug effects/*metabolism ; Young Adult ; },
abstract = {We studied the effect of peptide AEDG on telomere length and mitotic index of PHA-stimulated blood lymphocytes from young (18-22 years, N=5) and middle-aged (49-54 years, N=6) men. In the younger age group, no significant changes in the mitotic index were detected, while in the middle-aged group, a decrease in this parameter was found in one case. The relative length of telomeric regions of metaphase chromosomes was evaluated by in situ fluorescence hybridization with DNA probes specific to telomeres. After incubation with peptide AEDG, significant changes in the relative telomere length were found in 7 of 11 individuals (3 cases in the younger age group and 4 cases in the middle age group). Significant increase in telomere length after exposure to peptide AEDG was revealed in 5 cases, including two individuals of the younger age group (by 41 and 55%) and three individuals of the middle age group (by 156, 18, and 76%). In one individual of the younger age group and in one of the middle-age group, a significant decrease in telomere length (by 37 and 15%, respectively) was found. A tendency to normalization of telomere lengths was noted: this parameter increased in individuals with initially lower telomere length relative to the group mean value and decreased in individuals with initially longer telomeres compared to the mean length in the group.},
}
@article {pmid31759995,
year = {2020},
author = {PerezGrovas-Saltijeral, A and Ochoa-Morales, A and Miranda-Duarte, A and Martínez-Ruano, L and Jara-Prado, A and Camacho-Molina, A and Hidalgo-Bravo, A},
title = {Telomere length analysis on leukocytes derived from patients with Huntington Disease.},
journal = {Mechanisms of ageing and development},
volume = {185},
number = {},
pages = {111189},
doi = {10.1016/j.mad.2019.111189},
pmid = {31759995},
issn = {1872-6216},
mesh = {Asymptomatic Diseases ; *Biomarkers ; Cellular Senescence ; Correlation of Data ; DNA Damage ; Female ; Humans ; Huntingtin Protein/*genetics ; *Huntington Disease/diagnosis/genetics/metabolism ; Male ; Middle Aged ; Oxidative Stress ; Symptom Assessment/methods ; *Telomere Shortening ; Trinucleotide Repeat Expansion ; },
abstract = {INTRODUCTION: Huntington´s disease (HD) is a neurodegenerative disorder characterized by neuropsychiatric, motor and cognitive manifestations. It is caused by expansion of the trinucleotide CAG on HTT. The molecular bases are not completely understood, DNA damage, such as double and single strand breaks and oxidative stress (OS) have been implicated. At telomeres, DNA breaks are less efficiently repaired. Double strand breaks evoke the break induced replication (BIR) mechanism. BIR, plus inefficient repair can produce telomere shortening and cellular senescence. Our aim was to investigate the correlation between leukocyte relative telomeric length (RTL) and HD.<br><br>METHODS: 206 samples were analyzed, 71 patients with molecular diagnosis and symptomatology (HD), 29 individuals with positive molecular test but asymptomatic (PP) and 106 healthy individuals (NP).<br><br>RESULTS: We found a significant difference in RTL between HD patients compared with both, PP and NP, independently of subjects' age.<br><br>DISCUSSION: Here we present evidence supporting an association between telomere shortening and HD. Telomere shortening could be related to DNA damage caused by ROS and defective DNA repair mechanism. Both events have been probed to occur in the presence of a mutant Huntingtin. This study contributes with current evidence suggesting a potential role of telomere shortening as HD biomarker.},
}
@article {pmid31759730,
year = {2020},
author = {Hu, MH and Lin, XT and Liu, B and Tan, JH},
title = {Dimeric aryl-substituted imidazoles may inhibit ALT cancer by targeting the multimeric G-quadruplex in telomere.},
journal = {European journal of medicinal chemistry},
volume = {186},
number = {},
pages = {111891},
doi = {10.1016/j.ejmech.2019.111891},
pmid = {31759730},
issn = {1768-3254},
mesh = {Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology ; Apoptosis/drug effects ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; G-Quadruplexes/*drug effects ; Humans ; Imidazoles/chemical synthesis/chemistry/*pharmacology ; Molecular Structure ; Structure-Activity Relationship ; Telomere/*drug effects ; },
abstract = {In 10-15% of cancers, telomere maintenance is provided by a telomerase-independent mechanism known as alternative lengthening of telomere (ALT), making telomerase inhibitors ineffective on these cancers. Ligands that stabilize telomeric G-quadruplex (G4) are considered to be able to inhibit either the ALT process or disrupt the T-loop structure, which would be promising therapeutic agents for ALT cancers. Notably, the 3'-terminal overhang of telomeric DNA might fold into multimeric G4 containing consecutive G4 subunits, which offers an attractive target for selective ligands considering large numbers of G4s widespread in the genome. In this study, a dimeric aryl-substituted imidazole (DIZ-3) was developed as a selective multimeric G4 ligand based on a G4-ligand-dimerizing strategy. Biophysical experiments revealed that DIZ-3 intercalated into the G4-G4 interface, stabilizing the higher-order structure. Furthermore, this ligand was demonstrated to induce cell cycle arrest and apoptosis, and thus inhibited cell proliferation in an ALT cancer cell line. Cancer cells were more sensitive to DIZ-3, relative to normal cells. Notably, DIZ-3 had little effect on the transcription of several G4-dependent oncogenes. This study provides a nice example for discovering dimeric agents to potentially treat ALT cancers via targeting telomeric multimeric G4.},
}
@article {pmid31757935,
year = {2019},
author = {Lv, X and Wang, X and Wang, Y and Zhou, D and Li, W and Wilson, JX and Chang, H and Huang, G},
title = {Folic acid delays age-related cognitive decline in senescence-accelerated mouse prone 8: alleviating telomere attrition as a potential mechanism.},
journal = {Aging},
volume = {11},
number = {22},
pages = {10356-10373},
pmid = {31757935},
issn = {1945-4589},
mesh = {Aging/*drug effects ; Animals ; Brain/drug effects/pathology ; *Cognitive Dysfunction ; *Dietary Supplements ; Folic Acid/*pharmacology ; Male ; Mice ; Nerve Degeneration/pathology ; Telomere Shortening/*drug effects ; },
abstract = {The occurrence of telomere attrition in brain may cause senescence and death of neurons, leading to cognitive decline. Folic acid (FA) has been reported to improve cognitive performance in mild cognitive impairment; however, its association with telomere remains unclear. The study aimed to investigate if alleviation of telomere attrition by FA supplementation could act as a potential mechanism to delay age-related cognitive decline in senescence-accelerated mouse prone 8 (SAMP8). Aged SAMP8 mice were assigned to four treatment groups: FAdeficient diet (FA-D) group, FA-normal diet (FA-N) group, low FA-supplemented diet (FA-L) group and high FAsupplemented diet (FA-H) group. There was also an age-matched senescence-accelerated mouse resistant 1 (SAMR1) control group (Con-R), and a young SAMP8 control group (Con-Y). The results demonstrated that FA supplementation delayed age-related cognitive decline and neurodegeneration in SAMP8 mice. Importantly, this effect could be attributed to the alleviated telomere attrition, which might be interpreted by the decreased levels of reactive oxygen species. Additionally, improved telomere integrity stimulated mitochondrial function via telomere-p53-mithondria pathway, consequently delayed neuronal degeneration. In conclusion, we demonstrate that FA supplementation delays age-related neurodegeneration and cognitive decline in SAMP8 mice, in which alleviated telomere attrition could serve as one influential factor in the process.},
}
@article {pmid31757062,
year = {2019},
author = {Ackermann, S and Fischer, M},
title = {Telomere Maintenance in Pediatric Cancer.},
journal = {International journal of molecular sciences},
volume = {20},
number = {23},
pages = {},
pmid = {31757062},
issn = {1422-0067},
mesh = {Adolescent ; Brain Neoplasms/*genetics ; Child ; Genomic Instability ; Humans ; Infant ; Neuroblastoma/*genetics ; *Telomere Homeostasis ; },
abstract = {Telomere length has been proposed as a biomarker of biological age and a risk factor for age-related diseases and cancer. Substantial progress has been made in recent decades in understanding the complex molecular relationships in this research field. However, the majority of telomere studies have been conducted in adults. The data on telomere dynamics in pediatric cancers is limited, and interpretation can be challenging, especially in cases where results are contrasting to those in adult entities. This review describes recent advances in the molecular characterization of structure and function of telomeres, regulation of telomerase activity in cancer pathogenesis in general, and highlights the key advances that have expanded our views on telomere biology in pediatric cancer, with special emphasis on the central role of telomere maintenance in neuroblastoma. Furthermore, open questions in the field of telomere maintenance research are discussed in the context of recently published literature.},
}
@article {pmid31754622,
year = {2019},
author = {Giri, N and Ravichandran, S and Wang, Y and Gadalla, SM and Alter, BP and Fontana, J and Savage, SA},
title = {Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder.},
journal = {ERJ open research},
volume = {5},
number = {4},
pages = {},
pmid = {31754622},
issn = {2312-0541},
abstract = {Pulmonary fibrosis and pulmonary arteriovenous malformations are known manifestations of dyskeratosis congenita (DC), a telomere biology disorder (TBD) and inherited bone marrow failure syndrome caused by germline mutations in telomere maintenance genes resulting in very short telomeres. Baseline pulmonary function tests (PFTs) and long-term clinical outcomes have not been thoroughly studied in DC/TBDs. In this retrospective study, 43 patients with DC and 67 unaffected relatives underwent baseline PFTs and were followed for a median of 8 years (range 1-14). Logistic regression and competing risk models were used to compare PFT results in relation to clinical and genetic characteristics, and patient outcomes. Restrictive abnormalities on spirometry and moderate-to-severe reduction in diffusing capacity of the lung for carbon monoxide were significantly more frequent in patients with DC than relatives (42% versus 12%; p=0.008). The cumulative incidence of pulmonary disease by age 20 years was 55% in patients with DC with baseline PFT abnormalities compared with 17% in those with normal PFTs (p=0.02). None of the relatives developed pulmonary disease. X-linked recessive, autosomal recessive inheritance or heterozygous TINF2 variants were associated with early-onset pulmonary disease that mainly developed after haematopoietic cell transplantation (HCT). Overall, seven of 14 patients developed pulmonary disease post-HCT at a median of 4.7 years (range 0.7-12). The cumulative incidence of pulmonary fibrosis in patients with heterozygous non-TINF2 pathogenic variants was 70% by age 60 years. Baseline PFT abnormalities are common in patients with DC and associated with progression to significant pulmonary disease. Prospective studies are warranted to facilitate clinical trial development for patients with DC and related TBDs.},
}
@article {pmid31754456,
year = {2019},
author = {Yu, Y and Jia, W and Lyu, Y and Su, D and Bai, M and Shen, J and Qiao, J and Han, T and Liu, W and Chen, J and Chen, W and Ye, D and Guo, X and Zhu, S and Xi, J and Zhu, R and Wan, X and Gao, S and Zhu, J and Kang, J},
title = {Pwp1 regulates telomere length by stabilizing shelterin complex and maintaining histone H4K20 trimethylation.},
journal = {Cell discovery},
volume = {5},
number = {},
pages = {47},
pmid = {31754456},
issn = {2056-5968},
support = {R01 GM071725/GM/NIGMS NIH HHS/United States ; },
abstract = {Telomere maintenance is critical for chromosome stability. Here we report that periodic tryptophan protein 1 (PWP1) is involved in regulating telomere length homeostasis. Pwp1 appears to be essential for mouse development and embryonic stem cell (ESC) survival, as homozygous Pwp1-knockout mice and ESCs have never been obtained. Heterozygous Pwp1-knockout mice had shorter telomeres and decreased reproductive capacity. Pwp1 depletion induced rapid telomere shortening accompanied by reduced shelterin complex and increased DNA damage in telomeric regions. Mechanistically, PWP1 bound and stabilized the shelterin complex via its WD40 domains and regulated the overall level of H4K20me3. The rescue of telomere length in Pwp1-deficient cells by PWP1 overexpression depended on SUV4-20H2 co-expression and increased H4K20me3. Therefore, our study revealed a novel protein involved in telomere homeostasis in both mouse and human cells. This knowledge will improve our understanding of how chromatin structure and histone modifications are involved in maintaining telomere integrity.},
}
@article {pmid31750255,
year = {2019},
author = {Nersisyan, L and Hopp, L and Loeffler-Wirth, H and Galle, J and Loeffler, M and Arakelyan, A and Binder, H},
title = {Telomere Length Maintenance and Its Transcriptional Regulation in Lynch Syndrome and Sporadic Colorectal Carcinoma.},
journal = {Frontiers in oncology},
volume = {9},
number = {},
pages = {1172},
pmid = {31750255},
issn = {2234-943X},
abstract = {Background: Activation of telomere maintenance mechanisms (TMMs) is a hallmark of most cancers, and is required to prevent genome instability and to establish cellular immortality through reconstitution of capping of chromosome ends. TMM depends on the cancer type. Comparative studies linking tumor biology and TMM have potential impact for evaluating cancer onset and development. Methods: We have studied alterations of telomere length, their sequence composition and transcriptional regulation in mismatch repair deficient colorectal cancers arising in Lynch syndrome (LS-CRC) and microsatellite instable (MSI) sporadic CRC (MSI s-CRC), and for comparison, in microsatellite stable (MSS) s-CRC and in benign colon mucosa. Our study applied bioinformatics analysis of whole genome DNA and RNA sequencing data and a pathway model to study telomere length alterations and the potential effect of the "classical" telomerase (TEL-) and alternative (ALT-) TMM using transcriptomic signatures. Results: We have found progressive decrease of mean telomere length in all cancer subtypes compared with reference systems. Our results support the view that telomere attrition is an early event in tumorigenesis. TMM gets activated in all tumors studied due to concerted overexpression of a large fraction of genes with direct relation to telomere function, where only a very small fraction of them showed recurrent mutations. TEL-related transcriptional state was dominating in all CRC subtypes, showing, however, subtype-specific activation patterns; while contribution of the ALT-TMM was slightly more prominent in the hypermutated MSI s-CRC and LS-CRC. TEL-TMM is mainly activated by over-expression of DKC1 and/or TERT genes and their interaction partners, where DKC1 is more prominent in MSS than in MSI s-CRC and can serve as a transcriptomic marker of TMM activity. Conclusions: Our results suggest that transcriptional patterns are indicative for TMM pathway activation with subtle differences between TEL and ALT mechanisms in a CRC subtype-specific fashion. Sequencing data potentially provide a suited measure to study alterations of telomere length and of underlying transcriptional regulation. Further studies are needed to improve this method.},
}
@article {pmid31749836,
year = {2019},
author = {Ilska-Warner, JJ and Psifidi, A and Seeker, LA and Wilbourn, RV and Underwood, SL and Fairlie, J and Whitelaw, B and Nussey, DH and Coffey, MP and Banos, G},
title = {The Genetic Architecture of Bovine Telomere Length in Early Life and Association With Animal Fitness.},
journal = {Frontiers in genetics},
volume = {10},
number = {},
pages = {1048},
pmid = {31749836},
issn = {1664-8021},
abstract = {Health and survival are key goals for selective breeding in farm animals. Progress, however, is often limited by the low heritability of these animal fitness traits in addition to measurement difficulties. In this respect, relevant early-life biomarkers may be useful for breeding purposes. Telomere length (TL), measured in leukocytes, is a good candidate biomarker since TL has been associated with health, ageing, and stress in humans and other species. However, telomere studies are very limited in farm animals. Here, we examined the genetic background, genomic architecture, and factors affecting bovine TL measurements in early life, and the association of the latter with animal fitness traits expressed later in life associated with survival, longevity, health, and reproduction. We studied two TL measurements, one at birth (TLB) and another during the first lactation (TLFL) of a cow. We performed a genome-wide association study of dairy cattle TL, the first in a non-human species, and found that TLB and TLFL are complex, polygenic, moderately heritable, and highly correlated traits. However, genomic associations with distinct chromosomal regions were identified for the two traits suggesting that their genomic architecture is not identical. This is reflected in changes in TL throughout an individual's life. TLB had a significant association with survival, length of productive life and future health status of the animal, and could be potentially used as an early-life biomarker for disease predisposition and longevity in dairy cattle.},
}
@article {pmid31745564,
year = {2020},
author = {Nonaka, K and Aida, J and Takubo, K and Yamazaki, Y and Gao, X and Komatsu, A and Takakuma, S and Kakizaki, M and Inoshita, N and Gomi, F and Ishiwata, T and Chong, JM and Arai, T and Sasano, H},
title = {Correlation Between Telomere Attrition of Zona Fasciculata and Adrenal Weight Reduction in Older Men.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {105},
number = {3},
pages = {},
doi = {10.1210/clinem/dgz214},
pmid = {31745564},
issn = {1945-7197},
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Autopsy ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Infant, Newborn ; Longevity/*genetics ; Male ; Middle Aged ; *Sex Factors ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; Young Adult ; Zona Fasciculata/*cytology ; },
abstract = {CONTEXT: Although numerous theories are reported on sex differences in longevity, the underlying biological mechanisms remain unknown. We previously reported that telomere length in the zona reticularis cells of the human adrenal cortex was significantly longer in older than that in younger subjects. However, we could not evaluate sex differences in the telomere lengths.<br><br>OBJECTIVE: To compare the telomere lengths of adrenocortical and adrenal medullar cells between men and women from infancy through older adulthood.<br><br>METHODS: Adrenal glands of 30 male (aged 0 to 100 years) and 25 female (aged 0 to 104 years) autopsied subjects were retrieved from autopsy files. Using quantitative fluorescence in situ hybridization, relative telomere lengths were determined in the parenchymal cells of the 3 adrenocortical zones and medulla. Age-related changes in the weight of adrenal glands were also investigated.<br><br>MAIN RESULTS: Older male subjects (aged 65 years or older) had significantly shorter telomere lengths in zona fasciculata (ZF) cells compared to the corresponding female subjects. In men, older subjects exhibited a significant age-related reduction in adrenal weight; however, no age-related changes in adrenal weight were detected in women.<br><br>CONCLUSION: Telomere attrition of ZF cells was correlated with adrenal weight reduction in older men but not in older women, suggesting a decreased number of ZF cells in older men. This may help us understand the possible biological mechanisms of sex difference in longevity of humans.},
}
@article {pmid31745078,
year = {2019},
author = {Lu, R and O'Rourke, JJ and Sobinoff, AP and Allen, JAM and Nelson, CB and Tomlinson, CG and Lee, M and Reddel, RR and Deans, AJ and Pickett, HA},
title = {Author Correction: The FANCM-BLM-TOP3A-RMI complex suppresses alternative lengthening of telomeres (ALT).},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {5345},
doi = {10.1038/s41467-019-13097-2},
pmid = {31745078},
issn = {2041-1723},
abstract = {An amendment to this paper has been published and can be accessed via a link at the top of the paper.},
}
@article {pmid31740672,
year = {2019},
author = {Aguado, J and Sola-Carvajal, A and Cancila, V and Revêchon, G and Ong, PF and Jones-Weinert, CW and Wallén Arzt, E and Lattanzi, G and Dreesen, O and Tripodo, C and Rossiello, F and Eriksson, M and d'Adda di Fagagna, F},
title = {Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson-Gilford Progeria Syndrome.},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {4990},
pmid = {31740672},
issn = {2041-1723},
mesh = {Animals ; Cell Line ; Cell Proliferation ; Cellular Senescence ; *DNA Damage ; DNA Repair ; Disease Models, Animal ; Homeostasis ; Lamin Type A/genetics/metabolism ; Mice ; Mutation/genetics ; Oligonucleotides, Antisense/metabolism ; Phenotype ; Progeria/*pathology ; RNA, Untranslated/genetics/metabolism ; Skin/pathology ; Telomere/*metabolism ; },
abstract = {Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder characterized by premature aging features. Cells from HGPS patients express progerin, a truncated form of Lamin A, which perturbs cellular homeostasis leading to nuclear shape alterations, genome instability, heterochromatin loss, telomere dysfunction and premature entry into cellular senescence. Recently, we reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which control the DNA damage response (DDR) at dysfunctional telomeres. Here we show that progerin-induced telomere dysfunction induces the transcription of tncRNAs. Their functional inhibition by sequence-specific telomeric antisense oligonucleotides (tASOs) prevents full DDR activation and premature cellular senescence in various HGPS cell systems, including HGPS patient fibroblasts. We also show in vivo that tASO treatment significantly enhances skin homeostasis and lifespan in a transgenic HGPS mouse model. In summary, our results demonstrate an important role for telomeric DDR activation in HGPS progeroid detrimental phenotypes in vitro and in vivo.},
}
@article {pmid31739109,
year = {2020},
author = {Ling, P and Qian, C and Yu, J and Gao, F},
title = {Artificial nanozyme based on platinum nanoparticles anchored metal-organic frameworks with enhanced electrocatalytic activity for detection of telomeres activity.},
journal = {Biosensors &amp; bioelectronics},
volume = {149},
number = {},
pages = {111838},
doi = {10.1016/j.bios.2019.111838},
pmid = {31739109},
issn = {1873-4235},
mesh = {*Biosensing Techniques ; *Electrochemical Techniques ; HeLa Cells ; Humans ; Hydrogen Peroxide/chemistry ; Limit of Detection ; Metal Nanoparticles/*chemistry ; Metal-Organic Frameworks/chemistry ; Platinum/chemistry ; Telomerase/chemistry ; Telomere/chemistry/*genetics ; },
abstract = {This study reports a new artificial nanozyme based on ultra-small Pt nanoparticles (Pt NPs) grown on nanoscale metalloporphyrin metal organic frameworks (P-MOF(Fe)) (termed as Pt@P-MOF(Fe)) as biomimetic catalysts and redox mediator to detect the telomerase activity. In this system, the P-MOF(Fe) were used as nanocarrier and signal media. The DNA functionalized Pt@P-MOF(Fe) was as signal probe and exhibited enhanced electrochemical signal in the presence of H2O2, owing to the synergistic effect between P-MOF(Fe) and Pt NPs. Upon the addition cell extract, the telomerase primer could extend and then hybridize with assistant DNA2 in the triple-helix, leading to the structure of triple-helix changes and release the hairpin DNA to hybridize with the capture DNA on the surface of Pt@P-MOF(Fe), resulting in the electrochemical signal readout of H2O2 reduction. With the aid of recycling amplification of Exonuclease III, the telomeres sensor exhibited the detection down to 20 Hela cell mL[-1]. This work supplies a new avenue to design artificial enzyme catalysts and serves as an ideal platform to use metalloporphyrin metal organic frameworks as signal media for detection of analytes.},
}
@article {pmid31734351,
year = {2020},
author = {Beijers, R and Daehn, D and Shalev, I and Belsky, J and de Weerth, C},
title = {Biological embedding of maternal postpartum depressive symptoms: The potential role of cortisol and telomere length.},
journal = {Biological psychology},
volume = {150},
number = {},
pages = {107809},
doi = {10.1016/j.biopsycho.2019.107809},
pmid = {31734351},
issn = {1873-6246},
mesh = {Adult ; Child ; Child Behavior Disorders/*metabolism/psychology ; Defense Mechanisms ; Depression, Postpartum/*psychology ; Female ; Humans ; Hydrocortisone/*analysis ; Latent Class Analysis ; Male ; Mothers/*psychology ; Postpartum Period/psychology ; Problem Behavior/psychology ; Saliva/chemistry ; Telomere/*pathology ; },
abstract = {Although maternal postpartum depressive symptoms (PDS) are associated with child behavior problems, the underlying biological mechanisms are poorly understood. Thus, the current study focused on 193 healthy mother-child dyads and investigated child cortisol and telomere length as potential mediating factors. At 3 and 6 months postpartum, mothers reported on PDS. At age 6, children provided saliva and buccal swab samples. At age 10, mothers and children reported on child behavior problems. Structural equation modelling revealed (a) no association between PDS and child behavior problems and thus no possibility of mediation, but that (b) lower cortisol forecast more child-reported internalizing problems, and (c) shorter telomere length predicted more child-reported internalizing and externalizing problems. These findings raise mediational questions about the determinants of these biomarkers.},
}
@article {pmid31732749,
year = {2020},
author = {Nguyen, MT and Lycett, K and Olds, T and Matricciani, L and Vryer, R and Ranganathan, S and Burgner, D and Saffery, R and Wake, M},
title = {Objectively measured sleep and telomere length in a population-based cohort of children and midlife adults.},
journal = {Sleep},
volume = {43},
number = {1},
pages = {},
doi = {10.1093/sleep/zsz200},
pmid = {31732749},
issn = {1550-9109},
mesh = {Actigraphy ; Adult ; Aged ; Aging/physiology ; Australia ; Biomarkers ; Cellular Senescence/*physiology ; Child ; Cohort Studies ; Female ; Humans ; Male ; Middle Aged ; Self Report ; Sleep Latency/*physiology ; Sleep Wake Disorders/*physiopathology ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; Young Adult ; },
abstract = {STUDY OBJECTIVES: Poor sleep patterns in older adults are associated with chromosomal telomere shortening, a marker of cellular senescence. However, studies have relied on self-reported sleep characteristics, with few data for younger individuals. We investigated whether sleep measured via actigraphy was cross-sectionally associated with telomere length in children and midlife adults.<br><br>METHODS: A population-based sample of 1874 11-12 year olds and midlife adults (mean age 44 years, SD 5.1) had biological and physical assessments at centers across Australia in 2015-2016. Sleep characteristics, including duration, onset, offset, day-to-day variability, and efficiency, were derived from actigraphy. Relative telomere length (T/S ratio) was measured by quantitative polymerase chain reaction on genomic DNA from peripheral blood. Multivariable regression models estimated associations, adjusting for prespecified confounders.<br><br>RESULTS: Both sleep and telomere data were available for 728 children and 1070 adults. Mean (SD) T/S ratio was 1.09 (0.55) in children and 0.81 (0.38) in adults. T/S ratio was not predicted by sleep duration (&#x3b2; 0.04, 95% confidence interval [CI] -0.02 to 0.09, p = .16, children; &#x3b2; -0.004, 95% CI -0.03 to 0.02, p = .70, adults) or most other sleep metrics. The only exception was a weak association between later sleep timing (the midpoint of sleep onset and offset) and longer telomeres in adults (&#x3b2; 0.03, 95% CI 0.01 to 0.06, p = .01).<br><br>CONCLUSIONS: Objective sleep characteristics show no convincing associations with telomere length in two largely healthy populations up to at least midlife. Sleep-telomere associations may be a late-life occurrence or may present only with a trigger such as presence of other morbidities.},
}
@article {pmid31728621,
year = {2020},
author = {Wattis, JAD and Qi, Q and Byrne, HM},
title = {Mathematical modelling of telomere length dynamics.},
journal = {Journal of mathematical biology},
volume = {80},
number = {4},
pages = {1039-1076},
pmid = {31728621},
issn = {1432-1416},
mesh = {Aging/genetics ; Cell Division/genetics ; Cellular Senescence/genetics ; Chromosomes, Human/genetics ; Computer Simulation ; DNA Replication/genetics ; Humans ; Mathematical Concepts ; *Models, Genetic ; Models, Statistical ; Normal Distribution ; Stochastic Processes ; Telomere/genetics ; Telomere Homeostasis/*genetics ; Telomere Shortening/genetics ; },
abstract = {Telomeres are repetitive DNA sequences located at the ends of chromosomes. During cell division, an incomplete copy of each chromosome's DNA is made, causing telomeres to shorten on successive generations. When a threshold length is reached replication ceases and the cell becomes 'senescent'. In this paper, we consider populations of telomeres and, from discrete models, we derive partial differential equations which describe how the distribution of telomere lengths evolves over many generations. We initially consider a population of cells each containing just a single telomere. We use continuum models to compare the effects of various mechanisms of telomere shortening and rates of cell division during normal ageing. For example, the rate (or probability) of cell replication may be fixed or it may decrease as the telomeres shorten. Furthermore, the length of telomere lost on each replication may be constant, or may decrease as the telomeres shorten. Where possible, explicit solutions for the evolution of the distribution of telomere lengths are presented. In other cases, expressions for the mean of the distribution are derived. We extend the models to describe cell populations in which each cell contains a distinct subpopulation of chromosomes. As for the simpler models, constant telomere shortening leads to a linear reduction in telomere length over time, whereas length-dependent shortening results in initially rapid telomere length reduction, slowing at later times. Our analysis also reveals that constant telomere loss leads to a Gaussian (normal) distribution of telomere lengths, whereas length-dependent loss leads to a log-normal distribution. We show that stochastic models, which include a replication probability, also lead to telomere length distributions which are skewed.},
}
@article {pmid31728577,
year = {2020},
author = {Smith, EM and Pendlebury, DF and Nandakumar, J},
title = {Structural biology of telomeres and telomerase.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {77},
number = {1},
pages = {61-79},
pmid = {31728577},
issn = {1420-9071},
support = {T32 AG000114/AG/NIA NIH HHS/United States ; RSG-17-037-01-DMC//American Cancer Society/ ; R01GM120094//Funded by/ ; T32AG000114/AG/NIA NIH HHS/United States ; R01AG050509//Funded by/ ; R01 AG050509/AG/NIA NIH HHS/United States ; R01 GM120094/GM/NIGMS NIH HHS/United States ; },
mesh = {Aminopeptidases/chemistry/metabolism ; Animals ; Chromosomes/chemistry/metabolism ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/chemistry/metabolism ; Humans ; Models, Molecular ; Protein Conformation ; Serine Proteases/chemistry/metabolism ; Shelterin Complex ; Telomerase/chemistry/*metabolism ; Telomere/chemistry/*metabolism ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {Telomeres are protein-DNA complexes that protect chromosome ends from illicit ligation and resection. Telomerase is a ribonucleoprotein enzyme that synthesizes telomeric DNA to counter telomere shortening. Human telomeres are composed of complexes between telomeric DNA and a six-protein complex known as shelterin. The shelterin proteins TRF1 and TRF2 provide the binding affinity and specificity for double-stranded telomeric DNA, while the POT1-TPP1 shelterin subcomplex coats the single-stranded telomeric G-rich overhang that is characteristic of all our chromosome ends. By capping chromosome ends, shelterin protects telomeric DNA from unwanted degradation and end-to-end fusion events. Structures of the human shelterin proteins reveal a network of constitutive and context-specific interactions. The shelterin protein-DNA structures reveal the basis for both the high affinity and DNA sequence specificity of these interactions, and explain how shelterin efficiently protects chromosome ends from genome instability. Several protein-protein interactions, many provided by the shelterin component TIN2, are critical for upholding the end-protection function of shelterin. A survey of these protein-protein interfaces within shelterin reveals a series of "domain-peptide" interactions that allow for efficient binding and adaptability towards new functions. While the modular nature of shelterin has facilitated its part-by-part structural characterization, the interdependence of subunits within telomerase has made its structural solution more challenging. However, the exploitation of several homologs in combination with recent advancements in cryo-EM capabilities has led to an exponential increase in our knowledge of the structural biology underlying telomerase function. Telomerase homologs from a wide range of eukaryotes show a typical retroviral reverse transcriptase-like protein core reinforced with elements that deliver telomerase-specific functions including recruitment to telomeres and high telomere-repeat addition processivity. In addition to providing the template for reverse transcription, the RNA component of telomerase provides a scaffold for the catalytic and accessory protein subunits, defines the limits of the telomeric repeat sequence, and plays a critical role in RNP assembly, stability, and trafficking. While a high-resolution definition of the human telomerase structure is only beginning to emerge, the quick pace of technical progress forecasts imminent breakthroughs in this area. Here, we review the structural biology surrounding telomeres and telomerase to provide a molecular description of mammalian chromosome end protection and end replication.},
}
@article {pmid31728493,
year = {2019},
author = {Crous-Bou, M and Molinuevo, JL and Sala-Vila, A},
title = {Plant-Rich Dietary Patterns, Plant Foods and Nutrients, and Telomere Length.},
journal = {Advances in nutrition (Bethesda, Md.)},
volume = {10},
number = {Suppl_4},
pages = {S296-S303},
pmid = {31728493},
issn = {2156-5376},
mesh = {*Aging ; Carotenoids ; Diet, Mediterranean ; *Diet, Vegetarian ; *Feeding Behavior ; Healthy Aging ; Humans ; Nutrients ; *Nutritional Status ; Plant Extracts ; Plants ; *Public Health ; Seeds ; *Telomere ; *Telomere Shortening ; },
abstract = {The world's population is aging as a consequence of an increased global life expectancy. Identifying simple strategies to promote healthy aging (i.e., absence of major chronic diseases, preserved physical and cognitive functions, intact mental health, and good quality of life) have emerged as a major public health concern. Identifying biomarkers to better characterize the aging process is a research priority. Telomeres are repetitive DNA sequences at chromosome ends that prevent the loss of genomic DNA, protecting its physical integrity. Telomere length (TL) is considered a biomarker of aging: shorter telomeres are associated with a decreased life expectancy and increased rates of age-related chronic diseases. Telomere attrition has been shown to be accelerated by oxidative stress and inflammation. Since edible plants contain plenty of compounds with antioxidant and anti-inflammatory properties, it is plausible that their sustained consumption might help counteract telomere attrition. In this narrative review, we update evidence on the association between plant-rich dietary patterns and plant-based foods and TL. First, we summarize findings from observational studies on the association between TL and 1) adherence to plant-rich dietary patterns (mainly, but not only, focused on the Mediterranean diet); 2) consumption of seeds (mostly focused on nuts, grains, and coffee); and 3) intake of carotenoids, one of the plant-derived bioactives most studied in health and disease. Second, we summarize the main randomized controlled trials evaluating the effect on TL of dietary interventions involving either plant-rich dietary patterns or plant foods. Even though evidence from trials is very limited, several observational studies have reinforced the suggestive benefits of adherence to the Mediterranean diet (a plant-rich dietary pattern), consumption of seeds (and its derivatives), and dietary intake of carotenoids on TL, which further supports the research benefits of plant-rich dietary patterns and plant foods to promote health and longevity.},
}
@article {pmid31727634,
year = {2020},
author = {Chen, R and Zhan, Y and Pedersen, N and Fall, K and Valdimarsdóttir, UA and Hägg, S and Fang, F},
title = {Marital status, telomere length and cardiovascular disease risk in a Swedish prospective cohort.},
journal = {Heart (British Cardiac Society)},
volume = {106},
number = {4},
pages = {267-272},
doi = {10.1136/heartjnl-2019-315629},
pmid = {31727634},
issn = {1468-201X},
mesh = {Aged ; Cardiovascular Diseases/*epidemiology ; Cohort Studies ; Female ; Humans ; Leukocytes/*metabolism ; Linear Models ; Male ; Marital Status/statistics &amp; numerical data ; Marriage/*statistics &amp; numerical data ; Middle Aged ; Multivariate Analysis ; Proportional Hazards Models ; Prospective Studies ; Protective Factors ; Residence Characteristics ; Risk Factors ; Sweden/epidemiology ; Telomere/*metabolism ; },
abstract = {OBJECTIVE: To investigate if marital status is associated with risk of cardiovascular disease (CVD) and to explore the potential influence of leucocyte telomere length (LTL), a marker of biological ageing, on such association.<br><br>DESIGN: Population-based prospective cohort study SETTINGS: Swedish Twin Registry.<br><br>PARTICIPANTS: Based on the Screening Across the Lifespan Twin Study from the Swedish Twin Registry, we included 10 058 twins born between 1900 and 1958 who underwent an interview between 1998 and 2002 during which information about marital status was collected. Blood samples from these participants were subsequently collected between 2004 and 2008 and used for LTL assessment using quantitative PCR technique.<br><br>MAIN OUTCOME MEASURES: Incident cases of CVD were identified through the Swedish Patient Register and Causes of Death Register through December 31, 2016. Multivariable linear regression and Cox proportional hazards regression models were used to estimate the regression coefficients (&#x3b2;s) and HRs with 95% CIs respectively. Potential confounders included age, sex, educational attainment and body mass index.<br><br>RESULTS: A total of 2010 participants were diagnosed with CVD during a median follow-up of 9.8 years. LTL was shorter among individuals living singly, including those who were divorced or separated (&#x3b2;:-0.014, 95% CI: -0.035, 0.007), widowed (&#x3b2;:-0.035, 95% CI: -0.061, -0.010), or living alone (&#x3b2;:-0.033, 95% CI: -0.052, -0.014), than individuals who were married or cohabitating. One SD increase of LTL was associated with a lower risk of CVD (HR: 0.79, 95%&#x2009;CI: 0.66, 0.93). Individuals who were divorced or separated, widowed, or living alone had a higher risk of CVD than individuals who were married or cohabitating. The summary HR of CVD was 1.21 (95% CI: 1.08, 1.35) when comparing individuals who were living singly, regardless of reason, with the individuals who were married or cohabitating. LTL appeared to mediate little of the association between marital status and CVD (HR additionally adjusted for LTL: 1.20; 95%&#x2009;CI: 1.08, 1.34).<br><br>CONCLUSIONS: Living singly, regardless of reason, was associated with a shorter LTL and a higher risk of CVD. The association between marital status and CVD was however not greatly attributable to telomere shortening.},
}
@article {pmid31724724,
year = {2019},
author = {Hua, R and Wei, H and Liu, C and Zhang, Y and Liu, S and Guo, Y and Cui, Y and Zhang, X and Guo, X and Li, W and Liu, M},
title = {FBXO47 regulates telomere-inner nuclear envelope integration by stabilizing TRF2 during meiosis.},
journal = {Nucleic acids research},
volume = {47},
number = {22},
pages = {11755-11770},
pmid = {31724724},
issn = {1362-4962},
mesh = {Animals ; Cell Cycle Proteins/*physiology ; F-Box Proteins/*physiology ; Female ; HEK293 Cells ; Humans ; Male ; Meiosis/*physiology ; Mice ; Mice, Knockout ; Nuclear Envelope/genetics/*metabolism ; Protein Stability ; Spermatocytes/physiology ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; Transcription Factors/*physiology ; },
abstract = {During meiosis, telomere attachment to the inner nuclear envelope is required for proper pairing of homologous chromosomes and recombination. Here, we identified F-box protein 47 (FBXO47) as a regulator of the telomeric shelterin complex that is specifically expressed during meiotic prophase I. Knockout of Fbxo47 in mice leads to infertility in males. We found that the Fbxo47 deficient spermatocytes are unable to form a complete synaptonemal complex. FBXO47 interacts with TRF1/2, and the disruption of Fbxo47 destabilizes TRF2, leading to unstable telomere attachment and slow traversing through the bouquet stage. Our findings uncover a novel mechanism of FBXO47 in telomeric shelterin subunit stabilization during meiosis.},
}
@article {pmid31723429,
year = {2019},
author = {Mickle, AT and Brenner, DR and Beattie, T and Williamson, T and Courneya, KS and Friedenreich, CM},
title = {The Dietary Inflammatory Index® and Alternative Healthy Eating Index 2010 in relation to leucocyte telomere length in postmenopausal women: a cross-sectional study.},
journal = {Journal of nutritional science},
volume = {8},
number = {},
pages = {e35},
pmid = {31723429},
issn = {2048-6790},
support = {MOP-130238//CIHR/Canada ; },
mesh = {Aged ; Alberta ; Breast Neoplasms/prevention &amp; control ; Cross-Sectional Studies ; *Diet ; *Diet, Healthy ; Energy Intake ; Exercise ; Feeding Behavior ; Female ; Humans ; Inflammation ; *Leukocytes ; Life Style ; Linear Models ; Middle Aged ; Multivariate Analysis ; Oxidative Stress ; *Postmenopause ; Risk Factors ; Surveys and Questionnaires ; *Telomere ; },
abstract = {Telomeres are nucleoprotein complexes that form the ends of eukaryotic chromosomes where they protect DNA from genomic instability, prevent end-to-end fusion and limit cellular replicative capabilities. Increased telomere attrition rates, and relatively shorter telomere length, is associated with genomic instability and has been linked with several chronic diseases, malignancies and reduced longevity. Telomeric DNA is highly susceptible to oxidative damage and dietary habits may make an impact on telomere attrition rates through the mediation of oxidative stress and chronic inflammation. The aim of this study was to examine the association between leucocyte telomere length (LTL) with both the Dietary Inflammatory Index[®] 2014 (DII[®]) and the Alternative Healthy Eating Index 2010 (AHEI-2010). This is a cross-sectional analysis using baseline data from 263 postmenopausal women from the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial, in Calgary and Edmonton, Alberta, Canada. No statistically significant association was detected between LTL z-score and the AHEI-2010 (P = 0·20) or DII[®] (P = 0·91) in multivariable adjusted models. An exploratory analysis of AHEI-2010 and DII[®] parameters and LTL revealed anthocyanidin intake was associated with LTL (P < 0·01); however, this association was non-significant after a Bonferroni correction was applied (P = 0·27). No effect modification by age, smoking history, or recreational physical activity was detected for either relationship. Increased dietary antioxidant and decreased oxidant intake were not associated with LTL in this analysis.},
}
@article {pmid31720244,
year = {2019},
author = {Suh, DI and Kang, MJ and Park, YM and Lee, JK and Lee, SY and Sheen, YH and Kim, KW and Ahn, K and Hong, SJ},
title = {The risk of preschool asthma at 2-4 years is not associated with leukocyte telomere length at birth or at 1 year of age.},
journal = {Asia Pacific allergy},
volume = {9},
number = {4},
pages = {e33},
pmid = {31720244},
issn = {2233-8276},
abstract = {BACKGROUND: Exposure to prenatal stress is associated with offspring allergic-disease development, and oxidative stress may mediate this relationship.<br><br>OBJECTIVE: We aimed to evaluate whether leukocyte telomere length (LTL) shortening, a marker for exposure to oxidative stress, in early life is associated with increased risk of asthma development during the preschool period.<br><br>METHODS: We assessed the follow-up clinical data of a subgroup from a birth cohort whose LTLs had been measured from cord-blood and 1-year peripheral-blood samples. We examined whether the LTLs would be associated with asthma development at the age of 2-4 years.<br><br>RESULTS: The data of 84 subjects were analyzed. LTLs were measured from the cord-blood and 1-year peripheral blood of 75 and 79 subjects, respectively. Among them, 14 subjects (16.7%) developed bronchial asthma between 2-4 years old. Prenatally stressed subjects had marginally increased odds of developing asthma (p = 0.097). There was no significant difference in the odds of preschool-asthma development between the groups with shorter and longer cord-blood LTLs (odds ratio [OR], 0.651; 95% confidence interval [CI], 0.184-2.306) or in the odds between the groups with shorter and longer 1-year peripheral-blood LTLs (OR, 0.448; 95% CI, 0.135-1.483). Finally, subjects with both higher prenatal stress and shorter LTLs did not have significantly higher odds of preschool-asthma development (for cord-blood: OR, 1.242; 95% CI, 0.353-4.368; for 1-year peripheral-blood: OR, 1.451; 95% CI, 0.428-4.919).<br><br>CONCLUSION: There was no significant association between early life LTLs and higher risk of bronchial-asthma development during the preschool years.},
}
@article {pmid31711660,
year = {2020},
author = {Shoeb, M and Mustafa, GM and Kodali, VK and Smith, K and Roach, KA and Boyce, G and Meighan, T and Roberts, JR and Erdely, A and Antonini, JM},
title = {A possible relationship between telomere length and markers of neurodegeneration in rat brain after welding fume inhalation exposure.},
journal = {Environmental research},
volume = {180},
number = {},
pages = {108900},
pmid = {31711660},
issn = {1096-0953},
support = {CC999999/ImCDC/Intramural CDC HHS/United States ; },
mesh = {*Air Pollutants, Occupational/toxicity ; Animals ; Brain ; Cats ; DNA Methylation ; Endothelial Cells ; Gene Expression Regulation/*drug effects ; Humans ; *Inhalation Exposure ; Male ; Rats ; Rats, Sprague-Dawley ; *Telomere ; *Welding ; },
abstract = {Inhalation of welding fume (WF) can result in the deposition of toxic metals, such as manganese (Mn), in the brain and may cause neurological changes in exposed workers. Alterations in telomere length are indicative of cellular aging and, possibly, neurodegeneration. Here, we investigated the effect of WF inhalation on telomere length and markers of neurodegeneration in whole brain tissue in rats. Male Fischer-344 (F-344) rats were exposed by inhalation to stainless steel WF (20 mg/m[3] x 3 h/d x 4 d/wk x 5 wk) or filtered air (control). Telomere length, DNA-methylation, gene expression of Trf1, Trf2, ATM, and APP, protein expression of p-Tau, α-synuclein, and presenilin 1 and 2 were assessed in whole brain tissue at 12 wk after WF exposure ended. Results suggest that WF inhalation increased telomere length without affecting telomerase in whole brain. Moreover, we observed that components of the shelterin complex, Trf1 and Trf2, play an important role in telomere end protection, and their regulation may be responsible for the increase in telomere length. In addition, expression of different neurodegeneration markers, such as p-Tau, presenilin 1-2 and α-synuclein proteins, were increased in brain tissue from the WF-exposed rats as compared to control. These findings suggest a possible correlation between epigenetic modifications, telomere length alteration, and neurodegeneration because of the presence of factors in serum after WF exposure that may cause extra-pulmonary effects as well as the translocation of potentially neurotoxic metals associated with WF to the central nervous system (CNS). Further studies are needed to investigate the brain region specificity and temporal response of these effects.},
}
@article {pmid31707361,
year = {2019},
author = {Yun, M and Li, S and Yan, Y and Zhang, T and Bazzano, L and He, J and Chen, W},
title = {Suppression effect of body weight on the association between cigarette smoking and telomere length: the Bogalusa Heart Study.},
journal = {Aging},
volume = {11},
number = {21},
pages = {9893-9900},
pmid = {31707361},
issn = {1945-4589},
support = {U54 GM104940/GM/NIGMS NIH HHS/United States ; R03 AG060619/AG/NIA NIH HHS/United States ; R01 HL121230/HL/NHLBI NIH HHS/United States ; P20 GM109036/GM/NIGMS NIH HHS/United States ; },
mesh = {Adult ; Black or African American/genetics ; Body Mass Index ; Body Weight/*genetics/*physiology ; Cigarette Smoking/*adverse effects/*genetics ; Cohort Studies ; Female ; Humans ; Leukocytes/pathology ; Longitudinal Studies ; Male ; Middle Aged ; Sex Factors ; Telomere/*pathology ; Telomere Homeostasis/genetics/physiology ; Telomere Shortening/genetics/physiology ; White People/genetics ; },
abstract = {This study aimed to dissect the direct effect of smoking and its indirect effect through body mass index (BMI) on leukocyte telomere length (LTL) and to distinguish the mediation and suppression effects of BMI. The study cohort included 1,037 adults (729 Whites and 308 African Americans; 42.1% males; mean age: 40.3 years) with LTL measurements by Southern blotting. General third variable models were used to distinguish the mediation and suppression effects of BMI on the smoking-LTL association. After adjusting for age, race, sex and alcohol drinking, the total effect of smoking on LTL was significant (standardized regression coefficient, β= -0.061, p=0.034) without BMI included in the model. With additional adjustment for BMI, the indirect effect of smoking on LTL through BMI was estimated at β= 0.011 (p=0.023), and the direct effect of smoking on LTL was strengthened to β= -0.072 (p=0.012). The results were similar when pack-years of smoking was used. The effect parameters did not differ significantly between race and sex groups. These results suggest that BMI has a suppression effect, not a mediation effect, on the smoking-LTL association, which potentially contributes to previous inconsistencies in the effect of smoking on LTL.},
}
@article {pmid31706351,
year = {2019},
author = {Grandin, N and Pereira, B and Cohen, C and Billard, P and Dehais, C and Carpentier, C and Idbaih, A and Bielle, F and Ducray, F and Figarella-Branger, D and Delattre, JY and Sanson, M and Lomonte, P and Poncet, D and Verrelle, P and Charbonneau, M and , },
title = {The level of activity of the alternative lengthening of telomeres correlates with patient age in IDH-mutant ATRX-loss-of-expression anaplastic astrocytomas.},
journal = {Acta neuropathologica communications},
volume = {7},
number = {1},
pages = {175},
pmid = {31706351},
issn = {2051-5960},
support = {Grand Ouest//Ligue Contre le Cancer/International ; subvention fixe//Fondation ARC pour la Recherche sur le Cancer/International ; Oncostarter//Cancerop&#xf4;le Lyon Auvergne Rhone-Alpes (FR)/International ; DEVweCAN//Labex/International ; POLA network//Institut National Du Cancer/International ; },
mesh = {Adult ; Aged ; Astrocytoma/genetics/*metabolism/pathology ; Brain Neoplasms/genetics/*metabolism/pathology ; Cohort Studies ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Isocitrate Dehydrogenase/*physiology ; Male ; Middle Aged ; Mutation/physiology ; Telomere Homeostasis/*physiology ; X-linked Nuclear Protein/*biosynthesis/genetics ; },
abstract = {All cancer cells need to maintain functional telomeres to sustain continuous cell division and proliferation. In human diffuse gliomas, functional telomeres are maintained due either to reactivation of telomerase expression, the main pathway in most cancer types, or to activation of a mechanism called the alternative lengthening of telomeres (ALT). The presence of IDH1/2 mutations (IDH-mutant) together with loss of ATRX expression (ATRX-lost) are frequently associated with ALT in diffuse gliomas. However, detection of ALT, and a fortiori its quantification, are rarely, if ever, measured in neuropathology laboratories. We measured the level of ALT activity using the previously described quantitative "C-circle" assay and analyzed it in a well characterized cohort of 104 IDH-mutant and ATRX-lost adult diffuse gliomas. We report that in IDH-mutant ATRX-lost anaplastic astrocytomas, the intensity of ALT was inversely correlated with age (p < 0.001), the younger the patient, the higher the intensity of ALT. Strikingly, glioblastomas having progressed from anaplastic astrocytomas did not exhibit this correlation. ALT activity level in the tumor did not depend on telomere length in healthy tissue cells from the same patient. In summary, we have uncovered the existence, in anaplastic astrocytomas but not in glioblastomas with the same IDH and ATRX mutations, of a correlation between patient age and the level of activity of ALT, a telomerase-independent pathway of telomere maintenance.},
}
@article {pmid31706071,
year = {2019},
author = {Rebello, K and Moura, LM and Xavier, G and Spindola, LM and Carvalho, CM and Hoexter, MQ and Gadelha, A and Picon, F and Pan, PM and Zugman, A and Grassi-Oliveira, R and Brietzke, E and Belangero, SI and Salum, GA and Rohde, LA and Miguel, EC and Bressan, R and Jackowski, A and Sato, JR},
title = {Association between spontaneous activity of the default mode network hubs and leukocyte telomere length in late childhood and early adolescence.},
journal = {Journal of psychosomatic research},
volume = {127},
number = {},
pages = {109864},
doi = {10.1016/j.jpsychores.2019.109864},
pmid = {31706071},
issn = {1879-1360},
mesh = {Adolescent ; Brain Mapping/*methods ; Child ; Female ; Humans ; Leukocytes/*metabolism ; Magnetic Resonance Imaging/*methods ; Male ; Telomere/*metabolism ; },
abstract = {The impact of early life stress on mental health and telomere length shortening have been reported. Changes in brain default mode network (DMN) were found to be related to a myriad of psychiatric conditions in which stress may play a role. In this context, family environment and adverse childhood experiences (ACEs) are potential causes of stress. This is a hypothesis-driven study focused on testing two hypotheses: (i) there is an association between telomere length and the function of two main hubs of DMN: the posterior cingulate cortex (PCC) and the medial prefrontal cortex (mPFC); (ii) this association is modulated by family environment and/or ACEs. To the best of our knowledge, this is the first study investigating these hypotheses. Resting-state functional magnetic resonance imaging data and blood sample were collected from 389 subjects (6-15 age range). We assessed DMN fractional amplitude of low-frequency fluctuations (fALFF) and leukocyte telomere length (LTL). We fitted general linear models to test the main effects of LTL on DMN hubs and the interaction effects with Family Environment Scale (FES) and ACEs. The results did not survive a strict Bonferroni correction. However, uncorrected p-values suggest that LTL was positively correlated with fALFF in PCC and a FES interaction between FES and LTL at mPFC. Although marginal, our results encourage further research on the interaction between DMN hubs, telomere length and family environment, which may play a role on the biological embedding of stress.},
}
@article {pmid31705512,
year = {2019},
author = {Muneer, A},
title = {Interventions Addressing the Telomere-Telomerase System.},
journal = {Advances in experimental medicine and biology},
volume = {1192},
number = {},
pages = {521-544},
doi = {10.1007/978-981-32-9721-0_26},
pmid = {31705512},
issn = {0065-2598},
mesh = {Aged ; Cellular Senescence/*genetics ; Humans ; Leukocytes/*metabolism ; Mental Disorders/diagnosis/*genetics ; *Telomerase ; Telomere/*metabolism ; Telomere Homeostasis ; Telomere Shortening ; },
abstract = {Major psychiatric disorders are linked to early mortality and patients afflicted with these ailments demonstrate an increased risk of developing physical diseases that are characteristically seen in the elderly. Psychiatric conditions like major depressive disorder, bipolar disorder, and schizophrenia may be associated with accelerated cellular aging, indicated by shortened leukocyte telomere length (LTL), which could underlie this connection. Telomere shortening occurs with repeated cell division and is reflective of a cell's mitotic history. It is also influenced by cumulative exposure to inflammation and oxidative stress as well as the availability of telomerase, the telomere-lengthening enzyme. Precariously short telomeres can cause cells to undergo senescence, apoptosis, or genomic instability; shorter LTL correlates with compromised general health and foretells mortality. Important data specify that LTL may be reduced in principal psychiatric illnesses, possibly in proportion to exposure to the ailment. Telomerase, as measured in peripheral blood monocytes, has been less well characterized in psychiatric illnesses, but a role in mood disorder has been suggested by preclinical and clinical studies. In this manuscript, the most recent studies on LTL and telomerase activity in mood disorders are comprehensively reviewed, potential mediators are discussed, and future directions are suggested. An enhanced comprehension of cellular aging in psychiatric illnesses could lead to their re-conceptualizing as systemic ailments with manifestations both inside and outside the brain. At the same time, this paradigm shift could identify new treatment targets, helpful in bringing about lasting cures to innumerable sufferers across the globe.},
}
@article {pmid31697380,
year = {2020},
author = {Zeng, Z and Zhang, W and Qian, Y and Huang, H and Wu, DJH and He, Z and Ye, D and Mao, Y and Wen, C},
title = {Association of telomere length with risk of rheumatoid arthritis: a meta-analysis and Mendelian randomization.},
journal = {Rheumatology (Oxford, England)},
volume = {59},
number = {5},
pages = {940-947},
doi = {10.1093/rheumatology/kez524},
pmid = {31697380},
issn = {1462-0332},
mesh = {Arthritis, Rheumatoid/*epidemiology/*genetics/physiopathology ; Case-Control Studies ; Female ; Genetic Predisposition to Disease/*epidemiology ; Genome-Wide Association Study ; Humans ; Male ; *Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide/genetics ; Prevalence ; Prognosis ; Reference Values ; Telomere/*genetics ; },
abstract = {OBJECTIVE: To evaluate the telomere length (TL) in patients with RA relative to that in controls and to test whether TL is causally associated with risk of RA.<br><br>METHODS: Systematic review and meta-analysis of relevant literature was conducted to evaluate the association between TL and RA. Standardized mean differences with 95% CIs of TL in RA patients relative to controls were pooled using fixed or random-effects models. TL-related single-nucleotide polymorphisms were selected from a genome-wide association study of 37 684 individuals, and summary statistics of RA were obtained from a genome-wide association study meta-analysis including 14 361 RA patients and 43 923 controls. Mendelian randomization was performed using the inverse-variance weighted, weighted-median and likelihood-based methods. Sensitivity analyses were performed to test the robustness of the association.<br><br>RESULTS: In the meta-analysis of 911 RA patients and 2498 controls, we found that patients with RA had a significantly shorter TL compared with controls (standardized mean differences = -0.50; 95% CI -0.88, -0.11; P = 0.012). In the Mendelian randomization analysis, we found that genetically predicted longer TL was associated with a reduced risk of RA [odds ratio = 0.68; 95% CI 0.54, 0.86; P = 0.002 using the inverse-variance weighted method]. Sensitivity analyses using alternative Mendelian randomization approaches yielded similar findings, suggesting the robustness of the causal association.<br><br>CONCLUSION: Our study provides evidence for a negative causal association of TL with risk of RA. Further studies are warranted to elucidate the underlying mechanism for the role of telomeres in the development of RA.},
}
@article {pmid31694204,
year = {2019},
author = {Vecoli, C and Borghini, A and Pulignani, S and Mercuri, A and Turchi, S and Picano, E and Andreassi, MG},
title = {Independent and Combined Effects of Telomere Shortening and mtDNA[4977] Deletion on Long-term Outcomes of Patients with Coronary Artery Disease.},
journal = {International journal of molecular sciences},
volume = {20},
number = {21},
pages = {},
pmid = {31694204},
issn = {1422-0067},
mesh = {Aged ; Aged, 80 and over ; Coronary Artery Disease/diagnosis/epidemiology/*genetics ; DNA, Mitochondrial/*genetics ; Female ; Humans ; Kaplan-Meier Estimate ; Leukocytes/metabolism ; Male ; Middle Aged ; Mitochondria/genetics ; Prognosis ; Proportional Hazards Models ; Sequence Deletion ; *Telomere Shortening ; },
abstract = {Aging is one of the main risk factors for cardiovascular disease, resulting in a progressive organ and cell decline. This study evaluated a possible joint impact of two emerging hallmarks of aging, leucocyte telomere length (LTL) and common mitochondrial DNA deletion (mtDNA[4977]), on major adverse cardiovascular events (MACEs) and all-cause mortality in patients with coronary artery disease (CAD). We studied 770 patients (673 males, 64.8 ± 8.3 years) with known or suspected stable CAD. LTL and mtDNA[4977] deletion were assessed in peripheral blood using qRT-PCR. During a median follow-up of 5.4 ± 1.2 years, MACEs were 140 while 86 deaths were recorded. After adjustments for confounding risk factors, short LTLs and high mtDNA[4977] deletion levels acted independently as predictors of MACEs (HR: 2.2, 95% CI: 1.2-3.9, p = 0.01 and HR: 1.7, 95% CI: 1.1-2.9, p = 0.04; respectively) and all-cause mortality events (HR: 2.1, 95% CI: 1.1-4.6, p = 0.04 and HR: 2.3, 95% CI: 1.1-4.9, p = 0.02; respectively). Patients with both short LTLs and high mtDNA[4977] deletion levels had an increased risk for MACEs (HR: 4.3; 95% CI: 1.9-9.6; p = 0.0006) and all-cause mortality (HR: 6.0; 95% CI: 2.0-18.4; p = 0.001). The addition of mtDNA[4977] deletion to a clinical reference model was associated with a significant net reclassification improvement (NRI = 0.18, p = 0.01). Short LTL and high mtDNA[4977] deletion showed independent and joint predictive value on adverse cardiovascular outcomes and all-cause mortality in patients with CAD. These findings strongly support the importance of evaluating biomarkers of physiological/biological age, which can predict disease risk and mortality more accurately than chronological age.},
}
@article {pmid31692873,
year = {2019},
author = {Guha, M and Srinivasan, S and Sheehan, MM and Kijima, T and Ruthel, G and Whelan, K and Tanaka, K and Klein-Szanto, A and Chandramouleeswaran, PM and Nakagawa, H and Avadhani, NG},
title = {Esophageal 3D organoids of MPV17[-/-] mouse model of mitochondrial DNA depletion show epithelial cell plasticity and telomere attrition.},
journal = {Oncotarget},
volume = {10},
number = {58},
pages = {6245-6259},
pmid = {31692873},
issn = {1949-2553},
support = {P01 CA098101/CA/NCI NIH HHS/United States ; R01 AA026297/AA/NIAAA NIH HHS/United States ; R01 DK114436/DK/NIDDK NIH HHS/United States ; },
abstract = {Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with late-stage detection and poor prognosis. This emphasizes the need to identify new markers for early diagnosis and treatment. Altered mitochondrial genome (mtDNA) content in primary tumors correlates with poor patient prognosis. Here we used three-dimensional (3D) organoids of esophageal epithelial cells (EECs) from the MPV17[-/-] mouse model of mtDNA depletion to investigate the contribution of reduced mtDNA content in ESCC oncogenicity. To test if mtDNA defects are a contributing factor in ESCC, we used oncogenic stimuli such as ESCC carcinogen 4-nitroquinoline oxide (4-NQO) treatment, or expressing p53[R175H] oncogenic driver mutation. We observed that EECs and 3D-organoids with mtDNA depletion had cellular, morphological and genetic alterations typical of an oncogenic transition. Furthermore, mitochondrial dysfunction induced cellular transformation is accompanied by elevated mitochondrial fission protein, DRP1 and pharmacologic inhibition of mitochondrial fission by mDivi-1 in the MPV17[-/-] organoids reversed the phenotype to that of normal EEC organoids. Our studies show that mtDNA copy number depletion, activates a mitochondrial retrograde response, potentiates telomere defects, and increases the oncogenic susceptibility towards ESCC. Furthermore, mtDNA depletion driven cellular plasticity is mediated via altered mitochondrial fission-fusion dynamics.},
}
@article {pmid31692866,
year = {2019},
author = {Lirussi, L and Nilsen, H},
title = {Telomere maintenance: regulating hTERC fate through RNA modifications.},
journal = {Molecular &amp; cellular oncology},
volume = {6},
number = {6},
pages = {e1670489},
pmid = {31692866},
issn = {2372-3556},
abstract = {Disturbances in telomere maintenance are common in cancer. We recently showed that Single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1) promotes telomere homeostasis by regulating the stability of the telomeric RNA component (hTERC). SMUG1-mediated recognition of base modifications may function in a regulated process serving to fine-tune the levels of hTERC.},
}
@article {pmid31688893,
year = {2020},
author = {Galiè, S and Canudas, S and Muralidharan, J and García-Gavilán, J and Bulló, M and Salas-Salvadó, J},
title = {Impact of Nutrition on Telomere Health: Systematic Review of Observational Cohort Studies and Randomized Clinical Trials.},
journal = {Advances in nutrition (Bethesda, Md.)},
volume = {11},
number = {3},
pages = {576-601},
pmid = {31688893},
issn = {2156-5376},
mesh = {Cohort Studies ; Humans ; *Nutritional Status ; Randomized Controlled Trials as Topic ; *Telomere ; Telomere Shortening ; },
abstract = {Diet, physical activity, and other lifestyle factors have been implicated in the pathophysiology of several chronic diseases, but also in a lower total mortality and longer life expectancy. One of the mechanisms in which diet can reduce the risk of disease is with regard to its impact on telomeres. Telomere length (TL) is highly correlated to chronological age and metabolic status. Individuals with shorter telomeres are at higher risk of chronic diseases and mortality. Diet may influence TL by several mechanisms such as regulating oxidative stress and inflammation or modulating epigenetic reactions. The present systematic review aims to examine the results from epidemiologic and clinical trials conducted in humans evaluating the role of nutrients, food groups, and dietary patterns on TL. We also discuss the possible mechanisms of action that influence this process, with the perspective that TL could be a novel biomarker indicating the risk of metabolic disturbances and age-related diseases. The available evidence suggests that some antioxidant nutrients, the consumption of fruits and vegetables, and Mediterranean diet are mainly associated with longer telomeres. However, most of the evidence is based on high heterogenic observational studies and very few randomized clinical trials (RCTs). Therefore, the associations summarized in the present review need to be confirmed with larger prospective cohort studies and better-designed RCTs.},
}
@article {pmid31688458,
year = {2020},
author = {Kim, ES and Tindle, HA and Kubzansky, LD and Liu, S and Duncan, MS and Manson, JE and Springfield, S and Salmoirago-Blotcher, E and Shadyab, AH and Liu, B and Grodstein, F and De Vivo, I},
title = {The Relation of Optimism to Relative Telomere Length in Older Men and Women.},
journal = {Psychosomatic medicine},
volume = {82},
number = {2},
pages = {165-171},
pmid = {31688458},
issn = {1534-7796},
support = {R01 DK062290/DK/NIDDK NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; U01 AG009740/AG/NIA NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; R01 AG053273/AG/NIA NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; K99 AG055696/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*metabolism/*psychology ; Cross-Sectional Studies ; Humans ; Leukocytes/metabolism ; Middle Aged ; *Optimism ; Telomere/*metabolism ; },
abstract = {OBJECTIVE: Mounting evidence suggests that higher optimism is associated with reduced risk of age-related morbidities and premature mortality. However, possible biological mechanisms underlying these associations remain understudied. One hypothesized mechanism is a slower rate of cellular aging, which in turn delays age-related declines in health.<br><br>METHODS: We used data from two large cohort studies to test the hypothesis that higher optimism is associated with longer leukocyte telomere length. With cross-sectional data from the Health and Retirement Study (HRS; n = 6417; mean age = 70 years) and the Women's Health Initiative (WHI; N = 3582; mean age = 63 years), we used linear regression models to examine the association of optimism with relative telomere length (assessed in leukocytes from saliva [HRS] or plasma [WHI]). Models adjusted for sociodemographics, depression, health status, and health behaviors.<br><br>RESULTS: Considering both optimism and telomere length as continuous variables, we found consistently null associations in both cohorts, regardless of which covariates were included in the models. In models adjusting for demographics, depression, comorbidities, and health behaviors, optimism was not associated with mean relative telomere length (HRS: &#x3b2; = -0.002, 95% confidence interval = -0.014 to 0.011; WHI: &#x3b2; = -0.004, 95% confidence interval = -0.017 to 0.009).<br><br>CONCLUSIONS: Findings do not support mean telomere length as a mechanism that explains observed relations of optimism with reduced risk of chronic disease in older adults. Future research is needed to evaluate other potential biological markers and pathways.},
}
@article {pmid31687079,
year = {2019},
author = {Tucker, LA},
title = {Serum and Dietary Folate and Vitamin B12 Levels Account for Differences in Cellular Aging: Evidence Based on Telomere Findings in 5581 U.S. Adults.},
journal = {Oxidative medicine and cellular longevity},
volume = {2019},
number = {},
pages = {4358717},
pmid = {31687079},
issn = {1942-0994},
mesh = {Adult ; *Cellular Senescence ; *Diet ; Female ; Folic Acid/*blood ; Humans ; Male ; Middle Aged ; Telomere/*metabolism ; Telomere Homeostasis ; Vitamin B 12/*blood ; },
abstract = {Folate and vitamin B12 are essential for a variety of metabolic processes. Both micronutrients have been shown to reduce oxidative stress significantly. The present cross-sectional investigation evaluated the association between serum and dietary folate and vitamin B12 levels and leukocyte telomere length, an index of cellular aging influenced by oxidative stress. The study included 5581 adults from the National Health and Nutrition Examination Survey (NHANES). Because participants were randomly selected, results are generalizable to all civilian, noninstitutionalized U.S. adults. A blood draw provided DNA and serum folate and B12 information. The quantitative polymerase chain reaction method was used to measure telomere length. The Bio-Rad Quantaphase II folate and vitamin B12 radioassay kit was used to quantify levels of folate and vitamin B12. Dietary folate and vitamin B12 were assessed using a multipass 24 h recall. In some models, age, race, smoking pack-years, alcohol use, body mass index, total physical activity, hours fasted before the blood draw, and diabetes status were employed as covariates to minimize their influence. Findings showed that for each additional year of chronological age, telomeres were 15.6 base pairs shorter, on average (F = 378.8, p < 0.0001). Men had shorter telomeres than women after adjusting for all the covariates (F = 6.8, p = 0.0146). Serum (F = 10.5, p = 0.0030) and dietary (F = 5.0, p = 0.0325) folate concentrations were each linearly related to telomere length in women, but not in men, after controlling for age and race. Serum vitamin B12 and telomere length had a nonsignificant, inverse relationship in women, with age and race controlled (F = 2.8, p = 0.1056), but no relation in men. Dietary vitamin B12 was linearly related to telomere length in women, after adjusting for age and race (F = 4.3, p = 0.0468), but not in men. Overall, evidence indicates that folate and vitamin B12 levels, especially folate, account for meaningful differences in cell aging in women, but not in men.},
}
@article {pmid31685617,
year = {2019},
author = {Xu, M and Kiselar, J and Whited, TL and Hernandez-Sanchez, W and Taylor, DJ},
title = {POT1-TPP1 differentially regulates telomerase via POT1 His266 and as a function of single-stranded telomere DNA length.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {116},
number = {47},
pages = {23527-23533},
pmid = {31685617},
issn = {1091-6490},
support = {P30 EB009998/EB/NIBIB NIH HHS/United States ; P30 CA091842/CA/NCI NIH HHS/United States ; R01 GM133841/GM/NIGMS NIH HHS/United States ; R01 CA240993/CA/NCI NIH HHS/United States ; R01 GM126218/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Substitution ; CRISPR-Cas Systems ; DNA, Single-Stranded/*metabolism ; HCT116 Cells ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics/metabolism ; *Mutation, Missense ; *Point Mutation ; *Polymorphism, Single Nucleotide ; Protein Binding ; Recombinant Proteins/metabolism ; Shelterin Complex ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; Telomere-Binding Proteins/genetics/*physiology ; },
abstract = {Telomeres cap the ends of linear chromosomes and terminate in a single-stranded DNA (ssDNA) overhang recognized by POT1-TPP1 heterodimers to help regulate telomere length homeostasis. Here hydroxyl radical footprinting coupled with mass spectrometry was employed to probe protein-protein interactions and conformational changes involved in the assembly of telomere ssDNA substrates of differing lengths bound by POT1-TPP1 heterodimers. Our data identified environmental changes surrounding residue histidine 266 of POT1 that were dependent on telomere ssDNA substrate length. We further determined that the chronic lymphocytic leukemia-associated H266L substitution significantly reduced POT1-TPP1 binding to short ssDNA substrates; however, it only moderately impaired the heterodimer binding to long ssDNA substrates containing multiple protein binding sites. Additionally, we identified a telomerase inhibitory role when several native POT1-TPP1 proteins coat physiologically relevant lengths of telomere ssDNA. This POT1-TPP1 complex-mediated inhibition of telomerase is abrogated in the context of the POT1 H266L mutation, which leads to telomere overextension in a malignant cellular environment.},
}
@article {pmid31682833,
year = {2020},
author = {Saha, A and Nanavaty, VP and Li, B},
title = {Telomere and Subtelomere R-loops and Antigenic Variation in Trypanosomes.},
journal = {Journal of molecular biology},
volume = {432},
number = {15},
pages = {4167-4185},
pmid = {31682833},
issn = {1089-8638},
support = {R01 AI066095/AI/NIAID NIH HHS/United States ; R01 AI127562/AI/NIAID NIH HHS/United States ; S10 OD025252/OD/NIH HHS/United States ; },
mesh = {Antigenic Variation ; Cell Plasticity ; Genetic Variation ; R-Loop Structures ; RNA, Transfer/genetics/*metabolism ; Telomere/*metabolism ; Trypanosoma brucei brucei/*genetics/metabolism ; Variant Surface Glycoproteins, Trypanosoma/*genetics ; },
abstract = {Trypanosoma brucei is a kinetoplastid parasite that causes African trypanosomiasis, which is fatal if left untreated. T. brucei regularly switches its major surface antigen, VSG, to evade the host immune responses. VSGs are exclusively expressed from subtelomeric expression sites (ESs) where VSG genes are flanked by upstream 70 bp repeats and downstream telomeric repeats. The telomere downstream of the active VSG is transcribed into a long-noncoding RNA (TERRA), which forms RNA:DNA hybrids (R-loops) with the telomeric DNA. At an elevated level, telomere R-loops cause more telomeric and subtelomeric double-strand breaks (DSBs) and increase VSG switching rate. In addition, stabilized R-loops are observed at the 70 bp repeats and immediately downstream of ES-linked VSGs in RNase H defective cells, which also have an increased amount of subtelomeric DSBs and more frequent VSG switching. Although subtelomere plasticity is expected to be beneficial to antigenic variation, severe defects in subtelomere integrity and stability increase cell lethality. Therefore, regulation of the telomere and 70 bp repeat R-loop levels is important for the balance between antigenic variation and cell fitness in T. brucei. In addition, the high level of the active ES transcription favors accumulation of R-loops at the telomere and 70 bp repeats, providing an intrinsic mechanism for local DSB formation, which is a strong inducer of VSG switching.},
}
@article {pmid31680455,
year = {2020},
author = {Verhulst, S},
title = {Improving comparability between qPCR-based telomere studies.},
journal = {Molecular ecology resources},
volume = {20},
number = {1},
pages = {11-13},
pmid = {31680455},
issn = {1755-0998},
mesh = {Blotting, Southern ; Humans ; Real-Time Polymerase Chain Reaction ; Reproducibility of Results ; Telomere/*genetics/metabolism ; },
abstract = {Comparability of findings from qPCR-based telomere studies is hampered by such measurement results being assay-specific, precluding a direct quantitative comparisons of observed differences and/or slopes of associations between studies. It is proposed that this can be partially alleviated by expressing qPCR-based telomere data as Z-scores.},
}
@article {pmid31675136,
year = {2020},
author = {Pisanu, C and Tsermpini, EE and Skokou, M and Kordou, Z and Gourzis, P and Assimakopoulos, K and Congiu, D and Meloni, A and Balasopoulos, D and Patrinos, GP and Squassina, A},
title = {Leukocyte telomere length is reduced in patients with major depressive disorder.},
journal = {Drug development research},
volume = {81},
number = {3},
pages = {268-273},
doi = {10.1002/ddr.21612},
pmid = {31675136},
issn = {1098-2299},
support = {F72F16003090002//Fondazione di Sardegna and Regione Sardegna/International ; //Fondazione Umberto Veronesi/International ; //Fondazione di Sardegna/International ; },
mesh = {Adult ; Aged ; Aging/physiology ; Antidepressive Agents/*administration &amp; dosage ; Case-Control Studies ; Depressive Disorder, Major/drug therapy/*physiopathology ; Depressive Disorder, Treatment-Resistant/drug therapy/physiopathology ; Female ; Humans ; Leukocytes/physiology ; Male ; Middle Aged ; Telomere/*physiology ; Telomere Shortening/*physiology ; },
abstract = {Major depressive disorder (MDD) is a chronic, severe psychiatric illness with an incidence of 3% worldwide. MDD patients have a significantly impaired quality of life and reduced life expectancy compared to unaffected individuals, the latter being largely accounted for by an increased incidence of suicide and cardiovascular disorders. The premature mortality observed in MDD has been considered a signature of accelerated aging, a hypothesis supported by data showing altered functioning and morphology of several brain regions that are typically present in the aging population. Telomere shortening is a hallmark of cellular aging, and as such several studies explored the involvement of disrupted telomere dynamics in MDD, reporting contrasting findings. In the current study, we measured leukocyte telomere length (LTL) in a sample of 54 MDD patients and 47 non-psychiatric controls characterized for response to antidepressant treatment. After correcting for age, sex, and body mass index, we showed significantly reduced LTL in affected individuals compared to controls (beta = -.22, p = .02). There was no difference in LTL between treatment resistant or responsive MDD patients. Moreover, we observed no correlation between lifetime exposure to antidepressants and LTL. Our study showed that MDD patients have shorter telomeres compared to controls, supporting the hypothesis of accelerated aging in this disorder. However, LTL seemed not to be influenced by antidepressant treatment or to correlate with clinical response to these antidepressants. Further investigations in larger samples and possibly with longitudinal design are warranted to elucidate the role of altered telomere dynamics in MDD.},
}
@article {pmid31672366,
year = {2020},
author = {Grunst, AS and Grunst, ML and Bervoets, L and Pinxten, R and Eens, M},
title = {Proximity to roads, but not exposure to metal pollution, is associated with accelerated developmental telomere shortening in nestling great tits.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {256},
number = {},
pages = {113373},
doi = {10.1016/j.envpol.2019.113373},
pmid = {31672366},
issn = {1873-6424},
mesh = {Animals ; Belgium ; Environmental Monitoring/*methods ; Environmental Pollutants/*blood ; Female ; Male ; Metals, Heavy/*blood ; Noise/*adverse effects ; Passeriformes/blood/*genetics ; *Telomere Shortening ; },
abstract = {Comprehensively understanding the factors affecting physiology and fitness in urban wildlife requires concurrently considering multiple stressors. To this end, we simultaneously assessed how metal pollution and proximity to roads affect body condition and telomere shortening between days 8 and 15 of age in nestling great tits (Parus major), a common urban bird. We employed a repeated-measures sampling design to compare telomere shortening and body condition between nestlings from four urban study sites south of Antwerp, Belgium, which are located at different distances from a metal pollution point source. In addition, we explored associations between metal exposure and telomere dynamics on the individual level by measuring blood concentrations of five metals/metalloids, of which lead, copper and zinc were present at concentrations above the limit of detection. To assess whether roadway-associated stressors (e.g. noise and air pollution) might affect nestling condition and telomere shortening, we measured the proximity of nest boxes to roads. Metal exposure was not associated with nestling telomere length or body condition, despite elevated blood lead concentrations close to the metal pollution source (mean ± SE = 0.270 ± 0.095 μg/g wet weight at the most polluted study site), suggesting that nestlings may have some capacity to detoxify metals. However, nestlings from nest boxes near roads exhibited more telomere shortening between days 8 and 15 of age, and shorter telomeres at day 15. Nestlings in poorer condition also had shorter telomeres, but proximity to the road was unrelated to body condition. Thus, nutritional stress is unlikely to mediate the relationship between proximity to roads and telomere length. Rather, proximity to roads could have affected telomere shortening by exposing nestlings to air or noise pollution. Our study highlights that traffic-related pollution, which is implicated in human health problems, might also affect urban wildlife.},
}
@article {pmid31664887,
year = {2019},
author = {Bizarro, J and Bhardwaj, A and Smith, S and Meier, UT},
title = {Nopp140-mediated concentration of telomerase in Cajal bodies regulates telomere length.},
journal = {Molecular biology of the cell},
volume = {30},
number = {26},
pages = {3136-3150},
pmid = {31664887},
issn = {1939-4586},
support = {R01 HL079566/HL/NHLBI NIH HHS/United States ; R01 CA116352/CA/NCI NIH HHS/United States ; R01 HL136662/HL/NHLBI NIH HHS/United States ; S10 OD016214/OD/NIH HHS/United States ; P30 CA013330/CA/NCI NIH HHS/United States ; R01 CA200751/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Coiled Bodies/*metabolism ; Dyskeratosis Congenita/genetics ; HeLa Cells ; Humans ; Molecular Chaperones/*genetics ; Nuclear Proteins/genetics/*metabolism ; Phosphoproteins/genetics/*metabolism ; RNA Interference ; RNA, Small Interfering/genetics ; Telomerase/genetics/*metabolism ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; },
abstract = {Cajal bodies (CBs) are nuclear organelles concentrating two kinds of RNA--protein complexes (RNPs), spliceosomal small nuclear (sn), and small CB-specific (sca)RNPs. Whereas the CB marker protein coilin is responsible for retaining snRNPs, the tether for scaRNPs is not known. Here we show that Nopp140, an intrinsically disordered CB phosphoprotein, is required to recruit and retain all scaRNPs in CBs. Knockdown (KD) of Nopp140 releases all scaRNPs leading to an unprecedented reduction in size of CB granules, hallmarks of CB ultrastructure. The CB-localizing protein WDR79 (aka TCAB1), which is mutated in the inherited bone marrow failure syndrome dyskeratosis congenita, is a specific component of all scaRNPs, including telomerase. Whereas mislocalization of telomerase by mutation of WDR79 leads to critically shortened telomeres, mislocalization of telomerase by Nopp140 KD leads to gradual extension of telomeres. Our studies suggest that the dynamic distribution of telomerase between CBs and nucleoplasm uniquely impacts telomere length maintenance and identify Nopp140 as a novel player in telomere biology.},
}
@article {pmid31663812,
year = {2019},
author = {O'Rourke, JJ and Bythell-Douglas, R and Dunn, EA and Deans, AJ},
title = {ALT control, delete: FANCM as an anti-cancer target in Alternative Lengthening of Telomeres.},
journal = {Nucleus (Austin, Tex.)},
volume = {10},
number = {1},
pages = {221-230},
pmid = {31663812},
issn = {1949-1042},
mesh = {DNA Helicases/*antagonists &amp; inhibitors/deficiency/*metabolism ; DNA Repair/drug effects ; DNA Replication/drug effects ; Humans ; Neoplasms/*drug therapy/*genetics/metabolism/pathology ; Telomere Homeostasis/*drug effects ; },
abstract = {Break-induced replication is a specific type of DNA repair that has a co-opted role in telomere extension by telomerase-negative cancer cells. This Alternative Lengthening of Telomeres (or 'ALT') is required for viability in approximately 10% of all carcinomas, but up to 50% of the soft-tissue derived sarcomas. In several recent studies, we and others demonstrate that expression and activity of FANCM, a DNA translocase protein, is essential for the viability of ALT-associated cancers. Here we provide a summary of how and why FANCM depletion leads to deletion of ALT-controlled cancers, predominantly through a hyper-activation of break-induced replication. We also discuss how FANCM can and has been targeted in cancer cell killing, including potential opportunities in ALT and other genetic backgrounds.},
}
@article {pmid31663728,
year = {2019},
author = {Saha, P and Kumar, YP and Das, T and Müller, D and Bessi, I and Schwalbe, H and Dash, J},
title = {G-Quadruplex-Specific Cell-Permeable Guanosine-Anthracene Conjugate Inhibits Telomere Elongation and Induces Apoptosis by Repressing the c-MYC Gene.},
journal = {Bioconjugate chemistry},
volume = {30},
number = {12},
pages = {3038-3045},
doi = {10.1021/acs.bioconjchem.9b00655},
pmid = {31663728},
issn = {1520-4812},
mesh = {Anthracenes/chemistry ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Membrane Permeability ; *G-Quadruplexes ; Genes, myc/*drug effects/genetics ; Guanosine/chemistry ; Humans ; Molecular Probes/*chemistry/metabolism/pharmacology ; Neoplasms/pathology ; Promoter Regions, Genetic/drug effects ; Telomere Homeostasis/*drug effects ; },
abstract = {We herein report a cell-membrane-permeable molecular probe ADG, prepared by conjugating guanosine with anthracene, selectively interacts with c-MYC G-quadruplex over other promoter and telomeric quadruplexes as well as duplex DNA. NMR spectroscopy suggests that ADG interacts with terminal G-quartets as well as with the nearby G-rich tract (G13-G14-G15 and G8-G9-G10) of c-MYC quadruplex. In vitro cellular studies indicate that ADG represses c-MYC expression by stabilizing its promoter G-quadruplex and alters c-MYC-related cellular events. ADG suppresses hTERT and BCL2 gene expressions in a promoter-independent manner, inhibits elongation of telomere length, and activates apoptotic cascades in cancer cells.},
}
@article {pmid31662013,
year = {2019},
author = {Liu, P and Zhang, Y and Ma, L},
title = {Telomere length and associated factors in older adults with hypertension.},
journal = {The Journal of international medical research},
volume = {47},
number = {11},
pages = {5465-5474},
pmid = {31662013},
issn = {1473-2300},
mesh = {Adult ; Aged ; Aging/metabolism/*pathology ; Humans ; Hypertension/*physiopathology ; *Oxidative Stress ; Telomerase/*metabolism ; *Telomere Homeostasis ; },
abstract = {Telomeres and telomerase play important roles in the occurrence and development of hypertension. This review was performed to clarify the factors that influence telomere length and telomerase activity in older patients and elucidate the association of these factors with hypertension. A PubMed search and critical review of studies assessing the risk factors underlying the association of hypertension with telomere length and telomerase activity was performed. Telomere length and telomerase activity were found to be associated with hypertension. The factors that influence telomere length and telomerase activity in older patients with hypertension include genetics, demographics, social and environmental factors, chronic disease, psychological factors, and antihypertensive drug treatment. A better understanding of the molecular mechanisms underlying the association of hypertension with telomere length and telomerase activity may help to reduce the incidence of hypertension.},
}
@article {pmid31658437,
year = {2020},
author = {Yeap, BB and Hui, J and Knuiman, MW and S A Paul, C and Ken K Y, H and Flicker, L and Divitini, ML and Arscott, GM and Twigg, SM and Almeida, OP and Hankey, GJ and Golledge, J and Beilby, JP},
title = {Associations of plasma IGF1, IGFBP3 and estradiol with leucocyte telomere length, a marker of biological age, in men.},
journal = {European journal of endocrinology},
volume = {182},
number = {1},
pages = {23-33},
doi = {10.1530/EJE-19-0638},
pmid = {31658437},
issn = {1479-683X},
mesh = {Aged ; Aged, 80 and over ; Biomarkers/*blood ; Estradiol/*blood ; Humans ; Immunoassay ; Insulin-Like Growth Factor Binding Protein 1/*blood ; Insulin-Like Growth Factor Binding Protein 3/*blood ; Insulin-Like Growth Factor I/*metabolism ; Leukocytes/*metabolism ; Male ; Risk Factors ; Telomere/*metabolism ; Testosterone/blood ; },
abstract = {OBJECTIVE: Effects of insulin-like growth factor 1 (IGF1) and its binding proteins (IGFBPs) on ageing, and their interaction with sex hormones, remain uncertain. We examined associations of plasma IGF1, IGFBP1, IGFBP3, estradiol and testosterone, with leucocyte telomere length (LTL), a marker of biological age, in 2999 community-dwelling men aged 70-84 years.<br><br>METHODS: Plasma IGF1, IGFBP1 and IGFBP3 measured using immunoassay, sex hormones using mass spectrometry. LTL measured by PCR, expressed as ratio of telomeric to single-copy control gene DNA (T/S ratio). Linear regression models adjusted for age and cardio-metabolic risk factors, median splits defined low/high groups.<br><br>RESULTS: Mean age was 76.7 &#xb1; 3.2 years. IGF1 and IGFBP3 showed age-adjusted correlations with LTL (coefficient 0.59, P = 0.001 and 0.45, P = 0.013 respectively), IGFBP1 did not. In multivariable-adjusted models IGF1 and IGFBP3 (but not IGFBP1) were associated with LTL (T/S ratio 0.015 higher per 1 s.d. increase in IGF1, P = 0.007, and 0.011 per 1 s.d. IGFBP3, P = 0.049). IGF1 and estradiol were independently associated with longer telomeres (T/S ratio 0.012 higher per 1 s.d. increase in estradiol, P = 0.027, when included in model with IGF1). Testosterone was not associated with LTL. Men with both high IGF1 (>133 &#xb5;g/L) and high estradiol (>70 pmol/L) had longer LTL compared to men with lower values (multivariable-adjusted T/S ratio 1.20 vs 1.16, P = 0.018).<br><br>CONCLUSIONS: Higher IGF1 and IGFBP3 are independently associated with longer telomeres in older men. Additive associations of higher IGF1 and higher estradiol with telomere length are present. Further studies are needed to determine whether these hormonal exposures cooperate to slow biological aging.},
}
@article {pmid31657606,
year = {2019},
author = {Navarro-Ibarra, MJ and Hernández, J and Caire-Juvera, G},
title = {Diet, physical activity and telomere length in adults.},
journal = {Nutricion hospitalaria},
volume = {36},
number = {6},
pages = {1403-1417},
doi = {10.20960/nh.02673},
pmid = {31657606},
issn = {1699-5198},
mesh = {Biomedical Research/trends ; *Diet ; *Exercise ; Fatty Acids, Essential ; Forecasting ; Humans ; Inflammation ; Micronutrients ; Oxidative Stress ; Telomere/*ultrastructure ; },
abstract = {Telomere length (TL) is a predictive biomarker of premature aging. Telomere shortening has been linked to age-related diseases and noncommunicable diseases (NCD), and may reflect the effects of behavioral, psychosocial and environmental factors on health status. Telomere attrition can be affected by lifestyle factors such as diet and physical activity. The search of studies included in this review was conducted on PubMed Central database. A majority of studies are cross-sectional, as there is a clear lack of prospective studies to evaluate the individual effect of dietary components, dietary patterns, and physical activity on TL in the long term. The current literature suggests that high adherence to Mediterranean diet (MD), with consumption of antioxidants, fiber and vegetables, as well as seeds and walnuts, is associated with longer TL. The dietary components of a healthy diet, such as carotenoids, vitamins A, C, D, E, polyphenols, fiber, and omega-3 fatty acids could help maintain TL. In contrast, a high consumption of sugary beverages, processed meat, and proinflammatory diets is associated with telomere shortening. In a majority of studies TL is positively associated with moderate physical activity. The predominant mechanisms through which a healthy diet and moderate physical exercise could mitigate telomere attrition include decreasing oxidative stress and inflammation. We shall not discuss the associations of possible risk or protective factors in terms of causality since the majority of studies are cross-sectional and randomized controlled trials are limited; accordingly, some results are inconclusive. For future research, we suggest evaluating the individual effects of dietary components, dietary patterns and physical activity, considering repeated measurements and exercise intensity, on TL. It is also advisable to include biomarkers of oxidative stress and inflammation proteins, and to measure telomerase activity.},
}
@article {pmid31653936,
year = {2019},
author = {Wang, H and Zhuang, Y and Peng, H and Cao, M and Li, Y and Xu, Q and Xin, X and Zhou, K and Liang, G and Cai, H and Dai, J},
title = {The relationship between MUC5B promoter, TERT polymorphisms and telomere lengths with radiographic extent and survival in a Chinese IPF cohort.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {15307},
pmid = {31653936},
issn = {2045-2322},
mesh = {Adult ; Aged ; Aged, 80 and over ; *Asian People ; Case-Control Studies ; Cohort Studies ; Female ; Gene Frequency/genetics ; Humans ; Idiopathic Pulmonary Fibrosis/*diagnostic imaging/*genetics ; Male ; Middle Aged ; Mucin-5B/*genetics ; Polymorphism, Single Nucleotide/*genetics ; *Promoter Regions, Genetic ; Proportional Hazards Models ; Survival Analysis ; Telomerase/*genetics ; *Telomere Homeostasis ; Tomography, X-Ray Computed ; },
abstract = {Genetic factors were identified to be associated with the development of idiopathic pulmonary fibrosis (IPF). We aimed to investigate associations between mucin 5B (MUC5B) and telomerase reverse transcriptase (TERT) polymorphisms and telomere length (TL) with honeycombing extent and survival in a Chinese IPF cohort. Seventy-nine patients diagnosed with IPF were enrolled. The honeycombing extents in high resolution CT scan (HRCT) were quantitatively scored and defined as mild (<10%), moderate (10-50%), and severe (>50%) upon the honeycombing extents involving the total lung. We tested five single-nucleotide polymorphisms [rs35705950, rs868903 in MUC5B, rs2736100, rs2853676 in TERT and rs1881984 in Telomerase RNA Gene (TERC) and TLs in peripheral blood leucocytes, and evaluated their associations with radiographic extent and survival in IPF. The minor allele frequencies (MAF) were significantly greater for MUC5B rs868903 (P = 0.042) and TERT rs2853676 (P = 0.041) in IPF than those in healthy controls. CT/CC genotype of MUC5B rs868903 (p = 0.045) and short TLs (p = 0.035) were correlated with the more extensive honeycombing opacities in HRCT. After adjustment for age, sex, and smoking status, MUC5B rs868903 polymorphism was the significant gene risk factors for reduced survival (p = 0.044) in IPF. MUC5B promoter rs868903 polymorphism and TLs were associated with radiographic extent and survival in a Chinese IPF cohort. These findings suggested a genetic clue for exploring the underlying molecular basis and pathogenesis of IPF.},
}
@article {pmid31652401,
year = {2019},
author = {Benetos, A and Verhulst, S and Labat, C and Lai, TP and Girerd, N and Toupance, S and Zannad, F and Rossignol, P and Aviv, A},
title = {Telomere length tracking in children and their parents: implications for adult onset diseases.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {33},
number = {12},
pages = {14248-14253},
pmid = {31652401},
issn = {1530-6860},
support = {R01 HD071180/HD/NICHD NIH HHS/United States ; R01 HL116446/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; *Aging ; Child ; Female ; Humans ; Longitudinal Studies ; Male ; Parents ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Adults with comparatively short or long leukocyte telomere length (LTL) typically continue to display comparatively short or long LTL throughout life. This LTL tracking stems from the inability of person-to-person variation in age-dependent LTL shortening during adulthood to offset the wide interindividual LTL variation established prior to adult life. However, LTL tracking in children is unstudied. This study aimed to examine LTL shortening rates and tracking in children and their parents. Longitudinal study in children (n = 67) and their parents (n = 99), whose ages at baseline were 11.4 ± 0.3 and 43.4 ± 0.4 yr, respectively. LTL was measured by Southern blotting at baseline and ∼14 yr thereafter. LTL displayed tracking in both children [intraclass correlation coefficient (ICC) = 0.905, P < 0.001] and their parents (ICC = 0.856, P < 0.001). The children's rate of LTL shortening was twice that of their parents (40.7 ± 2.5 bp/yr; 20.3 ± 2.1 bp/yr, respectively; P < 0.0001). LTL tracking applies not only to adulthood but also to the second decade of life. Coupled with previous work showing that the interindividual variation in LTL across newborns is as wide as in their parents, these findings support the thesis that the LTL-adult disease connection is principally determined before the second decade of life, perhaps mainly at birth.-Benetos, A., Verhulst, S., Labat, C., Lai, T.-P., Girerd, N., Toupance, S., Zannad, F., Rossignol, P., Aviv, A. Telomere length tracking in children and their parents: implications for adult onset diseases.},
}
@article {pmid31650883,
year = {2019},
author = {Alrefaei, GI and Alkarim, SA and Abduljabbar, HS},
title = {Impact of Mothers' Age on Telomere Length and Human Telomerase Reverse Transcriptase Expression in Human Fetal Membrane-Derived Mesenchymal Stem Cells.},
journal = {Stem cells and development},
volume = {28},
number = {24},
pages = {1632-1645},
doi = {10.1089/scd.2019.0144},
pmid = {31650883},
issn = {1557-8534},
mesh = {Adult ; Adult Stem Cells/*enzymology/metabolism ; Age Factors ; Cell Differentiation/genetics ; Cell Proliferation/genetics ; Extraembryonic Membranes/enzymology/growth &amp; development ; Female ; Flow Cytometry ; Humans ; Mesenchymal Stem Cells/*enzymology/metabolism ; Mothers ; Placenta/cytology ; Pregnancy ; Telomerase/*genetics ; Telomere/genetics ; Telomere Homeostasis/*genetics ; Umbilical Cord/growth &amp; development/metabolism ; },
abstract = {Age-related cellular changes and limited replicative capacity of adult mesenchymal stem cells (MSCs) are few of the challenges confronting stem cell research. MSCs from human fetal membranes (hFM-MSCs), including placental, umbilical cord, and amniotic membrane, are considered an alternative to adult MSCs. However, the effect of mothers' age on hFM-MSC cellular properties is still not clearly established. This study aimed to evaluate the effect of mothers' age on hFM-MSC telomere length, telomerase activity, and proliferation ability in three different age groups: GI (20-29 years), GII (30-39 years), and GIII (≥40 years). hFM samples were collected from pregnant women ≤37 weeks after obtaining consent. hFM-MSCs were isolated and cultured to characterize them by flow cytometry and assess proliferation by MTT assay and doubling time. Telomere length and expression levels of human telomerase reverse transcriptase were assessed by quantitative real-time polymerase chain reaction (qRT-RCR). hFM-MSCs in the three age groups were spindle-shaped, plastic-adherent, and exhibited high proliferation rates and strong expression of hMSC markers. GI showed the longest telomere length in hMSCs in various FM regions, whereas GIII showed the highest level of telomerase expression. There was no difference in telomere length between GII and GIII, and both groups showed the same hMSC characteristics. In conclusion, although the hFM-MSCs derived from different fetal membranes maintained the MSC characteristics in all study groups, the hFM-MSCs of older mothers had shorter telomeres and higher telomerase activity and proliferation rate than did those derived from younger mothers. Thus, the hFM-MSCs of older mothers could be unsuitable for expansion in vitro or stem cell therapy. Determination of telomere length and telomerase expression level of hFM might help characterizing and understanding the biological differences of hFM-MSCs in different age groups.},
}
@article {pmid31647584,
year = {2020},
author = {Ferreira, MSV and Kirschner, M and Halfmeyer, I and Estrada, N and Xicoy, B and Isfort, S and Vieri, M and Zamora, L and Abels, A and Bouillon, AS and Begemann, M and Schemionek, M and Maurer, A and Koschmieder, S and Wilop, S and Panse, J and Brümmendorf, TH and Beier, F},
title = {Comparison of flow-FISH and MM-qPCR telomere length assessment techniques for the screening of telomeropathies.},
journal = {Annals of the New York Academy of Sciences},
volume = {1466},
number = {1},
pages = {93-103},
doi = {10.1111/nyas.14248},
pmid = {31647584},
issn = {1749-6632},
mesh = {Adult ; Aged ; Bone Marrow Failure Disorders/diagnosis/genetics/pathology ; Case-Control Studies ; Cohort Studies ; Dyskeratosis Congenita/diagnosis/genetics/pathology ; Female ; Genetic Diseases, Inborn/*diagnosis/genetics/pathology ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Male ; Middle Aged ; Multiplex Polymerase Chain Reaction/*methods ; Real-Time Polymerase Chain Reaction/methods ; Telomere/*genetics ; Telomere Homeostasis/*physiology ; Telomere Shortening/genetics ; Young Adult ; },
abstract = {Assessment of telomere length (TL) in peripheral blood leukocytes is part of the diagnostic algorithm applied to patients with acquired bone marrow failure syndromes (BMFSs) and dyskeratosis congenita (DKC). Monochrome multiplex-quantitative polymerase chain reaction (MM-qPCR) and fluorescence in situ hybridization (flow-FISH) are methodologies available for TL screening. Dependent on TL expressed in relation to percentiles of healthy controls, further genetic testing for inherited mutations in telomere maintenance genes is recommended. However, the correct threshold to trigger this genetic workup is still under debate. Here, we prospectively compared MM-qPCR and flow-FISH regarding their capacity for accurate identification of DKC patients. All patients (n = 105) underwent genetic testing by next-generation sequencing and in 16 patients, mutations in DKC-relevant genes were identified. Whole leukocyte TL of patients measured by MM-qPCR was found to be moderately correlated with lymphocyte TL measured by flow-FISH (r[2] = 0.34; P < 0.0001). The sensitivity of both methods was high, but the specificity of MM-qPCR (29%) was significantly lower compared with flow-FISH (58%). These results suggest that MM-qPCR of peripheral blood cells is inferior to flow-FISH for clinical routine screening for suspected DKC in adult patients with BMFS due to lower specificity and a higher rate of false-positive results.},
}
@article {pmid31647544,
year = {2020},
author = {Wang, Z and Rice, SV and Chang, TC and Liu, Y and Liu, Q and Qin, N and Putnam, DK and Shelton, K and Lanctot, JQ and Wilson, CL and Ness, KK and Rusch, MC and Edmonson, MN and Wu, G and Easton, J and Kesserwan, CA and Downing, JR and Chen, X and Nichols, KE and Yasui, Y and Robison, LL and Zhang, J},
title = {Molecular Mechanism of Telomere Length Dynamics and Its Prognostic Value in Pediatric Cancers.},
journal = {Journal of the National Cancer Institute},
volume = {112},
number = {7},
pages = {756-764},
pmid = {31647544},
issn = {1460-2105},
support = {P30 CA014236/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Child ; Child, Preschool ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Mutation ; Neoplasms/*genetics ; Telomerase/genetics ; Telomere/*genetics ; *Telomere Homeostasis ; *Telomere Shortening ; Whole Genome Sequencing ; },
abstract = {BACKGROUND: We aimed to systematically evaluate telomere dynamics across a spectrum of pediatric cancers, search for underlying molecular mechanisms, and assess potential prognostic value.<br><br>METHODS: The fraction of telomeric reads was determined from whole-genome sequencing data for paired tumor and normal samples from 653 patients with 23 cancer types from the Pediatric Cancer Genome Project. Telomere dynamics were characterized as the ratio of telomere fractions between tumor and normal samples. Somatic mutations were gathered, RNA sequencing data for 330 patients were analyzed for gene expression, and Cox regression was used to assess the telomere dynamics on patient survival.<br><br>RESULTS: Telomere lengthening was observed in 28.7% of solid tumors, 10.5% of brain tumors, and 4.3% of hematological cancers. Among 81 samples with telomere lengthening, 26 had somatic mutations in alpha thalassemia/mental retardation syndrome X-linked gene, corroborated by a low level of the gene expression in the subset of tumors with RNA sequencing. Telomerase reverse transcriptase gene amplification and/or activation was observed in 10 tumors with telomere lengthening, including two leukemias of the E2A-PBX1 subtype. Among hematological cancers, pathway analysis for genes with expressions most negatively correlated with telomere fractions suggests the implication of a gene ontology process of antigen presentation by Major histocompatibility complex class II. A higher ratio of telomere fractions was statistically significantly associated with poorer survival for patients with brain tumors (hazard ratio = 2.18, 95% confidence interval = 1.37 to 3.46).<br><br>CONCLUSION: Because telomerase inhibitors are currently being explored as potential agents to treat pediatric cancer, these data are valuable because they identify a subpopulation of patients with reactivation of telomerase who are most likely to benefit from this novel therapeutic option.},
}
@article {pmid31647542,
year = {2019},
author = {Huang, YQ and Lo, K and Feng, YQ and Zhang, B},
title = {The association of mean telomere length with all-cause, cerebrovascular and cardiovascular mortality.},
journal = {Bioscience reports},
volume = {39},
number = {10},
pages = {},
pmid = {31647542},
issn = {1573-4935},
mesh = {Aged ; *Cerebrovascular Disorders/metabolism/mortality ; Disease-Free Survival ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Survival Rate ; Telomere/*metabolism ; *Telomere Homeostasis ; United States/epidemiology ; },
abstract = {Mean telomere length (MLT) is a marker of cell aging and may associate with age-related diseases. However, the relationship between MLT and mortality risk remains unclear. We aimed to investigate the relationship between MLT and all-cause, cerebrovascular and cardiovascular mortality among adults in United States. We analyzed data were from National Health and Nutrition Examination Survey (NHANES, 1999-2002) with follow-up data through 31 December 2015. Based on MLT, participants were categorized into low, middle and high groups. Multivariate Cox proportional hazards regression, subgroup analysis and generalized additive model (GAM) were performed by using hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 7827 participants were included in analysis (48.18% male). After 158.26 months of follow-up on average, there were 1876 (23.97%), 87 (1.11%) and 243 (3.10%) onset of all-cause, cerebrovascular and cardiovascular mortality. After adjustment for potential confounders, using the low group as the reference, HRs for all-cause (0.87 and 0.86), cerebrovascular (0.75 and 0.75) and cardiovascular mortality (1.01 and 0.69) for the middle to high groups were not statistically significant (all P>0.05 for trend). MLT was non-linearly related to all-cause mortality but not to cerebrovascular and cardiovascular mortality. It was the first study to demonstrate the non-linear relationship between MLT and all-cause mortality.},
}
@article {pmid31646458,
year = {2020},
author = {Liu, D and Zhu, Z and Zhou, L and Yang, M},
title = {The joint effects of frailty and telomere length for predicting mortality in older adults: the National Health and Nutrition Examination Survey 1999-2002.},
journal = {Aging clinical and experimental research},
volume = {32},
number = {9},
pages = {1839-1847},
pmid = {31646458},
issn = {1720-8319},
mesh = {Aged ; Aging/genetics ; Frail Elderly ; *Frailty/genetics ; Humans ; Mortality ; Nutrition Surveys ; Proportional Hazards Models ; Telomere/genetics ; },
abstract = {BACKGROUND: Frailty and short telomere length, which address different aspects of biological aging, are separately associated with mortality in older adults.<br><br>AIMS: To evaluate whether the combination of these two biomarkers would be a better predictor of mortality than either alone.<br><br>METHODS: This present study included participants 60&#xa0;years of age or older from the National Health and Nutrition Examination Survey in the 1999-2002 phase. The frailty phenotype was identified based on the Fried definition. Telomere length relative to standard reference DNA (T/S ratio) was assessed using quantitative polymerase chain reaction (PCR). Cox proportional hazards regression models were used to estimate the individual and combined effects of frailty phenotype and telomere length on all-cause and cardiovascular mortality.<br><br>RESULTS: Compared with participants with neither impairment, the mortality risks increased slightly among participants with short telomere length only (hazard ratio [HR] 1.19, 95% confidence interval [CI]: 1.00-1.42) or pre-frailty only (HR 2.16, 95% CI 1.80-2.60) and gradually elevated approximately 3 folds with both short telomere length and pre-frailty (HR 2.23, 95% CI 1.81-2.74) or frailty (HR 3.57, 95% CI 2.56-4.98). Moreover, participants with both short telomere length and frailty had the highest increased all-cause mortality (HR 5.16, 95% CI 3.38-7.85) and cardiovascular mortality (HR 4.67, 95% CI 2.02-10.82).<br><br>DISCUSSION AND CONCLUSIONS: The combined predictor had more capability of predicting mortality, which suggested that integrating both molecular biomarkers and physiological functional parameters would be a more informative measure of biological aging.},
}
@article {pmid31646401,
year = {2020},
author = {Gedvilaite, G and Vilkeviciute, A and Kriauciuniene, L and Banevičius, M and Liutkeviciene, R},
title = {The relationship between leukocyte telomere length and TERT, TRF1 single nucleotide polymorphisms in healthy people of different age groups.},
journal = {Biogerontology},
volume = {21},
number = {1},
pages = {57-67},
doi = {10.1007/s10522-019-09843-0},
pmid = {31646401},
issn = {1573-6768},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; DNA Replication ; Female ; Genotype ; Humans ; Leukocytes/cytology ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Shortening ; Telomeric Repeat Binding Protein 1/*genetics ; Young Adult ; },
abstract = {Telomeres are nucleoprotein structures that cap the end of each chromosome and function to maintain genome stability. The length of telomeres is known to shorten with each cell division and it is well-established that telomere attrition is related to replicative capacity in vitro. Moreover, telomere loss is also correlated with the process of aging in vivo. That is why we aimed to find any associations of leukocyte telomere shortening with different age groups. We enrolled 291 healthy people in a study group. Samples of DNA from peripheral blood leukocytes were purified by the DNA salting-out method. The genotyping was carried out using the real-time polymerase chain reaction. The results were assessed using the statistical analysis software ''IBM SPSS Statistics 23.0". To determine the relationship between the leukocyte telomere length and single nucleotide polymorphisms of TERT and TRF1 and the age of healthy individuals. The relative leukocyte telomere length (T/S) measurement was performed in study subjects and compared between different age groups. We found that T/S in the first age group was statistically significantly higher than in the second group (p = 0.040), while in the second and the third age groups T/S was statistically significantly lower than in the fourth age group (p < 0.001 and p = 0.001 respectively). There was also a weak negative but statistically significant inverse correlation between the age of the subjects and the length of telomeres (p = 0.025). We found that TRF1 rs10107605 CC genotype was statistically significantly more frequent in subjects with long telomeres than in subjects with short telomeres (p = 0.009). The TRF1 rs10107605 CC genotype compared to AA genotype was associated with 75% decreased odds of telomere shortening (p = 0.017), and the CC genotype compared to AA + AC genotypes was associated with 75% decreased odds (p = 0.014). T/S correlates with age negatively. The frequencies of genotypes and alleles of TERT rs2736098, rs401681 and TRF1 rs1545827 did not differ between different age groups. The TRF1 rs10107605 polymorphism is associated with telomere shortening.},
}
@article {pmid31645360,
year = {2019},
author = {Keener, R and Connelly, CJ and Greider, CW},
title = {Tel1 Activation by the MRX Complex Is Sufficient for Telomere Length Regulation but Not for the DNA Damage Response in Saccharomyces cerevisiae.},
journal = {Genetics},
volume = {213},
number = {4},
pages = {1271-1288},
pmid = {31645360},
issn = {1943-2631},
support = {T32 GM007445/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Motifs ; *DNA Damage ; Intracellular Signaling Peptides and Proteins/*metabolism ; Multiprotein Complexes/*metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases/*metabolism ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; Signal Transduction ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Previous models suggested that regulation of telomere length in Saccharomyces cerevisiae by Tel1(ATM) and Mec1(ATR) would parallel the established pathways regulating the DNA damage response. Here, we provide evidence that telomere length regulation differs from the DNA damage response in both the Tel1 and Mec1 pathways. We found that Rad53 mediates a Mec1 telomere length regulation pathway but is dispensable for Tel1 telomere length regulation, whereas in the DNA damage response, Rad53 is regulated by both Mec1 and Tel1 Using epistasis analysis with a Tel1 hypermorphic allele, Tel1-hy909, we found that the MRX complex is not required downstream of Tel1 for telomere elongation but is required downstream of Tel1 for the DNA damage response. Our data suggest that nucleolytic telomere end processing is not a required step for telomerase to elongate telomeres.},
}
@article {pmid31645134,
year = {2019},
author = {Yang, L and Liu, X and Song, L and Su, G and Di, A and Bai, C and Wei, Z and Li, G},
title = {Inhibiting repressive epigenetic modification promotes telomere rejuvenation in somatic cell reprogramming.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {33},
number = {12},
pages = {13982-13997},
doi = {10.1096/fj.201901486RR},
pmid = {31645134},
issn = {1530-6860},
mesh = {Animals ; *Cellular Reprogramming ; Cloning, Organism ; Embryo Culture Techniques ; Embryo, Mammalian/*drug effects ; Embryonic Development/drug effects ; Epigenetic Repression/*drug effects ; Melatonin/pharmacology ; Mice ; Oxidative Stress/drug effects ; Telomere/*physiology ; },
abstract = {The efficiency of somatic cell nuclear transfer (SCNT) reprogramming is extremely low in terms of production of cloned animals. Here, we found that telomere rejuvenation is a critical event for SCNT reprogramming. Through small-molecule screening, we identified that melatonin significantly improved the in vitro and in vivo developmental competence of SCNT-derived embryos. Through use of embryonic biopsy, single-cell RNA sequencing, and quantitative FISH experiments, we revealed that melatonin not only attenuated the zygotic genome activation defect but also facilitated telomere elongation in the SCNT embryos. Further investigation indicated that melatonin inhibited heterochromatic epigenetic modification related to gene silencing including DNA methylation and histone H3 lysine 9 trimethylation. In addition, melatonin could increase the level of activation markers such as acetylated histone H3. This is the first study to characterize melatonin-treatment and telomere rejuvenation in SCNT-mediated reprogramming. Moreover, combinational use of melatonin-treated donor embryos and pseudopregnant recipients achieved synergistic enhancement of the production of cloned animals.-Yang, L., Liu, X., Song, L., Su, G., Di, A., Bai, C., Wei, Z., Li, G. Inhibiting repressive epigenetic modification promotes telomere rejuvenation in somatic cell reprogramming.},
}
@article {pmid31640985,
year = {2019},
author = {Hailemariam, S and De Bona, P and Galletto, R and Hohl, M and Petrini, JH and Burgers, PM},
title = {The telomere-binding protein Rif2 and ATP-bound Rad50 have opposing roles in the activation of yeast Tel1[ATM] kinase.},
journal = {The Journal of biological chemistry},
volume = {294},
number = {49},
pages = {18846-18852},
pmid = {31640985},
issn = {1083-351X},
support = {R35 GM118129/GM/NIGMS NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; U54 OD020355/OD/NIH HHS/United States ; R37 GM059413/GM/NIGMS NIH HHS/United States ; R01 GM098509/GM/NIGMS NIH HHS/United States ; R01 GM059413/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA-Binding Proteins/*metabolism ; Intracellular Signaling Peptides and Proteins/*metabolism ; Protein Serine-Threonine Kinases/*metabolism ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomere/metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Saccharomyces cerevisiae Tel1 is the ortholog of human ATM kinase and initiates a cell cycle checkpoint in response to dsDNA breaks (DSBs). Tel1[ATM] kinase is activated synergistically by naked dsDNA and the Mre11-Rad50-Xrs2[NBS1] complex (MRX). A multisubunit protein complex, which is related to human shelterin, protects telomeres from being recognized as DSBs, thereby preventing a Tel1[ATM] checkpoint response. However, at very short telomeres, Tel1[ATM] can be recruited and activated by the MRX complex, resulting in telomere elongation. Conversely, at long telomeres, Rap1-interacting-factor 2 (Rif2) is instrumental in suppressing Tel1 activity. Here, using an in vitro reconstituted Tel1 kinase activation assay, we show that Rif2 inhibits MRX-dependent Tel1 kinase activity. Rif2 discharges the ATP-bound form of Rad50, which is essential for all MRX-dependent activities. This conclusion is further strengthened by experiments with a Rad50 allosteric ATPase mutant that maps outside the conserved ATP binding pocket. We propose a model in which Rif2 attenuates Tel1 activity at telomeres by acting directly on Rad50 and discharging its activated ATP-bound state, thereby rendering the MRX complex incompetent for Tel1 activation. These findings expand our understanding of the mechanism by which Rif2 controls telomere length.},
}
@article {pmid31637754,
year = {2020},
author = {Denham, J},
title = {Telomere regulation: lessons learnt from mice and men, potential opportunities in horses.},
journal = {Animal genetics},
volume = {51},
number = {1},
pages = {3-13},
doi = {10.1111/age.12870},
pmid = {31637754},
issn = {1365-2052},
mesh = {Animals ; Genomic Instability ; Horses/*genetics ; Humans ; Telomere/*ultrastructure ; *Telomere Shortening ; },
abstract = {Telomeres are genetically conserved nucleoprotein complexes located at the ends of chromosomes that preserve genomic stability. In large mammals, somatic cell telomeres shorten with age, owing to the end replication problem and lack of telomere-lengthening events (e.g. telomerase and ALT activity). Therefore, telomere length reflects cellular replicative reserve and mitotic potential. Environmental insults can accelerate telomere attrition in response to cell division and DNA damage. As such, telomere shortening is considered one of the major hallmarks of ageing. Much effort has been dedicated to understanding the environmental perturbations that accelerate telomere attrition and therapeutic strategies to preserve or extend telomeres. As telomere dynamics seem to reflect cumulative cellular stress, telomere length could serve as a biomarker of animal welfare. The assessment of telomere dynamics (i.e. rate of shortening) in conjunction with telomere-regulating genes and telomerase activity in racehorses could monitor long-term animal health, yet it could also provide some unique opportunities to address particular limitations with the use of other animal models in telomere research. Considering the ongoing efforts to optimise the health and welfare of equine athletes, the purpose of this review is to discuss the potential utility of assessing telomere length in Thoroughbred racehorses. A brief review of telomere biology in large and small mammals will be provided, followed by discussion on the biological implications of telomere length and environmental (e.g. lifestyle) factors that accelerate or attenuate telomere attrition. Finally, the utility of quantifying telomere dynamics in horses will be offered with directions for future research.},
}
@article {pmid31634774,
year = {2020},
author = {Germann, CB},
title = {The Psilocybin-Telomere Hypothesis: An empirically falsifiable prediction concerning the beneficial neuropsychopharmacological effects of psilocybin on genetic aging.},
journal = {Medical hypotheses},
volume = {134},
number = {},
pages = {109406},
doi = {10.1016/j.mehy.2019.109406},
pmid = {31634774},
issn = {1532-2777},
mesh = {Aging/*drug effects/genetics/psychology ; Aging, Premature/drug therapy/genetics/prevention &amp; control ; Animals ; Anxiety/drug therapy/genetics ; Brain-Derived Neurotrophic Factor/physiology ; Consciousness/drug effects ; DNA Methylation/drug effects ; Depression/drug therapy/genetics ; Disease Models, Animal ; Endocrine System/physiopathology ; Humans ; *Models, Genetic ; *Models, Psychological ; Neurotransmitter Agents/physiology ; Oxidative Stress/drug effects ; Personality/drug effects ; Psilocybin/pharmacology/*therapeutic use ; Psychotropic Drugs/pharmacology/*therapeutic use ; Research Design ; Serotonin Plasma Membrane Transport Proteins/physiology ; Stress, Psychological/drug therapy/genetics ; Telomere Shortening/*drug effects/physiology ; },
abstract = {We introduce a novel hypothesis which states that the therapeutic utilisation of psilocybin has beneficial effects on genetic aging. Ex hypothesi, we predict a priori that controlled psilocybin interventions exert quantifiable positive impact on leucocyte telomere length (telomeres are a robust predictor of mortality and multifarious aging-related diseases). Our hypothesising follows the Popperian logic of scientific discovery, viz., bold (and refutable) conjectures form the very foundation of scientific progress. The 'psilocybin-telomere hypothesis' is formalised as a logically valid deductive (syllogistic) argument and we provide substantial evidence to support the underlying premises. Impetus for our theorising derives from a plurality of converging empirical sources indicating that psilocybin has persistent beneficial effects on various aspects of mental health (e.g., in the context of depression, anxiety, PTSD, OCD, addiction, etc.). Additional support is based on a large corpus of studies that establish reliable correlations between mental health and telomere attrition (improved mental health is generally correlated with longer telomeres). Another pertinent component of our argument is based on recent studies which demonstrate that "meditative states of consciousness" provide beneficial effects on genetic aging. Similarly, psilocybin can induce states of consciousness that are neurophysiologically and phenomenologically significantly congruent with meditative states. Furthermore, prior research has demonstrated that a single dose of psilocybin can occasion life-changing transformative experiences (≈ 70% of healthy volunteers rate their experience with psilocybin amongst the five personally most meaningful lifetime events, viz., ranked next to giving birth to a child or losing a loved one). We postulate that these profound psychological events leave quantifiable marks at the molecular genetic/epigenetic level. Given the ubiquitous availability and cost effectiveness of telomere length assays, we suggest that quantitative telomere analysis should be regularly included in future psilocybin studies as an adjunctive biological marker (i.e., to facilitate scientific consilience via methodological triangulation). In order to substantiate the 'psilocybin-telomere hypothesis' potential neuropsychopharmacological, endocrinological, and genetic mechanisms of action are discussed (e.g., HPA-axis reactivity, hippocampal neurogenesis, neurotropic growth factors such as BDNF, 5-HT2A receptor agonism, neuroplasticity/synaptoplasticity, brain-wide alterations in neuronal functional connectivity density, involvement of the SLC6A4 serotonin transporter gene, inter alia). The proposed research agenda is thus intrinsically highly interdisciplinary, and it has deep ramifications from a philosophy of science perspective as it connects the epistemic level (qualitative experiential phenomenology) with the ontic level (quantitative molecular genetics) of analysis. In the long term, multidisciplinary and innovative investigations of the 'psilocybin-telomere hypothesis' could contribute to the improvement of senotherapeutic psychological interventions and the identification of novel geroprotective and neuroprotective/restorative pharmaceutical targets to decelerate genetic aging and improve well-being and quality of life during the aging process.},
}
@article {pmid31633821,
year = {2019},
author = {Victorelli, S and Lagnado, A and Halim, J and Moore, W and Talbot, D and Barrett, K and Chapman, J and Birch, J and Ogrodnik, M and Meves, A and Pawlikowski, JS and Jurk, D and Adams, PD and van Heemst, D and Beekman, M and Slagboom, PE and Gunn, DA and Passos, JF},
title = {Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction.},
journal = {The EMBO journal},
volume = {38},
number = {23},
pages = {e101982},
pmid = {31633821},
issn = {1460-2075},
support = {BB/K017314/1//UK Research and Innovation|Biotechnology and Biological Sciences Research Council (BBSRC)/International ; //Ted Nash Foundation/International ; P01 AG031862/AG/NIA NIH HHS/United States ; //Unilever/International ; PD1921//Glenn Foundation for Medical Research (Glenn Foundation)/International ; BB/L502066/1//UK Research and Innovation|Biotechnology and Biological Sciences Research Council (BBSRC)/International ; UL1TR002377//National Center for Advancing Translational Science (NCATS)/International ; UL1 TR002377/TR/NCATS NIH HHS/United States ; SBF003_1179/AMS_/Academy of Medical Sciences/United Kingdom ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/drug effects/*pathology ; Atrophy/chemically induced/*pathology ; Cells, Cultured ; *Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Epidermis/drug effects/pathology ; Female ; Humans ; Male ; Melanocytes/metabolism/*pathology ; Middle Aged ; Paracrine Communication ; Reactive Oxygen Species/metabolism ; Receptors, CXCR4/metabolism ; Skin/metabolism/*pathology ; Telomere/metabolism/*pathology ; Young Adult ; },
abstract = {Cellular senescence has been shown to contribute to skin ageing. However, the role of melanocytes in the process is understudied. Our data show that melanocytes are the only epidermal cell type to express the senescence marker p16[INK4A] during human skin ageing. Aged melanocytes also display additional markers of senescence such as reduced HMGB1 and dysfunctional telomeres, without detectable telomere shortening. Additionally, senescent melanocyte SASP induces telomere dysfunction in paracrine manner and limits proliferation of surrounding cells via activation of CXCR3-dependent mitochondrial ROS. Finally, senescent melanocytes impair basal keratinocyte proliferation and contribute to epidermal atrophy in vitro using 3D human epidermal equivalents. Crucially, clearance of senescent melanocytes using the senolytic drug ABT737 or treatment with mitochondria-targeted antioxidant MitoQ suppressed this effect. In conclusion, our study provides proof-of-concept evidence that senescent melanocytes affect keratinocyte function and act as drivers of human skin ageing.},
}
@article {pmid31633067,
year = {2019},
author = {Spindler, MC and Redolfi, J and Helmprobst, F and Kollmannsberger, P and Stigloher, C and Benavente, R},
title = {Electron tomography of mouse LINC complexes at meiotic telomere attachment sites with and without microtubules.},
journal = {Communications biology},
volume = {2},
number = {},
pages = {376},
pmid = {31633067},
issn = {2399-3642},
mesh = {Animals ; Binding Sites ; Cell Cycle Proteins/metabolism ; Chromosome Pairing ; Cytoskeletal Proteins/metabolism ; Electron Microscope Tomography ; Male ; Meiosis ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Microtubule-Associated Proteins/metabolism ; Microtubules/metabolism/*ultrastructure ; Multiprotein Complexes/metabolism/ultrastructure ; Nuclear Envelope/metabolism/ultrastructure ; Nuclear Proteins/metabolism ; Telomere/metabolism/*ultrastructure ; Telomere-Binding Proteins/metabolism ; Testis/metabolism/ultrastructure ; },
abstract = {Telomere movements during meiotic prophase I facilitate synapsis and recombination of homologous chromosomes. Hereby, chromosome movements depend on the dynamic attachment of meiotic telomeres to the nuclear envelope and generation of forces that actively move the telomeres. In most eukaryotes, forces that move telomeres are generated in the cytoplasm by microtubule-associated motor proteins and transduced into the nucleus through the LINC complexes of the nuclear envelope. Meiotic LINC complexes, in mouse comprised of SUN1/2 and KASH5, selectively localize to the attachment sites of meiotic telomeres. For a better understanding of meiotic telomere dynamics, here we provide quantitative information of telomere attachment sites that we have generated with the aid of electron microscope tomography (EM tomography). Our data on the number, length, width, distribution and relation with microtubules of the reconstructed structures indicate that an average number of 76 LINC complexes would be required to move a telomere attachment site.},
}
@article {pmid31633027,
year = {2019},
author = {Xu, M and Qin, J and Wang, L and Lee, HJ and Kao, CY and Liu, D and Songyang, Z and Chen, J and Tsai, MJ and Tsai, SY},
title = {Nuclear receptors regulate alternative lengthening of telomeres through a novel noncanonical FANCD2 pathway.},
journal = {Science advances},
volume = {5},
number = {10},
pages = {eaax6366},
pmid = {31633027},
issn = {2375-2548},
support = {R01 CA211653/CA/NCI NIH HHS/United States ; R01 HL114539/HL/NHLBI NIH HHS/United States ; P01 DK059820/DK/NIDDK NIH HHS/United States ; P30 CA125123/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Motifs ; COUP Transcription Factor II/antagonists &amp; inhibitors/genetics/*metabolism ; Cell Line, Tumor ; DNA Polymerase III/metabolism ; DNA Repair ; DNA-Binding Proteins/metabolism ; Endonucleases/metabolism ; Fanconi Anemia/genetics/pathology ; Fanconi Anemia Complementation Group D2 Protein/antagonists &amp; inhibitors/genetics/*metabolism ; G2 Phase ; Humans ; Mutagenesis, Site-Directed ; Nuclear Receptor Subfamily 2, Group C, Member 2/antagonists &amp; inhibitors/genetics/*metabolism ; Proliferating Cell Nuclear Antigen/chemistry/metabolism ; Protein Binding ; RNA Interference ; RNA, Small Interfering/metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Alternative lengthening of telomeres (ALT) is known to use homologous recombination (HR) to replicate telomeric DNA in a telomerase-independent manner. However, the detailed process remains largely undefined. It was reported that nuclear receptors COUP-TFII and TR4 are recruited to the enriched GGGTCA variant repeats embedded within ALT telomeres, implicating nuclear receptors in regulating ALT activity. Here, we identified a function of nuclear receptors in ALT telomere maintenance that involves a direct interaction between COUP-TFII/TR4 and FANCD2, the key protein in the Fanconi anemia (FA) DNA repair pathway. The COUP-TFII/TR4-FANCD2 complex actively induces the DNA damage response by recruiting endonuclease MUS81 and promoting the loading of the PCNA-POLD3 replication complex in ALT telomeres. Furthermore, the COUP-TFII/TR4-mediated ALT telomere pathway does not require the FA core complex or the monoubiquitylation of FANCD2, key steps in the canonical FA pathway. Thus, our findings reveal that COUP-TFII/TR4 regulates ALT telomere maintenance through a novel noncanonical FANCD2 pathway.},
}
@article {pmid31630890,
year = {2019},
author = {Niu, Z and Li, K and Xie, C and Wen, X},
title = {Adverse Birth Outcomes and Birth Telomere Length: A Systematic Review and Meta-Analysis.},
journal = {The Journal of pediatrics},
volume = {215},
number = {},
pages = {64-74.e6},
doi = {10.1016/j.jpeds.2019.08.040},
pmid = {31630890},
issn = {1097-6833},
mesh = {Fetal Growth Retardation/*genetics ; Gestational Age ; Humans ; Infant, Newborn ; *Infant, Small for Gestational Age ; *Premature Birth ; Telomere/*genetics ; },
abstract = {OBJECTIVES: To synthesize previous findings on the difference in birth telomere length between newborns with and without intrauterine growth restriction (IUGR) or with and without preterm birth.<br><br>STUDY DESIGN: We systematically searched 3 databases (PubMed, Embase, and Web of Science) for publications that examined the relationships of IUGR or preterm birth with birth telomere length. We conducted meta-analysis to pool the estimated difference in birth telomere length either between IUGR and non-IUGR or between preterm birth and full-term birth. Subgroup analyses were conducted by tissues (newborn blood vs placenta) and techniques used for telomere length measurement (quantitative polymerase chain reaction [qPCR] vs telomere restriction fragment).<br><br>RESULTS: We included 11 articles on comparing birth telomere length between IUGR (combined n&#xa0;=&#xa0;227) and non-IUGR (n&#xa0;=&#xa0;1897) and 7 articles on comparing birth telomere length between preterm birth (n&#xa0;=&#xa0;182) and full-term birth (n&#xa0;=&#xa0;1320). We found IUGR was associated with shorter birth telomere length only when birth telomere length was measured in placenta (pooled standardized mean difference [SMD]&#xa0;=&#xa0;-0.85; 95% CI -1.13 to -0.57; IUGR/non-IUGR n&#xa0;=&#xa0;87/173), but not in newborn blood (pooled SMD&#xa0;=&#xa0;0.00, 95% CI -0.18 to 0.19; IUGR/non-IUGR n&#xa0;=&#xa0;148/1733). Birth telomere length was significantly longer in preterm birth than in full-term birth when birth telomere length was measured by qPCR (pooled SMD&#xa0;=&#xa0;0.40, 95% CI 0.18-0.63; preterm birth/full-term birth n&#xa0;=&#xa0;137/682) but not by telomere restriction fragment (pooled SMD&#xa0;=&#xa0;0.05, 95% CI -0.29 to 0.38; preterm birth/full-term birth n&#xa0;=&#xa0;44/444).<br><br>CONCLUSIONS: IUGR is associated with shorter placental telomere length and preterm birth is associated with longer birth telomere length measured by qPCR.},
}
@article {pmid31628984,
year = {2020},
author = {Humphreys, KL and Sisk, LM and Manczak, EM and Lin, J and Gotlib, IH},
title = {Depressive Symptoms Predict Change in Telomere Length and Mitochondrial DNA Copy Number Across Adolescence.},
journal = {Journal of the American Academy of Child and Adolescent Psychiatry},
volume = {59},
number = {12},
pages = {1364-1370.e2},
pmid = {31628984},
issn = {1527-5418},
support = {F32 MH107129/MH/NIMH NIH HHS/United States ; R37 MH101495/MH/NIMH NIH HHS/United States ; T32 MH019938/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Child ; Cross-Sectional Studies ; DNA Copy Number Variations/genetics ; DNA, Mitochondrial/genetics ; *Depression/genetics ; *Depressive Disorder, Major ; Female ; Humans ; Male ; Prospective Studies ; Telomere/genetics ; },
abstract = {OBJECTIVE: Several studies have found associations between a diagnosis or symptoms of major depressive disorder and markers of cellular aging and dysfunction. These investigations, however, are predominantly cross-sectional and focus on adults. In the present study, we used a prospective longitudinal design to test the cross-sectional association between depressive symptoms in adolescents and telomere length (TL) as well as mitochondrial DNA copy number (mtDNA-cn).<br><br>METHOD: A total of 121 adolescents (mean age&#xa0;= 11.38 years, SD&#xa0;= 1.03; 39% male adolescents and 61% female adolescents) were followed for approximately 2 years. At baseline and follow-up, participants provided saliva for DNA extraction, from which measures of TL and mtDNA-cn were obtained. Depressive symptoms were obtained via the Children's Depression Inventory.<br><br>RESULTS: There was no association between depressive symptoms and markers of cellular aging at baseline; however, depressive symptoms at baseline predicted higher rates of telomere erosion (&#x3b2;&#xa0;=&#xa0;-0.201, p&#xa0;= .016) and greater increases in mtDNA-cn (&#x3b2;&#xa0;= 0.190, p&#xa0;= .012) over the follow-up period. Markers of cellular aging at baseline did not predict subsequent changes in depressive symptoms. Furthermore, including the number of stressful life events did not alter these patterns of findings.<br><br>CONCLUSION: These results indicate that depressive symptoms precede changes in cellular aging and dysfunction, rather than the reverse.},
}
@article {pmid31625455,
year = {2020},
author = {Amir, M and Mohammad, T and Prasad, K and Hasan, GM and Kumar, V and Dohare, R and Islam, A and Ahmad, F and Imtaiyaz Hassan, M},
title = {Virtual high-throughput screening of natural compounds in-search of potential inhibitors for protection of telomeres 1 (POT1).},
journal = {Journal of biomolecular structure &amp; dynamics},
volume = {38},
number = {15},
pages = {4625-4634},
doi = {10.1080/07391102.2019.1682052},
pmid = {31625455},
issn = {1538-0254},
mesh = {*High-Throughput Screening Assays ; *Telomere ; Telomere-Binding Proteins/genetics ; },
abstract = {Communicated by Ramaswamy H. Sarma.},
}
@article {pmid31624261,
year = {2019},
author = {Muñoz-Lorente, MA and Cano-Martin, AC and Blasco, MA},
title = {Mice with hyper-long telomeres show less metabolic aging and longer lifespans.},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {4723},
pmid = {31624261},
issn = {2041-1723},
mesh = {Aging/*genetics/metabolism ; Animals ; DNA Damage ; Embryonic Stem Cells/*metabolism ; Humans ; Longevity/*genetics ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Transgenic ; Neoplasms/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Short telomeres trigger age-related pathologies and shorter lifespans in mice and humans. In the past, we generated mouse embryonic (ES) cells with longer telomeres than normal (hyper-long telomeres) in the absence of genetic manipulations, which contributed to all mouse tissues. To address whether hyper-long telomeres have deleterious effects, we generated mice in which 100% of their cells are derived from hyper-long telomere ES cells. We observe that these mice have longer telomeres and less DNA damage with aging. Hyper-long telomere mice are lean and show low cholesterol and LDL levels, as well as improved glucose and insulin tolerance. Hyper-long telomere mice also have less incidence of cancer and an increased longevity. These findings demonstrate that longer telomeres than normal in a given species are not deleterious but instead, show beneficial effects.},
}
@article {pmid31622416,
year = {2019},
author = {Wan, ES and Goldstein, RL and Fan, VS and Nguyen, HQ and Hart, JE and Garshick, E and Orr, EH and DeVivo, I and Moy, ML},
title = {Telomere length in COPD: Relationships with physical activity, exercise capacity, and acute exacerbations.},
journal = {PloS one},
volume = {14},
number = {10},
pages = {e0223891},
pmid = {31622416},
issn = {1932-6203},
support = {UL1 RR025014/RR/NCRR NIH HHS/United States ; IK2 RX002165/RX/RRD VA/United States ; R01 HL093146/HL/NHLBI NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; I21 RX002197/RX/RRD VA/United States ; },
mesh = {Accelerometry ; Aged ; Aged, 80 and over ; Exercise Tolerance ; Female ; Humans ; Male ; Middle Aged ; Observational Studies as Topic ; Prognosis ; Prospective Studies ; Pulmonary Disease, Chronic Obstructive/*genetics/physiopathology ; Quality of Life ; Telomere/*metabolism ; Walk Test/*instrumentation ; },
abstract = {RATIONALE: Shorter leukocyte telomere length (LTL) is associated with reduced health-related quality of life and increased risk for acute exacerbations (AEs) and mortality in chronic obstructive pulmonary disease (COPD). Increased physical activity and exercise capacity are associated with reduced risk for AEs and death. However, the relationships between LTL and physical activity, exercise capacity, and AEs in COPD are unknown.<br><br>METHODS: Data from 3 COPD cohorts were examined: Cohort 1 (n = 112, physical activity intervention trial), Cohorts 2 and 3 (n = 182 and 294, respectively, separate observational studies). Subjects completed a 6-minute walk test (6MWT) and provided blood for LTL assessment using real-time PCR. Physical activity was measured as average daily step count using an accelerometer or pedometer. Number of self-reported AEs was available for 1) the year prior to enrollment (Cohorts 1 and 3) and 2) prospectively after enrollment (all cohorts). Multivariate models examined associations between LTL and average daily step count, 6MWT distance, and AEs.<br><br>RESULTS: A significant association between longer LTL and increased 6MWT distance was observed in the three combined cohorts (&#x3b2; = 3x10-5, p = 0.045). No association between LTL and average daily step count was observed. Shorter LTL was associated with an increased number of AEs in the year prior to enrollment (Cohorts 1 and 3 combined, &#x3b2; = -1.93, p = 0.04) and with prospective AEs (Cohort 3, &#x3b2; = -1.3388, p = 0.0003).<br><br>CONCLUSIONS: Among COPD patients, increased LTL is associated with higher exercise capacity, but not physical activity. Shorter LTL was associated with AEs in a subgroup of cohorts.},
}
@article {pmid31620874,
year = {2019},
author = {Fitzpatrick, LJ and Olsson, M and Parsley, LM and Pauliny, A and Pinfold, TL and Pirtle, T and While, GM and Wapstra, E},
title = {Temperature and telomeres: thermal treatment influences telomere dynamics through a complex interplay of cellular processes in a cold-climate skink.},
journal = {Oecologia},
volume = {191},
number = {4},
pages = {767-776},
pmid = {31620874},
issn = {1432-1939},
support = {Endeavour Research Fellowship//Australia Awards/ ; W0024143//Holsworth Wildlife Research Endowment/ ; },
mesh = {Animals ; Cold Climate ; Cold Temperature ; *Lizards ; *Telomere ; Temperature ; },
abstract = {Telomere dynamics vary fundamentally between endothermic populations and species as a result of differences in life history, yet we know little about these patterns in ectotherms. In ectotherms, the relationships between climate, metabolism and life history suggest that telomere attrition should be higher at relatively high environmental temperatures compared to relatively low environmental temperatures, but these effects may vary between populations due to local adaptation. To address this hypothesis, we sampled reactive oxygen species (ROS) and telomere length of lizards from warm lowland and cool highland populations of a climatically widespread lizard species that we exposed to hot or cold basking treatments. The hot treatment increased relative telomere length compared to the cold treatment independent of climatic origin or ROS levels. Lizards from the cool highland region had lower ROS levels than those from the warm lowland region. Within the highland lizards, ROS increased more in the cold basking treatment than the hot basking treatment. These results are in the opposite direction to those predicted, suggesting that the relationships between temperature, metabolism, ROS and telomere dynamics are not straightforward. Future work incorporating detailed understanding of the thermal reaction norms of these and other linked traits is needed to fully understand these processes.},
}
@article {pmid31619475,
year = {2020},
author = {Liu, S and Wang, C and Green, G and Zhuo, H and Liu, KD and Kangelaris, KN and Gomez, A and Jauregui, A and Vessel, K and Ke, S and Hendrickson, C and Matthay, MA and Calfee, CS and Ware, LB and Wolters, PJ},
title = {Peripheral blood leukocyte telomere length is associated with survival of sepsis patients.},
journal = {The European respiratory journal},
volume = {55},
number = {1},
pages = {},
pmid = {31619475},
issn = {1399-3003},
support = {R01 HL135849/HL/NHLBI NIH HHS/United States ; R35 HL140026/HL/NHLBI NIH HHS/United States ; R01 HL051856/HL/NHLBI NIH HHS/United States ; R01 HL131621/HL/NHLBI NIH HHS/United States ; K23 HL133495/HL/NHLBI NIH HHS/United States ; R37 HL051856/HL/NHLBI NIH HHS/United States ; R01 HL139897/HL/NHLBI NIH HHS/United States ; K24 HL103836/HL/NHLBI NIH HHS/United States ; },
mesh = {Cohort Studies ; Humans ; Leukocytes ; Prospective Studies ; *Sepsis/genetics ; *Telomere ; },
abstract = {Shorter peripheral blood leukocyte (PBL) telomere length (TL) has been associated with poor outcomes in various chronic lung diseases. Whether PBL-TL is associated with survival from critical illness was tested in this study.We analysed data from a prospective observational cohort study of 937 critically ill patients at Vanderbilt University Medical Center (VUMC). PBL-TL was measured using quantitative PCR of DNA isolated from PBLs. Findings were validated in an independent cohort of 394 critically ill patients with sepsis admitted to the University of California San Francisco (UCSF).In the VUMC cohort, shorter PBL-TL was associated with worse 90-day survival (adjusted hazard ratio (aHR) 1.3, 95% CI 1.1-1.6 per 1 kb TL decrease; p=0.004); in subgroup analyses, shorter PBL-TL was associated with worse 90-day survival for patients with sepsis (aHR 1.5, 95% CI 1.2-2.0 per 1 kb TL decrease; p=0.001), but not trauma. Although not associated with development of acute respiratory distress syndrome (ARDS), among ARDS subjects, shorter PBL-TL was associated with more severe ARDS (OR 1.7, 95% CI 1.2-2.5 per 1 kb TL decrease; p=0.006). The associations of PBL-TL with survival (adjusted HR 1.6, 95% CI 1.2-2.1 per 1 kb TL decrease; p=0.003) and risk for developing severe ARDS (OR 2.5, 95% CI 1.1-6.3 per 1 kb TL decrease; p=0.044) were validated in the UCSF cohort.Short PBL-TL is strongly associated with worse survival and more severe ARDS in critically ill patients, especially patients with sepsis. These findings suggest that telomere dysfunction may contribute to outcomes from critical illness.},
}
@article {pmid31616780,
year = {2019},
author = {Perera, ON and Sobinoff, AP and Teber, ET and Harman, A and Maritz, MF and Yang, SF and Pickett, HA and Cesare, AJ and Arthur, JW and MacKenzie, KL and Bryan, TM},
title = {Telomerase promotes formation of a telomere protective complex in cancer cells.},
journal = {Science advances},
volume = {5},
number = {10},
pages = {eaav4409},
pmid = {31616780},
issn = {2375-2548},
mesh = {Cell Line, Tumor ; DNA Damage ; Gene Expression Regulation ; HSP70 Heat-Shock Proteins/genetics/*metabolism ; Humans ; Inhibitor of Apoptosis Proteins/genetics/metabolism ; Neoplasms/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomerase is a ribonucleoprotein complex that catalyzes addition of telomeric DNA repeats to maintain telomeres in replicating cells. Here, we demonstrate that the telomerase protein hTERT performs an additional role at telomeres that is independent of telomerase catalytic activity yet essential for telomere integrity and cell proliferation. Short-term depletion of endogenous hTERT reduced the levels of heat shock protein 70 (Hsp70-1) and the telomere protective protein Apollo at telomeres, and induced telomere deprotection and cell cycle arrest, in the absence of telomere shortening. Short-term expression of hTERT promoted colocalization of Hsp70-1 with telomeres and Apollo and reduced numbers of deprotected telomeres, in a manner independent of telomerase catalytic activity. These data reveal a previously unidentified noncanonical function of hTERT that promotes formation of a telomere protective complex containing Hsp70-1 and Apollo and is essential for sustained proliferation of telomerase-positive cancer cells, likely contributing to the known cancer-promoting effects of both hTERT and Hsp70-1.},
}
@article {pmid31616481,
year = {2019},
author = {Parolini, M and Possenti, CD and Romano, A and Caprioli, M and Rubolini, D and Saino, N},
title = {Perinatal variation and covariation of oxidative status and telomere length in yellow-legged gull chicks.},
journal = {Current zoology},
volume = {65},
number = {5},
pages = {509-516},
pmid = {31616481},
issn = {1674-5507},
abstract = {The perinatal period is critical to survival and performance of many organisms. In birds, rapid postnatal growth and sudden exposure to aerial oxygen around hatching markedly affect the chick redox status, with potentially negative consequences on physiology mediated by oxidative stress. In addition, telomere length (TL) undergoes reduction during birds' early life, partly depending on oxidative status. However, relatively few studies have focused specifically on the changes in oxidative status and TL that occur immediately after hatching. In this study of the yellow-legged gull Larus michahellis, we found that chicks undergo a marked increase in plasma total antioxidant capacity and a marked decrease in the concentration of pro-oxidant molecules during the first days after hatching. In addition, TL in erythrocytes decreased by 1 standard deviation over the 4 days post-hatching. Body mass and tarsus length covaried with total antioxidant capacity and concentration of pro-oxidants in a complex way, that partly depended on sex and laying order, suggesting that oxidative status can affect growth. Moreover, TL positively covaried with the concentration of pro-oxidant molecules, possibly because retention of high concentrations of pro-oxidant molecules results from mechanisms of prevention of their negative effects, including reduction in TL. Thus, this study shows that chicks undergo marked variation in oxidative status, which predicts growth and subsequent TL, prompting for more studies of the perinatal changes in the critical post-hatching stages.},
}
@article {pmid31614016,
year = {2019},
author = {Li, W and Mjekiqi, E and Douma, W and Wang, X and Kavatsyuk, O and Hoekstra, R and Poully, JC and Schlathölter, T},
title = {Hole Migration in Telomere-Based Oligonucleotide Anions and G-Quadruplexes.},
journal = {Chemistry (Weinheim an der Bergstrasse, Germany)},
volume = {25},
number = {70},
pages = {16114-16119},
pmid = {31614016},
issn = {1521-3765},
support = {a//Chinese Government Scholarship/ ; },
abstract = {Vacuum ultraviolet photoionization of a gas-phase oligonucleotide anion leads to the formation of a valence hole. This hole migrates towards an energetically favorable site where it can weaken bonds and ultimately lead to bond cleavage. We have studied Vacuum UV photoionization of deprotonated oligonucleotides containing the human telomere sequence dTTAGGG and G-quadruplex structures consisting of four dTGGGGT single strands, stabilized by NH4 [+] counter ions. The oligonucleotide and G-quadruplex anions were confined in a radiofrequency ion trap, interfaced with a synchrotron beamline and the photofragmentation was studied using time-of-flight mass spectrometry. Oligonucleotide 12-mers containing the 5'-TTAGGG sequence were found to predominantly break in the GGG region, whereas no selective bond cleavage region was observed for the reversed 5'-GGGATT sequence. For G-quadruplex structures, fragmentation was quenched and mostly non-dissociative single and double electron removal was observed.},
}
@article {pmid31613132,
year = {2020},
author = {Leibel, DK and Shaked, D and Beatty Moody, DL and Liu, HB and Weng, NP and Evans, MK and Zonderman, AB and Waldstein, SR},
title = {Telomere length and cognitive function: Differential patterns across sociodemographic groups.},
journal = {Neuropsychology},
volume = {34},
number = {2},
pages = {186-198},
pmid = {31613132},
issn = {1931-1559},
support = {//National Institutes of Health; National Institute on Aging; Intramural Research Program/ ; P30 AG028747/AG/NIA NIH HHS/United States ; R01 AG034161/AG/NIA NIH HHS/United States ; //University of Maryland; Claude D. Pepper Older Americans Independence Center/ ; Z01 AG000513-07/ImNIH/Intramural NIH HHS/United States ; /NH/NIH HHS/United States ; ZIA AG000513/ImNIH/Intramural NIH HHS/United States ; K01 AG043581/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; *Black or African American ; *Attention ; *Cognition ; *Executive Function ; Female ; Humans ; Leukocytes, Mononuclear/*metabolism ; Male ; Memory ; Mental Recall ; Middle Aged ; Neuropsychological Tests ; *Poverty ; Telomere/*metabolism ; Trail Making Test ; *White People ; },
abstract = {OBJECTIVE: The present study investigates whether associations between telomere length (TL) and cognitive performance across multiple domains are moderated by poverty status and race.<br><br>METHOD: Participants were 325 African American and White urban-dwelling adults (M age = 47.9 years; 49.5% African American; 50.2% female; 48.9% living in poverty) from the Healthy Aging in Neighborhoods of Diversity across the Life Span study. TL was assayed from peripheral blood mononuclear cells using quantitative polymerase chain reactions. Multivariable regression analyses examined interactions of TL, poverty status, and race with performance on the following cognitive tests: Trail-Making Test Parts A and B, Digit Span Forward and Backward, semantic verbal fluency, Brief Test of Attention, Benton Visual Retention Test (BVRT), and California Verbal Learning Test-II total learning, short-delay free recall, and long-delay free recall scores. Analyses adjusted for age, sex, and high school-or-greater educational attainment.<br><br>RESULTS: Significant three-way interactions of TL &#xd7; Poverty Status &#xd7; Race revealed that, among White participants living in poverty, shorter TL was associated with worse performance on Digit Span Forward and Backward (ps<.05). Additionally, significant two-way interactions of TL &#xd7; Poverty Status revealed that, among all participants living in poverty, shorter TL was associated with worse performance on the Trail-Making Test Part B and the BVRT (ps<.05).<br><br>CONCLUSIONS: TL may be differentially associated with aspects of attention, executive functioning, and memory among individuals living in poverty, who may be uniquely vulnerable to adverse effects of shorter telomeres. Replication of these findings is needed to determine their generalizability. (PsycINFO Database Record (c) 2020 APA, all rights reserved).},
}
@article {pmid31612868,
year = {2019},
author = {Min, J and Shay, JW},
title = {Telomere clustering drives ALT.},
journal = {Aging},
volume = {11},
number = {19},
pages = {8046-8047},
pmid = {31612868},
issn = {1945-4589},
mesh = {Humans ; Neoplasms/*metabolism ; Protein Engineering ; Telomere/*physiology ; *Telomere Homeostasis ; },
}
@article {pmid31612326,
year = {2019},
author = {Kärkkäinen, T and Teerikorpi, P and Panda, B and Helle, S and Stier, A and Laaksonen, T},
title = {Impact of continuous predator threat on telomere dynamics in parent and nestling pied flycatchers.},
journal = {Oecologia},
volume = {191},
number = {4},
pages = {757-766},
pmid = {31612326},
issn = {1432-1939},
support = {658085//H2020 Marie Sk&#x142;odowska-Curie Actions/ ; None//Koneen S&#xe4;&#xe4;ti&#xf6;/ ; None//Finnish Society for Nature Conservation/ ; None//Kuopio Naturalists' Society/ ; None//Turun Yliopisto/ ; },
mesh = {Animals ; Female ; Male ; *Passeriformes ; Predatory Behavior ; *Songbirds ; Telomere ; Telomere Shortening ; },
abstract = {In addition to direct mortality, predators can have indirect effects on prey populations by affecting prey behaviour or physiology. For example, predator presence can increase stress hormone levels, which can have physiological costs. Stress exposure accelerates the shortening of telomeres (i.e. the protective caps of chromosomes) and shorter telomeres have been linked to increased mortality risk. However, the effect of perceived predation risk on telomeres is not known. We investigated the effects of continuous predator threat (nesting Eurasian pygmy owl Glaucidium passerinum) on telomere dynamics of both adult and partially cross-fostered nestling pied flycatchers (Ficedula hypoleuca) in the wild. Females nesting at owl-inhabited sites showed impaired telomere maintenance between incubation and chick rearing compared to controls, and both males and females ended up with shorter telomeres at owl-inhabited sites in the end of chick rearing. On the contrary, both original and cross-fostered chicks reared in owl sites had consistently longer telomeres during growth than chicks reared at control sites. Thus, predation risk may cause a long-term cost in terms of telomeres for parents but not for their offspring. Predators may therefore affect telomere dynamics of their preys, which could have implications for their ageing rate and consequently for population dynamics.},
}
@article {pmid31611308,
year = {2019},
author = {Graham, MK and Kim, J and Da, J and Brosnan-Cashman, JA and Rizzo, A and Baena Del Valle, JA and Chia, L and Rubenstein, M and Davis, C and Zheng, Q and Cope, L and Considine, M and Haffner, MC and De Marzo, AM and Meeker, AK and Heaphy, CM},
title = {Functional Loss of ATRX and TERC Activates Alternative Lengthening of Telomeres (ALT) in LAPC4 Prostate Cancer Cells.},
journal = {Molecular cancer research : MCR},
volume = {17},
number = {12},
pages = {2480-2491},
pmid = {31611308},
issn = {1557-3125},
support = {F32 CA213742/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; R01 CA172380/CA/NCI NIH HHS/United States ; T32 CA009110/CA/NCI NIH HHS/United States ; },
mesh = {CRISPR-Cas Systems/genetics ; Cell Line, Tumor ; Chromatin Assembly and Disassembly/genetics ; Chromosomal Instability/genetics ; Gene Expression Regulation, Neoplastic/genetics ; Gene Knockout Techniques ; Humans ; Male ; Mutation ; Prostate/metabolism/pathology ; Prostatic Neoplasms/*genetics/pathology ; RNA/*genetics ; Telomerase/*genetics ; Telomere/genetics ; Telomere Homeostasis/*genetics ; X-linked Nuclear Protein/*genetics ; },
abstract = {A key hallmark of cancer, unlimited replication, requires cancer cells to evade both replicative senescence and potentially lethal chromosomal instability induced by telomere dysfunction. The majority of cancers overcome these critical barriers by upregulating telomerase, a telomere-specific reverse transcriptase. However, a subset of cancers maintains telomere lengths by the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway. The presence of ALT is strongly associated with recurrent cancer-specific somatic inactivating mutations in the ATRX-DAXX chromatin-remodeling complex. Here, we generate an ALT-positive adenocarcinoma cell line following functional inactivation of ATRX and telomerase in a telomerase-positive adenocarcinoma cell line. Inactivating mutations in ATRX were introduced using CRISPR-cas9 nickase into two prostate cancer cell lines, LAPC-4 (derived from a lymph node metastasis) and CWR22Rv1 (sourced from a xenograft established from a primary prostate cancer). In LAPC-4, but not CWR22Rv1, abolishing ATRX was sufficient to induce multiple ALT-associated hallmarks, including the presence of ALT-associated promyelocytic leukemia bodies (APB), extrachromosomal telomere C-circles, and dramatic telomere length heterogeneity. However, telomerase activity was still present in these ATRX[KO] cells. Telomerase activity was subsequently crippled in these LAPC-4 ATRX[KO] cells by introducing mutations in the TERC locus, the essential RNA component of telomerase. These LAPC-4 ATRX[KO] TERC[mut] cells continued to proliferate long-term and retained ALT-associated hallmarks, thereby demonstrating their reliance on the ALT mechanism for telomere maintenance. IMPLICATIONS: These prostate cancer cell line models provide a unique system to explore the distinct molecular alterations that occur upon induction of ALT, and may be useful tools to screen for ALT-specific therapies.},
}
@article {pmid31610015,
year = {2019},
author = {Lamprokostopoulou, A and Moschonis, G and Manios, Y and Critselis, E and Nicolaides, NC and Stefa, A and Koniari, E and Gagos, S and Charmandari, E},
title = {Childhood obesity and leucocyte telomere length.},
journal = {European journal of clinical investigation},
volume = {49},
number = {12},
pages = {e13178},
doi = {10.1111/eci.13178},
pmid = {31610015},
issn = {1365-2362},
mesh = {Adolescent ; Aging/*metabolism ; Body Mass Index ; Case-Control Studies ; Child ; Female ; Greece ; Humans ; Leukocytes/*metabolism ; Linear Models ; Male ; Multiplex Polymerase Chain Reaction ; Multivariate Analysis ; Pediatric Obesity/*metabolism ; Real-Time Polymerase Chain Reaction ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Obesity in adulthood is associated with decreased leucocyte telomere length (LTL), which is associated with cardiovascular disease and diabetes mellitus type 2. The aim of our study was to investigate whether increased body mass index (BMI) is associated with decreased LTL in children and adolescents, and to identify other risk factors of shorter LTL in this population.<br><br>MATERIALS AND METHODS: A cross-sectional study was conducted among 919 Greek children aged 9-13&#xa0;years (The Healthy Growth Study). Participants were classified as obese (n&#xa0;=&#xa0;124), overweight (n&#xa0;=&#xa0;276) or of normal BMI (n&#xa0;=&#xa0;519). LTL was determined by monochrome multiplex quantitative real-time polymerase chain reaction. Univariate and multivariable linear regression analyses were applied to determine the predictive factors of LTL.<br><br>RESULTS: Both overweight and obese children had significantly shorter LTL than their normal-BMI counterparts. Following adjustment for age, sex, total daily energy intake and average weekly physical activity (average total steps per day), increasing weight category was inversely associated with LTL in children and adolescents (&#x3b2;: -0.110&#xa0;&#xb1;&#xa0;0.035; P&#xa0;=&#xa0;.002).<br><br>CONCLUSION: Overweight and obesity in childhood and adolescence are associated with shorter LTL, even following adjustment for potential confounding effects. Therefore, the increased BMI in childhood and adolescence may be associated with accelerated biological ageing and may have an adverse impact on future health in adulthood.},
}
@article {pmid31605466,
year = {2019},
author = {Cao, X and Huang, M and Zhu, M and Fang, R and Ma, Z and Jiang, T and Dai, J and Ma, H and Jin, G and Shen, H and Du, J and Xu, L and Hu, Z},
title = {Mendelian randomization study of telomere length and lung cancer risk in East Asian population.},
journal = {Cancer medicine},
volume = {8},
number = {17},
pages = {7469-7476},
pmid = {31605466},
issn = {2045-7634},
support = {2017YFC0907905//National Key Research and Development Program of China/International ; BK20160046//Science Foundation for Distinguished Young Scholars in Jiangsu/International ; 81521004//National Natural Science of China/International ; PPZY2015A067//Top-notch Academic Programs Project of Jiangsu Higher Education Institutions/International ; KYZZ15_0268//Innovation of Graduate Student Training Project in Jiangsu Province/International ; //Priority Academic Program Development of Jiangsu Higher Education Institutions/International ; },
mesh = {Adenocarcinoma of Lung/epidemiology/*genetics ; Asian People/genetics ; Carcinoma, Squamous Cell/epidemiology/*genetics ; Case-Control Studies ; Asia, Eastern/epidemiology ; *Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Lung Neoplasms/epidemiology/*genetics ; Mendelian Randomization Analysis ; Odds Ratio ; Polymorphism, Single Nucleotide ; Risk Factors ; Telomere/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Associations between telomere length and cancer risk have been investigated in many epidemiological studies, but the results are controversial. These associations may be biased by reverse causation or confounded by environmental exposures. To avoid potential biases, we used Mendelian randomization method to evaluate whether TL is the causal risk factor for lung cancer. We conducted Mendelian randomization analysis in two published East Asian GWAS studies (7127 cases and 6818 controls). We used both weighted genetic risk score and inverse-variance weighting method to estimate the relationship between TL and lung cancer risk. Nonlinear test also used to detect potential association trends. We observed that increased weight GRS was associated with increased risk of lung cancer (OR = 2.25, 95%CI: 1.81-2.78, P = 1.18 × 10[-13]). In different subtypes, weight GRS was significantly associated with lung adenocarcinoma risk (OR = 2.69, 95% CI: 2.11-3.42, P = 7.20 × 10[-16]); while lung squamous cell carcinoma showed a marginal association (OR = 1.45, 95% CI = 1.01-2.10, P = .047). Nonlinear analysis suggested a log-linear dose-response relationship between increased weight GRS and lung cancer risk. Our results indicated that longer TL increases lung cancer risk. Those biological mechanisms changes caused by long TL may play an important role in lung carcinogenesis.},
}
@article {pmid31603979,
year = {2021},
author = {Demanelis, K and Tong, L and Pierce, BL},
title = {Genetically Increased Telomere Length and Aging-Related Traits in the U.K. Biobank.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {76},
number = {1},
pages = {15-22},
pmid = {31603979},
issn = {1758-535X},
support = {MC_QA137853/MRC_/Medical Research Council/United Kingdom ; R01 ES020506/ES/NIEHS NIH HHS/United States ; T32 AG000243/AG/NIA NIH HHS/United States ; MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; R35 ES028379/ES/NIEHS NIH HHS/United States ; U01 HG007601/HG/NHGRI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging/*genetics ; Biological Specimen Banks ; Female ; Humans ; Male ; Mendelian Randomization Analysis ; Middle Aged ; Prospective Studies ; *Telomere Homeostasis ; United Kingdom ; },
abstract = {Telomere length (TL) shortens over time in most human cell types and is a potential biomarker of aging. However, the causal association of TL on physical and cognitive traits that decline with age has not been extensively examined in middle-aged adults. Using a Mendelian randomization (MR) approach, we utilized genetically increased TL (GI-TL) to estimate the impact of TL on aging-related traits among U.K. Biobank (UKB) participants (age 40-69 years). We manually curated 53 aging-related traits from the UKB and restricted to unrelated participants of British ancestry (n = 337,522). We estimated GI-TL as a linear combination of nine TL-associated single nucleotide polymorphisms (SNPs), each weighted by its previously-reported association with leukocyte TL. Regression models were used to assess the associations between GI-TL and each trait. We obtained MR estimates using the two-sample inverse variance weighted (IVW) approach. We identified six age-related traits associated with GI-TL (Bonferroni-corrected threshold p < .001): pulse pressure (PP) (p = 5.2 × 10-14), systolic blood pressure (SBP) (p = 2.9 × 10-15), diastolic blood pressure (DBP) (p = 5.5 × 10-6), hypertension (p = 5.5 × 10-11), forced expiratory volume (FEV1) (p = .0001), and forced vital capacity (FVC) (p = 3.8 × 10-6). Under MR assumptions, one standard deviation increase in TL (~1,200 base pairs) increased PP, SBP, and DBP by 1.5, 2.3, and 0.8 mmHg, respectively, while FEV1 and FVC increased by 34.7 and 52.2 mL, respectively. The observed associations appear unlikely to be due to selection bias based on analyses including inverse probability weights and analyses of simulated data. These findings suggest that longer TL increases pulmonary function and blood pressure traits among middle-aged UKB participants.},
}
@article {pmid31603943,
year = {2019},
author = {Rosero-Bixby, L and Rehkopf, DH and Dow, WH and Lin, J and Epel, ES and Azofeifa, J and Leal, A},
title = {Correlates of longitudinal leukocyte telomere length in the Costa Rican Longevity Study of Healthy Aging (CRELES): On the importance of DNA collection and storage procedures.},
journal = {PloS one},
volume = {14},
number = {10},
pages = {e0223766},
pmid = {31603943},
issn = {1932-6203},
support = {072406/Z/03/Z/WT_/Wellcome Trust/United Kingdom ; R01 AG031716/AG/NIA NIH HHS/United States ; P30 AG012839/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; K01 AG047280/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Blood Specimen Collection/*methods ; Costa Rica ; DNA/*standards ; Female ; Healthy Aging ; Humans ; Leukocytes/*chemistry ; *Longevity ; Longitudinal Studies ; Male ; Middle Aged ; Regression Analysis ; Telomere/*genetics ; Telomere Homeostasis ; Time Factors ; },
abstract = {The objective is to identify cofactors of leukocyte telomere length (LTL) in a Latin American population, specifically the association of LTL with 36 socio-demographic, early childhood, and health characteristics, as well as with DNA sample collection and storage procedures. The analysis is based on longitudinal information from a subsample of 1,261 individuals aged 60+ years at baseline from the Costa Rican Study of Longevity and Healthy Aging (CRELES): a nationally representative sample of elderly population. Random effects regression models for panel data were used to estimate the associations with LTL and its longitudinal changes. Sample collection procedures and DNA refrigerator storage time were strongly associated with LTL: telomeres are longer in blood collected in October-December, in DNA extracted from <1-year-old blood cells, and in DNA stored at 4°C for longer periods of time up to five years. The data confirmed that telomeres are shorter at older ages, as well as among males, and diabetic individuals, whereas telomeres are longer in the high-longevity Nicoya region. Most health, biomarkers, and early childhood indicators did not show significant associations with LTL. Longitudinal LTL variation over approximately two years was mainly associated with baseline LTL levels, as found in other studies. Our findings suggest that if there is unavoidable variability in season of sample collection and DNA storage time, these factors should be controlled for in all demographic and epidemiologic studies of LTL. However, due to unobserved components of measurement variation, statistical control may be inadequate as compared to standardization of data collection procedures.},
}
@article {pmid31601364,
year = {2019},
author = {Walker, AE and Fenstermacher, E and Ross, DA},
title = {Telomeres, Trauma, and Training.},
journal = {Biological psychiatry},
volume = {86},
number = {9},
pages = {e29-e30},
doi = {10.1016/j.biopsych.2019.08.019},
pmid = {31601364},
issn = {1873-2402},
support = {R44 MH115546/MH/NIMH NIH HHS/United States ; },
mesh = {*Cellular Senescence ; *Telomere ; },
}
@article {pmid31595153,
year = {2019},
author = {Li, P and Meng, Y and Wang, Y and Li, J and Lam, M and Wang, L and Di, LJ},
title = {Nuclear localization of Desmoplakin and its involvement in telomere maintenance.},
journal = {International journal of biological sciences},
volume = {15},
number = {11},
pages = {2350-2362},
pmid = {31595153},
issn = {1449-2288},
mesh = {CRISPR-Cas Systems ; Cell Line, Tumor ; Cell Nucleus/*metabolism ; DNA Damage ; Desmoplakins/chemistry/metabolism/*physiology ; HEK293 Cells ; Humans ; Telomerase/metabolism ; Telomere/metabolism ; *Telomere Homeostasis ; Telomere Shortening ; Telomere-Binding Proteins/chemistry/metabolism/*physiology ; },
abstract = {The interaction between genomic DNA and protein fundamentally determines the activity and the function of DNA elements. Capturing the protein complex and identifying the proteins associated with a specific DNA locus is difficult. Herein, we employed CRISPR, the well-known gene-targeting tool in combination with the proximity-dependent labeling tool BioID to capture a specific genome locus associated proteins and to uncover the novel functions of these proteins. By applying this research tool on telomeres, we identified DSP, out of many others, as a convincing telomere binding protein validated by both biochemical and cell-biological approaches. We also provide evidence to demonstrate that the C-terminal domain of DSP is required for its binding to telomere after translocating to the nucleus mediated by NLS sequence of DSP. In addition, we found that the telomere binding of DSP is telomere length dependent as hTERT inhibition or knockdown caused a decrease of telomere length and diminished DSP binding to the telomere. Knockdown of TRF2 also negatively influenced DSP binding to the telomere. Functionally, loss of DSP resulted in the shortened telomere DNA and induced the DNA damage response and cell apoptosis. In conclusion, our studies identified DSP as a novel potential telomere binding protein and highlighted its role in protecting against telomere DNA damage and resultant cell apoptosis.},
}
@article {pmid31594634,
year = {2020},
author = {Lara-Molina, EE and Franasiak, JM and Marin, D and Tao, X and Díaz-Gimeno, P and Florensa, M and Martin, M and Seli, E and Pellicer, A},
title = {Cumulus cells have longer telomeres than leukocytes in reproductive-age women.},
journal = {Fertility and sterility},
volume = {113},
number = {1},
pages = {217-223},
doi = {10.1016/j.fertnstert.2019.08.089},
pmid = {31594634},
issn = {1556-5653},
mesh = {Adolescent ; Adult ; Cumulus Cells/*physiology ; Female ; Humans ; Leukocytes/*physiology ; Oocyte Donation/methods ; *Proof of Concept Study ; Prospective Studies ; Reproduction/*physiology ; Telomere/physiology ; Telomere Homeostasis/*physiology ; Young Adult ; },
abstract = {OBJECTIVE: To investigate whether telomere length (TL) in granulosa cells (GC) or cumulus cells (CC) correlates with TL in leukocytes (L).<br><br>DESIGN: Prospective noninterventional study.<br><br>SETTING: Private assisted reproductive technology center.<br><br>PATIENT(S): Thirty-five egg donors were included in the study.<br><br>INTERVENTIONS(S): None.<br><br>MAIN OUTCOME MEASURE(S): Average relative leukocyte telomere length (LTL), cumulus cell telomere length (CCTL), and granulosa cell telomere length (GCTL) measurements from each study subject.<br><br>RESULT(S): Participants had a mean age of 25.43 &#xb1; 4.57&#xa0;years, antim&#xfc;llerian hormone level of 1.90 &#xb1; 0.92&#xa0;ng/mL, antral follicle count of 23.29 &#xb1; 5.11, and the mean number of mature oocytes retrieved was 23.29 &#xb1; 9.13. No significant association between these variables and GCTL, CCTL, or LTL was found. In addition, no correlation was observed between TL measurements of L vs. CC, L vs. GC, or CC vs. GC. Interestingly, CCTL was significantly higher than LTL (1.54-fold), although no significant differences were found between GCTL vs. CCTL or GCTL vs. LTL.<br><br>CONCLUSION(S): CC from mature follicles have significantly longer telomeres than L, suggesting that the follicular environment could possess different mechanisms to cope against telomere shortening compared with other somatic tissues. Furthermore, these data do not support the utility of telomere DNA measurement in L as an estimate of TL in follicular cells.},
}
@article {pmid31585101,
year = {2019},
author = {Barroso-González, J and García-Expósito, L and Hoang, SM and Lynskey, ML and Roncaioli, JL and Ghosh, A and Wallace, CT and Modesti, M and Bernstein, KA and Sarkar, SN and Watkins, SC and O'Sullivan, RJ},
title = {RAD51AP1 Is an Essential Mediator of Alternative Lengthening of Telomeres.},
journal = {Molecular cell},
volume = {76},
number = {1},
pages = {217},
doi = {10.1016/j.molcel.2019.08.009},
pmid = {31585101},
issn = {1097-4164},
support = {R01 CA207209/CA/NCI NIH HHS/United States ; },
}
@article {pmid31579434,
year = {2019},
author = {Grozeva, S and Anokhin, BA and Simov, N and Kuznetsova, VG},
title = {New evidence for the presence of the telomere motif (TTAGG) n in the family Reduviidae and its absence in the families Nabidae and Miridae (Hemiptera, Cimicomorpha).},
journal = {Comparative cytogenetics},
volume = {13},
number = {3},
pages = {283-295},
pmid = {31579434},
issn = {1993-0771},
abstract = {Male karyotype and meiosis in four true bug species belonging to the families Reduviidae, Nabidae, and Miridae (Cimicomorpha) were studied for the first time using Giemsa staining and FISH with 18S ribosomal DNA and telomeric (TTAGG)n probes. We found that Rhynocoris punctiventris (Herrich-Schäffer, 1846) and R. iracundus (Poda, 1761) (Reduviidae: Harpactorinae) had 2n = 28 (24 + X1X2X3Y), whereas Nabis sareptanus Dohrn, 1862 (Nabidae) and Horistus orientalis (Gmelin, 1790) (Miridae) had 2n = 34 (32 + XY) and 2n = 32 (30 + XY), respectively. FISH for 18S rDNA revealed hybridization signals on a sex chromosome, the X or the Y, in H. orientalis, on both X and Y chromosomes in N. sareptanus, and on two of the four sex chromosomes, Y and one of the Xs, in both species of Rhynocoris Hahn, 1834. The results of FISH with telomeric probes support with confidence the absence of the "insect" telomere motif (TTAGG)n in the families Nabidae and Miridae and its presence in both species of genus Rhynocoris of the Reduviidae, considered as a basal family of Cimicomorpha. Increasing evidence reinforces the hypothesis of the loss of the canonical "insect" telomere motif (TTAGG)n by at least four cimicomorphan families, Nabidae, Miridae, Tingidae, and Cimicidae, for which data are currently available.},
}
@article {pmid31578036,
year = {2020},
author = {Liu, B and Song, L and Zhang, L and Wu, M and Wang, L and Cao, Z and Xiong, C and Zhang, B and Li, Y and Xia, W and Xu, S and Wang, Y},
title = {Prenatal second-hand smoke exposure and newborn telomere length.},
journal = {Pediatric research},
volume = {87},
number = {6},
pages = {1081-1085},
pmid = {31578036},
issn = {1530-0447},
mesh = {Adult ; Age Factors ; Female ; Humans ; Infant, Newborn ; Maternal Exposure/*adverse effects ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Risk Factors ; Sex Factors ; Telomere/*genetics ; *Telomere Shortening ; Tobacco Smoke Pollution/*adverse effects ; },
abstract = {BACKGROUND: Cigarette smoking is associated with shorter telomere lengths in adults, but evidence on the effect of prenatal tobacco exposure is limited. We aimed to investigate the association between prenatal second-hand smoke exposure and newborn telomere length.<br><br>METHODS: We recruited 762 mother-newborn pairs from Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital) between November 2013 and March 2015. Information on second-hand smoke exposure was obtained via questionnaires. Relative telomere length was measured in DNA extracted from umbilical cord blood. We used linear regression to assess the associations between prenatal second-hand smoke exposure and newborn telomere length.<br><br>RESULTS: In the fully adjusted model, prenatal second-hand smoke exposure was associated with 9.7% shorter newborn telomere length (percent difference: -9.7%; 95% confidence interval (CI): -15.0, -4.0). The estimate for boys was lower (percent difference: -10.9%; 95% CI: -18.6, -2.5) than that for girls (percent difference: -8.5%; 95% CI: -15.8, -0.5), but the interaction term between newborn sex and prenatal second-hand smoke was not significant (P&#x2009;=&#x2009;0.751).<br><br>CONCLUSIONS: This study demonstrated that prenatal second-hand smoke exposure may be a preventable risk factor for accelerated biological aging in the intrauterine stage, and further suggested possible sex differences in the susceptibility to prenatal second-hand smoke.},
}
@article {pmid31577044,
year = {2019},
author = {Sudyka, J},
title = {Does Reproduction Shorten Telomeres? Towards Integrating Individual Quality with Life-History Strategies in Telomere Biology.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {41},
number = {11},
pages = {e1900095},
doi = {10.1002/bies.201900095},
pmid = {31577044},
issn = {1521-1878},
mesh = {Animals ; Biomarkers/metabolism ; Humans ; Reproduction/*genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Reproduction, a basic property of biological life, entails costs for an organism, ultimately detectable as reduction in survival prospects. Telomeres are an excellent candidate biomarker for explaining these reproductive costs, because their shortening correlates with increased mortality risk. For similar reasons, telomeres are perceived as biomarkers of individual "quality." The relationship between reproduction and telomere dynamics is reviewed, emphasizing that cost and quality perspectives, commonly presented in isolation, should be integrated. While a majority of correlative studies have confirmed the relationship between telomere dynamics and various reproductive outputs, only limited experimental support exists showing that reproduction causes telomeres to shorten. A shift of focus to experimental manipulations of reproductive effort/telomere dynamics is crucial. However, the observation of survival reduction in response to these manipulations is essential for establishing telomeres as genuine biomarkers, allowing to unravel trade-offs related to reproduction.},
}
@article {pmid31575660,
year = {2019},
author = {Mukherjee, AK and Sharma, S and Bagri, S and Kutum, R and Kumar, P and Hussain, A and Singh, P and Saha, D and Kar, A and Dash, D and Chowdhury, S},
title = {Telomere repeat-binding factor 2 binds extensively to extra-telomeric G-quadruplexes and regulates the epigenetic status of several gene promoters.},
journal = {The Journal of biological chemistry},
volume = {294},
number = {47},
pages = {17709-17722},
pmid = {31575660},
issn = {1083-351X},
support = {//Wellcome Trust/United Kingdom ; 500127-Z-09-Z/WTDBT_/DBT-Wellcome Trust India Alliance/India ; },
mesh = {Base Sequence ; Binding Sites/genetics ; Cell Line, Tumor ; *Epigenesis, Genetic ; *G-Quadruplexes ; Gene Expression Regulation ; Genome, Human ; Histone Code ; Humans ; Ligands ; Nucleotide Motifs/genetics ; *Promoter Regions, Genetic ; Protein Binding/genetics ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; Transcription, Genetic ; },
abstract = {The role of the telomere repeat-binding factor 2 (TRF2) in telomere maintenance is well-established. However, recent findings suggest that TRF2 also functions outside telomeres, but relatively little is known about this function. Herein, using genome-wide ChIP-Seq assays of TRF2-bound chromatin from HT1080 fibrosarcoma cells, we identified thousands of TRF2-binding sites within the extra-telomeric genome. In light of this observation, we asked how TRF2 occupancy is organized within the genome. Interestingly, we found that extra-telomeric TRF2 sites throughout the genome are enriched in potential G-quadruplex-forming DNA sequences. Furthermore, we validated TRF2 occupancy at several promoter G-quadruplex motifs, which did adopt quadruplex forms in solution. TRF2 binding altered expression and the epigenetic state of several target promoters, indicated by histone modifications resulting in transcriptional repression of eight of nine genes investigated here. Furthermore, TRF2 occupancy and target gene expression were also sensitive to the well-known intracellular G-quadruplex-binding ligand 360A. Together, these results reveal an extensive genome-wide association of TRF2 outside telomeres and that it regulates gene expression in a G-quadruplex-dependent fashion.},
}
@article {pmid31575358,
year = {2019},
author = {Marasco, V and Boner, W and Griffiths, K and Heidinger, B and Monaghan, P},
title = {Intergenerational effects on offspring telomere length: interactions among maternal age, stress exposure and offspring sex.},
journal = {Proceedings. Biological sciences},
volume = {286},
number = {1912},
pages = {20191845},
pmid = {31575358},
issn = {1471-2954},
mesh = {Age Factors ; Animals ; Cross-Sectional Studies ; Female ; Finches/physiology ; Longitudinal Studies ; Male ; *Maternal Age ; Songbirds/*physiology ; *Stress, Physiological ; Telomere/*physiology ; },
abstract = {Offspring produced by older parents often have reduced longevity, termed the Lansing effect. Because adults usually have similar-aged mates, it is difficult to separate effects of maternal and paternal age, and environmental circumstances are also likely to influence offspring outcomes. The mechanisms underlying the Lansing effect are poorly understood. Variation in telomere length and loss, particularly in early life, is linked to longevity in many vertebrates, and therefore changes in offspring telomere dynamics could be very important in this context. We examined the effect of maternal age and environment on offspring telomere length in zebra finches. We kept mothers under either control (ad libitum food) or more challenging (unpredictable food) circumstances and experimentally minimized paternal age and mate choice effects. Irrespective of the maternal environment, there was a substantial negative effect of maternal age on offspring telomere length, evident in longitudinal and cross-sectional comparisons (average of 39% shorter). Furthermore, in young mothers, sons reared by challenged mothers had significantly shorter telomere lengths than sons reared by control mothers. This effect disappeared when the mothers were old, and was absent in daughters. These findings highlight the importance of telomere dynamics as inter-generational mediators of the evolutionary processes determining optimal age-specific reproductive effort and sex allocation.},
}
@article {pmid31574531,
year = {2020},
author = {Chen, L and Zhu, H and Gutin, B and Sesso, HD and Dong, Y},
title = {Higher chocolate intake is associated with longer telomere length among adolescents.},
journal = {Pediatric research},
volume = {87},
number = {3},
pages = {602-607},
pmid = {31574531},
issn = {1530-0447},
mesh = {Adolescent ; *Adolescent Behavior ; Age Factors ; Apolipoprotein A-I/blood ; Biomarkers/blood ; *Chocolate ; Cross-Sectional Studies ; *Feeding Behavior ; Female ; Humans ; Lipoproteins, HDL/blood ; Male ; Serving Size ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Chocolate intake has shown cardiometabolic health benefits. Whether chocolate has any effect on cellular aging remains unknown. We aimed to test the hypothesis that higher chocolate intake is associated with longer leukocyte telomere length (LTL) in adolescents.<br><br>METHODS: A total of 660 adolescents (aged 14-18 years) were included in the analysis. The chocolate intake was assessed by 7-day, 24-h dietary recalls and split into three groups, which were none, <2 servings/week, and 2 servings/week or more. LTL (T/S ratio) was determined by a modified quantitative polymerase chain reaction-based assay.<br><br>RESULTS: Among the 660 adolescents, 58% did not take any chocolate, 25% consumed <2 servings/week, and 17% consumed &#x2265;2 servings/week. Compared to non-consumers, adolescents who consumed chocolate of &#x2265;2 servings/week had 0.27 standard deviation (SD) longer LTL (p&#x2009;=&#x2009;0.014). Higher chocolate consumption was associated with increased apolipoprotein A1 (ApoA1) (p&#x2009;=&#x2009;0.038) and ApoA1/high-density lipoprotein (HDL) (p&#x2009;=&#x2009;0.046). Moreover, higher ApoA1/HDL levels were correlated with longer LTL (p&#x2009;=&#x2009;0.026).<br><br>CONCLUSION: Adolescents who consume 2 servings/week or more of chocolate candy have longer LTL compared with non-consumers, and ApoA1/HDL pathway may be involved in this relationship.},
}
@article {pmid31573426,
year = {2019},
author = {Nowack, J and Tarmann, I and Hoelzl, F and Smith, S and Giroud, S and Ruf, T},
title = {Always a price to pay: hibernation at low temperatures comes with a trade-off between energy savings and telomere damage.},
journal = {Biology letters},
volume = {15},
number = {10},
pages = {20190466},
pmid = {31573426},
issn = {1744-957X},
support = {P 27267/FWF_/Austrian Science Fund FWF/Austria ; },
mesh = {Animals ; Body Temperature ; Cold Temperature ; *Hibernation ; Telomere ; Temperature ; *Torpor ; },
abstract = {We experimentally tested the costs of deep torpor at low temperatures by comparing telomere dynamics in two species of rodents hibernating at either 3 or 14°C. Our data show that hibernators kept at the warmer temperature had higher arousal frequencies, but maintained longer telomeres than individuals hibernating at the colder temperature. We suggest that the high-energy demand of frequent arousals is counteracted by a lower temperature differential between torpid and euthermic body temperature and that telomere length is restored during arousals when the body temperature is returned to normothermic values. Taken together, our study shows that hibernation at low body temperatures comes with costs on a cellular level and that hibernators need to actively counterbalance the shortening of telomeres.},
}
@article {pmid31570690,
year = {2019},
author = {Chan, KL and Lo, CKM and Ho, FK and Leung, WC and Yee, BK and Ip, P},
title = {The association between intimate partner violence against women and newborn telomere length.},
journal = {Translational psychiatry},
volume = {9},
number = {1},
pages = {239},
pmid = {31570690},
issn = {2158-3188},
mesh = {Adult ; Female ; Hong Kong ; Humans ; Infant, Newborn ; *Intimate Partner Violence ; Polymerase Chain Reaction ; Pregnancy ; Prenatal Exposure Delayed Effects ; Regression Analysis ; Risk Factors ; *Telomere ; Telomere Shortening/*genetics ; },
abstract = {Intimate partner violence (IPV) against women negatively impacts infant health. However, its impact on infant's biology, in particular on telomere length (TL) is unknown. The aim of this study was to examine the association between IPV against women before childbirth and cord blood TL in their newborn. A total of 774 pregnant women in the 20th-24th week of gestation were recruited at a public hospital in Hong Kong. The mothers' exposure to IPV before childbirth, demographic characteristics, obstetric outcomes, health and mental health were measured at the time of recruitment and 4 weeks after childbirth. Umbilical cord blood was collected by midwives at the time of delivery. The newborn TL was quantified using quantitative PCR method and expressed in T/S ratio (the ratio of telomere repeat copy numbers to single-copy gene numbers). After adjusting for a number of confounding variables, the mothers' exposure to any IPV before childbirth (β = -0.08, 95% CI = -0.14, -0.01) was associated with shorter TL. Specifically, psychological abuse against women before childbirth (β = -0.08, 95% CI = -0.15, -0.02) and sexual abuse against women before childbirth (β = -0.22, 95% CI = -0.43 to -0.01) were significantly associated with reduced newborn TL. This study is the first to provide evidence of an association between IPV against women before childbirth and TL shortening in their newborns. Through TL- dependent transcription and epigenetic mechanisms, our finding suggests maternal exposure to IPV may exert a life-long impact on the offspring's health.},
}
@article {pmid31569793,
year = {2019},
author = {Zribi, B and Uziel, O and Lahav, M and Mesilati Stahy, R and Singer, P},
title = {Telomere Length Changes during Critical Illness: A Prospective, Observational Study.},
journal = {Genes},
volume = {10},
number = {10},
pages = {},
pmid = {31569793},
issn = {2073-4425},
mesh = {Adult ; Aged ; Critical Illness/epidemiology ; Female ; Humans ; Intensive Care Units/statistics &amp; numerical data ; Leukocyte Count ; Male ; Middle Aged ; Sepsis/*epidemiology ; *Telomere Homeostasis ; },
abstract = {OBJECTIVE: evaluation of telomere length change in acutely ill adult patients.<br><br>DESIGN: Blood samples were drawn on the first and seventh day of intensive care unit (ICU) stay to assess telomere length using a polymerase chain reaction (PCR)-based technique. Demographic data collected included age, weight, admission diagnosis, baseline laboratory values (pH, C- reactive protein (CRP), serum albumin level, white blood cell count (WBC) count, platelet count), and baseline SOFA and APACHE II scores. Additional data collected during the ICU stay included a repeated WBC count, the presence of positive blood cultures and outcome data, including death in the ICU or following discharge, whether ventilated or not at ICU discharge, and destination following discharge, i.e., medical ward or rehabilitation.<br><br>SETTING: General ICU in tertiary hospital.<br><br>PATIENTS: Forty patients admitted to the ICU within 72 h of hospital admission suffering from an acute illness were included in this prospective, observational study.<br><br>MAIN RESULTS: Of the 40 patients studied, telomere shortening was noted in 21, telomere lengthening in 11, and no significant change in the other eight. The age of patients demonstrating telomere shortening was statistically significantly younger (45.4 vs. 61.5 years, p < 0.023) compared to those showing increased telomere length. In addition, a significant correlation was observed between the difference in telomere length and the corresponding difference in WBC count (telomere shortening was associated with a decreased WBC count and vice versa). A trend toward shortening was seen in patients with sepsis (p = 0.07). No significant correlations were found for any other demographic or outcome parameter and changes in telomere length.<br><br>CONCLUSION: Changes in telomere length, both shortening and lengthening, were evident in the acute setting, but no associations between such changes with outcome were noted. Further studies in more homogeneous groups of patients appear to be warranted.},
}
@article {pmid33335644,
year = {2019},
author = {Brown, L and García, C and Ailshire, J},
title = {Does Salivary Telomere Length Explain Race/Ethnic Differences in Aging?.},
journal = {Biodemography and social biology},
volume = {65},
number = {4},
pages = {351-369},
pmid = {33335644},
issn = {1948-5573},
support = {L30 AG064751/AG/NIA NIH HHS/United States ; T32 AG000221/AG/NIA NIH HHS/United States ; R25 AT010664/AT/NCCIH NIH HHS/United States ; T32 AG000037/AG/NIA NIH HHS/United States ; R36 AG057949/AG/NIA NIH HHS/United States ; R00 AG039528/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*ethnology/psychology ; Biomarkers/analysis ; Black People/*ethnology/psychology/statistics &amp; numerical data ; Female ; Humans ; Logistic Models ; Male ; Racial Groups/ethnology/statistics &amp; numerical data ; Retirement/statistics &amp; numerical data ; Saliva/*enzymology ; Telomere/*classification/physiology ; White People/*ethnology/psychology/statistics &amp; numerical data ; },
abstract = {Telomere length (TL) is a biomarker that can be used to characterize variability in aging and may explain race/ethnic differences in aging. Yet, it remains unclear if TL is related to aging-associated health risks in multi-ethnic populations or if it explains race/ethnic differences in health. We examine whether salivary TL (STL) explains any of the race/ethnic variability in 15 indicators of high-risk biological, physical and cognitive health among 4,074 white, black, and Latinx older adults ages 54+ in the 2008 Health and Retirement Study. TL was assayed from saliva using quantitative PCR (T/S ratio). Decomposition analyses from logistic regression models show variation in STL does not account for any of the observed race/ethnic differences health. In age-adjusted, race-stratified models, STL was associated with HDL, total cholesterol, and lung function among whites, but was not associated with any markers of health among black or Latinx groups. In this diverse national sample of older adults, STL does not account for race/ethnic differences in late life health, is associated with relatively few indicators of health among whites, and is not associated with indicators of health among black or Latinx groups. STL may not be a useful biomarker for understanding racial/ethnic differences in population aging among older adults.},
}
@article {pmid31569148,
year = {2019},
author = {Lin, Y and Zhu, Y and Wu, J and Hinkle, SN and Rawal, S and Han, J and Weir, NL and Tsai, MY and Zhang, C},
title = {A Prospective Study of Leukocyte Telomere Length and Risk of Gestational Diabetes in a Multiracial Cohort.},
journal = {Epidemiology (Cambridge, Mass.)},
volume = {30 Suppl 2},
number = {Suppl 2},
pages = {S10-S16},
pmid = {31569148},
issn = {1531-5487},
support = {ZIA HD008887/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Case-Control Studies ; Diabetes, Gestational/*etiology ; Female ; Gestational Age ; Humans ; Logistic Models ; Pregnancy ; Prospective Studies ; Risk Factors ; *Telomere Shortening ; Young Adult ; },
abstract = {BACKGROUND: Short telomere length (TL), an indicator of cellular aging and oxidative stress, has been implicated in glucose homeostasis. Additionally, studies have illustrated that the association of TL with health outcomes may vary by age. Yet, data on the association between TL and gestational diabetes mellitus (GDM) are sparse and the potential effect modification by age remains unknown.<br><br>METHODS: We prospectively investigated TL in early pregnancy in relation to the subsequent GDM risk in a case-control study of 93 women with GDM and 186 randomly selected controls matched on age, race/ethnicity, and gestational weeks at blood collection. TL was measured using blood samples collected at 10-14 gestational weeks and reported as the T/S ratio, a ratio of telomere repeat length T to copy number of a single copy gene S. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression adjusted for major risk factors.<br><br>RESULTS: Overall, TL was not significantly associated with GDM risk. The TL-GDM association was significantly modified by age (Pinteraction = 0.02). Shorter TL in early pregnancy was associated with an increased GDM risk among women <30 years old (adjusted OR comparing the shortest vs. longest tertile: 3.1, 95% CI = 1.2, 8.1), but not associated with GDM risk among women &#x2265;30 years.<br><br>CONCLUSION: Our findings suggest that TL in early pregnancy may be implicated in GDM development, particularly among younger women.},
}
@article {pmid31564046,
year = {2020},
author = {Scheller Madrid, A and Rasmussen, KL and Rode, L and Frikke-Schmidt, R and Nordestgaard, BG and Bojesen, SE},
title = {Observational and genetic studies of short telomeres and Alzheimer's disease in 67,000 and 152,000 individuals: a Mendelian randomization study.},
journal = {European journal of epidemiology},
volume = {35},
number = {2},
pages = {147-156},
pmid = {31564046},
issn = {1573-7284},
support = {NA//Overl&#xe6;ge Johan Boserup og Lise Boserups Legat/ ; NA//Copenhagen County Foundation/ ; },
mesh = {Adult ; Alzheimer Disease/*diagnosis/epidemiology/*genetics ; Female ; Genetic Predisposition to Disease/*genetics ; Genetic Variation ; Humans ; Male ; Mendelian Randomization Analysis/*methods ; Middle Aged ; Risk Factors ; Telomere ; Telomere Shortening/*genetics ; },
abstract = {Short telomeres might lead to increased risk of Alzheimer's disease, but observational analyses have been inconclusive and potentially confounded by the strong association of both telomere length and risk of Alzheimer's disease with age and adverse lifestyle. To circumvent this, analyses including single nucleotide polymorphisms associated with telomere length used in an instrumental variable analysis produces risk estimates likely free of distortions from reverse causation and of most confounding. We tested the hypothesis that short telomeres are associated with increased risk of Alzheimer's disease, observationally and causal, genetically. Telomere length was measured in 66,567 individuals, and genotyped for rs2487999 in OBFC1, rs7726159 in TERT, and rs1317082 in TERC causing lifelong telomere shortening in 98,146 individuals from two Copenhagen studies. Genetic data on 54,162 individuals from the International Genomics of Alzheimer's Project were also included. Observationally, multifactorially adjusted hazard ratio for Alzheimer's disease was 1.02 (95% CI 1.00-1.03) per 200 base pair shorter telomeres. Telomere length was 335 base pairs shorter in individuals with 6 versus 0-1 alleles (p = 5 × 10[-105]). Genetically, odds ratio for Alzheimer's disease was 1.08 (1.01-1.16) per 200 base pairs shorter telomeres. Similar results were found in strata of age and comorbidities. In comparative analyses, genetically predicted shorter telomeres were associated with increased risk of myocardial infarction, and with decreased risks of lung cancer and melanoma as previously reported. Short telomeres were associated observationally and causal, genetically with increased risk of Alzheimer's disease. Telomere biology is therefore a potential pathway involved in the development of Alzheimer's disease.},
}
@article {pmid31553468,
year = {2019},
author = {Puhlmann, LMC and Valk, SL and Engert, V and Bernhardt, BC and Lin, J and Epel, ES and Vrticka, P and Singer, T},
title = {Association of Short-term Change in Leukocyte Telomere Length With Cortical Thickness and Outcomes of Mental Training Among Healthy Adults: A Randomized Clinical Trial.},
journal = {JAMA network open},
volume = {2},
number = {9},
pages = {e199687},
pmid = {31553468},
issn = {2574-3805},
mesh = {Aging/*physiology/psychology ; Cerebral Cortex/pathology/*physiology ; Cognition/*physiology ; Comprehension/*physiology ; Female ; Humans ; Interoception/*physiology ; Leukocytes/*metabolism/pathology ; Longitudinal Studies ; Male ; *Mental Health ; Middle Aged ; Telomere/pathology/*physiology ; },
abstract = {IMPORTANCE: Telomere length is associated with the development of age-related diseases and structural differences in multiple brain regions. It remains unclear, however, whether change in telomere length is linked to brain structure change, and to what extent telomere length can be influenced through mental training.<br><br>OBJECTIVES: To assess the dynamic associations between leukocyte telomere length (LTL) and cortical thickness (CT), and to determine whether LTL is affected by a longitudinal contemplative mental training intervention.<br><br>An open-label efficacy trial of three 3-month mental training modules with healthy, meditation-naive adults was conducted. Data on LTL and CT were collected 4 times over 9 months between April 22, 2013, and March 31, 2015, as part of the ReSource Project. Data analysis was performed between September 23, 2016, and June 21, 2019. Of 1582 eligible individuals, 943 declined to participate; 362 were randomly selected for participation and assigned to training or retest control cohorts, with demographic characteristics matched. The retest control cohorts underwent all testing but no training. Intention-to-treat analysis was performed.<br><br>INTERVENTIONS: Training cohort participants completed 3 modules cultivating interoception and attention (Presence), compassion (Affect), or perspective taking (Perspective).<br><br>MAIN OUTCOMES AND MEASURES: Change in LTL and CT.<br><br>RESULTS: Of the 362 individuals randomized, 30 participants dropped out before study initiation (initial sample, 332). Data were available for analysis of the training intervention in 298 participants (n&#x2009;=&#x2009;222 training; n&#x2009;=&#x2009;76 retest control) (175 women [58.7%]; mean [SD] age, 40.5 [9.3] years). The training modules had no effect on LTL. In 699 observations from all 298 participants, mean estimated changes in the relative ratios of telomere repeat copy number to single-copy gene (T/S) were for no training, 0.004 (95% CI, -0.010 to 0.018); Presence, -0.007 (95% CI, -0.025 to 0.011); Affect, -0.005 (95% CI, -0.019 to 0.010); and Perspective, -0.001 (95% CI, -0.017 to 0.016). Cortical thickness change data were analyzed in 167 observations from 67 retest control participants (37 women [55.2%], mean [SD] age, 39.6 [9.0] years). In this retest control cohort subsample, naturally occurring LTL change was related to CT change in the left precuneus extending to the posterior cingulate cortex (mean t161&#x2009;=&#x2009;3.22; P&#x2009;<&#x2009;.001; r&#x2009;=&#x2009;0.246). At the individual participant level, leukocyte telomere shortening as well as lengthening were observed. Leukocyte telomere shortening was related to cortical thinning (t77&#x2009;=&#x2009;2.38; P&#x2009;=&#x2009;.01; r&#x2009;=&#x2009;0.262), and leukocyte telomere lengthening was related to cortical thickening (t77&#x2009;=&#x2009;2.42; P&#x2009;=&#x2009;.009; r&#x2009;=&#x2009;0.266). All analyses controlled for age, sex, and body mass index.<br><br>CONCLUSIONS AND RELEVANCE: The findings of this trial indicate an association between short-term change in LTL and concomitant change in plasticity of the left precuneus extending to the posterior cingulate cortex. This result contributes to the evidence that LTL changes more dynamically on the individual level than previously thought. Further studies are needed to determine potential long-term implications of such change in relation to cellular aging and the development of neurodegenerative disorders. No effect of contemplative mental training was noted in what may be, to date, the longest intervention with healthy adults.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01833104.},
}
@article {pmid31552268,
year = {2019},
author = {Domingues-Silva, B and Silva, B and Azzalin, CM},
title = {ALTernative Functions for Human FANCM at Telomeres.},
journal = {Frontiers in molecular biosciences},
volume = {6},
number = {},
pages = {84},
pmid = {31552268},
issn = {2296-889X},
abstract = {The human FANCM ATPase/translocase is involved in various cellular pathways including DNA damage repair, replication fork remodeling and R-loop resolution. Recently, reports from three independent laboratories have disclosed a previously unappreciated role for FANCM in telomerase-negative human cancer cells that maintain their telomeres through the Alternative Lengthening of Telomeres (ALT) pathway. In ALT cells, FANCM limits telomeric replication stress and damage, and, in turn, ALT activity by suppressing accumulation of telomeric R-loops and by regulating the action of the BLM helicase. As a consequence, FANCM inactivation leads to exaggerated ALT activity and ultimately cell death. The studies reviewed here not only unveil a novel function for human FANCM, but also point to this enzyme as a promising target for anti-ALT cancer therapy.},
}
@article {pmid31551201,
year = {2020},
author = {Yang, Y and Tan, J and Duan, X and Zhang, H and Feng, X and Wang, T and Wang, P and Ding, M and Liu, S and Li, L and Liang, H and Yao, W and Wang, W and Zhou, X},
title = {The association between polymorphisms in tankyrase gene and telomere length in omethoate-exposed workers.},
journal = {Chemosphere},
volume = {238},
number = {},
pages = {124863},
doi = {10.1016/j.chemosphere.2019.124863},
pmid = {31551201},
issn = {1879-1298},
mesh = {Adult ; Cyclin-Dependent Kinase Inhibitor p21/genetics ; DNA/genetics ; DNA Damage/drug effects ; Dimethoate/*analogs &amp; derivatives/toxicity ; Female ; Genotype ; Glutathione Transferase/genetics ; Humans ; Leukocytes/cytology ; Male ; MicroRNAs/genetics ; Middle Aged ; Occupational Exposure/*adverse effects ; Polymorphism, Single Nucleotide/genetics ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods ; Tankyrases/*genetics ; Telomere/genetics/*physiology ; Telomere Homeostasis/*drug effects ; },
abstract = {Peripheral blood leukocyte telomere length in omethoate-exposed workers is related to environmental exposure and single nucleotide polymorphisms (SNPs) in genes including p21, GSTM1, miR-145, etc. However, the roles of SNPs in tankyrase (TNKS) gene in telomere length are still unknown. The aim of this study was to explore the association between SNPs in TNKS gene and telomere length in omethoate-exposed workers. Telomere length in peripheral blood leukocyte DNA from 180 omethoate-exposed workers and 115 healthy controls was measured using Real-time quantitative polymerase chain reaction (PCR). Genotyping of the selected functional and susceptible SNPs was performed by the flight mass spectrometry based on PCR and single-base extension. The analysis of covariance was performed to find effects of SNPs on telomere length. Generalized linear models were used to analyze the environment, gene, and interaction on telomere length. The results showed that telomere length in the CG + CC genotypes in rs1055328 in TNKS gene was significantly longer than that in the wild homozygous GG genotype both in exposure group (P = 0.017) and in control group (P = 0.038) after adjusting the covariates. The variables kept in the generalized linear models included omethoate-exposure (β = 0.580, P = 0.001) and rs1055328 (CG + CC) in TNKS gene (β = 0.339, P = 0.002). The study suggests that the prolongation of telomere length is associated with omethoate-exposure and the CG + CC genotypes in rs1055328 in TNKS gene.},
}
@article {pmid31550289,
year = {2019},
author = {Rodriguez-Centeno, J and Manguán-García, C and Perona, R and Sastre, L},
title = {Structure of Dictyostelium discoideum telomeres. Analysis of possible replication mechanisms.},
journal = {PloS one},
volume = {14},
number = {9},
pages = {e0222909},
pmid = {31550289},
issn = {1932-6203},
mesh = {Cell Proliferation/genetics ; DNA, Ribosomal/*genetics/metabolism ; Dictyostelium/*physiology ; Heterochromatin/genetics/metabolism ; Homologous Recombination ; Mutation ; Tandem Repeat Sequences/*genetics ; Telomerase/genetics/*metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres are nucleo-protein structures that protect the ends of eukaryotic chromosomes. They are not completely synthesized during DNA replication and are elongated by specific mechanisms. The structure of the telomeres and the elongation mechanism have not been determined in Dictyostelium discoideum. This organism presents extrachromosomal palindromic elements containing two copies of the rDNA, also present at the end of the chromosomes. In this article the structure of the terminal region of the rDNA is shown to consist of repetitions of the A(G)n sequence where the number of Gs is variable. These repeats extend as a 3' single stranded region. The G-rich region is preceded by four tandem repetitions of two different DNA motifs. D. discoideum telomere reverse transcriptase homologous protein (TERTHP) presented RNase-sensitive enzymatic activity and was required to maintain telomere structure since terthp-mutant strains presented reorganizations of the DNA terminal regions. These modifications were different in several terthp-mutants and changed with their prolonged culture and subcloning. However, the terthp gene is not essential for D. discoideum proliferation. Telomeres could be maintained in terthp-mutant strains by homologous recombination mechanisms such as ALT (Alternative Lengthening of Telomeres) or HAATI (heterochromatin amplification-mediated and telomerase-independent). In agreement with this hypothesis, the expression of mRNAs coding for several proteins involved in homologous recombination was induced in terthp-mutant strains. Extrachromosomal rDNA could serve as substrate in these DNA homologous recombination reactions.},
}
@article {pmid31548285,
year = {2019},
author = {Criscuolo, F and Cornell, A and Zahn, S and Williams, TD},
title = {Oxidative status and telomere length are related to somatic and physiological maturation in chicks of European starlings (Sturnus vulgaris).},
journal = {The Journal of experimental biology},
volume = {222},
number = {Pt 20},
pages = {},
doi = {10.1242/jeb.204719},
pmid = {31548285},
issn = {1477-9145},
mesh = {Animals ; Models, Biological ; Oxidation-Reduction ; Principal Component Analysis ; Starlings/growth &amp; development/*physiology ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Telomere length can be considered as an indicator of an organism's somatic state, long telomeres reflecting higher energy investment in self-maintenance. Early-life is a period of intense investment in somatic growth and in physiological maturation but how this is reflected in telomere length remains unclear. Using European starling chicks we tested: (i) how telomere length measured at asymptotic mass is related to proxies of somatic growth and physiological maturity in 17-day-old nestlings; (ii) how telomere length measured at 17 days then predicts the changes in somatic and physiological maturity occurring in fledglings (between 17 and 21 days); (iii) how growth and telomere length co-vary when chicks are under experimentally good (fed) growth conditions. Depending on environmental conditions, our data suggest links between somatic growth, physiological maturation and body maintenance parameters (positive with oxidative stress and negative with telomere length) in nestlings. Telomere length measured at day 17 predicted a subsequent change in physiological maturation variables observed in fledglings, but only in second-brood chicks: chicks with shorter telomeres had a higher pre-fledging rate of increase in haematocrit and haemoglobin content and a greater decrease in reticulocyte count. Finally, food supplementation of chicks did not change telomere length compared with that in control siblings. Our results suggest that physiological maturation prior to fledging may occur at the expense of telomere length but only when environmental conditions are sub-optimal.},
}
@article {pmid31541974,
year = {2020},
author = {Wang, L and Koenig, HG and Al Shohaib, S and Wang, Z},
title = {Religiosity, depression and telomere length in Chinese older adults.},
journal = {Journal of affective disorders},
volume = {260},
number = {},
pages = {624-628},
doi = {10.1016/j.jad.2019.09.066},
pmid = {31541974},
issn = {1573-2517},
mesh = {Aged ; Asian People ; Cellular Senescence ; China ; Cross-Sectional Studies ; Depression/*psychology ; Female ; Humans ; Islam/*psychology ; Male ; Middle Aged ; Psychiatric Status Rating Scales ; Real-Time Polymerase Chain Reaction ; Telomere/*physiology ; },
abstract = {BACKGROUND: The mechanism explaining how religiosity is linked to telomere length (TL) is unclear. The current study examines depression as a possible mediator.<br><br>METHODS: In this cross-sectional study of 1,742 community-dwelling residents aged 55 or over, the Duke University Religion Index (DUREL) and Geriatric Depression Scale (GDS) were administrated during a routine health check. Peripheral blood leukocyte TL was determined using a q-PCR procedure. The Bootstrap methods PROCESS program was used to detect mediation.<br><br>RESULTS: After controlling for sociodemographic variables, the religiosity was positively correlated with TL (p<0.05) and negatively correlated with depressive symptom (p<0.001). Depressive symptoms, in turn, was negatively correlated with TL (p<0.05) in the overall sample. Depressive symptoms significantly mediated the relationship between religiosity and TL (explaining 31.8% of the total variance) in the 65 years and older subgroup (p&#x202f;=&#x202f;0.015). No significant mediation was found in the 55-64 age subgroup.<br><br>LIMITATIONS: The cross-sectional design prevents making causal inferences. The non-random sampling method used in selecting participants may affect the external validity of the findings in terms of generalizing to Muslims throughout China or other religious groups. Potential mediators of the relationship between religiosity and TL and confounders such as physical health status, were not assessed.<br><br>CONCLUSION: Religiosity was positively associated with TL in older mainland Chinese adults, and this association was partially mediated by depressive symptom in the 65 or older age group. This finding helps to explain why religiosity is related to cellular aging in older adults.},
}
@article {pmid31541246,
year = {2020},
author = {Dhillon, VS and Deo, P and Chua, A and Thomas, P and Fenech, M},
title = {Shorter Telomere Length in Carriers of APOE-ε4 and High Plasma Concentration of Glucose, Glyoxal and Other Advanced Glycation End Products (AGEs).},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {75},
number = {10},
pages = {1894-1898},
doi = {10.1093/gerona/glz203},
pmid = {31541246},
issn = {1758-535X},
mesh = {Alleles ; Apolipoprotein E4/*genetics ; Blood Glucose/*metabolism ; Carrier State ; Female ; Genotype ; Glycation End Products, Advanced/*blood ; Glyoxal/*blood ; Humans ; Male ; Middle Aged ; Risk Factors ; *Telomere Shortening ; },
abstract = {Apolipoprotein-ε4 (APOE-ε4)-common variant is a major genetic risk factor for cognitive decline and Alzheimer's disease (AD). An accelerated rate of biological aging could contribute to this increased risk. Glycation of serum proteins due to excessive glucose and reactive oxygen species leads to the formation of advanced glycation end products (AGEs)-a risk factor for diabetes and AD, and decline in motor functioning in elderly adults. Aim of present study was to investigate impact of APOE-ε4 allele containing genotype and accumulation of AGEs in plasma on telomere length (TL). Results showed that TL is significantly shorter in APOE-ε4 carriers compared with non-APOE-ε4 carriers (p = .0003). Higher plasma glucose level was associated with shorter TL irrespective of APOE-ε4 allele containing genotype (r = -.26; p = .0004). With regard to AGEs, higher plasma glyoxal and fluorescent AGEs concentrations were inversely related to TL (r = -.16; p = .03; r = -.28; p = .0001), however, plasma Nε-(carboxymethyl)lysine levels didn't correlate with TL (r = -.04; p = .57). Results support the hypotheses that APOE-ε4 carriers have shorter telomeres than noncarriers and telomere erosion is increased with higher concentration of glucose, fluorescent AGEs, and glyoxal.},
}
@article {pmid31532902,
year = {2019},
author = {Alejos, B and Stella-Ascariz, N and Montejano, R and Rodriguez-Centeno, J and Schwimmer, C and Bernardino, JI and Rodes, B and Esser, S and Goujard, C and Sarmento-Castro, R and De Miguel, R and Esteban-Cantos, A and Wallet, C and Raffi, F and Arribas, JR and , },
title = {Determinants of blood telomere length in antiretroviral treatment-naïve HIV-positive participants enrolled in the NEAT 001/ANRS 143 clinical trial.},
journal = {HIV medicine},
volume = {20},
number = {10},
pages = {691-698},
doi = {10.1111/hiv.12791},
pmid = {31532902},
issn = {1468-1293},
support = {//NEAT-ID Foundation/International ; //The French National Institute for Health and Medical Research-France Recherche Nord&amp;Sud Sida-HIV Hepatites (Inserm-ANRS)/International ; LSHP-CT-2006-37570//Instituto Superiore di Sanita-Rome/International ; PI13/01467//Red Tem&#xe1;tica Cooperativa de Investigaci&#xf3;n en Sida/International ; //Gilead Sciences/International ; //Merck/International ; //Janssen Pharmaceuticals/International ; },
mesh = {Adult ; Aged ; Anti-Retroviral Agents/*therapeutic use ; Cross-Sectional Studies ; Darunavir/therapeutic use ; Emtricitabine/therapeutic use ; Female ; *HIV Infections/drug therapy/genetics ; Humans ; Logistic Models ; Male ; Middle Aged ; RNA, Viral/analysis ; Raltegravir Potassium/therapeutic use ; Ritonavir/therapeutic use ; *Telomere ; Tenofovir/therapeutic use ; },
abstract = {OBJECTIVES: Our aim was to investigate factors associated with baseline blood telomere length in participants enrolled in NEAT 001/ANRS 143, a randomized, open-label trial comparing ritonavir-boosted darunavir (DRV/r) plus raltegravir (RAL) with DRV/r plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in antiretroviral therapy (ART)-naïve HIV-positive adults.<br><br>METHODS: A cross-sectional study of 201 randomly selected participants who had stored samples available was carried out. We measured telomere length (i.e. the relative telomere length, calculated as the telomere to single copy gene ratio) at baseline with monochrome quantitative multiplex polymerase chain reaction (PCR). We used multivariable predictive linear regression to calculate mean differences and 95% confidence intervals (CIs) for the association between baseline telomere length and baseline characteristics.<br><br>RESULTS: The baseline characteristics of the 201 participants did not differ from those of the 805 participants in the parent trial population: 89% were male, the mean age was 39&#xa0;years, 83.6% were Caucasian, 93% acquired HIV infection via sexual transmission, the mean estimated time since HIV diagnosis was 2.1&#xa0;years, the mean HIV-1 RNA load was 4.7 log10 HIV-1 RNA copies/mL, the mean nadir and baseline CD4 counts were 301 and 324 cells/&#x3bc;L, respectively, and the mean CD4:CD8 ratio was 0.4. In the univariate analysis, shorter telomere length was associated with older age (per 10&#xa0;years) (P&#xa0;<&#xa0;0.001), HIV-1 RNA &#x2265;&#xa0;100&#xa0;000 copies/mL (P&#xa0;=&#xa0;0.001), CD4 count <&#xa0;200 cells/&#x3bc;L (P&#xa0;=&#xa0;0.037), lower CD4:CD8 ratio (P&#xa0;=&#xa0;0.018), statin treatment (P&#xa0;=&#xa0;0.004), and current alcohol consumption (P&#xa0;=&#xa0;0.035). In the multivariable analysis, older age (P&#xa0;<&#xa0;0.001) and HIV RNA &#x2265;&#xa0;100&#xa0;000 copies/mL (P&#xa0;=&#xa0;0.054) were independently associated with shorter telomere length.<br><br>CONCLUSIONS: Both age and HIV RNA viral load correlated with shorter blood telomere length in untreated persons living with HIV. These results suggest that HIV infection and age have synergistic and independent impacts upon immunosenescence.},
}
@article {pmid31530811,
year = {2019},
author = {Masamsetti, VP and Low, RRJ and Mak, KS and O'Connor, A and Riffkin, CD and Lamm, N and Crabbe, L and Karlseder, J and Huang, DCS and Hayashi, MT and Cesare, AJ},
title = {Replication stress induces mitotic death through parallel pathways regulated by WAPL and telomere deprotection.},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {4224},
pmid = {31530811},
issn = {2041-1723},
support = {P30 CA014195/CA/NCI NIH HHS/United States ; R01 CA174942/CA/NCI NIH HHS/United States ; R01 CA234047/CA/NCI NIH HHS/United States ; R01 GM087476/GM/NIGMS NIH HHS/United States ; },
mesh = {*Apoptosis ; Carrier Proteins/*metabolism ; Cell Death ; Cell Line, Tumor ; *DNA Replication ; Humans ; *Mitosis ; Neoplasms/genetics/*metabolism/physiopathology ; Nuclear Proteins/*metabolism ; Proto-Oncogene Proteins/*metabolism ; Telomere/genetics/*metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; bcl-2 Homologous Antagonist-Killer Protein/genetics/metabolism ; bcl-2-Associated X Protein/genetics/metabolism ; },
abstract = {Mitotic catastrophe is a broad descriptor encompassing unclear mechanisms of cell death. Here we investigate replication stress-driven mitotic catastrophe in human cells and identify that replication stress principally induces mitotic death signalled through two independent pathways. In p53-compromised cells we find that lethal replication stress confers WAPL-dependent centromere cohesion defects that maintain spindle assembly checkpoint-dependent mitotic arrest in the same cell cycle. Mitotic arrest then drives cohesion fatigue and triggers mitotic death through a primary pathway of BAX/BAK-dependent apoptosis. Simultaneously, a secondary mitotic death pathway is engaged through non-canonical telomere deprotection, regulated by TRF2, Aurora B and ATM. Additionally, we find that suppressing mitotic death in replication stressed cells results in distinct cellular outcomes depending upon how cell death is averted. These data demonstrate how replication stress-induced mitotic catastrophe signals cell death with implications for cancer treatment and cancer genome evolution.},
}
@article {pmid31529714,
year = {2020},
author = {Noll, B and Bahrani Mougeot, F and Brennan, MT and Mougeot, JC},
title = {Telomere erosion in Sjögren's syndrome: A multi-tissue comparative analysis.},
journal = {Journal of oral pathology &amp; medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology},
volume = {49},
number = {1},
pages = {63-71},
doi = {10.1111/jop.12961},
pmid = {31529714},
issn = {1600-0714},
mesh = {Humans ; Saliva ; Salivary Glands ; Salivary Glands, Minor ; *Sjogren's Syndrome ; Telomere ; Tripeptidyl-Peptidase 1 ; },
abstract = {BACKGROUND: Acinar progenitor cells within salivary glands have decreased regenerative capacity and exhibit shorter telomeres in primary Sjögren's syndrome (pSS) patients. We investigated whether DNA of saliva, PBMCs, and labial salivary gland (LSG) biopsy tissue have shorter telomeres in pSS compared to controls. mRNA expression of genes associated with pSS pathogenesis (ETS1, LEF1, and MMP9), telomere DNA damage response (ATM), senescence (CDKN2A), telomerase inhibition (IFN-y, TGFβ1), and the shelterin complex (TPP1, POT1) were assessed in LSG tissue by qRT-PCR to examine potential defects in telomere maintenance.<br><br>METHODS: Relative telomere length in DNA of saliva, PBMCs, and LSGs from non-pSS sicca and pSS patients was measured using qPCR. Saliva DNA telomere length was further compared to healthy controls. Expression of genes affecting telomere maintenance was analyzed in LSGs using qRT-PCR.<br><br>RESULTS: Primary Sj&#xf6;gren's syndrome patients have shorter telomeres in saliva DNA (n&#xa0;=&#xa0;21) than healthy controls (n&#xa0;=&#xa0;27) (P&#xa0;=&#xa0;.0035). ATM mRNA expression was higher in pSS LSG tissue (n&#xa0;=&#xa0;16) vs non-pSS sicca patients (n&#xa0;=&#xa0;13) (P&#xa0;=&#xa0;.0283) and strongly correlated with LEF1, TPP1, and POT1 (P&#xa0;<&#xa0;.01, r&#xa0;>&#xa0;0.6).<br><br>CONCLUSIONS: Patients with pSS exhibited significant telomere erosion in saliva DNA. Overexpression of ATM in LSGs could represent a compensatory response to telomere shortening. The role of LEF1 in telomere erosion remains to be elucidated.},
}
@article {pmid31528700,
year = {2019},
author = {Amano, H and Sahin, E},
title = {Telomeres and sirtuins: at the end we meet again.},
journal = {Molecular &amp; cellular oncology},
volume = {6},
number = {5},
pages = {e1632613},
pmid = {31528700},
issn = {2372-3556},
support = {R01 AG047924/AG/NIA NIH HHS/United States ; },
abstract = {Telomeres and sirtuins are independently implicated in causing disease and aging, but how they cooperate is not well understood. A recent study demonstrates that telomere shortening represses sirtuins and increasing sirtuin activity stabilizes telomeres and improves telomere-dependent disease, suggesting that these two pathways are tightly intertwined.},
}
@article {pmid31527614,
year = {2019},
author = {Červenák, F and Juríková, K and Devillers, H and Kaffe, B and Khatib, A and Bonnell, E and Sopkovičová, M and Wellinger, RJ and Nosek, J and Tzfati, Y and Neuvéglise, C and Tomáška, &#x13d;},
title = {Identification of telomerase RNAs in species of the Yarrowia clade provides insights into the co-evolution of telomerase, telomeric repeats and telomere-binding proteins.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {13365},
pmid = {31527614},
issn = {2045-2322},
support = {FDN 154315//CIHR/Canada ; },
mesh = {Biological Evolution ; DNA Repeat Expansion/genetics ; Evolution, Molecular ; Fungal Proteins/metabolism ; RNA/genetics ; Telomerase/*genetics/metabolism ; Telomere/metabolism ; Telomere-Binding Proteins/*genetics ; Yarrowia/*genetics ; },
abstract = {Telomeric repeats in fungi of the subphylum Saccharomycotina exhibit great inter- and intra-species variability in length and sequence. Such variations challenged telomeric DNA-binding proteins that co-evolved to maintain their functions at telomeres. Here, we compare the extent of co-variations in telomeric repeats, encoded in the telomerase RNAs (TERs), and the repeat-binding proteins from 13 species belonging to the Yarrowia clade. We identified putative TER loci, analyzed their sequence and secondary structure conservation, and predicted functional elements. Moreover, in vivo complementation assays with mutant TERs showed the functional importance of four novel TER substructures. The TER-derived telomeric repeat unit of all species, except for one, is 10 bp long and can be represented as 5'-TTNNNNAGGG-3', with repeat sequence variations occuring primarily outside the vertebrate telomeric motif 5'-TTAGGG-3'. All species possess a homologue of the Yarrowia lipolytica Tay1 protein, YlTay1p. In vitro, YlTay1p displays comparable DNA-binding affinity to all repeat variants, suggesting a conserved role among these species. Taken together, these results add significant insights into the co-evolution of TERs, telomeric repeats and telomere-binding proteins in yeasts.},
}
@article {pmid31526614,
year = {2019},
author = {Flynn, RL and Heaphy, CM},
title = {Surviving Telomere Attrition with the MiDAS Touch.},
journal = {Trends in genetics : TIG},
volume = {35},
number = {11},
pages = {783-785},
doi = {10.1016/j.tig.2019.08.008},
pmid = {31526614},
issn = {0168-9525},
support = {R01 CA201446/CA/NCI NIH HHS/United States ; },
mesh = {DNA ; DNA Replication ; Telomerase/*genetics ; *Telomere ; Telomere Homeostasis ; Touch ; },
abstract = {Cancer cells maintain telomere lengths through telomerase activity or by alternative lengthening of telomeres (ALT). Using an engineered model system, a recent study by Min et al. reveals that the combination of BLM-mediated DNA resection and telomere clustering, a characteristic of ALT telomeres, catalyzes RAD52-dependent mitotic DNA synthesis (MiDAS) specifically at telomeres to drive ALT activity.},
}
@article {pmid31518356,
year = {2019},
author = {Liu, N and Yin, Y and Wang, H and Zhou, Z and Sheng, X and Fu, H and Guo, R and Wang, H and Yang, J and Gong, P and Ning, W and Ju, Z and Liu, Y and Liu, L},
title = {Telomere dysfunction impairs epidermal stem cell specification and differentiation by disrupting BMP/pSmad/P63 signaling.},
journal = {PLoS genetics},
volume = {15},
number = {9},
pages = {e1008368},
pmid = {31518356},
issn = {1553-7404},
mesh = {Animals ; Atrophy/genetics ; Bone Morphogenetic Proteins/metabolism ; Cell Differentiation/genetics ; Cell Lineage/genetics ; Cell Proliferation/genetics ; Epidermal Cells/metabolism ; Epidermis/metabolism ; Gene Expression Regulation/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Signal Transduction/genetics ; Smad Proteins/metabolism ; Stem Cells/*metabolism ; Telomere/genetics ; Telomere Shortening/genetics/*physiology ; Trans-Activators/metabolism ; },
abstract = {Telomere shortening is associated with aging and age-associated diseases. Additionally, telomere dysfunction resulting from telomerase gene mutation can lead to premature aging, such as apparent skin atrophy and hair loss. However, the molecular signaling linking telomere dysfunction to skin atrophy remains elusive. Here we show that dysfunctional telomere disrupts BMP/pSmad/P63 signaling, impairing epidermal stem cell specification and differentiation of skin and hair follicles. We find that telomere shortening mediated by Terc loss up-regulates Follistatin (Fst), inhibiting pSmad signaling and down-regulating P63 and epidermal keratins in an ESC differentiation model as well as in adult development of telomere-shortened mice. Mechanistically, short telomeres disrupt PRC2/H3K27me3-mediated repression of Fst. Our findings reveal that skin atrophy due to telomere dysfunction is caused by a previously unappreciated link with Fst and BMP signaling that could be explored in the development of therapies.},
}
@article {pmid31515401,
year = {2019},
author = {Hoffman, TW and van der Vis, JJ and van der Smagt, JJ and Massink, MPG and Grutters, JC and van Moorsel, CHM},
title = {Pulmonary fibrosis linked to variants in the ACD gene, encoding the telomere protein TPP1.},
journal = {The European respiratory journal},
volume = {54},
number = {6},
pages = {},
doi = {10.1183/13993003.00809-2019},
pmid = {31515401},
issn = {1399-3003},
mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Netherlands ; Pedigree ; Pulmonary Fibrosis/diagnostic imaging/*genetics ; Shelterin Complex ; Telomere-Binding Proteins/*genetics ; },
}
@article {pmid31515236,
year = {2019},
author = {Wilbur, SM and Barnes, BM and Kitaysky, AS and Williams, CT},
title = {Tissue-specific telomere dynamics in hibernating arctic ground squirrels (Urocitellus parryii).},
journal = {The Journal of experimental biology},
volume = {222},
number = {Pt 18},
pages = {},
pmid = {31515236},
issn = {1477-9145},
support = {P20 GM103395/GM/NIGMS NIH HHS/United States ; },
mesh = {Adipose Tissue, Brown/physiology ; Animals ; Female ; Heart/physiology ; Hibernation/*physiology ; Liver/physiology ; Male ; Muscle, Skeletal/physiology ; Sciuridae/*physiology ; Sex Factors ; *Telomere Shortening ; },
abstract = {Hibernation is used by a variety of mammals to survive seasonal periods of resource scarcity. Reactive oxygen species (ROS) released during periodic rewarming throughout hibernation, however, may induce oxidative damage in some tissues. Telomeres, which are the terminal sequences of linear chromosomes, may shorten in the presence of ROS, and thus the telomere length of an individual reflects the degree of accrued oxidative damage. This study quantified telomere length dynamics throughout hibernation in arctic ground squirrels (Urocitellus parryii). We hypothesized that telomere dynamics are tissue specific and predicted that telomere shortening would be most pronounced in brown adipose tissue (BAT), the organ that directly supports non-shivering thermogenesis during arousals. We used qPCR to determine relative telomere length (RTL) in DNA extracted from liver, heart, skeletal muscle (SM) and BAT of 45 juvenile and adult animals sampled either at mid- or late hibernation. Age did not have a significant effect on RTL in any tissue. At mid-hibernation, RTL of juvenile females was longer in BAT and SM than in liver and heart. In juvenile females, RTL in BAT and SM, but not in liver and heart, was shorter at late hibernation than at mid-hibernation. At late hibernation, juvenile males had longer RTL in BAT than did juvenile females, perhaps due to the naturally shorter hibernation duration of male arctic ground squirrels. Finally, BAT RTL at late hibernation negatively correlated with arousal frequency. Overall, our results suggest that, in a hibernating mammal, telomere shortening is tissue specific and that metabolically active tissues might incur higher levels of molecular damage.},
}
@article {pmid31514556,
year = {2020},
author = {Bhattacharya, M and Bhaumik, P and Ghosh, P and Majumder, P and Kumar Dey, S},
title = {Telomere Length Inheritance and Shortening in Trisomy 21.},
journal = {Fetal and pediatric pathology},
volume = {39},
number = {5},
pages = {390-400},
doi = {10.1080/15513815.2019.1661049},
pmid = {31514556},
issn = {1551-3823},
mesh = {Biomarkers ; Child ; Chromosomes, Human, Pair 14 ; *Down Syndrome/genetics ; Humans ; Infant ; *Telomere/genetics ; Trisomy ; },
abstract = {Objective: Trisomy 21 is a genetic disorder that shows premature aging symptoms. As an aging marker, telomere length is therefore of importance in trisomy families. Methods: We included 63 maternally originated trisomy 21 and 77 control families with infants in the first data set; 48 trisomy 21 and 60 control children in the second set; and 14 paternally originated trisomy 21 families in the third data set. We used Southern blot to measure the telomere length. Results: (1) Offsprings' telomere length increased with parents' age (p < .0001). (2) Trisomy 21 infants had longer telomere than the controls (p < .0001). (3) Post-birth, the telomere attrition rate was higher in cases than in controls (58 bps/year vs. 38 bps/year). Conclusion: (1) Our data supports the older parents-longer gamete telomere hypothesis. (2) Trisomy 21 patients are born with longer telomeres, (3) with advancing trisomy 21 age, the telomere shortens more quickly than euploids.},
}
@article {pmid31510074,
year = {2019},
author = {Pompili, L and Maresca, C and Dello Stritto, A and Biroccio, A and Salvati, E},
title = {BRCA2 Deletion Induces Alternative Lengthening of Telomeres in Telomerase Positive Colon Cancer Cells.},
journal = {Genes},
volume = {10},
number = {9},
pages = {},
pmid = {31510074},
issn = {2073-4425},
mesh = {BRCA1 Protein/*genetics ; Colonic Neoplasms/*genetics ; Gene Deletion ; HCT116 Cells ; Humans ; *Telomere Homeostasis ; },
abstract = {BRCA1/2 are tumor suppressor genes controlling genomic stability also at telomeric and subtelomeric loci. Their mutation confers a predisposition to different human cancers but also sensitivity to antitumor drugs including poly(ADP-ribose) polymerase (PARP) inhibitors and G-quadruplex stabilizers. Here we demonstrate that BRCA2 deletion triggers TERRA hyperexpression and alternative lengthening mechanisms (ALT) in colon cancer cells in presence of telomerase activity. This finding opens the question if cancer patients bearing BRCA2 germline or sporadic mutation are suitable for anti-telomerase therapies, or how ALT activation could influence the short or long-term response to anti-PARP inhibitors or anti-G-quadruplex therapies.},
}
@article {pmid31509825,
year = {2020},
author = {Cokan Vujkovac, A and Novaković, S and Vujkovac, B and Števanec, M and Škerl, P and Šabovič, M},
title = {Aging in Fabry Disease: Role of Telomere Length, Telomerase Activity, and Kidney Disease.},
journal = {Nephron},
volume = {144},
number = {1},
pages = {5-13},
doi = {10.1159/000502909},
pmid = {31509825},
issn = {2235-3186},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*physiology ; Biomarkers/metabolism ; Cardiovascular Diseases/metabolism ; Case-Control Studies ; Fabry Disease/drug therapy/enzymology/*physiopathology ; Female ; Humans ; Inflammation Mediators/metabolism ; Kidney Diseases/enzymology/*physiopathology ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Telomerase/*metabolism ; *Telomere ; Young Adult ; alpha-Galactosidase/therapeutic use ; },
abstract = {INTRODUCTION: The lifespan of patients with Fabry disease (FD) is shorter than that seen in the general population. Leukocyte telomere length (LTL) and telomerase activity (TA) are potential markers of biologic aging. The aim of the current study was to determine the LTL and TA in FD patients and to assess the correlation between LTL and TA and renal involvement.<br><br>METHODS: We included 33 FD patients and 66 healthy matched controls. LTL and TA were measured using a quantitative PCR assay and gene expression assay. FD patients were stratified by renal function (estimated glomerular filtration rate [eGFR] higher or lower than 60 mL/min/1.73 m2) and proteinuria (urine protein creatinine ratio higher or lower than 0.5 g/g).<br><br>RESULTS: LTL was significantly shorter (0.69 vs. 0.73, p = 0.015) and TA significantly higher (1.55 vs. 1.19, p = 0.047) in FD patients compared to controls. Males with FD had significantly shorter LTL (p = 0.020) and lower, but non-significant, TA compared to male controls (p = 0.333). Female FD patients had similar LTL (p = 0.285) but significantly higher TA compared to female controls (p = 0.005). LTL was not influenced by eGFR, but TA was significantly lower in the low eGFR group (p = 0.003).<br><br>CONCLUSIONS: FD patients have significantly shorter LTL, but significantly higher TA compared to healthy controls. Increased TA activity in FD patients could be the compensation mechanism to prevent LTL decrease (and accelerated ageing), which seems to be exhausted at the advanced stage of renal disease.},
}
@article {pmid31509004,
year = {2020},
author = {Esteves, KC and Jones, CW and Wade, M and Callerame, K and Smith, AK and Theall, KP and Drury, SS},
title = {Adverse Childhood Experiences: Implications for Offspring Telomere Length and Psychopathology.},
journal = {The American journal of psychiatry},
volume = {177},
number = {1},
pages = {47-57},
pmid = {31509004},
issn = {1535-7228},
support = {K12 HD043451/HD/NICHD NIH HHS/United States ; R01 MH101533/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Affective Symptoms/*epidemiology ; Biomarkers/metabolism ; Child Abuse ; Child of Impaired Parents/*psychology ; Female ; Humans ; Infant ; Longitudinal Studies ; Male ; Prospective Studies ; Psychopathology ; Social Problems/*statistics &amp; numerical data ; *Telomere Shortening ; },
abstract = {OBJECTIVE: Adverse childhood experiences (ACEs) are associated with mental and physical health risks that, through biological and psychosocial pathways, likely span generations. Within an individual, telomere length (TL), an established marker of cellular stress and aging, is associated with both ACE exposure and psychopathology, providing the basis for an emerging literature suggesting that TL is a biomarker of the health risks linked to early-life adversity both within and across generations. The authors tested the effect of maternal ACEs on both the trajectory of infant TL and infant social-emotional problems at 18 months of age.<br><br>METHODS: Pregnant women were recruited, and maternal scores on the Adverse Childhood Experience questionnaire were obtained, along with demographic and prenatal stress measures. Postnatal visits with 155 mother-infant dyads occurred when infants were 4, 12, and 18 months of age. At each visit, infant buccal swabs were collected for TL measurement, and mothers completed measures of maternal depression. Mothers also completed the Child Behavior Checklist at the 18-month visit. Mixed-effects modeling was used to test how maternal ACEs influenced infant TL trajectory. Linear regression was used to test the association between maternal ACEs and infant internalizing and externalizing behaviors. Finally, the interaction between telomere attrition from 4 to 18 months and maternal ACEs was examined as a predictor of infant scores on the Child Behavior Checklist.<br><br>RESULTS: Higher maternal ACEs were associated with shorter infant TL across infancy and higher infant externalizing behavioral problems at 18 months. No associations were found with internalizing behavioral problems. Telomere attrition from 4 to 18 months interacted with maternal ACEs to predict externalizing behaviors. In infants whose mothers reported higher scores on the Adverse Childhood Experience questionnaire, greater telomere attrition predicted higher externalizing problems, even when accounting for maternal postnatal depression and prenatal stress.<br><br>CONCLUSIONS: These data demonstrate an interactive pathway between maternal early-life adversity and infant TL that predicts emerging behavioral problems in the next generations.},
}
@article {pmid31500249,
year = {2019},
author = {Vaquero-Sedas, MI and Vega-Palas, MA},
title = {Assessing the Epigenetic Status of Human Telomeres.},
journal = {Cells},
volume = {8},
number = {9},
pages = {},
pmid = {31500249},
issn = {2073-4409},
mesh = {Chromatin/genetics ; Chromatin Immunoprecipitation/methods ; Epigenesis, Genetic/*genetics/physiology ; Epigenomics/*methods ; Histones/genetics ; Humans ; Microscopy/methods ; Telomere/*genetics/metabolism/physiology ; },
abstract = {The epigenetic modifications of human telomeres play a relevant role in telomere functions and cell proliferation. Therefore, their study is becoming an issue of major interest. These epigenetic modifications are usually analyzed by microscopy or by chromatin immunoprecipitation (ChIP). However, these analyses could be challenged by subtelomeres and/or interstitial telomeric sequences (ITSs). Whereas telomeres and subtelomeres cannot be differentiated by microscopy techniques, telomeres and ITSs might not be differentiated in ChIP analyses. In addition, ChIP analyses of telomeres should be properly controlled. Hence, studies focusing on the epigenetic features of human telomeres have to be carefully designed and interpreted. Here, we present a comprehensive discussion on how subtelomeres and ITSs might influence studies of human telomere epigenetics. We specially focus on the influence of ITSs and some experimental aspects of the ChIP technique on ChIP analyses. In addition, we propose a specific pipeline to accurately perform these studies. This pipeline is very simple and can be applied to a wide variety of cells, including cancer cells. Since the epigenetic status of telomeres could influence cancer cells proliferation, this pipeline might help design precise epigenetic treatments for specific cancer types.},
}
@article {pmid31499418,
year = {2019},
author = {Yang, L and Kost, SEF and Beiggi, S and Zhang, Y and Schmidt, R and Nugent, Z and Marshall, A and Banerji, V and Gibson, SB and Johnston, JB},
title = {Buccal cell telomere length is not a useful marker for comorbidities in chronic lymphocytic leukemia.},
journal = {Leukemia research},
volume = {86},
number = {},
pages = {106220},
doi = {10.1016/j.leukres.2019.106220},
pmid = {31499418},
issn = {1873-5835},
mesh = {Aged ; Biomarkers, Tumor/*genetics ; Case-Control Studies ; Comorbidity ; Female ; Follow-Up Studies ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*diagnosis/genetics ; Male ; Mouth Mucosa/metabolism/*pathology ; Prognosis ; *Severity of Illness Index ; Telomere Homeostasis/*genetics ; },
}
@article {pmid31492885,
year = {2019},
author = {Zhao, B and Lin, J and Rong, L and Wu, S and Deng, Z and Fatkhutdinov, N and Zundell, J and Fukumoto, T and Liu, Q and Kossenkov, A and Jean, S and Cadungog, MG and Borowsky, ME and Drapkin, R and Lieberman, PM and Abate-Shen, CT and Zhang, R},
title = {ARID1A promotes genomic stability through protecting telomere cohesion.},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {4067},
pmid = {31492885},
issn = {2041-1723},
support = {R01 CA173481/CA/NCI NIH HHS/United States ; P01 AG031862/AG/NIA NIH HHS/United States ; P50 CA228991/CA/NCI NIH HHS/United States ; R50 CA211199/CA/NCI NIH HHS/United States ; R01 CA202919/CA/NCI NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; R01 CA239128/CA/NCI NIH HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; R50 CA221838/CA/NCI NIH HHS/United States ; R01 CA160331/CA/NCI NIH HHS/United States ; R01 CA163377/CA/NCI NIH HHS/United States ; P01 CA221757/CA/NCI NIH HHS/United States ; R01 CA183929/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Apoptosis/genetics ; Cell Cycle Proteins/genetics/metabolism ; Cell Line ; Cell Line, Tumor ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; DNA Copy Number Variations ; DNA-Binding Proteins ; Female ; *Genomic Instability ; Humans ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; Mice, Transgenic ; *Mutation ; Nuclear Proteins/*genetics/metabolism ; Ovarian Neoplasms/*genetics/metabolism/pathology ; Telomere/*genetics/metabolism ; Transcription Factors/*genetics/metabolism ; Transplantation, Heterologous/methods ; Tumor Burden/genetics ; Cohesins ; },
abstract = {ARID1A inactivation causes mitotic defects. Paradoxically, cancers with high ARID1A mutation rates typically lack copy number alterations (CNAs). Here, we show that ARID1A inactivation causes defects in telomere cohesion, which selectively eliminates gross chromosome aberrations during mitosis. ARID1A promotes the expression of cohesin subunit STAG1 that is specifically required for telomere cohesion. ARID1A inactivation causes telomere damage that can be rescued by STAG1 expression. Colony formation capability of single cells in G2/M, but not G1 phase, is significantly reduced by ARID1A inactivation. This correlates with an increase in apoptosis and a reduction in tumor growth. Compared with ARID1A wild-type tumors, ARID1A-mutated tumors display significantly less CNAs across multiple cancer types. Together, these results show that ARID1A inactivation is selective against gross chromosome aberrations through causing defects in telomere cohesion, which reconciles the long-standing paradox between the role of ARID1A in maintaining mitotic integrity and the lack of genomic instability in ARID1A-mutated cancers.},
}
@article {pmid31492825,
year = {2019},
author = {Pusceddu, I and Herrmann, W and Kleber, ME and Scharnagl, H and März, W and Herrmann, M},
title = {Telomere length, vitamin B12 and mortality in persons undergoing coronary angiography: the Ludwigshafen risk and cardiovascular health study.},
journal = {Aging},
volume = {11},
number = {17},
pages = {7083-7097},
pmid = {31492825},
issn = {1945-4589},
mesh = {Aged ; Cohort Studies ; Coronary Angiography ; Female ; Germany/epidemiology ; Humans ; Male ; Middle Aged ; *Telomere Shortening ; Vitamin B 12 Deficiency/*mortality ; },
abstract = {BACKGROUND: Vitamin B12 (B12) deficiency and excess are associated with increased risk of age-related-diseases and mortality. It has been suggested that high- and low-B12 concentrations link to increased mortality through accelerated genomic aging and inflammation. Evidence to support this is limited.<br><br>RESULTS: B12 was associated with all-cause-mortality, RTL and hsCRP in a non-linear fashion. The association between B12 and mortality was not independent, as it lost significance after adjustment for potential confounders. In the lowest-(LB12) and highest-(HB12) quartiles of B12 mortality was higher than in the mid-range (HR:LB12:1.23;CI95%:1.06-1.43; HR:HB12:1.24;CI95%:1.06-1.44). We divided subjects with LB12 in quartiles of their RTL. Those with the longest-telomeres had a lower mortality-rate (HR:0.57;95%CI:0.39-0.83) and lower homocysteine than those with the shortest-telomeres. Amongst subjects with HB12, those with long-telomeres also had a lower mortality than those with short-telomeres (HR:0.40;95%CI:0.27-0.59). IL-6 and hsCRP concentrations were low in HB12LT but were high in HB12ST.<br><br>METHODS: B12, homocysteine, telomere length (RTL), interleukin-6 (IL-6) and high-sensitive-C-reactive-protein (hsCRP) were measured in 2970 participants of the LURIC study.<br><br>CONCLUSIONS: Mortality, stratified according to B12 and RTL, seems to be driven by different mechanisms. In LB12 and HB12 subjects, mortality and accelerated telomere shortening might be driven by homocysteine and inflammation, respectively.},
}
@article {pmid31491428,
year = {2019},
author = {Åström, MJ and von Bonsdorff, MB and Perälä, MM and Salonen, MK and Rantanen, T and Kajantie, E and Simonen, M and Pohjolainen, P and Haapanen, MJ and Guzzardi, MA and Iozzo, P and Kautiainen, H and Eriksson, JG},
title = {Telomere length and physical performance among older people-The Helsinki Birth Cohort Study.},
journal = {Mechanisms of ageing and development},
volume = {183},
number = {},
pages = {111145},
doi = {10.1016/j.mad.2019.111145},
pmid = {31491428},
issn = {1872-6216},
mesh = {Aged ; Aging/*physiology ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; *Sex Characteristics ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {Telomere length has been suggested a biomarker of aging and is associated with several chronic diseases. However, the association between telomere length and physical performance is not well known. Using both cross-sectional and longitudinal data, we studied 582 women and 453 men from the Helsinki Birth Cohort Study at two time-points; a baseline examination in 2001-2004 at a mean age of 61 years and a follow-up examination approximately 10 years later in 2011-2013. Telomere length was measured both at baseline and at follow-up using real-time quantitative polymerase chain reaction. Physical performance was evaluated only at follow-up using the Senior Fitness Test (SFT), which assesses strength, flexibility and endurance. In women, shorter telomere length at follow-up (p = 0.044) and greater telomere attrition during follow-up time (p = 0.022) were associated with poorer physical performance after adjusting for covariates (age at baseline, smoking status, body mass index at baseline, follow-up time and educational attainment). No similar associations were found for men. This indicates that, at least in women, telomere length could potentially be used as a biomarker for physical performance, however, more longitudinal studies are needed to confirm this association.},
}
@article {pmid31486104,
year = {2019},
author = {Krysko, KM and Henry, RG and Cree, BAC and Lin, J and , and Caillier, S and Santaniello, A and Zhao, C and Gomez, R and Bevan, C and Smith, DL and Stern, W and Kirkish, G and Hauser, SL and Oksenberg, JR and Graves, JS},
title = {Telomere Length Is Associated with Disability Progression in Multiple Sclerosis.},
journal = {Annals of neurology},
volume = {86},
number = {5},
pages = {671-682},
pmid = {31486104},
issn = {1531-8249},
support = {FP-1605-08753//National Multiple Sclerosis Society/International ; RG-1607-25103//National Multiple Sclerosis Society/International ; R35 NS111644/NS/NINDS NIH HHS/United States ; R01 NS026799/NS/NINDS NIH HHS/United States ; },
mesh = {Adult ; Aging/physiology ; Cellular Senescence/physiology ; Cohort Studies ; Cross-Sectional Studies ; Disability Evaluation ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; *Multiple Sclerosis/metabolism/pathology ; Telomere/*metabolism/pathology ; Telomere Homeostasis/physiology ; },
abstract = {OBJECTIVE: To assess whether biological aging as measured by leukocyte telomere length (LTL) is associated with clinical disability and brain volume loss in multiple sclerosis (MS).<br><br>METHODS: Adults with MS/clinically isolated syndrome in the University of California, San Francisco EPIC cohort study were included. LTL was measured on DNA samples by quantitative polymerase chain reaction and expressed as telomere to somatic DNA (T/S) ratio. Expanded Disability Status Scale (EDSS) and 3-dimensional T1-weighted brain magnetic resonance imaging were performed at baseline and follow-up. Associations of baseline LTL with cross-sectional and longitudinal outcomes were assessed using simple and mixed effects linear regression models. A subset (n = 46) had LTL measured over time, and we assessed the association of LTL change with EDSS change with mixed effects models.<br><br>RESULTS: Included were 356 women and 160 men (mean age = 43&#x2009;years, median disease duration = 6&#x2009;years, median EDSS = 1.5 [range = 0-7], mean T/S ratio = 0.97 [standard deviation = 0.18]). In baseline analyses adjusted for age, disease duration, and sex, for every 0.2 lower LTL, EDSS was 0.27 higher (95% confidence interval [CI] = 0.13-0.42, p&#x2009;<&#x2009;0.001) and brain volume was 7.4mm[3] lower (95% CI = 0.10-14.7, p = 0.047). In longitudinal adjusted analyses, those with lower baseline LTL had higher EDSS and lower brain volumes over time. In adjusted analysis of the subset, LTL change was associated with EDSS change over 10&#x2009;years; for every 0.2 LTL decrease, EDSS was 0.34 higher (95% CI = 0.08-0.61, p = 0.012).<br><br>INTERPRETATION: Shorter telomere length was associated with disability independent of chronological age, suggesting that biological aging may contribute to neurological injury in MS. Targeting aging-related mechanisms is a potential therapeutic strategy against MS progression. ANN NEUROL 2019;86:671-682.},
}
@article {pmid31479877,
year = {2019},
author = {Donaires, FS and Alves-Paiva, RM and Gutierrez-Rodrigues, F and da Silva, FB and Tellechea, MF and Moreira, LF and Santana, BA and Traina, F and Dunbar, CE and Winkler, T and Calado, RT},
title = {Telomere dynamics and hematopoietic differentiation of human DKC1-mutant induced pluripotent stem cells.},
journal = {Stem cell research},
volume = {40},
number = {},
pages = {101540},
pmid = {31479877},
issn = {1876-7753},
support = {ZIA HL006062/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/*genetics ; *Cell Differentiation ; Cells, Cultured ; Cellular Reprogramming ; Dyskeratosis Congenita/genetics/pathology ; Fibroblasts/cytology ; *Hematopoiesis ; Humans ; Induced Pluripotent Stem Cells/cytology/metabolism ; Karyotype ; Mutation ; Nuclear Proteins/*genetics ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Telomere Shortening ; },
abstract = {Telomeropathies are a group of phenotypically heterogeneous diseases molecularly unified by pathogenic mutations in telomere-maintenance genes causing critically short telomeres. X-linked dyskeratosis congenita (DC), the prototypical telomere disease, manifested with ectodermal dysplasia, cancer predisposition, and severe bone marrow failure, is caused by mutations in DKC1, encoding a protein responsible for telomerase holoenzyme complex stability. To investigate the effects of pathogenic DKC1 mutations on telomere repair and hematopoietic development, we derived induced pluripotent stem cells (iPSCs) from fibroblasts of a DC patient carrying the most frequent mutation: DKC1 p.A353V. Telomeres eroded immediately after reprogramming in DKC1-mutant iPSCs but stabilized in later passages. The telomerase activity of mutant iPSCs was comparable to that observed in human embryonic stem cells, and no evidence of alternative lengthening of telomere pathways was detected. Hematopoietic differentiation was carried out in DKC1-mutant iPSC clones that resulted in increased capacity to generate hematopoietic colony-forming units compared to controls. Our study indicates that telomerase-dependent telomere maintenance is defective in pluripotent stem cells harboring DKC1 mutation and unable to elongate telomeres, but sufficient to maintain cell proliferation and self-renewal, as well as to support the primitive hematopoiesis, the program that is recapitulated with our differentiation protocol.},
}
@article {pmid31479729,
year = {2019},
author = {Denham, J and Stevenson, K and Denham, MM},
title = {Age-associated telomere shortening in Thoroughbred horses.},
journal = {Experimental gerontology},
volume = {127},
number = {},
pages = {110718},
doi = {10.1016/j.exger.2019.110718},
pmid = {31479729},
issn = {1873-6815},
mesh = {Aging/*genetics ; Animals ; Blotting, Southern ; Horses/*genetics ; Leukocytes/physiology ; Telomere Shortening/*physiology ; },
abstract = {Telomeres are genetically conserved repetitive terminal DNA that protect against genomic instability and shorten with ageing. Here, we reveal the leukocyte telomere length of Equus caballus by measuring terminal restriction fragments (TRFs) using Southern Blot analysis in a cohort of 43 Thoroughbred horses (age: 24 h-25 years). Heterogeneous TRFs were observed in each animal and large inter-animal variation in mean TRF was observed (range: 10.5-18.7 kbp). Mean TRFs were inversely correlated with age (r = -0.47). The estimated yearly rate of telomere attrition was 134 bp. Horses should be considered as an alternative animal model to investigate environmental and lifestyle factors that regulate telomeres and promote healthy ageing.},
}
@article {pmid31478401,
year = {2019},
author = {Niewisch, MR and Savage, SA},
title = {An update on the biology and management of dyskeratosis congenita and related telomere biology disorders.},
journal = {Expert review of hematology},
volume = {12},
number = {12},
pages = {1037-1052},
pmid = {31478401},
issn = {1747-4094},
support = {ZIA CP010144/ImNIH/Intramural NIH HHS/United States ; },
mesh = {*Dyskeratosis Congenita/diagnosis/genetics/metabolism/pathology ; *Germ-Line Mutation ; Humans ; *Telomere/genetics/metabolism/pathology ; },
abstract = {Introduction: Telomere biology disorders (TBDs) encompass a group of illnesses caused by germline mutations in genes regulating telomere maintenance, resulting in very short telomeres. Possible TBD manifestations range from complex multisystem disorders with onset in childhood such as dyskeratosis congenita (DC), Hoyeraal-Hreidarsson syndrome, Revesz syndrome and Coats plus to adults presenting with one or two DC-related features.Areas covered: The discovery of multiple genetic causes and inheritance patterns has led to the recognition of a spectrum of clinical features affecting multiple organ systems. Patients with DC and associated TBDs are at high risk of bone marrow failure, cancer, liver and pulmonary disease. Recently, vascular diseases, including pulmonary arteriovenous malformations and gastrointestinal telangiectasias, have been recognized as additional manifestations. Diagnostics include detection of very short leukocyte telomeres and germline genetic testing. Hematopoietic cell transplantation and lung transplantation are the only current therapeutic modalities but are complicated by numerous comorbidities. This review summarizes the pathophysiology underlying TBDs, associated clinical features, management recommendations and therapeutic options.Expert opinion: Understanding TBDs as complex, multisystem disorders with a heterogenous genetic background and diverse phenotypes, highlights the importance of clinical surveillance and the urgent need to develop new therapeutic strategies to improve health outcomes.},
}
@article {pmid31477194,
year = {2020},
author = {Ryan, KM and McLoughlin, DM},
title = {Telomere length in depression and association with therapeutic response to electroconvulsive therapy and cognitive side-effects.},
journal = {Psychological medicine},
volume = {50},
number = {12},
pages = {2096-2106},
doi = {10.1017/S0033291719002228},
pmid = {31477194},
issn = {1469-8978},
mesh = {Adult ; Aged ; *Cognition ; Depressive Disorder, Treatment-Resistant/genetics/*therapy ; Electroconvulsive Therapy/*adverse effects/*psychology ; Female ; Humans ; Linear Models ; Male ; Memory, Episodic ; Middle Aged ; Telomere Shortening/genetics/*physiology ; Treatment Outcome ; },
abstract = {BACKGROUND: Electroconvulsive therapy (ECT) is the most acutely effective treatment for severe treatment-resistant depression. However, there are concerns about its cognitive side-effects and we cannot yet confidently predict who will experience these. Telomeres are DNA-protein complexes that maintain genomic integrity. In somatic cells, telomeres shorten with each cell division. Telomere length (TL) can thus provide a measure of 'biological' aging. TL appears to be reduced in depression, though results are mixed. We sought to test the following hypotheses: (1) that TL would be shorter in patients with depression compared to controls; (2) that TL would be a predictor of response to ECT; and (3) that shorter TL would predict cognitive side-effects following ECT.<br><br>METHOD: We assessed TL in whole blood DNA collected from severely depressed patients (n = 100) recruited as part of the EFFECT-Dep Trial and healthy controls (n = 80) using quantitative real-time polymerase chain reaction. Mood and selected cognitive measures, including global cognition, re-orientation time, and autobiographical memory, were obtained pre-/post-ECT and from controls.<br><br>RESULTS: Our results indicate that TL does not differ between patients with depression compared to controls. TL itself was not associated with mood ratings and did not predict the therapeutic response to ECT. Furthermore, shorter baseline TL is not a predictor of cognitive side-effects post-ECT.<br><br>CONCLUSIONS: Overall, TL assessed by PCR does not represent a useful biomarker for predicting the therapeutic outcomes or risk for selected cognitive deficits following ECT.},
}
@article {pmid31475042,
year = {2019},
author = {Tomaska, L and Nosek, J and Kar, A and Willcox, S and Griffith, JD},
title = {A New View of the T-Loop Junction: Implications for Self-Primed Telomere Extension, Expansion of Disease-Related Nucleotide Repeat Blocks, and Telomere Evolution.},
journal = {Frontiers in genetics},
volume = {10},
number = {},
pages = {792},
pmid = {31475042},
issn = {1664-8021},
support = {P01 CA019014/CA/NCI NIH HHS/United States ; },
abstract = {Telomere loops (t-loops) are formed at the ends of chromosomes in species ranging from humans to worms, plants, and with genetic manipulation, some yeast. Recent in vitro studies demonstrated that transcription of telomeric DNA leads to highly efficient t-loop formation. It was also shown that both DNA termini are inserted into the preceding DNA to generate a highly stable t-loop junction. Furthermore, some telomeric RNA remains present at the junction, potentially acting as a plug to further protect and stabilize the t-loop. Modeling the loop junction reveals two mechanisms by which the canonical chromosomal replication factors could extend the telomere in the absence of telomerase. One mechanism would utilize the annealed 3' terminus as a de novo replication origin. In vitro evidence for the ability of the t-loop to prime telomere extension using the T7 replication factors is presented. A second mechanism would involve resolution of the Holliday junction present in the t-loop bubble by factors such as GEN1 to generate a rolling circle template at the extreme terminus of the telomere. This could lead to large expansions of the telomeric tract. Here, we propose that telomeres evolved as terminal elements containing long arrays of short nucleotide repeats due to the ability of such arrays to fold back into loops and self-prime their replicative extension. In this view, telomerase may have evolved later to provide a more precise mechanism of telomere maintenance. Both pathways have direct relevance to the alternative lengthening of telomeres (ALT) pathway. This view also provides a possible mechanism for the very large repeat expansions observed in nucleotide repeat diseases such as Fragile X syndrome, myotonic dystrophy, familial amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). The evolution of telomeres is discussed in the framework of these models.},
}
@article {pmid31470349,
year = {2019},
author = {Somkuti, J and Adányi, M and Smeller, L},
title = {Self-crowding influences the temperature - pressure stability of the human telomere G-quadruplex.},
journal = {Biophysical chemistry},
volume = {254},
number = {},
pages = {106248},
doi = {10.1016/j.bpc.2019.106248},
pmid = {31470349},
issn = {1873-4200},
mesh = {*G-Quadruplexes ; Humans ; Nucleic Acid Denaturation ; Pressure ; Spectrometry, Fluorescence ; Spectroscopy, Fourier Transform Infrared ; Telomere/*genetics ; Temperature ; },
abstract = {We measured the effect of crowded environment on G-quadruplex structures, formed by guanine rich DNA sequences. Fluorescence and infrared spectroscopy were used to determine the temperature stability of G-quadruplex structure formed by the human telomere sequence. We determined the T-p phase diagram of Htel aptamer up to 1 GPa at different self-crowding conditions. The unfolding volume change was determined from the pressure induced shift of the unfolding temperature of the quadruplex form. The unfolding volume change decreased in magnitude, and even its sign changed from negative (-19 ml/mol) to positive (7 ml/mol) under self-crowded conditions. The possible explanations are the appearance of the parallel GQ structure at high concentration or the fact that the volume decrease caused by the released central K[+] ion during the unfolding is less significant in crowded environment.},
}
@article {pmid31469870,
year = {2019},
author = {Ghimire, S and Hill, CV and Sy, FS and Rodriguez, R},
title = {Decline in telomere length by age and effect modification by gender, allostatic load and comorbidities in National Health and Nutrition Examination Survey (1999-2002).},
journal = {PloS one},
volume = {14},
number = {8},
pages = {e0221690},
pmid = {31469870},
issn = {1932-6203},
support = {R01 AG033592/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aging/*genetics/metabolism ; Allostasis/*genetics ; Comorbidity ; Cross-Sectional Studies ; Female ; Humans ; Male ; Middle Aged ; Nutrition Surveys ; Public Health Surveillance ; Sex Factors ; Telomere/*genetics/metabolism ; *Telomere Shortening ; United States/epidemiology ; },
abstract = {BACKGROUND: This study aims to assess the decline in telomere length (TL) with age and evaluate effect modification by gender, chronic stress, and comorbidity in a representative sample of the US population.<br><br>METHODS: Cross-sectional data on 7826 adults with a TL measurement, were included from the National Health and Nutrition Examination Survey, years 1999-2002. The population rate of decline in TL across 10-year age categories was estimated using crude and adjusted regression.<br><br>RESULTS: In an adjusted model, the population rate of decline in TL with age was consistent and linear for only three age categories: 20-29 (&#x3b2; = -0.0172, 95% CI: -0.0342, -0.0002), 50-59 (&#x3b2; = -0.0182, 95% CI: -0.0311, -0.0054) and 70-79 (&#x3b2; = -0.0170, 95% CI: -0.0329, -0.0011) years. The population rate of decline in TL with age was significantly greater for males and those with high allostatic load and a history of comorbidities. When the population rate of decline in TL was analyzed by gender in 10-year age bins, a fairly consistent yet statistically non-significant decline for males was observed; however, a trough in the rate was observed for females in the age categories 20-29 years (&#x3b2; = -0.0284, 95% CI: -0.0464, -0.0103) and 50-59 years (&#x3b2; = -0.0211, 95% CI: -0.0391, -0.0032). To further elucidate the gender difference observed in the primary analyses, secondary analyses were conducted with reproductive and hormonal status; a significant inverse association was found between TL and parity, menopause, and age at menopause.<br><br>CONCLUSIONS: TL was shorter with increasing age and this decline was modified by gender, chronic stress and comorbidities; individuals with chronic morbidity and/or chronic stress and females in their twenties and fifties experienced greater decline. Female reproductive factors, i.e., parity and menopause, were associated with TL.},
}
@article {pmid31467287,
year = {2019},
author = {Bottoni, G and Katarkar, A and Tassone, B and Ghosh, S and Clocchiatti, A and Goruppi, S and Bordignon, P and Jafari, P and Tordini, F and Lunardi, T and Hoetzenecker, W and Neel, V and Lingner, J and Paolo Dotto, G},
title = {CSL controls telomere maintenance and genome stability in human dermal fibroblasts.},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {3884},
pmid = {31467287},
issn = {2041-1723},
support = {R01 AR039190/AR/NIAMS NIH HHS/United States ; R01 AR064786/AR/NIAMS NIH HHS/United States ; },
mesh = {Cancer-Associated Fibroblasts/*metabolism ; Carcinoma, Squamous Cell/genetics/*metabolism ; DNA Damage ; DNA-Binding Proteins ; Fibroblasts/*metabolism ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; *Genomic Instability ; HEK293 Cells ; Homeostasis ; Humans ; Immunoglobulin J Recombination Signal Sequence-Binding Protein/*genetics/*metabolism ; Ku Autoantigen/metabolism ; Membrane Proteins ; Molecular Docking Simulation ; Mutagenesis ; RNA Helicases/metabolism ; Receptors, Notch/metabolism ; Signal Transduction ; Skin/metabolism ; Skin Neoplasms/genetics/metabolism ; Telomere/*metabolism ; Trans-Activators/metabolism ; },
abstract = {Genomic instability is a hallmark of cancer. Whether it also occurs in Cancer Associated Fibroblasts (CAFs) remains to be carefully investigated. Loss of CSL/RBP-Jκ, the effector of canonical NOTCH signaling with intrinsic transcription repressive function, causes conversion of dermal fibroblasts into CAFs. Here, we find that CSL down-modulation triggers DNA damage, telomere loss and chromosome end fusions that also occur in skin Squamous Cell Carcinoma (SCC)-associated CAFs, in which CSL is decreased. Separately from its role in transcription, we show that CSL is part of a multiprotein telomere protective complex, binding directly and with high affinity to telomeric DNA as well as to UPF1 and Ku70/Ku80 proteins and being required for their telomere association. Taken together, the findings point to a central role of CSL in telomere homeostasis with important implications for genomic instability of cancer stromal cells and beyond.},
}
@article {pmid31465482,
year = {2019},
author = {Luu, HN and Huang, JY and Wang, R and Adams-Haduch, J and Jin, A and Koh, WP and Yuan, JM},
title = {Association between leukocyte telomere length and the risk of pancreatic cancer: Findings from a prospective study.},
journal = {PloS one},
volume = {14},
number = {8},
pages = {e0221697},
pmid = {31465482},
issn = {1932-6203},
support = {P20 CA210300/CA/NCI NIH HHS/United States ; R01 CA144034/CA/NCI NIH HHS/United States ; UM1 CA182876/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; *Disease Susceptibility ; Female ; Follow-Up Studies ; Humans ; Incidence ; Leukocytes/*metabolism ; Male ; Middle Aged ; Pancreatic Neoplasms/*epidemiology/*etiology/metabolism/pathology ; Population Surveillance ; Prospective Studies ; Risk Factors ; Singapore/epidemiology ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {INTRODUCTION: Telomeres and telomerase play important role in maintaining chromosome integrity and genomic stability. Recent epidemiologic data showed inconsistent findings which suggested that both short and long leukocyte telomeres could be associated with increased risk of pancreatic cancer. We prospectively examined the association between telomere length and pancreatic cancer risk in a population-based cohort study.<br><br>METHODS: The Singapore Chinese Health Study recruited 63,257 Chinese aged 45 to 74 years from 1993 to 1998 in Singapore. Relative telomere length in peripheral blood leukocytes was quantified using a validated monochrome multiplex quantitative polymerase chain reaction method in 26,540 participants, including 116 participants who later developed pancreatic cancer after an average of 13 years of follow-up. Cox proportional hazard regression method was used to calculate hazard ratio (HR) and its 95% confidence interval (CI) of pancreatic cancer risk associated with telomere length, with adjustment for confounding factors.<br><br>RESULTS: Longer telomeres were significantly associated with higher risk of pancreatic cancer (Ptrend = 0.02). Compared with lowest quartile, subjects with highest quartile of telomere length had an HR of 2.18 (95% CI: 1.25-3.80) for developing pancreatic cancer. In stratified analysis, this association remained among pancreatic adenocarcinoma patients but not among pancreatic non-adenocarcinoma patients. In continuous scale, the HRs and 95% CIs were 3.08 (1.17-8.11) for adenocarcinoma patients and 1.47 (0.43-5.06) for non-adenocarcinoma patients. The HRs and 95% CIs of the highest quartile of telomere length, compared with the lowest quartile, for adenocarcinoma and non-adenocarcinoma were 2.50 (1.22-5.13) and 1.63 (0.66-4.03), respectively. The length of follow-up from the collection of blood for the measurement of telomere length to the diagnosis of cancer (median = 8.0, range: from 5.0 months to 16.2 years) had no significant impact on the association between telomere length and pancreatic cancer risk.<br><br>CONCLUSIONS: The present study demonstrates that longer telomeres are associated with increased risk of overall pancreatic cancer.},
}
@article {pmid31465289,
year = {2020},
author = {Gorenjak, V and Petrelis, AM and Stathopoulou, MG and Visvikis-Siest, S},
title = {Telomere length determinants in childhood.},
journal = {Clinical chemistry and laboratory medicine},
volume = {58},
number = {2},
pages = {162-177},
doi = {10.1515/cclm-2019-0235},
pmid = {31465289},
issn = {1437-4331},
mesh = {Biomarkers/metabolism ; Child ; Genetic Variation ; Humans ; Infant, Newborn ; Neoplasms/genetics/pathology ; Risk Factors ; Stress, Psychological ; Telomere/*physiology ; *Telomere Shortening ; },
abstract = {Telomere length (TL) is a dynamic marker that reflects genetic predispositions together with the environmental conditions of an individual. It is closely related to longevity and a number of pathological conditions. Even though the extent of telomere research in children is limited compared to that of adults, there have been a substantial number of studies providing first insights into child telomere biology and determinants. Recent discoveries revealed evidence that TL is, to a great extent, determined already in childhood and that environmental conditions in adulthood have less impact than first believed. Studies have demonstrated that large inter-individual differences in TL are present among newborns and are determined by diverse factors that influence intrauterine development. The first years of child growth are associated with high cellular turnover, which results in fast shortening of telomeres. The rate of telomere loss becomes stable in early adulthood. In this review article we summarise the existing knowledge on telomere dynamics during the first years of childhood, highlighting the conditions that affect newborn TL. We also warn about the knowledge gaps that should be filled to fully understand the regulation of telomeres, in order to implement them as biomarkers for use in diagnostics or treatment.},
}
@article {pmid31462927,
year = {2019},
author = {Stindl, R},
title = {Transgenerational telomere erosion in the monogametic sex: human telomeres progressively erode in the female germline and do not lengthen in aged testes.},
journal = {Molecular cytogenetics},
volume = {12},
number = {},
pages = {37},
pmid = {31462927},
issn = {1755-8166},
abstract = {Long telomeres, the protective caps of eukaryotic chromosomes, which erode during aging, have been the symbol of youth and regenerative potential. It therefore came as a surprise, when several cross-sectional studies reported that telomeres in sperm cells of old men are longer than in young men and that paternal age is positively linked to telomere length of children. To explain the puzzling data, several theories have been put forward, from Darwinian selection to high telomerase activity or alternative telomere lengthening in sperms of geriatrics. Unfortunately, the idea of a birth-cohort effect has been ignored, despite existing theoretical models and despite findings of progressive telomere erosion between human generations. The old theoretical model of progressive telomere erosion in the female germline is discussed here and updated with the hypothesis that progressive telomere erosion is tied to the monogametic sex in all higher animals. Longitudinal studies of germline telomere length in humans are much needed, since a limited regenerative capacity of somatic tissues will most likely result in an increase in and earlier onset of the so-called age-associated diseases.},
}
@article {pmid31462295,
year = {2019},
author = {Rodriguez, FJ and Graham, MK and Brosnan-Cashman, JA and Barber, JR and Davis, C and Vizcaino, MA and Palsgrove, DN and Giannini, C and Pekmezci, M and Dahiya, S and Gokden, M and Noë, M and Wood, LD and Pratilas, CA and Morris, CD and Belzberg, A and Blakeley, J and Heaphy, CM},
title = {Telomere alterations in neurofibromatosis type 1-associated solid tumors.},
journal = {Acta neuropathologica communications},
volume = {7},
number = {1},
pages = {139},
pmid = {31462295},
issn = {2051-5960},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; T32 CA009110/CA/NCI NIH HHS/United States ; T32 CA193145/CA/NCI NIH HHS/United States ; U54 CA196519/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Brain Neoplasms/*genetics ; Female ; Glioma/genetics ; Humans ; Kaplan-Meier Estimate ; Male ; Mutation ; Neurofibromatosis 1/*genetics ; Neurofibromin 1/genetics ; Neurofibrosarcoma/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Young Adult ; },
abstract = {The presence of Alternative lengthening of telomeres (ALT) and/or ATRX loss, as well as the role of other telomere abnormalities, have not been formally studied across the spectrum of NF1-associated solid tumors. Utilizing a telomere-specific FISH assay, we classified tumors as either ALT-positive or having long (without ALT), short, or normal telomere lengths. A total of 426 tumors from 256 NF1 patients were evaluated, as well as 99 MPNST tumor samples that were sporadic or of unknown NF1 status. In the NF1-glioma dataset, ALT was present in the majority of high-grade gliomas: 14 (of 23; 60%) in contrast to only 9 (of 47; 19%) low-grade gliomas (p = 0.0009). In the subset of ALT-negative glioma cases, telomere lengths were estimated and we observed 17 (57%) cases with normal, 12 (40%) cases with abnormally long, and only 1 (3%) case with short telomeres. In the NF1-associated malignant nerve sheath tumor (NF1-MPNST) set (n = 75), ALT was present in 9 (12%). In the subset of ALT-negative NF1-MPNST cases, telomeres were short in 9 (38%), normal in 14 (58%) and long in 1 (3%). In the glioma set, overall survival was significantly decreased for patients with ALT-positive tumors (p < 0.0001). In the NF1-MPNST group, overall survival was superior for patients with tumors with short telomeres (p = 0.003). ALT occurs in a subset of NF1-associated solid tumors and is usually restricted to malignant subsets. In contrast, alterations in telomere lengths are more prevalent than ALT.},
}
@article {pmid31462251,
year = {2019},
author = {Gibson, EA and Nunez, Y and Abuawad, A and Zota, AR and Renzetti, S and Devick, KL and Gennings, C and Goldsmith, J and Coull, BA and Kioumourtzoglou, MA},
title = {An overview of methods to address distinct research questions on environmental mixtures: an application to persistent organic pollutants and leukocyte telomere length.},
journal = {Environmental health : a global access science source},
volume = {18},
number = {1},
pages = {76},
pmid = {31462251},
issn = {1476-069X},
support = {ES030263/ES/NIEHS NIH HHS/United States ; ES028811/ES/NIEHS NIH HHS/United States ; T32 ES007322/ES/NIEHS NIH HHS/United States ; ES028805/ES/NIEHS NIH HHS/United States ; R25 GM062454/GM/NIGMS NIH HHS/United States ; R01 ES028811/ES/NIEHS NIH HHS/United States ; U2C ES026555/ES/NIEHS NIH HHS/United States ; P30 ES023515/ES/NIEHS NIH HHS/United States ; F31 ES030263/ES/NIEHS NIH HHS/United States ; R01 ES028805/ES/NIEHS NIH HHS/United States ; T32 ES007142/ES/NIEHS NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; ES028800/ES/NIEHS NIH HHS/United States ; P30 ES000002/ES/NIEHS NIH HHS/United States ; R01 ES028800/ES/NIEHS NIH HHS/United States ; R01 ES028805-S1/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Environmental Exposure/*analysis ; Environmental Monitoring/*methods ; Environmental Pollutants/*adverse effects ; Female ; Humans ; Leukocytes ; Male ; Middle Aged ; Research Design/statistics &amp; numerical data ; Telomere Homeostasis/*drug effects ; Telomere Shortening/*drug effects ; Young Adult ; },
abstract = {BACKGROUND: Numerous methods exist to analyze complex environmental mixtures in health studies. As an illustration of the different uses of mixture methods, we employed methods geared toward distinct research questions concerning persistent organic chemicals (POPs) as a mixture and leukocyte telomere length (LTL) as an outcome.<br><br>METHODS: With information on 18 POPs and LTL among 1,003 U.S. adults (NHANES, 2001-2002), we used unsupervised methods including clustering to identify profiles of similarly exposed participants, and Principal Component Analysis (PCA) and Exploratory Factor Analysis (EFA) to identify common exposure patterns. We also employed supervised learning techniques, including penalized, weighted quantile sum (WQS), and Bayesian kernel machine (BKMR) regressions, to identify potentially toxic agents, and characterize nonlinear associations, interactions, and the overall mixture effect.<br><br>RESULTS: Clustering separated participants into high, medium, and low POP exposure groups; longer log-LTL was found among those with high exposure. The first PCA component represented overall POP exposure and was positively associated with log-LTL. Two EFA factors, one representing furans and the other PCBs 126 and 118, were positively associated with log-LTL. Penalized regression methods selected three congeners in common (PCB 126, PCB 118, and furan 2,3,4,7,8-pncdf) as potentially toxic agents. WQS found a positive overall effect of the POP mixture and identified six POPs as potentially toxic agents (furans 1,2,3,4,6,7,8-hxcdf, 2,3,4,7,8-pncdf, and 1,2,3,6,7,8-hxcdf, and PCBs 99, 126, 169). BKMR found a positive linear association with furan 2,3,4,7,8-pncdf, suggestive evidence of linear associations with PCBs 126 and 169, and a positive overall effect of the mixture, but no interactions among congeners.<br><br>CONCLUSIONS: Using different methods, we identified patterns of POP exposure, potentially toxic agents, the absence of interaction, and estimated the overall mixture effect. These applications and results may serve as a guide for mixture method selection based on specific research questions.},
}
@article {pmid31461406,
year = {2019},
author = {Lee, Y and Sun, D and Ori, APS and Lu, AT and Seeboth, A and Harris, SE and Deary, IJ and Marioni, RE and Soerensen, M and Mengel-From, J and Hjelmborg, J and Christensen, K and Wilson, JG and Levy, D and Reiner, AP and Chen, W and Li, S and Harris, JR and Magnus, P and Aviv, A and Jugessur, A and Horvath, S},
title = {Epigenome-wide association study of leukocyte telomere length.},
journal = {Aging},
volume = {11},
number = {16},
pages = {5876-5894},
pmid = {31461406},
issn = {1945-4589},
support = {R03 AG060619/AG/NIA NIH HHS/United States ; R01 AG016592/AG/NIA NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; MR/M01311/1/MRC_/Medical Research Council/United Kingdom ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; HHSN268201500001I/HL/NHLBI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; HHSN268201800010I/HB/NHLBI NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; BB/F019394/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; HHSN268201800012I/HB/NHLBI NIH HHS/United States ; MR/K026992/1/MRC_/Medical Research Council/United Kingdom ; HHSN268201800012C/HL/NHLBI NIH HHS/United States ; U01 AG060908/AG/NIA NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; HHSN268201500001C/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; HHSN268201800014I/HB/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; R01 AG029451/AG/NIA NIH HHS/United States ; P01 AG008761/AG/NIA NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; U54 GM115428/GM/NIGMS NIH HHS/United States ; R01 HL134840/HL/NHLBI NIH HHS/United States ; },
mesh = {Aging/*genetics ; CpG Islands/genetics ; *DNA Methylation ; *Epigenome ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Telomere/*metabolism ; },
abstract = {Telomere length is associated with age-related diseases and is highly heritable. It is unclear, however, to what extent epigenetic modifications are associated with leukocyte telomere length (LTL). In this study, we conducted a large-scale epigenome-wide association study (EWAS) of LTL using seven large cohorts (n=5,713) - the Framingham Heart Study, the Jackson Heart Study, the Women's Health Initiative, the Bogalusa Heart Study, the Lothian Birth Cohorts of 1921 and 1936, and the Longitudinal Study of Aging Danish Twins. Our stratified analysis suggests that EWAS findings for women of African ancestry may be distinct from those of three other groups: males of African ancestry, and males and females of European ancestry. Using a meta-analysis framework, we identified DNA methylation (DNAm) levels at 823 CpG sites to be significantly associated (P<1E-7) with LTL after adjusting for age, sex, ethnicity, and imputed white blood cell counts. Functional enrichment analyses revealed that these CpG sites are near genes that play a role in circadian rhythm, blood coagulation, and wound healing. Weighted correlation network analysis identified four co-methylation modules associated with LTL, age, and blood cell counts. Overall, this study reveals highly significant relationships between two hallmarks of aging: telomere biology and epigenetic changes.},
}
@article {pmid31459122,
year = {2018},
author = {Villani, G},
title = {Quantum Mechanical Investigation of the G-Quadruplex Systems of Human Telomere.},
journal = {ACS omega},
volume = {3},
number = {8},
pages = {9934-9944},
pmid = {31459122},
issn = {2470-1343},
abstract = {The three G-quadruplexes involved in the human telomere have been studied with an accurate quantum mechanical approach, and the possibility of reducing them to a simpler model has been tested. The similarities and the differences of these three systems are shown and discussed. Each system has been analyzed through different properties and compared to the others. In particular, we have considered: (1) the shape of the cavity and the atomic charges around it; (2) the electric field in and out of the cavity; (3) the stabilization energy due to the stacking of G-tetrads, to the H-bonds and to the ion interactions; and, finally, (4) to study the mechanism of the process of the ion inclusion in the cavity, the curves of potential energy due to the movement of the Na[+] and K[+] ions toward the cavity. The results suggest that a detailed study is essential in order to obtain the quantitative properties of these complex systems, but also that some qualitative behaviors can be schematized. Our study makes it clear that the entry of an ion in the cavity of these systems is a complex process, where it is possible to find stable structures with the ion out and in the cavity. Moreover, it is possible that more than one diabatic state is involved in this process.},
}
@article {pmid31456360,
year = {2019},
author = {Nguyen, MT and Saffery, R and Burgner, D and Lycett, K and Vryer, R and Grobler, A and Dwyer, T and Ranganathan, S and Wake, M},
title = {Telomere length and lung function in a population-based cohort of children and mid-life adults.},
journal = {Pediatric pulmonology},
volume = {54},
number = {12},
pages = {2044-2052},
doi = {10.1002/ppul.24489},
pmid = {31456360},
issn = {1099-0496},
mesh = {Aged ; Asthma/physiopathology ; Body Mass Index ; Child ; Cohort Studies ; Cross-Sectional Studies ; Exercise ; Female ; Forced Expiratory Volume ; Humans ; Lung/*physiology/physiopathology ; Male ; Respiratory Function Tests ; Risk Factors ; Smoking ; Spirometry ; *Telomere ; Vital Capacity ; },
abstract = {OBJECTIVE: Telomere length is associated with poorer lung health in older adults, possibly from cumulative risk factor exposure, but data are lacking in pediatric and population-based cohorts. We examined associations of telomere length with lung function in children and mid-life adults.<br><br>METHODS: Data were drawn from a population-based cross-sectional study of 11 to 12 year-olds and mid-life adults. Lung function was assessed by spirometric FEV1 , FVC, FEV 1 /FVC ratio, and MMEF 25-75 . Telomere length was measured by quantitative polymerase chain reaction from blood and expressed as the amount of telomeric genomic DNA to the beta-globin gene (T/S ratio). Associations of telomere length with spirometric parameters were tested by linear and logistic regression models, adjusting for potential confounders of sex, age, body mass index, socioeconomic position, physical activity, inflammation, asthma, pubertal status, and smoking.<br><br>RESULTS: Mean T/S ratio was 1.09 (n&#x2009;=&#x2009;1206; SD 0.55) in children and 0.81 (n&#x2009;=&#x2009;1343; SD 0.38) in adults. In adults, for every additional unit in T/S ratio, FEV 1 /FVC and MMEF 25-75 z-scores were higher (&#x3b2; 0.21 [95% confidence interval, CI; 0.06-0.36] and 0.23 [95% CI; 0.08-0.38], respectively), and the likelihood of being in the lowest quartile for FEV 1 /FVC and MMEF 25-75 z-scores was lower (odds ratios 0.59 [95% CI, 0.39-0.89] and 0.64 [95% CI, 0.41-0.99], respectively). No evidence of association was seen for adult FEV 1 or FVC, or any childhood spirometric index after adjustments.<br><br>CONCLUSION: Shorter telomere length showed moderate associations with poorer airflow parameters, but not vital capacity (lung volume) in mid-life adults. However, there was no convincing evidence of associations in children.},
}
@article {pmid31455861,
year = {2020},
author = {Cabeza de Baca, T and Prather, AA and Lin, J and Sternfeld, B and Adler, N and Epel, ES and Puterman, E},
title = {Chronic psychosocial and financial burden accelerates 5-year telomere shortening: findings from the Coronary Artery Risk Development in Young Adults Study.},
journal = {Molecular psychiatry},
volume = {25},
number = {5},
pages = {1141-1153},
pmid = {31455861},
issn = {1476-5578},
support = {T32 MH019391/MH/NIMH NIH HHS/United States ; HHSN268201300028C/AG/NIA NIH HHS/United States ; HHSN268201300027C/HL/NHLBI NIH HHS/United States ; HHSN268200900041C/HL/NHLBI NIH HHS/United States ; HHSN268201300029C/HL/NHLBI NIH HHS/United States ; HHSN268201300025C/AG/NIA NIH HHS/United States ; HHSN268201300026C/HL/NHLBI NIH HHS/United States ; R00 HL109247/HL/NHLBI NIH HHS/United States ; K99 HL109247/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; *Coronary Vessels/pathology ; Cross-Sectional Studies ; Female ; Health Behavior ; Humans ; Leukocytes/metabolism ; Longitudinal Studies ; Male ; Resilience, Psychological ; Risk Factors ; Social Support ; *Socioeconomic Factors ; Telomere/genetics/*metabolism ; *Telomere Shortening ; Time Factors ; Young Adult ; },
abstract = {Leukocyte telomere length, a marker of immune system function, is sensitive to exposures such as psychosocial stressors and health-maintaining behaviors. Past research has determined that stress experienced in adulthood is associated with shorter telomere length, but is limited to mostly cross-sectional reports. We test whether repeated reports of chronic psychosocial and financial burden is associated with telomere length change over a 5-year period (years 15 and 20) from 969 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a longitudinal, population-based cohort, ages 18-30 at time of recruitment in 1985. We further examine whether multisystem resiliency, comprised of social connections, health-maintaining behaviors, and psychological resources, mitigates the effects of repeated burden on telomere attrition over 5 years. Our results indicate that adults with high chronic burden do not show decreased telomere length over the 5-year period. However, these effects do vary by level of resiliency, as regression results revealed a significant interaction between chronic burden and multisystem resiliency. For individuals with high repeated chronic burden and low multisystem resiliency (1 SD below the mean), there was a significant 5-year shortening in telomere length, whereas no significant relationships between chronic burden and attrition were evident for those at moderate and higher levels of resiliency. These effects apply similarly across the three components of resiliency. Results imply that interventions should focus on establishing strong social connections, psychological resources, and health-maintaining behaviors when attempting to ameliorate stress-related decline in telomere length among at-risk individuals.},
}
@article {pmid31454352,
year = {2019},
author = {Irie, H and Yamamoto, I and Tarumoto, Y and Tashiro, S and Runge, KW and Ishikawa, F},
title = {Telomere-binding proteins Taz1 and Rap1 regulate DSB repair and suppress gross chromosomal rearrangements in fission yeast.},
journal = {PLoS genetics},
volume = {15},
number = {8},
pages = {e1008335},
pmid = {31454352},
issn = {1553-7404},
support = {R01 AG051601/AG/NIA NIH HHS/United States ; },
mesh = {DNA Breaks, Double-Stranded ; *DNA Repair ; *Gene Rearrangement ; Genomic Instability ; Mutation ; Schizosaccharomyces/*genetics ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Shelterin Complex ; Telomere Homeostasis ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Genomic rearrangements (gross chromosomal rearrangements, GCRs) threatens genome integrity and cause cell death or tumor formation. At the terminus of linear chromosomes, a telomere-binding protein complex, called shelterin, ensures chromosome stability by preventing chromosome end-to-end fusions and regulating telomere length homeostasis. As such, shelterin-mediated telomere functions play a pivotal role in suppressing GCR formation. However, it remains unclear whether the shelterin proteins play any direct role in inhibiting GCR at non-telomeric regions. Here, we have established a GCR assay for the first time in fission yeast and measured GCR rates in various mutants. We found that fission yeast cells lacking shelterin components Taz1 or Rap1 (mammalian TRF1/2 or RAP1 homologues, respectively) showed higher GCR rates compared to wild-type, accumulating large chromosome deletions. Genetic dissection of Rap1 revealed that Rap1 contributes to inhibiting GCRs via two independent pathways. The N-terminal BRCT-domain promotes faithful DSB repair, as determined by I-SceI-mediated DSB-induction experiments; moreover, association with Poz1 mediated by the central Poz1-binding domain regulates telomerase accessibility to DSBs, leading to suppression of de novo telomere additions. Our data highlight unappreciated functions of the shelterin components Taz1 and Rap1 in maintaining genome stability, specifically by preventing non-telomeric GCRs.},
}
@article {pmid31454099,
year = {2019},
author = {Li, F and Deng, Z and Zhang, L and Wu, C and Jin, Y and Hwang, I and Vladimirova, O and Xu, L and Yang, L and Lu, B and Dheekollu, J and Li, JY and Feng, H and Hu, J and Vakoc, CR and Ying, H and Paik, J and Lieberman, PM and Zheng, H},
title = {ATRX loss induces telomere dysfunction and necessitates induction of alternative lengthening of telomeres during human cell immortalization.},
journal = {The EMBO journal},
volume = {38},
number = {19},
pages = {e96659},
pmid = {31454099},
issn = {1460-2075},
support = {R01AG 048284//National Institute for health (NIH/NIA)/International ; 15-0338/AICR_/Worldwide Cancer Research/United Kingdom ; R01CA140652//National Institute for Health (NIH/NCI)/International ; P30CA10815//National Institute for Health (NIH/NCI)/International ; //Chen &amp; Xiao Anti-Cancer Foundation/International ; P30 CA045508/CA/NCI NIH HHS/United States ; P01 CA013106/CA/NCI NIH HHS/United States ; //CSHL/Northwell Institutional Fund/International ; //Sontag Foundation/International ; //Sidney Kimmel Foundation/International ; 81672783//National Natural Science Foundation of China/International ; P30 CA010815/CA/NCI NIH HHS/United States ; //Bradley Zankel Foundation/International ; },
mesh = {Cell Line ; Co-Repressor Proteins/*genetics ; DNA Repair ; Gene Deletion ; HEK293 Cells ; Humans ; Molecular Chaperones/*genetics ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; X-linked Nuclear Protein/*genetics ; },
abstract = {Loss of the histone H3.3-specific chaperone component ATRX or its partner DAXX frequently occurs in human cancers that employ alternative lengthening of telomeres (ALT) for chromosomal end protection, yet the underlying mechanism remains unclear. Here, we report that ATRX/DAXX does not serve as an immediate repressive switch for ALT. Instead, ATRX or DAXX depletion gradually induces telomere DNA replication dysfunction that activates not only homology-directed DNA repair responses but also cell cycle checkpoint control. Mechanistically, we demonstrate that this process is contingent on ATRX/DAXX histone chaperone function, independently of telomere length. Combined ATAC-seq and telomere chromatin immunoprecipitation studies reveal that ATRX loss provokes progressive telomere decondensation that culminates in the inception of persistent telomere replication dysfunction. We further show that endogenous telomerase activity cannot overcome telomere dysfunction induced by ATRX loss, leaving telomere repair-based ALT as the only viable mechanism for telomere maintenance during immortalization. Together, these findings implicate ALT activation as an adaptive response to ATRX/DAXX loss-induced telomere replication dysfunction.},
}
@article {pmid31451640,
year = {2019},
author = {Qian, W and Kumar, N and Roginskaya, V and Fouquerel, E and Opresko, PL and Shiva, S and Watkins, SC and Kolodieznyi, D and Bruchez, MP and Van Houten, B},
title = {Chemoptogenetic damage to mitochondria causes rapid telomere dysfunction.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {116},
number = {37},
pages = {18435-18444},
pmid = {31451640},
issn = {1091-6490},
support = {R33 ES025606/ES/NIEHS NIH HHS/United States ; R35 ES030396/ES/NIEHS NIH HHS/United States ; P30 CA047904/CA/NCI NIH HHS/United States ; R01 EB017268/EB/NIBIB NIH HHS/United States ; },
mesh = {Apoptosis/drug effects ; Cell Cycle ; Cell Proliferation/drug effects ; DNA Breaks, Double-Stranded ; DNA Damage ; DNA Repair ; DNA, Mitochondrial/metabolism ; HEK293 Cells ; Humans ; Hydrogen Peroxide/metabolism/toxicity ; Membrane Potentials ; Mitochondria/*chemistry/*drug effects/*metabolism ; Mitochondrial Diseases/metabolism ; Oxidative Stress ; Oxygen/metabolism ; Reactive Oxygen Species/metabolism/toxicity ; Signal Transduction ; Superoxides/metabolism/toxicity ; Telomere/*metabolism ; Tumor Suppressor p53-Binding Protein 1/metabolism ; },
abstract = {Reactive oxygen species (ROS) play important roles in aging, inflammation, and cancer. Mitochondria are an important source of ROS; however, the spatiotemporal ROS events underlying oxidative cellular damage from dysfunctional mitochondria remain unresolved. To this end, we have developed and validated a chemoptogenetic approach that uses a mitochondrially targeted fluorogen-activating peptide (Mito-FAP) to deliver a photosensitizer MG-2I dye exclusively to this organelle. Light-mediated activation (660 nm) of the Mito-FAP-MG-2I complex led to a rapid loss of mitochondrial respiration, decreased electron transport chain complex activity, and mitochondrial fragmentation. Importantly, one round of singlet oxygen produced a persistent secondary wave of mitochondrial superoxide and hydrogen peroxide lasting for over 48 h after the initial insult. By following ROS intermediates, we were able to detect hydrogen peroxide in the nucleus through ratiometric analysis of the oxidation of nuclear cysteine residues. Despite mitochondrial DNA (mtDNA) damage and nuclear oxidative stress induced by dysfunctional mitochondria, there was a lack of gross nuclear DNA strand breaks and apoptosis. Targeted telomere analysis revealed fragile telomeres and telomere loss as well as 53BP1-positive telomere dysfunction-induced foci (TIFs), indicating that DNA double-strand breaks occurred exclusively in telomeres as a direct consequence of mitochondrial dysfunction. These telomere defects activated ataxia-telangiectasia mutated (ATM)-mediated DNA damage repair signaling. Furthermore, ATM inhibition exacerbated the Mito-FAP-induced mitochondrial dysfunction and sensitized cells to apoptotic cell death. This profound sensitivity of telomeres through hydrogen peroxide induced by dysregulated mitochondria reveals a crucial mechanism of telomere-mitochondria communication underlying the pathophysiological role of mitochondrial ROS in human diseases.},
}
@article {pmid31450905,
year = {2019},
author = {Calastri, MCJ and Hattori, G and Rodrigues, NLTO and Gregorio, ML and Brancati, CIFO and Zanovelo, EM and Ferraz Filho, JRL and Neiva, CM and Rodrigues Junior, ACP and de Godoy, MF and Lancellotti, CLP and Tognola, WA and Souza, DRS},
title = {Genetic Variants Related to Cell Cycle and Stability of Telomere in Patients with Glioma.},
journal = {Asian Pacific journal of cancer prevention : APJCP},
volume = {20},
number = {8},
pages = {2345-2351},
pmid = {31450905},
issn = {2476-762X},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/*genetics ; Brain Neoplasms/genetics/pathology ; Case-Control Studies ; Child ; Child, Preschool ; Cyclin D1/*genetics ; DNA Helicases/*genetics ; Female ; Follow-Up Studies ; Gene Expression Regulation, Neoplastic ; Genotype ; Glioma/*genetics/*pathology ; Humans ; Infant ; Male ; Middle Aged ; Neoplasm Grading ; *Polymorphism, Genetic ; Survival Rate ; Telomere/chemistry/genetics ; X-ray Repair Cross Complementing Protein 1/*genetics ; Young Adult ; },
abstract = {Background: Glioma, most common primary malignant brain tumor in adults, is highly aggressive and associated with a poor prognosis. Evaluate the association of polymorphisms related of to the cell cycle, integrity and DNA repair with gliomas, as well as lifestyle habits, comorbidities, survival and response to treatment. Methods: Were studied 303 individuals distributed into: Study Group - 100 patients with gliomas, regardless of the degree of malignancy, and Control Group - 203 individuals without clinical signs of the disease. These polymorphisms were genotyped by TaqMan® SNP Genotyping Assay. Significance level was set at 5%. Results: Smoking, alcohol consumption, systemic arterial hypertension (SAH) and diabetes mellitus (DM) prevailed in patients, compared to controls (P=0.0088, P=0.0001, P=0.0001, P=0.0011, respectively). In the logistic regression analysis, alcohol consumption and SAH were identified as independent risk factors for gliomas (P=0.0001, P=0.0027, respectively). Patients with low-grade gliomas showed survival in one year (92.0±6.8%), compared to patients with high-grade gliomas (24.0±5.3; P=0.011). Conclusion: Polymorphisms involved in cell cycle, telomere protection and stability and DNA repair are not associated with gliomas. On the other hand, alcohol consumption and SAH stand out as independent risk factors for the disease. Low-grade gliomas, response to treatment and the combination of chemotherapy with Temozolomide and radiation therapy show increased survival of patients.},
}
@article {pmid31449465,
year = {2019},
author = {Song, L and Liu, B and Wu, M and Zhang, L and Wang, L and Zhang, B and Xiong, C and Li, Y and Cao, Z and Wang, Y and Xu, S},
title = {Prenatal Exposure to Phthalates and Newborn Telomere Length: A Birth Cohort Study in Wuhan, China.},
journal = {Environmental health perspectives},
volume = {127},
number = {8},
pages = {87007},
pmid = {31449465},
issn = {1552-9924},
mesh = {China ; Cohort Studies ; Environmental Pollutants/*adverse effects ; Female ; Fetal Blood/chemistry ; Humans ; Infant, Newborn ; Male ; Maternal Exposure/*adverse effects ; Parturition ; Phthalic Acids/*adverse effects ; Pregnancy ; Sex Factors ; Telomere Shortening/*drug effects ; },
abstract = {BACKGROUND: Telomere length (TL) is a marker of biological aging and is inversely related to aging-related diseases. The setting of TL at birth may have important implications for lifelong telomere dynamics; however, its determinants remain poorly understood.<br><br>OBJECTIVES: The purpose of our study was to explore the relationships between prenatal exposure to phthalates and umbilical cord blood TL.<br><br>METHODS: A total of 762 mother&#x2013;newborn pairs were recruited from a birth cohort study performed between November 2013 and March 2015 in Wuhan, China. Relative cord blood TL was measured using quantitative real-time polymerase chain reaction. Six phthalate metabolites were measured in urine samples acquired from pregnant women during the three trimesters. Multiple informant models were applied to estimate the associations between prenatal exposure to phthalates and cord blood TL and to evaluate potential windows of vulnerability.<br><br>RESULTS: Exposure to mono-ethyl phthalate (MEP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-butyl phthalate (MBP), and di(2-ethylhexyl) phthalate ([Formula: see text]) during the first trimester were inversely related to cord blood TL. In addition, we observed a female-specific association between maternal exposure to MEP during the first trimester and cord blood TL ([Formula: see text]). The associations between maternal exposure to MECPP, MEHHP, MEOHP, and [Formula: see text] during the first trimester and cord blood TL were consistent between males and females (all [Formula: see text]).<br><br>CONCLUSION: This prospective study demonstrated that prenatal exposure to some phthalate metabolites were associated with shorter cord blood TL. Our results, if confirmed in other populations, may provide more evidence of adverse health outcomes of phthalate exposure and support the hypothesis that the intrauterine environment may be one of the major determinants for newborn TL. https://doi.org/10.1289/EHP4492.},
}
@article {pmid31448843,
year = {2019},
author = {Dodson, LM and Baldan, A and Nissbeck, M and Gunja, SMR and Bonnen, PE and Aubert, G and Birchansky, S and Virtanen, A and Bertuch, AA},
title = {From incomplete penetrance with normal telomere length to severe disease and telomere shortening in a family with monoallelic and biallelic PARN pathogenic variants.},
journal = {Human mutation},
volume = {40},
number = {12},
pages = {2414-2429},
pmid = {31448843},
issn = {1098-1004},
support = {Bridge Award//American Society of Hematology/International ; T32GM007330/GM/NIGMS NIH HHS/United States ; //The Cullen Foundation/International ; R01 HL131744/HL/NHLBI NIH HHS/United States ; R01NS08372/NS/NINDS NIH HHS/United States ; T32 GM007330/GM/NIGMS NIH HHS/United States ; F31 HL142185/HL/NHLBI NIH HHS/United States ; //Linnaeus Support from the Swedish Research Council to the Uppsala RNA Research Centre/International ; T32DK060445/DK/NIDDK NIH HHS/United States ; R01HL131744/HL/NHLBI NIH HHS/United States ; T32 DK060445/DK/NIDDK NIH HHS/United States ; R01 NS083726/NS/NINDS NIH HHS/United States ; },
mesh = {Adolescent ; Cell Line ; Child, Preschool ; Down-Regulation ; Dyskeratosis Congenita/*genetics ; Exoribonucleases/*genetics/metabolism ; Female ; Fetal Growth Retardation/*genetics ; Humans ; Intellectual Disability/*genetics ; Male ; MicroRNAs/*genetics ; Microcephaly/*genetics ; *Mutagenesis, Insertional ; *Mutation, Missense ; Pedigree ; Penetrance ; Telomere Shortening ; },
abstract = {PARN encodes poly(A)-specific ribonuclease. Biallelic and monoallelic PARN variants are associated with Hoyeraal-Hreidarsson syndrome/dyskeratosis congenita and idiopathic pulmonary fibrosis (IPF), respectively. The molecular features associated with incomplete penetrance of PARN-associated IPF have not been described. We report a family with a rare missense, p.Y91C, and a novel insertion, p.(I274*), PARN variant. We found PARN p.Y91C had reduced deadenylase activity and the p.(I274*) transcript was depleted. Detailed analysis of the consequences of these variants revealed that, while PARN protein was lowest in the severely affected biallelic child who had the shortest telomeres, it was also reduced in his mother with the p.(I274*) variant but telomeres at the 50th percentile. Increased adenylation of telomerase RNA, human telomerase RNA, and certain small nucleolar RNAs, and impaired ribosomal RNA maturation were observed in cells derived from the severely affected biallelic carrier, but not in the other, less affected biallelic carrier, who had less severely shortened telomeres, nor in the monoallelic carriers who were unaffected and had telomeres ranging from the 1st to the 50th percentiles. We identified hsa-miR-202-5p as a potential negative regulator of PARN. We propose one or more genetic modifiers influence the impact of PARN variants on its targets and this underlies incomplete penetrance of PARN-associated disease.},
}
@article {pmid31446635,
year = {2019},
author = {van Lieshout, SHJ and Bretman, A and Newman, C and Buesching, CD and Macdonald, DW and Dugdale, HL},
title = {Individual variation in early-life telomere length and survival in a wild mammal.},
journal = {Molecular ecology},
volume = {28},
number = {18},
pages = {4152-4165},
doi = {10.1111/mec.15212},
pmid = {31446635},
issn = {1365-294X},
mesh = {Animals ; Animals, Wild/*genetics ; Confidence Intervals ; Female ; *Genetic Variation ; Leukocytes/metabolism ; Longevity/genetics ; Male ; Mustelidae/*genetics ; Reproducibility of Results ; Sex Characteristics ; Survival Analysis ; Telomere Homeostasis/*genetics ; },
abstract = {Individual variation in survival probability due to differential responses to early-life environmental conditions is important in the evolution of life histories and senescence. A biomarker allowing quantification of such individual variation, and which links early-life environmental conditions with survival by providing a measure of conditions experienced, is telomere length. Here, we examined telomere dynamics among 24 cohorts of European badgers (Meles meles). We found a complex cross-sectional relationship between telomere length and age, with no apparent loss over the first 29 months, but with both decreases and increases in telomere length at older ages. Overall, we found low within-individual consistency in telomere length across individual lifetimes. Importantly, we also observed increases in telomere length within individuals, which could not be explained by measurement error alone. We found no significant sex differences in telomere length, and provide evidence that early-life telomere length predicts lifespan. However, while early-life telomere length predicted survival to adulthood (≥1 year old), early-life telomere length did not predict adult survival probability. Furthermore, adult telomere length did not predict survival to the subsequent year. These results show that the relationship between early-life telomere length and lifespan was driven by conditions in early-life, where early-life telomere length varied strongly among cohorts. Our data provide evidence for associations between early-life telomere length and individual life history, and highlight the dynamics of telomere length across individual lifetimes due to individuals experiencing different early-life environments.},
}
@article {pmid31446212,
year = {2019},
author = {Yuan, P and Huang, S and Bao, FC and Cao, JL and Sheng, HX and Shi, L and Lv, W and Hu, J},
title = {Discriminating association of a common telomerase reverse transcriptase promoter polymorphism with telomere parameters in non-small cell lung cancer with or without epidermal growth factor receptor mutation.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {120},
number = {},
pages = {10-19},
doi = {10.1016/j.ejca.2019.06.024},
pmid = {31446212},
issn = {1879-0852},
mesh = {Biomarkers, Tumor/genetics ; Carcinoma, Non-Small-Cell Lung/*genetics/pathology/surgery ; ErbB Receptors/genetics ; Female ; Follow-Up Studies ; Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms/genetics/pathology/surgery ; Male ; Middle Aged ; *Mutation ; *Polymorphism, Single Nucleotide ; Prognosis ; *Promoter Regions, Genetic ; Retrospective Studies ; Survival Rate ; Telomerase/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: The role of epidermal growth factor receptor (EGFR) pathways in regulating telomerase is increasingly being recognised. We analysed the impact of rs2853669 single nucleotide polymorphism (SNP) on telomere parameters and its prognostic value for non-small cell lung cancer (NSCLC) with or without EGFR mutation.<br><br>METHODS: The association of rs2853669 with telomerase reverse transcriptase (TERT) mRNA level and relative telomere length (RTL) was analysed using resected tumour samples from 250 NSCLC patients. We also investigated the patients' clinical outcomes with a median follow-up of 57 months (2-99 months).<br><br>RESULTS: The rs2853669&#xa0;T/C allele was significantly associated with lower TERT mRNA expression (versus C/C and versus T/T; p&#xa0;<&#xa0;0.001 for both) and shorter RTL (versus C/C and versus&#xa0;T/T; p&#xa0;=&#xa0;0.039 and 0.023) in patients without EGFR mutation. Such difference was not observed in their counterparts harbouring EGFR mutation. When considering the cohort as a whole, T/C allele was significantly associated with shortest overall survival compared with T/T or C/C allele (mean: 61.8, 80.9 and 88.7 months, plog-rank&#xa0;<&#xa0;0.001) and disease-free survival (mean: 78.3, 87.9 and 91.5 months, plog-rank&#xa0;=&#xa0;0.019). Stratification analyses showed that the negative prognostic effect of T/C on OS was constrained in patients without EGFR mutation.<br><br>CONCLUSION: Our study revealed significant associations of a common SNP within TERT promoter region on telomere parameters and survival in NSCLC patients without EGFR mutation. The result may help providing instruction for therapeutic interventions targeting telomerase and evidence for investigation of TERT-EGFR interacting mechanism in telomere biology.},
}
@article {pmid31444995,
year = {2019},
author = {Kuo, CL and Pilling, LC and Kuchel, GA and Ferrucci, L and Melzer, D},
title = {Telomere length and aging-related outcomes in humans: A Mendelian randomization study in 261,000 older participants.},
journal = {Aging cell},
volume = {18},
number = {6},
pages = {e13017},
pmid = {31444995},
issn = {1474-9726},
support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; /AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Cohort Studies ; Female ; Humans ; Male ; *Mendelian Randomization Analysis ; Middle Aged ; Risk Factors ; Telomere Homeostasis/*genetics ; },
abstract = {Inherited genetic variation influencing leukocyte telomere length provides a natural experiment for testing associations with health outcomes, more robust to confounding and reverse causation than observational studies. We tested associations between genetically determined telomere length and aging-related health outcomes in a large European ancestry older cohort. Data were from n = 379,758 UK Biobank participants aged 40-70, followed up for mean of 7.5 years (n = 261,837 participants aged 60 and older by end of follow-up). Thirteen variants strongly associated with longer telomere length in peripheral white blood cells were analyzed using Mendelian randomization methods with Egger plots to assess pleiotropy. Variants in TERC, TERT, NAF1, OBFC1, and RTEL1 were included, and estimates were per 250 base pairs increase in telomere length, approximately equivalent to the average change over a decade in the general white population. We highlighted associations with false discovery rate-adjusted p-values smaller than .05. Genetically determined longer telomere length was associated with lowered risk of coronary heart disease (CHD; OR = 0.95, 95% CI: 0.92-0.98) but raised risk of cancer (OR = 1.11, 95% CI: 1.06-1.16). Little evidence for associations were found with parental lifespan, centenarian status of parents, cognitive function, grip strength, sarcopenia, or falls. The results for those aged 60 and older were similar in younger or all participants. Genetically determined telomere length was associated with increased risk of cancer and reduced risk of CHD but little change in other age-related health outcomes. Telomere lengthening may offer little gain in later-life health status and face increasing cancer risks.},
}
@article {pmid31443537,
year = {2019},
author = {Hognon, C and Gebus, A and Barone, G and Monari, A},
title = {Human DNA Telomeres in Presence of Oxidative Lesions: The Crucial Role of Electrostatic Interactions on the Stability of Guanine Quadruplexes.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {8},
number = {9},
pages = {},
pmid = {31443537},
issn = {2076-3921},
abstract = {By using all atom molecular dynamics simulations, we studied the behavior of human DNA telomere sequences in guanine quadruplex (G4) conformation and in the presence of oxidative lesions, namely abasic sites. In particular, we evidenced that while removing one guanine base induces a significant alteration and destabilization of the involved leaflet, human telomere oligomers tend, in most cases, to maintain at least a partial quadruplex structure, eventually by replacing the empty site with undamaged guanines of different leaflets. This study shows that (i) the disruption of the quadruplex leaflets induces the release of at least one of the potassium cations embedded in the quadruplex channel and that (ii) the electrostatic interactions of the DNA sequence with the aforementioned cations are fundamental to the maintenance of the global quadruplex structure.},
}
@article {pmid31440584,
year = {2019},
author = {Robinson, NJ and Taylor, DJ and Schiemann, WP},
title = {Stem cells, immortality, and the evolution of metastatic properties in breast cancer: telomere maintenance mechanisms and metastatic evolution.},
journal = {Journal of cancer metastasis and treatment},
volume = {5},
number = {},
pages = {},
pmid = {31440584},
issn = {2394-4722},
support = {TL1 TR002549/TR/NCATS NIH HHS/United States ; R01 CA236273/CA/NCI NIH HHS/United States ; TL1 TR000441/TR/NCATS NIH HHS/United States ; R01 GM133841/GM/NIGMS NIH HHS/United States ; T32 GM007250/GM/NIGMS NIH HHS/United States ; },
abstract = {Breast cancer is the most significant cause of cancer-related death in women around the world. The vast majority of breast cancer-associated mortality stems from metastasis, which remains an incurable disease state. Metastasis results from evolution of clones that possess the insidious properties required for dissemination and colonization of distant organs. These clonal populations are descended from breast cancer stem cells (CSCs), which are also responsible for their prolonged maintenance and continued evolution. Telomeres impose a lifespan on cells that can be extended when they are actively elongated, as occurs in CSCs. Thus, changes in telomere structure serve to promote the survival of CSCs and subsequent metastatic evolution. The selection of telomere maintenance mechanism (TMM) has important consequences not only for CSC survival and evolution, but also for their coordination of various signaling pathways that choreograph the metastatic cascade. Targeting the telomere maintenance machinery may therefore provide a boon to the treatment of metastatic breast cancer. Here we review the two major TMMs and the roles they play in the development of stem and metastatic breast cancer cells. We also highlight current and future approaches to targeting these mechanisms in clinical settings to alleviate metastatic breast cancers.},
}
@article {pmid31437841,
year = {2019},
author = {Ma, F and Lv, X and Du, Y and Chen, H and Liu, S and Zhao, J and Gao, Y and An, P and Zhou, X and Song, A and Sun, C and Wang, G and Ji, Y and Wang, X and Xu, W and Huang, G},
title = {Association of Leukocyte Telomere Length with Mild Cognitive Impairment and Alzheimer's Disease: Role of Folate and Homocysteine.},
journal = {Dementia and geriatric cognitive disorders},
volume = {48},
number = {1-2},
pages = {56-67},
doi = {10.1159/000501958},
pmid = {31437841},
issn = {1421-9824},
mesh = {Aged ; *Alzheimer Disease/blood/diagnosis ; Case-Control Studies ; *Cognitive Dysfunction/blood/diagnosis ; Correlation of Data ; Female ; Folic Acid/*blood ; Homocysteine/blood ; Humans ; Leukocytes/*pathology ; Male ; Middle Aged ; *Telomere Shortening ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) is associated with the aging process and age-related degenerative diseases. The relation of peripheral blood LTL to mild cognitive impairment (MCI) and Alzheimer's disease (AD) and the role of folate and homocysteine (Hcy) in this relation remain unclear.<br><br>OBJECTIVES: We aimed to investigate the association between LTL and the risks of MCI/AD, and to explore whether folate and Hcy may play a role in this association.<br><br>METHODS: This case-control study included 129 MCI subjects, 131 AD patients and 134 healthy controls. LTL was assessed using real-time polymerase chain reaction assay. Serum folate levels were tested by chemiluminescence enzyme immunoassay, and serum Hcy levels were measured using the enzymatic cycling method. Data were analyzed using multivariate logistic regression and multivariable linear regression with adjustment for potential confounders.<br><br>RESULTS: The mean LTL was 1.56 &#xb1; 0.25 in controls, 1.44 &#xb1; 0.23 in MCI, and 1.28 &#xb1; 0.28 in AD patients (p< 0.01). In multivariate logistic regression, subjects in the longest LTL tertile had lower OR for MCI (OR 0.246; 95% CI 0.101-0.597) and AD (OR 0.123; 95% CI 0.044-0.345) in comparison to subjects in the shortest tertile. Shorter LTL was dose-dependently related to the ORs of MCI and AD. Further, serum folate concentration was positively associated with LTL (p < 0.01), while serum Hcy level was negatively associated with LTL (p < 0.05). In stratified analyses, LTL-MCI/AD association varied by serum folate and Hcy level.<br><br>CONCLUSIONS: Shorter LTL is associated with the risks of MCI/AD. Folate and Hcy might play an important role in this association.},
}
@article {pmid31435394,
year = {2019},
author = {Yuseran, H and Hartoyo, E and Nurseta, T and Kalim, H},
title = {Molecular docking of genistein on estrogen receptors, promoter region of BCLX, caspase-3, Ki-67, cyclin D1, and telomere activity.},
journal = {Journal of Taibah University Medical Sciences},
volume = {14},
number = {1},
pages = {79-87},
pmid = {31435394},
issn = {1658-3612},
abstract = {OBJECTIVES: This study aims to investigate the modulation of estrogen receptors by estrogen and the role of genistein in the transcriptional process that regulates genes involved in the proliferation, apoptosis, and telomere activity.<br><br>METHODS: The research was conducted in silico, wherein docking, the most important method, was carried out using Hex 8.0 software and HADDOCK web server. Interaction analysis was subsequently done to observe the interactions between genistein and several related proteins and BCLX, Casp3, Ki-67, CyclinD1, hTERT, and POT1 genes using Discovery Studio, LigPlus, and NUCPLOT.<br><br>RESULTS: The interaction between ER&#x3b1; with genistein was not found to form a single bond. Thus, the interaction that may occur will not be effective because it is not stable. Conversely, when interacting with ER&#x3b2;, two hydrogen bonds and four hydrophobic bonds, MPP dihydrochloride interacted with ER&#x3b1; via two hydrogen bonds and three hydrophobic bonds. The ER&#x3b2;/eNOS complex will be comparatively easier to induced by the transcriptional activation of BCLX, Casp3, Ki-67, CyclinD1, hTERT and POT1 genes.<br><br>CONCLUSIONS: Administration of genistein can increase the genomic activities of the estrogen-eNOS receptor complexes related to apoptosis, proliferation, and telomere activity.},
}
@article {pmid31434740,
year = {2019},
author = {Barbero Barcenilla, B and Shippen, DE},
title = {Back to the future: The intimate and evolving connection between telomere-related factors and genotoxic stress.},
journal = {The Journal of biological chemistry},
volume = {294},
number = {40},
pages = {14803-14813},
pmid = {31434740},
issn = {1083-351X},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; R01 GM127402/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Damage/*genetics ; DNA Repair/genetics ; Eukaryotic Cells ; Gene Expression Regulation/genetics ; Humans ; Mitochondria/genetics ; Oxidative Stress/genetics ; Shelterin Complex ; Telomerase/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {The conversion of circular genomes to linear chromosomes during molecular evolution required the invention of telomeres. This entailed the acquisition of factors necessary to fulfill two new requirements: the need to fully replicate terminal DNA sequences and the ability to distinguish chromosome ends from damaged DNA. Here we consider the multifaceted functions of factors recruited to perpetuate and stabilize telomeres. We discuss recent theories for how telomere factors evolved from existing cellular machineries and examine their engagement in nontelomeric functions such as DNA repair, replication, and transcriptional regulation. We highlight the remarkable versatility of protection of telomeres 1 (POT1) proteins that was fueled by gene duplication and divergence events that occurred independently across several eukaryotic lineages. Finally, we consider the relationship between oxidative stress and telomeres and the enigmatic role of telomere-associated proteins in mitochondria. These findings point to an evolving and intimate connection between telomeres and cellular physiology and the strong drive to maintain chromosome integrity.},
}
@article {pmid31427453,
year = {2019},
author = {Cohn, M and Andersson, AK and Mateo, RQ and Möller, MC},
title = {Alternative Lengthening of Telomeres in the Budding Yeast Naumovozyma castellii.},
journal = {G3 (Bethesda, Md.)},
volume = {9},
number = {10},
pages = {3345-3358},
pmid = {31427453},
issn = {2160-1836},
mesh = {Chromosomes, Fungal ; Genome, Fungal ; Genomics/methods ; Humans ; Saccharomycetales/*genetics ; Telomerase/metabolism ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {The enzyme telomerase ensures the integrity of linear chromosomes by maintaining telomere length. As a hallmark of cancer, cell immortalization and unlimited proliferation is gained by reactivation of telomerase. However, a significant fraction of cancer cells instead uses alternative telomere lengthening mechanisms to ensure telomere function, collectively known as Alternative Lengthening of Telomeres (ALT). Although the budding yeast Naumovozyma castellii (Saccharomyces castellii) has a proficient telomerase activity, we demonstrate here that telomeres in N. castellii are efficiently maintained by a novel ALT mechanism after telomerase knockout. Remarkably, telomerase-negative cells proliferate indefinitely without any major growth crisis and display wild-type colony morphology. Moreover, ALT cells maintain linear chromosomes and preserve a wild-type DNA organization at the chromosome termini, including a short stretch of terminal telomeric sequence. Notably, ALT telomeres are elongated by the addition of ∼275 bp repeats containing a short telomeric sequence and the subtelomeric DNA located just internally (TelKO element). Although telomeres may be elongated by several TelKO repeats, no dramatic genome-wide amplification occurs, thus indicating that the repeat addition may be regulated. Intriguingly, a short interstitial telomeric sequence (ITS) functions as the initiation point for the addition of the TelKO element. This implies that N. castellii telomeres are structurally predisposed to efficiently switch to the ALT mechanism as a response to telomerase dysfunction.},
}
@article {pmid31427306,
year = {2019},
author = {Hamada, T and Yuan, C and Bao, Y and Zhang, M and Khalaf, N and Babic, A and Morales-Oyarvide, V and Cochrane, BB and Gaziano, JM and Giovannucci, EL and Kraft, P and Manson, JE and Ng, K and Nowak, JA and Rohan, TE and Sesso, HD and Stampfer, MJ and Amundadottir, LT and Fuchs, CS and De Vivo, I and Ogino, S and Wolpin, BM},
title = {Prediagnostic Leukocyte Telomere Length and Pancreatic Cancer Survival.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {28},
number = {11},
pages = {1868-1875},
pmid = {31427306},
issn = {1538-7755},
support = {R35 CA197735/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; K07 CA222159/CA/NCI NIH HHS/United States ; R01 HL034595/HL/NHLBI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; R01 CA034944-03/CA/NCI NIH HHS/United States ; R01 CA205406/CA/NCI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; R01 HL026490/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; R01 HL034595-07/HL/NHLBI NIH HHS/United States ; R01 CA097193/CA/NCI NIH HHS/United States ; R01 CA034944/CA/NCI NIH HHS/United States ; U01 CA210171/CA/NCI NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; R01 CA040360/CA/NCI NIH HHS/United States ; R01 HL026490-03/HL/NHLBI NIH HHS/United States ; P50 CA127003/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Pancreatic Neoplasms/mortality/*physiopathology ; Prospective Studies ; Risk Factors ; Survival Analysis ; Telomere/pathology ; },
abstract = {BACKGROUND: Leukocyte telomere length has been associated with risk of subsequent pancreatic cancer. Few prospective studies have evaluated the association of prediagnostic leukocyte telomere length with pancreatic cancer survival.<br><br>METHODS: We prospectively examined the association of prediagnostic leukocyte telomere length with overall survival (OS) time among 423 participants diagnosed with pancreatic adenocarcinoma between 1984 and 2008 within the Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study, and Women's Health Initiative. We measured prediagnostic leukocyte telomere length in banked blood samples using quantitative PCR. Cox proportional hazards models were used to estimate HRs for OS with adjustment for potential confounders. We also evaluated 10 SNPs at the telomerase reverse transcriptase locus.<br><br>RESULTS: Shorter prediagnostic leukocyte telomere length was associated with reduced OS among patients with pancreatic cancer (P trend = 0.04). The multivariable-adjusted HR for OS comparing the lowest with highest quintiles of leukocyte telomere length was 1.39 (95% confidence interval, 1.01-1.93), corresponding to a 3-month difference in median OS time. In an analysis excluding cases with blood collected within 2 years of cancer diagnosis, the association was moderately stronger (HR, 1.55; 95% confidence interval, 1.09-2.21; comparing the lowest with highest quintiles; P trend = 0.01). No prognostic association or effect modification for the prognostic association of prediagnostic leukocyte telomere length was noted in relation to the studied SNPs.<br><br>CONCLUSIONS: Prediagnostic leukocyte telomere length was associated with pancreatic cancer survival.<br><br>IMPACT: Prediagnostic leukocyte telomere length can be a prognostic biomarker in pancreatic cancer.},
}
@article {pmid31426295,
year = {2019},
author = {Bilgili, H and Białas, AJ and Górski, P and Piotrowski, WJ},
title = {Telomere Abnormalities in the Pathobiology of Idiopathic Pulmonary Fibrosis.},
journal = {Journal of clinical medicine},
volume = {8},
number = {8},
pages = {},
pmid = {31426295},
issn = {2077-0383},
abstract = {Idiopathic pulmonary fibrosis (IPF) occurs primarily in older adults and the incidence is clearly associated with aging. This disease seems to be associated with several hallmarks of aging, including telomere attrition and cellular senescence. Increasing evidence suggests that abnormalities involving telomeres and their proteome play a significant role in the pathobiology of IPF. The aim of this study is to summarize present knowledge in the field, as well as to discuss its possible clinical implications. Numerous mutations in genes associated with telomere functioning were studied in the context of IPF, mainly for Telomerase Reverse Transcriptase (TERT) and Telomerase RNA Component (TERC). Such mutations may lead to telomere shortening, which seems to increase the risk of IPF, negatively influence disease progression, and contribute to worse prognosis after lung transplantation. Some evidence indicates the possibility for the use of telomerase activators as potential therapeutic agents in pulmonary fibrosis. To sum up, increasing evidence suggests the role of telomere abnormalities in the pathobiology of IPF, natural history and prognosis of the disease. There are also possibilities for telomerase targeting in the potential development of new treatment agents. However, all these aspects require further research.},
}
@article {pmid31426123,
year = {2020},
author = {Wang, Y and McReynolds, LJ and Dagnall, C and Katki, HA and Spellman, SR and Wang, T and Hicks, B and Freedman, ND and Jones, K and Lee, SJ and Savage, SA and Gadalla, SM},
title = {Pre-transplant short telomeres are associated with high mortality risk after unrelated donor haematopoietic cell transplant for severe aplastic anaemia.},
journal = {British journal of haematology},
volume = {188},
number = {2},
pages = {309-316},
pmid = {31426123},
issn = {1365-2141},
support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/International ; N00014-16-1-2020//Office of Naval Research/International ; 4U10HL069294/CA/NCI NIH HHS/United States ; N0014-17-1-2850/CA/NCI NIH HHS/United States ; N00014-17-1-2388//Office of Naval Research/International ; HHSH234200637015C/CA/NCI NIH HHS/United States ; //National Heart Lung and Blood Institute/International ; U24 CA076518/CA/NCI NIH HHS/United States ; ZIA CP010190/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adult ; Anemia, Aplastic/*etiology/mortality ; Female ; Hematopoietic Stem Cell Transplantation/*adverse effects/methods ; Humans ; Male ; Risk Factors ; Telomere Shortening/*genetics ; Transplantation Conditioning/*adverse effects/methods ; Unrelated Donors ; Young Adult ; },
abstract = {Telomeres are essential for chromosomal stability and markers of biological age. We evaluated the effect of pre-transplant short (<10th percentile-for-age) or very short (<5th or <1st percentile-for-age) leucocyte telomere length on survival after unrelated donor haematopoietic cell transplantation (HCT) for acquired severe aplastic anaemia (SAA). Patient pre-transplant blood samples and clinical data were available at the Center for International Blood and Marrow Transplant Research. We used quantitative real time polymerase chain reaction to measure relative telomere length (RTL) in 490 SAA patients who received HCT between 1990 and 2013 (median age = 20 years). One hundred and twelve patients (22·86%) had pre-HCT RTL <10th percentile-for-age, with the majority below the 5th percentile (N = 80, 71·43%). RTL <10th percentile-for-age was associated with a higher risk of post-HCT mortality (hazard ratio [HR] = 1·78, 95% confidence interval [CI]=1·18-2·69, P = 0·006) compared with RTL ≥50th percentile; no survival differences were noted in longer RTL categories (P > 0·10). Time-dependent effects for post-HCT mortality were only observed in relation to very short RTL; HR comparing RTL <5th versus ≥5th percentile = 1·38, P = 0·15 for the first 12 months after HCT, and HR = 3·91, P < 0·0001, thereafter, P-heterogeneity = 0·008; the corresponding HRs for RTL <1st versus ≥1st percentile = 1·29, P = 0·41, and HR = 5·18, P < 0·0001, P-heterogeneity = 0·005. The study suggests a potential role for telomere length in risk stratification of SAA patients in regard to their HCT survival.},
}
@article {pmid31425926,
year = {2019},
author = {Mehrez, F and Bougatef, K and Monache, ED and Arisi, I and Proietti-De-Santis, L and Prantera, G and Zouiten, L and Caputo, M and Ben Ammar Elgaaied, A and Bongiorni, S},
title = {Telomere length measurement in tumor and non-tumor cells as a valuable prognostic for tumor progression.},
journal = {Cancer genetics},
volume = {238},
number = {},
pages = {50-61},
doi = {10.1016/j.cancergen.2019.07.007},
pmid = {31425926},
issn = {2210-7762},
mesh = {Biomarkers, Tumor/metabolism ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Neoplasms/genetics/metabolism/*pathology ; Prognosis ; *Telomere ; },
abstract = {Telomere shortening has been supposed to be implicated in both aging and various human diseases especially carcinogenesis process. This phenomenon can lead to a chromosomal instability, contributing to a cell immortalization and tumor induction. In our study, we analyzed the role of telomere shortening in cancer progression, in Tunisian patients with digestive cancer. We measured the absolute telomere length in tumoral vs healthy adjacent tissues of each patient by using a q-RT PCR method and we investigated the relationship between telomere length and various sociodemographic and clinical parameters such as age, sex, tumor stage. In this pathological situation, we observed that, starting from 60 years of age, the telomere length increases in healthy mucosa and that in both healthy and cancer tissues, patients under 60 years have shorter telomeres, suggesting the telomere lengthening becomes more active with age. Finally, a positive correlation between normal and cancer tissues in both non-metastatic and metastatic stages, indicates telomere length in cancer tissue depends essentially on tumor stages. Our data allow us to suggest that telomere length depends on sex and age in healthy tissue while shortening and lengthening fluctuates considerably according to the tumor stage.},
}
@article {pmid31422934,
year = {2020},
author = {Zalzman, M and Meltzer, WA and Portney, BA and Brown, RA and Gupta, A},
title = {The Role of Ubiquitination and SUMOylation in Telomere Biology.},
journal = {Current issues in molecular biology},
volume = {35},
number = {},
pages = {85-98},
pmid = {31422934},
issn = {1467-3045},
support = {R01 AR070819/AR/NIAMS NIH HHS/United States ; },
mesh = {Animals ; Chromatin/enzymology/*metabolism ; DNA Repair ; DNA Replication/*genetics ; Humans ; Neoplasms/enzymology/genetics/*metabolism ; Shelterin Complex ; *Sumoylation ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/metabolism ; *Ubiquitination ; },
abstract = {Telomeres are a unique structure of DNA repeats covered by proteins at the ends of the chromosomes that protect the coding regions of the genome and function as a biological clock. They require a tight regulation of the factors covering and protecting their structure, as they are shortened with each cell division to limit the ability of cells to replicate uncontrollably. Additionally, they protect the chromosome ends from DNA damage responses and thereby, prevent genomic instability. Telomere dysfunction can lead to chromosomal abnormalities and cancer. Therefore, dysregulation of any of the factors that regulate the integrity of the telomeres will have implications to chromosomal stability, replicative lifespan and may lead to cell transformation. This review will cover the main factors participating in the normal function of the telomeres and how these are regulated by the ubiquitin and SUMO systems. Accumulating evidence indicate that the ubiquitin and SUMO pathways are significant regulators of the shelterin complex and other chromatin modifiers, which are important for telomere structure integrity. Furthermore, the crosstalk between these two pathways has been reported in telomeric DNA repair. A better understanding of the factors contributing to telomere biology, and how they are regulated, is important for the design of new strategies for cancer therapies and regenerative medicine.},
}
@article {pmid31422385,
year = {2019},
author = {Lu, AT and Seeboth, A and Tsai, PC and Sun, D and Quach, A and Reiner, AP and Kooperberg, C and Ferrucci, L and Hou, L and Baccarelli, AA and Li, Y and Harris, SE and Corley, J and Taylor, A and Deary, IJ and Stewart, JD and Whitsel, EA and Assimes, TL and Chen, W and Li, S and Mangino, M and Bell, JT and Wilson, JG and Aviv, A and Marioni, RE and Raj, K and Horvath, S},
title = {DNA methylation-based estimator of telomere length.},
journal = {Aging},
volume = {11},
number = {16},
pages = {5895-5923},
pmid = {31422385},
issn = {1945-4589},
support = {R01 ES020836/ES/NIEHS NIH HHS/United States ; HHSN268201300048C/HL/NHLBI NIH HHS/United States ; HHSN268201300049C/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; HHSN268201500001I/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; U54 GM115428/GM/NIGMS NIH HHS/United States ; BB/F019394/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; U01 AG060908/AG/NIA NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; HHSN268201500001C/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; HHSN268201300047C/HL/NHLBI NIH HHS/United States ; HHSN268201300050C/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; HHSN268201300046C/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Cohort Studies ; *DNA Methylation ; Diet ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; *Telomere ; Young Adult ; },
abstract = {Telomere length (TL) is associated with several aging-related diseases. Here, we present a DNA methylation estimator of TL (DNAmTL) based on 140 CpGs. Leukocyte DNAmTL is applicable across the entire age spectrum and is more strongly associated with age than measured leukocyte TL (LTL) (r ~-0.75 for DNAmTL versus r ~ -0.35 for LTL). Leukocyte DNAmTL outperforms LTL in predicting: i) time-to-death (p=2.5E-20), ii) time-to-coronary heart disease (p=6.6E-5), iii) time-to-congestive heart failure (p=3.5E-6), and iv) association with smoking history (p=1.21E-17). These associations are further validated in large scale methylation data (n=10k samples) from the Framingham Heart Study, Women's Health Initiative, Jackson Heart Study, InChianti, Lothian Birth Cohorts, Twins UK, and Bogalusa Heart Study. Leukocyte DNAmTL is also associated with measures of physical fitness/functioning (p=0.029), age-at-menopause (p=0.039), dietary variables (omega 3, fish, vegetable intake), educational attainment (p=3.3E-8) and income (p=3.1E-5). Experiments in cultured somatic cells show that DNAmTL dynamics reflect in part cell replication rather than TL per se. DNAmTL is not only an epigenetic biomarker of replicative history of cells, but a useful marker of age-related pathologies that are associated with it.},
}
@article {pmid31419512,
year = {2019},
author = {Ding, X and Cheng, J and Pang, Q and Wei, X and Zhang, X and Wang, P and Yuan, Z and Qian, D},
title = {BIBR1532, a Selective Telomerase Inhibitor, Enhances Radiosensitivity of Non-Small Cell Lung Cancer Through Increasing Telomere Dysfunction and ATM/CHK1 Inhibition.},
journal = {International journal of radiation oncology, biology, physics},
volume = {105},
number = {4},
pages = {861-874},
doi = {10.1016/j.ijrobp.2019.08.009},
pmid = {31419512},
issn = {1879-355X},
mesh = {Aminobenzoates/administration &amp; dosage/*pharmacology ; Animals ; Ataxia Telangiectasia Mutated Proteins/antagonists &amp; inhibitors ; Carcinoma, Non-Small-Cell Lung/enzymology/*radiotherapy ; Cell Death ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cellular Senescence/drug effects ; DNA Damage/drug effects ; DNA Repair/drug effects ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Enzyme Inhibitors/administration &amp; dosage/pharmacology ; Enzyme Reactivators/pharmacology ; Female ; Humans ; Lung Neoplasms/enzymology/*radiotherapy ; Mice ; Mice, Nude ; Naphthalenes/administration &amp; dosage/*pharmacology ; Phosphorylation/drug effects ; Radiation Tolerance/*drug effects ; Radiation-Sensitizing Agents/*pharmacology ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/drug effects ; Telomere Homeostasis/drug effects ; Xenograft Model Antitumor Assays ; },
abstract = {PURPOSE: Telomerase is reactivated in non-small cell lung cancer (NSCLC), and it increases cell resistance to irradiation through protecting damaged telomeres and enhancing DNA damage repair. We investigated the radiosensitizing effect of BIBR1532, a highly selective telomerase inhibitor, and its corresponding mechanism in NSCLC.<br><br>METHODS AND MATERIALS: Cell proliferation, telomerase activity, and telomere dysfunction-induced foci were measured with CCK-8 assay, real-time fluorescent quantitative polymerase chain reaction, and immunofluorescence. The effect of BIBR1532 on the response of NSCLC cells to radiation was analyzed using clonogenic survival and xenograft tumor assays. Cell death and cell senescence induced by BIBR1532 or ionizing radiation (IR), or both, were detected with western blotting, flow cytometry, and senescence-association &#x3b2;-galactosidase staining assay.<br><br>RESULTS: We observed dose-dependent direct cytotoxicity of BIBR1532 at relatively high concentrations in NSCLC cells. Low concentrations of BIBR1532 did not appear toxic to NSCLC cells; however, they substantially increased the therapeutic efficacy of IR in&#xa0;vitro by enhancing IR-induced apoptosis, senescence, and mitotic catastrophe. Moreover, in a mouse xenograft model, BIBR1532 treatment synergized with IR at nontoxic dose levels promoted the antitumor efficacy of IR without toxicity to hematologic and internal organs. Mechanistically, lower concentrations of BIBR1532 effectively inhibited telomerase activity and increased IR-induced telomere dysfunction, resulting in disruption of chromosomal stability and inhibition of the ATM/CHK1 (ataxia-telangiectasia-mutated/Checkpoint kinase 1) pathway, which impaired DNA damage repair.<br><br>CONCLUSIONS: Our findings demonstrate that disturbances in telomerase function by nontoxic dose levels of BIBR1532 effectively enhance the radiosensitivity of NSCLC cells. This finding provides a rationale for the clinical assessment of BIBR1532 as a radiosensitizer.},
}
@article {pmid31418732,
year = {2019},
author = {Nemtsova, V and Bilovol, O and Vysotska, O and Falyova, H},
title = {[INFLUENCE OF LIPID METABOLISM CONTROL ON THE TELOMERES RELATIVE LENGTH IN PATIENTS WITH ISOLATED HYPERTENSION AND IN COMBINATION WITH DIABETES MELLITUS TYPE 2].},
journal = {Georgian medical news},
volume = {},
number = {291},
pages = {58-63},
pmid = {31418732},
issn = {1512-0112},
mesh = {Cholesterol, HDL ; Cholesterol, LDL ; Diabetes Mellitus, Type 2/*complications/genetics/*metabolism ; Humans ; Hypertension/*complications/genetics/*metabolism ; *Lipid Metabolism ; Telomere/genetics/*metabolism ; Telomere Shortening ; Triglycerides ; },
abstract = {Aim - to determine the influence of different levels of lipid metabolism on the relative blood leukocytes telomeres length (RLTL), relative buccal epithelium cells telomeres length (RBTL) in hypertensive (H) individuals with type 2 diabetes mellitus (DM2T) and without DM2T. In 60 patients with H stage II (group 1), and 96 patients with H and DM2T (group 2) lipid metabolism indexes (total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C)), anthropometric parameters were measured. Relative telomeres length (RTL) was determined by a real time quantitative PCR. The most significant shortening of RLTL and RBTL were found in group 2. In both groups, the achievement of target blood lipid levels was accompanied by multidirectional changes in RTL. Analysis of variance revealed a significant effect of TC (p=0.036) on the RBTL, LDL -C (p=0.036) on the RBTL in group 1, and significant influence of TG (p = 0.049) on RBTL, TC (p=0.019) and HDL-C (p=0.032) on RLTL in group 2. Achieving target levels of lipid metabolism did not demonstrate the expected significant effect on the elongation of the relative length of telomeres, both with isolated hypertension and with a combined course of hypertension and DM2T.},
}
@article {pmid31416141,
year = {2019},
author = {Wark, L and Quon, H and Ong, A and Drachenberg, D and Rangel-Pozzo, A and Mai, S},
title = {Long-Term Dynamics of Three Dimensional Telomere Profiles in Circulating Tumor Cells in High-Risk Prostate Cancer Patients Undergoing Androgen-Deprivation and Radiation Therapy.},
journal = {Cancers},
volume = {11},
number = {8},
pages = {},
pmid = {31416141},
issn = {2072-6694},
support = {111//CancerCare Manitoba Foundation/ ; },
abstract = {Patient-specific assessment, disease monitoring, and the development of an accurate early surrogate of the therapeutic efficacy of locally advanced prostate cancer still remain a clinical challenge. Contrary to prostate biopsies, circulating tumor cell (CTC) collection from blood is a less-invasive method and has potential as a real-time liquid biopsy and as a surrogate marker for treatment efficacy. In this study, we used size-based filtration to isolate CTCs from the blood of 100 prostate cancer patients with high-risk localized disease. CTCs from five time points: +0, +2, +6, +12 and +24 months were analyzed. Consenting treatment-naïve patients with cT3, Gleason 8-10, or prostate-specific antigen > 20 ng/mL and non-metastatic prostate cancer were included. For all time points, we performed 3D telomere-specific quantitative fluorescence in situ hybridization on a minimum of thirty isolated CTCs. The patients were divided into five groups based on the changes of number of telomeres vs telomere lengths over time and into three clusters based on all telomere parameters found on diagnosis. Group 2 was classified as non-respondent to treatment and the Cluster 3 presented more aggressive phenotype. Additionally, we compared our telomere results with the PSA levels for each patient at 6 months of ADT, at 6 months of completed RT, and at 36 months post-initial therapy. CTCs of patients with PSA levels above or equal to 0.1 ng/mL presented significant increases of nuclear volume, number of telomeres, and telomere aggregates. The 3D telomere analysis of CTCs identified disease heterogeneity among a clinically homogeneous group of patients, which suggests differences in therapeutic responses. Our finding suggests a new opportunity for better treatment monitoring of patients with localized high-risk prostate cancer.},
}
@article {pmid31412240,
year = {2019},
author = {Kroustallaki, P and Lirussi, L and Carracedo, S and You, P and Esbensen, QY and Götz, A and Jobert, L and Alsøe, L and Sætrom, P and Gagos, S and Nilsen, H},
title = {SMUG1 Promotes Telomere Maintenance through Telomerase RNA Processing.},
journal = {Cell reports},
volume = {28},
number = {7},
pages = {1690-1702.e10},
doi = {10.1016/j.celrep.2019.07.040},
pmid = {31412240},
issn = {2211-1247},
mesh = {Animals ; Exoribonucleases/genetics/metabolism ; Exosome Multienzyme Ribonuclease Complex/genetics/metabolism ; Female ; HeLa Cells ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; RNA/*physiology ; *RNA Processing, Post-Transcriptional ; Telomerase/genetics/*metabolism/physiology ; Telomere/*physiology ; Uracil-DNA Glycosidase/genetics/*metabolism/physiology ; },
abstract = {Telomerase biogenesis is a complex process where several steps remain poorly understood. Single-strand-selective uracil-DNA glycosylase (SMUG1) associates with the DKC1-containing H/ACA ribonucleoprotein complex, which is essential for telomerase biogenesis. Herein, we show that SMUG1 interacts with the telomeric RNA component (hTERC) and is required for co-transcriptional processing of the nascent transcript into mature hTERC. We demonstrate that SMUG1 regulates the presence of base modifications in hTERC, in a region between the CR4/CR5 domain and the H box. Increased levels of hTERC base modifications are accompanied by reduced DKC1 binding. Loss of SMUG1 leads to an imbalance between mature hTERC and its processing intermediates, leading to the accumulation of 3'-polyadenylated and 3'-extended intermediates that are degraded in an EXOSC10-independent RNA degradation pathway. Consequently, SMUG1-deprived cells exhibit telomerase deficiency, leading to impaired bone marrow proliferation in Smug1-knockout mice.},
}
@article {pmid31406173,
year = {2019},
author = {van der Spek, A and Broer, L and Draisma, HHM and Pool, R and Albrecht, E and Beekman, M and Mangino, M and Raag, M and Nyholt, DR and Dharuri, HK and Codd, V and Amin, N and de Geus, EJC and Deelen, J and Demirkan, A and Yet, I and Fischer, K and Haller, T and Henders, AK and Isaacs, A and Medland, SE and Montgomery, GW and Mooijaart, SP and Strauch, K and Suchiman, HED and Vaarhorst, AAM and van Heemst, D and Wang-Sattler, R and Whitfield, JB and Willemsen, G and Wright, MJ and Martin, NG and Samani, NJ and Metspalu, A and Eline Slagboom, P and Spector, TD and Boomsma, DI and van Duijn, CM and Gieger, C},
title = {Metabolomics reveals a link between homocysteine and lipid metabolism and leukocyte telomere length: the ENGAGE consortium.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {11623},
pmid = {31406173},
issn = {2045-2322},
support = {/WT_/Wellcome Trust/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; 619667/DH_/Department of Health/United Kingdom ; WT205915/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Adult ; Aged ; Cohort Studies ; Female ; Homocysteine/*metabolism ; Humans ; Leukocytes/*ultrastructure ; *Lipid Metabolism ; Male ; Metabolomics/*methods ; Middle Aged ; *Telomere ; Telomere Shortening ; },
abstract = {Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10[-6]), methionine (p-value = 9.2 × 10[-5]), tyrosine (p-value = 2.1 × 10[-4]), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10[-4]), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10[-4]), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10[-4]). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.},
}
@article {pmid31405990,
year = {2019},
author = {Hu, Y and Bennett, HW and Liu, N and Moravec, M and Williams, JF and Azzalin, CM and King, MC},
title = {RNA-DNA Hybrids Support Recombination-Based Telomere Maintenance in Fission Yeast.},
journal = {Genetics},
volume = {213},
number = {2},
pages = {431-447},
pmid = {31405990},
issn = {1943-2631},
support = {DP2 OD008429/OD/NIH HHS/United States ; T32 GM007205/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA, Fungal/chemistry/genetics ; DNA-Binding Proteins/genetics ; RNA, Fungal/chemistry/genetics ; Recombinational DNA Repair/genetics ; Schizosaccharomyces/genetics ; Schizosaccharomyces pombe Proteins/*genetics ; Shelterin Complex ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere Shortening/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {A subset of cancers rely on telomerase-independent mechanisms to maintain their chromosome ends. The predominant "alternative lengthening of telomeres" pathway appears dependent on homology-directed repair (HDR) to maintain telomeric DNA. However, the molecular changes needed for cells to productively engage in telomeric HDR are poorly understood. To gain new insights into this transition, we monitored the state of telomeres during serial culture of fission yeast (Schizosaccharomyces pombe) lacking the telomerase recruitment factor Ccq1. Rad52 is loaded onto critically short telomeres shortly after germination despite continued telomere erosion, suggesting that recruitment of recombination factors is not sufficient to maintain telomeres in the absence of telomerase function. Instead, survivor formation coincides with the derepression of telomeric repeat-containing RNA (TERRA). In this context, degradation of TERRA associated with the telomere in the form of R-loops drives a severe growth crisis, ultimately leading to a novel type of survivor with linear chromosomes and altered cytological telomere characteristics, including the loss of the shelterin component Rap1 (but not the TRF1/TRF2 ortholog, Taz1) from the telomere. We demonstrate that deletion of Rap1 is protective in this context, preventing the growth crisis that is otherwise triggered by degradation of telomeric R-loops in survivors with linear chromosomes. These findings suggest that upregulation of telomere-engaged TERRA, or altered recruitment of shelterin components, can support telomerase-independent telomere maintenance.},
}
@article {pmid31405322,
year = {2019},
author = {Wang, W and Liu, B and Duan, X and Feng, X and Wang, T and Wang, P and Ding, M and Liu, S and Li, L and Liu, J and Tang, L and Niu, X and Zhang, Y and Li, G and Yao, W and Yang, Y},
title = {Telomere length in workers was effected by omethoate exposure and interaction between smoking and p21 polymorphisms.},
journal = {Journal of environmental science and health. Part. B, Pesticides, food contaminants, and agricultural wastes},
volume = {54},
number = {12},
pages = {948-953},
doi = {10.1080/03601234.2019.1652074},
pmid = {31405322},
issn = {1532-4109},
mesh = {Adult ; DNA Damage/drug effects ; Dimethoate/*analogs &amp; derivatives/toxicity ; Genotype ; Humans ; Male ; Middle Aged ; Occupational Exposure/*adverse effects ; Pesticides/*toxicity ; Polymorphism, Genetic/drug effects ; Proto-Oncogene Proteins c-mdm2/genetics ; Smoking/*adverse effects ; Telomere/genetics/*metabolism ; Tumor Suppressor Protein p53/genetics ; },
abstract = {Omethoate is an organophosphorus pesticide that poses a major health hazard, especially DNA damage. The purpose of this study was to investigate the factors affecting telomere length in workers exposed to omethoate by analyzing the interaction between cell cycle gene polymorphism and environmental factors. The exposure group consisted of 118 workers exposed to omethoate for 8-10 years, the control group comprised 115 healthy people without occupational toxicant exposure history. The telomere length of genomic DNA from peripheral blood leucocyte was determined with real-time PCR. Polymerase chain reaction and restriction fragment length polymorphism was used to detect the polymorphisms in p53, p21 and MDM2 gene. The telomere length in the (CA + AA) genotypes for p21 rs1801270 polymorphism was longer than that in the CC genotype in control group (P = 0.015). The generalized linear model analysis indicated the interaction of the p21 rs1801270 polymorphic (CA + AA) genotypes and smoking has a significant effect on telomere length (β = -0.258, P = 0.085). The prolongation of telomere length in omethoate-exposed workers was associated with genotypes (CA + AA) of p21 rs1801270, and interactions of (CA + AA) genotypes and smoking factor.},
}
@article {pmid31404747,
year = {2019},
author = {Gatinois, V and Desprat, R and Becker, F and Pichard, L and Bernex, F and Corsini, C and Pellestor, F and Lemaitre, JM},
title = {Reprogramming of Human Peripheral Blood Mononuclear Cell (PBMC) from a patient suffering of a Werner syndrome resulting in iPSC line (REGUi003-A) maintaining a short telomere length.},
journal = {Stem cell research},
volume = {39},
number = {},
pages = {101515},
doi = {10.1016/j.scr.2019.101515},
pmid = {31404747},
issn = {1876-7753},
mesh = {Cells, Cultured ; Flow Cytometry ; Fluorescent Antibody Technique ; Genetic Predisposition to Disease/genetics ; Humans ; Induced Pluripotent Stem Cells/*cytology ; Karyotyping ; Leukocytes, Mononuclear/*cytology/metabolism ; Microsatellite Repeats/genetics ; Telomere/genetics ; Werner Syndrome/*genetics ; },
abstract = {Werner syndrome (WS) is a rare human autosomal recessive disorder characterized by early onset of aging-associated diseases, chromosomal instability, and cancer predisposition, without therapeutic treatment solution. Major clinical symptoms of WS include common age-associated diseases, such as insulin-resistant diabetes mellitus, and atherosclerosis. WRN, the gene responsible for the disease, encodes a RECQL-type DNA helicase with a role in telomere metabolism. We derived a stable iPSC line from 53 years old patient's PBMC, with a normal karyotype, but exhibiting a short telomere length, as a major aspect of the cellular phenotype involved in the pathology.},
}
@article {pmid31404388,
year = {2019},
author = {Zhdanova, NS and Vaskova, EA and Karamysheva, TV and Minina, JM and Rubtsov, NB and Zakian, SM},
title = {Dysfunction telomeres in embryonic fibroblasts and cultured in vitro pluripotent stem cells of Rattus norvegicus (Rodentia, Muridae).},
journal = {Comparative cytogenetics},
volume = {13},
number = {3},
pages = {1-14},
pmid = {31404388},
issn = {1993-0771},
abstract = {We studied the level of spontaneous telomere dysfunction in Rattus norvegicus (Berkenhout, 1769) (Rodentia, Muridae) embryonic fibroblasts (rEFs) and in cultured in vitro rat pluripotent stem cells (rPSCs), embryonic stem cells (rESCs) and induced pluripotent stem cells (riPSCs), on early passages and after prolonged cultivation. Among studied cell lines, rESCs showed the lowest level of telomere dysfunction, while the riPSCs demonstrated an elevated level on early passages of cultivation. In cultivation, the frequency of dysfunctional telomeres has increased in all studied cell lines; this is particularly true for dysfunctional telomeres occurring in G1 stage in riPSCs. The obtained data are mainly discussed in the connection with the specific structure of the telomere regions and their influence on the differential DNA damage response in them.},
}
@article {pmid31402483,
year = {2020},
author = {Aida, J and Yokoyama, A and Hara, S and Ishizaki, T and Fujiwara, M and Arai, T and Ishiwata, T and Takubo, K},
title = {Telomere shortening in the oral epithelium in relation to alcohol intake, alcohol dehydrogenase (ADH-1B), and acetaldehyde dehydrogenase (ALDH-2) genotypes and clinicopathologic features.},
journal = {Journal of oral pathology &amp; medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology},
volume = {49},
number = {1},
pages = {82-90},
doi = {10.1111/jop.12947},
pmid = {31402483},
issn = {1600-0714},
mesh = {Adult ; Alcohol Dehydrogenase/*genetics ; Alcohol Drinking ; Aldehyde Dehydrogenase, Mitochondrial/*genetics ; Genotype ; Humans ; In Situ Hybridization, Fluorescence ; Polymorphism, Genetic ; *Telomere Shortening ; },
abstract = {BACKGROUND: Progressive telomere shortening with age or chronic inflammation may lead to genomic instability that characterizes the early stage of carcinogenesis. Certain risk factors, such as drinking alcoholic beverages or smoking, predispose the oral mucosa to squamous cell carcinoma. The ADH1B and ALDH2 genotypes can influence the risk of cancer due to alcohol drinking. In the present study, we analyzed chromosomal instability due to telomere shortening in the oral mucosa in relation to cancer risk factors.<br><br>DESIGN: Using our quantitative fluorescence in situ hybridization (Q-FISH) technique, we estimated telomere lengths (TL) in the background mucosa from 23 cases of mucosal carcinoma, 12 cases of oral epithelial dysplasia, and 21 non-neoplasia cases. ALDH2 and ADH1B genotypes were determined using DNA extracted from paraffin sections. We analyzed TL in relation to alcohol drinking, smoking, and cancer multiplicity.<br><br>RESULTS: Telomeres in the backgrounds of dysplasia and mucosal carcinoma were significantly shorter than in controls. In comparison with adult controls, telomeres were significantly (P&#xa0;=&#xa0;.038) shorter in the ADH1B less-active type (ADH1B*1/*1), but not (P&#xa0;=&#xa0;.841) in the ALDH2 inactive type (ALDH2*1/*2 or *2/*2). Cancer multiplicity and smoking had no significant relationship with TL.<br><br>CONCLUSION: Telomeres in the oral epithelium are shorter in cases of oral dysplasia or mucosal carcinoma than in non-neoplasia. Unlike the esophageal epithelium of alcoholics, they are also shorter in individuals with the less-active rather than the active ADH1B gene. Telomeres in the oral epithelium may be directly affected by alcohol drinking.},
}
@article {pmid31401411,
year = {2019},
author = {Bilsland, AE and Liu, Y and Turnbull, A and Sumpton, D and Stevenson, K and Cairney, CJ and Boyd, SM and Roffey, J and Jenkinson, D and Keith, WN},
title = {A Novel Pyrazolopyrimidine Ligand of Human PGK1 and Stress Sensor DJ1 Modulates the Shelterin Complex and Telomere Length Regulation.},
journal = {Neoplasia (New York, N.Y.)},
volume = {21},
number = {9},
pages = {893-907},
pmid = {31401411},
issn = {1476-5586},
support = {C2193/A15584/CRUK_/Cancer Research UK/United Kingdom ; C301/A12962/CRUK_/Cancer Research UK/United Kingdom ; C301/A14762/CRUK_/Cancer Research UK/United Kingdom ; C301/A6691/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Cell Line, Tumor ; Humans ; Ligands ; Models, Molecular ; Molecular Structure ; Multiprotein Complexes/chemistry/*metabolism ; Phosphoglycerate Kinase/chemistry/*metabolism ; Protein Binding ; Protein Deglycase DJ-1/chemistry/*metabolism ; Pyrazoles/chemical synthesis/chemistry/*pharmacology ; Pyrimidines/chemical synthesis/chemistry/*pharmacology ; Shelterin Complex ; *Stress, Physiological ; Structure-Activity Relationship ; Telomere/genetics/metabolism ; Telomere Homeostasis/*drug effects ; Telomere Shortening/drug effects/genetics ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {Telomere signaling and metabolic dysfunction are hallmarks of cell aging. New agents targeting these processes might provide therapeutic opportunities, including chemoprevention strategies against cancer predisposition. We report identification and characterization of a pyrazolopyrimidine compound series identified from screens focused on cell immortality and whose targets are glycolytic kinase PGK1 and oxidative stress sensor DJ1. We performed structure-activity studies on the series to develop a photoaffinity probe to deconvolute the cellular targets. In vitro binding and structural analyses confirmed these targets, suggesting that PGK1/DJ1 interact, which we confirmed by immunoprecipitation. Glucose homeostasis and oxidative stress are linked to telomere signaling and exemplar compound CRT0063465 blocked hypoglycemic telomere shortening. Intriguingly, PGK1 and DJ1 bind to TRF2 and telomeric DNA. Compound treatment modulates these interactions and also affects Shelterin complex composition, while conferring cellular protection from cytotoxicity due to bleomycin and desferroxamine. These results demonstrate therapeutic potential of the compound series.},
}
@article {pmid31400850,
year = {2019},
author = {Barroso-González, J and García-Expósito, L and Hoang, SM and Lynskey, ML and Roncaioli, JL and Ghosh, A and Wallace, CT and de Vitis, M and Modesti, M and Bernstein, KA and Sarkar, SN and Watkins, SC and O'Sullivan, RJ},
title = {RAD51AP1 Is an Essential Mediator of Alternative Lengthening of Telomeres.},
journal = {Molecular cell},
volume = {76},
number = {1},
pages = {11-26.e7},
pmid = {31400850},
issn = {1097-4164},
support = {S10 OD019973/OD/NIH HHS/United States ; R01 ES024872/ES/NIEHS NIH HHS/United States ; S10 OD010625/OD/NIH HHS/United States ; P30 CA047904/CA/NCI NIH HHS/United States ; R01 CA207209/CA/NCI NIH HHS/United States ; },
mesh = {Autophagy ; Autophagy-Related Protein 7/genetics/metabolism ; Autophagy-Related Protein-1 Homolog/genetics/metabolism ; Cell Proliferation ; DNA Polymerase III/genetics/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Gene Expression Regulation, Neoplastic ; HEK293 Cells ; HeLa Cells ; Homologous Recombination ; Humans ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Ligases/genetics/metabolism ; Lysine ; Neoplasms/genetics/*metabolism/pathology ; Nucleotidyltransferases/genetics/metabolism ; Protein Stability ; RNA-Binding Proteins/genetics/*metabolism ; Rad52 DNA Repair and Recombination Protein/genetics/metabolism ; Signal Transduction ; Sumoylation ; Telomere/genetics/*metabolism/pathology ; *Telomere Homeostasis ; },
abstract = {Alternative lengthening of telomeres (ALT) is a homology-directed repair (HDR) mechanism of telomere elongation that controls proliferation in aggressive cancers. We show that the disruption of RAD51-associated protein 1 (RAD51AP1) in ALT+ cancer cells leads to generational telomere shortening. This is due to RAD51AP1's involvement in RAD51-dependent homologous recombination (HR) and RAD52-POLD3-dependent break induced DNA synthesis. RAD51AP1 KO ALT+ cells exhibit telomere dysfunction and cytosolic telomeric DNA fragments that are sensed by cGAS. Intriguingly, they activate ULK1-ATG7-dependent autophagy as a survival mechanism to mitigate DNA damage and apoptosis. Importantly, RAD51AP1 protein levels are elevated in ALT+ cells due to MMS21 associated SUMOylation. Mutation of a single SUMO-targeted lysine residue perturbs telomere dynamics. These findings indicate that RAD51AP1 is an essential mediator of the ALT mechanism and is co-opted by post-translational mechanisms to maintain telomere length and ensure proliferation of ALT+ cancer cells.},
}
@article {pmid31396941,
year = {2019},
author = {Fali, T and K'Ros, C and Appay, V and Sauce, D},
title = {Assessing T Lymphocyte Aging Using Telomere Length and Telomerase Activity Measurements in Low Cell Numbers.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2048},
number = {},
pages = {231-243},
doi = {10.1007/978-1-4939-9728-2_18},
pmid = {31396941},
issn = {1940-6029},
mesh = {Cell Culture Techniques/instrumentation/methods ; DNA/isolation &amp; purification ; Enzyme Assays/instrumentation/*methods ; HEK293 Cells ; Humans ; Real-Time Polymerase Chain Reaction/instrumentation/methods ; Single-Cell Analysis/instrumentation/*methods ; T-Lymphocyte Subsets/*physiology ; Telomerase/*metabolism ; Telomere/genetics/metabolism ; Telomere Shortening/*physiology ; },
abstract = {As T lymphocytes proliferate and differentiate in vivo or in vitro, their functional capacity can change dramatically. In particular, extensive cell division is often associated with telomere shortening and the onset of cellular senescence, thus impacting the proliferative potential of the cells. Telomere length and integrity represent therefore key molecular markers of the status and aging of the cells. To assess these markers, we established qPCR-based methods to measure telomere length as well as telomerase activity, applied to low cell numbers, which is necessary when working with rare or small subsets of T lymphocytes.},
}
@article {pmid31396577,
year = {2019},
author = {Mennie, AK and Moser, BA and Hoyle, A and Low, RS and Tanaka, K and Nakamura, TM},
title = {Tpz1[TPP1] prevents telomerase activation and protects telomeres by modulating the Stn1-Ten1 complex in fission yeast.},
journal = {Communications biology},
volume = {2},
number = {},
pages = {297},
pmid = {31396577},
issn = {2399-3642},
support = {R01 GM078253/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Motifs ; Conserved Sequence ; DNA-Binding Proteins/genetics/*metabolism ; Enzyme Activation ; Gene Expression Regulation, Fungal ; Protein Binding ; Schizosaccharomyces/*enzymology/genetics ; Schizosaccharomyces pombe Proteins/chemistry/genetics/*metabolism ; Sumoylation ; Telomerase/*metabolism ; Telomere/*enzymology/genetics ; *Telomere Homeostasis ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {In both mammalian and fission yeast cells, conserved shelterin and CST (CTC1-STN1-TEN1) complexes play critical roles in protection of telomeres and regulation of telomerase, an enzyme required to overcome the end replication problem. However, molecular details that govern proper coordination among shelterin, CST, and telomerase have not yet been fully understood. Here, we establish a conserved SWSSS motif, located adjacent to the Lys242 SUMOylation site in the fission yeast shelterin subunit Tpz1, as a new functional regulatory element for telomere protection and telomere length homeostasis. The SWSSS motif works redundantly with Lys242 SUMOylation to promote binding of Stn1-Ten1 at telomere and sub-telomere regions to protect against single-strand annealing (SSA)-dependent telomere fusions, and to prevent telomerase accumulation at telomeres. In addition, we provide evidence that the SWSSS motif defines an unanticipated role of Tpz1 in limiting telomerase activation at telomeres to prevent uncontrolled telomere elongation.},
}
@article {pmid31393792,
year = {2019},
author = {Clemente, DBP and Vrijheid, M and Martens, DS and Bustamante, M and Chatzi, L and Danileviciute, A and de Castro, M and Grazuleviciene, R and Gutzkow, KB and Lepeule, J and Maitre, L and McEachan, RRC and Robinson, O and Schwarze, PE and Tamayo, I and Vafeiadi, M and Wright, J and Slama, R and Nieuwenhuijsen, M and Nawrot, TS},
title = {Prenatal and Childhood Traffic-Related Air Pollution Exposure and Telomere Length in European Children: The HELIX Project.},
journal = {Environmental health perspectives},
volume = {127},
number = {8},
pages = {87001},
pmid = {31393792},
issn = {1552-9924},
support = {MR/K006665/1/MRC_/Medical Research Council/United Kingdom ; MR/L01341X/1/MRC_/Medical Research Council/United Kingdom ; MR/N024397/1/MRC_/Medical Research Council/United Kingdom ; P30 ES007048/ES/NIEHS NIH HHS/United States ; },
mesh = {Air Pollutants/*analysis ; Air Pollution/*analysis ; Child, Preschool ; Cohort Studies ; *Environmental Exposure ; Europe ; Female ; Humans ; Infant ; Leukocytes/cytology ; Male ; Maternal Exposure ; Nitrogen Dioxide/analysis ; Particulate Matter/analysis ; Pregnancy ; Telomere Shortening/*drug effects ; Traffic-Related Pollution/*analysis ; },
abstract = {BACKGROUND: Telomere length is a molecular marker of biological aging.<br><br>OBJECTIVE: Here we investigated whether early-life exposure to residential air pollution was associated with leukocyte telomere length (LTL) at 8 y of age.<br><br>METHODS: In a multicenter European birth cohort study, HELIX (Human Early Life Exposome) ([Formula: see text]), we estimated prenatal and 1-y childhood exposure to nitrogen dioxide ([Formula: see text]), particulate matter with aerodynamic diameter [Formula: see text] ([Formula: see text]), and proximity to major roads. Average relative LTL was measured using quantitative real-time polymerase chain reaction (qPCR). Effect estimates of the association between LTL and prenatal, 1-y childhood air pollution, and proximity to major roads were calculated using multiple linear mixed models with a random cohort effect and adjusted for relevant covariates.<br><br>RESULTS: LTL was inversely associated with prenatal and 1-y childhood [Formula: see text] and [Formula: see text] exposures levels. Each standard deviation (SD) increase in prenatal [Formula: see text] was associated with a [Formula: see text] (95% CI: [Formula: see text], [Formula: see text]) change in LTL. Prenatal [Formula: see text] was nonsignificantly associated with LTL ([Formula: see text] per SD increase; 95% CI: [Formula: see text], 0.6). For each SD increment in 1-y childhood [Formula: see text] and [Formula: see text] exposure, LTL shortened by [Formula: see text] (95% CI: [Formula: see text], [Formula: see text]) and [Formula: see text] (95% CI: [Formula: see text], 0.1), respectively. Each doubling in residential distance to nearest major road during childhood was associated with a 1.6% (95% CI: 0.02, 3.1) lengthening in LTL.<br><br>CONCLUSION: Lower exposures to air pollution during pregnancy and childhood were associated with longer telomeres in European children at 8 y of age. These results suggest that reductions in traffic-related air pollution may promote molecular longevity, as exemplified by telomere length, from early life onward. https://doi.org/10.1289/EHP4148.},
}
@article {pmid31393791,
year = {2019},
author = {Li, S and Yang, M and Carter, E and Schauer, JJ and Yang, X and Ezzati, M and Goldberg, MS and Baumgartner, J},
title = {Exposure–Response Associations of Household Air Pollution and Buccal Cell Telomere Length in Women Using Biomass Stoves.},
journal = {Environmental health perspectives},
volume = {127},
number = {8},
pages = {87004},
pmid = {31393791},
issn = {1552-9924},
support = {MR/L01341X/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Air Pollution, Indoor/*analysis ; Biomass ; China ; Cooking/*methods ; Environmental Exposure/*analysis ; Female ; Humans ; Middle Aged ; Particulate Matter/analysis ; Real-Time Polymerase Chain Reaction ; Soot/analysis ; Telomere Shortening/*drug effects ; },
abstract = {BACKGROUND: Telomere shortening is associated with early mortality and chronic disease. Recent studies indicate that environmental exposures, including urban and traffic-related air pollution, may shorten telomeres. Associations between exposure to household air pollution from solid fuel stoves and telomere length have not been evaluated.<br><br>METHODS: Among 137 rural Chinese women using biomass stoves ([Formula: see text] of age), we measured 48-h personal exposures to fine particulate matter [PM [Formula: see text] in aerodynamic diameter ([Formula: see text])] and black carbon and collected oral DNA on up to three occasions over a period of 2.5 y. Relative telomere length (RTL) was quantified using a modified real-time polymerase chain reaction protocol. Mixed effects regression models were used to investigate the exposure&#x2013;response associations between household air pollution and RTL, adjusting for key sociodemographic, behavioral, and environmental covariates.<br><br>RESULTS: Women's daily exposures to air pollution ranged from [Formula: see text] for [Formula: see text] ([Formula: see text]) and [Formula: see text] for black carbon ([Formula: see text]). Natural cubic spline models indicated a mostly linear association between increased exposure to air pollution and shorter RTL, except at very high concentrations where there were few observations. We thus modeled the linear associations with all observations, excluding the highest 3% and 5% of exposures. In covariate-adjusted models, an interquartile range (IQR) increase in exposure to black carbon ([Formula: see text]) was associated with shorter RTL [all observations: [Formula: see text] (95% CI: [Formula: see text], [Formula: see text]); excluding highest 5% exposures: [Formula: see text] (95% CI: [Formula: see text], [Formula: see text])]. Further adjustment for outdoor temperature brought the estimates closer to zero [all observations: [Formula: see text] (95% CI: [Formula: see text], 0.06); excluding highest 5% exposures: [Formula: see text] (95% CI: [Formula: see text], [Formula: see text])]. Models with [Formula: see text] as the exposure metric followed a similar pattern.<br><br>CONCLUSION: Telomere shortening, which is a biomarker of biological aging and chronic disease, may be associated with exposure to air pollution in settings where household biomass stoves are commonly used. https://doi.org/10.1289/EHP4041.},
}
@article {pmid31388112,
year = {2019},
author = {Wang, S and Chang, E and Byanyima, P and Huang, P and Sanyu, I and Musisi, E and Sessolo, A and Davis, JL and Worodria, W and Huang, L and Lin, J and , },
title = {Association between common telomere length genetic variants and telomere length in an African population and impacts of HIV and TB.},
journal = {Journal of human genetics},
volume = {64},
number = {10},
pages = {1033-1040},
pmid = {31388112},
issn = {1435-232X},
support = {D43 TW009607/TW/FIC NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; R01 HL128156/HL/NHLBI NIH HHS/United States ; K24 HL087713/HL/NHLBI NIH HHS/United States ; R01 HL090335/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Africa ; Alleles ; Cohort Studies ; DNA Helicases/genetics ; Demography ; Female ; Genome-Wide Association Study ; HIV Infections/*genetics ; Humans ; Leukocytes/metabolism ; Male ; Polymorphism, Single Nucleotide ; RNA/genetics ; Ribonucleoproteins/genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics ; Tuberculosis/*genetics ; },
abstract = {Prior studies in predominantly European (Caucasian) populations have discovered common genetic variants (single nucleotide polymorphisms, SNPs) associated with leukocyte telomere length (LTL), but whether these same variants affect LTL in non-Caucasian populations are largely unknown. We investigated whether six genetic variants previously associated with LTL (TERC (rs10936599), TERT (rs2736100), NAF1 (7675998), OBFC1 (rs9420907), ZNF208 (rs8105767), and RTEL1 (rs755017)) are correlated with telomere length (TL) in peripheral blood mononuclear cells (PBMCs) in a cohort of Africans living with and without HIV and undergoing evaluation for tuberculosis (TB). We found OBFC1 and the genetic sum score of the effect alleles across all six loci to be associated with shorter TL (adjusted for age, gender, HIV status, and smoking pack-years (p < 0.02 for both OBFC1 and the genetic sum score). In an analysis stratified by HIV status, the genetic sum score is associated with LTL in both groups with and without HIV. On the contrary, a stratified analysis according to TB status revealed that in the TB-positive subgroup, the genetic sum score is not associated with LTL, whereas the relationship remains in the TB-negative subgroup. The different impacts of HIV and TB on the association between the genetic sum score and LTL indicate different modes of modification and suggest that the results found in this cohort with HIV and TB participants may not be applied to the African general population. Future studies need to carefully consider these confounding factors.},
}
@article {pmid31387775,
year = {2019},
author = {Lu, D and Palmer, JR and Rosenberg, L and Shields, AE and Orr, EH and DeVivo, I and Cozier, YC},
title = {Perceived racism in relation to telomere length among African American women in the Black Women's Health Study.},
journal = {Annals of epidemiology},
volume = {36},
number = {},
pages = {33-39},
pmid = {31387775},
issn = {1873-2585},
support = {R01 CA058420/CA/NCI NIH HHS/United States ; U01 CA164974/CA/NCI NIH HHS/United States ; UM1 CA164974/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Black or African American/*psychology ; Aged ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Prejudice ; Racism/*psychology ; Real-Time Polymerase Chain Reaction ; Surveys and Questionnaires ; Telomere/*genetics/metabolism ; Telomere Shortening ; Women's Health ; },
abstract = {PURPOSE: Telomere length is considered a biomarker of human aging and premature morbidity and mortality which has been associated with chronic stress.<br><br>METHODS: We assessed the relation between perceived racism and telomere length in the Black Women's Health Study, a follow-up study of U.S. black women begun in 1995. Participants were asked about frequency of "everyday racism" (e.g., "people act as if they think you are not intelligent") and "institutional racism" (e.g., "ever treated unfairly due to race by police"). Using quantitative real-time polymerase chain reaction assay, relative telomere lengths (RTL) were measured as the copy number ratio of telomere repeat to a single control gene in 997 participants. Associations of racism variables with log-RTL were estimated by multivariable linear regression, with adjustment for age at blood draw and potential confounders.<br><br>RESULTS: Participants were aged 40-70&#xa0;years (mean&#xa0;=&#xa0;55.6&#xa0;years), and mean telomere length was 0.77 (range 0.21-1.38). In stratified analyses, there was an inverse association between everyday racism and log-RTL among women who did not discuss their experiences of racism with others (&#x3b2;&#xa0;=&#xa0;-0.1104; 95% CI&#xa0;=&#xa0;-0.2140 to&#xa0;-0.0067; P&#xa0;=&#xa0;.045).<br><br>CONCLUSIONS: Everyday racism was associated with shorter telomere length among women who reported not discussing those experiences with others.},
}
@article {pmid31383950,
year = {2019},
author = {Monroe, DM and Goldstein, RL and Teylan, MA and Hart, JE and DeVivo, I and Orr, EH and Garshick, E},
title = {Clinical associations with telomere length in chronic spinal cord injury.},
journal = {Spinal cord},
volume = {57},
number = {12},
pages = {1084-1093},
pmid = {31383950},
issn = {1476-5624},
support = {I01 RX000792/RX/RRD VA/United States ; I01RX000596//VHA Office of Research and Development | Rehabilitation Research and Development Service (VA Rehabilitation Research and Development)/ ; R01 AR059270/AR/NIAMS NIH HHS/United States ; B6618R//VHA Office of Research and Development | Rehabilitation Research and Development Service (VA Rehabilitation Research and Development)/ ; I01RX000792//VHA Office of Research and Development | Rehabilitation Research and Development Service (VA Rehabilitation Research and Development)/ ; I21 RX000596/RX/RRD VA/United States ; },
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Chronic Disease ; Cohort Studies ; Cross-Sectional Studies ; Female ; Humans ; Male ; Middle Aged ; Mobility Limitation ; Spinal Cord Injuries/*diagnosis/epidemiology/*physiopathology ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; Urinary Bladder Diseases/diagnosis/epidemiology/physiopathology ; Wheelchairs/adverse effects/trends ; },
abstract = {STUDY DESIGN: Cross-sectional study OBJECTIVES: To determine clinical factors associated with telomere length in persons with chronic spinal cord injury (SCI).<br><br>SETTING: Veterans Affairs Medical Center, Boston, MA.<br><br>METHODS: Two hundred seventy-eight participants with chronic SCI provided blood samples for measurement of C-reactive protein (CRP), interleukin-6 (IL-6), and telomere length, completed respiratory health questionnaires, underwent dual X-ray absorptiometry (DXA) to assess body fat, and completed spirometry. High-throughput real-time PCR assays were used to assess telomere length in leukocyte genomic DNA. Linear regression models were used to assess cross-sectional associations with telomere length.<br><br>RESULTS: Telomere length was inversely related to age (p&#x2009;<&#x2009;0.0001). In age-adjusted models, gender, race, injury duration, %-total and %-trunk fat, body mass index (BMI), %-predicted forced vital capacity (FVC) and forced expiratory volume in 1&#x2009;s (FEV1), chronic cough or phlegm, CRP, IL-6, wheeze, smoking, diabetes, heart disease, chronic obstructive pulmonary disease (COPD), skin ulcer, urinary tract infection (UTI), or chest illness history were not significantly associated with telomere length. There was a suggestive age-adjusted association between persons with the most severe SCI (cervical motor complete and AIS C) and shorter telomere length (p&#x2009;=&#x2009;0.055), an effect equivalent to ~8.4 years of premature aging. There were similar age-adjusted associations with telomere length between persons using a wheelchair (p&#x2009;=&#x2009;0.059) and persons with chronic urinary catheter use (p&#x2009;=&#x2009;0.082) compared to persons without these characteristics.<br><br>CONCLUSIONS: Our results suggest that clinical characteristics such as decreased mobility and bladder dysfunction that are common in individuals with more severe SCI are associated with shorter telomere length.},
}
@article {pmid31380804,
year = {2019},
author = {McNally, EJ and Luncsford, PJ and Armanios, M},
title = {Long telomeres and cancer risk: the price of cellular immortality.},
journal = {The Journal of clinical investigation},
volume = {129},
number = {9},
pages = {3474-3481},
pmid = {31380804},
issn = {1558-8238},
support = {R01 CA225027/CA/NCI NIH HHS/United States ; R01 HL119476/HL/NHLBI NIH HHS/United States ; T32 CA009071/CA/NCI NIH HHS/United States ; },
mesh = {Algorithms ; Alleles ; Aminopeptidases/genetics ; Animals ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics ; Genome-Wide Association Study ; Humans ; Incidence ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Melanoma/genetics ; Mice ; *Mutation ; Neoplasms/epidemiology/*genetics ; Phenotype ; Polymorphism, Single Nucleotide ; Serine Proteases/genetics ; Shelterin Complex ; Skin Neoplasms/genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; Telomeric Repeat Binding Protein 2/genetics ; Tripeptidyl-Peptidase 1 ; Melanoma, Cutaneous Malignant ; },
abstract = {The distribution of telomere length in humans is broad, but it has finite upper and lower boundaries. Growing evidence shows that there are disease processes that are caused by both short and long telomere length extremes. The genetic basis of these short and long telomere syndromes may be linked to mutations in the same genes, such as the telomerase reverse transcriptase (TERT), but through differential effects on telomere length. Short telomere syndromes have a predominant degenerative phenotype marked by organ failure that most commonly manifests as pulmonary fibrosis and are associated with a relatively low cancer incidence. In contrast, insights from studies of cancer-prone families as well as genome-wide association studies (GWAS) have identified both rare and common variants that lengthen telomeres as being strongly associated with cancer risk. We have hypothesized that these cancers represent a long telomere syndrome that is associated with a high penetrance of cutaneous melanoma and chronic lymphocytic leukemia. In this Review, we will synthesize the clinical and human genetic observations with data from mouse models to define the role of telomeres in cancer etiology and biology.},
}
@article {pmid31380592,
year = {2019},
author = {Masterson, EE and Hayes, MG and Kuzawa, CW and Lee, NR and Eisenberg, DTA},
title = {Early life growth and adult telomere length in a Filipino cohort study.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {31},
number = {6},
pages = {e23299},
pmid = {31380592},
issn = {1520-6300},
support = {P30 ES010126/ES/NIEHS NIH HHS/United States ; 8111//Wenner-Gren Foundation/International ; //Northwestern University/International ; P2C HD042828/HD/NICHD NIH HHS/United States ; BCS-1519110//National Science Foundation/International ; T90 DE021984/DE/NIDCR NIH HHS/United States ; /NH/NIH HHS/United States ; P30 DK056350/DK/NIDDK NIH HHS/United States ; R24 HD042828/HD/NICHD NIH HHS/United States ; R01 DK078150/DK/NIDDK NIH HHS/United States ; BCS-0962282//National Science Foundation/International ; P20 RR020649/RR/NCRR NIH HHS/United States ; R01 TW005596/TW/FIC NIH HHS/United States ; },
mesh = {*Growth ; Humans ; Longitudinal Studies ; Male ; Philippines ; Telomere/*physiology ; *Weight Gain ; Young Adult ; },
abstract = {OBJECTIVE: We investigated the relationship between early life growth patterns and blood telomere length (TL) in adulthood using conditional measures of lean and fat mass growth to evaluate potentially sensitive periods of early life growth.<br><br>METHODS: This study included data from 1562 individuals (53% male; age 20-22&#x2009;years) participating in the Cebu Longitudinal Health and Nutrition Survey, located in metropolitan Cebu, Philippines. Primary exposures included length-for-age z-score (HAZ) and weight-for-age z-score (WAZ) at birth and conditional measures of linear growth and weight gain during four postnatal periods: 0-6, 6-12, and 12-24&#x2009;months, and 24&#x2009;months to 8.5&#x2009;years. TL was measured at ~21&#x2009;years of age. We estimated associations using linear regression.<br><br>RESULTS: The study sample had an average gestational age (38.5&#x2009;&#xb1;&#x2009;2&#x2009;weeks) and birth size (HAZ = -0.2&#x2009;&#xb1;&#x2009;1.1, WAZ = -0.7&#x2009;&#xb1;&#x2009;1.0), but by age 8.5&#x2009;years had stunted linear growth (HAZ = -2.1&#x2009;&#xb1;&#x2009;0.9) and borderline low weight (WAZ = -1.9&#x2009;&#xb1;&#x2009;1.0) relative to World Health Organization references. Heavier birth weight was associated with longer TL in early adulthood (P = .03), but this association was attenuated when maternal age at birth was included in the model (P = .07). Accelerated linear growth between 6 and 12&#x2009;months was associated with longer TL in adulthood (P = .006), whereas weight gain between 12 and 24&#x2009;months was associated with shorter TL in adulthood (P = .047).<br><br>CONCLUSIONS: In Cebu, individuals who were born heavier have longer TL in early adulthood, but that birthweight itself may not explain the association. Findings suggest that childhood growth is associated with the cellular senescence process in adulthood, implying early life well-being may be linked to adult health.},
}
@article {pmid31380080,
year = {2019},
author = {Belmaker, A and Hallinger, KK and Glynn, RA and Winkler, DW and Haussmann, MF},
title = {The environmental and genetic determinants of chick telomere length in Tree Swallows (Tachycineta bicolor).},
journal = {Ecology and evolution},
volume = {9},
number = {14},
pages = {8175-8186},
pmid = {31380080},
issn = {2045-7758},
abstract = {Conditions during early life can have dramatic effects on adult characteristics and fitness. However, we still know little about the mechanisms that mediate these relationships. Telomere shortening is one possibility. Telomeres are long sequences of DNA that protect the ends of chromosomes. They shorten naturally throughout an individual's life, and individuals with short telomeres tend to have poorer health and reduced survival. Given this connection between telomere length (TL) and fitness, natural selection should favor individuals that are able to retain longer telomeres for a greater portion of their lives. However, the ability of natural selection to act on TL depends on the extent to which genetic and environmental factors influence TL. In this study, we experimentally enlarged broods of Tree Swallows (Tachycineta bicolor) to test the effects of demanding early-life conditions on TL, while simultaneously cross-fostering chicks to estimate heritable genetic influences on TL. In addition, we estimated the effects of parental age and chick sex on chick TL. We found that TL is highly heritable in Tree Swallow chicks, and that the maternal genetic basis for TL is stronger than is the paternal genetic basis. In contrast, the experimental manipulation of brood size had only a weak effect on chick TL, suggesting that the role of environmental factors in influencing TL early in life is limited. There was no effect of chick sex or parental age on chick TL. While these results are consistent with those reported in some studies, they are in conflict with others. These disparate conclusions might be attributable to the inherent complexity of telomere dynamics playing out differently in different populations or to study-specific variation in the age at which subjects were measured.},
}
@article {pmid31378812,
year = {2019},
author = {Stroik, S and Kurtz, K and Hendrickson, EA},
title = {CtIP is essential for telomere replication.},
journal = {Nucleic acids research},
volume = {47},
number = {17},
pages = {8927-8940},
pmid = {31378812},
issn = {1362-4962},
support = {R01 CA190492/CA/NCI NIH HHS/United States ; T32 AG029796/AG/NIA NIH HHS/United States ; },
mesh = {Carrier Proteins/*metabolism ; *DNA Breaks, Double-Stranded ; DNA End-Joining Repair ; DNA Replication ; DNA, Circular/metabolism ; Endodeoxyribonucleases ; *Genomic Instability ; Humans ; Nuclear Proteins/*metabolism ; Telomere/enzymology/*metabolism ; Telomere Shortening/*genetics ; Telomere-Binding Proteins/metabolism ; },
abstract = {The maintenance of telomere length is critical to longevity and survival. Specifically, the failure to properly replicate, resect, and/or form appropriate telomeric structures drives telomere shortening and, in turn, genomic instability. The endonuclease CtIP is a DNA repair protein that is well-known to promote genome stability through the resection of endogenous DNA double-stranded breaks. Here, we describe a novel role for CtIP. We show that in the absence of CtIP, human telomeres shorten rapidly to non-viable lengths. This telomere dysfunction results in an accumulation of fusions, breaks, and frank telomere loss. Additionally, CtIP suppresses the generation of circular, extrachromosomal telomeric DNA. These latter structures appear to arise from arrested DNA replication forks that accumulate in the absence of CtIP. Hence, CtIP is required for faithful replication through telomeres via its roles at stalled replication tracts. Our findings demonstrate a new role for CtIP as a protector of human telomere integrity.},
}
@article {pmid31376711,
year = {2019},
author = {Li, Y and Han, H and Wu, Y and Yu, C and Ren, C and Zhang, X},
title = {Telomere elongation-based DNA-Catalytic amplification strategy for sensitive SERS detection of telomerase activity.},
journal = {Biosensors &amp; bioelectronics},
volume = {142},
number = {},
pages = {111543},
doi = {10.1016/j.bios.2019.111543},
pmid = {31376711},
issn = {1873-4235},
mesh = {Biosensing Techniques/*methods ; Cell Line, Tumor ; DNA, Catalytic/*metabolism ; Drug Evaluation, Preclinical ; Enzyme Assays/methods ; Humans ; Nucleic Acid Amplification Techniques/methods ; Spectrum Analysis, Raman/*methods ; Substrate Specificity ; Telomerase/antagonists &amp; inhibitors/*metabolism ; Telomere/metabolism ; },
abstract = {Telomerase has been regarded as a biomarker for cancer diagnosis as well as the clinical treatment and the reliable detection of intracellular telomerase activity is of great significance. By developing a telomere elongation-based DNA-catalytic amplification strategy, a novel surface-enhanced Raman scattering (SERS) method is proposed for the assay of telomerase activity. In the presence of telomerase and nucleotide mixture dNTPs, the telomerase substrate (TS) primer extended and generated a long single-strand DNA (ssDNA) containing the telomere repeat units (TTAGGG)n, which could catalyze the entropy-driven circuit reaction (EDCR). One of the products of EDCR was ingeniously used as the catalyst of catalytic hairpin assembly (CHA) occured on magnetic beads (MBs). As a result, a large amount of ROX-labeled Raman probes could be anchored on the surface of MBs and used for SERS detection. Using this strategy, the assay can detect telomerase activity from cell extracts equivalent down to single HeLa cell.},
}
@article {pmid31372311,
year = {2019},
author = {Wisse, RPL and Kuiper, JJW and Radstake, TRD and Broen, JCA},
title = {Quantification of Double Stranded DNA Breaks and Telomere Length as Proxies for Corneal Damage and Replicative Stress in Human Keratoconus Corneas.},
journal = {Translational vision science &amp; technology},
volume = {8},
number = {4},
pages = {10},
pmid = {31372311},
issn = {2164-2591},
abstract = {PURPOSE: The pathogenesis of keratoconus (KC) is multifactorial, and associated with oxidative stress and subsequent DNA damage. We investigate differences in DNA damage and replicative stress in patients with KC, and in healthy and diseased controls.<br><br>METHODS: We obtained 64 corneal buttons from 27 patients with KC after corneal transplant surgery, 21 with a decompensated graft (DG), and 16 healthy controls (HC). The amount of intact Alu elements per genome copy as measured by quantitative polymerase chain reaction (qPCR) was used to quantify intact DNA. Telomere length was measured as a proxy for replicative stress. In addition, telomerase reverse transcriptase (hTERT) gene expression level was assessed.<br><br>RESULTS: Mean (&#xb1; standard deviation [SD]) DNA damage was similar between the KC (5.56 &#xb1; 14.08), DG (3.16 &#xb1; 8.22), and HC (3.51 &#xb1; 6.66) groups (P = 0.807). No associations were found between DNA damage and patient age (P = 0.523), atopic constitution (P = 0.240), or contact lens wear (P = 0.393). Telomere length differed (P = 0.034), most notably in the KC group, and hTERT was not detected in any corneal sample. Three cross-linked (CXL) KC corneas did not contain significantly more DNA damage (&#xd7;2.6, P = 0.750).<br><br>CONCLUSIONS: Based on these findings, differences in actual corneal DNA damage in KC could not be identified, and the longer telomere length in KC did not support replicative stress as a major etiologic factor in the pathogenesis of KC. Future longitudinal investigations on KC etiology should assess progressively early cases to better comprehend the cellular and molecular processes preceding the archetypical morphologic changes.<br><br>TRANSLATIONAL RELEVANCE: The standard treatment for progressive keratoconus promotes the crosslinking of collagen fibers through ultraviolet radiation and the subsequent formation of reactive oxygen species. Our study helps to underline the safety of this treatment approach.},
}
@article {pmid31370740,
year = {2021},
author = {Momany, AM and Lussier, S and Nikolas, MA and Stevens, H},
title = {Telomere Length and ADHD Symptoms in Young Adults.},
journal = {Journal of attention disorders},
volume = {25},
number = {7},
pages = {906-919},
pmid = {31370740},
issn = {1557-1246},
support = {T32 GM108540/GM/NIGMS NIH HHS/United States ; },
mesh = {Adult ; *Attention Deficit Disorder with Hyperactivity/genetics ; Child ; Humans ; Neuropsychological Tests ; Telomere/genetics ; Young Adult ; },
abstract = {Objective: Previous research examining telomeres in individuals with neuropsychiatric disorders shows that greater illness, symptoms, or cognitive impairment are linked with shorter telomeres. However, the relationships of telomere length and neuropsychological processes or psychiatric symptoms are not understood in individuals with Attention Deficit/Hyperactivity Disorder (ADHD). Method: 390 young adults with and without ADHD completed a multi-informant diagnostic assessment and neuropsychological testing battery. Participant DNA was isolated from saliva samples, and telomere length was determined using qPCR. Results: Linear regression models demonstrated the only significant association to survive correction for multiple testing was for childhood hyperactivity-impulsivity symptoms and longer telomere length. Conclusion: Contrary to expectations, longer telomere length in young adults was associated only with childhood ADHD symptoms, particularly hyperactivity-impulsivity, in this sample. These findings are an important demonstration that the neuropsychological deficits and symptoms experienced by individuals diagnosed with ADHD during adulthood may not be negatively associated with telomere length.},
}
@article {pmid31365307,
year = {2019},
author = {Parolini, M and Possenti, CD and Caprioli, M and Rubolini, D and Romano, A and Saino, N},
title = {Egg Testosterone Differentially Affects Telomere Length in Somatic Tissues of Yellow-Legged Gull Embryos.},
journal = {Physiological and biochemical zoology : PBZ},
volume = {92},
number = {5},
pages = {459-462},
doi = {10.1086/705037},
pmid = {31365307},
issn = {1537-5293},
mesh = {Androgens/administration &amp; dosage/*pharmacology ; Animals ; Charadriiformes/*embryology ; Embryo, Nonmammalian/*drug effects ; Ovum ; Telomere ; Telomere Homeostasis/*drug effects ; Testosterone/administration &amp; dosage/*pharmacology ; },
abstract = {Maternal decisions on egg composition have major consequences for offspring. Maternal egg androgens have diverse, often contrasting, effects depending on offspring trait and life stage, suggesting that mothers face trade-offs in egg hormone transfer. However, the effect of egg androgens on embryonic telomere length, which is a major trait potentially affecting performance, has been never investigated. We administered a physiological dose of testosterone (T) to yellow-legged gull (Larus michahellis) eggs and found that, compared to controls, telomere length shortly before hatching was reduced in the liver but unaffected in the brain, heart, and pectoralis muscle. Telomere length varied across somatic tissues, and, independent of egg treatment, it was not correlated between them, suggesting independent telomere dynamics. Thus, we showed for the first time that increased egg T can increase telomere shortening in the embryo and that maternal T allocation strategies may evolve also in response to such effect. Moreover, contrary to observations in adult birds, at the embryonic stage telomere length in one somatic tissue may not reflect telomere length in other body districts.},
}
@article {pmid31361513,
year = {2019},
author = {Cavalcante, SG and Silva, CPN and Sola, PR and Tanaka, LY and Oba-Shinjo, SM and Marie, SKN},
title = {ATRX-DAXX Complex Expression Levels and Telomere Length in Normal Young and Elder Autopsy Human Brains.},
journal = {DNA and cell biology},
volume = {38},
number = {9},
pages = {955-961},
doi = {10.1089/dna.2019.4752},
pmid = {31361513},
issn = {1557-7430},
mesh = {Adaptor Proteins, Signal Transducing/*genetics/metabolism ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Brain/growth &amp; development/*metabolism ; Co-Repressor Proteins ; Humans ; Middle Aged ; Molecular Chaperones ; Nuclear Proteins/*genetics/metabolism ; Telomere Homeostasis ; X-linked Nuclear Protein/*genetics/metabolism ; },
abstract = {The chromatin-remodeling complex ATRX/DAXX is one of the major epigenetic factors that controls heterochromatin maintenance due to its role in histone deposition. ATRX is involved in nucleosome configuration and maintenance of higher order chromatin structure, and DAXX is a specific histone chaperone for H3.3 deposition. Dysfunctions in this complex have been associated with telomere shortening, which influences cell senescence. However, data about this complex in brain tissue related to aging are still scarce. Therefore, in the present study, we analyzed ATRX and DAXX expressions in autopsied human brain specimens and the telomere length. A significant decrease in gene and protein expressions was observed in the brain tissues from the elderly compared with those from the young, which were related to short telomeres. These findings may motivate further functional analysis to confirm the ATRX-DAXX complex involvement in telomere maintenance and brain aging.},
}
@article {pmid31353226,
year = {2019},
author = {Iglesias, M and Felix, DA and Gutiérrez-Gutiérrez, &#xd3; and De Miguel-Bonet, MDM and Sahu, S and Fernández-Varas, B and Perona, R and Aboobaker, AA and Flores, I and González-Estévez, C},
title = {Downregulation of mTOR Signaling Increases Stem Cell Population Telomere Length during Starvation of Immortal Planarians.},
journal = {Stem cell reports},
volume = {13},
number = {2},
pages = {405-418},
pmid = {31353226},
issn = {2213-6711},
support = {MR/M000133/1/MRC_/Medical Research Council/United Kingdom ; BB/K007564/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Adult Stem Cells/cytology/metabolism ; Animals ; Argonaute Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Down-Regulation ; Helminth Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Models, Biological ; Planarians/genetics/*physiology ; RNA Interference ; RNA, Double-Stranded/metabolism ; Signal Transduction ; Starvation ; TOR Serine-Threonine Kinases/*metabolism ; Telomere/*genetics ; Telomere Homeostasis ; },
abstract = {Reduction of caloric intake delays and prevents age-associated diseases and extends the life span in many organisms. It may be that these benefits are due to positive effects of caloric restriction on stem cell function. We use the planarian model Schmidtea mediterranea, an immortal animal that adapts to long periods of starvation by shrinking in size, to investigate the effects of starvation on telomere length. We show that the longest telomeres are a general signature of planarian adult stem cells. We also observe that starvation leads to an enrichment of stem cells with the longest telomeres and that this enrichment is dependent on mTOR signaling. We propose that one important effect of starvation for the rejuvenation of the adult stem cell pool is through increasing the median telomere length in somatic stem cells. Such a mechanism has broad implications for how dietary effects on aging are mediated at the whole-organism level.},
}
@article {pmid31352701,
year = {2019},
author = {Muneer, A and Minhas, FA},
title = {Telomere Biology in Mood Disorders: An Updated, Comprehensive Review of the Literature.},
journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology},
volume = {17},
number = {3},
pages = {343-363},
pmid = {31352701},
issn = {1738-1088},
abstract = {Major psychiatric disorders are linked to early mortality and patients afflicted with these ailments demonstrate an increased risk of developing physical diseases that are characteristically seen in the elderly. Psychiatric conditions like major depressive disorder, bipolar disorder and schizophrenia may be associated with accelerated cellular aging, indicated by shortened leukocyte telomere length (LTL), which could underlie this connection. Telomere shortening occurs with repeated cell division and is reflective of a cell's mitotic history. It is also influenced by cumulative exposure to inflammation and oxidative stress as well as the availability of telomerase, the telomere-lengthening enzyme. Precariously short telomeres can cause cells to undergo senescence, apoptosis or genomic instability; shorter LTL correlates with compromised general health and foretells mortality. Important data specify that LTL may be reduced in principal psychiatric illnesses, possibly in proportion to exposure to the ailment. Telomerase, as measured in peripheral blood monocytes, has been less well characterized in psychiatric illnesses, but a role in mood disorder has been suggested by preclinical and clinical studies. In this manuscript, the most recent studies on LTL and telomerase activity in mood disorders are comprehensively reviewed, potential mediators are discussed, and future directions are suggested. An enhanced comprehension of cellular aging in psychiatric illnesses could lead to their re-conceptualizing as systemic ailments with manifestations both inside and outside the brain. At the same time this paradigm shift could identify new treatment targets, helpful in bringing about lasting cures to innumerable sufferers across the globe.},
}
@article {pmid31352262,
year = {2019},
author = {Louzon, M and Coeurdassier, M and Gimbert, F and Pauget, B and de Vaufleury, A},
title = {Telomere dynamic in humans and animals: Review and perspectives in environmental toxicology.},
journal = {Environment international},
volume = {131},
number = {},
pages = {105025},
doi = {10.1016/j.envint.2019.105025},
pmid = {31352262},
issn = {1873-6750},
mesh = {Animals ; Ecotoxicology ; Environmental Pollutants/*toxicity ; Humans ; Pesticides/analysis/toxicity ; Polycyclic Aromatic Hydrocarbons/analysis/toxicity ; *Telomere/drug effects ; Telomere Homeostasis ; Telomere Shortening ; },
abstract = {Telomeres (TLs) play major roles in stabilizing the genome and are usually shortened with ageing. The maintenance of TLs is ensured by two mechanisms involving telomerase (TA) enzyme and alternative lengthening telomeres (ALT). TL shortening and/or TA inhibition have been related to health effects on organisms (leading to reduced reproductive lifespan and survival), suggesting that they could be key processes in toxicity mechanisms (at molecular and cellular levels) and relevant as an early warning of exposure and effect of chemicals on human health and animal population dynamics. Consequently, a critical analysis of knowledge about relationships between TL dynamic and environmental pollution is essential to highlight the relevance of TL measurement in environmental toxicology. The first objective of this review is to provide a survey on the basic knowledge about TL structure, roles, maintenance mechanisms and causes of shortening in both vertebrates (including humans) and invertebrates. Overall, TL length decreases with ageing but some unexpected exceptions are reported (e.g., in species with different lifespans, such as the nematode Caenorhabditis elegans or the crustacean Homarus americanus). Inconsistent results reported in various biological groups or even between species of the same genus (e.g., the microcrustacean Daphnia sp.) indicate that the relation usually proposed between TL shortening and a decrease in TA activity cannot be generalized and depends on the species, stage of development or lifespan. Although the scientific literature provides evidence of the effect of ageing on TL shortening, much less information on the relationships between shortening, maintenance of TLs, influence of other endogenous and environmental drivers, including exposure to chemical pollutants, is available, especially in invertebrates. The second objective of this review is to connect knowledge on TL dynamic and exposure to contaminants. Most of the studies published on humans rely on correlative epidemiological approaches and few in vitro experiments. They have shown TL attrition when exposed to contaminants, such as polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB), pesticides and metallic elements (ME). In other vertebrates, the studies we found deals mainly with birds and, overall, report a disturbance of TL dynamic consecutively to exposure to chemicals, including metals and organic compounds. In invertebrates, no data are available and the potential of TL dynamic in environmental risk assessment remains to be explored. On the basis of the main gaps identified some research perspectives (e.g., impact of endogenous and environmental drivers, dose response effects, link between TL length, TA activity, longevity and ageing) are proposed to better understand the potential of TL and TA measurements in humans and animals in environmental toxicology.},
}
@article {pmid31350723,
year = {2020},
author = {Li, F and Ge, Y and Liu, D and Songyang, Z},
title = {The role of telomere-binding modulators in pluripotent stem cells.},
journal = {Protein &amp; cell},
volume = {11},
number = {1},
pages = {60-70},
pmid = {31350723},
issn = {1674-8018},
mesh = {Animals ; *Cellular Reprogramming ; Histones/metabolism ; Humans ; Mice ; *Pluripotent Stem Cells/cytology/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/metabolism ; },
abstract = {Pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs), ESCs derived by somatic cell nuclear transfer (ntESCs), and induced pluripotent stem cells (iPSCs) have unlimited capacity for self-renewal and pluripotency and can give rise to all types of somatic cells. In order to maintain their self-renewal and pluripotency, PSCs need to preserve their telomere length and homeostasis. In recent years, increasing studies have shown that telomere reprogramming is essential for stem cell pluripotency maintenance and its induced pluripotency process. Telomere-associated proteins are not only required for telomere maintenance in both stem cells, their extra-telomeric functions have also been found to be critical as well. Here, we will discuss how telomeres and telomere-associated factors participate and regulate the maintenance of stem cell pluripotency.},
}
@article {pmid31349105,
year = {2019},
author = {Wang, W and Wang, P and Wang, S and Duan, X and Wang, T and Feng, X and Li, L and Zhang, Y and Li, G and Zhao, J and Li, L and Wang, Y and Yan, Z and Feng, F and Zhou, X and Yao, W and Zhang, Y and Yang, Y},
title = {Benchmark dose assessment for coke oven emissions-induced telomere length effects in occupationally exposed workers in China.},
journal = {Ecotoxicology and environmental safety},
volume = {182},
number = {},
pages = {109453},
doi = {10.1016/j.ecoenv.2019.109453},
pmid = {31349105},
issn = {1090-2414},
mesh = {Adolescent ; Adult ; Air Pollutants, Occupational/*analysis/toxicity ; Benchmarking ; Biomarkers/analysis ; Case-Control Studies ; China ; Coke/*analysis/toxicity ; Dose-Response Relationship, Drug ; Female ; Humans ; Male ; Middle Aged ; Occupational Exposure/adverse effects/*analysis ; Oxidative Stress/drug effects/genetics ; Telomere/*drug effects/ultrastructure ; Young Adult ; },
abstract = {Telomeres are DNA-protein structures that protect chromosome ends from degradation and fusion, which are shortened by oxidative stress, for example air pollution including benzene, toluene, Coke Oven Emissions (COEs), and so on. As a biomarker of health and disease, telomere length is associated with cardiovascular, diabetes and cancers. The aim of this study was to estimate the effects of COEs exposure on telomere length and the benchmark dose (BMD) of COEs. A total of 542 coke oven workers and 235 healthy controls without exposure to toxicants were recruited. Quantitative PCR was used to determine the telomere length in human peripheral blood leukocytes DNA. Propensity scoring was used to match coke oven workers to healthy controls. Linear regression models and trend tests were used to the relationship between COEs exposure and telomere length. Telomere length in COEs exposed group 0.764 (0.536, 1.092) was significantly shorter than that in the control group 1.064(0.762, 1.438), (P < 0.001). There were significantly dose-response relationships between COEs exposure and telomere damage with telomere length as a biomarker. A BMDL value lower than the present occupational exposure limits (OELs) of COEs exposure was evaluated using the BMD approach in coke oven workers. Our results suggested that shorter telomere length is related to occupational exposure to COEs and the level of COEs exposure lower than the current national OELs in China and many other countries could induce telomere damage.},
}
@article {pmid31341884,
year = {2019},
author = {J, W and J J, B and M, K and S A R, M and S M J, M},
title = {Is Telomere Length a Biomarker of Adaptive Response in Space? Curious Findings from NASA and Residents of High Background Radiation Areas.},
journal = {Journal of biomedical physics &amp; engineering},
volume = {9},
number = {3},
pages = {381-388},
pmid = {31341884},
issn = {2251-7200},
abstract = {Telomere length and stability is a biomarker of aging, stress, and cancer. Shortening of telomeres and high level of DNA damages are known to be associated with aging. Telomere shortening normally occurs during cell division in most cells and when telomeres reach a critically short length, DNA damage signaling and cellular senescence can be triggered. The induction of an adaptive response by space radiation was first documented in 2003. Telomere length alterations are among the most fascinating observations in astronauts and residents of high background radiation areas. While study of the chronic exposure to high levels of background ionizing radiation in Kerala, India failed to show a significant influence on telomere length, limited data about the NASA astronaut Scott Kelly show that exposure to space radiation can induce telomeres to regain length. Interestingly, his telomeres shortened again only a couple of days after returning to Earth. The difference between these situations may be due to the differences in radiation dose, dose-rate, and/or type of radiation. Moreover, Scott Kelly's spacewalks (EVA) could have significantly increased his cumulative radiation dose. It is worth noting that the spacewalks not only confer a higher dose activity but are also characterized by a different radiation spectrum than inside the space craft since the primary particles would not interact with the vehicle shell to generate secondary radiation. Generally, these differences can possibly indicate the necessity of a minimum dose/dose-rate for induction of adaptive response (the so called Window effect).},
}
@article {pmid31340612,
year = {2019},
author = {Gao, J and Xiao, H and Li, J and Guo, X and Cai, W and Li, D},
title = {N-3 Polyunsaturated Fatty Acids Decrease Long-Term Diabetic Risk of Offspring of Gestational Diabetes Rats by Postponing Shortening of Hepatic Telomeres and Modulating Liver Metabolism.},
journal = {Nutrients},
volume = {11},
number = {7},
pages = {},
pmid = {31340612},
issn = {2072-6643},
mesh = {Age Factors ; Animals ; Diabetes Mellitus/genetics/metabolism/*prevention &amp; control ; Diabetes, Gestational/genetics/*metabolism ; *Dietary Supplements ; Disease Models, Animal ; Fatty Acids, Omega-3/*administration &amp; dosage/metabolism ; Female ; Liver/*metabolism ; Male ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Rats, Wistar ; Risk Factors ; Telomere/genetics/*metabolism ; *Telomere Shortening ; Time Factors ; },
abstract = {The long-term influence of gestational diabetes mellitus (GDM) on offspring and the effect of omega-3 polyunsaturated fatty acids (n-3 PUFA) on GDM offspring are poorly understood. We studied the long-term diabetic risk in GDM offspring and evaluated the effect of n-3 PUFA intervention. Healthy offspring rats were fed standard diet (soybean oil) after weaning. GDM offspring were divided into three groups: GDM offspring (soybean oil), n-3 PUFA adequate offspring (fish oil), and n-3 PUFA deficient offspring (safflower oil), fed up to 11 months old. The diabetic risk of GDM offspring gradually increased from no change at weaning to obvious impaired glucose and insulin tolerance at 11 months old. N-3 PUFA decreased oxidative stress and inflammation in the liver of older GDM offspring. There was a differential effect of n-3 PUFA and n-6 PUFA on hepatic telomere length in GDM offspring. Non-targeted metabolomics showed that n-3 PUFA played a modulating role in the liver, in which numerous metabolites and metabolic pathways were altered when GDM offspring grew to old age. Many metabolites were related to diabetes risk, such as α-linolenic acid, palmitic acid, ceramide, oxaloacetic acid, tocotrienol, tetrahydro-11-deoxycortisol, andniacinamide. In summary, GDM offspring exhibited obvious diabetes risk at old age, whereas n-3 PUFA decreased this risk.},
}
@article {pmid31340127,
year = {2019},
author = {Maeda, T and Horiuchi, T and Makino, N},
title = {The approximate formulas predicting personal somatic telomere length using patient blood test data.},
journal = {Canadian journal of physiology and pharmacology},
volume = {97},
number = {11},
pages = {1090-1093},
doi = {10.1139/cjpp-2019-0262},
pmid = {31340127},
issn = {1205-7541},
mesh = {Aged ; Biometry/*methods ; *Blood Chemical Analysis ; DNA/genetics ; Female ; Hemoglobins/analysis ; Humans ; Male ; Telomere/*genetics ; },
abstract = {Biological aging underlies lifestyle-related diseases. It can be assessed by measuring personal somatic cell telomere length. However, measuring the telomere length is laborious, and its clinical surrogate parameters have not been developed. This study analyzed the correlation between telomere length in peripheral leukocytes and laboratory data to select test items relating closely to biological aging. We established formulas from these clinical data to predict the personal telomere length. The subjects were patients having visited Kyushu University Beppu Hospital from 2012 to 2015. Two hundred and thirty-two patients were enrolled. The blood data were collected and telomere lengths were measured by Southern blotting method. The patients showed significant correlations between the telomere length and several blood test data with a sex-related difference. Candidate formulas are as follows: Predicted telomere length (kb) in men = 8.59 - 0.037 × Age (years) + 0.024 × Hemoglobin (g/dL); Predicted telomere length (kb) in women = 4.83 - 0.019 × Age (years) + 0.23 × Albumin (g/dL) + 0.0001 × White blood cells (/mm[3]) + 0.0020 × Red blood cells (× 10[4]/mm[3]) + 0.0032 × Total cholesterol (mg/dL). Thus, the derived formulas allow for the accurate differential prediction of telomeric length in male and female patients.},
}
@article {pmid31339412,
year = {2020},
author = {Wang, L and Koenig, HG and He, Z and Sun, X and Shohaib, SA and Wang, Z},
title = {Religiosity and Telomere Length: Moderating Effect of Religiosity on the Relationship Between High-Risk Polymorphisms of the Apolipoprotein E and TOMM40 Gene and Telomere Length.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {39},
number = {6},
pages = {627-634},
doi = {10.1177/0733464819865415},
pmid = {31339412},
issn = {1552-4523},
mesh = {Aged ; Apolipoproteins E/*genetics ; Asian People ; Cross-Sectional Studies ; Female ; Humans ; Male ; Membrane Transport Proteins/*genetics ; Middle Aged ; Mitochondrial Precursor Protein Import Complex Proteins ; Polymorphism, Single Nucleotide ; *Religion ; Telomere/*genetics ; },
abstract = {Objective: The current study seeks to examine the relationship between religiosity and telomere length (TL) in an older Chinese Muslim sample and to explore the moderating effect of religiosity on the relationship between high-risk polymorphisms and TL. Methods: A cross-sectional study of 1,692 community-dwelling adults aged 55 or older was conducted. Apolipoprotein E and TOMM40 (rs2075650) gene polymorphisms and TL were determined using standard procedures. Ordinal logistic regression was used to examine the associations. Results: Religiosity was significantly and positively related to TL. A significant interaction emerged between religiosity and the rs2075650 G polymorphism in predicting TL. Stratified multivariate analyses demonstrated that the relationship between the rs2075650 G state and TL was particularly strong among those who were more religious, as hypothesized. Conclusion: The findings revealed that religiosity may influence cellular aging in part by modifying the effect that high-risk genes have on increasing vulnerability to dementia and cognitive impairment.},
}
@article {pmid31337791,
year = {2019},
author = {Lemon, LD and Morris, DK and Bertuch, AA},
title = {Loss of Ku's DNA end binding activity affects telomere length via destabilizing telomere-bound Est1 rather than altering TLC1 homeostasis.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {10607},
pmid = {31337791},
issn = {2045-2322},
support = {T32 AG000183/AG/NIA NIH HHS/United States ; R01 GM077509/GM/NIGMS NIH HHS/United States ; T32 GM008231/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatin Immunoprecipitation ; DNA End-Joining Repair ; DNA, Fungal/*metabolism ; DNA-Binding Proteins/*metabolism ; Immunoprecipitation ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomerase/*metabolism ; Telomere/metabolism ; *Telomere Homeostasis ; },
abstract = {Saccharomyces cerevisiae telomerase, which maintains telomere length, is comprised of an RNA component, TLC1, the reverse transcriptase, Est2, and regulatory subunits, including Est1. The Yku70/Yku80 (Ku) heterodimer, a DNA end binding (DEB) protein, also contributes to telomere length maintenance. Ku binds TLC1 and telomere ends in a mutually exclusive fashion, and is required to maintain levels and nuclear localization of TLC1. Ku also interacts with Sir4, which localizes to telomeres. Here we sought to determine the role of Ku's DEB activity in telomere length maintenance by utilizing yku70-R456E mutant strains, in which Ku has reduced DEB and telomere association but proficiency in TLC1 and Sir4 binding, and TLC1 nuclear retention. Telomere lengths in a yku70-R456E strain were nearly as short as those in yku∆ strains and shorter than in strains lacking either Sir4, Ku:Sir4 interaction, or Ku:TLC1 interaction. TLC1 levels were decreased in the yku70-R456E mutant, yet overexpression of TLC1 failed to restore telomere length. Reduced DEB activity did not impact Est1's ability to associate with telomerase but did result in decreased association of Est1 with the telomere. These findings suggest Ku's DEB activity maintains telomere length homeostasis by preserving Est1's interaction at the telomere rather than altering TLC1 levels.},
}
@article {pmid31336906,
year = {2019},
author = {Fice, HE and Robaire, B},
title = {Telomere Dynamics Throughout Spermatogenesis.},
journal = {Genes},
volume = {10},
number = {7},
pages = {},
pmid = {31336906},
issn = {2073-4425},
support = {TE1-138298//CIHR/Canada ; },
mesh = {Aging/genetics ; Animals ; Male ; Rats ; Rats, Inbred BN ; Rats, Sprague-Dawley ; Spermatids/ultrastructure ; Spermatocytes/ultrastructure ; Spermatogenesis/*genetics ; Telomere/genetics/*metabolism ; Telomere Shortening ; },
abstract = {Telomeres are repeat regions of DNA that cap either end of each chromosome, thereby providing stability and protection from the degradation of gene-rich regions. Each cell replication causes the loss of telomeric repeats due to incomplete DNA replication, though it is well-established that progressive telomere shortening is evaded in male germ cells by the maintenance of active telomerase. However, germ cell telomeres are still susceptible to disruption or insult by oxidative stress, toxicant exposure, and aging. Our aim was to examine the relative telomere length (rTL) in an outbred Sprague Dawley (SD) and an inbred Brown Norway (BN) rat model for paternal aging. No significant differences were found when comparing pachytene spermatocytes (PS), round spermatids (RS), and sperm obtained from the caput and cauda of the epididymis of young and aged SD rats; this is likely due to the high variance observed among individuals. A significant age-dependent decrease in rTL was observed from 115.6 (±6.5) to 93.3 (±6.3) in caput sperm and from 142.4 (±14.6) to 105.3 (±2.5) in cauda sperm from BN rats. Additionally, an increase in rTL during epididymal maturation was observed in both strains, most strikingly from 115.6 (±6.5) to 142 (±14.6) in young BN rats. These results confirm the decrease in rTL in rodents, but only when an inbred strain is used, and represent the first demonstration that rTL changes as sperm transit through the epididymis.},
}
@article {pmid31335885,
year = {2019},
author = {Song, DY and Kim, JA and Jeong, D and Yun, J and Kim, SM and Lim, K and Park, SN and Im, K and Choi, S and Yoon, SS and Lee, DS},
title = {Telomere length and its correlation with gene mutations in chronic lymphocytic leukemia in a Korean population.},
journal = {PloS one},
volume = {14},
number = {7},
pages = {e0220177},
pmid = {31335885},
issn = {1932-6203},
mesh = {Adaptor Proteins, Signal Transducing/genetics ; Aged ; Ataxia Telangiectasia Mutated Proteins/genetics ; Biomarkers, Tumor/genetics ; Female ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/pathology ; Male ; Middle Aged ; *Mutation ; Republic of Korea ; *Telomere Homeostasis ; Tumor Suppressor Protein p53/genetics ; },
abstract = {Telomere length (TL) is a prognostic indicator in Caucasian chronic lymphocytic leukemia (CLL), but its significance in Asian CLL remains unknown. To investigate the prognostic significance of TL and its correlation with cytogenetic aberrations and somatic mutations, we analyzed TL measurements at the cellular level by interphase fluorescence in situ hybridization in patients with CLL in Korea. The present study enrolled 110 patients (41 females and 69 males) diagnosed with CLL according to the World Health Organization criteria (2001-2017). TLs of bone marrow nucleated cells at the single-cell level were measured by quantitative fluorescence in situ hybridization (Q-FISH) in 71 patients. The correlations of TL with clinical characteristics, cytogenetic aberrations, genetic mutations, and overall survival were assessed. The median value of mean TL in CLL patients (T/C ratio 7.46 (range 1.19-18.14) was significantly shorter than that in the normal controls (T/C ratio 15.28 (range 8.59-24.93) (p < 0.001). Shorter TLs were associated with complex karyotypes (p = 0.030), del(11q22) (p = 0.023), presence of deletion and/or mutation in ATM and/or TP53 (p = 0.019), and SH2B3 mutation (p = 0.015). A shorter TL was correlated with lower hemoglobin levels and adverse survival (mean TL < 9.35, p = 0.021). When the proportion of cells with extremely short TLs (< 7.61) was greater than 90%, CLL patients showed poor survival (p = 0.002). Complex karyotypes, TP53 mutation, and the number of mutated genes were determined to be significant adverse variables by multivariable Cox analysis (p = 0.011, p = 0.002, and p = 0.002, respectively). TL was attrited in CLL, and attrited telomeres were correlated with adverse survival and other well-known adverse prognostic factors. We infer that TL is an independent adverse prognostic predictor in Korean CLL.},
}
@article {pmid31335808,
year = {2019},
author = {Wang, Y and Brummel, SS and Beilstein-Wedel, E and Dagnall, CL and Hazra, R and Kacanek, D and Chadwick, EG and Marsit, CJ and Chanock, SJ and Savage, SA and Poirier, MC and Machiela, MJ and Engels, EA and , },
title = {Association between zidovudine-containing antiretroviral therapy exposure in utero and leukocyte telomere length at birth.},
journal = {AIDS (London, England)},
volume = {33},
number = {13},
pages = {2091-2096},
pmid = {31335808},
issn = {1473-5571},
support = {U01 HD052102/HD/NICHD NIH HHS/United States ; U01 HD052104/HD/NICHD NIH HHS/United States ; Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Anti-HIV Agents/*therapeutic use ; Female ; HIV Infections/drug therapy ; Humans ; Infant, Newborn ; Leukocytes, Mononuclear/drug effects/pathology ; Male ; *Maternal-Fetal Exchange ; Middle Aged ; Pregnancy ; Pregnancy Complications, Infectious/drug therapy ; Telomere/*ultrastructure ; United States ; Young Adult ; Zidovudine/*therapeutic use ; },
abstract = {OBJECTIVES: Zidovudine (ZDV) is a nucleoside reverse transcriptase inhibitor that could cause telomere shortening through inhibition of telomerase. We examined the association between in utero exposure to ZDV and telomere length at birth in HIV-exposed-uninfected (HEU) newborns.<br><br>METHODS: We selected 94 ZDV-exposed HEU children and 85 antiretroviral therapy (ART)-unexposed HEU children from the Surveillance Monitoring for ART Toxicities Study and the Women and Infants Transmission Study. We assessed relative telomere length in stored peripheral blood mononuclear cells taken in the first 7 days of life using quantitative polymerase chain reaction. We used linear regression to compare relative telomere length between ZDV-exposed and ART-unexposed children. We additionally evaluated relative telomere length according to maternal and infant characteristics.<br><br>RESULTS: Relative telomere length was longer in ZDV-exposed children compared with ART-unexposed individuals (adjusted mean ratio difference 0.21, 95% confidence interval 0.15-0.28, P&#x200a;<&#x200a;0.001). We found an inverse correlation between maternal HIV RNA levels and infant relative telomere length (-0.06 per log10 copies, 95% confidence interval -0.08 to -0.03, P&#x200a;<&#x200a;0.001). Relative telomere length was not associated with maternal CD4 cell count, maternal age, gestational age, sex, sample storage time, or maternal substance use (P&#x200a;>&#x200a;0.05).<br><br>CONCLUSION: Relative telomere length was longer in ZDV-exposed infants. This difference may reflect beneficial health effects of ART during pregnancy, as we observed an inverse association with maternal HIV RNA levels.},
}
@article {pmid31332860,
year = {2019},
author = {Wood, EM and Young, AJ},
title = {Telomere attrition predicts reduced survival in a wild social bird, but short telomeres do not.},
journal = {Molecular ecology},
volume = {28},
number = {16},
pages = {3669-3680},
pmid = {31332860},
issn = {1365-294X},
support = {BB/H022716/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/J0144004/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Biomarkers ; Models, Biological ; South Africa ; Sparrows/*physiology ; *Survival Rate ; *Telomere ; *Telomere Shortening ; },
abstract = {Attempts to understand the causes of variation in senescence trajectories would benefit greatly from biomarkers that reflect the progressive declines in somatic integrity (SI) that lead to senescence. While telomere length has attracted considerable interest in this regard, sources of variation in telomere length potentially unrelated to declines in SI could, in some contexts, leave telomere attrition rates a more effective biomarker than telomere length alone. Here, we investigate whether telomere length and telomere attrition rates predict the survival of wild white-browed sparrow-weaver nestlings (Plocepasser mahali). Our analyses of telomere length reveal counterintuitive patterns: telomere length soon after hatching negatively predicted nestling survival to fledging, a pattern that appears to be driven by differentially high in-nest predation of broods with longer telomeres. Telomere length did not predict survival outside this period: neither hatchling telomere length nor telomere length in the mid-nestling period predicted survival from fledging to adulthood. Our analyses using within-individual telomere attrition rates, by contrast, revealed the expected relationships: nestlings that experienced a higher rate of telomere attrition were less likely to survive to adulthood, regardless of their initial telomere length and independent of effects of body mass. Our findings support the growing use of telomeric traits as biomarkers of SI, but lend strength to the view that longitudinal assessments of within-individual telomere attrition since early life may be a more effective biomarker in some contexts than telomere length alone.},
}
@article {pmid32145158,
year = {2019},
author = {Mustafin, RN},
title = {[Aging and interrelation of telomeres with transposable elements.].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {32},
number = {5},
pages = {693-701},
pmid = {32145158},
issn = {1561-9125},
mesh = {Aging/*genetics ; *DNA Transposable Elements ; Epigenesis, Genetic ; Humans ; Telomere/*genetics ; },
abstract = {Telomere dysfunction and changes in their length during aging of an organism is a reflection of more global processes in the genome, which are caused by the regulatory influence of transposable elements sequentially activated during ontogenesis. This consequence is due to the fact that centromeres and centromeric proteins, telomeres and telomerases, introns and spliceosome components, transcription factors and their binding sites, noncoding RNAs and their targets in protein coding gene sequences have evolved from transposable elements. The relationship of these structural-functional elements of the genome dynamically changes in individual development and depends on the characteristics of successive activations and transpositions of the transposable elements. Each species is characterized by a specific set of transposable elements and associated tandem repeats, which affects the epigenetic regulation of ontogenesis. These tandem repeats are mainly contained in centromeres and telomeres, the specific influence of researchers on which is promising for developing ways of regulating life expectancy. This is due to the ability of ribozymes and peptides to interact with specific DNA nucleotide sequences, especially as part of tandem repeats. An important approach to the study of the relationship of transposons with telomeres, centromeres and subtelomeric regions for the regulation of aging can be the study of the role of their uniting peptides and miRNA, whose complex application has a high potential of geroprotective efficiency.},
}
@article {pmid32010796,
year = {2018},
author = {Kaewtunjai, N and Wongpoomchai, R and Imsumran, A and Pompimon, W and Athipornchai, A and Suksamrarn, A and Lee, TR and Tuntiwechapikul, W},
title = {Ginger Extract Promotes Telomere Shortening and Cellular Senescence in A549 Lung Cancer Cells.},
journal = {ACS omega},
volume = {3},
number = {12},
pages = {18572-18581},
pmid = {32010796},
issn = {2470-1343},
abstract = {Replicative senescence, which is caused by telomere shortening from the end replication problem, is considered one of the tumor-suppressor mechanisms in eukaryotes. However, most cancers escape this replicative senescence by reactivating telomerase, an enzyme that extends the 3'-ends of the telomeres. Previously, we reported the telomerase inhibitory effect of a crude Zingiber officinale extract (ZOE), which suppressed hTERT expression, leading to a reduction in hTERT protein and telomerase activity in A549 lung cancer cells. In the present study, we found that ZOE-induced telomere shortening and cellular senescence during the period of 60 days when these A549 cells were treated with subcytotoxic doses of ZOE. Using assay-guided fractionation and gas chromatography/mass spectrometry analysis, we found that the major compounds in the active subfractions were paradols and shogaols of various chain lengths. The results from studies of pure 6-paradol and 6-shogaol confirmed that these two compounds could suppress hTERT expression as well as telomerase activity in A549 cells. These results suggest that these paradols and shogaols are likely the active compounds in ZOE that suppress hTERT expression and telomerase activity in these cells. Furthermore, ZOE was found to be nontoxic and had an anticlastogenic effect against diethylnitrosamine-induced liver micronucleus formation in rats. These findings suggest that ginger extract can potentially be useful in dietary cancer prevention.},
}
@article {pmid31966846,
year = {2017},
author = {Niu, F and Li, J and Li, J and Yan, M and Shi, X and Jin, T},
title = {Polymorphisms of telomere-length related genes in three China ethnic groups.},
journal = {International journal of clinical and experimental pathology},
volume = {10},
number = {9},
pages = {9654-9665},
pmid = {31966846},
issn = {1936-2625},
abstract = {Little is known about polymorphic distribution of telomere-length related genes among ethnicities, which play important roles in the progression of high-altitude pulmonary edema (HAPE). We genotyped 45 single nucleotide polymorphism (SNP) in 300 unrelated healthy volunteers from the following three Chinese ethnic populations: Han (n = 100), Tibetan (n = 100) and Sherpa (n = 100). We used χ[2] test, pairwise FST values, and structure clustering analyses to investigate the genetic differences between these populations. Our results first indicated that rs12615793 (ACYP2), rs10936599 (TERC), rs10069690 (TERT) and rs6010620, rs4809324 (RTEL1) showed the greatest number of significant differences between Han and Tibetan, Sherpa and 11 HapMap populations. Meanwhile, we found that rs1056654 and rs1056629 (MPHOSPH6), rs2320615 (NAF1), rs6010621 (RTEL1), rs8105767 and rs2188972 (ZNF208) genotype frequencies showed considerable divergence among Tibetan and Sherpa. Besides, pairwise FST values and structure clustering analyses revealed that Han exhibited a close genetic affinity with CHD and CHB, but revealed a great genetic heterogeneity with YRI and MKK. This work greatly expanded our understanding of the distribution of telomere-length related genes in Chinese populations and may be helpful to forensic applications and population genetic studies.},
}
@article {pmid31966722,
year = {2017},
author = {Hao, F and Liu, J and Zhong, M and Wang, J and Liu, J},
title = {Association between clincopathological characteristics and hTERT expression as well as telomere length in ameloblastoma.},
journal = {International journal of clinical and experimental pathology},
volume = {10},
number = {8},
pages = {8647-8653},
pmid = {31966722},
issn = {1936-2625},
abstract = {OBJECTIVE: This study aimed to investigate the human telomerase reverse transcriptase (hTERT) expression and telomere length in ameloblastoma, and expolre the role of hTERT in the invasiveness and recurrence of ameloblastoma.<br><br>METHODS: hTERT expression was detected by immunohistochemistry and Western blotting and telomere length by fluorescence in situ hybridization (FISH) in human ameloblastoma, normal mucosa, and oral squamous cell carcinoma (OSCC). Association between clincopathological characteristics and hTERT expression as well as telomere length in ameloblastoma was analyzed.<br><br>RESULTS: hTERT expression in ameloblastoma was higher than that in normal oral mucosa, and the highest in OSCC (P<0.05). The hTERT positive rate and expression increased with the recurrence and malignant transformation. hTERT expression was significantly different among different types of ameloblastoma. The telomere was the shortest in OSCC and the longest in normal oral mucosa.<br><br>CONCLUSION: Ameloblastoma has shortened telomere, and is positive for hTERT expression which is related to the recurrence and malignancy of ameloblastoma. These findings indicate that telomerase is involved in the occurrence and development of ameloblastoma.},
}
@article {pmid32161788,
year = {2017},
author = {Jenkins, EC and Ye, L and Marchi, E and Krinsky-McHale, SJ and Zigman, WB and Schupf, N and Silverman, WP},
title = {An improved method for detecting telomere size differences in T-lymphocyte interphases from older people with Down syndrome with and without mild cognitive impairment.},
journal = {Biology methods &amp; protocols},
volume = {2},
number = {1},
pages = {bpx005},
pmid = {32161788},
issn = {2396-8923},
support = {P01 HD035897/HD/NICHD NIH HHS/United States ; R01 AG014673/AG/NIA NIH HHS/United States ; R01 HD037425/HD/NICHD NIH HHS/United States ; U54 HD079123/HD/NICHD NIH HHS/United States ; },
abstract = {Telomere size (quantified by fluorescence intensity and physical lengths) in short-term T-lymphocyte cultures from adults with Down syndrome (DS) with and without mild cognitive impairment (MCI-DS) or dementia was compared. For these studies, dementia status was determined based on longitudinal assessments employing a battery of cognitive and functional assessments developed to distinguish adult-onset impairment from preexisting developmental disability. In the course of our studies using a MetaSystems Image Analyzer in combination with ISIS software and a Zeiss Axioskop 2, we found that Fluorescein isothiocyanate (FITC) telomere fluorescence referenced to chromosome 2-identified FITC probe fluorescence as a nontelomere standard (telomere/cen2 ratio) showed great promise as a biomarker of early decline associated with Alzheimer's disease (AD) in this high-risk population. We have now obtained a cen (2) CY3 probe that can clearly be distinguished from the blue-green FITC interphase telomere probe, providing a clear distinction between telomere and centromere fluorescence in both interphase and metaphase. We used FITC/CY3 light intensity ratios to compare telomere length in interphases in adults with DS with and without MCI-DS or dementia. Five age-matched female and five age-matched male pairs (n = 10) all showed clear evidence of telomere shortening associated with clinical progression of AD (P < 0.002 - P < 0.000001), with distributions of mean values for cases and controls showing no overlap. We also examined the time needed for microscopy using interphase versus metaphase fluorescence preparations. With interphase preparations, examination time was reduced by an order of magnitude compared with metaphase preparations, indicating that the methods employed herein have considerable practical promise for translation into broad diagnostic practice.},
}
@article {pmid31725959,
year = {2016},
author = {Swyers, NC and Cody, JP and McCaw, ME and Graham, ND and Zhao, C and Gaeta, RT and Birchler, JA},
title = {Telomere-Mediated Chromosomal Truncation for Generating Engineered Minichromosomes in Maize.},
journal = {Current protocols in plant biology},
volume = {1},
number = {3},
pages = {488-500},
doi = {10.1002/cppb.20031},
pmid = {31725959},
issn = {2379-8068},
abstract = {Minichromosomes have been generated in maize using telomere-mediated truncation. Telomere DNA, because of its repetitive nature, can be difficult to manipulate. The protocols in this unit describe two methods for generating the telomere DNA required for the initiation of telomere-mediated truncation. The resulting DNA can then be used with truncation cassettes for introduction into maize via transformation. © 2016 by John Wiley &amp; Sons, Inc.},
}
@article {pmid31394654,
year = {2004},
author = {Pathak, S and Multani, AS and Narayan, S and Furlong, CL and Hsu, TC},
title = {Germline Telomere Length Dynamics and Mutagen Sensitivity Studies in a Family with Acute Reactions to Sun Exposure: Involvement of Three Generations.},
journal = {Cancer genomics &amp; proteomics},
volume = {1},
number = {3},
pages = {199-208},
pmid = {31394654},
issn = {1790-6245},
abstract = {Most cancers are the result of an interaction between germline genetic susceptibility and exposure to environmental carcinogens. We studied chromosomal aberrations, telomeric associations, telomere signal intensity by fluorescence in situ hybridization, p53 germline mutation, bleomycin (Bleo) and 4-nitroquinoline-1-oxide (4NQO) sensitivity, and chromosome-specific telomere signals in T and B lymphocytes in a Caucasian family involving three generations and 13 family members. This family was chosen because eight of its members are extremely sensitive to sunlight and burn easily even upon short exposure. The family members have shown: (a) hypersensitivity either to Bleo or 4NQO mutagens, with values much higher than 1.00 breaks/cell (b/c) for Bleo and 0.40 b/c for 4NQO; (b) an increased rate of telomeric associations; (c) variable amounts of telomeric DNA not common for the person's age; (d) the presence of intron 7 polymorphism in the proband and no significant effect on N-methyl-N'-nitosoguanidine (MNNG)-induced p53 expression in two key family members; and (e) an incidence of epithelial malignancies in two family members. Seven additional members showed polymorphism of telomeric signals in the short arm of two homologous chromosome 17s, where the p53 gene is localized. A 78-year-old grandmother, who had developed colon cancer, was predicted to have metastatic cancer based on the telomeric DNA amount in her lymphocytes (2.90%); she subsequently developed metastatic lesions within a year and died. Based on these observations, we conclude that telomere erosion is the initial cause of genomic instability/susceptibility which, in turn, may be causal for the reproductive complications, premature aging phenotypes and, in some cases, predisposition to cancer development.},
}
@article {pmid31332096,
year = {2019},
author = {Xu, YJ and Khan, S and Didier, AC and Wozniak, M and Liu, Y and Singh, A and Nakamura, TM},
title = {A tel2 Mutation That Destabilizes the Tel2-Tti1-Tti2 Complex Eliminates Rad3[ATR] Kinase Signaling in the DNA Replication Checkpoint and Leads to Telomere Shortening in Fission Yeast.},
journal = {Molecular and cellular biology},
volume = {39},
number = {20},
pages = {},
pmid = {31332096},
issn = {1098-5549},
support = {R01 GM078253/GM/NIGMS NIH HHS/United States ; R01 GM110132/GM/NIGMS NIH HHS/United States ; },
mesh = {Checkpoint Kinase 2/genetics/*metabolism ; DNA Damage/drug effects ; DNA Replication ; Hydroxyurea/pharmacology ; Intracellular Signaling Peptides and Proteins/*genetics/*metabolism ; Multiprotein Complexes ; Mutation, Missense ; Schizosaccharomyces/*genetics/metabolism ; Schizosaccharomyces pombe Proteins/*genetics/*metabolism ; Signal Transduction ; *Telomere Shortening ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {In response to perturbed DNA replication, ATR (ataxia telangiectasia and Rad3-related) kinase is activated to initiate the checkpoint signaling necessary for maintaining genome integrity and cell survival. To better understand the signaling mechanism, we carried out a large-scale genetic screen in fission yeast looking for mutants with enhanced sensitivity to hydroxyurea. From a collection of ∼370 primary mutants, we found a few mutants in which Rad3 (ATR ortholog)-mediated phospho-signaling was significantly compromised. One such mutant carried an uncharacterized mutation in tel2, a gene encoding an essential and highly conserved eukaryotic protein. Previous studies in various biological models have shown that Tel2 mainly functions in Tel2-Tti1-Tti2 (TTT) complex that regulates the steady-state levels of all phosphatidylinositol 3-kinase-like protein kinases, including ATR. We show here that although the levels of Rad3 and Rad3-mediated phospho-signaling in DNA damage checkpoint were moderately reduced in the tel2 mutant, the phospho-signaling in the DNA replication checkpoint was almost completely eliminated. In addition, the tel2 mutation caused telomere shortening. Since the interactions of Tel2 with Tti1 and Tti2 were significantly weakened by the mutation, destabilization of the TTT complex likely contributes to the observed checkpoint and telomere defects.},
}
@article {pmid31331401,
year = {2019},
author = {Keng, SL and Yim, OS and Lai, PS and Chew, SH and Ebstein, RP},
title = {Association among dispositional mindfulness, self-compassion, and leukocyte telomere length in Chinese adults.},
journal = {BMC psychology},
volume = {7},
number = {1},
pages = {47},
pmid = {31331401},
issn = {2050-7283},
support = {TWCF-0087//Templeton World Charity Foundation/ ; },
mesh = {Adaptation, Psychological ; Adult ; Asian People/*psychology ; *Empathy ; Female ; Humans ; Male ; Meditation/*methods ; Mindfulness/*methods ; Personality ; Self Report ; Telomere/*physiology ; },
abstract = {BACKGROUND: Whereas meditation training has been purported to support slower cellular aging, little work has explored the association among different facets of dispositional mindfulness, self-compassion, and cellular aging. The present study aimed to examine the relationship between leukocyte telomere length (LTL), an index of cellular aging, dispositional mindfulness, and self-compassion in a sample of Singaporean Chinese adults.<br><br>METHODS: One hundred and fifty-eight Chinese adults (mean age&#x2009;=&#x2009;27.24&#x2009;years; 63.3% female) were recruited from the community and completed self-report measures assessing dispositional mindfulness, self-compassion, and psychological symptoms, as well as provided blood samples for analyses of LTL. Multiple regression analyses were conducted to examine the role of trait mindfulness and self-compassion in predicting LTL, taking into consideration potential covariates such as chronological age and psychological symptoms.<br><br>RESULTS: Results showed that nonreactivity, one of the five facets of dispositional mindfulness, was significantly associated with LTL, after controlling for chronological age. There was also a trend for dispositional mindfulness, self-compassion, and their selected facets (i.e., nonjudging, common humanity, and de-identification) to each be associated with longer LTL.<br><br>CONCLUSIONS: Overall, the findings provide preliminary support for the association among aspects of dispositional mindfulness, self-compassion, and aging. In particular, individuals high on nonreactivity experience slower aging at the cellular level, likely through engaging in more adaptive coping mechanisms.},
}
@article {pmid31331390,
year = {2019},
author = {Muhsen, K and Sinnreich, R and Merom, D and Nassar, H and Cohen, D and Kark, JD},
title = {Helicobacter pylori infection, serum pepsinogens as markers of atrophic gastritis, and leukocyte telomere length: a population-based study.},
journal = {Human genomics},
volume = {13},
number = {1},
pages = {32},
pmid = {31331390},
issn = {1479-7364},
support = {TA-MOU-01-M21-002//USAID/International ; NA//DCURE Israel/International ; NA//Stanley Steyer Institute for Cancer Epidemiology and Research at Tel Aviv University, School of Public Health/International ; MAOF//Planning and Budgeting Committee of the Council for Higher Education of Israel/International ; },
mesh = {Adult ; Aged ; Antibodies, Bacterial/blood ; Arabs/genetics ; Biomarkers/blood ; Female ; Gastritis, Atrophic/*blood/genetics/microbiology/pathology ; Helicobacter Infections/*blood/genetics/microbiology/pathology ; Helicobacter pylori/pathogenicity ; Humans ; Immunoglobulin G/*blood ; Israel/epidemiology ; Leukocytes/metabolism/pathology ; Male ; Middle Aged ; Pepsinogens/*blood/genetics ; Telomere/genetics/microbiology ; },
abstract = {BACKGROUND: Persistent infections that induce prolonged inflammation might negatively affect the leukocyte telomere length (LTL); however, the role in LTL of Helicobacter pylori (H. pylori) infection, which persistently colonizes the stomach, remains unknown. The study objective was to examine associations of sero-prevalence of H. pylori immunoglobulin G (IgG) antibody and serum pepsinogens (PGs), as markers of atrophic gastritis, with LTL. A cross-sectional study was performed among 934 Arab residents of East Jerusalem, aged 27-78 years, randomly selected from Israel's national population registry. Sera were tested for H. pylori IgG and PG levels by ELISA. LTL was measured by southern blots. Multiple linear regression models were fitted to adjust for sociodemographic and lifestyle factors.<br><br>RESULTS: LTL decreased significantly with age (p < 0.001) and was shorter in men than women (p = 0.032). The mean LTL was longer in H. pylori sero-positive persons than negative ones: mean difference 0.13 kb (95% CI 0.02, 0.24), p = 0.016. Participants with atrophic gastritis (PGI < 30 &#x3bc;g/L or a PGI: PGII < 3.0) had shorter LTL than did those without: mean difference -&#x2009;0.18 (95% CI -&#x2009;0.32, -&#x2009;0.04). The difference was of larger magnitude between persons who had past H. pylori infection (sero-negative to H. pylori IgG antibody) and atrophic gastritis, compared to those who were H. pylori sero-negative and did not have atrophic gastritis: mean difference -&#x2009;0.32 kb (95% CI -&#x2009;0.55, -&#x2009;0.10). This association remained significant after adjustment for age, sex, and religiosity: beta coefficient -&#x2009;0.21 kb (95% CI -&#x2009;0.41, -&#x2009;0.001), p = 0.049. The results were similar after further adjustment for lifestyle factors. In bivariate analysis, mean LTL was longer in physically active persons than non-active ones, and shorter in persons with than without obesity; however, these differences were diminished and were not significant in the multivariable model.<br><br>CONCLUSIONS: H. pylori IgG sero-positivity per se was not related to reduced LTL. However, persons with past H. pylori infection (i.e., lacking H. pylori IgG serum antibody) and with serological evidence of atrophic gastritis, had a significantly shorter LTL than did those without atrophic gastritis.},
}
@article {pmid31326965,
year = {2019},
author = {Cinegaglia, N and Antoniazzi, L and Rosa, D and Miranda, D and Acosta-Navarro, J and Bortolotto, L and Hong, V and Sandrim, V},
title = {Shortening telomere is associated with subclinical atherosclerosis biomarker in omnivorous but not in vegetarian healthy men.},
journal = {Aging},
volume = {11},
number = {14},
pages = {5070-5080},
pmid = {31326965},
issn = {1945-4589},
mesh = {Atherosclerosis/*pathology ; *Carotid Intima-Media Thickness ; Cross-Sectional Studies ; Diet, Vegetarian ; Humans ; Male ; Middle Aged ; *Telomere Shortening ; *Vegetarians ; },
abstract = {Telomere length is considered to be a biomarker of biological aging and age-related disease. There are few studies that have evaluated the association between telomere length and diet, and none of them have evaluated the impact of a vegetarian diet on telomere length and its correlation with cardiovascular biomarkers in apparently healthy subjects. Therefore, our objectives were to evaluate leukocyte telomere length (LTL) in vegetarians and omnivorous subjects and its association with classical cardiovascular risk biomarkers. From the total of 745 participants initially recruited, 44 omnivorous and 44 vegetarian men apparently healthy were selected for this study and LTL was measured in 39 omnivorous and 41 vegetarians by Real-Time Quantitative PCR reaction. Although telomere length was not different between omnivorous and vegetarians, we found a strong negative correlation between LTL and IMT (intima-media thickness) in omnivorous, but not in vegetarian group. In addition, omnivorous who were classified with short telomere length had higher carotid IMT compared to vegetarians. Our data suggest that telomere length can be a marker of subclinical atherosclerosis in the omnivorous group.},
}
@article {pmid31325087,
year = {2019},
author = {Chiriacò, M and Georgiopoulos, G and Duranti, E and Antonioli, L and Puxeddu, I and Nannipieri, M and Rosada, J and Blandizzi, C and Taddei, S and Virdis, A and Masi, S},
title = {Inflammation and Vascular Ageing: From Telomeres to Novel Emerging Mechanisms.},
journal = {High blood pressure &amp; cardiovascular prevention : the official journal of the Italian Society of Hypertension},
volume = {26},
number = {4},
pages = {321-329},
pmid = {31325087},
issn = {1179-1985},
mesh = {Age Factors ; Aging/genetics/*metabolism/pathology ; Animals ; Cardiovascular Diseases/genetics/*metabolism/pathology/physiopathology ; Cellular Senescence ; Humans ; Inflammation/genetics/*metabolism/pathology/physiopathology ; Inflammation Mediators/*metabolism ; Risk Assessment ; Risk Factors ; Signal Transduction ; Telomere/genetics/*metabolism/pathology ; Telomere Homeostasis ; Telomere Shortening ; Time Factors ; },
abstract = {Cardiovascular disease (CVD) remains the leading cause of morbility and mortality worldwide. The identification of common cardiovascular risk factors has led to the development of effective treatments that enabled a significant reduction of the global cardiovascular disease burden. However, a significant proportion of cardiovascular risk remains unexplained by these risk factors leaving many individuals at risk of cardiovascular events despite good control of the risk factors. Recent randomized clinical trials and Mendelian randomization studies have suggested that inflammation explains a significant proportion of the residual cardiovascular risk in subjects with good control of risk factors. An accelerated process of vascular ageing is increasingly recognized as a potential mechanism by which inflammation might increase the risk of CVD. In turn, cellular ageing represents an important source of inflammation within the vascular wall, potentially creating a vicious cycle that might promote progression of atherosclerosis, independently from the individual cardiovascular risk factor burden. In this review, we summarise current evidence suggesting a role for biological ageing in CVD and how inflammation might act as a key mediator of this association.},
}
@article {pmid31322561,
year = {2019},
author = {Nudelman, KNH and Lin, J and Lane, KA and Nho, K and Kim, S and Faber, KM and Risacher, SL and Foroud, TM and Gao, S and Davis, JW and Weiner, MW and Saykin, AJ and , },
title = {Telomere Shortening in the Alzheimer's Disease Neuroimaging Initiative Cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {71},
number = {1},
pages = {33-43},
pmid = {31322561},
issn = {1875-8908},
support = {U54 CA137788/CA/NCI NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; R01 AG019771/AG/NIA NIH HHS/United States ; R00 LM011384/LM/NLM NIH HHS/United States ; R44 AG049540/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; P30 CA082709/CA/NCI NIH HHS/United States ; R01 MH101472/MH/NIMH NIH HHS/United States ; R01 LM011360/LM/NLM NIH HHS/United States ; R01 CA129769/CA/NCI NIH HHS/United States ; R01 AG053798/AG/NIA NIH HHS/United States ; R35 CA197289/CA/NCI NIH HHS/United States ; R01 MH098062/MH/NIMH NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; R03 AG054936/AG/NIA NIH HHS/United States ; R01 EB022574/EB/NIBIB NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; U54 CA132378/CA/NCI NIH HHS/United States ; R03 AG050856/AG/NIA NIH HHS/United States ; K01 AG049050/AG/NIA NIH HHS/United States ; R01 LM012535/LM/NLM NIH HHS/United States ; },
mesh = {Age Factors ; Aged ; *Alzheimer Disease/diagnosis/genetics ; Databases, Factual ; Disease Progression ; Female ; Humans ; Male ; Neuroimaging/*methods ; Sex Factors ; Telomere Homeostasis/physiology ; *Telomere Shortening ; },
abstract = {BACKGROUND: Although shorter telomeres have been associated with Alzheimer's disease (AD), it is unclear whether longitudinal change in telomere length is associated with AD progression.<br><br>OBJECTIVE: To investigate the association of telomere length change with AD diagnosis and progression.<br><br>METHODS: In 653 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, T/S ratio (telomere versus single copy gene), a proxy of telomere length, was measured for up to five visits per participant (N&#x200a;=&#x200a;1918 samples post-QC) using quantitative PCR (qPCR). T/S ratio was adjusted for batch effects and DNA storage time. A mixed effects model was used to evaluate association of telomere length with AD diagnostic group and interaction of age and diagnosis. Another mixed effects model was used to compare T/S ratio changes pre- to post-conversion to MCI or AD to telomere change in participants with stable diagnoses.<br><br>RESULTS: Shorter telomeres were associated with older age (Effect Size (ES)&#x200a;=&#x200a;-0.23) and male sex (ES&#x200a;=&#x200a;-0.26). Neither baseline T/S ratio (ES&#x200a;=&#x200a;-0.036) nor T/S ratio change (ES&#x200a;=&#x200a;0.046) differed significantly between AD diagnostic groups. MCI/AD converters showed greater, but non-significant, telomere shortening compared to non-converters (ES&#x200a;=&#x200a;-0.186).<br><br>CONCLUSIONS: Although AD compared to controls showed small, non-significant effects for baseline T/S ratio and T/S ratio shortening, we did observe a larger, though still non-significant effect for greater telomere shortening in converters compared to non-converters. Although our results do not support telomere shortening as a robust biomarker of AD progression, further investigation in larger samples and for subgroups of participants may be informative.},
}
@article {pmid31319405,
year = {2019},
author = {Kogure, GS and Miranda-Furtado, CL and Pedroso, DCC and Ribeiro, VB and Eiras, MC and Silva, RC and Caetano, LC and Ferriani, RA and Calado, RT and Dos Reis, RM},
title = {Effects of Progressive Resistance Training on Obesity Indices in Polycystic Ovary Syndrome and the Relationship With Telomere Length.},
journal = {Journal of physical activity &amp; health},
volume = {16},
number = {8},
pages = {601-607},
doi = {10.1123/jpah.2018-0256},
pmid = {31319405},
issn = {1543-5474},
mesh = {Adolescent ; Adult ; Female ; Humans ; Obesity/*therapy ; Polycystic Ovary Syndrome/*genetics ; Resistance Training/*methods ; Telomere/*metabolism ; Young Adult ; },
abstract = {BACKGROUND: Physical activity is prescribed as a component of primary management for polycystic ovary syndrome (PCOS). This nonrandomized, therapeutic, open, single-arm study investigated the effects of progressive resistance training (PRT) on obesity indices in women with PCOS, and the relationship between obesity indices and telomere content.<br><br>METHODS: A total of 45 women with PCOS and 52 with non-PCOS (controls), aged 18 to 37 years, with body mass indexes of 18 to 39.9&#xa0;kg/m2, performed three 1-hour sessions of PRT per week, for 16 weeks. Before and after PRT, measures included anthropometric indices and regions of interest of fat mass distribution, quantified by dual-energy X-ray absorptiometry, metabolic and hormonal parameters, and telomere content. The general linear mixed models were used to determine the effects of PRT.<br><br>RESULTS: PRT did reduce the waist-to-height ratio, waist circumference, and the index of conicity among PCOS (P < .01). However, PRT did not influence regions of interest, body mass index, and WHR. After PRT, the telomere content was associated with regions of interest and anthropometric indices in whole group independent of PCOS (P < .05).<br><br>CONCLUSION: Resistance exercise improves obesity indices in PCOS, independent of changes in body weight, and the relationship between telomeres and obesity parameters in PCOS remain to be fully clarified.},
}
@article {pmid31316106,
year = {2019},
author = {Ly, K and Walker, C and Berry, S and Snell, R and Marks, E and Thayer, Z and Atatoa-Carr, P and Morton, S},
title = {Telomere length in early childhood is associated with sex and ethnicity.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {10359},
pmid = {31316106},
issn = {2045-2322},
mesh = {Asia/ethnology ; Asian People/genetics ; Child, Preschool ; Ethnicity/*genetics ; Europe/ethnology ; Female ; Humans ; Indigenous Peoples/genetics ; Longitudinal Studies ; Male ; Maternal Age ; Native Hawaiian or Other Pacific Islander/genetics ; New Zealand ; Paternal Age ; *Sex Characteristics ; Social Class ; Telomere/ultrastructure ; *Telomere Homeostasis ; White People/genetics ; },
abstract = {Telomeres are repetitive DNA sequences at the end of chromosomes that function to protect chromosomes from degradation. Throughout the life course, telomere length decreases with age and is influenced by environmental factors and health conditions. This study aimed to determine the relative telomere lengths in a diverse cohort of about 4000 four-year-old children in New Zealand. Linear regression was used to investigate the relationship between telomere length, child gender, ethnicity, paternal age and deprivation. We observed substantial variation in telomere length according to sex and self-identified ethnicity. Telomere length was longer in females compared to males (coefficient of 0.042, 95% confidence interval (CI) 0.024-0.060). European children had shorter telomere than both the indigenous Māori (coefficient of 0.03, CI 0.007-0.055) and Pacific children (coefficient of 0.15, CI 0.12-0.18). The data suggest that telomere lengths are highly variable and variability between individuals arise from early age, influenced partly by sex and ethnicity. Longer telomeres in indigenous Māori and Pacific children may reflect the heritability of telomere length in genetically less complex populations. This study increases our understanding of telomere dynamics in young children since the majority of telomere studies are conducted in adults.},
}
@article {pmid31312500,
year = {2019},
author = {Bateson, M and Aviv, A and Bendix, L and Benetos, A and Ben-Shlomo, Y and Bojesen, SE and Cooper, C and Cooper, R and Deary, IJ and Hägg, S and Harris, SE and Kark, JD and Kronenberg, F and Kuh, D and Labat, C and Martin-Ruiz, CM and Meyer, C and Nordestgaard, BG and Penninx, BWJH and Pepper, GV and Révész, D and Said, MA and Starr, JM and Syddall, H and Thomson, WM and van der Harst, P and Whooley, M and von Zglinicki, T and Willeit, P and Zhan, Y and Nettle, D},
title = {Smoking does not accelerate leucocyte telomere attrition: a meta-analysis of 18 longitudinal cohorts.},
journal = {Royal Society open science},
volume = {6},
number = {6},
pages = {190420},
pmid = {31312500},
issn = {2054-5703},
support = {MC_UP_A620_1015/MRC_/Medical Research Council/United Kingdom ; MC_UU_12011/2/MRC_/Medical Research Council/United Kingdom ; G0500997/MRC_/Medical Research Council/United Kingdom ; MR/K026992/1/MRC_/Medical Research Council/United Kingdom ; MC_UP_A620_1014/MRC_/Medical Research Council/United Kingdom ; G0700704/MRC_/Medical Research Council/United Kingdom ; G0400491/MRC_/Medical Research Council/United Kingdom ; MC_U147585824/MRC_/Medical Research Council/United Kingdom ; MC_U147585827/MRC_/Medical Research Council/United Kingdom ; MR/J50001X/1/MRC_/Medical Research Council/United Kingdom ; MC_U147585819/MRC_/Medical Research Council/United Kingdom ; G0601333/MRC_/Medical Research Council/United Kingdom ; MC_UU_12011/1/MRC_/Medical Research Council/United Kingdom ; NC/K000802/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; BB/F019394/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MR/K00381X/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Smoking is associated with shorter leucocyte telomere length (LTL), a biomarker of increased morbidity and reduced longevity. This association is widely interpreted as evidence that smoking causes accelerated LTL attrition in adulthood, but the evidence for this is inconsistent. We analysed the association between smoking and LTL dynamics in 18 longitudinal cohorts. The dataset included data from 12 579 adults (4678 current smokers and 7901 non-smokers) over a mean follow-up interval of 8.6 years. Meta-analysis confirmed a cross-sectional difference in LTL between smokers and non-smokers, with mean LTL 84.61 bp shorter in smokers (95% CI: 22.62 to 146.61). However, LTL attrition was only 0.51 bp yr[-1] faster in smokers than in non-smokers (95% CI: -2.09 to 1.08), a difference that equates to only 1.32% of the estimated age-related loss of 38.33 bp yr[-1]. Assuming a linear effect of smoking, 167 years of smoking would be required to generate the observed cross-sectional difference in LTL. Therefore, the difference in LTL between smokers and non-smokers is extremely unlikely to be explained by a linear, causal effect of smoking. Selective adoption, whereby individuals with short telomeres are more likely to start smoking, needs to be considered as a more plausible explanation for the observed pattern of telomere dynamics.},
}
@article {pmid31312029,
year = {2019},
author = {Kroupa, M and Rachakonda, SK and Liska, V and Srinivas, N and Urbanova, M and Jiraskova, K and Schneiderova, M and Vycital, O and Vymetalkova, V and Vodickova, L and Kumar, R and Vodicka, P},
title = {Relationship of telomere length in colorectal cancer patients with cancer phenotype and patient prognosis.},
journal = {British journal of cancer},
volume = {121},
number = {4},
pages = {344-350},
pmid = {31312029},
issn = {1532-1827},
mesh = {Adult ; Aged ; Aged, 80 and over ; Colorectal Neoplasms/*genetics/mortality/pathology ; Female ; Humans ; Lymphatic Metastasis ; Male ; Microsatellite Instability ; Middle Aged ; Phenotype ; Prognosis ; *Telomere ; },
abstract = {BACKGROUND: Telomeres, repetitive DNA capping ends of eukaryotic chromosomes, are important in the maintenance of genomic integrity. Perturbed telomeres are common features of many human malignancies, including colorectal cancer.<br><br>METHODS: Telomere length (TL), measured by a Monochrome Multiplex Real-Time qPCR, was investigated in tumour tissues, adjacent mucosa, and blood from patients with colorectal cancer with different clinicopathological features and its impact on patient survival. TL was also measured in a limited number of liver metastases, non-cancerous liver tissues or corresponding tissues from the same patients.<br><br>RESULTS: TL in tumour tissues was shorter than in the adjacent mucosa (P&#x2009;<&#x2009;0.0001). Shorter TL was observed in tumours with lower stage than in those with advanced stages (P&#x2009;=&#x2009;0.001). TL was shorter in tumours at the proximal than at the distal sites of the colon (P&#x2009;<&#x2009;0.0001). Shorter TL was also associated with microsatellite instability (P&#x2009;=&#x2009;0.001) and mucinous tumour histology (P&#x2009;<&#x2009;0.0001). Patients with a smaller TL ratio between tumour tissues and the adjacent mucosa were associated with increased overall survival (P&#x2009;=&#x2009;0.022). Metastasised tumours had shorter telomeres than the adjacent non-cancerous liver tissues (P&#x2009;=&#x2009;0.0005).<br><br>CONCLUSIONS: Overall, the results demonstrate differences in TL between tumours and the adjacent mucosa, between tumours located at different sites and association with patient survival.},
}
@article {pmid31311193,
year = {2019},
author = {Yu, PLI and Wang, Y and Tammur, P and Tamm, A and Punab, M and Rangel-Pozzo, A and Mai, S},
title = {Distinct Nuclear Organization of Telomeresand Centromeres in Monoclonal Gammopathyof Undetermined Significance and Multiple Myeloma.},
journal = {Cells},
volume = {8},
number = {7},
pages = {},
pmid = {31311193},
issn = {2073-4409},
mesh = {Aged ; Aged, 80 and over ; Biomarkers, Tumor/*genetics ; Centromere/*genetics ; Female ; Genomic Instability ; Humans ; Leukocytes/pathology ; Male ; Middle Aged ; Monoclonal Gammopathy of Undetermined Significance/*genetics ; Multiple Myeloma/*genetics ; Telomere/*genetics ; },
abstract = {Both multiple myeloma (MM) and its precursor state of monoclonal gammopathy of undetermined significance (MGUS) are characterized by an infiltration of plasma cells into the bone marrow, but the mechanisms underlying the disease progression remain poorly understood. Previous research has indicated that 3D nuclear telomeric and centromeric organization may represent important structural indicators for numerous malignancies. Here we corroborate with previously noted differences in the 3D telomeric architecture and report that modifications in the nuclear distribution of centromeres may serve as a novel structural marker with potential to distinguish MM from MGUS. Our findings improve the current characterization of the two disease stages, providing two structural indicators that may become altered in the progression of MGUS to MM.},
}
@article {pmid31306622,
year = {2019},
author = {Liew, PS and Chen, Q and Ng, AWR and Chew, YC and Ravin, NV and Sim, EUH and Lee, CW and Narayanan, K},
title = {Phage N15 protelomerase resolves its tos recognition site into hairpin telomeres within mammalian cells.},
journal = {Analytical biochemistry},
volume = {583},
number = {},
pages = {113361},
doi = {10.1016/j.ab.2019.113361},
pmid = {31306622},
issn = {1096-0309},
mesh = {Animals ; DNA/*metabolism ; DNA Replication/*physiology ; *Enzyme Precursors/biosynthesis/physiology ; Escherichia coli ; Genetic Engineering/methods ; HeLa Cells ; Humans ; Mice ; NIH 3T3 Cells ; *Telomerase/biosynthesis/physiology ; *Viral Proteins/biosynthesis/physiology ; beta-Globins/*genetics ; },
abstract = {Phage N15 protelomerase (TelN) cleaves double-stranded circular DNA containing a telomerase-occupancy-site (tos) and rejoins the resulting linear-ends to form closed-hairpin-telomeres in Escherichia coli (E. coli). Continued TelN expression is essential to support resolution of the linear structure. In mammalian cells, no enzyme with TelN-like activities has been found. In this work, we show that phage TelN, expressed transiently and stably in human and mouse cells, recapitulates its native activities in these exogenous environments. We found TelN to accurately resolve tos-DNA in vitro and in vivo within human and mouse cells into linear DNA-containing terminal telomeres that are resistant to RecBCD degradation, a hallmark of protelomerase processing. In stable cells, TelN activity was detectable for at least 60 days, which suggests the possibility of limited silencing of its expression. Correspondingly, linear plasmid containing a 100 kb human β-globin gene expressed for at least 120 h in non-β-globin-expressing mouse cells with TelN presence. Our results demonstrate TelN is able to cut and heal DNA as hairpin-telomeres within mammalian cells, providing a tool for creating novel structures by DNA resolution in these hosts. The TelN protelomerase may be useful for exploring novel technologies for genome interrogation and chromosome engineering.},
}
@article {pmid31297925,
year = {2019},
author = {Endén, K and Tainio, J and Hou, M and Suominen, A and Pakarinen, M and Huang, T and Söder, O and Jalanko, H and Jahnukainen, K and Jahnukainen, T},
title = {Telomere length regulators are activated in young men after pediatric kidney transplantation compared to healthy controls and survivors of childhood cancer-A cross-sectional study.},
journal = {Pediatric transplantation},
volume = {23},
number = {7},
pages = {e13550},
doi = {10.1111/petr.13550},
pmid = {31297925},
issn = {1399-3046},
mesh = {Adolescent ; Adult ; Biomarkers/metabolism ; *Cancer Survivors ; Case-Control Studies ; Cross-Sectional Studies ; Humans ; *Kidney Transplantation ; Male ; *Telomere Shortening ; Telomere-Binding Proteins/*metabolism ; Young Adult ; },
abstract = {Chronic diseases are known to cause premature aging and frailty. Data about telomere length and telomere length-regulating proteins after pediatric KTx are scarce. Leukocyte telomere length and gene expression level of eight telomere-binding proteins were analyzed in 20 KTx recipients, eight childhood NBL survivors, and nine healthy controls. The influence of key clinical parameters on telomere length and on regulators of telomere length was evaluated. The telomere length in the KTx recipients tended to be shorter (0.53 AU) than in the healthy controls (0.64 AU) but longer than in the NBL survivors (0.38 AU). There was no significant difference in telomere length between the NBL survivors and the KTx recipients (P = .110). The gene expression level of telomere length-preserving protein RPA1 was significantly higher in the KTx recipients than among the NBL survivors or healthy controls, while the expression of TRF2 and the tumor suppressor gene p16 was significantly higher in the KTX recipients when compared to the controls. TRF2 and TIN2 correlated significantly with hsCRP; additionally, TRF2 showed significant correlation with plasma creatinine and eGFR. KTx recipients have near to normal telomere length, but they have significantly higher gene expression levels of telomere regulatory proteins compared with healthy controls, suggesting activation of mechanisms preserving telomere length among KTx recipients. Our results suggest that declined graft function and consequent inflammatory response may have influence on telomerase activity.},
}
@article {pmid31296842,
year = {2019},
author = {Liu, R and Liu, J and Wang, S and Wang, Y and Zhang, T and Liu, Y and Geng, X and Wang, F},
title = {Combined treatment with emodin and a telomerase inhibitor induces significant telomere damage/dysfunction and cell death.},
journal = {Cell death &amp; disease},
volume = {10},
number = {7},
pages = {527},
pmid = {31296842},
issn = {2041-4889},
mesh = {Aminobenzoates/*therapeutic use ; Animals ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Damage/drug effects ; Emodin/chemistry/*therapeutic use ; G-Quadruplexes/*drug effects ; Humans ; Ligands ; Mice ; Mice, Inbred BALB C ; Molecular Docking Simulation ; Naphthalenes/*therapeutic use ; Neoplasms/drug therapy/enzymology/genetics ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/chemistry/*drug effects/enzymology/pathology ; Telomere Shortening/*drug effects ; Transplantation, Heterologous ; },
abstract = {G-quadruplex telomeric secondary structures represent natural replication fork barriers and must be resolved to permit efficient replication. Stabilization of telomeric G4 leads to telomere dysfunctions demonstrated by telomere shortening or damage, resulting in genome instability and apoptosis. Chemical compounds targeting G4 structures have been reported to induce telomere disturbance and tumor suppression. Here, virtual screening was performed in a natural compound library using PyRx to identify novel G4 ligands. Emodin was identified as one of the best candidates, showing a great G4-binding potential. Subsequently, we confirmed that emodin could stabilize G4 structures in vitro and trigger telomere dysfunctions including fragile telomeres, telomere loss, and telomeric DNA damage. However, this telomere disturbance could be rescued by subsequent elevation of telomerase activity; in contrast, when we treated the cells with the telomerase inhibitor BIBR1532 upon emodin treatment, permanent telomere disturbance and obvious growth inhibition of 4T1-cell xenograft tumors were observed in mice. Taken together, our results show for the first time that emodin-induced telomeric DNA damage can upregulate telomerase activity, which may weaken its anticancer effect. The combined use of emodin and the telomerase inhibitor synergistically induced telomere dysfunction and inhibited tumor generation.},
}
@article {pmid31294341,
year = {2019},
author = {Shin, YA},
title = {How Does Obesity and Physical Activity Affect Aging?: Focused on Telomere as a Biomarker of Aging.},
journal = {Journal of obesity &amp; metabolic syndrome},
volume = {28},
number = {2},
pages = {92-104},
pmid = {31294341},
issn = {2508-7576},
abstract = {Obesity is known to continuously increase systemic inflammation and oxidative stress, leading to shorter telomere length. However, research regarding the correlation between physical activity, exercise, obesity, and telomere length is not consistent. Therefore, this review aims to summarize the effects of obesity, physical activity, and exercise on telomere length. Our search for effects of obesity, physical activity, and exercise, on telomeres was conducted using three computerized databases: Medline, PubMed, and EBSCO. Keywords in the search were "physical activity, exercise and obesity," "physical activity, exercise and telomere," and "obesity and telomere." Improving chronic inflammation and oxidative stress levels can prevent telomere attrition due to obesity. In addition, differences in the anti-aging effects of physical activity and exercise are shown in the post-middle-age period, when telomere length changes, rather than in past exercise habits. Maintaining high cardiorespiratory fitness levels through regular exercise and physical activity in the post-middle-age period minimizes obesity-related diseases and helps maintain telomere length, which is an index of cell senescence.},
}
@article {pmid31290100,
year = {2020},
author = {Ma, S and Sun, G and Yang, S and Ju, Z and Cheng, T and Cheng, H},
title = {Effects of telomere length on leukemogenesis.},
journal = {Science China. Life sciences},
volume = {63},
number = {2},
pages = {308-311},
doi = {10.1007/s11427-019-9588-7},
pmid = {31290100},
issn = {1869-1889},
mesh = {Animals ; Carcinogenesis/*metabolism ; Cell Line, Tumor ; Genetic Variation ; Humans ; Leukemia/*mortality ; Mice ; Mice, Knockout ; RNA/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; Telomere Shortening ; Transplants ; Tumor Microenvironment/genetics ; },
}
@article {pmid31289327,
year = {2019},
author = {Hasegawa, Y and Yamamoto, M and Miyamori, J and Kanoh, J},
title = {Telomere DNA length-dependent regulation of DNA replication timing at internal late replication origins.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {9946},
pmid = {31289327},
issn = {2045-2322},
mesh = {Cell Cycle ; DNA Replication Timing/*genetics ; DNA, Fungal/genetics/*metabolism ; *Replication Origin ; Schizosaccharomyces/*genetics/growth &amp; development/metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Shelterin Complex ; Telomere/*genetics ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {DNA replication is initiated at replication origins on chromosomes at their scheduled time during S phase of the cell cycle. Replication timing control is highly conserved among eukaryotes but the underlying mechanisms are not fully understood. Recent studies have revealed that some telomere-binding proteins regulate replication timing at late-replicating origins throughout the genome. To investigate the molecular basis of this process, we analyzed the effects of excessive elongation of telomere DNA on replication timing by deleting telomere-associated shelterin proteins in Schizosaccharomyces pombe. We found that rap1∆ and poz1∆ cells showed abnormally accelerated replication at internal late origins but not at subtelomere regions. These defects were suppressed by removal of telomere DNA and by deletion of the telomere-binding protein Taz1. Furthermore, Sds21-a counter protein phosphatase against Dbf4-dependent kinase (DDK)-accumulated at elongated telomeres in a Taz1-dependent manner but was depleted at internal late origins, indicating that highly elongated telomeres sequester Sds21 at telomeres and perturb replication timing at internal regions. These results demonstrate that telomere DNA length is an important determinant of replication timing at internal regions of chromosomes in eukaryotes.},
}
@article {pmid31288685,
year = {2019},
author = {Fitzpatrick, LJ and Olsson, M and Parsley, LM and Pauliny, A and While, GM and Wapstra, E},
title = {Tail loss and telomeres: consequences of large-scale tissue regeneration in a terrestrial ectotherm.},
journal = {Biology letters},
volume = {15},
number = {7},
pages = {20190151},
pmid = {31288685},
issn = {1744-957X},
mesh = {Animals ; *Lizards ; Oxidative Stress ; Reactive Oxygen Species ; Regeneration ; Tail ; *Telomere ; },
abstract = {Large-scale tissue regeneration has potential consequences for telomere length through increases in cell division and changes in metabolism which increase the potential for oxidative stress damage to telomeres. The effects of regeneration on telomere dynamics have been studied in fish and marine invertebrates, but the literature is scarce for terrestrial species. We experimentally induced tail autotomy in a lizard (Niveoscincus ocellatus) and assessed relative telomere length (RTL) in blood samples before and after partial tail regeneration while concurrently measuring reactive oxygen species (ROS) levels. The change in ROS levels was a significant explanatory variable for the change in RTL over the 60-day experiment. At the average value of ROS change, the mean RTL increased significantly in the control group (intact tails), but there was no such evidence in the regenerating group. By contrast, ROS levels decreased significantly in the regenerating group, but there was no such evidence in the control group. Combined, these results suggest that tail regeneration following autotomy involves a response to oxidative stress and this potentially comes at a cost to telomere repair. This change in telomere maintenance demonstrates a potential long-term cost of tail regeneration beyond the regrowth of tissue itself.},
}
@article {pmid31285747,
year = {2019},
author = {Ji, Y and Dang, X and Nguyen, LNT and Nguyen, LN and Zhao, J and Cao, D and Khanal, S and Schank, M and Wu, XY and Morrison, ZD and Zou, Y and El Gazzar, M and Ning, S and Wang, L and Moorman, JP and Yao, ZQ},
title = {Topological DNA damage, telomere attrition and T cell senescence during chronic viral infections.},
journal = {Immunity &amp; ageing : I &amp; A},
volume = {16},
number = {},
pages = {12},
pmid = {31285747},
issn = {1742-4933},
support = {R01 CA219342/CA/NCI NIH HHS/United States ; R15 AG050456/AG/NIA NIH HHS/United States ; R15 AI143377/AI/NIAID NIH HHS/United States ; S10 OD021572/OD/NIH HHS/United States ; },
abstract = {BACKGROUND: T cells play a key role in controlling viral infections; however, the underlying mechanisms regulating their functions during human viral infections remain incompletely understood. Here, we used CD4 T cells derived from individuals with chronic viral infections or healthy T cells treated with camptothecin (CPT) - a topoisomerase I (Top 1) inhibitor - as a model to investigate the role of DNA topology in reprogramming telomeric DNA damage responses (DDR) and remodeling T cell functions.<br><br>RESULTS: We demonstrated that Top 1 protein expression and enzyme activity were significantly inhibited, while the Top 1 cleavage complex (TOP1cc) was trapped in genomic DNA, in T cells derived from individuals with chronic viral (HCV, HBV, or HIV) infections. Top 1 inhibition by CPT treatment of healthy CD4 T cells caused topological DNA damage, telomere attrition, and T cell apoptosis or dysfunction via inducing Top1cc accumulation, PARP1 cleavage, and failure in DNA repair, thus recapitulating T cell dysregulation in the setting of chronic viral infections. Moreover, T cells from virally infected subjects with inhibited Top 1 activity were more vulnerable to CPT-induced topological DNA damage and cell apoptosis, indicating an important role for Top 1 in securing DNA integrity and cell survival.<br><br>CONCLUSION: These findings provide novel insights into the molecular mechanisms for immunomodulation by chronic viral infections via disrupting DNA topology to induce telomeric DNA damage, T cell senescence, apoptosis and dysfunction. As such, restoring the impaired DNA topologic machinery may offer a new strategy for maintaining T cell function against human viral diseases.},
}
@article {pmid31285335,
year = {2019},
author = {Whittemore, K and Vera, E and Martínez-Nevado, E and Sanpera, C and Blasco, MA},
title = {Telomere shortening rate predicts species life span.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {116},
number = {30},
pages = {15122-15127},
pmid = {31285335},
issn = {1091-6490},
mesh = {Animals ; Bottle-Nosed Dolphin/genetics ; Cellular Senescence ; Charadriiformes/genetics ; Elephants/genetics ; Falconiformes/genetics ; Goats/genetics ; Humans ; Longevity/*genetics ; Mice ; Regression Analysis ; Reindeer/genetics ; Species Specificity ; Telomere/*ultrastructure ; *Telomere Shortening ; },
abstract = {Telomere shortening to a critical length can trigger aging and shorter life spans in mice and humans by a mechanism that involves induction of a persistent DNA damage response at chromosome ends and loss of cellular viability. However, whether telomere length is a universal determinant of species longevity is not known. To determine whether telomere shortening can be a single parameter to predict species longevities, here we measured in parallel the telomere length of a wide variety of species (birds and mammals) with very different life spans and body sizes, including mouse (Mus musculus), goat (Capra hircus), Audouin's gull (Larus audouinii), reindeer (Rangifer tarandus), griffon vulture (Gyps fulvus), bottlenose dolphin (Tursiops truncatus), American flamingo (Phoenicopterus ruber), and Sumatran elephant (Elephas maximus sumatranus). We found that the telomere shortening rate, but not the initial telomere length alone, is a powerful predictor of species life span. These results support the notion that critical telomere shortening and the consequent onset of telomeric DNA damage and cellular senescence are a general determinant of species life span.},
}
@article {pmid31273937,
year = {2019},
author = {Benyelles, M and Episkopou, H and O'Donohue, MF and Kermasson, L and Frange, P and Poulain, F and Burcu Belen, F and Polat, M and Bole-Feysot, C and Langa-Vives, F and Gleizes, PE and de Villartay, JP and Callebaut, I and Decottignies, A and Revy, P},
title = {Impaired telomere integrity and rRNA biogenesis in PARN-deficient patients and knock-out models.},
journal = {EMBO molecular medicine},
volume = {11},
number = {7},
pages = {e10201},
pmid = {31273937},
issn = {1757-4684},
support = {//La Ligue contre le Cancer/International ; //Institut National Du Cancer (INCa)/International ; //GIS Institut des maladies rares/International ; //Institut National de la Sant&#xe9; et de la Recherche M&#xe9;dicale (Inserm)/International ; //Fonds De La Recherche Scientifique - FNRS (FNRS)/International ; //Agence Nationale de la Recherche (ANR)/International ; ANR-15-RAR3-0007-04//ERA-NET program/International ; //T&#xe9;l&#xe9;vie/FNRS and FRIA/FNRS/International ; //Centre National de la Recherche Scientifique (CNRS)/International ; },
mesh = {Animals ; Child, Preschool ; Disease Models, Animal ; Dyskeratosis Congenita/genetics/*metabolism/pathology ; Exoribonucleases/*deficiency/metabolism ; Female ; Fetal Growth Retardation/genetics/*metabolism/pathology ; Humans ; Intellectual Disability/genetics/*metabolism/pathology ; Male ; Mice ; Mice, Knockout ; Microcephaly/genetics/*metabolism/pathology ; RNA, Ribosomal/*biosynthesis/genetics ; Shelterin Complex ; Telomere/genetics/*metabolism/pathology ; *Telomere Homeostasis ; Telomere-Binding Proteins ; },
abstract = {PARN, poly(A)-specific ribonuclease, regulates the turnover of mRNAs and the maturation and stabilization of the hTR RNA component of telomerase. Biallelic PARN mutations were associated with Høyeraal-Hreidarsson (HH) syndrome, a rare telomere biology disorder that, because of its severity, is likely not exclusively due to hTR down-regulation. Whether PARN deficiency was affecting the expression of telomere-related genes was still unclear. Using cells from two unrelated HH individuals carrying novel PARN mutations and a human PARN knock-out (KO) cell line with inducible PARN complementation, we found that PARN deficiency affects both telomere length and stability and down-regulates the expression of TRF1, TRF2, TPP1, RAP1, and POT1 shelterin transcripts. Down-regulation of dyskerin-encoding DKC1 mRNA was also observed and found to result from p53 activation in PARN-deficient cells. We further showed that PARN deficiency compromises ribosomal RNA biogenesis in patients' fibroblasts and cells from heterozygous Parn KO mice. Homozygous Parn KO however resulted in early embryonic lethality that was not overcome by p53 KO. Our results refine our knowledge on the pleiotropic cellular consequences of PARN deficiency.},
}
@article {pmid31273935,
year = {2019},
author = {Cherfils-Vicini, J and Gilson, E},
title = {Inhibiting TRF1 upstream signaling pathways to target telomeres in cancer cells.},
journal = {EMBO molecular medicine},
volume = {11},
number = {7},
pages = {e10845},
pmid = {31273935},
issn = {1757-4684},
mesh = {Antineoplastic Agents/*therapeutic use ; *Drug Delivery Systems ; Humans ; Neoplasms/*drug therapy/genetics/metabolism ; Signal Transduction/*drug effects/genetics ; Telomere/genetics/*metabolism/pathology ; Telomeric Repeat Binding Protein 1/*antagonists &amp; inhibitors/genetics/metabolism ; },
abstract = {In the context of tumorigenesis, telomere shortening is associated with apparent antagonistic outcomes: On one side, it favors cancer initiation through mechanisms involving genome instability, while on the other side, it prevents cancer progression, due to the activation of the DNA damage response (DDR) checkpoint behaving as a cell-intrinsic proliferation barrier. Consequently, telomerase, which can compensate for replicative erosion by adding telomeric DNA repeats at the chromosomal DNA extremities, is crucial for cancer progression and is upregulated in nearly 90% of human cancers. Therefore, telomeres are considered potential anti-cancer targets and, to date, most of the studies have focused on telomerase inhibition. However, the development of clinically efficient telomerase targeting therapies is still in its infancy. In this context, the findings reported in this issue of EMBO Molecular Medicine by Bejarano et al (2019) open new avenues for alternative telomere therapies.},
}
@article {pmid31273934,
year = {2019},
author = {Bejarano, L and Bosso, G and Louzame, J and Serrano, R and Gómez-Casero, E and Martínez-Torrecuadrada, J and Martínez, S and Blanco-Aparicio, C and Pastor, J and Blasco, MA},
title = {Multiple cancer pathways regulate telomere protection.},
journal = {EMBO molecular medicine},
volume = {11},
number = {7},
pages = {e10292},
pmid = {31273934},
issn = {1757-4684},
support = {SAF2013-45111-R//Ministerio de Econom&#xed;a y Competitividad (MEC)/International ; //Fundacion Botin and Banco Santander/International ; 16-1177//World Wide Cancer Research/International ; //La-Caixa Severo Ochoa International PHD Programme/International ; },
mesh = {Animals ; Cell Line, Tumor ; Female ; Gene Deletion ; Glioma/*drug therapy/genetics/metabolism/pathology ; Humans ; MAP Kinase Signaling System/*drug effects/genetics ; Mice ; Mice, Nude ; *Neoplasm Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Protein Kinase Inhibitors/*pharmacology ; Telomere/genetics/*metabolism/pathology ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Xenograft Model Antitumor Assays ; },
abstract = {Telomeres are considered as universal anti-cancer targets, as telomere maintenance is essential to sustain indefinite cancer growth. Mutations in telomerase, the enzyme that maintains telomeres, are among the most frequently found in cancer. In addition, mutations in components of the telomere protective complex, or shelterin, are also found in familial and sporadic cancers. Most efforts to target telomeres have focused in telomerase inhibition; however, recent studies suggest that direct targeting of the shelterin complex could represent a more effective strategy. In particular, we recently showed that genetic deletion of the TRF1 essential shelterin protein impairs tumor growth in aggressive lung cancer and glioblastoma (GBM) mouse models by direct induction of telomere damage independently of telomere length. Here, we screen for TRF1 inhibitory drugs using a collection of FDA-approved drugs and drugs in clinical trials, which cover the majority of pathways included in the Reactome database. Among other targets, we find that inhibition of several kinases of the Ras pathway, including ERK and MEK, recapitulates the effects of Trf1 genetic deletion, including induction of telomeric DNA damage, telomere fragility, and inhibition of cancer stemness. We further show that both bRAF and ERK2 kinases phosphorylate TRF1 in vitro and that these modifications are essential for TRF1 location to telomeres in vivo. Finally, we use these new TRF1 regulatory pathways as the basis to discover novel drug combinations based on TRF1 inhibition, with the goal of effectively blocking potential resistance to individual drugs in patient-derived glioblastoma xenograft models.},
}
@article {pmid31273022,
year = {2019},
author = {Nguyen, MT and Lycett, K and Vryer, R and Burgner, DP and Ranganathan, S and Grobler, AC and Wake, M and Saffery, R},
title = {Telomere length: population epidemiology and concordance in Australian children aged 11-12 years and their parents.},
journal = {BMJ open},
volume = {9},
number = {Suppl 3},
pages = {118-126},
pmid = {31273022},
issn = {2044-6055},
mesh = {Adult ; Australia ; Child ; Cross-Sectional Studies ; Female ; Humans ; Linear Models ; Longitudinal Studies ; Male ; Middle Aged ; *Parents ; Telomere/*ultrastructure ; *Telomere Shortening ; },
abstract = {OBJECTIVES: To (1) describe the epidemiology of child and adult telomere length, and (2) investigate parent-child telomere length concordance.<br><br>DESIGN: Population-based cross-sectional study within the Longitudinal Study of Australian Children.<br><br>SETTING: Assessment centres in seven major Australian cities and eight selected regional towns; February 2015 to March 2016.<br><br>PARTICIPANTS: Of 1874 participating families, telomere data were available for analysis for 1206 children and 1343 parents, of whom 1143 were parent-child pairs. There were 589 boys and 617 girls; 175 fathers and 1168 mothers.<br><br>OUTCOME MEASURES: Relative telomere length (T/S ratio), calculated by comparing telomeric DNA (T) level with the single copy (S) beta-globin gene in venous blood-derived genomic DNA by quantitative real-time PCR.<br><br>RESULTS: Mean T/S ratio for all children, boys and girls was 1.09 (SD 0.56), 1.05 (SD 0.53) and 1.13 (SD 0.59), respectively. Mean T/S ratio for all parents, fathers and mothers was 0.81 (SD 0.37), 0.82 (SD 0.36) and 0.81 (SD 0.38), respectively. Parent-child T/S ratio concordance was moderate (correlation 0.24). In adjusted regression models, one unit higher parent T/S ratio was associated with 0.36 (estimated linear regression coefficient (&#x3b2;); 95%&#x2009;CI 0.28 to 0.45) higher child T/S ratio. Concordance was higher in the youngest parent-age tertile (&#x3b2; 0.49; 95%&#x2009;CI 0.34 to 0.64) compared with the middle (&#x3b2; 0.35; 95%&#x2009;CI 0.21 to 0.48) and oldest tertile (&#x3b2; 0.26; 95%&#x2009;CI 0.11 to 0.41; p-trend 0.04). Father-child concordance was 0.34 (95% CI 0.18 to 0.48), while mother-child was 0.22 (95% CI 0.17 to 0.28).<br><br>CONCLUSIONS: We provide telomere length population values for children aged 11-12 years and their mid-life parents. Relative telomere length was shorter in adults than children, as expected. There was modest evidence of parent-child concordance, which diminished with increasing parent age.},
}
@article {pmid31270544,
year = {2019},
author = {Wynchank, D and Bijlenga, D and Penninx, BW and Lamers, F and Beekman, AT and Kooij, JJS and Verhoeven, JE},
title = {Delayed sleep-onset and biological age: late sleep-onset is associated with shorter telomere length.},
journal = {Sleep},
volume = {42},
number = {10},
pages = {},
doi = {10.1093/sleep/zsz139},
pmid = {31270544},
issn = {1550-9109},
mesh = {Adult ; Aging/*physiology ; Anxiety/epidemiology/genetics/physiopathology ; Cellular Senescence/*physiology ; Circadian Rhythm/physiology ; Cohort Studies ; Depression/epidemiology/genetics/physiopathology ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Netherlands/epidemiology ; Sleep/*physiology ; Sleep Disorders, Circadian Rhythm/epidemiology/genetics/*physiopathology ; Surveys and Questionnaires ; Telomere Shortening/*physiology ; },
abstract = {STUDY OBJECTIVES: We evaluated the relationship between leukocyte telomere length (LTL) and sleep duration, insomnia symptoms, and circadian rhythm, to test whether sleep and chronobiological dysregulations are associated with cellular aging.<br><br>METHODS: Data from the Netherlands Study of Depression and Anxiety (N = 2,936) were used at two waves 6 years apart, to measure LTL. Telomeres shorten during the life span and are important biomarkers for cellular aging. LTL was assessed by qualitative polymerase chain reaction and converted into base pair number. Sleep parameters were: sleep duration and insomnia symptoms from the Insomnia Rating Scale. Circadian rhythm variables were: indication of Delayed Sleep Phase Syndrome (DSPS), mid-sleep corrected for sleep debt on free days (MSFsc), sleep-onset time, and self-reported chronotype, from the Munich Chronotype Questionnaire. Generalized estimating equations analyzed the associations between LTL, sleep, and chronobiological factors, adjusted for baseline age, sex, North European ancestry, and additionally for current smoking, depression severity, obesity, and childhood trauma.<br><br>RESULTS: Indicators of delayed circadian rhythm showed a strong and consistent effect on LTL, after adjustment for sociodemographic and health indicators. Late MSFsc (B = -49.9, p = .004), late sleep-onset time (B = -32.4, p = .001), indication of DSPS (B = -73.8, p = .036), and moderately late chronotype in adulthood (B = -71.6, p = .003) were associated with significantly shorter LTL across both waves; whereas sleep duration and insomnia symptoms were not. Extremely early chronotype showed significantly less LTL shortening than intermediate chronotype (B = 161.40, p = .037). No predictors showed accelerated LTL attrition over 6 years.<br><br>CONCLUSIONS: Individuals with delayed circadian rhythm have significantly shorter LTL, but not faster LTL attrition rates.},
}
@article {pmid31269352,
year = {2019},
author = {Szczotka, M and Kocki, J and Iwan, E and Pluta, A},
title = {Determination of telomere length and telomerase activity in cattle infected with bovine leukaemia virus (BLV).},
journal = {Polish journal of veterinary sciences},
volume = {22},
number = {2},
pages = {391-403},
doi = {10.24425/pjvs.2019.129299},
pmid = {31269352},
issn = {2300-2557},
mesh = {Animals ; Cattle ; Cell Line ; Enzootic Bovine Leukosis/*virology ; Gene Expression Regulation, Enzymologic ; Humans ; *Leukemia Virus, Bovine ; Telomerase/*metabolism ; *Telomere Homeostasis ; },
abstract = {Telomeres are repetitive sequence structures at the ends of chromosomes. They consist of the double stranded DNA repeats followed by the short single stranded DNA. In humans and other verterbrates the telomeric sequence is composed of tandem of TTAGGG repeats. With each cells division telomeres shorten by up to 200 base pairs. Telomerase is an enzyme responsible for continuous cell growth and is repressed in most somatic cells, except proliferating progenitor cells, but in more than 85% of cancer cells telomerase expression is observed. Tumour cells with metastatic potential may demonstrate a high telomerase activity, allowing cells to escape from the inhibition of cell proliferation due to shortened telomeres. Determination of telomerase expression was performed with the use of PCR ELISA in samples isolated from bovine leukaemia virus (BLV) infected cows. Telomerase activity was found in almost all investigated samples. The relative telomerase activity (RTA) was higher in infected cows than in healthy animals and the differences were statistically significant (α=0.05). In blood lymphocytes of BLV-infected cows the mean values of telomerase expression determined in real-time PCR were 3534.12 copies, in the healthy group there were 1010.10 copies and these differences were also statistically significant. For telomere length evaluation the Telomere PNA/FITC FISH and Telomere PNA/FITC FISH for flow cytometry were used. The mean fluorescence intensity of telomere sequences calculated on the surface of interphase nuclei of leukaemic blood lymphocytes was lower than that in the control animals and the difference was statistically significant. The mean length of telomeres in BLV- infected and healthy cows was 31.63 ± 12.62 and 38.4 ± 4.03, (p=0.112), respectively.},
}
@article {pmid31268371,
year = {2019},
author = {Ley, B and Torgerson, DG and Oldham, JM and Adegunsoye, A and Liu, S and Li, J and Elicker, BM and Henry, TS and Golden, JA and Jones, KD and Dressen, A and Yaspan, BL and Arron, JR and Noth, I and Hoffmann, TJ and Wolters, PJ},
title = {Rare Protein-Altering Telomere-related Gene Variants in Patients with Chronic Hypersensitivity Pneumonitis.},
journal = {American journal of respiratory and critical care medicine},
volume = {200},
number = {9},
pages = {1154-1163},
pmid = {31268371},
issn = {1535-4970},
support = {K23 HL138190/HL/NHLBI NIH HHS/United States ; KL2 TR001870/TR/NCATS NIH HHS/United States ; R01 HL130796/HL/NHLBI NIH HHS/United States ; R01 HL139897/HL/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Alveolitis, Extrinsic Allergic/*genetics ; Case-Control Studies ; Cell Cycle Proteins/genetics ; Cohort Studies ; DNA Helicases/genetics ; Exoribonucleases/genetics ; Female ; Humans ; Male ; Middle Aged ; Mutation/*genetics ; Nuclear Proteins/genetics ; RNA/genetics ; Shelterin Complex ; Telomerase/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {Rationale: Rare genetic variants in telomere-related genes have been identified in familial, idiopathic, and rheumatoid arthritis-associated pulmonary fibrosis. Short peripheral blood leukocyte (PBL) telomere length predicts poor outcomes in chronic hypersensitivity pneumonitis (CHP).Objectives: Determine the prevalence and clinical relevance of rare protein-altering variants in telomere-related genes in patients with CHP.Methods: Next-generation sequences from two CHP cohorts were analyzed to identify variants in TERT (telomerase reverse transcriptase), TERC (telomerase RNA component), DKC1 (dyskerin pseudouridine synthase 1), RTEL1 (regulator of telomere elongation helicase 1), PARN (poly[A]-specific RNase), and TINF2 (TERF1-interacting nuclear factor 2). To qualify, variants were required to have a minor allele frequency less than 0.005 and be predicted to be damaging to protein function. Variant status (binary variable) was used in statistical association tests, including Cox proportional hazard models for transplant-free survival. PBL telomere length was measured using quantitative PCR.Measurements and Main Results: Qualifying variants were identified in 16 of 144 patients (11.1%; 95% confidence interval [CI], 6.5-17.4) in the discovery cohort and 17 of 209 patients (8.1%; 95% CI, 4.8-12.7) in the replication cohort. Age- and ancestry-adjusted PBL telomere length was significantly shorter in the presence of a variant in both cohorts (discovery: -561 bp; 95% CI, -933 to -190; P = 0.003; replication: -612 bp; 95% CI, -870 to -354; P = 5.30 × 10[-6]). Variant status was significantly associated with transplant-free survival in both cohorts (discovery: age-, sex-, and ancestry-adjusted hazard ratio, 3.73; 95% CI, 1.92-7.28; P = 0.0001; replication: hazard ratio, 2.72; 95% CI, 1.26-5.88; P = 0.011).Conclusions: A substantial proportion of patients diagnosed with CHP have rare, protein-altering variants in telomere-related genes, which are associated with short peripheral blood telomere length and significantly reduced transplant-free survival.},
}
@article {pmid31267425,
year = {2019},
author = {Cartwright, IM},
title = {Modified PNA Telomere and Centromere FISH Protocols.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1984},
number = {},
pages = {101-105},
doi = {10.1007/978-1-4939-9432-8_12},
pmid = {31267425},
issn = {1940-6029},
mesh = {Animals ; Centromere/*metabolism ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Microwaves ; Peptide Nucleic Acids/*chemistry ; Telomere/*metabolism ; },
abstract = {Fluorescence in situ Hybridization (FISH) utilizes peptide nucleic acid (PNA) probes to identify specific DNA sequences. PNA probes have been effectively used to identify chromosome aberrations and have been shown to greatly aid in biodosimetery assays involved in identifying dicentrics. Traditional techniques have required the heat denaturing of the DNA in formamide followed by multiple hours at moderated temperatures to allow the probe to hybridize to its specific target. Over the past 30 years, advancements in both protocols and probes have made FISH a more reliable technique for both biological research and medical diagnostics, additionally the protocol has been shortened to several minutes. We will introduce two modified PNA FISH protocols, a rapid microwave-based approach and nonclassical hybridization protocol.},
}
@article {pmid31267424,
year = {2019},
author = {Cartwright, IM and Haskins, JS and Kato, TA},
title = {PNA Telomere and Centromere FISH Staining for Accurate Analysis of Radiation-Induced Chromosomal Aberrations.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1984},
number = {},
pages = {95-100},
doi = {10.1007/978-1-4939-9432-8_11},
pmid = {31267424},
issn = {1940-6029},
mesh = {Animals ; Centromere/*metabolism ; Chromosome Aberrations/*radiation effects ; Humans ; In Situ Hybridization, Fluorescence ; Metaphase/radiation effects ; Mice ; Peptide Nucleic Acids/*chemistry ; *Radiation ; *Staining and Labeling ; Telomere/*metabolism ; },
abstract = {Dicentric and centric ring chromosomes are used for radiation-induced damage analysis and biodosimetry after radiation exposure. However, Giemsa stain-based cytogenetic analysis is labor-intense and time-consuming. Moreover, the disadvantage of Giemsa based chromosome analysis is a potential poor reproducibility when researchers are not fully trained for analysis. These problems come from analysis of morphological abnormality of chromosomal aberrations. Locus-specific FISH probes were used to overcome this problem. Centromere probes can visualize centromere locations and help identify dicentric chromosomes and centric rings. Telomere probes help to identify terminal deletion and telomere fusions. Probes were originally designed with a DNA probe but Peptide nucleic acid (PNA) probes took the place of DNA probes. This chapter introduces PNA telomere and centromere FISH staining and accurate analysis of chromosomal aberrations.},
}
@article {pmid31266154,
year = {2019},
author = {Adwan Shekhidem, H and Sharvit, L and Leman, E and Manov, I and Roichman, A and Holtze, S and M Huffman, D and Y Cohen, H and Bernd Hildebrandt, T and Shams, I and Atzmon, G},
title = {Telomeres and Longevity: A Cause or an Effect?.},
journal = {International journal of molecular sciences},
volume = {20},
number = {13},
pages = {},
pmid = {31266154},
issn = {1422-0067},
support = {193/16//Israel Science Foundation/ ; },
mesh = {Aging/*genetics ; Animals ; Female ; Longevity ; Male ; Mice ; Mole Rats ; Organ Specificity ; Spalax ; Species Specificity ; Telomere/*genetics ; *Telomere Shortening ; },
abstract = {Telomere dynamics have been found to be better predictors of survival and mortality than chronological age. Telomeres, the caps that protect the end of linear chromosomes, are known to shorten with age, inducing cell senescence and aging. Furthermore, differences in age-related telomere attrition were established between short-lived and long-lived organisms. However, whether telomere length is a "biological thermometer" that reflects the biological state at a certain point in life or a biomarker that can influence biological conditions, delay senescence and promote longevity is still an ongoing debate. We cross-sectionally tested telomere length in different tissues of two long-lived (naked mole-rat and Spalax) and two short-lived (rat and mice) species to tease out this enigma. While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR, suggest an age buffering mechanism, while in Spalax tissues the shortening of the telomeres are in spite of its extreme longevity traits. Therefore, using long-lived species as models for understanding the role of telomeres in longevity is of great importance since they may encompass mechanisms that postpone aging.},
}
@article {pmid31263449,
year = {2019},
author = {Tian, Y and Wang, S and Jiao, F and Kong, Q and Liu, C and Wu, Y},
title = {Telomere Length: A Potential Biomarker for the Risk and Prognosis of Stroke.},
journal = {Frontiers in neurology},
volume = {10},
number = {},
pages = {624},
pmid = {31263449},
issn = {1664-2295},
abstract = {Stroke is one of the leading causes of death and disability worldwide. Age is associated with increased risk of stroke, while telomere length shortening plays a pivotal role in the process of aging. Moreover, telomere length shortening is associated with many risk factors of stroke in addition to age. Accumulated evidence shows that short leukocyte telomere length is not only associated with stroke occurrence but also associated with post-stroke recovery in the elderly population. In this review, we aimed to summarize the association between leukocyte telomere length and stroke, and discuss that telomere length might serve as a potential biomarker to predict the risk and prognosis of stroke.},
}
@article {pmid31263055,
year = {2019},
author = {Kachuri, L and Helby, J and Bojesen, SE and Christiani, DC and Su, L and Wu, X and Tardón, A and Fernández-Tardón, G and Field, JK and Davies, MP and Chen, C and Goodman, GE and Shepherd, FA and Leighl, NB and Tsao, MS and Brhane, Y and Brown, MC and Boyd, K and Shepshelovich, D and Sun, L and Amos, CI and Liu, G and Hung, RJ},
title = {Investigation of Leukocyte Telomere Length and Genetic Variants in Chromosome 5p15.33 as Prognostic Markers in Lung Cancer.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {28},
number = {7},
pages = {1228-1237},
pmid = {31263055},
issn = {1538-7755},
support = {U19 CA148127/CA/NCI NIH HHS/United States ; R35 CA197449/CA/NCI NIH HHS/United States ; U01 CA209414/CA/NCI NIH HHS/United States ; GSD-137441//CIHR/Canada ; U01 CA167462/CA/NCI NIH HHS/United States ; U19 CA203654/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Female ; Genetic Variation/*genetics ; Humans ; Leukocytes/*metabolism ; Lung Neoplasms/*genetics ; Male ; Middle Aged ; Prognosis ; Risk Factors ; Telomere/*genetics ; },
abstract = {BACKGROUND: Lung cancer remains the leading cause of cancer mortality with relatively few prognostic biomarkers. We investigated associations with overall survival for telomere length (TL) and genetic variation in chromosome 5p15.33, an established telomere maintenance locus.<br><br>METHODS: Leukocyte TL was measured after diagnosis in 807 patients with non-small cell lung cancer (NSCLC) from the Princess Margaret Cancer Center in Toronto and assessed prospectively in 767 NSCLC cases from the Copenhagen City Heart Study and the Copenhagen General Population Study. Associations with all-cause mortality were tested for 723 variants in 5p15.33, genotyped in 4,672 NSCLC cases.<br><br>RESULTS: Short telomeres (&#x2264;10th percentile) were associated with poor prognosis for adenocarcinoma in both populations: TL measured 6 months after diagnosis [HR = 1.65; 95% confidence intervals (CI), 1.04-2.64] and for those diagnosed within 5 years after blood sampling (HR = 2.42; 95% CI, 1.37-4.28). Short TL was associated with mortality in never smokers with NSCLC (HR = 10.29; 95% CI, 1.86-56.86) and adenocarcinoma (HR = 11.31; 95% CI, 1.96-65.24). Analyses in 5p15.33 identified statistically significant prognostic associations for rs56266421-G in LPCAT1 (HR = 1.86; 95% CI, 1.38-2.52; P = 4.5 &#xd7; 10[-5]) in stage I-IIIA NSCLC, and for the SLC6A3 gene with OS in females with NSCLC (P = 1.6 &#xd7; 10[-3]).<br><br>CONCLUSIONS: Our findings support the potential clinical utility of TL, particularly for adenocarcinoma patients, while associations in chromosome 5p15.33 warrant further exploration.<br><br>IMPACT: This is the largest lung cancer study of leukocyte TL and OS, and the first to examine the impact of the timing of TL measurement. Our findings suggest that extremely short telomeres are indicative of poor prognosis in NSCLC.},
}
@article {pmid31261650,
year = {2019},
author = {Carugno, M and Maggioni, C and Crespi, E and Bonzini, M and Cuocina, S and Dioni, L and Tarantini, L and Consonni, D and Ferrari, L and Pesatori, AC},
title = {Night Shift Work, DNA Methylation and Telomere Length: An Investigation on Hospital Female Nurses.},
journal = {International journal of environmental research and public health},
volume = {16},
number = {13},
pages = {},
pmid = {31261650},
issn = {1660-4601},
mesh = {Adult ; *DNA Methylation ; Female ; Genomic Instability ; Humans ; Middle Aged ; *Nursing Staff, Hospital ; *Shift Work Schedule ; *Telomere ; Young Adult ; },
abstract = {Increased breast cancer risk has been reported in some night shift (NS) workers but underlying biological mechanisms are still unclear. We assessed the association between NS work and DNA methylation of tumor suppressor (TP53, CDKN2A, BRCA1, BRCA2) and estrogen receptor (ESR1, ESR2) genes, methylation of repetitive elements (LINE-1, Alu), and telomere length (TL). Forty six female nurses employed in NS for at least two years were matched by age (30-45 years) and length of service (≥1 year) with 51 female colleagues not working in NS. Each subject underwent a semi-structured interview and gave a blood sample. We applied linear regression and spline models adjusted for age, BMI, smoking habit, oral contraceptive use, parity and marital status/age at marriage. Currently working in NS was associated with ESR1 hypomethylation (β: -1.85 (95%CI: -3.03; -0.67), p = 0.003). In current and former NS workers we observed TP53 (-0.93 (-1.73; -0.12), p = 0.03) and BRCA1 (-1.14 (-1.71; -0.58), p <0.001) hypomethylation. We found an increase between TL and number of years in NS in subjects employed in NS <12 years (0.06 (0.03; 0.09), p <0.001), while a decrease if employed in NS ≥12 years (-0.07 -0.10; -0.04), p <0.001). Our findings show NS-associated markers potentially involved in cellular aging, genomic instability, and cancer development.},
}
@article {pmid31259399,
year = {2019},
author = {Toland, AE},
title = {POT1 pathogenic variants: not all telomere pathway genes are equal in risk of hereditary cutaneous melanoma.},
journal = {The British journal of dermatology},
volume = {181},
number = {1},
pages = {14-15},
pmid = {31259399},
issn = {1365-2133},
support = {R21 CA219884/CA/NCI NIH HHS/United States ; R03 CA173788/CA/NCI NIH HHS/United States ; R01 CA215151/CA/NCI NIH HHS/United States ; },
mesh = {Germ-Line Mutation ; Humans ; *Melanoma ; Mutation ; Shelterin Complex ; *Skin Neoplasms ; *Telomerase ; Telomere ; Telomere-Binding Proteins ; },
}
@article {pmid31255955,
year = {2019},
author = {Konečná, K and Lyčka, M and Nohelová, L and Petráková, M and Fňašková, M and Koriťáková, E and Sováková, PP and Brabencová, S and Preiss, M and Rektor, I and Fajkus, J and Fojtová, M},
title = {Holocaust history is not reflected in telomere homeostasis in survivors and their offspring.},
journal = {Journal of psychiatric research},
volume = {117},
number = {},
pages = {7-14},
doi = {10.1016/j.jpsychires.2019.06.018},
pmid = {31255955},
issn = {1879-1379},
mesh = {Adaptation, Psychological/*physiology ; Adolescent ; Adult ; *Adult Children ; *Adult Survivors of Child Adverse Events ; Age Factors ; Aged ; Aged, 80 and over ; Aging/*physiology ; Female ; *Holocaust ; Humans ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; *Stress Disorders, Post-Traumatic/metabolism/physiopathology ; *Stress, Psychological/metabolism/physiopathology ; *Survivors ; Telomere Homeostasis/*physiology ; Telomere Shortening/*physiology ; Young Adult ; },
abstract = {Telomeres, nucleoprotein structures at the ends of eukaryotic chromosomes, are crucial for the maintenance of genome integrity. While the lengths of telomeres at birth are determined genetically, many factors including environmental and living conditions affect the telomere lengths during a lifespan. In this context, extreme and long-term stress has been shown to negatively impact telomeres and their protective function, with even offspring being influenced by the stress experienced by parents. Using quantitative PCR, the relative lengths of telomeres of survivors of the Holocaust during World War II and two generations of their offspring were analyzed. These data were related to those of control groups, persons of comparable age without a strong life stress experience. In contrast to previous studies of other stress-exposed groups, the relative lengths of telomeres were comparable in groups of persons exposed to Holocaust-related stress and their progenies, and in control groups. Interestingly, shorter telomeres of Holocaust survivors of the age under 12 in the year 1945 compared to Holocaust survivors of the age above 12 were detected. Our results are discussed with respect to certain exceptionality of persons having been able to cope with an extreme stress more than 70 years ago and living to a very old age.},
}
@article {pmid31255876,
year = {2019},
author = {Welendorf, C and Nicoletti, CF and Pinhel, MAS and Noronha, NY and de Paula, BMF and Nonino, CB},
title = {Obesity, weight loss, and influence on telomere length: New insights for personalized nutrition.},
journal = {Nutrition (Burbank, Los Angeles County, Calif.)},
volume = {66},
number = {},
pages = {115-121},
doi = {10.1016/j.nut.2019.05.002},
pmid = {31255876},
issn = {1873-1244},
mesh = {Humans ; *Nutritional Status ; Obesity/*therapy ; Telomere ; *Telomere Shortening ; *Weight Loss ; },
abstract = {Telomeres are structures located at the ends of chromosomes associated with proteins, from the shelterin complex, which are responsible for the protection and preservation of the genetic material. The telomere length (TL) progressively decreases with each cell division, and recent evidence suggests that lifestyle can lead to telomere shortening. In individuals with obesity, excess adipose tissue plays a key role in inducing a chronic and systemic inflammatory state, which can cause TL shortening. Thus, the aim of the present review was to show the relationship between obesity and TL in addition to the possible risk factors for its shortening and how the different strategies for weight loss can modulate TL. As the crucial result, we can consider the association between TL and weight loss, and adiposity changes after different interventions, showing that TL may be used as a biomarker of responses to obesity treatment.},
}
@article {pmid31253940,
year = {2019},
author = {Nault, JC and Ningarhari, M and Rebouissou, S and Zucman-Rossi, J},
title = {The role of telomeres and telomerase in cirrhosis and liver cancer.},
journal = {Nature reviews. Gastroenterology &amp; hepatology},
volume = {16},
number = {9},
pages = {544-558},
pmid = {31253940},
issn = {1759-5053},
mesh = {Animals ; Biomarkers, Tumor/genetics/metabolism ; Carcinoma, Hepatocellular/genetics/*metabolism ; Cell Division/physiology ; Cell Survival/physiology ; Cell Transformation, Neoplastic/genetics/metabolism ; Disease Models, Animal ; Humans ; Liver/metabolism ; Liver Cirrhosis/genetics/*metabolism ; Liver Neoplasms/genetics/*metabolism ; Mice ; Mutation ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomerase is a key enzyme for cell survival that prevents telomere shortening and the subsequent cellular senescence that is observed after many rounds of cell division. In contrast, inactivation of telomerase is observed in most cells of the adult liver. Absence of telomerase activity and shortening of telomeres has been implicated in hepatocyte senescence and the development of cirrhosis, a chronic liver disease that can lead to hepatocellular carcinoma (HCC) development. During hepatocarcinogenesis, telomerase reactivation is required to enable the uncontrolled cell proliferation that leads to malignant transformation and HCC development. Part of the telomerase complex, telomerase reverse transcriptase, is encoded by TERT, and several mechanisms of telomerase reactivation have been described in HCC that include somatic TERT promoter mutations, TERT amplification, TERT translocation and viral insertion into the TERT gene. An understanding of the role of telomeres and telomerase in HCC development is important to develop future targeted therapies and improve survival of this disease. In this Review, the roles of telomeres and telomerase in liver carcinogenesis are discussed, in addition to their potential translation to clinical practice as biomarkers and therapeutic targets.},
}
@article {pmid31249642,
year = {2019},
author = {Manna, S and McCarthy, C and McCarthy, FP},
title = {Placental Ageing in Adverse Pregnancy Outcomes: Telomere Shortening, Cell Senescence, and Mitochondrial Dysfunction.},
journal = {Oxidative medicine and cellular longevity},
volume = {2019},
number = {},
pages = {3095383},
pmid = {31249642},
issn = {1942-0994},
mesh = {Aging/genetics/*pathology ; *Cellular Senescence ; Female ; Fetal Growth Retardation/*epidemiology ; Humans ; Placenta/*physiopathology ; Pregnancy ; Pregnancy Complications/*epidemiology ; Pregnancy Outcome/*epidemiology ; *Telomere Shortening ; },
abstract = {Preeclampsia is a multisystemic pregnancy disorder and a major cause of maternal and neonatal morbidity and mortality worldwide. The exact pathophysiology of preeclampsia remains unclear; however, it is speculated that the various pathologies can be attributed to impaired vascular remodelling and elevated oxidative stress within the placenta. Oxidative stress plays a key role in cell ageing, and the persistent presence of elevated oxidative stress precipitates cellular senescence and mitochondrial dysfunction, resulting in premature ageing of the placenta. Premature ageing of the placenta is associated with placental insufficiency, which reduces the functional capacity of this critical organ and leads to abnormal pregnancy outcomes. The changes brought about by oxidative insults are irreversible and often lead to deleterious modifications in macromolecules such as lipids and proteins, DNA mutations, and alteration of mitochondrial functioning and dynamics. In this review, we have summarized the current knowledge of placental ageing in the aetiology of adverse pregnancy outcomes and discussed the hallmarks of ageing which could be potential markers for preeclampsia and fetal growth restriction.},
}
@article {pmid31248154,
year = {2019},
author = {Arish, N and Petukhov, D and Wallach-Dayan, SB},
title = {The Role of Telomerase and Telomeres in Interstitial Lung Diseases: From Molecules to Clinical Implications.},
journal = {International journal of molecular sciences},
volume = {20},
number = {12},
pages = {},
pmid = {31248154},
issn = {1422-0067},
mesh = {Animals ; Cell Transformation, Neoplastic/genetics/metabolism ; Disease Susceptibility ; Gene Expression Regulation ; Genetic Association Studies ; Humans ; Lung Diseases, Interstitial/*genetics/*metabolism/pathology ; Mutation ; RNA, Long Noncoding ; Telomerase/*genetics/*metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres are distal chromosome regions associated with specific protein complexes that protect the chromosome against degradation and aberrations. Telomere maintenance capacity is an essential indication of healthy cell populations, and telomere damage is observed in processes such as malignant transformation, apoptosis, or cell senescence. At a cellular level, telomere damage may result from genotoxic stress, decreased activity of telomerase enzyme complex, dysfunction of shelterin proteins, or changes in expression of telomere-associated RNA such as TERRA. Clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.). Thus, telomere length and maintenance can serve as an important prognostic factor as well as a potential target for new strategies of treatment for interstitial lung diseases (ILDs) and associated pulmonary pathologies.},
}
@article {pmid31247265,
year = {2019},
author = {Lee, EY and Oh, SS and White, MJ and Eng, CS and Elhawary, JR and Borrell, LN and Nuckton, TJ and Zeiger, AM and Keys, KL and Mak, ACY and Hu, D and Huntsman, S and Contreras, MG and Samedy, LA and Goddard, PC and Salazar, SL and Brigino-Buenaventura, EN and Davis, A and Meade, KE and LeNoir, MA and Lurmann, FW and Burchard, EG and Eisen, EA and Balmes, JR},
title = {Ambient air pollution, asthma drug response, and telomere length in African American youth.},
journal = {The Journal of allergy and clinical immunology},
volume = {144},
number = {3},
pages = {839-845.e10},
pmid = {31247265},
issn = {1097-6825},
support = {R01 HL141992/HL/NHLBI NIH HHS/United States ; R01 GM075316/GM/NIGMS NIH HHS/United States ; K01 HL140218/HL/NHLBI NIH HHS/United States ; T32 HG000044/HG/NHGRI NIH HHS/United States ; R01 HL128439/HL/NHLBI NIH HHS/United States ; R01 HL117004/HL/NHLBI NIH HHS/United States ; R21 ES024844/ES/NIEHS NIH HHS/United States ; R01 ES015794/ES/NIEHS NIH HHS/United States ; T42 OH008429/OH/NIOSH CDC HHS/United States ; R01 HL135156/HL/NHLBI NIH HHS/United States ; T32 GM007546/GM/NIGMS NIH HHS/United States ; RL5 GM118984/GM/NIGMS NIH HHS/United States ; R01 MD010443/MD/NIMHD NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; *Black or African American ; Air Pollutants ; *Air Pollution ; Asthma/*drug therapy/ethnology ; Child ; *Environmental Exposure ; Humans ; Ozone ; Particulate Matter ; Steroids/*therapeutic use ; *Telomere ; Young Adult ; },
abstract = {BACKGROUND: Telomere length (TL) can serve as a potential biomarker for conditions associated with chronic oxidative stress and inflammation, such as asthma. Air pollution can induce oxidative stress. Understanding the relationship between TL, asthma, and air pollution is important for identifying risk factors contributing to unhealthy aging in children.<br><br>OBJECTIVES: We sought to investigate associations between exposures to ambient air pollutants and TL in African American children and adolescents and to examine whether African ancestry, asthma status, and steroid medication use alter the association.<br><br>METHODS: Linear regression was used to examine associations between absolute telomere length (aTL) and estimated annual average residential ozone (O3) and fine particulate matter with a diameter of 2.5&#xa0;&#x3bc;m or less (PM2.5) exposures in a cross-sectional analysis of 1072 children in an existing asthma case-control study. African ancestry, asthma status, and use of steroid medications were examined as effect modifiers.<br><br>RESULTS: Participants' aTLs were measured by using quantitative PCR. A&#xa0;1-ppb and 1&#xa0;&#x3bc;g/m[3] increase in annual average exposure to O3 and PM2.5 were associated with a decrease in aTL of 37.1 kilo-base pair (kb; 95% CI, -66.7 to -7.4 kb) and 57.1 kb (95% CI, -118.1 to 3.9 kb), respectively. African ancestry and asthma were not effect modifiers; however, exposure to steroid medications modified the relationships between TL and pollutants. Past-year exposure to O3 and PM2.5 was associated with shorter TLs in patients without steroid use.<br><br>CONCLUSION: Exposure to air pollution was associated with shorter TLs in nonasthmatic children and adolescents. This was not the case for asthmatic children as a group, but those receiving steroid medication had less shortening than those not using steroids. Reduced exposure to air pollution in childhood might help to preserve TL.},
}
@article {pmid31246986,
year = {2019},
author = {Minami, R and Takahama, S and Yamamoto, M},
title = {Correlates of telomere length shortening in peripheral leukocytes of HIV-infected individuals and association with leukoaraiosis.},
journal = {PloS one},
volume = {14},
number = {6},
pages = {e0218996},
pmid = {31246986},
issn = {1932-6203},
mesh = {Adult ; Age Factors ; Aged ; Anti-Retroviral Agents/therapeutic use ; Case-Control Studies ; Female ; HIV Infections/drug therapy/*genetics ; Humans ; Leukoaraiosis/*diagnostic imaging/genetics ; Leukocytes/*chemistry ; Male ; Middle Aged ; Regression Analysis ; Telomere/*genetics ; Telomere Shortening ; Young Adult ; },
abstract = {Telomere length (TL) is a marker of cellular and biological aging. Human immunodeficiency virus (HIV) infection has been reported to be associated with short TLs, which suggests that accelerated biological aging occurs in some cellular compartments of HIV+ individuals. In this study, we measured the TLs of peripheral leukocytes of HIV+ and healthy individuals and examined the biological and environmental correlates of TL. We also investigated the influence of TL on leukoaraiosis, an indicator of cerebral small vessel disease, in HIV+ individuals. Three hundred and twenty-five HIV+ individuals who received stable combination antiretroviral therapy (cART) for >1 year and achieved viral loads of <40 RNA copies/mL were enrolled along with 147 healthy individuals. Relative TLs of leukocytes were estimated by quantitative real-time polymerase chain reaction. Leukoaraiosis was assessed in 184 HIV+ individuals by fluid-attenuated inversion recovery magnetic resonance imaging. We analyzed several covariates, including markers of HIV infection, cART, and social/environmental factors; variables associated with TL length in univariate analyses were incorporated into multivariate models. The TLs of peripheral leukocytes of HIV+ individuals were significantly shorter than those of healthy individuals, and the rate of LT length decline with increasing age was greater. Linear regression analysis showed that in HIV+ individuals, increasing age, cART without integrase-stand transfer inhibitors (INSTI), failure to achieve viral loads of <40 copies/mL within 1 year of initiating cART, and substance use were significantly associated with shorter TLs, even after adjustment for the effects of age. Logistic regression analysis indicated an increasing risk of leukoaraiosis was associated with older age, shorter TLs, hypertension, and carotid artery plaque. Multivariate regression analysis indicated that older age and shorter TLs were significant risk factors for leukoaraiosis. In summary, our data showed that TL shortening in HIV+ individuals was independently associated with leukoaraiosis, and was associated with age, control of viral loads, use of INSTI, and substance use. Our results suggest that effective viral control and less toxic cART can help reduce TL shortening and improve outcomes among HIV+ individuals.},
}
@article {pmid31243901,
year = {2019},
author = {Chen, X and Wei, S and Ma, H and Jin, G and Hu, Z and Suping, H and Li, D and Hang, D and Wu, X and Li, N},
title = {Telomere length in cervical exfoliated cells, interaction with HPV genotype, and cervical cancer occurrence among high-risk HPV-positive women.},
journal = {Cancer medicine},
volume = {8},
number = {10},
pages = {4845-4851},
pmid = {31243901},
issn = {2045-7634},
mesh = {Adult ; Case-Control Studies ; DNA, Viral/genetics ; Early Detection of Cancer ; Female ; Genotype ; Humans ; Logistic Models ; Middle Aged ; Neoplasm Staging ; Papillomaviridae/*genetics/isolation &amp; purification ; Papillomavirus Infections/pathology/*virology ; Prospective Studies ; *Telomere Shortening ; Uterine Cervical Neoplasms/genetics/*pathology/virology ; },
abstract = {BACKGROUND: Although high-risk human papillomavirus (HR-HPV) infection is recognized as the main cause of cervical cancer, only a minority of HPV-infected women develop this malignancy. Increasing evidence suggests that alterations of telomere length might be implicated in carcinogenesis. However, the association between cervical cancer and telomere length remains unknown.<br><br>METHODS: This case-control study included 591 cervical cancer patients and 373 cancer-free controls, all of whom were infected with HR-HPV. Relative telomere length (RTL) in cervical cancer exfoliated cells was measured by quantitative PCR. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression analysis.<br><br>RESULTS: HPV16, 18, 52, and 58 were common in both case and control groups. The proportion of HPV16 infection tended to increase across the quartiles of RTL (Ptrend &#xa0;<&#xa0;0.001). There was no statistically significant association of RTL with tumor differentiation, histological type, and FIGO stage. After adjustment for age and HPV types, the lowest quartile of RTL presented a 49% lower risk (OR&#xa0;=&#xa0;0.51, 95% CI: 0.35, 0.76; P&#xa0;<&#xa0;0.001) than those with the highest quartile of RTL. There was also a dose-response relationship of shorter RTL on lower risk of cervical cancer (Ptrend &#xa0;<&#xa0;0.001).<br><br>CONCLUSION: Shortened telomere length in cervical exfoliated cells was related to the lower risk of cervical cancer among HR-HPV-positive women, which might help to improve cervical cancer screening and surveillance. Further prospective studies with large sample should be designed to validate our preliminary findings, and evaluate the potential efficacy of telomere length for cervical cancer screening.},
}
@article {pmid31239704,
year = {2019},
author = {Wysoczanska, B and Dratwa, M and Gebura, K and Mizgala, J and Mazur, G and Wrobel, T and Bogunia-Kubik, K},
title = {Variability within the human TERT gene, telomere length and predisposition to chronic lymphocytic leukemia.},
journal = {OncoTargets and therapy},
volume = {12},
number = {},
pages = {4309-4320},
pmid = {31239704},
issn = {1178-6930},
abstract = {Background: The human telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase that is essential for maintenance of telomere length. We aimed to find out whether variability within the TERT gene could be associated with telomere length and development of the disease in non-treated patients with chronic lymphocytic leukemia (CLL). Materials and methods: Telomere length, rs2736100, rs2853690, rs33954691, rs35033501 single-nucleotide polymorphisms, and variable number of tandem repeats (VNTR-MNS16A) were assessed in patients at diagnosis. In addition, blood donors served as controls for the polymorphism studies. Results: The minor rs35033501 A variant was more frequent among CLL patients than in healthy controls (OR=3.488, p=0.039). CLL patients over 60 years of age were characterized with lower disease stage at diagnosis (p=0.001 and p=0.008, for the Rai and Binet criteria, respectively). The MNS16A VNTR-243 short allele was more frequent in patients with a low disease stage (p=0.020 and p=0.028, for the Rai and Binet staging system) and also among older patients having longer telomeres (p=0.046). Patients with Rai 0-I stage were characterized with longer telomeres than those with more advanced disease (p=0.030). This relationship was especially pronounced in patients carrying the rs2736100 C allele, independently of the criteria used, ie, Binet (p=0.048) or Rai (p=0.001). Conclusion: Our results showed that the genetic variation within the TERT gene seems to play a regulatory role in CLL and telomere length.},
}
@article {pmid31236227,
year = {2019},
author = {Singchat, W and Kraichak, E and Tawichasri, P and Tawan, T and Suntronpong, A and Sillapaprayoon, S and Phatcharakullawarawat, R and Muangmai, N and Suntrarachun, S and Baicharoen, S and Punyapornwithaya, V and Peyachoknagul, S and Chanhome, L and Srikulnath, K},
title = {Dynamics of telomere length in captive Siamese cobra (Naja kaouthia) related to age and sex.},
journal = {Ecology and evolution},
volume = {9},
number = {11},
pages = {6366-6377},
pmid = {31236227},
issn = {2045-7758},
abstract = {Telomeres comprise tandem repeated DNA sequences that protect the ends of chromosomes from deterioration or fusion with neighboring chromosomes, and their lengths might vary with sex and age. Here, age- and sex-related telomere lengths in male and female captive Siamese cobras (Naja kaouthia) were investigated using quantitative real-time polymerase chain reaction based on cross-sectional data. A negative correlation was shown between telomere length and body size in males but not in females. Age-related sex differences were also recorded. Juvenile female snakes have shorter telomeres relative to males at up to 5 years of age, while body size also rapidly increases during this period. This suggests that an accelerated increase in telomere length of female cobra results from sex hormone stimulation to telomerase activity, reflecting sexually dimorphic phenotypic traits. This might also result from amplification of telomeric repeats on sex chromosomes. By contrast, female Siamese cobras older than 5 years had longer telomeres than males. Diverse sex hormone levels and oxidative stress parameters between sexes may affect telomere length.},
}
@article {pmid31236215,
year = {2019},
author = {Rollings, N and Friesen, CR and Whittington, CM and Johansson, R and Shine, R and Olsson, M},
title = {Sex- And tissue-specific differences in telomere length in a reptile.},
journal = {Ecology and evolution},
volume = {9},
number = {11},
pages = {6211-6219},
pmid = {31236215},
issn = {2045-7758},
abstract = {The usage of telomere length (TL) in blood as a proxy for the TL of other tissues relies on the assumption that telomere dynamics across all tissues are similar. However, telomere attrition can be caused by reactive oxygen species (ROS) which may vary with metabolic rate, which itself varies across organs depending upon the life history strategy of an organism. Thus, we chose to measure the telomeres of various cell types in juvenile painted dragon lizards, Ctenophorus pictus, given their unusual life history strategy. Individuals typically only experience a single mating season. We measured the TL of male and female dragons using qPCR and observed that TL varied with tissue type and sex. Telomeres of blood cells were longer than those of liver, heart, brain, and spleen, and females had longer telomeres than males. Brain telomeres in males were approximately half the length of those in females. Telomeric attrition in the male brain may be due to the need for rapid learning of reproductive tactics (territory patrol and defense, mate-finding). Significant correlations between the TL of tissue types suggest that blood TL may be a useful proxy for the TL of other tissues. Our comparison of organ-specific telomere dynamics, the first in a reptile, suggests that the usage of blood TL as a proxy requires careful consideration of the life history strategy of the organism.},
}
@article {pmid31234328,
year = {2019},
author = {Banszerus, VL and Vetter, VM and Salewsky, B and König, M and Demuth, I},
title = {Exploring the Relationship of Relative Telomere Length and the Epigenetic Clock in the LipidCardio Cohort.},
journal = {International journal of molecular sciences},
volume = {20},
number = {12},
pages = {},
pmid = {31234328},
issn = {1422-0067},
support = {118185//Sanofi/ ; #16SV5536K, #16SV5537, #16SV5538,#16SV5837, #01UW0808, 01GL1716A and 01GL1716B//Bundesministerium f&#xfc;r Bildung und Forschung/ ; },
mesh = {Aged ; Aged, 80 and over ; *Aging ; Cardiovascular Diseases/epidemiology/genetics ; Cohort Studies ; CpG Islands ; *DNA Methylation ; Epigenesis, Genetic ; Female ; Humans ; Male ; Middle Aged ; *Telomere Homeostasis ; },
abstract = {Telomere length has been accepted widely as a biomarker of aging. Recently, a novel candidate biomarker has been suggested to predict an individual's chronological age with high accuracy: The epigenetic clock is based on the weighted DNA methylation (DNAm) fraction of a number of cytosine-phosphate-guanine sites (CpGs) selected by penalized regression analysis. Here, an established methylation-sensitive single nucleotide primer extension method was adapted, to estimate the epigenetic age of the 1005 participants of the LipidCardio Study, a patient cohort characterised by high prevalence of cardiovascular disease, based on a seven CpGs epigenetic clock. Furthermore, we measured relative leukocyte telomere length (rLTL) to assess the relationship between the established and the promising new measure of biological age. Both rLTL (0.79 ± 0.14) and DNAm age (69.67 ± 7.27 years) were available for 773 subjects (31.6% female; mean chronological age= 69.68 ± 11.01 years; mean DNAm age acceleration = -0.01 ± 7.83 years). While we detected a significant correlation between chronological age and DNAm age (n = 779, R = 0.69), we found neither evidence of an association between rLTL and the DNAm age (β = 3.00, p = 0.18) nor rLTL and the DNAm age acceleration (β = 2.76, p = 0.22) in the studied cohort, suggesting that DNAm age and rLTL measure different aspects of biological age.},
}
@article {pmid31230193,
year = {2019},
author = {Subedi, P and Nembrini, S and An, Q and Zhu, Y and Peng, H and Yeh, F and Cole, SA and Rhoades, DA and Lee, ET and Zhao, J},
title = {Telomere length and cancer mortality in American Indians: the Strong Heart Study.},
journal = {GeroScience},
volume = {41},
number = {3},
pages = {351-361},
pmid = {31230193},
issn = {2509-2723},
support = {U01HL41642/NH/NIH HHS/United States ; K01 AG034259/AG/NIA NIH HHS/United States ; R01 DK091369/DK/NIDDK NIH HHS/United States ; U01HL65520/NH/NIH HHS/United States ; R21 HL092363/HL/NHLBI NIH HHS/United States ; U01HL41652/NH/NIH HHS/United States ; R01 HL109319/HL/NHLBI NIH HHS/United States ; U01HL65521/NH/NIH HHS/United States ; R01DK091369/NH/NIH HHS/United States ; U01HL41654/NH/NIH HHS/United States ; },
mesh = {Aged ; Cardiovascular Diseases/mortality/physiopathology ; Correlation of Data ; Diabetes Mellitus/mortality/physiopathology ; Female ; Health Status ; Humans ; *Indians, North American ; Life Style ; Longitudinal Studies ; Male ; Middle Aged ; Neoplasms/*mortality/physiopathology ; Proportional Hazards Models ; Risk ; Risk Factors ; Sex Factors ; Telomere Homeostasis/*physiology ; United States ; },
abstract = {The objective of this study was to investigate whether leukocyte telomere length (LTL) predicts the risk for cancer mortality among American Indians participating in the Strong Heart Study (1989-1991). Participants (aged 45-74 years) were followed annually until December 2015 to collect information on morbidity/mortality. LTL was measured by qPCR using genomic DNA isolated from peripheral blood. The association between LTL and risk for cancer mortality was examined using a multivariable Cox proportional hazard model, adjusting for age, gender, education, study site, smoking, alcohol use, physical activity, systolic blood pressure, fasting blood glucose, obesity, and low- and high-density lipoprotein. Of 1945 participants (mean age 56.10 ± 8.17 at baseline, 57% women) followed for an average 20.5 years, 220 died of cancer. Results showed that longer LTL at baseline significantly predicts an increased risk of cancer death among females (HR 1.57, 95% CI 1.08-2.30), but not males (HR 0.74, 95% CI 0.49-1.12) (p for interaction 0.009). Specifically, compared with the women with the longest LTL (fourth quartile), those in the third, second, and first quartiles showed 53%, 41%, and 44% reduced risk for cancer death, respectively. The findings highlight the importance of sex-specific analysis in future telomere research.},
}
@article {pmid31219569,
year = {2019},
author = {Nonaka, K and Aida, J and Takubo, K and Yamazaki, Y and Takakuma, S and Kakizaki, M and Matsuda, Y and Ishikawa, N and Ishiwata, T and Chong, JM and Arai, T and Sasano, H},
title = {Correlation Between Differentiation of Adrenocortical Zones and Telomere Lengths Measured by Q-FISH.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {104},
number = {11},
pages = {5642-5650},
doi = {10.1210/jc.2019-00592},
pmid = {31219569},
issn = {1945-7197},
mesh = {Adolescent ; Adrenal Cortex/cytology/*metabolism ; Adult ; Aged ; Child ; Child, Preschool ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; Infant, Newborn ; Male ; Middle Aged ; *Telomere ; Young Adult ; },
abstract = {CONTEXT: Adrenocortical zonation is associated with a markedly complex developmental process, and the pathogenesis and/or etiology of many disorders of adrenocortical zonal development have remained unknown. Cells from the three adrenocortical zones are morphologically and functionally differentiated, and the mature stage of cell development or senescence has been recently reported to be correlated with telomere length. However, the telomere length of each adrenocortical zonal cell has not yet been studied in human adrenal glands.<br><br>OBJECTIVE: We aimed to study the telomere lengths of adrenocortical parenchymal cells from three different zones of the adrenal glands present during childhood, adolescence, and adulthood.<br><br>METHODS: Adrenal glands of 30 autopsied subjects, aged between 0 and 68 years, were retrieved from pathology files. The normalized telomere to centromere ratio (NTCR), an index of telomere length, was determined in the parenchymal cells of the zona glomerulosa, zona fasciculata, and zona reticularis (ZR), using quantitative fluorescence in situ hybridization.<br><br>RESULTS: NTCR of ZR cells was the longest, followed in decreasing order by that of zona glomerulosa and zona fasciculata cells in subjects aged 20 to 68 years, but no substantial differences in NTCR were detected among these three zones in the group <20 years of age. NTCR of ZR increased with age in subjects aged 20 to 68 years, whereas no important age-dependent changes in NTCR were detected in the group <20 years of age.<br><br>CONCLUSION: The telomere lengths for three zones in adrenal cortex were correlated with their differentiation in adulthood but not in childhood and adolescence.},
}
@article {pmid31217894,
year = {2019},
author = {Tutton, S and Deng, Z and Gulve, N and Vladimirova, O and Beishline, K and Wiedmer, A and Murphy, M and Lieberman, PM},
title = {Elevated telomere dysfunction in cells containing the African-centric Pro47Ser cancer-risk variant of TP53.},
journal = {Oncotarget},
volume = {10},
number = {38},
pages = {3581-3591},
pmid = {31217894},
issn = {1949-2553},
support = {P30 CA010815/CA/NCI NIH HHS/United States ; T32 CA009171/CA/NCI NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; T32 CA115299/CA/NCI NIH HHS/United States ; R01 CA102184/CA/NCI NIH HHS/United States ; R01 CA201430/CA/NCI NIH HHS/United States ; },
abstract = {Subtelomeric transcription and chromatin can have a significant impact on telomere repeat maintenance and chromosome stability. We have previously found that tumor suppressor protein p53 (TP53) can bind to retrotransposon-like elements in a majority of human subtelomeres to regulate TERRA transcription and telomeric histone acetylation in response to DNA damage. TP53 also prevents the accumulation of γH2AX DNA-damage signaling at telomeres. We now show that the inherited TP53 polymorphism Pro47Ser (hereafter S47), which is enriched in populations of African descent, is associated with elevated marks of telomere dysfunction. We found that human and mouse cells carrying the S47 variant show increased γH2AX DNA-damage signals at telomeres, as well as reduced TERRA transcription and subtelomeric histone acetylation in response to DNA damage stress. Cell-lines containing inducible genes for P47 or S47 versions of p53, as well mouse embryo fibroblasts (MEFs) reconstituted with human p53, showed elevated telomere-induced DNA damage foci and metaphase telomere signal loss in cells with S47. Human lymphoblastoid cell lines (LCLs) derived from individuals homozygous for S47, show increased accumulation of subtelomeric γH2AX and unstable telomere repeats in response to DNA damage relative to age matched LCLs homozygous for P47. Furthermore, LCLs with S47 had reduced replicative lifespan. These studies indicate that the naturally occurring S47 variant of p53 can affect telomeric chromatin, telomere repeat stability, and replicative capacity. We discuss the potential evolutionary significance of the S47 variant to African populations with respect to telomere regulation and the implications for inherited health disparities.},
}
@article {pmid31216382,
year = {2019},
author = {Tarik, M and Ramakrishnan, L and Sinha, S and Sachdev, HPS and Tandon, N and Roy, A and Bhargava, SK},
title = {Association of birth outcomes and postnatal growth with adult leukocyte telomere length: Data from New Delhi Birth Cohort.},
journal = {Maternal &amp; child nutrition},
volume = {15},
number = {4},
pages = {e12857},
pmid = {31216382},
issn = {1740-8709},
mesh = {Adult ; Birth Weight/*physiology ; Body Mass Index ; Body Weight/*physiology ; Child ; Child, Preschool ; Chronic Disease ; Cohort Studies ; Female ; Humans ; Leukocytes/*chemistry ; Pediatric Obesity/epidemiology ; Pregnancy ; Telomere/*chemistry ; },
abstract = {Born small for gestational age due to undernutrition in utero and subsequent catch-up growth is associated with risk of developing chronic diseases in adulthood. Telomere length has been shown to be a predictor of these age-related diseases and may be a link between birth size, a surrogate for foetal undernutrition, and adult chronic diseases. We assessed the relationship of leukocyte telomere length in adult life with birth outcomes and serial change in body mass index (BMI) from birth to adulthood. Leukocyte relative telomere length (RTL) was measured by MMqPCR in 1,309 subjects from New Delhi Birth Cohort who participated in two phases of the study between 2006-2009 (Phase 6) and 2012-2015 (Phase 7) at a mean age of 39.08 (±3.29), and its association with birth outcomes and conditional BMI gain at 2, 11, and 29 years was assessed in a mixed regression model. We did not find any significant association of RTL with body size at birth including birthweight, birth length, and birth BMI. Gestational age was positively associated with RTL (P = .017, multivariate model: P = .039). Conditional BMI gain at 2 and 11 years was not associated with RTL. BMI gain at 29 year was negatively associated with RTL in multivariate model (P = .015). Born small for gestational age was not associated with RTL in adulthood. Leukocyte telomere attrition was observed in those born before 37 weeks of gestational age as well as in those who gained weight as adults, which may predispose to chronic diseases.},
}
@article {pmid31211757,
year = {2019},
author = {Soumboundou, M and Nkengurutse, I and Dossou, J and Colicchio, B and Djebou, C and Gadji, M and Houenon, G and Dem, A and Dedjan, A and Diarra, M and Adjibade, R and Finot, F and Hempel, W and Dieterlen, A and Jeandidier, E and Rodriguez-Lafrasse, C and M'kacher, R},
title = {Biological Dosimetry Network in Africa: Establishment of a Dose-Response Curve Using Telomere and Centromere Staining.},
journal = {Health physics},
volume = {117},
number = {6},
pages = {618-624},
doi = {10.1097/HP.0000000000001102},
pmid = {31211757},
issn = {1538-5159},
mesh = {Adult ; Africa ; Blood Cells/*metabolism/radiation effects ; Centromere/*metabolism ; Chromosome Aberrations/*radiation effects ; Female ; Humans ; Lymphocytes/*metabolism/radiation effects ; Male ; Radiation Dosage ; Radiation Protection ; Radiation, Ionizing ; Radiometry/instrumentation/*methods/standards ; Staining and Labeling/*methods ; Telomere/*metabolism ; X-Rays ; Young Adult ; },
abstract = {PURPOSE: Biological dosimetry, based on the relationship between the absorbed dose after exposure to ionizing radiation and the frequency of scored aberrations, has been and continues to be an important tool for estimating the dose after exposure. Dicentric chromosomes are considered to be the most specific and sensitive aberration related to radiation exposure. Here, we established the dose-response curve following in vitro irradiation of circulating lymphocytes from healthy donors from three African countries after scoring unstable chromosomal aberrations.<br><br>MATERIALS AND METHODS: Blood samples from 16 African donors were exposed to various doses (0 to 4 Gy) using an X-RAD320 x-ray system with a maximum photon energy of 250 kV at a dose rate of 0.1 Gy min. Blood lymphocytes were cultured for 48 h, and chromosomal aberrations were scored during the first mitosis by telomere and centromere staining. The distribution of dicentric chromosomes was determined.<br><br>RESULTS: No dicentric chromosomes were found after the analysis of 2,669 first-division metaphases before in vitro exposure. We established a linear-quadratic dose-response curve based on the frequency of dicentric and ring chromosomes and calculated double-strand breaks, taking into account all scored aberrations.<br><br>CONCLUSION: The generation of a specific dose-response curve for African donors will allow the practice of precise biological dosimetry in these countries. This work is the first step towards realizing an African biodosimetry network and the establishment of a biological dosimetry laboratory, which could play a major role in the application of radioprotection norms.},
}
@article {pmid31211452,
year = {2019},
author = {Borbora, D and Dutta, HK and Devi, KR and Mahanta, J and Medhi, P and Narain, K},
title = {Long telomeres cooperate with p53, MDM2, and p21 polymorphisms to raise pediatric solid tumor risk.},
journal = {Pediatrics international : official journal of the Japan Pediatric Society},
volume = {61},
number = {8},
pages = {759-767},
doi = {10.1111/ped.13915},
pmid = {31211452},
issn = {1442-200X},
mesh = {Adolescent ; Amplified Fragment Length Polymorphism Analysis ; Biomarkers, Tumor/*genetics ; Case-Control Studies ; Child ; Child, Preschool ; Cyclin-Dependent Kinase Inhibitor p21/*genetics ; Female ; Genes, p53/*genetics ; Genetic Predisposition to Disease ; Humans ; Infant ; Infant, Newborn ; Male ; Neoplasms/diagnosis/*genetics ; *Polymorphism, Single Nucleotide ; Proto-Oncogene Proteins c-mdm2/*genetics ; Real-Time Polymerase Chain Reaction ; Risk Assessment ; Sensitivity and Specificity ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: While leukocyte telomere length has been linked with altered risk in adult cancer, limited information is available on its association with risk in pediatric solid tumors. We investigated the association of telomeric alterations with risk of pediatric solid tumors. We also investigated whether altered telomeres cooperated with the TP53 rs1042522, MDM2 rs2279744 and CDKN1A (p21[cip1]) rs1059234 single-nucleotide polymorphisms to modify cancer risk.<br><br>METHODS: A total of 101 tumor patients and 202 controls were recruited for this age- and gender-matched case-control study. Relative telomere length (RTL) was determined in peripheral blood leukocytes using quantitative real-time polymerase chain reaction (PCR), and the polymorphisms were genotyped using PCR-restriction fragment length polymorphism.<br><br>RESULTS: Using median RTL in the healthy controls as a cut-off, children with longer telomeres were at an increased risk of developing a solid tumor (OR, 2.70; P&#xa0;<&#xa0;0.01). When participants were categorized according to control RTL quartiles, a significant dose-response relationship was observed (&#x3c7;[2] &#xa0;=&#xa0;10.95; P&#xa0;<&#xa0;0.001). The risk for tumors increased nearly threefold (P&#xa0;=&#xa0;0.001) for the triple interaction RTL &#xd7; TP53 rs1042522&#xa0;&#xd7;&#xa0;p21[cip1] rs1059234 compared with the maximum effect of any single factor, although the interaction effect was less than additive. The MDM2 rs2279744 GG genotype reduced pediatric solid tumor risk significantly (OR, 0.51).<br><br>CONCLUSION: Combined analysis of telomeres and genetic polymorphisms in the TP53 pathway can provide important clues to understanding pediatric solid tumor etiology.},
}
@article {pmid31209959,
year = {2019},
author = {Ramos-Ibeas, P and Pericuesta, E and Peral-Sanchez, I and Heras, S and Laguna-Barraza, R and Pérez-Cerezales, S and Gutiérrez-Adán, A},
title = {Longitudinal analysis of somatic and germ-cell telomere dynamics in outbred mice.},
journal = {Molecular reproduction and development},
volume = {86},
number = {8},
pages = {1033-1043},
doi = {10.1002/mrd.23218},
pmid = {31209959},
issn = {1098-2795},
mesh = {Animals ; Animals, Outbred Strains ; Female ; Male ; Mice ; Oocytes/*metabolism ; Spermatozoa/*metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Although telomere length (TL) shortens with age in most tissues, an age-related increase in length has been described in sperm through a mechanism that is not yet fully understood. Changes in TL with age in the same individual have not been explored. This longitudinal study examines TL dynamics in somatic tissue and gametes during an entire lifespan in an outbred mouse population (from 8 to up to 114 weeks of age). Our findings indicate a reduced life expectancy in males compared to females (84.75 ± 9.23 vs. 113.16 ± 0.20 weeks) and significant variability in TL dynamics between individuals. While with aging, a clear reduction in TL was produced in somatic cells and oocytes, telomeres in sperm cells significantly lengthened. Finally, we found evidence indicating that telomere elongation in sperm during aging may be dependent on different mechanisms, such as the survival of spermatogonia with longer telomeres and the alternative lengthening of telomeres mechanism in meiotic and postmeiotic spermatogenic cells.},
}
@article {pmid31207547,
year = {2019},
author = {Gong, P and Wang, H and Zhang, J and Fu, Y and Zhu, Z and Wang, J and Yin, Y and Wang, H and Zhou, Z and Yang, J and Liu, L and Gou, M and Zeng, M and Yuan, J and Wang, F and Pan, X and Xiang, R and Weissman, SM and Qi, F and Liu, L},
title = {Telomere Maintenance-Associated PML Is a Potential Specific Therapeutic Target of Human Colorectal Cancer.},
journal = {Translational oncology},
volume = {12},
number = {9},
pages = {1164-1176},
pmid = {31207547},
issn = {1936-5233},
abstract = {Telomere length maintenance is essential for cell proliferation, which is particularly prominent in cancer. We validate that the primary colorectal tumors exhibit heterogeneous telomere lengths but mostly (90%) short telomeres relative to normal tissues. Intriguingly, relatively short telomeres are associated with tumor malignancy as indicated by poorly differentiated state, and these tumors contain more cancer stem-like cells (CSLCs) identified by several commonly used markers CD44, EPHB2 or LGR5. Moreover, promyelocytic leukemia (PML) and ALT-associated PML nuclear bodies (APBs) are frequently found in tumors with short telomeres and high proliferation. In contrast, distant normal tissues rarely or only minimally express PML. Inhibition of PML and APBs by an ATR inhibitor decreases proliferation of CSLCs and organoids, suggesting a potential therapeutic target to progressive colorectal tumors. Together, telomere maintenance underling tumor progression is connected with CSLCs.},
}
@article {pmid31204167,
year = {2019},
author = {Guérin, TM and Béneut, C and Barinova, N and López, V and Lazar-Stefanita, L and Deshayes, A and Thierry, A and Koszul, R and Dubrana, K and Marcand, S},
title = {Condensin-Mediated Chromosome Folding and Internal Telomeres Drive Dicentric Severing by Cytokinesis.},
journal = {Molecular cell},
volume = {75},
number = {1},
pages = {131-144.e3},
doi = {10.1016/j.molcel.2019.05.021},
pmid = {31204167},
issn = {1097-4164},
mesh = {Adenosine Triphosphatases/*genetics/metabolism ; Chromosome Breakpoints ; Chromosomes, Fungal/*metabolism/ultrastructure ; Cytokinesis/genetics ; DNA, Fungal/*genetics/metabolism ; DNA-Binding Proteins/*genetics/metabolism ; Gene Expression ; Karyotype ; Models, Genetic ; Multiprotein Complexes/*genetics/metabolism ; Saccharomyces cerevisiae/*genetics/metabolism/ultrastructure ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Shelterin Complex ; Telomere/*metabolism/ultrastructure ; Telomere-Binding Proteins/*genetics/metabolism ; Transcription Factors/*genetics/metabolism ; },
abstract = {In Saccharomyces cerevisiae, dicentric chromosomes stemming from telomere fusions preferentially break at the fusion. This process restores a normal karyotype and protects chromosomes from the detrimental consequences of accidental fusions. Here, we address the molecular basis of this rescue pathway. We observe that tandem arrays tightly bound by the telomere factor Rap1 or a heterologous high-affinity DNA binding factor are sufficient to establish breakage hotspots, mimicking telomere fusions within dicentrics. We also show that condensins generate forces sufficient to rapidly refold dicentrics prior to breakage by cytokinesis and are essential to the preferential breakage at telomere fusions. Thus, the rescue of fused telomeres results from a condensin- and Rap1-driven chromosome folding that favors fusion entrapment where abscission takes place. Because a close spacing between the DNA-bound Rap1 molecules is essential to this process, Rap1 may act by stalling condensins.},
}
@article {pmid31203557,
year = {2019},
author = {Sutanto, SSI and McLennan, SV and Keech, AC and Twigg, SM},
title = {Shortening of telomere length by metabolic factors in diabetes: protective effects of fenofibrate.},
journal = {Journal of cell communication and signaling},
volume = {13},
number = {4},
pages = {523-530},
pmid = {31203557},
issn = {1873-9601},
abstract = {People with diabetes mellitus have shorter telomeres compared with non-diabetic subjects. The aim of this study was to investigate an in-vitro model of telomere shortening under diabetes metabolic conditions. The mechanisms of the accelerated telomere length attrition and the potential telomere protective action of fenofibrate with related cellular mechanisms were also examined. Human dermal fibroblasts were passaged and cultured in normal (5.5 mM) or high (25 mM) D-glucose, across 7 days with hydrogen peroxide (H2O2), glucosamine (GA), or glycated albumin (AGEs-BSA). Relative telomere length (RTL) was determined by qPCR. The expression of shelterin complex members which regulate telomere stability were measured by qRT-PCR and Western immunoblot. Culture in high glucose decreased RTL compared with normal glucose: H2O2 and GA lowered the RTL after 7 days (each P < 0.05 vs untreated control), whereas AGEs-BSA had no effect compared with control-BSA. At day 7 the mRNA levels of most shelterin complex members, were induced by H2O2 and to a lesser extent by GA. Trf1 and Trf2 protein were induced by H2O2. Co-treatment with fenofibrate (100 μM) significantly attenuated the reduction in RTL caused by H2O2 and GA and prevented Trf induction by H2O2. However knockdown of Trf1 and Trf2 expression using specific siRNA did not prevent H2O2 effects to lower RTL, thus implicating factors other than these Trfs alone in the fenofibrate protection against the H2O2 induction of RTL lowering. These in vitro findings demonstrate that diabetic conditions can induce telomere shortening and that fenofibrate has protective effects on telomere attrition, through as yet undefined mechanisms.},
}
@article {pmid31202459,
year = {2019},
author = {Miura, A and Matsuura, A},
title = {Phosphatase-dependent fluctuations in DNA-damage checkpoint activation at partially defective telomeres.},
journal = {Biochemical and biophysical research communications},
volume = {516},
number = {1},
pages = {133-137},
doi = {10.1016/j.bbrc.2019.06.030},
pmid = {31202459},
issn = {1090-2104},
mesh = {*DNA Damage ; DNA, Fungal/genetics ; Gene Deletion ; Gene Expression Regulation, Fungal ; Phosphoprotein Phosphatases/*genetics ; Saccharomyces cerevisiae/cytology/*genetics ; Saccharomyces cerevisiae Proteins/*genetics ; Telomere/*genetics ; *Telomere Shortening ; },
abstract = {Telomeres protect the ends of eukaryotic chromosomes, and telomere shortening causes irreversible cell-cycle arrest through activation of the DNA-damage checkpoint. In this study, we found that deletion of PPH3, encoding a 2A-like protein phosphatase, accelerated telomere-shortening-mediated senescence without affecting normal telomere length or the telomere erosion rate in Saccharomyces cerevisiae. Moreover, the loss of PPH3 increased sensitivity to telomere dysfunction. The detection of telomere abnormalities by DNA-damage sensors was not an all-or-none response, implying that Pph3 helps determine the border between normal and dysfunctional telomeres by suppressing premature activation of the DNA-damage checkpoint.},
}
@article {pmid31200515,
year = {2019},
author = {Donati, B and Ciarrocchi, A},
title = {Telomerase and Telomeres Biology in Thyroid Cancer.},
journal = {International journal of molecular sciences},
volume = {20},
number = {12},
pages = {},
pmid = {31200515},
issn = {1422-0067},
mesh = {Animals ; Biomarkers, Tumor/*genetics ; Humans ; Mutation ; Telomerase/*genetics/metabolism ; *Telomere Homeostasis ; Thyroid Neoplasms/*genetics/pathology ; },
abstract = {Telomere and telomerase regulation contributes to the onset and evolution of several tumors, including highly aggressive thyroid cancers (TCs). TCs are the most common endocrine malignancies and are generally characterized by a high rate of curability. However, a small but significant percentage develops distant metastasis or progresses into undifferentiated forms associated with bad prognosis and for which poor therapeutic options are available. Mutations in telomerase reverse transcriptase (TERT) promoter are among the most credited prognostic marker of aggressiveness in TCs. Indeed, their frequency progressively increases passing from indolent lesions to aggressive and anaplastic forms. TERT promoter mutations create binding sites for transcription factors, increasing TERT expression and telomerase activity. Furthermore, aggressiveness of TCs is associated with TERT locus amplification. These data encourage investigating telomerase regulating pathways as relevant drivers of TC development and progression to foster the identification of new therapeutics targets. Here, we summarize the current knowledge about telomere regulation and TCs, exploring both canonical and less conventional pathways. We discuss the possible role of telomere homeostasis in mediating response to cancer therapies and the possibility of using epigenetic drugs to re-evaluate the use of telomerase inhibitors. Combined treatments could be of support to currently used therapies still presenting weaknesses.},
}
@article {pmid31198785,
year = {2019},
author = {Xu, X and Hu, H and Lin, Y and Huang, F and Ji, H and Li, Y and Lin, S and Chen, X and Duan, S},
title = {Differences in Leukocyte Telomere Length between Coronary Heart Disease and Normal Population: A Multipopulation Meta-Analysis.},
journal = {BioMed research international},
volume = {2019},
number = {},
pages = {5046867},
pmid = {31198785},
issn = {2314-6141},
mesh = {Coronary Disease/*metabolism/pathology ; Female ; Humans ; Male ; Severity of Illness Index ; Telomere/*metabolism/pathology ; *Telomere Shortening ; },
abstract = {Coronary heart disease (CHD) is one of the most common causes of death in the world. Numerous studies have shown that as the degree of atherosclerotic disease increases, leukocyte telomere length gradually decreases. Short telomeres increase the risk of all-cause death and cardiovascular death. However, the reported results are not consistent, since the experimental design method, the measurement method, and the disease outcome are different. Therefore, we searched five major literature databases (Pubmed, Web of science, Embase, CNKI, and Wangfang) and finally included 18 eligible articles (including 5,150 patients with CHD and 9341 controls). We found that telomere length in patients with CHD was significantly shorter than that in controls, and the telomere length was inversely correlated with the severity of CHD. Subgroup analysis showed that telomere shortening was the most significant in Asian patients with CHD, in CHD patients with an average age <65 years, and in men with CHD. The mechanism of shortening the telomere length leading to the occurrence and development of CHD is worthy of further study.},
}
@article {pmid31196315,
year = {2019},
author = {Zhang, Y and Guo, Y and Zhou, G and Li, S},
title = {Regulation of Telomere Length and Atherosclerosis by Protection of Telomeres 1 Protein.},
journal = {Journal of nanoscience and nanotechnology},
volume = {19},
number = {12},
pages = {7953-7959},
doi = {10.1166/jnn.2019.16938},
pmid = {31196315},
issn = {1533-4899},
mesh = {*Atherosclerosis/genetics ; DNA ; Humans ; Leukocytes ; *Neoplasms ; Telomere/genetics ; },
abstract = {The aim of this study was to investigate the manifestation and significance of changes in both telomere length and the expression of human telomere protective protein (hPOT1) in the peripheral blood leukocytes of patients with atherosclerosis (AS). One hundred subjects-excluding those with acute or chronic inflammation, cancer, and autoimmune diseases-were enrolled in this study and divided into two groups: the atherosclerosis group (AS group) and control group. We extracted peripheral blood leukocyte DNA along with its peripheral proteins. After purity testing, a digoxigeninlabeled telomere probe was used for Southern blotting; the length of the telomeres was obtained by image scanning and software analysis. After extracting the peripheral proteins, hPOT1 expression was detected by western blotting and scanned with an image analysis software system. We found that the telomere lengths in the peripheral blood leukocytes of AS and control groups were 7.45 ± 1.15 kb versus 8.11 ± 0.69 kb, respectively, and that the difference between them was statistically significant (p < 0.005). The expression level of hPOT1 protein in the peripheral blood leukocytes of the AS group was significantly higher than that of the control group (t = 3.77, p < 0.01). As can be determined from these results, telomere length in the peripheral blood leukocytes of AS patients was significantly shorter compared with that of the control group. The regulation of telomere length by hPOT1 by negative regulation may be one of the influencing factors in AS. Therefore, it is suggested that change in telomere length may play a role in the occurrence and development of AS.},
}
@article {pmid31194209,
year = {2019},
author = {Zhang, Y and Hua, RN and Xiang, D and Zhang, CY},
title = {Single-molecule counting of oxidative DNA damage in telomeres from cancer cells.},
journal = {Chemical communications (Cambridge, England)},
volume = {55},
number = {53},
pages = {7627-7630},
doi = {10.1039/c9cc03766g},
pmid = {31194209},
issn = {1364-548X},
mesh = {DNA Damage ; DNA, Neoplasm/*drug effects ; Dose-Response Relationship, Drug ; HeLa Cells ; Humans ; Hydrogen Peroxide/*pharmacology ; Oxidation-Reduction ; Structure-Activity Relationship ; Telomere/*drug effects ; },
abstract = {We demonstrate for the first time the single-molecule counting of oxidative DNA damage in telomeres from a human cervical carcinoma cell line (HeLa cells). This method exhibits high sensitivity towards oxidative DNA damage with a detection limit as low as 9.3 × 10[-17] M and good discrimination capability down to the 0.001% oxidative damage level. Moreover, this method can quantify the number of oxidative damaged bases (34-44) in telomeres in each HeLa cell treated with 1000 μM H2O2.},
}
@article {pmid31193582,
year = {2019},
author = {Khan, RJ and Gebreab, SY and Gaye, A and Crespo, PR and Xu, R and Davis, SK},
title = {Associations of smoking indicators and cotinine levels with telomere length: National Health and Nutrition Examination Survey.},
journal = {Preventive medicine reports},
volume = {15},
number = {},
pages = {100895},
pmid = {31193582},
issn = {2211-3355},
abstract = {The influence of smoking exposure on telomere length with a focus on the impact of race has rarely been discussed. We performed a cross sectional analysis into the associations of smoking indicators with leukocyte telomere length (LTL) by race among 5864 nationally representative sample of US adults (≥20 years). Data from 1999 to 2002 National Health and Nutrition Examination Survey was used for the analysis. Smoking indicators were assessed by interviews and serum cotinine levels. LTL was quantified by polymerase chain reaction. Multiple linear regressions were used to assess the association with adjustment for covariates, sample weights and design effects separately for Whites, Blacks and Mexican Americans. The intensity of smoking, measured by the average number of cigarettes consumed per day, was negatively associated with LTL among Whites (β: -3.87, 95% CI: -5.98 to -1.21) and among Blacks (β: -15.46, 95% CI: -29.79 to -2.12) participants. Compared with cotinine level < 0.05 ng/ml, cotinine level ≥3 ng/ml was associated with shorter LTL (β: -77.92, 95% CI = -143.05 to -11.70) among Whites, but not among Blacks. We found increased number of cigarette consumption to be associated with shorter LTL in both Blacks and Whites, indicating that the impact of smoking on life-shortening diseases could partly be explained by telomere biology. Increased cotinine concentration however, was associated with shorter LTL only among Whites, not among Blacks. This differential relationship that we observed may have implications in interpreting cotinine as an objective biomarker of smoking exposure across races and warrant additional prospective investigation.},
}
@article {pmid31191531,
year = {2019},
author = {Cao, D and Zhao, J and Nguyan, LN and Nguyen, LNT and Khanal, S and Dang, X and Schank, M and Chand Thakuri, BK and Wu, XY and Morrison, ZD and El Gazzar, M and Zou, Y and Ning, S and Wang, L and Moorman, JP and Yao, ZQ},
title = {Disruption of Telomere Integrity and DNA Repair Machineries by KML001 Induces T Cell Senescence, Apoptosis, and Cellular Dysfunctions.},
journal = {Frontiers in immunology},
volume = {10},
number = {},
pages = {1152},
pmid = {31191531},
issn = {1664-3224},
support = {S10 OD021572/OD/NIH HHS/United States ; I01 BX004281/BX/BLRD VA/United States ; R01 CA219342/CA/NCI NIH HHS/United States ; I01 BX002670/BX/BLRD VA/United States ; R21 AI138598/AI/NIAID NIH HHS/United States ; R01 AI114748/AI/NIAID NIH HHS/United States ; R15 AI143377/AI/NIAID NIH HHS/United States ; },
mesh = {Adult ; Aged ; Apoptosis/drug effects ; Arsenites/*pharmacology ; CD4-Positive T-Lymphocytes/*drug effects/physiology ; Cell Proliferation/drug effects ; Cells, Cultured ; Cellular Senescence/drug effects ; Coculture Techniques ; Cytokines/immunology ; DNA Damage ; DNA Repair/*drug effects ; Female ; HIV Infections/immunology ; Hepatitis C/immunology ; Humans ; Male ; Middle Aged ; Sodium Compounds/*pharmacology ; Telomere/*drug effects ; },
abstract = {T cells in chronic viral infections are featured by premature aging with accelerated telomere erosion, but the mechanisms underlying telomere attrition remain unclear. Here, we employed human CD4 T cells treated with KML001 (a telomere-targeting drug) as a model to investigate the role of telomere integrity in remodeling T cell senescence. We demonstrated that KML001 could inhibit cell proliferation, cytokine production, and promote apoptosis via disrupting telomere integrity and DNA repair machineries. Specifically, KML001-treated T cells increased dysfunctional telomere-induced foci (TIF), DNA damage marker γH2AX, and topoisomerase cleavage complex (TOPcc) accumulation, leading to telomere attrition. Mechanistically, KML001 compromised telomere integrity by inhibiting telomeric repeat binding factor 2 (TRF2), telomerase, topoisomerase I and II alpha (Top1/2a), and ataxia telangiectasia mutated (ATM) kinase activities. Importantly, these KML001-induced telomeric DNA damage and T cell senescent phenotype and machineries recapitulated our findings in patients with clinical HCV or HIV infection in that their T cells were also senescent with short telomeres and thus more vulnerable to KML001-induced apoptosis. These results shed new insights on the T cell aging network that is critical and essential in protecting chromosomal telomeres from unwanted DNA damage and securing T cell survival during cell crisis upon genomic insult.},
}
@article {pmid31191214,
year = {2019},
author = {Bürgin, D and O'Donovan, A and d'Huart, D and di Gallo, A and Eckert, A and Fegert, J and Schmeck, K and Schmid, M and Boonmann, C},
title = {Adverse Childhood Experiences and Telomere Length a Look Into the Heterogeneity of Findings-A Narrative Review.},
journal = {Frontiers in neuroscience},
volume = {13},
number = {},
pages = {490},
pmid = {31191214},
issn = {1662-4548},
support = {K01 MH109871/MH/NIMH NIH HHS/United States ; },
abstract = {Background: Adverse childhood experiences (ACEs) have been associated with poor mental and somatic health. Accumulating evidence indicates that accelerated biological aging-indexed by altered telomere-related markers-may contribute to associations between ACEs and negative long-term health outcomes. Telomeres are repeated, non-coding deoxyribonucleic acid (DNA) sequences at the end of chromosomes. Telomeres shorten during repeated cell divisions over time and are being used as a marker of biological aging. Objectives: The aim of the current paper is to review the literature on the relationship between ACEs and telomere length (TL), with a specific focus on how the heterogeneity of sample and ACEs characteristics lead to varying associations between ACEs and TL. Methods: Multiple databases were searched for relevant English peer-reviewed articles. Thirty-eight papers were found to be eligible for inclusion in the current review. Results: Overall, the studies indicated a negative association between ACEs and TL, although many papers presented mixed findings and about a quarter of eligible studies found no association. Studies with smaller sample sizes more often reported significant associations than studies with larger samples. Also, studies reporting on non-clinical and younger samples more often found associations between ACEs and TL compared to studies with clinical and older samples. Reviewing the included studies based on the "Stressor Exposure Characteristics" recently proposed by Epel et al. (2018) revealed a lack of detailed information regarding ACEs characteristics in many studies. Conclusion: Overall, it is difficult to achieve firm conclusions about associations of ACEs with TL due to the heterogeneity of study and ACE characteristics and the heterogeneity in reported findings. The field would benefit from more detailed descriptions of study samples and measurement of ACEs.},
}
@article {pmid31188416,
year = {2019},
author = {Shah, A and Shah, J},
title = {Concerning Greater Social Contexts in Bariatric Surgery Availability and Telomere Length Outcomes.},
journal = {JAMA surgery},
volume = {154},
number = {9},
pages = {884},
doi = {10.1001/jamasurg.2019.1717},
pmid = {31188416},
issn = {2168-6262},
mesh = {*Bariatric Surgery ; *Gastric Bypass ; Humans ; *Laparoscopy ; Obesity ; Telomere ; },
}
@article {pmid31188413,
year = {2019},
author = {Morton, J and Garg, T and Leva, N},
title = {Concerning Greater Social Contexts in Bariatric Surgery Availability and Telomere Length Outcomes-Reply.},
journal = {JAMA surgery},
volume = {154},
number = {9},
pages = {884},
doi = {10.1001/jamasurg.2019.1727},
pmid = {31188413},
issn = {2168-6262},
mesh = {*Bariatric Surgery ; *Gastric Bypass ; Humans ; *Laparoscopy ; Obesity ; Telomere ; },
}
@article {pmid31186623,
year = {2019},
author = {Willis, M and Staudinger, UM and Factor-Litvak, P and Calvo, E},
title = {Stress and Salivary Telomere Length in the Second Half of Life: A Comparison of Life-course Models.},
journal = {Advances in life course research},
volume = {39},
number = {},
pages = {34-41},
pmid = {31186623},
issn = {1879-6974},
support = {T32 ES023772/ES/NIEHS NIH HHS/United States ; },
mesh = {Adverse Childhood Experiences/*statistics &amp; numerical data ; Aged ; Child ; Female ; Humans ; Life Change Events ; Male ; Risk Factors ; *Saliva ; Stress, Psychological/*psychology ; Surveys and Questionnaires ; Telomere/*genetics ; },
abstract = {BACKGROUND: Previous research has explored the relationship between childhood and adulthood stressful life events (SLEs) and adult salivary telomere length (TL), but no research to date has tested different life-course models in which stress in adulthood may fully, partly, or not mediate the relationship between childhood stress and adult TL.<br><br>METHODS: To fill this gap, we elaborate over previous work by Puterman et al. (2016) and other standard models that do not account for the temporal order of stressors in childhood and adulthood, by using structural equation modeling (SEM) for a sample of 5,754 Health and Retirement Study (HRS) participants to compare the fit of three nested life-course models-social trajectory, early critical period, and cumulative risk.<br><br>RESULTS: Results indicated that the social trajectory model, in which the association between childhood SLEs and TL in later adulthood is fully mediated by adulthood SLEs, fit the data better than the early critical period (no mediation) and cumulative risk (partial mediation) models.<br><br>CONCLUSION: In the social trajectory model, childhood SLEs are related to TL in later life only through adulthood SLEs. The direct physiological effect of childhood SLEs on TL in later life would be overestimated if adulthood SLEs are overlooked.},
}
@article {pmid31186510,
year = {2019},
author = {Weng, Q and Deng, K and Wu, F and Gan, M and Li, J and Dai, Y and Jiang, Y and Chen, J and Dai, J and Ma, H and Hu, Z and Shen, H and Du, J and Hu, Y and Jin, G},
title = {Leukocyte telomere length, lipid parameters and gestational diabetes risk: a case-control study in a Chinese population.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {8483},
pmid = {31186510},
issn = {2045-2322},
mesh = {Adult ; *Asian People ; Case-Control Studies ; Diabetes, Gestational/*blood ; Female ; Humans ; Lipids/*blood ; Pregnancy ; Risk Factors ; *Telomere Homeostasis ; },
abstract = {Telomere length (TL) is linked to various age-related diseases, but little is known about telomeres in gestational diabetes mellitus (GDM). We surveyed 509 subjects (113 GDM patients and 396 frequency matched controls) in Nanjing Drum Tower Hospital, Jiangsu province of eastern China. Relative telomere length (RTL) of genomic DNA extracted from peripheral blood leukocytes was measured using quantitative polymerase chain reaction (qPCR). Odds ratios (OR) and 95% confidence interval (CI) of GDM risk were calculated across tertiles of RTL using logistic regression model. Lipid parameters during the third trimesters of gestation (after 32 weeks) were collected from medical records. The general linear correlation test was used to explore the associations of lipid parameters with RTL. Our results showed that the RTL in GDM patients were significantly shorter than controls (0.302 ± 0.112 vs. 0.336 ± 0.164, P = 0.046). However, the GDM risk was significantly increased in subjects with median RTL (adjusted OR [aOR]: 1.936, 95% CI: 1.086, 3.453, P = 0.025) and the shortest RTL (aOR: 1.795, 95% CI: 1.004, 3.207, P = 0.048), compared to subjects with longest RTL. We also demonstrated that the lipid ratios (TC/TG, LDL/TG, HDL/TG, LDL/TC, TC/LDL) were significantly associated with RTL among controls. Overall, the present study indicated that attrition of telomeres would increase GDM risk among pregnant women, and the altered lipid levels may play an important role in RTL related GDM risk and pathogenesis.},
}
@article {pmid31173155,
year = {2019},
author = {Vasilopoulos, E and Fragkiadaki, P and Kalliora, C and Fragou, D and Docea, AO and Vakonaki, E and Tsoukalas, D and Calina, D and Buga, AM and Georgiadis, G and Mamoulakis, C and Makrigiannakis, A and Spandidos, DA and Tsatsakis, A},
title = {The association of female and male infertility with telomere length (Review).},
journal = {International journal of molecular medicine},
volume = {44},
number = {2},
pages = {375-389},
pmid = {31173155},
issn = {1791-244X},
mesh = {Aging ; Female ; Humans ; Infertility, Female/etiology/*genetics/pathology ; Infertility, Male/etiology/*genetics/pathology ; Male ; Telomere/genetics ; *Telomere Shortening ; },
abstract = {Telomere length (TL) has long been associated with aging, as telomeres serve as protective caps of chromosomes, and are thus deeply involved in the preservation of genome integrity and are vital to cellular functions. Traditionally, a strong link connects aging and infertility in both sexes, with an earlier onset in females. Over the past decade, telomeres have attracted increasing attention due to the role they play in fertility. In this review, we investigated the potential positive or negative association between relative TL and different factors of female and male infertility. A systematic search of the PubMed database was conducted. Out of the 206 studies identified, 45 were reviewed as they fulfilled the criteria of validity and relevance. Following an analysis and a comparison of the study outcomes, several clear trends were observed. The majority of female infertility factors were associated with a shorter TL, with the exception of endometriosis, premature ovarian failure and clear cell carcinoma that were associated with a longer TL and polycystic ovary syndrome (PCOS), which revealed conflicting results among several studies, leading to ambiguous conclusions. Male infertility factors were associated with a shorter TL. Although this review can provide an outline of general trends in the association of TL with infertility factors, further epidemiological and original research studies are required to focus on investigating the basis of these varying lengths of telomeres.},
}
@article {pmid31171785,
year = {2019},
author = {Dorajoo, R and Chang, X and Gurung, RL and Li, Z and Wang, L and Wang, R and Beckman, KB and Adams-Haduch, J and M, Y and Liu, S and Meah, WY and Sim, KS and Lim, SC and Friedlander, Y and Liu, J and van Dam, RM and Yuan, JM and Koh, WP and Khor, CC and Heng, CK},
title = {Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies.},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {2491},
pmid = {31171785},
issn = {2041-1723},
support = {R01 CA144034/CA/NCI NIH HHS/United States ; UM1 CA182876/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Asian People/*genetics ; Cohort Studies ; DNA Repair/*genetics ; Female ; Genome-Wide Association Study ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Prospective Studies ; Respiratory Tract Infections/genetics ; Singapore ; Telomere/*metabolism ; Telomere Homeostasis/*genetics ; White People/genetics ; Young Adult ; },
abstract = {Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci (P < 5 × 10[-8]). Several of these contain candidate genes (TINF2, PARP1, TERF1, ATM and POT1) with potential roles in telomere biology and DNA repair mechanisms. Meta-analyses with additional 37,505 European individuals reveals six more genome-wide loci, including associations at MPHOSPH6, NKX2-3 and TYMS. We demonstrate that longer LTL associates with protection against respiratory disease mortality [HR = 0.854(0.804-0.906), P = 1.88 × 10[-7]] in the Singaporean Chinese samples. We further show that the LTL reducing SNP rs7253490 associates with respiratory infections (P = 7.44 × 10[-4]) although this effect may not be strongly mediated through LTL. Our data expands on the genetic basis of LTL and may indicate on a potential role of LTL in immune competence.},
}
@article {pmid31171703,
year = {2019},
author = {Min, J and Wright, WE and Shay, JW},
title = {Clustered telomeres in phase-separated nuclear condensates engage mitotic DNA synthesis through BLM and RAD52.},
journal = {Genes &amp; development},
volume = {33},
number = {13-14},
pages = {814-827},
pmid = {31171703},
issn = {1549-5477},
support = {C06 RR030414/RR/NCRR NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Motifs ; Cell Line, Tumor ; Cell Nucleus/*metabolism ; DNA/*biosynthesis ; Gene Expression ; Humans ; Leukemia, Promyelocytic, Acute/genetics/*physiopathology ; *Mitosis ; Phenotype ; Protein Transport ; Rad52 DNA Repair and Recombination Protein/*metabolism ; RecQ Helicases/*metabolism ; SUMO-1 Protein/metabolism ; Telomere/genetics/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. One of the hallmarks of ALT cancer is the excessively clustered telomeres in promyelocytic leukemia (PML) bodies, represented as large bright telomere foci. Here, we present a model system that generates telomere clustering in nuclear polySUMO (small ubiquitin-like modification)/polySIM (SUMO-interacting motif) condensates, analogous to PML bodies, and thus artificially engineered ALT-associated PML body (APB)-like condensates in vivo. We observed that the ALT-like phenotypes (i.e., a small fraction of heterogeneous telomere lengths and formation of C circles) are rapidly induced by introducing the APB-like condensates together with BLM through its helicase domain, accompanied by ssDNA generation and RPA accumulation at telomeres. Moreover, these events lead to mitotic DNA synthesis (MiDAS) at telomeres mediated by RAD52 through its highly conserved N-terminal domain. We propose that the clustering of large amounts of telomeres in human cancers promotes ALT that is mediated by MiDAS, analogous to Saccharomyces cerevisiae type II ALT survivors.},
}
@article {pmid31170852,
year = {2021},
author = {Myers, KO and Ibrahimou, B and Yusuf, KK and Mauck, DE and Salihu, HM},
title = {The effect of maternal vitamin C intake on fetal telomere length.},
journal = {The journal of maternal-fetal &amp; neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians},
volume = {34},
number = {7},
pages = {1143-1148},
doi = {10.1080/14767058.2019.1628940},
pmid = {31170852},
issn = {1476-4954},
mesh = {Adult ; Ascorbic Acid ; Female ; *Fetal Blood ; Fetus ; Humans ; Pregnancy ; Prospective Studies ; *Telomere ; Telomere Shortening ; },
abstract = {BACKGROUND: A telomere is a nucleoprotein structure that is located at the end of a chromosome. Reduced telomere length manifests as physical ailments such as the increased risk of age-related illnesses. These age-related illnesses include heart disease and failure. Telomere length has been studied extensively in adults; however, limited information exists regarding maternal dietary influences on fetal telomere length.<br><br>OBJECTIVES: The objective of this study is to investigate the relationship between maternal vitamin C intake and fetal telomere length.<br><br>METHODS: Data for this analysis were collected as part of a prospective cohort study that recruited pregnant women upon admission into labor and delivery. Umbilical cord serum was collected for 96 maternal-fetal dyads, and DNA analysis was performed using a quantitative polymerase chain reaction. The telomere to single copy gene ratio method was used to determine telomere length, and maternal vitamin C intake was measured using the Dietary History Questionnaire (DHQ). Statistical analysis was conducted using generalized linear modeling-based analyses.<br><br>RESULTS: The linear model indicates that maternal vitamin C intake (OR = 1.0032, 95%CI: 1.0014-1.0052, p&#x2009;&#x2264;&#x2009;.05) was positively associated with fetal telomere length. BMI (OR = 1.1096, 95%CI: 1.0619-1.1660, p&#x2009;&#x2264;&#x2009;.05) had a significant positive association with fetal telomere length while sodium intake was negatively associated with this outcome (OR = 0.9997, 95%CI: 0.9995-0.9998, p&#x2009;&#x2264;&#x2009;.05). Black ethnicity had a significant negative association with fetal telomere length (OR = 0.0186, 95%CI: 0.0031-0.0824, p&#x2009;&#x2264;&#x2009;.05).<br><br>CONCLUSIONS: Our study shows a positive association between maternal vitamin C intake and fetal telomere length. These findings may provide a method of understanding and preventing adult-onset disease and mortality through intrauterine reprograming.},
}
@article {pmid31170457,
year = {2019},
author = {Araújo Carvalho, AC and Tavares Mendes, ML and da Silva Reis, MC and Santos, VS and Tanajura, DM and Martins-Filho, PRS},
title = {Telomere length and frailty in older adults-A systematic review and meta-analysis.},
journal = {Ageing research reviews},
volume = {54},
number = {},
pages = {100914},
doi = {10.1016/j.arr.2019.100914},
pmid = {31170457},
issn = {1872-9649},
mesh = {Aged ; *Aging ; Biomarkers ; Female ; *Frail Elderly ; Frailty/*genetics ; Humans ; Male ; *Telomere Shortening ; },
abstract = {Telomere shortening has been proposed as a potentially useful biomarker of human ageing and age-related morbidity and mortality. We performed a systematic review and meta-analysis to summarize results from individual studies on the telomere length according to the frailty status and frailty index in older adults. We searched the PubMed, SCOPUS and Web of Science databases to identify studies that evaluated the telomere length in frail and non-frail older adults and the relationship between telomere length and frailty index score. We used the base pairs (bp) as a measure of the telomere length. Summary estimates were calculated using random-effects models. Nine studies were included in the present systematic review and a total of 10,079 older adults were analyzed. We found that the frail older adults (n = 355) had shorter telomeres than the non-frail (n = 1894) (Standardized Mean Difference [SMD] -0.41; 95% CI -0.73 to -0.09; P = 0.01; I[2] = 82%). Significant differences in telomere length between frail and non-frail older adults were identified in Hispanic (SMD -1.31; 95% CI -1.71 to -0.92; P < 0.0001; I[2] = 0%) but not in Non-Hispanic countries (SMD -0.13; 95% CI -0.26 to 0.00; P = 0.06; I[2] = 0%). Similar results were found in the adjusted meta-analysis (SMD -0.56; 95% -1.12 to 0.00; P = 0.05; I[2] = 85%). A significant but weak relationship was found between telomere length and frailty index analyzing 8244 individuals (SMD -0.06; 95% IC -0.10 to 0.01; P = 0.01; I[2] = 0%). The current available evidence suggests that telomere length may be not a meaningful biomarker for frailty. Because the potential influence of ethnicity in shortening of telomeres and decline in physiologic reserves associated with aging, additional multiethnic studies are needed.},
}
@article {pmid31169183,
year = {2019},
author = {Mantuano, E and Peconi, M and Scarabino, D},
title = {Can leukocyte telomere shortening be a possible biomarker to track Huntington's disease progression?.},
journal = {Neural regeneration research},
volume = {14},
number = {10},
pages = {1709-1710},
pmid = {31169183},
issn = {1673-5374},
}
@article {pmid31169070,
year = {2020},
author = {Bansal, A and Kukreti, S},
title = {The four repeat Giardia lamblia telomere forms tetramolecular G-quadruplex with antiparallel topology.},
journal = {Journal of biomolecular structure &amp; dynamics},
volume = {38},
number = {7},
pages = {1975-1983},
doi = {10.1080/07391102.2019.1623074},
pmid = {31169070},
issn = {1538-0254},
mesh = {DNA ; *G-Quadruplexes ; *Giardia lamblia/genetics ; Humans ; Nucleic Acid Conformation ; Repetitive Sequences, Nucleic Acid/genetics ; Telomere/genetics ; },
abstract = {Guanine rich DNA sequences of regulatory genomic regions form secondary structures known as G-quadruplexes usually stabilized by tetrads of Hoogsteen hydrogen bonded guanines. The in vivo existence of G-quadruplexes ascertains their biological roles. Human telomeric repeats are the most studied G-rich sequences. The four repeat Giardia telomeric sequence (TAGGG)4 differs from its human counterpart (TTAGGG)4, by deletion of one T at the G-tract intervening site of each repeat. We show here that whilst the two repeat Giardia telomeric sequence (TAGGG)2 forms parallel and antiparallel quadruplexes with tetramolecular topology exclusively, the four repeat version (TAGGG)4 forms a tetramolecular (antiparallel) and unimolecular (parallel) quadruplexes in Na[+]. The tetramolecular (antiparallel) G-quadruplex formed by four repeats of Giardia telomeric sequence is stabilized by the additional Watson-Crick bonding between its intervening TA bases aligned in antiparallel fashion. Four stranded antiparallel quadruplex for four repeats of any telomeric sequence have not been characterized till date. We hypothesize that telomeric association in antiparallel fashion, (via G-overhangs to form tetramolecular quadruplex) could be a biologically relevant molecular event. Further, coexistence of Hoogsteen as well as Watson-Crick base pairing might give insight for recognition of conformationally diverse DNA structures by ligands. Communicated by Ramaswamy H. Sarma.},
}
@article {pmid31168464,
year = {2019},
author = {Park, WJ and Lee, JH},
title = {Positive correlation between telomere length and mitochondrial copy number in breast cancers.},
journal = {Annals of translational medicine},
volume = {7},
number = {8},
pages = {183},
pmid = {31168464},
issn = {2305-5839},
}
@article {pmid31165156,
year = {2019},
author = {Niedzwiedz, CL and Katikireddi, SV and Pell, JP and Smith, DJ},
title = {Sex differences in the association between salivary telomere length and multimorbidity within the US Health &amp; Retirement Study.},
journal = {Age and ageing},
volume = {48},
number = {5},
pages = {703-710},
pmid = {31165156},
issn = {1468-2834},
support = {MR/R024774/1/MRC_/Medical Research Council/United Kingdom ; U01 AG009740/AG/NIA NIH HHS/United States ; MC_UU_12017/13/MRC_/Medical Research Council/United Kingdom ; SPHSU13/CSO_/Chief Scientist Office/United Kingdom ; SPHSU15/CSO_/Chief Scientist Office/United Kingdom ; SCAF/15/02/CSO_/Chief Scientist Office/United Kingdom ; MC_PC_17217/MRC_/Medical Research Council/United Kingdom ; MC_UU_12017/15/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aged ; Aged, 80 and over ; Biomarkers/metabolism ; Cross-Sectional Studies ; Female ; Humans ; Lung Diseases/*epidemiology/metabolism ; Male ; Mental Disorders/*epidemiology/metabolism ; *Mental Health ; Middle Aged ; Multimorbidity ; Prospective Studies ; *Retirement ; Saliva/*metabolism ; Sex Factors ; Telomere/*metabolism ; United Kingdom/epidemiology ; },
abstract = {BACKGROUND: Telomere length is associated with several physical and mental health conditions, but whether it is a marker of multimorbidity is unclear. We investigated associations between telomere length and multimorbidity by sex.<br><br>METHODS: Data from adults (N = 5,495) aged &#x2265;50 years were taken from the US Health and Retirement Study (2008-14). Telomere length was measured in 2008 from salivary samples. The cross-sectional associations between telomere length and eight chronic health conditions were explored using logistic regression, adjusting for confounders and stratified by sex. Logistic, ordinal and multinomial regression models were calculated to explore relationships between telomere length and multimorbidity (using a binary variable and a sum of the number of health conditions) and the type of multimorbidity (no multimorbidity, physical multimorbidity, or multimorbidity including psychiatric problems). Using multilevel logistic regression, prospective relationships between telomere length and incident multimorbidity were also explored.<br><br>RESULTS: In cross-sectional analyses, longer telomeres were associated with reduced likelihood of lung disease and psychiatric problems among men, but not women. Longer telomeres were associated with lower risk of multimorbidity that included psychiatric problems among men (OR=0.521, 95% CI: 0.284 to 0.957), but not women (OR=1.188, 95% CI: 0.771 to 1.831). Prospective analyses suggested little association between telomere length and the onset of multimorbidity in men (OR=1.378, 95% CI: 0.931 to 2.038) nor women (OR=1.224, 95% CI: 0.825 to 1.815).<br><br>CONCLUSIONS: Although telomere length does not appear to be a biomarker of overall multimorbidity, further exploration of the relationships is merited particularly for multimorbidity including psychiatric conditions among men.},
}
@article {pmid31160377,
year = {2019},
author = {Eberhard, S and Valuchova, S and Ravat, J and Fulneček, J and Jolivet, P and Bujaldon, S and Lemaire, SD and Wollman, FA and Teixeira, MT and Riha, K and Xu, Z},
title = {Molecular characterization of Chlamydomonas reinhardtii telomeres and telomerase mutants.},
journal = {Life science alliance},
volume = {2},
number = {3},
pages = {},
pmid = {31160377},
issn = {2575-1077},
mesh = {Amino Acid Sequence ; Base Sequence ; Chlamydomonas reinhardtii/*genetics ; Genetic Variation ; Polymorphism, Restriction Fragment Length ; Repetitive Sequences, Nucleic Acid ; Telomerase/chemistry/*genetics/metabolism ; Telomere/*genetics ; Telomere Homeostasis ; Telomere Shortening ; },
abstract = {Telomeres are repeated sequences found at the end of the linear chromosomes of most eukaryotes and are required for chromosome integrity. Expression of the reverse-transcriptase telomerase allows for extension of telomeric repeats to counteract natural telomere shortening. Although Chlamydomonas reinhardtii, a photosynthetic unicellular green alga, is widely used as a model organism in photosynthesis and flagella research, and for biotechnological applications, the biology of its telomeres has not been investigated in depth. Here, we show that the C. reinhardtii (TTTTAGGG)n telomeric repeats are mostly nondegenerate and that the telomeres form a protective structure, with a subset ending with a 3' overhang and another subset presenting a blunt end. Although telomere size and length distributions are stable under various standard growth conditions, they vary substantially between 12 genetically close reference strains. Finally, we identify CrTERT, the gene encoding the catalytic subunit of telomerase and show that telomeres shorten progressively in mutants of this gene. Telomerase mutants eventually enter replicative senescence, demonstrating that telomerase is required for long-term maintenance of telomeres in C. reinhardtii.},
}
@article {pmid31158562,
year = {2019},
author = {Song, L and Liu, B and Zhang, L and Wu, M and Wang, L and Cao, Z and Zhang, B and Li, Y and Wang, Y and Xu, S},
title = {Association of prenatal exposure to arsenic with newborn telomere length: Results from a birth cohort study.},
journal = {Environmental research},
volume = {175},
number = {},
pages = {442-448},
doi = {10.1016/j.envres.2019.05.042},
pmid = {31158562},
issn = {1096-0953},
mesh = {Arsenic/*analysis ; China ; Cohort Studies ; Female ; Humans ; Infant ; Infant, Newborn ; *Maternal Exposure ; Pregnancy ; *Prenatal Exposure Delayed Effects ; *Telomere ; },
abstract = {OBJECTIVES: The telomere length at birth has important implications for telomere dynamics over the lifespan; however, few studies have explored the relationship between prenatal arsenic exposure and newborn telomere length (TL). We investigated whether newborn TL is related to prenatal arsenic exposure.<br><br>METHODS: We used data from a birth cohort study of 762 mother-newborn pairs conducted between November 2013 and March 2015 in Wuhan, China. We measured relative cord blood TL using quantitative real-time polymerase chain reaction. Arsenic concentrations were measured in spot urine samples collected during three trimesters using inductively coupled plasma mass spectrometry. We applied multiple informant models to explore the relationships between prenatal urinary arsenic concentrations and cord blood TL.<br><br>RESULTS: The geometric means of urinary arsenic concentrations were 21.7 &#x3bc;g/g creatinine, 27.3 &#x3bc;g/g creatinine, and 27.1 &#x3bc;g/g creatinine in the first, second, and third trimesters, respectively. After adjustment for potential confounders, a doubling of maternal urinary arsenic concentration during the third trimester was related to a 5.75% (95% CI: 1.70%, 9.95%) increase in cord blood TL, particularly in female infants. Similarly, mothers in the highest quartile of urinary arsenic during the third trimester had an 11.45% (95% CI: 1.91%, 21.88%) longer cord blood TL than those in the lowest quartile. However, no significant association was found between maternal urinary arsenic concentration and cord blood TL during the first and second trimesters.<br><br>CONCLUSION: Our findings suggested that maternal arsenic exposure during the third trimester was positively associated with newborn TL. The elongation of newborn telomeres due to prenatal arsenic exposure may offer new insights into the mechanisms underlying arsenic-related disorders.},
}
@article {pmid31158366,
year = {2019},
author = {Janovič, T and Stojaspal, M and Veverka, P and Horáková, D and Hofr, C},
title = {Human Telomere Repeat Binding Factor TRF1 Replaces TRF2 Bound to Shelterin Core Hub TIN2 when TPP1 Is Absent.},
journal = {Journal of molecular biology},
volume = {431},
number = {17},
pages = {3289-3301},
doi = {10.1016/j.jmb.2019.05.038},
pmid = {31158366},
issn = {1089-8638},
mesh = {DNA-Binding Proteins/chemistry/metabolism ; Humans ; Models, Molecular ; Protein Binding ; Protein Domains ; Protein Multimerization ; *Shelterin Complex/metabolism ; Telomerase/metabolism ; Telomere/metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; },
abstract = {Human telomeric repeat binding factors TRF1 and TRF2 along with TIN2 form the core of the shelterin complex that protects chromosome ends against unwanted end-joining and DNA repair. We applied a single-molecule approach to assess TRF1-TIN2-TRF2 complex formation in solution at physiological conditions. Fluorescence cross-correlation spectroscopy was used to describe the complex assembly by analyzing how coincident fluctuations of differently labeled TRF1 and TRF2 correlate when they move together through the confocal volume of the microscope. We observed, at the single-molecule level, that TRF1 effectively substitutes TRF2 on TIN2. We assessed also the effect of another telomeric factor TPP1 that recruits telomerase to telomeres. We found that TPP1 upon binding to TIN2 induces changes that expand TIN2 binding capacity, such that TIN2 can accommodate both TRF1 and TRF2 simultaneously. We suggest a molecular model that explains why TPP1 is essential for the stable formation of TRF1-TIN2-TRF2 core complex.},
}
@article {pmid31157162,
year = {2019},
author = {Alnafakh, RAA and Adishesh, M and Button, L and Saretzki, G and Hapangama, DK},
title = {Telomerase and Telomeres in Endometrial Cancer.},
journal = {Frontiers in oncology},
volume = {9},
number = {},
pages = {344},
pmid = {31157162},
issn = {2234-943X},
abstract = {Telomeres at the termini of human chromosomes are shortened with each round of cell division due to the "end replication problem" as well as oxidative stress. During carcinogenesis, cells acquire or retain mechanisms to maintain telomeres to avoid initiation of cellular senescence or apoptosis and halting cell division by critically short telomeres. The unique reverse transcriptase enzyme complex, telomerase, catalyzes the maintenance of telomeres but most human somatic cells do not have sufficient telomerase activity to prevent telomere shortening. Tissues with high and prolonged replicative potential demonstrate adequate cellular telomerase activity to prevent telomere erosion, and high telomerase activity appears to be a critical feature of most (80-90%) epithelial cancers, including endometrial cancer. Endometrial cancers regress in response to progesterone which is frequently used to treat advanced endometrial cancer. Endometrial telomerase is inhibited by progestogens and deciphering telomere and telomerase biology in endometrial cancer is therefore important, as targeting telomerase (a downstream target of progestogens) in endometrial cancer may provide novel and more effective therapeutic avenues. This review aims to examine the available evidence for the role and importance of telomere and telomerase biology in endometrial cancer.},
}
@article {pmid31156167,
year = {2019},
author = {Guo, Y and Yu, H},
title = {Leukocyte Telomere Length Shortening and Alzheimer's Disease Etiology.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {69},
number = {3},
pages = {881-885},
doi = {10.3233/JAD-190134},
pmid = {31156167},
issn = {1875-8908},
mesh = {Algorithms ; Alleles ; Alzheimer Disease/*etiology/*genetics ; Genome-Wide Association Study ; Humans ; Leukocytes/*ultrastructure ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; Risk Assessment ; Telomere Homeostasis ; Telomere Shortening/*genetics ; },
abstract = {BACKGROUND: Several observational studies have found leukocyte telomere length (TL) to be associated with Alzheimer's diseases (AD) or dementia. However, these findings were based on small sample sizes and cannot clarify whether this relationship was causal. Genome-wide association studies (GWAS) have identified common variants associated with TL, providing a valuable resource for examining the causal effect of TL on AD using Mendelian Randomization (MR) methods.<br><br>OBJECTIVE: To examine if TL was causally associated with AD using GWAS summary statistics.<br><br>METHODS: Using a genetic risk score comprised of seven variants associated with leukocyte TL as an instrumental variable, we tested whether shorter TL was associated with a higher risk of AD by applying an MR approach to the summarized genome-wide association study data.<br><br>RESULTS: The genetic risk score for TL was associated with higher risk of AD [log-odds ratio (OR)&#x200a;=&#x200a;0.003 for per TL-decreasing allele; 95% confidence interval (CI): 0.001, 0.005, p&#x200a;=&#x200a;0.005]. Moreover, the MR analysis provided support for shorter TL to be causally associated with a higher risk of AD (log-OR&#x200a;=&#x200a;0.04 per SD-decrease of TL; 95% CI: 0.01, 0.08, p&#x200a;=&#x200a;0.01).<br><br>CONCLUSION: We suggest that TL has a causal effect on the risk of AD.},
}
@article {pmid31155651,
year = {2021},
author = {Aloni, R and Levin, Y and Uziel, O and Solomon, Z},
title = {Premature Aging Among Trauma Survivors-The Longitudinal Implications of Sleep Disruptions on Telomere Length and Cognitive Performance.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {76},
number = {2},
pages = {262-272},
pmid = {31155651},
issn = {1758-5368},
mesh = {Aged ; *Aging, Premature/diagnosis/etiology/metabolism/psychology ; Biomarkers/analysis ; Cognition/*physiology ; Female ; Humans ; Intelligence Tests ; Israel ; Longitudinal Studies ; Male ; Prisoners of War/*psychology ; *Sleep Wake Disorders/epidemiology/etiology/metabolism/psychology ; Survivors/psychology ; Telomere Shortening ; *Trauma and Stressor Related Disorders/complications/metabolism/psychology ; Veterans Health ; },
abstract = {OBJECTIVES: Sleep is necessary for brain function as well as physical and cognitive processes. Sleep disruptions, common with aging, intensify among trauma survivors. Moreover, former prisoners-of-war (ex-POWs) often experience premature aging. This study investigates the longitudinal effects of sleep disruptions for ex-POWs in relation to cognitive performance and telomere length as well as between cognition and telomeres.<br><br>METHOD: This study included Israeli veterans from the 1973 Yom Kippur War who participated in four assessments (1991, 2003, 2008, 2015): (a) ex-POWs (n = 99), and (b) veterans who not were captured (controls) (n = 101). Among both groups, sleep disruptions were assessed using a self-report item in all four assessments. Cognitive performance was assessed using the Montreal Cognitive Assessment (MOCA) and telomere length was assessed via total white blood cells (leukocytes) from whole blood samples using Southern blot, both were measured only among ex-POWs in 2015. We conducted descriptive statistics, repeated measures, correlations, and path analyses.<br><br>RESULTS: Sleep disruptions were related to lower cognitive performance but not to shorter telomeres. Moreover, cognitive performance and telomere length were found to be related when sleep disruptions were taken into consideration.<br><br>CONCLUSION: Interpersonal trauma was shown to be a unique experience resulting in sleep disruptions over time, leading to cognitive impairment. These findings highlight the importance of viewing trauma survivors at high-risk for sleep disruptions. Therefore, it is imperative to inquire about sleep and diagnose cognitive disorders to help identify and treat premature aging.},
}
@article {pmid31148570,
year = {2019},
author = {Clouston, SAP and Edelman, NH and Aviv, A and Stewart, C and Luft, BJ},
title = {Shortened leukocyte telomere length is associated with reduced pulmonary function and greater subsequent decline in function in a sample of World Trade Center responders.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {8148},
pmid = {31148570},
issn = {2045-2322},
support = {R01 AG049953/AG/NIA NIH HHS/United States ; U01 OH011478/OH/NIOSH CDC HHS/United States ; 200-2011-39361//U.S. Department of Health &amp; Human Services | Centers for Disease Control and Prevention (CDC)/International ; U01 OH011478/OH/NIOSH CDC HHS/United States ; },
mesh = {Adult ; Biomarkers/metabolism ; Female ; Forced Expiratory Volume ; Humans ; Leukocytes/*cytology ; Longitudinal Studies ; Lung/*physiopathology ; Lung Injury/*physiopathology ; Male ; Middle Aged ; Multivariate Analysis ; Occupational Exposure ; Prospective Studies ; Respiratory Function Tests ; Respiratory Insufficiency/*physiopathology ; Retrospective Studies ; *September 11 Terrorist Attacks ; Spirometry ; Telomere/*ultrastructure ; Vital Capacity ; },
abstract = {The objective of this study was to examine whether shorter leukocyte telomere length (LTL) is associated with more rapid pulmonary function decline in a longitudinal study of World Trade Center (WTC) responders. WTC responders (N = 284) participating in a monitoring study underwent blood sampling and were followed prospectively for spirometric outcomes. A single blood sample was taken to measure LTL using southern blotting. Outcomes included percent-predicted one-second forced expiratory volume (FEV1%), forced vital capacity (FVC%), and the FEV1/FVC ratio. In a subset, percent-predicted diffusing capacity (DLCO%) was also measured. Longitudinal modeling examined prospectively collected information over five years since blood was banked was used to examine the rate of change in pulmonary functioning over time. Severity of WTC exposure was assessed. Shorter LTL was associated with lower FEV1% and FVC% at baseline. For example, 29.9% of those with LTL <6.5 kbps had FEV1% <80% whereas only 12.4% of those with LTL ≥6.5 had FEV1% <80% (RR = 2.53, 95%CI = [1.70-3.76]). Lower DLCO% was also significantly associated with shorter LTL. Longitudinal models identified a prospective association between shorter LTL and greater yearly rates of decline in FEV1% (0.46%/year, 95%CI = [0.05-0.87]) and in the FEV1/FVC ratio (0.19%/year, 95%CI = [0.03-0.36]). There were no associations between severity of exposure and either LTL or pulmonary function. Longitudinal analyses revealed that shorter LTL, but not severity of WTC exposures, was associated with poorer pulmonary functioning and with greater subsequent decline in pulmonary functioning over time. These findings are consistent with the idea that shortened LTL may act as a biomarker for enhanced pulmonary vulnerability in the face of acute severe toxic inhalation exposures.},
}
@article {pmid31146136,
year = {2019},
author = {Duan, X and Yang, Y and Zhang, D and Wang, S and Feng, X and Wang, T and Wang, P and Ding, M and Zhang, H and Liu, B and Wei, W and Yao, W and Cui, L and Zhou, X and Wang, W},
title = {Genetic polymorphisms, mRNA expression levels of telomere-binding proteins, and associates with telomere damage in PAHs-Exposure workers.},
journal = {Chemosphere},
volume = {231},
number = {},
pages = {442-449},
doi = {10.1016/j.chemosphere.2019.05.134},
pmid = {31146136},
issn = {1879-1298},
mesh = {Adult ; Air Pollutants, Occupational/analysis/*toxicity ; Carcinogens/analysis ; Coke/analysis ; DNA Damage ; Genotype ; Humans ; Leukocytes/chemistry ; Male ; Occupational Exposure/analysis/*statistics &amp; numerical data ; Polycyclic Aromatic Hydrocarbons/analysis/*toxicity ; Polymorphism, Single Nucleotide ; RNA, Messenger/*metabolism ; Shelterin Complex ; Telomere ; Telomere-Binding Proteins/*genetics/metabolism ; Telomeric Repeat Binding Protein 2 ; },
abstract = {Coke oven emissions (COEs), confirmed human carcinogens, are mainly composed of polycyclic aromatic hydrocarbons (PAHs). Telomere shortening in blood leukocytes has been associated with COEs, and polymorphisms in metabolic enzymes. However, the relationship between polymorphisms in telomere related genes and telomere shortening in COEs exposed workers has never been evaluated. Therefore, we measured telomere length and mRNA expression levels of telomere-binding proteins (TBPs) by qPCR method in leucocyte from 544 COEs exposed workers and 238 office staffs (referents). Flight mass spectrometry was used to perform the genotyping of selected functional and susceptible SNPs. The results showed that the telomere length in the exposure group 0.75(0.51,1.08) was significantly shorter than that in the control group 1.05(0.76,1.44) (P < 0.001). The mRNA expression levels of TPP1, TERF1 and TERF2 genes in the exposure group were significantly lower than those in the control group (P < 0.05), the mRNA expression level of POT1 in the exposure group was significantly higher than that in the control group (P < 0.05). We used the wild homozygous genotype as a reference, subjects carrying TERT rs2736109 AA, TERT rs3215401 CC and TERT rs2736100 GT + GG genotypes had significantly longer telomere length in the exposure group (P < 0.05). In conclusion, the workers exposed to COEs had shorter telomere length, which was regulated by the TPP1, TERF1, TERF2 and POT1 genes expression levels, and the gene polymorphisms of TERT gene were associated with the telomere length among PAHs-exposure workers.},
}
@article {pmid31145433,
year = {2019},
author = {Grieshober, L and Wactawski-Wende, J and Hageman Blair, R and Mu, L and Liu, J and Nie, J and Carty, CL and Hale, L and Kroenke, CH and LaCroix, AZ and Reiner, AP and Ochs-Balcom, HM},
title = {A Cross-Sectional Analysis of Telomere Length and Sleep in the Women's Health Initiative.},
journal = {American journal of epidemiology},
volume = {188},
number = {9},
pages = {1616-1626},
pmid = {31145433},
issn = {1476-6256},
support = {HHSN268201600018C/HL/NHLBI NIH HHS/United States ; T32 CA113951/CA/NCI NIH HHS/United States ; HHSN268201300007C/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; TL1 TR002540/TR/NCATS NIH HHS/United States ; R25 CA113951/CA/NCI NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; },
mesh = {Black or African American ; Aged ; Cross-Sectional Studies ; Female ; Humans ; Linear Models ; Middle Aged ; Postmenopause ; Prospective Studies ; Self Report ; *Sleep/genetics/physiology ; Socioeconomic Factors ; Telomere/*ultrastructure ; White People ; Women's Health ; },
abstract = {Telomere length is a heritable marker of cellular age that is associated with morbidity and mortality. Poor sleep behaviors, which are also associated with adverse health events, may be related to leukocyte telomere length (LTL). We studied a subpopulation of 3,145 postmenopausal women (1,796 European-American (EA) and 1,349 African-American (AA)) enrolled in the Women's Health Initiative in 1993-1998 with data on Southern blot-measured LTL and self-reported usual sleep duration and sleep disturbance. LTL-sleep associations were analyzed separately for duration and disturbance using weighted and confounder-adjusted linear regression models in the entire sample (AAs + EAs; adjusted for race/ethnicity) and in racial/ethnic strata, since LTL differs by ancestry. After adjustment for covariates, each additional daily hour of sleep beyond 5 hours, approximately, was associated with a 27-base-pair (95% confidence interval (CI): 6, 48) longer LTL in the entire sample. Associations between sleep duration and LTL were strongest among AAs (adjusted β = 37, 95% CI: 4, 70); a similar, nonsignificant association was observed for EAs (adjusted β = 20, 95% CI: -7, 48). Sleep disturbance was not associated with LTL in our study. Our models did not show departure from linearity (quadratic sleep terms: P ≥ 0.55). Our results suggest that longer sleep duration is associated with longer LTL in postmenopausal women.},
}
@article {pmid31140977,
year = {2019},
author = {Whittemore, K and Derevyanko, A and Martinez, P and Serrano, R and Pumarola, M and Bosch, F and Blasco, MA},
title = {Telomerase gene therapy ameliorates the effects of neurodegeneration associated to short telomeres in mice.},
journal = {Aging},
volume = {11},
number = {10},
pages = {2916-2948},
pmid = {31140977},
issn = {1945-4589},
mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Animals ; Brain/enzymology ; Dependovirus ; Disease Models, Animal ; Gene Transfer Techniques ; Genetic Therapy/*methods ; Male ; Memory ; Mice, Knockout ; Neurodegenerative Diseases/etiology/*therapy ; Telomerase/deficiency/*genetics ; *Telomere Shortening ; },
abstract = {Neurodegenerative diseases associated with old age such as Alzheimer's disease present major problems for society, and they currently have no cure. The telomere protective caps at the ends of chromosomes shorten with age, and when they become critically short, they can induce a persistent DNA damage response at chromosome ends, triggering secondary cellular responses such as cell death and cellular senescence. Mice and humans with very short telomeres owing to telomerase deficiencies have an earlier onset of pathologies associated with loss of the regenerative capacity of tissues. However, the effects of short telomeres in very low proliferative tissues such as the brain have not been thoroughly investigated. Here, we describe a mouse model of neurodegeneration owing to presence of short telomeres in the brain as the consequence of telomerase deficiency. Interestingly, we find similar signs of neurodegeneration in very old mice as the consequence of physiological mouse aging. Next, we demonstrate that delivery of telomerase gene therapy to the brain of these mice results in amelioration of some of these neurodegeneration phenotypes. These findings suggest that short telomeres contribute to neurodegeneration diseases with aging and that telomerase activation may have a therapeutic value in these diseases.},
}
@article {pmid31140354,
year = {2019},
author = {Nguyen, MT and Vryer, R and Ranganathan, S and Lycett, K and Grobler, A and Dwyer, T and Juonala, M and Saffery, R and Burgner, D and Wake, M},
title = {Telomere Length and Vascular Phenotypes in a Population-Based Cohort of Children and Midlife Adults.},
journal = {Journal of the American Heart Association},
volume = {8},
number = {11},
pages = {e012707},
pmid = {31140354},
issn = {2047-9980},
mesh = {Adult ; Age Factors ; Australia ; Cardiovascular Diseases/diagnostic imaging/*genetics/*physiopathology ; Carotid Arteries/diagnostic imaging/*physiopathology ; Carotid Intima-Media Thickness ; Carotid-Femoral Pulse Wave Velocity ; Child ; Cross-Sectional Studies ; Female ; Humans ; Male ; Middle Aged ; Phenotype ; Risk Assessment ; Risk Factors ; Telomere/*genetics ; *Telomere Homeostasis ; *Telomere Shortening ; *Vascular Remodeling ; *Vascular Stiffness ; },
abstract = {Background Telomere length has been inversely associated with cardiovascular disease in adulthood, but its relationship to preclinical cardiovascular phenotypes across the life course remains unclear. We investigated associations of telomere length with vascular structure and function in children and midlife adults. Methods and Results Population-based cross-sectional CheckPoint (Child Health CheckPoint) study of 11- to 12-year-old children and their parents, nested within the LSAC (Longitudinal Study of Australian Children). Telomere length (telomeric genomic DNA [T]/β-globin single-copy gene [S] [T/S ratio]) was measured by quantitative polymerase chain reaction from blood-derived genomic DNA. Vascular structure was assessed by carotid intima-media thickness, and vascular function was assessed by carotid-femoral pulse-wave velocity and carotid elasticity. Mean (SD) T/S ratio was 1.09 (0.55) in children (n=1206; 51% girls) and 0.81 (0.38) in adults (n=1343; 87% women). Linear regression models, adjusted for potential confounders, revealed no evidence of an association between T/S ratio and carotid intima-media thickness, carotid-femoral pulse-wave velocity, or carotid elasticity in children. In adults, longer telomeres were associated with greater carotid elasticity (0.14% per 10-mm Hg higher per unit of T/S ratio; 95% CI, 0.04%-0.2%; P=0.007), but not carotid intima-media thickness (-0.9 μm; 95% CI, -14 to 13 μm; P=0.9) or carotid-femoral pulse-wave velocity (-0.10 m/s; 95% CI, -0.3 to 0.07 m/s; P=0.2). In logistic regression analysis, telomere length did not predict poorer vascular measures at either age. Conclusions In midlife adults, but not children, there was some evidence that telomere length was associated with vascular elasticity but not thickness. Associations between telomere length and cardiovascular phenotypes may become more evident in later life, with advancing pathological changes.},
}
@article {pmid31138797,
year = {2019},
author = {Lu, R and O'Rourke, JJ and Sobinoff, AP and Allen, JAM and Nelson, CB and Tomlinson, CG and Lee, M and Reddel, RR and Deans, AJ and Pickett, HA},
title = {The FANCM-BLM-TOP3A-RMI complex suppresses alternative lengthening of telomeres (ALT).},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {2252},
pmid = {31138797},
issn = {2041-1723},
support = {1123100//Department of Health | National Health and Medical Research Council (NHMRC)/International ; RG-16-09//Cancer Council NSW (Cancer Council New South Wales)/International ; },
mesh = {Carrier Proteins/*metabolism ; Cell Line, Tumor ; DNA Helicases/*metabolism ; DNA Replication ; DNA Topoisomerases, Type I/*metabolism ; DNA-Binding Proteins/*metabolism ; HCT116 Cells ; HEK293 Cells ; HeLa Cells ; Humans ; Neoplasms/*metabolism ; Nuclear Proteins/*metabolism ; RecQ Helicases/*metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {The collapse of stalled replication forks is a major driver of genomic instability. Several committed mechanisms exist to resolve replication stress. These pathways are particularly pertinent at telomeres. Cancer cells that use Alternative Lengthening of Telomeres (ALT) display heightened levels of telomere-specific replication stress, and co-opt stalled replication forks as substrates for break-induced telomere synthesis. FANCM is a DNA translocase that can form independent functional interactions with the BLM-TOP3A-RMI (BTR) complex and the Fanconi anemia (FA) core complex. Here, we demonstrate that FANCM depletion provokes ALT activity, evident by increased break-induced telomere synthesis, and the induction of ALT biomarkers. FANCM-mediated attenuation of ALT requires its inherent DNA translocase activity and interaction with the BTR complex, but does not require the FA core complex, indicative of FANCM functioning to restrain excessive ALT activity by ameliorating replication stress at telomeres. Synthetic inhibition of FANCM-BTR complex formation is selectively toxic to ALT cancer cells.},
}
@article {pmid31138619,
year = {2019},
author = {Saint-Leandre, B and Nguyen, SC and Levine, MT},
title = {Diversification and collapse of a telomere elongation mechanism.},
journal = {Genome research},
volume = {29},
number = {6},
pages = {920-931},
pmid = {31138619},
issn = {1549-5469},
support = {R00 GM107351/GM/NIGMS NIH HHS/United States ; R35 GM124684/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cytogenetic Analysis ; Drosophila melanogaster/physiology ; Humans ; In Situ Hybridization, Fluorescence ; Phylogeny ; Polymerase Chain Reaction ; Retroelements ; Telomerase/metabolism ; Telomere/*genetics/*metabolism ; Telomere Homeostasis ; },
abstract = {In most eukaryotes, telomerase counteracts chromosome erosion by adding repetitive sequence to terminal ends. Drosophila melanogaster instead relies on specialized retrotransposons that insert exclusively at telomeres. This exchange of goods between host and mobile element-wherein the mobile element provides an essential genome service and the host provides a hospitable niche for mobile element propagation-has been called a "genomic symbiosis." However, these telomere-specialized, jockey family retrotransposons may actually evolve to "selfishly" overreplicate in the genomes that they ostensibly serve. Under this model, we expect rapid diversification of telomere-specialized retrotransposon lineages and, possibly, the breakdown of this ostensibly symbiotic relationship. Here we report data consistent with both predictions. Searching the raw reads of the 15-Myr-old melanogaster species group, we generated de novo jockey retrotransposon consensus sequences and used phylogenetic tree-building to delineate four distinct telomere-associated lineages. Recurrent gains, losses, and replacements account for this retrotransposon lineage diversity. In Drosophila biarmipes, telomere-specialized elements have disappeared completely. De novo assembly of long reads and cytogenetics confirmed this species-specific collapse of retrotransposon-dependent telomere elongation. Instead, telomere-restricted satellite DNA and DNA transposon fragments occupy its terminal ends. We infer that D. biarmipes relies instead on a recombination-based mechanism conserved from yeast to flies to humans. Telomeric retrotransposon diversification and disappearance suggest that persistently "selfish" machinery shapes telomere elongation across Drosophila rather than completely domesticated, symbiotic mobile elements.},
}
@article {pmid31138115,
year = {2019},
author = {Feuerbach, L and Sieverling, L and Deeg, KI and Ginsbach, P and Hutter, B and Buchhalter, I and Northcott, PA and Mughal, SS and Chudasama, P and Glimm, H and Scholl, C and Lichter, P and Fröhling, S and Pfister, SM and Jones, DTW and Rippe, K and Brors, B},
title = {TelomereHunter - in silico estimation of telomere content and composition from cancer genomes.},
journal = {BMC bioinformatics},
volume = {20},
number = {1},
pages = {272},
pmid = {31138115},
issn = {1471-2105},
support = {01KU1505E//Bundesministerium f&#xfc;r Bildung und Forschung/ ; 01KU1505A//Bundesministerium f&#xfc;r Bildung und Forschung/ ; 01KU1001A//Bundesministerium f&#xfc;r Bildung und Forschung/ ; 01ZX1302//Bundesministerium f&#xfc;r Bildung und Forschung/ ; 01KU1505E//Bundesministerium f&#xfc;r Bildung und Forschung/ ; 01ZX1302//Bundesministerium f&#xfc;r Bildung und Forschung/ ; },
mesh = {Base Sequence ; *Computer Simulation ; *Genome ; Glioblastoma/genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Medulloblastoma/genetics ; Neoplasms/*genetics ; *Software ; Telomere/*genetics ; Exome Sequencing ; Whole Genome Sequencing ; },
abstract = {BACKGROUND: Establishment of telomere maintenance mechanisms is a universal step in tumor development to achieve replicative immortality. These processes leave molecular footprints in cancer genomes in the form of altered telomere content and aberrations in telomere composition. To retrieve these telomere characteristics from high-throughput sequencing data the available computational approaches need to be extended and optimized to fully exploit the information provided by large scale cancer genome data sets.<br><br>RESULTS: We here present TelomereHunter, a software for the detailed characterization of telomere maintenance mechanism footprints in the genome. The tool is implemented for the analysis of large cancer genome cohorts and provides a variety of diagnostic diagrams as well as machine-readable output for subsequent analysis. A novel key feature is the extraction of singleton telomere variant repeats, which improves the identification and subclassification of the alternative lengthening of telomeres phenotype. We find that whole genome sequencing-derived telomere content estimates strongly correlate with telomere qPCR measurements (r&#x2009;=&#x2009;0.94). For the first time, we determine the correlation of in silico telomere content quantification from whole genome sequencing and whole genome bisulfite sequencing data derived from the same tumor sample (r&#x2009;=&#x2009;0.78). An analogous comparison of whole exome sequencing data and whole genome sequencing data measured slightly lower correlation (r&#x2009;=&#x2009;0.79). However, this is considerably improved by normalization with matched controls (r&#x2009;=&#x2009;0.91).<br><br>CONCLUSIONS: TelomereHunter provides new functionality for the analysis of the footprints of telomere maintenance mechanisms in cancer genomes. Besides whole genome sequencing, whole exome sequencing and whole genome bisulfite sequencing are suited for in silico telomere content quantification, especially if matched control samples are available. The software runs under a GPL license and is available at https://www.dkfz.de/en/applied-bioinformatics/telomerehunter/telomerehunter.html .},
}
@article {pmid31138065,
year = {2019},
author = {Eisenberg, DTA and Lee, NR and Rej, PH and Hayes, MG and Kuzawa, CW},
title = {Older paternal ages and grandpaternal ages at conception predict longer telomeres in human descendants.},
journal = {Proceedings. Biological sciences},
volume = {286},
number = {1903},
pages = {20190800},
pmid = {31138065},
issn = {1471-2954},
mesh = {*Fertilization ; Humans ; Male ; *Paternal Age ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; },
abstract = {Telomere length (TL) declines with age in most human tissues, and shorter TL appears to accelerate senescence. By contrast, men's sperm TL is positively correlated with age. Correspondingly, in humans, older paternal age at conception (PAC) predicts longer offspring TL. We have hypothesized that this PAC effect could persist across multiple generations, and thereby contribute to a transgenerational genetic plasticity that increases expenditures on somatic maintenance as the average age at reproduction is delayed within a lineage. Here, we examine TL data from 3282 humans together with PAC data across four generations. In this sample, the PAC effect is detectable in children and grandchildren. The PAC effect is transmitted through the matriline and patriline with similar strength and is characterized by a generational decay. PACs of more distant male ancestors were not significant predictors, although statistical power was limited in these analyses. Sensitivity analyses suggest that the PAC effect is linear, not moderated by offspring age, or maternal age, and is robust to controls for income, urbanicity and ancestry. These findings show that TL reflects the age at the reproduction of recent male matrilineal and patrilineal ancestors, with an effect that decays across generations.},
}
@article {pmid31134349,
year = {2019},
author = {Kobayashi, CR and Castillo-González, C and Survotseva, Y and Canal, E and Nelson, ADL and Shippen, DE},
title = {Recent emergence and extinction of the protection of telomeres 1c gene in Arabidopsis thaliana.},
journal = {Plant cell reports},
volume = {38},
number = {9},
pages = {1081-1097},
pmid = {31134349},
issn = {1432-203X},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; GM065383//Foundation for the National Institutes of Health/ ; },
mesh = {Arabidopsis/enzymology/*genetics/physiology ; Arabidopsis Proteins/genetics/*metabolism ; DNA Transposable Elements/genetics ; Evolution, Molecular ; *Gene Dosage ; Gene Duplication ; Mutation ; Promoter Regions, Genetic/genetics ; Shelterin Complex ; Telomerase/genetics/metabolism ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Duplicate POT1 genes must rapidly diverge or be inactivated. Protection of telomeres 1 (POT1) encodes a conserved telomere binding protein implicated in both chromosome end protection and telomere length maintenance. Most organisms harbor a single POT1 gene, but in the few lineages where the POT1 family has expanded, the duplicate genes have diversified. Arabidopsis thaliana bears three POT1-like loci, POT1a, POT1b and POT1c. POT1a retains the ancestral function of telomerase regulation, while POT1b is implicated in chromosome end protection. Here we examine the function and evolution of the third POT1 paralog, POT1c. POT1c is a new gene, unique to A. thaliana, and was derived from a duplication event involving the POT1a locus and a neighboring gene encoding ribosomal protein S17. The duplicate S17 locus (dS17) is highly conserved across A. thaliana accessions, while POT1c is highly divergent, harboring multiple deletions within the gene body and two transposable elements within the promoter. The POT1c locus is transcribed at very low to non-detectable levels under standard growth conditions. In addition, no discernable molecular or developmental defects are associated with plants bearing a CRISPR mutation in the POT1c locus. However, forced expression of POT1c leads to decreased telomerase enzyme activity and shortened telomeres. Evolutionary reconstruction indicates that transposons invaded the POT1c promoter soon after the locus was formed, permanently silencing the gene. Altogether, these findings argue that POT1 dosage is critically important for viability and duplicate gene copies are retained only upon functional divergence.},
}
@article {pmid31132093,
year = {2019},
author = {Patanè, S},
title = {Differential effects of training on telomerase activity and telomere length: the role of microRNAs regulation.},
journal = {European heart journal},
volume = {40},
number = {38},
pages = {3200},
doi = {10.1093/eurheartj/ehz325},
pmid = {31132093},
issn = {1522-9645},
mesh = {Humans ; *MicroRNAs ; *Resistance Training ; Telomerase/*genetics ; Telomere ; },
}
@article {pmid31132084,
year = {2019},
author = {Jiménez-Pavón, D and Carbonell-Baeza, A and Lavie, CJ},
title = {Are changes in telomerase activity and telomere length due to different exercise modalities, intensity, or methods: intermittency?.},
journal = {European heart journal},
volume = {40},
number = {38},
pages = {3198-3199},
doi = {10.1093/eurheartj/ehz323},
pmid = {31132084},
issn = {1522-9645},
mesh = {Exercise ; Humans ; *Resistance Training ; Telomerase/*genetics ; Telomere ; },
}
@article {pmid31131414,
year = {2019},
author = {Inoue, H and Horiguchi, M and Ono, K and Kanoh, J},
title = {Casein kinase 2 regulates telomere protein complex formation through Rap1 phosphorylation.},
journal = {Nucleic acids research},
volume = {47},
number = {13},
pages = {6871-6884},
pmid = {31131414},
issn = {1362-4962},
mesh = {CDC2 Protein Kinase/physiology ; Casein Kinase II/*physiology ; Cell Cycle ; Chromatin/ultrastructure ; DNA-Binding Proteins/metabolism ; Meiosis ; Membrane Proteins/metabolism ; Multiprotein Complexes ; Nuclear Envelope/*metabolism ; Nuclear Proteins/metabolism ; Phosphorylation ; Protein Processing, Post-Translational ; Schizosaccharomyces pombe Proteins/metabolism/*physiology ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomeres located at the ends of linear chromosomes play important roles in the maintenance of life. Rap1, a component of the shelterin telomere protein complex, interacts with multiple proteins to perform various functions; further, formation of shelterin requires Rap1 binding to other components such as Taz1 and Poz1, and telomere tethering to the nuclear envelope (NE) involves interactions between Rap1 and Bqt4, a nuclear membrane protein. Although Rap1 is a hub for telomere protein complexes, the regulatory mechanisms of its interactions with partner proteins are not fully understood. Here, we show that Rap1 is phosphorylated by casein kinase 2 (CK2) at multiple sites, which promotes interactions with Bqt4 and Poz1. Among the multiple CK2-mediated phosphorylation sites of Rap1, phosphorylation at Ser496 was found to be crucial for both Rap1-Bqt4 and Rap1-Poz1 interactions. These mechanisms mediate proper telomere tethering to the NE and the formation of the silenced chromatin structure at chromosome ends.},
}
@article {pmid31129702,
year = {2020},
author = {Pusceddu, I and Herrmann, W and Kleber, ME and Scharnagl, H and Hoffmann, MM and Winklhofer-Roob, BM and März, W and Herrmann, M},
title = {Subclinical inflammation, telomere shortening, homocysteine, vitamin B6, and mortality: the Ludwigshafen Risk and Cardiovascular Health Study.},
journal = {European journal of nutrition},
volume = {59},
number = {4},
pages = {1399-1411},
pmid = {31129702},
issn = {1436-6215},
support = {Integrated Project Bloodomics//Sixth Framework Programme/ ; Grant LSHM-CT-2004-503485//Sixth Framework Programme/ ; Integrated Projects AtheroRemo//Seventh Framework Programme/ ; Grant no. 201668//Seventh Framework Programme/ ; RiskyCAD//Seventh Framework Programme/ ; Project no. 305739//Seventh Framework Programme/ ; Project Genetic Mechanisms of Cardiovascular Diseases//Wissenschaftsinitiative Oberrhein/ ; Project AtheroSysMed//Bundesministerium f&#xfc;r Bildung und Forschung/ ; },
mesh = {Cardiovascular Diseases/*blood/*mortality ; Female ; Germany/epidemiology ; Health Surveys/methods/statistics &amp; numerical data ; Homocysteine/*blood ; Humans ; Inflammation/*epidemiology ; Male ; Middle Aged ; Risk Assessment ; *Telomere Shortening ; Vitamin B 6/*blood ; },
abstract = {PURPOSE: Short telomeres and B vitamin deficiencies have been proposed as risk factors for age-related diseases and mortality that interact through oxidative stress and inflammation. However, available data to support this concept are insufficient. We aimed to investigate the predictive role of B vitamins and homocysteine (HCY) for mortality in cardiovascular patients. We explored potential relationships between HCY, B vitamins, relative telomere length (RTL), and indices of inflammation.<br><br>METHODS: Vitamin B6, HCY, interleukin-6 (IL-6), high-sensitive-C-reactive protein (hs-CRP), and RTL were measured in participants of the Ludwigshafen Risk and Cardiovascular Health Study. Death events were recorded over a median follow-up of 9.9&#xa0;years.<br><br>RESULTS: All-cause mortality increased with higher concentrations of HCY and lower vitamin B6. Patients in the 4th quartile of HCY and vitamin B6 had hazard ratios (HR) for all-cause mortality of 2.77 (95% CI 2.28-3.37) and 0.41(95% CI 0.33-0.49), respectively, and for cardiovascular mortality of 2.78 (95% CI 2.29-3.39) and 0.40 (95% CI 0.33-0.49), respectively, compared to those in the 1st quartile. Multiple adjustments for confounders did not change these results. HCY and vitamin B6 correlated with age-corrected RTL (r&#x2009;=&#x2009;-&#xa0;0.086, p&#x2009;<&#x2009;0.001; r&#x2009;=&#x2009;0.04, p&#x2009;=&#x2009;0.031, respectively), IL-6 (r&#x2009;=&#x2009;0.148, p&#x2009;<&#x2009;0.001; r&#x2009;=&#x2009;-&#xa0;0.249, p&#x2009;<&#x2009;0.001, respectively), and hs-CRP (r&#x2009;=&#x2009;0.101, p&#x2009;<&#x2009;0.001; r&#x2009;=&#x2009;-&#xa0;0.320, p&#x2009;<&#x2009;0.001, respectively). Subjects with the longest telomeres had a significantly higher concentration of vitamin B6, but lower concentrations of HCY, IL-6, and hs-CRP. Multiple regression analyses identified HCY as an independent negative predictor of age-corrected RTL.<br><br>CONCLUSIONS: In conclusion, hyperhomocysteinemia and vitamin B6 deficiency are risk factors for death from any cause. Hyperhomocysteinemia and vitamin B6 deficiency correlate with increased mortality. This correlation might, at least partially, be explained by accelerated telomere shortening induced by oxidative stress and systemic inflammation in these circumstances.},
}
@article {pmid31128432,
year = {2019},
author = {Yu, EY and Cheung, IY and Feng, Y and Rabie, MO and Roboz, GJ and Guzman, ML and Cheung, NV and Lue, NF},
title = {Telomere Trimming and DNA Damage as Signatures of High Risk Neuroblastoma.},
journal = {Neoplasia (New York, N.Y.)},
volume = {21},
number = {7},
pages = {689-701},
pmid = {31128432},
issn = {1476-5586},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; },
mesh = {Cell Proliferation/genetics ; DNA Damage/*genetics ; Female ; Genomic Instability/genetics ; HeLa Cells ; Humans ; Male ; Mutation/genetics ; N-Myc Proto-Oncogene Protein/genetics ; Neuroblastoma/*genetics/pathology ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; X-linked Nuclear Protein/genetics ; },
abstract = {Telomeres play important roles in genome stability and cell proliferation. High risk neuroblastoma (HRNB), an aggressive childhood cancer, is especially reliant on telomere maintenance. Three recurrent genetic aberrations in HRNB (MYCN amplification, TERT re-arrangements, and ATRX mutations) are mutually exclusive and each capable of promoting telomere maintenance mechanisms (i.e., through telomerase or ALT). We analyzed a panel of 5 representative HRNB cell lines and 30 HRNB surgical samples using assays that assess average telomere lengths, length distribution patterns, single-stranded DNA on the G- and C-strand, as well as extra-chromosomal circular telomeres. Our analysis pointed to substantial and variable degrees of telomere DNA damage in HRNB, including pervasive oxidative lesions. Moreover, unlike other cancers, neuroblastoma consistently harbored high levels of C-strand ssDNA overhangs and t-circles, which are consistent with active "telomere trimming". This feature is observed in both telomerase- and ALT-positive tumors and irrespective of telomere length distribution. Moreover, evidence for telomere trimming was detected in normal neural tissues, raising the possibility that TMMs in HRNB evolved in the face of a canonical developmental program of telomere shortening. Telomere trimming by itself appears to distinguish neuroectodermal derived tumors from other human cancers, a distinguishing characteristic with both biologic and therapeutic implications.},
}
@article {pmid31127589,
year = {2019},
author = {Zhang, M and Liu, R and Wang, F},
title = {Telomere and G-Quadruplex Colocalization Analysis by Immunofluorescence Fluorescence In Situ Hybridization (IF-FISH).},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1999},
number = {},
pages = {327-333},
doi = {10.1007/978-1-4939-9500-4_23},
pmid = {31127589},
issn = {1940-6029},
mesh = {Antibodies/chemistry/metabolism ; Cell Line ; Fluorescent Antibody Technique, Direct/methods ; *G-Quadruplexes ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Microscopy, Fluorescence/methods ; Molecular Imaging/*methods ; Telomere/chemistry/*genetics ; },
abstract = {Four-stranded G-quadruplexes consists of tracks of guanines that are stabilized by Hoogsteen base pairing. The formation of G-quadruplexes in genomic DNA contribute to numerous biological processes in vivo, including replication, transcription, and telomere maintenance. Here, we present a detailed method to detect the colocalization of G-quadruplexes with telomeres in vivo, using the BG4 antibody developed from Dr. Shankar Balasubramanian's lab.},
}
@article {pmid31127588,
year = {2019},
author = {Gali, H and Mason-Osann, E and Flynn, RL},
title = {Direct Visualization of DNA Replication at Telomeres Using DNA Fiber Combing Combined with Telomere FISH.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1999},
number = {},
pages = {319-325},
doi = {10.1007/978-1-4939-9500-4_22},
pmid = {31127588},
issn = {1940-6029},
support = {R01 CA201446/CA/NCI NIH HHS/United States ; T32 GM008541/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line ; DNA/chemistry/*genetics ; *DNA Replication ; Deoxyuridine/analogs &amp; derivatives/chemistry ; Fluorescent Antibody Technique, Direct/methods ; Genetic Loci ; Humans ; Idoxuridine/chemistry ; In Situ Hybridization, Fluorescence/*methods ; Microscopy, Fluorescence/instrumentation/methods ; Molecular Imaging/instrumentation/*methods ; Molecular Probes/chemistry ; Staining and Labeling/methods ; Telomere/*metabolism ; },
abstract = {The ability to analyze individual DNA fibers undergoing active DNA synthesis has emerged as a powerful technique in the field of DNA replication. Much of the initial analysis has focused on replication throughout the genome. However, more recent advancements in this technique have allowed for the visualization of replication patterns at distinct loci or regions within the genome. This type of locus-specific resolution will greatly enhance our understanding of the dynamics of DNA replication in regions that provide a challenge to the replication machinery. Here, we describe a protocol that will allow for the visualization of DNA replication through one of the most structurally complex regions in the human genome, the telomeric DNA.},
}
@article {pmid31127586,
year = {2019},
author = {Fouquerel, E and Barnes, RP and Wang, H and Opresko, PL},
title = {Measuring UV Photoproduct Repair in Isolated Telomeres and Bulk Genomic DNA.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1999},
number = {},
pages = {295-306},
pmid = {31127586},
issn = {1940-6029},
support = {P30 ES025128/ES/NIEHS NIH HHS/United States ; K99 ES027028/ES/NIEHS NIH HHS/United States ; R21 ES025606/ES/NIEHS NIH HHS/United States ; R01 ES028242/ES/NIEHS NIH HHS/United States ; R01 GM123246/GM/NIGMS NIH HHS/United States ; R01 ES022944/ES/NIEHS NIH HHS/United States ; R21 ES027641/ES/NIEHS NIH HHS/United States ; R01 GM107559/GM/NIGMS NIH HHS/United States ; R33 ES025606/ES/NIEHS NIH HHS/United States ; },
mesh = {Antibodies/immunology ; Cell Line ; DNA/analysis/genetics/radiation effects ; DNA Damage/radiation effects ; DNA Repair ; Genomic Instability ; Genomics/*methods ; Humans ; Immunoblotting/*methods ; Pyrimidine Dimers/*analysis/genetics/radiation effects ; Telomere/genetics/immunology/*radiation effects ; Telomere-Binding Proteins/immunology ; Ultraviolet Rays/*adverse effects ; },
abstract = {Telomere repeats at chromosomal ends are essential for genome stability and sustained cellular proliferation but are susceptible to DNA damage. Repair of damage at telomeres is influenced by numerous factors including telomeric binding proteins, sequence and structure. Ultraviolet (UV) light irradiation induces DNA photoproducts at telomeres that can interfere with telomere maintenance. Here we describe a highly sensitive method for quantifying the formation and removal of UV photoproducts in telomeres isolated from UV irradiated cultured human cells. Damage is detected by immunospot blotting of telomeres with highly specific antibodies against UV photoproducts. This method is adaptable for measuring other types of DNA damage at telomeres as well.},
}
@article {pmid31127568,
year = {2019},
author = {Mason-Osann, E and Gali, H and Flynn, RL},
title = {Resolving Roadblocks to Telomere Replication.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1999},
number = {},
pages = {31-57},
doi = {10.1007/978-1-4939-9500-4_2},
pmid = {31127568},
issn = {1940-6029},
support = {R01 CA201446/CA/NCI NIH HHS/United States ; T32 GM008541/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA/*metabolism ; DNA Damage/genetics ; *DNA Replication ; G-Quadruplexes ; Genome, Human ; Genomic Instability ; Humans ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {The maintenance of genome stability in eukaryotic cells relies on accurate and efficient replication along each chromosome following every cell division. The terminal position, repetitive sequence, and structural complexities of the telomeric DNA make the telomere an inherently difficult region to replicate within the genome. Thus, despite functioning to protect genome stability mammalian telomeres are also a source of replication stress and have been recognized as common fragile sites within the genome. Telomere fragility is exacerbated at telomeres that rely on the Alternative Lengthening of Telomeres (ALT) pathway. Like common fragile sites, ALT telomeres are prone to chromosome breaks and are frequent sites of recombination suggesting that ALT telomeres are subjected to chronic replication stress. Here, we will review the features of telomeric DNA that challenge the replication machinery and also how the cell overcomes these challenges to maintain telomere stability and ensure the faithful duplication of the human genome.},
}
@article {pmid31122612,
year = {2019},
author = {Anitha, A and Thanseem, I and Vasu, MM and Viswambharan, V and Poovathinal, SA},
title = {Telomeres in neurological disorders.},
journal = {Advances in clinical chemistry},
volume = {90},
number = {},
pages = {81-132},
doi = {10.1016/bs.acc.2019.01.003},
pmid = {31122612},
issn = {2162-9471},
mesh = {Animals ; Blotting, Southern ; Humans ; In Situ Hybridization, Fluorescence ; Nervous System Diseases/*genetics ; Polymerase Chain Reaction ; Telomere/*genetics/*metabolism ; },
abstract = {Ever since their discovery, the telomeres and the telomerase have been topics of intensive research, first as a mechanism of cellular aging and later as an indicator of health and diseases in humans. By protecting the chromosome ends, the telomeres play a vital role in preserving the information in our genome. Telomeres shorten with age and the rate of telomere erosion provides insight into the proliferation history of cells. The pace of telomere attrition is known to increase at the onset of several pathological conditions. Telomere shortening has been emerging as a potential contributor in the pathogenesis of several neurological disorders including autism spectrum disorders (ASD), schizophrenia, Alzheimer's disease (AD), Parkinson's disease (PD) and depression. The rate of telomere attrition in the brain is slower than that of other tissues owing to the low rate of cell proliferation in brain. Telomere maintenance is crucial for the functioning of stem cells in brain. Taking together the studies on telomere attrition in various neurological disorders, an association between telomere shortening and disease status has been demonstrated in schizophrenia, AD and depression, in spite of a few negative reports. But, studies in ASD and PD have failed to produce conclusive results. The cause-effect relationship between TL and neurological disorders is yet to be elucidated. The factors responsible for telomere erosion, which have also been implicated in the pathogenesis of neurological disorders, need to be explored in detail. Telomerase activation is now being considered as a potential therapeutic strategy for neurological disorders.},
}
@article {pmid31119896,
year = {2019},
author = {He, C and Jing, S and Dai, C and Tu, C and Tan, Z and Du, J and Lu, GX and Lin, G and Zeng, S},
title = {Telomerase insufficiency induced telomere erosion accumulation in successive generations in dyskeratosis congenita family.},
journal = {Molecular genetics &amp; genomic medicine},
volume = {7},
number = {7},
pages = {e00709},
pmid = {31119896},
issn = {2324-9269},
mesh = {Child, Preschool ; Dyskeratosis Congenita/genetics/*pathology ; Heterozygote ; Humans ; Male ; Pedigree ; Polymorphism, Single Nucleotide ; Prenatal Diagnosis ; Protein Structure, Tertiary ; Telomerase/chemistry/*genetics ; Telomere/*genetics ; Telomere Homeostasis ; Exome Sequencing ; },
abstract = {BACKGROUND: Dyskeratosis congenita (DC) is a rare heritable bone marrow failure syndrome that is associated with telomere dysfunction, and has high genetic heterogeneity and varied features.<br><br>OBJECTIVE: This study aimed to identify the underlying genetic etiology of a DC family with more severe symptoms in the younger generation and to explore the relationship between the genetic causes and the severity of DC phenotype.<br><br>METHODS: Whole-exome sequencing was performed on the proband to screen the candidate causative gene. The protein structure was then predicted by SWISS-MODEL software. Telomere length (TL) assay was performed on family members along with large-scale population controls. The prenatal diagnosis (PND) was performed on the fetus of parents with secondary pregnancy.<br><br>RESULTS: Novel heterozygous mutations in TERT (NM_198253.2), c.1796G>A (p.Arg599Gln), c.2839T>C (p.Ser947Pro), and c.3346G>C (p.Glu1116Gln) were identified in the proband. His TL was below the first percentile of the peers, which also appeared on the fetus with epidermal dyskeratosis through PND. The TL data of large-scale population and members of the DC family implied the accumulation of telomere erosion in successive generations in this family.<br><br>CONCLUSIONS: Our study identified three clinical pathologic TERT mutations and implied that telomere erosion might be accumulated through successive generations, contributing to the severity of DC in the younger generation.},
}
@article {pmid31118363,
year = {2019},
author = {Pan, KL and Hsiao, YW and Lin, YJ and Lo, LW and Hu, YF and Chung, FP and Tsai, YN and Chao, TF and Liao, JN and Lin, CY and Jhuo, SJ and Lin, CH and Suresh, A and Walia, R and Te, ALD and Yamada, S and Chang, YT and Chang, SL and Chen, SA},
title = {Shorter Leukocyte Telomere Length Is Associated With Atrial Remodeling and Predicts Recurrence in Younger Patients With Paroxysmal Atrial Fibrillation After Radiofrequency Ablation.},
journal = {Circulation journal : official journal of the Japanese Circulation Society},
volume = {83},
number = {7},
pages = {1449-1455},
doi = {10.1253/circj.CJ-18-0880},
pmid = {31118363},
issn = {1347-4820},
mesh = {Adult ; Age Factors ; Atrial Fibrillation/*metabolism/pathology/*therapy ; *Atrial Remodeling ; Female ; Humans ; Leukocytes/*metabolism/pathology ; Male ; Middle Aged ; *Radiofrequency Ablation ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Telomere length is a biologic aging marker. This study investigated leukocyte telomere length (LTL) as a new biomarker to predict recurrence after paroxysmal atrial fibrillation (PAF) ablation.Methods and Results:A total of 131 participants (26 healthy individuals and 105 symptomatic PAF patients) were enrolled. PAF patients (54.1±10.8 years) who received catheter ablation therapy were divided into 2 groups: recurrent AF (n=25) and no recurrent AF after catheter ablation (n=80). Peripheral blood mononuclear cells were collected from all subjects to measure LTL. Under 50 years old, LTL in healthy individuals (n=17) was longer than in PAF patients (n=31; 7.34±0.58 kbp vs. 6.44±0.91 kbp, P=0.01). In PAF patients, LTL was positively correlated with left atrial bipolar voltage (R=0.497, P<0.001), and negatively correlated with biatrial scar area (R=-0.570, P<0.001) and left atrial diameter (R=-0.214, P=0.028). LTL was shorter in the patients with recurrent AF than in those without recurrent AF after catheter ablation (5.68±0.82 kbp vs. 6.66±0.71 kbp; P<0.001). On receiver operating characteristic curve analysis, LTL cut-off <6.14 kbp had a specificity of 0.68 and sensitivity of 0.79 to predict recurrent AF after catheter ablation.<br><br>CONCLUSIONS: Young PAF patients (&#x2264;50 years) had shorter LTL. Shorter LTL was associated with a degenerative atrial substrate and recurrence after catheter ablation in younger PAF patients.},
}
@article {pmid31117156,
year = {2019},
author = {Chamorro, CI and Asghar, M and Ekblad, &#xc5; and Färnert, A and Götherström, C and Fossum, M},
title = {Urothelial cell senescence is not linked with telomere shortening.},
journal = {Journal of tissue engineering and regenerative medicine},
volume = {13},
number = {9},
pages = {1518-1527},
doi = {10.1002/term.2900},
pmid = {31117156},
issn = {1932-7005},
mesh = {3T3 Cells ; Animals ; Biomarkers/metabolism ; Cell Separation ; *Cellular Senescence ; Feeder Cells/cytology ; Gene Expression Regulation ; Humans ; Mesoderm/metabolism ; Mice ; Stem Cells/metabolism ; Telomerase/metabolism ; *Telomere Shortening ; Urinary Bladder/cytology ; Urothelium/*cytology ; },
abstract = {The success of regenerative medicine relies in part on the quality of the cells implanted. Cell cultures from cells isolated from bladder washes have been successfully established, but molecular changes and cell characteristics have not been explored in detail. In this work, we analysed the role of telomere shortening in relation to the regenerative potential and senescence of cells isolated from bladder washes and expanded in culture. We also analysed whether bladder washes would be a potential source for attaining stem cells or promoting stem cell proliferation by using two different substrates to support their growth: a feeder layer of growth-arrested murine fibroblasts J2 3T3 cells and a xeno-free human recombinant laminin-coated surface. We found no association between telomere shortening and senescence in urothelial cells in vitro. Urothelial cells had a stable telomere length and expressed mesenchymal stem cells markers but failed to differentiate into bone or adipocytes. Feeder layer showed an advantage to laminin-coated surfaces in respect to proliferative capacity with the expense of risking that feeder layer cells could persist in later passages. This emphasizes the importance of using carefully controlled culture conditions and molecular quality controls before autotransplantation in future clinical settings. In conclusion, urothelial cells isolated by bladder washes show regenerative potential that need further understanding. Senescence in vitro might be due to cellular stress, and if so, further improvements in culture conditions may lead to longer cell life and higher proliferative capacity.},
}
@article {pmid31117113,
year = {2019},
author = {Luu, HN and Qi, M and Wang, R and Adams-Haduch, J and Miljkovic, I and Opresko, PL and Jin, A and Koh, WP and Yuan, JM},
title = {Association Between Leukocyte Telomere Length and Colorectal Cancer Risk in the Singapore Chinese Health Study.},
journal = {Clinical and translational gastroenterology},
volume = {10},
number = {5},
pages = {1-9},
pmid = {31117113},
issn = {2155-384X},
support = {R01 CA144034/CA/NCI NIH HHS/United States ; UM1 CA182876/CA/NCI NIH HHS/United States ; P20 CA210300/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Asian People/genetics ; Colorectal Neoplasms/blood/*epidemiology/genetics ; Female ; Follow-Up Studies ; Humans ; Incidence ; Leukocytes/*metabolism ; Male ; Middle Aged ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; Risk Assessment/methods ; Risk Factors ; Singapore ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {OBJECTIVES: Telomeres and telomerase play important roles in maintaining chromosome integrity and genomic stability. To address a lack of consensus about the association between leukocyte telomere length and colorectal cancer, we investigated this association in the Singapore Chinese Health Study.<br><br>METHODS: Relative telomere length in white blood cells was quantified using a validated quantitative polymerase chain reaction method in 26,761 participants, including 776 incident colorectal cancer cases. The Cox proportional hazard regression method was used to calculate the hazard ratio and the corresponding 95% confidence interval (CI) for colorectal cancer associated with longer telomeres.<br><br>RESULTS: Longer telomeres were significantly associated with a higher risk of colorectal cancer (Ptrend = 0.02). Compared with the lowest quartile, subjects with the highest quartile of telomere length had a hazard ratio of 1.32 (95% CI: 1.08-1.62) for developing colorectal cancer. The corresponding elevation in rectal cancer risk for the highest quartile of telomere length was 71% (95% CI: 22-140, Ptrend = 0.02). There was no statistically significant association between telomere length and risk of colon cancer.<br><br>DISCUSSION: This large cohort study of Singapore Chinese, the first study using a cohort study design with more than 26,000 participants that yielded 776 incidence colorectal cancer cases during 12 years of follow-up, provides evidence in support of longer telomeres being associated with a higher risk of colorectal cancer, particularly rectal cancer.},
}
@article {pmid31115552,
year = {2019},
author = {Tsoukalas, D and Fragkiadaki, P and Docea, AO and Alegakis, AK and Sarandi, E and Vakonaki, E and Salataj, E and Kouvidi, E and Nikitovic, D and Kovatsi, L and Spandidos, DA and Tsatsakis, A and Calina, D},
title = {Association of nutraceutical supplements with longer telomere length.},
journal = {International journal of molecular medicine},
volume = {44},
number = {1},
pages = {218-226},
pmid = {31115552},
issn = {1791-244X},
mesh = {Adult ; *Dietary Supplements ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; *Sex Characteristics ; Telomere/*metabolism ; Telomere Homeostasis/*drug effects ; },
abstract = {Telomeres are nucleotide tandem repeats located at the tip of eukaryotic chromosomes that maintain genomic integrity. The gradual shortening of telomeres leads to cellular senescence and apoptosis, a key mechanism of aging and age‑related chronic diseases. Epigenetic factors, such as nutrition, exercise and tobacco can affect the rate at which telomeres shorten and can modify the risk of developing chronic diseases. In this study, we evaluated the effects of a combination of nutraceutical supplements (NS) on telomere length (TL) in healthy volunteers with no medical history of any disease. Participants (n=47) were selected from healthy outpatients visiting a private clinic and were divided into the experimental group (n=16), that received the NS and the control group (n=31). We estimated the length of single telomeres in metaphase spread leukocytes, isolated from peripheral blood, using quantitative‑fluorescent in situ hybridization (Q‑FISH) analysis. The length of the whole telomere genome was significantly increased (P<0.05) for the mean, 1st quartile and median measurements in the experimental group. Similar findings were observed for short TL (20th percentile) (P<0.05) for the median and 3rd quartile measurements in the NS group, compared to the control group. The beneficial effects of the supplements on the length of short telomeres remained significant (P<0.05) following adjustment for age and sex. Telomeres were moderately longer in female patients compared to the male patients. On the whole, the findings of this study suggest that the administration of NS may be linked to sustaining the TL.},
}
@article {pmid31114915,
year = {2019},
author = {Li, N and Wang, J and Ma, K and Liang, L and Mi, L and Huang, W and Ma, X and Wang, Z and Zheng, W and Xu, L and Chen, JH and Yu, Z},
title = {The dynamics of forming a triplex in an artificial telomere inferred by DNA mechanics.},
journal = {Nucleic acids research},
volume = {47},
number = {15},
pages = {e86},
pmid = {31114915},
issn = {1362-4962},
mesh = {Base Pairing ; Base Sequence ; Biomechanical Phenomena ; Buffers ; Click Chemistry/methods ; DNA/*chemistry/genetics ; DNA, Single-Stranded/*chemistry/genetics ; Humans ; Magnetometry/instrumentation/methods ; Nucleic Acid Conformation ; Optical Tweezers ; Polymerase Chain Reaction/methods ; Telomere/*chemistry ; },
abstract = {A telomere carrying repetitive sequences ends with a single-stranded overhang. The G-rich overhang could fold back and bind in the major groove of its upstream duplex, forming an antiparallel triplex structure. The telomeric triplex has been proposed to function in protecting chromosome ends. However, we lack strategies to mechanically probe the dynamics of a telomeric triplex. Here, we show that the topological dynamics of a telomeric triplex involves 3' overhang binding at the ds/ssDNA junction inferred by DNA mechanics. Assisted by click chemistry and branched polymerase chain reaction, we developed a rescue-rope-strategy for mechanically manipulating an artificial telomeric DNA with a free end. Using single-molecule magnetic tweezers, we identified a rarely forming (5%) telomeric triplex which pauses at an intermediate state upon unzipping the Watson-Crick paired duplex. Our findings revealed that a mechanically stable triplex formed in a telomeric DNA can resist a force of 20 pN for a few seconds in a physiological buffer. We also demonstrated that the rescue-rope-strategy assisted mechanical manipulation can directly rupture the interactions between the third strand and its targeting duplex in a DNA triplex. Our single-molecule rescue-rope-strategy will serve as a general tool to investigate telomere dynamics and further develop triplex-based biotechnologies.},
}
@article {pmid31113969,
year = {2019},
author = {Grunnet, LG and Pilgaard, K and Alibegovic, A and Jensen, CB and Hjort, L and Ozanne, SE and Bennett, M and Vaag, A and Brøns, C},
title = {Leukocyte telomere length is associated with elevated plasma glucose and HbA1c in young healthy men independent of birth weight.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {7639},
pmid = {31113969},
issn = {2045-2322},
support = {PG/16/11/32021/BHF_/British Heart Foundation/United Kingdom ; RG/13/14/30314/BHF_/British Heart Foundation/United Kingdom ; MC_UU_00014/4/MRC_/Medical Research Council/United Kingdom ; MC_UU_12012/4/MRC_/Medical Research Council/United Kingdom ; MC_UU_12012/5/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; *Birth Weight ; Blood Glucose/*genetics/metabolism ; Glycated Hemoglobin/*genetics/metabolism ; Humans ; Infant, Low Birth Weight ; Infant, Newborn ; Leukocytes/metabolism ; Male ; Metabolic Syndrome/blood/epidemiology/*genetics ; *Telomere Homeostasis ; },
abstract = {Telomeres are protein-bound regions of repetitive nucleotide sequences (TTAGGG) at the end of human chromosomes, and their length is a marker of cellular aging. Intrauterine growth restriction is associated with shorter blood cell telomeres at birth and individuals with type 2 diabetes have shorter telomeres. Individuals with a low birth weight (LBW) have an increased risk of metabolic disease and type 2 diabetes. Therefore, we aimed to investigate the relationship between birth weight and telomere length and the association between birth weight, telomere length and cardiometabolic phenotype in adulthood. Young, healthy men with LBW (n = 55) and normal birth weight (NBW) (n = 65) were examined including blood pressure, blood samples and body composition. Leukocyte telomere length was determined using a high-throughput qPCR method. The LBW men were more insulin resistant as determined by the HOMA-IR index. There was no difference in telomere length between LBW and NBW subjects. When adjusting for birth weight and cohort effect, significant negative associations between telomere length and fasting glucose (P = 0.003) and HbA1c (P = 0.0008) were found. In conclusion, no significant difference in telomere length was found between LBW and NBW men. The telomere length was negatively associated with glucose concentrations and HbA1c levels within the normal non-diabetic range independent of birth weight.},
}
@article {pmid31113307,
year = {2019},
author = {Giraudeau, M and Heidinger, B and Bonneaud, C and Sepp, T},
title = {Telomere shortening as a mechanism of long-term cost of infectious diseases in natural animal populations.},
journal = {Biology letters},
volume = {15},
number = {5},
pages = {20190190},
pmid = {31113307},
issn = {1744-957X},
mesh = {Aging ; Animals ; Humans ; Mammals ; *Telomerase ; Telomere ; *Telomere Shortening ; },
abstract = {Pathogens are potent selective forces that can reduce the fitness of their hosts. While studies of the short-term energetic costs of infections are accumulating, the long-term costs have only just started to be investigated. Such delayed costs may, at least in part, be mediated by telomere erosion. This hypothesis is supported by experimental investigations conducted on laboratory animals which show that infection accelerates telomere erosion in immune cells. However, the generalizability of such findings to natural animal populations and to humans remains debatable. First, laboratory animals typically display long telomeres relative to their wild counterparts. Second, unlike humans and most wild animals, laboratory small-bodied mammals are capable of telomerase-based telomere maintenance throughout life. Third, the effect of infections on telomere shortening and ageing has only been studied using single pathogen infections, yet hosts are often simultaneously confronted with a range of pathogens in the wild. Thus, the cost of an infection in terms of telomere-shortening-related ageing in natural animal populations is likely to be strongly underestimated. Here, we discuss how investigations into the links between infection, immune response and tissue ageing are now required to improve our understanding of the long-term impact of disease.},
}
@article {pmid31112903,
year = {2019},
author = {Meier, HCS and Hussein, M and Needham, B and Barber, S and Lin, J and Seeman, T and Diez Roux, A},
title = {Cellular response to chronic psychosocial stress: Ten-year longitudinal changes in telomere length in the Multi-Ethnic Study of Atherosclerosis.},
journal = {Psychoneuroendocrinology},
volume = {107},
number = {},
pages = {70-81},
pmid = {31112903},
issn = {1873-3360},
support = {HHSN268201500003C/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; N01 HC095161/HC/NHLBI NIH HHS/United States ; UL1 RR024156/RR/NCRR NIH HHS/United States ; R01 HL076831/HL/NHLBI NIH HHS/United States ; N01HC95162/HL/NHLBI NIH HHS/United States ; N01HC95168/HL/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; N01HC95167/HL/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; N01HC95166/HL/NHLBI NIH HHS/United States ; N01 HC095159/HC/NHLBI NIH HHS/United States ; N01HC95160/HL/NHLBI NIH HHS/United States ; R01 HL101161/HL/NHLBI NIH HHS/United States ; R01 HL071759/HL/NHLBI NIH HHS/United States ; UL1 RR025005/RR/NCRR NIH HHS/United States ; N01HC95163/HL/NHLBI NIH HHS/United States ; N01HC95164/HL/NHLBI NIH HHS/United States ; N01 HC095160/HC/NHLBI NIH HHS/United States ; P30 AG028748/AG/NIA NIH HHS/United States ; N01HC95165/HL/NHLBI NIH HHS/United States ; N01HC95161/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; P30 AG017265/AG/NIA NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/genetics/physiology ; Atherosclerosis/genetics ; Biomarkers ; Cellular Senescence/*genetics/physiology ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/physiology ; Longitudinal Studies ; Male ; Middle Aged ; Risk Factors ; Stress, Psychological/*genetics/metabolism ; Telomere/genetics ; Telomere Homeostasis/genetics/physiology ; Telomere Shortening/*genetics/physiology ; },
abstract = {Previous studies have demonstrated an inverse association between chronic psychosocial stress and leukocyte telomere length (LTL), a potential marker of cellular aging. However, due to paucity of longitudinal data, responses of LTL and the LTL aging trajectory to changes in chronic stress exposure remain less well understood. Using data from the Stress I and II ancillary studies of the Multi-Ethnic Study of Atherosclerosis, we estimated the 10-year longitudinal (n = 1,158) associations of within-person changes in chronic stress with changes in LTL, as well as the pooled, cross-sectional associations of chronic stress and LTL (total n = 2,231). We measured chronic stress from both individual and neighborhood-environment sources. At the individual level, we calculated a summary score of each participant's rating of their ongoing (>6 months) material/social problems as moderately/very stressful on the Chronic Burden Scale. Neighborhood-level stress was measured using a summary score of reverse-coded MESA Neighborhood safety, aesthetic quality, and social cohesion scales. Quantiles of these scores were empirically categorized as high, moderate, or low stress. We then summed these individual- and neighborhood-level categorical variables for a total stress measure. Longitudinal within-person associations were estimated with fixed-effects models, which control for all time-invariant confounding, with additional control for time-varying demographics, lagged behaviors and chronic conditions, and specimen storage duration, as well as correction for regression to the mean. Change from low to high total chronic stress was associated with telomere shortening by 0.054 units [95% confidence interval: -0.095, -0.013] over 10 years. This was consistent with, though stronger in magnitude than, cross-sectional estimates. Change in individual-level stress was the primary driver of this effect. We also found suggestive evidence that 1) individuals with persistently high stress experienced the least shortening of telomeres, and 2) changes in individual-level stress were associated with stronger telomere shortening among women, whereas changes in neighborhood stress were associated with stronger shortening among men. Our findings provide longitudinal support to existing evidence, and point to interesting dynamics in telomere attrition across stress levels and genders.},
}
@article {pmid31111068,
year = {2019},
author = {Pavanello, S and Stendardo, M and Mastrangelo, G and Casillo, V and Nardini, M and Mutti, A and Campisi, M and Andreoli, R and Boschetto, P},
title = {Higher Number of Night Shifts Associates with Good Perception of Work Capacity and Optimal Lung Function but Correlates with Increased Oxidative Damage and Telomere Attrition.},
journal = {BioMed research international},
volume = {2019},
number = {},
pages = {8327629},
pmid = {31111068},
issn = {2314-6141},
mesh = {Adolescent ; Adult ; Aged ; Aging/physiology ; Allied Health Personnel ; Biological Clocks ; Circadian Rhythm/physiology ; Cross-Sectional Studies ; DNA Methylation ; Female ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Oxidation-Reduction ; *Oxidative Stress ; Regression Analysis ; *Respiratory Physiological Phenomena ; Shift Work Schedule ; Sleep/physiology ; Sleep Disorders, Circadian Rhythm/psychology ; Surveys and Questionnaires ; Telomere/*metabolism ; Work Schedule Tolerance/*physiology/*psychology ; Young Adult ; },
abstract = {Sleep deprivation and the consequent circadian clock disruption has become an emergent health question being associated with premature aging and earlier chronic diseases onset. Night-shift work leads to circadian clock misalignment, which is linked to several age-related diseases. However, mechanisms of this association are not well understood. Aim of this study is to explore in night-shift workers early indicators of oxidative stress response and biological aging [oxidized/methylated DNA bases and leukocytes telomere length (LTL)] and late indicators of functional aging [lung function measurements (FEV1 and FVC)] in relation to personal evaluation of work capacity, measured by work ability index (WAI). One hundred fifty-five hospital workers were studied within the framework of a cross-sectional study. We collected physiological, pathological, and occupational history including pack-years, alcohol consumption, physical activity, and night shifts, together with blood and urine samples. Relationships were appraised by univariate and multivariate ordered-logistic regression models. We found that workers with good and excellent WAI present higher FEV1 (p< 0.01) and number of night-work shifts (p<0.05), but they reveal higher urinary levels of 8-oxoGua (p<0.01) and shorter LTL (p<0.05). We confirmed that higher work ability was prevalent among chronological younger workers (p<0.05), who have also a significant reduced number of diseases, particularly chronic (p<0.01) and musculoskeletal diseases (p<0.01). The new findings which stem from our work are that subjects with the highest work ability perception may have more demanding and burdensome tasks; they in fact present the highest number of night-shift work and produce unbalanced oxidative stress response that might induce premature aging.},
}
@article {pmid31110492,
year = {2019},
author = {Zhan, Y and Song, H},
title = {Editorial: Telomeres and Epigenetics in Endocrinology.},
journal = {Frontiers in endocrinology},
volume = {10},
number = {},
pages = {257},
pmid = {31110492},
issn = {1664-2392},
}
@article {pmid31109116,
year = {2019},
author = {Shin, D and Shin, J and Lee, KW},
title = {Effects of Inflammation and Depression on Telomere Length in Young Adults in the United States.},
journal = {Journal of clinical medicine},
volume = {8},
number = {5},
pages = {},
pmid = {31109116},
issn = {2077-0383},
abstract = {Little is known about the associations of inflammation and depression with telomere length. Using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002, the current study assessed the effects of inflammation and depression on telomere length in 1141 young adults in the USA. Depression status was assessed from the World Health Organization Composite International Diagnostic Interview and inflammation status was measured based on C-reactive protein (CRP) concentrations. Information on telomere length was obtained using the quantitative polymerase chain reaction method to measure telomere length relative to standard reference DNA (T/S ratio). Unadjusted and adjusted linear and logistic regression models were used to assess the relationship between the tertiles of CRP concentration and the telomere length stratified by the status of depression such as major depression or depressed affect vs. no depression. The adjusted models were controlled for age, family poverty income ratio, race/ethnicity, marital status, physical activity, body mass index, and alcohol drinking status. A significant and decreasing linear trend in telomere length was found as CRP levels increased in men, regardless of the depression status, and women with major depression or depressed affect (p values < 0.05). Among men without depression, those with an elevated CRP level had increased odds of having a shortened telomere length compared to men with low CRP levels after controlling for covariates (adjusted odds ratio 1.77, 95% confidence interval (CI) 1.09-2.90). In women, there was no association between CRP and telomere length, regardless of the depression status. In conclusion, there was a significant and inverse association between inflammation and telomere length according to the depression status in men but not in women. The present findings may be of clinical significance for the monitoring of inflammation levels and depression status as determinants of telomere length.},
}
@article {pmid31108918,
year = {2019},
author = {Koriath, M and Müller, C and Pfeiffer, N and Nickels, S and Beutel, M and Schmidtmann, I and Rapp, S and Münzel, T and Westermann, D and Karakas, M and Wild, PS and Lackner, KJ and Blankenberg, S and Zeller, T},
title = {Relative Telomere Length and Cardiovascular Risk Factors.},
journal = {Biomolecules},
volume = {9},
number = {5},
pages = {},
pmid = {31108918},
issn = {2218-273X},
support = {81Z1710101//German Center for Cardiovascular Research (DZHK)/International ; AZ 961 - 386261/733//Stiftung Rheinland-Pfalz f&#xfc;r Innovation/International ; PREMED-CAD//European Research Area Network (ERA-Net)/International ; },
mesh = {Age Factors ; Aged ; Body Mass Index ; Cardiovascular Diseases/epidemiology/*genetics ; Cholesterol/blood ; Female ; Humans ; Male ; Middle Aged ; Smoking/epidemiology ; *Telomere Homeostasis ; Triglycerides/blood ; },
abstract = {(1) Background: Telomeres are repetitive DNA sequences located at the extremities of chromosomes that maintain genetic stability. Telomere biology is relevant to several human disorders and diseases, specifically cardiovascular disease. To better understand the link between cardiovascular disease and telomere length, we studied the effect of relative telomere length (RTL) on cardiovascular risk factors in a large population-based sample. (2) Methods: RTL was measured by a real-time quantitative polymerase chain reaction in subjects of the population-based Gutenberg Health Study (n = 4944). We then performed an association study of RTL with known cardiovascular risk factors of smoking status as well as systolic and diastolic blood pressure, body mass index (BMI), LDL cholesterol, HDL cholesterol, and triglycerides. (3) Results: A significant correlation was shown for RTL, with age as a quality control in our study (effect = -0.004, p = 3.2 × 10[-47]). Analysis of the relation between RTL and cardiovascular risk factors showed a significant association of RTL in patients who were current smokers (effect = -0.016, p = 0.048). No significant associations with RTL were seen for cardiovascular risk factors of LDL cholesterol (p = 0.127), HDL cholesterol (p = 0.713), triglycerides (p = 0.359), smoking (p = 0.328), diastolic blood pressure (p = 0.615), systolic blood pressure (p = 0.949), or BMI (p = 0.903). In a subsequent analysis, we calculated the tertiles of RTL. No significant difference across RTL tertiles was detectable for BMI, blood pressure, lipid levels, or smoking status. Finally, we studied the association of RTL and cardiovascular risk factors stratified by tertiles of age. We found a significant association of RTL and LDL cholesterol in the oldest tertile of age (effect = 0.0004, p = 0.006). (4) Conclusions: We determined the association of relative telomere length and cardiovascular risk factors in a population setting. An association of telomere length with age, current smoking status, as well as with LDL cholesterol in the oldest tertile of age was found, whereas no associations were observed between telomere length and triglycerides, HDL cholesterol, blood pressure, or BMI.},
}
@article {pmid31107721,
year = {2019},
author = {Asaka, S and Davis, C and Lin, SF and Wang, TL and Heaphy, CM and Shih, IM},
title = {Analysis of Telomere Lengths in p53 Signatures and Incidental Serous Tubal Intraepithelial Carcinomas Without Concurrent Ovarian Cancer.},
journal = {The American journal of surgical pathology},
volume = {43},
number = {8},
pages = {1083-1091},
pmid = {31107721},
issn = {1532-0979},
support = {P50 CA228991/CA/NCI NIH HHS/United States ; U01 CA200469/CA/NCI NIH HHS/United States ; },
mesh = {Biomarkers, Tumor/analysis/*genetics ; Carcinoma in Situ/chemistry/*genetics/pathology/surgery ; Fallopian Tube Neoplasms/chemistry/*genetics/pathology/surgery ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Neoplasms, Cystic, Mucinous, and Serous/chemistry/*genetics/pathology/surgery ; Telomere/*genetics ; *Telomere Shortening ; *Transcriptome ; Tumor Suppressor Protein p53/analysis/*genetics ; },
abstract = {Telomere alterations represent one of the major molecular changes in the development of human cancer. We have previously reported that telomere lengths in most serous tubal intraepithelial carcinomas (STIC) are shorter than they are in ovarian high-grade serous carcinomas (HGSC) or in normal-appearing fallopian tube epithelium from the same patients. However, it remains critical to determine if similar telomere alterations occur in TP53-mutated but histologically unremarkable "p53 signature" lesions, as well as incidental STICs without concurrent HGSC. In this study, we quantitatively measured telomere lengths by performing telomere-specific fluorescence in situ hybridization in conjunction with p53 immunolabeling in 15 p53 signatures and 30 incidental STICs without concurrent HGSC. We compared these new results with our previous data in paired STICs and concurrent HGSCs. We found that most p53 signatures (80%) and incidental STICs without HGSC (77%) exhibited significant telomere shortening compared with adjacent normal-appearing fallopian tube epithelium (P<0.01). Interestingly, however, p53 signatures and incidental STICs without HGSC displayed longer telomeres and less cell-to-cell telomere length heterogeneity than STICs associated with HGSC (P<0.001). These findings indicate that telomere shortening occurs in p53 signatures, the earliest precancer lesion. Moreover, incidental STICs without concurrent HGSC are indeed similar to p53 signatures as they have less telomere shortening and less cell-to-cell telomere length heterogeneity than STICs associated with HGSC.},
}
@article {pmid31107456,
year = {2019},
author = {Sayed, ME and Slusher, AL and Ludlow, AT},
title = {Droplet Digital TRAP (ddTRAP): Adaptation of the Telomere Repeat Amplification Protocol to Droplet Digital Polymerase Chain Reaction.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {147},
pages = {},
doi = {10.3791/59550},
pmid = {31107456},
issn = {1940-087X},
support = {R00 CA197672/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Polymerase Chain Reaction/*methods ; Telomere/*metabolism ; },
abstract = {The telomere repeat amplification protocol (TRAP) is the most widely used assay to detect telomerase activity within a given a sample. The polymerase chain reaction (PCR)-based method allows for robust measurements of enzyme activity from most cell lysates. The gel-based TRAP with fluorescently labeled primers limits sample throughput, and the ability to detect differences in samples is restricted to two fold or greater changes in enzyme activity. The droplet digital TRAP, ddTRAP, is a highly sensitive approach that has been modified from the traditional TRAP assay, enabling the user to perform a robust analysis on 96 samples per run and obtain absolute quantification of the DNA (telomerase extension products) input within each PCR. Therefore, the newly developed ddTRAP assay overcomes the limitations of the traditional gel-based TRAP assay and provides a more efficient, accurate, and quantitative approach to measuring telomerase activity within laboratory and clinical settings.},
}
@article {pmid31105579,
year = {2019},
author = {Stenbäck, V and Mutt, SJ and Leppäluoto, J and Gagnon, DD and Mäkelä, KA and Jokelainen, J and Keinänen-Kiukaanniemi, S and Herzig, KH},
title = {Association of Physical Activity With Telomere Length Among Elderly Adults - The Oulu Cohort 1945.},
journal = {Frontiers in physiology},
volume = {10},
number = {},
pages = {444},
pmid = {31105579},
issn = {1664-042X},
abstract = {Introduction: Physical activity (PA) has been associated with telomere shortening. The association of PA intensity or volume with telomere length (TL) is nonetheless unclear. The aim of our study was to investigate the associations of exercise intensity and volume with TL in elderly adults from Northern Finland (65° latitude North). Methods: Seven hundred elderly subjects born in 1945 in the Oulu region were investigated. PA was measured during a 2-week period with a wrist-worn accelerometer. In addition, a questionnaire was used to assess sedentary time and to achieve a longitudinal PA history and intensity. Relative telomere lengths (RTL) were determined from frozen whole blood samples using a qPCR-based method. Results: Relative telomere lengths were significantly longer in women than men and negatively correlated with age in both genders (men r = -0.210, p = 0.000, women r = -0.174, and p = 0.000). During the 2-week study period, women took more steps than men (p = 0.001), but the association between steps and RTL was only seen in men (p = 0.05). Total steps taken (r = 0.202 and p = 0.04) and sedentary time (r = -0.247 and p = 0.007) significantly correlated with RTLs in 70-year old subjects. Moderate PA was associated with RTL in subjects with the highest quartile of moderate PA compared to the three lower quartiles (p-values: 0.023 between 4th and 1st, 0.04 between 4th and 2nd, and 0.027 between 4th and 3rd) in the 70-year old subjects. Conclusion: Women had longer RTL and a higher step count compared to men. However, exercise volume and RTL correlated positively only in men. Surprisingly, age correlated negatively with RTL already within an age difference of 2 years. This suggests that telomere attrition rate may accelerate in older age. Moderate physical activity at the time of study was associated with RTL.},
}
@article {pmid31101542,
year = {2019},
author = {Dlouha, D and Vymetalova, J and Hubacek, JA and Lanska, V and Malek, I},
title = {Association between aortic telomere length and cardiac post-transplant allograft function.},
journal = {International journal of cardiology},
volume = {290},
number = {},
pages = {129-133},
doi = {10.1016/j.ijcard.2019.05.006},
pmid = {31101542},
issn = {1874-1754},
mesh = {Adult ; Aorta/*physiology ; Female ; Graft Rejection/*diagnosis/*genetics/physiopathology ; Heart Transplantation/*trends ; Humans ; Male ; Middle Aged ; Telomere/physiology ; Telomere Shortening/*physiology ; Tissue Donors ; Transplantation, Homologous/*trends ; },
abstract = {BACKGROUND: In patients having undergone orthotopic heart transplantation, a number of complications exist that are known to be connected to both telomerase activity and telomere length. The aim of this study was to determine how telomere length in aortic DNA correlates with the subsequent post-transplantation development of the patients.<br><br>MATERIALS AND METHODS: Between 2005 and 2015, we collected aortic samples from 376 heart recipients (age 50.8&#x202f;&#xb1;&#x202f;11.8&#x202f;years) and 383 donors (age 38.6&#x202f;&#xb1;&#x202f;12.2&#x202f;years). Relative telomere length in aortic tissue DNA was determined using quantitative PCR.<br><br>RESULTS: Shorter telomere length was detected in heart allograft recipients compared to donors (P&#x202f;<&#x202f;0.0001). Patients suffering acute cellular rejection had significantly shorter telomere length (P&#x202f;<&#x202f;0.01) than patients without rejection. Shorter telomere length was observed in patients with implanted mechanical circulatory support before heart transplantation (P&#x202f;<&#x202f;0.03), as well as in subjects with cardiac allograft vasculopathy (P&#x202f;<&#x202f;0.05). Overall survival time after heart transplantation was associated with shorter donor telomeres (P&#x202f;<&#x202f;0.004).<br><br>CONCLUSIONS: Telomere length differed between donors and recipients independent of the sex and age of the patients. Our findings suggest a potential new linkage between the aortic telomere length of recipients and post-heart transplant complications. Further studies focusing on epigenetic modifications and gene regulation involved in telomere maintenance in transplanted patients should verify our results.},
}
@article {pmid31101499,
year = {2019},
author = {Fouquerel, E and Barnes, RP and Uttam, S and Watkins, SC and Bruchez, MP and Opresko, PL},
title = {Targeted and Persistent 8-Oxoguanine Base Damage at Telomeres Promotes Telomere Loss and Crisis.},
journal = {Molecular cell},
volume = {75},
number = {1},
pages = {117-130.e6},
pmid = {31101499},
issn = {1097-4164},
support = {K99 ES027028/ES/NIEHS NIH HHS/United States ; R21 ES025606/ES/NIEHS NIH HHS/United States ; R01 ES028242/ES/NIEHS NIH HHS/United States ; P30 CA047904/CA/NCI NIH HHS/United States ; R01 CA207342/CA/NCI NIH HHS/United States ; R01 EB017268/EB/NIBIB NIH HHS/United States ; R01 ES022944/ES/NIEHS NIH HHS/United States ; R00 ES027028/ES/NIEHS NIH HHS/United States ; R35 ES030396/ES/NIEHS NIH HHS/United States ; R33 ES025606/ES/NIEHS NIH HHS/United States ; },
mesh = {Cell Division/radiation effects ; Cell Line, Tumor ; Cell Survival/radiation effects ; Chromosome Aberrations/*radiation effects ; DNA Damage ; DNA Glycosylases/deficiency/*genetics ; DNA Repair/*radiation effects ; DNA Replication/radiation effects ; Gene Expression ; Genomic Instability/*radiation effects ; Guanine/agonists/*analogs &amp; derivatives/biosynthesis ; HeLa Cells ; Humans ; Light/adverse effects ; Micronuclei, Chromosome-Defective/radiation effects ; Optogenetics ; Osteoblasts/cytology/metabolism/radiation effects ; Oxidative Stress/radiation effects ; Singlet Oxygen/agonists/metabolism ; Telomere/metabolism/*radiation effects ; Telomere Homeostasis/radiation effects ; },
abstract = {Telomeres are essential for genome stability. Oxidative stress caused by excess reactive oxygen species (ROS) accelerates telomere shortening. Although telomeres are hypersensitive to ROS-mediated 8-oxoguanine (8-oxoG) formation, the biological effect of this common lesion at telomeres is poorly understood because ROS have pleiotropic effects. Here we developed a chemoptogenetic tool that selectively produces 8-oxoG only at telomeres. Acute telomeric 8-oxoG formation increased telomere fragility in cells lacking OGG1, the enzyme that removes 8-oxoG, but did not compromise cell survival. However, chronic telomeric 8-oxoG induction over time shortens telomeres and impairs cell growth. Accumulation of telomeric 8-oxoG in chronically exposed OGG1-deficient cells triggers replication stress, as evidenced by mitotic DNA synthesis at telomeres, and significantly increases telomere losses. These losses generate chromosome fusions, leading to chromatin bridges and micronucleus formation upon cell division. By confining base damage to the telomeres, we show that telomeric 8-oxoG accumulation directly drives telomere crisis.},
}
@article {pmid31100911,
year = {2019},
author = {Weale, CJ and Davison, GM and Hon, GM and Kengne, AP and Erasmus, RT and Matsha, TE},
title = {Leucocyte Telomere Length and Glucose Tolerance Status in Mixed-Ancestry South Africans.},
journal = {Cells},
volume = {8},
number = {5},
pages = {},
pmid = {31100911},
issn = {2073-4409},
mesh = {Age Factors ; Aged ; Blood Glucose/*analysis ; Diabetes Mellitus, Type 2/genetics ; Female ; Follow-Up Studies ; Glucose Tolerance Test ; Humans ; Hyperglycemia/*epidemiology ; Insulin/blood ; Leukocytes/*cytology ; Longitudinal Studies ; Male ; Middle Aged ; Obesity/genetics ; South Africa/epidemiology ; Telomere/*genetics ; Telomere Shortening/*genetics ; gamma-Glutamyltransferase/blood ; },
abstract = {Telomeres are DNA-tandem repeats situated at the ends of chromosomes and are responsible for genome stabilization. They are eroded by increased cell division, age and oxidative stress with shortened leucocyte telomeres (LTL) being associated with inflammatory disorders, including Type II diabetes. We assessed LTL in 205 participants across glucose tolerance groups at baseline and after three years in the mixed ancestry population of South Africa which have been shown to have high rates of obesity and T2DM. Baseline and follow-up data included glucose tolerance status, anthropometric measurements, lipids, insulin, γ-glutamyl transferase (GGT), cotinine, and HbA1c. Telomere length was measured using the absolute telomere q-PCR method performed on a Bio-Rad MiniOpticon Detector. No significant difference was detected in LTL across glucose tolerance groups at both time points, including in subjects who showed a deterioration of their glucose tolerance status. There was, however, a significant negative correlation between LTL and age which was more pronounced in diabetes (r = -0.18, p = 0.04) and with GGT (r = -0.16, p = 0.027). This longitudinal study has demonstrated that LTL shortening is not evident within three years, nor is it associated with glycaemia. Further studies in a larger sample and over a longer time period is required to confirm these results.},
}
@article {pmid31100684,
year = {2019},
author = {Iberl, S and Meyer, AL and Müller, G and Peters, S and Johannesen, S and Kobor, I and Beier, F and Brümmendorf, TH and Hart, C and Schelker, R and Herr, W and Bogdahn, U and Grassinger, J},
title = {Effects of continuous high-dose G-CSF administration on hematopoietic stem cell mobilization and telomere length in patients with amyotrophic lateral sclerosis - a pilot study.},
journal = {Cytokine},
volume = {120},
number = {},
pages = {192-201},
doi = {10.1016/j.cyto.2019.05.003},
pmid = {31100684},
issn = {1096-0023},
mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/blood/*drug therapy/*genetics ; Antigens, CD34/metabolism ; Blood Cell Count ; Colony-Forming Units Assay ; Cytokines/blood ; Dose-Response Relationship, Drug ; Female ; Granulocyte Colony-Stimulating Factor/*administration &amp; dosage ; *Hematopoietic Stem Cell Mobilization ; Hematopoietic Stem Cells/drug effects/metabolism ; Humans ; Male ; Middle Aged ; Pilot Projects ; *Telomere Homeostasis ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of complex and still poorly understood etiology. Loss of upper and lower motoneurons results in death within few years after diagnosis. Recent studies have proposed neuroprotective and disease-slowing effects of granulocyte-colony stimulating factor (G-CSF) treatment in ALS mouse models as well as humans. In this study, six ALS patients were monitored up to 3.5 years during continuous high-dose G-CSF administration. Repetitive analyses were performed including blood count parameters, CD34[+] hematopoietic stem and progenitor cell (HSPC) and colony forming cell (CFC) counts, serum cytokine levels and leukocyte telomere length. We demonstrate that continuous G-CSF therapy was well tolerated and safe resulting in only mild adverse events during the observation period. However, no mobilization of CD34[+] HSPC was detected as compared to baseline values. CFC mobilization was equally low and even a decrease of myeloid precursors was observed in some patients. Assessment of telomere length within ALS patients' leukocytes revealed that G-CSF did not significantly shorten telomeres, while those of ALS patients were shorter compared to age-matched healthy controls, irrespective of G-CSF treatment. During G-CSF stimulation, TNF-alpha, CRP, IL-16, sVCAM-1, sICAM-1, Tie-2 and VEGF were significantly increased in serum whereas MCP-1 levels decreased. In conclusion, our data show that continuous G-CSF treatment fails to increase circulating CD34[+] HSPC in ALS patients. Cytokine profiles revealed G-CSF-mediated immunomodulatory and proteolytic effects. Interestingly, despite intense G-CSF stimulation, telomere length was not significantly shortened.},
}
@article {pmid31097032,
year = {2019},
author = {Farooqi, A and Yang, J and Sharin, V and Ezhilarasan, R and Danussi, C and Alvarez, C and Dharmaiah, S and Irvin, D and Huse, J and Sulman, EP},
title = {Identification of patient-derived glioblastoma stem cell (GSC) lines with the alternative lengthening of telomeres phenotype.},
journal = {Acta neuropathologica communications},
volume = {7},
number = {1},
pages = {76},
pmid = {31097032},
issn = {2051-5960},
support = {Prince Resident Research Grant 2018-2019//Radiological Society of North America/International ; },
mesh = {Animals ; Brain Neoplasms/*metabolism ; Cell Line, Tumor ; Glioblastoma/*metabolism ; Humans ; Mice ; Neoplastic Stem Cells/*metabolism ; RNA, Messenger/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; X-linked Nuclear Protein/metabolism ; },
}
@article {pmid31093683,
year = {2019},
author = {Lin, X and Zhou, J and Dong, B},
title = {Effect of different levels of exercise on telomere length: A systematic review and meta-analysis.},
journal = {Journal of rehabilitation medicine},
volume = {51},
number = {7},
pages = {473-478},
doi = {10.2340/16501977-2560},
pmid = {31093683},
issn = {1651-2081},
mesh = {Exercise/*physiology ; Exercise Therapy/*methods ; Female ; Humans ; Male ; Motor Activity/*physiology ; Randomized Controlled Trials as Topic ; Telomere/*physiology ; },
abstract = {OBJECTIVE: To investigate the effect of different levels of exercise on telomere length.<br><br>METHODS: CINAHL, SPORTDiscus (EBSCO), OVID (Medline) and EMBASE databases were searched for eligible studies. Methodological quality was evaluated using the Newcastle-Ottawa Scale, and heterogeneity among the studies was assessed using the I-squared test. When heterogeneity among studies was high (I2&#x2009;>&#x2009;50%), a random-effects model was used (Review Manager version 5, Cochrane Collaboration, Copenhagen, Denmark); otherwise, a fixed-effects model was used.<br><br>RESULTS: Eleven eligible studies involving 19,292 participants were included in this meta-analysis. Longer telomere length was associated with physically active individuals, with a mean difference (MD) of 0.15 (95% confidence interval; 95% CI 0.05, 0.24); I2&#x2009;=&#x2009;99%. Longer telomere length was significantly associated with robust exercise (MD 0.08 (95% CI 0.04, 0.12)); I2&#x2009;=&#x2009;99%, as was moderate exercise (MD 0.07 (95% CI 0.03, 0.11)); I2&#x2009;=&#x2009;100%. Subgroup analysis revealed that longer telomere length was positively associated with exercise, regardless of sex, but was not statistically significant in elderly populations.<br><br>CONCLUSION: Compared with inactive individuals, telomere lengths were longer in active subjects, regardless of the intensity of exercise.},
}
@article {pmid31090230,
year = {2019},
author = {Hu, R and Hua, XG and Jiang, QC},
title = {Associations of telomere length in risk and recurrence of prostate cancer: A meta-analysis.},
journal = {Andrologia},
volume = {51},
number = {7},
pages = {e13304},
doi = {10.1111/and.13304},
pmid = {31090230},
issn = {1439-0272},
mesh = {Datasets as Topic ; Humans ; Male ; Neoplasm Recurrence, Local/epidemiology/*genetics/pathology ; Prostate/pathology ; Prostatic Neoplasms/*genetics/pathology ; Risk Assessment ; Telomere/*genetics ; *Telomere Shortening ; },
abstract = {Over the past decades, there is an increasing number of association studies of telomere length (TL) and the risk and recurrence of prostate cancer (PCa), but the results are inconsistent. Hence, we identify the relevant studies published in English on or before 10 January 2019 conducting a literature review in the electronic databases including PubMed, EMBASE and Cochrane Library. Twelve studies (with 19 data sets) were included in this meta-analysis, five of which were associated with risk assessment, six of which reported recurrence of PCa and one of which included them. Our meta-analysis demonstrated a positive association of shorter telomeres in patients with PCa, but without statistical significance (OR, 1.23; 95% CI: 0.91-1.66). Shorter telomeres in stroma (OR, 2.40; 95% CI: 1.61-3.56) and epithelium (OR, 1.70; 95% CI: 1.33-2.16) were positively correlated with PCa, but in leucocyte (OR, 0.81; 95% CI: 0.73-0.91) had negative association with PCa. Furthermore, two studies combined yielded a pooled OR of 2.87 (95% CI: 1.22-6.76) for the association between shorter TL and metastasis. These results are novel and give further strength to formulate eligible individualising treatment and surveillance strategies.},
}
@article {pmid31086817,
year = {2019},
author = {Gauchier, M and Kan, S and Barral, A and Sauzet, S and Agirre, E and Bonnell, E and Saksouk, N and Barth, TK and Ide, S and Urbach, S and Wellinger, RJ and Luco, RF and Imhof, A and Déjardin, J},
title = {SETDB1-dependent heterochromatin stimulates alternative lengthening of telomeres.},
journal = {Science advances},
volume = {5},
number = {5},
pages = {eaav3673},
pmid = {31086817},
issn = {2375-2548},
mesh = {Animals ; Cell Line, Tumor ; Heterochromatin/*metabolism ; Histone Chaperones/metabolism ; Histone-Lysine N-Methyltransferase/antagonists &amp; inhibitors/deficiency/genetics/*metabolism ; Humans ; Methyltransferases/deficiency/genetics ; Mice ; Mice, Inbred C57BL ; Mouse Embryonic Stem Cells/cytology/metabolism ; RNA Interference ; RNA, Small Interfering/metabolism ; Repressor Proteins/deficiency/genetics ; Telomere/*metabolism ; *Telomere Shortening ; Telomeric Repeat Binding Protein 2/metabolism ; X-linked Nuclear Protein/metabolism ; },
abstract = {Alternative lengthening of telomeres, or ALT, is a recombination-based process that maintains telomeres to render some cancer cells immortal. The prevailing view is that ALT is inhibited by heterochromatin because heterochromatin prevents recombination. To test this model, we used telomere-specific quantitative proteomics on cells with heterochromatin deficiencies. In contrast to expectations, we found that ALT does not result from a lack of heterochromatin; rather, ALT is a consequence of heterochromatin formation at telomeres, which is seeded by the histone methyltransferase SETDB1. Heterochromatin stimulates transcriptional elongation at telomeres together with the recruitment of recombination factors, while disrupting heterochromatin had the opposite effect. Consistently, loss of SETDB1, disrupts telomeric heterochromatin and abrogates ALT. Thus, inhibiting telomeric heterochromatin formation in ALT cells might offer a new therapeutic approach to cancer treatment.},
}
@article {pmid31083651,
year = {2019},
author = {Reddy, V and Iskander, A and Hwang, C and Divine, G and Menon, M and Barrack, ER and Reddy, GP and Kim, SH},
title = {Castration-resistant prostate cancer: Androgen receptor inactivation induces telomere DNA damage, and damage response inhibition leads to cell death.},
journal = {PloS one},
volume = {14},
number = {5},
pages = {e0211090},
pmid = {31083651},
issn = {1932-6203},
mesh = {Alternative Splicing ; Animals ; Antineoplastic Agents/pharmacology ; Cell Death ; Cell Line, Tumor ; *DNA Damage ; Disease Models, Animal ; Drug Resistance, Neoplasm/genetics ; Heterografts ; Humans ; Male ; Mice ; Prostatic Neoplasms, Castration-Resistant/*genetics/*metabolism/pathology ; RNA Interference ; Receptors, Androgen/genetics/*metabolism ; *Stress, Physiological ; Telomere/*genetics ; },
abstract = {Telomere stability is important for cell viability, as cells with telomere DNA damage that is not repaired do not survive. We reported previously that androgen receptor (AR) antagonist induces telomere DNA damage in androgen-sensitive LNCaP prostate cancer cells; this triggers a DNA damage response (DDR) at telomeres that includes activation of ATM, and blocking ATM activation prevents telomere DNA repair and leads to cell death. Remarkably, AR antagonist induces telomere DNA damage and triggers ATM activation at telomeres also in 22Rv1 castration-resistant prostate cancer (CRPC) cells that are not growth inhibited by AR antagonist. Treatment with AR antagonist enzalutamide (ENZ) or ATM inhibitor (ATMi) by itself had no effect on growth in vitro or in vivo, but combined treatment with ENZ plus ATMi significantly inhibited cell survival in vitro and tumor growth in vivo. By inducing telomere DNA damage and activating a telomere DDR, an opportunity to inhibit DNA repair and promote cell death was created, even in CRPC cells. 22Rv1 cells express both full-length AR and AR splice variant AR-V7, but full-length AR was found to be the predominant form of AR associated with telomeres and required for telomere stability. Although 22Rv1 growth of untreated 22Rv1 cells appears to be driven by AR-V7, it is, ironically, expression of full-length AR that makes them sensitive to growth inhibition by combined treatment with ENZ plus ATMi. Notably, this combined treatment approach to induce telomere DNA damage and inhibit the DDR was effective in inducing cell death also in other CRPC cell lines (LNCaP/AR and C4-2B). Thus, the use of ENZ in combination with a DDR inhibitor, such as ATMi, may be effective in prolonging disease-free survival of patients with AR-positive metastatic CRPC, even those that co-express AR splice variant.},
}
@article {pmid31075257,
year = {2019},
author = {Ghanem, NZ and Malla, SRL and Araki, N and Lewis, LK},
title = {Quantitative assessment of changes in cell growth, size and morphology during telomere-initiated cellular senescence in Saccharomyces cerevisiae.},
journal = {Experimental cell research},
volume = {381},
number = {1},
pages = {18-28},
pmid = {31075257},
issn = {1090-2422},
support = {R15 AG028520/AG/NIA NIH HHS/United States ; },
mesh = {*Cell Proliferation ; *Cell Size ; *Cellular Senescence ; Gene Knockout Techniques ; *Microbiological Techniques ; Models, Biological ; Saccharomyces cerevisiae/*cytology/genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/*physiology ; Telomere Shortening ; },
abstract = {Telomerase-deficient cells of the budding yeast S. cerevisiae experience progressive telomere shortening and undergo senescence in a manner similar to that seen in cultured human fibroblasts. The cells exhibit a DNA damage checkpoint-like stress response, undergo changes in size and morphology, and eventually stop dividing. In this study, a new assay is described that allowed quantitation of senescence in telomerase-deficient est2 cells with applied statistics. Use of the new technique revealed that senescence was strongly accelerated in est2 mutants that had homologous recombination genes RAD51, RAD52 or RAD54 co-inactivated, but was only modestly affected when RAD55, RAD57 or RAD59 were knocked out. Additionally, a new approach for calculating population doublings indicated that loss of growth capacity occurred after approximately 64 generations in est2 cells but only 42 generations in est2 rad52 cells. Phase contrast microscopy experiments demonstrated that senescing est2 cells became enlarged in a time-dependent manner, ultimately exhibiting a 60% increase in cell size. Progressive alterations in physical properties were also observed, including striking changes in light scattering characteristics and cellular sedimentation rates. The results described herein will facilitate future studies of genetic and environmental factors that affect telomere shortening-associated cell senescence rates using the yeast model system.},
}
@article {pmid31069615,
year = {2019},
author = {Tanpaisankit, M and Hongsaprabhas, C and Chareonlap, C and Honsawek, S},
title = {Relative telomere length and oxidative stress in musculoskeletal tumors.},
journal = {Molecular biology reports},
volume = {46},
number = {4},
pages = {4009-4016},
pmid = {31069615},
issn = {1573-4978},
mesh = {8-Hydroxy-2'-Deoxyguanosine/analysis/metabolism ; Adult ; Aged ; Biomarkers, Tumor/metabolism ; Bone Neoplasms/*pathology ; Female ; Humans ; Leukocytes ; Male ; Middle Aged ; Musculoskeletal System/physiopathology ; Neoplasms/pathology ; Neoplasms, Muscle Tissue/*pathology ; Oxidative Stress/physiology ; Prognosis ; Risk Factors ; Telomere/metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {Telomeres are capped at the end of the chromosome and gradually shorten when the cell divides. When there is an oxidative stress, it can cause the DNA to be damaged. Hence, 8-hydroxy-2'-deoxyguanosine (8-OHdG) has been shown to be an indicator for oxidative DNA damage. This study aimed to determine the relative telomere length (RTL) and 8-OHdG levels in neoplastic tissues, adjacent non-neoplastic tissues, and blood leukocytes of musculoskeletal (MS) tumor patients. Neoplastic tissues were compared to adjacent non-neoplastic tissues in MS tumor patients (n = 46). Peripheral blood leukocytes (PBLs) of MS tumor subjects were compared to those of age-matched healthy controls (n = 107). RTL was evaluated by quantitative real-time polymerase chain reaction and 8-OHdG levels were quantified by enzyme-linked immunosorbent assay. The RTL in neoplastic tissues was significantly shorter than that in non-neoplastic tissues [1.12 (0.86-1.46) vs 1.45 (1.25-1.65), P = 0.001]. PBLs had lower RTL than non-neoplastic tissues in MS tumor patients [1.04 (0.85-1.13) vs 1.45 (1.25-1.65), P < 0.001]. However, there was no significant difference between RTL in PBLs and in neoplastic tissues. In addition, PBLs of MS tumor patients had higher RTL than those of the controls [1.04 (0.85-1.13) versus 0.78 (0.68-0.90), P < 0.001]. The 8-OHdG levels in neoplastic tissues were remarkably higher than those in non-neoplastic tissues [8.14 (6.81-11.37) nM/μg/μl vs. 3.79 (2.53-6.17) nM/μg/μl, P < 0.001]. Furthermore, plasma 8-OHdG levels in MS tumor patients were markedly greater than those in the controls [102.50 (73.16-133.50) nM vs. 41.09 (6.81-11.37) nM, P < 0.001]. Area under the curve (AUC) was 0.7536 (95% confident interval (CI) 0.6602-0.8469) when the cut-off value of RTL in PBLs was 0.97. Also, plasma 8-OHdG levels depicted that when the cut-off value was 38.67 nM, the AUC was 0.7723 (95% CI 0.6920-0.8527). Moreover, ROC curve analysis showed that both RTL and 8-OHdG appeared to improve the sensitivity (85.68%) and specificity (70.91%) with the AUC 0.8639 (95% CI 0.7500-0.9500). This study suggested that blood leukocyte RTL and plasma 8-OHdG could serve as promising non-invasive biomarkers to differentiate between MS tumor patients and healthy controls. Additionally, telomere attrition and increased oxidative DNA damage might play contributory roles in the pathogenesis of MS tumors.},
}
@article {pmid31068970,
year = {2019},
author = {Wang, J and Peng, X and Chen, C and Ning, X and Peng, S and Li, T and Liu, S and Hong, B and Zhou, J and Ma, K and Cai, L and Gong, K},
title = {Intra-Familial Phenotypic Heterogeneity and Telomere Abnormality in von Hippel- Lindau Disease: Implications for Personalized Surveillance Plan and Pathogenesis of VHL-Associated Tumors.},
journal = {Frontiers in genetics},
volume = {10},
number = {},
pages = {358},
pmid = {31068970},
issn = {1664-8021},
abstract = {von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome with poor survival. The current recommendations have proposed uniform surveillance strategies for all patients, neglecting the obvious phenotypic varieties. In this study, we aim to confirm the phenotypic heterogeneity in VHL disease and the underlying mechanism. A total of 151 parent-child pairs were enrolled for genetic anticipation analysis, and 77 sibling pairs for birth order effect analysis. Four statistical methods were used to compare the onset age of patients among different generations and different birth orders. The results showed that the average onset age was 18.9 years earlier in children than in their parents, which was statistically significant in all of the four statistical methods. Furthermore, the first-born siblings were affected 8.3 years later than the other ones among the maternal patients. Telomere shortening was confirmed to be associated with genetic anticipation in VHL families, while it failed to explain the birth order effect. Moreover, no significant difference was observed for overall survival between parents and children (p = 0.834) and between first-born patients and the other siblings (p = 0.390). This study provides definitive evidence and possible mechanisms of intra-familial phenotypic heterogeneity in VHL families, which is helpful to the update of surveillance guidelines.},
}
@article {pmid31067621,
year = {2019},
author = {Niederberger, C},
title = {Re: Non-Obstructive Azoospermia and Shortened Leukocyte Telomere Length: Further Evidence Linking Poor Health and Infertility.},
journal = {The Journal of urology},
volume = {201},
number = {6},
pages = {1040-1041},
doi = {10.1097/01.JU.0000559579.63436.58},
pmid = {31067621},
issn = {1527-3792},
mesh = {*Azoospermia ; Humans ; Leukocytes ; Male ; Telomere ; },
}
@article {pmid31067611,
year = {2019},
author = {},
title = {Re: Shorter Leukocyte Telomere Length is Associated with Risk of Nonobstructive Azoospermia.},
journal = {The Journal of urology},
volume = {201},
number = {6},
pages = {1040},
doi = {10.1097/01.JU.0000559578.55813.89},
pmid = {31067611},
issn = {1527-3792},
mesh = {*Azoospermia ; Humans ; Leukocytes ; Male ; Telomere ; },
}
@article {pmid31062416,
year = {2019},
author = {Sugarman, ET and Zhang, G and Shay, JW},
title = {In perspective: An update on telomere targeting in cancer.},
journal = {Molecular carcinogenesis},
volume = {58},
number = {9},
pages = {1581-1588},
pmid = {31062416},
issn = {1098-2744},
support = {R01 AG001228/AG/NIA NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; C06 RR030414/RR/NCRR NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; },
mesh = {Antineoplastic Agents/*therapeutic use ; Humans ; Neoplasms/*drug therapy/metabolism ; Telomerase/metabolism ; Telomere/*drug effects ; Telomere Homeostasis/drug effects ; },
abstract = {Engaging a telomere maintenance mechanism during DNA replication is essential for almost all advanced cancers. The conversion from normal and premalignant somatic cells to advanced malignant cells often results (85%-90%) from the reactivation of the functional ribonucleoprotein holoenzyme complex, referred to as telomerase. Modulation of the human telomerase reverse transcriptase (hTERT) appears to be rate limiting to produce functional telomerase and engage a telomere maintenance mechanism. The remaining 10% to 15% of cancers overcome progressively shortened telomeres by activating an alternative lengthening of telomeres (ALT) maintenance mechanism, through a DNA recombination pathway. Exploration into the specific mechanisms of telomere maintenance in cancer have led to the development of drugs such as Imetelstat (GRN163L), BIBR1532, 6-thio-dG, VE-822, and NVP-BEZ235 being investigated as therapeutic approaches for treating telomerase and ALT tumors. The successful use of 6-thio-dG (a nucleoside preferentially recognized by telomerase) that targets and uncaps telomeres in telomerase positive but not normal telomerase silent cells has recently shown impressive effects on multiple types of cancer. For example, 6-thio-dG overcomes therapy-resistant cancers in a fast-acting mechanism potentially providing an alternative or additional route of treatment for patients with cancer. In this perspective, we provide a synopsis of the current landscape of telomeres and telomerase processing in cancer development and how this new knowledge may improve outcomes for patients with cancer.},
}
@article {pmid31060240,
year = {2019},
author = {Huda, N and Xu, Y and Bates, AM and Rankin, DA and Kannan, N and Gilley, D},
title = {Onset of Telomere Dysfunction and Fusions in Human Ovarian Carcinoma.},
journal = {Cells},
volume = {8},
number = {5},
pages = {},
pmid = {31060240},
issn = {2073-4409},
mesh = {Adult ; Aged ; Aged, 80 and over ; Anaphase ; Female ; Humans ; Middle Aged ; Ovarian Neoplasms/*genetics/pathology ; Telomerase/metabolism ; Telomere/*pathology ; },
abstract = {Telomere dysfunction has been strongly implicated in the initiation of genomic instability and is suspected to be an early event in the carcinogenesis of human solid tumors. Recent findings have established the presence of telomere fusions in human breast and prostate malignancies; however, the onset of this genomic instability mechanism during progression of other solid cancers is not well understood. Herein, we explored telomere dynamics in patient-derived epithelial ovarian cancers (OC), a malignancy characterized by multiple distinct subtypes, extensive molecular heterogeneity, and widespread genomic instability. We discovered a high frequency of telomere fusions in ovarian tumor tissues; however, limited telomere fusions were detected in normal adjacent tissues or benign ovarian samples. In addition, we found relatively high levels of both telomerase activity and hTERT expression, along with anaphase bridges in tumor tissues, which were notably absent in adjacent normal ovarian tissues and benign lesions. These results suggest that telomere dysfunction may occur early in ovarian carcinogenesis and, importantly, that it may play a critical role in the initiation and progression of the disease. Recognizing telomere dysfunction as a pervasive feature of this heterogeneous malignancy may facilitate the future development of novel diagnostic tools and improved methods of disease monitoring and treatment.},
}
@article {pmid31059920,
year = {2019},
author = {Song, L and Zhang, B and Liu, B and Wu, M and Zhang, L and Wang, L and Xu, S and Cao, Z and Wang, Y},
title = {Effects of maternal exposure to ambient air pollution on newborn telomere length.},
journal = {Environment international},
volume = {128},
number = {},
pages = {254-260},
doi = {10.1016/j.envint.2019.04.064},
pmid = {31059920},
issn = {1873-6750},
mesh = {Adult ; Air Pollution/*analysis ; China ; Cohort Studies ; Female ; Fetal Blood/chemistry ; Humans ; Infant, Newborn ; Male ; *Maternal Exposure ; Mothers ; Pregnancy ; Pregnancy Trimester, Third ; Pregnancy Trimesters ; *Telomere ; },
abstract = {BACKGROUND: Telomere length (TL) is considered as a surrogate of biological aging and has been related to aging-related diseases. The initial setting of newborn TL has important implications for telomere dynamics in adulthood, and is affected by the intrauterine environment. However, the effects of prenatal air pollution exposure on the initial setting of newborn TL are poor understood.<br><br>OBJECTIVES: We aimed to explore the trimester-specific relationships between maternal air pollution exposure and newborn TL.<br><br>METHODS: Between November 2013 and March 2015, a total of 762 mother-newborn pairs were recruited in a birth cohort study in Wuhan, China. Relative cord blood TL was assessed using quantitative real-time polymerase chain reaction. Maternal exposures to PM2.5, PM10, SO2, CO, and NO2, were determined using spatial-temporal land use regression models. Multiple informant models were applied to explore the trimester-specific associations of maternal air pollution exposure with cord blood TL.<br><br>RESULTS: In single-pollutant models, a 10&#x202f;&#x3bc;g/m[3] increase in PM2.5, PM10, SO2, and a 100&#x202f;&#x3bc;g/m[3] increase in CO during the third trimester were related to 3.71% (95% confidence interval [CI]: -6.06%, -1.30%), 3.24% (95% CI: -5.29%, -1.14%), 11.07% (95% CI: -18.86%, -2.53%), and 3.67% (95% CI: -6.27%, -1.00%) shorter cord blood TL, respectively. The inverse relationships between exposures to PM2.5, PM10, SO2, and CO during the third trimester and cord blood TL were more evident in male infants. In multi-pollutant models, exposures to PM2.5 and PM10 during the third trimester were both related to shorter cord blood TL, but not SO2 and CO.<br><br>CONCLUSION: This study suggested that maternal exposures to PM2.5, PM10, CO, and SO2 during the third trimester were related to shorter newborn TL, which highlights the importance of improving air quality in favor of subsequent health in later life of newborns.},
}
@article {pmid31057003,
year = {2021},
author = {Gurugubelli Krishna, R and Bhat, BV and Bobby, Z and Papa, D and Badhe, B and Chinnakali, P},
title = {Are Global DNA methylation and telomere length useful biomarkers for identifying intrauterine growth restricted neonates?.},
journal = {The journal of maternal-fetal &amp; neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians},
volume = {34},
number = {5},
pages = {761-764},
doi = {10.1080/14767058.2019.1615875},
pmid = {31057003},
issn = {1476-4954},
mesh = {Biomarkers ; Cohort Studies ; *DNA Methylation ; *Fetal Growth Retardation/diagnosis/genetics ; Gestational Age ; Humans ; Infant, Newborn ; Telomere/genetics ; },
abstract = {Background: Intrauterine growth restriction (IUGR) is manifested by decreased growth rate of fetus than its normal genetic growth potential. Global DNA methylation is a crucial investigation for identification of epigenetic changes. Epigenetic change regulates Gene transcription, maintenance of genomic stability, and telomere length.Objectives: To investigate whether the global DNA methylation and telomere length are useful for identifying intrauterine growth restriction.Methods: This cohort study was conducted in the Neonatology Department of JIPMER during the period of November 2016 to December 2017. Forty (40) IUGR and forty (40) AGA neonates were recruited. Umbilical cord blood samples were collected at birth. DNA has been separated from the blood samples and using 5-mC DNA ELISA method, the percentage of genomic DNA methylated in these neonates was established. Telomere length (T/S ratio) was measured by using quantitative real time PCR. Data were expressed as a mean ± standard deviation.Results: Genomic DNA methylation varied significantly between IUGR and AGA neonates (IUGR: 3.12 ± 1.24; AGA: 4.40 ± 2.03; p: < .01). There was significant DNA hypo methylation in IUGR neonates. However, telomere length (T/S ratio) was (IUGR: 1.25 ± 0.13; AGA: 1.26 ± 0.22; p: 0.228 (NS)) similar in both groups.Conclusion: Although there is no significant difference in telomere length between IUGR and AGA neonates, global DNA methylation of 3.45 would identify IUGR with a sensitivity and specificity of 69 and 65% respectively.},
}
@article {pmid31055168,
year = {2019},
author = {Nie, J and Li, J and Cheng, L and Deng, Y and Li, Y and Yan, Z and Duan, L and Niu, Q and Tang, D},
title = {Prenatal polycyclic aromatic hydrocarbons metabolites, cord blood telomere length, and neonatal neurobehavioral development.},
journal = {Environmental research},
volume = {174},
number = {},
pages = {105-113},
doi = {10.1016/j.envres.2019.04.024},
pmid = {31055168},
issn = {1096-0953},
mesh = {Child ; *Child Development ; Cities ; Environmental Pollutants/*metabolism ; Female ; Fetal Blood ; Humans ; Infant ; Infant, Newborn ; Maternal Exposure/*statistics &amp; numerical data ; Polycyclic Aromatic Hydrocarbons/*metabolism ; Pregnancy ; *Telomere ; },
abstract = {BACKGROUND: Prenatal exposure to polycyclic aromatic hydrocarbon (PAH) is a potential risk factor for child neurobehavioral development. Telomere length (TL) has important implications for health over the life course.<br><br>OBJECTIVE: In this study, we aimed to investigate whether prenatal urinary PAH metabolites were associated with adverse neonatal neurobehavioral development and altered cord blood TL and to explore whether the change of TL was a predictor of neonatal neurobehavioral development.<br><br>METHOD: We enrolled 283 nonsmoking pregnant women in Taiyuan city. Eleven PAH metabolites were measured in maternal urine samples. TL in cord blood was measured by real time quantitative polymerase chain reaction. Neonatal behavioral neurological assessment (NBNA) tests were conducted when the infants were three days old. Multiple linear regression models were used to analyze the associations of maternal urinary PAH metabolites with NBNA scores and cord blood TL, and restricted cubic spline models were further used to examine the shapes of dose-response relationships. A mediation analysis was also conducted.<br><br>RESULT: We observed dose-response associations of maternal urinary 2-hydroxyfluorene (2-OHFlu) and 2-hydroxyphenanthrene (2-OH Phe) with decreased active tone scores, sum of NBNA scores, and cord blood TL (P for trend<0.05). Each 1 unit increase in urinary levels of Ln (2-OH Flu) or Ln (2-OH Phe) was associated with a 0.092 or 0.135 decrease in the active tone scores and a 0.174 or 0.199 decrease in the sum of NBNA scores. Mediation analysis showed TL could explained 21.74% of the effect of sum of NBNA scores change related to prenatal exposure to 2-OH Phe (P for mediator&#x202f;=&#x202f;0.047).<br><br>CONCLUSION: Our data indicates maternal urinary specific PAH metabolites are inversely associated with neonatal neurobehavioral development and cord blood TL. TL mediates the associations of 2-OH Phe with neonatal neurobehavioral development and partly explains the effect of 2-OH Phe on neonatal neurobehavioral development.},
}
@article {pmid31051499,
year = {2019},
author = {Canudas, S and Hernández-Alonso, P and Galié, S and Muralidharan, J and Morell-Azanza, L and Zalba, G and García-Gavilán, J and Martí, A and Salas-Salvadó, J and Bulló, M},
title = {Pistachio consumption modulates DNA oxidation and genes related to telomere maintenance: a crossover randomized clinical trial.},
journal = {The American journal of clinical nutrition},
volume = {109},
number = {6},
pages = {1738-1745},
pmid = {31051499},
issn = {1938-3207},
mesh = {Adult ; Aged ; Blood Glucose/metabolism ; DNA/*metabolism ; DNA Damage ; Female ; Humans ; Insulin/blood ; Insulin Resistance ; Male ; Middle Aged ; Molecular Chaperones/genetics/metabolism ; Nuts/chemistry/metabolism ; Oxidation-Reduction ; Pistacia/chemistry/*metabolism ; Prediabetic State/*diet therapy/*genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {BACKGROUND: Telomere attrition may play an important role in the pathogenesis and severity of type 2 diabetes (T2D), increasing the probability of β cell senescence and leading to reduced cell mass and decreased insulin secretion. Nutrition and lifestyle are known factors modulating the aging process and insulin resistance/secretion, determining the risk of T2D.<br><br>OBJECTIVES: The aim of this study was to evaluate the effects of pistachio intake on telomere length and other cellular aging-related parameters of glucose and insulin metabolism.<br><br>METHODS: Forty-nine prediabetic subjects were included in a randomized crossover clinical trial. Subjects consumed a pistachio-supplemented diet (PD, 50 E% [energy percentage] carbohydrates and 33 E% fat, including 57 g pistachios/d) and an isocaloric control diet (CD, 55 E% carbohydrates and 30 E% fat) for 4 mo each, separated by a 2-wk washout period. DNA oxidation was evaluated by DNA damage (via 8-hydroxydeoxyguanosine). Leucocyte telomere length and gene expression related to either oxidation, telomere maintenance or glucose, and insulin metabolism were analyzed by multiplexed quantitative reverse transcriptase-polymerase chain reaction after the dietary intervention.<br><br>RESULTS: Compared with the CD, the PD reduced oxidative damage to DNA (mean: -3.5%; 95% CI: -8.07%, 1.05%; P&#xa0;=&#xa0;0.009). Gene expression of 2 telomere-related genes (TERT and WRAP53) was significantly upregulated (164% and 53%) after the PD compared with the CD (P&#xa0;=&#xa0;0.043 and P&#xa0;=&#xa0;0.001, respectively). Interestingly, changes in TERT expression were negatively correlated to changes in fasting plasma glucose concentrations and in the homeostatic model assessment of insulin resistance.<br><br>CONCLUSIONS: Chronic pistachio consumption reduces oxidative damage to DNA and increases the gene expression of some telomere-associated genes. Lessening oxidative damage to DNA and telomerase expression through diet may represent an intriguing way to promote healthspan in humans, reversing certain deleterious metabolic consequences of prediabetes. This study was registered at clinicaltrials.gov as NCT01441921.},
}
@article {pmid31050187,
year = {2019},
author = {Agrusa, JE and Bertuch, AA and DiNardo, CD and Plon, SE and Eckstein, OS},
title = {Severe therapy-related toxicities after treatment for Hodgkin lymphoma due to a pathogenic TERT variant and shortened telomeres.},
journal = {Pediatric blood &amp; cancer},
volume = {66},
number = {8},
pages = {e27779},
pmid = {31050187},
issn = {1545-5017},
support = {SPORE P50 CA10063/NH/NIH HHS/United States ; R01 HL131744/HL/NHLBI NIH HHS/United States ; L40 TR001681/TR/NCATS NIH HHS/United States ; K12 CA090433/CA/NCI NIH HHS/United States ; 2K12CA090433-16/NH/NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Antineoplastic Combined Chemotherapy Protocols/*adverse effects ; Female ; Hodgkin Disease/*drug therapy/genetics/pathology ; Humans ; Male ; *Mutation ; Neutropenia/chemically induced/genetics/*pathology ; Peripheral Nervous System Diseases/chemically induced/genetics/*pathology ; Prognosis ; Severity of Illness Index ; Telomerase/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Telomere biology disorders predispose affected individuals to specific malignancies and organ fibrosis in tissues sensitive to telomere length (TL) shortening, especially after exposure to chemotherapy and radiation. We report a case of a 17-year-old female with Hodgkin lymphoma who developed severe chemotherapy-related toxicities. She was subsequently found to have peripheral blood lymphocyte TL < 1st percentile and a pathogenic variant in TERT inherited from her father. This case demonstrates that early genetic evaluation of patients who experience greater than expected therapy-related toxicities may be warranted to help guide further decisions regarding therapy, imaging modalities, and lifelong cancer prevention surveillance.},
}
@article {pmid31042766,
year = {2019},
author = {Nettle, D and Seeker, L and Nussey, D and Froy, H and Bateson, M},
title = {Consequences of measurement error in qPCR telomere data: A simulation study.},
journal = {PloS one},
volume = {14},
number = {5},
pages = {e0216118},
pmid = {31042766},
issn = {1932-6203},
support = {NC/K000802/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; },
mesh = {Computer Simulation/statistics &amp; numerical data ; Cross-Sectional Studies ; Humans ; Real-Time Polymerase Chain Reaction/*methods ; Scientific Experimental Error/*statistics &amp; numerical data ; Telomere/genetics ; Telomere Homeostasis/physiology ; },
abstract = {The qPCR method provides an inexpensive, rapid method for estimating relative telomere length across a set of biological samples. Like all laboratory methods, it involves some degree of measurement error. The estimation of relative telomere length is done subjecting the actual measurements made (the Cq values for telomere and a control gene) to non-linear transformations and combining them into a ratio (the TS ratio). Here, we use computer simulations, supported by mathematical analysis, to explore how errors in measurement affect qPCR estimates of relative telomere length, both in cross-sectional and longitudinal data. We show that errors introduced at the level of Cq values are magnified when the TS ratio is calculated. If the errors at the Cq level are normally distributed and independent of true telomere length, those in the TS ratio are positively skewed and proportional to true telomere length. The repeatability of the TS ratio declines sharply with increasing error in measurement of the Cq values for telomere and/or control gene. In simulated longitudinal data, measurement error alone can produce a pattern of low correlation between successive measures of relative telomere length, coupled with a strong negative dependency of the rate of change on initial relative telomere length. Our results illustrate the importance of reducing measurement error: a small increase in error in Cq values can have large consequences for the power and interpretability of qPCR estimates of relative telomere length. The findings also illustrate the importance of characterising the measurement error in each dataset-coefficients of variation are generally unhelpful, and researchers should report standard deviations of Cq values and/or repeatabilities of TS ratios-and allowing for the known effects of measurement error when interpreting patterns of TS ratio change over time.},
}
@article {pmid31042328,
year = {2019},
author = {Kaufman, ES},
title = {Recurrent atrial fibrillation after ablation: Can telomere length identify patients who are young at heart?.},
journal = {Journal of cardiovascular electrophysiology},
volume = {30},
number = {7},
pages = {1125-1126},
doi = {10.1111/jce.13960},
pmid = {31042328},
issn = {1540-8167},
mesh = {Atrial Fibrillation/*surgery ; *Catheter Ablation ; Heart ; Humans ; Recurrence ; Telomere ; },
}
@article {pmid31042327,
year = {2019},
author = {Su, C and Liu, Z and Gao, Y and Liu, Y and Hu, RM and Liu, J and Yang, X and Li, S and Zhang, Y and Zuo, K and Cao, B and Luo, J and Li, J and Li, K and Yin, X and Chen, M and Yang, X},
title = {Study on the relationship between telomere length changes and recurrence of atrial fibrillation after radiofrequency catheter ablation.},
journal = {Journal of cardiovascular electrophysiology},
volume = {30},
number = {7},
pages = {1117-1124},
doi = {10.1111/jce.13958},
pmid = {31042327},
issn = {1540-8167},
support = {2-17M620836//China Postdoctoral Science Foundation/International ; 81700295//National Natural Science Foundation of China/International ; 81670214//National Natural Science Foundation of China/International ; 81500383//National Natural Science Foundation of China/International ; 7172080//Beijing Natural Science Foundation/International ; },
mesh = {Aged ; Atrial Fibrillation/diagnosis/genetics/physiopathology/*surgery ; Catheter Ablation/*adverse effects ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; Recurrence ; Registries ; Risk Assessment ; Risk Factors ; Telomere/*genetics ; *Telomere Shortening ; Time Factors ; Treatment Outcome ; },
abstract = {INTRODUCTION: Advanced age is the foremost risk factor for atrial fibrillation (AF). Telomere length is a surrogate for biological aging, but the association between shortened leukocyte telomere length (LTL) and recurrence of AF (RAF) after ablation remains inconclusive.<br><br>METHODS: In this prospective analysis, 282 patients underwent an initial catheter ablation for paroxysmal or persistent AF. The association between RAF and LTL was analyzed by univariate and multivariate Cox regression, as well as time-dependent receiver operating characteristic (ROC) analysis and Kaplan-Meier analysis.<br><br>RESULTS: After a mean follow-up of 14.20&#x2009;&#xb1;&#x2009;5.04 months, RAF was documented in 78 of the 277 patients who completed the study (28.16%). In Cox proportional hazards models, LTL, age, diagnosis to ablation time (DTAT), N-terminal pronatriuretic peptide, and CHA2DS2-VASc score were significantly associated with RAF. After multivariable adjustment, LTL and DTAT were predicted as independent risk factors for RAF with hazard ratio (HR) of 3.17 (95% confidence interval [CI]: 1.23-8.15, P&#x2009;=&#x2009;0.017) and 1.43 (95% CI: 1.10-1.86, P&#x2009;=&#x2009;0.007), respectively. In addition, ROC analysis indicated the potential diagnostic value of LTL with an area under the curve of 0.64 (P&#x2009;<&#x2009;0.001; sensitivity&#x2009;=&#x2009;60.3%, specificity&#x2009;=&#x2009;57.8%), and an optimum cut-off value of 1.040. LTL less than or equal to 1.040 was defined as shortened LTL, while LTL greater than 1.040 nonshortened LTL. Kaplan-Meier analysis showed RAF rate curve was separated significantly between two groups (21.2% vs 35.9%, log-rank test result P&#x2009;=&#x2009;0.007). Patients with shortened LTL might have a higher risk for RAF with HR&#x2009;=&#x2009;1.84 (P&#x2009;=&#x2009;0.008).<br><br>CONCLUSIONS: Shortened LTL is an independent risk factor for AF recurrence. Shortened LTL could be a potential biomarker in predicting RAF after ablation.},
}
@article {pmid31041893,
year = {2019},
author = {Morsczeck, C and Reck, A and Reichert, TE},
title = {Short telomeres correlate with a strong induction of cellular senescence in human dental follicle cells.},
journal = {BMC molecular and cell biology},
volume = {20},
number = {1},
pages = {5},
pmid = {31041893},
issn = {2661-8850},
mesh = {Cell Line ; DNA Damage/physiology ; Dental Sac/*cytology ; Genomic Instability/*physiology ; Humans ; Phenotype ; Regenerative Medicine ; Reverse Transcriptase Polymerase Chain Reaction ; Stem Cell Transplantation ; Stem Cells/*cytology ; Telomere/*physiology ; Telomere Shortening/*genetics ; Transcriptome ; Transfection ; beta-Galactosidase/metabolism ; },
abstract = {BACKGROUND: Dental follicle cells (DFCs) are dental stem cells and interesting options for regenerative therapies in dentistry. However, DFCs acquire replicative senescence in long-term cultures, but little is known about molecular processes. In previous studies, we observed that DFC cell lines become senescent at different rates. We hypothesized that short telomere length and increased DNA damage with genomic instability correlate with the accelerated induction of cellular senescence.<br><br>RESULTS: For this study we compared DFC cell lines that became senescent at different rates (DFC_F: strong senescent phenotype; DFC_S: weak senescent phenotype). The telomeres of DFC_F were shorter than those of the telomeres of DFC_S prior senescence. Interestingly, telomere lengths of both cell lines were nearly unchanged after induction of senescence. Gene expression analyses with genes associated with DNA damage before and after the induction of cellular senescence revealed that almost all genes in DFCs_F were down-regulated while the gene expression in DFC_S was almost constitutive. Moreover, number of aneuploid DFC_F were significantly higher after induction of cellular senescence.<br><br>CONCLUSION: Our results supported our initial hypothesis that telomere length and genomic instability correlate with the accelerated induction of cellular senescence in DFC_F.},
}
@article {pmid31039427,
year = {2019},
author = {Zhang, L and Hu, XZ and Russell, DW and Benedek, DM and Fullerton, CS and Naifeh, JA and Li, X and Chen, Z and Wu, H and Ng, THH and Aliaga, P and Kao, TC and Yu, T and Dohl, J and Wynn, G and Ursano, RJ},
title = {Association between leukocyte telomere length and hostility in US army service members.},
journal = {Neuroscience letters},
volume = {706},
number = {},
pages = {24-29},
doi = {10.1016/j.neulet.2019.04.020},
pmid = {31039427},
issn = {1872-7972},
mesh = {Adult ; Female ; *Hostility ; Humans ; Leukocytes/*metabolism ; Male ; Military Personnel/*psychology ; Stress Disorders, Post-Traumatic/*diagnosis/genetics/psychology ; *Telomere ; Telomere Homeostasis/*physiology ; Young Adult ; },
abstract = {Hostility is a common form of emotionally charged anger which can lead to maladaptive and unhealthy behaviors. Significant association between shortened telomeres and greater levels of hostility has been observed in civilian populations, but has not yet been comprehensively studied in military populations. Our study investigates the relationship between hostility, post-traumatic stress disorder (PTSD), and leukocyte telomere length (LTL) in a sample of United States Army Special Operations personnel (n = 474) who deployed to Iraq and/or Afghanistan as part of combat operations. Hostility was measured with five items from the Brief Symptom Inventory (BSI). PTSD was determined using the PTSD Checklist (PCL) total score. The LTL was assessed using quantitative polymerase chain reaction methods and regression analyses were conducted to determine the association of hostility and telomere length. PTSD subjects reported higher hostility scores compared with those without PTSD. Among the participants with PTSD, those with medium or high level of hostility had shorter LTL than those with low level hostility (P < 0.01). Stepwise regression indicated that hostility level and age, but not gender and PTSD, were negatively correlated with LTL. Univariate regression showed that total hostility score was negatively associated with LTL (CI= -0.06 to -0.002, Beta= -0.095, p < 0.039) as well as a significant correlation between LTL and hostility impulses (HI) (CI= -0.108 to -0.009, Beta= -0.106, p < 0.021) and hostility controlling (HC) (CI= -0.071 to -0.002, Beta= -0.095, p < 0.004). Multiple regression analyses revealed that, while HC has no significant association with LTL, HI was still negatively correlated with LTL (p = 0.021). Our data indicates that LTL is associated with HI levels. Prevention and treatment efforts designed to reduce hostility may help mitigate risk for LTL shortening, a process of cellular aging, and thus slow accelerated aged-related health outcomes.},
}
@article {pmid31038377,
year = {2019},
author = {Movahedi, A and Mostajaboddavati, M and Rajabibazl, M and Mirfakhraie, R and Enferadi, M},
title = {Association of telomere length with chronic exposure to ionizing radiation among inhabitants of natural high background radiation areas of Ramsar, Iran.},
journal = {International journal of radiation biology},
volume = {95},
number = {8},
pages = {1113-1121},
doi = {10.1080/09553002.2019.1605460},
pmid = {31038377},
issn = {1362-3095},
mesh = {Adult ; Aged ; *Background Radiation ; Female ; Humans ; Iran ; Male ; Middle Aged ; *Radiation Exposure ; *Telomere ; },
abstract = {Purpose: There are few areas in the world where ionizing radiation (IR) dose received by the public from radon gas and other radioactive elements are much higher than recommended limits. Telomere length is a potential biomarker of genomic instability due to oxidative stress from IR exposure. In this study, we investigated the impact of chronic exposure to environmental IR on relative telomere length (RTL) in white blood cells (WBC) among inhabitants of high background radiation areas (HBRA) of Ramsar, Iran. Materials and methods: One hundred and four individuals from HBRAs of Ramsar and 104 age-matched subjects from normal background radiation areas (NBRA) of Iran were enrolled in the study. The RTLs of WBC DNA samples were measured by a quantitative polymerase chain reaction (q-PCR) approach. Results: Mean RTL in HBRA and NBRA groups did not show any significant difference (1.21 ± 0.71 versus 1.22 ± 0.66, p = .306). After controlling for all demographic variables, less than 1% of the variances in RTL values were related to background radiation exposure. Conclusion: We conclude that chronic exposure to natural IR has no statistically significant effect on RTL among the inhabitants of HBRAs of Ramsar compared with a control group.},
}
@article {pmid31035374,
year = {2019},
author = {Hong, J and Yun, CO},
title = {Telomere Gene Therapy: Polarizing Therapeutic Goals for Treatment of Various Diseases.},
journal = {Cells},
volume = {8},
number = {5},
pages = {},
pmid = {31035374},
issn = {2073-4409},
mesh = {*Cardiovascular Diseases/genetics/therapy ; *Cellular Senescence/drug effects/genetics ; Genetic Therapy/*methods ; Humans ; *Neoplasms/genetics/therapy ; *Telomere/drug effects/genetics ; *Telomere Shortening/drug effects/genetics ; },
abstract = {Modulation of telomerase maintenance by gene therapy must meet two polarizing requirements to achieve different therapeutic outcomes: Anti-aging/regenerative applications require upregulation, while anticancer applications necessitate suppression of various genes integral to telomere maintenance (e.g., telomerase, telomerase RNA components, and shelterin complex). Patients suffering from aging-associated illnesses often exhibit telomere attrition, which promotes chromosomal instability and cellular senescence, thus requiring the transfer of telomere maintenance-related genes to improve patient outcomes. However, reactivation and overexpression of telomerase are observed in 85% of cancer patients; this process is integral to cancer immortality. Thus, telomere-associated genes in the scope of cancer gene therapy must be inactivated or inhibited to induce anticancer effects. These contradicting requirements for achieving different therapeutic outcomes mean that any vector-mediated upregulation of telomere-associated genes must be accompanied by rigorous evaluation of potential oncogenesis. Thus, this review aims to discuss how telomere-associated genes are being targeted or utilized in various gene therapy applications and provides some insight into currently available safety hazard assessments.},
}
@article {pmid31035352,
year = {2019},
author = {Izumi, H and Funa, K},
title = {Telomere Function and the G-Quadruplex Formation are Regulated by hnRNP U.},
journal = {Cells},
volume = {8},
number = {5},
pages = {},
pmid = {31035352},
issn = {2073-4409},
mesh = {Animals ; Cell Line ; DNA/metabolism ; G-Quadruplexes ; Heterogeneous-Nuclear Ribonucleoprotein U/*physiology ; Humans ; Oligonucleotides/metabolism ; Protein Binding ; Replication Protein A/metabolism ; Telomere/*metabolism ; },
abstract = {We examine the role of the heterogenous ribonucleoprotein U (hnRNP U) as a G-quadruplex binding protein in human cell lines. Hypothesizing that hnRNP U is associated with telomeres, we investigate what other telomere-related functions it may have. Telomeric G-quadruplexes have been fully characterized in vitro, but until now no clear evidence of their function or in vivo interactions with proteins has been revealed in mammalian cells. Techniques used were immunoprecipitation, DNA pull-down, binding assay, and Western blots. We identified hnRNP U as a G-quadruplex binding protein. Immunoprecipitations disclosed that endogenous hnRNP U associates with telomeres, and DNA pull-downs showed that the hnRNP U C-terminus specifically binds telomeric G-quadruplexes. We have compared the effect of telomere repeat containing RNA (TERRA) on binding between hnRNP U and telomeric (Tel) or single- stranded Tel (ssTel) oligonucleotides and found that ssTel binds stronger to TERRA than to Tel. We also show that hnRNP U prevents replication protein A (RPA) accumulation at telomeres, and the recognition of telomeric ends by hnRNP suggests that a G-quadruplex promoting protein regulates its accessibility. Thus, hnRNP U-mediated formation has important functions for telomere biology.},
}
@article {pmid31035221,
year = {2019},
author = {Seibt, KD and Häussler, S and Vecchio, D and DeCarlo, E and Ceciliani, F and Sauerwein, H},
title = {Comparison of telomere lengths in leukocytes and in nasal and vaginal epithelial cells from Water Buffaloes (Bubalus bubalis) of different ages.},
journal = {Research in veterinary science},
volume = {124},
number = {},
pages = {328-333},
doi = {10.1016/j.rvsc.2019.04.013},
pmid = {31035221},
issn = {1532-2661},
mesh = {Animals ; Buffaloes/*physiology ; Epithelial Cells/*physiology ; Female ; Leukocytes/*physiology ; Nasal Mucosa/*physiology ; Telomere Homeostasis ; *Telomere Shortening ; Vagina/*physiology ; },
abstract = {Telomeres are short and repetitive sequences at the ends of linear chromosomes which shorten with every cell-division in vitro. Telomere length (TL) is reported to decrease with age and stress. The domesticated water buffalo (Bubalus bubalis) is the second most important milk producing animal worldwide. The productive lifespan of water buffalo cows is reported to be longer than that of dairy cows (Bos taurus). With this background, we aimed to compare TL in leukocytes obtained from blood samples from water buffaloes across different ages. In addition, we tested the suitability of assessing TL in DNA derived from nasal and vaginal epithelial cells via swabs as potential non-invasive alternatives to blood sampling Samples were collected from 20 calves (3 months of age), 20 heifers (2 years old), 20 cows (1st lactation, 3 years old), and 13 cows (3rd lactation, about 5 years old). We found that TL in leukocytes from water buffalo calves, heifers, and from cows in their first lactation was not different, but shorter telomeres were observed in cows in their third lactation. The results thus support an age-dependent decrease of TL in water buffaloes. Leukocyte TL was weakly correlated with TL measured in DNA from nasal epithelial cells (r = 0.327; P = .025), but not with TL from vaginal epithelial cells. Due to the poor correlation between epithelial cell and leukocyte TL and to the difficulties with collecting nasal swabs, we conclude that they are no suitable alternatives to blood samples for telomere studies in water buffaloes.},
}
@article {pmid31027347,
year = {2019},
author = {Polonis, K and Sompalli, S and Becari, C and Xie, J and Covassin, N and Schulte, PJ and Druliner, BR and Johnson, RA and Narkiewicz, K and Boardman, LA and Singh, P and Somers, VK},
title = {Telomere Length and Risk of Major Adverse Cardiac Events and Cancer in Obstructive Sleep Apnea Patients.},
journal = {Cells},
volume = {8},
number = {5},
pages = {},
pmid = {31027347},
issn = {2073-4409},
support = {R01 CA204013/CA/NCI NIH HHS/United States ; R01 HL065176/HL/NHLBI NIH HHS/United States ; UL1 TR002377/TR/NCATS NIH HHS/United States ; UL1 TR000135/TR/NCATS NIH HHS/United States ; },
mesh = {Adult ; Cardiovascular Diseases/*epidemiology ; Female ; Humans ; Incidence ; Male ; Middle Aged ; Neoplasms/*epidemiology ; Risk ; Sleep Apnea, Obstructive/*epidemiology/*genetics ; *Telomere Homeostasis ; *Telomere Shortening ; Young Adult ; },
abstract = {Telomere length (TL) is associated with cardiovascular disease (CVD) and cancer. Obstructive sleep apnea (OSA) is also linked to higher risk of CVD and cancer, and to TL. We investigated the association between TL and risk of major adverse cardiac events (MACE) and cancer in OSA patients. We studied 210 individuals undergoing sleep-related studies between 2000 and 2007. Baseline characteristics and follow-up data (available in 164 subjects) were obtained from clinic records. Incidence rates were calculated for the entire group and by OSA status. Hazard ratios were calculated to estimate effects of OSA and TL on risk of MACE and cancer. In total, 32 individuals (20%) developed MACE and/or cancer during 12.7-year follow-up. The OSA group had a higher likelihood of cancer (16.0 vs. 4.9 events per 1000 person-years, P = 0.044) but no clear evidence of an elevated incidence of MACE (10.8 vs. 4.8 events per 1000 person-years, P = 0.293) compared to the non-OSA group. There was no association between TL and MACE- (HR = 1.01, 95% CI 0.78-1.28), or cancer-risk (HR = 1.18, 95% CI 0.96-1.43). Our study warrants further investigation of any modulating effect of OSA on TL and the risk of MACE and cancer.},
}
@article {pmid31026396,
year = {2019},
author = {Yu, Z and Fenk, KD and Huang, D and Sen, S and Cowan, JA},
title = {Rapid Telomere Reduction in Cancer Cells Induced by G-Quadruplex-Targeting Copper Complexes.},
journal = {Journal of medicinal chemistry},
volume = {62},
number = {10},
pages = {5040-5048},
doi = {10.1021/acs.jmedchem.9b00215},
pmid = {31026396},
issn = {1520-4804},
mesh = {Antineoplastic Agents/*chemical synthesis/*pharmacology ; Cell Division/drug effects ; Cell Line, Tumor ; Cellular Senescence/drug effects ; Comet Assay ; *Copper ; DNA Fragmentation/drug effects ; DNA Replication/drug effects ; DNA, Neoplasm/drug effects ; Drug Design ; G-Quadruplexes/*drug effects ; Humans ; Organometallic Compounds/*chemical synthesis/*pharmacology ; Reactive Oxygen Species/metabolism ; S Phase/drug effects ; Telomere Shortening/*drug effects ; Tumor Cells, Cultured ; },
abstract = {Telomere length determines the replicative capacity of mammalian cells. Successive telomere reduction to a critically short length can lead to cellular senescence that irreversibly prevents cells from further cell division. A series of Cu complexes has been designed as selective artificial nucleases that degrade G-quadruplex telomeric DNA and exhibit selective DNA binding affinity and cleavage reactivity toward G-quadruplex telomeric DNA over duplex DNA. In contrast to protein-based nucleases that usually lack membrane permeability, significant cellular uptake and nuclear localization of these Cu complexes was observed. Rapid telomere reduction of cancer cells was also observed after only 1 day incubation, while the absence of DNA fragmentation indicates a low level of nonselective DNA cleavage. Robust telomere reduction by the designed Cu complexes is an S-phase-specific event that is associated with increased formation of the G-quadruplex structure during DNA replication.},
}
@article {pmid31026358,
year = {2019},
author = {Udroiu, I and Marinaccio, J and Sgura, A},
title = {Epigallocatechin-3-gallate induces telomere shortening and clastogenic damage in glioblastoma cells.},
journal = {Environmental and molecular mutagenesis},
volume = {60},
number = {8},
pages = {683-692},
doi = {10.1002/em.22295},
pmid = {31026358},
issn = {1098-2280},
mesh = {Catechin/*analogs &amp; derivatives/pharmacology ; Cell Line, Tumor ; Cellular Senescence/*drug effects ; DNA Damage/drug effects ; Glioblastoma/*genetics ; Histones/metabolism ; Humans ; Phosphorylation ; Telomerase/*antagonists &amp; inhibitors ; Telomere/physiology ; Telomere Shortening/*drug effects ; },
abstract = {Epigallocatechingallate (EGCG) is the major polyphenol in green tea, to which many anticancer features, such as antioxidative, antigenotoxic, and antiangiogenetic properties, are attributed. Moreover, it is also well known as a telomerase inhibitor. In this work, we have chronically treated U251 glioblastoma cells with low, physiologically realistic concentrations, of EGCG, in order to investigate its effects both on telomeres and on genome integrity. Inhibition of telomerase activity caused telomere shortening, ultimately leading to senescence and telomere dysfunction at 98 days. Remarkably, we have observed DNA damage through an increase of phosphorylation of γ-H2AX histone and micronuclei also with doses and at timepoints when telomere shortening was not present. Therefore, we concluded that this DNA damage was not correlated with telomere shortening and that EGCG treatment induced not only an increase of telomere-shortening-induced senescence but also telomere-independent genotoxicity. This study questions the common knowledge about EGCG properties, but confirms the few works that indicated the clastogenic properties of this molecule, probably due to DNA reductive damage and topoisomerase II poisoning. Environ. Mol. Mutagen., 60:683-692, 2019. © 2019 Wiley Periodicals, Inc.},
}
@article {pmid31026066,
year = {2019},
author = {Wallace, HA and Rana, V and Nguyen, HQ and Bosco, G},
title = {Condensin II subunit NCAPH2 associates with shelterin protein TRF1 and is required for telomere stability.},
journal = {Journal of cellular physiology},
volume = {234},
number = {11},
pages = {20755-20768},
pmid = {31026066},
issn = {1097-4652},
support = {R01 GM069462/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases/*metabolism ; Amino Acid Sequence ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Biomarkers/metabolism ; Cell Line ; Chromosomes, Human/metabolism ; DNA Damage ; DNA-Binding Proteins/*metabolism ; Humans ; Multiprotein Complexes/*metabolism ; Protein Binding ; Protein Subunits/*metabolism ; Replication Protein A/metabolism ; Serine Endopeptidases/chemistry/*metabolism ; Shelterin Complex ; Signal Transduction ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; Tumor Suppressor p53-Binding Protein 1/metabolism ; },
abstract = {Condensin II subunits are known to be expressed and localized to interphase nuclei of eukaryotic cells. Although some studies have shown that condensin II likely exerts axial compaction forces, organizes chromosome territories, and has possible transcriptional modulatory functions, the full range of condensin II interphase activities are not known. In particular, it is not known if condensin II interphase activities are generally genome-wide or if they have additional local activities unique to specific chromosomal structures such as telomeres. Here, we find that NCAPH2 interacts with TRF1 and these two proteins co-localize at telomeres. Depletion of NCAPH2 leads to ATR-dependent accumulation of 53BP1 and γH2AX DNA damage foci, including damage specific to telomeres. Furthermore, depletion of NCAPH2 results in a fragile telomere phenotype and apparent sister-telomere fusions only days after NCAPH2 depletion. Taken together these observations suggest that NCAPH2 promotes telomere stability, possibly through a direct interaction with the TRF1 shelterin component, and prevents telomere dysfunction resulting from impaired DNA replication. Because proper telomere function is essential for chromosome integrity these observations reveal a previously unappreciated function for NCAPH2 in ensuring genome and telomere stability.},
}
@article {pmid31025211,
year = {2019},
author = {Tao, L and Huang, Q and Yang, R and Dai, Y and Zeng, Y and Li, C and Li, X and Zeng, J and Wang, Q},
title = {The age modification to leukocyte telomere length effect on bone mineral density and osteoporosis among Chinese elderly women.},
journal = {Journal of bone and mineral metabolism},
volume = {37},
number = {6},
pages = {1004-1012},
pmid = {31025211},
issn = {1435-5604},
support = {81573235//National Natural Science Foundation of China/ ; },
mesh = {Age Factors ; Aged ; *Asian People ; Bone Density/*physiology ; Female ; Humans ; Leukocytes/*metabolism ; Linear Models ; Male ; Osteoporosis/epidemiology/*physiopathology ; Sex Characteristics ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Critically short telomeres indicate cellular senescence. Leukocyte telomere length (LTL) is regarded as an aging predictor. Osteoporosis is an age-related disease. The purpose of our study is to examine the association between LTL, and BMD and osteoporosis among an elderly Chinese population. A total of 1017 participants (584 postmenopausal women) with a mean age of 66.4 years were recruited from April 2016 to August 2017. Dual-energy X-ray absorptiometry was used for BMD measurement at skeleton sites of lumbar spine (LS), femoral neck (FN), and total hip (TH). LTL was measured using quantitative real-time polymerase chain reaction. Among women, age significantly modified the effect of LTL on BMD at FN. Additionally, significant age modification was observed for the association between LTL and LS BMD category (indicative of control or osteopenia or osteoporosis), and the number of osteoporotic sites at LS or TH. The corresponding estimates (95% CI) for the relative excess risk due to interaction (RERI) were - 0.07 (- 0.11, - 0.01) and - 0.11 (- 0.16, - 0.03) sequentially in ordinal logistic regression models. The estimated RERIs (95% CI) were - 0.11 (- 0.25, - 0.02) and - 0.23 (- 0.39, - 0.10) in multinomial logistic regression models for LS/FN/TH BMD category, and - 0.20 (- 0.31, - 0.09) and - 0.34 (- 0.49, - 0.21) for FN BMD category. However, similar findings did not show in men. The effect of LTL on BMD and osteoporosis risk is modified by age in elderly women but not in men, suggesting that the predictive role of LTL in bone loss differs by sex.},
}
@article {pmid31023993,
year = {2019},
author = {Boccardi, M and Boccardi, V},
title = {Psychological Wellbeing and Healthy Aging: Focus on Telomeres.},
journal = {Geriatrics (Basel, Switzerland)},
volume = {4},
number = {1},
pages = {},
pmid = {31023993},
issn = {2308-3417},
abstract = {Stress and depression are known to modulate the aging process, and might also affect telomere biology. In fact, exposure to some biochemical pathways involved in stress-related depression may contribute to an ''accelerated aging" phenotype, as well as the incidence of age-related diseases, including metabolic disorders and dementia. Basic studies support the notion that the telomere and telomerase system plays a pivotal role in the aging process and disease promotion. Interestingly, short and dysfunctional telomeres are associated with reduced lifespan, as shown in animal models. In this context, telomeres are very sensitive to stress, mindset, and lifestyle, and their rescue may be sufficient to restore cell and organism viability. This mini-review discusses conceptual models of healthy and active aging and their relationship with telomere biology and mental health.},
}
@article {pmid31022960,
year = {2019},
author = {Doksani, Y},
title = {The Response to DNA Damage at Telomeric Repeats and Its Consequences for Telomere Function.},
journal = {Genes},
volume = {10},
number = {4},
pages = {},
pmid = {31022960},
issn = {2073-4425},
mesh = {Animals ; DNA Damage ; *DNA Repair ; Humans ; Telomere/*genetics/*metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomeric repeats, coated by the shelterin complex, prevent inappropriate activation of the DNA damage response at the ends of linear chromosomes. Shelterin has evolved distinct solutions to protect telomeres from different aspects of the DNA damage response. These solutions include formation of t-loops, which can sequester the chromosome terminus from DNA-end sensors and inhibition of key steps in the DNA damage response. While blocking the DNA damage response at chromosome ends, telomeres make wide use of many of its players to deal with exogenous damage and replication stress. This review focuses on the interplay between the end-protection functions and the response to DNA damage occurring inside the telomeric repeats, as well as on the consequences that telomere damage has on telomere structure and function.},
}
@article {pmid31019963,
year = {2019},
author = {Fathi, E and Charoudeh, HN and Sanaat, Z and Farahzadi, R},
title = {Telomere shortening as a hallmark of stem cell senescence.},
journal = {Stem cell investigation},
volume = {6},
number = {},
pages = {7},
pmid = {31019963},
issn = {2306-9759},
abstract = {Stem cells, especially mesenchymal stem cells (MSCs)-based therapies have been greatly attentioned in regenerative medicine through multi-lineage differentiation, self-renewal properties, etc. Despite the above advantages of MSCs, the defined properties of these cells are strongly affected by aging. Thus, the use of MSCs from older donors is lower than younger one, which limits clinical applications in cell therapy. According to the theories of aging, it is determined that aging is most likely caused by telomere shortening and telomere shortening is considered hallmarks of aging. Finding out the most mechanisms of these changes will probably reveal novel therapeutic targets for prolonging human health and for ameliorating age-associated phenotypes. This review focuses on prevalent knowledge about the mechanisms of stem cell senescence by telomere shortening and the molecular mechanism details involved in it.},
}
@article {pmid31019071,
year = {2019},
author = {Jansson, LI and Hentschel, J and Parks, JW and Chang, TR and Lu, C and Baral, R and Bagshaw, CR and Stone, MD},
title = {Telomere DNA G-quadruplex folding within actively extending human telomerase.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {116},
number = {19},
pages = {9350-9359},
pmid = {31019071},
issn = {1091-6490},
support = {F99 CA212439/CA/NCI NIH HHS/United States ; K00 CA212439/CA/NCI NIH HHS/United States ; R01 GM095850/GM/NIGMS NIH HHS/United States ; T32 GM008646/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA/*chemistry/genetics/metabolism ; DNA Primers/genetics/metabolism ; Fluorescence Resonance Energy Transfer ; G-Quadruplexes ; Humans ; Kinetics ; Shelterin Complex ; Telomerase/chemistry/genetics/*metabolism ; Telomere/chemistry/genetics/*metabolism ; Telomere-Binding Proteins ; },
abstract = {Telomerase reverse transcribes short guanine (G)-rich DNA repeat sequences from its internal RNA template to maintain telomere length. G-rich telomere DNA repeats readily fold into G-quadruplex (GQ) structures in vitro, and the presence of GQ-prone sequences throughout the genome introduces challenges to replication in vivo. Using a combination of ensemble and single-molecule telomerase assays, we discovered that GQ folding of the nascent DNA product during processive addition of multiple telomere repeats modulates the kinetics of telomerase catalysis and dissociation. Telomerase reactions performed with telomere DNA primers of varying sequence or using GQ-stabilizing K[+] versus GQ-destabilizing Li[+] salts yielded changes in DNA product profiles consistent with formation of GQ structures within the telomerase-DNA complex. Addition of the telomerase processivity factor POT1-TPP1 altered the DNA product profile, but was not sufficient to recover full activity in the presence of Li[+] cations. This result suggests GQ folding synergizes with POT1-TPP1 to support telomerase function. Single-molecule Förster resonance energy transfer experiments reveal complex DNA structural dynamics during real-time catalysis in the presence of K[+] but not Li[+], supporting the notion of nascent product folding within the active telomerase complex. To explain the observed distributions of telomere products, we globally fit telomerase time-series data to a kinetic model that converges to a set of rate constants describing each successive telomere repeat addition cycle. Our results highlight the potential influence of the intrinsic folding properties of telomere DNA during telomerase catalysis, and provide a detailed characterization of GQ modulation of polymerase function.},
}
@article {pmid31016380,
year = {2019},
author = {Zhu, J and Liu, W and Chen, C and Zhang, H and Yue, D and Li, C and Zhang, L and Gao, L and Huo, Y and Liu, C and Giaccone, G and Zhang, B and Wang, C},
title = {TPP1 OB-fold domain protein suppresses cell proliferation and induces cell apoptosis by inhibiting telomerase recruitment to telomeres in human lung cancer cells.},
journal = {Journal of cancer research and clinical oncology},
volume = {145},
number = {6},
pages = {1509-1519},
pmid = {31016380},
issn = {1432-1335},
support = {81472182//National Natural Science Foundation of China/ ; },
mesh = {A549 Cells ; Animals ; Apoptosis/physiology ; Cell Proliferation/physiology ; Female ; Heterografts ; Humans ; Lung Neoplasms/metabolism/pathology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Oligonucleotides/*metabolism ; Oligosaccharides/*metabolism ; Protein Domains ; Shelterin Complex ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {PURPOSE: Maintaining telomeres by recruiting telomerase-to-chromosome ends is essential for cancer cell survival. Inhibiting telomerase recruitment to telomeres represents a novel strategy for telomere-based lung cancer therapy. However, approaches for interrupting telomerase recruitment for cancer therapy still need to be explored.<br><br>METHODS: The telomere-binding protein TPP1 is responsible for recruiting telomerase to telomeres and synthesizing telomeres through the association between the oligosaccharide/oligonucleotide-binding (OB)-fold domain of TPP1 and telomerase reverse transcriptase. We overexpressed the TPP1 OB domain (TPP1-OB) by lentivirus infection in lung cancer cells. Telomere length was examined by Southern blot analysis of terminal restriction fragments. The effects of TPP1-OB on cell proliferation, the cell cycle, apoptosis, chemosensitivity, and tumor growth were evaluated in vitro and in vivo.<br><br>RESULT: TPP1-OB inhibited the recruitment of telomerase to telomeres and shortened telomere length by acting as a dominant-negative mutant of TPP1. TPP1-OB resulted in reduced cell proliferation, G1 cell cycle arrest, and increased cell apoptosis in lung cancer cells. Cell apoptosis occurred mainly through the caspase-3-dependent signaling pathway. TPP1-OB also suppressed anchorage-independent growth and tumor growth in vivo. Moreover, we demonstrated that TPP1-OB enhances the sensitivity of lung cancer cells to the chemotherapeutic drug paclitaxel.<br><br>CONCLUSION: Our results suggest that inhibiting TPP1-mediated telomerase recruitment by expressing the TPP1-OB domain is a potential novel strategy for telomere-targeted lung cancer therapy.},
}
@article {pmid31014977,
year = {2019},
author = {Udomsinprasert, W and Poovorawan, Y and Chongsrisawat, V and Vejchapipat, P and Jittikoon, J and Honsawek, S},
title = {Leukocyte mitochondrial DNA copy number as a potential biomarker indicating poor outcome in biliary atresia and its association with oxidative DNA damage and telomere length.},
journal = {Mitochondrion},
volume = {47},
number = {},
pages = {1-9},
doi = {10.1016/j.mito.2019.04.006},
pmid = {31014977},
issn = {1872-8278},
mesh = {Biliary Atresia/*genetics/metabolism/mortality ; Child ; *DNA Copy Number Variations ; *DNA Damage ; DNA, Mitochondrial/*genetics/metabolism ; Humans ; *Leukocytes ; Male ; Oxidation-Reduction ; Oxidative Stress ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {Biliary atresia (BA) is a chronic obstructive liver disease, leading to advanced liver failure. Mitochondria dysfunction-mediated aberrant telomere length has been implicated in various pathological processes including cholestasis. Herein, we aimed to investigate associations between mitochondrial DNA (mtDNA) copy number, oxidative DNA damage, telomere length, and disease severity in BA patients. mtDNA copy number and relative telomere length (RTL) were assessed using real-time PCR. Circulating 8-hydroxy-2'-deoxyguanosine (8-OHdG) was measured using ELISA. Our findings showed that BA patients had significantly lower mtDNA copy number and RTL than healthy controls, whereas plasma 8-OHdG levels were significantly elevated in BA patients. mtDNA copy number was remarkably reduced in advanced BA patients. Furthermore, mtDNA copy number was independently associated with age and degree of liver fibrosis in BA patients. Decreased mtDNA copy number was significantly associated with elevated risks of BA, severe fibrosis, jaundice, and hepatic dysfunction. Low mtDNA copy number can be utilized to distinguish patients with poor-outcome from those with good-outcome. Survival curve analysis revealed that low mtDNA copy number was significantly associated with poor survival of BA patients. Interestingly, there was a positive association between mtDNA copy number and plasma 8-OHdG in BA patients, while a negative association of mtDNA copy number with RTL was observed in BA patients. Alternatively, RTL was negatively correlated with plasma 8-OHdG in BA patients. These data demonstrated relationships between leukocytes mtDNA copy number, oxidative stress, telomere length, and clinical parameters in BA patients. Accordingly, our findings indicate that mtDNA copy number may serve as a potential biomarker reflecting BA severity.},
}
@article {pmid31014199,
year = {2020},
author = {Amir, M and Ahmad, S and Ahamad, S and Kumar, V and Mohammad, T and Dohare, R and Alajmi, MF and Rehman, T and Hussain, A and Islam, A and Ahmad, F and Hassan, MI},
title = {Impact of Gln94Glu mutation on the structure and function of protection of telomere 1, a cause of cutaneous familial melanoma.},
journal = {Journal of biomolecular structure &amp; dynamics},
volume = {38},
number = {5},
pages = {1514-1524},
doi = {10.1080/07391102.2019.1610500},
pmid = {31014199},
issn = {1538-0254},
mesh = {Humans ; *Melanoma/genetics ; Mutation ; Protein Binding ; Shelterin Complex ; *Telomere-Binding Proteins/genetics/metabolism ; Tripeptidyl-Peptidase 1 ; },
abstract = {Protection of telomere 1 (POT1) is a key component of shelterin complex, essential for maintaining telomere length and its regulation. It consists of N-terminal domain (residues 1-299), which interacts with telomeric ssDNA, and the C-terminal domain (residues 320-634) that binds to the tripeptidyl-peptidase I (TPP1). A large number of naturally occurring mutations in the POT1 gene are associated with glioma, cardiac angiosarcoma and cutaneous familial melanoma (FM). In particular, Q94E mutation disrupts the interaction of POT1 with telomeric DNA which subsequently enhances telomere uncapping and elongation and promotes the development of cutaneous familial melanoma. To understand the underlying mechanism of familial melanoma developed by Q94E-mutation, we have performed extensive structure analysis of WT and mutant protein followed by molecular dynamics simulations. Q94E mutation causes a dramatic change in the structure and stability of POT1 protein. A considerable decrease in the flexibility, fluctuation and solvent accessibility of Q94E was observed in comparison to the WT, indicating overall destabilization of protein. Essential dynamics and Anisotropic Network Mode analysis have quantified a significant change in direction and magnitude of conformational motion in Q94E mutant compared to WT. A significant loss of frustration due to Q94E mutation was also observed. Our findings indicate the loss of protein stability and dynamics of POT1 protein by Q94E mutation may be associated with the familial melanoma. AbbreviationsANManisotropic network modeEDessential dynamicsFMfamilial melanomaMDmolecular dynamicsPOT1protection of telomere 1Rgradius of gyrationRMSDroot-mean-square deviationRMSFroot-mean-square fluctuationsSASAsolvent accessible surface areaSIFTsorting Intolerant from TolerantTPP1tripeptidyl-peptidase IWTwild typeCommunicated by Ramaswamy H. Sarma.},
}
@article {pmid31013622,
year = {2019},
author = {Wu, G and Chen, L and Liu, W and Yang, D},
title = {Molecular Recognition of the Hybrid-Type G-Quadruplexes in Human Telomeres.},
journal = {Molecules (Basel, Switzerland)},
volume = {24},
number = {8},
pages = {},
pmid = {31013622},
issn = {1420-3049},
support = {R01CA177585/NH/NIH HHS/United States ; P30CA023168/NH/NIH HHS/United States ; R01 CA122952/CA/NCI NIH HHS/United States ; R01 CA177585/CA/NCI NIH HHS/United States ; R01CA122952/NH/NIH HHS/United States ; P30 CA023168/CA/NCI NIH HHS/United States ; },
mesh = {*G-Quadruplexes ; Humans ; Neoplasm Proteins/antagonists &amp; inhibitors/*chemistry/metabolism ; Nuclear Magnetic Resonance, Biomolecular ; Telomerase/antagonists &amp; inhibitors/*chemistry/metabolism ; Telomere/*chemistry/metabolism ; *Telomere Homeostasis ; },
abstract = {G-quadruplex (G4) DNA secondary structures formed in human telomeres have been shown to inhibit cancer-specific telomerase and alternative lengthening of telomere (ALT) pathways. Thus, human telomeric G-quadruplexes are considered attractive targets for anticancer drugs. Human telomeric G-quadruplexes are structurally polymorphic and predominantly form two hybrid-type G-quadruplexes, namely hybrid-1 and hybrid-2, under physiologically relevant solution conditions. To date, only a handful solution structures are available for drug complexes of human telomeric G-quadruplexes. In this review, we will describe two recent solution structural studies from our labs. We use NMR spectroscopy to elucidate the solution structure of a 1:1 complex between a small molecule epiberberine and the hybrid-2 telomeric G-quadruplex, and the structures of 1:1 and 4:2 complexes between a small molecule Pt-tripod and the hybrid-1 telomeric G-quadruplex. Structural information of small molecule complexes can provide important information for understanding small molecule recognition of human telomeric G-quadruplexes and for structure-based rational drug design targeting human telomeric G-quadruplexes.},
}
@article {pmid31012504,
year = {2019},
author = {Morais, KDS and Arcanjo, DDS and de Faria Lopes, GP and da Silva, GG and da Mota, THA and Gabriel, TR and Rabello Ramos, DDA and Silva, FP and de Oliveira, DM},
title = {Long-term in vitro treatment with telomerase inhibitor MST-312 induces resistance by selecting long telomeres cells.},
journal = {Cell biochemistry and function},
volume = {37},
number = {4},
pages = {273-280},
doi = {10.1002/cbf.3398},
pmid = {31012504},
issn = {1099-0844},
support = {0193.001063/2015//Federal District Research Support Foundation (FAPDF)/ ; //National Council for Scientific and Technological Development (CNPq)/ ; },
mesh = {Antineoplastic Agents/chemistry/*pharmacology ; Benzamides/chemistry/*pharmacology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm/*drug effects ; Enzyme Inhibitors/chemistry/*pharmacology ; Humans ; Structure-Activity Relationship ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere Homeostasis/*drug effects ; Tumor Cells, Cultured ; },
abstract = {Telomerase is a good target for new anticancer drug development because it is present in over 85% of human tumours. However, despite chronic therapy is a condition for anti-telomerase approach, the effects of long-term treatment with telomerase inhibitors remain not well understood. In this work, it was evaluated the effects of long-term treatment of human MDA-MB-231 breast cancer cells with the telomerase inhibitor MST-312. Cells were treated for 72 hours or 140 days, and it was accessed their viability, proliferation rate, morphology, telomeric DNA content, and resistance mechanism. The drug had a clear short-term effect, including chemosensitizing cells for docetaxel and irinotecan, but the chronic exposition led to selection of long telomeres clones, changing characteristics of original cell line. This effect was confirmed in a clonal culture with homogenous karyotype. MRP-1 expression and alternative lengthening of telomeres (ALT) were discarded as additional mechanisms of resistance. This data suggest that, considering the intra-tumour heterogeneity (ITH), what is already a big challenge for treatment of cancer, chronic exposition to telomerase inhibitors can promote tumour adaptations with potential clinical repercussion, drawing attention to ongoing clinical trials and pointing important considerations most times neglected on studies about use of these inhibitors on cancer therapy. SIGNIFICANCE OF THE STUDY: Antitumour action of telomerase inhibitors is well known, but it depends on a long-term exposition because cells will undergo telomere erosion only after many duplication cycles. Recently, the frustrating results of clinical trials with these inhibitors aroused the interest of the scientific community to understand the mechanisms of resistance to anti-telomerase therapy. In this study, we conducted an 18-week experiment to show that telomerase inhibition can lead to cell adaptations and selection of long-telomeres clones, leading to acquisition of resistance. However, we also showed that this inhibitor can sensitize cells to the chemotherapeutic drugs docetaxel and irinotecan.},
}
@article {pmid31006054,
year = {2020},
author = {Flannagan, KS and Bowman, AA and Mora-Plazas, M and Marín, C and Rentschler, KM and Rozek, LS and Villamor, E},
title = {Micronutrient status and leukocyte telomere length in school-age Colombian children.},
journal = {European journal of nutrition},
volume = {59},
number = {3},
pages = {1055-1065},
pmid = {31006054},
issn = {1436-6215},
mesh = {Biomarkers/blood ; Child ; Child, Preschool ; Colombia ; Cross-Sectional Studies ; Female ; Humans ; *Leukocytes ; Male ; Micronutrients/*blood ; Nutrition Surveys/*methods/*statistics &amp; numerical data ; Sex Factors ; *Telomere ; },
abstract = {PURPOSE: Leukocyte telomere length (LTL) is a biomarker of inflammation and oxidative stress that predicts chronic disease risk. Nutritional factors are related to LTL in adulthood, but these associations are not well characterized in children. We examined whether micronutrient status biomarkers were associated with LTL in school-age children.<br><br>METHODS: We conducted a cross-sectional study of 330 boys and 393 girls aged 5-12&#xa0;years from Bogot&#xe1;, Colombia. We quantified blood concentrations of hemoglobin, ferritin, zinc, vitamin A, folate, and vitamin B-12; and measured LTL using qPCR in DNA extracted from buffy coat. We estimated mean differences in LTL by quartiles of micronutrient status biomarkers and categories of relevant sociodemographic and anthropometric covariates with the use of linear regression.<br><br>RESULTS: In girls, plasma vitamin B-12 was positively associated with LTL (adjusted LTL difference between extreme vitamin B-12 quartiles&#x2009;=&#x2009;0.11; P, trend&#x2009;=&#x2009;0.02). LTL was also positively associated with birth order in girls (P, trend&#x2009;=&#x2009;0.02). In boys, LTL was not related to the micronutrient status biomarkers but, unexpectedly, it was positively associated with birth weight (P&#x2009;=&#x2009;0.02), height-for-age Z score (P, trend&#x2009;=&#x2009;0.01), and serum C-reactive protein (P, trend&#x2009;=&#x2009;0.01).<br><br>CONCLUSIONS: LTL is associated with vitamin B-12 status among girls. LTL is also associated with birth weight, height, and C-reactive protein in boys.},
}
@article {pmid31005804,
year = {2019},
author = {Zole, E and Ranka, R},
title = {Mitochondrial DNA copy number and telomere length in peripheral blood mononuclear cells in comparison with whole blood in three different age groups.},
journal = {Archives of gerontology and geriatrics},
volume = {83},
number = {},
pages = {131-137},
doi = {10.1016/j.archger.2019.04.007},
pmid = {31005804},
issn = {1872-6976},
mesh = {Adult ; Age Factors ; Aged ; DNA, Mitochondrial/*genetics ; Female ; *Gene Dosage ; Humans ; Leukocytes, Mononuclear/*metabolism ; Male ; Middle Aged ; *Telomere ; },
abstract = {There are more and more studies on telomere length (TL) and mitochondrial DNA (mtDNA), and it has been proven that these factors play a significant role in the aging of the immune system thereby it is important to understand how it varies in different cell types for more accurate conclusions. The aim of this study was to look into dynamics of mtDNA amount in conjunction with TL in peripheral blood mononuclear cells (PBMC) during aging in comparison with whole blood (WB) cells. Overall, 53 samples were divided into three age groups: 20-39 year age group, 40-59 year age group and 60-79 year age group. MtDNA amount was determined by qPCR TaqMan, and TL was measured by Southern blotting of terminal restriction fragments (TRFs). PBMC had much higher mtDNA copy number (CN) amount than WB samples. Furthermore, with age, it increased in PBMC, while in WB mtDNA CN count did not change. TL in the elderly group was shorter in PBMC fraction than in WB cells. It also looked like that in PBMC TL shortened faster than in WB. In conclusions, it appears that during the aging process both mtDNA CN and TL were more stable in WB than in PBMC fraction where changes were more drastically pronounced, but more studies using larger sample cohorts should be performed to confirm this observation.},
}
@article {pmid31004106,
year = {2019},
author = {Matzenbacher, CA and Da Silva, J and Garcia, ALH and Cappetta, M and de Freitas, TRO},
title = {Anthropogenic Effects on Natural Mammalian Populations: Correlation Between Telomere Length and Coal Exposure.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {6325},
pmid = {31004106},
issn = {2045-2322},
mesh = {Animals ; Coal/*adverse effects ; *Coal Mining ; DNA Damage/*drug effects ; Humans ; Population Dynamics ; *Rodentia/genetics/metabolism ; Telomere Homeostasis/*drug effects ; },
abstract = {The Candiota coal mine in Rio Grande do Sul (RS) is one of the largest in Brazil. Coal is a fossil fuel that causes environmental impacts from its extraction to combustion due to the release of different agents, such as polycyclic aromatic hydrocarbons (PAH) and heavy metals. Ctenomys torquatus are herbivorous and subterranean rodents that dig tunnels with their paws and teeth and can be exposed to coal through contaminated food. Exposure to pollutants can cause DNA damage and affect different tissues, inducing alterations in the population structure and genetic diversity. Our study aimed to evaluate the effect of exposure to coal and its derivatives on the C. torquatus population and to examine the relationship of coal exposure with variations in absolute telomere length (aTL), global DNA methylation and genotoxicity. Our study showed an inverse correlation between telomere length and coal exposure in addition to an increase in DNA damage. The results indicate that coal and its byproducts can contribute to the alteration of the C. torquatus population structure, as evidenced by a reduction in the number of adults.},
}
@article {pmid31001377,
year = {2019},
author = {Daechavijit, P and Siridonthanakasem, J and Wongsupha, P and Yuktanandana, P and Honsawek, S},
title = {Relative Telomere Length in Blood Leukocytes of Patients with Anterior Cruciate Ligament Injury: A Pilot Study.},
journal = {Malaysian orthopaedic journal},
volume = {13},
number = {1},
pages = {8-13},
pmid = {31001377},
issn = {1985-2533},
abstract = {Introduction: Anterior cruciate ligament (ACL) tear is the most common knee ligament injury, especially in athletes. The objective of this study was to investigate relative telomere length (RTL) in blood leukocytes of patients with ACL injury compared with that of controls. Materials and Methods: A total of 187 subjects were invited to participate in this study. Ninety-two patients with clinically diagnosed ACL rupture were enrolled. Ninety-five age and gender-matched healthy controls were also recruited. Blood leukocyte RTL were analysed using quantitative real-time polymerase chain reaction. Results: Patients with ACL rupture had significantly longer relative telomere length than healthy controls (P=0.002). The patients with ACL rupture were classified into two groups according to the sport history of patients which are contact sports and non-contact sports. RTL in patients with non-contact sports was significantly greater than those with contact sports (P=0.006). Moreover, RTL was inversely correlated with body mass index of patients with ACL injury (r=-0.34, P=0.001). Logistic regression analysis indicated that long RTL was associated with a higher risk of ACL rupture. Conclusion: The present study showed that subjects with ACL rupture had significantly greater telomere length compared with their age and gender-matched controls. This finding may result from the increases in physical activity and overexpression of telomerase which acts as a protective mechanism against ACL injury. RTL in blood leukocytes is associated with a risk of ACL rupture.},
}
@article {pmid30995937,
year = {2019},
author = {Samavat, H and Xun, X and Jin, A and Wang, R and Koh, WP and Yuan, JM},
title = {Association between prediagnostic leukocyte telomere length and breast cancer risk: the Singapore Chinese Health Study.},
journal = {Breast cancer research : BCR},
volume = {21},
number = {1},
pages = {50},
pmid = {30995937},
issn = {1465-542X},
support = {T32 CA186873/CA/NCI NIH HHS/United States ; R01 CA144034/CA/NCI NIH HHS/United States ; UM1 CA182876/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Biomarkers ; Biomarkers, Tumor ; Breast Neoplasms/epidemiology/*genetics/*mortality ; Female ; Follow-Up Studies ; Humans ; Leukocytes/*metabolism ; Middle Aged ; Prognosis ; Proportional Hazards Models ; Singapore/epidemiology/ethnology ; Telomere/*genetics ; },
abstract = {BACKGROUND: Telomeres and telomerase play key roles in the chromosomal maintenance and stability. Recent epidemiological studies have shown that longer telomeres are associated with increased risk of several cancer types. However, epidemiological data for telomere length and risk of breast cancer are sparse.<br><br>METHODS: We prospectively studied the association between telomere length and risk of breast cancer in 14,305 middle-aged or older Chinese women of the Singapore Chinese Health Study including 442 incident breast cancer cases after 12.3&#x2009;years of follow-up. Relative telomere length in peripheral blood leukocytes was quantified using a validated monochrome multiple quantitative polymerase chain reaction method. The Cox proportional hazard regression method was used to estimate hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) for breast cancer associated with longer telomeres after adjustment for potential confounders.<br><br>RESULTS: Longer telomeres were significantly associated with higher risk of breast cancer in a dose-dependent manner (Ptrend&#x2009;=&#x2009;0.006); the highest quartile of telomere length was associated with a statistically significant 47% higher risk of breast cancer compared with the lowest quartile of telomere length after the adjustment for age and other known risk factors for breast cancer (HRQ4 vs Q1&#x2009;=&#x2009;1.47, 95% CI&#x2009;=&#x2009;1.11, 1.94).<br><br>CONCLUSIONS: The findings of the present study support the hypothesis that longer telomeres may be a risk factor for breast cancer. Telomere length in peripheral blood leukocytes may be developed as a biomarker for breast cancer risk prediction.},
}
@article {pmid30995915,
year = {2019},
author = {Arias-Salgado, EG and Galvez, E and Planas-Cerezales, L and Pintado-Berninches, L and Vallespin, E and Martinez, P and Carrillo, J and Iarriccio, L and Ruiz-Llobet, A and Catalá, A and Badell-Serra, I and Gonzalez-Granado, LI and Martín-Nalda, A and Martínez-Gallo, M and Galera-Miñarro, A and Rodríguez-Vigil, C and Bastos-Oreiro, M and Perez de Nanclares, G and Leiro-Fernández, V and Uria, ML and Diaz-Heredia, C and Valenzuela, C and Martín, S and López-Muñiz, B and Lapunzina, P and Sevilla, J and Molina-Molina, M and Perona, R and Sastre, L},
title = {Genetic analyses of aplastic anemia and idiopathic pulmonary fibrosis patients with short telomeres, possible implication of DNA-repair genes.},
journal = {Orphanet journal of rare diseases},
volume = {14},
number = {1},
pages = {82},
pmid = {30995915},
issn = {1750-1172},
support = {PI14-01495//Instituto de Salud Carlos III/International ; PI17-01401//Instituto de Salud Carlos III/International ; TC0000100//Fundaci&#xf3;n General CSIC/International ; },
mesh = {Adolescent ; Adult ; Anemia, Aplastic/*genetics ; Child ; Child, Preschool ; DNA Repair/*genetics ; Dyskeratosis Congenita/*genetics ; Exons/genetics ; Female ; Humans ; Infant ; Male ; Pedigree ; Pulmonary Fibrosis/*genetics ; RNA/genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {BACKGROUND: Telomeres are nucleoprotein structures present at the terminal region of the chromosomes. Mutations in genes coding for proteins involved in telomere maintenance are causative of a number of disorders known as telomeropathies. The genetic origin of these diseases is heterogeneous and has not been determined for a significant proportion of patients.<br><br>METHODS: This article describes the genetic characterization of a cohort of patients. Telomere length was determined by Southern blot and quantitative PCR. Nucleotide variants were analyzed either by high-resolution melting analysis and Sanger sequencing of selected exons or by massive sequencing of a panel of genes.<br><br>RESULTS: Forty-seven patients with telomere length below the 10% of normal population, affected with three telomeropathies: dyskeratosis congenita (4), aplastic anemia (22) or pulmonary fibrosis (21) were analyzed. Eighteen of these patients presented known pathogenic or novel possibly pathogenic variants in the telomere-related genes TERT, TERC, RTEL1, CTC1 and ACD. In addition, the analyses of a panel of 188 genes related to haematological disorders indicated that a relevant proportion of the patients (up to 35%) presented rare variants in genes related to DNA repair or in genes coding for proteins involved in the resolution of complex DNA structures, that participate in telomere replication. Mutations in some of these genes are causative of several syndromes previously associated to telomere shortening.<br><br>CONCLUSION: Novel variants in telomere, DNA repair and replication genes are described that might indicate the contribution of variants in these genes to the development of telomeropathies. Patients carrying variants in telomere-related genes presented worse evolution after diagnosis than the rest of patients analyzed.},
}
@article {pmid30994174,
year = {2019},
author = {Carroll, JE and Irwin, MR and Seeman, TE and Diez-Roux, AV and Prather, AA and Olmstead, R and Epel, E and Lin, J and Redline, S},
title = {Obstructive sleep apnea, nighttime arousals, and leukocyte telomere length: the Multi-Ethnic Study of Atherosclerosis.},
journal = {Sleep},
volume = {42},
number = {7},
pages = {},
pmid = {30994174},
issn = {1550-9109},
support = {N01HC95169/HL/NHLBI NIH HHS/United States ; R01 HL076831/HL/NHLBI NIH HHS/United States ; N01HC95161/HL/NHLBI NIH HHS/United States ; N01HC95162/HL/NHLBI NIH HHS/United States ; UL1 TR000124/TR/NCATS NIH HHS/United States ; K01 AG044462/AG/NIA NIH HHS/United States ; N01HC95163/HL/NHLBI NIH HHS/United States ; R01 HL101161/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; N01HC95164/HL/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; N01HC95168/HL/NHLBI NIH HHS/United States ; R01 CA160245/CA/NCI NIH HHS/United States ; N01HC95165/HL/NHLBI NIH HHS/United States ; R35 HL135818/HL/NHLBI NIH HHS/United States ; R01 HL098433/HL/NHLBI NIH HHS/United States ; R01 CA119159/CA/NCI NIH HHS/United States ; N01HC95167/HL/NHLBI NIH HHS/United States ; R01 AG034588/AG/NIA NIH HHS/United States ; R01 AG026364/AG/NIA NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; N01HC95166/HL/NHLBI NIH HHS/United States ; R01 HL142051/HL/NHLBI NIH HHS/United States ; N01HC95160/HL/NHLBI NIH HHS/United States ; },
mesh = {Actigraphy ; Adult ; Aged ; Aged, 80 and over ; Aging ; Arousal/physiology ; Atherosclerosis/*physiopathology ; Ethnicity ; Female ; Humans ; Leukocytes/metabolism ; Male ; Middle Aged ; Polysomnography ; Sex Factors ; Sleep/*physiology ; Sleep Apnea, Obstructive/*physiopathology ; Sleep Arousal Disorders/*physiopathology ; Sleep Deprivation/*physiopathology ; Telomere/physiology ; Telomere Homeostasis/*physiology ; Time Factors ; },
abstract = {STUDY OBJECTIVES: Sleep disturbances and sleep apnea are associated with increased vulnerability to age-related disease, altering molecular pathways affecting biological aging. Telomere length captures one component of biological aging. We evaluated whether objectively assessed sleep and sleep apnea relate to leukocyte telomere length (LTL) in the Multi-Ethnic Study of Atherosclerosis (MESA).<br><br>METHODS: Men and women aged 44-84 years (n = 672) from the MESA Stress and MESA Sleep studies underwent polysomnography and 7 day actigraphy (at Exam 5) and assessment of LTL (at baseline [Exam 1] and about 10 years later [Exam 5]).<br><br>RESULTS: General linear models adjusting for age, sex, race/ethnicity, BMI, physical activity, and smoking found that severe obstructive sleep apnea (OSA; apnea-hypopnea index > 30) was cross-sectionally associated with shorter LTL (p = 0.007). Modest associations of shorter LTL with less rapid eye movement sleep, more stage 1 sleep, wake after sleep onset >30 min, and long sleep duration were found, but these effects were diminished after adjusting for lifestyle and OSA. Exploratory analyses found that higher arousal index at Exam 5 was associated with greater LTL decline over the prior 10 years (p = 0.004).<br><br>CONCLUSIONS: OSA was associated with shorter LTL. Individuals with high-arousal frequency had greater leukocyte telomere attrition over the prior decade. These findings suggest that sleep apnea and sleep fragmentation are associated with accelerated biological aging.},
}
@article {pmid30987070,
year = {2019},
author = {Rangel-Pozzo, A and Corrêa de Souza, D and Schmid-Braz, AT and de Azambuja, AP and Ferraz-Aguiar, T and Borgonovo, T and Mai, S},
title = {3D Telomere Structure Analysis to DetectGenomic Instability and Cytogenetic Evolutionin Myelodysplastic Syndromes.},
journal = {Cells},
volume = {8},
number = {4},
pages = {},
pmid = {30987070},
issn = {2073-4409},
support = {321106-341700-2000//CIHR/Canada ; },
mesh = {Adolescent ; Adult ; Aged ; Child ; Child, Preschool ; *Cytogenetic Analysis ; Disease Progression ; Female ; *Genomic Instability ; Humans ; Infant ; Male ; Middle Aged ; Myelodysplastic Syndromes/*genetics ; Telomere/*chemistry ; Young Adult ; },
abstract = {The disease course of myelodysplastic syndromes (MDS) features chromosome instability and clonal evolution, leading to the sequential acquisition of novel cytogenetic aberrations and the accumulation of these abnormalities in the bone marrow. Although clonal cytogenetic abnormalities can be detected by conventional cytogenetics in 50% of patients with MDS, such distinguishing patterns are lacking in the other 50%. Despite the increase in the prognostic value of some biomarkers, none of them is specific and able to discriminate between stable and unstable patients that subsequently progress to acute myeloid leukemia. This pilot study aimed to investigate the potential use of the 3D telomere profiling to detect genomic instability in MDS patients with or without clonal cytogenetic evolution. The comparison between different time points in patients with cytogenetic changes showed that in the CD34+ MDS cells, there was a significant decrease in the total number of telomeric signals, the average intensity of signals and the total intensity of telomeres. By contrast, the number of aggregates increased during cytogenetic evolution (p < 0.001). This pattern was observed only for MDS patients with cytogenetic evolution but was absent in patients without cytogenetic changes. In conclusion, we demonstrated that the 3D nuclear telomere organization was significantly altered during the MDS disease course, and may have contributed to cytogenetic clonal evolution.},
}
@article {pmid30985056,
year = {2019},
author = {Sweetlove, L and Gutierrez, C},
title = {The journey to the end of the chromosome: delivering active telomerase to telomeres in plants.},
journal = {The Plant journal : for cell and molecular biology},
volume = {98},
number = {2},
pages = {193-194},
doi = {10.1111/tpj.14328},
pmid = {30985056},
issn = {1365-313X},
mesh = {Plants ; *Telomerase ; *Telomere ; },
}
@article {pmid30979972,
year = {2019},
author = {Jongbloed, F and Meijers, RWJ and IJzermans, JNM and Klaassen, RA and Dollé, MET and van den Berg, S and Betjes, MGH and de Bruin, RWF and van der Harst, E and Litjens, NHR},
title = {Effects of bariatric surgery on telomere length and T-cell aging.},
journal = {International journal of obesity (2005)},
volume = {43},
number = {11},
pages = {2189-2199},
doi = {10.1038/s41366-019-0351-y},
pmid = {30979972},
issn = {1476-5497},
mesh = {Adolescent ; Adult ; *Bariatric Surgery ; Cellular Senescence/*physiology ; Female ; Humans ; Male ; Metabolic Syndrome ; Middle Aged ; *Obesity/metabolism/physiopathology/surgery ; Prospective Studies ; T-Lymphocytes/*physiology ; Telomere/*physiology ; Young Adult ; },
abstract = {BACKGROUND: Obesity adversely affects health and is associated with subclinical systemic inflammation and features of accelerated aging, including the T-cell immune system. The presence of metabolic syndrome (MetS) may accelerate, while bariatric surgery might reverse these phenomena. To examine the effects of MetS and bariatric surgery on T-cell aging, we measured relative telomere length (RTL) and T-cell differentiation status in obese patients before and after bariatric surgery.<br><br>METHODS: WHO II/III classified obese patients scheduled for bariatric surgery were included: 41 without MetS and 67 with MetS. RTL and T-cell differentiation status were measured in circulating CD4[+] and CD8[+] T cells via flow cytometry. T-cell characteristics were compared between patients with and without MetS prior to and at 3, 6, and 12 months after surgery considering effects of age, cytomegalovirus-serostatus, and weight loss.<br><br>RESULTS: Thymic output, represented by numbers of CD31-expressing naive T cells, showed an age-related decline in patients with MetS. MetS significantly enhanced CD8[+] T-cell differentiation. Patients with MetS had significant lower CD4[+] RTL than patients without MetS. Within the first 6 months after bariatric surgery, RTL increased in CD4[+] T cells after which it decreased at month 12. A decline in both thymic output and more differentiated T cells was seen following bariatric surgery, more pronounced in the MetS group and showing an association with percentage of body weight loss.<br><br>CONCLUSIONS: In obese patients, MetS results in attrition of RTL and accelerated T-cell differentiation. Bariatric surgery temporarily reverses these effects. These data suggest that MetS is a risk factor for accelerated aging of T cells and that MetS should be a more prominent factor in the decision making for eligibility for bariatric surgery.},
}
@article {pmid30979667,
year = {2019},
author = {Omidpanah, N and Darvishi, FZ and Saadat, M},
title = {No alteration in leukocyte telomere length in schizophrenia; evidence from a meta-analysis.},
journal = {Schizophrenia research},
volume = {208},
number = {},
pages = {447-448},
doi = {10.1016/j.schres.2019.04.004},
pmid = {30979667},
issn = {1573-2509},
mesh = {Humans ; Leukocytes ; *Schizophrenia ; *Telomere ; },
}
@article {pmid30978531,
year = {2019},
author = {Sullivan, S and Hammadah, M and Al Mheid, I and Shah, A and Sun, YV and Kutner, M and Ward, L and Blackburn, E and Zhao, J and Lin, J and Bremner, JD and Quyyumi, AA and Vaccarino, V and Lewis, TT},
title = {An investigation of racial/ethnic and sex differences in the association between experiences of everyday discrimination and leukocyte telomere length among patients with coronary artery disease.},
journal = {Psychoneuroendocrinology},
volume = {106},
number = {},
pages = {122-128},
pmid = {30978531},
issn = {1873-3360},
support = {R56 HL126558/HL/NHLBI NIH HHS/United States ; R38 AI140299/AI/NIAID NIH HHS/United States ; K24 HL077506/HL/NHLBI NIH HHS/United States ; R01 DK091369/DK/NIDDK NIH HHS/United States ; R01 MH097018/MH/NIMH NIH HHS/United States ; T32 HL130025/HL/NHLBI NIH HHS/United States ; K23 HL127251/HL/NHLBI NIH HHS/United States ; P01 HL086773/HL/NHLBI NIH HHS/United States ; UL1 TR000454/TR/NCATS NIH HHS/United States ; UL1 TR002378/TR/NCATS NIH HHS/United States ; KL2 TR000455/TR/NCATS NIH HHS/United States ; R01 HL109413/HL/NHLBI NIH HHS/United States ; K12 HD085850/HD/NICHD NIH HHS/United States ; U54 AG062334/AG/NIA NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; R01 HL125246/HL/NHLBI NIH HHS/United States ; K24 MH076955/MH/NIMH NIH HHS/United States ; R01 HL088726/HL/NHLBI NIH HHS/United States ; P20 HL113451/HL/NHLBI NIH HHS/United States ; P01 HL101398/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Black or African American/psychology ; Aged ; Anxiety/psychology ; Cohort Studies ; Coronary Artery Disease/epidemiology/*etiology ; Depression/psychology ; Ethnicity ; Female ; Humans ; Leukocytes/physiology ; Male ; Middle Aged ; Prospective Studies ; Racism ; Risk Factors ; Sex Characteristics ; Sexism ; Stress, Psychological/metabolism/*psychology ; Telomere/physiology ; Telomere Homeostasis/*physiology ; White People/psychology ; },
abstract = {Leukocyte telomere length (LTL) may be sensitive to psychosocial stressors such as discrimination. An inclusive examination of experiences of discrimination on LTL across racial/ethnic and sex groups is currently lacking. Baseline data were obtained from 369 White and African American patients with coronary artery disease (CAD) in the Mental Stress Ischemia Mechanisms and Prognosis Study. LTL was measured from peripheral blood leukocytes by quantitative polymerase chain reaction and calculated in kilobase pairs. Discrimination was measured using the 10-item Everyday Discrimination Scale (EDS). Responses were rated using 4-point Likert scales ranging from never = 1 to often = 4 and summed. Regression models were stratified by race/ethnicity and sex to estimate associations between discrimination and LTL. Each 10-unit increase in experiences of everyday discrimination was associated with an average of .20 fewer kilobase pairs (or 200 base pairs) among both African American women (β = -0.19; 95% CI: -0.35, -0.04; p-value: 0.02) and White women (β = -0.19; 95% CI: -0.37, -0.01; p-value: 0.04), after adjusting for basic demographic factors. Results were similar after further adjusting for behavioral, disease, and psychosocial risk factors (depression and stress). There were no significant associations between experiences of everyday discrimination and LTL for White men or African American men. Overall, experiences of discrimination were associated with shorter LTL among women and not in men. Discrimination may be a potential source of stress associated with shorter LTL among women with CAD. Future studies should explore longitudinal associations between everyday experiences of discrimination and telomere length and also with adverse cardiovascular outcomes.},
}
@article {pmid30978332,
year = {2019},
author = {Swaminathan, AC and Neely, ML and Frankel, CW and Kelly, FL and Petrovski, S and Durheim, MT and Bush, E and Snyder, L and Goldstein, DB and Todd, JL and Palmer, SM},
title = {Lung Transplant Outcomes in Patients With Pulmonary Fibrosis With Telomere-Related Gene Variants.},
journal = {Chest},
volume = {156},
number = {3},
pages = {477-485},
doi = {10.1016/j.chest.2019.03.030},
pmid = {30978332},
issn = {1931-3543},
mesh = {Aged ; Cohort Studies ; DNA Helicases/*genetics ; Exoribonucleases/*genetics ; Female ; Graft Rejection/epidemiology/genetics ; Humans ; *Lung Transplantation ; Male ; Middle Aged ; Primary Graft Dysfunction/epidemiology/genetics ; Pulmonary Fibrosis/*genetics/mortality/*surgery ; Survival Rate ; Telomerase/*genetics ; Telomere/genetics ; Treatment Outcome ; },
abstract = {BACKGROUND: Pulmonary fibrosis (PF) is the most common disease indication for lung transplantation. Our recent work implicated an excess of rare genetic variants in the telomere-related genes TERT, RTEL1, and PARN in PF disease risk. The impact of such variants on posttransplant outcomes is uncertain. The objective of this study was to determine if patients with these PF-associated variants have altered rates of posttransplant acute rejection (AR), chronic lung allograft dysfunction (CLAD), and survival.<br><br>METHODS: The study cohort consisted of 262 PF lung transplant recipients previously genetically characterized by whole exome sequencing. Thirty-one patients (11.8%) had variants in TERT, RTEL1, or PARN, whereas 231 (88.2%) did not. Multivariate Cox proportional hazards models adjusted for relevant clinical variables were used to assess the outcomes of death and CLAD. The AR burden was quantified and compared over the first posttransplant year.<br><br>RESULTS: Patients with PF with disease-associated variants in TERT, RTEL1, or PARN had a significantly higher risk of death (adjusted hazard ratio [HR], 1.82; 95%&#xa0;CI, 1.07-3.08; P&#xa0;= .03) and CLAD (adjusted HR, 2.88; 95%&#xa0;CI, 1.42-5.87; P&#xa0;= .004) than patients without these variants. There was no difference in AR burden or rates of grade 3 primary graft dysfunction between the two groups.<br><br>CONCLUSIONS: Rare variants in the telomere-related genes TERT, RTEL1, or PARN are associated with poor posttransplant outcomes among PF lung transplant recipients. Further research is needed to understand the biological mechanisms by which telomere-related variants increase the risk for death and CLAD.},
}
@article {pmid30976813,
year = {2019},
author = {Bao, HL and Liu, HS and Xu, Y},
title = {Hybrid-type and two-tetrad antiparallel telomere DNA G-quadruplex structures in living human cells.},
journal = {Nucleic acids research},
volume = {47},
number = {10},
pages = {4940-4947},
pmid = {30976813},
issn = {1362-4962},
mesh = {Circular Dichroism ; DNA/*chemistry/genetics/metabolism ; Fluorine/chemistry ; *G-Quadruplexes ; HeLa Cells ; Humans ; Models, Molecular ; Proton Magnetic Resonance Spectroscopy ; Telomere/*genetics ; *Thermodynamics ; },
abstract = {Although the telomeric sequence has been reported to form various G-quadruplex topologies in vitro and in Xenopus laevis oocytes, in living human cells, the topology of telomeric DNA G-quadruplex remains a challenge. To investigate the human telomeric DNA G-quadruplex in a more realistic human cell environment, in the present study, we demonstrated that the telomeric DNA sequence can form two hybrid-type and two-tetrad antiparallel G-quadruplex structures by in-cell 19F NMR in living human cells (HELA CELLS). This result provides valuable information for understanding the structures of human telomeric DNA in living human cells and for the design of new drugs that target telomeric DNA.},
}
@article {pmid30974172,
year = {2019},
author = {Lazarides, C and Epel, ES and Lin, J and Blackburn, EH and Voelkle, MC and Buss, C and Simhan, HN and Wadhwa, PD and Entringer, S},
title = {Maternal pro-inflammatory state during pregnancy and newborn leukocyte telomere length: A prospective investigation.},
journal = {Brain, behavior, and immunity},
volume = {80},
number = {},
pages = {419-426},
pmid = {30974172},
issn = {1090-2139},
support = {UG3 OD023349/OD/NIH HHS/United States ; R01 MD010738/MD/NIMHD NIH HHS/United States ; R01 HD065825/HD/NICHD NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; R01 HD060628/HD/NICHD NIH HHS/United States ; R01 AG050455/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Female ; Humans ; Infant, Newborn ; Inflammation/*blood/complications/*immunology ; Interleukin-10/blood ; Leukocytes/*immunology ; Longitudinal Studies ; Pregnancy ; Pregnancy Complications/*blood/*immunology ; Prospective Studies ; Telomere/*immunology ; Tumor Necrosis Factor-alpha/blood ; Young Adult ; },
abstract = {INTRODUCTION: Telomere biology plays a fundamental role in maintaining the integrity of the genome and cell, and shortened telomeres have been linked to several age-related diseases. The initial (newborn) telomere length (TL) represents a critically important feature of the telomere biology system. Exposure to a variety of adverse prenatal conditions such as maternal stress, suboptimal diet, obesity, and obstetric complications, is associated with shorter offspring TL at birth and in adult life. Many, if not all, of these exposures are believed to have an inflammatory component. In this context, stress-related immunological processes during pregnancy may constitute a potential additional biological pathway because they can affect telomere length and telomerase activity via transcriptions factors such as cyclic adenosine monophosphate-dependent transcription factor (ATF7) and nuclear factor-kappa B (NF-κB). Thus, in the present study we examined the hypothesis that maternal pro-inflammatory state across pregnancy, operationalized as the balance between tumor necrosis factor (TNF)-α, a major pro-inflammatory cytokine, and interleukin-10 (IL-10), the major anti-inflammatory cytokine, is associated with newborn leukocyte telomere length (LTL) at birth.<br><br>METHODS AND MATERIALS: Participants were healthy women (N&#x202f;=&#x202f;112) recruited in early pregnancy. Concentrations of TNF- &#x3b1; and IL-10 were quantified in early, mid and late pregnancy from maternal blood samples. Telomere length was assessed in newborn blood samples soon after birth.<br><br>RESULTS: After adjusting for maternal age, maternal pre-pregnancy BMI, birth weight percentile, and infant sex, a higher mean TNF-&#x3b1;/IL-10 ratio across pregnancy was significantly associated with shorter newborn TL (&#x3b2;&#x202f;=&#x202f;-.205, p&#x202f;=&#x202f;.030). Newborn TL was, on average, 10% shorter in offspring of women in the upper compared to lower quartile of the TNF-&#x3b1;/IL-10 ratio during pregnancy.<br><br>DISCUSSION: These findings provide new evidence in humans for a potential "programming" mechanism linking maternal systemic pro-inflammatory processes during pregnancy with the initial (newborn) setting of her offspring's telomere system.},
}
@article {pmid30971237,
year = {2019},
author = {Herlin, M and Broberg, K and Igra, AM and Li, H and Harari, F and Vahter, M},
title = {Exploring telomere length in mother-newborn pairs in relation to exposure to multiple toxic metals and potential modifying effects by nutritional factors.},
journal = {BMC medicine},
volume = {17},
number = {1},
pages = {77},
pmid = {30971237},
issn = {1741-7015},
mesh = {Adolescent ; Adult ; Antioxidants/*administration &amp; dosage ; Argentina/epidemiology ; Child ; Cohort Studies ; Diet ; Environmental Exposure/*analysis/prevention &amp; control ; Female ; Fetal Blood/drug effects/metabolism ; Humans ; Infant, Newborn ; Male ; *Maternal Exposure/statistics &amp; numerical data ; *Maternal Nutritional Physiological Phenomena/drug effects ; Maternal-Fetal Exchange/drug effects/genetics ; Metals, Heavy/analysis/blood/*toxicity/urine ; Mothers ; Placenta/drug effects/metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects/chemically induced/epidemiology/genetics/prevention &amp; control ; Telomere/drug effects/*physiology ; Telomere Homeostasis/drug effects/*physiology ; Young Adult ; },
abstract = {BACKGROUND: The uterine environment may influence telomere length at birth, which is essential for cellular function, aging, and disease susceptibility over the lifespan. However, little is known about the impact of toxic chemicals on early-life telomeres. Therefore, we assessed the potential impact of multiple toxic metals on relative telomere length (rTL) in the maternal blood, cord blood, and placenta, as well as the potential modifying effects of pro-oxidants.<br><br>METHOD: In a mother-child cohort in northern Argentina (n&#xa0;=&#x2009;169), we measured multiple toxic metals in the maternal blood or urine collected during late pregnancy, as well as the placenta and cord blood collected at delivery, using inductively coupled plasma mass spectrometry (ICP-MS). We assessed associations of log2-transformed metal concentrations with rTL, measured in maternal and cord blood leukocytes and the placenta by real-time PCR, using multivariable-adjusted linear regression. Additionally, we tested for modifications by antioxidants (zinc, selenium, folate, and vitamin D3).<br><br>RESULTS: Exposure to boron and antimony during pregnancy was associated with shorter maternal rTL, and lithium with longer maternal rTL; a doubling of exposure was associated with changes corresponding to 0.2-0.4 standard deviations (SD) of the rTL. Arsenic concentrations in the placenta (n&#xa0;=&#x2009;98), blood, and urine were positively associated with placental rTL, about 0.2 SD by doubled arsenic. In the cord blood (n&#xa0;=&#x2009;88), only lead was associated with rTL (inversely), particularly in boys (p for interaction 0.09). Stratifying by newborn sex showed ten times stronger association in boys (about 0.6 SD) than in girls. The studied antioxidants did not modify the associations, except that with antimony.<br><br>CONCLUSIONS: Elevated exposure to boron, lithium, arsenic, and antimony was associated&#xa0;with maternal or newborn rTL in a tissue-specific, for lead also sex-specific, manner. Nutritional antioxidants did not generally influence the associations.},
}
@article {pmid30968208,
year = {2020},
author = {Lang, J and McKie, J and Smith, H and McLaughlin, A and Gillberg, C and Shiels, PG and Minnis, H},
title = {Adverse childhood experiences, epigenetics and telomere length variation in childhood and beyond: a systematic review of the literature.},
journal = {European child &amp; adolescent psychiatry},
volume = {29},
number = {10},
pages = {1329-1338},
pmid = {30968208},
issn = {1435-165X},
mesh = {Adolescent ; Adverse Childhood Experiences/*methods ; Child ; Child, Preschool ; Epigenesis, Genetic/*genetics ; Female ; Humans ; Male ; Telomere/*genetics ; },
abstract = {A systematic review following PRISMA guidelines was conducted to answer the question: What epigenetic, telomeric and associated biological changes are associated with exposure to adverse childhood experiences (ACEs) in the under 12s? Using PRISMA guidelines, appropriate databases were searched. 190 papers were returned with 38 articles fully reviewed. Articles were each independently quality rated by two authors using the Crowe Critical Appraisal Tool and data were extracted. Of the 38 articles, 23 were rated as very high quality. Most study participants were adults (n = 7769) with n = 727 child participants. Only seven of the very/high-quality studies were prospective and involved children. Methylation was the most studied method of epigenetic modification. There is some evidence supporting epigenetic modification of certain markers in participants exposed to ACEs measured in adulthood. Research is lacking on non-coding aspects of the epigenome and on coding aspects other than DNA methylation. There is some evidence of a more powerful effect on telomere length if physical neglect was involved. Much further work is required to model biological and psychological effects of epigenetic changes during childhood using prospective study designs. The effect of ACEs on the cellular ageing process during childhood is inadequately investigated and relies solely on measure of telomere length. Future research suggestions are proposed.},
}
@article {pmid30961458,
year = {2019},
author = {Karimi, B and Yunesian, M and Nabizadeh, R and Mehdipour, P},
title = {Serum Level of Total Lipids and Telomere Length in the Male Population: A Cross-Sectional Study.},
journal = {American journal of men's health},
volume = {13},
number = {2},
pages = {1557988319842973},
pmid = {30961458},
issn = {1557-9891},
mesh = {Adult ; Anthropometry ; Cross-Sectional Studies ; Humans ; Iran ; Lipids/*blood ; Male ; Surveys and Questionnaires ; *Telomere Shortening ; },
abstract = {Telomeres contain TTAGGG (T; Thymine, A; Adenine and G; Guanine) repetitive sequences and are placed at the end of human chromosomes. Telomere dysfunction is implicated in some age-related and chronic diseases, but its association with total serum lipids and obesity is unknown. Our objective was to determine influenced of total serum lipids on leukocyte telomere lengths (TLs). Participants were selected by cluster sampling from 22 districts of Tehran. The questionnaires were completed by 500 subjects and after the initial assessment in terms of lifestyle, nutrition, home, and job, 300 healthy people, aged 25-40 years were finally selected. TLs and serum level of total lipids were measured by quantitative real-time PCR and the Phillips method, respectively. The average telomere length (T/S) and total lipids were 1.05 ± 0.3 mg/dl and 643.3 ± 70.8 mg/dl, respectively. We found that a one unit difference in the following parameters were associated with kilo base pair differences in TL: Age -0.0002 (95% CI [-0.0022, -0.0018]), BMI -0.0019 (95% CI [-0.0003, -0.0034]), TC 0.0001 (95% CI [-0.0006, -0.0007]), TG -0.0010 (95% CI [-0.0015, -0.0004]), PL 0.0001 (95% CI [-0.0005, -0.0007]), and TSL -0.0003 (95% CI [-0.0008, 0.0001]). Spearman correlation analysis revealed an inverse relationship between TC (R = -0.53; 95% CI [-0.61, -0.44]), TG (R = -0.50; 95% CI [-0.58, -0.41]), PL (R = -0.46; 95% CI [-0.54-0.36]), and TSL (R = -0.63; 95% CI [-0.69, -0.56]) with T/S. Our research suggests that the inverse relationship was found between TL and weight, BMI, age, and TSL which were associated with obesity. High serum lipids concentration may be associated with systemic inflammation and atherosclerosis and may lead to oxidative stress, resulting in telomere shortening.},
}
@article {pmid30958913,
year = {2019},
author = {Gillis, JC and Chang, SC and Wang, W and Simon, NM and Normand, SL and Rosner, BA and Blacker, D and DeVivo, I and Okereke, OI},
title = {The relation of telomere length at midlife to subsequent 20-year depression trajectories among women.},
journal = {Depression and anxiety},
volume = {36},
number = {6},
pages = {565-575},
pmid = {30958913},
issn = {1520-6394},
support = {T42 OH008416/OH/NIOSH CDC HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 MH096776/MH/NIMH NIH HHS/United States ; T32 MH017119/MH/NIMH NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aging/*genetics/*psychology ; Depression/*diagnosis/*genetics ; Depressive Disorder/diagnosis/genetics ; Female ; Humans ; Logistic Models ; Middle Aged ; Prospective Studies ; Risk Factors ; Telomere/genetics/*metabolism ; Telomere Shortening/genetics/*physiology ; },
abstract = {BACKGROUND: Telomeres cap and protect DNA but shorten with each somatic cell division. Aging and environmental and lifestyle factors contribute to the speed of telomere attrition. Current evidence suggests a link between relative telomere length (RTL) and depression but the directionality of the relationship remains unclear. We prospectively examined associations between RTL and subsequent depressive symptom trajectories.<br><br>METHODS: Among 8,801 women of the Nurses' Health Study, depressive symptoms were measured every 4 years from 1992 to 2012; group-based trajectories of symptoms were identified using latent class growth-curve analysis. Multinomial logistic models were used to relate midlife RTLs to the probabilities of assignment to subsequent depressive symptom trajectory groups.<br><br>RESULTS: We identified four depressive symptom trajectory groups: minimal depressive symptoms (62%), worsening depressive symptoms (14%), improving depressive symptoms (19%), and persistent-severe depressive symptoms (5%). Longer midlife RTLs were related to significantly lower odds of being in the worsening symptoms trajectory versus minimal trajectory but not to other trajectories. In comparison with being in the minimal symptoms group, the multivariable-adjusted odds ratio of being in the worsening depressive symptoms group was 0.78 (95% confidence interval, 0.62-0.97; p&#x2009;=&#x2009;0.02), for every standard deviation increase in baseline RTL.<br><br>CONCLUSIONS: In this large prospective study of generally healthy women, longer telomeres at midlife were associated with significantly lower risk of a subsequent trajectory of worsening mood symptoms over 20 years. The results raise the possibility of telomere shortening as a novel contributing factor to late-life depression.},
}
@article {pmid30958221,
year = {2019},
author = {Sudyka, J and Arct, A and Drobniak, SM and Gustafsson, L and Cichoń, M},
title = {Birds with high lifetime reproductive success experience increased telomere loss.},
journal = {Biology letters},
volume = {15},
number = {1},
pages = {20180637},
pmid = {30958221},
issn = {1744-957X},
mesh = {Animals ; *Passeriformes ; Reproduction ; *Telomere ; Telomere Shortening ; },
abstract = {Lifetime reproductive success (LRS) is what counts in terms of evolution, but investments in reproduction entail costs for an organism. The idea that telomere dynamics may be shaped in response to such costs is already established; however, we still lack information on whether this relation translates to overall fitness. Here, we quantified LRS (number of fledged young) and longitudinal telomere dynamics of small passerine birds-the blue tits (Cyanistes caeruleus). We found that individual telomere erosion rate was positively associated with lifetime fledgling number. Birds with more fledged young experienced increased telomere attrition. We show that telomere attrition rate, but not telomere length, is related to individual fitness and suggest that telomere dynamics may underlie reproductive costs experienced by animals as a consequence of prioritizing their lifetime fitness. This is the first study, to our knowledge, to provide evidence that more pronounced telomere erosion is associated with higher fitness gain.},
}
@article {pmid30943453,
year = {2019},
author = {Marshall, WF and Fung, JC},
title = {Modeling meiotic chromosome pairing: a tug of war between telomere forces and a pairing-based Brownian ratchet leads to increased pairing fidelity.},
journal = {Physical biology},
volume = {16},
number = {4},
pages = {046005},
pmid = {30943453},
issn = {1478-3975},
support = {R01 GM116895/GM/NIGMS NIH HHS/United States ; },
mesh = {Biophysical Phenomena ; Chromosome Pairing/*physiology ; Chromosomes/metabolism ; *Computer Simulation ; Meiosis/physiology ; *Models, Biological ; Telomere/*metabolism ; Thermodynamics ; },
abstract = {Meiotic homolog pairing involves associations between homologous DNA regions scattered along the length of a chromosome. When homologs associate, they tend to do so by a processive zippering process, which apparently results from avidity effects. Using a computational model, we show that this avidity-driven processive zippering reduces the selectivity of pairing. When active random forces are applied to telomeres, this drop in selectivity is eliminated in a force-dependent manner. Further simulations suggest that active telomere forces are engaged in a tug-of-war against zippering, which can be interpreted as a Brownian ratchet with a stall force that depends on the dissociation constant of pairing. When perfectly homologous regions of high affinity compete with homeologous regions of lower affinity, the affinity difference can be amplified through this tug of war effect provided the telomere force acts in a range that is strong enough to oppose zippering of homeologs while still permitting zippering of correct homologs. The degree of unzippering depends on the radius of the nucleus, such that complete unzippering of homeologous regions can only take place if the nucleus is large enough to pull the two chromosomes completely apart. A picture of meiotic pairing thus emerges that is fundamentally mechanical in nature, possibly explaining the purpose of active telomere forces, increased nuclear diameter, and the presence of 'Maverick' chromosomes in meiosis.},
}
@article {pmid30935966,
year = {2019},
author = {Derenzini, E and Risso, A and Ruella, M and Spatola, T and Milone, G and Pioltelli, P and Iori, AP and Santarone, S and Bosi, A and Rambaldi, A and Bacigalupo, AP and Arcese, W and Tarella, C},
title = {Influence of Donor and Recipient Gender on Telomere Maintenance after Umbilical Cord Blood Cell Transplantation: A Study by the Gruppo Italiano Trapianto Di Midollo Osseo.},
journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation},
volume = {25},
number = {7},
pages = {1387-1394},
doi = {10.1016/j.bbmt.2019.03.026},
pmid = {30935966},
issn = {1523-6536},
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Child ; Child, Preschool ; *Cord Blood Stem Cell Transplantation ; Female ; Follow-Up Studies ; Humans ; Italy ; Male ; Middle Aged ; Sex Factors ; Telomere/*metabolism ; *Telomere Homeostasis ; *Tissue Donors ; },
abstract = {Physiologic loss of telomerase activity in adult life determines progressive telomere length (TL) shortening. Inflammation and oxidative damage are established causes of TL loss; moreover, males have shorter telomeres compared with females. Despite these notions, mechanisms regulating TL maintenance are poorly defined. Because umbilical cord blood (UCB) cells harbor very long telomeres, not yet exposed to environmental damages, UCB transplantation (UCBT) provides a unique experimental setting to study determinants of TL in humans. TL dynamics were analyzed on peripheral blood mononuclear cells (MNCs) from 36 patients (median age, 42 years) undergoing UCBT. TL was studied at a median of 20 months after UCBT. A significantly longer TL (mean, 8698 bp; range, 6521 to 11,960) was documented in UCBT recipients compared with age-matched healthy control subjects (mean, 7396 bp; range, 4375 to 11,108; P < .01). Among variables potentially influencing TL maintenance, including recipient features, graft type, transplant procedure, and engraftment kinetics, only donor-recipient gender combination was associated with TL, with the longest TL in women receiving male UCB (mean, 10,063 bp; range, 8381 to 11,960). To further investigate this trend, telomerase activation was assessed in vitro. Experiments showed that telomerase subunits were preferentially upregulated in male-derived bone marrow MNCs exposed ex vivo to estradiol as compared with female MNCs. This implies an increased sensitivity of male-derived MNCs to telomerase activation induced by estradiol. The results suggest that extrinsic and modifiable factors such as hormonal status and female milieu could be major determinants of TL in humans, providing the rationale for investigating hormonal-based approaches to counteract telomere erosion and aging-related diseases.},
}
@article {pmid30935416,
year = {2019},
author = {Chen, YF and Zhou, KW and Yang, GZ and Chen, C},
title = {Association between lipoproteins and telomere length in US adults: data from the NHANES 1999-2002.},
journal = {Lipids in health and disease},
volume = {18},
number = {1},
pages = {80},
pmid = {30935416},
issn = {1476-511X},
mesh = {Adult ; Aged ; Cholesterol, HDL/blood ; Cholesterol, LDL/blood ; Diet ; Female ; Humans ; Hyperlipoproteinemia Type II/blood/*epidemiology/genetics/pathology ; Leukocytes/cytology/metabolism ; Lipoproteins/blood/*genetics ; Male ; Middle Aged ; Nutrition Surveys ; Risk Factors ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Triglycerides/blood ; },
abstract = {BACKGROUND: Evidence regarding the correlation between lipoproteins and telomere length in US adults is limited. We aimed to investigate whether lipoproteins was associated with telomere length using US National Health and Nutrition Examination Survey (NHANES) database.<br><br>METHODS: A total of 6468 selected participants were identified in the NHANES Data Base (1999-2002). The independent and dependent variables were lipoproteins and telomere length, respectively. The covariates included demographic data, dietary data, physical examination data, and comorbidities.<br><br>RESULTS: In fully-adjusted model, we found that 0.1 differences of telomere length were positively associated with HDL-C [0.19 (95% CI 0.07, 0.31)], while the associations between LDL-C [0.19 (95% CI -0.27, 0.65)], TG [-&#x2009;1.00 (95% CI -2.09, 0.07) and telomere length were not detected. By nonlinearity test, only the relationship between HDL-C and telomere length was nonlinear. The inflection point we got was 1.25. On the left side of the inflection point (telomere length&#x2009;&#x2264;&#x2009;1.25), a difference in 0.1 of telomere length was associated with 0.50 difference in HDL-C.<br><br>CONCLUSION: After adjusting for demographic data, dietary data, physical examination data, and comorbidities, telomere length is not associated with LDL-C and TG, but is positively associated with HDL-C when telomere length is less than 1.25.},
}
@article {pmid30931641,
year = {2019},
author = {Al Khleifat, A and Iacoangeli, A and Shatunov, A and Fang, T and Sproviero, W and Jones, AR and Opie-Martin, S and Morrison, KE and Shaw, PJ and Shaw, CE and Powell, JF and Dobson, R and Newhouse, SJ and Al-Chalabi, A},
title = {Telomere length is greater in ALS than in controls: a whole genome sequencing study.},
journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration},
volume = {20},
number = {3-4},
pages = {229-234},
pmid = {30931641},
issn = {2167-9223},
support = {AL-CHALABI/APR15/844-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MC_PC_17115/MRC_/Medical Research Council/United Kingdom ; G1100695/MRC_/Medical Research Council/United Kingdom ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MC_G1000733/MRC_/Medical Research Council/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; SHAW/NOV14/985-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; MR/L021803/1/MRC_/Medical Research Council/United Kingdom ; G0900635/MRC_/Medical Research Council/United Kingdom ; MC_PC_17214/MRC_/Medical Research Council/United Kingdom ; JONES/OCT15/958-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; 171/ALZS_/Alzheimer's Society/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Age of Onset ; Aged ; Amyotrophic Lateral Sclerosis/genetics/*pathology ; Case-Control Studies ; Computational Biology ; DNA/chemistry ; Female ; Genetic Variation ; Humans ; Introns/genetics ; Leukocytes/chemistry ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Survival Analysis ; Telomere/genetics/*ultrastructure ; Whole Genome Sequencing ; },
abstract = {Background: Amyotrophic lateral sclerosis is a neurodegenerative disease of motor neurons resulting in progressive paralysis and death, typically within 3-5 years. Although the heritability of ALS is about 60%, only about 11% is explained by common gene variants, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication and shorten naturally with age. Gender and age are risk factors for ALS and also associated with telomere length. We therefore investigated telomere length in ALS. Methods: We estimated telomere length by applying a bioinformatics analysis to whole genome sequence data of leukocyte-derived DNA from people with ALS and age and gender-matched matched controls in a UK population. We tested the association of telomere length with ALS and ALS survival. Results: There were 1241 people with ALS and 335 controls. The median age for ALS was 62.5 years and for controls, 60.1 years, with a male-female ratio of 62:38. Accounting for age and sex, there was a 9% increase of telomere length in ALS compared to matched controls. Those with longer telomeres had a 16% increase in median survival. Of nine SNPs associated with telomere length, two were also associated with ALS: rs8105767 near the ZNF208 gene (p = 1.29 × 10[-4]) and rs6772228 (p = 0.001), which is in an intron for the PXK gene. Conclusions: Longer telomeres in leukocyte-derived DNA are associated with ALS, and with increased survival in those with ALS.},
}
@article {pmid30930403,
year = {2019},
author = {Kaewtunjai, N and Summart, R and Wongnoppavich, A and Lojanapiwat, B and Lee, TR and Tuntiwechapikul, W},
title = {Telomerase Inhibition, Telomere Shortening, and Cellular Uptake of the Perylene Derivatives PM2 and PIPER in Prostate Cancer Cells.},
journal = {Biological &amp; pharmaceutical bulletin},
volume = {42},
number = {6},
pages = {906-914},
doi = {10.1248/bpb.b18-00860},
pmid = {30930403},
issn = {1347-5215},
mesh = {Antineoplastic Agents/*pharmacology ; Cell Line, Tumor ; Cellular Senescence/drug effects ; Humans ; Male ; PC-3 Cells ; Perylene/*analogs &amp; derivatives/chemistry/*pharmacology ; Prostatic Neoplasms, Castration-Resistant/*drug therapy/metabolism/pathology ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere Shortening/*drug effects ; },
abstract = {Prostate cancer is the second most common cancer among men worldwide, and it is ranked first in the United States and Europe. Since prostate cancer is slow-growing, active surveillance for low-risk cancer has been increasingly supported by various guidelines. Most prostate cancers reactivate telomerase to circumvent the replicative senescence caused by the end replication problem; therefore, telomerase inhibition is potentially useful for the suppression of prostate cancer progression during this active surveillance or for the prevention of cancer recurrence after conventional therapies. In this study, we demonstrated that the perylene derivatives, PM2 and PIPER, could suppress human telomerase reverse transcriptase (hTERT) expression and telomerase activity in the short-term treatment of androgen-dependent prostate cancer cell line LNCaP and the androgen-independent prostate cancer cell line PC3 prostate cancer cells. Long-term treatment with subcytotoxic doses of these compounds in both prostate cancer cells showed telomere shortening and a significant increase in senescent cells. Although the acute cytotoxicity of PM2 was about 30 times higher than that of PIPER in both prostate cancer cells, the cellular uptake of both compounds was comparable as determined by flow cytometry and fluorescent microscopy.},
}
@article {pmid30930169,
year = {2019},
author = {Amano, H and Chaudhury, A and Rodriguez-Aguayo, C and Lu, L and Akhanov, V and Catic, A and Popov, YV and Verdin, E and Johnson, H and Stossi, F and Sinclair, DA and Nakamaru-Ogiso, E and Lopez-Berestein, G and Chang, JT and Neilson, JR and Meeker, A and Finegold, M and Baur, JA and Sahin, E},
title = {Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease.},
journal = {Cell metabolism},
volume = {29},
number = {6},
pages = {1274-1290.e9},
pmid = {30930169},
issn = {1932-7420},
support = {R01 CA190467/CA/NCI NIH HHS/United States ; R21 DE027490/DE/NIDCR NIH HHS/United States ; P30 DK056338/DK/NIDDK NIH HHS/United States ; R01 DK100263/DK/NIDDK NIH HHS/United States ; R01 AG019719/AG/NIA NIH HHS/United States ; R01 AG043483/AG/NIA NIH HHS/United States ; R01 DK098656/DK/NIDDK NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; P30 CA125123/CA/NCI NIH HHS/United States ; R01 AG047924/AG/NIA NIH HHS/United States ; R37 AG028730/AG/NIA NIH HHS/United States ; DP1 AG058605/AG/NIA NIH HHS/United States ; R01 DK115454/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; Down-Regulation/drug effects/genetics ; Embryo, Mammalian ; Female ; Gene Expression Regulation, Enzymologic/drug effects ; HEK293 Cells ; Humans ; Liver/drug effects/metabolism/pathology ; Liver Cirrhosis/*genetics/pathology/prevention &amp; control ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria, Liver/drug effects/metabolism ; Nicotinamide Mononucleotide/pharmacology ; Sirtuin 1/genetics/metabolism ; Sirtuins/*genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere Homeostasis/drug effects/physiology ; Telomere Shortening/drug effects/genetics/*physiology ; },
abstract = {Telomere shortening is associated with stem cell decline, fibrotic disorders, and premature aging through mechanisms that are incompletely understood. Here, we show that telomere shortening in livers of telomerase knockout mice leads to a p53-dependent repression of all seven sirtuins. P53 regulates non-mitochondrial sirtuins (Sirt1, 2, 6, and 7) post-transcriptionally through microRNAs (miR-34a, 26a, and 145), while the mitochondrial sirtuins (Sirt3, 4, and 5) are regulated in a peroxisome proliferator-activated receptor gamma co-activator 1 alpha-/beta-dependent manner at the transcriptional level. Administration of the NAD(+) precursor nicotinamide mononucleotide maintains telomere length, dampens the DNA damage response and p53, improves mitochondrial function, and, functionally, rescues liver fibrosis in a partially Sirt1-dependent manner. These studies establish sirtuins as downstream targets of dysfunctional telomeres and suggest that increasing Sirt1 activity alone or in combination with other sirtuins stabilizes telomeres and mitigates telomere-dependent disorders.},
}
@article {pmid30929712,
year = {2019},
author = {Kim, H and Cho, SJ and Yoo, SH and Kim, SH and Ahn, YM},
title = {Association between telomere length and completed suicide observed in 71 suicide victims - Preliminary findings.},
journal = {Journal of psychosomatic research},
volume = {120},
number = {},
pages = {8-11},
doi = {10.1016/j.jpsychores.2019.02.008},
pmid = {30929712},
issn = {1879-1360},
mesh = {Adult ; Aged ; Case-Control Studies ; Female ; Humans ; Leukocytes/metabolism ; Life Style ; Male ; Middle Aged ; *Suicide, Completed ; Telomere/*genetics ; },
abstract = {OBJECTIVE: Telomere length has emerged as a cumulative marker for lifestyle, psychosocial stress, and cytotoxic environments. We aimed to examine the possible association between leukocyte telomere length (LTL) and completed suicide.<br><br>METHODS: This study included 71 suicide completers and 117 healthy controls for whom LTL was determined by the ratio of the telomere repeat copy number to the single-copy gene copy number (T/S ratio). We compared the LTL between the suicide completers and the healthy controls and estimated the odds ratio (OR) for suicide for each age group, applying a generalized estimating equation (GEE).<br><br>RESULTS: LTL was significantly shortened in the suicide completers as compared with the controls, overall subjects, or within-age categories (&#x2264;29 and 30-49&#x202f;years). Furthermore, a longer LTL was associated with significantly decreased odds of completed suicide for those aged &#x2264;29&#x202f;years and 30-49&#x202f;years (OR&#x202f;=&#x202f;0.11, 95% confidence interval [CI] 0.03-0.37, p&#x202f;<&#x202f;.001 for the &#x2264;29-year age group; OR&#x202f;=&#x202f;0.54, 95% CI 0.34-0.84, p&#x202f;=&#x202f;.006 for the 30- to 49-year age group).<br><br>CONCLUSIONS: This study provides evidence regarding the relationship between shortened LTL and completed suicide, especially in those aged <50&#x202f;years. Future research should further assess potential confounders and examine underlying mechanisms.},
}
@article {pmid30927408,
year = {2019},
author = {Martin, LF and Richardson, LS and da Silva, MG and Sheller-Miller, S and Menon, R},
title = {Dexamethasone induces primary amnion epithelial cell senescence through telomere-P21 associated pathway†.},
journal = {Biology of reproduction},
volume = {100},
number = {6},
pages = {1605-1616},
pmid = {30927408},
issn = {1529-7268},
support = {R01 HD084532/HD/NICHD NIH HHS/United States ; T32 ES007254/ES/NIEHS NIH HHS/United States ; },
mesh = {Amnion/*cytology/drug effects/physiology ; Cell Proliferation/drug effects ; Cells, Cultured ; Cellular Senescence/*drug effects ; Cyclin-Dependent Kinase Inhibitor p21/metabolism/physiology ; Dexamethasone/*pharmacology ; Epithelial Cells/cytology/*drug effects/*physiology ; Female ; Humans ; Pregnancy ; Primary Cell Culture ; Signal Transduction/drug effects ; Telomere/drug effects/metabolism ; Up-Regulation/drug effects ; p38 Mitogen-Activated Protein Kinases/metabolism ; },
abstract = {Dexamethasone (Dex), a corticosteroid hormone, is used during the perinatal period to help fetal lung and other organ development. Conversely, Dex-induced cell proliferation has been associated with accelerated aging. Using primary amnion epithelial cells (AECs) from term, not in labor, fetal membranes, we tested the effects of Dex on cell proliferation, senescence, and inflammation. Primary AECs treated with Dex (100 and 200 nM) for 48 h were tested for cell viability (crystal violet dye exclusion), cell cycle progression and/or type of cell death (flow cytometry), expression patterns of steroid receptors (glucocorticoid receptor, progesterone receptor membrane component 1&amp;2), inflammatory mediators (IL-6 and IL-8), and telomere length (quantitative RT-PCR). Mechanistic mediators of senescence (p38MAPK and p21) were determined by western blot analysis. Dex treatment did not induce AEC proliferation, cell cycle, influence viability, or morphology. However, Dex caused dependent telomere length reduction and p38MAPK-independent but p21-dependent (confirmed by treatment with p21 inhibitor UC2288). Senescence was not associated with an increase in inflammatory mediators, which is often associated with senescence. Co-treatment with RU486 produced DNA damage, cell cycle arrest, and cellular necrosis with an increase in inflammatory mediators. The effect of Dex was devoid of changes to steroid receptors, whereas RU486 increased GR expression. Dex treatment of AECs produced nonreplicative and noninflammatory senescence. Extensive use of Dex during the perinatal period may lead to cellular senescence, contributing to cellular aging associated pathologies during the perinatal and neonatal periods.},
}
@article {pmid30926765,
year = {2019},
author = {Ge, J and Li, C and Li, C and Huang, Z and Zeng, J and Han, L and Wang, Q},
title = {SIRT6 participates in the quality control of aged oocytes via modulating telomere function.},
journal = {Aging},
volume = {11},
number = {7},
pages = {1965-1976},
pmid = {30926765},
issn = {1945-4589},
mesh = {Aging/metabolism/pathology ; Animals ; Apoptosis/physiology ; Cellular Senescence/physiology ; Cleavage Stage, Ovum/cytology/metabolism ; DNA Damage ; Female ; Gene Knockdown Techniques ; Mice ; Mice, Inbred ICR ; Oocytes/cytology/*metabolism ; Pregnancy ; RNA, Messenger/genetics/metabolism ; Sirtuins/antagonists &amp; inhibitors/genetics/*metabolism ; Telomere Shortening/physiology ; Up-Regulation ; },
abstract = {It has been well recognized that oocyte quality declines in aging animals. However, to date, the underlying mechanism remains to be explored. In the present study, we report that oocytes and embryos from aged mice (42-45 weeks old) display the reduced expression of SIRT6 protein, accompanying with telomere shortening and DNA lesions. Moreover, we demonstrate that specific depletion of SIRT6 in oocytes induces dysfunctional telomeres and apoptosis of the resultant early embryos, leading to the developmental delay and cytoplasmic fragmentation. Importantly, we further find that overexpression of SIRT6 in aged oocytes promotes the telomere elongation in 2-cell embryos and lowers the incidence of apoptotic blastomeres. In summary, our data indicate a role for SIRT6 in modulating telomere function during oocyte maturation and embryonic development, and discover that SIRT6 reduction is an important point connecting maternal aging and quality control of oocyte/embryos.},
}
@article {pmid30921599,
year = {2019},
author = {Wang, XB and Cui, NH and Zhang, S and Liu, ZJ and Ma, JF and Ming, L},
title = {Leukocyte telomere length, mitochondrial DNA copy number, and coronary artery disease risk and severity: A two-stage case-control study of 3064 Chinese subjects.},
journal = {Atherosclerosis},
volume = {284},
number = {},
pages = {165-172},
doi = {10.1016/j.atherosclerosis.2019.03.010},
pmid = {30921599},
issn = {1879-1484},
mesh = {Asian People ; Case-Control Studies ; Coronary Artery Disease/*genetics ; DNA Copy Number Variations ; DNA, Mitochondrial/*genetics ; Female ; Humans ; *Leukocytes ; Male ; Middle Aged ; Retrospective Studies ; Risk Assessment ; Severity of Illness Index ; *Telomere ; },
abstract = {BACKGROUND AND AIMS: Leukocyte telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN), as hallmarks of cellular aging, may be involved in the development of coronary artery disease (CAD) by modulating oxidative stress. This study aimed to investigate the effects of leukocyte TL and mtDNA-CN alone or in combination on CAD risk and severity in the Chinese population.<br><br>METHODS: In this two-stage case-control study with 1511 CAD patients and 1553 controls, leukocyte TL and mtDNA-CN were determined by a quantitative PCR assay. Three oxidative parameters, including leukocyte 8-hydroxy-2'-deoxyguanosine (8-OHdG), plasma malondialdehyde, and plasma reactive oxygen species (ROS), were quantified by ELISA or colorimetric kits in a subset of 129 cases and 129 controls.<br><br>RESULTS: In the combined cohort, each 1-SD decrease in TL and mtDNA-CN was significantly associated with a 1.17-fold and 1.14-fold increased risk of CAD (p&#x202f;<&#x202f;0.001 for all), respectively, after adjusting for confounders. The aggregated score, which reflected the cumulative dosage of the tertiles of TL and mtDNA-CN, showed inverse dose-response correlations with CAD risk (ptrend&#x202f;<&#x202f;0.001), and severity, as determined by the severity of clinical presentations (ptrend&#x202f;=&#x202f;0.037), the presence of multi-vessel CAD (ptrend&#x202f;=&#x202f;0.004), and modified Gensini scores (ptrend&#x202f;=&#x202f;0.009). Similar dose-response relations of the aggregated score to leukocyte 8-OHdG and plasma ROS were also identified.<br><br>CONCLUSIONS: Our data suggested reductions in both TL and mtDNA-CN as independent risk factors for CAD. The combination of TL and mtDNA-CN might jointly contribute to CAD risk, CAD severity, and oxidative stress.},
}
@article {pmid30921393,
year = {2019},
author = {Ellaway, A and Dundas, R and Robertson, T and Shiels, PG},
title = {More miles on the clock: Neighbourhood stressors are associated with telomere length in a longitudinal study.},
journal = {PloS one},
volume = {14},
number = {3},
pages = {e0214380},
pmid = {30921393},
issn = {1932-6203},
support = {MC_UU_12017/13/MRC_/Medical Research Council/United Kingdom ; MC_A540_53462/MRC_/Medical Research Council/United Kingdom ; MC_UU_12017/10/MRC_/Medical Research Council/United Kingdom ; SPHSU13/CSO_/Chief Scientist Office/United Kingdom ; SPHSU10/CSO_/Chief Scientist Office/United Kingdom ; },
mesh = {Adolescent ; Adult ; Body Mass Index ; Diet ; Exercise ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Prospective Studies ; Smoking ; Social Class ; *Stress, Psychological ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {BACKGROUND: There is a substantial gap in health and longevity between more affluent and more deprived areas, and more knowledge of the determinants of this health divide is required. Experience of the local residential environment is important for health although few studies have examined this in relation to biological markers of age such as telomere length. We sought to examine if residents' perceptions of neighbourhood stressors over time were associated with telomere length in a community study.<br><br>In a prospective cohort study of 2186 adults in the West of Scotland, we measured neighbourhood stressors at three time points over a 12-year period and telomere length at the end of the study. Using linear regression models, we found that a higher accumulation of neighbourhood stressors over time was associated with shorter telomere length, even after taking cohort, social class, health behaviours (smoking status, diet, physical activity), BMI and depression into account among females only (Beta = 0.007; 95%CI [0.001, 0.012]; P<0.014).<br><br>CONCLUSIONS/SIGNIFICANCE: Neighborhood environments are potentially modifiable, and future efforts directed towards improving deleterious local environments may be useful to lessen telomere attrition.},
}
@article {pmid30918138,
year = {2019},
author = {Hubacek, JA and Pelclova, D and Dlouha, D and Mikuska, P and Dvorackova, S and Vlckova, S and Fenclova, Z and Ondracek, J and Kostejn, M and Schwarz, J and Popov, A and Krumal, K and Lanska, V and Coufalik, P and Zakharov, S and Zdimal, V},
title = {Leukocyte telomere length is not affected by long-term occupational exposure to nano metal oxides.},
journal = {Industrial health},
volume = {57},
number = {6},
pages = {741-744},
pmid = {30918138},
issn = {1880-8026},
mesh = {Adult ; Air Pollutants, Occupational/adverse effects ; Czech Republic/epidemiology ; Female ; Humans ; Leukocytes ; Male ; Metal Nanoparticles/*adverse effects ; Middle Aged ; Occupational Exposure/*adverse effects ; Oxides ; *Research Personnel ; Telomere Shortening/*drug effects ; },
abstract = {The aim of this study was to ascertain whether long-term occupational exposure to nanoparticles would affect relative leukocyte telomere length (LrTL). We analysed occupational exposure to size-resolved aerosol particles, with special emphasis on nanoparticles at two workshops: i/ the production of nanocomposites containing metal oxides; ii/ laboratory to test experimental exposure of nano-CuO to rodents. Thirty five exposed researchers (age 39.5 ± 12.6 yr; exposure duration 6.0 ± 3.7 yr) and 43 controls (40.4 ± 10.5 yr) were examined. LrTL did not significantly (p=0.14) differ between the exposed researchers (0.92 ± 0.13) and controls (0.86 ± 0.15). In addition, no significant correlation (r=-0.22, p=0.22) was detected between the duration of occupational exposure and LrTL. The results remained non-significant after multiple adjustments for age, sex and smoking status. Our pilot results suggest that relative leukocyte telomere length is not affected by occupational exposure to nanoparticles.},
}
@article {pmid30913032,
year = {2019},
author = {Mangge, H and Renner, W and Almer, G and Gruber, HJ and Zelzer, S and Moeller, R and Horejsi, R and Herrmann, M},
title = {Subcutaneous adipose tissue distribution and telomere length.},
journal = {Clinical chemistry and laboratory medicine},
volume = {57},
number = {9},
pages = {1358-1363},
doi = {10.1515/cclm-2018-0801},
pmid = {30913032},
issn = {1437-4331},
mesh = {Adipose Tissue/metabolism ; Adult ; Body Mass Index ; Cohort Studies ; Female ; Humans ; Male ; Middle Aged ; Obesity/*genetics/metabolism ; Subcutaneous Fat/*metabolism/physiology ; Telomere/genetics/*physiology ; Telomere Shortening/genetics/*physiology ; Waist-Hip Ratio ; },
abstract = {Background Overweight and obese individuals have a reduced life expectancy due to cardiovascular disease (CVD), type 2 diabetes, stroke and cancer. Systemic inflammation and premature telomere shortening have been discussed as potential mechanisms linking these conditions. We investigated the relation of subcutaneous adipose tissue (SAT) distribution to leukocyte relative telomere length (RTL). Methods We measured RTL in 375 participants of the observational STYJOBS/EDECTA cohort (ClinicalTrials.gov Identifier NCT00482924) using a qPCR based method. SAT distribution was determined by lipometry yielding a percent body fat value and SAT thicknesses at 15 standardized locations across the entire body. A correlation analysis between RTL, age, sex, lipometry data and conventional body measures (body mass index [BMI], waist-, hip circumference, waist-to-hip ratio, waist-to-height ratio) was calculated. The strongest determinants of RTL were determined by a stepwise multiple regression analysis. Results RTL was not associated with age or sex. RTL was significantly negatively correlated with BMI, percent body fat, waist-, hip circumference and waist-to-height ratio. Furthermore, RTL correlated with SAT at the following locations: neck, triceps, biceps, upper back, front chest, lateral chest, upper abdomen, lower abdomen, lower back, hip, front thigh, lateral thigh, rear thigh and calf. Stepwise regression analysis revealed nuchal and hip SAT as the strongest predictors of RTL. No significant association was seen between RTL and waist-to-hip ratio. Conclusions RTL is negatively associated with parameters describing body fat composure. Nuchal and hip SAT thicknesses are the strongest predictors of RTL. Central obesity appears to correlate with premature genomic aging.},
}
@article {pmid30912325,
year = {2019},
author = {Suh, DI and Kang, MJ and Park, YM and Lee, JK and Lee, SY and Sheen, YH and Kim, KW and Ahn, K and Won, HS and Lee, MY and Choi, SJ and Kwon, JY and Park, HJ and Jun, JK and Hong, SJ and Koh, YY},
title = {Leukocyte Telomere Length Reflects Prenatal Stress Exposure, But Does Not Predict Atopic Dermatitis Development at 1 Year.},
journal = {Allergy, asthma &amp; immunology research},
volume = {11},
number = {3},
pages = {357-366},
pmid = {30912325},
issn = {2092-7355},
support = {800-2015-0099//Seoul National University College of Medicine/Korea ; 2008-E33030-00/KCDC/Korea Centers for Disease Control &amp; Prevention/Korea ; 2009-E33033-00/KCDC/Korea Centers for Disease Control &amp; Prevention/Korea ; 2011-E33021-00/KCDC/Korea Centers for Disease Control &amp; Prevention/Korea ; 2012-E33012-00/KCDC/Korea Centers for Disease Control &amp; Prevention/Korea ; 2013-E51003-00/KCDC/Korea Centers for Disease Control &amp; Prevention/Korea ; 2014-E51004-00/KCDC/Korea Centers for Disease Control &amp; Prevention/Korea ; 2014-E51004-01/KCDC/Korea Centers for Disease Control &amp; Prevention/Korea ; 2014-E51004-02/KCDC/Korea Centers for Disease Control &amp; Prevention/Korea ; },
abstract = {PURPOSE: Prenatal maternal stress affects offspring's atopic dermatitis (AD) development, which is thought to be mediated by the oxidative stress. We aimed to evaluate the difference in leukocyte telomere length (LTL), a marker for exposure to oxidative stress, according to the prenatal stress exposure and the later AD development.<br><br>METHODS: From a birth cohort (the COhort for Childhood Origin of Asthma and allergic diseases) that had displayed a good epidemiologic association between the exposure to prenatal stress and AD development in the offspring, we selected 68 pairs of samples from 4 subject groups based on the level of prenatal maternal stress and later AD development. The LTL was measured from both cord blood and 1-year peripheral blood, and their LTLs were compared between subject groups. Finally, the proportion of AD development was examined in the subject groups that are reclassified based on subjects' exposure to prenatal stress and there LTL.<br><br>RESULTS: Cord-blood LTL was shorter in prenatally stressed infants than in unstressed ones (P = 0.026), which difference was still significant when subjects became 1 year old (P = 0.008). LTL of cord blood, as well as one of the 1-year peripheral blood, was not different according to later AD development at 1 year (P = 0.915 and 0.174, respectively). Shorter LTL made no increase in the proportion of later AD development in either prenatally high-stressed or low-stressed groups (P = 1.000 and 0.473, respectively).<br><br>CONCLUSIONS: Cord-blood LTL may reflect subjects' exposure to maternal prenatal stress. However, the LTL shortening is not a risk factor of increasing AD development until the age of 1, and a longer investigation may be necessary for validation. Currently, the results doubt the role of LTL shortening as a marker for risk assessment tool for the prenatal stress associated with AD development in the offspring.},
}
@article {pmid30911113,
year = {2019},
author = {Jebaraj, BMC and Tausch, E and Landau, DA and Bahlo, J and Robrecht, S and Taylor-Weiner, AN and Bloehdorn, J and Scheffold, A and Mertens, D and Böttcher, S and Kneba, M and Jäger, U and Zenz, T and Wenger, MK and Fingerle-Rowson, G and Wendtner, C and Fink, AM and Wu, CJ and Eichhorst, B and Fischer, K and Hallek, M and Döhner, H and Stilgenbauer, S},
title = {Short telomeres are associated with inferior outcome, genomic complexity, and clonal evolution in chronic lymphocytic leukemia.},
journal = {Leukemia},
volume = {33},
number = {9},
pages = {2183-2194},
pmid = {30911113},
issn = {1476-5551},
support = {R01 CA216273/CA/NCI NIH HHS/United States ; P01 CA206978/CA/NCI NIH HHS/United States ; SFB 1074 B2//Deutsche Forschungsgemeinschaft (German Research Foundation)/International ; P30 CA006516/CA/NCI NIH HHS/United States ; 031L0076C PRECISe//Bundesministerium f&#xfc;r Bildung und Forschung (Federal Ministry of Education and Research)/International ; T32 HG002295/HG/NHGRI NIH HHS/United States ; SFB 1074 B1//Deutsche Forschungsgemeinschaft (German Research Foundation)/International ; 2010_Kolleg24//Else Kr&#xf6;ner-Fresenius-Stiftung (Else Kroner-Fresenius Foundation)/International ; UG1 CA233338/CA/NCI NIH HHS/United States ; },
mesh = {Case-Control Studies ; Clonal Evolution/*genetics ; Female ; Genomics/methods ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics ; Male ; Middle Aged ; Prognosis ; Prospective Studies ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Telomere length in chronic lymphocytic leukemia (CLL) has been shown to be of prognostic importance, but the analyses have largely been executed on heterogeneous patient cohorts outside of clinical trials. In the present study, we performed a comprehensive analysis of telomere length associations in the well characterized CLL8 trial (n = 620) of the German CLL study group, with validation in a representative cohort of the CLL4 trial (n = 293). Absolute telomere length was analyzed using quantitative-PCR. Apart from identifying associations of short telomere length with adverse prognostic factors and survival, the study identified cases with 17p- and 11q- associated with TP53 and ATM loss, respectively, to have the shortest telomeres, even when these aberrations were present in small subclones. Thus, telomere shortening may precede acquisition of the high-risk aberrations, contributing to disease evolution. In line with this, telomere shortening was associated with an increase in genomic complexity as well as clonal evolution, highlighting its importance as a biomarker especially in monitoring disease progression in non-high-risk CLL.},
}
@article {pmid30907229,
year = {2019},
author = {Nera, B and Huang, HS and Hendrickson, EA and Xu, L},
title = {Both the classical and alternative non-homologous end joining pathways contribute to the fusion of drastically shortened telomeres induced by TRF2 overexpression.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {18},
number = {8},
pages = {880-888},
pmid = {30907229},
issn = {1551-4005},
support = {R01 CA190492/CA/NCI NIH HHS/United States ; R01 GM088351/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatids/metabolism ; Colorectal Neoplasms/*metabolism ; DNA End-Joining Repair/*genetics ; DNA Ligase ATP/deficiency ; Evolution, Molecular ; Genetic Vectors ; Genomic Instability/genetics ; HCT116 Cells ; Humans ; Plasmids/genetics ; Poly-ADP-Ribose Binding Proteins/deficiency ; Sister Chromatid Exchange/genetics ; Telomere/*metabolism ; Telomere Shortening/*genetics ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; },
abstract = {The double-stranded telomeric binding protein TRF2 is expressed in many human cancers at elevated levels. Moreover, experimental overexpression of TRF2 in human cells causes replication stalling in telomeric tracts, which leads to drastic telomere shortening and fusion of deprotected chromosome ends. To understand which end joining pathway is involved in mediating these chromosome fusions, we overexpressed TRF2 in human HCT116 cell lines that were deficient for the DNA Ligase 4 (Lig4)-dependent classical non-homologous end joining (C-NHEJ) or the DNA Ligase 3 (Lig3)-dependent alternative non-homologous end joining (A-NHEJ) pathway. Surprisingly, abrogation of either Lig4 or nuclear Lig3 significantly reduced inter-chromosomal fusion of drastically shortened telomeres, suggesting that both the C-NHEJ and A-NHEJ pathways are involved in mediating this type of fusion. Fusion between deprotected sister chromatids, however, only required the Lig3-dependent A-NHEJ pathway. Interestingly, a previous study reported similar end joining pathway requirements for the fusion of critically shortened telomeres during a telomere attrition-based cellular crisis. We speculate that, as in cellular crisis, the same repair pathway(s) may drive clonal and genomic evolution in human cancers containing elevated TRF2 levels.},
}
@article {pmid30901604,
year = {2019},
author = {Lewinska, A and Klukowska-Rötzler, J and Deregowska, A and Adamczyk-Grochala, J and Wnuk, M},
title = {c-Myc activation promotes cofilin-mediated F-actin cytoskeleton remodeling and telomere homeostasis as a response to oxidant-based DNA damage in medulloblastoma cells.},
journal = {Redox biology},
volume = {24},
number = {},
pages = {101163},
pmid = {30901604},
issn = {2213-2317},
mesh = {Actin Cytoskeleton/*metabolism ; Actin Depolymerizing Factors/*metabolism ; Cell Cycle/drug effects ; Cell Line, Tumor ; DNA Damage/*drug effects ; Humans ; Medulloblastoma/genetics/metabolism ; Models, Biological ; Oxidants/*pharmacology ; Oxidative Stress/drug effects ; Proto-Oncogene Proteins c-myc/*genetics ; Telomere Homeostasis/*genetics ; *Transcriptional Activation ; },
abstract = {Medulloblastoma (MB) is a common and highly aggressive pediatric brain tumor of a heterogeneous nature. According to transcriptome-based profiling, four molecular subgroups of MB have been revealed, namely WNT, SHH, Group 3 and Group 4. High MYC mRNA expression and MYC gene amplification in MB have been considered as indicators of poor prognosis. However, the role of c-Myc in MB biology is still not well established. In the present study, the effects of c-Myc activation in UW228-MycER MB cell line were investigated using 4-hydroxytamoxifen (4-OHT) induction system. Upon 4-OHT stimulation, an increase in metabolic activity, large-cell/anaplastic (LC/A) phenotype and oxidative stress-mediated DNA damage were observed. However, 53BP1 foci were not implicated in DNA damage response. Instead, cofilin nuclear translocation, changes in F-actin cytoskeleton and the levels of cytoskeletal proteins were shown. Moreover, the telomere length was found to be unaffected that may be associated with the upregulation of TRF proteins. Transcription of nascent RNA (synthesis of new rRNA) and the expression of RNA polymerase I-specific transcription initiation factor RRN3/TIF-IA were also elevated. Moreover, increased levels of DNMT2, a modulator of stress responses, were observed. A small fraction of cells responded differently as oncogene-induced senescence was also noticed. We postulate that c-Myc-mediated modulation of genetic stability of MB cells may trigger cellular heterogeneity and affect adaptive responses to changing environment.},
}
@article {pmid30900102,
year = {2019},
author = {Zhang, N and Zheng, Y and Liu, J and Lei, T and Xu, Y and Yang, M},
title = {Genetic variations associated with telomere length confer risk of gastric cardia adenocarcinoma.},
journal = {Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association},
volume = {22},
number = {6},
pages = {1089-1099},
pmid = {30900102},
issn = {1436-3305},
support = {31671300//National Natural Science Foundation of China/International ; 31871306//National Natural Science Foundation of China-Yunnan Joint Fund/International ; },
mesh = {Adenocarcinoma/genetics/*pathology ; Aged ; Cardia/*pathology ; Case-Control Studies ; Female ; Genetic Predisposition to Disease ; Genetic Variation ; Genome-Wide Association Study ; Genotype ; Humans ; Leukocytes/metabolism ; Male ; Polymorphism, Single Nucleotide ; Stomach Neoplasms/genetics/*pathology ; Telomere/*genetics ; },
abstract = {BACKGROUND: Aberrant telomere lengthening is a critical feature of malignant cells. Short leukocyte telomere length (LTL) confers elevated risk of gastric cardia adenocarcinoma (GCA). Multiple genome-wide association studies (GWAS) identified various single-nucleotide polymorphisms (SNPs) associated with LTL in different ethnic populations. However, it remains largely unexplored how these genetic variants are involved in GCA susceptibility.<br><br>METHODS: We systematically screened GWAS-identified candidate SNPs and tested the impact of 30 polymorphisms in genes associated with interindividual LTL variation on GCA using two-stage case-control comparisons consisting of 1024 GCA patients and 1118 controls.<br><br>RESULTS: We observed that CXCR4 rs6430612, TERT rs10069690, and rs2853676 as well as VPS34 rs2162440 are significantly associated with GCA development. A 0.64-fold decreased risk of GCA is associated with the CXCR4 rs6430612 CT genotype compared with the CC genotype (P&#x2009;=&#x2009;0.002). On the contrary, the TERT rs10069690 TT genotype carriers had a 1.83-fold increased risk to develop GCA compared to the CC genotype carriers (P&#x2009;=&#x2009;5.8&#xd7;10[-6]). We also detected a 2.17-fold increased OR for GCA that was associated with the TERT rs2853676 TT genotype (P&#x2009;=&#x2009;2.6&#xd7;10[-6]). In addition, the odds of having the VPS34 rs2162440 GA genotype in GCA patients were 1.35 compared with the GG genotype (P&#x2009;=&#x2009;0.002). In stratified analyses, the association between TERT rs10069690 polymorphism and GCA was more pronounced in nonsmokers (Pinteraction&#xa0;=&#xa0;9.7&#x2009;&#xd7;&#x2009;10[-5]) and nondrinkers (Pinteraction&#xa0;=&#xa0;4.6&#x2009;&#xd7;&#x2009;10[-5]).<br><br>CONCLUSIONS: Our results highlight the importance of both LTL and LTL-related genetic variants to GCA predisposition.},
}
@article {pmid30898995,
year = {2019},
author = {Aas, M and Elvsåshagen, T and Westlye, LT and Kaufmann, T and Athanasiu, L and Djurovic, S and Melle, I and van der Meer, D and Martin-Ruiz, C and Steen, NE and Agartz, I and Andreassen, OA},
title = {Telomere length is associated with childhood trauma in patients with severe mental disorders.},
journal = {Translational psychiatry},
volume = {9},
number = {1},
pages = {97},
pmid = {30898995},
issn = {2158-3188},
support = {22327//Norges Forskningsr&#xe5;d (Research Council of Norway)/International ; 22327//Norges Forskningsr&#xe5;d (Research Council of Norway)/International ; },
mesh = {Adult ; Bipolar Disorder/genetics/*pathology ; Brain/diagnostic imaging/*pathology ; Case-Control Studies ; Child ; Child Abuse/*psychology ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Norway ; Schizophrenia/genetics/*pathology ; Surveys and Questionnaires ; Telomere/*pathology ; *Telomere Shortening ; Young Adult ; },
abstract = {Reduced telomere length (TL) and structural brain abnormalities have been reported in patients with schizophrenia (SZ) and bipolar disorder (BD). Childhood traumatic events are more frequent in SZ and BD than in healthy individuals (HC), and based on recent findings in healthy individuals could represent one important factor for TL and brain aberrations in patients. The study comprised 1024 individuals (SZ [n = 373]; BD [n = 249] and HC [n = 402]). TL was measured by quantitative polymerase chain reaction (qPCR), and childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Diagnosis was obtained by the Structured Clinical Interview (SCID) for the diagnostic and statistical manual of mental disorders-IV (DSM-IV). FreeSurfer was used to obtain regional and global brain volumes from T1-weighted magnetic resonance imaging (MRI) brain scans. All analyses were adjusted for current age and sex. Patients had on average shorter TL (F = 7.87, p = 0.005, Cohen's d = 0.17) and reported more childhood trauma experiences than HC (χ[2] = 148.9, p < 0.001). Patients with a history of childhood sexual, physical or emotional abuse had shorter TL relative to HC and to patients without a history of childhood abuse (F = 6.93, p = 0.006, Cohen's d = 0.16). After adjusting for childhood abuse, no difference in TL was observed between patients and HC (p = 0.12). There was no statistically significant difference in reported childhood abuse exposure or TL between SZ and BD. Our analyses revealed no significant associations between TL and clinical characteristics or brain morphometry. We demonstrate shorter TL in SZ and BD compared with HC and showed that TL is sensitive to childhood trauma experiences. Further studies are needed to identify the biological mechanisms of this relationship.},
}
@article {pmid30891747,
year = {2019},
author = {Shen, W and Kerr, CM and Przychozen, B and Mahfouz, RZ and LaFramboise, T and Nagata, Y and Hanna, R and Radivoyevitch, T and Nazha, A and Sekeres, MA and Maciejewski, JP},
title = {Impact of germline CTC1 alterations on telomere length in acquired bone marrow failure.},
journal = {British journal of haematology},
volume = {185},
number = {5},
pages = {935-939},
pmid = {30891747},
issn = {1365-2141},
support = {R01 HL118281/HL/NHLBI NIH HHS/United States ; K12 CA076917/CA/NCI NIH HHS/United States ; R35 HL135795/HL/NHLBI NIH HHS/United States ; R01 HL123904/HL/NHLBI NIH HHS/United States ; R01 HL132071/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Bone Marrow Failure Disorders/*genetics/metabolism/pathology ; Female ; *Germ-Line Mutation ; Humans ; Male ; Middle Aged ; Telomere/*genetics/metabolism/pathology ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {Compound heterozygous germline mutations in CTC1 gene have been found in patients with atypical dyskeratosis congenita (DC), whereas heterozygous carriers are unaffected. Through screening of a large cohort of adult patients with acquired bone marrow failure syndromes, in addition to a DC case, we have also found extremely rare or novel heterozygous deleterious germline variants of CTC1 in patients with aplastic anaemia (AA; n = 5), paroxysmal nocturnal haemoglobinuria (PNH; n = 3) and myelodysplastic syndrome (MDS; n = 2). A compound heterozygous case of AA showed clonal evolution. Our results suggest that some of the inherited CTC1 variants may represent predisposition factors for acquired bone marrow failure.},
}
@article {pmid30890069,
year = {2019},
author = {Casagrande, S and Hau, M},
title = {Telomere attrition: metabolic regulation and signalling function?.},
journal = {Biology letters},
volume = {15},
number = {3},
pages = {20180885},
pmid = {30890069},
issn = {1744-957X},
mesh = {Oxidative Stress ; Signal Transduction ; Social Control, Formal ; *Telomere ; *Telomere Shortening ; },
abstract = {Stress exposure can leave long-term footprints within the organism, like in telomeres (TLs), protective chromosome caps that shorten during cell replication and following exposure to stressors. Short TLs are considered to indicate lower fitness prospects, but why TLs shorten under stressful conditions is not understood. Glucocorticoid hormones (GCs) increase upon stress exposure and are thought to promote TL shortening by increasing oxidative damage. However, evidence that GCs are pro-oxidants and oxidative stress is causally linked to TL attrition is mixed . Based on new biochemical findings, we propose the metabolic telomere attrition hypothesis: during times of substantially increased energy demands, TLs are shortened as part of the transition into an organismal 'emergency state', which prioritizes immediate survival functions over processes with longer-term benefits. TL attrition during energy shortages could serve multiple roles including amplified signalling of cellular energy debt to re-direct critical resources to immediately important processes. This new view of TL shortening as a strategy to resolve major energetic trade-offs can improve our understanding of TL dynamics. We suggest that TLs are master regulators of cell homeostasis and propose future research avenues to understand the interactions between energy homeostasis, metabolic regulators and TL.},
}
@article {pmid30884806,
year = {2019},
author = {Ventura, A and Pellegrini, C and Cardelli, L and Rocco, T and Ciciarelli, V and Peris, K and Fargnoli, MC},
title = {Telomeres and Telomerase in Cutaneous Squamous Cell Carcinoma.},
journal = {International journal of molecular sciences},
volume = {20},
number = {6},
pages = {},
pmid = {30884806},
issn = {1422-0067},
mesh = {Bowen's Disease/genetics/pathology ; Carcinoma, Squamous Cell/*genetics/pathology ; Disease Progression ; Germ Cells/pathology ; Humans ; Keratosis, Actinic/genetics/pathology ; Mutation ; Skin Neoplasms/*genetics/pathology ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Shortening/genetics ; },
abstract = {The role of telomere biology and telomerase activation in skin cancers has been investigated in melanoma and basal cell carcinoma but limited evidence is available for cutaneous squamous cell carcinoma (cSCC). We will review the current knowledge on the role of telomere and telomerase pathway in cSCC pathogenesis. At the somatic level, both long and short telomere lengths have been described in cSCC. This telomere dichotomy is probably related to two different mechanisms of tumour initiation which determines two tumour subtypes. Telomere shortening is observed during the invasive progression from in situ forms of cSCC, such as Bowen's disease (BD) and actinic keratosis (AK), to invasive cSCC. At the germline level, controversial results have been reported on the association between constitutive telomere length and risk of cSCC. Approximately 75[-]85% of cSCC tumours are characterized by a high level of telomerase activity. Telomerase activation has been also reported in AKs and BD and in sun-damaged skin, thus supporting the hypothesis that UV modulates telomerase activity in the skin. Activating TERT promoter mutations have been identified in 32[-]70% of cSCCs, with the majority showing the UV-signature. No significant correlation was observed between TERT promoter mutations and cSCC clinico-pathological features. However, TERT promoter mutations have been recently suggested to be independent predictors of an adverse outcome. The attention on telomere biology and telomerase activity in cSCC is increasing for the potential implications in the development of effective tools for prognostic assessment and of therapeutic strategies in patients with cutaneous cSCC.},
}
@article {pmid30884304,
year = {2019},
author = {Mayer, SE and Prather, AA and Puterman, E and Lin, J and Arenander, J and Coccia, M and Shields, GS and Slavich, GM and Epel, ES},
title = {Cumulative lifetime stress exposure and leukocyte telomere length attrition: The unique role of stressor duration and exposure timing.},
journal = {Psychoneuroendocrinology},
volume = {104},
number = {},
pages = {210-218},
pmid = {30884304},
issn = {1873-3360},
support = {K08 MH103443/MH/NIMH NIH HHS/United States ; R01 AG030424/AG/NIA NIH HHS/United States ; R24 AG048024/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Adverse Childhood Experiences ; Aging ; Female ; Humans ; Leukocytes ; Life Change Events ; Longitudinal Studies ; Middle Aged ; Mothers ; Stress, Psychological/genetics/*physiopathology ; Telomere/*genetics/physiology ; Telomere Shortening/*physiology ; },
abstract = {BACKGROUND: Stress exposure occurring across the lifespan increases risk for disease, potentially involving telomere length shortening. Stress exposure during childhood and adulthood has been cross-sectionally linked with shorter telomere length. However, few longitudinal studies have examined telomere length attrition over time, and none have investigated how stressor duration (acute life events vs. chronic difficulties), timing (childhood vs. adulthood), and perceived severity may be uniquely related to telomere length shortening.<br><br>METHODS: To address these issues, we administered a standardized instrument for assessing cumulative lifetime stress exposure (Stress and Adversity Inventory; STRAIN) to 175 mothers of children with Autism Spectrum Disorder or neurotypical children and measured their leukocyte telomere length (LTL) at baseline and 2 years later.<br><br>RESULTS: Greater count of lifetime stressors was associated with shorter LTL at baseline and greater LTL attrition over time. When separating lifetime stressors into acute life events and chronic difficulties, only greater count of chronic difficulties significantly predicted shorter baseline LTL and greater LTL attrition. Similarly, when examining timing of stressor exposure, only greater count of chronic childhood difficulties (age < 18) significantly predicted shorter baseline LTL and greater LTL attrition over the 2-year period in mid-life. Importantly, these results were robust while controlling for stressors occurring during the interim 2-year period. Post-hoc analyses suggested that chronic difficulties occurring during earlier childhood (0-12 years) were associated with greater LTL attrition. Cumulative stressor severity predicted LTL attrition in a parallel manner, but was less consistently associated with baseline LTL.<br><br>CONCLUSIONS: These data are the first to examine the effects of different aspects of cumulative lifetime stress exposure on LTL attrition over time, suggesting that accumulated chronic difficulties during childhood may play a unique role in shaping telomere shortening in midlife.},
}
@article {pmid30878023,
year = {2018},
author = {Libertini, G and Ferrara, N and Rengo, G and Corbi, G},
title = {Elimination of Senescent Cells: Prospects According to the Subtelomere-Telomere Theory.},
journal = {Biochemistry. Biokhimiia},
volume = {83},
number = {12},
pages = {1477-1488},
doi = {10.1134/S0006297918120064},
pmid = {30878023},
issn = {1608-3040},
mesh = {Animals ; Cellular Senescence/drug effects/*genetics ; Humans ; Models, Biological ; Neoplasms/genetics/pathology ; Risk ; Telomere/*genetics ; },
abstract = {Cell senescence is an artificially reversible condition activated by various factors and characterized by replicative senescence and typical general alteration of cell functions, including extra-cellular secretion. The number of senescent cells increases with age and contributes strongly to the manifestations of aging. For these reasons, research is under way to obtain "senolytic" compounds, defined as drugs that eliminate senescent cells and therefore reduce aging-associated decay, as already shown in some experiments on animal models. This objective is analyzed in the context of the programmed aging paradigm, as described by the mechanisms of the subtelomere-telomere theory. In this regard, positive effects of the elimination of senescent cells and limits of this method are discussed. For comparison, positive effects and limits of telomerase activation are also analyzed, as well of the combined action of the two methods and the possible association of opportune gene modifications. Ethical issues associated with the use of these methods are outlined.},
}
@article {pmid30875959,
year = {2019},
author = {Baek, JH and Son, H and Jeong, YH and Park, SW and Kim, HJ},
title = {Chronological Aging Standard Curves of Telomere Length and Mitochondrial DNA Copy Number in Twelve Tissues of C57BL/6 Male Mouse.},
journal = {Cells},
volume = {8},
number = {3},
pages = {},
pmid = {30875959},
issn = {2073-4409},
mesh = {Aging/*genetics ; Animals ; DNA, Mitochondrial/*genetics ; *Gene Dosage ; Immobilization ; Male ; Mice, Inbred C57BL ; Reference Standards ; Stress, Physiological/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {The changes in telomere length and mitochondrial DNA copy number (mtDNAcn) are considered to be aging markers. However, many studies have provided contradictory or only fragmentary information about changes of these markers in animal models, due to inaccurate analysis methods and a lack of objective aging standards. To establish chronological aging standards for these two markers, we analyzed telomere length and mtDNAcn in 12 tissues-leukocytes, prefrontal cortex, hippocampus, pituitary gland, adrenal gland, retina, aorta, liver, kidney, spleen, skeletal muscle, and skin-from a commonly used rodent model, C57BL/6 male mice aged 2[-]24 months. It was found that at least one of the markers changed age-dependently in all tissues. In the leukocytes, hippocampus, retina, and skeletal muscle, both markers changed age-dependently. As a practical application, the aging marker changes were analyzed after chronic immobilization stress (CIS) to see whether CIS accelerated aging or not. The degree of tissue-aging was calculated using each standard curve and found that CIS accelerated aging in a tissue-specific manner. Therefore, it is expected that researchers can use our standard curves to objectively estimate tissue-specific aging accelerating effects of experimental conditions for least 12 tissues in C57BL/6 male mice.},
}
@article {pmid30875900,
year = {2019},
author = {Bettin, N and Oss Pegorar, C and Cusanelli, E},
title = {The Emerging Roles of TERRA in Telomere Maintenance and Genome Stability.},
journal = {Cells},
volume = {8},
number = {3},
pages = {},
pmid = {30875900},
issn = {2073-4409},
mesh = {Chromatin/metabolism ; *Genomic Instability ; Humans ; RNA/*genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; Stress, Physiological/genetics ; Telomere/*metabolism ; },
abstract = {The finding that transcription occurs at chromosome ends has opened new fields of study on the roles of telomeric transcripts in chromosome end maintenance and genome stability. Indeed, the ends of chromosomes are required to be protected from activation of DNA damage response and DNA repair pathways. Chromosome end protection is achieved by the activity of specific proteins that associate with chromosome ends, forming telomeres. Telomeres need to be constantly maintained as they are in a heterochromatic state and fold into specific structures (T-loops), which may hamper DNA replication. In addition, in the absence of maintenance mechanisms, chromosome ends shorten at every cell division due to limitations in the DNA replication machinery, which is unable to fully replicate the extremities of chromosomes. Altered telomere structure or critically short chromosome ends generate dysfunctional telomeres, ultimately leading to replicative senescence or chromosome instability. Telomere biology is thus implicated in multiple human diseases, including cancer. Emerging evidence indicates that a class of long noncoding RNAs transcribed at telomeres, known as TERRA for "TElomeric Repeat-containing RNA," actively participates in the mechanisms regulating telomere maintenance and chromosome end protection. However, the molecular details of TERRA activities remain to be elucidated. In this review, we discuss recent findings on the emerging roles of TERRA in telomere maintenance and genome stability and their implications in human diseases.},
}
@article {pmid30874445,
year = {2019},
author = {Chahine, MN and Toupance, S and El-Hakim, S and Labat, C and Gautier, S and Moussallem, T and Yared, P and Asmar, R and Benetos, A},
title = {Telomere length and age-dependent telomere attrition: the blood-and-muscle model [1].},
journal = {Canadian journal of physiology and pharmacology},
volume = {97},
number = {4},
pages = {328-334},
doi = {10.1139/cjpp-2018-0582},
pmid = {30874445},
issn = {1205-7541},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/blood/*genetics ; Body Mass Index ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Muscle, Skeletal/*metabolism ; Smoking/genetics ; Telomere/*genetics ; },
abstract = {Short telomere length (TL) is associated with atherosclerotic cardiovascular disease (ACVD) and other age-related diseases. It is unclear whether these associations originate from having inherently short TL or a faster TL attrition before or during disease development. We proposed the blood-and-muscle model to assess TL dynamics throughout life course. Our objective was to measure TL in leukocytes (LTL) and in skeletal muscle (MTL), which served as a proxy of TL at birth. The delta (MTL-LTL) represented life-long telomere attrition. Blood draws and skeletal muscle biopsies were performed on 35 Lebanese individuals undergoing surgery. Following DNA extraction, LTL and MTL were measured by Southern blot. In every individual aged between 30 and 85 years, MTL was longer than LTL. With age, MTL and LTL decreased, but the delta (MTL-LTL) increased by 14 bp/year. We validated the blood-and-muscle model that allowed us to identify TL, TL at birth, and lifelong TL attrition in a cross-sectional study. This model can be used in larger cross-sectional studies to evaluate the association of telomere dynamics with age-related diseases onset and progression.},
}
@article {pmid30874287,
year = {2019},
author = {Srinivas, N and Rachakonda, S and Hielscher, T and Calderazzo, S and Rudnai, P and Gurzau, E and Koppova, K and Fletcher, T and Kumar, R},
title = {Telomere length, arsenic exposure and risk of basal cell carcinoma of skin.},
journal = {Carcinogenesis},
volume = {40},
number = {6},
pages = {715-723},
doi = {10.1093/carcin/bgz059},
pmid = {30874287},
issn = {1460-2180},
mesh = {Aged ; Arsenic/*toxicity ; Carcinoma, Basal Cell/*chemically induced/*genetics ; Case-Control Studies ; *Environmental Exposure ; Female ; *Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Skin Neoplasms/*chemically induced/*genetics ; Telomere/*drug effects ; },
abstract = {Telomere length per se a heritable trait has been reported to be associated with different diseases including cancers. In this study, based on arsenic-exposed 528 cases with basal cell carcinoma (BCC) of skin and 533 healthy controls, we investigated effect of telomere length, measured by real-time PCR, on the disease risk. We observed a statistically significant association between decreased telomere length and increased BCC risk [odds ratio (OR) = 5.92, 95% confidence interval (CI) = 3.92 to 9.01, P < 0.0001]. Due to confounder effect of arsenic exposure, in a two-sample Mendelian randomization (MR), telomere length associated single-nucleotide polymorphisms as instrument variables violated valid assumptions; however, one-sample MR adjusted for arsenic exposure indicated an increased risk of BCC with short telomeres. The interaction between arsenic exposure and telomere length on BCC risk was statistically significant (P = 0.02). Within each tertile based on arsenic exposure, the individuals with shorter telomeres were at an increased risk of BCC, with highest risk being in the highest exposed group (OR = 16.13, 95% CI = 6.71 to 40.00, P < 0.0001), followed by those in medium exposure group and low exposure group. The combined effect of highest arsenic exposure and shortest telomeres on BCC risk (OR = 10.56, 95% CI = 5.14 to 21.70) showed a statistically significant departure from additivity (interaction contrast ratio 6.56, P = 0.03). Our results show that in the presence of arsenic exposure, decreased telomere length predisposes individuals to increased risk of BCC, with the effect being synergistic in individuals with highest arsenic exposure and shortest telomeres.},
}
@article {pmid30873125,
year = {2019},
author = {Khalangot, MD and Krasnienkov, DS and Chizhova, VP and Korkushko, OV and Shatilo, VB and Kukharsky, VM and Kravchenko, VI and Kovtun, VA and Guryanov, VG and Vaiserman, AM},
title = {Additional Impact of Glucose Tolerance on Telomere Length in Persons With and Without Metabolic Syndrome in the Elderly Ukraine Population.},
journal = {Frontiers in endocrinology},
volume = {10},
number = {},
pages = {128},
pmid = {30873125},
issn = {1664-2392},
abstract = {Rationale: Association between different components of metabolic syndrome and the rate of age-related telomere shortening was reported repeatedly, although some findings are inconsistent across studies, suggesting the need for further research on the topic. In the present study, we examined relationships between different components of metabolic syndrome (MetS); glucose tolerance reflected in 2-h post-load plasma glucose (2hPG) levels and age on the leukocyte telomere length (LTL) in Ukraine population. Methods: The study was conducted on the 115 adult individuals residing in the Kyiv region (Ukraine). Among them, 79 were diagnosed with MetS according to the International Diabetes Federation definition. LTL were determined by a qPCR-based method. Multivariate logistic regression (MLR) and artificial neural networks (ANN) modeling were used for the analysis of the results. ROC-analysis was also performed to compare the predictively values of this models. Results: MetS was associated with a high (OR = 3.0 CI 1.3-6.7; p = 0.01) risk of having shorter telomeres that remained significant after adjusting for age, gender and 2hPG levels. Fasting plasma glucose (FPG) levels and other MetS components did not affect the magnitude of the relationship and did not reveal the independent influence of these factors. The level of 2hPG in turn, demonstrated a significant relationship (OR = 1.3 CI 1.0-1.6 per 1 mmol/l; p = 0.04) with LTL regardless of the presence of MetS. The non-linearity of the interactions between age, gender and 2hPG level was revealed by neural network modeling (AUC = 0.76 CI 0.68-0.84). Conclusion: Our study found that impaired glucose tolerance, but not FPG levels, affected the association between LTL and MetS, which may be also indicative for pathophysiological differences in these hyperglycemia categories. 2hPG levels can provide an opportunity for a more accurate diagnostics of MetS and for evaluating the rate of aging in patients with MetS. Further research, however, is needed to verify this assumption.},
}
@article {pmid30872351,
year = {2019},
author = {Cleal, K and Jones, RE and Grimstead, JW and Hendrickson, EA and Baird, DM},
title = {Chromothripsis during telomere crisis is independent of NHEJ, and consistent with a replicative origin.},
journal = {Genome research},
volume = {29},
number = {5},
pages = {737-749},
pmid = {30872351},
issn = {1549-5469},
support = {18246/CRUK_/Cancer Research UK/United Kingdom ; R01 CA154461/CA/NCI NIH HHS/United States ; 17199/A18246/CRUK_/Cancer Research UK/United Kingdom ; R01 GM088351/GM/NIGMS NIH HHS/United States ; R01 CA190492/CA/NCI NIH HHS/United States ; },
mesh = {Chromosome Inversion/genetics ; *Chromothripsis ; DNA Copy Number Variations/genetics ; DNA End-Joining Repair/genetics ; *Genomic Instability ; Genomic Structural Variation/genetics ; HCT116 Cells ; Humans ; Mutation ; Neoplasms/genetics ; Replication Origin/genetics ; Telomere/*genetics/metabolism/physiology ; Whole Genome Sequencing ; },
abstract = {Telomere erosion, dysfunction, and fusion can lead to a state of cellular crisis characterized by large-scale genome instability. We investigated the impact of a telomere-driven crisis on the structural integrity of the genome by undertaking whole-genome sequence analyses of clonal populations of cells that had escaped crisis. Quantification of large-scale structural variants revealed patterns of rearrangement consistent with chromothripsis but formed in the absence of functional nonhomologous end-joining pathways. Rearrangements frequently consisted of short fragments with complex mutational patterns, with a repair topology that deviated from randomness showing preferential repair to local regions or exchange between specific loci. We find evidence of telomere involvement with an enrichment of fold-back inversions demarcating clusters of rearrangements. Our data suggest that chromothriptic rearrangements caused by a telomere crisis arise via a replicative repair process involving template switching.},
}
@article {pmid30871494,
year = {2019},
author = {Lawlor, RT and Veronese, N and Pea, A and Nottegar, A and Smith, L and Pilati, C and Demurtas, J and Fassan, M and Cheng, L and Luchini, C},
title = {Alternative lengthening of telomeres (ALT) influences survival in soft tissue sarcomas: a systematic review with meta-analysis.},
journal = {BMC cancer},
volume = {19},
number = {1},
pages = {232},
pmid = {30871494},
issn = {1471-2407},
support = {12182//Fondazione Italiana per la Ricerca sul Cancro/ ; },
mesh = {Humans ; Middle Aged ; Prognosis ; Proportional Hazards Models ; Risk Assessment ; Sarcoma/metabolism/mortality/*pathology ; Survival Analysis ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism used by a broad range of neoplasms to maintain telomere length, permitting uncontrolled replication during their progression. ALT has been described in different types of sarcoma, but a comprehensive analysis of its clinical significance is still lacking. Therefore, we provide here the first meta-analysis on this topic.<br><br>METHODS: We searched SCOPUS and PubMed through July 2018 to identify all studies that investigated the prognostic role of ALT in sarcomas. We considered the risk of death (risk ratio, RR) calculated as the number of death vs. total participants during follow-up in ALT+ versus ALT- patients as the primary outcome. The secondary outcome was the hazard ratio (HR), adjusted for the maximum number of covariates available, using ALT- patients as reference.<br><br>RESULTS: Eight articles comprising a total of 551 patients with sarcomas (226 ALT+ and 325 ALT-) were selected. The ALT+ group showed a higher mitotic count and a higher tumor grade compared with the ALT- group (p&#x2009;<&#x2009;0.01). Furthermore, we demonstrate a strong impact of ALT on survival. In fact, ALT+ patients showed a statistically significant higher risk of death than ALT- patients, when also considering data from multivariate analyses (RR&#x2009;=&#x2009;1.50; 95% CI: 1.15-1.96; p&#x2009;=&#x2009;0.003; HR&#x2009;=&#x2009;2.02; 95% CI: 1.22-3.38; p&#x2009;=&#x2009;0.007).<br><br>CONCLUSIONS: Our results indicate that ALT is associated with an increased risk of death in patients with sarcoma. In these neoplasms, ALT should be taken into account for a precise prognostic stratification and design of potential therapeutic strategies.},
}
@article {pmid30870624,
year = {2019},
author = {Casavant, SG and Cong, X and Moore, J and Starkweather, A},
title = {Associations between preterm infant stress, epigenetic alteration, telomere length and neurodevelopmental outcomes: A systematic review.},
journal = {Early human development},
volume = {131},
number = {},
pages = {63-74},
doi = {10.1016/j.earlhumdev.2019.03.003},
pmid = {30870624},
issn = {1872-6232},
mesh = {Angiomotins ; Brain-Derived Neurotrophic Factor/genetics ; *Epigenesis, Genetic ; Humans ; Infant, Newborn ; Infant, Premature/growth &amp; development/*physiology ; Insulin-Like Growth Factor II/genetics ; Intensive Care Units, Neonatal ; Intercellular Signaling Peptides and Proteins/genetics ; Membrane Proteins/genetics ; Microfilament Proteins ; NF-KappaB Inhibitor alpha/genetics ; Neurodevelopmental Disorders/genetics ; Receptors, Glucocorticoid/genetics ; Stress, Physiological/genetics ; Tacrolimus Binding Proteins/genetics ; Telomere/*genetics ; },
abstract = {BACKGROUND: Every year, an estimated 15 million babies are born preterm (<37 weeks' gestational age [GA]) globally. These preterm infants are exposed to repeated stressful and often painful procedures as part of routine life-saving care within the neonatal intensive care unit (NICU). Preterm birth continues to be a major health issue associated with increased risk of neurodevelopmental and behavioral disorders such as cerebral palsy, cognitive impairment, autism spectrum disorders and psychiatric disease.<br><br>OBJECTIVE: This paper identifies epigenetic alterations and incidence of telomere erosion that have been studied in preterm infants while in the NICU and as a long-term outcome measure. Better understanding of epigenetic alterations and telomere erosion might aid in early detection and prevention/alleviation of the negative effects of cumulative painful/stressful experiences in this population.<br><br>METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards were used to guide this review. Systematic searches of databases included PubMed, CINAHL, SCOPUS and PsychInfo.<br><br>RESULTS: Twenty-one studies were included, appraised and then synthesized into a narrative summary.<br><br>DISCUSSION: Several putative epigenetic markers were identified although there was a paucity of studies related to telomere length. The interaction of disease entity combined with therapeutic interventions intended to treat may inadvertently increase infant allostatic load or ability to adapt to stress. Future research should include not only human studies but leverage newly available large data sets to conduct additional analysis.},
}
@article {pmid30870238,
year = {2019},
author = {Wang, J and Nguyen, MT and Sung, V and Grobler, A and Burgner, D and Saffery, R and Wake, M},
title = {Associations Between Telomere Length and Hearing Status in Mid-Childhood and Midlife: Population-Based Cross-Sectional study.},
journal = {Ear and hearing},
volume = {40},
number = {5},
pages = {1256-1259},
doi = {10.1097/AUD.0000000000000705},
pmid = {30870238},
issn = {1538-4667},
mesh = {Adult ; Auditory Threshold ; Child ; Female ; *Hearing ; Hearing Loss/*epidemiology ; Humans ; Linear Models ; Logistic Models ; Male ; Middle Aged ; Telomere/*metabolism ; },
abstract = {OBJECTIVES: The purpose of this study is to determine if telomere length (a biomarker of aging) is associated with hearing acuity in mid-childhood and midlife.<br><br>DESIGN: The study was based on the population-based cross-sectional study within the Longitudinal Study of Australian Children with telomere length and audiometry data. We calculated high Fletcher Index (hFI, mean threshold of 1, 2, and 4&#x2009;kHz), defining hearing loss as threshold >15 dB HL (better ear). Linear and logistic regression analyses quantified associations of telomere length with continuous hearing threshold and binary hearing loss outcomes, respectively.<br><br>RESULTS: One thousand one hundred ninety-five children (mean age 11.4 years, SD 0.5) and 1334 parents (mean age 43.9 years, SD 5.1) were included in analyses. Mean (SD) telomere length (T/S ratio) was 1.09 (0.55) for children and 0.81 (0.38) for adults; hFI (dB HL) was 8.0 (5.6) for children and 13.1 (7.0) for adults, with 8.4% and 25.9%, respectively, showing hearing loss.Telomere length was not associated with hearing threshold or hearing loss in children (hFI: OR, 0.99; 95% confidence interval, 0.55 to 1.78) or adults (hFI: OR, 1.35; 95% confidence interval, 0.81 to 2.25).<br><br>CONCLUSIONS: Telomere length was not associated with hearing acuity in children or their midlife parents.},
}
@article {pmid30868555,
year = {2019},
author = {Mohanty, P and Jadhav, P and Shanmukhaiah, C and Kumar, S and Vundinti, BR},
title = {A novel DKC1 gene mutation c.1177 A&gt;T (p.I393F) in a case of dyskeratosis congenita with severe telomere shortening.},
journal = {International journal of dermatology},
volume = {58},
number = {12},
pages = {1468-1471},
doi = {10.1111/ijd.14424},
pmid = {30868555},
issn = {1365-4632},
support = {56/1/2014-BMS//Indian Council of Medical Research/ ; },
mesh = {Amino Acid Substitution ; Cell Cycle Proteins/*genetics/metabolism ; DNA Mutational Analysis ; Dyskeratosis Congenita/diagnosis/*genetics ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Male ; Molecular Docking Simulation ; Mutation ; Nuclear Proteins/*genetics/metabolism ; Pedigree ; Protein Binding/genetics ; *Telomere Shortening ; Young Adult ; },
}
@article {pmid30867501,
year = {2019},
author = {Tahamtan, S and Tavalaee, M and Izadi, T and Barikrow, N and Zakeri, Z and Lockshin, RA and Abbasi, H and Nasr-Esfahani, MH},
title = {Reduced sperm telomere length in individuals with varicocele is associated with reduced genomic integrity.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {4336},
pmid = {30867501},
issn = {2045-2322},
mesh = {Adult ; DNA/metabolism ; Humans ; Infertility, Male/genetics ; Lipid Peroxidation ; Male ; Protamines/metabolism ; Spermatozoa/metabolism/*ultrastructure ; *Telomere Shortening ; Varicocele/*genetics ; },
abstract = {Varicocele, defined as enlarged varicose veins in the scrotum, is the most common identifiable cause of male infertility. There are significant correlations between oxidative stress and varicocele-related infertility due to testicular hyperthermia, which can result in low sperm function. In addition, recent excessive oxidative stress can affect sperm telomere length and integrity of sperm DNA. Therefore, we assessed sperm telomere length as a potential marker of paternal genome integrity and leukocyte telomere length as an internal control (real-time PCR), along with sperm chromatin status (TUNEL and chromomycin A3 assay), and lipid peroxidation (Bodipy probe) in 18 infertile men with grade II or III varicocele, and 20 fertile men. Means of sperm parameters, sperm and leukocyte telomere length were significantly lower, while means of sperm DNA fragmentation, protamine deficiency, and lipid peroxidation were significantly higher in infertile men with varicocele compared to fertile men. Therefore, shortened telomere length in sperm and leukocytes is likely associated with increased oxidative stress related to the state of varicocele, which also accounts for increase in sperm DNA fragmentation. Thus, assessment of leukocyte telomere length could be taken as an indicator of antioxidant capacity in an individual, which also affects sperm function.},
}
@article {pmid30864244,
year = {2019},
author = {Koslow, M and Shitrit, D and Israeli-Shani, L and Uziel, O and Beery, E and Osadchy, A and Refaely, Y and Shochet, GE and Amiel, A},
title = {Peripheral blood telomere alterations in ground glass opacity (GGO) lesions may suggest malignancy.},
journal = {Thoracic cancer},
volume = {10},
number = {4},
pages = {1009-1015},
pmid = {30864244},
issn = {1759-7714},
mesh = {Adenocarcinoma of Lung/*diagnostic imaging/genetics/surgery ; Aged ; Cellular Senescence ; Diagnosis, Differential ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes, Mononuclear/*chemistry ; Lung/chemistry/*diagnostic imaging/pathology/surgery ; Male ; Telomere/*genetics/pathology ; Telomere Homeostasis ; },
abstract = {A ground glass opacity (GGO) lung lesion may represent early stage adenocarcinoma, which has an excellent prognosis upon prompt surgical resection. However, GGO lesions have broad differential diagnoses, including both benign and malignant lesions. Our objective was to study telomere length and telomerase activity in patients with suspected lung cancer in which GGO was the predominant radiographic feature. Knowledge of telomere biology may help distinguish malignant from benign radiographic lesions and guide risk assessment of these lesions. Peripheral blood samples were taken from 22 patients with suspected adenocarcinoma with the GGO radiographic presentation. Multidisciplinary discussion confirmed the need for surgery in all cases. We used an age and gender-matched group without known lung disease as a control. Telomere length and aggregates were assessed by quantitative fluorescence in situ hybridization (QFISH) and quantitative PCR. Cell senescence was evaluated by senescence-associated heterochromatin foci. Subjects with GGO lesions had a higher percentage of lymphocytes with shorter telomeres (Q-FISH, P = 0.003). Furthermore, relative telomere length was also reduced among the GGO cases (qPCR, P < 0.05). Increased senescence was observed in the GGO group compared to controls (P < 0.001), with significant correlation between the senescence-associated heterochromatin foci and aggregate formation (r = -0.7 and r = -0.44 for cases and controls, respectively). In conclusion, patients with resectable early adenocarcinoma demonstrate abnormal telomere length and cell senescence in peripheral blood leukocytes compared to control subjects. Abnormal telomere biology in the peripheral blood may increase suspicion of early adenocarcinoma among patients with GGO lesions.},
}
@article {pmid30862510,
year = {2020},
author = {Keefe, DL},
title = {Telomeres and genomic instability during early development.},
journal = {European journal of medical genetics},
volume = {63},
number = {2},
pages = {103638},
doi = {10.1016/j.ejmg.2019.03.002},
pmid = {30862510},
issn = {1878-0849},
mesh = {Animals ; Chromosome Aberrations ; Embryonic Development/*genetics ; *Genomic Instability ; Humans ; Oocytes/cytology/metabolism ; Recombination, Genetic ; Telomere/*genetics/*metabolism ; },
abstract = {Genomic instability is widespread during early embryo development. Aneuploidy, mosaicism, and copy number variants (CNVs) commonly appear in human preimplantation embryos. Both age-dependent meiotic aneuploidy and age-independent mitotic aneuploidy and CNVs occur In human embryos. Telomere attrition, which contributes to genomic instability in somatic cells, also may promote genomic instability in preimplantation embryos. Telomere dynamics during gametogenesis are strikingly dimorphic between females and males. Sperm telomeres lengthen with advancing paternal age, while oocyte telomeres are among the shortest in the body. Spermatogonia express telomerase activity throughout the life of the male, while oocytes and cleavage stage embryos express low or un-measureable levels of telomerase activity. Telomere attrition in oocytes contributes to meiotic dysfunction, including spindle dysmorphologies, reduced synapsis and chiasmata, as well as delayed, arrested and fragmented embryos. Cleavage stage embryos, with such inefficient telomere reconstitution, likely undergo NHEJ, which produces anaphase lag, chromosome bridges, micronuclei, and genomic instability, including mosaicism and CNVs. Cleavage stage embryos reconstitute the short telomeres inherited from their mothers by Alternative Lengthening of Telomeres (ALT), a DNA recombination based method involving RAD 50, MRE 11, Werner and Bloom proteins, as well as telomere sister chromatid exchange. ALT robustly reconstitutes telomeres, but also predisposes to genomic instability.},
}
@article {pmid30861019,
year = {2019},
author = {Steinmetz, M and Schmitter, C and Radecke, T and Stundl, A and Nickenig, G and Schaefer, C and Schahab, N and Vasa-Nicotera, M and Sinning, JM},
title = {Brief report - Telomere length is a poor biomarker to predict 1-year mortality or cardiovascular comorbidity in patients with transcatheter aortic valve replacement.},
journal = {PloS one},
volume = {14},
number = {3},
pages = {e0213250},
pmid = {30861019},
issn = {1932-6203},
mesh = {Aged ; Aged, 80 and over ; Aortic Valve Stenosis/*mortality/pathology ; Biomarkers/*metabolism ; Female ; Humans ; Kaplan-Meier Estimate ; Leukocytes/metabolism ; Male ; Telomere/*genetics ; Telomere Shortening ; Transcatheter Aortic Valve Replacement ; Ventricular Function, Left ; },
abstract = {BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a therapeutic option for patients with aortic valve stenosis at increased surgical risk. Telomeres are an established marker for cellular senescence and have served to evaluate cardiovascular diseases including severe aortic valve stenosis. In our study, we hypothesized that telomere length may be a predictor for outcome and associated with comorbidities in patients with TAVR.<br><br>METHODS AND RESULTS: We analyzed leucocyte telomere length from 155 patients who underwent TAVR and correlated the results with 1-year mortality and severe comorbidities. The cohort was subdivided into 3 groups according to telomere length. Although a trend for a positive correlation of telomere length with a lower EuroSCORE could be found, telomere length was not associated with survival, aortic valve opening area or cardiovascular comorbidities (peripheral, coronary or cerebrovascular disease). Interestingly, long telomeres were significantly correlated to a reduced left ventricular ejection fraction (LVEF).<br><br>CONCLUSION: In elderly patients with severe aortic valve stenosis, leucocyte telomere length did not predict post-procedural survival. The correlation between long telomere length and reduced LVEF in these patients deserves further attention.},
}
@article {pmid30857946,
year = {2019},
author = {Zeng, JB and Liu, HB and Ping, F and Li, W and Li, YX},
title = {Insulin treatment affects leukocyte telomere length in patients with type 2 diabetes: 6-year longitudinal study.},
journal = {Journal of diabetes and its complications},
volume = {33},
number = {5},
pages = {363-367},
doi = {10.1016/j.jdiacomp.2019.02.003},
pmid = {30857946},
issn = {1873-460X},
mesh = {Aged ; Diabetes Mellitus, Type 2/*drug therapy/pathology ; Female ; Humans ; Hypoglycemic Agents/*therapeutic use ; Insulin/*therapeutic use ; Leukocytes/*pathology ; Longitudinal Studies ; Male ; Middle Aged ; Risk Factors ; Telomere Homeostasis/*drug effects ; Telomere Shortening/*drug effects ; },
abstract = {OBJECTIVE: Many studies demonstrated a close relationship between type 2 diabetes mellitus (T2DM) and leukocyte telomere length (LTL). However, how the LTL changes in T2DM and what are the potential causal factors in it, particularly in patients during a long period treatment, have not been studied. Here we performed a longitudinal observation of LTL in trained T2DM patients during a 6-year follow-up and evaluated the possible risk factors that were associated with LTL alteration.<br><br>METHODS: Seventy-six patients with T2DM were enrolled in this 6-year longitudinal study. The enrolled patients had no severe complication and had never received insulin therapy by the time. Patients were scheduled to visit once every one or two months and their medication changes were recorded. The LTL at the time when patients were enrolled was used as baseline, which was compared with the LTL at 6&#x202f;year. Multivariable linear regression and exact logistic regression model were adopted to identify independent predictors of telomere length change and telomere length shortening, respectively.<br><br>RESULTS: Sixty-four patients were successfully followed up. Although mean LTL decreased after 6&#x202f;years, 30% (19/64) of patients demonstrated LTL lengthening and 70% (45/64) of patients demonstrated LTL shortening. Among them, 18 Patients received insulin treatment during the 6&#x202f;years. Of these 18 patients, 16 patients showed decreased LTL and only two showed increased LTL. Linear regression analysis demonstrated that change in telomere length during the 6&#x202f;years was associated inversely with insulin use (&#x3b2;-coefficients: -0.587, 95% CI: -0.198, -0.085, P&#x202f;<&#x202f;0.001). Exact logistic regression analysis showed insulin use (OR: 17.355, 95% CI: 2.659, 35.627, P&#x202f;=&#x202f;0.013) and LDL-C(OR: 3.493, 95% CI: 1.559, 10.063, P&#x202f;=&#x202f;0.007)were independent predicts of telomere length shortening.<br><br>CONCLUSIONS: LTL may increase as well as decrease in T2DM who received antidiabetic treatment. Insulin use may accelerate telomere attrition. Insulin use and LDL-C can predict telomere shortening.},
}
@article {pmid30857208,
year = {2019},
author = {Wang, TH and Chen, CC and Hsiao, YC and Lin, YH and Pi, WC and Huang, PR and Wang, TV and Chen, CY},
title = {Heterogeneous Nuclear Ribonucleoproteins A1 and A2 Function in Telomerase-Dependent Maintenance of Telomeres.},
journal = {Cancers},
volume = {11},
number = {3},
pages = {},
pmid = {30857208},
issn = {2072-6694},
support = {CMRPD1F0452; CMRPF1G0121; MOST 106-2320-B-255-006-//Chang Gung Memorial Hospital; Ministry of Science and Technology, Taiwan/ ; },
abstract = {The A/B subfamily of heterogeneous nuclear ribonucleoproteins (hnRNPs A/B), which includes hnRNP A1, A2/B1, and A3, plays an important role in cell proliferation. The simultaneous suppression of hnRNP A1/A2, but not the suppression of hnRNP A1 or A2 alone, has been shown to inhibit cell proliferation and induce apoptosis in cancer cells, but not in mortal normal cells. However, the molecular basis for such a differential inhibition of cell proliferation remains unknown. Here, we show that the simultaneous suppression of hnRNP A1 and hnRNP A2 resulted in dysfunctional telomeres and induced DNA damage responses in cancer cells. The inhibition of apoptosis did not alleviate the inhibition of cell proliferation nor the formation of dysfunctional telomeres in cancer cells depleted of hnRNP A1/A2. Moreover, while proliferation of mortal normal fibroblasts was not sensitive to the depletion of hnRNP A1/A2, the ectopic expression of hTERT in normal fibroblasts rendered these cells sensitive to proliferation inhibition, which was associated with the production of dysfunctional telomeres. Our study demonstrates that hnRNP A1 and A2 function to maintain telomeres in telomerase-expressing cells only, suggesting that the maintenance of functional telomeres in telomerase-expressing cancer cells employs factors that differ from those used in the telomerase-negative normal cells.},
}
@article {pmid30852617,
year = {2019},
author = {Jensen, DM and Løhr, M and Sheykhzade, M and Lykkesfeldt, J and Wils, RS and Loft, S and Møller, P},
title = {Telomere length and genotoxicity in the lung of rats following intragastric exposure to food-grade titanium dioxide and vegetable carbon particles.},
journal = {Mutagenesis},
volume = {34},
number = {2},
pages = {203-214},
doi = {10.1093/mutage/gez003},
pmid = {30852617},
issn = {1464-3804},
mesh = {A549 Cells ; Animals ; Caco-2 Cells ; Carbon/toxicity ; DNA Damage/*drug effects ; Epithelial Cells/drug effects/metabolism ; Female ; Food Additives/*toxicity ; Humans ; Intestines/*drug effects ; Lung/*drug effects/metabolism ; Nanoparticles/toxicity/ultrastructure ; Occludin/genetics/metabolism ; Particle Size ; Rats ; Rats, Zucker ; Reactive Oxygen Species/metabolism ; Stomach ; Telomere/*drug effects/genetics/*metabolism ; Tight Junctions/*drug effects/metabolism ; Titanium/*toxicity ; },
abstract = {Vegetable carbon (E153) and titanium dioxide (E171) are widely used as black and white food colour additives. The aim of this study was to assess gastrointestinal tight junction and systemic genotoxic effects in rats following exposure to E153 and E171 for 10 weeks by oral gavage once a week. The expression of tight junction proteins was assessed in intestinal tissues. Levels of DNA strand breaks, oxidatively damaged DNA and telomere length were assessed in secondary organs. Hydrodynamic suspensions of E153 and E173 indicated mean particles sizes of 230 and 270 nm, respectively, and only E153 gave rise to intracellular production of reactive oxygen species in colon epithelial (Caco-2) cells. Rats exposed to E153 (6.4 mg/kg/week) or E171 (500 mg/kg/week) had decreased gene expression of the tight junction protein TJP1 (P < 0.05). E153 (6.4 mg/kg/week) also decreased OCLN (P < 0.05) in the colon and occludin protein expression in the small intestine (P < 0.05). Furthermore, E153 or E171 exposed rats had shorter telomeres in the lung (P < 0.05). Plasma from particle-exposed rats also produced telomere shortening in cultured lung epithelial cells. There were unaltered levels of oxidatively damaged DNA in the liver and lung and no changes in the DNA repair activity of oxidatively damaged DNA in the lung. Altogether, these results indicate that intragastric exposure to E153 and E171 is associated with reduced tight junction protein expression in the intestinal barrier and telomere length shortening in the lung in rats.},
}
@article {pmid30852452,
year = {2019},
author = {Rosa, MJ and Hsu, HL and Just, AC and Brennan, KJ and Bloomquist, T and Kloog, I and Pantic, I and Mercado García, A and Wilson, A and Coull, BA and Wright, RO and Téllez Rojo, MM and Baccarelli, AA and Wright, RJ},
title = {Association between prenatal particulate air pollution exposure and telomere length in cord blood: Effect modification by fetal sex.},
journal = {Environmental research},
volume = {172},
number = {},
pages = {495-501},
pmid = {30852452},
issn = {1096-0953},
support = {R00 ES027496/ES/NIEHS NIH HHS/United States ; R01 ES013744/ES/NIEHS NIH HHS/United States ; R24 ES028522/ES/NIEHS NIH HHS/United States ; P30 ES023515/ES/NIEHS NIH HHS/United States ; R01 ES014930/ES/NIEHS NIH HHS/United States ; K99 ES027496/ES/NIEHS NIH HHS/United States ; R00 ES023450/ES/NIEHS NIH HHS/United States ; },
mesh = {*Air Pollutants/toxicity ; *Air Pollution/adverse effects ; Bayes Theorem ; Child ; Female ; Fetal Blood ; Humans ; Infant, Newborn ; Male ; *Maternal Exposure ; Mexico ; Particulate Matter/toxicity ; Pregnancy ; Sex Factors ; *Telomere/drug effects ; },
abstract = {INTRODUCTION: In utero particulate matter exposure produces oxidative stress that impacts cellular processes that include telomere biology. Newborn telomere length is likely critical to an individual's telomere biology; reduction in this initial telomere setting may signal increased susceptibility to adverse outcomes later in life. We examined associations between prenatal particulate matter with diameter ≤2.5 µm (PM2.5) and relative leukocyte telomere length (LTL) measured in cord blood using a data-driven approach to characterize sensitive windows of prenatal PM2.5 effects and explore sex differences.<br><br>METHODS: Women who were residents of Mexico City and affiliated with the Mexican Social Security System were recruited during pregnancy (n&#x202f;=&#x202f;423 for analyses). Mothers' prenatal exposure to PM2.5 was estimated based on residence during pregnancy using a validated satellite-based spatio-temporally resolved prediction model. Leukocyte DNA was extracted from cord blood obtained at delivery. Duplex quantitative polymerase chain reaction was used to compare the relative amplification of the telomere repeat copy number to single gene (albumin) copy number. A distributed lag model incorporating weekly averages for PM2.5 over gestation was used in order to explore sensitive windows. Sex-specific associations were examined using Bayesian distributed lag interaction models.<br><br>RESULTS: In models that included child's sex, mother's age at delivery, prenatal environmental tobacco smoke exposure, pre-pregnancy BMI, gestational age, birth season and assay batch, we found significant associations between higher PM2.5 exposure during early pregnancy (4-9 weeks) and shorter LTL in cord blood. We also identified two more windows at 14-19 and 34-36 weeks in which increased PM2.5 exposure was associated with longer LTL. In stratified analyses, the mean and cumulative associations between PM2.5 and shortened LTL were stronger in girls when compared to boys.<br><br>CONCLUSIONS: Increased PM2.5 during specific prenatal windows was associated with shorter LTL and longer LTL. PM2.5 was more strongly associated with shortened LTL in girls when compared to boys. Understanding sex and temporal differences in response to air pollution may provide unique insight into mechanisms.},
}
@article {pmid30845248,
year = {2019},
author = {Liu, B and Anno, K and Kobayashi, T and Piao, J and Tahara, H and Ohdan, H},
title = {Influence of donor liver telomere and G-tail on clinical outcome after living donor liver transplantation.},
journal = {PloS one},
volume = {14},
number = {3},
pages = {e0213462},
pmid = {30845248},
issn = {1932-6203},
mesh = {Adult ; Female ; Graft Survival/genetics ; Humans ; Kidney Failure, Chronic/genetics/mortality/surgery/therapy ; Liver/*physiology/surgery ; Liver Failure/genetics/mortality/surgery/therapy ; Liver Regeneration/genetics ; Liver Transplantation/*mortality ; Living Donors ; Male ; Risk Factors ; Survival Rate ; Telomere/*genetics ; Telomere Shortening/genetics ; Treatment Outcome ; },
abstract = {It has been reported that donor age affects patient outcomes after liver transplantation, and that telomere length is associated with age. However, to our knowledge, the impact of donor age and donor liver telomere length in liver transplantation has not been well investigated. This study aimed to clarify the influence of the length of telomere and G-tail from donor livers on the outcomes of living donors and recipients after living donor liver transplantation. The length of telomere and G-tail derived from blood samples and liver tissues of 55 living donors, measured using the hybridization protection assay. The length of telomeres from blood samples was inversely correlated with ages, whereas G-tail length from blood samples and telomere and G-tail lengths from liver tissues were not correlated with ages. Age, telomere, and G-tail length from blood did not affect postoperative liver failure and early liver regeneration of donors. On the other hand, the longer the liver telomere, the poorer the liver regeneration tended to be, especially with significant difference in donor who underwent right hemihepatectomy. We found that the survival rate of recipients who received liver graft with longer telomeres was inferior to that of those who received liver graft with shorter ones. An elderly donor, longer liver telomere, and higher Model for End-Stage Liver Disease score were identified as independent risk factors for recipient survival after transplantation. In conclusion, telomere shortening in healthy liver does not correlate with age, whereas longer liver telomeres negatively influence donor liver regeneration and recipient survival after living donor liver transplantation. These results can direct future studies and investigations on telomere shortening in the clinical and experimental transplant setting.},
}
@article {pmid30844465,
year = {2020},
author = {Wade, M and Fox, NA and Zeanah, CH and Nelson, CA and Drury, SS},
title = {Telomere Length and Psychopathology: Specificity and Direction of Effects Within the Bucharest Early Intervention Project.},
journal = {Journal of the American Academy of Child and Adolescent Psychiatry},
volume = {59},
number = {1},
pages = {140-148.e3},
pmid = {30844465},
issn = {1527-5418},
support = {K12 AR084224/AR/NIAMS NIH HHS/United States ; K12 HD043451/HD/NICHD NIH HHS/United States ; R01 MH091363/MH/NIMH NIH HHS/United States ; R21 MH094688/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Child ; Female ; Humans ; Longitudinal Studies ; Male ; *Psychopathology ; Psychosocial Deprivation ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {OBJECTIVE: Telomere length (TL) has been linked to several psychiatric conditions in children and adults. Telomere shortening is accelerated by early adversity, including maltreatment and psychosocial deprivation. These experiences also increase the risk of psychopathology in many domains. Two fundamental issues remain unresolved. The first concerns the specificity of the relations between TL and different dimensions of psychopathology; and the second relates to the direction of association between TL and psychopathology.<br><br>METHOD: This study addressed these shortcomings in a 2-fold manner. First, the association between TL and statistically independent general, internalizing, and externalizing psychopathology factors was examined to determine the specificity of this relation. Second, a 2-wave longitudinal cross-lagged model was used to explicitly examine the direction of the relation between TL and each psychopathology factor. Data were drawn from the Bucharest Early Intervention Project, a longitudinal study exploring the impact of severe psychosocial deprivation on child health and development (N&#xa0;= 195). At 8 to 10 and 12 to 14 years of age, buccal DNA was collected and teachers and/or caregivers reported on different domains of psychopathology.<br><br>RESULTS: Longitudinal path analyses showed that shorter TL was specifically associated with higher internalizing psychopathology at 8 to 10 years of age. In contrast, at 12 to 14 years, shorter TL was associated with higher general psychopathology. Most telling, internalizing psychopathology at 8 to 10 years predicted shorter TL at 12 to 14 years, with no reciprocal effects.<br><br>CONCLUSION: Results suggest that telomere erosion could be a consequence of distress-related psychopathology rather than a selection mechanism for later psychiatric problems.<br><br>The Bucharest Early Intervention Project; https://clinicaltrials.gov/; NCT00747396.},
}
@article {pmid30840638,
year = {2019},
author = {Saberi, S and Kalloger, SE and Zhu, MMT and Sattha, B and Maan, EJ and van Schalkwyk, J and Money, DM and Côté, HCF and , },
title = {Dynamics of leukocyte telomere length in pregnant women living with HIV, and HIV-negative pregnant women: A longitudinal observational study.},
journal = {PloS one},
volume = {14},
number = {3},
pages = {e0212273},
pmid = {30840638},
issn = {1932-6203},
support = {HET-85515//CIHR/Canada ; TCO-125269//CIHR/Canada ; },
mesh = {Adolescent ; Adult ; Cross-Sectional Studies ; Female ; HIV Infections/*genetics ; Humans ; Leukocytes/physiology ; Longitudinal Studies ; Multivariate Analysis ; Pregnancy ; Prospective Studies ; Smoking/adverse effects ; Telomerase/genetics ; Telomere/*genetics ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {BACKGROUND: HIV-mediated inflammation and immune activation can accelerate telomere attrition. In addition, antiretrovirals can inhibit telomerase, possibly shortening telomeres. We examined the longitudinal dynamics of leukocyte telomere length (LTL) during pregnancy in a unique cohort of women living with HIV (WLWH) treated with combination antiretroviral therapy (cART), and HIV-negative control women.<br><br>METHODS: Blood was collected at three visits during pregnancy, at 13-23, >23-30, and >30-40 weeks of gestation, and for WLWH only, at 6 weeks post-partum. LTL was measured by qPCR and both cross-sectional and longitudinal (MANOVA) models were used to examine possible predictors of LTL among participants who attended all three visits during pregnancy.<br><br>RESULTS: Among WLWH (n = 64) and HIV-negative women (n = 41), within participant LTL were correlated throughout pregnancy (p<0.001). LTL was shorter among WLWH at first visit, but this difference waned by the second visit. WLWH who discontinued cART post-partum experienced a decrease in LTL. Longitudinally, LTL was similar in both groups and increased as gestation progressed, a change that was more pronounced among women under 35 years. Among WLWH, both smoking throughout pregnancy (p = 0.04) and receiving a ritonavir-boosted protease inhibitor-based regimen (p = 0.03) were independently associated with shorter LTL.<br><br>CONCLUSIONS: LTL increases as pregnancy progresses; the reasons for this are unknown but may relate to changes in blood volume, hormones, and/or cell subset distribution. While our observations need confirmation in an independent cohort, our data suggest that although some cART regimens may influence LTL, being on cART appears overall protective and that stopping cART post-partum may negatively impact LTL. The effect of smoking on LTL is clearly negative, stressing the importance of smoking cessation.},
}
@article {pmid30840539,
year = {2019},
author = {Pegan, TM and Winkler, DW and Haussmann, MF and Vitousek, MN},
title = {Brief Increases in Corticosterone Affect Morphology, Stress Responses, and Telomere Length but Not Postfledging Movements in a Wild Songbird.},
journal = {Physiological and biochemical zoology : PBZ},
volume = {92},
number = {3},
pages = {274-285},
doi = {10.1086/702827},
pmid = {30840539},
issn = {1537-5293},
mesh = {Animal Distribution/*drug effects ; Animals ; Corticosterone/administration &amp; dosage/*pharmacology ; Glucocorticoids/administration &amp; dosage/*pharmacology ; Motor Activity/*drug effects ; Stress, Physiological/*drug effects ; Swallows/anatomy &amp; histology/*physiology ; Telomere/*drug effects/physiology ; },
abstract = {Organisms are frequently exposed to challenges during development, such as poor weather and food shortage. Such challenges can initiate the hormonal stress response, which involves secretion of glucocorticoids. Although the hormonal stress response helps organisms deal with challenges, long-term exposure to high levels of glucocorticoids can have morphological, behavioral, and physiological consequences, especially during development. Glucocorticoids are also associated with telomere shortening, and they have a complex relationship with survival. To investigate whether brief, acute exposures to glucocorticoids can also produce these phenotypic effects in free-living birds, we exposed wild tree swallow (Tachycineta bicolor) nestlings to a brief exogenous dose of corticosterone once per day for 5 d and then measured their morphology, baseline and stress-induced corticosterone levels, and telomere length. We also deployed radio tags on a subset of nestlings, which allowed us to determine the age at which tagged nestlings left the nest (fledged) and their pattern of presence and absence at the natal site during the postbreeding period. Corticosterone-treated nestlings had lower mass, higher baseline and stress-induced corticosterone, and reduced telomeres; other metrics of morphology were affected weakly or not at all. Our treatment resulted in no significant effect on survival to fledging, fledge age, or age at first departure from the natal site, and we found no negative effect of corticosterone on interannual return rate. These results show that brief acute corticosterone exposure during development can have measurable effects on phenotype in free-living tree swallows. Corticosterone may therefore mediate correlations between rearing environment and phenotype in developing organisms, even in the absence of prolonged stressors.},
}
@article {pmid30838410,
year = {2019},
author = {Jørgensen, SW and Liberti, SE and Larsen, NB and Lisby, M and Mankouri, HW and Hickson, ID},
title = {Esc2 promotes telomere stability in response to DNA replication stress.},
journal = {Nucleic acids research},
volume = {47},
number = {9},
pages = {4597-4611},
pmid = {30838410},
issn = {1362-4962},
mesh = {Cell Cycle Proteins ; DEAD-box RNA Helicases/*genetics ; DNA Replication/*genetics ; DNA-Binding Proteins/genetics ; Escherichia coli/genetics ; Homologous Recombination/genetics ; Nuclear Proteins/*genetics ; Nucleic Acid Conformation ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/*genetics ; Telomere/*genetics ; },
abstract = {Telomeric regions of the genome are inherently difficult-to-replicate due to their propensity to generate DNA secondary structures and form nucleoprotein complexes that can impede DNA replication fork progression. Precisely how cells respond to DNA replication stalling within a telomere remains poorly characterized, largely due to the methodological difficulties in analysing defined stalling events in molecular detail. Here, we utilized a site-specific DNA replication barrier mediated by the 'Tus/Ter' system to define the consequences of DNA replication perturbation within a single telomeric locus. Through molecular genetic analysis of this defined fork-stalling event, coupled with the use of a genome-wide genetic screen, we identified an important role for the SUMO-like domain protein, Esc2, in limiting genome rearrangements at a telomere. Moreover, we showed that these rearrangements are driven by the combined action of the Mph1 helicase and the homologous recombination machinery. Our findings demonstrate that chromosomal context influences cellular responses to a stalled replication fork and reveal protective factors that are required at telomeric loci to limit DNA replication stress-induced chromosomal instability.},
}
@article {pmid30838025,
year = {2019},
author = {Tsatsakis, A and Tsoukalas, D and Fragkiadaki, P and Vakonaki, E and Tzatzarakis, M and Sarandi, E and Nikitovic, D and Tsilimidos, G and Alegakis, AK},
title = {Developing BIOTEL: A Semi-Automated Spreadsheet for Estimating Telomere Length and Biological Age.},
journal = {Frontiers in genetics},
volume = {10},
number = {},
pages = {84},
pmid = {30838025},
issn = {1664-8021},
abstract = {Introduction: Telomere length (TL) is causally related to aging and several age-related diseases. Specifically, the abundance of short telomeres and the rate of telomere shortening are strong determinants of cell homeostasis. Thus, tools for analyzing and manipulating TL data can vastly improve research focused on aging. Aim: In this study, we developed a semi-automated worksheet, BIOTEL, to generate individual and group TL statistics and provide a crude estimation of biological age. Results: Data from the Telomere Length Database Project (TLDP) were implemented to the spreadsheet to produce TL statistics. 150 participants were included, and their age was from 21 to 82 years, and the sex distribution ratio was 52.3%: 47.7% (male: female). Initially, we analyzed the fluorescence intensities of telomeres that were measured on metaphase spread leukocytes using three-dimensional (3D) quantitative-fluorescent in situ hybridization (Q-FISH) procedures (3D DNA FISH) with a (C3TA2)3 peptide nucleic acid (PNA) probe. Raw data of fluorescence intensities, demographic data and medical records from the participants were imported into the worksheet. Basic statistical analyses of TL data were provided through BIOTEL, including TL percentiles, specialized charts for TL distribution including the percentage of critically short telomeres (< 3,000 kilobases), individual telomere profiles, and graphs of biological age vs. chronological age. Conclusion: BIOTEL ver. 2.4 is a functional semi-automated worksheet that calculates a wide range of TL statistics, thus a useful tool with applications in research of telomeres and biological age estimation.},
}
@article {pmid30834585,
year = {2019},
author = {Goffová, I and Vágnerová, R and Peška, V and Franek, M and Havlová, K and Holá, M and Zachová, D and Fojtová, M and Cuming, A and Kamisugi, Y and Angelis, KJ and Fajkus, J},
title = {Roles of RAD51 and RTEL1 in telomere and rDNA stability in Physcomitrella patens.},
journal = {The Plant journal : for cell and molecular biology},
volume = {98},
number = {6},
pages = {1090-1105},
doi = {10.1111/tpj.14304},
pmid = {30834585},
issn = {1365-313X},
support = {BB/1006710/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Bryopsida/*enzymology/genetics ; DNA Helicases/genetics/metabolism ; DNA, Ribosomal/*genetics ; Genetic Loci ; *Genomic Instability ; Mutation ; Plant Proteins/genetics/metabolism ; RNA, Ribosomal/genetics ; RNA, Ribosomal, 18S/genetics ; RNA, Ribosomal, 5S/genetics ; Rad51 Recombinase/genetics/metabolism ; Telomere/*genetics ; Transcription Factors/genetics/metabolism ; },
abstract = {Telomeres and ribosomal RNA genes (rDNA) are essential for cell survival and particularly sensitive to factors affecting genome stability. Here, we examine the role of RAD51 and its antagonist, RTEL1, in the moss Physcomitrella patens. In corresponding mutants, we analyse their sensitivity to DNA damage, the maintenance of telomeres and rDNA, and repair of double-stranded breaks (DSBs) induced by genotoxins with various modes of action. While the loss of RTEL1 results in rapid telomere shortening, concurrent loss of both RAD51 genes has no effect on telomere lengths. We further demonstrate here the linked arrangement of 5S and 45S rRNA genes in P. patens. The spacer between 5S and 18S rRNA genes, especially the region downstream from the transcription start site, shows conspicuous clustering of sites with a high propensity to form quadruplex (G4) structures. Copy numbers of 5S and 18S rDNA are reduced moderately in the pprtel1 mutant, and significantly in the double pprad51-1-2 mutant, with no progression during subsequent cultivation. While reductions in 45S rDNA copy numbers observed in pprtel1 and pprad51-1-2 plants apply also to 5S rDNA, changes in transcript levels are different for 45S and 5S rRNA, indicating their independent transcription by RNA polymerase I and III, respectively. The loss of SOL (Sog One-Like), a transcription factor regulating numerous genes involved in DSB repair, increases the rate of DSB repair in dividing as well as differentiated tissue, and through deactivation of G2/M cell-cycle checkpoint allows the cell-cycle progression manifested as a phenotype resistant to bleomycin.},
}
@article {pmid30833786,
year = {2019},
author = {Kim, J and Sun, C and Tran, AD and Chin, PJ and Ruiz, PD and Wang, K and Gibbons, RJ and Gamble, MJ and Liu, Y and Oberdoerffer, P},
title = {The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening.},
journal = {Nature structural &amp; molecular biology},
volume = {26},
number = {3},
pages = {213-219},
pmid = {30833786},
issn = {1545-9985},
support = {R01 CA155232/CA/NCI NIH HHS/United States ; ZIA BC011282-08/ImNIH/Intramural NIH HHS/United States ; MC_UU_00016/3/MRC_/Medical Research Council/United Kingdom ; T32 GM007491/GM/NIGMS NIH HHS/United States ; MC_UU_12009/3/MRC_/Medical Research Council/United Kingdom ; Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Chromatin/*metabolism ; DNA Breaks, Double-Stranded ; DNA Repair/*genetics ; HEK293 Cells ; HeLa Cells ; Histones/*genetics ; Homologous Recombination/*genetics ; Humans ; Telomerase/metabolism ; Telomere Homeostasis/*genetics ; X-linked Nuclear Protein/*genetics ; },
abstract = {The growth of telomerase-deficient cancers depends on the alternative lengthening of telomeres (ALT), a homology-directed telomere-maintenance pathway. ALT telomeres exhibit a unique chromatin environment and generally lack the nucleosome remodeler ATRX, pointing to an epigenetic basis for ALT. Recently, we identified a protective role for the ATRX-interacting macroH2A1.2 histone variant during homologous recombination and replication stress (RS). Consistent with an inherent susceptibility to RS, we show that human ALT telomeres are highly enriched for macroH2A1.2. However, in contrast to ATRX-proficient cells, ALT telomeres transiently lose macroH2A1.2 during acute RS to facilitate DNA double-strand break (DSB) formation, a process that is almost completely prevented by ectopic ATRX expression. Telomeric macroH2A1.2 is re-deposited in a DNA damage response (DDR)-dependent manner to promote homologous recombination-associated ALT pathways. Our findings thus identify the dynamic exchange of macroH2A1.2 on chromatin as an epigenetic link among ATRX loss, RS-induced DDR initiation and telomere maintenance via homologous recombination.},
}
@article {pmid30830680,
year = {2019},
author = {Minasi, S and Baldi, C and Pietsch, T and Donofrio, V and Pollo, B and Antonelli, M and Massimino, M and Giangaspero, F and Buttarelli, FR},
title = {Telomere elongation via alternative lengthening of telomeres (ALT) and telomerase activation in primary metastatic medulloblastoma of childhood.},
journal = {Journal of neuro-oncology},
volume = {142},
number = {3},
pages = {435-444},
pmid = {30830680},
issn = {1573-7373},
support = {121//Associazione Fabrizio Procaccini Onlus/ ; 212//Associazione con Lorenzo per mano/ ; },
mesh = {Adolescent ; Adult ; Cerebellar Neoplasms/genetics/metabolism/*secondary ; Child ; Child, Preschool ; Female ; Humans ; Male ; Medulloblastoma/genetics/metabolism/*pathology ; *Mutation ; Prognosis ; *Promoter Regions, Genetic ; Telomerase/genetics/*metabolism ; Telomere/*genetics ; *Telomere Homeostasis ; Young Adult ; },
abstract = {PURPOSE: Elongation of telomeres is necessary for tumor cell immortalization and senescence escape; neoplastic cells use to alternative pathways to elongate telomeres: telomerase reactivation or a telomerase-independent mechanism termed alternative lengthening of telomeres (ALT). Telomerase and ALT pathway has been explored in adult and pediatric gliomas and medulloblastomas (MDBs); however, these mechanisms were not previously investigated in MDBs metastatic at the onset. Therefore, we analyzed the activation of telomerase and ALT pathway in a homogenous cohort of 43 pediatric metastatic medulloblastomas, to investigate whether telomere elongation could play a role in the biology of metastatic MDB.<br><br>METHODS: We evaluated telomeres length via telomere-specific fluorescence in situ hybridization (Telo-FISH); we assessed nuclear expression of ATRX by immunohistochemistry (IHC). H3F3A and TERT promoter mutations were analyzed by pyrosequencing, while UTSS methylation status was analyzed via methylation-specific-PCR (MS-PCR).<br><br>RESULTS: H3F3A mutations were absent in all MDBs, 30% of samples showed ATRX nuclear loss, 18.2% of cases were characterized by TERT promoter mutations, while 60.9% harboured TERT promoter hyper-methylation in the UTSS region. Elongation of telomeres was found in 42.8% of cases. Metastatic MDBs control telomere elongation via telomerase activation (10.7%), induced by TERT promoter mutations in association with UTSS hyper-methylation, and ALT mechanism (32.1%), triggered by ATRX inactivation. Among non-metastatic MDBs, only 5.9% (1/17) showed ATRX nuclear loss with activation of ALT.<br><br>CONCLUSIONS: Our metastatic cases frequently activate ALT pathway, suggesting that it is a common process for senescence escape in primary metastatic medulloblastomas. Furthermore, the activation of mechanisms for telomere elongation is not restricted to certain molecular subgroups in this high-risk group of MDBs.},
}
@article {pmid30826299,
year = {2019},
author = {Perales-Puchalt, A and Soberón, N and Monterde, M and Hervas-Marin, D and Foronda, M and Desantes, D and Soler, I and Perales-Marin, A and Pellicer, A and Blasco, MA},
title = {Maternal telomere length is shorter in intrauterine growth restriction versus uncomplicated pregnancies, but not in the offspring or in IVF-conceived newborns.},
journal = {Reproductive biomedicine online},
volume = {38},
number = {4},
pages = {606-612},
doi = {10.1016/j.rbmo.2018.12.008},
pmid = {30826299},
issn = {1472-6491},
mesh = {Adult ; Cross-Sectional Studies ; Female ; *Fertilization in Vitro ; Fetal Growth Retardation/*diagnosis/pathology ; Humans ; In Situ Hybridization, Fluorescence ; Infant, Newborn ; Male ; Maternal Age ; Mothers ; Pregnancy ; Prospective Studies ; Smoking ; Telomere/*ultrastructure ; *Telomere Shortening ; Tertiary Care Centers ; Treatment Outcome ; },
abstract = {RESEARCH QUESTION: The study aimed to determine whether IVF or intrauterine growth restriction (IUGR) result in short neonatal telomeres, which could explain the higher risk of cardiovascular and metabolic disease described in these populations.<br><br>DESIGN: This was an observational, analytical, cross-sectional, prospective study with controls in a tertiary hospital. The main outcome was to determine the leukocyte telomere length in 126 newborns and their mothers (n&#x202f;=&#x202f;109). Newborns were conceived spontaneously or by IVF, and uncomplicated and IUGR pregnancies were studied. Telomere lengths were measured using high-throughput telomere quantitative fluorescent in-situ hybridization.<br><br>RESULTS: There was no difference in average telomere length between newborns conceived by IVF or those with IUGR and spontaneously conceived healthy newborns (P&#x202f;=&#x202f;0.466 and P&#x202f;=&#x202f;0.732, respectively); this remained after controlling for confounders (P&#x202f;=&#x202f;0.218 and P&#x202f;=&#x202f;0.991, respectively). Mothers of newborns with IUGR had a shorter average telomere length than women with uncomplicated pregnancies (P&#x202f;=&#x202f;0.023), which was confirmed after controlling for age, body mass index and smoking habit (P&#x202f;=&#x202f;0.034).<br><br>CONCLUSIONS: The results support the safety of IVF and IUGR in terms of the postnatal health of the newborns. The shorter telomeres of IUGR mothers may represent a higher cardiovascular risk, which would have clinical implications under the stress of pregnancy in otherwise healthy adults.},
}
@article {pmid30824709,
year = {2019},
author = {Petti, E and Buemi, V and Zappone, A and Schillaci, O and Broccia, PV and Dinami, R and Matteoni, S and Benetti, R and Schoeftner, S},
title = {SFPQ and NONO suppress RNA:DNA-hybrid-related telomere instability.},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {1001},
pmid = {30824709},
issn = {2041-1723},
mesh = {Animals ; Cell Line, Tumor ; DNA/*metabolism ; DNA Replication ; DNA-Binding Proteins ; Homologous Recombination ; Humans ; Mice ; Nuclear Matrix-Associated Proteins/*metabolism ; *Nucleic Acid Hybridization ; Octamer Transcription Factors/*metabolism ; PTB-Associated Splicing Factor/*metabolism ; RNA/*metabolism ; RNA, Untranslated ; RNA-Binding Proteins/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/metabolism ; },
abstract = {In vertebrates, the telomere repeat containing long, non-coding RNA TERRA is prone to form RNA:DNA hybrids at telomeres. This results in the formation of R-loop structures, replication stress and telomere instability, but also contributes to alternative lengthening of telomeres (ALT). Here, we identify the TERRA binding proteins NONO and SFPQ as novel regulators of RNA:DNA hybrid related telomere instability. NONO and SFPQ locate at telomeres and have a common role in suppressing RNA:DNA hybrids and replication defects at telomeres. NONO and SFPQ act as heterodimers to suppress fragility and homologous recombination at telomeres, respectively. Combining increased telomere fragility with unleashing telomere recombination upon NONO/SFPQ loss of function causes massive recombination events, involving 35% of telomeres in ALT cells. Our data identify the RNA binding proteins SFPQ and NONO as novel regulators at telomeres that collaborate to ensure telomere integrity by suppressing telomere fragility and homologous recombination triggered by RNA:DNA hybrids.},
}
@article {pmid30823596,
year = {2019},
author = {Jezek, M and Green, EM},
title = {Histone Modifications and the Maintenance of Telomere Integrity.},
journal = {Cells},
volume = {8},
number = {2},
pages = {},
pmid = {30823596},
issn = {2073-4409},
support = {R01 GM124342/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromatin/metabolism ; Disease ; Histones/*metabolism ; Humans ; Models, Biological ; *Protein Processing, Post-Translational ; Telomere/*metabolism ; },
abstract = {Telomeres, the nucleoprotein structures at the ends of eukaryotic chromosomes, play an integral role in protecting linear DNA from degradation. Dysregulation of telomeres can result in genomic instability and has been implicated in increased rates of cellular senescence and many diseases, including cancer. The integrity of telomeres is maintained by a coordinated network of proteins and RNAs, such as the telomerase holoenzyme and protective proteins that prevent the recognition of the telomere ends as a DNA double-strand breaks. The structure of chromatin at telomeres and within adjacent subtelomeres has been implicated in telomere maintenance pathways in model systems and humans. Specific post-translational modifications of histones, including methylation, acetylation, and ubiquitination, have been shown to be necessary for maintaining a chromatin environment that promotes telomere integrity. Here we review the current knowledge regarding the role of histone modifications in maintaining telomeric and subtelomeric chromatin, discuss the implications of histone modification marks as they relate to human disease, and highlight key areas for future research.},
}
@article {pmid30820532,
year = {2019},
author = {Mandal, S and Kawamoto, Y and Yue, Z and Hashiya, K and Cui, Y and Bando, T and Pandey, S and Hoque, ME and Hossain, MA and Sugiyama, H and Mao, H},
title = {Submolecular dissection reveals strong and specific binding of polyamide-pyridostatin conjugates to human telomere interface.},
journal = {Nucleic acids research},
volume = {47},
number = {7},
pages = {3295-3305},
pmid = {30820532},
issn = {1362-4962},
support = {R01 CA236350/CA/NCI NIH HHS/United States ; },
mesh = {Aminoquinolines/*chemistry ; Base Sequence ; DNA/chemical synthesis/chemistry/metabolism ; Humans ; Nylons/*chemistry ; Picolinic Acids/*chemistry ; Substrate Specificity ; Telomere/*chemistry/metabolism ; },
abstract = {To modulate biological functions, G-quadruplexes in genome are often non-specifically targeted by small molecules. Here, specificity is increased by targeting both G-quadruplex and its flanking duplex DNA in a naturally occurring dsDNA-ssDNA telomere interface using polyamide (PA) and pyridostatin (PDS) conjugates (PA-PDS). We innovated a single-molecule assay in which dissociation constant (Kd) of the conjugate can be separately evaluated from the binding of either PA or PDS. We found Kd of 0.8 nM for PA-PDS, which is much lower than PDS (Kd ∼ 450 nM) or PA (Kd ∼ 35 nM). Functional assays further indicated that the PA-PDS conjugate stopped the replication of a DNA polymerase more efficiently than PA or PDS. Our results not only established a new method to dissect multivalent binding into actions of individual monovalent components, they also demonstrated a strong and specific G-quadruplex targeting strategy by conjugating highly specific duplex-binding molecules with potent quadruplex ligands.},
}
@article {pmid30818839,
year = {2019},
author = {Ventura Marra, M and Drazba, MA and Holásková, I and Belden, WJ},
title = {Nutrition Risk is Associated with Leukocyte Telomere Length in Middle-Aged Men and Women with at Least One Risk Factor for Cardiovascular Disease.},
journal = {Nutrients},
volume = {11},
number = {3},
pages = {},
pmid = {30818839},
issn = {2072-6643},
support = {R01 GM101378/GM/NIGMS NIH HHS/United States ; U54 GM104942/GM/NIGMS NIH HHS/United States ; },
mesh = {Body Mass Index ; *Cardiovascular Diseases ; Cross-Sectional Studies ; Diet, Healthy ; Female ; Humans ; *Leukocytes ; Male ; Middle Aged ; Nutrition Assessment ; Nutritional Status ; Risk Factors ; *Telomere Shortening ; },
abstract = {Poor diet quality has been associated with several age-related chronic conditions, but its relationship to telomere length, a biological marker of cellular aging, is unclear. The purpose of this cross-sectional study was to determine whether overall diet quality was associated with relative leukocyte telomere length (rLTL) in a sample (n = 96) of nonsmoking middle-aged adults in Appalachia with at least one risk factor for cardiovascular disease. Diet quality was assessed using the Healthy Eating Index (HEI-2015), the alternate Mediterranean diet score (aMed), and the Dietary Screening Tool (DST). Peripheral rLTL was measured by quantitative real-time polymerase chain reaction. The associations between potentially confounding sociodemographic, lifestyle and health-related factors and the first and fourth rLTL quartile groups were examined using Chi-square or Fisher's Exact tests or logistic regression. The relationships between diet quality index scores and rLTL as a continuous variable were analyzed using simple linear regression and multivariate linear models, analogous to linear covariance analyses. The rLTL ranged from 0.46 to 1.49 (mean ± SEM was 1.02 ± 0.18). Smoking history, income level, and cardiovascular health (Life's Simple 7) were associated with the lowest and highest quartiles of rLTL and were used as covariates. In adjusted and unadjusted models, participants considered "at nutrition risk" by the DST were more likely to have shorter rLTL than those "not at risk or at potential risk" (p = 0.004). However, there was no evidence that adherence to the 2015[-]2020 Dietary Guidelines for Americans or to a Mediterranean diet was associated with rLTL in this sample. Intervention studies are needed to determine if improving the diet quality of those at nutrition risk results in reduced telomere attrition over time.},
}
@article {pmid30817819,
year = {2019},
author = {Li, J and An, C and Zheng, H and Lei, T and Zhang, N and Zheng, Y and Yang, M},
title = {Leukocyte Telomere Length and Risk of Papillary Thyroid Carcinoma.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {104},
number = {7},
pages = {2712-2718},
doi = {10.1210/jc.2018-02471},
pmid = {30817819},
issn = {1945-7197},
mesh = {Adult ; Carcinoma, Papillary/epidemiology/metabolism/pathology ; Case-Control Studies ; China/epidemiology ; Female ; Humans ; Leukocytes ; Logistic Models ; Male ; Middle Aged ; Neoplasm Invasiveness ; Risk Factors ; Telomere/*metabolism ; Thyroid Cancer, Papillary/*epidemiology/metabolism/pathology ; Thyroid Neoplasms/*epidemiology/metabolism/pathology ; },
abstract = {CONTEXT: Telomere length may contribute to predisposition to papillary thyroid cancer (PTC).<br><br>OBJECTIVE: To test this hypothesis, we examined the association between leukocyte telomere length and PTC risk.<br><br>DESIGN/SETTING: Case-control study in a Chinese Han population.<br><br>PARTICIPANTS/INTERVENTION: A total of 1200 PTC cases and 1201 age- and sex-matched healthy controls were included in the study. ORs and 95% CIs were calculated by logistic regression.<br><br>RESULTS: Short relative telomere length (RTL) was significantly associated with elevated risk of PTC (OR = 1.61, 95% CI = 1.35 to 1.92; P = 1.30 &#xd7; 10-7). Interestingly, when individuals were categorized into four groups on the basis of quartile distribution of relative telomere length (RTL) in controls, we observed a reverse U-shaped association between telomere length and PTC risk. Compared with those in the first (the longest) quartile as the reference group, ORs (95% CIs) were 5.61 (4.04 to 7.78) (P = 6.10 &#xd7; 10-25), 9.33 (6.78 to 12.83) (P = 6.99 &#xd7; 10-43), and 1.23 (0.83 to 1.81) (P = 0.300) for individuals in the second, third, and fourth (the shortest) quartiles, respectively. This reverse U-shaped relationship was more apparent in younger individuals.<br><br>CONCLUSIONS: Our findings suggest that RTL is significantly associated with susceptibility to PTC. There is an obvious reverse U-shaped association between telomere length and PTC risk. Telomere length may be a potential pronouncing biomarker to identify individuals with a high risk of developing PTC.},
}
@article {pmid30816301,
year = {2019},
author = {Maciejowski, J and de Lange, T},
title = {Author Correction: Telomeres in cancer: tumour suppression and genome instability.},
journal = {Nature reviews. Molecular cell biology},
volume = {20},
number = {4},
pages = {259},
doi = {10.1038/s41580-019-0113-7},
pmid = {30816301},
issn = {1471-0080},
abstract = {In the original Fig. 2a, telomeres are erroneously depicted having blunt ends following resection and CST-mediated fill-in. Instead, telomeres retain 3' overhangs, as depicted below.},
}
@article {pmid30814509,
year = {2019},
author = {Subramanian, VV and Zhu, X and Markowitz, TE and Vale-Silva, LA and San-Segundo, PA and Hollingsworth, NM and Keeney, S and Hochwagen, A},
title = {Persistent DNA-break potential near telomeres increases initiation of meiotic recombination on short chromosomes.},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {970},
pmid = {30814509},
issn = {2041-1723},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; R01 GM050717/GM/NIGMS NIH HHS/United States ; R01 GM111715/GM/NIGMS NIH HHS/United States ; R35 GM118092/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosome Pairing/genetics ; Chromosomes, Fungal/*genetics/metabolism ; *DNA Breaks, Double-Stranded ; DNA-Binding Proteins/metabolism ; Meiosis/*genetics ; Nuclear Pore Complex Proteins/metabolism ; Nuclear Proteins/metabolism ; Recombination, Genetic ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/metabolism ; Sirtuin 2/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Faithful meiotic chromosome inheritance and fertility rely on the stimulation of meiotic crossover recombination by potentially genotoxic DNA double-strand breaks (DSBs). To avoid excessive damage, feedback mechanisms down-regulate DSBs, likely in response to initiation of crossover repair. In Saccharomyces cerevisiae, this regulation requires the removal of the conserved DSB-promoting protein Hop1/HORMAD during chromosome synapsis. Here, we identify privileged end-adjacent regions (EARs) spanning roughly 100 kb near all telomeres that escape DSB down-regulation. These regions retain Hop1 and continue to break in pachynema despite normal synaptonemal complex deposition. Differential retention of Hop1 requires the disassemblase Pch2/TRIP13, which preferentially removes Hop1 from telomere-distant sequences, and is modulated by the histone deacetylase Sir2 and the nucleoporin Nup2. Importantly, the uniform size of EARs among chromosomes contributes to disproportionately high DSB and repair signals on short chromosomes in pachynema, suggesting that EARs partially underlie the curiously high recombination rate of short chromosomes.},
}
@article {pmid30811824,
year = {2019},
author = {Kwon, MS and Lee, JJ and Min, J and Hwang, K and Park, SG and Kim, EH and Kim, BC and Bhak, J and Lee, H},
title = {Brca2 abrogation engages with the alternative lengthening of telomeres via break-induced replication.},
journal = {The FEBS journal},
volume = {286},
number = {10},
pages = {1841-1858},
doi = {10.1111/febs.14796},
pmid = {30811824},
issn = {1742-4658},
mesh = {Animals ; BRCA2 Protein/*genetics/metabolism ; DNA Replication/*physiology ; Fibroblasts/metabolism/pathology ; G2 Phase ; MRE11 Homologue Protein/genetics/metabolism ; Mice, Knockout ; Mice, Transgenic ; Rad52 DNA Repair and Recombination Protein/genetics/metabolism ; Telomere/*genetics ; Telomere Shortening/genetics ; },
abstract = {A subset of cancer cells maintains their telomeres without telomerase through the recombination-based alternative lengthening of telomeres (ALT) pathway. Currently, it is not yet clear in what context ALT is induced and how the pathway choice is made. Here, we show that abrogation of Brca2 reinforces break-induced replication (BIR) and engages with ALT pathway. Brca2 depletion in telomerase-null mouse cells alleviated the growth defect, accompanied by telomere elongation, suggesting the induction of ALT. We also found that Brca2-depleted telomerase-null cells exhibited dynamic clustering of telomeres from G2 phase in Promyelocytic Nuclear (PML) bodies. For Brca2-deficient ALT induction, Rad51 was dispensable but Mre11 and Rad52 were required. Congruently, conservative telomeric DNA synthesis was apparent in mitosis, indicating that the absence of Brca2 directed towards Rad52-mediated BIR. Collectively, we propose that Brca2 abrogation can instigate ALT tumourigenesis through the induction of BIR. This study implies that inhibitors of BIR may be useful for BRCA2-associated ALT-type cancers. Assessing ALT features may be considered for the tailored therapy of BRCA2-associated cancers.},
}
@article {pmid30805617,
year = {2019},
author = {Gürünlüoğlu, K and Demircan, M and Koç, A and Koçbıyık, A and Taşçı, A and Durmuş, K and Gürünlüoğlu, S and Gözükara Bağ, H},
title = {The Effects of Different Burn Dressings on Length of Telomere and Expression of Telomerase in Children With Thermal Burns.},
journal = {Journal of burn care &amp; research : official publication of the American Burn Association},
volume = {40},
number = {3},
pages = {302-311},
doi = {10.1093/jbcr/irz019},
pmid = {30805617},
issn = {1559-0488},
mesh = {Adolescent ; Anti-Infective Agents, Local/pharmacology ; *Bandages ; Biopsy, Needle ; Burns/*genetics/pathology/*therapy ; Child ; Child, Preschool ; Cohort Studies ; Female ; Gene Expression Regulation ; Humans ; Immunohistochemistry ; Infant ; Injury Severity Score ; Male ; Prognosis ; Prospective Studies ; Risk Assessment ; Silver Sulfadiazine/pharmacology ; Telomerase/*genetics ; Telomere/*genetics ; Wound Healing/*drug effects/genetics ; },
abstract = {BACKGROUND: Burns are a common traumatic injury triggered by local tissue damage and a systemic response. In this study, we evaluated the effects of different burn dressings on telomere kinetics in children with thermal burn injury.<br><br>METHODS: Sixty children with thermal burn were included in this prospective study. The burn area of the patients included 20 to 50% total body surface area. Three different dressings (hydrofiber with silver [HFAg], poylactic membrane [PLM], and silver sulfadiazine [SSD]) and control groups were created. Telomere length in nucleated blood cells and telomerase expression in the skin tissue were evaluated in control and burn groups.<br><br>RESULTS: In the whole burn groups, telomere length in blood cells increased. The length of telomeres increased the most in the SSD group. The PLM group is the treatment that increases the number of squamous cell counts in the basal layer and telomerase expression in the skin. In HFAg and SSD groups, the expression of telomerase in the skin is decreased. In the HFAg group, the basal layer in the skin was also reduced in squamous cells.<br><br>CONCLUSION: In all burn groups, the telomere length of nucleated cells in the blood was higher than in the control group. SSD dressing along with autografting is the treatment method that maximizes telomere length in blood cells. The PLM has the most increased telomerase expression in the skin of burned patients. The PLM application increases the number of cells on both burned and normal skin.},
}
@article {pmid30796896,
year = {2019},
author = {Injaian, AS and Gonzalez-Gomez, PL and Taff, CC and Bird, AK and Ziur, AD and Patricelli, GL and Haussmann, MF and Wingfield, JC},
title = {Traffic noise exposure alters nestling physiology and telomere attrition through direct, but not maternal, effects in a free-living bird.},
journal = {General and comparative endocrinology},
volume = {276},
number = {},
pages = {14-21},
doi = {10.1016/j.ygcen.2019.02.017},
pmid = {30796896},
issn = {1095-6840},
mesh = {Animals ; Corticosterone/blood ; *Environmental Exposure ; Female ; Models, Theoretical ; Nesting Behavior/*physiology ; *Noise ; Stress, Physiological ; Swallows/blood/*physiology ; Telomere/*metabolism ; Telomere Homeostasis ; *Traffic-Related Pollution ; },
abstract = {Anthropogenic impacts, such as noise pollution from transportation networks, can serve as stressors to some wildlife species. For example, increased exposure to traffic noise has been found to alter baseline and stress-induced corticosterone levels, reduce body condition and reproductive success, and increase telomere attrition in free-living birds. However, it remains unknown if alterations in nestling phenotype are due to direct or indirect effects of noise exposure. For example, indirect (maternal) effects of noise may occur if altered baseline and stress-induced corticosterone in mothers results in differential deposition of yolk steroids or other components in eggs. Noise exposure may also alter nestling corticosterone levels directly, given that nestlings cannot escape the nest during development. Here, we examined maternal versus direct effects of traffic noise exposure on baseline and stress-induced corticosterone levels, and body condition (as measured by size-corrected mass) in nestling tree swallows (Tachycineta bicolor). We used a two-way factorial design and partially cross-fostered eggs between nests exposed to differing levels (i.e. amplitudes) of traffic noise. For nestlings that were not cross-fostered, we also investigated the effects of traffic noise on telomere dynamics. Our results show a positive relationship between nestling baseline and stress-induced corticosterone and nestling noise exposure, but not maternal noise exposure. While we did not find a relationship between noise and body condition in nestlings, nestling baseline corticosterone was negatively associated with body condition. We also found greater telomere attrition for nestlings from nests with greater traffic noise amplitudes. These results suggest that direct, rather than maternal, effects result in potentially long-lasting consequences of noise exposure. Reduced nestling body condition and increased telomere attrition have been shown to reduce post-fledging survival in this species. Given that human transportation networks continue to expand, strategies to mitigate noise exposure on wildlife during critical periods (i.e. breeding) may be needed to maintain local population health in free-living passerines, such as tree swallows.},
}
@article {pmid30796745,
year = {2019},
author = {Muskens, IS and Hansen, HM and Smirnov, IV and Molinaro, AM and Bondy, ML and Schildkraut, JM and Wrensch, M and Wiemels, JL and Claus, EB},
title = {Longer genotypically-estimated leukocyte telomere length is associated with increased meningioma risk.},
journal = {Journal of neuro-oncology},
volume = {142},
number = {3},
pages = {479-487},
pmid = {30796745},
issn = {1573-7373},
support = {R25 CA112355/CA/NCI NIH HHS/United States ; CA52689/NH/NIH HHS/United States ; R01 CA109473/CA/NCI NIH HHS/United States ; R01 CA109468/CA/NCI NIH HHS/United States ; CA109745/NH/NIH HHS/United States ; Not applicable//University of California, San Francisco/ ; Not applicable//Brain Science Foundation/ ; R01 CA109461/CA/NCI NIH HHS/United States ; CA109473/NH/NIH HHS/United States ; R01 CA109745/CA/NCI NIH HHS/United States ; CA109468/NH/NIH HHS/United States ; R01 CA052689/CA/NCI NIH HHS/United States ; Not applicable//Meningioma Mommas/ ; CA109461/NH/NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; CA097257/NH/NIH HHS/United States ; R01 CA151933/CA/NCI NIH HHS/United States ; P50 CA097257/CA/NCI NIH HHS/United States ; CA109475//National Institutes of Health (US)/ ; CA112355/NH/NIH HHS/United States ; R01 CA109475/CA/NCI NIH HHS/United States ; },
mesh = {Case-Control Studies ; Female ; Follow-Up Studies ; Genotype ; Humans ; Leukocytes/metabolism/*pathology ; Male ; Meningeal Neoplasms/*etiology/pathology ; Meningioma/*etiology/pathology ; *Polymorphism, Single Nucleotide ; Prognosis ; Risk Factors ; *Telomere Homeostasis ; },
abstract = {PURPOSE: Telomere length-associated SNPs have been associated with incidence and survival rates for malignant brain tumors such as glioma. Here, we study the influence of genetically determined lymphocyte telomere length (LTL) by comparing telomerase associated SNPs between the most common non-malignant brain tumor, i.e. meningioma, and healthy controls.<br><br>METHODS/PATIENTS: One thousand fifty-three (1053) surgically treated meningioma patients and 4437 controls of Western European ancestry were included. Germline DNA was genotyped for 8 SNPs previously significantly associated with LTL. Genotypically-estimated LTL was then calculated by summing each SNP's genotypically-specified telomere length increase in base pairs (bp) for each person. Odds ratios for genotypically-estimated LTL in meningioma cases and controls were evaluated using logistic regression with the first two ancestral principal components and sex as covariates.<br><br>RESULTS: Three out of the eight evaluated LTL SNPs were significantly associated with increased meningioma risk (rs10936599: OR 1.14, 95% CI 1.01-1.28, rs2736100: OR 1.13, 95% CI 1.03-1.25, rs9420907: OR 1.22, 95% CI 1.07-1.39). Only rs9420907 remained significant after correction for multiple testing. Average genotypically-estimated LTL was significantly longer for those with meningioma compared to controls [mean cases: 560.2&#xa0;bp (standard error (SE): 4.05&#xa0;bp), mean controls: 541.5&#xa0;bp (SE: 2.02&#xa0;bp), logistic regression p value&#x2009;=&#x2009;2.13&#x2009;&#xd7;&#x2009;10[-5]].<br><br>CONCLUSION: Increased genotypically-estimated LTL was significantly associated with increased meningioma risk. A role for telomere length in the pathophysiology of meningioma is novel, and could lead to new insights on the etiology of meningioma.},
}
@article {pmid30796637,
year = {2019},
author = {Zhang, X and Liu, Z and Liu, X and Wang, S and Zhang, Y and He, X and Sun, S and Ma, S and Shyh-Chang, N and Liu, F and Wang, Q and Wang, X and Liu, L and Zhang, W and Song, M and Liu, GH and Qu, J},
title = {Telomere-dependent and telomere-independent roles of RAP1 in regulating human stem cell homeostasis.},
journal = {Protein &amp; cell},
volume = {10},
number = {9},
pages = {649-667},
pmid = {30796637},
issn = {1674-8018},
mesh = {Animals ; Cell Adhesion Molecules, Neuronal/*metabolism ; Extracellular Matrix Proteins/*metabolism ; Human Embryonic Stem Cells/*cytology ; Humans ; Male ; Mesenchymal Stem Cells/*cytology ; Methylation ; Mice, Inbred NOD ; Mice, SCID ; Nerve Tissue Proteins/*metabolism ; Neural Stem Cells/*cytology ; Reelin Protein ; Serine Endopeptidases/*metabolism ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/*physiology ; },
abstract = {RAP1 is a well-known telomere-binding protein, but its functions in human stem cells have remained unclear. Here we generated RAP1-deficient human embryonic stem cells (hESCs) by using CRISPR/Cas9 technique and obtained RAP1-deficient human mesenchymal stem cells (hMSCs) and neural stem cells (hNSCs) via directed differentiation. In both hMSCs and hNSCs, RAP1 not only negatively regulated telomere length but also acted as a transcriptional regulator of RELN by tuning the methylation status of its gene promoter. RAP1 deficiency enhanced self-renewal and delayed senescence in hMSCs, but not in hNSCs, suggesting complicated lineage-specific effects of RAP1 in adult stem cells. Altogether, these results demonstrate for the first time that RAP1 plays both telomeric and nontelomeric roles in regulating human stem cell homeostasis.},
}
@article {pmid30796307,
year = {2019},
author = {Escudero, L and Cleal, K and Ashelford, K and Fegan, C and Pepper, C and Liddiard, K and Baird, DM},
title = {Telomere fusions associate with coding sequence and copy number alterations in CLL.},
journal = {Leukemia},
volume = {33},
number = {8},
pages = {2093-2097},
pmid = {30796307},
issn = {1476-5551},
support = {12023/LLR_/Blood Cancer UK/United Kingdom ; 18246/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {*DNA Copy Number Variations ; Gene Fusion ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics ; *Telomere ; },
}
@article {pmid30796050,
year = {2019},
author = {Escandell, JM and Carvalho, ES and Gallo-Fernandez, M and Reis, CC and Matmati, S and Luís, IM and Abreu, IA and Coulon, S and Ferreira, MG},
title = {Ssu72 phosphatase is a conserved telomere replication terminator.},
journal = {The EMBO journal},
volume = {38},
number = {7},
pages = {},
pmid = {30796050},
issn = {1460-2075},
mesh = {Amino Acid Sequence ; Carrier Proteins/genetics ; Conserved Sequence ; *DNA Replication ; *Evolution, Molecular ; Humans ; Phosphoprotein Phosphatases/*genetics ; Phosphoric Monoester Hydrolases/*genetics ; Phosphorylation ; Schizosaccharomyces/enzymology/*genetics ; Schizosaccharomyces pombe Proteins/*genetics ; Sequence Homology ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {Telomeres, the protective ends of eukaryotic chromosomes, are replicated through concerted actions of conventional DNA polymerases and elongated by telomerase, but the regulation of this process is not fully understood. Telomere replication requires (Ctc1/Cdc13)-Stn1-Ten1, a telomeric ssDNA-binding complex homologous to RPA Here, we show that the evolutionarily conserved phosphatase Ssu72 is responsible for terminating the cycle of telomere replication in fission yeast. Ssu72 controls the recruitment of Stn1 to telomeres by regulating Stn1 phosphorylation at Ser74, a residue located within its conserved OB-fold domain. Consequently, ssu72∆ mutants are defective in telomere replication and exhibit long 3'-ssDNA overhangs, indicative of defective lagging-strand DNA synthesis. We also show that hSSU72 regulates telomerase activation in human cells by controlling recruitment of hSTN1 to telomeres. These results reveal a previously unknown yet conserved role for the phosphatase SSU72, whereby this enzyme controls telomere homeostasis by activating lagging-strand DNA synthesis, thus terminating the cycle of telomere replication.},
}
@article {pmid30795542,
year = {2019},
author = {Brane, AC and Tollefsbol, TO},
title = {Targeting Telomeres and Telomerase: Studies in Aging and Disease Utilizing CRISPR/Cas9 Technology.},
journal = {Cells},
volume = {8},
number = {2},
pages = {},
pmid = {30795542},
issn = {2073-4409},
support = {P30 DK079626/DK/NIDDK NIH HHS/United States ; R01 CA178441/CA/NCI NIH HHS/United States ; R01 CA204346/CA/NCI NIH HHS/United States ; },
mesh = {Aging/*genetics ; CRISPR-Cas Systems/*genetics ; Disease/*genetics ; Epigenesis, Genetic ; Humans ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres and telomerase provide a unique and important avenue of study in improving both life expectancy and quality of life due to their close association with aging and disease. While major advances in our understanding of these two biological mediators have characterized the last two decades, previous studies have been limited by the inability to affect change in real time within living cells. The last three years, however, have witnessed a huge step forward to overcome this limitation. The advent of the clustered regularly interspaced short palindromic repeats/CRISPR-associated (CRISPR/Cas) system has led to a wide array of targeted genetic studies that are already being employed to modify telomeres and telomerase, as well as the genes that affect them. In this review, we analyze studies utilizing the technology to target and modify telomeres, telomerase, and their closely associated genes. We also discuss how these studies can provide insight into the biology and mechanisms that underlie aging, cancer, and other diseases.},
}
@article {pmid30793350,
year = {2019},
author = {Giraudeau, M and Angelier, F and Sepp, T},
title = {Do Telomeres Influence Pace-of-Life-Strategies in Response to Environmental Conditions Over a Lifetime and Between Generations?.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {41},
number = {3},
pages = {e1800162},
doi = {10.1002/bies.201800162},
pmid = {30793350},
issn = {1521-1878},
mesh = {Age Factors ; Animals ; Ecosystem ; Environmental Exposure ; Female ; Gametogenesis/physiology ; Germ Cells/physiology ; Humans ; Immunity/physiology ; Longevity/*physiology ; Male ; Metabolism/physiology ; Oxidative Stress/physiology ; Personality/physiology ; *Phenotype ; Reproduction/physiology ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; Telomere Shortening/*physiology ; },
abstract = {The complexity of the physiological phenotype currently prevents us from identifying an integrative measure to assess how the internal state and environmental conditions modify life-history strategies. In this article, it is proposed that shorter telomeres should lead to a faster pace-of-life where investment in self-maintenance is decreased as a means of saving energy for reproduction, but at the cost of somatic durability. Inversely, longer telomeres would favor an increased investment in soma maintenance and thus a longer reproductive lifespan (i.e., slower pace-of-life). Under this hypothesis, telomere dynamics could be such an integrative mediator, which will assemble the information about oxidative stress levels, inflammation status and stress reactivity, and relate this information to the potential lifespan of the organism and its pace-of-life strategy. The signaling function of telomere dynamics can also reach over generations, a phenomenon in which the telomere lengths of gametes would provide a channel through which offspring would receive information about their environment early in their development, hence increasing the possibilities for developmental plasticity.},
}
@article {pmid30791107,
year = {2019},
author = {Kapuria, D and Ben-Yakov, G and Ortolano, R and Cho, MH and Kalchiem-Dekel, O and Takyar, V and Lingala, S and Gara, N and Tana, M and Kim, YJ and Kleiner, DE and Young, NS and Townsley, DM and Koh, C and Heller, T},
title = {The Spectrum of Hepatic Involvement in Patients With Telomere Disease.},
journal = {Hepatology (Baltimore, Md.)},
volume = {69},
number = {6},
pages = {2579-2585},
pmid = {30791107},
issn = {1527-3350},
support = {Z99 DK999999/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Distribution ; Aged ; Biopsy, Needle ; Cohort Studies ; Comorbidity ; Female ; Genetic Diseases, Inborn/diagnosis/*epidemiology ; Genetic Testing ; Genetic Variation ; Humans ; Immunohistochemistry ; Liver Diseases/diagnosis/*epidemiology/*genetics ; Liver Function Tests ; Male ; Middle Aged ; Mutation/genetics ; Prevalence ; Prognosis ; Prospective Studies ; Risk Assessment ; Sex Distribution ; Survival Analysis ; Telomere/*genetics ; },
abstract = {Loss-of-function mutations in genes that encode for components of the telomere repair complex cause accelerated telomere shortening. Hepatic involvement has been recognized as a cause of morbidity in telomere diseases, but very few studies have characterized the nature and extent of liver involvement in affected patients. We report the prevalence and characteristics of liver involvement in a large cohort of patients with telomere disease evaluated serially at the National Institutes of Health. One hundred twenty-one patients with known or suspected telomere disease were screened; 40 patients with liver involvement were included in the current study. Median follow-up was 2.4 years. Data were collected regarding their demographic information, laboratory analysis, imaging, and histopathology. Forty patients (40% of the cohort) with a median age of 42 years were found to have liver involvement. Liver enzyme elevation was cholestatic in pattern; 8 (21%) had drug-related enzyme elevations. The most common imaging finding was increased hepatic echogenicity on ultrasound in 39% (9) of patients, followed by hepatomegaly in 26% (6). Biopsies were infrequent because of risk associated with thrombocytopenia, but in 6 patients, there were varying findings: nodular regenerative hyperplasia, steatohepatitis, hemosiderosis, cholestasis, and cirrhosis with hepatic steatosis. Almost half the cohort had pulmonary diffusion abnormalities, and 25% died during the follow-up period. Conclusion: In patients with telomere disease, hepatic involvement is common and can present in diverse ways, including elevated liver enzymes as well as histopathologic and imaging abnormalities. Liver disease has important implications for morbidity and mortality in patients with telomere disease.},
}
@article {pmid30788677,
year = {2020},
author = {Stögbauer, L and Stummer, W and Senner, V and Brokinkel, B},
title = {Telomerase activity, TERT expression, hTERT promoter alterations, and alternative lengthening of the telomeres (ALT) in meningiomas - a systematic review.},
journal = {Neurosurgical review},
volume = {43},
number = {3},
pages = {903-910},
doi = {10.1007/s10143-019-01087-3},
pmid = {30788677},
issn = {1437-2320},
support = {BB221703//Innovative Medical Research, University of M?nster Medical School/ ; },
mesh = {Brain Neoplasms/*genetics/ultrastructure ; Humans ; Meningioma/*genetics/ultrastructure ; Telomerase/biosynthesis/*genetics/*metabolism ; Telomere/*genetics/ultrastructure ; Telomere Homeostasis/*genetics ; },
abstract = {Telomerase activity and (human) Telomerase Reverse Transcriptase (hTERT) expression are considered hallmarks in oncogenesis of neoplasms and are upregulated by alterations of the hTERT promoter. In meningiomas, numerous studies investigated hTERT expression, telomerase activity, promoter mutations, and methylations. Moreover, reports about hTERT-targeted chemotherapy in meningiomas have recently been published. We provide a systematic review of the literature about the role of hTERT in meningiomas. TERT expression and telomerase activity is found in benign and high-grade meningiomas and increase with WHO grade. Remarkably, rates of TERT expression/telomerase activity usually exceed mutation frequency and both telomerase activity and TERT expression have also been found in hTERT promoter wildtype meningiomas, indicating further mechanisms of TERT upregulation. Although hTERT promoter methylation has been reported in the vast majority of meningiomas, correlation with TERT expression remains controversial. Rates of promoter mutations, and methylation were shown to increase with rising WHO grade. Moreover, promoter methylation and mutations strongly correlate with prognosis. Although mutations predicted malignant progression, de novo mutations in high-grade recurrences of former benign lesions were also observed. Retroviral transduction of the TERT gene enabled immortalization in several grade I-III meningioma cell lines. In vitro analyses revealed significant effects on viability in hTERT-mutated meningioma cells after targeted treatment. Alternative mechanisms of telomere lengthening are usually absent in meningiomas. TERT and hTERT promoter alterations play a major role during oncogenesis of meningiomas with implications for prognosis and potentially treatment.},
}
@article {pmid30788057,
year = {2019},
author = {Shin, PK and Zoh, Y and Choi, J and Kim, MS and Kim, Y and Choi, SW},
title = {Walnut phenolic extracts reduce telomere length and telomerase activity in a colon cancer stem cell model.},
journal = {Nutrition research and practice},
volume = {13},
number = {1},
pages = {58-63},
pmid = {30788057},
issn = {1976-1457},
abstract = {BACKGROUND/OBJECTIVES: Telomeres are located at the chromosomal ends and progressively shortened during each cell cycle. Telomerase, which is regulated by hTERT and c-MYC, maintains telomeric DNA sequences. Especially, telomerase is active in cancer and stem cells to maintain telomere length for replicative immortality. Recently we reported that walnut phenolic extract (WPE) can reduce cell viability in a colon cancer stem cell (CSC) model. We, therefore, investigated the effect of WPE on telomere maintenance in the same model.<br><br>MATERIALS/METHODS: CD133[+]CD44[+] cells from HCT116, a human colon cancer cell line, were sorted by Fluorescence-activated cell sorting (FACS) and treated with WPE at the concentrations of 0, 10, 20, and 40 &#xb5;g/mL for 6 days. Telomere lengths were assessed by quantitative real-time PCR (qRT-PCR) using telomere specific primers and DNA extracted from the cells, which was further adjusted with single-copy gene and reference DNA (ddCt). Telomerase activity was also measured by qRT-PCR after incubating the PCR mixture with cell protein extracts, which was adjusted with reference DNA (dCt). Transcriptions of hTERT and c-MYC were determined using conventional RT-PCR.<br><br>RESULTS: Telomere length of WPE-treated cells was significantly decreased in a dose-dependent manner (5.16 &#xb1; 0.13 at 0 &#xb5;g/mL, 4.79 &#xb1; 0.12 at 10 &#xb5;g/mL, 3.24 &#xb1; 0.08 at 20 &#xb5;g/mL and 3.99 &#xb1; 0.09 at 40 &#xb5;g/mL; P = 0.0276). Telomerase activities concurrently decreased with telomere length (1.47 &#xb1; 0.04, 1.09 &#xb1; 0.01, 0.76 &#xb1; 0.08, and 0.88 &#xb1; 0.06; P = 0.0067). There was a positive correlation between telomere length and telomerase activity (r = 0.9090; P < 0.0001). Transcriptions of both hTERT and c-MYC were also significantly decreased in the same manner.<br><br>CONCLUSION: In the present cell culture model, WPE reduced telomere maintenance, which may provide a mechanistic link to the effect of walnuts on the viability of colon CSCs.},
}
@article {pmid30785764,
year = {2019},
author = {Makino, N and Maeda, T and Abe, N},
title = {Short telomere subtelomeric hypomethylation is associated with telomere attrition in elderly diabetic patients [1].},
journal = {Canadian journal of physiology and pharmacology},
volume = {97},
number = {4},
pages = {335-339},
doi = {10.1139/cjpp-2018-0568},
pmid = {30785764},
issn = {1205-7541},
mesh = {Aged ; *DNA Methylation ; Diabetes Mellitus, Type 2/*genetics ; Female ; Humans ; Male ; Middle Aged ; Telomere/*genetics ; },
abstract = {Telomere shortening is well known to be associated with the aging process and aging-associated diseases, including diabetes. The telomere length and subtelomeric methylation status in peripheral leucocytes (LTL) were compared in elderly type 2 diabetes (T2D) patients and diabetes-free controls (C). The methylation status was analyzed between MspI-TRF lengths and HpaII-TRF lengths by using methylation-sensitive and -insensitive restriction enzyme isoschizomers, MspI and HpaII, respectively. The mean telomere lengths, MspI-TRF or HpaII-TRF, were not significantly different between C and T2D patients. The percentage of fractionated densitometry showed that long and middle telomeres (>9.4 kb, 4.4-9.4 kb) were unaltered but short telomeres (<4.4 kb) in T2D patients were increased compared with C group. The methylation status revealed subtelomeric hypomethylation in short telomeres of T2D patients. When some patients with T2D were treated with 3-hydroxy-3-methylglutaril coenzyme A (HMG-CoA) reductase inhibitors (statin), results seen in short telomere of T2D patients were not observed and were not different from C. This suggested that this altered subtelomeric hypomethylation may be associated with the accelerated telomere shortening in elderly diabetic patients. These results also mean that the subtelomeric hypomethylation can also be influenced by statin treatment in T2D.},
}
@article {pmid30781491,
year = {2019},
author = {Turner, K and Lynch, C and Rouse, H and Vasu, V and Griffin, DK},
title = {Direct Single-Cell Analysis of Human Polar Bodies and Cleavage-Stage Embryos Reveals No Evidence of the Telomere Theory of Reproductive Ageing in Relation to Aneuploidy Generation.},
journal = {Cells},
volume = {8},
number = {2},
pages = {},
pmid = {30781491},
issn = {2073-4409},
support = {G1000392//Medical Research Council/United Kingdom ; },
mesh = {Adult ; Aging/*physiology ; *Aneuploidy ; Blastomeres/metabolism ; Cleavage Stage, Ovum/*metabolism ; Embryo, Mammalian/*metabolism ; Humans ; Maternal Age ; Polar Bodies/*metabolism ; *Reproduction ; *Single-Cell Analysis ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Reproductive ageing in women, particularly after the age of 35, is associated with an exponential increase in the proportion of chromosomally abnormal oocytes produced. Several hypotheses have attempted to explain this observation, including the 'limited oocyte pool' hypothesis and the 'two-hit' hypothesis, the latter explaining that a depletion in oocyte quality with age results from the multiple opportune stages for errors to occur in meiosis. Recently however, the telomere theory of reproductive ageing in women has been proposed. This suggests that shortened telomeres in oocytes of women of advanced maternal age render oocytes unable to support fertilization and embryogenesis. Despite a credible rationale for the telomere theory of reproductive ageing in women, very few studies have assessed telomere length directly in human oocytes or preimplantation embryos. Therefore, we directly assessed relative telomere length in first polar bodies and blastomeres from cleavage stage (day 3) embryos. In both cell types we tested the hypothesis that (1) older women have shorter telomeres and (2) chromosomally abnormal (aneuploid) gametes/embryos have shorter telomeres. In all cases, we found no evidence of altered telomere length associated with age-related aneuploidy.},
}
@article {pmid30779012,
year = {2018},
author = {Saretzki, G},
title = {Telomeres, Telomerase and Ageing.},
journal = {Sub-cellular biochemistry},
volume = {90},
number = {},
pages = {221-308},
doi = {10.1007/978-981-13-2835-0_9},
pmid = {30779012},
issn = {0306-0225},
mesh = {Aging/*genetics ; DNA Replication ; Humans ; Oxidative Stress ; *Telomerase/metabolism ; *Telomere ; },
abstract = {Telomeres are specialised structures at the end of linear chromosomes. They consist of tandem repeats of the hexanucleotide sequence TTAGGG, as well as a protein complex called shelterin. Together, they form a protective loop structure against chromosome fusion and degradation. Shortening or damage to telomeres and opening of the loop induce an uncapped state that triggers a DNA damage response resulting in senescence or apoptosis.Average telomere length, usually measured in human blood lymphocytes, was thought to be a biomarker for ageing, survival and mortality. However, it becomes obvious that regulation of telomere length is very complex and involves multiple processes. For example, the "end replication problem" during DNA replication as well as oxidative stress are responsible for the shortening of telomeres. In contrast, telomerase activity can potentially counteract telomere shortening when it is able to access and interact with telomeres. However, while highly active during development and in cancer cells, the enzyme is down-regulated in most human somatic cells with a few exceptions such as human lymphocytes. In addition, telomeres can be transcribed, and the transcription products called TERRA are involved in telomere length regulation.Thus, telomere length and their integrity are regulated at many different levels, and we only start to understand this process under conditions of increased oxidative stress, inflammation and during diseases as well as the ageing process.This chapter aims to describe our current state of knowledge on telomeres and telomerase and their regulation in order to better understand their role for the ageing process.},
}
@article {pmid30777668,
year = {2019},
author = {Darmishonnejad, Z and Tavalaee, M and Izadi, T and Tanhaei, S and Nasr-Esfahani, MH},
title = {Evaluation of sperm telomere length in infertile men with failed/low fertilization after intracytoplasmic sperm injection.},
journal = {Reproductive biomedicine online},
volume = {38},
number = {4},
pages = {579-587},
doi = {10.1016/j.rbmo.2018.12.022},
pmid = {30777668},
issn = {1472-6491},
mesh = {Adult ; Boron Compounds ; Cell Nucleus/metabolism ; Chromatin/metabolism ; DNA Damage ; DNA Fragmentation ; Fertilization ; Humans ; Infertility, Male/*diagnosis/*therapy ; Leukocytes/cytology ; Lipid Peroxidation ; Male ; Oocytes/metabolism ; Oxidative Stress ; Protamines/metabolism ; *Sperm Injections, Intracytoplasmic ; Spermatozoa/*pathology ; Telomere/pathology ; *Telomere Shortening ; },
abstract = {RESEARCH QUESTION: Telomeres are non-coding, repetitive DNA sequences (TTAGGG repeats) that play an important role in maintaining genome integrity. Unlike in somatic cells, telomere length in spermatozoa increases with male age and is considered as a molecular marker of sperm quality. The aetiology of failed fertilization following intracytoplasmic sperm injection (ICSI) is multifactorial; perhaps one of the reasons for this failure in these individuals is shortened sperm telomere length. This study therefore aimed to assess sperm telomere length in addition to DNA damage, lipid peroxidation and protamine deficiency in infertile men with previously failed/low fertilization post-ICSI.<br><br>DESIGN: Semen samples were obtained from infertile men with previous failed/low fertilization rates (n&#x202f;=&#x202f;10). Chromatin integrity (chromomycin A3 staining and TUNEL assay), lipid peroxidation (BODIPY probe) and telomere length (real-time PCR) for semen samples from these men were compared with samples obtained from fertile individuals (n&#xa0;=&#xa0;10).<br><br>RESULTS: The results showed significantly higher mean values for sperm DNA damage, lipid peroxidation and reduced telomere length in spermatozoa of infertile men with previous failed/low fertilization compared with fertile individuals (P&#xa0;<&#xa0;0.05).<br><br>CONCLUSIONS: Failed/low fertilization rates could be related to oxidative stress resulting in short telomere length, and also increased sperm chromatin damage and lipid peroxidation. From literature sources, shortened telomere length may lead to detachment of chromosomes from the nuclear membrane, the consequences of which are defects in the process of spermatogenesis, pronuclei formation, and delayed or arrested cell cycle post-ICSI.},
}
@article {pmid30776705,
year = {2019},
author = {Çevik, B and Mançe-Çalışır, &#xd6; and Atbaşoğlu, EC and Saka, MC and Alptekin, K and Üçok, A and Sırmatel, B and Gülöksüz, S and Tükün, A and van Os, J and Gümüş-Akay, G},
title = {Psychometric liability to psychosis and childhood adversities are associated with shorter telomere length: A study on schizophrenia patients, unaffected siblings, and non-clinical controls.},
journal = {Journal of psychiatric research},
volume = {111},
number = {},
pages = {169-185},
doi = {10.1016/j.jpsychires.2019.01.022},
pmid = {30776705},
issn = {1879-1379},
mesh = {Adolescent ; Adult ; *Adverse Childhood Experiences ; *Disease Susceptibility ; Female ; Gene-Environment Interaction ; Humans ; Loneliness/*psychology ; Male ; Middle Aged ; Psychological Trauma/*psychology ; Psychometrics ; Psychotic Disorders/*genetics/*psychology ; Resilience, Psychological ; Schizophrenia/*genetics ; Siblings ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {Compared to the general population, individuals diagnosed with Schizophrenia (SCZ) experience a higher frequency and an earlier onset of chronic medical disorders, resulting in a reduction in life expectancy by an average of 15-25 years. Recently, it has been hypothesized that SCZ is a syndrome of accelerated aging. Childhood adversity was also associated with the pathogenesis and course of SCZ. Our hypothesis was that both SCZ patients and their unaffected siblings would have shorter telomere length (TL) compared to of non-clinical controls. Our additional goals were to determine (1) whether shorter TL correlates with intermediate phenotypes of SCZ (i.e. Psychosis-like symptoms and schizotypal traits); and (2) whether childhood adversities have a moderating role in TL shortening among SCZ and their unaffected siblings. To this end, SCZ patients (n = 100), their unaffected siblings (n = 100) and non-clinical controls (n = 100) were enrolled. The main variables were TL, measured by aTL-qPCR; psychotic-like and schizotypal symptoms, assessed by The Community Assessment of Psychic Experience (CAPE) and the Structured Interview for Schizotypy-Revised (SIS-R), respectively; and childhood adversities evaluated by the Childhood Experience of Care and Abuse (CECA)-Interview. Potentially relevant variables also included in the analyses were: Global Assessment of Functioning (GAF) scores, cognitive performance, and socio-demographic features. In contrast to our hypothesis patients had similar TL when compared to the non-clinical controls. Interestingly, unaffected siblings had longer TL compared to both patients and controls (p < 0.001). Independent from group status a negative correlation was observed between TL and psychotic-like symptoms as rated by the CAPE (p < 0.01). Childhood adversities, especially loneliness between ages 0 and 11 were also negatively associated with TL (p < 0.05). Our findings suggest that psychometric liability to psychosis and childhood adversities may be associated with shorter TL. Unaffected siblings had longer TL, suggesting the potential role of resilience on both the TL and the clinical presentation. These findings must be considered preliminary, calling for larger-scale replication efforts.},
}
@article {pmid30776454,
year = {2019},
author = {Smith, L and Luchini, C and Demurtas, J and Soysal, P and Stubbs, B and Hamer, M and Nottegar, A and Lawlor, RT and Lopez-Sanchez, GF and Firth, J and Koyanagi, A and Roberts, J and Willeit, P and Waldhoer, T and Loosemore, M and Abbs, AD and Johnstone, J and Yang, L and Veronese, N},
title = {Telomere length and health outcomes: An umbrella review of systematic reviews and meta-analyses of observational studies.},
journal = {Ageing research reviews},
volume = {51},
number = {},
pages = {1-10},
doi = {10.1016/j.arr.2019.02.003},
pmid = {30776454},
issn = {1872-9649},
support = {ICA-CL-2017-03-001/DH_/Department of Health/United Kingdom ; },
mesh = {Alzheimer Disease/epidemiology/*genetics ; Case-Control Studies ; Diabetes Mellitus/epidemiology/*genetics ; Humans ; Incidence ; Observational Studies as Topic/*methods ; Stomach Neoplasms/epidemiology/*genetics ; Telomere/*physiology ; Treatment Outcome ; },
abstract = {The aim of the present study was to map and grade evidence for the relationships between telomere length with a diverse range of health outcomes, using an umbrella review of systematic reviews with meta-analyses. We searched for meta-analyses of observational studies reporting on the association of telomere length with any health outcome (clinical disease outcomes and intermediate traits). For each association, random-effects summary effect size, 95% confidence interval (CI), and 95% prediction interval were calculated. To evaluate the credibility of the identified evidence, we assessed also heterogeneity, evidence for small-study effect and evidence for excess significance bias. Twenty-one relevant meta-analyses were identified reporting on 50 different outcomes. The level of evidence was high only for the association of short telomeres with higher risk of gastric cancer in the general population (relative risk, RR = 1.95, 95%CI: 1.68-2.26), and moderate for the association of shorter telomeres with diabetes or with Alzheimer's disease, even if limited to meta-analyses of case-control studies. There was weak evidence for twenty outcomes and not significant association for 27 health outcomes. The present umbrella review demonstrates that shorter telomere length may have an important role in incidence gastric cancer and, probably, diabetes and Alzheimer's disease. At the same time, conversely to general assumptions, it does not find strong evidence supporting the notion that shorter telomere length plays an important role in many health outcomes that have been studied thus far.},
}
@article {pmid30773064,
year = {2020},
author = {Weeg, N and Hershko Klement, A and Haikin, E and Amiel, A and Shulman, A and Biron-Shental, T and Wiser, A},
title = {The effect of maternal body mass index (BMI) and telomere function on in vitro fertilization (IVF) outcome: a preliminary cohort study.},
journal = {Human fertility (Cambridge, England)},
volume = {23},
number = {4},
pages = {282-288},
doi = {10.1080/14647273.2019.1575988},
pmid = {30773064},
issn = {1742-8149},
mesh = {Adult ; *Body Mass Index ; Case-Control Studies ; Cohort Studies ; Female ; Fertilization in Vitro/*statistics &amp; numerical data ; Humans ; Pregnancy ; *Telomere Homeostasis ; Young Adult ; },
abstract = {Telomeres are a specific base sequence of DNA, responsible for chromosome stability and DNA protection. We aimed to investigate the association between telomere systems and IVF outcomes according to patients' BMI. For all telomere characteristics, there was a distinct trend towards shorter telomeres and activation of telomere shortening compensatory mechanisms in the BMI group >25[ ]kg/m[2], reaching statistical significance for senescence only (r = 0.7, p value <0.01). There was a trend towards a relationship between telomere length and number of oocytes between telomere length and fertilization rate, but these did not reach a statistical significance. For pregnancy outcome, all telomere characteristics were better for the patients who achieved a pregnancy. While there is paucity of data in the literature concerning the association between telomere characteristics and infertility, telomeres might contribute to the association between obesity and sub-optimal IVF results.},
}
@article {pmid30770342,
year = {2019},
author = {Brand, T},
title = {Length doesn't matter-telomere damage triggers cellular senescence in the ageing heart.},
journal = {The EMBO journal},
volume = {38},
number = {5},
pages = {},
pmid = {30770342},
issn = {1460-2075},
mesh = {Cellular Senescence ; Myocytes, Cardiac ; *Telomerase ; *Telomere ; },
abstract = {Telomere shortening induces cellular senescence in proliferative cells. Yet, it is presently unclear how it is triggered in post‐mitotic cells such as cardiac myocytes. A new study by Anderson et al (2019) reports that during ageing of the heart, cellular senescence develops independently of telomere length, but is evoked by DNA damage, which preferentially accumulates at the telomere. Removal of senescent cells using senolytic drugs ameliorated cardiac hypertrophy and fibrosis and may inform novel approaches to improve the conditions for the ageing heart.},
}
@article {pmid30769869,
year = {2019},
author = {Cao, W and Li, X and Zhang, X and Zhang, J and Sun, Q and Xu, X and Sun, M and Tian, Q and Li, Q and Wang, H and Liu, J and Meng, X and Wu, L and Song, M and Hou, H and Wang, Y and Wang, W},
title = {No Causal Effect of Telomere Length on Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study.},
journal = {Cells},
volume = {8},
number = {2},
pages = {},
pmid = {30769869},
issn = {2073-4409},
mesh = {Brain Ischemia/*complications/*genetics ; Genome-Wide Association Study ; Humans ; *Mendelian Randomization Analysis ; Odds Ratio ; Polymorphism, Single Nucleotide/genetics ; Stroke/*complications/*genetics ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Epidemiological studies observing inconsistent associations of telomere length (TL) with ischemic stroke (IS) are susceptible to bias according to reverse causation and residual confounding. We aimed to assess the causal association between TL, IS, and the subtypes of IS, including large artery stroke (LAS), small vessel stroke (SVS), and cardioembolic stroke (CES) by performing a series of two-sample Mendelian randomization (MR) approaches.<br><br>METHODS: Seven single nucleotide polymorphisms (SNPs) were involved as candidate instrumental variables (IVs), summarized from a genome-wide meta-analysis including 37,684 participants of European descent. We analyzed the largest ever genome-wide association studies of stroke in Europe from the MEGASTROKE collaboration with 40,585 stroke cases and 406,111 controls. The weighted median (WM), the penalized weighted median (PWM), the inverse variance weighted (IVW), the penalized inverse variance weighted (PIVW), the robust inverse variance weighted (RIVW), and the Mendelian randomization-Egger (MR-Egger) methods were conducted for the MR analysis to estimate a causal effect and detect the directional pleiotropy.<br><br>RESULTS: No significant association between genetically determined TL with overall IS, LAS, or CES were found (all p > 0.05). SVS was associated with TL by the RIVW method (odds ratio (OR) = 0.72, 95% confidence interval (CI): 0.54&#x207b;0.97, p = 0.028), after excluding rs9420907, rs10936599, and rs2736100.<br><br>CONCLUSIONS: By a series of causal inference approaches using SNPs as IVs, no strong evidence to support the causal effect of shorter TL on IS and its subtypes were found.},
}
@article {pmid30765145,
year = {2019},
author = {Lustig, AJ},
title = {Towards the Mechanism of Yeast Telomere Dynamics.},
journal = {Trends in cell biology},
volume = {29},
number = {5},
pages = {361-370},
pmid = {30765145},
issn = {1879-3088},
support = {R01 GM069943/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; Saccharomyces cerevisiae/*cytology/*genetics ; Telomere/genetics/*metabolism ; },
abstract = {A mechanistic understanding of the yeast telomere requires an integrated understanding of telomere chromatin structure (telosomes), telomeric origins of replications, telomere length homeostasis, and telosome epigenetics. Recent molecular and genetic studies of the yeast telosomal components Rap1, Rif1, and Rif2, the Mre11 complex, and Tel1[ATM] promise to increase our insight into the coordination between these processes. Here, an intricate relationship is proposed between these multiple components that has resulted in increased appreciation of the multiple levels of telomere length control and their differentiation from double-strand repair. The mre11A470 motif (A470-A482) alleles have also opened new avenues to the exploration of telosome structure and function.},
}
@article {pmid30763310,
year = {2019},
author = {Eisenberg, DTA},
title = {Paternal age at conception effects on offspring telomere length across species-What explains the variability?.},
journal = {PLoS genetics},
volume = {15},
number = {2},
pages = {e1007946},
pmid = {30763310},
issn = {1553-7404},
mesh = {Animals ; *Birds ; Epigenomics ; Fertilization ; Paternal Age ; Telomere ; },
}
@article {pmid30763308,
year = {2019},
author = {Bauch, C and Boonekamp, JJ and Korsten, P and Mulder, E and Verhulst, S},
title = {Epigenetic inheritance of telomere length in wild birds.},
journal = {PLoS genetics},
volume = {15},
number = {2},
pages = {e1007827},
pmid = {30763308},
issn = {1553-7404},
mesh = {Animals ; Animals, Wild/*genetics ; Birds/*genetics ; Cross-Sectional Studies ; Epigenesis, Genetic/*genetics ; Epigenomics/methods ; Fathers ; Female ; Heredity/*genetics ; Male ; Paternal Age ; Reproduction/genetics ; Spermatozoa/physiology ; Telomere/*genetics ; },
abstract = {Telomere length (TL) predicts health and survival across taxa. Variation in TL between individuals is thought to be largely of genetic origin, but telomere inheritance is unusual, because zygotes already express a TL phenotype, the TL of the parental gametes. Offspring TL changes with paternal age in many species including humans, presumably through age-related TL changes in sperm, suggesting an epigenetic inheritance mechanism. However, present evidence is based on cross-sectional analyses, and age at reproduction is confounded with between-father variation in TL. Furthermore, the quantitative importance of epigenetic TL inheritance is unknown. Using longitudinal data of free-living jackdaws Corvus monedula, we show that erythrocyte TL of subsequent offspring decreases with parental age within individual fathers, but not mothers. By cross-fostering eggs, we confirmed the paternal age effect to be independent of paternal age dependent care. Epigenetic inheritance accounted for a minimum of 34% of the variance in offspring TL that was explained by paternal TL. This is a minimum estimate, because it ignores the epigenetic component in paternal TL variation and sperm TL heterogeneity within ejaculates. Our results indicate an important epigenetic component in the heritability of TL with potential consequences for offspring fitness prospects.},
}
@article {pmid30762812,
year = {2019},
author = {Xiao, J and Yuan, Q and Zhang, S and Li, X and Bai, H and Wang, Y and Duan, S},
title = {The telomere length of peripheral blood cells is associated with the risk of ischemic stroke in Han population of northern China.},
journal = {Medicine},
volume = {98},
number = {7},
pages = {e14593},
pmid = {30762812},
issn = {1536-5964},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Asian People/*genetics ; Biomarkers ; China/epidemiology ; Female ; Homocysteine/metabolism ; Humans ; Male ; Middle Aged ; ROC Curve ; Real-Time Polymerase Chain Reaction ; Risk Factors ; Stroke/ethnology/*genetics ; *Telomere ; },
abstract = {BACKGROUND: Telomere length is closely related to the onset and prognosis of ischemic stroke. This study was to investigate the relationship between telomere length and the incidence of ischemic stroke in Han population of northern China.<br><br>METHODS: In the present study, 152 patients with ischemic stroke were selected as the case group, and 152 healthy persons were used as the control group. Detection of telomere length was done by real-time polymerase chain reaction after extraction of genomic DNA from peripheral venous blood.<br><br>RESULTS: Our results showed that the telomere length of the patients in the case group was significantly lower than that of the control group (Z&#x200a;=&#x200a;-11.843, P&#x200a;<&#x200a;.0001). Further analysis found that the telomere length of the control group was inversely correlated with age (r&#x200a;=&#x200a;-0.234, P&#x200a;=&#x200a;.004), and the telomere length and homocysteine (HCY) were inversely correlated in the case group (r&#x200a;=&#x200a;-0.176, P&#x200a;=&#x200a;.03), especially in women (r&#x200a;=&#x200a;-0.357, P&#x200a;=&#x200a;.024). Multivariate regression analysis showed that telomere length was a protective factor for ischemic stroke (odds ratio [OR] 95% confidence interval [95% CI]&#x200a;=&#x200a;0.748 [0.681-0.823], &#x3b2;&#x200a;=&#x200a;-0.29, P&#x200a;<&#x200a;.0001). The receiver operating characteristic curve showed that telomere length was a good diagnostic biomarker of ischemic stroke (area under the curve: 0.894, sensitivity: 84.7%, specificity: 93.4%).<br><br>CONCLUSION: Our results indicate that shorter telomere length has some connection with the risk of ischemic stroke in the northern Chinese Han population. Telomere length might serve as a potential candidate biomarker for ischemic stroke. This requires a large sample to be further verified.},
}
@article {pmid30762424,
year = {2019},
author = {Ye, Y and Yang, Z and Lei, J},
title = {Stochastic Telomere Shortening and the Route to Limitless Replicative Potential.},
journal = {Journal of computational biology : a journal of computational molecular cell biology},
volume = {26},
number = {4},
pages = {350-363},
doi = {10.1089/cmb.2018.0234},
pmid = {30762424},
issn = {1557-8666},
mesh = {Cell Proliferation ; Cells, Cultured ; Computational Biology/*methods ; DNA Replication ; Humans ; Stem Cells/*cytology ; Stochastic Processes ; Telomere/*physiology ; Telomere Shortening ; },
abstract = {In human tissues, the replicative potential of stem cells is limited by the shortening of telomere, limitless replicative potential is a hallmark of cancer. Telomere length changes stochastically during cell division mainly due to the competition between the end replication problem and telomerase, short telomere can lead to replicative senescence and cell apoptosis. Here, we investigate how stochastic changes of telomere length in individual cells may affect the population dynamics of clonal growth. We established a computational model that couples telomerase-regulated stochastic telomere length changes with the replicative potential of clones. Model simulations reveal qualitative dependence of clone proliferation potential with activities of telomerase; mutations in cells to alter the activities of telomerase and its inhibitors can induce abnormal tissue growth and lead to limitless replicative potential.},
}
@article {pmid30761946,
year = {2019},
author = {Wu, Q and Han, D and Zhang, J and Li, X},
title = {Expression of telomere repeat binding factor 1 and TRF2 in Alzheimer's disease and correlation with clinical parameters.},
journal = {Neurological research},
volume = {41},
number = {6},
pages = {504-509},
doi = {10.1080/01616412.2019.1580456},
pmid = {30761946},
issn = {1743-1328},
mesh = {Alzheimer Disease/*blood/*pathology/therapy ; Female ; Humans ; Male ; RNA, Messenger/metabolism ; Shelterin Complex ; Telomere-Binding Proteins/*blood ; Telomeric Repeat Binding Protein 2/*blood ; Treatment Outcome ; },
abstract = {OBJECTIVE: The objective of this study was to investigate the expression of serum telomere repeat binding factor 1 (TRF1) and TRF2 in patients with Alzheimer's disease (AD) and their correlation with clinicopathological features.<br><br>METHODS: Fifty AD subjects and 50 healthy controls were enrolled in this study. Enzyme-linked immunosorbent assay (ELISA) was used to determine the expression of TRF1 and TRF2 in the peripheral blood plasma. Correlation analysis was used to evaluate the correlation between the protein expression and AD clinical parameters.<br><br>RESULTS: The expression of TRF1 in peripheral blood serum of AD patients was significantly higher than that of the control group (t =&#xa0;5.533, P <&#xa0;0.01) and TRF2 was lower than the control group (t =&#xa0;2.627, P =&#xa0;0.010). The expression of TRF1 was positively correlated with the history of coronary heart disease (Spearman's r =&#xa0;0.298&#xff0c;P =&#xa0;0.035). The expression of TRF1 and TRF2 was positively correlated with age (Pearson's r1&#xa0;=&#xa0;0.830&#xff0c;P1&#xa0;<&#xa0;0.01&#xff1b;Pearson's r2&#xa0;=&#xa0;0.942&#xff0c;P2&#xa0;<&#xa0;0.01), BMI (Pearson's r1&#xa0;=&#xa0;0.791&#xff0c;P1&#xa0;<&#xa0;0.01&#xff1b;Pearson's r2&#xa0;=&#xa0;0.941&#xff0c;P2&#xa0;<&#xa0;0.01), A&#x3b2;42 (Pearson's r1&#xa0;=&#xa0;0.765&#xff0c;P1&#xa0;<&#xa0;0.01&#xff1b;Pearson's r2&#xa0;=&#xa0;0.926&#xff0c;P2&#xa0;<&#xa0;0.01) and Tau protein (Pearson's r1&#xa0;=&#xa0;0.648&#xff0c;P1&#xa0;<&#xa0;0.01&#xff1b;Pearson's r2&#xa0;=&#xa0;0.691&#xff0c;P2&#xa0;<&#xa0;0.01) in blood serum of AD patients. However, there was no significant difference between both proteins expression and the history of hypertension, diabetes or stroke.<br><br>CONCLUSION: TRF1 and TRF2 may be both specific to peripheral blood serum of AD, and may be related to the development of AD.},
}
@article {pmid30760854,
year = {2019},
author = {Shay, JW and Wright, WE},
title = {Telomeres and telomerase: three decades of progress.},
journal = {Nature reviews. Genetics},
volume = {20},
number = {5},
pages = {299-309},
pmid = {30760854},
issn = {1471-0064},
mesh = {Abnormalities, Multiple/genetics/metabolism/pathology ; Aging/*genetics/metabolism ; Animals ; Cell Cycle Proteins/genetics/metabolism ; DNA/chemistry/genetics/metabolism ; Gene Expression Regulation ; Genomics/*history/methods ; History, 20th Century ; History, 21st Century ; Humans ; Molecular Chaperones ; Neoplasms/*genetics/metabolism/pathology ; Nuclear Proteins/genetics/metabolism ; Progeria/genetics/metabolism/pathology ; Ribonucleoproteins, Small Nuclear/genetics/metabolism ; Ribonucleoproteins, Small Nucleolar/genetics/metabolism ; Shelterin Complex ; Telomerase/*genetics/metabolism ; Telomere/*chemistry/metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Many recent advances have emerged in the telomere and telomerase fields. This Timeline article highlights the key advances that have expanded our views on the mechanistic underpinnings of telomeres and telomerase and their roles in ageing and disease. Three decades ago, the classic view was that telomeres protected the natural ends of linear chromosomes and that telomerase was a specific telomere-terminal transferase necessary for the replication of chromosome ends in single-celled organisms. While this concept is still correct, many diverse fields associated with telomeres and telomerase have substantially matured. These areas include the discovery of most of the key molecular components of telomerase, implications for limits to cellular replication, identification and characterization of human genetic disorders that result in premature telomere shortening, the concept that inhibiting telomerase might be a successful therapeutic strategy and roles for telomeres in regulating gene expression. We discuss progress in these areas and conclude with challenges and unanswered questions in the field.},
}
@article {pmid30760804,
year = {2019},
author = {Antonini, JM and Kodali, V and Meighan, TG and Roach, KA and Roberts, JR and Salmen, R and Boyce, GR and Zeidler-Erdely, PC and Kashon, M and Erdely, A and Shoeb, M},
title = {Effect of Age, High-Fat Diet, and Rat Strain on Serum Biomarkers and Telomere Length and Global DNA Methylation in Peripheral Blood Mononuclear Cells.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {1996},
pmid = {30760804},
issn = {2045-2322},
mesh = {Age Factors ; Animals ; Biomarkers/blood ; DNA Methylation/*genetics ; Diet, High-Fat ; Environmental Exposure/*adverse effects ; Leukocytes, Mononuclear/*physiology ; Male ; Models, Animal ; Rats ; Rats, Inbred BN ; Rats, Inbred F344 ; Rats, Sprague-Dawley ; Telomere/physiology ; Telomere Homeostasis/*physiology ; Triglycerides/blood ; Weight Gain ; },
abstract = {The objective of the current study was to determine if age, diet, and genetic disposition (animal strain) in an animal model had early effects on specific molecular markers in circulating peripheral blood mononuclear cells (PBMCs). Three strains [Sprague-Dawley (SD), Fischer 344 (F344), and Brown-Norway (BN)] of male rats were maintained on a high-fat (HF) or regular diet. Blood was collected at 4, 12, and 24 wk to assess chemistry and to recover PBMCs. Triglycerides and body weight gain increased at all time points in the HF diet group for each strain. Telomere length in PBMCs decreased in the HF diet group compared to the regular diet group up to 24 wk in all strains. Telomere length decreased in PBMCs at 24 wk compared to baseline in all strains, indicating an age-related effect. These findings highlight that diet and age cause changes in PBMCs recovered from different strains of rats. The next tier of studies will examine the contribution of an occupational exposure (e.g., welding fume inhalation) in combination with diet, age, and strain, to assess changes in the molecular responses of isolated PBMCs. In addition, studies involving lifestyle exposure (e.g., tobacco smoke) are in the planning stages and will assess the long-term effects of exposure in our animal model.},
}
@article {pmid30747731,
year = {2019},
author = {Zhan, Y and Hägg, S},
title = {Telomere length and cardiovascular disease risk.},
journal = {Current opinion in cardiology},
volume = {34},
number = {3},
pages = {270-274},
doi = {10.1097/HCO.0000000000000613},
pmid = {30747731},
issn = {1531-7080},
mesh = {Aging ; Biomarkers ; *Cardiovascular Diseases/genetics ; Humans ; Risk Factors ; *Telomere ; *Telomere Shortening ; },
abstract = {PURPOSE OF REVIEW: Telomere length has been hypothesized as a putative biomarker for cardiovascular disease. However, the findings are mixed and shared confounding factors may explain these associations. The current review aims to summarize the recent literature on the role of telomere length in cardiovascular disease and give directions for future potential as a predictive biomarker.<br><br>RECENT FINDINGS: In this review, we outline the biology of telomeres as a biomarker of aging through its shortening capacity across the life course. Recent epidemiological evidence for its associations with cardiovascular risk factors and disease is discussed. Then we highlight the possible causal role of telomeres in coronary heart disease and summarize the potential biological mechanisms and pathways known.<br><br>SUMMARY: The current research and results presented on telomere length may implicate that short telomeres are causal risk factors for cardiovascular disease, partially through insulin-mediated pathways. Nevertheless, further studies with refined quantification methods and larger populations are needed to clarify the added role of telomere length in predicting future risks of cardiovascular disease on top of existing risk biomarkers, and whether it may be amenable for intervention.},
}
@article {pmid30744200,
year = {2019},
author = {Shishkin, SS and Kovalev, LI and Pashintseva, NV and Kovaleva, MA and Lisitskaya, K},
title = {Heterogeneous Nuclear Ribonucleoproteins Involved in the Functioning of Telomeres in Malignant Cells.},
journal = {International journal of molecular sciences},
volume = {20},
number = {3},
pages = {},
pmid = {30744200},
issn = {1422-0067},
mesh = {Carrier Proteins/metabolism ; Cell Line, Tumor ; Heterogeneous-Nuclear Ribonucleoproteins/genetics/*metabolism ; Humans ; Multigene Family ; Multiprotein Complexes/metabolism ; Neoplasms/*genetics/*metabolism ; Protein Binding ; Telomerase/metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {Heterogeneous nuclear ribonucleoproteins (hnRNPs) are structurally and functionally distinct proteins containing specific domains and motifs that enable the proteins to bind certain nucleotide sequences, particularly those found in human telomeres. In human malignant cells (HMCs), hnRNP-A1-the most studied hnRNP-is an abundant multifunctional protein that interacts with telomeric DNA and affects telomerase function. In addition, it is believed that other hnRNPs in HMCs may also be involved in the maintenance of telomere length. Accordingly, these proteins are considered possible participants in the processes associated with HMC immortalization. In our review, we discuss the results of studies on different hnRNPs that may be crucial to solving molecular oncological problems and relevant to further investigations of these proteins in HMCs.},
}
@article {pmid30741474,
year = {2019},
author = {Jackson-Cook, C},
title = {A hypothesis: Could telomere length and/or epigenetic alterations contribute to infertility in females with Turner syndrome?.},
journal = {American journal of medical genetics. Part C, Seminars in medical genetics},
volume = {181},
number = {1},
pages = {108-116},
doi = {10.1002/ajmg.c.31684},
pmid = {30741474},
issn = {1552-4876},
support = {UL1 TR000371/TR/NCATS NIH HHS/United States ; },
mesh = {Animals ; Epigenomics ; Female ; Humans ; Infertility, Female/*etiology/genetics ; Primary Ovarian Insufficiency/*etiology ; Telomere/ultrastructure ; Turner Syndrome/*complications ; },
abstract = {One of the traits most consistently seen in females with Turner syndrome is premature ovarian insufficiency (POI). The biological mechanisms underlying the germ cell atresia that leads to infertility in most women with Turner syndrome are unclear. Given that telomeres are important for proper chromosomal pairing and other early steps in meiosis and oogenesis, one can conjecture that perturbations in telomere length and/or function might contribute to the POI associated with Turner syndrome. Also, one can speculate that epigenetic modifications that arise in response to asynapsis, as well as the resetting of the epigenome during embryogenesis, could contribute to monosomy X-related germ cell atresia. Moreover, errors in recombination-based DNA repair might contribute to the failure of cells lacking all, or a portion of, a second sex chromosome to successfully complete oogenesis. This article presents a review of the extant literature related to telomere length and/or epigenetic patterns associated with POI in females with a monosomy X complement (in humans and animal models). A goal of this review is to inspire researchers to use new technological advances to better characterize the components of the biological cascade leading to early germ cell loss in females with Turner syndrome.},
}
@article {pmid30738962,
year = {2019},
author = {Slykerman, RF and Joglekar, MV and Hardikar, AA and Satoor, SN and Thompson, JMD and Jenkins, A and Mitchell, EA and Murphy, R},
title = {Maternal stress during pregnancy and small for gestational age birthweight are not associated with telomere length at 11 years of age.},
journal = {Gene},
volume = {694},
number = {},
pages = {97-101},
doi = {10.1016/j.gene.2019.01.017},
pmid = {30738962},
issn = {1879-0038},
mesh = {Adult ; Birth Weight/*genetics/physiology ; Body Mass Index ; Child ; Female ; Gestational Age ; Humans ; Infant, Newborn ; Infant, Small for Gestational Age/metabolism ; Leukocytes ; Male ; Maternal Inheritance/genetics ; Pregnancy ; Prenatal Exposure Delayed Effects/genetics ; Stress, Psychological/*genetics/metabolism ; Telomere/genetics ; Telomere Homeostasis/*genetics ; Telomere Shortening/genetics ; },
abstract = {BACKGROUND: Previous studies indicate that low birth weight and exposure to maternal stress during pregnancy may result in shortened telomeres in infants. Shorter telomere length has in turn been linked with accelerated ageing and with age-related diseases. This study aimed to investigate the association between pregnancy and birth factors and relative telomere length in offspring at 11 years of age.<br><br>METHODS: Participants were aged 11&#x202f;years enrolled in the Auckland Birthweight Collaborative Study at birth (n&#x202f;=&#x202f;380). Half of the children were born small for gestational age (SGA&#x202f;=&#x202f;birthweight&#x202f;&#x2264;&#x202f;10th percentile) and half were appropriate for gestational age (AGA&#x202f;=&#x202f;birthweight&#x202f;>&#x202f;10th percentile). Maternal stress during pregnancy was assessed using the Perceived Stress Scale. Relative leukocyte telomere length (RTL) in leukocytes was measured at 11&#x202f;years of age using quantitative real-time PCR.<br><br>RESULTS: RTL was normally distributed (mean&#x202f;=&#x202f;3.78, SD&#x202f;=&#x202f;1.05). There were no significant associations between RTL at age 11&#x202f;years and birthweight, sex, maternal smoking, maternal stress during pregnancy or maternal pre-pregnancy body mass index.<br><br>CONCLUSION: At age 11&#x202f;years, RTL did not differ between children by birthweight or pregnancy-related stressors. Further telomere-related studies in newborns, children and adolescents are merited to increase knowledge of potential telomere modulating factors.},
}
@article {pmid30737273,
year = {2019},
author = {Fali, T and Papagno, L and Bayard, C and Mouloud, Y and Boddaert, J and Sauce, D and Appay, V},
title = {New Insights into Lymphocyte Differentiation and Aging from Telomere Length and Telomerase Activity Measurements.},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {202},
number = {7},
pages = {1962-1969},
doi = {10.4049/jimmunol.1801475},
pmid = {30737273},
issn = {1550-6606},
mesh = {Adult ; Aged ; Aging/*immunology/metabolism ; Cell Differentiation/immunology ; Humans ; Lymphocyte Subsets/cytology/*immunology/metabolism ; Middle Aged ; Telomerase/*immunology/metabolism ; Telomere/*immunology/metabolism/pathology ; Young Adult ; },
abstract = {αβ CD8[+], γδ, and NK lymphocytes are fundamental effector cells against viruses and tumors. These cells can be divided into multiple subsets according to their phenotype. Based on progressive telomere attrition from naive to late effector memory cells, human CD8[+] T cell subsets have been positioned along a pathway of differentiation, which is also considered as a process of lymphocyte aging or senescence. A similar categorization has not been clearly established for γδ and NK cell populations. Moreover, the distinction between the aging of these populations due to cellular differentiation or due to the chronological age of the donor has not been formally considered. In this study, we performed systematic measurements of telomere length and telomerase activity in human αβ CD8[+], γδ, and NK lymphocytes based on subset division and across age to address these points and better understand the dichotomy between differentiation and temporal aging. This approach enables us to position phenotypically distinct γδ or NK subsets along a putative pathway of differentiation, such as for CD8[+] T cells. Moreover, our data show that both cellular differentiation and donor aging have profound but independent effects on telomere length and telomerase activity of lymphocyte subpopulations, implying distinct mechanisms and consequences on the immune system.},
}
@article {pmid30737259,
year = {2019},
author = {Anderson, R and Lagnado, A and Maggiorani, D and Walaszczyk, A and Dookun, E and Chapman, J and Birch, J and Salmonowicz, H and Ogrodnik, M and Jurk, D and Proctor, C and Correia-Melo, C and Victorelli, S and Fielder, E and Berlinguer-Palmini, R and Owens, A and Greaves, LC and Kolsky, KL and Parini, A and Douin-Echinard, V and LeBrasseur, NK and Arthur, HM and Tual-Chalot, S and Schafer, MJ and Roos, CM and Miller, JD and Robertson, N and Mann, J and Adams, PD and Tchkonia, T and Kirkland, JL and Mialet-Perez, J and Richardson, GD and Passos, JF},
title = {Length-independent telomere damage drives post-mitotic cardiomyocyte senescence.},
journal = {The EMBO journal},
volume = {38},
number = {5},
pages = {},
pmid = {30737259},
issn = {1460-2075},
support = {PG/14/86/31177/BHF_/British Heart Foundation/United Kingdom ; R01 HL141819/HL/NHLBI NIH HHS/United States ; R37 AG013925/AG/NIA NIH HHS/United States ; MR/L016354/1/MRC_/Medical Research Council/United Kingdom ; P01 AG031862/AG/NIA NIH HHS/United States ; PG/15/85/31744/BHF_/British Heart Foundation/United Kingdom ; R01 AG013925/AG/NIA NIH HHS/United States ; PG/19/15/34269/BHF_/British Heart Foundation/United Kingdom ; G0700718/MRC_/Medical Research Council/United Kingdom ; BB/H022384/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Aging ; Animals ; Cardiomegaly/etiology/*pathology ; *Cellular Senescence ; *DNA Damage ; Female ; Fibrosis/etiology/*pathology ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; *Mitosis ; Monoamine Oxidase/physiology ; Myocytes, Cardiac/metabolism/*pathology ; Phenotype ; RNA/physiology ; Rats, Sprague-Dawley ; Telomerase/physiology ; *Telomere Shortening ; },
abstract = {Ageing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age-related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent-like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction and crucially can occur independently of cell division and telomere length. Length-independent telomere damage in cardiomyocytes activates the classical senescence-inducing pathways, p21[CIP] and p16[INK4a], and results in a non-canonical senescence-associated secretory phenotype, which is pro-fibrotic and pro-hypertrophic. Pharmacological or genetic clearance of senescent cells in mice alleviates detrimental features of cardiac ageing, including myocardial hypertrophy and fibrosis. Our data describe a mechanism by which senescence can occur and contribute to age-related myocardial dysfunction and in the wider setting to ageing in post-mitotic tissues.},
}
@article {pmid30736276,
year = {2019},
author = {Hwang, IP and Mailliet, P and Hossard, V and Riou, JF and Bugaut, A and Roger, L},
title = {Investigating the Effect of Mono- and Dimeric 360A G-Quadruplex Ligands on Telomere Stability by Single Telomere Length Analysis (STELA).},
journal = {Molecules (Basel, Switzerland)},
volume = {24},
number = {3},
pages = {},
pmid = {30736276},
issn = {1420-3049},
mesh = {Cell Line, Tumor ; Cell Proliferation ; *G-Quadruplexes ; Genomic Instability ; Humans ; *Ligands ; Telomere/*chemistry/*genetics ; *Telomere Homeostasis ; },
abstract = {Telomeres are nucleoprotein structures that cap and protect the natural ends of chromosomes. Telomeric DNA G-rich strands can form G-quadruplex (or G4) structures. Ligands that bind to and stabilize G4 structures can lead to telomere dysfunctions by displacing shelterin proteins and/or by interfering with the replication of telomeres. We previously reported that two pyridine dicarboxamide G4 ligands, 360A and its dimeric analogue (360A)2A, were able to displace in vitro hRPA (a single-stranded DNA-binding protein of the replication machinery) from telomeric DNA by stabilizing the G4 structures. In this paper, we perform for the first time single telomere length analysis (STELA) to investigate the effect of G4 ligands on telomere length and stability. We used the unique ability of STELA to reveal the full spectrum of telomere lengths at a chromosome terminus in cancer cells treated with 360A and (360A)2A. Upon treatment with these ligands, we readily detected an increase of ultrashort telomeres, whose lengths are significantly shorter than the mean telomere length, and that could not have been detected by other methods.},
}
@article {pmid30735724,
year = {2019},
author = {Abrahin, O and Cortinhas-Alves, EA and Vieira, RP and Guerreiro, JF},
title = {Elite athletes have longer telomeres than sedentary subjects: A meta-analysis.},
journal = {Experimental gerontology},
volume = {119},
number = {},
pages = {138-145},
doi = {10.1016/j.exger.2019.01.023},
pmid = {30735724},
issn = {1873-6815},
mesh = {*Athletes ; *Exercise ; Humans ; Sedentary Behavior ; Telomere/*ultrastructure ; },
abstract = {The aim of this meta-analysis was to investigate the effects of high levels of physical activity (in elite athletes) and sedentary lifestyle on telomere length. Our meta-analysis was carried out using the following electronic databases: PubMed, Cochrane Library, LILACS, Science Direct and EBSCO. After study selection, nine articles were included in our meta-analysis. All of the included subjects were elite athletes (with experience in national or international competitions) or sedentary subjects, which served as the control group. The analysis showed that elite athletes (n = 306) had longer telomeres (P = 0.001) compared with the control group (n = 322). The difference in the standardized means was 0.91 (95% CI = 0.43-1.33; I[2] 83.4% P value for heterogeneity = 0.001), favoring the athlete group. The analysis of the funnel plot did not detect any risk of publication bias in the studies that reported differences in means. Our results suggest that high level chronic physical training may provide protective effects on telomere length.},
}
@article {pmid30735171,
year = {2019},
author = {Avogaro, L and Oss Pegorar, C and Bettin, N and Cusanelli, E},
title = {Generation of Cancer Cell Clones to Visualize Telomeric Repeat-containing RNA TERRA Expressed from a Single Telomere in Living Cells.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {143},
pages = {},
doi = {10.3791/58790},
pmid = {30735171},
issn = {1940-087X},
mesh = {Animals ; Cell Line, Tumor ; Cell Survival/drug effects ; Cells, Cultured ; Clone Cells ; Drug Resistance, Microbial/drug effects ; Humans ; Mice ; Neomycin/pharmacology ; RNA/*genetics ; RNA, Long Noncoding/*genetics ; RNA, Messenger/genetics/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres are transcribed, giving rise to telomeric repeat-containing long noncoding RNAs (TERRA), which have been proposed to play important roles in telomere biology, including heterochromatin formation and telomere length homeostasis. Recent findings revealed that TERRA molecules also interact with internal chromosomal regions to regulate gene expression in mouse embryonic stem (ES) cells. In line with this evidence, RNA fluorescence in situ hybridization (RNA-FISH) analyses have shown that only a subset of TERRA transcripts localize at chromosome ends. A better understanding of the dynamics of TERRA molecules will help define their function and mechanisms of action. Here, we describe a method to label and visualize single-telomere TERRA transcripts in cancer cells using the MS2-GFP system. To this aim, we present a protocol to generate stable clones, using the AGS human stomach cancer cell line, containing MS2 sequences integrated at a single subtelomere. Transcription of TERRA from the MS2-tagged telomere results in the expression of MS2-tagged TERRA molecules that are visualized by live-cell fluorescence microscopy upon co-expression of a MS2 RNA-binding protein fused to GFP (MS2-GFP). This approach enables researchers to study the dynamics of single-telomere TERRA molecules in cancer cells, and it can be applied to other cell lines.},
}
@article {pmid30723310,
year = {2019},
author = {Dixit, S and Whooley, MA and Vittinghoff, E and Roberts, JD and Heckbert, SR and Fitzpatrick, AL and Lin, J and Leung, C and Mukamal, KJ and Marcus, GM},
title = {Alcohol consumption and leukocyte telomere length.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {1404},
pmid = {30723310},
issn = {2045-2322},
support = {HHSN268201200036C/HL/NHLBI NIH HHS/United States ; TL1 TR000144/TR/NCATS NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; U01 HL130114/HL/NHLBI NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/drug effects ; Binge Drinking/blood/*metabolism/mortality ; Biomarkers ; Ethanol/*pharmacology ; Female ; Follow-Up Studies ; Humans ; Leukocytes/*metabolism ; Longevity/drug effects ; Longitudinal Studies ; Male ; Middle Aged ; Telomere/*metabolism ; Telomere Shortening/*drug effects ; },
abstract = {The relationship between alcohol consumption and mortality generally exhibits a U-shaped curve. The longevity observed with moderate alcohol consumption may be explained by other confounding factors, and, if such a relationship is present, the mechanism is not well understood. Indeed, the optimal amount of alcohol consumption for health has yet to be determined. Leukocyte telomere length is an emerging quantifiable marker of biological age and health, and a shorter telomere length is a predictor of increased mortality. Because leukocyte telomere length is a quantifiable and objectively measurable biomarker of aging, we sought to identify the amount of alcohol consumption associated with the longest telomere length and least telomere length attrition. Among over 2,000 participants from two distinct cohort studies, we found no pattern of alcohol consumption that was associated with longer telomere length or less telomere length attrition over time. Binge drinking may reduce telomere length. Using telomere length as a marker of age and health, these data fail to demonstrate any benefits of alcohol consumption, even when consumed in moderation.},
}
@article {pmid30722777,
year = {2019},
author = {Zhang, L and Song, L and Liu, B and Wu, M and Wang, L and Zhang, B and Xiong, C and Xia, W and Li, Y and Cao, Z and Wang, Y and Xu, S},
title = {Prenatal cadmium exposure is associated with shorter leukocyte telomere length in Chinese newborns.},
journal = {BMC medicine},
volume = {17},
number = {1},
pages = {27},
pmid = {30722777},
issn = {1741-7015},
mesh = {Adult ; Cadmium/*adverse effects/urine ; China ; Cohort Studies ; Female ; Fetal Blood/drug effects ; Humans ; Infant, Newborn ; Leukocytes/pathology ; Linear Models ; Male ; Mothers ; Pregnancy ; Prenatal Exposure Delayed Effects/blood/*pathology ; Prospective Studies ; Telomere/*drug effects/*pathology ; },
abstract = {BACKGROUND: Newborn telomere length (TL) is considered a potential marker for future disease and lifelong health, but few epidemiological studies have examined the determinants of TL in early life. The study aim was to investigate whether there is an association between prenatal cadmium exposure and relative cord blood TL in Chinese newborns.<br><br>METHODS: Participants were 410 mother-newborn pairs drawn from a prospective birth cohort study conducted in Wuhan, China, between November 2013 and March 2015. Urine samples were collected from pregnant women during their period of institutional delivery. Urinary cadmium concentrations were measured by inductively coupled plasma mass spectrometry. The real-time quantitative polymerase chain reaction detection was used to measure relative TL using genomic DNA isolated from umbilical cord blood leukocytes. Multivariate linear regression models were used to estimate the effect of prenatal urinary cadmium concentration on relative cord blood TL.<br><br>RESULTS: The geometric mean of maternal urinary cadmium concentration was 0.68&#x2009;&#x3bc;g/g creatinine. In the multivariate-adjusted linear regression model, per doubling of maternal urinary cadmium concentration was associated with 6.83% (95% CI -&#x2009;11.44%, -&#x2009;1.97%; P&#x2009;=&#x2009;0.006) shorter relative cord blood TL. Stratified analyses indicated that the inverse association between prenatal urinary cadmium and newborn relative TL was more pronounced among female infants and mothers <&#x2009;29&#x2009;years, while there were no significant effect modification according to infant sex (P for interaction&#x2009;=&#x2009;0.907) and maternal age (P for interaction&#x2009;=&#x2009;0.797).<br><br>CONCLUSIONS: The findings indicated that increased maternal urinary cadmium was associated with shortened relative cord blood TL. The results provide more evidence of the negative effects of environmental cadmium exposure and suggest that accelerated aging or cadmium-related diseases may begin in early life.},
}
@article {pmid30721961,
year = {2019},
author = {Luo, X and Sturgis, EM and Yang, Z and Sun, Y and Wei, P and Liu, Z and Wei, Q and Li, G},
title = {Lymphocyte telomere length predicts clinical outcomes of HPV-positive oropharyngeal cancer patients after definitive radiotherapy.},
journal = {Carcinogenesis},
volume = {40},
number = {6},
pages = {735-741},
pmid = {30721961},
issn = {1460-2180},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; },
mesh = {Alphapapillomavirus/*isolation &amp; purification ; Disease-Free Survival ; Female ; Humans ; Lymphocytes/*ultrastructure ; Male ; Middle Aged ; Oropharyngeal Neoplasms/genetics/*radiotherapy/virology ; Squamous Cell Carcinoma of Head and Neck/genetics/*radiotherapy/virology ; *Telomere ; Treatment Outcome ; Tumor Virus Infections/*radiotherapy/virology ; },
abstract = {Because lymphocyte telomere length (LTL) plays critical roles in the maintenance of genomic stability and integrity, LTL thus may influence the etiology and prognosis of squamous cell carcinoma of the oropharynx (SCCOP). However, given the association between LTL and risk of human papillomavirus (HPV)-associated SCCOP and between LTL and tumor HPV status of SCCOP, we hypothesized that LTL is associated with SCCOP prognosis, particularly in HPV-positive patients after definitive radiotherapy. LTL and tumor HPV type 16 (HPV16) status were determined in 564 incident SCCOP patients before radiotherapy or chemoradiation. Both univariate and multivariable Cox regression analyses were performed to estimate the association between LTL and prognosis. Eighty-five percent patients had HPV16-positive tumors. Patients with shorter telomeres had significantly better overall, disease-specific and disease-free survival than did those with longer telomeres (log-rank P < 0.001). Moreover, patients with shorter telomeres had significantly lower risk of death overall [hazard ratio (HR) = 0.2; 95% confidence interval (CI) = 0.1-0.4], death due to SCCOP (HR = 0.2; 95% CI = 0.1-0.4) and SCCOP recurrence (HR = 0.3; 95% CI = 0.2-0.5) after adjusting for other important prognostic confounders. Finally, we found more pronounced effects of LTL on survival in HPV16-positive SCCOP patients after stratified analysis according to tumor HPV status. These findings indicate that LTL plays a significant role in the survival of patients with SCCOP, especially HPV16-positive patients who undergo definitive radiotherapy. Therefore, pretreatment LTL may be an independent prognostic biomarker for HPV16-positive SCCOP. Prospective studies with larger sample sizes are needed to confirm these findings.},
}
@article {pmid30721442,
year = {2019},
author = {Dickinson, SL and Golzarri-Arroyo, L and Brown, AW and McComb, B and Kahathuduwa, CN and Allison, DB},
title = {Change in study randomization allocation needs to be included in statistical analysis: comment on 'Randomized controlled trial of weight loss versus usual care on telomere length in women with breast cancer: the lifestyle, exercise, and nutrition (LEAN) study'.},
journal = {Breast cancer research and treatment},
volume = {175},
number = {1},
pages = {263-264},
pmid = {30721442},
issn = {1573-7217},
support = {R25DK099080/DK/NIDDK NIH HHS/United States ; U24AG056053//American Federation for Aging Research/International ; R25 DK099080/DK/NIDDK NIH HHS/United States ; R25HL124208/HL/NHLBI NIH HHS/United States ; U24 AG056053/AG/NIA NIH HHS/United States ; P30 AG050886/AG/NIA NIH HHS/United States ; P30AG050886//National Institute on Aging (US)/International ; R25 HL124208/HL/NHLBI NIH HHS/United States ; },
mesh = {*Breast Neoplasms ; Female ; Humans ; Life Style ; Random Allocation ; Telomere ; *Weight Loss ; },
}
@article {pmid30721396,
year = {2019},
author = {Mizuno, Y and Konishi, S and Imai, H and Fujimori, E and Kojima, N and Yoshinaga, J},
title = {Cadmium Exposure and Blood Telomere Length in Female University Students in Japan.},
journal = {Biological trace element research},
volume = {192},
number = {2},
pages = {98-105},
doi = {10.1007/s12011-019-1656-3},
pmid = {30721396},
issn = {1559-0720},
support = {16H05254//Japan Society for the Promotion of Science/ ; 16H05254//Japan Society for the Promotion of Science/ ; },
mesh = {Cadmium/*adverse effects/analysis ; DNA/analysis/*drug effects ; Female ; Humans ; Japan ; Students ; Telomere/*drug effects ; Universities ; Young Adult ; },
abstract = {Cadmium is a toxic metal found ubiquitously throughout the world. Our study evaluated whether cadmium exposure was associated with telomere length in 73 female university students. Determination of telomere length was performed by quantitative polymerase chain reaction using DNA in blood. Urinary cadmium concentration was measured by inductively coupled plasma mass spectrometry. The students' physiological attributes and lifestyle were surveyed by means of a self-administered questionnaire. The geometric mean of urinary cadmium concentration was 0.312 μg/g creatinine, which was lower than the levels previously reported for Japan. Urinary cadmium concentration was not significantly associated with telomere length, though the exposure level of the present subjects was similar to that of previous study subjects which found significantly negative associations. It is possible that other factors affected telomere length in this study population.},
}
@article {pmid30718482,
year = {2019},
author = {Wang, Y and Chen, Y and Chen, J and Wang, L and Nie, L and Long, J and Chang, H and Wu, J and Huang, C and Lei, M},
title = {The meiotic TERB1-TERB2-MAJIN complex tethers telomeres to the nuclear envelope.},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {564},
pmid = {30718482},
issn = {2041-1723},
mesh = {Animals ; Apoptosis Regulatory Proteins/genetics/*metabolism ; Cell Line ; Female ; Humans ; Male ; Meiosis ; Membrane Proteins/genetics/*metabolism ; Mice ; Mice, Knockout ; Nuclear Envelope/*metabolism ; Nuclear Proteins/genetics/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Telomeric Repeat Binding Protein 1 ; },
abstract = {During meiotic prophase I, telomeres attach to and move on the nuclear envelope (NE), regulating chromosome movement to promote homologous pairing. Meiosis-specific proteins TERB1, TERB2 and MAJIN play a key role in this process. Here, we report the crystal structures of human TERB1-TERB2 and TERB2-MAJIN subcomplexes. Specific disruption of the TERB1-TERB2 or the TERB2-MAJIN interaction in the mouse Terb2 gene abolishes the telomere attachment to the NE and causes aberrant homologous pairing and disordered synapsis. In addition, depletion of SUN1 also partially disrupts the telomere-NE connection. We propose that the telomere-TRF1-TERB1-TERB2-MAJIN-NE interaction network and the telomere-LINC complex connection are likely two separate but cooperative pathways to stably recruit telomeres to the NE in meiosis prophase I. Our work provides a molecular model of the connection between telomeres and the NE and reveals the correlation between aberrant synapsis and the defective telomere attachment to the NE.},
}
@article {pmid30717558,
year = {2018},
author = {Cao, DW and Han, WB and He, JS and Zhao, M and Jiang, CM and Zhang, QY and Wan, C and Liu, J and Feng, Y and Jin, B and Yang, B and Zhu, DL and Han, X},
title = {[Tea polyphenols delays human glomerular mesangial cells senescence induced by high glucose via regulating STAT3/miR-126/telomere signaling pathway activation].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {43},
number = {23},
pages = {4678-4684},
doi = {10.19540/j.cnki.cjcmm.20181031.003},
pmid = {30717558},
issn = {1001-5302},
mesh = {Cells, Cultured ; Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p21 ; Glucose ; Humans ; *Mesangial Cells ; MicroRNAs ; Polyphenols ; STAT3 Transcription Factor ; Tea ; Telomere ; Tumor Suppressor Protein p53 ; },
abstract = {The aim of this paper was to explore the effects and possible mechanisms in vitro of tea polyphenols (TP) delaying human glomerular mesangial cells (HGMCs) senescence induced by high glucose (HG). HGMCs were cultured in vitro and divided into the normal group (N, 5.5 mmol·L[-1] glucose), the mannitol group(MNT, 5.5 mmol·L[-1] glucose plus 24.5 mmol·L[-1] mannitol), the high dose of D-glucose group (HG, 30 mmol·L[-1] glucose), the low dose of TP group (L-TP, 30 mmol·L[-1] glucose plus 5 mg·L[-1] TP) and the high dose of TP group (H-TP, 30 mmol·L[-1] glucose plus 20 mg·L[-1] TP), which were cultured in 5% CO2 at 37 °C, respectively. Firstly, the effects of TP on the cell morphology of HGMCs were observed after 72 h-intervention. Secondly, the cell cycle, the positive rate of senescence-associated-β-galactosidase (SA-β-gal) staining and the telomere length were detected, respectively. Finally, the protein expressions of p53, p21 and Rb in the p53-p21-Rb signaling pathway were investigated, respectively. And the expressions of p-STAT3 and miR-126 were examined severally. The results indicated that HG not only arrested the cell cycle in G1 phase but also increased the positive rate of SA-β-gal staining, and shortened the telomere length. HG led to the protein over-expressions of p53, p21 and Rb and HGMCs senescence by activating the p53-p21-Rb signaling pathway. In addition, L-TP delayed HGMCs senescence by improving the cell cycle G1 arrest, reducing SA-β-gal staining positive rate and lengthening the telomere length. L-TP reduced the protein over-expressions of p53, P21 and Rb induced by HG and inhibited the telomere-p53-p21-Rb signaling pathway. Moreover, the expression of p-STAT3 was increased and the expression of miR-126 was decreased in HGMCs induced by HG. L-TP reduced the expression of p-STAT3 and increased the expression of miR-126 in HGMCs. In conclusion, HG could induce HGMCs senescence by activating the telomere-p53-p21-Rb signaling pathway in vitro. L-TP could delay HGMCs senescence through regulating STAT3/miR-126 expressions and inhibiting the telomere-p53-p21-Rb signaling pathway activation. These findings could provide the effective interventions in clinic for preventing and treating renal cell senescence in diabetic kidney disease.},
}
@article {pmid30714852,
year = {2019},
author = {McKenna, MJ and Robinson, E and Taylor, L and Tompkins, C and Cornforth, MN and Simon, SL and Bailey, SM},
title = {Chromosome Translocations, Inversions and Telomere Length for Retrospective Biodosimetry on Exposed U.S. Atomic Veterans.},
journal = {Radiation research},
volume = {191},
number = {4},
pages = {311-322},
pmid = {30714852},
issn = {1938-5404},
support = {Y02 AI005077/AI/NIAID NIH HHS/United States ; Y03 CO5117/CO/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged, 80 and over ; Calibration ; Chromosome Inversion/*radiation effects ; Humans ; Male ; *Nuclear Weapons ; Occupational Exposure/adverse effects/analysis ; Radiometry/*methods ; Retrospective Studies ; Telomere/*genetics ; Translocation, Genetic/*radiation effects ; *Veterans ; },
abstract = {It has now been over 60 years since U.S. nuclear testing was conducted in the Pacific islands and Nevada, exposing military personnel to varying levels of ionizing radiation. Actual doses are not well-established, as film badges in the 1950s had many limitations. We sought a means of independently assessing dose for comparison with historical film badge records and dose reconstruction conducted in parallel. For the purpose of quantitative retrospective biodosimetry, peripheral blood samples from 12 exposed veterans and 12 age-matched (>80 years) veteran controls were collected and evaluated for radiation-induced chromosome damage utilizing directional genomic hybridization (dGH), a cytogenomics-based methodology that facilitates simultaneous detection of translocations and inversions. Standard calibration curves were constructed from six male volunteers in their mid-20s to reflect the age range of the veterans at time of exposure. Doses were estimated for each veteran using translocation and inversion rates independently; however, combining them by a weighted-average generally improved the accuracy of dose estimations. Various confounding factors were also evaluated for potential effects on chromosome aberration frequencies. Perhaps not surprisingly, smoking and age-associated increases in background frequencies of inversions were observed. Telomere length was also measured, and inverse relationships with both age and combined weighted dose estimates were observed. Interestingly, smokers in the non-exposed control veteran cohort displayed similar telomere lengths as those in the never-smoker exposed veteran group, suggesting that chronic smoking had as much effect on telomere length as a single exposure to radioactive fallout. Taken together, we find that our approach of combined chromosome aberration-based retrospective biodosimetry provided reliable dose estimation capability, particularly on a group average basis, for exposures above statistical detection limits.},
}
@article {pmid30711896,
year = {2019},
author = {Chen, X and Zeng, C and Gong, C and Zhang, L and Wan, Y and Tao, F and Sun, Y},
title = {Associations between early life parent-child separation and shortened telomere length and psychopathological outcomes during adolescence.},
journal = {Psychoneuroendocrinology},
volume = {103},
number = {},
pages = {195-202},
doi = {10.1016/j.psyneuen.2019.01.021},
pmid = {30711896},
issn = {1873-3360},
mesh = {Adolescent ; Adverse Childhood Experiences ; Cellular Senescence/genetics ; Child ; Child, Abandoned/*psychology ; China ; Female ; Humans ; Male ; Maternal Deprivation ; Mental Disorders/etiology/genetics ; Mental Health/ethnology/trends ; Parents ; Paternal Deprivation ; Stress, Psychological/*genetics/*psychology ; Surveys and Questionnaires ; Telomere/genetics/metabolism ; Telomere Homeostasis/*genetics ; Telomere Shortening/genetics/physiology ; },
abstract = {BACKGROUND: Given the ethical limitations of exposing children to experimentally manipulated adverse experiences, evidence of the effects of parent-child separation on subsequent psychopathology are based mostly on animal studies. Left-behind children phenomenon resulting from rural-urban mobility in China offers unique "natural experiments" to explore the long-term physical and mental health consequences of parent-child separation in childhood.<br><br>OBJECTIVE: To test the associations between parent-child separation with telomere length (TL) and psychopathology during adolescence.<br><br>METHOD: A total of 710 adolescents (age: M&#x2009;=&#x2009;16.86, SD&#x2009;=&#x2009;1.52) were recruited from local schools in rural area of Fuyang, one of the top inland areas for outward migration in Anhui province, China. Parent-child separation was collected through face to face interview. The MacArthur Health &amp; Behavior Questionnaire (HBQ) was used to assess internalizing and externalizing symptoms. Quantitative polymerase chain reaction was used to measure buccal TL.<br><br>RESULTS: Nearly 60% (399/695) of the participants experienced separation from both parents. Childhood or persistent separation from parents was associated with increased internalizing symptoms (childhood: &#x3b2;&#x2009;=&#x2009;0.13, 95% CI: 0.02, 0.23; persistent: &#x3b2; &#x2009;=&#x2009;0.23, 95% CI: 0.14, 0.31), increased externalizing symptoms (childhood: &#x3b2;&#x2009;=&#x2009;0.17, 95% CI: 0.03, 0.32; persistent: &#x3b2; &#x2009;=&#x2009;0.23, 95% CI: 0.10, 0.35) and shorter telomere length (childhood: &#x3b2;&#x2009;=&#x2009;-0.16, 95% CI: -0.26, -0.05; persistent: &#x3b2;&#x2009;=&#x2009;-0.13, 95% CI: -0.22, -0.03). Shortened TL was estimated to explain 15.2% and 12.7% of the total effect of separation on internalizing and externalizing symptoms, while internalizing and externalizing symptoms explained 23.4% and 12.3% of the effect of separation on shortened TL.<br><br>CONCLUSION: Childhood and persistent parent-child separation, as experienced by rural left-behind children in China, associates with increased vulnerability for psychopathological symptoms and makers of cellular aging. The challenge for future research is to determine whether short telomere length is in fact a long-term consequence or an underlying vulnerability factor for future mental disorders.},
}
@article {pmid30711895,
year = {2019},
author = {Rej, PH and Tennyson, RL and Lee, NR and Eisenberg, DTA},
title = {Years of caregiving for chronically ill and disabled family members is not associated with telomere length in the Philippines.},
journal = {Psychoneuroendocrinology},
volume = {103},
number = {},
pages = {188-194},
pmid = {30711895},
issn = {1873-3360},
support = {R01 AG039443/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging/genetics ; Caregivers/*psychology ; Cellular Senescence/physiology ; Chronic Disease ; Cohort Studies ; Family ; Female ; Humans ; Leukocytes/physiology ; Male ; Middle Aged ; Philippines ; Stress, Psychological/*psychology ; Telomere/physiology ; Telomere Homeostasis/physiology ; Telomere Shortening/*physiology ; },
abstract = {BACKGROUND: Caring for chronically disabled family members is a stressful experience. In turn, psychosocial stress is linked to premature aging. Telomere length (TL) is a plastic genetic trait that is a biomarker of aging, and a possible mechanism linking psychosocial stress and accelerated aging.<br><br>METHODS: TL was measured using qPCR method from blood samples in 1233 Filipino adults from Cebu, Philippines. Caregiving was measured as chronicity of care, or the sum total number of years an individual was the primary caregiver for any household member with a chronic illness or disability. Linear regression models were used to test for associations between chronicity of care and TL. Interaction terms were used to test whether or not the association between chronicity of care and TL differed by sex, age, and relationship to the caregiver. Specific statistical designs were publicly pre-registered before analysis began.<br><br>RESULTS: Chronicity of care was not associated with TL. Neither did we find any evidence for caregiving varying in its effect on TL by caregiver sex, age, or relationship to the chronically ill/disabled.<br><br>CONCLUSIONS: We found no evidence of an association between chronicity of care and TL. This result coupled with a recent study of a similarly sized cohort suggests that previous significant results linking caregiving and TL may be due to very particular types of caregiving populations or are possibly artifacts of small sample sizes.},
}
@article {pmid30710559,
year = {2019},
author = {Nassrally, MS and Lau, A and Wise, K and John, N and Kotecha, S and Lee, KL and Brooks, RF},
title = {Cell cycle arrest in replicative senescence is not an immediate consequence of telomere dysfunction.},
journal = {Mechanisms of ageing and development},
volume = {179},
number = {},
pages = {11-22},
doi = {10.1016/j.mad.2019.01.009},
pmid = {30710559},
issn = {1872-6216},
mesh = {Adult ; Cell Culture Techniques ; *Cell Cycle Checkpoints ; Cell Cycle Proteins/genetics ; Cellular Senescence/*genetics ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; *DNA Damage ; DNA Replication ; Doxorubicin/chemistry ; Fibroblasts/metabolism ; Gene Deletion ; Histones/metabolism ; Homozygote ; Humans ; Microscopy, Fluorescence ; Mitosis ; Telomere/*pathology ; *Telomere Shortening ; Tumor Suppressor p53-Binding Protein 1 ; },
abstract = {In replicative senescence, cells with critically-short telomeres activate a DNA-damage response leading to cell-cycle arrest, while those without telomere dysfunction would be expected to cycle normally. However, population growth declines more gradually than such a simple binary switch between cycling and non-cycling states would predict. We show here that late-passage cultures of human fibroblasts are not a simple mixture of cycling and non-cycling cells. Rather, although some cells had short cycle times comparable to those of younger cells, others continued to divide but with greatly extended cycle times, indicating a more-gradual approach to permanent arrest. Remarkably, in late passage cells, the majority showed prominent DNA-damage foci positive for 53BP1, yet many continued to divide. Evidently, the DNA-damage-response elicited by critically-short telomeres is not initially strong enough for complete cell-cycle arrest. A similar continuation of the cell cycle in the face of an active DNA-damage response was also seen in cells treated with a low dose of doxorubicin sufficient to produce multiple 53BP1 foci in all nuclei. Cell cycle checkpoint engagement in response to DNA damage is thus weaker than generally supposed, explaining why an accumulation of dysfunctional telomeres is needed before marked cell cycle elongation or permanent arrest is achieved.},
}
@article {pmid30709063,
year = {2019},
author = {Okamoto, K and Seimiya, H},
title = {Revisiting Telomere Shortening in Cancer.},
journal = {Cells},
volume = {8},
number = {2},
pages = {},
pmid = {30709063},
issn = {2073-4409},
mesh = {Animals ; Epigenesis, Genetic ; Humans ; Mutation/genetics ; Neoplasms/*genetics ; Promoter Regions, Genetic/genetics ; Telomerase/genetics/metabolism ; Telomere Shortening/*genetics ; },
abstract = {Telomeres, the protective structures of chromosome ends are gradually shortened by each cell division, eventually leading to senescence or apoptosis. Cancer cells maintain the telomere length for unlimited growth by telomerase reactivation or a recombination-based mechanism. Recent genome-wide analyses have unveiled genetic and epigenetic alterations of the telomere maintenance machinery in cancer. While telomerase inhibition reveals that longer telomeres are more advantageous for cell survival, cancer cells often have paradoxically shorter telomeres compared with those found in the normal tissues. In this review, we summarize the latest knowledge about telomere length alterations in cancer and revisit its rationality. Finally, we discuss the potential utility of telomere length as a prognostic biomarker.},
}
@article {pmid30708136,
year = {2019},
author = {Huang, Y and Yim, OS and Lai, PS and Yu, R and Chew, SH and Gwee, X and Nyunt, MSZ and Gao, Q and Ng, TP and Ebstein, RP and Gouin, JP},
title = {Successful aging, cognitive function, socioeconomic status, and leukocyte telomere length.},
journal = {Psychoneuroendocrinology},
volume = {103},
number = {},
pages = {180-187},
doi = {10.1016/j.psyneuen.2019.01.015},
pmid = {30708136},
issn = {1873-3360},
mesh = {Aged ; Aged, 80 and over ; Aging/psychology ; Asian People ; Biomarkers ; Cellular Senescence/physiology ; Cognition/*physiology ; Female ; Healthy Aging/genetics/*psychology ; Humans ; Leukocytes/metabolism/physiology ; Male ; Social Class ; Telomere/*metabolism/physiology ; Telomere Homeostasis/genetics/physiology ; Telomere Shortening/genetics/physiology ; },
abstract = {In a rapidly greying world, the notion that some individuals maintain successful aging trajectories, viz. high physical, cognitive, emotional, and social functioning in older age, is increasingly germane. Biomarkers of such successful aging are increasingly sought. Leukocyte telomere length (LTL), an emerging yardstick of cellular aging that is influenced by but distinct from chronological age, may also be associated to successful aging. Furthermore, given that socio-economic status (SES) influences successful aging trajectories, socioeconomic status may also moderate the association between chronological age and LTL. The goals of this study are to examine 1) whether successful aging is associated with LTL; 2) whether successful aging accounts for age-related LTL and 3) whether SES moderates the effect of age on LTL. Singaporean Chinese (n = 353) aged 65-80 completed a multidimensional assessment of successful aging and provided blood samples for LTL analysis. Results show that LTL negatively correlates with chronological age and positively correlates with successful aging. Successful aging mediates the association between chronological age and LTL. Moderated mediation analyses show that lower SES is associated with stronger negative associations of chronological age with successful aging and LTL. Moreover, the cognitive functioning dimension of successful aging is uniquely associated with LTL and its association with chronological age is moderated by SES. This study provides evidence that among older Singaporean Chinese with lower SES, declines in successful aging and in cognitive functioning are linked to age-related LTL shortening and hence to accelerated aging at the cellular level.},
}
@article {pmid30701351,
year = {2019},
author = {Sudyka, J and Podmokła, E and Drobniak, SM and Dubiec, A and Arct, A and Gustafsson, L and Cichoń, M},
title = {Sex-specific effects of parasites on telomere dynamics in a short-lived passerine-the blue tit.},
journal = {Die Naturwissenschaften},
volume = {106},
number = {1-2},
pages = {6},
pmid = {30701351},
issn = {1432-1904},
support = {DEC-2013/09/N/NZ8/03211//Narodowe Centrum Nauki/ ; },
mesh = {Age Factors ; Aging/physiology ; Animals ; Female ; Haemosporida/*physiology ; Islands/epidemiology ; Linear Models ; Longitudinal Studies ; Malaria, Avian/epidemiology/genetics/parasitology/*physiopathology ; Male ; Passeriformes/*genetics ; Prevalence ; Protozoan Infections, Animal/epidemiology/genetics/parasitology/*physiopathology ; Regression Analysis ; Sex Factors ; Sweden/epidemiology ; Telomere/*physiology ; },
abstract = {Parasitic infections potentially drive host's life-histories since they can have detrimental effects on host's fitness. Telomere dynamics is a candidate mechanism to underlie life-history trade-offs and as such may correlate with observed fitness reduction in infected animals. We examined the relationship of chronic infection with two genera of haemosporidians causing avian malaria and malaria-like disease with host's telomere length (TL) in a longitudinal study of free-ranging blue tits. The observed overall infection prevalence was 80% and increased with age, constituting a potentially serious selective pressure in our population. We found longer telomeres in individuals infected with a parasite causing lesser blood pathologies i.e. Haemoproteus compared to Plasmodium genus, but this only held true among males. Female TL was independent of the infection type. Our results indicate that parasitic infections could bring about other types of costs to females than to males with respect to TL. Additionally, we detected linear telomere loss with age, however a random regression analysis did not confirm significant heterogeneity in TL of first breeders and telomere shortening rates in further life.},
}
@article {pmid30700843,
year = {2019},
author = {Norris, K and Hillmen, P and Rawstron, A and Hills, R and Baird, DM and Fegan, CD and Pepper, C},
title = {Telomere length predicts for outcome to FCR chemotherapy in CLL.},
journal = {Leukemia},
volume = {33},
number = {8},
pages = {1953-1963},
pmid = {30700843},
issn = {1476-5551},
support = {07/01/38/DH_/Department of Health/United Kingdom ; 18246/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Cyclophosphamide/administration &amp; dosage ; Disease-Free Survival ; Humans ; Immunoglobulin Heavy Chains/genetics ; Immunoglobulin Variable Region/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/*genetics/mortality ; Mutation ; Rituximab/administration &amp; dosage ; *Telomere ; Vidarabine/administration &amp; dosage/analogs &amp; derivatives ; },
abstract = {We have previously shown that dividing patients with CLL into those with telomeres inside the fusogenic range (TL-IFR) and outside the fusogenic range (TL-OFR) is powerful prognostic tool. Here, we used a high-throughput version of the assay (HT-STELA) to establish whether telomere length could predict for outcome to fludarabine, cyclophosphamide, rituximab (FCR)-based treatment using samples collected from two concurrent phase II studies, ARCTIC and ADMIRE (n = 260). In univariate analysis, patients with TL-IFR had reduced progression-free survival (PFS) (P < 0.0001; HR = 2.17) and shorter overall survival (OS) (P = 0.0002; HR = 2.44). Bifurcation of the IGHV-mutated and unmutated subsets according to telomere length revealed that patients with TL-IFR in each subset had shorter PFS (HR = 4.35 and HR = 1.48, respectively) and shorter OS (HR = 3.81 and HR = 2.18, respectively). In addition, the OS of the TL-OFR and TL-IFR subsets were not significantly altered by IGHV mutation status (P = 0.61; HR = 1.24 and P = 0.41; HR = 1.47, respectively). In multivariate modeling, telomere length was the dominant co-variable for PFS (P = 0.0002; HR = 1.85) and OS (P = 0.05; HR = 1.61). Taken together, our data suggest that HT-STELA is a powerful predictor of outcome to FCR-based treatment and could be used to inform the design of future risk-adapted clinical trials.},
}
@article {pmid30700812,
year = {2019},
author = {Zlotorynski, E},
title = {Telomere crisis activates autophagic death.},
journal = {Nature reviews. Molecular cell biology},
volume = {20},
number = {3},
pages = {133},
doi = {10.1038/s41580-019-0105-7},
pmid = {30700812},
issn = {1471-0080},
mesh = {Autophagic Cell Death ; Chromosomal Instability ; Humans ; Telomerase/*genetics ; *Telomere ; },
}
@article {pmid30697232,
year = {2018},
author = {Tomáška, &#x139; and Nosek, J and Sepšiová, R and Červenák, F and Juríková, K and Procházková, K and Neboháčová, M and Willcox, S and Griffith, JD},
title = {Commentary: Single-stranded telomere-binding protein employs a dual rheostat for binding affinity and specificity that drives function.},
journal = {Frontiers in genetics},
volume = {9},
number = {},
pages = {742},
pmid = {30697232},
issn = {1664-8021},
support = {P01 CA019014/CA/NCI NIH HHS/United States ; },
}
@article {pmid30696885,
year = {2019},
author = {Kesäniemi, J and Lavrinienko, A and Tukalenko, E and Boratyński, Z and Kivisaari, K and Mappes, T and Milinevsky, G and Møller, AP and Mousseau, TA and Watts, PC},
title = {Exposure to environmental radionuclides associates with tissue-specific impacts on telomerase expression and telomere length.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {850},
pmid = {30696885},
issn = {2045-2322},
mesh = {Animals ; Arvicolinae/*physiology ; Chernobyl Nuclear Accident ; Environmental Exposure/*adverse effects ; Gene Expression Regulation ; Liver/*physiology ; Male ; Organ Specificity ; Radiation, Ionizing ; Radioisotopes/*adverse effects ; Telomerase/genetics/*metabolism ; Telomere/*genetics ; Telomere Homeostasis ; Testis/*physiology ; },
abstract = {Telomeres, the protective structures at the ends of chromosomes, can be shortened when individuals are exposed to stress. In some species, the enzyme telomerase is expressed in adult somatic tissues, and potentially protects or lengthens telomeres. Telomeres can be damaged by ionizing radiation and oxidative stress, although the effect of chronic exposure to elevated levels of radiation on telomere maintenance is unknown for natural populations. We quantified telomerase expression and telomere length (TL) in different tissues of the bank vole Myodes glareolus, collected from the Chernobyl Exclusion Zone, an environment heterogeneously contaminated with radionuclides, and from uncontaminated control sites elsewhere in Ukraine. Inhabiting the Chernobyl Exclusion Zone was associated with reduced TL in the liver and testis, and upregulation of telomerase in brain and liver. Thus upregulation of telomerase does not appear to associate with longer telomeres but may reflect protective functions other than telomere maintenance or an attempt to maintain shorter telomeres in a stressful environment. Tissue specific differences in the rate of telomere attrition and apparent radiosensitivity weaken the intra-individual correlation in telomere length among tissues in voles exposed to radionuclides. Our data show that ionizing radiation alters telomere homeostasis in wild animal populations in tissue specific ways.},
}
@article {pmid30695740,
year = {2019},
author = {Jiang, Y and Da, W and Qiao, S and Zhang, Q and Li, X and Ivey, G and Zilioli, S},
title = {Basal cortisol, cortisol reactivity, and telomere length: A systematic review and meta-analysis.},
journal = {Psychoneuroendocrinology},
volume = {103},
number = {},
pages = {163-172},
pmid = {30695740},
issn = {1873-3360},
support = {R01 HD074221/HD/NICHD NIH HHS/United States ; R01 NR013466/NR/NINR NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Child ; Cross-Sectional Studies ; Female ; Humans ; Hydrocortisone/*analysis/genetics/metabolism ; Male ; Middle Aged ; Stress, Psychological/psychology ; Telomere/genetics/physiology ; Telomere Homeostasis/genetics/*physiology ; Telomere Shortening/genetics/*physiology ; },
abstract = {The objective of the present study is to synthesize the existing empirical literature and perform a meta-analysis of published data on the relationship between cortisol and telomere length. We systematically searched studies that examined the relationship between cortisol and telomere length in humans on electronic databases and screened reference sections of included articles. Fourteen studies were included in the meta-analysis, with effect sizes being extracted for two cortisol measures: basal cortisol levels and cortisol reactivity to acute psychological stress. Results from random effects models showed that basal cortisol levels (13 effect sizes from 12 cross-sectional studies, N = 3675 participants) were not significantly correlated with telomere length (r =-0.05, 95% CI [-0.11, 0.02]). Further, results stratified by the specimen type for cortisol measurement (i.e., saliva, urine, blood) showed that none of the three basal cortisol level measures were correlated with telomere length. However, we found a statistically significant correlation between salivary cortisol reactivity to acute psychosocial stress (6 cross-sectional studies, N = 958 participants) and telomere length (r = -0.13, 95% CI [-0.23, -0.03]). Subgroup analyses revealed that correlations between salivary cortisol reactivity and telomere length were more evident in studies conducted among children (vs. adults) and in studies that included female participants only (vs. both genders). However, the small number of available studies limits the conclusions derived from subgroup analyses, and more studies are needed before moderator effects can be properly established. Overall, findings of this study support the existence of a relationship between cortisol reactivity and telomere shortening.},
}
@article {pmid30694216,
year = {2019},
author = {Liu, J and Ge, Y and Wu, S and Ma, D and Xu, W and Zhang, Y and Yang, Y},
title = {Association between antidiabetic agents use and leukocyte telomere shortening rates in patients with type 2 diabetes.},
journal = {Aging},
volume = {11},
number = {2},
pages = {741-755},
pmid = {30694216},
issn = {1945-4589},
mesh = {Acarbose/*therapeutic use ; Adult ; Cross-Sectional Studies ; Diabetes Mellitus, Type 2/*drug therapy ; Female ; Humans ; Hypoglycemic Agents/*therapeutic use ; Leukocytes/*drug effects ; Male ; Middle Aged ; *Telomere Shortening ; },
abstract = {Telomere length and telomere shortening rate (TSR) are accepted indicators of aging in cross-sectional population studies. This study aimed to investigate the potential influence of common antidiabetic agents on telomere length and TSR in patients with type 2 diabetes mellitus (T2DM). Leukocyte telomere length was measured through terminal restriction fragment analysis, and TSR was calculated in 388 T2DM patients. Depending on whether or not they received antidiabetic medication, patients were first divided into a treatment group and a nontreatment group. Treated patients were further subdivided into an acarbose-free group (patients taking antidiabetic agents without acarbose) and an acarbose group (patients using acarbose for more than 3 months). Results showed that untreated patients had higher TSRs than patients on antidiabetic drugs. Interestingly, patients in the acarbose group had significantly higher TSRs than patients in the acarbose-free group. Compared to the nontreatment group, the acarbose group showed better glycemic control of HbA1c, but the TSR was also higher. Our results suggest that antidiabetic treatments without acarbose can slow aging. By contrast, acarbose may accelerate biological aging in patients with T2DM, independently of glycemic control.},
}
@article {pmid30692206,
year = {2019},
author = {Verma, P and Dilley, RL and Zhang, T and Gyparaki, MT and Li, Y and Greenberg, RA},
title = {RAD52 and SLX4 act nonepistatically to ensure telomere stability during alternative telomere lengthening.},
journal = {Genes &amp; development},
volume = {33},
number = {3-4},
pages = {221-235},
pmid = {30692206},
issn = {1549-5477},
support = {R01 CA174904/CA/NCI NIH HHS/United States ; R01 GM101149/GM/NIGMS NIH HHS/United States ; T32 GM007170/GM/NIGMS NIH HHS/United States ; T32 GM008216/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; DNA Breaks, Double-Stranded ; Gene Knockout Techniques ; Genomic Instability/genetics ; HEK293 Cells ; HeLa Cells ; Humans ; Interphase ; Rad52 DNA Repair and Recombination Protein/genetics/*metabolism ; Recombinases/genetics/*metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Approximately 15% of cancers use homologous recombination for alternative lengthening of telomeres (ALT). How the initiating genomic lesions invoke homology-directed telomere synthesis remains enigmatic. Here, we show that distinct dependencies exist for telomere synthesis in response to replication stress or DNA double-strand breaks (DSBs). RAD52 deficiency reduced spontaneous telomeric DNA synthesis and replication stress-associated recombination in G2, concomitant with telomere shortening and damage. However, viability and proliferation remained unaffected, suggesting that alternative telomere recombination mechanisms compensate in the absence of RAD52. In agreement, RAD52 was dispensable for DSB-induced telomere synthesis. Moreover, a targeted CRISPR screen revealed that loss of the structure-specific endonuclease scaffold SLX4 reduced the proliferation of RAD52-null ALT cells. While SLX4 was dispensable for RAD52-mediated ALT telomere synthesis in G2, combined SLX4 and RAD52 loss resulted in elevated telomere loss, unresolved telomere recombination intermediates, and mitotic infidelity. These findings establish that RAD52 and SLX4 mediate distinct postreplicative DNA repair processes that maintain ALT telomere stability and cancer cell viability.},
}
@article {pmid30691026,
year = {2019},
author = {Scarabino, D and Peconi, M and Pelliccia, F and Corbo, RM},
title = {Analysis of the Association Between TERC and TERT Genetic Variation and Leukocyte Telomere Length and Human Lifespan-A Follow-Up Study.},
journal = {Genes},
volume = {10},
number = {2},
pages = {},
pmid = {30691026},
issn = {2073-4425},
mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Longevity/*genetics ; Male ; Microsatellite Repeats ; *Polymorphism, Single Nucleotide ; RNA/genetics ; Telomerase/*genetics ; Telomere Homeostasis ; },
abstract = {We investigated the possible influence of TERC and TERT genetic variation and leukocyte telomere length (LTL) on human lifespan. Four polymorphisms of TERT and three polymorphisms of TERC were examined in a sample of elderly subjects (70[-]100 years). After nine years of follow-up, mortality data were collected, and sub-samples of long-lived/not long-lived were defined. TERT VNTR MNS16A L/L genotype and TERT rs2853691 A/G or G/G genotypes were found to be associated with a significantly higher risk to die before the age of 90 years, and with a significantly lower age at death. The association between lifespan and LTL at baseline was analyzed in a subsample of 163 subjects. Age at baseline was inversely associated with LTL (p < 0.0001). Mean LTL was greater in the subjects still living than in those no longer living at follow-up (0.79 T/S ± 0.09 vs 0.63 T/S ± 0.08, p < 0.0001). Comparison of age classes showed that, among the 70[-]79-year-olds, the difference in mean LTL between those still living and those no longer living at follow-up was greater than among the 80[-]90-year-olds. Our data provide evidence that shorter LTL at baseline may predict a shorter lifespan, but the reliability of LTL as a lifespan biomarker seems to be limited to a specific age (70[-]79 years).},
}
@article {pmid30690361,
year = {2019},
author = {Grunst, ML and Raap, T and Grunst, AS and Pinxten, R and Eens, M},
title = {Artificial light at night does not affect telomere shortening in a developing free-living songbird: A field experiment: Artificial light at night and telomere dynamics.},
journal = {The Science of the total environment},
volume = {662},
number = {},
pages = {266-275},
doi = {10.1016/j.scitotenv.2018.12.469},
pmid = {30690361},
issn = {1879-1026},
mesh = {Animals ; Belgium ; *Body Composition ; Female ; Light/*adverse effects ; Lighting/*adverse effects ; Male ; Nitric Oxide/blood ; Songbirds/growth &amp; development/*physiology ; Stress, Physiological ; *Telomere Shortening ; },
abstract = {Artificial light at night (ALAN) is an increasingly pervasive anthropogenic disturbance factor. ALAN can seriously disrupt physiological systems that follow circadian rhythms, and may be particularly influential early in life, when developmental trajectories are sensitive to stressful conditions. Using great tits (Parus major) as a model species, we experimentally examined how ALAN affects physiological stress in developing nestlings. We used a repeated-measure design to assess effects of ALAN on telomere shortening, body mass, tarsus length and body condition. Telomeres are repetitive nucleotide sequences that protect chromosomes from damage and malfunction. Early-life telomere shortening can be accelerated by environmental stressors, and has been linked to later-life declines in survival and reproduction. We also assayed nitric oxide, as an additional metric of physiological stress, and determined fledging success. Change in body condition between day 8 and 15 differed according to treatment. Nestlings exposed to ALAN displayed a trend towards a decline in condition, whereas control nestlings displayed a trend towards increased condition. This pattern was driven by a greater increase in tarsus length relative to mass in nestlings exposed to ALAN. Nestlings in poorer condition and nestlings that were smaller than their nest mates had shorter telomeres. However, exposure to ALAN was unrelated to telomere shortening, and also had no effect on nitric oxide concentrations or fledging success. Thus, exposure to ALAN may not have led to sufficient stress to induce telomere shortening. Indeed, plasticity in other physiological systems could allow nestlings to maintain telomere length despite moderate stress. Alternatively, the cascade of physiological and behavioral responses associated with light exposure may have no net effect on telomere dynamics.},
}
@article {pmid30690015,
year = {2019},
author = {Phillippe, M and Sawyer, MR and Edelson, PK},
title = {The telomere gestational clock: increasing short telomeres at term in the mouse.},
journal = {American journal of obstetrics and gynecology},
volume = {220},
number = {5},
pages = {496.e1-496.e8},
doi = {10.1016/j.ajog.2019.01.218},
pmid = {30690015},
issn = {1097-6868},
mesh = {Animals ; Extraembryonic Membranes/*pathology ; Female ; *Gestational Age ; In Situ Hybridization, Fluorescence ; Mice ; Placenta/*pathology ; Pregnancy ; *Telomere Shortening ; },
abstract = {BACKGROUND: The biologic mechanism(s) regulating the length of gestation are currently poorly understood. After peaking at the blastocyst stage, the average telomere lengths have been reported to shorten during the remainder of gestation in the placenta and fetal membranes in both human and mouse pregnancies, thereby providing a potential countdown biologic clock. These previous studies have reported changes in the average telomere lengths, whereas it has now been shown that the shortest telomeres, not the average telomere lengths, are the mediators of telomere dysfunction which limits cellular survival and results in aging.<br><br>OBJECTIVE: These studies sought to assess for the first time a significant increase in short telomeres in the fetal membrane and placental tissue near the end of pregnancy in the mouse.<br><br>STUDY DESIGN: Placental and fetal membrane tissues were harvested from timed-pregnant CD-1 mice on gestational days 14-18 prior to the onset of parturition. Telomere lengths were determined for 30 DNA samples (5 each for&#xa0;gestational days 14, 16, and 18 from placentas and fetal membranes) using a&#xa0;commercial high-throughput quantitative fluorescence in situ hybridization technique. Quantitative measurements of representative short telomeres (ie, 3&#xa0;kb&#xa0;and 5 kb telomere fragments) were performed for 29-30 DNA samples (4-7 each for gestational days 14, 15, 16, 17, and 18 from placentas, fetal membranes, and maternal liver) using a real-time quantitative polymerase chain reaction modification of the classic telomere restriction fragment technique.<br><br>RESULTS: The median telomere lengths of fetal membrane tissue decreased from gestational days 14-18 (18,705-16,364 kb) and were significantly shorter than telomeres in placental tissue (P < .05). Representative histograms for the distribution of telomere lengths in mouse fetal membranes (as shown in the Figure) confirm a curve skewed to the left (toward shorter telomere lengths).The relative quantity of the representative short telomeres (ie, 3 kb and 5 kb fragments) increased significantly as gestation progressed in both placenta and fetal membrane tissue. In gestational day 18 fetal membranes, the relative quantity of 3 kb and 5 kb telomeres increased 5.5-fold and 9.3-fold compared with gestational day 14 tissues (P < .05). In placental tissue the relative quantity of 3 kb and 5 kb telomeres increased 9.3-fold and 7.8-fold compared with gestational day 14 tissues (P < .05). Studies performed using adult liver tissue demonstrated little variation of the representative short telomeres and no significant difference between the nonpregnant and pregnant samples.<br><br>CONCLUSION: These mouse studies have demonstrated that the distribution of telomere lengths in fetal membrane and placental tissues are skewed toward shorter lengths and that the quantity of representative short telomeres increase significantly prior to parturition. The telomere gestational clock is a novel hypothesis supported by several preliminary mouse studies and interesting associations in human pregnancies between maternal conditions and telomere lengths. (eg, stress, education, pollution, neighborhood quality, and race). As such, the current hypothesis generating study provides a foundation for future research regarding the potential role for a telomere-based biologic clock that determines gestational length in human and other mammalian pregnancies.},
}
@article {pmid30685566,
year = {2019},
author = {Avetyan, D and Zakharyan, R and Petrek, M and Arakelyan, A},
title = {Telomere shortening in blood leukocytes of patients with posttraumatic stress disorder.},
journal = {Journal of psychiatric research},
volume = {111},
number = {},
pages = {83-88},
doi = {10.1016/j.jpsychires.2019.01.018},
pmid = {30685566},
issn = {1879-1379},
mesh = {Adult ; Aged ; Armenia ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; RNA/*genetics ; Risk ; Stress Disorders, Post-Traumatic/*blood/enzymology/*genetics ; Telomerase/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Telomeres are protective fragments on chromosome ends involved in maintaining genome stability, preventing chromosomal fusions, regulation of cell division. It was shown that telomere attrition rate is accelerated in age-related diseases, as well as in response to physiological and psychosocial stress. The aim of this study was to evaluate relative leukocyte telomere length (LTL) in patients with post traumatic stress disorder (PTSD), as well as to investigate association of functional SNPs of telomerase TERC and TERT genes with LTL and PTSD. The relative LTL was measured by multiplex quantitative PCR method; genotyping of TERC rs12696304, TERT rs7726159 and rs2736100 was performed by PCR with sequence specific primers. Comparison of LTL in diseased and healthy subjects showed that PTSD patients had shorter average LTL than controls. Also, the frequency and the carriage rate of the TERT rs2736100*T allele was higher in PTSD patients compared to controls. Overall our results are in line with previous research in different populations. Furthermore, we have demonstrated that rs2736100 of TERT gene was significantly associated with PTSD and the minor allele of this polymorphism may be considered as a risk factor for PTSD in the Armenian population.},
}
@article {pmid30684755,
year = {2019},
author = {Wang, W and Zhang, H and Duan, X and Feng, X and Wang, T and Wang, P and Ding, M and Zhou, X and Liu, S and Li, L and Liu, J and Tang, L and Niu, X and Zhang, Y and Li, G and Yao, W and Yang, Y},
title = {Association of genetic polymorphisms of miR-145 gene with telomere length in omethoate-exposed workers.},
journal = {Ecotoxicology and environmental safety},
volume = {172},
number = {},
pages = {82-88},
doi = {10.1016/j.ecoenv.2019.01.023},
pmid = {30684755},
issn = {1090-2414},
mesh = {Adult ; Case-Control Studies ; DNA/genetics ; DNA Damage/drug effects ; Dimethoate/*analogs &amp; derivatives/toxicity ; Female ; Genetic Loci ; Genotype ; Humans ; Leukocytes/drug effects/metabolism ; Male ; MicroRNAs/*genetics ; Middle Aged ; *Polymorphism, Single Nucleotide ; Telomere/*drug effects ; Telomere Homeostasis/*drug effects ; },
abstract = {Omethoate, an organophosphorous pesticide, causes a variety of health effects, especially the damage of chromosome DNA. The aim of the study was to assess the correlation between polymorphisms of encoding miRNA genes and telomere length in omethoate-exposure workers. 180 workers with more than 8 years omethoate-exposure and 115 healthy controls were recruited in the study. Genotyping for the selected single nucleotide polymorphisms loci were performed using the flight mass spectrometry. Real-time fluorescent quantitative polymerase chain reaction(PCR) method was applied to determine the relative telomere length(RTL) in human peripheral blood leukocytes DNA. After adjusting the covariate of affecting RTL, covariance analysis showed that the female was significantly longer than that of the male in control group(P < 0.046). For the miR-145 rs353291 locus, this study showed that RTL of mutation homozygous AG+GG individuals was longer than that of wild homozygous AA in the exposure group (P = 0.039). In the control group, RTL with wild homozygous TT genotype in miR-30a rs2222722 polymorphism locus was longer than that of the mutation homozygous CC genotype (P = 0.038). After multiple linear regression analysis, the independent variables of entering into the model were omethoate-exposure (b = 0.562, P < 0.001), miR-145 rs353291 (AG+GG) (b = 0.205, P = 0.010). The prolongation of relative telomere length in omethoate exposed workers was associated with AG+GG genotypes in rs353291 polymorphism of encoding miR-145 gene.},
}
@article {pmid30684534,
year = {2019},
author = {Opstad, TB and Kalstad, AA and Pettersen, A&#xc5; and Arnesen, H and Seljeflot, I},
title = {Novel biomolecules of ageing, sex differences and potential underlying mechanisms of telomere shortening in coronary artery disease.},
journal = {Experimental gerontology},
volume = {119},
number = {},
pages = {53-60},
doi = {10.1016/j.exger.2019.01.020},
pmid = {30684534},
issn = {1873-6815},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Bone Morphogenetic Proteins/genetics ; Coronary Artery Disease/*genetics ; Cross-Sectional Studies ; Female ; Genetic Markers ; Growth Differentiation Factors/genetics ; Humans ; Leukocytes/physiology ; Logistic Models ; Male ; Middle Aged ; Multivariate Analysis ; Norway ; Sex Characteristics ; Sirtuin 1/genetics ; Telomere/genetics/*physiology ; *Telomere Shortening ; },
abstract = {UNLABELLED: Telomere length (TL), growth differentiate factor (GDF)11, insulin growth factor (IGF)1, sirtuin (SIRT)1 and inflammatory processes have been related to ageing and age-related diseases, like coronary artery disease (CAD). We aimed to investigate the associations between leukocyte TLs (LTLs), chronological age, sex and comorbidities in CAD patients. Any covariations between LTL, GDF11, IGF1, SIRT-1 and pro-inflammatory cytokines were further assessed.<br><br>METHODS: In 300 patients with stable CAD (age 36-81&#x202f;years, 20% females), DNA and RNA were isolated from whole blood for PCR analysis and relative quantification of LTLs and gene-expression of GDF11, IGF1,SIRT1, IL-12, IL-18 and IFN&#x1b4;, respectively. Serum was prepared for the analyses of circulating IL-18, IL-12, IL-6 and TNF&#x3b1;.<br><br>RESULTS: Patients with previous myocardial infarction (MI) presented with 20% shorter LTLs vs. patients without (p&#x202f;=&#x202f;0.019) indicating LTLs to be of importance for CAD severity. The observation however, was only observed in men (p&#x202f;=&#x202f;0.009, n&#x202f;=&#x202f;115), in which the upper LTL quartile associated with 64% lower frequency of previous MI compared to quartile 1-3 (p&#x202f;=&#x202f;0.005, adjusted). LTLs were not differently distributed according to sex or comorbidities such as hypertension, diabetes type 2 and metabolic syndrome. LTLs and GDF11 were inversely correlated to age (r&#x202f;=&#x202f;-0.17; p&#x202f;=&#x202f;0.007 and r&#x202f;=&#x202f;-0.16; p&#x202f;=&#x202f;0.010, respectively), however, separated in gender, LTL only in women (r&#x202f;=&#x202f;-0.37) and GDF11 only in men (r&#x202f;=&#x202f;-0.19) (p&#x202f;=&#x202f;0.006, both). GDF11 and SIRT1 were strongly inter-correlated (r&#x202f;=&#x202f;0.56, p&#x202f;&#x2264;&#x202f;0.001), suggesting common upstream regulators. LTLs were moderately correlated to GDF11 and SIRT1 in overweight women (BMI&#x202f;&#x2265;&#x202f;25&#x202f;kg/m[2]) (r&#x202f;=&#x202f;0.41; p&#x202f;=&#x202f;0.027 and 0.43; p&#x202f;=&#x202f;0.020, respectively), which may reflect common life-style influences on LTLs and these markers. In all women, we observed further that the highest LTL quartile associated with higher GDF11 and SIRT expression and lower circulating levels of IL-12, IL-18 and TNF&#x3b1;, as compared to quartile 1, which may indicate lifestyle influences on female LTLs. In men, the highest LTL quartile associated with lower IFN&#x1b4; expression and lower circulating TNF&#x3b1;. Overall, the results indicate an association between chronic low-grade inflammation and LTLs.<br><br>CONCLUSIONS: Shorter LTLs in CAD patients with previously suffered MI may indicate telomere attrition as part of its pathophysiology in men. The inverse association between LTLs and age exclusively in women underpins the previously reported decline in attrition rate in men with increasing age. As elevated GDF11 and SIRT1 along with attenuated pro-inflammatory cytokines seem to positively affect LTL in women, we hypothesize a potential sex-dimorphism in LTL regulation, which may implicate sex- adjusted health-preventive therapies.},
}
@article {pmid30680798,
year = {2019},
author = {Li, Y and Xiang, C and Shen, N and Deng, L and Luo, X and Yuan, P and Ji, Z and Li, J and Cheng, L},
title = {Functional polymorphisms on chromosome 5p15.33 disturb telomere biology and confer the risk of non-small cell lung cancer in Chinese population.},
journal = {Molecular carcinogenesis},
volume = {58},
number = {6},
pages = {913-921},
doi = {10.1002/mc.22980},
pmid = {30680798},
issn = {1098-2744},
mesh = {A549 Cells ; Aged ; Carcinoma, Non-Small-Cell Lung/*genetics ; Case-Control Studies ; Cell Line, Tumor ; China ; Chromosomes, Human, Pair 5/*genetics ; Female ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Lung Neoplasms/*genetics ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; Proto-Oncogene Proteins c-myc/metabolism ; Sequence Analysis, DNA ; Telomerase/*genetics/metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {The chromosome 5p15.33 has been reported as a susceptibility locus for lung cancer. However, causal variants in this region have not been fully uncovered. In this study, we intended to identify functional polymorphisms associated with non-small cell lung cancer (NSCLC) susceptibility in Chinese population. A targeted sequencing on 5p15.33 region was conducted in 400 NSCLC cases. We selected candidate variants by comparing genotypic frequency with data from 1000 Genomes Project, and their associations with NSCLC were validated in 985 cases and 970 controls. The relationships between risk variants and telomere length were evaluated in 774 healthy subjects. Luciferase assays and electrophoretic mobility shift assays (EMSA) were performed to explore potential functions and reveal carcinogenic mechanisms. As a result, we identified 1478 variants through targeted sequencing and selected 17 candidates. Four polymorphisms exhibited prominent associations with lung cancer risk, including rs7726159 (OR = 1.34, 95%CI: 1.18-1.52, P = 7.78 × 10[-6]), rs10054203 (OR = 1.29, 95%CI: 1.13-1.46, P = 1.37 × 10[-4]), rs2736107 (OR = 1.28, 95%CI: 1.11-1.47, P = 5.14 × 10[-4]), and rs2853677 (OR = 1.23, 95%CI: 1.08-1.39, P = 0.002). The minor allele of rs7726159 and rs10053203 were associated with long telomeres (P = 0.008 and 0.036, respectively). Mechanistically, the rs7726159-A increased TERT transcription through mediating allele-specific MYC binding. In conclusion, the functional variant rs7726159 confers lung cancer susceptibility might by affecting MYC binding and inducing telomere lengthening, which provides a new insight into the crucial role of telomere biology in tumorigenesis.},
}
@article {pmid30680132,
year = {2019},
author = {Apfelbeck, B and Haussmann, MF and Boner, W and Flinks, H and Griffiths, K and Illera, JC and Mortega, KG and Sisson, Z and Smiddy, P and Helm, B},
title = {Divergent patterns of telomere shortening in tropical compared to temperate stonechats.},
journal = {Ecology and evolution},
volume = {9},
number = {1},
pages = {511-521},
pmid = {30680132},
issn = {2045-7758},
support = {R15 HD083870/HD/NICHD NIH HHS/United States ; },
abstract = {Telomeres have emerged as important biomarkers of health and senescence as they predict chances of survival in various species. Tropical birds live in more benign environments with lower extrinsic mortality and higher juvenile and adult survival than temperate birds. Therefore, telomere biology may play a more important role in tropical compared to temperate birds. We measured mean telomere length of male stonechats (Saxicola spp.) at four age classes from tropical African and temperate European breeding regions. Tropical and temperate stonechats had similarly long telomeres as nestlings. However, while in tropical stonechats pre-breeding first-years had longer telomeres than nestlings, in temperate stonechats pre-breeding first-years had shorter telomeres than nestlings. During their first breeding season, telomere length was again similar between tropical and temperate stonechats. These patterns may indicate differential survival of high-quality juveniles in tropical environments. Alternatively, more favorable environmental conditions, that is, extended parental care, may enable tropical juveniles to minimize telomere shortening. As suggested by previous studies, our results imply that variation in life history and life span may be reflected in different patterns of telomere shortening rather than telomere length. Our data provide first evidence that distinct selective pressures in tropical and temperate environments may be reflected in diverging patterns of telomere loss in birds.},
}
@article {pmid30680069,
year = {2018},
author = {Ngo, G and Hyatt, S and Grimstead, J and Jones, R and Hendrickson, E and Pepper, C and Baird, D},
title = {PARP inhibition prevents escape from a telomere-driven crisis and inhibits cell immortalisation.},
journal = {Oncotarget},
volume = {9},
number = {101},
pages = {37549-37563},
pmid = {30680069},
issn = {1949-2553},
support = {18246/CRUK_/Cancer Research UK/United Kingdom ; R01 CA190492/CA/NCI NIH HHS/United States ; },
abstract = {Telomeric crisis is the final replicative barrier to cell immortalisation; it is characterised by genome instability and cell death and is triggered when telomeres become critically short and are subjected to fusion. Pre-cancerous lesions, or early stage cancers, often show signs of a telomere crisis, suggesting that escape from telomere crisis is a prerequisite for disease progression. Telomeric crisis therefore represents an attractive, and as yet unexplored, opportunity for therapeutic intervention. Here, we show that two clinically approved PARP inhibitors, selectively eliminate human cells undergoing a telomere-driven crisis. Clonal populations of a colorectal cancer cell line (HCT116), or the plasma cell leukaemia cell line (JJN-3), expressing a dominant-negative telomerase, entered a telomere-driven crisis at defined population doubling points and telomere lengths. The addition of the PARP inhibitors, olaparib or rucaparib prevented these cells from escaping crisis. PARP inhibition did not alter cellular proliferation prior to crisis, rates of telomere erosion or the telomere length at which crisis was initiated, but affected repair of eroded telomeres, resulting in an increased in intra-chromosomal telomere fusion. This was accompanied by enhanced DNA damage checkpoint activation and elevated levels of apoptosis. We propose that PARP inhibitors impair the repair of dysfunctional telomeres and/or induce replicative stress at telomeres to inhibit escape from a telomere crisis. This is the first demonstration that a drug can selectively kill cells experiencing telomeric crisis. We propose that this type of drug, which we term 'crisolytic', has the potential to eliminate pre-cancerous lesions and tumours exhibiting short dysfunctional telomeres.},
}
@article {pmid30679552,
year = {2019},
author = {Toupance, S and Villemonais, D and Germain, D and Gegout-Petit, A and Albuisson, E and Benetos, A},
title = {The individual's signature of telomere length distribution.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {685},
pmid = {30679552},
issn = {2045-2322},
mesh = {Aged ; Aged, 80 and over ; Blotting, Southern ; Female ; Humans ; Leukocytes/physiology ; Linear Models ; Male ; Middle Aged ; Telomere/*genetics ; Telomere Homeostasis/genetics ; },
abstract = {Mean telomere length in human leukocyte DNA samples reflects the different lengths of telomeres at the ends of the 23 chromosomes and in an admixture of cells. However, only rudimentary information is available regarding the distribution of telomere lengths in all chromosomes and the different cell types in leukocyte samples. Understanding the configuration of leukocyte telomere length distribution (LTLD) could be helpful in capturing intrinsic elements that are not provided by the mean leukocyte telomere length (mLTL). The objective of this study was to analyse LTLD and its temporal variation in adults. Leukocyte samples were donated on two occasions (8 years apart) by 72 participants in the ADELAHYDE study. Telomere length was measured by Southern blotting of the terminal restriction fragments. Individuals with comparable mLTLs displayed different shapes of LTLDs. Inter-individual variation in LTLD shape was much larger than intra-individual variation in LTLD shape between baseline and follow-up leukocyte samples. These results show an important individual stability of LTLD shape over time indicating that each individual has a characteristic LTLD signature.},
}
@article {pmid30679155,
year = {2019},
author = {Lakota, K and Hanumanthu, VS and Agrawal, R and Carns, M and Armanios, M and Varga, J},
title = {Short lymphocyte, but not granulocyte, telomere length in a subset of patients with systemic sclerosis.},
journal = {Annals of the rheumatic diseases},
volume = {78},
number = {8},
pages = {1142-1144},
doi = {10.1136/annrheumdis-2018-214499},
pmid = {30679155},
issn = {1468-2060},
mesh = {Cohort Studies ; Female ; Granulocytes/cytology ; Humans ; Lung Diseases, Interstitial/epidemiology/*genetics/physiopathology ; Lymphocytes/cytology ; Male ; Predictive Value of Tests ; Prognosis ; Retrospective Studies ; Scleroderma, Systemic/epidemiology/*genetics/physiopathology ; Sensitivity and Specificity ; Statistics, Nonparametric ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere Shortening/*genetics ; United Kingdom ; },
}
@article {pmid30673617,
year = {2019},
author = {Zhang, JM and Yadav, T and Ouyang, J and Lan, L and Zou, L},
title = {Alternative Lengthening of Telomeres through Two Distinct Break-Induced Replication Pathways.},
journal = {Cell reports},
volume = {26},
number = {4},
pages = {955-968.e3},
pmid = {30673617},
issn = {2211-1247},
support = {R01 CA197779/CA/NCI NIH HHS/United States ; R01 GM076388/GM/NIGMS NIH HHS/United States ; R01 GM118833/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; *DNA Breaks ; DNA Polymerase III/genetics/*metabolism ; DNA Replication/*physiology ; Humans ; Rad52 DNA Repair and Recombination Protein/genetics/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {Alternative lengthening of telomeres (ALT) is a telomerase-independent but recombination-dependent pathway that maintains telomeres. Here, we describe an assay to visualize ALT-mediated telomeric DNA synthesis in ALT-associated PML bodies (APBs) without DNA-damaging agents or replication inhibitors. Using this assay, we find that ALT occurs through two distinct mechanisms. One of the ALT mechanisms requires RAD52, a protein implicated in break-induced DNA replication (BIR). We demonstrate that RAD52 directly promotes telomeric D-loop formation in vitro and is required for maintaining telomeres in ALT-positive cells. Unexpectedly, however, RAD52 is dispensable for C-circle formation, a hallmark of ALT. In RAD52-knockout ALT cells, C-circle formation and RAD52-independent ALT DNA synthesis gradually increase as telomeres are shortened, and these activities are dependent on BLM and BIR proteins POLD3 and POLD4. These results suggest that ALT occurs through a RAD52-dependent and a RAD52-independent BIR pathway, revealing the bifurcated framework and dynamic nature of this process.},
}
@article {pmid30672119,
year = {2019},
author = {Atema, E and Mulder, E and van Noordwijk, AJ and Verhulst, S},
title = {Ultralong telomeres shorten with age in nestling great tits but are static in adults and mask attrition of short telomeres.},
journal = {Molecular ecology resources},
volume = {19},
number = {3},
pages = {648-658},
pmid = {30672119},
issn = {1755-0998},
support = {821.01.003//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; },
mesh = {Age Factors ; Aging ; Animals ; Birds/*genetics ; *Telomere ; },
abstract = {Telomere length (TL) is increasingly being used as a biomarker of senescence, but measuring telomeres remains a challenge. Within tissue samples, TL varies between cells and chromosomes. Class I telomeres are (presumably static) interstitial telomeric sequences, while terminal telomeres have been divided in shorter (Class II) telomeres and ultralong (Class III) telomeres, and the presence of the latter varies strongly between species. Class II telomeres typically shorten with age, but little is known of Class III telomere dynamics. Using multiple experimental approaches, we show great tits to have ultralong telomeres, and we investigated age effects on Class II and III telomeres using a longitudinal approach (our method excludes Class I telomeres). In adults, TL averaged over the whole distribution did not significantly change with age. However, more detailed analyses showed that Class II TL did shorten with age, and, as in other species, the longest Class II telomeres within individuals shortened more quickly with age. In contrast, Class III TL did not shorten with age within individual adults. Surprisingly, we found the opposite pattern in nestlings: Class III TL shortened significantly with age, while the age effect on Class II TL was close to zero. Thus, Class III TL may provide information on developmental history, while Class II TL provides information on telomere dynamics in adulthood. These findings have practical implications for telomere studies and raise the interesting question of what causes variation in TL dynamics between chromosomes within individuals and how this is related to development.},
}
@article {pmid30671916,
year = {2019},
author = {Sosnowski, DW and Kliewer, W and York, TP and Amstadter, AB and Jackson-Cook, CK and Winter, MA},
title = {Familial support following childhood sexual abuse is associated with longer telomere length in adult females.},
journal = {Journal of behavioral medicine},
volume = {42},
number = {5},
pages = {911-923},
pmid = {30671916},
issn = {1573-3521},
support = {R01 AG037986/AG/NIA NIH HHS/United States ; R01AG037986/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Adult Survivors of Child Abuse/*statistics &amp; numerical data ; Aged ; Child ; Child Abuse, Sexual/*statistics &amp; numerical data ; Female ; Humans ; Middle Aged ; Optimism/*psychology ; *Social Support ; *Telomere Shortening ; Twins, Monozygotic/genetics/psychology ; Young Adult ; },
abstract = {Robust associations between adverse childhood experiences and shortened telomere length exist, but few studies have examined factors that may moderate this association, particularly with a resilience framework. The present study examined the association between exposure to childhood sexual abuse (and abuse severity) and mean telomere length, and whether social support and optimism moderated this association. The sample included 99 White monozygotic female twins, ranging in age from 35 to 70 (Mage = 52.74, SD = 8.55 years), who provided a blood sample for telomere assay, and data on their childhood sexual abuse history, trait optimism, and current social support. Linear mixed effects models were employed to test study hypotheses. There were no effects of exposure to abuse or abuse severity on mean telomere length, nor were there main or moderating effects of optimism, in analyses of the full sample. However, in analyses that only included women exposed to abuse, there was an abuse type × support interaction: among women who experienced abuse in forms other than intercourse, higher levels of social support were associated with longer mean telomere length. Findings from the current study clarify the role of childhood sexual abuse in telomere attrition, and identify one factor that may protect against the negative biological effects of childhood sexual abuse.},
}
@article {pmid30671630,
year = {2019},
author = {Weber, J and Jörres, R and Kronseder, A and Müller, A and Weigl, M and Chmelar, C},
title = {Learning on the job, the use of selection, optimization, and compensation strategies, and their association with telomere length as an indicator of biological aging.},
journal = {International archives of occupational and environmental health},
volume = {92},
number = {3},
pages = {361-370},
pmid = {30671630},
issn = {1432-1246},
mesh = {*Adaptation, Psychological ; Adult ; Aging/blood/*genetics ; Biomarkers/blood ; Cross-Sectional Studies ; Female ; Germany ; Homes for the Aged ; Humans ; Learning/*physiology ; Leukocytes ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Telomere/genetics ; *Telomere Shortening ; Workplace/psychology ; },
abstract = {PURPOSE: Due to the increased need for retention of older workforce caused by demographic changes in industrialized countries, support of healthy aging in occupational settings is of increasing relevance. This study examines the relationship between leucocyte telomere length (LTL), a potential biomarker for biological aging, and selection, optimization, and compensation (SOC) and learning opportunities as strategies involving efficient management and gain of resources at work.<br><br>METHODS: Within a cross-sectional study, blood samples were drawn from 141 geriatric care professionals to measure LTL by quantitative real-time polymerase-chain reaction. Furthermore, all participants were asked with standardized questionnaires to rate their learning opportunities at work and use of SOC strategies. Analyses were performed by multiple linear regressions.<br><br>RESULTS: SOC use, especially compensation, tended to be negatively, and learning opportunities tended to be positively associated with LTL. Furthermore, a significant interaction was found between optimization and learning opportunities, such that LTL and learning opportunities were only positively associated when optimization was high.<br><br>CONCLUSIONS: Resources at work were weakly associated with telomere length, which is not unexpected in view of the multiplicity of factors affecting LTL. The results further suggest that a mismatch between SOC and learning opportunities may negatively affect successful aging. They also suggest that more detailed research on biological aging and its relation to resources at work is needed.},
}
@article {pmid30670828,
year = {2019},
author = {Pintado-Berninches, L and Fernandez-Varas, B and Benitez-Buelga, C and Manguan-Garcia, C and Serrano-Benitez, A and Iarriccio, L and Carrillo, J and Guenechea, G and Egusquiaguirre, SP and Pedraz, JL and Hernández, RM and Igartua, M and Arias-Salgado, EG and Cortés-Ledesma, F and Sastre, L and Perona, R},
title = {GSE4 peptide suppresses oxidative and telomere deficiencies in ataxia telangiectasia patient cells.},
journal = {Cell death and differentiation},
volume = {26},
number = {10},
pages = {1998-2014},
pmid = {30670828},
issn = {1476-5403},
mesh = {Ataxia Telangiectasia/genetics/*metabolism/pathology ; Ataxia Telangiectasia Mutated Proteins/genetics/metabolism ; Cell Cycle Proteins/biosynthesis/chemistry/genetics/*metabolism ; Cell Line ; DNA Breaks, Double-Stranded ; DNA Damage ; Fibroblasts/metabolism/pathology ; Humans ; Nanoparticles/chemistry ; Nuclear Proteins/biosynthesis/chemistry/genetics/*metabolism ; Oxidative Stress/physiology ; Peptide Fragments/biosynthesis/chemistry/genetics/*metabolism ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Telomerase/metabolism ; Telomere/genetics/*metabolism/pathology ; },
abstract = {Ataxia telangiectasia (AT) is a genetic disease caused by mutations in the ATM gene but the mechanisms underlying AT are not completely understood. Key functions of the ATM protein are to sense and regulate cellular redox status and to transduce DNA double-strand break signals to downstream effectors. ATM-deficient cells show increased ROS accumulation, activation of p38 protein kinase, and increased levels of DNA damage. GSE24.2 peptide and a short derivative GSE4 peptide corresponding to an internal domain of Dyskerin have proved to induce telomerase activity, decrease oxidative stress, and protect from DNA damage in dyskeratosis congenita (DC) cells. We have found that expression of GSE24.2 and GSE4 in human AT fibroblast is able to decrease DNA damage, detected by γ-H2A.X and 53BP1 foci. However, GSE24.2/GSE4 expression does not improve double-strand break signaling and repair caused by the lack of ATM activity. In contrast, they cause a decrease in 8-oxoguanine and OGG1-derived lesions, particularly at telomeres and mitochondrial DNA, as well as in reactive oxygen species, in parallel with increased expression of SOD1. These cells also showed lower levels of IL6 and decreased p38 phosphorylation, decreased senescence and increased ability to divide for longer times. Additionally, these cells are more resistant to treatment with H202 and the radiomimetic-drug bleomycin. Finally, we found shorter telomere length (TL) in AT cells, lower levels of TERT expression, and telomerase activity that were also partially reverted by GSE4. These observations suggest that GSE4 may be considered as a new therapy for the treatment of AT that counteracts the cellular effects of high ROS levels generated in AT cells and in addition increases telomerase activity contributing to increased cell proliferation.},
}
@article {pmid30669451,
year = {2019},
author = {Turner, KJ and Vasu, V and Griffin, DK},
title = {Telomere Biology and Human Phenotype.},
journal = {Cells},
volume = {8},
number = {1},
pages = {},
pmid = {30669451},
issn = {2073-4409},
mesh = {Aging ; DNA Replication ; Homeostasis ; Humans ; Phenotype ; Telomere/chemistry/*metabolism ; Telomere Homeostasis ; },
abstract = {Telomeres are nucleoprotein structures that cap the end of each chromosome arm and function to maintain genome stability. The length of telomeres is known to shorten with each cell division and it is well-established that telomere attrition is related to replicative capacity in vitro. Moreover, telomere loss is also correlated with the process of aging in vivo. In this review, we discuss the mechanisms that lead to telomere shortening and summarise telomere homeostasis in humans throughout a lifetime. In addition, we discuss the available evidence that shows that telomere shortening is related to human aging and the onset of age-related disease.},
}
@article {pmid30654521,
year = {2019},
author = {Procházková Schrumpfová, P and Fojtová, M and Fajkus, J},
title = {Telomeres in Plants and Humans: Not So Different, Not So Similar.},
journal = {Cells},
volume = {8},
number = {1},
pages = {},
pmid = {30654521},
issn = {2073-4409},
mesh = {Cellular Senescence/genetics ; Chromatin/metabolism ; Epigenesis, Genetic ; Humans ; Plants/*metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {Parallel research on multiple model organisms shows that while some principles of telomere biology are conserved among all eukaryotic kingdoms, we also find some deviations that reflect different evolutionary paths and life strategies, which may have diversified after the establishment of telomerase as a primary mechanism for telomere maintenance. Much more than animals, plants have to cope with environmental stressors, including genotoxic factors, due to their sessile lifestyle. This is, in principle, made possible by an increased capacity and efficiency of the molecular systems ensuring maintenance of genome stability, as well as a higher tolerance to genome instability. Furthermore, plant ontogenesis differs from that of animals in which tissue differentiation and telomerase silencing occur during early embryonic development, and the "telomere clock" in somatic cells may act as a preventive measure against carcinogenesis. This does not happen in plants, where growth and ontogenesis occur through the serial division of apical meristems consisting of a small group of stem cells that generate a linear series of cells, which differentiate into an array of cell types that make a shoot and root. Flowers, as generative plant organs, initiate from the shoot apical meristem in mature plants which is incompatible with the human-like developmental telomere shortening. In this review, we discuss differences between human and plant telomere biology and the implications for aging, genome stability, and cell and organism survival. In particular, we provide a comprehensive comparative overview of telomere proteins acting in humans and in Arabidopsis thaliana model plant, and discuss distinct epigenetic features of telomeric chromatin in these species.},
}
@article {pmid30653507,
year = {2019},
author = {Blokhina, YP and Nguyen, AD and Draper, BW and Burgess, SM},
title = {The telomere bouquet is a hub where meiotic double-strand breaks, synapsis, and stable homolog juxtaposition are coordinated in the zebrafish, Danio rerio.},
journal = {PLoS genetics},
volume = {15},
number = {1},
pages = {e1007730},
pmid = {30653507},
issn = {1553-7404},
support = {R01 GM075119/GM/NIGMS NIH HHS/United States ; R01 GM047915/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromosome Pairing/genetics ; Chromosomes/*genetics ; DNA Breaks, Double-Stranded ; Embryonic Development/genetics ; Endodeoxyribonucleases/*genetics ; Female ; In Situ Hybridization, Fluorescence ; Male ; Meiosis/*genetics ; Prophase/genetics ; Spermatocytes/growth &amp; development/metabolism ; Telomere/*genetics ; Testis/growth &amp; development/pathology ; Zebrafish/genetics ; },
abstract = {Meiosis is a cellular program that generates haploid gametes for sexual reproduction. While chromosome events that contribute to reducing ploidy (homologous chromosome pairing, synapsis, and recombination) are well conserved, their execution varies across species and even between sexes of the same species. The telomere bouquet is a conserved feature of meiosis that was first described nearly a century ago, yet its role is still debated. Here we took advantage of the prominent telomere bouquet in zebrafish, Danio rerio, and super-resolution microscopy to show that axis morphogenesis, synapsis, and the formation of double-strand breaks (DSBs) all take place within the immediate vicinity of telomeres. We established a coherent timeline of events and tested the dependence of each event on the formation of Spo11-induced DSBs. First, we found that the axis protein Sycp3 loads adjacent to telomeres and extends inward, suggesting a specific feature common to all telomeres seeds the development of the axis. Second, we found that newly formed axes near telomeres engage in presynaptic co-alignment by a mechanism that depends on DSBs, even when stable juxtaposition of homologous chromosomes at interstitial regions is not yet evident. Third, we were surprised to discover that ~30% of telomeres in early prophase I engage in associations between two or more chromosome ends and these interactions decrease in later stages. Finally, while pairing and synapsis were disrupted in both spo11 males and females, their reproductive phenotypes were starkly different; spo11 mutant males failed to produce sperm while females produced offspring with severe developmental defects. Our results support zebrafish as an important vertebrate model for meiosis with implications for differences in fertility and genetically derived birth defects in males and females.},
}
@article {pmid30650660,
year = {2019},
author = {Liu, J and Wang, L and Wang, Z and Liu, JP},
title = {Roles of Telomere Biology in Cell Senescence, Replicative and Chronological Ageing.},
journal = {Cells},
volume = {8},
number = {1},
pages = {},
pmid = {30650660},
issn = {2073-4409},
mesh = {Animals ; *Cellular Senescence ; DNA Repair/physiology ; Humans ; *Longevity ; Mice ; Models, Biological ; Saccharomyces cerevisiae ; Telomere/*physiology ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Telomeres with G-rich repetitive DNA and particular proteins as special heterochromatin structures at the termini of eukaryotic chromosomes are tightly maintained to safeguard genetic integrity and functionality. Telomerase as a specialized reverse transcriptase uses its intrinsic RNA template to lengthen telomeric G-rich strand in yeast and human cells. Cells sense telomere length shortening and respond with cell cycle arrest at a certain size of telomeres referring to the "Hayflick limit." In addition to regulating the cell replicative senescence, telomere biology plays a fundamental role in regulating the chronological post-mitotic cell ageing. In this review, we summarize the current understandings of telomere regulation of cell replicative and chronological ageing in the pioneer model system Saccharomyces cerevisiae and provide an overview on telomere regulation of animal lifespans. We focus on the mechanisms of survivals by telomere elongation, DNA damage response and environmental factors in the absence of telomerase maintenance of telomeres in the yeast and mammals.},
}
@article {pmid30650526,
year = {2019},
author = {Squassina, A and Pisanu, C and Vanni, R},
title = {Mood Disorders, Accelerated Aging, and Inflammation: Is the Link Hidden in Telomeres?.},
journal = {Cells},
volume = {8},
number = {1},
pages = {},
pmid = {30650526},
issn = {2073-4409},
mesh = {Aging, Premature/complications/*genetics ; Animals ; Humans ; Inflammation/complications/*genetics ; Mice ; Mood Disorders/drug therapy/*etiology ; Psychotropic Drugs/*pharmacology/therapeutic use ; Rats ; Telomere Shortening/*drug effects ; },
abstract = {Mood disorders are associated with an increased risk of aging-related diseases, which greatly contribute to the excess morbidity and mortality observed in affected individuals. Clinical and molecular findings also suggest that mood disorders might be characterized by a permanent state of low-grade inflammation. At the cellular level, aging translates into telomeres shortening. Intriguingly, inflammation and telomere shortening show a bidirectional association: a pro-inflammatory state seems to contribute to aging and telomere dysfunction, and telomere attrition is able to induce low-grade inflammation. Several independent studies have reported shorter telomere length and increased levels of circulating inflammatory cytokines in mood disorders, suggesting a complex interplay between altered inflammatory[-]immune responses and telomere dynamics in the etiopathogenesis of these disorders. In this review, we critically discuss studies investigating the role of telomere attrition and inflammation in the pathogenesis and course of mood disorders, and in pharmacological treatments with psychotropic medications.},
}
@article {pmid30643221,
year = {2019},
author = {Meinilä, J and Perälä, MM and Kautiainen, H and Männistö, S and Kanerva, N and Shivappa, N and Hébert, JR and Iozzo, P and Guzzardi, MA and Eriksson, JG},
title = {Healthy diets and telomere length and attrition during a 10-year follow-up.},
journal = {European journal of clinical nutrition},
volume = {73},
number = {10},
pages = {1352-1360},
doi = {10.1038/s41430-018-0387-4},
pmid = {30643221},
issn = {1476-5640},
mesh = {Cross-Sectional Studies ; Diet ; *Diet, Healthy ; Diet, Mediterranean ; Female ; Finland ; Follow-Up Studies ; Humans ; Inflammation/epidemiology ; Longitudinal Studies ; Male ; Middle Aged ; Surveys and Questionnaires ; Telomere/*ultrastructure ; Telomere Shortening/*physiology ; },
abstract = {BACKGROUND: Telomeres are repeats of DNA that contain the sequence TTAGGG at the ends of each chromosome, and their function is to protect DNA from damage. Little evidence exists regarding the relationship between dietary patterns and telomere length, especially derived applying longitudinal design. The aim was to study if overall dietary pattern is associated with leukocyte telomere length (LTL) or faster telomere attrition or both.<br><br>METHODS: The setting was longitudinal and observational. Participants were 456 men and 590 women whose birth settled in between 1934 and 1944 and who participated in the Helsinki Birth Cohort Study. Baltic sea diet score (BSDS), modified Mediterranean diet score (mMED), and dietary inflammatory index (DII[&#xae;]) were calculated based on a 128-item food frequency questionnaire (FFQ) collected in 2001-2004. LTL was measured twice, in 2001-2004 and in 2011-2013 by quantitative real-time polymerase chain reaction. Association between the dietary patterns and LTL were analysed by general linear models with appropriate contrasts.<br><br>RESULTS: BSDS, mMED, and DII did not associate with LTL in the cross-sectional analysis in men or women. Higher mMED at baseline (2001-2004) was associated with slightly faster LTL shortening during the follow-up (standardized &#xdf; -0.08, 95% CI -0.15, -0.01). No association between mMED and LTL change was found in men. Adherence to BSDS and DII did not associate with LTL change in men or women.<br><br>CONCLUSION: Baltic sea diet, Mediterranean diet, and diet's inflammatory potential seem to have only little impact on telomere length and telomere attrition in elderly Finnish men and women.},
}
@article {pmid30640301,
year = {2021},
author = {Aguiar, SS and Rosa, TS and Sousa, CV and Santos, PA and Barbosa, LP and Deus, LA and Rosa, EC and Andrade, RV and Simões, HG},
title = {Influence of Body Fat on Oxidative Stress and Telomere Length of Master Athletes.},
journal = {Journal of strength and conditioning research},
volume = {35},
number = {6},
pages = {1693-1699},
doi = {10.1519/JSC.0000000000002932},
pmid = {30640301},
issn = {1533-4287},
mesh = {Adipose Tissue ; Aging ; *Athletes ; Humans ; Middle Aged ; Oxidative Stress ; *Telomere/genetics ; },
abstract = {Aguiar, SS, Rosa, TS, Sousa, CV, Santos, PA, Barbosa, LP, Deus, LA, Rosa, EC, Andrade, RV, and Simões, HG. Influence of body fat on oxidative stress and telomere length of master athletes. J Strength Cond Res 35(6): 1693-1699, 2021-The present investigation analyzed the role of body fat and training history on biological aging of master athletes by comparing and verifying the relationships between markers of adiposity, oxidative balance, and telomere length (TL) in middle-aged runners and untrained individuals. Master athletes (sprinters and endurance runners, n = 21; 51.62 ± 8.19 years) and untrained age-matched controls (n = 11; 45.41 ± 10.34 years) had blood samples collected for biochemical and biomolecular analyzes. Pro-oxidant and antioxidant measures as well as DNA extraction were performed using commercial kits. Relative TL (T/S) was determined in leukocytes through quantitative polymerase chain reaction analyses. Master athletes had lower body fat and longer TL than untrained controls (body fat: 12.21 ± 4.14% vs. 26.03 ± 4.29%; TL: 1.10 ± 0.84 vs. 0.56 ± 0.56 T/S; p < 0.05). Furthermore, master athletes also showed a better oxidative balance than untrained controls (p < 0.05). A negative correlation was observed between TL and body fat (r = -0.471; p = 0.007), and conicity index (r = -0.407; p = 0.021), catalase activity (r = -0.569; p = 0.001), and CAT/TBARS ratio (r = -0.463; p = 0.008) for the whole sample. In conclusion, master athletes have longer TL, better oxidative profile, and lower body fat than untrained individuals. Moreover, for this middle-aged sample, body fat was inversely correlated with both TL and markers of oxidative balance, demonstrating the key role of adiposity in biological aging.},
}
@article {pmid30635297,
year = {2019},
author = {Newton, CA and Oldham, JM and Ley, B and Anand, V and Adegunsoye, A and Liu, G and Batra, K and Torrealba, J and Kozlitina, J and Glazer, C and Strek, ME and Wolters, PJ and Noth, I and Garcia, CK},
title = {Telomere length and genetic variant associations with interstitial lung disease progression and survival.},
journal = {The European respiratory journal},
volume = {53},
number = {4},
pages = {},
pmid = {30635297},
issn = {1399-3003},
support = {KL2 TR001870/TR/NCATS NIH HHS/United States ; UL1 TR001105/TR/NCATS NIH HHS/United States ; R01 HL093096/HL/NHLBI NIH HHS/United States ; R01 HL130796/HL/NHLBI NIH HHS/United States ; KL2 TR001103/TR/NCATS NIH HHS/United States ; K23 HL138190/HL/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Cohort Studies ; Disease Progression ; Female ; Genetic Variation ; Humans ; Intracellular Signaling Peptides and Proteins/*genetics ; Leukocytes ; Lung Diseases, Interstitial/etiology/*genetics/*mortality ; Male ; Middle Aged ; Mucin-5B/*genetics ; Retrospective Studies ; Survival Rate ; Telomere/*ultrastructure ; },
abstract = {Leukocyte telomere length (LTL), MUC5B rs35705950 and TOLLIP rs5743890 have been associated with idiopathic pulmonary fibrosis (IPF).In this observational cohort study, we assessed the associations between these genomic markers and outcomes of survival and rate of disease progression in patients with interstitial pneumonia with autoimmune features (IPAF, n=250) and connective tissue disease-associated interstitial lung disease (CTD-ILD, n=248). IPF (n=499) was used as a comparator.The LTL of IPAF and CTD-ILD patients (mean age-adjusted log-transformed T/S of -0.05±0.29 and -0.04±0.25, respectively) is longer than that of IPF patients (-0.17±0.32). For IPAF patients, LTL <10th percentile is associated with faster lung function decline compared to LTL ≥10th percentile (-6.43% per year versus -0.86% per year; p<0.0001) and worse transplant-free survival (hazard ratio 2.97, 95% CI 1.70-5.20; p=0.00014). The MUC5B rs35705950 minor allele frequency (MAF) is greater for IPAF patients (23.2, 95% CI 18.8-28.2; p<0.0001) than controls and is associated with worse transplant-free IPAF survival (hazard ratio 1.92, 95% CI 1.18-3.13; p=0.0091). Rheumatoid arthritis (RA)-associated ILD (RA-ILD) has a shorter LTL than non-RA CTD-ILD (-0.14±0.27 versus -0.01±0.23; p=0.00055) and higher MUC5B MAF (34.6, 95% CI 24.4-46.3 versus 14.1, 95% CI 9.8-20.0; p=0.00025). Neither LTL nor MUC5B are associated with transplant-free CTD-ILD survival.LTL and MUC5B MAF have different associations with lung function progression and survival for IPAF and CTD-ILD.},
}
@article {pmid30633884,
year = {2019},
author = {Špoljarić, AM and Rubelj, I and Huzak, M},
title = {Mathematical model and computer simulations of telomere loss.},
journal = {Journal of theoretical biology},
volume = {465},
number = {},
pages = {78-89},
doi = {10.1016/j.jtbi.2019.01.007},
pmid = {30633884},
issn = {1095-8541},
mesh = {*Algorithms ; Cells, Cultured ; Cellular Senescence/genetics ; Chromosome Deletion ; *Computer Simulation ; Fibroblasts/cytology/metabolism ; Humans ; *Models, Genetic ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {The molecular mechanisms that control the limited number of human cell divisions has occupied researchers ever since its first description in 1961. There is evidence that this limited growth capacity, referred to as cellular or replicative senescence, is the basis for organismal ageing. Numerous studies point to the molecular mechanisms of telomere involvement in this phenomenon. A hallmark of cell senescence is high stochasticity where individual cells enter senescence in a completely random and stochastic fashion. Therefore, mathematical modelling and computational simulations of telomere dynamics are often used to explain this stochastic nature of cell ageing. Models published thus far were based on the molecular mechanisms of telomere biology and how they dictate the dynamics of cell culture proliferation. In the present work we propose an advanced model of telomere controlled cell senescence based on abrupt telomere shortening, thus explaining some important but thus far overlooked aspects of cell senescence. We test our theory by simulating the proliferative potential and two-sister experiment originally conducted by Smith and Whitney in 1980.},
}
@article {pmid30631211,
year = {2019},
author = {Olbertova, H and Plevova, K and Stranska, K and Pospisilova, S},
title = {Telomere dynamics in adult hematological malignancies.},
journal = {Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia},
volume = {163},
number = {1},
pages = {1-7},
doi = {10.5507/bp.2018.084},
pmid = {30631211},
issn = {1804-7521},
mesh = {Adult ; Aging/genetics/*physiology ; Biomarkers, Tumor/metabolism ; Cell Division ; Cellular Senescence/genetics/*physiology ; Chromosomal Instability/genetics ; Hematologic Neoplasms/genetics/*physiopathology ; Humans ; Telomerase/*metabolism ; Telomere/*physiology ; },
abstract = {Telomeres are repetitive DNA sequences protecting physical ends of linear chromosomes against degradation and end-to-end chromosomal fusion. Telomeres shorten with each cell division, which regulates the cellular lifespan in somatic cells and limits their renewal capacity. Cancer cells are often able to overcome this physiological barrier and become immortal with unlimited replicative capacity. In this review, we present current knowledge on the role of telomeres in human aging with a focus on their behavior in hematological malignancies of adults. Associations of telomere length to age-related diseases and to the prevention of telomere shortening are also discussed.},
}
@article {pmid30631124,
year = {2019},
author = {Horvath, K and Eisenberg, D and Stone, R and Anderson, J and Kark, J and Aviv, A},
title = {Paternal Age and Transgenerational Telomere Length Maintenance: A Simulation Model.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {20},
pmid = {30631124},
issn = {2045-2322},
support = {R01 HL116446/HL/NHLBI NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; },
mesh = {Computer Simulation ; Humans ; *Models, Biological ; *Paternal Age ; *Telomere Homeostasis ; },
abstract = {Telomere length (TL) in offspring is positively correlated with paternal age at the time of the offspring conception. The paternal-age-at-conception (PAC) effect on TL is puzzling, and its biological implication at the population level is unknown. Using a probabilistic model of transgenerational TL and population dynamics, we simulated the effect of PAC on TL in individuals over the course of 1,000 years. Findings suggest a key role for an isometric PAC midpoint (PACmp) in modulating TL across generations, such that offspring conceived by males younger than the isometric PACmp have comparatively short telomeres, while offspring conceived by males older than the isometric PACmp have comparatively long telomeres. We further show that when cancer incidence escalates, the average PAC drops below the isometric PACmp and transgenerational adaptation to cancer ensues through TL shortening. We propose that PAC serves to maintain an optimal TL across generations.},
}
@article {pmid30626097,
year = {2019},
author = {Laberthonnière, C and Magdinier, F and Robin, JD},
title = {Bring It to an End: Does Telomeres Size Matter?.},
journal = {Cells},
volume = {8},
number = {1},
pages = {},
pmid = {30626097},
issn = {2073-4409},
mesh = {Aging/metabolism ; Animals ; Cellular Senescence ; Epigenesis, Genetic ; Humans ; Telomere/*genetics/*metabolism ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Telomeres are unique nucleoprotein structures. Found at the edge of each chromosome, their main purpose is to mask DNA ends from the DNA-repair machinery by formation of protective loops. Through life and cell divisions, telomeres shorten and bring cells closer to either cell proliferation crisis or senescence. Beyond this mitotic clock role attributed to the need for telomere to be maintained over a critical length, the very tip of our DNA has been shown to impact transcription by position effect. TPE and a long-reach counterpart, TPE-OLD, are mechanisms recently described in human biology. Still in infancy, the mechanism of action of these processes and their respective genome wide impact remain to be resolved. In this review, we will discuss recent findings on telomere dynamics, TPE, TPE-OLD, and lessons learnt from model organisms.},
}
@article {pmid30625144,
year = {2019},
author = {Tannous, J and Mwangi, B and Hasan, KM and Narayana, PA and Steinberg, JL and Walss-Bass, C and Moeller, FG and Schmitz, JM and Lane, SD},
title = {Measures of possible allostatic load in comorbid cocaine and alcohol use disorder: Brain white matter integrity, telomere length, and anti-saccade performance.},
journal = {PloS one},
volume = {14},
number = {1},
pages = {e0199729},
pmid = {30625144},
issn = {1932-6203},
support = {P50 DA009262/DA/NIDA NIH HHS/United States ; U54 DA038999/DA/NIDA NIH HHS/United States ; UL1 TR002649/TR/NCATS NIH HHS/United States ; },
mesh = {Adult ; Aged ; *Alcoholism/diagnostic imaging/metabolism ; *Brain/diagnostic imaging/metabolism ; *Cocaine-Related Disorders/diagnostic imaging/metabolism ; *Diffusion Tensor Imaging ; Female ; Humans ; Male ; Middle Aged ; Telomere/*metabolism/pathology ; *Telomere Homeostasis ; *White Matter/diagnostic imaging/metabolism ; },
abstract = {Chronic cocaine and alcohol use impart significant stress on biological and cognitive systems, resulting in changes consistent with an allostatic load model of neurocognitive impairment. The present study measured potential markers of allostatic load in individuals with comorbid cocaine/alcohol use disorders (CUD/AUD) and control subjects. Measures of brain white matter (WM), telomere length, and impulsivity/attentional bias were obtained. WM (CUD/AUD only) was indexed by diffusion tensor imaging metrics, including radial diffusivity (RD) and fractional anisotropy (FA). Telomere length was indexed by the telomere to single copy gene (T/S) ratio. Impulsivity and attentional bias to drug cues were measured via eye-tracking, and were also modeled using the Hierarchical Diffusion Drift Model (HDDM). Average whole-brain RD and FA were associated with years of cocaine use (R2 = 0.56 and 0.51, both p < .005) but not years of alcohol use. CUD/AUD subjects showed more anti-saccade errors (p < .01), greater attentional bias scores (p < .001), and higher HDDM drift rates on cocaine-cue trials (Bayesian probability CUD/AUD > control = p > 0.99). Telomere length was shorter in CUD/AUD, but the difference was not statistically significant. Within the CUD/AUD group, exploratory regression using an elastic-net model determined that more years of cocaine use, older age, larger HDDM drift rate differences and shorter telomere length were all predictive of WM as measured by RD (model R2 = 0.79). Collectively, the results provide modest support linking CUD/AUD to putative markers of allostatic load.},
}
@article {pmid30624965,
year = {2019},
author = {Molina-Molina, M},
title = {Telomere Shortening Is behind the Harm of Immunosuppressive Therapy in Idiopathic Pulmonary Fibrosis.},
journal = {American journal of respiratory and critical care medicine},
volume = {200},
number = {3},
pages = {274-275},
pmid = {30624965},
issn = {1535-4970},
mesh = {Humans ; *Idiopathic Pulmonary Fibrosis ; Telomerase/*genetics ; Telomere ; Telomere Shortening ; },
}
@article {pmid30623606,
year = {2019},
author = {Lu, S and Zhong, J and Wu, M and Huang, K and Zhou, Y and Zhong, Z and Li, Q and Zhou, H},
title = {Genetic analysis of the relation of telomere length-related gene (RTEL1) and coronary heart disease risk.},
journal = {Molecular genetics &amp; genomic medicine},
volume = {7},
number = {3},
pages = {e550},
pmid = {30623606},
issn = {2324-9269},
mesh = {Adult ; Aged ; Aged, 80 and over ; Coronary Disease/*genetics ; DNA Helicases/*genetics ; Female ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; },
abstract = {BACKGROUND: Regulator of telomere elongation helicase 1 (RTEL1), a telomere length-related gene, is closely linked to cancer and age-related diseases. The aim of this study was to investigate the association between genetic polymorphisms in the RTEL1 gene and coronary heart disease (CHD) risk.<br><br>METHODS: In this case-control study, which includes samples from 596 CHD patients and 603 healthy controls, five SNPs in RTEL1 were selected. The genotypes were studied using the Agena MassARRAY platform, and the statistical analyses were performed using the chi-square and Fisher's exact tests, genetic model analysis, and haplotype analysis.<br><br>RESULTS: In the allele model, using the chi-square test, we found that the patients with the "G" allele of rs6010620 and the "C" allele of rs4809324 in the RTEL1 gene showed a decreased risk of CHD once the results were adjusted for age and gender. In the genetic model, logistic regression analyses revealed that the rs6010620 polymorphism conferred a decreased risk of CHD in the codominant model (OR&#xa0;=&#xa0;0.52, 95% CI: 0.31-0.88, p&#xa0;=&#xa0;0.007 for the "G/G" genotype) and the recessive model (OR&#xa0;=&#xa0;0.49, 95% CI: 0.30-0.80, p&#xa0;=&#xa0;0.004 for the "G/G" genotype). In addition, the haplotype "Grs6010620 Trs6010621 Trs4809324 " of RTEL1 was associated with a 0.03-fold decreased risk of CHD once the results were adjusted for age and gender (OR&#xa0;=&#xa0;0.03, 95% CI: 0.01-0.12, p&#xa0;<&#xa0;0.001).<br><br>CONCLUSION: Our findings have demonstrated that the genetic variants of RTEL1 may have a protective role against CHD risk.},
}
@article {pmid30618810,
year = {2018},
author = {Nomikos, NN and Nikolaidis, PT and Sousa, CV and Papalois, AE and Rosemann, T and Knechtle, B},
title = {Exercise, Telomeres, and Cancer: "The Exercise-Telomere Hypothesis".},
journal = {Frontiers in physiology},
volume = {9},
number = {},
pages = {1798},
pmid = {30618810},
issn = {1664-042X},
abstract = {Telomeres are genomic complex at the end of chromosomes that protects the DNA and telomere length (TL) is related to several age-related diseases, lifespan, and cancer. On the other hand, cancer is a multifactorial disease that is responsible for reduce the quality of life and kills millions of people every year. Both, shorter TL and cancer are related and could be treated or prevented depending of the lifestyle. In this review we discuss the possible role of exercise in the relationship between shorter telomeres, telomerase activity, and cancer. In summary, there is evidence that exercise leads to less telomere attrition and exercise also may diminish the risk of cancer, these two outcomes are possible intermediated by a reduction in oxidative stress, and chronic inflammation. Although, there is evidence that shorter TL are associated with cancer, the possible mechanisms that one may lead to the other remains to be clarified. We assume that humans under cancer treatment may suffer a great decrease in quality of life, which may increase sedentary behavior and lead to increased telomere attrition. And those humans with already shorter TL likely lived under a poor lifestyle and might have an increased risk to have cancer.},
}
@article {pmid30616218,
year = {2019},
author = {Kim, N and Sung, JY and Park, JY and Kong, ID and Hughes, TL and Kim, DK},
title = {Association between internet gaming addiction and leukocyte telomere length in Korean male adolescents.},
journal = {Social science &amp; medicine (1982)},
volume = {222},
number = {},
pages = {84-90},
doi = {10.1016/j.socscimed.2018.12.026},
pmid = {30616218},
issn = {1873-5347},
mesh = {Adolescent ; Age Factors ; Behavior, Addictive/epidemiology/*physiopathology ; Cross-Sectional Studies ; Dopamine/blood ; Epinephrine/blood ; Humans ; Hydrocortisone/blood ; *Internet ; Leukocytes/*metabolism ; Male ; Norepinephrine/blood ; Real-Time Polymerase Chain Reaction ; Republic of Korea/epidemiology ; Stress, Psychological/epidemiology ; Telomere/*metabolism ; Time Factors ; *Video Games ; },
abstract = {Internet gaming addiction (IGA) has been associated with many negative health outcomes, especially for youth. In particular, the potential association between IGA and leukocyte telomere length (LTL) has yet to be examined. In this study we compared LTL in Korean male adolescents with and without IGA and examined the association between LTL and autonomic functions. Specifically, plasma catecholamine, serum cortisol, and psychological stress levels were measured as autonomic functions. Data were collected using participant blood samples analyzed for LTL, catecholamine, and cortisol levels and a set of questionnaires to assess IGA and psychological stress levels of the participants. The LTL measurements were made using a qPCR-based technique, and the relative LTL was calculated as the telomere/single copy (T/S) ratio. T/S ratio was significantly shorter in the IGA group than in the non-IGA group (150.43 ± 6.20 and 187.23 ± 6.42, respectively; p < .001) after adjusting for age. In a univariate regression analysis, age, daily Internet gaming time, IGA score, and catecholamine level (epinephrine and norepinephrine) were significantly associated with T/S ratio. However, duration of Internet gaming exposure, dopamine, cortisol, and psychological stress levels were not found to be associated with T/S ratio. In the final multiple linear regression model, age, daily Internet gaming time, and epinephrine level showed statistically significant relationships with T/S ratio. Our results indicate that in addition to age, involvement in excessive Internet gaming may induce LTL shortening in male adolescents, which may be partially attributable to changes in autonomic function such as catecholamine level. These findings further understanding of the health effects of IGA and highlight the need for screening and intervention strategies for male adolescents with IGA.},
}
@article {pmid30616055,
year = {2019},
author = {Igari, R and Davy, P and Sato, H and Takahashi, Y and Iseki, C and Kato, H and Sato, H and Koyama, S and Ishizawa, K and Allsopp, R and Kato, T},
title = {Cognitive impairment, brain ischemia and shorter telomeres are predictors of mortality in the Japanese elderly: A 13-year prospective community-based study.},
journal = {Journal of the neurological sciences},
volume = {397},
number = {},
pages = {129-134},
doi = {10.1016/j.jns.2018.12.038},
pmid = {30616055},
issn = {1878-5883},
mesh = {Aged ; Aged, 80 and over ; Brain/*diagnostic imaging ; Brain Ischemia/*diagnostic imaging/mortality ; Cognition/physiology ; Cognitive Dysfunction/*diagnosis/mortality ; Female ; Humans ; Independent Living ; Japan/epidemiology ; Magnetic Resonance Imaging ; Male ; Prospective Studies ; Risk Factors ; Survival Rate ; *Telomere ; },
abstract = {OBJECTIVE: To examine whether cognitive impairment, deep white matter hyperintensity (DWMH) on brain MRI, and shorter telomere length would be predictors of mortality in community-dwelling Japanese elderly.<br><br>METHODS: We followed 259 individuals (74% of all the residents at age 70) from age 70 to 83&#x202f;years. The mean observation period was 133&#x202f;&#xb1;&#x202f;34&#x202f;months. The key clinical characteristics examined included DWMH on brain MRI and cognitive function. Telomere length was also measured in 81 subjects. Both univariate and multivariate analyses were performed.<br><br>RESULTS: Of the 259 subjects, 69 subjects (30 men, 39 women; 26.6%) died during the follow-up period. Cognitive impairment, smoking habits, diabetes mellitus, and moderate to severe DWMH were significant predictors of total mortality in univariate analysis. However, only cognitive impairment and moderate to severe DWMH remained as significant independent predictors of death in multivariate analysis. The rate of mortality increased with additional number of risk factors (cognitive impairment and DWMH). The total mortality of subjects with both cognitive impairment and DWMH was 71.4%. The median telomere length was 7.8&#x202f;kb in the deceased and 8.2&#x202f;kb in the living subjects. The deceased subjects had significantly shorter telomere length (P&#x202f;=&#x202f;.0025) than the living subjects. Telomere length with moderate to severe DWMH was higher than without moderate to severe DWMH on brain MRI (P&#x202f;=&#x202f;.017).<br><br>CONCLUSIONS: The present study revealed that cognitive impairment, DWMH, and shorter telomere length were significant predictors of total mortality in the community-dwelling Japanese elderly. Furthermore, the combination of cognitive impairment and DWMH increased the mortality rate, as compared with a single risk factor. It is also clarified that a significant difference was present in telomere length by severity of DWMH.},
}
@article {pmid30615937,
year = {2019},
author = {Mensà, E and Latini, S and Ramini, D and Storci, G and Bonafè, M and Olivieri, F},
title = {The telomere world and aging: Analytical challenges and future perspectives.},
journal = {Ageing research reviews},
volume = {50},
number = {},
pages = {27-42},
doi = {10.1016/j.arr.2019.01.004},
pmid = {30615937},
issn = {1872-9649},
mesh = {Aging/genetics/*metabolism ; Animals ; DNA/genetics/metabolism ; Forecasting ; Humans ; RNA, Long Noncoding/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {Telomeres, the terminal nucleoprotein structures of eukaryotic chromosomes, play pleiotropic functions in cellular and organismal aging. Telomere length (TL) varies throughout life due to the influence of genetic factors and to a complex balancing between "shortening" and "elongation" signals. Telomerase, the only enzyme that can elongate a telomeric DNA chain, and telomeric repeat-containing RNA (TERRA), a long non-coding RNA involved in looping maintenance, play key roles in TL during life. Despite recent advances in the knowledge of TL, TERRA and telomerase activity (TA) biology and their measurement techniques, the experimental and theoretical issues involved raise a number of problems that should carefully be considered by researchers approaching the "telomere world". The increasing use of such parameters - hailed as promising clinically relevant biomarkers - has failed to be paralleled by the development of automated and standardized measurement technology. Consequently, associating given TL values to specific pathological conditions involves on the one hand technological issues and on the other clinical-biological issues related to the planning of clinically relevant association studies. Addressing these issues would help avoid major biases in association studies involving TL and a number of outcomes, especially those focusing on psychological and bio-behavioral variables. The main challenge in telomere research is the development of accurate and reliable measurement methods to achieve simple and sensitive TL, TERRA, and TA detection. The discovery of the localization of telomeres and TERRA in cellular and extracellular compartments had added an additional layer of complexity to the measurement of these age-related biomarkers. Since combined analysis of TL, TERRA and TA may well provide more exhaustive clinical information than a single parameter, we feel it is important for researchers in the various fields to become familiar with their most common measurement techniques and to be aware of the respective merits and drawbacks of these approaches.},
}
@article {pmid30614587,
year = {2019},
author = {Behrens, YL and Thomay, K and Hagedorn, M and Ebersold, J and Schmidt, G and Lentes, J and Davenport, C and Schlegelberger, B and Göhring, G},
title = {Jumping translocations: Short telomeres or pathogenic TP53 variants as underlying mechanism in acute myeloid leukemia and myelodysplastic syndrome?.},
journal = {Genes, chromosomes &amp; cancer},
volume = {58},
number = {3},
pages = {139-148},
doi = {10.1002/gcc.22665},
pmid = {30614587},
issn = {1098-2264},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Chromosome Breakpoints ; Female ; Humans ; Infant ; Karyotype ; Leukemia, Myeloid, Acute/*genetics ; Male ; Middle Aged ; Mutation ; Myelodysplastic Syndromes/*genetics ; *Telomere Shortening ; *Translocation, Genetic ; Tumor Suppressor Protein p53/*genetics ; },
abstract = {Chromosomal rearrangements involving one donor chromosome and two or more recipient chromosomes are called jumping translocations. To date only few cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with jumping translocations have been described and the underlying mechanisms remain unclear. Here, we analyzed 11 AML and 5 MDS cases with jumping translocations. The cases were analyzed by karyotyping, FISH, telomere length measurement, and next-generation sequencing with an AML/MDS gene panel. Cases with jumping translocations showed significantly (P < .01) shorter telomeres in comparison to healthy age-matched controls. Additional neo-telomeres were found in two cases. In total, eight cases showed recipient chromosomes with a breakpoint in the centromeric region all of them harboring a pathogenic variant in the TP53 gene (n = 6) and/or a loss of TP53 (n = 5). By contrast, no pathogenic variant or loss of TP53 was identified in the six cases showing recipient chromosomes with a breakpoint in the telomeric region. In conclusion, our results divide the cohort of AML and MDS cases with jumping translocations into two groups: the first group with a telomeric breakpoint of the recipient chromosome is characterized by short telomeres and a possibly telomere-based mechanism of chromosomal instability formation. The second group with a centromeric breakpoint of the recipient chromosome is defined by mutation and/or loss of TP53. We, therefore, assume that both critically short telomeres as well as pathogenic variants of TP53 influence jumping translocation formation.},
}
@article {pmid30609792,
year = {2019},
author = {Coluzzi, E and Leone, S and Sgura, A},
title = {Oxidative Stress Induces Telomere Dysfunction and Senescence by Replication Fork Arrest.},
journal = {Cells},
volume = {8},
number = {1},
pages = {},
pmid = {30609792},
issn = {2073-4409},
mesh = {Cells, Cultured ; Cellular Senescence/*genetics ; DNA Damage ; *DNA Replication ; Fibroblasts/cytology ; Guanine/analogs &amp; derivatives/pharmacology ; Histones/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Oxidative Stress/*genetics ; Primary Cell Culture ; Shelterin Complex ; Telomere/*genetics ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; Tumor Suppressor p53-Binding Protein 1/metabolism ; },
abstract = {Oxidative DNA damage, particularly 8-oxoguanine, represents the most frequent DNA damage in human cells, especially at the telomeric level. The presence of oxidative lesions in the DNA can hinder the replication fork and is able to activate the DNA damage response. In this study, we wanted to understand the mechanisms by which oxidative damage causes telomere dysfunction and senescence in human primary fibroblasts. After acute oxidative stress at telomeres, our data demonstrated a reduction in TRF1 and TRF2, which are involved in proper telomere replication and T-loop formation, respectively. Furthermore, we observed a higher level of γH2AX with respect to 53BP1 at telomeres, suggesting a telomeric replication fork stall rather than double-strand breaks. To confirm this finding, we studied the replication of telomeres by Chromosome Orientation-FISH (CO-FISH). The data obtained show an increase in unreplicated telomeres after hydrogen peroxide treatment, corroborating the idea that the presence of 8-oxoG can induce replication fork arrest at telomeres. Lastly, we analyzed the H3K9me3 histone mark after oxidative stress at telomeres, and our results showed an increase of this marker, most likely inducing the heterochromatinization of telomeres. These results suggest that 8-oxoG is fundamental in oxidative stress-induced telomeric damage, principally causing replication fork arrest.},
}
@article {pmid30607160,
year = {2018},
author = {Wang, Z and Zhang, Z and Guo, Y and Shui, H and Liu, G and Jin, T and Wang, H},
title = {Shorter Telomere Length Is Associated with Increased Breast Cancer Risk in a Chinese Han Population: A Case-Control Analysis.},
journal = {Journal of breast cancer},
volume = {21},
number = {4},
pages = {391-398},
pmid = {30607160},
issn = {1738-6756},
abstract = {PURPOSE: The aim of this study was to investigate the association of telomere length with breast cancer risk. We simultaneously explored the association between telomerase reverse transcriptase gene polymorphisms and telomere length.<br><br>METHODS: We used real-time quantitative polymerase chain reaction to measure relative telomere length (RTL) in genomic DNA extracted from peripheral blood from 183 breast cancer cases and 191 healthy controls. Genotyping was performed using the Sequenom MassARRAY platform.<br><br>RESULTS: Our results show that breast cancer patients had significantly shorter RTLs than control subjects (p<0.05). When the RTLs were categorized into tertiles, we found that the lowest RTL was significantly associated with increased breast cancer risk compared with the highest RTL (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.40-3.90; p=0.001). Subgroup analyses indicated that risk of breast cancer was also significantly increased in the lowest RTL compared with the highest RTL in age >40 years (OR, 2.41; 95% CI, 1.31-4.43; p=0.005), body mass index &#x2264;24 kg/m[2] (OR, 2.81; 95% CI, 1.55-5.10; p=0.001), and postmenopausal women (OR, 3.94; 95% CI, 1.63-9.51; p=0.002), respectively. In addition, individuals with the AA genotype of rs2853677 have longer telomeres than those of breast cancer patients with the AG genotype (p=0.011).<br><br>CONCLUSION: Our results suggest that shorter RTL was associated with an increased risk of breast cancer. An association was found between the AA genotype of rs2853677 and longer RTLs in the case group. Functional studies are warranted to validate this association and further investigate our findings.},
}
@article {pmid30601031,
year = {2019},
author = {Santana, VP and Miranda-Furtado, CL and Pedroso, DCC and Eiras, MC and Vasconcelos, MAC and Ramos, ES and Calado, RT and Ferriani, RA and Esteves, SC and Dos Reis, RM},
title = {The relationship among sperm global DNA methylation, telomere length, and DNA fragmentation in varicocele: a cross-sectional study of 20 cases.},
journal = {Systems biology in reproductive medicine},
volume = {65},
number = {2},
pages = {95-104},
doi = {10.1080/19396368.2018.1557762},
pmid = {30601031},
issn = {1939-6376},
mesh = {Adult ; Cross-Sectional Studies ; DNA Fragmentation ; *DNA Methylation ; Humans ; Infertility, Male/genetics ; Male ; Spermatozoa/metabolism ; *Telomere ; Varicocele/*genetics ; },
abstract = {Varicocele pathophysiology is related to increased oxidative stress, which might result in loss sperm DNA integrity as well as in genomic instability. Sperm telomere shortening and loss of global DNA methylation are the main features of genomic instability, leading to cell senescence and death, whereas sperm DNA fragmentation (SDF) characterizes the loss of chromatin integrity. We hypothesize that sperm genomic stability and DNA integrity is reduced in infertile men with moderate and large-sized varicoceles, thus being candidate markers of sperm quality in varicocele-related infertility. Here, we assessed the sperm global DNA methylation, telomere length, and SDF in men with and without clinically palpable varicoceles. While the rates of SDF and telomere length were not statistically different between varicocele patients and controls, global sperm DNA methylation seems to be lower in men with varicocele (49.7% ± 20.7%) than controls (64.7% ± 17.1%). A negative correlation between SDF and sperm motility and a positive correlation between sperm morphology and telomere length were observed. Our results suggest that varicocele may result in genomic instability, in particular, global DNA hypomethylation. However, a large sample size may confirm these findings. The understanding of the molecular mechanisms involved in the pathophysiology of varicocele-related infertility may help to better select candidates for varicocele repair.},
}
@article {pmid30595356,
year = {2019},
author = {Barraclough, JY and Skilton, MR and Garden, FL and Toelle, BG and Marks, GB and Celermajer, DS},
title = {Early and late childhood telomere length predict subclinical atherosclerosis at age 14 yrs. - The CardioCAPS study.},
journal = {International journal of cardiology},
volume = {278},
number = {},
pages = {250-253},
doi = {10.1016/j.ijcard.2018.12.065},
pmid = {30595356},
issn = {1874-1754},
mesh = {Adolescent ; Asymptomatic Diseases/epidemiology ; Atherosclerosis/*diagnosis/epidemiology/physiopathology ; Carotid Intima-Media Thickness/*trends ; Cohort Studies ; Female ; Humans ; Male ; Predictive Value of Tests ; Prospective Studies ; Telomere/pathology/*physiology ; Telomere Homeostasis/*physiology ; },
abstract = {INTRODUCTION: Carotid Intima Media Thickness (CIMT) is a marker of subclinical atherosclerosis, associated with cardiovascular risk in adults. Telomere length (TL) is a marker of cellular ageing. We sought to determine whether telomere length in early childhood and/or at 14-years is associated with CIMT in adolescence, in a community-based cohort study.<br><br>METHODS: 118 children had TL measured at mean age 3.6-years and 165 children had TL and CIMT, measured at 14-years, from the community-based Childhood Asthma Prevention Study.<br><br>RESULTS: TL in early childhood was significantly inversely associated with CIMT at 14&#x202f;years, p&#x202f;=&#x202f;0.04. TL in teenage life was also significantly inversely associated with CIMT at 14&#x202f;years, p&#x202f;=&#x202f;0.03. This latter association was no longer significant, however, after adjusting for early life TL.<br><br>CONCLUSION: TL measured in early childhood and adolescence is significantly associated with CIMT at 14-years, suggesting that telomere length is a biological marker or even early determinant of late cardiovascular risk.},
}
@article {pmid30595252,
year = {2018},
author = {Piplani, S and Alemao, NN and Prabhu, M and Ambar, S and Chugh, Y and Chugh, SK},
title = {Correlation of the telomere length with type 2 diabetes mellitus in patients with ischemic heart disease.},
journal = {Indian heart journal},
volume = {70 Suppl 3},
number = {Suppl 3},
pages = {S173-S176},
pmid = {30595252},
issn = {2213-3763},
mesh = {Adult ; Aged ; Body Mass Index ; Cross-Sectional Studies ; DNA/*genetics ; Diabetes Mellitus, Type 2/*complications/genetics ; Female ; Humans ; Male ; Middle Aged ; Myocardial Ischemia/etiology/*genetics/metabolism ; Real-Time Polymerase Chain Reaction ; Risk Factors ; Telomere/*genetics/metabolism ; },
abstract = {OBJECTIVE: The study aimed to explore the relationship of the telomere length with type 2 diabetes mellitus (DM) among patients with ischemic heart disease (IHD).<br><br>METHOD: This 2-year cross-sectional study included 130 male patients diagnosed with IHD through echocardiography and coronary angiography, wherein consecutive IHD patients with type 2 DM (65) and without type 2 DM (65) were selected. Baseline characteristics including age, gender, body mass index, and blood pressure were recorded. Laboratory investigations such as random blood sugar (RBS), fasting lipid profile, serum creatinine, and serum urea levels were measured. Quantitative real-time polymerase chain reaction was used for the measurement of the telomere length. The logistic regression analysis was used to predict the relationship of the telomere length with age and type 2 DM among patients with IHD.<br><br>RESULTS: All the patients in the study were men, and most of them (diabetics&#xa0;=&#xa0;22; nondiabetics&#xa0;=&#xa0;20) were aged between 56 and 65 years. Age (p&#xa0;=&#xa0;0.003), telomere length (p&#xa0;<&#xa0;0.001), RBS (p&#xa0;<&#xa0;0.001), serum creatinine (p&#xa0;<&#xa0;0013), and serum urea (p&#xa0;<&#xa0;0.04) were significantly higher in the diabetic subset than in the nondiabetic subset. No significant relationship was observed between age and the telomere length (p&#xa0;=&#xa0;0.813); however, the mean telomere length was significantly high among the patients with type 2 DM than those without type 2 DM (p&#xa0;=&#xa0;0.005). The logistic regression analysis showed that the telomere shortening (p&#xa0;=&#xa0;0.00019) and RBS (p&#xa0;<&#xa0;0.0001) were the significant risk factors for type 2 DM in patients with IHD.<br><br>CONCLUSION: The telomere shortening was significantly correlated with type 2 DM among the patients with IHD. However, multicentric studies with larger samples are required to validate the current observation.},
}
@article {pmid30592345,
year = {2019},
author = {Eastwood, JR and Hall, ML and Teunissen, N and Kingma, SA and Hidalgo Aranzamendi, N and Fan, M and Roast, M and Verhulst, S and Peters, A},
title = {Early-life telomere length predicts lifespan and lifetime reproductive success in a wild bird.},
journal = {Molecular ecology},
volume = {28},
number = {5},
pages = {1127-1137},
doi = {10.1111/mec.15002},
pmid = {30592345},
issn = {1365-294X},
support = {DP150103595//Australian Research Council/International ; FT10100505//Australian Research Council/International ; //Max Planck Society Minerva Program/International ; //Monash University/International ; },
mesh = {Animals ; Animals, Wild ; Birds/*genetics/growth &amp; development ; Female ; Longevity/genetics ; Male ; Reproduction/*genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Poor conditions during early development can initiate trade-offs that favour current survival at the expense of somatic maintenance and subsequently, future reproduction. However, the mechanisms that link early and late life-history are largely unknown. Recently it has been suggested that telomeres, the nucleoprotein structures at the terminal end of chromosomes, could link early-life conditions to lifespan and fitness. In wild purple-crowned fairy-wrens, we combined measurements of nestling telomere length (TL) with detailed life-history data to investigate whether early-life TL predicts fitness prospects. Our study differs from previous studies in the completeness of our fitness estimates in a highly philopatric population. The association between TL and survival was age-dependent with early-life TL having a positive effect on lifespan only among individuals that survived their first year. Early-life TL was not associated with the probability or age of gaining a breeding position. Interestingly, early-life TL was positively related to breeding duration, contribution to population growth and lifetime reproductive success because of their association with lifespan. Thus, early-life TL, which reflects growth, accumulated early-life stress and inherited TL, predicted fitness in birds that reached adulthood but not noticeably among fledglings. These findings suggest that a lack of investment in somatic maintenance during development particularly affects late life performance. This study demonstrates that factors in early-life are related to fitness prospects through lifespan, and suggests that the study of telomeres may provide insight into the underlying physiological mechanisms linking early- and late-life performance and trade-offs across a lifetime.},
}
@article {pmid30590694,
year = {2019},
author = {Liddiard, K and Ruis, B and Kan, Y and Cleal, K and Ashelford, KE and Hendrickson, EA and Baird, DM},
title = {DNA Ligase 1 is an essential mediator of sister chromatid telomere fusions in G2 cell cycle phase.},
journal = {Nucleic acids research},
volume = {47},
number = {5},
pages = {2402-2424},
pmid = {30590694},
issn = {1362-4962},
support = {18246/CRUK_/Cancer Research UK/United Kingdom ; P30 CA077598/CA/NCI NIH HHS/United States ; R01 CA190492/CA/NCI NIH HHS/United States ; },
mesh = {Chromatids/*genetics ; DNA Breaks, Double-Stranded ; DNA End-Joining Repair/*genetics ; DNA Ligase ATP/*genetics ; DNA Repair/genetics ; DNA Replication/genetics ; G2 Phase Cell Cycle Checkpoints/genetics ; HCT116 Cells ; Humans ; Mitosis/*genetics ; Poly-ADP-Ribose Binding Proteins/genetics ; Sister Chromatid Exchange/genetics ; Telomere/genetics ; },
abstract = {Fusion of critically short or damaged telomeres is associated with the genomic rearrangements that support malignant transformation. We have demonstrated the fundamental contribution of DNA ligase 4-dependent classical non-homologous end-joining to long-range inter-chromosomal telomere fusions. In contrast, localized genomic recombinations initiated by sister chromatid fusion are predominantly mediated by alternative non-homologous end-joining activity that may employ either DNA ligase 3 or DNA ligase 1. In this study, we sought to discriminate the relative involvement of these ligases in sister chromatid telomere fusion through a precise genetic dissociation of functional activity. We have resolved an essential and non-redundant role for DNA ligase 1 in the fusion of sister chromatids bearing targeted double strand DNA breaks that is entirely uncoupled from its requisite engagement in DNA replication. Importantly, this fusogenic repair occurs in cells fully proficient for non-homologous end-joining and is not compensated by DNA ligases 3 or 4. The dual functions of DNA ligase 1 in replication and non-homologous end-joining uniquely position and capacitate this ligase for DNA repair at stalled replication forks, facilitating mitotic progression.},
}
@article {pmid30590340,
year = {2019},
author = {Bosquet Enlow, M and Sideridis, G and Bollati, V and Hoxha, M and Hacker, MR and Wright, RJ},
title = {Maternal cortisol output in pregnancy and newborn telomere length: Evidence for sex-specific effects.},
journal = {Psychoneuroendocrinology},
volume = {102},
number = {},
pages = {225-235},
pmid = {30590340},
issn = {1873-3360},
support = {P30 ES023515/ES/NIEHS NIH HHS/United States ; R01 HD082078/HD/NICHD NIH HHS/United States ; R01 HL095606/HL/NHLBI NIH HHS/United States ; R01 HL114396/HL/NHLBI NIH HHS/United States ; },
mesh = {Female ; Hair/chemistry ; Humans ; Hydrocortisone/*adverse effects/analysis ; Hypothalamo-Hypophyseal System/physiology ; Infant, Newborn ; Male ; Maternal Exposure/adverse effects ; Mothers/psychology ; Pituitary-Adrenal System/physiology ; Pregnancy ; Prenatal Exposure Delayed Effects/*metabolism ; Sex Characteristics ; Sex Factors ; Social Class ; Stress, Psychological ; Telomere/*drug effects/metabolism ; Telomere Shortening/physiology ; },
abstract = {Newborn telomere length is a potential biomarker of the effects of maternal-fetal processes on offspring long-term health. A number of maternal psychosocial and environmental factors in pregnancy (e.g., stress, health, socioeconomic status) have been associated with shortened telomere length at birth. The physiological mechanisms responsible for potential effects of maternal factors on newborn telomere length have yet to be identified. Indirect evidence suggests that disruptions in maternal hypothalamic-pituitary-adrenal (HPA) axis functioning in pregnancy may be involved. Studies are needed that test whether maternal HPA axis functioning in pregnancy is associated with newborn telomere length. This study examined whether maternal HPA axis functioning across pregnancy, reflected in hair cortisol collected within one week after delivery, predicted newborn telomere length assessed from leukocyte cord blood collected at birth among 93 sociodemographically diverse mother-infant dyads. We further tested whether associations between maternal hair cortisol and newborn telomere length differed by infant sex, given documented sex differences in prenatal environmental exposure effects on offspring health, patterns of cortisol exposure during gestation, and telomere biology across the lifespan. In a multi-group structural equation modeling analysis that accounted for cortisol exposures across trimesters, maternal cortisol levels in pregnancy were not associated with newborn telomere length in the sample as a whole. However, significant sex differences emerged, with a significant positive association among females and a lack of a significant association among males. In addition, analyses revealed that cortisol levels were higher across trimesters among mothers of male infants than mothers of female infants. The results suggest that functioning of the maternal HPA axis in pregnancy may differ by fetal sex and have sex-specific effects on newborn telomere biology. These findings have implications for understanding the mechanisms by which maternal psychosocial and environmental exposures influence newborn telomere length and for elucidating mechanisms contributing to sex disparities in health.},
}
@article {pmid30589155,
year = {2019},
author = {Alves-Paiva, RM and Gutierrez-Rodrigues, F and Pereira-Martins, DA and Figueiredo, DLA and Clé, DV and Conti-Freitas, LC and Mamede, RCM and Calado, RT},
title = {Short telomere length in peripheral blood leukocytes in head and neck cancer: Findings in a Brazilian cohort.},
journal = {Head &amp; neck},
volume = {41},
number = {3},
pages = {672-677},
doi = {10.1002/hed.25472},
pmid = {30589155},
issn = {1097-0347},
support = {2013/08135-3//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/International ; 2013/08135-3//INCT-CTC/International ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Brazil ; Case-Control Studies ; Cohort Studies ; Female ; Head and Neck Neoplasms/mortality/*pathology ; Humans ; Leukocytes/*pathology ; Male ; Middle Aged ; Risk Factors ; Survival Rate ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {BACKGROUND: Telomeres are specialized DNA structures that are critical to maintain cell homeostasis and to avoid genomic instability. Epidemiological studies have examined the association between leukocyte telomere length (LTL) and risk of cancers, but the findings remain conflicting.<br><br>METHODS: Mean LTL was measured by quantitative PCR in 97 patients with head and neck cancer (HNC) and 262 healthy controls. The association between LTL and patients' clinical status, such as smoke, alcoholism, and overall survival, were also evaluated.<br><br>RESULTS: The age-adjusted LTL was significantly shorter in patients with HNC in comparison to healthy controls (P&#x2009;=&#x2009;.0003). Patients with shortest LTL had an increased risk to develop HNC (P&#x2009;<&#x2009;0.0001). No significant correlation was observed between LTL and patients' clinical features and personal habits.<br><br>CONCLUSIONS: Our data support the hypothesis that LTL is a risk factor for HNC. The use of LTL as a biomarker can help physicians to identify high-risk individuals for HNC.},
}
@article {pmid30584242,
year = {2018},
author = {Chen, CF and Sung, TL and Chen, LY and Chen, JH},
title = {Telomere maintenance during anterior regeneration and aging in the freshwater annelid Aeolosoma viride.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {18078},
pmid = {30584242},
issn = {2045-2322},
mesh = {Aging/*genetics ; Animals ; Annelida/*genetics/growth &amp; development/physiology ; *Regeneration ; Telomerase/genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {Aging is a complex process involving declines in various cellular and physical functionalities, including regenerative ability. Telomere maintenance is thought to be necessary for regeneration, and telomere attrition is one mechanism that contributes to aging. However, it is unclear if aging affects regeneration owing to deterioration of telomeric maintenance. We introduce Aeolosoma viride-a freshwater annelid with strong regenerative abilities-as a new model for studying the effects of aging on telomere functions and regeneration. We show that the anterior regenerative ability of A. viride declines with age. We characterized the A. viride telomere sequence as being composed of TTAGGG repeats and identifyied the telomerase gene Avi-tert. In adult A. viride, telomerase was constantly active and telomere lengths were similar among different body sections and stably maintained with age. Notably, we found that regeneration did not result in telomere shortening at regenerating sites. Moreover, transient up-regulation of Avi-tert expression and telomerase activity was observed at regenerating sites, which might promote telomere lengthening to counteract telomere erosion resulting from cell proliferation. Our study suggests that although aging affects A. viride regeneration independent of steady-state telomere length, timely regulation of telomerase functions is critical for the regeneration process in A. viride.},
}
@article {pmid30579939,
year = {2019},
author = {Mason, AE and Adler, JM and Puterman, E and Lakmazaheri, A and Brucker, M and Aschbacher, K and Epel, ES},
title = {Stress resilience: Narrative identity may buffer the longitudinal effects of chronic caregiving stress on mental health and telomere shortening.},
journal = {Brain, behavior, and immunity},
volume = {77},
number = {},
pages = {101-109},
pmid = {30579939},
issn = {1090-2139},
support = {K23 HL112955/HL/NHLBI NIH HHS/United States ; K23 HL133442/HL/NHLBI NIH HHS/United States ; R01 AG030424/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Caregivers/*psychology ; Cellular Senescence/physiology ; Depression/psychology ; Female ; Humans ; Leukocytes ; Mental Health ; Mothers ; Narration ; Narrative Therapy/methods ; Parenting/psychology ; Prospective Studies ; Reproducibility of Results ; Resilience, Psychological ; Stress, Physiological/*physiology ; Stress, Psychological/genetics/psychology ; Surveys and Questionnaires ; Telomere/*physiology ; Telomere Shortening/physiology ; },
abstract = {BACKGROUND: Chronic caregiving stress may accelerate biological aging; however, the ability to integrate the meaning of caregiving through self-awareness, adaptation, and growth can buffer the negative effects of stress. Narrative researchers have shown that people who coherently integrate difficult experiences into their life story tend to have better mental health, but no prior study has examined the prospective association between narrative identity and biological indicators, such as telomere length. We tested whether narrative identity might be prospectively associated with resilience to long-term parenting stress, depressive symptoms, and protection from telomere shortening, especially among caregivers.<br><br>METHODS: We conducted a semi-structured interview about parenting and quantified narrative themes by applying well-validated, standardized coding systems with high inter-rater reliability among 88 mothers: 32 "caregivers" (mothers with a child diagnosed with an autism spectrum disorder), and 56 "controls" (mothers with a neurotypical child). To assess longitudinal changes, we measured mental health (parenting stress [PS], depressive symptoms [DS]) and leukocyte telomere length [LTL], a biomarker of aging, at baseline and again 18&#x202f;months later. We examined whether narrative identity themes were related to these outcomes and whether associations differed across caregivers versus controls.<br><br>RESULTS: Caregivers exhibited significantly higher basal levels of PS and DS relative to controls (all p's&#x202f;<&#x202f;.05), but no significant difference in LTL (p&#x202f;>&#x202f;.05). Caregivers rated higher in the narrative theme of integration showed healthier future 18-month trajectories in PS (B&#x202f;=&#x202f;-0.832, 99% CI: [-1.315, -0.155], p&#x202f;<&#x202f;.01) and LTL (B&#x202f;=&#x202f;1.193, 99% CI: [0.526, 2.130], p&#x202f;<&#x202f;.01), but no differences in depressive symptoms (p&#x202f;>&#x202f;.05), adjusting for age and antidepressant use. Analyses examining affective themes in caregiver narratives did not demonstrate significant associations. Narrative themes did not predict outcomes in controls.<br><br>CONCLUSIONS: The data suggest that narratives reflecting coherent integration, but not necessarily affect, prospectively relate to psychological and biological stress resilience. Maternal caregivers' ability to tell an integrated story of their parenting experiences forecasts lower parenting stress and telomere shortening over time. This study suggests the possibility that helping individuals better integrate the meaning of stressful experiences, but not necessarily to affectively redeem them, may constitute a potential novel target for intervention among chronically stressed populations such as caregivers.},
}
@article {pmid30578676,
year = {2019},
author = {Zheng, GQ and Zhang, GH and Wu, HT and Tu, YT and Tian, W and Fang, Y and Lu, Y and Gong, SY and Zhang, YN and Yu, LB and Zhang, H and Shao, H and Brandt-Rauf, P and Xia, ZL},
title = {Relative telomere length and gene expression of shelterin complex proteins among vinyl chloride monomer-exposed workers in China.},
journal = {Environmental and molecular mutagenesis},
volume = {60},
number = {4},
pages = {361-367},
doi = {10.1002/em.22270},
pmid = {30578676},
issn = {1098-2280},
mesh = {Adult ; Carcinogens/*toxicity ; China ; Female ; Gene Expression Regulation/drug effects ; Humans ; Male ; Middle Aged ; Occupational Exposure/*adverse effects ; Shelterin Complex ; Telomere Homeostasis/*drug effects ; Telomere Shortening/drug effects ; Telomere-Binding Proteins/*genetics ; Vinyl Chloride/*toxicity ; },
abstract = {Vinyl chloride monomer (VCM) is a confirmed carcinogen. The effects of VCM on telomeres and the gene expression of telomere complex proteins, shelterin, have not been well studied but could be of potential relevance to the carcinogenic mechanism of VCM and the health surveillance of VCM-exposed workers. A group of 241 VCM-exposed workers and 101 internal controls from the same plant in Shandong, China were recruited and quantitative polymerase chain reaction was preformed to measure relative telomere length (RTL) and gene expression of shelterin proteins. VCM cumulative exposure dose (CED) was estimated for the exposed workers. The differences in RTL and gene expression between groups were compared by Wald test fitted with robust regression. Shorter RTL was observed in VCM-exposed workers than in the controls (P < 0.001) and was related to CED of VCM. Shortened RTL was also significantly related to increasing age (P = 0.012) and high blood pressure (P = 0.056). Levels of gene expression of shelterin components in exposed workers were all lower than in controls except increased TIN2 expression, and the gene expression differences in TIN2 and POT1 among exposed and control groups were significant (P = 0.014 for TIN2 and P < 0.001 for POT1, respectively). VCM exposure is found associated with altered telomere length and gene expression of shelterin components. This provides new insights into the potential carcinogenic mechanisms of VCM and could be helpful for the health surveillance for VCM-exposed workers. Environ. Mol. Mutagen. 60:361-367, 2019. © 2018 Wiley Periodicals, Inc.},
}
@article {pmid30576944,
year = {2019},
author = {Needham, BL and Wang, X and Carroll, JE and Barber, S and Sánchez, BN and Seeman, TE and Diez Roux, AV},
title = {Sociodemographic correlates of change in leukocyte telomere length during mid- to late-life: The Multi-Ethnic Study of Atherosclerosis.},
journal = {Psychoneuroendocrinology},
volume = {102},
number = {},
pages = {182-188},
pmid = {30576944},
issn = {1873-3360},
support = {HHSN268201500003C/HL/NHLBI NIH HHS/United States ; N01HC95160/HL/NHLBI NIH HHS/United States ; R01 HL101161/HL/NHLBI NIH HHS/United States ; N01HC95163/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; R01 HL076831/HL/NHLBI NIH HHS/United States ; N01HC95164/HL/NHLBI NIH HHS/United States ; N01HC95162/HL/NHLBI NIH HHS/United States ; N01HC95168/HL/NHLBI NIH HHS/United States ; P30 AG028748/AG/NIA NIH HHS/United States ; N01HC95165/HL/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; N01HC95161/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; P30 AG017265/AG/NIA NIH HHS/United States ; N01HC95167/HL/NHLBI NIH HHS/United States ; K01 AG044462/AG/NIA NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; N01HC95166/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Black or African American ; Aged ; Aged, 80 and over ; Aging ; Atherosclerosis/*ethnology/*genetics ; Cohort Studies ; Female ; Hispanic or Latino ; Humans ; Leukocytes/metabolism ; Longitudinal Studies ; Male ; Middle Aged ; Socioeconomic Factors ; Telomere/*metabolism ; Telomere Shortening/genetics ; White People ; },
abstract = {Although epidemiologic studies of telomere length have become increasingly common, few population-based, multi-ethnic studies include data on telomere shortening, which may be a better predictor of morbidity and mortality than a single measure of telomere length. This study used stored blood samples from 1169 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) to examine age, sex, race/ethnicity, marital status, income, and education as predictors of change in telomere length over a 10-year period in linear mixed effects models. Mean age at baseline was 61 years, and the sample was 54% female, 27% white, 30% African-American, and 43% Hispanic. At baseline, 58% of the sample was married; 32% had household income below $25,000 per year, 35% had income between $25,000 and $49,999 per year, and 34% had income above $50,000 per year; 41% had a high school education or less, 30% had some college, and 29% had a college degree or more. Relative telomere length (T/S ratio) was measured by the quantitative polymerase chain reaction method. In general, ten-year telomere attrition was greater for groups that had longer telomere length at baseline, including younger people, whites, and women. After adjusting for baseline telomere length, race/ethnic differences in telomere attrition were attenuated, and age and sex differences were reversed, such that older people and men showed greater telomere shortening. There were no significant differences in telomere attrition by marital status, income, or education. There is not yet a consensus in the field regarding whether to adjust for baseline telomere length in models examining predictors of telomere attrition. To ensure comparability across studies, researchers should report results both with and without adjustment for baseline telomere length.},
}
@article {pmid30574414,
year = {2018},
author = {Ding, Y and Lin, H and Zhou, S and Wang, K and Li, L and Zhang, Y and Yao, Y and Gao, M and Liu, X and He, N},
title = {Stronger Association between Insomnia Symptoms and Shorter Telomere Length in Old HIV-Infected Patients Compared with Uninfected Individuals.},
journal = {Aging and disease},
volume = {9},
number = {6},
pages = {1010-1019},
pmid = {30574414},
issn = {2152-5250},
abstract = {Growing evidence suggests that HIV infection may accelerate biological aging. Insomnia symptoms, particularly in later life, exacerbate cellular aging. We examined the association between insomnia symptoms and leukocyte telomere length (LTL), and further explored how this association was affected by HIV serostatus and age. Data were assessed from 244 HIV-infected individuals ≥40 years and 244 HIV-uninfected individuals who were frequency-matched by age, gender and education level. Insomnia symptoms were assessed by responses to four sleep-related questions covering the past month. We performed multivariable linear regression with logarithmically transformed LTL and reported exponentiated coefficients. HIV-infected individuals had shorter LTL compared to uninfected individuals (geometric mean 0.82 vs 0.89, P=0.052), and this association remained after adjustment for gender, education level, and smoking history (-7.4%, P=0.051) but markedly attenuated after additional adjustment for insomnia and depressive symptoms (-3.7%, P=0.367). Significant interactions between age group (55-82 vs 40-54 years) and insomnia symptoms on LTL were observed in the HIV-infected individuals (-28.4%, P=0.033) but not the uninfected (-17.9%, P=0.250). After stratifying by age group, LTL was independently associated with insomnia symptoms in those 55 years and older among the HIV-infected individuals (-24.5%, P=0.026) but not those 40-54 years old (-9.8%, P=0.428). Our findings suggest that elevated insomnia and depressive symptoms may partly explain the correlation between HIV serostatus and shorter LTL. Significant association between insomnia and shorter LTL observed in elderly HIV-infected but not in uninfected individuals suggest that such adverse effect may begin at an earlier age or is more pronounced in HIV-infected individuals but requires further investigation.},
}
@article {pmid30572327,
year = {2018},
author = {McPherson, MC and Cheng, HH and Smith, JM and Delany, ME},
title = {Vaccination and Host Marek's Disease-Resistance Genotype Significantly Reduce Oncogenic Gallid alphaherpesvirus 2 Telomere Integration in Host Birds.},
journal = {Cytogenetic and genome research},
volume = {156},
number = {4},
pages = {204-214},
pmid = {30572327},
issn = {1424-859X},
mesh = {Animals ; Chickens/*genetics/virology ; Disease Resistance ; Genotype ; Herpesvirus 2, Gallid/drug effects/*physiology ; Marek Disease/prevention &amp; control/virology ; Marek Disease Vaccines/*administration &amp; dosage/pharmacology ; Poultry Diseases/prevention &amp; control/virology ; Telomere/*virology ; Vaccination ; Virus Integration/drug effects ; Virus Replication ; },
abstract = {Marek's disease (MD) is an infectious disease characterized by lymphomas and high mortality in susceptible chickens. The causative and ubiquitous alpha-herpesvirus known as MD virus (MDV) integrates into host telomeres during early infection through latency, known to be an important phase for oncogenic transformation. Herein, we sought to determine the influence of vaccination and host genetics on the temporal dynamics of MDV-host genome interactions. We studied integration profiles using 2 MD vaccines that vary in protective efficacy in 2 genetic lines that differ in MD resistance/susceptibility. Virus integration of both oncogenic MDV and vaccine strains was observed in both MD susceptible and resistant birds, however, the lines differed in their dynamic telomere-integration profiles. Notably, the resistant host genotype exhibited a smaller percentage of replicating cells with the virus telomere-integrated only phenotype as compared to the susceptible genotype. Vaccination with Rispens, the most protective MD vaccine, also reduced the establishment of the virus telomere-integrated only phenotype, suggesting a significant role of the phenotype in MD lymphoma development. The effect of Rispens vaccination was most dramatic in the susceptible genotype. These results suggest important connections between vaccinal immunity, MDV telomere integration, virus-induced oncogenesis, and virus-host genome interactions in the context of host genetics and disease susceptibility.},
}
@article {pmid30570381,
year = {2018},
author = {Møller, P and Wils, RS and Jensen, DM and Andersen, MHG and Roursgaard, M},
title = {Telomere dynamics and cellular senescence: an emerging field in environmental and occupational toxicology.},
journal = {Critical reviews in toxicology},
volume = {48},
number = {9},
pages = {761-788},
doi = {10.1080/10408444.2018.1538201},
pmid = {30570381},
issn = {1547-6898},
mesh = {*Cellular Senescence ; *Ecotoxicology ; Humans ; Occupational Exposure/*analysis ; Telomere ; Telomere Shortening/*physiology ; },
abstract = {There has been a steady output of epidemiological studies linking environmental and occupational exposures to altered telomere length, showing mainly positive associations with persistent organic pollutants, inverse association with cadmium and inconsistent results with arsenic and lead. A bell-shaped dose-response relationship has been observed for ionizing radiation with telomere shortening at a low dose. Long-term air pollution is associated with telomere shortening, whereas the short-term exposure studies have shown mixed results. There are surprisingly few studies on telomere dynamics in animals. Studies on telomere dynamics and senescence in target tissues of animal strains used in toxicology are warranted. Cell culture studies on ionizing radiation have shown mixed results on telomere length, whereas both telomerase activity and cellular senescence are increased. Studies on persistent organic pollutants indicate telomere shortening, decreased telomerase activity and increased cellular senescence. Cell culture studies on heavy metals and air pollution particles are inconsistent. There is no coherent relationship between exposures, oxidative stress, telomere length, telomerase activity and cellular senescence in experimental studies on environmental or occupational exposures. This may be due to differences in exposure levels (including dose rate), exposure time and models (i.e. cell types and animal strains). Guidelines are needed for best practices on assays for telomere dynamics and cellular senescence in toxicology. However, it deserves notice that experimental studies in cells and animals have revealed important information on the effects of environmental and occupational agents on the maintenance of telomeres and cellular senescence.},
}
@article {pmid30566847,
year = {2019},
author = {Newton, CA and Zhang, D and Oldham, JM and Kozlitina, J and Ma, SF and Martinez, FJ and Raghu, G and Noth, I and Garcia, CK},
title = {Telomere Length and Use of Immunosuppressive Medications in Idiopathic Pulmonary Fibrosis.},
journal = {American journal of respiratory and critical care medicine},
volume = {200},
number = {3},
pages = {336-347},
pmid = {30566847},
issn = {1535-4970},
support = {UL1 TR001105/TR/NCATS NIH HHS/United States ; R01 HL093096/HL/NHLBI NIH HHS/United States ; R01 HL130796/HL/NHLBI NIH HHS/United States ; T32 HL098040/HL/NHLBI NIH HHS/United States ; KL2 TR001103/TR/NCATS NIH HHS/United States ; K23 HL138190/HL/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Anti-Inflammatory Agents/therapeutic use ; Azathioprine/therapeutic use ; Cohort Studies ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/mortality/*pathology/*therapy ; Immunosuppressive Agents/*therapeutic use ; Leukocytes/pathology ; Lung Transplantation ; Male ; Middle Aged ; Prednisone/therapeutic use ; Survival Rate ; Telomere/*pathology ; },
abstract = {Rationale: Immunosuppression was associated with adverse events for patients with idiopathic pulmonary fibrosis (IPF) in the PANTHER-IPF (Evaluating the Effectiveness of Prednisone, Azathioprine and N-Acetylcysteine in Patients with IPF) clinical trial. The reason why some patients with IPF experience harm is unknown.Objectives: To determine whether age-adjusted leukocyte telomere length (LTL) was associated with the harmful effect of immunosuppression in patients with IPF.Methods: LTL was measured from available DNA samples from PANTHER-IPF (interim analysis, n = 79; final analysis, n = 118). Replication cohorts included ACE-IPF (Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis) (n = 101) and an independent observational cohort (University of Texas Southwestern Medical Center-IPF, n = 170). LTL-stratified and medication-stratified survival analyses were performed using multivariable Cox regression models for composite endpoint-free survival.Measurements and Main Results: Of the subjects enrolled in the PANTHER-IPF and ACE-IPF, 62% (49/79) and 56% (28/50) had an LTL less than the 10th percentile of normal, respectively. In PANTHER-IPF, exposure to prednisone/azathioprine/N-acetylcysteine was associated with a higher composite endpoint of death, lung transplantation, hospitalization, or FVC decline for those with an LTL less than the 10th percentile (hazard ratio, 2.84; 95% confidence interval, 1.02-7.87; P = 0.045). This finding was replicated in the placebo arm of ACE-IPF for those exposed to immunosuppression (hazard ratio, 7.18; 95% confidence interval, 1.52-33.84; P = 0.013). A propensity-matched University of Texas Southwestern Medical Center IPF cohort showed a similar association between immunosuppression and composite endpoints (death, lung transplantation, or FVC decline) for those with an LTL less than the 10th percentile (hazard ratio, 3.79; 95% confidence interval, 1.73-8.30; P = 0.00085). An interaction was found between immunosuppression and LTL for the combined PANTHER-IPF and ACE-IPF clinical trials (Pinteraction = 0.048), and the University of Texas Southwestern Medical Center IPF cohort (Pinteraction = 0.00049).Conclusions: LTL is a biomarker that may identify patients with IPF at risk for poor outcomes when exposed to immunosuppression.},
}
@article {pmid30566188,
year = {2019},
author = {Morton, JM and Garg, T and Leva, N},
title = {Association of Laparoscopic Gastric Bypass Surgery With Telomere Length in Patients With Obesity.},
journal = {JAMA surgery},
volume = {154},
number = {3},
pages = {266-268},
pmid = {30566188},
issn = {2168-6262},
mesh = {Adult ; Aged ; Biomarkers/blood ; Female ; *Gastric Bypass ; Humans ; *Laparoscopy ; Male ; Middle Aged ; Obesity, Morbid/*surgery ; Polymerase Chain Reaction ; *Telomere Homeostasis ; },
abstract = {This study examines whether telomeres lengthen in obese patients before and after laparoscopic gastric bypass surgery.},
}
@article {pmid30565787,
year = {2019},
author = {Graham, JL and Bauer, CM and Heidinger, BJ and Ketterson, ED and Greives, TJ},
title = {Early-breeding females experience greater telomere loss.},
journal = {Molecular ecology},
volume = {28},
number = {1},
pages = {114-126},
doi = {10.1111/mec.14952},
pmid = {30565787},
issn = {1365-294X},
support = {IOS-1257474//Division of Integrative Organismal Systems/International ; IOS-1257527//Division of Integrative Organismal Systems/International ; //Office of Experimental Program to Stimulate Competitive Research/International ; //Wilson Ornithological Society/International ; //North Dakota State University/International ; //Sigma Xi: The Scientific Research Society through Grants-In-Aid of Research/International ; //American Ornithologists Union Hesse Research Award/International ; //North Dakota EPSCoR Doctoral Dissertation Assistantship/International ; },
mesh = {Animals ; Breeding ; Female ; Male ; Reproduction/*genetics/physiology ; Seasons ; Songbirds/*genetics/physiology ; Telomere/*genetics ; },
abstract = {Annual reproductive success is often highest in individuals that initiate breeding early, yet relatively few individuals start breeding during this apparently optimal time. This suggests that individuals, particularly females who ultimately dictate when offspring are born, incur costs by initiating reproduction early in the season. We hypothesized that increases in the ageing rate of somatic cells may be one such cost. Telomeres, the repetitive DNA sequences on the ends of chromosomes, may be good proxies of biological wear and tear as they shorten with age and in response to stress. Using historical data from a long-term study population of dark-eyed juncos (Junco hyemalis), we found that telomere loss between years was greater in earlier breeding females, regardless of chronological age. There was no relationship between telomere loss and the annual number of eggs laid or chicks that reached independence. However, telomere loss was greater when temperatures were cooler, and cooler temperatures generally occur early in the season. This suggests that environmental conditions could be the primary cause of accelerated telomere loss in early breeders.},
}
@article {pmid30563782,
year = {2019},
author = {Liu, B and Sun, Y and Xu, G and Snetselaar, LG and Ludewig, G and Wallace, RB and Bao, W},
title = {Association between Body Iron Status and Leukocyte Telomere Length, a Biomarker of Biological Aging, in a Nationally Representative Sample of US Adults.},
journal = {Journal of the Academy of Nutrition and Dietetics},
volume = {119},
number = {4},
pages = {617-625},
pmid = {30563782},
issn = {2212-2672},
support = {P30 ES005605/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging/*blood ; Biomarkers/blood ; Cross-Sectional Studies ; Female ; Ferritins/blood ; Humans ; Iron/*blood ; Leukocytes/*pathology ; Male ; Middle Aged ; Nutrition Surveys ; *Nutritional Status ; Prevalence ; Telomere/*pathology ; United States/epidemiology ; Young Adult ; },
abstract = {BACKGROUND: Excess iron levels can induce oxidative stress and could therefore affect telomere attrition. However, little is known about the impact of body iron status on telomere length.<br><br>OBJECTIVE: Our aim was to examine the association between serum ferritin concentrations, an indicator of body iron status, and leukocyte telomere length in US adults.<br><br>DESIGN: We conducted a nationwide, population-based, cross-sectional study.<br><br>PARTICIPANTS/SETTING: We used data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. We included 7,336 adults aged 20 years or older who had available data on serum ferritin levels and telomere length. High ferritin levels were defined as a serum ferritin level >200 ng/mL (449.4 pmol/L) in women and >300 ng/mL (674.1 pmol/L) in men. Low ferritin levels were defined as a serum ferritin level <30 ng/mL (67.4 pmol/L).<br><br>MAIN OUTCOME MEASURES: Leukocyte telomere length was assayed using the quantitative polymerase chain reaction method.<br><br>STATISTICAL ANALYSES: Linear regression with survey weights was performed to estimate the association between serum ferritin levels and telomere length.<br><br>RESULTS: The prevalence of adults with high and low serum ferritin levels was 10.9% and 17.6%, respectively. High ferritin levels were inversely associated with telomere length compared to normal ferritin levels. After adjustment for demographic, socioeconomic and lifestyle factors, body mass index, C-reactive protein, and leukocyte cell type composition, the &#x3b2; coefficient for log-transformed telomere length was -0.020 (standard error [SE]=0.009; P=0.047). The association was stronger in adults aged 65 years or older (&#x3b2; coefficient -0.081, SE=0.017; P<0.001) than in adults 20 to 44 years old (&#x3b2;&#xa0;coefficient -0.023, SE=0.019; P=0.24) or adults aged 45 to 64 years old (&#x3b2; coefficient 0.024, SE=0.015; P=0.10) (P for interaction 0.003). Low ferritin levels were not significantly associated with telomere length compared with normal ferritin levels.<br><br>CONCLUSIONS: In a US nationally representative population, high body iron status was associated with shorter telomeres, especially in adults aged 65 years or older.},
}
@article {pmid30561819,
year = {2019},
author = {Yeap, BB and Hui, J and Knuiman, MW and Handelsman, DJ and Flicker, L and Divitini, ML and Arscott, GM and McLennan, SV and Twigg, SM and Almeida, OP and Hankey, GJ and Golledge, J and Norman, PE and Beilby, JP},
title = {Cross-sectional associations of sex hormones with leucocyte telomere length, a marker of biological age, in a community-based cohort of older men.},
journal = {Clinical endocrinology},
volume = {90},
number = {4},
pages = {562-569},
doi = {10.1111/cen.13918},
pmid = {30561819},
issn = {1365-2265},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/genetics/physiology ; Cross-Sectional Studies ; Dihydrotestosterone/blood ; Estradiol/blood ; Gonadal Steroid Hormones/*blood ; Humans ; Linear Models ; Male ; Middle Aged ; Telomere/*genetics ; Testosterone/blood ; Young Adult ; },
abstract = {CONTEXT: Telomeres protect chromosomes from damage, and shorter leucocyte telomere length (LTL) is a marker of advancing biological age. The association between testosterone (T) and its bioactive metabolites, dihydrotestosterone (DHT) and oestradiol (E2) with telomere length, particularly in older men, is uncertain. The study aimed to clarify associations of sex hormones with LTL in older men.<br><br>PARTICIPANTS AND METHODS: We used cross-sectional data from 2913 men aged 76.7&#xa0;&#xb1;&#xa0;3.2&#xa0;years with morning blood samples assayed for T, DHT, E2 (mass spectrometry), and sex hormone-binding globulin (SHBG, immunoassay), to correlate sex hormones with LTL measured using PCR and expressed as T/S ratio in multivariable linear regression models adjusted for age, cardiometabolic risk factors and cardiovascular disease history.<br><br>RESULTS: Average difference per decade of age was T -0.46&#xa0;nmol/L, DHT -0.11&#xa0;nmol/L, E2 -7.5&#xa0;pmol/L, SHBG +10.2&#xa0;nmol/L and LTL (T/S ratio) -0.065. E2 correlated with T/S ratio (r&#xa0;=&#xa0;0.038, P&#xa0;=&#xa0;0.039) and SHBG was inversely correlated (r&#xa0;=&#xa0;-0.053, P&#xa0;=&#xa0;0.004). After multivariable adjustment, E2 was associated with T/S ratio (per 1&#xa0;SD increase E2: coefficient 0.011, P&#xa0;=&#xa0;0.043), T and DHT were not associated. When E2 and SHBG were simultaneously included, E2 remained positively (coefficient 0.014, P&#xa0;=&#xa0;0.014) and SHBG inversely (coefficient -0.013, P&#xa0;=&#xa0;0.037) associated with T/S ratio.<br><br>CONCLUSIONS: In older men, neither T nor DHT is associated with LTL while E2 is independently associated with LTL and SHBG is inversely associated, thus relating sex hormone exposure to lower biological age. Further research is needed to determine causality and clarify the role of sex hormones in male ageing.},
}
@article {pmid30560391,
year = {2019},
author = {Andersson, U and Degerman, S and Dahlin, AM and Wibom, C and Johansson, G and Bondy, ML and Melin, BS},
title = {The association between longer relative leukocyte telomere length and risk of glioma is independent of the potentially confounding factors allergy, BMI, and smoking.},
journal = {Cancer causes &amp; control : CCC},
volume = {30},
number = {2},
pages = {177-185},
doi = {10.1007/s10552-018-1120-2},
pmid = {30560391},
issn = {1573-7225},
support = {R01 CA119215/CA/NCI NIH HHS/United States ; R01 CA139020/CA/NCI NIH HHS/United States ; 5R01CA119215, 5R01CA139020//National Cancer Institute NIH/ ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Body Mass Index ; Brain Neoplasms/*epidemiology/genetics ; Case-Control Studies ; Confounding Factors, Epidemiologic ; Female ; Glioma/*epidemiology/genetics ; Humans ; Hypersensitivity/epidemiology ; *Leukocytes ; Male ; Middle Aged ; Phenotype ; Risk Factors ; Smoking/epidemiology ; Sweden/epidemiology ; *Telomere ; },
abstract = {PURPOSE: Previous studies have suggested an association between relative leukocyte telomere length (rLTL) and glioma risk. This association may be influenced by several factors, including allergies, BMI, and smoking. Previous studies have shown that individuals with asthma and allergy have shortened relative telomere length, and decreased risk of glioma. Though, the details and the interplay between rLTL, asthma and allergies, and glioma molecular phenotype is largely unknown.<br><br>METHODS: rLTL was measured by qPCR in a Swedish population-based glioma case-control cohort (421 cases and 671 controls). rLTL was related to glioma risk and health parameters associated with asthma and allergy, as well as molecular events in glioma including IDH1 mutation, 1p/19q co-deletion, and EGFR amplification.<br><br>RESULTS: Longer rLTL was associated with increased risk of glioma (OR&#x2009;=&#x2009;1.16; 95% CI 1.02-1.31). Similar to previous reports, there was an inverse association between allergy and glioma risk. Specific, allergy symptoms including watery eyes was most strongly associated with glioma risk. High body mass index (BMI) a year prior diagnosis was significantly protective against glioma in our population. Adjusting for allergy, asthma, BMI, and smoking did not markedly change the association between longer rLTL and glioma risk. rLTL among cases was not associated with IDH1 mutation, 1p/19q co-deletion, or EGFR amplification, after adjusting for age at diagnosis and sex.<br><br>CONCLUSIONS: In this Swedish glioma case-control cohort, we identified that long rLTL increases the risk of glioma, an association not confounded by allergy, BMI, or smoking. This highlights the complex interplay of the immune system, rLTL and cancer risk.},
}
@article {pmid30559463,
year = {2019},
author = {Coutts, F and Palmos, AB and Duarte, RRR and de Jong, S and Lewis, CM and Dima, D and Powell, TR},
title = {The polygenic nature of telomere length and the anti-ageing properties of lithium.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {44},
number = {4},
pages = {757-765},
pmid = {30559463},
issn = {1740-634X},
support = {MR/N014863/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Animals ; Bipolar Disorder/drug therapy/*genetics ; Caenorhabditis elegans ; Case-Control Studies ; Female ; Gene Expression/drug effects ; Genome-Wide Association Study ; Humans ; Lithium/*pharmacology ; Longevity/*drug effects ; Male ; Middle Aged ; Telomere/*drug effects/genetics ; },
abstract = {Telomere length is a promising biomarker for age-related disease and a potential anti-ageing drug target. Here, we study the genetic architecture of telomere length and the repositioning potential of lithium as an anti-ageing medication. LD score regression applied to the largest telomere length genome-wide association study to-date, revealed SNP-chip heritability estimates of 7.29%, with polygenic risk scoring capturing 4.4% of the variance in telomere length in an independent cohort (p = 6.17 × 10[-5]). Gene-enrichment analysis identified 13 genes associated with telomere length, with the most significant being the leucine rich repeat gene, LRRC34 (p = 3.69 × 10[-18]). In the context of lithium, we confirm that chronic use in a sample of 384 bipolar disorder patients is associated with longer telomeres (p = 0.03). As complementary evidence, we studied three orthologs of telomere length regulators in a Caenorhabditis elegans model of lithium-induced extended longevity and found all transcripts to be affected post-treatment (p < 0.05). Lithium may therefore confer its anti-ageing effects by moderating the expression of genes responsible for normal telomere length regulation. This is supported by our bipolar disorder sample, which shows that polygenic risk scores explain a higher proportion of the variance in telomere length amongst chronic lifetime lithium users (variance explained = 8.9%, p = 0.01), compared to non-users (p > 0.05). Consequently, this suggests that lithium may be catalysing the activity of endogenous mechanisms that promote telomere lengthening, whereby its efficacy eventually becomes limited by each individual's inherent telomere maintenance capabilities. Our work indicates a potential use of polygenic risk scoring for the prediction of adult telomere length and consequently lithium's anti-ageing efficacy.},
}
@article {pmid30559341,
year = {2018},
author = {Dunce, JM and Milburn, AE and Gurusaran, M and da Cruz, I and Sen, LT and Benavente, R and Davies, OR},
title = {Structural basis of meiotic telomere attachment to the nuclear envelope by MAJIN-TERB2-TERB1.},
journal = {Nature communications},
volume = {9},
number = {1},
pages = {5355},
pmid = {30559341},
issn = {2041-1723},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Apoptosis Regulatory Proteins/*genetics ; Carrier Proteins/genetics/*metabolism ; Cell Cycle Proteins/genetics/*metabolism ; Cell Line ; Crystallography, X-Ray ; DNA-Binding Proteins ; Humans ; Meiosis/genetics ; Multiprotein Complexes/metabolism ; Nuclear Envelope/*metabolism ; Nuclear Proteins/*genetics ; Protein Folding ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/*genetics ; Telomeric Repeat Binding Protein 1/*genetics ; },
abstract = {Meiotic chromosomes undergo rapid prophase movements, which are thought to facilitate the formation of inter-homologue recombination intermediates that underlie synapsis, crossing over and segregation. The meiotic telomere complex (MAJIN, TERB1, TERB2) tethers telomere ends to the nuclear envelope and transmits cytoskeletal forces via the LINC complex to drive these rapid movements. Here, we report the molecular architecture of the meiotic telomere complex through the crystal structure of MAJIN-TERB2, together with light and X-ray scattering studies of wider complexes. The MAJIN-TERB2 2:2 hetero-tetramer binds strongly to DNA and is tethered through long flexible linkers to the inner nuclear membrane and two TRF1-binding 1:1 TERB2-TERB1 complexes. Our complementary structured illumination microscopy studies and biochemical findings reveal a telomere attachment mechanism in which MAJIN-TERB2-TERB1 recruits telomere-bound TRF1, which is then displaced during pachytene, allowing MAJIN-TERB2-TERB1 to bind telomeric DNA and form a mature attachment plate.},
}
@article {pmid30557805,
year = {2019},
author = {Grau-Perez, M and Zhao, J and Pierce, B and Francesconi, KA and Goessler, W and Zhu, Y and An, Q and Umans, J and Best, L and Cole, SA and Navas-Acien, A and Tellez-Plaza, M},
title = {Urinary metals and leukocyte telomere length in American Indian communities: The Strong Heart and the Strong Heart Family Study.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {246},
number = {},
pages = {311-318},
pmid = {30557805},
issn = {1873-6424},
support = {U01 HL041642/HL/NHLBI NIH HHS/United States ; U01 HL041654/HL/NHLBI NIH HHS/United States ; R01 DK091369/DK/NIDDK NIH HHS/United States ; R01 ES025216/ES/NIEHS NIH HHS/United States ; R01 HL090863/HL/NHLBI NIH HHS/United States ; U01 HL041652/HL/NHLBI NIH HHS/United States ; P42 ES010349/ES/NIEHS NIH HHS/United States ; R01 HL109315/HL/NHLBI NIH HHS/United States ; R01 HL109319/HL/NHLBI NIH HHS/United States ; R01 HL109284/HL/NHLBI NIH HHS/United States ; U01 HL065521/HL/NHLBI NIH HHS/United States ; R01 HL109301/HL/NHLBI NIH HHS/United States ; R01 HL109282/HL/NHLBI NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; U01 HL065520/HL/NHLBI NIH HHS/United States ; R01 ES021367/ES/NIEHS NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Arsenic/toxicity/*urine ; Cadmium/toxicity/*urine ; Environmental Exposure/*analysis ; Female ; Humans ; *Indians, North American ; Leukocytes/*drug effects ; Male ; Middle Aged ; Telomere/*drug effects ; Tungsten/toxicity/*urine ; United States ; },
abstract = {INTRODUCTION: While several mechanisms may explain metal-related health effects, the exact cellular processes are not fully understood. We evaluated the association between leukocyte telomere length (LTL) and urine arsenic (ΣAs), cadmium (Cd) and tungsten (W) exposure in the Strong Heart Study (SHS, N = 1702) and in the Strong Heart Family Study (SHFS, N = 1793).<br><br>METHODS: Urine metal concentrations were measured using ICP-MS. Arsenic exposure was assessed as the sum of inorganic arsenic, monomethylarsonate and dimethylarsinate levels (&#x3a3;As). LTL was measured by quantitative polymerase chain reaction.<br><br>RESULTS: In the SHS, median levels were 1.09 for LTL, and 8.8, 1.01 and 0.11&#x202f;&#x3bc;g/g creatinine for &#x3a3;As, Cd, and W, respectively. In the SHFS, median levels were 1.01 for LTL, and 4.3, 0.44, and 0.10&#x202f;&#x3bc;g/g creatinine. Among SHS participants, increased urine &#x3a3;As, Cd, and W was associated with shorter LTL. The adjusted geometric mean ratio (95% confidence interval) of LTL per an increase equal to the difference between the percentiles 90th and 10th in metal distributions was 0.85 (0.79, 0.92) for &#x3a3;As, 0.91 (0.84, 1.00) for Cd and 0.93 (0.88, 0.98) for W. We observed no significant associations among SHFS participants. The findings also suggest that the association between arsenic and LTL might be differential depending on the exposure levels or age.<br><br>CONCLUSIONS: Additional research is needed to confirm the association between metal exposures and telomere length.},
}
@article {pmid30556624,
year = {2019},
author = {Kannengiesser, C and Borie, R and Renzoni, EA},
title = {Pulmonary fibrosis: Genetic analysis of telomere-related genes, telomere length measurement-or both?.},
journal = {Respirology (Carlton, Vic.)},
volume = {24},
number = {2},
pages = {97-98},
doi = {10.1111/resp.13456},
pmid = {30556624},
issn = {1440-1843},
support = {20719/VAC_/Versus Arthritis/United Kingdom ; PB-PG-0712-28073/DH_/Department of Health/United Kingdom ; },
mesh = {Humans ; *Idiopathic Pulmonary Fibrosis ; Prognosis ; Telomerase/*genetics ; Telomere ; Telomere Shortening ; },
}
@article {pmid30556003,
year = {2018},
author = {Sabale, PM and Ambi, UB and Srivatsan, SG},
title = {Clickable PNA Probes for Imaging Human Telomeres and Poly(A) RNAs.},
journal = {ACS omega},
volume = {3},
number = {11},
pages = {15343-15352},
pmid = {30556003},
issn = {2470-1343},
support = {/WT_/Wellcome Trust/United Kingdom ; IA/S/16/1/502360/WTDBT_/DBT-Wellcome Trust India Alliance/India ; },
abstract = {The ability to bind strongly to complementary nucleic acid sequences, invade complex nucleic acid structures, and resist degradation by cellular enzymes has made peptide nucleic acid (PNA) oligomers as very useful hybridization probes in molecular diagnosis. For such applications, the PNA oligomers have to be labeled with appropriate reporters as they lack intrinsic labels that can be used in biophysical assays. Although solid-phase synthesis is commonly used to attach reporters onto PNA, development of milder and modular labeling methods will provide access to PNA oligomers labeled with a wider range of biophysical tags. Here, we describe the establishment of a postsynthetic modification strategy based on bioorthogonal chemical reactions in functionalizing PNA oligomers in solution with a variety of tags. A toolbox composed of alkyne- and azide-modified monomers were site-specifically incorporated into PNA oligomers and postsynthetically click-functionalized with various tags, ranging from sugar, amino acid, biotin, to fluorophores, by using copper(I)-catalyzed azide-alkyne cycloaddition, strain-promoted azide-alkyne cycloaddition, and Staudinger ligation reactions. As a proof of utility of this method, fluorescent PNA hybridization probes were developed and used in imaging human telomeres in chromosomes and poly(A) RNAs in cells. Taken together, this simple approach of generating a wide range of functional PNA oligomers will expand the use of PNA in molecular diagnosis.},
}
@article {pmid30542661,
year = {2017},
author = {Guyatt, AL and Rodriguez, S and Gaunt, TR and Fraser, A and Anderson, EL},
title = {Early life adiposity and telomere length across the life course: a systematic review and meta-analysis.},
journal = {Wellcome open research},
volume = {2},
number = {},
pages = {118},
pmid = {30542661},
issn = {2398-502X},
support = {/WT_/Wellcome Trust/United Kingdom ; MC_UU_12013/8/MRC_/Medical Research Council/United Kingdom ; MR/M009351/1/MRC_/Medical Research Council/United Kingdom ; MR/P014437/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Background: The relationship between adiposity at birth and in childhood, and telomere length is yet to be determined. We aimed to systematically review and meta-analyse the results of studies assessing associations between neonatal and later childhood adiposity, and telomere length. Methods: We searched Medline, EMBASE and PubMed for studies reporting associations between adiposity measured in the neonatal period or later childhood/adolescence, and leucocyte telomere length, measured at any age via quantitative polymerase chain reaction, or terminal restriction fragment analysis, either cross-sectionally, or longitudinally. Papers published before April 2017 were included. Results: Out of 230 abstracts assessed, 23 papers (32 estimates) were retained, from which 19 estimates were meta-analysed (15 cross-sectional, four longitudinal). Of the 15 cross-sectional estimates, seven reported on neonates: four used binary exposures of small-for-gestational-age vs. appropriate-for-gestational age (or appropriate- and large-for-gestational age), and three studied birth weight continuously. Eight estimates reported on later childhood or adolescent measures; five estimates were from studies of binary exposures (overweight/obese vs. non-obese children), and three studies used continuous measures of body mass index. All four longitudinal estimates were of neonatal adiposity, with two estimates for small-for-gestational-age vs. appropriate-for-gestational age neonates, and two estimates of birth weight studied continuously, in relation to adult telomere (49-61 years). There was no strong evidence of an association between neonatal or later childhood/adolescent adiposity, and telomere length. However, between study heterogeneity was high, and there were few combinable studies. Conclusions: Our systematic review and meta-analysis found no strong evidence of an association between neonatal or later childhood or adolescent adiposity and telomere length.},
}
@article {pmid30553820,
year = {2019},
author = {Beatty Moody, DL and Leibel, DK and Darden, TM and Ashe, JJ and Waldstein, SR and Katzel, LI and Liu, HB and Weng, NP and Evans, MK and Zonderman, AB},
title = {Interpersonal-level discrimination indices, sociodemographic factors, and telomere length in African-Americans and Whites.},
journal = {Biological psychology},
volume = {141},
number = {},
pages = {1-9},
pmid = {30553820},
issn = {1873-6246},
support = {Z99 AG999999/ImNIH/Intramural NIH HHS/United States ; P30 AG028747/AG/NIA NIH HHS/United States ; R01 AG034161/AG/NIA NIH HHS/United States ; R25 GM055036/GM/NIGMS NIH HHS/United States ; ZIA AG000199-06/ImNIH/Intramural NIH HHS/United States ; K01 AG043581/AG/NIA NIH HHS/United States ; Z01 AG000513/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Black or African American/*psychology ; Age Factors ; Cellular Senescence/*genetics ; Cross-Sectional Studies ; Depression/epidemiology/ethnology ; Female ; Humans ; Male ; Middle Aged ; Racism/ethnology/*statistics &amp; numerical data ; Regression Analysis ; Risk Factors ; Self Report ; Sex Factors ; Social Class ; Substance-Related Disorders/epidemiology/ethnology ; Telomere/*physiology ; Urban Population/statistics &amp; numerical data ; White People/*psychology ; },
abstract = {OBJECTIVE: Studies have linked self-reported discrimination to telomere attrition, a biological marker of accelerated cellular aging. However, it is unknown whether intersections between social categories-race, socioeconomic status (SES), sex, and age-influence the association of varying forms of discrimination with telomere length. We examined these associations in a socioeconomically and racially/ethnically diverse urban sample.<br><br>METHODS: Cross-sectional data were from 341 middle-aged (30-64 years) African American and White, community participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span Study (HANDLS). Multiple regression models examined up to 3-way interactions between a discrimination measure (i.e., everyday, racial, gender, lifetime burden, and frequency of discrimination across sources) and two social categories.<br><br>RESULTS: After adjusting for depressive symptoms, waist circumference, and lifetime substance use, two themes emerged: 1) among women with higher SES, a) greater lifetime discrimination burden (b = -0.23, p&#x2009;=&#x2009; .011), gender discrimination (b = -0.29, p&#x2009;=&#x2009; .040), and racial discrimination (b = -0.24, p = 0.023) and 2) among younger adults, irrespective of race and sex, greater frequency of discrimination across sources (b&#x2009;=&#x2009;0.002, p&#x2009;=&#x2009; .008) was associated with shorter telomeres.<br><br>CONCLUSIONS: Irrespective of race, women with higher SES and younger adults reporting greater discrimination may be at particular risk for accelerated aging. Telomere attrition promotes and accelerates chronic health conditions for which there are health disparities. Future research explicating intersections among specific discrimination indices and social categories is warranted.},
}
@article {pmid30553080,
year = {2019},
author = {Conklin, QA and Crosswell, AD and Saron, CD and Epel, ES},
title = {Meditation, stress processes, and telomere biology.},
journal = {Current opinion in psychology},
volume = {28},
number = {},
pages = {92-101},
pmid = {30553080},
issn = {2352-2518},
support = {K01 AG057859/AG/NIA NIH HHS/United States ; R24 AG048024/AG/NIA NIH HHS/United States ; T32 MH020006/MH/NIMH NIH HHS/United States ; },
mesh = {Cellular Senescence/*physiology ; Humans ; *Meditation ; Stress, Psychological/*metabolism/*therapy ; Telomere/*metabolism ; },
abstract = {Both theoretical and empirical work support the notion that meditation training can improve telomere regulation, which may ultimately contribute to healthy aging. Yet, the psychological and biological mechanisms underlying these changes remain underspecified, as do the contexts and boundary conditions in which these changes occur. Here we summarize studies investigating the effects of various meditation-based interventions on telomere biology, making suggestions for future research. We then propose a model describing how meditation training may impact acute and habitual stress responses as pathways to improved cell aging.},
}
@article {pmid30552465,
year = {2019},
author = {Rinelli, M and Bellacchio, E and Berardinelli, F and Pascolini, G and Grammatico, P and Sgura, A and Iori, AP and Quattrocchi, L and Novelli, A and Majore, S and Agolini, E},
title = {Correction to: Structural modeling of a novel TERC variant in a patient with aplastic anemia and short telomeres.},
journal = {Annals of hematology},
volume = {98},
number = {3},
pages = {809},
doi = {10.1007/s00277-018-3581-5},
pmid = {30552465},
issn = {1432-0584},
abstract = {The original version of this article contained a mistake in the affiliation of E. Bellacchio. Correct affiliation is presented here.},
}
@article {pmid30552372,
year = {2018},
author = {Rachakonda, S and Srinivas, N and Mahmoudpour, SH and Garcia-Casado, Z and Requena, C and Traves, V and Soriano, V and Cardelli, M and Pjanova, D and Molven, A and Gruis, N and Nagore, E and Kumar, R},
title = {Author Correction: Telomere length and survival in primary cutaneous melanoma patients.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {17963},
doi = {10.1038/s41598-018-36657-w},
pmid = {30552372},
issn = {2045-2322},
abstract = {A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.},
}
@article {pmid30546303,
year = {2018},
author = {Fernández-Eulate, G and Alberro, A and Muñoz-Culla, M and Zulaica, M and Zufiría, M and Barandiarán, M and Etxeberria, I and Yanguas, JJ and Gallardo, MM and Soberón, N and Lacosta, AM and Pérez-Grijalba, V and Canudas, J and Fandos, N and Pesini, P and Sarasa, M and Indakoetxea, B and Moreno, F and Vergara, I and Otaegui, D and Blasco, M and López de Munain, A},
title = {Blood Markers in Healthy-Aged Nonagenarians: A Combination of High Telomere Length and Low Amyloidβ Are Strongly Associated With Healthy Aging in the Oldest Old.},
journal = {Frontiers in aging neuroscience},
volume = {10},
number = {},
pages = {380},
pmid = {30546303},
issn = {1663-4365},
abstract = {Many factors may converge in healthy aging in the oldest old, but their association and predictive power on healthy or functionally impaired aging has yet to be demonstrated. By detecting healthy aging and in turn, poor aging, we could take action to prevent chronic diseases associated with age. We conducted a pilot study comparing results of a set of markers (peripheral blood mononuclear cell or PBMC telomere length, circulating Aβ peptides, anti-Aβ antibodies, and ApoE status) previously associated with poor aging or cognitive deterioration, and their combinations, in a cohort of "neurologically healthy" (both motor and cognitive) nonagenarians (n = 20) and functionally impaired, institutionalized nonagenarians (n = 38) recruited between 2014 and 2015. We recruited 58 nonagenarians (41 women, 70.7%; mean age: 92.37 years in the neurologically healthy group vs. 94.13 years in the functionally impaired group). Healthy nonagenarians had significantly higher mean PBMC telomere lengths (mean = 7, p = 0.001), this being inversely correlated with functional impairment, and lower circulating Aβ40 (total in plasma fraction or TP and free in plasma fraction or FP), Aβ42 (TP and FP) and Aβ17 (FP) levels (FP40 131.35, p = 0.004; TP40 299.10, p = 0.007; FP42 6.29, p = 0.009; TP42 22.53, p = 0.019; FP17 1.32 p = 0.001; TP17 4.47, p = 0.3), after adjusting by age. Although healthy nonagenarians had higher anti-Aβ40 antibody levels (net adsorbed signal or NAS ± SD: 0.211 ± 0.107), the number of participants that pass the threshold (NAS > 3) to be considered as positive did not show such a strong association. There was no association with ApoE status. Additionally, we propose a "Composite Neurologically Healthy Aging Score" combining TP40 and mean PBMC telomere length, the strongest correlation of measured biomarkers with neurologically healthy status in nonagenarians (AUC = 0.904).},
}
@article {pmid30544511,
year = {2018},
author = {Balan, E and Decottignies, A and Deldicque, L},
title = {Physical Activity and Nutrition: Two Promising Strategies for Telomere Maintenance?.},
journal = {Nutrients},
volume = {10},
number = {12},
pages = {},
pmid = {30544511},
issn = {2072-6643},
support = {-//Universit&#xe9; catholique de Louvain/ ; },
mesh = {Animals ; *Exercise ; Humans ; Nutritional Physiological Phenomena/*genetics ; *Nutritional Status ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {As the world demographic structure is getting older, highlighting strategies to counteract age-related diseases is a major public health concern. Telomeres are nucleoprotein structures that serve as guardians of genome stability by ensuring protection against both cell death and senescence. A hallmark of biological aging, telomere health is determined throughout the lifespan by a combination of both genetic and non-genetic influences. This review summarizes data from recently published studies looking at the effect of lifestyle variables such as nutrition and physical activity on telomere dynamics.},
}
@article {pmid30544048,
year = {2019},
author = {Kaja, R and Reyes, SM and Rossetti, HC and Brown, ES},
title = {Association between telomere length and cognitive ability in a community-based sample.},
journal = {Neurobiology of aging},
volume = {75},
number = {},
pages = {51-53},
doi = {10.1016/j.neurobiolaging.2018.11.006},
pmid = {30544048},
issn = {1558-1497},
mesh = {Aging/*physiology ; Biomarkers/*analysis ; Cognition/*physiology ; Female ; Humans ; Male ; Patient Compliance ; Residence Characteristics ; Telomere/*metabolism ; },
abstract = {Prior research suggests that telomere length is a biomarker of cognitive aging; however, literature has demonstrated conflicting findings to date. The present study uses data from the Dallas Heart Study, N = 2606, to assess the association between telomere length and cognitive ability on the Montreal Cognitive Assessment. The data do not support a relationship between telomere length and general cognitive functioning, (β = 0.016, SE = 0.31, p = 0.407). The data further replicate the negative findings within current literature.},
}
@article {pmid30544003,
year = {2019},
author = {Verhoeven, JE and Penninx, BWJH and Milaneschi, Y},
title = {Unraveling the association between depression and telomere length using genomics.},
journal = {Psychoneuroendocrinology},
volume = {102},
number = {},
pages = {121-127},
doi = {10.1016/j.psyneuen.2018.11.029},
pmid = {30544003},
issn = {1873-3360},
support = {RC2 MH089951/MH/NIMH NIH HHS/United States ; RC2 MH089995/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Cross-Sectional Studies ; Depression/*genetics/physiopathology ; Depressive Disorder/genetics/physiopathology ; Depressive Disorder, Major/genetics ; Female ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genomics/*methods ; Humans ; Male ; Middle Aged ; Multifactorial Inheritance/genetics ; Netherlands ; Telomere/*genetics/physiology ; Telomere Shortening/genetics ; },
abstract = {OBJECTIVE: While there is robust evidence for a cross-sectional association between depression and shorter telomere length, suggestive of advanced biological aging, the nature of this association remains unclear. Here, we tested whether both traits share a common genetic liability with novel methods using genomics.<br><br>METHODS: Data were from 2032 participants of the Netherlands Study of Depression and Anxiety (NESDA) with genome-wide genetic information and multiple waves of data on DSM-IV lifetime depression diagnosis, depression severity, neuroticism and telomere length. Polygenic risk scores (PRS) for both traits were built using summary results from the largest genome-wide association studies (GWAS) on depression (59,851 cases and 113,154 controls) and telomere length (37,684 samples). Additionally, a PRS for neuroticism was built (337,000 samples). Genetic overlap between the traits was tested using PRS for same- and cross-trait associations. Furthermore, GWAS summary statistics were used to estimate the genome-wide genetic correlation between traits.<br><br>RESULTS: In NESDA data, the PRS for depression was associated with lifetime depression (odds ratio&#x2009;=&#x2009;1.36; p&#x2009;=&#x2009;6.49e-7) and depression severity level (&#x3b2;&#x2009;=&#x2009;0.13; p&#x2009;=&#x2009;1.24e-8), but not with telomere length. Similar results were found for the PRS for neuroticism. Conversely, the PRS for telomere length was associated with telomere length (&#x3b2;&#x2009;=&#x2009;0.07; p&#x2009;=&#x2009;8.42e-4) and 6-year telomere length attrition rate (&#x3b2;&#x2009;=&#x2009;0.04; p&#x2009;=&#x2009;2.15e-2), but not with depression variables. In summary-level analyses, the genetic correlation between the traits was small and not significant (rg=-0.08; p&#x2009;=&#x2009;.300).<br><br>CONCLUSION: The use of genetic methods in this paper indicated that the established phenotypic association between telomere length and depression is unlikely due to shared underlying genetic vulnerability. Our findings suggest that short telomeres in depressed patients may simply represent a generic marker of disease or may originate from non-genetic environmental factors.},
}
@article {pmid30524658,
year = {2018},
author = {Iodice, S and Hoxha, M and Ferrari, L and Carbone, IF and Anceschi, C and Miragoli, M and Pesatori, AC and Persico, N and Bollati, V},
title = {Particulate Air Pollution, Blood Mitochondrial DNA Copy Number, and Telomere Length in Mothers in the First Trimester of Pregnancy: Effects on Fetal Growth.},
journal = {Oxidative medicine and cellular longevity},
volume = {2018},
number = {},
pages = {5162905},
pmid = {30524658},
issn = {1942-0994},
mesh = {Adolescent ; Adult ; *DNA Copy Number Variations ; DNA, Mitochondrial/blood/*genetics ; Female ; Fetal Growth Retardation/*etiology/pathology ; Humans ; Infant, Low Birth Weight ; Infant, Newborn ; Male ; Maternal Exposure/*adverse effects ; Middle Aged ; Mothers ; Particulate Matter/*adverse effects ; Pregnancy ; Pregnancy Trimester, First ; *Telomere Homeostasis ; Young Adult ; },
abstract = {Growing evidences have shown that particulate matter (PM) exposures during pregnancy are associated with impaired fetal development and adverse birth outcomes, possibly as a result of an exaggerated systemic oxidative stress and inflammation. Telomere length (TL) is strongly linked to biological age and is impacted by oxidative stress. We hypothesized that PM exposure during different time windows in the first trimester of pregnancy influences both mitochondrial DNA copy number (mtDNAcn), an established biomarker for oxidative stress, and TL. Maternal blood TL and mtDNAcn were analysed in 199 healthy pregnant women recruited at the 11th week of pregnancy by quantitative polymerase chain reaction. We also examined whether maternal mtDNAcn and TL were associated with fetal growth outcomes measured at the end of the first trimester of pregnancy (fetal heart rate, FHR; crown-rump length, CRL; and nuchal translucency, NT) and at delivery (birth weight, length, head circumference). The possible modifying effect of prepregnancy maternal body mass index was evaluated. PM10 exposure during the first pregnancy trimester was associated with an increased maternal mtDNAcn and a reduced TL. As regards ultrasound fetal outcomes, both FHR and CRL were positively associated with PM2.5, whereas the association with FHR was confirmed only when examining PM10 exposure. PM10 was also associated with a reduced birth weight. While no association was found between mtDNAcn and CRL, we found a negative relationship between mtDNAcn and fetal CRL only in overweight women, whereas normal-weight women exhibited a positive, albeit nonsignificant, association. As abnormalities of growth in utero have been associated with postnatal childhood and adulthood onset diseases and as PM is a widespread pollutant relevant to the large majority of the human population and obesity a rising risk factor, our results, if confirmed in a larger population, might represent an important contribution towards the development of more targeted public health strategies.},
}
@article {pmid30523342,
year = {2019},
author = {Gutierrez-Rodrigues, F and Donaires, FS and Pinto, A and Vicente, A and Dillon, LW and Clé, DV and Santana, BA and Pirooznia, M and Ibanez, MDPF and Townsley, DM and Kajigaya, S and Hourigan, CS and Cooper, JN and Calado, RT and Young, NS},
title = {Pathogenic TERT promoter variants in telomere diseases.},
journal = {Genetics in medicine : official journal of the American College of Medical Genetics},
volume = {21},
number = {7},
pages = {1594-1602},
pmid = {30523342},
issn = {1530-0366},
support = {Z99 HL999999//Intramural NIH HHS/United States ; Z99 HL999999/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Anemia, Aplastic/genetics ; Blood Cell Count ; Bone Marrow Diseases/genetics ; Child ; Child, Preschool ; Cohort Studies ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/genetics ; Liver Diseases/genetics ; Male ; Middle Aged ; *Promoter Regions, Genetic ; Retrospective Studies ; Telomerase/deficiency/*genetics ; Telomere/*pathology ; Young Adult ; },
abstract = {PURPOSE: The acquisition of pathogenic variants in the TERT promoter (TERTp) region is a mechanism of tumorigenesis. In nonmalignant diseases, TERTp variants have been reported only in patients with idiopathic pulmonary fibrosis (IPF) due to germline variants in telomere biology genes.<br><br>METHODS: We screened patients with a broad spectrum of telomeropathies (n&#x2009;=&#x2009;136), their relatives (n&#x2009;=&#x2009;52), and controls (n&#x2009;=&#x2009;195) for TERTp variants using a customized massively parallel amplicon-based sequencing assay.<br><br>RESULTS: Pathogenic -124 and -146 TERTp variants were identified in nine (7%) unrelated patients diagnosed with IPF (28%) or moderate aplastic anemia (4.6%); five of them also presented cirrhosis. Five (10%) relatives were also found with these variants, all harboring a pathogenic germline variant in telomere biology genes. TERTp clone selection did not associate with peripheral blood counts, telomere length, and response to danazol treatment. However, it was specific for patients with telomeropathies, more frequently co-occurring with TERT germline variants and associated with aging.<br><br>CONCLUSION: We extend the spectrum of nonmalignant diseases associated with pathogenic TERTp variants to marrow failure and liver disease due to inherited telomerase deficiency. Specificity of pathogenic TERTp variants for telomerase dysfunction may help to assess the pathogenicity of unclear constitutional variants in the telomere diseases.},
}
@article {pmid30523160,
year = {2019},
author = {Borie, R and Bouvry, D and Cottin, V and Gauvain, C and Cazes, A and Debray, MP and Cadranel, J and Dieude, P and Degot, T and Dominique, S and Gamez, AS and Jaillet, M and Juge, PA and Londono-Vallejo, A and Mailleux, A and Mal, H and Boileau, C and Menard, C and Nunes, H and Prevot, G and Quetant, S and Revy, P and Traclet, J and Wemeau-Stervinou, L and Wislez, M and Kannengiesser, C and Crestani, B},
title = {Regulator of telomere length 1 (RTEL1) mutations are associated with heterogeneous pulmonary and extra-pulmonary phenotypes.},
journal = {The European respiratory journal},
volume = {53},
number = {2},
pages = {},
doi = {10.1183/13993003.00508-2018},
pmid = {30523160},
issn = {1399-3003},
mesh = {Adult ; Aged ; Aged, 80 and over ; DNA Helicases/*genetics ; Exome ; Female ; Follow-Up Studies ; *Gene Expression Regulation ; Heterozygote ; Humans ; Lung Diseases/genetics/*metabolism ; Lung Diseases, Interstitial/*genetics ; Male ; Middle Aged ; *Mutation ; Pedigree ; Phenotype ; Sequence Analysis, DNA ; Telomerase/genetics ; Vital Capacity ; },
abstract = {Regulator of telomere length 1 (RTEL1) mutations have been evidenced in 5-9% of familial pulmonary fibrosis; however, the phenotype of patients with interstitial lung disease (ILD) and RTEL1 mutations is poorly understood.Whole exome sequencing was performed in 252 probands with ILD and we included all patients with ILD and RTEL1 mutation. RTEL1 expression was evaluated by immunochemistry in the lungs of controls, as well as in RTEL1 and telomerase reverse transcriptase (TERT) mutation carriers.We identified 35 subjects from 17 families. Median age at diagnosis of ILD was 53.1 years (range 28.0-80.6). The most frequent pulmonary diagnoses were idiopathic pulmonary fibrosis (n=20, 57%), secondary ILD (n=7, 20%) and unclassifiable fibrosis or interstitial pneumonia with autoimmune features (n=7, 20%). The median transplant-free and overall survival periods were 39.2 months and 45.3 months, respectively. Forced vital capacity at diagnosis was the only factor associated with decreased transplant-free survival. Extra-pulmonary manifestations were less frequent as compared to other telomere-related gene mutation carriers. A systematic analysis of the literature identified 110 patients with ILD and RTEL1 mutations (including this series) and confirmed the heterogeneity of the pulmonary phenotype, the prevalence of non-idiopathic diseases and the low prevalence of extra-pulmonary manifestations.Immunohistochemistry showed that RTEL1 was expressed by bronchial and alveolar epithelial cells, as well as by alveolar macrophages and lymphocytes, but not by fibroblasts.},
}
@article {pmid30540921,
year = {2019},
author = {Courtwright, AM and El-Chemaly, S},
title = {Telomeres in Interstitial Lung Disease: The Short and the Long of It.},
journal = {Annals of the American Thoracic Society},
volume = {16},
number = {2},
pages = {175-181},
pmid = {30540921},
issn = {2325-6621},
support = {R01 HL130275/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; Idiopathic Pulmonary Fibrosis/*genetics/therapy ; Lung Diseases, Interstitial/*genetics/therapy ; Lung Transplantation ; Mutation ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Shortening ; },
abstract = {Telomeres are repetitive nucleotide sequences that cap linear chromosomes, thereby limiting progressive chromosomal shortening during cell replication. In conjunction with environmental factors, common single-nucleotide polymorphisms and rare and ultra-rare telomere-related mutations are associated with accelerated telomere shortening resulting in organ dysfunction, including interstitial lung disease (ILD). The most common telomere-related mutation-associated ILD is idiopathic pulmonary fibrosis (IPF). Up to one-third of individuals with familial IPF have shortened telomeres and/or carry a telomere-related mutation, and 1 in 10 individuals with sporadic IPF have telomere-related mutations. Regardless of ILD phenotype, individuals with short telomeres and/or known telomere-related mutations have more rapid disease progression and shorter lung transplant-free survival. Management should include initiation of antifibrotic agents for those with an IPF phenotype and early referral to a transplant center. Patients with ILD being considered for transplant should be screened for short telomeres if there is a significant family history of pulmonary fibrosis or evidence of extrapulmonary organ dysfunction associated with a short telomere syndrome. Post-transplant management of recipients with telomere-related mutations should include careful adjustment of immunosuppression regimens on the basis of bone marrow reserve. Data on the impact of shortened telomeres on post-transplant outcomes, however, remain mixed.},
}
@article {pmid30539406,
year = {2018},
author = {Ingles, ED and Deakin, JE},
title = {The methylation and telomere landscape in two families of marsupials with different rates of chromosome evolution.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {26},
number = {4},
pages = {317-332},
pmid = {30539406},
issn = {1573-6849},
mesh = {Animals ; Biological Evolution ; Chromosomes/*genetics ; *DNA Methylation ; Epigenomics ; *Karyotype ; Macropodidae ; Marsupialia/*genetics ; Telomere/*genetics ; Telomere Homeostasis ; X Chromosome/genetics ; },
abstract = {Two marsupial families exemplify divergent rates of karyotypic change. The Dasyurid family has an extremely conserved karyotype. In contrast, there is significant chromosomal variation within the Macropodidae family, best exemplified by members of the genus Petrogale (rock-wallabies). Both families are also distinguished by their telomere landscape (length and epigenetics), with the dasyurids having a unique telomere length dimorphism not observed in other marsupials and hypothesised to be regulated in a parent-of-origin fashion. Previous work has shown that proximal ends of chromosomes are enriched in cytosine methylation in dasyurids, but that the chromosomes of a macropod, the tammar wallaby, have DNA methylation enrichment of pericentric regions. Using a combination of telomere and 5-methylcytosine immunofluorescence staining, we investigated the telomere landscape of four dasyurid and three Petrogale species. As part of this study, we also further examined the parent-of-origin hypothesis for the regulation of telomere length dimorphism in dasyurids, using epigenetic modifications known to differentiate the active maternal X chromosome, including 5-methylcytosine methylation and histone modifications H3K4me2, H3K9ac and H4Kac. Our results give further support to the parent-of-origin hypothesis for the regulation of telomere length dimorphism in dasyurids, where the paternally derived X chromosome in females was associated with long telomeres and the maternally derived with short telomeres. In contrast to the tammar wallaby, rock-wallabies demonstrated a similar 5-methylcytosine staining pattern across all chromosomes to that of dasyurids, suggesting that DNA methylation of telomeric regions is not responsible for differences in the rates of chromosome evolution between these two families.},
}
@article {pmid30536049,
year = {2019},
author = {Delgado, DA and Zhang, C and Gleason, K and Demanelis, K and Chen, LS and Gao, J and Roy, S and Shinkle, J and Sabarinathan, M and Argos, M and Tong, L and Ahmed, A and Islam, T and Rakibuz-Zaman, M and Sarwar, G and Shahriar, H and Rahman, M and Yunus, M and Doherty, JA and Jasmine, F and Kibriya, MG and Ahsan, H and Pierce, BL},
title = {The contribution of parent-to-offspring transmission of telomeres to the heritability of telomere length in humans.},
journal = {Human genetics},
volume = {138},
number = {1},
pages = {49-60},
pmid = {30536049},
issn = {1432-1203},
support = {R01 ES020506/NH/NIH HHS/United States ; R24 ES028532/ES/NIEHS NIH HHS/United States ; P30 CA014599/CA/NCI NIH HHS/United States ; P42 ES10349/NH/NIH HHS/United States ; P42 ES010349/ES/NIEHS NIH HHS/United States ; U01 HG007601/NH/NIH HHS/United States ; R01 CA107431/CA/NCI NIH HHS/United States ; U01 HG007601/HG/NHGRI NIH HHS/United States ; R01 CA102484/NH/NIH HHS/United States ; R01 CA107431/NH/NIH HHS/United States ; R35 ES028379/ES/NIEHS NIH HHS/United States ; R01 CA102484/CA/NCI NIH HHS/United States ; P30 CA014599/NH/NIH HHS/United States ; R25 GM109439/GM/NIGMS NIH HHS/United States ; R01 ES020506/ES/NIEHS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Female ; Follow-Up Studies ; Humans ; Leukocytes/*metabolism/*pathology ; Male ; Middle Aged ; *Parents ; *Polymorphism, Single Nucleotide ; Prospective Studies ; Telomere/*genetics ; *Telomere Homeostasis ; Young Adult ; },
abstract = {Leukocyte telomere length (LTL) is a heritable trait with two potential sources of heritability (h[2]): inherited variation in non-telomeric regions (e.g., SNPs that influence telomere maintenance) and variability in the lengths of telomeres in gametes that produce offspring zygotes (i.e., "direct" inheritance). Prior studies of LTL h[2] have not attempted to disentangle these two sources. Here, we use a novel approach for detecting the direct inheritance of telomeres by studying the association between identity-by-descent (IBD) sharing at chromosome ends and phenotypic similarity in LTL. We measured genome-wide SNPs and LTL for a sample of 5069 Bangladeshi adults with substantial relatedness. For each of the 6318 relative pairs identified, we used SNPs near the telomeres to estimate the number of chromosome ends shared IBD, a proxy for the number of telomeres shared IBD (Tshared). We then estimated the association between Tshared and the squared pairwise difference in LTL ((ΔLTL)[2]) within various classes of relatives (siblings, avuncular, cousins, and distant), adjusting for overall genetic relatedness (ϕ). The association between Tshared and (ΔLTL)[2] was inverse among all relative pair types. In a meta-analysis including all relative pairs (ϕ > 0.05), the association between Tshared and (ΔLTL)[2] (P = 0.01) was stronger than the association between ϕ and (ΔLTL)[2] (P = 0.43). Our results provide strong evidence that telomere length (TL) in parental germ cells impacts TL in offspring cells and contributes to LTL h[2] despite telomere "reprogramming" during embryonic development. Applying our method to larger studies will enable robust estimation of LTL h[2] attributable to direct transmission of telomeres.},
}
@article {pmid30535086,
year = {2018},
author = {Gielen, M and Hageman, GJ and Antoniou, EE and Nordfjall, K and Mangino, M and Balasubramanyam, M and de Meyer, T and Hendricks, AE and Giltay, EJ and Hunt, SC and Nettleton, JA and Salpea, KD and Diaz, VA and Farzaneh-Far, R and Atzmon, G and Harris, SE and Hou, L and Gilley, D and Hovatta, I and Kark, JD and Nassar, H and Kurz, DJ and Mather, KA and Willeit, P and Zheng, YL and Pavanello, S and Demerath, EW and Rode, L and Bunout, D and Steptoe, A and Boardman, L and Marti, A and Needham, B and Zheng, W and Ramsey-Goldman, R and Pellatt, AJ and Kaprio, J and Hofmann, JN and Gieger, C and Paolisso, G and Hjelmborg, JBH and Mirabello, L and Seeman, T and Wong, J and van der Harst, P and Broer, L and Kronenberg, F and Kollerits, B and Strandberg, T and Eisenberg, DTA and Duggan, C and Verhoeven, JE and Schaakxs, R and Zannolli, R and Dos Reis, RMR and Charchar, FJ and Tomaszewski, M and Mons, U and Demuth, I and Iglesias Molli, AE and Cheng, G and Krasnienkov, D and D'Antono, B and Kasielski, M and McDonnell, BJ and Ebstein, RP and Sundquist, K and Pare, G and Chong, M and Zeegers, MP and , },
title = {Body mass index is negatively associated with telomere length: a collaborative cross-sectional meta-analysis of 87 observational studies.},
journal = {The American journal of clinical nutrition},
volume = {108},
number = {3},
pages = {453-475},
pmid = {30535086},
issn = {1938-3207},
support = {UL1 TR001105/TR/NCATS NIH HHS/United States ; K01 AG034259/AG/NIA NIH HHS/United States ; RG/10/005/28296/BHF_/British Heart Foundation/United Kingdom ; PG/16/49/32176/BHF_/British Heart Foundation/United Kingdom ; N01HC95159/HL/NHLBI NIH HHS/United States ; RG008/08/BHF_/British Heart Foundation/United Kingdom ; R01 DA012854/DA/NIDA NIH HHS/United States ; K01 DK082729/DK/NIDDK NIH HHS/United States ; R01 AG033592/AG/NIA NIH HHS/United States ; U01 HL065520/HL/NHLBI NIH HHS/United States ; R01 HL116381/HL/NHLBI NIH HHS/United States ; P30 ES010126/ES/NIEHS NIH HHS/United States ; U01 HL041642/HL/NHLBI NIH HHS/United States ; P30 CA016056/CA/NCI NIH HHS/United States ; U01 HL041654/HL/NHLBI NIH HHS/United States ; R01 DK091369/DK/NIDDK NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; PG/12/9/29376/BHF_/British Heart Foundation/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; R01 HL076831/HL/NHLBI NIH HHS/United States ; R56 DA012854/DA/NIDA NIH HHS/United States ; U01 HL041652/HL/NHLBI NIH HHS/United States ; P20 RR020649/RR/NCRR NIH HHS/United States ; R21 HL092363/HL/NHLBI NIH HHS/United States ; P60 AR064464/AR/NIAMS NIH HHS/United States ; FS/06/053/BHF_/British Heart Foundation/United Kingdom ; T32 AR007611/AR/NIAMS NIH HHS/United States ; /MRC_/Medical Research Council/United Kingdom ; N01HC95165/HL/NHLBI NIH HHS/United States ; U01 HL065521/HL/NHLBI NIH HHS/United States ; Z01 ES044005/ImNIH/Intramural NIH HHS/United States ; K24 AR002138/AR/NIAMS NIH HHS/United States ; R01 HD012252/HD/NICHD NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R03 AG023251/AG/NIA NIH HHS/United States ; P60 AR030692/AR/NIAMS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; *Body Mass Index ; Cross-Sectional Studies ; Ethnicity ; Humans ; Leukocytes/ultrastructure ; Male ; Middle Aged ; Obesity/pathology ; Sex Factors ; Telomere/*ultrastructure ; Telomere Shortening/*physiology ; },
abstract = {BACKGROUND: Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes.<br><br>OBJECTIVE: A collaborative cross-sectional meta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span.<br><br>DESIGN: Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Study-specific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories ("young": 18-60 y; "middle": 61-75 y; and "old": >75 y), sex, and ethnicity.<br><br>RESULTS: Each unit increase in BMI corresponded to a -3.99 bp (95% CI: -5.17, -2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -7.67 bp (95% CI: -10.03, -5.31 bp) difference. Each unit increase in BMI corresponded to a -1.58 &#xd7; 10(-3) unit T/S ratio (0.16% decrease; 95% CI: -2.14 &#xd7; 10(-3), -1.01 &#xd7; 10(-3)) difference in age- and sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -2.58 &#xd7; 10(-3) unit T/S ratio (0.26% decrease; 95% CI: -3.92 &#xd7; 10(-3), -1.25 &#xd7; 10(-3)). The associations were predominantly for the white pooled population. No sex differences were observed.<br><br>CONCLUSIONS: A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL are warranted.},
}
@article {pmid30533193,
year = {2018},
author = {Zhang, G and Shay, JW},
title = {Inducing rapid telomere irreparable damage in telomerase-expressing cancers.},
journal = {Oncotarget},
volume = {9},
number = {88},
pages = {35803-35804},
pmid = {30533193},
issn = {1949-2553},
}
@article {pmid30533028,
year = {2018},
author = {Garcia-Martin, I and Penketh, RJA and Janssen, AB and Jones, RE and Grimstead, J and Baird, DM and John, RM},
title = {Metformin and insulin treatment prevent placental telomere attrition in boys exposed to maternal diabetes.},
journal = {PloS one},
volume = {13},
number = {12},
pages = {e0208533},
pmid = {30533028},
issn = {1932-6203},
support = {18246/CRUK_/Cancer Research UK/United Kingdom ; C17199/A18246/CRUK_/Cancer Research UK/United Kingdom ; MR/M013960/1/MRC_/Medical Research Council/United Kingdom ; BB/F016557/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Adult ; Analysis of Variance ; Case-Control Studies ; Diabetes, Gestational/*drug therapy ; Female ; Humans ; Hypoglycemic Agents/*therapeutic use ; Insulin/*therapeutic use ; Male ; Metformin/*therapeutic use ; Placenta/*metabolism ; Pregnancy ; Risk Reduction Behavior ; Telomere/chemistry/*metabolism ; Telomere Shortening ; },
abstract = {Shortened leukocyte and placental telomeres associated with gestational diabetes mellitus (GDM) suggest this exposure triggers telomere attrition contributing to adverse outcomes. We applied high resolution Single Telomere Length Analysis (STELA) to placenta from GDM pregnancies with different treatment pathways to determine their effectiveness at preventing telomere attrition. Differences in telomere length between control (N = 69), GDM lifestyle intervention (n = 14) and GDM treated with metformin and/or insulin (n = 17) was tested by Analysis of Covariance (ANCOVA) followed by group comparisons using Fisher's least significant difference. For male placenta only, there were differences in mean telomere length (F(2,54) = 4.98, P = 0.01) and percentage of telomeres under 5 kb (F(2,54) = 4.65, P = 0.01). Telomeres were shorter in the GDM lifestyle intervention group compared to both controls (P = 0.02) and medically treated pregnancies (P = 0.003). There were more telomeres under 5 kb in the GDM lifestyle intervention group compared to the other two groups (P = 0.03 and P = 0.004). Although further work is necessary, we suggest that early adoption of targeted medical treatment of GDM pregnancies where the fetus is known to be male may be an effective strategy for ameliorating adverse outcomes for children.},
}
@article {pmid30530921,
year = {2018},
author = {Morin, SJ and Tao, X and Marin, D and Zhan, Y and Landis, J and Bedard, J and Scott, RT and Seli, E},
title = {DNA methylation-based age prediction and telomere length in white blood cells and cumulus cells of infertile women with normal or poor response to ovarian stimulation.},
journal = {Aging},
volume = {10},
number = {12},
pages = {3761-3773},
pmid = {30530921},
issn = {1945-4589},
mesh = {Adult ; *Aging ; Anti-Mullerian Hormone ; Cumulus Cells/*physiology ; *DNA Methylation ; Estradiol ; Female ; Follicle Stimulating Hormone/administration &amp; dosage/pharmacology ; Gonadotropins/administration &amp; dosage/pharmacology ; Humans ; Leukocytes/*physiology ; Luteinizing Hormone/metabolism ; Ovarian Reserve/*physiology ; Ovulation Induction ; Telomere Homeostasis ; },
abstract = {An algorithm assessing the methylation levels of 353 informative CpG sites in the human genome permits accurate prediction of the chronologic age of a subject. Interestingly, when there is discrepancy between the predicted age and chronologic age (age acceleration or "AgeAccel"), patients are at risk for morbidity and mortality. Identification of infertile patients at risk for accelerated reproductive senescence may permit preventative action. This study aimed to assess the accuracy of the "epigenetic clock" concept in reproductive age women undergoing fertility treatment by applying the age prediction algorithm in peripheral (white blood cells [WBCs]) and follicular somatic cells (cumulus cells [CCs]), and to identify whether women with premature reproductive aging (diminished ovarian reserve) were at risk of AgeAccel in their age prediction. Results indicated that the epigenetic algorithm accurately predicts age when applied to WBCs but not to CCs. The age prediction of CCs was substantially younger than chronologic age regardless of the patient's age or response to stimulation. In addition, telomeres of CCs were significantly longer than that of WBCs. Our findings suggest that CCs do not demonstrate changes in methylome-predicted age or telomere-length in association with increasing female age or ovarian response to stimulation.},
}
@article {pmid30530269,
year = {2019},
author = {Provenzi, L and Giorda, R and Fumagalli, M and Brambilla, M and Mosca, F and Borgatti, R and Montirosso, R},
title = {Telomere length and salivary cortisol stress reactivity in very preterm infants.},
journal = {Early human development},
volume = {129},
number = {},
pages = {1-4},
doi = {10.1016/j.earlhumdev.2018.12.002},
pmid = {30530269},
issn = {1872-6232},
mesh = {Female ; Humans ; Hydrocortisone/*metabolism ; Hypothalamo-Hypophyseal System/metabolism ; Infant, Extremely Premature/*metabolism/psychology ; Infant, Newborn ; Infant, Very Low Birth Weight/*metabolism/psychology ; Male ; Pituitary-Adrenal System/metabolism ; Saliva/metabolism ; Stress, Psychological/*genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {During the Neonatal Intensive Care Unit (NICU) stay, very preterm (VPT) infants are exposed to life-saving yet pain-inducing skin-breaking procedures (i.e., NICU pain-related stress) which contribute to the programming of hypo-responsive HPA axis development during the first months of life. Unfortunately, to date the mechanisms linking NICU pain-related stress and altered HPA axis regulation are only limitedly known. Telomere length (TL) regulation is an epigenetic mechanism previously shown to be affected by early stress exposures and capable of associating with HPA axis reactivity in children. In VPT infants, NICU pain-related stress was found to associate with decreased TL from birth to discharge, but there is no evidence for the association between TL and HPA axis in these infants. In this study, we prospectively examined the relationship between NICU pain-related stress and HPA axis reactivity to an age-appropriate socio-emotional condition (i.e., the Still-Face Procedure, SFP) in healthy VPT infants at 3-month corrected age. NICU pain-related stress was computed as the ratio between the number of skin-breaking procedures and length of NICU stay. A differential score (i.e., ∆TL) was obtained subtracting TL at birth from TL at discharge. A normalized (log10) cortisol reactivity index (CRI) was obtained by averaging post-stress (20 min after SFP) salivary cortisol sample on baseline value. A regression model controlling for neonatal and socio-demographic confounders showed that ∆TL was the only significant predictor of CRI. Although preliminary, these findings contribute to our knowledge of the mechanisms linking early exposures to adversity and later in life regulation of the HPA axis in VPT infants.},
}
@article {pmid30518572,
year = {2018},
author = {Criscuolo, F and Sorci, G and Behaim-Delarbre, M and Zahn, S and Faivre, B and Bertile, F},
title = {Age-related response to an acute innate immune challenge in mice: proteomics reveals a telomere maintenance-related cost.},
journal = {Proceedings. Biological sciences},
volume = {285},
number = {1892},
pages = {},
pmid = {30518572},
issn = {1471-2954},
mesh = {Age Factors ; Animals ; Immunity, Innate/drug effects/*immunology ; Lipopolysaccharides/pharmacology ; Mice ; Mice, Inbred C57BL ; Proteome/drug effects/*immunology ; Proteomics ; Telomere Homeostasis/*physiology ; },
abstract = {Ageing is characterized by the impairment of the acute innate immune response and the upregulation of low-grade inflammation, i.e. inflammaging. At the cellular level, telomeres are considered as a marker of biological ageing as their length is progressively eroded in the absence of repair mechanisms. However, the link between telomeres and inflammaging remains underexplored. We aimed to identify proteins that are differentially expressed between age classes in response to an acute inflammatory challenge. We challenged young (two months) and old (12 months) C57BL/6 mice using bacterial lipopolysaccharide (LPS) and measured telomere length and proteomic profiles in splenocytes. In total, 233 out of the 1966 proteins we quantified differed among experimental groups. A hierarchical clustering analysis revealed that nine of those 233 proteins were differently expressed among the experimental groups. Young mice responded to LPS by increasing the expression of proteins involved in the innate immune response, and interestingly, in telomere length maintenance. However, this regulation was impaired at older ages. These results are in agreement with the assumption that the strength of selection declines with age, potentially explaining the maintenance of costly, dysregulated, immune responses at old age. We suggest that the immune response is competing with the telomere maintenance process, highlighting how telomeres reflect the ageing trade-off even in a species where telomere length is not related to lifespan.},
}
@article {pmid30518458,
year = {2018},
author = {Vgontzas, AN and Fernandez-Mendoza, J and Bixler, EO},
title = {Short Telomere Length and Endophenotypes in Sleep Medicine.},
journal = {Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine},
volume = {14},
number = {12},
pages = {1975-1977},
pmid = {30518458},
issn = {1550-9397},
mesh = {Endophenotypes ; Humans ; Sleep ; *Sleep Initiation and Maintenance Disorders ; Telomere ; Time Factors ; },
}
@article {pmid30518442,
year = {2018},
author = {Tempaku, P and Hirotsu, C and Mazzotti, D and Xavier, G and Maurya, P and Brietzke, E and Belangero, S and Poyares, D and Bittencourt, L and Tufik, S},
title = {Long Sleep Duration, Insomnia, and Insomnia With Short Objective Sleep Duration Are Independently Associated With Short Telomere Length.},
journal = {Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine},
volume = {14},
number = {12},
pages = {2037-2045},
pmid = {30518442},
issn = {1550-9397},
mesh = {Adult ; Aged ; Correlation of Data ; Female ; Humans ; Male ; Middle Aged ; Polysomnography ; Sleep/*physiology ; Sleep Initiation and Maintenance Disorders/*physiopathology ; Surveys and Questionnaires ; Telomere Shortening/*physiology ; Time Factors ; },
abstract = {STUDY OBJECTIVES: We aimed to determine the association between short telomere length, sleep parameters, and sleep disorders in an adult general population sample.<br><br>METHODS: As part of the EPISONO cohort (S&#xe3;o Paulo, Brazil), 925 individuals answered questionnaires, underwent a full-night polysomnography and clinical assessment, and had peripheral blood collected for DNA extraction. Insomnia was diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition; and obstructive sleep apnea was defined according to apnea-hypopnea index. For the objective insomnia phenotype, we combined insomnia diagnosis with total sleep time from polysomnography with a cutoff of 360 minutes, allowing the classification of six groups. Self-reported sleep duration was used to classify the individuals as short (< 6 hours), average (6 to 8 hours) and long (> 8 hours) sleepers. The leukocyte telomere length was measured using quantitative real-time polymerase chain reaction. Based on its distribution, we considered leukocyte telomere length < 10th percentile as short telomere and leukocyte telomere length &#x2265; 10th percentile as non-short telomere.<br><br>RESULTS: After adjusting for sex, age, and body mass index, only insomnia disorder (odds ratio [OR] = 2.654, 95% confidence interval [CI] = 1.025-6.873, P = .044), insomnia disorder total sleep time < 360 minutes (OR = 4.205, 95% CI = 1.097-16.117, P = .036) and long sleepers (OR = 2.177, 95% CI = 1.189- 3.987, P = .012) were associated with short telomere.<br><br>CONCLUSIONS: Our findings support the existence of an association among insomnia, insomnia phenotype, and self-reported long sleep duration with the maintenance of telomere length.<br><br>COMMENTARY: A commentary on this article appears in this issue on page 1975.},
}
@article {pmid30518050,
year = {2018},
author = {Freitas-Simoes, TM and Cofán, M and Blasco, MA and Soberón, N and Foronda, M and Serra-Mir, M and Roth, I and Valls-Pedret, C and Doménech, M and Ponferrada-Ariza, E and Calvo, C and Rajaram, S and Sabaté, J and Ros, E and Sala-Vila, A},
title = {Walnut Consumption for Two Years and Leukocyte Telomere Attrition in Mediterranean Elders: Results of a Randomized Controlled Trial.},
journal = {Nutrients},
volume = {10},
number = {12},
pages = {},
pmid = {30518050},
issn = {2072-6643},
support = {CP12/03299//Instituto de Salud Carlos III/ ; PI15/01014//Instituto de Salud Carlos III/ ; N/A//California Walnut Commission/ ; },
mesh = {Aged ; Aging/physiology ; Biomarkers/blood ; California ; *Diet ; Female ; Humans ; *Juglans ; Leukocytes/*chemistry ; Male ; Middle Aged ; Spain ; Telomere/*genetics ; alpha-Linolenic Acid/blood ; },
abstract = {Randomized controlled trials on diet and shortening of leukocyte telomere length (LTL) mostly focus on marine-derived n-3 polyunsaturated fatty acids (PUFA). Walnuts are a sustainable source of n-3 PUFA. We investigated whether inclusion of walnuts (15% of energy) in the diet for 2 years would maintain LTL in cognitively healthy elders (63[-]79 years old) compared to a control group (habitual diet, abstaining from walnuts). This opportunistic sub-study was conducted within the Walnuts and Healthy Aging study, a dual-centre (Barcelona, Spain and Loma Linda University, California) parallel trial. A sub-set of the Barcelona site participants were randomly assigned to the walnut (n = 80) or control group (n = 69). We assessed LTL at baseline and at 2 years and we conducted repeated-measures ANCOVA with 2 factors: time (baseline, 2 years) and group (control, walnut) and their interaction. Adjusted means (95% confidence interval) of LTL (in kb) in controls were 7.360 (7.084,7.636) at baseline and 7.061 (6.835,7.288) after 2 years; corresponding values in the walnut group were 7.064 (6.807,7.320) and 7.074 (6.864,7.284). The time × intervention interaction was nearly significant (p = 0.079), suggestive of a trend of walnut consumption in preserving LTL. This exploratory research finding should be confirmed in trials with adequate statistical power.},
}
@article {pmid30507277,
year = {2019},
author = {Colon, M and Hodgson, A and Donlon, E and Murphy, JEJ},
title = {Effects of Competitive Triathlon Training on Telomere Length.},
journal = {Journal of aging and physical activity},
volume = {27},
number = {4},
pages = {510-514},
doi = {10.1123/japa.2018-0248},
pmid = {30507277},
issn = {1543-267X},
mesh = {Adult ; *Athletic Performance/physiology ; Case-Control Studies ; Exercise Test ; Humans ; Lactic Acid/blood ; Male ; Oxygen Consumption ; *Physical Endurance/physiology ; Polymerase Chain Reaction ; *Telomere Homeostasis/genetics/physiology ; },
abstract = {Telomeres act as a mitotic clock and telomere-related senescence has been linked to age-related physiological decline. There is increasing evidence lifestyle factors can influence telomere length (TL). The purpose of this study was to determine the effect of competitive triathlon training on TL. Seven competitive male triathletes and seven recreationally active males participated in the study. Relative TL was measured using quantitative polymerase chain reaction. Physiological parameters key to athletic performance such as maximal oxygen intake, lactate threshold, and running economy were also measured. Triathletes had longer telomeres than the recreationally active (1.257 ± 0.028 vs. 1.002 ± 0.014; p < .0001). Positive association was found between TL and maximal oxygen intake, lactate threshold, and running economy (R[2] = .677, .683, and .696, respectively). This study indicates that competitive triathlon training buffers against age-related telomere shortening, and there is a correlation between exercise behaviors, higher maximal oxygen intake, and TL.},
}
@article {pmid30503780,
year = {2019},
author = {Hu, C and Inoue, H and Sun, W and Takeshita, Y and Huang, Y and Xu, Y and Kanoh, J and Chen, Y},
title = {The Inner Nuclear Membrane Protein Bqt4 in Fission Yeast Contains a DNA-Binding Domain Essential for Telomere Association with the Nuclear Envelope.},
journal = {Structure (London, England : 1993)},
volume = {27},
number = {2},
pages = {335-343.e3},
doi = {10.1016/j.str.2018.10.010},
pmid = {30503780},
issn = {1878-4186},
mesh = {Binding Sites ; Cell Nucleus/metabolism ; Crystallography, X-Ray ; DNA-Binding Proteins/*chemistry/*metabolism ; Meiosis ; Membrane Proteins/*chemistry/*metabolism ; Mitosis ; Models, Molecular ; Nuclear Envelope/*metabolism ; Nuclear Proteins/*chemistry/*metabolism ; Protein Binding ; Protein Domains ; Schizosaccharomyces/*metabolism ; Schizosaccharomyces pombe Proteins/*chemistry/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres, the protective caps at the end of the chromosomes, are often associated with the nuclear envelope (NE). Telomere positioning to the NE is dynamically regulated during mitosis and meiosis. One inner nuclear membrane protein, Bqt4, in Schizosaccharomyces pombe plays essential roles in connecting telomeres to the NE. However, the structural basis of Bqt4 in mediating telomere-NE association is not clear. Here, we report the crystal structure of the N-terminal domain of Bqt4. The N-terminal domain of Bqt4 structurally resembles the APSES-family DNA-binding domain and has a moderate double-stranded DNA-binding activity. Disruption of Bqt4-DNA interaction results in telomere detachment from the NE. These data suggest that the DNA-binding activity of Bqt4 may function to prime the chromosome onto the NE and promote telomere-NE association.},
}
@article {pmid30502348,
year = {2019},
author = {Morgan, RG and Walker, AE and Trott, DW and Machin, DR and Henson, GD and Reihl, KD and Cawthon, RM and Denchi, EL and Liu, Y and Bloom, SI and Phuong, TT and Richardson, RS and Lesniewski, LA and Donato, AJ},
title = {Induced Trf2 deletion leads to aging vascular phenotype in mice associated with arterial telomere uncapping, senescence signaling, and oxidative stress.},
journal = {Journal of molecular and cellular cardiology},
volume = {127},
number = {},
pages = {74-82},
pmid = {30502348},
issn = {1095-8584},
support = {R44 AG053131/AG/NIA NIH HHS/United States ; I01 BX002151/BX/BLRD VA/United States ; K01 AG046326/AG/NIA NIH HHS/United States ; R01 AG050238/AG/NIA NIH HHS/United States ; R01 AG048366/AG/NIA NIH HHS/United States ; K02 AG045339/AG/NIA NIH HHS/United States ; R01 AG040297/AG/NIA NIH HHS/United States ; R21 AG033755/AG/NIA NIH HHS/United States ; K99 AT010017/AT/NCCIH NIH HHS/United States ; },
mesh = {Adipose Tissue/metabolism ; Aging/*metabolism ; Animals ; Arteries/*metabolism ; Blood Pressure ; Body Weight ; *Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; *Gene Deletion ; Glycocalyx/metabolism ; Mice ; Microvessels/metabolism ; *Oxidative Stress ; Perfusion ; Phenotype ; *Signal Transduction ; Telomere/*metabolism ; Telomere Homeostasis ; Telomeric Repeat Binding Protein 2/*deficiency/metabolism ; Vasodilation ; },
abstract = {Age-related vascular dysfunction in large elastic and resistance arteries is associated with reductions in microvascular perfusion and elevations in blood pressure. Recent evidence indicates that telomere uncapping-induced senescence in vascular cells may be an important source of oxidative stress and vascular dysfunction in aging, but the causal relationship between these processes has yet to be elucidated. To test this important unexplored hypothesis, we measured arterial senescence signaling and oxidative stress, carotid and mesenteric artery endothelium-dependent vasodilatory capacity, markers of mesenteric microvascular perfusion and endothelial glycocalyx deterioration, and blood pressure in a novel mouse model of Cre-inducible whole body Trf2 deletion and telomere uncapping. Trf2 deletion led to a 320% increase in arterial senescence signaling (P < .05). There was a concurrent 29% and 22% reduction in peak endothelium-dependent vasodilation in carotid and mesenteric arteries, respectively, as well as a 63% reduction in mesenteric microvascular endothelial glycocalyx thickness (all P ≤ .01). Mesenteric microvascular perfusion was reduced by 8% and systolic blood pressure was increased by 9% following Trf2 deletion (both P < .05). Trf2 deletion also led to a pro-oxidative arterial phenotype characterized by increased in NADPH oxidase gene expression; a 210% increase in superoxide levels that was partly dependent on NADPH oxidase activity; and an oxidative stress mediated reduction in carotid artery vasodilation (all P ≤ .05). Collectively, our findings demonstrate that induced Trf2 deletion leads to telomere uncapping, increased senescence signaling, and oxidative stress mediated functional impairments in the vasculature similar to those seen in human aging.},
}
@article {pmid30498568,
year = {2018},
author = {Audry, J and Wang, J and Eisenstatt, JR and Berkner, KL and Runge, KW},
title = {The inhibition of checkpoint activation by telomeres does not involve exclusion of dimethylation of histone H4 lysine 20 (H4K20me2).},
journal = {F1000Research},
volume = {7},
number = {},
pages = {1027},
pmid = {30498568},
issn = {2046-1402},
support = {UL1 RR024989/RR/NCRR NIH HHS/United States ; R01 AG051601/AG/NIA NIH HHS/United States ; R01 GM050752/GM/NIGMS NIH HHS/United States ; R01 HL081093/HL/NHLBI NIH HHS/United States ; R01 HL055666/HL/NHLBI NIH HHS/United States ; },
mesh = {*Cell Cycle Checkpoints ; DNA Damage ; *Histones/genetics/metabolism ; Methylation ; *Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; *Schizosaccharomyces/genetics/metabolism ; *Schizosaccharomyces pombe Proteins/genetics/metabolism ; *Telomere/genetics/metabolism ; },
abstract = {DNA double-strand breaks (DSBs) activate the DNA damage checkpoint machinery to pause or halt the cell cycle. Telomeres, the specific DNA-protein complexes at linear eukaryotic chromosome ends, are capped DSBs that do not activate DNA damage checkpoints. This "checkpoint privileged" status of telomeres was previously investigated in the yeast Schizosaccharomyces pombelacking the major double-stranded telomere DNA binding protein Taz1. Telomeric DNA repeats in cells lacking Taz1 are 10 times longer than normal and contain single-stranded DNA regions. DNA damage checkpoint proteins associate with these damaged telomeres, but the DNA damage checkpoint is not activated. This severing of the DNA damage checkpoint signaling pathway was reported to stem from exclusion of histone H4 lysine 20 dimethylation (H4K20me2) from telomeric nucleosomes in both wild type cells and cells lacking Taz1. However, experiments to identify the mechanism of this exclusion failed, prompting our re-evaluation of H4K20me2 levels at telomeric chromatin. In this short report, we used an extensive series of controls to identify an antibody specific for the H4K20me2 modification and show that the level of this modification is the same at telomeres and internal loci in both wild type cells and those lacking Taz1. Consequently, telomeres must block activation of the DNA Damage Response by another mechanism that remains to be determined.},
}
@article {pmid30517874,
year = {2018},
author = {Sobecki, M and Souaid, C and Boulay, J and Guerineau, V and Noordermeer, D and Crabbe, L},
title = {MadID, a Versatile Approach to Map Protein-DNA Interactions, Highlights Telomere-Nuclear Envelope Contact Sites in Human Cells.},
journal = {Cell reports},
volume = {25},
number = {10},
pages = {2891-2903.e5},
pmid = {30517874},
issn = {2211-1247},
support = {714653/ERC_/European Research Council/International ; },
mesh = {Adenosine/analogs &amp; derivatives/metabolism ; Cell Cycle ; Cell Line ; DNA/*metabolism ; DNA Methylation ; DNA Modification Methylases/metabolism ; DNA-Binding Proteins/*metabolism ; High-Throughput Nucleotide Sequencing ; Humans ; Lamins/metabolism ; Nuclear Envelope/*metabolism ; Protein Binding ; Telomere/*metabolism ; },
abstract = {Mapping the binding sites of DNA- or chromatin-interacting proteins is essential to understanding biological processes. DNA adenine methyltransferase identification (DamID) has emerged as a comprehensive method to map genome-wide occupancy of proteins of interest. A caveat of DamID is the specificity of Dam methyltransferase for GATC motifs that are not homogenously distributed in the genome. Here, we developed an optimized method named MadID, using proximity labeling of DNA by the methyltransferase M.EcoGII. M.EcoGII mediates N6-adenosine methylation in any DNA sequence context, resulting in deeper and unbiased coverage of the genome. We demonstrate, using m6A-specific immunoprecipitation and deep sequencing, that MadID is a robust method to identify protein-DNA interactions at the whole-genome level. Using MadID, we revealed contact sites between human telomeres, repetitive sequences devoid of GATC sites, and the nuclear envelope. Overall, MadID opens the way to identification of binding sites in genomic regions that were largely inaccessible.},
}
@article {pmid30517099,
year = {2018},
author = {Ravindranathan, A and Cimini, B and Diolaiti, ME and Stohr, BA},
title = {Preliminary development of an assay for detection of TERT expression, telomere length, and telomere elongation in single cells.},
journal = {PloS one},
volume = {13},
number = {12},
pages = {e0206525},
pmid = {30517099},
issn = {1932-6203},
mesh = {*Gene Expression Regulation, Enzymologic ; HeLa Cells ; Humans ; Telomerase/*biosynthesis/genetics ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; },
abstract = {The telomerase enzyme enables unlimited proliferation of most human cancer cells by elongating telomeres and preventing replicative senescence. Despite the critical importance of telomerase in cancer biology, challenges detecting telomerase activity and expression in individual cells have hindered the ability to study patterns of telomerase expression and function across heterogeneous cell populations. While sensitive assays to ascertain telomerase expression and function exist, these approaches have proven difficult to implement at the single cell level. Here, we validate in situ RNAscope detection of the telomerase TERT mRNA and couple this assay with our recently described TSQ1 method for in situ detection of telomere elongation. This approach enables detection of TERT expression, telomere length, and telomere elongation within individual cells of the population. Using this assay, we show that the heterogeneous telomere elongation observed across a HeLa cell population is in part driven by variable expression of the TERT gene. Furthermore, we show that the absence of detectable telomere elongation in some TERT-positive cells is the result of inhibition by the telomeric shelterin complex. This combined assay provides a new approach for understanding the integrated expression, function, and regulation of telomerase at the single cell level.},
}
@article {pmid30511786,
year = {2019},
author = {Powell, TR and De Jong, S and Breen, G and Lewis, CM and Dima, D},
title = {Telomere length as a predictor of emotional processing in the brain.},
journal = {Human brain mapping},
volume = {40},
number = {6},
pages = {1750-1759},
pmid = {30511786},
issn = {1097-0193},
support = {Marie Sklodowska-Curie grant agreement 658195//European Union's Horizon 2020 Research and Innovation Programme/International ; /DH_/Department of Health/United Kingdom ; //King's College London/International ; MR/N014863/1/MRC_/Medical Research Council/United Kingdom ; 22471//NARSAD 2014 Young Investigator Award/International ; YI 60373//NARSAD Young Investigator Grant/International ; 658195//European Union's Horizon 2020 Research and Innovation Programme/International ; MRN014863/1//Medical Research Council (MRC)/International ; 92//Psychiatry Research Trust Grant/International ; 60373//NARSAD Young Investigator Grant/International ; //National Institute for Health Research/International ; MRN014863/1/MRC_/Medical Research Council/United Kingdom ; //South London and Maudsley NHS Foundation Trust/International ; },
mesh = {Adult ; Bipolar Disorder/diagnostic imaging/genetics/*physiopathology ; Brain/diagnostic imaging/*physiopathology ; Brain Mapping ; Emotions/*physiology ; Facial Expression ; Female ; Genetic Predisposition to Disease ; Humans ; Image Processing, Computer-Assisted ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Reaction Time/physiology ; Recognition, Psychology/*physiology ; *Telomere ; },
abstract = {Shorter telomere length (TL) has been associated with the development of mood disorders as well as abnormalities in brain morphology. However, so far, no studies have considered the role TL may have on brain function during tasks relevant to mood disorders. In this study, we examine the relationship between TL and functional brain activation and connectivity, while participants (n = 112) perform a functional magnetic resonance imaging (fMRI) facial affect recognition task. Additionally, because variation in TL has a substantial genetic component we calculated polygenic risk scores for TL to test if they predict face-related functional brain activation. First, our results showed that TL was positively associated with increased activation in the amygdala and cuneus, as well as increased connectivity from posterior regions of the face network to the ventral prefrontal cortex. Second, polygenic risk scores for TL show a positive association with medial prefrontal cortex activation. The data support the view that TL and genetic loading for shorter telomeres, influence the function of brain regions known to be involved in emotional processing.},
}
@article {pmid30509719,
year = {2018},
author = {Desai, K and Berkman, N and Cohen-Manheim, I and Sinnreich, R and Aviv, A and Kark, JD},
title = {Rapid shortening of leukocyte telomeres is associated with poorer pulmonary function among healthy adults.},
journal = {Respiratory medicine},
volume = {145},
number = {},
pages = {73-79},
doi = {10.1016/j.rmed.2018.10.026},
pmid = {30509719},
issn = {1532-3064},
mesh = {Adult ; Age Factors ; Female ; Forced Expiratory Volume ; *Healthy Volunteers ; Humans ; *Leukocytes ; Linear Models ; Longitudinal Studies ; Lung/*physiology/*physiopathology ; Male ; Middle Aged ; *Respiratory Function Tests ; Telomere/*genetics ; *Telomere Homeostasis ; *Telomere Shortening ; Time Factors ; Vital Capacity ; },
abstract = {AIM: The study aimed to examine the association between leukocyte telomere length (LTL) attrition over 13 years (between mean age 30 and mean age 43) and lung function at mean age 50.<br><br>MATERIALS &amp; METHODS: In a longitudinal observational study LTL was determined twice on a population-based sample of 481 Jewish residents of Jerusalem at mean ages 30 and 43 years. Pulmonary function was determined at mean age 50 years. Multiple linear regression and multivariable ordinal logistic modeling were applied. Akaike's Information Criteria (AIC) was used for model selection.&#x2028; RESULTS: In unadjusted analysis, Forced Expiratory Volume in 1&#x202f;s (FEV1%) was inversely associated with the LTL attrition rate (standardized beta&#x202f;=&#x202f;-0.110, P&#x202f;=&#x202f;0.023) but not with the baseline LTL. Forced Vital Capacity (FVC%) was inversely associated with the LTL attrition rate (standardized beta&#x202f;=&#x202f;-0.108, P&#x202f;=&#x202f;0.026). Multivariable adjustment mildly attenuated the association with the LTL attrition rate (standardized beta&#x202f;=&#x202f;-0.100, P&#x202f;=&#x202f;0.034 for FEV1% and -0.093, P&#x202f;=&#x202f;0.042 for FVC%). This would be consistent with a 3.3% [95% Confidence Interval (CI): 3.1-3.4%] decline in FEV1% and a 3.0% (95% CI:2.8-3.1%) decline in FVC% per year. In linear regression models the LTL-pulmonary function association did not differ by sex, social mobility, pack-years smoking exposure, or level of GlycA, a novel systemic inflammatory marker.<br><br>CONCLUSIONS: Greater LTL attrition between mean age 30 and mean age 43 was associated with poorer lung function at mean age 50 years. The availability of longitudinal data on LTL attrition for the first time in the current study strengthens the case for LTL change preceding change in lung function.},
}
@article {pmid30496493,
year = {2019},
author = {Werner, CM and Hecksteden, A and Morsch, A and Zundler, J and Wegmann, M and Kratzsch, J and Thiery, J and Hohl, M and Bittenbring, JT and Neumann, F and Böhm, M and Meyer, T and Laufs, U},
title = {Differential effects of endurance, interval, and resistance training on telomerase activity and telomere length in a randomized, controlled study.},
journal = {European heart journal},
volume = {40},
number = {1},
pages = {34-46},
pmid = {30496493},
issn = {1522-9645},
mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Physical Endurance/*physiology ; Prospective Studies ; *Resistance Training ; Telomerase/*physiology ; Telomere/ultrastructure ; *Telomere Homeostasis ; },
abstract = {AIMS: It is unknown whether different training modalities exert differential cellular effects. Telomeres and telomere-associated proteins play a major role in cellular aging with implications for global health. This prospective training study examines the effects of endurance training, interval training (IT), and resistance training (RT) on telomerase activity and telomere length (TL).<br><br>METHODS AND RESULTS: One hundred and twenty-four healthy previously inactive individuals completed the 6&#x2009;months study. Participants were randomized to three different interventions or the control condition (no change in lifestyle): aerobic endurance training (AET, continuous running), high-intensive IT (4&#x2009;&#xd7;&#x2009;4 method), or RT (circle training on 8 devices), each intervention consisting of three 45 min training sessions per week. Maximum oxygen uptake (VO2max) was increased by all three training modalities. Telomerase activity in blood mononuclear cells was up-regulated by two- to three-fold in both endurance exercise groups (AET, IT), but not with RT. In parallel, lymphocyte, granulocyte, and leucocyte TL increased in the endurance-trained groups but not in the RT group. Magnet-activated cell sorting with telomerase repeat-ampliflication protocol (MACS-TRAP) assays revealed that a single bout of endurance training-but not RT-acutely increased telomerase activity in CD14+ and in CD34+ leucocytes.<br><br>CONCLUSION: This randomized controlled trial shows that endurance training, IT, and RT protocols induce specific cellular pathways in circulating leucocytes. Endurance training and IT, but not RT, increased telomerase activity and TL which are important for cellular senescence, regenerative capacity, and thus, healthy aging.},
}
@article {pmid30488553,
year = {2019},
author = {Tedone, E and Huang, E and O'Hara, R and Batten, K and Ludlow, AT and Lai, TP and Arosio, B and Mari, D and Wright, WE and Shay, JW},
title = {Telomere length and telomerase activity in T cells are biomarkers of high-performing centenarians.},
journal = {Aging cell},
volume = {18},
number = {1},
pages = {e12859},
pmid = {30488553},
issn = {1474-9726},
support = {AG01228/NH/NIH HHS/United States ; CA142543//Harold Simmons National Cancer Institute Designated Comprehensive Cancer Center/International ; C06 RR30414/GF/NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/genetics ; Biomarkers/metabolism ; Cell Proliferation ; DNA Replication ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Genome, Human ; Humans ; Lymphocyte Activation/genetics/immunology ; Male ; Middle Aged ; T-Lymphocytes/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; Young Adult ; },
abstract = {It is generally recognized that the function of the immune system declines with increased age and one of the major immune changes is impaired T-cell responses upon antigen presentation/stimulation. Some "high-performing" centenarians (100+ years old) are remarkably successful in escaping, or largely postponing, major age-related diseases. However, the majority of centenarians ("low-performing") have experienced these pathologies and are forced to reside in long-term nursing facilities. Previous studies have pooled all centenarians examining heterogeneous populations of resting/unstimulated peripheral blood mononuclear cells (PBMCs). T cells represent around 60% of PBMC and are in a quiescence state when unstimulated. However, upon stimulation, T cells rapidly divide and exhibit dramatic changes in gene expression. We have compared stimulated T-cell responses and identified a set of transcripts expressed in vitro that are dramatically different in high- vs. low-performing centenarians. We have also identified several other measurements that are different between high- and low-performing centenarians: (a) The amount of proliferation following in vitro stimulation is dramatically greater in high-performing centenarians compared to 67- to 83-year-old controls and low-performing centenarians; (b) telomere length is greater in the high-performing centenarians; and (c) telomerase activity following stimulation is greater in the high-performing centenarians. In addition, we have validated a number of genes whose expression is directly related to telomere length and these are potential fundamental biomarkers of aging that may influence the risk and progression of multiple aging conditions.},
}
@article {pmid30488497,
year = {2019},
author = {Mosquera, A and Rego-Pérez, I and Blanco, FJ and Fernández, JL},
title = {Leukocyte Telomere Length in Patients with Radiographic Knee Osteoarthritis.},
journal = {Environmental and molecular mutagenesis},
volume = {60},
number = {3},
pages = {298-301},
doi = {10.1002/em.22247},
pmid = {30488497},
issn = {1098-2280},
mesh = {Aged ; Aging/physiology ; Body Mass Index ; Chondrocytes/pathology ; Female ; Humans ; Hypertension/pathology ; Leukocytes/*cytology ; Male ; Middle Aged ; Osteoarthritis, Knee/diagnostic imaging/*pathology ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; Telomere Shortening/*physiology ; },
abstract = {Relative mean telomere sequence amount was determined by quantitative PCR (qPCR) of peripheral blood leukocyte (PBL) samples obtained at recruitment (n = 310) from individuals from the Osteoarthritis (OA) Initiative consortium. Knees were radiologically evaluated according to the Kellgren-Lawrence (KL) score, ranging from 0 to 4, considering a KL grade ≥ 2 as radiographic evidence of OA (n = 124). Telomere size decreased as baseline KL score increased, being significantly shorter in subjects with KL ≥2 (Mann-Whitney U-test, P < 0.0001). PBL telomere size was also associated with age, hypertension, body mass index (BMI) and waist circumference. Nevertheless, logistic regression analysis showed that PBL telomere size was a consistent risk factor for concurrent knee OA, independent of these health parameters. Shorter PBL telomeres may indicate a premature aging status which enhances chondrocyte senescence and degenerative joint disease. Environ. Mol. Mutagen. 60:298-301, 2019. © 2018 Wiley Periodicals, Inc.},
}
@article {pmid30483879,
year = {2019},
author = {Pernickova, K and Linc, G and Gaal, E and Kopecky, D and Samajova, O and Lukaszewski, AJ},
title = {Out-of-position telomeres in meiotic leptotene appear responsible for chiasmate pairing in an inversion heterozygote in wheat (Triticum aestivum L.).},
journal = {Chromosoma},
volume = {128},
number = {1},
pages = {31-39},
pmid = {30483879},
issn = {1432-0886},
mesh = {Cell Nucleus/genetics/ultrastructure ; Centromere/chemistry/ultrastructure ; Chimera/genetics ; *Chromosome Inversion ; Chromosome Pairing ; Chromosomes, Plant/chemistry/*ultrastructure ; Heterozygote ; Image Processing, Computer-Assisted/statistics &amp; numerical data ; Imaging, Three-Dimensional/methods ; In Situ Hybridization, Fluorescence ; *Meiotic Prophase I ; Microscopy, Confocal ; Plant Cells/metabolism/ultrastructure ; Secale/*genetics/ultrastructure ; Species Specificity ; Telomere/chemistry/*ultrastructure ; Triticum/*genetics/ultrastructure ; },
abstract = {Chromosome pairing in meiosis usually starts in the vicinity of the telomere attachment to the nuclear membrane and congregation of telomeres in the leptotene bouquet is believed responsible for bringing homologue pairs together. In a heterozygote for an inversion of a rye (Secale cereale L.) chromosome arm in wheat, a distal segment of the normal homologue is capable of chiasmate pairing with its counterpart in the inverted arm, located near the centromere. Using 3D imaging confocal microscopy, we observed that some telomeres failed to be incorporated into the bouquet and occupied various positions throughout the entire volume of the nucleus, including the centromere pole. Rye telomeres appeared ca. 21 times more likely to fail to be included in the telomere bouquet than wheat telomeres. The frequency of the out-of-bouquet rye telomere position in leptotene was virtually identical to the frequency of telomeres deviating from Rabl's orientation in the nuclei of somatic cells, and was similar to the frequency of synapsis of the normal and inverted chromosome arms, but lower than the MI pairing frequency of segments of these two arms normally positioned across the volume of the nucleus. Out-of-position placement of the rye telomeres may be responsible for reduced MI pairing of rye chromosomes in hybrids with wheat and their disproportionate contribution to aneuploidy, but appears responsible for initiating chiasmate pairing of distantly positioned segments of homology in an inversion heterozygote.},
}
@article {pmid30482235,
year = {2018},
author = {von Morgen, P and Maciejowski, J},
title = {The ins and outs of telomere crisis in cancer.},
journal = {Genome medicine},
volume = {10},
number = {1},
pages = {89},
pmid = {30482235},
issn = {1756-994X},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; R00 CA212290/CA/NCI NIH HHS/United States ; R00CA212290/CP/NCI NIH HHS/United States ; },
mesh = {DNA Damage ; Genome ; Humans ; Neoplasms/*genetics ; *Telomere ; },
abstract = {Telomere crisis is linked with many of the genomic alterations found in cancer genomes. A new understanding of how these alterations arise points towards an active role for innate immune sensors during crisis and to new opportunities for the treatment and diagnosis of cancer.},
}
@article {pmid30481549,
year = {2019},
author = {Sousa, CV and Aguiar, SS and Santos, PA and Barbosa, LP and Knechtle, B and Nikolaidis, PT and Deus, LA and Sales, MM and Rosa, ECCC and Rosa, TS and Lewis, JE and Andrade, RV and Simões, HG},
title = {Telomere length and redox balance in master endurance runners: The role of nitric oxide.},
journal = {Experimental gerontology},
volume = {117},
number = {},
pages = {113-118},
doi = {10.1016/j.exger.2018.11.018},
pmid = {30481549},
issn = {1873-6815},
mesh = {Adult ; Aged ; Aging/genetics/*physiology ; Athletes ; Body Composition/physiology ; Case-Control Studies ; Humans ; Leukocytes/metabolism ; Lipid Peroxidation/physiology ; Male ; Middle Aged ; Nitric Oxide/*physiology ; Oxidation-Reduction ; Oxidative Stress/physiology ; Physical Endurance/physiology ; Running/*physiology ; Telomere Homeostasis/*physiology ; },
abstract = {Leukocyte telomere length (LTL), a biological marker of aging that is associated with age-related diseases, is longer in master endurance runners (ER) than age-matched controls, but the underlying mechanisms are poorly investigated. The LTL, nitric oxide (NO), and redox balance of ER master runners were analyzed and compared to untrained middle-aged and young adults. We hypothesized that NO and redox balance at baseline would be related to longer LTL in ER athletes. Participants (n = 38) were long-term ER runners (n = 10; 51.6 ± 5.2 yrs.; 28.4 ± 9.4 yrs. of experience) and untrained age-matched (n = 17; 46.6 ± 7.1 yrs) and young controls (n = 11; 21.8 ± 4.0 yrs). Volunteers were assessed for anamnesis, anthropometrics, and blood sampling. Measurements of pro-and anti-oxidant status and DNA extraction were performed using commercial kits. Relative LTL was determined with qPCR analyses (T/S). While the middle-aged controls had shorter LTL than the young group, no difference was observed between ER athletes and young participants. A large effect size between the LTL of ER athletes and middle-aged controls (d = 0.85) was also observed. The ER athletes and untrained young group had better redox balance according to antioxidant/pro-oxidant ratios compared to middle-aged untrained participants, which also had lower values for redox parameters (TEAC/TBARS, SOD/TBARS, and CAT/TBARS; all p < 0.05). Furthermore, the NO level of ER athletes (175.2 ± 31.9 μM) was higher (p < 0.05) than middle-aged controls (67.2 ± 23.3 μM) and young participants (129.2 ± 17.3 μM), with a significant correlation with LTL (r = 0.766; p = 0.02). In conclusion, ER runners have longer LTL than age-matched controls, which in turn may be related to better NO bioavailability and redox balance status.},
}
@article {pmid30480434,
year = {2018},
author = {Abraham Punnoose, J and Ma, Y and Hoque, ME and Cui, Y and Sasaki, S and Guo, AH and Nagasawa, K and Mao, H},
title = {Random Formation of G-Quadruplexes in the Full-Length Human Telomere Overhangs Leads to a Kinetic Folding Pattern with Targetable Vacant G-Tracts.},
journal = {Biochemistry},
volume = {57},
number = {51},
pages = {6946-6955},
pmid = {30480434},
issn = {1520-4995},
support = {R01 CA236350/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; DNA, Cruciform/chemistry/genetics/metabolism ; *G-Quadruplexes ; Humans ; Kinetics ; Models, Molecular ; Nucleic Acid Conformation ; Single Molecule Imaging ; Telomere/*chemistry/genetics/*metabolism ; Thermodynamics ; },
abstract = {G-Quadruplexes formed in the 3' telomere overhang (∼200 nucleotides) have been shown to regulate biological functions of human telomeres. The mechanism governing the population pattern of multiple telomeric G-quadruplexes is yet to be elucidated inside the telomeric overhang in a time window shorter than thermodynamic equilibrium. Using a single-molecule force ramping assay, we quantified G-quadruplex populations in telomere overhangs over a full physiological range of 99-291 nucleotides. We found that G-quadruplexes randomly form in these overhangs within seconds, which leads to a population governed by a kinetic, rather than a thermodynamic, folding pattern. The kinetic folding gives rise to vacant G-tracts between G-quadruplexes. By targeting these vacant G-tracts using complementary DNA fragments, we demonstrated that binding to the telomeric G-quadruplexes becomes more efficient and specific for telomestatin derivatives.},
}
@article {pmid30475314,
year = {2019},
author = {Wang, W and Zhang, H and Duan, X and Feng, X and Wang, T and Wang, P and Ding, M and Liu, S and Li, L and Liu, J and Tang, L and Niu, X and Zhang, Y and Li, G and Yao, W and Yang, Y},
title = {Telomere Length in Workers Was Effected by Omethoate Exposure, GSTM1 Deletion, Interaction Between Smoking and GSTP1 Polymorphisms.},
journal = {Journal of occupational and environmental medicine},
volume = {61},
number = {1},
pages = {e19-e23},
doi = {10.1097/JOM.0000000000001503},
pmid = {30475314},
issn = {1536-5948},
mesh = {Adult ; Case-Control Studies ; Dimethoate/adverse effects/*analogs &amp; derivatives ; Female ; Gene Deletion ; Gene-Environment Interaction ; Glutathione S-Transferase pi/*genetics ; Glutathione Transferase/*genetics ; Humans ; Male ; Occupational Exposure/*adverse effects/statistics &amp; numerical data ; Polymorphism, Single Nucleotide/genetics ; Smoking/*adverse effects ; Telomere/*drug effects/genetics ; },
abstract = {OBJECTIVE: The aim of this study was to explore the association between telomere length and metabolizing enzyme gene polymorphisms and environmental factors in omethoate-exposed workers.<br><br>METHODS: The gene-environment interactions were analyzed with generalized linear model method.<br><br>RESULTS: The relative telomere lengths in the individuals with GSTM1-deletion were longer than that in non-deletion genotype in the control group (P&#x200a;=&#x200a;0.011); the relative telomere lengths with GG+AG genotypes in GSTP1 rs1695 were longer than that of AA genotype in the exposure group (P&#x200a;=&#x200a;0.039). The interaction between the GG+AG genotypes in GSTP1 rs1695 and smoking exposure had significant effect on telomere length (P&#x200a;<&#x200a;0.05).<br><br>CONCLUSIONS: The prolongation of relative telomere length in omethoate-exposed workers was associated with GSTM1-deletion, GG+AG genotypes, and interactions of GG+AG genotypes and smoking factor.},
}
@article {pmid30474838,
year = {2019},
author = {Vasilishina, A and Kropotov, A and Spivak, I and Bernadotte, A},
title = {Relative Human Telomere Length Quantification by Real-Time PCR.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1896},
number = {},
pages = {39-44},
doi = {10.1007/978-1-4939-8931-7_5},
pmid = {30474838},
issn = {1940-6029},
mesh = {DNA Primers ; Humans ; Interferon-beta/*genetics ; Real-Time Polymerase Chain Reaction/*methods ; *Telomere ; *Telomere Homeostasis ; },
abstract = {Telomere measurement by quantitative PCR amplification is a well-known simple method to detect telomere length that involves large numbers of samples. The method has been developed by Cawthon in 2002 (Cawthon, Nucleic Acids Res 30:47e-47, 2002) and remains the most frequently used technique either in original or modified version. Telomere length is estimated by comparing the amount of telomere repeat amplification product (T) to a single copy gene (S) product. The T/S ratio correlates with the average telomere length. Cawthon suggested and recommended the use of 36B4 (RPLP0) as a single copy gene. However, Cawthon's suggestion was no longer considered a single copy gene and the gene was not suitable and appropriate for normalization.We thereby introduced a simple method for relative measurement of average human telomere length using quantitative real-time PCR. Our protocol was based on Cawthon's initial technique (Cawthon, Nucleic Acids Res 30:47e-47, 2002), modified by single-copy gene (SCG) primers and optimized.This technique is rapid, low cost, not demanding on DNA amount (or live cells), and can be used for a high-throughput screening and time monitoring.},
}
@article {pmid30474505,
year = {2019},
author = {Farladansky-Gershnabel, S and Gal, H and Kidron, D and Krizhanovsky, V and Amiel, A and Sukenik-Halevy, R and Biron-Shental, T},
title = {Telomere Homeostasis and Senescence Markers Are Differently Expressed in Placentas From Pregnancies With Early- Versus Late-Onset Preeclampsia.},
journal = {Reproductive sciences (Thousand Oaks, Calif.)},
volume = {26},
number = {9},
pages = {1203-1209},
doi = {10.1177/1933719118811644},
pmid = {30474505},
issn = {1933-7205},
mesh = {Adult ; Biomarkers/metabolism ; Cellular Senescence/*physiology ; Female ; Gestational Age ; Humans ; Placenta/*metabolism ; Pre-Eclampsia/*metabolism ; Pregnancy ; Telomere Homeostasis/*physiology ; Time Factors ; Trophoblasts/metabolism ; Young Adult ; },
abstract = {BACKGROUND: Early-onset preeclampsia (EOPE; <34 weeks' gestation) usually has more severe morbidity for the mother and fetus compared to late-onset preeclampsia (LOPE). Telomere homeostasis is disrupted in preeclampsia (PE) and senescence markers are increased. The pathophysiologic differences between early and LOPE are not fully unraveled yet.<br><br>METHODS: We studied placental biopsies from 7 pregnancies with EOPE, 6 pregnancies with LOPE, and 13 healthy gestational age-matched controls. Telomere length and aggregate formation were assessed using qualitative fluorescence in situ hybridization and electronic quantitative methods. Senescence markers were evaluated including senescence-associated heterochromatin foci, &#x3b2;-galactosidase (SA&#x3b2;-Gal), and P16 staining, as was the expression of P16 complementary DNA (cDNA) using real-time quantitative polymerase chain reaction (RT-qPCR).<br><br>RESULTS: There were no differences in maternal age, gravidity, parity, body mass index, and mode of conception between the study and the control groups. The percentage of trophoblasts with short telomeres was higher in placental samples from EOPE (52.61% [12.27%]) versus LOPE (28.72% [10.14%]); both were higher compared to controls (7.53% [5.14%], P = .03). Aggregate formation was enhanced in EOPE (8.72% [2.49%]) compared to LOPE (4.54% [1.45%]); both were higher than in healthy controls (2.72% [1.08%], P = .03). Trophoblasts from EOPE versus LOPE were more likely to stain positive for SA&#x3b2;-Gal and P16 compared to controls (P < .001). P16 cDNA expression assayed by RT-qPCR was 7.51 times higher in EOPE compared to controls and 5.86 times higher than in LOPE.<br><br>CONCLUSIONS: Impaired telomere homeostasis and senescence markers are more prominent in EOPE versus LOPE. These findings may contribute to our understanding of the pathophysiology and explain their different clinical presentations and outcomes.},
}
@article {pmid30474255,
year = {2019},
author = {Bikkul, MU and Faragher, RGA and Worthington, G and Meinke, P and Kerr, ARW and Sammy, A and Riyahi, K and Horton, D and Schirmer, EC and Hubank, M and Kill, IR and Anderson, RM and Slijepcevic, P and Makarov, E and Bridger, JM},
title = {Telomere elongation through hTERT immortalization leads to chromosome repositioning in control cells and genomic instability in Hutchinson-Gilford progeria syndrome fibroblasts, expressing a novel SUN1 isoform.},
journal = {Genes, chromosomes &amp; cancer},
volume = {58},
number = {6},
pages = {341-356},
pmid = {30474255},
issn = {1098-2264},
support = {MR/R018073/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {*Abnormal Karyotype ; Cell Line ; Cells, Cultured ; Fibroblasts/cytology/metabolism ; *Genomic Instability ; Humans ; Membrane Proteins/*genetics/metabolism ; Microtubule-Associated Proteins/*genetics/metabolism ; Nuclear Proteins/*genetics/metabolism ; Progeria/*genetics ; Protein Isoforms/genetics/metabolism ; Telomerase/*genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {Immortalizing primary cells with human telomerase reverse transcriptase (hTERT) has been common practice to enable primary cells to be of extended use in the laboratory because they avoid replicative senescence. Studying exogenously expressed hTERT in cells also affords scientists models of early carcinogenesis and telomere behavior. Control and the premature ageing disease-Hutchinson-Gilford progeria syndrome (HGPS) primary dermal fibroblasts, with and without the classical G608G mutation have been immortalized with exogenous hTERT. However, hTERT immortalization surprisingly elicits genome reorganization not only in disease cells but also in the normal control cells, such that whole chromosome territories normally located at the nuclear periphery in proliferating fibroblasts become mislocalized in the nuclear interior. This includes chromosome 18 in the control fibroblasts and both chromosomes 18 and X in HGPS cells, which physically express an isoform of the LINC complex protein SUN1 that has previously only been theoretical. Additionally, this HGPS cell line has also become genomically unstable and has a tetraploid karyotype, which could be due to the novel SUN1 isoform. Long-term treatment with the hTERT inhibitor BIBR1532 enabled the reduction of telomere length in the immortalized cells and resulted that these mislocalized internal chromosomes to be located at the nuclear periphery, as assessed in actively proliferating cells. Taken together, these findings reveal that elongated telomeres lead to dramatic chromosome mislocalization, which can be restored with a drug treatment that results in telomere reshortening and that a novel SUN1 isoform combined with elongated telomeres leads to genomic instability. Thus, care should be taken when interpreting data from genomic studies in hTERT-immortalized cell lines.},
}
@article {pmid30472697,
year = {2018},
author = {Ain, Q and Schmeer, C and Penndorf, D and Fischer, M and Bondeva, T and Förster, M and Haenold, R and Witte, OW and Kretz, A},
title = {Cell cycle-dependent and -independent telomere shortening accompanies murine brain aging.},
journal = {Aging},
volume = {10},
number = {11},
pages = {3397-3420},
pmid = {30472697},
issn = {1945-4589},
mesh = {Aging/*physiology ; Animals ; Cell Cycle/*physiology ; Cerebral Cortex/*cytology/physiology ; Mice ; Neurons/physiology ; Telomerase/metabolism ; Telomere Shortening/*physiology ; Transcription Factor RelA/metabolism ; },
abstract = {Replication-based telomere shortening during lifetime is species- and tissue-specific, however, its impact on healthy aging is unclear. In particular, the contribution of telomere truncation to the aging process of the CNS, where replicative senescence alone fails to explain organ aging due to low to absent mitotic activity of intrinsic populations, is undefined. Here, we assessed changes in relative telomere length in non-replicative and replicative neural brain populations and telomerase activity as a function of aging in C57BL/6 mice. Telomeres in neural cells and sub-selected neurons shortened with aging in a cell cycle-dependent and -independent manner, with preponderance in replicative moieties, implying that proliferation accelerates, but is not prerequisite for telomere shortening. Consistent with this telomere erosion, telomerase activity and nuclear TERT protein were not induced with aging. Knockdown of the Rela subunit of NF-κB, which controls both telomerase enzyme and subcellular TERT protein allocation, did also not influence telomerase activity or telomere length, in spite of its naive up-regulation selectively under aging conditions. We conclude that telomere instability is intrinsic to physiological brain aging beyond cell replication, and appears to occur independently of a functional interplay with NF-κB, but rather as a failure to induce or relocate telomerase.},
}
@article {pmid30469324,
year = {2018},
author = {Wight, DJ and Wallaschek, N and Sanyal, A and Weller, SK and Flamand, L and Kaufer, BB},
title = {Viral Proteins U41 and U70 of Human Herpesvirus 6A Are Dispensable for Telomere Integration.},
journal = {Viruses},
volume = {10},
number = {11},
pages = {},
pmid = {30469324},
issn = {1999-4915},
support = {R01 AI021747/AI/NIAID NIH HHS/United States ; R01 AI069136/AI/NIAID NIH HHS/United States ; Stg 677673/ERC_/European Research Council/International ; },
mesh = {Cell Line ; Gene Silencing ; Herpesvirus 6, Human/*physiology ; Humans ; Telomere/*virology ; Viral Proteins/genetics/*metabolism ; *Virus Integration ; },
abstract = {Human herpesvirus-6A and -6B (HHV-6A and -6B) are two closely related betaherpesviruses that infect humans. Upon primary infection they establish a life-long infection termed latency, where the virus genome is integrated into the telomeres of latently infected cells. Intriguingly, HHV-6A/B can integrate into germ cells, leading to individuals with inherited chromosomally-integrated HHV-6 (iciHHV-6), who have the HHV-6 genome in every cell. It is known that telomeric repeats flanking the virus genome are essential for integration; however, the protein factors mediating integration remain enigmatic. We have previously shown that the putative viral integrase U94 is not essential for telomere integration; thus, we set out to assess the contribution of potential viral recombination proteins U41 and U70 towards integration. We could show that U70 enhances dsDNA break repair via a homology-directed mechanism using a reporter cell line. We then engineered cells to produce shRNAs targeting both U41 and U70 to inhibit their expression during infection. Using these cells in our HHV-6A in vitro integration assay, we could show that U41/U70 were dispensable for telomere integration. Furthermore, additional inhibition of the cellular recombinase Rad51 suggested that it was also not essential, indicating that other cellular and/or viral factors must mediate telomere integration.},
}
@article {pmid30466069,
year = {2019},
author = {Yamaki, N and Matsushita, S and Hara, S and Yokoyama, A and Hishimoto, A and Higuchi, S},
title = {Telomere shortening in alcohol dependence: Roles of alcohol and acetaldehyde.},
journal = {Journal of psychiatric research},
volume = {109},
number = {},
pages = {27-32},
doi = {10.1016/j.jpsychires.2018.11.007},
pmid = {30466069},
issn = {1879-1379},
mesh = {Acetaldehyde/*adverse effects ; Aged ; *Aging, Premature/chemically induced/etiology/genetics ; *Alcoholism/complications/genetics ; Aldehyde Dehydrogenase, Mitochondrial/genetics ; Ethanol/*adverse effects ; Humans ; Japan ; Male ; Middle Aged ; *Telomere Shortening/drug effects/genetics ; *Thiamine Deficiency/chemically induced/genetics ; },
abstract = {Heavy drinking leads to premature aging and precipitates the onset of age-related diseases. Acetaldehyde (AcH), a toxic metabolite of ethanol, has been implicated in various types of cancer. However, whether alcohol accelerates biological aging at a cellular level is controversial and the mechanism involved is unclear. We addressed these questions by measuring telomere length (TL) in peripheral blood leukocytes of Japanese patients with alcohol dependence (AD) and examined the association between TL, genetic variants of alcohol dehydrogenase (ADH)1B and aldehyde dehydrogenase (ALDH)2, and other clinical characteristics. A total of 134 male AD patients and 121 age- and sex-matched healthy controls were evaluated. All patients received endoscopic screening for cancer of the upper aerodigestive tract (UADT). TL was almost 50% shorter in AD patients relative to controls. There were no significant differences in TL between AD patients with and without UADT cancer, and no associations between ADH1B and ALDH2 genotypes and TL. AD patients with thiamine (vitamin B1) deficiency at admission had significantly shorter TL than those with normal thiamine status. Although the exact mechanism underlying the shorter TL in AD patients remain unclear, our findings suggest that alcohol rather than AcH is associated with telomere shortening in AD, which may be accelerated by thiamine deficiency. Future studies should also focus on the association between telomere shortening and TD in the context of oxidative stress.},
}
@article {pmid30460867,
year = {2018},
author = {Tsur, N and Levin, Y and Abumock, H and Solomon, Z},
title = {One 'knows': self-rated health and telomere length among ex-prisoners of war.},
journal = {Psychology &amp; health},
volume = {33},
number = {12},
pages = {1503-1518},
doi = {10.1080/08870446.2018.1509977},
pmid = {30460867},
issn = {1476-8321},
mesh = {Aged ; *Diagnostic Self Evaluation ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Prisoners of War/*psychology/statistics &amp; numerical data ; Prospective Studies ; Stress Disorders, Post-Traumatic/physiopathology ; *Telomere ; Telomere Shortening/physiology ; },
abstract = {OBJECTIVE: Ill-health and early mortality are amongst the most significant ramifications of trauma. Furthermore, trauma alters the subjective perception and experience of the body. The aim of this study is to examine the extent to which deteriorations in perceived health among traumatised individuals are associated with cellular health as manifested in telomere length.<br><br>METHODS: Specifically, 88 former prisoners of war (ex-POWs) evaluated their health (self-rated health; SRH) at 18 (T1), 35 (T2) and 42 (T3) years after the war, and were assessed for telomere length at T3. Health behaviour, BMI, morbidity and PTSD were also examined at T3.<br><br>RESULTS: The findings demonstrated that SRH was cross-sectionally correlated with telomere length. Furthermore, a significant sequential indirect effect was found, in which worse SRH in T1 was associated with shorter telomere length at T3, through worse SRH at T2 and at T3.<br><br>CONCLUSIONS: These findings demonstrate that long-term deteriorations in the subjective evaluations of health are implicated in actual cellular health among individuals exposed to trauma.},
}
@article {pmid30459805,
year = {2018},
author = {Palmos, AB and Breen, G and Goodwin, L and Frissa, S and Hatch, SL and Hotopf, M and Thuret, S and Lewis, CM and Powell, TR},
title = {Genetic Risk for Psychiatric Disorders and Telomere Length.},
journal = {Frontiers in genetics},
volume = {9},
number = {},
pages = {468},
pmid = {30459805},
issn = {1664-8021},
support = {MR/N014863/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Background: Previous studies have revealed associations between psychiatric disorder diagnosis and shorter telomere length. Here, we attempt to discern whether genetic risk for psychiatric disorders, or use of pharmacological treatments (i.e., antidepressants), predict shorter telomere length and risk for aging-related disease in a United Kingdom population sample. Methods: DNA samples from blood were available from 351 participants who were recruited as part of the South East London Community Health (SELCoH) Study, and for which whole-genome genotype data was available. Leukocyte telomere length was characterized using quantitative polymerase chain reactions. Individualized polygenic risk scores for major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) were calculated using Psychiatric Genomics Consortium summary statistics. We subsequently performed linear models, to discern the impact polygenic risk for psychiatric disorders (an etiological risk factor) and antidepressant use (common pharmacological treatment) have on telomere length, whilst accounting for other lifestyle/health factors (e.g., BMI, smoking). Results: There were no significant associations between polygenic risk for any of the psychiatric disorders tested and telomere length (p > 0.05). Antidepressant use was significantly associated with shorter telomere length and this was independent from a depression diagnosis or current depression severity (p ≤ 0.01). Antidepressant use was also associated with a significantly higher risk of aging-related disease, which was independent from depression diagnosis (p ≤ 0.05). Conclusion: Genetic risk for psychiatric disorders is not associated with shorter telomere length. Further studies are now needed to prospectively characterize if antidepressant use increases risk for aging-related disease and telomere shortening, or whether people who age faster and have aging-related diseases are just more likely to be prescribed antidepressants.},
}
@article {pmid30456372,
year = {2018},
author = {Majerska, J and Feretzaki, M and Glousker, G and Lingner, J},
title = {Transformation-induced stress at telomeres is counteracted through changes in the telomeric proteome including SAMHD1.},
journal = {Life science alliance},
volume = {1},
number = {4},
pages = {e201800121},
pmid = {30456372},
issn = {2575-1077},
abstract = {Telomeres play crucial roles during tumorigenesis, inducing cellular senescence upon telomere shortening and extensive chromosome instability during telomere crisis. However, it has not been investigated if and how cellular transformation and oncogenic stress alter telomeric chromatin composition and function. Here, we transform human fibroblasts by consecutive transduction with vectors expressing hTERT, the SV40 early region, and activated H-RasV12. Pairwise comparisons of the telomeric proteome during different stages of transformation reveal up-regulation of proteins involved in chromatin remodeling, DNA repair, and replication at chromosome ends. Depletion of several of these proteins induces telomere fragility, indicating their roles in replication of telomeric DNA. Depletion of SAMHD1, which has reported roles in DNA resection and homology-directed repair, leads to telomere breakage events in cells deprived of the shelterin component TRF1. Thus, our analysis identifies factors, which accumulate at telomeres during cellular transformation to promote telomere replication and repair, resisting oncogene-borne telomere replication stress.},
}
@article {pmid30456332,
year = {2018},
author = {Wang, CY},
title = {Asynchronous Shortening of Telomere Length and Cardiovascular Outcomes.},
journal = {JACC. Basic to translational science},
volume = {3},
number = {5},
pages = {601-603},
pmid = {30456332},
issn = {2452-302X},
}
@article {pmid30456331,
year = {2018},
author = {Yin, H and Akawi, O and Fox, SA and Li, F and O'Neil, C and Balint, B and Arpino, JM and Watson, A and Wong, J and Guo, L and Quantz, MA and Nagpal, AD and Kiaii, B and Chu, MWA and Pickering, JG},
title = {Cardiac-Referenced Leukocyte Telomere Length and Outcomes After Cardiovascular Surgery.},
journal = {JACC. Basic to translational science},
volume = {3},
number = {5},
pages = {591-600},
pmid = {30456331},
issn = {2452-302X},
abstract = {Leukocyte telomere shortening reflects stress burdens and has been associated with cardiac events. However, the patient-specific clinical value of telomere assessment remains unknown. Moreover, telomere shortening cannot be inferred from a single telomere length assessment. The authors investigated and developed a novel strategy for gauging leukocyte telomere shortening using autologous cardiac atrial referencing. Using multitissue assessments from 163 patients who underwent cardiovascular surgery, we determined that the cardiac atrium-leukocyte telomere length difference predicted post-operative complexity. This constituted the first evidence that a single-time assessment of telomere dynamics might be salient to acute cardiac care.},
}
@article {pmid30448616,
year = {2019},
author = {Davinelli, S and Trichopoulou, A and Corbi, G and De Vivo, I and Scapagnini, G},
title = {The potential nutrigeroprotective role of Mediterranean diet and its functional components on telomere length dynamics.},
journal = {Ageing research reviews},
volume = {49},
number = {},
pages = {1-10},
doi = {10.1016/j.arr.2018.11.001},
pmid = {30448616},
issn = {1872-9649},
mesh = {Aging/*physiology ; *Diet, Mediterranean ; Epidemiologic Studies ; Humans ; Inflammation/diet therapy ; Nutritional Status ; Risk Factors ; Telomere ; *Telomere Homeostasis ; Telomere Shortening ; },
abstract = {The Mediterranean diet (MD) is a gold standard for nutrition and the most evidence-based diet to delay the onset of age-associated pathologies. Telomeres are the heterochromatic repeat regions found at the ends of eukaryotic chromosomes, whose length is considered a reliable hallmark of biological ageing. Telomere shortening is, at least in part, a modifiable factor and there is evidence that adherence to the MD is associated with longer telomeres. Data from several studies indicate an association between "inflammatory/oxidative status" and telomere length (TL). The MD, as a complex exposome with thousands of nutrients and phytochemicals, may positively influence telomere attrition by reducing inflammation and oxidative stress. However, it is unclear whether the protective effects on TL provided by the MD result from its individual constituents or some combination of these. Furthermore, these properties of the MD and its components are not yet fully validated by clinical endpoints in randomized trials or observational studies. Here, we summarize the data from experimental and population-based studies on the effects of the MD on TL maintenance. We will both highlight the possible role of the MD in the prevention of age-associated diseases, and attempt to identify certain aspects of the diet that are particularly important for telomere maintenance.},
}
@article {pmid30444746,
year = {2019},
author = {Demerdash, HM and Elyamany, AS and Arida, E},
title = {Impact of direct-acting antivirals on leukocytic DNA telomere length in hepatitis C virus-related hepatic cirrhosis.},
journal = {European journal of gastroenterology &amp; hepatology},
volume = {31},
number = {4},
pages = {494-498},
doi = {10.1097/MEG.0000000000001306},
pmid = {30444746},
issn = {1473-5687},
mesh = {Adult ; Antiviral Agents/*pharmacology/therapeutic use ; Case-Control Studies ; Female ; Hepatitis C, Chronic/complications/*drug therapy/genetics ; Humans ; Leukocytes/drug effects ; Liver Cirrhosis/*drug therapy/genetics/virology ; Male ; Middle Aged ; Telomere/drug effects ; Telomere Shortening/*drug effects ; },
abstract = {BACKGROUND: Direct-acting antiviral (DAAs) represent advancement in the management of hepatitis C virus (HCV)-related hepatic cirrhosis. A high proportion of patients achieve a sustained virologic response; eradication of HCV is coupled with a decreased risk of hepatocellular carcinoma. Recent evidence suggests that shortening of the DNA telomere may be linked to cellular senescence as well as predisposition to malignant transformation.<br><br>OBJECTIVE: This study aimed to assess pretreatment leukocytic DNA telomere length in HCV-related cirrhosis and post viral eradication using DAAs.<br><br>PATIENTS AND METHODS: This study included 24 patients with HCV-related cirrhosis, Child-Pugh A. Whole-blood samples were obtained from patients before treatment and 12 weeks after the end of treatment, as well as from 24 healthy controls. Terminal restriction fragment, corresponding to telomere length, was measured using a nonradioactive Southern blot technique, detected by chemiluminescence.<br><br>RESULTS: DNA telomere length was significantly shorter before treatment compared with 12 weeks after end of treatment in HCV-related cirrhotic patients. Also, it was significantly shorter in patients before treatment compared with healthy individuals.<br><br>CONCLUSION: Telomere elongation in blood leukocytes can be considered a marker of recovery of inflammation after DAAs-induced HCV eradication. Still, the possibility of activation by cancer initiation cannot be excluded.},
}
@article {pmid30442342,
year = {2018},
author = {de Souza, MR and Kahl, VFS and Rohr, P and Kvitko, K and Cappetta, M and Lopes, WM and da Silva, J},
title = {Shorter telomere length and DNA hypermethylation in peripheral blood cells of coal workers.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {836},
number = {Pt B},
pages = {36-41},
doi = {10.1016/j.mrgentox.2018.03.009},
pmid = {30442342},
issn = {1879-3592},
mesh = {Adult ; Aged ; Case-Control Studies ; Cells, Cultured ; *Coal Mining ; Comet Assay/*methods ; *DNA Damage ; *DNA Methylation ; Environmental Monitoring/*methods ; Female ; Humans ; Lymphocytes/drug effects/metabolism/pathology ; Male ; Middle Aged ; Occupational Exposure/adverse effects/*analysis ; Oxidative Stress ; *Telomere Homeostasis ; Young Adult ; },
abstract = {Coal is a mixture of several chemicals, mainly inorganic elements and polycyclic aromatic hydrocarbons, many of which have mutagenic and carcinogenic effects. Pneumoconiosis, fibrosis, asbestosis, silicosis, emphysema, loss of lung function and cancer are some examples of coal-related disorders. The aim of this study was to analyze coal miners with respect to telomere length (TL) and percentage (%) of global DNA methylation. The study involved 82 participants divided into two groups: 55 workers exposed to coal and 27 non-exposed individuals. DNA was isolated from peripheral blood samples from all individuals. Telomeres were measured by quantitative real time polymerase chain reaction (qPCR) and global DNA methylation levels were performed by the relative quantitation of 5-methyl-2'-deoxycytidine (5-mdC) by high-performance liquid chromatography (HPLC). TL measurements showed a mean of 9,199 bp (±4,196) for non-exposed and 7,545 bp (±2,703) for exposed groups, and% of global DNA methylation a mean of 2.78% (±0.41) for non-exposed and 3.00% (±0.37) for exposed individuals. Occupationally exposed individuals showed a significant decrease of TL (P < 0.05; Mann-Whitney test) and increase in the percentage of global DNA methylation (P < 0.05; Mann-Whitney test) when compared to the non-exposed group. This study showed that occupational exposure to coal and products of combustion is positively associated with TL and DNA methylation. Previously, we have evaluated the same individuals using comet assay, micronucleus (MN) test, oxidative stress and inorganic elements. No correlations were observed between TL and methylation with previous data in the exposed group. Further studies are needed to determine whether these alterations are associated with induced disease outcomes and if these events could be determinants to identify cancer risk.},
}
@article {pmid30439955,
year = {2018},
author = {Mukherjee, AK and Sharma, S and Sengupta, S and Saha, D and Kumar, P and Hussain, T and Srivastava, V and Roy, SD and Shay, JW and Chowdhury, S},
title = {Telomere length-dependent transcription and epigenetic modifications in promoters remote from telomere ends.},
journal = {PLoS genetics},
volume = {14},
number = {11},
pages = {e1007782},
pmid = {30439955},
issn = {1553-7404},
support = {500127-Z-09-Z/WTDBT_/DBT-Wellcome Trust India Alliance/India ; 500127/Z/09/Z//Wellcome Trust/DBT India Alliance/International ; },
mesh = {Cell Line ; Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism ; *Epigenesis, Genetic ; Gene Expression ; Genome, Human ; Histone Code/genetics/physiology ; Humans ; *Promoter Regions, Genetic ; Protein Binding ; Shelterin Complex ; Telomere/*genetics/*metabolism ; Telomere Homeostasis/genetics/physiology ; Telomere-Binding Proteins/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; *Transcription, Genetic ; },
abstract = {Telomere-binding proteins constituting the shelterin complex have been studied primarily for telomeric functions. However, mounting evidence shows non-telomeric binding and gene regulation by shelterin factors. This raises a key question-do telomeres impact binding of shelterin proteins at distal non-telomeric sites? Here we show that binding of the telomere-repeat-binding-factor-2 (TRF2) at promoters ~60 Mb from telomeres depends on telomere length in human cells. Promoter TRF2 occupancy was depleted in cells with elongated telomeres resulting in altered TRF2-mediated transcription of distal genes. In addition, histone modifications-activation (H3K4me1 and H3K4me3) as well as silencing marks (H3K27me3)-at distal promoters were telomere length-dependent. These demonstrate that transcription, and the epigenetic state, of telomere-distal promoters can be influenced by telomere length. Molecular links between telomeres and the extra-telomeric genome, emerging from findings here, might have important implications in telomere-related physiology, particularly ageing and cancer.},
}
@article {pmid30427907,
year = {2018},
author = {Guha, M and Srinivasan, S and Johnson, FB and Ruthel, G and Guja, K and Garcia-Diaz, M and Kaufman, BA and Glineburg, MR and Fang, J and Nakagawa, H and Basha, J and Kundu, T and Avadhani, NG},
title = {hnRNPA2 mediated acetylation reduces telomere length in response to mitochondrial dysfunction.},
journal = {PloS one},
volume = {13},
number = {11},
pages = {e0206897},
pmid = {30427907},
issn = {1932-6203},
support = {R01 GM100021/GM/NIGMS NIH HHS/United States ; R01 AA022986/AA/NIAAA NIH HHS/United States ; S10 RR027128/RR/NCRR NIH HHS/United States ; },
mesh = {Acetylation ; Animals ; Cell Line ; Cell Transformation, Neoplastic/genetics ; Chromosomal Instability/physiology ; Epigenesis, Genetic/physiology ; Fibroblasts ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/*metabolism ; Histones/*metabolism ; Humans ; Lysine/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Mitochondria/*metabolism ; Mutagenesis, Site-Directed ; Mutation ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere Shortening/*genetics ; },
abstract = {Telomeres protect against chromosomal damage. Accelerated telomere loss has been associated with premature aging syndromes such as Werner's syndrome and Dyskeratosis Congenita, while, progressive telomere loss activates a DNA damage response leading to chromosomal instability, typically observed in cancer cells and senescent cells. Therefore, identifying mechanisms of telomere length maintenance is critical for understanding human pathologies. In this paper we demonstrate that mitochondrial dysfunction plays a causal role in telomere shortening. Furthermore, hnRNPA2, a mitochondrial stress responsive lysine acetyltransferase (KAT) acetylates telomere histone H4at lysine 8 of (H4K8) and this acetylation is associated with telomere attrition. Cells containing dysfunctional mitochondria have higher telomere H4K8 acetylation and shorter telomeres independent of cell proliferation rates. Ectopic expression of KAT mutant hnRNPA2 rescued telomere length possibly due to impaired H4K8 acetylation coupled with inability to activate telomerase expression. The phenotypic outcome of telomere shortening in immortalized cells included chromosomal instability (end-fusions) and telomerase activation, typical of an oncogenic transformation; while in non-telomerase expressing fibroblasts, mitochondrial dysfunction induced-telomere attrition resulted in senescence. Our findings provide a mechanistic association between dysfunctional mitochondria and telomere loss and therefore describe a novel epigenetic signal for telomere length maintenance.},
}
@article {pmid30427547,
year = {2019},
author = {Warny, M and Helby, J and Sengeløv, H and Nordestgaard, BG and Birgens, H and Bojesen, SE},
title = {Bone marrow mononuclear cell telomere length in acute myeloid leukaemia and high-risk myelodysplastic syndrome.},
journal = {European journal of haematology},
volume = {102},
number = {3},
pages = {218-226},
doi = {10.1111/ejh.13196},
pmid = {30427547},
issn = {1600-0609},
mesh = {Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Biomarkers ; Bone Marrow Cells/*metabolism/pathology ; Disease Progression ; Female ; Humans ; Leukemia, Myeloid, Acute/diagnosis/drug therapy/*genetics ; Male ; Middle Aged ; Myelodysplastic Syndromes/diagnosis/drug therapy/*genetics ; Recurrence ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Treatment Outcome ; },
abstract = {OBJECTIVE: Short telomere length is a known risk factor for developing clonal haematopoietic stem cell disorders, probably due to chromosomal instability. We tested the hypotheses that bone marrow mononuclear cell telomere length change from diagnosis through chemotherapy-induced remission and relapse, and that long telomere length is associated with low risk of relapse and all-cause mortality in patients with acute myeloid leukaemia or high-risk myelodysplastic syndrome.<br><br>METHODS: We measured telomere length in bone marrow mononuclear cells from 233 patients at diagnosis, 112 patients at chemotherapy-induced remission and 58 patients at relapse of disease.<br><br>RESULTS: In patients with acute myeloid leukaemia or high-risk myelodysplastic syndrome, bone marrow mononuclear cell telomere length was similar at diagnosis and relapse, but increased after chemotherapy-induced remission. Furthermore, bone marrow mononuclear cell telomere length was longer in patients with higher age at diagnosis. There was no association between telomere length at diagnosis, remission or relapse and all-cause mortality, nor did we find any association between telomere length at diagnosis or remission and risk of relapse.<br><br>CONCLUSION: In patients with acute myeloid leukaemia or high-risk myelodysplastic syndrome, bone marrow mononuclear cell telomere length increased from diagnosis to remission. Furthermore, telomere length paradoxically was longer at higher age at diagnosis, even after adjusting for known risk factors of disease severity. Finally, we did not detect any prognostic information in telomere length.},
}
@article {pmid30423196,
year = {2018},
author = {Ahvenainen, TV and Mäkinen, NM and von Nandelstadh, P and Vahteristo, MEA and Pasanen, AM and Bützow, RC and Vahteristo, PM},
title = {Loss of ATRX/DAXX expression and alternative lengthening of telomeres in uterine leiomyomas.},
journal = {Cancer},
volume = {124},
number = {24},
pages = {4650-4656},
doi = {10.1002/cncr.31754},
pmid = {30423196},
issn = {1097-0142},
support = {//Sy&#xf6;p&#xe4;j&#xe4;rjest&#xf6;t/International ; //Sigrid Jus&#xe9;liuksen S&#xe4;&#xe4;ti&#xf6;/International ; 260370//Suomen Akatemia/International ; 307773//Suomen Akatemia/International ; //Sigrid Jus&#xe9;lius Foundation/International ; //Cancer Society of Finland/International ; //Academy of Finland/International ; },
mesh = {Adaptor Proteins, Signal Transducing/*metabolism ; Adult ; Co-Repressor Proteins ; Diagnosis, Differential ; Female ; Gene Deletion ; Gene Expression Regulation, Neoplastic ; Humans ; In Situ Hybridization, Fluorescence ; Leiomyoma/*diagnosis/genetics/metabolism ; Leiomyosarcoma/diagnosis/genetics/metabolism ; Lung Neoplasms/genetics/secondary ; Middle Aged ; Molecular Chaperones ; Nuclear Proteins/*metabolism ; Survival Analysis ; Telomere/*genetics ; Telomere Homeostasis ; Uterine Neoplasms/*diagnosis/genetics/metabolism ; X-linked Nuclear Protein/*metabolism ; },
abstract = {BACKGROUND: Uterine leiomyomas (ULs) are the most common gynecologic tumors and affect 3 of every 4 women by the age of 50 years. The majority of ULs are classified as conventional tumors, whereas 10% represent various histopathological subtypes with features that mimic malignancy. These subtypes include cellular and mitotically active ULs and ULs with bizarre nuclei. Uterine leiomyosarcoma (ULMS), the malignant counterpart of UL, is an aggressive cancer with poor overall survival. The early diagnosis and preoperative differentiation of ULMS from UL are often challenging because their symptoms and morphology resemble one another. Recent studies have shown frequent loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated protein (DAXX) expression in ULMS, and this is often associated with an alternative lengthening of telomeres (ALT) phenotype.<br><br>METHODS: To investigate ATRX and DAXX expression and the presence of ALT in UL subtypes, immunohistochemical and telomere-specific fluorescence in situ hybridization analyses were performed. The study material consisted of 142 formalin-fixed, paraffin-embedded tissue samples representing various UL subtypes and 64 conventional ULs.<br><br>RESULTS: A loss of ATRX or DAXX and/or ALT was detected in 6.3% of the histopathological UL subtype samples (9 of 142). Two patients whose ULs showed either ATRX loss or ALT were later diagnosed with a pulmonary smooth muscle tumor. Pulmonary tumors displayed molecular alterations found in the corresponding uterine tumors, which indicated metastasis to the lungs. All conventional ULs displayed normal ATRX, DAXX, and telomeres.<br><br>CONCLUSIONS: These results highlight the differences between conventional and histopathologically atypical ULs and indicate that some UL subtype tumors may harbor long-term malignant potential.},
}
@article {pmid30422111,
year = {2018},
author = {Faraji, J and Karimi, M and Soltanpour, N and Moharrerie, A and Rouhzadeh, Z and Lotfi, H and Hosseini, SA and Jafari, SY and Roudaki, S and Moeeini, R and Metz, GA},
title = {Oxytocin-mediated social enrichment promotes longer telomeres and novelty seeking.},
journal = {eLife},
volume = {7},
number = {},
pages = {},
pmid = {30422111},
issn = {2050-084X},
mesh = {Animals ; Exploratory Behavior/*drug effects ; Female ; Housing, Animal ; Male ; Oxytocin/antagonists &amp; inhibitors/blood/*pharmacology ; Phenotype ; Piperidines/pharmacology ; Rats, Wistar ; *Social Behavior ; Spiro Compounds/pharmacology ; Task Performance and Analysis ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {The quality of social relationships is a powerful determinant of lifetime health. Here, we explored the impact of social experiences on circulating oxytocin (OT) concentration, telomere length (TL), and novelty-seeking behaviour in male and female rats. Prolonged social housing raised circulating OT levels in both sexes while elongating TL only in females. Novelty-seeking behaviour in females was more responsive to social housing and increased OT levels than males. The OT antagonist (OT ANT) L-366,509 blocked the benefits of social housing in all conditions along with female-specific TL erosion and novelty-seeking deficit. Thus, females seem more susceptible than males to genetic and behavioural changes when the secretion of endogenous OT in response to social life is interrupted. Social enrichment may, therefore, provide a therapeutic avenue to promote stress resiliency and chances of healthy aging across generations.},
}
@article {pmid30421359,
year = {2019},
author = {Tang, H and Geng, A and Zhang, T and Wang, C and Jiang, Y and Mao, Z},
title = {Single senescent cell sequencing reveals heterogeneity in senescent cells induced by telomere erosion.},
journal = {Protein &amp; cell},
volume = {10},
number = {5},
pages = {370-375},
pmid = {30421359},
issn = {1674-8018},
mesh = {Cells, Cultured ; *Cellular Senescence ; *Fibroblasts/cytology/metabolism ; Humans ; Single-Cell Analysis ; Telomere/*metabolism ; },
}
@article {pmid30417689,
year = {2018},
author = {McFarland, MJ and Taylor, J and McFarland, CAS and Friedman, KL},
title = {Perceived Unfair Treatment by Police, Race, and Telomere Length: A Nashville Community-based Sample of Black and White Men.},
journal = {Journal of health and social behavior},
volume = {59},
number = {4},
pages = {585-600},
doi = {10.1177/0022146518811144},
pmid = {30417689},
issn = {2150-6000},
support = {R01 AG034067/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; *Black or African American ; Aged ; Humans ; Male ; Middle Aged ; *Police ; *Racism ; Stress, Psychological/*genetics ; *Telomere ; *White People ; Young Adult ; },
abstract = {Police maltreatment, whether experienced personally or indirectly through one's family or friends, represents a structurally rooted public health problem that disproportionately affects minorities. Researchers, however, know little about the physiological mechanisms connecting unfair treatment by police (UTBP) to poor health. Shortened telomeres due to exposure to this stressor represent one plausible mechanism. Using data from a community sample of black (n = 262) and white (n = 252) men residing in Nashville-Davidson County, we test four hypotheses: (1) Black men will be more likely to report UTBP than white men, (2) those reporting UTBP will have shorter telomeres than those not reporting UTBP, (3) this association will be more pronounced among black men, and (4) these hypotheses will extend to those who report vicarious UTBP. Results reveal support for all hypotheses. The implications for our findings are discussed as they pertain to debates on policing practices and health disparities research.},
}
@article {pmid30417475,
year = {2019},
author = {Grunst, AS and Grunst, ML and Gonser, RA and Tuttle, EM},
title = {Developmental stress and telomere dynamics in a genetically polymorphic species.},
journal = {Journal of evolutionary biology},
volume = {32},
number = {2},
pages = {134-143},
doi = {10.1111/jeb.13400},
pmid = {30417475},
issn = {1420-9101},
support = {R01 GM084229/GM/NIGMS NIH HHS/United States ; },
mesh = {Aging/*physiology ; Animals ; Female ; Male ; *Nesting Behavior ; *Oxidative Stress ; Pigmentation ; Polymorphism, Genetic ; Sparrows/genetics/*metabolism ; *Telomere Shortening ; },
abstract = {A central objective of evolutionary biology is understanding variation in life-history trajectories and the rate of aging, or senescence. Senescence can be affected by trade-offs and behavioural strategies in adults but may also be affected by developmental stress. Developmental stress can accelerate telomere degradation, with long-term longevity and fitness consequences. Little is known regarding whether variation in developmental stress and telomere dynamics contributes to patterns of senescence during adulthood. We investigated this question in the dimorphic white-throated sparrow (Zonotrichia albicollis), a species in which adults of the two morphs exhibit established differences in behavioural strategy and patterns of senescence, and also evaluated the relationship between oxidative stress and telomere length. Tan morph females, which exhibit high levels of unassisted parental care, display faster reproductive senescence than white females, and faster actuarial senescence than all of the other morph-sex classes. We hypothesized that high oxidative stress and telomere attrition in tan female nestlings could contribute to this pattern, since tan females are small and potentially at a competitive disadvantage even as nestlings. Nestlings that were smaller than nest mates had higher oxidative stress, and nestlings with high oxidative stress and fast growth rates displayed shorter telomeres. However, we found no consistent morph-sex differences in oxidative stress or telomere length. Results suggest that oxidative stress and fast growth contribute to developmental telomere attrition, with potential ramifications for adults, but that developmental oxidative stress and telomere dynamics do not account for morph-sex differences in senescence during adulthood.},
}
@article {pmid30414584,
year = {2019},
author = {Huang, H and Wang, Q and He, X and Wu, Y and Xu, C},
title = {Association between polyfluoroalkyl chemical concentrations and leucocyte telomere length in US adults.},
journal = {The Science of the total environment},
volume = {653},
number = {},
pages = {547-553},
doi = {10.1016/j.scitotenv.2018.10.400},
pmid = {30414584},
issn = {1879-1026},
mesh = {Adult ; Aged ; Aged, 80 and over ; Cross-Sectional Studies ; Environmental Exposure/*statistics &amp; numerical data ; Female ; Fluorocarbons/*blood ; Humans ; Leukocytes/drug effects/*physiology ; Male ; Middle Aged ; Telomere/drug effects/*physiology ; United States ; Young Adult ; },
abstract = {Exposure to some environmental chemicals is reportedly associated with the leucocyte telomere length (LTL), but the effects of the non-occupational exposure to polyfluoroalkyl chemical (PFCs) on the LTL are not well understood. Using data from 773 participants in the National Health and Nutrition Examination Survey (NHANES) conducted in 1999-2000, we analysed the association between blood PFC concentrations and LTL. Coefficients (betas) and 95% confidence intervals (CIs) for the blood PFC concentrations in association with the LTL were estimated using multivariate linear regression models after adjustment for age, gender, race, body mass index (BMI), poverty income ratio, educational level, white blood cell count, C-reactive protein and other PFCs. The results identified a strong positive association between the blood perfluorooctane sulfonic acid (PFOS) concentration and LTL in adults, and no associations were found between the LTL and other PFCs. In the linear regression models, each increment of one standard deviation (SD) in the base-10-logarithm-transformed PFOS concentration was associated with a 21-bp increase in the LTL in the fully adjusted model (P = 0.033). Moreover, serum PFOS was associated with the LTL mainly in females and individuals aged 40-50, as demonstrated by stratified analyses. These results provide epidemiological evidence showing that environment-related levels of serum PFOS are positively associated with the LTL in adults.},
}
@article {pmid30413768,
year = {2018},
author = {Stefler, D and Malyutina, S and Maximov, V and Orlov, P and Ivanoschuk, D and Nikitin, Y and Gafarov, V and Ryabikov, A and Voevoda, M and Bobak, M and Holmes, MV},
title = {Leukocyte telomere length and risk of coronary heart disease and stroke mortality: prospective evidence from a Russian cohort.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {16627},
pmid = {30413768},
issn = {2045-2322},
support = {FS/18/23/33512/BHF_/British Heart Foundation/United Kingdom ; R01 AG023522/AG/NIA NIH HHS/United States ; //Wellcome Trust/United Kingdom ; WT081081/WT_/Wellcome Trust/United Kingdom ; WT064947/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Aged ; Coronary Disease/etiology/*mortality/pathology ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Prognosis ; Prospective Studies ; Risk Factors ; Russia ; Stroke/etiology/*mortality/pathology ; Survival Rate ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Previous studies suggest that reduced leukocyte telomere length (LTL) is related to higher risk of mortality and several chronic conditions, including coronary heart disease (CHD) and stroke. However, the consistency of this association differs across populations. We investigated the relationship of LTL with CHD, stroke and all-cause mortality together with non-fatal CHD and stroke events in a Russian cohort with a mean age of 58 years at baseline. Data from 1,144 individuals in the Russian subset of the Health Alcohol and Psychosocial Factors in Eastern Europe (HAPIEE) cohort study were used. The associations between LTL at baseline and fatal/non-fatal outcomes during 12 years of follow-up were assessed using multivariable Cox regression models, which yielded adjusted hazard ratios (HR). Compared to individuals in the shortest tertile, those in the longest tertile of LTL had a 42% lower risk of death from all-causes (HR 0.58; 95% CI: 0.39-0.88) and 58% lower risk of death from CHD (HR 0.42; 95%CI: 0.19-0.97). Similar patterns of association were identified for non-fatal and combined fatal/non-fatal CHD and stroke events but the associations were weaker. Consistent with results of previous studies in Western populations, this cohort of elderly Russian adults found an inverse association between LTL and CHD and all-cause mortality. These findings reinforce the hypothesis that LTL may play (or be a marker of) an aetiological role in human health across diverse populations.},
}
@article {pmid30407711,
year = {2019},
author = {Jordan, CD and Glover, LM and Gao, Y and Musani, SK and Mwasongwe, S and Wilson, JG and Reiner, A and Diez-Roux, A and Sims, M},
title = {Association of psychosocial factors with leukocyte telomere length among African Americans in the Jackson Heart Study.},
journal = {Stress and health : journal of the International Society for the Investigation of Stress},
volume = {35},
number = {2},
pages = {138-145},
doi = {10.1002/smi.2848},
pmid = {30407711},
issn = {1532-2998},
support = {HHSN268201800013I//Jackson Heart Study (JHS), Jackson State University/ ; HHSN268201800014I//Tougaloo College/ ; HHSN268201800015I//Mississippi State Department of Health/ ; HHSN268201800010I//University of Mississippi Medical Center/ ; HHSN268201800011I//University of Mississippi Medical Center/ ; HHSN268201800012I//University of Mississippi Medical Center/ ; //National Heart, Lung, and Blood Institute (NHLBI)/ ; //National Institute for Minority Health and Health Disparities (NIMHD)/ ; },
mesh = {Adult ; Affect ; Black or African American/*psychology ; Aged ; Anger ; Depression/diagnosis/genetics ; Female ; Humans ; *Leukocytes ; Linear Models ; Longitudinal Studies ; Male ; Middle Aged ; Mississippi ; Multivariate Analysis ; Risk Factors ; Stress, Psychological/*diagnosis/*ethnology/genetics ; *Telomere Shortening ; Trust ; },
abstract = {Leukocyte telomere length (LTL) is a biomarker of cellular aging. African Americans report more stress than other groups; however, the association of psychosocial stressors with biological aging among African Americans remains unclear. The current study evaluated the association of psychosocial factors (negative affect and stressors) with LTL in a large sample of African American men and women (n = 2,516) from the Jackson Heart Study. Using multivariable linear regression, we examined the sex-specific associations of psychosocial factors (cynical distrust, anger in and out, depressive symptoms, negative affect summary scores, global stress, weekly stress, major life events, and stress summary scores) with LTL. Model 1 adjusted for demographics and education. Model 2 adjusted for model 1, smoking, alcohol intake, physical activity, diabetes, hypertension, and high-sensitivity C-reactive protein. Among women, high (vs. low) cynical distrust was associated with shorter mean LTL in model 1 (b = -0.12; p = 0.039). Additionally, high (vs. low) anger out and expressed negative affect summary scores were associated with shorter LTL among women after full adjustment (b = -0.13; p = 0.011; b = -0.12, p = 0.031, respectively). High levels of cynical distrust, anger out, and negative affect summary scores may be risk factors for shorter LTL, particularly among African-American women.},
}
@article {pmid30407585,
year = {2018},
author = {Bianchi, F and Comez, L and Biehl, R and D'Amico, F and Gessini, A and Longo, M and Masciovecchio, C and Petrillo, C and Radulescu, A and Rossi, B and Sacchetti, F and Sebastiani, F and Violini, N and Paciaroni, A},
title = {Structure of human telomere G-quadruplex in the presence of a model drug along the thermal unfolding pathway.},
journal = {Nucleic acids research},
volume = {46},
number = {22},
pages = {11927-11938},
pmid = {30407585},
issn = {1362-4962},
mesh = {Anti-Bacterial Agents/*chemistry ; Antineoplastic Agents/*chemistry ; Binding Sites ; Dactinomycin/*chemistry ; Dimerization ; *G-Quadruplexes ; Hot Temperature ; Humans ; Kinetics ; Ligands ; Models, Molecular ; Nucleic Acid Denaturation ; Telomere/*chemistry ; Thermodynamics ; },
abstract = {A multi-technique approach, combining circular dichroism spectroscopy, ultraviolet resonance Raman spectroscopy and small angle scattering techniques, has been deployed to elucidate how the structural features of the human telomeric G-quadruplex d[A(GGGTTA)3GGG] (Tel22) change upon thermal unfolding. The system is studied both in the free form and when it is bound to Actinomycin D (ActD), an anticancer ligand with remarkable conformational flexibility. We find that at room temperature binding of Tel22 with ActD involves end-stacking upon the terminal G-tetrad. Structural evidence for drug-driven dimerization of a significant fraction of the G-quadruplexes is provided. When the temperature is raised, both free and bound Tel22 undergo melting through a multi-state process. We show that in the intermediate states of Tel22 the conformational equilibrium is shifted toward the (3+1) hybrid-type, while a parallel structure is promoted in the complex. The unfolded state of the free Tel22 is consistent with a self-avoiding random-coil conformation, whereas the high-temperature state of the complex is observed to assume a quite compact form. Such an unprecedented high-temperature arrangement is caused by the persistent interaction between Tel22 and ActD, which stabilizes compact conformations even in the presence of large thermal structural fluctuations.},
}
@article {pmid30407559,
year = {2019},
author = {Liu, B and Maekawa, T and Yoshida, K and Ly, NH and Inoue, K and Hasegawa, A and Chatton, B and Ogura, A and Ishii, S},
title = {Telomere shortening by transgenerational transmission of TNF-α-induced TERRA via ATF7.},
journal = {Nucleic acids research},
volume = {47},
number = {1},
pages = {283-298},
pmid = {30407559},
issn = {1362-4962},
mesh = {Activating Transcription Factors/*genetics ; Animals ; Chromatin/genetics ; DNA-Binding Proteins/*genetics ; Heterochromatin/genetics ; Humans ; Mice ; Phosphorylation ; Promoter Regions, Genetic ; Stress, Psychological ; Telomere/genetics ; Telomere Shortening/genetics ; Transcription Factors/*genetics ; *Transcription, Genetic ; Tumor Necrosis Factor-alpha/*genetics ; p38 Mitogen-Activated Protein Kinases/*genetics ; },
abstract = {Various stresses increase disease susceptibility and accelerate aging, and increasing evidence suggests that these effects can be transmitted over generation. Epidemiological studies suggest that stressors experienced by parents affect the longevity of their offspring, possibly by regulating telomere dynamics. Telomeres are elongated by telomerase and shortened by certain stresses as well as telomere repeat-containing RNA (TERRA), a telomere transcript. However, the mechanism underlying the transgenerational effects is poorly understood. Here, we show that TNF-α, which is induced by various psychological stresses, induces the p38-dependent phosphorylation of ATF7, a stress-responsive chromatin regulator, in mouse testicular germ cells. This caused a release of ATF7 from the TERRA gene promoter in the subtelomeric region, which disrupted heterochromatin and induced TERRA. TERRA was transgenerationally transmitted to zygotes via sperm and caused telomere shortening. These results suggest that ATF7 and TERRA play key roles in paternal stress-induced telomere shortening in the offspring.},
}
@article {pmid30405890,
year = {2018},
author = {Assani, G and Xiong, Y and Zhou, F and Zhou, Y},
title = {Effect of therapies-mediated modulation of telomere and/or telomerase on cancer cells radiosensitivity.},
journal = {Oncotarget},
volume = {9},
number = {79},
pages = {35008-35025},
pmid = {30405890},
issn = {1949-2553},
abstract = {Cancer is one of the leading causes of death in the world. Many strategies of cancer treatment such as radiotherapy which plays a key role in cancer treatment are developed and used nowadays. However, the side effects post-cancer radiotherapy and cancer radioresistance are two major causes of the limitation of cancer radiotherapy effectiveness in the cancer patients. Moreover, reduction of the limitation of cancer radiotherapy effectiveness by reducing the side effects post-cancer radiotherapy and cancer radioresistance is the aim of several radiotherapy-oncologic teams. Otherwise, Telomere and telomerase are two cells components which play an important role in cancer initiation, cancer progression and cancer therapy resistance such as radiotherapy resistance. For resolving the problems of the limitation of cancer radiotherapy effectiveness especially the cancer radio-resistance problems, the radio-gene-therapy strategy which is the use of gene-therapy via modulation of gene expression combined with radiotherapy was developed and used as a new strategy to treat the patients with cancer. In this review, we summarized the information concerning the implication of telomere and telomerase modulation in cancer radiosensitivity.},
}
@article {pmid30404996,
year = {2018},
author = {He, L and Chen, Z and Dai, B and Li, G and Zhu, G},
title = {Low-level lead exposure and cardiovascular disease: the roles of telomere shortening and lipid disturbance.},
journal = {The Journal of toxicological sciences},
volume = {43},
number = {11},
pages = {623-630},
doi = {10.2131/jts.43.623},
pmid = {30404996},
issn = {1880-3989},
mesh = {Cardiovascular Diseases/*etiology/genetics/metabolism ; Dose-Response Relationship, Drug ; Environmental Exposure/*adverse effects ; Humans ; Lead/*adverse effects ; Lipid Metabolism/drug effects ; Occupational Exposure/*adverse effects ; Telomere Shortening/*drug effects ; },
abstract = {Lead exposure contributing to cardiovascular diseases is known and recognized widely. As the deleterious effects of low lead exposure attained increasing attention over the last decades, there have been numerous studies exploring the association of low levels of lead exposure and cardiovascular diseases. Moreover, it has been observed that lead exposure could cause telomere shortening and lipid disturbance, and that telomere shortening and lipid disturbance are closely related with cardiovascular diseases. Hence, telomere shortening and lipid disturbance might play an important role in the pathophysiological process of chronic low levels of lead exposure contributing to cardiovascular diseases. This review is intended to explore views of the rarely mentioned mechanism, telomere shortening and lipid disturbance, and the cardiovascular effects of low levels of lead exposure.},
}
@article {pmid30400735,
year = {2019},
author = {Barnard, A and Moch, A and Saab, S},
title = {Relationship between Telomere Maintenance and Liver Disease.},
journal = {Gut and liver},
volume = {13},
number = {1},
pages = {11-15},
pmid = {30400735},
issn = {2005-1212},
mesh = {Hepatocytes/*physiology ; Humans ; Liver/cytology/pathology ; Liver Cirrhosis/*genetics/pathology ; Liver Diseases/*genetics/pathology ; Lymphocytes/*physiology ; Telomere/*physiology ; Telomere Shortening ; },
abstract = {Previous studies have established a correlation between increasing chronological age and risk of cirrhosis. This pattern raised interest in the role of telomeres and the telomerase complex in the pathogenesis of liver fibrosis and cirrhosis. This review aims to summarize and analyze the current understanding of telomere regulation in hepatocytes and lymphocytes and how this ultimately relates to the development of liver fibrosis. Notably, in chronic viral hepatitis, telomere shortening in hepatocytes and lymphocytes occurs in such a way that may promote further viral replication while also leading to liver damage. However, while telomere shortening occurs in both hepatocytes and lymphocytes and ultimately results in cellular death, the mechanisms of telomere loss appear to be initiated by independent processes. The understanding of telomere maintenance on a hepatic and immune system level in both viral and non-viral etiologies of cirrhosis may open doors to novel therapeutic strategies.},
}
@article {pmid30400186,
year = {2018},
author = {Oliveira, BS and Pirkle, CM and Zunzunegui, MV and Batistuzzo de Medeiros, SR and Thomasini, RL and Guerra, RO},
title = {Leukocyte Telomere Length and Chronic Conditions in Older Women of Northeast Brazil: A Cross-Sectional Study.},
journal = {Cells},
volume = {7},
number = {11},
pages = {},
pmid = {30400186},
issn = {2073-4409},
support = {U54 MD007584/MD/NIMHD NIH HHS/United States ; 480322/2012-0//National Council for Scientific and Technological Development/ ; },
abstract = {This study assessed whether telomere length is related to chronic conditions, cardiovascular risk factors, and inflammation in women aged 65 to 74 from Northeast Brazil. Participants were selected from two sources, a representative sample of the International Mobility in Aging Study (n = 57) and a convenience sample (n = 49) recruited at senior centers. Leukocyte telomere length was measured by quantitative polymerase chain reaction from blood samples in 83 women. Natural log-transformed telomere/single copy gene ratio was used as the dependent variable in the analysis. Blood analyses included inflammatory markers (high-sensitivity C-reactive protein and interleukin-6), total, low-density lipoprotein and high-density lipoprotein cholesterol, triglycerides, glucose and glycosylated hemoglobin. Self-rated health, chronic conditions, cardiovascular risk factors and inflammatory markers were not associated with telomere length. No significant independent association was found between telomere length and anthropometric measures or blood markers, even after adjusting for age, education and adverse childhood events among these older women in Northeast Brazil. Our results did not confirm the hypothesis that chronic conditions, cardiovascular risk factors or inflammation are associated with shorter telomere length in these women who have exceptional survival relative to the life expectancy of their birth cohort.},
}
@article {pmid30397981,
year = {2018},
author = {Ding, Y and Zhou, X and Wu, C and Li, Q and Sun, J and Niu, H and Lin, D and Sun, D and Xie, P and Wu, D and Zhao, J and He, P},
title = {Telomere length, ZNF208 genetic variants and risk of chronic obstructive pulmonary disease in the Hainan Li population.},
journal = {The journal of gene medicine},
volume = {20},
number = {12},
pages = {e3061},
doi = {10.1002/jgm.3061},
pmid = {30397981},
issn = {1521-2254},
mesh = {Adult ; Aged ; Asian People/genetics ; DNA-Binding Proteins ; Female ; Gene Frequency ; Genetic Predisposition to Disease/ethnology/*genetics ; Genotype ; Humans ; Kruppel-Like Transcription Factors/*genetics ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; Pulmonary Disease, Chronic Obstructive/ethnology/*genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Transcription Factors ; },
abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a disease characterized by airflow limitation. It is not completely reversible and shows progressive development. ZNF208 rs8105767 affects telomere length, although the impact of telomere on COPD is still controversial. In the present study, we aimed to explore the impact of the ZNF208 gene polymorphism on telomere length and also that of telomere length on COPD in the Hainan Li population.<br><br>METHODS: In total, 270 COPD patients and 288 controls were recruited. Telomere length was measured by a quantitative real-time polymerase chain reaction. Five single nucleotide polymorphisms in ZNF208 were selected and genotyping was performed using MassARRAY software (Agena Bioscience Co. Ltd, San Diego, CA, USA). Differences in telomere length among the subjects with three genotypes of related genes were assessed using analysis of variance. Unconditional logistic regression was used to calculate odds ratios (OR) as the indicator of association between telomere length and COPD risk.<br><br>RESULTS: Relative telomere length in the COPD group and control group was 0.66&#xa0;&#xb1;&#xa0;0.47 and 1.44&#xa0;&#xb1;&#xa0;0.89, respectively. We grouped according to a median of 0.8284 for telomere length and observed that the risk of COPD for individuals with a telomere length less than 0.8284 is 2.92 times that for individuals with a telomere length longer than 0.8284 (OR&#xa0;=&#xa0;2.92, 95% confidence interval&#xa0;=&#xa0;2.01-4.25, p&#xa0;=&#xa0;1.91&#xa0;&#xd7;&#xa0;10[-8]). Subjects carrying the G allele of rs2188972 had a longer telomere length. Subjects carrying the carrying the CA genotype of rs8103163 and AC genotype of rs7248488 had a longer telomere length compared to wild-type individuals.<br><br>CONCLUSIONS: Shorter telomeres increase COPD risk and the ZNF208 polymorphism affects telomere length in COPD patients.},
}
@article {pmid30396032,
year = {2019},
author = {Scarabino, D and Veneziano, L and Peconi, M and Frontali, M and Mantuano, E and Corbo, RM},
title = {Leukocyte telomere shortening in Huntington's disease.},
journal = {Journal of the neurological sciences},
volume = {396},
number = {},
pages = {25-29},
doi = {10.1016/j.jns.2018.10.024},
pmid = {30396032},
issn = {1878-5883},
mesh = {Adult ; Age Factors ; Aged ; Analysis of Variance ; Case-Control Studies ; Disease Progression ; Female ; Humans ; Huntingtin Protein/genetics ; Huntington Disease/*pathology ; Leukocytes/*physiology ; Male ; Middle Aged ; RNA, Messenger/metabolism ; Regression Analysis ; Telomere/*genetics ; Telomere Shortening/*physiology ; Trinucleotide Repeat Expansion/*genetics ; Young Adult ; },
abstract = {Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded CAG repeat. Though symptom onset commonly occurs at midlife and inversely correlates with the CAG repeat expansion, age at clinical onset and progression rate are variable. In the present study we investigated the relationship between leukocyte telomere length (LTL) and HD development. LTL was measured by real-time PCR in manifest HD patients (HD, n = 62), pre-manifest HD patients (pre-HD, n = 38), and age-matched controls (n = 76). Significant LTL differences were observed between the three groups (p < .0001), with LTL values in the order: HD < pre-HD < controls. The relationship between LTL and age was different in the three groups. An inverse relationship between mean LTL and CAG repeat number was found in the pre-HD (p = .03). The overall data seem to indicate that after age 30 years, LT begins to shorten markedly in pre-HD patients according to CAG number and increasing age, up to the values observed in HD. This very suggestive picture allowed us to hypothesize that in pre-manifest HD, LTL could be a measure of time to clinical HD onset. The possible use of LTL as a reliable biomarker to track HD development and progression was evaluated and discussed.},
}
@article {pmid30393615,
year = {2018},
author = {Goh, F and Yang, IA and Bowman, RV and Fong, KM},
title = {Subtype variation and actionability of telomere length abnormality in lung cancer.},
journal = {Translational lung cancer research},
volume = {7},
number = {Suppl 3},
pages = {S251-S253},
pmid = {30393615},
issn = {2218-6751},
}
@article {pmid30393241,
year = {2019},
author = {Sato, S and Imaichi, Y and Yoshiura, Y and Nakazawa, K and Takenaka, S},
title = {Synthesis of a Peptide-Human Telomere DNA Conjugate as a Fluorometric Imaging Reagent for Biological Sodium Ion.},
journal = {Analytical sciences : the international journal of the Japan Society for Analytical Chemistry},
volume = {35},
number = {1},
pages = {85-90},
doi = {10.2116/analsci.18SDP05},
pmid = {30393241},
issn = {1348-2246},
mesh = {*Biosensing Techniques ; Circular Dichroism ; DNA/*chemistry ; *Fluorescence Resonance Energy Transfer ; Fluorescent Dyes/*chemical synthesis/chemistry ; HeLa Cells ; Humans ; Nucleic Acid Conformation ; Peptides/*chemistry ; Sodium/*analysis ; *Telomere ; },
abstract = {A peptide-oligonucleotide conjugate (1) was synthesized by the attachment of FAM, TAMRA, and biotin moieties to a telomere DNA sequence of 5'-TAG GGT TAG GGT TAG GGT TAG GG-3'. This conjugate was induced to be an anti-parallel structure in the presence of sodium ion (Na[+]), whereas a hybrid one was formed under potassium ion (K[+]) as a monitoring by circular dichromic spectra. The conformation change of this conjugate gave an effective FRET signal change upon the addition of NaCl, compared with the case of KCl. Under 5 mM KCl as an extracellular condition, a FRET change was observed upon addition of NaCl and quantitative FRET change was observed in 0 - 250 mM NaCl. This conjugate was immobilized on the cell surface through a sugar chain on the cell, biotinyl concanavallin A and streptavidin. This conjugate was utilized for Na[+] sensing based on anti-parallel tetraplex formation with Na[+].},
}
@article {pmid30392550,
year = {2018},
author = {Mangaonkar, AA and Patnaik, MM},
title = {In Reply-Short Telomere Syndromes, Biological Aging, and Hematopoietic Stem Cell Transplantation.},
journal = {Mayo Clinic proceedings},
volume = {93},
number = {11},
pages = {1685-1687},
doi = {10.1016/j.mayocp.2018.08.012},
pmid = {30392550},
issn = {1942-5546},
mesh = {Growth Disorders ; *Hematopoietic Stem Cell Transplantation ; Humans ; Syndrome ; *Telomere ; Transplantation, Homologous ; },
}
@article {pmid30392549,
year = {2018},
author = {Testori, A},
title = {Short Telomere Syndromes, Biological Aging, and Hematopoietic Stem Cell Transplantation.},
journal = {Mayo Clinic proceedings},
volume = {93},
number = {11},
pages = {1684-1685},
doi = {10.1016/j.mayocp.2018.08.013},
pmid = {30392549},
issn = {1942-5546},
mesh = {*Hematopoietic Stem Cell Transplantation ; Humans ; Syndrome ; *Telomere ; Transplantation, Homologous ; Treatment Outcome ; },
}
@article {pmid30389168,
year = {2018},
author = {Roy, S and Roy, S and Rana, A and Akhter, Y and Hande, MP and Banerjee, B},
title = {The role of p38 MAPK pathway in p53 compromised state and telomere mediated DNA damage response.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {836},
number = {Pt A},
pages = {89-97},
doi = {10.1016/j.mrgentox.2018.05.018},
pmid = {30389168},
issn = {1879-3592},
mesh = {Animals ; *DNA Damage ; Humans ; *Signal Transduction ; *Telomere ; Tumor Suppressor Protein p53/genetics/*metabolism ; p38 Mitogen-Activated Protein Kinases/genetics/*metabolism ; },
abstract = {There is an intricate balance of DNA damage response and repair which determines the homeostasis of human genome function. p53 protein is widely known for its role in cell cycle regulation and tumor suppressor activity. In case of several cancers where function of p53 gene gets compromised either by mutation or partial inactivation, the role of p53 in response to DNA damage needs to be supplemented by another molecule or pathway. Due to sedentary lifestyle and exposure to genotoxic agents, genome is predisposed to chronic stress, which ultimately leads to unrepaired or background DNA damage. p38 MAPK signaling pathway is strongly activated in response to various environmental and cellular stresses. DNA damage response and the repair options have crucial links with chromosomal integrity. Telomere that regulates integrity of genome is protected by a six member shielding unit called shelterin complex which communicates with other pathways for functionality of telomeres. There are evidences that p38 gets activated through ATM in response to DNA damage. Dysfunctional telomere leads to activation of ATM which subsequently activates p38 suggesting a crosstalk between p38, ATM and shelterin complex. This review focuses on activation of p38 in response to genotoxic stress induced DNA damage in p53 mutated or compromised state and its possible cross talk with telomere shelterin proteins. Thus p38 may act as an important target to treat various diseases and in majority of cancers in p53 mutated state.},
}
@article {pmid30389167,
year = {2018},
author = {Chatterjee, D and Adak, S and Banerjee, N and Bhattacharjee, P and Bandyopadhyay, AK and Giri, AK},
title = {Evaluatıon of health effects, genetıc damage and telomere length ın children exposed to arsenic in West Bengal, İndia.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {836},
number = {Pt A},
pages = {82-88},
doi = {10.1016/j.mrgentox.2018.06.012},
pmid = {30389167},
issn = {1879-3592},
mesh = {Adolescent ; Arsenic/*adverse effects ; Child ; Child, Preschool ; DNA Damage/*drug effects ; Environmental Exposure/*adverse effects ; Female ; Humans ; India ; Lymphocytes/drug effects/*pathology ; Male ; Micronucleus Tests ; Mouth Mucosa/drug effects/*pathology ; Telomere Homeostasis/drug effects/*genetics ; },
abstract = {Increasing evidence of arsenic contamination in ground water and its associated adverse health outcomes affects millions of people worldwide. However, arsenic toxicity studies in children have gained impetus very recently due to the non-prominence of the hallmarks of arsenic toxicity i.e skin lesions. We recognized the need to evaluate the status of genetic damage brought about by early life exposure to arsenic in children as measured by micronucleus (MN) assay for three cell types namely buccal mucosa, urothelial cells and lymphocytes. A thorough health checkup and complete haematogram of the study participants was performed to measure overall health effects and changes in the blood profile in children exposed to arsenic through drinking water in West Bengal, India. Since telomere length alteration has been identified as a good indicator of arsenic toxicity in adults, we measured the telomere length of the arsenic exposed and unexposed children. We found that all the three cell types had significantly higher (P < 0.0001) MN frequency in the arsenic exposed children when compared to the unexposed. Blood profiling showed significantly altered neutrophil, eosinophil, lymphocyte and haemoglobin levels in the arsenic exposed children than their unexposed counterparts. Telomere length in the arsenic exposed children was slightly higher than the unexposed. This is a firsthand report of the genetic damage observed in children exposed to arsenic through drinking water in West Bengal, India.},
}
@article {pmid30388200,
year = {2020},
author = {Boccardi, V and Cari, L and Nocentini, G and Riccardi, C and Cecchetti, R and Ruggiero, C and Arosio, B and Paolisso, G and Herbig, U and Mecocci, P},
title = {Telomeres Increasingly Develop Aberrant Structures in Aging Humans.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {75},
number = {2},
pages = {230-235},
pmid = {30388200},
issn = {1758-535X},
support = {R01 CA136533/CA/NCI NIH HHS/United States ; R01 CA184572/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*pathology ; Female ; Healthy Volunteers ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes, Mononuclear ; Male ; Middle Aged ; Polymerase Chain Reaction ; Telomere/*pathology ; Telomere Shortening ; },
abstract = {Telomeres progressively shorten with age, and it has been proposed that critically short and dysfunctional telomeres contribute to aging and aging-associated diseases in humans. For many years it was thought that telomere erosion was strictly a consequence of the "end replication problem," or the inability of replicative polymerases to completely duplicate linear DNA ends. It is becoming increasingly evident, however, that telomere shortening of cultured human cells is also caused because of other replication defects in telomeric repeats, those that cause fragile telomeres and other aberrant telomeric structures that can be detected on metaphase chromosomes. Whether these replication defects contribute to telomere erosion also in human tissues is currently unknown. By analyzing peripheral blood mononuclear cells from a total of 35 healthy subjects ranging in age from 23 to 101 years, we demonstrated that telomeres increasingly display aberrant structures with advancing donor age. Although the percentages of fragile telomeres increased only until adulthood, the percentages of chromosomes displaying sister telomere loss and sister telomere chromatid fusions increased consistently throughout the entire human life span. Our data, therefore, suggest that telomeric replication defects other than the end replication problem contribute to aging-associated telomere erosion in humans.},
}
@article {pmid30387533,
year = {2019},
author = {Gil, D and Alfonso-Iñiguez, S and Pérez-Rodríguez, L and Muriel, J and Monclús, R},
title = {Harsh conditions during early development influence telomere length in an altricial passerine: Links with oxidative stress and corticosteroids.},
journal = {Journal of evolutionary biology},
volume = {32},
number = {1},
pages = {111-125},
doi = {10.1111/jeb.13396},
pmid = {30387533},
issn = {1420-9101},
mesh = {Animals ; Antioxidants/metabolism ; Corticosterone/*blood ; Female ; Longevity ; Male ; Oxidative Stress/*physiology ; *Starlings/growth &amp; development/physiology ; Stress, Physiological ; Telomere Shortening ; },
abstract = {Stress during early development can induce substantial long-term effects in organisms. In the case of birds, despite growth compensations, nestlings reared under harsh conditions typically show reduced survival chances in adulthood. It has been proposed that environmental early-life stressors could affect longevity via effects on telomere length, possibly mediated through oxidative stress. However, the link between these processes is not clear. In this study, we experimentally manipulated brood size in spotless starlings (Sturnus unicolor) to test the causal relationship between early stress, oxidative and corticosterone-mediated stress and telomere shortening. Our results show that experimentally enlarged brood sizes led to a reduction in morphometric development on nestlings, the effect being stronger for females than males. Additionally, basal corticosterone levels increased with increasing brood size in female nestlings. Neither plasma antioxidant status nor malondialdehyde levels (a marker of lipid peroxidation) were affected by experimental brood size, although the levels of a key intracellular antioxidant (glutathione) decreased with increasing brood size. We found that the treatment showed a quadratic effect on nestling telomere lengths: these were shortened either by increases or by decreases in the original brood size. Our study provides experimental evidence for a link between developmental stress and telomere length, but does not support a direct causal link of this reduction with corticosterone or oxidative stress. We suggest that future studies should focus on how telomere length responds to additional markers of allostatic load.},
}
@article {pmid30384145,
year = {2018},
author = {Shivakumar, V and Kalmady, SV and Rajasekaran, A and Chhabra, H and Anekal, AC and Narayanaswamy, JC and Ravi, V and Gangadhar, BN and Venkatasubramanian, G},
title = {Telomere length and its association with hippocampal gray matter volume in antipsychotic-naïve/free schizophrenia patients.},
journal = {Psychiatry research. Neuroimaging},
volume = {282},
number = {},
pages = {11-17},
doi = {10.1016/j.pscychresns.2018.10.002},
pmid = {30384145},
issn = {1872-7506},
mesh = {Adult ; *Antipsychotic Agents ; Cross-Sectional Studies ; Female ; Gray Matter/*diagnostic imaging/physiology ; Hippocampus/*diagnostic imaging/physiology ; Humans ; Male ; Organ Size ; Schizophrenia/blood/*diagnostic imaging ; Telomere/physiology ; *Telomere Homeostasis/physiology ; Telomere Shortening/physiology ; Young Adult ; },
abstract = {Accelerated ageing processes are postulated to underlie schizophrenia pathogenesis. This postulate is supported by observations of reduced telomere length in schizophrenia patients. Hippocampus, one of the most important brain regions implicated in schizophrenia, is shown to atrophy at a faster rate in aging. In this study, telomere length (TL) was measured in 30 antipsychotic-naive/free schizophrenia patients and 60 healthy controls using quantitative PCR assay. Hippocampus volume was measured using voxel-based morphometry. Schizophrenia was associated with differential TL between sexes [Status × Sex; F(1,85) = 5.9, p = 0.017, η[2] = 0.065]. Male schizophrenia patients had significantly lower relative TL than female patients [F(1,85) = 7.38, p = 0.008], while such sex difference was not observed in healthy controls [F(1,85) = 0.16, p = 0.69]. Schizophrenia patients showed a significant sex-by-telomere interaction with both right &amp; left hippocampus, with male patients showing positive association of telomere length with volume, while female patients showed negative association. Telomere shortening and the positive association of telomere length with hippocampus volume was observed only in male patients with schizophrenia. Since correlational observations in this cross-sectional study does not necessarily support definitive causal relationship, further longitudinal studies examining hippocampus volume and telomere in schizophrenia patients are needed.},
}
@article {pmid30384090,
year = {2018},
author = {Xavier, G and Spindola, LM and Ota, VK and Carvalho, CM and Maurya, PK and Tempaku, PF and Moretti, PN and Mazotti, DR and Sato, JR and Brietzke, E and Miguel, EC and Grassi-Oliveira, R and Mari, J and Bressan, RA and Gadelha, A and Pan, PM and Belangero, SI},
title = {Effect of male-specific childhood trauma on telomere length.},
journal = {Journal of psychiatric research},
volume = {107},
number = {},
pages = {104-109},
doi = {10.1016/j.jpsychires.2018.10.012},
pmid = {30384090},
issn = {1879-1379},
mesh = {Adolescent ; *Behavioral Symptoms/epidemiology ; Brazil/epidemiology ; Child ; *Child Abuse/statistics &amp; numerical data ; Cross-Sectional Studies ; Female ; Humans ; Male ; Sex Factors ; *Telomere ; *Telomere Shortening ; },
abstract = {Child maltreatment (CM) is a global issue with serious lifelong consequences. In fact, maltreatment during childhood might be an important risk factor for the development of psychiatric disorders. Furthermore, previous studies showed a strong relationship between telomere length (TL) and early life stress. Considering that only a few studies have evaluated this relationship in children and that even fewer considered the sex as a possible moderator, we investigated whether TL in the blood of both children and adolescents was associated with psychopathology and with a history of CM, and whether these associations were moderated by the sex. In this cross-sectional study, 561 individuals (ranging between 6 and 14 years of age) from a large prospective community school-based study, i.e., the Brazilian High-Risk Cohort (HRC), were evaluated. The Child Behavior Checklist (CBCL) score was used to assess psychopathology, whereas a latent variable encompassing some questions about history of adverse environment and trauma was employed to determine the CM history. TL was measured in blood cells using a multiplex quantitative polymerase chain reaction. Additionally, TL was inserted in two moderation models, in which the CBCL score/CM, TL and sex were the independent variables, the outcome, and the moderator variable, respectively. Although an association between psychiatric symptoms and TL was not observed, a relation between CM and TL moderated by the sex was seen, indicating that males with higher CM scores presented with shorter telomeres than did females. Our results suggest that child maltreatment could influence telomere length in both children and adolescents and that this effect is mediated by the sex.},
}
@article {pmid30384069,
year = {2019},
author = {Miri, M and Nazarzadeh, M and Alahabadi, A and Ehrampoush, MH and Rad, A and Lotfi, MH and Sheikhha, MH and Sakhvidi, MJZ and Nawrot, TS and Dadvand, P},
title = {Air pollution and telomere length in adults: A systematic review and meta-analysis of observational studies.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {244},
number = {},
pages = {636-647},
doi = {10.1016/j.envpol.2018.09.130},
pmid = {30384069},
issn = {1873-6424},
mesh = {Adult ; Air Pollutants/*analysis ; Air Pollution/*analysis ; Environmental Exposure/*adverse effects/analysis ; Female ; Humans ; Male ; Polycyclic Aromatic Hydrocarbons/analysis ; Prospective Studies ; Retrospective Studies ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; },
abstract = {Telomere length (TL) has been suggested to be a surrogate for cellular ageing, and a record of cumulative inflammation and oxidative stress over life. An emerging body of evidence has associated exposure to air pollution to changes in TL. To date there is no available systematic review of literature on this association. We aimed to systematically review and conduct meta-analysis of published studies on the relationship between air pollution and TL in adults. Electronic databases were systematically searched for available English language studies on the association between air pollution and TL published up to 1 July 2018. Meta-analyses were conducted following MOOSE guidelines. The heterogeneity in the reported associations was assessed using Cochran's Q test and quantified as I[2] index. Publication bias was assessed using Egger's regression. Our search identified 19 eligible studies including 11 retrospective and eight prospective studies of which, four had excellent quality, ten had good quality and five had fair quality. Meta-analysis result of two studies on long-term exposure to PM2.5 showed an inverse association between these exposures and TL (for 5 μg/m[3] PM2.5-0.03 95% CI; -0.05, -0.01). Meta-analysis of short-term exposure to PM2.5 with three studies and Polychlorinated Biphenyls (PCBs) with two studies revealed a direct association between these exposures and TL (0.03 95% CI; 0.02, 0.04 and 0.10 95% CI; 0.06, 0.15 respectively). No statistically significant relationship between exposure to PM10 and polycyclic aromatic hydrocarbons (PAHs) exposure and TL were observed. We observed suggestive evidence for associations between air pollution and TL with potentially different direction of associations for short- and long-term exposures.},
}
@article {pmid30383762,
year = {2018},
author = {Fletcher, JM},
title = {Spousal concordance in telomere length: New evidence from older adults in the US.},
journal = {PloS one},
volume = {13},
number = {11},
pages = {e0202388},
pmid = {30383762},
issn = {1932-6203},
support = {P30 AG017266/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; *Aging ; Cellular Senescence ; Educational Status ; Female ; Humans ; Male ; Marriage ; Spouses ; Telomere/*genetics ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Telomere length (TL) has been associated with a range of aging outcomes as well as mortality. Recent research has shown both high heritability (~70%) of TL as well as moderate spousal similarity (r~0.3) using European datasets. This paper explores the level of spousal concordance in telomere length in the Health and Retirement Study, a national sample of adults in the US. The results show that the spousal correlations are lower (r~0.11). Regression-based associations in TL in the US are low (beta~0.08) and also vary by the number of times respondents have been married, where spouses married a single time have higher associations in TL (beta~.12) than spouses married more once (beta~0.03). I also find variation in spousal TL association levels based on husband's education level. These findings suggest the possibility of both assortative mating patterns related to telomere length as well as likelihood of shared environmental factors that cause TL similarity in people who are socially connected.},
}
@article {pmid30377209,
year = {2019},
author = {Gramatges, MM and Morton, LM and Yasui, Y and Arnold, MA and Neglia, JP and Leisenring, WM and Machiela, MJ and Dagnall, CL and Chanock, SJ and Armstrong, GT and Robison, LL and Bhatia, S and Lupo, PJ},
title = {Telomere Length-Associated Genetic Variants and the Risk of Thyroid Cancer in Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study (CCSS).},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {28},
number = {2},
pages = {417-419},
pmid = {30377209},
issn = {1538-7755},
support = {L40 CA153043/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; R01 CA194473/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; },
mesh = {*Cancer Survivors ; Female ; *Genetic Predisposition to Disease ; Humans ; Leukocytes/metabolism ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; Telomere Homeostasis/*genetics ; Thyroid Neoplasms/*epidemiology/*genetics ; },
abstract = {BACKGROUND: Given the inverse relationship described previously between telomere content and thyroid subsequent malignant neoplasm (thyroid SMN) in survivors of childhood cancer, we investigated the relationship between known genetic determinants of leukocyte telomere length (LTL) and thyroid SMN among survivors.<br><br>METHODS: Leveraging data from a large, genotyped survivor cohort, the Childhood Cancer Survivor Study, we used a well-described genetic risk score method to estimate the HR for thyroid SMN among 5,324 genotyped survivors.<br><br>RESULTS: We identified 118 survivors with thyroid SMN and 5,206 without thyroid SMN. No association between genetically estimated LTL and risk for thyroid SMN was identified.<br><br>CONCLUSIONS: Our results suggest that variation in common SNPs influencing LTL is not strongly associated with risk for thyroid SMN in survivors of childhood cancer.<br><br>IMPACT: The previously observed inverse relationship between LTL and thyroid SMN risk in survivors of childhood cancer may be related to alternative molecular mechanisms and warrants further study.},
}
@article {pmid30375983,
year = {2018},
author = {Yuan, X and Kronström, M and Hellenius, ML and Cederholm, T and Xu, D and Sjögren, P},
title = {Longitudinal changes in leukocyte telomere length and mortality in elderly Swedish men.},
journal = {Aging},
volume = {10},
number = {10},
pages = {3005-3016},
pmid = {30375983},
issn = {1945-4589},
mesh = {Age Factors ; Aged ; Aged, 80 and over ; Aging/*genetics ; Cardiovascular Diseases/genetics/*mortality/pathology ; Cause of Death ; Humans ; *Leukocytes ; Longitudinal Studies ; Male ; Neoplasms/genetics/*mortality/pathology ; Risk Assessment ; Risk Factors ; Sex Factors ; Sweden/epidemiology ; *Telomere ; *Telomere Shortening ; Time Factors ; },
abstract = {Telomere length (TL) is considered an indicator of aging and age-related diseases, but longitudinal studies on TL changes and mortality are few. We therefore analyzed TL and longitudinal changes in TL in relation to all-cause, cardiovascular, and cancer mortality in 247 elderly Swedish men. TL was determined by the qPCR method at ages 71 and 81 and subsequent mortality cases were identified from the Swedish cause-of-death registry. Cox proportional hazard ratios were calculated during a mean follow-up of 7.4 years, during which 178 deaths occurred. Short telomeres at baseline was strongly associated with mortality risks, with a 40 to 70% increased risk of all-cause mortality, and a 2-fold increased risk of cancer mortality. Longitudinal changes in TL revealed shortening in 83% of individuals, whilst 10% extended their telomeres. TL attrition did not predict all-cause or cancer mortality, but we found a 60% decreased risk for cardiovascular mortality in those who shortened their telomeres. Our data show an increased risk of mortality in individuals with short baseline telomeres, but no relations to all-cause, and cancer mortality for changes in TL. Intriguingly, our data indicate lower risk of cardiovascular mortality with shortening of telomeres. The latter should be interpreted cautiously.},
}
@article {pmid30371905,
year = {2019},
author = {Schöttker, B and Hagen, L and Zhang, Y and Gào, X and Holleczek, B and Gao, X and Brenner, H},
title = {Serum 25-Hydroxyvitamin D Levels as an Aging Marker: Strong Associations With Age and All-Cause Mortality Independent From Telomere Length, Epigenetic Age Acceleration, and 8-Isoprostane Levels.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {74},
number = {1},
pages = {121-128},
doi = {10.1093/gerona/gly253},
pmid = {30371905},
issn = {1758-535X},
mesh = {Aged ; Aging/*blood ; Biomarkers/blood ; Cause of Death/trends ; Dinoprost/*analogs &amp; derivatives/blood ; Epigenesis, Genetic/*genetics ; Epigenomics/*methods ; Female ; Follow-Up Studies ; Germany/epidemiology ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Telomere/*metabolism ; Vitamin D/*analogs &amp; derivatives/blood ; Vitamin D Deficiency/*blood/genetics/mortality ; },
abstract = {BACKGROUND: A strong association of serum 25-hydroxyvitamin-D levels (25(OH)D) with all-cause mortality has been shown previously and 25(OH)D could be a useful aging marker.<br><br>METHODS: The analysis was performed in a population-based, cohort study from Germany with 9,940 participants, aged 50-74 years at baseline. A general linear model was used to assess associations of 25(OH)D levels with chronological age and the aging markers leukocyte telomere length (LTL), epigenetic age acceleration, and 8-isoprostane levels. A multivariate Cox regression model was applied to explore the independent and combined associations of these biomarkers with all-cause mortality (2,204 deaths occurred during a median follow-up of 14.3 years).<br><br>RESULTS: On average, study participants lost 2.9 nmol/L 25(OH)D each 10 years of age. Increasing 25(OH)D levels were significantly associated with decreasing levels of 8-isoprostane levels but neither with LTL nor epigenetic age acceleration. The association of 25(OH)D quartiles with mortality was almost unchanged after adjusting for all aging markers (1.6-fold increased mortality in bottom quartile compared with top quartile). All aging markers were independent mortality predictors and subjects with unfavorable values for 4, 3, 2, and 1 aging marker(s) had 4.3-, 2.9-, 2.2, and 1.4-fold increased mortality, respectively.<br><br>CONCLUSIONS: The 25(OH)D level can be regarded as an aging marker because it is linearly associated with age and an independent mortality predictor. Mechanisms linking vitamin D to healthy aging are unique and can neither be fully explained by aging of the epigenome, loss of telomeres, or antioxidative effects of vitamin D metabolites.},
}
@article {pmid30371886,
year = {2019},
author = {Deng, T and Huang, Y and Weng, K and Lin, S and Li, Y and Shi, G and Chen, Y and Huang, J and Liu, D and Ma, W and Songyang, Z},
title = {TOE1 acts as a 3' exonuclease for telomerase RNA and regulates telomere maintenance.},
journal = {Nucleic acids research},
volume = {47},
number = {1},
pages = {391-405},
pmid = {30371886},
issn = {1362-4962},
mesh = {Cerebellar Diseases/*genetics/pathology ; Exonucleases/genetics ; Exoribonucleases/genetics ; HeLa Cells ; Humans ; Mutation ; Nuclear Proteins/*genetics ; RNA/genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {In human cells, telomeres are elongated by the telomerase complex that contains the reverse transcriptase hTERT and RNA template TERC/hTR. Poly(A)-specific ribonuclease (PARN) is known to trim hTR precursors by removing poly(A) tails. However, the precise mechanism of hTR 3' maturation remains largely unknown. Target of Egr1 (TOE1) is an Asp-Glu-Asp-Asp (DEDD) domain containing deadenylase that is mutated in the human disease Pontocerebella Hypoplasia Type 7 (PCH7) and implicated in snRNA and hTR processing. We have previously found TOE1 to localize specifically in Cajal bodies, where telomerase RNP complex assembly takes place. In this study, we showed that TOE1 could interact with hTR and the telomerase complex. TOE1-deficient cells accumulated hTR precursors, including oligoadenylated and 3'-extended forms, which was accompanied by impaired telomerase activity and shortened telomeres. Telomerase activity in TOE1-deficient cells could be rescued by wild-type TOE1 but not the catalytically inactive mutant. Our results suggest that hTR 3' end processing likely involves multiple exonucleases that work in parallel and/or sequentially, where TOE1 may function non-redundantly as a 3'-to-5' exonuclease in conjunction with PARN. Our study highlights a mechanistic link between TOE1 mutation, improper hTR processing and telomere dysfunction in diseases such as PCH7.},
}
@article {pmid30368957,
year = {2018},
author = {Olsson, M and Friesen, CR and Rollings, N and Sudyka, J and Lindsay, W and Whittington, CM and Wilson, M},
title = {Long-term effects of superoxide and DNA repair on lizard telomeres.},
journal = {Molecular ecology},
volume = {27},
number = {24},
pages = {5154-5164},
doi = {10.1111/mec.14913},
pmid = {30368957},
issn = {1365-294X},
support = {//Swedish Science Council/International ; //Australian Research Council/International ; },
mesh = {Animals ; Australia ; DNA Damage ; *DNA Repair ; Female ; In Situ Hybridization, Fluorescence ; Lizards/*genetics ; Male ; Mitochondria/genetics ; Oxidative Stress ; *Seasons ; Superoxides/*chemistry ; Telomere/*genetics ; Telomere Shortening ; },
abstract = {Telomeres are the non-coding protein-nucleotide "caps" at chromosome ends that contribute to chromosomal stability by protecting the coding parts of the linear DNA from shortening at cell division, and from erosion by reactive molecules. Recently, there has been some controversy between molecular and cell biologists, on the one hand, and evolutionary ecologists on the other, regarding whether reactive molecules erode telomeres during oxidative stress. Many studies of biochemistry and medicine have verified these relationships in cell culture, but other researchers have failed to find such effects in free-living vertebrates. Here, we use a novel approach to measure free radicals (superoxide), mitochondrial "content" (a combined measure of mitochondrial number and size in cells), telomere length and DNA damage at two primary time points during the mating season of an annual lizard species (Ctenophorus pictus). Superoxide levels early in the mating season vary widely and elevated levels predict shorter telomeres both at that time as well as several months later. These effects are likely driven by mitochondrial content, which significantly impacts late season superoxide (cells with more mitochondria have more superoxide), but superoxide effects on telomeres are counteracted by DNA repair as revealed by 8-hydroxy-2'-deoxyguanosine assays. We conclude that reactive oxygen species and DNA repair are fundamental for both short- and long-term regulation of lizard telomere length with pronounced effects of early season cellular stress detectable on telomere length near lizard death.},
}
@article {pmid30368702,
year = {2018},
author = {Sanei, B and Zavar Reza, J and Momtaz, M and Azimi, M and Zare Sakhvidi, MJ},
title = {Occupational exposure to particulate matters and telomere length.},
journal = {Environmental science and pollution research international},
volume = {25},
number = {36},
pages = {36298-36305},
pmid = {30368702},
issn = {1614-7499},
mesh = {Adult ; Air Pollutants, Occupational/adverse effects/*analysis ; Dust/*analysis ; Humans ; Inhalation Exposure/analysis ; Leukocytes ; Male ; Occupational Exposure/adverse effects/*analysis ; Particulate Matter/adverse effects/*analysis ; Prospective Studies ; Risk Factors ; Telomere/*drug effects ; Telomere Homeostasis/drug effects ; },
abstract = {Little is known about the possible association between occupational exposure to mineral particulate matters and change in leukocyte telomere length (LTL) as a hallmark of aging. The present study studied the relationship between occupational exposures to mineral dust and LTL in the exposed group of workers and compared to non-exposed workers. One hundred and ten male workers (80 exposed and 30 non-exposed) from different units of a ceramic factory were recruited in the study. Personal air samples were collected in the breathing zone of the workers for inhalable and respirable fractions. Relative LTL was measured in blood genomic DNA using the quantitative real-time PCR method and expressed as telomere/single copy gene ratio. Exposure to inhalable and respirable dusts in the exposed group was 22.66 ± 52.38 and 2.54 ± 9.34 mg/m[3] respectively. Inhalable and respirable exposure values were highly correlated (r[2] = 0.43; p < 0.001). Exposure to respirable and inhalable particles in 38.75% and 8.75% of exposed workers was higher than threshold limit value respectively. Mean LTL in the exposed workers (0.64 ± 0.06) was significantly shorter than the non-exposed workers (0.73 ± 0.07) (p < 0.001). Despite the significant difference in exposure intensity according to working units in the exposed group, there was no significant difference in LTL according to the working units (p = 0.60). In the adjusted regression models, but not crude models, marginally significant and positive association was found between both size fractions and LTL. The observed effect size for respirable particles was five times of that found for the inhalable fraction (beta 0.005 and 0.001 respectively). Mineral dust-and not only traffic-related air pollutant exposure-could be regarded as a risk factor in the process of cell aging. Our findings imply that early biological aging, as reflected in telomere shortening, may mediate the effects of occupational air pollution exposure on human health.},
}
@article {pmid30365552,
year = {2018},
author = {Parolini, M and Possenti, CD and Romano, A and Caprioli, M and Rubolini, D and Saino, N},
title = {Physiological increase of yolk testosterone level does not affect oxidative status and telomere length in gull hatchlings.},
journal = {PloS one},
volume = {13},
number = {10},
pages = {e0206503},
pmid = {30365552},
issn = {1932-6203},
mesh = {Androgens/metabolism ; Animals ; Antioxidants/metabolism ; Charadriiformes/*metabolism/*physiology ; Egg Yolk/*metabolism ; Embryo, Nonmammalian/metabolism ; Longevity/physiology ; Oxidation-Reduction ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; Telomere/metabolism ; Testosterone/*metabolism ; },
abstract = {Conditions experienced during early-life can cause the onset of oxidative stress, resulting in pervasive effects on diverse life-history traits, including lifespan. In birds, maternally-transferred egg substances may exert positive or negative influence over the offspring phenotype. Among these, testosterone can upregulate the bioavailability of certain antioxidants but simultaneously promotes the production of pro-oxidants, leading to an oxidative stress situation, which is one of the main forces causing telomere attrition However, no study has investigated the role of this androgen on telomere dynamics in birds and little is known about the effects of yolk testosterone on oxidative status in early-life of these species. We physiologically increased the levels of yolk testosterone by in ovo injections in yellow-legged gull (Larus michahellis) to evaluate the effects induced by this androgen on hatchlings plasma total antioxidant capacity, amount of pro-oxidant molecules and telomere length at hatching. Testosterone supplementation did not increase hatchling body growth, did not result in the overproduction of pro-oxidant molecules nor a reduction of antioxidant capacity. Accordingly, telomere length at hatching was not affected by testosterone treatment, although hatchlings from the third-laid eggs showed shorter telomeres than their siblings from first- and second-laid eggs, independently of testosterone treatment. Our results suggest that injection of physiological levels of testosterone does not induce oxidative stress to hatchlings and, consequently do not affect telomere dynamics during early post-natal periods.},
}
@article {pmid30355447,
year = {2018},
author = {Ivanyi-Nagy, R and Ahmed, SM and Peter, S and Ramani, PD and Ong, PF and Dreesen, O and Dröge, P},
title = {The RNA interactome of human telomerase RNA reveals a coding-independent role for a histone mRNA in telomere homeostasis.},
journal = {eLife},
volume = {7},
number = {},
pages = {},
pmid = {30355447},
issn = {2050-084X},
mesh = {Cell Line ; Histones/*genetics ; Humans ; RNA/*metabolism ; RNA, Messenger/*metabolism ; Telomerase/*metabolism ; *Telomere Homeostasis ; },
abstract = {Telomerase RNA (TR) provides the template for DNA repeat synthesis at telomeres and is essential for genome stability in continuously dividing cells. We mapped the RNA interactome of human TR (hTR) and identified a set of non-coding and coding hTR-interacting RNAs, including the histone 1C mRNA (HIST1H1C). Disruption of the hTR-HIST1H1C RNA association resulted in markedly increased telomere elongation without affecting telomerase enzymatic activity. Conversely, over-expression of HIST1H1C led to telomere attrition. By using a combination of mutations to disentangle the effects of histone 1 RNA synthesis, protein expression, and hTR interaction, we show that HIST1H1C RNA negatively regulates telomere length independently of its protein coding potential. Taken together, our data provide important insights into a surprisingly complex hTR-RNA interaction network and define an unexpected non-coding RNA role for HIST1H1C in regulating telomere length homeostasis, thus offering a glimpse into the mostly uncharted, vast space of non-canonical messenger RNA functions.},
}
@article {pmid30355079,
year = {2018},
author = {Martínez, P and Blasco, MA},
title = {Heart-Breaking Telomeres.},
journal = {Circulation research},
volume = {123},
number = {7},
pages = {787-802},
doi = {10.1161/CIRCRESAHA.118.312202},
pmid = {30355079},
issn = {1524-4571},
mesh = {Age Factors ; Aging/*genetics/metabolism/pathology ; Animals ; Cardiovascular Diseases/*genetics/metabolism/pathology/physiopathology ; *Cardiovascular System/metabolism/pathology/physiopathology ; Genetic Predisposition to Disease ; Humans ; Phenotype ; Risk Factors ; Telomere/*genetics/metabolism ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Telomeres, the protective ends of linear chromosomes, shorten throughout an individual's lifetime. Accumulation of critically short telomeres is proposed to be a primary molecular cause of aging and age-associated diseases. Mutations in telomere maintenance genes are associated with pathologies referred to as or telomeropathies. The rate of telomere shortening throughout life is determined by endogenous (genetic) and external (nongenetic) factors. Therapeutic strategies based on telomerase activation are being developed to treat and prevent telomere-associated diseases, namely aging-related diseases and telomeropathies. Here, we review the molecular mechanisms underlying telomere driven diseases with particular emphasis on cardiovascular diseases.},
}
@article {pmid30353495,
year = {2019},
author = {Maeda, T and Horiuchi, T and Makino, N},
title = {Shorter somatic telomere can be an increased risk for hospitalization.},
journal = {Molecular and cellular biochemistry},
volume = {455},
number = {1-2},
pages = {1-5},
pmid = {30353495},
issn = {1573-4919},
support = {15K08919//Grant-in-Aid from the Ministry of Education, Science, and Culture of Japan/ ; },
mesh = {Aged ; Aged, 80 and over ; Anemia/*blood/pathology ; Blood Glucose/metabolism ; Blood Proteins/metabolism ; Chronic Disease ; Creatinine/blood ; Erythrocyte Count ; Female ; Hospitalization ; Humans ; Male ; Middle Aged ; *Nutritional Status ; *Sex Characteristics ; Telomere/*metabolism/pathology ; Urea/blood ; },
abstract = {Somatic telomere DNA length is known to shorten with certain disease states and senescence. Furthermore, we have reported that the telomere length of a sub-healthy population also correlates with the blood data of laboratory tests. These facts suggest that patients with shorter telomere length tend to be hospitalized more easily than patients with longer telomere length. And such hospitalization tendencies can also be reflected in differences in clinical laboratory data. To address this issue, we evaluated and compared the telomere length and clinical laboratory data of outpatients and inpatients. In this study, 35 inpatients with chronic illness and 38 outpatients with one or more weeks without hospitalization experience were enrolled. Telomere length was shorter in hospitalized patients than outpatients. Inpatients and outpatients showed significant differences in some laboratory test results. Male outpatients showed higher values of fast blood sugar, HbA1c, blood urea nitrogen, creatinine, C-reactive protein, red blood cell count, and hemoglobin. Among female outpatients, the values of aspartate aminotransferase, alanine aminotransferase, albumin, creatine kinase, red blood cell count and hemoglobin were high. Of these, only albumin levels showed a positive correlation with telomere length in both sexes. Unexpectedly, all the other clinical data distinguishing outpatients and inpatients showed no significant association with telomere length. These items appeared to be related to hospital risk independently of TL. Having a shorter somatic telomere length appeared to be at a higher risk of hospitalization. This risk can be augmented by further complications such as deterioration of nutritional status and anemia. Maintaining sufficiently high nutritional status and erythropoietic potential may lead to avoidance of clinical events that require hospitalization.},
}
@article {pmid30352968,
year = {2018},
author = {Wang, Y and Savage, SA and Alsaggaf, R and Aubert, G and Dagnall, CL and Spellman, SR and Lee, SJ and Hicks, B and Jones, K and Katki, HA and Gadalla, SM},
title = {Telomere Length Calibration from qPCR Measurement: Limitations of Current Method.},
journal = {Cells},
volume = {7},
number = {11},
pages = {},
pmid = {30352968},
issn = {2073-4409},
support = {The Intramural Research Program of the Division of Cancer Epidemiology and Genetics//National Cancer Institute, National Institutes of Health/ ; 5U24CA076518//National Cancer Institute, National Heart, Lung and Blood Institute and National Institute of Allergy and Infectious Diseases/ ; 4U10HL069294//National Heart, Lung and Blood Institute and National Cancer Institute/ ; HHSH250201200018C//Health Resources and Services Administration (HRSA/DHHS)/ ; N00014-17-1-2388//The Office of Naval Research/ ; N0014-17-1-2850//The Office of Naval Research/ ; },
abstract = {Telomere length (TL) comparisons from different methods are challenging due to differences in laboratory techniques and data configuration. This study aimed to assess the validity of converting the quantitative polymerase chain reaction (qPCR) telomere/single copy gene (T/S) ratio to TL in kilobases (kb). We developed a linear regression equation to predict TL from qPCR T/S using flow cytometry with fluorescence in situ hybridization (flow FISH) TL data from 181 healthy donors (age range = 19[-]53) from the National Marrow Donor Program (NMDP) biorepository. TL measurements by qPCR and flow FISH were modestly correlated (R[2] = 0.56, p < 0.0001). In Bland-Altman analyses, individuals with the shortest (≤10th percentile) or longest (≥90th) flow FISH TL had an over- or under-estimated qPCR TL (bias = 0.89 and -0.77 kb, respectively). Comparisons of calculated TL from the NMDP samples and 1810 age- and sex-matched individuals from the National Health and Nutrition Examination Survey showed significant differences (median = 7.1 versus 5.8 kb, respectively, p < 0.0001). Differences in annual TL attrition were also noted (31 versus 13 bp/year, respectively, p = 0.02). Our results demonstrate that TL calculated in kb from qPCR T/S may yield biased estimates for individuals with the shortest or longest TL, those often of high clinical interest. We also showed that calculated TL in kb from qPCR data are not comparable across populations and therefore are not necessarily useful.},
}
@article {pmid30352410,
year = {2018},
author = {Athanasoulia-Kaspar, AP and Auer, MK and Stalla, GK and Jakovcevski, M},
title = {Shorter telomeres associated with high doses of glucocorticoids: the link to increased mortality?.},
journal = {Endocrine connections},
volume = {7},
number = {11},
pages = {1217-1226},
pmid = {30352410},
issn = {2049-3614},
abstract = {OBJECTIVE: Patients with non-functioning pituitary adenomas exhibit high morbidity and mortality rates. Growth hormone deficiency and high doses of glucocorticoid substitution therapy have been identified as corresponding risk factors. Interestingly, high levels of endogenous cortisol in, e.g., patients with post-traumatic stress disorder or patients with Cushing's disease have been linked to shorter telomere length. Telomeres are noncoding DNA regions located at the end of chromosomes consisting of repetitive DNA sequences which shorten with ageing and hereby determine cell survival. Therefore, telomere length can serve as a predictor for the onset of disease and mortality in some endocrine disorders (e.g., Cushing's disease).<br><br>DESIGN/METHODS: We examine telomere length from blood in patients (n = 115) with non-functioning pituitary adenomas (NFPA) in a cross-sectional case control (n = 106, age-, gender- matched) study using qPCR. Linear regression models were used to identify independent predictors of telomere length.<br><br>RESULTS: We show that patients with NFPA exhibited shorter telomeres than controls. No significant association of indices of growth hormone deficiency (IGF-1-level-SDS, years of unsubstituted growth hormone deficiency etc.) with telomere length was detected. Interestingly, linear regression analysis showed that hydrocortisone replacement dosage in patients with adrenal insufficiency (n = 52) was a significant predictor for shorter telomere length (&#x3b2; = 0.377; p = 0.018) independent of potential confounders. Median split analysis revealed that higher hydrocortisone intake (> 20 mg) was associated with significantly shorter telomeres.<br><br>CONCLUSION: These observations strengthen the importance of adjusted glucocorticoid treatment in NFPA patients with respect to morbidity and mortality rates.},
}
@article {pmid30345460,
year = {2018},
author = {Gao, D and Zhang, R and Ji, G and Li, C and Guo, D and Jin, T and Chen, M},
title = {Relative Telomere Length and Stroke Risk in a Chinese Han Population.},
journal = {Journal of molecular neuroscience : MN},
volume = {66},
number = {4},
pages = {475-481},
pmid = {30345460},
issn = {1559-1166},
support = {201002011//Special Foundation for Public Health of Ministry of Health of China/ ; },
mesh = {Aged ; China ; DNA Helicases/genetics ; Female ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Stroke/*genetics ; Telomere/genetics ; *Telomere Homeostasis ; },
abstract = {This study aimed to further understand the role of relative telomere length (RTL) in susceptibility to stroke and investigate the association regulator of telomere elongation helicase 1 (RETL1) gene polymorphisms and RTL. RTL was measured using the real-time quantitative polymerase chain reaction (qPCR) from 300 stroke patients and 299 healthy controls. Genotyping was performed using the Sequenom MassARRAY platform. The results indicated that stroke patients had significantly shorter median RTL than controls (P < 0.001). Compared with the longer RTL (≥ 0.766), the shorter RTL (< 0.766) was significantly increased the risk of stroke (odds ratio [OR] = 8.44, 95% confidence interval [CI] 5.42-13.14, P < 0.001). The RTL was categorized into tertiles, we found that the shorter RTL (0.515-1.366) (OR = 16.27, 95% CI 7.72-34.29, P < 0.001) and lowest RTL (< 0.515) (OR = 30.63, 95% CI 14.27-65.75, P < 0.001) were significantly increased stroke risk compared with the highest RTL (> 1.366). Stratified analysis showed that the shorter RTL was also significantly increased the risk of stroke compared with the longer RTL in male, age < 60 years and ≥ 60 years, except the female participants. In addition, individuals with the genotypes AA (rs2297441) and GG (rs6089953) have shorter telomeres than the genotypes GG (P = 0.031) and AA (P = 0.032), respectively. Our results suggested that shorter RTL was associated with an increased risk of stroke. The association was found between the genotypes AA (rs2297441) and GG (rs6089953) and shorter RTL in case group. Further studies in larger sample size and biological functional assays are warranted to validate our findings.},
}
@article {pmid30343983,
year = {2019},
author = {Lin, J and Smith, DL and Esteves, K and Drury, S},
title = {Telomere length measurement by qPCR - Summary of critical factors and recommendations for assay design.},
journal = {Psychoneuroendocrinology},
volume = {99},
number = {},
pages = {271-278},
pmid = {30343983},
issn = {1873-3360},
support = {R01 HL128156/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; Real-Time Polymerase Chain Reaction/*methods/standards ; Reference Standards ; Reproducibility of Results ; Specimen Handling/*methods/standards ; Telomere/physiology ; Telomere Homeostasis/genetics/*physiology ; },
abstract = {Research in the last decade has explored the length of telomeres, the protective ends of eukaryotic chromosomes, as a biomarker for the cumulative effects of environmental exposures and life experiences as well as a risk factor for major diseases. With a growing interest in telomere biology across biomedical, epidemiological and public health research, it is critical to ensure that the measurement of telomere length is performed with high precision and accuracy. Of the several major methods utilized to determine telomere length, quantitative PCR (qPCR) remains the most cost-effective and suitable method for large-scale epidemiological and population studies. However, inconsistencies in recent reports utilizing the qPCR method highlight the need for a careful methodological analysis of each step of this process. In this review, we summarize each critical step in qPCR telomere length assay, including sample type selection, sample collection, storage, processing issues and assay procedures. We provide guidance and recommendations for each step based on current knowledge. It is clear that a collaborative and rigorous effort is needed to characterize and resolve existing issues related to sample storage, both before and after DNA extraction, as well as the impact of different extraction protocols, reagents and post extraction processing across all tissue types (e.g. blood, saliva, buccal swabs, etc.) to provide the needed data upon which best practices for TL analyses can be agreed upon. Additionally, we suggest that the whole telomere research community be invited to collaborate on the development and implementation of standardized protocols for the assay itself as well as for reporting in scientific journals. The existing evidence provides substantial support for the continuation of telomere research across a range of different exposures and health outcomes. However, as with any technological or methodologic advance in science, reproducibility, reliability and rigor need to be established to ensure the highest quality research.},
}
@article {pmid30341510,
year = {2018},
author = {Cao, DW and Jiang, CM and Wan, C and Zhang, M and Zhang, QY and Zhao, M and Yang, B and Zhu, DL and Han, X},
title = {Upregulation of MiR-126 Delays the Senescence of Human Glomerular Mesangial Cells Induced by High Glucose via Telomere-p53-p21-Rb Signaling Pathway.},
journal = {Current medical science},
volume = {38},
number = {5},
pages = {758-764},
pmid = {30341510},
issn = {2523-899X},
mesh = {Cellular Senescence/*genetics ; Cyclin-Dependent Kinase Inhibitor p21/genetics ; Diabetic Nephropathies/blood/*genetics/pathology ; Flow Cytometry ; Gene Expression Regulation ; Glucose/metabolism ; Humans ; Mesangial Cells/*metabolism/pathology ; MicroRNAs/blood/*genetics ; Retinoblastoma Protein/genetics ; STAT1 Transcription Factor/genetics ; STAT3 Transcription Factor/genetics ; Telomere/genetics ; Tumor Suppressor Protein p53/*genetics ; },
abstract = {Diabetic kidney disease (DKD) is a microvascular complication of type 2 diabetes. The study of DKD mechanisms is the most important target for the prevention of DKD. Renal senescence is one of the important pathogeneses for DKD, but the mechanism of renal and cellular senescence is unclear. Decreased expression of circulating miR-126 is associated with the development of DKD and may be a promising blood-based biomarker for DKD. This study is to probe the effect and mechanism of miR-126 on the aging of human glomerular mesangial cells (HGMCs) induced by high glucose. HGMCs were cultured with Roswell Park Memorial Institute (RPMI-1640) in vitro. The effect of high glucose on morphology of HGMCs was observed 72 h after intervention. The cell cycle was examined by flow cytometry. The telomere length was measured by Southern blotting. The expression levels of p53, p21 and Rb proteins in p53-p21-Rb signaling pathway and p-stat1, p-stat3 in JAK/STAT signaling pathway were detected by Western blotting respectively. The expression of miR-126 was examined by qRT-PCR. MiR-126 mimics was transfected into HGMCs. The effects of miR-126 mimics transfection on cell morphology, cell cycle, telomere length, p53, p21, Rb, p-stat1 and p-stat3 were observed. The results showed that high glucose not only arrested the cell cycle in G1 phase but also shortened the telomere length. High glucose led to high expression of p53, p21, Rb, p-stat1 and p-stat3 and premature senescence of HGMCs by activating the telomere-p53-p21-Rb and JAK/STAT signaling pathways. Moreover, the miR-126 was decreased in HGMCs induced by high glucose. It was suggested that the transfection of miR-126 mimics could inhibit the telomere-p53-p21-Rb and JAK/STAT signaling pathway activity in vitro and delay the senescence of HGMCs. The results may serve as a new strategy for the treatment of DKD.},
}
@article {pmid30340343,
year = {2018},
author = {Solana, C and Pereira, D and Tarazona, R},
title = {Early Senescence and Leukocyte Telomere Shortening in SCHIZOPHRENIA: A Role for Cytomegalovirus Infection?.},
journal = {Brain sciences},
volume = {8},
number = {10},
pages = {},
pmid = {30340343},
issn = {2076-3425},
support = {GR18085 to INPATT (CTS040) research group//Junta de Extremadura co-financed by European Regional Development Funds "Una manera de hacer Europa"/ ; SAF2017-87538-R//Ministry of Economy and Competitiveness of Spain/ ; },
abstract = {Schizophrenia is a severe, chronic mental disorder characterized by delusions and hallucinations. Several evidences support the link of schizophrenia with accelerated telomeres shortening and accelerated aging. Thus, schizophrenia patients show higher mortality compared to age-matched healthy donors. The etiology of schizophrenia is multifactorial, involving genetic and environmental factors. Telomere erosion has been shown to be accelerated by different factors including environmental factors such as cigarette smoking and chronic alcohol consumption or by psychosocial stress such as childhood maltreatment. In humans, telomere studies have mainly relied on measurements of leukocyte telomere length and it is generally accepted that individuals with short leukocyte telomere length are considered biologically older than those with longer ones. A dysregulation of both innate and adaptive immune systems has been described in schizophrenia patients and other mental diseases supporting the contribution of the immune system to disease symptoms. Thus, it has been suggested that abnormal immune activation with high pro-inflammatory cytokine production in response to still undefined environmental agents such as herpesviruses infections can be involved in the pathogenesis and pathophysiology of schizophrenia. It has been proposed that chronic inflammation and oxidative stress are involved in the course of schizophrenia illness, early onset of cardiovascular disease, accelerated aging, and premature mortality in schizophrenia. Prenatal or neonatal exposures to neurotropic pathogens such as Cytomegalovirus or Toxoplasma gondii have been proposed as environmental risk factors for schizophrenia in individuals with a risk genetic background. Thus, pro-inflammatory cytokines and microglia activation, together with genetic vulnerability, are considered etiological factors for schizophrenia, and support that inflammation status is involved in the course of illness in schizophrenia.},
}
@article {pmid30333904,
year = {2018},
author = {Brosnan-Cashman, JA and Graham, MK and Heaphy, CM},
title = {Genetic alterations associated with ALTered telomeres.},
journal = {Oncotarget},
volume = {9},
number = {73},
pages = {33739-33740},
pmid = {30333904},
issn = {1949-2553},
support = {T32 CA009110/CA/NCI NIH HHS/United States ; },
}
@article {pmid30333284,
year = {2018},
author = {Ye, X and He, Z and Deng, P and Wei, Y and Zhou, J and Huang, H},
title = {[Characteristics of distribution and changes of telomere length in human].},
journal = {Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences},
volume = {43},
number = {9},
pages = {945-949},
doi = {10.11817/j.issn.1672-7347.2018.09.003},
pmid = {30333284},
issn = {1672-7347},
mesh = {Adult ; Age Factors ; Humans ; Leukocytes, Mononuclear ; Regression Analysis ; *Telomere/genetics ; Young Adult ; },
abstract = {To explore the relationship between telomere length changes and age, and to provide data and reference for further study of geriatric medical problems. Methods: The healthy people over 20 years old were chosen as subject from several hospitals by random sampling method, and their peripheral blood samples were collected. The relative length of telomere was detected by quantitative real-time PCR, and the relationship between age and telomere length was analyzed by statistical software. Results: A total of 1 022 samples were obtained. There were significant differences in the relative telomere length among different age groups (F=21.492, P<0.001). Telomere length and age showed negative correlation (r=-0.325, P<0.001), the regression equation was y=-0.008x+1.772 (x for age, y for the average telomere length, P<0.001). Conclusion: The telomere length for peripheral blood leukocytes in healthy people varies between different age groups, suggesting that telomere length gradually decreases with age.},
}
@article {pmid30332457,
year = {2018},
author = {Peacock, SD and Massey, TE and Vanner, SJ and King, WD},
title = {Telomere length in the colon is related to colorectal adenoma prevalence.},
journal = {PloS one},
volume = {13},
number = {10},
pages = {e0205697},
pmid = {30332457},
issn = {1932-6203},
mesh = {Adenoma/epidemiology/*genetics/pathology ; Adult ; Biopsy ; Carcinogenesis/genetics ; Case-Control Studies ; Colon/diagnostic imaging/pathology ; Colonoscopy ; Colorectal Neoplasms/diagnostic imaging/epidemiology/*genetics/pathology ; Female ; Genetic Predisposition to Disease/*epidemiology ; Humans ; Intestinal Mucosa/diagnostic imaging/pathology ; Male ; Middle Aged ; Prevalence ; Real-Time Polymerase Chain Reaction ; Risk Factors ; Telomere/*genetics ; },
abstract = {Telomere length has been associated with risk of several cancers. However, studies of the relationship between telomere length and colorectal cancer risk have been inconsistent. This study examined the relationship between telomere length in normal colon tissue and the prevalence of colorectal adenoma, a precursor to colorectal cancer. This nested case-control study consisted of 85 patients aged 40 to 65 undergoing a screening colonoscopy: 40 cases with adenoma(s) detected at colonoscopy and 45 controls with normal colonoscopy. During the colonoscopy, two pinch biopsies of healthy, normal appearing mucosa were obtained from the descending colon. Relative telomere length (rTL) was quantified in DNA extracted from colon mucosa using quantitative real-time PCR. Logistic regression was used to assess the relationship between telomere length and adenoma prevalence and estimate odds ratios and 95% confidence intervals. rTL was significantly longer in colon tissue of individuals with adenomas compared to healthy individuals (p = 0.008). When rTL was categorized into quartiles according to the distribution of rTL among controls, individuals with the longest telomeres had increased odds of adenoma when compared to individuals with shortest telomeres (OR = 4.58, 95% CI: 1.19, 17.7). This study suggests that long telomeres in normal colon tissue are associated with increased colorectal cancer risk.},
}
@article {pmid30328966,
year = {2019},
author = {Jiménez, KM and Pereira-Morales, AJ and Adan, A and Forero, DA},
title = {Telomere length and childhood trauma in Colombians with depressive symptoms.},
journal = {Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)},
volume = {41},
number = {3},
pages = {194-198},
pmid = {30328966},
issn = {1809-452X},
mesh = {Child ; Child Abuse/classification/*psychology ; Colombia ; Depressive Disorder, Major/blood/*genetics ; Female ; Humans ; Male ; Polymerase Chain Reaction ; Surveys and Questionnaires ; *Telomere ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {OBJECTIVE: Childhood trauma and telomere length (TL) are important risk factors for major depressive disorder. We examined whether there was an association between childhood trauma and TL in a sample of Colombians who were assessed for depressive symptoms.<br><br>METHODS: We applied the Center for Epidemiologic Studies Depression scale, the Patient Health Questionnaire-9, the Hospital Anxiety and Depression scale and the Childhood Trauma Questionnaire to 92 Colombian subjects (mean age = 21). TL was measured with quantitative PCR. Spearman's correlation coefficient (rs) was used to analyze the relationship between childhood trauma scores and TL.<br><br>RESULTS: We found a significant correlation between TL and sexual abuse scores (rs = 0.428, p = 0.002) in individuals with higher depressive symptom scores.<br><br>CONCLUSION: This is the first report of a significant association between TL and sexual abuse in a Latin American sample and provides additional evidence about the role of childhood trauma and TL in neuropsychiatric disorders.},
}
@article {pmid30328617,
year = {2019},
author = {Caria, P and Dettori, T and Frau, DV and Lichtenzstejn, D and Pani, F and Vanni, R and Mai, S},
title = {Characterizing the three-dimensional organization of telomeres in papillary thyroid carcinoma cells.},
journal = {Journal of cellular physiology},
volume = {234},
number = {4},
pages = {5175-5185},
doi = {10.1002/jcp.27321},
pmid = {30328617},
issn = {1097-4652},
mesh = {Cell Line, Tumor ; Cell Nucleus/genetics/*ultrastructure ; Genotype ; Humans ; Imaging, Three-Dimensional ; In Situ Hybridization, Fluorescence ; Mutation ; Neoplastic Stem Cells/*ultrastructure ; Nucleic Acid Conformation ; Phenotype ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins c-ret/genetics ; Spheroids, Cellular ; Telomere/genetics/*ultrastructure ; Telomere Homeostasis ; Telomere Shortening ; Thyroid Cancer, Papillary/genetics/*ultrastructure ; Thyroid Neoplasms/genetics/*ultrastructure ; Tumor Suppressor Protein p53/genetics ; },
abstract = {The relationship between the three-dimensional (3D) nuclear telomere architecture and specific genetic alterations in papillary thyroid carcinoma (PTC), in particular in cancer stem-like cells (CSLCs), has not yet been investigated. We isolated thyrospheres containing CSLCs from B-CPAP, K1, and TPC-1 PTC-derived cell lines, representative of tumors with different genetic backgrounds within the newly identified BRAF[V600E] -like PTC subgroup, and used immortalized normal human thyrocytes (Nthy-ori 3.1) as control. We performed quantitative fluorescence in situ hybridization, 3D imaging, and 3D telomere analysis using TeloView software to examine telomere dysfunction in both parental and thyrosphere cells. Among the 3D telomere profile, a wide heterogeneity was observed, except for telomere intensity. Our findings indicate that CSLCs of each cell line had longer telomeres than parental cells, according to telomere intensity values, which correlate with telomere length. Indeed, the thyrosphere cells had lower numbers of lower-intensity telomeres (≤5,000 arbitrary fluorescent units, a.u.), compared with parental cancer cells, as well as parental control cells, (p < 0.0001). The B-CPAP thyrospheres showed a decreased number of higher intensity telomeres (>17,000 a.u.) than K1 and TPC-1 cells, as well as control cells (p < 0.0001). By selecting PTC-derived cell lines with different genetic backgrounds characteristic of BRAF[V600E] -like PTC subgroups, we demonstrate that thyrosphere cells with BRAF[V600E] and TP53 mutations show shorter telomeres than those harboring RET/PTC or BRAF[V600E] and wild-type TP53. Hence, our data reveal a trend towards a decrease in telomere shortening in CSLCs, representing the early cancer-promoting subpopulation, as opposed to parental cells representing the tumor bulk cells.},
}
@article {pmid30328024,
year = {2018},
author = {Gamal, RM and Hammam, N and Zakary, MM and Abdelaziz, MM and Razek, MRA and Mohamed, MSE and Emad, Y and Elnaggar, MG and Furst, DE},
title = {Telomere dysfunction-related serological markers and oxidative stress markers in rheumatoid arthritis patients: correlation with diseases activity.},
journal = {Clinical rheumatology},
volume = {37},
number = {12},
pages = {3239-3246},
pmid = {30328024},
issn = {1434-9949},
mesh = {Adolescent ; Adult ; Aged ; Antioxidants/metabolism ; Arthritis, Rheumatoid/*blood/*genetics ; Biomarkers/blood ; Case-Control Studies ; Chitinases/metabolism ; Colorimetry ; Cross-Sectional Studies ; Female ; Humans ; Inflammation ; Male ; Middle Aged ; Multivariate Analysis ; Nitric Oxide ; *Oxidative Stress ; Social Class ; Spectrophotometry ; Superoxide Dismutase/metabolism ; Telomere/*ultrastructure ; Young Adult ; },
abstract = {Rheumatoid arthritis (RA) is an inflammatory autoimmune polyarthritis with progressive destruction of the synovial joints associated with systemic manifestations. RA is characterized by infiltration of the synovial joints with inflammatory immune cells with premature immunosenescence. Shorter telomere length in the peripheral blood cells and increase in the oxidative stress have been detected in patients with RA. The aim of the present study was to study the association of markers of telomere shortening and oxidative stress with RA disease activity. Sixty-one RA patients and 15 healthy controls were enrolled in the study. Demographic data, clinical examination, and disease activity status were evaluated for the RA patients. Serum levels of chitinase and NAG (telomere markers) were determined by biochemical reactions using colloidal chitin and NAG as substrates, respectively. Nitric oxide and superoxide dismutase (oxidative stress markers) were determined colometrically and spectrophotometrically, respectively, in the sera of RA patients and controls. Results were correlated with disease activity. Indices of telomere shortening and oxidative markers were significantly higher in RA patients compared to controls. These indices were correlated with signs of disease activity (including number of swollen and tender joints, DAS-28, and inflammatory markers). Rheumatoid arthritis is a disease in which markers of telomere shortening and elevated oxidant stress correlate with disease activity.},
}
@article {pmid30326633,
year = {2018},
author = {Harpaz, T and Abumock, H and Beery, E and Edel, Y and Lahav, M and Rozovski, U and Uziel, O},
title = {The Effect of Ethanol on Telomere Dynamics and Regulation in Human Cells.},
journal = {Cells},
volume = {7},
number = {10},
pages = {},
pmid = {30326633},
issn = {2073-4409},
abstract = {Telomeres (TLs) protect chromosome ends from chromosomal fusion and degradation, thus conferring genomic stability, and play crucial roles in cellular aging and disease. Recent studies have found a correlation between environmental, physiological and even mental stresses on TL dynamics in humans. However, the causal relationship between stress and TL length and the molecular mechanisms underlying that relationship are far from being understood. This study describes the effect of moderate concentrations of ethanol, equivalent to social drinking, on human TL dynamics and partially elucidates the mechanism mediating this effect. The exposure of Immortalized human foreskin fibroblast, primary human foreskin fibroblast and human hepatocellular carcinoma cells to 25 mM ethanol for one week moderately shortened telomeres in all cells. Similar TL shortening was obtained following cells' exposure to 25 µM acetaldehyde (AcH) and to a much lower extent after exposure to 4-methylpyrazolean, an inhibitor of alcoholdehydrogenase, suggesting that AcH plays a key role in ethanol-dependent telomere shortening. Telomerase activity was not involved in this effect. TRF2 and several TRF2 binding proteins increased their binding to TLs after ethanol treatment, implying their involvement in this effect. The methylation status of several sub-telomeric regions increased in response to EtOH exposure. Gene expression profiling showed distinct patterns in cells treated with EtOH and in cells recovered from EtOH. In addition to cellular ageing, the described telomere shortening may contribute to the carcinogenic potential of acute alcohol consumption; both are associated with the shortening of TLs and provide new insights regarding the moderate consumption of alcohol referred to as "social drinking."},
}
@article {pmid30325019,
year = {2019},
author = {Campa, D and Matarazzi, M and Greenhalf, W and Bijlsma, M and Saum, KU and Pasquali, C and van Laarhoven, H and Szentesi, A and Federici, F and Vodicka, P and Funel, N and Pezzilli, R and Bueno-de-Mesquita, HB and Vodickova, L and Basso, D and Obazee, O and Hackert, T and Soucek, P and Cuk, K and Kaiser, J and Sperti, C and Lovecek, M and Capurso, G and Mohelnikova-Duchonova, B and Khaw, KT and König, AK and Kupcinskas, J and Kaaks, R and Bambi, F and Archibugi, L and Mambrini, A and Cavestro, GM and Landi, S and Hegyi, P and Izbicki, JR and Gioffreda, D and Zambon, CF and Tavano, F and Talar-Wojnarowska, R and Jamroziak, K and Key, TJ and Fave, GD and Strobel, O and Jonaitis, L and Andriulli, A and Lawlor, RT and Pirozzi, F and Katzke, V and Valsuani, C and Vashist, YK and Brenner, H and Canzian, F},
title = {Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study.},
journal = {International journal of cancer},
volume = {144},
number = {6},
pages = {1275-1283},
doi = {10.1002/ijc.31928},
pmid = {30325019},
issn = {1097-0215},
support = {MR/N003284/1/MRC_/Medical Research Council/United Kingdom ; G0401527/MRC_/Medical Research Council/United Kingdom ; G1000143/MRC_/Medical Research Council/United Kingdom ; 16491/CRUK_/Cancer Research UK/United Kingdom ; 14136/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Aged ; Carcinoma, Pancreatic Ductal/*genetics ; Case-Control Studies ; Europe ; Female ; Genome-Wide Association Study ; Humans ; Lymphocytes/metabolism ; Male ; Middle Aged ; Pancreatic Neoplasms/*genetics ; Polymorphism, Single Nucleotide ; Ribonucleoproteins/*genetics ; Telomerase/*genetics/metabolism ; Telomere/*metabolism ; Telomere Shortening/*genetics ; },
abstract = {Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score ("teloscore", which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35-1.76; p = 1.54 × 10[-10]) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87 × 10[-6] , ptrend = 3.27 × 10[-7]). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10[-9] for highest vs. lowest quintile; p = 1.82 × 10[-10] as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.},
}
@article {pmid30320420,
year = {2019},
author = {Planas-Cerezales, L and Arias-Salgado, EG and Buendia-Roldán, I and Montes-Worboys, A and López, CE and Vicens-Zygmunt, V and Hernaiz, PL and Sanuy, RL and Leiro-Fernandez, V and Vilarnau, EB and Llinás, ES and Sargatal, JD and Abellón, RP and Selman, M and Molina-Molina, M},
title = {Predictive factors and prognostic effect of telomere shortening in pulmonary fibrosis.},
journal = {Respirology (Carlton, Vic.)},
volume = {24},
number = {2},
pages = {146-153},
doi = {10.1111/resp.13423},
pmid = {30320420},
issn = {1440-1843},
mesh = {Age Factors ; Cohort Studies ; Correlation of Data ; Female ; Humans ; *Idiopathic Pulmonary Fibrosis/epidemiology/genetics/physiopathology/surgery ; Lung Transplantation/*statistics &amp; numerical data ; Male ; Middle Aged ; Mortality ; Prognosis ; Risk Assessment ; Risk Factors ; Spain/epidemiology ; Telomere Shortening/*physiology ; },
abstract = {BACKGROUND AND OBJECTIVE: The abnormal shortening of telomeres is a mechanism linking ageing to idiopathic pulmonary fibrosis (IPF) that could be useful in the clinical setting. The objective of this study was to identify the IPF patients with higher risk for telomere shortening and to investigate the outcome implications.<br><br>METHODS: Consecutive Spanish patients were included at diagnosis and followed up for 3&#x2009;years. DNA blood samples from a Mexican cohort were used to validate the results found in Spanish sporadic IPF. Prior to treatment, telomere length was measured through quantitative polymerase chain reaction (qPCR) and Southern blot. Outcome was assessed according to mortality or need for lung transplantation. A multivariate regression logistic model was used for statistical analysis.<br><br>RESULTS: Family aggregation, age of <60&#x2009;years and the presence of non-specific immunological or haematological abnormalities were associated with a higher probability of telomere shortening. Overall, 66.6% of patients younger than 60&#x2009;years with telomere shortening died or required lung transplantation, independent of functional impairment at diagnosis. By contrast, in patients older than 60&#x2009;years with telomere shortening, the negative impact of telomere shortening in outcome was not significant.<br><br>CONCLUSION: Our data indicate that young sporadic IPF patients (<60&#x2009;years) with some non-specific immunological or haematological abnormalities had higher risk of telomere shortening, and furthermore, they presented a poorer prognosis.},
}
@article {pmid30315815,
year = {2019},
author = {Rodriguez-Brenes, IA and Komarova, NL and Wodarz, D},
title = {The role of telomere shortening in carcinogenesis: A hybrid stochastic-deterministic approach.},
journal = {Journal of theoretical biology},
volume = {460},
number = {},
pages = {144-152},
pmid = {30315815},
issn = {1095-8541},
support = {U01 CA187956/CA/NCI NIH HHS/United States ; },
mesh = {Algorithms ; Animals ; Carcinogenesis/*genetics ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Genomic Instability ; Humans ; Mice ; Telomerase/genetics ; Telomere Shortening/*physiology ; },
abstract = {Genome instability is a characteristic of most cancers, contributing to the acquisition of genetic alterations that drive tumor progression. One important source of genome instability is linked to telomere dysfunction in cells with critically short telomeres that lack p53-mediated surveillance of genomic integrity. Here we research the probability that cancer emerges through an evolutionary pathway that includes a telomere-induced phase of genome instability. To implement our models we use a hybrid stochastic-deterministic approach, which allows us to perform large numbers of simulations using biologically realistic population sizes and mutation rates, circumventing the traditional limitations of fully stochastic algorithms. The hybrid methodology should be easily adaptable to a wide range of evolutionary problems. In particular, we model telomere shortening and the acquisition of two mutations: Telomerase activation and p53 inactivation. We find that the death rate of unstable cells, and the number of cell divisions that p53 mutants can sustain beyond the normal senescence setpoint determine the likelihood that the first double mutant originates in a cell with telomere-induced instability. The model has applications to an influential telomerase-null mouse model and p16 silenced human cells. We end by discussing algorithmic performance and a measure for the accuracy of the hybrid approximation.},
}
@article {pmid30305488,
year = {2018},
author = {Tahara, H},
title = {[Risk assessment of age-associated diseases using telomere and microRNA technologies].},
journal = {[Rinsho ketsueki] The Japanese journal of clinical hematology},
volume = {59},
number = {10},
pages = {1880-1885},
doi = {10.11406/rinketsu.59.1880},
pmid = {30305488},
issn = {0485-1439},
mesh = {Aging/*pathology ; Dementia/diagnosis ; Early Diagnosis ; Humans ; MicroRNAs/*analysis ; Neoplasms/diagnosis ; Risk Assessment ; Telomere/*ultrastructure ; },
abstract = {Prevention and early detection of age-associated diseases are critical to achieve healthy longevity among the super-aged individuals. To this end, technology that can assess the risk of diseases before onset and that can detect diseases at an early stage for early treatment intervention is essential. Technology that measures telomere G-tail length can be used to examine the risk of age-associated diseases, while miRNAs may serve as a novel diagnostic marker for the early detection of diseases, such as cancer and dementia. In this review, the potential of telomere and microRNA technologies as disease risk assessment tools is explored.},
}
@article {pmid30301461,
year = {2018},
author = {Wang, S and Qu, F and Han, W and You, J},
title = {A resonance Rayleigh scattering sensor for sensitive differentiation of telomere DNA length and monitoring special motifs (G-quadruplex and i-motif) based on the Ag nanoclusters and NAND logic gate responding to chemical input signals.},
journal = {Journal of nanobiotechnology},
volume = {16},
number = {1},
pages = {78},
pmid = {30301461},
issn = {1477-3155},
support = {21405093//National Natural Science Foundation of China/ ; },
mesh = {DNA/*chemistry ; *G-Quadruplexes ; Hydrophobic and Hydrophilic Interactions ; *Logic ; Metal Nanoparticles/*chemistry ; Polyethyleneimine/chemistry ; *Scattering, Radiation ; Silver/*chemistry ; Telomere/*chemistry ; },
abstract = {BACKGROUND: Differentiation of telomere length is of vital importance because telomere length is closely related with several deadly diseases such as cancer. Additionally, G-quadruplex and i-motif formation in telomeric DNA have been shown to act as a negative regulator of telomere elongation by telomerase in vivo and are considered as an attractive drug target for cancer chemotherapy.<br><br>RESULTS: In this assay, Ag nanoclusters templated by hyperbranched polyethyleneimine (PEI-Ag NCs) are designed as a new novel resonance Rayleigh scattering (RRS) probe for sensitive differentiation of telomere length and monitoring special motifs (G-quadruplex and i-motif). In this assay, free PEI-Ag NC probe or DNA sequence alone emits low intensities of RRS, while the formation of PEI-Ag NCs/DNA complexes yields greatly enhanced RRS signals; however, when PEI-Ag NCs react with G-quadruplex or i-motif, the intensities of RRS exhibit slight changes. At the same concentration, the enhancement of RRS signal is directly proportional to the length of telomere, and the sensitivity of 64 bases is the highest with the linear range of 0.3-50&#xa0;nM (limit of detection 0.12&#xa0;nM). On the other hand, due to the conversion of telomere DNA molecules among multiple surrounding conditions, a DNA logic gate is developed on the basis of two chemical input signals (K[+] and H[+]) and a change in RRS intensity as the output signal.<br><br>CONCLUSION: Our results indicate that PEI-Ag NCs can serve as a novel RRS probe to identify DNA length and monitor G-quadruplex/i-motif through the different increasing degrees of RRS intensity. Meanwhile, the novel attributes of the nanoprobe stand superior to those involving dyes or labeled DNA because of no chemical modification, low cost, green, and high efficiency.},
}
@article {pmid30296917,
year = {2019},
author = {Arias-Sosa, LA},
title = {Understanding the Role of Telomere Dynamics in Normal and Dysfunctional Human Reproduction.},
journal = {Reproductive sciences (Thousand Oaks, Calif.)},
volume = {26},
number = {1},
pages = {6-17},
doi = {10.1177/1933719118804409},
pmid = {30296917},
issn = {1933-7205},
mesh = {*Aging ; Female ; Homeostasis ; Humans ; Infertility, Male/physiopathology ; Male ; Pregnancy ; Pregnancy Complications/physiopathology ; *Reproduction ; Telomere/*physiology ; },
abstract = {In modern society, fertility problems and demand of treatment seem to be on the rise, which led to an increased interest in research regarding human reproduction. Among these efforts, the study of the molecular senescence process has gain notorious popularity as aging is one of the most important variables involved in reproductive capacity and since the comprehension of telomere dynamics has become an important and influential theme. This new knowledge regarding the reproductive aging process is expected to offer new tools to understand the acquisition, maintenance, and loss of fertility potential. Therefore, this review seeks to clarify the relevance of molecular aging (evaluated by telomere shortening) in human reproduction, showing that it is a dynamic and variable process modulated according to the specific tissue and stage of development. As well, it is discussed how telomere status influence the development and progression of some fertility pathologies, the outcome of assisted reproductive treatments, and programming of aging in the offspring.},
}
@article {pmid30291661,
year = {2018},
author = {Jimenez Villarreal, J and Murillo Ortiz, B and Martinez Garza, S and Rivas Armendáriz, DI and Boone Villa, VD and Carranza Rosales, P and Betancourt Martínez, ND and Delgado Aguirre, H and Morán Martínez, J},
title = {Telomere length analysis in residents of a community exposed to arsenic.},
journal = {Journal of biochemical and molecular toxicology},
volume = {},
number = {},
pages = {e22230},
doi = {10.1002/jbt.22230},
pmid = {30291661},
issn = {1099-0461},
abstract = {Differentiated cells telomere length is an indicator of senescence or lifespan; however, in peripheral blood leukocytes the relative shortening of the telomere has been considered as a biological marker of aging, and lengthening telomere as an associated risk to cancer. Individual's age, type of tissue, lifestyle, and environmental factors make telomere length variable. The presence of environmental carcinogens such as arsenic (As) influence as causal agents of these alterations, the main modes of action for As described are oxidative stress, reduction in DNA repair capacity, overexpression of genes, alteration of telomerase activity, and damage to telomeres. The telomeres of leukocytes resulting a finite capacity of replication due to the low or no activity of the telomerase enzyme, therefore, elongation telomere in this kind of cells is a potential biological marker associated with the development of chronic diseases and carcinogenesis.},
}
@article {pmid30287851,
year = {2018},
author = {Fujiwara, C and Muramatsu, Y and Nishii, M and Tokunaka, K and Tahara, H and Ueno, M and Yamori, T and Sugimoto, Y and Seimiya, H},
title = {Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {14827},
pmid = {30287851},
issn = {2045-2322},
support = {24650639//Japan Society for the Promotion of Science (JSPS)/International ; 18K19487//Japan Society for the Promotion of Science (JSPS)/International ; N/A//Kobayashi Foundation for Cancer Research/International ; 16cm0106102h0001//Japan Agency for Medical Research and Development (AMED)/International ; 18H04633//Ministry of Education, Culture, Sports, Science, and Technology (MEXT)/International ; },
mesh = {Artificial Cells ; Benzamides/metabolism ; Cell Line, Tumor ; *Cell Proliferation ; *DNA Damage ; *DNA Repair ; Enzyme Inhibitors/metabolism ; Humans ; Lamin Type A/*metabolism ; Neoplasms/*pathology ; Peptide Mapping ; Sensitivity and Specificity ; Telomerase/antagonists &amp; inhibitors ; Telomere/*metabolism ; Topoisomerase II Inhibitors/metabolism ; },
abstract = {Telomere maintenance by telomerase activity supports the infinite growth of cancer cells. MST-312, a synthetic telomerase inhibitor, gradually shortens telomeres at non-acute lethal doses and eventually induces senescence and apoptosis of telomerase-positive cancer cells. Here we report that MST-312 at higher doses works as a dual inhibitor of telomerase and DNA topoisomerase II and exhibits acute anti-proliferative effects on cancer cells and xenografted tumours in vivo. Our cell-based chemical fingerprinting approach revealed that cancer cells with shorter telomeres and lower expression of lamin A, a nuclear architectural protein, exhibited higher sensitivity to the acute deleterious effects of MST-312, accompanied by formation of telomere dysfunction-induced foci and DNA double-strand breaks. Telomere elongation and lamin A overexpression attenuated telomeric and non-telomeric DNA damage, respectively, and both conferred resistance to apoptosis induced by MST-312 and other DNA damaging anticancer agents. These observations suggest that sufficient pools of telomeres and a nuclear lamina component contribute to the cellular robustness against DNA damage induced by therapeutic treatment in human cancer cells.},
}
@article {pmid30285264,
year = {2018},
author = {Salihu, HM and Adegoke, KK and King, LM and Daas, R and Paothong, A and Pradhan, A and Aliyu, MH and Whiteman, VE},
title = {Effects of Maternal Carbohydrate and Fat Intake on Fetal Telomere Length.},
journal = {Southern medical journal},
volume = {111},
number = {10},
pages = {591-596},
doi = {10.14423/SMJ.0000000000000871},
pmid = {30285264},
issn = {1541-8243},
mesh = {Adult ; Cohort Studies ; *Diet ; *Dietary Carbohydrates ; *Dietary Fats ; Female ; Fetal Blood ; Humans ; Linear Models ; Polymerase Chain Reaction ; Pregnancy ; Socioeconomic Factors ; *Telomere ; Young Adult ; },
abstract = {OBJECTIVES: Telomere length can be affected by dietary factors in adults. We investigated the association between maternal carbohydrate and fat intake during pregnancy and telomere length in neonatal cord blood leukocytes. We hypothesized that high fat consumption and high carbohydrate consumption would be associated with shortened fetal telomere length.<br><br>METHODS: We collected umbilical cord blood at delivery from women admitted for labor and delivery in a university hospital (N = 62) and extracted genomic DNA using quantitative polymerase chain reaction. We quantified telomere length using the telomere-to-single copy gene ratio method (T:S ratio). High carbohydrate intake was defined as consumption of >175 g/day and high fat intake as >35 g/day. We performed generalized linear regression modeling and bootstrap statistical analyses to derive precise estimates of association.<br><br>RESULTS: Of the 62 maternal-fetal dyads included in this study, 79% were classified as high carbohydrate consumers and 37% were classified as high fat consumers. High fat consumption had a significant negative effect on T:S ratio (P < 0.05). Although high carbohydrate consumption was associated with a decreased T:S ratio, this relation did not attain statistical significance.<br><br>CONCLUSIONS: To our knowledge, this study is the first evidence of an association between maternal high fat consumption and shortened fetal telomere length. These findings could enhance our understanding of the role of maternal diet in fetal programming.},
}
@article {pmid30285087,
year = {2019},
author = {Lopes, AC and Oliveira, PF and Sousa, M},
title = {Shedding light into the relevance of telomeres in human reproduction and male factor infertility†.},
journal = {Biology of reproduction},
volume = {100},
number = {2},
pages = {318-330},
doi = {10.1093/biolre/ioy215},
pmid = {30285087},
issn = {1529-7268},
mesh = {Gene Expression Regulation ; Humans ; Infertility, Male/*genetics ; Male ; Spermatozoa/physiology ; *Telomere ; },
abstract = {Sperm telomere length (STL) is a promising new parameter for sperm quality analysis that may elucidate the molecular mechanisms underlying the idiopathic cases of male factor infertility, which represent almost half of all the male factor infertility cases worldwide. Telomeres consist of nucleoprotein structures present at the ends of eukaryotic chromosomes, whose protective functions maintain the genomic stability. Their role in reproduction includes an active intervention during gametogenesis, fertilization, and preimplantation embryo development. In consonance, studies have shown that compromised telomere homeostasis is associated with male infertility. Since critically short telomeres have their function affected, assessing STL may be a fast and economic method for sperm quality analysis and expectantly contribute to improve the success of fertility treatments. This hypothesis is supported by several reports associating STL with seminal parameters, sperm genome integrity, and clinical outcomes. However, there are other studies in the literature that do not demonstrate these associations. Additionally, it is still not clear whether the lengthening mechanisms of telomeres occurring during early embryo development resume the inherited telomere length. Further research is essential to clarify the suitability of STL as a biomarker for male infertility, before it could be routinely implemented in medically assisted reproduction centers. Understanding the molecular mechanisms underlying STL function and dynamics will provide us new insights into the origins of male infertility and a possible new useful tool as an outcome predictor for assisted reproduction.},
}
@article {pmid30281650,
year = {2018},
author = {Kazemi Noureini, S and Fatemi, L and Wink, M},
title = {Telomere shortening in breast cancer cells (MCF7) under treatment with low doses of the benzylisoquinoline alkaloid chelidonine.},
journal = {PloS one},
volume = {13},
number = {10},
pages = {e0204901},
pmid = {30281650},
issn = {1932-6203},
mesh = {Benzophenanthridines/*pharmacology ; Breast Neoplasms/drug therapy/*genetics/metabolism ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; MCF-7 Cells ; RNA Splicing/drug effects ; Telomerase/antagonists &amp; inhibitors/*genetics ; *Telomere Shortening ; Time Factors ; },
abstract = {Telomeres, the specialized dynamic structures at chromosome ends, regularly shrink with every replication. Thus, they function as an internal molecular clock counting down the number of cell divisions. However, most cancer cells escape this limitation by activating telomerase, which can maintain telomere length. Previous studies showed that the benzylisoquinoline alkaloid chelidonine stimulates multiple modes of cell death and strongly down-regulates telomerase. It is still unknown if down-regulation of telomerase by chelidonine boosts substantial telomere shortening. The breast cancer cell line MCF7 was sequentially treated with very low concentrations of chelidonine over several cell passages. Telomere length and telomerase activity were measured by a monochrome multiplex quantitative PCR and a q-TRAP assay, respectively. Changes in population size and doubling time correlated well with telomerase inhibition and telomere shortening. MCF7 cell growth was arrested completely after three sequential treatments with 0.1 μM chelidonine, each ending after 48 h, while telomere length was reduced to almost 10% of the untreated control. However, treatment with 0.01 μM chelidonine did not have any apparent consequence. In addition to dose and time dependent telomerase inhibition, chelidonine changed the splicing pattern of hTERT towards non-enzyme coding isoforms of the transcript. In conclusion, telomere length and telomere stability are strongly affected by chelidonine in addition to microtubule formation.},
}
@article {pmid30281200,
year = {2019},
author = {Gurung, RL and M, Y and Liu, S and Liu, JJ and Chan, SM and Moh, MC and Ang, K and Tang, WE and Sum, CF and Tavintharan, S and Lim, SC and , },
title = {Ethnic disparities in relationships of obesity indices with telomere length in Asians with type 2 diabetes.},
journal = {Journal of diabetes},
volume = {11},
number = {5},
pages = {386-393},
doi = {10.1111/1753-0407.12864},
pmid = {30281200},
issn = {1753-0407},
support = {NMRC/PPG/AH [KTPH]/2011//Singapore National Medical Research Council/ ; NMRC/CIRG/1398/2014//Singapore National Medical Research Council/ ; AHEG1714//Alexandra Health/ ; AHEG1622//Alexandra Health/ ; STAR16109//Alexandra Health/ ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Asia/epidemiology ; Body Mass Index ; Cross-Sectional Studies ; Diabetes Mellitus, Type 2/*epidemiology/*etiology ; Ethnicity/*statistics &amp; numerical data ; Female ; Follow-Up Studies ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Obesity/*complications ; Prognosis ; *Telomere Homeostasis ; Young Adult ; },
abstract = {BACKGROUND: Obesity and shorter telomeres increase the risk for diabetes complications and mortality. However, the relationship between obesity and telomere length in diverse Asian populations with type 2 diabetes (T2D) is not well understood. This study examined the association of baseline and changes in obesity indices with telomere length in multiethnic Asian populations with T2D.<br><br>METHODS: Leukocyte telomere length (LTL) was measured by quantitative polymerase chain reaction in the SMART2D cohort (n&#x2009;=&#x2009;1431 at baseline, n&#x2009;=&#x2009;1039 after 3.2 years median follow-up). Associations between obesity indices and LTL were assessed by linear regression.<br><br>RESULTS: Compared with Chinese, LTL was longer in Malays (P&#x2009;<&#x2009;0.0001) and similar in Indians. Cross-sectionally, body mass index (BMI)-adjusted (residual) visceral fat area (VFA; &#x3b2;&#x2009;=&#x2009;-0.004, P&#x2009;=&#x2009;0.006), and waist-to-hip ratio (&#x3b2;&#x2009;=&#x2009;-1.95, P&#x2009;=&#x2009;0.030) were significantly associated with LTL in Chinese but not in Malays and Indians. Changes in BMI (r&#x2009;=&#x2009;-0.080; P&#x2009;=&#x2009;0.053) and VFA (r&#x2009;=&#x2009;-0.126; P&#x2009;=&#x2009;0.002) were inversely correlated with changes in LTL only in Chinese. Furthermore, in Chinese, 1-SD incremental changes in BMI (&#x3b2;&#x2009;=&#x2009;-0.070; P&#x2009;=&#x2009;0.040) and VFA (&#x3b2;&#x2009;=&#x2009;-0.088, P&#x2009;=&#x2009;0.028) were significantly associated with larger telomere attrition, independent of age, sex, diabetes condition, baseline LTL, obesity, and inflammation markers.<br><br>CONCLUSIONS: Three-year changes in BMI and VFA were associated with telomere dynamics in Chinese but not in Malays and Indians with T2D. Reducing obesity may reduce the risk of diabetes complications associated with shorter LTL in the Chinese population.},
}
@article {pmid30280102,
year = {2018},
author = {Swapna, G and Yu, EY and Lue, NF},
title = {Single telomere length analysis in Ustilago maydis, a high-resolution tool for examining fungal telomere length distribution and C-strand 5'-end processing.},
journal = {Microbial cell (Graz, Austria)},
volume = {5},
number = {9},
pages = {393-403},
pmid = {30280102},
issn = {2311-2638},
abstract = {Telomeres play important roles in genome stability and cell proliferation. Telomere lengths are heterogeneous and because just a few abnormal telomeres are sufficient to trigger significant cellular response, it is informative to have accurate assays that reveal not only average telomere lengths, but also the distribution of the longest and shortest telomeres in a given sample. Herein we report for the first time, the development of single telomere length analysis (STELA) - a PCR-based assay that amplifies multiple, individual telomeres - for Ustilago maydis, a basidiomycete fungus. Compared to the standard telomere Southern technique, STELA revealed a broader distribution of telomere size as well as the existence of relatively short telomeres in wild type cells. When applied to blm∆, a mutant thought to be defective in telomere replication, STELA revealed preferential loss of long telomeres, whose maintenance may thus be especially dependent upon efficient replication. In comparison to blm∆, the trt1∆ (telomerase null) mutant exhibited greater erosion of short telomeres, consistent with a special role for telomerase in re-lengthening extra-short telomeres. We also used STELA to characterize the 5' ends of telomere C-strand, and found that in U. maydis, they terminate preferentially at selected nucleotide positions within the telomere repeat. Deleting trt1 altered the 5'-end distributions, suggesting that telomerase may directly or indirectly modulate C-strand 5' end formation. These findings illustrate the utility of STELA as well as the strengths of U. maydis as a model system for telomere research.},
}
@article {pmid30279093,
year = {2018},
author = {Zhang, LL and Wu, Z and Zhou, JQ},
title = {Tel1 and Rif2 oppositely regulate telomere protection at uncapped telomeres in Saccharomyces cerevisiae.},
journal = {Journal of genetics and genomics = Yi chuan xue bao},
volume = {45},
number = {9},
pages = {467-476},
doi = {10.1016/j.jgg.2018.09.001},
pmid = {30279093},
issn = {1673-8527},
mesh = {Caenorhabditis elegans Proteins/genetics/metabolism ; DNA, Single-Stranded/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Endodeoxyribonucleases/genetics/metabolism ; Epistasis, Genetic ; Exodeoxyribonucleases/genetics/metabolism ; Intracellular Signaling Peptides and Proteins/genetics/*metabolism ; Mutation ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Rad51 Recombinase/genetics/metabolism ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {It has been well documented that Tel1 positively regulates telomere-end resection by promoting Mre11-Rad50-Xrs2 (MRX) activity, while Rif2 negatively regulates telomere-end resection by inhibiting MRX activity. At uncapped telomeres, whether Tel1 or Rif2 plays any role remains largely unknown. In this work, we examined the roles of Tel1 and Rif2 at uncapped telomeres in yku70Δ and/or cdc13-1 mutant cells cultured at non-permissive temperature. We found that deletion of TEL1 exacerbates the temperature sensitivity of both yku70Δ and cdc13-1 cells. Further epistasis analysis indicated that MRX and Tel1 function in the same pathway in telomere protection. Consistently, TEL1 deletion increases accumulation of Exo1-dependent telomeric single-stranded DNA (ssDNA) at uncapped telomeres, which stimulates checkpoint-dependent cell cycle arrest. Moreover, TEL1 deletion in yku70Δ cells facilitates Rad51-dependent Y' recombination. In contrast, RIF2 deletion in yku70Δ cells decreases the accumulation of telomeric ssDNA after 8 h of incubation at the non-permissive temperature of 37 °C and suppresses the temperature sensitivity of yku70Δ cells, likely due to the increase of Mre11 association at telomeres. Collectively, our findings indicate that Tel1 and Rif2 regulate telomere protection at uncapped telomeres via their roles in balancing MRX activity in telomere resection.},
}
@article {pmid30278538,
year = {2018},
author = {Jin, X and Pan, B and Dang, X and Wu, H and Xu, D},
title = {Relationship between short telomere length and stroke: A meta-analysis.},
journal = {Medicine},
volume = {97},
number = {39},
pages = {e12489},
pmid = {30278538},
issn = {1536-5964},
mesh = {Aged ; Aged, 80 and over ; Female ; Genetic Predisposition to Disease/epidemiology/*genetics ; Humans ; Male ; Middle Aged ; Prospective Studies ; Publication Bias ; Retrospective Studies ; Risk Factors ; Stroke/epidemiology/*genetics ; Telomere/*genetics ; },
abstract = {BACKGROUND: Several epidemiological studies had been carried out in different population cohorts to estimate the relationship between the shortened telomere length and stroke. However, the results still remained dispute. Consequently, we conducted this meta-analysis to estimate the relationship between them.<br><br>METHODS: PubMed, EMBASE, and Web of Science were systematically searched for related articles to evaluate the association between "stroke" and "telomere length. STATA 12.0 software was used to perform the meta-analysis. The Cochran Q test and inconsistency index (I) were used to assess the heterogeneity. Begg funnel plot and Egger test were used to assess publication bias.<br><br>RESULTS: The meta-analysis was composed of 11 studies, consisting of 25,340 participants. We found a significant relationship between shortened telomere length and stroke (OR: 1.50, 95% CI: 1.13-2.0; P&#x200a;=&#x200a;.005); however, in the prospective and retrospective study subgroup, we did not find a statistical significant relationship between shortened telomere length and stroke (the prospective subgroup: OR: 1.41, 95% CI: 1-1.98; P&#x200a;=&#x200a;.051) (the retrospective subgroup: OR: 1.89, 95% CI: 0.96-3.72; P&#x200a;=&#x200a;.067).},
}
@article {pmid30278415,
year = {2018},
author = {Wai, KM and Umezaki, M and Kosaka, S and Mar, O and Umemura, M and Fillman, T and Watanabe, C},
title = {Impact of prenatal heavy metal exposure on newborn leucocyte telomere length: A birth-cohort study.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {243},
number = {Pt B},
pages = {1414-1421},
doi = {10.1016/j.envpol.2018.09.090},
pmid = {30278415},
issn = {1873-6424},
mesh = {Adult ; Arsenic/urine ; Cadmium/blood ; Cohort Studies ; Environmental Pollutants/*toxicity ; Female ; Humans ; Infant, Newborn ; Lead/blood ; Maternal Exposure/*statistics &amp; numerical data ; Metals, Heavy/blood/*toxicity ; Pregnancy ; Telomere ; },
abstract = {Arsenic, cadmium and lead are toxic environmental contaminants. They were shown to be associated with telomere length (TL) in adults. Although they can cross the placental barrier, the effect of prenatal exposure of these metals on newborn TL is unknown. The aim of this study was to examine whether prenatal exposure to heavy metals has an impact on newborn leucocyte TL. A birth-cohort study was conducted with 409 pregnant women and their newborns in Myanmar. During the first visit, face-to-face interviews were conducted, and maternal spot urine sampling was performed. Cord blood samples were collected during follow-up. Urinary heavy metal concentration was measured by ICP-MS and adjusted for creatinine. Relative TL was measured by quantitative real-time polymerase chain reaction. The extent of prenatal arsenic, cadmium and lead exposure and their associations with newborn leucocyte TL were assessed using multivariate linear regression. The median values of maternal urinary arsenic, cadmium, and lead concentrations were 73.9, 0.9, and 1.8 μg/g creatinine, respectively. Prenatal arsenic and cadmium exposure was significantly associated with newborn TL shortening (lowest vs highest quartile, coefficient = - 0.13, 95% CI: - 0.22, - 0.03, p = 0.002, and coefficient = - 0.17, 95% CI: - 0.27, - 0.07, p = 0.001, respectively), and the associations remained robust after adjusting for confounders. There was no significant association between prenatal lead exposure and newborn TL. The present study identified the effect of arsenic and cadmium exposure on TL shortening, even in utero exposure at a lower concentration.},
}
@article {pmid30277797,
year = {2018},
author = {Li, J and Zhang, L and Zhu, H and Pan, W and Zhang, N and Li, Y and Yang, M},
title = {Leukocyte Telomere Length and Clinical Outcomes of Advanced Lung Adenocarcinoma Patients with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Treatment.},
journal = {DNA and cell biology},
volume = {37},
number = {11},
pages = {903-908},
doi = {10.1089/dna.2018.4337},
pmid = {30277797},
issn = {1557-7430},
mesh = {Adenocarcinoma/*drug therapy/enzymology/genetics/mortality ; Adenocarcinoma of Lung ; Aged ; Antineoplastic Agents/*therapeutic use ; Biomarkers, Pharmacological/metabolism ; Cohort Studies ; Drug Resistance, Neoplasm/genetics ; ErbB Receptors/antagonists &amp; inhibitors/*genetics/metabolism ; Female ; Gefitinib ; Gene Expression ; Humans ; Leukocytes/drug effects/enzymology/pathology ; Lung Neoplasms/*drug therapy/enzymology/genetics/mortality ; Male ; Middle Aged ; Mutation ; Neoplasm Staging ; Prognosis ; Protein Kinase Inhibitors/*therapeutic use ; Quinazolines/*therapeutic use ; Survival Analysis ; Telomere/*chemistry ; },
abstract = {Gefitinib is currently one of the mostly used epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) recommended for treating nonsmall cell lung cancer. However, drug resistance is observed among the majority of patients after initial treatment. Factors that predict treatment prognosis and drug resistance to EGFR-TKIs remain elusive. The objective of this study is to investigate whether leukocyte relative telomere length (RTL) can be used as a prognostic biomarker of EGFR-TKIs therapy. In this study, 369 patients with stage IIIB or IV lung adenocarcinoma were recruited and treated with gefitinib as first-line monotherapy. Leukocyte RTL of each patient was measured using quantitative polymerase chain reaction protocol and calculated according to Cawthon's formula. Finally, we examined the association between leukocyte RTL and prognosis or drug resistance of advanced lung adenocarcinoma to gefitinib treatment. Our results indicated that compared with long RTL, short leukocyte RTL was significantly associated with poor prognosis in all patients after gefitinib treatment (overall survival [OS]: 12.9 months vs. 17.8 months, p = 1.2 × 10[-4]; progression-free survival: 7.8 months vs. 13.0 months, p = 0.043). In addition, statistically significant association between short leukocyte RTL and short OS still existed among the EGFR mutant patients (hazards ratio [HR] = 1.65, 95% confidence interval [CI] = 1.28-2.12; p = 0.006). Besides EGFR mutation status, short RTL also contributed to remarkably elevated risk of gefitinib primary resistance (HR = 1.50, 95% CI = 1.05-2.15, p = 0.027). Our results highlight the clinical potential of leukocyte RTL as a novel biomarker in advanced lung adenocarcinoma treated with EGFR-TKIs.},
}
@article {pmid30277496,
year = {2019},
author = {Rocca, MS and Foresta, C and Ferlin, A},
title = {Telomere length: lights and shadows on their role in human reproduction.},
journal = {Biology of reproduction},
volume = {100},
number = {2},
pages = {305-317},
doi = {10.1093/biolre/ioy208},
pmid = {30277496},
issn = {1529-7268},
mesh = {*Embryonic Development ; Female ; Humans ; *Infertility ; Male ; *Ovary ; *Spermatozoa ; *Telomere ; *Telomere Homeostasis ; },
abstract = {Telomeres are repeated DNA sequences whose main function is to preserve genome stability, protecting chromosomes ends from shortening caused by progressive loss during each cell replication or DNA damage. Telomere length regulation is normally achieved by telomerase enzyme, whose activity is progressively shut off during embryonic differentiation in somatic tissues, whereas it is maintained in germ cells, activated lymphocytes, and certain types of stem cell populations. The maintenance of telomerase activity for a longer time is necessary for germ cells to delay telomere erosion, thus avoiding chromosome segregation defects that could contribute to aneuploid or unbalanced gametes. Over the last few years, telomere biology has become an important topic in the field of human reproduction, encouraging several studies to focus on the relation between telomere length and spermatogenesis and male fertility, embryo development and quality during assisted reproductive treatment, and female pathologies as polycystic ovary, premature ovarian insufficiency, and endometriosis. This review analyzes whether telomere length in germ cells is related to reproduction fitness, whether telomere length is related to pathologies associated with male and female fertility, and whether measurement of telomere length could represent a biomarker of germ cell and embryo quality. Telomere length could be considered a molecular marker of spermatogenesis and sperm quality and is somewhat related to male fertility potential. Fewer evidence, although promising, is available for oocytes, female (in)fertility, and embryo quality. The increasing evidence for a role of telomeres and telomere length in human reproduction, indeed, has expanded the historical view of considering them just a marker of aging. Telomere length might have in the future a prognostic potential in couple infertility, especially useful to select best germ cells with the greatest potential of fertilization.},
}
@article {pmid30275518,
year = {2018},
author = {Liu, Y and Lei, T and Zhang, N and Zheng, Y and Kou, P and Shang, S and Yang, M},
title = {Leukocyte telomere length and risk of gastric cardia adenocarcinoma.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {14584},
pmid = {30275518},
issn = {2045-2322},
mesh = {Adenocarcinoma/*epidemiology/genetics/pathology ; Adult ; Aged ; Aged, 80 and over ; Cardia/*pathology ; Case-Control Studies ; China ; Ethnicity ; Female ; *Genetic Predisposition to Disease ; Humans ; Leukocytes/*pathology ; Male ; Middle Aged ; Risk Assessment ; Stomach Neoplasms/*epidemiology/genetics/*pathology ; *Telomere ; Young Adult ; },
abstract = {As a chromosome stabilizer, telomeres play an essential part in maintaining the stability and integrity of human genome. Shortened telomeres have been associated with the development of cancers but it is still largely unclear whether leukocyte telomere length contributes to predisposition of gastric cardia adenocarcinoma (GCA). We conducted a case-control study consisting of 524 GCA cases and 510 controls to assess the association between telomere length in peripheral blood leukocytes and GCA risk in a Chinese Han population. The GCA patients had significantly overall shorter relative leukocyte telomere length (RTL) (median ± SD: 1.10 ± 0.54) when compared with the controls (1.24 ± 0.58). Individuals with the shortest quartile of RTL performed a doubled GCA risk (OR = 2.18; 95% CI = 1.47-3.22, P = 9.90 × 10[-5]) when compared with those with the highest quartile. We also found that telomere shortening and smoking have a significantly synergistic effect in intensifying risk of GCA (OR = 7.03, 95% CI = 4.55-10.86, P = 1.43 × 10[-18]). These findings indicate that short RTL contributes to increased susceptibility of gastric cardia adenocarcinoma and might be a promising marker to identify high-risk individuals combined with lifestyle risk factors.},
}
@article {pmid30274365,
year = {2018},
author = {Autsavapromporn, N and Klunklin, P and Threeratana, C and Tuntiwechapikul, W and Hosoda, M and Tokonami, S},
title = {Short Telomere Length as a Biomarker Risk of Lung Cancer Development Induced by High Radon Levels: A Pilot Study.},
journal = {International journal of environmental research and public health},
volume = {15},
number = {10},
pages = {},
pmid = {30274365},
issn = {1660-4601},
mesh = {Air Pollutants, Radioactive/*toxicity ; *Air Pollution, Indoor ; Biomarkers, Tumor ; Female ; *Housing ; Humans ; Lung Neoplasms/*etiology ; Pilot Projects ; *Radon ; Risk Factors ; *Telomere Shortening ; Thailand ; },
abstract = {Long-term exposure to radon has been determined to be the second leading cause of lung cancer after tobacco smoking. However, an in-depth study of this topic has not been explicitly carried out in Chiang Mai (Thailand). This paper presents the results of an indoor radon level measurement campaign in dwellings of Chiang Mai using total of 110 detectors (CR-39) during one year. The results show that the average radon levels varied from 35 to 219 Bq/m[3], with an overall average of 57 Bq/m[3]. The finding also shows that the average value is higher than the global average value of 39 Bq/m[3]. In addition, to examine the cause of lung cancer development among people with risk of chronic exposure to radon during their lifetime, 35 non-smoker lung cancer patients and 33 healthy nonsmokers were analyzed for telomere length. As expected, telomere length was significantly shorter in lung cancer patients than in healthy nonsmokers. Among healthy nonsmokers, the telomere length was significantly shorter in a high radon group than in an unaffected low radon group. To the best of our knowledge, our research provides the first attempt in describing the shortened telomeres in areas with high levels of environmental radon that might be related to lung cancer development.},
}
@article {pmid30272225,
year = {2018},
author = {Gallicchio, L and Gadalla, SM and Murphy, JD and Simonds, NI},
title = {The Effect of Cancer Treatments on Telomere Length: A Systematic Review of the Literature.},
journal = {Journal of the National Cancer Institute},
volume = {110},
number = {10},
pages = {1048-1058},
pmid = {30272225},
issn = {1460-2105},
support = {HHSN261201400011I/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Antineoplastic Agents/pharmacology/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use ; Humans ; Neoplasms/drug therapy/*epidemiology/*genetics ; Telomere Homeostasis/*drug effects/*genetics ; Treatment Outcome ; },
abstract = {BACKGROUND: It has been hypothesized that cancer treatments cause accelerated aging through a mechanism involving the shortening of telomeres. However, the effect of cancer treatments on telomere length is unclear.<br><br>METHODS: We systematically reviewed the epidemiological evidence evaluating the associations between cancer treatment and changes in telomere length. Searches were performed in PubMed for the period of January 1966 through November 2016 using the following search strategy: telomere AND (cancer OR tumor OR carcinoma OR neoplasm) AND (survivor OR patient). Data were extracted and the quality of studies was assessed.<br><br>RESULTS: A total of 25 studies were included in this review. Ten were solid cancer studies, 11 were hematological malignancy studies, and 4 included a mixed sample of both solid and hematological cancers. Three of the 10 solid tumor studies reported a statistically significant association between cancer treatment and telomere length shortening, and one reported longer telomere length after treatment. Among the hematological cancer studies, three showed statistically significant decreases in telomere length with treatment, and two showed elongation. When these studies were rated using quality criteria, most of the studies were judged to be of moderate quality.<br><br>CONCLUSIONS: The findings from this review indicate that the effect of cancer treatment on telomere length may differ by cancer type and treatment as well as other factors. Definitive conclusions cannot be made based on the published literature, because sample sizes tended to be small; treatments, cancer types, and biospecimens were heterogenous; and the length of follow-up times differed greatly.},
}
@article {pmid30270279,
year = {2018},
author = {Kosebent, EG and Uysal, F and Ozturk, S},
title = {Telomere length and telomerase activity during folliculogenesis in mammals.},
journal = {The Journal of reproduction and development},
volume = {64},
number = {6},
pages = {477-484},
pmid = {30270279},
issn = {1348-4400},
mesh = {Animals ; Female ; Granulosa Cells/metabolism ; Ovarian Follicle/*metabolism ; Telomerase/*metabolism ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; },
abstract = {Telomeres are repetitive non-coding DNA sequences located at the ends of chromosomes in eukaryotic cells. Their most important function is to protect chromosome ends from being recognized as DNA damage. They are also implicated in meiosis and synapse formation. The length of telomeres inevitably shortens at the end of each round of DNA replication and, also, as a consequence of the exposure to oxidative stress and/or genotoxic agents. The enzyme telomerase contributes to telomere lengthening. It has been reported that telomerase is exclusively expressed in germ cells, granulosa cells, early embryos, stem cells, and various types of cancerous cells. Granulosa cells undergo many mitotic divisions and either granulosa cells or oocytes are exposed to a variety of genotoxic agents throughout folliculogenesis; thus, telomerase plays an important role in the maintenance of telomere length. In this review article, we have comprehensively evaluated the studies focusing on the regulation of telomerase expression and activity, as well as telomere length, during folliculogenesis from primordial to antral follicles, in several mammalian species including mice, bovines, and humans. Also, the possible relationships between female infertility caused by follicular development defects and alterations in the telomeres and/or telomerase activity are discussed.},
}
@article {pmid30268887,
year = {2018},
author = {Grun, LK and Teixeira, NDR and Mengden, LV and de Bastiani, MA and Parisi, MM and Bortolin, R and Lavandoski, P and Pierdoná, V and Alves, LB and Moreira, JCF and Mottin, CC and Jones, MH and Klamt, F and Padoin, AV and Guma, FCR and Barbé-Tuana, FM},
title = {TRF1 as a major contributor for telomeres' shortening in the context of obesity.},
journal = {Free radical biology &amp; medicine},
volume = {129},
number = {},
pages = {286-295},
doi = {10.1016/j.freeradbiomed.2018.09.039},
pmid = {30268887},
issn = {1873-4596},
mesh = {Adult ; Cross-Sectional Studies ; Female ; Gene Expression Regulation ; Glutathione/metabolism ; Humans ; Leukocytes, Mononuclear/*metabolism/pathology ; Lipid Peroxidation ; Male ; Obesity/*genetics/metabolism/pathology ; Primary Cell Culture ; Principal Component Analysis ; Protein Carbonylation ; Shelterin Complex ; Signal Transduction ; Telomere/*metabolism/ultrastructure ; *Telomere Shortening ; Telomere-Binding Proteins/*genetics/metabolism ; Telomeric Repeat Binding Protein 1/*genetics/metabolism ; },
abstract = {Obesity is a prevalent multifactorial chronic disorder characterized by metabolic dysregulation. Sustained pro-oxidative mediators trigger harmful consequences that reflect at systemic level and contribute for the establishment of a premature senescent phenotype associated with macromolecular damage (DNA, protein, and lipids). Telomeres are structures that protect chromosome ends and are associated with a six-protein complex called the shelterin complex and subject to regulation. Under pro-oxidant conditions, telomere attrition and the altered expression of the shelterin proteins are central for the establishment of many pathophysiological conditions such as obesity. Thus, considering that individuals with obesity display a systemic oxidative stress profile that may compromise the telomeres length or its regulation, the aim of this study was to investigate telomere homeostasis in patients with obesity and explore broad/systemic associations with the expression of shelterin genes and the plasma redox state. We performed a cross-sectional study in 39 patients with obesity and 27 eutrophic subjects. Telomere length (T/S ratio) and gene expression of shelterin components were performed in peripheral blood mononuclear cells by qPCR. The oxidative damage (lipid peroxidation and protein carbonylation) and non-enzymatic antioxidant system (total radical-trapping antioxidant potential/reactivity, sulfhydryl and GSH content) were evaluated in plasma. Our results demonstrate that independently of comorbidities, individuals with obesity had significantly shorter telomeres, augmented expression of negative regulators of the shelterin complex, increased lipid peroxidation and higher oxidized protein levels associated with increased non-enzymatic antioxidant defenses. Principal component analysis revealed TRF1 as a major contributor for firstly telomeres shortening. In conclusion, our study is first showing a comprehensive analysis of telomeres in the context of obesity, associated with dysregulation of the shelterin components that was partially explained by TRF1 upregulation that could not be reversed by the observed adaptive non-enzymatic antioxidant response.},
}
@article {pmid30266676,
year = {2019},
author = {Helby, J and Petersen, SL and Kornblit, B and Nordestgaard, BG and Mortensen, BK and Bojesen, SE and Sengeløv, H},
title = {Mononuclear Cell Telomere Attrition Is Associated with Overall Survival after Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies.},
journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation},
volume = {25},
number = {3},
pages = {496-504},
doi = {10.1016/j.bbmt.2018.09.025},
pmid = {30266676},
issn = {1523-6536},
mesh = {Adult ; Female ; Hematologic Neoplasms/*mortality/therapy ; Hematopoietic Stem Cell Transplantation/*methods/mortality ; Humans ; Leukocytes, Mononuclear/*ultrastructure ; Male ; Middle Aged ; Survival Analysis ; Telomere/*metabolism/ultrastructure ; *Telomere Shortening ; Transplantation Conditioning ; Transplantation, Homologous ; Young Adult ; },
abstract = {After allogeneic hematopoietic cell transplantation (allo-HCT), transplanted cells rapidly undergo multiple rounds of division. This may cause extensive telomere attrition, which could potentially prohibit further cell division and lead to increased mortality. We therefore characterized the development in telomere length after nonmyeloablative allo-HCT in 240 consecutive patients transplanted because of hematologic malignancies and tested the hypothesis that extensive telomere attrition post-transplant is associated with low overall survival. Telomere length was measured using quantitative PCR in mononuclear cells obtained from donors and recipients pretransplant and in follow-up samples from recipients post-transplant. Telomere attrition at 9 to 15 months post-transplant was calculated as the difference between recipient telomere length at 9 to 15 months post-transplant and donor pretransplant telomere length, divided by donor pretransplant telomere length. Although allo-HCT led to shorter mean telomere length in recipients when compared with donors, recipients had longer mean telomere length 9 to 15 months post-transplant than they had pretransplant. When compared with donor telomeres, recipients with extensive telomere attrition at 9 to 15 months post-transplant had low overall survival (10-year survival from 9 to 15 months post-transplant and onward: 68% in the tertile with least telomere attrition, 57% in the middle tertile, and 39% in the tertile with most attrition; log-rank P = .01). Similarly, after adjusting for potential confounders, recipients with extensive telomere attrition had high all-cause mortality (multivariable adjusted hazard ratio, 1.84 per standard deviation of telomere attrition at 9 to 15 months post-transplant; 95% confidence interval, 1.25 to 2.72; P = .002) and high relapse-related mortality (subhazard ratio, 2.07; 95% confidence interval, 1.14 to 3.76; P = .02). Taken together, telomere attrition may be a clinically relevant marker for identifying patients at high risk of mortality.},
}
@article {pmid30266522,
year = {2018},
author = {Puterman, E and Weiss, J and Lin, J and Schilf, S and Slusher, AL and Johansen, KL and Epel, ES},
title = {Aerobic exercise lengthens telomeres and reduces stress in family caregivers: A randomized controlled trial - Curt Richter Award Paper 2018.},
journal = {Psychoneuroendocrinology},
volume = {98},
number = {},
pages = {245-252},
doi = {10.1016/j.psyneuen.2018.08.002},
pmid = {30266522},
issn = {1873-3360},
support = {R00 HL109247/HL/NHLBI NIH HHS/United States ; UL1 TR000004/TR/NCATS NIH HHS/United States ; T32 HD007242/HD/NICHD NIH HHS/United States ; },
mesh = {Aged ; Body Mass Index ; Cardiorespiratory Fitness ; Caregivers/*psychology ; Exercise/*physiology ; Exercise Test ; Exercise Therapy ; Female ; Humans ; Leukocytes, Mononuclear/physiology ; Male ; Middle Aged ; Stress, Psychological/therapy ; Telomerase/analysis ; Telomere/physiology ; Telomere Homeostasis/*physiology ; },
abstract = {STUDY DESIGN: Family members caring for chronically ill relatives are typically sedentary, chronically stressed, and at high risk of disease. Observational reports suggest caregivers have accelerated cellular aging as indicated by shorter leukocyte telomere lengths. We performed a randomized controlled trial to examine the effect of aerobic exercise on changes in telomerase levels (primary outcome) and telomere lengths (secondary outcome) in inactive caregivers.<br><br>METHODS: 68 female and male community dwelling dementia caregivers who reported high stress and physical inactivity were randomly assigned to a highly supervised aerobic exercise intervention vs. waitlist control group for 24 weeks. Average leukocyte telomere lengths and peripheral blood mononuclear cells' telomerase activity were measured pre- and post-intervention. All staff completing blood draws, fitness testing and bioassays were blinded to group assignment.<br><br>RESULTS: The intervention group completed approximately 40&#x2009;min of aerobic exercise 3-5 times per week, verified by actigraphy. There was high (81%) adherence to 120&#x2009;min/week of aerobic exercise. Groups did not significantly differ in telomerase activity changes across time, but had significant different telomere length changes across time (67.3 base pairs, 95%CI 3.1, 131.5). There were also significant reductions in body mass index and perceived stress and an increase in cardiorespiratory fitness (i.e., VO2peak) in the exercising caregivers versus controls.<br><br>CONCLUSION: In the context of a highly controlled intervention, exercise can induce apparent telomere lengthening, though the mechanisms remain elusive. Our study underscores the importance of increasing participation in aerobic exercise to improve markers of health and attenuate cellular aging in high-risk samples.},
}
@article {pmid30265166,
year = {2018},
author = {Fasching, CL},
title = {Telomere length measurement as a clinical biomarker of aging and disease.},
journal = {Critical reviews in clinical laboratory sciences},
volume = {55},
number = {7},
pages = {443-465},
doi = {10.1080/10408363.2018.1504274},
pmid = {30265166},
issn = {1549-781X},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; *Cardiovascular Diseases/diagnosis/epidemiology/genetics ; Female ; Genetic Markers/*genetics ; Humans ; Male ; Mendelian Randomization Analysis ; Middle Aged ; Observational Studies as Topic ; Telomere/*genetics ; Young Adult ; },
abstract = {Telomere length measurement is increasingly recognized as a clinical gauge for age-related disease risk. There are several methods for studying blood telomere length (BTL) as a clinical biomarker. The first is an observational study approach, which directly measures telomere lengths using either cross-sectional or longitudinal patient cohorts and compares them to a population of age- and sex-matched individuals. These direct traceable measurements can be considered reflective of an individual's current health or disease state. Escalating interest in personalized medicine, access to high-throughput genotyping and resulting acquisition of large volumes of genetic data corroborates the second method, Mendelian randomization (MR). MR employs telomere length-associated genetic variants to indicate predisposition to disease risk based on the genomic composition of the individual. When assessed from cells in the bloodstream, telomeres can show variation from their genetically predisposed lengths due to environmental-induced changes. These alterations in telomere length act as an indicator of cellular health, which, in turn, can provide disease risk status. Overall, BTL measurement is a dynamic marker of biological health and well-being that together with genetically defined telomere lengths can provide insights into improved healthcare for the individual.},
}
@article {pmid30261026,
year = {2018},
author = {Fujishiro, K and Needham, BL and Landsbergis, PA and Seeman, T and Jenny, NS and Diez Roux, AV},
title = {Selected occupational characteristics and change in leukocyte telomere length over 10 years: The Multi-Ethnic Study of Atherosclerosis (MESA).},
journal = {PloS one},
volume = {13},
number = {9},
pages = {e0204704},
pmid = {30261026},
issn = {1932-6203},
support = {P30 AG017265/AG/NIA NIH HHS/United States ; R01 HL076831/HL/NHLBI NIH HHS/United States ; R01 HL101161/HL/NHLBI NIH HHS/United States ; P30 AG028748/AG/NIA NIH HHS/United States ; },
mesh = {Black or African American/genetics ; Aged ; Aged, 80 and over ; Aging/genetics ; Atherosclerosis/genetics ; Ethnicity/*genetics ; Female ; Hispanic or Latino/genetics ; Humans ; Leukocytes/metabolism ; Longitudinal Studies ; Male ; Middle Aged ; *Occupations ; Sex Factors ; Telomere Shortening/*genetics ; White People/genetics ; },
abstract = {Telomere length (TL) is considered as a marker of cell senescence, but factors influencing the rate of TL attrition are not well understood. While one previous study reported the association of occupation and TL, many subsequent studies have failed to find the association. This may be due to heterogeneity within the samples and cross-sectional designs. This longitudinal study examines two occupational characteristics, occupational complexity and hazardous conditions, as predictors of TL attrition in gender- and race/ethnicity-stratified analysis. Leukocyte TL (expressed as T/S ratio) was measured twice over a 10-year period in a multi-racial sample (n = 914). Linear mixed effect models were used to estimate TL attrition associated with occupational complexity and hazardous conditions. Analysis was stratified by gender and race/ethnicity (white, African American, and Latino) and controlled for baseline age, baseline TL, and time since baseline. Higher occupational complexity was associated with slower rates of TL attrition only among white men. Hazardous conditions were not associated with TL attrition for any gender-and-race/ethnicity stratified group. Occupational complexity may influence TL attrition, but the different findings for white men and other groups suggest that a more comprehensive framework is needed to better understand the potential link between occupational characteristics and biological aging.},
}
@article {pmid30256511,
year = {2018},
author = {Lonardo, A and Lugari, S and Nascimbeni, F},
title = {Telomere shortening: An innocent bystander at the crossroad of NASH with ageing and cardiometabolic risk?.},
journal = {Liver international : official journal of the International Association for the Study of the Liver},
volume = {38},
number = {10},
pages = {1730-1732},
doi = {10.1111/liv.13935},
pmid = {30256511},
issn = {1478-3231},
mesh = {Aging ; Humans ; Leukocytes ; *Non-alcoholic Fatty Liver Disease ; Telomere ; *Telomere Shortening ; },
}
@article {pmid30255964,
year = {2019},
author = {Gisselsson, D and Lichtenzstejn, D and Kachko, P and Karlsson, J and Manor, E and Mai, S},
title = {Clonal evolution through genetic bottlenecks and telomere attrition: Potential threats to in vitro data reproducibility.},
journal = {Genes, chromosomes &amp; cancer},
volume = {58},
number = {7},
pages = {452-461},
doi = {10.1002/gcc.22685},
pmid = {30255964},
issn = {1098-2264},
support = {//CIHR/Canada ; },
mesh = {Biomedical Research/*standards ; Cell Line, Tumor ; Clonal Evolution/*genetics ; Humans ; *Models, Genetic ; Mutation/genetics ; Neoplasms/genetics/pathology ; Oncogenes/genetics ; Scientific Experimental Error ; Serial Passage ; Telomere/*genetics/pathology ; },
abstract = {Tissue cultures of immortalized human cells, also known as established cell lines, are broadly accessible and cost-efficient tools for biomedical research. We here review potential genetic sources of systematic error in cell line experiments due to clonal evolution in vitro. In particular, the authors highlight alterations in telomere function over prolonged culture and population bottlenecks, respectively, as two commonly overlooked phenomena that can result in significant alterations in cell line genotypes over just one or a few passages in vitro. These alterations may include changes in mutation status of oncogenes and large scale chromosomal imbalances. We introduce a simple list of factors to be avoided in order to reduce the risk of data misinterpretation due to clonal evolution, including unacknowledged in vitro selection pressures, prolonged culture per se, harsh population size reductions, experiments at early phases after establishment, and the employment of cell lines not sufficiently analyzed by high resolution genetic techniques.},
}
@article {pmid30254011,
year = {2018},
author = {Wu, Z and He, MH and Zhang, LL and Liu, J and Zhang, QD and Zhou, JQ},
title = {Rad6-Bre1 mediated histone H2Bub1 protects uncapped telomeres from exonuclease Exo1 in Saccharomyces cerevisiae.},
journal = {DNA repair},
volume = {72},
number = {},
pages = {64-76},
doi = {10.1016/j.dnarep.2018.09.007},
pmid = {30254011},
issn = {1568-7856},
mesh = {DNA, Single-Stranded/metabolism ; Exodeoxyribonucleases/*metabolism ; Histones/*metabolism ; Nucleosomes/metabolism ; Recombination, Genetic ; Saccharomyces cerevisiae/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomere/*genetics ; Ubiquitin-Conjugating Enzymes/*metabolism ; },
abstract = {Histone H2B lysine 123 mono-ubiquitination (H2Bub1), catalyzed by Rad6 and Bre1 in Saccharomyces cerevisiae, modulates chromatin structure and affects diverse cellular functions. H2Bub1 plays roles in telomeric silencing and telomere replication. Here, we have explored a novel role of H2Bub1 in telomere protection at uncapped telomeres in yku70Δ and cdc13-1 cells. Deletion of RAD6 or BRE1, or mutation of H2BK123R enhances the temperature sensitivity of both yku70Δ and cdc13-1 telomere capping mutants. Consistently, BRE1 deletion increases accumulation of telomeric single-stranded DNA (ssDNA) in yku70Δ and cdc13-1 cells, and EXO1 deletion improves the growth of yku70Δ bre1Δ and cdc13-1 bre1Δ cells and decreases ssDNA accumulation. Additionally, deletion of BRE1 exacerbates the rate of entry into senescence of yku70Δ mre11Δ cells with telomere defects, and increases the recombination of subtelomeric Y' element that is required for telomere maintenance and survivor generation. Furthermore, Exo1 contributes to the abrupt senescence of yku70Δ mre11Δ bre1Δ cells, and Rad51 is essential for Y' recombination to generate survivors. Finally, deletion of BRE1 or mutation of H2BK123R results in nucleosome instability at subtelomeric regions. Collectively, this study provides a mechanistic link between H2Bub1-mediated chromatin structure and telomere protection after telomere uncapping.},
}
@article {pmid30254001,
year = {2018},
author = {Wang, Q and Zhan, Y and Pedersen, NL and Fang, F and Hägg, S},
title = {Telomere Length and All-Cause Mortality: A Meta-analysis.},
journal = {Ageing research reviews},
volume = {48},
number = {},
pages = {11-20},
doi = {10.1016/j.arr.2018.09.002},
pmid = {30254001},
issn = {1872-9649},
mesh = {Aged, 80 and over ; Cause of Death/*trends ; Cohort Studies ; Female ; Humans ; Male ; Mortality ; Registries ; Sweden/epidemiology ; Telomere/immunology/*metabolism/pathology ; Telomere Homeostasis/*physiology ; Telomere Shortening/*physiology ; },
abstract = {Telomere attrition is associated with increased morbidity and mortality of various age-related diseases. Reports of association between telomere length (TL) and all-cause mortality remain inconsistent. In the present study, a meta-analysis was performed using published cohort studies and un-published data from the Swedish Twin Registry (STR). Twenty-five studies were included: four STR cohorts (12,083 individuals with 2517 deaths) and 21 published studies. In the STR studies, one standard deviation (SD) decrement of leukocyte TL corresponded to 13% increased all-cause mortality risk (95% confidence interval [CI]: 7%-19%); individuals in the shortest TL quarter had 44% higher hazard (95% CI: 27%-63%) than those in the longest quarter. Meta-analysis of all eligible studies (121,749 individuals with 21,763 deaths) revealed one SD TL decrement-associated hazard ratio of 1.09 (95% CI: 1.06-1.13); those in the shortest TL quarter had 26% higher hazard (95% CI: 15%-38%) compared to the longest quarter, although between-study heterogeneity was observed. Analyses stratified by age indicated that the hazard ratio was smaller in individuals over 80 years old. In summary, short telomeres are associated with increased all-cause mortality risk in the general population. However, TL measurement techniques and age at measurement contribute to the heterogeneity of effect estimation.},
}
@article {pmid30249661,
year = {2018},
author = {Glustrom, LW and Lyon, KR and Paschini, M and Reyes, CM and Parsonnet, NV and Toro, TB and Lundblad, V and Wuttke, DS},
title = {Single-stranded telomere-binding protein employs a dual rheostat for binding affinity and specificity that drives function.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {115},
number = {41},
pages = {10315-10320},
pmid = {30249661},
issn = {1091-6490},
support = {P30 CA014195/CA/NCI NIH HHS/United States ; R01 GM059414/GM/NIGMS NIH HHS/United States ; R01 GM106060/GM/NIGMS NIH HHS/United States ; T32 GM007240/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites ; DNA, Single-Stranded/*metabolism ; Mutagenesis, Site-Directed ; Mutation ; Saccharomyces cerevisiae/*genetics/growth &amp; development/physiology ; Saccharomyces cerevisiae Proteins/chemistry/*genetics/*metabolism ; Telomere/genetics/metabolism ; Telomere-Binding Proteins/chemistry/*genetics/*metabolism ; },
abstract = {ssDNA, which is involved in numerous aspects of chromosome biology, is managed by a suite of proteins with tailored activities. The majority of these proteins bind ssDNA indiscriminately, exhibiting little apparent sequence preference. However, there are several notable exceptions, including the Saccharomyces cerevisiae Cdc13 protein, which is vital for yeast telomere maintenance. Cdc13 is one of the tightest known binders of ssDNA and is specific for G-rich telomeric sequences. To investigate how these two different biochemical features, affinity and specificity, contribute to function, we created an unbiased panel of alanine mutations across the Cdc13 DNA-binding interface, including several aromatic amino acids that play critical roles in binding activity. A subset of mutant proteins exhibited significant loss in affinity in vitro that, as expected, conferred a profound loss of viability in vivo. Unexpectedly, a second category of mutant proteins displayed an increase in specificity, manifested as an inability to accommodate changes in ssDNA sequence. Yeast strains with specificity-enhanced mutations displayed a gradient of viability in vivo that paralleled the loss in sequence tolerance in vitro, arguing that binding specificity can be fine-tuned to ensure optimal function. We propose that DNA binding by Cdc13 employs a highly cooperative interface whereby sequence diversity is accommodated through plastic binding modes. This suggests that sequence specificity is not a binary choice but rather is a continuum. Even in proteins that are thought to be specific nucleic acid binders, sequence tolerance through the utilization of multiple binding modes may be a broader phenomenon than previously appreciated.},
}
@article {pmid30247678,
year = {2018},
author = {Ghosh, M and Singh, M},
title = {RGG-box in hnRNPA1 specifically recognizes the telomere G-quadruplex DNA and enhances the G-quadruplex unfolding ability of UP1 domain.},
journal = {Nucleic acids research},
volume = {46},
number = {19},
pages = {10246-10261},
pmid = {30247678},
issn = {1362-4962},
mesh = {Amino Acid Sequence ; DNA/chemistry/metabolism ; Escherichia coli ; *G-Quadruplexes ; *Heterogeneous Nuclear Ribonucleoprotein A1/chemistry/metabolism ; Humans ; Nucleic Acid Conformation ; Protein Binding ; *Protein Folding ; Protein Interaction Domains and Motifs/*physiology ; Telomere/*chemistry/*metabolism ; },
abstract = {hnRNPA1 is a member of heteronuclear ribonucleoproteins that has been shown to promote telomere elongation apart from its roles in RNA transport and alternative splicing. It is a modular protein with an N-terminal domain called UP1 that consists of two RNA Recognition Motifs (RRM1 and RRM2 domains) and a C-terminal region that harbors functional motifs such as RGG-box, a prion-like domain, and a nuclear shuttling sequence. UP1 has been reported to bind and destabilize telomeric DNA G-quadruplexes and thereby participate in DNA telomere remodeling. An RGG-box motif that consists of four RGG repeats (containing arginine and glycine residues) is located C-terminal to the UP1 domain and constitutes an additional nucleic acid and protein-binding domain. However, the precise role of the RGG-box of hnRNPA1 in telomere DNA recognition and G-quadruplex DNA unfolding remains unexplored. Here, we show that the isolated RGG-box interacts specifically with the structured telomere G-quadruplex DNA but not with the single-stranded DNA. Further the interaction of the RGG-box with the G-quadruplex DNA is dependent on the loop nucleotides of the G-quadruplex. Finally, we show that the RGG-box enhances the G-quadruplex unfolding activity of the adjacent UP1 domain. We propose that UP1 and RGG-box act synergistically to achieve complete telomere G-quadruplex DNA unfolding.},
}
@article {pmid30244523,
year = {2018},
author = {Razdan, N and Vasilopoulos, T and Herbig, U},
title = {Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts.},
journal = {Aging cell},
volume = {17},
number = {6},
pages = {e12838},
pmid = {30244523},
issn = {1474-9726},
support = {R01 CA136533/CA/NCI NIH HHS/United States ; R01 CA184572/CA/NCI NIH HHS/United States ; },
mesh = {*Cell Transdifferentiation/drug effects ; Cellular Senescence/drug effects ; DNA Damage ; Humans ; Myofibroblasts/drug effects/metabolism/*pathology ; NADPH Oxidase 4/metabolism ; Paracrine Communication/drug effects ; Reactive Oxygen Species/metabolism ; Smad3 Protein/metabolism ; Telomerase/metabolism ; Telomere/metabolism/*pathology ; Transforming Growth Factor beta1/pharmacology ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Cells that had undergone telomere dysfunction-induced senescence secrete numerous cytokines and other molecules, collectively called the senescence-associated secretory phenotype (SASP). Although certain SASP factors have been demonstrated to promote cellular senescence in neighboring cells in a paracrine manner, the mechanisms leading to bystander senescence and the functional significance of these effects are currently unclear. Here, we demonstrate that TGF-β1, a component of the SASP, causes telomere dysfunction in normal somatic human fibroblasts in a Smad3/NOX4/ROS-dependent manner. Surprisingly, instead of activating cellular senescence, TGF-β1-induced telomere dysfunction caused fibroblasts to transdifferentiate into α-SMA-expressing myofibroblasts, a mesenchymal and contractile cell type that is critical for wound healing and tissue repair. Despite the presence of dysfunctional telomeres, transdifferentiated cells acquired the ability to contract collagen lattices and displayed a gene expression signature characteristic of functional myofibroblasts. Significantly, the formation of dysfunctional telomeres and downstream p53 signaling was necessary for myofibroblast transdifferentiation, as suppressing telomere dysfunction by expression of hTERT, inhibiting the signaling pathways that lead to stochastic telomere dysfunction, and suppressing p53 function prevented the generation of myofibroblasts in response to TGF-β1 signaling. Furthermore, inducing telomere dysfunction using shRNA against TRF2 also caused cells to develop features that are characteristic of myofibroblasts, even in the absence of exogenous TGF-β1. Overall, our data demonstrate that telomere dysfunction is not only compatible with cell functionality, but they also demonstrate that the generation of dysfunctional telomeres is an essential step for transdifferentiation of human fibroblasts into myofibroblasts.},
}
@article {pmid30243131,
year = {2018},
author = {Huang, YC and Wang, LJ and Tseng, PT and Hung, CF and Lin, PY},
title = {Leukocyte telomere length in patients with bipolar disorder: An updated meta-analysis and subgroup analysis by mood status.},
journal = {Psychiatry research},
volume = {270},
number = {},
pages = {41-49},
doi = {10.1016/j.psychres.2018.09.035},
pmid = {30243131},
issn = {1872-7123},
mesh = {Adult ; Bipolar Disorder/*metabolism ; Cellular Senescence/*physiology ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Telomere Shortening/*physiology ; Young Adult ; },
abstract = {The purpose of the present meta-analysis was to compare leukocyte telomere length (LTL), a proposed marker for cell aging, between patients with bipolar disorder (BD) and healthy controls and explore potential moderators for the LTL difference. We searched for the major research databases up to May 2018 for studies that examined LTL in patients with BD and healthy controls. The effect sizes (ESs) of LTL differences from the included studies were pooled using a random-effects model. Furthermore, we adopted subgroup analysis to investigate whether mood status of BD patients or methods for measuring telomere length may influence such differences. We included 10 studies, with a total of 579 patients and 551 controls, in the current meta-analysis and observed significantly shorter LTL in BD patients compared to control subjects. Such differences were found in studies with patients in all mood statuses and in studies using different methods for measuring telomere length. Late-stage BD patients demonstrated more significant LTL shortening than early-stage BD patients. Our current results support the hypothesis of accelerated aging in BD patients. In the future, further properly controlled longitudinal studies are warranted to determine whether LTL changes with disease status or medication use in BD patients.},
}
@article {pmid30243019,
year = {2018},
author = {Kresovich, JK and Parks, CG and Sandler, DP and Taylor, JA},
title = {Reproductive history and blood cell telomere length.},
journal = {Aging},
volume = {10},
number = {9},
pages = {2383-2393},
pmid = {30243019},
issn = {1945-4589},
support = {Z01 ES049032/ImNIH/Intramural NIH HHS/United States ; Z01 ES049033/ImNIH/Intramural NIH HHS/United States ; Z01 ES044005/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; Aged ; Estrogens/physiology ; Female ; Humans ; Male ; Middle Aged ; *Reproductive History ; Sex Characteristics ; *Telomere ; },
abstract = {Telomeres are repetitive nucleotide sequences that protect against chromosomal shortening. They are replenished by telomerase, an enzyme that may be activated by estrogen. Women have longer telomeres than men; this difference might be due to estrogen exposure. We hypothesized that reproductive histories reflecting greater estrogen exposure will be associated with longer blood cell telomeres. Among women in the Sister Study (n= 1,048), we examined telomere length in relation to self-reported data on reproductive history. The difference between age at menarche and last menstrual period was used to approximate the reproductive period. Relative telomere length (rTL) was measured using qPCR. After adjustment, rTL decreased with longer reproductive period (β= -0.019, 95% CI: -0.04, -0.00, p= 0.03). Premenopausal women had shorter rTL than postmenopausal women (β= -0.051, 95% CI: -0.12, 0.01, p= 0.13). Longer breastfeeding duration was associated with longer rTL (β= 0.027, 95% CI: 0.01, 0.05, p=0.01); increasing parity was associated with shorter rTL (β = -0.016, 95% CI: -0.03, 0.00, p=0.07). Duration of exogenous hormone use was not associated with rTL. Reproductive histories reflecting greater endogenous estrogen exposure were associated with shorter rTL. Our findings suggest that longer telomeres in women are unlikely to be explained by greater estrogen exposure.},
}
@article {pmid30233111,
year = {2018},
author = {Rathore, M and Abraham, J},
title = {Implication of Asana, Pranayama and Meditation on Telomere Stability.},
journal = {International journal of yoga},
volume = {11},
number = {3},
pages = {186-193},
pmid = {30233111},
issn = {0973-6131},
abstract = {Telomeres, the repetitive sequences that protect the ends of chromosomes, help to maintain genomic integrity and are of key importance to human health. Telomeres progressively shorten throughout life and a number of studies have shown shorter telomere length to be associated with lifestyle disorders. Previous studies also indicate that yoga and lifestyle-based intervention have significant role on oxidative DNA damage and cellular aging. However, very few publications investigate telomere stability and its implication from the point of view of asana, pranayama, and meditation. In this context, a review was conducted to systematically assess the available data on the effectiveness of asana, pranayama, and meditation in maintaining telomere and telomerase. Literature search was performed using the following electronic databases: Cochrane Library, NCBI, PubMed, Google Scholar, EMBASE, and Web of Science. We explored the possible mechanisms of how asana, pranayama, and meditation might be affecting telomere length and telomerase. Moreover, results showed that asana and pranayama increase the oxygen flow to the cells and meditation reduces the stress level by modulating the hypothalamic-pituitary-adrenal axis. Summing up the result, it can be concluded that practice of asana, pranayama, and meditation can help to maintain genomic integrity and are of key importance to human health and lifestyle disorders.},
}
@article {pmid30229407,
year = {2019},
author = {Zhu, Y and Liu, X and Ding, X and Wang, F and Geng, X},
title = {Telomere and its role in the aging pathways: telomere shortening, cell senescence and mitochondria dysfunction.},
journal = {Biogerontology},
volume = {20},
number = {1},
pages = {1-16},
pmid = {30229407},
issn = {1573-6768},
mesh = {Aging/*physiology ; Cellular Senescence/physiology ; Humans ; Mitochondrial Turnover/physiology ; Telomere/*physiology ; Telomere Shortening ; },
abstract = {Aging is a biological process characterized by a progressive functional decline in tissues and organs, which eventually leads to mortality. Telomeres, the repetitive DNA repeat sequences at the end of linear eukaryotic chromosomes protecting chromosome ends from degradation and illegitimate recombination, play a crucial role in cell fate and aging. Due to the mechanism of replication, telomeres shorten as cells proliferate, which consequently contributes to cellular senescence and mitochondrial dysfunction. Cells are the basic unit of organismal structure and function, and mitochondria are the powerhouse and metabolic center of cells. Therefore, cellular senescence and mitochondrial dysfunction would result in tissue or organ degeneration and dysfunction followed by somatic aging through multiple pathways. In this review, we summarized the main mechanisms of cellular senescence, mitochondrial malfunction and aging triggered by telomere attrition. Understanding the molecular mechanisms involved in the aging process may elicit new strategies for improving health and extending lifespan.},
}
@article {pmid30226859,
year = {2018},
author = {Brosnan-Cashman, JA and Yuan, M and Graham, MK and Rizzo, AJ and Myers, KM and Davis, C and Zhang, R and Esopi, DM and Raabe, EH and Eberhart, CG and Heaphy, CM and Meeker, AK},
title = {ATRX loss induces multiple hallmarks of the alternative lengthening of telomeres (ALT) phenotype in human glioma cell lines in a cell line-specific manner.},
journal = {PloS one},
volume = {13},
number = {9},
pages = {e0204159},
pmid = {30226859},
issn = {1932-6203},
support = {T32 CA009110/CA/NCI NIH HHS/United States ; F32 CA213742/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Chromatin ; DNA Helicases ; Glioma/*genetics ; Humans ; Phenotype ; Telomerase ; Telomere/*genetics ; Telomere Homeostasis/genetics ; X-linked Nuclear Protein/*genetics ; },
abstract = {Cancers must maintain their telomeres at lengths sufficient for cell survival. In several cancer subtypes, a recombination-like mechanism termed alternative lengthening of telomeres (ALT), is frequently used for telomere length maintenance. Cancers utilizing ALT often have lost functional ATRX, a chromatin remodeling protein, through mutation or deletion, thereby strongly implicating ATRX as an ALT suppressor. Herein, we have generated functional ATRX knockouts in four telomerase-positive, ALT-negative human glioma cell lines: MOG-G-UVW, SF188, U-251 and UW479. After loss of ATRX, two of the four cell lines (U-251 and UW479) show multiple characteristics of ALT-positive cells, including ultrabright telomeric DNA foci, ALT-associated PML bodies, and c-circles. However, telomerase activity and overall telomere length heterogeneity are unaffected after ATRX loss, regardless of cellular context. The two cell lines that showed ALT hallmarks after complete ATRX loss also did so upon ATRX depletion via shRNA-mediated knockdown. These results suggest that other genomic or epigenetic events, in addition to ATRX loss, are necessary for the induction of ALT in human cancer.},
}
@article {pmid30225068,
year = {2018},
author = {Pepper, GV and Bateson, M and Nettle, D},
title = {Telomeres as integrative markers of exposure to stress and adversity: a systematic review and meta-analysis.},
journal = {Royal Society open science},
volume = {5},
number = {8},
pages = {180744},
pmid = {30225068},
issn = {2054-5703},
support = {NC/K000802/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; },
abstract = {Telomeres have been proposed as a biomarker that integrates the impacts of different kinds of stress and adversity into a common currency. There has as yet been no overall comparison of how different classes of exposure associate with telomeres. We present a meta-analysis of the literature relating telomere measures to stresses and adversities in humans. The analysed dataset contained 543 associations from 138 studies involving 402 116 people. Overall, there was a weak association between telomere variables and exposures (greater adversity, shorter telomeres: r = -0.15, 95% CI -0.18 to -0.11). This was not driven by any one type of exposure, because significant associations were found separately for physical diseases, environmental hazards, nutrition, psychiatric illness, smoking, physical activity, psychosocial and socioeconomic exposures. Methodological features of the studies did not explain any substantial proportion of the heterogeneity in association strength. There was, however, evidence consistent with publication bias, with unexpectedly strong negative associations reported by studies with small samples. Restricting analysis to sample sizes greater than 100 attenuated the overall association substantially (r = -0.09, 95% CI -0.13 to -0.05). Most studies were underpowered to detect the typical association magnitude. The literature is dominated by cross-sectional and correlational studies which makes causal interpretation problematic.},
}
@article {pmid30224051,
year = {2018},
author = {Jokhun, DS and Shang, Y and Shivashankar, GV},
title = {Actin Dynamics Couples Extracellular Signals to the Mobility and Molecular Stability of Telomeres.},
journal = {Biophysical journal},
volume = {115},
number = {7},
pages = {1166-1179},
pmid = {30224051},
issn = {1542-0086},
mesh = {Actins/*metabolism ; Animals ; Biomechanical Phenomena ; Cytoskeleton/metabolism ; Extracellular Space/*metabolism ; Lamin Type A/metabolism ; Mice ; NIH 3T3 Cells ; Nuclear Matrix/metabolism ; *Signal Transduction ; Telomere/*metabolism ; },
abstract = {Genome regulatory programs such as telomere functioning require extracellular signals to be transmitted from the microenvironment to the nucleus and chromatin. Although the cytoskeleton has been shown to directly transmit stresses, we show that the intrinsically dynamic nature of the actin cytoskeleton is important in relaying extracellular signals to telomeres. Interestingly, this mechanical pathway not only transmits physical stimuli but also chemical stimuli. The cytoskeletal network continuously reorganizes and applies dynamic forces on the nucleus and feeds into the regulation of telomere dynamics. We further found that distal telomeres are mechanically coupled in a length- and timescale-dependent manner and identified nesprin 2G as well as lamin A/C as being essential to regulate their translational dynamics. Finally, we demonstrated that such mechanotransduction events impinge on the binding dynamics of critical telomere binding proteins. Our results highlight an overarching physical pathway that regulates positional and molecular stability of telomeres.},
}
@article {pmid30223372,
year = {2018},
author = {Zhao, K and Li, Y},
title = {Can telomere length predict contrast-induced nephropathy?.},
journal = {International journal of cardiology},
volume = {271},
number = {},
pages = {350},
doi = {10.1016/j.ijcard.2018.07.021},
pmid = {30223372},
issn = {1874-1754},
mesh = {Humans ; *Kidney Diseases ; *Telomere ; },
}
@article {pmid30223048,
year = {2018},
author = {Wulaningsih, W and Hardy, R and Wong, A and Kuh, D},
title = {Parental age and offspring leukocyte telomere length and attrition in midlife: Evidence from the 1946 British birth cohort.},
journal = {Experimental gerontology},
volume = {112},
number = {},
pages = {92-96},
pmid = {30223048},
issn = {1873-6815},
support = {/WT_/Wellcome Trust/United Kingdom ; MC_UU_12019/1/MRC_/Medical Research Council/United Kingdom ; MC_UU_12019/2/MRC_/Medical Research Council/United Kingdom ; MC_UU_12019/4/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Female ; Humans ; Leukocytes/*physiology ; Linear Models ; Male ; Middle Aged ; *Parents ; Parturition ; Reproductive Health ; Telomere/*genetics ; },
abstract = {BACKGROUND: There is evidence that paternal age may influence offspring telomere length, but the joint effects of father's and mother's age are unclear. We evaluated whether parental ages, individually and jointly, were associated with offspring telomere length and shortening.<br><br>METHODS: We included 2305 British birth cohort participants with measured leukocyte telomere length (LTL) at age 53, among whom 941 had a second measurement at age 60-64. Linear regressions were performed to assess the associations of father's and mother's age at birth and the parental age gap, i.e. the difference between maternal and paternal age with LTL and LTL change.<br><br>RESULTS: A one year increase in father's age corresponded to a 0.26% (95% CI: 0.04-0.47%) increase in offspring LTL at age 53 in the sex-adjusted model. No association was observed for mother's age. Associations of father's or mother's age with offspring LTL at age 53 went to opposite directions when both parental ages were included together. For the difference in parental age, every year that fathers were older than mothers corresponded to a 0.94% (95% CI, 0.38-1.50%) increase in LTL at age 53 after adjustment for potential confounders. Neither parental ages nor the difference in parental ages were correlated with LTL change.<br><br>CONCLUSION: There was a joint effect of parental ages on offspring telomere length, further denoting a complex role of reproductive age in offspring health and ageing.},
}
@article {pmid30220704,
year = {2018},
author = {Esch, T and Kream, RM and Stefano, GB},
title = {Chromosomal Processes in Mind-Body Medicine: Chronic Stress, Cell Aging, and Telomere Length.},
journal = {Medical science monitor basic research},
volume = {24},
number = {},
pages = {134-140},
pmid = {30220704},
issn = {2325-4416},
mesh = {Aging/physiology ; Cellular Senescence/*physiology ; Chronic Disease ; Humans ; Mind-Body Therapies/*methods/psychology ; Relaxation Therapy/methods ; Stress, Psychological/complications ; Telomere/physiology ; Telomere Homeostasis/*physiology ; },
abstract = {Stress affects cellular aging and inflammatory and chromosomal processes, including telomere length, thereby potentially compromising health and facilitating disease onset and progression. Stress-related diseases and strategies to manage stress usually require integrative or behavioral therapeutic approaches that also operate on cellular levels. Mind-body medicine (MBM) uses the interaction between the mind, body, behavior, and the environment to correct physical and psychological malfunctions, thus ameliorating disease states and improving health. The relaxation response (RR) is a physiological opponent of stress and the stress response (SR) (i.e., fight-or-flight response), also invoking molecular anti-stress processes. Techniques that elicit the RR are at the core of practically all MBM interventions. We surmise that these techniques can also affect chromosomal and telomere processes, molecular aging, and the modulation of inflammatory states on cellular levels.},
}
@article {pmid30217473,
year = {2019},
author = {Thriveni, K and Raju, A and Kumar, RV and Krishnamurthy, S and Chaluvarayaswamy, R},
title = {Patterns of Relative Telomere Length is Associated With hTERT Gene Expression in the Tissue of Patients With Breast Cancer.},
journal = {Clinical breast cancer},
volume = {19},
number = {1},
pages = {27-34},
doi = {10.1016/j.clbc.2018.07.021},
pmid = {30217473},
issn = {1938-0666},
mesh = {Adult ; Biomarkers, Tumor/*genetics ; Breast Neoplasms/genetics/*pathology/surgery ; Carcinoma, Ductal, Breast/genetics/*pathology/surgery ; Carcinoma, Lobular/genetics/*pathology/surgery ; Case-Control Studies ; Cross-Sectional Studies ; Female ; Follow-Up Studies ; Humans ; Neoplasm Grading ; Neoplasm Staging ; Receptor, ErbB-2/metabolism ; Receptors, Estrogen/metabolism ; Receptors, Progesterone/metabolism ; Telomerase/*genetics ; Telomere Shortening/*genetics ; },
abstract = {BACKGROUND: Homeostasis of telomere in breast cancer might be altered as a result of cumulative effects of various factors causing genomic instability and affecting prognosis. This study aimed to compare the relative telomere length (RTL) and hTERT mRNA expression in the tissue of patients with breast cancer along with the clinicopathologic parameters.<br><br>PATIENTS AND METHODS: Frozen tumor tissues and adjacent normal breast tissue from 98 patients with invasive ductal breast cancer were used for the analysis. RTL and hTERT mRNA expression were measured using quantitative real time polymerase chain reaction.<br><br>RESULTS: Among the 98 cases, 51% had an early-stage carcinoma, 66% were tumor size&#xa0;< 5 cm, 30% were node-negative, and 20% were low-grade tumors. In this study, 63% of cases showed higher hTERT gene expression with an odds ratio of 2.77 (P&#xa0;= .02). The median RTL for elongated telomere was 3.49, and the value was significantly elevated when compared with the shorter telomere. Shortened RTL was present in 60% of early-stage cancer cases, 55% where the tumor size was&#xa0;< 5 cm, 72% of the lymph node-negative cases, and 68% of low-grade carcinoma. Significantly elongated RTL, with median 4.22, 3.19, 3.17, and 3.28 was observed (P&#xa0;< .05) in the advanced stage, larger tumor size, node-positive, and high-grade cases respectively.<br><br>CONCLUSION: In this study, shortened telomere was observed in early-stage cancer, and elongated telomere was found in advanced diseases. However, 13% of patients with lower hTERT gene expression showed elongated telomeres, indicating relative telomere length measurement in tissue is different from blood leukocyte, showing the dynamic process of tumorigenesis in tissue.},
}
@article {pmid30214863,
year = {2018},
author = {Zhao, B and Vo, HQ and Johnston, FH and Negishi, K},
title = {Air pollution and telomere length: a systematic review of 12,058 subjects.},
journal = {Cardiovascular diagnosis and therapy},
volume = {8},
number = {4},
pages = {480-492},
pmid = {30214863},
issn = {2223-3652},
abstract = {BACKGROUND: Over recent decades, adverse effects of ambient air pollution on the cardiovascular system have been clearly demonstrated. However, the underlying mechanisms are not fully elucidated. Air pollution may accelerates biological aging and thereby the susceptibility to cardiovascular diseases (CVDs). Telomeres are tandem repetitive DNA complexes that play a critical role in maintaining chromosome stability. There are, however, heterogeneities among the reported effects of air pollution on telomere. This study sought to evaluate the existing literature on the association between air pollution and telomere length (TL).<br><br>METHODS: Two reviewers independently searched on electronic databases including PUBMED, EMBASE, SCOPUS, WEB OF SCIENCE and Ovid. The key terms were "air pollution" and "telomere" without language restriction. Articles relating to tobacco smoke were excluded.<br><br>RESULTS: A total of 12,058 subjects from 25 articles remained for final review. All were observational studies: 14 cross-sectional, 6 cohort and 5 case-control studies. Nineteen (76%) assessed leukocyte telomere length (LTL) of which 15 found associations between air pollution and shorter TL, 2 with longer TL, 1 had mixed results, and a study of patients with type 2 diabetes found non-significant associations with TL. One found longer TL from saliva. The remaining studies were of placental cells, buccal cells or sperm and all reported shorter TL associated with air pollution. Particulate matter (PM) was investigated in 8 articles, and the remainder assessed black carbon (BC), benzene, lead, cadmium and polycyclic aromatic hydrocarbon (PAH). Geographically, 11 studies were conducted in Europe, with 10 in Asia and 4 in North America. While all followed Cawthon's protocol for TL assessment, discordance in the reporting formats did not allow us to perform a quantitative meta-analysis.<br><br>CONCLUSIONS: Most of the studies support the association of shorter TL with air pollution. Uniform reporting format would be warranted for future studies to estimate true effect size of air pollution on TL.},
}
@article {pmid30212832,
year = {2018},
author = {Wang, F and Sheng, JF and Cai, L and Xu, Y and Liao, H and Tao, ZZ},
title = {The Telomerase and Alternative Lengthening of Telomeres Mechanisms Regulate Laryngeal Cancer Cell Apoptosis via the PI3K/Akt Pathway.},
journal = {ORL; journal for oto-rhino-laryngology and its related specialties},
volume = {80},
number = {5-6},
pages = {227-237},
doi = {10.1159/000489461},
pmid = {30212832},
issn = {1423-0275},
mesh = {Animals ; Apoptosis/*physiology ; Blotting, Western ; Carcinoma, Squamous Cell/pathology/*physiopathology ; Cell Line, Tumor ; Disease Models, Animal ; Flow Cytometry ; *Gene Silencing ; Laryngeal Neoplasms/pathology/*physiopathology ; Mice, Nude ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Plasmids ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/*metabolism ; RNA, Small Interfering/physiology ; Telomerase/genetics/*metabolism ; Telomere/*physiology ; },
abstract = {PURPOSE: To investigate the possible telomerase and alternative lengthening of telomeres (ALT) mechanisms influencing the apoptosis of laryngeal squamous cells.<br><br>MATERIALS AND METHODS: The effects of the telomerase mechanism were observed by knockdown of human telomerase reverse transcriptase (hTERT). The ALT mechanism was induced by silencing related genes including TRF2, RAD51, and NBS1. Effects of telomerase and ALT mechanisms on tumor development were confirmed by xenograft tumors model. Tumor cell apoptosis was investigated by flow cytometry and Hoechst staining. Caspase-3 activity assay and Western blot were performed to investigate the possible mechanisms.<br><br>RESULTS: After silencing ALT- and telomerase mechanism-related genes, Bax and Bcl-2 were increased, and nuclear factor (NF)-&#x3ba;B translocation and PI3K/Akt phosphorylation were inhibited.<br><br>CONCLUSIONS: The inhibition of telomere-related genes inhibited the growth of laryngeal squamous cell carcinoma by promoting cell apoptosis via the PI3K/Akt pathway.},
}
@article {pmid30208911,
year = {2018},
author = {Tsamou, M and Martens, DS and Cox, B and Madhloum, N and Vrijens, K and Nawrot, TS},
title = {Sex-specific associations between telomere length and candidate miRNA expression in placenta.},
journal = {Journal of translational medicine},
volume = {16},
number = {1},
pages = {254},
pmid = {30208911},
issn = {1479-5876},
support = {ERC-2012-StG 310898//H2020 European Research Council/International ; FWO G073315N//Fonds Wetenschappelijk Onderzoek/International ; 12D7718N//Fonds Wetenschappelijk Onderzoek/International ; 12Q0517N//Fonds Wetenschappelijk Onderzoek/International ; },
mesh = {Adult ; Female ; *Gene Expression Regulation ; Humans ; Infant, Newborn ; Male ; MicroRNAs/*genetics/metabolism ; Placenta/*metabolism ; Pregnancy ; *Sex Characteristics ; },
abstract = {BACKGROUND: In the early-life environment, proper development of the placenta is essential for both fetal and maternal health. Telomere length at birth has been related to life expectancy. MicroRNAs (miRNAs) as potential epigenetic determinants of telomere length at birth have not been identified. In this study, we investigate whether placental miRNA expression is associated with placental telomere length at birth.<br><br>METHODS: We measured the expression of seven candidate miRNAs (miR-16-5p, -20a-5p, -21-5p, -34a-5p, 146a-5p, -210-3p and -222-3p) in placental tissue at birth in 203 mother-newborn (51.7% girls) pairs from the ENVIRONAGE birth cohort. We selected miRNAs known to be involved in crucial cellular processes such as inflammation, oxidative stress, cellular senescence related to aging. Placental miRNA expression and relative average placental telomere length were measured using RT-qPCR.<br><br>RESULTS: Both before and after adjustment for potential covariates including newborn's ethnicity, gestational age, paternal age, maternal smoking status, maternal educational status, parity, date of delivery and outdoor temperature during the 3rd trimester of pregnancy, placental miR-34a, miR-146a, miR-210 and miR-222 expression were significantly (p&#x2009;&#x2264;&#x2009;0.03) and positively associated with placental relative telomere length in newborn girls. In newborn boys, only higher expression of placental miR-21 was weakly (p&#x2009;=&#x2009;0.08) associated with shorter placental telomere length. Significant miRNAs explain around 6-8% of the telomere length variance at birth.<br><br>CONCLUSIONS: Placental miR-21, miR-34a, miR-146a, miR-210 and miR-222 exhibit sex-specific associations with telomere length in placenta. Our results indicate miRNA expression in placental tissue could be an important determinant in the process of aging starting from early life onwards.},
}
@article {pmid30208292,
year = {2018},
author = {de Lange, T},
title = {Shelterin-Mediated Telomere Protection.},
journal = {Annual review of genetics},
volume = {52},
number = {},
pages = {223-247},
doi = {10.1146/annurev-genet-032918-021921},
pmid = {30208292},
issn = {1545-2948},
support = {R01 AG016642/AG/NIA NIH HHS/United States ; R01 CA160924/CA/NCI NIH HHS/United States ; R35 CA210036/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins/genetics ; Chromosomes ; DNA Breaks, Double-Stranded ; DNA Damage/genetics ; DNA End-Joining Repair ; DNA Repair/*genetics ; Humans ; Mice ; Poly (ADP-Ribose) Polymerase-1/genetics ; Recombinational DNA Repair/*genetics ; Telomere/*genetics ; Telomeric Repeat Binding Protein 2/*genetics ; },
abstract = {For more than a decade, it has been known that mammalian cells use shelterin to protect chromosome ends. Much progress has been made on the mechanism by which shelterin prevents telomeres from inadvertently activating DNA damage signaling and double-strand break (DSB) repair pathways. Shelterin averts activation of three DNA damage response enzymes [the ataxia-telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases and poly(ADP-ribose) polymerase 1 (PARP1)], blocks three DSB repair pathways [classical nonhomologous end joining (c-NHEJ), alternative (alt)-NHEJ, and homology-directed repair (HDR)], and prevents hyper-resection at telomeres. For several of these functions, mechanistic insights have emerged. In addition, much has been learned about how shelterin maintains the telomeric 3' overhang, forms and protects the t-loop structure, and promotes replication through telomeres. These studies revealed that shelterin is compartmentalized, with individual subunits dedicated to distinct aspects of the end-protection problem. This review focuses on the current knowledge of shelterin-mediated telomere protection, highlights differences between human and mouse shelterin, and discusses some of the questions that remain.},
}
@article {pmid30203894,
year = {2018},
author = {Rachakonda, S and Kong, H and Srinivas, N and Garcia-Casado, Z and Requena, C and Fallah, M and Heidenreich, B and Planelles, D and Traves, V and Schadendorf, D and Nagore, E and Kumar, R},
title = {Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk.},
journal = {Genes, chromosomes &amp; cancer},
volume = {57},
number = {11},
pages = {564-572},
doi = {10.1002/gcc.22669},
pmid = {30203894},
issn = {1098-2264},
support = {01KT15511//German Ministry of Education and Research/International ; //German Consortium for Translational Research (DKTK)/International ; },
mesh = {Adult ; Case-Control Studies ; Female ; *Genetic Predisposition to Disease/epidemiology/genetics ; Genome-Wide Association Study ; Humans ; Male ; *Melanoma/epidemiology/genetics ; Middle Aged ; Mutation/genetics ; Promoter Regions, Genetic/*genetics ; Telomerase/*genetics ; Telomere/*genetics ; Young Adult ; },
abstract = {Telomere repeats at chromosomal ends, critical for genomic integrity, undergo age-dependent attrition and telomere length has been associated with different disorders including cancers. In this study, based on 1469 patients and 1158 healthy controls, we show a statistically significant (P = 6 × 10[-10]) association between increased telomere length and melanoma risk. Mendelian randomization, using 5 telomere length-associated polymorphisms, ruled out confounding factors or reverse causality and showed association between increased telomere length and melanoma risk with odds ratio of 2.66 (95% confidence interval: 2.07-3.25). Age-dependent telomere attrition was faster in melanoma cases than controls (P = .01). The carriers of a highly penetrant germline -57A>C TERT promoter mutation, in a previously reported melanoma family, had longer telomeres than the noncarriers. The mutation causes increased TERT and telomerase levels through creation of a binding motif for E-twenty six (ETS) transcription factors and the carriers develop melanoma with an early age of onset and rapid progression to metastasis. In analogy, we hypothesize that increased telomere length in melanoma patients reflects stochastic increased telomerase levels due to common genetic variation. Paradoxically, we observed shorter telomeres (P = 1 × 10[-5]) in primary tumors from unrelated melanoma patients with (121) than without (170) somatic TERT promoter mutations that similar to the germline mutation, also create binding motifs for ETS transcription factors. However, the age-dependent telomere attrition was faster in tumors with the TERT promoter mutations than in those without such mutations. Besides a robust association between increased telomere length and risk, our data show a perturbed telomere homeostasis in melanoma.},
}
@article {pmid30203702,
year = {2018},
author = {Chen, B and Zhang, Y and Yang, Y and Chen, S and Xu, A and Wu, L and Xu, S},
title = {Involvement of telomerase activity inhibition and telomere dysfunction in silver nanoparticles anticancer effects.},
journal = {Nanomedicine (London, England)},
volume = {13},
number = {16},
pages = {2067-2082},
doi = {10.2217/nnm-2018-0036},
pmid = {30203702},
issn = {1748-6963},
mesh = {A549 Cells ; Cell Survival/drug effects ; Enzyme Activation/drug effects ; HeLa Cells ; Hep G2 Cells ; Humans ; Metal Nanoparticles/*chemistry/*therapeutic use ; Silver/*chemistry ; Telomerase/*metabolism ; Telomere/drug effects/*metabolism/pathology ; },
abstract = {AIM: To investigate the possible mechanisms of telomerase and telomere underlying the anticancer effects of silver nanoparticles (AgNPs).<br><br>MATERIALS &amp; METHODS: 25nm polyvinylpyrrolidone-coated AgNPs were used. The telomerase activity and telomere function were evaluated. The anticancer effects of AgNPs were gauged with cell viability assay under different statement of telomerase and telomere.<br><br>RESULTS &amp; CONCLUSION: AgNPs could inhibit telomerase activity and lead to telomere shortening and dysfunction. Overexpression of telomerase attenuated the anticancer activity of AgNPs, whereas downregulation of telomerase activity or dysfunction of the telomere enhanced the cytotoxicity of AgNPs in HeLa cells. Our findings provided strong evidence that the anticancer effects of AgNPs were mediated via interference with the telomerase/telomere.},
}
@article {pmid30198739,
year = {2018},
author = {Stein, JY and Levin, Y and Lahav, Y and Uziel, O and Abumock, H and Solomon, Z},
title = {Perceived social support, loneliness, and later life telomere length following wartime captivity.},
journal = {Health psychology : official journal of the Division of Health Psychology, American Psychological Association},
volume = {37},
number = {11},
pages = {1067-1076},
doi = {10.1037/hea0000669},
pmid = {30198739},
issn = {1930-7810},
support = {//I-CORE Program of the Planning and Budgeting Committee/ ; //Israel Science Foundation/ ; },
mesh = {Aged ; Female ; Humans ; *Loneliness ; Longevity ; Male ; Middle Aged ; Military Personnel/*psychology ; Perception ; *Social Support ; Stress Disorders, Post-Traumatic/*psychology ; Surveys and Questionnaires ; *Telomere Shortening ; *Warfare ; },
abstract = {OBJECTIVES: Telomere length (TL) is a robust indicator of cellular aging. TL erosion has been associated with exposure to social and traumatic stressors. Loneliness and perceived social support are strongly linked to increased morbidity and mortality, but have yet to be investigated in relation to TL after extreme stress. The present study examined whether loneliness and lack of perceived social support following wartime captivity may be associated with TL as repatriated prisoners of war (ex-POWs) enter old age and contribute to its prediction.<br><br>METHOD: A cohort of Israeli ex-POWs from the 1973 Yom Kippur War (n = 83) were assessed. Questionnaires were utilized to assess loneliness and perceived social support 18 years after the repatriation (T1), and Southern blotting was used to measure TL 24 years later (T2). A zero-order Pearson correlation test and a hierarchical regression analysis were utilized in order to examine the research questions.<br><br>RESULTS: Loneliness and lack of perceived social support each significantly predicted shorter TL in later life, and together added 25.8% to the overall explained variance.<br><br>CONCLUSIONS: This is the first study to empirically demonstrate that loneliness and lack of perceived social support in early adulthood may be associated with shorter TL during transition to old age in a population that has endured extreme stress. Although the study design precludes causal inferences, several psychobiological mechanisms may explain the findings. The potential clinical significance of social deficits for longevity and heath in related populations is therefore addressed, and an agenda for future investigations is suggested. (PsycINFO Database Record (c) 2018 APA, all rights reserved).},
}
@article {pmid30198385,
year = {2018},
author = {Piekna-Przybylska, D and Maggirwar, SB},
title = {CD4+ memory T cells infected with latent HIV-1 are susceptible to drugs targeting telomeres.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {17},
number = {17},
pages = {2187-2203},
pmid = {30198385},
issn = {1551-4005},
support = {P30 AI078498/AI/NIAID NIH HHS/United States ; R01 NS054578/NS/NINDS NIH HHS/United States ; R01 NS066801/NS/NINDS NIH HHS/United States ; R21 AI131961/AI/NIAID NIH HHS/United States ; },
mesh = {CD4-Positive T-Lymphocytes/drug effects/*virology ; DNA Damage/immunology ; HIV Infections/metabolism/*virology ; HIV-1/*pathogenicity ; Humans ; Immunologic Memory/immunology ; Telomere/*virology ; Virus Latency/genetics ; Virus Replication/immunology ; },
abstract = {The population of HIV reservoir in infected person is very small, but extremely long-lived and is a major obstacle for an HIV cure. We previously showed that cells with established HIV latency have deficiencies in DNA damage response (DDR). Here, we investigated ability of HIV-1 to interfere with telomere maintenance, and the effects of targeting telomeres on latently infected cells. Our results show that telomeres are elongated in cultured primary memory CD4 + T cells (TCM) after HIV-1 infection and when virus latency is established. Similarly, much longer telomeres were found in several Jurkat-derived latently infected cell lines, indicating that virus stimulates telomere elongation. Exposing primary CD4+ TCM cells to BRACO19, an agent targeting telomeres, resulted in a higher rate of apoptosis for infected cultures at day 3 post-infection, during HIV-1 latency and for PMA-stimulated cultures with low level of HIV-1 reactivation. Importantly, BRACO19 induced apoptosis in infected cells with potency similar to etoposide and camptothecin, whereas uninfected cells were less affected by BRACO19. We also determined that apoptosis induced by BRACO19 is not caused by telomeres shortening, but is related to formation of gamma-H2AX, implicating DNA damage or uncapping of telomeres, which triggers genome instability. In conclusion, our results indicate that HIV-1 stimulates telomere elongation during latency, suggesting that HIV reservoir has greater capacity for clonal expansion and extended lifespan. Higher rates of apoptosis in response to BRACO19 treatment suggest that HIV reservoirs are more susceptible to targeting telomere maintenance and to inhibitors targeting DDR, which is also involved in stabilizing telomeres.},
}
@article {pmid30196961,
year = {2018},
author = {Yang, Q and Luo, X and Bai, R and Zhao, F and Dai, S and Li, F and Zhu, J and Liu, J and Niu, W and Sun, Y},
title = {Shorter leukocyte telomere length is associated with risk of nonobstructive azoospermia.},
journal = {Fertility and sterility},
volume = {110},
number = {4},
pages = {648-654.e1},
doi = {10.1016/j.fertnstert.2018.05.008},
pmid = {30196961},
issn = {1556-5653},
mesh = {Adult ; Azoospermia/*diagnosis/etiology/*physiopathology ; Humans ; Infertility, Male/diagnosis/etiology/physiopathology ; Leukocytes/pathology/physiology ; Male ; Retrospective Studies ; Risk Factors ; Telomere/*pathology/*physiology ; Telomere Shortening/*physiology ; },
abstract = {OBJECTIVE: To determine the association between leukocyte telomere length and the risk of nonobstructive azoospermia (NOA).<br><br>DESIGN: The mean leukocyte telomere length (LTL) among men with NOA, obstructive azoospermia (OA), and normospermic subjects was determined by quantitative polymerase chain reaction (PCR). We used logistic regression to investigate the association between LTL and the risk of NOA after adjustment for age and body mass index (BMI). Partial correlation analysis was also used to evaluate the relationship of clinical parameters with the mean LTL among men with OA and NOA.<br><br>SETTING: Reproductive medicine center.<br><br>PATIENTS(S): A total of 866 men, including 270 normospermic controls, 247 OA and 349 NOA patients.<br><br>INTERVENTION(S): None.<br><br>MAIN OUTCOME MEASURE(S): Leukocyte telomere length.<br><br>RESULT(S): The mean relative LTL of men with NOA was significantly shorter than that of those with OA and in normospermic controls (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.64-0.98 vs. OR 0.92, 95% CI 0.70-1.24 vs. OR 0.99, 95% CI 0.83-1.22), respectively). Subjects with shorter telomeres (lowest tertile) had a significantly higher risk of NOA than those with longer telomeres (highest tertile). Interestingly, we also found that a low relative LTL was associated with poor efficiency of spermatogenesis using the Johnsen score after testis biopsy and histopathology in azoospermic patients, after adjusting for patient age and BMI.<br><br>CONCLUSION(S): This is the first report that short LTL is associated with NOA, shedding light on an important biological pathway involved in the etiology of this form of male factor infertility.},
}
@article {pmid30196950,
year = {2018},
author = {Kohn, TP and Pastuszak, AW},
title = {Non-obstructive azoospermia and shortened leukocyte telomere length: further evidence linking poor health and infertility.},
journal = {Fertility and sterility},
volume = {110},
number = {4},
pages = {629-630},
doi = {10.1016/j.fertnstert.2018.06.013},
pmid = {30196950},
issn = {1556-5653},
mesh = {*Azoospermia ; Humans ; Leukocytes ; Male ; *Telomere ; },
}
@article {pmid30192712,
year = {2018},
author = {Booth, SA and Wadley, GD and Marques, FZ and Wlodek, ME and Charchar, FJ},
title = {Fetal growth restriction shortens cardiac telomere length, but this is attenuated by exercise in early life.},
journal = {Physiological genomics},
volume = {50},
number = {11},
pages = {956-963},
doi = {10.1152/physiolgenomics.00042.2018},
pmid = {30192712},
issn = {1531-2267},
mesh = {Animals ; Animals, Newborn/growth &amp; development ; Birth Weight ; Female ; Fetal Growth Retardation/*genetics ; Gene Expression Regulation ; Heart/growth &amp; development/*physiology ; Litter Size ; Male ; Physical Conditioning, Animal ; Pregnancy ; Rats, Inbred WKY ; TATA Box Binding Protein-Like Proteins/genetics ; Telomere/*genetics ; },
abstract = {BACKGROUND AND AIMS: Fetal and postnatal growth restriction cause a predisposition to cardiovascular disease (CVD) in adulthood. Telomeres are repetitive DNA-protein structures that protect chromosome ends, and the loss of these repeats (a reduction in telomere length) is associated with CVD. As exercise preserves telomere length and cardiovascular health, the aim of this study was to determine the effects of growth restriction and exercise training on cardiac telomere length and telomeric genes.<br><br>METHODS AND RESULTS: Pregnant Wistar Kyoto rats underwent bilateral uterine vessel ligation to induce uteroplacental insufficiency and fetal growth restriction ("Restricted"). Sham-operated rats had either intact litters ("Control") or their litters reduced to five pups with slowed postnatal growth ("Reduced"). Control, Restricted, and Reduced male rats were assigned to Sedentary, Early exercise (5-9 wk of age), or Late exercise (20-24 wk of age) groups. Hearts were excised at 24 wk of age for telomere length and gene expression measurements by quantitative PCR. Growth restriction shortened cardiac telomere length (P < 0.001), but this was rescued by early exercise (P < 0.001). Early and Late exercise increased cardiac weight index (P < 0.001), but neither this nor telomere length was associated with expression of the telomeric genes Tert, Terc, Trf2, Pnuts, or Sirt1.<br><br>DISCUSSION AND CONCLUSIONS: Growth restriction shortens cardiac telomere length, reflecting the cardiac pathologies associated with low birth weight. Exercise in early life may offer long-term protective effects on cardiac telomere length, which could help prevent CVD in later life.},
}
@article {pmid30192422,
year = {2019},
author = {Rodriguez, FJ and Brosnan-Cashman, JA and Allen, SJ and Vizcaino, MA and Giannini, C and Camelo-Piragua, S and Webb, M and Matsushita, M and Wadhwani, N and Tabbarah, A and Hamideh, D and Jiang, L and Chen, L and Arvanitis, LD and Alnajar, HH and Barber, JR and Rodríguez-Velasco, A and Orr, B and Heaphy, CM},
title = {Alternative lengthening of telomeres, ATRX loss and H3-K27M mutations in histologically defined pilocytic astrocytoma with anaplasia.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {29},
number = {1},
pages = {126-140},
pmid = {30192422},
issn = {1750-3639},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; T32 CA009110/CA/NCI NIH HHS/United States ; 2T32CA009110-39A1//Foundation for the National Institutes of Health/International ; },
mesh = {Adolescent ; Adult ; Aged ; Anaplasia/pathology ; Astrocytoma/*genetics/*pathology ; Biomarkers, Tumor/genetics ; Brain/pathology ; Brain Neoplasms/*pathology ; Child ; Child, Preschool ; Female ; Glioma/pathology ; Histones/genetics/metabolism ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Mutation ; Nuclear Proteins/genetics ; Telomere/genetics/physiology ; Telomere Homeostasis/genetics ; X-linked Nuclear Protein/genetics/physiology ; },
abstract = {Anaplasia may be identified in a subset of tumors with a presumed pilocytic astrocytoma (PA) component or piloid features, which may be associated with aggressive behavior, but the biologic basis of this change remains unclear. Fifty-seven resections from 36 patients (23 M, 13 F, mean age 32 years, range 3-75) were included. A clinical diagnosis of NF1 was present in 8 (22%). Alternative lengthening of telomeres (ALT) was assessed by telomere-specific FISH and/or CISH. A combination of immunohistochemistry, DNA sequencing and FISH were used to study BRAF, ATRX, CDKN2A/p16, mutant IDH1 p.R132H and H3-K27M proteins. ALT was present in 25 (69%) cases and ATRX loss in 20 (57%), mostly in the expected association of ALT+/ATRX- (20/24, 83%) or ALT-/ATRX+ (11/11, 100%). BRAF duplication was present in 8 (of 26) (31%). H3-K27M was present in 5 of 32 (16%) cases, all with concurrent ATRX loss and ALT. ALT was also present in 9 (of 11) cases in the benign PA precursor, 7 of which also had ATRX loss in both the precursor and the anaplastic tumor. In a single pediatric case, ALT and ATRX loss developed in the anaplastic component only, and in another adult case, ALT was present in the PA-A component only, but ATRX was not tested. Features associated with worse prognosis included subtotal resection, adult vs. pediatric, presence of a PA precursor preceding a diagnosis of anaplasia, necrosis, presence of ALT and ATRX expression loss. ALT and ATRX loss, as well as alterations involving the MAPK pathway, are frequent in PA with anaplasia at the time of development of anaplasia or in their precursors. Additionally, a small subset of PA with anaplasia have H3-K27M mutations. These findings further support the concept that PA with anaplasia is a neoplasm with heterogeneous genetic features and alterations typical of both PA and diffuse gliomas.},
}
@article {pmid30189661,
year = {2018},
author = {Schrank, Z and Khan, N and Osude, C and Singh, S and Miller, RJ and Merrick, C and Mabel, A and Kuckovic, A and Puri, N},
title = {Oligonucleotides Targeting Telomeres and Telomerase in Cancer.},
journal = {Molecules (Basel, Switzerland)},
volume = {23},
number = {9},
pages = {},
pmid = {30189661},
issn = {1420-3049},
mesh = {Animals ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; *Gene Targeting ; Genetic Therapy ; Humans ; MicroRNAs/genetics ; Molecular Targeted Therapy ; Neoplasms/*genetics/metabolism/therapy ; Oligonucleotides/chemistry/*genetics/therapeutic use ; RNA Interference ; Telomerase/antagonists &amp; inhibitors/*genetics/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres and telomerase have become attractive targets for the development of anticancer therapeutics due to their involvement in cancer cell immortality. Currently, several therapeutics have been developed that directly target telomerase and telomeres, such as telomerase inhibitors and G-quadruplex stabilizing ligands. Telomere-specific oligonucleotides that reduce telomerase activity and disrupt telomere architecture are also in development as novel anticancer therapeutics. Specifically, GRN163L and T-oligos have demonstrated promising anticancer activity in multiple cancers types via induction of potent DNA damage responses. Currently, several miRNAs have been implicated in the regulation of telomerase activity and may prove to be valuable targets in the development of novel therapies by reducing expression of telomerase subunits. Targeting miRNAs that are known to increase expression of telomerase subunits may be another strategy to reduce carcinogenesis. This review aims to provide a comprehensive understanding of current oligonucleotide-based anticancer therapies that target telomeres and telomerase. These studies may help design novel therapeutic approaches to overcome the challenges of oligonucleotide therapy in a clinical setting.},
}
@article {pmid30185935,
year = {2019},
author = {Hirvonen, EAM and Peuhkuri, S and Norberg, A and Degerman, S and Hannula-Jouppi, K and Välimaa, H and Kilpivaara, O and Wartiovaara-Kautto, U},
title = {Characterization of an X-chromosome-linked telomere biology disorder in females with DKC1 mutation.},
journal = {Leukemia},
volume = {33},
number = {1},
pages = {275-278},
doi = {10.1038/s41375-018-0243-5},
pmid = {30185935},
issn = {1476-5551},
mesh = {Adult ; Cell Cycle Proteins/*genetics ; *Chromosomes, Human, X ; Female ; Genetic Diseases, X-Linked/*genetics/*pathology ; Humans ; Male ; Middle Aged ; *Mutation ; Nuclear Proteins/*genetics ; Pedigree ; Phenotype ; Prognosis ; Telomere/*genetics ; *Telomere Homeostasis ; },
}
@article {pmid30185882,
year = {2018},
author = {Zeiger, AM and White, MJ and Eng, C and Oh, SS and Witonsky, J and Goddard, PC and Contreras, MG and Elhawary, JR and Hu, D and Mak, ACY and Lee, EY and Keys, KL and Samedy, LA and Risse-Adams, O and Magaña, J and Huntsman, S and Salazar, S and Davis, A and Meade, K and Brigino-Buenaventura, E and LeNoir, MA and Farber, HJ and Bibbins-Domingo, K and Borrell, LN and Burchard, EG},
title = {Genetic Determinants of Telomere Length in African American Youth.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {13265},
pmid = {30185882},
issn = {2045-2322},
support = {R01 ES015794/ES/NIEHS NIH HHS/United States ; TL4 GM118986/GM/NIGMS NIH HHS/United States ; T34 GM008574/GM/NIGMS NIH HHS/United States ; R01 HL141992/HL/NHLBI NIH HHS/United States ; K01 HL140218/HL/NHLBI NIH HHS/United States ; K12 GM081266/GM/NIGMS NIH HHS/United States ; R01 HL135156/HL/NHLBI NIH HHS/United States ; T32 GM007546/GM/NIGMS NIH HHS/United States ; R01 HL128439/HL/NHLBI NIH HHS/United States ; R01 HL117004/HL/NHLBI NIH HHS/United States ; P60 MD006902/MD/NIMHD NIH HHS/United States ; R21 ES024844/ES/NIEHS NIH HHS/United States ; 24RT-0025//Tobacco-Related Disease Research Program (TRDRP)/International ; X01HL134589//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/International ; UL1 GM118985/GM/NIGMS NIH HHS/United States ; RL5 GM118984/GM/NIGMS NIH HHS/United States ; R01 MD010443/MD/NIMHD NIH HHS/United States ; 27IR-0030//Tobacco-Related Disease Research Program (TRDRP)/International ; },
mesh = {Adolescent ; Black or African American/*genetics ; Asian People/genetics ; Child ; Female ; Genetic Predisposition to Disease/genetics ; Genetic Variation/genetics ; Genome-Wide Association Study ; Humans ; Male ; Polymorphism, Single Nucleotide/genetics ; Telomere/*genetics/physiology ; Telomere Homeostasis/*genetics ; White People/genetics ; Young Adult ; },
abstract = {Telomere length (TL) is associated with numerous disease states and is affected by genetic and environmental factors. However, TL has been mostly studied in adult populations of European or Asian ancestry. These studies have identified 34 TL-associated genetic variants recently used as genetic proxies for TL. The generalizability of these associations to pediatric populations and racially diverse populations, specifically of African ancestry, remains unclear. Furthermore, six novel variants associated with TL in a population of European children have been identified but not validated. We measured TL from whole blood samples of 492 healthy African American youth (children and adolescents between 8 and 20 years old) and performed the first genome-wide association study of TL in this population. We were unable to replicate neither the 34 reported genetic associations found in adults nor the six genetic associations found in European children. However, we discovered a novel genome-wide significant association between TL and rs1483898 on chromosome 14. Our results underscore the importance of examining genetic associations with TL in diverse pediatric populations such as African Americans.},
}
@article {pmid30185784,
year = {2018},
author = {Nguyen, LN and Zhao, J and Cao, D and Dang, X and Wang, L and Lian, J and Zhang, Y and Jia, Z and Wu, XY and Morrison, Z and Xie, Q and Ji, Y and Zhang, Z and El Gazzar, M and Ning, S and Moorman, JP and Yao, ZQ},
title = {Inhibition of TRF2 accelerates telomere attrition and DNA damage in naïve CD4 T cells during HCV infection.},
journal = {Cell death &amp; disease},
volume = {9},
number = {9},
pages = {900},
pmid = {30185784},
issn = {2041-4889},
support = {S10 OD021572/OD/NIH HHS/United States ; R21 AI138598/AI/NIAID NIH HHS/United States ; R01AI114748//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/International ; R01 DK093526/DK/NIDDK NIH HHS/United States ; },
mesh = {Apoptosis/physiology ; CD4-Positive T-Lymphocytes/*metabolism/virology ; Cells, Cultured ; DNA Damage/*physiology ; DNA-Binding Proteins/metabolism ; HEK293 Cells ; Hepacivirus/pathogenicity ; Hepatitis C/*metabolism/virology ; Humans ; Leukocytes, Mononuclear/metabolism/virology ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/*antagonists &amp; inhibitors ; Tumor Suppressor Proteins/metabolism ; },
abstract = {T cells play a crucial role in viral clearance and vaccine responses; however, the mechanisms that regulate their homeostasis during viral infections remain unclear. In this study, we investigated the machineries of T-cell homeostasis and telomeric DNA damage using a human model of hepatitis C virus (HCV) infection. We found that naïve CD4 T cells in chronically HCV-infected patients (HCV T cells) were significantly reduced due to apoptosis compared with age-matched healthy subjects (HSs). These HCV T cells were not only senescent, as demonstrated by overexpression of aging markers and particularly shortened telomeres; but also DNA damaged, as evidenced by increased dysfunctional telomere-induced foci (TIF). Mechanistically, the telomere shelterin protein, in particular telomeric repeat binding factor 2 (TRF2) that functions to protect telomeres from DNA damage, was significantly inhibited posttranscriptionally via the p53-dependent Siah-1a ubiquitination. Importantly, knockdown of TRF2 in healthy T cells resulted in increases in telomeric DNA damage and T-cell apoptosis, whereas overexpression of TRF2 in HCV T cells alleviated telomeric DNA damage and T-cell apoptosis. To the best of our knowledge, this is the first report revealing that inhibition of TRF2 promotes T-cell telomere attrition and telomeric DNA damage that accelerates T-cell senescent and apoptotic programs, which contribute to naïve T-cell loss during viral infection. Thus, restoring the impaired T-cell telomeric shelterin machinery may offer a new strategy to improve immunotherapy and vaccine response against human viral diseases.},
}
@article {pmid30181761,
year = {2018},
author = {Dorado-Correa, AM and Zollinger, SA and Heidinger, B and Brumm, H},
title = {Timing matters: traffic noise accelerates telomere loss rate differently across developmental stages.},
journal = {Frontiers in zoology},
volume = {15},
number = {},
pages = {29},
pmid = {30181761},
issn = {1742-9994},
abstract = {BACKGROUND: Noise pollution is one of the leading environmental health risks for humans, linked to a myriad of stress-related health problems. Yet little is known about the long-term effects of noise on the health and fitness of wildlife. We experimentally investigated the direct and cross-generational effects of traffic noise on telomeres; a measure of cellular ageing that is predictive of disease and longevity in humans and other organisms. We exposed zebra finches (Taenopygia guttata) to three different treatment groups: 1) parents were exposed to traffic noise before and during breeding, together with their nestling young, 2) fledged juveniles but not their parents were exposed to traffic noise, and 3) control group birds were never exposed to traffic noise.<br><br>RESULTS: Although there was no significant effect of traffic noise exposure at early (pre-fledging) stages of offspring telomere length or loss rate, traffic noise exposure accelerated telomere loss in older (post-fledging) juveniles.<br><br>CONCLUSIONS: The age-dependent differences found in this study in telomere loss could occur if parents buffer younger offspring against the detrimental effects of noise exposure and/or if younger offspring are less sensitive to noise exposure. Telomere length during early life has been shown to be positively related to lifespan and the observed noise-induced increase of telomere attrition rate could reduce the fitness of the affected birds and potentially alter the population dynamics of birds in noise polluted areas. Our data highlight the need to consider the developmental stage of an organism to better understand the ecological consequences of anthropogenic change.},
}
@article {pmid30181605,
year = {2018},
author = {Chow, TT and Shi, X and Wei, JH and Guan, J and Stadler, G and Huang, B and Blackburn, EH},
title = {Local enrichment of HP1alpha at telomeres alters their structure and regulation of telomere protection.},
journal = {Nature communications},
volume = {9},
number = {1},
pages = {3583},
pmid = {30181605},
issn = {2041-1723},
support = {K99 GM126136/GM/NIGMS NIH HHS/United States ; R01 CA096840/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Chromatin/genetics/metabolism ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; DNA Damage ; Heterochromatin/genetics/metabolism ; Histones/metabolism ; Humans ; Lysine/metabolism ; Microscopy/methods ; Mutation ; Protein Domains ; Recombinant Fusion Proteins/genetics/metabolism ; Telomere/genetics/*metabolism/ultrastructure ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; },
abstract = {Enhanced telomere maintenance is evident in malignant cancers. While telomeres are thought to be inherently heterochromatic, detailed mechanisms of how epigenetic modifications impact telomere protection and structures are largely unknown in human cancers. Here we develop a molecular tethering approach to experimentally enrich heterochromatin protein HP1α specifically at telomeres. This results in increased deposition of H3K9me3 at cancer cell telomeres. Telomere extension by telomerase is attenuated, and damage-induced foci at telomeres are reduced, indicating augmentation of telomere stability. Super-resolution STORM imaging shows an unexpected increase in irregularity of telomeric structure. Telomere-tethered chromo shadow domain (CSD) mutant I165A of HP1α abrogates both the inhibition of telomere extension and the irregularity of telomeric structure, suggesting the involvement of at least one HP1α-ligand in mediating these effects. This work presents an approach to specifically manipulate the epigenetic status locally at telomeres to uncover insights into molecular mechanisms underlying telomere structural dynamics.},
}
@article {pmid30179220,
year = {2018},
author = {Wagner, CL and Hanumanthu, VS and Talbot, CC and Abraham, RS and Hamm, D and Gable, DL and Kanakry, CG and Applegate, CD and Siliciano, J and Jackson, JB and Desiderio, S and Alder, JK and Luznik, L and Armanios, M},
title = {Short telomere syndromes cause a primary T cell immunodeficiency.},
journal = {The Journal of clinical investigation},
volume = {128},
number = {12},
pages = {5222-5234},
pmid = {30179220},
issn = {1558-8238},
support = {R01 CA160433/CA/NCI NIH HHS/United States ; R01 CA225027/CA/NCI NIH HHS/United States ; R01 HL110907/HL/NHLBI NIH HHS/United States ; R01 HL119476/HL/NHLBI NIH HHS/United States ; R00 HL113105/HL/NHLBI NIH HHS/United States ; T32 GM007814/GM/NIGMS NIH HHS/United States ; R01 HL135062/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aging/genetics/immunology/pathology ; Animals ; Apoptosis/genetics/*immunology ; DNA Damage/immunology ; Female ; *Growth Disorders/complications/genetics/immunology/pathology ; Humans ; *Hypercalcemia/complications/genetics/immunology/pathology ; *Immunologic Deficiency Syndromes/etiology/genetics ; Male ; *Metabolic Diseases/complications/genetics/immunology/pathology ; Mice ; Mice, Knockout ; *Mutation ; *Nephrocalcinosis/complications/genetics/immunology/pathology ; Primary Immunodeficiency Diseases ; T-Lymphocytes/immunology/pathology ; *Telomerase/genetics/immunology ; Telomere Homeostasis/*immunology ; },
abstract = {The mechanisms that drive T cell aging are not understood. We report that children and adult telomerase mutation carriers with short telomere length (TL) develop a T cell immunodeficiency that can manifest in the absence of bone marrow failure and causes life-threatening opportunistic infections. Mutation carriers shared T cell-aging phenotypes seen in adults 5 decades older, including depleted naive T cells, increased apoptosis, and restricted T cell repertoire. T cell receptor excision circles (TRECs) were also undetectable or low, suggesting that newborn screening may identify individuals with germline telomere maintenance defects. Telomerase-null mice with short TL showed defects throughout T cell development, including increased apoptosis of stimulated thymocytes, their intrathymic precursors, in addition to depleted hematopoietic reserves. When we examined the transcriptional programs of T cells from telomerase mutation carriers, we found they diverged from older adults with normal TL. Short telomere T cells upregulated DNA damage and intrinsic apoptosis pathways, while older adult T cells upregulated extrinsic apoptosis pathways and programmed cell death 1 (PD-1) expression. T cells from mice with short TL also showed an active DNA-damage response, in contrast with old WT mice, despite their shared propensity to apoptosis. Our data suggest there are TL-dependent and TL-independent mechanisms that differentially contribute to distinct molecular programs of T cell apoptosis with aging.},
}
@article {pmid30177810,
year = {2018},
author = {Farmery, JHR and Smith, ML and , and Lynch, AG},
title = {Publisher Correction: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {13376},
doi = {10.1038/s41598-018-31524-0},
pmid = {30177810},
issn = {2045-2322},
support = {MC_UU_00002/10/MRC_/Medical Research Council/United Kingdom ; FS/15/59/31839/BHF_/British Heart Foundation/United Kingdom ; MR/J011711/1/MRC_/Medical Research Council/United Kingdom ; MR/L006340/1/MRC_/Medical Research Council/United Kingdom ; G84/6443/MRC_/Medical Research Council/United Kingdom ; },
abstract = {A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.},
}
@article {pmid30173859,
year = {2018},
author = {Behravan, E and Moallem, SA and Kalalinia, F and Ahmadimanesh, M and Blain, P and Jowsey, P and Khateri, S and Forghanifard, MM and BalaliMood, M},
title = {Telomere shortening associated with increased levels of oxidative stress in sulfur mustard-exposed Iranian veterans.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {834},
number = {},
pages = {1-5},
doi = {10.1016/j.mrgentox.2018.06.017},
pmid = {30173859},
issn = {1879-3592},
mesh = {Adult ; Aged ; Case-Control Studies ; Chemical Warfare Agents/*adverse effects ; Dinoprost/analogs &amp; derivatives/metabolism ; Humans ; Iran ; Lymphocytes/drug effects/metabolism/*pathology ; Male ; Middle Aged ; Mustard Gas/*adverse effects ; *Oxidative Stress ; *Telomere Shortening ; Veterans/*statistics &amp; numerical data ; },
abstract = {Sulfur Mustard (SM) is the most widely used chemical weapon. It was used in World War 1 and in the more recent Iran-Iraq conflict. Genetic toxicity and DNA alkylation effects of SM in molecular and animal experiments are well documented. In this study, lymphocytic telomere lengths and serum levels of isoprostane F2α were measured using q-PCR and enzyme immunoassay-based methods in 40 Iranian veterans who had been exposed to SM between 1983-88 and 40 non-exposed healthy volunteers. The relative telomere length in SM-exposed individuals was found to be significantly shorter than the non-exposed individuals. In addition, the level of 8-isoprostane F2α was significantly higher in the SM-exposed group compared to controls. Oxidative stress can be caused by defective antioxidant responses following gene mutations or altered activities of antioxidant enzymes. Chronic respiratory diseases and infections may also increaseoxidative stress. The novel finding of this study was a the identification of 'premature ageing phenotype'. More specifically, telomere shortening which occurs naturally with aging is accelerated in SM-exposed individuals. Oxidative stress, mutations in DNA repair genes and epimutaions may be among the major mechanisms of telomere attrition. These findings may help for a novel therapeutic strategy by telomere elongation or for validation of an exposure biomarker for SM toxicity.},
}
@article {pmid30172836,
year = {2018},
author = {McAlindon, T and Roberts, M and Driban, J and Schaefer, L and Haugen, IK and Smith, SE and Duryea, J and Cunha, D and Blanco, F and Fernández-Garcia, JL and Eaton, C},
title = {Incident hand OA is strongly associated with reduced peripheral blood leukocyte telomere length.},
journal = {Osteoarthritis and cartilage},
volume = {26},
number = {12},
pages = {1651-1657},
pmid = {30172836},
issn = {1522-9653},
support = {R01 AR065977/AR/NIAMS NIH HHS/United States ; R01 AR066378/AR/NIAMS NIH HHS/United States ; },
mesh = {Aged ; Cross-Sectional Studies ; Female ; Hand Joints/*diagnostic imaging ; Humans ; Incidence ; Leukocytes/*physiology ; Longitudinal Studies ; Male ; Middle Aged ; Osteoarthritis/blood/diagnostic imaging/epidemiology/*genetics ; Prevalence ; Telomere/physiology ; Telomere Shortening/*physiology ; United States/epidemiology ; },
abstract = {OBJECTIVE: To evaluate the relationship of telomere length to the prevalence and incidence of hand osteoarthritis in a longitudinal cohort.<br><br>DESIGN: We conducted a cross-sectional and longitudinal analysis of data from a subset of participants in the Osteoarthritis Initiative (OAI) recruited between February 2004 and May 2006. 274 individuals were eligible for the study based on availability of both baseline and 48-month hand radiographs and peripheral blood leucocyte telomere length data. Mean telomere length of peripheral blood leukocytes (PBL)s from the DNA samples was determined using a validated quantitative polymerase chain reaction (PCR)-based assay, and hand radiographs were analyzed and graded using the Kellgren-Lawrence scale.<br><br>RESULTS: In joint -level analyses, prevalent Interphalangeal Joint Osteoarthritis (IPJOA) was significantly associated with PBL telomere length in the baseline sample in unadjusted analyses (RR&#xa0;=&#xa0;2.84; 95% CI:0.87-9.29) or in models adjusted for age, sex, and body mass index (aRR&#xa0;=&#xa0;1.10; 95% CI: 0.96-1.27). The association in crude and adjusted analyses appeared slightly stronger with incident IPJOA, especially in the subset with normal hands at baseline (aRR&#xa0;=&#xa0;1.62; 95% CI: 1.02-2.57). PBL telomere length was also associated with prevalent HOA at baseline (significant in unadjusted analysis: RR&#xa0;=&#xa0;1.22; 95% CI 1.06-1.42), but not after adjusting for covariates: aRR&#xa0;=&#xa0;1.12; 95% CI: 0.96-1.30). The magnitude of association was stronger for incident HOA, especially incident symptomatic HOA (aRR&#xa0;=&#xa0;1.53; 95% CI: 1.09-2.15).<br><br>CONCLUSIONS: In summary, the results of this exploratory analysis are confirmatory of previous work showing a cross-sectional relationship between telomere length and HOA and add to the field by demonstrating an even stronger association with incident IPJOA, both radiographic and symptomatic.},
}
@article {pmid30168024,
year = {2019},
author = {Higgs, C and Crow, YJ and Adams, DM and Chang, E and Hayes, D and Herbig, U and Huang, JN and Himes, R and Jajoo, K and Johnson, FB and Reynolds, SD and Yonekawa, Y and Armanios, M and Boulad, F and DiNardo, CD and Dufour, C and Goldman, FD and Khan, S and Kratz, C and Myers, KC and Raghu, G and Alter, BP and Aubert, G and Bhala, S and Cowen, EW and Dror, Y and El-Youssef, M and Friedman, B and Giri, N and Helms Guba, L and Khincha, PP and Lin, TF and Longhurst, H and McReynolds, LJ and Nelson, A and Olson, T and Pariser, A and Perona, R and Sasa, G and Schratz, K and Simonetto, DA and Townsley, D and Walsh, M and Stevens, K and Agarwal, S and Bertuch, AA and Savage, SA and , },
title = {Understanding the evolving phenotype of vascular complications in telomere biology disorders.},
journal = {Angiogenesis},
volume = {22},
number = {1},
pages = {95-102},
doi = {10.1007/s10456-018-9640-7},
pmid = {30168024},
issn = {1573-7209},
mesh = {Animals ; *Arteriovenous Fistula/genetics/metabolism/pathology ; Education ; Humans ; Pulmonary Artery/*abnormalities/metabolism/pathology ; Pulmonary Veins/*abnormalities/metabolism/pathology ; *Telangiectasis/genetics/metabolism/pathology ; *Telomere/genetics/metabolism/pathology ; },
abstract = {Vascular complications such as bleeding due to gastrointestinal telangiectatic anomalies, pulmonary arteriovenous malformations, hepatopulmonary syndrome, and retinal vessel abnormalities are being reported in patients with telomere biology disorders (TBDs) more frequently than previously described. The international clinical care consortium of telomere-associated ailments and family support group Dyskeratosis Congenita Outreach, Inc. held a workshop on vascular abnormalities in the TBDs at the National Cancer Institute in October 2017. Clinicians and basic scientists reviewed current data on vascular complications, hypotheses for the underlying biology and developed new collaborations to address the etiology and clinical management of vascular complications in TBDs.},
}
@article {pmid30166419,
year = {2018},
author = {Lee, HS and Carmena, M and Liskovykh, M and Peat, E and Kim, JH and Oshimura, M and Masumoto, H and Teulade-Fichou, MP and Pommier, Y and Earnshaw, WC and Larionov, V and Kouprina, N},
title = {Systematic Analysis of Compounds Specifically Targeting Telomeres and Telomerase for Clinical Implications in Cancer Therapy.},
journal = {Cancer research},
volume = {78},
number = {21},
pages = {6282-6296},
pmid = {30166419},
issn = {1538-7445},
support = {/WT_/Wellcome Trust/United Kingdom ; 073915/WT_/Wellcome Trust/United Kingdom ; Z01 BC006150/ImNIH/Intramural NIH HHS/United States ; Z01 BC010413-07/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Antineoplastic Agents/*pharmacology ; Cell Line ; Cell Line, Tumor ; Cell Survival ; Chromatin ; Chromosomes ; Chromosomes, Artificial, Human ; DNA Damage ; Drug Design ; HCT116 Cells ; Humans ; Hydroxamic Acids/pharmacology ; Mitosis ; Neoplasms/*drug therapy/genetics ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects ; Transgenes ; },
abstract = {The targeting of telomerase and telomere maintenance mechanisms represents a promising therapeutic approach for various types of cancer. In this work, we designed a new protocol to screen for and rank the efficacy of compounds specifically targeting telomeres and telomerase. This approach used two isogenic cell lines containing a circular human artificial chromosome (HAC, lacking telomeres) and a linear HAC (containing telomeres) marked with the EGFP transgene; compounds that target telomerase or telomeres should preferentially induce loss of the linear HAC but not the circular HAC. Our assay allowed quantification of chromosome loss by routine flow cytometry. We applied this dual-HAC assay to rank a set of known and newly developed compounds, including G-quadruplex (G4) ligands. Among the latter group, two compounds, Cu-ttpy and Pt-ttpy, induced a high rate of linear HAC loss with no significant effect on the mitotic stability of a circular HAC. Analysis of the mitotic phenotypes induced by these drugs revealed an elevated rate of chromatin bridges in late mitosis and cytokinesis as well as UFB (ultrafine bridges). Chromosome loss after Pt-ttpy or Cu-ttpy treatment correlated with the induction of telomere-associated DNA damage. Overall, this platform enables identification and ranking of compounds that greatly increase chromosome mis-segregation rates as a result of telomere dysfunction and may expedite the development of new therapeutic strategies for cancer treatment.Significance: An assay provides a unique opportunity to screen thousands of chemical compounds for their ability to inactivate replication of telomeric ends in cancer cells and holds potential to lay the foundation for the discovery of new treatments for cancer. Cancer Res; 78(21); 6282-96. ©2018 AACR.},
}
@article {pmid30165413,
year = {2018},
author = {Banach, M and Mazidi, M and Mikhailidis, DP and Toth, PP and Jozwiak, J and Rysz, J and Watts, GF},
title = {Association between phenotypic familial hypercholesterolaemia and telomere length in US adults: results from a multi-ethnic survey.},
journal = {European heart journal},
volume = {39},
number = {40},
pages = {3635-3640},
doi = {10.1093/eurheartj/ehy527},
pmid = {30165413},
issn = {1522-9645},
mesh = {Cross-Sectional Studies ; Female ; Humans ; Hyperlipoproteinemia Type II/*epidemiology/*genetics ; Male ; Middle Aged ; Nutrition Surveys ; Telomere/*genetics ; United States/epidemiology ; },
abstract = {AIMS: Familial hypercholesterolaemia (FH) accelerates atherosclerotic cardiovascular disease (ASCVD) and accordingly is the most potent hereditary cause of premature coronary heart disease. The association between telomere length (TL), a biological index of ageing, and FH has not been hitherto investigated. We addressed this question using data from the US National Health and Education National Surveys (NHANES, 1999-2002).<br><br>METHODS AND RESULTS: We included individuals, who had TL measurements (with quantitative polymerase chain reaction method) and a phenotypic diagnosis of FH based on the Dutch Lipid Clinic Network (DLCN) criteria. Sample weights were applied for unequal probabilities of selection, non-response bias, and oversampling by complex sample analysis. The adult prevalence of FH in NHANES was 0.43% [95% confidence interval (95% CI) 0.33-0.57]. The frequencies of probable FH (mean DLCN score: 6.2) and definite FH (mean DLCN score: 8.9) were 0.42% (95% CI 0.32-0.48) and 0.03% (95% CI 0.02-0.06), respectively. Subjects with FH had a higher prevalence of non-communicable diseases (hypertension, diabetes 2 type, and obesity) and early atherosclerosis (2.9% in overall population vs. 42.2% in FH). Overall, the mean TL in the non-FH population was 1.09 (95% CI 1.06-1.12) (T/S ratio) and 1.09 (95% CI 1.03-1.12) [(T/S ratio) for total FH]. Telomere length adjusted for age, sex, race, and body mass index was shorter in FH compared with healthy subjects (FH 0.89, 95% CI 0.84-0.93 vs. healthy: 1.05, 95% CI 0.97-1.11 T/S ratio; P&#x2009;<&#x2009;0.001). Subjects with longer TL (highest quartile) had 12% less chance of having FH compared with those with TL in the lowest quartile (Q1, 95% CI 0.78-0.93).<br><br>CONCLUSIONS: These preliminary data suggest an association between TL, an index of biological age, and the presence of FH, the most common inherited cause of premature ASCVD. Given our relatively low sample size, the findings need confirmation in larger studies.},
}
@article {pmid30160983,
year = {2018},
author = {McGovern, JM and Singhi, AD and Borhani, AA and Furlan, A and McGrath, KM and Zeh, HJ and Bahary, N and Dasyam, AK},
title = {CT Radiogenomic Characterization of the Alternative Lengthening of Telomeres Phenotype in Pancreatic Neuroendocrine Tumors.},
journal = {AJR. American journal of roentgenology},
volume = {211},
number = {5},
pages = {1020-1025},
doi = {10.2214/AJR.17.19490},
pmid = {30160983},
issn = {1546-3141},
support = {UL1 TR001857/TR/NCATS NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Contrast Media ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Neuroendocrine Tumors/*diagnostic imaging/*genetics/pathology/surgery ; Pancreatic Neoplasms/*diagnostic imaging/*genetics/pathology/surgery ; Phenotype ; Radiographic Image Interpretation, Computer-Assisted ; Retrospective Studies ; *Telomere Homeostasis ; Tomography, X-Ray Computed/*methods ; },
abstract = {OBJECTIVE: The objective of this study was to identify imaging characteristics in patients with known pancreatic neuroendocrine tumors (PanNETs) that predict the alternative lengthening of telomeres (ALT) phenotype by blinded retrospective review of preoperative multiphasic CT scans.<br><br>MATERIALS AND METHODS: For this retrospective study of 121 preoperative CT examinations of patients with resected PanNETs, two radiologists independently reviewed the CT examinations for tumor characteristics including size, shape, cystic or necrotic elements, calcifications, invasion of adjacent organs and vessels, biliary duct dilatation, pancreatic duct dilatation, and hepatic metastases. Univariate analysis of association of CT characteristics with ALT phenotype was performed with Fisher exact tests or t tests, and multivariate analysis was assessed by multiple logistic regression.<br><br>RESULTS: Univariate analysis showed that the following CT features were significantly associated with the ALT phenotype: lobulated or irregular tumor shape (p = 0.001), tumor necrosis (p = 0.002), vascular invasion (p < 0.001), pancreatic duct dilatation (p < 0.001), and hepatic metastasis (p < 0.001). Multivariate analysis found that the combination of pancreatic duct dilatation, hepatic metastasis, and size of tumor &#x2265; 3 cm was a strong predictor of ALT phenotype (odds ratio = 20.3; 95% CI = 2.3-176.3; AUC = 0.58; p = 0.006).<br><br>CONCLUSION: This study showed that several preoperative CT features of PanNETs are associated with the ALT phenotype, which is known to predict poor prognosis. Additionally, CT findings of intratumoral calcifications and metastases predicted poor survival independent of the ALT status.},
}
@article {pmid30160976,
year = {2019},
author = {Greenland, JR},
title = {Where the Chromosome Ends: Telomeres and Cytomegalovirus Risk in Lung Transplant Recipients.},
journal = {American journal of respiratory and critical care medicine},
volume = {199},
number = {3},
pages = {265-267},
doi = {10.1164/rccm.201808-1472ED},
pmid = {30160976},
issn = {1535-4970},
support = {IK2 CX001034/CX/CSRD VA/United States ; },
mesh = {Cytomegalovirus ; *Cytomegalovirus Infections ; Humans ; *Idiopathic Pulmonary Fibrosis ; *Lung Transplantation ; Telomere ; Transplant Recipients ; },
}
@article {pmid30152726,
year = {2018},
author = {Gao, X and Zhang, Y and Mons, U and Brenner, H},
title = {Leukocyte telomere length and epigenetic-based mortality risk score: associations with all-cause mortality among older adults.},
journal = {Epigenetics},
volume = {13},
number = {8},
pages = {846-857},
pmid = {30152726},
issn = {1559-2308},
mesh = {Aged ; *DNA Methylation ; *Epigenesis, Genetic ; Female ; Humans ; Leukocytes/metabolism ; Longevity/*genetics ; Male ; Middle Aged ; *Mortality ; *Telomere Homeostasis ; },
abstract = {Telomere length (TL) has been established as a biomarker of aging and aging-related health outcomes, but showed only a weak or inconsistent association with all-cause mortality in previous epidemiological studies. Recently, an epigenetic 'mortality risk score' (MS) based on whole blood DNA methylation at 10 mortality-related CpG sites has been demonstrated to be strongly related to all-cause mortality at the population level. This study aimed to address the association between TL and this MS, and to assess and compare their associations with all-cause mortality. The MS was derived from the DNA methylation profiles measured by Illumina Human Methylation450K Beadchip and TL was measured by quantitative PCR at baseline among 1517 participants aged 50-75 of the German ESTHER cohort study. In cross-sectional bi- and multivariable analyses, the MS was strongly associated and showed monotonic dose-response relationships with TL (p-values <0.05). However, only the MS but not TL was associated with all-cause mortality during a median follow-up of 12.5 years. After controlling for potential covariates and TL, hazard ratios (95% CI) for all-cause mortality for low, moderate and high levels of the MS defined by 1, 2-5 and >5 CpG sites with aberrant methylation were 2.24 (1.13-4.41), 3.31 (1.76-6.22) and 6.33 (3.22-12.41) compared to a MS of 0, respectively. Our investigation shows that the epigenetic-based MS is strongly associated with TL, a broadly accepted aging biomarker, and at the same time shows much stronger associations with all-cause mortality than the latter.},
}
@article {pmid30150400,
year = {2018},
author = {Chang, ACY and Chang, ACH and Kirillova, A and Sasagawa, K and Su, W and Weber, G and Lin, J and Termglinchan, V and Karakikes, I and Seeger, T and Dainis, AM and Hinson, JT and Seidman, J and Seidman, CE and Day, JW and Ashley, E and Wu, JC and Blau, HM},
title = {Telomere shortening is a hallmark of genetic cardiomyopathies.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {115},
number = {37},
pages = {9276-9281},
pmid = {30150400},
issn = {1091-6490},
support = {R01 HL130020/HL/NHLBI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; R21 AG044815/AG/NIA NIH HHS/United States ; R01 HL123968/HL/NHLBI NIH HHS/United States ; R24 HL117756/HL/NHLBI NIH HHS/United States ; K08 HL125807/HL/NHLBI NIH HHS/United States ; R00 HL104002/HL/NHLBI NIH HHS/United States ; K99 HL104002/HL/NHLBI NIH HHS/United States ; 201411MFE-338745-169197//CIHR/Canada ; T32 HL094274/HL/NHLBI NIH HHS/United States ; T32 GM007790/GM/NIGMS NIH HHS/United States ; R01 HL126527/HL/NHLBI NIH HHS/United States ; R01 AR063963/AR/NIAMS NIH HHS/United States ; },
mesh = {*Cardiomyopathy, Dilated/genetics/metabolism/pathology ; *Cardiomyopathy, Hypertrophic, Familial/genetics/metabolism/pathology ; *Cell Division ; Female ; Humans ; *Induced Pluripotent Stem Cells/metabolism/pathology ; Male ; *Muscle Proteins/genetics/metabolism ; *Mutation ; *Telomere Shortening ; },
abstract = {This study demonstrates that significantly shortened telomeres are a hallmark of cardiomyocytes (CMs) from individuals with end-stage hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM) as a result of heritable defects in cardiac proteins critical to contractile function. Positioned at the ends of chromosomes, telomeres are DNA repeats that serve as protective caps that shorten with each cell division, a marker of aging. CMs are a known exception in which telomeres remain relatively stable throughout life in healthy individuals. We found that, relative to healthy controls, telomeres are significantly shorter in CMs of genetic HCM and DCM patient tissues harboring pathogenic mutations: TNNI3, MYBPC3, MYH7, DMD, TNNT2, and TTN Quantitative FISH (Q-FISH) of single cells revealed that telomeres were significantly reduced by 26% in HCM and 40% in DCM patient CMs in fixed tissue sections compared with CMs from age- and sex-matched healthy controls. In the cardiac tissues of the same patients, telomere shortening was not evident in vascular smooth muscle cells that do not express or require the contractile proteins, an important control. Telomere shortening was recapitulated in DCM and HCM CMs differentiated from patient-derived human-induced pluripotent stem cells (hiPSCs) measured by two independent assays. This study reveals telomere shortening as a hallmark of genetic HCM and DCM and demonstrates that this shortening can be modeled in vitro by using the hiPSC platform, enabling drug discovery.},
}
@article {pmid30148739,
year = {2018},
author = {Freitas-Simoes, TM and Ros, E and Sala-Vila, A},
title = {Telomere length as a biomarker of accelerated aging: is it influenced by dietary intake?.},
journal = {Current opinion in clinical nutrition and metabolic care},
volume = {21},
number = {6},
pages = {430-436},
doi = {10.1097/MCO.0000000000000506},
pmid = {30148739},
issn = {1473-6519},
mesh = {Aged ; Aging/*genetics ; Diet/*adverse effects ; Eating/*genetics ; Female ; Genetic Markers/physiology ; Humans ; Male ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; Telomere Shortening/physiology ; },
abstract = {PURPOSE OF REVIEW: There is increasing interest in exploring whether age-related diseases can be prevented by dietary means through nutrients or food bioactives, whole foods, or specific dietary patterns. Because of the slow nature of the aging process, biomarkers such as telomere length are helpful for this purpose. Here we update the developments in the area during the last 2 years.<br><br>RECENT FINDINGS: Most data stem from epidemiologic studies, often cross-sectional in design. Recent articles strengthened the link between consumption of sugar-sweetened beverages and telomere shortening, whereas a novel association between telomere length and drinking coffee has been uncovered. Controversy on meat consumption and telomere length persists, mostly because of the presumed different effects of total meat and processed meat. In general terms, increasing consumption of antioxidant-rich plant foods relates to maintained telomere length. Feeding intervention trials with outcomes on telomere length are few and thus far have contributed little to further knowledge on this topic.<br><br>SUMMARY: Epidemiologic studies provide support for the putative effects of diet components on telomere length and on the aging process in general. Dietary associations with telomere length should be confirmed with adequately powered randomized controlled trials.},
}
@article {pmid30147659,
year = {2018},
author = {Montiel Rojas, D and Nilsson, A and Ponsot, E and Brummer, RJ and Fairweather-Tait, S and Jennings, A and de Groot, LCPGM and Berendsen, A and Pietruszka, B and Madej, D and Caumon, E and Meunier, N and Malpuech-Brugère, C and Guidarelli, G and Santoro, A and Franceschi, C and Kadi, F},
title = {Short Telomere Length Is Related to Limitations in Physical Function in Elderly European Adults.},
journal = {Frontiers in physiology},
volume = {9},
number = {},
pages = {1110},
pmid = {30147659},
issn = {1664-042X},
abstract = {The present study aims to explore the potential influence of leucocyte telomere length (LTL) on both a single indicator and a composite construct of physical functioning in a large European population of elderly men and women across diverse geographical locations. A total of 1,221 adults (65-79 years) were recruited from five European countries within the framework of NU-AGE study. The physical functioning construct was based on the 36-item Short Form Health Survey. Handgrip strength was used as a single indicator of muscle function and LTL was assessed using quantitative real-time PCR. Women had significantly longer (p < 0.05) LTL than men. Participants in Poland had significantly shorter LTL than in the other study centers, whereas participants in the Netherlands had significantly longer LTL than most of the other centers (p < 0.01). An analysis of LTL as a continuous outcome against physical functioning by using linear models revealed inconsistent findings. In contrast, based on an analysis of contrasting telomere lengths (first vs. fifth quintile of LTL), a significant odds ratio (OR) of 1.7 (95% CI: 1.1 - 2.6; p < 0.05) of having functional limitation was observed in those belonging to the first LTL quintile compared to the fifth. Interestingly, having the shortest LTL was still related to a higher likelihood of having physical limitation when compared to all remaining quintiles (OR: 1.5, 95% CI: 1.1 - 2.1; p < 0.05), even after adjustment by study center, age, sex, and overweight status. Collectively, our findings suggest that short LTL is an independent risk factor that accounts for functional decline in elderly European populations. The influence of LTL on functional limitation seems driven by the detrimental effect of having short telomeres rather than reflecting a linear dose-response relationship.},
}
@article {pmid30143784,
year = {2018},
author = {Seeker, LA and Ilska, JJ and Psifidi, A and Wilbourn, RV and Underwood, SL and Fairlie, J and Holland, R and Froy, H and Salvo-Chirnside, E and Bagnall, A and Whitelaw, B and Coffey, MP and Nussey, DH and Banos, G},
title = {Bovine telomere dynamics and the association between telomere length and productive lifespan.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {12748},
pmid = {30143784},
issn = {2045-2322},
support = {BB/L007312/1//Biotechnology and Biological Sciences Research Council (BBSRC)/International ; },
mesh = {Animals ; Cattle/*genetics/*physiology ; Environment ; Kaplan-Meier Estimate ; Leukocytes/metabolism ; Longevity/*physiology ; Models, Biological ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Average telomere length (TL) in blood cells has been shown to decline with age in a range of vertebrate species, and there is evidence that TL is a heritable trait associated with late-life health and mortality in humans. In non-human mammals, few studies to date have examined lifelong telomere dynamics and no study has estimated the heritability of TL, despite these being important steps towards assessing the potential of TL as a biomarker of productive lifespan and health in livestock species. Here we measured relative leukocyte TL (RLTL) in 1,328 samples from 308 Holstein Friesian dairy cows and in 284 samples from 38 female calves. We found that RLTL declines after birth but remains relatively stable in adult life. We also calculated the first heritability estimates of RLTL in a livestock species which were 0.38 (SE = 0.03) and 0.32 (SE = 0.08) for the cow and the calf dataset, respectively. RLTL measured at the ages of one and five years were positively correlated with productive lifespan (p < 0.05). We conclude that bovine RLTL is a heritable trait, and its association with productive lifespan may be used in breeding programmes aiming to enhance cow longevity.},
}
@article {pmid30138832,
year = {2018},
author = {Pantesco, EJ and Leibel, DK and Ashe, JJ and Waldstein, SR and Katzel, LI and Liu, HB and Weng, NP and Evans, MK and Zonderman, AB and Beatty Moody, DL},
title = {Multiple forms of discrimination, social status, and telomere length: Interactions within race.},
journal = {Psychoneuroendocrinology},
volume = {98},
number = {},
pages = {119-126},
pmid = {30138832},
issn = {1873-3360},
support = {R25 GM055036/GM/NIGMS NIH HHS/United States ; ZIA AG000199-06//Intramural NIH HHS/United States ; P30 AG028747/AG/NIA NIH HHS/United States ; L60 MD003309/MD/NIMHD NIH HHS/United States ; R01 AG034161/AG/NIA NIH HHS/United States ; K01 AG043581/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Black or African American ; Cellular Senescence/physiology ; Discrimination, Psychological/physiology ; Female ; *Health Status Disparities ; Humans ; Male ; Maryland ; Middle Aged ; Racial Groups/ethnology/*psychology ; Racism/*psychology ; Social Class ; Social Environment ; Telomere Homeostasis/*physiology ; United States ; White People ; },
abstract = {Previous research has demonstrated inverse associations between experiences of interpersonal discrimination and telomere length, a marker of cellular aging. Here, we investigate within-race interactions between multiple indices of interpersonal discrimination and sociodemographic characteristics in relation to telomere length in African American and White adults. Participants were from the Healthy Aging in Neighborhoods of Diversity across the Life Span study (Baltimore, Maryland). Ages ranged from 30 to 64 years old and all self-identified as either African American (n = 176) or White (n = 165). Using linear regression, three patterns were observed within African Americans: (1) women reporting greater lifetime burden of discrimination (p = .02), racial (p = .03), or gender (p = .01) discrimination; (2) those with higher socioeconomic status reporting greater lifetime burden (p = .03) or racial discrimination (p = .02); and (3) younger adults reporting greater exposure to multiple sources of discrimination (p = .03) had shorter telomere length. Among Whites, younger and older men reporting greater racial discrimination had shorter and longer telomeres, respectively (p = .02). Findings demonstrate within-race patterns of interpersonal discrimination and cellular aging, which may contribute to racial health disparities.},
}
@article {pmid30137208,
year = {2019},
author = {Vetter, VM and Meyer, A and Karbasiyan, M and Steinhagen-Thiessen, E and Hopfenmüller, W and Demuth, I},
title = {Epigenetic Clock and Relative Telomere Length Represent Largely Different Aspects of Aging in the Berlin Aging Study II (BASE-II).},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {74},
number = {1},
pages = {27-32},
doi = {10.1093/gerona/gly184},
pmid = {30137208},
issn = {1758-535X},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; DNA/*genetics ; DNA Methylation ; *Epigenesis, Genetic ; Female ; Follow-Up Studies ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Telomere/*genetics/metabolism ; Telomere Homeostasis ; Young Adult ; },
abstract = {DNA methylation age (DNAm age; "epigenetic clock") has recently been described as highly correlated with chronological age. Several studies suggest that DNAm age reflects, at least in part, biological age. Here, we adapted a recently published methylation-sensitive single nucleotide primer extension method for epigenetic age estimation and calculated the DNAm age based on only seven cytosine-phosphate-guanine sites in 1,895 DNA samples of the Berlin Aging Study II. In a second step, we explored the relationship between this new potential measure of biological age with an established marker of biological age, relative leukocyte telomere length (rLTL), in the same cohort. Our results showed a positive and significant correlation between DNAm age estimation and chronological age (N = 1,895, Rs2 = .47), which persisted after adjustment for covariates (sex, leukocyte distribution, alcohol and smoking). We found a significant but weak negative association between DNAm age acceleration and rLTL in linear regression analysis adjusted for age, sex, alcohol and smoking (β = -0.002, p = .007). Therefore, DNAm age appears to be a promising biomarker in the analysis of phenotypes of aging, which are not (only) related to pathways associated with mitotic age as measured by rLTL.},
}
@article {pmid30135115,
year = {2018},
author = {Pauliny, A and Miller, E and Rollings, N and Wapstra, E and Blomqvist, D and Friesen, CR and Olsson, M},
title = {Effects of male telomeres on probability of paternity in sand lizards.},
journal = {Biology letters},
volume = {14},
number = {8},
pages = {},
pmid = {30135115},
issn = {1744-957X},
mesh = {Animals ; Female ; Fertility ; Genotype ; Lizards/blood/genetics/*physiology ; Male ; Spermatozoa/*physiology ; *Telomere ; },
abstract = {Standardized swim-up trials are used in in vitro fertilization clinics to select particularly motile spermatozoa in order to increase the probability of a successful fertilization. Such trials demonstrate that sperm with longer telomeres have higher motility and lower levels of DNA damage. Regardless of whether sperm motility, and successful swim-up to fertilization sites, is a direct or correlational effect of telomere length or DNA damage, covariation between telomere length and sperm performance predicts a relationship between telomere length and probability of paternity in sperm competition, a prediction that for ethical reasons cannot be tested on humans. Here, we test this prediction in sand lizards (Lacerta agilis) using experimental data from twice-mated females in a laboratory population, and telomere length in blood from the participating lizards. Female identity influenced paternity (while the mechanism was not identified), while relatively longer male telomeres predicted higher probability of paternity. We discuss potential mechanisms underpinning this result.},
}
@article {pmid30133038,
year = {2020},
author = {Manczak, EM and Gotlib, IH},
title = {Relational Victimization and Telomere Length in Adolescent Girls.},
journal = {Journal of research on adolescence : the official journal of the Society for Research on Adolescence},
volume = {30 Suppl 1},
number = {},
pages = {39-45},
pmid = {30133038},
issn = {1532-7795},
support = {R01 MH074849/MH/NIMH NIH HHS/United States ; R01 MH101495/MH/NIMH NIH HHS/United States ; T32 MH019938/MH/NIMH NIH HHS/United States ; R37 MH101495/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Adverse Childhood Experiences/psychology ; Bullying/*psychology ; Case-Control Studies ; Child ; Depression/physiopathology/psychology ; Female ; Humans ; Mothers/psychology ; Peer Group ; Saliva/chemistry ; Stress, Psychological/physiopathology/*psychology ; *Telomere Shortening ; },
abstract = {An emerging body of research suggests that telomere length (TL)-a measure of cellular aging-is inversely associated with experiences of childhood stress. Given the salience of peer relationships in childhood and adolescence, we tested whether relational victimization is a unique and specific predictor of salivary TL in girls. Results examining 122 girls (ages 9-15) revealed that greater relational victimization was related to shorter TL but that similar associations were not evident for other measures of social relationships nor accounted for by factors related to depression, life stress, or 5-HTTLPR genotype. The present findings suggest that relational victimization is uniquely associated with TL in adolescence, revealing a link between key aspects of social relationships and biological processes.},
}
@article {pmid30129279,
year = {2018},
author = {Tennyson, RL and Gettler, LT and Kuzawa, CW and Hayes, MG and Agustin, SS and Eisenberg, DTA},
title = {Lifetime socioeconomic status and early life microbial environments predict adult blood telomere length in the Philippines.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {30},
number = {5},
pages = {e23145},
pmid = {30129279},
issn = {1520-6300},
support = {P30 ES010126/ES/NIEHS NIH HHS/United States ; T32 HD007543/HD/NICHD NIH HHS/United States ; P2C HD042828/HD/NICHD NIH HHS/United States ; P30 DK056350/DK/NIDDK NIH HHS/United States ; R01 DK078150/DK/NIDDK NIH HHS/United States ; P20 RR020649/RR/NCRR NIH HHS/United States ; R01 TW005596/TW/FIC NIH HHS/United States ; R24 HD042828/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Feces/*microbiology ; Female ; Humans ; Leukocytes/chemistry ; Longitudinal Studies ; Male ; Parturition ; Philippines ; Prospective Studies ; Seasons ; *Social Class ; Stress, Psychological/*psychology ; Telomere/*physiology ; Young Adult ; },
abstract = {OBJECTIVES: Psychosocial stress is postulated to hasten senescence in part by accelerating the shortening of telomere length (TL). One pathway through which this may happen is via increasing inflammation and innate immune system activation-a pathway which recent studies suggest acts more strongly for those who grew up in low microbial environments. Thus, we hypothesized that: (1) Psychosocial stress will be inversely associated with TL, (2) early life microbial environments will predict TL, and (3) microbial environments will moderate the association between psychosocial stress and TL.<br><br>METHODS: We utilized data from the Cebu Longitudinal Health and Nutrition Survey based in the Philippines (N&#x2009;=&#x2009;1410). We determined early life microbial environments by season of birth and exposure to animal feces. Psychosocial stress measures included perceived stress in adulthood, lifetime socioeconomic status (SES), and parental instability in childhood. TL was measured in blood from young adults by qPCR.<br><br>RESULTS: Contrary to predictions, we found that higher SES was associated with shorter TL and no association of TL with the other stress variables. Individuals born in the higher microbial exposure season had shorter TL, but early life microbial environments did not moderate the association between psychosocial stress and TL.<br><br>CONCLUSIONS: The unexpected inverse association between SES and TL suggests that higher SES, while indexing lower psychosocial stress, may impact TL more strongly through nonstress factors in the Philippines, such as unhealthy behavior. The inverse association between microbial environments and TL is consistent with other evidence connecting early life infections to decreased life expectancies.},
}
@article {pmid30128721,
year = {2018},
author = {Sováková, PP and Magdolenová, A and Konečná, K and Rájecká, V and Fajkus, J and Fojtová, M},
title = {Telomere elongation upon transfer to callus culture reflects the reprogramming of telomere stability control in Arabidopsis.},
journal = {Plant molecular biology},
volume = {98},
number = {1-2},
pages = {81-99},
pmid = {30128721},
issn = {1573-5028},
support = {16-04653S//Grantov&#xe1; Agentura &#x10c;esk&#xe9; Republiky/ ; CEITEC 2020 (LQ1601)//Ministerstvo &#x160;kolstv&#xed;, Ml&#xe1;de&#x17e;e a T&#x11b;lov&#xfd;chovy/ ; CZ.02.1.01/0.0 /0.0/15_003/0000477//Ministerstvo &#x160;kolstv&#xed;, Ml&#xe1;de&#x17e;e a T&#x11b;lov&#xfd;chovy/ ; },
mesh = {Arabidopsis/drug effects/genetics/*metabolism ; Arabidopsis Proteins/metabolism ; Chromatin/genetics ; Cytidine/analogs &amp; derivatives/pharmacology ; Ecotype ; Epigenesis, Genetic/drug effects ; Genes, Plant ; Histones/metabolism ; Mutation/genetics ; RNA, Messenger/genetics/metabolism ; Regeneration/drug effects ; Species Specificity ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis/drug effects ; *Tissue Culture Techniques ; Nicotiana/genetics ; },
abstract = {Standard pathways involved in the regulation of telomere stability do not contribute to gradual telomere elongation observed in the course of A. thaliana calli propagation. Genetic and epigenetic changes accompanying the culturing of plant cells have frequently been reported. Here we aimed to characterize the telomere homeostasis during long term callus propagation. While in Arabidopsis thaliana calli gradual telomere elongation was observed, telomeres were stable in Nicotiana tabacum and N. sylvestris cultures. Telomere elongation during callus propagation is thus not a general feature of plant cells. The long telomere phenotype in Arabidopsis calli was correlated neither with changes in telomerase activity nor with activation of alternative mechanisms of telomere elongation. The dynamics of telomere length changes was maintained in mutant calli with loss of function of important epigenetic modifiers but compromised in the presence of epigenetically active drug zebularine. To examine whether the cell culture-induced disruption of telomere homeostasis is associated with the modulated structure of chromosome ends, epigenetic properties of telomere chromatin were analysed. Albeit distinct changes in epigenetic modifications of telomere histones were observed, these were broadly stochastic. Our results show that contrary to animal cells, the structure and function of plant telomeres is not determined significantly by the epigenetic character of telomere chromatin. Set of differentially transcribed genes was identified in calli, but considering the known telomere- or telomerase-related functions of respective proteins, none of these changes per se was apparently related to the elongated telomere phenotype. Based on our data, we propose that the disruption in telomere homeostasis in Arabidopsis calli arises from the interplay of multiple factors, as a part of reprogramming of plant cells to long-term culture conditions.},
}
@article {pmid30124895,
year = {2018},
author = {Damiao Gouveia, AC and Skovman, A and Jensen, A and Koponen, IK and Loft, S and Roursgaard, M and Møller, P},
title = {Telomere shortening and aortic plaque progression in Apoliprotein E knockout mice after pulmonary exposure to candle light combustion particles.},
journal = {Mutagenesis},
volume = {33},
number = {3},
pages = {253-261},
doi = {10.1093/mutage/gey015},
pmid = {30124895},
issn = {1464-3804},
mesh = {Air Pollutants/*adverse effects/chemistry ; Animals ; Aorta/drug effects/pathology ; Apolipoproteins E/*genetics ; Atherosclerosis/*genetics/physiopathology ; Humans ; Lung/drug effects ; Mice ; Mice, Knockout ; Oxidative Stress/drug effects ; Particle Size ; Particulate Matter/adverse effects/chemistry ; Plaque, Atherosclerotic/pathology ; Reactive Oxygen Species/metabolism ; Telomere Shortening/*drug effects/genetics ; },
abstract = {Particles from burning candles contribute to the overall indoor exposure to particulate matter (PM). However, little is known about the effects of indoor sources of particles on cardiovascular disease endpoints. This study investigated the effect of pulmonary exposure to particles from combustion of candles and progression of atherosclerosis. Telomere shortening was assessed in tissues due to its relationship to risk of cardiovascular diseases. The particles were collected from burning candles and used for toxicological studies in cultured endothelial cells and apolipoprotein E (ApoE) knockout mice. Three hours exposure to particles increased the production of reactive oxygen species in endothelial cells, whereas there was no effect on cytotoxicity. Intratracheal instillation of particles (0.5 or 5 mg/kg) once a week for 5 weeks in ApoE-/- mice was associated with an accelerated progression of atherosclerosis in aorta and telomere shortening in the lung and spleen, whereas there was no effect on inflammation in the lungs (i.e. cell numbers), cell damage (i.e. lactate dehydrogenase) and lung barrier damage (i.e. protein concentration) as measured in bronchoalveolar lavage fluid. The results indicate that particles from burning candles are hazardous and this indoor emission source is an important contribution to the health risk of exposure to PM.},
}
@article {pmid30123710,
year = {2018},
author = {Dechsupa, S and Yingsakmongkol, W and Limthongkul, W and Singhatanadgige, W and Honsawek, S},
title = {Relative telomere length and oxidative DNA damage in hypertrophic ligamentum flavum of lumbar spinal stenosis.},
journal = {PeerJ},
volume = {6},
number = {},
pages = {e5381},
pmid = {30123710},
issn = {2167-8359},
abstract = {BACKGROUND: Lumbar spinal stenosis (LSS) is a common cause of low back pain with degenerative spinal change in older adults. Telomeres are repetitive nucleoprotein DNA sequences of TTAGGG at the ends of chromosomes. Oxidative stress originates from an imbalance in pro-oxidant and antioxidant homeostasis that results in the production of reactive oxygen species (ROS). The purpose of this study was to investigate relative telomere length (RTL) and oxidative DNA damage in ligamentum flavum (LF) tissue from LSS patients.<br><br>METHODS: Forty-eight patients with LSS participated in this study. Genomic DNA from non-hypertrophic and hypertrophic LF tissue were analyzed by real-time polymerase chain reaction for relative telomere length (RTL). 8-hydroxy 2'-deoxygaunosine (8-OHdG) levels were determined by using enzyme-linked immunosorbent assay. We cultivated LF fibroblast cells from patients in different ages (61, 66, and 77 years). After each cultivation cycle, we examined RTL and senescence-associated &#x3b2;-galactosidase (SA-&#x3b2;-gal) expression.<br><br>RESULTS: The hypertrophic LF had significantly lower RTL than non-hypertrophic LF (P&#xa0;=&#xa0;0.04). The levels of 8-OHdG were significantly higher in hypertrophic LF compared to non-hypertrophic LF (P&#xa0;=&#xa0;0.02). With advancing cell culture passage, the number of cells in each passage was significantly lower in hypertrophic LF fibroblast cells than non-hypertrophic LF fibroblast cells. When evaluated with SA-&#x3b2;-gal staining, all senescent LF fibroblast cells were observed at earlier passages in hypertrophic LF compared with non-hypertrophic LF fibroblast cells.<br><br>DISCUSSION: Our results showed that patients with LSS displayed an accelerated RTL shortening and high oxidative stress in hypertrophic LF. These findings implied that telomere shortening and oxidative stress may play roles in the pathogenesis of hypertrophic LF in lumbar spinal stenosis.},
}
@article {pmid30118998,
year = {2018},
author = {Liu, H and Xie, Y and Zhang, Z and Mao, P and Liu, J and Ma, W and Zhao, Y},
title = {Telomeric Recombination Induced by DNA Damage Results in Telomere Extension and Length Heterogeneity.},
journal = {Neoplasia (New York, N.Y.)},
volume = {20},
number = {9},
pages = {905-916},
pmid = {30118998},
issn = {1476-5586},
mesh = {CRISPR-Cas Systems ; Cell Cycle/genetics ; Cell Line ; DNA Breaks, Double-Stranded ; *DNA Damage ; DNA Repair ; Gene Editing ; Gene Targeting ; Humans ; *Recombination, Genetic ; Sister Chromatid Exchange ; Telomerase/metabolism ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {About 15% of human cancers counteract telomere loss by alternative lengthening of telomeres (ALT), which is attributed to homologous recombination (HR)-mediated events. But how telomeric HR leads to length elongation is poorly understood. Here, we explore telomere clustering and telomeric HR induced by double-stranded breaks (DSBs). We show that telomere clustering could occur at G1 and S phase of cell cycle and that three types of telomeric HR occur based on the manner of telomeric DNA exchange: equivalent telomeric sister chromatin exchange (T-SCE), inequivalent T-SCE, and No-SCE. While inequivalent T-SCE increases telomere length heterogeneity with no net gain of telomere length, No-SCE, which is presumably induced by interchromatid HR and/or break-induced replication, results in telomere elongation. Accordingly, cells subjected to long-term telomeric DSBs display increased heterogeneity of length and longer telomeres. We also demonstrate that DSBs-induced telomere elongation is telomerase independent. Moreover, telomeric recombination induced by DSBs is associated with formation of ALT-associated PML body and C-circle. Thus, DNA damage triggers recombination mediated elongation, leading to the induction of multiple ALT phenotypes.},
}
@article {pmid30115091,
year = {2018},
author = {Trotta, L and Norberg, A and Taskinen, M and Béziat, V and Degerman, S and Wartiovaara-Kautto, U and Välimaa, H and Jahnukainen, K and Casanova, JL and Seppänen, M and Saarela, J and Koskenvuo, M and Martelius, T},
title = {Diagnostics of rare disorders: whole-exome sequencing deciphering locus heterogeneity in telomere biology disorders.},
journal = {Orphanet journal of rare diseases},
volume = {13},
number = {1},
pages = {139},
pmid = {30115091},
issn = {1750-1172},
support = {NKIR-ANR-13-PDOC-0025-01//ANR/International ; },
mesh = {Adult ; Child ; Child, Preschool ; DNA Helicases/genetics ; Dyskeratosis Congenita/diagnosis/genetics ; Female ; Humans ; Male ; Mutation/genetics ; Pedigree ; Rare Diseases/genetics ; Telomerase/genetics ; Telomere/genetics ; Exome Sequencing/*methods ; Young Adult ; },
abstract = {BACKGROUND: The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKC), the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs.<br><br>METHODS: Clinical sequencing was performed on a cohort of patients presenting with variable immune phenotypes lacking molecular diagnoses. Hypothesis-free whole-exome sequencing (WES) was selected in the absence of compelling diagnostic hints in patients with variable immunological and haematological conditions.<br><br>RESULTS: In four patients belonging to three families, we have detected five novel variants in known TBD-causing genes (DKC1, TERT and RTEL1). In addition to the molecular findings, they all presented shortened blood cell telomeres. These findings are consistent with the displayed TBD phenotypes, addressing towards the molecular diagnosis and subsequent clinical follow-up of the patients.<br><br>CONCLUSIONS: Our results strongly support the utility of WES-based approaches for routine genetic diagnostics of TBD patients with heterogeneous or atypical clinical presentation who otherwise might remain undiagnosed.},
}
@article {pmid30109098,
year = {2018},
author = {Klegarth, AR and Eisenberg, DTA},
title = {Mammalian chromosome-telomere length dynamics.},
journal = {Royal Society open science},
volume = {5},
number = {7},
pages = {180492},
pmid = {30109098},
issn = {2054-5703},
abstract = {Individual chromosome arms have specific individual telomere lengths (TLs). Past studies within species have shown strong positive correlations between individual chromosome length and TL at that chromosome. While the reasons for these associations are unclear, the strength and consistency of the associations across disparate taxa suggest that this is important to telomere biology and should be explored further. If TL is primarily determined by chromosome length, then chromosome length should be considered and controlled for in cross-species analyses of TL. Here, we employ a cross-species approach to explore whether the chromosome length-TL association observed intraspecifically is a determinant of mean TL across species. Data were compiled from two studies characterizing TL across a range of mammalian taxa and analysed in a phylogenetic framework. We found no significant relationship between TL and chromosome size across mammals or within mammalians orders. The pattern trends in the expected direction and we suggest may be masked by evolutionary lag effects.},
}
@article {pmid30107521,
year = {2019},
author = {Wilson, SJ and Woody, A and Padin, AC and Lin, J and Malarkey, WB and Kiecolt-Glaser, JK},
title = {Loneliness and Telomere Length: Immune and Parasympathetic Function in Associations With Accelerated Aging.},
journal = {Annals of behavioral medicine : a publication of the Society of Behavioral Medicine},
volume = {53},
number = {6},
pages = {541-550},
pmid = {30107521},
issn = {1532-4796},
support = {UL1 TR001070/TR/NCATS NIH HHS/United States ; K99 AG056667/AG/NIA NIH HHS/United States ; R01 AG038621/AG/NIA NIH HHS/United States ; R01 AG029562/AG/NIA NIH HHS/United States ; K05 CA172296/CA/NCI NIH HHS/United States ; T32 DE014320/DE/NIDCR NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; *Aging, Premature/immunology/metabolism/physiopathology ; *Cytomegalovirus Infections/immunology ; *Epstein-Barr Virus Infections/immunology ; Female ; *Heart Rate/physiology ; Humans ; *Immunosenescence/physiology ; *Loneliness ; Male ; Middle Aged ; *Parasympathetic Nervous System/physiopathology ; *Telomere Shortening/physiology ; },
abstract = {BACKGROUND: Lonely people's heightened risks for chronic health conditions and early mortality may emerge in part through cellular aging. Lonelier people have more severe sympathetic responses to acute stress, increasing their risk for herpesvirus reactivation, a possible path to shorter telomeres. Parasympathetic function may modulate this risk.<br><br>PURPOSE: The current study aimed to examine the associations among loneliness, herpesvirus reactivation, and telomere length, with parasympathetic activity as a moderator, in healthy middle-aged and older adults.<br><br>METHODS: A sample of 113 healthy men and women of ages 40-85 provided blood samples that were assayed for telomere length, as well as the latent herpesviruses cytomegalovirus (CMV) and Epstein-Barr virus (EBV). They also provided heart rate variability (HRV), a measure of parasympathetic activity, and reported on their feelings of loneliness.<br><br>RESULTS: Lonelier people with lower HRV (i.e., lower parasympathetic activity) had greater CMV reactivation and shorter telomeres compared with their less lonely counterparts, above and beyond demographics, health behaviors, resting heart rate, and social network size. However, loneliness was not associated with viral reactivation or telomere length among those with higher HRV. In turn, greater CMV and EBV reactivation was associated with shorter telomeres.<br><br>CONCLUSIONS: Taken together, these data implicate parasympathetic function in novel links between loneliness and accelerated cellular aging.},
}
@article {pmid30105003,
year = {2018},
author = {Lin, Z and Gao, H and Wang, B and Wang, Y},
title = {Dietary Copper Intake and Its Association With Telomere Length: A Population Based Study.},
journal = {Frontiers in endocrinology},
volume = {9},
number = {},
pages = {404},
pmid = {30105003},
issn = {1664-2392},
abstract = {Background: Telomere is regarded as the fundamental aspect of cellular aging and copper is recognized as one of the most essential trace elements. The role of dietary copper intake in telomere length maintenance is seldom examined. This study aims to investigate if telomere length is to be associated with daily dietary copper intake. Methods: We used epidemiological data from a large national population-based health and nutrition survey. Dietary intake was assessed during the 24-h period before the interview date when blood sample was collected. Telomere length was measured from blood leukocyte using PCR method. The relationship between telomere length and dietary copper intake was assessed using multivariable linear regression models. We also examined if obesity, measured by body mass index, could modify the observed association. Results: There are 7,324 participants had both leukocyte telomere length measured and dietary copper intake assessed, around 48.0% of them were men. Telomere length was longer in women than that in men (1.05 ± 0.26 vs. 1.00 ± 0.26 T/S ratio), while dietary copper intake was less in women than that in men (1.12 ± 0.80 vs. 1.51 ± 1.61 mg). After controlling for age, sex, ethnicity, physical activity, current smoking status, hypertension, cardiovascular diseases, and body mass index in the multivariable linear regression models, one unit increase of log-transformed dietary copper intake was significantly associated with longer telomere length (β = 0.02, 95% confidence interval: 0.01, 0.04). We did not find a significant sex difference for this association. Conclusions: Dietary copper intake was significantly associated telomere length.The role of copper in human health might be involved in biological aging process.},
}
@article {pmid30098699,
year = {2018},
author = {Miranda-Furtado, CL and Luchiari, HR and Chielli Pedroso, DC and Kogure, GS and Caetano, LC and Santana, BA and Santana, VP and Benetti-Pinto, CL and Reis, FM and Maciel, MA and Ferriani, RA and Ramos, ES and Calado, RT and Dos Reis, RM},
title = {Skewed X-chromosome inactivation and shorter telomeres associate with idiopathic premature ovarian insufficiency.},
journal = {Fertility and sterility},
volume = {110},
number = {3},
pages = {476-485.e1},
doi = {10.1016/j.fertnstert.2018.04.017},
pmid = {30098699},
issn = {1556-5653},
mesh = {Adolescent ; Adult ; Case-Control Studies ; Female ; Fragile X Mental Retardation Protein/genetics ; Humans ; Primary Ovarian Insufficiency/*diagnosis/*genetics ; Prospective Studies ; Receptors, Androgen/genetics ; Telomere/*genetics ; Telomere Shortening/*genetics ; X Chromosome Inactivation/*genetics ; Young Adult ; },
abstract = {OBJECTIVE: To analyze whether telomere length, X-chromosome inactivation (XCI), and androgen receptor (AR) GAG polymorphism are related to idiopathic premature ovarian insufficiency (POI).<br><br>DESIGN: Case-control study.<br><br>SETTING: University hospital.<br><br>PATIENT(S): A total of 121 women, including 46 nonsyndromic POI and 75 controls.<br><br>INTERVENTION(S): None.<br><br>MAIN OUTCOME MEASURE(S): Age, weight, height, body mass index (BMI), systolic and diastolic arterial pressure, E2, androstenedione, T, and C-reactive protein were assessed. Telomere length was estimated by quantitative real-time polymerase chain reaction, XCI was measured using the Human Androgen Receptor and X-linked retinitis pigmentosa 2 (RP2) methylation assays. AR and FMR1 polymorphism was assessed by quantitative fluorescent polymerase chain reaction and sequencing.<br><br>RESULT(S): Premature ovarian insufficiency women had a higher mean age, weighed less, and exhibited lower C-reactive protein, E2, and androstenedione levels. The AR polymorphism did not differ between the groups. Four patients had premutation (55-200 CGG repeats), and none displayed a full mutation in the FMR1 gene. However, patients with POI showed shorter telomere length and higher frequency of skewed XCI. Extreme skewing (&#x2265;90%) was observed in 15% of women with POI, and shorter telomeres correlated with XCI skewing in both groups.<br><br>CONCLUSION(S): Skewed XCI and shortened telomere length were associated with idiopathic POI, despite no alterations in the AR and FMR1 genes. Additionally, there is a tendency for women with short telomeres to exhibit skewed XCI.},
}
@article {pmid30098092,
year = {2018},
author = {Aida, S and Aida, J and Naoi, M and Kato, M and Tsuura, Y and Natsume, I and Takubo, K},
title = {Measurement of telomere length in cells from pleural effusion: Asbestos exposure causes telomere shortening in pleural mesothelial cells.},
journal = {Pathology international},
volume = {68},
number = {9},
pages = {503-508},
doi = {10.1111/pin.12710},
pmid = {30098092},
issn = {1440-1827},
support = {JP C26460457//JSPS KAKENHI/ ; },
mesh = {Adenocarcinoma of Lung/pathology ; Adult ; Aged ; Aged, 80 and over ; Asbestos/adverse effects ; Biomarkers, Tumor/*metabolism ; Female ; Humans ; Lung Neoplasms/*diagnosis/pathology ; Male ; Mesothelioma/*diagnosis/pathology ; Mesothelioma, Malignant ; Middle Aged ; Pleural Effusion/pathology ; Pleural Effusion, Malignant/*pathology ; Telomere/*pathology ; },
abstract = {We estimated the telomere lengths of neoplastic and non-neoplastic mesothelial cells and examined their correlation with asbestos exposure and the expression of markers of mesothelial malignancy. Cell blocks of pleural effusion obtained from 35 cases of non-neoplastic disease (NN), 12 cases of malignant mesothelioma (MM) and 12 cases of carcinomatous effusion due to lung adenocarcinoma (LA) were examined. Fifteen of the 35 NN cases had pleural plaques (NNpp+) suggestive of asbestos exposure, and the other 20 cases had no pleural plaques (NNpp-). Telomere length was measured using the tissue quantitative fluorescence in situ hybridization method, and expressed as normalized telomere-to-centromere ratio. NN cases had significantly longer telomeres than MM (P < 0.001) and LA (P < 0.001) cases. Telomeres in NNpp+ cases were slightly shorter than those of NNpp- cases (P = 0.047). MM and LA showed almost the same telomere length. NN cases with shorter telomeres tended to show aberrant expression of epithelial membrane antigen (EMA), CD146, glucose transporter 1 (GLUT1) and IGF-II messenger RNA-binding protein 3 (IMP3). These results suggest that telomere shortening and subsequent genetic instability play an important role in the development of MM. Measurement of telomere length of cells in pleural effusion might be helpful for earlier detection of MM.},
}
@article {pmid30097281,
year = {2018},
author = {Fu, W and Chen, Z and Bai, Y and Wu, X and Li, G and Chen, W and Wang, G and Wang, S and Li, X and He, M and Zhang, X and Wu, T and Guo, H},
title = {The interaction effects of polycyclic aromatic hydrocarbons exposure and TERT- CLPTM1L variants on longitudinal telomere length shortening: A prospective cohort study.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {242},
number = {Pt B},
pages = {2100-2110},
doi = {10.1016/j.envpol.2018.05.026},
pmid = {30097281},
issn = {1873-6424},
mesh = {Adult ; Coke/analysis ; Environmental Exposure/*analysis ; Environmental Pollutants/*toxicity/urine ; Female ; Genotype ; Humans ; Male ; Membrane Proteins ; Neoplasm Proteins ; Occupational Exposure/analysis ; Polycyclic Aromatic Hydrocarbons/analysis/*toxicity/urine ; Prospective Studies ; Pyrenes ; Telomerase ; Telomere/*drug effects/physiology ; },
abstract = {Telomere length (TL) is an index of cellular aging and can predict the incidences of many age-related diseases. Change of TL might be affected by environmental pollution and individual's genetic background. In this cohort study, we aimed to evaluate the associations between polycyclic aromatic hydrocarbons (PAHs) exposure and longitudinal TL shortening, and investigate whether genetic variations in TERT-CLPTM1L can modify these associations. We measured the baseline concentrations of twelve urinary PAH metabolites and genotyped six variants at TERT-CLPTM1L among 1243 coke-oven workers. The relative leukocyte TL was detected in both baseline and follow-up (4 years later) visits. The TL shortening were estimated by TL decline and TL ratio. We found that the urinary level of 1-hydroxypyrene (1-OHP) had significant dose-response relationships with increased TL decline [β(95%CI) = 0.078(0.023, 0.133), P = 0.005] and TL ratio [β(95%CI) = 0.096(0.037, 0.155), P = 0.002]. Besides, urinary 1-hydroxynaphthalene (1-OHNa) was marginally dose-related with elevated TL decline [β(95%CI) = 0.053(-0.001, 0.107), P = 0.055] and TL ratio [β(95%CI) = 0.057(-0.002, 0.116), P = 0.058]. Analyses of TERT-CLPTM1L variants showed that the rs401681 and rs465498 could modify the effect of 1-OHP on increasing TL decline (Pinteraction = 0.012 and 0.035, respectively) and TL ratio (Pinteraction = 0.014 and 0.067, respectively), which were pronounced among rs401681TT and rs465498CC carriers, but not seen among rs401681TC + CC and rs465498CT + TT carriers. In conclusion, elevated exposure to PAHs can accelerate the TL shortening and this effect can be modified by TERT-CLPTM1L variants. These results may add potential evidence for gene-environment interactions on dynamic changes of telomere length. Further studies are warranted to validate these findings and uncover the underlying mechanisms.},
}
@article {pmid30095207,
year = {2018},
author = {Tomita, KI and Aida, J and Izumiyama-Shimomura, N and Nakamura, KI and Ishikawa, N and Matsuda, Y and Arai, T and Ishiwata, T and Kumasaka, T and Takahashi-Fujigasaki, J and Hiraishi, N and Yamada, M and Fujiwara, M and Takubo, K},
title = {Changes in telomere length with aging in human neurons and glial cells revealed by quantitative fluorescence in situ hybridization analysis.},
journal = {Geriatrics &amp; gerontology international},
volume = {18},
number = {10},
pages = {1507-1512},
doi = {10.1111/ggi.13500},
pmid = {30095207},
issn = {1447-0594},
support = {JP C26460431//JSPS KAKENHI/ ; },
mesh = {Age Factors ; Aged ; Aged, 80 and over ; Aging/*genetics ; Biopsy, Needle ; Cells, Cultured ; Child, Preschool ; Cross-Sectional Studies ; Female ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Infant ; Infant, Newborn ; Longevity/*genetics ; Male ; Neuroglia/*pathology ; Neurons/*pathology ; Risk Factors ; Sensitivity and Specificity ; Telomere/*pathology ; Tissue Culture Techniques ; },
abstract = {AIM: The telomere is a structure present at the ends of chromosomes, and is known to shorten with aging and successive rounds of cell division. However, very little is known about telomere attrition in post-mitotic cells, such as neurons.<br><br>METHODS: Using our originally developed quantitative fluorescence in situ hybridization method, we analyzed age-dependent alterations of telomere length in three types of cells in the human cerebrum: neurons and glial cells in both the gray and white matter.<br><br>RESULTS: In adults, telomeres were significantly longer in neurons than in glial cells, whereas in infants, telomere lengths did not differ among the three cell types. No aging-related telomere attrition was evident in neurons. However, the telomeres of glial cells were shorter in older individuals than in younger individuals, and attrition was more rapid in the white matter than in the gray matter.<br><br>CONCLUSIONS: The present results suggest that the telomeres of neurons remain stable throughout life, whereas telomeres in white matter glial cells become significantly shorter with age. Examination of adults showed no significant correlation between telomere length and age in the three cell types. Although the present study was cross-sectional, the results suggest that telomere shortening before adolescence contributes to the significant decrease of telomere length in white matter glial cells. The present findings in normal cerebral tissues will be informative for future studies of telomere stability in the diseased brain. Geriatr Gerontol Int 2018; 18: 1507-1512.},
}
@article {pmid30094266,
year = {2018},
author = {Danese, E and Lippi, G},
title = {Telomere length: is the future in our "ends"?.},
journal = {Annals of translational medicine},
volume = {6},
number = {13},
pages = {280},
pmid = {30094266},
issn = {2305-5839},
abstract = {Telomeres, repetitive nucleotide sequences located at the end of each chromosome, play the important function of preserving chromosome stability and preventing molecular contact with neighboring chromosomes. Albeit the concept that telomere length may be a marker of health and disease seems hence counterintuitive, the translation of this clear-cut concept from the bench to the beside has appeared so far less straightforward. In particular, controversial evidence has emerged so far about the fact that telomere length may actually predict morbidity and mortality across many clinical settings. This uncertainty is actually due to a kaleidoscope of biological and technical factors, including preanalytical issues (e.g., sample matrix), poor standardization of techniques used for their assessment, and dependence of telomere structure upon genetics, epigenetics, environment and behavioral attitudes, which may be present at a variable extent in various physiological or pathological conditions. Therefore, although it is now undeniable that our future is largely in our "hands" (i.e., genotype, diet, exposure to environmental factors and so forth), larger and more solid evidence will be necessary before concluding that the future is also written in our (chromosome) "ends".},
}
@article {pmid30092957,
year = {2018},
author = {De Meyer, T and Nawrot, T and Bekaert, S and De Buyzere, ML and Rietzschel, ER and Andrés, V},
title = {Telomere Length as Cardiovascular Aging Biomarker: JACC Review Topic of the Week.},
journal = {Journal of the American College of Cardiology},
volume = {72},
number = {7},
pages = {805-813},
doi = {10.1016/j.jacc.2018.06.014},
pmid = {30092957},
issn = {1558-3597},
mesh = {Aging/pathology/*physiology ; Animals ; Atherosclerosis/metabolism/pathology ; Biomarkers/metabolism ; Cardiovascular Diseases/metabolism/*pathology ; Cardiovascular System/metabolism/pathology ; Humans ; Telomere/metabolism/*pathology ; Telomere Shortening/*physiology ; },
abstract = {Telomeres shorten with age, the major risk factor for atherosclerotic cardiovascular disease (aCVD). The observation of shorter telomeres in aCVD patients thus suggested that critical telomere shortening may contribute to premature biological aging and aCVD. Therefore, telomere length often is suggested as a causal aCVD risk factor, a proposal supported by recent Mendelian randomization studies; however, epidemiological research has shown disappointingly low effect sizes. It therefore remains uncertain whether telomere shortening is a cause of aCVD or merely a consequence. The authors argue that elucidating the mechanistic foundation of these findings is essential for any possible translation of telomere biology to the clinic. Here, they critically evaluate evidence for causality in animal models and human studies, and review popular hypotheses and discuss their clinical implications. The authors identify 4 key questions that any successful mechanistic theory should address, and they discuss how atherosclerosis-associated local telomere attrition may provide the answers.},
}
@article {pmid30088779,
year = {2019},
author = {Popescu, I and Mannem, H and Winters, SA and Hoji, A and Silveira, F and McNally, E and Pipeling, MR and Lendermon, EA and Morrell, MR and Pilewski, JM and Hanumanthu, VS and Zhang, Y and Gulati, S and Shah, PD and Iasella, CJ and Ensor, CR and Armanios, M and McDyer, JF},
title = {Impaired Cytomegalovirus Immunity in Idiopathic Pulmonary Fibrosis Lung Transplant Recipients with Short Telomeres.},
journal = {American journal of respiratory and critical care medicine},
volume = {199},
number = {3},
pages = {362-376},
pmid = {30088779},
issn = {1535-4970},
support = {R01 AI079175/AI/NIAID NIH HHS/United States ; R01 CA225027/CA/NCI NIH HHS/United States ; R01 HL119476/HL/NHLBI NIH HHS/United States ; R01 HL133184/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Cytomegalovirus/immunology ; Cytomegalovirus Infections/*complications/*immunology ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/*complications/immunology ; Immunity ; *Lung Transplantation ; Male ; Middle Aged ; Telomere/*immunology ; Transplant Recipients/*statistics &amp; numerical data ; },
abstract = {RATIONALE: Cytomegalovirus (CMV)-related morbidities remain one of the most common complications after lung transplantation and have been linked to allograft dysfunction, but the factors that predict high risk for CMV complications and effective immunity are incompletely understood.<br><br>OBJECTIVES: To determine if short telomeres in idiopathic pulmonary fibrosis (IPF) lung transplant recipients (LTRs) predict the risk for CMV-specific T-cell immunity and viral control.<br><br>METHODS: We studied IPF-LTRs (n&#x2009;=&#x2009;42) and age-matched non-IPF-LTRs (n&#x2009;=&#x2009;42) and assessed CMV outcomes. We measured lymphocyte telomere length and DNA sequencing, and assessed CMV-specific T-cell immunity in LTRs at high risk for CMV events, using flow cytometry and fluorescence in situ hybridization.<br><br>MEASUREMENTS AND MAIN RESULTS: We identified a high prevalence of relapsing CMV viremia in IPF-LTRs compared with non-IPF-LTRs (69% vs. 31%; odds ratio, 4.98; 95% confidence interval, 1.95-12.50; P&#x2009;<&#x2009;0.001). Within this subset, IPF-LTRs who had short telomeres had the highest risk of CMV complications (P&#x2009;<&#x2009;0.01) including relapsing-viremia episodes, end-organ disease, and CMV resistance to therapy, as well as shorter time to viremia versus age-matched non-IPF control subjects (P&#x2009;<&#x2009;0.001). The short telomere defect in IPF-LTRs was associated with significantly impaired CMV-specific proliferative responses, T-cell effector functions, and induction of the major type-1 transcription factor T-bet (T-box 21;TBX21).<br><br>CONCLUSIONS: Because the short telomere defect has been linked to the pathogenesis of IPF in some cases, our data indicate that impaired CMV immunity may be a systemic manifestation of telomere-mediated disease in these patients. Identifying this high-risk subset of LTRs has implications for risk assessment, management, and potential strategies for averting post-transplant CMV morbidities.},
}
@article {pmid30082901,
year = {2018},
author = {Renner, W and Krenn-Pilko, S and Gruber, HJ and Herrmann, M and Langsenlehner, T},
title = {Relative telomere length and prostate cancer mortality.},
journal = {Prostate cancer and prostatic diseases},
volume = {21},
number = {4},
pages = {579-583},
doi = {10.1038/s41391-018-0068-3},
pmid = {30082901},
issn = {1476-5608},
mesh = {Aged ; Biomarkers, Tumor ; Combined Modality Therapy ; Humans ; Leukocyte Count ; Male ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; Prognosis ; Proportional Hazards Models ; Prostatic Neoplasms/diagnosis/*genetics/*mortality/therapy ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {PURPOSE: Telomeres are essential for the maintenance of chromosomal integrity and telomere length has been associated with cancer risk and development. Aim of the present study was to analyze the prognostic value of leukocyte relative telomere (RTL) length in long-term prostate cancer (PCa) mortality.<br><br>METHODS: Blood samples of PCa patients were obtained before initiation of radiotherapy. RTL of peripheral blood leukocytes was determined by a quantitative polymerase chain reaction method in 533 patients with PCa. Main outcome was overall mortality.<br><br>RESULTS: During a median follow-up time of 149 months, 188 (35.3%) patients died. In a univariate Cox regression analysis, RTL quartiles (longer RTL) were significantly associated with higher overall mortality (hazard ration (HR) = 1.20; 95% confidence interval (CI): 1.05-1.36; p&#x2009;=&#x2009;0.006). In a multivariate Cox regression model including age at diagnosis, androgen deprivation therapy, and risk group (based on PSA level, GS, and T stage), RTL quartiles remained a significant predictor of higher overall mortality (HR = 1.22; 95% CI: 1.07-1.39; p&#x2009;=&#x2009;0.003).<br><br>CONCLUSIONS: Longer leukocyte RTL predicts higher overall mortality in patients with PCa.},
}
@article {pmid30082315,
year = {2018},
author = {Kratz, K and de Lange, T},
title = {Protection of telomeres 1 proteins POT1a and POT1b can repress ATR signaling by RPA exclusion, but binding to CST limits ATR repression by POT1b.},
journal = {The Journal of biological chemistry},
volume = {293},
number = {37},
pages = {14384-14392},
pmid = {30082315},
issn = {1083-351X},
support = {R01 AG016642/AG/NIA NIH HHS/United States ; R56 AG016642/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Cells, Cultured ; DNA/metabolism ; DNA-Binding Proteins/*metabolism ; HEK293 Cells ; Humans ; Mice ; Models, Theoretical ; Protein Binding ; Replication Protein A/*metabolism ; *Signal Transduction ; *Telomere ; },
abstract = {Comprised of telomeric TTAGGG repeats and shelterin, telomeres ensure that the natural ends of chromosomes remain impervious to the DNA damage response. Telomeres carry a long constitutive 3' overhang that can bind replication protein A (RPA) and activate the ATR Ser/Thr kinase (ATR), which induces cell cycle arrest. A single-stranded (ss) TTAGGG repeat-binding protein in mouse shelterin, POT1a, has been proposed to repress ATR signaling by preventing RPA binding. Repression of ATR at telomeres requires tethering of POT1a to the other shelterin subunits situated on the double-stranded (ds) telomeric DNA. The simplest model of ATR repression, the "tethered exclusion model," suggests that the only critical features of POT1a are its connection to shelterin and its binding to ss telomeric DNA. In agreement with the model, we show here that a shelterin-tethered variant of RPA70 (lacking the ATR recruitment domain) can repress ATR signaling at telomeres that lack POT1a. However, arguing against the tethered exclusion model, the nearly identical POT1b subunit of shelterin has been shown to be much less proficient than POT1a in repression of ATR. We now show that POT1b has the intrinsic ability to fully repress ATR but is prevented from doing so when bound to Ctc1, Stn1, Ten1 (CST), the complex needed for telomere end processing. These results establish that shelterin represses ATR with a tethered ssDNA-binding domain that excludes RPA from the 3' overhang and also reveal an unexpected effect of CST on the ability of POT1b to repress ATR.},
}
@article {pmid30080989,
year = {2018},
author = {Polito, F and Cucinotta, M and Abbritti, RV and Brogna, A and Pergolizzi, S and Tomasello, C and Barresi, V and Angileri, FF and Di Giorgio, R and Conti, A and La Torre, D and Germanò, A and Aguennouz, M},
title = {Silencing of telomere-binding protein adrenocortical dysplasia (ACD) homolog enhances radiosensitivity in glioblastoma cells.},
journal = {Translational research : the journal of laboratory and clinical medicine},
volume = {202},
number = {},
pages = {99-108},
doi = {10.1016/j.trsl.2018.07.005},
pmid = {30080989},
issn = {1878-1810},
mesh = {Brain Neoplasms/*metabolism/pathology ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Survival ; Cyclin D1/metabolism ; *Gene Silencing ; Glioblastoma/*metabolism/pathology ; Humans ; Neoplasm Grading ; Neuronal Apoptosis-Inhibitory Protein/metabolism ; *Radiation Tolerance ; Shelterin Complex ; Telomerase/metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Adrenocortical dysplasia (ACD) is a shelterin protein involved in the maintenance of telomere length and in cancer radioresistance. This study investigated the expression profile of ACD in human gliomas and its role in radioresistance of glioma cells. The expression of ACD was analyzed in 62 different grades of glioma tissues and correlated with prognosis. A radioresistant cell line was generated from U87MG cells. For mechanistic studies, ACD was inhibited by small interfering RNA-targeting ACD and the effect on cell radioresistance, telomerase activity, cyclinD1, caspase-3, hTERT, and BIRC1 was evaluated. Clonogenic assay was performed after irradiation, to investigate the effect of ACD silencing on radiation sensitivity. ACD expression appeared strongly upregulated in higher grade gliomas, and its expression was significantly correlated to grading and poor prognosis. In glioma cell lines, ACD expression pattern was similar to those observed in glioma tissues. In irradiated cells, ACD expression was increased in an ionizing radiation dose-dependent manner. A higher expression of ACD was observed in the radioresistant clones than parental cells. Silencing of ACD led to the enhanced radiation sensitivity, decreased telomerase activity and cyclin D1 expression, reduced expression of BIRC1, and finally to the upregulation of caspase-3. This study represents the first report, which demonstrated the expression pattern of ACD in gliomas and its prognostic value. Our results suggested that ACD is involved in glioblastoma radioresistance, likely through the modulation of telomerase activity, proliferation, and apoptosis. ACD might represent a potential molecular biomarker and a novel therapeutic target in glioblastoma.},
}
@article {pmid30077435,
year = {2018},
author = {Conklin, QA and King, BG and Zanesco, AP and Lin, J and Hamidi, AB and Pokorny, JJ and Jesús Álvarez-López, M and Cosín-Tomás, M and Huang, C and Kaliman, P and Epel, ES and Saron, CD},
title = {Corrigendum to "Insight meditation and telomere biology: The effects of intensive retreat and the moderating role of personality" [Brain Behav. Immun. 70 (2018) 233-245].},
journal = {Brain, behavior, and immunity},
volume = {73},
number = {},
pages = {736-737},
doi = {10.1016/j.bbi.2018.07.015},
pmid = {30077435},
issn = {1090-2139},
}
@article {pmid30076493,
year = {2018},
author = {Buschiazzo, LM and Caraballo, DA and Cálcena, E and Longarzo, ML and Labaroni, CA and Ferro, JM and Rossi, MS and Bolzán, AD and Lanzone, C},
title = {Integrative analysis of chromosome banding, telomere localization and molecular genetics in the highly variable Ctenomys of the Corrientes group (Rodentia; Ctenomyidae).},
journal = {Genetica},
volume = {146},
number = {4-5},
pages = {403-414},
pmid = {30076493},
issn = {1573-6857},
mesh = {Animals ; Chromosome Banding/methods ; Chromosomes, Mammalian/genetics ; Cytochromes b/*genetics ; Cytogenetic Analysis/methods ; Evolution, Molecular ; Genetic Variation/genetics ; Karyotyping/methods ; Octodon/*genetics ; Phylogeny ; Rodentia/genetics ; Telomere/genetics ; },
abstract = {The genus Ctenomys comprises about 70 species with great chromosome diversity. The Corrientes group is one of the most chromosomally variable lineages in the genus, where the diploid number (2n) varies from 41 to 70. In this group, three nominal species and numerous polymorphic and polytypic populations have been described. In order to get insight into the chromosomal evolution of this species complex, we applied different banding and molecular cytogenetic techniques. The results were interpreted in an evolutionary context, based on mitochondrial cytochrome b analyses. Studied samples are representative of the broad chromosomal variability in the group, including specimens with 2n = 42 to 2n = 70. Heterochromatin was scarce but concentrated in a few chromosomes. Centromeric DAPI-negative heterochromatin was observed in some autosomal pairs, which differed among populations. Location and amount of DAPI-neutral heterochromatin within the Y chromosome varied among populations. The variable distribution of heterochromatin indicates its dynamic behavior. NORs were detected in one pair of autosomes, which also differed among some populations. Telomeric FISH signals were observed in all complements only at the chromosome ends. The Corrientes group belongs to a clade that also includes C. pearsoni, C. lami, C. minutus, C. ibicuiensis and C. torquatus. Almost all of these species are variable at the chromosomal level, suggesting that this is the ancestral condition of the clade. Within the Corrientes group, the observed low genetic divergence, in contrast with its high chromosomal variability, is indicative of decoupling between the rates of chromosomal and mitochondrial evolution.},
}
@article {pmid30075329,
year = {2018},
author = {Friedenreich, CM and Wang, Q and Ting, NS and Brenner, DR and Conroy, SM and McIntyre, JB and Mickle, A and Courneya, KS and Beattie, T},
title = {Effect of a 12-month exercise intervention on leukocyte telomere length: Results from the ALPHA Trial.},
journal = {Cancer epidemiology},
volume = {56},
number = {},
pages = {67-74},
doi = {10.1016/j.canep.2018.07.012},
pmid = {30075329},
issn = {1877-783X},
support = {130238//CIHR/Canada ; },
mesh = {Aged ; Canada ; Exercise/*physiology ; Female ; Humans ; *Leukocytes ; Middle Aged ; Postmenopause ; *Telomere ; },
abstract = {BACKGROUND: Short telomeres may indicate a higher risk of cancer and other chronic diseases. Some observational studies show positive associations between leukocyte telomere length (LTL) and physical activity levels. We hypothesized, therefore, that exercise may be one strategy for slowing telomere attrition.<br><br>METHODS: We conducted an ancillary analysis of blood from a year-long, two-centred, two-armed (1:1) randomized controlled trial of aerobic exercise versus usual inactivity. The analysis included 212 physically inactive, disease-free, non-smoking, postmenopausal women (n&#x202f;=&#x202f;99 exercisers, n&#x202f;=&#x202f;113 controls) in Alberta, Canada (2003-2006). The exercise prescription was aerobic exercise five days/week (supervised three days/week), 45&#x202f;min/session, achieving 70-80% heart rate reserve. Baseline and 12-month LTL were analyzed using quantitative real-time polymerase chain reactions (qPCR). The primary statistical analysis was intention-to-treat, comparing the ratio of mean LTLs (12-months:baseline) for exercisers versus controls from a general linear model. Secondary analyses included a per-protocol analysis (&#x2265;90% adherence) and analyses stratified by baseline LTL, age, body mass index, and fitness level, respectively.<br><br>RESULTS: Participants were overweight at baseline (mean BMI&#x202f;=&#x202f;29&#x202f;kg/m[2]). The primary analysis showed no evidence that LTL change differed between groups (12-month mean LTL change for the exercise group: -13% (95% CI: -32%, 11%) versus controls: -8% (95%CI: -27%, 15%); treatment effect ratio (TER, Exercise/Control)&#x202f;=&#x202f;0.95 (95% CI: 0.68, 1.32). Per-protocol results were similar (TER&#x202f;=&#x202f;0.87, 95% CI: 0.59, 1.30). In stratified models, TERs ranged from 0.68 to 1.35 across strata and P-interaction&#x202f;>&#x202f;0.05).<br><br>CONCLUSION: We found no evidence to suggest that one year of aerobic exercise alters telomere attrition significantly in healthy postmenopausal women.},
}
@article {pmid30071286,
year = {2018},
author = {Arts, MHL and Collard, RM and Comijs, HC and de Jonge, L and Penninx, BWJH and Naarding, P and Kok, RM and Oude Voshaar, RC},
title = {Leucocyte telomere length is no molecular marker of physical frailty in late-life depression.},
journal = {Experimental gerontology},
volume = {111},
number = {},
pages = {229-234},
doi = {10.1016/j.exger.2018.07.016},
pmid = {30071286},
issn = {1873-6815},
mesh = {Aged ; Aged, 80 and over ; Biomarkers ; Depressive Disorder/*genetics/*physiopathology ; Female ; Frailty/*psychology ; Humans ; Leukocytes ; Linear Models ; Male ; Middle Aged ; Netherlands ; *Polymorphism, Restriction Fragment Length ; Prospective Studies ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Although average life-expectancy is still increasing worldwide, ageing processes markedly differ between individuals, which has stimulated the search for biomarkers of biological ageing.<br><br>OBJECTIVES: Firstly, to explore the cross-sectional and longitudinal association between leucocyte telomere length (LTL) as molecular marker of ageing and the physical frailty phenotype (PFP) as a clinical marker of ageing and secondly, to examine whether these associations are moderated by the presence of a depressive disorder, as depression can be considered a condition of accelerated ageing.<br><br>METHODS: Among 378 depressed older patients (according to DSM-IV criteria) and 132 non-depressed older persons participating in the Netherlands Study of Depression in Older persons, we have assessed the physical frailty phenotype and LTL. The PFP was defined according to Fried's criteria and its components were reassessed at two-year follow-up.<br><br>RESULTS: LTL was neither associated with the PFP at baseline by Spearman rank correlation tests, nor did it predict change in frailty parameters over a two-year follow-up using regression analyses adjusted for potential confounders.<br><br>CONCLUSION: LTL is not associated with frailty; neither in non-depressed nor in depressed older persons. As LTL and physical frailty appear to represent different aspects of ageing, they may complement each other in future studies.},
}
@article {pmid30067734,
year = {2018},
author = {Torrance, V and Lydall, D},
title = {Overlapping open reading frames strongly reduce human and yeast STN1 gene expression and affect telomere function.},
journal = {PLoS genetics},
volume = {14},
number = {8},
pages = {e1007523},
pmid = {30067734},
issn = {1553-7404},
support = {BB/J014516/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/M002314/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Alleles ; Base Sequence ; Cell Cycle Proteins/*genetics/metabolism ; Cell Line ; Computational Biology ; Gene Expression Regulation ; HCT116 Cells ; Humans ; Nonsense Mediated mRNA Decay ; *Open Reading Frames ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {The levels of telomeric proteins, such as telomerase, can have profound effects on telomere function, cell division and human disease. Here we demonstrate how levels of Stn1, a component of the conserved telomere capping CST (Cdc13, Stn1, Ten1) complex, are tightly regulated by an upstream overlapping open reading frame (oORF). In budding yeast inactivation of the STN1 oORF leads to a 10-fold increase in Stn1 levels, reduced telomere length, suppression of cdc13-1 and enhancement of yku70Δ growth defects. The STN1 oORF impedes translation of the main ORF and reduces STN1 mRNA via the nonsense mediated mRNA decay (NMD) pathway. Interestingly, the homologs of the translation re-initiation factors, MCT-1Tma20/DENRTma22 also reduce Stn1 levels via the oORF. Human STN1 also contains oORFs, which reduce expression, demonstrating that oORFs are a conserved mechanism for reducing Stn1 levels. Bioinformatic analyses of the yeast and human transcriptomes show that oORFs are more underrepresented than upstream ORFs (uORFs) and associated with lower protein abundance. We propose that oORFs are an important mechanism to control expression of a subset of the proteome.},
}
@article {pmid30067291,
year = {2018},
author = {Ridout, KK and Khan, M and Ridout, SJ},
title = {Adverse Childhood Experiences Run Deep: Toxic Early Life Stress, Telomeres, and Mitochondrial DNA Copy Number, the Biological Markers of Cumulative Stress.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {40},
number = {9},
pages = {e1800077},
doi = {10.1002/bies.201800077},
pmid = {30067291},
issn = {1521-1878},
mesh = {Adverse Childhood Experiences/methods ; Animals ; Biomarkers/*metabolism ; DNA Copy Number Variations/*genetics ; DNA, Mitochondrial/*genetics ; Humans ; Mental Disorders/*genetics ; Mitochondria/genetics ; Stress, Psychological/*genetics ; Telomere/*genetics ; },
abstract = {This manuscript reviews recent evidence supporting the utility of telomeres and mitochondrial DNA copy number (mtDNAcn) in detecting the biological impacts of adverse childhood experiences (ACEs) and outlines mechanisms that may mediate the connection between early stress and poor physical and mental health. Critical to interrupting the health sequelae of ACEs such as abuse, neglect, and neighborhood disorder, is the discovery of biomarkers of risk and resilience. The molecular markers of chronic stress exposure, telomere length and mtDNAcn, represent critical biological links between ACEs and poor health outcomes. We examine how telomeres and mtDNAcn may exacerbate health disparities and contribute to the intergenerational transmission of trauma. Finally, we explore how these molecular markers of early stress exposure may help define the role of resilience and develop effective interventions to moderate ACE health risk impact.},
}
@article {pmid30067250,
year = {2018},
author = {Molina-Molina, M and Borie, R},
title = {Clinical implications of telomere dysfunction in lung fibrosis.},
journal = {Current opinion in pulmonary medicine},
volume = {24},
number = {5},
pages = {440-444},
doi = {10.1097/MCP.0000000000000506},
pmid = {30067250},
issn = {1531-6971},
mesh = {Humans ; Idiopathic Pulmonary Fibrosis/genetics/*physiopathology ; Mutation ; Survival Rate ; Telomerase/genetics ; Telomere/*physiology ; *Telomere Shortening ; },
abstract = {PURPOSE OF REVIEW: Telomere attrition has been proposed as one of the aging hallmarks in pulmonary fibrosis. Telomere shortening and telomerase gene mutations have been widely evaluated in recent years. Reduced telomere length may be identified in a quarter of patients with sporadic idiopathic pulmonary fibrosis (IPF) and half of those cases with family aggregation. However, telomere studies have not transferred from the research field to the clinic. This review is focused on our current understanding of the pathogenic implication of telomere dysfunction in lung fibrosis and its relevance in the clinical setting.<br><br>RECENT FINDINGS: The most prevalent clinical expression of telomere dysfunction is IPF. Disease onset is usually seen at a younger age and family aggregation is frequently present. Short telomere syndrome is associated in a minority of cases and includes premature hair greying, bone marrow failure and liver cirrhosis. However, patients often present with some extrapulmonary associated telomeric features and related comorbidities that may help to suspect telomere defects. Telomere shortening confers a poor prognosis and reduced lung-transplant free survival time in IPF and other nonidiopathic pulmonary fibrotic entities.<br><br>SUMMARY: Telomere dysfunction associates some common clinical features that could modify patient management in pulmonary fibrosis.},
}
@article {pmid30066139,
year = {2019},
author = {Mersaoui, SY and Wellinger, RJ},
title = {Fine tuning the level of the Cdc13 telomere-capping protein for maximal chromosome stability performance.},
journal = {Current genetics},
volume = {65},
number = {1},
pages = {109-118},
pmid = {30066139},
issn = {1432-0983},
support = {FDN 154315//CIHR/ ; },
mesh = {Chromosomal Instability/*genetics ; DNA Replication/genetics ; Humans ; Models, Genetic ; Mutation ; Protein Binding ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/enzymology/*genetics ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {Chromosome stability relies on an adequate length and complete replication of telomeres, the physical ends of chromosomes. Telomeres are composed of short direct repeat DNA and the associated nucleoprotein complex is essential for providing end-stability. In addition, the so-called end-replication problem of the conventional replication requires that telomeres be elongated by a special mechanism which, in virtually all organisms, is based by a reverse transcriptase, called telomerase. Although, at the conceptual level, telomere functions are highly similar in most organisms, the telomeric nucleoprotein composition appears to diverge significantly, in particular if it is compared between mammalian and budding yeast cells. However, over the last years, the CST complex has emerged as a central hub for telomere replication in most systems. Composed of three proteins, it is related to the highly conserved replication protein A complex, and in all systems studied, it coordinates telomerase-based telomere elongation with lagging-strand DNA synthesis. In budding yeast, the Cdc13 protein of this complex also is essential for telomerase recruitment and this specialisation is accompanied by additional regulatory adaptations. Based on recent results obtained in yeast, here, we review these issues and present an updated telomere replication hypothesis. We speculate that the similarities between systems far outweigh the differences, once we detach ourselves from the historic descriptions of the mechanisms in the various organisms.},
}
@article {pmid30064976,
year = {2018},
author = {Tummala, H and Collopy, LC and Walne, AJ and Ellison, A and Cardoso, S and Aksu, T and Yarali, N and Aslan, D and Fikret Akata, R and Teo, J and Songyang, Z and Pontikos, N and Fitzgibbon, J and Tomita, K and Vulliamy, T and Dokal, I},
title = {Homozygous OB-fold variants in telomere protein TPP1 are associated with dyskeratosis congenita-like phenotypes.},
journal = {Blood},
volume = {132},
number = {12},
pages = {1349-1353},
pmid = {30064976},
issn = {1528-0020},
support = {12097/CRUK_/Cancer Research UK/United Kingdom ; MR/P018440/1//Medical Research Council/United Kingdom ; },
mesh = {Adult ; Aminopeptidases/chemistry/*genetics ; Child ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/chemistry/*genetics ; Dyskeratosis Congenita/*genetics ; Female ; HEK293 Cells ; Humans ; Male ; Models, Molecular ; Mutation, Missense ; Pedigree ; Phenotype ; *Point Mutation ; Protein Conformation ; Serine Proteases/chemistry/*genetics ; *Shelterin Complex/genetics ; Telomere Shortening ; *Telomere-Binding Proteins/genetics ; },
}
@article {pmid30062572,
year = {2018},
author = {Sanft, T and Usiskin, I and Harrigan, M and Cartmel, B and Lu, L and Li, FY and Zhou, Y and Chagpar, A and Ferrucci, LM and Pusztai, L and Irwin, ML},
title = {Randomized controlled trial of weight loss versus usual care on telomere length in women with breast cancer: the lifestyle, exercise, and nutrition (LEAN) study.},
journal = {Breast cancer research and treatment},
volume = {172},
number = {1},
pages = {105-112},
doi = {10.1007/s10549-018-4895-7},
pmid = {30062572},
issn = {1573-7217},
mesh = {Adult ; Aged ; Body Mass Index ; Breast Neoplasms/complications/*genetics/physiopathology ; *Exercise ; Female ; Health Behavior/physiology ; Humans ; Middle Aged ; Neoplasm Staging ; Quality of Life ; Survivors ; Telomere/genetics ; Telomere Homeostasis/*genetics ; Weight Loss/*genetics ; },
abstract = {PURPOSE: Some studies suggest that telomere shortening may be associated with increased breast cancer risk and mortality. Obesity is also associated with increased breast cancer risk and mortality. Few studies have examined changes in telomere length in overweight or obese breast cancer survivors. The purpose of our study was to examine the effect of a 6-month diet- and exercise-induced weight loss intervention versus usual care on telomere length in breast cancer survivors.<br><br>METHODS: 151 breast cancer survivors with body mass index (BMI)&#x2009;&#x2265;&#x2009;25&#xa0;kg/m[2] were randomly assigned to a 6-month weight loss intervention (n&#x2009;=&#x2009;93) or to usual care (n&#x2009;=&#x2009;58). Fasting blood samples, height, weight, physical activity, and diet were measured at baseline and 6-months. Relative telomere length (RTL) was measured by quantitative-polymerase chain reaction (qPCR) done on buffy coat-extracted genomic DNA. Mean baseline to 6-month changes were compared between groups (intention-to-treat) using generalized estimating equations.<br><br>RESULTS: Complete telomere data were available in 125 participants. Women were 58&#x2009;&#xb1;&#x2009;8 years, with BMI 33.0&#x2009;&#xb1;&#x2009;6.2&#xa0;kg/m[2] and were 2.9&#x2009;&#xb1;&#x2009;2.5&#xa0;years from diagnosis; 90% were non-Hispanic white, and 76% had stage 0/I breast cancer. After 6 months, women randomized to weight loss had 3% telomere lengthening compared to 5% shortening in the usual care group (p&#x2009;=&#x2009;0.12). Among women with stage 0/I, the intervention group experienced 7% telomere lengthening compared to 8% shortening in the usual care group (p&#x2009;=&#x2009;0.01). No intervention effect was observed in women with stage II/III breast cancer.<br><br>CONCLUSION: Our findings suggest a weight loss intervention in stage 0 and 1 breast cancer survivors may lead to telomere lengthening, compared to a shortening in their usual care counterparts.},
}
@article {pmid30060819,
year = {2018},
author = {Hiraishi, N and Terai, M and Fujiwara, M and Aida, J and Izumiyama-Shimomura, N and Ishikawa, N and Tomita, KI and Matsuda, Y and Arai, T and Takubo, K and Ishiwata, T},
title = {Quantitative fluorescence in situ hybridization for investigation of telomere length dynamics in the pituitary gland using samples from 128 autopsied patients.},
journal = {Tissue &amp; cell},
volume = {53},
number = {},
pages = {1-7},
doi = {10.1016/j.tice.2018.05.008},
pmid = {30060819},
issn = {1532-3072},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*metabolism ; Autopsy ; Child ; Child, Preschool ; Female ; Humans ; *In Situ Hybridization, Fluorescence ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Pituitary Gland/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {In order to investigate the population dynamics of telomere status, we measured the telomere lengths of glandular cells in the adenohypophysis (AH) and pituicytes, a type of glial cell, in the neurohypophysis (NH) of 128 autopsied humans (65 men, 63 women, 0 and 102 years) using our original quantitative fluorescence in situ hybridization (Q-FISH) method. Telomeres in the AH shortened with aging in both men and women, but those of pituicytes did not. Pituicyte telomeres were significantly longer in women than in men. The data suggest that telomeres shorten with age in the AH, whereas those in pituicytes maintain a constant length throughout life. Comparison of pituicyte telomere lengths among 5 generations, <18, 18-69, 70-79, 80-89, and >90 years, revealed a tendency for telomeres to be longer in individuals in their 80 s and 90 s than in those in their 70 s. These findings lend support to the widely held notion that humans with longer telomeres may have a longer life span, and shed light on the biology of pituitary gland in terms of telomere length dynamics, as well contributing to the development of bioengineered hormone-producing cell replacement strategies and regenerative therapies.},
}
@article {pmid30059977,
year = {2019},
author = {Kachuri, L and Saarela, O and Bojesen, SE and Davey Smith, G and Liu, G and Landi, MT and Caporaso, NE and Christiani, DC and Johansson, M and Panico, S and Overvad, K and Trichopoulou, A and Vineis, P and Scelo, G and Zaridze, D and Wu, X and Albanes, D and Diergaarde, B and Lagiou, P and Macfarlane, GJ and Aldrich, MC and Tardón, A and Rennert, G and Olshan, AF and Weissler, MC and Chen, C and Goodman, GE and Doherty, JA and Ness, AR and Bickeböller, H and Wichmann, HE and Risch, A and Field, JK and Teare, MD and Kiemeney, LA and van der Heijden, EHFM and Carroll, JC and Haugen, A and Zienolddiny, S and Skaug, V and Wünsch-Filho, V and Tajara, EH and Ayoub Moysés, R and Daumas Nunes, F and Lam, S and Eluf-Neto, J and Lacko, M and Peters, WHM and Le Marchand, L and Duell, EJ and Andrew, AS and Franceschi, S and Schabath, MB and Manjer, J and Arnold, S and Lazarus, P and Mukeriya, A and Swiatkowska, B and Janout, V and Holcatova, I and Stojsic, J and Mates, D and Lissowska, J and Boccia, S and Lesseur, C and Zong, X and McKay, JD and Brennan, P and Amos, CI and Hung, RJ},
title = {Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers.},
journal = {International journal of epidemiology},
volume = {48},
number = {3},
pages = {751-766},
pmid = {30059977},
issn = {1464-3685},
support = {RP-PG-0707-10034/DH_/Department of Health/United Kingdom ; U01 CA063673/CA/NCI NIH HHS/United States ; P50 CA119997/CA/NCI NIH HHS/United States ; UL1 TR000117/TR/NCATS NIH HHS/United States ; K07 CA172294/CA/NCI NIH HHS/United States ; P50 CA097190/CA/NCI NIH HHS/United States ; R01 CA111703/CA/NCI NIH HHS/United States ; 19169/CRUK_/Cancer Research UK/United Kingdom ; G0902313/MRC_/Medical Research Council/United Kingdom ; UL1 TR000445/TR/NCATS NIH HHS/United States ; R35 CA197449/CA/NCI NIH HHS/United States ; P30 ES010126/ES/NIEHS NIH HHS/United States ; U01 CA167462/CA/NCI NIH HHS/United States ; U19 CA203654/CA/NCI NIH HHS/United States ; MR/L01341X/1/MRC_/Medical Research Council/United Kingdom ; MC_UU_00011/1/MRC_/Medical Research Council/United Kingdom ; P30 CA047904/CA/NCI NIH HHS/United States ; C18281/A19169/CRUK_/Cancer Research UK/United Kingdom ; P20 RR018787/RR/NCRR NIH HHS/United States ; R01 CA151989/CA/NCI NIH HHS/United States ; U19 CA148127/CA/NCI NIH HHS/United States ; UM1 CA167462/CA/NCI NIH HHS/United States ; P30 CA177558/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma of Lung/*epidemiology ; Aged ; Aged, 80 and over ; Carcinoma, Squamous Cell/*epidemiology ; Chromosomes, Human, Pair 5/genetics ; Female ; Head and Neck Neoplasms/*epidemiology ; Humans ; Leukocytes/*metabolism ; Lung Neoplasms/*epidemiology ; Male ; Mendelian Randomization Analysis ; Middle Aged ; Squamous Cell Carcinoma of Head and Neck/*epidemiology ; Telomere/*metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses.<br><br>METHODS: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16&#xa0;396 cases, 13&#xa0;013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects.<br><br>RESULTS: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p&#x2009;=&#x2009;2.6&#x2009;&#xd7;&#x2009;10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR)&#x2009;=&#x2009;1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR&#x2009;=&#x2009;1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR&#x2009;=&#x2009;1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR&#x2009;=&#x2009;0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR&#x2009;=&#x2009;1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk.<br><br>CONCLUSIONS: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.},
}
@article {pmid30058830,
year = {2018},
author = {Lucas, T and Woerner, J and Pierce, J and Granger, DA and Lin, J and Epel, ES and Assari, S and Lumley, MA},
title = {Justice for all? Beliefs about justice for self and others and telomere length in African Americans.},
journal = {Cultural diversity &amp; ethnic minority psychology},
volume = {24},
number = {4},
pages = {498-509},
pmid = {30058830},
issn = {1099-9809},
support = {R21 HL097191/HL/NHLBI NIH HHS/United States ; //National Heart, Lung, and Blood Institute/ ; //Wayne State University/ ; },
mesh = {Adult ; Black or African American/*psychology ; Female ; Humans ; Male ; Minority Groups ; Racial Groups ; Social Justice/psychology ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; Telomere Shortening/physiology ; },
abstract = {OBJECTIVE: Believing in justice can protect health. Among marginalized racial minorities however, both endorsing and rejecting beliefs about justice might be critical. The current research examined links between African Americans' beliefs about justice for self and for others and telomere length (TL)-an indicator of biological aging that is increasingly implicated in racial health disparities, with shorter telomeres indicating poorer health.<br><br>METHOD: Healthy African Americans (N = 118; 30% male; M age = 31.63 years) completed individual differences measures of justice beliefs for self and others and then provided dried blood spot samples that were assayed for TL.<br><br>RESULTS: We expected that a belief in justice for self would be positively associated with TL, whereas a belief in justice for others would be negatively associated. A significant 3-way interaction with chronological age confirmed this hypothesis-among older African Americans, TL was positively associated with believing in justice for self, but only when this belief was accompanied by a weak endorsement of the belief in justice for others.<br><br>CONCLUSION: Findings underscore that for racial minorities, health might be best protected when justice beliefs are both endorsed and rebuffed. (PsycINFO Database Record (c) 2018 APA, all rights reserved).},
}
@article {pmid30057621,
year = {2018},
author = {Sorochynska, K and Sych, N and Duda, A and Kulebyakina, K and Krasnienkov, D and Vaiserman, A and Vatlitsov, D},
title = {Dynamics of Telomere Length and Telomerase Activity in the Human Fetal Liver at 5-12 Weeks of Gestation.},
journal = {Stem cells international},
volume = {2018},
number = {},
pages = {1385903},
pmid = {30057621},
issn = {1687-966X},
abstract = {Fetal stem cell- (FSC-) based therapy is a promising treatment option for many diseases. The differentiation potential of FSCs is greater than that in adult stem cells, and they are more tissue-specific and have lower immunogenicity and better intrinsic homing than embryonic ones. Embryonic stem cells have higher proliferative potential than FSCs but can cause teratomas. Therefore, an evaluation of this potential represents an important biomedical challenge. Since regulation of telomere length (TL) is one mechanism governing cellular proliferation, TL is a useful surrogate marker for cell replicative potential. The prenatal dynamics of TL, however, has never been comprehensively studied. In the present study, dynamics of TL and telomerase activity in the human fetal liver during 5-12 weeks of gestation is examined. Both TL and telomerase activity were positively correlated with week of gestation. For both parameters studied, the trend to increase was evident up to 10th week of gestation. After that, they reached a plateau and remained stable. These findings indicate that telomerase activity remains high during the fetal stage, suggesting high replicative capacity of FSCs and their considerable potential for transplantation therapies. These findings, however, are preliminary only due to small sample size and require further evaluation.},
}
@article {pmid30057163,
year = {2018},
author = {Zhang, N and Tse, G and Liu, T},
title = {Telomere length and contrast-induced nephropathy.},
journal = {International journal of cardiology},
volume = {270},
number = {},
pages = {244},
doi = {10.1016/j.ijcard.2018.07.116},
pmid = {30057163},
issn = {1874-1754},
mesh = {Humans ; Kidney Diseases ; *Telomere ; *Telomere Homeostasis ; },
}
@article {pmid30056950,
year = {2018},
author = {Haapanen, MJ and Perälä, MM and Salonen, MK and Guzzardi, MA and Iozzo, P and Kajantie, E and Rantanen, T and Simonen, M and Pohjolainen, P and Eriksson, JG and von Bonsdorff, MB},
title = {Telomere Length and Frailty: The Helsinki Birth Cohort Study.},
journal = {Journal of the American Medical Directors Association},
volume = {19},
number = {8},
pages = {658-662},
doi = {10.1016/j.jamda.2018.05.011},
pmid = {30056950},
issn = {1538-9375},
mesh = {Age Factors ; Aged ; Aging/*genetics ; Body Composition/*genetics ; Cohort Studies ; Cross-Sectional Studies ; Electric Impedance ; Female ; Finland ; Frailty/*genetics ; Humans ; Longevity/*genetics ; Longitudinal Studies ; Male ; Middle Aged ; Risk Factors ; Sex Factors ; Socioeconomic Factors ; Telomere Shortening/*genetics ; },
abstract = {OBJECTIVES: Telomere length is associated with aging-related pathologies. Although the association between telomere length and frailty has been studied previously, only a few studies assessing longitudinal changes in telomere length and frailty exist.<br><br>DESIGN: Longitudinal cohort study.<br><br>SETTING AND PARTICIPANTS: A subpopulation of the Helsinki Birth Cohort Study consisting of 1078 older adults aged 67 to 79&#xa0;years born in Helsinki, Finland, between 1934 and&#xa0;1944.<br><br>MEASURES: Relative leukocyte telomere length (LTL) was measured using quantitative real-time polymerase chain reaction at the average ages of 61 and 71&#xa0;years, and at the latter the participants were assessed for frailty according to Fried criteria.<br><br>RESULTS: The mean&#xa0;&#xb1;&#xa0;SD relative LTLs were 1.40&#xa0;&#xb1;&#xa0;0.29 (average age 61&#xa0;years) and 0.86&#xa0;&#xb1;&#xa0;0.30 (average age 71&#xa0;years) for the cohort. A trend of shorter mean relative LTL across frailty groups was observed at 61&#xa0;years (P&#xa0;=&#xa0;.016) and at 71&#xa0;years (P&#xa0;=&#xa0;.057). Relative LTL at age 61&#xa0;years was significantly associated with frailty: per 1-unit increase in relative LTL, the corresponding relative risk ratio (RRR) of frailty was 0.28 (95% confidence interval [CI] 0.08-0.97), adjusting for several confounders. Also, LTL at age 71&#xa0;years was associated with frailty (RRR 0.18, 95% CI 0.04-0.81) after adjustment for sex, age, and adult socioeconomic status, but further adjustment attenuated the association. No associations between telomere shortening and frailty were observed during the 10-year follow-up.<br><br>CONCLUSIONS: Shorter relative LTL was associated with frailty in cross-sectional and longitudinal analyses, but telomere shortening was not, suggesting that short LTL may be a biomarker of frailty.},
}
@article {pmid30056220,
year = {2018},
author = {Luke, B},
title = {Telomere regulation.},
journal = {Differentiation; research in biological diversity},
volume = {102},
number = {},
pages = {27-29},
doi = {10.1016/j.diff.2018.06.002},
pmid = {30056220},
issn = {1432-0436},
mesh = {Animals ; Humans ; Reactive Oxygen Species/*metabolism ; Research ; Telomerase/*genetics ; *Telomere ; Telomeric Repeat Binding Protein 2/*metabolism ; },
}
@article {pmid30052781,
year = {2018},
author = {Gokarn, R and Solon-Biet, S and Youngson, NA and Wahl, D and Cogger, VC and McMahon, AC and Cooney, GJ and Ballard, JWO and Raubenheimer, D and Morris, MJ and Simpson, SJ and Le Couteur, DG},
title = {The Relationship Between Dietary Macronutrients and Hepatic Telomere Length in Aging Mice.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {73},
number = {4},
pages = {446-449},
doi = {10.1093/gerona/glx186},
pmid = {30052781},
issn = {1758-535X},
mesh = {Age Factors ; Amino Acids/blood ; Animals ; Biomarkers/blood ; *Diet ; Dietary Carbohydrates/pharmacology ; Dietary Fats/pharmacology ; Dietary Proteins/pharmacology ; Energy Intake ; Liver/*drug effects ; Longevity/*drug effects ; Mice ; Mice, Inbred C57BL ; Nutrients/*pharmacology ; Polymerase Chain Reaction ; Telomere Homeostasis/*drug effects ; },
abstract = {Macronutrients and dietary energy influence aging, age-related health, and life span. Reduction in telomere length has been proposed as one mechanism for aging. Therefore, this study investigated the effects of varying ratios of dietary macronutrients and energy on telomere length in older adult mice. C57Bl/6 mice were fed ad libitum their entire life on one of 25 diets varying in protein, carbohydrates, fat, and energy. Average telomere length ratio (ATLR) was measured by polymerase chain reaction in livers of a subset of 161 mice aged 15 months. There was a significant positive relationship between ATLR and carbohydrate intake and a negative relationship with protein intake, but no relationships with fat or energy intake. Analysis using the Geometric Framework and Generalized Additive Models confirmed that carbohydrate intake was positively associated with ATLR, while the longest ATLR was achieved by mice restricted to low protein, high carbohydrate diets. ATLR distribution across the diets was parallel to median life-span results previously published. ATLR was associated with blood levels of some amino acids (asparagine, glutamate, taurine) but not with blood levels of fatty acids, hepatic mitochondrial function, or nutrient sensing pathways. In conclusion, mice on low protein, high carbohydrate diets have the longest hepatic telomeres and longest life span.},
}
@article {pmid30051918,
year = {2018},
author = {Denham, J and Denham, MM},
title = {Leukocyte telomere length in the Thoroughbred racehorse.},
journal = {Animal genetics},
volume = {49},
number = {5},
pages = {452-456},
doi = {10.1111/age.12681},
pmid = {30051918},
issn = {1365-2052},
mesh = {Animals ; Australia ; Female ; Horses/*classification/*genetics/physiology ; Leukocytes/*cytology ; Male ; Physical Conditioning, Animal ; Telomere/*genetics ; },
abstract = {Thoroughbred racehorses possess superior cardiorespiratory fitness levels and are at the pinnacle of athletic performance compared to other breeds of horses. Although equine athletes have undergone years of artificial selection for racing performance, musculoskeletal injuries and illnesses are common and concerns relating to animal welfare have been proposed. Leukocyte telomere length is indicative of biological age, and accelerated telomere shortening occurs with excess physical and psychological stress. This study was designed to explore the association between leukocyte telomere length, biological factors (age, sex and coat colour), training status, winnings and race history parameters. Blood was collected from 146 Thoroughbred racehorses from around Geelong, Victoria, Australia. DNA was extracted from leukocytes; telomere length was measured using qPCR and analysed in context with traits obtained from the Racing Australia website. Age was inversely correlated with telomere length (r = -0.194, P = 0.019). The oldest horses (≥11 years) in the highest age quartile possessed shorter telomeres compared to younger horses in the first, second and third quartiles (≤2, 3-5 and 6-10 years respectively; P < 0.05). No statistically significant associations were observed between telomere length and biological factors, training status, winnings or race history parameters in age-adjusted analyses. The study findings suggest that Thoroughbred horses may undergo age-related telomere shortening similar to other mixed breeds and humans. Despite concerns from some quarters regarding the welfare of racehorses, there was a lack of accelerated biological ageing observed in the present study, as indicated by leukocyte telomere length.},
}
@article {pmid30048807,
year = {2018},
author = {Willis, M and Reid, SN and Calvo, E and Staudinger, UM and Factor-Litvak, P},
title = {A scoping systematic review of social stressors and various measures of telomere length across the life course.},
journal = {Ageing research reviews},
volume = {47},
number = {},
pages = {89-104},
pmid = {30048807},
issn = {1872-9649},
support = {T32 ES023772/ES/NIEHS NIH HHS/United States ; },
mesh = {Aged ; Child ; Humans ; Longevity/*physiology ; Middle Aged ; *Socioeconomic Factors ; Stress, Psychological/economics/*metabolism/pathology ; Telomere/*metabolism/pathology ; Telomere Shortening/physiology ; },
abstract = {Numerous studies examine the relationship between social stressors and telomere length (TL). Beyond considering methods and major findings, this scoping systematic review takes a novel approach as it groups studies according to the types of social stressor considered and by age groups. Following PRISMA guidelines, we searched PubMed, Web of Science, Embase, and Scopus. We included all English-language human subject research articles that modeled any measure of TL as a dependent variable and exposure to a social stressor as an independent variable. For the sample of 105 articles, we summarized methods and findings by type of social stressor (socioeconomic stressors, stressful life events, work-related stressors, and neighborhood stressors) and by age of the study population (infants/children, middle-aged adults, older adults, and mixed samples of middle-aged and older adults). We found more variation in TL measurement methodology in studies of infants/children and older adults than in studies focusing on middle-aged adults. The most consistent finding was a relationship between early-life stressors and shorter TL. Work and neighborhood stressors, and older populations, are currently understudied. Across all stressors, limited evidence suggests that the stress-TL relationship may be moderated by characteristics such as age, sex, and race/ethnicity. We conclude with specific suggestions for future research.},
}
@article {pmid30046372,
year = {2018},
author = {Zhang, Y and Wang, C and Jin, Y and Yang, Q and Meng, Q and Liu, Q and Dai, Y and Cai, L and Liu, Z and Liu, K and Sun, H},
title = {Activating the PGC-1α/TERT Pathway by Catalpol Ameliorates Atherosclerosis via Modulating ROS Production, DNA Damage, and Telomere Function: Implications on Mitochondria and Telomere Link.},
journal = {Oxidative medicine and cellular longevity},
volume = {2018},
number = {},
pages = {2876350},
pmid = {30046372},
issn = {1942-0994},
mesh = {Animals ; Atherosclerosis/drug therapy/metabolism ; Blotting, Western ; Cell Line ; Cell Survival/drug effects ; Comet Assay ; DNA Damage/drug effects/genetics ; Humans ; Immunohistochemistry ; In Situ Nick-End Labeling ; Iridoid Glucosides/*pharmacology/therapeutic use ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/drug effects/metabolism ; Oxidative Stress/genetics/physiology ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; THP-1 Cells ; Telomerase/genetics/*metabolism ; Telomere/*drug effects/*metabolism ; },
abstract = {Catalpol, an iridoid glucoside, has been found present in large quantities in the root of Rehmannia glutinosa L. and showed a strong antioxidant capacity in the previous study. In the present work, the protective effect of catalpol against AS via inhibiting oxidative stress, DNA damage, and telomere shortening was found in LDLr[-/-] mice. This study also shows that activation of the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)/telomerase reverse transcriptase (TERT) pathway, which is the new link between mitochondria and telomere, was involved in the protective effects of catalpol. Further, by using PGC-1α or TERT siRNA in oxLDL-treated macrophages, it is proved that catalpol reduced oxidative stress, telomere function, and related DNA damage at least partly through activating the PGC-1α/TERT pathway. Moreover, dual luciferase activity assay-validated catalpol directly enhanced PGC-1α promoter activity. In conclusion, our study revealed that the PGC-1α/TERT pathway might be a possible therapeutic target in AS and catalpol has highly favorable characteristics for the treatment of AS via modulating this pathway.},
}
@article {pmid30046139,
year = {2018},
author = {Chatterjee, S and de Gonzalo-Calvo, D and Derda, AA and Schimmel, K and Sonnenschein, K and Bavendiek, U and Bauersachs, J and Bär, C and Thum, T},
title = {Leukocyte telomere length correlates with hypertrophic cardiomyopathy severity.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {11227},
pmid = {30046139},
issn = {2045-2322},
support = {IJCI-2016-29393//Ministerio de Econom&#x00ED;a y Competitividad (Ministry of Economy and Competitiveness)/International ; KFO311//Deutsche Forschungsgemeinschaft (German Research Foundation)/International ; KFO311//Deutsche Forschungsgemeinschaft (German Research Foundation)/International ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Cardiomyopathy, Hypertrophic/genetics/*pathology ; Female ; Humans ; Leukocytes/*pathology ; Male ; Middle Aged ; Severity of Illness Index ; Telomere/*genetics/pathology ; Telomere Homeostasis/*genetics ; },
abstract = {Telomere length is a marker of biological aging. Short leukocyte telomere length has been associated with various conditions including cardiovascular disorders. Here, we evaluated if patients with hypertrophic cardiomyopathy have altered leukocyte telomere length and whether this is associated with disease severity. A quantitative polymerase chain reaction-based method was used to measure peripheral blood leukocyte telomere length in 59 healthy control subjects and a well-characterized cohort of 88 patients diagnosed with hypertrophic cardiomyopathy: 32 patients with non-obstructive cardiomyopathy (HNCM) and 56 patients with obstructive cardiomyopathy (HOCM). We observed shorter leukocyte telomeres in both HNCM and HOCM patients compared to healthy controls. Furthermore, leukocyte telomere length was inversely associated with HCM even after adjusting for age and sex. Telomere length of HOCM patients was also inversely correlated with left ventricular outflow tract obstruction. Therefore, HOCM patients were categorized by tertiles of telomere length. Patients in the first tertile (shortest telomeres) had a significantly increased left ventricular posterior wall thickness at end-diastole and higher left ventricular outflow tract gradients, whereas the left ventricular end-diastolic diameter was lower compared with patients in the second and third tertile. In summary, telomere length is associated with the severity of the disease in the HOCM subtype.},
}
@article {pmid30045876,
year = {2018},
author = {Yang, SF and Sun, AA and Shi, Y and Li, F and Pickett, HA},
title = {Structural and functional characterization of the RBBP4-ZNF827 interaction and its role in NuRD recruitment to telomeres.},
journal = {The Biochemical journal},
volume = {475},
number = {16},
pages = {2667-2679},
doi = {10.1042/BCJ20180310},
pmid = {30045876},
issn = {1470-8728},
mesh = {Cell Line ; *DNA-Binding Proteins/chemistry/genetics/metabolism ; Humans ; *Mi-2 Nucleosome Remodeling and Deacetylase Complex/chemistry/genetics/metabolism ; *Retinoblastoma-Binding Protein 4/chemistry/genetics/metabolism ; Structure-Activity Relationship ; Telomere/chemistry/genetics/metabolism ; },
abstract = {The nucleosome remodeling and histone deacetylase (NuRD) complex is an essential multi-subunit protein complex that regulates higher-order chromatin structure. Cancers that use the alternative lengthening of telomere (ALT) pathway of telomere maintenance recruit NuRD to their telomeres. This interaction is mediated by the N-terminal domain of the zinc-finger protein ZNF827. NuRD-ZNF827 plays a vital role in the ALT pathway by creating a molecular platform for recombination-mediated repair. Disruption of NuRD binding results in loss of ALT cell viability. Here, we present the crystal structure of the NuRD subunit RBBP4 bound to the N-terminal 14 amino acids of ZNF827. RBBP4 forms a negatively charged channel that binds to ZNF827 through a network of electrostatic interactions. We identify the precise amino acids in RBBP4 required for this interaction and demonstrate that disruption of these residues prevents RBBP4 binding to both ZNF827 and telomeres, but is insufficient to decrease ALT activity. These data provide insights into the structural and functional determinants of NuRD activity at ALT telomeres.},
}
@article {pmid30043450,
year = {2018},
author = {Li, Y and Dorfman, DM},
title = {Highly atypical myeloblasts in acute myeloid leukaemia with myelodysplasia-related changes in a patient with short telomere syndrome.},
journal = {British journal of haematology},
volume = {183},
number = {4},
pages = {536},
doi = {10.1111/bjh.15505},
pmid = {30043450},
issn = {1365-2141},
mesh = {*Genetic Diseases, Inborn/genetics/metabolism/pathology ; Humans ; *Leukemia, Myeloid, Acute/metabolism/pathology ; Male ; Middle Aged ; *Myelodysplastic Syndromes/genetics/metabolism/pathology ; *Pulmonary Fibrosis/genetics/metabolism/pathology ; },
}
@article {pmid30038336,
year = {2018},
author = {Ryan, CP and Hayes, MG and Lee, NR and McDade, TW and Jones, MJ and Kobor, MS and Kuzawa, CW and Eisenberg, DTA},
title = {Reproduction predicts shorter telomeres and epigenetic age acceleration among young adult women.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {11100},
pmid = {30038336},
issn = {2045-2322},
support = {P20 RR020649/RR/NCRR NIH HHS/United States ; P30 ES010126/ES/NIEHS NIH HHS/United States ; },
mesh = {Cellular Senescence/*genetics ; DNA Methylation/genetics ; *Epigenesis, Genetic ; Female ; Humans ; Mitosis/genetics ; Parity ; Pregnancy ; Reproduction/*genetics ; Telomere/*genetics ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {Evolutionary theory predicts that reproduction entails costs that detract from somatic maintenance, accelerating biological aging. Despite support from studies in human and non-human animals, mechanisms linking 'costs of reproduction' (CoR) to aging are poorly understood. Human pregnancy is characterized by major alterations in metabolic regulation, oxidative stress, and immune cell proliferation. We hypothesized that these adaptations could accelerate blood-derived cellular aging. To test this hypothesis, we examined gravidity in relation to telomere length (TL, n = 821) and DNA-methylation age (DNAmAge, n = 397) in a cohort of young (20-22 year-old) Filipino women. Age-corrected TL and accelerated DNAmAge both predict age-related morbidity and mortality, and provide markers of mitotic and non-mitotic cellular aging, respectively. Consistent with theoretical predictions, TL decreased (p = 0.031) and DNAmAge increased (p = 0.007) with gravidity, a relationship that was not contingent upon resource availability. Neither biomarker was associated with subsequent fertility (both p > 0.3), broadly consistent with a causal effect of gravidity on cellular aging. Our findings provide evidence that reproduction in women carries costs in the form of accelerated aging through two independent cellular pathways.},
}
@article {pmid30033372,
year = {2018},
author = {Van Ly, D and Low, RRJ and Frölich, S and Bartolec, TK and Kafer, GR and Pickett, HA and Gaus, K and Cesare, AJ},
title = {Telomere Loop Dynamics in Chromosome End Protection.},
journal = {Molecular cell},
volume = {71},
number = {4},
pages = {510-525.e6},
doi = {10.1016/j.molcel.2018.06.025},
pmid = {30033372},
issn = {1097-4164},
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins/*genetics/metabolism ; Cell Line ; Cell Line, Tumor ; DNA Damage ; *DNA End-Joining Repair ; Fibroblasts/cytology/metabolism ; G1 Phase Cell Cycle Checkpoints/genetics ; HEK293 Cells ; HeLa Cells ; Humans ; Mice ; Mitosis ; Protein Domains ; Telomere/*metabolism/ultrastructure ; Telomeric Repeat Binding Protein 2/chemistry/*genetics/metabolism ; },
abstract = {Telomeres regulate DNA damage response (DDR) and DNA repair activity at chromosome ends. How telomere macromolecular structure contributes to ATM regulation and its potential dissociation from control over non-homologous end joining (NHEJ)-dependent telomere fusion is of central importance to telomere-dependent cell aging and tumor suppression. Using super-resolution microscopy, we identify that ATM activation at mammalian telomeres with reduced TRF2 or at human telomeres during mitotic arrest occurs specifically with a structural change from telomere loops (t-loops) to linearized telomeres. Additionally, we find the TRFH domain of TRF2 regulates t-loop formation while suppressing ATM activity. Notably, we demonstrate that ATM activation and telomere linearity occur separately from telomere fusion via NHEJ and that linear DDR-positive telomeres can remain resistant to fusion, even during an extended G1 arrest, when NHEJ is most active. Collectively, these results suggest t-loops act as conformational switches that specifically regulate ATM activation independent of telomere mechanisms to inhibit NHEJ.},
}
@article {pmid30030618,
year = {2019},
author = {Lin, CC and Wang, HY and Liaw, SF and Chiu, CH and Lin, MW},
title = {Effect of oral appliance on circulating leukocyte telomere length and SIRT1 in obstructive sleep apnea.},
journal = {Clinical oral investigations},
volume = {23},
number = {3},
pages = {1397-1405},
pmid = {30030618},
issn = {1436-3771},
support = {103-2314-B-303-014-MY2//Ministry of Science and Technology/ ; },
mesh = {Female ; Humans ; Leukocytes, Mononuclear ; Male ; *Mandibular Advancement ; Sirtuin 1/*genetics ; Sleep Apnea, Obstructive/genetics/*therapy ; Telomere/*ultrastructure ; },
abstract = {OBJECTIVES: The increased cardiovascular risk seen in patients with obstructive sleep apnea (OSA) may be due to combination of oxidative stress, systemic inflammation and damage to leukocyte telomere length (LTL) seen with aging. Another molecule, Sirtuin 1 (SIRT1), a histone/protein deacetylase, regulates endothelial nitric oxide synthase and is involved in different aspects of cardiovascular disease, aging and stress resistance. The aim of this study was to evaluate the effects of mandibular advancement device (MAD) on the circulating LTL and SIRT1 protein level in peripheral blood mononuclear cells (PBMCs) in patients with OSA.<br><br>MATERIALS AND METHODS: Forty patients with moderately severe to severe OSA who desired MAD and 20 healthy controls were prospectively enrolled. The LTL was measured by quantitative polymerase chain reaction while SIRT1 protein levels in PBMC was assessed using a Sirtuin 1 ELISA Kit. All study subjects underwent baseline sleep study, with OSA patients having repeat testing at 3&#xa0;months after MAD.<br><br>RESULTS: Compared to healthy subjects, patients with OSA at baseline had lower LTL and SIRT1 protein levels in PBMC. After 3&#xa0;months of MAD, 24 OSA patients, designated as MAD responders, median (range) LTL increased from (0.556 [0.393-0.748]) to (0.708 [0.533-0.893]) and SIRT1 protein levels in PBMC increased from 0.58&#x2009;&#xb1;&#x2009;0.23&#xa0;pg/&#x3bc;g of total protein to 0.95&#x2009;&#xb1;&#x2009;0.26&#xa0;pg/&#x3bc;g of total protein. For the 16 MAD unresponsive patients, LTL and SIRT1 protein levels remained low.<br><br>CONCLUSIONS: Successful treatment of OSA with MAD can restore LTL and SIRT1 protein levels in PBMC.<br><br>CLINICAL RELEVANCE: LTL and SIRT1 protein levels in PBMC can be improved following effective treatment of OSA using MAD.},
}
@article {pmid30029639,
year = {2018},
author = {Mazidi, M and Kengne, AP and Cheskin, LJ and Banach, M},
title = {Serum lipophilic antioxidants levels are associated with leucocyte telomere length among US adults.},
journal = {Lipids in health and disease},
volume = {17},
number = {1},
pages = {164},
pmid = {30029639},
issn = {1476-511X},
mesh = {Adult ; Antioxidants/*metabolism ; Beta-Cryptoxanthin/blood ; Carotenoids/blood ; Female ; Humans ; Leukocytes/*physiology ; Male ; Middle Aged ; Nutrition Surveys ; Nutritional Status ; *Telomere ; United States ; Zeaxanthins/blood ; beta Carotene/blood ; gamma-Tocopherol/blood ; },
abstract = {BACKGROUND: To examine the association between serum concentrations of antioxidant and telomere length (TL) in U.S adults.<br><br>METHODS: Participants of the National Health and Nutrition Examination Survey (NHANES) with data available on TL measures from 2001 to 2002 were included. Serum lipophilic antioxidants level was measured using high performance liquid chromatography with photodiode array detection. We used analysis of co-variance and multivariable-adjusted linear regression models, accounting for the survey design and sample weights.<br><br>RESULTS: Of the 5992 eligible participants, 47.5% (n&#x2009;=&#x2009;2844) were men. The mean age was 46.9&#xa0;years overall, 47.2&#xa0;years in men and 46.6 in women (p&#x2009;=&#x2009;0.071). In age, sex, race, education, marital status, adiposity, smoking, C-reactive protein adjusted linear regressions, antioxidant, serum &#x3b1;-carotene, trans-&#x3b2;-carotene, cis- &#x3b2;-carotene, &#x3b2;-cryptoxanthin and combined Lutein/zeaxanthin were positively and significantly associated with TL (all p&#x2009;<&#x2009;0.001).<br><br>CONCLUSIONS: Our findings support a possible positive association between serum concentrations of lipophylic antioxidant and TL. The implications of this association deserve further investigation.},
}
@article {pmid30026606,
year = {2018},
author = {Rachakonda, S and Srinivas, N and Mahmoudpour, SH and Garcia-Casado, Z and Requena, C and Traves, V and Soriano, V and Cardelli, M and Pjanova, D and Molven, A and Gruis, N and Nagore, E and Kumar, R},
title = {Telomere length and survival in primary cutaneous melanoma patients.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {10947},
pmid = {30026606},
issn = {2045-2322},
mesh = {Adult ; Age Distribution ; Aged ; Aged, 80 and over ; Case-Control Studies ; Female ; Humans ; Male ; Melanoma/*genetics/*pathology ; Middle Aged ; Neoplasm Staging ; Regression Analysis ; Skin Neoplasms/*genetics/*pathology ; Survival Analysis ; *Telomere Shortening ; Melanoma, Cutaneous Malignant ; },
abstract = {Telomere repeats at chromosomal ends, critical to genomic integrity, undergo age-dependent attrition. Telomere length, a polygenic trait, has been associated with risk of several disorders including cancers. In contrast to association of long telomeres with increased risk of several cancers, including melanoma, emerging reports suggest that short telomeres predict poor survival in patients with different cancers. In this study based on 1019 stage I and II cutaneous melanoma patients, we show an association between the patients with short telomeres and poor melanoma-specific survival (HR 2.05, 95% CI 1.33-3.16) compared to patients with long telomeres. Due to inverse correlation between age and telomere length (r -0.19, P < 0.0001), we stratified the patients into quantiles based on age at diagnosis and also carried out age-matched analysis. The effect of short telomeres on survival was determined by using multivariate Cox regression that included composite genetic risk score computed from genotyping of the patients for telomere-length associated polymorphisms. The effect of decreased telomere length on poor melanoma-specific survival was particularly strong in patients within the age quantile below 30 years (HR 3.82, 95% CI 1.10-13.30) and between 30-40 years (HR 2.69, 95% CI 1.03-7.03). Our study shows that in contrast to increased melanoma risk associated with increased telomere length, decreased telomere length predicts poor survival in melanoma subgroups.},
}
@article {pmid30026550,
year = {2018},
author = {Feng, X and Hsu, SJ and Bhattacharjee, A and Wang, Y and Diao, J and Price, CM},
title = {CTC1-STN1 terminates telomerase while STN1-TEN1 enables C-strand synthesis during telomere replication in colon cancer cells.},
journal = {Nature communications},
volume = {9},
number = {1},
pages = {2827},
pmid = {30026550},
issn = {2041-1723},
support = {R01 GM041803/GM/NIGMS NIH HHS/United States ; T32 CA117846/CA/NCI NIH HHS/United States ; RO1 GM041803//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/International ; },
mesh = {CRISPR-Cas Systems ; DNA/*biosynthesis ; DNA Damage ; DNA Polymerase I/genetics/metabolism ; Gene Editing ; *Gene Expression Regulation, Neoplastic ; HCT116 Cells ; HEK293 Cells ; Humans ; Plasmids/chemistry/metabolism ; Protein Binding ; Signal Transduction ; Telomerase/*genetics/metabolism ; Telomere/chemistry/ultrastructure ; *Telomere Homeostasis ; Telomere Shortening ; Telomere-Binding Proteins/*genetics/metabolism ; Transfection ; },
abstract = {Telomerase elongates the telomeric G-strand to prevent telomere shortening through conventional DNA replication. However, synthesis of the complementary C-strand by DNA polymerase α is also required to maintain telomere length. Polymerase α cannot perform this role without the ssDNA binding complex CST (CTC1-STN1-TEN1). Here we describe the roles of individual CST subunits in telomerase regulation and G-overhang maturation in human colon cancer cells. We show that CTC1-STN1 limits telomerase action to prevent G-overhang overextension. CTC1[-/-] cells exhibit telomeric DNA damage and growth arrest due to overhang elongation whereas TEN1[-/-] cells do not. However, TEN1 is essential for C-strand synthesis and TEN1[-/-] cells exhibit progressive telomere shortening. DNA binding analysis indicates that CTC1-STN1 retains affinity for ssDNA but TEN1 stabilizes binding. We propose CTC1-STN1 binding is sufficient to terminate telomerase action but altered DNA binding dynamics renders CTC1-STN1 unable to properly engage polymerase α on the overhang for C-strand synthesis.},
}
@article {pmid30025223,
year = {2018},
author = {Zhdanov, DD and Gladilina, YA and Grishin, DV and Grachev, VA and Orlova, VS and Pokrovskaya, MV and Alexandrova, SS and Pokrovsky, VS and Sokolov, NN},
title = {Contact-independent suppressive activity of regulatory T cells is associated with telomerase inhibition, telomere shortening and target lymphocyte apoptosis.},
journal = {Molecular immunology},
volume = {101},
number = {},
pages = {229-244},
doi = {10.1016/j.molimm.2018.07.017},
pmid = {30025223},
issn = {1872-9142},
mesh = {Adult ; Alternative Splicing ; Animals ; *Apoptosis ; Cell Death ; Cell Survival ; Female ; Humans ; Mice, Inbred C57BL ; Mucins/metabolism ; T-Lymphocytes, Regulatory/*metabolism ; Telomerase/*antagonists &amp; inhibitors/metabolism ; *Telomere Shortening ; Time Factors ; },
abstract = {Regulatory T cells (Tregs) play a fundamental role in the maintenance of immunological tolerance by suppressing effector target T, B and NK lymphocytes. Contact-dependent suppression mechanisms have been well-studied, though contact-independent Treg activity is not fully understood. In the present study, we showed that human native Tregs, as well as induced ex vivo Tregs, can cause in vitro telomere-dependent senescence in target T, B and NK cells in a contact-independent manner. The co-cultivation of target cells with Tregs separated through porous membranes induced alternative splicing of the telomerase catalytic subunit hTERT (human Telomerase Reverse Transcriptase), which suppressed telomerase activity. Induction of the hTERT splicing variant was associated with increased expression of the apoptotic endonuclease EndoG, a splicing regulator. Inhibited telomerase in target cells co-cultivated with Tregs for a long period of time led to a decrease in their telomere lengths, cell cycle arrest, conversion of the target cells to replicative senescence and apoptotic death. Induced Tregs showed the ability to up-regulate EndoG expression, TERT alternative splicing and telomerase inhibition in mouse T, B and NK cells after in vivo administration. The results of the present study describe a novel mechanism of contact-independent Treg cell suppression that induces telomerase inhibition through the EndoG-provoked alternative splicing of hTERT and converts cells to senescence and apoptosis phenotypes.},
}
@article {pmid30019006,
year = {2018},
author = {Massey, DS and Wagner, B and Donnelly, L and McLanahan, S and Brooks-Gunn, J and Garfinkel, I and Mitchell, C and Notterman, DA},
title = {Neighborhood Disadvantage and Telomere Length: Results from the Fragile Families Study.},
journal = {The Russell Sage Foundation journal of the social sciences : RSF},
volume = {4},
number = {4},
pages = {28-42},
pmid = {30019006},
issn = {2377-8253},
support = {P2C HD047879/HD/NICHD NIH HHS/United States ; },
abstract = {Telomeres are repetitive nucleotide sequences located at the ends of chromosomes that protect genetic material. We use data from the Fragile Families and Child Wellbeing Study to analyze the relationship between exposure to spatially concentrated disadvantage and telomere length for white and black mothers. We find that neighborhood disadvantage is associated with shorter telomere length for mothers of both races. This finding highlights a potential mechanism through which the unique spatially concentrated disadvantage faced by African Americans contributes to racial health disparities. We conclude that equalizing the health and socioeconomic status of black and white Americans will be very difficult without reducing levels of residential segregation in the United States.},
}
@article {pmid30018248,
year = {2018},
author = {Bernal, A and Zafon, E and Domínguez, D and Bertran, E and Tusell, L},
title = {Generation of Immortalised But Unstable Cells after hTERT Introduction in Telomere-Compromised and p53-Deficient vHMECs.},
journal = {International journal of molecular sciences},
volume = {19},
number = {7},
pages = {},
pmid = {30018248},
issn = {1422-0067},
mesh = {Cell Line, Transformed ; Cells, Cultured ; Chromosomal Instability ; Chromosome Aberrations ; Epithelial Cells/cytology/*metabolism ; Female ; Humans ; In Situ Hybridization, Fluorescence/methods ; Karyotype ; Karyotyping ; Mammary Glands, Human/*cytology ; Telomerase/*genetics/metabolism ; Telomere/*genetics/metabolism ; Tumor Suppressor Protein p53/deficiency/*genetics ; },
abstract = {Telomeres, the natural ends of chromosomes, hide the linear telomeric DNA from constitutive exposure to the DNA damage response with a lariat structure or t-loop. Progressive telomere shortening associated with DNA replication in the absence of a compensatory mechanism culminates in t-loop collapse and unmasked telomeres. Dysfunctional telomeres can suppress cancer development by engaging replicative senescence or apoptosis, but they can also promote tumour initiation when cell cycle checkpoints are disabled. In this setting, telomere dysfunction promotes increasing chromosome instability (CIN) through breakage-fusion-bridge cycles. Excessive instability may hamper cell proliferation but might allow for the appearance of some rare advantageous mutations that could be selected and ultimately favour neoplastic progression. With the aim of generating pre-malignant immortalised cells, we ectopically expressed telomerase in telomere-compromised variant human mammary epithelial cells (vHMECs), proficient and deficient for p53, and analysed structural and numerical chromosomal aberrations as well as abnormal nuclear morphologies. Importantly, this study provides evidence that while immortalisation of vHMECs at early stages results in an almost stable karyotype, a transient telomere-dependent CIN period-aggravated by p53 deficiency-and followed by hTERT overexpression serves as a mechanism for the generation of immortal unstable cells which, due to their evolving karyotype, could attain additional promoting properties permissive to malignancy.},
}
@article {pmid30017346,
year = {2018},
author = {Jin, M and Lee, EC and Ra, SW and Fishbane, N and Tam, S and Criner, GJ and Woodruff, PG and Lazarus, SC and Albert, R and Connett, JE and Han, MK and Martinez, FJ and Aaron, SD and Reed, RM and Man, SFP and Leung, JM and Sin, DD},
title = {Relationship of Absolute Telomere Length With Quality of Life, Exacerbations, and Mortality in COPD.},
journal = {Chest},
volume = {154},
number = {2},
pages = {266-273},
doi = {10.1016/j.chest.2018.05.022},
pmid = {30017346},
issn = {1931-3543},
mesh = {Aged ; Disease Progression ; Female ; Health Status Indicators ; Humans ; Leukocytes, Mononuclear/metabolism ; Male ; Predictive Value of Tests ; Pulmonary Disease, Chronic Obstructive/*genetics/*mortality/physiopathology ; *Quality of Life ; Real-Time Polymerase Chain Reaction ; Respiratory Function Tests ; Telomere/*genetics ; Telomere Homeostasis/genetics ; },
abstract = {BACKGROUND: COPD is an age-related disease. The role of cellular senescence in COPD has not been fully elucidated. This study examined the relationship between telomere length of peripheral blood leukocytes and clinical outcomes, including health status, rate of exacerbations, and risk of mortality in individuals with COPD.<br><br>METHODS: Using quantitative polymerase chain reaction, we measured the absolute telomere length (aTL) of DNA extracted from blood samples of 576 participants with moderate-to-severe COPD treated with either azithromycin or placebo for 12&#xa0;months in the Macrolide Azithromycin for Prevention of Exacerbations of COPD (MACRO) study. All participants were followed for approximately 13&#xa0;months, during which time health status and exacerbations were carefully ascertained, and an additional 29&#xa0;months for mortality. The rates of exacerbation and mortality were determined by dividing the aTL into two groups using the median value as the cutoff.<br><br>RESULTS: Participants with shorter telomere length had worse health status defined by higher St. George's Respiratory Questionnaire scores (&#x3b2;&#xa0;=&#xa0;-0.09, P&#xa0;= .034). In the placebo arm of the study, the rate of exacerbation (rate ratio, 1.50; 95%&#xa0;CI, 1.16-1.95; P&#xa0;= .002) and the risk of mortality (hazard ratio, 9.45; 95%&#xa0;CI, 2.85-31.36; P&#xa0;= .015) were significantly higher in the shorter telomere group than in the longer telomere group; these differences were not observed in the azithromycin arm (interaction P&#xa0;= .008 for exacerbation and interaction P&#xa0;=&#xa0;.017 for mortality) CONCLUSIONS: These data suggest that replicative senescence may help to predict poor outcomes in COPD. Shorter leukocyte telomere lengths may represent a clinically translatable biomarker for identifying individuals at increased risk of poor clinical outcomes in COPD.},
}
@article {pmid30014738,
year = {2018},
author = {Somanathan, I and Baysdorfer, C},
title = {A bioinformatics approach to identify telomere sequences.},
journal = {BioTechniques},
volume = {65},
number = {1},
pages = {20-25},
doi = {10.2144/btn-2018-0057},
pmid = {30014738},
issn = {1940-9818},
mesh = {Allium/*genetics ; Amaryllidaceae/*genetics ; *Computational Biology ; Conserved Sequence/genetics ; High-Throughput Nucleotide Sequencing ; In Situ Hybridization, Fluorescence ; Nucleotide Motifs/genetics ; Sequence Analysis, DNA ; Tandem Repeat Sequences/genetics ; Telomere/*genetics ; },
abstract = {Conventional approaches to identify a telomere motif in a new genome are laborious and time-intensive. An efficient new methodology based on next-generation sequencing (NGS), de novo sequence repeat finder (SERF) and fluorescence in situ hybridization (FISH) is presented. Unlike existing heuristic approaches, SERF utilizes an exhaustive analysis of raw NGS reads or assembled contigs for rapid de novo detection of conserved tandem repeats representing telomere motifs. SERF was validated using the NGS data from Ipheion uniflorum and Allium cepa with known telomere motifs. The analysis program was then used on NGS data to investigate the telomere motifs in several additional plant species and together with FISH proved to be an efficient approach to identify as yet unknown telomere motifs.},
}
@article {pmid30013585,
year = {2018},
author = {Naranjo, T},
title = {Variable Patterning of Chromatin Remodeling, Telomere Positioning, Synapsis, and Chiasma Formation of Individual Rye Chromosomes in Meiosis of Wheat-Rye Additions.},
journal = {Frontiers in plant science},
volume = {9},
number = {},
pages = {880},
pmid = {30013585},
issn = {1664-462X},
abstract = {Meiosis, the type of cell division that halves the chromosome number, shows a considerable degree of diversity among species. Unraveling molecular mechanisms of the meiotic machinery has been mainly based on meiotic mutants, where the effects of a change were assessed on chromosomes of the particular species. An alternative approach is to study the meiotic behavior of the chromosomes introgressed into different genetic backgrounds. As an allohexaploid, common wheat tolerates introgression of chromosomes from related species, such as rye. The behavior of individual pairs of rye homologues added to wheat has been monitored in meiotic prophase I and metaphase I. Chromosome 4R increased its length in early prophase I much more than other chromosomes studied, implying chromosome specific patterns of chromatin organization. Chromosome conformation affected clustering of telomeres but not their dispersion. Telomeres of the short arm of submetacentric chromosomes 4R, 5R, and 6R failed more often to be included in the telomere cluster either than the telomeres of the long arms or telomeres of metacentrics such as 2R, 3R, and 7R. The disturbed migration of the telomeres of 5RS and 6RS was associated with failure of synapsis and chiasma formation. However, despite the failed convergence of its telomere, the 4RS arm developed normal synapsis, perhaps because the strong increase of its length in early prophase I facilitated homologous encounters in intercalary regions. Surprisingly, chiasma frequencies in both arms of 4R were reduced. Similarly, the short arm of metacentric chromosome 2R often failed to form chiasmata despite normal synapsis. Chromosomes 1R, 3R, and 7R showed a regular meiotic behavior. These observations are discussed in the context of the behavior that these chromosomes show in rye itself.},
}
@article {pmid30010842,
year = {2018},
author = {Beh, CW and Zhang, Y and Zheng, YL and Sun, B and Wang, TH},
title = {Fluorescence spectroscopic detection and measurement of single telomere molecules.},
journal = {Nucleic acids research},
volume = {46},
number = {19},
pages = {e117},
pmid = {30010842},
issn = {1362-4962},
mesh = {Aging/genetics ; Cells, Cultured ; Chromosomal Instability/genetics ; DNA Mutational Analysis/*methods ; Humans ; Lab-On-A-Chip Devices ; Microfluidic Analytical Techniques/*methods ; Neoplasms/genetics ; Nucleic Acid Hybridization/methods ; Peptide Nucleic Acids/chemistry ; Polymorphism, Genetic ; Reproducibility of Results ; Single Molecule Imaging/*methods ; Spectrometry, Fluorescence/methods ; Telomere/*chemistry/genetics/metabolism ; Telomere Homeostasis/genetics ; Telomere Shortening/genetics ; },
abstract = {Telomeres are the end-caps of chromosomes that serve to protect the integrity of the genome. Below certain critical lengths, the telomeres can no longer fulfill their protective function, and chromosomal instability ensues. Telomeres shorten during normal cell division due to the end replication problem and are implicated in the development of various aging-associated diseases, including cancer. Telomere length has the potential to serve as a useful biomarker in the field of aging and cancer. However, existing methods of telomere measurement are either too laborious, unable to provide absolute measurement of individual telomere lengths, or limited to certain chromosomes or cell types. Here, we describe an easy single-molecule, fluorescence spectroscopic method for measuring the length of telomeres that permits the profiling of absolute telomere lengths in any DNA sample. We have demonstrated the accurate detection of telomeres as short as 100 bp using cloned telomere standards, and have profiled telomere lengths in human cancer cell lines and primary cells. Since this method allows direct comparison between samples, it could greatly improve the clinical utility of telomere biomarkers.},
}
@article {pmid30003765,
year = {2018},
author = {Benderli Cihan, Y},
title = {Importance of telomere length and telomerase activity in radiosensitivity.},
journal = {Journal of B.U.ON. : official journal of the Balkan Union of Oncology},
volume = {23},
number = {3},
pages = {838-839},
pmid = {30003765},
issn = {1107-0625},
mesh = {Animals ; Disease-Free Survival ; Humans ; Neoplasms/*metabolism ; Prognosis ; Radiation Tolerance/*physiology ; Rats ; Telomerase/*metabolism ; Telomere/*metabolism ; },
}
@article {pmid30003356,
year = {2018},
author = {Aziz, NA and Weydt, P},
title = {Telomere length as a modifier of age-at-onset in Huntington disease: a two-sample Mendelian randomization study.},
journal = {Journal of neurology},
volume = {265},
number = {9},
pages = {2149-2151},
pmid = {30003356},
issn = {1432-1459},
mesh = {*Age of Onset ; Genome-Wide Association Study ; Humans ; *Huntington Disease ; Mendelian Randomization Analysis/*methods ; Polymorphism, Single Nucleotide ; *Telomere Shortening ; },
}
@article {pmid30001973,
year = {2018},
author = {Russo, P and Prinzi, G and Proietti, S and Lamonaca, P and Frustaci, A and Boccia, S and Amore, R and Lorenzi, M and Onder, G and Marzetti, E and Valdiglesias, V and Guadagni, F and Valente, MG and Cascio, GL and Fraietta, S and Ducci, G and Bonassi, S},
title = {Shorter telomere length in schizophrenia: Evidence from a real-world population and meta-analysis of most recent literature.},
journal = {Schizophrenia research},
volume = {202},
number = {},
pages = {37-45},
doi = {10.1016/j.schres.2018.07.015},
pmid = {30001973},
issn = {1573-2509},
mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Italy/epidemiology ; Male ; Middle Aged ; Psychotic Disorders/*epidemiology/*metabolism ; Schizophrenia/*epidemiology/*metabolism ; *Telomere Shortening ; Young Adult ; },
abstract = {Schizophrenia is a severe, chronic mental disorder. Schizophrenia is visualized as an accelerated cellular aging syndrome characterized by early onset of cardiovascular disease causing premature mortality. In human aging involves alterations in telomere length (TL). To investigate the presence of TL shortening in schizophrenia and psychiatric syndromes associated, this condition was studied in leukocytes (LTL) of a sample of patients suffering from schizophrenia and other psychotic disorders, and compared with a group of non-psychiatric controls. We explored the relationship between LTL and age, gender, and smoking habit with the aim to control whether these potential confounding factors may influence the rate of telomeres shortening. We also performed a new comprehensive meta-analysis including studies on LTL in schizophrenia patients compared to healthy subjects published in the last two years and the results of the present study. Our results suggest that a diagnosis of schizophrenia, more than gender, age, cigarette smoking or alcohol drinking, is the most important condition responsible of the LTL shortening. A strong LTL shortening was observed in patients affected by schizophrenia, Schizoaffective disorder, and Psychosis not otherwise specified when they were younger than 50 years, while in the group of older subjects no major differences were observed. Additional evidence supporting the causal link of schizophrenia with accelerated telomeres shortening came from the analysis of the updated meta-analysis. The availability of a personalized profile of mechanistic pathways, risk factors, and clinical features may pose the basis for a rehabilitative treatment addressing individual needs of the psychiatric patients.},
}
@article {pmid30001204,
year = {2018},
author = {Radion, E and Morgunova, V and Ryazansky, S and Akulenko, N and Lavrov, S and Abramov, Y and Komarov, PA and Glukhov, SI and Olovnikov, I and Kalmykova, A},
title = {Key role of piRNAs in telomeric chromatin maintenance and telomere nuclear positioning in Drosophila germline.},
journal = {Epigenetics &amp; chromatin},
volume = {11},
number = {1},
pages = {40},
pmid = {30001204},
issn = {1756-8935},
support = {16-14-10167//Russian Science Foundation/International ; 16-04-01107//Russian Foundation for Basic Research/International ; Systems Biology Fellowship//Skolkovo Institute of Science and Technology/International ; },
mesh = {Animals ; Cell Nucleus/*genetics ; Chromatin/genetics ; Chromatin Assembly and Disassembly ; Drosophila melanogaster ; Germ Cells/chemistry ; RNA, Small Interfering/*metabolism ; Telomere/*genetics ; },
abstract = {BACKGROUND: Telomeric small RNAs related to PIWI-interacting RNAs (piRNAs) have been described in various eukaryotes; however, their role in germline-specific telomere function remains poorly understood. Using a Drosophila model, we performed an in-depth study of the biogenesis of telomeric piRNAs and their function in telomere homeostasis in the germline.<br><br>RESULTS: To fully characterize telomeric piRNA clusters, we integrated the data obtained from analysis of endogenous telomeric repeats, as well as transgenes inserted into different telomeric and subtelomeric regions. The small RNA-seq data from strains carrying telomeric transgenes demonstrated that all transgenes belong to a class of dual-strand piRNA clusters; however, their capacity to produce piRNAs varies significantly. Rhino, a paralog of heterochromatic protein 1 (HP1) expressed exclusively in the germline, is associated with all telomeric transgenes, but its enrichment correlates with the abundance of transgenic piRNAs. It is likely that this heterogeneity is determined by the sequence peculiarities of telomeric retrotransposons. In contrast to the heterochromatic non-telomeric germline piRNA clusters, piRNA loss leads to a dramatic decrease in HP1, Rhino, and trimethylated histone H3 lysine 9 in telomeric regions. Therefore, the presence of piRNAs is required for the maintenance of telomere chromatin in the germline. Moreover, piRNA loss causes telomere translocation from the nuclear periphery toward the nuclear interior but does not affect telomere end capping. Analysis of the telomere-associated sequences (TASs) chromatin revealed strong tissue specificity. In the germline, TASs are enriched with HP1 and Rhino, in contrast to somatic tissues, where they are repressed by Polycomb group proteins.<br><br>CONCLUSIONS: piRNAs play an essential role in the assembly of telomeric chromatin, as well as in nuclear telomere positioning in the germline. Telomeric arrays and TASs belong to a unique type of Rhino-dependent piRNA clusters with transcripts that serve simultaneously as piRNA precursors and as their only targets. Telomeric chromatin is highly sensitive to piRNA loss, implying the existence of a novel developmental checkpoint that depends on telomere integrity in the germline.},
}
@article {pmid29997179,
year = {2018},
author = {Ogawa, S and Kido, S and Handa, T and Ogawa, H and Asakawa, H and Takahashi, TS and Nakagawa, T and Hiraoka, Y and Masukata, H},
title = {Shelterin promotes tethering of late replication origins to telomeres for replication-timing control.},
journal = {The EMBO journal},
volume = {37},
number = {15},
pages = {},
pmid = {29997179},
issn = {1460-2075},
mesh = {DNA Replication/genetics ; DNA-Binding Proteins/metabolism ; G1 Phase/genetics ; Membrane Proteins/metabolism ; Nuclear Proteins/metabolism ; Recombinant Fusion Proteins/metabolism ; Replication Origin/*genetics ; S Phase/genetics ; Schizosaccharomyces/*genetics ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {DNA replication initiates at many discrete loci on eukaryotic chromosomes, and individual replication origins are regulated under a spatiotemporal program. However, the underlying mechanisms of this regulation remain largely unknown. In the fission yeast Schizosaccharomyces pombe, the telomere-binding protein Taz1, ortholog of human TRF1/TRF2, regulates a subset of late replication origins by binding to the telomere-like sequence near the origins. Here, we showed using a lacO/LacI-GFP system that Taz1-dependent late origins were predominantly localized at the nuclear periphery throughout interphase, and were localized adjacent to the telomeres in the G1/S phase. The peripheral localization that depended on the nuclear membrane protein Bqt4 was not necessary for telomeric association and replication-timing control of the replication origins. Interestingly, the shelterin components Rap1 and Poz1 were required for replication-timing control and telomeric association of Taz1-dependent late origins, and this requirement was bypassed by a minishelterin Tpz1-Taz1 fusion protein. Our results suggest that Taz1 suppresses replication initiation through shelterin-mediated telomeric association of the origins at the onset of S phase.},
}
@article {pmid29992129,
year = {2018},
author = {Fontana, GA and Reinert, JK and Thomä, NH and Rass, U},
title = {Shepherding DNA ends: Rif1 protects telomeres and chromosome breaks.},
journal = {Microbial cell (Graz, Austria)},
volume = {5},
number = {7},
pages = {327-343},
pmid = {29992129},
issn = {2311-2638},
abstract = {Cells have evolved conserved mechanisms to protect DNA ends, such as those at the termini of linear chromosomes, or those at DNA double-strand breaks (DSBs). In eukaryotes, DNA ends at chromosomal termini are packaged into proteinaceous structures called telomeres. Telomeres protect chromosome ends from erosion, inadvertent activation of the cellular DNA damage response (DDR), and telomere fusion. In contrast, cells must respond to damage-induced DNA ends at DSBs by harnessing the DDR to restore chromosome integrity, avoiding genome instability and disease. Intriguingly, Rif1 (Rap1-interacting factor 1) has been implicated in telomere homeostasis as well as DSB repair. The protein was first identified in Saccharomyces cerevisiae as being part of the proteinaceous telosome. In mammals, RIF1 is not associated with intact telomeres, but was found at chromosome breaks, where RIF1 has emerged as a key mediator of pathway choice between the two evolutionary conserved DSB repair pathways of non-homologous end-joining (NHEJ) and homologous recombination (HR). While this functional dichotomy has long been a puzzle, recent findings link yeast Rif1 not only to telomeres, but also to DSB repair, and mechanistic parallels likely exist. In this review, we will provide an overview of the actions of Rif1 at DNA ends and explore how exclusion of end-processing factors might be the underlying principle allowing Rif1 to fulfill diverse biological roles at telomeres and chromosome breaks.},
}
@article {pmid29989281,
year = {2018},
author = {Ortiz-Ramírez, M and Sánchez-García, S and García-Dela Torre, P and Reyes-Maldonado, E and Sánchez-Arenas, R and Rosas-Vargas, H},
title = {Telomere shortening and frailty in Mexican older adults.},
journal = {Geriatrics &amp; gerontology international},
volume = {18},
number = {8},
pages = {1286-1292},
doi = {10.1111/ggi.13463},
pmid = {29989281},
issn = {1447-0594},
mesh = {Aged ; Aged, 80 and over ; Aging/*genetics ; Analysis of Variance ; Confidence Intervals ; Cross-Sectional Studies ; Exercise/*physiology ; Female ; Frailty/*genetics ; Geriatric Assessment/methods ; Humans ; Life Style ; Male ; Mexico ; Multivariate Analysis ; *Quality of Life ; Telomere Shortening/*genetics ; },
abstract = {AIM: Telomere shortening has been associated with several age-related diseases, in addition to being considered a hallmark of aging. Frailty is a clinical syndrome characterized by an accentuated physiological and functional decline that might be a predictor of an adverse condition in older age. The present study evaluated the relationship between frailty and telomere shortening in older adults from Mexico City, Mexico.<br><br>METHODS: This was a cross-sectional study. Data were collected from 323 frail older adults, including physical and environmental factors, such as body mass index, comorbidities, physical activity and tobacco consumption. Telomere length was measured by real-time polymerase chain reaction. The frailty syndrome was diagnosed using the Fried criteria.<br><br>RESULTS: An association between frailty and telomere shortening was found in both sexes. Telomere length decreased from 6.05&#x2009;kb (5.54-6.48&#x2009;kb) to 4.20&#x2009;kb (3.80-4.54&#x2009;kb; P&#x2009;<&#x2009;0.001). It was also observed that tobacco consumption could be a significant modifying factor in the association between these two variables. Previous reports are contradictory, suggesting that there is no relationship between telomere length and frailty; however, it is possible that there are genetic and/or environmental variables to be elucidated, that might influence this association, particularly in the studied population.<br><br>CONCLUSIONS: Telomere length is inversely related to frailty in Mexican frail older adults, and tobacco consumption is the main environmental modifying factor. Geriatr Gerontol Int 2018; 18: 1286-1292.},
}
@article {pmid29986708,
year = {2018},
author = {McDonough, JE and Martens, DS and Tanabe, N and Ahangari, F and Verleden, SE and Maes, K and Verleden, GM and Kaminski, N and Hogg, JC and Nawrot, TS and Wuyts, WA and Vanaudenaerde, BM},
title = {A role for telomere length and chromosomal damage in idiopathic pulmonary fibrosis.},
journal = {Respiratory research},
volume = {19},
number = {1},
pages = {132},
pmid = {29986708},
issn = {1465-993X},
support = {R01 HL127349/HL/NHLBI NIH HHS/United States ; R01HL127349//National Institutes of Health (US)/International ; ERC-2012-StG310898//Universiteit Hasselt/International ; C2/15/30//KU Leuven (BE)/International ; RESPIRE2-2015-9192//European Respiratory Society (CH)/International ; FWO12G8715N//FWO/International ; },
mesh = {Aged ; *Chromosome Aberrations ; DNA Damage/*physiology ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/*diagnostic imaging/*genetics ; Male ; Middle Aged ; Telomere/pathology/physiology ; Telomere Shortening/*physiology ; X-Ray Microtomography/trends ; },
abstract = {BACKGROUND: Idiopathic pulmonary fibrosis is a fatal lung disease characterized by a progressive formation of fibroblastic foci in the interstitium. This disease is strongly associated with telomere dysfunction but the extent of telomere shortening and consequent chromosomal damage within IPF lungs and with regional disease severity remains unknown.<br><br>METHODS: Explanted IPF lungs (n&#x2009;=&#x2009;10) were collected from transplant surgeries with six samples per lung analysed to capture the regional heterogeneity ranging from mild to severe disease. Non-used donor lungs (n&#x2009;=&#x2009;6) were collected as "healthy" controls. Structural changes related to disease severity (microCT surface density), relative telomere length (real-time qPCR), and quantitative histology of chromosomal damage (&#x3b3;-H2A.X) and extracellular matrix (elastin, total collagen, collagen 1, and collagen 3) were measured. A multivariate linear mixed-effects model controlling for subject was used to identify association of disease severity or fibrotic markers with telomere length and chromosomal damage.<br><br>RESULTS: We observed shorter telomere length (p&#x2009;=&#x2009;0.001) and increased chromosomal damage (p&#x2009;=&#x2009;0.018) in IPF lungs compared to controls. In IPF lungs, telomere length was associated with total collagen (p&#x2009;<&#x2009;0.001) but not with structural changes of disease severity. Chromosomal damage was positively associated with increased elastin (p&#x2009;=&#x2009;0.006) and negatively with structural disease severity (p&#x2009;=&#x2009;0.046). Extensive &#x3b3;-H2A.X staining was also present in airway epithelial cells.<br><br>CONCLUSIONS: Telomere length and chromosomal damage are involved in IPF with regional variation in telomere length and chromosomal damage associated with pathological changes in tissue structure and the extracellular matrix.},
}
@article {pmid29982509,
year = {2018},
author = {Stella-Ascariz, N and Montejano, R and Rodriguez-Centeno, J and Alejos, B and Schwimmer, C and Bernardino, JI and Rodes, B and Allavena, C and Hoffmann, C and Gisslén, M and de Miguel, R and Esteban-Cantos, A and Wallet, C and Raffi, F and Arribas, JR and , },
title = {Blood Telomere Length Changes After Ritonavir-Boosted Darunavir Combined With Raltegravir or Tenofovir-Emtricitabine in Antiretroviral-Naive Adults Infected With HIV-1.},
journal = {The Journal of infectious diseases},
volume = {218},
number = {10},
pages = {1523-1530},
doi = {10.1093/infdis/jiy399},
pmid = {29982509},
issn = {1537-6613},
mesh = {Adult ; Analysis of Variance ; *Anti-HIV Agents/administration &amp; dosage/pharmacology/therapeutic use ; DNA/blood ; Darunavir/administration &amp; dosage/pharmacology/therapeutic use ; Emtricitabine/administration &amp; dosage/pharmacology/therapeutic use ; Female ; *HIV Infections/blood/drug therapy/epidemiology/genetics ; Humans ; Male ; Middle Aged ; Prospective Studies ; Raltegravir Potassium/administration &amp; dosage/pharmacology/therapeutic use ; Randomized Controlled Trials as Topic ; Ritonavir/administration &amp; dosage/pharmacology/therapeutic use ; Telomere/*drug effects ; Tenofovir/administration &amp; dosage/pharmacology/therapeutic use ; },
abstract = {BACKGROUND: Tenofovir is a potent inhibitor of human telomerase. The clinical relevance of this inhibition is unknown.<br><br>METHODS: NEAT001/ANRS143 is a randomized trial that showed noninferiority over 96 weeks of ritonavir-boosted darunavir plus raltegravir versus tenofovir disoproxil fumarate/emtricitabine in 805 antiretroviral antiretrovrial-naive HIV-infected adults. We compared changes in whole-blood telomere length measured with quantitative polymerase chain reaction in 201 randomly selected participants (104 raltegravir and 97 tenofovir disoproxil fumarate/emtricitabine). We performed multivariable estimative and predictive linear regression.<br><br>RESULTS: At week 96, participants receiving tenofovir disoproxil fumarate/emtricitabine had a statistically significant higher gain in telomere length than participants receiving raltegravir. Difference in mean telomere length change between groups (tenofovir disoproxil fumarate/emtricitabine minus raltegravir) from baseline to week 96 adjusted by baseline telomere length was 0.031 (P = .009). This difference was not significantly confounded by age, gender, known duration of HIV infection, CD4 (baseline/nadir), CD8 cells, CD4/CD8 ratio, HIV viral load (baseline/week 96), tobacco and alcohol consumption, statins, or hepatitis C.<br><br>CONCLUSION: Antiretroviral-naive HIV-infected adults receiving ritonavir-boosted darunavir and tenofovir disoproxil fumarate/emtricitabine had a significant higher gain in blood telomere length than those receiving ritonavir-boosted darunavir and raltegravir, suggesting a better initial recovery from HIV-associated immunosenescence.},
}
@article {pmid29980985,
year = {2018},
author = {Weber, KA and Heaphy, CM and Joshu, CE and Lu, J and Rohrmann, S and Bienstock, JL and Agurs-Collins, T and Meeker, AK and Platz, EA},
title = {Racial differences in maternal and umbilical cord blood leukocyte telomere length and their correlations.},
journal = {Cancer causes &amp; control : CCC},
volume = {29},
number = {8},
pages = {759-767},
pmid = {29980985},
issn = {1573-7225},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; U54 CA091409/CA/NCI NIH HHS/United States ; F32 CA093140/CA/NCI NIH HHS/United States ; T32 CA009314/CA/NCI NIH HHS/United States ; },
mesh = {*Black People/genetics/statistics &amp; numerical data ; Cohort Studies ; Female ; Fetal Blood/*cytology ; Humans ; Pregnancy ; *Telomere/genetics/physiology ; *White People/genetics/statistics &amp; numerical data ; },
abstract = {PURPOSE: Telomere length at birth sets the baseline for telomere shortening and may influence adult disease risk like cancer. Telomere length is heritable, but may also be a marker of exposures in utero, including those influencing racial differences in risk. We examined racial differences in telomere length in maternal and umbilical cord blood from male neonates, and maternal-neonate correlations to generate hypotheses.<br><br>METHODS: Black and white pregnant women were recruited in 2006-2007 and followed to postpartum. Data came from questionnaires and medical records. Relative telomere length was measured by qPCR in leukocyte DNA. We estimated mean telomere length in mothers and neonates (n&#x2009;=&#x2009;55 pairs) using linear regression and maternal-cord blood Spearman correlations, overall and by race.<br><br>RESULTS: Black mothers had shorter age- and plate-adjusted telomere length (2.49, 95% CI 2.11-2.86) than whites (2.92, 95% CI 2.63-3.22; p&#x2009;=&#x2009;0.1) and black neonates had shorter telomere length (2.58, 95% CI 2.16-3.01) than whites (3.13, 95% CI 2.79-3.47; p&#x2009;=&#x2009;0.1), though not statistically significant. Differences were attenuated after further adjustment for maternal factors. Maternal-cord blood correlations were moderate (r&#x2009;=&#x2009;0.53, p&#x2009;<&#x2009;0.0001), and did not differ by race.<br><br>CONCLUSION: Telomere length may differ by race at birth due to both inherited and racial differences in maternal factors. This study was for hypothesis generation and results should be followed up in larger studies.},
}
@article {pmid29980875,
year = {2019},
author = {Rinelli, M and Bellacchio, E and Berardinelli, F and Pascolini, G and Grammatico, P and Sgura, A and Iori, AP and Quattrocchi, L and Novelli, A and Majore, S and Agolini, E},
title = {Structural modeling of a novel TERC variant in a patient with aplastic anemia and short telomeres.},
journal = {Annals of hematology},
volume = {98},
number = {3},
pages = {805-807},
doi = {10.1007/s00277-018-3415-5},
pmid = {29980875},
issn = {1432-0584},
mesh = {Adult ; Anemia, Aplastic/*genetics ; Female ; Hematologic Diseases/genetics ; Heterozygote ; Humans ; Male ; Models, Molecular ; Nucleic Acid Conformation ; Pedigree ; RNA/*genetics ; Telomerase/*genetics ; Telomere/*ultrastructure ; Telomere Homeostasis/*genetics ; },
}
@article {pmid29980572,
year = {2018},
author = {Bouillon, AS and Ventura Ferreira, MS and Awad, SA and Richter, J and Hochhaus, A and Kunzmann, V and Dengler, J and Janssen, J and Ossenkoppele, G and Westerweel, PE and Te Boekhorst, PAW and Mahon, FX and Hjorth-Hansen, H and Isfort, S and Fioretos, T and Hummel, S and Schemionek, M and Wilop, S and Koschmieder, S and Saußele, S and Mustjoki, S and Beier, F and Brümmendorf, TH},
title = {Telomere shortening correlates with leukemic stem cell burden at diagnosis of chronic myeloid leukemia.},
journal = {Blood advances},
volume = {2},
number = {13},
pages = {1572-1579},
pmid = {29980572},
issn = {2473-9537},
mesh = {Adult ; Aged ; Female ; Hematopoietic Stem Cells/*metabolism ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis/drug therapy/genetics/*metabolism ; Male ; Middle Aged ; Protein Kinase Inhibitors/administration &amp; dosage ; *Telomere Homeostasis ; },
abstract = {Telomere length (TL) in peripheral blood (PB) cells of patients with chronic myeloid leukemia (CML) has been shown to correlate with disease stage, prognostic scores, response to therapy, and disease progression. However, due to considerable genetic interindividual variability, TL varies substantially between individuals, limiting its use as a robust prognostic marker in individual patients. Here, we compared TL of BCR-ABL[-], nonleukemic CD34[+]CD38[-] hematopoietic stem cells (HSC) in the bone marrow of CML patients at diagnosis to their individual BCR-ABL[+] leukemic stem cell (LSC) counterparts. We observed significantly accelerated telomere shortening in LSC compared with nonleukemic HSC. Interestingly, the degree of LSC telomere shortening was found to correlate significantly with the leukemic clone size. To validate the diagnostic value of nonleukemic cells as internal controls and to rule out effects of tyrosine kinase inhibitor (TKI) treatment on these nontarget cells, we prospectively assessed TL in 134 PB samples collected in deep molecular remission after TKI treatment within the EURO-SKI study (NCT01596114). Here, no significant telomere shortening was observed in granulocytes compared with an age-adjusted control cohort. In conclusion, this study provides proof of principle for accelerated telomere shortening in LSC as opposed to HSC in CML patients at diagnosis. The fact that the degree of telomere shortening correlates with leukemic clone's size supports the use of TL in leukemic cells as a prognostic parameter pending prospective validation. TL in nonleukemic myeloid cells seems unaffected even by long-term TKI treatment arguing against a reduction of telomere-mediated replicative reserve in normal hematopoiesis under TKI treatment.},
}
@article {pmid29980010,
year = {2018},
author = {Lin, J and Sun, J and Wang, S and Milush, JM and Baker, CAR and Coccia, M and Effros, RB and Puterman, E and Blackburn, E and Prather, AA and Epel, E},
title = {In vitro proinflammatory gene expression predicts in vivo telomere shortening: A preliminary study.},
journal = {Psychoneuroendocrinology},
volume = {96},
number = {},
pages = {179-187},
doi = {10.1016/j.psyneuen.2018.06.020},
pmid = {29980010},
issn = {1873-3360},
support = {R01 AG030424/AG/NIA NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; },
mesh = {Adult ; Biomarkers ; Caregivers/*psychology ; Cellular Senescence ; Cyclooxygenase 2 ; Cytokines ; Female ; Humans ; Immunity/genetics ; Leukocytes, Mononuclear ; Lymphocyte Activation ; Middle Aged ; NF-kappa B/genetics ; Preliminary Data ; Primary Cell Culture ; Signal Transduction/genetics ; Stress, Psychological/*genetics ; Telomere/physiology ; Telomere Shortening/*genetics ; Th17 Cells/physiology ; Transcriptome/genetics ; },
abstract = {The chronic psychological stress of caregiving leads to higher risks for many diseases. One of the mechanisms through which caregiving is associated with disease risk is chronic inflammation. Chronic inflammation may accelerate cellular aging via telomere dysfunction and cell senescence, although this has not been examined in human cells from healthy people. We examined peripheral blood mononuclear cells (PBMCs) from 20 healthy mothers of children with autism (caregivers) and 19 mothers of neurotypical children (controls) in an in vitro culture system where PBMCs were stimulated with phytohaemagglutinin (PHA). We measured RNA expression levels of a panel of immune function genes before and after PHA stimulation, as well as telomere length from PBMCs collected from the participants at baseline and 15 months later. Caregivers and controls had similar gene expression profiles in unstimulated PBMCs, but after PHA stimulation, caregivers had increased RNA levels of the master inflammatory regulator NF-κB and its proinflammatory cytokine targets IL-1β, IL-6 and its receptor IL-6R as well as inflammatory chemokines IL-8, CXCL1 and CXCL2. Gene expression analysis suggested caregivers have increased Treg and Th17 T cell differentiation. Additionally, key signaling molecules involved in the upregulation of COX-2, a critical enzyme in the synthesis of the inflammatory mediator prostaglandin, were elevated. When both groups were examined together, higher expression levels of proinflammatory genes were associated with shorter telomere length in PBMCs from blood drawn 15 months later, independent of baseline telomere length. Taken together, these results suggest that chronic stress is associated with an exaggerated inflammatory response in PBMCs, which in turn is associated with shorter telomere length measured from PBMCs collected 15 months later. To our knowledge, this is the first human study that shows increased proinflammatory expression predicts future telomere shortening.},
}
@article {pmid29976922,
year = {2018},
author = {Guo, R and Ye, X and Yang, J and Zhou, Z and Tian, C and Wang, H and Wang, H and Fu, H and Liu, C and Zeng, M and Yang, J and Liu, L},
title = {Feeders facilitate telomere maintenance and chromosomal stability of embryonic stem cells.},
journal = {Nature communications},
volume = {9},
number = {1},
pages = {2620},
pmid = {29976922},
issn = {2041-1723},
mesh = {Animals ; Bone Morphogenetic Protein 4/genetics/metabolism ; Cell Proliferation/genetics ; Cells, Cultured ; Chromosomal Instability/*genetics ; Embryo, Mammalian/cytology ; Feeder Cells/cytology ; Fibroblasts/cytology ; Follistatin-Related Proteins/genetics/metabolism ; Gene Expression Profiling ; Mice ; Mouse Embryonic Stem Cells/cytology/*metabolism ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics ; Transcription Factors/genetics/metabolism ; },
abstract = {Feeder cells like mouse embryonic fibroblasts (MEFs) have been widely applied for culture of pluripotent stem cells, but their roles remain elusive. Noticeably, ESCs cultured on the feeders display transcriptional heterogeneity. We investigated roles of feeder cells by examining the telomere maintenance. Here we show that telomere is longer in mESCs cultured with than without the feeders. mESC cultures without MEF feeders exhibit telomere loss, chromosomal fusion, and aneuploidy with increasing passages. Notably, feeders facilitate heterogeneous transcription of 2-cell genes including Zscan4 and telomere elongation. Moreover, feeders produce Fstl1 that together with BMP4 periodically activate Zscan4. Interestingly, Zscan4 is repressed in mESCs cultured in 2i (inhibitors of Mek and Gsk3β signaling) media, associated with shorter telomeres and increased chromosome instability. These data suggest the important role of feeders in maintaining telomeres for long-term stable self-renewal and developmental pluripotency of mESCs.},
}
@article {pmid29976374,
year = {2018},
author = {Mangaonkar, AA and Ferrer, A and Pinto E Vairo, F and Cousin, MA and Kuisle, RJ and Klee, EW and Kennedy, CC and Peters, SG and Scott, JP and Utz, JP and Baqir, M and Sekiguchi, H and Khan, SP and Rodriguez, V and Simonetto, DA and Kamath, PS and Abraham, RS and Wylam, ME and Patnaik, MM},
title = {Clinical Correlates and Treatment Outcomes for Patients With Short Telomere Syndromes.},
journal = {Mayo Clinic proceedings},
volume = {93},
number = {7},
pages = {834-839},
pmid = {29976374},
issn = {1942-5546},
support = {KL2 TR000136/TR/NCATS NIH HHS/United States ; KL2 TR002379/TR/NCATS NIH HHS/United States ; },
mesh = {Adolescent ; Aged ; Child, Preschool ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Survival Rate ; Syndrome ; *Telomere Shortening ; Treatment Outcome ; },
abstract = {Short telomere syndromes (STSs) are accelerated aging syndromes with multisystemic manifestations that present complex management challenges. In this article, we discuss a single-institution experience in diagnosing and managing patients with inherited STSs. In total, we identified 17 patients with short telomeres, defined by flow-fluorescence in-situ hybridization telomere lengths of less than first centile in granulocytes/lymphocytes OR the presence of a characteristic germline pathogenic variant in the context of a highly suggestive clinical phenotype. Genetic variations in the telomere complex were identified in 6 (35%) patients, with 4 being known pathogenic variants involving TERT (n=2), TERC (n=1), and DKC1 (n=1) genes, while 2 were variants of uncertain significance in TERT and RTEL1 genes. Idiopathic interstitial pneumonia (IIP) (n=12 [71%]), unexplained cytopenias (n=5 [29%]), and cirrhosis (n=2 [12%]) were most frequent clinical phenotypes at diagnosis. At median follow-up of 48 (range, 0-316) months, Kaplan-Meier estimate of overall survival, median (95% CI), was 182 (113, not reached) months. Treatment modalities included lung transplantation for IIP (n=5 [29%]), with 3 patients developing signs of acute cellular rejection (2, grade A2; 1, grade A1); danazol therapy for cytopenias (n=4 [24%]), with only 1 out of 4 patients showing a partial hematologic response; and allogeneic hematopoietic stem cell transplant for progressive bone marrow failure (n=2), with 1 patient dying from transplant-related complications. In summary, patients with STSs present with diverse clinical manifestations and require a multidisciplinary approach to management, with organ-specific transplantation capable of providing clinical benefit.},
}
@article {pmid29976370,
year = {2018},
author = {Armanios, M},
title = {Telomeres in the Clinic, Not on TV.},
journal = {Mayo Clinic proceedings},
volume = {93},
number = {7},
pages = {815-817},
doi = {10.1016/j.mayocp.2018.05.024},
pmid = {29976370},
issn = {1942-5546},
mesh = {Growth Disorders ; Humans ; *Hypercalcemia ; *Nephrocalcinosis ; Syndrome ; Telomere ; },
}
@article {pmid29975447,
year = {2018},
author = {Raeisi, S and Ghorbanihaghjo, A and Argani, H and Dastmalchi, S and Seifi, M and Ghasemi, B and Ghazizadeh, T and Abbasi, MM and Karimi, P},
title = {Oxidative stress-induced renal telomere shortening as a mechanism of cyclosporine-induced nephrotoxicity.},
journal = {Journal of biochemical and molecular toxicology},
volume = {32},
number = {8},
pages = {e22166},
doi = {10.1002/jbt.22166},
pmid = {29975447},
issn = {1099-0461},
mesh = {Aging/genetics ; Animals ; Biomarkers/metabolism ; Body Weight ; Creatinine/blood ; Cyclosporine/*toxicity ; Immunosuppressive Agents/*toxicity ; Kidney/*drug effects/enzymology/metabolism/physiology ; Male ; Oxidative Stress/*drug effects ; Rats, Wistar ; Telomerase/metabolism ; *Telomere Shortening ; Urea/blood ; },
abstract = {Due to the association of oxidative stress and telomere shortening, it was aimed in the present study to investigate the possibility whether cyclosporine-A exerts its nephrotoxic side effects via induction of oxidative stress-induced renal telomere shortening and senescent phenotype in renal tissues of rats. Renal oxidative stress markers, 8-hydroxydeoxyguanosine, malondialdehyde, and protein carbonyl groups were measured by standard methods. Telomere length and telomerase activity were also evaluated in kidney tissue samples. Results showed that cyclosporine-A treatment significantly (P < 0.05) enhanced renal malondialdehyde, 8-hydroxydeoxyguanosine, and protein carbonyl groups levels, decreased renal telomere length, and deteriorated renal function compared with the controls. Renal telomerase activity was not affected by cyclosporine-A. Renal telomere length could be considered as an important parameter of both oxidative stress and kidney function. Telomere shortening and accelerated kidney aging may be caused by cyclosporine-induced oxidative stress, indicating the potential mechanism of cyclosporine-induced nephrotoxicity.},
}
@article {pmid29974764,
year = {2018},
author = {Nonino, CB and Pinhanelli, VC and Noronha, NY and Quinhoneiro, DCG and Pinhel, MS and De Oliveira, BAP and Marchini, JS and Nicoletti, CF},
title = {Green tea supplementation promotes leukocyte telomere length elongation in obese women.},
journal = {Nutricion hospitalaria},
volume = {35},
number = {3},
pages = {570-575},
doi = {10.20960/nh.1392},
pmid = {29974764},
issn = {1699-5198},
mesh = {Adult ; Body Mass Index ; Catechin/*analogs &amp; derivatives/pharmacology ; Cross-Sectional Studies ; *Dietary Supplements ; Female ; Humans ; Leukocytes/drug effects/*ultrastructure ; Middle Aged ; Obesity/blood/*diet therapy ; *Tea ; Telomere/drug effects/*ultrastructure ; Telomere Shortening ; },
abstract = {INTRODUCTION: inflammation and oxidative stress are factors that may play a substantial role in telomere attrition. In line of this, obesity is associated with telomere shortening. Green tea had anti-inflammatory and antioxidant effects and may alter telomere length (TL).<br><br>OBJECTIVES: we evaluated the effect of decaffeinated green tea supplementation in obese women on TL.<br><br>METHODS: we conducted a cross-sectional interventional study with ten obese (body mass index [BMI] > 40 kg/m&#xb2;) and eight normal weight (BMI > 18.5 and < 24.9 kg/m&#xb2;) women (age between 27 and 48 years). The supplementation was carried out with capsules (each contained 450.7 mg of epigallocatechin-3-gallate) during eight weeks. Anthropometric and dietary intake assessment, and blood collection (for biochemical and TL analysis by quantitative PCR) were performed before and after supplementation. Normal weight patients were evaluated at a single moment.<br><br>RESULTS: we observed a significant increase on TL after supplementation (1.57 &#xb1; 1.1 to 3.2 &#xb1; 2.1 T/Sratio; p < 0.05). Moreover, we found shorter TL in obese patients (day 0) when compared to normal weight individuals (3.2 &#xb1; 1.9 T/Sratio; p < 0.05) and an inverse association between TL and BMI, even after age adjustment (beta = -0.527; r&#xb2; = 0.286; IC = -0.129, -0.009).<br><br>CONCLUSION: obesity is related to shorter telomeres. Green tea supplementation during eight weeks promotes telomere elongation in obese women.},
}
@article {pmid29974408,
year = {2019},
author = {Makarenko, MS and Chistyakov, VA and Usatov, AV and Mazanko, MS and Prazdnova, EV and Bren, AB and Gorlov, IF and Komarova, ZB and Chikindas, ML},
title = {The Impact of Bacillus subtilis KATMIRA1933 Supplementation on Telomere Length and Mitochondrial DNA Damage of Laying Hens.},
journal = {Probiotics and antimicrobial proteins},
volume = {11},
number = {2},
pages = {588-593},
pmid = {29974408},
issn = {1867-1314},
mesh = {Animals ; *Bacillus subtilis ; Chickens/*genetics ; *DNA Damage ; DNA, Mitochondrial/*genetics ; Dietary Supplements ; Eggs ; Female ; Probiotics/*administration &amp; dosage ; *Telomere ; },
abstract = {In the current study, we performed in vivo investigation of probiotic intake influence on nuclear and mitochondrial DNA damage of hens, using quantitative PCR techniques. The probiotic supplementation to the diet of Hisex Brown hens had no significant effect on the rate of telomere shortening. After prolonged probiotic intake (225 and 445 days), the 18-21% decrease in the mtDNA lesions was detected. Since avian mitochondrial DNA damage investigations are rare, the current study of the probiotic-enriched diet's impact on the damage of the hen mitochondrial DNA is novel and highly important. The decrease of mtDNA damage is a beneficial property, which could positively affect the reproductive aging of hens. The positive impact of probiotic supplementation on hens' performance traits such as hen-day egg production, egg weight and mass, and feed conversion ratio was observed.},
}
@article {pmid29970863,
year = {2018},
author = {Saker, L and Ali, S and Masserot, C and Kellermann, G and Poupon, J and Teulade-Fichou, MP and Ségal-Bendirdjian, E and Bombard, S},
title = {Platinum Complexes Can Bind to Telomeres by Coordination.},
journal = {International journal of molecular sciences},
volume = {19},
number = {7},
pages = {},
pmid = {29970863},
issn = {1422-0067},
mesh = {Cisplatin/*chemistry ; *G-Quadruplexes ; Molecular Structure ; Platinum/*chemistry ; Telomere/chemistry ; },
abstract = {It is suggested that several compounds, including G-quadruplex ligands, can target telomeres, inducing their uncapping and, ultimately, cell death. However, it has never been demonstrated whether such ligands can bind directly and quantitatively to telomeres. Here, we employed the property of platinum and platinum-G-quadruplex complexes to target G-rich sequences to investigate and quantify their covalent binding to telomeres. Using inductively coupled plasma mass spectrometry, surprisingly, we found that, in cellulo, in the presence of cisplatin, a di-functional platinum complex, telomeric DNA was platinated 13-times less than genomic DNA in cellulo, as compared to in vitro data. On the contrary, the amount of mono-functional platinum complexes (Pt-ttpy and Pt-tpy) bound either to telomeric or to genomic DNA was similar and occurred in a G-quadruplex independent-manner. Importantly, the quantification revealed that the low level of cisplatin bound to telomeric DNA could not be the direct physical cause of TRF2 displacement from telomeres. Altogether, our data suggest that platinum complexes can affect telomeres both directly and indirectly.},
}
@article {pmid29966475,
year = {2019},
author = {Kaifie, A and Schikowsky, C and Vasko, T and Kraus, T and Brümmendorf, TH and Ziegler, P},
title = {Additional benefits of telomere length (TL) measurements in chronic lymphocytic leukemia.},
journal = {Leukemia &amp; lymphoma},
volume = {60},
number = {2},
pages = {541-543},
doi = {10.1080/10428194.2018.1482544},
pmid = {29966475},
issn = {1029-2403},
mesh = {Disease Management ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*diagnosis/*genetics/mortality/therapy ; Proportional Hazards Models ; Telomere/*genetics ; Telomere Shortening ; },
}
@article {pmid29961868,
year = {2018},
author = {Zhan, Y and Liu, XR and Reynolds, CA and Pedersen, NL and Hägg, S and Clements, MS},
title = {Leukocyte Telomere Length and All-Cause Mortality: A Between-Within Twin Study With Time-Dependent Effects Using Generalized Survival Models.},
journal = {American journal of epidemiology},
volume = {187},
number = {10},
pages = {2186-2191},
doi = {10.1093/aje/kwy128},
pmid = {29961868},
issn = {1476-6256},
mesh = {Aged ; Aged, 80 and over ; Biological Variation, Population/*genetics ; Blotting, Southern ; Cause of Death ; Female ; Frailty/*genetics/*mortality ; Humans ; Leukocytes/cytology ; Male ; Middle Aged ; Registries ; Survival Analysis ; Sweden/epidemiology ; Telomere/*genetics ; Twins/*genetics ; },
abstract = {Although previous studies examining leukocyte telomere length (LTL) and all-cause mortality controlled for several confounders, the observed association could be biased due to unmeasured confounders, including familial factors. We aimed to examine the association of LTL with all-cause mortality in a Swedish twin sample while adjusting for familial factors and allowing for time-dependent effects. A total of 366 participants (174 twin pairs and 18 individuals) were recruited from the Swedish Twin Registry. LTL was assessed using the Southern blot method. All-cause mortality data were obtained through linkage with the Swedish Population Registry, updated through November 15, 2017. To control for familial factors within twin pairs, we applied a between-within shared frailty model based on generalized survival models. Overall, 115 (31.4%) participants were men and 251 (68.6%) were women. The average age of the study participants when blood was drawn was 79.1 years, and follow-up duration ranged from 10 days to 25.7 years (mean = 10.2 years). During the follow-up period, 341 (93.2%) participants died. Shorter LTL was associated with higher mortality rates when controlling for familial factors in the between-within shared frailty model. We found significant time-dependent effects of LTL on all-cause mortality, where the mortality rate ratios were attenuated with increasing age.},
}
@article {pmid29958997,
year = {2018},
author = {Krasnienkov, DS and Khalangot, MD and Kravchenko, VI and Kovtun, VA and Guryanov, VG and Chizhova, VP and Korkushko, OV and Shatilo, VB and Kukharsky, VM and Vaiserman, AM},
title = {Hyperglycemia attenuates the association between telomere length and age in Ukrainian population.},
journal = {Experimental gerontology},
volume = {110},
number = {},
pages = {247-252},
doi = {10.1016/j.exger.2018.06.027},
pmid = {29958997},
issn = {1873-6815},
mesh = {*Age Factors ; Aged ; Blood Glucose/metabolism ; Diabetes Mellitus, Type 2/diagnosis/*genetics ; Female ; Glucose Tolerance Test ; Humans ; Hyperglycemia/diagnosis/*genetics ; Leukocytes/metabolism ; Logistic Models ; Male ; Middle Aged ; Multivariate Analysis ; Oxidative Stress ; Telomere/ultrastructure ; *Telomere Shortening ; Ukraine ; },
abstract = {Diabetes-related conditions such as chronic hyperglycemia and related oxidative stress and inflammation were repeatedly associated with accelerated telomere shortening in epidemiological studies, although some findings are inconsistent. In present study, we aimed to assess the impact of disturbances in glucose metabolism on association between age and leukocyte telomere length (LTL) in the Ukrainian population. The study was conducted on the 119 adult subjects aged between 43 and 87 years residing in the Kyiv region, Ukraine. LTL was determined by a quantitative PCR-based method. LTL was negatively correlated with the measure of abdominal obesity such as waist-hip ratio, as well as with both fasting plasma glucose (FPG) and two-hour post-load glucose (2hPG) levels. Consistently with previous studies, a significant negative association between LTL and age was observed in individuals with normal (<5.6 mmol/L) FPG levels. Unexpectedly, however, no association was found in subjects with impaired glucose metabolism assessed by abnormal FPG or/and 2hPG levels. No association between LTL and age was observed in a logistic regression model; the association between LTL and age became significant after adjusting for FPG level. In the FPG-adjusted model, 1.6-time lower odds to have long telomere length were indicated for each 10 years increase in age. We hypothesize that the attenuation of association between LTL and age in hyperglycemic persons can likely be attributed to the interaction of multidirectional processes determining this relationship.},
}
@article {pmid29957485,
year = {2018},
author = {Tempaku, PF and Tufik, S},
title = {The paradigm of obstructive sleep apnea in aging: interactions with telomere length.},
journal = {Sleep medicine},
volume = {48},
number = {},
pages = {155-156},
doi = {10.1016/j.sleep.2018.05.009},
pmid = {29957485},
issn = {1878-5506},
mesh = {Humans ; *Sleep Apnea, Obstructive ; *Telomere ; Telomere Shortening ; },
}
@article {pmid29956293,
year = {2018},
author = {Baird, DM and Hendrickson, EA},
title = {Telomeres and Chromosomal Translocations : There's a Ligase at the End of the Translocation.},
journal = {Advances in experimental medicine and biology},
volume = {1044},
number = {},
pages = {89-112},
doi = {10.1007/978-981-13-0593-1_7},
pmid = {29956293},
issn = {0065-2598},
support = {18246/CRUK_/Cancer Research UK/United Kingdom ; R01 CA190492/CA/NCI NIH HHS/United States ; R01 CA154461/CA/NCI NIH HHS/United States ; R01 GM088351/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; DNA Damage ; DNA Ligases/*physiology ; DNA Repair ; Humans ; Mice ; *Telomere ; *Translocation, Genetic ; },
abstract = {Chromosomal translocations are now well understood to not only constitute signature molecular markers for certain human cancers but often also to be causative in the genesis of that tumor. Despite the obvious importance of such events, the molecular mechanism of chromosomal translocations in human cells remains poorly understood. Part of the explanation for this dearth of knowledge is due to the complexity of the reaction and the need to archaeologically work backwards from the final product (a translocation) to the original unrearranged chromosomes to infer mechanism. Although not definitive, these studies have indicated that the aberrant usage of endogenous DNA repair pathways likely lies at the heart of the problem. An equally obfuscating aspect of this field, however, has also originated from the unfortunate species-specific differences that appear to exist in the relevant model systems that have been utilized to investigate this process. Specifically, yeast and murine systems (which are often used by basic science investigators) rely on different DNA repair pathways to promote chromosomal translocations than human somatic cells. In this chapter, we will review some of the basic concepts of chromosomal translocations and the DNA repair systems thought to be responsible for their genesis with an emphasis on underscoring the differences between other species and human cells. In addition, we will focus on a specific subset of translocations that involve the very end of a chromosome (a telomere). A better understanding of the relationship between DNA repair pathways and chromosomal translocations is guaranteed to lead to improved therapeutic treatments for cancer.},
}
@article {pmid29954833,
year = {2018},
author = {García-Rubio, M and Aguilera, P and Lafuente-Barquero, J and Ruiz, JF and Simon, MN and Geli, V and Rondón, AG and Aguilera, A},
title = {Yra1-bound RNA-DNA hybrids cause orientation-independent transcription-replication collisions and telomere instability.},
journal = {Genes &amp; development},
volume = {32},
number = {13-14},
pages = {965-977},
pmid = {29954833},
issn = {1549-5477},
mesh = {Chromatin/metabolism ; Chromosomal Instability/*genetics ; *DNA Replication ; Nuclear Proteins/*genetics/*metabolism ; Nucleic Acid Hybridization ; Protein Binding ; RNA-Binding Proteins/*genetics/*metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/*metabolism ; Telomere/*genetics/metabolism ; *Transcription, Genetic ; },
abstract = {R loops are an important source of genome instability, largely due to their negative impact on replication progression. Yra1/ALY is an abundant RNA-binding factor conserved from yeast to humans and required for mRNA export, but its excess causes lethality and genome instability. Here, we show that, in addition to ssDNA and ssRNA, Yra1 binds RNA-DNA hybrids in vitro and, when artificially overexpressed, can be recruited to chromatin in an RNA-DNA hybrid-dependent manner, stabilizing R loops and converting them into replication obstacles in vivo. Importantly, an excess of Yra1 increases R-loop-mediated genome instability caused by transcription-replication collisions regardless of whether they are codirectional or head-on. It also induces telomere shortening in telomerase-negative cells and accelerates senescence, consistent with a defect in telomere replication. Our results indicate that RNA-DNA hybrids form transiently in cells regardless of replication and, after stabilization by excess Yra1, compromise genome integrity, in agreement with a two-step model of R-loop-mediated genome instability. This work opens new perspectives to understand transcription-associated genome instability in repair-deficient cells, including tumoral cells.},
}
@article {pmid29952119,
year = {2018},
author = {Masi, S and Georgiopoulos, G and Ribero, S and Taddei, S and Bataille, V and Steves, CJ},
title = {The relationship between naevus count, memory function and telomere length in the Twins UK cohort.},
journal = {Pigment cell &amp; melanoma research},
volume = {31},
number = {6},
pages = {720-724},
pmid = {29952119},
issn = {1755-148X},
support = {/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Cohort Studies ; Humans ; *Memory ; Middle Aged ; Nevus/*pathology/*physiopathology ; Reproducibility of Results ; *Telomere Homeostasis ; *Twins ; United Kingdom ; },
abstract = {The presence of a skin-brain connection whereby alterations in the skin can inform on mechanisms underlying neurodegenerative diseases is increasingly recognized. In this study, we used a discovery (n = 321) and replication (n = 147) sample from the Twins UK population to test the association between naevus count and memory function, and its mediation by telomeres. Memory function was assessed in 1999 and 2009 using the paired associates learning test (PAL), while naevus count and leucocyte telomere length (LTL, assessed by the terminal restriction fragment assay) were measured once. Higher baseline naevus count was significantly associated with fewer errors at the baseline and follow-up PAL, as well as with change in PAL score over 10 years. This association was significantly attenuated after adjustment for LTL. The significant association between naevus count and PAL score was reproduced in the replication sample. These findings suggest that melanocytes might be used as model system to study the biological ageing pathways involved in neurodegeneration.},
}
@article {pmid29951035,
year = {2018},
author = {Pavanello, S and Angelici, L and Hoxha, M and Cantone, L and Campisi, M and Tirelli, AS and Vigna, L and Pesatori, AC and Bollati, V},
title = {Sterol 27-Hydroxylase Polymorphism Significantly Associates With Shorter Telomere, Higher Cardiovascular and Type-2 Diabetes Risk in Obese Subjects.},
journal = {Frontiers in endocrinology},
volume = {9},
number = {},
pages = {309},
pmid = {29951035},
issn = {1664-2392},
abstract = {BACKGROUND/OBJECTIVES: The pathologic relationship linking obesity and lipid dismetabolism with earlier onset of aging-related disorders, including cardiovascular disease (CVD) and type-2 diabetes (T2D), is not fully elucidate. Chronic inflammatory state, in obese individuals, may accelerate cellular aging. However, leukocyte telomere length (LTL), the cellular biological aging indicator, is elusively linked with obesity. Recent studies indicate that sterol 27-hydroxylase (CYP27A1) is an emerging antiatherogenic enzyme, that, by converting extrahepatic cholesterol to 27-hydroxycholesterol, facilitates cholesterol removal via high-density lipoprotein-cholesterol (HDL-C). We tested the hypothesis that obese subjects who carry at least three copies of CYP27A1 low-hydroxylation (LH) activity genome-wide-validated alleles (rs4674345A, rs1554622A, and rs4674338G) present premature aging, as reflected in shorter LTL and higher levels of CVD/T2D risk factors, including reduced HDL-C.<br><br>SUBJECTS/METHODS: Obese subjects from SPHERE project {n&#x2009;=&#x2009;1,457; overweight [body mass index (BMI) 25-30&#x2009;kg/m[2]] 65.8% and severe-obese (BMI&#x2009;>&#x2009;30&#x2009;kg/m[2]) 34.2%}
were characterized for the presence from 0 to 6 LH-CYP27A1 allele copy number. Univariate and multivariable sex-age-smoking-adjusted linear-regression models were performed to compare CVD/T2D risk factors and biological aging (LTL) in relation to the combined BMI-LH groups: overweight-LH: 0-2, overweight-LH: 3-6, severe-obese-LH: 0-2, and severe-obese-LH: 3-6.<br><br>RESULTS: Higher LTL attrition was found in severe-obese than overweight individuals (p&#x2009;<&#x2009;0.001). Multivariable model reveals that among severe-obese patients those with LH: 3-6 present higher LTL attrition than LH: 0-2 (p&#x2009;<&#x2009;0.05). Univariate and multivariable models remarkably show that insulin resistance is higher both in overweight-LH: 3-6 vs overweight-LH: 0-2 (p&#x2009;<&#x2009;0.001) and in severe-obese-LH: 3-6 vs severe-obese-LH: 0-2 (p&#x2009;<&#x2009;0.0001), and HDL-C is lower in overweight-LH: 3-6 than overweight-LH: 0-2 (p&#x2009;<&#x2009;0.05 and p&#x2009;<&#x2009;001). Finally, most of the well-known (i.e., blood pressure, heart rate, waist to hip, triglycerides, and HDL-C) and novel CVD risk factors [i.e., inflammation markers (C-reactive protein, leukocytes, and chemoattractant protein-1), fibrinogen, and glucose homeostasis (i.e., insulin resistance, and glycated hemoglobin)] are substantially (p&#x2009;<&#x2009;0.0001) altered in severe-obese-LH: 0-2 vs overweight-LH: 0-2, pointing to the fact that obesity leads to worsen the CVD/T2D risk factor profile.<br><br>CONCLUSION: Our study supports evidence that CYP27A1 genetic characterization identifies persons at higher risk to develop CVD and T2D, on which better converge preventive measures, and opens new perspectives on mechanisms that link obesity with aging-related disorders.},
}
@article {pmid29950447,
year = {2018},
author = {Vedder, O and Verhulst, S and Zuidersma, E and Bouwhuis, S},
title = {Embryonic growth rate affects telomere attrition: an experiment in a wild bird.},
journal = {The Journal of experimental biology},
volume = {221},
number = {Pt 15},
pages = {},
doi = {10.1242/jeb.181586},
pmid = {29950447},
issn = {1477-9145},
mesh = {Animals ; Charadriiformes/*embryology ; Embryonic Development/*physiology ; Telomere ; *Telomere Shortening ; Temperature ; },
abstract = {High growth rate is associated with a short lifespan, but the physiological basis for this trade-off is not well known. Telomere length predicts individual lifespan and in this study we investigated whether embryonic growth rate, manipulated using incubation temperature, affects erythrocyte telomere length in a wild bird species, the common tern (Sterna hirundo). A 1°C lower incubation temperature decreased growth rate by 5%, without affecting size at hatching. The slower growth was associated with an average telomere length that was 147 base pairs longer at hatching. If carried through to adulthood, this effect would correspond with an approximately 3 year longer lifespan. Our results thus suggest that an effect of growth rate on lifespan may be mediated by telomere dynamics or a physiological process reflected by telomere length.},
}
@article {pmid29948614,
year = {2019},
author = {Mandal, P},
title = {Recent advances of Blood telomere length (BTL) shortening: A potential biomarker for development of cancer.},
journal = {Pathology oncology research : POR},
volume = {25},
number = {3},
pages = {1263-1265},
pmid = {29948614},
issn = {1532-2807},
mesh = {Cell Transformation, Neoplastic/*genetics/*pathology ; *Genomic Instability ; Humans ; Neoplasms/*genetics/*pathology ; Prognosis ; *Telomere Shortening ; },
abstract = {Telomeres, the specific DNA-protein structures remains at both ends of each chromosome and are crucial in the maintenance of chromosome integrity and genomic stability with protection of the chromosome from damage and degradation.. Increasing evidences suggest the correlation between telomere length and the development of cancers, but the findings remain obscure. Generally, the average length of telomere repeats at the ends of chromosomes that gives a clue in providing indirect information about their mitotic history. It plays immense role in preventing genome from nucleolytic degradation, unnecessary recombination, repair, and interchromosomal fusion. It has major role in storing the information in the genome. Telomere attrition during successive cell divisions induces chromosomal instability and contributes significantly to genomic rearrangements that can result in tumorigenesis. Convincing evidence documented that a meagre portion of telomeric DNA is expelled out during mitotic stage of cell division. But accelerated shortening telomere length at critical level triggers senescence and/or apoptosis. Various harmful agents with bad lifestyles are responsible in inducing shortening of telomere length with damage of DNA resulting to occurrence of disease with shortening of lifespan. Besides, telomerases, the specialized polymerase that synthesizes new telomere repeats and is strongly associated with cancer facilitating malignant transformation. Therefore, in the study, it is highlighted that the telomeres may play diverse roles in different cancers whereas shortening of telomere length may be risk factors for the development of tumors.},
}
@article {pmid29944903,
year = {2018},
author = {Martens, DS and Nawrot, TS},
title = {Ageing at the level of telomeres in association to residential landscape and air pollution at home and work: a review of the current evidence.},
journal = {Toxicology letters},
volume = {298},
number = {},
pages = {42-52},
doi = {10.1016/j.toxlet.2018.06.1213},
pmid = {29944903},
issn = {1879-3169},
mesh = {Age Factors ; Aging/*genetics ; Air Pollutants/*adverse effects ; Air Pollutants, Occupational/adverse effects ; Environmental Exposure/*adverse effects ; Genetic Markers ; Humans ; Inflammation/genetics ; *Job Description ; Life Style ; Occupational Exposure/adverse effects ; Occupational Health ; Oxidative Stress/genetics ; *Residence Characteristics ; Risk Assessment ; Telomere/*genetics ; Telomere Homeostasis ; Telomere Shortening ; },
abstract = {Studies suggest that leukocyte telomere length is an index of systemic ageing. Here, we discuss telomere length as a marker of biological ageing in relation to residential landscape (greenness), residential air pollution and work-related exposures. Telomere lengths are memories of cumulative oxidative and inflammatory stress, and show to have inverse associations with the risk of non-communicable diseases. For this reason, telomeres are considered as markers of biological ageing. Studies at birth, in children, young adulthood, and elderly show that residential green space, lower traffic exposure and long-term lower exposure to particulate air pollution are associated with longer telomeres. Work-related exposures including exposure to toxic metals, polycyclic aromatic hydrocarbons and particulate matter are associated with shorter telomeres for a given age. In contrast to chronic exposures, evidence is present of the observation that recent exposure is associated with longer telomeres. Our overview shows that the magnitude of residential and work-related environmental factors on telomere length are often as important as many classical lifestyle factors.},
}
@article {pmid29943516,
year = {2018},
author = {Zhang, N and Fan, C and Gong, M and Liang, X and Zhang, W and Li, G and Tse, G and Liu, T},
title = {Leucocyte telomere length and paroxysmal atrial fibrillation: A prospective cohort study and systematic review with meta-analysis.},
journal = {Journal of clinical laboratory analysis},
volume = {32},
number = {9},
pages = {e22599},
pmid = {29943516},
issn = {1098-2825},
support = {//Croucher Foundation of Hong Kong/ ; 81570298//National Natural Science Foundation of China/ ; 81270245//National Natural Science Foundation of China/ ; },
mesh = {Aged ; Atrial Fibrillation/*genetics/*pathology ; Cohort Studies ; Female ; Humans ; Leukocytes/chemistry/*pathology ; Male ; Middle Aged ; Sex Factors ; Statistics, Nonparametric ; Telomere/*genetics ; },
abstract = {BACKGROUND: Telomere length is a surrogate marker of biological aging. Whether telomere length predicts the risk of atrial fibrillation (AF) independently of biological aging is controversial. We conducted a cohort study to examine the relationship between telomere length and paroxysmal AF (PAF), followed by a systematic review and meta-analysis of the published literature, incorporating our own data.<br><br>METHODS: DNA was extracted from peripheral blood. Leucocyte telomere length was measured by a real-time polymerase chain reaction-based method, normalized to a single copy gene, and presented as telomere/single gene ratio (t/s).<br><br>RESULTS: A total of 100 non-AF patients and 50 PAF patients (mean age: 61.0&#xa0;&#xb1;&#xa0;9.4 and 64.0&#xa0;&#xb1;&#xa0;10.7&#xa0;years, respectively) were included. T/s for subjects without AF tended to be shorter than for those with AF (0.21 [0.06-0.36] vs 0.28 [0.11-0.71], P&#xa0;=&#xa0;.077). T/s was associated with a 1.60-fold increase in the risk of AF but this was not significant (95% CI: 0.988-2.597, P&#xa0;=&#xa0;.056). Our meta-analysis confirms no difference in telomere length between AF and non-AF patients and t/s was not associated with higher risk of AF in multivariate analysis.<br><br>CONCLUSIONS: Our prospective data showed that leucocyte telomere length was similar between AF and non-AF patients but was significantly longer in male patients with PAF than those without AF in our subgroup analysis. Our meta-analysis found that t/s did not predict AF. These findings support the notion that chronological aging, but not markers of biological aging, predicts the risk of AF.},
}
@article {pmid29941190,
year = {2018},
author = {Xu, Y},
title = {Recent progress in human telomere RNA structure and function.},
journal = {Bioorganic &amp; medicinal chemistry letters},
volume = {28},
number = {15},
pages = {2577-2584},
doi = {10.1016/j.bmcl.2018.06.021},
pmid = {29941190},
issn = {1464-3405},
mesh = {Circular Dichroism ; Crystallography, X-Ray ; DNA/*chemistry/*physiology ; *G-Quadruplexes ; Humans ; Magnetic Resonance Spectroscopy ; Nucleic Acid Hybridization ; RNA/*chemistry/*physiology ; Telomere/*genetics ; },
abstract = {Human telomeric DNA is transcribed into telomeric RNA in cells. Telomeric RNA performs the fundamental biological functions such as regulation and protection of chromosome ends. This digest highlights the human telomere RNA G-quadruplex structures, telomere RNA functions, G-quadruplex-binding small molecules, and future prospects.},
}
@article {pmid29939220,
year = {2019},
author = {},
title = {Erratum to: Minimal shortening of leukocyte telomere length across age groups in a cross-sectional study for carriers of a longevity-associated FOXO3 allele.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {74},
number = {2},
pages = {192},
doi = {10.1093/gerona/gly116},
pmid = {29939220},
issn = {1758-535X},
}
@article {pmid29936933,
year = {2018},
author = {Byun, MY and Cui, LH and Lee, H and Kim, WT},
title = {Telomere association of Oryza sativa telomere repeat-binding factor like 1 and its roles in telomere maintenance and development in rice, Oryza sativa L.},
journal = {BMB reports},
volume = {51},
number = {11},
pages = {578-583},
pmid = {29936933},
issn = {1976-670X},
mesh = {Amino Acid Sequence ; Cloning, Molecular ; Oryza/*genetics/*growth &amp; development ; Plant Development/genetics ; Plant Proteins/genetics/metabolism ; Plants, Genetically Modified ; Protein Binding ; Telomere/*metabolism ; *Telomere Homeostasis/genetics ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Telomeres are specialized nucleoprotein complexes that function to protect eukaryotic chromosomes from recombination and erosion. Several telomere binding proteins (TBPs) have been characterized in higher plants, but their detailed in vivo functions at the plant level are largely unknown. In this study, we identified and characterized OsTRFL1 (Oryza sativa Telomere Repeat-binding Factor Like 1) in rice, a monocot model crop. Although OsTRFL1 did not directly bind to telomere repeats (TTTAGGG)4 in vitro, it was associated with telomeric sequences in planta. OsTRFL1 interacted with rice TBPs, such as OsTRBF1 and RTBP1, in yeast and plant cells as well as in vitro. Thus, it seems likely that the association of OsTRFL1 with other TBPs enables OsTRFL1 to bind to telomeres indirectly. T-DNA inserted OsTRFL1 knock-out mutant rice plants displayed significantly longer telomeres (6-25 kb) than those (5-12 kb) in wild-type plants, indicating that OsTRFL1 is a negative factor for telomere lengthening. The reduced levels of OsTRFL1 caused serious developmental defects in both vegetative and reproductive organs of rice plants. These results suggest that OsTRFL1 is an essential factor for the proper maintenance of telomeres and normal development of rice. [BMB Reports 2018; 51(11): 578-583].},
}
@article {pmid29936725,
year = {2018},
author = {Eskandari, E and Hashemi, M and Naderi, M and Bahari, G and Safdari, V and Taheri, M},
title = {Leukocyte Telomere Length Shortening, hTERT Genetic Polymorphisms and Risk of Childhood Acute Lymphoblastic Leukemia.},
journal = {Asian Pacific journal of cancer prevention : APJCP},
volume = {19},
number = {6},
pages = {1515-1521},
pmid = {29936725},
issn = {2476-762X},
mesh = {Adolescent ; Biomarkers, Tumor/*genetics ; Case-Control Studies ; Child ; Child, Preschool ; Female ; Follow-Up Studies ; *Genetic Predisposition to Disease ; Genotype ; Humans ; Leukocytes/*pathology ; Male ; *Polymorphism, Single Nucleotide ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*etiology/pathology ; Prognosis ; Risk Factors ; Telomerase/*genetics ; *Telomere Shortening ; },
abstract = {Background: Telomeres are involved in chromosomal stability, cellular immortality and tumorigenesis. Human telomerase reverse transcriptase (TERT) is essential for the maintenance of telomere DNA length. Recently, a variable tandem-repeats polymorphism, MNS16A, located in the downstream region of the TERT gene, was reported to have an effect on TERT expression and telomerase activity. Previous studies have linked both relative telomere length (RTL) and TERT variants with cancer. Therefore, we evaluated associations between RTL, TERT gene polymorphisms (hTERT, rs2735940 C/T and MNS16A Ins/Del) and risk of childhood acute lymphoblastic leukemia (ALL) in an Iranian population. Methods: RTL was determined by a multiplex quantitative PCR-based method, and variants of the hTERT, rs2735940 C/T and MNS16A Ins/Del, were genotyped by amplification refractory mutation system PCR (ARMS-PCR), and PCR, respectively. Results: Our results indicated that RTL was shorter in ALL patients (1.53±0.12) compared to the control group (2.04±0.19) (P=0.029). However, no associations between hTERT gene variants or haplotypes and the risk of childhood ALL were observed (P>0.05). Also hTERT polymorphisms were not associated with RTL or patient clinicopathological characteristics, including age (P=0.304), sex (P=0.061) organomegally (P=0.212) CSF involvement (P=0.966) or response to treatment (P=0.58). Conclusions: We found that telomere attrition may be related to the pathogenesis of childhood ALL, irrespective to TERT variants.},
}
@article {pmid29935763,
year = {2018},
author = {Zhdanov, DD and Gladilina, YA and Pokrovsky, VS and Grishin, DV and Grachev, VA and Orlova, VS and Pokrovskaya, MV and Alexandrova, SS and Sokolov, NN},
title = {Murine regulatory T cells induce death of effector T, B, and NK lymphocytes through a contact-independent mechanism involving telomerase suppression and telomere-associated senescence.},
journal = {Cellular immunology},
volume = {331},
number = {},
pages = {146-160},
doi = {10.1016/j.cellimm.2018.06.008},
pmid = {29935763},
issn = {1090-2163},
mesh = {Alternative Splicing ; Animals ; Apoptosis/*immunology ; B-Lymphocytes/*immunology/metabolism ; Cell Communication/immunology ; Cell Survival/genetics/immunology ; Cells, Cultured ; Cellular Senescence/genetics/immunology ; Female ; Killer Cells, Natural/*immunology/metabolism ; Mice, Inbred C57BL ; T-Lymphocyte Subsets/*immunology/metabolism ; T-Lymphocytes, Regulatory/*immunology/metabolism ; Telomerase/genetics/immunology/metabolism ; Telomere/genetics/immunology/metabolism ; },
abstract = {Regulatory T cells (Tregs) suppress the activity of effector T, B and NK lymphocytes and sustain immunological tolerance, but the proliferative activity of suppressed cells remains unexplored. In the present study, we report that mouse Tregs can induce replicative senescence and the death of responder mouse CD4[+]CD25[-] T cells, CD8[+] T cells, B cells and NK cells in vitro and in vivo. Contact-independent in vitro co-cultivation with Tregs up-regulated endonuclease G (EndoG) expression and its translocation to the nucleus in responder cells. EndoG localization in the nucleus induced alternative mRNA splicing of the telomerase catalytic subunit Tert and telomerase inhibition. The lack of telomerase activity in proliferating cells led to telomere loss followed by the development of senescence and cell death. Injection of Tregs into mice resulted in EndoG-associated alternative splicing of Tert, telomerase inhibition, telomere loss, senescence development and increased cell death in vivo. The present study describes a novel contact-independent mechanism by which Tregs specify effector cell fate and provides new insights into cellular crosstalk related to immune suppression.},
}
@article {pmid29934676,
year = {2018},
author = {Kumar, M and Kaushik, M and Kukreti, S},
title = {A topological transition from bimolecular quadruplex to G-triplex/tri-G-quadruplex exhibited by truncated double repeats of human telomere.},
journal = {European biophysics journal : EBJ},
volume = {47},
number = {8},
pages = {903-915},
pmid = {29934676},
issn = {1432-1017},
mesh = {Base Sequence ; Computational Biology ; *G-Quadruplexes ; Humans ; *Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry/*genetics ; Temperature ; },
abstract = {Human telomeric G-rich sequences can fold back into various conformations depending upon the salt (Na[+] or K[+]) at physiological pH. On the basis of results obtained by native PAGE electrophoresis, circular dichroism, and UV-melting experiments, we report here that truncated sequences of human telomere (d-GGGTTAGGG; GM9, d-AGGGTTAGGG; GM10, d-TAGGGTTAGGG; GM11) adopt a varied range of quadruplex conformations as a function of the cation present. By correlating CD and gel electrophoresis experiments; it was concluded that the GM9 oligonucleotide can self-associate to form a tetramer quadruplex (antiparallel; AP) in Na[+] solution and a mixture of G-triplex (AP) or tri-G-quadruplex (parallel; P) along with a tetramer G-quadruplex structure (AP) in K[+]. The GM10 oligonucleotide formed a bimolecular G-quadruplex in both Na[+] and K[+] solutions, while GM11 associated to form a bimolecular G-quadruplex (AP) structure in Na[+] solution and a mixture of bimolecular G-quadruplex (AP) and bimolecular G-quadruplex (P) along with parallel G-triplex or antiparallel tri-G-quadruplex in K[+]. All the UV-melting profiles, thermal difference spectra, and CD melting curves suggested the formation of a variety of G-quadruplex conformations by the DNA sequences studied in Na[+] and K[+] ions. Hypothetical models for different conformations adopted by these DNA molecules have also been proposed, which may further enhance our knowledge about the divergent topologies of guanine quadruplexes.},
}
@article {pmid29931032,
year = {2018},
author = {Tesovnik, T and Kovac, J and Hovnik, T and Dovc, K and Bratina, N and Battelino, T and Trebušak Podkrajšek, K},
title = {Association of Glycemic Control and Cell Stress With Telomere Attrition in Type 1 Diabetes.},
journal = {JAMA pediatrics},
volume = {172},
number = {9},
pages = {879-881},
pmid = {29931032},
issn = {2168-6211},
mesh = {Adolescent ; Blood Glucose/*metabolism ; Diabetes Mellitus, Type 1/*metabolism ; Female ; Humans ; Male ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {This longitudinal study evaluates the association of glycemic control and associated cell stress with the telomere dynamics in a pediatric population with type 1 diabetes during a 7-year follow-up.},
}
@article {pmid29930757,
year = {2018},
author = {Bernal, A and Moltó-Abad, M and Domínguez, D and Tusell, L},
title = {Acute telomere deprotection prevents ongoing BFB cycles and rampant instability in p16[INK4a]-deficient epithelial cells.},
journal = {Oncotarget},
volume = {9},
number = {43},
pages = {27151-27170},
pmid = {29930757},
issn = {1949-2553},
abstract = {Telomere dysfunction drives chromosome instability through endless breakage-fusion-bridge (BFB) cycles that promote the formation of highly rearranged genomes. However, reactivation of telomerase or ALT-pathway is required for genome stabilisation and full malignant transformation. To allow the unrestricted proliferation of cells at risk of transformation, we have established a conditional system of telomere deprotection in p16[INK4a]-deficient MCF-10A cells with modified checkpoints. After sustained expression of a dominant negative form of the shelterin protein TRF2 (TRF2[ΔBΔM]), cells with telomere fusion did progress to anaphase but no signs of ongoing BFB cycles were observed, thus anticipating proliferation defects. Indeed, 96 h TRF2[ΔBΔM] expression resulted in noticeable growth proliferation defects in the absence of cell cycle disturbances. Further transient periods of 96 h telomere uncapping did not result in cell cycle disturbances either. And reduction of the telomere damage to short acute deprotection periods did not in any case engender cells with a reorganised karyotype. Strikingly, the growth arrest imposed in cells showing dysfunctional telomeres was not accompanied by an activation of the DNA damage response at cellular level, or by the presence of visible markers of senescence or apoptosis. We propose that the deprotection of many telomeres simultaneously, even for a short time, results in a local activation of the cellular stress response which consequently triggers gradual cell withdrawal from cell cycle, restraining the onset of genomic instability.},
}
@article {pmid29929132,
year = {2018},
author = {Ding, M and Yang, Y and Duan, X and Wang, S and Feng, X and Wang, T and Wang, P and Liu, S and Li, L and Liu, J and Tang, L and Niu, X and Zhang, Y and Li, G and Yao, W and Cui, L and Wang, W},
title = {Association of genetic polymorphisms of telomere binding proteins with cholinesterase activity in omethoate-exposed workers.},
journal = {Ecotoxicology and environmental safety},
volume = {161},
number = {},
pages = {563-568},
doi = {10.1016/j.ecoenv.2018.06.036},
pmid = {29929132},
issn = {1090-2414},
mesh = {Adult ; Air Pollutants, Occupational/*toxicity ; China ; Cholinesterases/*blood ; Dimethoate/*analogs &amp; derivatives/toxicity ; Erythrocytes/enzymology ; Genotype ; Humans ; Occupational Exposure/adverse effects/*analysis ; Polymerase Chain Reaction/methods ; *Polymorphism, Genetic ; Polymorphism, Restriction Fragment Length ; Telomere-Binding Proteins/*genetics ; Young Adult ; },
abstract = {Omethoate, an organophosphorous pesticide, can cause a variety of health effects, especially the decrease of cholinesterase activity. The aim of this study is to explore the association of genetic polymorphisms of telomere binding proteins with cholinesterase activity in omethoate-exposed population. Cholinesterase activities in whole blood, red blood cell and plasma were detected using acetylthiocholine and dithio-bis-(nitrobenzoic acid) method; Genetic Genotyping of POT1 rs1034794, POT1 rs10250202, TERF1 rs3863242 and TERT rs2736098 were performed with PCR-RFLP. The cholinesterase activities of whole blood, red blood cells and plasma in exposure group are significantly lower than that of the control group (P < 0.001). Multivariate analysis indicates that exposure group (b = - 1.016, P < 0.001), agender (b = 0.365, P < 0.001), drinking (b = 0.271, P = 0.004) and TERF1rs3863242 (b = - 0.368, P = 0.016) had an impact on cholinesterase activities. The results suggest that individual carrying AG+GG genotypes in TERF1 gene rs3863242 polymorphism were susceptible to damage in cholinesterase induced by omethoate.},
}
@article {pmid29925920,
year = {2018},
author = {Liu, YY and Shi, Y and Liu, Y and Pan, XH and Zhang, KX},
title = {Telomere shortening activates TGF-β/Smads signaling in lungs and enhances both lipopolysaccharide and bleomycin-induced pulmonary fibrosis.},
journal = {Acta pharmacologica Sinica},
volume = {39},
number = {11},
pages = {1735-1745},
pmid = {29925920},
issn = {1745-7254},
mesh = {Acute Lung Injury/physiopathology ; Animals ; Apoptosis/drug effects ; Bleomycin/adverse effects ; Female ; Idiopathic Pulmonary Fibrosis/chemically induced/*physiopathology ; Interleukin-6/metabolism ; Lipopolysaccharides/adverse effects ; Lung/metabolism/pathology/*physiopathology ; Male ; Mice ; NF-kappa B/metabolism ; Neutrophil Infiltration/drug effects ; Signal Transduction/physiology ; Smad Proteins/*metabolism ; Telomere Shortening/*physiology ; Transforming Growth Factor beta/*metabolism ; },
abstract = {Telomere shortening is associated with idiopathic pulmonary fibrosis (IPF), a high-morbidity and high-mortality lung disease of unknown etiology. However, the underlying mechanisms remain largely unclear. In this study, wild-type (WT) mice with normal telomeres and generation 3 (G3) or G2 telomerase RNA component (TERC) knockout Terc[-][/-] mice with short telomeres were treated with and without lipopolysaccharide (LPS) or bleomycin by intratracheal injection. We show that under LPS induction, G3 Terc[-][/-] mice develop aggravated pulmonary fibrosis as indicated by significantly increased α-SMA, collagen I and hydroxyproline content. Interestingly, TGF-β/Smads signaling is markedly activated in the lungs of G3 Terc[-][/-] mice, as indicated by markedly elevated levels of phosphorylated Smad3 and TGF-β1, compared with those of WT mice. This TGF-β/Smads signaling activation is significantly increased in the lungs of LPS-treated G3 Terc[-][/-] mice compared with those of LPS-treated WT or untreated G3 Terc[-][/-] mice. A similar pattern of TGF-β/Smads signaling activation and the enhancing role of telomere shortening in pulmonary fibrosis are also confirmed in bleomycin-induced model. Moreover, LPS challenge produced more present cellular senescence, apoptosis and infiltration of innate immune cells, including macrophages and neutrophils in the lungs of G3 Terc[-][/-] mice, compared with WT mice. To our knowledge, this is the first time to report telomere shortening activated TGF-β/Smads signaling in lungs. Our data suggest that telomere shortening cooperated with environment-induced lung injury accelerates the development of pulmonary fibrosis, and telomere shortening confers an inherent enhancing factor to the genesis of IPF through activation of TGF-β/Smads signaling.},
}
@article {pmid29925891,
year = {2018},
author = {Boeck, C and Salinas-Manrique, J and Calzia, E and Radermacher, P and von Arnim, CAF and Dietrich, DE and Kolassa, IT and Karabatsiakis, A},
title = {Targeting the association between telomere length and immuno-cellular bioenergetics in female patients with Major Depressive Disorder.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {9419},
pmid = {29925891},
issn = {2045-2322},
mesh = {Aged ; Depressive Disorder, Major/genetics/*metabolism ; Energy Metabolism/genetics/physiology ; Exercise/physiology ; Female ; Humans ; Leukocytes, Mononuclear/metabolism ; Middle Aged ; Socioeconomic Factors ; T-Lymphocyte Subsets/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Major Depressive Disorder (MDD) has been associated with telomere dysfunction and alterations in mitochondrial activity, which seem to be co-regulated in human cells. To investigate this co-regulation in MDD, we assessed telomere length (TL) in peripheral blood mononuclear cells (PBMC) and selected immune cell subsets by quantitative fluorescence in situ hybridization and mitochondrial respiratory activity in PBMC by high-resolution respirometry in a study cohort of 18 MDD patients and 21 non-depressed controls. We provide initial evidence for a differential vulnerability to telomere attrition in selected adaptive immune cell populations. Here we found the highest difference in TL between depressed and control subjects for memory cytotoxic T cells. Depression was associated with reduced mitochondrial activity (mitochondrial bioenergetics), but increased mitochondrial density (mitochondrial biogenesis) in PBMC. Exploratory post-hoc analyses indicated that the changes in TL and immune cell bioenergetics were most pronounced in MDD patients who reported experiences of childhood sexual abuse. Among MDD patients, PBMC TL was as a trend positively associated with mitochondrial density and negatively associated with mitochondrial leak respiration, but not with mitochondrial activity related to biological energy production. These initial findings support the hypothesis of a co-regulation between telomeres and mitochondrial biogenesis but not mitochondrial bioenergetics among MDD patients.},
}
@article {pmid29924435,
year = {2019},
author = {Liu, Y and Bloom, SI and Donato, AJ},
title = {The role of senescence, telomere dysfunction and shelterin in vascular aging.},
journal = {Microcirculation (New York, N.Y. : 1994)},
volume = {26},
number = {2},
pages = {e12487},
pmid = {29924435},
issn = {1549-8719},
support = {K02 AG045339/AG/NIA NIH HHS/United States ; R01 AG050238/AG/NIA NIH HHS/United States ; R44 AG053131/AG/NIA NIH HHS/United States ; T32 HL139451/HL/NHLBI NIH HHS/United States ; },
mesh = {*Aging ; Animals ; Blood Vessels/*physiology ; Cardiovascular Diseases/etiology ; Cellular Senescence/*physiology ; Humans ; Inflammation ; Oxidative Stress ; Shelterin Complex ; Telomere/*pathology ; Telomere-Binding Proteins/*physiology ; },
abstract = {In the United States and other westernized nations, CVDs are the leading cause of death in adults over 65 years of age. Large artery stiffness and endothelial dysfunction are increased with age and age-associated arterial dysfunction is an important antecedent of CVDs. One age-associated change that may contribute to vascular dysfunction and CVD risk is an increase in the number of resident senescent cells in the vasculature. Senescent cells display a pro-oxidant, pro-inflammatory phenotype known as the SASP. However, the mechanisms that drive the SASP and the vascular aging phenotype remain elusive. A putative mechanism is the involvement of oxidative stress and inflammation in telomere function. Telomeres are the end caps of chromosomes which are maintained by a six-protein complex known as shelterin. Disruption of shelterin can uncap telomeres and induce cellular senescence. Accordingly, in this review, we propose that oxidative stress and inflammation disrupt shelterin in vascular cells, driving telomere dysfunction and that this mechanism may be responsible for the induction of SASP. The proposed mechanisms may represent some of the initial changes that lead to vascular dysfunction in advanced age.},
}
@article {pmid29920523,
year = {2018},
author = {Pusceddu, I and Kleber, M and Delgado, G and Herrmann, W and März, W and Herrmann, M},
title = {Telomere length and mortality in the Ludwigshafen Risk and Cardiovascular Health study.},
journal = {PloS one},
volume = {13},
number = {6},
pages = {e0198373},
pmid = {29920523},
issn = {1932-6203},
mesh = {Age Factors ; Aged ; Cardiovascular Diseases/*diagnostic imaging/genetics/*mortality ; Case-Control Studies ; Cause of Death ; Coronary Angiography ; Female ; Germany ; Hospitalization ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Proportional Hazards Models ; *Telomere Shortening ; },
abstract = {INTRODUCTION: Short telomeres have been associated with adverse lifestyle factors, cardiovascular risk factors and age-related diseases, including cardiovascular disease (CVD), myocardial infarction, atherosclerosis, hypertension, diabetes, and also with mortality. However, previous studies report conflicting results.<br><br>OBJECTIVES: The aim of the present study has been to investigate the involvement of telomere length in all-cause and CVD mortality in subjects hospitalized for diagnostic coronary angiography of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.<br><br>METHODS: Relative telomere length (RTL) was measured with a Q-PCR based method in 3,316 participants of the LURIC study. Age-corrected RTL was calculated as the ratio between RTL and age. Median follow-up was 9.9 years. Cox regression and Kaplan-Maier analyses were performed to evaluate the role of RTL for all-cause and cardiovascular mortality.<br><br>RESULTS: RTL correlated negatively with age (r = -0.09; p<0.001). In surviving patients the correlation between age and RTL was statistically significant (r = -0.088; p<0.001), but not in patients who died during follow-up (r = -0.043; p = 0.20). Patients in quartiles 2-4 of RTL had a lower hazard ratio for all-cause mortality (HR:0.822; 95%CI 0.712-0.915; p = 0.008) and CVD-mortality (HR:0.836; 95%CI 0.722-0.969; p = 0.017) when compared to those in the 1st quartile. Adjustment for major cardiovascular risk factors did not change this result, however additional adjustment for age attenuated this effect. Patients in the 4th quartile of age-corrected RTL compared to those in the 1st quartile had a lower hazard ratio for all-cause mortality, even with adjustment for major cardiovascular risk factors.<br><br>CONCLUSIONS: The present study supports the hypothesis that short telomere length increases the risk of all-cause and CVD mortality. Age appears to be an important co-variate that explains a substantial fraction of this effect. It remains unclear whether short telomeres contribute directly to the increase in mortality or if they are simply a surrogate marker for other adverse processes of aging.},
}
@article {pmid29912474,
year = {2018},
author = {Côté, HCF and Hsieh, AYY},
title = {Leukocyte Telomere Length in HIV Infection: A Marker of Persistent Immune Aging or Transient Immune Reconstitution?.},
journal = {The Journal of infectious diseases},
volume = {218},
number = {10},
pages = {1521-1522},
doi = {10.1093/infdis/jiy365},
pmid = {29912474},
issn = {1537-6613},
mesh = {Adult ; HIV ; Humans ; *Immune Reconstitution ; Leukocytes ; Prospective Studies ; *Reverse Transcriptase Inhibitors ; Telomere ; },
}
@article {pmid29912427,
year = {2018},
author = {Montejano, R and Stella-Ascariz, N and Monge, S and Bernardino, JI and Pérez-Valero, I and Montes, ML and Valencia, E and Martín-Carbonero, L and Moreno, V and González-Garcia, J and Rodriguez-Centeno, J and Rodes, B and Cantos, AE and Alejos, B and de Miguel, R and Arnalich, F and Perona, R and Arribas, JR},
title = {Impact of Nucleos(t)ide Reverse Transcriptase Inhibitors on Blood Telomere Length Changes in a Prospective Cohort of Aviremic HIV-Infected Adults.},
journal = {The Journal of infectious diseases},
volume = {218},
number = {10},
pages = {1531-1540},
doi = {10.1093/infdis/jiy364},
pmid = {29912427},
issn = {1537-6613},
mesh = {Adult ; Dideoxynucleosides/pharmacology/therapeutic use ; Female ; *HIV Infections/drug therapy/genetics/virology ; Humans ; Male ; Middle Aged ; Prospective Studies ; RNA, Viral/blood ; *Reverse Transcriptase Inhibitors/pharmacology/therapeutic use ; Telomerase ; Telomere/*drug effects ; Tenofovir/pharmacology/therapeutic use ; Viral Load ; },
abstract = {BACKGROUND: Tenofovir is a potent inhibitor of human telomerase. The clinical relevance of this inhibition is unknown.<br><br>METHODS: A prospective cohort of human immunodeficiency virus (HIV)-infected participants with suppressed virological replication was recruited to compare whole-blood telomere length (measured by quantitative multiplex polymerase chain reaction analysis) in participants with current exposure to tenofovir disoproxil fumarate (TDF) to that in participants never exposed to TDF.<br><br>RESULTS: A total of 172 participants were included: 67 were in the TDF group, and 105 were in the non-TDF group (75 were receiving 2 nucleosides [of whom 69 were receiving abacavir], 25 were receiving a nucleos[t]ide reverse transcriptase inhibitor [N{t}
RTI]-sparing regimen, and 5 were receiving lamivudine as the only nucleoside). After 2 years, the mean blood telomere length increased significantly in the whole cohort. The TDF group had significantly smaller gains in telomere length than the non-TDF group. In the analysis restricted to participants receiving N(t)RTIs, TDF exposure was not associated with an independent negative effect. In the non-TDF group, participants treated with 2 nucleosides also had significantly smaller gains in telomere length than those receiving N(t)RTI-sparing regimens or lamivudine as the only nucleoside.<br><br>DISCUSSION: In HIV-infected adults with prolonged virological suppression, treatment with TDF or abacavir was associated with smaller gains in blood telomere length after 2 years of follow-up.},
}
@article {pmid29912268,
year = {2018},
author = {Leung, CW and Fung, TT and McEvoy, CT and Lin, J and Epel, ES},
title = {Diet Quality Indices and Leukocyte Telomere Length Among Healthy US Adults: Data From the National Health and Nutrition Examination Survey, 1999-2002.},
journal = {American journal of epidemiology},
volume = {187},
number = {10},
pages = {2192-2201},
pmid = {29912268},
issn = {1476-6256},
support = {K99 HD084758/HD/NICHD NIH HHS/United States ; R01 AG033592/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging/genetics ; Chronic Disease/*epidemiology ; Diet/adverse effects ; Diet, Healthy/*statistics &amp; numerical data ; Female ; Healthy Volunteers ; Humans ; Leukocytes/cytology ; Longevity/genetics ; Male ; Middle Aged ; Nutrition Surveys ; Nutritional Status ; Risk Factors ; Telomere/*genetics ; United States/epidemiology ; Young Adult ; },
abstract = {Aging is the biggest risk factor for the development of chronic diseases. Telomere length may represent one important mechanism by which dietary intake influences risk of age-related diseases; however, it is unknown which diet pattern is most strongly related to telomere length. We compared the relationships between 4 evidence-based diet quality indices and leukocyte telomere length in a nationally representative sample of healthy adults, and the extent to which these associations differed between men and women. Data on 4,758 adults aged 20-65 years with no prior diagnosis of major chronic disease were obtained from the 1999-2002 cycles of the National Health and Nutrition Examination Survey. Diet was assessed using one 24-hour dietary recall. After adjustment for sociodemographic and health characteristics, comparison of the top and bottom quintiles showed that higher Healthy Eating Index 2010 scores (β = 0.065, 95% confidence interval (CI): 0.018, 0.112; P-trend = 0.007), Alternate Healthy Eating Index 2010 scores (β = 0.054, 95% CI: 0.010, 0.097; P-trend = 0.007), Mediterranean Diet scores (β = 0.058, 95% CI: 0.017, 0.098; P-trend = 0.008), and Dietary Approaches to Stop Hypertension (DASH) scores (β = 0.052, 95% CI: 0.014, 0.090; P-trend = 0.007) were each associated with longer telomere length in women. These results may provide insight into the complex associations between optimal nutrition and longevity. Further investigation is needed to understand why associations were not observed in men.},
}
@article {pmid29910124,
year = {2018},
author = {Liu, Q and Wang, G and Lyu, Y and Bai, M and Jiapaer, Z and Jia, W and Han, T and Weng, R and Yang, Y and Yu, Y and Kang, J},
title = {The miR-590/Acvr2a/Terf1 Axis Regulates Telomere Elongation and Pluripotency of Mouse iPSCs.},
journal = {Stem cell reports},
volume = {11},
number = {1},
pages = {88-101},
pmid = {29910124},
issn = {2213-6711},
mesh = {Activin Receptors, Type II/genetics/metabolism ; Animals ; Cell Differentiation/genetics ; Cell Line ; Cell Self Renewal/genetics ; *Gene Expression Regulation, Developmental ; Induced Pluripotent Stem Cells/*cytology/*metabolism ; Mice ; MicroRNAs/genetics ; RNA Interference ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; },
abstract = {During reprogramming, telomere re-elongation is important for pluripotency acquisition and ensures the high quality of induced pluripotent stem cells (iPSCs), but the regulatory mechanism remains largely unknown. Our study showed that fully reprogrammed mature iPSCs or mouse embryonic stem cells expressed higher levels of miR-590-3p and miR-590-5p than pre-iPSCs. Ectopic expression of either miR-590-3p or miR-590-5p in pre-iPSCs improved telomere elongation and pluripotency. Activin receptor II A (Acvr2a) is the downstream target and mediates the function of miR-590. Downregulation of Acvr2a promoted telomere elongation and pluripotency. Overexpression of miR-590 or inhibition of ACTIVIN signaling increased telomeric repeat binding factor 1 (Terf1) expression. The p-SMAD2 showed increased binding to the Terf1 promoter in pre-iPSCs compared with mature iPSCs. Downregulation of Terf1 blocked miR-590- or shAcvr2a-mediated promotion of telomere elongation and pluripotency in pre-iPSCs. This study elucidated the role of the miR-590/Acvr2a/Terf1 signaling pathway in modulating telomere elongation and pluripotency in pre-iPSCs.},
}
@article {pmid29909006,
year = {2018},
author = {Wang, H and Ni, J and Guo, X and Zhou, T and Ma, X and Xue, J and Wang, X},
title = {Shelterin differentially respond to oxidative stress induced by TiO2-NPs and regulate telomere length in human hepatocytes and hepatocarcinoma cells in vitro.},
journal = {Biochemical and biophysical research communications},
volume = {503},
number = {2},
pages = {697-702},
doi = {10.1016/j.bbrc.2018.06.063},
pmid = {29909006},
issn = {1090-2104},
mesh = {Cell Line ; Cell Line, Tumor ; Chromosomal Instability ; Down-Regulation ; Hepatocytes/*metabolism/pathology ; Humans ; Liver Neoplasms/genetics/*metabolism/pathology ; Nanoparticles/*adverse effects ; *Oxidative Stress ; Shelterin Complex ; Telomere/*metabolism/pathology ; Telomere Shortening ; Telomere-Binding Proteins/genetics/*metabolism ; Titanium/*adverse effects ; Up-Regulation ; },
abstract = {Titanium dioxide nanoparticles (TiO2-NPs) have raised serious attention for their widely use and potential adverse effects on human mainly due to producing ROS. However, the influence of TiO2-NPs on telomere maintaining has not been studied clearly. Shelterin plays core roles in telomere length (TL) regulation. Abnormal TL are associated with chromosome instability (CIN) and high risk of diseases. This study investigated whether TiO2-NPs affect TL to induce CIN through ROS generation and the possible mechanisms. Human hepatocyte L-02 and hepatocarcinoma cells QGY were exposed to TiO2-NPs (0, 40, 80 μg/mL) for 72 h. The intracellular hydrogen dioxide (H2O2) concentration were measured. The TL, Nrf-2, and three core shelterin components (TRF1, TRF2, and POT1) transcription level were determined by quantitative real-time PCR. CIN was measured by cytokinesis-block micronucleus assay. TiO2-NPs exposure increased intracellular H2O2 in both L-02 and QGY cells, and induced Nrf-2, TRF1, TRF2, POT1 downregulated transcription compared with control (P < 0.001) in L-02 but all upregulated (P < 0.05) in QGY. Significant TL shortening (P < 0.001) and CIN increase (P < 0.01) in L-02 cells were observed but not in QGY cells. The differentially responses of the tested components of shelterin and Nrf-2 to oxidative stress induced by TiO2-NPs led to the weakened telomere protection in normal cells and effective telomere maintenance in cancer cells, respectively. The upregulation of Nrf-2 and shelterin could protect TL and chromosome stability against TiO2-NPs exposure.},
}
@article {pmid29908233,
year = {2018},
author = {Lopez-Doriga, A and Valle, L and Alonso, MH and Aussó, S and Closa, A and Sanjuan, X and Barquero, D and Rodríguez-Moranta, F and Sanz-Pamplona, R and Moreno, V},
title = {Telomere length alterations in microsatellite stable colorectal cancer and association with the immune response.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {1864},
number = {9 Pt B},
pages = {2992-3000},
doi = {10.1016/j.bbadis.2018.06.010},
pmid = {29908233},
issn = {0925-4439},
mesh = {Adult ; Aged ; Aged, 80 and over ; Chromosomal Instability/genetics ; Colon/immunology/pathology ; Colonic Neoplasms/*genetics/immunology/pathology ; DNA Copy Number Variations/immunology ; Datasets as Topic ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/genetics/immunology ; Humans ; Intestinal Mucosa/immunology/pathology ; Male ; Microsatellite Repeats/genetics ; Middle Aged ; Signal Transduction/genetics/immunology ; Telomere/*genetics ; Telomere Shortening/*genetics/immunology ; Exome Sequencing ; },
abstract = {Telomeres are repetitive sequences (TTAGGG) located at the end of chromosomes. Telomeres progressively shorten with each cell replication cycle, ultimately leading to chromosomal instability and loss of cell viability. Telomere length anomaly appears to be one of the earliest and most prevalent genetic alterations in malignant transformation. Here we aim to estimate telomere length from whole-exome sequencing data in colon tumors and normal colonic mucosa, and to analyze the potential association of telomere length with clinical factors and gene expression in colon cancer. Reads containing at least five repetitions of the telomere sequence (TTAGGG) were extracted from the raw sequences of 42 adjacent normal-tumor paired samples. The number of reads from the tumor sample was normalized to build the Tumor Telomere Length Ratio (TTLR), considered an estimation of telomere length change in the tumor compared to the paired normal tissue. We evaluated the associations between TTLR and clinical factors, gene expression and copy number (CN) aberrations measured in the same tumor samples. Colon tumors showed significantly shorter telomeres than their paired normal samples. No significant association was observed between TTLR and gender, age, tumor location, prognosis, stromal infiltration or molecular subtypes. The functional gene set enrichment analysis showed pathways related to immune response significantly associated with TLLR. By extracting a relative measure of telomere length from whole-exome sequencing data, we have assessed that colon tumor cells predominantly shorten telomeres, and this alteration is associated with expression changes in genes related to immune response and inflammation in tumor cells.},
}
@article {pmid29899134,
year = {2018},
author = {Bouwhuis, S and Verhulst, S and Bauch, C and Vedder, O},
title = {Reduced telomere length in offspring of old fathers in a long-lived seabird.},
journal = {Biology letters},
volume = {14},
number = {6},
pages = {},
pmid = {29899134},
issn = {1744-957X},
mesh = {*Aging ; Animals ; Charadriiformes/*physiology ; DNA/blood ; Female ; Male ; Reproduction ; *Telomere Shortening ; },
abstract = {Evidence for transgenerational effects of senescence, whereby offspring from older parents have a reduced lifetime reproductive success, is increasing. Such effects could arise from compromised germline maintenance in old parents, potentially reflected in reduced telomere length in their offspring. We test the relationship between parental age and offspring early-life telomere length in a natural population of common terns and find a significant negative correlation between paternal age and offspring telomere length. Offspring telomere length is reduced by 35 base pairs for each additional year of paternal age. We find no correlation with maternal age. These results fit with the idea of compromised germline maintenance in males, whose germline stem cells require continued division.},
}
@article {pmid29895583,
year = {2018},
author = {Joyce, BT and Zheng, Y and Nannini, D and Zhang, Z and Liu, L and Gao, T and Kocherginsky, M and Murphy, R and Yang, H and Achenbach, CJ and Roberts, LR and Hoxha, M and Shen, J and Vokonas, P and Schwartz, J and Baccarelli, A and Hou, L},
title = {DNA Methylation of Telomere-Related Genes and Cancer Risk.},
journal = {Cancer prevention research (Philadelphia, Pa.)},
volume = {11},
number = {8},
pages = {511-522},
pmid = {29895583},
issn = {1940-6215},
support = {R01 ES015172/ES/NIEHS NIH HHS/United States ; R01 ES025225/ES/NIEHS NIH HHS/United States ; D43 TW009575/TW/FIC NIH HHS/United States ; U54 CA221205/CA/NCI NIH HHS/United States ; R01 CA207468/CA/NCI NIH HHS/United States ; P30 AI117943/AI/NIAID NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; P30 ES000002/ES/NIEHS NIH HHS/United States ; R01 ES021733/ES/NIEHS NIH HHS/United States ; },
mesh = {Aged ; Aging/genetics ; Carcinogenesis/*genetics ; Cell Cycle Proteins/genetics ; CpG Islands/genetics ; Cross-Sectional Studies ; DNA Helicases/genetics/metabolism ; *DNA Methylation ; Female ; Humans ; Incidence ; Leukocytes/*metabolism ; Longitudinal Studies ; Male ; Middle Aged ; Neoplasms/blood/epidemiology/*genetics ; Nuclear Proteins/genetics ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Telomere Shortening/genetics ; Telomere-Binding Proteins/genetics/metabolism ; United States/epidemiology ; United States Department of Veterans Affairs/statistics &amp; numerical data ; },
abstract = {Researchers hypothesized that telomere shortening facilitates carcinogenesis. Previous studies found inconsistent associations between blood leukocyte telomere length (LTL) and cancer. Epigenetic reprogramming of telomere maintenance mechanisms may help explain this inconsistency. We examined associations between DNA methylation in telomere-related genes (TRG) and cancer. We analyzed 475 participants providing 889 samples 1 to 3 times (median follow-up, 10.1 years) from 1999 to 2013 in the Normative Aging Study. All participants were cancer-free at each visit and blood leukocytes profiled using the Illumina 450K array. Of 121 participants who developed cancer, 34 had prostate cancer, 10 melanoma, 34 unknown skin malignancies, and 43 another cancer. We examined 2,651 CpGs from 80 TRGs and applied a combination of Cox and mixed models to identify CpGs prospectively associated with cancer (at FDR < 0.05). We also explored trajectories of DNA methylation, logistic regression stratified by time to diagnosis/censoring, and cross-sectional models of LTL at first blood draw. We identified 30 CpGs on 23 TRGs whose methylation was positively associated with cancer incidence (β = 1.0-6.93) and one protective CpG in MAD1L1 (β = -0.65), of which 87% were located in TRG promoters. Methylation trajectories of 21 CpGs increased in cancer cases relative to controls; at 4 to 8 years prediagnosis/censoring, 17 CpGs were positively associated with cancer. Three CpGs were cross-sectionally associated with LTL. TRG methylation may be a mechanism through which LTL dynamics reflect cancer risk. Future research should confirm these findings and explore potential mechanisms underlying these findings, including telomere maintenance and DNA repair dysfunction. Cancer Prev Res; 11(8); 511-22. ©2018 AACR.},
}
@article {pmid29895291,
year = {2018},
author = {Xu, S and Vucic, EA and Shaipanich, T and Lam, S and Lam, W and Montaner, JS and Sin, DD and Paul Man, SF and Leung, JM},
title = {Decreased telomere length in the small airway epithelium suggests accelerated aging in the lungs of persons living with human immunodeficiency virus (HIV).},
journal = {Respiratory research},
volume = {19},
number = {1},
pages = {117},
pmid = {29895291},
issn = {1465-993X},
support = {//CIHR/Canada ; },
mesh = {Aged ; Aging/*genetics/metabolism ; Cohort Studies ; Female ; HIV Infections/*genetics/metabolism/pathology ; Humans ; Lung/pathology/physiology ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/*genetics/metabolism/pathology ; Respiratory Mucosa/pathology/*physiology ; Smoking/genetics/metabolism/pathology ; Telomere/*genetics/metabolism/pathology ; Telomere Homeostasis/*physiology ; Viral Load/trends ; },
abstract = {Human immunodeficiency virus (HIV) infection is associated with an increased risk of chronic obstructive pulmonary disease (COPD) independent of cigarette smoke exposure. Previous studies have demonstrated that decreased peripheral leukocyte telomere length is associated with HIV, suggesting an accelerated aging phenomenon. We demonstrate that this process of telomere shortening also occurs in the lungs, with significant decreases in telomere length observed in small airway epithelial cells collected during bronchoscopy. Molecular evidence of accelerated aging in the small airway epithelium of persons living with HIV may be one clue into the predisposition for chronic lung disease observed in this population.},
}
@article {pmid29893967,
year = {2018},
author = {Pontremoli, C and Forni, D and Cagliani, R and Pozzoli, U and Clerici, M and Sironi, M},
title = {Evolutionary rates of mammalian telomere-stability genes correlate with karyotype features and female germline expression.},
journal = {Nucleic acids research},
volume = {46},
number = {14},
pages = {7153-7168},
pmid = {29893967},
issn = {1362-4962},
mesh = {Animals ; *Evolution, Molecular ; Female ; *Gene Expression ; Germ Cells/*metabolism ; Humans ; Karyotype ; Male ; Mammals ; Meiosis/genetics ; Mice ; Phylogeny ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/classification/genetics/metabolism ; },
abstract = {Telomeres protect the ends of eukaryotic chromosomes and are essential for cell viability. In mammals, telomere dynamics vary with life history traits (e.g. body mass and longevity), suggesting differential selection depending on physiological characteristics. Telomeres, in analogy to centromeric regions, also represent candidate meiotic drivers and subtelomeric DNA evolves rapidly. We analyzed the evolutionary history of mammalian genes implicated in telomere homeostasis (TEL genes). We detected widespread positive selection and we tested two alternative hypotheses: (i) fast evolution is driven by changes in life history traits; (ii) a conflict with selfish DNA elements at the female meiosis represents the underlying selective pressure. By accounting for the phylogenetic relationships among mammalian species, we show that life history traits do not contribute to shape diversity of TEL genes. Conversely, the evolutionary rate of TEL genes correlates with expression levels during meiosis and episodes of positive selection across mammalian species are associated with karyotype features (number of chromosome arms). We thus propose a telomere drive hypothesis, whereby (sub)telomeres and telomere-binding proteins are engaged in an intra-genomic conflict similar to the one described for centromeres.},
}
@article {pmid29892551,
year = {2018},
author = {Ong, SY and Li, ST and Wong, GC and Ho, AYL and Nagarajan, C and Ngeow, J},
title = {Delayed diagnosis of Shwachman diamond syndrome with short telomeres and a review of cases in Asia.},
journal = {Leukemia research reports},
volume = {9},
number = {},
pages = {54-57},
pmid = {29892551},
issn = {2213-0489},
abstract = {Inherited bone marrow failure syndrome (IBMFS) including Shwachman Diamond Syndrome (SDS) can present initially to the hematologist with myelodysplastic syndrome (MDS). Accurate diagnosis affects choice of chemotherapy, donor selection, and transplant conditioning. We report a case of delayed diagnosis of SDS in a family with another child with aplastic anemia, and review reported cases of SDS in Asia. This highlights the gap in identifying inherited bone marrow failure syndromes in adults with hematologic malignancies.},
}
@article {pmid29891727,
year = {2018},
author = {Li, J and Chang, J and Tian, J and Ke, J and Zhu, Y and Yang, Y and Gong, Y and Zou, D and Peng, X and Yang, N and Mei, S and Wang, X and Cheng, L and Hu, W and Gong, J and Zhong, R and Miao, X},
title = {A Rare Variant P507L in TPP1 Interrupts TPP1-TIN2 Interaction, Influences Telomere Length, and Confers Colorectal Cancer Risk in Chinese Population.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {27},
number = {9},
pages = {1029-1035},
doi = {10.1158/1055-9965.EPI-18-0099},
pmid = {29891727},
issn = {1538-7755},
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; Case-Control Studies ; China/epidemiology ; Colorectal Neoplasms/epidemiology/*etiology/metabolism/pathology ; Female ; Follow-Up Studies ; Humans ; Incidence ; Male ; Middle Aged ; *Mutation, Missense ; Prognosis ; Protein Interaction Domains and Motifs ; Shelterin Complex ; Telomere Homeostasis ; Telomere-Binding Proteins/*genetics/*metabolism ; },
abstract = {Background: Telomere dysfunction triggers cellular senescence and constitutes a driving force for cancer initiation. Genetic variants in genes involved in telomere maintenance may contribute to colorectal cancer susceptibility.Methods: In this study, we firstly captured germline mutations in 192 patients with colorectal cancer by sequencing the coding regions of 13 core components implicated in telomere biology. Five potential functional variants were then genotyped and assessed in a case-control set with 3,761 colorectal cancer cases and 3,839 healthy controls. The promising association was replicated in additional 6,765 cases and 6,906 controls. Functional experiments were used to further clarify the potential function of the significant variant and uncover the underlying mechanism in colorectal cancer development.Results: The two-stage association studies showed that a rare missense variant rs149418249 (c.C1520T and p.P507L) in the 11th exon of TPP1 (also known as ACD, gene ID 65057) was significantly associated with colorectal cancer risk with the ORs being 2.90 [95% confidence interval (CI), 1.04-8.07; P = 0.041], 2.50 (95% CI, 1.04-6.04; P = 0.042), and 2.66 (95% CI, 1.36-5.18; P = 0.004) in discovery, replication, and the combined samples, respectively. Further functional annotation indicated that the TPP1 P507L substitution interrupted TPP1-TIN2 interaction, impaired telomerase processivity, and shortened telomere length, which subsequently facilitated cell proliferation and promoted colorectal cancer development.Conclusions: A rare variant P507L in TPP1 confers increased risk of colorectal cancer through interrupting TPP1-TIN2 interaction, impairing telomerase processivity, and shrinking telomere length.Impact: These findings emphasize the important role of telomere dysfunction in colorectal cancer development, and provide new insights about the prevention of this type of cancer. Cancer Epidemiol Biomarkers Prev; 27(9); 1029-35. ©2018 AACR.},
}
@article {pmid29886505,
year = {2018},
author = {Andert, A and Alizai, HP and Ulmer, TF and Heidenhain, C and Ziegler, P and Brümmendorf, TH and Neumann, UP and Beier, F and Klink, CD},
title = {Influence of Telomere Length in Hepatocytes on Liver Regeneration after Partial Hepatectomy in Rats.},
journal = {European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes},
volume = {59},
number = {1-2},
pages = {83-90},
doi = {10.1159/000489090},
pmid = {29886505},
issn = {1421-9921},
mesh = {Animals ; Cell Proliferation ; *Hepatectomy ; Hepatocytes/*metabolism ; *Liver Regeneration ; Male ; Organ Size ; Rats ; Rats, Wistar ; *Telomere ; },
abstract = {BACKGROUND: The aim of this study was to investigate telomere length in hepatocytes as a biomarker for liver regeneration after partial hepatectomy (PH) in rats.<br><br>MATERIALS AND METHODS: Sixty male Wistar rats underwent a 70% PH. One-month-old rats were assigned to group Y (n = 30) and 4-month-old rats were assigned to group O (n = 30). The rats were euthanized, and their livers were then harvested at postoperative day (POD) 1, 2, 3, 4, or 7. Telomere lengths and established parameters for liver regeneration (residual liver weight and levels of proliferating cell nuclear antigen [PCNA], Ki67, and interleukin [IL]-6) were measured.<br><br>RESULTS: We observed a significant increase in residual liver weight in group Y compared to that in group O (p = 0.001). The levels of Ki67 (p = 0.016), PCNA (p < 0.0001), and IL-6 (p < 0.001) were significantly higher in group Y. Furthermore, the rats in group Y had significantly earlier peak values of Ki67 and PCNA. Telomeres were significantly longer at the time of PH in group Y (p = 0.001). We showed a correlation between telomere length at the day of PH and liver regeneration. Animals with longer telomeres at the time of PH had better liver regeneration (p = 0.015). In group Y, animals with increased liver regeneration (median cut-off: > 122%) did not show any significant difference in telomere length (p = 0.587) compared to rats with regular regeneration (< 122%). However, in the older animals, rats with increased regeneration had significantly longer telomeres (p = 0.019) than rats with regular regeneration.<br><br>CONCLUSION: Telomere length in rat hepatocytes depends on age, and animals with long telomeres had earlier and better regeneration of healthy liver tissue than rats with short telomeres. Our data confirms that telomere length in rat hepatocytes could be used as a possible predictive marker for liver regeneration, and could help to identify older individuals with a high capacity for hepatic regeneration.},
}
@article {pmid29883927,
year = {2018},
author = {Huang, P and Zhou, J and Chen, S and Zou, C and Zhao, X and Li, J},
title = {The association between obstructive sleep apnea and shortened telomere length: a systematic review and meta-analysis.},
journal = {Sleep medicine},
volume = {48},
number = {},
pages = {107-112},
doi = {10.1016/j.sleep.2017.09.034},
pmid = {29883927},
issn = {1878-5506},
mesh = {Humans ; Sleep Apnea, Obstructive/*genetics ; Telomere Shortening/*physiology ; },
abstract = {OBJECTIVE: We aimed to provide a more precise estimate of the relationship between telomere length and obstructive sleep apnea (OSA) by systematically reviewing evidence.<br><br>METHOD: We conducted a systematic electronic search in the databases of the PUBMED, PsycINFO, OVID (Medline), EMBASE and other resources (such as Google Scholar). The methodological quality of the articles was assessed according to the Newcastle Ottawa Scale. Heterogeneity was assessed using the chi-square test for Cochrane's Q statistic and I-squared. When heterogeneity was found to be reasonably high between studies, the random-effects model with the mean difference (95% confidence interval [CI]) was conducted using RevMan 5 software by using the inverse variance method (P&#xa0;<&#xa0;0.05; chi-square test). By contrast, the fixed-effects model was carried out.<br><br>RESULTS: Eight eligible studies involving 2639 participants were included in our meta-analysis. Shortened telomere length was significantly associated with OSA with mean difference of&#xa0;-0.03 (95% CI:&#xa0;-0.06,&#xa0;-0.00; P&#xa0;=&#xa0;0.003 with I-square of 85%&#xff09;. The results of subgroup analysis preformed by age and sample number suggested that shorter telomere length was significantly associated with OSA, with mean difference of&#xa0;-0.07 (95% CI:&#xa0;-0.07,&#xa0;-0.01; P&#xa0;=&#xa0;0.005) for adult group and&#xa0;-0.04 (95% CI:&#xa0;-0.02,&#xa0;-0.06; P&#xa0;=&#xa0;0.005) for large-sample studies.<br><br>CONCLUSION: Compared to healthy people, individuals with OSA have shorter telomere lengths which implicates early intervention and timely treatment for preventing future adverse outcomes.},
}
@article {pmid29883926,
year = {2018},
author = {Chang, SC and Prescott, J and De Vivo, I and Kraft, P and Okereke, OI},
title = {Polygenic risk score of shorter telomere length and risk of depression and anxiety in women.},
journal = {Journal of psychiatric research},
volume = {103},
number = {},
pages = {182-188},
pmid = {29883926},
issn = {1879-1379},
support = {P01 CA087969/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 MH096776/MH/NIMH NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; U01 CA049449/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Anxiety/*genetics ; Cohort Studies ; Cross-Sectional Studies ; Depression/*genetics ; Female ; Genetic Predisposition to Disease/*genetics ; Genome-Wide Association Study ; Humans ; Logistic Models ; Middle Aged ; Multifactorial Inheritance/*genetics ; Polymorphism, Single Nucleotide/*genetics ; Self Report ; Telomere Shortening/*genetics ; },
abstract = {Prior studies have reported significant cross-sectional associations between depression or anxiety and shorter telomere lengths, but the temporality of associations is uncertain. Little is known regarding whether shorter telomere length is related to increased risk of developing depression or anxiety. In this study, using the genetic tool of polygenic risk score (PRS), we evaluated the association between genetic predisposition to shorter telomere length and the risks of lifetime clinically significant depression (defined by self-reported clinician/physician diagnosis, antidepressant use, and/or presence of severe depressive symptoms) and of clinically meaningful anxiety symptoms among 17,693 female participants of European ancestry. The weighted PRS of telomere lengths (TLs) combined the dosage of nine alleles that were significantly associated with inter-individual variation in TLs in published genome-wide association studies. Higher score of PRS, corresponding to shorter TL in the literature, was significantly associated with shorter relative TLs (p = 0.008). However, higher PRS was not associated with the lifetime risk of either depression or anxiety. Furthermore, higher PRS was not associated with long-term patterns of depressive symptom trajectories or specifically with later-life onset of depression or anxiety. In summary, this study did not observe a significant association between genetic predisposition to shorter telomere length and risk of depression and anxiety in a large sample of mid-life and older white women. However, these genetic variants jointly account for a limited proportion of interpersonal variation in leukocyte telomere length. Future studies will need to incorporate more genetic variants to improve the accuracy of predicted power, as such data become available.},
}
@article {pmid29879607,
year = {2018},
author = {Stein, JY and Levin, Y and Uziel, O and Abumock, H and Solomon, Z},
title = {Traumatic stress and cellular senescence: The role of war-captivity and homecoming stressors in later life telomere length.},
journal = {Journal of affective disorders},
volume = {238},
number = {},
pages = {129-135},
doi = {10.1016/j.jad.2018.05.037},
pmid = {29879607},
issn = {1573-2517},
mesh = {Adult ; Aged ; Cellular Senescence/*genetics ; Depression/*genetics/psychology ; Female ; Humans ; Israel ; Loneliness ; Male ; Middle Aged ; Prisoners of War/*psychology ; Social Support ; Stress Disorders, Post-Traumatic/*genetics/psychology ; *Telomere ; },
abstract = {BACKGROUND: Telomere length (TL) serves as a biomarker of cellular senescence and is a robust predictor of mortality. The association between traumatic stress and TL erosion is rapidly realized, as are the complexities of this relation that include links to posttraumatic stress disorder (PTSD), depression, and psychosocial factors. Nevertheless, the relation between specific stressors in early adulthood and TL in later life, specifically among populations that have undergone extreme stress in early adulthood are largely uninvestigated.<br><br>METHOD: Examining 99 Israeli former prisoners of war (ex-POWs) 18 and 42 years after repatriation, the current study investigated the role that specific stressors during captivity (i.e., physical abuse, nourishment deprivation and solitary confinement) and homecoming (i.e., received social-support, loss of place in the family, loneliness and sense of being accused) play in predicting TL 42 years post-repatriation. Intercorrelations analysis and a hierarchical linear regression were utilized. Variables that have been empirically associated with TL: age, BMI, physical activity, smoking, substance abuse, negative life events since repatriation, depression and PTSD symptoms were controlled for in the regression.<br><br>RESULTS: Solitary confinement during captivity, and loss of place in the family, loneliness and being accused at homecoming predicted shorter telomeres in later life. The remaining stressors did not significantly predict TL.<br><br>CONCLUSION: These findings suggest that an adequate understanding of TL after trauma must consider the unique contributions of specific types of stressors across the lifespan, and particularly account for interpersonal deficits. The findings may inform preventive interventions aimed at improving ex-POWs' longevity and well-being.},
}
@article {pmid29879139,
year = {2018},
author = {Barrientos-Moreno, M and Murillo-Pineda, M and Muñoz-Cabello, AM and Prado, F},
title = {Histone depletion prevents telomere fusions in pre-senescent cells.},
journal = {PLoS genetics},
volume = {14},
number = {6},
pages = {e1007407},
pmid = {29879139},
issn = {1553-7404},
mesh = {Cellular Senescence/*genetics ; DNA Breaks, Double-Stranded ; DNA End-Joining Repair/genetics ; DNA Repair Enzymes/genetics/metabolism ; Histones/*genetics ; Intracellular Signaling Peptides and Proteins/*genetics/metabolism ; Protein Serine-Threonine Kinases/*genetics/metabolism ; Recombinational DNA Repair/genetics ; Saccharomyces cerevisiae/*physiology ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {Upon telomerase inactivation, telomeres gradually shorten with each cell division until cells enter replicative senescence. In Saccharomyces cerevisiae, the kinases Mec1/ATR and Tel1/ATM protect the genome during pre-senescence by preventing telomere-telomere fusions (T-TFs) and the subsequent genetic instability associated with fusion-bridge-breakage cycles. Here we report that T-TFs in mec1Δ tel1Δ cells can be suppressed by reducing the pool of available histones. This protection associates neither with changes in bulk telomere length nor with major changes in the structure of subtelomeric chromatin. We show that the absence of Mec1 and Tel1 strongly augments double-strand break (DSB) repair by non-homologous end joining (NHEJ), which might contribute to the high frequency of T-TFs in mec1Δ tel1Δ cells. However, histone depletion does not prevent telomere fusions by inhibiting NHEJ, which is actually increased in histone-depleted cells. Rather, histone depletion protects telomeres from fusions by homologous recombination (HR), even though HR is proficient in maintaining the proliferative state of pre-senescent mec1Δ tel1Δ cells. Therefore, HR during pre-senescence not only helps stalled replication forks but also prevents T-TFs by a mechanism that, in contrast to the previous one, is promoted by a reduction in the histone pool and can occur in the absence of Rad51. Our results further suggest that the Mec1-dependent depletion of histones that occurs during pre-senescence in cells without telomerase (tlc1Δ) prevents T-TFs by favoring the processing of unprotected telomeres by Rad51-independent HR.},
}
@article {pmid29876252,
year = {2018},
author = {Wright, DK and O'Brien, TJ and Mychasiuk, R and Shultz, SR},
title = {Telomere length and advanced diffusion MRI as biomarkers for repetitive mild traumatic brain injury in adolescent rats.},
journal = {NeuroImage. Clinical},
volume = {18},
number = {},
pages = {315-324},
pmid = {29876252},
issn = {2213-1582},
mesh = {Analysis of Variance ; Animals ; Brain Concussion/*diagnostic imaging/*pathology/physiopathology ; Brain Mapping ; Diffusion Magnetic Resonance Imaging/*methods ; Disease Models, Animal ; Female ; Image Processing, Computer-Assisted ; Male ; Neurologic Examination ; Rats ; Rats, Sprague-Dawley ; Sex Factors ; Telomere/*pathology ; Telomere Shortening/*physiology ; },
abstract = {Mild traumatic brain injuries (mTBI) are of worldwide concern in adolescents of both sexes, and repeated mTBI (RmTBI) may have serious long-term neurological consequences. As such, the study of RmTBI and discovery of objective biomarkers that can help guide medical decisions is an important undertaking. Diffusion-weighted MRI (DWI), which provides markers of axonal injury, and telomere length (TL) are two clinically relevant biomarkers that have been implicated in a number of neurological conditions, and may also be affected by RmTBI. Therefore, this study utilized the lateral impact injury model of RmTBI to investigate changes in diffusion MRI and TL, and how these changes relate to each other. Adolescent male and female rats received either three mTBIs or three sham injuries. The first injury was given on postnatal day 30 (P30), with the repeated injuries separated by four days each. Seven days after the final injury, a sample of ear tissue was collected for TL analysis. Rats were then euthanized and whole brains were collected and fixated for MRI analyses that included diffusion and high-resolution structural sequences. Compared to the sham-injured group, RmTBI rats had significantly shorter TL at seven days post-injury. Analysis of advanced DWI measures found that RmTBI rats had abnormalities in the corpus callosum and cortex at seven days post-injury. Notably, many of the DWI changes were correlated with TL. These findings demonstrate that TL and DWI measurements are changed by RmTBI and may represent clinically applicable biomarkers for this.},
}
@article {pmid29873071,
year = {2018},
author = {Ko, JM and Tsang, KH and Dai, W and Choi, SSA and Leong, MM and Ngan, RK and Kwong, DL and Cheng, A and Lee, AW and Ng, WT and Tung, S and Lee, VH and Lam, KO and Chan, CK and Lung, ML},
title = {Leukocyte telomere length associates with nasopharyngeal carcinoma risk and survival in Hong Kong Chinese.},
journal = {International journal of cancer},
volume = {143},
number = {9},
pages = {2289-2298},
doi = {10.1002/ijc.31617},
pmid = {29873071},
issn = {1097-0215},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Asian People/*genetics ; Case-Control Studies ; Child ; Female ; Follow-Up Studies ; Hong Kong ; Humans ; Leukocytes/metabolism/*pathology ; Male ; Middle Aged ; Nasopharyngeal Carcinoma/*blood/genetics/*mortality ; Prognosis ; Retrospective Studies ; Risk Factors ; Survival Rate ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {Telomere shortening occurs as an early event in tumorigenesis. The TERT-CLPTM1L locus associates with nasopharyngeal carcinoma (NPC) risk. It remains unknown if leukocyte telomere length (LTL) associates with NPC risk and survival. The relative LTL (rLTL) was measured by quantitative-PCR in 2,996 individuals comprised of 1,284 NPC cases and 1712 matched controls. The odds ratio (OR) and 95% confidence intervals (CI) were calculated by logistic regression. The hazard ratio (HR) and 95% CI were calculated by Cox regression for survival analysis with rLTL and other clinical parameters in 1,243 NPC with a minimum follow-up period of 25 months. NPC patients had significantly shorter telomere length than controls. Shorter rLTL significantly associated with increased NPC risk, when the individuals were dichotomized into long and short telomeres based on median-split rLTL in the control group (OR = 2.317; 95% CI = 1.989-2.700, p = 4.10 × 10[-27]). We observed a significant dose-response association (ptrend = 3.26 × 10[-34]) between rLTL and NPC risk with OR being 3.555 (95% CI = 2.853-4.429) for the individuals in the first quartile (shortest) compared with normal individuals in the fourth quartile (longest). A multivariate Cox regression analysis adjusted by age demonstrated an independent effect of rLTL on NPC survival for late-stage NPC patients, when the individuals were categorized into suboptimal rLTL versus the medium rLTL based on a threshold set from normal (HR = 1.471, 95% CI = 1.056-2.048, p = 0.022). Shorter blood telomeres may be markers for higher susceptibility for NPC risk. Suboptimal rLTL may be a poor prognostic factor for advanced NPC patients, as it associates independently with poor survival.},
}
@article {pmid29870951,
year = {2018},
author = {Zhan, Y and Clements, MS and Roberts, RO and Vassilaki, M and Druliner, BR and Boardman, LA and Petersen, RC and Reynolds, CA and Pedersen, NL and Hägg, S},
title = {Association of telomere length with general cognitive trajectories: a meta-analysis of four prospective cohort studies.},
journal = {Neurobiology of aging},
volume = {69},
number = {},
pages = {111-116},
pmid = {29870951},
issn = {1558-1497},
support = {RC4 AG039029/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; R01 MD011716/MD/NIMHD NIH HHS/United States ; R01 AG028555/AG/NIA NIH HHS/United States ; R01 CA204013/CA/NCI NIH HHS/United States ; R01 AG010175/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; R01 AG034676/AG/NIA NIH HHS/United States ; U01 AG009740/AG/NIA NIH HHS/United States ; R25 AG053227/AG/NIA NIH HHS/United States ; R01 AR030582/AR/NIAMS NIH HHS/United States ; },
mesh = {Aged ; Cognition/*physiology ; *Cognitive Aging ; Female ; Humans ; Longitudinal Studies ; Male ; Prospective Studies ; Sweden ; Telomere/*physiology ; Twins ; },
abstract = {To investigate the association of telomere length (TL) with trajectories of general cognitive abilities, we used data on 5955 participants from the Sex Differences in Health and Aging Study and the Swedish Adoption/Twin Study of Aging in Sweden, and the Mayo Clinic Study of Aging, and the Health and Retirement Study in the United States. TL was measured at baseline, while general cognitive ability was assessed repeatedly up to 7 occasions. Latent growth curve models were used to examine the associations. One standard deviation increase of TL was associated with 0.021 unit increase (95% confidence interval [CI]: 0.001, 0.042) of standardized mean general cognitive ability. After controlling for sex, the point estimate remained similar (0.019) with a wider CI (95% CI: -0.002, 0.039). The association was attenuated with adjustment for educational attainment (0.009, 95% CI: -0.009, 0.028). No strong evidence was observed for the association of TL and decline in general cognitive ability. Longer TL was associated with higher general cognitive ability levels in the age-adjusted models but not in the models including all covariates, nor with cognitive decline.},
}
@article {pmid29870917,
year = {2018},
author = {Zhang, Y and Hishimoto, A and Otsuka, I and Watanabe, Y and Numata, S and Yamamori, H and Boku, S and Horai, T and Someya, T and Ohmori, T and Hashimoto, R and Sora, I},
title = {Longer telomeres in elderly schizophrenia are associated with long-term hospitalization in the Japanese population.},
journal = {Journal of psychiatric research},
volume = {103},
number = {},
pages = {161-166},
doi = {10.1016/j.jpsychires.2018.05.014},
pmid = {29870917},
issn = {1879-1379},
mesh = {Adolescent ; Adult ; Aged ; Aging/*genetics ; Female ; Hospitalization/*statistics &amp; numerical data ; Humans ; Japan/epidemiology ; Leukocytes/metabolism ; Male ; Middle Aged ; Psychiatric Status Rating Scales ; Schizophrenia/*epidemiology/*genetics/nursing ; Telomere/*genetics/physiology ; Telomere Shortening ; Young Adult ; },
abstract = {Several previous studies have investigated an association between leukocyte telomere length (LTL) and schizophrenia (SCZ). However, results have been largely inconsistent, partially due to the relatively small sample sizes in each study and heterogeneity caused by various uncontrolled confounders (e.g., duration of illness or hospitalization, lifetime antipsychotic dose, and LTL assay methods). Here, we investigate the association of LTL with SCZ with the quantitative polymerase chain reaction method in independent cohorts consisting of 1241 patients with SCZ and 1042 controls (the largest independent sample in this field). Furthermore, we examined whether duration of hospitalization and lifetime antipsychotic dose had an effect on LTL in SCZ. In all samples, we observed significantly longer LTL in patients with SCZ relative to controls. In subgroup analyses, we observed that longer telomeres in SCZ were only visible in elderly patients and not in patients under 50 years old. Moreover, significantly longer LTL in elderly patients with SCZ was only specific to those with long-term hospitalization, but not outpatients or those with short-term hospitalization. This may be because the former received more appropriate lifestyle management. Meanwhile, lifetime antipsychotic dose had no effect on LTL. Our findings suggest that consideration of the effect of age and duration of hospitalization on LTL may improve our understanding of controversial results obtained in previous studies of telomeres in SCZ.},
}
@article {pmid29870526,
year = {2018},
author = {Aljarbou, F and Almousa, N and Bazzi, M and Aldaihan, S and Alanazi, M and Alharbi, O and Almadi, M and Aljebreen, AM and Azzam, NA and Arafa, M and Aldbass, A and Shaik, J and Alasirri, S and Warsy, A and Alamri, A and Parine, NR and Alamro, G},
title = {The expression of telomere-related proteins and DNA damage response and their association with telomere length in colorectal cancer in Saudi patients.},
journal = {PloS one},
volume = {13},
number = {6},
pages = {e0197154},
pmid = {29870526},
issn = {1932-6203},
mesh = {Adult ; Aged ; Colorectal Neoplasms/genetics/*metabolism/pathology ; *DNA Damage ; Female ; *Gene Expression Regulation, Neoplastic ; Humans ; Intestinal Mucosa/metabolism/pathology ; Male ; Middle Aged ; Neoplasm Proteins/*biosynthesis/genetics ; *Telomere Homeostasis ; Telomere-Binding Proteins/*biosynthesis/genetics ; },
abstract = {BACKGROUND: Colorectal cancer is the leading cause of cancer-related deaths in Saudi Arabia. Cancer has a multifactorial nature and can be described as a disease of altered gene expression. The profiling of gene expression has been used to identify cancer subtypes and to predict patients' responsiveness. Telomere-associated proteins that regulate telomere biology are essential molecules in cancer development. Thus, the present study examined their contributions to colorectal cancer progression in Saudi patients.<br><br>METHODS: The expression of hTERT, TRF1, TRF2, POT1, ATR, ATM, Chk1 and Chk2 were measured via real-time PCR in matched cancerous and adjacent tissues of CRC patients. The protein level of hTERT, TRF1, TRF2, ATR, ATM, Chk1 and Chk2 were measured using immunohistochemistry. A region of hTERT core promoter was sequenced via Sanger sequencing. Methylation of CTCF binding site was examined via methylation-specific PCR. Finally, the length of telomere was estimated using q-PCR.<br><br>RESULTS: Our results showed that POT1, ATR, Chk1 and Chk2 show increased expression in CRC relative to the adjacent mucosa. The expression levels of each gene were associated with clinicopathological characteristics of patients with CRC. There was a positive correlation between the age of the patients and hTERT expression. Regarding tumor site, telomere length, ATR, ATM and Chk1 were shown to be altered. No somatic mutation was detected in hTERT core promoter, and no differences in methylation patterns at CTCF binding site in the promoter between normal and cancer tissues.<br><br>CONCLUSION: Analysis of targeted genes expression in colorectal cancer based on the clinical variables revealed that tumor location and age could have a role in gene expression and telomere length variations and this could be taken under consideration during CRC diagnosis and therapy. Other epigenetic mechanisms could influence hTERT expression in cancers. Our findings warrant further validation through experiments involving a larger number of patients.},
}
@article {pmid29866222,
year = {2018},
author = {Ding, LX and Zhang, YH and Xu, XZ and Zhang, J and SUNg, M and Liu, D and Zhao, ZY and Zhou, Y and Zhang, Q and Wang, YX},
title = {Association between Physical Activity and Telomere Length in a North Chinese Population: A China Suboptimal Health Cohort Study.},
journal = {Biomedical and environmental sciences : BES},
volume = {31},
number = {5},
pages = {394-398},
doi = {10.3967/bes2018.051},
pmid = {29866222},
issn = {0895-3988},
mesh = {Adult ; Asian People/*genetics ; China ; Cohort Studies ; Cross-Sectional Studies ; Exercise/*physiology ; Female ; Humans ; Male ; Middle Aged ; *Telomere ; Young Adult ; },
abstract = {Several studies have demonstrated an association between physical activity and telomere length; however, the association remains inconsistent. A cross-sectional study consisting of 588 participants (375 females, median age of 33.8 years) was carried out to investigate the association between telomere length and physical activity in a general population from North China. The results show that relative telomere length is not significantly different in participants in the northern Chinese population with different levels of physical activity, either in the model only adjusted for age (F = 2.127, P = 0.120) or in the model adjusted for demographics and lifestyle (F = 1.227, P = 0.294). The gender-stratified analysis also produced insignificant results. Our study confirmed a non-significant association between physical activity and telomere length in the northern Chinese population, which adds to the inconsistent association between physical activity and telomere length across different ethnic populations.},
}
@article {pmid29861168,
year = {2018},
author = {Fu, H and Tian, CL and Ye, X and Sheng, X and Wang, H and Liu, Y and Liu, L},
title = {Dynamics of Telomere Rejuvenation during Chemical Induction to Pluripotent Stem Cells.},
journal = {Stem cell reports},
volume = {11},
number = {1},
pages = {70-87},
pmid = {29861168},
issn = {2213-6711},
mesh = {Animals ; Cell Differentiation/drug effects/genetics ; Cells, Cultured ; Cellular Reprogramming ; Crotonates/pharmacology ; Fluorescent Antibody Technique ; Gene Expression Profiling ; Gene Expression Regulation, Developmental/drug effects ; Genomic Instability ; Histones/metabolism ; Induced Pluripotent Stem Cells/cytology/drug effects/metabolism ; Mice ; Pluripotent Stem Cells/*cytology/drug effects/*metabolism ; *Rejuvenation ; Telomere/*genetics/metabolism ; Telomere Homeostasis ; Telomere Shortening ; Transcription Factors/genetics/metabolism ; },
abstract = {Chemically induced pluripotent stem cells (CiPSCs) may provide an alternative and attractive source for stem cell-based therapy. Sufficient telomere lengths are critical for unlimited self-renewal and genomic stability of pluripotent stem cells. Dynamics and mechanisms of telomere reprogramming of CiPSCs remain elusive. We show that CiPSCs acquire telomere lengthening with increasing passages after clonal formation. Both telomerase activity and recombination-based mechanisms are involved in the telomere elongation. Telomere lengths strongly indicate the degree of reprogramming, pluripotency, and differentiation capacity of CiPSCs. Nevertheless, telomere damage and shortening occur at a late stage of lengthy induction, limiting CiPSC formation. We find that histone crotonylation induced by crotonic acid can activate two-cell genes, including Zscan4; maintain telomeres; and promote CiPSC generation. Crotonylation decreases the abundance of heterochromatic H3K9me3 and HP1α at subtelomeres and Zscan4 loci. Taken together, telomere rejuvenation links to reprogramming and pluripotency of CiPSCs. Crotonylation facilitates telomere maintenance and enhances chemically induced reprogramming to pluripotency.},
}
@article {pmid29860472,
year = {2018},
author = {Suchy-Dicey, AM and Muller, CJ and Madhyastha, TM and Shibata, D and Cole, SA and Zhao, J and Longstreth, WT and Buchwald, D},
title = {Telomere Length and Magnetic Resonance Imaging Findings of Vascular Brain Injury and Central Brain Atrophy: The Strong Heart Study.},
journal = {American journal of epidemiology},
volume = {187},
number = {6},
pages = {1231-1239},
pmid = {29860472},
issn = {1476-6256},
support = {U01 HL041642/HL/NHLBI NIH HHS/United States ; K01 AG034259/AG/NIA NIH HHS/United States ; R01 DK091369/DK/NIDDK NIH HHS/United States ; R01 HL109315/HL/NHLBI NIH HHS/United States ; K01 AG057821/AG/NIA NIH HHS/United States ; R01 HL109319/HL/NHLBI NIH HHS/United States ; R01 HL109284/HL/NHLBI NIH HHS/United States ; U01 HL065521/HL/NHLBI NIH HHS/United States ; R01 HL109301/HL/NHLBI NIH HHS/United States ; R01 HL109282/HL/NHLBI NIH HHS/United States ; U01 HL065520/HL/NHLBI NIH HHS/United States ; U01 HL041654/HL/NHLBI NIH HHS/United States ; R01 HL093086/HL/NHLBI NIH HHS/United States ; U01 HL041652/HL/NHLBI NIH HHS/United States ; P50 AG005136/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/pathology ; Atrophy ; Brain/*diagnostic imaging/pathology ; Cerebrovascular Trauma/*diagnostic imaging ; Cross-Sectional Studies ; Female ; Humans ; Indians, North American/*statistics &amp; numerical data ; Magnetic Resonance Imaging ; Male ; Middle Aged ; *Telomere Homeostasis ; },
abstract = {Telomeres are repeating regions of DNA that cap chromosomes. They shorten over the mammalian life span, especially in the presence of oxidative stress and inflammation. Telomeres may play a direct role in cell senescence, serving as markers of premature vascular aging. Leukocyte telomere length (LTL) may be associated with premature vascular brain injury and cerebral atrophy. However, reports have been inconsistent, especially among minority populations with a heavy burden of illness related to vascular aging. We examined associations between LTL and magnetic resonance imaging in 363 American Indians aged 64-93 years from the Strong Heart Study (1989-1991) and its ancillary study, Cerebrovascular Disease and Its Consequences in American Indians (2010-2013). Our results showed significant associations of LTL with ventricular enlargement and the presence of white matter hyperintensities. Secondary models indicated that renal function may mediate these associations, although small case numbers limited inference. Hypertension and diabetes showed little evidence of effect modification. Results were most extreme among participants who evinced the largest decline in LTL. Although this study was limited to cross-sectional comparisons, it represents (to our knowledge) the first consideration of associations between telomere length and brain aging in American Indians. Findings suggest a relationship between vascular aging by cell senescence and severity of brain disease.},
}
@article {pmid29859365,
year = {2018},
author = {Staffaroni, AM and Tosun, D and Lin, J and Elahi, FM and Casaletto, KB and Wynn, MJ and Patel, N and Neuhaus, J and Walters, SM and Epel, ES and Blackburn, EH and Kramer, JH},
title = {Telomere attrition is associated with declines in medial temporal lobe volume and white matter microstructure in functionally independent older adults.},
journal = {Neurobiology of aging},
volume = {69},
number = {},
pages = {68-75},
pmid = {29859365},
issn = {1558-1497},
support = {P50 AG023501/AG/NIA NIH HHS/United States ; R01 AG032289/AG/NIA NIH HHS/United States ; R01 AG048234/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; *Aging ; Atrophy ; Diffusion Magnetic Resonance Imaging ; Female ; Humans ; Male ; Memory, Episodic ; *Telomere Shortening ; Temporal Lobe/*pathology ; White Matter/*pathology ; },
abstract = {Although leukocyte telomere length (TL) shortens over the lifespan and is associated with diseases of aging, little is known about the relationships between TL, memory, and brain structure. Sixty-nine functionally normal older adults (mean age = 71.7) were assessed at 2 time points (mean interval = 2.9 years). Linear mixed models assessed relationships between TL and hippocampal volume, fractional anisotropy, and mean diffusivity (MD) of the fornix and verbal and visual episodic memory. Unstandardized coefficients are reported in the following, and p values are not corrected for multiple comparisons. A negative baseline trend was observed between TL and fornix MD (b = -0.01, p = 0.06), but no other cross-sectional associations were significant (ps > 0.16). Greater TL shortening at follow-up was associated with greater hippocampal volume loss (b = 27.09, p < 0.001), even after controlling for global volume loss (b = 10.83, p = 0.002). Greater telomere attrition was also associated with larger increases in fornix MD (b = -0.01, p = 0.012) and decreases in fornix fractional anisotropy (b = 0.004, p = 0.002). TL was not associated with changes in episodic memory (ps > 0.23). These relationships may reflect neurobiological influences that affect both TL and brain structure, as well as the effect of TL on brain aging via mechanisms such as cellular senescence and inflammation.},
}
@article {pmid29857903,
year = {2018},
author = {Ilias, I and Alexiou, M and Mastorakos, G},
title = {Telomere length, thyroid dysfunction/autoimmunity and parity.},
journal = {Medical hypotheses},
volume = {116},
number = {},
pages = {28-29},
doi = {10.1016/j.mehy.2018.04.015},
pmid = {29857903},
issn = {1532-2777},
mesh = {Abortion, Spontaneous ; Autoimmunity/*genetics ; Biopsy, Fine-Needle ; Female ; Humans ; Models, Theoretical ; Parity ; Polymerase Chain Reaction ; Pregnancy ; Pregnancy Complications ; Telomere/*ultrastructure ; Thyroid Diseases/*genetics ; Thyroiditis, Autoimmune/genetics ; },
abstract = {There may exist an association between thyroid dysfunction/autoimmunity and parity. Autoimmune thyroiditis shows some degree of telomere shortening. Parity was recently found to be associated with telomere shortening. We hypothesize that among the factors affecting the tentative association between parity and thyroid dysfunction/autoimmunity shortened telomeres' may also be implicated. This could also be another facet of the processes leading to autoimmune thyroiditis.},
}
@article {pmid29854966,
year = {2018},
author = {Gurung, RL and M, Y and Liu, S and Liu, JJ and Lim, SC},
title = {Short Leukocyte Telomere Length Predicts Albuminuria Progression in Individuals With Type 2 Diabetes.},
journal = {Kidney international reports},
volume = {3},
number = {3},
pages = {592-601},
pmid = {29854966},
issn = {2468-0249},
abstract = {INTRODUCTION: Telomere length, a marker for biological aging, is implicated with diabetic kidney disease (DKD); however, the association between telomere length and albuminuria progression among Asian patients with type 2 diabetes (T2D) is not well understood. Here, we aim to study whether leukocyte telomere length (LTL) may independently predict albuminuria progression in patients with T2D with preserved renal filtration function (estimated GFR >60 ml/min per 1.73 m[2] and urine albumin-to-creatinine ratio [uACR] <300 mg/g).<br><br>METHODS: The baseline LTL was measured by real-time polymerase chain reaction in the SMART2D cohort (n&#xa0;= 691) with a median follow-up of 3 years. Albuminuria progression was defined as a change in albuminuria category to a higher category and at least 30% increase in uACR from baseline in 3 years.<br><br>RESULTS: Progressors (n&#xa0;= 123) had significantly shorter median LTL compared with nonprogressors (n&#xa0;= 568) (0.58 [0.38-0.79] vs. 0.62 [0.45-0.88], P&#xa0;= 0.039). Compared with subjects with longer LTL (fourth quartile), subjects with shorter LTL (first quartile) had 1.93-fold (1.04-3.60, P&#xa0;= 0.038) increased risk for albuminuria progression after adjustment for traditional risk factors. The association of LTL with microalbuminuria to macroalbuminuria progression was stronger than its association with normoalbuminuria to microalbuminuria (odds ratio [OR]: 1.54; 95% confidence interval [CI]: 1.02-2.32; P&#xa0;= 0.042 vs. OR: 1.13; 95% CI: 0.91-1.40; P&#xa0;= 0.263 per 1-SD decrement in natural log-transformed LTL).<br><br>CONCLUSION: Therefore, our results demonstrated that in patients with T2D with preserved renal filtration function, LTL predicts albuminuria progression beyond traditional risk factors, suggesting LTL may be novel biomarker for DKD progression.},
}
@article {pmid29853525,
year = {2018},
author = {Khincha, PP and Bertuch, AA and Gadalla, SM and Giri, N and Alter, BP and Savage, SA},
title = {Similar telomere attrition rates in androgen-treated and untreated patients with dyskeratosis congenita.},
journal = {Blood advances},
volume = {2},
number = {11},
pages = {1243-1249},
pmid = {29853525},
issn = {2473-9537},
mesh = {Adolescent ; Adult ; Androgens/*administration &amp; dosage/adverse effects ; Child ; Child, Preschool ; *Dyskeratosis Congenita/drug therapy/metabolism/pathology ; Female ; Humans ; Infant ; Infant, Newborn ; Longitudinal Studies ; Male ; Middle Aged ; Telomere/*metabolism/pathology ; Telomere Homeostasis/*drug effects ; },
abstract = {Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome and the prototypic telomere biology disorder (TBD). Leukocyte telomere length (TL) less than the first percentile for age, measured by flow cytometry with in situ hybridization (flow FISH), is diagnostic of DC. Androgens are a therapeutic option for DC/TBD-associated bone marrow failure (BMF). One report has shown an apparent increase in TL in patients while on treatment with the attenuated androgen danazol. The aim of this study was to compare TL over time in 10 androgen-treated and 16 untreated patients with DC. All subjects were enrolled in institutional review board-approved longitudinal cohort studies of inherited BMF. TL in 6-panel leukocyte subsets was measured by flow FISH. Generalized estimating equations (GEE) methodology was used to compare TL changes over time between groups. Unadjusted analyses showed annual median total lymphocyte TL attrition of -62 base pairs/year (bp/y) in androgen-treated patients with DC compared with -76 bp/y in untreated DC patients (P = .71). Longitudinal analysis using a GEE model, adjusted for age at sample collection, showed no statistically significant difference in TL change over time between treated and untreated patients (P = .24). The results were similar for each individual leukocyte subset evaluated. In summary, our data show the expected age-associated longitudinal telomere shortening in patients with DC, irrespective of androgen therapy. Caution is warranted when recommending androgen therapy for non-BMF manifestations of DC or TBDs until the biological mechanisms are better understood.},
}
@article {pmid29853305,
year = {2018},
author = {Machiela, MJ and Hofmann, JN and Carreras-Torres, R and Brown, KM and Johansson, M and Wang, Z and Foll, M and Li, P and Rothman, N and Savage, SA and Gaborieau, V and McKay, JD and Ye, Y and Henrion, M and Bruinsma, F and Jordan, S and Severi, G and Hveem, K and Vatten, LJ and Fletcher, T and Koppova, K and Larsson, SC and Wolk, A and Banks, RE and Selby, PJ and Easton, DF and Pharoah, P and Andreotti, G and Freeman, LEB and Koutros, S and Albanes, D and Mannisto, S and Weinstein, S and Clark, PE and Edwards, TE and Lipworth, L and Gapstur, SM and Stevens, VL and Carol, H and Freedman, ML and Pomerantz, MM and Cho, E and Kraft, P and Preston, MA and Wilson, KM and Gaziano, JM and Sesso, HS and Black, A and Freedman, ND and Huang, WY and Anema, JG and Kahnoski, RJ and Lane, BR and Noyes, SL and Petillo, D and Colli, LM and Sampson, JN and Besse, C and Blanche, H and Boland, A and Burdette, L and Prokhortchouk, E and Skryabin, KG and Yeager, M and Mijuskovic, M and Ognjanovic, M and Foretova, L and Holcatova, I and Janout, V and Mates, D and Mukeriya, A and Rascu, S and Zaridze, D and Bencko, V and Cybulski, C and Fabianova, E and Jinga, V and Lissowska, J and Lubinski, J and Navratilova, M and Rudnai, P and Szeszenia-Dabrowska, N and Benhamou, S and Cancel-Tassin, G and Cussenot, O and Bueno-de-Mesquita, HBA and Canzian, F and Duell, EJ and Ljungberg, B and Sitaram, RT and Peters, U and White, E and Anderson, GL and Johnson, L and Luo, J and Buring, J and Lee, IM and Chow, WH and Moore, LE and Wood, C and Eisen, T and Larkin, J and Choueiri, TK and Lathrop, GM and Teh, BT and Deleuze, JF and Wu, X and Houlston, RS and Brennan, P and Chanock, SJ and Scelo, G and Purdue, MP},
title = {Corrigendum re "Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma" [Eur Urol 2017;72:747-54].},
journal = {European urology},
volume = {74},
number = {3},
pages = {e85-e86},
doi = {10.1016/j.eururo.2018.05.017},
pmid = {29853305},
issn = {1873-7560},
support = {10119/CRUK_/Cancer Research UK/United Kingdom ; 16561/CRUK_/Cancer Research UK/United Kingdom ; RP-PG-0707-10101/DH_/Department of Health/United Kingdom ; ZIA CP010187/ImNIH/Intramural NIH HHS/United States ; },
}
@article {pmid29853162,
year = {2018},
author = {Tran, PT and Meeker, AK and Platz, EA},
title = {Association between statin drug use and peripheral blood leukocyte telomere length in the National Health and Nutrition Examination Survey 1999-2002: a cross-sectional study.},
journal = {Annals of epidemiology},
volume = {28},
number = {8},
pages = {529-534},
pmid = {29853162},
issn = {1873-2585},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Cholesterol/blood ; Cross-Sectional Studies ; Female ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use ; Hyperlipidemias/*drug therapy ; Leukocytes/*physiology ; Male ; Middle Aged ; Nutrition Surveys ; Telomere/genetics/*physiology ; Telomere Homeostasis/drug effects/*physiology ; United States ; },
abstract = {PURPOSE: To evaluate the association between statin drug use and peripheral blood leukocyte telomere length in a U.S. nationally representative sample of adults.<br><br>METHODS: We conducted a cross-sectional analysis of data from National Health and Nutrition Examination Survey 1999-2002, representative of the noninstitutionalized U.S.<br><br>POPULATION: The analytic study population included 3496 men and women aged 40-84&#xa0;years without a history of cancer and who had information of telomere length and statin use.<br><br>RESULTS: Compared with nonusers, statin users were more likely to be former smokers, older, white, male, and had more comorbidities. Statin users did not have longer telomeres than nonusers after age (coefficient&#xa0;-0.013, p&#xa0;= .30) and multivariable (0.0003, p&#xa0;= .98) adjustment. After multivariable adjustment, log-transformed telomere length nonstatistically significantly increased with increasing duration of use (0.003, p-trend&#xa0;= .11), which did not differ by number of comorbidities (p-interaction&#xa0;= 0.18). Compared with nonuse, more than 5&#xa0;years of use had an odds ratio of telomere length above the 75th percentile of 1.62 (95% confidence interval 0.90-2.92; p-trend&#xa0;= .10).<br><br>CONCLUSIONS: Although telomere length appeared to be longer with longer duration of use of a statin, this association was not statistically significant, and we could not rule out bias as the explanation.},
}
@article {pmid29851556,
year = {2018},
author = {Limbo, O and Yamada, Y and Russell, P},
title = {Mre11-Rad50-dependent activity of ATM/Tel1 at DNA breaks and telomeres in the absence of Nbs1.},
journal = {Molecular biology of the cell},
volume = {29},
number = {11},
pages = {1389-1399},
pmid = {29851556},
issn = {1939-4586},
support = {R01 CA077325/CA/NCI NIH HHS/United States ; R01 CA117638/CA/NCI NIH HHS/United States ; R01 GM059447/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenosine Triphosphate/metabolism ; *DNA Breaks, Double-Stranded ; Mutation/genetics ; Protein Binding ; Schizosaccharomyces/*metabolism ; Schizosaccharomyces pombe Proteins/chemistry/*metabolism ; Signal Transduction ; Telomere/*metabolism ; },
abstract = {The Mre11-Rad50-Nbs1 (MRN) protein complex and ATM/Tel1 kinase protect genome integrity through their functions in DNA double-strand break (DSB) repair, checkpoint signaling, and telomere maintenance. Nbs1 has a conserved C-terminal motif that binds ATM/Tel1, but the full extent and significance of ATM/Tel1 interactions with MRN are unknown. Here, we show that Tel1 overexpression bypasses the requirement for Nbs1 in DNA damage signaling and telomere maintenance. These activities require Mre11-Rad50, which localizes to DSBs and bind Tel1 in the absence of Nbs1. Fusion of the Tel1-binding motif of Nbs1 to Mre11 is sufficient to restore Tel1 signaling in nbs1Δ cells. Tel1 overexpression does not restore Tel1 signaling in cells carrying the rad50-I1192W mutation, which impairs the ability of Mre11-Rad50 to form the ATP-bound closed conformation. From these findings, we propose that Tel1 has a high-affinity interaction with the C-terminus of Nbs1 and a low-affinity association with Mre11-Rad50, which together accomplish efficient localization and activation of Tel1 at DSBs and telomeres.},
}
@article {pmid29851064,
year = {2018},
author = {},
title = {Paternal and grandpaternal ages at conception and descendant telomere lengths in chimpanzees and humans.},
journal = {American journal of physical anthropology},
volume = {166},
number = {2},
pages = {494},
doi = {10.1002/ajpa.23477},
pmid = {29851064},
issn = {1096-8644},
}
@article {pmid29848621,
year = {2018},
author = {van Mourik, PM and de Jong, J and Sharma, S and Kavšek, A and Chabes, A and Chang, M},
title = {Upregulation of dNTP Levels After Telomerase Inactivation Influences Telomerase-Independent Telomere Maintenance Pathway Choice in Saccharomyces cerevisiae.},
journal = {G3 (Bethesda, Md.)},
volume = {8},
number = {8},
pages = {2551-2558},
pmid = {29848621},
issn = {2160-1836},
mesh = {Cell Cycle Proteins/genetics/metabolism ; DNA-Directed DNA Polymerase/genetics/metabolism ; Deoxyribonucleosides/*metabolism ; Protein Serine-Threonine Kinases/genetics/metabolism ; Rad52 DNA Repair and Recombination Protein/genetics/metabolism ; Repressor Proteins/genetics/metabolism ; Ribonucleases/genetics/metabolism ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomerase/genetics/metabolism ; *Telomere Homeostasis ; Ubiquitin-Protein Ligases/genetics/metabolism ; },
abstract = {In 10-15% of cancers, telomere length is maintained by a telomerase-independent, recombination-mediated pathway called alternative lengthening of telomeres (ALT). ALT mechanisms were first seen, and have been best studied, in telomerase-null Saccharomyces cerevisiae cells called "survivors". There are two main types of survivors. Type I survivors amplify Y' subtelomeric elements while type II survivors, similar to the majority of human ALT cells, amplify the terminal telomeric repeats. Both types of survivors require Rad52, a key homologous recombination protein, and Pol32, a non-essential subunit of DNA polymerase δ. A number of additional proteins have been reported to be important for either type I or type II survivor formation, but it is still unclear how these two pathways maintain telomeres. In this study, we performed a genome-wide screen to identify novel genes that are important for the formation of type II ALT-like survivors. We identified 23 genes that disrupt type II survivor formation when deleted. 17 of these genes had not been previously reported to do so. Several of these genes (DUN1, CCR4, and MOT2) are known to be involved in the regulation of dNTP levels. We find that dNTP levels are elevated early after telomerase inactivation and that this increase favors the formation of type II survivors.},
}
@article {pmid29806548,
year = {2019},
author = {Wang, Z and Li, J and Liu, JP},
title = {Effects of cation charges on the binding of stabilizers with human telomere and TERRA G-quadruplexes.},
journal = {Journal of biomolecular structure &amp; dynamics},
volume = {37},
number = {7},
pages = {1908-1921},
doi = {10.1080/07391102.2018.1471416},
pmid = {29806548},
issn = {1538-0254},
mesh = {Binding Sites ; Cations/*chemistry ; DNA-Binding Proteins/*chemistry/metabolism ; Drug Design ; *G-Quadruplexes ; Humans ; Hydrogen Bonding ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Molecular Structure ; Porphyrins/chemistry/metabolism ; Protein Binding ; Protein Conformation ; Telomere/*chemistry/metabolism ; Transcription Factors/*chemistry/metabolism ; },
abstract = {Both telomere and telomeric repeat-containing RNAs (TERRA) can fold into G-quadruplexes (G4) in eukaryotic cells. Given their key roles in the regulation of telomere length and translation, telomere and TERRA G4 are interesting targets of novel drug development strategies. It is known that the cation charge of a stabilizer is crucial to the binding of G4 and stabilizer. However, the quantitative relationship between the cation charge of a stabilizer and the binding strengths with telomere and TERRA G4 remain unclear. In the current study, by substituting positive charged TMPyP4 with neutral and negative charged groups, the effects of cation charges on the binding conformation and binding strength of porphyrin stabilizers are investigated via molecular docking and molecular dynamic (MD) simulations. The results show that all TMPyP4 analogs form stable binding complexes with telomere and TERRA G4 and that, stabilizer charges have limited effects on binding conformation and can hardly lead to any special conformational alternations of G4. Our hydrogen bond analysis shows that all stabilizers can hardly form stable intermolecular hydrogen bonds with G4. Regarding binding strength levels, a linear correlation is found between the binding free energies and cation charges of stabilizers in all G4‒stabilizer complexes, revealing the pivotal role of electrostatic interactions. The present work is the first to reveal a quantitative correlation between the charges and binding strengths of stabilizers in their binding with human telomere and TERRA G4, which will prove pivotal for G4 targeted drug design and development.},
}
@article {pmid29804726,
year = {2018},
author = {Mangaonkar, AA and Patnaik, MM},
title = {Short Telomere Syndromes in Clinical Practice: Bridging Bench and Bedside.},
journal = {Mayo Clinic proceedings},
volume = {93},
number = {7},
pages = {904-916},
pmid = {29804726},
issn = {1942-5546},
support = {KL2 TR000136/TR/NCATS NIH HHS/United States ; KL2 TR002379/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; Syndrome ; Telomere Shortening/*genetics ; },
abstract = {Short telomere syndromes (STSs) are accelerated aging syndromes often caused by inheritable gene mutations resulting in decreased telomere lengths. Consequently, organ systems with increased cell turnover, such as the skin, bone marrow, lungs, and gastrointestinal tract, are commonly affected. Owing to diverse clinical presentations, STSs pose a diagnostic challenge, with bone marrow failure and idiopathic pulmonary fibrosis being frequent manifestations, occurring in association with gene mutations involving DKC1 (for expansion of gene symbols, use search tool at www.genenames.org), TERT, TERC, and others. Inherited STSs demonstrate genetic anticipation, occurring at an earlier age with more severe manifestations in the affected progeny. Telomere lengths can be assessed in peripheral blood granulocytes and lymphocytes using a sensitive technique called flow cytometry-fluorescence in situ hybridization, and mutational analysis can be performed using next-generation sequencing assays. In approximately 40% of patients with shortened telomere lengths, gene mutations cannot be identified due to the fact that all STS-associated genes have not yet been defined or due to alternative mechanisms of telomere shortening. Danazol, an anabolic steroid, has been associated with hematologic responses in patients with STSs and associated bone marrow failure; however, its reported ability to increase telomerase activity and reduce telomere attrition needs further elucidation. Organ transplant is reserved for patients with end-organ failure and is associated with substantial morbidity and mortality. Herein, we summarize the clinical and laboratory characteristics of STSs and offer a stepwise approach to diagnose and manage complications in affected patients.},
}
@article {pmid29804714,
year = {2018},
author = {Liu, YY and He, MH and Liu, JC and Lu, YS and Peng, J and Zhou, JQ},
title = {Yeast KEOPS complex regulates telomere length independently of its t[6]A modification function.},
journal = {Journal of genetics and genomics = Yi chuan xue bao},
volume = {45},
number = {5},
pages = {247-257},
doi = {10.1016/j.jgg.2018.03.004},
pmid = {29804714},
issn = {1673-8527},
mesh = {Adenosine/*analogs &amp; derivatives/metabolism ; DNA, Single-Stranded/genetics ; DNA-Binding Proteins/metabolism ; Saccharomyces cerevisiae/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomere/*genetics ; },
abstract = {In Saccharomyces cerevisiae, the highly conserved Sua5 and KEOPS complex (including five subunits Kae1, Bud32, Cgi121, Pcc1 and Gon7) catalyze a universal tRNA modification, namely N[6]-threonylcarbamoyladenosine (t[6]A), and regulate telomere replication and recombination. However, whether telomere regulation function of Sua5 and KEOPS complex depends on the t[6]A modification activity remains unclear. Here we show that Sua5 and KEOPS regulate telomere length in the same genetic pathway. Interestingly, the telomere length regulation by KEOPS is independent of its t[6]A biosynthesis activity. Cytoplasmic overexpression of Qri7, a functional counterpart of KEOPS in mitochondria, restores cytosolic tRNA t[6]A modification and cell growth, but is not sufficient to rescue telomere length in the KEOPS mutant kae1Δ cells, indicating that a t[6]A modification-independent function is responsible for the telomere regulation. The results of our in vitro biochemical and in vivo genetic assays suggest that telomerase RNA TLC1 might not be modified by Sua5 and KEOPS. Moreover, deletion of KEOPS subunits results in a dramatic reduction of telomeric G-overhang, suggesting that KEOPS regulates telomere length by promoting G-overhang generation. These findings support a model in which KEOPS regulates telomere replication independently of its function on tRNA modification.},
}
@article {pmid29803207,
year = {2018},
author = {Boresowicz, J and Kober, P and Rusetska, N and Maksymowicz, M and Goryca, K and Kunicki, J and Bonicki, W and Bujko, M},
title = {Telomere length and TERT abnormalities in pituitary adenomas.},
journal = {Neuro endocrinology letters},
volume = {39},
number = {1},
pages = {49-55},
pmid = {29803207},
issn = {0172-780X},
mesh = {Adenoma/*genetics/*pathology ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; DNA Methylation ; Female ; Gene Dosage ; Gene Expression Regulation, Neoplastic/genetics ; Genome-Wide Association Study ; Humans ; Incidence ; Male ; Middle Aged ; Mutation, Missense/genetics ; Pituitary Neoplasms/*genetics/*pathology ; RNA, Messenger/biosynthesis ; Telomerase/*genetics ; Telomere/*pathology ; Young Adult ; },
abstract = {OBJECTIVES: Pituitary adenomas (PAs) are among the most frequent intracranial tumors in humans. Abnormal telomerase activity and telomere lengthening are features of tumor cells. They may result from mutations in TERT promoter region, gene amplification or aberrant DNA methylation pattern. Such changes were found in variety of tumors including those of brain. Aim of the study was to evaluate the incidence of TERT abnormalities and to assess their role in telomere lengthening in PAs.<br><br>METHODS: Study involved 101 patients with PA including both nonfunctioning and functioning subtypes. Telomerase length as well as TERT mRNA level and gene amplification were estimated using quantitative PCR (qPCR). Promoter mutations were assessed using Sanger sequencing. The results from genome-wide DNA methylation profiling with HumanMethylation 450K (Illumina) were used for the analysis of TERT locus.<br><br>RESULTS: Variable telomere length was observed in patients, however no relationship with clinicopathological features was found. We observed a missense variant in TERT promoter in one patient only whereas increased TERT copy number were identified in 6 patients (5.6%). However no relationship between these results and telomere length or TERT expression was found. DNA methylation at TERT locus was not found to be changed when adenoma samples and normal tissue sections were compared.<br><br>CONCLUSION: The results indicate that telomerase abnormalities do not play a&#xa0;role in pathogenesis of pituitary tumors.},
}
@article {pmid29803183,
year = {2018},
author = {Bosquet Enlow, M and Bollati, V and Sideridis, G and Flom, JD and Hoxha, M and Hacker, MR and Wright, RJ},
title = {Sex differences in effects of maternal risk and protective factors in childhood and pregnancy on newborn telomere length.},
journal = {Psychoneuroendocrinology},
volume = {95},
number = {},
pages = {74-85},
pmid = {29803183},
issn = {1873-3360},
support = {R01 HD082078/HD/NICHD NIH HHS/United States ; R01 HL095606/HL/NHLBI NIH HHS/United States ; R01 HL114396/HL/NHLBI NIH HHS/United States ; P30 ES023515/ES/NIEHS NIH HHS/United States ; U54 HD090255/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Birth Weight ; Child ; Female ; Fetal Blood ; Humans ; Infant ; Infant, Newborn ; Male ; Maternal Exposure ; Mothers ; Parturition ; Pregnancy ; Pregnancy Complications ; Prenatal Exposure Delayed Effects/*physiopathology ; Protective Factors ; Risk Factors ; Sex Characteristics ; Sex Factors ; Social Class ; Telomere ; Telomere Homeostasis/*physiology ; Telomere Shortening/*physiology ; },
abstract = {Little research has examined determinants of newborn telomere length, a potential biomarker of lifetime disease risk impacted by prenatal exposures. No study has examined whether maternal exposures in childhood influence newborn telomere length or whether there are sex differences in the maternal factors that influence newborn telomere length. We tested whether a range of maternal risk and protective factors in childhood and pregnancy were associated with newborn telomere length among 151 sociodemographically diverse mother-infant dyads. We further examined whether the pattern of associations differed by infant sex. Newborn telomere length was assessed from cord blood collected at birth. Risk/protective factors included maternal health (smoking, body mass index), socioeconomic status (education, income), stress exposures, and mental health (depressive and posttraumatic stress disorder symptoms) in pregnancy as well as maternal experiences of abuse (physical, emotional, sexual) and familial emotional support in childhood. When examined within the whole sample, only maternal smoking in pregnancy and familial emotional support in childhood emerged as significant predictors of newborn telomere length. Male and female newborns differed in their pattern of associations between the predictors and telomere length. Among males, maternal smoking, higher body mass index, and elevated depressive symptoms in pregnancy and maternal sexual abuse in childhood were associated with shorter newborn telomere length; higher maternal educational attainment and household income in pregnancy and greater maternal familial emotional support in childhood were associated with longer newborn telomere length. Together, these factors accounted for 34% of the variance in male newborn telomere length. None of the risk/protective factors were associated with female newborn telomere length. The results suggest that male fetuses are particularly susceptible to maternal exposure effects on newborn telomere length. These findings have implications for elucidating mechanisms contributing to sex disparities in health.},
}
@article {pmid29803135,
year = {2018},
author = {Behboudi, H and Noureini, SK and Ghazanfari, T and Ardestani, SK},
title = {DNA damage and telomere length shortening in the peripheral blood leukocytes of 20 years SM-exposed veterans.},
journal = {International immunopharmacology},
volume = {61},
number = {},
pages = {37-44},
doi = {10.1016/j.intimp.2018.05.008},
pmid = {29803135},
issn = {1878-1705},
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Adult ; *Cellular Senescence ; Chemical Warfare Agents/*toxicity ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; *DNA Damage ; DNA Glycosylases/genetics/metabolism ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Humans ; Iran ; Leukocytes, Mononuclear/*physiology ; Middle Aged ; Mustard Gas/*toxicity ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Telomere/*genetics ; Time Factors ; Veterans ; },
abstract = {Sulfur mustard (SM) is a vesicant chemical warfare agent, and a very potent alkylating agent. SM exerts its cytotoxicity via direct alkylation of biomacromolecules, and overproduction of reactive oxygen species (ROS). Previous studies have shown that SM-induced oxidative stress has adverse effects on antioxidant defense system, and damages lipids and proteins. The aim of this study was to investigate the effect of SM-induced oxidative stress on DNA damage, and cellular senescence in SM-exposed victims. For this purpose, MDA levels as a measure of oxidative stress in the serum, 8-oxo-dG content of the genomic DNA, and OGG1 expression as two biomarkers of oxidative DNA damage, as well as, telomere length, and p16[INK4a] expression as two biomarkers of cellular senescence were measured in the peripheral blood leukocytes of 215 males who were exposed to SM 20 to 25 years ago, and 53 unexposed healthy males as the control group. Our results indicated that the levels of 8-oxo-dG, and OGG1 mRNA expression were significantly higher in SM-exposed individuals. Furthermore, a significant increase in the expression of p16[INK4a] was observed in SM-exposed patients, and leukocyte telomere length (LTL) was also significantly shorter in severe/very severe cases of SM-exposed patients when compared with unexposed controls. In conclusion, our data indicate that oxidative DNA damage is higher in SM-exposed patients, and their immune system has subjected to cellular senescence.},
}
@article {pmid29797393,
year = {2018},
author = {Kim, D and Li, AA and Ahmed, A},
title = {Leucocyte telomere shortening is associated with nonalcoholic fatty liver disease-related advanced fibrosis.},
journal = {Liver international : official journal of the International Association for the Study of the Liver},
volume = {38},
number = {10},
pages = {1839-1848},
doi = {10.1111/liv.13886},
pmid = {29797393},
issn = {1478-3231},
mesh = {Adult ; Age Factors ; Cross-Sectional Studies ; Female ; Humans ; *Leukocytes ; Linear Models ; Liver/pathology ; Liver Cirrhosis/*etiology ; Male ; Middle Aged ; Multivariate Analysis ; Non-alcoholic Fatty Liver Disease/*genetics/pathology ; Nutrition Surveys ; Risk Factors ; Severity of Illness Index ; Telomere/ultrastructure ; *Telomere Shortening ; United States ; Young Adult ; },
abstract = {BACKGROUND &amp; AIM: Telomere length and telomerase have been linked with cirrhosis and hepatocellular carcinoma. However, the impact of telomere length on nonalcoholic fatty liver disease and advanced fibrosis in a large national population sample is not well understood.<br><br>METHODS: Cross-sectional data from the National Health and Nutrition Examination Survey 1999-2002 were utilized. Suspected nonalcoholic fatty liver disease was diagnosed if serum alanine aminotransferase was >30&#xa0;IU/L for men and >19&#xa0;IU/L for women in the absence of other causes of chronic liver disease. Presence of advanced fibrosis was determined by the nonalcoholic fatty liver disease fibrosis score, aspartate aminotransferase to platelet ratio index and FIB-4 score.<br><br>RESULTS: Of the 6738 participants (mean age 46.3&#xa0;years, 48.4% male), suspected nonalcoholic fatty liver disease prevalence was inversely associated with leucocyte telomere length in young adults aged 20-39&#xa0;years, though this was not seen in the overall population. Percentage of participants with advanced fibrosis increased corresponding with leucocyte telomere length (longest to shortest). The shortest quartile of leucocyte telomere length was associated with a significantly higher odds ratio (95% confidence interval) of advanced fibrosis of 2.36 (1.32-4.24) in a univariate model compared to the longest quartile, and 2.01 (1.13-3.58) in a multivariate model adjusted for age, gender, ethnicity, waist circumference, smoking, diabetes, hypertension, total cholesterol and high-density lipoprotein cholesterol (P for trend <.05 respectively).<br><br>CONCLUSIONS: In this large nationally representative sample of American adults, leucocyte telomere shortening was associated with increased risk of advanced fibrosis in the setting of suspected nonalcoholic fatty liver disease independent of other known risk factors.},
}
@article {pmid29790605,
year = {2018},
author = {Cura Daball, P and Ventura Ferreira, MS and Ammann, S and Klemann, C and Lorenz, MR and Warthorst, U and Leahy, TR and Conlon, N and Roche, J and Soler-Palacín, P and Garcia-Prat, M and Fuchs, I and Fuchs, S and Beier, F and Brümmendorf, TH and Speckmann, C and Olbrich, P and Neth, O and Schwarz, K and Ehl, S and Rensing-Ehl, A},
title = {CD57 identifies T cells with functional senescence before terminal differentiation and relative telomere shortening in patients with activated PI3 kinase delta syndrome.},
journal = {Immunology and cell biology},
volume = {96},
number = {10},
pages = {1060-1071},
doi = {10.1111/imcb.12169},
pmid = {29790605},
issn = {1440-1711},
mesh = {CD57 Antigens/*metabolism ; *Cell Differentiation/genetics/immunology ; Cellular Senescence/genetics/immunology ; Class I Phosphatidylinositol 3-Kinases/metabolism ; Cytokines/metabolism ; Humans ; Immunologic Deficiency Syndromes/*etiology/*metabolism ; Immunophenotyping ; Lymphocyte Count ; Phosphatidylinositol 3-Kinases/*metabolism ; Primary Immunodeficiency Diseases ; Sirolimus/pharmacology ; T-Lymphocyte Subsets/drug effects/*immunology/*metabolism ; *Telomere Shortening ; },
abstract = {Premature T-cell immunosenescence with CD57[+] CD8[+] T-cell accumulation has been linked to immunodeficiency and autoimmunity in primary immunodeficiencies including activated PI3 kinase delta syndrome (APDS). To address whether CD57 marks the typical senescent T-cell population seen in adult individuals or identifies a distinct population in APDS, we compared CD57[+] CD8[+] T cells from mostly pediatric APDS patients to those of healthy adults with similarly prominent senescent T cells. CD57[+] CD8[+] T cells from APDS patients were less differentiated with more CD27[+] CD28[+] effector memory T cells showing increased PD1 and Eomesodermin expression. In addition, transition of naïve to CD57[+] CD8[+] T cells was not associated with the characteristic telomere shortening. Nevertheless, they showed the increased interferon-gamma secretion, enhanced degranulation and reduced in vitro proliferation typical of senescent CD57[+] CD8[+] T cells. Thus, hyperactive PI3 kinase signaling favors premature accumulation of a CD57[+] CD8[+] T-cell population, which shows most functional features of typical senescent T cells, but is different in terms of differentiation and relative telomere shortening. Initial observations indicate that this specific differentiation state may offer the opportunity to revert premature T-cell immunosenescence and its potential contribution to inflammation and immunodeficiency in APDS.},
}
@article {pmid29787435,
year = {2018},
author = {Ahmed, EA and Rosemann, M and Scherthan, H},
title = {NHEJ Contributes to the Fast Repair of Radiation-induced DNA Double-strand Breaks at Late Prophase I Telomeres.},
journal = {Health physics},
volume = {115},
number = {1},
pages = {102-107},
doi = {10.1097/HP.0000000000000852},
pmid = {29787435},
issn = {1538-5159},
mesh = {Animals ; Cells, Cultured ; DNA Breaks, Double-Stranded/*radiation effects ; *DNA End-Joining Repair ; *Gamma Rays ; Male ; Meiotic Prophase I/*genetics/radiation effects ; Mice ; Mice, SCID ; Spermatocytes/*metabolism/radiation effects ; Telomere/*genetics/radiation effects ; },
abstract = {Exposure of cells to ionizing radiation induces DNA double-strand breaks. To repair double-strand breaks correctly, cells must distinguish between the ends of chromosomes (telomeres) and DNA double-strand breaks within chromosomes. Double-strand breaks in telomeric DNA may lead to telomere shortening and mutagenesis. Eukaryotic cells repair double-strand breaks primarily by two mechanisms: error-free homologous recombination and error-prone nonhomologous end joining, of which homologous recombination is used in early meiotic prophase I to create recombined haploid gametes by two meiotic cell divisions lacking an intervening S-phase. Genotoxic exposures put meiosis at risk to transmit mutations, and ionizing radiation is known to induce large double-strand break-marking phospho (gamma)-H2AX foci along the cores and ends of mouse meiotic chromosomes. However, it remained unclear through which repair pathway the ionizing radiation-induced telomeric double-strand breaks are repaired in late prophase I spermatocytes. Using male wild-type and nonhomologous end joining-deficient (severe combined immunodeficient) mice, this study investigated the kinetics of in vivo double-strand break formation and repair at telomeres of late prophase I chromosomes up to 12 h after 0.5 Gy of whole-body gamma irradiation. Late pachytene and diplotene spermatocytes revealed overlapping gamma-H2AX and telomere repeat signal foci, indicating telomeric DNA damage. The comparison of double-strand break repair rates at telomeres and internal prophase chromosome sites revealed a more rapid double-strand break repair at wild-type telomeres during the first hour after irradiation. Increased double-strand break foci numbers at nonhomologous end joining-deficient telomeres and chromosomes and a slowed repair rate in this DNA-dependent protein kinase catalytic subunit mutant suggest that the fast repair of double-strand breaks in telomeric DNA repeats during late prophase I is largely mediated by canonical nonhomologous end joining.},
}
@article {pmid29784772,
year = {2018},
author = {Wang, J and Eisenstatt, JR and Audry, J and Cornelius, K and Shaughnessy, M and Berkner, KL and Runge, KW},
title = {A Heterochromatin Domain Forms Gradually at a New Telomere and Is Dynamic at Stable Telomeres.},
journal = {Molecular and cellular biology},
volume = {38},
number = {15},
pages = {},
pmid = {29784772},
issn = {1098-5549},
support = {R01 AG051601/AG/NIA NIH HHS/United States ; R01 GM050752/GM/NIGMS NIH HHS/United States ; R01 HL055666/HL/NHLBI NIH HHS/United States ; R01 HL081093/HL/NHLBI NIH HHS/United States ; },
mesh = {Base Sequence ; DNA Breaks, Double-Stranded ; DNA, Fungal/genetics/metabolism ; Gene Silencing ; Genome, Fungal ; Heterochromatin/genetics/*metabolism ; Histone Code ; Kinetics ; Models, Biological ; Schizosaccharomyces/genetics/growth &amp; development/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/metabolism ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; Telomere Homeostasis ; },
abstract = {Heterochromatin domains play important roles in chromosome biology, organismal development, and aging, including centromere function, mammalian female X chromosome inactivation, and senescence-associated heterochromatin foci. In the fission yeast Schizosaccharomyces pombe and metazoans, heterochromatin contains histone H3 that is dimethylated at lysine 9. While factors required for heterochromatin have been identified, the dynamics of heterochromatin formation are poorly understood. Telomeres convert adjacent chromatin into heterochromatin. To form a new heterochromatic region in S. pombe, an inducible DNA double-strand break (DSB) was engineered next to 48 bp of telomere repeats in euchromatin, which caused formation of a new telomere and the establishment and gradual spreading of a new heterochromatin domain. However, spreading was dynamic even after the telomere had reached its stable length, with reporter genes within the heterochromatin domain showing variegated expression. The system also revealed the presence of repeats located near the boundaries of euchromatin and heterochromatin that are oriented to allow the efficient healing of a euchromatic DSB to cap the chromosome end with a new telomere. Telomere formation in S. pombe therefore reveals novel aspects of heterochromatin dynamics and fail-safe mechanisms to repair subtelomeric breaks, with implications for similar processes in metazoan genomes.},
}
@article {pmid29783641,
year = {2018},
author = {Kalyan, S and Pick, N and Mai, A and Murray, MCM and Kidson, K and Chu, J and Albert, AYK and Côté, HCF and Maan, EJ and Goshtasebi, A and Money, DM and Prior, JC},
title = {Premature Spinal Bone Loss in Women Living with HIV is Associated with Shorter Leukocyte Telomere Length.},
journal = {International journal of environmental research and public health},
volume = {15},
number = {5},
pages = {},
pmid = {29783641},
issn = {1660-4601},
support = {TCO 125269//CIHR/Canada ; },
mesh = {Adult ; Anti-Retroviral Agents/therapeutic use ; *Bone Density ; Cellular Senescence ; Female ; HIV Infections/drug therapy/*physiopathology ; Humans ; Leukocytes/*physiology ; Lumbar Vertebrae/*physiology ; Middle Aged ; Osteoporosis/*physiopathology ; *Telomere ; },
abstract = {With advances in combination antiretroviral therapy (cART), people living with HIV are now surviving to experience aging. Evidence suggests that individuals living with HIV are at greater risk for low bone mineral density (BMD), osteoporosis, and fractures. Better understanding of the pathophysiology of bone health in women living with HIV (WLWH) is important for treatment strategies. The goal of this study was to explore new biological factors linked to low BMD in WLWH. Standardized BMD measures of WLWH were compared to reference values from an unselected population of women from the same geographical region of the same age range. Linear regression analysis was used to assess relationships among health-related characteristics, cellular aging (measured by leukocyte telomere length; LTL), cART, and BMD of WLWH. WLWH (n = 73; mean age 43 ± 9 years) had lower BMD Z-scores at the lumbar spine (LS) (mean difference = -0.39, p < 0.001) and total hip (TH) (-0.29, p = 0.012) relative to controls (n = 290). WLWH between 50 and 60 years (n = 17) had lower Z-scores at the LS (p = 0.008) and TH (p = 0.027) compared to controls (n = 167). Among WLWH, LS BMD was significantly associated with LTL (R[2] = 0.09, p = 0.009) and BMI (R[2] = 0.06, p = 0.042). Spinal BMD was adversely affected in WLWH. Reduction of LTL was strongly associated with lower BMD and may relate to its pathophysiology and premature aging in WLWH.},
}
@article {pmid29782524,
year = {2018},
author = {Pavanello, S and Varesco, L and Gismondi, V and Bruzzi, P and Bolognesi, C},
title = {Leucocytes telomere length and breast cancer risk/ susceptibility: A case-control study.},
journal = {PloS one},
volume = {13},
number = {5},
pages = {e0197522},
pmid = {29782524},
issn = {1932-6203},
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/genetics ; Breast Neoplasms/*blood/*genetics ; Case-Control Studies ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genomic Instability ; Humans ; Leukocytes/*ultrastructure ; Linear Models ; Middle Aged ; Multivariate Analysis ; Mutation ; Risk Factors ; Telomere/*genetics/*ultrastructure ; Telomere Homeostasis/genetics ; Young Adult ; },
abstract = {BACKGROUND: Telomere length in peripheral blood leukocytes (PBL-TL) was proposed as a biomarker of cancer risk. Recent scientific evidence suggested PBL-TL plays a diverse role in different cancers. Inconsistent results were obtained on PBL-TL in relation to breast cancer risk and specifically to the presence of BRCA1 and BRCA2 mutations. The aim of the present case-control study was to analyse the correlation between family history of breast cancer or presence of a BRCA mutation and PBL-TL in the hypothesis that TL is a modifier of cancer risk.<br><br>METHODS: PBL-TL was measured using the real-time quantitative PCR method in DNA for 142 cases and 239 controls. All the women enrolled were characterized for cancer family history. A subgroup of 48 women were classified for the presence of a BRCA mutation. PBL-TL were summarized as means and standard deviations, and compared by standard analysis of variance. A multivariable Generalised Linear Model was fitted to the data with PBL-TL as the dependent variable, case/control status and presence of a BRCA/VUS mutation as factors, and age in 4 strata as a covariate.<br><br>RESULTS: Age was significantly associated with decreasing PBL-TL in controls (p = 0.01), but not in BC cases. The telomere length is shorter in cases than in controls after adjusting for age. No effect on PBL-TL of BMI, smoke nor of the most common risk factors for breast cancer was observed. No association between PBL-TL and family history was detected both in BC cases and controls. In the multivariate model, no association was observed between BRCA mutation and decreased PBL-TL. A statistically significant interaction (p = 0.031) between case-control status and a BRCA-mutation/VUS was observed, but no effect was detected for the interaction of cancer status and BRCA or VUS.<br><br>CONCLUSION: Our study fails to provide support to the hypothesis that PBL-TL is associated with the risk of hereditary BC, or that is a marker of inherited mutations in BRCA genes.},
}
@article {pmid29780161,
year = {2018},
author = {Fernandez-Rozadilla, C and Kartsonaki, C and Woolley, C and McClellan, M and Whittington, D and Horgan, G and Leedham, S and Kriaucionis, S and East, JE and Tomlinson, I},
title = {Author Correction: Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel.},
journal = {British journal of cancer},
volume = {118},
number = {12},
pages = {1683},
doi = {10.1038/s41416-018-0111-0},
pmid = {29780161},
issn = {1532-1827},
support = {206314/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; },
abstract = {Since the publication of this paper, the authors noticed that James E. East was assigned to the incorrect affiliation. The affiliation information is provided correctly, above.},
}
@article {pmid29779414,
year = {2019},
author = {Stefa, A and Lamprokostopoulou, A and Briana, DD and Kontogeorgou, A and Papageorgiou, I and Malamitsi-Puchner, A and Tsitsilonis, O and Gagos, S and Charmandari, E},
title = {The effect of intrauterine growth on leukocyte telomere length at birth.},
journal = {The journal of maternal-fetal &amp; neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians},
volume = {32},
number = {23},
pages = {3948-3953},
doi = {10.1080/14767058.2018.1479392},
pmid = {29779414},
issn = {1476-4954},
mesh = {Adult ; Case-Control Studies ; Female ; Fetal Blood/*cytology/*metabolism ; Fetal Development/*genetics ; Fetal Growth Retardation/blood/genetics ; Fetal Macrosomia/blood/genetics ; Gestational Age ; Humans ; Infant, Newborn ; Infant, Small for Gestational Age/blood/metabolism ; Leukocytes/*metabolism/pathology ; Male ; *Parturition/blood/genetics ; Pregnancy ; Telomere/*genetics/metabolism ; Telomere Homeostasis/physiology ; },
abstract = {Objective: Telomeres are specialized nucleoprotein structures located at the ends of chromosomes, which play a crucial role in genomic stability. Telomere shortening has been proposed as a biomarker for the onset of age-related diseases. This study aimed to determine whether restricted or increased intrauterine growth affects leukocyte telomere length (LTL) at birth. Materials and methods: One hundred sixty-five (n = 165) full-term neonates participated in the study. Fetuses were classified as intrauterine growth restriction (IUGR, n = 21), large-for-gestational-age (LGA, n = 15), or appropriate-for-gestational-age (AGA, n = 129), based on customized birth-weight standards. Mixed arteriovenous cord blood samples were collected for isolation of leukocyte DNA. The LTL was measured using multiplex monochrome quantitative real-time PCR and telomeric restriction fragments through Southern blot analysis (terminal restriction fragment [TRF]). Results: Despite differences among groups in birth weight, length and head circumference, LTL did not differ among AGA (6.78 ± 0.58), IUGR (10.54 ± 1.80), and LGA (11.95 ± 2.42) neonates (p = .098). Cord blood IGF-1 and IGFBP-3 concentrations were higher in the LGA group. LTL positively correlated with birth length (r = 0.176, p = .032). Conclusions: Intrauterine growth does not seem to affect LTL at birth. Further studies, comprising a larger sample size of IUGR, LGA, and AGA neonates, are required to determine whether growth at birth influences LTL.},
}
@article {pmid29777397,
year = {2018},
author = {Pańczyszyn, A and Boniewska-Bernacka, E and Głąb, G},
title = {Telomeres and Telomerase During Human Papillomavirus-Induced Carcinogenesis.},
journal = {Molecular diagnosis &amp; therapy},
volume = {22},
number = {4},
pages = {421-430},
pmid = {29777397},
issn = {1179-2000},
mesh = {Carcinogenesis/*genetics ; Cell Transformation, Viral ; Disease Progression ; Female ; Humans ; Oncogene Proteins, Viral/metabolism ; Papillomaviridae/metabolism/*pathogenicity ; Papillomavirus Infections/*genetics/metabolism ; RNA/genetics ; Retinoblastoma Protein/metabolism ; Telomerase/*genetics ; *Telomere Shortening ; Tumor Suppressor Protein p53/metabolism ; Virus Internalization ; },
abstract = {Human papillomaviruses (HPVs) belong to a small spherical virus family and are transmitted through direct contact, most often through sexual behavior. More than 200 types of HPV are known, a dozen or so of which are classified as high-risk viruses (HR HPV) and may contribute to the development of cervical cancer. HPV is a small virus with a capsid composed of L1 and L2 proteins, which are crucial for entry to the cell. The infection begins at the basal cell layer and progresses to involve cells from higher layers of the cervical epithelium. E6 and E7 viral proteins are involved in the process of carcinogenesis. They interact with suppressors of oncogenesis, including p53 and Rb proteins. This leads to DNA replication and intensive cell divisions. The persistent HR HPV infection leads to the development of dysplasia and these changes may progress to invasive cancer. During the initial stage of carcinogenesis, telomeres shorten until telomerase activates. The activation of telomerase, the enzyme necessary to extend chromosome ends (telomeres) is the key step in cell immortalization. Analyzing the expression level of hTERT and hTERC genes encoding telomerase and telomere length measurement may constitute new markers of the early carcinogenesis.},
}
@article {pmid29777050,
year = {2018},
author = {Laterreur, N and Lemieux, B and Neumann, H and Berger-Dancause, JC and Lafontaine, D and Wellinger, RJ},
title = {The yeast telomerase module for telomere recruitment requires a specific RNA architecture.},
journal = {RNA (New York, N.Y.)},
volume = {24},
number = {8},
pages = {1067-1079},
pmid = {29777050},
issn = {1469-9001},
support = {MOP97874//CIHR/Canada ; FDN154315//CIHR/Canada ; PJT153205//CIHR/Canada ; },
mesh = {*Nucleic Acid Conformation ; RNA/*chemistry/genetics ; Ribonuclease P/*metabolism ; Ribonucleoproteins/*metabolism ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomerase/*genetics/*metabolism ; Telomere/*genetics ; },
abstract = {Telomerases are ribonucleoprotein (RNP) reverse transcriptases. While telomerases maintain genome stability, their composition varies significantly between species. Yeast telomerase RNPs contain an RNA that is comparatively large, and its overall folding shows long helical segments with distal functional parts. Here we investigated the essential stem IVc module of the budding yeast telomerase RNA, called Tlc1. The distal part of stem IVc includes a conserved sequence element CS2a and structurally conserved features for binding Pop1/Pop6/Pop7 proteins, which together function analogously to the P3 domains of the RNase P/MRP RNPs. A more proximal bulged stem with the CS2 element is thought to associate with Est1, a telomerase protein required for telomerase recruitment to telomeres. Previous work found that changes in CS2a cause a loss of all stem IVc proteins, not just the Pop proteins. Here we show that the association of Est1 with stem IVc indeed requires both the proximal bulged stem and the P3 domain with the associated Pop proteins. Separating the P3 domain from the Est1 binding site by inserting only 2 base pairs into the helical stem between the two sites causes a complete loss of Est1 from the RNP and hence a telomerase-negative phenotype in vivo. Still, the distal P3 domain with the associated Pop proteins remains intact. Moreover, the P3 domain ensures Est2 stability on the RNP independently of Est1 association. Therefore, the Tlc1 stem IVc recruitment module of the RNA requires a very tight architectural organization for telomerase function in vivo.},
}
@article {pmid29776332,
year = {2018},
author = {Braun, DM and Chung, I and Kepper, N and Deeg, KI and Rippe, K},
title = {TelNet - a database for human and yeast genes involved in telomere maintenance.},
journal = {BMC genetics},
volume = {19},
number = {1},
pages = {32},
pmid = {29776332},
issn = {1471-2156},
mesh = {*Databases, Genetic ; Humans ; Saccharomyces cerevisiae Proteins/*genetics ; Telomerase/*genetics ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {BACKGROUND: The ends of linear chromosomes, the telomeres, comprise repetitive DNA sequences in complex with proteins that protects them from being processed by the DNA repair machinery. Cancer cells need to counteract the shortening of telomere repeats during replication for their unlimited proliferation by reactivating the reverse transcriptase telomerase or by using the alternative lengthening of telomeres (ALT) pathway. The different telomere maintenance (TM) mechanisms appear to involve hundreds of proteins but their telomere repeat length related activities are only partly understood. Currently, a database that integrates information on TM relevant genes is missing.<br><br>DESCRIPTION: To provide a resource for studies that dissect TM features, we here introduce the TelNet database at http://www.cancertelsys.org/telnet/ . It offers a comprehensive compilation of more than 2000 human and 1100 yeast genes linked to telomere maintenance. These genes were annotated in terms of TM mechanism, associated specific functions and orthologous genes, a TM significance score and information from peer-reviewed literature. This TM information can be retrieved via different search and view modes and evaluated for a set of genes as demonstrated for an exemplary application.<br><br>CONCLUSION: TelNet supports the annotation of genes identified from bioinformatics analysis pipelines to reveal possible connections with TM networks. We anticipate that TelNet will be a helpful resource for researchers that study telomeres.},
}
@article {pmid29774655,
year = {2018},
author = {Gu, P and Jia, S and Takasugi, T and Smith, E and Nandakumar, J and Hendrickson, E and Chang, S},
title = {CTC1-STN1 coordinates G- and C-strand synthesis to regulate telomere length.},
journal = {Aging cell},
volume = {17},
number = {4},
pages = {e12783},
pmid = {29774655},
issn = {1474-9726},
support = {T32 AG000114/AG/NIA NIH HHS/United States ; R01 CA202816/CA/NCI NIH HHS/United States ; R00 CA167644/CA/NCI NIH HHS/United States ; R21 CA200506/CA/NCI NIH HHS/United States ; T32 GM007205/GM/NIGMS NIH HHS/United States ; R01 AG050509/AG/NIA NIH HHS/United States ; RSG-17-037-01-DMC//American Cancer Society Research Scholar/International ; R01 GM120094/GM/NIGMS NIH HHS/United States ; R21 CA182280/CA/NCI NIH HHS/United States ; R01 GM088351/GM/NIGMS NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; R01 CA190492/CA/NCI NIH HHS/United States ; },
mesh = {DNA Polymerase I/metabolism ; *DNA Replication ; HCT116 Cells ; HEK293 Cells ; Humans ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Coats plus (CP) is a rare autosomal recessive disorder caused by mutations in CTC1, a component of the CST (CTC1, STN1, and TEN1) complex important for telomere length maintenance. The molecular basis of how CP mutations impact upon telomere length remains unclear. The CP CTC1[L1142H] mutation has been previously shown to disrupt telomere maintenance. In this study, we used CRISPR/Cas9 to engineer this mutation into both alleles of HCT116 and RPE cells to demonstrate that CTC1:STN1 interaction is required to repress telomerase activity. CTC1[L1142H] interacts poorly with STN1, leading to telomerase-mediated telomere elongation. Impaired interaction between CTC1[L1142H] :STN1 and DNA Pol-α results in increased telomerase recruitment to telomeres and further telomere elongation, revealing that C:S binding to DNA Pol-α is required to fully repress telomerase activity. CP CTC1 mutants that fail to interact with DNA Pol-α resulted in loss of C-strand maintenance and catastrophic telomere shortening. Our findings place the CST complex as an important regulator of both G-strand extensions by telomerase and C-strand synthesis by DNA Pol-α.},
}
@article {pmid29774234,
year = {2018},
author = {Matmati, S and Vaurs, M and Escandell, JM and Maestroni, L and Nakamura, TM and Ferreira, MG and Géli, V and Coulon, S},
title = {The fission yeast Stn1-Ten1 complex limits telomerase activity via its SUMO-interacting motif and promotes telomeres replication.},
journal = {Science advances},
volume = {4},
number = {5},
pages = {eaar2740},
pmid = {29774234},
issn = {2375-2548},
support = {R01 GM078253/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Replication ; DNA, Single-Stranded ; Gene Expression ; Models, Biological ; Molecular Chaperones/chemistry/genetics/*metabolism ; Mutation ; Protein Binding ; *Protein Interaction Domains and Motifs ; SUMO-1 Protein/chemistry/metabolism ; Schizosaccharomyces/*physiology ; Schizosaccharomyces pombe Proteins/chemistry/genetics/*metabolism ; Telomerase/*metabolism ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {Mammalian CST (CTC1-STN1-TEN1) complex fulfills numerous functions including rescue of the stalled replication forks and termination of telomerase action. In fission yeast lacking the CTC1 ortholog, the Stn1-Ten1 complex restricts telomerase action via its sumoylation-mediated interaction with Tpz1[TPP1]. We identify a small ubiquitin-like modifier (SUMO)-interacting motif (SIM) in the carboxyl-terminal part of Stn1 and show that this domain is crucial for SUMO and Tpz1-SUMO interactions. Point mutations in the SIM (Stn1-226) lead to telomere elongation, impair Stn1-Ten1 recruitment to telomeres, and enhance telomerase binding, revealing that Stn1 SIM domain contributes to the inhibition of telomerase activity at chromosome ends. Our results suggest that Stn1-Ten1 promotes DNA synthesis at telomeres to limit single-strand DNA accumulation. We further demonstrate that Stn1 functions in the replication of telomeric and subtelomeric regions in a Taz1-independent manner. Genetic analysis reveals that misregulation of origin firing and/or telomerase inhibition circumvents the replication defects of the stn1-226 mutant. Together, our results show that the Stn1-Ten1 complex has a dual function at telomeres by limiting telomerase action and promoting chromosome end replication.},
}
@article {pmid29770205,
year = {2018},
author = {Savage, SA},
title = {Beginning at the ends: telomeres and human disease.},
journal = {F1000Research},
volume = {7},
number = {},
pages = {},
pmid = {29770205},
issn = {2046-1402},
abstract = {Studies of rare and common illnesses have led to remarkable progress in the understanding of the role of telomeres (nucleoprotein complexes at chromosome ends essential for chromosomal integrity) in human disease. Telomere biology disorders encompass a growing spectrum of conditions caused by rare pathogenic germline variants in genes encoding essential aspects of telomere function. Dyskeratosis congenita, a disorder at the severe end of this spectrum, typically presents in childhood with the classic triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia, accompanied by a very high risk of bone marrow failure, cancer, pulmonary fibrosis, and other medical problems. In contrast, the less severe end of the telomere biology disorder spectrum consists of middle-age or older adults with just one feature typically seen in dyskeratosis congenita, such as pulmonary fibrosis or bone marrow failure. In the common disease realm, large-scale molecular epidemiology studies have discovered novel associations between illnesses, such as cancer, heart disease, and mental health, and both telomere length and common genetic variants in telomere biology genes. This review highlights recent findings of telomere biology in human disease from both the rare and common disease perspectives. Multi-disciplinary collaborations between clinicians, basic scientists, and epidemiologist are essential as we seek to incorporate new telomere biology discoveries to improve health outcomes.},
}
@article {pmid29761887,
year = {2019},
author = {Nacopoulos, C and Gkouskou, K and Karypidis, D and Vlastos, I and Vesala, AM and Choukroun, J and Miron, RJ and Prokopakis, E},
title = {Telomere length and genetic variations affecting telomere length as biomarkers for facial regeneration with platelet-rich fibrin based on the low-speed centrifugation concept.},
journal = {Journal of cosmetic dermatology},
volume = {18},
number = {1},
pages = {408-413},
doi = {10.1111/jocd.12666},
pmid = {29761887},
issn = {1473-2165},
support = {1/26/09/2016//Plastic and Reconstructive Surgery Department of Agioi Anargyroi General Oncological Hospital of Kifisia/ ; },
mesh = {Biomarkers ; Centrifugation/methods ; Cosmetic Techniques ; Face ; Female ; Genetic Variation ; Humans ; Middle Aged ; Patient Satisfaction ; *Platelet-Rich Fibrin ; Polymorphism, Single Nucleotide ; Regeneration/*genetics ; Skin Aging/*genetics ; Skin Physiological Phenomena/*genetics ; Surveys and Questionnaires ; *Telomere Shortening ; Treatment Outcome ; },
abstract = {BACKGROUND: Platelet-Rich Fibrin (PRF), a fibrin matrix produced by single blood centrifugation that contains leukocytes, platelets, and growth factors, is increasingly being utilized for facial regeneration purposes. However, our understanding of the involved pathophysiological mechanisms affecting regeneration is limited and current protocols require better optimization. Biomarkers that are related to skin aging such as telomere length (TL) have been proposed as a mean to analyze patients' stratification.<br><br>OBJECTIVE: Our aim is to study whether the outcomes of a facial regeneration protocol performed with PRF are related to TL and genetic variations affecting TL. This can aid in the standardization of a surgical aesthetic protocol.<br><br>PATIENTS AND METHODS: In all, 41 patients treated with PRF produced with the low-speed centrifugation concept were included in this observational study. The correlation between TL and genetic variations were assessed versus treatment outcomes, namely the number of sessions and aesthetic results utilizing the FACE-Q skin satisfaction questionnaire.<br><br>RESULTS: In all, 39 of the 41 patients completed the treatment. TL correlated with the initial responses to FACE-Q (&#x3c1;&#xa0;=&#xa0;.33, P&#xa0;=&#xa0;.05). Genetic variations affecting TL was related to the change of FACE-Q (&#x3c1;&#xa0;=&#xa0;.35, P&#xa0;=&#xa0;.034) as well as to the number of treatment sessions (&#x3c1;&#xa0;=&#xa0;.38, P&#xa0;=&#xa0;.019).<br><br>CONCLUSIONS: Telomere length (TL) was related to patient perceived facial skin appearance. In addition, genetic variations affecting TL were related to the final outcomes (number of sessions and improvements of FACE-Q results) and may be a useful biomarker for future regenerative procedures performed with PRF for facial regeneration.},
}
@article {pmid29761675,
year = {2018},
author = {Laish, I and Mari, A and Mannasse, B and Hadary, R and Konikoff, FM and Amiel, A and Kitay-Cohen, Y},
title = {Telomere Length, Aggregates, and Capture in Cirrhosis.},
journal = {The Israel Medical Association journal : IMAJ},
volume = {20},
number = {5},
pages = {295-299},
pmid = {29761675},
issn = {1565-1088},
mesh = {Female ; Humans ; In Situ Hybridization, Fluorescence ; Israel ; Liver/metabolism/pathology ; Liver Cirrhosis/*diagnosis/metabolism/*pathology ; Male ; Middle Aged ; Prospective Studies ; Telomere/metabolism/*pathology ; },
abstract = {BACKGROUND: Shortened telomeres were found in patients with cirrhosis, probably reflecting chronic liver injury, continuous regeneration, and destruction of hepatic nodules.<br><br>OBJECTIVES: To test whether telomere shortening is a general marker of cirrhosis, independent of disease etiology.<br><br>METHODS: We evaluated telomere length in patients with cryptogenic cirrhosis (largely a late sequela of steatohepatitis) compared to patients with cirrhosis caused by chronic hepatitis B and C (HBV/HCV). We also evaluated telomere aggregates, a sensitive parameter of telomere dysfunction and genetic instability. We analyzed peripheral lymphocytes from 25 patients with cryptogenic cirrhosis, 15 patients with cirrhosis due to chronic viral hepatitis, and 20 age-matched controls. Telomere length was analyzed using quantitative fluorescence in situ hybridization. Aggregate size was divided into three fusion groups of 2-5, 6-10, and 11-15 telomeres, relative to the size of a single telomere.<br><br>RESULTS: Shorter telomere length was found in patients with cirrhosis from all three etiologies (mean 121.3 &#xb1; 24.1) compared to controls (mean 63.5 &#xb1; 23.5). In contrast, there was significantly more fusion of > 5 telomeres only in the HBV/HCV cirrhosis group compared to healthy controls (P = 0.023), but not in the cryptogenic cirrhosis group.<br><br>CONCLUSIONS: While shortened telomeres in peripheral lymphocytes are a general marker of liver cirrhosis, telomere aggregates may signify a more sensitive genetic instability parameter for the diverse, etiology-based malignant potential of cirrhosis. This finding is in agreement with the well-known higher tendency toward developing hepatocellular carcinoma with cirrhosis caused by chronic hepatitis relative to steatohepatitis.},
}
@article {pmid29760601,
year = {2018},
author = {Zhang, M and Guo, X and Gao, Y and Lu, D and Li, W},
title = {Tumor Cell-Accelerated Senescence Is Associated With DNA-PKcs Status and Telomere Dysfunction Induced by Radiation.},
journal = {Dose-response : a publication of International Hormesis Society},
volume = {16},
number = {2},
pages = {1559325818771527},
pmid = {29760601},
issn = {1559-3258},
abstract = {Whether telomere structure integrity is related to radiosensitivity is not well investigated thus far. In this study, we investigated the relation between telomere instability and radiation-induced accelerated senescence. Partial knockdown of DNA-dependent catalytic subunit of protein kinase (DNA-PKcs) in human breast cancer cell line MCF-7 was established by small interfering RNA. Radiosensitivity of control and DNA-PKcs knockdown MCF-7 cells was analyzed by clonogenetic assay. Cell growth was measured by real-time cell electronic sensing. Senescence and apoptosis were evaluated by β-galactosidase histochemical staining and fluorescence-activated cell sorting, respectively. DNA damage was determined by long polymerase chain reaction (PCR). Telomere length and integrity were analyzed by real-time PCR and cytogenetic assay, respectively. DNA-PKcs knockdown MCF-7 cells were more sensitive to X-irradiation than control cells. Further investigation revealed that accelerated senescence is more pronounced than apoptosis in cells after radiation, particularly in DNA-PKcs knockdown cells. The cytogenetic assay and kinetics of DNA damage repair revealed that the role of telomere end-capping in DNA-PKcs, rather than DNA damage repair, was more relevant to radiosensitivity. To our knowledge, this is the first study to show that DNA-PKcs plays an important role in radiation-induced accelerated senescence via maintenance of telomere integrity in MCF-7 cells. These results could be useful for future understanding of the radiation-induced genome instability and its consequences.},
}
@article {pmid29758336,
year = {2018},
author = {Patnaik, MM and Kamath, PS and Simonetto, DA},
title = {Hepatic manifestations of telomere biology disorders.},
journal = {Journal of hepatology},
volume = {69},
number = {3},
pages = {736-743},
doi = {10.1016/j.jhep.2018.05.006},
pmid = {29758336},
issn = {1600-0641},
support = {KL2 TR000136/TR/NCATS NIH HHS/United States ; },
mesh = {*Aging, Premature/genetics/physiopathology/therapy ; Disease Management ; Humans ; *Hypertension, Portal/diagnosis/etiology ; *Liver Cirrhosis/etiology/physiopathology ; Telomere Homeostasis ; Telomere Shortening/*genetics ; },
abstract = {A 51-year-old Caucasian male was referred for evaluation of variceal bleeding. Laboratory tests were remarkable for mild thrombocytopenia and moderate alkaline phosphatase elevation. Synthetic liver function was well preserved. Abdominal computed tomography scan revealed moderate splenomegaly, gastric varices, and normal hepatic contour. A transjugular liver biopsy was performed revealing findings of nodular regenerative hyperplasia with no significant fibrosis or necroinflammatory activity. Hepatic venous pressure gradient was elevated at 31 mmHg, consistent with clinically significant portal hypertension. The clinical course was complicated by refractory gastric variceal bleeding requiring a surgical portosystemic shunt. Approximately seven years after the initial presentation, the patient developed progressive dyspnoea and a diagnosis of idiopathic pulmonary fibrosis was made. Contrast-enhanced echocardiogram was not suggestive of hepatopulmonary syndrome or portopulmonary hypertension. Given this new diagnosis a telomere biology disorder was suspected. A flow-fluorescence in situ hybridisation analysis for telomere length assessment revealed telomere lengths below the first percentile in both lymphocytes and granulocytes. Next generation sequencing analysis identified a heterozygous mutation involving the hTERT gene (Histidine983Threonine). The lung disease unfortunately progressed in the subsequent two years, leading to the patient's death nine years after his initial presentation with portal hypertension. During those nine years two brothers also developed idiopathic pulmonary fibrosis. The questions that arise from this case include.},
}
@article {pmid29757418,
year = {2018},
author = {Mannan, T and Ahmed, S and Akhtar, E and Ahsan, KB and Haq, A and Kippler, M and Vahter, M and Raqib, R},
title = {Associations of Arsenic Exposure With Telomere Length and Naïve T Cells in Childhood-A Birth Cohort Study.},
journal = {Toxicological sciences : an official journal of the Society of Toxicology},
volume = {164},
number = {2},
pages = {539-549},
doi = {10.1093/toxsci/kfy105},
pmid = {29757418},
issn = {1096-0929},
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Arsenic/blood/metabolism/urine ; Arsenic Poisoning/blood/*genetics/*immunology/metabolism ; Child ; Child, Preschool ; Cohort Studies ; DNA Damage ; Deoxyguanosine/analogs &amp; derivatives/blood ; Environmental Exposure/*adverse effects ; Female ; Gene Rearrangement, T-Lymphocyte/drug effects ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Oxidative Stress/drug effects ; Pregnancy ; Prenatal Exposure Delayed Effects ; Randomized Controlled Trials as Topic ; T-Lymphocytes/*drug effects/immunology ; Telomere/*drug effects/genetics ; },
abstract = {There is limited knowledge of association between arsenic exposure and telomere length (TL) and signal joint T-cell receptor excision circle (sjTREC) that are potential biomarkers of immune senescence and disease susceptibility. We aimed to clarify whether long-term inorganic arsenic exposure influences TL and sjTRECs in childhood. Children born in a longitudinal mother-child cohort were followed-up at 4.5 (n = 275) and 9 years (n = 351) of age. Arsenic exposure was assessed by metabolite concentrations in urine (U-As) from mothers at gestational week 8 (prenatal) and their children at 4.5 and 9 years. TL and sjTRECs were determined in blood cells using quantitative PCR. The oxidative DNA damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG) in plasma was measured by ELISA. In multivariable-adjusted spline regression analyses, both prenatal and childhood arsenic exposure above U-As of 45 µg/l were significantly inversely associated with TL and sjTRECs at 9 years. Fraction of monomethylarsonic acid (MMA) above spline knot 7% were significantly inversely associated with both TL and sjTRECs reflecting increased toxicity due to less-efficient arsenic metabolism in 9--year-old children. Prenatal and childhood arsenic exposure were positively associated with 8-OHdG at 9 years which in turn was inversely associated with sjTRECs at 9 years. However, adjustment with 8-OHdG did not change the estimates of the association of U-As with sjTRECs reflecting little contribution from 8-OHdG-induced oxidative stress. Our findings suggest that chronic arsenic exposure from early life can result in TL attrition and lower production of naïve T cells potentially leading to immunosenescence and immunodeficiency.},
}
@article {pmid29752772,
year = {2018},
author = {Coburn, SB and Graubard, BI and Trabert, B and McGlynn, KA and Cook, MB},
title = {Associations between circulating sex steroid hormones and leukocyte telomere length in men in the National Health and Nutrition Examination Survey.},
journal = {Andrology},
volume = {6},
number = {4},
pages = {542-546},
pmid = {29752772},
issn = {2047-2927},
support = {Z01 CP010183//Intramural NIH HHS/United States ; Z99 CA999999//Intramural NIH HHS/United States ; },
mesh = {Adult ; Aged ; Cross-Sectional Studies ; Gonadal Steroid Hormones/*blood ; Humans ; Leukocytes/metabolism ; Male ; Middle Aged ; Nutrition Surveys ; Sex Hormone-Binding Globulin/metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {Preliminary evidence suggests that sex steroid hormones, such as danazol (a synthetic sex steroid hormone), may be involved in enhancing telomerase activity. Elucidating underlying mechanisms of telomerase activity may further therapeutic options for individuals with telomeropathies and potentially avert certain age-related conditions. Therefore, we conducted a cross-sectional study to investigate the relationship between circulating sex steroid hormones and SHBG with leukocyte telomere length among 499 males in NHANES (1999-2002 surveys). Sample-weighted linear regression analyses were conducted to assess age-adjusted and multivariable-adjusted estimates of associations. Estimates were rescaled to represent telomere length change in base pairs per half the value of the interquartile range of the independent variable. Estradiol and free estradiol were significantly inversely associated with leukocyte telomere length (βcontinuous per §IQR = -61, p = 0.04; free estradiol βcontinuous per §IQR = -67, p = 0.03). Testosterone, free testosterone, androstanediol glucuronide, and SHBG were not associated with leukocyte telomere length. The inverse association seen in this study indicates that a danazol-induced hypoestrogenic state could partly underlie the previously observed association between danazol therapy and increased leukocyte telomere length.},
}
@article {pmid29752677,
year = {2018},
author = {Dos Santos, A and Campagnari, F and Krepischi, ACV and Ribeiro Câmara, ML and de Arruda Brasil, RCE and Vieira, L and Vianna-Morgante, AM and Otto, PA and Pearson, PL and Rosenberg, C},
title = {Insight into the mechanisms and consequences of recurrent telomere capture associated with a sub-telomeric deletion.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {26},
number = {3},
pages = {191-198},
pmid = {29752677},
issn = {1573-6849},
mesh = {Cell Lineage ; *Chromosome Deletion ; Chromosomes, Human, Pair 1/*genetics ; Humans ; *Mosaicism ; Polymorphism, Single Nucleotide ; Telomere/*genetics ; Uniparental Disomy ; },
abstract = {A complex mosaicism of the short arm of chromosome 1 detected by SNP microarray analysis is described in a patient presenting a 4-Mb 1p36 terminal deletion and associated phenotypic features. The array pattern of chromosome 1p displayed an intriguing increase in divergence of the SNP heterozygote frequency from the expected 50% from the centromere towards the 1p36 breakpoint. This suggests that various overlapping segments of UPD were derived by somatic recombination between the 1p homologues. The most likely explanation was the occurrence of a series of events initiated in either a gamete or an early embryonic cell division involving a 1pter deletion rapidly followed by multiple telomere captures, resulting in additive, stepped increases in frequency of homozygosity towards the telomere. The largest segment involved the entire 1p, and at least four other capture events were observed, indicating that at least five independent telomere captures occurred in separate cell lineages. The determination of breakpoint position by detection of abrupt changes in B-allele frequency using a moving window analysis demonstrated that they were identical in blood and saliva, the tissues available for analysis. We developed a model to explain the interaction of parameters determining the mosaic clones and concluded that, while number, size, and position of telomere captures were important initiating determinants, variation in individual clone frequencies was the main contributor to mosaic differences between tissues. All previous reports of telomere capture have been restricted to single events. Other cases involving multiple telomere capture probably exist but require investigation by SNP microarrays for their detection.},
}
@article {pmid29752006,
year = {2019},
author = {AlAhwal, MS and Zaben, FA and Sehlo, MG and Khalifa, DA and Al-Aama, JY and Edris, S and Ashy, JA and Koenig, HG},
title = {Depression and telomere length in colorectal cancer patients in Saudi Arabia.},
journal = {Asian journal of psychiatry},
volume = {40},
number = {},
pages = {130-131},
doi = {10.1016/j.ajp.2018.04.039},
pmid = {29752006},
issn = {1876-2026},
mesh = {*Colorectal Neoplasms/epidemiology/genetics ; Comorbidity ; *Depression/epidemiology/genetics ; *Depressive Disorder/epidemiology/genetics ; Female ; Humans ; Male ; Middle Aged ; Saudi Arabia/epidemiology ; *Telomere Shortening/genetics ; },
}
@article {pmid29751799,
year = {2018},
author = {Everaerts, S and Lammertyn, EJ and Martens, DS and De Sadeleer, LJ and Maes, K and van Batenburg, AA and Goldschmeding, R and van Moorsel, CHM and Dupont, LJ and Wuyts, WA and Vos, R and Gayan-Ramirez, G and Kaminski, N and Hogg, JC and Janssens, W and Verleden, GM and Nawrot, TS and Verleden, SE and McDonough, JE and Vanaudenaerde, BM},
title = {The aging lung: tissue telomere shortening in health and disease.},
journal = {Respiratory research},
volume = {19},
number = {1},
pages = {95},
pmid = {29751799},
issn = {1465-993X},
support = {C24/15/030//KU Leuven/International ; 603038//FP7 Ideas: European Research Council/International ; },
mesh = {Adolescent ; Adult ; Aged ; Child ; Female ; *Health Status ; Humans ; Lung/*pathology ; Lung Diseases/*genetics/*pathology ; Male ; Middle Aged ; Telomere Shortening/*physiology ; Young Adult ; },
abstract = {BACKGROUND: Telomere shortening has been associated with several lung diseases. However, telomere length is generally measured in peripheral blood leucocytes rather than in lung tissue, where disease occurs. Consequently, telomere dynamics have not been established for the normal human lung nor for diseased lung tissue. We hypothesized an age- and disease-dependent shortening of lung tissue telomeres.<br><br>METHODS: At time of (re-)transplantation or autopsy, 70 explant lungs were collected: from unused donors (normal, n&#xa0;=&#xa0;13) and patients with cystic fibrosis (CF, n&#xa0;=&#xa0;12), chronic obstructive pulmonary disease (COPD, n&#xa0;=&#xa0;11), chronic hypersensitivity pneumonitis (cHP, n&#xa0;=&#xa0;9), bronchiolitis obliterans syndrome (BOS) after prior transplantation (n&#xa0;=&#xa0;11) and restrictive allograft syndrome (RAS) after prior transplantation (n&#xa0;=&#xa0;14). Lungs were inflated, frozen and then scanned using CT. Four tissue cores from distinct lung regions were sampled for analysis. Disease severity was evaluated using CT and micro CT imaging. DNA was extracted from the samples and average relative telomere length (RTL) was determined using real-time qPCR.<br><br>RESULTS: The normal lungs showed a decrease in RTL with age (p&#xa0;<&#xa0;0.0001). Of the diseased lungs, only BOS and RAS showed significant RTL decrease with increasing lung age (p&#xa0;=&#xa0;0.0220 and p&#xa0;=&#xa0;0.0272 respectively). Furthermore, we found that RTL showed considerable variability between samples within both normal and diseased lungs. cHP, BOS and RAS lungs had significant shorter RTL in comparison with normal lungs, after adjustment for lung age, sex and BMI (p&#xa0;<&#xa0;0.0001, p&#xa0;=&#xa0;0.0051 and p&#xa0;=&#xa0;0.0301 respectively). When investigating the relation between RTL and regional disease severity in CF, cHP and RAS, no association was found.<br><br>CONCLUSION: These results show a progressive decline in telomere length with age in normal, BOS and RAS lungs. cHP, BOS and RAS lungs demonstrated shorter RTL compared to normal lungs. Lung tissue RTL does not associate with regional disease severity within the lung. Therefore, tissue RTL does not seem to fully reflect peripheral blood telomere length.},
}
@article {pmid29751586,
year = {2018},
author = {Gaspar, TB and Sá, A and Lopes, JM and Sobrinho-Simões, M and Soares, P and Vinagre, J},
title = {Telomere Maintenance Mechanisms in Cancer.},
journal = {Genes},
volume = {9},
number = {5},
pages = {},
pmid = {29751586},
issn = {2073-4425},
abstract = {Tumour cells can adopt telomere maintenance mechanisms (TMMs) to avoid telomere shortening, an inevitable process due to successive cell divisions. In most tumour cells, telomere length (TL) is maintained by reactivation of telomerase, while a small part acquires immortality through the telomerase-independent alternative lengthening of telomeres (ALT) mechanism. In the last years, a great amount of data was generated, and different TMMs were reported and explained in detail, benefiting from genome-scale studies of major importance. In this review, we address seven different TMMs in tumour cells: mutations of the TERT promoter (TERTp), amplification of the genes TERT and TERC, polymorphic variants of the TERT gene and of its promoter, rearrangements of the TERT gene, epigenetic changes, ALT, and non-defined TMM (NDTMM). We gathered information from over fifty thousand patients reported in 288 papers in the last years. This wide data collection enabled us to portray, by organ/system and histotypes, the prevalence of TERTp mutations, TERT and TERC amplifications, and ALT in human tumours. Based on this information, we discuss the putative future clinical impact of the aforementioned mechanisms on the malignant transformation process in different setups, and provide insights for screening, prognosis, and patient management stratification.},
}
@article {pmid29750592,
year = {2018},
author = {Wojcicki, JM and Elwan, D and Lin, J and Blackburn, E and Epel, E},
title = {Chronic Obesity and Incident Hypertension in Latina Women Are Associated with Accelerated Telomere Length Loss over a 1-Year Period.},
journal = {Metabolic syndrome and related disorders},
volume = {16},
number = {6},
pages = {262-266},
pmid = {29750592},
issn = {1557-8518},
mesh = {Adult ; Age Factors ; Ethnicity ; Female ; Hispanic or Latino ; Humans ; Hypertension/complications/epidemiology/*pathology ; Metabolic Diseases/epidemiology/etiology ; Middle Aged ; Obesity/complications/epidemiology/*pathology ; Risk Assessment ; San Francisco/epidemiology ; Socioeconomic Factors ; *Telomere Shortening ; Weight Loss ; },
abstract = {AIMS: Shorter telomere length is associated with increased chronic disease risk in adulthood including diabetes mellitus and cardiovascular risk. Few studies have evaluated the relationship between telomere length change and incident disease risk in populations with a high percentage of overweight and obesity.<br><br>RESULTS: In an urban Latina population recruited in San Francisco (n&#x2009;=&#x2009;82) with a high prevalence of overweight and obesity (78.4%), we assessed leukocyte telomere length and telomere length change over a 1-year period in relation to obesity, chronicity of obesity, and incident metabolic disease risk 5-6 years later. We also assessed the relationship between telomere length change over a 1-year period and weight loss. There were no significant associations between baseline telomere length and socio-demographics including age and ethnicity, or current weight status. Telomere length change, however, was associated with being obese at baseline and previous years of chronic obesity. A high percentage of women who were obese at baseline were also obese the year before (90%) and 2 years before (85%). Obesity at baseline was an independent predictor for increased telomere length attrition (&#x3b2;&#x2009;=&#x2009;-346.9, -568.4 to -125.4; P&#x2009;<&#x2009;0.01). Similarly, chronic obesity was associated with increased risk for accelerated attrition (&#x3b2;&#x2009;=&#x2009;-280.6, -518.4 to -42.8; P&#x2009;<&#x2009;0.01).<br><br>INNOVATION: We speculate that accelerated attrition may be a harbinger of metabolic disease. We also found that those who had or developed hypertension had accelerated attrition [-407.4&#x2009;&#xb1;&#x2009;464.0 vs. -168.1&#x2009;&#xb1;&#x2009;643.6 (P&#x2009;=&#x2009;0.03)].<br><br>CONCLUSION: In populations with chronic and long-standing obesity, telomere length attrition rate, rather than baseline telomere length may be a more sensitive indicator of health status including chronic disease development.},
}
@article {pmid29750556,
year = {2018},
author = {Bauer, CM and Graham, JL and Abolins-Abols, M and Heidinger, BJ and Ketterson, ED and Greives, TJ},
title = {Chronological and Biological Age Predict Seasonal Reproductive Timing: An Investigation of Clutch Initiation and Telomeres in Birds of Known Age.},
journal = {The American naturalist},
volume = {191},
number = {6},
pages = {777-782},
doi = {10.1086/697224},
pmid = {29750556},
issn = {1537-5323},
mesh = {Aging/*physiology ; Animals ; Female ; Passeriformes/*physiology ; *Reproduction ; *Sexual Behavior, Animal ; *Telomere ; },
abstract = {Female vertebrates that breed earlier in the season generally have greater reproductive success. However, evidence suggests that breeding early may be costly, thus leading to the prediction that females with fewer future reproductive events will breed earlier in the season. While chronological age is a good indicator of remaining life span, telomere lengths may also be good biomarkers of longevity as they potentially reflect lifetime wear and tear (i.e., biological age). We examined whether variation in the timing of the first seasonal clutch was related to age and telomere length in female dark-eyed juncos (Junco hyemalis), predicting that older females and those with shorter telomeres would breed earlier. Both predictions held true and were independent of each other, as telomere length did not significantly vary with age. These results suggest that females may adjust their reproductive effort based on both chronological and biological age.},
}
@article {pmid29748631,
year = {2018},
author = {Esteves, KC and Jones, CW and Drury, SS},
title = {Reponse to Send et al. telomere length in newborns is related to maternal stress during pregnancy.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {43},
number = {11},
pages = {2163},
pmid = {29748631},
issn = {1740-634X},
mesh = {Female ; Humans ; Infant, Newborn ; Pregnancy ; Pregnancy Complications ; *Telomere ; *Telomere Shortening ; },
}
@article {pmid29748384,
year = {2018},
author = {Panneer Selvam, S and Roth, BM and Nganga, R and Kim, J and Cooley, MA and Helke, K and Smith, CD and Ogretmen, B},
title = {Balance between senescence and apoptosis is regulated by telomere damage-induced association between p16 and caspase-3.},
journal = {The Journal of biological chemistry},
volume = {293},
number = {25},
pages = {9784-9800},
pmid = {29748384},
issn = {1083-351X},
support = {R01 CA173687/CA/NCI NIH HHS/United States ; R01 CA088932/CA/NCI NIH HHS/United States ; P30 CA138313/CA/NCI NIH HHS/United States ; P01 CA203628/CA/NCI NIH HHS/United States ; R01 CA214461/CA/NCI NIH HHS/United States ; C06 RR015455/RR/NCRR NIH HHS/United States ; P30 GM103339/GM/NIGMS NIH HHS/United States ; R01 DE016572/DE/NIDCR NIH HHS/United States ; },
mesh = {Animals ; *Apoptosis ; Caspase 3/genetics/*metabolism ; Cell Proliferation ; *Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p16/genetics/*metabolism ; Female ; Humans ; Lung Neoplasms/genetics/metabolism/*pathology ; Lysophospholipids/metabolism ; Mice ; Mice, Knockout ; Mice, SCID ; Phosphotransferases (Alcohol Group Acceptor)/genetics/metabolism/*physiology ; Sphingosine/analogs &amp; derivatives/metabolism ; Telomere/genetics/*pathology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; },
abstract = {Telomerase activation protects cells from telomere damage by delaying senescence and inducing cell immortalization, whereas telomerase inhibition mediates rapid senescence or apoptosis. However, the cellular mechanisms that determine telomere damage-dependent senescence versus apoptosis induction are largely unknown. Here, we demonstrate that telomerase instability mediated by silencing of sphingosine kinase 2 (SPHK2) and sphingosine 1-phosphate (S1P), which binds and stabilizes telomerase, induces telomere damage-dependent caspase-3 activation and apoptosis, but not senescence, in p16-deficient lung cancer cells or tumors. These outcomes were prevented by knockdown of a tumor-suppressor protein, transcription factor 21 (TCF21), or by ectopic expression of WT human telomerase reverse transcriptase (hTERT) but not mutant hTERT with altered S1P binding. Interestingly, SphK2-deficient mice exhibited accelerated aging and telomerase instability that increased telomere damage and senescence via p16 activation especially in testes tissues, but not in apoptosis. Moreover, p16 silencing in SphK2[-/-] mouse embryonic fibroblasts activated caspase-3 and apoptosis without inducing senescence. Furthermore, ectopic WT p16 expression in p16-deficient A549 lung cancer cells prevented TCF21 and caspase-3 activation and resulted in senescence in response to SphK2/S1P inhibition and telomere damage. Mechanistically, a p16 mutant with impaired caspase-3 association did not prevent telomere damage-induced apoptosis, indicating that an association between p16 and caspase-3 proteins forces senescence induction by inhibiting caspase-3 activation and apoptosis. These results suggest that p16 plays a direct role in telomere damage-dependent senescence by limiting apoptosis via binding to caspase-3, revealing a direct link between telomere damage-dependent senescence and apoptosis with regards to aging and cancer.},
}
@article {pmid29743162,
year = {2018},
author = {Doherty, JA and Grieshober, L and Houck, JR and Barnett, MJ and Tapsoba, JD and Thornquist, M and Wang, CY and Goodman, GE and Chen, C},
title = {Telomere Length and Lung Cancer Mortality among Heavy Smokers.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {27},
number = {7},
pages = {829-837},
pmid = {29743162},
issn = {1538-7755},
support = {U01 CA063673/CA/NCI NIH HHS/United States ; U01 CA167462/CA/NCI NIH HHS/United States ; R01 CA151989/CA/NCI NIH HHS/United States ; UM1 CA167462/CA/NCI NIH HHS/United States ; R01 CA111703/CA/NCI NIH HHS/United States ; P30 CA042014/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Female ; Humans ; Lung Neoplasms/*genetics/mortality ; Male ; Middle Aged ; Smoking/*adverse effects/*genetics/mortality ; Telomere/*genetics ; },
abstract = {Background: Accumulating evidence suggests that short telomere length is associated with increased overall mortality, but the relationship with cancer mortality is less clear. We examined whether telomere length (global, and chromosome arm 5p- and 13q-specific) is associated with lung cancer mortality among cases from the β-Carotene and Retinol Efficacy Trial of heavy smokers.Methods: Telomere length was measured on average 6 years before diagnosis for 788 lung cancer cases. Adjusted Cox proportional hazards models of all-cause and lung cancer-specific mortality were assessed for lung cancer overall and by histotype.Results: Short telomere length was associated with increased mortality for small cell lung cancer (SCLC), particularly stage III/IV SCLC [HR and 95% confidence interval for shortest vs. longest telomere length tertile: 3.32 (1.78-6.21)]. Associations were strongest for those randomized to the active intervention and when telomere length was measured ≤5 years before diagnosis. All-cause mortality patterns were similar. Short chromosome 5p telomere length was suggestively associated with lung cancer mortality, but there was no association with chromosome 13q telomere length.Conclusions: Our large prospective study suggests that among heavy smokers who developed lung cancer, short prediagnosis telomere length is associated with increased risk of death from SCLC.Impact: This is the first study to examine telomere length and mortality in lung cancer cases by histotype. If the association between short telomere length and SCLC mortality is replicated, elucidation of mechanisms through which telomere length influences survival for this highly aggressive cancer may inform more effective use of telomere-targeted therapeutics. Cancer Epidemiol Biomarkers Prev; 27(7); 829-37. ©2018 AACR.},
}
@article {pmid29741164,
year = {2018},
author = {Mekhail, K},
title = {Corrigendum: Defining the Damaged DNA Mobility Paradox as Revealed by the Study of Telomeres, DSBs, Microtubules and Motors.},
journal = {Frontiers in genetics},
volume = {9},
number = {},
pages = {157},
doi = {10.3389/fgene.2018.00157},
pmid = {29741164},
issn = {1664-8021},
abstract = {[This corrects the article on p. 95 in vol. 9, PMID: 29616083.].},
}
@article {pmid29734785,
year = {2018},
author = {Toufektchan, E and Toledo, F},
title = {The Guardian of the Genome Revisited: p53 Downregulates Genes Required for Telomere Maintenance, DNA Repair, and Centromere Structure.},
journal = {Cancers},
volume = {10},
number = {5},
pages = {},
pmid = {29734785},
issn = {2072-6694},
abstract = {The p53 protein has been extensively studied for its capacity to prevent proliferation of cells with a damaged genome. Surprisingly, however, our recent analysis of mice expressing a hyperactive mutant p53 that lacks the C-terminal domain revealed that increased p53 activity may alter genome maintenance. We showed that p53 downregulates genes essential for telomere metabolism, DNA repair, and centromere structure and that a sustained p53 activity leads to phenotypic traits associated with dyskeratosis congenita and Fanconi anemia. This downregulation is largely conserved in human cells, which suggests that our findings could be relevant to better understand processes involved in bone marrow failure as well as aging and tumor suppression.},
}
@article {pmid29730834,
year = {2018},
author = {Siebert, C and Dos Santos, TM and Bertó, CG and Parisi, MM and Coelho, RP and Manfredini, V and Barbé-Tuana, FM and Wyse, ATS},
title = {Vitamin D Supplementation Reverses DNA Damage and Telomeres Shortening Caused by Ovariectomy in Hippocampus of Wistar Rats.},
journal = {Neurotoxicity research},
volume = {34},
number = {3},
pages = {538-546},
pmid = {29730834},
issn = {1476-3524},
mesh = {Age Factors ; Animals ; Catalase/metabolism ; Comet Assay ; DNA Damage/*drug effects ; Female ; Hippocampus/*drug effects ; Ovariectomy/*adverse effects ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Statistics, Nonparametric ; Superoxide Dismutase/metabolism ; Telomere Shortening/drug effects/*physiology ; Thiobarbituric Acid Reactive Substances/metabolism ; Time Factors ; Vitamin D/*pharmacology ; },
abstract = {The aim of this study was to investigate the effect of ovariectomy (OVX), a surgical model of menopause, and/or vitamin D (VIT D) supplementation on oxidative status, DNA damage, and telomere length in hippocampus of rats at two ages. Ninety-day-old (adult) or 180-day-old (older) female Wistar rats were divided into four groups: SHAM, OVX, VIT D, and OVX + VIT D. Thirty days after OVX, rats were supplemented with VIT D (500 IU/kg) by gavage, for a period of 30 days. Results showed that OVX altered antioxidant enzymes, increasing the activities of catalase in adult rats and superoxide dismutase in older rats. VIT D per se increased the activities of catalase and superoxide dismutase in older rats, but not in adult rats. VIT D supplementation to OVX (OVX + VIT D) rats did not reverse the effect of OVX on catalase in adult rats, but it partially reversed the increase in superoxide dismutase activity in older rats. OVX increased DNA damage in hippocampus of adult and older rats. VIT D per se reduced DNA damage, and when associated to OVX, it partially reversed this alteration. Additionally, OVX caused a telomere shortening in older rats, and VIT D was able to reverse such effect. Taken together, these results demonstrate that surgical menopause in rats causes hippocampal biochemical changes and VIT D appears, at least in part, to act in a beneficial way.},
}
@article {pmid29730783,
year = {2018},
author = {ElBadre, HM and El-Mahdy, RI and Mohamed, NA and Zakhary, MM and Maximous, DW},
title = {Tissue Indices of Telomere Length and p53 in Patients with Different Gastrointestinal Tumors: Correlation with Clinicopathological Status.},
journal = {Applied biochemistry and biotechnology},
volume = {186},
number = {3},
pages = {764-778},
doi = {10.1007/s12010-018-2759-6},
pmid = {29730783},
issn = {1559-0291},
mesh = {Acetylglucosaminidase/blood ; Adolescent ; Adult ; Biomarkers/metabolism ; Biomarkers, Tumor/*blood ; Case-Control Studies ; Catalase/blood ; Chitinases/blood ; DNA Damage ; Female ; Gastrointestinal Neoplasms/blood/*genetics/*pathology ; Glutathione Peroxidase/blood ; Humans ; Lipid Peroxides/blood ; Male ; Middle Aged ; *Oxidative Stress ; Superoxide Dismutase/blood ; *Telomere ; Tumor Suppressor Protein p53/*genetics ; Young Adult ; },
abstract = {Telomere length dysfunction is involved in the generation of genomic rearrangements that drive progression to malignancy. A set of serological markers for telomere dysfunction, namely chitinase and N-acetylglucosaminidase (NAG), DNA damage, and tissue alteration of p53 have been identified. The probability that genomic damage, accumulation of reactive oxygen species, and shorter telomeres may be related to the onset and advancement of gastrointestinal (GI) tumors. A total of 40 patients with GI tumors and 20 healthy controls with matched age and sex were included. Estimation of serum chitinase, NAG, lipid peroxide (LPER), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase by colorimetric methods, and p53 by ELISA were assessed. Related clinicopathological features were determined. Serological chitinase, NO, LPER, and p53 were significantly increased, SOD was significantly decreased (p ˂ 0.001 for each) in GI tumor patients compared with controls and correlated significantly with age. There was a significant correlation between telomere dysfunction indices, p53, oxidative stress indices, and malignant stages of GI cancer patients. Moreover, a significant difference in the mean serum levels of indices between control, malignant, and benign subjects was found. Accordingly, these biomarkers play an important role in the pathogenesis of GI cancer and their estimation may predict the GI tumor behavior.},
}
@article {pmid29728662,
year = {2018},
author = {Martens, DS and Wei, FF and Cox, B and Plusquin, M and Thijs, L and Winckelmans, E and Zhang, ZY and Nawrot, TS and Staessen, JA},
title = {Retinal microcirculation and leukocyte telomere length in the general population.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {7095},
pmid = {29728662},
issn = {2045-2322},
mesh = {Adult ; Aged ; Comorbidity ; Female ; Humans ; *Leukocytes ; Male ; *Microcirculation ; Middle Aged ; Phenotype ; Public Health Surveillance ; *Retinal Vessels ; Risk Factors ; Sensitivity and Specificity ; *Telomere ; Telomere Homeostasis ; Young Adult ; },
abstract = {Retinal arteriolar narrowing increases with age and predict adverse cardiovascular outcomes. Telomere length keeps track of the division of somatic cells and is a biomarker of biological age. We investigated to what extent retinal arteriolar diameters are associated with biological age, as captured by leukocyte telomere length (LTL). In 168 randomly selected Flemish participants from the family-based population study FLEMENGHO (mean age, 46.2 years) at baseline, of whom 85 underwent a follow-up examination (median, 4.1 years), we post-processed nonmydriatic retinal photographs and measured LTL. In men only, central retinal arteriolar equivalents (CRAE) and arteriole-to-venule ratio (AVR) were associated with LTL with stronger associations at higher age and body mass index. In men aged 57.6 years (75th percentile) a 20% shorter LTL was associated with a decrease in CRAE of 4.57 µm. A 20% shorter LTL was associated with a decrease of 5.88 µm in CRAE at a BMI of 29.9 kg/m[2] (75th percentile). Similar associations were observed between AVR and LTL. In women, no retinal microvascular traits were associated with LTL. Retinal arteriolar narrowing in men but not in women is associated with biological age. Our findings support the idea that avoiding overweight contributes to maintaining a healthier microcirculation.},
}
@article {pmid29727665,
year = {2018},
author = {Shibuya, H and Hernández-Hernández, A and Morimoto, A and Negishi, L and Höög, C and Watanabe, Y},
title = {MAJIN Links Telomeric DNA to the Nuclear Membrane by Exchanging Telomere Cap.},
journal = {Cell},
volume = {173},
number = {4},
pages = {1058},
doi = {10.1016/j.cell.2018.04.025},
pmid = {29727665},
issn = {1097-4172},
}
@article {pmid29727617,
year = {2018},
author = {Mendez-Bermudez, A and Lototska, L and Bauwens, S and Giraud-Panis, MJ and Croce, O and Jamet, K and Irizar, A and Mowinckel, M and Koundrioukoff, S and Nottet, N and Almouzni, G and Teulade-Fichou, MP and Schertzer, M and Perderiset, M and Londoño-Vallejo, A and Debatisse, M and Gilson, E and Ye, J},
title = {Genome-wide Control of Heterochromatin Replication by the Telomere Capping Protein TRF2.},
journal = {Molecular cell},
volume = {70},
number = {3},
pages = {449-461.e5},
doi = {10.1016/j.molcel.2018.03.036},
pmid = {29727617},
issn = {1097-4164},
mesh = {Cell Line, Tumor ; Centromere/genetics ; Chromatin/genetics ; DNA Helicases/genetics ; DNA Replication/*genetics ; G-Quadruplexes ; Genome/*genetics ; HeLa Cells ; Heterochromatin/*genetics ; Humans ; S Phase/genetics ; Telomere/*genetics ; Telomeric Repeat Binding Protein 2/*genetics ; },
abstract = {Hard-to-replicate regions of chromosomes (e.g., pericentromeres, centromeres, and telomeres) impede replication fork progression, eventually leading, in the event of replication stress, to chromosome fragility, aging, and cancer. Our knowledge of the mechanisms controlling the stability of these regions is essentially limited to telomeres, where fragility is counteracted by the shelterin proteins. Here we show that the shelterin subunit TRF2 ensures progression of the replication fork through pericentromeric heterochromatin, but not centromeric chromatin. In a process involving its N-terminal basic domain, TRF2 binds to pericentromeric Satellite III sequences during S phase, allowing the recruitment of the G-quadruplex-resolving helicase RTEL1 to facilitate fork progression. We also show that TRF2 is required for the stability of other heterochromatic regions localized throughout the genome, paving the way for future research on heterochromatic replication and its relationship with aging and cancer.},
}
@article {pmid29727616,
year = {2018},
author = {Li, F and Kim, H and Ji, Z and Zhang, T and Chen, B and Ge, Y and Hu, Y and Feng, X and Han, X and Xu, H and Zhang, Y and Yu, H and Liu, D and Ma, W and Songyang, Z},
title = {The BUB3-BUB1 Complex Promotes Telomere DNA Replication.},
journal = {Molecular cell},
volume = {70},
number = {3},
pages = {395-407.e4},
pmid = {29727616},
issn = {1097-4164},
support = {P30 CA125123/CA/NCI NIH HHS/United States ; R01 CA211653/CA/NCI NIH HHS/United States ; R01 HL131744/HL/NHLBI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Cell Cycle Proteins/*genetics ; Cell Line ; Cell Line, Tumor ; DNA Helicases/genetics ; DNA Replication/*genetics ; HEK293 Cells ; HeLa Cells ; Humans ; M Phase Cell Cycle Checkpoints/genetics ; Poly-ADP-Ribose Binding Proteins/*genetics ; Protein Serine-Threonine Kinases/*genetics ; S Phase/genetics ; Spindle Apparatus/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; },
abstract = {Telomeres and telomere-binding proteins form complex secondary nucleoprotein structures that are critical for genome integrity but can present serious challenges during telomere DNA replication. It remains unclear how telomere replication stress is resolved during S phase. Here, we show that the BUB3-BUB1 complex, a component in spindle assembly checkpoint, binds to telomeres during S phase and promotes telomere DNA replication. Loss of the BUB3-BUB1 complex results in telomere replication defects, including fragile and shortened telomeres. We also demonstrate that the telomere-binding ability of BUB3 and kinase activity of BUB1 are indispensable to BUB3-BUB1 function at telomeres. TRF2 targets BUB1-BUB3 to telomeres, and BUB1 can directly phosphorylate TRF1 and promote TRF1 recruitment of BLM helicase to overcome replication stress. Our findings have uncovered previously unknown roles for the BUB3-BUB1 complex in S phase and shed light on how proteins from diverse pathways function coordinately to ensure proper telomere replication and maintenance.},
}
@article {pmid29725455,
year = {2018},
author = {Ren, X and Tu, C and Tang, Z and Ma, R and Li, Z},
title = {Alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas.},
journal = {Oncology letters},
volume = {15},
number = {5},
pages = {7489-7496},
pmid = {29725455},
issn = {1792-1074},
abstract = {Sarcoma is a rare and heterogeneous type of cancer with an early mean onset age and a poor prognosis. However, its genetic basis remains unclear. A series of recent genomic studies in sarcomas have identified the occurrence of mutations in the α-thalassemia/mental retardation syndrome X-linked (ATRX) gene. The ATRX protein belongs to the SWI/SNF family of chromatin remodeling proteins, which are frequently associated with α-thalassemia syndrome. Cancer cells depend on telomerase or the alternative lengthening of telomeres (ALT) pathway to overcome replicative programmed mortality. Loss of ATRX is associated with ALT in sarcoma. In the present review, recent whole genome and/or whole exome genomic studies are summarized. In addition ATRX immunohistochemistry and ALT fluorescence in situ hybridization in sarcomas of various subtypes and at diverse sites, including osteosarcoma, leiomyosarcoma, liposarcoma, angiosarcoma and chondrosarcoma are evaluated. The present review involves certain studies associated with the molecular mechanisms underlying the loss of ATRX controlling the activation of ALT in sarcomas. Identification of the loss of ATRX and ALT in sarcomas may provide novel methods for the treatment of aggressive sarcomas.},
}
@article {pmid29724383,
year = {2018},
author = {Córdoba-Lanús, E and Cabrera-López, C and Cazorla-Rivero, S and Rodríguez-Pérez, MC and Aguirre-Jaime, A and Celli, B and Casanova, C},
title = {Shorter telomeres in non-smoking patients with airflow limitation.},
journal = {Respiratory medicine},
volume = {138},
number = {},
pages = {123-128},
doi = {10.1016/j.rmed.2018.04.002},
pmid = {29724383},
issn = {1532-3064},
mesh = {Adult ; Aged ; Case-Control Studies ; Female ; Forced Expiratory Volume/physiology ; Humans ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/*genetics/physiopathology ; Smoking/genetics/physiopathology ; *Telomere Shortening ; Vital Capacity/physiology ; },
abstract = {BACKGROUND: Cross-sectional and longitudinal studies describe shorter telomeres in patients with chronic obstructive pulmonary disease (COPD) compared to matched non-COPD controls, but the relationship is confounded by tobacco consumption. We hypothesized that telomere shortening would be similar between non-smoking and smoking individuals with airflow limitation and shorter than non-obstructed controls.<br><br>METHODS: Telomere length (T/S) was measured by qPCR in blood leukocytes of 80 non-smoking patients and 80 age-matched smokers with airflow limitation. Forty non-smoker healthy individuals served as controls. Anthropometrics, lung function, previous and current comorbidities were recorded in all individuals. Relationship between telomere length and clinical and functional variables were explored in the three groups.<br><br>RESULTS: Telomeres length was similar in non-smokers and smoker individuals with airflow limitation (T/S&#x202f;=&#x202f;0.61&#x202f;&#xb1;&#x202f;0.19 vs. 0.60&#x202f;&#xb1;&#x202f;0.23, p&#x202f;>&#x202f;0.05) respectively. Telomere length was significantly shorter in both groups compared to healthy controls (T/S 0.79&#x202f;&#xb1;&#x202f;0.40; p&#x202f;=&#x202f;0.01) independent from age and sex. No significant association was found between the telomere length and clinical or lung function parameters.<br><br>CONCLUSIONS: Telomere shortening is associated with airflow limitation independent of smoking status. Weather premature ageing or biologically determined shorter telomeres are responsible for this finding remain to be determined.},
}
@article {pmid29722029,
year = {2018},
author = {Fernandez, RJ and Johnson, FB},
title = {A regulatory loop connecting WNT signaling and telomere capping: possible therapeutic implications for dyskeratosis congenita.},
journal = {Annals of the New York Academy of Sciences},
volume = {1418},
number = {1},
pages = {56-68},
pmid = {29722029},
issn = {1749-6632},
support = {R21 AG054209/AG/NIA NIH HHS/United States ; T32 AG000255/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Dyskeratosis Congenita/genetics/metabolism/pathology/*therapy ; Humans ; *Telomere ; *Wnt Signaling Pathway/drug effects ; },
abstract = {The consequences of telomere dysfunction are most apparent in rare inherited syndromes caused by genetic deficiencies in factors that normally maintain telomeres. The principal disease is known as dyskeratosis congenita (DC), but other syndromes with similar underlying genetic defects share some clinical aspects with this disease. Currently, there are no curative therapies for these diseases of telomere dysfunction. Here, we review recent findings demonstrating that dysfunctional (i.e., uncapped) telomeres can downregulate the WNT pathway, and that restoration of WNT signaling helps to recap telomeres by increasing expression of shelterins, proteins that naturally bind and protect telomeres. We discuss how these findings are different from previous observations connecting WNT and telomere biology, and discuss potential links between WNT and clinical manifestations of the DC spectrum of diseases. Finally, we argue for exploring the use of WNT agonists, specifically lithium, as a possible therapeutic approach for patients with DC.},
}
@article {pmid29720120,
year = {2018},
author = {Hardikar, S and Burnett-Hartman, AN and Phipps, AI and Upton, MP and Zhu, LC and Newcomb, PA},
title = {Telomere length differences between colorectal polyp subtypes: a colonoscopy-based case-control study.},
journal = {BMC cancer},
volume = {18},
number = {1},
pages = {513},
pmid = {29720120},
issn = {1471-2407},
support = {R25 CA094880/CA/NCI NIH HHS/United States ; R25CA094880//National Cancer Institute/ ; KL2 TR000421//National Center for Advancing Translational Sciences/ ; R01 CA097325//National Cancer Institute/ ; K07CA172298//National Cancer Institute/ ; P01 CA074184//National Cancer Institute/ ; KL2 TR002317/TR/NCATS NIH HHS/United States ; K05 CA152715/CA/NCI NIH HHS/United States ; KL2 TR000421/TR/NCATS NIH HHS/United States ; K07 CA172298/CA/NCI NIH HHS/United States ; R01 CA097325/CA/NCI NIH HHS/United States ; },
mesh = {Adenoma/pathology ; Adult ; Aged ; Carcinoma/pathology ; Case-Control Studies ; Colonic Polyps/*pathology ; Colonoscopy ; Female ; Humans ; Male ; Middle Aged ; Telomere/*pathology ; },
abstract = {BACKGROUND: Short telomeres have been associated with increased risk of many cancers, particularly cancers of the gastrointestinal tract including esophagus and stomach. However, the association between telomere length (TL) and colorectal cancer and its precursors, colorectal polyps, is not clear.<br><br>METHODS: We investigated the relationship between TL and risk of colorectal polyp subtypes in a colonoscopy-based study in western Washington. Participants were 35-79&#xa0;year-old enrollees at an integrated health care system, who underwent a colonoscopy between 1998 and 2007 (n&#x2009;=&#x2009;190), completed a self-administered questionnaire, provided blood samples, and were distinguished as having adenomas, serrated polyps, or as polyp-free controls through a standardized pathology review. Telomere length (T) relative to a single copy gene (S) was measured in circulating leukocytes from stored buffy coat samples using quantitative polymerase chain reaction. Multivariable polytomous logistic regression was used to compare case groups with polyp-free controls and other case groups; adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated.<br><br>RESULTS: TL in the shortest tertile (T/S ratio&#x2009;<&#x2009;0.58) was associated with increased risk of adenomas and serrated polyps [OR (95%CI) were 1.77(0.81-3.88) and 2.98(1.15-7.77), respectively). When evaluated by lesion severity within each pathway, short TL was more strongly associated with advanced adenomas and sessile serrated polyps [OR (95% CI)&#x2009;=&#x2009;1.90(0.76-4.73) and 3.82(0.86-16.86), respectively], although the associations were not statistically significant.<br><br>CONCLUSIONS: Our results suggest that short TL may be associated with an increased risk of colorectal polyps in both the adenoma-carcinoma and serrated pathways. The risk was particularly notable for sessile serrated polyps, although the association was not statistically significant and sample size was limited.},
}
@article {pmid29718321,
year = {2018},
author = {Lee, M and Teber, ET and Holmes, O and Nones, K and Patch, AM and Dagg, RA and Lau, LMS and Lee, JH and Napier, CE and Arthur, JW and Grimmond, SM and Hayward, NK and Johansson, PA and Mann, GJ and Scolyer, RA and Wilmott, JS and Reddel, RR and Pearson, JV and Waddell, N and Pickett, HA},
title = {Telomere sequence content can be used to determine ALT activity in tumours.},
journal = {Nucleic acids research},
volume = {46},
number = {10},
pages = {4903-4918},
pmid = {29718321},
issn = {1362-4962},
mesh = {Adaptor Proteins, Signal Transducing/genetics ; Co-Repressor Proteins ; Computational Biology/*methods ; Databases, Genetic ; Female ; Humans ; Machine Learning ; Melanoma/genetics/mortality ; Molecular Chaperones ; Mutation ; Neoplasms/*genetics/mortality ; Nuclear Proteins/genetics ; Promoter Regions, Genetic ; Survival Analysis ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Exome Sequencing ; X-linked Nuclear Protein/genetics ; },
abstract = {The replicative immortality of human cancer cells is achieved by activation of a telomere maintenance mechanism (TMM). To achieve this, cancer cells utilise either the enzyme telomerase, or the Alternative Lengthening of Telomeres (ALT) pathway. These distinct molecular pathways are incompletely understood with respect to activation and propagation, as well as their associations with clinical outcomes. We have identified significant differences in the telomere repeat composition of tumours that use ALT compared to tumours that do not. We then employed a machine learning approach to stratify tumours according to telomere repeat content with an accuracy of 91.6%. Importantly, this classification approach is applicable across all tumour types. Analysis of pathway mutations that were under-represented in ALT tumours, across 1,075 tumour samples, revealed that the autophagy, cell cycle control of chromosomal replication, and transcriptional regulatory network in embryonic stem cells pathways are involved in the survival of ALT tumours. Overall, our approach demonstrates that telomere sequence content can be used to stratify ALT activity in cancers, and begin to define the molecular pathways involved in ALT activation.},
}
@article {pmid29718105,
year = {2018},
author = {Brown, LL and Zhang, YS and Mitchell, C and Ailshire, JA},
title = {Corrigendum to: Does Telomere Length Indicate Biological, Physical, and Cognitive Health Among Older Adults? Evidence from the Health and Retirement Study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {73},
number = {7},
pages = {905},
doi = {10.1093/gerona/gly088},
pmid = {29718105},
issn = {1758-535X},
support = {R00 AG039528/AG/NIA NIH HHS/United States ; T32 AG000037/AG/NIA NIH HHS/United States ; U01 AG009740/AG/NIA NIH HHS/United States ; },
}
@article {pmid29704891,
year = {2018},
author = {Heidary, H and Pouresmaeili, F and Mirfakhraie, R and Omrani, MD and Ghaedi, H and Fazeli, Z and Sayban, S and Ghafouri-Fard, S and Azargashb, E and Shokri, F},
title = {An Association Study between Longitudinal Changes of Leukocyte Telomere and the Risk of Azoospermia in a Population of Iranian Infertile Men.},
journal = {Iranian biomedical journal},
volume = {22},
number = {4},
pages = {231-236},
pmid = {29704891},
issn = {2008-823X},
mesh = {Adult ; Azoospermia/*diagnosis/*genetics ; Case-Control Studies ; DNA/analysis ; Follicle Stimulating Hormone/blood ; Humans ; Iran ; Karyotyping ; Leukocytes/*cytology ; Longitudinal Studies ; Luteinizing Hormone/blood ; Male ; ROC Curve ; Real-Time Polymerase Chain Reaction ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Telomeres are evolutionary, specialized terminal structures at the ends of eukaryotic chromosomes containing TTAGGG repeats in human. Several human diseases have been known to be associated with dramatic changes in telomere length. The aim of the present study was to assess the correlation between the relative leukocyte telomere length (LTL) and infertility in a group of Iranian azoospermic males.<br><br>METHODS: : In this case-control pilot study, relative telomere length (RTL) of peripheral blood leukocytes from a total of 30 idiopathic non-obstructive azoospermic males and 30 healthy fertile males was evaluated using real-time PCR. RTL was calculated as T (telomere)/S (single copy gene) ratio and compared between infertile and fertile groups.<br><br>RESULTS: Patients with azoospermia showed significantly shorter RTL than fertile males (0.54 vs. 0.84, p < 0.05). The area under the receiver operating characteristic (ROC) curve was estimated to be 99.8%, suggesting LTL as a potential marker for the diagnosis of azoospermia.<br><br>CONCLUSION: Our findings demonstrated a probable association between telomere shortening and azoospermia in a population of Iranian infertile men affected by idiopathic azoospermia.},
}
@article {pmid29696806,
year = {2018},
author = {Hancarova, M and Malikova, M and Kotrova, M and Drabova, J and Trkova, M and Sedlacek, Z},
title = {Association of 17q24.2-q24.3 deletions with recognizable phenotype and short telomeres.},
journal = {American journal of medical genetics. Part A},
volume = {176},
number = {6},
pages = {1438-1442},
doi = {10.1002/ajmg.a.38711},
pmid = {29696806},
issn = {1552-4833},
mesh = {Child ; Chromosome Deletion ; *Chromosomes, Human, Pair 17/genetics ; Developmental Disabilities/etiology/*genetics ; Eczema/etiology ; Face/abnormalities ; Facies ; Female ; Fibromatosis, Gingival/genetics ; Growth Disorders/etiology ; Humans ; Hypertrichosis/genetics ; Intellectual Disability/etiology ; Microcephaly/etiology ; Phenotype ; *Telomere ; },
abstract = {Microdeletions of 17q24.2-q24.3 have been described in several patients with developmental and speech delay, growth retardation, and other features. The relatively large size and limited overlap of the deletions complicate the genotype-phenotype correlation. We identified a girl with intellectual disability, growth retardation, dysmorphic features, and a de novo 2.8 Mb long deletion of 17q24.2-q24.3. Her phenotype was strikingly similar to one previously described boy with Dubowitz syndrome (MIM 223370) and a de novo 3.9 Mb long deletion encompassing the deletion of our patient. In addition, both patients had the shortest telomeres among normal age-matched controls. Our review of all 17q24.2-q24.3 deletion patients revealed additional remarkable phenotypic features shared by the patients, some of which have consequences for their management. Proposed novel genotype-phenotype correlations based on new literature information on the region include the role of PSMD12 and BPTF, the genes recently associated with syndromic neurodevelopmental disorders, and a possible role of the complex topologically associated domain structure of the region, which may explain some of the phenotypic discrepancies observed between patients with similar but not identical deletions. Nevertheless, although different diagnoses including the Dubowitz, Nijmegen breakage (MIM 251260), Silver-Russell (MIM 180860), or Myhre (MIM 139210) syndromes were originally considered in the 17q24.2-q24.3 deletion patients, they clearly belong to one diagnostic entity defined by their deletions and characterized especially by developmental delay, specific facial dysmorphism, abnormalities of extremities and other phenotypes, and possibly also short telomere length.},
}
@article {pmid29695838,
year = {2018},
author = {De Meyer, T and Bekaert, S and De Buyzere, ML and De Bacquer, DD and Langlois, MR and Shivappa, N and Hébert, JR and Gillebert, TC and Rietzschel, ER and Huybrechts, I},
title = {Leukocyte telomere length and diet in the apparently healthy, middle-aged Asklepios population.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {6540},
pmid = {29695838},
issn = {2045-2322},
support = {R44 DK103377/DK/NIDDK NIH HHS/United States ; },
mesh = {Adult ; Biomarkers/metabolism ; Diet/methods ; Female ; Humans ; Inflammation/metabolism ; Leukocytes/*metabolism ; Longitudinal Studies ; Male ; Middle Aged ; Oxidative Stress/physiology ; Telomere/*metabolism ; Telomere Shortening/physiology ; },
abstract = {Telomere length is a prognostic biomarker for aging diseases. As it is unknown whether diet plays a role in these associations, we aimed to assess the impact of diet on telomere length. Moreover, given that telomere length is modulated by oxidative stress and inflammation, an additional goal was to evaluate whether the latter may mediate possible telomere - diet associations. Southern blot measured leukocyte telomere length and food frequency questionnaire data were compared for 2509 apparently healthy men and women (~35 to 55 years) from the Asklepios population. No significant associations were found between telomere length and overall dietary characteristics, such as dietary diversity, quality, equilibrium, and the dietary inflammatory index. Exploratory analysis of individual dietary variables revealed that a higher daily intake of deep fried potato products was associated with shorter telomeres (P = 0.002, 151 bp per 100 g/day), also in both sexes separately. Deep fried potato product consumption was also significantly associated with C-reactive protein (P = 0.032) and uric acid (P = 0.042), but not other inflammation and oxidative stress markers. These results suggest an at most limited association between overall dietary patterns and telomere length in the general population. Nevertheless, the association between telomere length and deep fried potato product intake warrants additional research.},
}
@article {pmid29695617,
year = {2018},
author = {Özer, &#xd6; and Hickson, ID},
title = {Pathways for maintenance of telomeres and common fragile sites during DNA replication stress.},
journal = {Open biology},
volume = {8},
number = {4},
pages = {},
pmid = {29695617},
issn = {2046-2441},
mesh = {*Chromosome Fragile Sites ; DNA Repair ; DNA Replication/*physiology ; Genomic Instability ; Humans ; Neoplasms/genetics ; Telomere Homeostasis/*physiology ; },
abstract = {Oncogene activation during tumour development leads to changes in the DNA replication programme that enhance DNA replication stress. Certain regions of the human genome, such as common fragile sites and telomeres, are particularly sensitive to DNA replication stress due to their inherently 'difficult-to-replicate' nature. Indeed, it appears that these regions sometimes fail to complete DNA replication within the period of interphase when cells are exposed to DNA replication stress. Under these conditions, cells use a salvage pathway, termed 'mitotic DNA repair synthesis (MiDAS)', to complete DNA synthesis in the early stages of mitosis. If MiDAS fails, the ensuing mitotic errors threaten genome integrity and cell viability. Recent studies have provided an insight into how MiDAS helps cells to counteract DNA replication stress. However, our understanding of the molecular mechanisms and regulation of MiDAS remain poorly defined. Here, we provide an overview of how DNA replication stress triggers MiDAS, with an emphasis on how common fragile sites and telomeres are maintained. Furthermore, we discuss how a better understanding of MiDAS might reveal novel strategies to target cancer cells that maintain viability in the face of chronic oncogene-induced DNA replication stress.},
}
@article {pmid29694906,
year = {2018},
author = {Hafner, L and Lezaja, A and Zhang, X and Lemmens, L and Shyian, M and Albert, B and Follonier, C and Nunes, JM and Lopes, M and Shore, D and Mattarocci, S},
title = {Rif1 Binding and Control of Chromosome-Internal DNA Replication Origins Is Limited by Telomere Sequestration.},
journal = {Cell reports},
volume = {23},
number = {4},
pages = {983-992},
doi = {10.1016/j.celrep.2018.03.113},
pmid = {29694906},
issn = {2211-1247},
mesh = {Chromosomes, Fungal/genetics/*metabolism ; Replication Origin/*physiology ; Repressor Proteins/genetics/*metabolism ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {The Saccharomyces cerevisiae telomere-binding protein Rif1 plays an evolutionarily conserved role in control of DNA replication timing by promoting PP1-dependent dephosphorylation of replication initiation factors. However, ScRif1 binding outside of telomeres has never been detected, and it has thus been unclear whether Rif1 acts directly on the replication origins that it controls. Here, we show that, in unperturbed yeast cells, Rif1 primarily regulates late-replicating origins within 100 kb of a telomere. Using the chromatin endogenous cleavage ChEC-seq technique, we robustly detect Rif1 at late-replicating origins that we show are targets of its inhibitory action. Interestingly, abrogation of Rif1 telomere association by mutation of its Rap1-binding module increases Rif1 binding and origin inhibition elsewhere in the genome. Our results indicate that Rif1 inhibits replication initiation by interacting directly with origins and suggest that Rap1-dependent sequestration of Rif1 increases its effective concentration near telomeres, while limiting its action at chromosome-internal sites.},
}
@article {pmid29694602,
year = {2018},
author = {Araújo, ML and Duarte, W and Oliveira, ACP and Gascón, MRP and Fonseca, LAM and Paiva, RMA and Santana, B and Calado, RT and Casseb, J},
title = {Is the telomere length associated with neurocognitive disabilities in HIV-1-infected subjects?.},
journal = {Revista do Instituto de Medicina Tropical de Sao Paulo},
volume = {60},
number = {},
pages = {e16},
pmid = {29694602},
issn = {1678-9946},
mesh = {Age Factors ; Analysis of Variance ; Case-Control Studies ; Female ; HIV Infections/*genetics/*psychology ; *HIV-1 ; Humans ; Leukocytes/virology ; Male ; Middle Aged ; Neurocognitive Disorders/*genetics/*virology ; Neuropsychological Tests ; Real-Time Polymerase Chain Reaction ; Reference Values ; Statistics, Nonparametric ; Surveys and Questionnaires ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Viral Load ; },
abstract = {OBJECTIVE: We evaluated the association between cognitive deficits and leukocyte telomere length (LTL) in HIV-1-infected individuals.<br><br>DESIGN: 73 HIV-1-infected patients undergoing neuropsychological evaluation and 91 healthy controls were included in this study. Fifteen HIV-1 positive patients did not have cognitive disorders whereas 26 had asymptomatic neurocognitive disorder (ANI), 13 presented mild to moderate neurocognitive disorder (MND), and 10 had HIV-associated dementia (HAD).<br><br>METHODS: DNA from the peripheral blood of HIV-1-infected patients was used for measurement of telomere length by real-time PCR. HIV-1 viral load was determined in blood.<br><br>RESULTS: LTL decreased with age in healthy controls (p=0.0001). Regardless of the HIV status, age-matched LTL from HIV patients, including those with ANI and MND, were shortened in comparison to the healthy control group (p=0.0073); however, no association was found among the HIV-1-infected individuals with cognitive deficits (p=0.01). In addition, no gender-related association with LTL was observed (p=0.80), smoking, physical exercise, and plasma viral load were not correlated to telomere length (p=0.66).<br><br>CONCLUSIONS: We concluded that leukocyte telomere length may not be a marker of cellular senescence in individuals with HIV infection and neurocognitive disorders.},
}
@article {pmid29693246,
year = {2018},
author = {McMaster, ML and Sun, C and Landi, MT and Savage, SA and Rotunno, M and Yang, XR and Jones, K and Vogt, A and Hutchinson, A and Zhu, B and Wang, M and Hicks, B and Thirunavukarason, A and Stewart, DR and Koutros, S and Goldstein, AM and Chanock, SJ and Caporaso, NE and Tucker, MA and Goldin, LR and Liu, Y},
title = {Germline mutations in Protection of Telomeres 1 in two families with Hodgkin lymphoma.},
journal = {British journal of haematology},
volume = {181},
number = {3},
pages = {372-377},
pmid = {29693246},
issn = {1365-2141},
support = {Z01 CP004410-31//Intramural NIH HHS/United States ; Z01 CP004410-32//Intramural NIH HHS/United States ; Z99 CA999999//Intramural NIH HHS/United States ; },
mesh = {Amino Acid Substitution ; Cell Line, Tumor ; *Chromosomal Instability ; *Family ; Female ; *Germ-Line Mutation ; *Hodgkin Disease/genetics/metabolism/pathology ; Humans ; Male ; *Mutation, Missense ; Shelterin Complex ; Telomere/genetics/metabolism ; *Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {In a previous whole exome sequencing of patients from 41 families with Hodgkin lymphoma, we identified two families with distinct heterozygous rare coding variants in POT1 (D224N and Y36H), both in a highly conserved region of the gene. POT1 D224N mutant did not bind to a single-stranded telomere oligonucleotide in vitro suggesting the mutation perturbs POT1's ability to bind to the telomeric G-rich overhang. Human HT1080 cells expressing POT1 D224N and lymphoblastoid cells carrying Y36H both showed increased telomere length and fragility in comparison to wild type cells. This strongly suggests that mutant POT1 causes chromosome instability and may play a role in lymphomagenesis in these families.},
}
@article {pmid29688278,
year = {2018},
author = {Davy, PMC and Willcox, DC and Shimabukuro, M and Donlon, TA and Torigoe, T and Suzuki, M and Higa, M and Masuzaki, H and Sata, M and Chen, R and Murkofsky, RL and Morris, BJ and Lim, E and Allsopp, RC and Willcox, BJ},
title = {Minimal Shortening of Leukocyte Telomere Length Across Age Groups in a Cross-Sectional Study for Carriers of a Longevity-Associated FOXO3 Allele.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {73},
number = {11},
pages = {1448-1452},
pmid = {29688278},
issn = {1758-535X},
support = {U54 MD007584/MD/NIMHD NIH HHS/United States ; U54 MD007601/MD/NIMHD NIH HHS/United States ; G12 MD007601/MD/NIMHD NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Alleles ; Asian People/genetics ; Cross-Sectional Studies ; Female ; Forkhead Box Protein O3/*genetics ; Genotype ; Heterozygote ; Humans ; Japan ; Leukocytes/*metabolism ; Longevity/*genetics ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {FOXO3 is one of the most prominent genes demonstrating a consistently reproducible genetic association with human longevity. The mechanisms by which these individual gene variants confer greater organismal lifespan are not well understood. We assessed the effect of longevity-associated FOXO3 alleles on age-related leukocyte telomere dynamics in a cross-sectional study comprised of samples from 121 healthy Okinawan-Japanese donors aged 21-95 years. We found that telomere length for carriers of the longevity associated allele of FOXO3 single nucleotide polymorphism rs2802292 displayed no significant correlation with age, an effect that was most pronounced in older (>50 years of age) participants. This is the first validated longevity gene variant identified to date showing an association with negligible loss of telomere length with age in humans in a cross-sectional study. Reduced telomere attrition may be a key mechanism for the longevity-promoting effect of the FOXO3 genotype studied.},
}
@article {pmid29686093,
year = {2018},
author = {},
title = {Correction for Alder et al., Diagnostic utility of telomere length testing in a hospital-based setting.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {115},
number = {18},
pages = {E4312},
doi = {10.1073/pnas.1805407115},
pmid = {29686093},
issn = {1091-6490},
}
@article {pmid29682317,
year = {2018},
author = {Tarik, M and Ramakrishnan, L and Sachdev, HS and Tandon, N and Roy, A and Bhargava, SK and Pandey, RM},
title = {Validation of quantitative polymerase chain reaction with Southern blot method for telomere length analysis.},
journal = {Future science OA},
volume = {4},
number = {4},
pages = {FSO282},
pmid = {29682317},
issn = {2056-5623},
abstract = {AIM: Telomere length (TL) measurement by quantitative polymerase chain reaction (PCR) has been widely accepted, but limited information regarding its validation with a gold-standard technique is available.<br><br>MATERIALS &amp; METHODS: We measured TL by Southern blot and monochrome multiplex quantitative PCR (MMqPCR) and validated the results of TL in leukocytes of 94 participants with mean age 43.2&#xa0;years, BMI 19-41 (mean 27.8&#xa0;&#xb1;&#xa0;4.3) kg/m[2].<br><br>RESULTS: A significant positive correlation was observed between TL measured by MMqPCR and Southern blot assay (correlation coefficient r&#xa0;=&#xa0;+0.896, p&#xa0;<&#xa0;0.0001). The inter- and intra-assay CVs of the MMqPCR assay were 5.3 and 4.07%, respectively.<br><br>CONCLUSION: We observed that experimental discrepancies have an impact on TL analysis and there is a need to improve the optimum conditions.},
}
@article {pmid29681194,
year = {2019},
author = {Werlang, ICR and Hahn, MC and Bernardi, JR and Nast, M and Goldani, MZ and Michalowski, MB},
title = {Exposure to different intrauterine environments: implications for telomere attrition in early life.},
journal = {The journal of maternal-fetal &amp; neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians},
volume = {32},
number = {21},
pages = {3675-3684},
doi = {10.1080/14767058.2018.1468879},
pmid = {29681194},
issn = {1476-4954},
mesh = {Female ; Humans ; Infant ; Infant, Newborn ; Male ; Pregnancy ; *Pregnancy Complications/genetics/physiopathology ; Prenatal Exposure Delayed Effects/*genetics ; Stress, Psychological/complications/genetics/physiopathology ; Telomere/metabolism ; Telomere Shortening/*physiology ; },
abstract = {Objective: Studies focusing on telomere attrition in newborns and what factors could be involved in this issue are sparse; most reports have been in adult populations. Thereby, the aim of this study was to present an overview of what is currently known about the relationship between environmental exposure of the fetus during pregnancy and telomere length outcomes in early life. Methods: The MEDLINE (via PubMed) and Bireme databases were searched for studies published until 1 June 2016. Studies that reported telomere length measurement from birth to age 1 year were included. Results: Fifteen articles were selected that evaluated possible relationships between maternal smoking, hyperglycemia, hypertension, sleep apnea, psychological stress, folate concentration in early pregnancy, and radiation, in addition to small-for-gestational-age status and preterm birth. We found that sleep apnea, psychological stress, and folate concentration in early pregnancy were associated with telomere shortening in the newborn. No association was found with radiation, small-for-gestational-age status, or preterm birth. Results for maternal smoking, hyperglycemia, and hypertension were conflicting, and further studies should be considered. Conclusion: The actual clinical implications of these findings have yet to be investigated.},
}
@article {pmid29679477,
year = {2019},
author = {Merta, TJ and Geacintov, NE and Shafirovich, V},
title = {Generation of 8-oxo-7,8-dihydroguanine in G-Quadruplexes Models of Human Telomere Sequences by One-electron Oxidation.},
journal = {Photochemistry and photobiology},
volume = {95},
number = {1},
pages = {244-251},
pmid = {29679477},
issn = {1751-1097},
support = {C06 RR016572/RR/NCRR NIH HHS/United States ; R01 ES011589/ES/NIEHS NIH HHS/United States ; R01 ES027059/ES/NIEHS NIH HHS/United States ; CHE-0958457//National Science Foundation/International ; },
mesh = {*G-Quadruplexes ; Guanine/*analogs &amp; derivatives/chemistry ; Humans ; Kinetics ; *Models, Chemical ; Oxidation-Reduction ; *Telomere ; },
abstract = {The mechanistic aspects of one-electron oxidation of G-quadruplexes in the basket (Na[+] ions) and hybrid (K[+] ions) conformations were investigated by transient absorption laser kinetic spectroscopy and HPLC detection of the 8-oxo-7,8-dihydroguanine (8-oxoG) oxidation product. The photo-induced one-electron abstraction from G-quadruplexes was initiated by sulfate radical anions (SO4 ˙[-]) derived from the photolysis of persulfate ions by 308 nm excimer laser pulses. In neutral aqueous solutions (pH 7.0), the transient absorbance of neutral guanine radicals, G(-H)˙, is observed following the complete decay of SO4 ˙[-] radicals (~10 μs after the actinic laser flash). In both basket and hybrid conformations, the G(-H)˙ decay is biphasic with one component decaying with a lifetime of ~0.1 ms, and the other with a lifetime of 20-30 ms. The fast decay component (~0.1 ms) in G-quadruplexes is correlated with the formation of 8-oxoG lesions. We propose that in G-quadruplexes, G(-H)˙ radicals retain radical cation character by sharing the N1-proton with the O[6] -atom of G in the [G˙[+] : G] Hoogsteen base pair; this [G(-H)˙: H[+] G ⇄ G˙[+] : G] leads to the hydration of G˙[+] radical cation within the millisecond time domain, and is followed by the formation of the 8-oxoG lesions.},
}
@article {pmid29671751,
year = {2018},
author = {Wang, L and Zong, S and Wang, Z and Lu, J and Chen, C and Zhang, R and Cui, Y},
title = {Single molecule localization imaging of telomeres and centromeres using fluorescence in situ hybridization and semiconductor quantum dots.},
journal = {Nanotechnology},
volume = {29},
number = {28},
pages = {285602},
doi = {10.1088/1361-6528/aabf72},
pmid = {29671751},
issn = {1361-6528},
mesh = {Cadmium Compounds/chemistry ; Centromere/*metabolism ; HeLa Cells ; Humans ; *In Situ Hybridization, Fluorescence ; Lasers ; Molecular Probes/chemistry ; Quantum Dots/*chemistry/ultrastructure ; *Semiconductors ; Single Molecule Imaging/*methods ; Sulfides/chemistry ; Telomere/*metabolism ; Zinc Compounds/chemistry ; },
abstract = {Single molecule localization microscopy (SMLM) is a powerful tool for imaging biological targets at the nanoscale. In this report, we present SMLM imaging of telomeres and centromeres using fluorescence in situ hybridization (FISH). The FISH probes were fabricated by decorating CdSSe/ZnS quantum dots (QDs) with telomere or centromere complementary DNA strands. SMLM imaging experiments using commercially available peptide nucleic acid (PNA) probes labeled with organic fluorophores were also conducted to demonstrate the advantages of using QDs FISH probes. Compared with the PNA probes, the QDs probes have the following merits. First, the fluorescence blinking of QDs can be realized in aqueous solution or PBS buffer without thiol, which is a key buffer component for organic fluorophores' blinking. Second, fluorescence blinking of the QDs probe needs only one excitation light (i.e. 405 nm). While fluorescence blinking of the organic fluorophores usually requires two illumination lights, that is, the activation light (i.e. 405 nm) and the imaging light. Third, the high quantum yield, multiple switching times and a good optical stability make the QDs more suitable for long-term imaging. The localization precision achieved in telomeres and centromeres imaging experiments is about 30 nm, which is far beyond the diffraction limit. SMLM has enabled new insights into telomeres or centromeres on the molecular level, and it is even possible to determine the length of telomere and become a potential technique for telomere-related investigation.},
}
@article {pmid29670295,
year = {2018},
author = {Doherty, JA and Grieshober, L and Houck, JR and Barnett, MJ and De Dieu Tapsoba, J and Thornquist, MD and Wang, CY and Goodman, GE and Chen, C},
title = {Nested case-control study of telomere length and lung cancer risk among heavy smokers in the β-Carotene and Retinol Efficacy Trial.},
journal = {British journal of cancer},
volume = {118},
number = {11},
pages = {1513-1517},
pmid = {29670295},
issn = {1532-1827},
support = {U01 CA063673/CA/NCI NIH HHS/United States ; U01 CA167462/CA/NCI NIH HHS/United States ; UM1 CA167462/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma of Lung/*epidemiology/etiology/genetics ; Aged ; Case-Control Studies ; Female ; Genetic Predisposition to Disease ; Humans ; Logistic Models ; Lung Neoplasms/*epidemiology/etiology/genetics ; Male ; Middle Aged ; Risk Assessment ; Risk Factors ; Telomere/*genetics ; Telomere Homeostasis ; Tobacco Smoking/adverse effects/*epidemiology/genetics ; },
abstract = {BACKGROUND: Telomeres protect cells from genomic instability. We examined telomere length and lung cancer risk prospectively in heavy smokers.<br><br>METHODS: In a nested case-control study with 709 cases and 1313 controls, conditional logistic regression was used to evaluate associations between telomere length (global, chromosome 5p, and 13q) and lung cancer risk by histotype, controlling for detailed smoking history.<br><br>RESULTS: Risks of overall lung cancer and adenocarcinoma were suggestively elevated among individuals with telomere length in the longest tertile. No clear patterns were observed for other histotypes, or for chromosome 5p or 13q telomere length. Associations with adenocarcinoma were strongest among (OR, 95% CI for longest versus shortest tertile): former smokers (2.26, 1.03-4.96), individuals <65 years (2.22, 1.13-4.35), and women (2.21, 0.99-4.93).<br><br>CONCLUSIONS: Our large study of heavy smokers adds additional evidence that long telomere length prior to diagnosis is associated with risk of lung adenocarcinoma, but not other histotypes.},
}
@article {pmid29670207,
year = {2018},
author = {Arruda, LCM and Lima-Júnior, JR and Clave, E and Moraes, DA and Douay, C and Fournier, I and Moins-Teisserenc, H and Covas, DT and Simões, BP and Farge, D and Toubert, A and Malmegrim, KCR and Oliveira, MC},
title = {Homeostatic proliferation leads to telomere attrition and increased PD-1 expression after autologous hematopoietic SCT for systemic sclerosis.},
journal = {Bone marrow transplantation},
volume = {53},
number = {10},
pages = {1319-1327},
pmid = {29670207},
issn = {1476-5365},
mesh = {Adult ; CD8-Positive T-Lymphocytes/metabolism/pathology ; *Cell Proliferation ; Cytokines/blood ; Female ; Follow-Up Studies ; *Hematopoietic Stem Cell Transplantation ; Humans ; Male ; Middle Aged ; Programmed Cell Death 1 Receptor/*blood ; Prospective Studies ; *Scleroderma, Systemic/blood/pathology/therapy ; Telomere/*metabolism ; *Telomere Homeostasis ; Transplantation, Autologous ; },
abstract = {In the months that follow autologous hematopoietic stem cell transplantation (AHSCT), lymphopenia drives homeostatic proliferation, leading to oligoclonal expansion of residual cells. Here we evaluated how replicative senescent and exhausted cells associated with clinical outcomes of 25 systemic sclerosis (SSc) patients who underwent AHSCT. Patients were clinically monitored for skin (modified Rodnan's skin score, mRSS) and internal organ involvement and had blood samples collected before and semiannually, until 3 years post-AHSCT, for quantification of telomere length, CD8[+]CD28[-] and PD-1[+] cells, and serum cytokines. Patients were retrospectively classified as responders (n = 19) and non-responders (n = 6), according to clinical outcomes. At 6 months post-AHSCT, mRSS decreased (P < 0.001) and the pulmonary function stabilized, when compared with pre-transplant measures. In parallel, inflammatory cytokine (IL-6 and IL-1β) levels and telomere lengths decreased, whereas PD-1 expression on T-cells and the number of CD8[+]CD28[-] cells expressing CD57 and FoxP3 increased. After AHSCT, responder patients presented higher PD-1 expression on T- (P < 0.05) and B- (P < 0.01) cells, and lower TGF-β, IL-6, G-CSF (P < 0.01), and IL-1β, IL-17A, MIP-1α, and IL-12 (P < 0.05) levels than non-responders. Homeostatic proliferation after AHSCT results in transient telomere attrition and increased numbers of senescent and exhausted cells. High PD-1 expression is associated with better clinical outcomes after AHSCT.},
}
@article {pmid29670078,
year = {2018},
author = {Montero, JJ and López-Silanes, I and Megías, D and F Fraga, M and Castells-García, &#xc1; and Blasco, MA},
title = {TERRA recruitment of polycomb to telomeres is essential for histone trymethylation marks at telomeric heterochromatin.},
journal = {Nature communications},
volume = {9},
number = {1},
pages = {1548},
pmid = {29670078},
issn = {2041-1723},
mesh = {Animals ; Biotin/chemistry ; Biotinylation ; CRISPR-Cas Systems ; Catalysis ; Cell Line, Tumor ; HEK293 Cells ; Heterochromatin/*chemistry ; Histone Code ; Histones/*chemistry ; Humans ; In Situ Hybridization, Fluorescence ; Methylation ; Mice ; Mice, Knockout ; Polycomb Repressive Complex 2/metabolism ; Polycomb-Group Proteins/metabolism ; RNA, Long Noncoding/*genetics ; RNA, Small Interfering/metabolism ; Telomere/*chemistry/ultrastructure ; Telomere Homeostasis ; },
abstract = {TERRAs are long non-coding RNAs generated from the telomeres. Lack of TERRA knockout models has hampered understanding TERRAs' functions. We recently identified chromosome 20q as one of the main origins of human TERRAs, allowing us to generate the first 20q-TERRA knockout models and to demonstrate that TERRAs are essential for telomere length maintenance and protection. Here, we use ALT 20q-TERRA knockout cells to address a direct role of TERRAs in telomeric heterochromatin formation. We find that 20q-TERRAs are essential for the establishment of H3K9me3, H4K20me3, and H3K27me3 heterochromatin marks at telomeres. At the mechanistic level, we find that TERRAs bind to PRC2, responsible for catalyzing H3K27 tri-methylation, and that its localization to telomeres is TERRA-dependent. We further demonstrate that PRC2-dependent H3K27me3 at telomeres is required for the establishment of H3K9me3, H4K20me3, and HP1 binding at telomeres. Together, these findings demonstrate an important role for TERRAs in telomeric heterochromatin assembly.},
}
@article {pmid29668072,
year = {2019},
author = {Bell, WR and Meeker, AK and Rizzo, A and Rajpara, S and Rosenthal, IM and Flores Bellver, M and Aparicio Domingo, S and Zhong, X and Barber, JR and Joshu, CE and Canto-Soler, MV and Eberhart, CG and Heaphy, CM},
title = {A unique telomere DNA expansion phenotype in human retinal rod photoreceptors associated with aging and disease.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {29},
number = {1},
pages = {45-52},
pmid = {29668072},
issn = {1750-3639},
mesh = {Age Factors ; Aging/genetics ; Animals ; DNA ; Diabetic Retinopathy/genetics/physiopathology ; Female ; Glaucoma/genetics/physiopathology ; Humans ; Male ; Phenotype ; Photoreceptor Cells, Vertebrate/metabolism/physiology ; Retina/physiology ; Retinal Rod Photoreceptor Cells/metabolism/*physiology ; Telomere/*genetics/physiology ; Telomere Homeostasis/*genetics ; },
abstract = {We have identified a discrete, focal telomere DNA expansion phenotype in the photoreceptor cell layer of normal, non-neoplastic human retinas. This phenotype is similar to that observed in a subset of human cancers, including a large fraction of tumors of the central nervous system, which maintain their telomeres via the non-telomerase-mediated alternative lengthening of telomeres (ALT) mechanism. We observed that these large, ultra-bright telomere DNA foci are restricted to the rod photoreceptors and are not observed in other cell types. Additionally, focus-positive rod cells are dispersed homogeneously throughout the posterior retinal photoreceptor cell layer and appear to be human-specific. We examined 108 normal human retinas obtained at autopsy from a wide range of ages. These large, ultra-bright telomere DNA foci were not observed in infants before 6 months of age; however, the prevalence of focus-positive rod cells dramatically increased throughout life. To investigate associations between this phenotype and retinal pathology, we assessed adult glaucoma (N = 29) and diabetic retinopathy (N = 38) cases. Focus-positive rod cells were prominent in these diseases. When compared to the normal group, after adjusting for age, logistic regression modeling revealed significantly increased odds of falling in the high category of focus-positive rod cells for glaucoma and diabetic retinopathy. In summary, we have identified a dramatic telomere alteration associated with aging and diseases affecting the retina.},
}
@article {pmid29667481,
year = {2019},
author = {Bains, SK and Chapman, K and Bright, S and Senan, A and Kadhim, M and Slijepcevic, P},
title = {Effects of ionizing radiation on telomere length and telomerase activity in cultured human lens epithelium cells.},
journal = {International journal of radiation biology},
volume = {95},
number = {1},
pages = {54-63},
doi = {10.1080/09553002.2018.1466066},
pmid = {29667481},
issn = {1362-3095},
mesh = {Cell Line ; DNA Damage ; DNA Repair/radiation effects ; Dose-Response Relationship, Radiation ; Epithelial Cells/enzymology/*metabolism/*radiation effects ; Female ; Humans ; Lens, Crystalline/*cytology ; Telomerase/*metabolism ; Telomere/*genetics ; X-Rays/adverse effects ; Young Adult ; },
abstract = {PURPOSE: To investigate the effects of ionizing radiation on telomere length and telomerase activity in human lens epithelial cells. There are studies suggesting evidence of telomere length in association with opacity of the lens; however, these studies have been conducted on Canine Lens cells. Our study was designed to understand further the effects of different doses of ionizing radiation on telomere length and telomerase activity in cultured human lens epithelium cells from three Donors.<br><br>MATERIALS AND METHODS: For this study, embryonic human lens epithelial (HLE) cells from three donors, obtained commercially were cultured. Telomere length and telomerase activity were measured after each passage until cells stopped growing in culture. This was repeated on irradiated (0.001&#x2009;Gy, 0.01&#x2009;Gy, 0.02&#x2009;Gy, 0.1&#x2009;Gy, 1&#x2009;Gy and 2&#x2009;Gy) cells. DNA damage response using the H2AX and telomere dysfunction foci assays were also examined at 30 mins, 24&#x2009;hours, 48&#x2009;hours and 72&#x2009;hours postirradiation.<br><br>RESULTS AND CONCLUSION: We have demonstrated genetic changes in telomere length and oxidative stress, which may be relevant to cataractogenesis. Our study shows that in control cells telomere length increases as passage increases. We have also demonstrated that telomere length increases at higher doses of 1.0&#x2009;Gy and 2.0&#x2009;Gy. However, telomerase activity decreases dose dependently and as passages increase. These results are not conclusive and further studies ex vivo measuring lens opacity and telomere length in the model would be beneficial in a bigger cohort, hence confirming a link between telomere length, cataractogenesis and genetic factors.},
}
@article {pmid29666837,
year = {2018},
author = {Meeker, AK},
title = {Cancer telomeres and white crows.},
journal = {American journal of clinical and experimental urology},
volume = {6},
number = {2},
pages = {93-100},
pmid = {29666837},
issn = {2330-1910},
abstract = {This mini-review article discusses past and present prostate-focused research on telomere and telomerase biology conducted at Johns Hopkins, through the eyes of a Donald S Coffey trainee. Included are past discoveries of abnormalities in telomere biology in the context of prostate cancer and its pre-malignant precursor prostatic intraepithelial neoplasia (PIN); the finding that telomerase activity is androgen-regulated in the prostate, and the potential role of telomerase in prostate epithelial stem cells. Also reviewed are more recent results showing that in situ telomere length measurements in patient tissue specimens may have utility in risk assessment and as a prognostic biomarker. Highlighted throughout the article are some of the training and mentorship approaches employed by the late Dr. Coffey, former Director of Urologic Research at the Brady Urological Research Institute, which inspired new research ideas, team science, and discovery.},
}
@article {pmid29665866,
year = {2018},
author = {Campa, D and Barrdahl, M and Santoro, A and Severi, G and Baglietto, L and Omichessan, H and Tumino, R and Bueno-de-Mesquita, HBA and Peeters, PH and Weiderpass, E and Chirlaque, MD and Rodríguez-Barranco, M and Agudo, A and Gunter, M and Dossus, L and Krogh, V and Matullo, G and Trichopoulou, A and Travis, RC and Canzian, F and Kaaks, R},
title = {Mitochondrial DNA copy number variation, leukocyte telomere length, and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.},
journal = {Breast cancer research : BCR},
volume = {20},
number = {1},
pages = {29},
pmid = {29665866},
issn = {1465-542X},
support = {C570/A16491/CRUK_/Cancer Research UK/United Kingdom ; 14136/CRUK_/Cancer Research UK/United Kingdom ; C8221/A19170/CRUK_/Cancer Research UK/United Kingdom ; MR/N003284/1/MRC_/Medical Research Council/United Kingdom ; 1000143/MRC_/Medical Research Council/United Kingdom ; G0401527/MRC_/Medical Research Council/United Kingdom ; 16491/CRUK_/Cancer Research UK/United Kingdom ; MR/M012190/1/MRC_/Medical Research Council/United Kingdom ; G1000143/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Aged ; Breast Neoplasms/*epidemiology/*genetics/pathology ; Cohort Studies ; DNA Copy Number Variations/genetics ; DNA, Mitochondrial/*genetics ; Europe/epidemiology ; Female ; Humans ; Leukocytes/pathology ; Middle Aged ; Nutrition Assessment ; Prospective Studies ; Risk Factors ; Telomere/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) and mitochondrial genome (mtDNA) copy number and deletions have been proposed as risk markers for various cancer types, including breast cancer (BC).<br><br>METHODS: To gain a more comprehensive picture on how these markers can modulate BC risk, alone or in conjunction, we performed simultaneous measurements of LTL and mtDNA copy number in up to 570 BC cases and 538 controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. As a first step, we measured LTL and mtDNA copy number in 96 individuals for which a blood sample had been collected twice with an interval of 15 years.<br><br>RESULTS: According to the intraclass correlation (ICC), we found very good stability over the time period for both measurements, with ICCs of 0.63 for LTL and 0.60 for mtDNA copy number. In the analysis of the entire study sample, we observed that longer LTL was strongly associated with increased risk of BC (OR 2.71, 95% CI 1.58-4.65, p = 3.07 &#xd7; 10[-&#x2009;4] for highest vs. lowest quartile; OR 3.20, 95% CI 1.57-6.55, p = 1.41 &#xd7; 10[-&#x2009;3] as a continuous variable). We did not find any association between mtDNA copy number and BC risk; however, when considering only the functional copies, we observed an increased risk of developing estrogen receptor-positive BC (OR 2.47, 95% CI 1.05-5.80, p = 0.04 for highest vs. lowest quartile).<br><br>CONCLUSIONS: We observed a very good correlation between the markers over a period of 15 years. We confirm a role of LTL in BC carcinogenesis and suggest an effect of mtDNA copy number on BC risk.},
}
@article {pmid29664790,
year = {2018},
author = {Balmori, C and Varela, E},
title = {Should we consider telomere length and telomerase activity in male factor infertility?.},
journal = {Current opinion in obstetrics &amp; gynecology},
volume = {30},
number = {3},
pages = {197-202},
doi = {10.1097/GCO.0000000000000451},
pmid = {29664790},
issn = {1473-656X},
mesh = {Humans ; Infertility, Male/*genetics/*physiopathology ; Male ; Spermatozoa/*physiology ; Telomerase/analysis/*physiology ; Telomere/*physiology ; },
abstract = {PURPOSE OF REVIEW: The purpose of this review is to analyze what is known to date about the relation between telomeres and male fertility, and if it is possible for telomeres, or elements related to them, to be used as new prognostic biomarkers in fertility treatment.<br><br>RECENT FINDINGS: Cells in germ series, including spermatozoids, have longer telomeres (10-20 kb), and do not seem to undergo the shortening that takes place in somatic cells with age as they present telomerase activity. Longer telomere length found in the sperm of older fathers, influences their offspring possessing cells with longer telomere length. Infertile patients have spermatozoids with shorter telomere length than fertile people, but telomere length does neither correlate with the sperm concentration, mobility or morphology, nor with the DNA fragmentation indices (DFI) of spermatozoids. Embryo quality rate and transplantable embryo rate are related with the telomere length of spermatozoids (STL), but pregnancy rates are not affected.<br><br>SUMMARY: Telomere length and telomerase levels can be used as biomarkers of male fertility. Higher STL can have beneficial effects on fertility, thus the use of spermatozoids with longer telomere length in an assisted reproduction technique (ART) could be one way of solving some infertility cases.},
}
@article {pmid29663033,
year = {2018},
author = {Tomita, K},
title = {How long does telomerase extend telomeres? Regulation of telomerase release and telomere length homeostasis.},
journal = {Current genetics},
volume = {64},
number = {6},
pages = {1177-1181},
pmid = {29663033},
issn = {1432-0983},
support = {12097/CRUK_/Cancer Research UK/United Kingdom ; 281722/ERC_/European Research Council/International ; 281722-HRMCB//FP7 Ideas: European Research Council/ ; C36439/A12097/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Animals ; Humans ; Shelterin Complex ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomerase, the enzyme that replenishes telomeres, is essential for most eukaryotes to maintain their generations. Telomere length homeostasis is achieved via a balance between telomere lengthening by telomerase, and erosion over successive cell divisions. Impaired telomerase regulation leads to shortened telomeres and can cause defects in tissue maintenance. Telomeric DNA is composed of a repetitive sequence, which recruits the protective protein complex, shelterin. Shelterin, together with chromatin remodelling proteins, shapes the heterochromatic structure at the telomere and protects chromosome ends. Shelterin also provides a foothold for telomerase to be recruited and facilitates telomere extension. Such mechanisms of telomere recruitment and activation are conserved from unicellular eukaryotes to humans, with the rate of telomere extension playing an important role in determining the length maintained. Telomerase can be processive, adding multiple telomeric repeats before dissociating. However, a question remains: how does telomerase determine the number of repeats to add? In this review, I will discuss about how telomerase can monitor telomere extension using fission yeast as a model. I propose a model whereby the accumulation of the Pot1 complex on the synthesised telomere single-strand counteracts retention of telomerase via chromatin proteins and the similar system may be conserved in mammals.},
}
@article {pmid29662610,
year = {2018},
author = {Özer, &#xd6; and Bhowmick, R and Liu, Y and Hickson, ID},
title = {Human cancer cells utilize mitotic DNA synthesis to resist replication stress at telomeres regardless of their telomere maintenance mechanism.},
journal = {Oncotarget},
volume = {9},
number = {22},
pages = {15836-15846},
pmid = {29662610},
issn = {1949-2553},
abstract = {Telomeres resemble common fragile sites (CFSs) in that they are difficult-to-replicate and exhibit fragility in mitosis in response to DNA replication stress. At CFSs, this fragility is associated with a delay in the completion of DNA replication until early mitosis, whereupon cells are proposed to switch to a RAD52-dependent form of break-induced replication. Here, we show that this mitotic DNA synthesis (MiDAS) is also a feature of human telomeres. Telomeric MiDAS is not restricted to those telomeres displaying overt fragility, and is a feature of a wide range of cell lines irrespective of whether their telomeres are maintained by telomerase or by the alternative lengthening of telomeres (ALT) mechanism. MiDAS at telomeres requires RAD52, and is mechanistically similar to CFS-associated MiDAS, with the notable exception that telomeric MiDAS does not require the MUS81-EME1 endonuclease. We propose a model whereby replication stress initiates a RAD52-dependent form of break-induced replication that bypasses a requirement for MUS81-EME1 to complete DNA synthesis in mitosis.},
}
@article {pmid29660345,
year = {2018},
author = {Bian, C and Zhong, M and Nisar, MF and Wu, Y and Ouyang, M and Bartsch, JW and Zhong, JL},
title = {A novel heme oxygenase-1 splice variant, 14kDa HO-1, promotes cell proliferation and increases relative telomere length.},
journal = {Biochemical and biophysical research communications},
volume = {500},
number = {2},
pages = {429-434},
doi = {10.1016/j.bbrc.2018.04.096},
pmid = {29660345},
issn = {1090-2104},
mesh = {Alternative Splicing/*genetics ; Amino Acid Sequence ; Animals ; Base Sequence ; Cell Proliferation ; Heme Oxygenase-1/chemistry/*genetics/metabolism ; Humans ; Male ; Mice, Inbred BALB C ; Mice, Nude ; Molecular Weight ; Protein Transport ; Subcellular Fractions/metabolism ; Telomere/*metabolism ; },
abstract = {Alternative splicing is a routine phenomenon which greatly increases the diversity of proteins in eukaryotic cells. In humans, most multi-exonic genes are alternatively spliced and their splice variants confer distinct functions. Heme oxygenase-1 (HO-1, 32 kDa) is an inducible stress responsive protein, which possesses multiple functions in many cellular processes. In the current study, we identified a novel alternative splice isoform of 14 kDa HO-1 generated through exclusion of exon 3, and it is highly expressed in immortalized cells. In contrast to nuclear accumulation of the full-length 32 kDa HO-1, the novel 14 kDa HO-1 isoform is retained in the cytoplasm under ultraviolet (UV) irradiation. Interestingly, the 14 kDa HO-1 is shown to promote cell proliferation and an increase in relative telomere lengths in vivo and in vitro. Thus, we are pioneer to report and confirm the presence of a novel splice form of HO-1 and its distinct role in modulating telomere length and tumor growth.},
}
@article {pmid29659581,
year = {2018},
author = {Simoneau, A and Ricard, &#xc9; and Wurtele, H},
title = {An interplay between multiple sirtuins promotes completion of DNA replication in cells with short telomeres.},
journal = {PLoS genetics},
volume = {14},
number = {4},
pages = {e1007356},
pmid = {29659581},
issn = {1553-7404},
mesh = {Cell Cycle Proteins/genetics/metabolism ; Checkpoint Kinase 2/genetics/metabolism ; DNA Repair ; DNA Replication ; DNA, Fungal/genetics/*metabolism ; DNA-Binding Proteins/genetics/metabolism ; Genes, Fungal ; Histones/metabolism ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Mutation ; Niacinamide/pharmacology ; Protein Serine-Threonine Kinases/genetics/metabolism ; Saccharomyces cerevisiae/genetics/growth &amp; development/*metabolism ; Saccharomyces cerevisiae Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Sirtuins/antagonists &amp; inhibitors/genetics/*metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; },
abstract = {The evolutionarily-conserved sirtuin family of histone deacetylases regulates a multitude of DNA-associated processes. A recent genome-wide screen conducted in the yeast Saccharomyces cerevisiae identified Yku70/80, which regulate nonhomologous end-joining (NHEJ) and telomere structure, as being essential for cell proliferation in the presence of the pan-sirtuin inhibitor nicotinamide (NAM). Here, we show that sirtuin-dependent deacetylation of both histone H3 lysine 56 and H4 lysine 16 promotes growth of yku70Δ and yku80Δ cells, and that the NAM sensitivity of these mutants is not caused by defects in DNA double-strand break repair by NHEJ, but rather by their inability to maintain normal telomere length. Indeed, our results indicate that in the absence of sirtuin activity, cells with abnormally short telomeres, e.g., yku70/80Δ or est1/2Δ mutants, present striking defects in S phase progression. Our data further suggest that early firing of replication origins at short telomeres compromises the cellular response to NAM- and genotoxin-induced replicative stress. Finally, we show that reducing H4K16ac in yku70Δ cells limits activation of the DNA damage checkpoint kinase Rad53 in response to replicative stress, which promotes usage of translesion synthesis and S phase progression. Our results reveal a novel interplay between sirtuin-mediated regulation of chromatin structure and telomere-regulating factors in promoting timely completion of S phase upon replicative stress.},
}
@article {pmid29658398,
year = {2018},
author = {Avogaro, L and Querido, E and Dalachi, M and Jantsch, MF and Chartrand, P and Cusanelli, E},
title = {Live-cell imaging reveals the dynamics and function of single-telomere TERRA molecules in cancer cells.},
journal = {RNA biology},
volume = {15},
number = {6},
pages = {787-796},
pmid = {29658398},
issn = {1555-8584},
support = {MOP-89768//CIHR/Canada ; },
mesh = {Cell Line, Tumor ; Cell Nucleus/genetics/metabolism ; Humans ; Microscopy, Fluorescence ; Neoplasms/genetics/*metabolism/*pathology ; Oligonucleotides, Antisense/genetics/pharmacology ; RNA, Long Noncoding/genetics/*metabolism ; RNA, Neoplasm/genetics/*metabolism ; Telomere/*metabolism/pathology ; },
abstract = {Telomeres cap the ends of eukaryotic chromosomes, protecting them from degradation and erroneous recombination events which may lead to genome instability. Telomeres are transcribed giving rise to telomeric repeat-containing RNAs, called TERRA. The TERRA long noncoding RNAs have been proposed to play important roles in telomere biology, including heterochromatin formation and telomere length homeostasis. While TERRA RNAs are predominantly nuclear and localize at telomeres, little is known about the dynamics and function of TERRA molecules expressed from individual telomeres. Herein, we developed an assay to image endogenous TERRA molecules expressed from a single telomere in living human cancer cells. We show that single-telomere TERRA can be detected as TERRA RNA single particles which freely diffuse within the nucleus. Furthermore, TERRA molecules aggregate forming TERRA clusters. Three-dimensional size distribution and single particle tracking analyses revealed distinct sizes and dynamics for TERRA RNA single particles and clusters. Simultaneous time lapse confocal imaging of TERRA particles and telomeres showed that TERRA clusters transiently co-localize with telomeres. Finally, we used chemically modified antisense oligonucleotides to deplete TERRA molecules expressed from a single telomere. Single-telomere TERRA depletion resulted in increased DNA damage at telomeres and elsewhere in the genome. These results suggest that single-telomere TERRA transcripts participate in the maintenance of genomic integrity in human cancer cells.},
}
@article {pmid29654065,
year = {2018},
author = {Sengupta, S and Sobo, M and Lee, K and Senthil Kumar, S and White, AR and Mender, I and Fuller, C and Chow, LML and Fouladi, M and Shay, JW and Drissi, R},
title = {Induced Telomere Damage to Treat Telomerase Expressing Therapy-Resistant Pediatric Brain Tumors.},
journal = {Molecular cancer therapeutics},
volume = {17},
number = {7},
pages = {1504-1514},
doi = {10.1158/1535-7163.MCT-17-0792},
pmid = {29654065},
issn = {1538-8514},
mesh = {Animals ; Brain Neoplasms/genetics/pathology/*therapy ; Brain Stem Neoplasms/genetics/pathology/*therapy ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Damage/drug effects ; Deoxyguanosine/analogs &amp; derivatives/pharmacology ; Drug Resistance, Neoplasm/genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Glioma/genetics/pathology/*therapy ; Humans ; Medulloblastoma/genetics/pathology/therapy ; Mice ; Neoplastic Stem Cells/drug effects ; Prognosis ; Telomerase/*genetics/therapeutic use ; Telomere/drug effects/genetics ; Thionucleosides/pharmacology ; Xenograft Model Antitumor Assays ; },
abstract = {Brain tumors remain the leading cause of cancer-related deaths in children and often are associated with long-term sequelae among survivors of current therapies. Hence, there is an urgent need to identify actionable targets and to develop more effective therapies. Telomerase and telomeres play important roles in cancer, representing attractive therapeutic targets to treat children with poor-prognosis brain tumors such as diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG), and high-risk medulloblastoma. We have previously shown that DIPG, HGG, and medulloblastoma frequently express telomerase activity. Here, we show that the telomerase-dependent incorporation of 6-thio-2'deoxyguanosine (6-thio-dG), a telomerase substrate precursor analogue, into telomeres leads to telomere dysfunction-induced foci (TIF) along with extensive genomic DNA damage, cell growth inhibition, and cell death of primary stem-like cells derived from patients with DIPG, HGG, and medulloblastoma. Importantly, the effect of 6-thio-dG is persistent even after drug withdrawal. Treatment with 6-thio-dG elicits a sequential activation of ATR and ATM pathways and induces G2-M arrest. In vivo treatment of mice bearing medulloblastoma xenografts with 6-thio-dG delays tumor growth and increases in-tumor TIFs and apoptosis. Furthermore, 6-thio-dG crosses the blood-brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. Together, our findings suggest that 6-thio-dG is a promising novel approach to treat therapy-resistant telomerase-positive pediatric brain tumors. Mol Cancer Ther; 17(7); 1504-14. ©2018 AACR.},
}
@article {pmid29654060,
year = {2018},
author = {Begnis, M and Apte, MS and Masuda, H and Jain, D and Wheeler, DL and Cooper, JP},
title = {RNAi drives nonreciprocal translocations at eroding chromosome ends to establish telomere-free linear chromosomes.},
journal = {Genes &amp; development},
volume = {32},
number = {7-8},
pages = {537-554},
pmid = {29654060},
issn = {1549-5477},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; /CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {DNA Repair ; *DNA, Ribosomal ; DNA-Binding Proteins/physiology ; *Heterochromatin ; *RNA Interference ; Rad51 Recombinase/physiology ; Ribonuclease III/metabolism/physiology ; Schizosaccharomyces/genetics/metabolism ; Schizosaccharomyces pombe Proteins/metabolism/physiology ; Shelterin Complex ; Telomere ; Telomere-Binding Proteins/metabolism ; Terminal Repeat Sequences ; *Translocation, Genetic ; },
abstract = {The identification of telomerase-negative HAATI (heterochromatin amplification-mediated and telomerase-independent) cells, in which telomeres are superseded by nontelomeric heterochromatin tracts, challenged the idea that canonical telomeres are essential for chromosome linearity and raised crucial questions as to how such tracts translocate to eroding chromosome ends and confer end protection. Here we show that HAATI arises when telomere loss triggers a newly recognized illegitimate translocation pathway that requires RNAi factors. While RNAi is necessary for the translocation events that mobilize ribosomal DNA (rDNA) tracts to all chromosome ends (forming "HAATI[rDNA]" chromosomes), it is dispensable for HAATI[rDNA] maintenance. Surprisingly, Dicer (Dcr1) plays a separate, RNAi-independent role in preventing formation of the rare HAATI subtype in which a different repetitive element (the subtelomeric element) replaces telomeres. Using genetics and fusions between shelterin components and rDNA-binding proteins, we mapped the mechanism by which rDNA loci engage crucial end protection factors-despite the absence of telomere repeats-and secure end protection. Sequence analysis of HAATI[rDNA] genomes allowed us to propose RNA and DNA polymerase template-switching models for the mechanism of RNAi-triggered rDNA translocations. Collectively, our results reveal unforeseen roles for noncoding RNAs (ncRNAs) in assembling a telomere-free chromosome end protection device.},
}
@article {pmid29652549,
year = {2018},
author = {Li, AM and Thyagu, S and Maze, D and Schreiber, R and Sirrs, S and Stockler-Ipsiroglu, S and Sutherland, H and Vercauteren, S and Schultz, KR},
title = {Prolonged granulocyte colony stimulating factor use in glycogen storage disease type 1b associated with acute myeloid leukemia and with shortened telomere length.},
journal = {Pediatric hematology and oncology},
volume = {35},
number = {1},
pages = {45-51},
doi = {10.1080/08880018.2018.1440675},
pmid = {29652549},
issn = {1521-0669},
mesh = {Child ; Child, Preschool ; Female ; *Glycogen Storage Disease Type I/drug therapy/genetics/metabolism ; Granulocyte Colony-Stimulating Factor/*administration &amp; dosage/adverse effects ; Humans ; Infant ; *Leukemia, Myeloid, Acute/drug therapy/genetics/metabolism ; Male ; *Telomere Homeostasis ; Time Factors ; },
abstract = {Glycogen storage disease (GSD) type 1 is a rare autosomal recessive inherited condition. The 1b subtype comprises the minority of cases, with an estimated prevalence of 1 in 500,000 children. Patients with glycogen storage disease type 1b are often treated with granulocyte colony stimulating factor (G-CSF) for prolonged periods to improve symptoms of inflammatory bowel disease (IBD) and in the face of severe neutropenia to decrease risk of infection. Long-term G-CSF treatment may result in an increased risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) possibly due to increased marrow stress resulting in telomere shortening. To our knowledge, there have been two published cases of AML in GSD type 1b patients following long-term G-CSF exposure. Here, we report two further cases of AML/MDS-related changes in patients GSD type 1b treated with G-CSF. One patient developed AML with complex karyotype after 20 years of G-CSF treatment. The second patient was found to have short telomeres after 10 years of G-CSF exposure, but no evidence of acute leukemia at present. The third patient developed AML/MDS after 25 years of G-CSF use, with short telomeres prior to bone marrow transplant. Together these cases suggest that GSD type 1b patients with prolonged G-CSF exposure may be at an increased risk of MDS/AML states associated with G-CSF-induced shortened telomeres. We recommend that any GSD1b patients with prolonged G-CSF should have routine telomere assessments with monitoring for MDS if telomere shortening is observed, and with particular attention warranted if there is unexplained loss of G-CSF responsiveness.},
}
@article {pmid29650636,
year = {2018},
author = {Benetos, A and Kark, JD and Toupance, S and Verhulst, S and Aviv, A},
title = {Response by Benetos et al to Letter Regarding Article, "Short Leukocyte Telomere Length Precedes Clinical Expression of Atherosclerosis: The Blood-and-Muscle Model".},
journal = {Circulation research},
volume = {122},
number = {8},
pages = {e73-e74},
pmid = {29650636},
issn = {1524-4571},
support = {R01 HD071180/HD/NICHD NIH HHS/United States ; R01 HL116446/HL/NHLBI NIH HHS/United States ; R01 HL134840/HL/NHLBI NIH HHS/United States ; },
mesh = {*Atherosclerosis ; Humans ; Leukocytes ; Muscles ; *Telomere ; },
}
@article {pmid29650635,
year = {2018},
author = {De Meyer, T},
title = {Letter by De Meyer Regarding Article, "Short Leukocyte Telomere Length Precedes Clinical Expression of Atherosclerosis: The Blood-and-Muscle Model".},
journal = {Circulation research},
volume = {122},
number = {8},
pages = {e71-e72},
doi = {10.1161/CIRCRESAHA.118.312946},
pmid = {29650635},
issn = {1524-4571},
mesh = {*Atherosclerosis ; Humans ; Leukocytes ; *Telomere ; Telomere Shortening ; },
}
@article {pmid29644955,
year = {2018},
author = {Liu, JJ and Cahoon, EK and Linet, MS and Little, MP and Dagnall, CL and Higson, H and Savage, SA and Freedman, DM},
title = {Relationship between plasma 25-hydroxymitamin D and leucocyte telomere length by sex and race in a US study - CORRIGENDUM.},
journal = {The British journal of nutrition},
volume = {119},
number = {8},
pages = {966},
pmid = {29644955},
issn = {1475-2662},
support = {ZIA CP010135/ImNIH/Intramural NIH HHS/United States ; },
}
@article {pmid29643374,
year = {2019},
author = {Awada, Z and Sleiman, F and Mailhac, A and Mouneimne, Y and Tamim, H and Zgheib, NK},
title = {BPA exposure is associated with non-monotonic alteration in ESR1 promoter methylation in peripheral blood of men and shorter relative telomere length in peripheral blood of women.},
journal = {Journal of exposure science &amp; environmental epidemiology},
volume = {29},
number = {1},
pages = {118-128},
doi = {10.1038/s41370-018-0030-4},
pmid = {29643374},
issn = {1559-064X},
mesh = {Adult ; Benzhydryl Compounds/*metabolism ; Cohort Studies ; Creatinine/metabolism ; Environmental Pollutants/*metabolism ; Estrogen Receptor alpha/*metabolism ; Female ; Humans ; Male ; Methylation ; Phenols/*metabolism ; Promoter Regions, Genetic ; Real-Time Polymerase Chain Reaction ; Sex Factors ; Telomere/*metabolism/pathology ; },
abstract = {The aim of this study was to evaluate the potential association of urinary Bisphenol A (BPA) levels with estrogen receptor alpha (ESR1) promoter % methylation and relative telomere length in a sample of 482 participants. Urinary BPA concentration was measured using organic phase extraction followed by high performance liquid chromatography mass spectroscopy. Peripheral blood ESR1 promoter % methylation and relative telomere length were measured using direct bisulfite sequencing and real-time polymerase chain reaction, respectively. The mean ± SD urinary BPA concentration adjusted for urinary creatinine was 2.90 ± 4.81 (μg/g creatinine) with a median of 1.86 μg/g creatinine (min-max: <LOD -69.85). There was a potentially non-monotonic relationship between adjusted urinary BPA concentrations and ESR1 promoter % methylation in men. As a matter of fact, for the lowest tertile of ESR1 promoter % methylation, the OR and 95% CI of the middle and highest tertiles of urinary adjusted BPA were 2.54 (1.01-6.39) and 1.64 (0.55-4.86) when compared to the lowest BPA tertile, respectively. After adjustment for potential confounders, similar results remained in men and appeared in the whole cohort. As for relative telomere length, there was a significant trend whereby higher adjusted urinary BPA concentrations were significantly associated with shorter relative telomere length in females. For instance, for the shortest relative telomere length tertile, the OR and 95% CI of the middle and highest tertiles of urinary adjusted BPA were 2.91 (1.38-6.16) and 3.19 (1.57-6.49) when compared to the lowest BPA tertile, respectively. This trend remained significant after adjustment for potential confounders.},
}
@article {pmid29642537,
year = {2018},
author = {Song, S and Johnson, FB},
title = {Epigenetic Mechanisms Impacting Aging: A Focus on Histone Levels and Telomeres.},
journal = {Genes},
volume = {9},
number = {4},
pages = {},
pmid = {29642537},
issn = {2073-4425},
abstract = {Aging and age-related diseases pose some of the most significant and difficult challenges to modern society as well as to the scientific and medical communities. Biological aging is a complex, and, under normal circumstances, seemingly irreversible collection of processes that involves numerous underlying mechanisms. Among these, chromatin-based processes have emerged as major regulators of cellular and organismal aging. These include DNA methylation, histone modifications, nucleosome positioning, and telomere regulation, including how these are influenced by environmental factors such as diet. Here we focus on two interconnected categories of chromatin-based mechanisms impacting aging: those involving changes in the levels of histones or in the functions of telomeres.},
}
@article {pmid29637701,
year = {2018},
author = {Toubiana, S and Selig, S},
title = {DNA:RNA hybrids at telomeres - when it is better to be out of the (R) loop.},
journal = {The FEBS journal},
volume = {285},
number = {14},
pages = {2552-2566},
doi = {10.1111/febs.14464},
pmid = {29637701},
issn = {1742-4658},
mesh = {Base Composition ; DNA/*chemistry/genetics/metabolism ; Face/*abnormalities/pathology ; Gene Expression Regulation ; *Genome ; Genomic Instability ; Humans ; Immunologic Deficiency Syndromes/*genetics/immunology/pathology ; Nucleic Acid Conformation ; *Nucleic Acid Hybridization ; Primary Immunodeficiency Diseases ; RNA, Long Noncoding/*chemistry/genetics/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Telomere/*chemistry/metabolism ; Telomere Homeostasis ; Trypanosoma brucei brucei/genetics/metabolism ; },
abstract = {R-loops (RLs) are three-stranded nucleic acid structures that contain a DNA:RNA hybrid and a displaced DNA strand. Genomic regions with GC skew and a G-rich transcript are particularly prone to form RLs. RLs play important physiological roles in cells; however, when present at abnormally high levels, they may threaten genome stability. The perfect GC skew of telomeric repeats and the discovery of telomeric repeat-containing RNA (TERRA), a long noncoding transcript that consists of the G-rich telomeric sequence, make telomeric sequences the perfect candidates for generating RLs. Indeed, in the past 5 years, telomere R-loops (TRLs) have been demonstrated in Saccharomyces cerevisiae, Trypanosoma brucei, and human cells. The presence of TRLs in normal human cells that transcribe low levels of TERRA, suggests a physiological role for these nucleic structures in telomere maintenance. Abnormally enhanced TERRA transcription, as found in several human pathological conditions, leads to high TRL levels and various cellular outcomes, depending on the recombinogenic capabilities of the cells. Study of TRLs in various organisms highlights the necessity for tight regulation of these structures, which can switch from beneficial to detrimental under different conditions. Here, we review the current state of knowledge on TRLs, describe several means by which TRLs are regulated, and discuss how findings from yeast are relevant to human pathological scenarios in which TRLs are deregulated.},
}
@article {pmid29636409,
year = {2018},
author = {McLennan, D and Armstrong, JD and Stewart, DC and Mckelvey, S and Boner, W and Monaghan, P and Metcalfe, NB},
title = {Telomere elongation during early development is independent of environmental temperatures in Atlantic salmon.},
journal = {The Journal of experimental biology},
volume = {221},
number = {Pt 11},
pages = {},
pmid = {29636409},
issn = {1477-9145},
mesh = {Animals ; *Cell Proliferation ; DNA ; *Oxidative Stress ; Salmo salar/embryology/growth &amp; development/*physiology ; *Telomere Homeostasis ; Temperature ; },
abstract = {There is increasing evidence from endothermic vertebrates that telomeres, which cap the ends of chromosomes and play an important role in chromosome protection, decline in length during postnatal life and are a useful indicator of physiological state and expected lifespan. However, much less is currently known about telomere dynamics in ectothermic vertebrates, which are likely to differ from that of endotherms, at least in part due to the sensitivity of ectotherm physiology to environmental temperature. We report here on an experiment in which Atlantic salmon (Salmo salar) were reared through the embryonic and larval stages of development, and under differing temperatures, in order to examine the effects of environmental temperature during early life on telomere dynamics, oxidative DNA damage and cellular proliferation. Telomere length significantly increased between the embryonic and larval stages of development. Contrary to our expectations, variation in telomere length at the end of the larval stage was unrelated to either cell proliferation rate or the relative level of oxidative DNA damage, and did not vary between the temperature treatments. This study suggests that salmon are able to restore the length of their telomeres during early development, which may possibly help to buffer potentially harmful environmental effects experienced in early life.},
}
@article {pmid29635765,
year = {2018},
author = {La Torre, M and Merigliano, C and Burla, R and Mottini, C and Zanetti, G and Del Giudice, S and Carcuro, M and Virdia, I and Bucciarelli, E and Manni, I and Vinciguerra, GR and Piaggio, G and Riminucci, M and Cumano, A and Bartolazzi, A and Vernì, F and Soddu, S and Gatti, M and Saggio, I},
title = {Mice with reduced expression of the telomere-associated protein Ft1 develop p53-sensitive progeroid traits.},
journal = {Aging cell},
volume = {17},
number = {4},
pages = {e12730},
pmid = {29635765},
issn = {1474-9726},
support = {//Progeria Research Foundation/International ; //Fondazione Telethon/International ; //Associazione Italiana per la Ricerca sul Cancro/International ; 286071//EU FP7 Brainvectors/International ; },
mesh = {Animals ; Apoptosis Regulatory Proteins ; Cells, Cultured ; Gene Expression Profiling ; Mice ; Mice, Inbred C57BL ; Mutation ; Progeria/*genetics/metabolism/pathology ; Proteins/*genetics/metabolism ; Tumor Suppressor Protein p53/*genetics/metabolism ; },
abstract = {Human AKTIP and mouse Ft1 are orthologous ubiquitin E2 variant proteins involved in telomere maintenance and DNA replication. AKTIP also interacts with A- and B-type lamins. These features suggest that Ft1 may be implicated in aging regulatory pathways. Here, we show that cells derived from hypomorph Ft1 mutant (Ft1[kof/kof]) mice exhibit telomeric defects and that Ft1[kof/kof] animals develop progeroid traits, including impaired growth, skeletal and skin defects, abnormal heart tissue, and sterility. We also demonstrate a genetic interaction between Ft1 and p53. The analysis of mice carrying mutations in both Ft1 and p53 (Ft1[kof/kof] ; p53[ko/ko] and Ft1[kof/kof] ; p53[+/ko]) showed that reduction in p53 rescues the progeroid traits of Ft1 mutants, suggesting that they are at least in part caused by a p53-dependent DNA damage response. Conversely, Ft1 reduction alters lymphomagenesis in p53 mutant mice. These results identify Ft1 as a new player in the aging process and open the way to the analysis of its interactions with other progeria genes using the mouse model.},
}
@article {pmid29632022,
year = {2018},
author = {Gadalla, SM and Aubert, G and Wang, T and Haagenson, M and Spellman, SR and Wang, L and Katki, HA and Savage, SA and Lee, SJ},
title = {Donor telomere length and causes of death after unrelated hematopoietic cell transplantation in patients with marrow failure.},
journal = {Blood},
volume = {131},
number = {21},
pages = {2393-2398},
pmid = {29632022},
issn = {1528-0020},
support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Anemia, Aplastic/diagnosis/*etiology/metabolism/mortality ; Bone Marrow/immunology/metabolism/*pathology ; Cause of Death ; Child ; Child, Preschool ; Female ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods ; Hematopoietic Stem Cells/*immunology/metabolism ; Humans ; *Immune Tolerance ; Infant ; Male ; Treatment Outcome ; *Unrelated Donors ; Young Adult ; },
abstract = {Previous studies have suggested that longer donor leukocyte telomere length (TL) is associated with improved survival after hematopoietic cell transplantation (HCT) in severe aplastic anemia (SAA). This study aimed to determine whether cell-specific lymphocyte TL is associated with certain post-HCT causes of death. We used flow cytometry and fluorescence in situ hybridization to measure TL in donor total lymphocytes and subsets: naïve enriched T cells (CD45RA[+]CD20[-]), memory enriched T cells (CD45RA[-]CD20[-]), natural killer (NK) fully differentiated T cells (CD45RA[+]CD57[+]), and B cells (CD45RA[+]CD20[+]). Competing risk survival regression was used for cause-specific death analyses. Clinical data and biospecimens were available from the Center for International Blood and Marrow Transplant Research database and biorepository. The study included 197 patients who underwent unrelated-donor HCT for SAA between 1988 and 2004. The median age at HCT was 15 years (range, 0.5-40 years), and the median follow-up was 5 years (range, <1 month to 20.7 years). Longer donor TL in all cell subsets was associated with lower risk of all-cause mortality (P < .01). In cause-specific mortality analyses, longer TL in B cells (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.46-0.87; P = .006) and possibly NK fully differentiated T cells (HR, 0.7; 95% CI, 0.51 to 0.97; P = .03) was associated with lower risk of infection-related death. Donor TL in other tested lymphocyte subsets was not statistically significantly associated with death resulting from graft-versus-host disease or graft failure (P > .05). However, a trend toward excess risk of graft-versus-host mortality was noted (HR for total lymphocyte TL, 1.26; P = .15). In conclusion, longer donor TL was associated with reduced rate of infection-related deaths after HCT for SAA.},
}
@article {pmid29631336,
year = {2018},
author = {Dent, E and Hoogendijk, EO and Moldovan, M},
title = {Frailty index from routine laboratory measurements correlates with leukocyte telomere length.},
journal = {Geriatrics &amp; gerontology international},
volume = {18},
number = {4},
pages = {654-655},
doi = {10.1111/ggi.13257},
pmid = {29631336},
issn = {1447-0594},
mesh = {Aged ; Diagnostic Tests, Routine ; Frail Elderly ; Frailty/*diagnosis ; *Health Status Indicators ; Humans ; Leukocytes ; Reproducibility of Results ; Telomere ; },
}
@article {pmid29627866,
year = {2018},
author = {Minina, JM and Karamysheva, TV and Rubtsov, NB and Zhdanova, NS},
title = {Replication timing of large Sorex granarius (Soricidae, Eulipotyphla) telomeres.},
journal = {Protoplasma},
volume = {255},
number = {5},
pages = {1477-1486},
pmid = {29627866},
issn = {1615-6102},
support = {No 0324-2018-0019//Federal Research Center Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences/ ; },
mesh = {Animals ; DNA Damage/genetics ; DNA Replication/genetics/physiology ; RNA, Ribosomal, 18S/genetics ; Shrews/*genetics ; Telomere/*genetics ; },
abstract = {Previously, we described the unique feature of telomeric regions in Iberian shrew Sorex granarius: its telomeres have two ranges of size, very small (3.8 kb of telomeric repeats on average) and very large discontinuous telomeres (213 kb) interrupted with 18S rDNA. In this study, we have demonstrated extraordinary replication pattern of S. granarius large telomeres that have not been shown before in other studied mammal. Using the ReD-FISH procedure, we observed prolonged, through S period, large telomere replication. Furthermore, revealed ReD-FISH asymmetric signals were probably caused by partial replication of telomeres within an hour of 5-bromodeoxyuridine treatment due to the large size and special organization. We also found that in contrast to the telomeric halo from primary fibroblasts of bovine, mink, and common shrew, telomere halo of S. granarius consists of multiple loops bundled together, some of which contain rDNA. Here, we suggested several replicons firing possibly stochastic in each large telomere. Finally, we performed the TIF assay to reveal DNA damage responses at the telomeres, and along with TIF in nuclei, we found large bodies of telomeric DNA and ɤ-H2AX in the cytoplasm and on the surface of fibroblasts. We discuss the possibility of additional origin activation together with recombination-dependent replication pathways, mainly homologous recombination including BIR for replication fork stagnation overcoming and further S. granarius large telomere replication.},
}
@article {pmid29623565,
year = {2018},
author = {Jiménez, KM and Forero, DA},
title = {Effect of master mixes on the measurement of telomere length by qPCR.},
journal = {Molecular biology reports},
volume = {45},
number = {4},
pages = {633-638},
pmid = {29623565},
issn = {1573-4978},
support = {823-2015//Colciencias/ ; },
mesh = {Healthy Volunteers ; Humans ; Real-Time Polymerase Chain Reaction/*methods ; Sensitivity and Specificity ; Telomere/chemistry/*genetics ; Telomere Homeostasis ; },
abstract = {Alterations in telomere length (TL) have been associated with several diseases and a method based on qPCR, the Monochrome Multiplex Real-Time Quantitative PCR (MMQPCR) technique, has been used extensively for the analysis of TL. Some previous studies have been found that certain methodological conditions can affect the measurement of TL. The aim of the study was to evaluate the performance of eight different commercially available SYBR Green and High-Resolution Melting (HRM) mixes on the measurement of TL by the MMQPCR method. Four SYBR Green and four HRM mixes were tested and the measurement of TL was expressed by the T/S ratio. It was found that the type of master mix used in MMQPCR influences the measurement of TL, affecting aspects such as the specificity and consistency of the results. Our results are the first description of the effects of different master mixes on TL analysis by MMQPCR and highlight the importance of the future methodological improvement of this broadly used technique.},
}
@article {pmid29622687,
year = {2018},
author = {Charbonnel, C and Rymarenko, O and Da Ines, O and Benyahya, F and White, CI and Butter, F and Amiard, S},
title = {The Linker Histone GH1-HMGA1 Is Involved in Telomere Stability and DNA Damage Repair.},
journal = {Plant physiology},
volume = {177},
number = {1},
pages = {311-327},
pmid = {29622687},
issn = {1532-2548},
mesh = {Arabidopsis/growth &amp; development/*metabolism ; Arabidopsis Proteins/*metabolism ; Chromatin/metabolism ; *DNA Damage ; *DNA Repair ; DNA, Bacterial/genetics ; Fluorescence ; HMGA Proteins/*metabolism ; Histones/*metabolism ; Homologous Recombination/genetics ; Mutation/genetics ; Protein Binding ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Despite intensive searches, few proteins involved in telomere homeostasis have been identified in plants. Here, we used pull-down assays to identify potential telomeric interactors in the model plant species Arabidopsis (Arabidopsis thaliana). We identified the candidate protein GH1-HMGA1 (also known as HON4), an uncharacterized linker histone protein of the High Mobility Group Protein A (HMGA) family in plants. HMGAs are architectural transcription factors and have been suggested to function in DNA damage repair, but their precise biological roles remain unclear. Here, we show that GH1-HMGA1 is required for efficient DNA damage repair and telomere integrity in Arabidopsis. GH1-HMGA1 mutants exhibit developmental and growth defects, accompanied by ploidy defects, increased telomere dysfunction-induced foci, mitotic anaphase bridges, and degraded telomeres. Furthermore, mutants have a higher sensitivity to genotoxic agents such as mitomycin C and γ-irradiation. Our work also suggests that GH1-HMGA1 is involved directly in the repair process by allowing the completion of homologous recombination.},
}
@article {pmid29619669,
year = {2018},
author = {Hang, D and Nan, H and Kværner, AS and De Vivo, I and Chan, AT and Hu, Z and Shen, H and Giovannucci, E and Song, M},
title = {Longitudinal associations of lifetime adiposity with leukocyte telomere length and mitochondrial DNA copy number.},
journal = {European journal of epidemiology},
volume = {33},
number = {5},
pages = {485-495},
pmid = {29619669},
issn = {1573-7284},
support = {R01 HL034594/NH/NIH HHS/United States ; UM1 CA186107/NH/NIH HHS/United States ; MRSG-17-220-01 - NEC//American Cancer Society/ ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 HL088521/NH/NIH HHS/United States ; P01 CA87969/NH/NIH HHS/United States ; R01 CA49449/NH/NIH HHS/United States ; R01 HL088521/HL/NHLBI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; R01 HL034594/HL/NHLBI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; },
mesh = {Adiposity/*physiology ; Adolescent ; Adult ; Aging/physiology ; *Body Mass Index ; Child ; Child, Preschool ; Cohort Studies ; DNA Copy Number Variations/*physiology ; DNA, Mitochondrial/*physiology ; Female ; Humans ; Leukocytes/*physiology ; Longitudinal Studies ; Male ; Middle Aged ; Prospective Studies ; Risk Factors ; Telomere/*physiology ; United States ; Young Adult ; },
abstract = {Adiposity may cause adverse health outcomes by increasing oxidative stress and systemic inflammation, which can be reflected by altered telomere length (TL) and mitochondrial DNA copy number (mtCN) in peripheral blood leukocytes. However, little is known about the influence of lifetime adiposity on TL and mtCN in later life. This study was performed to investigate the associations of lifetime adiposity with leukocyte TL and mtCN in 9613 participants from the Nurses' Health Study. A group-based trajectory modelling approach was used to create trajectories of body shape from age 5 through 60 years, and a genetic risk score (GRS) was created based on 97 known adiposity susceptibility variants. Associations of body shape trajectories and GRS with dichotomized TL and mtCN were assessed by logistic regression models. After adjustment for lifestyle and dietary factors, compared with the lean-stable group, the lean-marked increase group had higher odds of having below-median TL (OR = 1.18, 95% CI 1.04, 1.35; P = 0.01), and the medium-marked increase group had higher odds of having below-median mtCN (OR = 1.28, 95% CI 1.00, 1.64; P = 0.047). There was a suggestive trend toward lower mtCN across the GRS quartiles (P for trend = 0.07). In conclusion, telomere attrition may be accelerated by marked weight gain in middle life, whereas mtCN is likely to be reduced persistently by adiposity over the life course. The findings indicate the importance of lifetime weight management to preserve functional telomeres and mitochondria.},
}
@article {pmid29618413,
year = {2018},
author = {Riley, G and Perrin, M and Vaez-Azizi, LM and Ruby, E and Goetz, RR and Dracxler, R and Walsh-Messinger, J and Keefe, DL and Buckley, PF and Szeszko, PR and Malaspina, D},
title = {Telomere length and early trauma in schizophrenia.},
journal = {Schizophrenia research},
volume = {199},
number = {},
pages = {426-430},
pmid = {29618413},
issn = {1573-2509},
support = {RC1 MH088843/MH/NIMH NIH HHS/United States ; T32 DA007294/DA/NIDA NIH HHS/United States ; },
mesh = {Adult ; *Adult Survivors of Child Adverse Events ; Female ; Humans ; Leukocytes/metabolism ; Male ; Middle Aged ; Psychological Trauma/*metabolism ; Schizophrenia/*metabolism ; Sex Factors ; *Telomere Shortening ; },
abstract = {BACKGROUND: Childhood trauma is emerging as a risk factor for schizophrenia, but its mechanism with respect to etiology is unknown. One possible pathway is through leucocyte telomere length (LTL) shortening, a measure of cellular aging associated with trauma. This study examined early trauma and LTL shortening in schizophrenia and considered sex effects.<br><br>METHODS: The early trauma inventory (ETI) was administered to 48 adults with DSM-5 schizophrenia and 18 comparison participants. LTL was measured using qPCR.<br><br>OUTCOMES: Cases had significantly more global trauma (F=4.10, p<0.01) and traumatic events (F=11.23, p<0.001), but case and control groups had similar LTL (1.91&#xb1;0.74 and 1.83&#xb1;0.62: p=0.68). The association of early trauma and LTL differed by sex in cases and controls (Fisher's R: Z<0.05). Significant negative associations were shown in male cases and, conversely, in female controls. For example, physical punishment was associated LTL shortening in males' cases (r=-0.429, p<01). Only female controls showed significant telomere shortening in association with early trauma.<br><br>INTERPRETATION: This data confirms the substantial excess of early trauma among schizophrenia cases. There were significant sex-differences in the relationship of the trauma to LTL, with only male cases showing the expected shortening. There were converse sex effects in the control group. Mean LTL was notably similar in cases and controls, despite the trauma-related shortening in male cases, cigarette smoking, older age and chronic illness of the cases. Factors may lengthen LTL in some schizophrenia cases. The converse sex differences in the cases are consistent with findings defective sexual differentiation in schizophrenia, consistent with other findings in the field.},
}
@article {pmid29618208,
year = {2018},
author = {Che, T and Chen, SB and Tu, JL and Wang, B and Wang, YQ and Zhang, Y and Wang, J and Wang, ZQ and Zhang, ZP and Ou, TM and Zhao, Y and Tan, JH and Huang, ZS},
title = {Discovery of Novel Schizocommunin Derivatives as Telomeric G-Quadruplex Ligands That Trigger Telomere Dysfunction and the Deoxyribonucleic Acid (DNA) Damage Response.},
journal = {Journal of medicinal chemistry},
volume = {61},
number = {8},
pages = {3436-3453},
doi = {10.1021/acs.jmedchem.7b01615},
pmid = {29618208},
issn = {1520-4804},
mesh = {Animals ; Antineoplastic Agents/chemical synthesis/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA/*genetics ; *DNA Damage ; Drug Discovery ; Female ; G-Quadruplexes ; G2 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Indoles/chemical synthesis/*pharmacology/therapeutic use ; Ligands ; Mice, Inbred BALB C ; Telomerase/antagonists &amp; inhibitors ; Telomere/genetics/*metabolism ; Telomere Shortening ; Telomere-Binding Proteins/metabolism ; Uterine Cervical Neoplasms/drug therapy ; Xenograft Model Antitumor Assays ; },
abstract = {Telomeric G-quadruplex targeting and telomere maintenance interference are emerging as attractive strategies for anticancer therapies. Here, a novel molecular scaffold is explored for telomeric G-quadruplex targeting. A series of novel schizocommunin derivatives was designed and synthesized as potential telomeric G-quadruplex ligands. The interaction of telomeric G-quadruplex DNA with the derivatives was explored by biophysical assay. The cytotoxicity of the derivatives toward cancer cell lines was evaluated by the methyl thiazolyl tetrazolium (MTT) assay. Among the derivatives, compound 16 showed great stabilization ability toward telomeric G-quadruplex DNA and good cytotoxicity toward cancer cell lines. Further cellular experiments indicated that 16 could induce the formation of telomeric G-quadruplex in cells, triggering a DNA damage response at the telomere and causing telomere dysfunction. These effects ultimately provoked p53-mediated cell cycle arrest and apoptosis, and suppressed tumor growth in a mouse xenograft model. Our work provides a novel scaffold for the development of telomeric G-quadruplex ligands.},
}
@article {pmid29616083,
year = {2018},
author = {Mekhail, K},
title = {Defining the Damaged DNA Mobility Paradox as Revealed by the Study of Telomeres, DSBs, Microtubules and Motors.},
journal = {Frontiers in genetics},
volume = {9},
number = {},
pages = {95},
pmid = {29616083},
issn = {1664-8021},
abstract = {Eukaryotic genomes are non-randomly arranged inside the nucleus. Despite this ordered spatial genome organization, damaged DNA exhibits increased random mobility within nuclear space. This increased random movement is thought to promote DNA repair by facilitating homology search, allowing targeting to repair-conducive nuclear domains, or releasing damage from repair-repressive locations. Recent studies focusing on the relationship between telomeres, DNA repair processes, and nuclear organization have revealed that the disruption of motor proteins or microtubules, which typically mediate the directed motion of cargo, disrupts the random mobility of damaged DNA. These findings define a new biological paradox. Here, I define this as the damaged DNA mobility paradox, describe how it uncovers key gaps in knowledge, and highlight key questions to help guide us toward paradox resolution.},
}
@article {pmid29614649,
year = {2018},
author = {Cardillo, GM and De-Paula, VJR and Ikenaga, EH and Costa, LR and Catanozi, S and Schaeffer, EL and Gattaz, WF and Kerr, DS and Forlenza, OV},
title = {Chronic Lithium Treatment Increases Telomere Length in Parietal Cortex and Hippocampus of Triple-Transgenic Alzheimer's Disease Mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {63},
number = {1},
pages = {93-101},
doi = {10.3233/JAD-170838},
pmid = {29614649},
issn = {1875-8908},
mesh = {Alzheimer Disease/blood/*drug therapy/genetics/*pathology ; Amyloid beta-Protein Precursor/genetics ; Animals ; Antipsychotic Agents/blood/*therapeutic use ; Disease Models, Animal ; Hippocampus/*drug effects/metabolism ; Humans ; Lithium Compounds/*therapeutic use ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation/genetics ; Parietal Lobe/*drug effects/metabolism ; Presenilin-1/genetics ; Telomere Homeostasis/*drug effects ; tau Proteins/genetics ; },
abstract = {Telomere length (TL) is a biomarker of cell aging, and its shortening has been linked to several age-related diseases. In Alzheimer's disease (AD), telomere shortening has been associated with neuroinflammation and oxidative stress. The majority of studies on TL in AD were based on leucocyte DNA, with little information about its status in the central nervous system. In addition to other neuroprotective effects, lithium has been implicated in the maintenance of TL. The present study aims to determine the effect of chronic lithium treatment on TL in different regions of the mouse brain, using a triple-transgenic mouse model (3xTg-AD). Eighteen transgenic and 22 wild-type (Wt) male mice were treated for eight months with chow containing 1.0 g (Li1) or 2.0 g (Li2) of lithium carbonate/kg, or standard chow (Li0). DNA was extracted from parietal cortex, hippocampus and olfactory epithelium and TL was quantified by real-time PCR. Chronic lithium treatment was associated with longer telomeres in the hippocampus (Li2, p = 0.0159) and in the parietal cortex (Li1, p = 0.0375) of 3xTg-AD compared to Wt. Our findings suggest that chronic lithium treatment does affect telomere maintenance, but the magnitude and nature of this effect depend on the working concentrations of lithium and characteristics of the tissue. This effect was observed when comparing 3xTg-AD with Wt mice, suggesting that the presence of AD pathology was required for the lithium modulation of TL.},
}
@article {pmid29610814,
year = {2018},
author = {Xiao, CD and Shibata, T and Yamamoto, Y and Xu, Y},
title = {An intramolecular antiparallel G-quadruplex formed by human telomere RNA.},
journal = {Chemical communications (Cambridge, England)},
volume = {54},
number = {32},
pages = {3944-3946},
doi = {10.1039/c8cc01427b},
pmid = {29610814},
issn = {1364-548X},
mesh = {Base Sequence ; Circular Dichroism ; Deoxyguanosine/analogs &amp; derivatives/chemistry ; *G-Quadruplexes ; Humans ; RNA/*chemistry ; Telomere/*genetics ; },
abstract = {Until now, RNA G-quadruplexes were believed to only adopt a parallel G-quadruplex structure. In this study, we describe the first observation of an antiparallel RNA G-quadruplex formed by human telomere RNA. This newly described topology is of great interest as it shows that RNA G-quadruplexes can also be polymorphic and adopt structures that are different from the parallel configuration.},
}
@article {pmid29610311,
year = {2018},
author = {},
title = {Correction for Jiang et al., Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {115},
number = {15},
pages = {E3600},
doi = {10.1073/pnas.1804185115},
pmid = {29610311},
issn = {1091-6490},
}
@article {pmid29609488,
year = {2019},
author = {Boniewska-Bernacka, E and Pańczyszyn, A and Cybulska, N},
title = {Telomeres as a molecular marker of male infertility.},
journal = {Human fertility (Cambridge, England)},
volume = {22},
number = {2},
pages = {78-87},
doi = {10.1080/14647273.2018.1456682},
pmid = {29609488},
issn = {1742-8149},
mesh = {Biomarkers ; Humans ; Infertility, Male/*diagnosis ; Male ; Spermatozoa/*cytology ; *Telomere ; Telomere Homeostasis ; },
abstract = {In recent years, male infertility has become a growing social problem. Standard diagnostic procedures, based on assessing seminological parameters, are often insufficient to explain the causes of male infertility. Because of this, new markers with better clinical application are being sought. One of the promising markers seems to be an assessment of telomere length of sperm. Sperm telomeres, in contrast to somatic cells, are elongated as men age. The results of some studies suggest that telomere length may be relevant in the case of fertilization and normal embryo development. Literature reports indicate that there is a correlation between telomere length of sperm and abnormal sperm parameters. The measurement of telomere length using the method of quantitative PCR could become a new marker of spermatogenesis, which can be useful for evaluating male reproductive age.},
}
@article {pmid29604323,
year = {2019},
author = {Barnes, RP and Fouquerel, E and Opresko, PL},
title = {The impact of oxidative DNA damage and stress on telomere homeostasis.},
journal = {Mechanisms of ageing and development},
volume = {177},
number = {},
pages = {37-45},
pmid = {29604323},
issn = {1872-6216},
support = {R21 ES025606/ES/NIEHS NIH HHS/United States ; R01 ES028242/ES/NIEHS NIH HHS/United States ; R44 GM108187/GM/NIGMS NIH HHS/United States ; R43 GM108187/GM/NIGMS NIH HHS/United States ; R01 CA207342/CA/NCI NIH HHS/United States ; R01 ES022944/ES/NIEHS NIH HHS/United States ; R35 ES030396/ES/NIEHS NIH HHS/United States ; R33 ES025606/ES/NIEHS NIH HHS/United States ; },
mesh = {Aging/*metabolism/pathology ; Animals ; *DNA Damage ; Environmental Exposure/*adverse effects ; Humans ; Mice ; Oxidation-Reduction ; *Oxidative Stress ; },
abstract = {Telomeres are dynamic nucleoprotein-DNA structures that cap and protect linear chromosome ends. Because telomeres shorten progressively with each replication, they impose a functional limit on the number of times a cell can divide. Critically short telomeres trigger cellular senescence in normal cells, or genomic instability in pre-malignant cells, which contribute to numerous degenerative and aging-related diseases including cancer. Therefore, a detailed understanding of the mechanisms of telomere loss and preservation is important for human health. Numerous studies have shown that oxidative stress is associated with accelerated telomere shortening and dysfunction. Oxidative stress caused by inflammation, intrinsic cell factors or environmental exposures, contributes to the pathogenesis of many degenerative diseases and cancer. Here we review the studies demonstrating associations between oxidative stress and accelerated telomere attrition in human tissue, mice and cell culture, and discuss possible mechanisms and cellular pathways that protect telomeres from oxidative damage.},
}
@article {pmid29602239,
year = {2018},
author = {Zheng, Q and Xu, J and Lin, Z and Lu, Y and Xin, X and Li, X and Yang, Y and Meng, Q and Wang, C and Xiong, W and Lu, D},
title = {Inflammatory factor receptor Toll-like receptor 4 controls telomeres through heterochromatin protein 1 isoforms in liver cancer stem cell.},
journal = {Journal of cellular and molecular medicine},
volume = {22},
number = {6},
pages = {3246-3258},
pmid = {29602239},
issn = {1582-4934},
mesh = {Cell Line, Tumor ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/*genetics ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA-Binding Proteins/genetics ; Gene Expression Regulation, Neoplastic ; Histone-Lysine N-Methyltransferase/genetics ; Humans ; Liver/metabolism/pathology ; Liver Neoplasms/*genetics/pathology ; Neoplastic Stem Cells/metabolism/pathology ; Protein Isoforms/genetics ; RNA, Long Noncoding/genetics ; Telomerase/*genetics ; Telomere/genetics ; Telomere Homeostasis/genetics ; Telomeric Repeat Binding Protein 2/genetics ; Toll-Like Receptor 4/*genetics ; Transcription Factors/genetics ; DNA Methyltransferase 3B ; },
abstract = {Toll-like receptor 4 (TLR4) which acts as a receptor for lipopolysaccharide (LPS) has been reported to be involved in carcinogenesis. However, the regulatory mechanism of it has not been elucidated. Herein, we demonstrate that TLR4 promotes the malignant growth of liver cancer stem cells. Mechanistically, TLR4 promotes the expression of histone-lysine N-methyltransferase (SUV39 h2) and increases the formation of trimethyl histone H3 lysine 9-heterochromatin protein 1-telomere repeat binding factor 2 (H3K9me3-HP1-TRF2) complex at the telomeric locus under mediation by long non coding RNA urothelial cancer-associated 1 (CUDR). At the telomeric locus, this complex promotes binding of POT1, pPOT1, Exo1, pExo1, SNM1B and pSNM1B but prevents binding of CST/AAF to telomere, thus controlling telomere and maintaining telomere length. Furthermore, TLR4 enhances interaction between HP1α and DNA methyltransferase (DNMT3b), which limits RNA polymerase II deposition on the telomeric repeat-containing RNA (TERRA) promoter region and its elongation, thus inhibiting transcription of TERRA. Ultimately, TLR4 enhances the telomerase activity by reducing the interplay between telomerase reverse transcriptase catalytic subunit (TERT) and TERRA. More importantly, our results reveal that tri-complexes of HP1 isoforms (α, β and γ) are required for the oncogenic action of TLR4. This study elucidates a novel protection mechanism of TLR4 in liver cancer stem cells and suggests that TLR4 can be used as a novel therapeutic target for liver cancer.},
}
@article {pmid29599436,
year = {2018},
author = {Gao, Y and Tan, J and Jin, J and Ma, H and Chen, X and Leger, B and Xu, J and Spagnol, ST and Dahl, KN and Levine, AS and Liu, Y and Lan, L},
title = {SIRT6 facilitates directional telomere movement upon oxidative damage.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {5407},
pmid = {29599436},
issn = {2045-2322},
support = {P30 CA047904/CA/NCI NIH HHS/United States ; R01 GM118833/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases/metabolism ; Cell Line ; Chromatin/chemistry/metabolism ; Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/metabolism ; DNA Damage ; DNA Repair ; Gene Editing ; Humans ; Microscopy, Fluorescence ; *Oxidative Stress ; Sirtuins/deficiency/genetics/*metabolism ; Telomere/*metabolism ; RNA, Guide, CRISPR-Cas Systems ; },
abstract = {Oxidative damage to telomeres leads to telomere attrition and genomic instability, resulting in poor cell viability. Telomere dynamics contribute to the maintenance of telomere integrity; however, whether oxidative damage induces telomere movement and how telomere mobility is regulated remain poorly understood. Here, we show that oxidative damage at telomeres triggers directional telomere movement. The presence of the human Sir2 homolog, Sirtuin 6 (SIRT6) is required for oxidative damage-induced telomeric movement. SIRT6 knock out (KO) cells show neither damage-induced telomere movement nor chromatin decondensation at damaged telomeres; both are observed in wild type (WT) cells. A deacetylation mutant of SIRT6 increases damage-induced telomeric movement in SIRT6 KO cells as well as WT SIRT6. SIRT6 recruits the chromatin-remodeling protein SNF2H to damaged telomeres, which appears to promote chromatin decondensation independent of its deacetylase activity. Together, our results suggest that SIRT6 plays a role in the regulation of telomere movement upon oxidative damage, shedding new light onto the function of SIRT6 in telomere maintenance.},
}
@article {pmid29593073,
year = {2018},
author = {Rodrigues, J and Banks, P and Lydall, D},
title = {Vps74 Connects the Golgi Apparatus and Telomeres in Saccharomyces cerevisiae.},
journal = {G3 (Bethesda, Md.)},
volume = {8},
number = {5},
pages = {1807-1816},
pmid = {29593073},
issn = {2160-1836},
support = {MR/L001284/1/MRC_/Medical Research Council/United Kingdom ; BB/M002314/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Carrier Proteins/*metabolism ; DNA Damage ; DNA Repair ; Gene Deletion ; Golgi Apparatus/*metabolism ; Models, Biological ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomere/*metabolism ; Telomere Shortening ; Temperature ; },
abstract = {In mammalian cell culture, the Golgi apparatus fragment upon DNA damage. GOLPH3, a Golgi component, is a phosphorylation target of DNA-PK after DNA damage and contributes to Golgi fragmentation. The function of the yeast (Saccharomyces cerevisiae) ortholog of GOLPH3, Vps74, in the DNA damage response has been little studied, although genome-wide screens suggested a role at telomeres. In this study we investigated the role of Vps74 at telomeres and in the DNA damage response. We show that Vps74 decreases the fitness of telomere defective cdc13-1 cells and contributes to the fitness of yku70Δ cells. Importantly, loss of Vps74 in yku70Δ cells exacerbates the temperature dependent growth defects of these cells in a Chk1 and Mec1-dependent manner. Furthermore, Exo1 reduces the fitness of vps74Δ yku70Δ cells suggesting that ssDNA contributes to the fitness defects of vps74Δ yku70Δ cells. Systematic genetic interaction analysis of vps74Δ, yku70Δ and yku70Δ vps74Δ cells suggests that vps74Δ causes a milder but similar defect to that seen in yku70Δ cells. vps74Δ cells have slightly shorter telomeres and loss of VPS74 in yku70Δ or mre11Δ cells further shortens the telomeres of these cells. Interestingly, loss of Vps74 leads to increased levels of Stn1, a partner of Cdc13 in the CST telomere capping complex. Overexpression of Stn1 was previously shown to cause telomere shortening, suppression of cdc13-1 and enhancement of yku70Δ growth defects, suggesting that increased levels of Stn1 may be the route by which Vps74 affects telomere function. These results establish Vps74 as a novel regulator of telomere biology.},
}
@article {pmid29590618,
year = {2018},
author = {Kang, Y and Zhang, H and Zhao, Y and Wang, Y and Wang, W and He, Y and Zhang, W and Zhang, W and Zhu, X and Zhou, Y and Zhang, L and Ju, Z and Shi, L},
title = {Telomere Dysfunction Disturbs Macrophage Mitochondrial Metabolism and the NLRP3 Inflammasome through the PGC-1α/TNFAIP3 Axis.},
journal = {Cell reports},
volume = {22},
number = {13},
pages = {3493-3506},
doi = {10.1016/j.celrep.2018.02.071},
pmid = {29590618},
issn = {2211-1247},
mesh = {Adult ; Animals ; Female ; Humans ; Inflammasomes/*metabolism ; Macrophages/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Middle Aged ; Mitochondria/*metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/*metabolism ; Signal Transduction ; Telomere/*metabolism ; Tumor Necrosis Factor alpha-Induced Protein 3/*metabolism ; },
abstract = {Immune and inflammation dysregulation have been associated with the aging process and contribute to age-related disorders, but the underlying mechanism remains elusive. Here, we employed late-generation Terc knockout (Terc[-/-]) mice to investigate the impact of telomere dysfunction on the host defense and function of innate immune cells. Terc[-/-] mice displayed exaggerated lung inflammation and increased mortality upon respiratory staphylococcal infection, although their pathogen-clearing capacity was uncompromised. Mechanistically, we found that telomere dysfunction caused macrophage mitochondrial abnormality, oxidative stress, and hyperactivation of the NLRP3 inflammasome. The ubiquitin-editing enzyme TNFAIP3, together with PGC-1α, was critically involved in the regulation of mitochondrial and inflammatory gene expression and essential for the homeostatic role of telomeres. Together, the study reveals a regulatory paradigm that connects telomeres to mitochondrial metabolism, innate immunity, and inflammation, shedding light on age-related pathologies.},
}
@article {pmid29589913,
year = {2018},
author = {Purohit, G and Mukherjee, AK and Sharma, S and Chowdhury, S},
title = {Extratelomeric Binding of the Telomere Binding Protein TRF2 at the PCGF3 Promoter Is G-Quadruplex Motif-Dependent.},
journal = {Biochemistry},
volume = {57},
number = {16},
pages = {2317-2324},
doi = {10.1021/acs.biochem.8b00019},
pmid = {29589913},
issn = {1520-4995},
mesh = {Binding Sites ; Chromosomes/chemistry/*genetics ; G-Quadruplexes ; Humans ; Polycomb-Group Proteins/chemistry/*genetics ; Promoter Regions, Genetic ; Protein Binding ; Telomere/chemistry/genetics ; Telomere-Binding Proteins/chemistry/*genetics ; Telomeric Repeat Binding Protein 2/chemistry/*genetics ; },
abstract = {Telomere repeat binding factor 2 (TRF2) is critical for the protection of chromosome ends. Mounting evidence suggests that TRF2 associates with extratelomeric sites and TRF2 functions may not be limited to telomeres. Here, we show that the PCGF3 promoter harbors a sequence capable of forming the DNA secondary structure G-quadruplex motif, which is required for binding of TRF2 at the PCGF3 promoter. We demonstrate that promoter binding by TRF2 mediates PCGF3 promoter activity, and both the N-terminal and C-terminal domains of TRF2 are necessary for promoter activity. Altogether, this shows for the first time that a telomere binding factor may regulate a component of the polycomb group of proteins.},
}
@article {pmid29589779,
year = {2018},
author = {Magi, F and Dimauro, I and Margheritini, F and Duranti, G and Mercatelli, N and Fantini, C and Ripani, FR and Sabatini, S and Caporossi, D},
title = {Telomere length is independently associated with age, oxidative biomarkers, and sport training in skeletal muscle of healthy adult males.},
journal = {Free radical research},
volume = {52},
number = {6},
pages = {639-647},
doi = {10.1080/10715762.2018.1459043},
pmid = {29589779},
issn = {1029-2470},
mesh = {Adult ; Age Factors ; Aldehydes/*metabolism ; Biomarkers/metabolism ; Biopsy ; Catalase/genetics/*metabolism ; *Exercise ; Gene Expression ; HSP27 Heat-Shock Proteins/genetics/metabolism ; HSP90 Heat-Shock Proteins/genetics/metabolism ; Heat-Shock Proteins ; Humans ; Male ; Middle Aged ; Molecular Chaperones ; Muscle, Skeletal/*metabolism ; Oxidative Stress ; Protein Carbonylation ; Telomere/*ultrastructure ; alpha-Crystallin B Chain/genetics/metabolism ; },
abstract = {In skeletal muscle, which mainly contains postmitotic myonuclei, it has been suggested that telomere length remains roughly constant throughout adult life, or shortens in response to physiopathological conditions in muscle diseases or in the elderly. However, telomere length results from both the replicative history of a specific tissue and the exposure to environmental, DNA damage-related factors, therefore the predictive biological significance of telomere measures should combine the analysis of the various interactive factors. In the present study, we analysed any relationship between telomere length [mean and minimum terminal restriction fragment (TRF) length] chronological age, oxidative damage (4-HNE, protein carbonyls), catalase activity, and heat shock proteins expression (αB-crystallin, Hsp27, Hsp90) in semitendinous muscle biopsies of 26 healthy adult males between 20 and 50 years of age, also exploring the influence of regular exercise participation. The multiple linear regression analysis identified age, 4-HNE, catalase, and training status as significant independent variables associated with telomere length and jointly accounting for ∼30-36% of interindividual variation in mean and/or minimum TRF length. No association has been identified between telomere length and protein carbonyl, αB-crystallin, Hsp27, and Hsp90, as well as between age and the variables related to stress response. Our results showed that skeletal muscle from healthy adults displays an age-dependent telomere attrition and that oxidised environment plays an age-independent contribution, partially influenced by exercise training.},
}
@article {pmid29589105,
year = {2018},
author = {Mason, JMO and McEachern, MJ},
title = {Chromosome ends as adaptive beginnings: the potential role of dysfunctional telomeres in subtelomeric evolvability.},
journal = {Current genetics},
volume = {64},
number = {5},
pages = {997-1000},
pmid = {29589105},
issn = {1432-0983},
mesh = {*Chromosomes, Fungal ; DNA Breaks, Double-Stranded ; DNA Replication ; *Evolution, Molecular ; Genomic Instability ; Mutation ; Saccharomyces cerevisiae/*genetics ; Telomere/*physiology ; },
abstract = {Telomeres serve as protective caps that help the cell differentiate between the naturally occurring ends of chromosomes and double-stranded breaks. When telomere capping function becomes compromised, chromosome ends are subjected to elevated rates of chromosome alterations. These effects can be particularly dramatic in the telomere-adjacent subtelomeric region. While the catastrophic impact of severe telomere dysfunction on genome stability has been well documented, the adaptive telomere failure hypothesis considers an alternative role telomere dysfunction may play in adaptive evolution. This hypothesis suggests that low levels of telomere failure, induced by certain environmental stresses, can lead to elevated subtelomeric recombination. Mutational loss, duplication, or modification of subtelomeric contingency genes could ultimately facilitate adaptation by generating novel mutants better able to survive environmental stress. In this perspective, we discuss recent work that examined mild telomere dysfunction and its role in altering the adaptive potential of subtelomeric genes.},
}
@article {pmid29579787,
year = {2018},
author = {Mohamadkhani, A and Pourasgari, M and Poustchi, H},
title = {Significant SNPs Related to Telomere Length and Hepatocellular Carcinoma Risk in Chronic Hepatitis B Carriers.},
journal = {Asian Pacific journal of cancer prevention : APJCP},
volume = {19},
number = {3},
pages = {585-590},
pmid = {29579787},
issn = {2476-762X},
mesh = {Carcinoma, Hepatocellular/*etiology/pathology ; Hepatitis B virus/*isolation &amp; purification ; Hepatitis B, Chronic/*complications/virology ; Heterozygote ; Humans ; Liver Neoplasms/*etiology/pathology ; *Polymorphism, Single Nucleotide ; Prognosis ; Risk Factors ; *Telomere Homeostasis ; },
abstract = {Chronic hepatitis B virus (HBV) infection increases the risk of developing cirrhosis and hepatocellular carcinoma (HCC) with suspected interactions between virus replication and host immune responses. A number of reports have suggested that telomerase function may be involved in chronic hepatitis B (CHB) pathogenesis, but positive or negative associations with HCC risk remain for discussion. Mean telomere length is an indicator of biological aging and it has been reported that reduction in NBV carriers compared to normal individuals. In somatic cells, telomeres contain simple, tandemly repeated G-rich sequences that frequently are reduced by 50 to 200 base pairs at each cell division. Several genome-wide association studies (GWAS) in diverse ethnic populations have revealed eleven single nucleotide polymorphisms (SNPs) linked to telomere length. Two of these, rs398652 and rs621559, have prognostic value and could be used as genetic markers. This review describes current knowledge concerning telomerase activity and telomere length as well as significant polymorphisms in HBV-related HCC patients. In particular, to cast light on genotype-phenotype interactions, we used SNPnexus to evaluate effects of the two SNPs on risk of disease and complex disorders.},
}
@article {pmid29579225,
year = {2019},
author = {Sun, H and Kim, P and Jia, P and Park, AK and Liang, H and Zhao, Z},
title = {Distinct telomere length and molecular signatures in seminoma and non-seminoma of testicular germ cell tumor.},
journal = {Briefings in bioinformatics},
volume = {20},
number = {4},
pages = {1502-1512},
pmid = {29579225},
issn = {1477-4054},
support = {U01 CA217842/CA/NCI NIH HHS/United States ; R01 LM012806/LM/NLM NIH HHS/United States ; R01 CA175486/CA/NCI NIH HHS/United States ; R21 CA196508/CA/NCI NIH HHS/United States ; U24 CA209851/CA/NCI NIH HHS/United States ; R01 LM011177/LM/NLM NIH HHS/United States ; },
mesh = {Computational Biology ; Gene Regulatory Networks ; Humans ; Kruppel-Like Factor 4 ; Male ; MicroRNAs/genetics ; Models, Genetic ; Neoplasms, Germ Cell and Embryonal/*genetics ; RNA, Messenger/genetics ; Seminoma/*genetics ; Telomere Homeostasis/*genetics ; Telomere Shortening/genetics ; Testicular Neoplasms/*genetics ; Transcriptome ; },
abstract = {Testicular germ cell tumors (TGCTs) are classified into two main subtypes, seminoma (SE) and non-seminoma (NSE), but their molecular distinctions remain largely unexplored. Here, we used expression data for mRNAs and microRNAs (miRNAs) from The Cancer Genome Atlas (TCGA) to perform a systematic investigation to explain the different telomere length (TL) features between NSE (n = 48) and SE (n = 55). We found that TL elongation was dominant in NSE, whereas TL shortening prevailed in SE. We further showed that both mRNA and miRNA expression profiles could clearly distinguish these two subtypes. Notably, four telomere-related genes (TelGenes) showed significantly higher expression and positively correlated with telomere elongation in NSE than SE: three telomerase activity-related genes (TERT, WRAP53 and MYC) and an independent telomerase activity gene (ZSCAN4). We also found that the expression of genes encoding Yamanaka factors was positively correlated with telomere lengthening in NSE. Among them, SOX2 and MYC were highly expressed in NSE versus SE, while POU5F1 and KLF4 had the opposite patterns. These results suggested that enhanced expression of both TelGenes (TERT, WRAP53, MYC and ZSCAN4) and Yamanaka factors might induce telomere elongation in NSE. Conversely, the relative lack of telomerase activation and low expression of independent telomerase activity pathway during cell division may be contributed to telomere shortening in SE. Taken together, our results revealed the potential molecular profiles and regulatory roles involving the TL difference between NSE and SE, and provided a better molecular understanding of this complex disease.},
}
@article {pmid29578263,
year = {2018},
author = {Matsuda, Y and Suzuki, A and Esaka, S and Hamashima, Y and Imaizumi, M and Kinoshita, M and Shirahata, H and Kiso, Y and Kojima, H and Matsukawa, M and Fujii, Y and Ishikawa, N and Aida, J and Takubo, K and Ishiwata, T and Nishimura, M and Arai, T},
title = {Telomere length determined by the fluorescence in situ hybridisation distinguishes malignant and benign cells in cytological specimens.},
journal = {Cytopathology : official journal of the British Society for Clinical Cytology},
volume = {29},
number = {3},
pages = {262-266},
doi = {10.1111/cyt.12535},
pmid = {29578263},
issn = {1365-2303},
mesh = {Ascites/genetics/pathology ; Chromosomal Instability/genetics ; Fluorescence ; Humans ; In Situ Hybridization, Fluorescence/methods ; Pancreas/pathology ; Pleural Effusion/genetics/pathology ; Telomere/*genetics ; },
abstract = {BACKGROUND: Telomeres are tandem repeats of TTAGGG at the end of eukaryotic chromosomes that play a key role in preventing chromosomal instability. The aim of the present study is to determine telomere length using fluorescence in situ hybridisation (FISH) on cytological specimens.<br><br>METHODS: Aspiration samples (n&#xa0;=&#xa0;41) were smeared on glass slides and used for FISH.<br><br>RESULTS: Telomere signal intensity was significantly lower in positive cases (cases with malignancy, n&#xa0;=&#xa0;25) as compared to negative cases (cases without malignancy, n&#xa0;=&#xa0;16), and the same was observed for centromere intensity. The difference in DAPI intensity was not statistically significant. The ratio of telomere to centromere intensity did not show a significant difference between positive and negative cases. There was no statistical difference in the signal intensities of aspiration samples from ascites or pleural effusion (n&#xa0;=&#xa0;23) and endoscopic ultrasound-guided FNA samples from the pancreas (n&#xa0;=&#xa0;18).<br><br>CONCLUSIONS: The present study revealed that telomere length can be used as an indicator to distinguish malignant and benign cells in cytological specimens. This novel approach may help improve diagnosis for cancer patients.},
}
@article {pmid29577468,
year = {2018},
author = {Cheng, SB and Davis, S and Sharma, S},
title = {Maternal-fetal cross talk through cell-free fetal DNA, telomere shortening, microchimerism, and inflammation.},
journal = {American journal of reproductive immunology (New York, N.Y. : 1989)},
volume = {79},
number = {5},
pages = {e12851},
pmid = {29577468},
issn = {1600-0897},
support = {K12 HD050108/HD/NICHD NIH HHS/United States ; P20 GM121298/GM/NIGMS NIH HHS/United States ; P30 GM114750/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chimerism ; DNA/*immunology ; Female ; Fetus/immunology ; Humans ; Inflammation/*immunology ; Maternal-Fetal Exchange/*immunology ; Pregnancy ; Pregnancy Complications/*immunology ; Pregnancy Outcome ; Telomere Shortening/*immunology ; },
abstract = {There exists a strong correlation between unscheduled inflammation at the maternal-fetal interface and the continuum of pregnancy complications. In normal pregnancy, immunological tolerance is established to protect the semi-allogeneic fetus. There has been extensive research on how the immunity, endovascular trophoblast migration, and hormonal nexus are orchestrated during pregnancy at the maternal-fetal interface to program a normal pregnancy outcome. It is not clear what contributes to the plasticity of uterine immune tolerance, fetal survial, and long-term post-partum health of the mother and the offspring. Old and new concepts have reemerged and emerged that include cell-free fetal DNA (cffDNA), telomere shortening, microchimerism involving bidirectional migration of maternal and fetal cells, and pregnancy as a stress factor. The question is how these pathways converge in a gestational age-dependent manner to contribute to the health of the mother and the offspring later in life and respond to an array of inflammatory challenges. In this Review, we provide pertinent discussion on maternal-fetal cross talk through cffDNA, telomere shortening, and microchimerism in the context of inflammatory and anti-inflammatory settings, particularly how these pathways lead to normal and adverse pregnancy outcomes.},
}
@article {pmid29573637,
year = {2018},
author = {Dahlgren, PN and Bishop, K and Dey, S and Herbert, BS and Tanaka, H},
title = {Development of a New Monochrome Multiplex qPCR Method for Relative Telomere Length Measurement in Cancer.},
journal = {Neoplasia (New York, N.Y.)},
volume = {20},
number = {5},
pages = {425-431},
pmid = {29573637},
issn = {1476-5586},
support = {R21 CA205434/CA/NCI NIH HHS/United States ; TL1 TR001107/TR/NCATS NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Blotting, Southern/methods ; Cell Line, Tumor ; DNA/genetics ; Female ; HCT116 Cells ; HT29 Cells ; HeLa Cells ; Humans ; MCF-7 Cells ; Male ; Middle Aged ; Multiplex Polymerase Chain Reaction/*methods ; Neoplasms/*genetics ; Reproducibility of Results ; Telomere/*genetics ; Telomere Shortening/genetics ; Young Adult ; },
abstract = {Excess telomere shortening has been observed in most cancer cells. The telomere quantitative polymerase chain reaction (qPCR) assay has become an important tool for epidemiological studies examining the effects of aging, stress, and other factors on the length of telomeres. Current telomere qPCR methods analyze the relative length of telomeres by amplifying telomere sequence products and normalizing with single-copy gene products. However, the current telomere qPCR does not always reflect absolute telomere length in cancer DNA. Because of genomic instability in cancer cells, we hypothesized that the use of single-copy genes (scg) is less accurate for normalizing data in cancer DNA and that new primer sets are required to better represent relative telomere length in cancer DNA. We first confirmed that cancer cells had a different copy ratio among different scg, implying that DNA is aneuploid. By using the new primer sets that amplify multiple-copy sequences (mcs) throughout the genome, the telomere qPCR results showed that the mcs primers were interchangeable with the scg primers as reference primers in normal DNA. By comparing results from the traditional southern blotting method (as kilobases) and results from monochrome multiplex qPCR using the mcs primers (as T/M ratios), we verified that the T/M ratio is highly correlated with absolute telomere length from the southern blot analysis. Together, the mcs primers were able to represent the telomere lengths accurately in cancer DNA samples. These results would allow for analyses of telomeres within cancerous DNA and the development of new, less invasive diagnostic tools for cancer.},
}
@article {pmid29571261,
year = {2018},
author = {Trajano, LADSN and Trajano, ETL and Silva, MADS and Stumbo, AC and Mencalha, AL and Fonseca, ASD},
title = {Genomic stability and telomere regulation in skeletal muscle tissue.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {98},
number = {},
pages = {907-915},
doi = {10.1016/j.biopha.2018.01.004},
pmid = {29571261},
issn = {1950-6007},
mesh = {DNA Damage ; DNA Repair ; *Genomic Instability ; Humans ; Muscle, Skeletal/injuries/*metabolism/pathology ; Reactive Oxygen Species/metabolism ; Telomere/*metabolism ; },
abstract = {Muscle injuries are common, especially in sports and cumulative trauma disorder, and their repair is influenced by free radical formation, which causes damages in lipids, proteins and DNA. Oxidative DNA damages are repaired by base excision repair and nucleotide excision repair, ensuring telomeric and genomic stability. There are few studies on this topic in skeletal muscle cells. This review focuses on base excision repair and nucleotide excision repair, telomere regulation and how telomeric stabilization influences healthy muscle, injured muscle, exercise, and its relationship with aging. In skeletal muscle, genomic stabilization and telomere regulation seem to play an important role in tissue health, influencing muscle injury repair. Thus, therapies targeting mechanisms of DNA repair and telomeric regulation could be new approaches for improving repair and prevention of skeletal muscle injuries in young and old people.},
}
@article {pmid29571043,
year = {2018},
author = {Kordyukova, M and Olovnikov, I and Kalmykova, A},
title = {Transposon control mechanisms in telomere biology.},
journal = {Current opinion in genetics &amp; development},
volume = {49},
number = {},
pages = {56-62},
doi = {10.1016/j.gde.2018.03.002},
pmid = {29571043},
issn = {1879-0380},
mesh = {Animals ; DNA Transposable Elements/*genetics ; Drosophila melanogaster/genetics ; *Evolution, Molecular ; Humans ; Long Interspersed Nucleotide Elements/genetics ; RNA, Small Interfering/genetics ; RNA-Directed DNA Polymerase/genetics ; Retroelements/*genetics ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {The ends of linear eukaryotic chromosomes, telomeres, are elongated by reverse transcriptase activity provided by the enzyme telomerase, or by specialized telomeric retrotransposons. Telomerase and telomeric retrotransposons represent unique examples of structurally different, but evolutionary and functionally related machineries that generate essential chromosome structures, namely telomeres. In fact, the telomere is an example of the taming of retroelements for the maintenance of essential genome function. Many features of telomere homeostasis are conserved between telomerase and retrotransposon maintained telomeres. The retrotransposon origin of telomeres suggests that mechanisms of transposon control could be adopted for telomere regulation. The discovery of the role of Drosophila telomeric piRNAs in telomere length control and the influence of LINE-1 retroelements on telomere regulation in human cells strongly support this idea and allow us to look at telomere regulation from a new angle.},
}
@article {pmid29570620,
year = {2018},
author = {Tucker, LA},
title = {Dietary Fiber and Telomere Length in 5674 U.S. Adults: An NHANES Study of Biological Aging.},
journal = {Nutrients},
volume = {10},
number = {4},
pages = {},
pmid = {29570620},
issn = {2072-6643},
mesh = {Aging/*genetics ; Cross-Sectional Studies ; Diet, Healthy ; Dietary Fiber/*administration &amp; dosage ; Female ; Humans ; Life Style ; Male ; Middle Aged ; Nutrition Surveys ; Recommended Dietary Allowances ; Risk Reduction Behavior ; Telomere/*genetics ; *Telomere Homeostasis ; *Telomere Shortening ; United States ; },
abstract = {The relationship between fiber intake and telomere length was evaluated using a cross-sectional design and an NHANES sample of 5674 U.S. adults. Another purpose was to test the impact of potential confounders on the association. Fiber consumption was measured using a 24 h recall and telomere length was indexed using the quantitative polymerase chain reaction method. Overall, the U.S. adults had low fiber intake (median: 6.6 g per 1000 kcal)-less than one-half the recommendation of the Dietary Guidelines for Americans. With age, gender, race, housing status, and misreported energy intake controlled, the relationship between fiber intake per 1000 kcal and telomere length was linear (F = 9.5, p = 0.0045). Specifically, for each 1 g increment in fiber intake per 1000 kcal, telomeres were 8.3 base pairs longer. Because each additional year of chronological age was associated with telomeres that were 15.5 base pairs shorter, results suggest that a 10 g increase in fiber intake per 1000 kcal would correspond with telomeres that are 83 base pairs longer. On average, this would equate to 5.4 fewer years of biologic aging (83 ÷ 15.5). With smoking, BMI, alcohol use, and physical activity controlled, as well as the other covariates, each 10 g increment in fiber accounted for telomeres that were 67 base pairs longer (F = 7.6, p = 0.0101), a biologic aging difference of about 4.3 years. In conclusion, significant fiber consumption accounts for longer telomeres and less biologic aging than lower levels of fiber intake.},
}
@article {pmid29568379,
year = {2018},
author = {Zöchmeister, C and Brezina, S and Hofer, P and Baierl, A and Bergmann, MM and Bachleitner-Hofmann, T and Karner-Hanusch, J and Stift, A and Gerger, A and Leeb, G and Mach, K and Rachakonda, S and Kumar, R and Gsur, A},
title = {Leukocyte telomere length throughout the continuum of colorectal carcinogenesis.},
journal = {Oncotarget},
volume = {9},
number = {17},
pages = {13582-13592},
pmid = {29568379},
issn = {1949-2553},
abstract = {Considering the high prevalence of colorectal cancer (CRC) and relatively high mortality there is strong interest in identification of clinically relevant biomarkers. Telomere shortening is supposed to contribute to genomic instability and crucially involved in process of carcinogenesis. Peripheral blood leukocyte (PBL) telomere length was previously investigated in several studies as potential biomarker for CRC but with controversial results. This prompted us to investigate relative PBL telomere length in association with different histological findings throughout the continuum of colorectal carcinogenesis in order to reflect the whole spectrum of putative CRC development in a large study involving 2011 individuals. The study based on the Colorectal Cancer Study of Austria (CORSA), including 384 CRC cases as well as age- and gender-matched 544 high-risk adenomas, 537 low-risk adenoma patients and 546 colonoscopy-negative controls. Relative expression of telomeric repeats and the single copy reference gene, albumin (T/S ratio) was determined using monochrome multiplex quantitative PCR (MMQPCR). Telomeres were found to be significantly longer in CRC patients compared to control subjects (P = 3.61x10[-6]). Yet, no significant differences in telomere length could be detected for high-risk (P = 0.05956) and low-risk colorectal adenoma patients (P = 0.05224). In addition, results presented in this manuscript highlight the impact of various epidemiological factors on PBL telomere length and its involvement in CRC. However, further large studies also including colorectal adenomas are necessary to confirm these results.},
}
@article {pmid29567420,
year = {2018},
author = {Zhang, C and Kibriya, MG and Jasmine, F and Roy, S and Gao, J and Sabarinathan, M and Shinkle, J and Delgado, D and Ahmed, A and Islam, T and Eunus, M and Islam, MT and Hasan, R and Graziano, JH and Ahsan, H and Pierce, BL},
title = {A study of telomere length, arsenic exposure, and arsenic toxicity in a Bangladeshi cohort.},
journal = {Environmental research},
volume = {164},
number = {},
pages = {346-355},
pmid = {29567420},
issn = {1096-0953},
support = {R24 ES028532/ES/NIEHS NIH HHS/United States ; P30 AG012857/AG/NIA NIH HHS/United States ; P42 ES010349/ES/NIEHS NIH HHS/United States ; R01 CA107431/CA/NCI NIH HHS/United States ; U01 HG007601/HG/NHGRI NIH HHS/United States ; R35 ES028379/ES/NIEHS NIH HHS/United States ; T32 AG000243/AG/NIA NIH HHS/United States ; R25 GM109439/GM/NIGMS NIH HHS/United States ; R01 ES020506/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; *Arsenic/toxicity ; Bangladesh ; Case-Control Studies ; Cross-Sectional Studies ; *Environmental Exposure ; Female ; Humans ; Longitudinal Studies ; Male ; *Telomere/drug effects ; },
abstract = {BACKGROUND: Chronic arsenic exposure is associated with increased risk for arsenical skin lesions, cancer, and other adverse health outcomes. One potential mechanism of arsenic toxicity is telomere dysfunction. However, prior epidemiological studies of arsenic exposure, telomere length (TL), and skin lesion are small and cross-sectional. We investigated the associations between arsenic exposure and TL and between baseline TL and incident skin lesion risk among individuals participating in the Health Effects of Arsenic Longitudinal Study in Bangladesh (2000-2009).<br><br>METHODS: Quantitative PCR was used to measure the average TL of peripheral blood DNA collected at baseline. The association between baseline arsenic exposure (well water and urine) and TL was estimated in a randomly-selected subcohort (n&#x202f;=&#x202f;1469). A nested case-control study (466 cases and 464 age- and sex-matched controls) was used to estimate the association between baseline TL and incident skin lesion risk (diagnosed <&#x202f;8 years after baseline).<br><br>RESULTS: No association was observed between arsenic exposure (water or urine) and TL. Among incident skin lesion cases and matched controls, we observed higher skin lesion risk among individuals with shorter TL (Ptrend =&#x202f;1.5 &#xd7; 10[-5]) with odds ratios of 2.60, 1.59, and 1.10 for the first (shortest), second, and third TL quartiles compared to the fourth (longest).<br><br>CONCLUSIONS: Arsenic exposure was not associated with TL among Bangladeshi adults, suggesting that leukocyte TL may not reflect a primary mode of action for arsenic's toxicity. However, short TL was associated with increased skin lesion risk, and may be a biomarker of arsenic susceptibility modifying arsenic's effect on skin lesion risk.},
}
@article {pmid29564829,
year = {2018},
author = {Samassekou, O and Bastien, N and Yan, J and Mai, S and Drouin, R},
title = {Expression of Genes Associated with Telomere Homeostasis in TP53 Mutant LoVo Cell Lines as a Model for Genomic Instability.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1769},
number = {},
pages = {253-262},
doi = {10.1007/978-1-4939-7780-2_16},
pmid = {29564829},
issn = {1940-6029},
mesh = {Cell Line ; *Gene Expression Regulation ; *Genomic Instability ; Humans ; *Mutation ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics ; Tumor Suppressor Protein p53/*genetics/metabolism ; },
abstract = {We describe a method that assesses the impact of specific mutations of TP53 and genomic instability on gene expression of the most important genes involved in telomere length and structure homeostasis. The approaches consist of using a reverse transcriptase method and a quantitative PCR that were applied to isogenic cell lines from a colon cancer.},
}
@article {pmid29564827,
year = {2018},
author = {Samassekou, O and Bastien, N and Yan, J and Mai, S and Drouin, R},
title = {Study of Telomere Dysfunction in TP53 Mutant LoVo Cell Lines as a Model for Genomic Instability.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1769},
number = {},
pages = {209-230},
doi = {10.1007/978-1-4939-7780-2_14},
pmid = {29564827},
issn = {1940-6029},
mesh = {Cell Cycle ; Cell Line ; *Genomic Instability ; In Situ Hybridization, Fluorescence ; *Models, Genetic ; *Mutation ; Telomere/*genetics/metabolism ; Telomere Homeostasis ; Tumor Suppressor Protein p53/*genetics ; },
abstract = {Telomere restriction fragment, 3D quantitative FISH on nuclei, and quantitative FISH on metaphases are complementary approaches that explore telomere dysfunction genomically, cellularly, and chromosomally, respectively. We used these approaches to study association between telomere dysfunction and degree of genomic instability related to TP53 mutations in LoVo isogenic cell lines. We found a strong correlation between degree of genomic instability, telomere dysfunction, and specific mutations of TP53. The use of complementary approaches to study telomere biology is essential to have a comprehensive understanding of telomere involvement in genomic instability.},
}
@article {pmid29563283,
year = {2018},
author = {Ibáñez-Álamo, JD and Pineda-Pampliega, J and Thomson, RL and Aguirre, JI and Díez-Fernández, A and Faivre, B and Figuerola, J and Verhulst, S},
title = {Urban blackbirds have shorter telomeres.},
journal = {Biology letters},
volume = {14},
number = {3},
pages = {},
pmid = {29563283},
issn = {1744-957X},
mesh = {Animals ; Cities ; *Ecosystem ; Female ; Forests ; France ; Male ; Songbirds/genetics/*physiology ; Spain ; Telomere/physiology ; Telomere Shortening/*physiology ; },
abstract = {Urbanization, one of the most extreme human-induced environmental changes, represents a major challenge for many organisms. Anthropogenic habitats can have opposing effects on different fitness components, for example, by decreasing starvation risk but also health status. Assessment of the net fitness effect of anthropogenic habitats is therefore difficult. Telomere length is associated with phenotypic quality and mortality rate in many species, and the rate of telomere shortening is considered an integrative measure of the 'life stress' experienced by an individual. This makes telomere length a promising candidate for examining the effects of urbanization on the health status of individuals. We investigated whether telomere length differed between urban and forest-dwelling common blackbirds (Turdus merula). Using the terminal restriction fragment assay, we analysed telomere length in yearlings and older adults from five population dyads (urban versus forest) across Europe. In both age classes, urban blackbirds had significantly shorter telomeres (547 bp) than blackbirds in natural habitats, indicating lower health status in urban blackbirds. We propose several potential hypotheses to explain our results. Our findings show that even successful city dwellers such as blackbirds pay a price for living in these anthropogenic habitats.},
}
@article {pmid29563139,
year = {2018},
author = {Zhang, G and Wu, LW and Mender, I and Barzily-Rokni, M and Hammond, MR and Ope, O and Cheng, C and Vasilopoulos, T and Randell, S and Sadek, N and Beroard, A and Xiao, M and Tian, T and Tan, J and Saeed, U and Sugarman, E and Krepler, C and Brafford, P and Sproesser, K and Murugan, S and Somasundaram, R and Garman, B and Wubbenhorst, B and Woo, J and Yin, X and Liu, Q and Frederick, DT and Miao, B and Xu, W and Karakousis, GC and Xu, X and Schuchter, LM and Mitchell, TC and Kwong, LN and Amaravadi, RK and Lu, Y and Boland, GM and Wei, Z and Nathanson, K and Herbig, U and Mills, GB and Flaherty, KT and Herlyn, M and Shay, JW},
title = {Induction of Telomere Dysfunction Prolongs Disease Control of Therapy-Resistant Melanoma.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {24},
number = {19},
pages = {4771-4784},
pmid = {29563139},
issn = {1557-3265},
support = {R01 CA136533/CA/NCI NIH HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; R01 CA198015/CA/NCI NIH HHS/United States ; P50 CA174523/CA/NCI NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Line, Tumor ; Deoxyguanosine/*analogs &amp; derivatives/pharmacology ; Drug Resistance, Neoplasm/drug effects ; Humans ; Melanoma/*drug therapy/genetics/pathology ; Mice ; Mutation ; Promoter Regions, Genetic/*genetics ; Telomerase/*genetics ; Telomere/drug effects/genetics ; Thionucleosides/*pharmacology ; },
abstract = {Purpose: Telomerase promoter mutations are highly prevalent in human tumors including melanoma. A subset of patients with metastatic melanoma often fail multiple therapies, and there is an unmet and urgent need to prolong disease control for those patients.Experimental Design: Numerous preclinical therapy-resistant models of human and mouse melanoma were used to test the efficacy of a telomerase-directed nucleoside, 6-thio-2'-deoxyguanosine (6-thio-dG). Integrated transcriptomics and proteomics approaches were used to identify genes and proteins that were significantly downregulated by 6-thio-dG.Results: We demonstrated the superior efficacy of 6-thio-dG both in vitro and in vivo that results in telomere dysfunction, leading to apoptosis and cell death in various preclinical models of therapy-resistant melanoma cells. 6-thio-dG concomitantly induces telomere dysfunction and inhibits the expression level of AXL.Conclusions: In summary, this study shows that indirectly targeting aberrant telomerase in melanoma cells with 6-thio-dG is a viable therapeutic approach in prolonging disease control and overcoming therapy resistance. Clin Cancer Res; 24(19); 4771-84. ©2018 AACR See related commentary by Teh and Aplin, p. 4629.},
}
@article {pmid29561856,
year = {2018},
author = {Dupont, SM and Barbraud, C and Chastel, O and Delord, K and Ruault, S and Weimerskirch, H and Angelier, F},
title = {Young parents produce offspring with short telomeres: A study in a long-lived bird, the Black-browed Albatross (Thalassarche melanophrys).},
journal = {PloS one},
volume = {13},
number = {3},
pages = {e0193526},
pmid = {29561856},
issn = {1932-6203},
mesh = {Age Factors ; Animals ; Animals, Wild/*genetics ; Birds/*genetics ; Breeding ; Female ; Longevity ; Male ; Reproduction ; *Telomere ; *Telomere Shortening ; },
abstract = {In wild vertebrates, young parents are less likely to successfully rear offspring relative to older ones because of lower parental skills ('the constraint hypothesis'), lower parental investment ('the restraint hypothesis') or because of a progressive disappearance of lower-quality individuals at young ages ('the selection hypothesis'). Because it is practically difficult to follow an offspring during its entire life, most studies have only focused on the ability of individuals to breed or produce young, while neglecting the ability of such young to subsequently survive and reproduce. Several proxies of individual quality can be useful to assess the ability of young to survive and recruit into the population. Among them, telomere length measurement appears especially promising because telomere length has been linked to longevity and fitness in captive and wild animals. By sampling 51 chicks reared by known-aged parents, we specifically tested whether parental age was correlated to offspring telomere length and body condition in a long-lived bird species, the Black-browed Albatross (Thalassarche melanophrys). Young Black-browed albatrosses produced chicks with shorter telomere relative to those raised by older ones. Short offspring telomeres could result from poor developmental conditions or heritability of telomere length. Moreover, young parents also had chicks of lower body condition when compared with older parents, although this effect was significant in female offspring only. Overall, our study demonstrates that parental age is correlated to two proxies of offspring fitness (body condition and telomere length), suggesting therefore that older individuals provide better parental cares to their offspring because of increased parental investment (restraint hypothesis), better foraging/parental skills (constraint hypothesis) or because only high-quality individuals reach older ages (selection hypothesis).},
}
@article {pmid29559500,
year = {2018},
author = {Markiewicz-Potoczny, M and Lisby, M and Lydall, D},
title = {A Critical Role for Dna2 at Unwound Telomeres.},
journal = {Genetics},
volume = {209},
number = {1},
pages = {129-141},
pmid = {29559500},
issn = {1943-2631},
support = {13314/CRUK_/Cancer Research UK/United Kingdom ; MR/L001284/1/MRC_/Medical Research Council/United Kingdom ; BB/M002314/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {DNA Helicases/genetics/*metabolism ; DNA, Single-Stranded ; Fungal Proteins/genetics/metabolism ; Genes, Lethal ; Mutation ; Sensitivity and Specificity ; Sequence Deletion ; Telomere/*genetics/*metabolism ; Temperature ; Yeasts/genetics/metabolism ; },
abstract = {Dna2 is a nuclease and helicase that functions redundantly with other proteins in Okazaki fragment processing, double-strand break resection, and checkpoint kinase activation. Dna2 is an essential enzyme, required for yeast and mammalian cell viability. Here, we report that numerous mutations affecting the DNA damage checkpoint suppress dna2∆ lethality in Saccharomyces cerevisiaedna2∆ cells are also suppressed by deletion of helicases PIF1 and MPH1, and by deletion of POL32, a subunit of DNA polymerase δ. All dna2∆ cells are temperature sensitive, have telomere length defects, and low levels of telomeric 3' single-stranded DNA (ssDNA). Interestingly, Rfa1, a subunit of the major ssDNA binding protein RPA, and the telomere-specific ssDNA binding protein Cdc13, often colocalize in dna2∆ cells. This suggests that telomeric defects often occur in dna2∆ cells. There are several plausible explanations for why the most critical function of Dna2 is at telomeres. Telomeres modulate the DNA damage response at chromosome ends, inhibiting resection, ligation, and cell-cycle arrest. We suggest that Dna2 nuclease activity contributes to modulating the DNA damage response at telomeres by removing telomeric C-rich ssDNA and thus preventing checkpoint activation.},
}
@article {pmid29552152,
year = {2018},
author = {Fu, F and Hu, H and Yang, S and Liang, X},
title = {Effects of TIN2 on telomeres and chromosomes in the human gastric epithelial cell line GES-1.},
journal = {Oncology letters},
volume = {15},
number = {4},
pages = {5161-5166},
pmid = {29552152},
issn = {1792-1074},
abstract = {TERF1-interacting nuclear factor 2 (TIN2) is a key member of the protein complexes that protect telomeres. TIN2 contributes an important role in biological processes. In a previous study by the present authors, an association was reported between high TIN2 protein expression and gastric cancer. Therefore, it was hypothesized that abnormal TIN2 expression may cause the development of malignancies, including, gastric carcinomas. To investigate this hypothesis, the present study employed peptide nucleic acid fluorescence in situ hybridization technology to analyze the human gastric epithelial GES-1 cells with high TIN2 expression or inhibited TIN2 expression. The results indicated that GES-1 cell lines with high TIN2 expression exhibited greater telomere dysfunction-induced damage compared with GES-1 cell lines with inhibited TIN2 expression. Chromosome analysis indicated that GES-1 cells with high TIN2 expression exhibited 2.48±1.30 aberrant chromosomal changes per 100 cells, that may contribute to telomere DNA damage. Therefore, aberrant chromosomal alterations may provide a novel perspective for the pathogenesis of gastric cancer.},
}
@article {pmid29550946,
year = {2018},
author = {Hosokawa, K and Arai, F},
title = {The role of telomere binding molecules for normal and abnormal hematopoiesis.},
journal = {International journal of hematology},
volume = {107},
number = {6},
pages = {646-655},
pmid = {29550946},
issn = {1865-3774},
support = {306240//European Union's Seventh Framework Programme (FP7)/ ; LS108//Next Generation World-Leading Researchers/ ; 26293228//Scientific Research (B) (General)/ ; 24689041//grant-in-aid for Young Scientists (A)/ ; 25670453//Challenging Exploratory Research/ ; },
mesh = {Aminopeptidases/genetics ; Animals ; Cell Division/genetics ; DNA Damage ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics ; Dyskeratosis Congenita ; Gene Deletion ; Hematopoiesis/*genetics ; *Hematopoietic Stem Cells/cytology/physiology ; Mice ; Mutation ; Serine Proteases/genetics ; Shelterin Complex ; *Telomere ; Telomere-Binding Proteins/genetics/*physiology ; Telomeric Repeat Binding Protein 2/deficiency/*physiology ; },
abstract = {In order to maintain the homeostasis of the hematopoietic system, hematopoietic stem cells (HSCs) need to be maintained while slowly dividing over their lifetime. However, repeated cell divisions lead to the gradual accumulation of DNA damage and ultimately impair HSC function. Since telomeres are particularly fragile when subjected to replication stress, cells have several defense machinery to protect telomeres. Moreover, HSCs must protect their genome against possible DNA damage, while maintaining telomere length. A group of proteins called the shelterin complex are deeply involved in this two-way role, and it is highly resistant to the replication stress to which HSCs are subjected. Most shelterin-deficient experimental models suffer acute cytotoxicity and severe phenotypes, as each shelterin component is essential for telomere protection. The Tin2 point mutant mice show a dyskeratosis congenita (DC) like phenotype, and the Tpp1 deletion impairs the hematopoietic system. POT1/Pot1a is highly expressed in HSCs and contributes to the maintenance of the HSC pool during in vitro culture. Here, we discuss the role of shelterin molecules in HSC regulation and review current understanding of how these are regulated in the maintenance of the HSC pool and the development of hematological disorders.},
}
@article {pmid29550242,
year = {2018},
author = {Lue, NF},
title = {Evolving Linear Chromosomes and Telomeres: A C-Strand-Centric View.},
journal = {Trends in biochemical sciences},
volume = {43},
number = {5},
pages = {314-326},
pmid = {29550242},
issn = {0968-0004},
support = {R01 GM107287/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes/*metabolism ; Humans ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Recent studies have resulted in deeper understanding of a variety of telomere maintenance mechanisms as well as plausible models of telomere evolution. Often overlooked in the discussion of telomere regulation and evolution is the synthesis of the DNA strand that bears the 5'-end (i.e., the C-strand). Herein, I describe a scenario for telomere evolution that more explicitly accounts for the evolution of the C-strand synthesis machinery. In this model, CTC1-STN1-TEN1 (CST), the G-strand-binding complex that regulates primase-Pol α-mediated C-strand synthesis, emerges as a pivotal player and evolutionary link. Itself arising from RPA, CST not only coordinates telomere synthesis, but also gives rise to the POT1-TPP1 complex, which became part of shelterin and regulates telomerase in G-strand elongation.},
}
@article {pmid29549539,
year = {2018},
author = {Lorenzi, M and Bonassi, S and Lorenzi, T and Giovannini, S and Bernabei, R and Onder, G},
title = {A review of telomere length in sarcopenia and frailty.},
journal = {Biogerontology},
volume = {19},
number = {3-4},
pages = {209-221},
doi = {10.1007/s10522-018-9749-5},
pmid = {29549539},
issn = {1573-6768},
mesh = {Aging/*physiology ; Frailty/*genetics ; Humans ; Sarcopenia/*genetics ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Sarcopenia and frailty are associated with several important health-related adverse events, including disability, loss of independence, institutionalization and mortality. Sarcopenia can be considered a biological substrate of frailty, and the prevalence of both these conditions progressively increases with age. Telomeres are nucleoprotein structures located at the end of linear chromosomes and implicated in cellular ageing, shorten with age, and are associated with various age-related diseases. In addition, telomere length (TL) is widely considered a molecular/cellular hallmark of the ageing process. This narrative review summarizes the knowledge about telomeres and analyzes for the first time a possible association of TL with sarcopenia and frailty. The overview provided by the present review suggests that leukocyte TL as single measurement, calculated by quantitative real-time polymerase chain reaction (qRT-PCR), cannot be considered a meaningful biological marker for complex, multidimensional age-related conditions, such as sarcopenia and frailty. Panels of biomarkers, including TL, may provide more accurate assessment and prediction of outcomes in these geriatric syndromes in elderly people.},
}
@article {pmid29547744,
year = {2018},
author = {Brazvan, B and Ebrahimi-Kalan, A and Velaei, K and Mehdipour, A and Aliyari Serej, Z and Ebrahimi, A and Ghorbani, M and Cheraghi, O and Nozad Charoudeh, H},
title = {Telomerase activity and telomere on stem progeny senescence.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {102},
number = {},
pages = {9-17},
doi = {10.1016/j.biopha.2018.02.073},
pmid = {29547744},
issn = {1950-6007},
mesh = {Animals ; Cellular Senescence/physiology ; Cytokines/immunology ; Gene Expression Regulation, Enzymologic ; Humans ; Stem Cells/*cytology ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {The end of linear chromosomes is formed of a special nucleoprotein heterochromatin structure with repetitive TTAGGG sequences called telomere. Telomere length is regulated by a special enzyme called telomerase, a specific DNA polymerase that adds new telomeric sequences to the chromosome ends. Telomerase consists of two parts; the central protein part and the accessory part which is a RNA component transported by the central part. Regulation of telomere length by this enzyme is a multi-stage process. Telomere length elongation is strongly influenced by the level of telomerase and has a strong correlation with the activity of telomerase enzyme. Human Telomerase Reverse Transcriptase (hTERT) gene expression plays an important role in maintaining telomere length and high proliferative property of cells. Except a low activity of telomerase enzyme in hematopoietic and few types of stem cells, most of somatic cells didn't showed telomerase activity. Moreover, cytokines are secretory proteins that control many aspects of hematopoiesis, especially immune responses and inflammation. Also, the induction of hTERT gene expression by cytokines is organized through the PI3K/AKT and NF/kB signaling pathways. In this review we have tried to talk about effects of immune cell cytokines on telomerase expression/telomere length and the induction of telomerase expression by cytokines.},
}
@article {pmid29547348,
year = {2018},
author = {López-Arrabé, J and Monaghan, P and Cantarero, A and Boner, W and Pérez-Rodríguez, L and Moreno, J},
title = {Sex-Specific Associations between Telomere Dynamics and Oxidative Status in Adult and Nestling Pied Flycatchers.},
journal = {Physiological and biochemical zoology : PBZ},
volume = {91},
number = {3},
pages = {868-877},
doi = {10.1086/697294},
pmid = {29547348},
issn = {1537-5293},
mesh = {*Aging ; Animals ; Female ; Lipid Peroxidation ; Male ; *Oxidative Stress ; Passeriformes/*physiology ; Sex Characteristics ; Telomere/*physiology ; },
abstract = {Oxidative stress can contribute to an acceleration of telomere erosion, leading to cellular senescence and aging. Increased investment in reproduction is known to accelerate senescence, generally resulting in reduced future reproductive potential and survival. To better understand the role played by oxidative status and telomere dynamics in the conflict between maintenance and reproduction, it is important to determine how these factors are related in parents and their offspring. We investigated the relationship between oxidative status and telomere measurements in pied flycatchers (Ficedula hypoleuca). Total antioxidant status (TAS) in plasma, total levels of glutathione in red blood cells (RBCs), and oxidative damage in plasma lipids (malondialdehyde [MDA]) were assessed in both parents and nestlings. Telomeres were measured in RBCs in adults. Our results showed sex differences in oxidative variables in adults that are likely to be mediated by sex steroids, with testosterone and estrogens increasing and reducing, respectively, the production of reactive oxygen and nitrogen species. We found a negative association between telomere length (TL) and MDA in adults in the previous season. Moreover, TL was positively associated with TAS in females, while telomere shortening (ΔTL) correlated positively with MDA in males in the current year. These associations could be reflecting differences between sexes in reproductive physiology. We found a positive correlation between parental ΔTL and nestling MDA, an example of how parental physiological aging could affect offspring quality in terms of oxidative stress that highlights the constraints imposed by higher rates of ΔTL during reproduction and rearing.},
}
@article {pmid29547021,
year = {2018},
author = {Morgan, RG and Donato, AJ and Walker, AE},
title = {Telomere uncapping and vascular aging.},
journal = {American journal of physiology. Heart and circulatory physiology},
volume = {315},
number = {1},
pages = {H1-H5},
pmid = {29547021},
issn = {1522-1539},
support = {K01 AG046326/AG/NIA NIH HHS/United States ; K02 AG045339/AG/NIA NIH HHS/United States ; R01 AG050238/AG/NIA NIH HHS/United States ; R44 AG053131/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Blood Vessels/growth &amp; development/*metabolism ; *Cellular Senescence ; Humans ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; },
abstract = {Although most telomere biology research continues to focus on telomere shortening, there is increasing evidence that telomere deprotection, or "uncapping," is more biologically and possibly clinically important. Telomeres form t-loops to prevent the chromosome ends from appearing as a double-stranded DNA break and initiating a DNA damage response. Breakdown of the t-loop structure, referred to as uncapping, can lead to cellular senescence, increased oxidative stress, and inflammation in tissues. In this review, we describe how telomere uncapping potentially leads to age-related vascular dysfunction and increased cellular senescence, oxidative stress, and inflammation. Importantly, we present evidence to argue that telomere uncapping is more biologically relevant than telomere shortening and a better marker of vascular aging and target for antiaging interventions.},
}
@article {pmid29545335,
year = {2018},
author = {Mukherjee, J and Johannessen, TC and Ohba, S and Chow, TT and Jones, L and Pandita, A and Pieper, RO},
title = {Mutant IDH1 Cooperates with ATRX Loss to Drive the Alternative Lengthening of Telomere Phenotype in Glioma.},
journal = {Cancer research},
volume = {78},
number = {11},
pages = {2966-2977},
pmid = {29545335},
issn = {1538-7445},
support = {R01 NS105087/NS/NINDS NIH HHS/United States ; },
mesh = {Astrocytes/pathology ; Astrocytoma/genetics ; Brain Neoplasms/*genetics ; Carcinogenesis/genetics ; Cell Line, Tumor ; Chromatin/genetics ; DNA Repair/genetics ; Down-Regulation/genetics ; Glioma/*genetics ; Homologous Recombination/genetics ; Humans ; Isocitrate Dehydrogenase/*genetics ; Mutation/*genetics ; Phenotype ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/genetics ; X-linked Nuclear Protein/*genetics ; },
abstract = {A subset of tumors use a recombination-based alternative lengthening of telomere (ALT) pathway to resolve telomeric dysfunction in the absence of TERT. Loss-of-function mutations in the chromatin remodeling factor ATRX are associated with ALT but are insufficient to drive the process. Because many ALT tumors express the mutant isocitrate dehydrogenase IDH1 R132H, including all lower grade astrocytomas and secondary glioblastoma, we examined a hypothesized role for IDH1 R132H in driving the ALT phenotype during gliomagenesis. In p53/pRb-deficient human astrocytes, combined deletion of ATRX and expression of mutant IDH1 were sufficient to create tumorigenic cells with ALT characteristics. The telomere capping complex component RAP1 and the nonhomologous DNA end joining repair factor XRCC1 were each downregulated consistently in these tumorigenic cells, where their coordinate reexpression was sufficient to suppress the ALT phenotype. RAP1 or XRCC1 downregulation cooperated with ATRX loss in driving the ALT phenotype. RAP1 silencing caused telomere dysfunction in ATRX-deficient cells, whereas XRCC1 silencing suppressed lethal fusion of dysfunctional telomeres by allowing IDH1-mutant ATRX-deficient cells to use homologous recombination and ALT to resolve telomeric dysfunction and escape cell death. Overall, our studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis.Significance: Studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis and suggesting new therapeutic options to treat low-grade gliomas. Cancer Res; 78(11); 2966-77. ©2018 AACR.},
}
@article {pmid29544213,
year = {2018},
author = {Wang, J and Zhang, H and Al Shibar, M and Willard, B and Ray, A and Runge, KW},
title = {Rif1 phosphorylation site analysis in telomere length regulation and the response to damaged telomeres.},
journal = {DNA repair},
volume = {65},
number = {},
pages = {26-33},
pmid = {29544213},
issn = {1568-7856},
support = {R01 AG019960/AG/NIA NIH HHS/United States ; R01 AG051601/AG/NIA NIH HHS/United States ; R01 GM050752/GM/NIGMS NIH HHS/United States ; S10 RR031537/RR/NCRR NIH HHS/United States ; UL1 RR024989/RR/NCRR NIH HHS/United States ; },
mesh = {DNA Damage ; DNA, Fungal ; Phosphorylation ; *Protein Processing, Post-Translational ; Repressor Proteins/*metabolism ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomeres, the ends of eukaryotic chromosomes, consist of repetitive DNA sequences and their bound proteins that protect the end from the DNA damage response. Short telomeres with fewer repeats are preferentially elongated by telomerase. Tel1, the yeast homolog of human ATM kinase, is preferentially recruited to short telomeres and Tel1 kinase activity is required for telomere elongation. Rif1, a telomere-binding protein, negatively regulates telomere length by forming a complex with two other telomere binding proteins, Rap1 and Rif2, to block telomerase recruitment. Rif1 has 14 SQ/TQ consensus phosphorylation sites for ATM kinases, including 6 in a SQ/TQ Cluster Domain (SCD) similar to other DNA damage response proteins. These 14 sites were analyzed as N-terminal, SCD and C-terminal domains. Mutating some sites to non-phosphorylatable residues increased telomere length in cells lacking Tel1 while a different set of phosphomimetic mutants increased telomere length in cells lacking Rif2, suggesting that Rif1 phosphorylation has both positive and negative effects on length regulation. While these mutations did not alter the sensitivity to DNA damaging agents, inducing telomere-specific damage by growing cells lacking YKU70 at high temperature revealed a role for the SCD. Mass spectrometry of Rif1 from wild type cells or those induced for telomere-specific DNA damage revealed increased phosphorylation in cells with telomere damage at an ATM consensus site in the SCD, S1351, and non-ATM sites S181 and S1637. A phosphomimetic rif1-S1351E mutation caused an increase in telomere length at synthetic telomeres but not natural telomeres. These results indicate that the Rif1 SCD can modulate Rif1 function. As all Rif1 orthologs have one or more SCD domains, these results for yeast Rif1 have implications for the regulation of Rif1 function in humans and other organisms.},
}
@article {pmid29542055,
year = {2019},
author = {Serakinci, N and Cagsin, H and Mavis, M},
title = {Use of U-STELA for Accurate Measurement of Extremely Short Telomeres.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2045},
number = {},
pages = {217-224},
doi = {10.1007/7651_2018_120},
pmid = {29542055},
issn = {1940-6029},
mesh = {Adult Stem Cells/cytology/metabolism ; Cell Division/genetics ; Cell Transformation, Neoplastic/genetics ; Cells, Cultured ; Cellular Senescence/genetics ; DNA/isolation &amp; purification ; Humans ; Mesenchymal Stem Cells/cytology/*metabolism ; Telomerase/genetics/*metabolism/physiology ; Telomere/*genetics/*metabolism ; Telomere Homeostasis/genetics ; Telomere Shortening/*genetics ; Workflow ; },
abstract = {Telomeres are repetitive genetic materials that protect the chromosomes by capping the ends of chromosomes. Each time a cell divides, telomeres get shorter. Telomere length is mainly maintained by telomerase. This enzyme is present in the embryonic stem cells in high concentrations and declines with age. It is still unclear to what extend there is telomerase in adult stem cells, but considering these are the founder cells to the cells of the all tissues in a body, understanding the telomere dynamics and expression of telomerase in adult stem cells is very important.Telomere length has been implicated as one of the markers for neoplastic transformation in both in vivo and in vitro studies. During cancerogenesis, telomeres shorten due to high cell turnover and repeats are added by active telomerase or alternative lengthening of telomeres (ALT). This gradual shortening is replication driven and does not necessarily explain the presence of ultrashort telomeres. Ultrashort telomeres are observed when there is a sudden shortening in telomeres not related with cell division and may arise from breaks in telomeres due to oxidative damage and replication slippage.Universal STELA is an accurate method for evaluation of ultrashort telomeres in hMSC-telo1 cells. Compared to TRF assay, U-STELA is developed to overcome several problems in detecting abrupt telomere shortening in a single chromosome.},
}
@article {pmid29540524,
year = {2018},
author = {Noguera, JC and Metcalfe, NB and Monaghan, P},
title = {Experimental demonstration that offspring fathered by old males have shorter telomeres and reduced lifespans.},
journal = {Proceedings. Biological sciences},
volume = {285},
number = {1874},
pages = {},
pmid = {29540524},
issn = {1471-2954},
support = {268926/ERC_/European Research Council/International ; },
mesh = {Age Factors ; Animals ; *Fathers ; Female ; *Longevity ; Male ; *Mothers ; Reproduction ; Songbirds/genetics/*physiology ; *Telomere Shortening ; },
abstract = {Offspring of older parents frequently show reduced longevity, but the mechanisms driving this so-called 'Lansing effect' are unknown. While inheritance of short telomeres from older parents could underlie this effect, studies to date in different species have found mixed results, reporting positive, negative or no association between parental age and offspring telomere length (TL). However, most of the existing evidence is from non-experimental studies in which it is difficult to exclude alternative explanations such as differential survival of parents with different telomere lengths. Here we provide evidence in the zebra finch that offspring from older parents have reduced lifespans. As a first step in disentangling possible causes, we used an experimental approach to examine whether or not we could detect pre-natal paternal effects on offspring TL. We found that zebra finch embryos fathered by old males have shorter telomeres than those produced by the same mothers but with younger fathers. Since variation in embryonic TL persists into post-natal life, and early life TL is predictive of longevity in this species, this experimental study demonstrates that a paternally driven pre-natal TL reduction could at least in part underlie the reduced lifespan of offspring from older parents.},
}
@article {pmid29529386,
year = {2018},
author = {van Batenburg, AA and Kazemier, KM and Peeters, T and van Oosterhout, MFM and van der Vis, JJ and Grutters, JC and Goldschmeding, R and van Moorsel, CHM},
title = {Cell Type-Specific Quantification of Telomere Length and DNA Double-strand Breaks in Individual Lung Cells by Fluorescence In Situ Hybridization and Fluorescent Immunohistochemistry.},
journal = {The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society},
volume = {66},
number = {7},
pages = {485-495},
pmid = {29529386},
issn = {1551-5044},
mesh = {A549 Cells ; *DNA Breaks, Double-Stranded ; Exoribonucleases/genetics ; Fluorescent Antibody Technique/*methods ; Histones/analysis ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Lung/*cytology/pathology ; Microscopy, Confocal/methods ; Mutation ; Myocytes, Smooth Muscle/cytology/metabolism/pathology ; Optical Imaging/methods ; Paraffin Embedding/methods ; Pulmonary Fibrosis/genetics/*pathology ; *Telomere Homeostasis ; },
abstract = {Telomeres are small repetitive DNA sequences at the ends of chromosomes which act as a buffer in age-dependent DNA shortening. Insufficient telomere repeats will be recognized as double-strand breaks. Presently, it is becoming more evident that telomere attrition, whether or not caused by mutations in telomere maintenance genes, plays an important role in many inflammatory and age-associated diseases. In this report, a method to (semi)quantitatively assess telomere length and DNA double-strand breaks in formalin-fixed paraffin-embedded (FFPE) tissue is described. Therefore, a novel combination of quantitative fluorescence in situ hybridization, tissue elution, and immunofluorescence staining techniques was developed. Caveolin-1 (type 1 pneumocytes), pro-surfactant protein C (type 2 pneumocytes), club cell-10 (club cells), and alpha smooth muscle actin (smooth muscle cells) markers were used to identify cell types. To visualize all the different probes, restaining the tissue by heat-mediated slide elution is essential. Fluorescent signals of telomeres and DNA double-strand breaks were quantified using the Telometer plugin of ImageJ. As example, we analyzed lung tissue from a familial pulmonary fibrosis patient with a mutation in the telomere-associated gene poly(A)-specific ribonuclease (PARN). The protocol displays a novel opportunity to directly quantitatively link DNA double-strand breaks to telomere length in specific FFPE cells.},
}
@article {pmid29529242,
year = {2018},
author = {Kedziora, S and Gali, VK and Wilson, RHC and Clark, KRM and Nieduszynski, CA and Hiraga, SI and Donaldson, AD},
title = {Rif1 acts through Protein Phosphatase 1 but independent of replication timing to suppress telomere extension in budding yeast.},
journal = {Nucleic acids research},
volume = {46},
number = {8},
pages = {3993-4003},
pmid = {29529242},
issn = {1362-4962},
support = {13356/CRUK_/Cancer Research UK/United Kingdom ; 19059/CRUK_/Cancer Research UK/United Kingdom ; BB/N016858/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; G0600774/MRC_/Medical Research Council/United Kingdom ; },
mesh = {DNA Replication Timing ; Intracellular Signaling Peptides and Proteins/metabolism ; Mutation ; Protein Phosphatase 1/*metabolism ; Protein Serine-Threonine Kinases/metabolism ; Replication Origin ; Repressor Proteins/genetics/*metabolism ; Saccharomyces cerevisiae/enzymology/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {The Rif1 protein negatively regulates telomeric TG repeat length in the budding yeast Saccharomyces cerevisiae, but how it prevents telomere over-extension is unknown. Rif1 was recently shown to control DNA replication by acting as a Protein Phosphatase 1 (PP1)-targeting subunit. Therefore, we investigated whether Rif1 controls telomere length by targeting PP1 activity. We find that a Rif1 mutant defective for PP1 interaction causes a long-telomere phenotype, similar to that of rif1Δ cells. Tethering PP1 at a specific telomere partially substitutes for Rif1 in limiting TG repeat length, confirming the importance of PP1 in telomere length control. Ablating Rif1-PP1 interaction is known to cause precocious activation of telomere-proximal replication origins and aberrantly early telomere replication. However, we find that Rif1 still limits telomere length even if late replication is forced through deletion of nearby replication origins, indicating that Rif1 can control telomere length independent of replication timing. Moreover we find that, even at a de novo telomere created after DNA synthesis during a mitotic block, Rif1-PP1 interaction is required to suppress telomere lengthening and prevent inappropriate recruitment of Tel1 kinase. Overall, our results show that Rif1 controls telomere length by recruiting PP1 to directly suppress telomerase-mediated TG repeat lengthening.},
}
@article {pmid29527774,
year = {2018},
author = {Jasmine, F and Shinkle, J and Sabarinathan, M and Ahsan, H and Pierce, BL and Kibriya, MG},
title = {A novel pooled-sample multiplex luminex assay for high-throughput measurement of relative telomere length.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {30},
number = {4},
pages = {e23118},
pmid = {29527774},
issn = {1520-6300},
support = {R01 CA107431/CA/NCI NIH HHS/United States ; R01 ES020506/ES/NIEHS NIH HHS/United States ; R35 ES028379/ES/NIEHS NIH HHS/United States ; U01 HG007601/HG/NHGRI NIH HHS/United States ; },
mesh = {Adult ; Aged ; High-Throughput Screening Assays/economics/*methods ; Humans ; Middle Aged ; Reproducibility of Results ; Telomere/*chemistry ; Telomere Shortening/*physiology ; Young Adult ; },
abstract = {OBJECTIVES: Relative telomere length (RTL) is a potential biomarker of aging and risk for chronic disease. Previously, we developed a probe-based RTL assay on Luminex platform, where probes for Telomere (T) and reference gene (R) for a given DNA sample were tested in a single well. Here, we describe a method of pooling multiple samples in one well to increase the throughput and cost-effectiveness.<br><br>METHODS: We used four different microbeads for the same T-probe and four different microbeads for the same R-probe. Each pair of probe sets were hybridized to DNA in separate plates and then pooled in a single plate for all the subsequent steps. We used DNA samples from 60 independent individuals and repeated in multiple batches to test the precision.<br><br>RESULTS: The precision was good to excellent with Intraclass correlation coefficient (ICC) of 0.908 (95% CI 0.856-0.942). More than 67% of the variation in the RTL could be explained by sample-to-sample variation; less than 0.1% variation was due to batch-to-batch variation and 0.3% variation was explained by bead-to-bead variation. We increased the throughput of RTL Luminex assay from 60 to 240 samples per run. The new assay was validated against the original Luminex assay without pooling (r&#x2009;=&#x2009;0.79, P&#x2009;=&#x2009;1.44 &#xd7; 10[-15]). In an independent set of samples (n&#x2009;=&#x2009;550), the new assay showed a negative correlation of RTL with age (r&#x2009;=&#x2009;-0.41), a result providing external validation for the method.<br><br>CONCLUSION: We describe a novel high throughput pooled-sample multiplex Luminex assay for RTL with good to excellent precision suitable for large-scale studies.},
}
@article {pmid29518528,
year = {2018},
author = {Conklin, QA and King, BG and Zanesco, AP and Lin, J and Hamidi, AB and Pokorny, JJ and Álvarez-López, MJ and Cosín-Tomás, M and Huang, C and Kaliman, P and Epel, ES and Saron, CD},
title = {Insight meditation and telomere biology: The effects of intensive retreat and the moderating role of personality.},
journal = {Brain, behavior, and immunity},
volume = {70},
number = {},
pages = {233-245},
doi = {10.1016/j.bbi.2018.03.003},
pmid = {29518528},
issn = {1090-2139},
mesh = {Adult ; Female ; Humans ; Male ; Meditation/methods/*psychology ; Neuroticism/physiology ; Personality/genetics/physiology ; Stress, Psychological/metabolism ; Telomerase/analysis ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; },
abstract = {A growing body of evidence suggests that meditation training may have a range of salubrious effects, including improved telomere regulation. Telomeres and the enzyme telomerase interact with a variety of molecular components to regulate cell-cycle signaling cascades, and are implicated in pathways linking psychological stress to disease. We investigated the effects of intensive meditation practice on these biomarkers by measuring changes in telomere length (TL), telomerase activity (TA), and telomere-related gene (TRG) expression during a 1-month residential Insight meditation retreat. Multilevel analyses revealed an apparent TL increase in the retreat group, compared to a group of experienced meditators, similarly comprised in age and gender, who were not on retreat. Moreover, personality traits predicted changes in TL, such that retreat participants highest in neuroticism and lowest in agreeableness demonstrated the greatest increases in TL. Changes observed in TRGs further suggest retreat-related improvements in telomere maintenance, including increases in Gar1 and HnRNPA1, which encode proteins that bind telomerase RNA and telomeric DNA. Although no group-level changes were observed in TA, retreat participants' TA levels at post-assessment were inversely related to several indices of retreat engagement and prior meditation experience. Neuroticism also predicted variation in TA across retreat. These findings suggest that meditation training in a retreat setting may have positive effects on telomere regulation, which are moderated by individual differences in personality and meditation experience. (ClinicalTrials.gov #NCT03056105).},
}
@article {pmid29518479,
year = {2018},
author = {Zhou, J and Wang, J and Shen, Y and Yang, Y and Huang, P and Chen, S and Zou, C and Dong, B},
title = {The association between telomere length and frailty: A systematic review and meta-analysis.},
journal = {Experimental gerontology},
volume = {106},
number = {},
pages = {16-20},
doi = {10.1016/j.exger.2018.02.030},
pmid = {29518479},
issn = {1873-6815},
mesh = {Aging/*physiology ; Frailty/*genetics ; Humans ; Risk Factors ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {BACKGROUND: Several studies have examined the association between telomere length and frailty, but results from these studies are contradictory. Therefore, we conducted a systematic review and meta-analysis to examine the association between telomere length and frailty.<br><br>METHODS: We searched the literature in Ovid (MEDLINE), Embase, PubMed, Web of Knowledge and Cochrane databases in July 2017 for studies evaluating the association of telomere length and the risk of frailty.<br><br>RESULTS: A total of 5 studies (3268 participants) were eligible in our study. The prevalence of frailty ranged from 5.4% to 51.1%. The pooled mean difference of telomere length for the non-frail versus frail was 0.06 (95% CI: -0.01, 0.13), suggesting that no significant association was found between telomere length and frailty. In addition, the subgroup analysis indicated that telomere length was not significantly associated with the risk of frailty in all gender groups. Similar results were also found when frailty was defined by the Fried criteria (mean difference&#x202f;=&#x202f;0.07, 95% CI: -0.03, 0.16) and frailty index (mean difference&#x202f;=&#x202f;-0.02, 95% CI: -0.05, 0.01), but not by the frailty scale (mean difference&#x202f;=&#x202f;0.18, 95% CI: 0.04, 0.32).<br><br>CONCLUSION: Telomere length is not associated with the risk of frailty. Well-designed prospective studies are needed to evaluate further whether telomere length is a meaningful biological marker for frailty.},
}
@article {pmid29512081,
year = {2018},
author = {Zhan, Y and Hägg, S},
title = {Telomere Length Shortening in Alzheimer's Disease: Procedures for a Causal Investigation Using Single Nucleotide Polymorphisms in a Mendelian Randomization Study.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1750},
number = {},
pages = {293-306},
doi = {10.1007/978-1-4939-7704-8_20},
pmid = {29512081},
issn = {1940-6029},
mesh = {Alzheimer Disease/*diagnosis/*genetics ; Genetic Predisposition to Disease ; Humans ; Mendelian Randomization Analysis/*methods ; *Polymorphism, Single Nucleotide ; Risk Assessment/methods ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {Measuring the length of telomeres, repetitive nucleotide sequences capping the chromosomes which shortens by each cell division, has become a popular way of attaining a marker of biological aging processes. Several observational studies have investigated the associations between telomere length and Alzheimer's disease (AD) with the overall conclusion being shorter telomeres provide an increased risk for AD development. Here we present an alternative approach for addressing the topic where additional evidence on causality can be drawn. To do so, we include information on single nucleotide polymorphisms (SNPs) using nature's own experiment with random segregation of alleles at conception. The protocol describes the full process of the so-called Mendelian Randomization by selecting appropriate SNPs for the analysis, discussing different data sources that can be used and inform about methods, assumptions and suitable software packages including Stata code.},
}
@article {pmid29504461,
year = {2019},
author = {Oerther, S and Lorenz, R},
title = {State of the Science: Using Telomeres as Biomarkers During the First 1,000 Days of Life.},
journal = {Western journal of nursing research},
volume = {41},
number = {2},
pages = {305-325},
doi = {10.1177/0193945918762806},
pmid = {29504461},
issn = {1552-8456},
mesh = {Biomarkers/*analysis ; Chronic Disease ; Humans ; Infant ; Infant Mortality ; Mass Screening/methods/standards ; *Telomere ; },
abstract = {Telomere biology shows promise as an integrative biomarker of exposures and increased occurrence of chronic disease and early mortality. This integrative review examined the state of the science regarding toxicokinetic risks and maternal factors in humans and in vivo models that are correlated with telomere length during the first 1,000 days of life. The Preferred Reporting Items of Systematic Reviews and Meta-Analyses framework assisted in guiding this integrative by aiding researchers in identifying, selecting, and critically appraising the literature. Ovid MEDLINE, CINAHL, Cochrane Systematic Reviews, Web of Science, and SCOPUS databases were searched. The initial search yielded a total of 381 published articles. Full-text screening resulted in 19 articles retained for review (14 quasi-experimental studies and five experimental studies). Findings suggest a relationship between toxicokinetic exposures creating inflammation or oxidative stress (i.e., smoking) and maternal health conditions such as sleep apnea to shorter telomere length in children below 2 years old.},
}
@article {pmid29500463,
year = {2018},
author = {Mazidi, M and Banach, M and Kengne, AP},
title = {Association between plasma trans fatty acids concentrations and leucocyte telomere length in US adults.},
journal = {European journal of clinical nutrition},
volume = {72},
number = {4},
pages = {581-586},
doi = {10.1038/s41430-017-0065-y},
pmid = {29500463},
issn = {1476-5640},
mesh = {Adult ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/*chemistry ; Male ; Middle Aged ; *Nutrition Surveys ; Telomere/*chemistry/genetics ; Trans Fatty Acids/*blood ; United States/epidemiology ; },
abstract = {BACKGROUND/OBJECTIVES: To assess the relationship between plasma trans-fatty acids (TFAs) levels and leucocyte telomere length (TL) in a US adult population sample.<br><br>SUBJECTS/METHODS: National Health and Nutrition Examination Survey (NHANES) database was used for this study. Gas chromatography was used to separate derivatised fatty acids (Four major TFAs [palmitelaidic acid (C16:1n-7t), trans vaccenic acid (C18:1n-7t), elaidic acid (C18:1n-9t), and linoelaidic acid (C18:2n-6t,9t)]) which were then quatified using negative chemical ionization mass spectrometry. Data analyses used multivariable linear regressions, while accounting for the survey design.<br><br>RESULTS: A total of 5446 eligible participants, with 46.8% (n&#x2009;=&#x2009;2550) being men, were included. Their average age was 47.1 years for the total sample, and 47.8 and 46.5 years in men and women respectively (p&#x2009;=&#x2009;0.085 for men vs. women difference). Concentrations of palmitelaidic acid and linolelaidic acid decreased with increasing length of the telomere (p&#x2009;<&#x2009;0.05). Univariable linear regressions revealed a significant negative association between levels of the palmitelaidic acid, elaidic acid, vaccenic acid, and linolelaidic acid with TL. However when models were adjusted for age, sex, ethnicity, education, marital status, sub-clinical inflammation, body mass index, and smoking, only palmitelaidic acid and linolelaidic acid remained significant (p&#x2009;<&#x2009;0.05).<br><br>CONCLUSIONS: TFAs levels and particularly palmitelaidic and linolelaidic acids, are likely negatively associated with telomere lenght. Future studies should explore the potential implications of these associations.},
}
@article {pmid29499965,
year = {2018},
author = {Balzan, RP and Dhillon, VS and Liu, D and Hahn, L and Fenech, MF and Galletly, C},
title = {Shorter telomere length in people with schizophrenia who live alone?.},
journal = {Schizophrenia research},
volume = {199},
number = {},
pages = {422-423},
doi = {10.1016/j.schres.2018.02.039},
pmid = {29499965},
issn = {1573-2509},
mesh = {Adult ; Humans ; *Loneliness ; Male ; Schizophrenia/*metabolism ; *Social Isolation ; Stress, Psychological/*metabolism ; *Telomere Shortening ; },
}
@article {pmid29499556,
year = {2018},
author = {Vance, MC and Bui, E and Hoeppner, SS and Kovachy, B and Prescott, J and Mischoulon, D and Walton, ZE and Dong, M and Nadal, MF and Worthington, JJ and Hoge, EA and Cassano, P and Orr, EH and Fava, M and de Vivo, I and Wong, KK and Simon, NM},
title = {Prospective association between major depressive disorder and leukocyte telomere length over two years.},
journal = {Psychoneuroendocrinology},
volume = {90},
number = {},
pages = {157-164},
pmid = {29499556},
issn = {1873-3360},
support = {R01 MH077700/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Aged ; Biomarkers ; Depression/genetics/pathology ; Depressive Disorder, Major/*genetics/pathology ; Female ; Humans ; Leukocytes/cytology ; Male ; Middle Aged ; Prospective Studies ; Telomere/*physiology ; Telomere Shortening/genetics/*physiology ; },
abstract = {BACKGROUND: Reduced leukocyte telomere length (LTL) has been found to be associated with multiple common age-related diseases, including heart disease, diabetes, and cancer. A link has also been suggested between shortened LTL and major depressive disorder (MDD), suggesting that MDD may be a disease of accelerated aging. This prospective, longitudinal study examined the association between depression diagnosis at baseline and change in LTL over two years in a well-characterized sample of N = 117 adults with or without MDD at baseline, using rigorous entry criteria.<br><br>METHODS: Participants aged 18-70 were assessed with validated instruments by trained, doctoral-level clinician raters at baseline and at two-year follow-up, and blood samples were obtained at both visits. LTL was assayed under identical methods using quantitative polymerase chain reaction (qPCR). The effect of an MDD diagnosis at baseline on change in LTL over two years was examined via hierarchical mixed models, which included potential confounders.<br><br>RESULTS: Individuals with MDD at baseline had greater LTL shortening over two years than individuals without MDD (p&#x202f;=&#x202f;0.03), even after controlling for differences in age, sex, and body mass index (BMI). In the sub-sample of individuals with MDD diagnoses at baseline, no significant associations between LTL change and symptom severity or duration were found.<br><br>CONCLUSION: A baseline diagnosis of MDD prospectively predicted LTL shortening over two years. Our results provide further support for MDD as a disease associated with accelerated aging in a well-characterized sample using validated, clinician-rated measures.},
}
@article {pmid29496020,
year = {2018},
author = {Zhang, Q and Han, X and Hao, X and Ma, L and Li, S and Wang, Y and Du, W},
title = {A simulated heat wave shortens the telomere length and lifespan of a desert lizard.},
journal = {Journal of thermal biology},
volume = {72},
number = {},
pages = {94-100},
doi = {10.1016/j.jtherbio.2018.01.004},
pmid = {29496020},
issn = {0306-4565},
mesh = {Animals ; Body Temperature ; Climate Change ; Infrared Rays/*adverse effects ; Lizards/metabolism/*physiology ; Superoxide Dismutase/metabolism ; Survival Analysis ; Telomere/*metabolism ; Temperature ; },
abstract = {Understanding how organisms respond to warming contributes important information to the conservation of biodiversity that is threatened by climate warming. Here, we conducted experiments on a desert agama (Phrynocephalus przewalskii) to test the hypothesis that climate warming (an increase in both mean temperature and heat waves) would induce oxidative stress, shortening telomere length, and thereby decreasing survival. Our results demonstrated that one week of exposure to a simulated heat wave significantly shortened telomere length, and decreased the overwinter survival of lizards, but mean temperature increase did not affect the survival of lizards. However, the antioxidant capacity (anti-oxidative enzyme) was not affected by the warming treatments. Therefore, heat waves might have negative impacts on the desert agama, with shortened telomeres likely causing the lifespan of lizards to decrease under climate warming.},
}
@article {pmid29494336,
year = {2018},
author = {Herrmann, M and Pusceddu, I and März, W and Herrmann, W},
title = {Telomere biology and age-related diseases.},
journal = {Clinical chemistry and laboratory medicine},
volume = {56},
number = {8},
pages = {1210-1222},
doi = {10.1515/cclm-2017-0870},
pmid = {29494336},
issn = {1437-4331},
mesh = {Aging/genetics/physiology ; Alzheimer Disease/genetics/*pathology ; Cardiovascular Diseases/genetics/*pathology ; Humans ; Leukocytes/cytology ; Neoplasms/genetics/*pathology ; Osteoporosis/genetics/*pathology ; Risk Factors ; Telomerase/physiology ; Telomere/*genetics ; *Telomere Shortening ; },
abstract = {Telomeres are the protective end caps of chromosomes and shorten with every cell division. Telomere length has been proposed as a biomarker of biological age and a risk factor for age-related diseases. Epidemiologic studies show an association between leukocyte telomere length (LTL) and mortality. There is solid evidence that links LTL with cardiovascular disease. Short telomeres promote atherosclerosis and impair the repair of vascular lesions. Alzheimer's disease patients have also a reduced LTL. Telomeres measured in tumor tissue from breast, colon and prostate are shorter than in healthy tissue from the same organ and the same patient. In healthy tissue directly adjacent to these tumors, telomeres are also shorter than in cells that are more distant from the cancerous lesion. A reduced telomere length in cancer tissue from breast, colon and prostate is associated with an advanced disease state at diagnosis, faster disease progression and poorer survival. By contrast, results regarding LTL and cancer are inconsistent. Furthermore, the majority of studies did not find significant associations between LTL, bone mineral density (BMD) and osteoporosis. The present manuscript gives an overview about our current understanding of telomere biology and reviews existing knowledge regarding the relationship between telomere length and age-related diseases.},
}
@article {pmid29494257,
year = {2018},
author = {Epel, ES and Prather, AA},
title = {Stress, Telomeres, and Psychopathology: Toward a Deeper Understanding of a Triad of Early Aging.},
journal = {Annual review of clinical psychology},
volume = {14},
number = {},
pages = {371-397},
pmid = {29494257},
issn = {1548-5951},
support = {K08 HL112961/HL/NHLBI NIH HHS/United States ; R01 AG030424/AG/NIA NIH HHS/United States ; R24 AG048024/AG/NIA NIH HHS/United States ; },
mesh = {*Adverse Childhood Experiences ; *Aging, Premature/etiology/genetics/metabolism ; Animals ; Humans ; *Mental Disorders/etiology/genetics/metabolism ; *Stress, Psychological/complications/genetics/metabolism ; *Telomerase/metabolism ; *Telomere Shortening/genetics ; },
abstract = {Telomeres play an important part in aging and show relationships to lifetime adversity, particularly childhood adversity. Meta-analyses demonstrate reliable associations between psychopathology (primarily depression) and shorter telomere length, but the nature of this relationship has not been fully understood. Here, we review and evaluate the evidence for impaired telomere biology as a consequence of psychopathology or as a contributing factor, and the important mediating roles of chronic psychological stress and impaired allostasis. There is evidence for a triadic relationship among stress, telomere shortening, and psychiatric disorders that is positively reinforcing and unfolds across the life course and, possibly, across generations. We review the role of genetics and biobehavioral responses that may contribute to shorter telomere length, as well as the neurobiological impact of impaired levels of telomerase. These complex interrelationships are important to elucidate because they have implications for mental and physical comorbidity and, potentially, for the prevention and treatment of depression.},
}
@article {pmid29490055,
year = {2018},
author = {Maekawa, T and Liu, B and Nakai, D and Yoshida, K and Nakamura, KI and Yasukawa, M and Koike, M and Takubo, K and Chatton, B and Ishikawa, F and Masutomi, K and Ishii, S},
title = {ATF7 mediates TNF-α-induced telomere shortening.},
journal = {Nucleic acids research},
volume = {46},
number = {9},
pages = {4487-4504},
pmid = {29490055},
issn = {1362-4962},
mesh = {Activating Transcription Factors/genetics/metabolism/*physiology ; Animals ; Fibroblasts ; HeLa Cells ; Histones/metabolism ; Humans ; Ku Autoantigen/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Phosphorylation ; Telomerase/metabolism ; Telomere/metabolism ; *Telomere Shortening ; Tumor Necrosis Factor-alpha/*physiology ; },
abstract = {Telomeres maintain the integrity of chromosome ends and telomere length is an important marker of aging. The epidemiological studies suggested that many types of stress including psychosocial stress decrease telomere length. However, it remains unknown how various stresses induce telomere shortening. Here, we report that the stress-responsive transcription factor ATF7 mediates TNF-α-induced telomere shortening. ATF7 and telomerase, an enzyme that elongates telomeres, are localized on telomeres via interactions with the Ku complex. In response to TNF-α, which is induced by various stresses including psychological stress, ATF7 was phosphorylated by p38, leading to the release of ATF7 and telomerase from telomeres. Thus, a decrease of ATF7 and telomerase on telomeres in response to stress causes telomere shortening, as observed in ATF7-deficient mice. These findings give credence to the idea that various types of stress might shorten telomere.},
}
@article {pmid29488130,
year = {2018},
author = {Zole, E and Ranka, R},
title = {Mitochondria, its DNA and telomeres in ageing and human population.},
journal = {Biogerontology},
volume = {19},
number = {3-4},
pages = {189-208},
doi = {10.1007/s10522-018-9748-6},
pmid = {29488130},
issn = {1573-6768},
support = {Nr. 1.1.1.1/16/A/101//ERDF Grant/International ; },
mesh = {Aging/*physiology ; *DNA Damage ; DNA, Mitochondrial/physiology ; Humans ; Mitochondria/*genetics ; *Telomere Shortening ; },
abstract = {In the last decades, studies about ageing have become more essential as our population grows older. The incidence of age-related diseases increases, which pose challenges both for societies and individuals in terms of life quality and economic impact. Understanding ageing and ageing-related processes will help us to slow down or even prevent these diseases and provide opportunities for healthy ageing; additionally, we all want to live longer. Ageing is a consequence of the interaction between processes that occur over time and genetics interacting with various disease states and an individual's lifestyle. There are several hallmarks of ageing that are generally accepted, but neither of the theories appears to be fully satisfactory. The focus of this article is on two theories of ageing: telomere shortening and mitochondrial DNA (mtDNA) alterations and dysfunction. We discuss characteristic molecular features such as mitochondrial haplogroups, telomere length, mtDNA copy number and heteroplasmy, and how all these traits come together in the ageing population. The recent evidence shows the existence of a strong linkage between these two theories suggesting common molecular mechanisms and a complicated telomere-mitochondria interplay during the humans' ageing. However, this relationship is still not completely understood, which is why it needs more attention.},
}
@article {pmid29486769,
year = {2018},
author = {Rajeevan, MS and Murray, J and Oakley, L and Lin, JS and Unger, ER},
title = {Association of chronic fatigue syndrome with premature telomere attrition.},
journal = {Journal of translational medicine},
volume = {16},
number = {1},
pages = {44},
pmid = {29486769},
issn = {1479-5876},
mesh = {Fatigue Syndrome, Chronic/*metabolism ; Female ; Humans ; Male ; Middle Aged ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {BACKGROUND: Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), is a severely debilitating condition of unknown etiology. The symptoms and risk factors of ME/CFS share features of accelerated aging implicated in several diseases. Using telomere length as a marker, this study was performed to test the hypothesis that ME/CFS is associated with accelerated aging.<br><br>METHODS: Participant (n&#xa0;=&#xa0;639) data came from the follow-up time point of the Georgia CFS surveillance study. Using the 1994 CFS Research Case Definition with questionnaire-based subscale thresholds for fatigue, function, and symptoms, participants were classified into four illness groups: CFS if all criteria were met (n&#xa0;=&#xa0;64), CFS-X if CFS with exclusionary conditions (n&#xa0;=&#xa0;77), ISF (insufficient symptoms/fatigue) if only some criteria were met regardless of exclusionary conditions (n&#xa0;=&#xa0;302), and NF (non-fatigued) if no criteria and no exclusionary conditions (n&#xa0;=&#xa0;196). Relative telomere length (T/S ratio) was measured using DNA from whole blood and real-time PCR. General linear models were used to estimate the association of illness groups or T/S ratio with demographics, biological measures and covariates with significance set at p&#xa0;<&#xa0;0.05.<br><br>RESULTS: The mean T/S ratio differed significantly by illness group (p&#xa0;=&#xa0;0.0017); the T/S ratios in CFS (0.90&#xa0;&#xb1;&#xa0;0.03) and ISF (0.94&#xa0;&#xb1;&#xa0;0.02) were each significantly lower than in NF (1.06&#xa0;&#xb1;&#xa0;0.04). Differences in T/S ratio by illness groups remained significant after adjustment for covariates of age, sex, body mass index, waist-hip ratio, post-exertional malaise and education attainment. Telomere length was shorter by 635, 254 and 424 base pairs in CFS, CFS-X and ISF, respectively, compared to NF. This shorter telomere length translates to roughly 10.1-20.5, 4.0-8.2 and 6.6-13.7&#xa0;years of additional aging in CFS, CFS-X and ISF compared to NF respectively. Further, stratified analyses based on age and sex demonstrated that the association of ME/CFS with short telomeres is largely moderated by female subjects&#xa0;<&#xa0;45&#xa0;years old.<br><br>CONCLUSIONS: This study found a significant association of ME/CFS with premature telomere attrition that is largely moderated by female subjects&#xa0;<&#xa0;45&#xa0;years old. Our results indicate that ME/CFS could be included in the list of conditions associated with accelerated aging. Further work is needed to evaluate the functional significance of accelerated aging in ME/CFS.},
}
@article {pmid29486096,
year = {2018},
author = {Chang, SC and Crous-Bou, M and Prescott, J and Rosner, B and Simon, NM and Wang, W and De Vivo, I and Okereke, OI},
title = {Prospective association of depression and phobic anxiety with changes in telomere lengths over 11 years.},
journal = {Depression and anxiety},
volume = {35},
number = {5},
pages = {431-439},
pmid = {29486096},
issn = {1520-6394},
support = {R01 CA049449/CA/NCI NIH HHS/United States ; R01 MH096776/MH/NIMH NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Cross-Sectional Studies ; Depression/blood/*epidemiology ; Depressive Disorder/blood/*epidemiology ; Female ; Humans ; *Leukocytes ; Middle Aged ; Phobic Disorders/blood/*epidemiology ; Prospective Studies ; Telomere Shortening/*physiology ; United States/epidemiology ; },
abstract = {BACKGROUND: Although depression and anxiety have been associated with shorter telomeres in cross-sectional studies, the data regarding the prospective relations of depression and anxiety to accelerated telomere length shortening are limited and findings are mixed. We prospectively examined relations of baseline depression and phobic anxiety to subsequent 11-year change in relative leukocyte telomere lengths (LTLs).<br><br>METHODS: We selected 1,250 women from a subcohort of the Nurses' Health Study who provided blood specimens at both blood collections (1989-1990 and 2000-2001). Depression was defined by self-reported regular antidepressant use or presence of severe depressive symptoms; anxiety symptoms were assessed using the Crown-Crisp Experiential Index. Using quantitative real-time polymerase chain reaction assay, LTLs were measured as the copy number ratio of telomere repeat to a single control gene. Changes in LTLs were defined in three ways: absolute change, symmetrized percent change, and decile shift.<br><br>RESULTS: Overall, there were no statistically significant associations of depression or phobic anxiety to subsequent 11-year LTL shortening, despite a point estimates in the direction of greater telomere shortening among participants with versus without depression, across all three metrics of telomere change. The strongest predictor of LTL change was baseline telomere length, and regression-to-the-mean was observed.<br><br>CONCLUSION: Baseline depression and phobic anxiety were not significantly associated with 11-year attrition in LTLs among 1,250 mid-life and older women. However, a suggestion of depression and greater subsequent LTL attrition, while not statistically significant, may warrant further inquiry, particularly in prospective studies with larger sample sizes and broader windows of the lifespan.},
}
@article {pmid29484667,
year = {2018},
author = {Guarneri-White, ME and Arana, AA and Boyd, EQ and Jensen-Campbell, LA},
title = {It's more than skin-deep: The relationship between social victimization and telomere length in adolescence.},
journal = {Aggressive behavior},
volume = {44},
number = {4},
pages = {337-347},
doi = {10.1002/ab.21755},
pmid = {29484667},
issn = {1098-2337},
mesh = {Adolescent ; Adult ; *Bullying ; Child ; *Crime Victims ; Female ; Humans ; Male ; *Peer Group ; *Telomere Shortening ; Young Adult ; },
abstract = {This study examined the relationship between peer victimization and telomere length (TL), an indicator of biological aging that is associated with stressors (Epel, 2009). It was predicted that social victimization would have a greater impact upon TL, as well as the frequency and severity of health complaints than physical victimization. Adolescents (Mage = 15.91 years, SDage = 1.65) and their parents completed measures of peer victimization and physical health problems; adolescents also submitted a DNA sample for telomere analysis. Greater instances of being socially, but not physically, victimized were associated with shorter telomeres, as well as more frequent and severe health complaints. TL was also negatively related to both the frequency and severity of health problems, even after controlling for BMI, age, and sex of participant. The relationship between social victimization and health complaints via TL held only at higher levels of social victimization. These findings are the first to find an association between peer victimization and shortened telomeres.},
}
@article {pmid29483835,
year = {2018},
author = {Si, X and Shao, C and Li, J and Jia, S and Tang, W and Zhang, J and Yang, J and Wu, X and Luo, Y},
title = {Loss of p21 promoted tumorigenesis in the background of telomere dysfunctions induced by TRF2 and Wrn deficiency.},
journal = {International journal of biological sciences},
volume = {14},
number = {2},
pages = {165-177},
pmid = {29483835},
issn = {1449-2288},
mesh = {Animals ; Carcinogenesis/*genetics ; Cyclin-Dependent Kinase Inhibitor p21/genetics/*physiology ; Gene Knockdown Techniques ; Genetic Predisposition to Disease ; Genomic Instability ; Mice ; Tumor Suppressor Protein p53/genetics ; Werner Syndrome/*genetics ; Werner Syndrome Helicase/genetics ; },
abstract = {Werner syndrome (WS) is a rare autosomal recessive progeria disease with genetic instability/cancer predisposition, thus a good model in understanding aging related carcinogenesis. Telomere dysfunction induced cellular senescence is essential in the manifestation of the WS phenotype. Our previous data has shown that p21 (encoded by Cdkn1a gene) could induce cellular senescence and suppress cellular growth of ALT (alternative lengthening of telomere) tumors derived from WS, suggested that p21 might play a key role in maintaining senescence of WS cells. To confirm the role of p21 in suppressing telomere dysfunction induced tumorigenesis, we overexpressed dominant negative protein TRF2[ΔBΔM] in p21[-/-] mouse embryonic fibroblasts (MEFs). To further stress the cell, we crossed Wrn[-/-] mice with p21[-/-] mice to obtained p21[-/-]Wrn[-/-] MEFs, and overexpressed TRF2[ΔBΔM] in these MEFs to induce telomere dysfunction similar to that in WS cells. Our data showed that, in the context of p21[-/-] TRF2[ΔBΔM], loss of p21 function rescued cellular senescence, and induced p53 mutation, but did not induce tumorigenesis. However, in the set of p21[-/-]Wrn[-/-] TRF2[ΔBΔM], loss of p21 function induced p53 mutation and tumorigenesis. To further verify the role of p21 in suppressing telomere dysfunction related tumorigenesis, we knocked down p21 in non-tumorigenic immortalized cells derived from WS MEFs (mTerc [-/-]Wrn[-/-]), and found that loss of p21 could induce ALT tumorigenesis, which displayed typical smear pattern of telomere length and arc-shaped telomeric DNA. In another hand, recovering telomerase activity in these MEFs could also induce tumorigenesis without affecting p21 expression level. Together our data suggested that p21 controlled cell cycle regulation played an essential role in suppressing telomere dysfunction-related tumorigenesis. These data also suggested that the genetic context is essential in determining the role of p21 in cancer prevention. Therefore, targeting p21 in the treatment of human degenerative diseases would require a personalized genetic background screen.},
}
@article {pmid29483670,
year = {2018},
author = {Norberg, A and Rosén, A and Raaschou-Jensen, K and Kjeldsen, L and Moilanen, JS and Paulsson-Karlsson, Y and Baliakas, P and Lohi, O and Ahmed, A and Kittang, AO and Larsson, P and Roos, G and Degerman, S and Hultdin, M},
title = {Novel variants in Nordic patients referred for genetic testing of telomere-related disorders.},
journal = {European journal of human genetics : EJHG},
volume = {26},
number = {6},
pages = {858-867},
pmid = {29483670},
issn = {1476-5438},
mesh = {Adolescent ; Adult ; Aged ; Cell Cycle Proteins/genetics ; Child ; Child, Preschool ; Dyskeratosis Congenita/*genetics/pathology ; Female ; Genetic Testing ; Humans ; Infant ; Male ; Middle Aged ; Mutation ; Nuclear Proteins/genetics ; RNA/*genetics ; Telomerase/*genetics ; Telomere/genetics ; Telomere Shortening/*genetics ; Telomere-Binding Proteins/genetics ; Young Adult ; },
abstract = {Telomere-related disorders are a clinically and genetically heterogeneous group of disorders characterized by premature telomere shortening and proliferative failure of a variety of tissues. This study reports the spectrum of telomere-related gene variants and telomere length in Nordic patients referred for genetic testing due to suspected telomere-related disorder. We performed Sanger sequencing of the genes TERT, TERC, DKC1, and TINF2 on 135 unrelated index patients and measured telomere length by qPCR on DNA from peripheral blood leukocytes. We identified pathogenic or likely pathogenic variants in 10 index patients, all of which had short telomeres compared to age-matched healthy controls. Six of the 10 variants were novel; three in TERC (n.69_74dupAGGCGC, n.122_125delGCGG, and n.407_408delinsAA) and three in TERT (p.(D684G), p.(R774*), and p.(*1133Wext*39)). The high proportion of novel variants identified in our study highlights the need for solid interpretation of new variants that may be detected. Measurement of telomere length is a useful approach for evaluating pathogenicity of genetic variants associated with telomere-related disorders.},
}
@article {pmid29482077,
year = {2018},
author = {Chang, ACY and Blau, HM},
title = {Short telomeres - A hallmark of heritable cardiomyopathies.},
journal = {Differentiation; research in biological diversity},
volume = {100},
number = {},
pages = {31-36},
pmid = {29482077},
issn = {1432-0436},
support = {R01 AR063963/AR/NIAMS NIH HHS/United States ; R21 AG044815/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Cardiomyopathies/*genetics/metabolism/pathology ; Humans ; Mitochondria, Heart/metabolism/pathology ; Telomere/genetics/pathology ; *Telomere Shortening ; },
abstract = {Cardiovascular diseases are the leading cause of death worldwide and the incidence increases with age. Genetic testing has taught us much about the pathogenic pathways that drive heritable cardiomyopathies. Here we discuss an unexpected link between shortened telomeres, a molecular marker of aging, and genetic cardiomyopathy. Positioned at the ends of chromosomes, telomeres are DNA repeats which serve as protective caps that shorten with each cell division in proliferative tissues. Cardiomyocytes are an anomaly, as they are largely non-proliferative post-birth and retain relatively stable telomere lengths throughout life in healthy individuals. However, there is mounting evidence that in disease states, cardiomyocyte telomeres significantly shorten. Moreover, this shortening may play an active role in the development of mitochondrial dysfunction central to the etiology of dilated and hypertrophic cardiomyopathies. Elucidation of the mechanisms that underlie the telomere-mitochondrial signaling axis in the heart will provide fresh insights into our understanding of genetic cardiomyopathies, and could lead to the identification of previously uncharacterized modes of therapeutic intervention.},
}
@article {pmid29481647,
year = {2018},
author = {Valerio, D and Luddi, A and De Leo, V and Labella, D and Longobardi, S and Piomboni, P},
title = {SA1/SA2 cohesion proteins and SIRT1-NAD+ deacetylase modulate telomere homeostasis in cumulus cells and are eligible biomarkers of ovarian aging.},
journal = {Human reproduction (Oxford, England)},
volume = {33},
number = {5},
pages = {887-894},
doi = {10.1093/humrep/dey035},
pmid = {29481647},
issn = {1460-2350},
mesh = {Adult ; Biomarkers/metabolism ; Cell Cycle Proteins/*metabolism ; Chromosomal Proteins, Non-Histone/*metabolism ; Cumulus Cells/*metabolism ; Female ; Humans ; Oocyte Retrieval ; Ovarian Follicle/metabolism ; Ovary/*metabolism ; Ovulation Induction ; Sirtuin 1/*metabolism ; Telomere/metabolism ; Telomere Homeostasis/*physiology ; Cohesins ; },
abstract = {STUDY QUESTION: Are cohesins SA1/SA2 and the NAD-dependent deacetylase SIRT1 involved in telomere homeostasis of cumulus cells and thus eligible as biomarkers of follicular physiology and ovarian aging?<br><br>SUMMARY ANSWER: SA1/SA2 cohesins and SIRT1 are associated with telomere length in cumulus cells and may be eligible biomarkers of follicular physiology and ovarian aging.<br><br>WHAT IS KNOWN ALREADY: In somatic cells, cohesins SA1/SA2 mediate sister chromatid cohesion at the telomere termini (for SA1) and along chromatid arms (for SA2). The NAD+-dependent protein deacetylase Sirtuin 1 (SIRT1), which preserves DNA integrity from oxidative stress, may also modulate genome stability and telomere length.<br><br>STUDY DESIGN, SIZE, DURATION: Collectively 280 cumulus/oocyte complex samples were recovered from a total of 50 women undergoing in vitro fertilization.<br><br>Cumulus cells were separated from the oocyte-cumulus complex. DNA and total mRNA were extracted from cumulus cells and assayed for telomere length and for SA1, SA2 and SIRT1 gene expression profiling. Telomere length was determined by quantitave PCR and analyzed relative to the single copy of the housekeeping gene (albumin) to generate a T/S ratio (Telomere/single copy gene). Gene expression levels of SA1, SA2 and SIRT1 mRNA were assayed by quantitative RT-PCR and confirmed by western blotting and immunofluorescent studies (SIRT1). SA1/SA2 and SIRT1 gene expression levels and telomere length analysis of patients/samples were ranked in relation to their clinical setting parameters (BMI, age) and to the number of oocyte retrieved.<br><br>SA1 and SA2 transcripts were both detected in all cumulus cells analyzed and the relative amount showed a clear decreasing trend according to the age of patients. A significant increase in SA1 and SA2 was disclosed in high responder women (>6 oocytes retrieved) compared to poor responders (<4 oocytes) (P < 0.05). Furthermore, statistically significant positive correlations were also recorded between the transcripts levels of the two cohesin molecules (r = 0.89; P < 0.05) and, to a lesser extent, between telomere length and SA1 (r = 0.42; P < 0.001) and SA2 (r = 0.36; P < 0.001) mRNA levels. SIRT1 expression was also significantly increased in high responders (>6 oocytes) compared to poor responders. Significant correlations were found between SIRT1 and SA1 (r = 0.69; P < 0.001), between SIRT1 and SA2 (r = 0.78; P < 0.001), and between SIRT1 and telomere length (r = 0.36; P < 0.001). However, in the older patient group (>38 years), SIRT1 mRNA levels were twice as high as the levels recorded in the younger patient cohort (<34 years). Western blot analysis and immunofluorescent studies confirmed the increments in SIRT1 protein levels in patients over 38 years old.<br><br>LARGE SCALE DATA: N/A.<br><br>Cumulus/oocyte complexes were retrieved by patients undergoing ovarian stimulation protocol for IVF. We cannot exclude the possibility that different stimulation protocols affect the correlations highlighted in this study. Future investigations should shed light on cumulus cells molecular profile according to different stimulation protocols.<br><br>The overall results of our study point to the involvement of cohesins SA1/SA2 and SIRT1 deacetylase in telomere homeostasis in cumulus cells and highlight their possible eligibility as biomarkers of follicular physiology and ovarian aging.<br><br>Merck Serono S.P.A Italy sponsored the study with financial support. There are no competing interests to declare.},
}
@article {pmid29480998,
year = {2018},
author = {Kritpetcharat, O and Charerntanyarak, L and Lek-Uthai, U and Sukon, P and Kitcharoen, S and Kritpetcharat, P},
title = {Chromosome Abnormalities and Absolute Telomere Lengths of Leukocytes from Silk Weavers with Emphasis on Potential Genotoxicity and Mutagenicity of Silk Dyes.},
journal = {Asian Pacific journal of cancer prevention : APJCP},
volume = {19},
number = {2},
pages = {541-548},
pmid = {29480998},
issn = {2476-762X},
mesh = {Chromosome Aberrations/*chemically induced ; Coloring Agents/*toxicity ; DNA Damage/drug effects ; Female ; Humans ; Leukocytes/*drug effects ; Male ; Middle Aged ; Mutagenesis/*drug effects ; Mutagenicity Tests/methods ; Mutagens/*toxicity ; Silk/*chemistry ; Telomere/*drug effects ; Thailand ; },
abstract = {Objectives: This study is aimed to assess the possible genotoxicity and mutagenicity of silk dyes on silk weavers. Methods: Peripheral blood leukocytes were obtained from 24 silk weavers and 24 age- and sex-matched controls in northeastern Thailand. After mitogen stimulation in culture, chromosome abnormalities were examined using Giemsa banding and the absolute telomere length (aTL) was measured with SYBR green qRT-PCR. To confirm genotoxic and mutagenic effects of silk dyes, leukocytes from one each of healthy male and female volunteers were cultured with various concentrations of 3 dark red silk dyes under the presence of mitogen. Chromosome abnormalities and the telomere length were determined as above. Results: The proportion of normal metaphase in the silk weaving workers was significantly lower than that in controls. The frequency of chromosome aberrations was higher in the silk weavers than in control group. Polyploidy was detected only in the silk weavers. The aTL was significantly shorter in the silk weavers than in control group (p < 0.05). When leukocytes from normal volunteers were stimulated with mitogen under the presence of various concentrations of 3 silk dyes, suppressed the mitotic index (MI) and normal metaphase, whereas the proportion of prophase and the incomplete chromosome forming increased significantly. All dyes induced polyploidy. Dye #CA5 induced structural changes in male leukocytes, whereas #30 induced the changes in female leukocytes. The #CA5 increased aTL of normal leukocytes in a dose-dependent manner. Conclusions: All dyes, especially #CA5, have high genotoxicity and mutagenicity to induce chromosome aberrations and telomeric instability. Taken all those results together, regular health checking of silk weavers who have been exposed to those dyes is critically necessary to prevent various chemical-induced carcinogenesis.},
}
@article {pmid29478886,
year = {2019},
author = {Freitas-Simoes, TM and Cofán, M and Blasco, MA and Soberón, N and Foronda, M and Corella, D and Asensio, EM and Serra-Mir, M and Roth, I and Calvo, C and Valls-Pedret, C and Casaroli-Marano, RP and Doménech, M and Rajaram, S and Sabaté, J and Ros, E and Sala-Vila, A},
title = {The red blood cell proportion of arachidonic acid relates to shorter leukocyte telomeres in Mediterranean elders: A secondary analysis of a randomized controlled trial.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {38},
number = {2},
pages = {958-961},
doi = {10.1016/j.clnu.2018.02.011},
pmid = {29478886},
issn = {1532-1983},
mesh = {Aged ; Aging/*physiology ; Arachidonic Acid/*blood ; Cross-Sectional Studies ; Erythrocytes/*chemistry ; Female ; Humans ; Leukocytes/*chemistry ; Male ; Middle Aged ; Spain/epidemiology ; Telomere/*chemistry ; },
abstract = {BACKGROUND &amp; AIMS: Shortening of leukocyte telomere length (LTL) is a biomarker of aging. Epidemiologic studies of LTL in relation to dietary fatty acids have reported conflicting results. The red blood cell (RBC) fatty acid status is a valid objective biomarker of long-term dietary intake of C18:2n-6, C18:3n-3 and long-chain n-3 polyunsaturated fatty acids (C20:5n-3 and C22:6n-3). In healthy older individuals, we investigated whether LTL relates to the RBC proportions of the main dietary polyunsaturated fatty acids (PUFA), and to the RBC proportion of arachidonic acid (C20:4n-6), a fatty acid that can generate pro-inflammatory lipid mediators once released from cell membranes.<br><br>DESIGN: Cross-sectional study in 344 subjects (mean age 68.8&#xa0;y, 68.6% women) who participated in a randomized controlled trial testing whether a diet enriched in walnuts can delay the onset of age-related diseases (https://clinicaltrials.gov/ct2/show/NCT01634841). At baseline, we assessed LTL by high-throughput quantitative fluorescence and determined fatty acids in RBCs by gas chromatography.<br><br>RESULTS: In multivariate models adjusted for age and gender, the RBC proportions of dietary PUFA were unrelated to LTL. In contrast, the RBC proportion of arachidonic acid inversely related to LTL (regression coefficient [95% confidence interval],&#xa0;-0.10 (-0.19 to&#xa0;-0.01), P&#xa0;=&#xa0;0.023).<br><br>CONCLUSION: An increasing proportion of C20:4n-6 in RBCs is associated with shorter telomeres. Further research is needed to investigate the role of this fatty acid and its derived lipid mediators in the aging process.},
}
@article {pmid29476624,
year = {2018},
author = {Henckel, E and Svenson, U and Nordlund, B and Berggren Broström, E and Hedlin, G and Degerman, S and Bohlin, K},
title = {Telomere length was similar in school-age children with bronchopulmonary dysplasia and allergic asthma.},
journal = {Acta paediatrica (Oslo, Norway : 1992)},
volume = {107},
number = {8},
pages = {1395-1401},
doi = {10.1111/apa.14294},
pmid = {29476624},
issn = {1651-2227},
mesh = {Age Factors ; Asthma/*genetics/immunology/*physiopathology ; Bronchopulmonary Dysplasia/*genetics/*physiopathology ; Case-Control Studies ; Cellular Senescence/genetics ; Child ; Female ; Follow-Up Studies ; Humans ; Infant, Newborn ; *Infant, Premature ; Inflammation Mediators/analysis ; Male ; Respiratory Function Tests ; Retrospective Studies ; Risk Assessment ; Sweden ; Telomere/*genetics ; Term Birth ; },
abstract = {AIM: Inflammation is a major factor in the pathophysiology of bronchopulmonary dysplasia (BPD), and it contributes to accelerated telomere shortening and cellular ageing. This study aimed to determine its effect on telomere length and lung function in school-aged children born preterm with BPD.<br><br>METHODS: We examined 29 children with BPD, born preterm in Stockholm county 1998-99, along with 28 children with allergic asthma born at term matched for age and gender. At 10&#xa0;years of age, we measured relative telomere length (RTL) in blood by quantitative polymerase chain reaction, lung function by spirometry and inflammation by fractional exhaled nitric oxide and blood cytokines.<br><br>RESULTS: RTL was not different in preterm born with BPD compared to term born children with asthma. The gender effect was strong in both groups; girls had significantly longer median RTL than boys (1.8 versus 1.5, p&#xa0;<&#xa0;0.01). Short RTL was associated with low forced expiratory flow, also after adjusting for gender, but was not affected by severity of BPD or ongoing inflammation.<br><br>CONCLUSION: Telomere length was similar in 10-year-old children born preterm with a history of BPD and term born children with allergic asthma. However, impaired lung function and male gender were associated with short telomeres.},
}
@article {pmid29474209,
year = {2018},
author = {Hoffman, TW and van Moorsel, CHM and Borie, R and Crestani, B},
title = {Pulmonary phenotypes associated with genetic variation in telomere-related genes.},
journal = {Current opinion in pulmonary medicine},
volume = {24},
number = {3},
pages = {269-280},
doi = {10.1097/MCP.0000000000000475},
pmid = {29474209},
issn = {1531-6971},
mesh = {DNA Helicases/genetics ; Genotype ; Humans ; Lung Diseases/*genetics ; Mutation ; Phenotype ; Polymorphism, Single Nucleotide ; RNA/genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomere Shortening ; Telomere-Binding Proteins/genetics ; },
abstract = {PURPOSE OF REVIEW: Genomic mutations in telomere-related genes have been recognized as a cause of familial forms of idiopathic pulmonary fibrosis (IPF). However, it has become increasingly clear that telomere syndromes and telomere shortening are associated with various types of pulmonary disease. Additionally, it was found that also single nucleotide polymorphisms (SNPs) in telomere-related genes are risk factors for the development of pulmonary disease. This review focuses on recent updates on pulmonary phenotypes associated with genetic variation in telomere-related genes.<br><br>RECENT FINDINGS: Genomic mutations in seven telomere-related genes cause pulmonary disease. Pulmonary phenotypes associated with these mutations range from many forms of pulmonary fibrosis to emphysema and pulmonary vascular disease. Telomere-related mutations account for up to 10% of sporadic IPF, 25% of familial IPF, 10% of connective-tissue disease-associated interstitial lung disease, and 1% of COPD. Mixed disease forms have also been found. Furthermore, SNPs in TERT, TERC, OBFC1, and RTEL1, as well as short telomere length, have been associated with several pulmonary diseases. Treatment of pulmonary disease caused by telomere-related gene variation is currently based on disease diagnosis and not on the underlying cause.<br><br>SUMMARY: Pulmonary phenotypes found in carriers of telomere-related gene mutations and SNPs are primarily pulmonary fibrosis, sometimes emphysema and rarely pulmonary vascular disease. Genotype-phenotype relations are weak, suggesting that environmental factors and genetic background of patients determine disease phenotypes to a large degree. A disease model is presented wherever genomic variation in telomere-related genes cause specific pulmonary disease phenotypes whenever triggered by environmental exposure, comorbidity, or unknown factors.},
}
@article {pmid29463756,
year = {2018},
author = {Alder, JK and Hanumanthu, VS and Strong, MA and DeZern, AE and Stanley, SE and Takemoto, CM and Danilova, L and Applegate, CD and Bolton, SG and Mohr, DW and Brodsky, RA and Casella, JF and Greider, CW and Jackson, JB and Armanios, M},
title = {Diagnostic utility of telomere length testing in a hospital-based setting.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {115},
number = {10},
pages = {E2358-E2365},
pmid = {29463756},
issn = {1091-6490},
support = {R01 CA160433/CA/NCI NIH HHS/United States ; T32 GM007309/GM/NIGMS NIH HHS/United States ; K23 HL123601/HL/NHLBI NIH HHS/United States ; R37 AG009383/AG/NIA NIH HHS/United States ; R01 HL119476/HL/NHLBI NIH HHS/United States ; R00 HL113105/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Child ; Child, Preschool ; Female ; Hospitals/statistics &amp; numerical data ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; Male ; Middle Aged ; Mutation ; Pulmonary Emphysema/diagnosis/genetics/*metabolism ; Pulmonary Fibrosis/diagnosis/genetics/*metabolism ; Telomerase/genetics/metabolism ; Telomere/chemistry/*metabolism ; *Telomere Shortening ; Young Adult ; },
abstract = {Telomere length (TL) predicts the onset of cellular senescence in vitro but the diagnostic utility of TL measurement in clinical settings is not fully known. We tested the value of TL measurement by flow cytometry and FISH (flowFISH) in patients with mutations in telomerase and telomere maintenance genes. TL had a discrete and reproducible normal range with definable upper and lower boundaries. While TL above the 50th age-adjusted percentile had a 100% negative predictive value for clinically relevant mutations, the lower threshold in mutation carriers was age-dependent, and adult mutation carriers often overlapped with the lowest decile of controls. The extent of telomere shortening correlated with the age at diagnosis as well as the short telomere syndrome phenotype. Extremely short TL caused bone marrow failure and immunodeficiency in children and young adults, while milder defects manifested as pulmonary fibrosis-emphysema in adults. We prospectively examined whether TL altered treatment decisions for newly diagnosed idiopathic bone marrow failure patients and found abnormally short TL enriched for patients with mutations in some inherited bone marrow failure genes, such as RUNX1, in addition to telomerase and telomere maintenance genes. The result was actionable, altering the choice of treatment regimen and/or hematopoietic stem cell donor in one-fourth of the cases (9 of 38, 24%). We conclude that TL measurement by flowFISH, when used for targeted clinical indications and in limited settings, can influence treatment decisions in ways that improve outcome.},
}
@article {pmid29463275,
year = {2018},
author = {Verstraete, S and Vanhorebeek, I and van Puffelen, E and Derese, I and Ingels, C and Verbruggen, SC and Wouters, PJ and Joosten, KF and Hanot, J and Guerra, GG and Vlasselaers, D and Lin, J and Van den Berghe, G},
title = {Leukocyte telomere length in paediatric critical illness: effect of early parenteral nutrition.},
journal = {Critical care (London, England)},
volume = {22},
number = {1},
pages = {38},
pmid = {29463275},
issn = {1466-609X},
support = {METH/08/07//Vlaamse Overheid/International ; METH14/06//Vlaamse Overheid/International ; METH14/06//Vlaamse Overheid/International ; IWT/070695/TBM//Vlaamse Overheid/International ; AdvG-2012-321670//FP7 Ideas: European Research Council/International ; },
mesh = {Adolescent ; Child ; Child, Preschool ; Critical Illness/therapy ; Female ; Humans ; Infant ; Intensive Care Units, Pediatric/organization &amp; administration ; Leukocytes/*pathology ; Male ; Parenteral Nutrition/*methods ; Pediatrics/methods/trends ; Propensity Score ; Survival Analysis ; Telomere/classification/*pathology ; *Time Factors ; },
abstract = {BACKGROUND: Children who have suffered from critical illnesses that required treatment in a paediatric intensive care unit (PICU) have long-term physical and neurodevelopmental impairments. The mechanisms underlying this legacy remain largely unknown. In patients suffering from chronic diseases hallmarked by inflammation and oxidative stress, poor long-term outcome has been associated with shorter telomeres. Shortened telomeres have also been reported to result from excessive food consumption and/or unhealthy nutrition. We investigated whether critically ill children admitted to the PICU have shorter-than-normal telomeres, and whether early parenteral nutrition (PN) independently affects telomere length when adjusting for known determinants of telomere length.<br><br>METHODS: Telomere length was quantified in leukocyte DNA from 342 healthy children and from 1148 patients who had been enrolled in the multicenter, randomised controlled trial (RCT), PEPaNIC. These patients were randomly allocated to initiation of PN within 24 h (early PN) or to withholding PN for one week in PICU (late PN). The impact of early PN versus late PN on the change in telomere length from the first to last PICU-day was investigated with multivariable linear regression analyses.<br><br>RESULTS: Leukocyte telomeres were 6% shorter than normal upon PICU admission (median 1.625 (IQR 1.446-1.825) telomere/single-copy-gene ratio (T/S) units vs. 1.727 (1.547-1.915) T/S-units in healthy children (P <&#x2009;0.0001)). Adjusted for potential baseline determinants and leukocyte composition, early PN was associated with telomere shortening during PICU stay as compared with late PN (estimate early versus late PN -0.021 T/S-units, 95% CI -0.038; 0.004, P = 0.01). Other independent determinants of telomere length identified in this model were age, gender, baseline telomere length and fraction of neutrophils in the sample from which the DNA was extracted. Telomere shortening with early PN was independent of post-randomisation factors affected by early PN, including longer length of PICU stay, larger amounts of insulin and higher risk of infection.<br><br>CONCLUSIONS: Shorter than normal leukocyte telomeres are present in critically ill children admitted to the PICU. Early initiation of PN further shortened telomeres, an effect that was independent of other determinants. Whether such telomere-shortening predisposes to long-term consequences of paediatric critical illness should be further investigated in a prospective follow-up study.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov, NCT01536275 . Registered on 16 February 2012.},
}
@article {pmid29463269,
year = {2018},
author = {Teubel, I and Elchinova, E and Roura, S and Fernández, MA and Gálvez-Montón, C and Moliner, P and de Antonio, M and Lupón, J and Bayés-Genís, A},
title = {Telomere attrition in heart failure: a flow-FISH longitudinal analysis of circulating monocytes.},
journal = {Journal of translational medicine},
volume = {16},
number = {1},
pages = {35},
pmid = {29463269},
issn = {1479-5876},
support = {SAF2014-59892//Ministerio de Econom&#xed;a y Competitividad (ES)/International ; 201502//Fundaci&#xf3; La MARAT&#xd3; de TV3/International ; 201516//Fundaci&#xf3; La MARAT&#xd3; de TV3/International ; CB16/11/00403//CIBER Cardiovascular/International ; },
mesh = {Aged ; Female ; Heart Failure/*metabolism ; Hospitalization ; Humans ; *In Situ Hybridization, Fluorescence ; Longitudinal Studies ; Male ; Monocytes/*metabolism ; Proportional Hazards Models ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {BACKGROUND: Cross-sectional investigations report shorter telomeres in patients with heart failure (HF); however, no studies describe telomere length (TL) trajectory and its relationship with HF progression. Here we aimed to investigate telomere shortening over time and its relationship to outcomes.<br><br>METHODS: Our study cohort included 101 ambulatory patients with HF. Blood samples were collected at baseline (n&#xa0;=&#xa0;101) and at the 1-year follow-up (n&#xa0;=&#xa0;54). Using flow-FISH analysis of circulating monocytes, we simultaneously measured three monocyte subsets-classical (CD14[++]CD16[-]), intermediate (CD14[++]CD16[+]), and nonclassical (CD14[+]CD16[++])-and their respective TLs based on FITC-labeled PNA probe hybridization. The primary endpoints were all-cause death and the composite of all-cause death or HF-related hospitalization, assessed at 2.3&#xa0;&#xb1;&#xa0;0.6&#xa0;years. All statistical analyses were executed by using the SPSS 15.0 software, and included Student's t test and ANOVA with post hoc Scheffe analysis, Pearson or Spearman rho correlation and univariate Cox regression when applicable.<br><br>RESULTS: We found high correlations between TL values of different monocyte subsets: CD14[++]CD16[+] vs. CD14[++]CD16[-], R&#xa0;=&#xa0;0.95, p&#xa0;<&#xa0;0.001; CD14[++]CD16[+] vs. CD14[+]CD16[++], R&#xa0;=&#xa0;0.90, p&#xa0;<&#xa0;0.001; and CD14[++]CD16[-] vs. CD14[+]CD16[++], R&#xa0;=&#xa0;0.89, p&#xa0;<&#xa0;0.001. Mean monocyte TL exhibited significant attrition from baseline to the 1-year follow-up (11.1&#xa0;&#xb1;&#xa0;3.3 vs. 8.3&#xa0;&#xb1;&#xa0;2.1, p&#xa0;<&#xa0;0.001). TL did not significantly differ between monocyte subsets at either sampling time-point (all p values&#xa0;>&#xa0;0.1). Cox regression analyses did not indicate that TL or &#x394;TL was associated with all-cause death or the composite endpoint.<br><br>CONCLUSIONS: Overall, this longitudinal study demonstrated a&#xa0;~&#xa0;22% reduction of TL in monocytes from ambulatory patients with HF within 1&#xa0;year. TL and &#x394;TL were not related to outcomes over long-term follow-up.},
}
@article {pmid29463038,
year = {2018},
author = {Ferreira, MSV and Crysandt, M and Braunschweig, T and Jost, E and Voss, B and Bouillon, AS and Knuechel, R and Brümmendorf, TH and Beier, F},
title = {Presence of TERT Promoter Mutations is a Secondary Event and Associates with Elongated Telomere Length in Myxoid Liposarcomas.},
journal = {International journal of molecular sciences},
volume = {19},
number = {2},
pages = {},
pmid = {29463038},
issn = {1422-0067},
mesh = {Base Sequence ; Bone Neoplasms/genetics ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Liposarcoma, Myxoid/*genetics ; Male ; Middle Aged ; Mutation/*genetics ; Neoplasm Grading ; *Promoter Regions, Genetic ; Sarcoma/genetics ; Telomerase/*genetics ; Telomere/*metabolism ; },
abstract = {The occurrence of TERT promoter mutations has been well described in soft tissue sarcomas (STS). However, the biological role of these mutations as well as their impact on telomere length in STS is still unclear. We analyzed 116 patient samples diagnosed with 22 distinct histological subtypes of bone and STS for the occurrence of TERT promoter mutations by Sanger sequencing. We observed TERT promoter mutations at an overall frequency of 9.5% distributed over 7 different sarcoma subtypes. Except for one chondrosarcoma case harboring a C250T mutation, all other mutations were detected at location C228T. By far the far highest frequency of TERT promoter mutations was found in myxoid liposarcoma (MLS) (4 out of 9 cases studied, i.e., 44%). Assessment of telomere length from tumor biopsies revealed that TERT promoter-mutated MLSs had significantly fewer shortened telomeres in comparison to TERT wildtype MLSs. Based on the frequency of TERT promoter mutations and the elongated telomere length in mutated compared to wildtype MLS, we hypothesize that occurrence of TERT promoter mutations has a pivotal role in the disease progression as a secondary genetic event at a time when tumor cells face the need for telomere elongation to allow further proliferation.},
}
@article {pmid29463031,
year = {2018},
author = {De Vitis, M and Berardinelli, F and Sgura, A},
title = {Telomere Length Maintenance in Cancer: At the Crossroad between Telomerase and Alternative Lengthening of Telomeres (ALT).},
journal = {International journal of molecular sciences},
volume = {19},
number = {2},
pages = {},
pmid = {29463031},
issn = {1422-0067},
mesh = {Animals ; Humans ; Neoplasms/*metabolism ; Phenotype ; Telomerase/*metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Eukaryotic cells undergo continuous telomere shortening as a consequence of multiple rounds of replications. During tumorigenesis, cells have to acquire telomere DNA maintenance mechanisms (TMMs) in order to counteract telomere shortening, to preserve telomeres from DNA damage repair systems and to avoid telomere-mediated senescence and/or apoptosis. For this reason, telomere maintenance is an essential step in cancer progression. Most human tumors maintain their telomeres expressing telomerase, whereas a lower but significant proportion activates the alternative lengthening of telomeres (ALT) pathway. However, evidence about the coexistence of ALT and telomerase has been found both in vivo in the same cancer populations and in vitro in engineered cellular models, making the distinction between telomerase- and ALT-positive tumors elusive. Indeed, after the development of drugs able to target telomerase, the capability for some cancer cells to escape death, switching from telomerase to ALT, was highlighted. Unfortunately, to date, the mechanism underlying the possible switching or the coexistence of telomerase and ALT within the same cell or populations is not completely understood and different factors could be involved. In recent years, different studies have tried to shed light on the complex regulation network that controls the transition between the two TMMs, suggesting a role for embryonic cancer origin, epigenetic modifications, and specific genes activation-both in vivo and in vitro. In this review, we examine recent findings about the cancer-associated differential activation of the two known TMMs and the possible factors implicated in this process. Furthermore, some studies on cancers are also described that did not display any TMM.},
}
@article {pmid29459277,
year = {2018},
author = {Kaulage, MH and Maji, B and Pasadi, S and Ali, A and Bhattacharya, S and Muniyappa, K},
title = {Targeting G-quadruplex DNA structures in the telomere and oncogene promoter regions by benzimidazole‒carbazole ligands.},
journal = {European journal of medicinal chemistry},
volume = {148},
number = {},
pages = {178-194},
doi = {10.1016/j.ejmech.2018.01.091},
pmid = {29459277},
issn = {1768-3254},
mesh = {Antineoplastic Agents/*chemistry/metabolism ; Benzimidazoles/*metabolism/pharmacology ; Carbazoles/*metabolism/pharmacology ; G-Quadruplexes/*drug effects ; Humans ; Ligands ; Molecular Docking Simulation ; Oncogene Proteins/*antagonists &amp; inhibitors ; Oncogenes/*genetics ; Promoter Regions, Genetic/*genetics ; Telomere/chemistry/*genetics ; },
abstract = {Recent studies support the idea that G-quadruplex structures in the promoter regions of oncogenes and telomere DNA can serve as potential therapeutic targets in the treatment of cancer. Accordingly, several different types of organic small molecules that stabilize G-quadruplex structures and inhibit telomerase activity have been discerned. Here, we describe the binding of benzimidazole-carbazole ligands to G-quadruplex structures formed in G-rich DNA sequences containing the promoter regions of human c-MYC, c-KIT1, c-KIT2, VEGF and BCL2 proto-oncogenes. The fluorescence spectroscopic data indicate that benzimidazole-carbazole ligands bind and stabilize the G-quadruplexes in the promoter region of oncogenes. The molecular docking studies provide insights into the mode and extent of binding of this class of ligands to the G-quadruplexes formed in oncogene promoters. The high stability of these G-quadruplex structures was validated by thermal denaturation and telomerase-catalyzed extension of the 3' end. Notably, benzimidazole-carbazole ligands suppress the expression of oncogenes in cancer cells in a dose-dependent manner. We anticipate that benzimidazole-carbazole ligands, by virtue of their ability to stabilize G-quadruplex structures in the promoter regions of oncogenes, might reduce the risk of cancer through the loss of function in the proteins encoded by these genes.},
}
@article {pmid29458755,
year = {2018},
author = {Verma, P and Dilley, RL and Gyparaki, MT and Greenberg, RA},
title = {Direct Quantitative Monitoring of Homology-Directed DNA Repair of Damaged Telomeres.},
journal = {Methods in enzymology},
volume = {600},
number = {},
pages = {107-134},
pmid = {29458755},
issn = {1557-7988},
support = {F30 GM120905/GM/NIGMS NIH HHS/United States ; R01 CA138835/CA/NCI NIH HHS/United States ; R01 CA174904/CA/NCI NIH HHS/United States ; R01 GM101149/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Culture Techniques/instrumentation/methods ; Cell Line, Tumor ; Click Chemistry/instrumentation/methods ; DNA/*analysis/chemistry/metabolism ; DNA Breaks, Double-Stranded ; DNA Replication ; Deoxyuridine/*analysis ; Humans ; Intravital Microscopy/instrumentation/*methods ; Microscopy, Fluorescence/instrumentation/methods ; *Recombinational DNA Repair ; Single Molecule Imaging/instrumentation/methods ; Telomere/*metabolism ; },
abstract = {Homology-directed DNA repair (HDR) is an evolutionary conserved mechanism that is required for genome integrity and organismal fitness across species. While a myriad of different factors and mechanisms are able to execute HDR, all forms necessitate common steps of DNA damage recognition, homology search and capture, and assembly of a DNA polymerase complex to conduct templated DNA synthesis. The central question of what determines HDR mechanism utilization in mammalian cells has been limited by an inability to directly monitor the DNA damage response and products of repair as they arise from a defined genomic lesion. In this chapter, we describe several methodologies to delineate major steps of HDR during alternative lengthening of telomeres in human cells. This includes procedures to visualize interchromosomal telomere homology searches in real time and quantitatively detect HDR synthesis of nascent telomeres emanating from synchronous activation of telomere DNA double-strand breaks. We highlight the critical details of these methods and their applicability to monitoring HDR at telomeres in a broad variety of mammalian cell types.},
}
@article {pmid29454386,
year = {2018},
author = {Wang, Y and Zhao, Z and Zhu, Z and Li, P and Li, X and Xue, X and Duo, J and Ma, Y},
title = {Telomere elongation protects heart and lung tissue cells from fatal damage in rats exposed to severe hypoxia.},
journal = {Journal of physiological anthropology},
volume = {37},
number = {1},
pages = {5},
pmid = {29454386},
issn = {1880-6805},
support = {81760334//National Natural Science Foundation of China/ ; 2015-ZJ-941Q//Natural Science Youth Foundation of Qinghai Province, China/ ; },
mesh = {Altitude ; Animals ; Aryl Hydrocarbon Receptor Nuclear Translocator/analysis/metabolism ; Heart/*physiology ; Hypoxia/*physiopathology ; Hypoxia-Inducible Factor 1, alpha Subunit/analysis/metabolism ; Lung/cytology/pathology/*physiology ; Male ; Myocardium/cytology/pathology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/analysis/metabolism ; Telomerase/analysis/metabolism ; Telomere/*physiology ; },
abstract = {BACKGROUND: The effects of acute hypoxia at high altitude on the telomere length of the cells in the heart and lung tissues remain unclear. This study aimed to investigate the change in telomere length of rat heart and lung tissue cells in response to acute exposure to severe hypoxia and its role in hypoxia-induced damage to heart and lung tissues.<br><br>METHODS: Forty male Wistar rats (6-week old) were randomized into control group (n&#x2009;=&#x2009;10) and hypoxia group (n&#x2009;=&#x2009;30). Rats in control group were kept at an altitude of 1500&#xa0;m, while rats in hypoxia group were exposed to simulated hypoxia with an altitude of 5000&#xa0;m in a low-pressure oxygen chamber for 1, 3, and 7&#xa0;days (n&#x2009;=&#x2009;10). The left ventricular and right middle lobe tissues of each rat were collected for measurement of telomere length and reactive oxygen species (ROS) content, and the mRNA and protein levels of telomerase reverse transcriptase (TERT), hypoxia-inducible factor1&#x3b1; (HIF-1&#x3b1;), and hypoxia-inducible factor1&#x3b1; (HIF-2&#x3b1;).<br><br>RESULTS: Increased exposure to hypoxia damaged rat heart and lung tissue cells and increased ROS production and telomere length. The mRNA and protein levels of TERT and HIF-1&#x3b1; were significantly higher in rats exposed to hypoxia and increased with prolonged exposure; mRNA and protein levels of HIF-2&#x3b1; increased only in rats exposed to hypoxia for 7&#xa0;days. TERT was positively correlated with telomere length and the levels of HIF-1&#x3b1; but not HIF-2&#x3b1;.<br><br>CONCLUSIONS: Acute exposure to severe hypoxia causes damage to heart and lung tissues due to the production of ROS but promotes telomere length and adaptive response by upregulating TERT and HIF-1&#x3b1;, which protect heart and lung tissue cells from fatal damage.},
}
@article {pmid29453108,
year = {2018},
author = {Aix, E and Gallinat, A and Flores, I},
title = {Telomeres and telomerase in heart regeneration.},
journal = {Differentiation; research in biological diversity},
volume = {100},
number = {},
pages = {26-30},
doi = {10.1016/j.diff.2018.01.003},
pmid = {29453108},
issn = {1432-0436},
mesh = {Animals ; Cell Proliferation ; Heart/physiology ; Humans ; Myocytes, Cardiac/*metabolism/physiology ; *Regeneration ; Telomerase/genetics/*metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Although recent advances have overturned the old view of the human heart as an inert postmitotic organ, it is clear that the adult heart´s capacity to regenerate after an ischemic episode is very limited. Unlike humans, zebrafish and other lower vertebrates vigorously regenerate damaged myocardium after cardiac injury. Understanding how the zebrafish is able to conserve life-long cardiac regeneration capacity while mammals lose it soon after birth is crucial for the development of new treatments for myocardial infarction. Mammals and lower vertebrates differ markedly in their rates of cardiomyocyte proliferation and levels of telomerase activity. Here, we review recent discoveries identifying lack of telomerase activity and concomitant telomere dysfunction as natural barriers to cardiomyocyte proliferation and cardiac regeneration.},
}
@article {pmid29452389,
year = {2018},
author = {Pollack, AZ and Rivers, K and Ahrens, KA},
title = {Parity associated with telomere length among US reproductive age women.},
journal = {Human reproduction (Oxford, England)},
volume = {33},
number = {4},
pages = {736-744},
doi = {10.1093/humrep/dey024},
pmid = {29452389},
issn = {1460-2350},
mesh = {Adult ; Cellular Senescence/physiology ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/*metabolism ; Live Birth ; Nutrition Surveys ; Parity/*physiology ; Pregnancy ; Pregnancy Outcome ; Telomere/*metabolism ; Telomere Shortening ; United States ; Young Adult ; },
abstract = {STUDY QUESTION: Is telomere length related to parity among a nationally representative sample of US reproductive age women?<br><br>SUMMARY ANSWER: History of live birth was associated with shorter telomere length.<br><br>WHAT IS KNOWN ALREADY: Shorter telomeres have been linked with a range of chronic health conditions and mortality and parity has been associated with health indicators. However, there is a lack of research on how parity relates to telomere length.<br><br>STUDY DESIGN, SIZE, DURATION: This nationally representative, cross-sectional study included 1954 women from the National Health and Nutrition Examination Survey, 1999-2002, the only survey period which includes measurement of telomere length.<br><br>Women aged 20-44 were included. Parity, defined as number of previous live births, was ascertained by questionnaire. Leukocyte telomere length was measured by polymerase chain reaction and reported as a ratio in relation to standard reference DNA (T/S ratio). The relationship between leukocyte T/S ratio and parity was examined using survey weighted linear regression. Models were adjusted for race/ethnicity, age, BMI, income-to-poverty ratio, education, early age at menarche and smoking status.<br><br>Among reproductive age women in the US, the adjusted mean leukocyte T/S ratio was 4.2% (95% CI: 0.9, 7.3) shorter in parous compared with nulliparous women. Parity was associated with 116 fewer base pairs (95% CI: 26, 204) on average, using estimated coefficients from the adjusted linear regression models and mean covariate values.<br><br>This study was cross-sectional and therefore was unable to establish temporality. The dataset lacked information on social factors, stress and fertility status, which may help explain these findings. Only two previous studies have examined this question and our findings should be interpreted with caution.<br><br>These findings in a nationally representative sample of US reproductive age women suggest that history of live birth may be associated with accelerated cellular aging. The magnitude of the observed association was greater than that of the impact of smoking or obesity on telomere length, suggesting that parity may have an independent influence on cellular aging and warrant further study.<br><br>The study was funded in part by the Undergraduate Research Scholars Program at George Mason University. The authors have no conflicts of interest.<br><br>TRIAL REGISTRATION NUMBER: NA.},
}
@article {pmid29451299,
year = {2018},
author = {Murdock, KW and Seiler, A and Chirinos, DA and Garcini, LM and Acebo, SL and Cohen, S and Fagundes, CP},
title = {Low childhood subjective social status and telomere length in adulthood: The role of attachment orientations.},
journal = {Developmental psychobiology},
volume = {60},
number = {3},
pages = {340-346},
pmid = {29451299},
issn = {1098-2302},
support = {UL1 RR024153/RR/NCRR NIH HHS/United States ; R01 HL127260/HL/NHLBI NIH HHS/United States ; R01 AT006694/AT/NCCIH NIH HHS/United States ; F32 HL131353/HL/NHLBI NIH HHS/United States ; P50 HL065111/HL/NHLBI NIH HHS/United States ; P50 HL065112/HL/NHLBI NIH HHS/United States ; R01 AI066367/AI/NIAID NIH HHS/United States ; },
mesh = {Adult ; *Adult Survivors of Child Adverse Events ; Anxiety/*physiopathology ; Female ; Humans ; *Interpersonal Relations ; Leukocytes, Mononuclear ; Male ; *Object Attachment ; *Social Class ; *Telomere ; Telomere Shortening/*physiology ; Young Adult ; },
abstract = {Low subjective social status (SSS) in childhood places one at greater risk of a number of health problems in adulthood. Theoretical and empirical evidence indicates that exposure to supportive parenting may buffer the negative effects of low childhood SSS on adult health. Given the importance of supportive caregivers and close others for the development of attachment orientations throughout the lifespan, attachment theory may be important for understanding why some individuals are resilient to the negative effects of low childhood SSS on adult health while others are not. We examined if attachment anxiety and attachment avoidance altered the association between childhood subjective social status (SSS) and length of telomeres in white blood cells in adulthood. Shorter telomere length is associated with increased risk of age-related diseases including cancer, type 2 diabetes, and cardiovascular disease. Participants (N = 128) completed self-report measures of childhood SSS and attachment orientations, as well as a blood draw. We found that among those with low childhood SSS, low attachment anxiety was associated with longer telomere length in white blood cells in comparison to high attachment anxiety controlling for participant age, sex, race, body mass index, and adult SSS. Among those with high childhood SSS, low attachment anxiety was associated with a slight decrease in telomere length. Attachment avoidance was unrelated to length of telomeres. Such findings provide further evidence for the role that close relationships may have on buffering SSS related health disparities.},
}
@article {pmid29449360,
year = {2018},
author = {Hägg, S},
title = {Telomere Length Dynamics and Atherosclerotic Disease.},
journal = {Circulation research},
volume = {122},
number = {4},
pages = {546-547},
doi = {10.1161/CIRCRESAHA.118.312567},
pmid = {29449360},
issn = {1524-4571},
mesh = {*Atherosclerosis ; Humans ; Leukocytes ; Muscles ; *Telomere ; },
}
@article {pmid29447390,
year = {2018},
author = {Zhou, Z and Wang, L and Ge, F and Gong, P and Wang, H and Wang, F and Chen, L and Liu, L},
title = {Pold3 is required for genomic stability and telomere integrity in embryonic stem cells and meiosis.},
journal = {Nucleic acids research},
volume = {46},
number = {7},
pages = {3468-3486},
pmid = {29447390},
issn = {1362-4962},
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins/genetics ; CRISPR-Cas Systems/genetics ; DNA Breaks, Double-Stranded ; DNA Damage/genetics ; DNA Polymerase III/*genetics ; DNA Repair/genetics ; DNA Replication/*genetics ; Embryonic Stem Cells/*metabolism ; Genomic Instability/*genetics ; Meiosis/genetics ; Mice, Knockout ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; Tumor Suppressor p53-Binding Protein 1/genetics ; },
abstract = {Embryonic stem cells (ESCs) and meiosis are featured by relatively higher frequent homologous recombination associated with DNA double strand breaks (DSB) repair. Here, we show that Pold3 plays important roles in DSB repair, telomere maintenance and genomic stability of both ESCs and spermatocytes in mice. By attempting to generate Pold3 deficient mice using CRISPR/Cas9 or transcription activator-like effector nucleases, we show that complete loss of Pold3 (Pold3-/-) resulted in early embryonic lethality at E6.5. Rapid DNA damage response and massive apoptosis occurred in both outgrowths of Pold3-null (Pold3-/-) blastocysts and Pold3 inducible knockout (iKO) ESCs. While Pold3-/- ESCs were not achievable, Pold3 iKO led to increased DNA damage response, telomere loss and chromosome breaks accompanied by extended S phase. Meanwhile, loss of Pold3 resulted in replicative stress, micronucleation and aneuploidy. Also, DNA repair was impaired in Pold3+/- or Pold3 knockdown ESCs. Moreover, Pold3 mediates DNA replication and repair by regulating 53BP1, RIF1, ATR and ATM pathways. Furthermore, spermatocytes of Pold3 haploinsufficient (Pold3+/-) mice with increasing age displayed impaired DSB repair, telomere shortening and loss, and chromosome breaks, like Pold3 iKO ESCs. These data suggest that Pold3 maintains telomere integrity and genomic stability of both ESCs and meiosis by suppressing replicative stress.},
}
@article {pmid29444496,
year = {2018},
author = {Qu, F and Chen, Z and You, J and Song, C},
title = {A colorimetric platform for sensitively differentiating telomere DNA with different lengths, monitoring G-quadruplex and dsDNA based on silver nanoclusters and unmodified gold nanoparticles.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {196},
number = {},
pages = {148-154},
doi = {10.1016/j.saa.2018.02.024},
pmid = {29444496},
issn = {1873-3557},
mesh = {Colorimetry/*methods ; *DNA/analysis/chemistry/classification ; *G-Quadruplexes ; Gold/chemistry ; Limit of Detection ; Linear Models ; Metal Nanoparticles/*chemistry ; Reproducibility of Results ; Silver/chemistry ; Telomere/*genetics ; },
abstract = {Human telomere DNA plays a vital role in genome integrity control and carcinogenesis as an indication for extensive cell proliferation. Herein, silver nanoclusters (Ag NCs) templated by polymer and unmodified gold nanoparticles (Au NPs) are designed as a new colorimetric platform for sensitively differentiating telomere DNA with different lengths, monitoring G-quadruplex and dsDNA. Ag NCs can produce the aggregation of Au NPs, so the color of Au NPs changes to blue and the absorption peak moves to 700nm. While the telomere DNA can protect Au NPs from aggregation, the color turns to red again and the absorption band blue shift. Benefiting from the obvious color change, we can differentiate the length of telomere DNA by naked eyes. As the length of telomere DNA is longer, the variation of color becomes more noticeable. The detection limits of telomere DNA containing 10, 22, 40, 64 bases are estimated to be 1.41, 1.21, 0.23 and 0.22nM, respectively. On the other hand, when telomere DNA forms G-quadruplex in the presence of K[+], or dsDNA with complementary sequence, both G-quadruplex and dsDNA can protect Au NPs better than the unfolded telomere DNA. Hence, a new colorimetric platform for monitoring structure conversion of DNA is established by Ag NCs-Au NPs system, and to prove this type of application, a selective K[+] sensor is developed.},
}
@article {pmid29444436,
year = {2018},
author = {Liu, Y and Liu, F and Cao, Y and Xu, H and Wu, Y and Wu, S and Liu, D and Zhao, Y and Songyang, Z and Ma, W},
title = {Shwachman-Diamond Syndrome Protein SBDS Maintains Human Telomeres by Regulating Telomerase Recruitment.},
journal = {Cell reports},
volume = {22},
number = {7},
pages = {1849-1860},
pmid = {29444436},
issn = {2211-1247},
support = {R01 CA211653/CA/NCI NIH HHS/United States ; P30 CA125123/CA/NCI NIH HHS/United States ; },
mesh = {Aminopeptidases/metabolism ; Bone Marrow Diseases/*metabolism ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism ; Exocrine Pancreatic Insufficiency/*metabolism ; Gene Knockdown Techniques ; HEK293 Cells ; HeLa Cells ; Humans ; Lipomatosis/*metabolism ; Mutation/genetics ; Protein Binding ; Protein Domains ; Proteins/chemistry/genetics/*metabolism ; S Phase ; Serine Proteases/metabolism ; Shelterin Complex/*metabolism ; Shwachman-Diamond Syndrome ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Shortening ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Shwachman-Diamond syndrome (SDS) is a rare pediatric disease characterized by various systemic disorders, including hematopoietic dysfunction. The mutation of Shwachman-Bodian-Diamond syndrome (SBDS) gene has been proposed to be a major causative reason for SDS. Although SBDS patients were reported to have shorter telomere length in granulocytes, the underlying mechanism is still unclear. Here we provide data to elucidate the role of SBDS in telomere protection. We demonstrate that SBDS deficiency leads to telomere shortening. We found that overexpression of disease-associated SBDS mutants or knockdown of SBDS hampered the recruitment of telomerase onto telomeres, while the overall reverse transcriptase activity of telomerase remained unaffected. Moreover, we show that SBDS could specifically bind to TPP1 during the S phase of cell cycle, likely functioning as a stabilizer for TPP1-telomerase interaction. Our findings suggest that SBDS is a telomere-protecting protein that participates in regulating telomerase recruitment.},
}
@article {pmid29443612,
year = {2018},
author = {Rain, M and Chaudhary, H and Kukreti, R and Thinlas, T and Mohammad, G and Pasha, Q},
title = {Elevated Vasodilatory Cyclases and Shorter Telomere Length Contribute to High-Altitude Pulmonary Edema.},
journal = {High altitude medicine &amp; biology},
volume = {19},
number = {1},
pages = {60-68},
doi = {10.1089/ham.2017.0136},
pmid = {29443612},
issn = {1557-8682},
mesh = {Adaptation, Physiological/genetics ; Adenylyl Cyclases/blood/*genetics ; Adolescent ; Adult ; *Altitude ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Pulmonary Edema/*genetics/*physiopathology ; Soluble Guanylyl Cyclase/blood/*genetics ; *Telomere Shortening ; Young Adult ; },
abstract = {UNLABELLED: Rain, Manjari, Himanshi Chaudhary, Ritushree Kukreti, Tashi Thinlas, Ghulam Mohammad, and Qadar Pasha. Elevated vasodilatory cyclases and shorter telomere length contribute to high-altitude pulmonary edema. High Alt Med Biol. 19:60-68, 2018.<br><br>AIM: High-altitude (HA) genetics is complex with respect to health and disease (HA pulmonary edema i.e., HAPE). Based on the widely recognized fact that oxidative stress is a major trigger of several physiological processes, this study was designed to establish the significance of vasodilatory cyclases and telomere length in HA physiology. The study was performed in three groups, namely HAPE-free sojourners (HAPE-f, n&#x2009;=&#x2009;150), HAPE patients (HAPE-p, n&#x2009;=&#x2009;150), and healthy highland natives or highlanders (HLs, n&#x2009;=&#x2009;150). Variations in soluble guanylyl cyclase &#x3b2;1-subunit (GUCY1B3) and adenylyl cyclase type 6 (ADCY6) were genotyped by the SNaPshot method and/or Fluidigm SNP type genotyping. Plasma GUCY1B3 and ADCY6 levels were estimated using ELISA, and relative telomere length was estimated by qRT-PCR.<br><br>RESULTS: The rs7638AA genotype was over-represented in HLs compared with HAPE-f and HAPE-p (p&#x2009;=&#x2009;0.035 and p&#x2009;=&#x2009;0.012, respectively). Similarly, the rs7638A allele was prevalent in HLs compared with both groups, but significance was attained against HAPE-p (p&#x2009;=&#x2009;0.012). Significantly elevated plasma levels of GUCY1B3 and ADCY6 were obtained in HAPE-p compared with HAPE-f (p&#x2009;=&#x2009;0.001 and p&#x2009;=&#x2009;0.006, respectively) and HLs (p&#x2009;=&#x2009;3.31E-05 and p&#x2009;=&#x2009;0.05, respectively). Shorter telomere length was observed in HAPE-p compared with HAPE-f (p&#x2009;>&#x2009;0.05) and HLs (p&#x2009;=&#x2009;0.017).<br><br>CONCLUSION: Elevated cyclases and shorter telomere length associate with HAPE pathophysiology.},
}
@article {pmid29441645,
year = {2018},
author = {Matsumoto, C and Jiang, Y and Emathinger, J and Quijada, P and Nguyen, N and De La Torre, A and Moshref, M and Nguyen, J and Levinson, AB and Shin, M and Sussman, MA and Hariharan, N},
title = {Short Telomeres Induce p53 and Autophagy and Modulate Age-Associated Changes in Cardiac Progenitor Cell Fate.},
journal = {Stem cells (Dayton, Ohio)},
volume = {36},
number = {6},
pages = {868-880},
pmid = {29441645},
issn = {1549-4918},
support = {P30 CA093373/CA/NCI NIH HHS/United States ; R01 HL122525/HL/NHLBI NIH HHS/United States ; T32 HL086350/HL/NHLBI NIH HHS/United States ; R01 HL105759/HL/NHLBI NIH HHS/United States ; R37 HL091102/HL/NHLBI NIH HHS/United States ; R01 HL113647/HL/NHLBI NIH HHS/United States ; R01 HL067245/HL/NHLBI NIH HHS/United States ; P01 HL085577/HL/NHLBI NIH HHS/United States ; R01 HL117163/HL/NHLBI NIH HHS/United States ; },
mesh = {Aging ; Animals ; Autophagy ; Cell Differentiation ; Heart/*physiology ; Humans ; Mice ; Stem Cells/*metabolism ; Telomere/*metabolism ; Telomere Shortening/*physiology ; Tumor Suppressor Protein p53/*metabolism ; },
abstract = {Aging severely limits myocardial repair and regeneration. Delineating the impact of age-associated factors such as short telomeres is critical to enhance the regenerative potential of cardiac progenitor cells (CPCs). We hypothesized that short telomeres activate p53 and induce autophagy to elicit the age-associated change in CPC fate. We isolated CPCs and compared mouse strains with different telomere lengths for phenotypic characteristics of aging. Wild mouse strain Mus musculus castaneus (CAST) possessing short telomeres exhibits early cardiac aging with cardiac dysfunction, hypertrophy, fibrosis, and senescence, as compared with common lab strains FVB and C57 bearing longer telomeres. CAST CPCs with short telomeres demonstrate altered cell fate as characterized by cell cycle arrest, senescence, basal commitment, and loss of quiescence. Elongation of telomeres using a modified mRNA for telomerase restores youthful properties to CAST CPCs. Short telomeres induce autophagy in CPCs, a catabolic protein degradation process, as evidenced by reduced p62 and increased accumulation of autophagic puncta. Pharmacological inhibition of autophagosome formation reverses the cell fate to a more youthful phenotype. Mechanistically, cell fate changes induced by short telomeres are partially p53 dependent, as p53 inhibition rescues senescence and commitment observed in CAST CPCs, coincident with attenuation of autophagy. In conclusion, short telomeres activate p53 and autophagy to tip the equilibrium away from quiescence and proliferation toward differentiation and senescence, leading to exhaustion of CPCs. This study provides the mechanistic basis underlying age-associated cell fate changes that will enable identification of molecular strategies to prevent senescence of CPCs. Stem Cells 2018;36:868-880.},
}
@article {pmid29441358,
year = {2018},
author = {Foley, NM and Hughes, GM and Huang, Z and Clarke, M and Jebb, D and Whelan, CV and Petit, EJ and Touzalin, F and Farcy, O and Jones, G and Ransome, RD and Kacprzyk, J and O'Connell, MJ and Kerth, G and Rebelo, H and Rodrigues, L and Puechmaille, SJ and Teeling, EC},
title = {Growing old, yet staying young: The role of telomeres in bats' exceptional longevity.},
journal = {Science advances},
volume = {4},
number = {2},
pages = {eaao0926},
pmid = {29441358},
issn = {2375-2548},
support = {//European Research Council/International ; },
mesh = {Animals ; Body Weight ; Chiroptera/*genetics/*physiology ; Longevity/*physiology ; Selection, Genetic ; Species Specificity ; Telomerase/metabolism ; Telomere/*genetics ; },
abstract = {Understanding aging is a grand challenge in biology. Exceptionally long-lived animals have mechanisms that underpin extreme longevity. Telomeres are protective nucleotide repeats on chromosome tips that shorten with cell division, potentially limiting life span. Bats are the longest-lived mammals for their size, but it is unknown whether their telomeres shorten. Using >60 years of cumulative mark-recapture field data, we show that telomeres shorten with age in Rhinolophus ferrumequinum and Miniopterus schreibersii, but not in the bat genus with greatest longevity, Myotis. As in humans, telomerase is not expressed in Myotis myotis blood or fibroblasts. Selection tests on telomere maintenance genes show that ATM and SETX, which repair and prevent DNA damage, potentially mediate telomere dynamics in Myotis bats. Twenty-one telomere maintenance genes are differentially expressed in Myotis, of which 14 are enriched for DNA repair, and 5 for alternative telomere-lengthening mechanisms. We demonstrate how telomeres, telomerase, and DNA repair genes have contributed to the evolution of exceptional longevity in Myotis bats, advancing our understanding of healthy aging.},
}
@article {pmid29439273,
year = {2017},
author = {Pérez, LM and Amaral, MA and Mundstock, E and Barbé-Tuana, FM and Guma, FTCR and Jones, MH and Machado, DC and Sarria, EE and Marques E Marques, M and Preto, LT and Epifanio, M and Meinem Garbin, JG and Mattiello, R},
title = {Effects of Diet on Telomere Length: Systematic Review and Meta-Analysis.},
journal = {Public health genomics},
volume = {20},
number = {5},
pages = {286-292},
doi = {10.1159/000486586},
pmid = {29439273},
issn = {1662-8063},
mesh = {Aged ; Diet/*methods ; Female ; Humans ; Life Expectancy ; Male ; Middle Aged ; Statistics as Topic ; Telomere/physiology ; Telomere Shortening/*physiology ; },
abstract = {BACKGROUND: The goal of this systematic review and meta-analysis is to determine the effect of diet on telomere length.<br><br>METHODS: We searched the following databases: MEDLINE, Embase, LILACS, CINAHL, ISI Web of Science, and Scopus, as well as the Cochrane Central Register of Controlled Trials and the National Institutes of Health, from inception to December 2016. Articles that assessed effects of diet on telomere length were included.<br><br>RESULTS: A total of 2,128 studies were identified, 30 were read in full, and 7 were systematically reviewed. Five RCTs were included in the meta-analysis, covering 9 diets; a total of 533 participants were included. Study heterogeneity (I2) was 89%, and differences were not identified regarding average telomere lengths (mean difference 1.06; 95% CI -1.53 to 3.65).<br><br>CONCLUSION: The available evidence suggests that there is no effect of diet on telomere length, but the strong heterogeneity in the type and duration of dietary interventions does not allow any final statement on the absence of an effect of diet on telomere length.},
}
@article {pmid29438415,
year = {2018},
author = {Seeker, LA and Ilska, JJ and Psifidi, A and Wilbourn, RV and Underwood, SL and Fairlie, J and Holland, R and Froy, H and Bagnall, A and Whitelaw, B and Coffey, M and Nussey, DH and Banos, G},
title = {Longitudinal changes in telomere length and associated genetic parameters in dairy cattle analysed using random regression models.},
journal = {PloS one},
volume = {13},
number = {2},
pages = {e0192864},
pmid = {29438415},
issn = {1932-6203},
support = {BBS/E/D/05251445/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Aging/*genetics ; Animals ; Cattle/*genetics ; DNA/genetics ; Female ; Leukocytes/metabolism ; Longevity/physiology ; *Models, Genetic ; Regression Analysis ; Telomere/genetics ; Telomere Shortening/*genetics ; },
abstract = {Telomeres cap the ends of linear chromosomes and shorten with age in many organisms. In humans short telomeres have been linked to morbidity and mortality. With the accumulation of longitudinal datasets the focus shifts from investigating telomere length (TL) to exploring TL change within individuals over time. Some studies indicate that the speed of telomere attrition is predictive of future disease. The objectives of the present study were to 1) characterize the change in bovine relative leukocyte TL (RLTL) across the lifetime in Holstein Friesian dairy cattle, 2) estimate genetic parameters of RLTL over time and 3) investigate the association of differences in individual RLTL profiles with productive lifespan. RLTL measurements were analysed using Legendre polynomials in a random regression model to describe TL profiles and genetic variance over age. The analyses were based on 1,328 repeated RLTL measurements of 308 female Holstein Friesian dairy cattle. A quadratic Legendre polynomial was fitted to the fixed effect of age in months and to the random effect of the animal identity. Changes in RLTL, heritability and within-trait genetic correlation along the age trajectory were calculated and illustrated. At a population level, the relationship between RLTL and age was described by a positive quadratic function. Individuals varied significantly regarding the direction and amount of RLTL change over life. The heritability of RLTL ranged from 0.36 to 0.47 (SE = 0.05-0.08) and remained statistically unchanged over time. The genetic correlation of RLTL at birth with measurements later in life decreased with the time interval between samplings from near unity to 0.69, indicating that TL later in life might be regulated by different genes than TL early in life. Even though animals differed in their RLTL profiles significantly, those differences were not correlated with productive lifespan (p = 0.954).},
}
@article {pmid29438375,
year = {2018},
author = {Fernandez-Rozadilla, C and Kartsonaki, C and Woolley, C and McClellan, M and Whittington, D and Horgan, G and Leedham, S and Kriaucionis, S and East, J and Tomlinson, I},
title = {Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel.},
journal = {British journal of cancer},
volume = {118},
number = {5},
pages = {727-732},
pmid = {29438375},
issn = {1532-1827},
support = {16581/CRUK_/Cancer Research UK/United Kingdom ; BB/M001873/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; 090532/Z/09/Z/WT_/Wellcome Trust/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; 16459/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/*genetics ; Case-Control Studies ; Colon/*chemistry ; Colonoscopy ; Colorectal Neoplasms/*diagnosis/genetics ; DNA Methylation ; Early Detection of Cancer ; Female ; Gene Regulatory Networks ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Rectum/*chemistry ; Risk Factors ; *Telomere Homeostasis ; Young Adult ; },
abstract = {BACKGROUND: Colorectal cancer (CRC) screening might be improved by using a measure of prior risk to modulate screening intensity or the faecal immunochemical test threshold. Intermediate molecular biomarkers could aid risk prediction by capturing both known and unknown risk factors.<br><br>METHODS: We sampled normal bowel mucosa from the proximal colon, distal colon and rectum of 317 individuals undergoing colonoscopy. We defined cases as having a personal history of colorectal polyp(s)/cancer, and controls as having no history of colorectal neoplasia. Molecular analyses were performed for: telomere length (TL); global methylation; and the expression of genes in molecular pathways associated with colorectal tumourigenesis. We also calculated a polygenic risk score (PRS) based on CRC susceptibility polymorphisms.<br><br>RESULTS: Bowel TL was significantly longer in cases than controls, but was not associated with blood TL. PRS was significantly and independently higher in cases. Hypermethylation showed a suggestive association with case:control status. No gene or pathway was differentially expressed between cases and controls. Gene expression often varied considerably between bowel locations.<br><br>CONCLUSIONS: PRS and bowel TL (but not blood TL) may be clinically-useful predictors of CRC risk. Sample collection to assess these biomarkers is feasible in clinical practice, especially where population screening uses flexible sigmoidoscopy or colonoscopy.},
}
@article {pmid29436385,
year = {2018},
author = {Zimetti, F and Freitas, WM and Campos, AM and Daher, M and Adorni, MP and Bernini, F and Sposito, AC and Zanotti, I},
title = {Cholesterol efflux capacity does not associate with coronary calcium, plaque vulnerability, and telomere length in healthy octogenarians.},
journal = {Journal of lipid research},
volume = {59},
number = {4},
pages = {714-721},
pmid = {29436385},
issn = {1539-7262},
mesh = {Aged, 80 and over ; Biomarkers/blood ; Calcium/*blood ; Cardiovascular Diseases/blood/genetics ; Cholesterol, HDL/*blood ; Female ; Healthy Volunteers ; Humans ; Male ; Plaque, Atherosclerotic/blood/*genetics ; Risk Factors ; Telomere/*genetics ; },
abstract = {Several studies have revealed that traditional risk factors are less effective in predicting CVD risk in the elderly, suggesting the need to identify new biomarkers. Here, we evaluated the association between serum cholesterol efflux capacity (CEC), an atheroprotective property of HDL recently identified as a novel marker of CVD risk, and atherosclerotic burden in a cohort of very old, healthy individuals. Serum CEC values were not significantly correlated either with calcium score or with markers of vulnerable plaque, such as positive remodeling, hypodensity, spotty calcification, or napking-ring sign. In addition, no association was detected between CEC and telomere length, a marker of biological aging that has been linked to atherosclerosis extent. Interestingly, elderly subjects presented a remarkably higher CEC (+30.2%; P < 0.0001) compared with values obtained from a cohort of sex-matched, cardiovascular event-free, middle-aged individuals. In conclusion, serum CEC is not related to traditional risk factors in very old, cardiovascular event-free subjects, but has significantly higher values compared with a healthy, younger population. Whether this improved HDL functionality may represent a protective factor in CVD onset must be established in future studies.},
}
@article {pmid29435268,
year = {2018},
author = {Vakonaki, E and Tsiminikaki, K and Plaitis, S and Fragkiadaki, P and Tsoukalas, D and Katsikantami, I and Vaki, G and Tzatzarakis, MN and Spandidos, DA and Tsatsakis, AM},
title = {Common mental disorders and association with telomere length.},
journal = {Biomedical reports},
volume = {8},
number = {2},
pages = {111-116},
pmid = {29435268},
issn = {2049-9434},
abstract = {Telomeres are repeated 5'-TTAGGG-3' sequences at the end of chromosomes, which maintain genomic stability. Their length is related to a number of diseases that affect humans. Apart from cancer, cardiovascular diseases, diabetes and other, telomere length has been associated with chronic diseases. Chronic mental illness includes various types of mental disorders with the most common being depression, schizophrenia and stress-anxiety. The aim of this review is to summarize the current state of knowledge on the role of telomeres in these disorders and to compare telomere length variations in patients receiving medication and patients not taking treatment. Most studies report reduced telomere length in patients suffering from mental disorders, compared to the general population. Since the factors that can affect telomere length are various, more experiments and investigations are required to understand the general impact of different factors on telomere length.},
}
@article {pmid29424808,
year = {2018},
author = {Antwi, SO and Petersen, GM},
title = {Leukocyte Telomere Length and Pancreatic Cancer Risk: Updated Epidemiologic Review.},
journal = {Pancreas},
volume = {47},
number = {3},
pages = {265-271},
pmid = {29424808},
issn = {1536-4828},
support = {P50 CA102701/CA/NCI NIH HHS/United States ; R25 CA092049/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Leukocytes/*metabolism ; Pancreatic Neoplasms/epidemiology/*genetics ; Risk Assessment/methods/statistics &amp; numerical data ; Risk Factors ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Many risk factors have been firmly established for pancreatic cancer (PC), but the molecular processes by which known risk factors influence susceptibility to PC are not clear. There has been a recent upsurge of interest in the role of telomere length (TL), the protective DNA sequence repeats at chromosome ends, in pancreatic carcinogenesis. Given this heightened interest, we performed an in-depth, focused, and up-to-date review of the epidemiological evidence linking leukocyte TL (LTL) with PC risk. We searched MEDLINE, Embase, and the Cochrane Library databases for all published studies on LTL and PC risk, up to May 2017. Five studies were identified for review: 4 nested case-control studies and 1 retrospective case-control study. Two studies found opposite associations between LTL and PC risk: 1 found a dose-response positive association and the other found a dose-response inverse association. Two studies also found a "U-shaped" association, whereas another reported a weak nonlinear relationship. We offer potential reasons for the conflicting findings including variation in study design, biospecimen characteristics, and differences in interlaboratory measurements of TL. Future studies should carefully control for risk factors of PC that are associated also with telomere attrition and investigate the role of genetic variation in TL maintenance.},
}
@article {pmid29417795,
year = {2019},
author = {Mormile, R},
title = {Telomere shortening and TNF-α: gateway for psoriasis in celiac disease?.},
journal = {Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia},
volume = {154},
number = {3},
pages = {370-371},
doi = {10.23736/S0392-0488.18.05789-9},
pmid = {29417795},
issn = {1827-1820},
mesh = {Celiac Disease/*complications/immunology ; Humans ; Psoriasis/*etiology/immunology ; Telomere Shortening/*immunology ; Tumor Necrosis Factor-alpha/*immunology ; },
}
@article {pmid29417315,
year = {2018},
author = {Fretts, AM and Mete, M and Howard, BV and Best, LG and Siscovick, DS and Eilat-Adar, S and Zhao, J},
title = {Physical activity and telomere length in American Indians: the Strong Heart Study.},
journal = {European journal of epidemiology},
volume = {33},
number = {5},
pages = {497-500},
pmid = {29417315},
issn = {1573-7284},
support = {U01 HL041642/HL/NHLBI NIH HHS/United States ; U01HL41652/HL/NHLBI NIH HHS/United States ; K01 AG034259/AG/NIA NIH HHS/United States ; R01 DK091369/DK/NIDDK NIH HHS/United States ; R01DK091369/DK/NIDDK NIH HHS/United States ; R21 HL092363/HL/NHLBI NIH HHS/United States ; U01HL41642/HL/NHLBI NIH HHS/United States ; R01 HL109319/HL/NHLBI NIH HHS/United States ; U01 HL065521/HL/NHLBI NIH HHS/United States ; KL2 TR000421/TR/NCATS NIH HHS/United States ; U01 HL065520/HL/NHLBI NIH HHS/United States ; U01HL65521/HL/NHLBI NIH HHS/United States ; U01HL65520/HL/NHLBI NIH HHS/United States ; U01 HL041654/HL/NHLBI NIH HHS/United States ; UL1 TR001409/TR/NCATS NIH HHS/United States ; R21HL092363/HL/NHLBI NIH HHS/United States ; U01 HL041652/HL/NHLBI NIH HHS/United States ; KL2TR000421/TR/NCATS NIH HHS/United States ; R01 HL109284/HL/NHLBI NIH HHS/United States ; K01AG034259/AG/NIA NIH HHS/United States ; KL2 TR002317/TR/NCATS NIH HHS/United States ; U01HL41654/HL/NHLBI NIH HHS/United States ; R01 DK107532/DK/NIDDK NIH HHS/United States ; R01 HL109301/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aging/*physiology ; Body Mass Index ; Cross-Sectional Studies ; Exercise/*physiology ; Female ; Humans ; Indians, North American ; Life Style ; Longitudinal Studies ; Male ; Middle Aged ; Telomere/*physiology ; },
abstract = {Telomere length, a marker of biological aging, has been associated with many chronic diseases, but its relations with physical activity remains unclear. The purpose of this study was to examine the association of objectively measured ambulatory activity with leukocyte telomere length (LTL), a marker of biological aging, among American Indians. This cross-sectional study included 2312 AI participants from the Strong Heart Family Study. Steps per day were measured using Accusplit AE120 pedometers. Quantitative PCR was used to measure LTL. Generalized estimating equations were used to examine the associations of steps per day with LTL. The median steps per day over a 1 week period was 5118 steps (interquartile range = 3163-7576 steps). Compared to participants in the lowest quartile of steps per day, participants in the upper three quartiles of steps per day had longer LTL: beta ± SE = 0.0195 ± 0.0144, 0.0273 ± 0.0139, and 0.0375 ± 0.0143 T/S ratio units longer (p trend = 0.010) after adjustment for potential confounders. These data suggest that ambulatory activity is associated with LTL. Further studies are needed to determine the mechanism by which ambulatory activity influences LTL.},
}
@article {pmid29416566,
year = {2018},
author = {Huleyuk, N and Tkach, I and Zastavna, D and Tyrka, M},
title = {Can telomere shortening be the main indicator of non-viable fetus elimination?.},
journal = {Molecular cytogenetics},
volume = {11},
number = {},
pages = {11},
pmid = {29416566},
issn = {1755-8166},
abstract = {BACKGROUND: Telomeres are transcriptionally inactive genomic areas, which, if shortened, are associated with pathological processes, unsuccessful fertilization, aging, and death. Telomere dysfunction has also been linked to chromosomal rearrangements and genomic instability. The role of telomeres in postnatal life has been extensively studied and discussed both in physiological as well as in pathological processes. However, the role of telomere length in prenatal development is still poorly understood, and mainly concerns the preimplantation stage. The aim of this study was to estimate relative telomere length in spontaneously eliminated human embryos between 5th and 12th week of gestation.<br><br>RESULTS: Relative telomere length was measured from total genomic DNA using a real-time polymerase chain reaction approach. In this study, we examined relative telomere length in 80 spontaneously eliminated embryos and in 25 embryos eliminated due to induced abortions. Relative telomere length in spontaneous abortions was significantly lower (P&#x2009;=&#x2009;0.000001) compared to the induced abortions. Spontaneous abortions with aneuploid anomalies (monosomy X, trisomy 21, trisomy 16 and triploidy) were characterized by shorter telomeres, compared to spontaneous abortions, subgroup with euploid (46,XN) karyotype.<br><br>CONCLUSION: Spontaneously lost pregnancies are characterized by shortened telomeres, especially in embryos with aneuploidies. We hypothesize that the shortening of telomeres is involved in the processes leading to spontaneous abortions.},
}
@article {pmid29415988,
year = {2018},
author = {Wang, J and Feng, Y and Han, P and Wang, F and Luo, X and Liang, J and Sun, X and Ye, J and Lu, Y and Sun, X},
title = {Photosensitization of A2E triggers telomere dysfunction and accelerates retinal pigment epithelium senescence.},
journal = {Cell death &amp; disease},
volume = {9},
number = {2},
pages = {178},
pmid = {29415988},
issn = {2041-4889},
mesh = {Acetylcysteine/pharmacology ; Cell Line ; Cellular Senescence/drug effects/radiation effects ; DNA Damage ; HEK293 Cells ; Humans ; Photosensitivity Disorders ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/*drug effects/*metabolism ; Retinoids/*pharmacology/*radiation effects ; Telomere/drug effects/*metabolism ; },
abstract = {Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in elderly people. AMD is classified as early, intermediate, advanced non-neovascular, and advanced neovascular forms depending on the clinical features. However, the exact pathogenesis remains unclear. Retinal pigment epithelium (RPE) cells degeneration is a hallmark of AMD. With aging, lipofuscin accumulates in RPE cells. N-retinylidene-N-retinylethanolamine (named A2E), a well-known fluorophore of lipofuscin, may contribute to RPE cells degeneration. In this study, we showed that photosensitization of A2E increased DNA damage, including telomere deprotection and deletion, and triggered cellular senescence. In addition, we found that the antioxidant N-acetyl-cysteine (NAC) partially alleviated this DNA damage. Telomerase overexpression rescued A2E-mediated RPE cell senescence, indicating that telomere dysfunction plays an important role in A2E-based senescence. We further showed that the senescence induced by A2E photosensitization may affect the microenvironment of the retina by expressing several factors of the secretory phenotype (SASP) including IL1B, IL13RA2, and CXCR4 through the NF-κB pathway. We propose that expression of these factors create a pro-inflammatory environment that drives retina degeneration. Moreover, our findings suggest that protecting telomeres is a valuable strategy for treating retinal degeneration diseases, such as AMD.},
}
@article {pmid29415479,
year = {2018},
author = {Cleal, K and Norris, K and Baird, D},
title = {Telomere Length Dynamics and the Evolution of Cancer Genome Architecture.},
journal = {International journal of molecular sciences},
volume = {19},
number = {2},
pages = {},
pmid = {29415479},
issn = {1422-0067},
support = {18246/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Animals ; Cell Transformation, Neoplastic/*genetics/metabolism ; Evolution, Molecular ; Genomic Instability ; *Genomics/methods ; Humans ; Neoplasms/*genetics/metabolism ; Prognosis ; Telomerase/metabolism ; Telomere/*genetics ; *Telomere Homeostasis ; Telomere Shortening ; },
abstract = {Telomeres are progressively eroded during repeated rounds of cell division due to the end replication problem but also undergo additional more substantial stochastic shortening events. In most cases, shortened telomeres induce a cell-cycle arrest or trigger apoptosis, although for those cells that bypass such signals during tumour progression, a critical length threshold is reached at which telomere dysfunction may ensue. Dysfunction of the telomere nucleoprotein complex can expose free chromosome ends to the DNA double-strand break (DSB) repair machinery, leading to telomere fusion with both telomeric and non-telomeric loci. The consequences of telomere fusions in promoting genome instability have long been appreciated through the breakage-fusion-bridge (BFB) cycle mechanism, although recent studies using high-throughput sequencing technologies have uncovered evidence of involvement in a wider spectrum of genomic rearrangements including chromothripsis. A critical step in cancer progression is the transition of a clone to immortality, through the stabilisation of the telomere repeat array. This can be achieved via the reactivation of telomerase, or the induction of the alternative lengthening of telomeres (ALT) pathway. Whilst telomere dysfunction may promote genome instability and tumour progression, by limiting the replicative potential of a cell and enforcing senescence, telomere shortening can act as a tumour suppressor mechanism. However, the burden of senescent cells has also been implicated as a driver of ageing and age-related pathology, and in the promotion of cancer through inflammatory signalling. Considering the critical role of telomere length in governing cancer biology, we review questions related to the prognostic value of studying the dynamics of telomere shortening and fusion, and discuss mechanisms and consequences of telomere-induced genome rearrangements.},
}
@article {pmid29415270,
year = {2020},
author = {Lahav, Y and Avidor, S and Stein, JY and Zhou, X and Solomon, Z},
title = {Telomere Length and Depression Among Ex-Prisoners of War: The Role of Subjective Age.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {75},
number = {1},
pages = {21-29},
doi = {10.1093/geronb/gby006},
pmid = {29415270},
issn = {1758-5368},
mesh = {Aged ; Aging, Premature/*metabolism ; Depression/*metabolism ; Female ; Humans ; Israel ; Longitudinal Studies ; Male ; Middle Aged ; *Prisoners of War ; Psychological Trauma/*metabolism ; Telomere Shortening/*physiology ; },
abstract = {OBJECTIVES: Exposure to captivity increases the risk for multiple disturbances that may intensify during old age. In later phases of life, former-prisoners-of-war (ex-POWs) may suffer from depression as well as from accelerated aging, manifested in older subjective age and leukocyte telomere shortening. The current study assesses the link between these varied facets of increased vulnerability during old age and explores (a) the associations between subjective age and telomere length; (b) the mediating role of changes in subjective age over time within the associations between depression and telomere length.<br><br>METHODS: Eighty-eight ex-POWs were assessed prospectively 30 (T1), 35 (T2), and 45 (T3) years after the 1973 Israeli Yom-Kippur War. Depression was assessed at T1; subjective age was assessed at T2 and T3; and telomere length and control variables were assessed at T3.<br><br>RESULTS: Older subjective age at T3 was associated with concurrent shorter telomeres, beyond the effect of chronological age. Change in subjective age between T2 and T3 mediated the relations between depression at T1 and shorter telomeres at T3 beyond the effects of control variables.<br><br>DISCUSSION: Findings suggest that the detrimental ramifications of accelerated subjective age involve premature cellular senesces, and may explain the relation between depression and accelerated aging processes among trauma victims. Hence, clinical interventions may seek to address accelerated subjective age among trauma survivors who suffer from depression.},
}
@article {pmid29414028,
year = {2018},
author = {Chang, SC and Crous-Bou, M and Prescott, J and Rosner, B and Simon, NM and Wang, W and De Vivo, I and Okereke, OI},
title = {Relation of long-term patterns in caregiving activity and depressive symptoms to telomere length in older women.},
journal = {Psychoneuroendocrinology},
volume = {89},
number = {},
pages = {161-167},
pmid = {29414028},
issn = {1873-3360},
support = {R01 CA049449/CA/NCI NIH HHS/United States ; R01 MH096776/MH/NIMH NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Caregivers/*psychology ; Cellular Senescence ; Depression/genetics/*metabolism/physiopathology ; Depressive Disorder/genetics/metabolism/physiopathology ; Female ; Humans ; Middle Aged ; Psychology ; Stress, Psychological ; Telomere/genetics/metabolism ; Telomere Homeostasis/*physiology ; Telomere Shortening/genetics/physiology ; },
abstract = {BACKGROUND: Research links psychological stress to accelerated cellular aging. Here we examined whether long-term patterns of depression and caregiving burden, forms of chronic psychological stress, were associated with shorter telomere length, a biomarker of cellular aging.<br><br>METHODS: The study included 1250 healthy older women (mean: 68.0; range: 60-81 years) in the Nurses' Health Study. Long-term patterns in depressive symptoms and caregiving activity (separated into care of children/grandchildren vs. ill or disabled family members/others) incorporated questionnaire data between 1992 and 2000; relative leukocyte telomere lengths (LTLs) were measured in 2000-2001. Least-squares means LTL z-scores were calculated across categories of depression patterns and caregiving intensity.<br><br>RESULTS: Six empirically-derived latent classes of depressive symptom trajectories were identified: minimal-stable (63.7%), mild-worsening (3.9%), subthreshold-improving (22.8%), subthreshold-worsening (2.7%), clinical range depressive-improving (6.2%), and clinical range depressive-persistent (0.6%). After collapsing trajectory patterns into 4 groups (combining those with minimal and mild symptoms into one group and those with clinical range depressive symptoms into one group) due to very small sample sizes in some groups, we observed marginal associations (p&#x202f;=&#x202f;0.07):&#x2009;e.g., the least-squares means LTL z-scores were lowest (-0.08; 95% CI: -0.22 to 0.06) for the clinical range depressive symptoms group and highest (0.12; 0.04-0.20) for the subthreshold-improving group (Tukey's post-hoc pairwise p&#x202f;=&#x202f;0.07). With six depressive symptom trajectories, no significant associations were observed with regard to telomere lengths. There were no significant associations between caregiving intensity and LTLs.<br><br>CONCLUSIONS: There were no associations between long-term patterns of caregiving burden and telomere lengths among older women. Possible differences in telomere lengths by types of long-term depressive symptom trajectories may warrant further investigation.},
}
@article {pmid29413749,
year = {2018},
author = {Li, JSZ and Denchi, EL},
title = {How stem cells keep telomeres in check.},
journal = {Differentiation; research in biological diversity},
volume = {100},
number = {},
pages = {21-25},
pmid = {29413749},
issn = {1432-0436},
support = {R01 GM122987/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Humans ; Pluripotent Stem Cells/cytology/*metabolism ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {In multicellular organisms, regulation of telomere length in pluripotent stem cells is critical to ensure organism development and survival. Telomeres consist of repetitive DNA that are progressively lost with each cellular division. When telomeres become critically short, they activate a DNA damage response that results in cell cycle arrest. To counteract telomere attrition, pluripotent stem cells are equipped with telomere elongation mechanisms that ensure prolonged proliferation capacity and self-renewal capacity. Excessive telomere elongation can also be deleterious and is counteracted by a rapid telomere deletion mechanism termed telomere trimming. While the consequences of critically short telomeres are well established, we are only beginning to understand the mechanisms that counteract excessive telomere elongation. The balance between telomere elongation and shortening determine the telomere length set point in pluripotent stem cells and ensures sustained proliferative potential without causing chromosome instability.},
}
@article {pmid29413748,
year = {2018},
author = {Hou, H and Cooper, JP},
title = {Stretching, scrambling, piercing and entangling: Challenges for telomeres in mitotic and meiotic chromosome segregation.},
journal = {Differentiation; research in biological diversity},
volume = {100},
number = {},
pages = {12-20},
doi = {10.1016/j.diff.2018.01.002},
pmid = {29413748},
issn = {1432-0436},
mesh = {Animals ; *Chromosome Segregation ; Humans ; Meiosis/*genetics ; Mitosis/*genetics ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {The consequences of telomere loss or dysfunction become most prominent when cells enter the nuclear division stage of the cell cycle. At this climactic stage when chromosome segregation occurs, telomere fusions or entanglements can lead to chromosome breakage, wreaking havoc on genome stability. Here we review recent progress in understanding the mechanisms of detangling and breaking telomere associations at mitosis, as well as the unique ways in which telomeres are processed to allow regulated sister telomere separation. Moreover, we discuss unexpected roles for telomeres in orchestrating nuclear envelope breakdown and spindle formation, crucial processes for nuclear division. Finally, we discuss the discovery that telomeres create microdomains in the nucleus that are conducive to centromere assembly, cementing the unexpectedly influential role of telomeres in mitosis.},
}
@article {pmid29410247,
year = {2018},
author = {Lai, S and Heaphy, CM and Rizzo, AJ and Celentano, DD and Gerstenblith, G and Li, J and Moore, RD and Treisman, G and Chen, S and Foster, P and Kickler, T and Lai, H},
title = {Cocaine use may induce telomere shortening in individuals with HIV infection.},
journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry},
volume = {84},
number = {Pt A},
pages = {11-17},
pmid = {29410247},
issn = {1878-4216},
support = {R01 DA012777/DA/NIDA NIH HHS/United States ; P30 AI094189/AI/NIAID NIH HHS/United States ; U01 DA036935/DA/NIDA NIH HHS/United States ; U01 DA040325/DA/NIDA NIH HHS/United States ; R01 DA015020/DA/NIDA NIH HHS/United States ; R01 DA025524/DA/NIDA NIH HHS/United States ; },
mesh = {Cocaine/*adverse effects ; Cross-Sectional Studies ; Ethanol/adverse effects ; Female ; HIV Infections/*genetics ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Reverse Transcriptase Inhibitors/adverse effects ; Telomere Homeostasis/drug effects ; Telomere Shortening/*drug effects ; },
abstract = {BACKGROUND: Although cocaine use may induce/accelerate HIV-associated comorbidities in HIV-infected individuals on antiretroviral therapy (ART), and that HIV itself may accelerate aging, the issue of whether cocaine use plays a role in HIV-associated aging in HIV-infected cocaine users has not been reported. The goals of this study were (1) to explore factor(s) associated with peripheral blood leukocyte telomere length, a marker of cellular replicative history, and telomere shortening in HIV-infected individuals, and (2) to assess whether cocaine use plays a role in accelerating telomere shortening in cocaine users with HIV infection.<br><br>METHODS: Between June 2010 and December 2016, 147 HIV-infected participants in Baltimore, Maryland, were enrolled in a cross-sectional study investigating factor(s) associated with telomere length. Of these 147, 93 participated in a follow-up study to examine factor(s) associated with telomere shortening. Robust regression model was used to analyze cross-sectional data and the generalized estimating equation approach was used to analyze follow-up data.<br><br>RESULTS: Cross-sectional analyses demonstrated that (1) both daily alcohol consumption and use of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were independently associated with telomere length, and cocaine use modified the associations of daily alcohol use and NNRTI use with telomere length. Longitudinal analyses suggested that both daily alcohol consumption and duration of NNRTI use were independently associated with telomere shortening, and (2) cocaine use induced/accelerated telomere shortening in HIV-infected individuals.<br><br>CONCLUSIONS: Our findings suggest that cocaine use may promote premature aging in HIV-infected individuals who are on ART. Our results emphasize the importance of cocaine abstinence/reduced use, which may retard HIV-associated premature aging.},
}
@article {pmid29410177,
year = {2018},
author = {Sugihara, A and Nguyen, LC and Shamim, HM and Iida, T and Nakase, M and Takegawa, K and Senda, M and Jida, S and Ueno, M},
title = {Mutation in fission yeast phosphatidylinositol 4-kinase Pik1 is synthetically lethal with defect in telomere protection protein Pot1.},
journal = {Biochemical and biophysical research communications},
volume = {496},
number = {4},
pages = {1284-1290},
doi = {10.1016/j.bbrc.2018.02.001},
pmid = {29410177},
issn = {1090-2104},
mesh = {Apoptosis/*genetics ; Mutation/*genetics ; Phosphoproteins/*genetics ; Saccharomyces cerevisiae Proteins/*genetics ; Schizosaccharomyces/cytology/*physiology ; Schizosaccharomyces pombe Proteins/*genetics ; Telomere/*genetics ; },
abstract = {Fission yeast Pik1p is one of three phosphatidylinositol 4-kinases associated with the Golgi complex, but its function is not fully understood. Deletion of pot1[+] causes telomere degradation and chromosome circularization. We searched for the gene which becomes synthetically lethal with pot1Δ. We obtained a novel pik1 mutant, pik1-1, which is synthetically lethal with pot1Δ. We found phosphoinositol 4-phosphate in the Golgi was reduced in pik1-1. To investigate the mechanism of the lethality of the pot1Δ pik1-1 double mutant, we constructed the nmt-pot1-aid pik1-1 strain, where Pot1 function becomes low by drugs, which leads to telomere loss and chromosome circularization, and found pik1-1 mutation does not affect telomere resection and chromosome circularization. Thus, our results suggest that pik1[+] is required for the maintenance of circular chromosomes.},
}
@article {pmid29408234,
year = {2018},
author = {Glousker, G and Lingner, J},
title = {When Telomerase Causes Telomere Loss.},
journal = {Developmental cell},
volume = {44},
number = {3},
pages = {281-283},
doi = {10.1016/j.devcel.2018.01.011},
pmid = {29408234},
issn = {1878-1551},
mesh = {Cellular Senescence ; Dyskeratosis Congenita ; Humans ; Microcephaly ; Mutation ; Telomerase/*genetics ; *Telomere ; Telomere Shortening ; },
abstract = {Telomerase counteracts telomere shortening, preventing cellular senescence. Telomerase deficiency causes telomere syndromes because of premature telomere exhaustion in highly proliferative cells. Paradoxically, in a recent issue of Cell, Margalef et al. (2018) demonstrate that telomerase causes telomere loss in cells lacking the RTEL1 helicase, which is defective in Hoyeraal-Hreidarsson syndrome (HHS).},
}
@article {pmid29396405,
year = {2018},
author = {Li, J and Feng, C and Li, L and Yang, S and Chen, Y and Hui, R and Zhang, M and Zhang, W},
title = {The association of telomere attrition with first-onset stroke in Southern Chinese: a case-control study and meta-analysis.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {2290},
pmid = {29396405},
issn = {2045-2322},
mesh = {Aged ; Aged, 80 and over ; Asian People ; Case-Control Studies ; Female ; *Genetic Predisposition to Disease ; Humans ; Leukocytes ; Male ; Middle Aged ; Retrospective Studies ; Stroke/*genetics ; *Telomere ; },
abstract = {The relationship between telomere length and stroke was inconsistent mostly due to different pathogenesis of subtypes, environment and genetics. We aimed to assess whether leukocyte telomere contributes to stroke in Southern Chinese by investigating a case-control study comprising 543 cases (224 atherothrombotic stroke, 94 hemorrhagic stroke and 225 lacunar infraction) and 616 controls and replicated the investigation in an independent study comprising 773 cases and 875 controls with the same diagnostic criteria. Telomere was inversely correlated with increasing age in controls (correlation coefficient γ = -0.28, P < 0.001) and in cases with atherothrombotic stroke (γ = -0.17, P = 0.012). Individuals within the lowest tertile of telomere showed a higher risk for atherothrombotic stroke [odds ratio 2.33, 95% confidence (CI) 1.42-3.83; P = 0.003], whereas had a lower presence of lacunar infarction (OR 0.49, 95% CI 0.30-0.81; P = 0.007). Similar results were obtained in the second replication study. A further meta-analysis showed a 12% increased pooled risk of ischemic stroke (95% CI 1.04-1.18) in relation to shorter telomere, but this association was stronger in the retrospective studies and in Asians when stratified by study design and ethnicity. Our data provided the first evidence that in Southern Chinese stroke population, leukocyte telomere is independently associated with atherothrombotic stroke and lacunar infarction.},
}
@article {pmid29396320,
year = {2018},
author = {Provenzi, L and Giorda, R and Fumagalli, M and Pozzoli, U and Morandi, F and Scotto di Minico, G and Mosca, F and Borgatti, R and Montirosso, R},
title = {Pain exposure associates with telomere length erosion in very preterm infants.},
journal = {Psychoneuroendocrinology},
volume = {89},
number = {},
pages = {113-119},
doi = {10.1016/j.psyneuen.2018.01.009},
pmid = {29396320},
issn = {1873-3360},
mesh = {Female ; Fetal Blood ; Gestational Age ; Hospitalization ; Humans ; Infant ; Infant, Newborn ; Infant, Premature/physiology/psychology ; Infant, Small for Gestational Age/physiology/psychology ; Intensive Care Units, Neonatal ; Male ; Pain/*genetics/physiopathology ; Pregnancy ; Stress, Psychological/genetics/*physiopathology ; Telomere/genetics/physiology ; Telomere Homeostasis/genetics/*physiology ; },
abstract = {Very preterm (VPT) infants (gestational age < 32 weeks) require long-lasting hospitalization in the Neonatal Intensive Care Unit (NICU), even in absence of severe morbidities. During NICU stay, life-saving interventions occur and include invasive and painful skin-breaking procedures (NICU-related stress), which constitute a major early adverse experience for VPT infants. Telomeres are repeat-sequence at the end of chromosomes, which shorten with age and are highly susceptible to life adversities: the exposure to early adverse experiences is associated with shorter telomere length (TL). Nonetheless, previous research did not assess longitudinally the association between NICU-related stress and TL in VPT infants. In the present study, leukocyte TL was assessed from cord blood at birth in 46 VPT infants and in a group of 31 full-term (FT) infants, as well as at NICU discharge in VPTs only. NICU-related stress was measured as the number of skin-breaking procedures occurring throughout the NICU stay. A significant difference emerged for TL between VPT infants and FT counterparts at birth. TL decreased from birth to discharge in VPT infants, although the change was not significant in the group as a whole. The amount of NICU-related stress emerged as the primary predictor of TL erosion in VPT infants, even controlling for neonatal and clinical confounders. Furthermore, VPT infants exposed to high NICU-related stress exhibited a marked and significant decrease in TL, whereas VPT exposed to low NICU-related stress exhibited a non-significant increase. The present study confirms previous evidence of longer telomeres in VPT infants at birth compared to FT controls. Moreover, NICU-related stress emerged as a key regulator of TL erosion from birth to discharge in VPT infants. Future research is warranted to further explore TL erosion in VPT infants and the factors associated with individual differences in NICU-related stress susceptibility at the epigenetic level.},
}
@article {pmid29395277,
year = {2018},
author = {Perera, F and Lin, CJ and Qu, L and Tang, D},
title = {Shorter telomere length in cord blood associated with prenatal air pollution exposure: Benefits of intervention.},
journal = {Environment international},
volume = {113},
number = {},
pages = {335-340},
doi = {10.1016/j.envint.2018.01.005},
pmid = {29395277},
issn = {1873-6750},
support = {P01 ES009600/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; Air Pollution/*adverse effects ; China/epidemiology ; Coal ; Cohort Studies ; DNA Adducts/analysis/*toxicity ; Female ; Fetal Blood ; Humans ; Infant, Newborn ; Male ; Polycyclic Aromatic Hydrocarbons/analysis/*toxicity ; Power Plants ; Pregnancy ; Prenatal Exposure Delayed Effects/*epidemiology ; Regression Analysis ; Telomere/*drug effects ; Telomere Homeostasis/*drug effects ; },
abstract = {BACKGROUND: To examine the molecular benefits of the government action to close the local coal burning power plant in Tongliang County, Chongqing Municipality, we compared biologic markers and health outcomes in two successive birth cohorts enrolled before and after the plant was shut down. In this city, polycyclic aromatic hydrocarbons (PAH) were primarily emitted by the coal burning facility. We previously reported that cord blood levels of PAH-DNA adducts (a biomarker of exposure) and various adverse health outcomes were reduced in the second cohort, whereas levels of brain-derived neurotrophic factor/BDNF (a protein involved in neuronal growth) were increased. Here we assessed telomere length (TL), which has been associated with risk of certain chronic diseases, early mortality, aging and cognitive decline in adults.<br><br>OBJECTIVES: The goals of the present study were to determine whether TL differed between the two cohorts and whether prenatal PAH exposure, estimated by PAH-DNA adducts in cord white blood cells of newborns in China, were predictive of shorter TL in cord blood, suggesting the potential accrual of risk of certain chronic diseases during the prenatal period. We explored relationships of TL with BDNF and neurodevelopmental outcomes, each previously associated with PAH-DNA adducts in these cohorts, as well as the potential mediating role of TL in the associations between adducts and neurodevelopmental outcomes.<br><br>METHODS: We analyzed TL in cord blood of 255 newborns who also had data on PAH-DNA adducts, BDNF, and relevant covariates. Multiple regression analysis was carried out to test associations between adducts and TL and between TL and BDNF, adjusting for relevant covariates. In the subset with developmental quotient (DQ) scores from Gesell testing at age 2 (N&#x202f;=&#x202f;210), we explored whether TL was a mediator of the relationship between PAH-DNA adducts and DQ scores by first examining the associations between cord adducts and DQ, cord adducts and TL, and TL and DQ, adjusting for the same covariates.<br><br>RESULTS: As hypothesized, the mean TL was significantly higher in the second cohort compared to the first cohort. Overall, PAH-DNA cord adducts were significantly and inversely correlated with TL. Multiple regression analysis showed a significant association between adducts and TL, after adjusting for key covariates: &#x3b2; (effect size per standard deviation adducts)&#x202f;=&#x202f;-0.019, p&#x202f;=&#x202f;.003. The regression coefficient of TL on (Ln) BDNF was also significant (&#x3b2;&#x202f;=&#x202f;0.167, p&#x202f;<&#x202f;.001). Exploratory analysis, regressing TL on Gesell developmental scores, showed generally inverse, but not significant associations. TL was not, therefore, deemed to be a potential mediator of the association between adducts and developmental scores at age two.<br><br>CONCLUSION: This study provides the first evidence that prenatal PAH exposure from coal burning may adversely affect TL, with potential implications for future risk of chronic diseases including cardiovascular disease. The improvement in TL in the second cohort and the observed correlation between increased TL and higher levels of BDNF indicate direct benefits to the health and development of children resulting from the government's closure of the power plant.},
}
@article {pmid29392401,
year = {2018},
author = {Xie, X and Shippen, DE},
title = {DDM1 guards against telomere truncation in Arabidopsis.},
journal = {Plant cell reports},
volume = {37},
number = {3},
pages = {501-513},
pmid = {29392401},
issn = {1432-203X},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; GM065383//Foundation for the National Institutes of Health/ ; },
mesh = {Arabidopsis/*genetics/metabolism ; Arabidopsis Proteins/*genetics/metabolism ; DNA Damage ; DNA Methylation/genetics ; DNA-Binding Proteins/*genetics/metabolism ; Gene Expression Regulation, Plant ; *Mutation ; Retroelements/genetics ; Telomere/*genetics/metabolism ; Telomere Homeostasis/genetics ; Time Factors ; Transcription Factors/*genetics/metabolism ; },
abstract = {Prolonged hypomethylation of DNA leads to telomere truncation correlated with increased telomere recombination, transposon mobilization and stem cell death. Epigenetic pathways, including DNA methylation, are crucial for telomere maintenance. Deficient in DNA Methylation 1 (DDM1) encodes a nucleosome remodeling protein, required to maintain DNA methylation in Arabidopsis thaliana. Plants lacking DDM1 can be self-propagated, but in the sixth generation (G6) hypomethylation leads to rampant transposon activation and infertility. Here we examine the role of DDM1 in telomere length homeostasis through a longitudinal study of successive generations of ddm1-2 mutants. We report that bulk telomere length remains within the wild-type range for the first five generations (G1-G5), and then precipitously drops in G6. While telomerase activity becomes more variable in later generation ddm1-2 mutants, there is no correlation between enzyme activity and telomere length. Plants lacking DDM1 also exhibit no dysregulation of several known telomere-associated transcripts, including TERRA. Instead, telomere shortening coincides with increased G-overhangs and extra-chromosomal circles, consistent with deletional recombination. Telomere shortening also correlates with transcriptional activation of retrotransposons, and a hypersensitive DNA damage response in root apical meristems. Since abiotic stresses, including DNA damage, stimulate homologous recombination, we hypothesize that telomere deletion in G6 ddm1-2 mutants is a by-product of elevated genome-wide recombination in response to transposon mobilization. Further, we speculate that telomere truncation may be beneficial in adverse environmental conditions by accelerating the elimination of stem cells with aberrant genomes.},
}
@article {pmid29392083,
year = {2018},
author = {Zgheib, NK and Sleiman, F and Nasreddine, L and Nasrallah, M and Nakhoul, N and Isma'eel, H and Tamim, H},
title = {Short Telomere Length is Associated with Aging, Central Obesity, Poor Sleep and Hypertension in Lebanese Individuals.},
journal = {Aging and disease},
volume = {9},
number = {1},
pages = {77-89},
pmid = {29392083},
issn = {2152-5250},
abstract = {In Lebanon, data stemming from national cross-sectional surveys indicated significant increasing trends in the prevalence of cardiovascular diseases and associated behavioral and age-related risk factors. To our knowledge, no data are available on relative telomere length (RTL) as a potential biomarker for age-related diseases in a Lebanese population. The aim of this study was to evaluate whether there is an association between RTL and demographic characteristics, lifestyle habits and diseases in the Lebanese. This was a cross-sectional study of 497 Lebanese subjects. Peripheral blood RTL was measured by amplifying telomere and single copy gene using real-time PCR. Mean ± SD RTL was 1.42 ± 0.83, and it was categorized into 3 tertiles. Older age (P=0.002) and wider waist circumference (WC) (P=0.001) were statistically significantly associated with shorter RTL. Multinomial logistic regression showed that subjects who had some level of sleeping difficulty had a statistically significantly shorter RTL when compared to those with no sleeping difficulties at all [OR (95% CI): 2.01 (1.11-3.62) in the first RTL tertile]. Importantly, statistically significantly shorter RTL was found with every additional 10 cm of WC [OR (95% CI): 1.30 (1.11-1.52) for first RTL tertile]. In addition, and after performing the multivariate logistic regression and adjusting for "predictors" of RTL, the odds of having hypertension or being treated for hypertension were higher in patients who had shorter RTL: OR (95% CI): 2.45 (1.36-4.44) and 2.28 (1.22-4.26) in the first RTL tertiles respectively with a similar trend, though not statistically significant, in the second RTL tertiles. This is the first study in Lebanon to show an association between age, central obesity, poor sleep and hypertension and RTL. It is hoped that telomere length measurement be potentially used as a biomarker for biological age and age-related diseases and progression in the Lebanese.},
}
@article {pmid29386295,
year = {2018},
author = {Schmidt, JC and Zaug, AJ and Kufer, R and Cech, TR},
title = {Dynamics of human telomerase recruitment depend on template-telomere base pairing.},
journal = {Molecular biology of the cell},
volume = {29},
number = {7},
pages = {869-880},
pmid = {29386295},
issn = {1939-4586},
support = {K99 GM120386/GM/NIGMS NIH HHS/United States ; R01 GM099705/GM/NIGMS NIH HHS/United States ; },
abstract = {The reverse transcriptase telomerase adds telomeric repeats to chromosome ends to counteract telomere shortening and thereby assures genomic stability in dividing human cells. Key parameters in telomere homeostasis are the frequency with which telomerase engages the chromosome end and the number of telomeric repeats it adds during each association event. To study telomere elongation in vivo, we have established a live-cell imaging assay to track individual telomerase ribonucleoproteins in CRISPR-edited HeLa cells. Using this assay and the drug imetelstat, which is a competitive inhibitor of telomeric DNA binding, we demonstrate that stable association of telomerase with the single-stranded overhang of the chromosome end requires telomerase-DNA base pairing. Furthermore, we show that telomerase processivity contributes to telomere elongation in vivo. Together, these findings provide new insight into the dynamics of telomerase recruitment and the importance of processivity in maintaining telomere length in human cancer cells.},
}
@article {pmid29386102,
year = {2018},
author = {Grill, S and Tesmer, VM and Nandakumar, J},
title = {The N Terminus of the OB Domain of Telomere Protein TPP1 Is Critical for Telomerase Action.},
journal = {Cell reports},
volume = {22},
number = {5},
pages = {1132-1140},
pmid = {29386102},
issn = {2211-1247},
support = {R00 CA167644/CA/NCI NIH HHS/United States ; R01 AG050509/AG/NIA NIH HHS/United States ; R01 GM120094/GM/NIGMS NIH HHS/United States ; T32 GM007544/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chimera ; Humans ; Mice ; Models, Molecular ; Protein Domains ; Shelterin Complex ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; Telomere-Binding Proteins/*chemistry/*metabolism ; },
abstract = {Telomerase recruitment to telomeres and enzymatic processivity are mediated by TPP1, an essential component of telomere integrity and telomerase function. A surface on the OB domain of TPP1 called the TEL patch is critical for TPP1's telomerase-associated functions. Here, we identify a separate region in the N terminus of the OB domain (termed NOB) of TPP1 that, like the TEL patch, is essential for telomerase repeat addition processivity in vitro as well as telomerase recruitment to telomeres and telomere lengthening in cells. Although well-conserved among most mammalian TPP1 homologs, the NOB region in mice is distinct. Swapping the sequence of human NOB into mouse TPP1 allows it to stimulate human telomerase, qualifying NOB as an important determinant of species specificity for TPP1-telomerase interaction. Our studies show that TPP1 NOB is critical for telomerase function and demonstrate that the telomerase interaction surface on TPP1 is more elaborate than previously appreciated.},
}
@article {pmid29385523,
year = {2018},
author = {Reis, H and Schwebs, M and Dietz, S and Janzen, CJ and Butter, F},
title = {TelAP1 links telomere complexes with developmental expression site silencing in African trypanosomes.},
journal = {Nucleic acids research},
volume = {46},
number = {6},
pages = {2820-2833},
pmid = {29385523},
issn = {1362-4962},
mesh = {Animals ; Base Sequence ; Cell Line ; Host-Parasite Interactions ; Kinetics ; Protein Binding ; Protozoan Proteins/genetics/*metabolism ; RNA Interference ; Telomere/genetics/*metabolism ; Transcription, Genetic ; Trypanosoma brucei brucei/genetics/*metabolism/physiology ; Trypanosomiasis, African/blood/*metabolism/parasitology ; Tsetse Flies/parasitology ; Variant Surface Glycoproteins, Trypanosoma/genetics/metabolism ; },
abstract = {During its life cycle, Trypanosoma brucei shuttles between a mammalian host and the tsetse fly vector. In the mammalian host, immune evasion of T. brucei bloodstream form (BSF) cells relies on antigenic variation, which includes monoallelic expression and periodic switching of variant surface glycoprotein (VSG) genes. The active VSG is transcribed from only 1 of the 15 subtelomeric expression sites (ESs). During differentiation from BSF to the insect-resident procyclic form (PCF), the active ES is transcriptionally silenced. We used mass spectrometry-based interactomics to determine the composition of telomere protein complexes in T. brucei BSF and PCF stages to learn more about the structure and functions of telomeres in trypanosomes. Our data suggest a different telomere complex composition in the two forms of the parasite. One of the novel telomere-associated proteins, TelAP1, forms a complex with telomeric proteins TbTRF, TbRAP1 and TbTIF2 and influences ES silencing kinetics during developmental differentiation.},
}
@article {pmid29380856,
year = {2018},
author = {Zhang, WG and Jia, LP and Ma, J and Zhu, SY and Nie, SS and Song, KK and Liu, XM and Zhang, YP and Cao, D and Yang, XP and Zhao, DL and Xiu, MJ and Lin, L and Li, ZX and Huang, Q and Chen, XZ and Chen, L and Wang, P and Bai, XJ and Feng, Z and Fu, B and Hunag, J and Zhang, JP and Cai, GY and Sun, XF and Chen, XM},
title = {Peripheral Blood Leukocyte Telomere Length Is Associated with Age but Not Renal Function: A Cross-Sectional Follow-Up Study.},
journal = {The journal of nutrition, health &amp; aging},
volume = {22},
number = {2},
pages = {276-281},
pmid = {29380856},
issn = {1760-4788},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging ; Biomarkers/*blood ; Cross-Sectional Studies ; Cystatin C/*blood ; Female ; Follow-Up Studies ; Healthy Volunteers ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Telomere Homeostasis/*physiology ; },
abstract = {OBJECTIVES: We aimed to evaluate the relationship between baseline renal function and changes in telomere length in Han Chinese.<br><br>METHODS: The telomere restriction fragment (TRF) length of leukocytes in the peripheral blood was measured in healthy volunteers recruited in 2014. The estimated glomerular filtration rate (eGFR) was calculated based on serum creatinine (Scr) and serum cystatin C (CysC)-eGFRcys and eGFRScr-cys through the Cockcroft-Gault formula (eGFRC-G) or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI / eGFRCKD-EPI) equation. The correlation between telomere length changes over time and renal function was analyzed.<br><br>RESULTS: Leukocyte TRF lengths were negatively correlated to age (r = -0.393, p < 0.001) and serum CysC (r = -0.180, p < 0.01), while positively associated with eGFRCKD-EPI, eGFRC-G, eGFRcys, and eGFRScr-cys (r = 0.182, 0.122, 0.290, and 0.254 respectively, p < 0.01). The 3-year change of telomere length was 46 bp/years. When adjusted for age, the associations between telomere length changes and baseline, subsequent TRF lengths, and serum CysC were no longer present. No association was observed between TRF length changes and renal function.<br><br>CONCLUSION: The rate of telomere length changes was affected by age and baseline telomere length. The telomere length changes might be important markers for aging.},
}
@article {pmid29380327,
year = {2018},
author = {Tarry-Adkins, JL and Ozanne, SE},
title = {Telomere Length Analysis: A Tool for Dissecting Aging Mechanisms in Developmental Programming.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1735},
number = {},
pages = {351-363},
doi = {10.1007/978-1-4939-7614-0_24},
pmid = {29380327},
issn = {1940-6029},
support = {MC_UU_12012/4/MRC_/Medical Research Council/United Kingdom ; MC UU12012/04/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aging/genetics ; Blotting, Southern ; Disease Susceptibility ; Electrophoresis, Gel, Pulsed-Field ; Humans ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {Accelerated cellular aging is known to play an important role in the etiology of phenotypes associated with developmental programming, such as cardiovascular disease and type 2 diabetes. Telomere length analysis is a powerful tool to quantify cellular aging. Here we describe a telomere length methodology, refined to quantify discrete telomere length fragments. We have shown this method to be more sensitive in detecting small changes in telomere length than the traditional average telomere length comparisons.},
}
@article {pmid29379846,
year = {2018},
author = {},
title = {Erratum: Telomeres and Stress: Promising Avenues for Research in Psycho-Oncology.},
journal = {Asia-Pacific journal of oncology nursing},
volume = {5},
number = {1},
pages = {129},
pmid = {29379846},
issn = {2347-5625},
abstract = {[This corrects the article on p. 137 in vol. 3, PMID: 27981152.].},
}
@article {pmid29378675,
year = {2018},
author = {Povedano, JM and Martinez, P and Serrano, R and Tejera, &#xc1; and Gómez-López, G and Bobadilla, M and Flores, JM and Bosch, F and Blasco, MA},
title = {Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres.},
journal = {eLife},
volume = {7},
number = {},
pages = {},
pmid = {29378675},
issn = {2050-084X},
mesh = {Alveolar Epithelial Cells/physiology ; Animals ; Disease Models, Animal ; Gene Expression Profiling ; Genetic Therapy/*methods ; Lung/pathology/physiology ; Mice ; Pulmonary Fibrosis/pathology/*therapy ; Respiratory Function Tests ; Telomerase/genetics/*pharmacology ; Telomere/*metabolism ; Therapeutic Uses ; },
abstract = {Pulmonary fibrosis is a fatal lung disease characterized by fibrotic foci and inflammatory infiltrates. Short telomeres can impair tissue regeneration and are found both in hereditary and sporadic cases. We show here that telomerase expression using AAV9 vectors shows therapeutic effects in a mouse model of pulmonary fibrosis owing to a low-dose bleomycin insult and short telomeres. AAV9 preferentially targets regenerative alveolar type II cells (ATII). AAV9-Tert-treated mice show improved lung function and lower inflammation and fibrosis at 1-3 weeks after viral treatment, and improvement or disappearance of the fibrosis at 8 weeks after treatment. AAV9-Tert treatment leads to longer telomeres and increased proliferation of ATII cells, as well as lower DNA damage, apoptosis, and senescence. Transcriptome analysis of ATII cells confirms downregulation of fibrosis and inflammation pathways. We provide a proof-of-principle that telomerase activation may represent an effective treatment for pulmonary fibrosis provoked or associated with short telomeres.},
}
@article {pmid29378012,
year = {2018},
author = {Dvoráková, Z and Renciuk, D and Kejnovská, I and Školáková, P and Bednárová, K and Sagi, J and Vorlícková, M},
title = {i-Motif of cytosine-rich human telomere DNA fragments containing natural base lesions.},
journal = {Nucleic acids research},
volume = {46},
number = {4},
pages = {1624-1634},
pmid = {29378012},
issn = {1362-4962},
mesh = {Adenine/analogs &amp; derivatives/chemistry ; Cytosine/chemistry ; DNA/*chemistry ; DNA Damage ; Humans ; Pentoxyl/analogs &amp; derivatives/chemistry ; Telomere/*chemistry ; Uracil/chemistry ; },
abstract = {i-Motif (iM) is a four stranded DNA structure formed by cytosine-rich sequences, which are often present in functionally important parts of the genome such as promoters of genes and telomeres. Using electronic circular dichroism and UV absorption spectroscopies and electrophoretic methods, we examined the effect of four naturally occurring DNA base lesions on the folding and stability of the iM formed by the human telomere DNA sequence (C3TAA)3C3T. The results demonstrate that the TAA loop lesions, the apurinic site and 8-oxoadenine substituting for adenine, and the 5-hydroxymethyluracil substituting for thymine only marginally disturb the formation of iM. The presence of uracil, which is formed by enzymatic or spontaneous deamination of cytosine, shifts iM formation towards substantially more acidic pH values and simultaneously distinctly reduces iM stability. This effect depends on the position of the damage sites in the sequence. The results have enabled us to formulate additional rules for iM formation.},
}
@article {pmid29375617,
year = {2017},
author = {Strazhesko, ID and Tkacheva, ON and Akasheva, DU and Dudinskaya, EN and Plokhova, EV and Pykhtina, VS and Kruglikova, AS and Brailova, NV and Sharashkina, NV and Kashtanova, DA and Isaykina, OY and Pokrovskaya, MS and Vygodin, VA and Ozerova, IN and Skvortsov, DA and Boytsov, SA},
title = {Growth Hormone, Insulin-Like Growth Factor-1, Insulin Resistance, and Leukocyte Telomere Length as Determinants of Arterial Aging in Subjects Free of Cardiovascular Diseases.},
journal = {Frontiers in genetics},
volume = {8},
number = {},
pages = {198},
pmid = {29375617},
issn = {1664-8021},
abstract = {Background: Increased arterial stiffness (AS), intima-media thickness (IMT), and the presence of atherosclerotic plaques (PP) have been considered as important aspects of vascular aging. It is well documented that the cardiovascular system is an important target organ for growth hormone (GH) and insulin-like growth factor (IGF)-1 in humans, and GH /IGF-1 deficiency significantly increases the risk for cardiovascular diseases (CVD). The telomere length of peripheral blood leukocytes (LTL) is a biomarker of cellular senescence and that has been proposed as an independent predictor of (CVD). The aim of this study is to determine the role of GH/IGF-1, LTL and their interaction cardiovascular risk factors (CVRF) in the vascular aging. Methods: The study group included 303 ambulatory participants free of known CVD (104 males and 199 females) with a mean age of 51.8 ± 13.3 years. All subjects had one or more CVRF [age, smoking, arterial hypertension, obesity, dyslipidemia, fasting hyperglycemia, insulin resistance-HOMA (homeostatic model assessment) >2.5, or high glycated hemoglobin]. The study sample was divided into the two groups according to age as "younger" (m ≤ 45 years, f ≤ 55 years) and "older" (m > 45 years, f > 55 years). IMT and PP were determined by ultrasonography, AS was determined by measuring the carotid-femoral pulse wave velocity (c-f PWV) using the SphygmoCor system (AtCor Medical). LTL was determined by PCR. Serum IGF-1 and GH concentrations we measured by immunochemiluminescence analysis. Results: Multiple linear regression analysis with adjustment for CVRF indicated that HOMA, GH, IGF-1, and LTL had an independent relationship with all the arterial wall parameters investigated in the younger group. In the model with c-f PWV as a dependent variable, p < 0.001 for HOMA, p = 0.03 for GH, and p = 0.004 for LTL. In the model with IMT as a dependent variable, p = 0.0001 for HOMA, p = 0.044 for GH, and p = 0.004 for IGF-1. In the model with the number of plaques as a dependent variable, p = 0.0001 for HOMA, and p = 0.045 for IGF-1. In the older group, there were no independent significant associations between GH/IGF-1, LTL, HOMA, and arterial wall characteristics. Conclusions: GH/IGF-1, IR, HOMA, and LTL were the important parameters of arterial aging in younger healthy participants.},
}
@article {pmid29374141,
year = {2018},
author = {Melguizo-Sanchis, D and Xu, Y and Taheem, D and Yu, M and Tilgner, K and Barta, T and Gassner, K and Anyfantis, G and Wan, T and Elango, R and Alharthi, S and El-Harouni, AA and Przyborski, S and Adam, S and Saretzki, G and Samarasinghe, S and Armstrong, L and Lako, M},
title = {iPSC modeling of severe aplastic anemia reveals impaired differentiation and telomere shortening in blood progenitors.},
journal = {Cell death &amp; disease},
volume = {9},
number = {2},
pages = {128},
pmid = {29374141},
issn = {2041-4889},
support = {BB/E012841/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; G0301182/MRC_/Medical Research Council/United Kingdom ; BB/I020209/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Anemia, Aplastic/*pathology ; Benzoates/pharmacology ; Case-Control Studies ; *Cell Differentiation/drug effects ; Cell Line ; Cell Proliferation/drug effects ; Colony-Forming Units Assay ; Fibroblasts/drug effects/metabolism/pathology ; Hematopoietic Stem Cells/metabolism/*pathology ; Humans ; Hydrazines/pharmacology ; Induced Pluripotent Stem Cells/drug effects/metabolism/*pathology ; *Models, Biological ; Pyrazoles/pharmacology ; Telomerase/metabolism ; Telomere/metabolism ; *Telomere Shortening/drug effects ; },
abstract = {Aplastic Anemia (AA) is a bone marrow failure (BMF) disorder, resulting in bone marrow hypocellularity and peripheral pancytopenia. Severe aplastic anemia (SAA) is a subset of AA defined by a more severe phenotype. Although the immunological nature of SAA pathogenesis is widely accepted, there is an increasing recognition of the role of dysfunctional hematopoietic stem cells in the disease phenotype. While pediatric SAA can be attributable to genetic causes, evidence is evolving on previously unrecognized genetic etiologies in a proportion of adults with SAA. Thus, there is an urgent need to better understand the pathophysiology of SAA, which will help to inform the course of disease progression and treatment options. We have derived induced pluripotent stem cell (iPSC) from three unaffected controls and three SAA patients and have shown that this in vitro model mimics two key features of the disease: (1) the failure to maintain telomere length during the reprogramming process and hematopoietic differentiation resulting in SAA-iPSC and iPSC-derived-hematopoietic progenitors with shorter telomeres than controls; (2) the impaired ability of SAA-iPSC-derived hematopoietic progenitors to give rise to erythroid and myeloid cells. While apoptosis and DNA damage response to replicative stress is similar between the control and SAA-iPSC-derived-hematopoietic progenitors, the latter show impaired proliferation which was not restored by eltrombopag, a drug which has been shown to restore hematopoiesis in SAA patients. Together, our data highlight the utility of patient specific iPSC in providing a disease model for SAA and predicting patient responses to various treatment modalities.},
}
@article {pmid29368815,
year = {2017},
author = {Lardy, S and Gasparini, J and Corbel, H and Frantz, A and Perret, S and Zahn, S and Criscuolo, F and Jacquin, L},
title = {Telomere erosion varies with sex and age at immune challenge but not with maternal antibodies in pigeons.},
journal = {Journal of experimental zoology. Part A, Ecological and integrative physiology},
volume = {327},
number = {9},
pages = {562-569},
doi = {10.1002/jez.2142},
pmid = {29368815},
issn = {2471-5646},
mesh = {Age Factors ; Animals ; Antibodies/immunology ; Columbidae/*immunology/physiology ; Female ; Immune System ; Immunity, Maternally-Acquired/*immunology ; Male ; Sex Factors ; Telomere Shortening/*immunology ; },
abstract = {Conditions experienced early in life have profound impact on adult fitness, and telomere erosion could be a key mechanism in this process. In particular, early exposure to parasites is a frequent phenomenon in young vertebrates, which is associated with several short- and long-term costs such as telomere erosion. However, the timing of exposure to parasites during ontogeny and maternal antibodies can strongly modulate the costs of immunity, and could differentially affect telomere erosion. Here, we compared the effects of an early or late immune challenge on telomere erosion rate in male and female young feral pigeons (Columba livia) having received or not maternal antibodies. More specifically, we tested whether (i) early or late injections of antigens had different effects on nestling telomere erosion rate, (ii) whether this effect was different between male and female nestlings, and (iii) whether maternal antibodies could modulate telomere erosion rate. Our results show an interaction between sex and age at injection. Late-injected nestlings (injected at 14 days of age) had an accelerated erosion rate compared with the early-injected nestlings (injected at 3 days of age), and this effect was higher in females compared with the males. However, we did not find any effect of maternal antibodies on telomere erosion rate. These results suggest that the age at which an immune challenge occurs is important for telomere erosion and that sex-specific approaches are needed to better understand the short-term and long-term costs of parasite exposure in young vertebrates.},
}
@article {pmid29362826,
year = {2018},
author = {Hjort, L and Vryer, R and Grunnet, LG and Burgner, D and Olsen, SF and Saffery, R and Vaag, A},
title = {Telomere length is reduced in 9- to 16-year-old girls exposed to gestational diabetes in utero.},
journal = {Diabetologia},
volume = {61},
number = {4},
pages = {870-880},
pmid = {29362826},
issn = {1432-0428},
support = {HHSN275201000020C/HD/NICHD NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Anthropometry ; Birth Weight ; Blood Glucose/metabolism ; Child ; Cohort Studies ; Denmark ; Diabetes, Gestational/*physiopathology ; Female ; Gestational Age ; Humans ; Insulin/blood ; K562 Cells ; Male ; Multivariate Analysis ; Polymerase Chain Reaction ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Sex Factors ; *Telomere Shortening ; },
abstract = {AIMS/HYPOTHESIS: Shortened telomere length is a marker of cell damage and is associated with oxidative stress, chronic inflammation and metabolic disease. We hypothesised that the offspring of women with gestational diabetes mellitus (GDM) with increased risk of cardiovascular and metabolic diseases might exhibit shorter telomere length.<br><br>METHODS: We investigated telomere length in 439 GDM and 469 control group offspring, aged between 9 and 16&#xa0;years, recruited from the Danish National Birth Cohort. Relative telomere length was measured in peripheral blood DNA (n&#x2009;=&#x2009;908) using a quantitative PCR approach. Multivariate regression analysis was used to investigate the association between mothers' GDM status and telomere length in the offspring.<br><br>RESULTS: Female offspring had longer telomeres than males. Offspring of mothers with GDM had significantly shorter telomere length than control offspring, but this difference was observed only in girls. There was a negative association between telomere length and GDM exposure among the female offspring (14% shorter telomeres, p&#x2009;=&#x2009;0.003) following adjustment for the age of the offspring. Telomere length in female offspring was negatively associated with fasting insulin levels and HOMA-IR (p&#x2009;=&#x2009;0.03). Maternal age, smoking, gestational age, birthweight and the offspring's anthropometric characteristics were not associated with telomere length (p&#x2009;&#x2265;&#x2009;0.1).<br><br>CONCLUSIONS/INTERPRETATION: The 9- to 16-year-old girls of mothers with GDM had shorter telomeres than those from the control population. Further studies are needed to understand the extent to which shortened telomere length predicts and/or contributes to the increased risk of disease later in life among the offspring of women with GDM.},
}
@article {pmid29361030,
year = {2018},
author = {Cubiles, MD and Barroso, S and Vaquero-Sedas, MI and Enguix, A and Aguilera, A and Vega-Palas, MA},
title = {Epigenetic features of human telomeres.},
journal = {Nucleic acids research},
volume = {46},
number = {5},
pages = {2347-2355},
pmid = {29361030},
issn = {1362-4962},
support = {15-0098/AICR_/Worldwide Cancer Research/United Kingdom ; },
mesh = {Cell Line, Tumor ; Chromatin Immunoprecipitation ; *Epigenesis, Genetic ; Heterochromatin/metabolism ; Histone Code ; Humans ; Telomere/*metabolism ; },
abstract = {Although subtelomeric regions in humans are heterochromatic, the epigenetic nature of human telomeres remains controversial. This controversy might have been influenced by the confounding effect of subtelomeric regions and interstitial telomeric sequences (ITSs) on telomeric chromatin structure analyses. In addition, different human cell lines might carry diverse epigenetic marks at telomeres. We have developed a reliable procedure to study the chromatin structure of human telomeres independently of subtelomeres and ITSs. This procedure is based on the statistical analysis of multiple ChIP-seq experiments. We have found that human telomeres are not enriched in the heterochromatic H3K9me3 mark in most of the common laboratory cell lines, including embryonic stem cells. Instead, they are labeled with H4K20me1 and H3K27ac, which might be established by p300. These results together with previously published data argue that subtelomeric heterochromatin might control human telomere functions. Interestingly, U2OS cells that exhibit alternative lengthening of telomeres have heterochromatic levels of H3K9me3 in their telomeres.},
}
@article {pmid29360938,
year = {2018},
author = {Yuan, J and Liu, Y and Wang, J and Zhao, Y and Li, K and Jing, Y and Zhang, X and Liu, Q and Geng, X and Li, G and Wang, F},
title = {Long-term Persistent Organic Pollutants Exposure Induced Telomere Dysfunction and Senescence-Associated Secretary Phenotype.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {73},
number = {8},
pages = {1027-1035},
pmid = {29360938},
issn = {1758-535X},
mesh = {Adult ; Aging/*drug effects ; Blotting, Southern ; DNA Methylation/drug effects ; Environmental Exposure/*adverse effects ; Environmental Pollutants/*adverse effects ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Lymphocytes/drug effects ; Male ; Microscopy, Fluorescence ; Real-Time Polymerase Chain Reaction ; Telomere/*drug effects ; Telomere Shortening/drug effects ; },
abstract = {Environmentally persistent organic pollutant (POP) is the general term for refractory organic compounds that show long-range atmospheric transport, environmental persistence, and bioaccumulation. It has been reported that the accumulation of POPs could lead to cellular DNA damage and adverse effects of on metabolic health. To better understand the mechanism of the health risks associated with POPs, we conducted an evidence-based cohort investigation (n = 5,955) at the Jinghai e-waste disposal center in China from 2009 to 2016, where people endure serious POP exposure. And high levels of aging-related diseases, including hypertension, diabetes, autoimmune diseases, and reproductive disorders were identified associated with the POP exposure. In the subsequent molecular level study, an increased telomere dysfunction including telomere multiple telomere signals, telomere signal-free ends, telomere shortening and activation of alternative lengthening of telomeres were observed, which might result from the hypomethylated DNA modification induced telomeric repeat-containing RNA overexpression. Moreover, dysfunctional telomere-leaded senescence-associated secretory phenotype was confirmed, as the proinflammatory cytokines and immunosenescence hallmarks including interleukin-6, P16INK4a, and P14ARF were stimulated. Thus, we proposed that the dysfunctional telomere and elevated systemic chronic inflammation contribute to the aging-associated diseases, which were highly developed among the POP exposure individuals.},
}
@article {pmid29360532,
year = {2018},
author = {Feiler, MO and Patel, D and Li, H and Meacham, PJ and Watson, GE and Shamlaye, C and Yeates, A and Broberg, K and van Wijngaarden, E},
title = {The association between early-life relative telomere length and childhood neurodevelopment.},
journal = {Neurotoxicology},
volume = {65},
number = {},
pages = {22-27},
pmid = {29360532},
issn = {1872-9711},
support = {P30 ES001247/ES/NIEHS NIH HHS/United States ; R01 ES010219/ES/NIEHS NIH HHS/United States ; R01 ES015578/ES/NIEHS NIH HHS/United States ; },
mesh = {Child Development/*physiology ; Child, Preschool ; Female ; Fetal Blood ; Humans ; Infant ; Infant, Newborn ; Male ; Neuropsychological Tests ; Telomere/*physiology ; Telomere Homeostasis/physiology ; },
abstract = {PURPOSE: To examine the association between telomere length and neurodevelopment in children.<br><br>METHODS: We examined the relationship between relative telomere length (rTL) and neurodevelopmental outcomes at 9 and 30 months, and 5 years of age in children enrolled in the Seychelles Child Development Study Nutrition Cohort 1 (NC1). Relative telomere length was measured in cord blood and in child blood at age five. Multivariable linear regression examined associations between neurodevelopmental outcomes and rTL adjusting for relevant covariates.<br><br>RESULTS: Mean rTL was 1.18 at birth and 0.71 at age five. Increased cord blood rTL was associated with better scores on two neurodevelopmental tests, the psychomotor developmental index (&#x3b2;&#x202f;=&#x202f;4.01; 95% confidence interval (CI)&#x202f;=&#x202f;0.17, 7.85) at age 30 months, and the Woodcock Johnson test of achievement letter-word score (&#x3b2;&#x202f;=&#x202f;2.88; CI&#x202f;=&#x202f;1.21-4.56) at age five. The Woodcock Johnson test of achievement letter-word score remained statistically significant after two outliers were excluded (&#x3b2;&#x202f;=&#x202f;2.83; CI&#x202f;=&#x202f;0.69, 4.97); the psychomotor developmental index did not (&#x3b2;&#x202f;=&#x202f;3.62; CI&#x202f;=&#x202f;-1.28, 8.52). None of the neurodevelopmental outcomes at age five were associated with five-year rTL.<br><br>CONCLUSION: Although increased cord blood rTL was associated with better test scores for a few neurodevelopmental outcomes, this study found little consistent evidence of an association between rTL and neurodevelopment. Future studies with a larger sample size, longer follow-up, and other relevant biological markers (e.g. oxidative stress) are needed to clarify the role of rTL in neurodevelopment and its relevance as a potential surrogate measure for oxidative stress in the field of developmental neurotoxicity.},
}
@article {pmid29359819,
year = {2018},
author = {Rackwitz, J and Bald, I},
title = {Low-Energy Electron-Induced Strand Breaks in Telomere-Derived DNA Sequences-Influence of DNA Sequence and Topology.},
journal = {Chemistry (Weinheim an der Bergstrasse, Germany)},
volume = {24},
number = {18},
pages = {4680-4688},
doi = {10.1002/chem.201705889},
pmid = {29359819},
issn = {1521-3765},
mesh = {DNA/*radiation effects ; DNA Damage ; Electrons ; G-Quadruplexes ; Neoplasms/radiotherapy ; Phototherapy ; Telomere/*metabolism ; },
abstract = {During cancer radiation therapy high-energy radiation is used to reduce tumour tissue. The irradiation produces a shower of secondary low-energy (<20 eV) electrons, which are able to damage DNA very efficiently by dissociative electron attachment. Recently, it was suggested that low-energy electron-induced DNA strand breaks strongly depend on the specific DNA sequence with a high sensitivity of G-rich sequences. Here, we use DNA origami platforms to expose G-rich telomere sequences to low-energy (8.8 eV) electrons to determine absolute cross sections for strand breakage and to study the influence of sequence modifications and topology of telomeric DNA on the strand breakage. We find that the telomeric DNA 5'-(TTA GGG)2 is more sensitive to low-energy electrons than an intermixed sequence 5'-(TGT GTG A)2 confirming the unique electronic properties resulting from G-stacking. With increasing length of the oligonucleotide (i.e., going from 5'-(GGG ATT)2 to 5'-(GGG ATT)4), both the variety of topology and the electron-induced strand break cross sections increase. Addition of K[+] ions decreases the strand break cross section for all sequences that are able to fold G-quadruplexes or G-intermediates, whereas the strand break cross section for the intermixed sequence remains unchanged. These results indicate that telomeric DNA is rather sensitive towards low-energy electron-induced strand breakage suggesting significant telomere shortening that can also occur during cancer radiation therapy.},
}
@article {pmid29359122,
year = {2017},
author = {He, J and Mansouri, A and Das, S},
title = {Alpha Thalassemia/Mental Retardation Syndrome X-Linked, the Alternative Lengthening of Telomere Phenotype, and Gliomagenesis: Current Understandings and Future Potential.},
journal = {Frontiers in oncology},
volume = {7},
number = {},
pages = {322},
pmid = {29359122},
issn = {2234-943X},
abstract = {Gliomas are the most common primary malignant brain tumor in humans. Lower grade gliomas are usually less aggressive but many cases eventually progress to a more aggressive secondary glioblastoma (GBM, WHO Grade IV), which has a universally fatal prognosis despite maximal surgical resection and concurrent chemo-radiation. With the identification of molecular markers, however, there is promise for improving diagnostic and therapeutic strategies. One of the key molecular alterations in gliomas is the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, which is frequently mutated. One-third of pediatric GBM cases are also found to have the ATRX mutation and the genetic signatures are different from adult cases. The exact role of ATRX mutations in gliomagenesis, however, is unclear. In this review, we describe the normal cellular function of the ATRX gene product followed by consequences of its dysfunction. Furthermore, its possible association with the alternative lengthening of telomeres (ALT) phenotype is outlined. Lastly, therapeutic options potentiated through a better understanding of ATRX and the ALT phenotype are explored.},
}
@article {pmid29358629,
year = {2018},
author = {Farmery, JHR and Smith, ML and , and Lynch, AG},
title = {Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {1300},
pmid = {29358629},
issn = {2045-2322},
support = {MC_UU_00002/10/MRC_/Medical Research Council/United Kingdom ; MR/L006197/1/MRC_/Medical Research Council/United Kingdom ; MC_EX_MR/S300011/1/MRC_/Medical Research Council/United Kingdom ; MR/K023489/1/MRC_/Medical Research Council/United Kingdom ; MR/L006340/1/MRC_/Medical Research Council/United Kingdom ; 20406/CRUK_/Cancer Research UK/United Kingdom ; G84/6443/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; },
mesh = {*Algorithms ; Carcinoma, Hepatocellular/*genetics/metabolism/pathology ; Gene Expression ; Genotype ; Humans ; Induced Pluripotent Stem Cells ; Liver Neoplasms/*genetics/metabolism/pathology ; Mesenchymal Stem Cells/cytology/metabolism ; Ploidies ; Primary Cell Culture ; Telomerase/*genetics/metabolism ; Telomere/*chemistry ; *Telomere Homeostasis ; Whole Genome Sequencing ; },
abstract = {Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype.},
}
@article {pmid29353868,
year = {2017},
author = {Kanoh, J},
title = {Telomeres and subtelomeres: new insights into the chromatin structures and functions of chromosome ends.},
journal = {Genes &amp; genetic systems},
volume = {92},
number = {3},
pages = {105},
doi = {10.1266/ggs.17-10001},
pmid = {29353868},
issn = {1880-5779},
mesh = {Animals ; Chromatin/chemistry/*physiology ; Chromosomes/chemistry/physiology ; Humans ; Molecular Structure ; Telomere/*physiology ; },
}
@article {pmid29353801,
year = {2018},
author = {Ling, X and Yang, W and Zou, P and Zhang, G and Wang, Z and Zhang, X and Chen, H and Peng, K and Han, F and Liu, J and Cao, J and Ao, L},
title = {TERT regulates telomere-related senescence and apoptosis through DNA damage response in male germ cells exposed to BPDE in vitro and to B[a]P in vivo.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {235},
number = {},
pages = {836-849},
doi = {10.1016/j.envpol.2017.12.099},
pmid = {29353801},
issn = {1873-6424},
mesh = {7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide/*toxicity ; Animals ; Apoptosis/drug effects ; Benzo(a)pyrene/*toxicity ; Cell Survival/drug effects ; Cells, Cultured ; Cellular Senescence/drug effects ; *DNA Damage/drug effects ; Gene Knockdown Techniques ; Male ; Mice ; Rats ; Spermatocytes/*drug effects ; Telomerase/genetics/metabolism ; Telomere/*drug effects ; },
abstract = {Increasing evidence shows that impaired telomere function is associated with male infertility, and various environmental factors are believed to play a pivotal role in telomerase deficiency and telomere shortening. Benzo[a]pyrene (B[a]P), a ubiquitous pollutant of polycyclic aromatic hydrocarbons (PAHs), can act as a reproductive toxicant; however, the adverse effect of B[a]P on telomeres in male reproductive cells has never been studied, and the related mechanisms remain unclear. In this study, we explored the effects of benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), the active metabolite of B[a]P, on telomere dysfunction in mouse spermatocyte-derived cells (GC-2) and also the potential role of telomerase in BPDE-induced spermatogenic cell damage. The results showed that BPDE induced cell viability inhibition, senescence, and apoptosis in GC-2 cells in a dose-dependent manner. Shortened telomeres, telomere-associated DNA damage, reduced telomerase activity, and TERT expression were also observed in BPDE-treated cells, accompanied with the activation of DNA damage response pathway (ATM/Chk1/p53/p21). Moreover, by establishing the TERT knockdown and re-expression cell models, we found that TERT regulated telomere length and the expression of DNA damage response-related proteins to influence senescence and apoptosis in GC-2 cells. These in vitro findings were further confirmed in vivo in the testicular cells of rats orally administrated with B[a]P for 7 days. B[a]P treatment resulted in histological lesions, apoptosis, and senescence in the testes of rats, which were accompanied by shortened telomeres, reduced levels of TERT protein, and increased expression of DNA damage response-related proteins. In conclusion, it can be concluded that TERT-mediated telomere dysfunction contributes to B[a]P- and BPDE-induced senescence and apoptosis through DNA damage response in male reproductive cells.},
}
@article {pmid29351238,
year = {2018},
author = {Bernal, A and Tusell, L},
title = {Telomeres: Implications for Cancer Development.},
journal = {International journal of molecular sciences},
volume = {19},
number = {1},
pages = {},
pmid = {29351238},
issn = {1422-0067},
mesh = {Apoptosis/genetics ; Carcinogenesis/*genetics ; Cellular Senescence/genetics ; Chromosomal Instability/genetics ; Genomic Instability/genetics ; Humans ; Neoplasms/*genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis/genetics ; },
abstract = {Telomeres facilitate the protection of natural ends of chromosomes from constitutive exposure to the DNA damage response (DDR). This is most likely achieved by a lariat structure that hides the linear telomeric DNA through protein-protein and protein-DNA interactions. The telomere shortening associated with DNA replication in the absence of a compensatory mechanism culminates in unmasked telomeres. Then, the subsequent activation of the DDR will define the fate of cells according to the functionality of cell cycle checkpoints. Dysfunctional telomeres can suppress cancer development by engaging replicative senescence or apoptotic pathways, but they can also promote tumour initiation. Studies in telomere dynamics and karyotype analysis underpin telomere crisis as a key event driving genomic instability. Significant attainment of telomerase or alternative lengthening of telomeres (ALT)-pathway to maintain telomere length may be permissive and required for clonal evolution of genomically-unstable cells during progression to malignancy. We summarise current knowledge of the role of telomeres in the maintenance of chromosomal stability and carcinogenesis.},
}
@article {pmid29346668,
year = {2018},
author = {Olivier, M and Charbonnel, C and Amiard, S and White, CI and Gallego, ME},
title = {RAD51 and RTEL1 compensate telomere loss in the absence of telomerase.},
journal = {Nucleic acids research},
volume = {46},
number = {5},
pages = {2432-2445},
pmid = {29346668},
issn = {1362-4962},
mesh = {Arabidopsis/enzymology/*genetics ; Arabidopsis Proteins/analysis/*physiology ; DNA Helicases/*physiology ; DNA Replication ; Genomic Instability ; Homologous Recombination ; Mutation ; Rad51 Recombinase/analysis/*physiology ; Repetitive Sequences, Nucleic Acid ; Ribonucleases/genetics ; Stochastic Processes ; Telomerase/genetics ; Telomere/chemistry ; *Telomere Shortening ; },
abstract = {Replicative erosion of telomeres is naturally compensated by telomerase and studies in yeast and vertebrates show that homologous recombination can compensate for the absence of telomerase. We show that RAD51 protein, which catalyzes the key strand-invasion step of homologous recombination, is localized at Arabidopsis telomeres in absence of telomerase. Blocking the strand-transfer activity of the RAD51 in telomerase mutant plants results in a strikingly earlier onset of developmental defects, accompanied by increased numbers of end-to-end chromosome fusions. Imposing replication stress through knockout of RNaseH2 increases numbers of chromosome fusions and reduces the survival of these plants deficient for telomerase and homologous recombination. This finding suggests that RAD51-dependent homologous recombination acts as an essential backup to the telomerase for compensation of replicative telomere loss to ensure genome stability. Furthermore, we show that this positive role of RAD51 in telomere stability is dependent on the RTEL1 helicase. We propose that a RAD51 dependent break-induced replication process is activated in cells lacking telomerase activity, with RTEL1 responsible for D-loop dissolution after telomere replication.},
}
@article {pmid29346517,
year = {2018},
author = {Brown, LL and Zhang, YS and Mitchell, C and Ailshire, J},
title = {Does Telomere Length Indicate Biological, Physical, and Cognitive Health Among Older Adults? Evidence from the Health and Retirement Study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {73},
number = {12},
pages = {1626-1632},
pmid = {29346517},
issn = {1758-535X},
support = {P30 AG066615/AG/NIA NIH HHS/United States ; K99 AG070274/AG/NIA NIH HHS/United States ; P30 AG017265/AG/NIA NIH HHS/United States ; R00 AG039528/AG/NIA NIH HHS/United States ; U01 AG009740/AG/NIA NIH HHS/United States ; T32 AG000037/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Cognition Disorders/*genetics/physiopathology ; Cohort Studies ; Female ; Healthy Aging/*genetics ; Humans ; Logistic Models ; Longevity/genetics ; Longitudinal Studies ; Male ; Middle Aged ; Physical Fitness/*physiology ; Predictive Value of Tests ; *Quality of Life ; Retirement ; Telomere/genetics ; Telomere Shortening/*genetics ; },
abstract = {Telomere length (TL) has been suggested as a biomarker that can indicate individual variability in the rate of aging. Yet, it remains unclear whether TL is related to recognized indicators of health in an aging, older nationally representative sample. We examine whether TL is associated with 15 biological, physical, and cognitive markers of health among older adults ages 54+. TL was assayed from saliva using quantitative polymerase chain reaction (T/S ratio) in the 2008 Health and Retirement Study (n = 4,074). We estimated probability of high-risk levels across indictors of health by TL and age-singly and jointly. TL was associated with seven indicators of poor functioning: high-density lipoprotein and total cholesterol, cystatin C, pulse pressure, body mass index, lung function, and walking speed. However, after adjusting for age, associations were substantially attenuated; only associations with cholesterol and lung function remained significant. Additionally, findings show TL did not add to the predictive power of chronological age in predicting poor functioning. While TL may not be a useful clinical marker of functional aging in an older adult population, it may still play an important role in longitudinal studies in young and middle aged populations that attempt to understand aging.},
}
@article {pmid29344960,
year = {2018},
author = {Sawhney, V and Brouilette, S and Campbell, N and Coppen, S and Baker, V and Hunter, R and Dhinoja, M and Johnston, A and Earley, M and Sporton, S and Suzuki, K and Schilling, R},
title = {Association of genetic variation in telomere-related SNP and telomerase with ventricular arrhythmias in ischemic cardiomyopathy.},
journal = {Pacing and clinical electrophysiology : PACE},
volume = {41},
number = {3},
pages = {261-266},
doi = {10.1111/pace.13284},
pmid = {29344960},
issn = {1540-8159},
mesh = {Aged ; Alleles ; Arrhythmias, Cardiac/enzymology/*genetics ; Cardiomyopathies/enzymology/*genetics ; Case-Control Studies ; Cross-Sectional Studies ; Defibrillators, Implantable ; Female ; Genetic Variation ; Genotype ; Humans ; Male ; Myocardial Ischemia/enzymology/*genetics ; Polymerase Chain Reaction ; *Polymorphism, Single Nucleotide ; Retrospective Studies ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {BACKGROUND: Telomeres are known to provide genomic stability and telomere length has been associated with cardiovascular diseases. Moreover, a higher telomerase activity has been shown to be associated with ventricular arrhythmias (VA) in ischemic cardiomyopathy. Increasing evidence suggests that genetic variation in key telomere genes has an impact on telomerase activity. Each copy of the minor allele of SNP rs12696304, at a locus including TERC (telomerase), has been associated with ∼75 base pairs reduction in mean telomere length likely mediated by an effect on TERC expression. We investigated the impact of genetic variation of this SNP on telomerase and its association with VA in ischemic cardiomyopathy patients.<br><br>METHODS AND RESULTS: Ninety ischemic cardiomyopathy patients with primary prevention implantable cardioverter defibrillators (ICDs) were recruited. Thirty-five received appropriate ICD therapy for potentially fatal VA (cases), while the remaining 55 patients did not (controls). No significant differences in baseline demographics were seen between the groups. TS was measured by qPCR, telomerase activity by TRAP assay, and SNP genotyping with Taqman probes. Telomerase was highest in C homozygous allele and had a significant association with VA in this group only (C/C,C/G,G/G; P-value 0.04, 0.33, 0.43).<br><br>CONCLUSION: The present study is the first to examine the association between telomerase, a SNP at a locus including TERC, and VA in ischemic cardiomyopathy patients. Homozygosity for C-allele significantly effects telomerase expression and its association with VA in this cohort. Large-scale prospective studies are required to determine if this genetic variation predisposes patients to greater arrhythmic tendency post-MI.},
}
@article {pmid29344273,
year = {2018},
author = {Gu, CY and Li, GX and Zhu, Y and Xu, H and Zhu, Y and Qin, XJ and Bo, D and Ye, DW},
title = {A single nucleotide polymorphism in CYP1B1 leads to differential prostate cancer risk and telomere length.},
journal = {Journal of Cancer},
volume = {9},
number = {2},
pages = {269-274},
pmid = {29344273},
issn = {1837-9664},
abstract = {BACKGROUND: Cytochrome P450 1B1 (CYP1B1) is a key enzyme in its oestrogen metabolism pathway, giving rise to hydroxylation and conjugation. Functionally relevant genetic variants within CYP1B1 may affect the telomere length and subsequently lead to prostate carcinogenesis. METHODS: We evaluated 8 CYP1B1 tag single nucleotide polymorphisms (SNPs) in 1015 men with prostate cancer (PCa) and 1052 cancer-free controls, and calculated odds ratios (ORs) and 95% confidence intervals (CIs) to estimate their association with risk of PCa. The influence of CYP1B1 SNPs on the relative telomere lengths was then appraised in peripheral blood leukocytes using real-time PCR. RESULTS:CYP1B1 rs1056836 variant was associated with decreased risk of PCa [odds ratio (OR): 0.80; 95% confidence interval (CI): 0.68-0.99, P = 0.041]. Longer telomere length showed a significantly higher proportion of the CYP1B1 rs1056836 CG/GG genotypes, compared with that of the CC genotype (OR: 1.60, 95% CI: 1.04-2.45). CONCLUSION: Our findings suggest that genetic variants within CYP1B1 may confer genetic susceptibility to PCa by altering telomere length.},
}
@article {pmid29344158,
year = {2017},
author = {Zeng, L and Wang, YL and Wang, F and Cui, SQ and Hu, L and Huang, DN and Hou, G},
title = {Construction of the POT1 promoter report gene vector, and the effect and underlying mechanism of the POT1 promoter in regulating telomerase and telomere length.},
journal = {Oncology letters},
volume = {14},
number = {6},
pages = {7232-7240},
pmid = {29344158},
issn = {1792-1074},
abstract = {By using human genomic DNA as a template to clone protection of telomere 1 (POT1) promoter gene segments and construct the POT1 promoter luciferase report gene vector (pGL3-Control-POT1-promoter), the association between POT1, and the regulation of telomerase and telomere length was investigated. In the present study, two recombinant luciferase report gene vectors were constructed, which included different regions of the POT1 promoter. The plasmids were transformed into DH5α and the positive clones were obtained. The two plasmids termed as pGL3-Control-POT1-promoter-1 and pGL3-Control-POT1-promoter-2, were confirmed using restriction enzyme analysis and sequencing. They were separately and transiently transfected into four types of human tumor cells (A549, H460, HepG2 and HeLa). The transcriptional activities of the POT1 promoter were verified using the dual-luciferase assay. The relative expression of POT1 and human telomerase reverse transcriptase (hTERT), and telomere length were analyzed using quantitative polymerase chain reaction in the four types of non-transfected tumor cells. Using SPSS software, correlations between POT1 promoter activity, and POT1 expression, hTERT expression and telomere length were analyzed. Two POT1 promoter fragments (POT1-promoter-1 and -2) were successfully constructed into the pGL3-Control luciferase report gene vector. POT1-promoter-1 exhibited significantly stronger transcription activity compared with POT1-promoter-2. The results of the partial correlation and linear regression analyses were similar: POT1 promoter activity was identified to be significantly and positively correlated with POT1 expression and telomere length (partial correlation coefficients, both P<0.05; linear regression, both P<0.01). However, POT1 promoter activity and hTERT expression were significantly negatively correlated (both P<0.05). The results obtained in the present study suggest that the POT1 promoter influences telomere length. Furthermore, these data indicated that POT1 promoter activity and POT1, as well as telomere length, may be a useful biomarker for tumor detection and future patient prognosis.},
}
@article {pmid29337080,
year = {2018},
author = {Biswas, U and Stevense, M and Jessberger, R},
title = {SMC1α Substitutes for Many Meiotic Functions of SMC1β but Cannot Protect Telomeres from Damage.},
journal = {Current biology : CB},
volume = {28},
number = {2},
pages = {249-261.e4},
pmid = {29337080},
issn = {1879-0445},
mesh = {Animals ; Cell Cycle Proteins/*metabolism ; Chromosomal Proteins, Non-Histone/*metabolism ; Female ; Male ; *Meiosis ; Mice ; Telomere/*physiology ; },
abstract = {The cohesin complex is built upon the SMC1/SMC3 heterodimer, and mammalian meiocytes feature two variants of SMC1 named SMC1α and SMC1β. It is unclear why these two SMC1 variants have evolved. To determine unique versus redundant functions of SMC1β, we asked which of the known functions of SMC1β can be fulfilled by SMC1α. Smc1α was expressed under control of the Smc1β promoter in either wild-type or SMC1β-deficient mice. No effect was seen in the former. However, several major phenotypes of SMC1β-deficient spermatocytes were rescued by SMC1α. We observed extended development before apoptosis and restoration of axial element and synaptonemal complex lengths, chromosome synapsis, sex body formation, processing of DNA double-strand breaks, and formation of MLH1 recombination foci. This supports the concept that the quantity rather than the specific quality of cohesin complexes is decisive for meiotic chromosome architecture. It also suggests plasticity in complex composition, because to replace SMC1β in many functions, SMC1α has to more extensively associate with other cohesins. The cells did not complete meiosis but died to the latest at the pachytene-to-diplotene transition. Telomere aberrations known from Smc1β[-/-] mice persisted, and DNA damage response and repair proteins accumulated there regardless of expression of SMC1α. Thus, whereas SMC1α can substitute for SMC1β in many functions, the protection of telomere integrity requires SMC1β.},
}
@article {pmid29335812,
year = {2018},
author = {Torra-Massana, M and Barragán, M and Bellu, E and Oliva, R and Rodríguez, A and Vassena, R},
title = {Sperm telomere length in donor samples is not related to ICSI outcome.},
journal = {Journal of assisted reproduction and genetics},
volume = {35},
number = {4},
pages = {649-657},
pmid = {29335812},
issn = {1573-7330},
support = {GENCAT 2015 DI 049//Secretary for Universities and Research of the Ministry of Economy and Knowledge of the Government of Catalonia/ ; },
mesh = {Adolescent ; Adult ; Female ; Fertilization in Vitro/*methods ; Humans ; Male ; Middle Aged ; Pregnancy ; Pregnancy Outcome ; Pregnancy Rate ; *Sperm Injections, Intracytoplasmic ; Spermatozoa/*metabolism ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; *Tissue Donors ; Young Adult ; },
abstract = {PURPOSE: Variations in sperm telomere length (STL) have been associated with altered sperm parameters, poor embryo quality, and lower pregnancy rates, but for normozoospermic men, STL relevance in IVF/ICSI is still uncertain. Moreover, in all studies reported so far, each man's STL was linked to the corresponding female partner characteristics. Here, we study STL in sperm donor samples, each used for up to 12 women, in order to isolate and determine the relationship between STL and reproductive outcomes.<br><br>METHODS: Relative STL was determined by qPCR in 60 samples used in a total of 676 ICSI cycles. Univariable and multivariable statistical analyses were used to study the STL effect on fertilization rate; embryo morphology; biochemical, clinical, and ongoing pregnancy rates; and live birth (LB) rates.<br><br>RESULTS: The average STL value was 4.5 (relative units; SD 1.9; range 2.4-14.2). Locally weighted scatterplot smoothing regression and the rho-Spearman test did not reveal significant correlations between STL and the outcomes analyzed. STL was not different between cycles resulting or not in pregnancy and LB (Mann-Whitney U test, p&#x2009;>&#x2009;0.05). No significant effect of STL on reproductive outcomes was found, with the OR for each unit increase in STL (95% CI) of 0.94 (0.86-1-04), 0.99 (0.9-1.09), 0.98 (0.89-1.09), and 0.93 (0.8-1.06) for biochemical, clinical, and ongoing pregnancy and LB, respectively. The multilevel analysis confirmed that the effect of STL on fertilization; biochemical, clinical, and ongoing pregnancy; and LB was not significant (p&#x2009;>&#x2009;0.05).<br><br>CONCLUSION: After addressing STL independently from female variables, results show that STL measurement is not useful to predict reproductive outcomes in ICSI cycles using donor semen.},
}
@article {pmid29335382,
year = {2018},
author = {Aviv, A},
title = {The mitochondrial genome, paternal age and telomere length in humans.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335382},
issn = {1471-2970},
support = {R01 HL116446/HL/NHLBI NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; R01 HL134840/HL/NHLBI NIH HHS/United States ; },
mesh = {Biological Evolution ; *Genome, Mitochondrial ; Humans ; Male ; *Paternal Age ; Polymorphism, Genetic ; Reactive Oxygen Species/metabolism ; Spermatozoa/metabolism ; Stem Cells ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Telomere length (TL) in humans is highly heritable and undergoes progressive age-dependent shortening in somatic cells. By contrast, sperm donated by older men display comparatively long telomeres, presumably because in the male germline, telomeres become longer with age. This puzzling phenomenon might explain why TL in the offspring correlates positively with paternal age. The present communication proposes that mitochondrial DNA polymorphisms and heteroplasmy cause variation in the production of reactive oxygen species, which, in turn, mediate age-dependent selection of germ stem cells with long telomeres and hence sperm with long telomeres. These long telomeres are then inherited by the offspring. The effect of paternal age on the offspring TL might be an evolutionarily driven mechanism that helps regulate TL across the human population.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.},
}
@article {pmid29335381,
year = {2018},
author = {Entringer, S and de Punder, K and Buss, C and Wadhwa, PD},
title = {The fetal programming of telomere biology hypothesis: an update.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335381},
issn = {1471-2970},
support = {R01 AG050455/AG/NIA NIH HHS/United States ; R01 HD060628/HD/NICHD NIH HHS/United States ; R01 HD065825/HD/NICHD NIH HHS/United States ; UG3 OD023349/OD/NIH HHS/United States ; },
mesh = {Age Factors ; Animals ; Disease Susceptibility ; Female ; *Fetal Development ; Humans ; Infant, Newborn ; Oxidative Stress ; Placenta/metabolism ; Pregnancy ; Risk Factors ; Stress, Psychological ; Telomerase/*metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Research on mechanisms underlying fetal programming of health and disease risk has focused primarily on processes that are specific to cell types, organs or phenotypes of interest. However, the observation that developmental conditions concomitantly influence a diverse set of phenotypes, the majority of which are implicated in age-related disorders, raises the possibility that such developmental conditions may additionally exert effects via a common underlying mechanism that involves cellular/molecular ageing-related processes. In this context, we submit that telomere biology represents a process of particular interest in humans because, firstly, this system represents among the most salient antecedent cellular phenotypes for common age-related disorders; secondly, its initial (newborn) setting appears to be particularly important for its long-term effects; and thirdly, its initial setting appears to be plastic and under developmental regulation. We propose that the effects of suboptimal intrauterine conditions on the initial setting of telomere length and telomerase expression/activity capacity may be mediated by the programming actions of stress-related maternal-placental-fetal oxidative, immune, endocrine and metabolic pathways in a manner that may ultimately accelerate cellular dysfunction, ageing and disease susceptibility over the lifespan. This perspectives paper provides an overview of each of the elements underlying this hypothesis, with an emphasis on recent developments, findings and future directions.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.},
}
@article {pmid29335379,
year = {2018},
author = {Young, AJ},
title = {The role of telomeres in the mechanisms and evolution of life-history trade-offs and ageing.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335379},
issn = {1471-2970},
support = {BB/H022716/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Adaptation, Physiological ; Aging/*genetics ; Animals ; *Biological Evolution ; Cellular Senescence ; Humans ; Telomere/*physiology ; *Telomere Homeostasis ; Telomere Shortening ; },
abstract = {Evolutionary biology and biomedicine have seen a surge of recent interest in the possibility that telomeres play a role in life-history trade-offs and ageing. Here, I evaluate alternative hypotheses for the role of telomeres in the mechanisms and evolution of life-history trade-offs and ageing, and highlight outstanding challenges. First, while recent findings underscore the possibility of a proximate causal role for telomeres in current-future trade-offs and ageing, it is currently unclear (i) whether telomeres ever play a causal role in either and (ii) whether any causal role for telomeres arises via shortening or length-independent mechanisms. Second, I consider why, if telomeres do play a proximate causal role, selection has not decoupled such a telomere-mediated trade-off between current and future performance. Evidence suggests that evolutionary constraints have not rendered such decoupling impossible. Instead, a causal role for telomeres would more plausibly reflect an adaptive strategy, born of telomere maintenance costs and/or a function for telomere attrition (e.g. in countering cancer), the relative importance of which is currently unclear. Finally, I consider the potential for telomere biology to clarify the constraints at play in life-history evolution, and to explain the form of the current-future trade-offs and ageing trajectories that we observe today.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.},
}
@article {pmid29335378,
year = {2018},
author = {Lai, TP and Wright, WE and Shay, JW},
title = {Comparison of telomere length measurement methods.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335378},
issn = {1471-2970},
mesh = {Animals ; Cellular Senescence/genetics ; Humans ; *In Situ Hybridization, Fluorescence ; *Real-Time Polymerase Chain Reaction ; Reproducibility of Results ; Sensitivity and Specificity ; Telomere/*genetics ; *Telomere Homeostasis ; Validation Studies as Topic ; },
abstract = {The strengths and limitations of the major methods developed to measure telomere lengths (TLs) in cells and tissues are presented in this review. These include Q-PCR (Quantitative Polymerase Chain Reaction), TRF (Terminal Restriction Fragment) analysis, a variety of Q-FISH (Quantitative Fluorescence In Situ Hybridization) methods, STELA (Single TElomere Length Analysis) and TeSLA (Telomere Shortest Length Assay). For each method, we will cover information about validation studies, including reproducibility in independent laboratories, accuracy, reliability and sensitivity for measuring not only the average but also the shortest telomeres. There is substantial evidence that it is the shortest telomeres that trigger DNA damage responses leading to replicative senescence in mammals. However, the most commonly used TL measurement methods generally provide information on average or relative TL, but it is the shortest telomeres that leads to telomere dysfunction (identified by TIF, Telomere dysfunction Induced Foci) and limit cell proliferation in the absence of a telomere maintenance mechanism, such as telomerase. As the length of the shortest telomeres is a key biomarker determining cell fate and the onset of senescence, a new technique (TeSLA) that provides quantitative information about all the shortest telomeres will be highlighted.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.},
}
@article {pmid29335377,
year = {2018},
author = {Dugdale, HL and Richardson, DS},
title = {Heritability of telomere variation: it is all about the environment!.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335377},
issn = {1471-2970},
mesh = {Age Factors ; Animals ; Biological Evolution ; *Environment ; *Genetic Variation ; Humans ; Linear Models ; Telomere/*genetics ; *Telomere Homeostasis ; Time Factors ; },
abstract = {Individual differences in telomere length have been linked to survival and senescence. Understanding the heritability of telomere length can provide important insight into individual differences and facilitate our understanding of the evolution of telomeres. However, to gain accurate and meaningful estimates of telomere heritability it is vital that the impact of the environment, and how this may vary, is understood and accounted for. The aim of this review is to raise awareness of this important, but much under-appreciated point. We outline the factors known to impact telomere length and discuss the fact that telomere length is a trait that changes with age. We highlight statistical methods that can separate genetic from environmental effects and control for confounding variables. We then review how well previous studies in vertebrate populations including humans have taken these factors into account. We argue that studies to date either use methodological techniques that confound environmental and genetic effects, or use appropriate methods but lack sufficient power to fully separate these components. We discuss potential solutions. We conclude that we need larger studies, which also span longer time periods, to account for changing environmental effects, if we are to determine meaningful estimates of the genetic component of telomere length.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.},
}
@article {pmid29335376,
year = {2018},
author = {Baird, DM},
title = {Telomeres and genomic evolution.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335376},
issn = {1471-2970},
support = {18246/CRUK_/Cancer Research UK/United Kingdom ; C17199/A18246/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Chromosomal Instability ; Chromosomes/genetics ; *Evolution, Molecular ; Genetic Variation ; Humans ; Neoplasms/genetics ; Recombinational DNA Repair ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {The terminal regions of eukaryotic chromosomes, composed of telomere repeat sequences and sub-telomeric sequences, represent some of the most variable and rapidly evolving regions of the genome. The sub-telomeric regions are characterized by segmentally duplicated repetitive DNA elements, interstitial telomere repeat sequences and families of variable genes. Sub-telomeric repeat sequence families are shared among multiple chromosome ends, often rendering detailed sequence characterization difficult. These regions are composed of constitutive heterochromatin and are subjected to high levels of meiotic recombination. Dysfunction within telomere repeat arrays, either due to disruption in the chromatin structure or because of telomere shortening, can lead to chromosomal fusion and the generation of large-scale genomic rearrangements across the genome. The dynamic nature of telomeric regions, therefore, provides functionally useful variation to create genetic diversity, but also provides a mechanism for rapid genomic evolution that can lead to reproductive isolation and speciation. This article is part of the theme issue 'Understanding diversity in telomere dynamics'.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.},
}
@article {pmid29335375,
year = {2018},
author = {Aviv, A and Shay, JW},
title = {Reflections on telomere dynamics and ageing-related diseases in humans.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335375},
issn = {1471-2970},
mesh = {Aging/*genetics ; Animals ; Cardiovascular Diseases/*genetics ; Child ; Female ; Humans ; Infant, Newborn ; Longevity ; Male ; Mice ; Neoplasms/*genetics ; Paternal Age ; Race Factors ; Sex Factors ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {Epidemiological studies have principally relied on measurements of telomere length (TL) in leucocytes, which reflects TL in other somatic cells. Leucocyte TL (LTL) displays vast variation across individuals-a phenomenon already observed in newborns. It is highly heritable, longer in females than males and in individuals of African ancestry than European ancestry. LTL is also longer in offspring conceived by older men. The traditional view regards LTL as a passive biomarker of human ageing. However, new evidence suggests that a dynamic interplay between selective evolutionary forces and TL might result in trade-offs for specific health outcomes. From a biological perspective, an active role of TL in ageing-related human diseases could occur because short telomeres increase the risk of a category of diseases related to restricted cell proliferation and tissue degeneration, including cardiovascular disease, whereas long telomeres increase the risk of another category of diseases related to increased proliferative growth, including major cancers. To understand the role of telomere biology in ageing-related diseases, it is essential to expand telomere research to newborns and children and seek further insight into the underlying causes of the variation in TL due to ancestry and geographical location.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.},
}
@article {pmid29335374,
year = {2018},
author = {Monaghan, P and Eisenberg, DTA and Harrington, L and Nussey, D},
title = {Understanding diversity in telomere dynamics.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335374},
issn = {1471-2970},
support = {BB/H021868/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Biological Evolution ; Chromosomal Instability ; *Genetic Variation ; Humans ; Longevity ; Mutation ; Telomerase/metabolism ; Telomere/*genetics ; *Telomere Homeostasis ; Telomere Shortening ; },
}
@article {pmid29335373,
year = {2018},
author = {Olsson, M and Wapstra, E and Friesen, C},
title = {Ectothermic telomeres: it's time they came in from the cold.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335373},
issn = {1471-2970},
mesh = {Animals ; *Body Temperature ; Fishes/genetics ; Neoplasms/metabolism ; Plants/genetics ; Reptiles/genetics ; Risk Factors ; Telomerase/metabolism ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {We review the evolutionary ecology and genetics of telomeres in taxa that cannot elevate their body temperature to a preferred level through metabolism but do so by basking or seeking out a warm environment. This group of organisms contains all living things on earth, apart from birds and mammals. One reason for our interest in this synthetic group is the argument that high, stable body temperature increases the risk of malignant tumours if long, telomerase-restored telomeres make cells 'live forever'. If this holds true, ectotherms should have significantly lower cancer frequencies. We discuss to what degree there is support for this 'anti-cancer' hypothesis in the current literature. Importantly, we suggest that ectothermic taxa, with variation in somatic telomerase expression across tissue and taxa, may hold the key to understanding ongoing selection and evolution of telomerase dynamics in the wild. We further review endotherm-specific effects of growth on telomeres, effects of autotomy ('tail dropping') on telomere attrition, and costs of maintaining sexual displays measured in telomere attrition. Finally, we cover plant ectotherm telomeres and life histories in a separate 'mini review'.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.},
}
@article {pmid29335372,
year = {2018},
author = {Risques, RA and Promislow, DEL},
title = {All's well that ends well: why large species have short telomeres.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335372},
issn = {1471-2970},
support = {R01 AG049494/AG/NIA NIH HHS/United States ; R01 CA181308/CA/NCI NIH HHS/United States ; },
mesh = {Age Factors ; Animals ; Biological Evolution ; *Body Size ; Cellular Senescence ; Female ; Humans ; Male ; Mammals/genetics/*growth &amp; development ; Models, Theoretical ; Neoplasms/*mortality ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {Among mammal species, almost all life-history traits are strongly size dependent. This size dependence even occurs at a molecular level. For example, both telomere length and telomerase expression show a size-dependent threshold. With some exceptions, species smaller than approximately 2 kg express telomerase, while species larger than that do not. Among species greater than approximately 5 kg, telomeres tend to be short-less than 25 kb-while among smaller species, some species have short and some have long telomeres. Here, we present a model to explore the role of body size-dependent trade-offs in shaping this threshold. We assume that selection favours short telomeres as a mechanism to protect against cancer. At the same time, selection favours long telomeres as a protective mechanism against DNA damage and replicative senescence. The relative importance of these two selective forces will depend on underlying intrinsic mortality and risk of cancer, both of which are size-dependent. Results from this model suggest that a cost-benefit model for the evolution of telomere length could explain phylogenetic patterns observed within the Class Mammalia. In addition, the model suggests a general conceptual framework to think about the role that body size plays in the evolution of tumour suppressor mechanisms.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.},
}
@article {pmid29335371,
year = {2018},
author = {Wilbourn, RV and Moatt, JP and Froy, H and Walling, CA and Nussey, DH and Boonekamp, JJ},
title = {The relationship between telomere length and mortality risk in non-model vertebrate systems: a meta-analysis.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335371},
issn = {1471-2970},
support = {BB/H021868/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/J01446X/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/L020769/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Age Factors ; Animals ; Birds/genetics/*physiology ; Longevity/*physiology ; Models, Statistical ; Mortality ; Odds Ratio ; Regression Analysis ; Risk Factors ; Sex Factors ; Telomere/genetics/*physiology ; *Telomere Shortening ; },
abstract = {Telomere length (TL) has become a biomarker of increasing interest within ecology and evolutionary biology, and has been found to predict subsequent survival in some recent avian studies but not others. Here, we undertake the first formal meta-analysis to test whether there is an overall association between TL and subsequent mortality risk in vertebrates other than humans and model laboratory rodents. We identified 27 suitable studies and obtained standardized estimates of the hazard ratio associated with TL from each. We performed a meta-analysis on these estimates and found an overall significant negative association implying that short telomeres are associated with increased mortality risk, which was robust to evident publication bias. While we found that heterogeneity in the hazard ratios was not explained by sex, follow-up period, maximum lifespan or the age group of the study animals, the TL-mortality risk association was stronger in studies using qPCR compared to terminal restriction fragment methodologies. Our results provide support for a consistent association between short telomeres and increased mortality risk in birds, but also highlight the need for more research into non-avian vertebrates and the reasons why different telomere measurement methods may yield different results.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.},
}
@article {pmid29335370,
year = {2018},
author = {Monaghan, P and Ozanne, SE},
title = {Somatic growth and telomere dynamics in vertebrates: relationships, mechanisms and consequences.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335370},
issn = {1471-2970},
support = {MC_UU_12012/4/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult Stem Cells/*physiology ; Animals ; Birds/growth &amp; development ; Body Size ; Humans ; Longevity ; Mice ; Oxidative Stress ; Rats ; Telomere/*physiology ; Telomere Shortening/*physiology ; },
abstract = {Much telomere loss takes place during the period of most rapid growth when cell proliferation and potentially energy expenditure are high. Fast growth is linked to reduced longevity. Therefore, the effects of somatic cell proliferation on telomere loss and cell senescence might play a significant role in driving the growth-lifespan trade-off. While different species will have evolved a growth strategy that maximizes lifetime fitness, environmental conditions encountered during periods of growth will influence individual optima. In this review, we first discuss the routes by which altered cellular conditions could influence telomere loss in vertebrates, with a focus on oxidative stress in both in vitro and in vivo studies. We discuss the relationship between body growth and telomere length, and evaluate the empirical evidence that this relationship is generally negative. We further discuss the potentially conflicting hypotheses that arise when other factors are taken into account, and the further work that needs to be undertaken to disentangle confounding variables.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.},
}
@article {pmid29335369,
year = {2018},
author = {Tricola, GM and Simons, MJP and Atema, E and Boughton, RK and Brown, JL and Dearborn, DC and Divoky, G and Eimes, JA and Huntington, CE and Kitaysky, AS and Juola, FA and Lank, DB and Litwa, HP and Mulder, EGA and Nisbet, ICT and Okanoya, K and Safran, RJ and Schoech, SJ and Schreiber, EA and Thompson, PM and Verhulst, S and Wheelwright, NT and Winkler, DW and Young, R and Vleck, CM and Haussmann, MF},
title = {The rate of telomere loss is related to maximum lifespan in birds.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335369},
issn = {1471-2970},
support = {R15 HD083870/HD/NICHD NIH HHS/United States ; WT107400MA/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Aging/genetics/*physiology ; Animals ; Biological Variation, Population ; Birds/genetics/*physiology ; Cellular Senescence ; Cross-Sectional Studies ; Female ; Longevity/genetics/*physiology ; Male ; Phylogeny ; Telomere/genetics/*physiology ; Telomere Shortening/genetics/*physiology ; },
abstract = {Telomeres are highly conserved regions of DNA that protect the ends of linear chromosomes. The loss of telomeres can signal an irreversible change to a cell's state, including cellular senescence. Senescent cells no longer divide and can damage nearby healthy cells, thus potentially placing them at the crossroads of cancer and ageing. While the epidemiology, cellular and molecular biology of telomeres are well studied, a newer field exploring telomere biology in the context of ecology and evolution is just emerging. With work to date focusing on how telomere shortening relates to individual mortality, less is known about how telomeres relate to ageing rates across species. Here, we investigated telomere length in cross-sectional samples from 19 bird species to determine how rates of telomere loss relate to interspecific variation in maximum lifespan. We found that bird species with longer lifespans lose fewer telomeric repeats each year compared with species with shorter lifespans. In addition, phylogenetic analysis revealed that the rate of telomere loss is evolutionarily conserved within bird families. This suggests that the physiological causes of telomere shortening, or the ability to maintain telomeres, are features that may be responsible for, or co-evolved with, different lifespans observed across species.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.},
}
@article {pmid29335368,
year = {2018},
author = {Harrington, L and Pucci, F},
title = {In medio stat virtus: unanticipated consequences of telomere dysequilibrium.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335368},
issn = {1471-2970},
support = {084637/WT_/Wellcome Trust/United Kingdom ; 133573//Canadian Institutes of Health Research/International ; 086580/WT_/Wellcome Trust/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; 148936//Canadian Institutes of Health Research/International ; 086580/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Cell Differentiation/genetics/*physiology ; Cellular Senescence/genetics/*physiology ; DNA Methylation/genetics/*physiology ; Epigenesis, Genetic ; Histones/metabolism ; Humans ; Primary Cell Culture ; Protein Processing, Post-Translational/genetics/*physiology ; Shelterin Complex ; Stem Cells ; Telomere/genetics/*physiology ; *Telomere Homeostasis ; Telomere-Binding Proteins/metabolism ; },
abstract = {The integrity of chromosome ends, or telomeres, depends on myriad processes that must balance the need to compact and protect the telomeric, G-rich DNA from detection as a double-stranded DNA break, and yet still permit access to enzymes that process, replicate and maintain a sufficient reserve of telomeric DNA. When unable to maintain this equilibrium, erosion of telomeres leads to perturbations at or near the telomeres themselves, including loss of binding by the telomere protective complex, shelterin, and alterations in transcription and post-translational modifications of histones. Although the catastrophic consequences of full telomere de-protection are well described, recent evidence points to other, less obvious perturbations that arise when telomere length equilibrium is altered. For example, critically short telomeres also perturb DNA methylation and histone post-translational modifications at distal sites throughout the genome. In murine stem cells for example, this dysregulated chromatin leads to inappropriate suppression of pluripotency regulator factors such as Nanog This review summarizes these recent findings, with an emphasis on how these genome-wide, telomere-induced perturbations can have profound consequences on cell function and fate.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.},
}
@article {pmid29335367,
year = {2018},
author = {Tian, X and Doerig, K and Park, R and Can Ran Qin, A and Hwang, C and Neary, A and Gilbert, M and Seluanov, A and Gorbunova, V},
title = {Evolution of telomere maintenance and tumour suppressor mechanisms across mammals.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335367},
issn = {1471-2970},
support = {P01 AG047200/AG/NIA NIH HHS/United States ; R01 AG027237/AG/NIA NIH HHS/United States ; R03 AG052365/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Carcinogenesis/*genetics ; Cellular Senescence/genetics ; *Evolution, Molecular ; Fibroblasts/cytology ; Genes, Retinoblastoma/genetics ; Genes, p53/genetics ; Genes, ras/genetics ; Humans ; Mice, Nude ; Primary Cell Culture ; Rodentia/*genetics ; Skin/cytology ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; Xenograft Model Antitumor Assays ; },
abstract = {Mammalian species differ dramatically in telomere biology. Species larger than 5-10 kg repress somatic telomerase activity and have shorter telomeres, leading to replicative senescence. It has been proposed that evolution of replicative senescence in large-bodied species is an anti-tumour mechanism counteracting increased risk of cancer due to increased cell numbers. By contrast, small-bodied species express high telomerase activity and have longer telomeres. To counteract cancer risk due to longer lifespan, long-lived small-bodied species evolved additional telomere-independent tumour suppressor mechanisms. Here, we tested the connection between telomere biology and tumorigenesis by analysing the propensity of fibroblasts from 18 rodent species to form tumours. We found a negative correlation between species lifespan and anchorage-independent growth. Small-bodied species required inactivation of Rb and/or p53 and expression of oncogenic H-Ras to form tumours. Large-bodied species displayed a continuum of phenotypes requiring additional genetic 'hits' for malignant transformation. Based on these data we refine the model of the evolution of tumour suppressor mechanisms and telomeres. We propose that two different strategies evolved in small and large species because small-bodied species cannot tolerate small tumours that form prior to activation of the telomere barrier, and must instead use telomere-independent strategies that act earlier, at the hyperplasia stage.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.},
}
@article {pmid29335366,
year = {2018},
author = {Eisenberg, DTA and Kuzawa, CW},
title = {The paternal age at conception effect on offspring telomere length: mechanistic, comparative and adaptive perspectives.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335366},
issn = {1471-2970},
mesh = {Adaptation, Physiological/*physiology ; Aging ; Animals ; Child ; Fertilization/*physiology ; Humans ; Male ; *Paternal Age ; Spermatozoa/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Telomeres are repeating DNA found at the ends of chromosomes that, in the absence of restorative processes, shorten with cell replications and are implicated as a cause of senescence. It appears that sperm telomere length (TL) increases with age in humans, and as a result offspring of older fathers inherit longer telomeres. We review possible mechanisms underlying this paternal age at conception (PAC) effect on TL, including sperm telomere extension due to telomerase activity, age-dependent changes in the spermatogonial stem cell population (possibly driven by 'selfish' spermatogonia) and non-causal confounding. In contrast to the lengthening of TL with PAC, higher maternal age at conception appears to predict shorter offspring TL in humans. We review evidence for heterogeneity across species in the PAC effect on TL, which could relate to differences in statistical power, sperm production rates or testicular telomerase activity. Finally, we review the hypothesis that the PAC effect on TL may allow a gradual multi-generational adaptive calibration of maintenance effort, and reproductive lifespan, to local demographic conditions: descendants of males who reproduced at a later age are likely to find themselves in an environment where increased maintenance effort, allowing later reproduction, represents a fitness improving resource allocation.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.},
}
@article {pmid29335364,
year = {2018},
author = {Criscuolo, F and Smith, S and Zahn, S and Heidinger, BJ and Haussmann, MF},
title = {Experimental manipulation of telomere length: does it reveal a corner-stone role for telomerase in the natural variability of individual fitness?.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335364},
issn = {1471-2970},
mesh = {*Animal Experimentation ; Animals ; Biological Evolution ; *Biological Variation, Individual ; Environment ; *Genetic Fitness ; Humans ; *Physical Fitness ; Telomerase/genetics/*physiology ; Telomere/genetics/*physiology ; *Telomere Homeostasis ; },
abstract = {Telomeres, the non-coding ends of linear chromosomes, are thought to be an important mechanism of individual variability in performance. Research suggests that longer telomeres are indicative of better health and increased fitness; however, many of these data are correlational and whether these effects are causal are poorly understood. Experimental tests are emerging in medical and laboratory-based studies, but these types of experiments are rare in natural populations, which precludes conclusions at an evolutionary level. At the crossroads between telomere length and fitness is telomerase, an enzyme that can lengthen telomeres. Experimental modulation of telomerase activity is a powerful tool to manipulate telomere length, and to look at the covariation of telomerase, telomeres and individual life-history traits. Here, we review studies that manipulate telomerase activity in laboratory conditions and emphasize the associated physiological and fitness consequences. We then discuss how telomerase's impact on ageing may go beyond telomere maintenance. Based on this overview, we then propose several research avenues for future studies to explore how individual variability in health, reproduction and survival may have coevolved with different patterns of telomerase activity and expression. Such knowledge is of prime importance to fully understand the role that telomere dynamics play in the evolution of animal ageing.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.},
}
@article {pmid29335363,
year = {2018},
author = {Bateson, M and Nettle, D},
title = {Why are there associations between telomere length and behaviour?.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {373},
number = {1741},
pages = {},
pmid = {29335363},
issn = {1471-2970},
mesh = {Animals ; Behavior/*physiology ; Birds ; Humans ; Leukocytes ; Longitudinal Studies ; Models, Theoretical ; Smoking ; Telomere/genetics/*physiology ; Telomere Shortening/genetics/*physiology ; },
abstract = {Individual differences in telomere length are associated with individual differences in behaviour in humans and birds. Within the human epidemiological literature this association is assumed to result from specific behaviour patterns causing changes in telomere dynamics. We argue that selective adoption-the hypothesis that individuals with short telomeres are more likely to adopt specific behaviours-is an alternative worthy of consideration. Selective adoption could occur either because telomere length directly affects behaviour or because behaviour and telomere length are both affected by a third variable, such as exposure to early-life adversity. We present differential predictions of the causation and selective adoption hypotheses and describe how these could be tested with longitudinal data on telomere length. Crucially, if behaviour is causal then it should be associated with differential rates of telomere attrition. Using smoking behaviour as an example, we show that the evidence that smoking accelerates the rate of telomere attrition within individuals is currently weak. We conclude that the selective adoption hypothesis for the association between behaviour and telomere length is both mechanistically plausible and, if anything, more compatible with existing empirical evidence than the hypothesis that behaviour is causal.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.},
}
@article {pmid29331736,
year = {2018},
author = {Fiorini, E and Santoni, A and Colla, S},
title = {Dysfunctional telomeres and hematological disorders.},
journal = {Differentiation; research in biological diversity},
volume = {100},
number = {},
pages = {1-11},
pmid = {29331736},
issn = {1432-0436},
support = {P50 CA100632/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Bone Marrow Diseases/*genetics/pathology ; Hematopoietic Stem Cells/cytology/metabolism ; Humans ; Telomere/genetics/metabolism/pathology ; *Telomere Shortening ; },
abstract = {Telomere biology disorders, which are characterized by telomerase activity haploinsufficiency and accelerated telomere shortening, most commonly manifest as degenerative diseases. Tissues with high rates of cell turnover, such as those in the hematopoietic system, are particularly vulnerable to defects in telomere maintenance genes that eventually culminate in bone marrow (BM) failure syndromes, in which the BM cannot produce sufficient new blood cells. Here, we review how telomere defects induce degenerative phenotypes across multiple organs, with particular focus on how they impact the hematopoietic stem and progenitor compartment and affect hematopoietic stem cell (HSC) self-renewal and differentiation. We also discuss how both the increased risk of myelodysplastic syndromes and other hematological malignancies that is associated with telomere disorders and the discovery of cancer-associated somatic mutations in the shelterin components challenge the conventional interpretation that telomere defects are cancer-protective rather than cancer-promoting.},
}
@article {pmid29322876,
year = {2019},
author = {López-Alcorocho, JM and Guillén-Vicente, I and Rodríguez-Iñigo, E and Guillén-Vicente, M and Fernández-Jaén, TF and Caballero, R and Casqueiro, M and Najarro, P and Abelow, S and Guillén-García, P},
title = {Study of Telomere Length in Preimplanted Cultured Chondrocytes.},
journal = {Cartilage},
volume = {10},
number = {1},
pages = {36-42},
pmid = {29322876},
issn = {1947-6043},
mesh = {Adult ; Cartilage Diseases/*pathology/therapy ; Cartilage, Articular/*cytology/pathology ; Cells, Cultured ; Chondrocytes/*pathology ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Knee Joint/cytology/pathology ; Male ; *Stem Cell Transplantation ; Telomere/*pathology ; Transplantation, Autologous ; },
abstract = {DESIGN: In the process of cell division, the extremes of the eukaryotic chromosomes are progressively shortening, and this phenomenon is related to cell degeneration and senescence. The treatment of cartilage lesions with autologous chondrocytes implies that cells proliferate in an artificial environment. We have studied the viability of cultured chondrocytes after measurement of their telomere length before implantation.<br><br>METHODS: Articular cartilage biopsies (B1, B2, and B3) were obtained from 3 patients (2 males and 1 female) with knee cartilage defects, who were going to be treated with chondrocyte implantation. Chondrocytes were cultured in DMEM with autologous serum. After the third passage, an aliquot of 1 million cells was removed to estimate the telomere length and the remaining cells were implanted. Telomere length was measured by quantitative fluorescent in situ hybridization (Q-FISH). Patients' clinical outcome was determined preoperatively, and 12 and 24 months postimplantation with the International Knee Documentation Committee (IKDC) questionnaire.<br><br>RESULTS: After chondrocyte implantation, IKDC score doubled at 12 and 24 months with regard to the basal value. After 3 passages, chondrocytes were cultured for a mean of 45.67 days, the mean duplication time being 4.53 days and the mean number of cell divisions being 10.04 during the culture period. The 20th percentile of telomere lengths were 6.84, 6.96, and 7.06 kbp and the median telomere lengths 10.30, 10.47, and 10.73 kbp, respectively. No significant correlation was found between IKDC score and telomere length.<br><br>CONCLUSION: Culturing autologous chondrocytes for implantation is not related to cell senescence in terms of telomere length.},
}
@article {pmid29320491,
year = {2018},
author = {Nene, RV and Putnam, CD and Li, BZ and Nguyen, KG and Srivatsan, A and Campbell, CS and Desai, A and Kolodner, RD},
title = {Cdc73 suppresses genome instability by mediating telomere homeostasis.},
journal = {PLoS genetics},
volume = {14},
number = {1},
pages = {e1007170},
pmid = {29320491},
issn = {1553-7404},
support = {F30 CA177240/NH/NIH HHS/United States ; R01 GM074215/GM/NIGMS NIH HHS/United States ; T32 GM007198/NH/NIH HHS/United States ; R01 GM026017/GM/NIGMS NIH HHS/United States ; P50 GM085764/GM/NIGMS NIH HHS/United States ; T32 GM007198/GM/NIGMS NIH HHS/United States ; P50 GM085764/NH/NIH HHS/United States ; F30 CA177240/CA/NCI NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics ; DNA-Binding Proteins/physiology ; Genomic Instability/*genetics ; Intracellular Signaling Peptides and Proteins/physiology ; Nuclear Proteins/genetics/*physiology ; Organisms, Genetically Modified ; Phenotype ; Protein Binding ; Protein Serine-Threonine Kinases/physiology ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*physiology ; Telomere/metabolism ; Telomere Homeostasis/*genetics ; Transcriptional Elongation Factors/genetics ; },
abstract = {Defects in the genes encoding the Paf1 complex can cause increased genome instability. Loss of Paf1, Cdc73, and Ctr9, but not Rtf1 or Leo1, caused increased accumulation of gross chromosomal rearrangements (GCRs). Combining the cdc73Δ mutation with individual deletions of 43 other genes, including TEL1 and YKU80, which are involved in telomere maintenance, resulted in synergistic increases in GCR rates. Whole genome sequence analysis of GCRs indicated that there were reduced relative rates of GCRs mediated by de novo telomere additions and increased rates of translocations and inverted duplications in cdc73Δ single and double mutants. Analysis of telomere lengths and telomeric gene silencing in strains containing different combinations of cdc73Δ, tel1Δ and yku80Δ mutations suggested that combinations of these mutations caused increased defects in telomere maintenance. A deletion analysis of Cdc73 revealed that a central 105 amino acid region was necessary and sufficient for suppressing the defects observed in cdc73Δ strains; this region was required for the binding of Cdc73 to the Paf1 complex through Ctr9 and for nuclear localization of Cdc73. Taken together, these data suggest that the increased GCR rate of cdc73Δ single and double mutants is due to partial telomere dysfunction and that Ctr9 and Paf1 play a central role in the Paf1 complex potentially by scaffolding the Paf1 complex subunits or by mediating recruitment of the Paf1 complex to the different processes it functions in.},
}
@article {pmid29318605,
year = {2018},
author = {Yuan, JM and Beckman, KB and Wang, R and Bull, C and Adams-Haduch, J and Huang, JY and Jin, A and Opresko, P and Newman, AB and Zheng, YL and Fenech, M and Koh, WP},
title = {Leukocyte telomere length in relation to risk of lung adenocarcinoma incidence: Findings from the Singapore Chinese Health Study.},
journal = {International journal of cancer},
volume = {142},
number = {11},
pages = {2234-2243},
pmid = {29318605},
issn = {1097-0215},
support = {P30 AG024827/AG/NIA NIH HHS/United States ; R01 CA144034/CA/NCI NIH HHS/United States ; U01 CA182876/CA/NCI NIH HHS/United States ; UM1 CA182876/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma/*epidemiology/*genetics ; Aged ; Female ; Humans ; Incidence ; Leukocytes/*metabolism ; Lung Neoplasms/*epidemiology/*genetics ; Male ; Middle Aged ; Proportional Hazards Models ; Risk ; Risk Assessment ; Singapore/epidemiology ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {Telomeres are crucial in the maintenance of chromosome integrity and genomic stability. Critically short telomeres can trigger programed cell death while cells with longer telomeres may have increased likelihood of replicative errors, resulting in genetic mutations and chromosomal alterations, and ultimately promoting oncogenesis. Data on telomere length and lung cancer risk from large prospective cohort studies are spare. Relative telomere length in peripheral blood leukocytes was quantified using a validated monochrome multiplex quantitative polymerase chain reaction (qPCR) method in 26,540 participants of the Singapore Chinese Health Study. After a follow-up of 12 years, 654 participants developed lung cancer including 288 adenocarcinoma, 113 squamous cell carcinoma and 253 other/unknown histological type. The Cox proportional hazard regression was used to estimate hazard ratio (HR) and 95% confidence interval (CI). HR of lung adenocarcinoma for individuals in the highest comparing the lowest 20 percentile of telomere length was 2.84 (95% CI 1.94-4.14, ptrend < 0.0001). This positive association was present in never smokers (ptrend < 0.0001), ever smokers (ptrend = 0.0010), men (ptrend = 0.0003), women (ptrend < 0.0001), and in shorter (ptrend = 0.0002) and longer (ptrend = 0.0001) duration of follow-up. There was no association between telomere length and risk of squamous cell carcinoma or other histological type of lung cancer in all or subgroups of individuals. The agreement of results from this prospective cohort study with those of previous prospective studies and Mendelian randomization studies suggest a possible etiological role of telomere length in the development of lung adenocarcinoma.},
}
@article {pmid29311622,
year = {2018},
author = {Wang, L and Tu, Z and Liu, C and Liu, H and Kaldis, P and Chen, Z and Li, W},
title = {Dual roles of TRF1 in tethering telomeres to the nuclear envelope and protecting them from fusion during meiosis.},
journal = {Cell death and differentiation},
volume = {25},
number = {6},
pages = {1174-1188},
pmid = {29311622},
issn = {1476-5403},
mesh = {Animals ; Cyclin-Dependent Kinase 2/genetics/metabolism ; Male ; Meiosis/*physiology ; Mice ; Mice, Knockout ; Nuclear Envelope/genetics/*metabolism ; Spermatocytes/cytology/*metabolism ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/*metabolism ; },
abstract = {Telomeres integrity is indispensable for chromosomal stability by preventing chromosome erosion and end-to-end fusions. During meiosis, telomeres attach to the inner nuclear envelope and cluster into a highly crowded microenvironment at the bouquet stage, which requires specific mechanisms to protect the telomeres from fusion. Here, we demonstrate that germ cell-specific knockout of a shelterin complex subunit, Trf1, results in arrest of spermatocytes at two different stages. The obliterated telomere-nuclear envelope attachment in Trf1-deficient spermatocytes impairs homologue synapsis and recombination, resulting in a pachytene-like arrest, while the meiotic division arrest might stem from chromosome end-to-end fusion due to the failure of recruiting meiosis specific telomere associated proteins. Further investigations uncovered that TRF1 could directly interact with Speedy A, and Speedy A might work as a scaffold protein to further recruit Cdk2, thus protecting telomeres from fusion at this stage. Together, our results reveal a novel mechanism of TRF1, Speedy A, and Cdk2 in protecting telomere from fusion in a highly crowded microenvironment during meiosis.},
}
@article {pmid29310088,
year = {2018},
author = {Liu, H and Chen, Q and Lei, L and Zhou, W and Huang, L and Zhang, J and Chen, D},
title = {Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances affects leukocyte telomere length in female newborns.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {235},
number = {},
pages = {446-452},
doi = {10.1016/j.envpol.2017.12.095},
pmid = {29310088},
issn = {1873-6424},
mesh = {Environmental Pollutants/*blood ; Female ; Fetal Blood ; Fluorocarbons/*blood ; Humans ; Infant, Newborn ; Leukocytes ; Male ; Maternal Exposure/*statistics &amp; numerical data ; Pregnancy ; Prenatal Exposure Delayed Effects/*epidemiology ; Prospective Studies ; Telomere/drug effects/*physiology ; },
abstract = {Evidence has shown that leukocyte telomere length (LTL) at birth is related to the susceptibility to various diseases in later life and the setting of newborn LTL is influenced by the intrauterine environment. Perfluoroalkyl and polyfluoroalkyl substances (PFASs), as a kind of persistent organic pollutants, are commonly used in commercial and domestic applications and are capable of crossing the maternal-fetal barrier during pregnancy. We hypothesized that intrauterine exposure to PFASs may affect fetal LTL by increasing oxidative stress. To verify this hypothesis, LTL, concentrations of PFASs and reactive oxygen species (ROS) were measured in umbilical cord blood of 581 newborns from a prospective cohort. Our results showed that there were interactions between PFOS/PFDA and sex on LTL and ROS. The LTL was significantly shorter (0.926 ± 0.053 vs 0.945 ± 0.054, P = .023 for PFOS; 0.919 ± 0.063 vs 0.940 ± 0.059, P = .011 for PFDA) and the ROS levels were extremely higher (252.9 ± 60.5 [M] vs 233.5 ± 53.6 [M], P = .031 for PFOS; 255.2 ± 62.9 [M] vs 232.9 ± 58.3 [M], P = .011 for PFDA) in the female newborns whose PFOS or PFDA concentrations fell in the upmost quartile compared with those in the lowest quartile after adjusting for potential confounders. ROS levels were inversely associated with LTL in female newborns (β = -1.42 × 10[-4], P = .022). 13% of the effect of PFOS on female LTL was mediated through ROS approximately by the mediation analyses. However, in male newborns, no relationships among PFASs, ROS and LTL were observed. Our findings suggest a "programming" role of PFASs on fetal telomere biology system in females in intrauterine stage.},
}
@article {pmid29303978,
year = {2018},
author = {Maguire, D and Neytchev, O and Talwar, D and McMillan, D and Shiels, PG},
title = {Telomere Homeostasis: Interplay with Magnesium.},
journal = {International journal of molecular sciences},
volume = {19},
number = {1},
pages = {},
pmid = {29303978},
issn = {1422-0067},
mesh = {Animals ; Circadian Rhythm ; Humans ; Magnesium/*metabolism ; Oxidative Stress ; *Telomere Homeostasis ; },
abstract = {Telomere biology, a key component of the hallmarks of ageing, offers insight into dysregulation of normative ageing processes that accompany age-related diseases such as cancer. Telomere homeostasis is tightly linked to cellular metabolism, and in particular with mitochondrial physiology, which is also diminished during cellular senescence and normative physiological ageing. Inherent in the biochemistry of these processes is the role of magnesium, one of the main cellular ions and an essential cofactor in all reactions that use ATP. Magnesium plays an important role in many of the processes involved in regulating telomere structure, integrity and function. This review explores the mechanisms that maintain telomere structure and function, their influence on circadian rhythms and their impact on health and age-related disease. The pervasive role of magnesium in telomere homeostasis is also highlighted.},
}
@article {pmid29299784,
year = {2018},
author = {Al Ahwal, MS and Al Zaben, F and Sehlo, MG and Khalifa, DA and Koenig, HG},
title = {Religiosity and Telomere Length in Colorectal Cancer Patients in Saudi Arabia.},
journal = {Journal of religion and health},
volume = {57},
number = {2},
pages = {672-682},
pmid = {29299784},
issn = {1573-6571},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Colorectal Neoplasms/ethnology/*genetics/*psychology ; Female ; Humans ; Interviews as Topic ; Islam/*psychology ; Middle Aged ; Quality of Life/*psychology ; Saudi Arabia/epidemiology ; *Spirituality ; Telomere/*physiology ; Telomere Shortening/*physiology ; Young Adult ; },
abstract = {Numerous studies have reported a significant relationship between psychological stress, depression, and telomere length (TL), an indicator of cellular lifespan. Religious involvement, which is associated with lower levels of stress and depression, has also recently been related to TL. To our knowledge, this relationship has not yet been examined in Muslims, colorectal cancer patients, cancer patients more generally, or any population outside the USA. A convenience sample of 50 colorectal patients was recruited from hospital-based oncology clinics in Jeddah, Saudi Arabia. Religious involvement was assessed with the 13-item Muslim Religiosity Scale. Social and psychological mediators were measured using established scales. TL was determined from whole-blood leukocytes using quantitative PCR technology. Bivariate analyses indicated a positive but nonsignificant relationship between religiosity and TL (r = 0.13, p = 0.35). Controlling for age, did not affect the relationship (B = 15.6, SE = 17.3, p = 0.37), nor did controlling for other demographic, social or psychological factors. Religious involvement was unrelated to TL in this small sample of colorectal patients. Future cross-sectional and prospective studies in different populations with larger samples are needed.},
}
@article {pmid29297465,
year = {2018},
author = {Jamieson, K and McNaught, KJ and Ormsby, T and Leggett, NA and Honda, S and Selker, EU},
title = {Telomere repeats induce domains of H3K27 methylation in Neurospora.},
journal = {eLife},
volume = {7},
number = {},
pages = {},
pmid = {29297465},
issn = {2050-084X},
support = {R01 GM093061/GM/NIGMS NIH HHS/United States ; T32 GM007413/GM/NIGMS NIH HHS/United States ; T32 HD007348/HD/NICHD NIH HHS/United States ; },
mesh = {*Gene Expression Regulation, Fungal ; Heterochromatin/metabolism ; Histones/*metabolism ; *Methylation ; Neurospora crassa/genetics/metabolism/*physiology ; *Protein Processing, Post-Translational ; *Repetitive Sequences, Nucleic Acid ; *Telomere ; },
abstract = {Development in higher organisms requires selective gene silencing, directed in part by di-/trimethylation of lysine 27 on histone H3 (H3K27me2/3). Knowledge of the cues that control formation of such repressive Polycomb domains is extremely limited. We exploited natural and engineered chromosomal rearrangements in the fungus Neurospora crassa to elucidate the control of H3K27me2/3. Analyses of H3K27me2/3 in strains bearing chromosomal rearrangements revealed both position-dependent and position-independent facultative heterochromatin. We found that proximity to chromosome ends is necessary to maintain, and sufficient to induce, transcriptionally repressive, subtelomeric H3K27me2/3. We ascertained that such telomere-proximal facultative heterochromatin requires native telomere repeats and found that a short array of ectopic telomere repeats, (TTAGGG)17, can induce a large domain (~225 kb) of H3K27me2/3. This provides an example of a cis-acting sequence that directs H3K27 methylation. Our findings provide new insight into the relationship between genome organization and control of heterochromatin formation.},
}
@article {pmid29296896,
year = {2017},
author = {Lansdorp, PM},
title = {Maintenance of telomere length in AML.},
journal = {Blood advances},
volume = {1},
number = {25},
pages = {2467-2472},
pmid = {29296896},
issn = {2473-9529},
abstract = {The importance of telomere length to human health, aging, and cancer continues to be underappreciated. This review examines some basics of telomere biology and relates how telomere function, telomerase activity, and mutations in TERC or TERT are involved in bone marrow failure, leukemias, and other cancers. Given the challenge to obtain accurate data on telomerase activity and telomere length in specific cell types, the situation in acute myeloid leukemia (AML) remains puzzling. In most cancers, telomerase levels are increased after cells have encountered a "telomere crisis," which is typically associated with poor prognosis. Cells emerging from "telomere crisis" have defective DNA damage responses, resulting, for example, from loss of p53. Such cells often express elevated telomerase levels as a result of point mutations in the TERT promoter or amplification of the TERT gene. While telomeres in AML blasts are typically shorter than expected for normal leukocytes, most AML cells do not show evidence of having gone through a "telomere crisis." In chronic myeloid leukemia (CML), the difference between the telomere length in nonmalignant T cells and malignant blasts from the same patient was found to correlate with the remaining duration of the chronic phase. This observation supports that a mitotic clock is ticking in CML stem cells and that disease progression in CML heralds the onset of a "telomere crisis." The presence of very short telomeres in tumor cells was found to predict disease progression in chronic lymphocytic leukemia, myeloma, and various solid tumors. In view of these findings longitudinal studies of telomere length in AML appear worthwhile.},
}
@article {pmid29293561,
year = {2018},
author = {Kalson, NS and Brock, TM and Mangino, M and Fabiane, SM and Mann, DA and Borthwick, LA and Deehan, DJ and Williams, FMK},
title = {Reduced telomere length is associated with fibrotic joint disease suggesting that impaired telomere repair contributes to joint fibrosis.},
journal = {PloS one},
volume = {13},
number = {1},
pages = {e0190120},
pmid = {29293561},
issn = {1932-6203},
support = {/WT_/Wellcome Trust/United Kingdom ; MR/K001949/1/MRC_/Medical Research Council/United Kingdom ; MR/L016354/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Female ; Fibrosis ; Humans ; Joint Diseases/*genetics/pathology ; Male ; Middle Aged ; *Telomere Shortening ; United Kingdom ; Young Adult ; },
abstract = {OBJECTIVE: Joint fibrosis affects many synovial joints (including hip, knee and shoulder) causing stiffness and pain. The mechanism of joint fibrosis remains unknown, although genetic factors may contribute. Defects in maintenance of telomere length resulting from impaired telomere repair have been shown to cause lung and liver fibrotic disease. Here we tested the hypothesis that joint fibrosis and other soft tissue fibrotic conditions are also associated with telomere length.<br><br>PATIENTS AND METHODS: 5,200 participants in the TwinsUK registry had data on telomere length (measured by qPCR) and the traits of interest (hip and knee stiffness, total joint replacement (TJR, hip or knee) and fibrotic conditions (Dupuytren's disease, frozen shoulder).<br><br>RESULTS: Multivariable logistic regression analyses showed a significant association between telomere length and fibrotic conditions (hip stiffness, knee stiffness and frozen shoulder, p = &#x2264;0.002) even after taking age into account. No association was found between TJR and telomere length.<br><br>CONCLUSION: These findings suggest that defects in telomere repair contribute to joint fibrosis, and that fibrosis shares a common mechanistic pathway in different organs. Therapeutic strategies to combat telomere shortening may offer novel treatments for fibrotic joint disease.},
}
@article {pmid29293454,
year = {2018},
author = {Gorenjak, V and Akbar, S and Stathopoulou, MG and Visvikis-Siest, S},
title = {The future of telomere length in personalized medicine.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {23},
number = {9},
pages = {1628-1654},
doi = {10.2741/4664},
pmid = {29293454},
issn = {2768-6698},
mesh = {Aging/*genetics ; Disease/*genetics ; Genome-Wide Association Study/methods ; Humans ; Neoplasms/*genetics ; Precision Medicine/*methods ; Prognosis ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Telomere length has been subject of studies for many decades, aiming to elucidate its role in physiological processes, in process of aging and in diverse pathologies. Yet today, there is still no "big title" discovery that would lead to a practical use of telomeres as a reliable biomarker or target for a new drug. However, therapies for chronic disease patients are being tested and companies are already offering commercial tests for telomere length measurement. The strong genetic heritability of telomeres is opening the place for pharmacogenomics researches that could promote the personalized treatment of diverse diseases. In this article, we present the recent knowledge of telomeres genetic determination obtained by genome-wide association studies (GWAS), important biomarkers related to telomere length and review the possibilities of telomere's practical implementation in the medical treatment of diverse diseases and as a potential biomarker in personalized medicine. Furthermore, we summarise commercial offers of telomere length measurements available and we discuss the actions that should be taken to make steps forward into final application of the accumulated knowledge into practical use.},
}
@article {pmid29291448,
year = {2018},
author = {Gunes, C and Avila, AI and Rudolph, KL},
title = {Telomeres in cancer.},
journal = {Differentiation; research in biological diversity},
volume = {99},
number = {},
pages = {41-50},
doi = {10.1016/j.diff.2017.12.004},
pmid = {29291448},
issn = {1432-0436},
mesh = {Animals ; Apoptosis/physiology ; Cell Cycle Checkpoints/genetics ; Cell Transformation, Neoplastic/genetics ; Humans ; Neoplasms/*genetics/*metabolism ; Telomerase/*genetics ; Telomere/*metabolism ; },
abstract = {Telomere shortening as a consequence of cell divisions during aging and chronic diseases associates with an increased cancer risk. Experimental data revealed that telomere shortening results in telomere dysfunction, which in turn affects tumorigenesis in two ways. First, telomere dysfunction suppresses tumor progression by the activation of DNA damage checkpoints, which induce cell cycle arrest (senescence) or apoptosis, as well as by inducing metabolic compromise and activation of immune responses directed against senescent cells. Second, telomere dysfunction promotes tumorigenesis by inducing chromosomal instability in tumor initiating cells, by inhibiting proliferative competition of non-transformed cells, and possibly, also by influencing tumor cell plasticity. The tumor promoting effects of telomere dysfunction are context dependent and require the loss of p53-dependent DNA damage checkpoints or other genetic modifiers that attenuate DNA damage responses possibly involving complex interactions of different genes. The activation of telomere stabilizing mechanisms appears as a subsequent step, which is required to enable immortal grotwh of emerging cancer cells. Here, we conceptually discuss our current knowledge and new, unpublished experimental data on telomere dependent influences on tumor initiation and progression.},
}
@article {pmid29290468,
year = {2018},
author = {Margalef, P and Kotsantis, P and Borel, V and Bellelli, R and Panier, S and Boulton, SJ},
title = {Stabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe.},
journal = {Cell},
volume = {172},
number = {3},
pages = {439-453.e14},
pmid = {29290468},
issn = {1097-4172},
support = {/WT_/Wellcome Trust/United Kingdom ; 11581/CRUK_/Cancer Research UK/United Kingdom ; FC0010048/CRUK_/Cancer Research UK/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; Cell Line ; Cells, Cultured ; DNA Helicases/*genetics/metabolism ; *DNA Replication ; Glycoside Hydrolases/metabolism ; Mice ; Poly (ADP-Ribose) Polymerase-1/metabolism ; RecQ Helicases/metabolism ; *Telomere Homeostasis ; Ubiquitin-Conjugating Enzymes/metabolism ; },
abstract = {Telomere maintenance critically depends on the distinct activities of telomerase, which adds telomeric repeats to solve the end replication problem, and RTEL1, which dismantles DNA secondary structures at telomeres to facilitate replisome progression. Here, we establish that reversed replication forks are a pathological substrate for telomerase and the source of telomere catastrophe in Rtel1[-/-] cells. Inhibiting telomerase recruitment to telomeres, but not its activity, or blocking replication fork reversal through PARP1 inhibition or depleting UBC13 or ZRANB3 prevents the rapid accumulation of dysfunctional telomeres in RTEL1-deficient cells. In this context, we establish that telomerase binding to reversed replication forks inhibits telomere replication, which can be mimicked by preventing replication fork restart through depletion of RECQ1 or PARG. Our results lead us to propose that telomerase inappropriately binds to and inhibits restart of reversed replication forks within telomeres, which compromises replication and leads to critically short telomeres.},
}
@article {pmid29290466,
year = {2018},
author = {Chen, H and Xue, J and Churikov, D and Hass, EP and Shi, S and Lemon, LD and Luciano, P and Bertuch, AA and Zappulla, DC and Géli, V and Wu, J and Lei, M},
title = {Structural Insights into Yeast Telomerase Recruitment to Telomeres.},
journal = {Cell},
volume = {172},
number = {1-2},
pages = {331-343.e13},
pmid = {29290466},
issn = {1097-4172},
support = {R01 GM077509/GM/NIGMS NIH HHS/United States ; R01 GM118757/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites ; DNA-Binding Proteins/*chemistry/genetics/metabolism ; *Molecular Docking Simulation ; Protein Binding ; RNA/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/*chemistry/genetics/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Telomerase/*chemistry/genetics/metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/*chemistry/genetics/metabolism ; },
abstract = {Telomerase maintains chromosome ends from humans to yeasts. Recruitment of yeast telomerase to telomeres occurs through its Ku and Est1 subunits via independent interactions with telomerase RNA (TLC1) and telomeric proteins Sir4 and Cdc13, respectively. However, the structures of the molecules comprising these telomerase-recruiting pathways remain unknown. Here, we report crystal structures of the Ku heterodimer and Est1 complexed with their key binding partners. Two major findings are as follows: (1) Ku specifically binds to telomerase RNA in a distinct, yet related, manner to how it binds DNA; and (2) Est1 employs two separate pockets to bind distinct motifs of Cdc13. The N-terminal Cdc13-binding site of Est1 cooperates with the TLC1-Ku-Sir4 pathway for telomerase recruitment, whereas the C-terminal interface is dispensable for binding Est1 in vitro yet is nevertheless essential for telomere maintenance in vivo. Overall, our results integrate previous models and provide fundamentally valuable structural information regarding telomere biology.},
}
@article {pmid29290038,
year = {2018},
author = {Melicher, D and Illés, A and Pállinger, &#xc9; and Kovács, &#xc1;F and Littvay, L and Tárnoki, &#xc1;D and Tárnoki, DL and Bikov, A and Molnár, MJ and Buzás, EI and Falus, A},
title = {Tight co-twin similarity of monozygotic twins for hTERT protein level of T cell subsets, for telomere length and mitochondrial DNA copy number, but not for telomerase activity.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {75},
number = {13},
pages = {2447-2456},
pmid = {29290038},
issn = {1420-9071},
support = {2015//Hungarian Pulmonology Foundation (2015)./International ; },
mesh = {Adult ; Aged ; Animals ; Cells, Cultured ; DNA, Mitochondrial/*genetics/metabolism ; Female ; Gene Dosage ; Humans ; Leukocytes, Mononuclear/metabolism ; Male ; Middle Aged ; T-Lymphocyte Subsets/*metabolism ; Telomerase/*genetics/metabolism ; Telomere/*genetics/metabolism ; Telomere Homeostasis ; *Twins, Monozygotic ; Young Adult ; },
abstract = {Our study analyzed lymphocyte subpopulations of 32 monozygotic twins and compared the level of the catalytic reverse transcriptase protein subunit (hTERT) in T lymphocytes (Tly), helper- (Th), cytotoxic- (Tc) and regulatory T cell (Treg) subgroups. Four variables related to telomere and mitochondrial biology were simultaneously assessed, applying multi-parametric flow cytometry, TRAP-ELISA assay and qPCR standard curve method on peripheral blood mononuclear cell (PBMC) samples of genetically matched individuals. Twin data of telomerase activity (TA), hTERT protein level, telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) were analyzed for co-twin similarity. The present study has provided novel information by demonstrating very high intraclass correlation (ICC) of hTERT protein level in T lymphocytes (0.891) and in both Th (0.896), Treg (0.885) and Tc (0.798) cell subgroups. When comparing results measured from PBMCs, intraclass correlation was also high for telomere length (0.815) and considerable for mtDNA copy number (0.524), and again exceptionally high for the rate-limiting telomerase subunit, hTERT protein level (0.946). In contrast, telomerase activity showed no co-twin similarity (ICC 0). By comparing relative amounts of hTERT protein levels in different lymphocyte subgroups of twin subjects, in Treg cells significantly higher level could be detected compared to Tly, Th or Tc cell subgroups. This is the first study that simultaneously analyzed co-twin similarity in MZ twins for the above four variables and alongside assessed their relationship, whereby positive association was found between TL and mtDNAcn.},
}
@article {pmid29286521,
year = {2017},
author = {Ilienko, IM and Lyaskivska, OV and Belayev, OA and Pleskach, OY and Shinkarenko, VI and Bazyka, DA},
title = {Impact of chronic blood viral infection on lymphocyte telomere length in Chornobyl clean-up workers in a remote period after radiation exposure.},
journal = {Problemy radiatsiinoi medytsyny ta radiobiolohii},
volume = {22},
number = {},
pages = {372-381},
pmid = {29286521},
issn = {2304-8336},
mesh = {Adult ; Antibodies, Viral/blood ; Antigens, CD/genetics/immunology ; Cellular Senescence/genetics/immunology ; *Chernobyl Nuclear Accident ; Cytomegalovirus/growth &amp; development/immunology ; Emergency Responders ; Hepacivirus/growth &amp; development/immunology ; Herpesvirus 4, Human/growth &amp; development/immunology ; Humans ; Immunity, Innate ; Immunophenotyping ; Lymphocytes/*immunology/pathology/virology ; Male ; Middle Aged ; Occupational Exposure/*adverse effects ; Primary Cell Culture ; Prospective Studies ; Radiation Dosage ; Radiation Exposure/*adverse effects ; Radiation Injuries/etiology/*immunology/pathology/virology ; Receptors, Antigen, T-Cell/genetics/immunology ; Simplexvirus/growth &amp; development/immunology ; Telomere/chemistry/immunology ; Telomere Shortening/*immunology ; Ukraine ; Virus Diseases/etiology/*immunology/pathology/virology ; },
abstract = {OBJECTIVE: To assess whether telomere length in lymphocytes of Chornobyl clean up workers at a late period 30 years after the exposure to ionizing radiation is influenced by a chronic blood viral infection and to determine role of viral carriage in cellular senescence.<br><br>PATIENTS AND METHODS: Study group included 70 Chornobyl cleanup male workers 30 years after exposure {doses of external exposure (602.67 &#xb1; 114.19) mSv (M &#xb1; m); age (59.75 &#xb1; 0.82) yrs}
. Relative telomere length (RTL) was analysed by fluorescence in situ hybridization and flow cytometry, immune cell subsets by standard combinations of monoclonal antibodies (CD45/14, CD3/19, CD4/8, CD3/HLADR, CD3/16/56, TCR&#x3b3;&#x3b4;) and flow cytometry; antiviral immunity was performed determining the chronic phase antibodies to viruses: Hepatitis C (HCV), Cytomegalovirus (CMV), Toxoplasma gondii (TOX), Herpes simplex (HSV) and Epstein Barr virus (EBV VCA IgG and EBV NA IgG). The object of the study was peripheral blood (PB) of clean up workers.<br><br>RESULTS: RTL changes were associated at the group level with the carrier state of the viral infection. RTL shortening was demonstrated as a significant difference between the groups (M &#xb1; SD) (HCV negative 15.27 &#xb1; 3.35, HCV posi tive 13.09 &#xb1; 3.05, p < 0.08, n = 12/52) or as a tendency (CMV negative 15.99 &#xb1; 5.41, CMV positive 14.86 &#xb1; 3.46 (M &#xb1; SD), p < 0.57, n = 11/53; HSV negative 17.01 &#xb1; 1.35, HSV positive 14.79 &#xb1; 3.80, p < 0.33, n = 13/51; TOX neg ative 15.94 &#xb1; 3.41, TOX positive 14.30 &#xb1; 3.81(M &#xb1; SD), p < 0.23, n = 27/37). These unidirectional changes can be associated with premature early cell aging of immune cells. To the contrary the significant RTL elongation was demonstrated in the group of EBV NA chronic carriers (EBV NA negative 11.25 &#xb1; 3.02 (M &#xb1; SD), EBV NA positive 16.15 &#xb1; 3.08 (M &#xb1; SD), p < 0.001, n = 15/49).<br><br>CONCLUSION: The study confirmed the assumption on a relationship existing between the telomere length, chronic viral infection and late effects in immune cells. The changes of telomeres length on the background of immune dys function may be a sign of cellular aging, and concomitant chronic blood viral infection such as Hepatitis C, Epstein Barr viruses carriage could form a background for an error prone DNA reparation system as a factor of accumulation of pathological conditions, including malignant transformation.},
}
@article {pmid29285505,
year = {2017},
author = {Donati, B and Valenti, L},
title = {Telomeric zinc-finger associated protein (TZAP): a new player in telomere diseases?.},
journal = {Annals of translational medicine},
volume = {5},
number = {23},
pages = {472},
pmid = {29285505},
issn = {2305-5839},
}
@article {pmid29285302,
year = {2017},
author = {Luo, D and Hou, Q and Yu, J and Yu, D},
title = {Telomere length associated with the risks of high-risk and ischemic stroke in southern Chinese Han population.},
journal = {Oncotarget},
volume = {8},
number = {62},
pages = {105915-105922},
pmid = {29285302},
issn = {1949-2553},
abstract = {Some previous studies suggested telomere length was associated with the risk of ischemic stroke (IS). The aim of this study was to further confirm the association between relative telomere length (RTL) and risk of IS and to especially explore its correlation with the risk of high-risk stroke population in southern Chinese Han. RTL was determined by using real-time quantitative polymerase chain reaction from 400 ischemic stroke patients, 409 high-risk stroke populations and 399 healthy controls. The correlations between the controls and the risk of high-risk and ischemic stroke were evaluated by using an unconditional logistic regression. IS patients have shown longer RTL than controls (median1.52vs1.11, p60 years) and gender suggested that the first and second tertile of RTL were correlated with the risk of IS in each group when the second tertile was used as a reference. However, the increased risk for high-risk stroke populations were only presented in the first tertile of RTL in the age≤60 years and female groups. the RTL was associated with an increased risk of ischemic stroke, while it elevated the risk of high-risk stroke in some specific subpopulations.},
}
@article {pmid29285197,
year = {2018},
author = {Yamada-Hishida, H and Nobeyama, Y and Nakagawa, H},
title = {Correlation of telomere length to malignancy potential in non-melanoma skin cancers.},
journal = {Oncology letters},
volume = {15},
number = {1},
pages = {393-399},
pmid = {29285197},
issn = {1792-1074},
abstract = {Telomeres are associated with cell fate and aging through their role in the cellular response to stress and growth stimulation resulting from previous cell divisions and DNA damage. Telomere shortening has been observed in most human cancers, and is known to be a feature of malignancy. The aim of this study is to clarify whether telomere length is related to the malignant potential of non-melanoma skin cancers. Telomere length was analyzed using tissue quantitative fluorescence in situ hybridization in 36 non-melanoma skin cancers including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), Bowen's disease (BD) and actinic keratosis (AK), and also in 26 samples of normal-appearing epidermal tissue surrounding or located close to each tumor. The fluorescence intensities of telomeres and centromeres within nuclei were determined, and the telomere-centromere ratio (TCR) was then calculated in each sample. The resulting histograms suggested that the TCR values for each type of tumor cell were distributed in a lower range than those for epidermal cells located close to the corresponding tumor type, and that the TCR values for SCC and BCC cells were distributed in a lower range than those for BD and AK cells. These results were completely consistent with the potential for metastasis and invasion of each tumor type, suggesting that telomere length in non-melanoma skin cancer cells is intrinsically linked to their biological behavior.},
}
@article {pmid29282377,
year = {2017},
author = {Crunkhorn, S},
title = {Cancer: Targeting telomeres.},
journal = {Nature reviews. Drug discovery},
volume = {17},
number = {1},
pages = {18},
pmid = {29282377},
issn = {1474-1784},
}
@article {pmid29281671,
year = {2017},
author = {Snetselaar, R and van Batenburg, AA and van Oosterhout, MFM and Kazemier, KM and Roothaan, SM and Peeters, T and van der Vis, JJ and Goldschmeding, R and Grutters, JC and van Moorsel, CHM},
title = {Short telomere length in IPF lung associates with fibrotic lesions and predicts survival.},
journal = {PloS one},
volume = {12},
number = {12},
pages = {e0189467},
pmid = {29281671},
issn = {1932-6203},
mesh = {Aged ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Lung/metabolism ; Male ; Middle Aged ; Multiplex Polymerase Chain Reaction ; Pulmonary Fibrosis/*genetics/pathology ; Survival Analysis ; Telomerase/genetics ; *Telomere ; },
abstract = {Telomere maintenance dysfunction has been implicated in the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). However, the mechanism of how telomere length is related to fibrosis in the lungs is unknown. Surgical lung biopsies of IPF patients typically show a heterogeneous pattern of non-fibrotic and fibrotic areas. Therefore, telomere length (TL) in both lung areas of patients with IPF and familial interstitial pneumonia was compared, specifically in alveolar type 2 (AT2) cells. Fluorescent in situ hybridization was used to determine TL in non-fibrotic and fibrotic areas of 35 subjects. Monochrome multiplex quantitative polymerase chain reaction (MMqPCR) was used for 51 whole lung biopsies and blood TL measurements. For sporadic IPF subjects, AT2 cell TL in non-fibrotic areas was 56% longer than in fibrotic areas. No such difference was observed in the surrounding lung cells. In subjects carrying a telomerase reverse transcriptase (TERT) mutation, AT2 cell TL was significantly shorter than in sporadic subjects. However, no difference in surrounding cell TL was observed between these subject groups. Finally, using biopsy MMqPCR TL measurements, it was determined that IPF subjects with shortest lung TL had a significantly worse survival than patients with long TL. This study shows that shortening of telomeres critically affects AT2 cells in fibrotic areas, implying TL as a cause of fibrogenesis. Furthermore, short lung telomere length is associated with decreased survival.},
}
@article {pmid29274896,
year = {2018},
author = {Ahmed, W and Lingner, J},
title = {Impact of oxidative stress on telomere biology.},
journal = {Differentiation; research in biological diversity},
volume = {99},
number = {},
pages = {21-27},
doi = {10.1016/j.diff.2017.12.002},
pmid = {29274896},
issn = {1432-0436},
mesh = {Animals ; Humans ; Neoplasms/genetics ; Oxidation-Reduction/*drug effects ; Oxidative Stress/*genetics ; Stem Cells/cytology ; Telomerase/*genetics ; Telomere/*genetics/metabolism ; },
abstract = {Telomere integrity is essential for genome stability and it regulates cell proliferation and tissue renewal. Several lines of evidence indicate that telomeres are particularly sensitive to oxidative damage. Moreover, recent studies demonstrate striking inhibitory effects of oxidative damage on telomerase activity. On the other hand, several mechanisms have been uncovered that either counteract oxidative damage at telomeres or remove the modified lesions. Here, we review the current understanding of oxidative damage and protection of telomeric DNA. We discuss how oxidative telomeric lesions impact on telomerase, the regenerative capacity of stem cells and cancer. Finally, we propose how through a better understanding of the involved pathways it may become possible to target telomerase in cancer cells in future cancer therapies.},
}
@article {pmid29274177,
year = {2018},
author = {McLennan, D and Armstrong, JD and Stewart, DC and McKelvey, S and Boner, W and Monaghan, P and Metcalfe, NB},
title = {Links between parental life histories of wild salmon and the telomere lengths of their offspring.},
journal = {Molecular ecology},
volume = {27},
number = {3},
pages = {804-814},
doi = {10.1111/mec.14467},
pmid = {29274177},
issn = {1365-294X},
mesh = {Animals ; Embryo, Nonmammalian/metabolism ; Fertilization ; Linear Models ; Male ; Salmo salar/embryology/*growth &amp; development/*metabolism ; Spermatozoa/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {The importance of parental contributions to offspring development and subsequent performance is self-evident at a genomic level; however, parents can also affect offspring fitness by indirect genetic and environmental routes. The life history strategy that an individual adopts will be influenced by both genes and environment; and this may have important consequences for offspring. Recent research has linked telomere dynamics (i.e., telomere length and loss) in early life to future viability and longevity. Moreover, a number of studies have reported a heritable component to telomere length across a range of vertebrates, although the effects of other parental contribution pathways have been far less studied. Using wild Atlantic salmon with different parental life histories in an experimental split-brood in vitro fertilization mating design and rearing the resulting families under standardized conditions, we show that there can be significant links between parental life history and offspring telomere length (studied at the embryo and fry stage). Maternal life history traits, in particular egg size, were most strongly related to offspring telomere length at the embryonic stage, but then became weaker through development. In contrast, paternal life history traits, such as the father's growth rate in early life, had a greater association in the later stages of offspring development. However, offspring telomere length was not significantly related to either maternal or paternal age at reproduction, nor to paternal sperm telomere length. This study demonstrates both the complexity and the importance of parental factors that can influence telomere length in early life.},
}
@article {pmid29272567,
year = {2018},
author = {Aravinthan, AD and Alexander, GJ},
title = {Telomere, telomerase and liver disease.},
journal = {Liver international : official journal of the International Association for the Study of the Liver},
volume = {38},
number = {1},
pages = {33-34},
doi = {10.1111/liv.13630},
pmid = {29272567},
issn = {1478-3231},
mesh = {Carcinoma, Hepatocellular ; Humans ; Liver Neoplasms ; Telomerase/*genetics ; *Telomere ; },
}
@article {pmid29271129,
year = {2018},
author = {Kjaer, TW and Faurholt-Jepsen, D and Mehta, KM and Christensen, VB and Epel, E and Lin, J and Blackburn, E and Wojcicki, JM},
title = {Shorter preschool, leukocyte telomere length is associated with obesity at age 9 in Latino children.},
journal = {Clinical obesity},
volume = {8},
number = {2},
pages = {88-94},
pmid = {29271129},
issn = {1758-8111},
support = {K01 DK080825/DK/NIDDK NIH HHS/United States ; P30 DK098722/DK/NIDDK NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; },
mesh = {Beverages/adverse effects/analysis ; Child ; Cohort Studies ; Energy Intake ; Female ; Follow-Up Studies ; Hispanic or Latino/statistics &amp; numerical data ; Humans ; Leukocytes/*metabolism ; Male ; Pediatric Obesity/ethnology/*metabolism/physiopathology ; Risk Factors ; San Francisco/ethnology ; Sugars/analysis/metabolism ; Telomere/*metabolism ; },
abstract = {The aim of this study was to determine the potential role of leukocyte telomere length as a biomarker for development of childhood obesity in a low-income Latino population. A birth cohort of Latino children (N = 201) in San Francisco (recruited May 2006-May 2007) was followed until age 9 and assessed annually for obesity and dietary intake. Leukocyte telomere length was measured at 4 and 5 years (n = 102) and assessed as a predictor for obesity at age 9, adjusting for known risk factors. Furthermore, leukocyte telomere length at age 4 and 5 was evaluated as a possible mediator of the relationship between excessive sugar-sweetened beverage consumption and obesity at age 9. Shorter leukocyte telomere length in preschoolers was associated with obesity at age 9 (adjusted odds ratio 0.35, 95% confidence interval 0.13-0.94) after adjustment for known risk factors. Telomere length mediated 11% of the relationship between excessive sugar-sweetened beverage consumption and obesity. Shorter leukocyte telomere length may be an indicator of future obesity risk in high-risk populations as it is particularly sensitive to damage from oxidative stress exposure, including those from sugar-sweetened beverages.},
}
@article {pmid29270121,
year = {2017},
author = {Stout, SA and Lin, J and Hernandez, N and Davis, EP and Blackburn, E and Carroll, JE and Glynn, LM},
title = {Validation of Minimally-Invasive Sample Collection Methods for Measurement of Telomere Length.},
journal = {Frontiers in aging neuroscience},
volume = {9},
number = {},
pages = {397},
pmid = {29270121},
issn = {1663-4365},
support = {P50 MH096889/MH/NIMH NIH HHS/United States ; R01 HD065823/HD/NICHD NIH HHS/United States ; },
abstract = {Objective: The discovery of telomere length (TL) as a biomarker of cellular aging and correlate of age-related disease has generated a new field of research in the biology of healthy aging. Although the most common method of sample collection for TL is venous blood draw, less-invasive DNA collection methods are becoming more widely used. However, how TL relates across tissues derived from these sample collection methods is poorly understood. The current study is the first to characterize the associations in TL across three sample collection methods: venous whole blood, finger prick dried blood spot and saliva. Methods: TL was measured in 24 healthy young adults using three modes of sample collection for each participant: venous whole blood, finger prick dried blood spot and saliva. Relative TL was measured using quantitative polymerase chain reaction. Results: TL in finger prick dried blood spots (DBS) washighly correlated with TL in whole blood (r = 0.84, p < 0.001). Salivary TL was also correlated with whole blood TL (r = 0.56, p = 0.005), but this association was not as strong as that of dried blood spot TL (Steiger's Z = 2.12, p = 0.034). TL was longer in saliva than in whole blood or DBS (p's < 0.001). Conclusions: These findings have important implications for future study design by supporting the validity of less-invasive methods that can be implemented with vulnerable populations or in the field. Further, these findings aid in interpreting the burgeoning area of biological aging research and may shed light on our understanding of inconsistencies in the empirical literature.},
}
@article {pmid29269807,
year = {2018},
author = {Gadalla, SM and Wang, T and Loftus, D and Friedman, L and Dagnall, C and Haagenson, M and Spellman, SR and Buturovic, L and Blauwkamp, M and Shelton, J and Fleischhauer, K and Hsu, KC and Verneris, MR and Krstajic, D and Hicks, B and Jones, K and Lee, SJ and Savage, SA},
title = {No association between donor telomere length and outcomes after allogeneic unrelated hematopoietic cell transplant in patients with acute leukemia.},
journal = {Bone marrow transplantation},
volume = {53},
number = {4},
pages = {383-391},
pmid = {29269807},
issn = {1476-5365},
support = {U24 CA076518/CA/NCI NIH HHS/United States ; ZIA CP010144-18/ImNIH/Intramural NIH HHS/United States ; ZIA CP010144-17/ImNIH/Intramural NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; P30 CA046934/CA/NCI NIH HHS/United States ; },
mesh = {Acute Disease ; Adolescent ; Adult ; Aged ; Child ; Child, Preschool ; Female ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation/*methods/standards ; Humans ; Infant ; Infant, Newborn ; Leukemia/diagnosis/*therapy ; Leukemia, Myeloid, Acute/diagnosis/therapy ; Male ; Middle Aged ; Neutrophils ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis/therapy ; Prognosis ; Recurrence ; *Telomere Homeostasis ; Transplantation, Homologous ; Treatment Outcome ; *Unrelated Donors ; Young Adult ; },
abstract = {Recent studies suggest improved survival in patients with severe aplastic anemia receiving hematopoietic cell transplant (HCT) from unrelated donors with longer telomeres. Here, we tested whether this effect is generalizable to patients with acute leukemia. From the Center for International Blood and Marrow Transplant Research (CIBMTR[®]) database, we identified 1097 patients who received 8/8 HLA-matched unrelated HCT for acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL) between 2004 and 2012 with myeloablative conditioning, and had pre-HCT blood sample from the donor in CIBMTR repository. The median age at HCT for recipients was 40 years (range ≤1-68), and 32 years for donors (range = 18-61). We used qPCR for relative telomere length (RTL) measurement, and Cox proportional hazard models for statistical analyses. In a discovery cohort of 300 patients, longer donor RTL (>25th percentile) was associated with reduced risks of relapse (HR = 0.62, p = 0.05) and acute graft-versus-host disease II-IV (HR = 0.68, p = 0.05), and possibly with a higher probability of neutrophil engraftment (HR = 1.3, p = 0.06). However, these results did not replicate in two validation cohorts of 297 and 488 recipients. There was one exception; a higher probability of neutrophil engraftment was observed in one validation cohort (HR = 1.24, p = 0.05). In a combined analysis of the three cohorts, no statistically significant associations (all p > 0.1) were found between donor RTL and any outcomes.},
}
@article {pmid29267235,
year = {2017},
author = {Pavanello, S and Carta, A and Mastrangelo, G and Campisi, M and Arici, C and Porru, S},
title = {Relationship between Telomere Length, Genetic Traits and Environmental/Occupational Exposures in Bladder Cancer Risk by Structural Equation Modelling.},
journal = {International journal of environmental research and public health},
volume = {15},
number = {1},
pages = {},
pmid = {29267235},
issn = {1660-4601},
mesh = {Adult ; Aged ; Aged, 80 and over ; Environmental Exposure/adverse effects ; *Gene-Environment Interaction ; *Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Occupational Exposure/adverse effects ; Phenotype ; Polymorphism, Genetic ; Protein Structural Elements/*genetics ; Risk Assessment/*statistics &amp; numerical data ; Risk Factors ; Telomere/*genetics ; Urinary Bladder Neoplasms/*genetics/*physiopathology ; },
abstract = {UNLABELLED: Background: Telomere length (TL) maintenance plays an important role in bladder cancer (BC) and prognosis. However the manifold influence of everyday life exposures and genetic traits on leucocyte TL (LTL), is not fully elucidated. Methods: Within the framework of a hospital-based case (n = 96)/control (n = 94) study (all Caucasian males), we investigated the extent to which LTL and BC risk were modulated by genetic polymorphisms and environmental and occupational exposures. Data on lifetime smoking, alcohol and coffee drinking, dietary habits and occupational exposures, pointing to aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs) were collected. Structural equation modelling (SEM) analysis appraised this complex relationships. Results: The SEM analysis indicates negative direct links (p < 0.05) between LTL with age, DNA adducts, alcohol and NAT2, and positive ones with coffee, MPO and XRCC3; and between BC risk (p < 0.01) with cigarettes, cumulative exposure to AAs and coffee, while are negative with LTL and age. There was evidence of indirect effects (p < 0.05) on BC risk, probably via LTL reduction, by age and NAT2 (positive link), MPO and XRCC3 (negative link).<br><br>CONCLUSIONS: Our study supports evidence that LTL attrition is a critical event in BC. The new finding that LTL erosion depends on some preventable everyday life exposures genetically modulated, opens new perspectives in BC prevention.},
}
@article {pmid29267201,
year = {2017},
author = {Aschacher, T and Salameh, O and Enzmann, F and Messner, B and Bergmann, M},
title = {Telomere Biology and Thoracic Aortic Aneurysm.},
journal = {International journal of molecular sciences},
volume = {19},
number = {1},
pages = {},
pmid = {29267201},
issn = {1422-0067},
mesh = {Aging/*metabolism ; Animals ; Aortic Aneurysm, Thoracic/*genetics/*pathology ; Biomarkers/metabolism ; DNA/metabolism ; Humans ; Mice ; Rats ; Risk Factors ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; *Telomere Shortening ; },
abstract = {Ascending aortic aneurysms are mostly asymptomatic and present a great risk of aortic dissection or perforation. Consequently, ascending aortic aneurysms are a source of lethality with increased age. Biological aging results in progressive attrition of telomeres, which are the repetitive DNA sequences at the end of chromosomes. These telomeres play an important role in protection of genomic DNA from end-to-end fusions. Telomere maintenance and telomere attrition-associated senescence of endothelial and smooth muscle cells have been indicated to be part of the pathogenesis of degenerative vascular diseases. This systematic review provides an overview of telomeres, telomere-associated proteins and telomerase to the formation and progression of aneurysms of the thoracic ascending aorta. A better understanding of telomere regulation in the vascular pathology might provide new therapeutic approaches. Measurements of telomere length and telomerase activity could be potential prognostic biomarkers for increased risk of death in elderly patients suffering from an aortic aneurysm.},
}
@article {pmid29253739,
year = {2018},
author = {Shay, JW},
title = {Telomeres and aging.},
journal = {Current opinion in cell biology},
volume = {52},
number = {},
pages = {1-7},
doi = {10.1016/j.ceb.2017.12.001},
pmid = {29253739},
issn = {1879-0410},
mesh = {Aging/*genetics ; Humans ; Telomere/*metabolism ; },
abstract = {Telomeres (the TTAGGG repetitive DNA at the ends of linear chromosomes) are part of the 3D spatial organization of the nuclear genome. Long-range 3D chromatin interactions also establish specific patterns of regulated gene expression. An emerging area of interest is the role of telomere 3D looping with interstitial telomeric sequences (ITS) through interactions with telomere shelterin proteins. Telomeres form interstitial telomere loops (ITL) that interact with ITS and modify gene expression at distal genomic regions. Human laminopathies and telomeropathies often correlate with short telomeres. Since telomeres progressively shorten with increased turnover and chronological age in dividing somatic cells, ITLs may also change and have functional roles in normal and pathophysiological processes. Overall, telomeres help stabilize the nuclear genome with high fidelity throughout early adult life but diminish in post-reproductive age-associated pathology.},
}
@article {pmid29250704,
year = {2018},
author = {Tardat, M and Déjardin, J},
title = {Telomere chromatin establishment and its maintenance during mammalian development.},
journal = {Chromosoma},
volume = {127},
number = {1},
pages = {3-18},
pmid = {29250704},
issn = {1432-0886},
mesh = {Animals ; Chromatin/*genetics ; Embryonic Development/genetics ; Humans ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {Telomeres are specialized structures that evolved to protect the end of linear chromosomes from the action of the cell DNA damage machinery. They are composed of tandem arrays of repeated DNA sequences with a specific heterochromatic organization. The length of telomeric repeats is dynamically regulated and can be affected by changes in the telomere chromatin structure. When telomeres are not properly controlled, the resulting chromosomal alterations can induce genomic instability and ultimately the development of human diseases, such as cancer. Therefore, proper establishment, regulation, and maintenance of the telomere chromatin structure are required for cell homeostasis. Here, we review the current knowledge on telomeric chromatin dynamics during cell division and early development in mammals, and how its proper regulation safeguards genome stability.},
}
@article {pmid29247743,
year = {2018},
author = {Westmoreland, JW and Mihalevic, MJ and Bernstein, KA and Resnick, MA},
title = {The global role for Cdc13 and Yku70 in preventing telomere resection across the genome.},
journal = {DNA repair},
volume = {62},
number = {},
pages = {8-17},
pmid = {29247743},
issn = {1568-7856},
support = {R01 ES024872/ES/NIEHS NIH HHS/United States ; Z01 ES065073//Intramural NIH HHS/United States ; },
mesh = {Chromosomes, Fungal/metabolism ; Cyclins/*metabolism ; Fungal Proteins/metabolism ; Ku Autoantigen/*metabolism ; Rad52 DNA Repair and Recombination Protein/*metabolism ; Telomere/*metabolism ; Yeasts ; },
abstract = {Yeast Cdc13 protein (related to human CTC1) maintains telomere stability by preventing 5'-3' end resection. While Cdc13 and Yku70/Yku80 proteins appear to prevent excessive resection, their combined contribution to maintenance of telomere ends across the genome and their relative roles at specific ends of different chromosomes have not been addressable because Cdc13 and Yku70/Yku80 double mutants are sickly. Using our PFGE-shift approach where large resected molecules have slower pulse field gel electrophoresis mobilities, along with methods for maintaining viable double mutants, we address end-resection on most chromosomes as well as telomere end differences. In this global approach to looking at ends of most chromosomes, we identify chromosomes with 1-end resections and end-preferences. We also identify chromosomes with resection at both ends, previously not possible. 10-20% of chromosomes exhibit PFGE-shift when cdc13-1 cells are switched to restrictive temperature (37 °C). In yku70Δ cdc13-1 mutants, there is a telomere resection "storm" with approximately half the chromosomes experiencing at least 1-end resection, ∼10 kb/telomere, due to exonuclease1 and many exhibiting 2-end resection. Unlike for random internal chromosome breaks, resection of telomere ends is not coordinated. Telomere restitution at permissive temperature is rapid (<1 h) in yku70Δ cdc13-1 cells. Surprisingly, survival can be high although strain background dependent. Given large amount of resected telomeres, we examined associated proteins. Up to 90% of cells have ≥1 Rfa1 (RPA) focus and 60% have multiple foci when ∼30-40 telomeres/cell are resected. The ends are dispersed in the nucleus suggesting wide distribution of resected telomeres across nuclear space. The previously reported Rad52 nuclear centers of repair for random DSBs also appear in cells with many resected telomere ends, suggesting a Rad52 commonality to the organization of single strand ends and/or limitation on interactions of single-strand ends with Rad52.},
}
@article {pmid29242289,
year = {2018},
author = {Mason, JMO and McEachern, MJ},
title = {Mild Telomere Dysfunction as a Force for Altering the Adaptive Potential of Subtelomeric Genes.},
journal = {Genetics},
volume = {208},
number = {2},
pages = {537-548},
pmid = {29242289},
issn = {1943-2631},
support = {T32 GM007103/GM/NIGMS NIH HHS/United States ; },
mesh = {Adaptation, Biological/*genetics ; Chromosomes, Fungal ; DNA Repair ; Gene Duplication ; Genes, Mating Type, Fungal/genetics ; Loss of Function Mutation ; Mutation ; Recombination, Genetic ; Telomere/*genetics/metabolism ; Yeasts/genetics ; },
abstract = {Subtelomeric regions have several unusual characteristics, including complex repetitive structures, increased rates of evolution, and enrichment for genes involved in niche adaptation. The adaptive telomere failure hypothesis suggests that certain environmental stresses can induce a low level of telomere failure, potentially leading to elevated subtelomeric recombination that could result in adaptive mutational changes within subtelomeric genes. Here, we tested a key prediction of the adaptive telomere failure hypothesis-that telomere dysfunction mild enough to have little or no overall effect on cell fitness could still lead to substantial increases in the mutation rates of subtelomeric genes. Our results show that a mutant of Kluyveromyces lactis with stably short telomeres produced a large increase in the frequency of mutations affecting the native subtelomeric β-galactosidase (LAC4) gene. All lac4 mutants examined from strains with severe telomere dysfunction underwent terminal deletion/duplication events consistent with being due to break-induced replication. In contrast, although cells with mild telomere dysfunction also exhibited similar terminal deletion and duplication events, up to 50% of lac4 mutants from this background unexpectedly contained base changes within the LAC4 coding region. This mutational bias for producing base changes demonstrates that mild telomere dysfunction can be well suited as a force for altering the adaptive potential of subtelomeric genes.},
}
@article {pmid29242238,
year = {2018},
author = {Benetos, A and Toupance, S and Gautier, S and Labat, C and Kimura, M and Rossi, PM and Settembre, N and Hubert, J and Frimat, L and Bertrand, B and Boufi, M and Flecher, X and Sadoul, N and Eschwege, P and Kessler, M and Tzanetakou, IP and Doulamis, IP and Konstantopoulos, P and Tzani, A and Korou, M and Gkogkos, A and Perreas, K and Menenakos, E and Samanidis, G and Vasiloglou-Gkanis, M and Kark, JD and Malikov, S and Verhulst, S and Aviv, A},
title = {Short Leukocyte Telomere Length Precedes Clinical Expression of Atherosclerosis: The Blood-and-Muscle Model.},
journal = {Circulation research},
volume = {122},
number = {4},
pages = {616-623},
pmid = {29242238},
issn = {1524-4571},
support = {R01 HD071180/NICHD NIH HHS/National Institute of Child Health &amp; Human Development/United States ; R01 HL116446/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United States ; },
mesh = {Aged ; Atherosclerosis/*genetics/pathology ; Female ; Humans ; Leukocytes/metabolism ; Male ; Middle Aged ; Muscle Fibers, Skeletal/metabolism ; *Telomere Shortening ; },
abstract = {RATIONALE: Short telomere length (TL) in leukocytes is associated with atherosclerotic cardiovascular disease (ASCVD). It is unknown whether this relationship stems from having inherently short leukocyte TL (LTL) at birth or a faster LTL attrition thereafter. LTL represents TL in the highly proliferative hematopoietic system, whereas TL in skeletal muscle represents a minimally replicative tissue.<br><br>OBJECTIVE: We measured LTL and muscle TL (MTL) in the same individuals with a view to obtain comparative metrics for lifelong LTL attrition and learn about the temporal association of LTL with ASCVD.<br><br>METHODS AND RESULTS: Our Discovery Cohort comprised 259 individuals aged 63&#xb1;14 years (mean&#xb1;SD), undergoing surgery with (n=131) or without (n=128) clinical manifestation of ASCVD. In all subjects, MTL adjusted for muscle biopsy site (MTLA) was longer than LTL and the LTL-MTLA gap similarly widened with age in ASCVD patients and controls. Age- and sex-adjusted LTL (P=0.005), but not MTLA (P=0.90), was shorter in patients with ASCVD than controls. The TL gap between leukocytes and muscle (LTL-MTLA) was wider (P=0.0003), and the TL ratio between leukocytes and muscle (LTL/MTLA) was smaller (P=0.0001) in ASCVD than in controls. Findings were replicated in a cohort comprising 143 individuals.<br><br>CONCLUSIONS: This first study to apply the blood-and-muscle TL model shows more pronounced LTL attrition in ASCVD patients than controls. The difference in LTL attrition was not associated with age during adulthood suggesting that increased attrition in early life is more likely to be a major explanation of the shorter LTL in ASCVD patients.<br><br>CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02176941.},
}
@article {pmid29240257,
year = {2018},
author = {Tanaka, H and Phipps, EA and Wei, T and Wu, X and Goswami, C and Liu, Y and Sledge, GW and Mina, L and Herbert, BS},
title = {Altered expression of telomere-associated genes in leukocytes among BRCA1 and BRCA2 carriers.},
journal = {Molecular carcinogenesis},
volume = {57},
number = {4},
pages = {567-575},
pmid = {29240257},
issn = {1098-2744},
support = {R21 CA205434/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; BRCA1 Protein/*genetics ; BRCA2 Protein/*genetics ; Breast Neoplasms/genetics ; Female ; *Gene Expression Profiling ; Genetic Predisposition to Disease/genetics ; Heterozygote ; Humans ; Leukocytes/*metabolism ; Middle Aged ; Mutation ; Telomere Homeostasis/*genetics ; },
abstract = {Telomere dysfunction resulting from telomere shortening and deregulation of shelterin components has been linked to the pathogenesis of age-related disorders, including cancer. Recent evidence suggests that BRCA1/2 (BRCA1 and BRCA2) tumor suppressor gene products play an important role in telomere maintenance. Although telomere shortening has been reported in BRCA1/2 carriers, the direct effects of BRCA1/2 haploinsufficiency on telomere maintenance and predisposition to cancer development are not completely understood. In this study, we assessed the telomere-associated and telomere-proximal gene expression profiles in peripheral blood leukocytes from patients with a BRCA1 or BRCA2 mutation, compared to samples from sporadic and familial breast cancer individuals. We found that 25 genes, including TINF2 gene (a negative regulator of telomere length), were significantly differentially expressed in BRCA1 carriers. Leukocyte telomere length analysis revealed that BRCA1/2 carriers had relatively shorter telomeres than healthy controls. Further, affected BRCA1/2 carriers were well differentiated from unaffected BRCA1/2 carriers by the expression of telomere-proximal genes. Our results link BRCA1/2 haploinsufficiency to changes in telomere length, telomere-associated as well as telomere-proximal gene expression. Thus, this work supports the effect of BRCA1/2 haploinsufficiency in the biology underlying telomere dysfunction in cancer development. Future studies evaluating these findings will require a large study population.},
}
@article {pmid29238037,
year = {2018},
author = {Rippberger, PL and Emeny, RT and Mackenzie, TA and Bartels, SJ and Batsis, JA},
title = {The association of sarcopenia, telomere length, and mortality: data from the NHANES 1999-2002.},
journal = {European journal of clinical nutrition},
volume = {72},
number = {2},
pages = {255-263},
pmid = {29238037},
issn = {1476-5640},
support = {T32 MH073553/MH/NIMH NIH HHS/United States ; UL1 TR001086/TR/NCATS NIH HHS/United States ; U48 DP005018/DP/NCCDPHP CDC HHS/United States ; U48DP005018//ACL HHS/United States ; K23 AG051681/AG/NIA NIH HHS/United States ; R01 MH102325/MH/NIMH NIH HHS/United States ; R01 MH104555/MH/NIMH NIH HHS/United States ; R25 CA134286/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Body Composition ; Body Mass Index ; Female ; Humans ; Male ; Middle Aged ; *Nutrition Surveys ; Sarcopenia/diagnosis/*mortality/pathology ; *Telomere Homeostasis ; },
abstract = {BACKGROUND/OBJECTIVES: Sarcopenia is defined as the loss of muscle mass or function with aging and is associated with adverse outcomes. Telomere shortening is associated with mortality, yet its relationship with sarcopenia is unknown.<br><br>SUBJECTS/METHODS: Adults &#x2265;60 years from the 1999-2002 NHANES with body composition measures were identified. Sarcopenia was defined using the two Foundation for the National Institute of Health definitions: appendicular lean mass (ALM) (men <19.75; women <15.02&#x2009;kg); or ALM divided by body mass index (BMI) (ALM:BMI, men <0.789; women <0.512). Telomere length was assessed using quantitative PCR. Regression models predicted telomere length with sarcopenia (referent&#x2009;=&#x2009;no sarcopenia).<br><br>RESULTS: We identified 2672 subjects. Mean age was 70.9 years (55.5% female). Prevalence of ALM and ALM:BMI sarcopenia was 29.2 and 22.1%. Deaths were higher in persons with sarcopenia as compared to those without sarcopenia (ALM: 46.4 vs. 33.4%, p&#x2009;<&#x2009;0.001; ALM:BMI: 46.7 vs. 33.2%, p&#x2009;<&#x2009;0.001). No adjusted differences were observed in telomere length in those with/without sarcopenia (ALM: 0.90 vs. 0.92, p&#x2009;=&#x2009;0.74, ALM:BMI 0.89 vs. 0.92, p&#x2009;=&#x2009;0.24). In men with ALM:BMI-defined sarcopenia, adjusted telomere length was significantly lower compared to men without sarcopenia (0.85 vs. 0.91, p&#x2009;=&#x2009;0.013). With sarcopenia, we did not observe a significant association between telomere length and mortality (ALM: HR 1.11 [0.64,1.82], p&#x2009;=&#x2009;0.68; ALM:BMI: HR 0.97 [0.53,1.77], p&#x2009;=&#x2009;0.91), but noted significance in those without sarcopenia with mortality (ALM: HR 0.59 [0.40,0.86], p&#x2009;=&#x2009;0.007; ALM:BMI: HR 0.62 [0.42,0.91]; p&#x2009;=&#x2009;0.01).<br><br>CONCLUSIONS: We observed a potentially inverse relationship between telomere length and mortality in those without sarcopenia but did not observe a significant relationship between telomere length and mortality in the presence of sarcopenia.},
}
@article {pmid29237161,
year = {2017},
author = {Himbert, C and Thompson, H and Ulrich, CM},
title = {Effects of Intentional Weight Loss on Markers of Oxidative Stress, DNA Repair and Telomere Length - a Systematic Review.},
journal = {Obesity facts},
volume = {10},
number = {6},
pages = {648-665},
pmid = {29237161},
issn = {1662-4033},
support = {R01 CA189184/CA/NCI NIH HHS/United States ; },
mesh = {Biomarkers/metabolism ; DNA Repair/*physiology ; Exercise/physiology ; Humans ; Obesity/genetics/*metabolism/therapy ; Oxidative Stress/*physiology ; Telomere/*physiology ; Treatment Outcome ; Weight Loss/genetics/*physiology ; },
abstract = {BACKGROUND: Altered levels of markers of oxidative stress, DNA repair, and telomere integrity have been detected in obese individuals and may underlie the pathogenesis of obesity-related diseases. However, whether or not such effects are reversed by intentional weight loss has not been systematically reviewed.<br><br>METHODS: A literature search in PubMed/Medline identified 2,388 articles of which 21 studies (randomized controlled trial (RCT) (n = 10) and non-randomized intervention studies (n = 11)) were classified as testing the effects of intentional weight loss on i) oxidative stress (n = 15), ii) DNA repair (n = 2), and iii) telomere length (n = 4).<br><br>RESULTS: Across a broad range of intervention designs, diet-, exercise-, surgery-, balloon-induced weight loss regimens decreased oxidative stress measures. Studies investigating DNA repair capacity or telomere length as endpoints after weight loss were less common in number and yielded null or inconsistent results, respectively.<br><br>CONCLUSION: While this systematic review supports a role for intentional weight loss in reducing obesity-associated oxidative stress, it is not clear whether the effects are primary outcomes or secondary to improvement in obesity-associated insulin resistance and/or chronic inflammation. Although the lack of effect of intentional weight loss on DNA repair capacity might be anticipated given that oxidative stress is reduced, additional studies are needed. The inconsistent effects of weight loss on telomere length or DNA repair suggest the need for a re-assessment of intervention designs and assay methodology to definitively address this topic.},
}
@article {pmid29235471,
year = {2017},
author = {Beishline, K and Vladimirova, O and Tutton, S and Wang, Z and Deng, Z and Lieberman, PM},
title = {CTCF driven TERRA transcription facilitates completion of telomere DNA replication.},
journal = {Nature communications},
volume = {8},
number = {1},
pages = {2114},
pmid = {29235471},
issn = {2041-1723},
support = {P30 CA010815/CA/NCI NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; T32 CA009171/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; CCCTC-Binding Factor/*genetics/metabolism ; CRISPR-Cas Systems ; *DNA Replication ; DNA-Binding Proteins/*genetics/metabolism ; Gene Editing/methods ; HCT116 Cells ; Humans ; Mutation ; Protein Binding ; Telomere/*genetics/metabolism ; Transcription Factors/*genetics/metabolism ; *Transcription, Genetic ; },
abstract = {Telomere repeat DNA forms a nucleo-protein structure that can obstruct chromosomal DNA replication, especially under conditions of replication stress. Transcription of telomere repeats can initiate at subtelomeric CTCF-binding sites to generate telomere repeat-encoding RNA (TERRA), but the role of transcription, CTCF, and TERRA in telomere replication is not known. Here, we have used CRISPR/Cas9 gene editing to mutate CTCF-binding sites at the putative start site of TERRA transcripts for a class of subtelomeres. Under replication stress, telomeres lacking CTCF-driven TERRA exhibit sister-telomere loss and upon entry into mitosis, exhibit the formation of ultra-fine anaphase bridges and micronuclei. Importantly, these phenotypes could be rescued by the forced transcription of TERRA independent of CTCF binding. Our findings indicate that subtelomeric CTCF facilitates telomeric DNA replication by promoting TERRA transcription. Our findings also demonstrate that CTCF-driven TERRA transcription acts in cis to facilitate telomere repeat replication and chromosome stability.},
}
@article {pmid29230034,
year = {2018},
author = {Powell, TR and Dima, D and Frangou, S and Breen, G},
title = {Telomere Length and Bipolar Disorder.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {43},
number = {2},
pages = {454},
doi = {10.1038/npp.2017.239},
pmid = {29230034},
issn = {1740-634X},
support = {R01 MH104284/MH/NIMH NIH HHS/United States ; },
abstract = {This corrects the article DOI: 10.1038/npp.2017.125.},
}
@article {pmid29230030,
year = {2017},
author = {Shoeb, M and Joseph, P and Kodali, V and Mustafa, G and Farris, BY and Umbright, C and Roberts, JR and Erdely, A and Antonini, JM},
title = {Silica inhalation altered telomere length and gene expression of telomere regulatory proteins in lung tissue of rats.},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {17284},
pmid = {29230030},
issn = {2045-2322},
mesh = {Animals ; Biomarkers/*analysis ; Gene Expression Profiling ; Gene Expression Regulation/*drug effects ; Inhalation Exposure/*adverse effects ; Lung/drug effects/*metabolism/pathology ; Male ; Rats ; Rats, Inbred F344 ; Silicon Dioxide/*toxicity ; *Telomere Homeostasis ; },
abstract = {Exposure to silica can cause lung fibrosis and cancer. Identification of molecular targets is important for the intervention and/or prevention of silica-induced lung diseases. Telomeres consist of tandem repeats of DNA sequences at the end of chromosomes, preventing chromosomal fusion and degradation. Regulator of telomere length-1 (RTEL1) and telomerase reverse transcriptase (TERT), genes involved in telomere regulation and function, play important roles in maintaining telomere integrity and length. The goal of this study was to assess the effect of silica inhalation on telomere length and the regulation of RTEL1 and TERT. Lung tissues and blood samples were collected from rats at 4, 32, and 44 wk after exposure to 15 mg/m[3] of silica × 6 h/d × 5 d. Controls were exposed to air. At all-time points, RTEL1 expression was significantly decreased in lung tissue of the silica-exposed animals compared to controls. Also, significant increases in telomere length and TERT were observed in the silica group at 4 and 32 wk. Telomere length, RTEL1 and TERT expression may serve as potential biomarkers related to silica exposure and may offer insight into the molecular mechanism of silica-induced lung disease and tumorigeneses.},
}
@article {pmid29229970,
year = {2018},
author = {Smith, DL and Thomas, DM and Siu, CO and Verhulst, S and Allison, DB},
title = {Regression to the mean, apparent data errors and biologically extraordinary results: letter regarding 'changes in telomere length 3-5 years after gastric bypass surgery'.},
journal = {International journal of obesity (2005)},
volume = {42},
number = {4},
pages = {949-950},
pmid = {29229970},
issn = {1476-5497},
support = {P30 DK056336/DK/NIDDK NIH HHS/United States ; R25 DK099080/DK/NIDDK NIH HHS/United States ; R25 HL124208/HL/NHLBI NIH HHS/United States ; },
mesh = {*Gastric Bypass ; Telomere ; },
}
@article {pmid29229290,
year = {2018},
author = {Hata, T and Dal Molin, M and McGregor-Das, A and Song, TJ and Wolfgang, C and Eshleman, JR and Hruban, RH and Goggins, M},
title = {Simple Detection of Telomere Fusions in Pancreatic Cancer, Intraductal Papillary Mucinous Neoplasm, and Pancreatic Cyst Fluid.},
journal = {The Journal of molecular diagnostics : JMD},
volume = {20},
number = {1},
pages = {46-55},
pmid = {29229290},
issn = {1943-7811},
support = {P50 CA062924/CA/NCI NIH HHS/United States ; R01 CA176828/CA/NCI NIH HHS/United States ; U01 CA210170/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma, Mucinous/*genetics ; Aged ; Body Fluids/*metabolism ; Carcinoma, Pancreatic Ductal/*genetics ; Carcinoma, Papillary/*genetics ; Cell Line, Tumor ; Female ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Pancreatic Cyst/*genetics ; Pancreatic Neoplasms/*genetics ; Telomere/*genetics ; Telomere Homeostasis/genetics ; },
abstract = {Telomere end-to-end fusions are an important source of chromosomal instability that arise in cells with critically shortened telomeres. We developed a nested real-time quantitative PCR method for telomere fusion detection in pancreatic ductal adenocarcinomas, intraductal papillary mucinous neoplasms (IPMNs), and IPMN cyst fluids. Ninety-one pancreatic cancer cell lines and xenograft samples, 93 IPMNs, and 93 surgically aspirated IPMN cyst fluid samples were analyzed. The association between telomere shortening, telomerase activity, and telomere fusion detection was evaluated. Telomere fusions were detected in 56 of 91 pancreatic cancers (61.5%). Telomere fusion-positive cell lines had significantly shorter telomere lengths than fusion-negative lines (P = 0.003). Telomere fusions were undetectable in normal pancreas or IPMNs with low-grade dysplasia (0.0%) and were detected in IPMN with high-grade dysplasia (HGD; 48.0%) (P < 0.001). In IPMN cyst fluids, telomere fusions were more frequent in IPMNs with HGD (26.9%) or associated invasive cancer (42.9%) than IPMN with intermediate-grade dysplasia (15.4%) or low-grade dysplasia (0%) (P = 0.025). Telomerase activity levels were higher in cyst fluids with fusions than in those without (P = 0.0414). Cyst fluid telomere fusion status was an independent predictor of HGD/invasive cancer by multivariate analysis (odds ratio, 6.23; 95% CI, 1.61-28.0). Telomere fusions are detected in later stages of IPMN progression and can serve as a marker for predicting the presence of HGD and/or invasive cancer.},
}
@article {pmid29228552,
year = {2017},
author = {Zhao, H and Han, L and Chang, D and Ye, Y and Shen, J and Daniel, CR and Gu, J and Chow, WH and Wu, X},
title = {Social-demographics, health behaviors, and telomere length in the Mexican American Mano a Mano Cohort.},
journal = {Oncotarget},
volume = {8},
number = {57},
pages = {96553-96567},
pmid = {29228552},
issn = {1949-2553},
abstract = {In the current study, we examined cross-sectional associations among social-demographics, lifestyle behaviors, and relative telomere length (RTL) in peripheral blood leukocytes, as well as longitudinal relationships among major chronic diseases, weight gain, and RTL, among 12,792 Mexican Americans aged 20 to 85 years in the Mano-A-Mano, the Mexican American Cohort. As expected, RTL was inversely correlated with age (ρ=-0.15, ρ<0.001). In the multivariate analysis, we found that RTL was positively correlated with levels of education (ρ=0.021), self-insurance (ρ=0.041), body mass index (BMI) (ρ<0.001), and sleeping time per day (ρ for trend<0.001), and RTL was inversely correlated with sitting time per day (ρ for trend =0.001). In longitudinal analysis, we found that longer RTL was modestly but positively associated with increased risks of overall cancer (adjusted hazard ratio (adj.HR)=1.05, 95% conference interval (95%CI)=1.02-1.09). In quartile analysis, 4[th] quartile (longest RTL) was associated with 1.53-fold increased risk of overall cancer (adj.HR=1.53, 95%CI=1.11-2.10), compared to 1[st] quartile (shortest RTL). RTL was reversely associated with the risk of type-2 diabetes (adj.HR=0.89, 95%CI=0.82-0.94). In quartile analysis, 4[th] quartile (longest RTL) was associated with 48% decreased risk of typle-2 diabetes (adj.HR=0.52, 95%CI=0.32-0.70), compared to 1[st] quartile (shortest RTL). In addition, longer RTL was a positive predictor of at least 10% weight gain (adj.HR=1.03, 95%CI=1.00-1.05). In summary, our results in Mexican Americans support the notion that telomere length is a biological mechanism by which social demographics and health behaviors "get under the skin" to affect health.},
}
@article {pmid29228317,
year = {2018},
author = {Ajaykumar, A and Soudeyns, H and Kakkar, F and Brophy, J and Bitnun, A and Alimenti, A and Albert, AYK and Money, DM and Côté, HCF and , and , },
title = {Leukocyte Telomere Length at Birth and During the Early Life of Children Exposed to but Uninfected With HIV After In Utero Exposure to Antiretrovirals.},
journal = {The Journal of infectious diseases},
volume = {217},
number = {5},
pages = {710-720},
pmid = {29228317},
issn = {1537-6613},
support = {//CIHR/Canada ; },
mesh = {Adolescent ; Anti-Retroviral Agents/administration &amp; dosage/*adverse effects ; Child ; Child, Preschool ; Female ; HIV Infections/drug therapy ; Humans ; Infant ; Infant, Newborn ; Leukocytes/*drug effects/*pathology ; Longitudinal Studies ; Male ; *Maternal-Fetal Exchange ; Pregnancy ; Pregnancy Complications, Infectious/drug therapy ; *Telomere ; Young Adult ; },
abstract = {BACKGROUND: Maternal combination antiretroviral therapy (cART) during pregnancy could impact the health of human immunodeficiency virus (HIV)-exposed, HIV-uninfected (HEU) children, because some antiretrovirals cross the placenta and can inhibit telomerase. Our objective was to compare leukocyte telomere length (LTL) in HEU children and HIV-unexposed, HIV-uninfected (HUU) children at birth and in early life and to investigate any relationship with cART exposure.<br><br>METHODS: HEU and HUU children's blood LTL was compared cross-sectionally at birth, and during the first three years of life. Longitudinal HEU LTL dynamics was evaluated over that same period.<br><br>RESULTS: At birth, the LTL in HEU children (n = 114) was not shorter than that in HUU children (n = 86), but female infants had longer LTL than male infants. Maternal cART (duration or type) showed no association with shorter infant LTL. Among 214 HEU children age- and sex-matched at a 1:1 ratio to HUU children, LTL declined similarly in both groups. In a longitudinal analysis, LTL attrition in HEU children was rapid from birth to 1 year of age and gradual thereafter. Zidovudine prophylaxis did not significantly alter LTL.<br><br>CONCLUSIONS: Our results indicate that from birth to 3 years of age, the LTL in HEU children is not negatively affected by exposure to maternal HIV infection and cART, at least not to the regimens used within this Canadian cohort, a reassuring finding.},
}
@article {pmid29228254,
year = {2018},
author = {Shastrula, PK and Rice, CT and Wang, Z and Lieberman, PM and Skordalakes, E},
title = {Structural and functional analysis of an OB-fold in human Ctc1 implicated in telomere maintenance and bone marrow syndromes.},
journal = {Nucleic acids research},
volume = {46},
number = {2},
pages = {972-984},
pmid = {29228254},
issn = {1362-4962},
support = {P30 CA010815/CA/NCI NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; R01 CA201312/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Bone Marrow/*metabolism/pathology ; Crystallography, X-Ray ; HEK293 Cells ; Humans ; Models, Molecular ; Mutation ; Protein Binding ; Protein Domains ; *Protein Folding ; Sequence Homology, Amino Acid ; Syndrome ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/*chemistry/genetics/metabolism ; },
abstract = {The human CST (Ctc1, Stn1 and Ten1) complex binds the telomeric overhang and regulates telomere length by promoting C-strand replication and inhibiting telomerase-dependent G-strand synthesis. Structural and biochemical studies on the human Stn1 and Ten1 complex revealed its mechanism of assembly and nucleic acid binding. However, little is known about the structural organization of the multi-domain Ctc1 protein and how each of these domains contribute to telomere length regulation. Here, we report the structure of a central domain of human Ctc1. The structure reveals a canonical OB-fold with the two identified disease mutations (R840W and V871M) contributing to the fold of the protein. In vitro assays suggest that although this domain is not contributing directly to Ctc1's substrate binding properties, it affects full-length Ctc1 localization to telomeres and Stn1-Ten1 binding. Moreover, functional assays show that deletion of the entire OB-fold domain leads to significant increase in telomere length, frequency of internal single G-strands and fragile telomeres. Our findings demonstrate that a previously unknown OB-fold domain contributes to efficient Ctc1 telomere localization and chromosome end maintenance.},
}
@article {pmid29221158,
year = {2017},
author = {Dinami, R and Buemi, V and Sestito, R and Zappone, A and Ciani, Y and Mano, M and Petti, E and Sacconi, A and Blandino, G and Giacca, M and Piazza, S and Benetti, R and Schoeftner, S},
title = {Epigenetic silencing of miR-296 and miR-512 ensures hTERT dependent apoptosis protection and telomere maintenance in basal-type breast cancer cells.},
journal = {Oncotarget},
volume = {8},
number = {56},
pages = {95674-95691},
pmid = {29221158},
issn = {1949-2553},
abstract = {The catalytic subunit of the telomerase complex, hTERT, ensures unlimited proliferative potential of cancer cells by maintaining telomere function and protecting from apoptosis. Using a miRNA screening approach we identified miR-296-5p and miR-512-5p as miRNAs that target hTERT in breast cancer cells. Ectopic miR-296-5p and miR-512-5p reduce telomerase activity, drive telomere shortening and cause proliferation defects by enhancing senescence and apoptosis in breast cancer cells. In line with the relevance of hTERT expression for human cancer we found that miR-296-5p and miR-512-5p expression is reduced in human breast cancer. Accordingly, high expression of miR-296-5p and miR-512-5p target genes including hTERT is linked with significantly reduced distant metastasis free survival and relapse free survival of basal type breast cancer patients. This suggests relevance of the identified miRNAs in basal type breast cancer. Epigenetic silencing of miR-296 and miR-512 encoding genes is responsible for low levels of miR-296-5p and miR-512-5p expression in basal type breast cancer cells. Disrupting gene silencing results in a dramatic upregulation of miR-296-5p and miR-512-5p levels leading to reduced hTERT expression and increased sensitivity to the induction of apoptosis. Altogether, our data suggest that epigenetic regulatory circuits in basal type breast cancer may contribute to high hTERT levels by silencing miR-296-5p and miR-512-5p expression, thereby contributing to the aggressiveness of basal type breast cancer.},
}
@article {pmid29218426,
year = {2018},
author = {Wang, Z and Koh, WP and Jin, A and Wang, R and Yuan, JM},
title = {Telomere length and risk of developing gastric adenocarcinoma: The Singapore Chinese Health Study.},
journal = {Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association},
volume = {21},
number = {4},
pages = {598-605},
pmid = {29218426},
issn = {1436-3305},
support = {R01 CA144034/CA/NCI NIH HHS/United States ; UM1 CA182876/CA/NCI NIH HHS/United States ; R01 CA144034//Division of Cancer Epidemiology and Genetics, National Cancer Institute/International ; UM1 CA182876//Division of Cancer Epidemiology and Genetics, National Cancer Institute/International ; },
mesh = {Adenocarcinoma/*genetics/microbiology/pathology ; Aged ; Female ; Helicobacter Infections/genetics ; Humans ; Leukocytes ; Logistic Models ; Male ; Middle Aged ; Proportional Hazards Models ; Prospective Studies ; Risk Factors ; Singapore ; Smoking ; Stomach Neoplasms/*genetics/microbiology/pathology ; *Telomere ; },
abstract = {BACKGROUND: Extreme telomere length has been previously reported to be associated with increased risk of gastric cancer. However, evidence from prospective studies on a relative large sample size with long-term follow-up to further corroborate previous study findings is meager.<br><br>METHODS: The association between peripheral blood leukocyte telomere length and risk of gastric adenocarcinoma was prospectively examined in a cohort of 26,540 middle-aged or older Chinese nested in the Singapore Chinese Health Study. Telomere length was determined using a validated qPCR-based method. The Cox proportional regression method was used to estimate hazard ratio (HR) and its 95% confidence interval (CI) of gastric adenocarcinoma associated with telomere length after adjustment for potential confounders. Restricted cubic spline analysis was applied to assess the nonlinear relationship between telomere length and gastric cancer risk.<br><br>RESULTS: A U-shaped association was found between telomere length and risk of gastric adenocarcinoma (P nonlinearity&#xa0;=&#xa0;0.020). Compared with the second quintile of telomere length, a statistically significant higher risk of gastric adenocarcinoma was associated with either the lowest quintile (HR&#xa0;=&#xa0;1.63, 95% CI, 1.07-2.47) or the highest quintile (HR&#xa0;=&#xa0;1.55, 95% CI, 0.97-2.47) of telomere length. This U-shaped relationship was more apparent in men and younger individuals.<br><br>CONCLUSIONS: This is the first prospective study demonstrating a higher risk of gastric cancer to be associated with either extremely short or extremely long telomere length. Short and long telomere length may function differently in the early and late stages of gastric carcinogenesis.},
}
@article {pmid29216888,
year = {2017},
author = {Wang, H and Zhang, K and Liu, Y and Fu, Y and Gao, S and Gong, P and Wang, H and Zhou, Z and Zeng, M and Wu, Z and Sun, Y and Chen, T and Li, S and Liu, L},
title = {Telomere heterogeneity linked to metabolism and pluripotency state revealed by simultaneous analysis of telomere length and RNA-seq in the same human embryonic stem cell.},
journal = {BMC biology},
volume = {15},
number = {1},
pages = {114},
pmid = {29216888},
issn = {1741-7007},
support = {2014DFA30450//China Ministry of Science and Technology Program of International S&amp;T Cooperation/ ; IRT13023//PCSIRT/ ; },
mesh = {Human Embryonic Stem Cells/*physiology ; Humans ; RNA/*metabolism ; Sequence Analysis, RNA/*methods ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; },
abstract = {BACKGROUND: Telomere length heterogeneity has been detected in various cell types, including stem cells and cancer cells. Cell heterogeneity in pluripotent stem cells, such as embryonic stem cells (ESCs), is of particular interest; however, the implication and mechanisms underlying the heterogeneity remain to be understood. Single-cell analysis technology has recently been developed and effectively employed to investigate cell heterogeneity. Yet, methods that can simultaneously measure telomere length and analyze the global transcriptome in the same cell have not been available until now.<br><br>RESULTS: We have established a robust method that can simultaneously measure telomere length coupled with RNA-sequencing analysis (scT&amp;R-seq) in the same human ESC (hESC). Using this method, we show that telomere length varies with pluripotency state. Compared to those with long telomere, hESCs with short telomeres exhibit the lowest expressions of TERF1/TRF1, and ZFP42/REX1, PRDM14 and NANOG markers for pluripotency, suggesting that these hESCs are prone to exit from the pluripotent state. Interestingly, hESCs ubiquitously express NOP10 and DKC1, stabilizing components of telomerase complexes. Moreover, new candidate genes, such as MELK, MSH6, and UBQLN1, are highly expressed in the cluster of cells with long telomeres and higher expression of known pluripotency markers. Notably, short telomere hESCs exhibit higher oxidative phosphorylation primed for lineage differentiation, whereas long telomere hESCs show elevated glycolysis, another key feature for pluripotency.<br><br>CONCLUSIONS: Telomere length is a marker of the metabolic activity and pluripotency state of individual hESCs. Single cell analysis of telomeres and RNA-sequencing can be exploited to further understand the molecular mechanisms of telomere heterogeneity.},
}
@article {pmid29215482,
year = {2017},
author = {Zheng, GQ and Zhang, GH and Xu, XW and Wang, JW and Yu, LB and Zhang, YN and Huang, JW and Li, YL and Braudt-Rauf, PW and Xia, ZL},
title = {Association of Telomere Length With Chromosomal Damage Among Chinese Workers Exposed to Vinyl Chloride Monomer.},
journal = {Journal of occupational and environmental medicine},
volume = {59},
number = {12},
pages = {e252-e256},
doi = {10.1097/JOM.0000000000001177},
pmid = {29215482},
issn = {1536-5948},
mesh = {Adult ; Asian People/genetics ; Biomarkers/metabolism ; DNA Damage/*genetics ; Female ; Humans ; Male ; Micronuclei, Chromosome-Defective/*chemically induced ; Micronucleus Tests ; Middle Aged ; Occupational Exposure/*adverse effects ; Real-Time Polymerase Chain Reaction ; Telomere/*genetics ; Telomere Homeostasis/genetics ; Vinyl Chloride/*adverse effects ; Young Adult ; },
abstract = {OBJECTIVE: To explore the relationship between relative telomere length (RTL) and chromosomal damage represented by micronucleus (MN) frequencies among vinyl chloride monomer (VCM) -exposed workers.<br><br>METHODS: A group of 126 VCM-exposed workers, 60 internal controls, and 25 external controls were examined for RTL by Quantitative polymerase chain reaction and MN frequencies by cytokinesis-block micronucleus test. Cumulative exposure dose was used to estimate the exposure of VCM-exposed workers.<br><br>RESULTS: The RTL were significantly shorter in exposed workers and internal controls than in external controls. The exposed workers had significantly increased MN frequencies than both control groups. Additionally, MN frequencies were negatively associated with RTL in VCM-exposed group.<br><br>CONCLUSIONS: VCM exposure may alter telomere length, which could be a potential biomarker of susceptibility to chromosomal damage.},
}
@article {pmid29213278,
year = {2017},
author = {Hastings, WJ and Shalev, I and Belsky, DW},
title = {Translating Measures of Biological Aging to Test Effectiveness of Geroprotective Interventions: What Can We Learn from Research on Telomeres?.},
journal = {Frontiers in genetics},
volume = {8},
number = {},
pages = {164},
pmid = {29213278},
issn = {1664-8021},
support = {P30 AG028716/AG/NIA NIH HHS/United States ; P30 AG034424/AG/NIA NIH HHS/United States ; R21 AG054846/AG/NIA NIH HHS/United States ; },
abstract = {Intervention studies in animals suggest molecular changes underlying age-related disease and disability can be slowed or reversed. To speed translation of these so-called "geroprotective" therapies to prevent age-related disease and disability in humans, biomarkers are needed that can track changes in the rate of human aging over the course of intervention trials. Algorithm methods that measure biological processes of aging from combinations of DNA methylation marks or clinical biomarkers show promise. To identify next steps for establishing utility of these algorithm-based measures of biological aging for geroprotector trials, we considered the history a candidate biomarker of aging that has received substantial research attention, telomere length. Although telomere length possesses compelling biology to recommend it as a biomarker of aging, mixed research findings have impeded clinical and epidemiologic translation. Strengths of telomeres that should be established for algorithm biomarkers of aging are correlation with chronological age across the lifespan, prediction of disease, disability, and early death, and responsiveness to risk and protective exposures. Key challenges in telomere research that algorithm biomarkers of aging must address are measurement precision and reliability, establishing links between longitudinal rates of change across repeated measurements and aging outcomes, and clarity over whether the biomarker is a causal mechanism of aging. These strengths and challenges suggest a research agenda to advance translation of algorithm-based aging biomarkers: establish validity in young-adult and midlife individuals; test responsiveness to exposures that shorten or extend healthy lifespan; and conduct repeated-measures longitudinal studies to test differential rates of change.},
}
@article {pmid29212750,
year = {2017},
author = {Reichert, S and Stier, A},
title = {Does oxidative stress shorten telomeres in vivo? A review.},
journal = {Biology letters},
volume = {13},
number = {12},
pages = {},
pmid = {29212750},
issn = {1744-957X},
mesh = {Animals ; Antioxidants/metabolism ; Biomarkers/metabolism ; Birds/genetics/*physiology ; Humans ; Mammals/genetics/*physiology ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; *Telomere Shortening ; },
abstract = {The length of telomeres, the protective caps of chromosomes, is increasingly used as a biomarker of individual health state because it has been shown to predict chances of survival in a range of endothermic species including humans. Oxidative stress is presumed to be a major cause of telomere shortening, but most evidence to date comes from in vitro cultured cells. The importance of oxidative stress as a determinant of telomere shortening in vivo remains less clear and has recently been questioned. We, therefore, reviewed correlative and experimental studies investigating the links between oxidative stress and telomere shortening in vivo While correlative studies provide equivocal support for a connection between oxidative stress and telomere attrition (10 of 18 studies), most experimental studies published so far (seven of eight studies) partially or fully support this hypothesis. Yet, this link seems to be tissue-dependent in some cases, or restricted to particular categories of individual (e.g. sex-dependent) in other cases. More experimental studies, especially those decreasing antioxidant protection or increasing pro-oxidant generation, are required to further our understanding of the importance of oxidative stress in determining telomere length in vivo Studies comparing growing versus adult individuals, or proliferative versus non-proliferative tissues would provide particularly important insights.},
}
@article {pmid29210325,
year = {2018},
author = {Karimi, B and Nabizadeh, R and Yunesian, M and Mehdipour, P and Rastkari, N and Aghaie, A},
title = {Foods, Dietary Patterns and Occupational Class and Leukocyte Telomere Length in the Male Population.},
journal = {American journal of men's health},
volume = {12},
number = {2},
pages = {479-492},
pmid = {29210325},
issn = {1557-9891},
mesh = {Adult ; Body Mass Index ; Cross-Sectional Studies ; *Diet ; Employment/*classification ; Humans ; Iran ; Leukocytes/*physiology ; Linear Models ; Male ; Nutrition Surveys ; Telomere/*genetics ; },
abstract = {Telomeres contain TTAGGG repetitive sequences and are located at the end of human chromosomes. Telomere dysfunction is associated with some age-related and chronic diseases, but its relationship with foods, dietary patterns, and occupational class in the young male population is not yet known. In this cross-sectional study, 300 healthy men, residents of Tehran, aged 25-40 years were enrolled from January to December 2016. We employed a cross-sectional study of 300 healthy people, residents of Tehran, aged 25-40 years. A food frequency questionnaire was used to obtain food intakes of all participants and converted into actual food intake (g/day). The principal components analysis was used to determine dietary patterns and other demographic characteristics. Leukocyte telomere length (TL) was measured by quantitative real-time polymerase chain reaction (PCR) to measure number of telomere repeat copy number (T) to the relative number of 36B4 copies (S) (T/S ratio). T/S in office-workers, waste recyclers, and other workers were 1.22 ± 0.4, 1.08 ± 0.3, and 1.094 ± 0.34, respectively. The results of multivariate linear regression adjusted for age, body mass index (BMI), and smoking were showed that whole grains (β = 0.02; p = .05), refined grains, fruits and vegetables, fish and dairy products were associated with an increase in log-T/S, but consumption of nuts and seeds (β = -0.00072; p = .06), meats (β = -0.00043; p = .9), produced meats (β = -0.00238; p = .03), oils and solid fats (β = -0.00146; p = .03) had a negative relationship with log-T/S in all studied occupational classes. A positive relationship was reported between the healthy (β = 0.017; p = .2) and traditional dietary pattern (β = 0.012; p = .4) with log-T/S, but western pattern identified negative relationship (β = -0.004; p = .7). Adherence to a healthy (with consumption whole grains, refined grains, dairy, and cereals) and then traditional pattern with increased consumption of fruits, vegetables and whole grains, fish and dairy products are necessary to prevent TL destruction in all studied occupational classes.},
}
@article {pmid30669856,
year = {2017},
author = {Thanseem, I and Viswambharan, V and Poovathinal, SA and Anitha, A},
title = {Is telomere length a biomarker of neurological disorders?.},
journal = {Biomarkers in medicine},
volume = {11},
number = {9},
pages = {799-810},
doi = {10.2217/bmm-2017-0032},
pmid = {30669856},
issn = {1752-0371},
mesh = {Alzheimer Disease/diagnosis/genetics ; Autistic Disorder/diagnosis/genetics ; Biomarkers/*metabolism ; Brain/metabolism ; Humans ; Nervous System Diseases/*diagnosis/genetics ; Parkinson Disease/diagnosis/genetics ; Schizophrenia/diagnosis/genetics ; Telomere/*metabolism ; Telomere Shortening ; },
abstract = {Telomeres are DNA-protein complexes that form protective caps at the termini of chromosomes, maintaining genomic stability. In this review, we provide a comprehensive overview on the usefulness of telomere length (TL) as biomarkers of neurological disorders. The implications of TL in relation to cognitive ability, cognitive aging and cognitive decline in neurodegenerative disorders are also briefly discussed. Our review suggests that at present it is difficult to draw a reliable conclusion regarding the contribution of TL to neurological disorders. Further, it needs to be examined whether leukocyte TL, which is generally considered as a surrogate marker of TL in other tissues, serves as an indicator of central nervous system TL.},
}
@article {pmid30460075,
year = {2017},
author = {Kim, YD and Jang, SJ and Lim, EJ and Ha, JS and Shivakumar, SB and Jeong, GJ and Rho, GJ and Jeon, BG},
title = {Induction of telomere shortening and cellular apoptosis by sodium meta-arsenite in human cancer cell lines.},
journal = {Animal cells and systems},
volume = {21},
number = {4},
pages = {241-254},
pmid = {30460075},
issn = {1976-8354},
abstract = {The present study assessed the cytotoxicity of sodium meta-arsenite (SMA) on telomere shortening and cellular apoptosis in human A-549, MDA-MB-231 and U87-MG cancer cell lines. Following 2 weeks of 1 μM SMA treatment, population doubling time (PDT) was significantly (P < .05) increased by the inhibition of cell proliferation in all the cancer cell lines compared to that in untreated controls. Level of telomerase activity by relative-quantitative telomerase repeat amplification protocol was significantly (P < .05) downregulated by SMA treatment with significant (P < .05) decrease of both telomerase reverse transcriptase and telomerase RNA component transcripts, responsible for telomerase activity. A significant (P < .05) shortening of telomeric repeats by telomere restriction fragment analysis was consequently observed in SMA-treated cells. Moreover, high incidence of cells with senescence-associated β-glucosidase activity was observed in SMA-treated cells and some cells were also differentiated into adipocytes probably due to the loss of tumorous characterizations. Cellular apoptosis proven by DNA fragmentation was observed, and intrinsic apoptotic transcripts (BAX, caspase 3 and caspase 9) and stress-related transcripts (p21, HSP70 and HSP90) were significantly (P < .05) increased in three cancer cell lines treated with SMA. Based on the present study, SMA treatment apparently induced a shortening of telomere length and cytotoxicity, such as induction of cell senescence, apoptosis and cell differentiation. Therefore, we conclude that SMA treatment at specific concentration can lead to gradual loss of tumorous characterizations and can be considered as a potential anti-cancer drug for chemotherapy treatment.},
}
@article {pmid30734006,
year = {2017},
author = {Shoeb, M and Kodali, VK and Farris, BY and Bishop, LM and Meighan, TG and Salmen, R and Eye, T and Friend, S and Schwegler-Berry, D and Roberts, JR and Zeidler-Erdely, PC and Erdely, A and Antonini, JM},
title = {Oxidative Stress, DNA Methylation, and Telomere Length Changes in Peripheral Blood Mononuclear Cells after Pulmonary Exposure to Metal-Rich Welding Nanoparticles.},
journal = {NanoImpact},
volume = {5},
number = {},
pages = {61-69},
pmid = {30734006},
issn = {2452-0748},
support = {CC999999//Intramural CDC HHS/United States ; },
abstract = {Welding fume is a complex mixture of different potentially cytotoxic and genotoxic metals, such as chromium (Cr), manganese (Mn), nickel (Ni), and iron (Fe). Documented health effects have been observed in workers exposed to welding fume. The objective of the study was to use an animal model to identify potential biomarkers of epigenetic changes (e.g., changes in telomere length, DNA methylation) in isolated peripheral blood mononuclear cells (PBMCs) after exposure to different welding fumes. Male Sprague-Dawley rats were exposed by intratracheal instillation (ITI) of 2.0 mg/rat of gas metal arc-mild steel (GMA-MS) or manual metal arc-stainless steel (MMA-SS) welding fume. Vehicle controls received sterile saline by ITI. At 4 h, 14 h, 1 d, 3 d, 10 d, and 30 d, bronchoalveolar lavage (BAL) was performed to assess lung inflammation. Whole blood was collected, and PBMCs were isolated. Dihydroethidium (DHE) fluorescence and 4-hydroxylnonenal protein adduct (P-HNE) formation were measured in PBMCs to assess reactive oxygen species (ROS) production. DNA alterations in PBMCs were determined by evaluating changes in DNA methylation and telomere length. Metal composition of the two fumes was different: MMA-SS (41 % Fe, 29 % Cr, 17 % Mn, 3 % Ni) versus GMA-MS (85 % Fe, 14 % Mn). The more soluble and chemically complex MMA-SS sample induced a more persistent and greater inflammatory response compared to the other groups. Also, oxidative stress markers increased at 24 h in the PBMCs recovered from the MMA-SS group compared to other group. No significant differences were observed when comparing DNA methylation between the welding fume and control groups at any of the time points, whereas the MMA-SS sample significantly increased telomere length at 1 and 30 d after a single exposure compared to the other groups. These findings suggest that genotoxic metals in MMA-SS fume (e.g., Cr and Ni), that are absent in the GMA-MS fume, may enhance lung toxicity, as well as induce markers of oxidative stress and increase telomere length in PBMCs. Importantly, the measurement of telomere length in cells isolated from peripheral blood may serve as a potential biomarker of response in the assessment of toxicity associated with welding fumes.},
}
@article {pmid30187728,
year = {2017},
author = {Sulastri, D and Lestari, Y and Afriwardi, and Desmawati, },
title = {Relationship Between Body Composition and Smoking Habit with Telomere Length of Minangkabau Ethnicity Men, in West Sumatera, Indonesia.},
journal = {Pakistan journal of biological sciences : PJBS},
volume = {20},
number = {10},
pages = {516-522},
doi = {10.3923/pjbs.2017.516.522},
pmid = {30187728},
issn = {1028-8880},
abstract = {BACKGROUND AND OBJECTIVE: An increase in body composition and smoking habit are risk factors for high free radical levels in the body. This can lead to oxidative stress, due to the imbalance of pro-oxidants and oxidants in the body that leads to telomere shortening. The purpose of this research was to investigate the correlation between body composition and smoking habit with telomere length of men in West Sumatera, Indonesia.<br><br>MATERIALS AND METHODS: This cross-sectional study was conducted in Padang City using a sample of 130 Minangkabau ethnic district civil servant men aged between 40-50 years. The smoking habit were collected using a questionnaire, body composition data with bioelectrical impedance analysis (BIA) and blood sample analysis using O'Callaghan and Fenech's technique to measure telomere length.<br><br>RESULTS: This research indicated an average telomere length was 580.37&#xb1;323.58 bp, BMI was 25.01&#xb1;4.15 and percentage body fat was 22.06&#xb1;6.16%. The proportion of subjects who smoke is 58.5% with heavy smoker 26.3%. The average length of smoked cigarettes was 25.2&#xb1;7.3 years and the average of cigarette consumption is 270.58&#xb1;343.18. There were no correlations between BMI and body fat percentage with telomere length (p>0.005). There is a negative correlation were significantly between smoking duration with telomere length (r = -0.270, p = 0.020). Telomere loss was 94.39 bp throughout the life-span equivalent to losing 3.4-3.8 years.<br><br>CONCLUSION: Body composition is not a risk factor but smoking duration is a risk factor for telomere shortening in ethnic Minangkabau men.},
}
@article {pmid29624350,
year = {2016},
author = {Hayashi, MT},
title = {[Mechanism of mitotic cell death during telomere crisis].},
journal = {Seikagaku. The Journal of Japanese Biochemical Society},
volume = {88},
number = {6},
pages = {756-760},
pmid = {29624350},
issn = {0037-1017},
mesh = {Cell Death ; Cellular Senescence ; Chromosomes ; Humans ; *M Phase Cell Cycle Checkpoints ; Telomere/*metabolism ; },
}
@article {pmid30557481,
year = {2016},
author = {Hayashi, MT},
title = {[Regulation of senescence by telomeres and telomerase].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {74},
number = {9},
pages = {1485-1490},
pmid = {30557481},
issn = {0047-1852},
mesh = {Animals ; *Cellular Senescence/genetics ; Humans ; Mice ; *Telomerase ; *Telomere/metabolism ; },
abstract = {Telomeres are vital for chromosome end protection against activation of DNA damage response. Telomere attrition leads to cell cycle arrest, which underlies cellular senescence and can restrict tissue replenishment. Although stem cells express telomerase reverse tran- scriptase, which elongates telomeric DNA, its activity is not enough to fully compensate for chronic telomere shortening. Growing lines of evidence, including telomerase knockout mouse models and human genetic diseases, suggest that a decline in the cellular renewal capacity of stem cells is a consequence of such telomere shortening. These findings highlight the critical importance of telomere protection control for human aging process, and may lead to new strategies for healthy life extension.},
}
@article {pmid30289640,
year = {2016},
author = {Cohen, HV},
title = {We All Get Older (Hopefully!) Is It Our Age, Our Genes, or Something Else? Do Telomeres "Tell It All"?.},
journal = {Journal of the New Jersey Dental Association},
volume = {87},
number = {3},
pages = {18-19},
pmid = {30289640},
issn = {0093-7347},
mesh = {Cellular Senescence/*physiology ; *Genomics ; Humans ; Telomere/*physiology ; Telomere Shortening/*physiology ; },
abstract = {As healthcare professionals, we deal daily with "aging"'factors relating to our patients' dental treatment planning (and to ourselves). We are all are expressions of our DNA-the long molecules in our cells' nuclei that contain our genes which determine how proteins will be made to express who we are. Although genetics can be a confusing subject to understand, when trying to understand DNA, perhaps consider that you Do Not Abandon learning some of the basics of genetics. In today's evolving world of medical science, there is a major focus on genetics and genomics; analyzing one's genetic makeup to help in diagnosing and managing disease, and prescribing of medications (pharmacogenetics/pharmacogenomics). One aspect of interest is what we call "aging" or getting older, an expression of cellular "senescence"-most of our cells are programmed to commit suicide (apoptosis) over time. So we get wrinkles, our stomach sags and our hair goes gray. As described below, a normal physiologic process takes place at the end of your chromosomes to protect them. Over many years, this process can no longer protect your chromosomes and the cells die. However, if normal processes are not functioning correctly, the chromosomes continue to reproduce-if this is a cancer cell, the lack of cell suicide allows tumors to grow.},
}
@article {pmid29861418,
year = {2015},
author = {Kwapisz, M and Ruault, M and van Dijk, E and Gourvennec, S and Descrimes, M and Taddei, A and Morillon, A},
title = {Expression of Subtelomeric lncRNAs Links Telomeres Dynamics to RNA Decay in S. cerevisiae.},
journal = {Non-coding RNA},
volume = {1},
number = {2},
pages = {94-126},
pmid = {29861418},
issn = {2311-553X},
abstract = {Long non-coding RNAs (lncRNAs) have been shown to regulate gene expression, chromatin domains and chromosome stability in eukaryotic cells. Recent observations have reported the existence of telomeric repeats containing long ncRNAs [-] TERRA in mammalian and yeast cells. However, their functions remain poorly characterized. Here, we report the existence in S. cerevisiae of several lncRNAs within Y' subtelomeric regions. We have called them subTERRA. These belong to Cryptic Unstable Transcripts (CUTs) and Xrn1p-sensitive Unstable Transcripts (XUTs) family. subTERRA transcription, carried out mainly by RNAPII, is initiated within the subtelomeric Y' element and occurs in both directions, towards telomeres as well as centromeres. We show that subTERRA are distinct from TERRA and are mainly degraded by the general cytoplasmic and nuclear 5'- and 3'- RNA decay pathways in a transcription-dependent manner. subTERRA accumulates preferentially during the G1/S transition and in C-terminal rap1 mutant but independently of Rap1p function in silencing. The accumulation of subTERRA in RNA decay mutants coincides with telomere misregulation: shortening of telomeres, loss of telomeric clustering in mitotic cells and changes in silencing of subtelomeric regions. Our data suggest that subtelomeric RNAs expression links telomere maintenance to RNA degradation pathways.},
}
@article {pmid29308145,
year = {2015},
author = {Kawamoto, Y and Sasaki, A and Hashiya, K and Ide, S and Bando, T and Maeshima, K and Sugiyama, H},
title = {Tandem trimer pyrrole-imidazole polyamide probes targeting 18 base pairs in human telomere sequences.},
journal = {Chemical science},
volume = {6},
number = {4},
pages = {2307-2312},
pmid = {29308145},
issn = {2041-6520},
abstract = {The binding of molecules to specific DNA sequences is important for imaging genome DNA and for studying gene expression. Increasing the number of base pairs targeted by these molecules would provide greater specificity. N-Methylpyrrole-N-methylimidazole (Py-Im) polyamides are one type of such molecules and can bind to the minor groove of DNA in a sequence-specific manner without causing denaturation of DNA. Our recent work has demonstrated that tandem hairpin Py-Im polyamides conjugated with a fluorescent dye can be synthesized easily and can serve as new probes for studying human telomeres under mild conditions. Herein, to improve their selectivities to telomeres by targeting longer sequences, we designed and synthesized a fluorescent tandem trimer Py-Im polyamide probe, comprising three hairpins and two connecting regions (hinges). The new motif bound to 18 bp dsDNA in human telomeric repeats (TTAGGG) n , the longest sequence for specific binding reported for Py-Im polyamides. We compared the binding affinities and the abilities to discriminate mismatch, the UV-visible absorption and fluorescence spectra, and telomere staining in human cells between the tandem trimer and a previously developed tandem hairpin. We found that the tandem trimer Py-Im polyamide probe has higher ability to recognize telomeric repeats and stains telomeres in chemically fixed cells with lower background signal.},
}
@article {pmid29788566,
year = {2010},
author = {Iniesta, P},
title = {Telomere length maintenance: a factor to be considered in personalized medicine?.},
journal = {Personalized medicine},
volume = {7},
number = {6},
pages = {609-610},
doi = {10.2217/pme.10.57},
pmid = {29788566},
issn = {1744-828X},
}
@article {pmid30147542,
year = {2001},
author = {Manning, EL and Van Zant, G},
title = {Role of Telomerase in Maintaining Hematopoietic Stem Cell Telomere Length during Replicative Stress and Aging.},
journal = {TheScientificWorldJournal},
volume = {1},
number = {},
pages = {69},
doi = {10.1100/tsw.2001.252},
pmid = {30147542},
issn = {1537-744X},
}
@article {pmid30147545,
year = {2001},
author = {Naka, KH and Matsu-Ura, A and Tachibana, A and Ishikawa, F and Ikeda, K and Motoyama, N},
title = {Introduction of Telomerase to Ataxia Teleangiectasia Cells Can Extend Shortend Telomere and Bypass Replicative Senescence.},
journal = {TheScientificWorldJournal},
volume = {1},
number = {},
pages = {70},
doi = {10.1100/tsw.2001.108},
pmid = {30147545},
issn = {1537-744X},
}
@article {pmid29209839,
year = {2018},
author = {Aoki, Y and Aida, J and Kawano, Y and Nakamura, KI and Izumiyama-Shimomura, N and Ishikawa, N and Arai, T and Nakamura, Y and Taniai, N and Uchida, E and Takubo, K and Ishiwata, T},
title = {Correction to: Telomere length of gallbladder epithelium is shortened in patients with congenital biliary dilatation: measurement by quantitative fluorescence in situ hybridization.},
journal = {Journal of gastroenterology},
volume = {53},
number = {2},
pages = {302-303},
doi = {10.1007/s00535-017-1418-y},
pmid = {29209839},
issn = {1435-5922},
abstract = {In the original publication of this article, Fig. 5 was published with incorrect color of the approximate lines of CBD and Control.},
}
@article {pmid29209649,
year = {2017},
author = {Pan, X and Ahmed, N and Kong, J and Zhang, D},
title = {Breaking the end: Target the replication stress response at the ALT telomeres for cancer therapy.},
journal = {Molecular &amp; cellular oncology},
volume = {4},
number = {6},
pages = {e1360978},
pmid = {29209649},
issn = {2372-3556},
abstract = {We recently reported that depletion of FANCM in ALT cells induces replication stress mainly at their telomeres. Additionally, we found that co-depletion of FANCM and BLM, or FANCM and BRCA1 induces synthetic lethality in the ALT cells. Our new findings could have important implications for cancer prevention and treatment.},
}
@article {pmid29209027,
year = {2017},
author = {Dupoué, A and Rutschmann, A and Le Galliard, JF and Clobert, J and Angelier, F and Marciau, C and Ruault, S and Miles, D and Meylan, S},
title = {Shorter telomeres precede population extinction in wild lizards.},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {16976},
pmid = {29209027},
issn = {2045-2322},
mesh = {Altitude ; Animals ; Body Size ; *Extinction, Biological ; Female ; France ; Lizards/genetics/*physiology ; Male ; Seasons ; Telomere/*genetics ; },
abstract = {Identifying the early warning signals of catastrophic extinctions has recently become a central focus for ecologists, but species' functional responses to environmental changes remain an untapped source for the sharpening of such warning signals. Telomere length (TL) analysis represents a promising molecular tool with which to raise the alarm regarding early population decline, since telomere attrition is associated with aging processes and accelerates after a recurrent exposure to environmental stressors. In the southern margin of their range, populations of the common lizard (Zootoca vivipara) recently became extinct at lowest elevations due to changes in climate conditions. However, the proximal signals involved in these demographic declines are still unknown. Here, we sampled 100 yearling lizards from 10 natural populations (n = 10 per population) along an extinction risk gradient. Relative lizard abundance dramatically dropped over 12 years in low-altitude populations characterized by warmer ambient temperatures and higher body growth of lizards early in life. A non-linear relationship was found between TL and population extinction risk, with shorter telomeres in populations facing high risk of extinction when compared to non-threatened ones. Our results identify TL as a promising biomarker and imply that population extinctions might be preceded by a loop of physiological aging.},
}
@article {pmid29203363,
year = {2018},
author = {Chhabra, G and Wojdyla, L and Frakes, M and Schrank, Z and Leviskas, B and Ivancich, M and Vinay, P and Ganapathy, R and Ramirez, BE and Puri, N},
title = {Mechanism of Action of G-Quadruplex-Forming Oligonucleotide Homologous to the Telomere Overhang in Melanoma.},
journal = {The Journal of investigative dermatology},
volume = {138},
number = {4},
pages = {903-910},
doi = {10.1016/j.jid.2017.11.021},
pmid = {29203363},
issn = {1523-1747},
mesh = {*Apoptosis ; Cell Line, Tumor ; DNA Damage ; DNA, Neoplasm/*genetics ; *G-Quadruplexes ; *Gene Expression Regulation, Neoplastic ; Humans ; Melanoma/*genetics/metabolism/pathology ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/biosynthesis/*genetics ; },
abstract = {T-oligo, a guanine-rich oligonucleotide homologous to the 3'-telomeric overhang of telomeres, elicits potent DNA-damage responses in melanoma cells; however, its mechanism of action is largely unknown. Guanine-rich oligonucleotides can form G-quadruplexes (G4), which are stabilized by the hydrogen bonding of guanine residues. In this study, we confirmed the G4-forming capabilities of T-oligo using nondenaturing PAGE, nuclear magnetic resonance, and immunofluorescence. Using an anti-G-quadruplex antibody, we showed that T-oligo can form G4 in the nuclei of melanoma cells. Furthermore, using DNase I in a nuclease degradation assay, G4-T-oligo was found to be more stable than single-stranded T-oligo. G4-T-oligo had decreased antiproliferative effects compared with single-stranded T-oligo. However, G4-T-oligo has similar cellular uptake as single-stranded T-oligo, as shown by FACS analysis. Inhibition of JNK, which causes DNA damage-induced apoptosis, partially reversed the antiproliferative activity of T-oligo. T-oligo also inhibited mRNA expression of human telomerase reverse transcriptase, a catalytic subunit of telomerase that was reversed by JNK inhibition. Furthermore, two shelterin complex proteins TRF2/POT1 were found to be up-regulated and bound by T-oligo, suggesting that T-oligo may mediate dissociation of these proteins from the telomere overhang. These studies show that T-oligo can form a G-quadruplex and that the antitumor effects of T-oligo may be mediated through POT1/TRF2 and via human telomerase reverse transcriptase inhibition through JNK activation.},
}
@article {pmid29197718,
year = {2018},
author = {Hsu, M and Lue, NF},
title = {The mechanisms of K. lactis Cdc13 in telomere DNA-binding and telomerase regulation.},
journal = {DNA repair},
volume = {61},
number = {},
pages = {37-45},
pmid = {29197718},
issn = {1568-7856},
support = {R01 GM107287/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Binding Sites ; Fungal Proteins/chemistry/*genetics/*metabolism ; Mutation ; Protein Binding ; Saccharomycetales/genetics/metabolism ; Telomerase/*genetics/*metabolism ; Telomere/metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/chemistry/*genetics/*metabolism ; },
abstract = {Eukaryotic chromosome ends, or telomeres, are essential for genome stability and are protected by an intricate nucleoprotein assembly. Cdc13, the major single-strand telomere-binding protein in budding yeasts, mediates critical functions in both telomere protection and telomere elongation by telomerase. In particular, the interaction between S. cerevisiae Cdc13 and telomerase subunit Est1 has long served as a paradigm for telomerase regulation. However, despite extensive investigations, the role of this interaction in regulating telomerase recruitment or activation remains controversial. In addition, budding yeast telomere repeat sequences are extraordinarily variable and how Cdc13 orthologs recognize diverse repeats is not well understood. In this report, we examined these issues using an alternative model, K. lactis. We reconstituted a direct physical interaction between purified K. lactis Cdc13 and Est1, and by analyzing point mutations, we demonstrated a close correspondence between telomere maintenance defects in vivo and Cdc13-Est1 binding defects in vitro, thus supporting a purely recruitment function for this interaction in K. lactis. Because mutations in well aligned residues of Cdc13 and Est1 in S. cerevisiae and K. lactis do not cause identical defects, our results also point to significant evolutionary divergence in the Cdc13-Est1 interface. In addition, we found that K. lactic Cdc13, unlike previously characterized orthologs, recognizes an unusually long and non-G-rich target sequence, underscoring the flexibility of the Cdc13 DNA-binding domain. Analysis of K. lactis Cdc13 and Est1 thus broadens understanding of telomere and telomerase regulation in budding yeast.},
}
@article {pmid29197683,
year = {2018},
author = {Kim, W and Shay, JW},
title = {Long-range telomere regulation of gene expression: Telomere looping and telomere position effect over long distances (TPE-OLD).},
journal = {Differentiation; research in biological diversity},
volume = {99},
number = {},
pages = {1-9},
pmid = {29197683},
issn = {1432-0436},
support = {R01 AG001228/AG/NIA NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; C06 RR030414/RR/NCRR NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; },
mesh = {DNA Damage/*physiology ; DNA Methylation/genetics ; Down-Regulation/physiology ; Gene Expression/physiology ; Humans ; Neoplasms/*metabolism ; Telomerase/*genetics ; Telomere/*metabolism ; },
abstract = {The human cellular reverse transcriptase, telomerase, is very tightly regulated in large long-lived species. Telomerase is expressed during early human fetal development, is turned off in most adult tissues, and then becomes reactivated in almost all human cancers. However, the exact mechanism regulating these switches in expression are not known. We recently described a phenomenon where genes are regulated by telomere length dependent loops (telomere position effects over long distances; TPE-OLD). The hTERT gene is ~ 1.2Mb from the human chromosome 5p end. We observed that when telomeres are long hTERT gene expression is repressed and a probe next to the 5p telomere and the hTERT locus are spatially co-localized. When telomeres are short at least one of the hTERT alleles is spatially separated from the telomere, developing more active histone marks and changes in DNA methylation in the hTERT promoter region. These findings have implications for how cells turn off telomerase when telomeres are long during fetal development and how cancer cells reactivate telomerase in cells that have short telomeres. In addition to TPE-OLD, in proliferating stem cells such as activated T-lymphocytes, telomerase can be reversibly activated and silenced by telomere looping. In telomerase positive cancer cells that are induced to differentiate and downregulate telomerase, telomere looping correlates with silencing of the hTERT gene. These studies and others support a role of telomeres in regulating gene expression via telomere looping that may involve interactions with internal telomeric sequences (ITS). In addition to telomere looping, TPE-OLD may be one mechanism of how cells time changes in physiology without initiating a DNA damage response.},
}
@article {pmid29192673,
year = {2018},
author = {Giraud-Panis, MJ and Ye, J and Gilson, E},
title = {TRFH domain: at the root of telomere protein evolution?.},
journal = {Cell research},
volume = {28},
number = {1},
pages = {7-8},
pmid = {29192673},
issn = {1748-7838},
mesh = {Animals ; Carrier Proteins ; DNA-Binding Proteins ; *Schizosaccharomyces ; Schizosaccharomyces pombe Proteins/*genetics ; Shelterin Complex ; Telomere ; Telomere-Binding Proteins/genetics ; Telomeric Repeat Binding Protein 2 ; },
abstract = {Two articles in Cell Research focus on the structure-function relationships in the shelterin complex that binds to telomeres and is essential for their stability and functions. These studies concerning both mammalian and Schizosaccharomyces pombe proteins reveal unexpected structural conservation of a motif called TRFH (Telomeric Repeat Factors Homology) domain between several subunits in these complexes, providing a rationale for further dissection of the role of telomeres in chromosome stability, aging and cancer, and encouraging us to revisit the evolution of telomere proteins.},
}
@article {pmid29191839,
year = {2018},
author = {Alimam, S and McLornan, DP and Jiang, J and Radia, D and Mufti, GJ and Harrison, CN},
title = {Shortened telomeres in essential thrombocythemia: clinicopathological and treatment correlations.},
journal = {Haematologica},
volume = {103},
number = {6},
pages = {e234-e236},
pmid = {29191839},
issn = {1592-8721},
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers ; Blood Cell Count ; Combined Modality Therapy ; Female ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Mutation ; Platelet Count ; *Telomere Shortening ; Thrombocythemia, Essential/diagnosis/*genetics/therapy ; Young Adult ; },
}
@article {pmid29190382,
year = {2018},
author = {Marioni, RE and Harris, SE and Shah, S and McRae, AF and von Zglinicki, T and Martin-Ruiz, C and Wray, NR and Visscher, PM and Deary, IJ},
title = {The epigenetic clock and telomere length are independently associated with chronological age and mortality.},
journal = {International journal of epidemiology},
volume = {47},
number = {1},
pages = {356},
doi = {10.1093/ije/dyx233},
pmid = {29190382},
issn = {1464-3685},
support = {G0601333/MRC_/Medical Research Council/United Kingdom ; MR/L016354/1/MRC_/Medical Research Council/United Kingdom ; G0500997/MRC_/Medical Research Council/United Kingdom ; MR/J50001X/1/MRC_/Medical Research Council/United Kingdom ; BB/F019394/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MR/K026992/1/MRC_/Medical Research Council/United Kingdom ; },
}
@article {pmid29189717,
year = {2017},
author = {Kjeldsen, E},
title = {Telomere Shortening in Hematological Malignancies with Tetraploidization-A Mechanism for Chromosomal Instability?.},
journal = {Cancers},
volume = {9},
number = {12},
pages = {},
pmid = {29189717},
issn = {2072-6694},
abstract = {Aneuploidy, the presence of an abnormal number of chromosomes in a cell, is one of the most obvious differences between normal and cancer cells. There is, however, debate on how aneuploid cells arise and whether or not they are a cause or a consequence of tumorigenesis. Further, it is important to distinguish aneuploidy (the "state" of the karyotype) from chromosomal instability (CIN; the "rate" of karyotypic change). Although CIN leads to aneuploidy, not all aneuploid cells exhibit CIN. One proposed route to aneuploid cells is through an unstable tetraploid intermediate because tetraploidy promotes chromosomal aberrations and tumorigenesis. Tetraploidy or near-tetraploidy (T/NT) (81-103 chromosomes) karyotypes with or without additional structural abnormalities have been reported in acute leukemia, T-cell and B-cell lymphomas, and solid tumors. In solid tumors it has been shown that tetraploidization can occur in response to loss of telomere protection in the early stages of tumorigenesis in colon cancer, Barrett's esophagus, and breast and cervical cancers. In hematological malignancies T/NT karyotypes are rare and the role of telomere dysfunction for the induction of tetraploidization is less well characterized. To further our understanding of possible telomere dysfunction as a mechanism for tetrapolydization in hematological cancers we here characterized the chromosomal complement and measured the telomere content by interphase nuclei quantitative fluorescence in situ hybridization (iQFISH) in seven hematological cancer patients with T/NT karyotypes, and after cytogenetic remission. The patients were identified after a search in our local cytogenetic registry in the 5-year period between June 2012 and May 2017 among more than 12,000 analyzed adult patients in this period. One advantage of measuring telomere content by iQFISH is that it is a single-cell analysis so that the telomere content can be distinguished between normal karyotype cells and cells with T/NT karyotypes. We find that the telomeres are particularly short in cells with T/NT karyotypes as compared with normal cells, and in T/NT karyotypes harboring additional chromosomal aberrations as well. These findings suggest that telomere dysfunction in hematological malignancies may be a mechanism for tetraploidization and CIN.},
}
@article {pmid29186077,
year = {2017},
author = {Chilton, W and O'Brien, B and Charchar, F},
title = {Telomeres, Aging and Exercise: Guilty by Association?.},
journal = {International journal of molecular sciences},
volume = {18},
number = {12},
pages = {},
pmid = {29186077},
issn = {1422-0067},
mesh = {Aging/genetics/*physiology ; Exercise/*physiology ; Humans ; Telomere/*genetics ; },
abstract = {Telomeres are repetitive tandem DNA sequences that cap chromosomal ends protecting genomic DNA from enzymatic degradation. Telomeres progressively shorten with cellular replication and are therefore assumed to correlate with biological and chronological age. An expanding body of evidence suggests (i) a predictable inverse association between telomere length, aging and age-related diseases and (ii) a positive association between physical activity and telomere length. Both hypotheses have garnered tremendous research attention and broad consensus; however, the evidence for each proposition is inconsistent and equivocal at best. Telomere length does not meet the basic criteria for an aging biomarker and at least 50% of key studies fail to find associations with physical activity. In this review, we address the evidence in support and refutation of the putative associations between telomere length, aging and physical activity. We finish with a brief review of plausible mechanisms and potential future research directions.},
}
@article {pmid29181128,
year = {2017},
author = {Park, WJ and Bae, SU and Heo, YR and Jung, SJ and Lee, JH},
title = {Telomere shortening in non-tumorous and tumor mucosa is independently related to colorectal carcinogenesis in precancerous lesions.},
journal = {International journal of molecular epidemiology and genetics},
volume = {8},
number = {5},
pages = {53-58},
pmid = {29181128},
issn = {1948-1756},
abstract = {Telomere shortening is associated with colorectal carcinogenesis and recent studies have focused on its characteristics in both normal mucosa and tumor tissues. To clarify the role of telomeres in colorectal carcinogenesis, we analyzed telomere shortening in normal and tumor regions of 93 colorectal precursor lesions. Telomere length was examined in 61 tubular adenomas (TAs) and 32 serrated polyps (SPs), and PIK3CA expression, KRAS mutation, BRAF mutation, and MSI were also analyzed. Telomere length was similar in normal and tumor tissues of TAs and SPs. In normal tissues of TAs, telomere shortening was associated with PIK3CA amplification (81.3% vs. 18.8%, p < 0.001), whereas it was associated with BRAF mutation in normal tissues of SPs (66.7% vs. 23.1%, p = 0.060). According to the analysis on tumor tissues, KRAS and BRAF mutations were mutually exclusive in TAs and SPs (p < 0.001), and telomere shortening was associated with mitochondrial microsatellite instability (63.6% vs. 36.4%, p = 0.030). These data suggested a pivotal role of telomere shortening in normal colorectal tissue for proceeding to TAs or SPs along with PIK3CA amplification and BRAF mutation, respectively. Moreover, telomeres in TAs may collaborate with mitochondrial instability for disease progression.},
}
@article {pmid29177769,
year = {2018},
author = {Nanić, L and Vidaček, N&#x160; and Ravlić, S and Šatović, E and Huzak, M and Rubelj, I},
title = {Mutual interactions between telomere heterogeneity and cell culture growth dynamics shape stochasticity of cell aging.},
journal = {Biogerontology},
volume = {19},
number = {1},
pages = {23-31},
doi = {10.1007/s10522-017-9736-2},
pmid = {29177769},
issn = {1573-6768},
mesh = {Autoradiography/methods ; Cell Cycle/physiology ; Cell Growth Processes/*physiology ; Cells, Cultured ; Cellular Senescence/*physiology ; Computer Simulation ; *Fibroblasts/cytology/physiology ; Humans ; Models, Theoretical ; Stochastic Processes ; Telomere Homeostasis/*physiology ; Telomere Shortening/*physiology ; beta-Galactosidase/metabolism ; },
abstract = {Mathematical modeling and computational simulations are often used to explain the stochastic nature of cell aging. The models published thus far are based on the molecular mechanisms of telomere biology and how they dictate the dynamics of cell culture proliferation. However, the influence of cell growth conditions on telomere dynamics has been widely overlooked. These conditions include interactions with surrounding cells through contact inhibition, gradual accumulation of non-dividing cells, culture propagation and other cell culture maintenance factors. In order to follow the intrinsic growth dynamics of normal human fibroblasts we employed the fluorescent dye DiI and FACS analysis which can distinguish cells that undergo different numbers of divisions within culture. We observed rapid generation of cell subpopulations undergoing from 0 to 9 divisions within growing cultures at each passage analyzed. These large differences in number of divisions among individual cells guarantee a strong impact on generation of telomere length heterogeneity in normal cell cultures and suggest that culture conditions should be included in future modeling of cell senescence.},
}
@article {pmid29169583,
year = {2018},
author = {Choi, ES and Chang, YK and Lee, DH and Ko, JH and Lim, I and Bang, H and Kim, JH},
title = {Gender-specific associations between quality of life and leukocyte telomere length.},
journal = {Maturitas},
volume = {107},
number = {},
pages = {68-70},
doi = {10.1016/j.maturitas.2017.10.008},
pmid = {29169583},
issn = {1873-4111},
mesh = {Aged ; Cross-Sectional Studies ; Female ; Humans ; *Leukocytes ; Male ; Middle Aged ; *Quality of Life ; Real-Time Polymerase Chain Reaction ; *Telomere ; },
abstract = {We conducted a study on the relationship between leukocyte telomere length (LTL) and quality of life (QoL) in 82 couples aged 55 and older. LTL was measured by quantitative real-time PCR. QoL was evaluated using the physical component score (PCS) and mental component score (MCS) on the Korean version of the Short-Form Health Survey (SF-36). LTL was found to be independently associated with the SF-36 PCS in males (β=0.014, p=0.03) and the SF-36 MCS in females (β=1.16, p<0.01). Thus LTL is associated with QoL in gender-specific ways.},
}
@article {pmid29167542,
year = {2017},
author = {Sandhu, R and Li, B},
title = {Telomerase activity is required for the telomere G-overhang structure in Trypanosoma brucei.},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {15983},
pmid = {29167542},
issn = {2045-2322},
support = {R01 AI066095/AI/NIAID NIH HHS/United States ; },
mesh = {DNA, Protozoan/genetics ; Protozoan Proteins/*genetics ; Telomerase/genetics/*metabolism ; Telomere/*genetics ; Telomere Homeostasis/genetics ; Trypanosoma brucei brucei/*genetics ; },
abstract = {Trypanosoma brucei causes fatal human African trypanosomiasis and evades the host immune response by regularly switching its major surface antigen, VSG, which is expressed exclusively from subtelomeric loci. Telomere length and telomere proteins play important roles in regulating VSG silencing and switching. T. brucei telomerase plays a key role in maintaining telomere length, and T. brucei telomeres terminate in a single-stranded 3' G-rich overhang. Understanding the detailed structure of the telomere G-overhang and its maintenance will contribute greatly to better understanding telomere maintenance mechanisms. Using an optimized adaptor ligation assay, we found that most T. brucei telomere G-overhangs end in 5' TTAGGG 3', while a small portion of G-overhangs end in 5' TAGGGT 3'. Additionally, the protein and the RNA components of the telomerase (TbTERT and TbTR) and TbKu are required for telomere G-overhangs that end in 5' TTAGGG 3' but do not significantly affect the 5' TAGGGT 3'-ending overhangs, indicating that telomerase-mediated telomere synthesis is important for the telomere G-overhang structure. Furthermore, using telomere oligo ligation-mediated PCR, we showed for the first time that the T. brucei telomere 5' end sequence - an important feature of the telomere terminal structure - is not random but preferentially 5' CCTAAC 3'.},
}
@article {pmid29167439,
year = {2017},
author = {Maestroni, L and Audry, J and Matmati, S and Arcangioli, B and Géli, V and Coulon, S},
title = {Eroded telomeres are rearranged in quiescent fission yeast cells through duplications of subtelomeric sequences.},
journal = {Nature communications},
volume = {8},
number = {1},
pages = {1684},
pmid = {29167439},
issn = {2041-1723},
mesh = {DNA, Fungal/genetics/metabolism ; Gene Rearrangement ; Genomic Instability ; Homologous Recombination ; Models, Genetic ; RNA, Fungal/genetics/metabolism ; Recombinational DNA Repair ; Resting Phase, Cell Cycle/genetics ; Schizosaccharomyces/cytology/*genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics ; Segmental Duplications, Genomic ; Telomere/*genetics/*metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {While the mechanisms of telomere maintenance has been investigated in dividing cells, little is known about the stability of telomeres in quiescent cells and how dysfunctional telomeres are processed in non-proliferating cells. Here we examine the stability of telomeres in quiescent cells using fission yeast. While wild type telomeres are stable in quiescence, we observe that eroded telomeres were highly rearranged during quiescence in telomerase minus cells. These rearrangements depend on homologous recombination (HR) and correspond to duplications of subtelomeric regions. HR is initiated at newly identified subtelomeric homologous repeated sequences (HRS). We further show that TERRA (Telomeric Repeat-containing RNA) is increased in post-mitotic cells with short telomeres and correlates with telomere rearrangements. Finally, we demonstrate that rearranged telomeres prevent cells to exit properly from quiescence. Taken together, we describe in fission yeast a mode of telomere repair mechanism specific to post-mitotic cells that is likely promoted by transcription.},
}
@article {pmid29164645,
year = {2018},
author = {Joshu, CE and Peskoe, SB and Heaphy, CM and Kenfield, SA and Mucci, LA and Giovannucci, EL and Stampfer, MJ and Yoon, G and Lee, TK and Hicks, JL and De Marzo, AM and Meeker, AK and Platz, EA},
title = {Current or recent smoking is associated with more variable telomere length in prostate stromal cells and prostate cancer cells.},
journal = {The Prostate},
volume = {78},
number = {3},
pages = {233-238},
pmid = {29164645},
issn = {1097-0045},
support = {P50 CA058236/CA/NCI NIH HHS/United States ; R01 CA072036/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; R01 CA133891/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; R01 HL035464/HL/NHLBI NIH HHS/United States ; R01 CA141298/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Humans ; Male ; Middle Aged ; Prospective Studies ; Prostate/*pathology ; Prostatic Neoplasms/*pathology ; *Smoking ; Stromal Cells/*pathology ; Telomere Homeostasis/*physiology ; Telomere Shortening/physiology ; },
abstract = {BACKGROUND: Current and recent smoking have been associated with a greater risk of prostate cancer recurrence and mortality, though the underlying mechanism is unknown.<br><br>METHODS: To determine if telomere shortening, which has been associated with poor outcomes, may be a potential underlying mechanism, we prospectively evaluated the association between smoking status and telomere length in 567 participants in the Health Professionals Follow-up Study, who were surgically treated for prostate cancer. Using tissue microarrays (TMA), we measured telomere length in cancer and benign tissue, specifically stromal cells in the same TMA spot using a telomere-specific fluorescence in situ hybridization assay. Smoking status was collected via questionnaire 2-years before diagnosis. Adjusting for age, pathologic stage and grade, the median and standard deviation of the per-cell telomere signals were determined for each man for stromal cells and cancer cells by smoking categories. In sub-analyses, we restricted to men without major co-morbidities diagnosed before prostate cancer.<br><br>RESULTS: Overall, there were no associations between smoking status and telomere length or variability in stromal cells or cancer cells. However, among men without comorbidities, current smokers and former smokers who quit&#x2009;<10 years ago had the most variable telomere length in stromal cells (29.3% more variable than never smokers; P-trend&#x2009;=&#x2009;0.0005) and in cancer cells (27.7% more variable than never smokers; P-trend&#x2009;=&#x2009;0.05). Among men without comorbidities, mean telomere length did not differ by smoking status in stromal cells or cancer cells.<br><br>CONCLUSION: Telomere variability in prostate cells may be one mechanism through which smoking influences poor prostate cancer outcomes.},
}
@article {pmid29163364,
year = {2017},
author = {Provenzi, L and Scotto di Minico, G and Giorda, R and Montirosso, R},
title = {Telomere Length in Preterm Infants: A Promising Biomarker of Early Adversity and Care in the Neonatal Intensive Care Unit?.},
journal = {Frontiers in endocrinology},
volume = {8},
number = {},
pages = {295},
pmid = {29163364},
issn = {1664-2392},
abstract = {Preterm infants present an immature neurobehavioral profile at birth, even in absence of severe brain injuries and perinatal complications. As such, they require a long-lasting hospitalization in the Neonatal Intensive Care Unit (NICU), which is thought to grant at-risk newborns' survival, but still entails a number of physical, painful, and socio-emotional stressors. Hence, preterm birth and NICU stay represent an early adverse experience, which has been linked to detrimental consequences for neurological, neuro-endocrinal, behavioral, and socio-emotional development, as well as to disease later in life. Recent advances in the behavioral epigenetic field are helping us to unveil the potential mechanisms through which early NICU-related stress may lead to negative developmental outcomes. From this perspective, telomere regulation might be a key programming mechanism. Telomeres are the terminal portion of chromosomes and are known to get shorter with age. Moreover, telomere length (TL) is affected by the exposure to stress during early development. As such, TL might be an innovative biomarker of early adverse exposures in young infants and children. Unfortunately, there is paucity of studies investigating TL in populations of preterm infants and its association with known NICU-related stressors remains unexplored. In the present paper, the potential relevance of TL for research and clinical work with preterm infants will be underlined in the light of recent contributions linking progressive telomere shortening and early exposure to adverse experiences and stressful environments in humans. Finally, insights will be provided to guide clinically relevant translational research on TL in the field of VPT birth and NICU stay.},
}
@article {pmid29162774,
year = {2018},
author = {Muraki, K and Murnane, JP},
title = {The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks.},
journal = {Genes &amp; genetic systems},
volume = {92},
number = {3},
pages = {135-152},
doi = {10.1266/ggs.17-00014},
pmid = {29162774},
issn = {1880-5779},
mesh = {Animals ; *DNA Breaks, Double-Stranded ; *DNA End-Joining Repair ; Humans ; Telomere/genetics/*metabolism ; },
abstract = {In mammals, DNA double-strand breaks (DSBs) are primarily repaired by classical non-homologous end joining (C-NHEJ), although homologous recombination repair and alternative NHEJ (A-NHEJ), which involve DSB processing, can also occur. These pathways are tightly regulated to maintain chromosome integrity. The ends of chromosomes, called telomeres, contain telomeric DNA that forms a cap structure in cooperation with telomeric proteins to prevent the activation of the DNA damage response and chromosome fusion at chromosome termini. Telomeres and subtelomeric regions are poor substrates for DNA replication; therefore, regions near telomeres are prone to replication fork stalling and chromosome breakage. Moreover, DSBs near telomeres are poorly repaired. As a result, when DSBs occur near telomeres in normal cells, the cells stop proliferating, while in cancer cells, subtelomeric DSBs induce rearrangements due to the absence of cell cycle checkpoints. The sensitivity of subtelomeric regions to DSBs is due to the improper regulation of processing, because although C-NHEJ is functional at subtelomeric DSBs, excessive processing results in an increased frequency of large deletions and chromosome rearrangements involving A-NHEJ.},
}
@article {pmid29162166,
year = {2017},
author = {Drury, SS and Howell, BR and Jones, C and Esteves, K and Morin, E and Schlesinger, R and Meyer, JS and Baker, K and Sanchez, MM},
title = {Shaping long-term primate development: Telomere length trajectory as an indicator of early maternal maltreatment and predictor of future physiologic regulation.},
journal = {Development and psychopathology},
volume = {29},
number = {5},
pages = {1539-1551},
pmid = {29162166},
issn = {1469-2198},
support = {R01 MH101533/MH/NIMH NIH HHS/United States ; P51 OD011132/OD/NIH HHS/United States ; P51 RR000165/RR/NCRR NIH HHS/United States ; T32 MH015755/MH/NIMH NIH HHS/United States ; P50 MH078105/MH/NIMH NIH HHS/United States ; },
mesh = {Animals ; Female ; Hair/chemistry ; Hydrocortisone/*analysis ; Male ; Maternal Behavior/*physiology ; Mothers ; *Primates ; *Telomere ; },
abstract = {The molecular, neurobiological, and physical health impacts of child maltreatment are well established, yet mechanistic pathways remain inadequately defined. Telomere length (TL) decline is an emerging molecular indicator of stress exposure with definitive links to negative health outcomes in maltreated individuals. The multiple confounders endemic to human maltreatment research impede the identification of causal pathways. This study leverages a unique randomized, cross-foster, study design in a naturalistic translational nonhuman primate model of infant maltreatment. At birth, newborn macaques were randomly assigned to either a maltreating or a competent control mother, balancing for sex, biological mother parenting history, and social rank. Offspring TL was measured longitudinally across the first 6 months of life (infancy) from peripheral blood. Hair cortisol accumulation was also determined at 6, 12, and 18 months of age. TL decline was greater in animals randomized to maltreatment, but also interacted with biological mother group. Shorter TL at 6 months was associated with higher mean cortisol levels through 18 months (juvenile period) when controlling for relevant covariates. These results suggest that even under the equivalent social, nutritional, and environmental conditions feasible in naturalistic translational nonhuman primate models, early adverse caregiving results in lasting molecular scars that foreshadow elevated health risk and physiologic dysregulation.},
}
@article {pmid29161636,
year = {2018},
author = {Nelson, BW and Allen, NB and Laurent, H},
title = {Infant HPA axis as a potential mechanism linking maternal mental health and infant telomere length.},
journal = {Psychoneuroendocrinology},
volume = {88},
number = {},
pages = {38-46},
doi = {10.1016/j.psyneuen.2017.11.008},
pmid = {29161636},
issn = {1873-3360},
mesh = {Adult ; Depression/metabolism ; Female ; Humans ; Hydrocortisone/analysis ; Hypothalamo-Hypophyseal System/metabolism ; Infant ; Male ; Mental Health ; Mindfulness ; Mother-Child Relations/*psychology ; Mothers/psychology ; Pituitary-Adrenal System/metabolism ; Postpartum Period/metabolism ; Saliva/chemistry/metabolism ; Stress, Psychological/metabolism ; Telomere/*metabolism/pathology ; Telomere Homeostasis/*physiology ; },
abstract = {Maternal depression has been suggested to be an independent risk factor for both dysregulated hypothalamic-pituitary-adrenal axis (HPA) functioning and shorter telomere length in offspring. In contrast, research suggests that individual differences in mindfulness may act as a protective factor against one's own telomere degradation. Currently, research has yet to investigate the association between longitudinal changes in maternal mental health (depressive symptoms and mindfulness) and salivary infant telomere length, and whether such changes might be mediated by alterations in infant cortisol response. In 48 mother-infant dyads, we investigated whether the changes in maternal mental health, when infants were 6-12 months of age, predicted change in infant cortisol reactivity and recovery over this period. We also investigated whether these changes in infant HPA functioning predicted subsequent infant salivary telomere length at 18 months of age. Furthermore, we investigated whether change in infant HPA functioning provided a potential pathway between changes in maternal mental health factors and infant salivary telomere length. Analyses revealed that increases in maternal depressive symptoms over that six-month period indirectly related to subsequent shorter infant telomere length through increased infant cortisol reactivity. Implications for the ways in which maternal mental health can impact offspring stress mechanisms related to aging and disease trajectories are discussed.},
}
@article {pmid29157235,
year = {2017},
author = {Bijnens, EM and Zeegers, MP and Derom, C and Martens, DS and Gielen, M and Hageman, GJ and Plusquin, M and Thiery, E and Vlietinck, R and Nawrot, TS},
title = {Telomere tracking from birth to adulthood and residential traffic exposure.},
journal = {BMC medicine},
volume = {15},
number = {1},
pages = {205},
pmid = {29157235},
issn = {1741-7015},
support = {ERC-2012-StG 310890//European Research Council/International ; G073315N//Fonds Wetenschappelijk Onderzoek/International ; },
mesh = {Adolescent ; Aging/genetics ; *Automobiles ; Child ; Child, Preschool ; *Environment ; Female ; Humans ; Infant ; Infant, Newborn ; Longitudinal Studies ; Male ; Maternal Exposure ; Mouth Mucosa ; Placenta ; Pregnancy ; Prospective Studies ; *Telomere ; Telomere Shortening ; Twins ; Young Adult ; },
abstract = {BACKGROUND: Telomere attrition is extremely rapid during the first years of life, while lifestyle during adulthood exerts a minor impact. This suggests that early life is an important period in the determination of telomere length. We investigated the importance of the early-life environment on both telomere tracking and adult telomere length.<br><br>METHODS: Among 184 twins of the East Flanders Prospective Twin Survey, telomere length in placental tissue and in buccal cells in young adulthood was measured. Residential addresses at birth and in young adulthood were geocoded and residential traffic and greenness exposure was determined.<br><br>RESULTS: We investigated individual telomere tracking from birth over a 20&#xa0;year period (mean age (SD), 22.6 (3.1) years) in association with residential exposure to traffic and greenness. Telomere length in placental tissue and in buccal cells in young adulthood correlated positively (r&#x2009;=&#x2009;0.31, P&#x2009;<&#x2009;0.0001). Persons with higher placental telomere length at birth were more likely to have a stronger downward shift in telomere ranking over life (P&#x2009;<&#x2009;0.0001). Maternal residential traffic exposure correlated inversely with telomere length at birth. Independent of birth placental telomere length, telomere ranking between birth and young adulthood was negatively and significantly associated with residential traffic exposure at the birth address, while traffic exposure at the residential address at adult age was not associated with telomere length.<br><br>CONCLUSIONS: Longitudinal evidence of telomere length tracking from birth to adulthood shows inverse associations of residential traffic exposure in association with telomere length at birth as well as accelerated telomere shortening in the first two decades of life.},
}
@article {pmid29155048,
year = {2018},
author = {Joseph, L},
title = {Telomere Diagnostics for Pancreatic Neoplasms and Cysts.},
journal = {The Journal of molecular diagnostics : JMD},
volume = {20},
number = {1},
pages = {31-33},
doi = {10.1016/j.jmoldx.2017.11.001},
pmid = {29155048},
issn = {1943-7811},
mesh = {Humans ; Pancreatic Cyst/*diagnosis/*genetics ; Pancreatic Neoplasms/*diagnosis/*genetics ; Pathology, Molecular/*methods ; Telomerase/metabolism ; Telomere/*genetics ; Telomere Homeostasis/genetics ; },
abstract = {This commentary highlights the article by Hata et al that examines markers for assessing pancreatic neoplastic progression.},
}
@article {pmid29151059,
year = {2018},
author = {Delgado, DA and Zhang, C and Chen, LS and Gao, J and Roy, S and Shinkle, J and Sabarinathan, M and Argos, M and Tong, L and Ahmed, A and Islam, T and Rakibuz-Zaman, M and Sarwar, G and Shahriar, H and Rahman, M and Yunus, M and Jasmine, F and Kibriya, MG and Ahsan, H and Pierce, BL},
title = {Genome-wide association study of telomere length among South Asians identifies a second RTEL1 association signal.},
journal = {Journal of medical genetics},
volume = {55},
number = {1},
pages = {64-71},
pmid = {29151059},
issn = {1468-6244},
support = {T42 OH008672/OH/NIOSH CDC HHS/United States ; P30 CA014599/CA/NCI NIH HHS/United States ; P42 ES010349/ES/NIEHS NIH HHS/United States ; R01 CA107431/CA/NCI NIH HHS/United States ; U01 HG007601/HG/NHGRI NIH HHS/United States ; R35 ES028379/ES/NIEHS NIH HHS/United States ; R01 CA102484/CA/NCI NIH HHS/United States ; R25 GM109439/GM/NIGMS NIH HHS/United States ; R01 ES020506/ES/NIEHS NIH HHS/United States ; },
mesh = {Asian People/*genetics ; DNA Helicases/*genetics ; Genetic Predisposition to Disease ; *Genome-Wide Association Study ; Humans ; Polymorphism, Single Nucleotide/genetics ; Telomere/*genetics ; },
abstract = {BACKGROUND: Leucocyte telomere length (TL) is a potential biomarker of ageing and risk for age-related disease. Leucocyte TL is heritable and shows substantial differences by race/ethnicity. Recent genome-wide association studies (GWAS) report ~10 loci harbouring SNPs associated with leucocyte TL, but these studies focus primarily on populations of European ancestry.<br><br>OBJECTIVE: This study aims to enhance our understanding of genetic determinants of TL across populations.<br><br>METHODS: We performed a GWAS of TL using data on 5075 Bangladeshi adults. We measured TL using one of two technologies (qPCR or a Luminex-based method) and used standardised variables as TL phenotypes.<br><br>RESULTS: Our results replicate previously reported associations in the TERC and TERT regions (P=2.2&#xd7;10[-8] and P=6.4&#xd7;10[-6], respectively). We observed a novel association signal in the RTEL1 gene (intronic SNP rs2297439; P=2.82&#xd7;10[-7]) that is independent of previously reported TL-associated SNPs in this region. The minor allele for rs2297439 is common in South Asian populations (&#x2265;0.25) but at lower frequencies in other populations (eg, 0.07 in Northern Europeans). Among the eight other previously reported association signals, all were directionally consistent with our study, but only rs8105767 (ZNF208) was nominally significant (P=0.003). SNP-based heritability estimates were as high as 44% when analysing close relatives but much lower when analysing distant relatives only.<br><br>CONCLUSIONS: In this first GWAS of TL in a South Asian population, we replicate some, but not all, of the loci reported in prior GWAS of individuals of European ancestry, and we identify a novel second association signal at the RTEL1 locus.},
}
@article {pmid29149257,
year = {2018},
author = {Belsky, DW and Moffitt, TE and Cohen, AA and Corcoran, DL and Levine, ME and Prinz, JA and Schaefer, J and Sugden, K and Williams, B and Poulton, R and Caspi, A},
title = {Eleven Telomere, Epigenetic Clock, and Biomarker-Composite Quantifications of Biological Aging: Do They Measure the Same Thing?.},
journal = {American journal of epidemiology},
volume = {187},
number = {6},
pages = {1220-1230},
pmid = {29149257},
issn = {1476-6256},
support = {R01 AG049789/AG/NIA NIH HHS/United States ; R01 AG061378/AG/NIA NIH HHS/United States ; T32 AG000139/AG/NIA NIH HHS/United States ; P30 AG034424/AG/NIA NIH HHS/United States ; //CIHR/Canada ; R01 AG066887/AG/NIA NIH HHS/United States ; P30 AG028716/AG/NIA NIH HHS/United States ; S10 OD018164/OD/NIH HHS/United States ; R01 AG032282/AG/NIA NIH HHS/United States ; MR/P005918/1/MRC_/Medical Research Council/United Kingdom ; R21 AG054846/AG/NIA NIH HHS/United States ; R01 AG048895/AG/NIA NIH HHS/United States ; R03 HD050374/HD/NICHD NIH HHS/United States ; },
mesh = {Aging/*physiology ; *Biological Clocks ; *Biomarkers ; Cohort Studies ; Female ; Humans ; Male ; Middle Aged ; *Telomere Homeostasis ; },
abstract = {The geroscience hypothesis posits that therapies to slow biological processes of aging can prevent disease and extend healthy years of life. To test such "geroprotective" therapies in humans, outcome measures are needed that can assess extension of disease-free life span. This need has spurred development of different methods to quantify biological aging. But different methods have not been systematically compared in the same humans. We implemented 7 methods to quantify biological aging using repeated-measures physiological and genomic data in 964 middle-aged humans in the Dunedin Study (New Zealand; persons born 1972-1973). We studied 11 measures in total: telomere-length and erosion, 3 epigenetic-clocks and their ticking rates, and 3 biomarker-composites. Contrary to expectation, we found low agreement between different measures of biological aging. We next compared associations between biological aging measures and outcomes that geroprotective therapies seek to modify: physical functioning, cognitive decline, and subjective signs of aging, including aged facial appearance. The 71-cytosine-phosphate-guanine epigenetic clock and biomarker composites were consistently related to these aging-related outcomes. However, effect sizes were modest. Results suggested that various proposed approaches to quantifying biological aging may not measure the same aspects of the aging process. Further systematic evaluation and refinement of measures of biological aging is needed to furnish outcomes for geroprotector trials.},
}
@article {pmid29145503,
year = {2017},
author = {Farahzadi, R and Fathi, E and Mesbah-Namin, SA and Zarghami, N},
title = {Zinc sulfate contributes to promote telomere length extension via increasing telomerase gene expression, telomerase activity and change in the TERT gene promoter CpG island methylation status of human adipose-derived mesenchymal stem cells.},
journal = {PloS one},
volume = {12},
number = {11},
pages = {e0188052},
pmid = {29145503},
issn = {1932-6203},
mesh = {Adipose Tissue/cytology/*metabolism ; Base Sequence ; Cell Differentiation ; Cell Lineage ; *CpG Islands ; *DNA ; Gene Expression Regulation, Enzymologic/*drug effects ; Humans ; Mesenchymal Stem Cells/*cytology ; *Promoter Regions, Genetic ; Real-Time Polymerase Chain Reaction ; Sequence Homology, Nucleic Acid ; Telomerase/*genetics ; *Telomere ; Zinc Sulfate/*pharmacology ; },
abstract = {The use of mesenchymal stem cells (MSCs) for cell therapy and regenerative medicine has received widespread attention over the past few years, but their application can be complicated by factors such as reduction in proliferation potential, the senescent tendency of the MSCs upon expansion and their age-dependent decline in number and function. It was shown that all the mentioned features were accompanied by a reduction in telomerase activity and telomere shortening. Furthermore, the role of epigenetic changes in aging, especially changes in promoter methylation, was reported. In this study, MSCs were isolated from the adipose tissue with enzymatic digestion. In addition, immunocytochemistry staining and flow cytometric analysis were performed to investigate the cell-surface markers. In addition, alizarin red-S, sudan III, toluidine blue, and cresyl violet staining were performed to evaluate the multi-lineage differentiation of hADSCs. In order to improve the effective application of MSCs, these cells were treated with 1.5 × 10-8 and 2.99 × 10-10 M of ZnSO4 for 48 hours. The length of the absolute telomere, human telomerase reverse transcriptase (hTERT) gene expression, telomerase activity, the investigation of methylation status of the hTERT gene promoter and the percentage of senescent cells were analyzed with quantitative real-time PCR, PCR-ELISA TRAP assay, methylation specific PCR (MSP), and beta-galactosidase (SA-β-gal) staining, respectively. The results showed that the telomere length, the hTERT gene expression, and the telomerase activity had significantly increased. In addition, the percentage of senescent cells had significantly decreased and changes in the methylation status of the CpG islands in the hTERT promoter region under treatment with ZnSO4 were seen. In conclusion, it seems that ZnSO4 as a proper antioxidant could improve the aging-related features due to lengthening of the telomeres, increasing the telomerase gene expression, telomerase activity, decreasing aging, and changing the methylation status of hTERT promoter; it could potentially beneficial for enhancing the application of aged-MSCs.},
}
@article {pmid29144994,
year = {2018},
author = {Varela-Lopez, A and Pérez-López, MP and Ramirez-Tortosa, CL and Battino, M and Granados-Principal, S and Ramirez-Tortosa, MDC and Ochoa, JJ and Vera-Ramirez, L and Giampieri, F and Quiles, JL},
title = {Gene pathways associated with mitochondrial function, oxidative stress and telomere length are differentially expressed in the liver of rats fed lifelong on virgin olive, sunflower or fish oils.},
journal = {The Journal of nutritional biochemistry},
volume = {52},
number = {},
pages = {36-44},
doi = {10.1016/j.jnutbio.2017.09.007},
pmid = {29144994},
issn = {1873-4847},
mesh = {Aging/genetics/physiology ; Animals ; Fatty Acids/analysis/metabolism ; Fish Oils/*pharmacology ; Liver/*drug effects/metabolism/ultrastructure ; Male ; Mitochondria, Liver/drug effects/genetics/metabolism ; Olive Oil/*pharmacology ; Oxidative Stress/drug effects/*genetics ; Protein Carbonylation ; Rats, Wistar ; Sunflower Oil/*pharmacology ; Telomere ; Transcriptome ; },
abstract = {This study investigates the effect of lifelong intake of different fat sources rich in monounsaturated (virgin olive oil), n6 polyunsaturated (sunflower oil) or n3 polyunsaturated (fish oil) fatty acids in the aged liver. Male Wistar rats fed lifelong on diets differing in the fat source were killed at 6 and at 24 months of age. Liver histopathology, mitochondrial ultrastructure, biogenesis, oxidative stress, mitochondrial electron transport chain, relative telomere length and gene expression profiles were studied. Aging led to lipid accumulation in the liver. Virgin olive oil led to the lowest oxidation and ultrastructural alterations. Sunflower oil induced fibrosis, ultrastructural alterations and high oxidation. Fish oil intensified oxidation associated with age, lowered electron transport chain activity and enhanced the relative telomere length. Gene expression changes associated with age in animals fed virgin olive oil and fish oil were related mostly to mitochondrial function and oxidative stress pathways, followed by cell cycle and telomere length control. Sunflower oil avoided gene expression changes related to age. According to the results, virgin olive oil might be considered the dietary fat source that best preserves the liver during the aging process.},
}
@article {pmid29143804,
year = {2017},
author = {Vasko, T and Kaifie, A and Stope, MB and Kraus, T and Ziegler, P},
title = {Telomeres and Telomerase in Hematopoietic Dysfunction: Prognostic Implications and Pharmacological Interventions.},
journal = {International journal of molecular sciences},
volume = {18},
number = {11},
pages = {},
pmid = {29143804},
issn = {1422-0067},
mesh = {Animals ; Gene Expression Regulation ; Hematologic Diseases/diagnosis/*etiology/*metabolism ; *Hematopoiesis/genetics ; Humans ; Leukocytes/*metabolism/pathology ; Telomerase/antagonists &amp; inhibitors/genetics/*metabolism ; Telomere/*genetics/*metabolism ; Telomere Homeostasis ; },
abstract = {Leukocyte telomere length (TL) has been suggested as a marker of biological age in healthy individuals, but can also reflect inherited and acquired hematopoietic dysfunctions or indicate an increased turnover of the hematopoietic stem and progenitor cell compartment. In addition, TL is able to predict the response rate of tyrosine kinase inhibitor therapy in chronic myeloid leukemia (CML), indicates clinical outcomes in chronic lymphocytic leukemia (CLL), and can be used as screening tool for genetic sequencing of selected genes in patients with inherited bone marrow failure syndromes (BMFS). In tumor cells and clonal hematopoietic disorders, telomeres are continuously stabilized by reactivation of telomerase, which can selectively be targeted by telomerase-specific therapy. The use of the telomerase inhibitor Imetelstat in patients with essential thrombocythmia or myelofibrosis as well as the use of dendritic cell-based telomerase vaccination in AML patients with complete remissions are promising examples for anti-telomerase targeted strategies in hematologic malignancies. In contrast, the elevation in telomerase levels through treatment with androgens has become an exciting clinical intervention for patients with BMFS. Here, we review recent developments, which highlight the impact of telomeres and telomerase targeted therapies in hematologic dysfunctions.},
}
@article {pmid29143121,
year = {2018},
author = {Aoki, Y and Aida, J and Kawano, Y and Nakamura, KI and Izumiyama-Shimomura, N and Ishikawa, N and Arai, T and Nakamura, Y and Taniai, N and Uchida, E and Takubo, K and Ishiwata, T},
title = {Telomere length of gallbladder epithelium is shortened in patients with congenital biliary dilatation: measurement by quantitative fluorescence in situ hybridization.},
journal = {Journal of gastroenterology},
volume = {53},
number = {2},
pages = {291-301},
pmid = {29143121},
issn = {1435-5922},
mesh = {Adult ; Bile Ducts, Extrahepatic/*abnormalities/diagnostic imaging ; Biliary Tract Neoplasms/diagnostic imaging/genetics ; Cholangiopancreatography, Endoscopic Retrograde ; Cholangiopancreatography, Magnetic Resonance ; Common Bile Duct/abnormalities/diagnostic imaging ; Dilatation, Pathologic/congenital/diagnostic imaging/genetics ; Epithelium/pathology ; Female ; Gallbladder/*pathology ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Pancreatic Ducts/*abnormalities/diagnostic imaging ; Precancerous Conditions/diagnostic imaging/genetics ; *Telomere Shortening ; Tomography, X-Ray Computed ; },
abstract = {BACKGROUND: Congenital biliary dilatation (CBD) is a congenital malformation involving both dilatation of the extrahepatic bile duct and pancreaticobiliary maljunction. Persistent reflux of pancreatic juice injures the biliary tract mucosa, resulting in chronic inflammation and higher rates of carcinogenesis in the biliary tract, including the gallbladder. Telomeres are repetitive DNA sequences located at the ends of chromosomes. Chromosomal instability due to telomere dysfunction plays an important role in the carcinogenesis of many organs. This study was performed to determine whether excessive shortening of telomeres occurs in the gallbladder mucosa of patients with CBD.<br><br>METHODS: Resected gallbladders were obtained from 17 patients with CBD, ten patients with cholecystolithiasis without pancreatic juice reflux, and 17 patients with normal gallbladders (controls) (median age of each group of patients: 37, 50, and 53&#xa0;years, respectively). The telomere lengths of the gallbladder epithelium were measured by quantitative fluorescence in situ hybridization using tissue sections, and the normalized telomere-to-centromere ratio (NTCR) was calculated.<br><br>RESULTS: The NTCRs in the CBD, cholecystolithiasis, and control groups were 1.24 [interquartile range (IQR) 1.125-1.52], 1.96 (IQR 1.56-2.295), and 1.77 (IQR 1.48-2.53), respectively. The NTCR in the CBD group was significantly smaller than that in the cholecystolithiasis and control groups (p&#xa0;=&#xa0;0.003 and 0.004, respectively), even in young patients.<br><br>CONCLUSIONS: Our findings indicate that telomere shortening in the gallbladder mucosa plays an important role in the process of carcinogenesis in patients with CBD. These results support the recommendation of established guidelines for prophylactic surgery in patients with CBD because CBD is a premalignant condition with excessive telomere shortening.},
}
@article {pmid29141207,
year = {2017},
author = {Zhang, J and Tu, Z and Watanabe, Y and Shibuya, H},
title = {Distinct TERB1 Domains Regulate Different Protein Interactions in Meiotic Telomere Movement.},
journal = {Cell reports},
volume = {21},
number = {7},
pages = {1715-1726},
doi = {10.1016/j.celrep.2017.10.061},
pmid = {29141207},
issn = {2211-1247},
mesh = {Animals ; Binding Sites ; Carrier Proteins/chemistry/genetics/*metabolism ; Cell Cycle Proteins/chemistry/genetics/*metabolism ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; Male ; *Meiosis ; Membrane Proteins/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; Nuclear Envelope/metabolism ; Protein Binding ; Spermatocytes/cytology/metabolism ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/chemistry/genetics/metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Cohesins ; },
abstract = {Meiotic telomeres attach to the nuclear envelope (NE) and drive the chromosome movement required for the pairing of homologous chromosomes. The meiosis-specific telomere proteins TERB1, TERB2, and MAJIN are required to regulate these events, but their assembly processes are largely unknown. Here, we developed a germ-cell-specific knockout mouse of the canonical telomere-binding protein TRF1 and revealed an essential role for TRF1 in directing the assembly of TERB1-TERB2-MAJIN. Further, we identified a TERB2 binding (T2B) domain in TERB1 that is dispensable for the TRF1-TERB1 interaction but is essential for the subsequent TERB1-TERB2 interaction and therefore for telomere attachment to the NE. Meanwhile, cohesin recruitment at telomeres, which is required for efficient telomere movement, is mediated by the MYB-like domain of TERB1, but not by TERB2-MAJIN. Our results reveal distinct protein interactions through various domains of TERB1, which enable the sequential assembly of the meiotic telomere complex for their movements.},
}
@article {pmid29138179,
year = {2017},
author = {Staerk, L and Wang, B and Lunetta, KL and Helm, RH and Ko, D and Sherer, JA and Ellinor, PT and Lubitz, SA and McManus, DD and Vasan, RS and Benjamin, EJ and Trinquart, L},
title = {Association Between Leukocyte Telomere Length and the Risk of Incident Atrial Fibrillation: The Framingham Heart Study.},
journal = {Journal of the American Heart Association},
volume = {6},
number = {11},
pages = {},
pmid = {29138179},
issn = {2047-9980},
support = {K23 HL114724/HL/NHLBI NIH HHS/United States ; R01 HL092577/HL/NHLBI NIH HHS/United States ; },
mesh = {Atrial Fibrillation/epidemiology/*genetics/metabolism ; Blotting, Southern ; Female ; Follow-Up Studies ; Humans ; Incidence ; Leukocytes/*physiology ; Male ; Massachusetts/epidemiology ; Middle Aged ; Retrospective Studies ; Risk Assessment/*methods ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: Advancing age is a prominent risk factor for atrial fibrillation (AF). Shorter telomere length is a biomarker of biological aging, but the link between shorter telomere length and increased risk of AF remains unclear. We examined the association between shorter leukocyte telomere length (LTL) and incident AF.<br><br>METHODS AND RESULTS: We included AF-free participants from the observational Framingham Heart Study Offspring cohort from 1995 to 1998, who had LTL measurements. We examined the association between baseline LTL and incident AF with multivariable Cox models adjusted for age, sex, current smoking, height, weight, systolic and diastolic blood pressure, use of antihypertensive medication, diabetes mellitus, history of myocardial infarction, and history of heart failure. The study sample comprised 1143 AF-free participants (52.8% women), with mean age of 60&#xb1;8&#xa0;years. The mean LTL at baseline was 6.95&#xb1;0.57&#xa0;kb. During 15.1&#xb1;4.2&#xa0;years mean follow-up, 184 participants (64 women) developed AF. Chronological age was associated with increased risk of AF (hazard ratio per 10-year increase, 2.16; 95% confidence interval, 1.71-2.72). There was no significant association between LTL and incident AF (hazard ratio per 1 SD decrease LTL, 1.01; 95% confidence interval, 0.86-1.19). Our study was observational in nature; hence, we could not exclude residual confounding and we were unable to establish causal pathways.<br><br>CONCLUSIONS: In our moderate-sized community-based cohort, we did not find evidence for a significant association between LTL and risk of incident AF.},
}
@article {pmid29136505,
year = {2017},
author = {Bejarano, L and Schuhmacher, AJ and Méndez, M and Megías, D and Blanco-Aparicio, C and Martínez, S and Pastor, J and Squatrito, M and Blasco, MA},
title = {Inhibition of TRF1 Telomere Protein Impairs Tumor Initiation and Progression in Glioblastoma Mouse Models and Patient-Derived Xenografts.},
journal = {Cancer cell},
volume = {32},
number = {5},
pages = {590-607.e4},
doi = {10.1016/j.ccell.2017.10.006},
pmid = {29136505},
issn = {1878-3686},
support = {16-1177/AICR_/Worldwide Cancer Research/United Kingdom ; },
mesh = {Animals ; Brain Neoplasms/*genetics/metabolism/pathology ; Cell Line, Tumor ; *Disease Models, Animal ; Disease Progression ; Gene Expression Regulation, Neoplastic ; Glioblastoma/*genetics/metabolism/pathology ; Humans ; Mice, Knockout ; Mice, Nude ; Neoplastic Stem Cells/metabolism ; RNA Interference ; Telomere/genetics/metabolism ; Telomeric Repeat Binding Protein 1/antagonists &amp; inhibitors/*genetics/metabolism ; Transplantation, Heterologous ; },
abstract = {Glioblastoma multiforme (GBM) is a deadly and common brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity, including glioma stem cells (GSCs). Telomere genes are frequently mutated. The telomere binding protein TRF1 is essential for telomere protection, and for adult and pluripotent stem cells. Here, we find TRF1 upregulation in mouse and human GBM. Brain-specific Trf1 genetic deletion in GBM mouse models inhibited GBM initiation and progression, increasing survival. Trf1 deletion increased telomeric DNA damage and reduced proliferation and stemness. TRF1 chemical inhibitors mimicked these effects in human GBM cells and also blocked tumor sphere formation and tumor growth in xenografts from patient-derived primary GSCs. Thus, targeting telomeres throughout TRF1 inhibition is an effective therapeutic strategy for GBM.},
}
@article {pmid29134494,
year = {2018},
author = {Sadhukhan, R and Chowdhury, P and Ghosh, S and Ghosh, U},
title = {Expression of Telomere-Associated Proteins is Interdependent to Stabilize Native Telomere Structure and Telomere Dysfunction by G-Quadruplex Ligand Causes TERRA Upregulation.},
journal = {Cell biochemistry and biophysics},
volume = {76},
number = {1-2},
pages = {311-319},
doi = {10.1007/s12013-017-0835-0},
pmid = {29134494},
issn = {1559-0283},
mesh = {A549 Cells ; Bleomycin/pharmacology ; G-Quadruplexes ; Humans ; In Situ Hybridization, Fluorescence ; Microscopy, Fluorescence ; Poly (ADP-Ribose) Polymerase-1/antagonists &amp; inhibitors/genetics/metabolism ; RNA Interference ; RNA, Long Noncoding/genetics/*metabolism ; RNA, Small Interfering/metabolism ; Recombinases/antagonists &amp; inhibitors/genetics/metabolism ; Telomere/chemistry/*metabolism ; Telomeric Repeat Binding Protein 1/antagonists &amp; inhibitors/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/antagonists &amp; inhibitors/genetics/*metabolism ; Up-Regulation/drug effects ; },
abstract = {Telomere DNA can form specialized nucleoprotein structure with telomere-associated proteins to hide free DNA ends or G-quadruplex structures under certain conditions especially in presence of G-quadruplex ligand. Telomere DNA is transcribed to form non-coding telomere repeat-containing RNA (TERRA) whose biogenesis and function is poorly understood. Our aim was to find the role of telomere-associated proteins and telomere structures in TERRA transcription. We silenced four [two shelterin (TRF1, TRF2) and two non-shelterin (PARP-1, SLX4)] telomere-associated genes using siRNA and verified depletion in protein level. Knocking down of one gene modulated expression of other telomere-associated genes and increased TERRA from 10q, 15q, XpYp and XqYq chromosomes in A549 cells. Telomere was destabilized or damaged by G-quadruplex ligand pyridostatin (PDS) and bleomycin. Telomere dysfunction-induced foci (TIFs) were observed for each case of depletion of proteins, treatment with PDS or bleomycin. TERRA level was elevated by PDS and bleomycin treatment alone or in combination with depletion of telomere-associated proteins.},
}
@article {pmid29130723,
year = {2017},
author = {Marti, A and Echeverría, R and Morell-Azanza, L and Ojeda-Rodríguez, A},
title = {[Telomeres and diet quality].},
journal = {Nutricion hospitalaria},
volume = {34},
number = {5},
pages = {1226-1245},
doi = {10.20960/nh.1181},
pmid = {29130723},
issn = {1699-5198},
mesh = {*Diet ; Diet, Mediterranean ; Health Status ; Humans ; Telomere/*physiology ; Telomere Shortening ; },
abstract = {BACKGROUND: Few studies have evaluated the relationship between diet quality and telomere integrity in humans. Telomeres are regions of non-coding DNA localized at the end of each chromosome whose length, in addition to indicating life expectancy, indicates an overall health status. The objective of this systematic review is to compile the existing evidence on the relationship between telomere length and diet quality to further explore the impact that some nutrients, foods and dietary patterns may have on telomere homeostasis and therefore, in precision nutrition strategies.<br><br>MATERIAL AND METHODS: A bibliographic review was performed in the PubMed database to identify published articles (in English or Spanish) until December 2016 that met the following criteria: included human subjects; cross-sectional studies; case-control studies; prospective cohort studies or intervention studies; evaluating the relationship of nutrients, foods or dietary patterns on telomere integrity. The search strategy included the following keywords: nutrients or food OR food groups OR diet OR dietary pattern OR eating pattern OR dietary habits OR diet type AND telomere attrition OR telomere length. In total, 19 cross-sectional studies, five case-control studies, five prospective cohort studies, and two intervention studies were included, including those articles that were found for being listed in other publications.<br><br>RESULTS: Positive associations were found between telomere length and adherence to the Mediterranean diet and consumption of vegetables and fruits. The results observed for other nutrients, foods or dietary patterns were incoherent although it seems that processed meats, cereals, alcohol and sweetened beverages could be associated with shorter telomeres.<br><br>CONCLUSIONS: Dietary intervention, and in particular the promotion of a Mediterranean-style diet, may play a role in the protection of telomere integrity.},
}
@article {pmid29130457,
year = {2017},
author = {Hartmann, K and Illing, A and Leithäuser, F and Baisantry, A and Quintanilla-Martinez, L and Rudolph, KL},
title = {Gene dosage reductions of Trf1 and/or Tin2 induce telomere DNA damage and lymphoma formation in aging mice.},
journal = {Leukemia},
volume = {31},
number = {12},
pages = {2853},
doi = {10.1038/leu.2017.224},
pmid = {29130457},
issn = {1476-5551},
abstract = {This corrects the article DOI: 10.1038/leu.2015.173.},
}
@article {pmid29123917,
year = {2017},
author = {Moiseeva, V and Amelina, H and Collopy, LC and Armstrong, CA and Pearson, SR and Tomita, K},
title = {The telomere bouquet facilitates meiotic prophase progression and exit in fission yeast.},
journal = {Cell discovery},
volume = {3},
number = {},
pages = {17041},
pmid = {29123917},
issn = {2056-5968},
support = {12097/CRUK_/Cancer Research UK/United Kingdom ; 281722/ERC_/European Research Council/International ; },
abstract = {During meiotic prophase, chromosome arrangement and oscillation promote the pairing of homologous chromosomes for meiotic recombination. This dramatic movement involves clustering of telomeres at the nuclear membrane to form the so-called telomere bouquet. In fission yeast, the telomere bouquet is formed near the spindle pole body (SPB), which is the microtubule organising centre, functionally equivalent to the metazoan centrosome. Disruption of bouquet configuration impedes homologous chromosome pairing, meiotic recombination and spindle formation. Here, we demonstrate that the bouquet is maintained throughout meiotic prophase and promotes timely prophase exit in fission yeast. Persistent DNA damages, induced during meiotic recombination, activate the Rad3 and Chk1 DNA damage checkpoint kinases and extend the bouquet stage beyond the chromosome oscillation period. The auxin-inducible degron system demonstrated that premature termination of the bouquet stage leads to severe extension of prophase and consequently spindle formation defects. However, this delayed exit from meiotic prophase was not caused by residual DNA damage. Rather, loss of chromosome contact with the SPB caused delayed accumulation of CDK1-cyclin B at the SPB, which correlated with impaired SPB separation. In the absence of the bouquet, CDK1-cyclin B localised near the telomeres but not at the SPB at the later stage of meiotic prophase. Thus, bouquet configuration is maintained throughout meiotic prophase, by which this spatial organisation may facilitate local and timely activation of CDK1 near the SPB. Our findings illustrate that chromosome contact with the nuclear membrane synchronises meiotic progression of the nucleoplasmic chromosomes with that of the cytoplasmic SPB.},
}
@article {pmid29122549,
year = {2018},
author = {Korandová, M and Krůček, T and Szakosová, K and Kodrík, D and Kühnlein, RP and Tomášková, J and Čapková Frydrychová, R},
title = {Chronic low-dose pro-oxidant treatment stimulates transcriptional activity of telomeric retroelements and increases telomere length in Drosophila.},
journal = {Journal of insect physiology},
volume = {104},
number = {},
pages = {1-8},
doi = {10.1016/j.jinsphys.2017.11.002},
pmid = {29122549},
issn = {1879-1611},
support = {P40 OD018537/OD/NIH HHS/United States ; },
mesh = {Animals ; Dose-Response Relationship, Drug ; Drosophila melanogaster/*drug effects/genetics ; *Hormesis ; Paraquat/*pharmacology ; Reactive Oxygen Species/*pharmacology ; Retroelements/drug effects ; Telomere/drug effects/physiology ; Telomere Homeostasis/*drug effects ; Telomere Shortening/*drug effects ; Transcription, Genetic/drug effects ; },
abstract = {It has been proposed that oxidative stress, elicited by high levels of reactive oxygen species, accelerates telomere shortening by erosion of telomeric DNA repeats. While most eukaryotes counteract telomere shortening by telomerase-driven addition of these repeats, telomeric loss in Drosophila is compensated by retrotransposition of the telomeric retroelements HeT-A, TART and TAHRE to chromosome ends. In this study we tested the effect of chronic exposure of flies to non-/sub-lethal doses of paraquat, which is a redox cycling compound widely used to induce oxidative stress in various experimental paradigms including telomere length analyses. Indeed, chronic paraquat exposure for five generations resulted in elevated transcriptional activity of both telomeric and non-telomeric transposable elements, and extended telomeric length in the tested fly lines. We propose that low oxidative stress leads to increased telomere length within Drosophila populations. For a mechanistic understanding of the observed phenomenon we discuss two scenarios: adaption, acting through a direct stimulation of telomere extension, or positive selection favoring individuals with longer telomeres within the population.},
}
@article {pmid29119271,
year = {2018},
author = {Maicher, A and Kupiec, M},
title = {Rnr1's role in telomere elongation cannot be replaced by Rnr3: a role beyond dNTPs?.},
journal = {Current genetics},
volume = {64},
number = {3},
pages = {547-550},
pmid = {29119271},
issn = {1432-0983},
mesh = {Deoxyribonucleotides/*physiology ; Humans ; Neoplasms/genetics ; Ribonucleoside Diphosphate Reductase/*physiology ; Ribonucleotide Reductases/metabolism/*physiology ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/*physiology ; Telomerase/metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {Telomeres, the nucleoprotein complexes at the end of eukaryotic chromosomes, protect them from degradation and ensure the replicative capacity of cells. In most human tumors and in budding yeast, telomere length is maintained by the activity of telomerase, an enzyme that adds dNTPs according to an internal RNA template. The dNTPs are generated with the help of the ribonucleotide reductase (RNR) complex. We have recently generated strains lacking the large subunit of RNR, Rnr1, which were kept viable by the expression of RNR complexes containing the Rnr1 homolog, Rnr3. Interestingly, we found that these Rnr1-deficient strains have short telomeres that are stably maintained, but cannot become efficiently elongated by telomerase. Thus, a basic maintenance of short telomeres is possible under conditions, where Rnr1 activity is absent, but a sustained elongation of short telomeres fully depends on Rnr1 activity. We show that Rnr3 cannot compensate for this telomeric function of Rnr1 even when overall cellular dNTP values are restored. This suggests that Rnr1 plays a role in telomere elongation beyond increasing cellular dNTP levels. Furthermore, our data indicate that telomerase may act in two different modes, one that is capable of coping with the "end-replication problem" and is functional even in the absence of Rnr1 and another required for the sustained elongation of short telomeres, which fully depends on the presence of Rnr1. Supply of dNTPs for telomere elongation is provided by the Mec1[ATR] checkpoint, both during regular DNA replication and upon replication fork stalling. We discuss the implications of these results on telomere maintenance in yeast and cancer cells.},
}
@article {pmid29116388,
year = {2018},
author = {Galán, A and García-Oliver, E and Nuño-Cabanes, C and Rubinstein, L and Kupiec, M and Rodríguez-Navarro, S},
title = {The evolutionarily conserved factor Sus1/ENY2 plays a role in telomere length maintenance.},
journal = {Current genetics},
volume = {64},
number = {3},
pages = {635-644},
pmid = {29116388},
issn = {1432-0983},
support = {BFU2011-23418//Secretar&#xed;a de Estado de Investigaci&#xf3;n, Desarrollo e Innovaci&#xf3;n/ ; BFU2014-57636-P//Secretar&#xed;a de Estado de Investigaci&#xf3;n, Desarrollo e Innovaci&#xf3;n/ ; PROMETEO/2016/093//Generalitat Valenciana/ ; ACOMP/2014/061//Generalitat Valenciana/ ; ACOMP/2015/096//Generalitat Valenciana/ ; },
mesh = {*Chromosomes, Fungal ; DNA Replication ; *Evolution, Molecular ; Mutation ; Nuclear Proteins/*genetics ; RNA-Binding Proteins/*genetics ; Saccharomyces cerevisiae Proteins/*genetics ; Telomere ; *Telomere Homeostasis ; Ubiquitination ; },
abstract = {Sus1 is a conserved protein involved in histone H2B de-ubiquitination and mRNA export from the nucleus in eukaryotes. Previous studies implicated Sus1 partners in genome integrity including telomere homeostasis. However, the implication of Sus1 in telomere maintenance remains largely unknown. In this study, we found that yeast Sus1 interacts physically and genetically with factors involved in telomere maintenance and its absence leads to elongated telomeres. Deletion of several of Sus1's partners also leads to longer telomeres. Our results rule out a direct role for Sus1 in recruiting telomerase subunits to telomeres. However, we observe that deletion of SUS1 leads to elongated telomeres even in the presence of mutations like sem1Δ, esc2Δ and rsc2Δ, which cause telomere shortening. We find that rsc2Δ (short telomeres) have reduced levels of mono-ubiquitinated histone H2B at lysine 123 (H2BK123ub[1]), whereas sus1Δ mutants or double-mutants sus1Δ rsc2Δ exhibit longer telomeres and higher H2BK123ub[1] levels. These results suggest that Sus1 activity as a H2B de-ubiquitination modulator plays a role in negatively regulating telomere length. Our results provide solid evidence for a role of Sus1 in negatively regulating telomere length through the modulation of H2BK123 mono-ubiquitination and its interaction with the nuclear pore complex.},
}
@article {pmid29116081,
year = {2017},
author = {Lai, TP and Zhang, N and Noh, J and Mender, I and Tedone, E and Huang, E and Wright, WE and Danuser, G and Shay, JW},
title = {A method for measuring the distribution of the shortest telomeres in cells and tissues.},
journal = {Nature communications},
volume = {8},
number = {1},
pages = {1356},
pmid = {29116081},
issn = {2041-1723},
support = {C06 RR030414/RR/NCRR NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging/*genetics ; Animals ; Blotting, Southern ; Female ; HeLa Cells ; Humans ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence/methods ; Male ; Mice ; Middle Aged ; NIH 3T3 Cells ; Neoplasms/*genetics ; Nucleic Acid Amplification Techniques/*methods ; Software ; Telomere/*genetics ; },
abstract = {Improved methods to measure the shortest (not just average) telomere lengths (TLs) are needed. We developed Telomere Shortest Length Assay (TeSLA), a technique that detects telomeres from all chromosome ends from <1 kb to 18 kb using small amounts of input DNA. TeSLA improves the specificity and efficiency of TL measurements that is facilitated by user friendly image-processing software to automatically detect and annotate band sizes, calculate average TL, as well as the percent of the shortest telomeres. Compared with other TL measurement methods, TeSLA provides more information about the shortest telomeres. The length of telomeres was measured longitudinally in peripheral blood mononuclear cells during human aging, in tissues during colon cancer progression, in telomere-related diseases such as idiopathic pulmonary fibrosis, as well as in mice and other organisms. The results indicate that TeSLA is a robust method that provides a better understanding of the shortest length of telomeres.},
}
@article {pmid29115638,
year = {2018},
author = {Wang, C and Zhang, T and Wang, Y and Li, Y and Liu, C and Liu, H and Li, L and Ding, K and Wang, T and Wang, H and Shao, Z and Fu, R},
title = {The shortening telomere length of T lymphocytes maybe associated with hyper‑function in servere aplastic anemia.},
journal = {Molecular medicine reports},
volume = {17},
number = {1},
pages = {1015-1021},
pmid = {29115638},
issn = {1791-3004},
mesh = {Adolescent ; Adult ; Anemia, Aplastic/diagnosis/*genetics/*immunology ; Apoptosis ; Biomarkers ; Child ; Child, Preschool ; Cytokines/metabolism ; Disease Susceptibility ; Female ; Humans ; Immunophenotyping ; Male ; Middle Aged ; Severity of Illness Index ; T-Lymphocyte Subsets/immunology/metabolism ; T-Lymphocytes/*immunology/*metabolism ; *Telomere Shortening ; Young Adult ; },
abstract = {Severe aplastic anemia (SAA) is a primary disorder of severe bone marrow failure characterizing with extreme pancytopenia and a profound diminution of bone marrow progenitor cells, which is associated with T cell hyper‑function. Abnormal telomere shortening of bone marrow mononuclear cell has been reported in AA, which may lead to genomic instability, and result in cell senescence or apoptosis. Notably, certain studies identfieid that lymphocytes of shortening telomere length have undergone apoptosis escape in autoimmune diseases. In order to investigate the association between telomere lengths and function of T lymphocytes in SAA, the relative telomere lengths (RTLs) of different subtypes of T lymphocytes were investigated by flow‑fluorescent in situ hybridization in 30 patients with SAA and 25 healthy controls. Then the levels of expression of cluster of differentiation 28 (CD28), CD158 and CD70 were measured, which represent the function of T lymphocytes. The apoptosis rate and the cell cycle progression of CD8+T lymphocytes, and the level of secretion interferon‑γ and tumor necrosis factor‑α were also measured. Finally, the correlation between telomere length and these functional events of CD8+T lymphocytes was analyzed in patients with SAA. The results showed that RTLs of CD8+T lymphocytes in SAA were significantly shorter compared with those in controls. Furthermore, in patients with SAA, CD8+T lymphocytes are associated with T cell hyper‑function, which is related to the RTL. Thus, the shorter RTLs of CD8+T lymphocytes in SAA may be associated with hyper‑function of these cells, which contribute to the pathogenesis of SAA.},
}
@article {pmid29113331,
year = {2017},
author = {Duan, X and Yang, Y and Wang, S and Feng, X and Wang, T and Wang, P and Liu, S and Li, L and Li, G and Yao, W and Cui, L and Wang, W},
title = {Cross-sectional associations between genetic polymorphisms in metabolic enzymes and longer leukocyte telomere length induced by omethoate.},
journal = {Oncotarget},
volume = {8},
number = {46},
pages = {80638-80644},
pmid = {29113331},
issn = {1949-2553},
abstract = {PURPOSE: This study aimed to explore the effects of genetic polymorphisms in metabolic enzymes on relative telomere length changes and explore the mechanism of canceration induced by omethoate.<br><br>MATERIALS AND METHODS: 180 long-term omethoate-exposed workers and 115 healthy controls were recruited. Real-time PCR method was applied to determine the relative telomere length in peripheral blood leukocytes DNA, and Six polymorphic loci of GSTT1(+/-), GSTM1(+/-), GSTP1 rs1695, CYP2E1 rs6413432, CYP2E1 rs3813867 and PON2 rs12026 were detected by polymerase chain reaction and restriction fragment length polymorphism method; Multiple linear regression was conducted to explore the effects of omethoate exposure and genetic polymorphisms on the telomere length.<br><br>RESULTS: The relative telomere lengths in the control group (0.94 [0.76, 1.32]) were significantly shorter than that in the exposure group (1.50 [1.11, 2.57]) (Z = 7.910, P < 0.001). Univariate analysis showed that the relative telomere lengths of the GSTM1-deletion individuals were significantly longer than that of the non - deletion genotype in the control group (Z = 2.911, P = 0.004), and the relative telomere lengths of GSTP1 rs1695 polymorphism locus (GG+AG) genotype individuals were longer than that of AA genotype in the exposure group. The difference was statistically significant (Z = 2.262, P = 0.024). Multivariate analysis found that pesticide-exposure (b = 0.524, P < 0.001) and GSTM1 polymorphism (b = -0.136, P = 0.029) had an impact on telomere length.<br><br>CONCLUSIONS: The relative telomere lengths of omethoate-exposure workers were longer than that in the control population. Also GSTM1 genetic polymorphism may influence the changes of the telomere length induced by omethoate.},
}
@article {pmid29113293,
year = {2017},
author = {Mazidi, M and Rezaie, P and Covic, A and Malyszko, J and Rysz, J and Kengne, AP and Banach, M},
title = {Telomere attrition, kidney function, and prevalent chronic kidney disease in the United States.},
journal = {Oncotarget},
volume = {8},
number = {46},
pages = {80175-80181},
pmid = {29113293},
issn = {1949-2553},
abstract = {BACKGROUND: Telomere length is an emerging novel biomarker of biologic age, cardiovascular risk and chronic medical conditions. Few studies have focused on the association between telomere length (TL) and kidney function.<br><br>OBJECTIVE: We investigated the association between TL and kidney function/prevalent chronic kidney disease (CKD) in US adults.<br><br>METHODS: The National Health and Nutrition Examination Survey (NHANES) participants with measured data on kidney function and TL from 1999 to 2002 were included. Estimated glomerular filtration rate (eGFR) was based on CKD Epidemiology Collaboration (CKD-EPI) equation. Urinary albumin excretion was assessed using urinary albumin-creatinine ratio (ACR). We used multivariable adjusted linear and logistic regression models, accounting for the survey design and sample weights.<br><br>RESULTS: Of the 10568 eligible participants, 48.0% (n=5020) were men. Their mean age was 44.1 years. eGFR significantly decreased and ACR significantly increased across increasing quarters of TL (all p<0.001). The association between TL and kidney function remained robust even after adjusting for potential confounding factors, but the association between TL and ACR was only borderline significant (&#x3b2;-coefficient= -0.012, p=0.056).<br><br>CONCLUSION: The association of kidney function with a marker of cellular senescence suggests an underlying mechanism influencing the progression of nephropathy.},
}
@article {pmid29113290,
year = {2017},
author = {Lagunas, AM and Wu, J and Crowe, DL},
title = {Telomere DNA damage signaling regulates cancer stem cell evolution, epithelial mesenchymal transition, and metastasis.},
journal = {Oncotarget},
volume = {8},
number = {46},
pages = {80139-80155},
pmid = {29113290},
issn = {1949-2553},
support = {T32 DE018381/DE/NIDCR NIH HHS/United States ; },
abstract = {Chromosome ends are protected by telomeres that prevent DNA damage response and degradation. When telomeres become critically short, the DNA damage response is activated at chromosome ends which induces cellular senescence or apoptosis. Telomeres are protected by the double stranded DNA binding protein TRF2 and maintained by telomerase or a recombination based mechanism known as alternative lengthening of telomeres (ALT). Telomerase is expressed in the basal layer of the epidermis, and stem cells in epidermis have longer telomeres than proliferating populations. Stem cell expansion has been associated with epithelial-mesenchymal transition (EMT) in cancer. EMT is a critical process in cancer progression in which cells acquire spindle morphology, migrate from the primary tumor, and spread to distant anatomic sites. Our previous study demonstrated that loss of TRF2 expression observed in human squamous cell carcinomas expanded metastatic cancer stem cells during mouse skin carcinogenesis. To determine if telomerase inhibition could block the TRF2-null mediated expansion of metastatic clones, we characterized skin carcinogenesis in a conditional TRF2/Terc double null mutant mouse. Loss of TRF2 and Terc expression resulted in telomere DNA damage, severely depleted CD34 + and Lgr6+ cancer stem cells, and induced terminal differentiation of metastatic cancer cells. However a novel cancer stem cell population evolved in primary tumors exhibiting genomic instability, ALT, and EMT. Surprisingly we discovered that metastatic clones evolved prior to histopathologic onset of primary tumors. These results have important implications for understanding the evolution and treatment of metastatic cancer.},
}
@article {pmid29108638,
year = {2017},
author = {Garcia-Martin, I and Janssen, AB and Jones, RE and Grimstead, JW and Penketh, RJA and Baird, DM and John, RM},
title = {Telomere length heterogeneity in placenta revealed with high-resolution telomere length analysis.},
journal = {Placenta},
volume = {59},
number = {},
pages = {61-68},
pmid = {29108638},
issn = {1532-3102},
support = {18246/CRUK_/Cancer Research UK/United Kingdom ; MR/M013960/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Delivery, Obstetric ; Female ; Fetal Growth Retardation/*metabolism ; Humans ; Infant, Newborn ; Male ; Placenta/*metabolism ; Pregnancy ; Sex Characteristics ; *Telomere Homeostasis ; Young Adult ; },
abstract = {INTRODUCTION: Telomeres, are composed of tandem repeat sequences located at the ends of chromosomes and are required to maintain genomic stability. Telomeres can become shorter due to cell division and specific lifestyle factors. Critically shortened telomeres are linked to cellular dysfunction, senescence and aging. A number of studies have used low resolution techniques to assess telomere length in the placenta. In this study, we applied Single Telomere Length Analysis (STELA) which provides high-resolution chromosome specific telomere length profiles to ask whether we could obtain more detailed information on the length of individual telomeres in the placenta.<br><br>METHODS: Term placentas (37-42 weeks) were collected from women delivering at University Hospital of Wales or Royal Gwent Hospital within 2&#xa0;h of delivery. Multiple telomere-length distributions were determined using STELA. Intraplacental variation of telomere length was analysed (N&#xa0;=&#xa0;5). Telomere length distributions were compared between labouring (N&#xa0;=&#xa0;10) and non-labouring (N&#xa0;=&#xa0;11) participants. Finally, telomere length was compared between female (N&#xa0;=&#xa0;17) and male (N&#xa0;=&#xa0;20) placenta.<br><br>RESULTS: There were no significant influences of sampling site, mode of delivery or foetal sex on the telomere-length distributions obtained. The mean telomere length was 7.7&#xa0;kb ranging from 5.0&#xa0;kb to 11.7&#xa0;kb across all samples (N&#xa0;=&#xa0;42) and longer compared with other human tissues at birth. STELA also revealed considerable telomere length heterogeneity within samples.<br><br>CONCLUSIONS: We have shown that STELA can be used to study telomere length homeostasis in the placenta regardless of sampling site, mode of delivery and foetal sex. Moreover, as each amplicon is derived from a single telomeric molecule, from a single cell, STELA can reveal the full detail of telomere-length distributions, including telomeres within the length ranges observed in senescent cells. STELA thus provides a new tool to interrogate the relationship between telomere length and pregnancy complications linked to placental dysfunction.},
}
@article {pmid29108468,
year = {2018},
author = {Tzadikevitch Geffen, K and Gal, H and Vainer, I and Markovitch, O and Amiel, A and Krizhanovsky, V and Biron-Shental, T},
title = {Senescence and Telomere Homeostasis Might Be Involved in Placenta Percreta-Preliminary Investigation.},
journal = {Reproductive sciences (Thousand Oaks, Calif.)},
volume = {25},
number = {8},
pages = {1254-1260},
doi = {10.1177/1933719117737852},
pmid = {29108468},
issn = {1933-7205},
mesh = {Adult ; *Cellular Senescence ; Female ; Humans ; Placenta Accreta/metabolism/*physiopathology ; Pregnancy ; *Telomere Homeostasis ; Trophoblasts/metabolism/physiology ; },
abstract = {OBJECTIVE: Placenta percreta (PP) is an abnormal condition of trophoblast maturation and terminal differentiation through the uterine wall. We opted to study telomere homeostasis and senescence expression in trophoblasts from PP, the most severe subgroup of placenta accreta.<br><br>STUDY DESIGN: Paraffin-embedded placental biopsies from pregnancies with percreta and normal placentation, matched by gestational age at delivery, were assessed for telomere length, aggregates, and senescence-associated heterochromatin foci using quantitative fluorescence in situ hybridization. Cyclin-dependent kinase inhibitors p21, p15, p16, and the tumor suppressor protein p53, known senescence-related markers, were assessed using immunohistochemical staining.<br><br>RESULTS: Short telomeres were found more often in trophoblasts from the samples of PP (n = 9) compared to controls (n = 8; 54% &#xb1; 20% vs 2.3% &#xb1; 1.16%, respectively; P < .05). More cells with telomere aggregates (18.3% &#xb1; 6.9%) were observed in the PP than in the control group (4.8% &#xb1; 5.4%; P = .0005). The percentage of nucleic senescence-associated heterochromatin foci in the PP and control samples was similar (10.9% &#xb1; 10.4% vs 10.7% &#xb1; 15%, respectively; P = .97). Immunohistochemistry of senescence markers was expressed differently in PP compared to the controls: higher p15 expression (46.42% &#xb1; 15.2% vs 36.63% &#xb1; 12.2%, P = .004), higher p21 expression (59.8% &#xb1; 22.1% vs 47.5% &#xb1; 21.9%, P = .011), lower p16 expression (54.8% &#xb1; 26.3% vs 73.4% &#xb1; 18.9%, P = .000), and lower p53 expression (24.4% &#xb1; 33.8% vs 34% &#xb1; 14.4%, P = .000).<br><br>CONCLUSION: Placenta percreta exhibits telomere alterations and changes in expression of several senescence markers. These might be related to altered trophoblast invasion maturation and placental detachment postpartum.},
}
@article {pmid29107760,
year = {2018},
author = {Rosa, ECCC and Dos Santos, RRC and Fernandes, LFA and Neves, FAR and Coelho, MS and Amato, AA},
title = {Leukocyte telomere length correlates with glucose control in adults with recently diagnosed type 2 diabetes.},
journal = {Diabetes research and clinical practice},
volume = {135},
number = {},
pages = {30-36},
doi = {10.1016/j.diabres.2017.10.020},
pmid = {29107760},
issn = {1872-8227},
mesh = {Cross-Sectional Studies ; Diabetes Mellitus, Type 2/*metabolism ; Female ; Glucose/*metabolism ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Telomere/*metabolism ; },
abstract = {AIMS: We investigated leukocyte relative telomere length (TL) in patients with type 2 diabetes (T2D) diagnosed for no longer than five years and its association with clinical and biochemical variables.<br><br>METHODS: Peripheral blood leukocyte relative TL was investigated in 108 patients with T2D (87 women, 21 men) and 125 (37 women, 88 men) age-matched control subjects with normal glucose tolerance, by quantitative polymerase chain reaction. Multiple linear regression analysis was used to examine the association between relative TL and demographic, anthropometric and biochemical indicators of metabolic control among patients with T2D.<br><br>RESULTS: Patients with T2D had a median time since diagnosis of 1&#x202f;year and most were on metformin monotherapy, with satisfactory glucose control determined by HbA1c levels. Median relative TL was not different between patients with T2D and control subjects. However, multiple linear regression analyses showed that relative TL was inversely associated with time since T2D diagnosis, fasting plasma glucose levels and HbA1c levels, but not with HbA1c levels assessed in the preceding 5-12&#x202f;months, after adjustment for age, sex and body mass index.<br><br>CONCLUSION: This study suggests that relative TL is not shorter in patients with recently diagnosed T2D, but is inversely correlated with glucose levels, even among patients with overall satisfactory glucose control.},
}
@article {pmid29106411,
year = {2017},
author = {Chen, YA and Shen, YL and Hsia, HY and Tiang, YP and Sung, TL and Chen, LY},
title = {Extrachromosomal telomere repeat DNA is linked to ALT development via cGAS-STING DNA sensing pathway.},
journal = {Nature structural &amp; molecular biology},
volume = {24},
number = {12},
pages = {1124-1131},
doi = {10.1038/nsmb.3498},
pmid = {29106411},
issn = {1545-9985},
mesh = {Adaptor Proteins, Signal Transducing/genetics/metabolism ; Cell Line, Tumor ; Cell Proliferation/*physiology ; Co-Repressor Proteins ; DNA/genetics ; Humans ; Interferon Regulatory Factor-3/*metabolism ; Interferon-beta/*biosynthesis ; Membrane Proteins/*metabolism ; Molecular Chaperones ; Neoplasms/genetics/pathology ; Nuclear Proteins/genetics/metabolism ; Nucleotidyltransferases/*metabolism ; Protein Serine-Threonine Kinases/*metabolism ; RNA Interference ; RNA, Small Interfering/genetics ; Signal Transduction/genetics ; Telomere/*genetics ; Telomere Homeostasis/genetics ; X-linked Nuclear Protein/genetics/metabolism ; },
abstract = {Extrachromosomal telomere repeat (ECTR) DNA is unique to cancer cells that maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, but the role of ECTRs in ALT development remains elusive. We found that induction of ECTRs in normal human fibroblasts activated the cGAS-STING-TBK1-IRF3 signaling axis to trigger IFNβ production and a type I interferon response, resulting in cell-proliferation defects. In contrast, ALT cancer cells are commonly defective in sensing cytosolic DNA. We found that STING expression was inhibited in ALT cancer cell lines and transformed ALT cells. Notably, the ALT suppressors histone H3.3 and the ATRX-Daxx histone chaperone complex were also required to activate the DNA-sensing pathway. Collectively, our data suggest that the loss of the cGAS-STING pathway may be required to evade ECTR-induced anti-proliferation effects and permit ALT development, and this requirement may be exploited for treatments specific to cancers utilizing the ALT pathway.},
}
@article {pmid29102816,
year = {2018},
author = {Maurya, PK and Rizzo, LB and Xavier, G and Tempaku, PF and Ota, VK and Santoro, ML and Spíndola, LM and Moretti, PS and Mazzotti, DR and Gadelha, A and Gouvea, ES and Noto, C and Maes, M and Cordeiro, Q and Bressan, RA and Brietzke, E and Belangero, SI},
title = {Leukocyte telomere length variation in different stages of schizophrenia.},
journal = {Journal of psychiatric research},
volume = {96},
number = {},
pages = {218-223},
doi = {10.1016/j.jpsychires.2017.10.016},
pmid = {29102816},
issn = {1879-1379},
mesh = {Acute Disease ; Adult ; Chronic Disease ; Educational Status ; Female ; Humans ; Interview, Psychological ; Leukocytes/*metabolism ; Linear Models ; Male ; Middle Aged ; Polymerase Chain Reaction ; Psychiatric Status Rating Scales ; Schizophrenia/genetics/*metabolism ; Severity of Illness Index ; Smoking/genetics/metabolism ; Telomere/*metabolism ; Telomere Shortening ; Young Adult ; },
abstract = {Recent research has demonstrated that telomere maintenance might be a key integrating point for the cumulative effect of genetic and environmental factors in patients with first-episode psychosis (FEP) and schizophrenia (SCZ). Eighty-one participants with antipsychotic-naïve FEP, 173 with SCZ and 438 HC were enrolled in this study. Psychiatric diagnosis was assessed using the Semi-Structured Clinical Interview for DSM-IV Axis-I (SCID-I). The Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale (YMRS) and Calgary Depression Scale for Schizophrenia (CDSS) were used to measure symptoms severity. Telomere length (TL) was determined using a multiplex qPCR assay. After adjustment for age, years of education, and smoking status, we found that patients with SCZ had longer TL (relative ratio (RR) = 1.08) than the HC group (RR = 1.00, Wald χ[2] = 12.48, p = 0.002). Further, non-remitted SCZ patients presented longer TL (RR = 1.00) compared to remitted SCZ (RR = 0.88, Wald χ[2] = 7.20, p = 0.007). TL in patients also correlated to psychopathology assessment in terms of total (p = 0.003) and positive PANSS scores (p = 0.001). No correlation with negative PANSS, YMRS, and CDSS or effects of medication was found on TL. Although the exact pathways underlying longer TL in SCZ patients remain unclear, these findings raise more questions than answers and suggest that TL may be of immense value on SCZ progression. Further studies are required to investigate the association of TL in FEP and SCZ.},
}
@article {pmid29100249,
year = {2017},
author = {Simoes, HG and Sousa, CV and Dos Santos Rosa, T and da Silva Aguiar, S and Deus, LA and Rosa, ECCC and Amato, AA and Andrade, RV},
title = {Longer Telomere Length in Elite Master Sprinters: Relationship to Performance and Body Composition.},
journal = {International journal of sports medicine},
volume = {38},
number = {14},
pages = {1111-1116},
doi = {10.1055/s-0043-120345},
pmid = {29100249},
issn = {1439-3964},
mesh = {Adult ; *Athletes ; *Athletic Performance ; *Body Composition ; Case-Control Studies ; Humans ; Male ; Middle Aged ; *Running ; Telomere/*ultrastructure ; },
abstract = {Emergent evidence suggests that the long-term healthy lifestyle of master athletes may attenuate aging. We compared telomere length (TL) of high-level master sprinters and non-athlete age-matched controls, and analyzed the relationships of TL with performance and body fat. Elite master sprinters (n=11; aged 50.1±9.2yrs) and healthy untrained controls (n=10; aged 45.4±10.9yrs) had blood samples collected for biochemical and biomolecular analyses. Master sprinters had longer TL, lower body fat and BMI, and a better lipid profile than age-matched controls (p<0.05). A large effect size was verified comparing TL between athletes vs. controls (Cohen's d=1.039), with a significant negative correlation between TL and performance decline per decade (r=-0.624, p<0.01) and a positive correlation of TL and actual performance level (r=0.641, p<0.01). In conclusion, TL of elite master sprinters was longer than their untrained peers, and seems to be not only a marker of health status, but also an indicator of sports longevity since both actual performance level and its decrease over years were related to TL. Further research might assess the TL of elite master endurance athletes for comparison with sprinters, and also investigate the underlying mechanisms by which the attenuation of telomere shortening occurs in master athletes.},
}
@article {pmid29097657,
year = {2017},
author = {Méndez-Pertuz, M and Martínez, P and Blanco-Aparicio, C and Gómez-Casero, E and Belen García, A and Martínez-Torrecuadrada, J and Palafox, M and Cortés, J and Serra, V and Pastor, J and Blasco, MA},
title = {Modulation of telomere protection by the PI3K/AKT pathway.},
journal = {Nature communications},
volume = {8},
number = {1},
pages = {1278},
pmid = {29097657},
issn = {2041-1723},
support = {16-1177/AICR_/Worldwide Cancer Research/United Kingdom ; },
mesh = {Aging/*genetics ; Animals ; Breast Neoplasms/*genetics ; Class I Phosphatidylinositol 3-Kinases ; DNA Damage/drug effects/*genetics ; Humans ; Mice ; Neoplasm Transplantation ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Phosphorylation ; Protein Stability ; Proto-Oncogene Proteins c-akt/*metabolism ; Telomere/drug effects/*genetics ; Telomeric Repeat Binding Protein 1/drug effects/*metabolism ; Thiazoles/pharmacology ; },
abstract = {Telomeres and the insulin/PI3K pathway are considered hallmarks of aging and cancer. Here, we describe a role for PI3K/AKT in the regulation of TRF1, an essential component of the shelterin complex. PI3K and AKT chemical inhibitors reduce TRF1 telomeric foci and lead to increased telomeric DNA damage and fragility. We identify the PI3Kα isoform as responsible for this TRF1 inhibition. TRF1 is phosphorylated at different residues by AKT and these modifications regulate TRF1 protein stability and TRF1 binding to telomeric DNA in vitro and are important for in vivo TRF1 telomere location and cell viability. Patient-derived breast cancer PDX mouse models that effectively respond to a PI3Kα specific inhibitor, BYL719, show decreased TRF1 levels and increased DNA damage. These findings functionally connect two of the major pathways for cancer and aging, telomeres and the PI3K pathway, and pinpoint PI3K and AKT as novel targets for chemical modulation of telomere protection.},
}
@article {pmid29093807,
year = {2017},
author = {Kishtagari, A and Watts, J},
title = {Biological and clinical implications of telomere dysfunction in myeloid malignancies.},
journal = {Therapeutic advances in hematology},
volume = {8},
number = {11},
pages = {317-326},
pmid = {29093807},
issn = {2040-6207},
support = {KL2 TR000461/TR/NCATS NIH HHS/United States ; },
abstract = {Telomeres at the ends of linear chromosomes protect the genome. Telomeres shorten with each round of cell division, placing a finite limit on cell growth. Telomere attrition is associated with cell senescence and apoptosis. Telomerase, a specialized ribonucleoprotein complex, maintains telomeres homeostasis through repeat addition of telomere sequences to the 3' telomeric overhang. Telomere biology is closely related to cancer and normal aging. Upregulation of telomerase or activation of the alternative pathway of telomere lengthening is a hallmark of cancer cells, making telomerase an attractive target for cancer therapeutics. In this review, we will discuss telomere biology and the prognostic implications of telomere length in acute myeloid leukemia, and review exciting new investigational approaches using telomerase inhibitors in acute myeloid leukemia and other myeloid malignancies.},
}
@article {pmid29091397,
year = {2017},
author = {Jeynes, JCG and Geraki, K and Jeynes, C and Zhaohong, M and Bettiol, AA and Latorre, E and Harries, LW and Soeller, C},
title = {Nanoscale Properties of Human Telomeres Measured with a Dual Purpose X-ray Fluorescence and Super Resolution Microscopy Gold Nanoparticle Probe.},
journal = {ACS nano},
volume = {11},
number = {12},
pages = {12632-12640},
pmid = {29091397},
issn = {1936-086X},
support = {//Wellcome Trust/United Kingdom ; WT105618MA//Wellcome Trust/United Kingdom ; },
mesh = {Cells, Cultured ; *Fluorescence ; Fluorescent Dyes/*chemistry ; Gold/*chemistry ; HEK293 Cells ; Humans ; Metal Nanoparticles/*chemistry ; Microscopy, Fluorescence ; Optical Imaging ; Telomere/*chemistry ; X-Rays ; },
abstract = {Techniques to analyze human telomeres are imperative in studying the molecular mechanism of aging and related diseases. Two important aspects of telomeres are their length in DNA base pairs (bps) and their biophysical nanometer dimensions. However, there are currently no techniques that can simultaneously measure these quantities in individual cell nuclei. Here, we develop and evaluate a telomere "dual" gold nanoparticle-fluorescent probe simultaneously compatible with both X-ray fluorescence (XRF) and super resolution microscopy. We used silver enhancement to independently visualize the spatial locations of gold nanoparticles inside the nuclei, comparing to a standard QFISH (quantitative fluorescence in situ hybridization) probe, and showed good specificity at ∼90%. For sensitivity, we calculated telomere length based on a DNA/gold binding ratio using XRF and compared to quantitative polymerase chain reaction (qPCR) measurements. The sensitivity was low (∼10%), probably because of steric interference prohibiting the relatively large 10 nm gold nanoparticles access to DNA space. We then measured the biophysical characteristics of individual telomeres using super resolution microscopy. Telomeres that have an average length of ∼10 kbps, have diameters ranging between ∼60-300 nm. Further, we treated cells with a telomere-shortening drug and showed there was a small but significant difference in telomere diameter in drug-treated vs control cells. We discuss our results in relation to the current debate surrounding telomere compaction.},
}
@article {pmid29088760,
year = {2017},
author = {Wu, Y and Cui, W and Zhang, D and Wu, W and Yang, Z},
title = {The shortening of leukocyte telomere length relates to DNA hypermethylation of LINE-1 in type 2 diabetes mellitus.},
journal = {Oncotarget},
volume = {8},
number = {43},
pages = {73964-73973},
pmid = {29088760},
issn = {1949-2553},
abstract = {BACKGROUND: We aim to investigate the cross-talking of leukocyte telomere length (LTL) and DNA methylation of LINE-1 in type 2 diabetes mellitus (T2DM).<br><br>RESULTS: LTL (ratio of the copy number of telomere [T] repeats to that of a single [S] gene) was significantly shortened in T2DM compared with controls (0.94 &#xb1; 0.41 vs. 1.14 &#xb1; 0.48, P < 0.001), and decreased steadily with age in both controls and T2DM. Conversely, significant increase of LINE-1 DNA methylation was found in T2DM compared with controls (49.60 &#xb1; 14.55 vs. 37.81 &#xb1; 9.07, P < 0.001). Moreover, age, HbA1c, and LINE-1 methylation ratio were stably negatively related with LTL after multi-adjustment. Shorter LTL was associated with an increased risk of T2DM [adjusted OR (95% CI) = 2.458 (1.192, 5.070), P = 0.015], while lower LINE-1 DNA methylation levels could reduce the risk of T2DM [adjusted OR (95% CI) = 0.189 (0.089, 0.400), P < 0.001].<br><br>MATERIALS AND METHODS: We performed a hospital-based case-control study of 205 T2DM patients and 213 subjects of healthy control with sex and age matched. LTL and DNA methylation of LINE-1 was measured by quantitative PCR and quantitative methylation-specific PCR (qMSP), respectively.<br><br>CONCLUSIONS: Our research demonstrates the association between shorter LTL and LINE-1 hyper-methylation in Chinese T2DM patients. These findings suggest that shorter LTL might be associated with T2DM in a manner dependent of epigenetic level.},
}
@article {pmid29085308,
year = {2017},
author = {Wang, R and An, C and Wang, J and Wang, Y and Song, M and Li, N and Chen, Y and Sun, F and Chen, X and Wang, X},
title = {Earthquake Experience at Different Trimesters during Pregnancy Is Associated with Leukocyte Telomere Length and Long-term Health in Adulthood.},
journal = {Frontiers in psychiatry},
volume = {8},
number = {},
pages = {208},
pmid = {29085308},
issn = {1664-0640},
abstract = {Leukocyte telomere length (LTL) is a predictor of age-related diseases, cancer, and even early mortality. Prenatal stress experience has been suggested to associate with short LTL and an increased disease risk in adult life. The present study aimed to evaluate the 39-year effects of prenatal earthquake stress (PES) exposure on LTL and increased age-related disease risk in adulthood. Here, we compared the LTL in the subjects who were exposed to PES to healthy controls (CN) and evaluated whether stress exposure at different times during pregnancy is associated with a shorter LTL and long-term health conditions in adulthood. LTL was measured in 100 adults who experienced the 1976 7.8 Richter scale Tangshan earthquake of the Hebei province in utero and divided them into first, second, and third trimester groups according to the exposure timing during pregnancy. A total of 80 healthy volunteers from Shijiazhuang of the Hebei province were also assessed for their LTL. The telomere-to-single copy gene (T/S) ratio of the PES group (0.78 ± 0.06, p = 0.04) showed a significantly lower LTL than the CN group (0.97 ± 0.08). The results of the LTL analysis indicated that the subjects who experienced PES in the second (0.69 ± 0.09, p = 0.04) or third trimester (0.67 ± 0.76, p = 0.02) showed significantly shorter LTLs compared with those in the first trimester group (0.99 ± 0.12). A fully adjusted regression model indicated the same conclusions. In addition, we found that systolic pressure (SBP; 129.32 ± 14.86 mmHg, p = 0.041), body mass index (BMI; 22.54 ± 2.71, p = 0.046), and low-density lipoprotein (LDL; 3.09 ± 0.98 mmol/L, p = 0.048) in the subjects with PES were significantly higher than those measurements in the CN subjects (SBP; 122.06 ± 10.55 mmHg; BMI; 20.24 ± 2.13; LDL; 2.91 ± 0.76 mmol/L), and there was a significant negative correlation between an increased adult hypertension risk and a shorter LTL.},
}
@article {pmid29083414,
year = {2017},
author = {Pendlebury, DF and Fujiwara, Y and Tesmer, VM and Smith, EM and Shibuya, H and Watanabe, Y and Nandakumar, J},
title = {Dissecting the telomere-inner nuclear membrane interface formed in meiosis.},
journal = {Nature structural &amp; molecular biology},
volume = {24},
number = {12},
pages = {1064-1072},
pmid = {29083414},
issn = {1545-9985},
support = {R00 CA167644/CA/NCI NIH HHS/United States ; R01 AG050509/AG/NIA NIH HHS/United States ; R01 GM120094/GM/NIGMS NIH HHS/United States ; T32 AG000114/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Binding Sites/genetics ; Carrier Proteins/genetics/*metabolism ; Cell Cycle Proteins/genetics/*metabolism ; Chromosome Pairing ; Meiosis/*physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nuclear Envelope/*metabolism ; Phosphorylation ; Protein Binding/physiology ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; rap1 GTP-Binding Proteins/metabolism ; },
abstract = {Tethering telomeres to the inner nuclear membrane (INM) allows homologous chromosome pairing during meiosis. The meiosis-specific protein TERB1 binds the telomeric protein TRF1 to establish telomere-INM connectivity and is essential for mouse fertility. Here we solve the structure of the human TRF1-TERB1 interface to reveal the structural basis for telomere-INM linkage. Disruption of this interface abrogates binding and compromises telomere-INM attachment in mice. An embedded CDK-phosphorylation site within the TRF1-binding region of TERB1 provides a mechanism for cap exchange, a late-pachytene phenomenon involving the dissociation of the TRF1-TERB1 complex. Indeed, further strengthening this interaction interferes with cap exchange. Finally, our biochemical analysis implicates distinct complexes for telomere-INM tethering and chromosome-end protection during meiosis. Our studies unravel the structure, stoichiometry, and physiological implications underlying telomere-INM tethering, thereby providing unprecedented insights into the unique function of telomeres in meiosis.},
}
@article {pmid29069086,
year = {2017},
author = {Maicher, A and Gazy, I and Sharma, S and Marjavaara, L and Grinberg, G and Shemesh, K and Chabes, A and Kupiec, M},
title = {Rnr1, but not Rnr3, facilitates the sustained telomerase-dependent elongation of telomeres.},
journal = {PLoS genetics},
volume = {13},
number = {10},
pages = {e1007082},
pmid = {29069086},
issn = {1553-7404},
mesh = {Cellular Senescence ; DNA Replication ; Ribonucleotide Reductases/*genetics ; Saccharomycetales/cytology/*genetics/growth &amp; development/metabolism ; Telomerase/genetics/*metabolism ; *Telomere ; *Telomere Homeostasis ; },
abstract = {Ribonucleotide reductase (RNR) provides the precursors for the generation of dNTPs, which are required for DNA synthesis and repair. Here, we investigated the function of the major RNR subunits Rnr1 and Rnr3 in telomere elongation in budding yeast. We show that Rnr1 is essential for the sustained elongation of short telomeres by telomerase. In the absence of Rnr1, cells harbor very short, but functional, telomeres, which cannot become elongated by increased telomerase activity or by tethering of telomerase to telomeres. Furthermore, we demonstrate that Rnr1 function is critical to prevent an early onset of replicative senescence and premature survivor formation in telomerase-negative cells but dispensable for telomere elongation by Homology-Directed-Repair. Our results suggest that telomerase has a "basal activity" mode that is sufficient to compensate for the "end-replication-problem" and does not require the presence of Rnr1 and a different "sustained activity" mode necessary for the elongation of short telomeres, which requires an upregulation of dNTP levels and dGTP ratios specifically through Rnr1 function. By analyzing telomere length and dNTP levels in different mutants showing changes in RNR complex composition and activity we provide evidence that the Mec1ATR checkpoint protein promotes telomere elongation by increasing both dNTP levels and dGTP ratios through Rnr1 upregulation in a mechanism that cannot be replaced by its homolog Rnr3.},
}
@article {pmid29067974,
year = {2017},
author = {Bhattacharyya, J and Mihara, K and Bhattacharjee, D and Mukherjee, M},
title = {Telomere length as a potential biomarker of coronary artery disease.},
journal = {The Indian journal of medical research},
volume = {145},
number = {6},
pages = {730-737},
pmid = {29067974},
issn = {0971-5916},
mesh = {*Biomarkers ; Coronary Artery Disease/*genetics/pathology ; Genetic Predisposition to Disease ; Humans ; Risk Factors ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Coronary artery disease (CAD) is a multifactorial disease whose prevalence remains unabated especially in developing countries. Both lifestyle factors and genetic predisposition contribute to this disorder. Though notable achievements have been made in the medical, interventional and surgical management of CAD, the need for its prevention is more important. Among other modalities, this calls for defining evidence-based new biomarkers, which on their own or in combination with other known biomarkers may predict the risk of CAD to enable institution of appropriate preventive strategies. In the present communication, we have discussed the usefulness of shortening of telomeres as a potential biomarker of CAD. Clinical research evidence in favour of telomere shortening in CAD is well documented in different ethnic populations of the world. Establishing a well-standardized and accurate method of evaluating telomere length is essential before its routine use in preventive cardiology.},
}
@article {pmid29067540,
year = {2018},
author = {Murdock, KW and Zilioli, S and Ziauddin, K and Heijnen, CJ and Fagundes, CP},
title = {Attachment and telomere length: more evidence for psychobiological connections between close relationships, health, and aging.},
journal = {Journal of behavioral medicine},
volume = {41},
number = {3},
pages = {333-343},
pmid = {29067540},
issn = {1573-3521},
support = {UL1 RR024153/RR/NCRR NIH HHS/United States ; R01 HL127260/HL/NHLBI NIH HHS/United States ; UL1 RT000005/NH/NIH HHS/United States ; P50 HL065112/HL/NHLBI NIH HHS/United States ; R01 AI066367/AI/NIAID NIH HHS/United States ; R01 AT006694/AT/NCCIH NIH HHS/United States ; F32 HL131353/HL/NHLBI NIH HHS/United States ; R01 AI066367//National Institute of Allergy and Infectious Diseases/International ; 1F32HL131353/HL/NHLBI NIH HHS/United States ; P50 HL065111/HL/NHLBI NIH HHS/United States ; RC1AT005799/AT/NCCIH NIH HHS/United States ; UL1 RR024153/NH/NIH HHS/United States ; },
mesh = {Adult ; Aging/*physiology ; Female ; Humans ; Leukocytes, Mononuclear/metabolism/physiology ; Male ; *Object Attachment ; Respiratory Sinus Arrhythmia/physiology ; Self Report ; Stress, Psychological/*physiopathology ; T-Lymphocyte Subsets/physiology ; Telomere Homeostasis/*physiology ; Young Adult ; },
abstract = {Individuals with a history of poor interpersonal relationships are more likely to demonstrate negative health outcomes than those who have had high quality relationships. We sought to evaluate how attachment orientations, stress-induced respiratory sinus arrhythmia (RSA), and self-reported stress were associated with length of telomeres measured from peripheral blood mononuclear cells. Participants (N = 213) completed self-report measures of attachment and stress. Measurement of RSA was conducted before and after a stressful task and a blood draw was completed for analysis of telomere length. Attachment orientations were not directly associated with telomere length; however, we found that high attachment anxiety was associated with shorter length of telomeres via high self-reported stress. Attachment avoidance was also associated with telomere length via self-reported stress, but only among those with high stress-induced RSA. Exploratory analyses of T cell subsets indicated that stress was most strongly associated with telomeres from CD8CD28+ cells in comparison to CD8CD28- and CD4 cells. Study findings indicate that attachment orientations are associated with telomere length via stress, providing novel insights into the mechanisms through which close relationships can impact health and aging.},
}
@article {pmid29063805,
year = {2018},
author = {Steinbrecher, D and Jebaraj, BMC and Schneider, C and Edelmann, J and Cymbalista, F and Leblond, V and Delmer, A and Ibach, S and Tausch, E and Scheffold, A and Bloehdorn, J and Hallek, M and Dreger, P and Döhner, H and Stilgenbauer, S},
title = {Telomere length in poor-risk chronic lymphocytic leukemia: associations with disease characteristics and outcome.},
journal = {Leukemia &amp; lymphoma},
volume = {59},
number = {7},
pages = {1614-1623},
doi = {10.1080/10428194.2017.1390236},
pmid = {29063805},
issn = {1029-2403},
mesh = {Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use ; Biomarkers, Tumor ; Chromosome Aberrations ; *Genetic Association Studies ; Genomic Instability ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/mortality/*pathology/therapy ; Mutation ; Polymorphism, Single Nucleotide ; Prognosis ; Survival Analysis ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere Shortening ; Treatment Outcome ; },
abstract = {Telomere length in chronic lymphocytic leukemia (CLL) is described as an independent prognostic factor based largely on previously untreated patients from chemotherapy based trials. Here, we studied telomere length associations in high-risk, relapsed/refractory CLL treated with alemtuzumab in the CLL2O study (n = 110) of German and French CLL study groups. Telomere length (median 3.28 kb, range 2.52-7.24 kb) was relatively short, since 84.4% of patients had 17p- which is generally associated with short telomeres. Median telomere length was used for dichotomization into short and long telomere subgroups. Telomere length was associated with s-TK (p = .025) and TP53 mutations (p = .050) in untreated patients, while no association with clinical/biological characteristics was observed in relapsed/refractory CLL. Short telomeres had significant association with shorter PFS (p = .018) only in refractory CLL. Presence of short telomeres, loss of genes maintaining genomic integrity (SMC5) and increased incidence of chromothripsis, indicated the prevalence of genomic instability in this high-risk cohort (clinicaltrials.gov: NCT01392079).},
}
@article {pmid29059467,
year = {2018},
author = {Ko, E and Seo, HW and Jung, G},
title = {Telomere length and reactive oxygen species levels are positively associated with a high risk of mortality and recurrence in hepatocellular carcinoma.},
journal = {Hepatology (Baltimore, Md.)},
volume = {67},
number = {4},
pages = {1378-1391},
doi = {10.1002/hep.29604},
pmid = {29059467},
issn = {1527-3350},
mesh = {Adult ; Animals ; Carcinoma, Hepatocellular/*metabolism/mortality/pathology ; Cell Line, Tumor ; Cell Migration Assays ; Female ; Heterografts ; Humans ; In Situ Hybridization, Fluorescence ; Liver Neoplasms/*metabolism/mortality/pathology ; Male ; Mice ; Mice, Nude ; Middle Aged ; Neoplasm Recurrence, Local ; Reactive Oxygen Species/*metabolism/pharmacology ; Real-Time Polymerase Chain Reaction ; Risk Factors ; Survival Rate ; Telomere/*metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {UNLABELLED: Telomeres protect chromosomal ends from deterioration and have been shown to be susceptible to shortening by reactive oxygen species (ROS)-induced damage. ROS levels increase during the progression from early to advanced hepatocellular carcinoma (HCC). An independent study found that the telomeres in most HCC tissues lengthened during carcinogenic advancement. Activated telomerase has been hypothesized to elongate telomeres during the progression of malignant HCC, but it remains unclear which signaling pathway is necessary for telomerase activation in HCC. Here, we showed using cell lines derived from human HCC that H2 O2 , which is a major component of ROS in living organisms, elongates telomeres by increasing telomerase activity through protein kinase B (AKT) activation. The AKT inhibitor, perifosine, decreased telomere length, cellular viability, and H2 O2 -mediated migration and invasion capacity in HCC cells while also inhibiting AKT activation, telomere maintenance, and tumor growth in nude mice. Advanced HCC tissues showed a positive correlation among ROS levels, phosphorylated AKT (pAKT) levels, and telomere length. Furthermore, patients with HCC tumors that have high ROS levels and long telomeres displayed poorer survival rates. These data demonstrate the significant utilities of ROS levels, pAKT levels, and telomere length for predicting a poor prognosis in patients with HCC. Taken together, AKT activation could be essential for telomere maintenance in advanced HCC tumors as well as being an important contributor to malignant HCC progression.<br><br>CONCLUSION: We showed that H2 O2 contributes to telomere elongation through AKT activation in advanced HCC, suggesting that an AKT inhibitor such as perifosine may be useful for treating patients with malignant HCC. (Hepatology 2018;67:1378-1391).},
}
@article {pmid29059385,
year = {2018},
author = {Mazzolini, R and Gonzàlez, N and Garcia-Garijo, A and Millanes-Romero, A and Peiró, S and Smith, S and García de Herreros, A and Canudas, S},
title = {Snail1 transcription factor controls telomere transcription and integrity.},
journal = {Nucleic acids research},
volume = {46},
number = {1},
pages = {146-158},
pmid = {29059385},
issn = {1362-4962},
mesh = {Animals ; Cell Line ; Cells, Cultured ; Epithelial-Mesenchymal Transition/genetics ; Gene Expression Profiling/methods ; *Gene Expression Regulation ; Humans ; Mesenchymal Stem Cells/metabolism ; Mice, Knockout ; Neoplastic Stem Cells/metabolism ; RNA, Long Noncoding/genetics ; Snail Family Transcription Factors/*genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/enzymology/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Besides controlling epithelial-to-mesenchymal transition (EMT) and cell invasion, the Snail1 transcriptional factor also provides cells with cancer stem cell features. Since telomere maintenance is essential for stemness, we have examined the control of telomere integrity by Snail1. Fluorescence in situ hybridization (FISH) analysis indicates that Snail1-depleted mouse mesenchymal stem cells (MSC) have both a dramatic increase of telomere alterations and shorter telomeres. Remarkably, Snail1-deficient MSC present higher levels of both telomerase activity and the long non-coding RNA called telomeric repeat-containing RNA (TERRA), an RNA that controls telomere integrity. Accordingly, Snail1 expression downregulates expression of the telomerase gene (TERT) as well as of TERRA 2q, 11q and 18q. TERRA and TERT are transiently downregulated during TGFβ-induced EMT in NMuMG cells, correlating with Snail1 expression. Global transcriptome analysis indicates that ectopic expression of TERRA affects the transcription of some genes induced during EMT, such as fibronectin, whereas that of TERT does not modify those genes. We propose that Snail1 repression of TERRA is required not only for telomere maintenance but also for the expression of a subset of mesenchymal genes.},
}
@article {pmid29052918,
year = {2018},
author = {Yu, EY and Hsu, M and Holloman, WK and Lue, NF},
title = {Contributions of recombination and repair proteins to telomere maintenance in telomerase-positive and negative Ustilago maydis.},
journal = {Molecular microbiology},
volume = {107},
number = {1},
pages = {81-93},
doi = {10.1111/mmi.13866},
pmid = {29052918},
issn = {1365-2958},
mesh = {DNA Repair Enzymes/*metabolism ; DNA Replication/genetics ; DNA-Binding Proteins/metabolism ; Gene Rearrangement/physiology ; Rad51 Recombinase/genetics ; RecQ Helicases/genetics ; Recombination, Genetic/genetics/physiology ; Telomerase/metabolism ; Telomere/metabolism/*physiology ; Ustilago/*genetics/metabolism ; },
abstract = {Homologous recombination and repair factors are known to promote both telomere replication and recombination-based telomere extension. Herein, we address the diverse contributions of several recombination/repair proteins to telomere maintenance in Ustilago maydis, a fungus that bears strong resemblance to mammals with respect to telomere regulation and recombination mechanisms. In telomerase-positive U. maydis, deletion of rad51 and blm separately caused shortened but stably maintained telomeres, whereas deletion of both engendered similar telomere loss, suggesting that the repair proteins help to resolve similar problems in telomere replication. In telomerase-negative cells, the loss of Rad51 or Brh2 caused accelerated senescence and failure to generate survivors on semi-solid medium. However, slow growing survivors can be isolated through continuous liquid culturing, and these survivors exhibit type II-like as well as ALT-like telomere features. In contrast, the trt1Δ blmΔ double mutant gives rise to survivors as readily as the trt1Δ single mutant, and like the single mutant survivors, exhibit almost exclusively type I-like telomere features. In addition, we observed direct physical interactions between Blm and two telomere-binding proteins, which may thus recruit or regulate Blm at telomeres. Our findings provide the basis for further analyzing the interplays between telomerase, telomere replication, and telomere recombination.},
}
@article {pmid29052312,
year = {2018},
author = {Kroupa, M and Polivkova, Z and Rachakonda, S and Schneiderova, M and Vodenkova, S and Buchler, T and Jiraskova, K and Urbanova, M and Vodickova, L and Hemminki, K and Kumar, R and Vodicka, P},
title = {Bleomycin-induced chromosomal damage and shortening of telomeres in peripheral blood lymphocytes of incident cancer patients.},
journal = {Genes, chromosomes &amp; cancer},
volume = {57},
number = {2},
pages = {61-69},
doi = {10.1002/gcc.22508},
pmid = {29052312},
issn = {1098-2264},
mesh = {Adult ; Aged ; Aged, 80 and over ; Bleomycin/*adverse effects/pharmacology ; Breast Neoplasms/genetics/metabolism ; Chromosome Aberrations/drug effects ; Chromosome Disorders/pathology ; Chromosomes/drug effects ; Colorectal Neoplasms/genetics/metabolism ; DNA Breaks, Double-Stranded/*drug effects ; DNA Repair/drug effects ; Female ; Humans ; Lymphocytes ; Male ; Middle Aged ; Pilot Projects ; Telomere/*drug effects/pathology ; },
abstract = {Disruption of genomic integrity due to deficient DNA repair capacity and telomere shortening constitute hallmarks of malignant diseases. Incomplete or deficient repair of DNA double-strand breaks (DSB) is manifested by chromosomal aberrations and their frequency reflects inter-individual differences of response to exposure to mutagenic compounds. In this study, we investigated chromosomal integrity in peripheral blood lymphocytes (PBL) from newly diagnosed cancer patients, including 47 breast (BC) and 44 colorectal cancer (CRC) patients and 90 matched healthy controls. Mutagen sensitivity was evaluated by measuring chromatid breaks (CTAs) induced by bleomycin and supplemented by the chemiluminescent measurement of γ-H2AX phosphorylation in 19 cancer patients (11 BC, 8 CRC). Relative telomere length (RTL) was determined in 22 BC, 32 CRC, and 64 controls. We observed statistically significant increased level of CTAs (P = .03) and increased percentage of aberrant cells (ACs) with CTAs (P = .05) in CRC patients compared with controls after bleomycin treatment. No differences were observed between BC cases and corresponding controls. CRC and BC patients with shorter RTL (below median) exhibited significantly higher amount of ACs (P = .02), CTAs (P = .02), and cells with high frequency of CTAs (≥12 CTAs/PBL; P = .03) after bleomycin treatment. No such associations were observed in healthy controls. γ-H2AX phosphorylation after bleomycin treatment in PBL did not differ between CRC and BC patients. Our results suggest that altered DSB repair measured by sensitivity towards mutagen in PBL occurs particularly in CRC carcinogenesis. Irrespective of cancer type, telomere shortening may be associated with a decreased capacity to repair DSB.},
}
@article {pmid29049439,
year = {2017},
author = {Factor-Litvak, P and Susser, E and Aviv, A},
title = {Environmental Exposures, Telomere Length at Birth, and Disease Susceptibility in Later Life.},
journal = {JAMA pediatrics},
volume = {171},
number = {12},
pages = {1143-1144},
pmid = {29049439},
issn = {2168-6211},
support = {R01 HD071180/HD/NICHD NIH HHS/United States ; },
mesh = {Air Pollution ; *Disease Susceptibility ; Environmental Exposure ; Female ; Humans ; Infant, Newborn ; Pregnancy ; *Telomere ; },
}
@article {pmid29049398,
year = {2017},
author = {Lane-Cordova, AD and Puterman, E and Gunderson, EP and Chan, C and Hou, L and Carnethon, M},
title = {Gravidity is not associated with telomere length in a biracial cohort of middle-aged women: The Coronary Artery Risk Development in Young Adults (CARDIA) study.},
journal = {PloS one},
volume = {12},
number = {10},
pages = {e0186495},
pmid = {29049398},
issn = {1932-6203},
support = {R01 DK090047/DK/NIDDK NIH HHS/United States ; R01 DK106201/DK/NIDDK NIH HHS/United States ; R00 HL109247/HL/NHLBI NIH HHS/United States ; HHSN268201300027C/HL/NHLBI NIH HHS/United States ; HHSN268200900041C/HL/NHLBI NIH HHS/United States ; HHSN268201300029C/HL/NHLBI NIH HHS/United States ; HHSN268201300025C/AG/NIA NIH HHS/United States ; HHSN268201300026C/HL/NHLBI NIH HHS/United States ; K01 DK059944/DK/NIDDK NIH HHS/United States ; HHSN268201300028C/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Cohort Studies ; Coronary Artery Disease/*genetics ; Female ; *Genetic Predisposition to Disease ; *Gravidity ; Humans ; Middle Aged ; *Telomere ; Young Adult ; },
abstract = {OBJECTIVE: Having experienced 2-3 births is associated with reduced mortality versus women with <2 or ≥4 births. The effect of 2-3 births on lifespan may be associated with delayed cellular aging. We hypothesized telomere length, a marker of cellular aging, would be longer in women who had 2-3 pregnancies.<br><br>METHODS: Leukocyte telomere length was measured using quantitative real-time polymerase chain reaction in 620 women in CARDIA at the year 15 and 20 exams, expressed as the ratio of telomere repeat copy number to single-copy gene copy number (T/S). Number of pregnancies at the time of telomere length measurement was obtained (mean age = 41&#xb1;0.1 years, average gravidity = 2.64&#xb1;0.1 pregnancies). Participants were divided into 4 groups by number of pregnancies: 0, 1, 2-3, and &#x2265;4, to test for differences in telomere length by gravidity group.<br><br>RESULTS: The mean and SD for telomere length was 0.98 &#xb1; 0.20 T/S in the whole cohort. There were no differences in mean telomere length between groups; 0.98&#xb1;0.02 T/S in women with 0 pregnancies, 1.01&#xb1;0.02 T/S in women with 1 pregnancy, 0.97&#xb1;0.01 T/S in women with 2-3 pregnancies, and 0.99&#xb1;0.02 T/S in women with &#x2265;4 pregnancies (p = 0.51). We defined high-risk (shorter) telomere length as &#x2264;25th percentile, and low-risk (longer) telomere length as &#x2265;75 percentile. There were no differences in the prevalence of high-risk or low-risk telomere length between gravidity groups.<br><br>CONCLUSIONS: Gravidity was not associated with telomere length in early middle age; the protective association of 2-3 births may act through other mechanisms.},
}
@article {pmid29043637,
year = {2018},
author = {Oshidari, R and Mekhail, K},
title = {Assays to Study Repair of Inducible DNA Double-Strand Breaks at Telomeres.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1672},
number = {},
pages = {375-385},
doi = {10.1007/978-1-4939-7306-4_26},
pmid = {29043637},
issn = {1940-6029},
support = {//CIHR/Canada ; },
mesh = {*DNA Breaks, Double-Stranded ; DNA End-Joining Repair ; *DNA Repair ; DNA, Fungal ; Homologous Recombination ; Humans ; *Telomere/genetics ; Yeasts/genetics/metabolism ; },
abstract = {The ends of linear chromosomes are constituted of repetitive DNA sequences called telomeres. Telomeres, nearby regions called subtelomeres, and their associated factors prevent chromosome erosion over cycles of DNA replication and prevent chromosome ends from being recognized as DNA double-strand breaks (DSBs). This raises the question of how cells repair DSBs that actually occur near chromosome ends. One approach is to edit the genome and engineer cells harboring inducible DSB sites within the subtelomeric region of different chromosome ends. This provides a reductionist and tractable genetic model system in which mechanisms mediating repair can be dissected via genetics, molecular biology, and microscopy tools.},
}
@article {pmid29043636,
year = {2018},
author = {Bonetti, D and Longhese, MP},
title = {Analysis of De Novo Telomere Addition by Southern Blot.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1672},
number = {},
pages = {363-373},
doi = {10.1007/978-1-4939-7306-4_25},
pmid = {29043636},
issn = {1940-6029},
mesh = {*Blotting, Southern/methods ; DNA, Fungal ; Genome, Fungal ; Saccharomyces cerevisiae/genetics/metabolism ; Telomerase ; *Telomere/genetics/metabolism ; },
abstract = {Telomere length is maintained in most eukaryotes by the action of a specialized enzyme, the telomerase. However, the complexity of mechanisms regulating telomeric DNA length as well as the heterogeneity in length of each telomere in a population of cells has made it very difficult to understand how telomerase is regulated in vivo. Here, we describe a method developed in Saccharomyces cerevisiae to monitor the addition of telomeric sequences to a single newly generated telomere in vivo. The primary strain consists of a HO endonuclease cleavage site that is placed directly adjacent to an 81-base-pair stretch of telomeric DNA inserted into the ADH4 locus of chromosome VII. Upon cleavage by HO, the de novo DNA end is rapidly healed by the telomerase enzyme and the analysis of this process allows to gain a mechanistic understanding of how telomerase action is regulated in the cell.},
}
@article {pmid29041881,
year = {2017},
author = {Boytsov, AS and Tkachyeva, NO and Streltsova, IL and Dudinskaya, NE and Akasheva, UD and Plokhova, VE and Strazhesko, DI},
title = {[Age-Related Changes of Heart Rate Variability at Various Insulin Sensitivity and Telomere Length].},
journal = {Kardiologiia},
volume = {57},
number = {7},
pages = {52-60},
doi = {10.18087/cardio.2017.7.10006},
pmid = {29041881},
issn = {0022-9040},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; *Aging/genetics/physiology ; Female ; *Heart Rate ; Humans ; *Insulin Resistance ; Male ; Middle Aged ; Telomere ; *Telomere Homeostasis ; },
abstract = {AIM: To study relationship between age-associated changes of heart rate variability (HRV), telomere length (TL), and lowering of insulin sensitivity (IS).<br><br>MATERIAL AND METHODS: We included in this study 229 individuals aged 23&#x2012;91 years without clinical manifestations of cardiovascular and other somatic diseases. In all participants, we analyzed HRV parameters obtained at 24-hour ECG monitoring (24-h ECG) and 5 minutes ECG recordings in the supine and standing positions. Leukocyte TL was estimated on genomic DNA using real time polymerase chain reaction. Insulin sensitivity was characterized by calculation of &#x41d;&#x41e;&#x41c;&#x410;-IR and Gutt's insulin sensitivity index (ISI).<br><br>RESULTS: Elderly people with short telomeres (.},
}
@article {pmid29040669,
year = {2017},
author = {Necasová, I and Janoušková, E and Klumpler, T and Hofr, C},
title = {Basic domain of telomere guardian TRF2 reduces D-loop unwinding whereas Rap1 restores it.},
journal = {Nucleic acids research},
volume = {45},
number = {21},
pages = {12599},
doi = {10.1093/nar/gkx968},
pmid = {29040669},
issn = {1362-4962},
}
@article {pmid29040594,
year = {2017},
author = {Lu, L and Johnman, C and McGlynn, L and Mackay, DF and Shiels, PG and Pell, JP},
title = {Association between exposure to second-hand smoke and telomere length: cross-sectional study of 1303 non-smokers.},
journal = {International journal of epidemiology},
volume = {46},
number = {6},
pages = {1978-1984},
doi = {10.1093/ije/dyx212},
pmid = {29040594},
issn = {1464-3685},
mesh = {Adult ; Aging/*physiology ; Cross-Sectional Studies ; Environmental Exposure/adverse effects ; Female ; Humans ; Linear Models ; Male ; Middle Aged ; Risk Factors ; Scotland ; Self Report ; Smoking/*epidemiology ; *Telomere Shortening ; Tobacco Smoke Pollution/*adverse effects ; },
abstract = {BACKGROUND: Both active smoking and second-hand smoke (SHS) are important risk factors for many age-related diseases. Active smoking is associated with shortened telomere length. However, whether SHS accelerates telomere attrition with age is uncertain. The aim of this study was to examine the association between SHS exposure and shortening by age of leukocyte telomere length among adult non-smokers.<br><br>METHODS: We undertook a cross-sectional study of the association between self-reported levels of SHS exposure and telomere length shortening per annum on a subgroup of participants from the Scottish Family Health Study. Inclusion was restricted to non-smokers aged &#x2265; 18 years, who had provided self-reported overall usual SHS exposure (total hours per week) and blood samples for telomere analysis. Linear regression models were used to compare the ratio of telomere repeat copy number to single copy gene number (T/S)by age according to SHS exposure.<br><br>RESULTS: Of the 1303 eligible participants, 779 (59.8%) reported no SHS exposure, 495 (38.0%) low exposure (1-19 h per week) and 29 (2.2%) high exposure (&#x2265;20 h per week). In the univariate linear regression analyses, relative T/S ratio declined with increasing age in all exposure groups. Telomere length decreased more rapidly with increasing age among those with high exposure to SHS [adjusted coefficient -0.019, 95% confidence interval (CI) -0.031- -0.007) when compared with both those with no exposure to SHS (adjusted coefficient -0.006, 95% CI -0.008- -0.004) (high vs no SHS: P = 0.010) and those with low exposure to SHS (adjusted coefficient -0.005, 95% CI -0.007- -0.003) (high vs low SHS: P = 0.005).<br><br>CONCLUSIONS: Our findings suggest that high SHS exposure may accelerate normal biological ageing, and support efforts to protect the public from SHS exposure. Further studies on relevant mechanisms should be conducted.},
}
@article {pmid29040510,
year = {2017},
author = {Kurjanowicz, P and Moskovtsev, S and Librach, C},
title = {Genomic fragmentation and extrachromosomal telomeric repeats impact assessment of telomere length in human spermatozoa: quantitative experiments and systematic review.},
journal = {Human reproduction (Oxford, England)},
volume = {32},
number = {11},
pages = {2170-2177},
doi = {10.1093/humrep/dex288},
pmid = {29040510},
issn = {1460-2350},
mesh = {Adult ; *DNA Fragmentation ; Humans ; Male ; Middle Aged ; Semen Analysis ; Spermatozoa/*metabolism ; *Telomere ; },
abstract = {STUDY QUESTION: Can differences in DNA isolation alter assessment of sperm telomere length (spTL) and do they account for conflicting results in the literature on spTL and male fertility?<br><br>SUMMARY ANSWER: DNA isolation methods preferentially include or exclude short, extrachromosomal (EC) telomere-specific sequences that alter spTL measurements, and are responsible for a proportion of the disparity observed between investigations.<br><br>WHAT IS KNOWN ALREADY: The relationship between spTL and male fertility has become an active area of research. The results across investigations, however, have been discordant, generating a need to critically evaluate the existing body of knowledge to guide future investigations.<br><br>STUDY DESIGN, SIZE, DURATION: Quantitative experiments determined the effect of DNA isolation on the integrity of sperm DNA and measures of spTL, while a systematic analysis of the current literature evaluated the effect of DNA isolation and study design on experimental outcomes.<br><br>Two DNA isolation methods were compared: Genomic Tips which isolate 'High Molecular Weight' (HMW) DNA exclusively, and QIAamp&#xae; DNA Mini which isolates 'Total' genomic DNA irrespective of size. DNA quality was assessed via field inversion gel electrophoresis (FIGE) and spTL was measured via terminal restriction fragment analysis. In addition, major databases in medicine, health and the life sciences were subject to a targeted search, and results were independently screened according to defined exclusion/inclusion criterion. Findings from primary articles were analyzed for concordance and study designs were compared across six moderator variables (sample size, participant age, fertility status, semen fraction, telomere population and type of analysis).<br><br>HMW DNA spTL was significantly longer than spTL measured from total DNA (P < 0.01), indicating that Total DNA contained short, EC telomeric repeats that shifted downstream assessment towards shorter spTL. HMW DNA spTL reflected the length of intact, chromosomal telomeres. Major findings on spTL showed the greatest concordance amongst studies that implemented HMW DNA isolation prior to spTL assessment. Studies that utilized Total DNA varied in concordance, but outcomes were similar if (i) a comparative analysis was applied or (ii) a sample size threshold of 81 was achieved for correlative analysis.<br><br>Chromosomal and EC telomeric DNA were distinguished based on outcomes of HMW DNA isolation and size. Further experiments are required to determine the nature and function of these two types of telomeric sequences.<br><br>This study reveals a dramatic impact of upstream DNA processing and study design on measurements of spTL, which accounts for conflicting results in the literature. Future assessments of spTL should incorporate independent detection of chromosomal and EC telomeric DNA and specific experimental planning.<br><br>This study was funded by CReATe Fertility Centre, Toronto, Ontario, Canada. The authors have declared no conflict of interest.<br><br>REGISTRATION NUMBER: N/A.},
}
@article {pmid29035711,
year = {2018},
author = {Mitchell, AM and Kowalsky, JM and Epel, ES and Lin, J and Christian, LM},
title = {Childhood adversity, social support, and telomere length among perinatal women.},
journal = {Psychoneuroendocrinology},
volume = {87},
number = {},
pages = {43-52},
pmid = {29035711},
issn = {1873-3360},
support = {R01 NR013661/NR/NINR NIH HHS/United States ; R21 HD067670/HD/NICHD NIH HHS/United States ; UL1 TR001070/TR/NCATS NIH HHS/United States ; },
mesh = {Adult ; Cellular Senescence/*physiology ; Family ; Female ; Humans ; Income ; Life Change Events ; Parturition/physiology ; Perinatal Care ; Postnatal Care ; Pregnancy/*physiology ; Prenatal Care ; Risk Factors ; Social Class ; Social Support ; Socioeconomic Factors ; Telomere/physiology ; Telomere Homeostasis/*physiology ; Telomere Shortening/physiology ; },
abstract = {Adverse perinatal health outcomes are heightened among women with psychosocial risk factors, including childhood adversity and a lack of social support. Biological aging could be one pathway by which such outcomes occur. However, data examining links between psychosocial factors and indicators of biological aging among perinatal women are limited. The current study examined the associations of childhood socioeconomic status (SES), childhood trauma, and current social support with telomere length in peripheral blood mononuclear cells (PBMCs) in a sample of 81 women assessed in early, mid, and late pregnancy as well as 7-11 weeks postpartum. Childhood SES was defined as perceived childhood social class and parental educational attainment. Measures included the Childhood Trauma Questionnaire, Center for Epidemiologic Studies-Depression Scale, Multidimensional Scale of Perceived Social Support, and average telomere length in PBMCs. Per a linear mixed model, telomere length did not change across pregnancy and postpartum visits; thus, subsequent analyses defined telomere length as the average across all available timepoints. ANCOVAs showed group differences by perceived childhood social class, maternal and paternal educational attainment, and current family social support, with lower values corresponding with shorter telomeres, after adjustment for possible confounds. No effects of childhood trauma or social support from significant others or friends on telomere length were observed. Findings demonstrate that while current SES was not related to telomeres, low childhood SES, independent of current SES, and low family social support were distinct risk factors for cellular aging in women. These data have relevance for understanding potential mechanisms by which early life deprivation of socioeconomic and relationship resources affect maternal health. In turn, this has potential significance for intergenerational transmission of telomere length. The predictive value of markers of biological versus chronological age on birth outcomes warrants investigation.},
}
@article {pmid29035107,
year = {2017},
author = {Needham, BL and Hicken, MT and Govia, IO and Mitchell, C and Abdou, CM},
title = {Maternal Social Disadvantage and Newborn Telomere Length in Archived Dried Blood Spots from the Michigan Neonatal Biobank.},
journal = {Biodemography and social biology},
volume = {63},
number = {3},
pages = {221-235},
doi = {10.1080/19485565.2017.1300520},
pmid = {29035107},
issn = {1948-5573},
mesh = {Adult ; Biological Specimen Banks ; Birth Certificates ; Black People/ethnology/statistics &amp; numerical data ; Female ; Hematologic Tests/methods/statistics &amp; numerical data ; Hispanic or Latino/statistics &amp; numerical data ; Humans ; Infant ; Infant Mortality ; Infant, Newborn ; Male ; Marital Status ; Michigan/ethnology ; Mothers/statistics &amp; numerical data ; Risk Factors ; *Socioeconomic Factors ; Telomere/*classification ; White People/ethnology/statistics &amp; numerical data ; },
abstract = {Telomeres are the protective caps at the ends of eukaryotic chromosomes. Short telomere length is associated with morbidity and mortality among adults and may mark the biological impact of social experiences. Using archived dried blood spots from the Michigan Neonatal Biobank, this study examined markers of maternal social disadvantage (educational attainment, receipt of public assistance, marital status, and race/ethnicity) from linked birth certificates as predictors of telomere length at birth in a sample of 192 singleton neonates born to non-Hispanic black, non-Hispanic white, and Latina mothers aged 20-35 years. Consistent with two recent studies in newborns, but counter to the idea that maternal social disadvantage is associated with shorter offspring telomere length, we found that infants born to black mothers had longer telomeres than those born to white mothers (b = 0.12, SE = 0.06, p = .05). However, black/white differences in newborn telomere length varied by receipt of public assistance. Among newborns whose mothers received WIC and/or Medicaid, there were no significant black/white differences in telomere length (b = 0.09, SE = 0.08, p = .25). In contrast, among those whose mothers did not receive public assistance-just 6 out of 69 infants born to black mothers versus 41 out of 69 infants born to white mothers-we found that babies born to black mothers had longer telomere length than babies born to white mothers (b = 0.37, SE = 0.16, p = .03). The interaction between black race/ethnicity and receipt of public assistance did not reach the conventional threshold for statistical significance (b = -0.22, SE = 0.15, p = .13), suggesting that this finding may be due to chance. No other markers of maternal social disadvantage were related to infant telomere length. Although replication of these results in a larger sample with more infants born to black mothers with relatively high socioeconomic status is needed, this study offers preliminary support for the hypothesis that race/ethnic differences in newborn telomere length depend on social context.},
}
@article {pmid29025896,
year = {2017},
author = {McCaffrey, J and Young, E and Lassahn, K and Sibert, J and Pastor, S and Riethman, H and Xiao, M},
title = {High-throughput single-molecule telomere characterization.},
journal = {Genome research},
volume = {27},
number = {11},
pages = {1904-1915},
pmid = {29025896},
issn = {1549-5469},
support = {R01 CA140652/CA/NCI NIH HHS/United States ; R21 CA177395/CA/NCI NIH HHS/United States ; R21 HG007205/HG/NHGRI NIH HHS/United States ; },
mesh = {CRISPR-Cas Systems ; Cell Line, Tumor ; Chromosome Mapping/*methods ; Deoxyribonuclease I/metabolism ; Humans ; Nanotechnology ; Single Molecule Imaging/*methods ; Telomere/*genetics ; Telomere Shortening ; },
abstract = {We have developed a novel method that enables global subtelomere and haplotype-resolved analysis of telomere lengths at the single-molecule level. An in vitro CRISPR/Cas9 RNA-directed nickase system directs the specific labeling of human (TTAGGG)n DNA tracts in genomes that have also been barcoded using a separate nickase enzyme that recognizes a 7-bp motif genome-wide. High-throughput imaging and analysis of large DNA single molecules from genomes labeled in this fashion using a nanochannel array system permits mapping through subtelomere repeat element (SRE) regions to unique chromosomal DNA while simultaneously measuring the (TTAGGG)n tract length at the end of each large telomere-terminal DNA segment. The methodology also permits subtelomere and haplotype-resolved analyses of SRE organization and variation, providing a window into the population dynamics and potential functions of these complex and structurally variant telomere-adjacent DNA regions. At its current stage of development, the assay can be used to identify and characterize telomere length distributions of 30-35 discrete telomeres simultaneously and accurately. The assay's utility is demonstrated using early versus late passage and senescent human diploid fibroblasts, documenting the anticipated telomere attrition on a global telomere-by-telomere basis as well as identifying subtelomere-specific biases for critically short telomeres. Similarly, we present the first global single-telomere-resolved analyses of two cancer cell lines.},
}
@article {pmid29017469,
year = {2017},
author = {Suzuki, A and Matsumoto, Y and Enokido, M and Shirata, T and Goto, K and Otani, K},
title = {Relationship between interpersonal sensitivity and leukocyte telomere length.},
journal = {BMC medical genetics},
volume = {18},
number = {1},
pages = {112},
pmid = {29017469},
issn = {1471-2350},
mesh = {Adult ; Asian People/genetics ; Cellular Senescence/genetics ; Cross-Sectional Studies ; Depression/genetics ; Female ; Genetic Markers ; Humans ; Leukocytes/*cytology ; Male ; Middle Aged ; Personality/*genetics ; Real-Time Polymerase Chain Reaction ; Risk Factors ; Sequence Analysis, DNA ; Telomere/*ultrastructure ; Telomere Homeostasis ; },
abstract = {BACKGROUND: Telomeres are repetitive DNA sequences located at the ends of chromosomes, and telomere length represents a biological marker for cellular aging. Interpersonal sensitivity, excessive sensitivity to the behavior and feelings of others, is one of the vulnerable factors to depression. In the present study, we examined the effect of interpersonal sensitivity on telomere length in healthy subjects.<br><br>METHODS: The subjects were 159 unrelated healthy Japanese volunteers. Mean age&#xa0;&#xb1;&#xa0;SD (range) of the subjects was 42.3&#xa0;&#xb1;&#xa0;7.8 (30-61) years. Interpersonal sensitivity was assessed by the Japanese version of the Interpersonal Sensitivity Measure (IPSM). Leukocyte telomere length was determined by a quantitative real-time PCR method.<br><br>RESULTS: Higher scores of the total IPSM were significantly (&#x3b2;&#xa0;=&#xa0;-0.163, p&#xa0;=&#xa0;0.038) related to shorter telomere length. In the sub-scale analysis, higher scores of timidity were significantly (&#x3b2;&#xa0;=&#xa0;-0.220, p&#xa0;=&#xa0;0.044) associated with shorter telomere length.<br><br>CONCLUSIONS: The present study suggests that subjects with higher interpersonal sensitivity have shorter leukocyte telomere length, implying that interpersonal sensitivity has an impact on cellular aging.},
}
@article {pmid28993556,
year = {2018},
author = {Hayashi, MT},
title = {Telomere biology in aging and cancer: early history and perspectives.},
journal = {Genes &amp; genetic systems},
volume = {92},
number = {3},
pages = {107-118},
doi = {10.1266/ggs.17-00010},
pmid = {28993556},
issn = {1880-5779},
mesh = {Aging/genetics/*metabolism ; Animals ; Heterochromatin/genetics/metabolism ; Humans ; Neoplasm Proteins/genetics/*metabolism ; Neoplasms/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; },
abstract = {The ends of eukaryotic linear chromosomes are protected from undesired enzymatic activities by a nucleoprotein complex called the telomere. Expanding evidence indicates that telomeres have central functions in human aging and tumorigenesis. While it is undoubtedly important to follow current advances in telomere biology, it is also fruitful to be well informed in seminal historical studies for a comprehensive understanding of telomere biology, and for the anticipation of future directions. With this in mind, I here summarize the early history of telomere biology and current advances in the field, mostly focusing on mammalian studies relevant to aging and cancer.},
}
@article {pmid28993210,
year = {2018},
author = {Stauffer, J and Panda, B and Ilmonen, P},
title = {Telomere length, sibling competition and development of antioxidant defense in wild house mice.},
journal = {Mechanisms of ageing and development},
volume = {169},
number = {},
pages = {45-52},
doi = {10.1016/j.mad.2017.10.002},
pmid = {28993210},
issn = {1872-6216},
mesh = {Aging/*metabolism ; Animals ; Antioxidants/*metabolism ; Female ; Glutathione/metabolism ; Male ; Mice ; *Sex Characteristics ; Stress, Physiological/*physiology ; Superoxide Dismutase/metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {Antioxidants and telomere length are potential biomarkers for individuals' exposure and ability to cope with environmental stressors. However, intraspecific variations in antioxidant alterations due to natural, life cycle related stress, have been rarely estimated. We investigated those changes in wild-derived house mice in a longitudinal study with natural sibling competition as a stressor. Blood was used for telomere length measurements at 8-weeks age and for several selected antioxidants at 8-weeks and 6-months age. Our results show that most of the antioxidants increase during that time, indicating that antioxidant-system continues to develop after early development and sexual maturation. In addition females had higher antioxidant-levels than males. Mice with longer telomeres had also higher superoxide dismutase-activity and more glutathione than mice with shorter telomeres, meaning that long telomeres are associated with better antioxidant defense at maturation and during later life. Sibling competition at early age affected superoxide dismutase-levels at 6-months, but only in females. Females, which were lighter than the average of the litter had low superoxide dismutase -activity in later adulthood, indicating delayed negative effect of sibling competition on antioxidant defense. Our results highlight that sex and developmental stage are crucial in intraspecific comparisons of the antioxidant status and its alterations.},
}
@article {pmid28991250,
year = {2018},
author = {Gaballa, A and Norberg, A and Stikvoort, A and Mattsson, J and Sundberg, B and Uzunel, M and Remberger, M and Uhlin, M},
title = {Assessment of TREC, KREC and telomere length in long-term survivors after allogeneic HSCT: the role of GvHD and graft source and evidence for telomere homeostasis in young recipients.},
journal = {Bone marrow transplantation},
volume = {53},
number = {1},
pages = {69-77},
doi = {10.1038/bmt.2017.216},
pmid = {28991250},
issn = {1476-5365},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Child, Preschool ; Female ; Graft vs Host Disease/*genetics ; Hematopoietic Stem Cell Transplantation/*methods ; Humans ; Infant ; Male ; Middle Aged ; Survivors ; Telomere/*genetics ; Transplantation Conditioning/*methods ; Transplantation, Homologous ; Young Adult ; },
abstract = {Reconstitution of the adaptive immune system following allogeneic hematopoietic stem cell transplantation is crucial for beneficial outcome and is affected by several factors, such as GvHD and graft source. The impact of these factors on immune reconstitution has been thoroughly investigated during the early phase after transplantation. However, little is known about their long-term effect. Similarly, leukocyte telomere length (TL) shortening has been reported shortly after transplantation. Nevertheless, whether TL shortening continues in long-term aspect is still unsettled. Here, we assessed T-cell receptor excision circle (TREC), kappa deleting recombination excision circle (KREC) and leukocyte TL in recipients and donors several years post transplantation (median 17 years). Our analysis showed that, recipients who received bone marrow (BM) as the graft source have higher levels of both TREC and KREC. Also, chronic GvHD affected TREC levels and TL but not KREC levels. Finally, we show that recipient's TL was longer than respective donors in a group of young age recipients with high KREC levels. Our results suggest that BM can be beneficial for long-term adaptive immune recovery. We also present supporting evidence for recipient telomere homeostasis, especially in young age recipients, rather than telomere shortening.},
}
@article {pmid28987319,
year = {2018},
author = {Birch, J and Barnes, PJ and Passos, JF},
title = {Mitochondria, telomeres and cell senescence: Implications for lung ageing and disease.},
journal = {Pharmacology &amp; therapeutics},
volume = {183},
number = {},
pages = {34-49},
doi = {10.1016/j.pharmthera.2017.10.005},
pmid = {28987319},
issn = {1879-016X},
support = {BB/H022384/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MR/L016354/1/MRC_/Medical Research Council/United Kingdom ; BB/K017314/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; *Cellular Senescence ; Humans ; Lung/metabolism ; Lung Diseases/*metabolism ; Mitochondria/*metabolism ; Telomere/*metabolism ; },
abstract = {Cellular senescence, the irreversible loss of replicative capacity in somatic cells, plays a causal role in the development of age-related pathology and in a number of age-related chronic inflammatory diseases. The ageing lung is marked by an increasing number of senescent cells, and evidence is mounting that senescence may directly contribute to a number of age-related respiratory diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Telomere dysfunction and alterations in mitochondrial homeostasis frequently occur in cellular senescence and are important to the development of the often detrimental senescence-associated secretory phenotype (SASP). The roles of telomeres, the mitochondria and cellular senescence in lung ageing and disease are discussed. Therapeutic interventions targeting cellular senescence are considered for delaying or potentially reversing age-related respiratory disease.},
}
@article {pmid28986560,
year = {2017},
author = {Hosokawa, K and MacArthur, BD and Ikushima, YM and Toyama, H and Masuhiro, Y and Hanazawa, S and Suda, T and Arai, F},
title = {The telomere binding protein Pot1 maintains haematopoietic stem cell activity with age.},
journal = {Nature communications},
volume = {8},
number = {1},
pages = {804},
pmid = {28986560},
issn = {2041-1723},
mesh = {Animals ; Cells, Cultured ; Cellular Senescence/genetics ; DNA Damage ; DNA-Binding Proteins/genetics/metabolism/*physiology ; Hematopoietic Stem Cells/metabolism/*physiology ; Humans ; Mice ; Reactive Oxygen Species/metabolism ; Shelterin Complex ; Telomere/metabolism/physiology ; Telomere-Binding Proteins ; },
abstract = {Repeated cell divisions and aging impair stem cell function. However, the mechanisms by which this occurs are not fully understood. Here we show that protection of telomeres 1A (Pot1a), a component of the Shelterin complex that protects telomeres, improves haematopoietic stem cell (HSC) activity during aging. Pot1a is highly expressed in young HSCs, but declines with age. In mouse HSCs, Pot1a knockdown increases DNA damage response (DDR) and inhibits self-renewal. Conversely, Pot1a overexpression or treatment with POT1a protein prevents DDR, maintained self-renewal activity and rejuvenated aged HSCs upon ex vivo culture. Moreover, treatment of HSCs with exogenous Pot1a inhibits the production of reactive oxygen species, suggesting a non-telomeric role for Pot1a in HSC maintenance. Consistent with these results, treatment with exogenous human POT1 protein maintains human HSC activity in culture. Collectively, these results show that Pot1a/POT1 sustains HSC activity and can be used to expand HSC numbers ex vivo.Repeated cell divisions induce DNA damage in haematopoietic stem cells (HSC) and telomeres are sensitive to this damage. Here, the authors show in murine HSCs that the telomere binding protein POT1a inhibited the production of reactive oxygen species, and rejuvenated aged HSCs.},
}
@article {pmid28986519,
year = {2017},
author = {Uno, N and Hiramatsu, K and Uno, K and Komoto, S and Kazuki, Y and Oshimura, M},
title = {CRISPR/Cas9-induced transgene insertion and telomere-associated truncation of a single human chromosome for chromosome engineering in CHO and A9 cells.},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {12739},
pmid = {28986519},
issn = {2045-2322},
mesh = {Animals ; CHO Cells ; CRISPR-Associated Protein 9/*metabolism ; CRISPR-Cas Systems/*genetics ; Cell Line, Tumor ; Chromosomes, Human/*genetics ; Cricetinae ; Cricetulus ; Gene Targeting ; *Genetic Engineering ; Genetic Vectors/metabolism ; Humans ; Melanoma, Experimental/pathology ; Mice ; Mutagenesis, Insertional/*genetics ; Plasmids/genetics ; Telomere ; *Transgenes ; },
abstract = {Chromosome engineering techniques including gene insertion, telomere-associated truncation and microcell-mediated chromosome transfer (MMCT) are powerful tools for generation of humanised model animal, containing megabase-sized genomic fragments. However, these techniques require two cell lines: homologous recombination (HR)-proficient DT40 cells for chromosome modification, and CHO cells for transfer to recipient cells. Here we show an improved technique using a combination of CRISPR/Cas9-induced HR in CHO and mouse A9 cells without DT40 cells following MMCT to recipient cells. Transgene insertion was performed in CHO cells with the insertion of enhanced green fluorescence protein (EGFP) using CRISPR/Cas9 and a circular targeting vector containing two 3 kb HR arms. Telomere-associated truncation was performed in CHO cells using CRISPR/Cas9 and a linearised truncation vector containing a single 7 kb HR arm at the 5' end, a 1 kb artificial telomere at the 3' end. At least 11% and 6% of the targeting efficiency were achieved for transgene insertion and telomere-associated truncation, respectively. The transgene insertion was also confirmed in A9 cells (29%). The modified chromosomes were transferrable to other cells. Thus, this CHO and A9 cell-mediated chromosome engineering using the CRISPR/Cas9 for direct transfer of the modified chromosome is a rapid technique that will facilitate chromosome manipulation.},
}
@article {pmid28984363,
year = {2018},
author = {Olsson, M and Wapstra, E and Friesen, CR},
title = {Evolutionary ecology of telomeres: a review.},
journal = {Annals of the New York Academy of Sciences},
volume = {1422},
number = {1},
pages = {5-28},
doi = {10.1111/nyas.13443},
pmid = {28984363},
issn = {1749-6632},
mesh = {Aging/genetics ; Animals ; Biomarkers ; *Evolution, Molecular ; Humans ; Reproduction/genetics ; Selection, Genetic ; Sex Chromosomes ; Telomerase/metabolism ; *Telomere ; },
abstract = {Telomere-induced selection could take place if telomere-associated disease risk shortens reproductive life span and differently reduces relative fitness among individuals. Some of these diseases first appear before reproductive senescence and could thus influence ongoing selection. We ask whether we can estimate the components of the breeder's equation for telomeres, in which the response to selection (R, by definition "evolution") is the product of ongoing selection (S) and heritability (h[2]). However, telomere inheritance is a conundrum: in quantitative genetics, traits can usually be allocated to categories with relatively high or low heritability, depending on their association with relative fitness. Telomere traits, however, show wide variation in heritability from zero to one, across taxa, gender, ethnicity, age, and disease status. In spite of this, there is divergence in telomere length among populations, supporting past and ongoing telomere evolution. Rates of telomere attrition and elongation vary among taxa with some, but not complete, taxonomic coherence. For example, telomerase is commonly referred to as "restricted to the germ line in mammals," but inbred mice and beavers have telomerase upregulation in somatic tissue, as do many ectotherms. These observations provoke a simplistic understanding of telomere evolutionary biology-clearly much is yet to be discovered.},
}
@article {pmid28982094,
year = {2017},
author = {Lee, JY and Kim, JH and Lee, DC},
title = {Combined Impact of Telomere Length and Mitochondrial DNA Copy Number on Cognitive Function in Community-Dwelling Very Old Adults.},
journal = {Dementia and geriatric cognitive disorders},
volume = {44},
number = {3-4},
pages = {232-243},
doi = {10.1159/000480427},
pmid = {28982094},
issn = {1421-9824},
mesh = {Aged ; Aged, 80 and over ; Cognitive Dysfunction/diagnosis/*genetics ; DNA Copy Number Variations/*genetics ; DNA, Mitochondrial/*genetics ; Female ; Follow-Up Studies ; Humans ; Leukocytes ; Male ; Odds Ratio ; Real-Time Polymerase Chain Reaction ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: This study was conducted to investigate the combined impact of telomere length and mitochondrial DNA (mtDNA) copy number on cognitive function in community-dwelling very old adults.<br><br>METHODS: In total, 186 subjects over 75 years participated in this study. Cognitive function was assessed using the Korean Mini-Mental State Examination, and leukocyte telomere length and mtDNA copy number were measured using real-time polymerase chain reaction methods.<br><br>RESULTS: Both the fourth quartile of telomere length and mtDNA copy number were associated with cognitive dysfunction with an adjusted odds ratio of 0.23 (95% confidence interval (CI), 0.10-0.75) and 0.18 (95% CI, 0.03-0.54), respectively. Participants in the high telomere length/high mtDNA copy number group were more likely to have cognitive dysfunction than participants in the low telomere/low mtDNA copy number group with an adjusted odds ratio of 0.19 (95% CI, 0.07-0.58).<br><br>CONCLUSION: Our results collectively suggest that the combination of telomere length and mtDNA copy number may be useful for monitoring cognitive decline in older adults.},
}
@article {pmid28981872,
year = {2017},
author = {Renault, AL and Mebirouk, N and Cavaciuti, E and Le Gal, D and Lecarpentier, J and d'Enghien, CD and Laugé, A and Dondon, MG and Labbé, M and Lesca, G and Leroux, D and Gladieff, L and Adenis, C and Faivre, L and Gilbert-Dussardier, B and Lortholary, A and Fricker, JP and Dahan, K and Bay, JO and Longy, M and Buecher, B and Janin, N and Zattara, H and Berthet, P and Combès, A and Coupier, I and , and Hall, J and Stoppa-Lyonnet, D and Andrieu, N and Lesueur, F},
title = {Telomere length, ATM mutation status and cancer risk in Ataxia-Telangiectasia families.},
journal = {Carcinogenesis},
volume = {38},
number = {10},
pages = {994-1003},
pmid = {28981872},
issn = {1460-2180},
mesh = {Ataxia Telangiectasia/*complications/genetics ; Ataxia Telangiectasia Mutated Proteins/*genetics ; Breast Neoplasms/genetics ; Female ; Genetic Predisposition to Disease ; Heterozygote ; Humans ; Male ; Middle Aged ; *Mutation ; Neoplasms/*genetics ; Polymorphism, Single Nucleotide ; Telomere/*genetics ; Telomere Shortening/genetics ; bcl-X Protein/genetics ; },
abstract = {Recent studies have linked constitutive telomere length (TL) to aging-related diseases including cancer at different sites. ATM participates in the signaling of telomere erosion, and inherited mutations in ATM have been associated with increased risk of cancer, particularly breast cancer. The goal of this study was to investigate whether carriage of an ATM mutation and TL interplay to modify cancer risk in ataxia-telangiectasia (A-T) families.The study population consisted of 284 heterozygous ATM mutation carriers (HetAT) and 174 non-carriers (non-HetAT) from 103 A-T families. Forty-eight HetAT and 14 non-HetAT individuals had cancer, among them 25 HetAT and 6 non-HetAT were diagnosed after blood sample collection. We measured mean TL using a quantitative PCR assay and genotyped seven single-nucleotide polymorphisms (SNPs) recurrently associated with TL in large population-based studies.HetAT individuals were at increased risk of cancer (OR = 2.3, 95%CI = 1.2-4.4, P = 0.01), and particularly of breast cancer for women (OR = 2.9, 95%CI = 1.2-7.1, P = 0.02), in comparison to their non-HetAT relatives. HetAT individuals had longer telomeres than non-HetAT individuals (P = 0.0008) but TL was not associated with cancer risk, and no significant interaction was observed between ATM mutation status and TL. Furthermore, rs9257445 (ZNF311) was associated with TL in HetAT subjects and rs6060627 (BCL2L1) modified cancer risk in HetAT and non-HetAT women.Our findings suggest that carriage of an ATM mutation impacts on the age-related TL shortening and that TL per se is not related to cancer risk in ATM carriers. TL measurement alone is not a good marker for predicting cancer risk in A-T families.},
}
@article {pmid28981702,
year = {2017},
author = {Necasová, I and Janoušková, E and Klumpler, T and Hofr, C},
title = {Basic domain of telomere guardian TRF2 reduces D-loop unwinding whereas Rap1 restores it.},
journal = {Nucleic acids research},
volume = {45},
number = {21},
pages = {12170-12180},
pmid = {28981702},
issn = {1362-4962},
mesh = {DNA/*chemistry/metabolism ; Humans ; Protein Binding ; Protein Domains ; Shelterin Complex ; Static Electricity ; Telomere/*chemistry/metabolism ; Telomere-Binding Proteins/*metabolism ; Telomeric Repeat Binding Protein 2/*chemistry/*metabolism ; },
abstract = {Telomeric repeat binding factor 2 (TRF2) folds human telomeres into loops to prevent unwanted DNA repair and chromosome end-joining. The N-terminal basic domain of TRF2 (B-domain) protects the telomeric displacement loop (D-loop) from cleavage by endonucleases. Repressor activator protein 1 (Rap1) binds TRF2 and improves telomeric DNA recognition. We found that the B-domain of TRF2 stabilized the D-loop and thus reduced unwinding by BLM and RPA, whereas the formation of the Rap1-TRF2 complex restored DNA unwinding. To understand how the B-domain of TRF2 affects DNA binding and D-loop processing, we analyzed DNA binding of full-length TRF2 and a truncated TRF2 construct lacking the B-domain. We quantified how the B-domain improves TRF2's interaction with DNA via enhanced long-range electrostatic interactions. We developed a structural envelope model of the B-domain bound on DNA. The model revealed that the B-domain is flexible in solution but becomes rigid upon binding to telomeric DNA. We proposed a mechanism for how the B-domain stabilizes the D-loop.},
}
@article {pmid28981470,
year = {2017},
author = {Bellon, M and Nicot, C},
title = {Telomere Dynamics in Immune Senescence and Exhaustion Triggered by Chronic Viral Infection.},
journal = {Viruses},
volume = {9},
number = {10},
pages = {},
pmid = {28981470},
issn = {1999-4915},
support = {R01 CA201309/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; CD8-Positive T-Lymphocytes/*immunology/physiology ; Cell Differentiation ; Cell Proliferation ; *Cellular Senescence ; Chronic Disease ; Herpesvirus 1, Human/immunology ; Herpesvirus 4, Human/immunology ; Herpesvirus 8, Human/immunology ; Humans ; Immunologic Memory ; *Immunosenescence ; Mice ; Telomere/*immunology/pathology ; Telomere Shortening ; Virus Diseases/*immunology/metabolism ; },
abstract = {The progressive loss of immunological memory during aging correlates with a reduced proliferative capacity and shortened telomeres of T cells. Growing evidence suggests that this phenotype is recapitulated during chronic viral infection. The antigenic volume imposed by persistent and latent viruses exposes the immune system to unique challenges that lead to host T-cell exhaustion, characterized by impaired T-cell functions. These dysfunctional memory T cells lack telomerase, the protein capable of extending and stabilizing chromosome ends, imposing constraints on telomere dynamics. A deleterious consequence of this excessive telomere shortening is the premature induction of replicative senescence of viral-specific CD8+ memory T cells. While senescent cells are unable to expand, they can survive for extended periods of time and are more resistant to apoptotic signals. This review takes a closer look at T-cell exhaustion in chronic viruses known to cause human disease: Epstein-Barr virus (EBV), Hepatitis B/C/D virus (HBV/HCV/HDV), human herpesvirus 8 (HHV-8), human immunodeficiency virus (HIV), human T-cell leukemia virus type I (HTLV-I), human papillomavirus (HPV), herpes simplex virus-1/2(HSV-1/2), and Varicella-Zoster virus (VZV). Current literature linking T-cell exhaustion with critical telomere lengths and immune senescence are discussed. The concept that enduring antigen stimulation leads to T-cell exhaustion that favors telomere attrition and a cell fate marked by enhanced T-cell senescence appears to be a common endpoint to chronic viral infections.},
}
@article {pmid28980942,
year = {2017},
author = {Lin, A and Arnold, BF and Mertens, AN and Lin, J and Benjamin-Chung, J and Ali, S and Hubbard, AE and Stewart, CP and Shoab, AK and Rahman, MZ and Hossen, MS and Mutsuddi, P and Famida, SL and Akther, S and Rahman, M and Unicomb, L and Dhabhar, FS and Fernald, LCH and Colford, JM and Luby, SP},
title = {Effects of water, sanitation, handwashing, and nutritional interventions on telomere length among children in a cluster-randomized controlled trial in rural Bangladesh.},
journal = {eLife},
volume = {6},
number = {},
pages = {},
pmid = {28980942},
issn = {2050-084X},
mesh = {Adult ; Bangladesh ; Child Development ; Child, Preschool ; Female ; Geography ; *Hand Disinfection ; Humans ; Infant ; Longitudinal Studies ; Male ; *Nutritional Status ; Random Allocation ; Rural Population ; *Sanitation ; Telomere/*metabolism/*ultrastructure ; *Water Purification ; Young Adult ; },
abstract = {BACKGROUND: Shorter childhood telomere length (TL) and more rapid TL attrition are widely regarded as manifestations of stress. However, the potential effects of health interventions on child TL are unknown. We hypothesized that a water, sanitation, handwashing (WSH), and nutritional intervention would slow TL attrition during the first two years of life.<br><br>METHODS: In a trial in rural Bangladesh, we randomized geographical clusters of pregnant women into individual water treatment, sanitation, handwashing, nutrition, combined WSH, combined nutrition plus WSH (N + WSH), or control arms. We conducted a substudy enrolling children from the control arm and the N + WSH intervention arm. Participants and outcome assessors were not masked; analyses were masked. Relative TL was measured at 1 and 2 years after intervention, and the change in relative TL was reported. Analysis was intention-to-treat.<br><br>RESULTS: Between May 2012 and July 2013, in the overall trial, we randomized 720 geographical clusters of 5551 pregnant women to a control or an intervention arm. In this substudy, after 1 year of intervention, we assessed a total of 662 children (341 intervention and 321 control) and 713 children after 2 years of intervention (383 intervention and 330 control). Children in the intervention arm had significantly shorter relative TL compared with controls after 1 year of intervention (difference &#x2212;163 base pairs (bp), p=0.001). Between years 1 and 2, TL increased in the intervention arm (+76 bp) and decreased in the controls (&#x2212;23 bp) (p=0.050). After 2 years, there was no difference between the arms (p=0.305).<br><br>CONCLUSIONS: Our unexpected finding of increased telomere attrition during the first year of life in the intervention group suggests that rapid telomere attrition during this critical period could reflect the improved growth in the intervention group, rather than accumulated stress.<br><br>FUNDING: Funded by The Bill and Melinda Gates Foundation.<br><br>CLINICAL TRIAL NUMBER: NCT01590095.},
}
@article {pmid28978678,
year = {2017},
author = {Yeates, AJ and Thurston, SW and Li, H and Mulhern, MS and McSorley, EM and Watson, GE and Shamlaye, CF and Strain, JJ and Myers, GJ and Davidson, PW and van Wijngaarden, E and Broberg, K},
title = {PUFA Status and Methylmercury Exposure Are Not Associated with Leukocyte Telomere Length in Mothers or Their Children in the Seychelles Child Development Study.},
journal = {The Journal of nutrition},
volume = {147},
number = {11},
pages = {2018-2024},
pmid = {28978678},
issn = {1541-6100},
support = {P30 ES001247/ES/NIEHS NIH HHS/United States ; R01 ES010219/ES/NIEHS NIH HHS/United States ; TL1 TR000096/TR/NCATS NIH HHS/United States ; UL1 TR002001/TR/NCATS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Animals ; Child Development/*drug effects ; Child, Preschool ; Cohort Studies ; Fatty Acids, Unsaturated/administration &amp; dosage/*blood ; Fishes ; Food Contamination/analysis ; Hair/chemistry ; Humans ; Leukocytes/*drug effects ; Linear Models ; Methylmercury Compounds/*analysis ; Mothers ; Seafood/analysis ; Seychelles ; Telomere/drug effects/*ultrastructure ; Young Adult ; },
abstract = {Background: Leukocyte telomere length (TL) is associated with age-related diseases and early mortality, but there is a lack of data on the determinants of TL in early life. Evidence suggests that dietary intake of marine n-3 (ω-3) polyunsaturated fatty acids (PUFAs) is protective of telomere attrition, yet the effect of methylmercury exposure, also found in fish, on TL is unknown.Objective: The aim of this study was to investigate the associations between prenatal PUFA status, methylmercury exposure, and TL in mothers and children in the SCDS (Seychelles Child Development Study), for whom fish consumption is high.Methods: Blood samples collected from 229 mothers (at 28 wk gestation and delivery) and children (at 5 y of age) in the SCDS first nutrition cohort were analyzed for PUFA concentrations. Prenatal mercury was measured in maternal hair collected at delivery. Postnatal mercury was also measured in children's hair samples with the use of a cumulative metric derived from values obtained at 3-5 y of age. Relative TL was measured in blood obtained from mothers at delivery, in cord blood, and in children at 5 y of age by quantitative polymerase chain reaction. Linear regression models were used to investigate the associations between PUFA status, methylmercury exposure, and TL.Results: Neither prenatal PUFA status or methylmercury exposure was associated with TL of the mother or child or with TL attrition rate. However, a higher prenatal n-6:n-3 PUFA ratio was significantly associated with longer TLs in the mothers (β = 0.001, P = 0.048). Child PUFA status and methylmercury exposure were not associated with child TL. However, higher family Hollingshead socioeconomic status (SES) scores at 9 mo of age were significantly associated with longer TLs in cord blood (β = 0.005, P = 0.03).Conclusions: We found no evidence that PUFA status or methylmercury exposure are determinants of TL in either the mother or child. However, our results support the hypothesis that family SES may be associated with child TL.},
}
@article {pmid28977964,
year = {2017},
author = {Wang, W and Zheng, L and Zhou, N and Li, N and Bulibu, G and Xu, C and Zhang, Y and Tang, Y},
title = {Meta-analysis of associations between telomere length and colorectal cancer survival from observational studies.},
journal = {Oncotarget},
volume = {8},
number = {37},
pages = {62500-62507},
pmid = {28977964},
issn = {1949-2553},
abstract = {BACKGROUND: Telomere length (TL) has been reported to be associated with the risk and survival of several cancers. But it is unclear for the prognostic role of TL in colorectal cancer (CRC).<br><br>MATERIALS AND METHODS: Relevant citations were searched and identified using several major online databases through April 2017 which investigated associations between TL and CRC prognosis. We combined summary estimates using hazard ratios (HRs) with 95% confidence interval (CI), which were pooled using a random-effects model. Overall survival (OS) was set as the primary outcome of interest.<br><br>RESULTS: There are 8 cohort studies encompassing 1622 patients included in the meta-analysis. Pooled estimate indicated that long TL was not significantly associated with patient OS (HR 1.26, 95% CI, 0.76 to 2.08). When we conducted subgroup analyses based on baseline charcteristics, we found that long TL (versus short TL) was significantly associated with poor OS in studies conducted in Europe (n = 4, HR 2.73, 95% CI, 1.65 to 4.52, I[2] = 0), using Southern blot to measure TL (n = 3, HR 2.93, 95% CI, 1.69 to 5.10, I[2] = 0) and patients' age more than 60 years (n = 3, HR 2.65, 95% CI, 1.22 to 5.76, I[2] = 0). We found no significant associations between TL and patient disease-free, recurrence-free or progression-free survival (HR 1.19, 95% CI, 0.45 to 3.15).<br><br>CONCLUSIONS: Current evidence did not provide solid indication that long TL is significantly associated with improved or poor survival for patients with CRC. Further large sample size prospective cohort studies are warranted to determine the true relationship for specific patients.},
}
@article {pmid28973513,
year = {2017},
author = {Sagie, S and Edni, O and Weinberg, J and Toubiana, S and Kozlovski, T and Frostig, T and Katzin, N and Bar-Am, I and Selig, S},
title = {Non-random length distribution of individual telomeres in immunodeficiency, centromeric instability and facial anomalies syndrome, type I.},
journal = {Human molecular genetics},
volume = {26},
number = {21},
pages = {4244-4256},
doi = {10.1093/hmg/ddx313},
pmid = {28973513},
issn = {1460-2083},
mesh = {Abnormalities, Multiple/genetics ; Cell Line ; Centromere/genetics/physiology ; Chromosome Aberrations ; DNA (Cytosine-5-)-Methyltransferases/*genetics/metabolism ; DNA Methylation/genetics ; Face/abnormalities ; Female ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Immunologic Deficiency Syndromes/genetics/metabolism ; Male ; Mutation ; Pedigree ; Primary Immunodeficiency Diseases ; Telomere/*genetics/physiology ; Telomere Shortening/genetics ; DNA Methyltransferase 3B ; },
abstract = {Mutations in the de novo DNA methyltransferase DNMT3B lead to Immunodeficiency, Centromeric Instability and Facial anomalies (ICF) syndrome, type I. This syndrome is characterized, among other hypomethylated genomic loci, by severe subtelomeric hypomethylation that is associated with abnormally short telomere length. While it was demonstrated that the mean telomere length is significantly shorter in ICF type I cells, it is unknown whether all telomeres are equally vulnerable to shortening. To study this question we determined by combined telomere-FISH and spectral karyotyping the relative length of each individual telomere in lymphoblastoid cell lines (LCLs) generated from multiple ICF syndrome patients and control individuals. Here we confirm the short telomere lengths, and demonstrate that telomere length variance in the ICF patient group is much larger than in the control group, suggesting that not all telomeres shorten in a uniform manner. We identified a subgroup of telomeres whose relatively short lengths can distinguish with a high degree of certainty between a control and an ICF metaphase, proposing that in ICF syndrome cells, certain individual telomeres are consistently at greater risk to shorten than others. The majority of these telomeres display high sequence identity at the distal 2 kb of their subtelomeres, suggesting that the attenuation in DNMT3B methylation capacity affects individual telomeres to different degrees based, at least in part, on the adjacent subtelomeric sequence composition.},
}
@article {pmid28972555,
year = {2017},
author = {Kim, H and Ham, S and Jo, M and Lee, GH and Lee, YS and Shin, JH and Lee, Y},
title = {CRISPR-Cas9 Mediated Telomere Removal Leads to Mitochondrial Stress and Protein Aggregation.},
journal = {International journal of molecular sciences},
volume = {18},
number = {10},
pages = {},
pmid = {28972555},
issn = {1422-0067},
mesh = {Aging ; *CRISPR-Cas Systems ; Cell Line ; Gene Deletion ; Humans ; Mitochondria/*genetics/pathology ; Parkinson Disease/*genetics/pathology ; Protein Aggregates ; Protein Aggregation, Pathological/*genetics/pathology ; Telomere/*genetics ; Telomere Shortening ; },
abstract = {Aging is considered the major risk factor for neurodegenerative diseases including Parkinson's disease (PD). Telomere shortening is associated with cellular senescence. In this regard, pharmacological or genetic inhibition of telomerase activity has been used to model cellular aging. Here, we employed CRISPR-Cas9 technology to instantly remove the telomere to induce aging in a neuroblastoma cell line. Expression of both Cas9 and guide RNA targeting telomere repeats ablated the telomere, leading to retardation of cell proliferation. Instant deletion of telomere in SH-SY5Y cells impaired mitochondrial function with diminished mitochondrial respiration and cell viability. Supporting the pathological relevance of cell aging by CRISPR-Cas9 mediated telomere removal, alterations were observed in the levels of PD-associated proteins including PTEN-induced putative kinase 1, peroxisome proliferator-activated receptor γ coactivator 1-α, nuclear respiratory factor 1, parkin, and aminoacyl tRNA synthetase complex interacting multifunctional protein 2. Significantly, α-synuclein expression in the background of telomere removal led to the enhancement of protein aggregation, suggesting positive feed-forward interaction between aging and PD pathogenesis. Collectively, our results demonstrate that CRISPR-Cas9 can be used to efficiently model cellular aging and PD.},
}
@article {pmid28971846,
year = {2017},
author = {Meena, JK and Cerutti, A and Beichler, C and Morita, Y and Bruhn, C and Kumar, M and Kraus, JM and Speicher, MR and Wang, ZQ and Kestler, HA and Fagagna, FDD and Günes, C and Rudolph, KL},
title = {Telomerase abrogates aneuploidy-induced telomere replication stress, senescence and cell depletion.},
journal = {The EMBO journal},
volume = {36},
number = {19},
pages = {2922-2924},
doi = {10.15252/embj.201797470},
pmid = {28971846},
issn = {1460-2075},
support = {P 23284/FWF_/Austrian Science Fund FWF/Austria ; },
abstract = {[Image: see text]},
}
@article {pmid28970831,
year = {2017},
author = {Lustig, A and Liu, HB and Metter, EJ and An, Y and Swaby, MA and Elango, P and Ferrucci, L and Hodes, RJ and Weng, NP},
title = {Telomere Shortening, Inflammatory Cytokines, and Anti-Cytomegalovirus Antibody Follow Distinct Age-Associated Trajectories in Humans.},
journal = {Frontiers in immunology},
volume = {8},
number = {},
pages = {1027},
pmid = {28970831},
issn = {1664-3224},
abstract = {A number of biological parameters have been cited as hallmarks of immune aging. However, it is not clear whether these multiple biological changes are the result of common underlying aging processes and follow correlated trajectories, or whether the patterns of change for multiple parameters vary across individuals and reflect heterogeneity in the aging process. Here, we have studied parameters of immune system aging through longitudinal analysis of telomere length, inflammatory cytokines, and antibody titer to cytomegalovirus (CMV) in 465 subjects ranging in age from 21 to 88 years at the first visit, with an average of 13 years (7-19 years) follow-up. We observed a highly variable rate of change in telomere length of PBMCs with a relatively slow average rate of telomere shortening (-16 bp/year). Similarly, there were significant increases with age in vivo in three inflammation-related cytokines (interferon gamma, IL-6, and IL-10) and in anti-CMV IgG titer, which varied widely across individuals as well. We further observed positive correlative changes among different inflammatory cytokines. However, we did not find significant correlations among the rate of changes in telomere length, inflammatory cytokines, and anti-CMV IgG titers. Our findings thus reveal that age-related trajectories of telomere attrition, elevated circulating inflammatory cytokines, and anti-CMV IgG are independent and that aging individuals do not show a uniform pattern of change in these variables. Immune aging processes are complex and vary across individuals, and the use of multiple biomarkers is essential to evaluation of biological aging of the immune system.},
}
@article {pmid28969871,
year = {2017},
author = {Sobinoff, AP and Pickett, HA},
title = {Alternative Lengthening of Telomeres: DNA Repair Pathways Converge.},
journal = {Trends in genetics : TIG},
volume = {33},
number = {12},
pages = {921-932},
doi = {10.1016/j.tig.2017.09.003},
pmid = {28969871},
issn = {0168-9525},
mesh = {Animals ; DNA Repair/*genetics ; DNA Replication/genetics ; Homologous Recombination/genetics ; Humans ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Telomeres shorten during each cellular division, with cumulative attrition resulting in telomeric damage and replicative senescence. Bypass of replicative senescence precipitates catastrophic telomere shortening or crisis, and is characterized by widespread genomic instability. Activation of a telomere maintenance mechanism (TMM) is necessary to stabilise the genome and establish cellular immortality through the reconstitution of telomere capping function. The alternative lengthening of telomeres (ALT) pathway is a TMM frequently activated in tumors of mesenchymal or neuroepithelial origin. ALT is a homology-directed recombination-dependent replication pathway that utilizes telomeric templates for synthesis; however, its precise protein requirements have remained elusive. Recently, several developments have shed light on the DNA repair pathways that become engaged at ALT telomeres, implicating ALT telomeres as DNA repair hot spots. Here, we review recent discoveries regarding the ALT mechanism, and discuss how DNA repair pathways converge to maintain the length and functional integrity of telomeres in ALT cancers.},
}
@article {pmid28969156,
year = {2017},
author = {Mazumdar, J and Chowdhury, P and Bhattacharya, T and Mondal, BC and Ghosh, U},
title = {Patients with Congenital Limb Anomaly Show Short Telomere, Shutdown of Telomerase and Deregulated Expression of Various Telomere-Associated Proteins in Peripheral Blood Mononuclear Cells-A Case Series.},
journal = {Journal of clinical and diagnostic research : JCDR},
volume = {11},
number = {8},
pages = {GR01-GR06},
pmid = {28969156},
issn = {2249-782X},
abstract = {Congenital limb anomalies are outcome of improper bone formation during embryonic development when cells divide, differentiate with high rate. So, telomerase activity is essential to maintain telomere length for such highly dividing cells. Here, we report four cases of congenital limb anomalies with detailed structures of limbs along with other clinical manifestations of age less than two years. We compared telomere length, expression of telomerase and telomere-associated genes of Peripheral Blood Mononuclear Cells (PBMC) in patient and four age-matched normal individual. Patient-1 was diagnosed with congenital limb hypogenesis ectrodactyly sequence, an autosomal dominant disorder, showing absence of digits and fibula in upper and lower limb respectively. Both mother and grandmother of Patient-1 showed similar hypogenesis of limbs. Patient-2 showed bilateral clenched hand with arthrogryposis, microcephaly and holoprosencephaly. Both Patient-3 and Patient-4 has no radius in upper limb. Additionally, Paient-3 showed right sided orbital Space Occupying Lesion (SOL) and Paranasal Sinuses (PNS) whereas Patient-4 showed fused kidney with fanconi anaemia. Furthermore, all the patients showed shorter telomere length, inactive telomerase and de-regulated expression of telomere-associated proteins in PBMC compared with age-matched control group. So, we can conclude that congenital limb anomalies may be linked with telomeropathy and a study with large number of samples is required to firmly establish such association.},
}
@article {pmid28964829,
year = {2018},
author = {Hares, MC and Vitikainen, EIK and Marshall, HH and Thompson, FJ and Blount, JD and Cant, MA},
title = {Telomere dynamics in wild banded mongooses: Evaluating longitudinal and quasi-longitudinal markers of senescence.},
journal = {Experimental gerontology},
volume = {107},
number = {},
pages = {67-73},
pmid = {28964829},
issn = {1873-6815},
mesh = {Animals ; Biomarkers ; Cellular Senescence/*genetics ; Female ; *Herpestidae ; Leukocytes/*physiology ; Longevity ; Longitudinal Studies ; Male ; Telomerase/metabolism ; Telomere/*physiology ; },
abstract = {Telomere length and the rate of telomere shortening have been suggested as particularly useful physiological biomarkers of the processes involved in senescent decline of somatic and reproductive function. However, longitudinal data on changes in telomere length across the lifespan are difficult to obtain, particularly for long-lived animals. Quasi-longitudinal studies have been proposed as a method to gain insight into telomere dynamics in long-lived species. In this method, minimally replicative cells are used as the baseline telomere length against which telomere length in highly replicative cells (which represent the current state) can be compared. Here we test the assumptions and predictions of the quasi-longitudinal approach using longitudinal telomere data in a wild cooperative mammal, the banded mongoose, Mungos mungo. Contrary to our prediction, telomere length (TL) was longer in leukocytes than in ear cartilage. Longitudinally, the TL of ear cartilage shortened with age, but there was no change in the TL of leukocytes, and we also observed many individuals in which TL increased rather than decreased with age. Leukocyte TL but not cartilage TL was a predictor of total lifespan, while neither predicted post-sampling survival. Our data do not support the hypothesis that cross-tissue comparison in TL can act as a quasi-longitudinal marker of senescence. Rather, our results suggest that telomere dynamics in banded mongooses are more complex than is typically assumed, and that longitudinal studies across whole life spans are required to elucidate the link between telomere dynamics and senescence in natural populations.},
}
@article {pmid28959237,
year = {2017},
author = {Yang, M and Jiang, P and Jin, C and Wang, J},
title = {Longer Telomere Length and its Association with Lower Levels of C-Peptide.},
journal = {Frontiers in endocrinology},
volume = {8},
number = {},
pages = {244},
pmid = {28959237},
issn = {1664-2392},
abstract = {BACKGROUND: Telomeres undergo shortening with each cell division, which could be accelerated by increase obesity and is also related to endocrinology systems. In this study, we aimed to examine the complex association between telomere, C-peptide, and obesity as well as chronic inflammation in a large population-based cross-sectional survey.<br><br>METHODS: We used data from a community-based population study, where around 1,382 participants were recruited and had telomere length measured. The association of telomere length with C-peptide was studied using multiple linear regression models. We also examined if obesity, measured by body mass index (BMI), and inflammation could affect this observed association.<br><br>RESULTS: Around 48% of these participants were men and 52% were women. The average ages were 51.7&#x2009;years old for men and 49.1&#x2009;years old for women. After controlling for age and sex, 1&#x2009;U increase of telomere length was associated with -0.17 (-0.28, -0.06) unit decrease of C-peptide. Additionally controlling for BMI, the association magnitude was decreased to -0.13 (-0.23, -0.04). Further adjusting for inflammation biomarker did not change the effect estimates.<br><br>CONCLUSION: Longer telomere was associated with lower levels of C-peptide. This association could be attenuated by adjusting for obesity.},
}
@article {pmid28957990,
year = {2018},
author = {Wulaningsih, W and Kuh, D and Wong, A and Hardy, R},
title = {Adiposity, Telomere Length, and Telomere Attrition in Midlife: the 1946 British Birth Cohort.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {73},
number = {7},
pages = {966-972},
pmid = {28957990},
issn = {1758-535X},
support = {//Wellcome Trust/United Kingdom ; MC_UU_12019/1/MRC_/Medical Research Council/United Kingdom ; MC_UU_12019/2/MRC_/Medical Research Council/United Kingdom ; 12019/4/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adiposity/*genetics ; Adolescent ; Adult ; Age Factors ; Aged ; Aging/*genetics ; Body Mass Index ; Child ; Cohort Studies ; Cross-Sectional Studies ; Female ; Health Surveys ; Humans ; Leukocytes/pathology ; Longitudinal Studies ; Male ; Middle Aged ; Obesity/genetics/pathology ; Overweight/genetics/pathology ; Risk Factors ; Telomere/*pathology ; Telomere Homeostasis/genetics ; Telomere Shortening/*genetics ; United Kingdom ; Waist Circumference ; },
abstract = {BACKGROUND: Obesity has been linked with shorter telomere length, both of which have been implicated in ageing, but the impact of early life adiposity on telomere length is unclear.<br><br>METHODS: We included 2,479 participants from the MRC National Survey of Health and Development with measurements of body mass index, waist and hip circumference, and leukocyte telomere length (LTL) at age 53, of whom 1,000 had second measurements at ages 60-64. Relative LTL was measured with rt-PCR. Linear regression was performed to investigate associations between adiposity and LTL. Body mass index from childhood through adulthood was used to assess adiposity across the life course.<br><br>RESULTS: We found no cross-sectional associations between adiposity measures and LTL at ages 53 or 60-64. Longitudinally, each unit gain in waist circumference weakly corresponded with a 0.06% (95% CI: -1.31 to 0.10) LTL decrease annually, with association approaching statistical significance (p = 0.09). Being overweight at ages 6 and 15 corresponded to a nonsignificant shorter LTL at age 53 and they were associated with 2.06% (95% CI: 0.05-4.08%) and 4.26% (1.98-6.54%) less LTL attrition in midlife, respectively, compared to those who were not overweight.<br><br>CONCLUSION: There is a weak indication that greater telomere loss was seen with greater concurrent body mass index gain. Adolescent overweight corresponded to shorter telomeres in midlife, albeit weakly, and with less subsequent attrition. Our findings point toward potential pathways which may link adiposity and ageing outcomes.},
}
@article {pmid28954855,
year = {2017},
author = {Wilbourn, RV and Froy, H and McManus, MC and Cheynel, L and Gaillard, JM and Gilot-Fromont, E and Regis, C and Rey, B and Pellerin, M and Lemaître, JF and Nussey, DH},
title = {Age-dependent associations between telomere length and environmental conditions in roe deer.},
journal = {Biology letters},
volume = {13},
number = {9},
pages = {},
pmid = {28954855},
issn = {1744-957X},
support = {BB/H021868/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/L020769/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Birds ; Cross-Sectional Studies ; Deer ; Environment ; *Telomere ; },
abstract = {Telomere length (TL) represents a promising biomarker of overall physiological state and of past environmental experiences, which could help us understand the drivers of life-history variation in natural populations. A growing number of studies in birds suggest that environmental stress or poor environmental conditions are associated with shortened TL, but studies of such relationships in wild mammals are lacking. Here, we compare leucocyte TL from cross-sectional samples collected from two French populations of roe deer which experience different environmental conditions. We found that, as predicted, TL was shorter in the population experiencing poor environmental conditions but that this difference was only significant in older individuals and was independent of sex and body mass. Unexpectedly, the difference was underpinned by a significant increase in TL with age in the population experiencing good environmental conditions, while there was no detectable relationship with age in poor conditions. These results demonstrate both the environmental sensitivity and complexity of telomere dynamics in natural mammal populations, and highlight the importance of longitudinal data to disentangle the within- and among-individual processes that generate them.},
}
@article {pmid28953687,
year = {2017},
author = {Rong, H and He, X and Zhu, L and Zhu, X and Kang, L and Wang, L and He, Y and Yuan, D and Jin, T},
title = {Association between regulator of telomere elongation helicase1 (RTEL1) gene and HAPE risk: A case-control study.},
journal = {Medicine},
volume = {96},
number = {39},
pages = {e8222},
pmid = {28953687},
issn = {1536-5964},
mesh = {Adult ; *Altitude Sickness/epidemiology/genetics ; Case-Control Studies ; China/epidemiology ; DNA Helicases/genetics ; Female ; Genetic Predisposition to Disease ; Humans ; *Hypertension, Pulmonary/epidemiology/genetics ; Male ; Mutation ; Polymorphism, Single Nucleotide ; Protective Factors ; Risk Assessment/methods ; },
abstract = {High altitude pulmonary edema (HAPE) is a paradigm of pulmonary edema. Mutations in regulator of telomere elongation helicase1 (RTEL1) represent an important contributor to risk for pulmonary fibrosis. However, little information is found about the association between RTEL1 and HAPE risk. The present study was undertaken to tentatively explore the potential relation between single-nucleotide polymorphisms (SNPs) in RTEL1 and HAPE risk in Chinese Han population. A total of 265 HAPE patients and 303 healthy controls were included in our case-control study. Four SNPs in RTEL1 were selected and genotyped using the Sequenom MassARRAY method. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by unconditional logistic regression with adjustment for gender and age. All P values were Bonferroni corrected, and statistical significance was set at P < .0025 (.05/20). In allelic model analysis, we found that the allele "G" of rs6089953 and rs6010621 and the allele "A" of rs2297441 were associated with decreased risk of HAPE. In the genetic model analysis, we found that rs6010621, rs6089953, and rs2297441 were relevant to decreased HAPE risk under dominant model (rs6010621: OR = 0.55; 95% CI = 0.39-0.78; P = .001; rs6089953: OR = 0.68; 95% CI = 0.48-0.96; P = .027; rs2297441: OR = 0.63; 95% CI = 0.45-0.89; P = .008, respectively) and additive model (rs6010621: OR = 0.51; 95% CI = 0.46-0.81; P < .001; rs6089953: OR = 0.72; 95% CI = 0.55-0.95; P = .022; rs2297441: OR = 0.73; 95% CI = 0.57-0.95; P = .019, respectively). SNPs rs6010621 remained significant after Bonferroni correction (P < .0025). In addition, haplotype "GG, GT, AT" of rs6089953-rs6010621 were detected significantly associated with HAPE risk (P < .05), haplotype "GG" remained significant after Bonferroni correction (P < .0025). Our findings provide new evidence for the association between SNPs in RTEL1 and a decreased risk HAPE in the Chinese population. The results need further confirmation.},
}
@article {pmid28951768,
year = {2017},
author = {Mazidi, M and Kengne, AP and Vatanparast, H},
title = {Food Security and Leukocyte Telomere Length in Adult Americans.},
journal = {Oxidative medicine and cellular longevity},
volume = {2017},
number = {},
pages = {5427657},
pmid = {28951768},
issn = {1942-0994},
mesh = {Adult ; Cross-Sectional Studies ; Female ; Food Supply/*methods ; Humans ; Leukocytes/*metabolism ; Male ; Telomere/*metabolism ; United States ; },
abstract = {BACKGROUND AND PURPOSE: Leukocyte telomere length (LTL) is a biomarker of biologic age. Whether food security status modulates LTL is still unknown. We investigated the association between food security and LTL in participants of the 1999-2002 US National Health and Nutrition Examination Survey (NHANES).<br><br>METHODS: Analysis of covariance (ANCOVA) was used to evaluate the association between food security categories and LTL controlling for sex, race, and education and accounting for the survey design and sample weights.<br><br>RESULTS: We included 10,888 participants with 5228 (48.0%) being men. They were aged on average 44.1 years. In all, 2362 (21.7%) had less than high school, 2787 (25.6%) had achieved high school, while 5705 (52.5%) had done more than high school. In sex-, race-, and education-adjusted ANCOVA, average LTL (T/S ratio) for participants with high food security versus those with marginal, low, or very low food security was 1.32 versus 1.20 for the age group 25-35 years and 1.26 versus 1.11 for the 35-45 years, (p < 0.001).<br><br>CONCLUSION: The association between food insecurity and LTL shortening in young adults suggest that some of the future effects of food insecurity on chronic disease risk in this population could be mediated by telomere shortening.},
}
@article {pmid28950166,
year = {2017},
author = {Mwasongwe, S and Gao, Y and Griswold, M and Wilson, JG and Aviv, A and Reiner, AP and Raffield, LM},
title = {Leukocyte telomere length and cardiovascular disease in African Americans: The Jackson Heart Study.},
journal = {Atherosclerosis},
volume = {266},
number = {},
pages = {41-47},
pmid = {28950166},
issn = {1879-1484},
support = {R01 HL116446/HL/NHLBI NIH HHS/United States ; HHSN268201300048C/HL/NHLBI NIH HHS/United States ; T32 HL129982/HL/NHLBI NIH HHS/United States ; HHSN268201300049C/HL/NHLBI NIH HHS/United States ; HHSN268201300047C/HL/NHLBI NIH HHS/United States ; HHSN268201300050C/HL/NHLBI NIH HHS/United States ; HHSN268201300046C/HL/NHLBI NIH HHS/United States ; U54 GM115428/GM/NIGMS NIH HHS/United States ; },
mesh = {Black or African American/*genetics ; Aged ; Asymptomatic Diseases ; Cardiovascular Diseases/diagnosis/*ethnology/*genetics/mortality ; Female ; Genetic Markers ; Humans ; Incidence ; Leukocytes/*chemistry ; Linear Models ; Logistic Models ; Male ; Middle Aged ; Mississippi/epidemiology ; Odds Ratio ; Prevalence ; Prognosis ; Proportional Hazards Models ; Prospective Studies ; Risk Factors ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {BACKGROUND AND AIMS: In European descent populations, shorter leukocyte telomere length (LTL) has been associated with subclinical atherosclerosis, cardiovascular disease (CVD), and mortality, while longer LTL has been associated with greater left ventricular hypertrophy. We evaluated the relationship of LTL with subclinical cardiovascular disease indices and incident clinical events and mortality in African Americans (AAs).<br><br>METHODS: Analyses were restricted to 2518 participants of the Jackson Heart Study (JHS) with LTL measured by Southern blot in baseline blood samples.<br><br>RESULTS: Adjusting for established CVD risk factors, longer LTL was significantly associated with lower prevalence of coronary artery calcification (CAC) (odds ratio (OR)&#xa0;=&#xa0;0.810) per 1&#xa0;kb increase in LTL; (95% confidence interval [CI] 0.656, 0.9998), p=0.0498). Longer LTL was also associated with higher ankle brachial index (ABI) (&#x3b2;&#xa0;=&#xa0;0.023; (95% CI 0.004, 0.042), p=0.017) when comparing the highest to the lowest LTL quartile. There were no significant associations between LTL and abdominal aortic calcification, carotid intima-media thickness, or left ventricular mass. After a median follow-up of 9 years, longer LTL was associated with lower risk of incident ischemic stroke (hazard ratio (HR) 0.69 (95% CI 0.48, 0.99), p=0.044) and total mortality (HR 0.81 (95% CI 0.67, 0.97), p=0.026) in age and sex adjusted models, but these associations were no longer significant in fully adjusted models.<br><br>CONCLUSIONS: Among a community-based cohort of AAs, longer LTL was nominally associated with lower odds of CAC and increased ABI, indicative of decreased prevalence of subclinical atherosclerosis and peripheral arterial disease. These findings do not offer strong support for LTL as an independent biomarker of CVD risk in AAs.},
}
@article {pmid28949426,
year = {2018},
author = {Goldman, EA and Eick, GN and Compton, D and Kowal, P and Snodgrass, JJ and Eisenberg, DTA and Sterner, KN},
title = {Evaluating minimally invasive sample collection methods for telomere length measurement.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {30},
number = {1},
pages = {},
pmid = {28949426},
issn = {1520-6300},
support = {001/WHO_/World Health Organization/International ; R01 AG034479/AG/NIA NIH HHS/United States ; R01 AG044917/AG/NIA NIH HHS/United States ; },
mesh = {Blood Chemical Analysis/*methods ; Dried Blood Spot Testing/*methods ; Multiplex Polymerase Chain Reaction/methods ; Saliva/*chemistry ; Specimen Handling/*methods ; Telomere/*physiology ; },
abstract = {OBJECTIVES: Telomere length (TL) is a biomarker of aging and age-related decline. Although venous blood is considered the "gold standard" for TL measurement, its collection is often not feasible or desired in nonclinical settings. Saliva and dried blood spots (DBS) have been used as alternatives when venipuncture cannot be performed. However, it is not known whether these sample types yield TL measurements comparable to those obtained from venous blood. We sought to determine whether different samples from the same individual yield comparable TL measurements.<br><br>METHODS: We extracted DNA from matched buffy coat, saliva (Oragene and Oasis), and DBS (venous and capillary) samples from 40 women aged 18-77 years. We used the monochrome multiplex qPCR (MMQPCR) assay to measure TL in all sample types for each participant and applied quality control measures to retain only high-quality samples for analysis. We then compared TL from buffy coat and saliva to examine how these measurements differ and to test if TL is correlated across sample types.<br><br>RESULTS: TL differed significantly across buffy coat, Oragene saliva, and Oasis saliva samples. TL from buffy coat and Oragene saliva was moderately correlated (&#x3c1;&#x2009;=&#x2009;0.48, P = .002) and the most similar in size. Oasis saliva TL was not correlated with buffy coat or Oragene saliva TL, and was the shortest. DBS DNA yields were inadequate for TL measurement using the MMQPCR assay.<br><br>CONCLUSIONS: Using a matched dataset we demonstrate that sample type significantly influences the TL measurement obtained using the MMQPCR assay.},
}
@article {pmid28944611,
year = {2017},
author = {Derevyanko, A and Whittemore, K and Schneider, RP and Jiménez, V and Bosch, F and Blasco, MA},
title = {Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span.},
journal = {Aging cell},
volume = {16},
number = {6},
pages = {1353-1368},
pmid = {28944611},
issn = {1474-9726},
mesh = {Aging/*genetics/metabolism ; Animals ; Cloning, Molecular ; DNA Damage ; Dependovirus/genetics ; Genetic Therapy/*methods ; Genetic Vectors/genetics ; HEK293 Cells ; Humans ; Mice ; Mice, Inbred C57BL ; Telomere/genetics ; Telomeric Repeat Binding Protein 1/administration &amp; dosage/biosynthesis/*genetics/metabolism ; Transfection ; },
abstract = {The shelterin complex protects telomeres by preventing them from being degraded and recognized as double-strand DNA breaks. TRF1 is an essential component of shelterin, with important roles in telomere protection and telomere replication. We previously showed that TRF1 deficiency in the context of different mouse tissues leads to loss of tissue homeostasis owing to impaired stem cell function. Here, we show that TRF1 levels decrease during organismal aging both in mice and in humans. We further show that increasing TRF1 expression in both adult (1-year-old) and old (2-year-old) mice using gene therapy can delay age-associated pathologies. To this end, we used the nonintegrative adeno-associated serotype 9 vector (AAV9), which transduces the majority of mouse tissues allowing for moderate and transient TRF1 overexpression. AAV9-TRF1 gene therapy significantly prevented age-related decline in neuromuscular function, glucose tolerance, cognitive function, maintenance of subcutaneous fat, and chronic anemia. Interestingly, although AAV9-TRF1 treatment did not significantly affect median telomere length, we found a lower abundance of short telomeres and of telomere-associated DNA damage in some tissues. Together, these findings suggest that rescuing naturally decreased TRF1 levels during mouse aging using AAV9-TRF1 gene therapy results in an improved mouse health span.},
}
@article {pmid28942525,
year = {2017},
author = {Lee, DM and Thomas, CM and Xu, F and Yeoman, RR and Xu, J and Stouffer, RL and Wolf, DP and Zelinski, MB},
title = {Subcutaneous ovarian tissue transplantation in nonhuman primates: duration of endocrine function and normalcy of subsequent offspring as demonstrated by reproductive competence, oocyte production, and telomere length.},
journal = {Journal of assisted reproduction and genetics},
volume = {34},
number = {11},
pages = {1427-1434},
pmid = {28942525},
issn = {1573-7330},
support = {P51 OD011092/OD/NIH HHS/United States ; RL1 HD058293/HD/NICHD NIH HHS/United States ; P51OD011092//National Institutes of Health/ ; PL1 EB008542/EB/NIBIB NIH HHS/United States ; UL1 RR024926/RR/NCRR NIH HHS/United States ; RL1 HD058295/HD/NICHD NIH HHS/United States ; U54 HD18185//National Institutes of Health/ ; UL1 RR024926//National Institutes of Health/ ; U54 HD018185/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Cryopreservation ; Estradiol/blood ; Female ; Fertility Preservation/*methods ; Macaca mulatta/genetics/physiology ; Oocytes/*growth &amp; development ; Ovarian Follicle/growth &amp; development/*transplantation ; Ovary/growth &amp; development/*transplantation ; Ovulation Induction/methods ; Pregnancy ; Progesterone/blood ; Reproduction/genetics/*physiology ; Telomere Homeostasis/genetics ; },
abstract = {PURPOSE: The main purposes of the study were to investigate the endocrine function of ovarian tissue transplanted to heterotopic subcutaneous sites and the reproductive competence and telomere length of a nonhuman primate originating from transplanted tissue.<br><br>METHODS: Ovarian cortex pieces were transplanted into the original rhesus macaques in the arm subcutaneously, in the abdomen next to muscles, or in the kidney. Serum estradiol (E2) and progesterone (P4) concentrations were measured weekly for up to 8&#xa0;years following tissue transplantation. A monkey derived from an oocyte in transplanted ovarian tissue entered time-mated breeding and underwent controlled ovarian stimulation. Pregnancy and offspring were evaluated. Telomere lengths and oocytes obtained following controlled ovarian stimulation were assessed.<br><br>RESULTS: Monkeys with transplants in the arm and abdomen had cyclic E2 of 100&#xa0;pg/ml, while an animal with arm transplants had E2 of 50&#xa0;pg/ml. One monkey with transplants in the abdomen and kidney had ovulatory cycles for 3&#xa0;years. A monkey derived from an oocyte in transplanted tissue conceived and had a normal gestation until intrapartum fetal demise. She conceived again and delivered a healthy offspring at term. Controlled ovarian stimulations of this monkey yielded mature oocytes comparable to controls. Her telomere length was long relative to controls.<br><br>CONCLUSIONS: Heterotopic ovarian tissue transplants yielded long-term endocrine function in macaques. A monkey derived from an oocyte in transplanted tissue was reproductively competent. Her telomere length did not show epigenetically induced premature cellular aging. Ovarian tissue transplantation to heterotopic sites for fertility preservation should move forward cautiously, yet optimistically.},
}
@article {pmid28942425,
year = {2017},
author = {Kurzhals, RL and Fanti, L and Ebsen, ACG and Rong, YS and Pimpinelli, S and Golic, KG},
title = {Chromosome Healing Is Promoted by the Telomere Cap Component Hiphop in Drosophila.},
journal = {Genetics},
volume = {207},
number = {3},
pages = {949-959},
pmid = {28942425},
issn = {1943-2631},
support = {P40 OD018537/OD/NIH HHS/United States ; R01 GM065604/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; *Chromosome Breakage ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster ; Female ; Germ Cells/metabolism ; Male ; Telomere/*genetics ; },
abstract = {The addition of a new telomere onto a chromosome break, a process termed healing, has been studied extensively in organisms that utilize telomerase to maintain their telomeres. In comparison, relatively little is known about how new telomeres are constructed on broken chromosomes in organisms that do not use telomerase. Chromosome healing was studied in somatic and germline cells of Drosophila melanogaster, a nontelomerase species. We observed, for the first time, that broken chromosomes can be healed in somatic cells. In addition, overexpression of the telomere cap component Hiphop increased the survival of somatic cells with broken chromosomes, while the cap component HP1 did not, and overexpression of the cap protein HOAP decreased their survival. In the male germline, Hiphop overexpression greatly increased the transmission of healed chromosomes. These results indicate that Hiphop can stimulate healing of a chromosome break. We suggest that this reflects a unique function of Hiphop: it is capable of seeding formation of a new telomeric cap on a chromosome end that lacks a telomere.},
}
@article {pmid28941155,
year = {2017},
author = {Albizua, I and Rambo-Martin, BL and Allen, EG and He, W and Amin, AS and Sherman, SL},
title = {Women who carry a fragile X premutation are biologically older than noncarriers as measured by telomere length.},
journal = {American journal of medical genetics. Part A},
volume = {173},
number = {11},
pages = {2985-2994},
pmid = {28941155},
issn = {1552-4833},
support = {U54 NS091859/NS/NINDS NIH HHS/United States ; },
mesh = {5' Untranslated Regions/genetics ; Adult ; Alleles ; Cellular Senescence/genetics ; DNA Methylation/genetics ; Female ; Fragile X Mental Retardation Protein/*genetics ; Fragile X Syndrome/epidemiology/*genetics/physiopathology ; Humans ; Middle Aged ; Mutation ; Primary Ovarian Insufficiency/epidemiology/*genetics/physiopathology ; Risk Factors ; Telomere/genetics ; Telomere Homeostasis/*genetics ; Young Adult ; },
abstract = {Women who carry a fragile X premutation, defined as having 55-200 unmethylated CGG repeats in the 5' UTR of the X-linked FMR1 gene, have a 20-fold increased risk for primary ovarian insufficiency (FXPOI). We tested the hypothesis that women with a premutation + FXPOI have shorter telomeres than those without FXPOI because they are "biologically older." Using linear regression, we found that women carrying a premutation (n = 172) have shorter telomeres and hence, are "biologically older" than women carrying the normal size allele (n = 81). Strikingly, despite having shorter telomeres, age was not statistically associated with their telomere length, in contrast to non-carrier controls. Further, telomere length within premutation carriers was not associated with repeat length but was associated with a diagnosis of FXPOI, although the latter finding may depend on FXPOI age of onset.},
}
@article {pmid28938175,
year = {2017},
author = {Lucas, T and Pierce, J and Lumley, MA and Granger, DA and Lin, J and Epel, ES},
title = {Telomere length and procedural justice predict stress reactivity responses to unfair outcomes in African Americans.},
journal = {Psychoneuroendocrinology},
volume = {86},
number = {},
pages = {104-109},
doi = {10.1016/j.psyneuen.2017.09.008},
pmid = {28938175},
issn = {1873-3360},
mesh = {Adult ; Black or African American/psychology ; Biomarkers ; Female ; Genetic Testing/*methods ; Humans ; Hydrocortisone/analysis/blood ; Male ; Middle Aged ; Psychology/methods ; Saliva ; Social Justice/psychology ; Stress, Physiological/*physiology ; Stress, Psychological/pathology/*psychology ; Telomere/metabolism ; Telomere Homeostasis/*physiology ; Telomere Shortening/physiology ; },
abstract = {This experiment demonstrates that chromosomal telomere length (TL) moderates response to injustice among African Americans. Based on worldview verification theory - an emerging psychosocial framework for understanding stress - we predicted that acute stress responses would be most pronounced when individual-level expectancies for justice were discordant with justice experiences. Healthy African Americans (N=118; 30% male; M age=31.63years) provided dried blood spot samples that were assayed for TL, and completed a social-evaluative stressor task during which high versus low levels of distributive (outcome) and procedural (decision process) justice were simultaneously manipulated. African Americans with longer telomeres appeared more resilient (in emotional and neuroendocrine response-higher DHEAs:cortisol) to receiving an unfair outcome when a fair decision process was used, whereas African Americans with shorter telomeres appeared more resilient when an unfair decision process was used. TL may indicate personal histories of adversity and associated stress-related expectancies that influence responses to injustice.},
}
@article {pmid28931225,
year = {2017},
author = {Dowd, JB and Bosch, JA and Steptoe, A and Jayabalasingham, B and Lin, J and Yolken, R and Aiello, AE},
title = {Persistent Herpesvirus Infections and Telomere Attrition Over 3 Years in the Whitehall II Cohort.},
journal = {The Journal of infectious diseases},
volume = {216},
number = {5},
pages = {565-572},
pmid = {28931225},
issn = {1537-6613},
support = {R01 AG040115/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Antibody Formation ; Body Mass Index ; *Cellular Senescence ; Cohort Studies ; Cytomegalovirus ; Female ; Follow-Up Studies ; Herpesviridae Infections/*diagnosis ; Herpesvirus 1, Human ; Herpesvirus 4, Human ; Herpesvirus 6, Human ; Humans ; Immunoglobulin G/blood ; Leukocytes/virology ; Male ; Middle Aged ; Multivariate Analysis ; Regression Analysis ; Sensitivity and Specificity ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {The determinants of telomere attrition, a potential marker of cellular aging, are not well understood. Persistent herpesvirus infections including cytomegalovirus (CMV) infection may be particularly important for telomere dynamics via mechanisms such as inflammation, oxidative stress, and their impact on peripheral blood lymphocyte composition. This study examined the association of 4 human herpesviruses (CMV, herpes simplex virus type 1, human herpesvirus type 6, and Epstein-Barr virus) with change in leukocyte telomere length (LTL) over 3 years in 400 healthy individuals (aged 53-76 years) from the Whitehall II cohort. CMV, herpes simplex virus type 1, and human herpesvirus 6 infection were independently associated with greater 3-year LTL attrition, with no association found for Epstein-Barr virus. The magnitudes of these associations were large, for example, the equivalent of almost 12 years of chronological age for those CMV seropositive. Seropositivity to more herpesviruses was additively associated with greater LTL attrition (3 herpesviruses vs none, β = -0.07 and P = .02; 4 infections vs none, β = -0.14 and P < .001). Higher immunoglobulin G antibody levels among those seropositive to CMV were also associated with shorter LTL at follow-up. These associations were robust to adjustment for age, sex, employment grade, body mass index, and smoking status. These results suggest that exposure to infectious agents should be an important consideration in future studies of telomere dynamics.},
}
@article {pmid28930701,
year = {2017},
author = {Chen, BH and Carty, CL and Kimura, M and Kark, JD and Chen, W and Li, S and Zhang, T and Kooperberg, C and Levy, D and Assimes, T and Absher, D and Horvath, S and Reiner, AP and Aviv, A},
title = {Leukocyte telomere length, T cell composition and DNA methylation age.},
journal = {Aging},
volume = {9},
number = {9},
pages = {1983-1995},
pmid = {28930701},
issn = {1945-4589},
support = {HHSN268201300007C/HL/NHLBI NIH HHS/United States ; U34 AG051425/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging/*physiology ; CD8-Positive T-Lymphocytes/*cytology ; DNA Methylation/*physiology ; Female ; Humans ; Leukocytes ; Male ; Middle Aged ; *Telomere ; },
abstract = {Both leukocyte telomere length (LTL) and DNA methylation age are strongly associated with chronological age. One measure of DNA methylation age─ the extrinsic epigenetic age acceleration (EEAA)─ is highly predictive of all-cause mortality. We examined the relation between LTL and EEAA. LTL was measured by Southern blots and leukocyte DNA methylation was determined using Illumina Infinium HumanMethylation450 BeadChip in participants in the Women's Health Initiative (WHI; n=804), the Framingham Heart Study (FHS; n=909) and the Bogalusa Heart study (BHS; n=826). EEAA was computed using 71 DNA methylation sites, further weighted by proportions of naïve CD8[+] T cells, memory CD8[+] T cells, and plasmablasts. Shorter LTL was associated with increased EEAA in participants from the WHI (r=-0.16, p=3.1x10[-6]). This finding was replicated in the FHS (r=-0.09, p=6.5x10[-3]) and the BHS (r=-0.07, p=3.8x 10[-2]). LTL was also inversely related to proportions of memory CD8[+] T cells (p=4.04x10[-16]) and positively related to proportions of naive CD8[+] T cells (p=3.57x10[-14]). These findings suggest that for a given age, an individual whose blood contains comparatively more memory CD8[+] T cells and less naive CD8[+] T cells would display a relatively shorter LTL and an older DNA methylation age, which jointly explain the striking ability of EEAA to predict mortality.},
}
@article {pmid28930601,
year = {2018},
author = {Mueller, C and Aschacher, T and Wolf, B and Bergmann, M},
title = {A role of LINE-1 in telomere regulation.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {23},
number = {7},
pages = {1310-1319},
doi = {10.2741/4645},
pmid = {28930601},
issn = {2768-6698},
mesh = {Animals ; Cell Proliferation/genetics ; Epithelial-Mesenchymal Transition/genetics ; Evolution, Molecular ; *Gene Expression Regulation, Neoplastic ; Humans ; Long Interspersed Nucleotide Elements/*genetics ; Neoplasms/*genetics/pathology ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Long interspersed nuclear elements (LINE-1) are well known as retrotransposons. A number of reports indicate that down-regulation of LINE-1 substantially affects growth of malignant cells and epithelial mesenchymal transition, which is difficult to be explained by its function as retrotransposon. More recent data indicate that LINE-1 is broadly involved in the regulation of telomere maintenance. This explains the essential role of LINE-1 for survival of malignant cells and further supports a global function of active LINE-1 elements in cell proliferation. We further discuss the implications of LINE-1-associated telomere regulation on evolution of telomeric structures, on embryogenesis and on therapy of malignancies.},
}
@article {pmid28928745,
year = {2017},
author = {Jose, SS and Bendickova, K and Kepak, T and Krenova, Z and Fric, J},
title = {Chronic Inflammation in Immune Aging: Role of Pattern Recognition Receptor Crosstalk with the Telomere Complex?.},
journal = {Frontiers in immunology},
volume = {8},
number = {},
pages = {1078},
pmid = {28928745},
issn = {1664-3224},
abstract = {Age-related decline in immunity is characterized by stem cell exhaustion, telomere shortening, and disruption of cell-to-cell communication, leading to increased patient risk of disease. Recent data have demonstrated that chronic inflammation exerts a strong influence on immune aging and is closely correlated with telomere length in a range of major pathologies. The current review discusses the impact of inflammation on immune aging, the likely molecular mediators of this process, and the various disease states that have been linked with immunosenescence. Emerging findings implicate NF-κB, the major driver of inflammatory signaling, in several processes that regulate telomere maintenance and/or telomerase activity. While prolonged triggering of pattern recognition receptors is now known to promote immunosenescence, it remains unclear how this process is linked with the telomere complex or telomerase activity. Indeed, enzymatic control of telomere length has been studied for many decades, but alternative roles of telomerase and potential influences on inflammatory responses are only now beginning to emerge. Crosstalk between these pathways may prove to be a key molecular mechanism of immunosenescence. Understanding how components of immune aging interact and modify host protection against pathogens and tumors will be essential for the design of new vaccines and therapies for a wide range of clinical scenarios.},
}
@article {pmid28927584,
year = {2017},
author = {Casuscelli, J and Hakimi, AA},
title = {Longer Telomere Length and Renal Cell Carcinoma.},
journal = {European urology},
volume = {72},
number = {5},
pages = {755-756},
doi = {10.1016/j.eururo.2017.08.008},
pmid = {28927584},
issn = {1873-7560},
mesh = {Biomarkers, Tumor ; *Carcinoma, Renal Cell ; Humans ; Kidney Neoplasms ; Telomerase ; *Telomere ; },
}
@article {pmid28927529,
year = {2017},
author = {Berardinelli, F and Coluzzi, E and Sgura, A and Antoccia, A},
title = {Targeting telomerase and telomeres to enhance ionizing radiation effects in in vitro and in vivo cancer models.},
journal = {Mutation research. Reviews in mutation research},
volume = {773},
number = {},
pages = {204-219},
doi = {10.1016/j.mrrev.2017.02.004},
pmid = {28927529},
issn = {1388-2139},
mesh = {Aminobenzoates/pharmacology ; Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects/radiation effects ; Disease Models, Animal ; Homeostasis/drug effects/radiation effects ; Humans ; Naphthalenes/pharmacology ; Neoplasms/*drug therapy/*radiotherapy ; Oligonucleotides/pharmacology ; RNA Interference ; *Radiation, Ionizing ; Radiation-Sensitizing Agents/pharmacology ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {One of the hallmarks of cancer consists in the ability of tumor cells to divide indefinitely, and to maintain stable telomere lengths throughout the activation of specific telomere maintenance mechanisms (TMM). Therefore in the last fifteen years, researchers proposed to target telomerase or telomeric structure in order to block limitless replicative potential of cancer cells providing a fascinating strategy for a broad-spectrum cancer therapy. In the present review, we report in vitro and in vivo evidence regarding the use of chemical agents targeting both telomerase or telomere structure and showing promising antitumor effects when used in combination with ionizing radiation (IR). RNA interference, antisense oligonucleotides (e.g., GRN163L), non-nucleoside inhibitors (e.g., BIBR1532) and nucleoside analogs (e.g., AZT) represent some of the most potent strategies to inhibit telomerase activity used in combination with IR. Furthermore, radiosensitizing effects were demonstrated also for agents acting directly on the telomeric structure such as G4-ligands (e.g., RHPS4 and Telomestatin) or telomeric-oligos (T-oligos). To date, some of these compounds are under clinical evaluation (e.g., GRN163L and KML001). Advantages of Telomere/Telomerase Targeting Compounds (T/TTCs) coupled with radiotherapy may be relevant in the treatment of radioresistant tumors and in the development of new optimized treatment plans with reduced dose adsorbed by patients and consequent attenuation of short- end long-term side effects. Pros and cons of possible future applications in cancer therapy based on the combination of T/TCCs and radiation treatment are discussed.},
}
@article {pmid28926727,
year = {2017},
author = {Mirzakhani, H and De Vivo, I and Leeder, JS and Gaedigk, R and Vyhlidal, CA and Weiss, ST and Tantisira, K},
title = {Early pregnancy intrauterine fetal exposure to maternal smoking and impact on fetal telomere length.},
journal = {European journal of obstetrics, gynecology, and reproductive biology},
volume = {218},
number = {},
pages = {27-32},
doi = {10.1016/j.ejogrb.2017.09.013},
pmid = {28926727},
issn = {1872-7654},
mesh = {Case-Control Studies ; Cotinine/analysis ; Female ; Gestational Age ; Humans ; Linear Models ; Lung/*embryology ; Male ; Maternal Exposure/*adverse effects ; Placenta/metabolism ; Pregnancy ; Real-Time Polymerase Chain Reaction ; Smoking/*adverse effects/genetics/metabolism ; *Telomere Shortening ; },
abstract = {BACKGROUND: Reduced telomere length, or its accelerated attrition, has been implicated in aging, mortality, and several human diseases, including respiratory diseases. Age dependent manifestation of telomere-mediated disease during life span indicates the role of developmental stage in these diseases and highlights the importance of fetal developmental process in utero and at earlier life stages. Environmental determinants during developmental and later stages of life could affect telomere length. Smoke exposure as one of these significant determinants have been investigated in association with telomere length in neonates at time of delivery, children and adults.<br><br>OBJECTIVE: We sought to investigate whether intrauterine fetal exposure to tobacco smoking characterized by placenta cotinine levels during early weeks of pregnancy might be associated with shorter relative telomere length (T/S ratio) as compared to fetuses without exposure to tobacco smoking.<br><br>STUDY DESIGN: 207 Human placenta and epithelial lung samples were used for both fetal lung telomere length assessment and measurement of placental cotinine levels. Tissues were obtained from two NICHD-supported tissue retrieval programs with registries for elective abortions, the University of Washington Center for Birth Defects Research (Seattle, WA) and the University of Maryland Brain and Tissue Bank for Developmental Disorders (Baltimore, MD). Cotinine levels (ng/g total placental tissue) were determined in whole cell extracts prepared from human placenta samples to characterize and confirm the cotinine exposure status associated with maternal smoking. Relative telomere length (T/S ratio) in genomic DNA extracted from fetal lung tissue was measured by use of quantitative real-time polymerase chain reaction. Multivariable linear regression was used to investigate the relationship between fetal Telomere-to-Single Copy (T/S) ratio and tobacco exposure.<br><br>RESULTS: The estimated post-conception ages for included samples in the study ranged from 54 to 137days (7-19 weeks of gestation); 47.37% of fetal samples had female sex. Of the samples included in the analysis 96 and 111 fetal samples with and without intrauterine tobacco smoking exposure were distinguished. While T/S ratio was not different between those with and without smoking exposure (1.24&#xb1;0.41 and 1.27&#xb1;0.48, respectively; P=0.70), a significant effect modification of post-conception age on the relationship of intrauterine smoke exposure on fetal T/S ratio was observed (adjusted coefficient=-0.008, 95% CI: -0.016, -0.0004). The smoke exposure status was associated with T/S ratio after 93-day post conception (adjusted coefficient=-0.29, 95% CI: -0.53, -0.052).<br><br>CONCLUSIONS: Our results demonstrate a significant association of smoke exposure in utero at early pregnancy with shortened fetal relative telomere length in the developing lung and suggest that the detrimental effect of smoking exposure on future disease sequelae may start at the early stages of pregnancy.},
}
@article {pmid28921472,
year = {2017},
author = {Wang, L and Yu, X and Liu, JP},
title = {Telomere Damage Response and Low-Grade Inflammation.},
journal = {Advances in experimental medicine and biology},
volume = {1024},
number = {},
pages = {213-224},
doi = {10.1007/978-981-10-5987-2_10},
pmid = {28921472},
issn = {0065-2598},
mesh = {Animals ; Cytokines/genetics/metabolism ; Gene Expression Regulation/immunology/physiology ; Humans ; Inflammation/metabolism/*pathology ; Stem Cells/physiology ; *Telomere ; },
abstract = {Telomeres at the ends of chromosomes safeguard genome integrity and stability in human nucleated cells. However, telomere repeats shed off during cell proliferation and other stress responses. Our recent studies show that telomere attrition induces not only epithelial stem cell senescence but also low-grade inflammation in the lungs. The senescence-associated low-grade inflammation (SALI) is characteristic of alveolar stem cell replicative senescence, increased proinflammatory and anti-inflammatory cytokines, infiltrated immune cells, and spillover effects. To date, the mechanisms underlying SALI remain unclear. Investigations demonstrate that senescent epithelial stem cells with telomere erosion are not the source of secreted cytokines, containing no significant increase in expression of the genes coding for increased cytokines, suggesting an alternative senescence-associated secretory phenotype (A-SASP). Given that telomere loss results in significant alterations in the genomes and accumulations of the cleaved telomeric DNA in the cells and milieu externe, we conclude that telomere position effects (TPEs) on gene expression and damage-associated molecular patterns (DAMPs) in antigen presentation are involved in A-SASP and SALI in response to telomere damage in mammals.},
}
@article {pmid28919432,
year = {2017},
author = {Steward, AM and Morgan, JD and Espinosa, JP and Turk, DC and Patel, KV},
title = {Chronic Pain and Telomere Length in Community-Dwelling Adults: Findings From the 1999 to 2002 National Health and Nutrition Examination Survey.},
journal = {The journal of pain},
volume = {18},
number = {12},
pages = {1517-1525},
doi = {10.1016/j.jpain.2017.08.006},
pmid = {28919432},
issn = {1528-8447},
mesh = {Adult ; Aged ; Aged, 80 and over ; Chronic Pain/*epidemiology/*metabolism ; Female ; Health Surveys/statistics &amp; numerical data ; Humans ; Leukocytes/physiology ; Male ; Middle Aged ; Nutrition Surveys/statistics &amp; numerical data ; Telomere Shortening/*physiology ; United States/epidemiology ; Young Adult ; },
abstract = {UNLABELLED: Chronic pain is a common condition associated with psychological distress, functional impairments, and age-associated comorbidity. Preliminary studies, on the basis of relatively small sample sizes, suggest that the combination of chronic pain and stress is associated with telomere shortening, a widely recognized marker of cellular aging. We sought to determine the cross-sectional association of chronic pain with telomere length in 7,816 community-dwelling adults ages 20 years and older who participated in the 1999 to 2002 National Health and Nutrition Examination Survey. Consistent with previous studies, leukocyte telomere length was assessed using the quantitative polymerase chain reaction method and compared with a DNA reference standard to compute a telomere to single copy gene ratio. Standardized, in-person interviews were used to identify chronic regional pain and chronic widespread pain in 784 (10.0%) and 266 (3.4%) participants, respectively. Older age, male sex, obesity, and less physical activity were associated with shorter telomere length (P <.05 for all comparisons); however, there was no association of chronic pain with telomere length. The age-adjusted means (standard error) of telomere length telomere to single copy gene ratios were 1.04 (.02), 1.03 (.02), and 1.02 (.02) in participants with no chronic pain, chronic regional pain, and chronic widespread pain, respectively (P = .69). In addition, chronic pain did not modify the effects of age, sex, race/ethnicity, education, or psychological distress on telomere length. In summary, chronic regional and widespread pain were not associated with telomere length in this nationally representative study; however, we could not determine associations of pain duration and severity with telomere length because of limitations in pain assessment data.<br><br>PERSPECTIVE: The findings from the current study do not support the hypothesis that chronic pain accelerates cellular aging measured according to leukocyte telomere length. Additional population-based studies with more detailed assessments of pain and stress are needed to further investigate potential interactive effects on telomere length and other biomarkers of aging.},
}
@article {pmid28918867,
year = {2018},
author = {Molina-Molina, M and Planas-Cerezales, L and Perona, R},
title = {Telomere Shortening in Idiopathic Pulmonary Fibrosis.},
journal = {Archivos de bronconeumologia},
volume = {54},
number = {1},
pages = {3-4},
doi = {10.1016/j.arbres.2017.07.026},
pmid = {28918867},
issn = {2173-5751},
mesh = {Aging/physiology ; Humans ; Idiopathic Pulmonary Fibrosis/*etiology ; Telomerase/genetics/*physiology ; *Telomere Shortening ; },
}
@article {pmid28910708,
year = {2017},
author = {van Mierlo, HC and Wichers, CGK and He, Y and Sneeboer, MAM and Radstake, TRDJ and Kahn, RS and Broen, JCA and de Witte, LD},
title = {Telomere quantification in frontal and temporal brain tissue of patients with schizophrenia.},
journal = {Journal of psychiatric research},
volume = {95},
number = {},
pages = {231-234},
doi = {10.1016/j.jpsychires.2017.09.006},
pmid = {28910708},
issn = {1879-1379},
mesh = {Aged ; Aged, 80 and over ; Aging, Premature/*metabolism ; *Cellular Senescence ; Female ; Frontal Lobe/*metabolism ; Gray Matter/*metabolism ; Humans ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Schizophrenia/*metabolism ; Telomere/*metabolism ; Temporal Lobe/*metabolism ; *Tissue Banks ; White Matter/*metabolism ; },
abstract = {Recent imaging studies have suggested that accelerated aging occurs in schizophrenia. However, the exact cause of these findings is still unclear. In this study we measured telomere length, a marker for cell senescence, in gray and white matter brain tissue from the medial frontal gyrus (MFG) and superior temporal gyrus (STG) of 9 patients with schizophrenia and 11 controls. No alterations in telomere length were found in MFG gray and white matter and in STG gray matter. A significant reduction in telomere length was observed in STG white matter of patients with schizophrenia as compared to controls (fold change of -0.42, U = 5, P = 0.008). Our results support previous findings that telomere length in gray matter is not affected, whereas they suggest that increased cell senescence may affect white matter temporal brain tissue.},
}
@article {pmid28904178,
year = {2017},
author = {Criscuolo, F and Zahn, S and Bize, P},
title = {Offspring telomere length in the long lived Alpine swift is negatively related to the age of their biological father and foster mother.},
journal = {Biology letters},
volume = {13},
number = {9},
pages = {},
pmid = {28904178},
issn = {1744-957X},
mesh = {Animals ; Birds ; Fathers ; Female ; Male ; Mothers ; *Telomere ; Telomere Shortening ; },
abstract = {A growing body of studies is showing that offspring telomere length (TL) can be influenced by the age of their parents. Such a relationship might be explained by variation in TL at conception (gamete effect) and/or by alteration of early growth conditions in species providing parental care. In a long-lived bird with bi-parental care, the Alpine swift (Apus melba), we exchanged an uneven number of 2 to 4-day-old nestlings between pairs as part of a brood size manipulation. Nestling TL was measured at 50 days after hatching, which allowed investigation of the influence of the age of both their biological and foster parents on offspring TL, after controlling for the manipulation. Nestling TL was negatively related to the age of their biological father and foster mother. Nestling TL did not differ between enlarged and reduced broods. These findings suggest that offspring from older males were fertilized by gametes with shorter telomeres, presumably due to a greater cell division history or a longer accumulation of damage, and that older females may have provided poorer parental care to their offspring.},
}
@article {pmid28900814,
year = {2018},
author = {Biron-Shental, T and Wiser, A and Hershko-Klement, A and Markovitch, O and Amiel, A and Berkovitch, A},
title = {Sub-fertile sperm cells exemplify telomere dysfunction.},
journal = {Journal of assisted reproduction and genetics},
volume = {35},
number = {1},
pages = {143-148},
pmid = {28900814},
issn = {1573-7330},
mesh = {Adult ; Humans ; Infertility/*pathology/physiopathology ; Male ; RNA/metabolism ; Semen Analysis ; Spermatozoa/pathology/*physiology ; Telomerase/metabolism ; Telomere/*pathology/physiology ; *Telomere Homeostasis ; },
abstract = {PURPOSE: The purpose of this study was to evaluate telomere homeostasis in sub-fertile compared to fertile human sperm.<br><br>METHODS: This observational, comparative study included 16 sub-fertile men who required intracytoplasmic sperm injection and 10 fertile men. At least 100 sperm cells from each participant were assessed. Main outcome measures were telomere length and telomere aggregates. Telomerase RNA component (TERC) copy number and telomere capture were assessed using fluorescence in situ hybridization technique and human telomerase reverse transcriptase (hTERT) using immunohistochemistry.<br><br>RESULTS: Clinical backgrounds were similar. The percentage of sperm cells with shorter telomeres was higher among the sub-fertile compared to the fertile participants (3.3&#xa0;&#xb1;&#xa0;3.1 vs. 0.6&#xa0;&#xb1;&#xa0;1.2%, respectively; P&#xa0;<&#xa0;0.005). The percentage of cells with telomere aggregates was significantly higher in the sub-fertile group (15.12&#xa0;&#xb1;&#xa0;3.73 vs. 4.73&#xa0;&#xb1;&#xa0;3.73%; P&#xa0;<&#xa0;0.005). TERC gene copy number was similar between groups. The percentage of cells that were positive for hTERT was lower in the sub-fertile group (3.81&#xa0;&#xb1;&#xa0;1.27 vs. 8.42&#xa0;&#xb1;&#xa0;1.80%; P&#xa0;<&#xa0;0.005). Telomere capture rates were higher among the sub-fertile sperm cells (P&#xa0;<&#xa0;0.005).<br><br>CONCLUSIONS: Sub-fertile sperm cells have short telomeres that are elongated by the alternative pathway of telomere capture. Dysfunctional telomeres may affect sperm fertilizability.},
}
@article {pmid28900791,
year = {2017},
author = {Stauffer, J and Bruneaux, M and Panda, B and Visse, M and Vasemägi, A and Ilmonen, P},
title = {Telomere length and antioxidant defense associate with parasite-induced retarded growth in wild brown trout.},
journal = {Oecologia},
volume = {185},
number = {3},
pages = {365-374},
pmid = {28900791},
issn = {1432-1939},
mesh = {Animals ; Antioxidants/*metabolism ; Fish Diseases/genetics/*parasitology ; Genetic Predisposition to Disease ; Kidney Diseases ; *Myxozoa ; Parasitic Diseases, Animal/genetics/*immunology ; *Telomere ; Trout/genetics/*parasitology ; },
abstract = {Early growth conditions can have profound impacts on individuals' development, growth and physiology, with subsequent long-term consequences for individuals' fitness and life expectancy. Telomere length (TL) has been suggested to indicate both individual fitness and life expectancy in wide range of species, as the telomere attrition rate at early age can be accelerated due to exposure to various stressors, including parasites and inflammatory diseases, which increase production of reactive oxygen species (ROS) and influence antioxidant (AO) levels. We investigated impacts of Tetracapsuloides bryosalmonae infection, a causative agent of proliferative kidney disease (PKD), on AO status and TL in a natural population of juvenile brown trout (Salmo trutta). The fish with higher parasite load showed more severe kidney hyperplasia, anemia and smaller body size compared to less parasitized fish. Furthermore, fish with severe PKD symptoms had lower SOD-, CAT- and GST activity than fish with milder kidney hyperplasia. However, parasite load was not directly correlated either with AOs or with TL. Smaller fish showed shorter TLs, potentially reflecting lower individual quality. The fish, which were less sensitive to parasite-induced impaired growth, quantified as parasite load-adjusted fork length, showed also longer TLs, lower GR- and GST activity and less GSHtot compared to more sensitive fish. These results provide novel knowledge about the impacts of the PKD in brown trout at the molecular level and support the idea that TL may reflect individual quality and ability to cope with parasitic infections.},
}
@article {pmid28892468,
year = {2017},
author = {Tian, R and Zhang, LN and Zhang, TT and Pang, HY and Chen, LF and Shen, ZJ and Liu, Z and Fang, Q and Zhang, SY},
title = {Association Between Oxidative Stress and Peripheral Leukocyte Telomere Length in Patients with Premature Coronary Artery Disease.},
journal = {Medical science monitor : international medical journal of experimental and clinical research},
volume = {23},
number = {},
pages = {4382-4390},
pmid = {28892468},
issn = {1643-3750},
mesh = {Adult ; Aged ; Asian People/genetics ; Atherosclerosis/genetics/physiopathology ; Biomarkers/blood ; China ; Coronary Artery Disease/*genetics/physiopathology ; Female ; Humans ; Leukocytes/physiology ; Male ; Middle Aged ; Oxidative Stress/*genetics/physiology ; Reactive Oxygen Species/blood/metabolism ; Telomere/genetics/*physiology ; Telomere Homeostasis/genetics/physiology ; },
abstract = {BACKGROUND Leukocyte telomere length (LTL) is regarded as a potential marker of biological aging. Oxidative stress plays a major role in the rate of telomeric DNA loss. The aim of this study was to explore whether the LTL was shorter in Chinese patients with premature coronary artery disease (PCAD) than in non-CAD controls and to determine the relationship between oxidative stress and LTL shortening in this population. MATERIAL AND METHODS Patients for coronary angiography were recruited. In total, 128 patients with PCAD and 128 non-CAD controls were enrolled. Samples of circulating leukocytes and plasma were collected. The mean LTL was measured using a polymerase chain reaction-based assay and expressed as the ratio of telomere repeat copies to single-copy gene (SCG) copies (T/S ratio). Reactive oxygen species (ROS) levels and total antioxidant capacity (T-AOC) were determined in plasma. RESULTS Both the T/S ratio (0.88±0.86 vs. 1.10±0.57, P=0.015) and telomere base pairs (4.97±1.37 kb vs. 5.32±0.91 kb, P=0.015) were significantly shorter in the PCAD group than in non-CAD controls. The T-AOC levels of the PCAD group were significantly lower than those of the non-CAD controls (0.482 mM [0.279, 0.603 mM]) vs. 0.778 mM [0.421, 0.924 mM], P=0.000). The ratio of T-AOC to ROS in the PCAD patients was significantly decreased compared to that of the non-CAD controls (0.1026±0. 1587 [Mm*ml/ng] vs. 0.1435±0.1946 [Mm*ml/ng], P=0.013). CONCLUSIONS The results point to a potential link between reduced LTLs in patients with PCAD and early onset of atherosclerosis. The decline in antioxidant capacity may play an important role in accelerating the attrition of telomeres in PCAD patients.},
}
@article {pmid28890163,
year = {2017},
author = {Tichy, ED and Sidibe, DK and Tierney, MT and Stec, MJ and Sharifi-Sanjani, M and Hosalkar, H and Mubarak, S and Johnson, FB and Sacco, A and Mourkioti, F},
title = {Single Stem Cell Imaging and Analysis Reveals Telomere Length Differences in Diseased Human and Mouse Skeletal Muscles.},
journal = {Stem cell reports},
volume = {9},
number = {4},
pages = {1328-1341},
pmid = {28890163},
issn = {2213-6711},
support = {P30 AR069619/AR/NIAMS NIH HHS/United States ; F31 AR065923/AR/NIAMS NIH HHS/United States ; UL1 TR001442/TR/NCATS NIH HHS/United States ; R01 AR064873/AR/NIAMS NIH HHS/United States ; UL1 TR000100/TR/NCATS NIH HHS/United States ; },
mesh = {Age Factors ; Animals ; Disease Susceptibility ; Female ; Flow Cytometry ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Mice ; *Molecular Imaging ; Muscle Fibers, Skeletal/metabolism/pathology ; Muscle, Skeletal/metabolism/pathology ; Muscular Dystrophy, Duchenne/genetics/metabolism/pathology ; Phenotype ; Reproducibility of Results ; *Single-Cell Analysis ; Stem Cells/*cytology/*metabolism ; *Telomere/genetics/metabolism ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Muscle stem cells (MuSCs) contribute to muscle regeneration following injury. In many muscle disorders, the repeated cycles of damage and repair lead to stem cell dysfunction. While telomere attrition may contribute to aberrant stem cell functions, methods to accurately measure telomere length in stem cells from skeletal muscles have not been demonstrated. Here, we have optimized and validated such a method, named MuQ-FISH, for analyzing telomere length in MuSCs from either mice or humans. Our analysis showed no differences in telomere length between young and aged MuSCs from uninjured wild-type mice, but MuSCs isolated from young dystrophic mice exhibited significantly shortened telomeres. In corroboration, we demonstrated that telomere attrition is present in human dystrophic MuSCs, which underscores its importance in diseased regenerative failure. The robust technique described herein provides analysis at a single-cell resolution and may be utilized for other cell types, especially rare populations of cells.},
}
@article {pmid28889809,
year = {2018},
author = {Schoormans, D and Verhoeven, JE and Denollet, J and van de Poll-Franse, L and Penninx, BWJH},
title = {Leukocyte telomere length and personality: associations with the Big Five and Type D personality traits.},
journal = {Psychological medicine},
volume = {48},
number = {6},
pages = {1008-1019},
pmid = {28889809},
issn = {1469-8978},
mesh = {Adult ; Anxiety Disorders ; Character ; Cooperative Behavior ; Depressive Disorder ; Extraversion, Psychological ; Female ; Humans ; *Leukocytes ; Longitudinal Studies ; Male ; Middle Aged ; Netherlands ; Neuroticism ; Personality/*genetics ; Personality Inventory ; Stress, Psychological/psychology ; *Telomere ; Type D Personality ; },
abstract = {UNLABELLED: Backgrounds Accelerated cellular ageing, which can be examined by telomere length (TL), may be an overarching mechanism underlying the association between personality and adverse health outcomes. This 6-year longitudinal study examined the relation between personality and leukocyte telomere length (LTL) across time among adults with a wide age-range.<br><br>METHODS: Data from the Netherlands Study of Depression and Anxiety were used and included patients with a depression and/or anxiety disorder and healthy controls. Overall, 2936 persons (18-65 years, 66% female) had data on LTL at baseline and 1883 persons had LTL at 6-year follow-up. The Big Five personality traits (neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness) and Type D personality were assessed.<br><br>RESULTS: Neuroticism was negatively (B = -2.11, p = 0.03) and agreeableness was positively (B = 3.84, p = 0.03) related to LTL measured across two time points, which became just non-significant after adjusting for somatic health, lifestyle factors, and recent life stress (B = -1.99, p = 0.06; and B = 3.01, p = 0.10). Type D personality was negatively (B = -50.16, p < 0.01) related to LTL across two time points, which still remained statistically significant after full adjustment (B = -47.37, p = 0.01). Associations did not differ by age, gender, and current psychiatric status.<br><br>CONCLUSIONS: The Big Five traits high neuroticism and low agreeableness, and Type D personality were associated with shorter LTL measured across a 6-year period. Associations with the Big Five traits became non-significant after controlling for somatic health, lifestyle factors, and recent life stress, yet similar trends were observed. Type D personality remained independently associated with shorter LTL after full adjustment.},
}
@article {pmid28889049,
year = {2018},
author = {Manoliu, A and Bosch, OG and Brakowski, J and Brühl, AB and Seifritz, E},
title = {The potential impact of biochemical mediators on telomere attrition in major depressive disorder and implications for future study designs: A narrative review.},
journal = {Journal of affective disorders},
volume = {225},
number = {},
pages = {630-646},
doi = {10.1016/j.jad.2017.08.022},
pmid = {28889049},
issn = {1573-2517},
mesh = {Biomarkers/metabolism ; Cross-Sectional Studies ; Depressive Disorder, Major/*metabolism/psychology ; Humans ; Hypothalamo-Hypophyseal System/metabolism ; Inflammation/*metabolism ; Oxidative Stress ; Pituitary-Adrenal System/metabolism ; Research Design ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Major depressive disorder (MDD) has been proposed to represent a "disease of premature aging", which is associated with certain biomarkers of cellular ageing and numerous other age-related diseases. Over the last decade, telomere length (TL) arose as a surrogate for cellular aging. Recent data suggests that TL might be reduced in patients with MDD, however, results are still inconclusive. This might be explained by the lack of assessment of potential biochemical mediators that are directly associated with telomere shortening and frequently observed in patients with MDD.<br><br>METHODS: A narrative review was performed. The PubMed database was searched for relevant studies.<br><br>RESULTS: We identified four major mediators, which are recurrently reported in patients with MDD and are associated with reduced TL: inflammation/oxidative stress, dysregulation of the hypothalamic-pituitary-adrenal axis, metabolic dysbalance including insulin resistance, and decreased brain-derived neurotrophic factor. These mediators are also mutually associated and were not systematically assessed in current studies investigating TL and MDD, which might explain inconclusive findings across current literature. Finally, we discuss possible ways to assess those mediators and potential implications of such approaches for future research.<br><br>LIMITATIONS: The majority of identified studies had cross-sectional designs and used heterogeneous methods to assess TL and associated relevant biochemical mediators.<br><br>CONCLUSIONS: A better understanding of the complex interactions between biochemical mediators, somatic comorbidities and shortened telomeres in patients with MDD might further specify the pathophysiology-based conceptualization and, based on that, personalized treatment of MDD.},
}
@article {pmid28888705,
year = {2017},
author = {Oliva-Rico, D and Herrera, LA},
title = {Regulated expression of the lncRNA TERRA and its impact on telomere biology.},
journal = {Mechanisms of ageing and development},
volume = {167},
number = {},
pages = {16-23},
doi = {10.1016/j.mad.2017.09.001},
pmid = {28888705},
issn = {1872-6216},
mesh = {Animals ; Biomarkers/metabolism ; Cell Lineage ; Chromatin/chemistry ; DNA Replication ; *Gene Expression Regulation ; Heterochromatin/*metabolism ; Humans ; Mice ; Mutation ; Neoplasms/genetics/*metabolism ; Prognosis ; *RNA, Long Noncoding ; Telomerase/genetics ; Telomere/*metabolism ; Transcription, Genetic ; },
abstract = {The telomere protects against genomic instability by minimizing the accelerated end resection of the genetic material, a phenomenon that results in severe chromosome instability that could favor the transformation of a cell by enabling the emergence of tumor-promoting mutations. Some mechanisms that avoid this fate, such as capping and loop formation, have been very well characterized; however, telomeric non-coding transcripts, such as long non-coding RNAs (lncRNAs), should also be considered in this context because they play roles in the organization of telomere dynamics, involving processes such as replication, degradation, extension, and heterochromatin stabilization. Although the mechanism through which the expression of telomeric transcripts regulates telomere dynamics is not yet clear, a non-coding RNA component opens the research options in telomere biology and the impact that it can have on telomere-associated diseases such as cancer.},
}
@article {pmid28887594,
year = {2018},
author = {Harari, Y and Kupiec, M},
title = {Do long telomeres affect cellular fitness?.},
journal = {Current genetics},
volume = {64},
number = {1},
pages = {173-176},
pmid = {28887594},
issn = {1432-0983},
mesh = {Animals ; Cell Survival/genetics ; Cellular Senescence/genetics ; *Genetic Fitness ; Humans ; Stress, Physiological/genetics ; Telomere/*genetics/*metabolism ; *Telomere Homeostasis ; Yeasts/genetics/metabolism ; },
abstract = {Telomeres protect the chromosome ends and maintain the genome stability; they, therefore, play important roles in aging and cancer. Despite the wide variability in telomere length among eukaryotes, in all telomerase-expressing cells telomere length is strictly controlled within a very narrow range. In humans, telomeres shorten with age, and it has been proposed that telomere shortening may play a causal role in aging. Using yeast strains with genetically or physiologically generated differences in telomere length, we have explored the question of whether having long telomeres affects telomere function and fitness or cellular lifespan. We found no effect of long telomeres on vegetative cell division, meiosis, or in cellular lifespan. No positive or negative effect on fitness was observed either under stressful conditions.},
}
@article {pmid28886728,
year = {2017},
author = {Lee, SP and Hande, P and Yeo, GS and Tan, EC},
title = {Correlation of cord blood telomere length with birth weight.},
journal = {BMC research notes},
volume = {10},
number = {1},
pages = {469},
pmid = {28886728},
issn = {1756-0500},
mesh = {*Birth Weight ; Female ; *Fetal Blood ; Humans ; *Infant, Low Birth Weight ; Infant, Newborn ; Male ; *Telomere ; },
abstract = {BACKGROUND: Intrauterine growth restriction affects 3% of newborns; and the lightest 10% of whom are classified as small for gestational age (SGA). These low-birth weight newborns are at increased risk of neonatal morbidity such as hypoxia and hypoglycaemia. In later life, they are at higher risk of several age-related diseases such as cardiovascular and metabolic disorders and dementia. As having short telomeres is also associated with these diseases, we tested if these newborns might already start with shorter telomeres at birth.<br><br>FINDINGS: Relative telomere lengths were determined using quantitative real-time PCR in cord blood samples from 195 newborns of Chinese ancestry. Based on the telomere length normalised to a single copy gene and a reference DNA sample as internal control, we found statistically significant correlations between relative telomere length and both unadjusted and gestational age-adjusted birth weight, with the lighter newborns having shorter telomeres. The SGA birth weight group comprising the bottom 10% of the samples also had the shortest telomeres compared to the medium and heaviest birth weight groups.<br><br>CONCLUSIONS: Our results indicate that there is reduction of cord blood telomere length for newborns with lower birth weight.},
}
@article {pmid28886414,
year = {2017},
author = {Callahan, CL and Pavuk, M and Birnbaum, LS and Ren, X and Olson, JR and Bonner, MR},
title = {Serum polychlorinated biphenyls and leukocyte telomere length in a highly-exposed population: The Anniston Community Health Survey.},
journal = {Environment international},
volume = {108},
number = {},
pages = {212-220},
pmid = {28886414},
issn = {1873-6750},
support = {R25 CA113951/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Alabama ; Cross-Sectional Studies ; *Environmental Exposure ; Female ; *Health Surveys ; Humans ; Leukocytes/*drug effects ; Male ; Middle Aged ; Polychlorinated Biphenyls/blood/*toxicity ; Public Health ; Telomere/*drug effects ; Telomere Homeostasis/drug effects ; },
abstract = {BACKGROUND: Serum polychlorinated biphenyls (PCBs) have previously been associated with longer leukocyte telomere length (LTL) in most, but not all, of the few previous studies. PCBs were produced in Anniston, Alabama from 1929 to 1971 and participants of the Anniston Community Health Survey (ACHS) were highly exposed.<br><br>OBJECTIVES: We evaluated serum levels of 35 PCBs and relative telomere length in 559 ACHS participants.<br><br>METHODS: Relative LTL was measured in DNA extracted from blood clots. We assessed PCBs individually, grouped by chlorination, and summed PCBs. We used linear regression to assess the association between each PCB metric while adjusting for pertinent covariates.<br><br>RESULTS: Serum PCBs were associated with longer LTL among white participants and the oldest age group of black participants. Among white participants, compared with those in the first quartile of sum PCBs those in the third quartile of sum PCBs had 8.09% longer relative LTL (95% CI: 1.99; 14.55) and those in the fourth had 7.58% longer relative LTL (95%CI: -0.01; 15.76) (p-quadratic=0.05). Among African American participants, serum PCBs were associated with longer relative LTL among those over age 64 only. Tests for interaction were not statistically significant.<br><br>CONCLUSIONS: We observed a non-linear positive association between serum PCBs and LTL among white participants. Serum PCBs were associated with longer LTL in the oldest age group of African Americans. This association may provide insight into the cancers previously associated with exposure to PCBs, melanoma and non-Hodgkin lymphoma, which have been associated with long LTL in previous studies.},
}
@article {pmid28886139,
year = {2017},
author = {Dagnall, CL and Hicks, B and Teshome, K and Hutchinson, AA and Gadalla, SM and Khincha, PP and Yeager, M and Savage, SA},
title = {Effect of pre-analytic variables on the reproducibility of qPCR relative telomere length measurement.},
journal = {PloS one},
volume = {12},
number = {9},
pages = {e0184098},
pmid = {28886139},
issn = {1932-6203},
mesh = {DNA/genetics/isolation &amp; purification ; Humans ; *Real-Time Polymerase Chain Reaction/methods/standards ; Reproducibility of Results ; Specimen Handling/methods/standards ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Telomeres, long nucleotide repeats and a protein complex at chromosome ends, shorten with each cell division and are susceptible to oxidative damage. Quantitative PCR (qPCR) is a widely-used technique to measure relative telomere length (RTL) in DNA samples but is challenging to optimize and significant lab-to-lab variability has been reported. In this study, we evaluated factors that may contribute to qPCR RTL measurement variability including DNA extraction methods, methods used for removing potential residual PCR inhibitors, sample storage conditions, and sample location in the PCR plate. Our results show that the DNA extraction and purification techniques, as well as sample storage conditions introduce significant variability in qPCR RTL results. We did not find significant differences in results based on sample location in the PCR plate or qPCR instrument used. These data suggest that lack of reproducibility in published association studies of RTL could be, in part, due to methodological inconsistencies. This study illustrates the importance of uniform sample handling, from DNA extraction through data generation and analysis, in using qPCR to determine RTL.},
}
@article {pmid28883279,
year = {2017},
author = {Hosokawa, K and Macarthur, BD and Ikushima, Y and Toyama, H and Masuhiro, Y and Hanazawa, S and Suda, T and Arai, F},
title = {[Functional analysis of Protection of Telomeres 1a (Pot1a) in regulation of hematopoietic stem cell aging].},
journal = {[Rinsho ketsueki] The Japanese journal of clinical hematology},
volume = {58},
number = {8},
pages = {942-949},
doi = {10.11406/rinketsu.58.942},
pmid = {28883279},
issn = {0485-1439},
mesh = {Aging ; Animals ; *Cellular Senescence ; DNA Damage ; DNA-Binding Proteins/*genetics/metabolism ; Hematopoietic Stem Cells/*metabolism ; Humans ; Telomere/*genetics/metabolism ; },
abstract = {Repeated cell divisions induce DNA damage accumulation, which impairs stem cell function during aging. However, the general molecular mechanisms by which this occurs remain unclear. Herein, we show that the expression of protection of telomeres 1a (Pot1a), a component of shelterin, is crucial for prevention of telomeric DNA damage response (DDR) and maintenance of hematopoietic stem cell (HSC) activity during aging. We observed that HSCs express high levels of Pot1a during development, and this expression declines with aging. Knockdown of Pot1a induced an age-related phenotype, characterized by increased telomeric DDR and reduced long-term reconstitution activity. In contrast, treatment with exogenous Pot1a protein prevented telomeric DDR, which decreased stem cell activity and partially rejuvenated HSC activity. These results highlight a general, reversible mechanism by which aging compromises mammalian stem cell activity, with widespread implications for regenerative medicine.},
}
@article {pmid28882819,
year = {2017},
author = {Sharifi-Sanjani, M and Oyster, NM and Tichy, ED and Bedi, KC and Harel, O and Margulies, KB and Mourkioti, F},
title = {Cardiomyocyte-Specific Telomere Shortening is a Distinct Signature of Heart Failure in Humans.},
journal = {Journal of the American Heart Association},
volume = {6},
number = {9},
pages = {},
pmid = {28882819},
issn = {2047-9980},
mesh = {Age Factors ; Cardiomyopathies/*genetics/pathology/physiopathology ; Case-Control Studies ; DNA Damage ; Female ; Heart Failure/*genetics/pathology/physiopathology ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Myocytes, Cardiac/*chemistry/pathology ; Sex Factors ; Single-Cell Analysis ; Stroke Volume ; Telomere/*genetics/pathology ; *Telomere Shortening ; Ventricular Function, Left ; Ventricular Remodeling ; },
abstract = {BACKGROUND: Telomere defects are thought to play a role in cardiomyopathies, but the specific cell type affected by the disease in human hearts is not yet identified. The aim of this study was to systematically evaluate the cell type specificity of telomere shortening in patients with heart failure in relation to their cardiac disease, age, and sex.<br><br>METHODS AND RESULTS: We studied cardiac tissues from patients with heart failure by utilizing telomere quantitative fluorescence in&#xa0;situ hybridization, a highly sensitive method with single-cell resolution. In this study, total of 63 human left ventricular samples, including 37 diseased and 26 nonfailing donor hearts, were stained for telomeres in combination with cardiomyocyte- or &#x3b1;-smooth muscle cell-specific markers, cardiac troponin T, and smooth muscle actin, respectively, and assessed for telomere length. Patients with heart failure demonstrate shorter cardiomyocyte telomeres compared with nonfailing donors, which is specific only to cardiomyocytes within diseased human hearts and is associated with cardiomyocyte DNA damage. Our data further reveal that hypertrophic hearts with reduced ejection fraction exhibit the shortest telomeres. In contrast to other reported cell types, no difference in cardiomyocyte telomere length is evident with age. However, under the disease state, telomere attrition manifests in both young and older patients with cardiac hypertrophy. Finally, we demonstrate that cardiomyocyte-telomere length is better sustained in women than men under diseased conditions.<br><br>CONCLUSIONS: This study provides the first evidence of cardiomyocyte-specific telomere shortening in heart failure.},
}
@article {pmid28879822,
year = {2017},
author = {Aiello, AE and Jayabalasingham, B and Simanek, AM and Diez-Roux, A and Feinstein, L and Meier, HCS and Needham, BL and Dowd, JB},
title = {The impact of pathogen burden on leukocyte telomere length in the Multi-Ethnic Study of Atherosclerosis.},
journal = {Epidemiology and infection},
volume = {145},
number = {14},
pages = {3076-3084},
pmid = {28879822},
issn = {1469-4409},
support = {HHSN268201500003C/HL/NHLBI NIH HHS/United States ; N01HC95163/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; N01HC95164/HL/NHLBI NIH HHS/United States ; N01HC95162/HL/NHLBI NIH HHS/United States ; N01HC95168/HL/NHLBI NIH HHS/United States ; N01HC95165/HL/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; N01HC95167/HL/NHLBI NIH HHS/United States ; T32 HD007168/HD/NICHD NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; P2C HD050924/HD/NICHD NIH HHS/United States ; R01 AG040115/AG/NIA NIH HHS/United States ; N01HC95160/HL/NHLBI NIH HHS/United States ; R01 HL101161/HL/NHLBI NIH HHS/United States ; N01HC95161/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; N01HC95166/HL/NHLBI NIH HHS/United States ; R24 HD050924/HD/NICHD NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Atherosclerosis/etiology ; *Bacterial Load ; Chlamydophila Infections/epidemiology/microbiology ; Chlamydophila pneumoniae/physiology ; Cytomegalovirus/physiology ; Cytomegalovirus Infections/epidemiology/virology ; Female ; Helicobacter Infections/epidemiology/microbiology ; Helicobacter pylori/physiology ; Herpes Simplex/epidemiology/virology ; Herpesvirus 1, Human/physiology ; Humans ; Leukocytes/*physiology ; Longitudinal Studies ; Male ; Middle Aged ; Seroepidemiologic Studies ; *Telomere Shortening ; United States/epidemiology ; *Viral Load ; },
abstract = {Several infections have been linked to telomere shortening and in some cases these associations have varied by sex. We assessed the association between seropositivity to four persistent pathogens (cytomegalovirus (CMV), herpes simplex virus-1, Helicobacter pylori, Chlamydia pneumoniae), and total pathogen burden on leukocyte telomere length in a diverse US sample. Data came from the Multi-Ethnic Study of Atherosclerosis, a population-based cohort study. We utilized cross-sectional survey data, and biological samples from participants tested for pathogens and telomere length (N = 163). Linear regression was used to examine the association between seropositivity for individual pathogens as well as total pathogen burden and telomere length, adjusting for various confounders. CMV seropositivity and increased total pathogen burden level were significantly associated with shorter telomere length among females (β = -0·1204 (standard error (s.e.) 0·06), P = 0·044) and (β = -0·1057 (s.e. = 0·05), P = 0·033), respectively. There was no statistically significant association among males. Our findings suggest that prevention or treatment of persistent pathogens, in particular CMV, may play an important role in reducing telomere shortening over the life course among women. Future research is needed to confirm these novel findings in larger longitudinal samples.},
}
@article {pmid28878065,
year = {2017},
author = {Salmón, P and Nilsson, JF and Watson, H and Bensch, S and Isaksson, C},
title = {Selective disappearance of great tits with short telomeres in urban areas.},
journal = {Proceedings. Biological sciences},
volume = {284},
number = {1862},
pages = {},
pmid = {28878065},
issn = {1471-2954},
mesh = {Animals ; Cities ; Environment ; *Genetic Fitness ; Passeriformes/*genetics ; Telomere/*ultrastructure ; *Telomere Shortening ; },
abstract = {Urban environments pose novel challenges, as well as opportunities, for urban-dwelling wildlife. Although differences have been reported in several phenotypic traits (e.g. morphology, physiology and behaviour) between urban and rural populations, it is poorly understood whether this affects individual fitness. Telomere dynamics are posited as one possible mechanism underlying senescence and mortality. It was recently shown that telomere shortening is accelerated when growing up in an urban, compared with a rural, environment. However, the implications of accelerated telomere attrition for fitness are still unclear. Here, we examine the relationship between telomere length (TL) and survival in a bird common to urban and rural environments, and during both early and later life. The results reveal that TL is a strong predictor of post-fledging survival and recruitment in both habitats but, crucially, selective disappearance of individuals with short telomeres early in life is more pronounced in the urban environment, resulting in a longer average TL among the adult population. However, following recruitment, we found no difference in the relationship between TL and survival between the urban and rural environments. This indicates that the urban environment has negative effects in early life, while during later life the benefits could potentially outweigh the costs.},
}
@article {pmid28877996,
year = {2017},
author = {Sobinoff, AP and Allen, JA and Neumann, AA and Yang, SF and Walsh, ME and Henson, JD and Reddel, RR and Pickett, HA},
title = {BLM and SLX4 play opposing roles in recombination-dependent replication at human telomeres.},
journal = {The EMBO journal},
volume = {36},
number = {19},
pages = {2907-2919},
pmid = {28877996},
issn = {1460-2075},
mesh = {Cells, Cultured ; DNA Replication/*genetics ; DNA Topoisomerases, Type I/metabolism/physiology ; DNA-Directed DNA Polymerase/metabolism/physiology ; Humans ; Multienzyme Complexes/metabolism/physiology ; RecQ Helicases/metabolism/*physiology ; Recombinases/metabolism/*physiology ; Recombination, Genetic/*genetics ; Telomere/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Alternative lengthening of telomeres (ALT) is a telomere lengthening pathway that predominates in aggressive tumors of mesenchymal origin; however, the underlying mechanism of telomere synthesis is not fully understood. Here, we show that the BLM-TOP3A-RMI (BTR) dissolvase complex is required for ALT-mediated telomere synthesis. We propose that recombination intermediates formed during strand invasion are processed by the BTR complex, initiating rapid and extensive POLD3-dependent telomere synthesis followed by dissolution, with no overall exchange of telomeric DNA. This process is counteracted by the SLX4-SLX1-ERCC4 complex, which promotes resolution of the recombination intermediate, resulting in telomere exchange in the absence of telomere extension. Our data are consistent with ALT being a conservative DNA replication process, analogous to break-induced replication, which is dependent on BTR and counteracted by SLX4 complex-mediated resolution events.},
}
@article {pmid28871486,
year = {2018},
author = {Kim, H and Ahn, D and Sohn, JH and Kim, YH and Lee, JH and Lee, H},
title = {Erratum to: TERT Promoter Mutation and Telomere Length in Salivary Gland Tumors.},
journal = {Pathology oncology research : POR},
volume = {24},
number = {3},
pages = {699},
doi = {10.1007/s12253-017-0294-3},
pmid = {28871486},
issn = {1532-2807},
}
@article {pmid28864660,
year = {2018},
author = {Marchesi, VT},
title = {De novo digenic mutations of telomere-associated proteins and inflammasomes initiate many chronic human diseases: a hypothesis.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {32},
number = {1},
pages = {16-19},
doi = {10.1096/fj.201700388RR},
pmid = {28864660},
issn = {1530-6860},
mesh = {Chronic Disease ; DNA Repair ; Humans ; Inflammasomes/*genetics/metabolism ; Inflammation/etiology/genetics ; Models, Biological ; Mutagenesis ; *Mutation ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; Telomerase/genetics ; Telomere/*genetics/metabolism ; },
abstract = {Many age-related human diseases have inflammatory components of uncertain causes. It has been proposed that some may be initiated or sustained by doubly mutated immune cells that have both inappropriately activated inflammasomes and enhanced replicative potential. Genes of cells that express mutant TERT and NLRP3 proteins are presumed to be at increased risk for mutagenesis because they reside in subtelomeric regions of chromatin that are deficient in DNA repair mechanisms. Expanded clones of proinflammatory cells can occur throughout one's lifetime and could represent an alternative explanation for some forms of pathologic scarring that are now attributed to truncated telomeres.-Marchesi, V. T. De novo digenic mutations of telomere-associated proteins and inflammasomes initiate many chronic human diseases: a hypothesis.},
}
@article {pmid28860610,
year = {2017},
author = {Liu, H and Luo, H and Yang, T and Wu, H and Chen, D},
title = {Association of leukocyte telomere length and the risk of age-related hearing impairment in Chinese Hans.},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {10106},
pmid = {28860610},
issn = {2045-2322},
mesh = {Aged ; Aged, 80 and over ; China ; Female ; Humans ; Male ; Presbycusis/*genetics ; *Telomere Homeostasis ; },
abstract = {Age-related hearing loss (ARHI) is the most common sensory disorder in the elderly. Although telomere attrition has been shown as a determinant in the pathobiology of various age-related diseases, it remains unknown whether telomere length is associated with ARHI. We hypothesized that decreased leukocyte telomere length (LTL) increased the risk of ARHI. Thus, we measured LTL of 666 ARHI and 43 controls by an established quantitative PCR technique. Four audiogram shape subtypes of ARHI, including "flat shape (FL)", "2-4 kHz abrupt loss (AL) shape", "8 kHz dip (8D) shape" and "sloping shape (SL)" could be identified among the cases using K-means cluster analysis. Longer LTL was associated with the reduced incidence of ARHI (adjusted OR = 0.550, 95% CI: 0.420-0.721, P < 0.0001 for all the ARHI; 0.498, 0.318-0.780, P = 0.0023 for FL subgroup; 0.428, 0.292-0.628, P < 0.0001 for AL subgroup; 0.552, 0.399-0.764, P = 0.0003 for mSL subgroup). Subjects in the highest tertile of LTL were at less risk for ARHI than those in the lowest and middle tertiles (OR for ARHI: 0.327, 95% CI 0.170-0.629, P = 0.0008). There was a descending trend of LTL as the degree of pure tone threshold average (PTA) aggravated. These results suggest that telomere attrition may be involved in the progression of ARHI.},
}
@article {pmid28859657,
year = {2017},
author = {Zhou, Y and Hambly, BD and McLachlan, CS},
title = {FTO associations with obesity and telomere length.},
journal = {Journal of biomedical science},
volume = {24},
number = {1},
pages = {65},
pmid = {28859657},
issn = {1423-0127},
mesh = {Alpha-Ketoglutarate-Dependent Dioxygenase FTO/*genetics/metabolism ; Humans ; Obesity/*genetics ; *Polymorphism, Single Nucleotide ; *Telomere Shortening ; },
abstract = {This review examines the biology of the Fat mass- and obesity-associated gene (FTO), and the implications of genetic association of FTO SNPs with obesity and genetic aging. Notably, we focus on the role of FTO in the regulation of methylation status as possible regulators of weight gain and genetic aging. We present a theoretical review of the FTO gene with a particular emphasis on associations with UCP2, AMPK, RBL2, IRX3, CUX1, mTORC1 and hormones involved in hunger regulation. These associations are important for dietary behavior regulation and cellular nutrient sensing via amino acids. We suggest that these pathways may also influence telomere regulation. Telomere length (TL) attrition may be influenced by obesity-related inflammation and oxidative stress, and FTO gene-involved pathways. There is additional emerging evidence to suggest that telomere length and obesity are bi-directionally associated. However, the role of obesity risk-related genotypes and associations with TL are not well understood. The FTO gene may influence pathways implicated in regulation of TL, which could help to explain some of the non-consistent relationship between weight phenotype and telomere length that is observed in population studies investigating obesity.},
}
@article {pmid28858636,
year = {2017},
author = {Sheller-Miller, S and Urrabaz-Garza, R and Saade, G and Menon, R},
title = {Damage-Associated molecular pattern markers HMGB1 and cell-Free fetal telomere fragments in oxidative-Stressed amnion epithelial cell-Derived exosomes.},
journal = {Journal of reproductive immunology},
volume = {123},
number = {},
pages = {3-11},
pmid = {28858636},
issn = {1872-7603},
support = {R01 HD084532/HD/NICHD NIH HHS/United States ; T32 ES007254/ES/NIEHS NIH HHS/United States ; },
mesh = {Alarmins/*metabolism ; Amnion/*physiology ; Cells, Cultured ; Cellular Senescence ; Cigarette Smoking/adverse effects ; Culture Media, Conditioned/adverse effects ; Epithelial Cells/*pathology ; Exosomes/*metabolism/pathology ; Female ; HMGB1 Protein/*metabolism ; Humans ; Inflammation/genetics/*metabolism ; Labor, Obstetric ; Oxidative Stress ; Parturition ; Pregnancy ; Primary Cell Culture ; Telomere/*metabolism ; },
abstract = {Term labor in humans is associated with increased oxidative stress (OS) -induced senescence and damages to amnion epithelial cells (AECs). Senescent fetal cells release alarmin high-mobility group box 1 (HMGB1) and cell-free fetal telomere fragments (cffTF) which can be carried by exosomes to other uterine tissues to produce parturition-associated inflammatory changes. This study characterized AEC-derived exosomes under normal and OS conditions and their packaging of HMGB1 and cffTF. Primary AECs were treated with either standard media or oxidative stress-induced media (exposure to cigarette smoke extract for 48h). Senescence was determined, and exosomes were isolated and characterized. To colocalize HMGB1 and cffTF in amnion exosomes, immunofluorescent staining and in situ hybridization were performed, followed by confocal microscopy. Next generation sequencing (NGS) determined exosomal cffTF and other cell-free amnion cell DNA specificity. Regardless of condition, primary AECs produce exosomes with a classic size, shape, and markers. OS and senescence caused the translocation of HMGB1 and cffTF from AECs' nuclei to cytoplasm compared to untreated cells, which was inhibited by antioxidant N-acetyl cysteine (NAC). Linescans confirmed colocalization of HMGB1 and cffTF in exosomes were higher in the cytoplasm after CSE treatment compared to untreated AECs. NGS determined that besides cffTF, AEC exosomes also carry genomic and mitochondrial DNA, regardless of growth conditions. Sterile inflammatory markers HMGB1 and cffTF from senescent fetal cells are packaged inside exosomes. We postulate that this exosomal cargo can act as a fetal signal at term and can cause labor-associated changes in neighboring tissues.},
}
@article {pmid28857340,
year = {2018},
author = {Sharpley, CF and Christie, DRH and Bitsika, V and Agnew, LL and Andronicos, NM and McMillan, ME},
title = {Associations between reduced telomere length, depressed mood, anhedonia, and irritability in prostate cancer patients: Further evidence for the presence of "male depression"?.},
journal = {Psycho-oncology},
volume = {27},
number = {3},
pages = {1072-1074},
doi = {10.1002/pon.4547},
pmid = {28857340},
issn = {1099-1611},
}
@article {pmid28856789,
year = {2017},
author = {Jenkins, EC and Marchi, EJ and Velinov, MT and Ye, L and Krinsky-McHale, SJ and Zigman, WB and Schupf, N and Silverman, WP},
title = {Longitudinal telomere shortening and early Alzheimer's disease progression in adults with down syndrome.},
journal = {American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics},
volume = {174},
number = {8},
pages = {772-778},
doi = {10.1002/ajmg.b.32575},
pmid = {28856789},
issn = {1552-485X},
mesh = {Adult ; Aged ; Alzheimer Disease/complications/genetics/*pathology ; Biomarkers/*analysis ; Cognitive Dysfunction/complications/genetics/*pathology ; Disease Progression ; Down Syndrome/complications/genetics/*pathology ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Prospective Studies ; *Telomere Shortening ; },
abstract = {Telomere shortening was shown to parallel Alzheimer's disease (AD) associated dementia. By using a dual PNA Probe system we have developed a practical method for comparing telomere length in T-lymphocyte interphases from individuals with Down syndrome (DS) with and without "mild cognitive impairment" (MCI-DS) and demonstrated that telomere length can serve as a valid biomarker for the onset of MCI-DS in this high-risk population. To verify progressive cognitive decline we have now examined sequential changes in telomere length in 10 adults with DS (N = 4 Female, N = 6 Male) developing MCI-DS. Cases were selected blind to telomere length from a sample of adults with DS previously enrolled in a prospective longitudinal study at 18-month intervals with clinical and telomere assessments: (1) MCI-DS group data were collected approximately three years prior to development of MCI-DS; (2) 18 months later; (3) when MCI-DS was first observed. These telomere measures were compared to those from another 10 adults with DS matched by sex and approximate age but without indications of MCI-DS (Controls). PNA (peptide nucleic acid) probes for telomeres together with a chromosome two centromere probe were used. Findings indicated telomere shortening over time for both Cases and Controls. Group differences emerged by 18-months prior to recognition of MCI-DS onset and completely non-overlapping distributions of telomere measures were observed by the time of MCI-DS onset. This study adds to accumulating evidence of the value of telomere length, as an early biomarker of AD progression in adults with Down syndrome.},
}
@article {pmid28855677,
year = {2017},
author = {Froy, H and Bird, EJ and Wilbourn, RV and Fairlie, J and Underwood, SL and Salvo-Chirnside, E and Pilkington, JG and Bérénos, C and Pemberton, JM and Nussey, DH},
title = {No evidence for parental age effects on offspring leukocyte telomere length in free-living Soay sheep.},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {9991},
pmid = {28855677},
issn = {2045-2322},
support = {BB/H021868/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Female ; *Fertilization ; Leukocytes/*cytology ; Male ; *Parents ; Real-Time Polymerase Chain Reaction ; Sheep ; *Telomere Homeostasis ; },
abstract = {In humans, the effect of paternal age at conception (PAC) on offspring leukocyte telomere length (LTL) is well established, with older fathers thought to pass on longer telomeres to their offspring in their sperm. Few studies have looked for PAC effects in other species, but it has been hypothesised that the effect will be exacerbated in polygamous species with higher levels of sperm competition and production. We test for maternal (MAC) and paternal age at conception effects on offspring LTL in Soay sheep, a primitive breed experiencing strong sperm competition. We use qPCR to measure relative telomere length in 389 blood samples (n = 318 individuals) collected from an unmanaged population of sheep on St Kilda, where individual age and parentage are known. We find no evidence that either MAC or PAC are associated with LTL in offspring across the age range, or when considering only young lambs (n = 164). This is the first study to test for parental age effects on offspring LTL in a wild mammal population, and the results contrast with the findings of numerous human studies that find a PAC effect, as well as predictions of a stronger PAC effect in polygamous species.},
}
@article {pmid28855418,
year = {2017},
author = {Cao, L and Zhang, L and Zeng, H and Wu, RT and Wu, TL and Cheng, WH},
title = {Analyses of Selenotranscriptomes and Selenium Concentrations in Response to Dietary Selenium Deficiency and Age Reveal Common and Distinct Patterns by Tissue and Sex in Telomere-Dysfunctional Mice.},
journal = {The Journal of nutrition},
volume = {147},
number = {10},
pages = {1858-1866},
doi = {10.3945/jn.117.247775},
pmid = {28855418},
issn = {1541-6100},
mesh = {Age Factors ; Animals ; Deficiency Diseases/blood/metabolism ; Diet ; Female ; Gene Expression Profiling ; Glutathione Peroxidase/metabolism ; Heart ; Kidney/*metabolism ; Liver/*metabolism ; Longevity ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Myocardium/*metabolism ; Oxidoreductases/metabolism ; RNA, Messenger/metabolism ; Selenium/*deficiency/metabolism ; Selenoproteins/blood/*metabolism ; Sex Factors ; Telomerase/genetics/metabolism ; *Telomere ; Testis/*metabolism ; },
abstract = {Background: The hierarchies of tissue selenium distribution and selenotranscriptomes are thought to critically affect healthspan and longevity.Objective: We determined selenium status and selenotranscriptomes in response to long-term dietary selenium deficiency and age in tissues of male and female mice.Methods: Weanling telomerase RNA component knockout C57BL/6 mice were fed a selenium-deficient (0.03 mg Se/kg) Torula yeast-based AIN-93G diet or a diet supplemented with sodium selenate (0.15 mg Se/kg) until age 18 or 24 mo. Plasma, hearts, kidneys, livers, and testes were collected to assay for selenotranscriptomes, selected selenoproteins, and tissue selenium concentrations. Data were analyzed with the use of 2-factor ANOVA (diet × age) in both sexes.Results: Dietary selenium deficiency decreased (P ≤ 0.05) selenium concentrations (65-72%) and glutathione peroxidase (GPX) 3 (82-94%) and selenoprotein P (SELENOP) (17-41%) levels in the plasma of both sexes of mice and mRNA levels (9-68%) of 4, 4, and 12 selenoproteins in the heart, kidney, and liver of males, respectively, and 5, 16, and 14 selenoproteins, respectively, in females. Age increased selenium concentrations and SELENOP levels (27% and 30%, respectively; P ≤ 0.05) in the plasma of males only but decreased (12-46%; P < 0.05) mRNA levels of 1, 5, and 13 selenoproteins in the heart, kidney, and liver of males, respectively, and 6, 5, and 0 selenoproteins, respectively, in females. Among these mRNAs, selenoprotein H (Selenoh), selenoprotein M (Selenom), selenoprotein W (Selenow), methionine-R-sulfoxide reductase 1 (MsrB1), Gpx1, Gpx3, thioredoxin reductase 1 (Txnrd1), Txnrd2, selenoprotein S (Selenos), selenoprotein F (Selenof), and selenoprotein O (Selenoo) responded in parallel to dietary selenium deficiency and age in ≥1 tissue or sex, or both. Dietary selenium deficiency upregulated (40-160%; P ≤ 0.05) iodothyronine deiodinase 2 (Dio2) and selenoprotein N (Selenon) in the kidneys of males. Age upregulated (11-44%; P < 0.05) Selenon in the kidneys of males, selenoprotein K (Selenok) and selenoprotein I (Selenoi) in the kidneys of females, and Selenof and Selenok in the testes.Conclusions: These results illustrate tissue-specific sexual dimorphisms of selenium status and selenotranscriptomes because of dietary selenium deficiency and age.},
}
@article {pmid28855370,
year = {2017},
author = {Cram, DL and Monaghan, P and Gillespie, R and Clutton-Brock, T},
title = {Effects of early-life competition and maternal nutrition on telomere lengths in wild meerkats.},
journal = {Proceedings. Biological sciences},
volume = {284},
number = {1861},
pages = {},
pmid = {28855370},
issn = {1471-2954},
support = {268926/ERC_/European Research Council/International ; 294494/ERC_/European Research Council/International ; },
mesh = {*Aging ; Animals ; Female ; Genetic Fitness ; Herpestidae/*genetics ; *Longevity ; Telomere/*ultrastructure ; *Telomere Shortening ; },
abstract = {Early-life adversity can affect health, survival and fitness later in life, and recent evidence suggests that telomere attrition may link early conditions with their delayed consequences. Here, we investigate the link between early-life competition and telomere length in wild meerkats. Our results show that, when multiple females breed concurrently, increases in the number of pups in the group are associated with shorter telomeres in pups. Given that pups from different litters compete for access to milk, we tested whether this effect is due to nutritional constraints on maternal milk production, by experimentally supplementing females' diets during gestation and lactation. While control pups facing high competition had shorter telomeres, the negative effects of pup number on telomere lengths were absent when maternal nutrition was experimentally improved. Shortened pup telomeres were associated with reduced survival to adulthood, suggesting that early-life competition for nutrition has detrimental fitness consequences that are reflected in telomere lengths. Dominant females commonly kill pups born to subordinates, thereby reducing competition and increasing growth rates of their own pups. Our work suggests that an additional benefit of infanticide may be that it also reduces telomere shortening caused by competition for resources, with associated benefits for offspring ageing profiles and longevity.},
}
@article {pmid28855279,
year = {2018},
author = {Sabharwal, S and Verhulst, S and Guirguis, G and Kark, JD and Labat, C and Roche, NE and Martimucci, K and Patel, K and Heller, DS and Kimura, M and Chuang, D and Chuang, A and Benetos, A and Aviv, A},
title = {Telomere length dynamics in early life: the blood-and-muscle model.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {32},
number = {1},
pages = {529-534},
pmid = {28855279},
issn = {1530-6860},
support = {R01 HD071180/HD/NICHD NIH HHS/United States ; R01 HL116446/HL/NHLBI NIH HHS/United States ; },
mesh = {Aborted Fetus/ultrastructure ; Adolescent ; Aging/genetics/pathology ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Leukocytes/ultrastructure ; Male ; *Models, Biological ; Muscle, Skeletal/ultrastructure ; Telomere Homeostasis/genetics/*physiology ; Young Adult ; },
abstract = {Telomere length (TL) trajectories in somatic tissues during human growth and development are poorly understood. We examined a blood-and-muscle model during early life, focusing on TL trajectories in leukocytes, representing the highly proliferative hematopoietic system, and skeletal muscle, a minimally proliferative tissue. Leukocyte TL (LTL) and skeletal muscle TL (MTL) were measured in 28 fetuses and 73 children. LTL and MTL were highly variable across individuals (sd: fetal LTL = 0.72 kb, MTL = 0.72 kb; children LTL = 0.81 kb, MTL = 0.82 kb) but were highly correlated within individuals (fetuses, r = 0.76, P < 0.0001; children, r = 0.87, P < 0.0001). LTL was shorter than MTL in fetuses (10.63 vs. 11.01 kb; P = 0.0004) and children (8.46 vs. 9.40 kb; <0.0001). The LTL-MTL gap was smaller in fetuses than children. TL in children was inversely correlated with body mass index (BMI) (LTL: -0.047 ± 0.016 kb/BMI, P < 0.005; MTL: -0.037 ± 0.017 kb/BMI, P = 0.03). We conclude that variations in TL across adults and differences in TL between somatic tissues are largely established in early life. Because TL plays a significant role in aging-related diseases, insight into the factors that fashion TL in somatic tissues during early development should contribute to an understanding of the relationship of TL with these disease and longevity in humans.-Sabharwal, S., Verhulst, S., Guirguis, G., Kark, J. D., Labat, C., Roche, N. E., Martimucci, K., Patel, K., Heller, D. S., Kimura, M., Chuang, D., Chuang, A., Benetos, A., Aviv, A. Telomere length dynamics in early life: the blood-and-muscle model.},
}
@article {pmid28854735,
year = {2017},
author = {Wang, S and Pike, AM and Lee, SS and Strong, MA and Connelly, CJ and Greider, CW},
title = {BRD4 inhibitors block telomere elongation.},
journal = {Nucleic acids research},
volume = {45},
number = {14},
pages = {8403-8410},
pmid = {28854735},
issn = {1362-4962},
support = {R01 CA160300/CA/NCI NIH HHS/United States ; T32 GM008752/GM/NIGMS NIH HHS/United States ; },
mesh = {Acetanilides/pharmacology ; Animals ; Azepines/pharmacology ; Blotting, Southern ; Cell Cycle Proteins ; Cell Line ; Dose-Response Relationship, Drug ; Fibroblasts/cytology/drug effects/metabolism ; Gene Expression/drug effects ; HeLa Cells ; Heterocyclic Compounds, 3-Ring/pharmacology ; Heterocyclic Compounds, 4 or More Rings/pharmacology ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; Morpholines/pharmacology ; Nuclear Proteins/antagonists &amp; inhibitors/*genetics/metabolism ; Pyrones/pharmacology ; RNA Interference ; Telomerase/genetics/metabolism ; Telomere/drug effects/enzymology/genetics ; Telomere Homeostasis/drug effects/*genetics ; Telomere Shortening/drug effects/*genetics ; Transcription Factors/antagonists &amp; inhibitors/*genetics/metabolism ; Triazoles/pharmacology ; },
abstract = {Cancer cells maintain telomere length equilibrium to avoid senescence and apoptosis induced by short telomeres, which trigger the DNA damage response. Limiting the potential for telomere maintenance in cancer cells has been long been proposed as a therapeutic target. Using an unbiased shRNA screen targeting known kinases, we identified bromodomain-containing protein 4 (BRD4) as a telomere length regulator. Four independent BRD4 inhibitors blocked telomere elongation, in a dose-dependent manner, in mouse cells overexpressing telomerase. Long-term treatment with BRD4 inhibitors caused telomere shortening in both mouse and human cells, suggesting BRD4 plays a role in telomere maintenance in vivo. Telomerase enzymatic activity was not directly affected by BRD4 inhibition. BRD4 is in clinical trials for a number of cancers, but its effects on telomere maintenance have not been previously investigated.},
}
@article {pmid28854357,
year = {2017},
author = {Zhou, J and Chan, J and Lambelé, M and Yusufzai, T and Stumpff, J and Opresko, PL and Thali, M and Wallace, SS},
title = {NEIL3 Repairs Telomere Damage during S Phase to Secure Chromosome Segregation at Mitosis.},
journal = {Cell reports},
volume = {20},
number = {9},
pages = {2044-2056},
pmid = {28854357},
issn = {2211-1247},
support = {R01 AI080302/AI/NIAID NIH HHS/United States ; R01 ES022944/ES/NIEHS NIH HHS/United States ; P01 CA098993/CA/NCI NIH HHS/United States ; R01 GM117839/GM/NIGMS NIH HHS/United States ; P20 GM103496/GM/NIGMS NIH HHS/United States ; },
mesh = {CD4-Positive T-Lymphocytes/metabolism ; Cell Cycle Checkpoints ; Cell Nucleus/metabolism ; *Chromosome Segregation ; DNA/metabolism ; *DNA Damage ; *DNA Repair ; Gene Knockdown Techniques ; HCT116 Cells ; HeLa Cells ; Humans ; Microtubules/metabolism ; *Mitosis ; N-Glycosyl Hydrolases/chemistry/*metabolism ; Oxidative Stress ; Protein Binding ; Protein Domains ; *S Phase ; Spindle Apparatus/metabolism ; Telomere/*pathology ; },
abstract = {Oxidative damage to telomere DNA compromises telomere integrity. We recently reported that the DNA glycosylase NEIL3 preferentially repairs oxidative lesions in telomere sequences in vitro. Here, we show that loss of NEIL3 causes anaphase DNA bridging because of telomere dysfunction. NEIL3 expression increases during S phase and reaches maximal levels in late S/G2. NEIL3 co-localizes with TRF2 and associates with telomeres during S phase, and this association increases upon oxidative stress. Mechanistic studies reveal that NEIL3 binds to single-stranded DNA via its intrinsically disordered C terminus in a telomere-sequence-independent manner. Moreover, NEIL3 is recruited to telomeres through its interaction with TRF1, and this interaction enhances the enzymatic activity of purified NEIL3. Finally, we show that NEIL3 interacts with AP Endonuclease 1 (APE1) and the long-patch base excision repair proteins PCNA and FEN1. Taken together, we propose that NEIL3 protects genome stability through targeted repair of oxidative damage in telomeres during S/G2 phase.},
}
@article {pmid28853973,
year = {2017},
author = {Cai, Y and Kandula, V and Kosuru, R and Ye, X and Irwin, MG and Xia, Z},
title = {Decoding telomere protein Rap1: Its telomeric and nontelomeric functions and potential implications in diabetic cardiomyopathy.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {16},
number = {19},
pages = {1765-1773},
pmid = {28853973},
issn = {1551-4005},
mesh = {Animals ; DNA/*genetics/metabolism ; *DNA Repair ; Diabetic Cardiomyopathies/*genetics/metabolism/pathology ; Gene Expression Regulation ; Humans ; Metabolic Networks and Pathways/genetics ; Mice ; Oxidative Stress ; Protein Binding ; Shelterin Complex ; Signal Transduction ; Telomere/*metabolism/ultrastructure ; *Telomere Homeostasis ; Telomere-Binding Proteins/chemistry/*genetics/metabolism ; },
abstract = {Mammalian Rap1, the most conserved telomere-interacting protein, beyond its role within nucleus for the maintenance of telomeric functions, is also well known for its pleiotropic functions in various physiological and pathological conditions associated with metabolism, inflammation and oxidative stress. For all these, nowadays Rap1 is the subject of critical investigations aimed to unveil its molecular signaling pathways and to scrutinize the applicability of its modulation as a promising therapeutic strategy with clinical relevance. However, the underlying intimate mechanisms of Rap1 are not extensively studied, but any modulation of this protein level has been associated with pathologies like inflammation, oxidative stress and deregulated metabolism. This is considerably important in light of the recent discovery of Rap1 modulation in diseases like cancer and cardiac metabolic disorders. In this review, we focus on both the telomeric and nontelomeric functions of Rap1 and its modulation in various health risks, especially on the heart.},
}
@article {pmid28851852,
year = {2017},
author = {Harari, Y and Zadok-Laviel, S and Kupiec, M},
title = {Long Telomeres Do Not Affect Cellular Fitness in Yeast.},
journal = {mBio},
volume = {8},
number = {4},
pages = {},
pmid = {28851852},
issn = {2150-7511},
mesh = {*Genetic Fitness ; Mutation ; Saccharomyces cerevisiae/*genetics/growth &amp; development/physiology ; Telomere/*genetics/physiology ; *Telomere Shortening ; },
abstract = {Telomeres, the ends of the eukaryotic chromosomes, help to maintain the genome's integrity and thus play important roles in aging and cancer. Telomere length is strictly controlled in all organisms. In humans, telomeres shorten with age, and it has been proposed that telomere shortening may play a causal role in aging. We took advantage of the availability of yeast strains with genetically or physiologically generated differences in telomere length to measure the effect that telomere length may have on cellular growth. By comparing the growth rates affecting telomere length of various yeast mutants we show that there is no correlation between their telomere length and cellular fitness. We also show that wild-type yeast cells carrying extremely long telomeres (~5 times longer than the average) showed no signs of mitotic or meiotic defects, and competition experiments found no differences in growth between strains with normal telomeres and strains with long telomeres. No advantage or disadvantage of cells with long telomeres was detected under stress conditions either. Finally, telomere length had no effect in a chronological life span assay, which measures survival of post-mitotic-stage cells. We conclude that extreme telomere length has no effects (positive or negative) on the fitness of yeast cells.IMPORTANCE Telomeres protect the chromosomal ends from fusion, degradation, and unwanted repair. Therefore, telomeres preserve genome stability and cell viability. In humans, telomeres shorten with each cell duplication event and with age. It has thus been proposed that telomere shortening may be responsible for human aging and that elongation of telomeres may be a way to rejuvenate cells and to combat aging. However, it is difficult to prove this hypothesis in human cells. Yeasts are easy to manipulate and have telomeres whose length is strictly maintained. Here we show that yeast cells manipulated to have extremely long telomeres (~5-fold those of normal cells) did not show any improvement or reduction in fitness compared to otherwise identical cells with telomeres of normal length under all the conditions tested. Moreover, an assay that measures cell aging showed no effect of the presence of extremely long telomeres. We thus conclude that extreme telomere length, at least in yeast cells, does not affect cellular fitness, aging, or senescence.},
}
@article {pmid28851004,
year = {2017},
author = {Parolini, M and Romano, A and Costanzo, A and Khoriauli, L and Santagostino, M and Nergadze, SG and Canova, L and Rubolini, D and Giulotto, E and Saino, N},
title = {Telomere length is reflected by plumage coloration and predicts seasonal reproductive success in the barn swallow.},
journal = {Molecular ecology},
volume = {26},
number = {21},
pages = {6100-6109},
doi = {10.1111/mec.14340},
pmid = {28851004},
issn = {1365-294X},
mesh = {Animals ; *Feathers ; Female ; Genetic Fitness ; Italy ; Linear Models ; Male ; Pigmentation ; Reproduction/*physiology ; Seasons ; Swallows/genetics/*physiology ; Telomere/*ultrastructure ; Telomere Shortening ; },
abstract = {Individuals differ in realized fitness but the genetic/phenotypic traits that underpin such variation are often unknown. Telomere dynamics may be a major source of variation in fitness traits because physiological telomere shortening depends on environmental and genetic factors and may impair individual performance. Here, we showed that, in a population of a socially monogamous, biparental passerine bird, the barn swallow (Hirundo rustica), breeding in northern Italy, telomere length (TL) of both adult males and females positively correlated with seasonal reproductive and fledging success, as expected because long telomeres are supposed to boost performance. Telomere length was correlated with sexually dimorphic coloration in both sexes, showing for the first time in any species that coloration reliably reflects TL and may mediate mutual mate choice, leading to the observed positive assortative mating for TL in the barn swallow. Thus, TL appears to be associated with variation in a major fitness trait and may be an ultimate target of mate choice, as individuals of both sexes can use coloration to adaptively choose high-quality mates that possess long telomeres.},
}
@article {pmid28850092,
year = {2017},
author = {Balc'h, EL and Grandin, N and Demattei, MV and Guyétant, S and Tallet, A and Pagès, JC and Ouaissi, M and Lecomte, T and Charbonneau, M},
title = {Measurement of Telomere Length in Colorectal Cancers for Improved Molecular Diagnosis.},
journal = {International journal of molecular sciences},
volume = {18},
number = {9},
pages = {},
pmid = {28850092},
issn = {1422-0067},
mesh = {Biomarkers, Tumor/genetics ; Class I Phosphatidylinositol 3-Kinases/*genetics ; Colorectal Neoplasms/*genetics/pathology ; Female ; Humans ; Male ; Microsatellite Instability ; Mutation ; Pathology, Molecular ; Proto-Oncogene Proteins B-raf/*genetics ; Proto-Oncogene Proteins p21(ras)/*genetics ; Telomere/*genetics ; Telomere Homeostasis/genetics ; },
abstract = {All tumors have in common to reactivate a telomere maintenance mechanism to allow for unlimited proliferation. On the other hand, genetic instability found in some tumors can result from the loss of telomeres. Here, we measured telomere length in colorectal cancers (CRCs) using TRF (Telomere Restriction Fragment) analysis. Telomeric DNA content was also quantified as the ratio of total telomeric (TTAGGG) sequences over that of the invariable Alu sequences. In most of the 125 CRCs analyzed, there was a significant diminution in telomere length compared with that in control healthy tissue. Only 34 tumors exhibited no telomere erosion and, in some cases, a slight telomere lengthening. Telomere length did not correlate with age, gender, tumor stage, tumor localization or stage of tumor differentiation. In addition, while telomere length did not correlate with the presence of a mutation in BRAF (V-raf murine sarcoma viral oncogene homolog B), PIK3CA (phosphatidylinositol 3-kinase catalytic subunit), or MSI status, it was significantly associated with the occurrence of a mutation in KRAS. Interestingly, we found that the shorter the telomeres in healthy tissue of a patient, the larger an increase in telomere length in the tumor. Our study points to the existence of two types of CRCs based on telomere length and reveals that telomere length in healthy tissue might influence telomere maintenance mechanisms in the tumor.},
}
@article {pmid28847485,
year = {2018},
author = {Ravlić, S and Škrobot Vidaček, N and Nanić, L and Laganović, M and Slade, N and Jelaković, B and Rubelj, I},
title = {Mechanisms of fetal epigenetics that determine telomere dynamics and health span in adulthood.},
journal = {Mechanisms of ageing and development},
volume = {174},
number = {},
pages = {55-62},
doi = {10.1016/j.mad.2017.08.014},
pmid = {28847485},
issn = {1872-6216},
mesh = {Animals ; Epigenesis, Genetic/*physiology ; Female ; Fetal Development/*physiology ; Fetus/*metabolism ; Gene Expression Regulation, Developmental/*physiology ; Humans ; Pregnancy ; Telomere Homeostasis/*physiology ; },
abstract = {Advances in epigenetics now enable us to better understand environmental influences on the genetic background of human diseases. This refers especially to fetal development where an adverse intrauterine environment impacts oxygen and nutrient supply to the fetus. Recently, differences in telomere length and telomere loss dynamics among individuals born with intrauterine growth restriction compared to normal controls have been described. In this paper we propose possible molecular mechanisms that (pre)program telomere epigenetics during pregnancy. This programming sets differences in telomere lengths and dynamics of telomere shortening in adulthood and therefore dictates the dynamics of aging and morbidity in later life.},
}
@article {pmid28844976,
year = {2017},
author = {Morea, EGO and Viviescas, MA and Fernandes, CAH and Matioli, FF and Lira, CBB and Fernandez, MF and Moraes, BS and da Silva, MS and Storti, CB and Fontes, MRM and Cano, MIN},
title = {A calmodulin-like protein (LCALA) is a new Leishmania amazonensis candidate for telomere end-binding protein.},
journal = {Biochimica et biophysica acta. General subjects},
volume = {1861},
number = {11 Pt A},
pages = {2583-2597},
doi = {10.1016/j.bbagen.2017.08.011},
pmid = {28844976},
issn = {0304-4165},
mesh = {Amino Acid Sequence/genetics ; Calmodulin/chemistry/*genetics ; DNA, Single-Stranded/chemistry/genetics ; Humans ; Leishmania/*genetics/pathogenicity ; Leishmaniasis/*genetics/parasitology ; Protein Binding ; Telomere ; Telomere-Binding Proteins/*chemistry/genetics ; },
abstract = {BACKGROUND: Leishmania spp. telomeres are composed of 5'-TTAGGG-3' repeats associated with proteins. We have previously identified LaRbp38 and LaRPA-1 as proteins that bind the G-rich telomeric strand. At that time, we had also partially characterized a protein: DNA complex, named LaGT1, but we could not identify its protein component.<br><br>METHODS AND RESULTS: Using protein-DNA interaction and competition assays, we confirmed that LaGT1 is highly specific to the G-rich telomeric single-stranded DNA. Three protein bands, with LaGT1 activity, were isolated from affinity-purified protein extracts in-gel digested, and sequenced de novo using mass spectrometry analysis. In silico analysis of the digested peptide identified them as a putative calmodulin with sequences identical to the T. cruzi calmodulin. In the Leishmania genome, the calmodulin ortholog is present in three identical copies. We cloned and sequenced one of the gene copies, named it LCalA, and obtained the recombinant protein. Multiple sequence alignment and molecular modeling showed that LCalA shares homology to most eukaryotes calmodulin. In addition, we demonstrated that LCalA is nuclear, partially co-localizes with telomeres and binds in vivo the G-rich telomeric strand. Recombinant LCalA can bind specifically and with relative affinity to the G-rich telomeric single-strand and to a 3'G-overhang, and DNA binding is calcium dependent.<br><br>CONCLUSIONS: We have described a novel candidate component of Leishmania telomeres, LCalA, a nuclear calmodulin that binds the G-rich telomeric strand with high specificity and relative affinity, in a calcium-dependent manner.<br><br>GENERAL SIGNIFICANCE: LCalA is the first reported calmodulin that binds in vivo telomeric DNA.},
}
@article {pmid28844059,
year = {2017},
author = {Clausen, ES and Snyder, LD},
title = {Do donors matter? Short telomeres and survival after lung transplant.},
journal = {Thorax},
volume = {72},
number = {11},
pages = {965-966},
doi = {10.1136/thoraxjnl-2017-210363},
pmid = {28844059},
issn = {1468-3296},
mesh = {Humans ; *Lung Transplantation ; Retrospective Studies ; Survival Rate ; *Telomere ; Tissue Donors ; },
}
@article {pmid28843010,
year = {2017},
author = {Marcon, F and Siniscalchi, E and Andreoli, C and Allione, A and Fiorito, G and Medda, E and Guarrera, S and Matullo, G and Crebelli, R},
title = {Telomerase activity, telomere length and hTERT DNA methylation in peripheral blood mononuclear cells from monozygotic twins with discordant smoking habits.},
journal = {Environmental and molecular mutagenesis},
volume = {58},
number = {8},
pages = {551-559},
doi = {10.1002/em.22127},
pmid = {28843010},
issn = {1098-2280},
mesh = {Adult ; DNA Methylation/*genetics ; Epigenesis, Genetic ; Female ; Humans ; Leukocytes, Mononuclear/drug effects/pathology ; Lung Neoplasms/etiology/*genetics/pathology ; Male ; Middle Aged ; Promoter Regions, Genetic ; Smoking/adverse effects/*genetics/pathology ; Telomerase/*genetics ; Telomere/genetics ; Telomere Homeostasis/genetics ; Twins, Monozygotic ; },
abstract = {Increased telomerase expression has been implicated in the pathogenesis of lung cancer and, since the primary cause of lung cancer is smoking, an association between telomerase reactivation and tobacco smoke has been proposed. In this work an investigation has been performed to assess the relationship between tobacco smoke exposure and telomerase activity (TA) in peripheral blood mononuclear cells of healthy smokers. The methylation status of the catalytic subunit of telomerase hTERT was concurrently investigated to assess the possible association between epigenetic modifications of hTERT and TA. Besides, the association between smoke and telomere length (TL) has been evaluated. Healthy monozygotic twins with discordant smoking habits were selected as study population to minimize inter-individual differences because of demographic characteristics and genetic heterogeneity. Statistically significant higher values of TA and TL were observed in smokers compared to nonsmoker co-twins. The multivariate analysis of data showed, besides smoking habits (P = 0.02), an influence of gender (P = 0.006) and BMI (P = 0.001) on TA and a borderline effect of gender (P = 0.05) on TL. DNA methylation analysis, focused on 100 CpG sites mapping in hTERT, highlighted nine CpG sites differentially methylated in smokers. When co-twins were contrasted, selecting as variables the intra-twin difference in TA and hTERT DNA methylation, a statistically significant inverse correlation (P = 0.003) was observed between TA and DNA methylation at the cg05521538 site. In conclusion, these results indicate an association of tobacco smoke with TA and TL and suggest a possible association between smoke-induced epigenetic effects and TA in healthy smokers. Environ. Mol. Mutagen. 58:551-559, 2017. © 2017 Wiley Periodicals, Inc.},
}
@article {pmid28838341,
year = {2017},
author = {Ruan, GP and Yao, X and Shu, J and Liu, JF and Pang, RQ and Pan, XH},
title = {Chicken egg-white extracts promote OCT4 and NANOG expression and telomeres growth in 293T cells.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {63},
number = {7},
pages = {59-65},
doi = {10.14715/cmb/2017.63.7.10},
pmid = {28838341},
issn = {1165-158X},
mesh = {Animals ; Blotting, Western ; Cell Extracts/*pharmacology ; Cell Proliferation/drug effects ; Chickens ; Coculture Techniques ; Egg White/*chemistry ; Electrophoresis, Polyacrylamide Gel ; Flow Cytometry ; Gene Expression Regulation/*drug effects ; HEK293 Cells ; Humans ; Nanog Homeobox Protein/*genetics/metabolism ; Octamer Transcription Factor-3/*genetics/metabolism ; Telomere/*metabolism ; Telomere Homeostasis/drug effects ; },
abstract = {It will have broad applications in cell biology if one of egg cell extracts has the roles to promote cell proliferation and reprogramming. It will provide a new method for easier reprogramming somatic cells and promote cell proliferation. We found chicken egg-white extracts have roles to promote cell proliferation and reprogramming. The different ingredients were then assessed for cell proliferation activity and somatic cell reprogramming. Chicken egg-white extract ingredients that were less than 3 kDa (LT3K) promoted cell proliferation. Those ingredients that were greater than 3 kDa (GT3K) promoted the increased expression of pluripotency factors in somatic cells and promote telomeres growth in 293T cells. Chicken egg-whites can be separated into ingredients of LT3K, which act to promote cell proliferation, and GT3K, which can be used to promote somatic cell reprogramming.},
}
@article {pmid28835501,
year = {2017},
author = {Zhang, E and Bell, AJ and Wilkie, GS and Suárez, NM and Batini, C and Veal, CD and Armendáriz-Castillo, I and Neumann, R and Cotton, VE and Huang, Y and Porteous, DJ and Jarrett, RF and Davison, AJ and Royle, NJ},
title = {Inherited Chromosomally Integrated Human Herpesvirus 6 Genomes Are Ancient, Intact, and Potentially Able To Reactivate from Telomeres.},
journal = {Journal of virology},
volume = {91},
number = {22},
pages = {},
pmid = {28835501},
issn = {1098-5514},
support = {CZD/16/6/CSO_/Chief Scientist Office/United Kingdom ; WT097828MF/WT_/Wellcome Trust/United Kingdom ; CGA/16/31/CSO_/Chief Scientist Office/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; MC_UU_12014/3/MRC_/Medical Research Council/United Kingdom ; G0901657/MRC_/Medical Research Council/United Kingdom ; MC_UU_12014/12/MRC_/Medical Research Council/United Kingdom ; },
mesh = {*Chromosomes, Human/genetics/virology ; Female ; *Genome, Human ; Genome-Wide Association Study ; Herpesvirus 6, Human/*genetics ; Humans ; Male ; *Quantitative Trait, Heritable ; *Telomere/genetics/virology ; Virus Integration/*genetics ; },
abstract = {The genomes of human herpesvirus 6A (HHV-6A) and HHV-6B have the capacity to integrate into telomeres, the essential capping structures of chromosomes that play roles in cancer and ageing. About 1% of people worldwide are carriers of chromosomally integrated HHV-6 (ciHHV-6), which is inherited as a genetic trait. Understanding the consequences of integration for the evolution of the viral genome, for the telomere, and for the risk of disease associated with carrier status is hampered by a lack of knowledge about ciHHV-6 genomes. Here, we report an analysis of 28 ciHHV-6 genomes and show that they are significantly divergent from the few modern nonintegrated HHV-6 strains for which complete sequences are currently available. In addition, ciHHV-6B genomes in Europeans are more closely related to each other than to ciHHV-6B genomes from China and Pakistan, suggesting regional variation of the trait. Remarkably, at least one group of European ciHHV-6B carriers has inherited the same ciHHV-6B genome, integrated in the same telomere allele, from a common ancestor estimated to have existed 24,500 ± 10,600 years ago. Despite the antiquity of some, and possibly most, germ line HHV-6 integrations, the majority of ciHHV-6B (95%) and ciHHV-6A (72%) genomes contain a full set of intact viral genes and therefore appear to have the capacity for viral gene expression and full reactivation.IMPORTANCE Inheritance of HHV-6A or HHV-6B integrated into a telomere occurs at a low frequency in most populations studied to date, but its characteristics are poorly understood. However, stratification of ciHHV-6 carriers in modern populations due to common ancestry is an important consideration for genome-wide association studies that aim to identify disease risks for these people. Here, we present full sequence analysis of 28 ciHHV-6 genomes and show that ciHHV-6B in many carriers with European ancestry most likely originated from ancient integration events in a small number of ancestors. We propose that ancient ancestral origins for ciHHV-6A and ciHHV-6B are also likely in other populations. Moreover, despite their antiquity, all of the ciHHV-6 genomes appear to retain the capacity to express viral genes, and most are predicted to be capable of full viral reactivation. These discoveries represent potentially important considerations in immunocompromised patients, in particular in organ transplantation and in stem cell therapy.},
}
@article {pmid28834755,
year = {2017},
author = {Dan, J and Rousseau, P and Hardikar, S and Veland, N and Wong, J and Autexier, C and Chen, T},
title = {Zscan4 Inhibits Maintenance DNA Methylation to Facilitate Telomere Elongation in Mouse Embryonic Stem Cells.},
journal = {Cell reports},
volume = {20},
number = {8},
pages = {1936-1949},
pmid = {28834755},
issn = {2211-1247},
support = {R01 AI121403/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; *DNA Methylation ; HEK293 Cells ; Humans ; Mice ; Mouse Embryonic Stem Cells/metabolism/*physiology ; Telomere/*genetics/metabolism ; Transcription Factors/*genetics/metabolism ; Transfection ; },
abstract = {Proper telomere length is essential for embryonic stem cell (ESC) self-renewal and pluripotency. Mouse ESCs (mESCs) sporadically convert to a transient totipotent state similar to that of two-cell (2C) embryos to recover shortened telomeres. Zscan4, which exhibits a burst of expression in 2C-like mESCs, is required for telomere extension in these cells. However, the mechanism by which Zscan4 extends telomeres remains elusive. Here, we show that Zscan4 facilitates telomere elongation by inducing global DNA demethylation through downregulation of Uhrf1 and Dnmt1, major components of the maintenance DNA methylation machinery. Mechanistically, Zscan4 recruits Uhrf1 and Dnmt1 and promotes their degradation, which depends on the E3 ubiquitin ligase activity of Uhrf1. Blocking DNA demethylation prevents telomere elongation associated with Zscan4 expression, suggesting that DNA demethylation mediates the effect of Zscan4. Our results define a molecular pathway that contributes to the maintenance of telomere length homeostasis in mESCs.},
}
@article {pmid28834142,
year = {2017},
author = {Sanderson, SL and Simon, AK},
title = {In aged primary T cells, mitochondrial stress contributes to telomere attrition measured by a novel imaging flow cytometry assay.},
journal = {Aging cell},
volume = {16},
number = {6},
pages = {1234-1243},
pmid = {28834142},
issn = {1474-9726},
support = {103830/Z/14/Z//Wellcome Trust/United Kingdom ; },
mesh = {Flow Cytometry/*methods ; Humans ; Mitochondria/*metabolism ; T-Lymphocyte Subsets/*metabolism ; Telomere/*metabolism ; },
abstract = {The decline of the immune system with age known as immune senescence contributes to inefficient pathogen clearance and is a key risk factor for many aged-related diseases. However, reversing or halting immune aging requires more knowledge about the cell biology of senescence in immune cells. Telomere shortening, low autophagy and mitochondrial dysfunction have been shown to underpin cell senescence. While autophagy has been found to control mitochondrial damage, no link has been made to telomere attrition. In contrast, mitochondrial stress can contribute to telomere attrition and vice versa. Whereas this link has been investigated in fibroblasts or cell lines, it is unclear whether this link exists in primary cells such as human lymphocytes and whether autophagy contributes to it. As traditional methods for measuring telomere length are low throughput or unsuitable for the analysis of cell subtypes within a mixed population of primary cells, we have developed a novel sensitive flow-FISH assay using the imaging flow cytometer. Using this assay, we show a correlation between age and increased mitochondrial reactive oxygen species in CD8[+] T-cell subsets, but not with autophagy. Telomere shortening within the CD8[+] subset could be prevented in vitro by treatment with a ROS scavenger. Our novel assay is a sensitive assay to measure relative telomere length in primary cells and has revealed ROS as a contributing factor to the decline in telomere length.},
}
@article {pmid28833123,
year = {2017},
author = {Ma, LJ and Wang, XY and Duan, M and Liu, LZ and Shi, JY and Dong, LQ and Yang, LX and Wang, ZC and Ding, ZB and Ke, AW and Cao, Y and Zhang, XM and Zhou, J and Fan, J and Gao, Q},
title = {Telomere length variation in tumor cells and cancer-associated fibroblasts: potential biomarker for hepatocellular carcinoma.},
journal = {The Journal of pathology},
volume = {243},
number = {4},
pages = {407-417},
pmid = {28833123},
issn = {1096-9896},
mesh = {Cancer-Associated Fibroblasts/*metabolism/pathology ; Carcinoma, Hepatocellular/genetics/*metabolism/pathology/therapy ; Cell Line, Tumor ; Chi-Square Distribution ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Kaplan-Meier Estimate ; Liver Neoplasms/genetics/*metabolism/pathology/therapy ; Male ; Middle Aged ; Multivariate Analysis ; Mutation ; Neoplasm Recurrence, Local ; Promoter Regions, Genetic ; Proportional Hazards Models ; Real-Time Polymerase Chain Reaction ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism/pathology ; *Telomere Homeostasis ; *Telomere Shortening ; Treatment Outcome ; Tumor Microenvironment ; },
abstract = {The role of telomere dysfunction and aberrant telomerase activities in hepatocellular carcinoma (HCC) has been overlooked for many years. This study aimed to delineate the variation and prognostic value of telomere length in HCC. Telomere-specific fluorescence in situ hybridization (FISH) and qPCR were used to evaluate telomere length in HCC cell lines, tumor tissues, and isolated non-tumor cells within the tumor. Significant telomere attrition was found in tumor cells and cancer-associated fibroblasts (CAFs) compared to their normal counterparts, but not in intratumor leukocytes or bile duct epithelial cells. Clinical relevance and prognostic value of telomere length were investigated on tissue microarrays of 257 surgically treated HCC patients. Reduced intensity of telomere signals in tumor cells or CAFs correlated with larger tumor size and the presence of vascular invasion (p < 0.05). Shortened telomeres in tumor cells or CAFs associated with reduced survival and increased recurrence, and were identified as independent prognosticators for HCC patients (p < 0.05). These findings were validated in an independent HCC cohort of 371 HCC patients from The Cancer Genome Atlas (TCGA) database, confirming telomere attrition and its prognostic value in HCC. We also showed that telomerase reverse transcriptase promoter (TERTp) mutation correlated with telomere shortening in HCC. Telomere variation in tumor cells and non-tumor cells within the tumor microenvironment of HCC was a valuable prognostic biomarker for this fatal malignancy. © 2017 The Authors. The Journal of Pathology published by John Wiley &amp; Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.},
}
@article {pmid28827085,
year = {2017},
author = {Scarabino, D and Broggio, E and Gambina, G and Corbo, RM},
title = {Leukocyte telomere length in mild cognitive impairment and Alzheimer's disease patients.},
journal = {Experimental gerontology},
volume = {98},
number = {},
pages = {143-147},
doi = {10.1016/j.exger.2017.08.025},
pmid = {28827085},
issn = {1873-6815},
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/blood/diagnosis/*genetics/*psychology ; Case-Control Studies ; *Cognition ; Cognitive Dysfunction/blood/diagnosis/*genetics/*psychology ; Disease Progression ; Female ; Humans ; Leukocytes/*chemistry ; Linear Models ; Male ; Mental Status and Dementia Tests ; Middle Aged ; Neuropsychological Tests ; Risk Factors ; Telomere/*genetics ; *Telomere Shortening ; },
abstract = {Numerous studies have reported an association between shortened leukocyte telomere length (LTL) and increased risk of Alzheimer's disease (AD). In this study we investigated the relationship between LTL and AD development, including in the analysis patients with amnestic mild cognitive impairment (aMCI), a clinical entity considered prodromal of AD. LTL (T/S ratio) was measured in patients with AD (n=61) or aMCI (n=46), and compared with LTL of age-matched controls (n=56). Significant LTL differences were observed between controls, aMCI and AD patients (p<0.0001), with mean LTL values (±s.d) in the order: AD patients (0.70±0.15)<aMCI patients (0.80±0.14)<controls (0.88±0.15). A positive relationship (linear regression p=0.004) was observed between LTL and cognitive performance (measured by Mini Mental State Examination score). LTL did not differ by APOE genotype. The shortened LTL observed in AD patients appears to stem from progressive telomere erosion possibly correlated with the cognitive decline characterizing conversion from aMCI to AD. LTL reduction, indicating active cell proliferation, may reflect immune system involvement in AD pathogenesis.},
}
@article {pmid28826474,
year = {2017},
author = {Strecker, J and Stinus, S and Caballero, MP and Szilard, RK and Chang, M and Durocher, D},
title = {A sharp Pif1-dependent threshold separates DNA double-strand breaks from critically short telomeres.},
journal = {eLife},
volume = {6},
number = {},
pages = {},
pmid = {28826474},
issn = {2050-084X},
support = {FDN143343//CIHR/Canada ; },
mesh = {Base Sequence ; Chromosomes ; *DNA Breaks, Double-Stranded ; DNA Helicases/*metabolism ; DNA, Fungal ; Gene Expression Profiling ; Gene Expression Regulation, Fungal ; Genes, Fungal/genetics ; Genetic Vectors ; Intracellular Signaling Peptides and Proteins/metabolism ; Mutagenesis ; Mutation ; Protein Serine-Threonine Kinases/metabolism ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {DNA double-strand breaks (DSBs) and short telomeres are structurally similar, yet they have diametrically opposed fates. Cells must repair DSBs while blocking the action of telomerase on these ends. Short telomeres must avoid recognition by the DNA damage response while promoting telomerase recruitment. In Saccharomyces cerevisiae, the Pif1 helicase, a telomerase inhibitor, lies at the interface of these end-fate decisions. Using Pif1 as a sensor, we uncover a transition point in which 34 bp of telomeric (TG1-3)n repeat sequence renders a DNA end insensitive to Pif1 action, thereby enabling extension by telomerase. A similar transition point exists at natural chromosome ends, where telomeres shorter than ~40 bp are inefficiently extended by telomerase. This phenomenon is not due to known Pif1 modifications and we instead propose that Cdc13 renders TG34+ ends insensitive to Pif1 action. We contend that the observed threshold of Pif1 activity defines a dividing line between DSBs and telomeres.},
}
@article {pmid28825101,
year = {2017},
author = {Wang, YP and Zhu, ZY and Tang, Y and Ma, YC},
title = {[Effects of acute hypoxia on telomere length of rat gastric mucosa tissue and underlying mechanism].},
journal = {Sheng li xue bao : [Acta physiologica Sinica]},
volume = {69},
number = {4},
pages = {429-436},
pmid = {28825101},
issn = {0371-0874},
mesh = {Animals ; Gastric Mucosa/*pathology ; Hypoxia/*pathology ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Male ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Telomerase/metabolism ; Telomere/*ultrastructure ; Transcriptional Activation ; Up-Regulation ; },
abstract = {The present study was aimed to investigate the effect of acute hypoxia on telomere length of rat gastric mucosa tissue and possible mechanism. Forty male Wistar rats were randomly divided into control group (resided in Lanzhou, 1 500 m) and experimental group (hypoxia chamber, 5 000 m). The experimental group was further divided into 3 subgroups and exposed to hypoxia for 1, 3, 7 d (n = 10), respectively. The morphological changes of the gastric mucosa tissue were observed by HE staining. By means of real-time PCR, ELISA and chemical immunofluorescence methods, the telomere length, the mRNA and protein levels of telomerase reverse transcriptase (TERT), hypoxia-inducible factor 1α (HIF-1α) and HIF-2α, and reactive oxygen species (ROS) level in gastric mucosa tissue were measured, respectively. The results showed that, with the extension of hypoxia-exposure time, the injury in gastric mucosa cells progressively became worse, and telomere length was increased gradually, along with intracellular ROS generation. The changes of TERT and HIF-1α expressions induced by acute hypoxia were in the same trend as that of telomere length. There were positive correlations between TERT mRNA expression and telomere length and between TERT and HIF-1α expressions, but not between TERT and HIF-2α mRNA expressions. These results suggest that under acute severe hypoxia environment, ROS could damage the gastric mucosa tissue cells, meanwhile the expressions of TERT and telomerase activity may be up-regulated by HIF-1α, which can elongate the telomere length and protect gastric mucosa tissue against fatal injury.},
}
@article {pmid28822964,
year = {2017},
author = {Polonis, K and Somers, VK and Becari, C and Covassin, N and Schulte, PJ and Druliner, BR and Johnson, RA and Narkiewicz, K and Boardman, LA and Singh, P},
title = {Moderate-to-severe obstructive sleep apnea is associated with telomere lengthening.},
journal = {American journal of physiology. Heart and circulatory physiology},
volume = {313},
number = {5},
pages = {H1022-H1030},
pmid = {28822964},
issn = {1522-1539},
support = {R01 CA204013/CA/NCI NIH HHS/United States ; R01 HL065176/HL/NHLBI NIH HHS/United States ; R01 HL114024/HL/NHLBI NIH HHS/United States ; R01 HL114676/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Case-Control Studies ; Chi-Square Distribution ; Comorbidity ; Cross-Sectional Studies ; Female ; Genetic Markers ; Humans ; Linear Models ; Male ; Middle Aged ; Multivariate Analysis ; Polysomnography ; Risk Factors ; Severity of Illness Index ; Sleep Apnea, Obstructive/diagnosis/*genetics/physiopathology ; Telomere/*genetics ; *Telomere Homeostasis ; Telomere Shortening ; },
abstract = {Obstructive sleep apnea (OSA) is associated with cardiometabolic diseases. Telomere shortening is linked to hypertension, diabetes mellitus, and cardiovascular diseases. Because these conditions are highly prevalent in OSA, we hypothesized that telomere length (TL) would be reduced in OSA patients. We identified 106 OSA and 104 non-OSA subjects who underwent polysomnography evaluation. Quantitative PCR was used to measure telomere length in genomic DNA isolated from peripheral blood samples. The association between OSA and TL was determined using unadjusted and adjusted linear models. There was no difference in TL between the OSA and non-OSA (control) group. However, we observed a J-shaped relationship between TL and OSA severity: the longest TL in moderate-to-severe OSA [4,918 ± 230 (SD) bp] and the shortest TL in mild OSA (4,735 ± 145 bp). Mean TL in moderate-to-severe OSA was significantly longer than in the control group after adjustment for age, sex, body mass index, hypertension, dyslipidemia, and depression (β = 96.0, 95% confidence interval: 15.4-176.6, P = 0.020). In conclusion, moderate-to-severe OSA is associated with telomere lengthening. Our findings support the idea that changes in TL are not unidirectional processes, such that telomere shortening occurs with age and disease but may be prolonged in moderate-to-severe OSA.NEW &amp; NOTEWORTHY Here, we show that moderate-to-severe obstructive sleep apnea is associated with longer telomeres, independent of age and cardiovascular risk factors, challenging the hypothesis that telomere shortening is a unidirectional process related to age/disease. A better understanding of the mechanisms underlying telomere dynamics may identify targets for therapeutic intervention in cardiovascular aging/other chronic diseases.},
}
@article {pmid28821750,
year = {2017},
author = {Runnberg, R and Narayanan, S and Cohn, M},
title = {Rap1 and Cdc13 have complementary roles in preventing exonucleolytic degradation of telomere 5' ends.},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {8729},
pmid = {28821750},
issn = {2045-2322},
mesh = {Amino Acid Sequence ; Base Sequence ; Binding Sites ; DNA, Single-Stranded/metabolism ; Exonucleases/metabolism ; Fungal Proteins/chemistry/*metabolism ; Protein Domains ; Saccharomyces/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomere DNA ends with a single-stranded 3' overhang. Long 3' overhangs may cause aberrant DNA damage responses and accelerate telomere attrition, which is associated with cancer and aging, respectively. Genetic studies have indicated several important players in preventing 5' end hyper-resection, yet detailed knowledge about the molecular mechanism in which they act is still lacking. Here, we use an in vitro DNA 5' end protection assay, to study how N. castellii Cdc13 and Rap1 protect against 5' exonucleolytic degradation by λ-exonuclease. The homogeneous telomeric repeat sequence of N. castellii allows us to study their protection ability at exact binding sites relative to the 5' end. We find efficient protection by both Cdc13 and Rap1 when bound close to the 5' end. Notably, Rap1 provides protection when binding dsDNA at a distance from the 5' end. The DNA binding domain of Rap1 is sufficient for 5' end protection, and its wrapping loop region is essential. Intriguingly, Rap1 facilitates protection also when its binding site contains 2 nt of ssDNA, thus spanning across the ds-ss junction. These results highlight a role of Rap1 in 5' end protection and indicate that Cdc13 and Rap1 have complementary roles in maintaining proper 3' overhang length.},
}
@article {pmid28819029,
year = {2017},
author = {Daniloski, Z and Smith, S},
title = {Loss of Tumor Suppressor STAG2 Promotes Telomere Recombination and Extends the Replicative Lifespan of Normal Human Cells.},
journal = {Cancer research},
volume = {77},
number = {20},
pages = {5530-5542},
pmid = {28819029},
issn = {1538-7445},
support = {R01 CA200751/CA/NCI NIH HHS/United States ; },
mesh = {Antigens, Nuclear/*genetics/metabolism ; Cell Cycle Proteins ; Cell Line, Tumor ; Cell Survival/genetics ; *Genes, Tumor Suppressor ; HCT116 Cells ; HeLa Cells ; Humans ; Neoplasms/genetics/pathology ; *Recombination, Genetic ; Telomere/*genetics/metabolism ; },
abstract = {Sister chromatids are held together by cohesin, a tripartite ring with a peripheral SA1/2 subunit, where SA1 is required for telomere cohesion and SA2 for centromere cohesion. The STAG2 gene encoding SA2 is often inactivated in human cancer, but not in in a manner associated with aneuploidy. Thus, how these tumors maintain chromosomal cohesion and how STAG2 loss contributes to tumorigenesis remain open questions. Here we show that, despite a loss in centromere cohesion, sister chromatids in STAG2 mutant tumor cells maintain cohesion in mitosis at chromosome arms and telomeres. Telomere maintenance in STAG2 mutant tumor cells occurred by either telomere recombination or telomerase activation mechanisms. Notably, these cells were refractory to telomerase inhibitors, indicating recombination can provide an alternative means of telomere maintenance. STAG2 silencing in normal human cells that lack telomerase led to increased recombination at telomeres, delayed telomere shortening, and postponed senescence onset. Insofar as telomere shortening and replicative senescence prevent genomic instability and cancer by limiting the number of cell divisions, our findings suggest that extending the lifespan of normal human cells due to inactivation of STAG2 could promote tumorigenesis by extending the period during which tumor-driving mutations occur. Cancer Res; 77(20); 5530-42. ©2017 AACR.},
}
@article {pmid28817217,
year = {2017},
author = {Beaulieu, M and Benoit, L and Abaga, S and Kappeler, PM and Charpentier, MJE},
title = {Mind the cell: Seasonal variation in telomere length mirrors changes in leucocyte profile.},
journal = {Molecular ecology},
volume = {26},
number = {20},
pages = {5603-5613},
doi = {10.1111/mec.14329},
pmid = {28817217},
issn = {1365-294X},
mesh = {*Aging ; Animals ; Cercopithecinae/*genetics ; Female ; Leukocytes/*cytology ; Male ; *Seasons ; Telomere/*ultrastructure ; },
abstract = {Leucocytes are typically considered as a whole in studies examining telomere dynamics in mammals. Such an approach may be precarious, as leucocytes represent the only nucleated blood cells in mammals, their composition varies temporally, and telomere length differs between leucocyte types. To highlight this limitation, we examined here whether seasonal variation in leucocyte composition was related to variation in telomere length in free-ranging mandrills (Mandrilllus sphinx). We found that the leucocyte profile of mandrills varied seasonally, with lower lymphocyte proportion being observed during the long dry season presumably because of the combined effects of high nematode infection and stress at that time of the year. Interestingly, this low lymphocyte proportion during the long dry season was associated with shorter telomeres. Accordingly, based on longitudinal data, we found that seasonal changes in lymphocyte proportion were reflected by corresponding seasonal variation in telomere length. Overall, these results suggest that variation in lymphocyte proportion in blood can significantly affect telomere measurements in mammals. However, lymphocyte proportion did not entirely explain variation in telomere length. For instance, a lower lymphocyte proportion with age could not fully explain shorter telomeres in older individuals. Overall, our results show that telomere length and leucocyte profile are strongly although imperfectly intertwined, which may obscure the relationship between telomere dynamics and ageing processes in mammals.},
}
@article {pmid28817123,
year = {2017},
author = {Sharifi-Sanjani, M and Meeker, AK and Mourkioti, F},
title = {Evaluation of telomere length in human cardiac tissues using cardiac quantitative FISH.},
journal = {Nature protocols},
volume = {12},
number = {9},
pages = {1855-1870},
pmid = {28817123},
issn = {1750-2799},
support = {P30 AR069619/AR/NIAMS NIH HHS/United States ; },
mesh = {Carbocyanines/chemistry ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Myocardium/*chemistry ; Peptide Nucleic Acids/chemistry ; Telomere/*chemistry ; },
abstract = {Telomere length has been correlated with various diseases, including cardiovascular disease and cancer. The use of currently available telomere-length measurement techniques is often restricted by the requirement of a large amount of cells (Southern-based techniques) or the lack of information on individual cells or telomeres (PCR-based methods). Although several methods have been used to measure telomere length in tissues as a whole, the assessment of cell-type-specific telomere length provides valuable information on individual cell types. The development of fluorescence in situ hybridization (FISH) technologies enables the quantification of telomeres in individual chromosomes, but the use of these methods is dependent on the availability of isolated cells, which prevents their use with fixed archival samples. Here we describe an optimized quantitative FISH (Q-FISH) protocol for measuring telomere length that bypasses the previous limitations by avoiding contributions from undesired cell types. We have used this protocol on small paraffin-embedded cardiac-tissue samples. This protocol describes step-by-step procedures for tissue preparation, permeabilization, cardiac-tissue pretreatment and hybridization with a Cy3-labeled telomeric repeat complementing (CCCTAA)3 peptide nucleic acid (PNA) probe coupled with cardiac-specific antibody staining. We also describe how to quantify telomere length by means of the fluorescence intensity and area of each telomere within individual nuclei. This protocol provides comparative cell-type-specific telomere-length measurements in relatively small human cardiac samples and offers an attractive technique to test hypotheses implicating telomere length in various cardiac pathologies. The current protocol (from tissue collection to image procurement) takes ∼28 h along with three overnight incubations. We anticipate that the protocol could be easily adapted for use on different tissue types.},
}
@article {pmid28816228,
year = {2018},
author = {Batsis, JA and Mackenzie, TA and Vasquez, E and Germain, CM and Emeny, RT and Rippberger, P and Lopez-Jimenez, F and Bartels, SJ},
title = {Association of adiposity, telomere length and mortality: data from the NHANES 1999-2002.},
journal = {International journal of obesity (2005)},
volume = {42},
number = {2},
pages = {198-204},
pmid = {28816228},
issn = {1476-5497},
support = {R01 MH078052/MH/NIMH NIH HHS/United States ; T32 MH073553/MH/NIMH NIH HHS/United States ; R01 MH089811/MH/NIMH NIH HHS/United States ; UL1 TR001086/TR/NCATS NIH HHS/United States ; U48 DP005018/DP/NCCDPHP CDC HHS/United States ; U48DP005018//ACL HHS/United States ; K23 AG051681/AG/NIA NIH HHS/United States ; R25 CA134286/CA/NCI NIH HHS/United States ; R24 MH102794/MH/NIMH NIH HHS/United States ; },
mesh = {Absorptiometry, Photon ; Adiposity/*genetics/*physiology ; Aged ; Body Composition ; Cross-Sectional Studies ; Female ; Humans ; Male ; Middle Aged ; *Nutrition Surveys ; Obesity/genetics/*mortality/physiopathology ; Proportional Hazards Models ; Telomere ; Telomere Shortening/*physiology ; },
abstract = {BACKGROUND/OBJECTIVES: Telomere shortening is associated with age and risk of medical comorbidity. We assessed the relationship between measures of adiposity, leukocyte telomere length, and mortality and whether it is modified by age.<br><br>SUBJECTS/METHODS: Subjects with dual-energy X-ray absorptiometry measures were identified using the National Health and Nutrition Examination Survey 1999-2002. Obesity was categorized using two body fat definitions (BF1%: men &#x2a7e;25%; females &#x2a7e;35%; BF2% &#x2a7e;28% and &#x2a7e;38%, respectively), body mass index (BMI) and waist circumference (WC; men &#x2a7e;102&#x2009;cm; females &#x2a7e;88&#x2009;cm). Telomere length relative to standard reference DNA (T/S ratio) was assessed using quantitative PCR. Weighted multivariable regression models evaluated the association of telomere length with adiposity, both continuously and categorically (low/normal BF%, low/high WC and standard BMI categories). Differences in telomere length by age and adiposity were ascertained and subsequent models were stratified by age. Proportional hazard models assessed the risk of mortality by adiposity status. A telomere by adiposity interaction was tested in the entire cohort and by age category (<60 vs &#x2a7e;60 years; <70 vs &#x2a7e;70 years).<br><br>RESULTS: We identified 7827 subjects. Mean age was 46.1 years. Overall telomere length was 1.05&#xb1;0.01 (s.e.) that differed by BF1% (low/high: 1.12&#xb1;0.02 vs 1.03&#xb1;0.02; P<0.001), BF2% (1.02&#xb1;0.02 vs 1.11&#xb1;0.02; P<0.001), BMI (underweight 1.08&#xb1;0.03; normal 1.09&#xb1;0.02; overweight 1.04&#xb1;0.02; and obese 1.03&#xb1;0.02;P<0.001) and WC (low/high 1.09&#xb1;0.02 vs 1.02&#xb1;0.02; P<0.001). Adjusted &#x3b2;-coefficients evaluating the relationship between telomere length and adiposity (measured continuously) were as follows: BF1% (&#x3b2;=-0.0033&#xb1;0.0008; P<0.001), BF2% (-0.041&#xb1;0.008; P<0.001), BMI (&#x3b2;=-0.025&#xb1;0.0008; P=0.005) and WC (&#x3b2;=-0.0011&#xb1;0.0004; P=0.007). High BF% (BF1%: &#x3b2;=-0.035&#xb1;0.011; P=0.002; BF2%: &#x3b2;=-0.041&#xb1;0.008; P<0.001) and WC (&#x3b2;=-0.035&#xb1;0.011; P=0.008) were inversely related to telomere length (TL). Stratifying by age, high BF1% (-0.061&#xb1;0.013), BF2% (-0.065&#xb1;0.01), BMI-obesity (-0.07&#xb1;0.015) and high WC (-0.048&#xb1;0.013) were significant (all P<0.001). This association diminished with increasing age. In older participants, TL was inversely related to mortality (hazard ratio 0.36 (0.27, 0.49)), as were those classified by BF1% (0.68 (0.56, 0.81)), BF2% (0.75 (0.65, 0.80)), BMI (0.50 (0.42, 0.60)) and WC (0.72 (0.63, 0.83)). No interaction was observed between adiposity status, telomere length and mortality.<br><br>CONCLUSIONS: Obesity is associated with shorter telomere length in young participants, a relationship that diminishes with increasing age. It does not moderate the relationship with mortality.},
}
@article {pmid28813500,
year = {2017},
author = {Donaires, FS and Scatena, NF and Alves-Paiva, RM and Podlevsky, JD and Logeswaran, D and Santana, BA and Teixeira, AC and Chen, JJ and Calado, RT and Martinelli, ALC},
title = {Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma.},
journal = {PloS one},
volume = {12},
number = {8},
pages = {e0183287},
pmid = {28813500},
issn = {1932-6203},
support = {R01 GM094450/GM/NIGMS NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Carcinoma, Hepatocellular/*enzymology/*genetics ; Female ; Humans ; Liver Cirrhosis/*enzymology/genetics ; Liver Neoplasms/*enzymology/genetics ; Male ; Middle Aged ; Mutation/genetics ; Polymerase Chain Reaction ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; Young Adult ; },
abstract = {Telomeres are repetitive DNA sequences at linear chromosome termini, protecting chromosomes against end-to-end fusion and damage, providing chromosomal stability. Telomeres shorten with mitotic cellular division, but are maintained in cells with high proliferative capacity by telomerase. Loss-of-function mutations in telomere-maintenance genes are genetic risk factors for cirrhosis development in humans and murine models. Telomerase deficiency provokes accelerated telomere shortening and dysfunction, facilitating genomic instability and oncogenesis. Here we examined whether telomerase mutations and telomere shortening were associated with hepatocellular carcinoma (HCC) secondary to cirrhosis. Telomere length of peripheral blood leukocytes was measured by Southern blot and qPCR in 120 patients with HCC associated with cirrhosis and 261 healthy subjects. HCC patients were screened for telomerase gene variants (in TERT and TERC) by Sanger sequencing. Age-adjusted telomere length was comparable between HCC patients and healthy subjects by both Southern blot and qPCR. Four non-synonymous TERT heterozygous variants were identified in four unrelated patients, resulting in a significantly higher mutation carrier frequency (3.3%) in patients as compared to controls (p = 0.02). Three of the four variants (T726M, A1062T, and V1090M) were previously observed in patients with other telomere diseases (severe aplastic anemia, acute myeloid leukemia, and cirrhosis). A novel TERT variant, A243V, was identified in a 65-year-old male with advanced HCC and cirrhosis secondary to chronic hepatitis C virus (HCV) and alcohol ingestion, but direct assay measurements in vitro did not detect modulation of telomerase enzymatic activity or processivity. In summary, constitutional variants resulting in amino acid changes in the telomerase reverse transcriptase were found in a small proportion of patients with cirrhosis-associated HCC.},
}
@article {pmid28813116,
year = {2017},
author = {Barbé-Tuana, FM and Parisi, MM and Panizzutti, BS and Fries, GR and Grun, LK and Guma, FT and Kapczinski, F and Berk, M and Gama, CS and Rosa, AR},
title = {Analyzing leukocyte telomere length in bipolar disorder: Authors' reply.},
journal = {Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)},
volume = {39},
number = {3},
pages = {275-276},
pmid = {28813116},
issn = {1809-452X},
mesh = {*Bipolar Disorder ; Humans ; Leukocytes ; Telomere ; Telomere Shortening ; },
}
@article {pmid28813115,
year = {2017},
author = {Monroy-Jaramillo, N},
title = {Analyzing leukocyte telomere length in bipolar disorder.},
journal = {Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)},
volume = {39},
number = {3},
pages = {274},
pmid = {28813115},
issn = {1809-452X},
mesh = {Aging ; *Bipolar Disorder ; Humans ; Leukocytes ; *Telomere ; },
}
@article {pmid28811878,
year = {2017},
author = {Cerchiara, JA and Risques, RA and Prunkard, D and Smith, JR and Kane, OJ and Boersma, PD},
title = {Magellanic penguin telomeres do not shorten with age with increased reproductive effort, investment, and basal corticosterone.},
journal = {Ecology and evolution},
volume = {7},
number = {15},
pages = {5682-5691},
pmid = {28811878},
issn = {2045-7758},
abstract = {All species should invest in systems that enhance longevity; however, a fundamental adult life-history trade-off exists between the metabolic resources allocated to maintenance and those allocated to reproduction. Long-lived species will invest more in reproduction than in somatic maintenance as they age. We investigated this trade-off by analyzing correlations among telomere length, reproductive effort and output, and basal corticosterone in Magellanic penguins (Spheniscus magellanicus). Telomeres shorten with age in most species studied to date, and may affect adult survival. High basal corticosterone is indicative of stressful conditions. Corticosterone, and stress, has been linked to telomere shortening in other species. Magellanic penguins are a particularly good model organism for this question as they are an unusually long-lived species, exceeding their mass-adjusted predicted lifespan by 26%. Contrary to our hypothesis, we found adults aged 5 years to over 24 years of age had similar telomere lengths. Telomeres of adults did not shorten over a 3-year period, regardless of the age of the individual. Neither telomere length, nor the rate at which the telomeres changed over these 3 years, correlated with breeding frequency or investment. Older females also produced larger volume clutches until approximately 15 years old and larger eggs produced heavier fledglings. Furthermore, reproductive success (chicks fledged/eggs laid) is maintained as females aged. Basal corticosterone, however, was not correlated with telomere length in adults and suggests that low basal corticosterone may play a role in the telomere maintenance we observed. Basal corticosterone also declined during the breeding season and was positively correlated with the age of adult penguins. This higher basal corticosterone in older individuals, and consistent reproductive success, supports the prediction that Magellanic penguins invest more in reproduction as they age. Our results demonstrate that telomere maintenance may be a component of longevity even with increased reproductive effort, investment, and basal corticosterone.},
}
@article {pmid28811689,
year = {2017},
author = {Pal, D and Singh, SK and Kakkar, N and Prasad, R},
title = {Expression of Telomere Binding Proteins (RAP1 and POT1) in Renal Cell Carcinoma and Their Correlation with Clinicopathological Parameters.},
journal = {Indian journal of clinical biochemistry : IJCB},
volume = {32},
number = {3},
pages = {301-305},
pmid = {28811689},
issn = {0970-1915},
abstract = {Telomere stability is indispensable for continuous proliferation of cells. Telomere structure is maintained by group of six proteins termed as shelterin. RAP1 and POT1 proteins are significant members of shelterin complex. Expression of RAP1 and POT1 are crucial for telomere maintenance and hence uncontrolled division of cells. Notably, expression of RAP1 and POT1 is unknown in renal cell carcinoma (RCC). In view of these facts, the present study was initiated to investigate the expression of RAP1 and POT1 in RCC and their relationships with clinicopathological features. In total 65 histopathologically confirmed RCC cases and their adjacent normal renal parenchyma were analyzed for gene expression. The mRNA expression of telomere binding proteins RAP1 and POT1 were measured using RT-PCR. Expression of RAP1 was observed to be significantly increased in tumour tissues as compared to corresponding normal renal tissues (P = 0.004). The gene expression of RAP1 was documented to be related to grades of RCC (P = 0.002) and subtypes of RCC (P = 0.01). Although, POT1 expression was up-regulated in RCC tissue, however it was not statistically significant. Also, POT1 expression was not related to grades, stages and subtypes of RCC. This is the first study which shows correlation RAP1 with grades and subtypes of RCC.},
}
@article {pmid28808664,
year = {2017},
author = {Chen, W and Wang, Y and Li, F and Lin, W and Liang, Y and Ma, Z},
title = {Expression of Telomere Repeat Binding Factor 1 and TRF2 in Prostate Cancer and Correlation with Clinical Parameters.},
journal = {BioMed research international},
volume = {2017},
number = {},
pages = {9764752},
pmid = {28808664},
issn = {2314-6141},
mesh = {Aged ; Biomarkers, Tumor/*genetics ; Cell Movement/genetics ; DNA-Binding Proteins/genetics ; Disease Progression ; Gene Expression Regulation, Neoplastic ; Humans ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Invasiveness/genetics/pathology ; Prostatic Neoplasms/*genetics/pathology ; Telomere/genetics ; Telomeric Repeat Binding Protein 1/*genetics ; Telomeric Repeat Binding Protein 2/*genetics ; },
abstract = {OBJECTIVE: The objective of this study was to investigate the expression of telomere repeat binding factor 1 (TRF1) and TRF2 in prostate cancer and their relationships with clinicopathological features.<br><br>METHODS: In total 50 prostate cancer tissues and paired benign prostate hyperplasia tissues were analyzed. The telomere-binding proteins TRF1 and TRF2 were measured using immunohistochemical method. Correlation analyses were used to evaluate the association between immunohistochemical score and clinical parameters.<br><br>RESULTS: The expression of TRF1 was significantly higher in prostate cancer tissue than in benign prostate hyperplasia tissue (&#x3c7;[2] = 62.69, P < 0.01). Elevated levels of TRF2 were observed in both prostate cancer and benign prostate hyperplasia tissue (&#x3c7;[2] = 1.13, P = 0.76). TRF1 expression was significantly positively correlated with surgical capsular invasion (Spearman's r = 0.43, P = 0.002), seminal vesicle invasion (Spearman's r = 0.35, P = 0.01), lymph nodes metastases (Spearman's r = 0.41, P = 0.003), total prostate specific antigen (r = 0.61, P < 0.05), and Gleason score (r = 0.47, P = 0.01). However, there were no significant statistical differences between prostate volume (r = 0.06, P = 0.75) and age (r = 0.14, P = 0.09).<br><br>CONCLUSION: Both TRF1 and TRF2 were overexpressed in prostate cancer. There was no specificity of TRF2 in prostate cancer, while TRF1 may be associated with prostate cancer progression.},
}
@article {pmid28805810,
year = {2017},
author = {Schmutz, I and Timashev, L and Xie, W and Patel, DJ and de Lange, T},
title = {TRF2 binds branched DNA to safeguard telomere integrity.},
journal = {Nature structural &amp; molecular biology},
volume = {24},
number = {9},
pages = {734-742},
pmid = {28805810},
issn = {1545-9985},
mesh = {Animals ; DNA/*metabolism ; Mice ; Models, Biological ; Poly (ADP-Ribose) Polymerase-1/antagonists &amp; inhibitors ; Protein Binding ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/*chemistry/*metabolism ; },
abstract = {Although t-loops protect telomeres, they are at risk of cleavage by Holliday junction (HJ) resolvases if branch migration converts the three-way t-loop junction into four-way HJs. T-loop cleavage is repressed by the TRF2 basic domain, which binds three- and four-way junctions and protects HJs in vitro. By replacing the basic domain with bacterial-protein domains binding three- and four-way junctions, we demonstrated the in vivo relevance of branched-DNA binding. Branched-DNA binding also repressed PARP1, presumably by masking the PARP1 site in the t-loop junction. Although PARP1 recruits HJ resolvases and promotes t-loop cleavage, PARP1 activation alone did not result in t-loop cleavage, thus suggesting that the basic domain also prevents formation of HJs. Concordantly, removal of HJs by BLM helicase mitigated t-loop cleavage in response to loss of the basic domain. We propose that TRF2 masks and stabilizes the t-loop three-way junction, thereby protecting telomeres from detrimental deletions and PARP1 activation.},
}
@article {pmid28805708,
year = {2017},
author = {Khincha, PP and Dagnall, CL and Hicks, B and Jones, K and Aviv, A and Kimura, M and Katki, H and Aubert, G and Giri, N and Alter, BP and Savage, SA and Gadalla, SM},
title = {Correlation of Leukocyte Telomere Length Measurement Methods in Patients with Dyskeratosis Congenita and in Their Unaffected Relatives.},
journal = {International journal of molecular sciences},
volume = {18},
number = {8},
pages = {},
pmid = {28805708},
issn = {1422-0067},
mesh = {Adolescent ; Adult ; Aged ; Blotting, Southern ; Child ; Child, Preschool ; Dyskeratosis Congenita/genetics/*pathology ; Female ; Flow Cytometry ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes/metabolism/*pathology ; Male ; Middle Aged ; Pedigree ; Real-Time Polymerase Chain Reaction ; Telomere/genetics/*pathology ; *Telomere Homeostasis ; Telomere Shortening ; Young Adult ; },
abstract = {Several methods have been employed to measure telomere length (TL) in human studies. It has been difficult to directly compare the results from these studies because of differences in the laboratory techniques and output parameters. We compared TL measurements (TLMs) by the three most commonly used methods, quantitative polymerase chain reaction (qPCR), flow cytometry with fluorescence in situ hybridization (flow FISH) and Southern blot, in a cohort of patients with the telomere biology disorder dyskeratosis congenita (DC) and in their unaffected relatives (controls). We observed a strong correlation between the Southern blot average TL and the flow FISH total lymphocyte TL in both the DC patients and their unaffected relatives (R[2] of 0.68 and 0.73, respectively). The correlation between the qPCR average TL and that of the Southern blot method was modest (R[2] of 0.54 in DC patients and of 0.43 in unaffected relatives). Similar results were noted when comparing the qPCR average TL and the flow FISH total lymphocyte TL (R[2] of 0.49 in DC patients and of 0.42 in unaffected relatives). In conclusion, the strengths of the correlations between the three widely used TL assays (qPCR, flow FISH, and Southern blot) were significantly different. Careful consideration is warranted when selecting the method of TL measurement for research and for clinical studies.},
}
@article {pmid28805012,
year = {2018},
author = {Eastwood, JR and Mulder, E and Verhulst, S and Peters, A},
title = {Increasing the accuracy and precision of relative telomere length estimates by RT qPCR.},
journal = {Molecular ecology resources},
volume = {18},
number = {1},
pages = {68-78},
doi = {10.1111/1755-0998.12711},
pmid = {28805012},
issn = {1755-0998},
mesh = {Animals ; *Blood ; Passeriformes/*genetics ; Real-Time Polymerase Chain Reaction/*methods/*standards ; Reproducibility of Results ; Specimen Handling/*methods ; *Telomere ; },
abstract = {As attrition of telomeres, DNA caps that protect chromosome integrity, is accelerated by various forms of stress, telomere length (TL) has been proposed as an indicator of lifetime accumulated stress. In ecological studies, it has been used to provide insights into ageing, life history trade-offs, the costs of reproduction and disease. qPCR is a high-throughput and cost-effective tool to measure relative TL (rTL) that can be applied to newly collected and archived ecological samples. However, qPCR is susceptible to error both from the method itself and pre-analytical steps. Here, repeatability was assessed overall and separately across multiple levels (intra-assay, inter-assay and inter-extraction) to elucidate the causes of measurement error, as a step towards improving precision. We also tested how accuracy, defined as the correlation between the "gold standard" for TL estimation (telomere restriction fragment length analysis with in-gel hybridization), could be improved. We find qPCR repeatability (intra- and inter-assay levels) to be at similar levels across three common storage media (ethanol, Longmire's and Queen's). However, inter-extraction repeatability was 50% lower for samples stored in Queen's lysis buffer, indicating storage medium can influence precision. Precision as well as accuracy could be increased by estimating rTL from multiple qPCR reactions and from multiple extractions. Repetition increased statistical power equivalent to a 25% (single extraction analysed twice) and 17% (two extractions) increase in sample size. Overall, this study identifies novel sources of variability in high-throughput telomere quantification and provides guidance on sampling strategy design and how to increase rTL precision and accuracy.},
}
@article {pmid28803568,
year = {2018},
author = {Boeck, C and Krause, S and Karabatsiakis, A and Schury, K and Gündel, H and Waller, C and Kolassa, IT},
title = {History of child maltreatment and telomere length in immune cell subsets: Associations with stress- and attachment-related hormones.},
journal = {Development and psychopathology},
volume = {30},
number = {2},
pages = {539-551},
doi = {10.1017/S0954579417001055},
pmid = {28803568},
issn = {1469-2198},
mesh = {Adult ; *Adult Survivors of Child Abuse ; Female ; Humans ; Hydrocortisone/*blood ; Monocytes/*metabolism ; *Object Attachment ; Oxytocin/*blood ; Stress, Psychological/*blood ; T-Lymphocytes/*metabolism ; *Telomere Shortening ; },
abstract = {Experiencing maltreatment during childhood can have long-lasting consequences for both mental and physical health. Immune cell telomere length (TL) shortening might be one link between child maltreatment (CM) experiences and adverse health outcomes later in life. While the stress hormone cortisol has been associated with TL attrition, the attachment-related hormone oxytocin may promote resilience. In 15 mothers with and 15 age- and body mass index-matched mothers without CM, we assessed TL in peripheral blood mononuclear cells and selected immune cell subsets (monocytes, naive, and memory cytotoxic T cells) by quantitative fluorescence in situ hybridization, as well as peripheral cortisol and oxytocin levels. Memory cytotoxic T cells showed significantly shorter TL in association with CM, whereas TL in monocytes and naive cytotoxic T cells did not significantly differ between the two groups. Across both groups, cortisol was negatively associated with TL, while oxytocin was positively associated with TL in memory cytotoxic T cells. These results indicate that long-lived memory cytotoxic T cells are most affected by the increased biological stress state associated with CM. Keeping in mind the correlational and preliminary nature of the results, the data suggest that cortisol may have a damaging and oxytocin a protective function on TL.},
}
@article {pmid28797893,
year = {2017},
author = {Cheng, Y and Yu, C and Huang, M and Du, F and Song, C and Ma, Z and Zhai, X and Yang, Y and Liu, J and Bei, JX and Jia, W and Jin, G and Li, S and Zhou, W and Liu, J and Dai, J and Hu, Z},
title = {Genetic association of telomere length with hepatocellular carcinoma risk: A Mendelian randomization analysis.},
journal = {Cancer epidemiology},
volume = {50},
number = {Pt A},
pages = {39-45},
doi = {10.1016/j.canep.2017.07.011},
pmid = {28797893},
issn = {1877-783X},
mesh = {Carcinoma, Hepatocellular/etiology/*genetics ; Case-Control Studies ; Female ; *Genetic Variation ; Genome-Wide Association Study ; Hepatitis B/*complications/virology ; Hepatitis B virus/genetics/isolation &amp; purification ; Humans ; Liver Neoplasms/etiology/*genetics ; Male ; Mendelian Randomization Analysis/*methods ; Middle Aged ; Risk Factors ; Telomere/*genetics ; },
abstract = {BACKGROUND: Observational studies show an association between telomere length and Hepatocellular carcinoma (HCC) risk, but the relationship is controversial. Particularly, it remains unclear whether the association is due to confounding or biases inherent in conventional epidemiological studies. Here, we applied Mendelian randomization approach to evaluate whether telomere length is causally associated with HCC risk.<br><br>METHODS: Individual-level data were from HBV-related HCC Genome-wide association studies (1,538 HBV positive HCC patients and 1,465 HBV positive controls). Genetic risk score, as proxy for actual measured telomere length, derived from nine telomere length-associated genetic variants was used to evaluate the effect of telomere length on HCC risk.<br><br>RESULTS: We observed a significant risk signal between genetically increased telomere length and HBV-related HCC risk (OR=2.09, 95% CI 1.32-3.31, P=0.002). Furthermore, a U-shaped curve was fitted by the restricted cubic spline curve, which indicated that either short or long telomere length would increase HCC risk (P=0.0022 for non-linearity test). Subgroup analysis did not reveal significant heterogeneity between different age, gender, smoking status and drinking status groups.<br><br>CONCLUSIONS: Our results indicated that a genetic background that favors longer or shorter telomere length may increase HBV-related HCC risk-a U-shaped association.},
}
@article {pmid28797570,
year = {2017},
author = {Machiela, MJ and Hofmann, JN and Carreras-Torres, R and Brown, KM and Johansson, M and Wang, Z and Foll, M and Li, P and Rothman, N and Savage, SA and Gaborieau, V and McKay, JD and Ye, Y and Henrion, M and Bruinsma, F and Jordan, S and Severi, G and Hveem, K and Vatten, LJ and Fletcher, T and Koppova, K and Larsson, SC and Wolk, A and Banks, RE and Selby, PJ and Easton, DF and Pharoah, P and Andreotti, G and Freeman, LEB and Koutros, S and Albanes, D and Mannisto, S and Weinstein, S and Clark, PE and Edwards, TE and Lipworth, L and Gapstur, SM and Stevens, VL and Carol, H and Freedman, ML and Pomerantz, MM and Cho, E and Kraft, P and Preston, MA and Wilson, KM and Gaziano, JM and Sesso, HS and Black, A and Freedman, ND and Huang, WY and Anema, JG and Kahnoski, RJ and Lane, BR and Noyes, SL and Petillo, D and Colli, LM and Sampson, JN and Besse, C and Blanche, H and Boland, A and Burdette, L and Prokhortchouk, E and Skryabin, KG and Yeager, M and Mijuskovic, M and Ognjanovic, M and Foretova, L and Holcatova, I and Janout, V and Mates, D and Mukeriya, A and Rascu, S and Zaridze, D and Bencko, V and Cybulski, C and Fabianova, E and Jinga, V and Lissowska, J and Lubinski, J and Navratilova, M and Rudnai, P and Szeszenia-Dabrowska, N and Benhamou, S and Cancel-Tassin, G and Cussenot, O and Bueno-de-Mesquita, HB and Canzian, F and Duell, EJ and Ljungberg, B and Sitaram, RT and Peters, U and White, E and Anderson, GL and Johnson, L and Luo, J and Buring, J and Lee, IM and Chow, WH and Moore, LE and Wood, C and Eisen, T and Larkin, J and Choueiri, TK and Lathrop, GM and Teh, BT and Deleuze, JF and Wu, X and Houlston, RS and Brennan, P and Chanock, SJ and Scelo, G and Purdue, MP},
title = {Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.},
journal = {European urology},
volume = {72},
number = {5},
pages = {747-754},
pmid = {28797570},
issn = {1873-7560},
support = {10124/CRUK_/Cancer Research UK/United Kingdom ; 20265/CRUK_/Cancer Research UK/United Kingdom ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; 6858/CRUK_/Cancer Research UK/United Kingdom ; R01 CA170298/CA/NCI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; RP-PG-0707-10101/DH_/Department of Health/United Kingdom ; MR/K012126/1/MRC_/Medical Research Council/United Kingdom ; ZIA CP010187-9/ImNIH/Intramural NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; 16561/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Carcinoma, Renal Cell/blood/*genetics/pathology ; Case-Control Studies ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Kidney Neoplasms/blood/*genetics/pathology ; Leukocytes/chemistry ; Mendelian Randomization Analysis ; Odds Ratio ; Phenotype ; *Polymorphism, Single Nucleotide ; Risk Assessment ; Risk Factors ; Telomere/*genetics/pathology ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.<br><br>OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.<br><br>Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.<br><br>Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.<br><br>RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R[2]>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13).<br><br>CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.<br><br>PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.},
}
@article {pmid28797026,
year = {2017},
author = {Gonzalez-Serna, A and Ajaykumar, A and Gadawski, I and Muñoz-Fernández, MA and Hayashi, K and Harrigan, PR and Côté, HCF},
title = {Rapid Decrease in Peripheral Blood Mononucleated Cell Telomere Length After HIV Seroconversion, but Not HCV Seroconversion.},
journal = {Journal of acquired immune deficiency syndromes (1999)},
volume = {76},
number = {1},
pages = {e29-e32},
pmid = {28797026},
issn = {1944-7884},
support = {U01 DA038886/DA/NIDA NIH HHS/United States ; //CIHR/Canada ; },
mesh = {Adult ; CD4-CD8 Ratio ; DNA Damage ; Disease Progression ; Female ; HIV Seropositivity/complications/*genetics/immunology/virology ; Hepatitis C/complications/*genetics/immunology/virology ; Humans ; Leukocytes, Mononuclear/*metabolism ; Longitudinal Studies ; Male ; Retrospective Studies ; *Seroconversion ; Substance Abuse, Intravenous/complications ; *Telomere Shortening ; Young Adult ; },
}
@article {pmid28796902,
year = {2018},
author = {Spurgin, LG and Bebbington, K and Fairfield, EA and Hammers, M and Komdeur, J and Burke, T and Dugdale, HL and Richardson, DS},
title = {Spatio-temporal variation in lifelong telomere dynamics in a long-term ecological study.},
journal = {The Journal of animal ecology},
volume = {87},
number = {1},
pages = {187-198},
pmid = {28796902},
issn = {1365-2656},
mesh = {Age Factors ; Animals ; Cohort Studies ; *Environment ; Female ; Male ; Sex Factors ; Seychelles ; Songbirds/*physiology ; Telomere/*physiology ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Understanding individual-level variation in response to the environment is fundamental to understanding life-history evolution and population dynamics. Telomeres, the protective caps at the ends of chromosomes, shorten in response to oxidative stress, and telomere shortening is correlated with reduced survival and life span. Investigating telomere dynamics may help us quantify individual variation in the costs experienced from social and ecological factors, and enhance our understanding of the dynamics of natural populations. Here, we study spatio-temporal variation in lifelong telomere dynamics in the Seychelles warbler, Acrocephalus sechellensis. We combine long-term life history and ecological data with a large longitudinal dataset of mean telomere lengths, consisting of 1,808 samples from 22 cohorts born between 1993 and 2014. We provide a detailed analysis of how telomere dynamics vary over individual life spans and cohorts, and with spatio-temporal variation in the social and ecological environment. We found that telomere length decreases with cross-sectional and longitudinal measures of age, and most rapidly very early in life. However, both cross-sectional and longitudinal data suggested that against this overall pattern of shortening, bouts of telomere length increase occur in some individuals. Using a large number of repeated measurements we show statistically that these increases are unlikely to be explained solely by qPCR measurement error. Telomere length varied markedly among cohorts. Telomere length was positively associated with temporal variation in island-wide insect abundance-a key resource for the insectivorous Seychelles warbler-suggesting that the costs associated with living in harsher environments can be studied by investigating telomere dynamics. We also found evidence for sex-specific relationships between telomeres and tarsus length, potentially reflecting differential costs of growth. Our long-term data show that in a natural population, telomere dynamics vary in a complex manner over individual life spans, and across space and time. Variance in telomere dynamics among individuals is the product of a wide array of genetic, parental and environmental factors. Explaining this variation more fully will require the integration of comprehensive long-term ecological and genetic data from multiple populations and species.},
}
@article {pmid28796865,
year = {2017},
author = {Haycock, PC and Hemani, G and Aviv, A},
title = {Telomere Length and Risk of Cancer and Non-neoplastic Diseases: Is Survivin the Ariadne's Thread?-Reply.},
journal = {JAMA oncology},
volume = {3},
number = {12},
pages = {1741-1742},
doi = {10.1001/jamaoncol.2017.2316},
pmid = {28796865},
issn = {2374-2445},
mesh = {Humans ; *Neoplasms ; *Survivin ; Telomere ; },
}
@article {pmid28796863,
year = {2017},
author = {Mormile, R},
title = {Telomere Length and Risk of Cancer and Non-neoplastic Diseases: Is Survivin the Ariadne's Thread?.},
journal = {JAMA oncology},
volume = {3},
number = {12},
pages = {1740-1741},
doi = {10.1001/jamaoncol.2017.2313},
pmid = {28796863},
issn = {2374-2445},
mesh = {Humans ; *Neoplasms ; Random Allocation ; *Survivin ; Telomere ; },
}
@article {pmid28796139,
year = {2017},
author = {Wu, H and Zou, WB and Zhou, DZ and Gu, YT and Liao, Z and Li, ZS},
title = {Longer Leukocyte Telomere Length is Associated With an Increased Risk of Chronic Pancreatitis.},
journal = {Pancreas},
volume = {46},
number = {8},
pages = {e65-e66},
doi = {10.1097/MPA.0000000000000887},
pmid = {28796139},
issn = {1536-4828},
mesh = {Adult ; Base Sequence ; Female ; Humans ; Leukocytes/*metabolism ; Logistic Models ; Male ; Middle Aged ; Multivariate Analysis ; Pancreatitis, Chronic/*genetics ; Risk Assessment/methods/statistics &amp; numerical data ; Risk Factors ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
}
@article {pmid28792435,
year = {2017},
author = {Kamranvar, SA and Masucci, MG},
title = {Regulation of Telomere Homeostasis during Epstein-Barr virus Infection and Immortalization.},
journal = {Viruses},
volume = {9},
number = {8},
pages = {},
pmid = {28792435},
issn = {1999-4915},
mesh = {B-Lymphocytes/virology ; Cell Cycle Checkpoints ; Cell Line ; *Cell Transformation, Viral ; Epstein-Barr Virus Infections/virology ; *Gene Expression Regulation ; Herpesvirus 4, Human/*genetics/*physiology ; Humans ; Telomerase/metabolism ; Telomere/*physiology ; *Telomere Homeostasis ; },
abstract = {The acquisition of unlimited proliferative potential is dependent on the activation of mechanisms for telomere maintenance, which counteracts telomere shortening and the consequent triggering of the DNA damage response, cell cycle arrest, and apoptosis. The capacity of Epstein Barr virus (EBV) to infect B-lymphocytes in vitro and transform the infected cells into autonomously proliferating immortal cell lines underlies the association of this human gamma-herpesvirus with a broad variety of lymphoid and epithelial cell malignancies. Current evidence suggests that both telomerase-dependent and -independent pathways of telomere elongation are activated in the infected cells during the early and late phases of virus-induced immortalization. Here we review the interaction of EBV with different components of the telomere maintenance machinery and the mechanisms by which the virus regulates telomere homeostasis in proliferating cells. We also discuss how these viral strategies may contribute to malignant transformation.},
}
@article {pmid28790317,
year = {2017},
author = {Burraco, P and Díaz-Paniagua, C and Gomez-Mestre, I},
title = {Different effects of accelerated development and enhanced growth on oxidative stress and telomere shortening in amphibian larvae.},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {7494},
pmid = {28790317},
issn = {2045-2322},
mesh = {Adipose Tissue/*physiology ; Animals ; Antioxidants/metabolism ; Anura/anatomy &amp; histology/*growth &amp; development/metabolism ; Body Size/*physiology ; Droughts ; Food Chain ; Larva/anatomy &amp; histology/enzymology/*growth &amp; development ; Longevity/*physiology ; Oxidative Stress ; Ponds ; Telomere/*chemistry ; Telomere Shortening ; },
abstract = {Organisms react to environmental changes through plastic responses that often involve physiological alterations with the potential to modify life-history traits and fitness. Environmentally induced shifts in growth and development in species with complex life cycles determine the timing of transitions between subsequent life stages, as well as body condition at transformation, which greatly determine survival at later stages. Here we show that spadefoot toad larvae surviving pond drying and predators experienced marked alterations in growth and development, and in their fat reserves, oxidative stress, and relative telomere length. Tadpoles accelerated development but reduced growth and consumed more fat reserves when facing pond drying. However, oxidative stress was buffered by increased antioxidant enzyme activity, and telomeres remained unchanged. Predators caused opposite effects: they reduced larval density, hence relaxing competition and allowing faster development and enhanced growth of survivors. Tadpoles surviving predators metamorphosed bigger and had larger fat bodies, increasing their short-term survival odds, but showed signs of oxidative stress and had shorter telomeres. Developmental acceleration and enhanced growth thus seemed to have different physiological consequences: reduced fat bodies and body size compromise short-term survival, but are reversible in the long run, whereas telomere shortening is non-reversible and could reduce long-term survival.},
}
@article {pmid28783753,
year = {2017},
author = {Johnsen, A and Pauliny, A and Lifjeld, JT and Blomqvist, D},
title = {Is telomere length associated with mate choice in a songbird with a high rate of extra-pair paternity?.},
journal = {PloS one},
volume = {12},
number = {8},
pages = {e0182446},
pmid = {28783753},
issn = {1932-6203},
mesh = {Animals ; Female ; Male ; *Paternity ; Reproduction/genetics ; *Sexual Behavior, Animal ; Songbirds/*genetics/physiology ; Telomere/*genetics ; },
abstract = {Telomere length is related to aging in many eukaryotes and the rate of telomere attrition has been suggested to reflect individual genetic quality. Telomere length could thus have implications for mate choice. We investigated telomere length variation in bluethroat Luscinia svecica families with mixed paternity, including social parents, extra-pair fathers and nestlings, testing whether telomere length is associated with social and/or extra-pair mate choice through assortative mating or selection of mates with relatively long telomeres. In adults, relative telomere length (rTL) did not differ between the sexes, nor between two age categories. In chicks, however, rTL decreased with body mass at sampling (an index of nestling age). We found a positive correlation between the rTL of social mates, suggesting assortative mating with respect to telomere length or a correlative thereof. However, extra-pair males did not differ from social mates in rTL, and accordingly there was also no difference between within- and extra-pair young (i.e. half-siblings) when controlling for the effect of mass. We found no relationships between telomere length, age and fitness-related traits in adults, but an intriguing year-difference in telomere length in both sexes. In conclusion, we found no support for the idea that females choose extra-pair males based on their telomere length, but social mate choice seems to be influenced by rTL, possibly through its co-variation with aspects reflecting individual quality, like early arrival at the breeding grounds.},
}
@article {pmid28780613,
year = {2018},
author = {Harari, Y and Kupiec, M},
title = {Mec1[ATR] is needed for extensive telomere elongation in response to ethanol in yeast.},
journal = {Current genetics},
volume = {64},
number = {1},
pages = {223-234},
pmid = {28780613},
issn = {1432-0983},
mesh = {Cell Cycle ; Chromatin Immunoprecipitation ; Ethanol/*pharmacology ; Intracellular Signaling Peptides and Proteins/*metabolism ; Models, Biological ; Mutation ; Phenotype ; Protein Serine-Threonine Kinases/*metabolism ; Saccharomyces cerevisiae/drug effects/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Stress, Physiological/drug effects/genetics ; Telomere/*genetics/*metabolism ; Telomere Homeostasis/*drug effects/*genetics ; },
abstract = {Telomere length homeostasis is essential for cell survival. In humans, telomeres shorten as a function of age. Short telomeres are known determinants of cell senescence and longevity. The yeast Saccharomyces cerevisiae expresses telomerase and maintains a strict telomere length homeostasis during vegetative growth. We have previously reported that different environmental signals promote changes in telomere length in S. cerevisiae. In particular, exposure to ethanol induces an extensive telomere elongation response due to a reduction in RAP1 mRNA and protein levels. Here we show that the reduction in Rap1 protein levels disrupts the physical interaction between Rap1 and Rif1, which in turn reduces the recruitment of these two proteins to telomeres during G2-phase. Although elongation of the shortest telomeres has been shown to depend on the Rif2 telomeric protein and on the Tel1(ATM) protein kinase, we show here that the extensive telomere elongation in response to ethanol exposure is Rif1 and Mec1 (ATR)-dependent. Our results fit a model in which Rif1 and Rap1 form a complex that is loaded onto telomeres at the end of S-phase. Reduced levels of the Rap1-Rif1 complex in ethanol lead to continuous telomere elongation in a Mec1-dependent process.},
}
@article {pmid28777749,
year = {2017},
author = {Sindi, S and Ngandu, T and Hovatta, I and Kåreholt, I and Antikainen, R and Hänninen, T and Levälahti, E and Laatikainen, T and Lindström, J and Paajanen, T and Peltonen, M and Khalsa, DS and Wolozin, B and Strandberg, T and Tuomilehto, J and Soininen, H and Kivipelto, M and Solomon, A and , },
title = {Baseline Telomere Length and Effects of a Multidomain Lifestyle Intervention on Cognition: The FINGER Randomized Controlled Trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {59},
number = {4},
pages = {1459-1470},
pmid = {28777749},
issn = {1875-8908},
support = {R01 AG050471/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Alzheimer Disease/*complications/psychology ; Cognition Disorders/*etiology/*rehabilitation ; Cognitive Behavioral Therapy ; Disabled Persons/rehabilitation ; Female ; Humans ; Leukocytes/*physiology ; *Life Style ; Male ; Neuropsychological Tests ; Telomere/pathology/*physiology ; },
abstract = {Leukocyte telomere length (LTL) is a biomarker of aging, and it is associated with lifestyle. It is currently unknown whether LTL is associated with the response to lifestyle interventions. The goal is to assess whether baseline LTL modified the cognitive benefits of a 2-year multidomain lifestyle intervention (exploratory analyses). The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was a 2-year randomized controlled trial including 1,260 people at risk of cognitive decline, aged 60-77 years identified from the general population. Participants were randomly assigned to the lifestyle intervention (diet, exercise, cognitive training, and vascular risk management) and control (general health advice) groups. Primary outcome was change in cognition (comprehensive neuropsychological test battery). Secondary outcomes were changes in cognitive domains: memory, executive functioning, and processing speed. 775 participants (392 control, 383 intervention) had baseline LTL (peripheral blood DNA). Mixed effects regression models with maximum likelihood estimation were used to analyze change in cognition as a function of randomization group, time, baseline LTL, and their interaction. Intervention and control groups did not significantly differ at baseline. Shorter LTL was related to less healthy baseline lifestyle. Intervention benefits on executive functioning were more pronounced among those with shorter baseline LTL (p-value for interaction was 0.010 adjusted for age and sex, and 0.007 additionally adjusted for baseline lifestyle factors). The FINGER intervention cognitive benefits were more pronounced with shorter baseline LTL, particularly for executive functioning, indicating that the multidomain lifestyle intervention was especially beneficial among higher-risk individuals.},
}
@article {pmid28777293,
year = {2017},
author = {Vecoli, C and Montano, L and Borghini, A and Notari, T and Guglielmino, A and Mercuri, A and Turchi, S and Andreassi, MG},
title = {Effects of Highly Polluted Environment on Sperm Telomere Length: A Pilot Study.},
journal = {International journal of molecular sciences},
volume = {18},
number = {8},
pages = {},
pmid = {28777293},
issn = {1422-0067},
mesh = {Adolescent ; Adult ; Demography ; *Environmental Pollution ; Humans ; Leukocytes/metabolism ; Male ; Pilot Projects ; Semen/metabolism ; Spermatozoa/*metabolism ; *Telomere Homeostasis ; Young Adult ; },
abstract = {High environmental pressure may impair male fertility by affecting sperm quality, but the real effect remains controversial. Herein, we assessed the influence of environmental exposure on telomere length (TL) in both leukocytes (LTL) and sperm cells (STL). A pilot biomonitoring study was conducted in 112 clinically healthy, normospermic men living in various areas of Campania region (South of Italy) with high (n = 57, High Group) or low (n = 55, Low Group) environmental pressure. TL analysis was assessed by quantitative real time-PCR. STL was not significantly correlated with either age (p = 0.6) or LTL (p = 0.7), but was significantly longer in the High Group compared with the Low Group (p = 0.04). No significant difference was observed between leukocyte TL in the High or Low Group. Our results showed that male residents in areas with high environment exposure had a significant increase in STL. This finding supports the view that the human semen is a sentinel biomarker of environmental exposure.},
}
@article {pmid28776935,
year = {2017},
author = {Wang, JY and Peng, SH and Ning, XH and Li, T and Liu, SJ and Liu, JY and Hong, BA and Qi, NN and Peng, X and Zhou, BW and Zhang, JF and Cai, L and Gong, K},
title = {Shorter telomere length increases age-related tumor risks in von Hippel-Lindau disease patients.},
journal = {Cancer medicine},
volume = {6},
number = {9},
pages = {2131-2141},
pmid = {28776935},
issn = {2045-7634},
mesh = {Adult ; Aged ; Aging/*genetics ; China ; Female ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Regression Analysis ; Risk Factors ; Telomere/*genetics ; *Telomere Shortening ; Young Adult ; von Hippel-Lindau Disease/*genetics ; },
abstract = {Von Hippel-Lindau (VHL) disease is a rare autosomal dominant cancer syndrome caused by alterations of VHL gene. Patients are predisposed to develop pheochromocytomas and solid or cystic tumors of the central nervous system, kidney, pancreas, and retina. Remarkable phenotypic heterogeneity exits in organ involvement and tumor onset age between and within VHL families. However, no reliable markers have been found to predict the age-related tumor risks in VHL patients. A large Chinese cohort composed of 300 VHL patients and 92 healthy family controls was enrolled in our study. Blood relative telomere length was measured in 184 patients and all the controls available for genomic DNA samples. Age-related risks for the five major VHL-associated tumors were evaluated using Kaplan-Meier plots and Cox regression analysis. Differences in clinical phenotype were observed between Chinese cohort and the United Kingdom cohort. VHL patients showed significantly shorter telomere length than healthy family controls(P = 0.0183), and a positive correlation was found between telomere length and onset age of the five major tumors, respectively. Moreover, patients in the shorter telomere group (age-adjusted telomere length ≤ 0.44) suffered higher age-related risks for VHL-associated central nervous system hemangioblastomas (HR: 1.879, P = 0.004), renal cell carcinoma (HR: 2.126, P = 0.002) and pancreatic cyst and neuroendocrine tumors (HR: 2.093, P = 0.001). These results indicate that blood shorter telomere length is a new biomarker for age-related tumor risks in VHL patients, which will be crucial to genetic counseling and future research about the role of telomere shortening in the pathogenesis of VHL-associated tumors.},
}
@article {pmid28770056,
year = {2017},
author = {Rollings, N and Friesen, CR and Sudyka, J and Whittington, C and Giraudeau, M and Wilson, M and Olsson, M},
title = {Telomere dynamics in a lizard with morph-specific reproductive investment and self-maintenance.},
journal = {Ecology and evolution},
volume = {7},
number = {14},
pages = {5163-5169},
pmid = {28770056},
issn = {2045-7758},
abstract = {Telomeres in human fibroblasts shorten progressively during in vitro culturing and trigger replicative senescence. Furthermore, shortened telomeres can be used as biomarkers of disease. These observations have led to the suggestion that telomere dynamics may also be associated with viability and selection for life history variation in non-human taxa. Model systems to examine this suggestion would particularly benefit from the coexistence of multiple phenotypes within the same species with different life history trade-offs, since those could be compared in terms of telomere characteristics. This scenario also provokes the classic question of why one morph does not have marginally higher fitness and replaces the others. One explanation is that different morphs have different reproductive tactics with equal relative fitness. In Australian painted dragons (Ctenophorus pictus), males differ in head color, the presence or absence of a gular bib, and reproductive expenditure. Red males out-compete yellow males in dominance contests, while yellow males copulate quickly and have higher success in sperm competition than red males. Males with bibs better defend partners against rival matings, at the cost of loss of body condition. We show that yellow-headed and bib-less males have longer telomeres than red, blue and bibbed males, suggesting that telomere length is positively associated with higher investment into self-maintenance and less reproductive expenditure.},
}
@article {pmid28765780,
year = {2017},
author = {Wang, H and Kim, H and Baik, I},
title = {Associations of alcohol consumption and alcohol flush reaction with leukocyte telomere length in Korean adults.},
journal = {Nutrition research and practice},
volume = {11},
number = {4},
pages = {334-339},
pmid = {28765780},
issn = {1976-1457},
abstract = {BACKGROUND/OBJECTIVES: Telomere length is a useful biomarker for determining general aging status. Some studies have reported an association between alcohol consumption and telomere length in a general population; however, it is unclear whether the alcohol flush reaction, which is an alcohol-related trait predominantly due to acetaldehyde dehydrogenase deficiency, is associated with telomere length. This cross-sectional study aimed to evaluate the associations of alcohol consumption and alcohol flush reaction with leukocyte telomere length (LTL).<br><br>SUBJECTS/METHODS: The study included 1,803 Korean adults. Participants provided blood specimens for LTL measurement assay and reported their alcohol drinking status and the presence of an alcohol flush reaction via a questionnaire-based interview. Relative LTL was determined by using a quantitative polymerase chain reaction. Statistical analysis used multiple linear regression models stratified by sex and age groups, and potential confounding factors were considered.<br><br>RESULTS: Age-specific analyses showed that heavy alcohol consumption (> 30 g/day) was strongly associated with a reduced LTL in participants aged &#x2265; 65 years (P < 0.001) but not in younger participants. Similarly, the alcohol flush reaction was associated with a reduced LTL only in older participants who consumed > 15 g/day of alcohol (P < 0.01). No significant alcohol consumption or alcohol flush reaction associations with LTL were observed in the sex-specific analyses.<br><br>CONCLUSIONS: The results suggest that older alcohol drinkers, particularly those with the alcohol flush reaction, may have an accelerated aging process.},
}
@article {pmid28764708,
year = {2017},
author = {Zhao, Y and Li, S and Liu, H},
title = {Estimating the survival advantage based on telomere length and serum biomarkers of aging.},
journal = {Journal of translational medicine},
volume = {15},
number = {1},
pages = {166},
pmid = {28764708},
issn = {1479-5876},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*blood ; Albumins/metabolism ; Biomarkers/*blood ; Case-Control Studies ; Cholesterol/blood ; Diabetes Mellitus/blood ; Humans ; Middle Aged ; Survival Analysis ; *Telomere Homeostasis ; Triglycerides/blood ; Young Adult ; },
abstract = {BACKGROUND: This study aimed to establish a model that estimates the survival advantage at the molecular level based on telomere length and serum biomarkers of aging, to explore clinical significance.<br><br>METHODS: The study consisted of 100 healthy subjects and 40 type 2 diabetes mellitus patients, 20-90&#xa0;years of age. Saliva telomere relative length (LnTL) was measured by the quantitative real-time polymerase chain reaction and the serum biochemical parameters, including albumin (ALB), total proteins, total cholesterol, triglycerides, and some enzyme parameters were detected by a biochemical analyzer. The Z values were transformed from mean values and standard deviations to estimate the survival advantage. A normal reference range (95% confidence interval) was set to the comprehensive advantage of the Z values (Zs) to evaluate the comprehensive survival advantage.<br><br>RESULTS: The Z values of serum ALB and saliva LnTL could be used to estimate the survival advantage, and effectively distinguish between the aging and nonaging individuals. The Zs was greater than 1.64 in the normal reference range, and type 2 diabetes mellitus patients had lower survival advantages compared to those of the control group (p&#xa0;<&#xa0;0.05).<br><br>CONCLUSIONS: Our two-dimensional model system using ALB and LnTL was valid and may have potential applications for evaluating the aging status at the molecular level, and for the observation of disease characteristics.},
}
@article {pmid28760773,
year = {2017},
author = {Min, J and Wright, WE and Shay, JW},
title = {Alternative Lengthening of Telomeres Mediated by Mitotic DNA Synthesis Engages Break-Induced Replication Processes.},
journal = {Molecular and cellular biology},
volume = {37},
number = {20},
pages = {},
pmid = {28760773},
issn = {1098-5549},
support = {R01 AG001228/AG/NIA NIH HHS/United States ; R13 CA113094/CA/NCI NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; C06 RR030414/RR/NCRR NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line ; DNA/*metabolism ; DNA Repair/*physiology ; DNA Replication/physiology ; Humans ; Rad52 DNA Repair and Recombination Protein/*metabolism ; Recombination, Genetic/genetics ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. By analyzing telomerase-positive cells and their human TERC knockout-derived ALT human cell lines, we show that ALT cells harbor more fragile telomeres representing telomere replication problems. ALT-associated replication defects trigger mitotic DNA synthesis (MiDAS) at telomeres in a RAD52-dependent, but RAD51-independent, manner. Telomeric MiDAS is a conservative DNA synthesis process, potentially mediated by break-induced replication, similar to type II ALT survivors in Saccharomyces cerevisiae Replication stresses induced by ectopic oncogenic expression of cyclin E, G-quadruplexes, or R-loop formation facilitate the ALT pathway and lead to telomere clustering, a hallmark of ALT cancers. The TIMELESS/TIPIN complex suppresses telomere clustering and telomeric MiDAS, whereas the SMC5/6 complex promotes them. In summary, ALT cells exhibit more telomere replication defects that result in persistent DNA damage responses at telomeres, leading to the engagement of telomeric MiDAS (spontaneous mitotic telomere synthesis) that is triggered by DNA replication stress, a potential driver of genomic duplications in cancer.},
}
@article {pmid28756275,
year = {2017},
author = {Dvořáková, Z and Vorlíčková, M and Renčiuk, D},
title = {Spectroscopic insights into quadruplexes of five-repeat telomere DNA sequences upon G-block damage.},
journal = {Biochimica et biophysica acta. General subjects},
volume = {1861},
number = {11 Pt A},
pages = {2750-2757},
doi = {10.1016/j.bbagen.2017.07.019},
pmid = {28756275},
issn = {0304-4165},
mesh = {Circular Dichroism ; G-Quadruplexes/*drug effects ; Guanine/chemistry ; Humans ; Nucleic Acid Conformation/drug effects ; Oxidative Stress/*genetics ; Point Mutation ; Repetitive Sequences, Nucleic Acid/genetics ; Sodium/toxicity ; Spectroscopy, Near-Infrared ; Telomere/*chemistry/drug effects/genetics ; },
abstract = {BACKGROUND: The DNA lesions, resulting from oxidative damage, were shown to destabilize human telomere four-repeat quadruplex and to alter its structure. Long telomere DNA, as a repetitive sequence, offers, however, other mechanisms of dealing with the lesion: extrusion of the damaged repeat into loop or shifting the quadruplex position by one repeat.<br><br>METHODS: Using circular dichroism and UV absorption spectroscopy and polyacrylamide electrophoresis, we studied consequences of lesions at different positions of the model five-repeat human telomere DNA sequences on the structure and stability of their quadruplexes in sodium and in potassium.<br><br>RESULTS: The repeats affected by lesion are preferentially positioned as terminal overhangs of the core quadruplex structurally similar to the four-repeat one. Forced affecting of the inner repeats leads to presence of variety of more parallel folds in potassium. In sodium the designed models form mixture of two dominant antiparallel quadruplexes whose population varies with the position of the affected repeat. The shapes of quadruplex CD spectra, namely the height of dominant peaks, significantly correlate with melting temperatures.<br><br>CONCLUSION: Lesion in one guanine tract of a more than four repeats long human telomere DNA sequence may cause re-positioning of its quadruplex arrangement associated with a shift of the structure to less common quadruplex conformations. The type of the quadruplex depends on the loop position and external conditions.<br><br>GENERAL SIGNIFICANCE: The telomere DNA quadruplexes are quite resistant to the effect of point mutations due to the telomere DNA repetitive nature, although their structure and, consequently, function might be altered.},
}
@article {pmid28755323,
year = {2017},
author = {Fogli, A and Demattei, MV and Corset, L and Vaurs-Barrière, C and Chautard, E and Biau, J and Kémény, JL and Godfraind, C and Pereira, B and Khalil, T and Grandin, N and Arnaud, P and Charbonneau, M and Verrelle, P},
title = {Detection of the alternative lengthening of telomeres pathway in malignant gliomas for improved molecular diagnosis.},
journal = {Journal of neuro-oncology},
volume = {135},
number = {2},
pages = {381-390},
pmid = {28755323},
issn = {1573-7373},
mesh = {Adult ; Brain/metabolism/pathology/surgery ; Brain Neoplasms/genetics/*metabolism/pathology/surgery ; Cell Line, Tumor ; Cohort Studies ; DNA Modification Methylases/genetics/metabolism ; DNA Repair Enzymes/genetics/metabolism ; Female ; Glioma/genetics/*metabolism/pathology/surgery ; Humans ; Isocitrate Dehydrogenase/genetics ; Male ; Middle Aged ; Neoplasm Grading ; RNA/metabolism ; Telomerase/metabolism ; *Telomere Homeostasis/physiology ; Tumor Suppressor Proteins/genetics/metabolism ; X-linked Nuclear Protein/metabolism ; },
abstract = {Human malignant gliomas exhibit acquisition of either one of two telomere maintenance mechanisms, resulting from either reactivation of telomerase expression or activation of an alternative lengthening of telomeres (ALT) mechanism. In the present study, we analyzed 63 human malignant gliomas for the presence of ALT-specific extrachromosomal circles of telomeric DNA (C-circles) and measured telomerase expression, telomeric DNA content (Telo/Alu method), and telomeric repeat-containing RNAs (TERRA) levels. We also assessed histomolecular markers routinely used in clinical practice. The presence of C-circles significantly correlated with IDH1/2 mutation, MGMT exon 1 methylation, low Ki-67 immunostaining, increased telomeric DNA content, absence of functional ATRX protein and level of HTERT gene expression. In multivariate analysis, we observed a trend to a correlation between elevated TERRA levels and increased survival. Interestingly, the C-circles assay allowed to detect ALT activation in glioblastomas exhibiting wild-type IDH1/2 and ATRX expression. These results suggest that, after the correlations uncovered here have been confirmed on larger numbers of tumors, telomeric markers might be useful in improving diagnosis. They also point out to the utility of using the specific, sensitive and quantitative C-circle and Telo/Alu assays that can work with as few as 30 ng of tumor DNA.},
}
@article {pmid28754961,
year = {2017},
author = {Huang, EE and Tedone, E and O'Hara, R and Cornelius, C and Lai, TP and Ludlow, A and Wright, WE and Shay, JW},
title = {The Maintenance of Telomere Length in CD28+ T Cells During T Lymphocyte Stimulation.},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {6785},
pmid = {28754961},
issn = {2045-2322},
support = {R00 CA197672/CA/NCI NIH HHS/United States ; K99 CA197672/CA/NCI NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; C06 RR030414/RR/NCRR NIH HHS/United States ; },
mesh = {Adult ; CD28 Antigens/genetics/metabolism ; Cells, Cultured ; Humans ; *Lymphocyte Activation ; T-Lymphocytes/*immunology ; Telomerase/metabolism ; *Telomere Homeostasis ; },
abstract = {Telomerase activity is not readily detected in resting human T lymphocytes, however upon antigen presentation, telomerase is transiently upregulated. Presently, it is not known if telomerase activation is necessary for the proliferation of T cells or for the maintenance of telomere lengths. In this study, we found that telomerase activation is not required for the short- term proliferation of T cells and that telomeres progressively shorten in a heterogeneous population of T cells, even if telomerase is detected. By measuring telomerase activity at the single-cell level using quantitative ddPCR techniques (ddTRAP) and by monitoring changes in the shortest telomeres with more sensitive telomere length measurement assays, we show that only a subset of CD28+ T-cells have robust telomerase activity upon stimulation and are capable of maintaining their telomere lengths during induced proliferation. The study of this T-cell subset may lead to a better understanding on how telomerase is regulated and functions in immune cells.},
}
@article {pmid28753967,
year = {2017},
author = {Casacuberta, E},
title = {Drosophila: Retrotransposons Making up Telomeres.},
journal = {Viruses},
volume = {9},
number = {7},
pages = {},
pmid = {28753967},
issn = {1999-4915},
mesh = {Animals ; Drosophila/*genetics ; Drosophila Proteins/genetics/metabolism ; Gene Products, gag/genetics/metabolism ; Retroelements/*genetics ; *Telomere ; },
abstract = {Drosophila and extant species are the best-studied telomerase exception. In this organism, telomere elongation is coupled with targeted retrotransposition of Healing Transposon (HeT-A) and Telomere Associated Retrotransposon (TART) with sporadic additions of Telomere Associated and HeT-A Related (TAHRE), all three specialized non-Long Terminal Repeat (non-LTR) retrotransposons. These three very special retroelements transpose in head to tail arrays, always in the same orientation at the end of the chromosomes but never in interior locations. Apparently, retrotransposon and telomerase telomeres might seem very different, but a detailed view of their mechanisms reveals similarities explaining how the loss of telomerase in a Drosophila ancestor could successfully have been replaced by the telomere retrotransposons. In this review, we will discover that although HeT-A, TART, and TAHRE are still the only examples to date where their targeted transposition is perfectly tamed into the telomere biology of Drosophila, there are other examples of retrotransposons that manage to successfully integrate inside and at the end of telomeres. Because the aim of this special issue is viral integration at telomeres, understanding the base of the telomerase exceptions will help to obtain clues on similar strategies that mobile elements and viruses could have acquired in order to ensure their survival in the host genome.},
}
@article {pmid28751647,
year = {2017},
author = {Xiao, CD and Ishizuka, T and Xu, Y},
title = {Antiparallel RNA G-quadruplex Formed by Human Telomere RNA Containing 8-Bromoguanosine.},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {6695},
pmid = {28751647},
issn = {2045-2322},
mesh = {Base Sequence ; Circular Dichroism ; *G-Quadruplexes ; Guanosine/*analogs &amp; derivatives/metabolism ; Humans ; Nuclear Magnetic Resonance, Biomolecular ; RNA/*metabolism ; Telomere/*metabolism ; },
abstract = {In this study, by combining nuclear magnetic resonance (NMR), circular dichroism (CD), liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS), and gel electrophoresis, we report an unusual topological structure of the RNA G-quadruplex motif formed by human telomere RNA r(UAGGGU) containing 8-bromoguanosine. Results showed that the RNA sequence formed an antiparallel tetramolecular G-quadruplex, in which each pair of diagonal strands run in opposite directions. Furthermore, guanosines were observed both in syn- and anti-conformations. In addition, two of these G-quadruplex subunits were found to be stacking on top of each other, forming a dimeric RNA G-quadruplex. Our findings provide a new insight into the behavior of RNA G-quadruplex structures.},
}
@article {pmid28747482,
year = {2017},
author = {Karell, P and Bensch, S and Ahola, K and Asghar, M},
title = {Pale and dark morphs of tawny owls show different patterns of telomere dynamics in relation to disease status.},
journal = {Proceedings. Biological sciences},
volume = {284},
number = {1859},
pages = {},
pmid = {28747482},
issn = {1471-2954},
mesh = {Animals ; Feathers ; Fertility ; Haemosporida/pathogenicity ; Longevity ; Parasite Load ; *Pigmentation ; Polymorphism, Genetic ; Protozoan Infections, Animal/*genetics ; Strigiformes/*genetics/*parasitology ; Telomere ; *Telomere Shortening ; },
abstract = {Parasites are expected to exert long-term costs on host fecundity and longevity. Understanding the consequences of heritable polymorphic variation in disease defence in wild populations is essential in order to predict evolutionary responses to changes in disease risk. Telomeres have been found to shorten faster in malaria-diseased individuals compared with healthy ones with negative effects on longevity and thereby fitness. Here, we study the impact of haemosporidian blood parasites on telomere dynamics in tawny owls, which display a highly heritable plumage colour polymorphism. Previously, it has been shown that blood parasites have morph-specific impact on body mass maintenance. Here, we show that telomeres shortened faster in individuals with shorter breeding lifespan. Telomere length was negatively associated with the degree of pheomelanic brown coloration and shorter in infected than uninfected individuals. The rate of telomere shortening between breeding seasons was faster in darker pheomelanic individuals and suppression of parasite intensity between seasons was associated with faster telomere shortening in the paler individuals but not in darker ones. We propose that morph-specific physiological profiles cause differential telomere shortening and that this is likely to be a mechanism involved in previously documented environment-driven survival selection against the pheomelanic morph in this population.},
}
@article {pmid28746203,
year = {2017},
author = {Yu, JH and Baik, I and Cho, HJ and Seo, JA and Kim, SG and Choi, KM and Baik, SH and Choi, DS and Shin, C and Kim, NH},
title = {The FTO rs9939609 polymorphism is associated with short leukocyte telomere length in nonobese individuals.},
journal = {Medicine},
volume = {96},
number = {30},
pages = {e7565},
pmid = {28746203},
issn = {1536-5964},
mesh = {Adiposity ; Age Factors ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/*genetics ; Body Mass Index ; Cholesterol, HDL/blood ; Cohort Studies ; DNA Mutational Analysis ; Female ; Genetic Predisposition to Disease ; Genotype ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Obesity/blood/genetics ; *Polymorphism, Single Nucleotide ; Real-Time Polymerase Chain Reaction ; Republic of Korea ; Risk Factors ; Telomere/*metabolism ; Telomere Shortening/genetics/physiology ; Waist Circumference ; },
abstract = {The fat mass and obesity-associated (FTO) rs9939609 polymorphism have been associated with the increased metabolic risk and mortality, irrespective of obesity. The mechanism underlying this association is not known. We aimed to evaluate whether the FTO rs9939609 risk variant is independently associated with metabolic risk factors and/or leukocyte telomere length (LTL). We further aimed to investigate whether this relationship is modified by obesity status.A total of 2133 participants were recruited from the Korean Genome and Epidemiology Study. LTL was measured using the real-time quantitative polymerase chain reaction methodology. The FTO rs9939609 polymorphism was genotyped using DNA samples collected at baseline.The proportions of the TT, TA, and AA genotypes were 76.7%, 21.5%, and 1.8%, respectively, and obese subjects comprised 44.5% of the total subjects. Among the 1184 nonobese subjects, body mass index, waist circumference, and visceral fat area were higher in subjects with the FTO risk allele than in noncarriers. In contrast, only high-sensitive C-reactive protein level was associated with the FTO risk allele in the obese subjects. LTL was significantly shorter in carriers of the FTO risk allele compared with noncarriers after controlling for several confounding factors (P < .01). Of particular note, this significant association between the FTO risk allele and LTL appeared only in nonobese subjects (P = .03). Multivariate linear regression analyses identified older age, low high-density lipoprotein cholesterol level, and the presence of the FTO risk allele as independent risk factors affecting LTL. This finding was evident only in nonobese subjects.The FTO rs9939609 polymorphism is an independent risk factor for obesity and also for biological aging in the nonobese population.},
}
@article {pmid28742796,
year = {2017},
author = {Callahan, CL and Schwartz, K and Ruterbusch, JJ and Shuch, B and Graubard, BI and Lan, Q and Cawthon, R and Baccarelli, AA and Chow, WH and Rothman, N and Hofmann, JN and Purdue, MP},
title = {Leukocyte telomere length and renal cell carcinoma survival in two studies.},
journal = {British journal of cancer},
volume = {117},
number = {5},
pages = {752-755},
pmid = {28742796},
issn = {1532-1827},
support = {UL1 TR001863/TR/NCATS NIH HHS/United States ; },
mesh = {Aged ; Biomarkers, Tumor/blood/genetics ; Carcinoma, Renal Cell/blood/genetics/mortality/*ultrastructure ; Case-Control Studies ; Colorectal Neoplasms/blood/genetics/mortality/*ultrastructure ; Female ; Humans ; Kidney Neoplasms/blood/genetics/mortality/*ultrastructure ; Leukocytes/*ultrastructure ; Lung Neoplasms/blood/genetics/mortality/*ultrastructure ; Male ; Middle Aged ; Ovarian Neoplasms/blood/genetics/mortality/*ultrastructure ; Prognosis ; Prostatic Neoplasms/blood/genetics/mortality/*ultrastructure ; Survival Rate ; Telomere/*ultrastructure ; *Telomere Shortening ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) is a potential biomarker of cancer prognosis; however, evidence for renal cell carcinoma (RCC) is inconsistent.<br><br>METHODS: We investigated LTL and RCC-specific survival among 684 cases from the US kidney cancer study (USKC) and 241 cases from the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO). Leukocyte telomere length was measured by quantitative polymerase chain reaction, and hazard ratios (HRs) and 95% confidence intervals (CIs) computed using multivariable Cox models.<br><br>RESULTS: Short LTL was associated with poorer disease-specific survival in both USKC (lowest vs highest quartile: HR: 2.3, 95% CI: 1.2-4.4; P for trend=0.02) and PLCO (HR: 2.4, 95% CI: 1.0-5.4; P=0.04). Among USKC cases, the association was strongest for stage-I RCC (HR: 5.5, 95% CI: 1.6-19.0; P=0.006).<br><br>CONCLUSIONS: Our findings suggest that shorter LTL is an independent marker of poor RCC prognosis, particularly for stage-I disease.},
}
@article {pmid28740738,
year = {2017},
author = {Wojcicki, JM and Rehkopf, D and Epel, E and Rosenthal, P},
title = {Shorter Leukocyte Telomere Length in Relation to Presumed Nonalcoholic Fatty Liver Disease in Mexican-American Men in NHANES 1999-2002.},
journal = {International journal of hepatology},
volume = {2017},
number = {},
pages = {8435178},
pmid = {28740738},
issn = {2090-3448},
support = {K01 AG047280/AG/NIA NIH HHS/United States ; },
abstract = {Leukocyte telomere length is shorter in response to chronic disease processes associated with inflammation such as diabetes mellitus and coronary artery disease. Data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002 was used to explore the relationship between leukocyte telomere length and presumed NAFLD, as indicated by elevated serum alanine aminotransferase (ALT) levels, obesity, or abdominal obesity. Logistic regression models were used to evaluate the relationship between telomere length and presumed markers of NAFLD adjusting for possible confounders. There was no relationship between elevated ALT levels, abdominal obesity, or obesity and telomere length in adjusted models in NHANES (OR 1.13, 95% CI 0.48-2.65; OR 1.17, 95% CI 0.52-2.62, resp.). Mexican-American men had shorter telomere length in relation to presumed NAFLD (OR 0.07, 95% CI 0.006-0.79) and using different indicators of NAFLD (OR 0.012, 95% CI 0.0006-0.24). Mexican origin with presumed NAFLD had shorter telomere length than men in other population groups. Longitudinal studies are necessary to evaluate the role of telomere length as a potential predictor to assess pathogenesis of NALFD in Mexicans.},
}
@article {pmid28740573,
year = {2017},
author = {Augustine, T and Maitra, R and Goel, S},
title = {Telomere length regulation through epidermal growth factor receptor signaling in cancer.},
journal = {Genes &amp; cancer},
volume = {8},
number = {5-6},
pages = {550-558},
pmid = {28740573},
issn = {1947-6019},
abstract = {Length of the telomere (TL), a structure at the tip of chromosome that protects and ensures stability, is determined by multi-protein complexes such as telosome/shelterin and telomerase. Earlier studies from our laboratory show that longer TL has potential to be positive predictive biomarker of clinical outcome to anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy in patients with KRAS WT metastatic colorectal cancer. Although there is extensive literature suggesting the role of shelterin and telomerase, not much literature exists that describes the role of EGFR and KRAS pathway in regulating TL. This detailed review focuses on an insight into various components, including proteins, enzymes and transcription factors, interlinking between EGFR pathways and telomerase that regulate TL.},
}
@article {pmid28738460,
year = {2017},
author = {Liu, HF and Li, F and Wang, YH and Chen, JH and Peng, DX and Chen, J and Tan, LH and Mi, X and Zhao, BH},
title = {[Association between sleep and leukocyte telomere length in middle-aged and older adults].},
journal = {Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi},
volume = {38},
number = {7},
pages = {889-892},
doi = {10.3760/cma.j.issn.0254-6450.2017.07.008},
pmid = {28738460},
issn = {0254-6450},
mesh = {Aged ; Aging ; Humans ; Leukocytes/metabolism ; Middle Aged ; Sleep/*genetics/*physiology ; Surveys and Questionnaires ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {Objective: To understand the association between peripheral leukocytes telomere length (TL) and sleep in middle-aged and old adults. Methods: A total of 176 middle-aged and old adults were investigated by using the Pittsburgh Sleep Quality Index and questionnaire. TL was measured by fluorescence quantitative PCR. The correlation and regression analysis between sleep and telomere length was performed. Results: TL had a mean T/S ratio of 0.995±0.23. There was a negative correlation between TL and age (r=-0.241, P=0.003). With increasing age, sleep quality became worse (r=-0.230, P<0.01), the time to fall asleep became longer (r=0.227, P<0.01), sleep duration was shorter (r=-0.486, P<0.01), sleep efficiency became worse (r=-0.226, P<0.01). After controlling for the effects of gender, age, marital status, income level, residence, smoking, drinking, physical exercise and disease status, multiple linear regression analysis indicated that sleep quality (β=0.057, P<0.01), time to fall asleep (β=-0.046, P<0.01), sleep duration (β=0.086, P<0.01) were independent influencing factors of telomere length, suggesting that the people who had better sleep quality, the shorter time to fall asleep, the longer sleep time would have longer telomere length. Conclusions: Sleep is a relevant factor affecting TL in middle-aged and elderly population. Good sleep may delay aging by slowing TL. We encourage to conduct health education about the importance of sleep quality in community.},
}
@article {pmid28737902,
year = {2017},
author = {Banyasz, A and Martínez-Fernández, L and Balty, C and Perron, M and Douki, T and Improta, R and Markovitsi, D},
title = {Absorption of Low-Energy UV Radiation by Human Telomere G-Quadruplexes Generates Long-Lived Guanine Radical Cations.},
journal = {Journal of the American Chemical Society},
volume = {139},
number = {30},
pages = {10561-10568},
doi = {10.1021/jacs.7b05931},
pmid = {28737902},
issn = {1520-5126},
mesh = {Absorption, Radiation ; Cations ; Free Radicals/chemistry ; *G-Quadruplexes ; Guanine/*chemistry ; Humans ; Molecular Structure ; Telomere/*chemistry ; *Ultraviolet Rays ; },
abstract = {Telomeres, which are involved in cell division, carcinogenesis, and aging and constitute important therapeutic targets, are prone to oxidative damage. This propensity has been correlated with the presence of guanine-rich sequences, capable of forming four-stranded DNA structures (G-quadruplexes). Here, we present the first study on oxidative damage of human telomere G-quadruplexes without mediation of external molecules. Our investigation has been performed for G-quadruplexes formed by folding of GGG(TTAGGG)3 single strands in buffered solutions containing Na[+] cations (TEL21/Na[+]). Associating nanosecond time-resolved spectroscopy and quantum mechanical calculations (TD-DFT), it focuses on the primary species, ejected electrons and guanine radicals, generated upon absorption of UV radiation directly by TEL21/Na[+]. We show that, at 266 nm, corresponding to an energy significantly lower than the guanine ionization potential, the one-photon ionization quantum yield is 4.5 × 10[-3]. This value is comparable to that of cyclobutane thymine dimers (the major UV-induced lesions) in genomic DNA; the quantum yield of these dimers in TEL21/Na[+] is found to be (1.1 ± 0.1) × 10[-3]. The fate of guanine radicals, generated in equivalent concentration with that of ejected electrons, is followed over 5 orders of magnitude of time. Such a quantitative approach reveals that an important part of radical cation population survives up to a few milliseconds, whereas radical cations produced by chemical oxidants in various DNA systems are known to deprotonate, at most, within a few microseconds. Under the same experimental conditions, neither one-photon ionization nor long-lived radical cations are detected for the telomere repeat TTAGGG in single-stranded configuration, showing that secondary structure plays a key role in these processes. Finally, two types of deprotonated radicals are identified: on the one hand, (G-H2)[•] radicals, stable at early times, and on the other hand, (G-H1)[•] radicals, appearing within a few milliseconds and decaying with a time constant of ∼50 ms.},
}
@article {pmid28732250,
year = {2017},
author = {Wang, Y and Feigon, J},
title = {Structural biology of telomerase and its interaction at telomeres.},
journal = {Current opinion in structural biology},
volume = {47},
number = {},
pages = {77-87},
pmid = {28732250},
issn = {1879-033X},
support = {R01 GM048123/GM/NIGMS NIH HHS/United States ; },
mesh = {Cryoelectron Microscopy ; Models, Biological ; Models, Molecular ; Nucleic Acid Conformation ; Protein Binding ; Protein Conformation ; Protein Interaction Domains and Motifs ; Structure-Activity Relationship ; Telomerase/*chemistry/*metabolism ; Telomere/*chemistry/genetics/*metabolism ; },
abstract = {Telomerase is an RNP that synthesizes the 3' ends of linear chromosomes and is an important regulator of telomere length. It contains a single long non-coding telomerase RNA (TER), telomerase reverse transcriptase (TERT), and other proteins that vary among organisms. Recent progress in structural biology of telomerase includes reports of the first cryo-electron microscopy structure of telomerase, from Tetrahymena, new crystal structures of TERT domains, telomerase RNA structures and models, and identification in Tetrahymena telomerase holoenzyme of human homologues of telomere-associated proteins that have provided a more unified view of telomerase interaction at telomeres as well as insights into the role of telomerase RNA in activity and assembly.},
}
@article {pmid28730662,
year = {2017},
author = {Wiwanitkit, V},
title = {Telomere length and angiogenic cytokines in knee osteoarthritis.},
journal = {International journal of rheumatic diseases},
volume = {20},
number = {12},
pages = {2141},
doi = {10.1111/1756-185X.13140},
pmid = {28730662},
issn = {1756-185X},
mesh = {Cytokines ; Humans ; Leukocytes ; *Osteoarthritis, Knee ; Telomere ; },
}
@article {pmid28730343,
year = {2017},
author = {Noreikiene, K and Kuparinen, A and Merilä, J},
title = {Age at maturation has sex- and temperature-specific effects on telomere length in a fish.},
journal = {Oecologia},
volume = {184},
number = {4},
pages = {767-777},
pmid = {28730343},
issn = {1432-1939},
support = {129662//Suomen Akatemia/International ; 134728//Suomen Akatemia/International ; 218343//Suomen Akatemia/International ; 265671//Suomen Akatemia/International ; 303685//Suomen Akatemia/International ; },
mesh = {Animals ; Female ; *Fishes/genetics ; Male ; Smegmamorpha ; *Telomere ; Temperature ; },
abstract = {Telomeres are highly conserved nucleoprotein structures which protect genome integrity. The length of telomeres is influenced by both genetic and environmental factors, but relatively little is known about how different hereditary and environmental factors interact in determining telomere length. We manipulated growth rates and timing of maturation by exposing full-sib nine-spined sticklebacks (Pungitius pungitius) to two different temperature treatments and quantified the effects of temperature treatments, sex, timing of maturation, growth rate and family (genetic influences) on telomere length. We did not find the overall effect of temperature treatment on the relative telomere length. However, we found that variation in telomere length was related to timing of maturation in a sex- and temperature-dependent manner. Telomere length was negatively related to age at maturation in elevated temperature and early maturing males and females differed in telomere length. Variation in growth rate did not explain any variation in telomere length. The broad sense heritability (h [2]) of telomere length was estimated at h [2] = 0.31 - 0.47, suggesting predominance of environmental over genetic determinants of telomere length variability. This study provides the first evidence that age at maturation together with factors associated with it are influencing telomere length in an ectotherm. Future studies are encouraged to identify the extent to which these results can be replicated in other ectotherms.},
}
@article {pmid28729448,
year = {2017},
author = {Morgan, RG},
title = {Network Mendelian Randomization Study Design to Assess Factors Mediating the Causal Link Between Telomere Length and Heart Disease.},
journal = {Circulation research},
volume = {121},
number = {3},
pages = {200-202},
doi = {10.1161/CIRCRESAHA.117.311387},
pmid = {28729448},
issn = {1524-4571},
mesh = {*Coronary Disease ; *Heart Diseases ; Humans ; Mendelian Randomization Analysis ; Random Allocation ; Telomere ; },
}
@article {pmid28728697,
year = {2017},
author = {Said, MA and Eppinga, RN and Hagemeijer, Y and Verweij, N and van der Harst, P},
title = {Telomere Length and Risk of Cardiovascular Disease and Cancer.},
journal = {Journal of the American College of Cardiology},
volume = {70},
number = {4},
pages = {506-507},
doi = {10.1016/j.jacc.2017.05.044},
pmid = {28728697},
issn = {1558-3597},
mesh = {*Cardiovascular Diseases/epidemiology/genetics ; Databases, Genetic/statistics &amp; numerical data ; Female ; Humans ; Male ; Mendelian Randomization Analysis ; Middle Aged ; Mortality ; *Neoplasms/epidemiology/genetics ; Prevalence ; Risk Assessment ; Risk Factors ; Sequence Analysis/methods ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; United Kingdom/epidemiology ; },
}
@article {pmid28727527,
year = {2017},
author = {Xue, HM and Liu, QQ and Tian, G and Quan, LM and Zhao, Y and Cheng, G},
title = {Television Watching and Telomere Length Among Adults in Southwest China.},
journal = {American journal of public health},
volume = {107},
number = {9},
pages = {1425-1432},
pmid = {28727527},
issn = {1541-0048},
mesh = {Adult ; Aged ; Body Mass Index ; China ; Exercise/physiology ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; Risk Factors ; *Sedentary Behavior ; Surveys and Questionnaires ; Television/*statistics &amp; numerical data ; Telomere/*genetics ; },
abstract = {OBJECTIVES: To explore the independent associations of sedentary behavior and physical activity with telomere length among Chinese adults.<br><br>METHODS: Data on total time of sedentary behavior, screen-based sedentary behavior (including television watching and computer or phone use), moderate to vigorous physical activity, and dietary intake of 518 adults in Chengdu, Guizhou, and Xiamen in China (54.25% women) aged 20 to 70 years were obtained between 2013 and 2015 through questionnaires. Height, weight, and waist circumference were measured to calculate body mass index and percentage of body fat. Telomere length was measured through Southern blot technique.<br><br>RESULTS: Television watching was inversely related to adjusted telomere length (-71.75 base pair; SE&#x2009;=&#x2009;34.40; P &#x2009;=&#x2009;.04). Furthermore, a similar trend between telomere length and television watching was found in the group aged 20 to 40 years after adjusting for all covariates. Adults aged 20 to 40 years in the highest tertile of daily time spent on watching television had 4.0% shorter telomere length than adults in the lowest tertile (P&#x2009;=&#x2009;.03).<br><br>CONCLUSIONS: Although the association is modest, television watching is inversely related to telomere length among Chinese adults, warranting further investigation in large prospective studies.},
}
@article {pmid28725051,
year = {2017},
author = {Erdmann, NJ and Harrington, LA and Martin, LJ},
title = {Mammographic density, blood telomere length and lipid peroxidation.},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {5803},
pmid = {28725051},
issn = {2045-2322},
support = {//Wellcome Trust/United Kingdom ; R01 AG024398/AG/NIA NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Adult ; Blood/*metabolism ; Breast Density/*physiology ; Female ; Humans ; *Lipid Peroxidation ; Malondialdehyde/urine ; *Mammography ; Middle Aged ; Telomere/*metabolism ; },
abstract = {Extensive mammographic density is a strong risk factor for breast cancer, but may also be an indicator of biological age. In this study we examined whether mammographic density is related to blood telomere length, a potential marker of susceptibility to age-related disease. We measured mammographic density by a computer assisted method and blood telomere length using a validated PCR method. Urinary malondialdehyde (MDA), a marker of lipid peroxidation, was measured in 24 hour urine collections. In the 342 women examined telomere length was negatively correlated with age, was lower in postmenopausal compared to premenopausal women and in smokers compared to non-smokers, and was positively correlated with urinary MDA. Telomere length was not associated with percent mammographic density or dense area, before or after adjustment for risk factors and MDA. However, there was a significant interaction between telomere length and MDA in their association with mammographic density. At lower levels of MDA, mammographic density and telomere length were inversely associated; while at high levels of MDA, there was evidence of a J-shaped association between mammographic density and telomere length. Further work is need to replicate these results and to examine the association of mammographic density with age-related chronic disease and mortality.},
}
@article {pmid28724638,
year = {2018},
author = {Andujar, P and Courbon, D and Bizard, E and Marcos, E and Adnot, S and Boyer, L and Demoly, P and Jarvis, D and Neukirch, C and Pin, I and Thabut, G and Boczkowski, J and Leynaert, B},
title = {Smoking, telomere length and lung function decline: a longitudinal population-based study.},
journal = {Thorax},
volume = {73},
number = {3},
pages = {283-285},
doi = {10.1136/thoraxjnl-2017-210294},
pmid = {28724638},
issn = {1468-3296},
mesh = {Adult ; Biomarkers/metabolism ; Cross-Sectional Studies ; Female ; Follow-Up Studies ; Forced Expiratory Volume/genetics/*physiology ; France ; Health Surveys ; Humans ; Leukocytes ; Longitudinal Studies ; Lung/*physiopathology ; Male ; Pulmonary Disease, Chronic Obstructive/*genetics ; Risk Factors ; Smoking/*adverse effects ; Spirometry/methods ; Telomere/*metabolism ; Telomere Homeostasis ; Telomere Shortening ; Young Adult ; },
abstract = {Telomere shortening is associated with COPD and impaired lung function in cross-sectional studies, but there is no longitudinal study. We used data from 448 participants recruited as part of the French follow-up of the European Community Respiratory Health Survey. We found no relationship between telomere length at baseline and FEV1 decline after 11 years of follow-up. However, heavy smoking was associated with an accelerated FEV1 decline in individuals with short telomeres, but not in subjects with longer telomeres (p for interaction p=0.08). Our findings suggest that short telomere length in peripheral leucocytes might be a marker for increased susceptibility to the effect of smoking.},
}
@article {pmid28718437,
year = {2017},
author = {Aviv, A and Anderson, JJ and Shay, JW},
title = {Mutations, Cancer and the Telomere Length Paradox.},
journal = {Trends in cancer},
volume = {3},
number = {4},
pages = {253-258},
pmid = {28718437},
issn = {2405-8025},
support = {R21 AG046760/AG/NIA NIH HHS/United States ; R01 AG030678/AG/NIA NIH HHS/United States ; R01 HL116446/HL/NHLBI NIH HHS/United States ; R01 AG020132/AG/NIA NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; R01 HL134840/HL/NHLBI NIH HHS/United States ; C06 RR030414/RR/NCRR NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; HHSN268201300007C/HL/NHLBI NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Mutation ; Neoplasms/*genetics ; Telomere/*genetics ; },
abstract = {Individuals with short telomeres should be at increased risk for cancer, since short telomeres lead to genomic instability - a hallmark of cancer. However, individuals with long telomeres also display an increased risk for major cancers, thus creating a cancer-telomere length (TL) paradox. The two-stage clonal expansion model we propose is based on the thesis that a series of mutational hits (1st Hit) at the stem-cell level generates a clone with replicative advantage. A series of additional mutational hits (2nd Hit) transforms the expanding clone into cancer. By proposing that the 1st Hit is largely telomere length-independent, while the 2nd Hit is largely TL-dependent, we resolve the paradox, highlighting a regulatory role of telomeres in cancer.},
}
@article {pmid28718371,
year = {2017},
author = {Duan, X and Yang, Y and Wang, S and Feng, X and Wang, T and Wang, P and Liu, S and Li, L and Yao, W and Cui, L and Wang, W},
title = {Changes in the expression of genes involved in cell cycle regulation and the relative telomere length in the process of canceration induced by omethoate.},
journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine},
volume = {39},
number = {7},
pages = {1010428317719782},
doi = {10.1177/1010428317719782},
pmid = {28718371},
issn = {1423-0380},
mesh = {Adult ; Carcinogenesis/*drug effects ; Cell Cycle/drug effects ; China ; Cyclin-Dependent Kinase Inhibitor p21/biosynthesis/*genetics ; DNA Damage/drug effects ; Dimethoate/analogs &amp; derivatives/toxicity ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Genotype ; Humans ; Lymphocytes/drug effects/pathology ; Male ; Middle Aged ; Neoplasms/chemically induced/*genetics/pathology ; Occupational Exposure ; Polymorphism, Single Nucleotide ; RNA, Messenger/biosynthesis/genetics ; Telomere Homeostasis/drug effects ; Tumor Suppressor Protein p53/biosynthesis/*genetics ; },
abstract = {Organophosphorous pesticides (OPs), with high efficiency, broad-spectrum and low residue, are widely used in China. Omethoate is a broad category of organophosphorous pesticides and is more domestically utilized which has chronic toxic effect on human health caused by long-term, low-dose exposure to Ops, recently its potential genotoxicity has attracted wide attention which can cause chromosomal DNA damage. Thus, the aim of this study is screen susceptible biomarkers and explore the mechanism of canceration induced by omethoate. 180 long-term organophosphorus pesticide-exposed workers and 115 healthy controls were recruited. Quantitative polymerase chain reaction method was applied to determine the relative telomere length in peripheral lymphocyte DNA as well as p53 and p21 gene expression levels. Genetic polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism method. Multiple linear regression was conducted to explore the effects of exposure, expression levels, and polymorphisms in genes on the telomere length. The results showed the relative telomere lengths in the exposure group were significantly longer than that in the control group. The messenger RNA expression levels of p53 and p21 in exposure group were significantly lower than that in the control group; telomere lengths of the CA genotype individuals of p21 rs1801270 polymorphism locus were significantly longer than that of the CC genotype in the control group that were estimated using the Bonferroni method; and bivariate correlation analysis showed that the messenger RNA expression level of gene p53 was negatively correlated with telomere length, and the messenger RNA expression level of gene p21 was positively correlated with telomere length. Multivariate analysis found that p53 messenger RNA and p21 messenger RNA had an impact on telomere length. These results demonstrated that the messenger RNA expression levels of p53 and p21 may have a relationship with the changes in telomere length induced by omethoate and provided strong evidence for the mechanism of canceration induced by poison.},
}
@article {pmid28716823,
year = {2017},
author = {Mitchell, C and McLanahan, S and Schneper, L and Garfinkel, I and Brooks-Gunn, J and Notterman, D},
title = {Father Loss and Child Telomere Length.},
journal = {Pediatrics},
volume = {140},
number = {2},
pages = {},
pmid = {28716823},
issn = {1098-4275},
support = {R25 HD074544/HD/NICHD NIH HHS/United States ; R01 HD039135/HD/NICHD NIH HHS/United States ; P2C HD047879/HD/NICHD NIH HHS/United States ; R01 HD036916/HD/NICHD NIH HHS/United States ; R01 HD076592/HD/NICHD NIH HHS/United States ; R01 HD040421/HD/NICHD NIH HHS/United States ; },
mesh = {Adolescent ; Age Factors ; Alleles ; Case-Control Studies ; Child ; Child, Preschool ; Cohort Studies ; Dopamine Plasma Membrane Transport Proteins/genetics ; Female ; Follow-Up Studies ; Humans ; Income ; Infant ; Infant, Newborn ; Male ; *Paternal Deprivation ; Polymorphism, Genetic/genetics ; Real-Time Polymerase Chain Reaction ; Residence Characteristics ; Risk Factors ; Serotonin Plasma Membrane Transport Proteins/genetics ; Signal Transduction/genetics ; Statistics as Topic ; Telomere Shortening/*genetics ; },
abstract = {BACKGROUND AND OBJECTIVES: Father loss during childhood has negative health and behavioral consequences, but the biological consequences are unknown. Our goal was to examine how father loss (because of separation and/or divorce, death, or incarceration) is associated with cellular function as estimated by telomere length.<br><br>METHODS: Data come from the 9-year follow-up of the Fragile Families and Child Wellbeing Study, a birth cohort study of children in 20 large American cities (N = 2420). Principal measures are as follows: salivary telomere length (sTL), mother reports of father loss, and polymorphisms in genes related to serotonergic and dopaminergic signaling.<br><br>RESULTS: At 9 years of age, children with father loss have significantly shorter telomeres (14% reduction). Paternal death has the largest association (16%), followed by incarceration (10%), and separation and/or divorce (6%). Changes in income partially mediate these associations (95% mediation for separation and/or divorce, 30% for incarceration, and 25% for death). Effects are 40% greater for boys and 90% greater for children with the most reactive alleles of the serotonin transporter genes when compared with those with the least reactive alleles. No differences were found by age at father loss or a child's race/ethnicity.<br><br>CONCLUSIONS: Father loss has a significant association with children's sTL, with the death of a father showing the largest effect. Income loss explains most of the association between child sTL and separation and/or divorce but much less of the association with incarceration or death. This underscores the important role of fathers in the care and development of children and supplements evidence of the strong negative effects of parental incarceration.},
}
@article {pmid28715381,
year = {2017},
author = {Jenkins, FJ and Kerr, CM and Fouquerel, E and Bovbjerg, DH and Opresko, PL},
title = {Modified Terminal Restriction Fragment Analysis for Quantifying Telomere Length Using In-gel Hybridization.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {125},
pages = {},
pmid = {28715381},
issn = {1940-087X},
support = {P30 CA047904/CA/NCI NIH HHS/United States ; },
mesh = {DNA/*genetics ; DNA Restriction Enzymes/*genetics ; Humans ; In Situ Hybridization/*methods ; Telomere/*metabolism ; },
abstract = {There are several different techniques for measuring telomere length, each with their own advantages and disadvantages. The traditional approach, Telomere Restriction Fragment (TRF) analysis, utilizes a DNA hybridization technique whereby genomic DNA samples are digested with restriction enzymes, leaving behind telomere DNA repeats and some sub-telomeric DNA. These are separated by agarose gel electrophoresis, transferred to a filter membrane and hybridized to oligonucleotide probes tagged with either chemiluminescence or radioactivity to visualize telomere restriction fragments. This approach, while requiring a larger quantity of DNA than other techniques such as PCR, can measure the telomere length distribution of a population of cells and allows measurement expressed in absolute kilobases. This manuscript demonstrates a modified DNA hybridization procedure for determining telomere length. Genomic DNA is first digested with restriction enzymes (that do not cut telomeres) and separated by agarose gel electrophoresis. The gel is then dried and the DNA is denatured and hybridized in situ to a radiolabeled oligonucleotide probe. This in situ hybridization avoids loss of telomere DNA and improves signal intensity. Following hybridization, the gels are imaged utilizing phosphor screens and the telomere length is quantified using a graphing program. This procedure was developed by the laboratories of Drs. Woodring Wright and Jerry Shay at the University of Texas Southwestern[1][,][2]. Here, we present a detailed description of this procedure, with some modifications.},
}
@article {pmid28713153,
year = {2017},
author = {Koch, L},
title = {Non-coding RNA: A protective role for TERRA at telomeres.},
journal = {Nature reviews. Genetics},
volume = {18},
number = {8},
pages = {453},
pmid = {28713153},
issn = {1471-0064},
mesh = {Humans ; RNA ; RNA, Long Noncoding ; Telomerase/*genetics ; *Telomere ; },
}
@article {pmid28712425,
year = {2017},
author = {Fair, B and Mellon, SH and Epel, ES and Lin, J and Révész, D and Verhoeven, JE and Penninx, BW and Reus, VI and Rosser, R and Hough, CM and Mahan, L and Burke, HM and Blackburn, EH and Wolkowitz, OM},
title = {Telomere length is inversely correlated with urinary stress hormone levels in healthy controls but not in un-medicated depressed individuals-preliminary findings.},
journal = {Journal of psychosomatic research},
volume = {99},
number = {},
pages = {177-180},
pmid = {28712425},
issn = {1879-1360},
support = {R01 MH083784/MH/NIMH NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; },
mesh = {Adult ; Aged ; Cellular Senescence ; Depression/*urine ; Female ; Healthy Volunteers ; Humans ; Hydrocortisone/*urine ; Male ; Middle Aged ; Pilot Projects ; Telomere/*metabolism ; },
abstract = {OBJECTIVE: Leukocyte telomere length (LTL) is a biomarker of cellular aging affected by chronic stress. The relationship of LTL to the stress hormones, cortisol and catecholamines, is unclear, as are possible differences between healthy controls (HC) and individuals with Major Depressive Disorder (MDD). This small pilot study is the first to examine the relationship between cortisol, catecholamines and LTL specifically in un-medicated MDD in comparison with HC.<br><br>METHODS: Participants included 16 un-medicated MDD subjects and 15 HC for assay of LTL, 12-hour overnight urinary free cortisol and catecholamine levels.<br><br>RESULTS: LTL, cortisol and catecholamine levels did not significantly differ between groups. In HC, a hierarchical regression analysis indicated that higher levels of cortisol were correlated with shorter LTL (p=0.003) above and beyond age and sex. Higher catecholamine levels were nearly-significant with shorter LTL (p=0.055). Neither hormone was correlated with shorter LTL in MDD (p's>0.28). To assess a possible cumulative effect of stress hormone activation, a summary score was calculated for each subject based on the number of stress hormone levels above the median for that group (HC or MDD). A significant inverse graded relationship was observed between LTL and the number of activated systems in HC (p=0.001), but not in MDD (p=0.96).<br><br>CONCLUSION: This pilot study provides preliminary evidence that stress hormone levels, especially cortisol, are inversely related to LTL in HC, but not in un-medicated MDD. Clarification of these relationships in larger samples could aid in understanding differential mechanisms underlying stress-related cellular aging in healthy and depressed populations.},
}
@article {pmid28710328,
year = {2017},
author = {Churikov, D and Géli, V},
title = {De novo telomere addition at chromosome breaks: Dangerous Liaisons.},
journal = {The Journal of cell biology},
volume = {216},
number = {8},
pages = {2243-2245},
pmid = {28710328},
issn = {1540-8140},
mesh = {*Chromosome Breakage ; DNA Breaks, Double-Stranded ; DNA Repair ; Telomerase/genetics ; *Telomere ; Telomere-Binding Proteins/genetics ; },
abstract = {Telomerase counteracts the loss of terminal DNA sequences from chromosome ends; however, it may erroneously add telomeric repeats to DNA double-strand breaks. In this issue, Ouenzar et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201610071) uncover cell cycle-dependent sequestration of the telomerase RNA in nucleoli, a process that excludes telomerase from DNA repair sites.},
}
@article {pmid28707432,
year = {2017},
author = {Samulin Erdem, J and Notø, H&#xd8; and Skare, &#xd8; and Lie, JS and Petersen-Øverleir, M and Reszka, E and Pepłońska, B and Zienolddiny, S},
title = {Mechanisms of breast cancer risk in shift workers: association of telomere shortening with the duration and intensity of night work.},
journal = {Cancer medicine},
volume = {6},
number = {8},
pages = {1988-1997},
pmid = {28707432},
issn = {2045-7634},
mesh = {Breast Neoplasms/*epidemiology/*etiology ; Case-Control Studies ; Circadian Rhythm ; Disease Susceptibility ; Female ; Gene Frequency ; Humans ; Middle Aged ; Norway/epidemiology ; Nurses ; Odds Ratio ; Polymorphism, Single Nucleotide ; RNA/genetics ; Risk Factors ; Shift Work Schedule/*adverse effects ; Telomerase/genetics ; Telomere Shortening ; },
abstract = {Occupational factors such as shiftwork and especially night work that involves disruption of the circadian rhythm may contribute to increased breast cancer risk. Circadian disruption may also affect telomere length (TL). While short TL generally is associated with increased cancer risk, its association with breast cancer risk is inconclusive. We suggest that working schedules might be an important factor in assessment of effects of TL on breast cancer risk. Moreover, telomere shortening might be a potential mechanism for night work-related breast cancer. In this study, effects of shift work on TL and its association with breast cancer risk were investigated in a nested breast cancer case-control study of Norwegian nurses. TL was assessed by qPCR in DNA from 563 breast cancer patients and 619 controls. Here, we demonstrate that TL is affected by intensive night work schedules, as work with six consecutive night for a period of more than 5 years was associated with decreased telomere lengths (-3.18, 95% CI: -6.46 to -0.58, P = 0.016). Furthermore, telomere shortening is associated with increased breast cancer risk in workers with long periods of consecutive night shifts. Thus, nurses with longer telomere lengths had a lower risk for breast cancer if they had worked more than four (OR: 0.37, 95% CI: 0.16-0.79, P = 0.014) or five (OR: 0.31, 95% CI: 0.10-0.83, P = 0.029) consecutive night shifts for a period of 5 years or more. These data suggest that telomere shortening is associated with the duration and intensity of night work and may be a contributing factor for breast cancer risk among female shift workers.},
}
@article {pmid28705731,
year = {2018},
author = {Angelier, F and Costantini, D and Blévin, P and Chastel, O},
title = {Do glucocorticoids mediate the link between environmental conditions and telomere dynamics in wild vertebrates? A review.},
journal = {General and comparative endocrinology},
volume = {256},
number = {},
pages = {99-111},
doi = {10.1016/j.ygcen.2017.07.007},
pmid = {28705731},
issn = {1095-6840},
mesh = {Animals ; *Environment ; Glucocorticoids/*metabolism ; Humans ; Oxidative Stress ; Telomere/*metabolism ; Telomere Shortening ; Vertebrates/*genetics ; },
abstract = {Following the discoveries of telomeres and of their implications in terms of health and ageing, there has been a growing interest into the study of telomere dynamics in wild vertebrates. Telomeres are repeated sequences of non-coding DNA located at the terminal ends of chromosomes and they play a major role in maintaining chromosome stability. Importantly, telomeres shorten over time and shorter telomeres seem to be related with lower survival in vertebrates. Because of this potential link with longevity, it is crucial to understand not only the ecological determinants of telomere dynamics but also the regulatory endocrine mechanisms that may mediate the effect of the environment on telomeres. In this paper, we review the relationships that link environmental conditions, glucocorticoids (GC, the main hormonal mediator of allostasis) and telomere length in vertebrates. First, we review current knowledge about the determinants of inter-individual variations in telomere length. We emphasize the potential strong impact of environmental stressors and predictable life-history events on telomere dynamics. Despite recent progress, we still lack crucial basic data to fully understand the costs of several life-history stages and biotic and abiotic factors on telomere length. Second, we review the link that exists between GCs, oxidative stress and telomere dynamics in vertebrates. Although circulating GC levels may be closely and functionally linked with telomere dynamics, data are still scarce and somewhat contradictory. Further laboratory and field studies are therefore needed not only to better assess the proximate link between GC levels and telomere dynamics, but also to ultimately understand to what extent GCs and telomere length could be informative to measure the fitness costs of specific life-history stages and environmental conditions. Finally, we highlight the importance of exploring the functional links that may exist between coping styles, the GC stress response, and telomere dynamics in a life-history framework. To conclude, we raise new hypotheses regarding the potential of the GC stress response to drive the trade-off between immediate survival and telomere protection.},
}
@article {pmid28704957,
year = {2017},
author = {Wood, ML and Royle, NJ},
title = {Chromosomally Integrated Human Herpesvirus 6: Models of Viral Genome Release from the Telomere and Impacts on Human Health.},
journal = {Viruses},
volume = {9},
number = {7},
pages = {},
pmid = {28704957},
issn = {1999-4915},
support = {G0901657/MRC_/Medical Research Council/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Chromosomes, Human/*virology ; DNA, Viral/genetics ; *Genome, Viral ; Herpesvirus 6, Human/*genetics/physiology ; Humans ; Roseolovirus Infections/virology ; Telomere/*genetics/virology ; Virion/genetics ; *Virus Integration ; Virus Latency ; Virus Replication/genetics ; },
abstract = {Human herpesvirus 6A and 6B, alongside some other herpesviruses, have the striking capacity to integrate into telomeres, the terminal repeated regions of chromosomes. The chromosomally integrated forms, ciHHV-6A and ciHHV-6B, are proposed to be a state of latency and it has been shown that they can both be inherited if integration occurs in the germ line. The first step in full viral reactivation must be the release of the integrated viral genome from the telomere and here we propose various models of this release involving transcription of the viral genome, replication fork collapse, and t-circle mediated release. In this review, we also discuss the relationship between ciHHV-6 and the telomere carrying the insertion, particularly how the presence and subsequent partial or complete release of the ciHHV-6 genome may affect telomere dynamics and the risk of disease.},
}
@article {pmid28704801,
year = {2017},
author = {Liu, JJ and Wei, YB and Forsell, Y and Lavebratt, C},
title = {Stress, depressive status and telomere length: Does social interaction and coping strategy play a mediating role?.},
journal = {Journal of affective disorders},
volume = {222},
number = {},
pages = {138-145},
doi = {10.1016/j.jad.2017.07.007},
pmid = {28704801},
issn = {1573-2517},
mesh = {Adaptation, Psychological/*physiology ; Adult ; Cohort Studies ; Depression/*genetics/psychology ; Female ; Humans ; Interpersonal Relations ; Longitudinal Studies ; Male ; Risk Factors ; Stress, Psychological/*genetics ; Sweden ; Telomere/*pathology ; *Telomere Shortening ; },
abstract = {BACKGROUND: Telomeres have been reported to be shorter in individuals exposed to psychosocial stress and in those with depression. Since negative environmental stress is a risk factor for depression, the present study tested whether stressors in childhood (CA) and recent adulthood (NLE) predicted telomere attrition directly and/or indirectly through individuals' depressive status 3-6 years before TL measurement; and then if social interaction and coping strategies in adulthood influenced the relationship between depressive status and TL.<br><br>METHODS: Participants were 337 individuals with a recent depression diagnosis and 574 screened controls that derived from a longitudinal population-based cohort study conducted in Stockholm, Sweden. Relative TL was determined using qPCR. Relationships between the key variables stressors, depressive status, social interaction, coping strategies and TL were explored by path analysis in males and females, adjusting for age.<br><br>RESULTS: The key variables were correlated in expected directions. In females, depressive status and age had direct negative effects on TL (p < 0.05) and both CA (p = 0.025) and NLE (p < 0.003) had indirect negative effects on TL. For males, the effects of stressors and depressive status on TL were mediated by social interaction (p = 0.005) and the coping strategy worry (p = 0.005). In females, no mediation effect of social interaction and coping strategy was detected.<br><br>LIMITATIONS: Only little of the TL variation was explained by the models. The environmental stress information was limited.<br><br>CONCLUSION: Our findings propose gender-specific paths from environmental stressors through depressive status, social interaction and coping strategy to TL.},
}
@article {pmid28704792,
year = {2017},
author = {Astuti, Y and Wardhana, A and Watkins, J and Wulaningsih, W and , },
title = {Cigarette smoking and telomere length: A systematic review of 84 studies and meta-analysis.},
journal = {Environmental research},
volume = {158},
number = {},
pages = {480-489},
pmid = {28704792},
issn = {1096-0953},
support = {MC_UU_12019/2//Medical Research Council/United Kingdom ; MC_UU_12019/4//Medical Research Council/United Kingdom ; },
mesh = {Humans ; Risk Factors ; Smoking/*adverse effects ; Telomere Homeostasis/*drug effects ; Telomere Shortening/*drug effects ; Tobacco Smoke Pollution ; },
abstract = {BACKGROUND: Cigarette smoking is a risk factor for ageing-related disease, but its association with biological ageing, indicated by telomere length, is unclear.<br><br>METHODS: We systematically reviewed evidence evaluating association between smoking status and telomere length. Searches were performed in MEDLINE (Ovid) and EMBASE (Ovid) databases, combining variation of keywords "smoking" and "telomere". Data was extracted for study characteristics and estimates for association between smoking and telomere length. Quality of studies was assessed with a risk of bias score, and publication bias was assessed with a funnel plot. I[2] test was used to observe heterogeneity. Meta-analysis was carried out to compare mean difference in telomere length by smoking status, and a dose-response approach was carried out for pack-years of smoking and telomere length. A sensitivity analysis was carried out to examine sources of heterogeneity.<br><br>RESULTS: A total of 84 studies were included in the review, and 30 among them were included in our meta-analysis. Potential bias was addressed in half of included studies, and there was little evidence of small study bias. Telomere length was shorter among ever smokers compared to never smokers (summary standard mean difference [SMD]: -0.11 (95% CI -0.16 to -0.07)). Similarly, shorter telomere length was found among smokers compared to non-smokers, and among current smokers compared to never or former smokers. Dose-response meta-analysis suggested an inverse trend between pack-years of smoking and telomere length. However, heterogeneity among some analyses was observed.<br><br>CONCLUSION: Shorter telomeres among ever smokers compared to those who never smoked may imply mechanisms linking tobacco smoke exposure to ageing-related disease.},
}
@article {pmid28700015,
year = {2018},
author = {Köse Çinar, R},
title = {Telomere length and hTERT in mania and subsequent remission.},
journal = {Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)},
volume = {40},
number = {1},
pages = {19-25},
pmid = {28700015},
issn = {1809-452X},
mesh = {Adult ; Bipolar Disorder/*diagnosis/genetics ; Case-Control Studies ; Genetic Markers ; Humans ; Male ; Real-Time Polymerase Chain Reaction ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Shortening/genetics ; },
abstract = {OBJECTIVE: The findings of telomere length (TL) studies in bipolar disorder (BD) are controversial. The aim of the present study was to detect TL, human telomerase reverse transcriptase (hTERT), and brain derived neurotrophic factor (BDNF) in severe mania and subsequent remission.<br><br>METHODS: Twenty-one medication-free male patients and 20 age and gender matched controls were recruited. The patients were followed in the inpatient clinic, and comparisons were made between the same patients in their remission state and controls. Patients received lithium plus antipsychotics during the follow-up period. Quantitative real-time polymerase chain reaction was performed to verify leukocyte TL and whole blood hTERT gene expression levels. Serum BDNF levels were verified by enzyme-linked immunosorbent assay (ELISA).<br><br>RESULTS: Compared to controls, manic patients presented shorter telomeres (p < 0.001) whose length increased with treatment (p = 0.001). Patients in the late stages showed shorter TL than those in the early stages and controls (p < 0.001). hTERT gene expression levels were up-regulated in mania and remission compared to controls (p = 0.03 and p = 0.01, respectively). BDNF changes did not reach statistically significant levels.<br><br>CONCLUSIONS: TL and hTERT gene expression might reflect a novel aspect of BD pathophysiology and TL might represent a novel biomarker for BD staging.},
}
@article {pmid28699658,
year = {2017},
author = {Park, HS and Park, SN and Im, K and Kim, SM and Kim, JA and Hwang, SM and Lee, DS},
title = {Telomere length and somatic mutations in correlation with response to immunosuppressive treatment in aplastic anaemia.},
journal = {British journal of haematology},
volume = {178},
number = {4},
pages = {603-615},
doi = {10.1111/bjh.14691},
pmid = {28699658},
issn = {1365-2141},
mesh = {Adult ; Aged ; Aged, 80 and over ; Anemia, Aplastic/drug therapy/*genetics ; Bone Marrow/pathology ; Bone Marrow Transplantation ; Chromosome Aberrations ; Disease Progression ; Female ; Genetic Markers ; Humans ; Immunosuppressive Agents/*therapeutic use ; In Situ Hybridization, Fluorescence/methods ; Kaplan-Meier Estimate ; Male ; Middle Aged ; *Mutation ; Prognosis ; Telomere Homeostasis/*genetics ; Young Adult ; },
abstract = {We investigated the frequencies of cytogenetic aberrations and somatic mutations of prognostic relevance in 393 patients with aplastic anaemia (AA). Clonality was determined by G-banding/fluorescence in situ hybridization (FISH) (n = 245), and targeted capture sequencing was performed for 88 haematopoiesis-related genes (n = 70). The telomere length (TL) of bone marrow nucleated cells was measured at the single cell level by FISH (n = 135). Eighteen (4·6%) patients showed disease progression, and monosomy 7 (50·0%) was the most predominant cytogenetic evolution at disease transformation. One third of patients (32·9%) presented at least 1 mutation; the most frequently mutated genes were NOTCH1, NF1, SCRIB, BCOR and DNMT3A. The patient group with clonal changes (30·7%) showed an adverse response to immunosuppressive treatment (IST), compared to the non-clonal group, but this finding did not show statistical significance. The TL of AA patients was significantly shorter than normal control and patients with clonal changes showed significantly shorter TLs. Patients with TL>5·9 showed a higher response rate to IST (P = 0·048). In conclusion, the patients with clonal changes or TL attrition showed a poor response to IST. Shorter TL can be used not only as a biomarker, but also as a predictive marker for treatment response to IST.},
}
@article {pmid28699608,
year = {2017},
author = {Sahoo, N and Padhi, S and Patra, S and Mishra, P and Kumar, R and Panigrahi, MK},
title = {Dyskeratosis congenita, bone marrow failure, and gastric adenocarcinoma: an insight into telomere biology.},
journal = {The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology},
volume = {28},
number = {4},
pages = {319-321},
doi = {10.5152/tjg.2017.17094},
pmid = {28699608},
issn = {2148-5607},
mesh = {Adenocarcinoma/*congenital ; Bone Marrow Diseases/*congenital ; Dyskeratosis Congenita/*genetics ; Humans ; Male ; Stomach Neoplasms/*congenital ; Telomere/*genetics ; Young Adult ; },
}
@article {pmid28699197,
year = {2018},
author = {Lafuente, R and Bosch-Rue, E and Ribas-Maynou, J and Alvarez, J and Brassesco, C and Amengual, MJ and Benet, J and Garcia-Peiró, A and Brassesco, M},
title = {Sperm telomere length in motile sperm selection techniques: A qFISH approach.},
journal = {Andrologia},
volume = {50},
number = {2},
pages = {},
doi = {10.1111/and.12840},
pmid = {28699197},
issn = {1439-0272},
mesh = {Biomarkers/analysis ; Centrifugation, Density Gradient ; Female ; Humans ; In Situ Hybridization, Fluorescence/methods ; Infertility, Male/*physiopathology ; Male ; Oxidative Stress/physiology ; Pregnancy ; Pregnancy Rate ; Semen Analysis/*methods ; Sperm Motility/*physiology ; Spermatozoa/*physiology ; Telomere/*physiology ; },
abstract = {Several studies have associated telomere shortening with alterations in reproductive function. The objective of the present study was to determine telomere length (TL) in spermatozoa selected by either density-gradient centrifugation (DGC) or swim-up. The analysis of TL was performed using quantitative fluorescent in situ hybridisation (qFISH) using PNA probes in combination with a chromatin decompaction protocol in sperm cells. Results of TL were 24.64 ± 5.00 Kb and 24.95 ± 4.60 Kb before and after DGC, respectively, and 19.59 ± 8.02 Kb and 20.22 ± 5.18 Kb before and after swim-up respectively. Sperm selected by DGC or swim-up did not show any significant differences in TL as compared to nonselected sperm (p > .05). Negative correlations between TL and sperm motility (r = -.308; p = .049) and concentration (r = -.353; p = .028) were found. Furthermore, exposure of sperm to increasing concentrations of hydrogen peroxide during incubation resulted in a reduction in TL. These data indicate that oxidative stress may be one of the main factors involved in the reduction of TL in sperm. Preliminary clinical results from patients included in this study indicate that TL was shorter in spermatozoa from couples who never achieved a pregnancy compared to couples who did achieve at least one natural pregnancy (p < .05); however, the clinical utility of this biomarker still needs to be confirmed in further studies.},
}
@article {pmid28697059,
year = {2017},
author = {Chmelar, C and Jörres, RA and Kronseder, A and Müller, A and Nowak, D and Weigl, M},
title = {Associations Between Age, Psychosocial Work Conditions, Occupational Well-Being, and Telomere Length in Geriatric Care Professionals: A Mixed-Methods Study.},
journal = {Journal of occupational and environmental medicine},
volume = {59},
number = {10},
pages = {949-955},
doi = {10.1097/JOM.0000000000001102},
pmid = {28697059},
issn = {1536-5948},
mesh = {Adult ; Age Factors ; Female ; Geriatric Nursing/statistics &amp; numerical data ; Health Status ; *Homes for the Aged ; Humans ; *Job Satisfaction ; Male ; Psychology ; *Telomere Homeostasis ; Workforce ; Workplace/psychology/standards ; },
abstract = {OBJECTIVE: We identified associations between age, psychosocial work characteristics, occupational well-being, and-as a measure of biological age-leukocyte telomere length in geriatric care professionals.<br><br>METHODS: This is a multisource study of self-reports on psychosocial work characteristics, standardized physician's evaluations of health, and relative telomere length measures of peripheral blood leukocytes. We included 141 geriatric care professionals. Telomere length was assessed by an improved polymerase chain reaction (PCR)-based method.<br><br>RESULTS: Increased depersonalization was associated with shorter telomeres. Their association with age was not moderated by psychosocial work conditions. There was, however, a significant three-way interaction of social support and work ability with the age-telomere association. Additionally, social support and adverse general health moderated the age-telomere length relationship.<br><br>CONCLUSIONS: A supportive work environment and work-related health may influence the association between age and telomere length.},
}
@article {pmid28693253,
year = {2017},
author = {Jung, SJ and Cho, JH and Park, WJ and Heo, YR and Lee, JH},
title = {Telomere length is correlated with mitochondrial DNA copy number in intestinal, but not diffuse, gastric cancer.},
journal = {Oncology letters},
volume = {14},
number = {1},
pages = {925-929},
pmid = {28693253},
issn = {1792-1074},
abstract = {A positive correlation between telomere length and mitochondrial DNA (mtDNA) copy number has previously been observed in healthy individuals, and in patients with psychiatric disorders. In the present study, telomere length and mtDNA copy number were evaluated in gastric cancer (GC) tissue samples. DNA was extracted from 109 GC samples (including 82 intestinal, and 27 diffuse cases), and the telomere length and mtDNA copy number were analyzed using a quantitative-polymerase chain reaction assay. The relative telomere length and mtDNA copy number in tumor tissue, as compared with in normal tissue, (mean ± standard deviation) in all GC samples were 11.48±1.14 and 14.86±1.35, respectively. Telomere length and mtDNA copy number were not identified as exhibiting clinical or prognostic value for GC. However, positive correlations between telomere length and mitochondrial DNA copy number were identified in GC (r=0.408, P<0.001) and in the adjacent normal mucosa (r=0.363; P<0.001). When stratified by Lauren classification, the correlation was identified in intestinal type GC samples (r=0.461; P<0.001), but not in diffuse type GC samples (r=0.225; P=0.260). This result indicated that loss of the correlation of telomeres and mitochondrial function may induce the initiation or progression of GC pathogenesis.},
}
@article {pmid28691153,
year = {2017},
author = {Thomay, K and Fedder, C and Hofmann, W and Kreipe, H and Stadler, M and Titgemeyer, J and Zander, I and Schlegelberger, B and Göhring, G},
title = {Telomere shortening, TP53 mutations and deletions in chronic lymphocytic leukemia result in increased chromosomal instability and breakpoint clustering in heterochromatic regions.},
journal = {Annals of hematology},
volume = {96},
number = {9},
pages = {1493-1500},
doi = {10.1007/s00277-017-3055-1},
pmid = {28691153},
issn = {1432-0584},
mesh = {Adult ; Aged ; Aged, 80 and over ; *Base Sequence ; *Chromosomal Instability ; Female ; Heterochromatin/*genetics/metabolism ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/metabolism ; Male ; Middle Aged ; *Sequence Deletion ; Telomere Homeostasis/*genetics ; Tumor Suppressor Protein p53/*genetics/metabolism ; },
abstract = {Complex karyotypes are associated with a poor prognosis in chronic lymphocytic leukemia (CLL). Using mFISH, iFISH, and T/C-FISH, we thoroughly characterized 59 CLL patients regarding parameters known to be involved in chromosomal instability: status of the genes ATM and TP53 and telomere length. Interestingly, a deletion of the ATM locus in 11q, independent of the cytogenetic context, was associated with significantly diminished risk (p<0.05) of carrying a mutation in TP53. In patients with loss or mutation of TP53, chromosomal breakage occurred more frequently (p<0.01) in (near-) heterochromatic regions. Median telomere length in patients with complex karyotypes was significantly shorter than that of healthy controls and shorter than in all other cytogenetic cohorts. Furthermore, the median telomere length of patients carrying a TP53 mutation was significantly shorter than without mutation. We conclude that telomere shortening in combination with loss of TP53 induces increased chromosomal instability with preferential involvement of (near-) heterochromatic regions.},
}
@article {pmid28688038,
year = {2017},
author = {Chavez, J and Murillo-Maldonado, JM and Bahena, V and Cruz, AK and Castañeda-Sortibrán, A and Rodriguez-Arnaiz, R and Zurita, M and Valadez-Graham, V},
title = {dAdd1 and dXNP prevent genome instability by maintaining HP1a localization at Drosophila telomeres.},
journal = {Chromosoma},
volume = {126},
number = {6},
pages = {697-712},
pmid = {28688038},
issn = {1432-0886},
support = {219673//CONACyT/ ; 219673//Consejo Nacional de Ciencia y Tecnolog&#xed;a/ ; 177393//Consejo Nacional de Ciencia y Tecnolog&#xed;a/ ; IN200315//Direcci&#xf3;n General de Asuntos del Personal Acad&#xe9;mico, Universidad Nacional Aut&#xf3;noma de M&#xe9;xico/ ; IN204915//Direcci&#xf3;n General de Asuntos del Personal Acad&#xe9;mico, Universidad Nacional Aut&#xf3;noma de M&#xe9;xico/ ; IA200613//Direcci&#xf3;n General de Asuntos del Personal Acad&#xe9;mico, Universidad Nacional Aut&#xf3;noma de M&#xe9;xico/ ; },
mesh = {Animals ; Animals, Genetically Modified ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/*metabolism ; Chromosome Aberrations ; DNA Helicases/*metabolism ; Drosophila/*genetics/*metabolism ; Drosophila Proteins/*metabolism ; Female ; Gene Silencing ; *Genomic Instability ; Heterochromatin/metabolism ; Loss of Heterozygosity ; Male ; Mutation ; Protein Transport ; Retroelements ; Telomere/*genetics/*metabolism ; },
abstract = {Telomeres are important contributors to genome stability, as they prevent linear chromosome end degradation and contribute to the avoidance of telomeric fusions. An important component of the telomeres is the heterochromatin protein 1a (HP1a). Mutations in Su(var)205, the gene encoding HP1a in Drosophila, result in telomeric fusions, retrotransposon regulation loss and larger telomeres, leading to chromosome instability. Previously, it was found that several proteins physically interact with HP1a, including dXNP and dAdd1 (orthologues to the mammalian ATRX gene). In this study, we found that mutations in the genes encoding the dXNP and dAdd1 proteins affect chromosome stability, causing chromosomal aberrations, including telomeric defects, similar to those observed in Su(var)205 mutants. In somatic cells, we observed that dXNP and dAdd1 participate in the silencing of the telomeric HTT array of retrotransposons, preventing anomalous retrotransposon transcription and integration. Furthermore, the lack of dAdd1 results in the loss of HP1a from the telomeric regions without affecting other chromosomal HP1a binding sites; mutations in dxnp also affected HP1a localization but not at all telomeres, suggesting a specialized role for dAdd1 and dXNP proteins in locating HP1a at the tips of the chromosomes. These results place dAdd1 as an essential regulator of HP1a localization and function in the telomere heterochromatic domain.},
}
@article {pmid28686874,
year = {2017},
author = {Takai, KK and Kibe, T and Donigian, JR and Frescas, D and de Lange, T},
title = {Telomere Protection by TPP1/POT1 Requires Tethering to TIN2.},
journal = {Molecular cell},
volume = {67},
number = {1},
pages = {162},
doi = {10.1016/j.molcel.2017.05.033},
pmid = {28686874},
issn = {1097-4164},
}
@article {pmid28686726,
year = {2017},
author = {Cheng, YY and Kao, TW and Chang, YW and Wu, CJ and Peng, TC and Wu, LW and Yang, HF and Liaw, FY and Chen, WL},
title = {Examining the gender difference in the association between metabolic syndrome and the mean leukocyte telomere length.},
journal = {PloS one},
volume = {12},
number = {7},
pages = {e0180687},
pmid = {28686726},
issn = {1932-6203},
mesh = {Adult ; Aged ; Blood Pressure ; C-Reactive Protein/genetics ; Cardiovascular Diseases/blood/*genetics/pathology ; Cholesterol/blood ; Female ; Humans ; Leukocytes/cytology/metabolism ; Male ; Metabolic Syndrome/blood/*genetics/pathology ; Middle Aged ; Sex Characteristics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Uric Acid/blood ; },
abstract = {The mechanism of cellular aging likely involves decreased telomere length and is associated with age-related diseases such as cardiovascular disease. Metabolic syndrome (MetS) is an important risk factor for CVD. The purpose of this study was to investigate the association between LTL and MetS. We evaluated 7370 participants in the National Health and Nutrition Examination Survey (1999-2002). The association between LTL and individual MetS components and the number of MetS components was analyzed by multivariable regression models, adjusting for gender, race/ethnicity, albumin, C-reactive protein, alanine transaminase, uric acid and medical condition. An increase in the number of MetS components was strongly associated with shorter telomere length, especially in female participants (p for trend < 0.05). In addition, triglycerides were negatively associated with LTL in female participants (p < 0.001). Waist circumstance was associated with decreased LTL (p < 0.05) in both males and females. In summary, our study indicated that an increment of MetS component is strongly associated with shorter LTL, especially in the female population.},
}
@article {pmid28677723,
year = {2017},
author = {Li, S and Jiang, Y and Li, A and Liu, X and Xing, X and Guo, Y and Xu, Y and Hao, Y and Zheng, C},
title = {Telomere length is positively associated with the expression of IL‑6 and MIP‑1α in bone marrow mesenchymal stem cells of multiple myeloma.},
journal = {Molecular medicine reports},
volume = {16},
number = {3},
pages = {2497-2504},
pmid = {28677723},
issn = {1791-3004},
mesh = {Aged ; Cell Differentiation ; Cell Line, Tumor ; Cells, Cultured ; Chemokine CCL3/*genetics ; Female ; *Gene Expression Regulation, Neoplastic ; Humans ; Interleukin-6/*genetics ; Male ; Mesenchymal Stem Cells/metabolism/*pathology ; Middle Aged ; Multiple Myeloma/genetics/*pathology ; Osteoblasts/metabolism/pathology ; Telomere Homeostasis ; Tumor Microenvironment ; },
abstract = {Potential roles of mesenchymal stem cells (MSCs) in the pathogenesis of multiple myeloma (MM) are largely unknown. In the current study, the authors analyzed telomere length and the expressions of interleukin (IL)‑6 and macrophage inflammatory protein (MIP)‑1α in MSCs derived from the bone marrow (BM) of MM patients and controls. The current results demonstrated that there was no significant difference in cell surface expression of CD73 and CD90, and the capacity to differentiate into bone tissue were identified between the BM MSCs derived from MM patients and controls. Interestingly, telomere length (TL) and mRNA expressions of IL‑6 and MIP‑1α were significantly longer or higher in BM MSCs of MM than those of controls. Moreover, TL is positively associated with the expressions of IL‑6 and MIP‑1α at the mRNA level in BM MSCs of MM. Additionally, IL‑6 and MIP‑1α expression were significantly upregulated when MSCs from MM patients were cultured in the myeloma associated condition medium. The present study indicated that myeloma‑associated elongation of TL of BM MSCs may be a key element contributing to the increased IL‑6 and MIP‑1α expression, by which MSCs in the tumor microenvironment may facilitate MM and/or MM bone disease development.},
}
@article {pmid28677643,
year = {2017},
author = {Kheimar, A and Previdelli, RL and Wight, DJ and Kaufer, BB},
title = {Telomeres and Telomerase: Role in Marek's Disease Virus Pathogenesis, Integration and Tumorigenesis.},
journal = {Viruses},
volume = {9},
number = {7},
pages = {},
pmid = {28677643},
issn = {1999-4915},
mesh = {Animals ; *Carcinogenesis ; Chickens ; Herpesvirus 2, Gallid/pathogenicity/*physiology ; Host-Pathogen Interactions ; Marek Disease/pathology/*virology ; Telomerase/*metabolism ; Telomere/*metabolism ; *Virus Integration ; },
abstract = {Telomeres protect the ends of vertebrate chromosomes from deterioration and consist of tandem nucleotide repeats (TTAGGG)n that are associated with a number of proteins. Shortening of the telomeres occurs during genome replication, thereby limiting the replication potential of somatic cells. To counteract this shortening, vertebrates encode the telomerase complex that maintains telomere length in certain cell types via de novo addition of telomeric repeats. Several herpesviruses, including the highly oncogenic alphaherpesvirus Marek's disease virus (MDV), harbor telomeric repeats (TMR) identical to the host telomere sequences at the ends of their linear genomes. These TMR facilitate the integration of the MDV genome into host telomeres during latency, allowing the virus to persist in the host for life. Integration into host telomeres is critical for disease and tumor induction by MDV, but also enables efficient reactivation of the integrated virus genome. In addition to the TMR, MDV also encodes a telomerase RNA subunit (vTR) that shares 88% sequence identity with the telomerase RNA in chicken (chTR). vTR is highly expressed during all stages of the virus lifecycle, enhances telomerase activity and plays an important role in MDV-induced tumor formation. This review will focus on the recent advances in understanding the role of viral TMR and vTR in MDV pathogenesis, integration and tumorigenesis.},
}
@article {pmid28676678,
year = {2017},
author = {Dershem, R and Chu, X and Wood, GC and Benotti, P and Still, CD and Rolston, DD},
title = {Changes in telomere length 3-5 years after gastric bypass surgery.},
journal = {International journal of obesity (2005)},
volume = {41},
number = {11},
pages = {1718-1720},
pmid = {28676678},
issn = {1476-5497},
support = {P30 DK072488/DK/NIDDK NIH HHS/United States ; },
mesh = {Adult ; Aged ; Female ; Follow-Up Studies ; *Gastric Bypass ; Genetic Markers ; Humans ; Male ; Middle Aged ; Obesity/*genetics/*surgery ; *Telomere Homeostasis ; Telomere Shortening ; Time Factors ; Treatment Outcome ; Weight Loss/genetics ; },
abstract = {Increased inflammation and oxidative stress associated with obesity can accelerate aging. Telomere length (TL) has the capacity to serve as an aging indicator at the cellular level. Obesity has a known association with shorter TL. This study evaluated TL of immune cells in a population of obese individuals who underwent gastric bypass surgery. Pre- and post-operative DNA samples were available for 50 subjects who had gastric bypass surgery. DNA was analyzed via quantitative polymerase chain reaction to determine TL. Changes in TL were evaluated by comparing TL at baseline to TL at 3-5 years post gastric bypass surgery. Sixty percent of the individuals in the study observed an increase in TL. Significant lengthening was observed for those with the shortest baseline TL (P=0.0011), but not for those with intermediate baseline TL (P=0.411) or longest baseline TL (P=0.207). Change in TL was negatively correlated with age and triglycerides but not correlated with weight loss induced by bariatric surgery. This study confirms that TL lengthening is observed post bariatric surgery and is the first to detect TL lengthening 3-5 years after surgery.},
}
@article {pmid28675175,
year = {2017},
author = {Graham, MK and Meeker, A},
title = {Telomeres and telomerase in prostate cancer development and therapy.},
journal = {Nature reviews. Urology},
volume = {14},
number = {10},
pages = {607-619},
pmid = {28675175},
issn = {1759-4820},
support = {F32 CA213742/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; R01 CA172380/CA/NCI NIH HHS/United States ; T32 CA009110/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Male ; Prostatic Neoplasms/*etiology/*therapy ; Telomerase/*physiology ; Telomere/*genetics ; },
abstract = {Aberrations in telomere biology are among the earliest events in prostate cancer tumorigenesis and continue during tumour progression. Substantial telomere shortening occurs in prostate cancer cells and high-grade prostatic intraepithelial neoplasia. Not all mechanisms of telomere shortening are understood, but oxidative stress from local inflammation might accelerate prostatic telomere loss. Critically short telomeres can drive the accumulation of tumour-promoting genomic alterations; however, continued telomere erosion is unsustainable and must be mitigated to ensure cancer cell survival and unlimited replication potential. Prostate cancers predominantly maintain telomeres by activating telomerase, but alternative mechanisms of telomere extension can occur in metastatic disease. Telomerase activity and telomere length assessment might be useful in prostate cancer diagnosis and prognosis. Telomere shortening in normal stromal cells has been associated with prostate cancer, whereas variable telomere lengths in prostate cancer cells and telomere shortening in cancer-associated stromal cells correlated with lethal disease. Single-agent telomerase-targeted treatments for solid cancers were ineffective in clinical trials but have not been investigated in prostate cancer and might be useful in combination with established regimens. Telomere-directed strategies have not been explored as extensively. Telomere deprotection strategies have the advantage of being effective in both telomerase-dependent and telomerase-independent cancers. Disruption of androgen receptor function in prostate cancer cells results in telomere dysfunction, indicating telomeres and telomerase as potential therapeutic targets in prostate cancer.},
}
@article {pmid28674830,
year = {2017},
author = {Ventura Ferreira, MS and Crysandt, M and Ziegler, P and Hummel, S and Wilop, S and Kirschner, M and Schemionek, M and Jost, E and Wagner, W and Brümmendorf, TH and Beier, F},
title = {Evidence for a pre-existing telomere deficit in non-clonal hematopoietic stem cells in patients with acute myeloid leukemia.},
journal = {Annals of hematology},
volume = {96},
number = {9},
pages = {1457-1461},
doi = {10.1007/s00277-017-3049-z},
pmid = {28674830},
issn = {1432-0584},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Female ; Follow-Up Studies ; Hematopoietic Stem Cells/*metabolism ; Humans ; Leukemia, Myeloid, Acute/diagnosis/*genetics/*metabolism/therapy ; Male ; Middle Aged ; Polymerase Chain Reaction ; *Telomere/genetics/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Telomere shortening represents an established mechanism connecting aging and cancer development. We sequentially analyzed telomere length (TL) of 49 acute myeloid leukemia (AML) patients at diagnosis (n = 24), once they achieved complete cytological remission (CCR) and/or during refractory disease or relapse and after 1-year follow-up, with all patients having at least two sequential samples. TL was analyzed by monochrome multiplex quantitative polymerase chain reaction. We have observed substantially shortened TL in the cells of patients at diagnosis compared to age-adjusted controls. In patients reaching CCR after chemotherapy, telomere shortening was less pronounced than in persistence or relapse but still significantly shortened compared to controls. We estimate patients harboring approximately 20 years of premature telomere loss compared to healthy aged-matched subjects at the time of AML onset. Our data indicate a pre-existing telomere deficit in non-clonal hematopoiesis of AML patients providing a link between age and AML development.},
}
@article {pmid28674277,
year = {2018},
author = {Masai, H and Kanoh, Y and Moriyama, K and Yamazaki, S and Yoshizawa, N and Matsumoto, S},
title = {Telomere-binding factors in the regulation of DNA replication.},
journal = {Genes &amp; genetic systems},
volume = {92},
number = {3},
pages = {119-125},
doi = {10.1266/ggs.17-00008},
pmid = {28674277},
issn = {1880-5779},
mesh = {Animals ; DNA Replication/*physiology ; Humans ; S Phase/*physiology ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Recent studies have indicated new roles for telomere-binding factors in the regulation of DNA replication, not only at the telomeres but also at the arm regions of the chromosome. Among these factors, Rif1, a conserved protein originally identified in yeasts as a telomere regulator, plays a major role in the spatiotemporal regulation of DNA replication during S phase. Its ability to interact with phosphatases and to create specific higher-order chromatin structures is central to the mechanism by which Rif1 exerts this function. In this review, we discuss recent progress in elucidating the roles of Rif1 and other telomere-binding factors in the regulation of chromosome events occurring at locations other than telomeres.},
}
@article {pmid28673972,
year = {2017},
author = {Pan, X and Drosopoulos, WC and Sethi, L and Madireddy, A and Schildkraut, CL and Zhang, D},
title = {FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {114},
number = {29},
pages = {E5940-E5949},
pmid = {28673972},
issn = {1091-6490},
support = {K99 HL136870/HL/NHLBI NIH HHS/United States ; R01 GM045751/GM/NIGMS NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins/genetics/metabolism ; BRCA1 Protein/genetics/*metabolism ; Cell Line ; Checkpoint Kinase 1/genetics/metabolism ; DNA Helicases/genetics/*metabolism ; DNA Replication/*physiology ; Homologous Recombination ; Humans ; RecQ Helicases/genetics/*metabolism ; Telomere/genetics/metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {In the mammalian genome, certain genomic loci/regions pose greater challenges to the DNA replication machinery (i.e., the replisome) than others. Such known genomic loci/regions include centromeres, common fragile sites, subtelomeres, and telomeres. However, the detailed mechanism of how mammalian cells cope with the replication stress at these loci/regions is largely unknown. Here we show that depletion of FANCM, or of one of its obligatory binding partners, FAAP24, MHF1, and MHF2, induces replication stress primarily at the telomeres of cells that use the alternative lengthening of telomeres (ALT) pathway as their telomere maintenance mechanism. Using the telomere-specific single-molecule analysis of replicated DNA technique, we found that depletion of FANCM dramatically reduces the replication efficiency at ALT telomeres. We further show that FANCM, BRCA1, and BLM are actively recruited to the ALT telomeres that are experiencing replication stress and that the recruitment of BRCA1 and BLM to these damaged telomeres is interdependent and is regulated by both ATR and Chk1. Mechanistically, we demonstrated that, in FANCM-depleted ALT cells, BRCA1 and BLM help to resolve the telomeric replication stress by stimulating DNA end resection and homologous recombination (HR). Consistent with their roles in resolving the replication stress induced by FANCM deficiency, simultaneous depletion of BLM and FANCM, or of BRCA1 and FANCM, leads to increased micronuclei formation and synthetic lethality in ALT cells. We propose that these synthetic lethal interactions can be explored for targeting the ALT cancers.},
}
@article {pmid28673689,
year = {2018},
author = {Gong, Y and Tian, G and Xue, H and Zhang, X and Zhao, Y and Cheng, G},
title = {Higher adherence to the 'vegetable-rich' dietary pattern is related to longer telomere length in women.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {37},
number = {4},
pages = {1232-1237},
doi = {10.1016/j.clnu.2017.05.005},
pmid = {28673689},
issn = {1532-1983},
mesh = {Adult ; Aged ; Asian People/statistics &amp; numerical data ; China/epidemiology ; Diet/*statistics &amp; numerical data ; Female ; Humans ; Male ; Middle Aged ; Telomere/*physiology ; *Vegetables ; },
abstract = {BACKGROUND &amp; AIMS: Increasing evidence suggests a role of nutrition in aging process measured by telomere length (TL). However, data from Chinese are scarce. Moreover, the potential mechanism underlying diet and aging is not clear. Although inflammation has been hypothesized as one of the main factors, direct evidence is lacking. We examined whether dietary patterns were associated with TL in Chinese adults, with particular attention paid to body fat (excessive accumulation of body fat is a state of high-systematic oxidative stress and inflammation) and C-reactive protein (CRP, a marker of inflammation).<br><br>METHODS: Principal components analysis was used to identify dietary patterns from a 66-item food frequency questionnaire. TL was measured by Southern blots-based assay (Telomere restriction fragments, TRF). Data on sociodemographic characteristics, lifestyle behaviors, anthropometry and metabolism were collected. Multivariate linear regressions were performed in 553 Chinese adults (50.8% men) aged 25-65 years.<br><br>RESULTS: Four main dietary patterns were identified. After adjustment for potential confounders, only the 'vegetable-rich' pattern characterized by higher intake of fruits, whole grains, various vegetable groups, dairy products, nuts, eggs and tea, was positively related to TL in women (&#x3b2;&#xa0;=&#xa0;160.81, P for trend <0.05). The strength of this relation was almost identical with further adjustment for body fat (&#x3b2;&#xa0;=&#xa0;160.50, P for trend <0.05), but was attenuated slightly with additional adjustment for CRP (&#x3b2;&#xa0;=&#xa0;152.02, P for trend <0.05). No significant relations were observed in men between dietary patterns and TL.<br><br>CONCLUSIONS: Chinese women with higher adherence to 'vegetable-rich' dietary pattern have a longer TL. This relation was partially explained by CRP but not by body fat.},
}
@article {pmid28672148,
year = {2017},
author = {Blévin, P and Angelier, F and Tartu, S and Bustamante, P and Herzke, D and Moe, B and Bech, C and Gabrielsen, GW and Bustnes, JO and Chastel, O},
title = {Perfluorinated substances and telomeres in an Arctic seabird: Cross-sectional and longitudinal approaches.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {230},
number = {},
pages = {360-367},
doi = {10.1016/j.envpol.2017.06.060},
pmid = {28672148},
issn = {1873-6424},
mesh = {Animals ; Arctic Regions ; Charadriiformes/*metabolism ; Cross-Sectional Studies ; *Environmental Monitoring ; Fluorocarbons/*metabolism ; Svalbard ; Telomere/*metabolism ; },
abstract = {Telomeres are non-coding DNA repeats located at the termini of eukaryotic chromosomes, regulated by dynamic processes balancing shortening and maintenance. Despite a mechanism to slow-down telomere shortening, cell division leads to progressive attrition of chromosomes, leading to the onset of cellular senescence or apoptosis. However, telomere restoration based on telomerase activity is the primary mechanism for telomere maintenance. Telomere length is associated to health and survival and can be impacted by a broad panel of environmental factors. However, the effect of contaminants on telomeres is poorly known for living organisms. The aim of this study was to investigate relationships between some poly- and perfluoroalkyl substances (PFASs), body condition and telomere length by using both a cross-sectional and longitudinal approach in adult breeding Black-legged kittiwakes (Rissa tridactyla) from Svalbard. First, we examined the associations between absolute telomere length and PFASs contamination in a given year (cross-sectional approach). Second, we investigated the relationships between telomere dynamics and PFASs contamination within a two years' time frame (longitudinal approach). Our results did not show any significant relationships of PFASs and body condition with absolute telomere length in a given year. Surprisingly, we found a positive and significant relationship between PFASs and telomere dynamics in both sexes with elongated telomere in birds bearing the highest concentrations of PFASs. Our study underlines (i) the need to investigate PFAS effects on telomere dynamics with a longitudinal approach and (ii) a potential positive effect of these contaminants on telomere length, with the most contaminated birds showing the slowest rate of telomere shortening or even displaying elongated ones. Our study is the first to report a relationship between PFASs and telomere length in free-living vertebrates. A possible underlying mechanism and other potential confounding factors are discussed.},
}
@article {pmid28666128,
year = {2017},
author = {Chu, HP and Cifuentes-Rojas, C and Kesner, B and Aeby, E and Lee, HG and Wei, C and Oh, HJ and Boukhali, M and Haas, W and Lee, JT},
title = {TERRA RNA Antagonizes ATRX and Protects Telomeres.},
journal = {Cell},
volume = {170},
number = {1},
pages = {86-101.e16},
pmid = {28666128},
issn = {1097-4172},
support = {/HHMI_/Howard Hughes Medical Institute/United States ; K99 GM115868/GM/NIGMS NIH HHS/United States ; R01 GM058839/GM/NIGMS NIH HHS/United States ; R37 GM058839/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; DNA Helicases/*metabolism ; Electrophoretic Mobility Shift Assay ; Mice ; Nuclear Proteins/*metabolism ; Nucleotide Motifs ; Proteome/*metabolism ; RNA, Long Noncoding/*metabolism ; Stem Cells/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; X-linked Nuclear Protein ; },
abstract = {Through an integration of genomic and proteomic approaches to advance understanding of long noncoding RNAs, we investigate the function of the telomeric transcript, TERRA. By identifying thousands of TERRA target sites in the mouse genome, we demonstrate that TERRA can bind both in cis to telomeres and in trans to genic targets. We then define a large network of interacting proteins, including epigenetic factors, telomeric proteins, and the RNA helicase, ATRX. TERRA and ATRX share hundreds of target genes and are functionally antagonistic at these loci: whereas TERRA activates, ATRX represses gene expression. At telomeres, TERRA competes with telomeric DNA for ATRX binding, suppresses ATRX localization, and ensures telomeric stability. Depleting TERRA increases telomerase activity and induces telomeric pathologies, including formation of telomere-induced DNA damage foci and loss or duplication of telomeric sequences. We conclude that TERRA functions as an epigenomic modulator in trans and as an essential regulator of telomeres in cis.},
}
@article {pmid28666126,
year = {2017},
author = {Graf, M and Bonetti, D and Lockhart, A and Serhal, K and Kellner, V and Maicher, A and Jolivet, P and Teixeira, MT and Luke, B},
title = {Telomere Length Determines TERRA and R-Loop Regulation through the Cell Cycle.},
journal = {Cell},
volume = {170},
number = {1},
pages = {72-85.e14},
doi = {10.1016/j.cell.2017.06.006},
pmid = {28666126},
issn = {1097-4172},
mesh = {*Cell Cycle ; Cellular Senescence ; DNA Damage ; Exoribonucleases/metabolism ; Nucleic Acid Hybridization ; Recombinational DNA Repair ; Repressor Proteins/metabolism ; Saccharomyces cerevisiae/*cytology/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Telomere/chemistry/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Maintenance of a minimal telomere length is essential to prevent cellular senescence. When critically short telomeres arise in the absence of telomerase, they can be repaired by homology-directed repair (HDR) to prevent premature senescence onset. It is unclear why specifically the shortest telomeres are targeted for HDR. We demonstrate that the non-coding RNA TERRA accumulates as HDR-promoting RNA-DNA hybrids (R-loops) preferentially at very short telomeres. The increased level of TERRA and R-loops, exclusively at short telomeres, is due to a local defect in RNA degradation by the Rat1 and RNase H2 nucleases, respectively. Consequently, the coordination of TERRA degradation with telomere replication is altered at shortened telomeres. R-loop persistence at short telomeres contributes to activation of the DNA damage response (DDR) and promotes recruitment of the Rad51 recombinase. Thus, the telomere length-dependent regulation of TERRA and TERRA R-loops is a critical determinant of the rate of replicative senescence.},
}
@article {pmid28665198,
year = {2017},
author = {Garcia, CK},
title = {Whole-Exome Sequencing Insights into Adult Pulmonary Fibrosis. Repeating the Telomere Theme.},
journal = {American journal of respiratory and critical care medicine},
volume = {196},
number = {1},
pages = {7-9},
pmid = {28665198},
issn = {1535-4970},
support = {R01 HL093096/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; *Exome ; Humans ; Mutation ; Pedigree ; Pulmonary Fibrosis/genetics ; *Telomere ; },
}
@article {pmid28664476,
year = {2018},
author = {Kim, H and Ahn, D and Sohn, JH and Kim, YH and Lee, JH and Lee, H},
title = {TERT Promoter Mutation and Telomere Length in Salivary Gland Tumors.},
journal = {Pathology oncology research : POR},
volume = {24},
number = {3},
pages = {697-698},
pmid = {28664476},
issn = {1532-2807},
support = {2016//Keimyung University (KR)/International ; },
mesh = {Humans ; *Mutation ; Prognosis ; *Promoter Regions, Genetic ; Salivary Gland Neoplasms/classification/*genetics/pathology ; Telomerase/*genetics ; *Telomere Homeostasis ; },
}
@article {pmid28663541,
year = {2017},
author = {Kim, TY and Kim, SJ and Choi, JR and Lee, ST and Kim, J and Hwang, IS and Chung, HG and Choi, JH and Kim, HW and Kim, SH and Kang, JI},
title = {The effect of trauma and PTSD on telomere length: An exploratory study in people exposed to combat trauma.},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {4375},
pmid = {28663541},
issn = {2045-2322},
mesh = {Aged ; Combat Disorders/epidemiology/*genetics ; Humans ; Middle Aged ; Risk Assessment ; Risk Factors ; Socioeconomic Factors ; Stress Disorders, Post-Traumatic/epidemiology/*genetics ; Stress, Physiological ; Stress, Psychological ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Veterans ; },
abstract = {Telomere length has been suggested to be a cellular marker for age-related diseases as well as psychosocial stress. The present study investigated whether telomere length is associated with post-traumatic stress disorder (PTSD) among veterans exposed to combat trauma in the Vietnam War. The potentially associated factors on cellular aging were considered. Korean male veterans with (n = 122) and without (n = 120) PTSD were included and leukocyte telomere length was measured with a quantitative PCR-based technique. As a whole, no significant difference in telomere length was found between PTSD and non-PTSD groups. In linear regression analysis stratified by trauma levels, among veterans exposed to severe combat (n = 45), PTSD status (B = -1.176, t = -2.259, p = 0.029), antidepressant use (B = 0.168, t = 2.528, p = 0.015), and education level (B = 0.019, t = 2.369, p = 0.023) affected telomere length. However, among veterans with light-to-moderate combat exposure (n = 197), only age (B = -0.007, t = -2.434, p = 0.016) and education level (B = 0.010, t = 2.295, p = 0.023) were associated with telomere length. In the Post-hoc analysis, antidepressant use was associated with longer telomere length in subjects exposed to severe combat. Our exploratory results suggest that PTSD status in combination with severe trauma may be associated with accelerated telomere shortening, and that antidepressant use may have a protective effect on telomere dynamics.},
}
@article {pmid28658264,
year = {2017},
author = {Vasu, V and Turner, KJ and George, S and Greenall, J and Slijepcevic, P and Griffin, DK},
title = {Preterm infants have significantly longer telomeres than their term born counterparts.},
journal = {PloS one},
volume = {12},
number = {6},
pages = {e0180082},
pmid = {28658264},
issn = {1932-6203},
mesh = {Adult ; Birth Weight ; Case-Control Studies ; Female ; Gestational Age ; Humans ; Infant, Newborn ; Infant, Premature/*metabolism ; Male ; Maternal Age ; Prospective Studies ; Telomere/*ultrastructure ; },
abstract = {There are well-established morbidities associated with preterm birth including respiratory, neurocognitive and developmental disorders. However several others have recently emerged that characterise an 'aged' phenotype in the preterm infant by term-equivalent age. These include hypertension, insulin resistance and altered body fat distribution. Evidence shows that these morbidities persist into adult life, posing a significant public health concern. In this study, we measured relative telomere length in leukocytes as an indicator of biological ageing in 25 preterm infants at term equivalent age. Comparing our measurements with those from 22 preterm infants sampled at birth and from 31 term-born infants, we tested the hypothesis that by term equivalent age, preterm infants have significantly shorter telomeres (thus suggesting that they are prematurely aged). Our results demonstrate that relative telomere length is highly variable in newborn infants and is significantly negatively correlated with gestational age and birth weight in preterm infants. Further, longitudinal assessment in preterm infants who had telomere length measurements available at both birth and term age (n = 5) suggests that telomere attrition rate is negatively correlated with increasing gestational age. Contrary to our initial hypothesis however, relative telomere length was significantly shortest in the term born control group compared to both preterm groups and longest in the preterm at birth group. In addition, telomere lengths were not significantly different between preterm infants sampled at birth and those sampled at term equivalent age. These results indicate that other, as yet undetermined, factors may influence telomere length in the preterm born infant and raise the intriguing hypothesis that as preterm gestation declines, telomere attrition rate increases.},
}
@article {pmid28657713,
year = {2017},
author = {Charif, R and Granotier-Beckers, C and Bertrand, HC and Poupon, J and Ségal-Bendirdjian, E and Teulade-Fichou, MP and Boussin, FD and Bombard, S},
title = {Association of a Platinum Complex to a G-Quadruplex Ligand Enhances Telomere Disruption.},
journal = {Chemical research in toxicology},
volume = {30},
number = {8},
pages = {1629-1640},
doi = {10.1021/acs.chemrestox.7b00131},
pmid = {28657713},
issn = {1520-5010},
mesh = {Acridines/toxicity ; Cell Cycle Checkpoints/drug effects ; Cell Line ; Cell Proliferation/drug effects ; Cisplatin/toxicity ; Coordination Complexes/*toxicity ; DNA Damage/drug effects ; G-Quadruplexes/*drug effects ; Humans ; Ligands ; Microscopy, Fluorescence ; Organoplatinum Compounds/toxicity ; Platinum/*chemistry ; Telomere/*drug effects/metabolism ; Telomere Shortening/drug effects ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Telomeres protect the ends of chromosomes against illegitimate recombination and repair. They can be targets for G-quadruplex ligands and platinum complexes due to their repeated G-rich sequences. Protection of telomeres is ensured by a complex of six proteins, including TRF2, which inhibits the DNA damage response pathway. We analyzed telomere modifications induced in cancer cells by the experimental hybrid platinum complex, Pt-MPQ, comprising both an ethylene diamine monofunctional platinum complex and a G-quadruplex recognition moiety (MPQ). Pt-MPQ promotes the displacement of two telomeric proteins (TRF2 and TRF1) from telomeres, as well as the formation of telomere damage and telomere sister losses, whereas the control compound MPQ does not. This suggests that the platinum moiety potentiates the targeting of the G-quadruplex ligand to telomeres, opening a new perspective for telomere biology and anticancer therapy. Interestingly, the chemotherapy drug cisplatin, which has no specific affinity for G-quadruplex structures, partially induces the TRF2 delocalization from telomeres but produces less telomeric DNA damage, suggesting that this TRF2 displacement could be independent of G-quadruplex recognition.},
}
@article {pmid28654015,
year = {2017},
author = {Knecht, H and Mai, S},
title = {LMP1 and Dynamic Progressive Telomere Dysfunction: A Major Culprit in EBV-Associated Hodgkin's Lymphoma.},
journal = {Viruses},
volume = {9},
number = {7},
pages = {},
pmid = {28654015},
issn = {1999-4915},
mesh = {Epstein-Barr Virus Infections/*complications ; Herpesvirus 4, Human/*pathogenicity ; Hodgkin Disease/*physiopathology ; *Host-Pathogen Interactions ; Humans ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; Viral Matrix Proteins/*metabolism ; },
abstract = {Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is expressed in germinal-center-derived, mononuclear Hodgkin (H) and multinuclear, diagnostic Reed-Sternberg (RS) cells in classical EBV-positive Hodgkin's lymphoma (cHL). LMP1 expression in EBV-negative H-cell lines results in a significantly increased number of RS cells. In a conditional, germinal-center-derived B-cell in vitro system, LMP1 reversibly down-regulates the shelterin proteins, telomeric repeat binding factor (TRF)1, TRF2, and protection of telomeres (POT)1. This down-regulation is associated with progressive 3D shelterin disruption, resulting in telomere dysfunction, progression of complex chromosomal rearrangements, and multinuclearity. TRF2 appears to be the key player. Thus, we hypothesize that the 3D interaction of telomeres and TRF2 is disrupted in H cells, and directly associated with the formation of H and RS cells. Using quantitative 3D co-immuno-TRF2-telomere fluorescent in situ hybridization (3D TRF2/Telo-Q-FISH) applied to monolayers of primary H and RS cells, we demonstrate TRF2-telomere dysfunction in EBV-positive cHL. However, in EBV-negative cHL a second molecular mechanism characterized by massive up-regulation of TRF2, but attrition of telomere signals, is also identified. These facts point towards a shelterin-related pathogenesis of cHL, where two molecularly disparate mechanisms converge at the level of 3D Telomere-TRF2 interactions, leading to the formation of RS cells.},
}
@article {pmid28650257,
year = {2017},
author = {Gopalakrishnan, V and Tan, CR and Li, S},
title = {Sequential phosphorylation of CST subunits by different cyclin-Cdk1 complexes orchestrate telomere replication.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {16},
number = {13},
pages = {1271-1287},
pmid = {28650257},
issn = {1551-4005},
mesh = {CDC2 Protein Kinase/*metabolism ; Cell Cycle Proteins/genetics/*metabolism ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; Cyclin B/genetics/metabolism ; Cyclins/*metabolism ; DNA Replication ; Mutagenesis ; Phosphorylation ; Proteolysis ; S Phase ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere Shortening ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Telomeres are nucleoprotein structures that cap the ends of linear chromosomes. Telomere homeostasis is central to maintaining genomic integrity. In budding yeast, Cdk1 phosphorylates the telomere-specific binding protein, Cdc13, promoting the recruitment of telomerase to telomere and thereby telomere elongation. Cdc13 is also an integral part of the CST (Cdc13-Stn1-Ten1) complex that is essential for telomere capping and counteracting telomerase-dependent telomere elongation. Therefore, telomere length homeostasis is a balance between telomerase-extendable and CST-unextendable states. In our earlier work, we showed that Cdk1 also phosphorylates Stn1 which occurs sequentially following Cdc13 phosphorylation during cell cycle progression. This stabilizes the CST complex at the telomere and results in telomerase inhibition. Hence Cdk1-dependent phosphorylations of Stn1 acts like a molecular switch that drives Cdc13 to complex with Stn1-Ten1 rather than with telomerase. However, the underlying mechanism of how a single cyclin-dependent kinase phosphorylates Cdc13 and Stn1 in temporally distinct windows is largely unclear. Here, we show that S phase cyclins are necessary for telomere maintenance. The S phase and mitotic cyclins facilitate Cdc13 and Stn1 phosphorylation respectively, to exert opposing outcomes at the telomere. Thus, our results highlight a previously unappreciated role for cyclins in telomere replication.},
}
@article {pmid28649877,
year = {2017},
author = {Frenzel, M and Ricoul, M and Benadjaoud, MA and Bellamy, M and Lenain, A and Haddy, N and Diallo, I and Mateus, C and de Vathaire, F and Sabatier, L},
title = {Retrospective cohort study and biobanking of patients treated for hemangioma in childhood - telomeres as biomarker of aging and radiation exposure.},
journal = {International journal of radiation biology},
volume = {93},
number = {10},
pages = {1040-1053},
doi = {10.1080/09553002.2017.1337278},
pmid = {28649877},
issn = {1362-3095},
mesh = {Adolescent ; Adult ; Aged ; Aging/*genetics/radiation effects ; *Biological Specimen Banks ; Bone Marrow/radiation effects ; Child ; Cohort Studies ; Dose-Response Relationship, Radiation ; Female ; Genetic Markers/genetics ; Hemangioma/*genetics/*radiotherapy ; Humans ; Male ; Middle Aged ; Radiation Exposure/*adverse effects/analysis ; Retrospective Studies ; Telomere/*genetics/*radiation effects ; },
abstract = {PURPOSE: Cohorts allowing joint epidemiological and biological analyses are essential for radiation risk assessment. The French Hemangioma Cohort (FHC), studied within the European project EpiRadBio, is one of the rare cohorts suitable for studying the effect of low dose radiation exposure (<100 mGy at organs), with a long-term follow-up. This highly homogeneous cohort consists of healthy individuals belonging to a normal population, except for the presence of skin hemangioma (age at exposure: between 6 months and 3 years of age). Published epidemiological studies have demonstrated that the risk of developing cancer is three times higher in the exposed individuals than in the general population. Here, we present the biobanking of samples (nucleated blood cells, cytogenetic slides of T and B lymphocytes) from the FHC and a primary feasibility study of biomarker analysis focusing on mean telomere length (MTL). Telomeres act as an internal clock, regulating the lifetime of the cell by their shortening during cell division. MTL is thus a biomarker of age. Many in vitro studies have linked MTL and radiosensitivity. The FHC will make it possible to discriminate between the effects of aging and radiation on this biomarker.<br><br>CONCLUSION: The establishment of a biobank of essentially healthy individuals (369 in total), exposed 40-70 years before, during their early childhood, is a logistical challenge. Even among those who previously participated to a self-questionnaire based study, the response rate was only 30%. The first biomarker to be studied was the MTL to discriminate age effects from those of radiation exposure. MTL showed significant variation within age groups (4-11&#x2009;kb) in both the exposed and non-exposed groups. MTL within the limited age window (i.e. 40-73 year) examined, showed age-dependent changes of 46&#x2009;bp/year, consistent with the age-dependent decline of 41&#x2009;bp/year previously reported. We observed no significant changes in MTL according to the average active bone marrow dose. However, we were able to demonstrate that exposure to radiation causes the loss of cells with, on average, shorter telomeres, by applying a model in which both the heterogeneity of the individual dose received at the bone marrow and the heterogeneity of the intercellular distribution of MTL were taken into account.},
}
@article {pmid28648751,
year = {2017},
author = {Ley, B and Newton, CA and Arnould, I and Elicker, BM and Henry, TS and Vittinghoff, E and Golden, JA and Jones, KD and Batra, K and Torrealba, J and Garcia, CK and Wolters, PJ},
title = {The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study.},
journal = {The Lancet. Respiratory medicine},
volume = {5},
number = {8},
pages = {639-647},
pmid = {28648751},
issn = {2213-2619},
support = {KL2 TR001870/TR/NCATS NIH HHS/United States ; UL1 TR001105/TR/NCATS NIH HHS/United States ; K24 AR051895/AR/NIAMS NIH HHS/United States ; R01 HL093096/HL/NHLBI NIH HHS/United States ; KL2 TR001103/TR/NCATS NIH HHS/United States ; },
mesh = {Aged ; Alveolitis, Extrinsic Allergic/blood/*genetics/mortality ; California ; Case-Control Studies ; Cohort Studies ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/blood/*genetics/mortality ; Intracellular Signaling Peptides and Proteins ; Male ; Middle Aged ; Mucin-5B/blood/*genetics ; *Polymorphism, Single Nucleotide ; Promoter Regions, Genetic/genetics ; Risk Factors ; *Telomere ; Texas ; White People/genetics ; },
abstract = {BACKGROUND: Patients with hypersensitivity pneumonitis are at risk of developing pulmonary fibrosis, which is associated with reduced survival. In families with multiple affected members, individuals might be diagnosed as having idiopathic pulmonary fibrosis (IPF) or chronic (fibrotic) hypersensitivity pneumonitis, which suggests these disorders share risk factors. We aimed to test whether the genomic risk factors associated with the development and progression of IPF are also associated with the development of fibrosis and reduced survival in people with chronic hypersensitivity pneumonitis.<br><br>METHODS: We did an observational study of two independent cohorts of patients with chronic hypersensitivity pneumonitis, one from the University of California San Francisco, CA, USA (UCSF), and one from the University of Texas Southwestern, TX, USA (UTSW). We measured two common single-nucleotide polymorphisms associated with IPF (MUC5B rs35705950 and TOLLIP rs5743890) and telomere length in peripheral blood leucocytes, and assessed their associations with chronic hypersensitivity pneumonitis risk, survival, and clinical, radiographic, and pathological features. We compared findings with those in patients with IPF from the UCSF and UTSW cohorts, and healthy controls from the European population of the 1000 Genomes Project Phase 3, version 1.<br><br>FINDINGS: The cohorts included 145 patients from UCSF and 72 from UTSW. The minor allele frequency (MAF) was greater for MUC5B rs35705950 in patients with chronic hypersensitivity pneumonitis than in healthy controls (24&#xb7;4% in UCSF and 32&#xb7;3% in UTSW vs 10&#xb7;7%, both p<0&#xb7;0001), but not for TOLLIP rs5743890. The MAFs were similar to those for IPF (UCSF 33&#xb7;3%, p=0&#xb7;09; UTSW 32&#xb7;0%, p=0&#xb7;95). In the combined UCSF and UTSW chronic hypersensitivity pneumonitis cohort, we saw associations between extent of radiographic fibrosis and MUC5B rs35705950 minor alleles (adjusted odds ratio [OR] 1&#xb7;91, 95% CI 1&#xb7;02-3&#xb7;59, p=0&#xb7;045) and short telomere length (adjusted OR per unit change in mean natural logarithm-transformed ratio of telomere repeat copy number to single gene copy number 0&#xb7;23, 0&#xb7;09-0&#xb7;59, p=0&#xb7;002). Telomere length less than the tenth percentile for age was also significantly associated with reduced survival (log-rank p=0&#xb7;006).<br><br>INTERPRETATION: The associations between MUC5B rs35705950 and short telomere length with extent of fibrosis, histopathological features of usual interstitial pneumonia, and reduced survival in patients with chronic hypersensitivity pneumonitis suggest shared pathobiology with IPF, and might help to stratify risk.<br><br>FUNDING: National Institutes of Health and Nina Ireland Program for Lung Health.},
}
@article {pmid28648750,
year = {2017},
author = {Zhang, Y},
title = {MUC5B and short telomere length in hypersensitivity pneumonitis.},
journal = {The Lancet. Respiratory medicine},
volume = {5},
number = {8},
pages = {603-604},
doi = {10.1016/S2213-2600(17)30210-2},
pmid = {28648750},
issn = {2213-2619},
mesh = {*Alveolitis, Extrinsic Allergic ; Humans ; Lung ; Mucin-5B ; *Telomere ; },
}
@article {pmid28646223,
year = {2017},
author = {Dimauro, I and Sgura, A and Pittaluga, M and Magi, F and Fantini, C and Mancinelli, R and Sgadari, A and Fulle, S and Caporossi, D},
title = {Regular exercise participation improves genomic stability in diabetic patients: an exploratory study to analyse telomere length and DNA damage.},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {4137},
pmid = {28646223},
issn = {2045-2322},
mesh = {Aged ; Apoptosis/drug effects/genetics ; Case-Control Studies ; DNA Damage ; Diabetes Mellitus, Type 2/*genetics/*metabolism ; *Exercise ; Gene Expression Profiling ; *Genomic Instability ; Humans ; Hydrogen Peroxide/metabolism/pharmacology ; In Situ Hybridization, Fluorescence ; Leukocytes/metabolism ; Male ; Middle Aged ; Telomere/genetics ; Telomere Homeostasis ; Telomere Shortening/drug effects/genetics ; },
abstract = {Physical activity has been demonstrated to be effective in the prevention and treatment of different chronic conditions, including type 2 diabetes (T2D). In particular, several studies highlighted how the beneficial effects of physical activity may be related to the stability of the DNA molecule, such as longer telomeric ends. Here we analyze the effect of exercise training on telomere length, spontaneous and H2O2-induced DNA damage, as well as the apoptosis level in leukocytes from untrained or trained T2D patients vs. age-matched control subjects (CS) (57-66 years). Moreover, expression analysis of selected genes belonging to DNA repair systems, cell cycle control, antioxidant and defence systems was performed. Subjects that participated in a regular exercise program showed a longer telomere sequence than untrained counterparts. Moreover, ex vivo treatment of leukocytes with H2O2 highlighted that: (1) oxidative DNA damage induced similar telomere attrition in all groups; (2) in T2D subjects, physical activity seemed to prevent a significant increase of genomic oxidative DNA damage induced by chronic exposure to pro-oxidant stimulus, and (3) decreased the sensitivity of leukocytes to apoptosis. Finally, the gene expression analysis in T2D subjects suggested an adaptive response to prolonged exercise training that improved the response of specific genes.},
}
@article {pmid28646162,
year = {2017},
author = {Dong, Y and Huang, Y and Gutin, B and Raed, A and Dong, Y and Zhu, H},
title = {Associations between Global DNA Methylation and Telomere Length in Healthy Adolescents.},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {4210},
pmid = {28646162},
issn = {2045-2322},
support = {R01 HL064157/HL/NHLBI NIH HHS/United States ; R01 HL131674/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; DNA Methylation/*genetics ; Ethnicity ; Female ; *Health ; Humans ; Linear Models ; Male ; Models, Theoretical ; Telomere Homeostasis/*genetics ; },
abstract = {Emerging evidence suggests that epigenetics regulates telomere dynamics in adults. However, the relationship between these pathways in children and youth remains unknown. Thus, we examined this association in 542 healthy adolescents aged 14 to 18 years old (44.8% African Americans; 55.2% females). Global DNA methylation level (%5-mC) was quantified using ELISA method. Leukocyte telomere length (LTL) was defined as relative telomere to single copy gene (T/S) ratio. Multiple linear regression models, adjusted for age, gender, ethnicity, Tanner stage, BMI, PA, and batch effect, revealed that %5 mC was associated with LTL (adjusted β = 0.17, p < 0.01). %5 mC accounted for 5.0% of the variation for LTL. A significant gender interaction was identified (p < 0.01). There was an association between %5 mC and LTL in females (all ps < 0.01), but not in males. Further sensitivity analyses by race revealed similar associations in African Americans and whites (all ps < 0.03). The present study, for the first time, shows that lower levels of global DNA methylation are associated with shorter telomere lengths in youth, which may decrease genome stability and augment the susceptibility to diseases. Longitudinal studies are warranted to establish the effects of global DNA methylation on LTL maintenance over time.},
}
@article {pmid28646123,
year = {2017},
author = {Satoh, M and Nasu, T and Takahashi, Y and Osaki, T and Hitomi, S and Morino, Y and Nakamura, M},
title = {Expression of miR-23a induces telomere shortening and is associated with poor clinical outcomes in patients with coronary artery disease.},
journal = {Clinical science (London, England : 1979)},
volume = {131},
number = {15},
pages = {2007-2017},
doi = {10.1042/CS20170242},
pmid = {28646123},
issn = {1470-8736},
mesh = {Aged ; Coronary Artery Disease/blood/*genetics/metabolism ; Female ; Humans ; Male ; MicroRNAs/blood/*genetics ; Middle Aged ; Telomere/genetics/*metabolism ; Telomere Shortening ; Telomeric Repeat Binding Protein 2/blood/genetics ; },
abstract = {Telomeric repeat binding factor (TRF) 2 (TRF2) plays an important role in telomere maintenance. miR-23a may directly inhibit TRF2 expression, thereby, inducing telomere shortening and cellular senescence. The present study aimed to determine whether miR-23a and TRF2 are expressed in patients with coronary artery disease (CAD), and whether pitavastatin might affect these levels. The present study included 104 patients with CAD and 50 controls. Patients with CAD were randomly divided into two subgroups (a moderate lipid lowering therapy (LLT) group and an aggressive LLT group). Peripheral blood mononuclear cells (PBMCs) were taken from patients with CAD and from controls at baseline and after 12 months. Levels of miR-23a were higher in the CAD group than in the controls. Levels of TRF2 protein were lower in the CAD group than in the controls. Our randomized clinical study showed that aggressive LLT decreased miR-23a and increased TRF2 levels, whereas moderate LLT generated no change in these levels. Our transfected cell model showed that miR-23a controlled TRF2 expression. After a mean follow-up of 339 days, cardiovascular events were associated with high miR-23a, low TRF2 or low relative telomere length. Multivariate analysis showed that levels of miR-23a (RR: 4.9, 95% CI: 1.9-14.3) were a strong predictor of cardiovascular events after adjustment for baseline characteristics. In conclusion, elevated levels of miR-23a play an important role in coronary atherosclerosis via down-regulated TRF2, and may provide important prognostic information in patients with CAD. Additionally, aggressive LLT may prevent telomere erosion via down-regulated miR-23a.},
}
@article {pmid28643740,
year = {2017},
author = {Poojary, SS and Mishra, G and Singh, TD and Gupta, S and Shrivastav, BR and Tiwari, PK},
title = {Telomere length variation and expression analysis of shelterin complex genes during gallbladder carcinogenesis.},
journal = {Journal of cancer research and therapeutics},
volume = {13},
number = {2},
pages = {235-239},
doi = {10.4103/0973-1482.184512},
pmid = {28643740},
issn = {1998-4138},
mesh = {Gallbladder Neoplasms/*genetics ; *Gene Expression Profiling ; Humans ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Shelterin Complex ; *Telomere ; Telomere-Binding Proteins/*genetics ; },
abstract = {BACKGROUND: Telomeres, which are bound with shelterin protein complex, play an important role in maintaining genomic stability and its dysfunction may lead to carcinogenesis. Here, we aimed to analyze whether shelterin complex gene expression and telomere length variation, play any role in gallbladder carcinogenesis.<br><br>METHODS: Telomere length analysis was carried out by monochrome multiplex qPCR, whereas expression analysis of shelterin genes was carried out using RT-qPCR. Statistical analysis was carried out using SigmaPlot 11 software.<br><br>RESULTS: We found significantly reduced telomere length in tumor tissues, and this reduction was seen in both, tumors with or without gallstones in comparison to adjacent non tumor and gallstone (chronic calculous cholecystitis: Inflamed) tissues. Inflamed tissues showed increased telomere length as compared to both adjacent non tumor and tumor tissues. Expression analysis of five shelterin genes showed significant downregulation of TERF1, POT1, and TINF2 genes in inflamed tissues as compared to non tumor and tumor tissues. POT1 was also found to be significantly upregulated in tumor tissues and specifically in tumor tissues with gallstones compared to inflamed tissues.<br><br>CONCLUSION: This study, thus, suggests that, gallstone does not affect telomere length and even after having increased telomere length, decreased expression of some shelterin genes in inflamed tissue might cause telomeres to cap improperly, possibly leading to telomere dysfunction and further, gallbladder carcinogenesis. Also, increased expression of POT1 in tumor tissues with gallstones could act as a diagnostic marker in patients with gallstones.},
}
@article {pmid28637256,
year = {2017},
author = {Rezvan, A},
title = {Telomeres, oxidative stress, and myocardial infarction.},
journal = {European heart journal},
volume = {38},
number = {41},
pages = {3105-3107},
pmid = {28637256},
issn = {1522-9645},
support = {K08 HL124292/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; *Myocardial Infarction ; Oxidative Stress ; *Telomere ; },
}
@article {pmid28636942,
year = {2017},
author = {Dagg, RA and Pickett, HA and Neumann, AA and Napier, CE and Henson, JD and Teber, ET and Arthur, JW and Reynolds, CP and Murray, J and Haber, M and Sobinoff, AP and Lau, LMS and Reddel, RR},
title = {Extensive Proliferation of Human Cancer Cells with Ever-Shorter Telomeres.},
journal = {Cell reports},
volume = {19},
number = {12},
pages = {2544-2556},
doi = {10.1016/j.celrep.2017.05.087},
pmid = {28636942},
issn = {2211-1247},
mesh = {Cell Line, Tumor ; *Cell Proliferation ; Enzyme Activation ; Gene Amplification ; Humans ; N-Myc Proto-Oncogene Protein/genetics ; Neuroblastoma/genetics/pathology ; Telomerase/metabolism ; *Telomere Shortening ; },
abstract = {Acquisition of replicative immortality is currently regarded as essential for malignant transformation. This is achieved by activating a telomere lengthening mechanism (TLM), either telomerase or alternative lengthening of telomeres, to counter normal telomere attrition. However, a substantial proportion of some cancer types, including glioblastomas, liposarcomas, retinoblastomas, and osteosarcomas, are reportedly TLM-negative. As serial samples of human tumors cannot usually be obtained to monitor telomere length changes, it has previously been impossible to determine whether tumors are truly TLM-deficient, there is a previously unrecognized TLM, or the assay results are false-negative. Here, we show that a subset of high-risk neuroblastomas (with ∼50% 5-year mortality) lacked significant TLM activity. Cancer cells derived from these highly aggressive tumors initially had long telomeres and proliferated for >200 population doublings with ever-shorter telomeres. This indicates that prevention of telomere shortening is not always required for oncogenesis, which has implications for inhibiting TLMs for cancer therapy.},
}
@article {pmid28636941,
year = {2017},
author = {Viceconte, N and Dheur, MS and Majerova, E and Pierreux, CE and Baurain, JF and van Baren, N and Decottignies, A},
title = {Highly Aggressive Metastatic Melanoma Cells Unable to Maintain Telomere Length.},
journal = {Cell reports},
volume = {19},
number = {12},
pages = {2529-2543},
doi = {10.1016/j.celrep.2017.05.046},
pmid = {28636941},
issn = {2211-1247},
mesh = {Adult ; Aged ; Animals ; Cell Line, Tumor ; Female ; Humans ; Lymphatic Metastasis ; Male ; Melanoma/genetics/metabolism/*secondary ; Mice, Inbred NOD ; Mice, SCID ; Middle Aged ; Neoplasm Transplantation ; Skin Neoplasms/genetics/metabolism/*pathology ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; Young Adult ; },
abstract = {Unlimited replicative potential is one of the hallmarks of cancer cells. In melanoma, hTERT (telomerase reverse transcriptase) is frequently overexpressed because of activating mutations in its promoter, suggesting that telomerase is necessary for melanoma development. We observed, however, that a subset of melanoma metastases and derived cell lines had no telomere maintenance mechanism. Early passages of the latter displayed long telomeres that progressively shortened and fused before cell death. We propose that, during melanoma formation, oncogenic mutations occur in precursor melanocytes with long telomeres, providing cells with sufficient replicative potential, thereby bypassing the need to re-activate telomerase. Our data further support the emerging idea that long telomeres promote melanoma formation. These observations are important when considering anticancer therapies targeting telomerase.},
}
@article {pmid28636901,
year = {2017},
author = {Rozman, JZ and Perme, MP and Jez, M and Malicev, E and Krasna, M and Novakovic, S and Vrtovec, B and Rozman, P},
title = {The effect of CD34[+] cell telomere length and hTERT expression on the outcome of autologous CD34[+] cell transplantation in patients with chronic heart failure.},
journal = {Mechanisms of ageing and development},
volume = {166},
number = {},
pages = {42-47},
doi = {10.1016/j.mad.2017.06.001},
pmid = {28636901},
issn = {1872-6216},
mesh = {Adolescent ; Adult ; Aged ; *Antigens, CD34 ; Autografts ; Chronic Disease ; Female ; *Gene Expression Regulation, Enzymologic ; Heart Failure/*enzymology/pathology/*therapy ; Humans ; Male ; Middle Aged ; *Stem Cell Transplantation ; Stem Cells/*enzymology ; Telomerase/*biosynthesis ; *Telomere Homeostasis ; },
abstract = {Age-related telomere attrition in stem/progenitor cells may diminish their functional capacity and thereby impair the outcome of cell-based therapies. The aim of the present study was to investigate the effect of CD34[+] cell telomere length and hTERT expression on the clinical outcome of autologous CD34[+] cell transplantation. We studied 43 patients with cardiomyopathy. Their peripheral blood CD34[+] cells were mobilized with granulocyte colony-stimulating factor, enriched by immunoselection and delivered transendocardially. Relative telomere length and expression levels of hTERT were measured using a real-time PCR assay. Immunoselected CD34[+] cells had longer telomere length compared to leukocytes in leukapheresis products (p=0.001). In multivariate analysis, CD34[+] cell telomere length was not associated with the clinical outcome (b=3.306, p=0.540). While hTERT expression was undetectable in all leukapheresis products, 94.4% of the CD34[+] enriched cell products expressed hTERT. Higher CD34[+]hTERT expression was associated with a better clinical outcome on univariate analysis (b=87.911, p=0.047). Our findings demonstrate that CD34[+] cell telomere length may not influence the clinical outcome in cardiomyopathy patients treated with autologous CD34[+] cell transplantation. Larger studies are needed to validate the impact of the CD34[+]hTERT expression on the clinical outcome of autologous CD34[+] cell transplantation.},
}
@article {pmid28634877,
year = {2018},
author = {Schrock, JM and Adler, NE and Epel, ES and Nuru-Jeter, AM and Lin, J and Blackburn, EH and Taylor, RJ and Chae, DH},
title = {Socioeconomic Status, Financial Strain, and Leukocyte Telomere Length in a Sample of African American Midlife Men.},
journal = {Journal of racial and ethnic health disparities},
volume = {5},
number = {3},
pages = {459-467},
pmid = {28634877},
issn = {2196-8837},
support = {K01AG041787/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; *Black or African American ; Cellular Senescence ; *Economic Status ; Gender Identity ; Humans ; Leukocytes/metabolism ; Logistic Models ; Male ; Masculinity ; Middle Aged ; Odds Ratio ; *Social Class ; Stress, Psychological/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: African American men in the USA experience poorer aging-related health outcomes compared to their White counterparts, partially due to socioeconomic disparities along racial lines. Greater exposure to socioeconomic strains among African American men may adversely impact health and aging at the cellular level, as indexed by shorter leukocyte telomere length (LTL). This study examined associations between socioeconomic factors and LTL among African American men in midlife, a life course stage when heterogeneity in both health and socioeconomic status are particularly pronounced.<br><br>METHODS: Using multinomial logistic regression, we examined associations between multiple measures of SES and tertiles of LTL in a sample of 92 African American men between 30 to 50&#xa0;years of age.<br><br>RESULTS: Reports of greater financial strain were associated with higher odds of short versus medium LTL (odds ratio (OR)=2.21, p&#xa0;=&#xa0;0.03). Higher income was associated with lower odds of short versus medium telomeres (OR=0.97, p&#xa0;=&#xa0;0.04). Exploratory analyses revealed a significant interaction between educational attainment and employment status (&#x3c7; [2]&#xa0;=&#xa0;4.07, p&#xa0;=&#xa0;0.04), with greater education associated with lower odds of short versus long telomeres only among those not employed (OR=0.10, p&#xa0;=&#xa0;0.040).<br><br>CONCLUSION: Cellular aging associated with multiple dimensions of socioeconomic adversity may contribute to poor aging-related health outcomes among African American men. Subjective appraisal of financial difficulty may impact LTL independently of objective dimensions of SES. Self-appraised success in fulfilling traditionally masculine gender roles, including being an economic provider, may be a particularly salient aspect of identity for African American men and have implications for cellular aging in this population.},
}
@article {pmid28634520,
year = {2017},
author = {Thimmapuram, J and Pargament, R and Sibliss, K and Grim, R and Risques, R and Toorens, E},
title = {Effect of heartfulness meditation on burnout, emotional wellness, and telomere length in health care professionals.},
journal = {Journal of community hospital internal medicine perspectives},
volume = {7},
number = {1},
pages = {21-27},
pmid = {28634520},
issn = {2000-9666},
abstract = {Background: Burnout poses significant challenges during training years in residency and later in the career. Meditation is a tool to treat stress-related conditions and promote wellness. Telomere length may be affected by burnout and stress. However, the benefits of meditation have not been fully demonstrated in health care professionals. Objective: We assessed the effects of a 12-week 'Heartfulness Meditation' program on burnout, emotional wellness, and telomere length in residents, faculty members, and nurses at a large community teaching hospital during the 2015-16 academic year. Methods: All subjects completed a baseline Maslach Burnout Inventory (MBI) and Emotional Wellness Assessment (EWA) at the beginning of the study. Meditators received instructions in Heartfulness Meditation. At week 12, subjects completed a follow up MBI and EWA scores. Salivary telomere length was measured at baseline and week 12. Results: Twenty-seven out of a total 155 residents (17.4%) along with eight faculty physicians and 12 nurses participated in the study. Thirty-five enrolled as meditators and 12 as controls. At 12 weeks, the meditators had statistically significant improvement in all measures of burnout and in nearly all attributes of EWA. Controls showed no statistically significant changes in either burnout or emotional wellness scores. Relative telomere length increased with statistical significance in a younger subset of meditators. Conclusion: Our results indicate that meditation offers an accessible and efficient method by which physician and nurse burnout can be ameliorated and wellness can be enhanced. The increased telomere length is an interesting finding but needs to be confirmed with further research. Abbreviations: EWA: Emotional wellness assessment; MBI: Maslach burnout inventory; EE: Emotional exhaustion; DP: Depersonalization; PA: Personal accomplishment; PI: Prinicipal investigator; JT: Jayaram Thimmapuram.},
}
@article {pmid28634187,
year = {2017},
author = {Antwi, SO and Boardman, LA and Petersen, GM},
title = {Telomere Length and Pancreatic Cancer Risk-Reply.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {26},
number = {7},
pages = {1158-1159},
pmid = {28634187},
issn = {1538-7755},
support = {P50 CA102701/CA/NCI NIH HHS/United States ; R25 CA092049/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Pancreas ; *Pancreatic Neoplasms ; Risk ; *Telomere ; },
}
@article {pmid28634186,
year = {2017},
author = {Mormile, R},
title = {Telomere Length and Pancreatic Cancer Risk-Letter.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {26},
number = {7},
pages = {1157},
doi = {10.1158/1055-9965.EPI-17-0225},
pmid = {28634186},
issn = {1538-7755},
mesh = {Humans ; Pancreas ; *Pancreatic Neoplasms ; Risk ; *Telomere ; },
}
@article {pmid28630379,
year = {2017},
author = {Dean, SG and Zhang, C and Gao, J and Roy, S and Shinkle, J and Sabarinathan, M and Argos, M and Tong, L and Ahmed, A and Islam, MT and Islam, T and Rakibuz-Zaman, M and Sarwar, G and Shahriar, H and Rahman, M and Yunus, M and Graziano, JH and Chen, LS and Jasmine, F and Kibriya, MG and Ahsan, H and Pierce, BL},
title = {The association between telomere length and mortality in Bangladesh.},
journal = {Aging},
volume = {9},
number = {6},
pages = {1537-1551},
pmid = {28630379},
issn = {1945-4589},
support = {P42 ES010349/ES/NIEHS NIH HHS/United States ; R01 ES020506/ES/NIEHS NIH HHS/United States ; R01 CA107431/CA/NCI NIH HHS/United States ; U01 HG007601/HG/NHGRI NIH HHS/United States ; R35 ES028379/ES/NIEHS NIH HHS/United States ; T32 AG000243/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Bangladesh ; Case-Control Studies ; Chromosomes, Human/*genetics ; Female ; Gene Expression Regulation/*physiology ; Humans ; Longevity ; Male ; Middle Aged ; *Mortality ; Odds Ratio ; Risk Factors ; *Telomere Homeostasis ; },
abstract = {Telomeres are tandem repeat sequences at the end of chromosomes that bind proteins to protect chromosome ends. Telomeres shorten with age, and shorter leukocyte telomere length (TL) has been associated with overall mortality in numerous studies. However, this association has not been tested in populations outside of Europe and the U.S. We assessed the association between TL and subsequent mortality using data on 744 mortality cases and 761 age-/sex-matched controls sampled from >27,000 participants from three longitudinal Bangladeshi cohorts: Health Effects of Arsenic Longitudinal Study (HEALS), HEALS Expansion (HEALS-E), and Bangladesh Vitamin E and Selenium Trial (BEST). We used conditional logistic regression to estimate odds ratios (ORs) for the association between a standardized TL variable and overall mortality, as well as mortality from chronic diseases, respiratory diseases, circulatory diseases, and cancer. In HEALS and BEST, we observed an association between shorter TL and increased overall mortality (P=0.03 and P=0.03), mortality from chronic disease (P=0.01 and P=0.03) and mortality from circulatory disease (P=0.03 and P=0.04). Results from pooled analyses of all cohorts were consistent with HEALS and BEST. This is the first study demonstrating an association between short TL and increased mortality in a population of non-European ancestry.},
}
@article {pmid28630210,
year = {2017},
author = {Toupance, S and Labat, C and Temmar, M and Rossignol, P and Kimura, M and Aviv, A and Benetos, A},
title = {Short Telomeres, but Not Telomere Attrition Rates, Are Associated With Carotid Atherosclerosis.},
journal = {Hypertension (Dallas, Tex. : 1979)},
volume = {70},
number = {2},
pages = {420-425},
pmid = {28630210},
issn = {1524-4563},
support = {R01 HD071180/HD/NICHD NIH HHS/United States ; R01 HL116446/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Age of Onset ; Aged ; *Carotid Artery Diseases/epidemiology/metabolism/pathology ; Disease Progression ; Female ; Follow-Up Studies ; France/epidemiology ; Humans ; Male ; Middle Aged ; *Plaque, Atherosclerotic/diagnostic imaging/pathology ; Telomere/*physiology ; Telomere Shortening/*physiology ; Time Factors ; Ultrasonography/methods ; },
abstract = {Short telomeres are associated with atherosclerosis. However, the temporal relationship between atherosclerosis and telomere length is unclear. The objective of this work was to examine the temporal formation and progression of carotid atherosclerotic plaques in relation to telomere dynamics. In a longitudinal study, comprising 154 French men and women (aged 31-76 years at baseline), carotid plaques were quantified by echography, and telomere length on leucocytes was measured by Southern blots at baseline and follow-up examinations. Telomere attrition rates during the 9.5-year follow-up period were not different in individuals with plaques at both baseline and follow-up examinations (23.3±2.0 base pairs/y) than in individuals who developed plaques during the follow-up period (26.5±2.0 base pairs/y) and those without plaques at either baseline or follow-up examination (22.5±2.3 base pairs/y; P=0.79). At baseline, telomere length was associated with presence of carotid plaques (P=0.02) and with the number of regions with plaques (P=0.005). An interaction (P=0.03) between age and the presence of plaques was observed, such that the association between plaques and telomere length was more pronounced at a younger age. In conclusion, carotid atherosclerosis is not associated with increased telomere attrition during a 9.5-year follow-up period. Short telomere length is more strongly associated with early-onset than late-onset carotid atherosclerosis. Our results support the thesis that heightened telomere attrition during adult life might not explain the short telomeres observed in subjects with atherosclerotic disease. Rather, short telomeres antecedes the clinical manifestation of the disease.},
}
@article {pmid28630208,
year = {2017},
author = {De Meyer, T and De Buyzere, ML},
title = {Telomeres and Atherosclerosis: The Intricate Pursuit of Mechanistic Insight Through Epidemiology.},
journal = {Hypertension (Dallas, Tex. : 1979)},
volume = {70},
number = {2},
pages = {243-244},
doi = {10.1161/HYPERTENSIONAHA.117.09454},
pmid = {28630208},
issn = {1524-4563},
mesh = {*Atherosclerosis ; Humans ; *Telomere ; },
}
@article {pmid28629193,
year = {2017},
author = {Venkatesan, S and Khaw, AK and Hande, MP},
title = {Telomere Biology-Insights into an Intriguing Phenomenon.},
journal = {Cells},
volume = {6},
number = {2},
pages = {},
pmid = {28629193},
issn = {2073-4409},
abstract = {Bacteria and viruses possess circular DNA, whereas eukaryotes with typically very large DNA molecules have had to evolve into linear chromosomes to circumvent the problem of supercoiling circular DNA of that size. Consequently, such organisms possess telomeres to cap chromosome ends. Telomeres are essentially tandem repeats of any DNA sequence that are present at the ends of chromosomes. Their biology has been an enigmatic one, involving various molecules interacting dynamically in an evolutionarily well-trimmed fashion. Telomeres range from canonical hexameric repeats in most eukaryotes to unimaginably random retrotransposons, which attach to chromosome ends and reverse-transcribe to DNA in some plants and insects. Telomeres invariably associate with specialised protein complexes that envelop it, also regulating access of the ends to legitimate enzymes involved in telomere metabolism. They also transcribe into repetitive RNA which also seems to be playing significant roles in telomere maintenance. Telomeres thus form the intersection of DNA, protein, and RNA molecules acting in concert to maintain chromosome integrity. Telomere biology is emerging to appear ever more complex than previously envisaged, with the continual discovery of more molecules and interplays at the telomeres. This review also includes a section dedicated to the history of telomere biology, and intends to target the scientific audience new to the field by rendering an understanding of the phenomenon of chromosome end protection at large, with more emphasis on the biology of human telomeres. The review provides an update on the field and mentions the questions that need to be addressed.},
}
@article {pmid28629117,
year = {2017},
author = {Tucker, LA},
title = {Alpha- and Gamma-Tocopherol and Telomere Length in 5768 US Men and Women: A NHANES Study.},
journal = {Nutrients},
volume = {9},
number = {6},
pages = {},
pmid = {28629117},
issn = {2072-6643},
mesh = {Cross-Sectional Studies ; DNA ; Diet ; Dietary Supplements ; Female ; Food Analysis ; Humans ; Leukocytes/cytology ; Male ; Middle Aged ; Nutrition Surveys ; Oxidative Stress ; Telomere Homeostasis/*drug effects ; United States ; Vitamin E/administration &amp; dosage ; alpha-Tocopherol/*blood/pharmacology ; gamma-Tocopherol/*blood/pharmacology ; },
abstract = {Antioxidants have a number of potential health benefits. The present investigation was designed to determine the relationship between serum alpha- and gamma-tocopherol levels (powerful antioxidants), and leukocyte telomere length (a biomarker of biological aging). A cross-sectional design was employed to study 5768 adults from the National Health and Nutrition Examination Survey (NHANES). DNA was obtained via blood samples. Telomere length was assessed using the quantitative polymerase chain reaction method. Serum concentrations of alpha- and gamma-tocopherol were measured using high performance liquid chromatography (HPLC). Results showed that for each one-year increase in age, telomeres were 15.6 base pairs shorter (F = 410.4, p < 0.0001). After adjusting for differences in the demographic covariates, for each µg/dL higher level of gamma-tocopherol, telomeres were 0.33 base pairs shorter (F = 7.1, p = 0.0126). Telomeres were approximately 1 year shorter (15.6 base pairs) for each increment of 47.3 to 55.7 µg/dL of gamma-tocopherol in the blood, depending on the variables controlled. Adults at the 75th percentile of gamma-tocopherol had 2.8-3.4 years greater cellular aging than those at the 25th percentile, depending on the covariates in the model. However, alpha-tocopherol was not related to telomere length. Evidently, gamma-tocopherol levels, but not alpha-tocopherol, account for meaningful increases in biological aging.},
}
@article {pmid28628186,
year = {2017},
author = {Zhou, S and Xiao, Y and Zhuang, Y and Liu, Y and Zhao, H and Yang, H and Xie, C and Zhou, F and Zhou, Y},
title = {Knockdown of homeobox containing 1 increases the radiosensitivity of cervical cancer cells through telomere shortening.},
journal = {Oncology reports},
volume = {38},
number = {1},
pages = {515-521},
doi = {10.3892/or.2017.5707},
pmid = {28628186},
issn = {1791-2431},
mesh = {Cell Line, Tumor ; Female ; Gene Knockdown Techniques ; Homeodomain Proteins/*genetics ; Humans ; Radiation Tolerance/*genetics ; Telomere Shortening/*genetics ; Uterine Cervical Neoplasms/*genetics ; },
abstract = {Homeobox containing 1 (HMBOX1) modulates telomere length in various types of tumor cells by binding to double‑stranded telomeric DNA. There is a negative correlation between telomere length and radiosensitivity in tumor cells. In the present study, we aimed to investigate the relationship among HMBOX1, telomere and radiosensitivity in cervical cancer cells. Lentivirus-based shRNAs were used to establish stable transfected cell lines in which protein and mRNA levels of HMBOX1 were notably decreased. Knockdown of HMBOX1 increased the radiosensitivity of HeLa and C33A cells. TERT protein was also decreased while HMBOX1 was downregulated. Knockdown of HMBOX1 shortened telomere length in the HeLa cells, while TERT overexpression rescued telomere shortening in the HeLa-HMBOX1 cells. Knockdown of HMBOX1 increased the apoptosis rate, decreased radiation-induced DNA damage foci, and inhibited the expression of ATM, ATR, p-ATM, p-ATR and BRCA1 in the homologous recombination repair pathway. Our data suggest a possible role of HMBOX1 in regulating radiosensitivity in cervical cancer cells. Moreover, HMBOX1 may be a potential factor in the radiotherapy of cervical cancer.},
}
@article {pmid28628024,
year = {2017},
author = {Khalturina, E and Nesterova, I},
title = {[EVALUATION OF DYNAMIC TELOMERE LENGTH SHORTENING OF LYMPHOCYTES IN IMMUNOCOMPROMISED CHILDREN WITH CHRONIC DISEASES OF THE RESPIRATORY].},
journal = {Georgian medical news},
volume = {},
number = {266},
pages = {99-103},
pmid = {28628024},
issn = {1512-0112},
mesh = {Child ; Child, Preschool ; Chlamydia Infections/blood/immunology ; Chronic Disease ; Coinfection ; Herpesviridae Infections/blood/immunology ; Humans ; Immunocompromised Host ; Lymphocytes/*ultrastructure ; Mycoplasma Infections/blood/immunology ; Respiratory Tract Infections/blood/*immunology ; *Telomere Shortening ; },
abstract = {Nowadays it is common to observe the growth of viral-viral and viral-bacterial co-infections in children of different ages, due to dysfunction of lymphocytes (DL), which can be connected with the process of the accelerated shortening of the end structures of chromosomal telomeres, telomere length changes are described in lymphocytes of children with chronic mono-infections. The conducted study has shown the shortening of telomere lymphocytes in children with CDRT seropositive for mixed-herpes viral infections (herpes simplex virus, virus, Epstein-Barr virus and cytomegalovirus in various combinations) and for bacterial co-infections - Chlamydia trachomatis and (or) Mycoplasma pneumoniae. The use of regression analysis and attribute analysis (in percent) made possible to neutralize age-groups differences of seropositive and seronegative children. Thus showed that children, who suffer from chronic diseases of the respiratory tract associated with mixed-herpes viral and bacterial co-infections, have more pronounced telomere shortening of lymphocytes than seronegative children of the same age.},
}
@article {pmid28623093,
year = {2017},
author = {Lugli, N and Sotiriou, SK and Halazonetis, TD},
title = {The role of SMARCAL1 in replication fork stability and telomere maintenance.},
journal = {DNA repair},
volume = {56},
number = {},
pages = {129-134},
doi = {10.1016/j.dnarep.2017.06.015},
pmid = {28623093},
issn = {1568-7856},
mesh = {Animals ; DNA Helicases/*metabolism ; DNA Repair ; *DNA Replication ; Humans ; Telomere/*metabolism ; },
abstract = {SMARCAL1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A-Like 1), also known as HARP, is an ATP-dependent annealing helicase that stabilizes replication forks during DNA damage. Mutations in this gene are the cause of Schimke immune-osseous dysplasia (SIOD), an autosomal recessive disorder characterized by T-cell immunodeficiency and growth dysfunctions. In this review, we summarize the main roles of SMARCAL1 in DNA repair, telomere maintenance and replication fork stability in response to DNA replication stress.},
}
@article {pmid28621334,
year = {2018},
author = {Powell, TR and Dima, D and Frangou, S and Breen, G},
title = {Telomere Length and Bipolar Disorder.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {43},
number = {2},
pages = {445-453},
pmid = {28621334},
issn = {1740-634X},
support = {MR/N014863/1/MRC_/Medical Research Council/United Kingdom ; R01 MH104284/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Anxiety Disorders/genetics/physiopathology ; Association Learning/physiology ; Bipolar Disorder/*genetics/*physiopathology ; Depressive Disorder, Major/genetics/physiopathology ; Female ; Genetic Predisposition to Disease ; Hippocampus/*diagnostic imaging ; Humans ; Magnetic Resonance Imaging ; Male ; *Memory, Episodic ; Mental Recall/physiology ; Middle Aged ; Nuclear Family ; Real-Time Polymerase Chain Reaction ; Sequence Analysis, DNA ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Variation in telomere length is heritable and is currently considered a promising biomarker of susceptibility for neuropsychiatric disorders, particularly because of its association with memory function and hippocampal morphology. Here, we investigate telomere length in connection to familial risk and disease expression in bipolar disorder (BD). We used quantitative PCRs and a telomere-sequence to single-copy-gene-sequence ratio method to determine telomere length in genomic DNA extracted from buccal smears from 63 patients with BD, 74 first-degree relatives (49 relatives had no lifetime psychopathology and 25 had a non-BD mood disorder), and 80 unrelated healthy individuals. Participants also underwent magnetic resonance imaging to determine hippocampal volumes and cognitive assessment to evaluate episodic memory using the verbal paired associates test. Telomere length was shorter in psychiatrically well relatives (p=0.007) compared with unrelated healthy participants. Telomere length was also shorter in relatives (regardless of psychiatric status; p<0.01) and patients with BD not on lithium (p=0.02) compared with lithium-treated patients with BD. In the entire sample, telomere length was positively associated with left and right hippocampal volume and with delayed recall. This study provides evidence that shortened telomere length is associated with familial risk for BD. Lithium may have neuroprotective properties that require further investigation using prospective designs.},
}
@article {pmid28619828,
year = {2017},
author = {Zhang, X and Zhao, Q and Zhu, W and Liu, T and Xie, SH and Zhong, LX and Cai, YY and Li, XN and Liang, M and Chen, W and Hu, QS and Zhang, B},
title = {The Association of Telomere Length in Peripheral Blood Cells with Cancer Risk: A Systematic Review and Meta-analysis of Prospective Studies.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {26},
number = {9},
pages = {1381-1390},
doi = {10.1158/1055-9965.EPI-16-0968},
pmid = {28619828},
issn = {1538-7755},
mesh = {Female ; Humans ; Male ; Neoplasms/*genetics ; Prospective Studies ; Risk Factors ; Telomere/*metabolism ; },
abstract = {The association between telomere length (TL) in peripheral blood cells and cancer risk remains inconclusive. We carried out a meta-analysis on prospective studies. The study-specific RR estimates were first transformed to a common comparable scale and then were pooled by a random-effects model. The dataset was composed of 13,894 cases and 71,672 controls from 28 studies in 25 articles. In the comparison of the longest versus shortest third of TL, we observed a marginally positive association between longer TL and higher risk of total cancers [OR = 1.086; 95% confidence interval (CI), 0.952-1.238]. Subgroup analyses showed that the association was stronger in lung cancer (n = 3; OR = 1.690; 95% CI, 1.253-2.280), in men (n = 6; OR = 1.302; 95% CI, 1.120-1.514) and in studies with more precise methods for DNA extraction (phenol-chloroform, salting-out or magnetic bead, n = 6, OR = 1.618; 95% CI, 1.320-1.985) and TL measurement (multiplex Q-PCR, n = 8; OR = 1.439; 95% CI, 1.118-1.852). Our meta-analysis suggested longer TL in peripheral blood cells is a likely risk factor for lung cancer or cancers in men. Accurate DNA extraction and TL measurement methods make it more liable to find significant associations between TL and cancer risk and thus should be taken into consideration in future epidemiologic studies. Cancer Epidemiol Biomarkers Prev; 26(9); 1381-90. ©2017 AACR.},
}
@article {pmid28617662,
year = {2017},
author = {Alzain, MA and Asweto, CO and Zhang, J and Fang, H and Zhao, Z and Guo, X and Song, M and Zhou, Y and Chang, N and Wang, Y and Wang, W},
title = {Telomere Length and Accelerated Biological Aging in the China Suboptimal Health Cohort: A Case-Control Study.},
journal = {Omics : a journal of integrative biology},
volume = {21},
number = {6},
pages = {333-339},
doi = {10.1089/omi.2017.0050},
pmid = {28617662},
issn = {1557-8100},
mesh = {Aged ; Aging/*genetics ; Cardiovascular Diseases/genetics ; Case-Control Studies ; China ; Confidence Intervals ; Female ; Humans ; Male ; Middle Aged ; Odds Ratio ; Risk Factors ; Surveys and Questionnaires ; Telomere/*genetics ; },
abstract = {Suboptimal health status (SHS) has been linked to cardiovascular risk factors, psychosocial stress, and unhealthy lifestyle. These factors also contribute to the shortening of telomere length (TL). A case-control study was conducted to examine the association between subjective health measures of SHS from the behavior perspective and also objective measures of TL at molecular level. SHS (cases = 294) was matched by age, sex, and body mass index with ideal health (controls = 294) using a propensity score matching method. Suboptimal health status questionnaire-25 (SHSQ-25) was used in the community-based health survey. A quantitative polymerase chain reaction was used to measure relative telomere length (RTL). Shorter RTL was found among the SHS group compared to the ideal health group (p < 0.05). SHS was almost four times likely to be in the first quartile (odds ratio [OR] = 3.81; 95% confidence interval [CI] 2.21-6.56), almost thrice in second quartile (OR = 2.84; 95% CI 1.65-4.90), and almost twice likely to be in the third quartile (OR = 1.71; 95% CI 1.00-2.94) compared to the fourth quartile (the longest) of RTL after adjusting for socioeconomic, dietary intake, anthropometric, blood pressure, and biochemistry variables (p < 0.05). Notably, SHS score was negatively correlated with RTL (r = -0.218, p < 0.05). Our study confirms an association between SHS and short RTL. Combination of subjective (SHS) and objective (RTL) measures is a novel tool for health aging investigation. Therefore, SHSQ-25 could be used as a screening tool for measuring biological aging in low-income countries at community level where the expensive technique for RTL measurement is not applicable.},
}
@article {pmid28615296,
year = {2017},
author = {Benetos, A and Aviv, A},
title = {Ancestry, Telomere Length, and Atherosclerosis Risk.},
journal = {Circulation. Cardiovascular genetics},
volume = {10},
number = {3},
pages = {},
pmid = {28615296},
issn = {1942-3268},
support = {R01 HD071180/HD/NICHD NIH HHS/United States ; R01 HL116446/HL/NHLBI NIH HHS/United States ; },
mesh = {Black or African American/genetics ; Aged, 80 and over ; Aging/genetics ; Animals ; Atherosclerosis/etiology/*genetics/mortality ; Evolution, Molecular ; Female ; Humans ; Longevity/genetics ; Male ; Mammals/genetics ; Risk Factors ; Telomere/genetics ; Telomere Homeostasis/*genetics ; United States/epidemiology ; White People/genetics ; },
}
@article {pmid28615293,
year = {2017},
author = {Zhang, T and Zhang, Z and Li, F and Hu, Q and Liu, H and Tang, M and Ma, W and Huang, J and Songyang, Z and Rong, Y and Zhang, S and Chen, BP and Zhao, Y},
title = {Looping-out mechanism for resolution of replicative stress at telomeres.},
journal = {EMBO reports},
volume = {18},
number = {8},
pages = {1412-1428},
pmid = {28615293},
issn = {1469-3178},
support = {R01 CA166677/CA/NCI NIH HHS/United States ; },
mesh = {Cellular Senescence ; DNA End-Joining Repair ; *DNA Replication ; DNA Topoisomerases, Type II/genetics/metabolism ; DNA, Circular/chemistry/metabolism ; DNA, Single-Stranded/chemistry/metabolism ; Genomic Instability ; Humans ; Nucleic Acid Conformation ; Telomere/genetics/*physiology ; *Telomere Shortening ; },
abstract = {Repetitive DNA is prone to replication fork stalling, which can lead to genome instability. Here, we find that replication fork stalling at telomeres leads to the formation of t-circle-tails, a new extrachromosomal structure that consists of circular telomeric DNA with a single-stranded tail. Structurally, the t-circle-tail resembles cyclized leading or lagging replication intermediates that are excised from the genome by topoisomerase II-mediated cleavage. We also show that the DNA damage repair machinery NHEJ is required for the formation of t-circle-tails and for the resolution of stalled replication forks, suggesting that NHEJ, which is normally constitutively suppressed at telomeres, is activated in the context of replication stress. Inhibition of NHEJ or knockout of DNA-PKcs impairs telomere replication, leading to multiple-telomere sites (MTS) and telomere shortening. Collectively, our results support a "looping-out" mechanism, in which the stalled replication fork is cut out and cyclized to form t-circle-tails, and broken DNA is religated. The telomere loss induced by replication stress may serve as a new factor that drives replicative senescence and cell aging.},
}
@article {pmid28613367,
year = {2017},
author = {Verhoeven, JE and van Oppen, P and Penninx, BWJH},
title = {[Associations between depression, anxiety and telomere length in a large Dutch psychiatric cohort study].},
journal = {Tijdschrift voor psychiatrie},
volume = {59},
number = {6},
pages = {350-359},
pmid = {28613367},
issn = {0303-7339},
mesh = {Aging/*physiology ; Anxiety Disorders/*genetics ; Cellular Senescence ; Depression/*genetics ; Humans ; Telomere ; *Telomere Shortening ; },
abstract = {Not only do depressive and anxiety disorders have psychological consequenses, they can also lead to impaired physical health. Persons with depressieve and anxiety disorders have increased risk of developing several ageing-related somatic ilnesses. This raises the question whether persons with depressive or anxiety disorder are subject to accelerated cellular ageing.<br/> AIM: To test the cross-sectional and longitudinal associations between depressive and anxiety disorders and telomere length, an indicator of cellular ageing.<br/> METHOD: We measured telomere length in participants of the Netherlands Study of Depression and Anxiety with and without psychopathology at baseline (N=2936) and we also studied a large number of these participants (N=1883) at 6-year follow-up.<br/> RESULTS: Telomere length of participants with a lifetime depressive or anxiety disorder was, on average, shorter than the telomere length in the control group. This association was attributed to dysregulations in physiological stress systems and an unhealthy lifestyle. Over time, however, telomere length was shown to have a stable, non-dynamic association with depressive and anxiety disorders.<br/> CONCLUSION: Our results suggest that psychological stress, as experienced by persons with depressive or anxiety disorders, might indeed be associated with increased 'wear and tear' of the human body. The challenge for future research is to determine whether short telomere length is in fact a long-term consequence or an underlying vulnerability factor for depressive or anxiety disorders.},
}
@article {pmid28609023,
year = {2018},
author = {Song, Y and Cho, M and Brennan, KM and Chen, BH and Song, Y and Manson, JE and Hevener, AL and You, NY and Butch, AW and Liu, S},
title = {Relationships of sex hormone levels with leukocyte telomere length in Black, Hispanic, and Asian/Pacific Islander postmenopausal women.},
journal = {Journal of diabetes},
volume = {10},
number = {6},
pages = {502-511},
pmid = {28609023},
issn = {1753-0407},
support = {HHSN268201100001I/HL/NHLBI NIH HHS/United States ; HHSN268201100004I/HL/NHLBI NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; HHSN268201100003C/WH/WHI NIH HHS/United States ; R21 DK084452/DK/NIDDK NIH HHS/United States ; HHSN271201100004C/AG/NIA NIH HHS/United States ; HHSN268201100002C/WH/WHI NIH HHS/United States ; R01 DK109724/DK/NIDDK NIH HHS/United States ; HHSN268201100002I/HL/NHLBI NIH HHS/United States ; HHSN268201100001C/WH/WHI NIH HHS/United States ; HHSN268201100004C/WH/WHI NIH HHS/United States ; },
mesh = {Black or African American/statistics &amp; numerical data ; Asian People/statistics &amp; numerical data ; Biomarkers/analysis ; Cohort Studies ; Cross-Sectional Studies ; Estradiol/*blood ; Ethnicity/*statistics &amp; numerical data ; Female ; Follow-Up Studies ; Hispanic or Latino/statistics &amp; numerical data ; Humans ; Leukocytes/*metabolism ; Middle Aged ; Native Hawaiian or Other Pacific Islander/statistics &amp; numerical data ; Postmenopause/*blood/*ethnology ; Prognosis ; Sex Hormone-Binding Globulin/analysis ; *Telomere Homeostasis ; Testosterone/*blood ; },
abstract = {BACKGROUND: Sex hormones may play important roles in sex-specific biological aging. In the study, we specifically examined associations between circulating sex hormone concentrations and leukocyte telomere length (TL).<br><br>METHODS: A cross-sectional study was conducted among 1124 Black, 444 Hispanic, and 289 Asian/Pacific Islander women in the Women's Health Initiative Observational Cohort. Estradiol and testosterone concentrations were measured using electrochemiluminescence immunoassays; TL was measured using quantitative polymerase chain reaction.<br><br>RESULTS: Women in the study were aged 50-79&#x2009;years. Estradiol concentrations were not significantly associated with TL in this sample. The associations between total and free testosterone and TL differed by race/ethnicity (Pinteraction &#x2009;=&#x2009;0.03 and 0.05 for total and free testosterone, respectively). Total and free testosterone concentrations were not associated with TL in Black and Hispanic women, whereas in Asian/Pacific Islander women their concentrations were inversely associated with TL (Ptrend &#x2009;=&#x2009;0.003 for both). These associations appeared robust in multiple subgroup analyses and multivariable models adjusted for potential confounding factors. In Asian/Pacific Islander women, a doubling of serum free and total testosterone concentrations was associated with a 202-bp shorter TL (95% confidence interval [CI] 51-353&#x2009;bp) and 203-bp shorter TL (95% CI 50-355&#x2009;bp), respectively.<br><br>CONCLUSIONS: Serum estradiol concentrations were not associated with leukocyte TL in this large sample of postmenopausal women. Total and free testosterone concentrations were inversely associated with TL in Asian/Pacific Islander women, but not in Black and Hispanic women, although future studies to replicate our observations are warranted particularly to address potential ethnicity-specific relationships.},
}
@article {pmid28604726,
year = {2017},
author = {Mattarocci, S and Reinert, JK and Bunker, RD and Fontana, GA and Shi, T and Klein, D and Cavadini, S and Faty, M and Shyian, M and Hafner, L and Shore, D and Thomä, NH and Rass, U},
title = {Rif1 maintains telomeres and mediates DNA repair by encasing DNA ends.},
journal = {Nature structural &amp; molecular biology},
volume = {24},
number = {7},
pages = {588-595},
pmid = {28604726},
issn = {1545-9985},
mesh = {Binding Sites ; Crystallography, X-Ray ; DNA/metabolism ; *DNA End-Joining Repair ; DNA-Binding Proteins/*chemistry/*metabolism ; Models, Molecular ; Protein Binding ; Protein Conformation ; Protein Multimerization ; Repressor Proteins/*chemistry/*metabolism ; Saccharomyces cerevisiae/enzymology ; Saccharomyces cerevisiae Proteins/*chemistry/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*chemistry/*metabolism ; },
abstract = {In yeast, Rif1 is part of the telosome, where it inhibits telomerase and checkpoint signaling at chromosome ends. In mammalian cells, Rif1 is not telomeric, but it suppresses DNA end resection at chromosomal breaks, promoting repair by nonhomologous end joining (NHEJ). Here, we describe crystal structures for the uncharacterized and conserved ∼125-kDa N-terminal domain of Rif1 from Saccharomyces cerevisiae (Rif1-NTD), revealing an α-helical fold shaped like a shepherd's crook. We identify a high-affinity DNA-binding site in the Rif1-NTD that fully encases DNA as a head-to-tail dimer. Engagement of the Rif1-NTD with telomeres proved essential for checkpoint control and telomere length regulation. Unexpectedly, Rif1-NTD also promoted NHEJ at DNA breaks in yeast, revealing a conserved role of Rif1 in DNA repair. We propose that tight associations between the Rif1-NTD and DNA gate access of processing factors to DNA ends, enabling Rif1 to mediate diverse telomere maintenance and DNA repair functions.},
}
@article {pmid28603779,
year = {2017},
author = {Hanssen, LM and Schutte, NS and Malouff, JM and Epel, ES},
title = {The Relationship Between Childhood Psychosocial Stressor Level and Telomere Length: A Meta-Analysis.},
journal = {Health psychology research},
volume = {5},
number = {1},
pages = {6378},
pmid = {28603779},
issn = {2420-8124},
abstract = {This meta-analysis examined the association between the level of childhood psychosocial stressors and telomere length, an important health biomarker. The meta-analysis, including 27 samples and 16,238 participants, found a significant association of -0.08 between a higher level of childhood stressors and shorter telomere length at a mean age of 42 across studies. Moderator analyses showed a trend in the direction of effect sizes being significantly larger with shorter times between the stressors and telomere measurement. Moderator analyses showed significantly higher effect sizes for studies that used a categorical method for assessing child stressor level and for assays completed with qPCR rather than with the Southern blot method. There was no significant moderation of effect size by whether study assayed leukocytes or buccal cells, whether the study assessed child stressor level by memory-based recall versus archival records, and whether the study controlled for age, sex, or additional variables. The results, focused on childhood events, add to prior findings that perceived stress and negative emotions are associated with telomere length.},
}
@article {pmid28603543,
year = {2017},
author = {Tucker, LA},
title = {Caffeine consumption and telomere length in men and women of the National Health and Nutrition Examination Survey (NHANES).},
journal = {Nutrition &amp; metabolism},
volume = {14},
number = {},
pages = {10},
pmid = {28603543},
issn = {1743-7075},
abstract = {BACKGROUND: The investigation evaluated the relationship between caffeine intake and coffee consumption and leukocyte telomere length, a biomarker of the senescence of cells.<br><br>METHODS: A total of 5826 adults from the National Health and Nutrition Examination Survey (NHANES) were studied cross-sectionally. Using the quantitative polymerase chain reaction method, telomere length was compared to standard reference DNA. Caffeine intake from foods and beverages and coffee consumption were measured using a validated, multi-pass, computer-assisted, 24-h recall system administered by NHANES interviewers. The following covariates were controlled: age, gender, race, marital status, education, housing, smoking, BMI, physical activity, alcohol use, and coffee intake (or caffeine consumption).<br><br>RESULTS: Caffeine consumption was inversely related to telomere length (F = 15.1, P = 0.0005). For each 100 mg of caffeine consumed, telomeres were 35.4 base pairs shorter, after adjusting for the covariates. For each 100 mg of caffeine consumed among coffee drinkers only, telomeres were 36.7 base pairs shorter (F = 9.0, P = 0.0054), and among non-coffee drinkers only, 40.0 base pairs shorter (F = 8.5, P = 0.0067). Conversely, coffee intake was positively related to telomere length (F = 12.6, P = 0.0013), independent of the covariates.<br><br>CONCLUSIONS: Results suggest that caffeine consumption accounts for shorter telomeres in U.S. adults, independent of numerous covariates, whereas coffee intake predicts longer telomeres.},
}
@article {pmid28602932,
year = {2017},
author = {Knijnenburg, J and Uytdewilligen, MEW and van Hassel, DACM and Oostenbrink, R and Eussen, BHJ and de Klein, A and Brooks, AS and van Zutven, LJCM},
title = {Postzygotic telomere capture causes segmental UPD, duplication and deletion of chromosome 8p in a patient with intellectual disability and obesity.},
journal = {European journal of medical genetics},
volume = {60},
number = {9},
pages = {445-450},
doi = {10.1016/j.ejmg.2017.06.003},
pmid = {28602932},
issn = {1878-0849},
mesh = {Child ; Chromosome Deletion ; Chromosome Disorders/diagnosis/*genetics ; Chromosome Duplication ; Chromosomes, Human, Pair 8/genetics ; Humans ; Intellectual Disability/diagnosis/*genetics ; Male ; Obesity/diagnosis/*genetics ; Syndrome ; Telomere/genetics ; },
abstract = {Using SNP array and FISH analysis, a patient with moderate intellectual disability and obesity was found to harbour an atypical 1.6 Mb inverted duplication on 8p23.1, directly flanked by a distally located interstitial deletion of 2.3 Mb and a terminal segmental uniparental disomy. The duplicated and deleted regions lie exactly between the two segmental duplication regions. These segmental duplications on chromosome 8p23.1 are known to be involved in chromosomal rearrangements because of mutual homology and homology to other genomic regions. Genomic instability mediated by these segmental duplications is generally caused by non-allelic homologous recombination, resulting in deletions, reciprocal duplications, inversions and translocations. Additional analysis of the parental origin of the fragments of this atypical inverted duplication/interstitial deletion shows paternal contribution in the maternal derivate chromosome 8. Combined with the finding that the normal chromosome 8 carries an inversion in 8p23.1 we hypothesize that a double strand break in 8p23.1 of the maternal chromosome was postzygotically repaired with the paternal inverted copy resulting in a duplication, deletion and segmental uniparental disomy, with no particular mediation of the 8p23.1 segmental duplication regions in recombination.},
}
@article {pmid28602428,
year = {2017},
author = {Guruprasad, KP and Dash, S and Shivakumar, MB and Shetty, PR and Raghu, KS and Shamprasad, BR and Udupi, V and Acharya, RV and Vidya, PB and Nayak, J and Mana, AE and Moni, R and Sankaran, MT and Satyamoorthy, K},
title = {Influence of Amalaki Rasayana on telomerase activity and telomere length in human blood mononuclear cells.},
journal = {Journal of Ayurveda and integrative medicine},
volume = {8},
number = {2},
pages = {105-112},
pmid = {28602428},
issn = {0975-9476},
abstract = {BACKGROUND: Indian traditional medicine practices use defined rasayana preparations to improve the quality of life in aged individuals. Amalaki Rasayana is one such rasayana prepared from the fruits of Phyllanthus emblica and is popularly used to prevent or treat various age related health conditions. Telomerase activity in the cells maintains telomere length and is implicated in ageing and various diseases wherein the shortening of telomere during ageing is controlled chiefly by the telomerase activity.<br><br>OBJECTIVE: In the present study, we investigated telomerase activity and telomere length in the peripheral blood mononuclear cells of aged individuals administered with Amalaki Rasayana.<br><br>MATERIALS AND METHODS: Amalaki Rasayana was administered to healthy, aged (45-60 years) volunteers for 45 days after koshta shuddhi procedure. The telomerase activity and telomere length were analyzed on 0, 45th and 90th days of Amalaki Rasayana administration in peripheral blood mononuclear cells from these individuals and compared with age-matched placebo group and young volunteers (22-30 years). The data were compared between the groups.<br><br>RESULTS: The results indicated an increase in telomerase activity with no discernible change in telomere length in the Amalaki administered participants. The comparison between young and aged participants revealed higher telomerase activity in young participants with no significant differences in telomere length.<br><br>CONCLUSION: The data indicate that the maintenance of telomere length is facilitated by an increase in telomerase activity upon rasayana administration in aged individuals and Amalaki Rasayana may prevent the erosion of telomeres over a period of time in aged individuals to promote healthy ageing.},
}
@article {pmid28602380,
year = {2017},
author = {James, S and McLanahan, S and Brooks-Gunn, J and Mitchell, C and Schneper, L and Wagner, B and Notterman, DA},
title = {Sleep Duration and Telomere Length in Children.},
journal = {The Journal of pediatrics},
volume = {187},
number = {},
pages = {247-252.e1},
pmid = {28602380},
issn = {1097-6833},
support = {R25 HD074544/HD/NICHD NIH HHS/United States ; P2C HD047879/HD/NICHD NIH HHS/United States ; R01 HD036916/HD/NICHD NIH HHS/United States ; P2C HD041028/HD/NICHD NIH HHS/United States ; R01 HD076592/HD/NICHD NIH HHS/United States ; },
mesh = {Child ; Child, Preschool ; Cross-Sectional Studies ; Female ; Humans ; Male ; Polysomnography ; Sleep/genetics/*physiology ; Telomere/*metabolism ; Time Factors ; },
abstract = {OBJECTIVE: To test the association between sleep duration and telomere length in a pediatric population.<br><br>STUDY DESIGN: We analyzed cross-sectional data for 1567 children from the age 9 study wave of the Fragile Families and Child Wellbeing Study, a population-based birth cohort of children born between 1998 and 2000 in large American cities (population >200&#x2009;000). We measured telomere length using quantitative polymerase chain reaction, and children's typical nightly sleep duration was reported by their primary caregivers. Using linear regression, we estimated the association between sleep duration and telomere length both in unadjusted models and adjusting for a number of covariates.<br><br>RESULTS: We found that children with shorter sleep durations have shorter telomeres than children with longer sleep durations. Each hour less of nightly sleep duration is associated with having telomeres that are 0.015 log-kilobases per chromosome shorter (P&#x2009;<&#x2009;.05). We found no difference in this association by race, sex, or socioeconomic status.<br><br>CONCLUSIONS: We provide preliminary evidence that children with shorter sleep durations have shorter telomeres. This finding is consistent with a broader literature indicating that suboptimal sleep duration is a risk for increased physiological stress and impaired health. Future research should address the limitations of our study design by using longitudinal study designs and telomere measurements, measuring sleep duration via polysomnography or actigraphy, and assessing the intermediate biological mechanisms of the link between sleep and telomere dynamics.},
}
@article {pmid28601667,
year = {2017},
author = {Li, Z and He, Y and Wang, D and Tang, J and Chen, X},
title = {Association between childhood trauma and accelerated telomere erosion in adulthood: A meta-analytic study.},
journal = {Journal of psychiatric research},
volume = {93},
number = {},
pages = {64-71},
doi = {10.1016/j.jpsychires.2017.06.002},
pmid = {28601667},
issn = {1879-1379},
mesh = {*Adult Survivors of Child Abuse ; Humans ; Telomere/*physiology ; *Telomere Shortening ; },
abstract = {BACKGROUND: Childhood trauma has long-term sequelae on health status and contributes to numbers of somatic and mental disorders in later life. Findings from experimental studies in animals suggest that telomere erosion may be a mediator of this relationship. However, results from human studies are heterogeneous. To address these inconsistencies, we performed a meta-analysis regarding the association between childhood trauma and telomere length in adulthood.<br><br>METHOD: Articles were identified by systematically searching the Medline, EMBASE and Web of Science databases. Twenty four studies, which include twenty six sample sets and 30,919 participants, met the inclusion criteria for meta-analyses.<br><br>RESULTS: This meta-analyses revealed that individuals experienced childhood trauma have accelerated telomere erosion in adulthood, with a small effect size (r&#xa0;=&#xa0;-0.05, 95% CI&#xa0;=&#xa0;-0.08-0.03, p&#xa0;<&#xa0;0.001). Subgroup analyses by type of childhood trauma revealed a trend in difference between groups (Q&#xa0;=&#xa0;5.24, p&#xa0;=&#xa0;0.07). Analyses for individual trauma types revealed a significant association between childhood separation and telomere erosion (r&#xa0;=&#xa0;-0.09, p&#xa0;<&#xa0;0.001), but not for physical abuse, sexual abuse and loss of a parent.<br><br>CONCLUSION: This meta-analysis demonstrated a significant association between childhood trauma and accelerated telomere erosion in adulthood, and further revealed that different trauma types have various impacts on telomere. Additional research on the mechanism that links the individual types of childhood trauma with telomere is needed in the future.},
}
@article {pmid28600518,
year = {2017},
author = {Otsuka, I and Izumi, T and Boku, S and Kimura, A and Zhang, Y and Mouri, K and Okazaki, S and Shiroiwa, K and Takahashi, M and Ueno, Y and Shirakawa, O and Sora, I and Hishimoto, A},
title = {Aberrant telomere length and mitochondrial DNA copy number in suicide completers.},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {3176},
pmid = {28600518},
issn = {2045-2322},
mesh = {Adult ; Autopsy ; DNA Copy Number Variations/genetics ; DNA, Mitochondrial/*genetics ; Female ; Humans ; Male ; Middle Aged ; Sex Characteristics ; Stress, Psychological/*genetics/physiopathology ; *Suicide ; Telomere Shortening/*genetics ; },
abstract = {Short telomere length (TL) occurs in individuals under psychological stress, and with various psychiatric diseases. Recent studies have also reported mitochondrial DNA copy number (mtDNAcn) alterations under several neuropsychiatric conditions. However, no study has examined whether aberrant TL or mtDNAcn occur in completed suicide, one of the most serious outcomes of mental illnesses. TL and mtDNAcn in post-mortem samples from 528 suicide completers without severe physical illness (508 peripheral bloods; 20 brains) and 560 samples from control subjects (peripheral bloods from 535 healthy individuals; 25 post-mortem brains) were analysed by quantitative polymerase chain reaction. Suicide completers had significantly shorter TL and higher mtDNAcn of peripheral bloods with sex/age-dependent differences (shorter TL was more remarkably in female/young suicides; higher mtDNAcn more so in male/elderly suicides). The normal age-related decline of TL and mtDNAcn were significantly altered in suicide completers. Furthermore, shorter TL and lower mtDNAcn of post-mortem prefrontal cortex were seen in suicide completers compared to controls. This study shows the first association of aberrant telomeres and mtDNA content with suicide completion. Our results indicate that further research on telomere shortening and mitochondrial dysfunction may help elucidate the molecular underpinnings of suicide-related pathophysiology.},
}
@article {pmid28599145,
year = {2017},
author = {Kang, JI and Hwang, SS and Choi, JR and Lee, ST and Kim, J and Hwang, IS and Kim, HW and Kim, CH and Kim, SJ},
title = {Telomere length in alcohol dependence: A role for impulsive choice and childhood maltreatment.},
journal = {Psychoneuroendocrinology},
volume = {83},
number = {},
pages = {72-78},
doi = {10.1016/j.psyneuen.2017.05.024},
pmid = {28599145},
issn = {1873-3360},
mesh = {Adult ; Alcohol Drinking/adverse effects/metabolism ; Alcoholism/*genetics/metabolism ; Cellular Senescence ; Choice Behavior/drug effects ; Delay Discounting ; Humans ; Impulsive Behavior/*drug effects ; Leukocytes ; Life Change Events ; Male ; Middle Aged ; Psychiatric Status Rating Scales ; Republic of Korea ; Stress, Psychological/genetics ; Surveys and Questionnaires ; Telomere/drug effects/physiology ; Telomere Shortening/*drug effects/physiology ; },
abstract = {Telomere shortening, a marker of cellular aging, has been considered to be linked with psychosocial stress as well as with chronic alcohol consumption, possibly mediated by oxidative stress and inflammatory response. Recent findings suggested that early life adversity on telomere dynamics may be related to impulsive choice. To further our understanding of the association of impulsive choice and childhood trauma on telomere length, we examined whether delayed discounting and childhood trauma or their interaction is related to leukocyte telomere length, while controlling for multiple potential confounding variables, in patients with alcohol dependence who are considered to have higher impulsive choice and shorter telomere length. We recruited 253 male patients with chronic alcohol dependence. All participants performed the delay discounting task, and the area under curve was used as a measure of delay discounting. Steeper delay discounting represents more impulsive choices. The modified Parent-Child Conflict Tactics Scale was used to measure childhood maltreatment. In addition, confounding factors, including socio-demographic characteristics, the Alcohol Use Disorders Identification Test, the Buss-Perry Aggression Questionnaire, the Resilience Quotient, the Beck Depression Inventory, and the Beck Anxiety Inventory, were also assessed. Hierarchical regression analyses showed a significant main effect of delay discounting (β=0.161, t=2.640, p=0.009), and an interaction effect between delay discounting and childhood maltreatment on leukocyte telomere length (β=0.173, t=2.138, p=0.034). In subsequent analyses stratified by childhood maltreatment, patients with alcohol dependence and high childhood trauma showed a significant relationship between delay discounting and leukocyte telomere length (β=0.279, t=3.183, p=0.002), while those with low trauma showed no association between them. Our findings suggest that higher impulsive choice is associated with shorter telomere length, and childhood trauma may exert a moderating effect in the relationship between impulsive choice and telomere length.},
}
@article {pmid28598004,
year = {2018},
author = {Kim, JH and Kim, GJ and Lee, D and Ko, JH and Lim, I and Bang, H and Koes, BW and Seong, B and Lee, DC},
title = {Higher maternal vitamin D concentrations are associated with longer leukocyte telomeres in newborns.},
journal = {Maternal &amp; child nutrition},
volume = {14},
number = {1},
pages = {},
pmid = {28598004},
issn = {1740-8709},
mesh = {25-Hydroxyvitamin D 2/blood ; Birth Weight ; Calcifediol/blood ; Cross-Sectional Studies ; Female ; Fetal Blood/cytology/metabolism ; Humans ; Infant, Newborn ; Leukocytes/cytology/metabolism/*pathology ; Male ; *Maternal Nutritional Physiological Phenomena ; Multivariate Analysis ; *Nutritional Status ; Pregnancy ; Pregnancy Complications/blood/epidemiology/*pathology/physiopathology ; Pregnancy Trimester, Third ; Prevalence ; Republic of Korea/epidemiology ; Severity of Illness Index ; *Telomere Shortening ; Vitamin D/*blood ; Vitamin D Deficiency/blood/epidemiology/*pathology/physiopathology ; },
abstract = {Gestational vitamin D insufficiency is related with increased risks of various diseases and poor health outcomes later in life. Telomere length at birth or early in life is known to be a predictor of individual health. Both vitamin D and telomere length are related with various health conditions, and vitamin D concentrations are associated with leukocyte telomere lengths in women. We investigated the association between maternal vitamin D concentrations and newborn leukocyte telomere lengths. This cross-sectional study included 106 healthy pregnant women without adverse obstetric outcomes and their offspring. We examined the maternal age, weight before pregnancy, health behaviours, and nutritional intakes, along with each newborn's sex and birthweight, and we measured maternal height, telomere length, total white blood cell count, and glycosylated haemoglobin as covariates. Pearson's correlation coefficients were calculated to evaluate the relationship between the baseline variables and newborn leukocyte telomere lengths. To confirm that there was an independent association between newborn leukocyte telomere lengths and maternal vitamin D concentrations, we performed a stepwise multiple linear regression analysis. Newborn leukocyte telomere lengths correlated positively with maternal leukocyte telomere lengths (r = .76, p < .01), maternal 25-hydroxyvitamin D concentrations (r = .72, p < .01), maternal energy intakes (r = .22, p = .03), and newborn body weights (r = .51, p < .01). In the multivariate model, newborn leukocyte telomere lengths were associated with maternal vitamin D concentrations (β = .33, p < .01). These findings suggest that the maternal vitamin D concentration during pregnancy may be a significant determinant of the offspring's telomere length.},
}
@article {pmid28593741,
year = {2017},
author = {Behrens, YL and Thomay, K and Hagedorn, M and Ebersold, J and Henrich, L and Nustede, R and Schlegelberger, B and Göhring, G},
title = {Comparison of different methods for telomere length measurement in whole blood and blood cell subsets: Recommendations for telomere length measurement in hematological diseases.},
journal = {Genes, chromosomes &amp; cancer},
volume = {56},
number = {9},
pages = {700-708},
doi = {10.1002/gcc.22475},
pmid = {28593741},
issn = {1098-2264},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Blotting, Southern/methods/standards ; Child ; Child, Preschool ; Female ; Genetic Testing/*methods/standards ; Hematologic Diseases/blood/*genetics ; Humans ; In Situ Hybridization, Fluorescence/methods/standards ; Infant ; Infant, Newborn ; Male ; Middle Aged ; *Telomere Shortening ; },
abstract = {Different methods of telomere length measurement are used to identify patients with telomeropathies. In our lab, we established four different methods for telomere length measurement, terminal restriction fragment (TRF) analysis by Southern blot analysis, quantitative PCR (qPCR), quantitative telomere/centromere fluorescence in situ hybridization (T/C-FISH) and fluorescence in situ hybridization combined with flow cytometry (FlowFISH). The methods each have distinct properties and apart from this-according to our experience and data-may have an impact on the individual result. In this study, we therefore compared and validated these methods measuring 154 healthy individuals of different age groups (newborn-81 years). A linear decline was found for every method (Southern blotting 64 bp per year; qPCR 31 bp per year; T/C-FISH 36 bp per year; FlowFISH 50 bp per year). With the equation of the regression line the values of each method (T/S ratio, T/C value, RTL value) can be expressed in absolute kb. All methods showed acceptable accuracy. The analysis indicated good agreement between all methods, with the best agreement between T/C-FISH and FlowFISH. Here, FlowFISH was the most precise, accurate, and reproducible method compared to the other methods. Based on our data, we emphasize the influence of expertise and experience that is required to produce robust and reliable telomere length analyses. Furthermore, we want to provide the scientific community working in diagnostics and research with data-funded advice on how to choose the appropriate method to safely discriminate between natural variability and pathological telomere shortening in individual cases.},
}
@article {pmid28593460,
year = {2017},
author = {Albertini, DF},
title = {Telegraphing your telomere length to the next generation.},
journal = {Journal of assisted reproduction and genetics},
volume = {34},
number = {7},
pages = {829-830},
pmid = {28593460},
issn = {1573-7330},
mesh = {Aging/*genetics ; Fertilization in Vitro ; Humans ; Reproductive Techniques, Assisted/*trends ; Telomere/*genetics ; },
}
@article {pmid28588610,
year = {2017},
author = {Yalçin, Z and Selenz, C and Jacobs, JJL},
title = {Ubiquitination and SUMOylation in Telomere Maintenance and Dysfunction.},
journal = {Frontiers in genetics},
volume = {8},
number = {},
pages = {67},
pmid = {28588610},
issn = {1664-8021},
support = {311565/ERC_/European Research Council/International ; },
abstract = {Telomeres are essential nucleoprotein structures at linear chromosomes that maintain genome integrity by protecting chromosome ends from being recognized and processed as damaged DNA. In addition, they limit the cell's proliferative capacity, as progressive loss of telomeric DNA during successive rounds of cell division eventually causes a state of telomere dysfunction that prevents further cell division. When telomeres become critically short, the cell elicits a DNA damage response resulting in senescence, apoptosis or genomic instability, thereby impacting on aging and tumorigenesis. Over the past years substantial progress has been made in understanding the role of post-translational modifications in telomere-related processes, including telomere maintenance, replication and dysfunction. This review will focus on recent findings that establish an essential role for ubiquitination and SUMOylation at telomeres.},
}
@article {pmid28586541,
year = {2017},
author = {Dantzer, B and Garratt, M},
title = {Sex differences in telomeres and lifespan in Soay sheep: From the beginning to the end.},
journal = {Molecular ecology},
volume = {26},
number = {12},
pages = {3090-3092},
doi = {10.1111/mec.14129},
pmid = {28586541},
issn = {1365-294X},
mesh = {Animals ; Female ; Humans ; *Longevity ; Male ; Mammals ; Sex Characteristics ; Sheep ; *Telomere ; Telomere Shortening ; },
abstract = {There is tremendous diversity in ageing rates and lifespan not only among taxa but within species, and particularly between the sexes. Women often live longer than men, and considerable research on this topic has revealed some of the potential biological, psychological and cultural causes of sex differences in human ageing and lifespan. However, sex differences in lifespan are widespread in nonhuman animals suggesting biology plays a prominent role in variation in ageing and lifespan. Recently, evolutionary biologists have borrowed techniques from biomedicine to identify whether similar mechanisms causing or contributing to variation in ageing and lifespan in humans and laboratory animals also operate in wild animals. Telomeres are repetitive noncoding DNA sequences capping the ends of chromosomes that are important for chromosomal stability but that can shorten during normal cell division and exposure to stress. Telomere shortening is hypothesized to directly contribute to the ageing process as once telomeres shorten to some length, the cells stop dividing and die. Men tend to have shorter telomeres and faster rates of telomere attrition with age than women, suggesting one possible biological cause of sex differences in lifespan. In this issue of Molecular Ecology, Watson et al. () show that telomere lengths in wild Soay sheep are similar between females and males near the beginning of life but quickly diverge with age because males but not females showed reduced telomere lengths at older ages. The authors further show that some of the observed sex difference in telomere lengths in old age may be due to male investment in horn growth earlier in life, suggesting that sexually dimorphic allocation to traits involved in sexual selection might underlie sex differences in telomere attrition. This study provides a rare example of how biological mechanisms potentially contributing to sex differences in lifespan in humans may also operate in free-living animals. However, future studies using a longitudinal approach are necessary to confirm these observations and identify the ultimate and proximate causes of any sex differences in telomere lengths. Collaborations between evolutionary biologists and gerontologists are especially needed to identify whether telomere lengths have a causal role in ageing, particularly in natural conditions, and whether this directly contributes to sex differences in lifespan.},
}
@article {pmid28586326,
year = {2017},
author = {Sarek, G and Marzec, P and Margalef, P and Boulton, SJ},
title = {Erratum: Molecular basis of telomere dysfunction in human genetic diseases.},
journal = {Nature structural &amp; molecular biology},
volume = {24},
number = {6},
pages = {553},
pmid = {28586326},
issn = {1545-9985},
}
@article {pmid28584918,
year = {2018},
author = {Heo, YR and Lee, JH},
title = {Association between telomere length and PIK3CA amplification in gastric cancer.},
journal = {Clinical and experimental medicine},
volume = {18},
number = {1},
pages = {133-134},
pmid = {28584918},
issn = {1591-9528},
support = {2014R1A6A3A04058057//Ministry of Education/International ; 2014R1A5A2010008//Ministry of Education/International ; },
mesh = {Humans ; *Stomach Neoplasms ; Telomerase/genetics ; *Telomere ; },
}
@article {pmid28584163,
year = {2017},
author = {Valuchova, S and Fulnecek, J and Prokop, Z and Stolt-Bergner, P and Janouskova, E and Hofr, C and Riha, K},
title = {Protection of Arabidopsis Blunt-Ended Telomeres Is Mediated by a Physical Association with the Ku Heterodimer.},
journal = {The Plant cell},
volume = {29},
number = {6},
pages = {1533-1545},
pmid = {28584163},
issn = {1532-298X},
mesh = {Arabidopsis/*genetics/*metabolism ; DNA Repair/genetics ; DNA, Plant/*genetics ; Ku Autoantigen/genetics/*metabolism ; Telomere/*genetics ; },
abstract = {Telomeres form specialized chromatin that protects natural chromosome termini from being recognized as DNA double-strand breaks. Plants possess unusual blunt-ended telomeres that are unable to form t-loops or complex with single-strand DNA binding proteins, raising the question of the mechanism behind their protection. We have previously suggested that blunt-ended telomeres in Arabidopsis thaliana are protected by Ku, a DNA repair factor with a high affinity for DNA ends. In nonhomologous end joining, Ku loads onto broken DNA via a channel consisting of positively charged amino acids. Here, we demonstrate that while association of Ku with plant telomeres also depends on this channel, Ku's requirements for DNA binding differ between DNA repair and telomere protection. We show that a Ku complex proficient in DNA loading but impaired in translocation along DNA is able to protect blunt-ended telomeres but is deficient in DNA repair. This suggests that Ku physically sequesters blunt-ended telomeres within its DNA binding channel, shielding them from other DNA repair machineries.},
}
@article {pmid28583002,
year = {2018},
author = {Mazidi, M and Kengne, AP and Sahebkar, A and Banach, M},
title = {Telomere Length Is Associated With Cardiometabolic Factors in US Adults.},
journal = {Angiology},
volume = {69},
number = {2},
pages = {164-169},
doi = {10.1177/0003319717712860},
pmid = {28583002},
issn = {1940-1574},
mesh = {Adult ; C-Reactive Protein/*metabolism ; Cross-Sectional Studies ; Female ; Humans ; Male ; Metabolic Syndrome/*diagnosis/*pathology ; Middle Aged ; Nutrition Surveys/methods ; Risk Factors ; Telomere/*pathology ; United States ; },
abstract = {Telomere length (TL) has been associated with age-related health outcomes. We investigated the relationship of TL with cardiometabolic risk profile in adult Americans. We used the National Health and Nutrition Examination Surveys for 1999 to 2002, accounting for complex sampling and survey design. Of the 8892 eligible participants, 47.8% (n = 4123) were men. Mean serum high-density lipoprotein cholesterol concentrations significantly increased across increasing TL quarters (P = .013), and mean fat mass, fat-free mass, hemoglobin A1c (HbA1c), and C-reactive protein significantly decreased across increasing TL quarters (all P < .001) in men. Only HbA1c levels significantly decreased across increasing TL quarters (P = .041) in women. Males in the upper quarter of TL had lower (38%) odds of prevalent metabolic syndrome compared with those in the lower quarter (P < .001). These results support the hypotheses that cardiometabolic factors are related to TL, especially in men.},
}
@article {pmid28577663,
year = {2017},
author = {Fok, WC and Batista, LFZ},
title = {Stressed ends: telomere attrition in chronic diseases.},
journal = {Revista brasileira de hematologia e hemoterapia},
volume = {39},
number = {2},
pages = {98-99},
pmid = {28577663},
issn = {1516-8484},
}
@article {pmid28577651,
year = {2017},
author = {Colella, MP and Santana, BA and Conran, N and Tomazini, V and Costa, FF and Calado, RT and Saad, STO},
title = {Telomere length correlates with disease severity and inflammation in sickle cell disease.},
journal = {Revista brasileira de hematologia e hemoterapia},
volume = {39},
number = {2},
pages = {140-145},
pmid = {28577651},
issn = {1516-8484},
abstract = {BACKGROUND: Telomeres, the ends of linear chromosomes, shorten during mitotic cell division and erosion may be aggravated by inflammation or proliferative and oxidative stress. As the bone marrow is under hyperproliferative pressure in sickle cell disease and several tissues are submitted to chronic inflammation, this study sought to determine the telomere length of patients with sickle cell disease.<br><br>METHODS: The mean telomere length was measured in peripheral blood leukocytes by quantitative polymerase chain reaction. The age-adjusted telomere to single copy gene ratio was compared between 91 adult sickle cell disease patients and 188 controls.<br><br>RESULTS: Sickle cell disease patients had significantly shorter telomeres than the controls (p-value<0.0001). Moreover, among sickle cell disease genotypes, Hb SS patients had significantly shorter telomeres compared to Hb SC and Hb S&#x3b2; patients (p-value<0.0001). Patients on hydroxyurea also had shorter telomeres in comparison to those off the drug (p-value=0.02). A positive correlation was observed between telomere length and hemoglobin level (r=0.3; p-value=0.004), whereas negative correlations were detected between telomere length and lymphocyte count (r=-0.3; p-value=0.005) and interleukin-8 serum levels (r=-0.4; p-value=0.02).<br><br>CONCLUSIONS: The findings of this study indicate that telomeres are short in sickle cell disease patients and that telomere erosion directly correlates with disease genotype, inflammation markers, and the use of hydroxyurea.},
}
@article {pmid28577567,
year = {2017},
author = {Cordoba-Lanus, E and Cazorla-Rivero, S and Espinoza-Jimenez, A and de-Torres, JP and Pajares, MJ and Aguirre-Jaime, A and Celli, B and Casanova, C},
title = {Erratum to: Telomere shortening and accelerated aging in COPD: findings from the BODE cohort.},
journal = {Respiratory research},
volume = {18},
number = {1},
pages = {113},
pmid = {28577567},
issn = {1465-993X},
}
@article {pmid28575419,
year = {2017},
author = {Yang, CW and Tseng, SF and Yu, CJ and Chung, CY and Chang, CY and Pobiega, S and Teng, SC},
title = {Telomere shortening triggers a feedback loop to enhance end protection.},
journal = {Nucleic acids research},
volume = {45},
number = {14},
pages = {8314-8328},
pmid = {28575419},
issn = {1362-4962},
mesh = {Ataxia Telangiectasia Mutated Proteins/genetics/metabolism ; Blotting, Western ; DNA Damage ; *Feedback, Physiological ; Models, Genetic ; Mutation ; Phosphorylation ; Protein Binding ; Repressor Proteins/genetics/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Serine/genetics/metabolism ; Shelterin Complex ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics ; Telomere Shortening/*genetics ; Telomere-Binding Proteins/genetics/metabolism ; Transcription Factors/genetics/metabolism ; Two-Hybrid System Techniques ; },
abstract = {Telomere homeostasis is controlled by both telomerase machinery and end protection. Telomere shortening induces DNA damage sensing kinases ATM/ATR for telomerase recruitment. Yet, whether telomere shortening also governs end protection is poorly understood. Here we discover that yeast ATM/ATR controls end protection. Rap1 is phosphorylated by Tel1 and Mec1 kinases at serine 731, and this regulation is stimulated by DNA damage and telomere shortening. Compromised Rap1 phosphorylation hampers the interaction between Rap1 and its interacting partner Rif1, which thereby disturbs the end protection. As expected, reduction of Rap1-Rif1 association impairs telomere length regulation and increases telomere-telomere recombination. These results indicate that ATM/ATR DNA damage checkpoint signal contributes to telomere protection by strengthening the Rap1-Rif1 interaction at short telomeres, and the checkpoint signal oversees both telomerase recruitment and end capping pathways to maintain telomere homeostasis.},
}
@article {pmid28575409,
year = {2017},
author = {Arkhipova, IR and Yushenova, IA and Rodriguez, F},
title = {Giant Reverse Transcriptase-Encoding Transposable Elements at Telomeres.},
journal = {Molecular biology and evolution},
volume = {34},
number = {9},
pages = {2245-2257},
pmid = {28575409},
issn = {1537-1719},
support = {R01 GM111917/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; DNA Transposable Elements/genetics ; Eukaryotic Cells/metabolism ; Gene Transfer, Horizontal/genetics ; Open Reading Frames ; Phylogeny ; RNA ; RNA, Catalytic/genetics ; RNA-Directed DNA Polymerase/genetics ; Retroelements/genetics ; Rotifera/genetics ; Sequence Homology, Amino Acid ; Telomere/*genetics/metabolism ; },
abstract = {Transposable elements are omnipresent in eukaryotic genomes and have a profound impact on chromosome structure, function and evolution. Their structural and functional diversity is thought to be reasonably well-understood, especially in retroelements, which transpose via an RNA intermediate copied into cDNA by the element-encoded reverse transcriptase, and are characterized by a compact structure. Here, we report a novel type of expandable eukaryotic retroelements, which we call Terminons. These elements can attach to G-rich telomeric repeat overhangs at the chromosome ends, in a process apparently facilitated by complementary C-rich repeats at the 3'-end of the RNA template immediately adjacent to a hammerhead ribozyme motif. Terminon units, which can exceed 40 kb in length, display an unusually complex and diverse structure, and can form very long chains, with host genes often captured between units. As the principal polymerizing component, Terminons contain Athena reverse transcriptases previously described in bdelloid rotifers and belonging to the enigmatic group of Penelope-like elements, but can additionally accumulate multiple cooriented ORFs, including DEDDy 3'-exonucleases, GDSL esterases/lipases, GIY-YIG-like endonucleases, rolling-circle replication initiator (Rep) proteins, and putatively structural ORFs with coiled-coil motifs and transmembrane domains. The extraordinary length and complexity of Terminons and the high degree of interfamily variability in their ORF content challenge the current views on the structural organization of eukaryotic retroelements, and highlight their possible connections with the viral world and the implications for the elevated frequency of gene transfer.},
}
@article {pmid28572671,
year = {2017},
author = {Attri, P and Gaur, J and Choi, S and Kim, M and Bhatia, R and Kumar, N and Park, JH and Cho, AE and Choi, EH and Lee, W},
title = {Interaction studies of carbon nanomaterials and plasma activated carbon nanomaterials solution with telomere binding protein.},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {2636},
pmid = {28572671},
issn = {2045-2322},
mesh = {Cell Line, Tumor ; Graphite/chemistry/pharmacology ; Humans ; Molecular Docking Simulation ; Nanostructures/chemistry ; Nanotubes, Carbon/*chemistry ; Plasma/*chemistry ; Protein Conformation ; Telomerase/*antagonists &amp; inhibitors/chemistry ; Telomere-Binding Proteins/chemistry/*pharmacology ; },
abstract = {Most cancer cells have telomerase activity because they can express the human telomerase reverse transcriptase (hTERT) gene. Therefore, the inhibition of the hTERT expression can play an important role in controlling cancer cell proliferation. Our current study aims to inhibit hTERT expression. For this, we synthesized graphene oxide (GO) and a functionalized multiwall carbon nanotube (f-MWCNT), latter treated them with cold atmospheric pressure plasma for further analysis of the hTERT expression. The inhibition of hTERT expression by GO, f-MWCNT, plasma activated GO solution (PGOS), and plasma activated f-MWCNT solution (PCNTS), was studied using two lung cancer cell lines, A549 and H460. The hTERT experimental results revealed that GO and PGOS sufficiently decreased the hTERT concentration, while f-MWCNT and PCNTS were unable to inhibit the hTERT concentration. Therefore, to understand the inhibition mechanism of hTERT, we studied the binding properties of GO and PGOS with telomere binding protein (AtTRB2). The interaction studies were carried out using circular dichroism, fluorescence, [1]H-[15]N NMR spectroscopy, and size-exclusion chromatography (SEC) binding assay. We also used docking simulation to have an better understanding of the interactions between GO nanosheets and AtTRB2 protein. Our results may provide new insights that can benefit in biomedical treatments.},
}
@article {pmid28566455,
year = {2017},
author = {Nakano, A and Masuda, K and Hiromoto, T and Takahashi, K and Matsumoto, Y and Habib, AGK and Darwish, AGG and Yukawa, M and Tsuchiya, E and Ueno, M},
title = {Correction for Nakano et al., "Rad51-Dependent Aberrant Chromosome Structures at Telomeres and Ribosomal DNA Activate the Spindle Assembly Checkpoint".},
journal = {Molecular and cellular biology},
volume = {37},
number = {12},
pages = {},
doi = {10.1128/MCB.00175-17},
pmid = {28566455},
issn = {1098-5549},
}
@article {pmid28560968,
year = {2017},
author = {Zhang, N and Tse, G and Liang, X and Li, G and Liu, T},
title = {Telomere length: A newly marker for predicting atrial fibrillation?.},
journal = {International journal of cardiology},
volume = {239},
number = {},
pages = {21},
doi = {10.1016/j.ijcard.2017.02.125},
pmid = {28560968},
issn = {1874-1754},
mesh = {*Atrial Fibrillation ; Biomarkers ; Humans ; Risk Factors ; *Telomere ; },
}
@article {pmid28559540,
year = {2017},
author = {Zhou, Y and Simmons, D and Lai, D and Hambly, BD and McLachlan, CS},
title = {rs9939609 FTO genotype associations with FTO methylation level influences body mass and telomere length in an Australian rural population.},
journal = {International journal of obesity (2005)},
volume = {41},
number = {9},
pages = {1427-1433},
pmid = {28559540},
issn = {1476-5497},
mesh = {Adult ; Aged ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics/*metabolism ; Australia/epidemiology ; Blood Pressure ; Body Mass Index ; DNA Methylation/genetics/*physiology ; DNA Mutational Analysis ; Female ; Genetic Predisposition to Disease/*genetics ; *Genome-Wide Association Study ; Genotype ; Humans ; Male ; Middle Aged ; *Obesity/epidemiology/genetics ; Retrospective Studies ; Risk Factors ; Rural Population ; Telomere/physiology ; Telomere Shortening/*physiology ; Waist Circumference ; },
abstract = {BACKGROUND: The fat mass- and obesity-associated (FTO) gene influences energy homeostasis in humans. Although the obesity-related variant, rs9939609 has been replicated across a number of cohort studies, there remains significant variance and a low to modest association. Telomere length is another commonly reported obesity risk factor. We hypothesize understanding the associations between FTO rs9939609 with FTO methylation and telomere length will provide a more accurate assessment of obesity risk.<br><br>METHODS: Overall, 942 participants free of diabetes or pre-diabetes were included in the retrospective study. Leukocyte genomic DNA was analyzed for rs9939609 genotyping, FTO gene methylation and leukocyte telomere length (LTL) measurement.<br><br>RESULTS: In general linear models, rs9939609 AA genotypes were associated with increased fat percentage (3.15%, P=0.001), fat mass (4.16&#x2009;kg, P=0.001), body mass index (BMI) (1.38, P=0.006) and waist circumference (3.35 cm, P=0.006), but not with FTO methylation or LTL in this overall population. However, when participants were stratified into higher and lower FTO methylation groups, the AA genotype possesses a 2.04-fold increased obesity risk in comparison to TT genotype (95%CI, 1.07-3.89, P=0.031) in participants with a higher FTO methylation level, but this association was absent in the lower FTO methylation sub-group. Moreover, AT and AA genotype carriers were associated with shorter LTL compared to TT carriers (P=0.020 and P=0.111, respectively) in the higher FTO methylation level group. However, this association was absent in the lower methylation group. Furthermore, FTO gene methylation level was significantly associated with LTL in the 942 samples (P=0.017).<br><br>CONCLUSIONS: FTO rs9939609 is associated with obesity risk and LTL in this study, where this association is only observed at higher, but not lower, FTO methylation levels of participants. Our data suggest association of multiple factors, including FTO methylation level, may be involved in one of several mechanisms underlying the commonly reported obesity risk of this FTO polymorphism.},
}
@article {pmid28557385,
year = {2017},
author = {Pavlov, KI and Mukhin, VN and Klimenko, VM and Anisimov, VN},
title = {[Telomere-telomerase system in aging, norm and pathology (literature review)].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {30},
number = {1},
pages = {17-26},
pmid = {28557385},
issn = {1561-9125},
mesh = {Aging/*physiology ; Bipolar Disorder/etiology ; Cognition/*physiology ; Cognitive Dysfunction/etiology ; Dementia/etiology ; Depression/etiology ; Emotions/*physiology ; Humans ; Research ; Schizophrenia/etiology ; Telomerase/*physiology ; Telomere/enzymology/*physiology ; },
abstract = {This literature review presents results of research showing association between functional activity of the telomere-telomerase system and mental cognitive and emotional processes in normal and various pathological states: chronic stress, depression, bipolar disorder, schizophrenia, mild cognitive impairment and dementia in aging. It also refers to age-specific, psycho-social, economic, immunological, genetic and epigenetic factors that influence these relationships.},
}
@article {pmid28552815,
year = {2017},
author = {Shadyab, AH and LaMonte, MJ and Kooperberg, C and Reiner, AP and Carty, CL and Manini, TM and Hou, L and Di, C and Macera, CA and Gallo, LC and Shaffer, RA and Jain, S and LaCroix, AZ},
title = {Leisure-time physical activity and leukocyte telomere length among older women.},
journal = {Experimental gerontology},
volume = {95},
number = {},
pages = {141-147},
pmid = {28552815},
issn = {1873-6815},
support = {HHSN268201100001I/HL/NHLBI NIH HHS/United States ; UL1 TR001412/TR/NCATS NIH HHS/United States ; R01 HL121023/HL/NHLBI NIH HHS/United States ; HHSN268201100004I/HL/NHLBI NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; T32 AR064194/AR/NIAMS NIH HHS/United States ; HHSN268201100003C/WH/WHI NIH HHS/United States ; HHSN268201300007C/HL/NHLBI NIH HHS/United States ; P30 AG028740/AG/NIA NIH HHS/United States ; HHSN271201100004C/AG/NIA NIH HHS/United States ; HHSN268201100002C/WH/WHI NIH HHS/United States ; HHSN268201100002I/HL/NHLBI NIH HHS/United States ; HHSN268201100001C/WH/WHI NIH HHS/United States ; HHSN268201100004C/WH/WHI NIH HHS/United States ; R01 HL105065/HL/NHLBI NIH HHS/United States ; },
mesh = {Black or African American/genetics ; Age Factors ; Aged ; Aged, 80 and over ; Aging/ethnology/*genetics/pathology ; Blotting, Southern ; Chi-Square Distribution ; Cross-Sectional Studies ; *Exercise ; Female ; Humans ; *Leisure Activities ; Linear Models ; Middle Aged ; Multivariate Analysis ; Sex Factors ; Surveys and Questionnaires ; Telomere/*genetics/pathology ; *Telomere Shortening ; Time Factors ; United States ; White People/genetics ; },
abstract = {BACKGROUND: Shortened leukocyte telomere length (LTL), a purported marker of cellular aging, is associated with morbidity and mortality. However, the association of physical activity, a modifiable lifestyle behavior, with LTL has not been adequately studied among older adults.<br><br>METHODS: In this cross-sectional study, we examined associations of various intensity levels of leisure-time physical activity with LTL among 1476 older white and African American women from the Women's Health Initiative Objective Physical Activity and Cardiovascular Health study. Self-reported physical activity was assessed by questionnaire, and LTL was measured by Southern blot. The association between physical activity and LTL was evaluated using multiple linear regression models adjusted for demographic characteristics, lifestyle behaviors, and health-related variables.<br><br>RESULTS: Women were on average aged 79.2 (standard deviation 6.7) years old. In the final model adjusted for age, race/ethnicity, education, marital status, smoking, alcohol, body mass index, a history of chronic diseases, and hormone therapy use, LTL was on average 110 (95% confidence interval, 20-190) base pairs longer among women in the highest (&#x2265;17.00MET-hours/week) compared with the lowest (<1.25MET-hours/week) level of total leisure-time physical activity (P for trend=0.02). Higher levels of moderate-to-vigorous physical activity (P for trend=0.04) and faster walking speed (P for trend=0.03) were also associated with longer LTL in the fully-adjusted models.<br><br>CONCLUSION: Older women participating in greater amounts of total leisure-time physical activity and moderate-to-vigorous physical activity had longer LTL.},
}
@article {pmid28550088,
year = {2017},
author = {Booth, SA and Charchar, FJ},
title = {Cardiac telomere length in heart development, function, and disease.},
journal = {Physiological genomics},
volume = {49},
number = {7},
pages = {368-384},
doi = {10.1152/physiolgenomics.00024.2017},
pmid = {28550088},
issn = {1531-2267},
mesh = {Heart/*embryology/*physiopathology ; Heart Diseases/*genetics/*physiopathology ; Humans ; Models, Animal ; Stem Cells/metabolism ; *Telomere Homeostasis ; },
abstract = {Telomeres are repetitive nucleoprotein structures at chromosome ends, and a decrease in the number of these repeats, known as a reduction in telomere length (TL), triggers cellular senescence and apoptosis. Heart disease, the worldwide leading cause of death, often results from the loss of cardiac cells, which could be explained by decreases in TL. Due to the cell-specific regulation of TL, this review focuses on studies that have measured telomeres in heart cells and critically assesses the relationship between cardiac TL and heart function. There are several lines of evidence that have identified rapid changes in cardiac TL during the onset and progression of heart disease as well as at critical stages of development. There are also many factors, such as the loss of telomeric proteins, oxidative stress, and hypoxia, that decrease cardiac TL and heart function. In contrast, antioxidants, calorie restriction, and exercise can prevent both cardiac telomere attrition and the progression of heart disease. TL in the heart is also indicative of proliferative potential and could facilitate the identification of cells suitable for cardiac rejuvenation. Although these findings highlight the involvement of TL in heart function, there are important questions regarding the validity of animal models, as well as several confounding factors, that need to be considered when interpreting results and planning future research. With these in mind, elucidating the telomeric mechanisms involved in heart development and the transition to disease holds promise to prevent cardiac dysfunction and potentiate regeneration after injury.},
}
@article {pmid28547790,
year = {2017},
author = {},
title = {Corrigendum: Human First-Trimester Fetal MSC Express Pluripotency Markers and Grow Faster and Have Longer Telomeres Than Adult MSC.},
journal = {Stem cells (Dayton, Ohio)},
volume = {35},
number = {6},
pages = {1651-1652},
doi = {10.1002/stem.2589},
pmid = {28547790},
issn = {1549-4918},
}
@article {pmid28547179,
year = {2017},
author = {Reichert, S and Froy, H and Boner, W and Burg, TM and Daunt, F and Gillespie, R and Griffiths, K and Lewis, S and Phillips, RA and Nussey, DH and Monaghan, P},
title = {Telomere length measurement by qPCR in birds is affected by storage method of blood samples.},
journal = {Oecologia},
volume = {184},
number = {2},
pages = {341-350},
pmid = {28547179},
issn = {1432-1939},
support = {BB/H021868/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Birds ; *DNA ; Real-Time Polymerase Chain Reaction ; *Specimen Handling ; *Telomere ; },
abstract = {Given the potential role of telomeres as biomarkers of individual health and ageing, there is an increasing interest in studying telomere dynamics in a wider range of taxa in the fields of ecology and evolutionary biology. Measuring telomere length across the lifespan in wild animal systems is essential for testing these hypotheses, and may be aided by archived blood samples collected as part of longitudinal field studies. However, sample collection, storage, and DNA extraction methods may influence telomere length measurement, and it may, therefore, be difficult to balance consistency in sampling protocol with making the most of available samples. We used two complementary approaches to examine the impacts of sample storage method on measurements of relative telomere length (RTL) by qPCR, particularly focusing on FTA (Flinders Technology Associates) cards as a long-term storage solution. We used blood samples from wandering albatrosses collected over 14 years and stored in three different ways (n = 179), and also blood samples from captive zebra finches (n = 30) that were each stored using three different methods. Sample storage method influenced RTL in both studies, and samples on FTA cards had significantly shorter RTL measurements. There was no significant correlation between RTL measured in zebra finch blood on FTA cards and the same samples stored either as frozen whole blood or as extracted DNA. These results highlight the importance of consistency of sampling protocol, particularly in the context of long-term field studies, and suggest that FTA cards should not be used as a long-term storage solution to measure RTL without validation.},
}
@article {pmid28546384,
year = {2017},
author = {Holstein, EM and Ngo, G and Lawless, C and Banks, P and Greetham, M and Wilkinson, D and Lydall, D},
title = {Systematic Analysis of the DNA Damage Response Network in Telomere Defective Budding Yeast.},
journal = {G3 (Bethesda, Md.)},
volume = {7},
number = {7},
pages = {2375-2389},
pmid = {28546384},
issn = {2160-1836},
support = {//Wellcome Trust/United Kingdom ; MR/L001284/1/MRC_/Medical Research Council/United Kingdom ; BB/M002314/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; WT093088MA//Wellcome Trust/United Kingdom ; },
mesh = {DNA Damage/*genetics ; DNA, Fungal/*genetics/metabolism ; *Mutation ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Functional telomeres are critically important to eukaryotic genetic stability. Scores of proteins and pathways are known to affect telomere function. Here, we report a series of related genome-wide genetic interaction screens performed on budding yeast cells with acute or chronic telomere defects. Genetic interactions were examined in cells defective in Cdc13 and Stn1, affecting two components of CST, a single stranded DNA (ssDNA) binding complex that binds telomeric DNA. For comparison, genetic interactions were also examined in cells with defects in Rfa3, affecting the major ssDNA binding protein, RPA, which has overlapping functions with CST at telomeres. In more complex experiments, genetic interactions were measured in cells lacking EXO1 or RAD9, affecting different aspects of the DNA damage response, and containing a cdc13-1 induced telomere defect. Comparing fitness profiles across these data sets helps build a picture of the specific responses to different types of dysfunctional telomeres. The experiments show that each context reveals different genetic interactions, consistent with the idea that each genetic defect causes distinct molecular defects. To help others engage with the large volumes of data, the data are made available via two interactive web-based tools: Profilyzer and DIXY. One particularly striking genetic interaction observed was that the chk1∆ mutation improved fitness of cdc13-1 exo1∆ cells more than other checkpoint mutations (ddc1∆, rad9∆, rad17∆, and rad24∆), whereas, in cdc13-1 cells, the effects of all checkpoint mutations were similar. We show that this can be explained by Chk1 stimulating resection-a new function for Chk1 in the eukaryotic DNA damage response network.},
}
@article {pmid28544179,
year = {2017},
author = {Sikri, G and Bhattachar, S},
title = {Risk of high altitude pulmonary edema and telomere length.},
journal = {The journal of gene medicine},
volume = {19},
number = {5},
pages = {},
doi = {10.1002/jgm.2953},
pmid = {28544179},
issn = {1521-2254},
mesh = {*Altitude ; Humans ; Pulmonary Edema/genetics/*physiopathology ; Risk Factors ; *Telomere Homeostasis ; },
}
@article {pmid28543303,
year = {2017},
author = {Cheung, AS and Yeap, BB and Hoermann, R and Hui, J and Beilby, JP and Grossmann, M},
title = {Effects of androgen deprivation therapy on telomere length.},
journal = {Clinical endocrinology},
volume = {87},
number = {4},
pages = {381-385},
doi = {10.1111/cen.13382},
pmid = {28543303},
issn = {1365-2265},
mesh = {Aged ; Aged, 80 and over ; Androgen Antagonists/*therapeutic use ; Bone Density/drug effects ; Case-Control Studies ; Estradiol/blood ; Humans ; Male ; Middle Aged ; Prospective Studies ; Prostatic Neoplasms/blood/*drug therapy/*genetics ; Telomere/*drug effects/*genetics ; Testosterone/blood ; },
abstract = {OBJECTIVE: Recent evidence suggests that androgens either directly or via aromatisation to oestradiol may regulate telomere length, hence providing a mechanism whereby reproductive steroids are linked to biological ageing in men. Using men with prostate cancer initiating androgen deprivation therapy (ADT), we tested the hypothesis that severe sex steroid deprivation would accelerate telomere shortening.<br><br>DESIGN: We conducted a secondary analysis of a 2-year prospective controlled study among 65 men with nonmetastatic prostate cancer newly commencing adjuvant ADT (n=40) and age- and radiotherapy-matched prostate cancer controls (n=25).<br><br>METHODS: We measured leucocyte telomere length (LTL) expressed as telomeric/single copy control gene (T/S) ratio at baseline, 6, 12 and 24&#xa0;months. Generalized linear models determined the mean adjusted difference (MAD) (95% confidence interval) between groups during follow-up.<br><br>RESULTS: Compared to controls over 24&#xa0;months, men receiving ADT had no change in LTL, MAD for T/S ratio (0.105 [-0.004; 0.213], P=.235).<br><br>CONCLUSIONS: Using men with prostate cancer receiving ADT as a model we found no evidence that prolonged and profound sex steroid deprivation is associated with accelerated telomere shortening. Larger studies will be required to confirm or refute these findings.},
}
@article {pmid28540339,
year = {2017},
author = {Aoki, Y and Aoki, M and Yamada, K},
title = {Leukocyte Telomere Length and Serum Levels of High-Molecular-Weight Adiponectin and Dehydroepiandrosterone-Sulfate Could Reflect Distinct Aspects of Longevity in Japanese Centenarians.},
journal = {Gerontology &amp; geriatric medicine},
volume = {3},
number = {},
pages = {2333721417696672},
pmid = {28540339},
issn = {2333-7214},
abstract = {Leukocyte telomere length and serum levels of high-molecular-weight adiponectin and dehydroepiandrosterone-sulfate (DHEA-S) were assessed in association with nutrition and performance status (PS) in Japanese centenarians. Twenty-three centenarians (five men, 18 women) were classified according to their PS 1 (nearly fully ambulatory, n = 2), 2 (in bed less than 50% of daytime, n = 10), 3 (in bed greater than 50%, n = 6), and 4 (completely bedridden, n = 5). Leukocyte telomere length was determined by the hybridization protection assay, and the adiponectin and DHEA-S levels were measured by chemiluminescent enzyme immunoassay. Among variables of PS, body mass index (BMI), albumin, adiponectin, DHEA-S, and telomere length, there were significant correlations between PS and albumin (r = -.694, p < .01), between telomere length and BMI (r = .522, p < .05), between adiponectin and BMI (r = -.574, p < .01), and between DHEA-S and albumin (r = .530, p < .01). When excluding two cancer-bearing centenarians with short telomere, telomere length significantly correlated with PS (r = -.632, p < .01). It was indicated that the short leukocyte telomere was associated with poor PS and cancer development and that the adiponectin or DHEA-S was associated with adiposity or nutritional status. Despite a small number of subjects, these biomarkers seemed to reflect distinct aspects of longevity in Japanese centenarians.},
}
@article {pmid28536575,
year = {2017},
author = {Pavanello, S and Stendardo, M and Mastrangelo, G and Bonci, M and Bottazzi, B and Campisi, M and Nardini, M and Leone, R and Mantovani, A and Boschetto, P},
title = {Inflammatory Long Pentraxin 3 is Associated with Leukocyte Telomere Length in Night-Shift Workers.},
journal = {Frontiers in immunology},
volume = {8},
number = {},
pages = {516},
pmid = {28536575},
issn = {1664-3224},
abstract = {Aging is an emerging worldwide threat to public health, even in the workplace, as it links with risk of illness and death. Bewildered inflammatory responses and stressful conditions associate with age-related disorders. Additionally, circadian rhythm disruption, a critical health issue in night-shift workers, correlates with premature aging. We investigated the hypothesis of a link between altered inflammatory response, detected by plasmatic long pentraxin 3 (PTX3), and biological aging, measured by leukocyte telomere length (LTL), attrition, and possibly induced by night-shift work. Within the framework of a cross-sectional study, such possible relationships were appraised by simultaneous equation model (SEM) technique among day and night-shift hospital workers. PTX3 levels, modulated by several aging conditions [i.e., body mass index (BMI) (beta = -0.22; p = 0.022), C-reactive protein (CRP) (beta = -0.07; p = 0.000), and cardiovascular diseases with hypertension included (CVD) (beta = -0.12; p = 0.000)], positively associate with LTL (coefficient = 0.15; p = 0.033). LTL, in turn is reduced by CVD (beta = -0.15; p = 0.000), binge drinking (beta = -0.10; p = 0.004), and CRP (beta = -0.05; p = 0.026). On the other hand, night-shift work, found to be remarkably free from aging risk factors [i.e., age (beta = -0.13; p = 0.017), BMI (beta = -0.17; p = 0.030), CVD (beta = -0.14; p = 0.000), and binge drinking (beta = -0.13; p = 0.000)], does associate almost significantly with reversed PTX3 (coefficient = -0.09; p = 0.089) and even with CRP (beta = 0.17; p = 0.000). In conclusion, the SEM analysis indicates that PTX3 is positively linked to LTL. The finding suggests a possible new role of this long pentraxin that, by orchestrating an efficient governance of inflammatory processes, may protect telomere from attrition, ensuring therefore the genetic stability of cells. The higher CRP levels among night-shift workers suggest that night-shift work is associated with increased systemic inflammation. This would make nocturnal workers more susceptible to premature aging.},
}
@article {pmid28535365,
year = {2017},
author = {Jones, HJ and Janson, SL and Lee, KA},
title = {Leukocyte Telomere Length in Postmenopausal Women.},
journal = {Journal of obstetric, gynecologic, and neonatal nursing : JOGNN},
volume = {46},
number = {4},
pages = {567-575},
pmid = {28535365},
issn = {1552-6909},
support = {T32 NR007088/NR/NINR NIH HHS/United States ; },
mesh = {Black People/*genetics ; Female ; Humans ; Leukocytes/*metabolism ; Middle Aged ; Postmenopause/*genetics ; Telomere/*metabolism ; Telomere Homeostasis/physiology ; White People/*genetics ; Women's Health ; },
abstract = {OBJECTIVE: To compare leukocyte telomere length (LTL) by race and describe demographic, health, and psychosocial factors associated with LTL in postmenopausal women.<br><br>DESIGN: Descriptive study with comparative analyses and correlations.<br><br>SETTING: Data were collected at the University of California-San Francisco, San Francisco Clinical and Translational Science Institute.<br><br>PARTICIPANTS: Thirty-nine African American and White postmenopausal women between 58 and 65 years of age (mean age&#xa0;= 61.3 &#xb1; 1.83 years).<br><br>METHODS: Measures included demographics, blood pressure, anthropometrics, scores on the Perceived Stress Scale and the Center for Epidemiologic Studies-Depression, and blood samples for LTL.<br><br>RESULTS: African American women (n&#xa0;= 14) had greater PSS-10 and CES-D scores, greater blood pressure, and greater body mass index than White women (n&#xa0;= 25; p&#xa0;< .05), but LTL did not significantly differ between the two groups. Age was inversely related to LTL (r&#xa0;=&#xa0;-.355, p&#xa0;< .05). After age and race were controlled, fewer children (p&#xa0;=&#xa0;.005) and greater perceived stress (p&#xa0;= .036) were related to shorter LTL.<br><br>CONCLUSION: Findings from this small sample support the association between age and LTL. The association between perceived stress, number of children, and shorter LTL in postmenopausal women requires further research and replication of findings in a larger, more diverse sample.},
}
@article {pmid28535013,
year = {2017},
author = {Barczak, W and Suchorska, WM and Sobecka, A and Bednarowicz, K and Machczynski, P and Golusinski, P and Rubis, B and Masternak, MM and Golusinski, W},
title = {hTERT C250T promoter mutation and telomere length as a molecular markers of cancer progression in patients with head and neck cancer.},
journal = {Molecular medicine reports},
volume = {16},
number = {1},
pages = {441-446},
doi = {10.3892/mmr.2017.6590},
pmid = {28535013},
issn = {1791-3004},
mesh = {Adult ; Aged ; Aged, 80 and over ; Alleles ; *Biomarkers, Tumor ; DNA Mutational Analysis ; Disease Progression ; Female ; Head and Neck Neoplasms/*genetics/*pathology ; Humans ; Male ; Middle Aged ; *Mutation ; Neoplasm Staging ; *Promoter Regions, Genetic ; Telomerase/*genetics ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {Squamous cell carcinoma of the head and neck (HNSCC) is the sixth leading cause of cancer worldwide, representing over half a million incidents every year. Cancer cells, including HNSCC, are characterized by increased telomerase activity. This enzymatic complex is active in ~90% of all cancer types and is responsible for the lengthening of telomeres. Highly recurrent point mutations in the human telomerase reverse transcriptase (hTERT) promoter have recently been reported in a number of human neoplasms. The aim of the present study was to analyze the prevalence of the hTERT promoter C250T mutation and telomere length in the blood leukocytes of 61 patients with HNSCC and 49 healthy individuals. Quantitative polymerase chain reaction identified the hTERT promoter mutation in 36% of patients with HNSCC. To the best of our knowledge this is first report indicating the presence of shorter telomeres in early stage tumors. In addition, the results suggest that the C250T hTERT promoter mutation and telomere length assessment may serve as important molecular markers of HNSCC progression.},
}
@article {pmid28524249,
year = {2017},
author = {Vedder, O and Verhulst, S and Bauch, C and Bouwhuis, S},
title = {Telomere attrition and growth: a life-history framework and case study in common terns.},
journal = {Journal of evolutionary biology},
volume = {30},
number = {7},
pages = {1409-1419},
doi = {10.1111/jeb.13119},
pmid = {28524249},
issn = {1420-9101},
mesh = {Animals ; Body Size ; Charadriiformes/*genetics ; Inheritance Patterns ; Mortality ; Phenotype ; Population Dynamics ; Telomere ; *Telomere Shortening ; },
abstract = {The relationship between growth and age-specific telomere length, as a proxy of somatic state, is increasingly investigated, but observed patterns vary and a predictive framework is lacking. We outline expectations based on the assumption that telomere maintenance is costly and argue that individual heterogeneity in resource acquisition is predicted to lead to positive covariance between growth and telomere length. However, canalization of resource allocation to the trait with a larger effect on fitness, rendering that trait relatively invariant, can cause the absence of covariance. In a case study of common tern (Sterna hirundo) chicks, in which hatching order is the main determinant of variation in resource acquisition within broods, we find that body mass, but not telomere length or attrition, varies with hatching order. Moreover, body mass and growth positively predict survival to fledging, whereas telomere length and attrition do not. Using a novel statistical method to quantify standardized variance in plasticity, we estimate between-individual variation in telomere attrition to be only 12% of that of growth. Consistent with the relative invariance of telomere attrition, we find no correlation between age-specific body mass or growth and telomere attrition. We suggest that common tern chicks prioritize investment in long-term somatic state (as indicated by canalization of telomere maintenance) over immediate survival benefits of growth as part of an efficient brood reduction strategy that benefits the parents. As such, interspecific variation in the growth-telomere length relationship may be explained by the extent to which parents benefit from rapid mortality of excess offspring.},
}
@article {pmid28522577,
year = {2017},
author = {Helby, J and Nordestgaard, BG and Benfield, T and Bojesen, SE},
title = {Shorter leukocyte telomere length is associated with higher risk of infections: a prospective study of 75,309 individuals from the general population.},
journal = {Haematologica},
volume = {102},
number = {8},
pages = {1457-1465},
pmid = {28522577},
issn = {1592-8721},
mesh = {Aged ; Female ; Follow-Up Studies ; Humans ; Immunocompetence ; Infections/etiology/*immunology ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Prospective Studies ; Risk ; Telomere/*immunology/ultrastructure ; Tissue Donors ; },
abstract = {In the general population, older age is associated with short leukocyte telomere length and with high risk of infections. In a recent study of allogeneic hematopoietic cell transplantation for severe aplastic anemia, long donor leukocyte telomere length was associated with improved survival in the recipients. These findings suggest that leukocyte telomere length could possibly be a marker of immune competence. Therefore, we tested the hypothesis that shorter leukocyte telomere length is associated with higher risk of infectious disease hospitalization and infection-related death. Relative peripheral blood leukocyte telomere length was measured using quantitative polymerase chain reaction in 75,309 individuals from the general population and the individuals were followed for up to 23 years. During follow up, 9228 individuals were hospitalized with infections and infection-related death occurred in 1508 individuals. Shorter telomere length was associated with higher risk of any infection (hazard ratio 1.05 per standard deviation shorter leukocyte telomere length; 95% confidence interval 1.03-1.07) and pneumonia (1.07; 1.03-1.10) after adjustment for conventional infectious disease risk factors. Corresponding hazard ratios for infection-related death were 1.10 (1.04-1.16) for any infection and 1.11 (1.04-1.19) for pneumonia. Telomere length was not associated with risk of skin infection, urinary tract infection, sepsis, diarrheal disease, endocarditis, meningitis or other infections. In conclusion, our findings indicate that leukocyte telomere length may be a marker of immune competence. Further studies are needed to determine whether risk of infections in allogeneic hematopoietic cell transplantation recipients can be reduced by considering donor leukocyte telomere length when selecting donors.},
}
@article {pmid28521619,
year = {2017},
author = {Hill, TD and Vaghela, P and Ellison, CG and Rote, S},
title = {Processes Linking Religious Involvement and Telomere Length.},
journal = {Biodemography and social biology},
volume = {63},
number = {2},
pages = {167-188},
doi = {10.1080/19485565.2017.1311204},
pmid = {28521619},
issn = {1948-5573},
mesh = {Cellular Senescence/*physiology ; Depressive Disorder/psychology ; Humans ; Inflammation/psychology ; *Religion ; Religion and Psychology ; Smoking/psychology ; Stress, Psychological/psychology ; Telomere/*physiology ; },
abstract = {Although numerous studies suggest that religious involvement is associated with better health and longer life expectancies, it is unclear whether these general patterns extend to cellular aging. The mechanisms linking indicators of religious involvement with indicators of cellular aging are also undefined. We employed longitudinal data from the 2004 and 2008 Health and Retirement Study, a national probability sample of Americans aged 50 and older, to test whether average telomere length varied according to level of religious attendance. We also tested several potential mechanisms. Our results showed that respondents who attended religious services more frequently in 2004 also exhibited fewer stressful events, lower rates of smoking, fewer symptoms of depression, and lower levels of C-reactive protein in 2008. Respondents who increased their level of attendance from 2004 to 2008 also exhibited lower rates of smoking in 2008. Although religious attendance was not directly associated with telomere length, our mediation analyses revealed significant indirect effects through depression and smoking, but not stressful events or C-reactive protein. We conclude that religious attendance may promote telomere length indirectly by reducing symptoms of depression and the risk of smoking. There was no evidence to support stressful events or C-reactive protein as mechanisms of religious attendance.},
}
@article {pmid28515879,
year = {2017},
author = {Taff, CC and Freeman-Gallant, CR},
title = {Sexual signals reflect telomere dynamics in a wild bird.},
journal = {Ecology and evolution},
volume = {7},
number = {10},
pages = {3436-3442},
pmid = {28515879},
issn = {2045-7758},
abstract = {Telomere dynamics in natural populations have been linked to survival, reproduction, and energetic investment. Given their putative role in mediating life-history trade-offs, telomeres are also a likely candidate for maintaining honesty in sexually selected signals; few studies to date, however, have demonstrated a correlation between sexual signals and telomere dynamics. Here, we show that plumage coloration in male common yellowthroats (Geothlypis trichas) is correlated with both relative telomere length and with the rate of telomere loss between years. Elevated antioxidant capacity is also associated with reduced telomere loss, but only among older males. Previous work in this population has demonstrated that males with brighter plumage are in better condition, have higher reproductive success, and are more likely to survive over winter. Thus, the signal attribute associated with mate choice in this system also conveys reliable information about telomere dynamics. At present, it is unclear whether telomere maintenance plays a causal role in maintaining signal honesty or whether the correlation arises due to underlying variation in individual resources or genotypes. We suggest that subsequent work should consider the possibility that fundamental trade-offs between signal investment and cell-level processes that influence aging and reproductive senescence may provide a foundation for understanding the maintenance of sexual signal honesty.},
}
@article {pmid28515044,
year = {2017},
author = {Zhan, Y and Karlsson, IK and Karlsson, R and Tillander, A and Reynolds, CA and Pedersen, NL and Hägg, S},
title = {Exploring the Causal Pathway From Telomere Length to Coronary Heart Disease: A Network Mendelian Randomization Study.},
journal = {Circulation research},
volume = {121},
number = {3},
pages = {214-219},
doi = {10.1161/CIRCRESAHA.116.310517},
pmid = {28515044},
issn = {1524-4571},
mesh = {Blood Glucose/genetics/metabolism ; Coronary Disease/*blood/diagnosis/*genetics ; Female ; Genetic Variation/physiology ; Genome-Wide Association Study/*methods ; Humans ; Insulin/blood/genetics ; Male ; Mendelian Randomization Analysis/*methods ; Polymorphism, Single Nucleotide/genetics ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {RATIONALE: Observational studies have found shorter leukocyte telomere length (TL) to be a risk factor for coronary heart disease (CHD), and recently the association was suggested to be causal. However, the relationship between TL and common metabolic risk factors for CHD is not well understood. Whether these risk factors could explain pathways from TL to CHD warrants further attention.<br><br>OBJECTIVE: To examine whether metabolic risk factors for CHD mediate the causal pathway from short TL to increased risk of CHD using a network Mendelian randomization design.<br><br>METHODS AND RESULTS: Summary statistics from several genome-wide association studies were used in a 2-sample Mendelian randomization study design. Network Mendelian randomization analysis-an approach using genetic variants as the instrumental variables for both the exposure and mediator to infer causality-was performed to examine the causal association between telomeres and CHD and metabolic risk factors. Summary statistics from the ENGAGE Telomere Consortium were used (n=37&#x2009;684) as a TL genetic instrument, CARDIoGRAMplusC4D Consortium data were used (case=22&#x2009;233 and control=64&#x2009;762) for CHD, and other consortia data were used for metabolic traits (fasting insulin, triglyceride, total cholesterol, low-density lipoprotein cholesterol, fasting glucose, diabetes mellitus, glycohemoglobin, body mass index, waist circumference, and waist:hip ratio). One-unit increase of genetically determined TL was associated with -0.07 (95% confidence interval, -0.01 to -0.12; P=0.01) lower log-transformed fasting insulin (pmol/L) and 21% lower odds (95% confidence interval, 3-35; P=0.02) of CHD. Higher genetically determined log-transformed fasting insulin level was associated with higher CHD risk (odds ratio, 1.86; 95% confidence interval, 1.01-3.41; P=0.04).<br><br>CONCLUSIONS: Overall, our findings support a role of insulin as a mediator on the causal pathway from shorter telomeres to CHD pathogenesis.},
}
@article {pmid28513547,
year = {2017},
author = {Naderlinger, E and Holzmann, K},
title = {Epigenetic Regulation of Telomere Maintenance for Therapeutic Interventions in Gliomas.},
journal = {Genes},
volume = {8},
number = {5},
pages = {},
pmid = {28513547},
issn = {2073-4425},
abstract = {High-grade astrocytoma of WHO grade 4 termed glioblastoma multiforme (GBM) is a common human brain tumor with poor patient outcome. Astrocytoma demonstrates two known telomere maintenance mechanisms (TMMs) based on telomerase activity (TA) and on alternative lengthening of telomeres (ALT). ALT is associated with lower tumor grades and better outcome. In contrast to ALT, regulation of TA in tumors by direct mutation and epigenetic activation of the hTERT promoter is well established. Here, we summarize the genetic background of TMMs in non-malignant cells and in cancer, in addition to clinical and pathological features of gliomas. Furthermore, we present new evidence for epigenetic mechanisms (EMs) involved in regulation of ALT and TA with special emphasis on human diffuse gliomas as potential therapeutic drug targets. We discuss the role of TMM associated telomeric chromatin factors such as DNA and histone modifying enzymes and non-coding RNAs including microRNAs and long telomeric TERRA transcripts.},
}
@article {pmid28512776,
year = {2017},
author = {Lee, SH and Griffiths, N and Shao, L},
title = {Can telomere length be used as a biomarker for cardiovascular diseases? Insights from a large clinical study.},
journal = {The Journal of physiology},
volume = {595},
number = {14},
pages = {4595-4596},
pmid = {28512776},
issn = {1469-7793},
mesh = {Aorta ; Biomarkers ; Cardiovascular Diseases ; Humans ; *Pulse Wave Analysis ; *Telomere ; },
}
@article {pmid28510637,
year = {2017},
author = {Vidacek, N&#x160; and Nanic, L and Ravlic, S and Sopta, M and Geric, M and Gajski, G and Garaj-Vrhovac, V and Rubelj, I},
title = {Telomeres, Nutrition, and Longevity: Can We Really Navigate Our Aging?.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {73},
number = {1},
pages = {39-47},
doi = {10.1093/gerona/glx082},
pmid = {28510637},
issn = {1758-535X},
mesh = {Aging/*genetics ; Animals ; Cellular Senescence/genetics ; Exercise/physiology ; Humans ; *Life Expectancy ; Longevity/*genetics ; *Nutritional Status ; Telomere/*genetics ; },
abstract = {Telomeres are dynamic chromosome-end structures that serve as guardians of genome stability. They are known to be one of the major determinants of aging and longevity in higher mammals. Studies have demonstrated a direct correlation between telomere length and life expectancy, stress, DNA damage, and onset of aging-related diseases. This review discusses the most important factors that influence our telomeres. Various genetic and environmental factors such as diet, physical activity, obesity, and stress are known to influence health and longevity as well as telomere dynamics. Individuals currently have the opportunity to modulate the dynamics of their aging and health span, monitor these processes, and even make future projections by following their telomere dynamics. As telomeres react to positive as well as negative health factors, we should be able to directly influence our telomere metabolism, slow their deterioration, and diminish our aging and perhaps extend our life and health span.},
}
@article {pmid28510424,
year = {2017},
author = {Liu, X and Ishizuka, T and Bao, HL and Wada, K and Takeda, Y and Iida, K and Nagasawa, K and Yang, D and Xu, Y},
title = {Structure-Dependent Binding of hnRNPA1 to Telomere RNA.},
journal = {Journal of the American Chemical Society},
volume = {139},
number = {22},
pages = {7533-7539},
pmid = {28510424},
issn = {1520-5126},
support = {P30 CA023168/CA/NCI NIH HHS/United States ; R01 CA122952/CA/NCI NIH HHS/United States ; R01 CA177585/CA/NCI NIH HHS/United States ; },
mesh = {Cross-Linking Reagents/chemistry ; Fluorescent Antibody Technique ; *G-Quadruplexes ; HeLa Cells ; Humans ; Magnetic Resonance Spectroscopy ; Microscopy, Fluorescence ; Models, Biological ; Molecular Structure ; Photochemistry ; Protein Binding ; RNA/*chemistry ; Small Molecule Libraries/chemistry ; Structure-Activity Relationship ; Substrate Specificity ; Telomerase/*chemistry ; },
abstract = {Telomeric repeat-containing RNA is a new noncoding RNA molecule that performs various biofunctions. Heterogeneous nuclear ribonucleoprotein (hnRNP) A1 is an RNA-binding protein involved in the telomere maintenance machinery. To date, little is known about how hnRNPA1 binds to telomeric RNA. In this study, we investigated the binding affinity and recognition mechanism of telomere RNA with the RNA recognition motif of hnRNPA1. Using the photochemical cross-linking method, we showed that the telomere RNA G-quadruplex with loops is important in the interaction of telomere RNA with hnRNPA1. Using small-molecule probes, we directly visualized the complex formed by the telomere RNA G-quadruplex and hnRNPA1 in vitro and in live cells. The results suggested that the structure-dependent binding of hnRNPA1 to telomere RNA regulates the telomere function. Therefore, our study provides new insights into the interactions between the RNA G-quadruplex and proteins at the telomere.},
}
@article {pmid28509419,
year = {2017},
author = {Dreissig, S and Schiml, S and Schindele, P and Weiss, O and Rutten, T and Schubert, V and Gladilin, E and Mette, MF and Puchta, H and Houben, A},
title = {Live-cell CRISPR imaging in plants reveals dynamic telomere movements.},
journal = {The Plant journal : for cell and molecular biology},
volume = {91},
number = {4},
pages = {565-573},
pmid = {28509419},
issn = {1365-313X},
mesh = {Bacterial Proteins/genetics/*metabolism ; CRISPR-Associated Protein 9 ; Cell Nucleus/metabolism ; Chromatin/genetics ; *Clustered Regularly Interspaced Short Palindromic Repeats ; Endonucleases/genetics/*metabolism ; Genetic Loci/*genetics ; Green Fluorescent Proteins ; Imaging, Three-Dimensional ; In Situ Hybridization, Fluorescence ; Staphylococcus aureus/enzymology/genetics ; Streptococcus pyogenes/enzymology/genetics ; Telomere/genetics/*metabolism ; Nicotiana/*cytology/genetics/metabolism ; },
abstract = {Elucidating the spatiotemporal organization of the genome inside the nucleus is imperative to our understanding of the regulation of genes and non-coding sequences during development and environmental changes. Emerging techniques of chromatin imaging promise to bridge the long-standing gap between sequencing studies, which reveal genomic information, and imaging studies that provide spatial and temporal information of defined genomic regions. Here, we demonstrate such an imaging technique based on two orthologues of the bacterial clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated protein 9 (Cas9). By fusing eGFP/mRuby2 to catalytically inactive versions of Streptococcus pyogenes and Staphylococcus aureus Cas9, we show robust visualization of telomere repeats in live leaf cells of Nicotiana benthamiana. By tracking the dynamics of telomeres visualized by CRISPR-dCas9, we reveal dynamic telomere movements of up to 2 μm over 30 min during interphase. Furthermore, we show that CRISPR-dCas9 can be combined with fluorescence-labelled proteins to visualize DNA-protein interactions in vivo. By simultaneously using two dCas9 orthologues, we pave the way for the imaging of multiple genomic loci in live plants cells. CRISPR imaging bears the potential to significantly improve our understanding of the dynamics of chromosomes in live plant cells.},
}
@article {pmid28507575,
year = {2017},
author = {Mazidi, M and Penson, P and Banach, M},
title = {Association between telomere length and complete blood count in US adults.},
journal = {Archives of medical science : AMS},
volume = {13},
number = {3},
pages = {601-605},
pmid = {28507575},
issn = {1734-1922},
abstract = {INTRODUCTION: Telomere length (TL) is related to age-related health outcomes, but little is known about the relationship between TL and complete blood count (CBC) parameters. We aimed to determine the relationship between TL and CBC in a sample of healthy US adults.<br><br>MATERIAL AND METHODS: Participants in the National Health and Nutrition Examination Survey (NHANES) recruited between 1999 and 2002 who had essential data on total CBC and TL were studied. We computed age- and race-adjusted mean values for total CBC using analysis of covariance (ANCOVA). All statistical analyses accounted for the survey design and sample weights by using SPSS Complex Samples v22.0 (IBM Corp, Armonk, NY).<br><br>RESULTS: Of the 8892 eligible participants, 47.8% (n = 4123) were men. The mean age was 41.8 years overall, 41.0 years in men and 42.6 in women (p = 0.238). The sex-stratified ANCOVA showed no significant difference in the total CBC across TL quartiles (all p > 0.05) in both sexes. In the adjusted model, there was a significant negative relationship with monocyte count (&#x3b2; = -0.051, 95% CI: -0.422; -0.142), mean cell hemoglobin (&#x3b2; = -0.051, 95% CI: -0.038; -0.011) and red cell distribution width (&#x3b2; = -0.031, 95% CI: -0.054; -0.003), while there was a significant positive relationship with basophil ratio (&#x3b2; = 0.046, 95% CI: 0.049-0.171).<br><br>CONCLUSIONS: These results support the possibility that telomere attrition may be a marker for reduced proliferative reserve in hematopoietic progenitor cells.},
}
@article {pmid28506770,
year = {2017},
author = {Adam, R and Díez-González, L and Ocaña, A and Šeruga, B and Amir, E and Templeton, AJ},
title = {Prognostic role of telomere length in malignancies: A meta-analysis and meta-regression.},
journal = {Experimental and molecular pathology},
volume = {102},
number = {3},
pages = {455-474},
doi = {10.1016/j.yexmp.2017.05.010},
pmid = {28506770},
issn = {1096-0945},
mesh = {Cell Division ; Disease Progression ; Disease-Free Survival ; Humans ; Neoplasms/*diagnosis ; Prognosis ; Telomere/*ultrastructure ; *Telomere Homeostasis ; },
abstract = {Telomere length (TL) has been associated with several health conditions including cancer. To quantify the effect of TL on outcomes in malignancies and explore the role of type of TL measurement we conducted a librarian-led systematic search of electronic databases identified publications exploring the prognostic role of TL on cancer outcomes. Overall survival (OS) was the primary outcome measure while other time-to-event endpoints were secondary outcomes. Data from studies reporting a hazard ratio (HR) with 95% confidence interval (CI) and/or p-value were pooled in a meta-analysis. HRs were weighted by generic inverse variance and computed by random effects modeling. All statistical tests were two-sided. Sixty-one studies comprising a total of 14,720 patients were included of which 41 (67%) reported OS outcomes. Overall, the pooled HR for OS was 0.88 (95%CI=0.69-1.11, p=0.28). Long (versus short) telomeres were associated with improved outcomes in chronic lymphatic leukemia (CLL) and urothelial cancer (HR=0.45, 95%CI=0.29-0.71 and HR=0.68, 95%CI=0.46-1.00, respectively), conversely worse OS was seen with hepatocellular carcinoma (HR=1.90, 95%CI=1.51-2.38). Pooled HRs (95% CI) for progression-free survival, relapse/disease-free survival, cancer-specific survival, and treatment-free survival were 0.56 (0.41-0.76), 0.76 (0.53-1.10), 0.72 (0.48-1.10), and 0.48 (0.39-0.60), respectively. There was substantial heterogeneity of tissues and methods used for TL measurement and no clear association between TL and outcome was identified in subgroups. In conclusion, there is inconsistent effect of TL on cancer outcomes possibly due to variable methods of measurement. Standardization of measurement and reporting of TL is warranted before the prognostic value of TL can be accurately assessed.},
}
@article {pmid28502062,
year = {2017},
author = {Wei, D and Xie, J and Yin, B and Hao, H and Song, X and Liu, Q and Zhang, C and Sun, Y},
title = {Significantly lengthened telomere in granulosa cells from women with polycystic ovarian syndrome (PCOS).},
journal = {Journal of assisted reproduction and genetics},
volume = {34},
number = {7},
pages = {861-866},
pmid = {28502062},
issn = {1573-7330},
mesh = {Adult ; Cell Proliferation/genetics ; Female ; Granulosa Cells/*pathology ; Humans ; Polycystic Ovary Syndrome/*genetics/pathology/ultrastructure ; Telomere/metabolism/ultrastructure ; },
abstract = {PURPOSE: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among women at reproductive age. However, its etiology remains poorly understood. Recent studies indicated that telomere length was related to PCOS. However, the association between telomere length and PCOS has only been shown in leucocytes and remained controversial across different studies. To clarify the association between telomere length and PCOS, the current study interrogated telomere length not only in leucocytes, but also in follicular granulosa cells, which is essential for folliculogenesis and steroidogenesis.<br><br>METHODS: Seventy-five patients with PCOS and 81 controls with mechanical infertility undergoing their first in vitro fertilization cycle were enrolled. Their peripheral blood and granulosa cells were collected on the oocyte retrieval day. Telomere length of both leucocytes in the blood and granulosa cells was assayed by quantitative polymerase chain reaction.<br><br>RESULTS: No significant difference was found in the leucocyte telomere length between controls and PCOS patients (0.99&#xa0;&#xb1;&#xa0;0.44 vs. 1.00&#xa0;&#xb1;&#xa0;0.38, p&#xa0;=&#xa0;0.93). Interestingly, when comparing telomere length in granulosa cells between controls and PCOS subjects, significantly lengthened telomere length was found in PCOS subjects (1.00&#xa0;&#xb1;&#xa0;0.37 vs. 1.57&#xb1;0.67, p&#xa0;<&#xa0;0.0001). After adjustments for age and body mass index, the p value remained significant (p&#xa0;<&#xa0;0.0001).<br><br>CONCLUSIONS: This finding reinforced the association between telomere abnormalities and PCOS. Given the importance of telomere length in cellular proliferation, our findings provided novel insights into the pathophysiology of PCOS that abnormalities in telomere length possibly disturb folliculogenesis and subsequently result in PCOS.},
}
@article {pmid28500683,
year = {2017},
author = {Yan, X and Li, C and Yang, J and Wang, L and Jiang, C and Wei, W},
title = {Induction of telomere-mediated chromosomal truncation and behavior of truncated chromosomes in Brassica napus.},
journal = {The Plant journal : for cell and molecular biology},
volume = {91},
number = {4},
pages = {700-713},
doi = {10.1111/tpj.13598},
pmid = {28500683},
issn = {1365-313X},
mesh = {Arabidopsis/*genetics ; Brassica napus/cytology/*genetics ; Chromosomes, Artificial/genetics ; Chromosomes, Plant/*genetics ; Diploidy ; Genetic Engineering ; In Situ Hybridization, Fluorescence ; Plants, Genetically Modified ; Recombination, Genetic ; Telomere/*genetics ; Transgenes ; },
abstract = {Engineered minichromosomes could be stably inherited and serve as a platform for simultaneously transferring and stably expressing multiple genes. Chromosomal truncation mediated by repeats of telomeric sequences is a promising approach for the generation of minichromosomes. In the present work, direct repetitive sequences of Arabidopsis telomere were used to study telomere-mediated truncation of chromosomes in Brassica napus. Transgenes containing alien Arabidopsis telomere were successfully obtained, and Southern blotting and fluorescence in situ hybridization (FISH) results show that the transgenes resulted in successful chromosomal truncation in B. napus. In addition, truncated chromosomes were inherited at rates lower than that predicted by Mendelian rules. To determine the potential manipulations and applications of the engineered chromosomes, such as the stacking of multiple transgenes and the Cre/lox and FRT/FLP recombination systems, both amenable to genetic manipulations through site-specific recombination in somatic cells, were tested for their ability to undergo recombination in B. napus. These results demonstrate that alien Arabidopsis telomere is able to mediate chromosomal truncation in B. napus. This technology would be feasible for chromosomal engineering and for studies on chromosome structure and function in B. napus.},
}
@article {pmid28500672,
year = {2017},
author = {Whiteman, VE and Goswami, A and Salihu, HM},
title = {Telomere length and fetal programming: A review of recent scientific advances.},
journal = {American journal of reproductive immunology (New York, N.Y. : 1989)},
volume = {77},
number = {5},
pages = {},
doi = {10.1111/aji.12661},
pmid = {28500672},
issn = {1600-0897},
mesh = {Female ; Fetal Development/*physiology ; Humans ; Pregnancy ; Prenatal Exposure Delayed Effects/genetics ; Telomere/*physiology ; Telomere Shortening/*physiology ; },
abstract = {We sought to synthesize a comprehensive literature review comprising recent research linking fetal programming to fetal telomere length. We also explored the potential effects fetal telomere length shortening has on fetal phenotypes. Utilizing the PubMed database as our primary search engine, we retrieved and reviewed 165 articles of published research. The inclusion criteria limited the articles to those that appeared within the last ten years, were pertinent to humans, and without restriction to language of publication. Our results showed that socio-demographic factors like age, sex, genetic inheritance, and acquired disease impact telomere length. Further, we found several maternal characteristics to be associated with fetal telomere length shortening, and these include maternal chemical exposure (eg, tobacco smoke), maternal stress during pregnancy, maternal nutritional and sleeping disorders during pregnancy as well as maternal disease status. Due to paucity of data, our review could not synthesize evidence directly linking fetal phenotypes to telomere length shortening. Although the research summarized in this review shows some association between determinants of intrauterine programming and fetal telomere length, there is still significant work that needs to be done to delineate the direct relationship of telomere attrition with specific fetal phenotypes.},
}
@article {pmid28500257,
year = {2017},
author = {Jahn, A and Rane, G and Paszkowski-Rogacz, M and Sayols, S and Bluhm, A and Han, CT and Draškovič, I and Londoño-Vallejo, JA and Kumar, AP and Buchholz, F and Butter, F and Kappei, D},
title = {ZBTB48 is both a vertebrate telomere-binding protein and a transcriptional activator.},
journal = {EMBO reports},
volume = {18},
number = {6},
pages = {929-946},
pmid = {28500257},
issn = {1469-3178},
mesh = {Animals ; Carrier Proteins/genetics/metabolism ; DNA-Binding Proteins/*genetics/*metabolism ; *Gene Expression Regulation ; Green Fluorescent Proteins/genetics ; Homeodomain Proteins/metabolism ; Humans ; Mitochondria/metabolism ; Proteomics ; Repetitive Sequences, Nucleic Acid ; Shelterin Complex ; Telomere/*metabolism ; Telomere Homeostasis/genetics ; Telomere-Binding Proteins/genetics/metabolism ; Transcription Factors/*genetics/*metabolism ; *Transcriptional Activation ; },
abstract = {Telomeres constitute the ends of linear chromosomes and together with the shelterin complex form a structure essential for genome maintenance and stability. In addition to the constitutive binding of the shelterin complex, other direct, yet more transient interactions are mediated by the CST complex and HOT1/HMBOX1, while subtelomeric variant repeats are recognized by NR2C/F transcription factors. Recently, the Kruppel-like zinc finger protein ZBTB48/HKR3/TZAP has been described as a novel telomere-associated factor in the vertebrate lineage. Here, we show that ZBTB48 binds directly both to telomeric and to subtelomeric variant repeat sequences. ZBTB48 is found at telomeres of human cancer cells regardless of the mode of telomere maintenance and it acts as a negative regulator of telomere length. In addition to its telomeric function, we demonstrate through a combination of RNAseq, ChIPseq and expression proteomics experiments that ZBTB48 acts as a transcriptional activator on a small set of target genes, including mitochondrial fission process 1 (MTFP1). This discovery places ZBTB48 at the interface of telomere length regulation, transcriptional control and mitochondrial metabolism.},
}
@article {pmid28500256,
year = {2017},
author = {Garcia-Exposito, L and O'Sullivan, RJ},
title = {TZAP-ing telomeres down to size.},
journal = {EMBO reports},
volume = {18},
number = {6},
pages = {861-863},
pmid = {28500256},
issn = {1469-3178},
support = {R01 CA207209/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Carrier Proteins ; Telomerase/*genetics ; *Telomere ; Telomere Homeostasis ; Telomere-Binding Proteins ; Vertebrates ; },
abstract = {The phenomenon of gradual telomere shortening has become a paradigm for how we understand the biology of aging and cancer. Cell proliferation is accompanied by cumulative telomere loss, and the aged cell either senesces, dies or transforms toward cancer. This transformation requires the activation of telomere elongation mechanisms in order to restore telomere length such that cell death or senescence programs are not induced. Most of the time, this occurs through telomerase reactivation. In other rare cases, the Alternative lengthening of telomeres (ALT) pathway hijacks DNA recombination-associated mechanisms to hyperextend telomeres, often to more than 50 kb. Why telomere length is restricted and what sets their maximal length has been a long-standing puzzle in cell biology. Two recent studies published in this issue of EMBO Reports [1] and recently in Science [2] sought to address this important question. Both built on omics approaches that identified ZBTB48 as a potential telomere-associated protein and reveal it to be a critical regulator of telomere length homeostasis by the telomere trimming mechanism. These discoveries provide fundamental insights for our understanding of telomere trimming and how it impacts telomere integrity in stem and cancer cells.},
}
@article {pmid28488129,
year = {2018},
author = {Lee, H and Cho, JH and Park, WJ and Jung, SJ and Choi, IJ and Lee, JH},
title = {Loss of the Association between Telomere Length and Mitochondrial DNA Copy Number Contribute to Colorectal Carcinogenesis.},
journal = {Pathology oncology research : POR},
volume = {24},
number = {2},
pages = {323-328},
pmid = {28488129},
issn = {1532-2807},
support = {2014R1A6A3A04058057//Ministry of Education/ ; 2014R1A5A2010008//Ministry of Education/ ; },
mesh = {Aged ; Carcinogenesis/*genetics ; Colorectal Neoplasms/*genetics/pathology ; *DNA Copy Number Variations ; DNA, Mitochondrial/*genetics ; Female ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Telomere/*pathology ; Telomere Homeostasis/*physiology ; },
abstract = {Positive association between telomere length and mitochondrial DNA (mtDNA) copy number were introduced in healthy and patients with psychiatric disorder. Based on frequent genetic changes of telomere and mitochondria in colorectal carcinomas (CRC), we studied their clinical characteristics and their association in colorectal carcinogenesis. DNA was extracted from 109 CRCs, 64 colorectal tubular adenomas (TAs), and 28 serrated polyps (SPs), and then, telomere length and mtDNA copy number were analyzed in these legions by using a real-time PCR assay. Telomere length and mtDNA copy number (mean ± S.D) in CRCs was 1.87 ± 1.52 and 1.61 ± 1.37, respectively. In TAs and SPs, relative mtDNA copy number was 0.92 ± 0.71 and 1.84 ± 1.06, respectively, shoing statistical difference (p = 0.017). However, telomere length was similar in these precancerous legions. Telomere length and mtDNA copy number did not show clinical and prognostic values in CRCs, however, positive correlation between telomere length and mitochondrial DNA copy number were found in CRC (r = 0.408, p < 0.001). However, this association was not shown in precancerous lesions (r = -0.031, p = 0.765). This result suggests that loss of co-regulation between telomeres and mitochondrial function may induce the initiation or play a role as trigger factor of colorectal carcinogenesis.},
}
@article {pmid28486748,
year = {2017},
author = {Williams, J and Heppel, NH and Britt-Compton, B and Grimstead, JW and Jones, RE and Tauro, S and Bowen, DT and Knapper, S and Groves, M and Hills, RK and Pepper, C and Baird, DM and Fegan, C},
title = {Telomere length is an independent prognostic marker in MDS but not in de novo AML.},
journal = {British journal of haematology},
volume = {178},
number = {2},
pages = {240-249},
doi = {10.1111/bjh.14666},
pmid = {28486748},
issn = {1365-2141},
support = {15954/CRUK_/Cancer Research UK/United Kingdom ; 18246/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Adult ; Aged ; Biomarkers, Tumor/metabolism ; Disease-Free Survival ; Female ; Humans ; Leukemia, Myeloid, Acute/enzymology/mortality/*pathology ; Male ; Middle Aged ; Myelodysplastic Syndromes/enzymology/mortality/*pathology ; Prognosis ; Prospective Studies ; Risk Factors ; Telomerase/metabolism ; Telomere/*pathology ; Young Adult ; },
abstract = {Telomere dysfunction is implicated in the generation of large-scale genomic rearrangements that drive progression to malignancy. In this study we used high-resolution single telomere length analysis (STELA) to examine the potential role of telomere dysfunction in 80 myelodysplastic syndrome (MDS) and 95 de novo acute myeloid leukaemia (AML) patients. Despite the MDS cohort being older, they had significantly longer telomeres than the AML cohort (P < 0·0001) where telomere length was also significantly shorter in younger AML patients (age <60 years) (P = 0·02) and in FLT3 internal tandem duplication-mutated AML patients (P = 0·03). Using a previously determined telomere length threshold for telomere dysfunction (3·81 kb) did not provide prognostic resolution in AML [Hazard ratio (HR) = 0·68, P = 0·2]. In contrast, the same length threshold was highly prognostic for overall survival in the MDS cohort (HR = 5·0, P < 0·0001). Furthermore, this telomere length threshold was an independent parameter in multivariate analysis when adjusted for age, gender, cytogenetic risk group, number of cytopenias and International Prognostic Scoring System (IPSS) score (HR = 2·27, P < 0·0001). Therefore, telomere length should be assessed in a larger prospective study to confirm its prognostic role in MDS with a view to integrating this variable into a revised IPSS.},
}
@article {pmid28486613,
year = {2019},
author = {Lincoln, KD and Lloyd, DA and Nguyen, AW},
title = {Social Relationships and Salivary Telomere Length Among Middle-Aged and Older African American and White Adults.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {74},
number = {6},
pages = {1053-1061},
pmid = {28486613},
issn = {1758-5368},
support = {P30 AG043073/AG/NIA NIH HHS/United States ; },
mesh = {Black or African American/*ethnology ; Aged ; Aged, 80 and over ; Aging, Premature/*ethnology/genetics ; Cellular Senescence/*genetics ; Cross-Sectional Studies ; Family Conflict ; *Family Relations ; Female ; Health Surveys ; Humans ; *Interpersonal Relations ; Longitudinal Studies ; Male ; Middle Aged ; Saliva/metabolism ; *Social Support ; *Telomere ; White People/*ethnology ; },
abstract = {OBJECTIVES: A common mechanism underlying premature morbidity may be accelerated biological aging as reflected by salivary telomere length (STL). This study examined the extent to which social relationships, both positive and negative, can be protective or confer risk relative to biological aging.<br><br>METHOD: Data from the Health and Retirement Study and multiple regression were used to examine cross-sectional associations between STL, self-reported social support, and negative interaction (e.g., conflict, criticism) with family in a nationally representative sample of African American and non-Hispanic White middle-aged and older adults (N = 4,080).<br><br>RESULTS: Social support from family was associated with shorter STL. Negative interaction with family had no main effect on STL but interactions characterized by high social support and more frequent negative interactions were associated with longer STL. Negative interaction with family was negatively associated with STL for African Americans and Whites but the magnitude of the effect was greater for African Americans.<br><br>DISCUSSION: Study findings highlight the role of social relationships in physiological deterioration among middle-aged and older adults and identify a potential mechanism whereby race is linked to accelerated biological aging. Findings highlight the importance of considering positive and negative aspects of social relationships to understand the consequences of social connections for cellular aging in diverse populations.},
}
@article {pmid28486341,
year = {2017},
author = {Lee, EY and Lin, J and Noth, EM and Hammond, SK and Nadeau, KC and Eisen, EA and Balmes, JR},
title = {Traffic-Related Air Pollution and Telomere Length in Children and Adolescents Living in Fresno, CA: A Pilot Study.},
journal = {Journal of occupational and environmental medicine},
volume = {59},
number = {5},
pages = {446-452},
pmid = {28486341},
issn = {1536-5948},
support = {T42 OH008429/OH/NIOSH CDC HHS/United States ; U01 AI147462/AI/NIAID NIH HHS/United States ; R01 ES020926/ES/NIEHS NIH HHS/United States ; P01 ES022849/ES/NIEHS NIH HHS/United States ; R01 HL081521/HL/NHLBI NIH HHS/United States ; P20 ES018173/ES/NIEHS NIH HHS/United States ; },
mesh = {Adolescent ; Air Pollution/*adverse effects/statistics &amp; numerical data ; Asthma/physiopathology ; California ; Child ; Cross-Sectional Studies ; Environmental Exposure/*adverse effects/statistics &amp; numerical data ; Female ; Humans ; Male ; Motor Vehicles ; Pilot Projects ; Polycyclic Aromatic Hydrocarbons/*toxicity ; Telomere Homeostasis/*drug effects ; Telomere Shortening/*drug effects ; Vehicle Emissions/*toxicity ; },
abstract = {OBJECTIVE: The main objective of this pilot study was to gather preliminary information about how telomere length (TL) varies in relation to exposure to polycyclic aromatic hydrocarbons (PAHs) in children living in a highly polluted city.<br><br>METHODS: We conducted a cross-sectional study of children living in Fresno, California (n&#x200a;=&#x200a;14). Subjects with and without asthma were selected based on their annual average PAH level in the 12-months prior to their blood draw. We measured relative telomere length from peripheral blood mononuclear cells (PBMC).<br><br>RESULTS: We found an inverse linear relationship between average PAH level and TL (R&#x200a;=&#x200a;0.69), as well as between age and TL (R&#x200a;=&#x200a;0.21). Asthmatics had shorter mean telomere length than non-asthmatics (TLasthmatic&#x200a;=&#x200a;1.13, TLnon-asthmatic&#x200a;=&#x200a;1.29).<br><br>CONCLUSIONS: These preliminary findings suggest that exposure to ambient PAH may play a role in telomere shortening.Become familiar with previous evidence suggesting that telomere length may be a biomarker of air pollution-induced cytotoxicity.Summarize the new findings on the association between polycyclic aromatic hydrocarbon (PAH) exposure and telomere length in adolescents, including those with asthma.Discuss the implications for recommendations and policies to mitigate the health and respiratory effects of traffic-related air pollution.},
}
@article {pmid28486180,
year = {2017},
author = {Li, X and Wang, J and Zhou, J and Huang, P and Li, J},
title = {The association between post-traumatic stress disorder and shorter telomere length: A systematic review and meta-analysis.},
journal = {Journal of affective disorders},
volume = {218},
number = {},
pages = {322-326},
doi = {10.1016/j.jad.2017.03.048},
pmid = {28486180},
issn = {1573-2517},
mesh = {Adult ; Female ; Humans ; Male ; Stress Disorders, Post-Traumatic/*genetics ; Telomere/*physiology ; *Telomere Shortening ; },
abstract = {OBJECTIVE: Post-traumatic stress disorder (PTSD) is a common psychiatric disorder, which may accelerate aging. Many study have investigated the association between telomeres length and PTSD, but results from published studies are contradictory. Therefore, Meta-analysis approaches were conducted to give more precise estimate of relationship between telomere length and PTSD.<br><br>METHOD: We systematically reviewed the databases of PUBMED, PsycINFO, Medline(Ovid SP) and EMBASE for all articles on the association between telomere length and PTSD. Data were summarized by using random-effects in the meta-analysis. The heterogeneity among studies were examined by using Cochrane's Q statistic and I-squared.<br><br>RESULTS: Five eligible studies containing 3851 participants were included in our meta-analysis. Shorten telomere length was significantly associated with PTSD with mean difference of -0.19(95% CI: -0.27, -0.01; P<0.001) with I-square of 96%. The results from subgroup analysis demonstrated that shorter telomere length was significantly associated with PTSD across all gender groups, with mean difference of -0.15(95% CI: -0.29, -0.01; P=0.04) for female, mean difference of -0.17(95% CI: -0.19, -0.15; P<0.001) for male. Meanwhile, shorten telomere length was significantly associated with sexual assault(mean difference =-0.15, 95% CI: -0.29, -0.01), childhood trauma (mean difference =-0.08, 95% CI: -0.19, -0.07), but not combat (mean difference =-0.39, 95% CI: -0.83, 0.05).<br><br>CONCLUSION: Compared to the individuals without PTSD, individuals with PTSD have shorter telomere length, which has implications for early intervention and timely treatment to prevent future adverse health outcomes.},
}
@article {pmid28482745,
year = {2018},
author = {Oliveira, BS and Zunzunegui, MV and Quinlan, J and Batistuzzo de Medeiros, SR and Thomasini, RL and Guerra, RO},
title = {Lifecourse Adversity and Telomere Length in Older Women from Northeast Brazil.},
journal = {Rejuvenation research},
volume = {21},
number = {4},
pages = {294-303},
doi = {10.1089/rej.2017.1937},
pmid = {28482745},
issn = {1557-8577},
mesh = {Aged ; Alcoholism/pathology ; Brazil ; Educational Status ; Female ; Humans ; *Life Change Events ; Parents ; Regression Analysis ; Telomere Shortening/*genetics ; },
abstract = {We examined associations between adverse childhood experiences (ACEs) and shorter telomere length (TL) in 83 older women, including 42 women with less than secondary education and 41 with secondary or more education in a city of Northeast Brazil, a region with substantial socioeconomic inequalities. The low education sample was selected from a representative survey at local neighborhood health centers, while the high education group consisted of a convenience sample recruited by advertising in community centers and centers affiliated with the local university. Relative leukocyte TL was measured by quantitative polymerase chain reaction from blood samples. ACEs were self-reported. Spline linear regression was fitted to assess the strength of the associations between ACEs and TL. Among women with low education, median TL was 1.02 compared with 0.64 in the high education group (p = 0.0001). Natural log-transformed T/S ratio as the dependent variable was used in analysis. Women with low education had been exposed to more ACEs, and among them those experiencing two or more ACEs had longer TL than women exposed to ≤1 ACEs (p = 0.03); among women with high education, this difference was not significant (p = 0.49). In analyses adjusted by age, education, and parental abuse of alcohol, the linear trend of higher TL with increasing ACEs was confirmed (p = 0.02), and the mean difference in TL between groups remained significant (p = 0.002). The unexpected positive relationship between low education and ACEs with TL suggests that older adults who have survived harsh conditions prevailing in Northeast Brazil have the longest TL of their birth cohort.},
}
@article {pmid28482730,
year = {2017},
author = {Woody, A and Hamilton, K and Livitz, IE and Figueroa, WS and Zoccola, PM},
title = {Buccal telomere length and its associations with cortisol, heart rate variability, heart rate, and blood pressure responses to an acute social evaluative stressor in college students.},
journal = {Stress (Amsterdam, Netherlands)},
volume = {20},
number = {3},
pages = {249-257},
doi = {10.1080/10253890.2017.1328494},
pmid = {28482730},
issn = {1607-8888},
mesh = {Adolescent ; Biomarkers ; *Blood Pressure ; Cellular Senescence/genetics ; Female ; *Heart Rate ; Humans ; Hydrocortisone/*metabolism ; Male ; Mouth Mucosa/cytology/*metabolism ; Saliva/chemistry ; Stress, Psychological/*metabolism/physiopathology/psychology ; Students/psychology ; Telomere/*metabolism ; Young Adult ; },
abstract = {OBJECTIVE: Understanding the relationship between stress and telomere length (a marker of cellular aging) is of great interest for reducing aging-related disease and death. One important aspect of acute stress exposure that may underlie detrimental effects on health is physiological reactivity to the stressor.<br><br>METHODS: This study tested the relationship between buccal telomere length and physiological reactivity (salivary cortisol reactivity and total output, heart rate (HR) variability, blood pressure, and HR) to an acute psychosocial stressor in a sample of 77 (53% male) healthy young adults.<br><br>RESULTS: Consistent with predictions, greater reductions in HR variability (HRV) in response to a stressor and greater cortisol output during the study session were associated with shorter relative buccal telomere length (i.e. greater cellular aging). However, the relationship between cortisol output and buccal telomere length became non-significant when adjusting for medication use. Contrary to past findings and study hypotheses, associations between cortisol, blood pressure, and HR reactivity and relative buccal telomere length were not significant. Overall, these findings may indicate there are limited and mixed associations between stress reactivity and telomere length across physiological systems.},
}
@article {pmid28482095,
year = {2017},
author = {Lian, S and Meng, L and Yang, Y and Ma, T and Xing, X and Feng, Q and Song, Q and Liu, C and Tian, Z and Qu, L and Shou, C},
title = {PRL-3 promotes telomere deprotection and chromosomal instability.},
journal = {Nucleic acids research},
volume = {45},
number = {11},
pages = {6546-6571},
pmid = {28482095},
issn = {1362-4962},
mesh = {Animals ; COS Cells ; Carcinogenesis/genetics ; Cell Line, Tumor ; Cellular Senescence ; Chlorocebus aethiops ; *Chromosomal Instability ; Colonic Neoplasms/chemically induced/genetics ; DNA Damage ; Humans ; Mice, Inbred C57BL ; Mice, Transgenic ; Neoplasm Proteins/*physiology ; Protein Tyrosine Phosphatases/*physiology ; Shelterin Complex ; *Telomere Homeostasis ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Phosphatase of regenerating liver (PRL-3) promotes cell invasiveness, but its role in genomic integrity remains unknown. We report here that shelterin component RAP1 mediates association between PRL-3 and TRF2. In addition, TRF2 and RAP1 assist recruitment of PRL-3 to telomeric DNA. Silencing of PRL-3 in colon cancer cells does not affect telomere integrity or chromosomal stability, but induces reactive oxygen species-dependent DNA damage response and senescence. However, overexpression of PRL-3 in colon cancer cells and primary fibroblasts promotes structural abnormalities of telomeres, telomere deprotection, DNA damage response, chromosomal instability and senescence. Furthermore, PRL-3 dissociates RAP1 and TRF2 from telomeric DNA in vitro and in cells. PRL-3-promoted telomere deprotection, DNA damage response and senescence are counteracted by disruption of PRL-3-RAP1 complex or expression of ectopic TRF2. Examination of clinical samples showed that PRL-3 status positively correlates with telomere deprotection and senescence. PRL-3 transgenic mice exhibit hallmarks of telomere deprotection and senescence and are susceptible to dextran sodium sulfate-induced colon malignancy. Our results uncover a novel role of PRL-3 in tumor development through its adverse impact on telomere homeostasis.},
}
@article {pmid28479693,
year = {2017},
author = {Chatterjee, S},
title = {Telomeres in health and disease.},
journal = {Journal of oral and maxillofacial pathology : JOMFP},
volume = {21},
number = {1},
pages = {87-91},
pmid = {28479693},
issn = {0973-029X},
abstract = {Telomeres are repetitive ribonucleoprotein complexes present at ends of chromosomes. To synthesize this manuscript, a thorough literature search was done using PubMed, MEDLINE and Cochrane review for English-language literature and data available from the period of 2005-2016 were analyzed for manuscript writing. Telomeres help in maintaining the cellular health, inbuilt cellular mechanisms, metabolism and normal cell cycle. Telomerase is a specialized enzyme that possesses catalytic subunits - reverse transcriptase, Terc and dyskerin. Mutations affecting telomere or any component of telomerase enzyme result in disorders such as dyskeratosis congenita, aplastic anemia, myelodysplastic syndromes and leukemias. Thus, it is important to understand the telomere biology so as to deal with normal physiologic processes such as apoptosis, aging and senescence and tumor development.},
}
@article {pmid28477298,
year = {2017},
author = {Li, Y and Deng, B and Ouyang, N and Yuan, P and Zheng, L and Wang, W},
title = {Telomere length is short in PCOS and oral contraceptive does not affect the telomerase activity in granulosa cells of patients with PCOS.},
journal = {Journal of assisted reproduction and genetics},
volume = {34},
number = {7},
pages = {849-859},
pmid = {28477298},
issn = {1573-7330},
mesh = {Adult ; Contraceptives, Oral/*pharmacology ; Female ; Fertilization in Vitro ; Granulosa Cells/drug effects/*enzymology/ultrastructure ; Humans ; Infertility, Female/complications/enzymology/genetics ; Polycystic Ovary Syndrome/complications/enzymology/*genetics ; Retrospective Studies ; Telomerase/genetics/metabolism/*physiology ; Telomere Homeostasis/drug effects/genetics ; Treatment Outcome ; },
abstract = {PURPOSE: Our study aimed to investigate the association of telomerase activity (TA) and telomere length (TL) in granulosa cells (GCs) with IVF outcomes of polycystic ovary syndrome (PCOS) patients, and the effects of oral contraceptive pill (OCP) pretreatment on these two parameters.<br><br>METHODS: One hundred sixty-three infertile women were enrolled and divided into a PCOS group (n&#xa0;=&#xa0;65) and a non-PCOS group (n&#xa0;=&#xa0;98). The PCOS group was further divided into an OCP pretreatment group (n&#xa0;=&#xa0;35) and a non-OCP pretreatment group (n&#xa0;=&#xa0;30), a TA <0.070 group (n&#xa0;=&#xa0;34) and a TA &#x2265;0.070 group (n&#xa0;=&#xa0;31), and a TL <1 group (n&#xa0;=&#xa0;41) and a TL &#x2265;1 group (n&#xa0;=&#xa0;24), respectively.<br><br>RESULTS: No obvious differences were observed in TA between these groups. The TL was 0.971 in PCOS group and 1.118 in non-PCOS group (P&#xa0;=&#xa0;0.005). The patients with TL &#x2265;1 accounted for 36.9% in PCOS group and 54.1% in non-PCOS group (P&#xa0;=&#xa0;0.032). The average duration of infertility for PCOS patients was 5&#xa0;years in TA <0.070 group and 4&#xa0;years in TA &#x2265;0.070 group (P&#xa0;=&#xa0;0.038), and 5&#xa0;years in TL <1 group and 3&#xa0;years in TL &#x2265;1 group (P&#xa0;=&#xa0;0.006), respectively. No obvious differences were observed in IVF outcomes between these groups. No obvious differences were observed in TA, TL, or IVF outcomes between OCP pretreatment group and non-OCP pretreatment group in PCOS patients.<br><br>CONCLUSIONS: Shorter TL was found in PCOS patients. The TA levels did not change significantly in PCOS patients. PCOS patients with a lower TA level and shorter telomeres had an earlier onset of infertility symptoms. No predictive value was found for TA and TL in terms of embryo quality or IVF outcomes in PCOS patients, and no effect OCP pretreatment was observed on either TA and TL.},
}
@article {pmid28472973,
year = {2017},
author = {Picarelli, MM and Danzmann, LC and Grun, LK and Júnior, NTR and Lavandovsky, P and Guma, FTCR and Stein, RT and Barbé-Tuana, F and Jones, MH},
title = {Arterial stiffness by oscillometric device and telomere lenght in juvenile idiopathic artrhitis with no cardiovascular risk factors: a cross-sectional study.},
journal = {Pediatric rheumatology online journal},
volume = {15},
number = {1},
pages = {34},
pmid = {28472973},
issn = {1546-0096},
mesh = {Adolescent ; Arthritis, Juvenile/epidemiology/*metabolism/physiopathology ; Cardiovascular Diseases/epidemiology ; Case-Control Studies ; Child ; Cross-Sectional Studies ; Female ; Humans ; Male ; Pulse Wave Analysis ; Risk Factors ; Telomere/*metabolism ; *Vascular Stiffness ; Young Adult ; },
abstract = {BACKGROUND: Advances in juvenile idiopathic arthritis (JIA) treatment is promoting free disease survival. Cardiovascular disease (CVD) may emerge as an important cause of morbidity and mortality. Pulse wave velocity (PWV), a surrogate marker of arterial stiffness, and telomere length (TL) are considered as potential predictors of CVD and its outcomes. The study aim was to assess PWV, TL in a JIA population and to test its correlation. In a cross sectional study, 24 JIA patients, 21 controls for TL and 20 controls for PWV were included. PWV was assessed by an oscillometric device. TL was assessed by qPCR. JIA activity was accessed by JADAS-27. Smoking, diabetes, obesity, renal impairment, hypertension, dyslipidemia and inflammatory diseases were excluded.<br><br>FINDINGS: Between cases and controls for TL, there was significant difference in age. No differences in gender, ethnics and bone mass index between JIA and control groups for PWV and TL. The JADAS-27 median was 8. TL was significantly reduced in JIA (0.85&#x2009;&#xb1;&#x2009;0.34 vs. 1. 67&#x2009;&#xb1;&#x2009;1.38, P&#x2009;=&#x2009;0.025). When age adjusted by ANCOVA, the difference remained significant (P&#x2009;=&#x2009;0,032). PWV was normal in all patients (5.1&#x2009;&#xb1;&#x2009;0.20&#xa0;m/s vs. 4.98&#x2009;&#xb1;&#x2009;0.06&#xa0;m/s, P&#x2009;=&#x2009;0, 66). There was no correlation between TL, PWV or JADAS-27.<br><br>CONCLUSION: Compared to controls, JIA with high disease activity and no CVD risk factors have shorter telomeres and normal PWV. As far as we know, this first time this correlation is being tested in rheumatic disease and in paediatrics.},
}
@article {pmid28471262,
year = {2018},
author = {Cheng, L and Cui, M and Rong, YS},
title = {MTV sings jubilation for telomere biology in Drosophila.},
journal = {Fly},
volume = {12},
number = {1},
pages = {41-45},
pmid = {28471262},
issn = {1933-6942},
mesh = {Animals ; Chromosomal Proteins, Non-Histone/metabolism ; DNA, Single-Stranded/metabolism ; Drosophila Proteins/chemistry/*metabolism ; Drosophila melanogaster/*metabolism ; Multiprotein Complexes/chemistry/*metabolism ; Retroelements ; Telomere/chemistry/*metabolism ; Telomere-Binding Proteins/metabolism ; Two-Hybrid System Techniques ; },
abstract = {Telomere protects the ends of linear chromosomes. Telomere dysfunction fuels genome instability that can lead to diseases such as cancer. For over 30 years, Drosophila has fascinated the field as the only major model organism that does not rely on the conserved telomerase enzyme for end protection. Instead of short DNA repeats at chromosome ends, Drosophila has domesticated retrotransposons. In addition, telomere protection can be entirely sequence-independent under normal laboratory conditions, again dissimilar to what has been established for telomerase-maintained systems. Despite these major differences, recent studies from us and others have revealed remarkable similarities between the 2 systems. In particular, with the identification of the MTV complex as an ssDNA binding complex essential for telomere integrity in Drosophila (Zhang et al. 2016 Plos Genetics), we have now established several universal principles that are intrinsic to chromosome extremities but independent of the underlying DNA sequences or the telomerase enzyme. Telomere studies in Drosophila will continue to yield fundamental insights that are instrumental to the understanding of the evolution of telomere and telomeric functions.},
}
@article {pmid28468913,
year = {2017},
author = {Boonekamp, JJ and Bauch, C and Mulder, E and Verhulst, S},
title = {Does oxidative stress shorten telomeres?.},
journal = {Biology letters},
volume = {13},
number = {5},
pages = {},
pmid = {28468913},
issn = {1744-957X},
mesh = {Animals ; Biomarkers ; *Oxidative Stress ; Telomere ; Telomere Shortening ; },
abstract = {Oxidative stress shortens telomeres in cell culture, but whether oxidative stress explains variation in telomere shortening in vivo at physiological oxidative stress levels is not well known. We therefore tested for correlations between six oxidative stress markers and telomere attrition in nestling birds (jackdaws Corvus monedula) that show a high rate of telomere attrition in early life. Telomere attrition was measured between ages 5 and 30 days, and was highly variable (average telomere loss: 323 bp, CV = 45%). Oxidative stress markers were measured in blood at age 20 days and included markers of oxidative damage (TBARS, dROMs and GSSG) and markers of antioxidant protection (GSH, redox state, uric acid). Variation in telomere attrition was not significantly related to these oxidative stress markers (|r| ≤ 0.08, n = 87). This finding raises the question whether oxidative stress accelerates telomere attrition in vivo The accumulation of telomere attrition over time depends both on the number of cell divisions and on the number of base pairs lost per DNA replication and, based on our findings, we suggest that in a growing animal cell proliferation, dynamics may be more important for explaining variation in telomere attrition than oxidative stress.},
}
@article {pmid28468887,
year = {2017},
author = {Gilbert-Girard, S and Gravel, A and Artusi, S and Richter, SN and Wallaschek, N and Kaufer, BB and Flamand, L},
title = {Stabilization of Telomere G-Quadruplexes Interferes with Human Herpesvirus 6A Chromosomal Integration.},
journal = {Journal of virology},
volume = {91},
number = {14},
pages = {},
pmid = {28468887},
issn = {1098-5514},
support = {MOP_123214//CIHR/Canada ; },
mesh = {Acridines/metabolism ; Cell Line ; Circular Dichroism ; *G-Quadruplexes ; Herpesvirus 6, Human/*physiology ; Humans ; *Nucleic Acid Conformation ; Telomere/*chemistry/*metabolism ; *Virus Integration ; },
abstract = {Human herpesviruses 6A and 6B (HHV-6A/B) can integrate their genomes into the telomeres of human chromosomes using a mechanism that remains poorly understood. To achieve a better understanding of the HHV-6A/B integration mechanism, we made use of BRACO-19, a compound that stabilizes G-quadruplex secondary structures and prevents telomere elongation by the telomerase complex. First, we analyzed the folding of telomeric sequences into G-quadruplex structures and their binding to BRACO-19 using G-quadruplex-specific antibodies and surface plasmon resonance. Circular dichroism studies indicate that BRACO-19 modifies the conformation and greatly stabilizes the G-quadruplexes formed in G-rich telomeric DNA. Subsequently we assessed the effects of BRACO-19 on the HHV-6A initial phase of infection. Our results indicate that BRACO-19 does not affect entry of HHV-6A DNA into cells. We next investigated if stabilization of G-quadruplexes by BRACO-19 affected HHV-6A's ability to integrate its genome into host chromosomes. Incubation of telomerase-expressing cells with BRACO-19, such as HeLa and MCF-7, caused a significant reduction in the HHV-6A integration frequency (P < 0.002); in contrast, BRACO-19 had no effect on HHV-6 integration frequency in U2OS cells that lack telomerase activity and elongate their telomeres through alternative lengthening mechanisms. Our data suggest that the fluidity of telomeres is important for efficient chromosomal integration of HHV-6A and that interference with telomerase activity negatively affects the generation of cellular clones containing integrated HHV-6A.IMPORTANCE HHV-6A/B can integrate their genomes into the telomeres of infected cells. Telomeres consist of repeated hexanucleotides (TTAGGG) of various lengths (up to several kilobases) and end with a single-stranded 3' extension. To avoid recognition and induce a DNA damage response, the single-stranded overhang folds back on itself and forms a telomeric loop (T-loop) or adopts a tertiary structure, referred to as a G-quadruplex. In the current study, we have examined the effects of a G-quadruplex binding and stabilizing agent, BRACO-19, on HHV-6A chromosomal integration. By stabilizing G-quadruplex structures, BRACO-19 affects the ability of the telomerase complex to elongate telomeres. Our results indicate that BRACO-19 reduces the number of clones harboring integrated HHV-6A. This study is the first of its kind and suggests that telomerase activity is essential to restore a functional telomere of adequate length following HHV-6A integration.},
}
@article {pmid28462056,
year = {2017},
author = {Nettle, D and Bateson, M},
title = {Detecting telomere elongation in longitudinal datasets: analysis of a proposal by Simons, Stulp and Nakagawa.},
journal = {PeerJ},
volume = {5},
number = {},
pages = {e3265},
pmid = {28462056},
issn = {2167-8359},
support = {NC/K000802/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; },
abstract = {Telomere shortening has emerged as an important biomarker of aging. Longitudinal studies consistently find that, although telomere length shortens over time on average, there is a subset of individuals for whom telomere length is observed to increase. This apparent lengthening could either be a genuine biological phenomenon, or simply due to measurement and sampling error. Simons, Stulp &amp; Nakagawa (2014) recently proposed a statistical test for detecting when the amount of apparent lengthening in a dataset exceeds that which should be expected due to error, and thus indicating that genuine elongation may be operative in some individuals. However, the test is based on a restrictive assumption, namely that each individual's true rate of telomere change is constant over time. It is not currently known whether this assumption is true. Here we show, using simulated datasets, that with perfect measurement and large sample size, the test has high power to detect true lengthening as long as the true rate of change is either constant, or moderately stable, over time. If the true rate of change varies randomly from year to year, the test systematically returns type-II errors (false negatives; that is, failures to detect lengthening even when a substantial fraction of the population truly lengthens each year). We also consider the impact of measurement error. Using estimates of the magnitude of annual attrition and of measurement error derived from the human telomere literature, we show that power of the test is likely to be low in several empirically-realistic scenarios, even in large samples. Thus, whilst a significant result of the proposed test is likely to indicate that true lengthening is present in a data set, type-II errors are a likely outcome, either if measurement error is substantial, and/or the true rate of telomere change varies substantially over time within individuals.},
}
@article {pmid28459963,
year = {2017},
author = {Mons, U and Müezzinler, A and Schöttker, B and Dieffenbach, AK and Butterbach, K and Schick, M and Peasey, A and De Vivo, I and Trichopoulou, A and Boffetta, P and Brenner, H},
title = {Leukocyte Telomere Length and All-Cause, Cardiovascular Disease, and Cancer Mortality: Results From Individual-Participant-Data Meta-Analysis of 2 Large Prospective Cohort Studies.},
journal = {American journal of epidemiology},
volume = {185},
number = {12},
pages = {1317-1326},
pmid = {28459963},
issn = {1476-6256},
support = {R03 CA139586/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA134958/CA/NCI NIH HHS/United States ; R01 CA163451/CA/NCI NIH HHS/United States ; R03 CA133914/CA/NCI NIH HHS/United States ; R01 AR059073/AR/NIAMS NIH HHS/United States ; R03 CA132175/CA/NCI NIH HHS/United States ; R01 CA065725/CA/NCI NIH HHS/United States ; R01 CA082838/CA/NCI NIH HHS/United States ; U54 CA155626/CA/NCI NIH HHS/United States ; R01 HL034594/HL/NHLBI NIH HHS/United States ; R03 CA132190/CA/NCI NIH HHS/United States ; K07 CA140790/CA/NCI NIH HHS/United States ; R01 HL088521/HL/NHLBI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; R01 HL060712/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Aged ; Cardiovascular Diseases/*mortality ; Cause of Death ; Europe ; Female ; Humans ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Neoplasms/*mortality ; Proportional Hazards Models ; Prospective Studies ; Telomere/*ultrastructure ; United States ; },
abstract = {We studied the associations of leukocyte telomere length (LTL) with all-cause, cardiovascular disease, and cancer mortality in 12,199 adults participating in 2 population-based prospective cohort studies from Europe (ESTHER) and the United States (Nurses' Health Study). Blood samples were collected in 1989-1990 (Nurses' Health Study) and 2000-2002 (ESTHER). LTL was measured by quantitative polymerase chain reaction. We calculated z scores for LTL to standardize LTL measurements across the cohorts. Cox proportional hazards regression models were used to calculate relative mortality according to continuous levels and quintiles of LTL z scores. The hazard ratios obtained from each cohort were subsequently pooled by meta-analysis. Overall, 2,882 deaths were recorded during follow-up (Nurses' Health Study, 1989-2010; ESTHER, 2000-2015). LTL was inversely associated with age in both cohorts. After adjustment for age, a significant inverse trend of LTL with all-cause mortality was observed in both cohorts. In random-effects meta-analysis, age-adjusted hazard ratios for the shortest LTL quintile compared with the longest were 1.23 (95% confidence interval (CI): 1.04, 1.46) for all-cause mortality, 1.29 (95% CI: 0.83, 2.00) for cardiovascular mortality, and 1.10 (95% CI: 0.88, 1.37) for cancer mortality. In this study population with an age range of 43-75 years, we corroborated previous evidence suggesting that LTL predicts all-cause mortality beyond its association with age.},
}
@article {pmid28459868,
year = {2017},
author = {Vazirpanah, N and Verhagen, FH and Rothova, A and Missotten, TOAR and van Velthoven, M and Den Hollander, AI and Hoyng, CB and Radstake, TRDJ and Broen, JCA and Kuiper, JJW},
title = {Aberrant leukocyte telomere length in Birdshot Uveitis.},
journal = {PloS one},
volume = {12},
number = {5},
pages = {e0176175},
pmid = {28459868},
issn = {1932-6203},
mesh = {Female ; Gene Expression ; Genetic Predisposition to Disease ; Humans ; Leukocytes/*immunology ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; Telomere Shortening ; Uveitis/genetics/*metabolism ; },
abstract = {PURPOSE: Birdshot Uveitis (BU) is an archetypical chronic inflammatory eye disease, with poor visual prognosis, that provides an excellent model for studying chronic inflammation. BU typically affects patients in the fifth decade of life. This suggests that it may represent an age-related chronic inflammatory disease, which has been linked to increased erosion of telomere length of leukocytes.<br><br>METHODS: To study this in detail, we exploited a sensitive standardized quantitative real-time polymerase chain reaction to determine the peripheral blood leukocyte telomere length (LTL) in 91 genotyped Dutch BU patients and 150 unaffected Dutch controls.<br><br>RESULTS: Although LTL erosion rates were very similar between BU patients and healthy controls, we observed that BU patients displayed longer LTL, with a median of log (LTL) = 4.87 (= 74131 base pair) compared to 4.31 (= 20417 base pair) in unaffected controls (P<0.0001). The cause underpinning the difference in LTL could not be explained by clinical parameters, immune cell-subtype distribution, nor genetic predisposition based upon the computed weighted genetic risk score of genotyped validated variants in TERC, TERT, NAF1, OBFC1 and RTEL1.<br><br>CONCLUSIONS: These findings suggest that BU is accompanied by significantly longer LTL.},
}
@article {pmid28454108,
year = {2017},
author = {Jones, RE and Grimstead, JW and Sedani, A and Baird, D and Upadhyaya, M},
title = {Telomere erosion in NF1 tumorigenesis.},
journal = {Oncotarget},
volume = {8},
number = {25},
pages = {40132-40139},
pmid = {28454108},
issn = {1949-2553},
support = {18246/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Carcinogenesis/genetics ; Comparative Genomic Hybridization ; Humans ; Loss of Heterozygosity ; Neoplasm Grading ; Neurilemmoma/genetics/pathology ; Neurofibroma/genetics/pathology ; Neurofibromatosis 1/*genetics/pathology ; Neurofibromin 1/*genetics ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Neurofibromatosis type 1 (NF1; MIM# 162200) is a familial cancer syndrome that affects 1 in 3,500 individuals worldwide and is inherited in an autosomal dominant fashion. Malignant Peripheral Nerve Sheath Tumors (MPNSTs) represent a significant cause of morbidity and mortality in NF1 and currently there is no treatment or definite prognostic biomarkers for these tumors. Telomere shortening has been documented in numerous tumor types. Short dysfunctional telomeres are capable of fusion and it is considered that the ensuing genomic instability may facilitate clonal evolution and the progression to malignancy. To evaluate the potential role of telomere dysfunction in NF1-associated tumors, we undertook a comparative analysis of telomere length in samples derived from 10 cutaneous and 10 diffused plexiform neurofibromas, and 19 MPNSTs. Telomere length was determined using high-resolution Single Telomere Length Analysis (STELA). The mean Xp/Yp telomere length detected in MPNSTs, at 3.282 kb, was significantly shorter than that observed in both plexiform neurofibromas (5.793 kb; [p = 0.0006]) and cutaneous neurofibromas (6.141 kb; [p = 0.0007]). The telomere length distributions of MPNSTs were within the length-ranges in which telomere fusion is detected and that confer a poor prognosis in other tumor types. These data indicate that telomere length may play a role in driving genomic instability and clonal progression in NF1-associated MPNSTs.},
}
@article {pmid28452859,
year = {2018},
author = {Duan, XF and Zhao, Q},
title = {TERT-mediated and ATRX-mediated Telomere Maintenance and Neuroblastoma.},
journal = {Journal of pediatric hematology/oncology},
volume = {40},
number = {1},
pages = {1-6},
doi = {10.1097/MPH.0000000000000840},
pmid = {28452859},
issn = {1536-3678},
mesh = {Humans ; Neuroblastoma/etiology/*genetics/pathology/ultrastructure ; Prognosis ; Proto-Oncogene Mas ; Telomerase/*physiology ; Telomere/*metabolism/ultrastructure ; X-linked Nuclear Protein/*physiology ; },
abstract = {Neuroblastomas (NB) are one of the most common extracranial solid tumors in children, and they frequently display high heterogeneity in the disease course. With ongoing research, more information regarding the genetic etiology and molecular mechanisms underlying these contrasting phenotypes is being uncovered. The proto-oncogene MYCN is amplified in approximately 20% of NB cases and is considered a indicator of poor prognosis and an indicator of high-risk NB. The poor prognosis of high risk NB is incompletely explained by MYCN amplification. Recently, massive parallel sequencing studies reported several relatively common gene alterations, such as ATRX mutation and TERT rearrangement that are involved in telomere maintenance through telomerase activity and alternative lengthening of telomeres. Thus, these are important for understanding the etiology and molecular pathogenesis of NB, and hence, for identifying diagnostic and treatment markers. Development of telomerase inhibitors and identification of alternative lengthening of telomeres related targets will contribute to the individualized treatment for high-risk NB. In this mini-review, we will discuss the research progress of TERT-mediated and ATRX-mediated telomere maintenance and NB, especially high-risk tumors.},
}
@article {pmid28450453,
year = {2017},
author = {Lawrimore, J and Barry, TM and Barry, RM and York, AC and Friedman, B and Cook, DM and Akialis, K and Tyler, J and Vasquez, P and Yeh, E and Bloom, K},
title = {Microtubule dynamics drive enhanced chromatin motion and mobilize telomeres in response to DNA damage.},
journal = {Molecular biology of the cell},
volume = {28},
number = {12},
pages = {1701-1711},
pmid = {28450453},
issn = {1939-4586},
support = {P30 CA016086/CA/NCI NIH HHS/United States ; R37 GM032238/GM/NIGMS NIH HHS/United States ; T32 GM007092/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatin/metabolism/*physiology ; Cytoskeleton ; *DNA Damage ; DNA Repair ; Gene Expression Regulation ; Interphase/genetics ; Microtubules/*metabolism/physiology ; Nuclear Envelope/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/genetics ; Telomere/metabolism/*physiology ; },
abstract = {Chromatin exhibits increased mobility on DNA damage, but the biophysical basis for this behavior remains unknown. To explore the mechanisms that drive DNA damage-induced chromosome mobility, we use single-particle tracking of tagged chromosomal loci during interphase in live yeast cells together with polymer models of chromatin chains. Telomeres become mobilized from sites on the nuclear envelope and the pericentromere expands after exposure to DNA-damaging agents. The magnitude of chromatin mobility induced by a single double-strand break requires active microtubule function. These findings reveal how relaxation of external tethers to the nuclear envelope and internal chromatin-chromatin tethers, together with microtubule dynamics, can mobilize the genome in response to DNA damage.},
}
@article {pmid28450121,
year = {2017},
author = {Tucker, LA},
title = {Physical activity and telomere length in U.S. men and women: An NHANES investigation.},
journal = {Preventive medicine},
volume = {100},
number = {},
pages = {145-151},
doi = {10.1016/j.ypmed.2017.04.027},
pmid = {28450121},
issn = {1096-0260},
mesh = {Adult ; Aged ; Aged, 80 and over ; *Cellular Senescence ; Cross-Sectional Studies ; Exercise/*physiology ; Female ; Humans ; Leukocytes/physiology ; Male ; Middle Aged ; Nutrition Surveys ; Self Report ; Telomere/*physiology ; },
abstract = {The principal objective was to determine the extent to which physical activity (PA) accounts for differences in leukocyte telomere length (LTL) in a large random sample of U.S. adults. Another purpose was to assess the extent to which multiple demographic and lifestyle covariates affect the relationship between PA and LTL. A total of 5823 adults from the National Health and Nutrition Examination Survey (NHANES 1999-2002) were studied cross-sectionally. Employing the quantitative polymerase chain reaction method, LTL was compared to standard reference DNA. PA was indexed using MET-minutes using self-reported frequency, intensity, and duration of participation in 62 physical activities. Covariates were controlled statistically. Telomeres were 15.6 base pairs shorter for each year of chronological age (F=723.2, P<0.0001). PA was inversely related to LTL after adjusting for all the covariates (F=8.3, P=0.0004). Telomere base pair differences between adults with High activity and those in the Sedentary, Low, and Moderate groups were 140, 137, and 111, respectively. Adults with High activity were estimated to have a biologic aging advantage of 9years (140 base pairs÷15.6) over Sedentary adults. The difference in cell aging between those with High and Low activity was also significant, 8.8years, as was the difference between those with High and Moderate PA (7.1years). Overall, PA was significantly and meaningfully associated with telomere length in U.S. men and women. Evidently, adults who participate in high levels of PA tend to have longer telomeres, accounting for years of reduced cellular aging compared to their more sedentary counterparts.},
}
@article {pmid28449562,
year = {2017},
author = {Cui, Y and Prabhu, VV and Nguyen, TB and Devi, SM and Chung, YC},
title = {Longer Telomere Length of T lymphocytes in Patients with Early and Chronic Psychosis.},
journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology},
volume = {15},
number = {2},
pages = {146-152},
pmid = {28449562},
issn = {1738-1088},
abstract = {OBJECTIVE: To investigate pathological conditions that act as sources of pro-inflammatory cytokines and cytotoxic substances to examine telomere length (TL) in patients with either early (duration of illness [DI] ≤5 years) or chronic (DI >5 years) psychosis using T lymphocytes.<br><br>METHODS: Based on these factors and the important role that T lymphocytes play in inflammation, the present study measured the TL of T lymphocytes in patients with either early or chronic psychosis. Additionally, smoking, metabolic syndrome, depression, and cognitive functioning were assessed to control for confounding effects.<br><br>RESULTS: TL was significantly longer in patients with early and chronic psychosis than in healthy control subjects and, moreover, the significance of these findings remained after controlling for age, smoking, metabolic syndrome, DI, chlorpromazine-equivalent dose, and cognitive functioning (F=9.57, degree of freedom=2, p<0.001). Additionally, the DI, chlorpromazine-equivalent doses, and the five-factor scores of the Positive and Negative Syndrome Scale were not significantly correlated with the TL of T lymphocytes in either all patients or each psychosis group.<br><br>CONCLUSION: Possible mechanisms underlying the effects of antipsychotic medications on telomerase are discussed in the present study, but further studies measuring both telomerase activity and TL using a prospective design will be required.},
}
@article {pmid28448823,
year = {2017},
author = {Lin, N and Mu, X and Wang, G and Ren, Y and Su, S and Li, Z and Wang, B and Tao, S},
title = {Accumulative effects of indoor air pollution exposure on leukocyte telomere length among non-smokers.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {227},
number = {},
pages = {1-7},
doi = {10.1016/j.envpol.2017.04.054},
pmid = {28448823},
issn = {1873-6424},
mesh = {Air Pollution/statistics &amp; numerical data ; Air Pollution, Indoor/analysis/*statistics &amp; numerical data ; Cooking ; Environmental Exposure/*analysis/statistics &amp; numerical data ; Family Characteristics ; Female ; Humans ; Leukocytes/*drug effects ; Male ; Middle Aged ; Risk Factors ; Telomere/drug effects ; Tobacco Smoke Pollution/adverse effects/*statistics &amp; numerical data ; },
abstract = {Indoor air pollution is an important environmental factor that contributes to the burden of various diseases. Long-term exposure to ambient air pollution is associated with telomere shortening. However, the association between chronic indoor air pollution from household fuel combustion and leukocyte telomere length has not been studied. In our study, 137 cancer-free non-smokers were recruited. Their exposure levels to indoor air pollution from 1985 to 2014 were assessed using a face-to-face interview questionnaire, and leukocyte telomere length (LTL) was measured using a monochrome multiplex quantitative PCR method. Accumulative exposure to solid fuel usage for cooking was negatively correlated with LTL. The LTL of residents who were exposed to solid fuel combustion for three decades (LTL = 0.70 ± 0.17) was significantly shorter than that of other populations. In addition, education and occupation were related to both exposure to solid fuel and LTL. Sociodemographic factors may play a mediating role in the correlation between leukocyte telomere length and environmental exposure to indoor air pollution. In conclusion, long-term exposure to indoor air pollution may cause LTL dysfunction.},
}
@article {pmid28448821,
year = {2017},
author = {Solomon, Z and Tsur, N and Levin, Y and Uziel, O and Lahav, M and Ohry, A},
title = {The implications of war captivity and long-term psychopathology trajectories for telomere length.},
journal = {Psychoneuroendocrinology},
volume = {81},
number = {},
pages = {122-128},
doi = {10.1016/j.psyneuen.2017.04.004},
pmid = {28448821},
issn = {1873-3360},
mesh = {Aged ; Case-Control Studies ; Depression/diagnosis/*physiopathology ; Female ; Humans ; Leukocytes/physiology ; Longitudinal Studies ; Male ; Middle Aged ; Prisoners of War/*psychology ; Prospective Studies ; Stress Disorders, Post-Traumatic/diagnosis/*physiopathology ; Telomere Shortening/*physiology ; Time Factors ; },
abstract = {BACKGROUND: Previous findings have demonstrated the link between trauma, its psychopathological aftermath and cellular aging, as reflected in telomere length. However, as long-term examinations of psychopathology following trauma are scarce, very little is known regarding the repercussions of depression and PTSD trajectories of psychopathology for telomeres. The current study examined the implications of war captivity and depression/PTSD trajectories on telomere length.<br><br>METHODS: Ninety-nine former prisoners of war (ex-POWs) from the 1973 Yom Kippur War were evaluated for depression and PTSD at 18, 30, 35 and 42 years after the war. Data on leukocyte telomere length of ex-POWs and 79 controls was collected 42 years after the war.<br><br>RESULTS: Ex-POWs had shorter telomeres compared to controls (Cohen's d=.5 indicating intermediate effect). Ex-POWs with chronic depression had shorter telomeres compared to those with delayed onset of depression (Cohen's d=4.89), and resilient ex-POWs (Cohen's d= 3.87), indicating high effect sizes. PTSD trajectories were not implicated in telomere length (Partial eta[2]=.16 and p=.11).<br><br>CONCLUSION: The findings suggest that the detrimental ramifications of war captivity are extensive, involving premature cellular senesces. These findings further point to the wear-and-tear effect of long-term depression, but not PTSD, on telomere length. Explanations for the findings are discussed.},
}
@article {pmid28446663,
year = {2017},
author = {Faust, HE and Golden, JA and Rajalingam, R and Wang, AS and Green, G and Hays, SR and Kukreja, J and Singer, JP and Wolters, PJ and Greenland, JR},
title = {Short lung transplant donor telomere length is associated with decreased CLAD-free survival.},
journal = {Thorax},
volume = {72},
number = {11},
pages = {1052-1054},
pmid = {28446663},
issn = {1468-3296},
support = {IK2 CX001034/CX/CSRD VA/United States ; P01 HL108794/HL/NHLBI NIH HHS/United States ; T32 HL007185/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Aged ; Biomarkers/metabolism ; California ; Cohort Studies ; Female ; Graft Rejection/*genetics ; Graft Survival/*genetics ; Humans ; *Living Donors ; Lung Transplantation/*adverse effects/mortality ; Male ; Middle Aged ; Risk Assessment ; Risk Factors ; Telomere/*genetics ; Telomere Shortening/*genetics ; *Transplant Recipients ; Treatment Outcome ; },
abstract = {Telomere length (TL) decreases with cellular ageing and biological stressors. As advanced donor and recipient ages are risk factors for chronic lung allograft dysfunction (CLAD), we hypothesised that decreased age-adjusted donor TL would predict earlier onset of CLAD. Shorter donor TL was associated with increased risk of CLAD or death (HR 1.26 per 1 kb TL decrease, 95% CI 1.03 to 1.54), particularly for young donors. Recipient TL was associated with cytopenias but not CLAD. Shorter TL was also seen in airway epithelium for subjects progressing to CLAD (p=0.02). Allograft TL may contribute to CLAD pathogenesis and facilitate risk stratification.},
}
@article {pmid28446302,
year = {2017},
author = {Wang, Y and Xu, RR and DU, YJ and Wang, JY and Liu, K and Zheng, W},
title = {[Telomere Length, Expression of MRE11 and Ku80 in Patients with Aplastic Anemia and Their Correlation with Pathogenesis].},
journal = {Zhongguo shi yan xue ye xue za zhi},
volume = {25},
number = {2},
pages = {503-509},
doi = {10.7534/j.issn.1009-2137.2017.02.036},
pmid = {28446302},
issn = {1009-2137},
mesh = {Anemia, Aplastic/*genetics/metabolism ; Case-Control Studies ; Disease Progression ; Humans ; Ku Autoantigen/*metabolism ; MRE11 Homologue Protein/*metabolism ; RNA, Messenger ; Real-Time Polymerase Chain Reaction ; Telomere ; *Telomere Shortening ; },
abstract = {OBJECTIVE: To detect the expression levels of MRE11 and Ku80 mRNA, and telomere length in bone marrow mononuclear cells of aplastic anemia(AA) patients, and to explore their correlation with pathogenesis of aplastic anemia.<br><br>METHODS: Bone marrow mononuclear cells were collected from 40 cases of AA and 20 normal controls for detecting mRNA expression of MRE11 and Ku80 and telomere length by using real-time quantitative polymerase chain reaction (qPCR), then MRE11, Ku80 and telomere length were analyzed for their correlation.<br><br>RESULTS: As compared with controls, the expression levels of MRE11 and Ku80 in patients with AA were significantly reduced, and the telomere length in patients with AA was obviously shortened, respectively (P<0. 05). The telomere length was significantly shorter in the persons aged &#x2265;45 years in comparison with the AA patients and normal control younger than 45 years old (P<0.05). For the AA patients older than or equal to 45 years and less than 45 years in comparison with the controls at the same age, the telomere length was significantly shorter(P<0.05). The expression levels of MRE11 and Ku80 didn't correlate with telomere length (P>0.05). The mRNA expression level of MRE11 correlated positively and significantly with that of Ku80 (r=0.863, P<0.05).<br><br>CONCLUSION: The change of telomere length may play an important role in the pathogenesis and progression of aplastic anemia. The lower expression of MRE11 and Ku80 may be involved in the pathogenesis of aplastic anemia.},
}
@article {pmid28444911,
year = {2017},
author = {Yuan, D},
title = {Response to the letter to the editor by D. Yuan: "Risk of high altitude pulmonary edema and telomere length".},
journal = {The journal of gene medicine},
volume = {19},
number = {5},
pages = {},
doi = {10.1002/jgm.2958},
pmid = {28444911},
issn = {1521-2254},
mesh = {Acid Anhydride Hydrolases/*genetics ; Adult ; *Altitude ; Case-Control Studies ; Female ; Humans ; Male ; *Polymorphism, Single Nucleotide ; Pulmonary Edema/genetics/*physiopathology ; Risk Factors ; *Telomere Homeostasis ; },
}
@article {pmid28444175,
year = {2017},
author = {Margaritis, M and Sanna, F and Lazaros, G and Akoumianakis, I and Patel, S and Antonopoulos, AS and Duke, C and Herdman, L and Psarros, C and Oikonomou, EK and Shirodaria, C and Petrou, M and Sayeed, R and Krasopoulos, G and Lee, R and Tousoulis, D and Channon, KM and Antoniades, C},
title = {Predictive value of telomere length on outcome following acute myocardial infarction: evidence for contrasting effects of vascular vs. blood oxidative stress.},
journal = {European heart journal},
volume = {38},
number = {41},
pages = {3094-3104},
pmid = {28444175},
issn = {1522-9645},
support = {RG/12/5/29576/BHF_/British Heart Foundation/United Kingdom ; PG/13/56/30383/BHF_/British Heart Foundation/United Kingdom ; FS/16/15/32047/BHF_/British Heart Foundation/United Kingdom ; RG/17/10/32859/BHF_/British Heart Foundation/United Kingdom ; RG/07/003/23133/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Aged ; Biomarkers/metabolism ; Cardiovascular Diseases/mortality ; Female ; Humans ; Leukocytes, Mononuclear/metabolism ; Male ; Mammary Arteries/metabolism ; Middle Aged ; Muscle, Smooth, Vascular/metabolism ; Myocardial Infarction/genetics/*mortality ; NADPH Oxidases/metabolism ; Oxidative Stress/genetics/*physiology ; Polymorphism, Genetic/genetics ; Prognosis ; Prospective Studies ; Saphenous Vein/metabolism ; Superoxides/metabolism ; Telomere/*physiology ; },
abstract = {AIMS: Experimental evidence suggests that telomere length (TL) is shortened by oxidative DNA damage, reflecting biological aging. We explore the value of blood (BTL) and vascular TL (VTL) as biomarkers of systemic/vascular oxidative stress in humans and test the clinical predictive value of BTL in acute myocardial infarction (AMI).<br><br>METHODS AND RESULTS: In a prospective cohort of 290 patients surviving recent AMI, BTL measured on admission was a strong predictor of all-cause [hazard ratio (HR) [95% confidence interval (CI)]: 3.21 [1.46-7.06], P&#x2009;=&#x2009;0.004] and cardiovascular mortality (HR [95% CI]: 3.96 [1.65-9.53], P&#x2009;=&#x2009;0.002) 1 year after AMI (for comparisons of short vs. long BTL, as defined by a T/S ratio cut-off of 0.916, calculated using receiver operating characteristic analysis; P adjusted for age and other predictors). To explore the biological meaning of these findings, BTL was quantified in 727 consecutive patients undergoing coronary artery bypass grafting (CABG), and superoxide (O2.-) was measured in peripheral blood mononuclear cells (PBMNC). VTL/vascular O2.- were quantified in saphenous vein (SV) and mammary artery (IMA) segments. Patients were genotyped for functional genetic polymorphisms in P22ph&#xb0;x (activating NADPH-oxidases) and vascular smooth muscle cells (VSMC) selected by genotype were cultured from vascular tissue. Short BTL was associated with high O2.- in PBMNC (P&#x2009;=&#x2009;0.04) but not in vessels, whereas VTL was related to O2.- in IMA (&#x3c1;&#x2009;=&#x2009;-0.49, P&#x2009;=&#x2009;0.004) and SV (&#x3c1;&#x2009;=&#x2009;-0.52, P&#x2009;=&#x2009;0.01). Angiotensin II (AngII) incubation of VSMC (30 days), as a means of stimulating NADPH-oxidases, increased O2.- and reduced TL in carriers of the high-responsiveness P22ph&#xb0;x alleles (P&#x2009;=&#x2009;0.007).<br><br>CONCLUSION: BTL predicts cardiovascular outcomes post-AMI, independently of age, whereas VTL is a tissue-specific (rather than a global) biomarker of vascular oxidative stress. The lack of a strong association between BTL and VTL reveals the importance of systemic vs. vascular factors in determining clinical outcomes after AMI.},
}
@article {pmid28442329,
year = {2017},
author = {Østhus, IB&#xd8; and Lydersen, S and Dalen, H and Nauman, J and Wisløff, U},
title = {Association of Telomere Length With Myocardial Infarction: A Prospective Cohort From the Population Based HUNT 2 Study.},
journal = {Progress in cardiovascular diseases},
volume = {59},
number = {6},
pages = {649-655},
doi = {10.1016/j.pcad.2017.04.001},
pmid = {28442329},
issn = {1873-1740},
mesh = {Age Factors ; Aged ; Aged, 80 and over ; Female ; Genetic Markers ; Humans ; Incidence ; Linear Models ; Male ; Multivariate Analysis ; Myocardial Infarction/diagnosis/epidemiology/*genetics ; Norway/epidemiology ; Polymerase Chain Reaction ; Predictive Value of Tests ; Prognosis ; Proportional Hazards Models ; Prospective Studies ; Risk Factors ; Sex Factors ; Telomere/*genetics ; *Telomere Homeostasis ; Time Factors ; },
abstract = {As possible markers of biological age, telomere length (TL) has been associated with age-related diseases such as myocardial infarction (MI) with conflicting findings. We sought to assess the relationship between TL and risk of future MI in 915 healthy participants (51.7% women) 65 years or older from a population-based prospective cohort (the HUNT 2 study, Norway). Mean TL was measured by quantitative PCR expressed as relative T (telomere repeat copy number) to S (single copy gene number) ratio, and log-transformed. During a mean follow up of 13.0 (SD, 3.2) years and 11,923 person-years, 82 participants were diagnosed with MI. We used Cox proportional hazard regressions to estimate hazard ratios (HR) and 95% confidence interval (CI). Relative TL was associated with age in women (P=0.01), but not in men (P=0.43). Using relative TL as a continuous variable, we observed a higher risk of MI in participants with longer telomeres with HRs of 2.46 (95% CI; 1.13 to 4.54) in men, and 2.93 (95% CI; 1.41 to 6.10) in women. Each 1-SD change in relative TL was associated with an HR of 1.54 (95% CI; 1.15 to 2.06) and 1.67 (95% CI; 1.18 to 2.37) in men and women, respectively. Compared with the bottom tertile of relative TL, HR of incident MI in top tertile was 2.71 (95% CI; 1.25 to 5.89) in men, and 3.65 (95% CI; 1.35 to 9.90) in women. Longer telomeres in healthy participants 65 years or older are associated with a high risk of incident MI. Future large scale prospective studies are needed to confirm these findings and explore the potential association between TL and MI.},
}
@article {pmid28441430,
year = {2017},
author = {Eguchi, K and Honig, LS and Lee, JH and Hoshide, S and Kario, K},
title = {Short telomere length is associated with renal impairment in Japanese subjects with cardiovascular risk.},
journal = {PloS one},
volume = {12},
number = {4},
pages = {e0176138},
pmid = {28441430},
issn = {1932-6203},
mesh = {Aged ; Cardiovascular Diseases/*etiology/physiopathology ; Female ; Humans ; Japan ; Kidney/*physiopathology ; Male ; Middle Aged ; Pulse Wave Analysis ; Risk Factors ; *Telomere ; Vascular Stiffness/*physiology ; },
abstract = {INTRODUCTION: Short telomere length has been suggested to be associated with atherosclerotic changes in Western populations. We examined the relationships between leukocyte telomere length and cardiovascular and renal function in a Japanese cohort.<br><br>PARTICIPANTS AND METHODS: We enrolled 770 subjects who each had at least one cardiovascular risk factor. The mean age was 59.5 &#xb1; 12.2 years; mean BMI was 25.1 &#xb1; 4.6 kg/m2. We measured leukocyte telomere length (LTL) by quantitative PCR (T/S ratio), and measured other biomarkers from blood and urine samples. In addition, we assessed surrogate markers of arterial stiffness, cardiovascular organ damage and kidney function, including flow-mediated vasodilation (FMD), pulse wave velocity (PWV), carotid artery augmentation index (CAAI), and urinary albumin creatinine ratio (UACR) and eGFR.<br><br>RESULTS: Leukocyte telomere length (T/S ratio) was inversely associated with age (r = -0.194, P<0.001), and was lower in men (1.13 &#xb1; 0.29%) than in women (1.20 &#xb1; 0.31%, P = 0.002). T/S ratio was positively associated with BMI in women (r = 0.11, P = 0.047), but not in men. LTL did not show a significant relationship to cardiovascular surrogate markers, including arterial stiffness, FMD, and PWV, but did show some relationship to CAAI, which was inversely associated with T/S ratio only in men (r = -0.159, P = 0.015). LTL did show a significant positive association with renal function measured by eGFR (r = 0.16, P<0.001) both in men and women.<br><br>CONCLUSIONS: In this Japanese sample of persons with increased cardiovascular risk, telomere length showed a relationship of longer telomere length to better renal function, but did not overall show convincing association with cardiovascular measures of arterial stiffness and target organ damage.},
}
@article {pmid28439695,
year = {2018},
author = {Márquez-Ruiz, AB and González-Herrera, L and Valenzuela, A},
title = {Usefulness of telomere length in DNA from human teeth for age estimation.},
journal = {International journal of legal medicine},
volume = {132},
number = {2},
pages = {353-359},
pmid = {28439695},
issn = {1437-1596},
support = {FPU13/03543//Ministerio de Educaci&#xf3;n, Cultura y Deporte/ ; Contrato 3193-00//Centro para la Excelencia en Investigaci&#xf3;n Forense en Andaluc&#xed;a (CEIFA)/ ; },
mesh = {Adolescent ; Adult ; Age Determination by Teeth/*methods ; Aged ; Aged, 80 and over ; Aging/*genetics ; DNA/*isolation &amp; purification ; Female ; Humans ; Linear Models ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Telomere/*genetics ; Tooth/*chemistry ; Young Adult ; },
abstract = {Age estimation is widely used to identify individuals in forensic medicine. However, the accuracy of the most commonly used procedures is markedly reduced in adulthood, and these methods cannot be applied in practice when morphological information is limited. Molecular methods for age estimation have been extensively developed in the last few years. The fact that telomeres shorten at each round of cell division has led to the hypothesis that telomere length can be used as a tool to predict age. The present study thus aimed to assess the correlation between telomere length measured in dental DNA and age, and the effect of sex and tooth type on telomere length; a further aim was to propose a statistical regression model to estimate the biological age based on telomere length. DNA was extracted from 91 tooth samples belonging to 77 individuals of both sexes and 15 to 85 years old and was used to determine telomere length by quantitative real-time PCR. Our results suggested that telomere length was not affected by sex and was greater in molar teeth. We found a significant correlation between age and telomere length measured in DNA from teeth. However, the equation proposed to predict age was not accurate enough for forensic age estimation on its own. Age estimation based on telomere length in DNA from tooth samples may be useful as a complementary method which provides an approximate estimate of age, especially when human skeletal remains are the only forensic sample available.},
}
@article {pmid28438147,
year = {2017},
author = {Wang, X and Sundquist, K and Hedelius, A and Palmér, K and Memon, AA and Sundquist, J},
title = {Leukocyte telomere length and depression, anxiety and stress and adjustment disorders in primary health care patients.},
journal = {BMC psychiatry},
volume = {17},
number = {1},
pages = {148},
pmid = {28438147},
issn = {1471-244X},
mesh = {Adult ; Aged ; Anxiety ; Anxiety Disorders/pathology/therapy ; Depressive Disorder/pathology/therapy ; Female ; Humans ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Multiplex Polymerase Chain Reaction/methods ; Telomere/*ultrastructure ; *Telomere Shortening ; },
abstract = {BACKGROUND: The primary aim was to examine possible differences in telomere length between primary health care patients, with depression, anxiety or stress and adjustment disorders, and healthy controls. The second aim was to examine the association between telomere length and baseline characteristics in the patients. The third aim was to examine the potential effects of the 8-week treatments (mindfulness-based group therapy or treatment as usual, i.e. mostly cognitive-based therapy) on telomere length, and to examine whether there was a difference in the potential effect on telomere length between the two groups.<br><br>METHODS: A total of 501 individuals including 181 patients (aged 20-64&#xa0;years), with depression, anxiety and stress and adjustment disorders, and 320 healthy controls (aged 19-70&#xa0;years) were recruited in the study. Patient data were collected from a randomized controlled trial comparing mindfulness-based group therapy with treatment as usual. We isolated genomic DNA from blood samples, collected at baseline and after the 8-week follow-up. Telomere length was measured by quantitative real-time (qRT)-PCR.<br><br>RESULTS: Telomere length was significantly shorter in the patients (mean&#xa0;=&#xa0;0.77&#xa0;&#xb1;&#xa0;0.12,), compared to the controls (mean&#xa0;=&#xa0;0.81&#xa0;&#xb1;&#xa0;0.14) (p&#xa0;=&#xa0;0.006). The difference in telomere length remained significant after controlling for age and sex. Old age, male sex and being overweight were associated with shorter telomere length. There was no significant difference in telomere length between baseline and at the 8-week follow-up in any of the treatment groups and no difference between the two groups.<br><br>CONCLUSION: Our findings confirm that telomere length, as compared with healthy controls, is shortened in patients with depression, anxiety and stress and adjustment disorders. In both groups (mindfulness-based group therapy or treatment as usual), the telomere length remained unchanged after the 8-week treatment/follow-up and there was no difference between the two groups.<br><br>TRIAL REGISTRATION: (ClinicalTrials.gov ID: NCT01476371) Registered November 11, 2011.},
}
@article {pmid28436953,
year = {2017},
author = {Knecht, H and Johnson, NA and Haliotis, T and Lichtensztejn, D and Mai, S},
title = {Disruption of direct 3D telomere-TRF2 interaction through two molecularly disparate mechanisms is a hallmark of primary Hodgkin and Reed-Sternberg cells.},
journal = {Laboratory investigation; a journal of technical methods and pathology},
volume = {97},
number = {7},
pages = {772-781},
pmid = {28436953},
issn = {1530-0307},
support = {MOP110982//CIHR/Canada ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Cell Line ; Female ; Hodgkin Disease/*metabolism ; Humans ; Male ; Middle Aged ; Reed-Sternberg Cells/cytology/*metabolism ; Telomere/chemistry/*metabolism/pathology/ultrastructure ; Telomeric Repeat Binding Protein 2/chemistry/*metabolism ; Young Adult ; },
abstract = {In classical Hodgkin's lymphoma (cHL), specific changes in the 3D telomere organization cause progression from mononuclear Hodgkin cells (H) to multinucleated Reed-Sternberg cells (RS). In a post-germinal center B-cell in vitro model, permanent latent membrane protein 1 (LMP1) expression, as observed in Epstein-Barr virus (EBV)-associated cHL, results in multinuclearity and complex chromosomal aberrations through downregulation of key element of the shelterin complex, the telomere repeat binding factor 2 (TRF2). Thus, we hypothesized that the three-dimensional (3D) telomere-TRF2 interaction was progressively disturbed during transition from H to RS cells. To this end, we developed and applied for the first time a combined quantitative 3D TRF2-telomere immune fluorescent in situ hybridization (3D TRF2/Telo-Q-FISH) technique to monolayers of primary H and RS cells, and adjacent benign internal control lymphocytes of lymph node biopsy suspensions from diagnostic lymph node biopsies of 14 patients with cHL. We show that H and RS cells are characterized by two distinct patterns of disruption of 3D telomere-TRF2 interaction. Disruption pattern A is defined by massive attrition of telomere signals and a considerable increase of TRF2 signals not associated with telomeres. This pattern is restricted to EBV-negative cHL. Disruption pattern B is defined by telomere de-protection due to an impressive loss of TRF2 signals, physically linked to telomeres. This pattern is typical of, but is not restricted to, LMP1+EBV-associated cHL. In the disruption pattern B group, so-called 'ghost' end-stage RS cells, void of both TRF2 and telomere signals, were identified, whether or not associated with EBV. Our findings demonstrate that two molecularly disparate mechanisms converge on the level of 3D telomere-TRF2 interaction in the formation of RS cells.},
}
@article {pmid28431907,
year = {2017},
author = {Prasad, KN and Wu, M and Bondy, SC},
title = {Telomere shortening during aging: Attenuation by antioxidants and anti-inflammatory agents.},
journal = {Mechanisms of ageing and development},
volume = {164},
number = {},
pages = {61-66},
doi = {10.1016/j.mad.2017.04.004},
pmid = {28431907},
issn = {1872-6216},
mesh = {Aging/*drug effects/metabolism ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Cellular Senescence/*drug effects ; Humans ; Oxidative Stress/*drug effects ; Telomere/*metabolism ; Telomere Homeostasis/*drug effects ; },
abstract = {Telomeres are a repeated sequence -of bases found at the ends of chromosomes. In humans, this sequence is TTAGGG, which is repeated over 2000 times. Telomeres protect the ends chromosomes from fusion with nearby chromosomes, and allow effective replication of DNA. Each time a cell divides, 25-200 base pairs are lost from the terminal sequence of chromosomes. By becoming truncated during cell division, telomeres protect essential genes from being shortened and thus inactivated. In addition, telomeres are sensitive to inflammation and oxidative stress, which can further promote telomere shortening. Reduction in the length of telomeres leads to the cessation of cell division and thus cellular senescence and apoptosis. This review discusses evidence for the role of oxidative stress and inflammation in regulating the length of telomeres in mammalian cells during senescence. Evidence is presented suggesting that antioxidants and anti-inflammatories can reduce the pace of shortening of telomere length during aging. The distinctive properties of transformed cells suggest that treatment with such materials will have a deleterious rather than a protective effect on such abnormal cells.},
}
@article {pmid28431234,
year = {2017},
author = {Kibe, T and Zimmermann, M and de Lange, T},
title = {TPP1 Blocks an ATR-Mediated Resection Mechanism at Telomeres.},
journal = {Molecular cell},
volume = {66},
number = {2},
pages = {300},
doi = {10.1016/j.molcel.2017.04.004},
pmid = {28431234},
issn = {1097-4164},
}
@article {pmid28430596,
year = {2017},
author = {Schmiester, M and Demuth, I},
title = {SNM1B/Apollo in the DNA damage response and telomere maintenance.},
journal = {Oncotarget},
volume = {8},
number = {29},
pages = {48398-48409},
pmid = {28430596},
issn = {1949-2553},
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins/metabolism ; *DNA Damage ; DNA Repair Enzymes/antagonists &amp; inhibitors/genetics/*metabolism ; DNA Replication ; Disease Susceptibility ; Exodeoxyribonucleases ; Humans ; Neoplasms/drug therapy/genetics/metabolism/pathology ; Nuclear Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Protein Interaction Maps ; Signal Transduction ; Stress, Physiological ; Telomere/*genetics/*metabolism ; *Telomere Homeostasis ; },
abstract = {hSNM1B/Apollo is a member of the highly conserved β-CASP subgroup within the MBL superfamily of proteins. It interacts with several DNA repair proteins and functions within the Fanconi anemia pathway in response to DNA interstrand crosslinks. As a shelterin accessory protein, hSNM1B/Apollo is also vital for the generation and maintenance of telomeric overhangs. In this review, we will summarize studies on hSNM1B/Apollo's function, including its contribution to DNA damage signaling, replication fork maintenance, control of topological stress and telomere protection. Furthermore, we will highlight recent studies illustrating hSNM1B/Apollo's putative role in human disease.},
}
@article {pmid28428263,
year = {2017},
author = {Lobanova, A and She, R and Pieraut, S and Clapp, C and Maximov, A and Denchi, EL},
title = {Different requirements of functional telomeres in neural stem cells and terminally differentiated neurons.},
journal = {Genes &amp; development},
volume = {31},
number = {7},
pages = {639-647},
pmid = {28428263},
issn = {1549-5477},
support = {R01 AG038677/AG/NIA NIH HHS/United States ; R01 NS087026/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; Behavior, Animal ; Cell Differentiation/genetics ; Gene Expression Regulation, Developmental ; Mice ; Mice, Knockout ; Neural Stem Cells/*metabolism ; Neurogenesis/*genetics ; Neurons/cytology/*metabolism ; Synaptic Transmission/genetics ; Telomere/*physiology ; Telomeric Repeat Binding Protein 2/*physiology ; },
abstract = {Telomeres have been studied extensively in peripheral tissues, but their relevance in the nervous system remains poorly understood. Here, we examine the roles of telomeres at distinct stages of murine brain development by using lineage-specific genetic ablation of TRF2, an essential component of the shelterin complex that protects chromosome ends from the DNA damage response machinery. We found that functional telomeres are required for embryonic and adult neurogenesis, but their uncapping has surprisingly no detectable consequences on terminally differentiated neurons. Conditional knockout of TRF2 in post-mitotic immature neurons had virtually no detectable effect on circuit assembly, neuronal gene expression, and the behavior of adult animals despite triggering massive end-to-end chromosome fusions across the brain. These results suggest that telomeres are dispensable in terminally differentiated neurons and provide mechanistic insight into cognitive abnormalities associated with aberrant telomere length in humans.},
}
@article {pmid28425738,
year = {2017},
author = {Lee, DB and Kim, ES and Neblett, EW},
title = {The link between discrimination and telomere length in African American adults.},
journal = {Health psychology : official journal of the Division of Health Psychology, American Psychological Association},
volume = {36},
number = {5},
pages = {458-467},
doi = {10.1037/hea0000450},
pmid = {28425738},
issn = {1930-7810},
support = {T32 HD079350/HD/NICHD NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; T32 HL098048/HL/NHLBI NIH HHS/United States ; },
mesh = {Black or African American/*psychology ; Discrimination, Psychological/*physiology ; Female ; Healthcare Disparities/*trends ; Humans ; Male ; Middle Aged ; Telomere Homeostasis/*physiology ; United States ; },
abstract = {OBJECTIVE: Prior work shows that discrimination is associated with a wide array of negative health outcomes. However, the biological mechanisms through which this link occurs require more study. We evaluated the association between discrimination and leukocyte telomere length (LTL; a biological marker of systemic aging).<br><br>METHOD: Cross-sectional data were from the Health and Retirement study, a study of people aged 51+ in the United States, and included 595 African American males and females. Multiple regression analyses were used to evaluate whether discrimination was independently associated with LTL. We also considered the role of potential confounders including sociodemographic factors, health factors, depressive symptoms, and stress.<br><br>RESULTS: High discrimination was associated with shorter LTL after controlling for sociodemographic factors (b = -.034, SE = 0.14, p = .017). This association persisted in analyses that further adjusted for health factors, depressive symptoms, and stress.<br><br>CONCLUSION: Results suggest that discrimination experiences accelerate biological aging in older African American males and females, alike. This finding helps advance our understanding of how discrimination generates greater disease vulnerability and premature death in African Americans. (PsycINFO Database Record},
}
@article {pmid28424424,
year = {2017},
author = {Fang, Q and Hui, L and Min, Z and Liu, L and Shao, Y},
title = {Leukocyte telomere length-related genetic variants in ACYP2 contribute to the risk of esophageal carcinoma in Chinese Han population.},
journal = {Oncotarget},
volume = {8},
number = {15},
pages = {25564-25570},
pmid = {28424424},
issn = {1949-2553},
mesh = {Acid Anhydride Hydrolases/*genetics ; Aged ; Alleles ; Asian People/genetics ; Case-Control Studies ; China/epidemiology ; Esophageal Neoplasms/*epidemiology/*genetics ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; *Genetic Variation ; Genotype ; Haplotypes ; Humans ; Leukocytes/*metabolism ; Linkage Disequilibrium ; Male ; Middle Aged ; Odds Ratio ; Polymorphism, Single Nucleotide ; Risk ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: Short leukocyte telomere length has been associated with significantly increased risk of esophageal carcinoma. A previous genome-wide association study demonstrated that ACYP2 was associated with leukocyte telomere length. However, the role of ACYP2 genetic variants on esophageal carcinoma susceptibility is still unknown. Therefore, we investigated whether ACYP2 polymorphisms have impact on the risk of esophageal carcinoma in Chinese.<br><br>MATERIALS AND METHODS: We conducted a case-control study among 386 cases and 495 healthy controls from northwest China. 14 SNPs in ACYP2 were selected and genotyped using Sequenom MassARRAY technology. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusting for age and gender.<br><br>RESULTS: We found that 1.34-fold increased risk of esophageal carcinoma is associated with the rs11125529 A allele compared with the rs11125529 C allele (OR=1.29, 95%CI: 1.02-1.62, p=0.030) under the additive model, after adjusted by age and gender. We also found rs11896604 and rs17045754 loci increased the esophageal carcinoma risk under the additive model (rs11896604: OR=1.34, 95%CI: 1.03-1.76, p=0.032; rs17045754: OR=1.36, 95%CI: 1.03-1.80, p=0.028). One main linkage block was observed across the locus. This block was comprised of seven closely linked SNPs: rs1682111, rs843752, rs10439478, rs843645, rs11125529, rs843711 and rs11896604. The haplotype analysis detected that haplotype "TTCTATG" increased the risk of esophageal carcinoma (OR=1.38, 95%CI: 1.04-1.82, p=0.025).<br><br>CONCLUSION: In conclusion, ACYP2 gene may be associated with an increased risk of esophageal carcinoma in Chinese Han populations. Future studies to address the biological function of this polymorphism in the development of esophageal carcinoma are warranted.},
}
@article {pmid28424414,
year = {2017},
author = {Heng, J and Zhang, F and Guo, X and Tang, L and Peng, L and Luo, X and Xu, X and Wang, S and Dai, L and Wang, J},
title = {Integrated analysis of promoter methylation and expression of telomere related genes in breast cancer.},
journal = {Oncotarget},
volume = {8},
number = {15},
pages = {25442-25454},
pmid = {28424414},
issn = {1949-2553},
mesh = {Breast Neoplasms/*genetics/pathology ; *DNA Methylation ; Female ; Gene Expression ; Humans ; Promoter Regions, Genetic ; Telomere/genetics/metabolism ; },
abstract = {Telomeres at the ends of eukaryotic chromosomes play a critical role in tumorgenesis. Using microfluidic PCR and next-generation bisulfite sequencing technology, we investigated the promoter methylation of 29 telomere related genes in paired tumor and normal tissues from 184 breast cancer patients. The expression of significantly differentially methylated genes was quantified using qPCR method.We observed that the average methylation level of the 29 telomere related genes was significant higher in tumor than that in normal tissues (P = 4.30E-21). A total of 4 genes (RAD50, RTEL, TERC and TRF1) showed significant hyper-methylation in breast tumor tissues. RAD51D showed significant methylation difference among the four breast cancer subtypes. The methylation of TERC showed significant association with ER status of breast cancer. The expression profiles of the 4 hyper-methylated genes showed significantly reduced expression in tumor tissues. The integration analysis of methylation and expression of these 4 genes showed a good performance in breast cancer prediction (AUC = 0.947).Our results revealed the methylation pattern of telomere related genes in breast cancer and suggested a novel 4-gene panel might be a valuable biomarker for breast cancer diagnosis.},
}
@article {pmid28423661,
year = {2017},
author = {Wu, CJ and Kao, TW and Lin, YY and Liaw, FY and Wu, LW and Chang, YW and Peng, TC and Chen, WL},
title = {Examining the association between anthropometric parameters and telomere length and mortality risk.},
journal = {Oncotarget},
volume = {8},
number = {21},
pages = {34057-34069},
pmid = {28423661},
issn = {1949-2553},
mesh = {Adult ; Aged ; Anthropometry ; Body Size ; Female ; Humans ; Male ; Middle Aged ; Mortality ; Nutrition Surveys ; Risk Factors ; Telomere/*genetics ; Telomere Shortening ; },
abstract = {A shorter telomere length is associated with several systemic disorders. Telomere length may be an informative biomarker for the maintenance of the overall health status and mortality. There are a limited number of empirical studies concerning the effect of anthropometric parameters on telomere length. The data are derived from the National Health and Nutrition Examination Survey from 1999 to 2002. The primary outcomes of this study were to examine the potential relationships between the anthropometric indices and the telomere length, while secondary outcomes of this study was to investigate the association between different anthropometric indices and mortality risk. A significant positive correlation was noted between the mean telomere length and the thigh circumference (TC) and calf circumference (CC) in all designed models. Participants in the highest TC and CC quartiles tended to have a longer telomere length and lowered the hazards for all-cause mortality to 43% and 57%, respectively. Notably, the anthropometric indices involving the CC with higher values seemed to be surrogate markers for the reduction of the risk of all-cause, cardiovascular and malignancy-related mortality (all P < 0.05). The CCmay be a valuable tool to guide public health policy and a clinical prognostic indicator for the risk of mortality.},
}
@article {pmid28423524,
year = {2017},
author = {Quintela-Fandino, M and Soberon, N and Lluch, A and Manso, L and Calvo, I and Cortes, J and Moreno-Antón, F and Gil-Gil, M and Martinez-Jánez, N and Gonzalez-Martin, A and Adrover, E and de Andres, R and Viñas, G and Llombart-Cussac, A and Alba, E and Mouron, S and Guerra, J and Bermejo, B and Zamora, E and García-Saenz, JA and Simon, SP and Carrasco, E and Escudero, MJ and Campo, R and Colomer, R and Blasco, MA},
title = {Critically short telomeres and toxicity of chemotherapy in early breast cancer.},
journal = {Oncotarget},
volume = {8},
number = {13},
pages = {21472-21482},
pmid = {28423524},
issn = {1949-2553},
mesh = {Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/*administration &amp; dosage/*adverse effects ; Breast Neoplasms/drug therapy/*genetics ; Chemotherapy, Adjuvant/adverse effects/methods ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Indoles/administration &amp; dosage/adverse effects ; Middle Aged ; Neoadjuvant Therapy/adverse effects/methods ; Paclitaxel/administration &amp; dosage/adverse effects ; Telomere/*pathology ; *Telomere Shortening ; },
abstract = {Cumulative toxicity from weekly paclitaxel (myalgia, peripheral neuropathy, fatigue) compromises long-term administration. Preclinical data suggest that the burden of critically short telomeres (< 3 kilobases, CSTs), but not average telomere length by itself, accounts for limited tissue renewal and turnover capacity. The impact of this parameter (which can be modified with different therapies) in chemotherapy-derived toxicity has not been studied.Blood from 115 treatment-naive patients from a clinical trial in early HER2-negative breast cancer that received weekly paclitaxel (80 mg/m2 for 12 weeks) either alone or in combination with nintedanib and from 85 healthy controls was prospectively obtained and individual CSTs and average telomere lenght were determined by HT Q-FISH (high-throughput quantitative FISH). Toxicity was graded according to NCI common toxicity criteria for adverse events (NCI CTCAE V.4.0). The variable under study was "number of toxic episodes" during the 12 weeks of therapy.The percentage of CSTs ranged from 6.5%-49.4% and was directly associated with the number of toxic events (R2 = 0.333; P < 0.001). According to a linear regression model, each 18% increase in the percentage of CSTs was associated to one additional toxic episode during the paclitaxel cycles; this effect was independent of the age or treatment arm. Patients in the upper quartile (> 21.9% CSTs) had 2-fold higher number of neuropathy (P = 0.04) or fatigue (P = 0.019) episodes and >3-fold higher number of myalgia episodes (P = 0.005). The average telomere length was unrelated to the incidence of side effects.The percentage of CSTs, but not the average telomere size, is associated with weekly paclitaxel-derived toxicity.},
}
@article {pmid28423121,
year = {2017},
author = {Furtado, FM and Scheucher, PS and Santana, BA and Scatena, NF and Calado, RT and Rego, EM and Matos, DM and Falcão, RP},
title = {Telomere length analysis in monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia Binet A.},
journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas},
volume = {50},
number = {5},
pages = {e6019},
pmid = {28423121},
issn = {1414-431X},
mesh = {Age Factors ; Aged ; Aged, 80 and over ; B-Lymphocytes/*pathology ; Case-Control Studies ; Disease Progression ; Female ; Flow Cytometry ; Genetic Markers ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/*pathology ; Lymphocyte Count ; Lymphocytosis/*genetics/*pathology ; Male ; Middle Aged ; Reference Standards ; Statistics, Nonparametric ; Telomere/pathology ; Telomere Shortening/*genetics ; },
abstract = {Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic clinical entity characterized by the proliferation of monoclonal B cells not meeting the diagnosis criteria for chronic lymphocytic leukemia (CLL). MBL may precede the development of CLL, but the molecular mechanisms responsible for disease progression and evolution are not completely known. Telomeres are usually short in CLL and their attrition may contribute to disease evolution. Here, we determined the telomere lengths of CD5+CD19+ cells in MBL, CLL, and healthy volunteers. Twenty-one CLL patients, 11 subjects with high-count MBL, and 6 with low-count MBL were enrolled. Two hundred and sixty-one healthy volunteers aged 0 to 88 years were studied as controls. After diagnosis confirmation, a flow cytometry CD19+CD5+-based cell sorting was performed for the study groups. Telomere length was determined by qPCR. Telomere length was similar in the 3 study groups but shorter in these groups compared to normal age-matched subjects that had been enrolled in a previous study from our group. These findings suggest that telomere shortening is an early event in CLL leukemogenesis.},
}
@article {pmid28420806,
year = {2017},
author = {Ko, JL and Cheng, YJ and Liu, GC and Hsin, IL and Chen, HL},
title = {The association of occupational metals exposure and oxidative damage, telomere shortening in fitness equipments manufacturing workers.},
journal = {Industrial health},
volume = {55},
number = {4},
pages = {345-353},
pmid = {28420806},
issn = {1880-8026},
mesh = {Adult ; Air Pollutants, Occupational/analysis ; Biomarkers/analysis ; DNA Damage ; Female ; Humans ; Male ; Malondialdehyde/blood ; Metals, Heavy/*blood ; Occupational Exposure/*analysis ; Oxidative Stress ; Taiwan/epidemiology ; *Telomere Shortening ; *Welding ; },
abstract = {The welding is the major working process in fitness equipment manufacturing industry, and International Agency for Research on Cancer has classified welding fumes as possibly carcinogenic to humans (Group 2B). The present study aimed to evaluate associations between the occupational exposure of metals and oxidative damage and telomere length shortening in workers involved in the manufacture of fitness equipment. The blood metal concentrations were monitored and malondialdehyde (MDA), alkaline Comet assay was determined as oxidative damage in 117 workers from two representative fitness equipment manufacturing plants. MDA levels varied according to workers' roles at the manufacturing plants, and showed a trend as cutting>painting>welding>administration workers. Welders had marginally shorter average telomere lengths than the administrative workers (p=0.058). Cr and Mn levels were significantly greater in welders than they were in administrative workers. There were significantly positive correlations between MDA and Cr and Mn levels, the major components of welding fume. However, the association would be eliminated if co-metals exposure were considered simultaneously. In future, telomere length and MDA might be potential biomarkers for predicting cardiovascular disease in co-metals exposed workers.},
}
@article {pmid28419065,
year = {2017},
author = {Pru, JK},
title = {Late maternal age at last childbirth and telomere homeostasis.},
journal = {Menopause (New York, N.Y.)},
volume = {24},
number = {5},
pages = {478-479},
doi = {10.1097/GME.0000000000000890},
pmid = {28419065},
issn = {1530-0374},
mesh = {*Maternal Age ; *Telomere Homeostasis ; },
}
@article {pmid28418989,
year = {2017},
author = {Montejano, R and Stella-Ascariz, N and Monge, S and Bernardino, JI and Pérez-Valero, I and Montes, ML and Valencia, E and Martín-Carbonero, L and Moreno, V and González-García, J and Arnalich, F and Mingorance, J and Pintado Berniches, L and Perona, R and Arribas, JR},
title = {Impact of Antiretroviral Treatment Containing Tenofovir Difumarate on the Telomere Length of Aviremic HIV-Infected Patients.},
journal = {Journal of acquired immune deficiency syndromes (1999)},
volume = {76},
number = {1},
pages = {102-109},
doi = {10.1097/QAI.0000000000001391},
pmid = {28418989},
issn = {1944-7884},
mesh = {Aging/*drug effects ; Anti-HIV Agents/*pharmacology/therapeutic use ; Cross-Sectional Studies ; Female ; HIV Infections/*drug therapy/pathology/*virology ; *HIV-1/physiology ; Humans ; Male ; Middle Aged ; Spain/epidemiology ; Telomerase/antagonists &amp; inhibitors ; Telomere/*drug effects ; Tenofovir/*pharmacology/therapeutic use ; Treatment Outcome ; Viral Load ; },
abstract = {OBJECTIVE: To evaluate the in vivo relevance of the inhibitory effect of tenofovir on telomerase activity observed in vitro.<br><br>DESIGN: Cross-sectional study of HIV-infected patients with suppressed virological replication (HIV RNA <50 copies/mL for more than 1 year).<br><br>METHODS: Telomere length in whole blood was measured by quantitative real-time polymerase chain reaction. We performed a multivariate analysis to elucidate variables associated with telomere length and also evaluated the association between telomere length and use of tenofovir difumarate (TDF) adjusted by significant confounders.<br><br>RESULTS: 200 patients included, 72% men, median age 49 (IQR 45-54.5), 103 with exposure to a TDF containing antiretroviral treatment (ART) regimen (69.9% for more than 5 years) and 97 never exposed to a TDF containing ART regimen. In the multivariate analysis, significant predictors of shorter telomere length were older age (P = 0.008), parental age at birth (P = 0.038), white race (P = 0.048), and longer time of known HIV infection (10-20 and &#x2265;20 years compared with <10 years, P = 0.003 and P = 0.056, respectively). There was no association between TDF exposure and telomere length after adjusting for possible confounding factors (age, parental age at birth, race, and time of HIV infection). Total time receiving ART and duration of treatment with nucleoside reverse transcriptase inhibitors were associated with shorter telomere length, but these associations were explained by time of known HIV infection.<br><br>CONCLUSIONS: Our data do not suggest that telomerase activity inhibition caused by TDF in vitro leads to telomere shortening in peripheral blood of HIV-infected patients.},
}
@article {pmid28418400,
year = {2017},
author = {Hägg, S and Zhan, Y and Karlsson, R and Gerritsen, L and Ploner, A and van der Lee, SJ and Broer, L and Deelen, J and Marioni, RE and Wong, A and Lundquist, A and Zhu, G and Hansell, NK and Sillanpää, E and Fedko, IO and Amin, NA and Beekman, M and de Craen, AJM and Degerman, S and Harris, SE and Kan, KJ and Martin-Ruiz, CM and Montgomery, GW and , and Adolfsson, AN and Reynolds, CA and Samani, NJ and Suchiman, HED and Viljanen, A and von Zglinicki, T and Wright, MJ and Hottenga, JJ and Boomsma, DI and Rantanen, T and Kaprio, JA and Nyholt, DR and Martin, NG and Nyberg, L and Adolfsson, R and Kuh, D and Starr, JM and Deary, IJ and Slagboom, PE and van Duijn, CM and Codd, V and Pedersen, NL},
title = {Short telomere length is associated with impaired cognitive performance in European ancestry cohorts.},
journal = {Translational psychiatry},
volume = {7},
number = {4},
pages = {e1100},
pmid = {28418400},
issn = {2158-3188},
support = {G0601333/MRC_/Medical Research Council/United Kingdom ; U01 HL130114/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; MC_UU_12019/1/MRC_/Medical Research Council/United Kingdom ; R01 AG033193/AG/NIA NIH HHS/United States ; G0500997/MRC_/Medical Research Council/United Kingdom ; MR/J50001X/1/MRC_/Medical Research Council/United Kingdom ; BB/F019394/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MR/K026992/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Aged ; Apolipoprotein E4/genetics ; Cognitive Dysfunction/diagnosis/*genetics ; Cohort Studies ; Female ; Genetic Carrier Screening ; Genotype ; Humans ; Male ; *Mendelian Randomization Analysis ; Middle Aged ; Neuropsychological Tests/statistics &amp; numerical data ; Psychometrics ; Statistics as Topic ; Telomere/*genetics ; White People/*genetics ; },
abstract = {The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (β=0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (β=0.025; 95% CI: 0.002, 0.047; P=0.03), and faster STROOP (β=-0.053; 95% CI: -0.087, -0.018; P=0.003). Effects for DSST were stronger in APOE ɛ4 non-carriers (β=0.081; 95% CI: 0.045, 0.117; P=1.0 × 10[-5]), whereas carriers performed better in STROOP (β=-0.074; 95% CI: -0.140, -0.009; P=0.03). Causal associations were found for STROOP only (β=-0.598 per s.d.-increase of TL; 95% CI: -1.125, -0.072; P=0.026), with a larger effect in ɛ4-carriers (β=-0.699; 95% CI: -1.330, -0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE ɛ4-carriers might be at differential risk.},
}
@article {pmid28417530,
year = {2017},
author = {Huang, D and Lu, W and Zou, S and Wang, H and Jiang, Y and Zhang, X and Li, P and Songyang, Z and Wang, L and Wang, J and Huang, J and Fang, L},
title = {Rho GDP-dissociation inhibitor α is a potential prognostic biomarker and controls telomere regulation in colorectal cancer.},
journal = {Cancer science},
volume = {108},
number = {7},
pages = {1293-1302},
pmid = {28417530},
issn = {1349-7006},
mesh = {Biomarkers, Tumor/analysis ; Blotting, Western ; Cell Movement/physiology ; Cell Proliferation/physiology ; Colorectal Neoplasms/metabolism/mortality/*pathology ; Gene Expression Regulation, Neoplastic/*physiology ; Humans ; Immunohistochemistry ; Kaplan-Meier Estimate ; Neoplasm Invasiveness/pathology ; Prognosis ; Proportional Hazards Models ; Real-Time Polymerase Chain Reaction ; Telomere/*metabolism ; Telomere Shortening ; Telomeric Repeat Binding Protein 1/*biosynthesis ; Tissue Array Analysis ; rho Guanine Nucleotide Dissociation Inhibitor alpha/*metabolism ; },
abstract = {Rho GDP-dissociation inhibitor α (RhoGDIα) is an essential regulator for Rho GTPases. Although RhoGDIα may serve as an oncogene in colorectal cancer (CRC), the underlying mechanism is still unclear. We investigated the function, mechanism, and clinical significance of RhoGDIα in CRC progression. We founded that downregulation of RhoGDIα repressed CRC cell proliferation, motility, and invasion. Overexpression of RhoGDIα increased DNA damage response signals at telomeres, and led to telomere shortening in CRC cells, also being validated in 26 pairs of CRC tissues. Mechanistic studies revealed that RhoGDIα could promote telomeric repeat factor 1 (TRF1) expression through the phosphatidylinositol 3-kinase-protein kinase B signal pathway. Moreover, RhoGDIα protein levels were strongly correlated with TRF1 in CRC tissues. A cohort of 297 CRC samples validated the positive relationship between RhoGDIα and TRF1, and revealed that RhoGDIα and TRF1 levels were negatively associated with CRC patients' survival. Taken together, our results suggest that RhoGDIα regulate TRF1 and telomere length and may be novel prognostic biomarkers in colorectal cancer.},
}
@article {pmid28415712,
year = {2017},
author = {Li, J and Ma, G and Zhu, X and Jin, T and Wang, J and Li, C},
title = {Association analysis of telomere length related gene ACYP2 with the gastric cancer risk in the northwest Chinese Han population.},
journal = {Oncotarget},
volume = {8},
number = {19},
pages = {31144-31152},
pmid = {28415712},
issn = {1949-2553},
mesh = {Acid Anhydride Hydrolases/*genetics ; Alleles ; Asian People/*genetics ; Case-Control Studies ; China ; Gene Frequency ; *Genetic Association Studies ; *Genetic Predisposition to Disease ; Genotype ; Haplotypes ; Humans ; Linkage Disequilibrium ; Polymorphism, Single Nucleotide ; Risk ; Stomach Neoplasms/*epidemiology/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Gastric cancer (GC) is a complex multifactorial disease, and genetic factors are believed the predominant cause to the occurrence of GC. We sought to investigate the associations between single nucleotide polymorphisms (SNPs) in ACYP2 gene and the risk of GC in the Northwest Chinese Han population. We recruited 302 GC cases and 300 controls from northwest China and selected 13 SNPs from ACYP2 gene. SNPs were genotyped using Sequenom Mass-ARRAY technology. Odds ratios (ORs) and 95 % confidence intervals (CIs) were used to assess the association. Bonferroni's multiple adjustment was applied to the level of significance, which was set at P < 0.00078 (0.05/65). We found that the minor alleles of rs6713088, rs11125529, rs12615793, rs843711, rs11896604, rs843706 and rs17045754 significantly stimulated the risk of GC, and homozygous alleles of above SNPs except rs6713088 were also found increasing the GC risk (P < 0.05). Under additive model and recessive model, rs11125529, rs12615793, rs843711, rs11896604, and rs17045754 also activated the risk of GC (P < 0.05). However, after Bonferroni's multiple adjusted was applied to our data, no SNP in our study was significantly related to GC risk. Further results of haplotype analysis founds that the haplotypes "TTCTAATG" (rs1682111, rs843752, rs10439478, rs843645, rs11125529, rs12615793, rs843711, and rs11896604) and "AC" (rs843706 and rs17045754) were more frequency among patients with GC, on the contrary, the haplotypes "CG" had a protective role in the GC risk (P < 0.05). Our results indicate that ACYP2 polymorphisms may influence the GC risk and may serve as a new precursory biomarker in the northwest Chinese Han population.},
}
@article {pmid28412741,
year = {2017},
author = {Jeitany, M and Bakhos-Douaihy, D and Silvestre, DC and Pineda, JR and Ugolin, N and Moussa, A and Gauthier, LR and Busso, D and Junier, MP and Chneiweiss, H and Chevillard, S and Desmaze, C and Boussin, FD},
title = {Opposite effects of GCN5 and PCAF knockdowns on the alternative mechanism of telomere maintenance.},
journal = {Oncotarget},
volume = {8},
number = {16},
pages = {26269-26280},
pmid = {28412741},
issn = {1949-2553},
mesh = {Cell Cycle/genetics ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression ; Gene Knockdown Techniques ; *Genetic Association Studies ; Genomic Instability ; Humans ; Intranuclear Inclusion Bodies/genetics/metabolism ; Leukemia, Promyelocytic, Acute/genetics/metabolism/pathology ; Protein Binding ; Sister Chromatid Exchange ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Translocation, Genetic ; p300-CBP Transcription Factors/*genetics ; },
abstract = {Cancer cells can use a telomerase-independent mechanism, known as alternative lengthening of telomeres (ALT), to elongate their telomeres. General control non-derepressible 5 (GCN5) and P300/CBP-associated factor (PCAF) are two homologous acetyltransferases that are mutually exclusive subunits in SAGA-like complexes. Here, we reveal that down regulation of GCN5 and PCAF had differential effects on some phenotypic characteristics of ALT cells. Our results suggest that GCN5 is present at telomeres and opposes telomere recombination, in contrast to PCAF that may indirectly favour them in ALT cells.},
}
@article {pmid28411413,
year = {2017},
author = {Cabeza de Baca, T and Epel, ES and Robles, TF and Coccia, M and Gilbert, A and Puterman, E and Prather, AA},
title = {Sexual intimacy in couples is associated with longer telomere length.},
journal = {Psychoneuroendocrinology},
volume = {81},
number = {},
pages = {46-51},
pmid = {28411413},
issn = {1873-3360},
support = {T32 MH019391/MH/NIMH NIH HHS/United States ; R21 HL117727/HL/NHLBI NIH HHS/United States ; R56 AG030424/AG/NIA NIH HHS/United States ; R01 AG030424/AG/NIA NIH HHS/United States ; K08 HL112961/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Female ; Granulocytes/physiology ; Humans ; Interpersonal Relations ; Leukocytes, Mononuclear/physiology ; Middle Aged ; *Personal Satisfaction ; Sexual Behavior/*physiology/*psychology ; Sexual Partners/*psychology ; Stress, Psychological/*metabolism ; Telomerase/metabolism ; Telomere Homeostasis/*physiology ; Young Adult ; },
abstract = {High-quality relationships have been shown to be beneficial for physical and mental health. This study examined overall relationship satisfaction and perceived stress as well as daily reports of partner support, partner conflict, and physical intimacy obtained over the course of one week in a sample of 129 high and low stress mothers. Telomere length was examined in whole blood, as well as the two cell subpopulations: peripheral blood mononuclear cells (PBMCs) and granulocytes. Telomerase activity was measured in PBMCs. Analyses revealed no statistically significant associations of telomere length with current relationship satisfaction, daily support or conflict, or perceived stress. In contrast, women who reported any sexual intimacy during the course of the week had significantly longer telomeres measured in whole blood and PBMCs, but not in granulocytes. These relationships held covarying for age, body mass index, perceived stress, the relationship indices, and caregiver status. Sexual intimacy was not significantly related to PBMC telomerase activity. These data provide preliminary data that sexual intimacy is associated with longer telomere length. Future studies investigating these associations are warranted.},
}
@article {pmid28410238,
year = {2017},
author = {Arsenis, NC and You, T and Ogawa, EF and Tinsley, GM and Zuo, L},
title = {Physical activity and telomere length: Impact of aging and potential mechanisms of action.},
journal = {Oncotarget},
volume = {8},
number = {27},
pages = {45008-45019},
pmid = {28410238},
issn = {1949-2553},
mesh = {Aging/physiology ; Animals ; *Exercise ; Humans ; Leukocytes/metabolism ; Oxidative Stress ; Telomerase/metabolism ; Telomere/*genetics/*metabolism ; *Telomere Homeostasis ; Telomere Shortening ; },
abstract = {Telomeres protect the integrity of information-carrying DNA by serving as caps on the terminal portions of chromosomes. Telomere length decreases with aging, and this contributes to cell senescence. Recent evidence supports that telomere length of leukocytes and skeletal muscle cells may be positively associated with healthy living and inversely correlated with the risk of several age-related diseases, including cancer, cardiovascular disease, obesity, diabetes, chronic pain, and stress. In observational studies, higher levels of physical activity or exercise are related to longer telomere lengths in various populations, and athletes tend to have longer telomere lengths than non-athletes. This relationship is particularly evident in older individuals, suggesting a role of physical activity in combating the typical age-induced decrements in telomere length. To date, a small number of exercise interventions have been executed to examine the potential influence of chronic exercise on telomere length, but these studies have not fully established such relationship. Several potential mechanisms through which physical activity or exercise could affect telomere length are discussed, including changes in telomerase activity, oxidative stress, inflammation, and decreased skeletal muscle satellite cell content. Future research is needed to mechanistically examine the effects of various modalities of exercise on telomere length in middle-aged and older adults, as well as in specific clinical populations.},
}
@article {pmid28407775,
year = {2017},
author = {Córdoba-Lanús, E and Cazorla-Rivero, S and Espinoza-Jiménez, A and de-Torres, JP and Pajares, MJ and Aguirre-Jaime, A and Celli, B and Casanova, C},
title = {Telomere shortening and accelerated aging in COPD: findings from the BODE cohort.},
journal = {Respiratory research},
volume = {18},
number = {1},
pages = {59},
pmid = {28407775},
issn = {1465-993X},
mesh = {Aging/*genetics ; Aging, Premature/*genetics ; Cohort Studies ; Disease Progression ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/epidemiology/*physiopathology ; Respiratory Function Tests/*statistics &amp; numerical data ; Severity of Illness Index ; Smoking/*genetics ; Spain/epidemiology ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) may be associated with accelerated aging. Telomere shortening is a biomarker of aging. Cross-sectional studies describe shorter telomeres in COPD compared with matched controls. No studies have described telomere length trajectory and its relationship with COPD progression. We investigated telomere shortening over time and its relationship to clinical and lung function parameters in a COPD cohort and smoker controls without COPD.<br><br>METHODS: At baseline leukocyte telomere length was measured by qPCR in 121 smokers with COPD and 121 without COPD matched by age (T/S0). The measurements were repeated in 70 of those patients with COPD and 73 non-COPD smokers after 3 years of follow up (T/S3).<br><br>RESULTS: At initial measurement, telomeres were shorter in COPD patients when compared to smoker controls (T/S&#x2009;=&#x2009;0.68&#x2009;&#xb1;&#x2009;0.25 vs. 0.88&#x2009;&#xb1;&#x2009;0.52, p&#x2009;=&#x2009;0.003) independent from age and sex. During the follow-up period, we observed an accelerated telomere shortening in individuals with COPD in contrast to smoker controls (T/S0&#x2009;=&#x2009;0.66&#x2009;&#xb1;&#x2009;0.21 vs. T/S3&#x2009;=&#x2009;0.46&#x2009;&#xb1;&#x2009;0.16, p&#x2009;<&#x2009;0.001, for the patients with COPD and T/S0&#x2009;=&#x2009;0.83&#x2009;&#xb1;&#x2009;0.56 vs. T/S3&#x2009;=&#x2009;0.74&#x2009;&#xb1;&#x2009;0.52, p&#x2009;=&#x2009;0.023 for controls; GLIM, p&#x2009;=&#x2009;0.001). This shortening was inversely related to the baseline telomere length (r&#x2009;=&#x2009;-0.49, p&#x2009;<&#x2009;0.001). No significant relationship was found between the rate of change in telomere length and change in lung function in the patients with COPD (p&#x2009;>&#x2009;0.05).<br><br>CONCLUSIONS: Compared with smokers, patients with COPD have accelerated telomere shortening and this rate of attrition depends on baseline telomere length. Furthermore, the telomere length and its rate of shortening did not relate to clinical and lung function parameters changes over 3 years of follow-up.},
}
@article {pmid28407508,
year = {2017},
author = {Coimbra, BM and Carvalho, CM and Moretti, PN and Mello, MF and Belangero, SI},
title = {Stress-related telomere length in children: A systematic review.},
journal = {Journal of psychiatric research},
volume = {92},
number = {},
pages = {47-54},
doi = {10.1016/j.jpsychires.2017.03.023},
pmid = {28407508},
issn = {1879-1379},
mesh = {Child ; Child, Preschool ; Developmental Disabilities/complications/*psychology ; Humans ; Stress, Psychological/complications/*genetics ; Telomere Shortening/*physiology ; },
abstract = {Telomeres are repetitive DNA sequences at the ends of chromatids that shorten following each cell replication. Once telomeres reach a critical length, DNA defense mechanisms can direct cells to either a state of arrest (senescence) or apoptosis. Stress induced by adversity is a probable cause of accelerated telomere shortening from an early age. However, few studies have examined the association between stress and telomere length in children, and it remains unclear whether young individuals may show signs of cellular aging early in life. Our aim was to examine whether adversity in childhood is associated with shortening of telomere length. We conducted a systematic review of studies that investigated the association between stress and telomere length in children from 3 to 15 years of age. Eleven studies met our selection criteria. We concluded that adversity in childhood (such as violence, low socioeconomic status, maternal depression, family disruption, and institutionalization) have an impact on telomere length. This suggests that exposed individuals show signs of accelerated erosion of telomeric ends from an early age. We discuss whether telomere shortening is related to negative health outcomes later in life or could be a biomarker predicting health outcomes. We believe that further large-scale longitudinal studies that repeatedly monitor telomere length are very important for providing a better assessment of telomere trajectory in psychologically stressed children. This will verify the extent to which adversity impacts upon the biological development of cell aging in childhood.},
}
@article {pmid28406492,
year = {2017},
author = {Druliner, BR and Ruan, X and Johnson, R and Grill, D and O'Brien, D and Lai, TP and Rashtak, S and Felmlee-Devine, D and Washechek-Aletto, J and Malykh, A and Smyrk, T and Oberg, A and Liu, H and Shay, JW and Ahlquist, DA and Boardman, LA},
title = {Time Lapse to Colorectal Cancer: Telomere Dynamics Define the Malignant Potential of Polyps.},
journal = {Clinical and translational gastroenterology},
volume = {8},
number = {4},
pages = {e88},
doi = {10.1038/ctg.2017.16},
pmid = {28406492},
issn = {2155-384X},
}
@article {pmid28406145,
year = {2017},
author = {Rossiello, F and Aguado, J and Sepe, S and Iannelli, F and Nguyen, Q and Pitchiaya, S and Carninci, P and d'Adda di Fagagna, F},
title = {Corrigendum: DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs.},
journal = {Nature communications},
volume = {8},
number = {},
pages = {15344},
doi = {10.1038/ncomms15344},
pmid = {28406145},
issn = {2041-1723},
}
@article {pmid28404999,
year = {2017},
author = {Onuora, S},
title = {Gout: Short telomeres in gout linked with flares and CVD.},
journal = {Nature reviews. Rheumatology},
volume = {13},
number = {6},
pages = {324},
pmid = {28404999},
issn = {1759-4804},
mesh = {*Cardiovascular Diseases ; *Gout ; Humans ; *Hyperuricemia ; Telomere ; },
}
@article {pmid28404540,
year = {2017},
author = {Liu, B and Yan, R and Zhang, J and Wang, B and Sun, H and Cui, X},
title = {Abnormal mRNA Expression Levels of Telomere-Binding Proteins Represent Biomarkers in Myelodysplastic Syndromes: A Case-Control Study.},
journal = {Turkish journal of haematology : official journal of Turkish Society of Haematology},
volume = {34},
number = {3},
pages = {200-206},
pmid = {28404540},
issn = {1308-5263},
mesh = {Adult ; Aged ; Biomarkers/metabolism ; Case-Control Studies ; Female ; *Gene Expression Regulation ; Humans ; Male ; Middle Aged ; Myelodysplastic Syndromes/genetics/*metabolism/pathology ; RNA, Messenger/*biosynthesis/genetics ; Risk Factors ; Shelterin Complex/*genetics ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/*biosynthesis/genetics ; },
abstract = {OBJECTIVE: As evidence was shown that abnormal shortening of telomeres begins to accumulate in myelodysplastic syndrome (MDS) patients, this study was conducted to determine the relationship between the mRNA expression levels of telomere-binding proteins (TRF1/TRF2/TIN2/TPP1/POT1/RAP1) and the risk level in MDS.<br><br>MATERIALS AND METHODS: There were 40 patients with MDS and 40 normal controls in this study. Methods including telomere content assays and quantitative reverse transcription-polymerase chain reaction were used to examine the mRNA levels of TRF1/TRF2/TIN2/TPP1/POT1/RAP1 in patients with MDS.<br><br>RESULTS: Compared to the normal group used as a control, the mRNA expression levels of RAP1/POT1/TPP1 of the patients with MDS were decreased, whereas their levels of TRF1/TRF2 and TIN2 were increased. A positive correlation was found between the TRF1, TRF2, and TIN2 mRNA expression levels and the risk level of the International Prognostic Scoring System (IPSS) and the World Health Organization Prognostic Scoring System (WPSS) criteria; however, a negative correlation was found between RAP1/POT1/TPP1 mRNA expression levels and the risk levels of IPSS and WPSS criteria.<br><br>CONCLUSION: Because the reduction of TRF1/TRF2/TIN2 mRNA expression and the increase of RAP1/POT1/TPP1 mRNA expression are closely related to the risk levels of the IPSS and WPSS criteria in MDS, it is thought that these telomere-binding proteins could lead to abnormal telomere length and function, which cause chromosomal abnormalities in MDS. With this evidence, we suggest that those proteins' mRNA expressions could be used as biomarkers for the assessment of the risk degree of MDS patients.},
}
@article {pmid28398700,
year = {2017},
author = {Martinez, AR and Kaul, Z and Parvin, JD and Groden, J},
title = {Differential requirements for DNA repair proteins in immortalized cell lines using alternative lengthening of telomere mechanisms.},
journal = {Genes, chromosomes &amp; cancer},
volume = {56},
number = {8},
pages = {617-631},
pmid = {28398700},
issn = {1098-2264},
support = {UL1 TR000090/TR/NCATS NIH HHS/United States ; R01 CA117898/CA/NCI NIH HHS/United States ; R21 CA198228/CA/NCI NIH HHS/United States ; T32 CA106196/CA/NCI NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; KL2 TR000112/TR/NCATS NIH HHS/United States ; TL1 TR000091/TR/NCATS NIH HHS/United States ; },
mesh = {DNA Repair ; DNA Repair Enzymes/*genetics/metabolism ; HeLa Cells ; Humans ; Neoplasms/*genetics ; *Telomere Homeostasis ; },
abstract = {Cancer cells require telomere maintenance to enable uncontrolled growth. Most often telomerase is activated, although a subset of human cancers are telomerase-negative and depend on recombination-based mechanisms known as ALT (Alternative Lengthening of Telomeres). ALT depends on proteins that are essential for homologous recombination, including BLM and the MRN complex, to extend telomeres. This study surveyed the requirement for requisite homologous recombination proteins, yet to be studied in human ALT cell lines, by protein depletion using RNA interference. Effects on ALT were evaluated by measuring C-circle abundance, a marker of ALT. Surprisingly, several proteins essential for homologous recombination, BARD1, BRCA2, and WRN, were dispensable for C-circle production, while PALB2 had varying effects on C-circles among ALT cell lines. Depletion of homologous recombination proteins BRCA1 and BLM, which have been previously studied in ALT, decreased C-circles in all ALT cell lines. Depletion of the non-homologous end joining proteins 53BP1 and LIG4 had no effect on C-circles in any ALT cell line. Proteins such as chromatin modifiers that recruit double-strand break proteins, RNF8 and RNF168, and other proteins loosely grouped into excision DNA repair processes, XPA, MSH2, and MPG, reduced C-circles in some ALT cell lines. MSH2 depletion also reduced recombination at telomeres as measured by intertelomeric exchanges. Collectively, the requirement for DNA repair proteins varied between the ALT cell lines compared. In sum, our study suggests that ALT proceeds by multiple mechanisms that differ between cell lines and that some of these depend on DNA repair proteins not associated with homologous recombination pathways.},
}
@article {pmid28397798,
year = {2017},
author = {Send, TS and Gilles, M and Codd, V and Wolf, I and Bardtke, S and Streit, F and Strohmaier, J and Frank, J and Schendel, D and Sütterlin, MW and Denniff, M and Laucht, M and Samani, NJ and Deuschle, M and Rietschel, M and Witt, SH},
title = {Telomere Length in Newborns is Related to Maternal Stress During Pregnancy.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {42},
number = {12},
pages = {2407-2413},
pmid = {28397798},
issn = {1740-634X},
support = {MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Cohort Studies ; Female ; Humans ; Infant, Newborn ; Male ; Pregnancy ; Pregnancy Complications/*genetics/*psychology ; Prospective Studies ; Self Report ; Stress, Psychological/complications/*genetics/*psychology ; Telomere/physiology ; Telomere Shortening/*physiology ; },
abstract = {Telomere length (TL) is a marker of biological aging, and numerous studies have shown associations between TL and somatic or psychiatric disorders. Research also indicates an association between maternal stress during pregnancy and TL in the offspring. The present study investigated possible associations between TL and: (1) maternal perceived stress during pregnancy; (2) a maternal lifetime history of psychiatric disorder (lifetime PD); and (3) paternal age. TL was analyzed in 319 newborns and 318 mothers from a predominantly Caucasian sample (n=273 Caucasian newborns and n=274 Caucasian mothers). Two key findings were observed. First, maternal perceived stress during pregnancy was associated with shorter telomeres in newborns but not with maternal TL. Second, maternal lifetime PD was associated with shorter maternal telomeres, but not with TL in newborns. Paternal age was not associated with TL in newborns. The finding that maternal stress during pregnancy is associated with shorter telomeres in newborns supports the results of smaller previous studies. The fact that a relation between maternal prenatal stress and TL was observed in the offspring but not in mothers may be attributable to a high vulnerability to stress during intrauterine development of a maturing organism. To our knowledge, this is the largest study to date to show that maternal stress during pregnancy but not maternal lifetime PD is associated with shorter telomeres in the offspring.},
}
@article {pmid28394764,
year = {2017},
author = {Steenstrup, T and Kark, JD and Verhulst, S and Thinggaard, M and Hjelmborg, JVB and Dalgård, C and Kyvik, KO and Christiansen, L and Mangino, M and Spector, TD and Petersen, I and Kimura, M and Benetos, A and Labat, C and Sinnreich, R and Hwang, SJ and Levy, D and Hunt, SC and Fitzpatrick, AL and Chen, W and Berenson, GS and Barbieri, M and Paolisso, G and Gadalla, SM and Savage, SA and Christensen, K and Yashin, AI and Arbeev, KG and Aviv, A},
title = {Telomeres and the natural lifespan limit in humans.},
journal = {Aging},
volume = {9},
number = {4},
pages = {1130-1142},
pmid = {28394764},
issn = {1945-4589},
support = {U10 HL054509/HL/NHLBI NIH HHS/United States ; R56 AG020098/AG/NIA NIH HHS/United States ; R01 HL087652/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; R01 HL080295/HL/NHLBI NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; U10 HL054472/HL/NHLBI NIH HHS/United States ; U01 HL054472/HL/NHLBI NIH HHS/United States ; U01 HL054471/HL/NHLBI NIH HHS/United States ; U01 HL054496/HL/NHLBI NIH HHS/United States ; R01 HL116446/HL/NHLBI NIH HHS/United States ; R01 AG015928/AG/NIA NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; N01 HC015103/HC/NHLBI NIH HHS/United States ; U01 HL054509/HL/NHLBI NIH HHS/United States ; R01 AG016592/AG/NIA NIH HHS/United States ; R01 ES021724/ES/NIEHS NIH HHS/United States ; UL1 TR000124/TR/NCATS NIH HHS/United States ; R01 HL080698/HL/NHLBI NIH HHS/United States ; N01HC55222/HL/NHLBI NIH HHS/United States ; P30 AG034424/AG/NIA NIH HHS/United States ; N01HC85086/HL/NHLBI NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; R01 AG020098/AG/NIA NIH HHS/United States ; N01HC75150/HL/NHLBI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; U10 HL054473/HL/NHLBI NIH HHS/United States ; U10 HL054495/HL/NHLBI NIH HHS/United States ; U10 HL054496/HL/NHLBI NIH HHS/United States ; U10 HL054471/HL/NHLBI NIH HHS/United States ; N01HC85079/HL/NHLBI NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; R01 AG027058/AG/NIA NIH HHS/United States ; N01 HC045133/HC/NHLBI NIH HHS/United States ; U01 HL054495/HL/NHLBI NIH HHS/United States ; N01 HC035129/HC/NHLBI NIH HHS/United States ; R56 AG023629/AG/NIA NIH HHS/United States ; R01 HL055673/HL/NHLBI NIH HHS/United States ; U01 HL054473/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/physiology ; Algorithms ; Blotting, Southern ; Cohort Studies ; Female ; Humans ; Leukocytes/ultrastructure ; Life Expectancy ; Longevity/*physiology ; Male ; Middle Aged ; Models, Biological ; Sex Characteristics ; Telomere/*physiology/ultrastructure ; *Telomere Shortening ; },
abstract = {An ongoing debate in demography has focused on whether the human lifespan has a maximal natural limit. Taking a mechanistic perspective, and knowing that short telomeres are associated with diminished longevity, we examined whether telomere length dynamics during adult life could set a maximal natural lifespan limit. We define leukocyte telomere length of 5 kb as the 'telomeric brink', which denotes a high risk of imminent death. We show that a subset of adults may reach the telomeric brink within the current life expectancy and more so for a 100-year life expectancy. Thus, secular trends in life expectancy should confront a biological limit due to crossing the telomeric brink.},
}
@article {pmid28393276,
year = {2017},
author = {Hinterberger, M and Fischer, P and Huber, K and Krugluger, W and Zehetmayer, S},
title = {Leukocyte telomere length is linked to vascular risk factors not to Alzheimer's disease in the VITA study.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {124},
number = {7},
pages = {809-819},
pmid = {28393276},
issn = {1435-1463},
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*pathology ; Cohort Studies ; Dementia, Vascular/*pathology ; Female ; Humans ; Leukocytes/pathology ; Longitudinal Studies ; Male ; Risk Factors ; *Telomere Shortening ; },
abstract = {Association of telomere shortening with overall dementia or Alzheimer's disease is described controversially and the pathophysiologic relevance is unclear. Whether patients, suffering from pure probable Alzheimer's disease or pure vascular dementia, have shorter leukocyte telomeres than cognitively healthy controls was determined. Leukocyte telomere lengths (LTLs) of 597 participants of the VITA study (longitudinal community-based age-cohort [mean 75.7 (±0.45) years] study: 243 male; 578 non-demented at baseline) were compared with different aspects of cognition, risk factors of dementia and survival. LTLs of 264 persons cognitively healthy at baseline (mild cognitive impaired excluded) and all follow-ups (mean = 5643 bp, SD = 736) did not show any difference to LTLs of 43 incident pure possible (mean = 5548 bp; SD = 666) or 34 incident pure probable Alzheimer's diseases (mean = 5712 bp; SD = 695; post hoc Dunnett test: MD = -95; SE = 119; p = 0.67 and MD =+68.3; SE = 132; p = 0.84, res.). 264 stably cognitively healthy showed a trend to longer telomeres than 6 incident vascular dementias (mean = 5643 bp, SD = 736 vs mean = 5101 bp, SD = 510; t test: T = 1.8; df = 268; p = 0.07). Males (n = 243; mean = 5470 bp; SD = 684) had significantly shorter telomeres than females (n = 354; mean = 5686 bp; SD = 714; t test: T = -3.7; df = 595; p = 0.0001) and died significantly earlier (113.7 vs 130.1 months: Log Rank Chi square = 12.2; p = 0.0001). Shorter telomeres were associated with prevalence of more than one vascular risk factor (n = 587; mean = 5728; SD = 723 vs mean = 5533; SD = 691; t test: T = 3.1; df = 576; p = 0.002) and, as a trend, with poorer survival (Cox Regression: Wald = 4.9; p = 0.026; OR = 0.98; 95% CI 0.96-0.99). In 75.7 years old persons, no association of LTL with incident pure Alzheimer's disease was found. Significantly shorter telomeres were associated with sum of vascular risk factors, males and early mortality in males. Exclusion of mixed dementias may improve the search for risk factors more specific for Alzheimer's disease.},
}
@article {pmid28392905,
year = {2017},
author = {Absalan, A and Mesbah-Namin, SA and Tiraihi, T and Taheri, T},
title = {Cinnamaldehyde and eugenol change the expression folds of AKT1 and DKC1 genes and decrease the telomere length of human adipose-derived stem cells (hASCs): An experimental and in silico study.},
journal = {Iranian journal of basic medical sciences},
volume = {20},
number = {3},
pages = {316-326},
pmid = {28392905},
issn = {2008-3866},
abstract = {OBJECTIVES: To investigate the effect of cinnamaldehyde and eugenol on the telomere-dependent senescence of stem cells. In addition, to search the probable targets of mentioned phytochemicals between human telomere interacting proteins (TIPs) using in silico studies.<br><br>MATERIALS AND METHODS: Human adipose derived stem cells (hASCs) were studied under treatments with 2.5 &#xb5;M/ml cinnamaldehyde, 0.1 &#xb5;g/ml eugenol, 0.01% DMSO or any additive. The expression of TERT, AKT1 and DKC1 genes and the telomere length were assessed over 48-hr treatment. In addition, docking study was conducted to show probable ways through which phytochemicals interact with TIPs.<br><br>RESULTS: Treated and untreated hASCs had undetectable TERT expression, but they had different AKT1 and DKC1 expression levels (CI=0.95; P<0.05). The telomere lengths were reduced in phytochemicals treated with hASCs when compared with the untreated cells (P<0.05). Docking results showed that the TIPs might be the proper targets for cinnamaldehyde and eugenol. Data mining showed there are many targets for cinnamaldehyde and eugenol in the intracellular environment.<br><br>CONCLUSION: The general effect of cinnamaldehyde and eugenol is their induction of stem cell senescence. Therefore, they could be applicable as chemo-preventive or antineoplastic agents.},
}
@article {pmid28389255,
year = {2017},
author = {Wang, Y and Wang, T and Dagnall, C and Haagenson, M and Spellman, SR and Hicks, B and Jones, K and Lee, SJ and Savage, SA and Gadalla, SM},
title = {Relative Telomere Length before Hematopoietic Cell Transplantation and Outcome after Unrelated Donor Hematopoietic Cell Transplantation for Acute Leukemia.},
journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation},
volume = {23},
number = {7},
pages = {1054-1058},
pmid = {28389255},
issn = {1523-6536},
support = {U24 CA076518/CA/NCI NIH HHS/United States ; Z99 CA999999//Intramural NIH HHS/United States ; ZIA CP010144-17//Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; Female ; Hematopoietic Stem Cell Transplantation/*methods ; Humans ; Infant ; Infant, Newborn ; Leukemia, Myeloid, Acute/pathology/*therapy ; Male ; Middle Aged ; Telomere/*genetics ; Transplantation Conditioning/*methods ; Treatment Outcome ; Young Adult ; },
abstract = {Telomeres are tandem nucleotide repeats and a protein complex located at the end of the chromosomes maintaining genomic stability. Their potential as a predictive biomarker for outcomes after allogeneic hematopoietic cell transplant (HCT) in hematologic malignancies is still unclear. From the Center for International Blood and Marrow Transplant Research we randomly selected 536 acute leukemia patients from those who underwent myeloablative 8/8 HLA-matched unrelated donor HCT between 2005 and 2012 and who had an available pre-HCT blood sample in the repository. Relative telomere length (RTL) was measured by real-time quantitative PCR. We used Kaplan-Meier and competing risk estimators to calculate survival probability and cumulative incidence, respectively, across patient RTL tertiles. Cox proportional hazard regression was used for adjusted analyses. The study included 396 acute myeloid leukemia (AML) and 140 acute lymphoblastic leukemia (ALL) patients. Median age at HCT was 41 years (range, .5 to 66), and median follow-up for survivors was 5.1 years (range, .4 to 8.3). Significant inverse correlations between age and RTL were observed in patients with AML (r = -.44, P < .0001) and ALL (r = -.48, P < .0001). Patients with ALL had longer RTL than those with AML (.48 versus .43, respectively); the difference was not statistically significant after adjusting for patient age (P = .96). Pre-HCT RTL in acute leukemia patients was not statistically significantly associated with overall survival (HR for longest RTL compared with shortest, .91; 95% CI, .65 to 1.28), disease-free survival (HR, .90; 95% CI, .64 to 1.25), transplant-related mortality (HR, .97; 95% CI, .60 to 1.59), incidence of relapse (HR, .89; 95% CI, .56 to 1.40), neutrophil engraftment (HR, 1.06; 95% CI, .85 to 1.32), or grades II to IV acute graft-versus-host disease (HR, 1.11; 95% CI, .81 to 1.53), grades III-IV acute graft-versus-host disease (HR, .92; 95% CI, .54 to 1.59), and chronic graft-versus-host disease (HR, 1.10; 95% CI, .81 to 1.50). In this study, recipient pre-HCT RTL had no prognostic role in post-transplant outcomes in acute leukemia patients.},
}
@article {pmid28384193,
year = {2017},
author = {Iglesias Molli, AE and Panero, J and Dos Santos, PC and González, CD and Vilariño, J and Sereday, M and Cerrone, GE and Slavutsky, I and Frechtel, GD},
title = {Metabolically healthy obese women have longer telomere length than obese women with metabolic syndrome.},
journal = {PloS one},
volume = {12},
number = {4},
pages = {e0174945},
pmid = {28384193},
issn = {1932-6203},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Humans ; Metabolic Syndrome/*genetics ; Middle Aged ; Obesity, Metabolically Benign/*genetics ; *Telomere ; Young Adult ; },
abstract = {INTRODUCTION: Obesity is the principal component in the Metabolic Syndrome (MetS) that determines the progression of metabolic complications. Metabolically healthy obese (MHO) individuals seem to be protected against those complications. Telomere length (TL) as a novel marker of cellular aging had a complex relationship to the MetS. The principal aim of this study was to investigate the TL in MHO, and to study the association between TL and the worsening of the metabolic condition.<br><br>MATERIAL AND METHODS: We have determined the absolute TL (aTL) in 400 women (mean age of 46.76 &#xb1; 15.47 years; range: 18-86 years), grouped according to the metabolic condition in three groups: metabolically healthy non-obese women (MHNO), MHO and obese women with MetS (MSO); and grouped according to the number of components of MetS.<br><br>RESULTS: We found that MHO displays significantly higher aTL than MSO (p = 0.033; r = -4.63; 95% CI r = -8.89 / -0.37), but did not differ from MHNO. A decrease in aTL with the progressive increase in the number of MetS components was also observed (p < 0.001; r = -2.06; 95% CI r = -3.13 / -0.99). In this way, our results indicate that aTL is influenced by the presence of MetS, but it is not affected by the presence of obesity.<br><br>DISCUSSION: We found that shorter aTL is not associated with MHO, but is related to MetS and with the increased number of metabolic abnormalities.},
}
@article {pmid28381620,
year = {2017},
author = {Rollings, N and Uhrig, EJ and Krohmer, RW and Waye, HL and Mason, RT and Olsson, M and Whittington, CM and Friesen, CR},
title = {Age-related sex differences in body condition and telomere dynamics of red-sided garter snakes.},
journal = {Proceedings. Biological sciences},
volume = {284},
number = {1852},
pages = {},
pmid = {28381620},
issn = {1471-2954},
mesh = {*Age Factors ; Animals ; Colubridae/*physiology ; Cross-Sectional Studies ; Female ; Male ; *Sex Characteristics ; Sexual Behavior, Animal ; Telomere/*ultrastructure ; },
abstract = {Life-history strategies vary dramatically between the sexes, which may drive divergence in sex-specific senescence and mortality rates. Telomeres are tandem nucleotide repeats that protect the ends of chromosomes from erosion during cell division. Telomeres have been implicated in senescence and mortality because they tend to shorten with stress, growth and age. We investigated age-specific telomere length in female and male red-sided garter snakes, Thamnophis sirtalis parietalis We hypothesized that age-specific telomere length would differ between males and females given their divergent reproductive strategies. Male garter snakes emerge from hibernation with high levels of corticosterone, which facilitates energy mobilization to fuel mate-searching, courtship and mating behaviours during a two to four week aphagous breeding period at the den site. Conversely, females remain at the dens for only about 4 days and seem to invest more energy in growth and cellular maintenance, as they usually reproduce biennially. As male investment in reproduction involves a yearly bout of physiologically stressful activities, while females prioritize self-maintenance, we predicted male snakes would experience more age-specific telomere loss than females. We investigated this prediction using skeletochronology to determine the ages of individuals and qPCR to determine telomere length in a cross-sectional study. For both sexes, telomere length was positively related to body condition. Telomere length decreased with age in male garter snakes, but remained stable in female snakes. There was no correlation between telomere length and growth in either sex, suggesting that our results are a consequence of divergent selection on life histories of males and females. Different selection on the sexes may be the physiological consequence of the sexual dimorphism and mating system dynamics displayed by this species.},
}
@article {pmid28381412,
year = {2017},
author = {Timashev, LA and Babcock, H and Zhuang, X and de Lange, T},
title = {The DDR at telomeres lacking intact shelterin does not require substantial chromatin decompaction.},
journal = {Genes &amp; development},
volume = {31},
number = {6},
pages = {578-589},
pmid = {28381412},
issn = {1549-5477},
support = {R01 GM105637/GM/NIGMS NIH HHS/United States ; 27302C0028/ES/NIEHS NIH HHS/United States ; R35 CA210036/CA/NCI NIH HHS/United States ; R56 AG016642/AG/NIA NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; Chromatin/physiology ; *DNA Damage ; Mice ; Microscopy, Fluorescence ; Telomere/*ultrastructure ; Telomeric Repeat Binding Protein 1/*physiology ; Telomeric Repeat Binding Protein 2/*physiology ; Tumor Suppressor p53-Binding Protein 1/physiology ; },
abstract = {Telomeres are protected by shelterin, a six-subunit protein complex that represses the DNA damage response (DDR) at chromosome ends. Extensive data suggest that TRF2 in shelterin remodels telomeres into the t-loop structure, thereby hiding telomere ends from double-stranded break repair and ATM signaling, whereas POT1 represses ATR signaling by excluding RPA. An alternative protection mechanism was suggested recently by which shelterin subunits TRF1, TRF2, and TIN2 mediate telomeric chromatin compaction, which was proposed to minimize access of DDR factors. We performed superresolution imaging of telomeres in mouse cells after conditional deletion of TRF1, TRF2, or both, the latter of which results in the complete loss of shelterin. Upon removal of TRF1 or TRF2, we observed only minor changes in the telomere volume in most of our experiments. Upon codeletion of TRF1 and TRF2, the telomere volume increased by varying amounts, but even those samples exhibiting small changes in telomere volume showed DDR at nearly all telomeres. Upon shelterin removal, telomeres underwent 53BP1-dependent clustering, potentially explaining at least in part the apparent increase in telomere volume. Furthermore, chromatin accessibility, as determined by ATAC-seq (assay for transposase-accessible chromatin [ATAC] with high-throughput sequencing), was not substantially altered by shelterin removal. These results suggest that the DDR induced by shelterin removal does not require substantial telomere decompaction.},
}
@article {pmid28380289,
year = {2017},
author = {Roberts, AL and Koenen, KC and Chen, Q and Gilsanz, P and Mason, SM and Prescott, J and Ratanatharathorn, A and Rimm, EB and Sumner, JA and Winning, A and De Vivo, I and Kubzansky, LD},
title = {Posttraumatic stress disorder and accelerated aging: PTSD and leukocyte telomere length in a sample of civilian women.},
journal = {Depression and anxiety},
volume = {34},
number = {5},
pages = {391-400},
pmid = {28380289},
issn = {1520-6394},
support = {R01 MH101269/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/metabolism ; Longitudinal Studies ; Middle Aged ; Nurses ; Stress Disorders, Post-Traumatic/*genetics ; Telomere Shortening/*genetics ; },
abstract = {BACKGROUND: Studies in male combat veterans have suggested posttraumatic stress disorder (PTSD) is associated with shorter telomere length (TL). We examined the cross-sectional association of PTSD with TL in women exposed to traumas common in civilian life.<br><br>METHODS: Data are from a substudy of the Nurses' Health Study II (N = 116). PTSD and subclinical PTSD were assessed in trauma-exposed women using diagnostic interviews. An array of health behaviors and conditions were assessed. DNA was extracted from peripheral blood leukocytes (collected 1996-1999). Telomere repeat copy number to single gene copy number (T/S) was determined by quantitative real-time PCR telomere assay. We used linear regression models to assess associations and examine whether a range of important health behaviors (e.g., cigarette smoking) and medical conditions (e.g., hypertension) previously associated with TL might explain a PTSD-TL association. We further examined whether type of trauma exposure (e.g., interpersonal violence) was associated with TL and whether trauma type might explain a PTSD-TL association.<br><br>RESULTS: Relative to not having PTSD, women with a PTSD diagnosis had shorter log-transformed TL (&#x3b2; = -.112, 95% confidence interval (CI) = -0.196, -0.028). Adjustment for health behaviors and medical conditions did not attenuate this association. Trauma type was not associated with TL and did not account for the association of PTSD with TL.<br><br>CONCLUSIONS: Our results add to growing evidence that PTSD may be associated with more rapid cellular aging as measured by telomere erosion. Moreover, the association could not be explained by health behaviors and medical conditions assessed in this study, nor by type of trauma exposure.},
}
@article {pmid28378522,
year = {2017},
author = {Peng, H and Yeh, F and Lin, J and Best, LG and Cole, SA and Lee, ET and Howard, BV and Zhao, J},
title = {Plasminogen activator inhibitor-1 is associated with leukocyte telomere length in American Indians: findings from the Strong Heart Family Study.},
journal = {Journal of thrombosis and haemostasis : JTH},
volume = {15},
number = {6},
pages = {1078-1085},
pmid = {28378522},
issn = {1538-7836},
support = {U01 HL041642/HL/NHLBI NIH HHS/United States ; U01 HL041654/HL/NHLBI NIH HHS/United States ; K01 AG034259/AG/NIA NIH HHS/United States ; R01 DK091369/DK/NIDDK NIH HHS/United States ; UL1 TR001409/TR/NCATS NIH HHS/United States ; R01 MH097018/MH/NIMH NIH HHS/United States ; U01 HL041652/HL/NHLBI NIH HHS/United States ; R21 HL092363/HL/NHLBI NIH HHS/United States ; R01 HL109284/HL/NHLBI NIH HHS/United States ; U01 HL065521/HL/NHLBI NIH HHS/United States ; R01 DK107532/DK/NIDDK NIH HHS/United States ; U01 HL065520/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Alcohol Drinking ; Arizona/ethnology ; Blood Glucose/analysis ; Blood Pressure ; Cross-Sectional Studies ; Exercise ; Female ; Healthy Volunteers ; Humans ; *Indians, North American ; Insulin/blood ; Kidney Function Tests ; Leukocytes/*cytology ; Life Style ; Longitudinal Studies ; Male ; Middle Aged ; North Dakota/ethnology ; Obesity/complications ; Oklahoma/ethnology ; Plasminogen Activator Inhibitor 1/*metabolism ; Smoking ; South Dakota/ethnology ; Telomere/*ultrastructure ; United States ; Young Adult ; },
abstract = {UNLABELLED: Essentials Plasminogen activator inhibitor-1 (PAI-1) advanced cellular senescence in experiment studies. No population study exists on the association between PAI-1 and biological aging in American Indians. We found cross-sectional and longitudinal associations between higher PAI-1 and shorter telomere length. Our findings suggest a pathway linking PAI-1 with biological aging beyond metabolic factors.<br><br>SUMMARY: Background Plasminogen activator inhibitor-1 (PAI-1) promotes cellular aging both in vitro and in vivo. Telomere length is a marker of biological aging. Objectives To examine the cross-sectional and longitudinal associations between plasma PAI-1 and leukocyte telomere length in a large-scale epidemiological study of American Indians. Methods We measured leukocyte telomere length (LTL) and plasma PAI-1 in 2560 American Indians who were free of overt cardiovascular disease (CVD) and participated in the Strong Heart Family Study (SHFS) clinical examination in 2001-2003. LTL and PAI-1 were repeatedly measured in 475 participants who attended SHFS clinical visits in both 2001-2003 and 1998-1999. A generalized estimating equation model was used to examine the cross-sectional and longitudinal associations between PAI-1 and LTL, adjusting for known risk factors. Results A higher level of plasma PAI-1 was negatively associated with shorter age-adjusted LTL (&#x3b2; = -0.023; 95% CI, -0.034 to -0.013). This association was attenuated (&#x3b2; = -0.015; 95% CI, -0.029 to -0.002) after adjustments for demographics, study site, lifestyle (smoking, drinking and physical activity) and metabolic factors (obesity, blood pressure, fasting glucose, insulin, lipids and kidney function). Further adjustment for hsCRP did not change this association (&#x3b2; = -0.015; 95% CI, -0.029 to -0.001). Longitudinal analysis revealed that change in plasma PAI-1 was also inversely associated with change in LTL after adjusting for demographics, follow-up years, lifestyle factors, changes in metabolic factors, baseline levels of PAI-1 and LTL (&#x3b2; = -0.0005; 95% CI, -0.0009 to -0.0001). Conclusions A higher level of plasma PAI-1 was associated with shorter LTL in American Indians. This finding may suggest a potential role of PAI-1 in biological aging among American Indians.},
}
@article {pmid28378341,
year = {2017},
author = {Liu, H and Lo, CM and Yeung, OWH and Li, CX and Liu, XB and Qi, X and Ng, KTP and Liu, J and Ma, YY and Lam, YF and Lian, Q and Chan, SC and Man, K},
title = {NLRP3 inflammasome induced liver graft injury through activation of telomere-independent RAP1/KC axis.},
journal = {The Journal of pathology},
volume = {242},
number = {3},
pages = {284-296},
doi = {10.1002/path.4901},
pmid = {28378341},
issn = {1096-9896},
mesh = {Acute Lung Injury/etiology/metabolism ; Adult ; Aged ; Animals ; Cytokines/metabolism ; Disease Models, Animal ; Female ; Gene Knockdown Techniques ; Hepatectomy/methods ; Humans ; Inflammasomes/*metabolism ; *Liver Transplantation ; Male ; Mice, Inbred C57BL ; Middle Aged ; NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism ; Neutrophils/metabolism ; Reperfusion Injury/metabolism ; Shelterin Complex ; Telomere-Binding Proteins/metabolism ; Up-Regulation/physiology ; Young Adult ; rap1 GTP-Binding Proteins/deficiency/metabolism ; },
abstract = {Acute-phase inflammation plays a critical role in liver graft injury. Inflammasomes, multi-molecular complexes in the cytoplasm, are responsible for initiating inflammation. Here, we aimed to explore the role of inflammasomes in liver graft injury and further to investigate the regulatory mechanism. In a clinical liver transplant cohort, we found that intragraft expression of nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes was significantly up-regulated post-transplantation. Importantly, overexpression of NLRP3 was strongly associated with poor liver function characterized by high levels of ALT, AST, and urea, as well as neutrophil infiltration after transplantation. The significant correlation between NLRP3 and IL-1β mRNA levels led us to focus on one of the associated upstream regulators, telomere-independent repressor activator protein 1 (RAP1), which was further proved to be co-localized with NLRP3 in neutrophils. In the liver of a mouse model (hepatic ischaemia/reperfusion and hepatectomy model) and isolated neutrophils from RAP1[-/-] mice, the expression levels of NLRP3 and keratinocyte chemoattractant (KC) were significantly down-regulated in contrast to those in wild types. The levels of ALT and AST, as well as the neutrophil infiltration, were also decreased by RAP1 deficiency. In our clinical validation, intragraft KC expression was associated with NLRP3 and co-localized with RAP1 in neutrophils. Furthermore, NLRP3 inflammasomes were up-regulated by recombinant KC in the isolated neutrophils and liver of the mouse model. Our data demonstrated that NLRP3 inflammasomes, activated by the RAP1/KC axis, played a critical role in initiating inflammation during the early stage of liver graft injury. Targeting RAP1/KC/NLRP3 inflammasomes may offer a new therapeutic strategy against liver graft injury. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.},
}
@article {pmid28376558,
year = {2017},
author = {Sierra-Miranda, M and Vembar, SS and Delgadillo, DM and Ávila-López, PA and Herrera-Solorio, AM and Lozano Amado, D and Vargas, M and Hernandez-Rivas, R},
title = {PfAP2Tel, harbouring a non-canonical DNA-binding AP2 domain, binds to Plasmodium falciparum telomeres.},
journal = {Cellular microbiology},
volume = {19},
number = {9},
pages = {},
doi = {10.1111/cmi.12742},
pmid = {28376558},
issn = {1462-5822},
mesh = {Antigenic Variation/*genetics/immunology ; Chromatin Immunoprecipitation ; DNA Probes/genetics ; DNA-Binding Proteins/*genetics/metabolism ; Electrophoretic Mobility Shift Assay ; High-Throughput Nucleotide Sequencing ; Malaria/immunology/parasitology ; Plasmodium falciparum/*genetics/immunology ; Protein Domains/*genetics ; Protein Serine-Threonine Kinases/genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*genetics/metabolism ; Transcription Factors/genetics ; },
abstract = {The telomeres of the malaria parasite Plasmodium falciparum are essential not only for chromosome end maintenance during blood stage development in humans but also to generate genetic diversity by facilitating homologous recombination of subtelomeric, multigene virulence families such as var and rifin. However, other than the telomerase PfTERT, proteins that act at P. falciparum telomeres are poorly characterised. To isolate components that bind to telomeres, we performed oligonucleotide pulldowns and electromobility shift assays with a telomeric DNA probe and identified a non-canonical member of the ApiAP2 family of transcription factors, PfAP2Tel (encoded by PF3D7_0622900), as a component of the P. falciparum telomere-binding protein complex. PfAP2Tel is expressed throughout the intra-erythrocytic life cycle and localises to the nuclear periphery, co-localising with telomeric clusters. Furthermore, EMSAs using the recombinant protein demonstrated direct binding of PfAP2Tel to telomeric repeats in vitro, while genome-wide chromatin immunoprecipitation followed by next generation sequencing corroborated the high specificity of this protein to telomeric ends of all 14 chromosomes in vivo. Taken together, our data describe a novel function for ApiAP2 proteins at chromosome ends and open new avenues to study the molecular machinery that regulates telomere function in P. falciparum.},
}
@article {pmid28375735,
year = {2017},
author = {Parks, JW and Stone, MD},
title = {Single-Molecule Studies of Telomeres and Telomerase.},
journal = {Annual review of biophysics},
volume = {46},
number = {},
pages = {357-377},
pmid = {28375735},
issn = {1936-1238},
support = {R01 GM095850/GM/NIGMS NIH HHS/United States ; R25 GM058903/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; DNA/genetics ; Humans ; Neoplasms/genetics/ultrastructure ; Single Molecule Imaging/methods ; Telomerase/chemistry/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres are specialized chromatin structures that protect chromosome ends from dangerous processing events. In most tissues, telomeres shorten with each round of cell division, placing a finite limit on cell growth. In rapidly dividing cells, including the majority of human cancers, cells bypass this growth limit through telomerase-catalyzed maintenance of telomere length. The dynamic properties of telomeres and telomerase render them difficult to study using ensemble biochemical and structural techniques. This review describes single-molecule approaches to studying how individual components of telomeres and telomerase contribute to function. Single-molecule methods provide a window into the complex nature of telomeres and telomerase by permitting researchers to directly visualize and manipulate the individual protein, DNA, and RNA molecules required for telomere function. The work reviewed in this article highlights how single-molecule techniques have been utilized to investigate the function of telomeres and telomerase.},
}
@article {pmid28373473,
year = {2017},
author = {Tahara, T and Tahara, S and Horiguchi, N and Kawamura, T and Okubo, M and Ishizuka, T and Yamada, H and Yoshida, D and Ohmori, T and Maeda, K and Komura, N and Ikuno, H and Jodai, Y and Kamano, T and Nagasaka, M and Nakagawa, Y and Tuskamoto, T and Urano, M and Shibata, T and Kuroda, M and Ohmiya, N},
title = {Telomere Length in Leukocyte DNA in Gastric Cancer Patients and its Association with Clinicopathological Features and Prognosis.},
journal = {Anticancer research},
volume = {37},
number = {4},
pages = {1997-2001},
doi = {10.21873/anticanres.11543},
pmid = {28373473},
issn = {1791-7530},
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/genetics ; DNA, Neoplasm/*genetics ; Female ; Humans ; Leukocytes/*pathology ; Liver Neoplasms/genetics/*secondary ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Invasiveness ; Neoplasm Staging ; Peritoneal Neoplasms/genetics/*secondary ; Prognosis ; Real-Time Polymerase Chain Reaction ; Risk Factors ; Stomach Neoplasms/genetics/*pathology ; Survival Rate ; Telomere/*genetics ; Telomere Shortening ; },
abstract = {BACKGROUND/AIM: Telomere shortening in leukocytes has been thought to be associated with reduced immune response capacity and increased chromosome instability. Several studies indicate that telomere length in the peripheral blood leukocyte DNA can predict clinical outcome of several cancers. We evaluated the potential association between telomere shortening in the leukocyte DNA and clinicopathological features and prognosis of gastric cancer (GC) in Japanese patients.<br><br>MATERIALS AND METHODS: Telomere length in leukocyte DNA was measured using quantitative real-time polymerase chain reaction (PCR) in 207 GC patients. The association between telomere length and clinicopathological features and prognosis was evaluated.<br><br>RESULTS: These short-telomere group was significantly associated with advanced stage (p=0.015), worse overall survival (OS) and progression-free survival (PFS) (p=0.046 and 0.026, respectively). The same group was also weakly associated with overall and peritoneal recurrences (p=0.052 and 0.059, respectively).<br><br>CONCLUSION: Telomere shortening in leukocyte DNA is associated with advanced stage and poor prognosis of GC, which may reflect their reduced immune response capacity or increased chromosome instability.},
}
@article {pmid28373169,
year = {2017},
author = {Lynch, SM and Mitra, N and Ravichandran, K and Mitchell, J and Spangler, E and Zhou, W and Paskett, ED and Gehlert, S and DeGraffinreid, C and Stowe, R and Dubowitz, T and Riethman, H and Branas, CC and Peek, MK and Rebbeck, TR},
title = {Telomere Length and Neighborhood Circumstances: Evaluating Biological Response to Unfavorable Exposures.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {26},
number = {4},
pages = {553-560},
pmid = {28373169},
issn = {1538-7755},
support = {P60 MD006900/MD/NIMHD NIH HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; R01 CA085074/CA/NCI NIH HHS/United States ; P50 CA105641/CA/NCI NIH HHS/United States ; F31 AG039986/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Biomarkers/blood ; Cross-Sectional Studies ; Female ; Humans ; Linear Models ; Male ; Middle Aged ; Residence Characteristics/*classification ; Social Class ; Surveys and Questionnaires ; Telomere/*physiology ; *Telomere Shortening ; United States ; *Urban Population ; },
abstract = {Background: Multilevel frameworks suggest neighborhood circumstances influence biology; however, this relationship is not well studied. Telomere length (TL) shortening has been associated with individual-level and neighborhood-level exposures and disease and may provide insights into underlying biologic mechanisms linking neighborhood with biology. To support neighborhood-biology investigations, we sought to determine the independent effect of neighborhood exposures on TL using standard multilevel linear regression models and quantile regression, a nonlinear, social science method applicable for testing the biologic hypothesis that extremes of the TL distribution are related to poor outcomes.Methods: In a multicenter, cross-sectional study, blood TL was measured in 1,488 individuals from 127 census tracts in three U.S. regions using terminal restriction fragment assays. Multilevel linear and quantile regression models were adjusted for individual-level race, education, perceived stress, and depression. Neighborhood exposures included population density, urban/residential crowding, residential stability/mobility, and socioeconomic status.Results: TL was not associated with any neighborhood variable using linear models, but quantile regression revealed inverse associations between population density and urban crowding at the lower tails of the TL distribution [5th (population density P = 0.03; urban crowding P = 0.002), 50th (both P < 0.001), 75th percentiles (both P < 0.001)]. TL was related to residential stability at the upper tail (95th percentile P = 0.006).Conclusions: Findings support the use of nonlinear statistical methods in TL research and suggest that neighborhood exposures can result in biological effects.Impact: TL may serve as an underlying example of a biologic mechanism that can link neighborhood with biology, thus supporting multilevel investigations in future studies. Cancer Epidemiol Biomarkers Prev; 26(4); 553-60. ©2017 AACRSee all the articles in this CEBP Focus section, "Geospatial Approaches to Cancer Control and Population Sciences."},
}
@article {pmid28373051,
year = {2017},
author = {Lopez-Anton, M and Rudolf, A and Baird, DM and Roger, L and Jones, RE and Witowski, J and Fraser, DJ and Bowen, T},
title = {Telomere length profiles in primary human peritoneal mesothelial cells are consistent with senescence.},
journal = {Mechanisms of ageing and development},
volume = {164},
number = {},
pages = {37-40},
doi = {10.1016/j.mad.2017.03.010},
pmid = {28373051},
issn = {1872-6216},
support = {18246/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Cellular Senescence/*physiology ; Epithelial Cells/cytology/*metabolism ; Epithelium/metabolism ; Humans ; Peritoneum/cytology/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {Mesothelial cell (MC) senescence contributes to malignancy and tissue fibrosis. The role of telomere erosion in MC senescence remains controversial, with evidence for both telomere-dependent and telomere-independent mechanisms reported. Single telomere length analysis revealed considerable telomere length heterogeneity in freshly isolated human peritoneal MCs, reflecting a heterogeneous proliferative history and providing high-resolution evidence for telomere-dependent senescence. By contrast the attenuated replicative lifespan, lack of telomere erosion and induction of p16 expression in in vitro-aged cells was consistent with stress-induced senescence. Given the potential pathophysiological impact of senescence in mesothelial tissues, high-resolution MC telomere length analysis may provide clinically useful information.},
}
@article {pmid28371511,
year = {2017},
author = {VandenBussche, CJ and Allison, DB and Graham, MK and Charu, V and Lennon, AM and Wolfgang, CL and Hruban, RH and Heaphy, CM},
title = {Alternative lengthening of telomeres and ATRX/DAXX loss can be reliably detected in FNAs of pancreatic neuroendocrine tumors.},
journal = {Cancer cytopathology},
volume = {125},
number = {7},
pages = {544-551},
pmid = {28371511},
issn = {1934-6638},
support = {P50 CA062924/CA/NCI NIH HHS/United States ; T32 GM007309/GM/NIGMS NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing/*genetics ; Adult ; Aged ; Biopsy, Fine-Needle ; Co-Repressor Proteins ; Cohort Studies ; DNA Helicases/*genetics ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Molecular Chaperones ; Neuroendocrine Tumors/*genetics/mortality/pathology ; Nuclear Proteins/*genetics ; Pancreatic Neoplasms/*genetics/mortality/pathology ; Proportional Hazards Models ; Retrospective Studies ; Survival Rate ; Telomere Homeostasis/*genetics ; X-linked Nuclear Protein ; },
abstract = {BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) frequently use the alternative lengthening of telomeres (ALT) pathway for telomere maintenance. ALT is strongly correlated with α thalassemia-mental retardation, X linked (ATRX), and death domain-associated protein 6 (DAXX) alterations and a poor prognosis in patients with primary PanNET. Because fine-needle aspiration (FNA) is a noninvasive way to sample tumors, the authors evaluated whether they could accurately detect ALT and loss of ATRX/DAXX in a primary PanNET cohort of FNAs.<br><br>METHODS: All preoperative FNA cytology cases (2005-2016) with adequate remnant FNA cell block material were assessed for ALT by telomere-specific fluorescence in situ hybridization and for ATRX and DAXX protein expression by immunohistochemistry. For 21 patients who underwent tumor resection, the resected specimen also was assessed to determine the concordance between the FNA and surgical specimens.<br><br>RESULTS: In the primary PanNET cohort of 65 FNAs, ALT was detected in 15 specimens (23%). Although all ATRX-negative and DAXX-negative tumors were ALT-positive, 3 of 14 (21%) ALT-positive tumors did not exhibit nuclear loss of either ATRX or DAXX. The ALT-positive tumors were associated with larger radiographic size (4.9 vs 2.4 cm, on average; P < .05) and higher grade (P < .05). Overall, there was 100% concordance in ALT status and ATRX/DAXX immunohistochemistry results between the FNA and surgical specimens.<br><br>CONCLUSIONS: Both ALT and loss of ATRX/DAXX can be accurately performed on FNA specimens with adequate material. Because ALT is a fundamental mechanism of pathogenesis, the ability to determine ALT in small biospecimens has implications for the design of clinical trials. Cancer Cytopathol 2017;125:544-51. &#xa9; 2017 American Cancer Society.},
}
@article {pmid28370751,
year = {2017},
author = {Young, RC and Welcker, J and Barger, CP and Hatch, SA and Merkling, T and Kitaiskaia, EV and Haussmann, MF and Kitaysky, AS},
title = {Effects of developmental conditions on growth, stress and telomeres in black-legged kittiwake chicks.},
journal = {Molecular ecology},
volume = {26},
number = {13},
pages = {3572-3584},
doi = {10.1111/mec.14121},
pmid = {28370751},
issn = {1365-294X},
mesh = {Animals ; *Body Size ; Charadriiformes/genetics/*growth &amp; development ; Clutch Size ; Female ; Food ; Male ; Phenotype ; Social Environment ; *Stress, Physiological ; Telomere/*ultrastructure ; },
abstract = {Early-life conditions can drive ageing patterns and life history strategies throughout the lifespan. Certain social, genetic and nutritional developmental conditions are more likely to produce high-quality offspring: those with good likelihood of recruitment and productivity. Here, we call such conditions "favoured states" and explore their relationship with physiological variables during development in a long-lived seabird, the black-legged kittiwake (Rissa tridactyla). Two favoured states were experimentally generated by manipulation of food availability and brood size, while hatching order and sex were also explored as naturally generating favoured states. Thus, the favoured states we explored were high food availability, lower levels of sibling competition, hatching first and male sex. We tested the effects of favoured developmental conditions on growth, stress, telomere length (a molecular marker associated with lifespan) and nestling survival. Generation of favoured states through manipulation of both the nutritional and social environments furthered our understanding of their relative contributions to development and phenotype: increased food availability led to larger body size, reduced stress and higher antioxidant status, while lower sibling competition (social environment) led to lower telomere loss and longer telomere lengths in fledglings. Telomere length predicted nestling survival, and wing growth was also positively correlated with telomere length, supporting the idea that telomeres may indicate individual quality, mediated by favoured states.},
}
@article {pmid28369711,
year = {2018},
author = {Ghione, P and Genuardi, E and Rossi, D and Drandi, D and Mantoan, B and Barbero, D and Bernocco, E and Monitillo, L and Cerri, M and Ruggeri, M and Omede, P and Deambrogi, C and De Paoli, L and Passera, R and Coscia, M and Cavallo, F and Massaia, M and Boccadoro, M and Gaidano, G and Ladetto, M and Ferrero, S},
title = {Progressive telomere shortening is part of the natural history of chronic lymphocytic leukaemia and impacts clinical outcome: evidences from long term follow-up.},
journal = {British journal of haematology},
volume = {181},
number = {5},
pages = {693-695},
doi = {10.1111/bjh.14681},
pmid = {28369711},
issn = {1365-2141},
mesh = {Aged ; Aged, 80 and over ; Disease-Free Survival ; Female ; Follow-Up Studies ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*metabolism/*mortality/pathology/therapy ; Male ; Survival Rate ; Telomere/*metabolism/pathology ; *Telomere Homeostasis ; },
}
@article {pmid28369633,
year = {2017},
author = {Carrillo, J and Calvete, O and Pintado-Berninches, L and Manguan-García, C and Sevilla Navarro, J and Arias-Salgado, EG and Sastre, L and Guenechea, G and López Granados, E and de Villartay, JP and Revy, P and Benitez, J and Perona, R},
title = {Mutations in XLF/NHEJ1/Cernunnos gene results in downregulation of telomerase genes expression and telomere shortening.},
journal = {Human molecular genetics},
volume = {26},
number = {10},
pages = {1900-1914},
doi = {10.1093/hmg/ddx098},
pmid = {28369633},
issn = {1460-2083},
mesh = {Cell Line ; Child ; DNA Repair Enzymes/blood/*genetics/*metabolism ; DNA-Binding Proteins/blood/*genetics/*metabolism ; Down-Regulation ; Gene Expression ; Humans ; Male ; Mutation/genetics ; Telomerase/*genetics ; Telomere/genetics/metabolism ; Telomere Homeostasis ; Telomere Shortening/genetics ; },
abstract = {NHEJ1-patients develop severe progressive lymphocytopenia and premature aging of hematopoietic stem cells (HSCs) at a young age. Here we show a patient with a homozygous-NHEJ1 mutation identified by whole exome-sequencing that developed severe pancytopenia and bone marrow aplasia correlating with the presence of short telomeres. The mutation resulted in a truncated protein. In an attempt to identify the mechanism behind the short telomere phenotype found in the NHEJ1-patient we downregulated NHEJ1 expression in 293T and CD34+cells. This downregulation resulted in reduced telomerase activity and decreased expression of several telomerase/shelterin genes. Interestingly, cell lines derived from two other NHEJ1-deficient patients with different mutations also showed increased p21 expression, inhibition in expression of several telomerase complex genes and shortened telomeres. Decrease in expression of telomerase/shelterin genes did not occur when we inhibited expression of other NHEJ genes mutated in SCID patients: DNA-PK, Artemis or LigaseIV. Because premature aging of HSCs is observed only in NHEJ1 patients, we propose that is the result of senescence induced by decreased expression of telomerase/shelterin genes that lead to an inhibition of telomerase activity. Previous reports failed to find this connection because of the use of patient´s cells immortalized by TERT expression or recombined telomeres by ALT pathway. In summary, defective regulation of telomere biology together with defective V(D)J recombination can negatively impact on the evolution of the disease in these patients. Identification of telomere shortening is important since it may open new therapeutic interventions for these patients by treatments aimed to recover the expression of telomerase genes.},
}
@article {pmid28369628,
year = {2017},
author = {Koskas, S and Decottignies, A and Dufour, S and Pezet, M and Verdel, A and Vourc'h, C and Faure, V},
title = {Heat shock factor 1 promotes TERRA transcription and telomere protection upon heat stress.},
journal = {Nucleic acids research},
volume = {45},
number = {11},
pages = {6321-6333},
pmid = {28369628},
issn = {1362-4962},
mesh = {HeLa Cells ; Heat Shock Transcription Factors/*physiology ; Heat-Shock Response ; Humans ; RNA Stability ; RNA, Long Noncoding/*genetics/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; Transcription, Genetic ; Transcriptional Activation ; },
abstract = {In response to metabolic or environmental stress, cells activate powerful defense mechanisms to prevent the formation and accumulation of toxic protein aggregates. The main orchestrator of this cellular response is HSF1 (heat shock factor 1), a transcription factor involved in the up-regulation of protein-coding genes with protective roles. It has become very clear that HSF1 has a broader function than initially expected. Indeed, our previous work demonstrated that, upon stress, HSF1 activates the transcription of a non-coding RNA, named Satellite III, at pericentromeric heterochromatin. Here, we observe that the function of HSF1 extends to telomeres and identify subtelomeric DNA as a new genomic target of HSF1. We show that the binding of HSF1 to subtelomeric regions plays an essential role in the upregulation of non-coding TElomeric Repeat containing RNA (TERRA) transcription upon heat shock. Importantly, our data show that telomere integrity is impacted by heat shock and that telomeric DNA damages are markedly enhanced in HSF1 deficient cells. Altogether, our findings reveal a new direct and essential function of HSF1 in the transcriptional activation of TERRA and in telomere protection upon stress.},
}
@article {pmid28369604,
year = {2017},
author = {Yang, CC and Tseng, SM and Pan, HY and Huang, CH and Chen, CW},
title = {Telomere associated primase Tap repairs truncated telomeres of Streptomyces.},
journal = {Nucleic acids research},
volume = {45},
number = {10},
pages = {5838-5849},
pmid = {28369604},
issn = {1362-4962},
mesh = {Bacterial Proteins/*genetics/metabolism ; Base Pairing ; Base Sequence ; Chromosomes, Bacterial/chemistry ; DNA Primase/*genetics/metabolism ; *DNA Repair ; *DNA Replication ; Nucleic Acid Conformation ; Plasmids/chemistry/metabolism ; Streptomyces coelicolor/*genetics/metabolism ; Streptomyces lividans/*genetics/metabolism ; Telomere/chemistry/*metabolism ; },
abstract = {Replication of the linear chromosomes of soil bacteria Streptomyces proceeds from an internal origin towards the telomeres, followed by patching of the resulting terminal single-strand overhangs by DNA synthesis using terminal proteins as the primer, which remains covalently bound to the 5΄ ends of the DNA. In most Streptomyces chromosomes, the end patching requires the single-strand overhangs, terminal protein Tpg, and terminal associated protein Tap. The telomere overhangs contain several palindromic sequences capable of forming stable hairpins. Previous in vitro deoxynucleotidylation studies indicated that Tap adds the Palindrome I sequence to Tpg, which is extended by a polymerase to fill the gap. In this study, the stringency of Palindrome I sequence was examined by an in vitro deoxynucleotidylation system and in vivo replication. Several nt in Palindrome I were identified to be critical for priming. While the first 3 G on the template were required for deoxynucleotidylation in vitro, deletions of them could be suppressed by the presence of dGTP. In vivo, deletions of these G were also tolerated, and the telomere sequence was restored in the linear plasmid DNA. Our results indicated that the truncated telomeres were repaired by extension synthesis by Tap on the foldback Palindrome I sequence.},
}
@article {pmid28366536,
year = {2017},
author = {Huang, C and Jia, P and Chastain, M and Shiva, O and Chai, W},
title = {The human CTC1/STN1/TEN1 complex regulates telomere maintenance in ALT cancer cells.},
journal = {Experimental cell research},
volume = {355},
number = {2},
pages = {95-104},
pmid = {28366536},
issn = {1090-2422},
support = {R01 GM112864/GM/NIGMS NIH HHS/United States ; R56 AG046292/AG/NIA NIH HHS/United States ; },
mesh = {Cell Proliferation ; Humans ; Telomere/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/*metabolism ; Tumor Cells, Cultured ; },
abstract = {Maintaining functional telomeres is important for long-term proliferation of cells. About 15% of cancer cells are telomerase-negative and activate the alternative-lengthening of telomeres (ALT) pathway to maintain their telomeres. Recent studies have shown that the human CTC1/STN1/TEN1 complex (CST) plays a multi-faceted role in telomere maintenance in telomerase-expressing cancer cells. However, the role of CST in telomere maintenance in ALT cells is unclear. Here, we report that human CST forms a functional complex localizing in the ALT-associated PML bodies (APBs) in ALT cells throughout the cell cycle. Suppression of CST induces telomere instabilities including telomere fragility and elevates telomeric DNA recombination, leading to telomere dysfunction. In addition, CST deficiency significantly diminishes the abundance of extrachromosomal circular telomere DNA known as C-circles and t-circles. Suppression of CST also results in multinucleation in ALT cells and impairs cell proliferation. Our findings imply that the CST complex plays an important role in regulating telomere maintenance in ALT cells.},
}
@article {pmid28362812,
year = {2017},
author = {Letsolo, BT and Jones, RE and Rowson, J and Grimstead, JW and Keith, WN and Jenkins, GJ and Baird, DM},
title = {Extensive telomere erosion is consistent with localised clonal expansions in Barrett's metaplasia.},
journal = {PloS one},
volume = {12},
number = {3},
pages = {e0174833},
pmid = {28362812},
issn = {1932-6203},
support = {18246/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Adenocarcinoma/genetics/*metabolism ; Barrett Esophagus/genetics/*metabolism ; Disease Progression ; Esophageal Neoplasms/genetics/*metabolism ; Gastric Mucosa/*metabolism ; Humans ; Telomere/*metabolism ; },
abstract = {Barrett's oesophagus is a premalignant metaplastic condition that predisposes patients to the development of oesophageal adenocarcinoma. However, only a minor fraction of Barrett's oesophagus patients progress to adenocarcinoma and it is thus essential to determine bio-molecular markers that can predict the progression of this condition. Telomere dysfunction is considered to drive clonal evolution in several tumour types and telomere length analysis provides clinically relevant prognostic and predictive information. The aim of this work was to use high-resolution telomere analysis to examine telomere dynamics in Barrett's oesophagus. Telomere length analysis of XpYp, 17p, 11q and 9p, chromosome arms that contain key cancer related genes that are known to be subjected to copy number changes in Barrett's metaplasia, revealed similar profiles at each chromosome end, indicating that no one specific telomere is likely to suffer preferential telomere erosion. Analysis of patient matched tissues (233 samples from 32 patients) sampled from normal squamous oesophagus, Z-line, and 2 cm intervals within Barrett's metaplasia, plus oesophago-gastric junction, gastric body and antrum, revealed extensive telomere erosion in Barrett's metaplasia to within the length ranges at which telomere fusion is detected in other tumour types. Telomere erosion was not uniform, with distinct zones displaying more extensive erosion and more homogenous telomere length profiles. These data are consistent with an extensive proliferative history of cells within Barrett's metaplasia and are indicative of localised clonal growth. The extent of telomere erosion highlights the potential of telomere dysfunction to drive genome instability and clonal evolution in Barrett's metaplasia.},
}
@article {pmid28362624,
year = {2017},
author = {Colicino, E and Wilson, A and Frisardi, MC and Prada, D and Power, MC and Hoxha, M and Dioni, L and Spiro, A and Vokonas, PS and Weisskopf, MG and Schwartz, JD and Baccarelli, AA},
title = {Erratum: "Telomere Length, Long-Term Black Carbon Exposure, and Cognitive Function in a Cohort of Older Men: The VA Normative Aging Study".},
journal = {Environmental health perspectives},
volume = {125},
number = {4},
pages = {A63},
doi = {10.1289/EHP1813},
pmid = {28362624},
issn = {1552-9924},
support = {P30 ES009089/ES/NIEHS NIH HHS/United States ; },
}
@article {pmid28353602,
year = {2017},
author = {Zhu, L and Liu, L and He, X and Yan, M and Du, J and Yang, H and Zhang, Y and Yuan, D and Jin, T},
title = {Association between genetic polymorphism of telomere-associated gene ACYP2 and the risk of HAPE among the Chinese Han population: A Case-control study.},
journal = {Medicine},
volume = {96},
number = {13},
pages = {e6504},
pmid = {28353602},
issn = {1536-5964},
mesh = {Acid Anhydride Hydrolases/*genetics ; Adult ; Altitude Sickness/*genetics ; Asian People/genetics ; Case-Control Studies ; China ; Female ; Humans ; Hypertension, Pulmonary/*genetics ; Male ; Polymorphism, Single Nucleotide ; Telomere Homeostasis ; Young Adult ; },
abstract = {High-altitude pulmonary edema (HAPE) is a hypoxia-induced, life-threatening, pulmonary edema, which is characterized by exaggerated pulmonary hypertension caused by stress failure. ACYP2 was found to associated with telomere length, the aim of this study was to identify whether ACYP2 polymorphisms increase or decrease HAPE risk in the Chinese Han individuals.In present study, we have genotyped 7 single-nucleotide polymorphisms (SNPs) in ACYP2 to determine the haplotypes in a case-control study with 265 HAPE patients and 303 healthy individuals. Genotypes were determined using the Sequenom MassARRAY method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression with adjustment for gender and age. We found 3 SNPs yielded significant evidence for association with HAPE risk which had not been investigated before. Rs6713088 was found to have a 1.85- and 1.30-fold increased risk of HAPE in the recessive and additive model. The GT of rs843752 also conferred an increased risk of HAPE (GT/TT: OR = 1.51, 95% CI: 1.05-2.16, P = 0.026) and the genotype frequency distributions of rs843752 had significant difference between cases and controls. The CC genotype of rs17045754 had a protect effect on HAPE patients, and it was found to have a 0.29-fold reduced risk of HAPE in the recessive model.Although additional, larger population-based studies are needed to confirm these findings, our study shed light on the association between ACYP2 variant and HAPE risk in Han Chinese population for the first time.},
}
@article {pmid28350373,
year = {2017},
author = {Higa, M and Fujita, M and Yoshida, K},
title = {DNA Replication Origins and Fork Progression at Mammalian Telomeres.},
journal = {Genes},
volume = {8},
number = {4},
pages = {},
pmid = {28350373},
issn = {2073-4425},
abstract = {Telomeres are essential chromosomal regions that prevent critical shortening of linear chromosomes and genomic instability in eukaryotic cells. The bulk of telomeric DNA is replicated by semi-conservative DNA replication in the same way as the rest of the genome. However, recent findings revealed that replication of telomeric repeats is a potential cause of chromosomal instability, because DNA replication through telomeres is challenged by the repetitive telomeric sequences and specific structures that hamper the replication fork. In this review, we summarize current understanding of the mechanisms by which telomeres are faithfully and safely replicated in mammalian cells. Various telomere-associated proteins ensure efficient telomere replication at different steps, such as licensing of replication origins, passage of replication forks, proper fork restart after replication stress, and dissolution of post-replicative structures. In particular, shelterin proteins have central roles in the control of telomere replication. Through physical interactions, accessory proteins are recruited to maintain telomere integrity during DNA replication. Dormant replication origins and/or homology-directed repair may rescue inappropriate fork stalling or collapse that can cause defects in telomere structure and functions.},
}
@article {pmid28348385,
year = {2018},
author = {Verhoeven, JE and Révész, D and Picard, M and Epel, EE and Wolkowitz, OM and Matthews, KA and Penninx, BWJH and Puterman, E},
title = {Depression, telomeres and mitochondrial DNA: between- and within-person associations from a 10-year longitudinal study.},
journal = {Molecular psychiatry},
volume = {23},
number = {4},
pages = {850-857},
pmid = {28348385},
issn = {1476-5578},
support = {HHSN268201300025C/HL/NHLBI NIH HHS/United States ; HHSN268201300026C/HL/NHLBI NIH HHS/United States ; HHSN268201300027C/HL/NHLBI NIH HHS/United States ; HHSN268201300028C/HL/NHLBI NIH HHS/United States ; HHSN268201300029C/HL/NHLBI NIH HHS/United States ; HHSN268200900041C/HL/NHLBI NIH HHS/United States ; K99 HL109247/HL/NHLBI NIH HHS/United States ; R00 HL109247/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Cellular Senescence ; Cross-Sectional Studies ; DNA Copy Number Variations/genetics ; DNA, Mitochondrial/*genetics ; Depression/*genetics/metabolism ; Depressive Disorder/metabolism ; Female ; Genetic Association Studies/methods ; Humans ; Leukocytes/metabolism ; Longitudinal Studies ; Male ; Middle Aged ; Mitochondria ; Risk Factors ; Telomere/*genetics ; Telomere Shortening ; },
abstract = {Alterations in cellular aging, indexed by leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn), might partly account for the increased health risks in persons with depression. Although some studies indeed found cross-sectional associations of depression with LTL and mtDNAcn, the longitudinal associations remain unclear. This 10-year longitudinal study examined between- and within-person associations of depressive symptoms with LTL and mtDNAcn in a large community sample. Data are from years 15, 20 and 25 follow-up evaluations in 977 subjects from the Coronary Artery Risk Development in Young Adults study. Depressive symptoms (years 15, 20, 25) were assessed with the Center for Epidemiologic Studies Depression (CES-D) scale; LTL (years 15, 20, 25) and mtDNAcn (years 15, 25) were measured in whole blood by quantitative PCR. With mixed-model analyses, we explored between- and within-person associations between CES-D scores and cellular aging markers. Results showed that high levels of depressive symptomatology throughout the 10-year time span was associated with shorter average LTL over 10 years (B=-4.2; P=0.014) after covarying for age, sex, race and education. However, no within-person association was found between depressive symptoms and LTL at each year (B=-0.8; P=0.548). Further, we found no between-person (B=-0.2; P=0.744) or within-person (B=0.4; P=0.497) associations between depressive symptomatology and mtDNAcn. Our results provide evidence for a long-term, between-person relationship of depressive symptoms with LTL, rather than a dynamic and direct within-person relationship. In this study, we found no evidence for an association between depressive symptoms and mtDNAcn.},
}
@article {pmid28347991,
year = {2017},
author = {Vazirpanah, N and Kienhorst, LBE and Van Lochem, E and Wichers, C and Rossato, M and Shiels, PG and Dalbeth, N and Stamp, LK and Merriman, TR and Janssen, M and Radstake, TRDJ and Broen, JC},
title = {Patients with gout have short telomeres compared with healthy participants: association of telomere length with flare frequency and cardiovascular disease in gout.},
journal = {Annals of the rheumatic diseases},
volume = {76},
number = {7},
pages = {1313-1319},
doi = {10.1136/annrheumdis-2016-210538},
pmid = {28347991},
issn = {1468-2060},
mesh = {Adult ; Aged ; Aged, 80 and over ; B-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/metabolism ; Cardiovascular Diseases/epidemiology/*metabolism ; Case-Control Studies ; Dendritic Cells/metabolism ; Disease Progression ; Female ; Gout/epidemiology/*metabolism ; Humans ; Killer Cells, Natural/metabolism ; Linear Models ; Male ; Middle Aged ; Monocytes/metabolism ; Telomerase/*genetics ; Telomere/*metabolism ; },
abstract = {AIM AND BACKGROUND: Chronic inflammation associates with increased senescence, which is a strong predictor for cardiovascular disease. We hypothesised that inflammation accelerates senescence and thereby enhances the risk of cardiovascular disease in gout.<br><br>METHODS: We assessed replicative senescence by quantifying telomere length (TL) in a discovery cohort of 145 Dutch patients with gout and 273 healthy individuals and validated our results in 474 patients with gout and 293 healthy participants from New Zealand. Subsequently, we investigated the effect of cardiovascular disease on TL of all participants. Also, we measured TL of CD4[+] and CD8[+] T lymphocytes, B lymphocytes, monocytes, natural killer cells and plasmacytoid dendritic cells. Additionally, we assessed the potential temporal difference in TL and telomerase activity.<br><br>RESULTS: TL in PBMCs of healthy donors decreased over time, reflecting normal ageing. Patients with gout demonstrated shorter telomeres (p=0.001, R[2]=0.01873). In fact, the extent of telomere erosion in patients with gout was higher at any age compared with healthy counterparts at any age (p<0.0001, R[2]=0.02847). Patients with gout with cardiovascular disease had the shortest telomeres and TL was an independent risk factor for cardiovascular disease in patients with gout (p=0.001). TL was inversely associated with the number of gouty flares (p=0.005).<br><br>CONCLUSIONS: Patients with gout have shorter telomeres than healthy participants, reflecting increased cellular senescence. Telomere shortening was associated with the number of flares and with cardiovascular disease in people with gout.},
}
@article {pmid28347656,
year = {2017},
author = {Victorelli, S and Passos, JF},
title = {Telomeres and Cell Senescence - Size Matters Not.},
journal = {EBioMedicine},
volume = {21},
number = {},
pages = {14-20},
pmid = {28347656},
issn = {2352-3964},
mesh = {Aging ; Animals ; *Cellular Senescence ; DNA Damage ; Humans ; Signal Transduction ; Stress, Physiological ; Telomere/*genetics/*metabolism ; *Telomere Homeostasis ; Telomere Shortening ; },
abstract = {Telomeres are protective structures present at the ends of linear chromosomes that are important in preventing genome instability. Telomeres shorten as a result of cellular replication, leading to a permanent cell cycle arrest, also known as replicative senescence. Senescent cells have been shown to accumulate in mammalian tissue with age and in a number of age-related diseases, suggesting that they might contribute to the loss of tissue function observed with age. In this review, we will first describe evidence suggesting a key role for senescence in the ageing process and elaborate on some of the mechanisms by which telomeres can induce cellular senescence. Furthermore, we will present multiple lines of evidence suggesting that telomeres can act as sensors of both intrinsic and extrinsic stress as well as recent data indicating that telomere-induced senescence may occur irrespectively of the length of telomeres.},
}
@article {pmid28346225,
year = {2017},
author = {Theodoris, CV and Mourkioti, F and Huang, Y and Ranade, SS and Liu, L and Blau, HM and Srivastava, D},
title = {Long telomeres protect against age-dependent cardiac disease caused by NOTCH1 haploinsufficiency.},
journal = {The Journal of clinical investigation},
volume = {127},
number = {5},
pages = {1683-1688},
pmid = {28346225},
issn = {1558-8238},
support = {R37 AG009521/AG/NIA NIH HHS/United States ; U01 HL098179/HL/NHLBI NIH HHS/United States ; R01 NS089533/NS/NINDS NIH HHS/United States ; T32 GM007618/GM/NIGMS NIH HHS/United States ; U01 HL100406/HL/NHLBI NIH HHS/United States ; R21 AG044815/AG/NIA NIH HHS/United States ; R01 AG020961/AG/NIA NIH HHS/United States ; R01 AG009521/AG/NIA NIH HHS/United States ; T32 HD007470/HD/NICHD NIH HHS/United States ; R01 AR063963/AR/NIAMS NIH HHS/United States ; C06 RR018928/RR/NCRR NIH HHS/United States ; },
mesh = {*Aging/genetics/metabolism/pathology ; Animals ; *Haploinsufficiency ; *Heart Septal Defects/genetics/metabolism ; *Heart Valve Diseases/genetics/metabolism/pathology ; Humans ; Mice ; Mice, Mutant Strains ; Promoter Regions, Genetic ; *Receptor, Notch1/genetics/metabolism ; *Telomere/genetics/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Diseases caused by gene haploinsufficiency in humans commonly lack a phenotype in mice that are heterozygous for the orthologous factor, impeding the study of complex phenotypes and critically limiting the discovery of therapeutics. Laboratory mice have longer telomeres relative to humans, potentially protecting against age-related disease caused by haploinsufficiency. Here, we demonstrate that telomere shortening in NOTCH1-haploinsufficient mice is sufficient to elicit age-dependent cardiovascular disease involving premature calcification of the aortic valve, a phenotype that closely mimics human disease caused by NOTCH1 haploinsufficiency. Furthermore, progressive telomere shortening correlated with severity of disease, causing cardiac valve and septal disease in the neonate that was similar to the range of valve disease observed within human families. Genes that were dysregulated due to NOTCH1 haploinsufficiency in mice with shortened telomeres were concordant with proosteoblast and proinflammatory gene network alterations in human NOTCH1 heterozygous endothelial cells. These dysregulated genes were enriched for telomere-contacting promoters, suggesting a potential mechanism for telomere-dependent regulation of homeostatic gene expression. These findings reveal a critical role for telomere length in a mouse model of age-dependent human disease and provide an in vivo model in which to test therapeutic candidates targeting the progression of aortic valve disease.},
}
@article {pmid28342451,
year = {2017},
author = {Heidenreich, B and Kumar, R},
title = {TERT promoter mutations in telomere biology.},
journal = {Mutation research. Reviews in mutation research},
volume = {771},
number = {},
pages = {15-31},
doi = {10.1016/j.mrrev.2016.11.002},
pmid = {28342451},
issn = {1388-2139},
mesh = {Humans ; *Mutation ; *Promoter Regions, Genetic ; Telomerase/*genetics ; *Telomere ; },
abstract = {Telomere repeats at chromosomal ends, critical to genome integrity, are maintained through an elaborate network of proteins and pathways. Shelterin complex proteins shield telomeres from induction of DNA damage response to overcome end protection problem. A specialized ribonucleic protein, telomerase, maintains telomere homeostasis through repeat addition to counter intrinsic shortcomings of DNA replication that leads to gradual sequence shortening in successive mitoses. The biogenesis and recruitment of telomerase composed of telomerase reverse transcriptase (TERT) subunit and an RNA component, takes place through the intricate machinery that involves an elaborate number of molecules. The synthesis of telomeres remains a controlled and limited process. Inherited mutations in the molecules involved in the process directly or indirectly cause telomeropathies. Telomerase, while present in stem cells, is deactivated due to epigenetic silencing of the rate-limiting TERT upon differentiation in most of somatic cells with a few exceptions. However, in most of the cancer cells telomerase reactivation remains a ubiquitous process and constitutes one of the major hallmarks. Discovery of mutations within the core promoter of the TERT gene that create de novo binding sites for E-twenty-six (ETS) transcription factors provided a mechanism for cancer-specific telomerase reactivation. The TERT promoter mutations occur mainly in tumors from tissues with low rates of self-renewal. In melanoma, glioma, hepatocellular carcinoma, urothelial carcinoma and others, the promoter mutations have been shown to define subsets of patients with adverse disease outcomes, associate with increased transcription of TERT, telomerase reactivation and affect telomere length; in stem cells the mutations inhibit TERT silencing following differentiation into adult cells. The TERT promoter mutations cause an epigenetic switch on the mutant allele along with recruitment of pol II following the binding of GABPA/B1 complex that leads to mono-allelic expression. Thus, the TERT promoter mutations hold potential as biomarkers as well as future therapeutic targets.},
}
@article {pmid28342200,
year = {2017},
author = {Hyatt, S and Jones, RE and Heppel, NH and Grimstead, JW and Fegan, C and Jackson, GH and Hills, R and Allan, JM and Pratt, G and Pepper, C and Baird, DM},
title = {Telomere length is a critical determinant for survival in multiple myeloma.},
journal = {British journal of haematology},
volume = {178},
number = {1},
pages = {94-98},
doi = {10.1111/bjh.14643},
pmid = {28342200},
issn = {1365-2141},
support = {15954/CRUK_/Cancer Research UK/United Kingdom ; 18246/CRUK_/Cancer Research UK/United Kingdom ; C17199/A18246/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {DNA, Neoplasm/genetics ; Genomic Instability ; Humans ; Kaplan-Meier Estimate ; Monoclonal Gammopathy of Undetermined Significance/genetics ; Multiple Myeloma/diagnosis/*genetics/pathology ; Neoplasm Staging ; Prognosis ; *Telomere Shortening ; },
abstract = {The variable clinical outcomes of Multiple Myeloma (MM) patients are incompletely defined by current prognostication tools. We examined the clinical utility of high-resolution telomere length analysis as a prognostic marker in MM. Cohort stratification, using a previously determined length threshold for telomere dysfunction, revealed that patients with short telomeres had a significantly shorter overall survival (P < 0·0001; HR = 3·4). Multivariate modelling using forward selection identified International Staging System (ISS) stage as the most important prognostic factor, followed by age and telomere length. Importantly, each ISS prognostic subset could be further risk-stratified according to telomere length, supporting the inclusion of this parameter as a refinement of the ISS.},
}
@article {pmid28340313,
year = {2018},
author = {Zole, E and Zadinane, K and Pliss, L and Ranka, R},
title = {Linkage between mitochondrial genome alterations, telomere length and aging population.},
journal = {Mitochondrial DNA. Part A, DNA mapping, sequencing, and analysis},
volume = {29},
number = {3},
pages = {431-438},
doi = {10.1080/24701394.2017.1303490},
pmid = {28340313},
issn = {2470-1408},
mesh = {Adult ; Age Distribution ; Aged ; Aged, 80 and over ; Aging/*genetics ; DNA, Mitochondrial/*genetics ; Female ; Humans ; Latvia ; Male ; Middle Aged ; Mitochondria/*genetics ; Telomere/*genetics ; Telomere Homeostasis ; White People/genetics ; Young Adult ; },
abstract = {We studied telomere length (TL) and mitochondrial DNA (mtDNA) copy number variations in individuals from Latvian Caucasian population in different age groups. We showed a positive correlation between TL and mtDNA copy number in individuals of up to 90 years of age; however, this correlation was not observed in the 90-100 years age group. While TL shortened with age and mtDNA content decreased with increasing age, in this study it was observed that mtDNA copy number in nonagenarians was slightly higher than in the 60-89 years age group. The presence of heteroplasmy in the mtDNA HVS-I control region did not correlate with TL and mtDNA copy number. TL and mtDNA values also did not differ between mitochondrial haplogroups. In conclusion, while both TL and mtDNA are involved in the aging process and link between these cell components exists, nonagenarians may have differences in senescence-related pathways and systems, which may function as a protective mechanism that allows them to live longer.},
}
@article {pmid28339618,
year = {2017},
author = {Vasconcelos-Moreno, MP and Fries, GR and Gubert, C and Dos Santos, BTMQ and Fijtman, A and Sartori, J and Ferrari, P and Grun, LK and Parisi, MM and Guma, FTCR and Barbé-Tuana, FM and Kapczinski, F and Rosa, AR and Yatham, LN and Kauer-Sant'Anna, M},
title = {Telomere Length, Oxidative Stress, Inflammation and BDNF Levels in Siblings of Patients with Bipolar Disorder: Implications for Accelerated Cellular Aging.},
journal = {The international journal of neuropsychopharmacology},
volume = {20},
number = {6},
pages = {445-454},
pmid = {28339618},
issn = {1469-5111},
mesh = {Biomarkers/blood ; Bipolar Disorder/drug therapy/*metabolism ; Cellular Senescence/*physiology ; Cross-Sectional Studies ; Female ; Genetic Predisposition to Disease ; Humans ; Inflammation/*blood ; Interview, Psychological ; Male ; Middle Aged ; Oxidative Stress/*physiology ; *Siblings ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Growing evidence supports the existence of neurobiological trait abnormalities in individuals at genetic risk for bipolar disorder. The aim of this study was to examine potential differences in brain-derived neurotrophic factor, cytokines, oxidative stress, and telomere length markers between patients with bipolar disorder, their siblings, and healthy controls.<br><br>METHODS: Thirty-six patients with bipolar disorder type I, 39 siblings, and 44 healthy controls were assessed. Serum levels of brain-derived neurotrophic factor, interleukin-6, interleukin-10, tumor necrosis factor-&#x3b1;, C-C motif chemokine 11, C-C motif chemokine 24, and 3-nitrotyrosine were measured, as were the activities of glutathione peroxidase, glutathione reductase, and glutathione S-transferase. Telomere length (T/S ratio) was measured using quantitative polymerase chain reaction.<br><br>RESULTS: Telomere length was different between the 3 groups (P = .041) with both patients and siblings showing a shorter T/S ratio compared with healthy controls. Patients showed increased levels of interleukin-6 (P = .005) and interleukin-10 (P = .002) compared with controls as well as increased levels of interleukin-6 (p = 0.014) and CCL24 (P = .016) compared with their siblings. C-C motif chemokine 11 levels were increased in siblings compared with controls (P = .015), and a similar tendency was found in patients compared with controls (P = .045). Glutathione peroxidase activity was decreased in patients compared with controls (P = .006) and siblings (P = .025). No differences were found for the other markers.<br><br>CONCLUSIONS: The present results suggest that unaffected siblings may present accelerated aging features. These neurobiological findings may be considered as endophenotypic traits. Further prospective studies are warranted.},
}
@article {pmid28338837,
year = {2017},
author = {Williams, DM and Buxton, JL and Kantomaa, MT and Tammelin, TH and Blakemore, AIF and Järvelin, MR},
title = {Associations of Leukocyte Telomere Length With Aerobic and Muscular Fitness in Young Adults.},
journal = {American journal of epidemiology},
volume = {185},
number = {7},
pages = {529-537},
pmid = {28338837},
issn = {1476-6256},
support = {R01 MH063706/MH/NIMH NIH HHS/United States ; R01 HL087679/HL/NHLBI NIH HHS/United States ; WT088431MA/WT_/Wellcome Trust/United Kingdom ; 08/0003775/DUK_/Diabetes UK/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; G0600705/MRC_/Medical Research Council/United Kingdom ; GR069224/WT_/Wellcome Trust/United Kingdom ; G0500539/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Age Factors ; Body Mass Index ; Cross-Sectional Studies ; Female ; Finland ; Hand Strength/physiology ; Humans ; Leukocytes/physiology ; Male ; Muscle Strength/*physiology ; Physical Endurance/physiology ; Physical Fitness/*physiology ; Sex Factors ; Telomere Homeostasis/*physiology ; },
abstract = {Decline in both telomere length and physical fitness over the life course may contribute to increased risk of several chronic diseases. The relationship between telomere length and aerobic and muscular fitness is not well characterized. We examined whether there are cross-sectional associations of mean relative leukocyte telomere length (LTL) with objective measures of aerobic fitness, muscle strength, and muscle endurance, using data on 31-year-old participants of the Northern Finland Birth Cohort 1966 (n = 4,952-5,205, varying by exposure-outcome analysis). Aerobic fitness was assessed by means of heart rate measurement following a standardized submaximal step test; muscular fitness was assessed by means of a maximal isometric handgrip strength test and a test of lower-back trunk muscle endurance. Longer LTL was associated with higher aerobic fitness and better trunk muscle endurance in models including adjustment for age, sex, body mass index, socioeconomic position, diet, smoking, alcohol consumption, physical activity level, and C-reactive protein. In a sex-stratified analysis, LTL was not associated with handgrip strength in either men or women. LTL may relate to aspects of physical fitness in young adulthood, but replication of these findings is required, along with further studies to help assess directions and causality in these associations.},
}
@article {pmid28338779,
year = {2018},
author = {Czepielewski, LS and Massuda, R and Panizzutti, B and Grun, LK and Barbé-Tuana, FM and Teixeira, AL and Barch, DM and Gama, CS},
title = {Telomere Length and CCL11 Levels are Associated With Gray Matter Volume and Episodic Memory Performance in Schizophrenia: Evidence of Pathological Accelerated Aging.},
journal = {Schizophrenia bulletin},
volume = {44},
number = {1},
pages = {158-167},
pmid = {28338779},
issn = {1745-1701},
mesh = {Adult ; *Aging, Premature/metabolism/pathology/physiopathology ; Biomarkers ; Chemokine CCL11/*blood ; *Cognitive Dysfunction/metabolism/pathology/physiopathology ; Female ; Gray Matter/*pathology ; Humans ; Magnetic Resonance Imaging ; Male ; *Memory, Episodic ; Middle Aged ; *Schizophrenia/metabolism/pathology/physiopathology ; Telomere Shortening/*physiology ; },
abstract = {Schizophrenia (SZ) is associated with increased somatic morbidity and mortality, in addition to cognitive impairments similar to those seen in normal aging, which may suggest that pathological accelerated aging occurs in SZ. Therefore, we aim to evaluate the relationships of age, telomere length (TL), and CCL11 (aging and inflammatory biomarkers, respectively), gray matter (GM) volume and episodic memory performance in individuals with SZ compared to healthy controls (HC). One hundred twelve participants (48 SZ and 64 HC) underwent clinical and memory assessments, structural MRI, and had their peripheral blood drawn for biomarkers analysis. Comparisons of group means and correlations were performed. Participants with SZ had decreased TL and GM volume, increased CCL11, and worse memory performance compared to HC. In SZ, shorter TL was related to increased CCL11, and both biomarkers were related to reduced GM volume, all of which were related to worse memory performance. Older age was only associated with reduced GM, but longer duration of illness was related with all the aforementioned variables. Younger age of disease onset was associated with increased CCL11 levels and worse memory performance. In HC, there were no significant correlations except between memory and GM. Our results are consistent with the hypothesis of accelerated aging in SZ. These results may indicate that it is not age itself, but the impact of the disease associated with a pathological accelerated aging that leads to impaired outcomes in SZ.},
}
@article {pmid28338178,
year = {2017},
author = {Li, C and Wei, GJ and Xu, L and Rong, JS and Tao, SQ and Wang, YS},
title = {The involvement of senescence induced by the telomere shortness in the decline of osteogenic differentiation in BMSCs.},
journal = {European review for medical and pharmacological sciences},
volume = {21},
number = {5},
pages = {1117-1124},
pmid = {28338178},
issn = {2284-0729},
mesh = {Animals ; Bone Marrow Cells/cytology ; *Cell Differentiation ; *Cell Proliferation ; Cells, Cultured ; Hydrogen Peroxide ; Mesenchymal Stem Cells/*cytology ; *Osteogenesis ; Rats ; Rats, Sprague-Dawley ; *Telomere Shortening ; },
abstract = {OBJECTIVE: BMSC (Bone marrow mesenchymal stem cells) is an important seed cell for the repair of bone and cartilage defect in the tissue engineering. The proliferation rate and differentiation capacity of BMSCs from the old donors were less than that from young donors; however, the related mechanism remained unclear.<br><br>MATERIALS AND METHODS: Sprague Dawley (SD) rats BMSCs were cultured and treated. Hydrogen peroxide (H2O2) and continual passage of BMSCs were performed to induce senescence. Senescence was detected by the SA-b-Gal staining and the telomere length analysis. Cell proliferation and osteogenic differentiation were also observed. Finally, Olaparib was used to maintain the telomere length and investigate the role of telomere length and senescence on the cell proliferation and differentiation.<br><br>RESULTS: H2O2 could increase the positive rate of SA-b-Gal staining in BMSCs and shorten the length of the telomere. The proliferation rate and ALP activity were also decreased by the H2O2. The senescence and decline of osteogenic differentiation could also be observed after prolonged passage of BMSCs. Inhibition of telomere length decline could attenuate the increased positive rate of SA-b-Gal staining induced by the H2O2, promote the cell proliferation, and enhance the capacity of osteogenic differentiation.<br><br>CONCLUSIONS: Senescence induced by the decline of telomere length could reduce the capacity of osteogenic differentiation and inhibit cell proliferation in BMSCs.},
}
@article {pmid28334836,
year = {2017},
author = {Nanavaty, V and Sandhu, R and Jehi, SE and Pandya, UM and Li, B},
title = {Trypanosoma brucei RAP1 maintains telomere and subtelomere integrity by suppressing TERRA and telomeric RNA:DNA hybrids.},
journal = {Nucleic acids research},
volume = {45},
number = {10},
pages = {5785-5796},
pmid = {28334836},
issn = {1362-4962},
support = {P01 CA095616/CA/NCI NIH HHS/United States ; R01 AI066095/AI/NIAID NIH HHS/United States ; },
mesh = {Base Pairing ; DNA Breaks, Double-Stranded ; DNA, Protozoan/*genetics/metabolism ; Nucleic Acid Hybridization ; Protozoan Proteins/genetics/metabolism ; RNA, Long Noncoding/*genetics/metabolism ; RNA, Messenger/genetics/metabolism ; RNA, Protozoan/*genetics/metabolism ; Ribonuclease H/genetics/metabolism ; Telomere/*chemistry/metabolism ; Transcription, Genetic ; Trypanosoma brucei brucei/*genetics/metabolism ; Variant Surface Glycoproteins, Trypanosoma/*genetics/metabolism ; rap1 GTP-Binding Proteins/*genetics/metabolism ; },
abstract = {Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen, VSG, thereby evading the host's immune response. VSGs are monoallelically expressed from subtelomeric expression sites (ESs), and VSG switching exploits subtelomere plasticity. However, subtelomere integrity is essential for T. brucei viability. The telomeric transcript, TERRA, was detected in T. brucei previously. We now show that the active ES-adjacent telomere is transcribed. We find that TbRAP1, a telomere protein essential for VSG silencing, suppresses VSG gene conversion-mediated switching. Importantly, TbRAP1 depletion increases the TERRA level, which appears to result from longer read-through into the telomere downstream of the active ES. Depletion of TbRAP1 also results in more telomeric RNA:DNA hybrids and more double strand breaks (DSBs) at telomeres and subtelomeres. In TbRAP1-depleted cells, expression of excessive TbRNaseH1, which cleaves the RNA strand of the RNA:DNA hybrid, brought telomeric RNA:DNA hybrids, telomeric/subtelomeric DSBs and VSG switching frequency back to WT levels. Therefore, TbRAP1-regulated appropriate levels of TERRA and telomeric RNA:DNA hybrid are fundamental to subtelomere/telomere integrity. Our study revealed for the first time an important role of a long, non-coding RNA in antigenic variation and demonstrated a link between telomeric silencing and subtelomere/telomere integrity through TbRAP1-regulated telomere transcription.},
}
@article {pmid28334768,
year = {2017},
author = {Guintini, L and Tremblay, M and Toussaint, M and D'Amours, A and Wellinger, RE and Wellinger, RJ and Conconi, A},
title = {Repair of UV-induced DNA lesions in natural Saccharomyces cerevisiae telomeres is moderated by Sir2 and Sir3, and inhibited by yKu-Sir4 interaction.},
journal = {Nucleic acids research},
volume = {45},
number = {8},
pages = {4577-4589},
pmid = {28334768},
issn = {1362-4962},
support = {//CIHR/Canada ; },
mesh = {DNA Damage ; *DNA Repair ; DNA, Fungal/genetics/metabolism ; DNA-Binding Proteins/*genetics/metabolism ; Kinetics ; Nucleosomes/chemistry/metabolism ; Protein Binding ; Protein Folding ; Saccharomyces cerevisiae/genetics/metabolism/*radiation effects ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/*genetics/metabolism ; Sirtuin 2/*genetics/metabolism ; Telomere/chemistry/metabolism/*radiation effects ; Ultraviolet Rays ; },
abstract = {Ultraviolet light (UV) causes DNA damage that is removed by nucleotide excision repair (NER). UV-induced DNA lesions must be recognized and repaired in nucleosomal DNA, higher order structures of chromatin and within different nuclear sub-compartments. Telomeric DNA is made of short tandem repeats located at the ends of chromosomes and their maintenance is critical to prevent genome instability. In Saccharomyces cerevisiae the chromatin structure of natural telomeres is distinctive and contingent to telomeric DNA sequences. Namely, nucleosomes and Sir proteins form the heterochromatin like structure of X-type telomeres, whereas a more open conformation is present at Y'-type telomeres. It is proposed that there are no nucleosomes on the most distal telomeric repeat DNA, which is bound by a complex of proteins and folded into higher order structure. How these structures affect NER is poorly understood. Our data indicate that the X-type, but not the Y'-type, sub-telomeric chromatin modulates NER, a consequence of Sir protein-dependent nucleosome stability. The telomere terminal complex also prevents NER, however, this effect is largely dependent on the yKu-Sir4 interaction, but Sir2 and Sir3 independent.},
}
@article {pmid28334750,
year = {2017},
author = {Feng, X and Hsu, SJ and Kasbek, C and Chaiken, M and Price, CM},
title = {CTC1-mediated C-strand fill-in is an essential step in telomere length maintenance.},
journal = {Nucleic acids research},
volume = {45},
number = {8},
pages = {4281-4293},
pmid = {28334750},
issn = {1362-4962},
support = {R01 GM041803/GM/NIGMS NIH HHS/United States ; T32 CA117846/CA/NCI NIH HHS/United States ; },
mesh = {DNA/*chemistry/genetics/metabolism ; DNA Damage ; DNA Polymerase I/genetics/metabolism ; DNA Replication ; Gene Deletion ; Gene Expression Regulation ; HCT116 Cells ; HEK293 Cells ; Humans ; Telomerase/*genetics/metabolism ; Telomere/*metabolism/ultrastructure ; *Telomere Homeostasis ; Telomere Shortening ; Telomere-Binding Proteins/deficiency/*genetics/metabolism ; },
abstract = {To prevent progressive telomere shortening as a result of conventional DNA replication, new telomeric DNA must be added onto the chromosome end. The de novo DNA synthesis involves elongation of the G-rich strand of the telomere by telomerase. In human cells, the CST complex (CTC1-STN1-TEN1) also functions in telomere replication. CST first aids in duplication of the telomeric dsDNA. Then after telomerase has extended the G-rich strand, CST facilitates fill-in synthesis of the complementary C-strand. Here, we analyze telomere structure after disruption of human CTC1 and demonstrate that functional CST is essential for telomere length maintenance due to its role in mediating C-strand fill-in. Removal of CTC1 results in elongation of the 3΄ overhang on the G-rich strand. This leads to accumulation of RPA and telomeric DNA damage signaling. G-overhang length increases with time after CTC1 disruption and at early times net G-strand growth is apparent, indicating telomerase-mediated G-strand extension. In contrast, C-strand length decreases continuously, indicating a deficiency in C-strand fill-in synthesis. The lack of C-strand maintenance leads to gradual shortening of the telomeric dsDNA, similar to that observed in cells lacking telomerase. Thus, telomerase-mediated G-strand extension and CST-mediated C-strand fill-in are equally important for telomere length maintenance.},
}
@article {pmid28334112,
year = {2017},
author = {Wan, S and Hann, HW and Ye, Z and Hann, RS and Lai, Y and Wang, C and Li, L and Myers, RE and Li, B and Xing, J and Yang, H},
title = {Prospective and longitudinal evaluations of telomere length of circulating DNA as a risk predictor of hepatocellular carcinoma in HBV patients.},
journal = {Carcinogenesis},
volume = {38},
number = {4},
pages = {439-446},
pmid = {28334112},
issn = {1460-2180},
mesh = {Biomarkers, Tumor/*genetics ; Carcinoma, Hepatocellular/*genetics/virology ; Case-Control Studies ; DNA/*genetics ; Female ; Hepatitis B virus ; Hepatitis B, Chronic/*genetics ; Humans ; Liver Neoplasms/*genetics/virology ; Longitudinal Studies ; Male ; Middle Aged ; Odds Ratio ; Proportional Hazards Models ; Prospective Studies ; ROC Curve ; Retrospective Studies ; Risk Factors ; Telomere/*genetics ; },
abstract = {Prospective and longitudinal epidemiological evidence is needed to assess the association between telomere length and risk of hepatocellular carcinoma (HCC). In 323 cancer-free Korean-American HBV patients with 1-year exclusion window (followed for >1 year and did not develop HCC within 1 year), we measured the relative telomere length (RTL) in baseline serum DNAs and conducted extensive prospective and longitudinal analyses to assess RTL-HCC relationship. We found that long baseline RTL conferred an increased HCC risk compared to short RTL [hazard ratio (HR) = 4.93, P = 0.0005). The association remained prominent when the analysis was restricted to patients with a more stringent 5-year exclusion window (HR = 7.51, P = 0.012), indicating that the association was unlikely due to including undetected HCC patients in the cohort, thus minimizing the reverse-causation limitation in most retrospective studies. Adding baseline RTL to demographic variables increased the discrimination accuracy of the time-dependent receiver operating characteristic analysis from 0.769 to 0.868 (P = 1.0 × 10-5). In a nested longitudinal subcohort of 16 matched cases-control pairs, using a mixed effects model, we observed a trend of increased RTL in cases and decreased RTL in controls along 5 years of follow-up, with a significant interaction of case/control status with time (P for interaction=0.002) and confirmed the association between long RTL and HCC risk [odds ratio [OR] = 3.63, P = 0.016]. In summary, serum DNA RTL may be a novel non-invasive prospective marker of HBV-related HCC. Independent studies are necessary to validate and generalize this finding in diverse populations and assess the clinical applicability of RTL in HCC prediction.},
}
@article {pmid28330934,
year = {2017},
author = {Armstrong, CA and Tomita, K},
title = {Fundamental mechanisms of telomerase action in yeasts and mammals: understanding telomeres and telomerase in cancer cells.},
journal = {Open biology},
volume = {7},
number = {3},
pages = {},
pmid = {28330934},
issn = {2046-2441},
support = {281722/ERC_/European Research Council/International ; C36439/A12097//Cancer Research UK/United Kingdom ; },
mesh = {Animals ; Cell Proliferation ; Enzyme Activation ; Humans ; Neoplasms/genetics/metabolism ; Saccharomycetales/chemistry/enzymology/genetics/metabolism ; Schizosaccharomyces/chemistry/enzymology/genetics/metabolism ; Telomerase/analysis/genetics/*metabolism ; Telomere/chemistry/genetics/metabolism ; *Telomere Homeostasis ; Transcriptional Activation ; },
abstract = {Aberrant activation of telomerase occurs in 85-90% of all cancers and underpins the ability of cancer cells to bypass their proliferative limit, rendering them immortal. The activity of telomerase is tightly controlled at multiple levels, from transcriptional regulation of the telomerase components to holoenzyme biogenesis and recruitment to the telomere, and finally activation and processivity. However, studies using cancer cell lines and other model systems have begun to reveal features of telomeres and telomerase that are unique to cancer. This review summarizes our current knowledge on the mechanisms of telomerase recruitment and activation using insights from studies in mammals and budding and fission yeasts. Finally, we discuss the differences in telomere homeostasis between normal cells and cancer cells, which may provide a foundation for telomere/telomerase targeted cancer treatments.},
}
@article {pmid28330827,
year = {2017},
author = {Blaze, J and Asok, A and Borrelli, K and Tulbert, C and Bollinger, J and Ronca, AE and Roth, TL},
title = {Intrauterine exposure to maternal stress alters Bdnf IV DNA methylation and telomere length in the brain of adult rat offspring.},
journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience},
volume = {62},
number = {},
pages = {56-62},
pmid = {28330827},
issn = {1873-474X},
support = {P20 GM103446/GM/NIGMS NIH HHS/United States ; P20 GM103653/GM/NIGMS NIH HHS/United States ; R01 HD050201/HD/NICHD NIH HHS/United States ; },
mesh = {Analysis of Variance ; Animals ; Brain/*metabolism ; Brain-Derived Neurotrophic Factor/genetics/*metabolism ; DNA Methylation/*genetics ; Epigenesis, Genetic/*physiology ; Female ; Male ; Pregnancy ; Pregnancy Outcome ; Prenatal Exposure Delayed Effects/*physiopathology ; Rats ; Rats, Sprague-Dawley ; Sex Factors ; *Stress, Psychological/genetics/metabolism/pathology ; Telomere Homeostasis/*physiology ; },
abstract = {DNA methylation (addition of methyl groups to cytosines) and changes in telomere length (TTAGGG repeats on the ends of chromosomes) are two molecular modifications that result from stress and could contribute to the long-term effects of intrauterine exposure to maternal stress on offspring behavior. Here, we measured methylation of DNA associated with the Brain-derived neurotrophic factor (Bdnf) gene, a gene important in development and plasticity, and telomere length in the brains of adult rat male and female offspring whose mothers were exposed to unpredictable and variable stressors throughout gestation. Males exposed to prenatal stress had greater methylation (Bdnf IV) in the medial prefrontal cortex (mPFC) compared to non-stressed male controls and stressed females. Further, prenatally-stressed animals had shorter telomeres than controls in the mPFC. Together findings indicate a long-term impact of prenatal stress on brain DNA methylation and telomere biology with relevance for behavioral and health outcomes, and contribute to a growing literature linking stress to intergenerational molecular changes.},
}
@article {pmid28329327,
year = {2017},
author = {Shadyab, AH and LaMonte, MJ and Kooperberg, C and Reiner, AP and Carty, CL and Manini, TM and Hou, L and Di, C and LaCroix, AZ},
title = {Association of Accelerometer-Measured Physical Activity With Leukocyte Telomere Length Among Older Women.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {72},
number = {11},
pages = {1532-1537},
pmid = {28329327},
issn = {1758-535X},
support = {P30 AG028740/AG/NIA NIH HHS/United States ; R01 HL105065/HL/NHLBI NIH HHS/United States ; R01 HL130483/HL/NHLBI NIH HHS/United States ; UL1 TR001412/TR/NCATS NIH HHS/United States ; },
mesh = {Accelerometry/*methods ; Black or African American ; Aged ; Aged, 80 and over ; Aging/ethnology/*genetics ; Blotting, Southern ; Cross-Sectional Studies ; Exercise/*physiology ; Female ; Humans ; Leukocytes ; Middle Aged ; Telomere/*genetics ; United States/epidemiology ; White People ; },
abstract = {BACKGROUND: Previous studies on physical activity and telomere length have relied largely upon self-reported physical activity data, and few studies have examined older adults. The association of objectively measured physical activity with leukocyte telomere length (LTL) is currently unknown.<br><br>METHODS: In this study, we examined cross-sectional associations between accelerometer-measured total, light, and moderate-to-vigorous physical activity (MVPA) and LTL, measured using Southern blot. The sample included 1,405 older (64-95 years old) white and African American women from the Women's Health Initiative. Multiple linear regression models adjusting for potential confounders were used to determine the association between accelerometer-measured physical activity and LTL.<br><br>RESULTS: Overall, the mean (standard deviation) of total, light, and moderate-to-vigorous activity was 5.5 (1.6), 4.7 (1.3), and 0.8 (0.5) h/d, respectively. Adjusting for accelerometer wear time, age, race/ethnicity, education, marital status, smoking, alcohol, body mass index, a history of chronic diseases, and hormone therapy use, LTL was 80 (95% confidence interval: 9, 150) base pairs longer among women with &#x2265;2.5 compared with <2.5 h/wk of MVPA. Light activity was not significantly associated with LTL. For total activity, the most physically active women had significantly longer LTL than the least active women after adjustment for demographic and lifestyle characteristics; however, findings were not significant after further adjustment for health-related factors.<br><br>CONCLUSIONS: Older women meeting current recommendations of &#x2265;2.5 h/wk of MVPA, as assessed by accelerometer, had longer LTL. Additional studies using accelerometers in large, diverse cohorts of older women are needed to confirm and extend these findings.},
}
@article {pmid28327364,
year = {2017},
author = {Bhaumik, P and Bhattacharya, M and Ghosh, P and Ghosh, S and Kumar Dey, S},
title = {Telomere length analysis in Down syndrome birth.},
journal = {Mechanisms of ageing and development},
volume = {164},
number = {},
pages = {20-26},
doi = {10.1016/j.mad.2017.03.006},
pmid = {28327364},
issn = {1872-6216},
mesh = {Adult ; *Aging/genetics/metabolism/pathology ; *Down Syndrome/genetics/metabolism/pathology ; Female ; *Genotyping Techniques ; Humans ; Infant, Newborn ; Male ; *Telomere/genetics/metabolism/pathology ; Telomere Homeostasis/*genetics ; },
abstract = {Human reproductive fitness depends upon telomere chemistry. Maternal age, meiotic nondisjunction error and telomere length of mother of trisomic child are someway associated. Reports exhibiting maternal inheritance of telomere length in Down syndrome child are very scanty. To investigate this, we collected peripheral blood from 170 mothers of Down syndrome child and 186 age matched mothers of euploid child with their newly born babies. Telomere length was measured by restriction digestion - southern blotting technique. Meiotic nondisjunction error was detected by STR genotyping. Subjects are classified by age (old >35 years and young ˂35 years) and by meiotic error (MI and MII). Linear regression was run to explore the age - telomere length relationship in each maternal groups. The study reveals that with age, telomere erodes in length. Old MII mothers carry the shortest (p˂0.001), control mothers have the longest telomere and MI lies in between. Babies from older mother have longer telomere (p˂0.001) moreover; telomeres are longer in Down syndrome babies than control babies (p˂0.001). To conclude, this study represents not only the relation between maternal aging and telomere length but also explore the maternal heritability of telomere length in families with Down syndrome child.},
}
@article {pmid28324511,
year = {2017},
author = {Liu, F and Feng, X and Ma, W},
title = {Analysis of Telomere Proteins by Chromatin Immunoprecipitation (ChIP).},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1587},
number = {},
pages = {205-214},
doi = {10.1007/978-1-4939-6892-3_19},
pmid = {28324511},
issn = {1940-6029},
mesh = {Chromatin/*genetics ; Chromatin Immunoprecipitation/methods ; DNA/genetics ; DNA-Binding Proteins/genetics ; Humans ; Protein Binding/genetics ; Telomere/*genetics ; },
abstract = {Telomere chromatin immunoprecipitation (ChIP) is an experimental method used to determine whether proteins are associated with telomere DNA inside the nuclei of cells and tissues. Telomere-associated proteins are first covalently crosslinked to telomere DNA, and then immunoprecipitated using an antibody specific for the protein of interest. This method has become one of the most indispensable tools for investigating the protein complexes that associate with telomeres.},
}
@article {pmid28324510,
year = {2017},
author = {Zhang, Z and Hu, Q and Zhao, Y},
title = {Analysis of Telomere-Homologous DNA with Different Conformations Using 2D Agarose Electrophoresis and In-Gel Hybridization.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1587},
number = {},
pages = {197-204},
doi = {10.1007/978-1-4939-6892-3_18},
pmid = {28324510},
issn = {1940-6029},
mesh = {Animals ; Chromosomes/genetics ; DNA, Circular/*genetics ; Electrophoresis, Gel, Two-Dimensional/methods ; Nucleic Acid Hybridization/*genetics ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {In mammalian cells, in addition to double-stranded telomeric DNA at chromosome ends, extra telomere-homologous DNA is present that adopts different conformations, including single-stranded G- or C-rich DNA, extrachromosomal circular DNA (T-circle), and telomeric complex (T-complex) with an unidentified structure. The formation of such telomere-homologous DNA is closely related to telomeric DNA metabolism and chromosome end protection by telomeres. Conventional agarose gel electrophoresis is unable to separate DNA based on conformation. Here, we introduce the method of two-dimensional (2D) agarose electrophoresis in combination with in-gel native/denatured hybridization to determine different conformations formed by telomere-homologous DNA.},
}
@article {pmid28324506,
year = {2017},
author = {Tan, R and Lan, L},
title = {Induction of Site-Specific Oxidative Damage at Telomeres by Killerred-Fused Shelretin Proteins.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1587},
number = {},
pages = {139-146},
doi = {10.1007/978-1-4939-6892-3_14},
pmid = {28324506},
issn = {1940-6029},
mesh = {Cell Line, Tumor ; Cellular Senescence/genetics ; DNA Damage/*genetics ; HeLa Cells ; Humans ; Oxidation-Reduction ; Oxidative Stress/*genetics ; Telomere/*genetics ; },
abstract = {Chronic oxidative stress is the major endogenous metabolic stress and contributes directly to telomere shortening and senescence. Understanding the dysfunction of telomeres under oxidative stress will greatly facilitate healthy aging and advance the treatment of aging-related diseases. Here, we describe the KR-TEL (KillerRed induced DNA damage at telomeres) system that induces site-specific oxidative damage at telomeres. We have developed the KR-TEL system by fusing killerred with the shelterin component TRF1 (KR-TRF1) or other shelterin proteins. Killerred (KR), an engineered red fluorescent chromophore, is capable of generating site-specific superoxide upon green light activation (550-580 nm). When KR-TRF1 expressing cells are exposed to green or laser light at defined wavelength to activate KR, localized oxidative DNA damage will be induced at telomeres. KR-induced oxidative DNA damage shows a high degree of resemblance to the complex spectrum of DNA damage induced by radiation in terms of the ratios of oxidized bases and DNA strand breaks. Unlike current oxidation-inducing methods (e.g., IR, chemical, and toxicants), which create damage throughout the genome, KR produces spatially limited oxidative DNA damage only in its immediate proximity. This property of KR allows us to engineer oxidative damage specifically at the telomere in a light dose-dependent manner. Using the KR-TEL system to determine the DNA damage response and repair mechanisms at telomeres has several advantages, which make it an ideal system to investigate the mechanism of how telomere integrity is maintained and how this mechanism plays a role in cancer biology.},
}
@article {pmid28324505,
year = {2017},
author = {Rai, R and Chang, S},
title = {Probing the Telomere Damage Response.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1587},
number = {},
pages = {133-138},
doi = {10.1007/978-1-4939-6892-3_13},
pmid = {28324505},
issn = {1940-6029},
support = {R21 AG043747/AG/NIA NIH HHS/United States ; R21 CA182280/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins/genetics ; Cell Cycle Proteins/genetics ; Cells, Cultured ; DNA/genetics ; DNA Breaks, Double-Stranded ; DNA Damage/*genetics ; DNA Repair/genetics ; DNA-Binding Proteins/genetics ; HEK293 Cells ; Humans ; Mice ; Signal Transduction/genetics ; Telomere/*genetics ; Tumor Suppressor p53-Binding Protein 1/genetics ; },
abstract = {Telomere dysfunctions, rendered through replicative attrition of telomeric DNA or due to the removal of shelterin components, are recognized as DNA double-stranded breaks (DSBs) by the DNA damage repair (DDR) pathway. This leads to the activation of DNA damage checkpoint sensors, including the Mre11-Rad50-Nbs1 (MRN) complex, γ-H2AX and 53BP1, the ATM and ATR signal-transducing kinases, and downstream effectors, including Chk1, Chk2, and p53. Robust DNA damage response signals at dysfunctional telomeres, achieved by the complete deletion of TRF2 or by expressing dominant-negative mutant TPP1ΔRD, can be detected by their association with γ-H2AX and 53BP1 forming "telomere dysfunction induced foci (TIFs)." Induction of TIFs at telomeres provides an opportunity to quantify the extent of telomere dysfunction and monitor downstream signaling pathways.},
}
@article {pmid28324504,
year = {2017},
author = {Rai, R and Multani, AS and Chang, S},
title = {Cytogenetic Analysis of Telomere Dysfunction.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1587},
number = {},
pages = {127-131},
doi = {10.1007/978-1-4939-6892-3_12},
pmid = {28324504},
issn = {1940-6029},
mesh = {Animals ; Cells, Cultured ; Cytogenetic Analysis/methods ; DNA Breaks, Double-Stranded ; DNA End-Joining Repair/genetics ; DNA Repair/genetics ; DNA-Binding Proteins/genetics ; Genomic Instability/genetics ; Mice ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {Dysfunctional telomeres arising either through natural attrition due to telomerase deficiency or by the removal of telomere-binding proteins are recognized as double-stranded breaks (DSBs). Repair of DSBs is crucial for the maintenance of genome stability. In mammals, DSBs are repaired by either error-prone nonhomologous end joining (NHEJ) or error-free homologous recombination (HR) and can be visualized as chromosomal fusions.},
}
@article {pmid28324502,
year = {2017},
author = {McKenna, MJ and Robinson, E and Goodwin, EH and Cornforth, MN and Bailey, SM},
title = {Telomeres and NextGen CO-FISH: Directional Genomic Hybridization (Telo-dGH™).},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1587},
number = {},
pages = {103-112},
doi = {10.1007/978-1-4939-6892-3_10},
pmid = {28324502},
issn = {1940-6029},
mesh = {Humans ; In Situ Hybridization, Fluorescence/methods ; Nucleic Acid Hybridization/*genetics ; Sister Chromatid Exchange/genetics ; Telomere/*genetics ; Translocation, Genetic/genetics ; },
abstract = {The cytogenomics-based methodology of Directional Genomic Hybridization (dGH™) emerged from the concept of strand-specific hybridization, first made possible by Chromosome Orientation FISH (CO-FISH), the utility of which was demonstrated in a variety of early applications, often involving telomeres. Similar to standard whole chromosome painting (FISH), dGH™ is capable of identifying inter-chromosomal rearrangements (translocations between chromosomes), but its distinctive strength stems from its ability to detect intra-chromosomal rearrangements (inversions within chromosomes), and to do so at higher resolution than previously possible. dGH™ brings together the strand specificity and directionality of CO-FISH with sophisticated bioinformatics-based oligonucleotide probe design to unique sequences. dGH™ serves not only as a powerful discovery tool-capable of interrogating the entire genome at the megabase level-it can also be used for high-resolution targeted detection of known inversions, a valuable attribute in both research and clinical settings. Detection of chromosomal inversions, particularly small ones, poses a formidable challenge for more traditional cytogenetic approaches, especially when they occur near the ends or telomeric regions. Here, we describe Telo-dGH™, a strand-specific scheme that utilizes dGH™ in combination with telomere CO-FISH to differentiate between terminal exchange events, specifically terminal inversions, and an altogether different form of genetic recombination that often occurs near the telomere, namely sister chromatid exchange (SCE).},
}
@article {pmid28324499,
year = {2017},
author = {Zhao, Y and Shay, JW and Wright, WE},
title = {Telomere Terminal G/C Strand Synthesis: Measuring Telomerase Action and C-Rich Fill-In.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1587},
number = {},
pages = {71-82},
doi = {10.1007/978-1-4939-6892-3_7},
pmid = {28324499},
issn = {1940-6029},
mesh = {Cell Cycle/genetics ; Cell Line, Tumor ; Cellular Senescence/genetics ; DNA/*genetics ; HeLa Cells ; Humans ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {Telomerase is present in most human cancers, and proliferative stem cells including germline cells. Telomerase plays an essential role in tumorigenesis by maintaining/elongating telomeric DNA, and thus preventing the telomere shortening that results in replicative senescence. Understanding telomerase action in vivo has important implication for both cancer and aging, but there are not robust methods for monitoring telomerase action. By combining a series of cell biological and biochemical approaches, and taking advantage of the enzyme DSN that specifically cuts double-stranded DNA and releases the telomeric overhangs, we have developed a method to monitor telomerase action during one cell cycle. Here, we describe this method using Hela carcinoma cells as an example.},
}
@article {pmid28324498,
year = {2017},
author = {Tahara, H},
title = {Telomere G-Overhang Length Measurement Method 2: G-Tail Telomere HPA.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1587},
number = {},
pages = {63-69},
doi = {10.1007/978-1-4939-6892-3_6},
pmid = {28324498},
issn = {1940-6029},
mesh = {DNA/genetics ; Humans ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {Both telomere length and telomere G-tail length are altered in human diseases such as cancer and age-related diseases. While most methods for measurement of G-tail and telomere length require electrophoresis, centrifugation, radioisotope labeling and autoradiography, G-tail telomere HPA provides a convenient and useful tool for the examination of G-tail length with a high-throughput platform using genomic DNA or cell lysate. G-tail telomere HPA may be applicable for clinical diagnostics as well as drug target screening.},
}
@article {pmid28324497,
year = {2017},
author = {Zhao, Y and Shay, JW and Wright, WE},
title = {Telomere G-Rich Overhang Length Measurement: DSN Method.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1587},
number = {},
pages = {55-62},
doi = {10.1007/978-1-4939-6892-3_5},
pmid = {28324497},
issn = {1940-6029},
mesh = {Animals ; Blotting, Southern/methods ; Cells, Cultured ; DNA/genetics ; DNA Replication/*genetics ; DNA, Single-Stranded/genetics ; Deoxyribonucleases/*genetics ; Mammals ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {Telomeres terminate in 3' single-stranded G-rich overhangs that function in telomere end protection and telomerase action. An accurate measurement of overhang length is challenging due to the presence of many kilobases of double-stranded telomere DNA. Here, a simple method is described that utilizes duplex specific nuclease (DSN) to digest all double-stranded DNA including telomeres to fragments of <10 bp, leaving the single-stranded overhangs intact. Their length can then be determined by Southern blot using super-sensitive telomere C-rich probes.},
}
@article {pmid28324496,
year = {2017},
author = {Ourliac-Garnier, I and Londoño-Vallejo, A},
title = {Telomere Strand-Specific Length Analysis by Fluorescent In Situ Hybridization (Q-CO-FISH).},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1587},
number = {},
pages = {41-54},
doi = {10.1007/978-1-4939-6892-3_4},
pmid = {28324496},
issn = {1940-6029},
mesh = {Chromosomes/genetics ; Humans ; In Situ Hybridization, Fluorescence/methods ; Telomere/*genetics ; },
abstract = {The implementation of quantitative approaches in telomere chromosome-oriented FISH (telomeric CO-FISH) allows the assessment of the relative efficiency of lagging versus leading strand telomere replication and thus provides information on the implicated mechanisms. Here we describe a simple method for telomere strand-specific analyses and discuss its potential applications.},
}
@article {pmid28324495,
year = {2017},
author = {Ourliac-Garnier, I and Londoño-Vallejo, A},
title = {Telomere Length Analysis by Quantitative Fluorescent in Situ Hybridization (Q-FISH).},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1587},
number = {},
pages = {29-39},
doi = {10.1007/978-1-4939-6892-3_3},
pmid = {28324495},
issn = {1940-6029},
mesh = {Chromosomes/genetics ; Humans ; In Situ Hybridization, Fluorescence/methods ; Interphase/genetics ; Metaphase/genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Telomere/*genetics ; },
abstract = {Length is a functional parameter of telomeres, the nucleoprotein structures that protect chromosome ends. The availability of highly specific, high affinity probes for telomeric repeat sequences allowed the development of quantitative approaches aimed at measuring telomere length directly on chromosomes or in interphase nuclei. Here, we describe a general method for telomere quantitative FISH on metaphase chromosomes and discuss its most common applications in research.},
}
@article {pmid28324494,
year = {2017},
author = {Xu, J and Songyang, Z and Liu, D and Kim, H},
title = {Analysis of Average Telomere Length in Human Telomeric Protein Knockout Cells Generated by CRISPR/Cas9.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1587},
number = {},
pages = {15-28},
doi = {10.1007/978-1-4939-6892-3_2},
pmid = {28324494},
issn = {1940-6029},
support = {P30 CA125123/CA/NCI NIH HHS/United States ; },
mesh = {CRISPR-Cas Systems/*physiology ; Cell Line ; Clustered Regularly Interspaced Short Palindromic Repeats/physiology ; Humans ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomeres play an important role in ensuring the integrity of the genome. Telomere shortening can lead to loss of genetic information and trigger DNA damage responses. Cultured mammalian cells have served as critical model systems for studying the function of telomere binding proteins and telomerase. Tremendous heterogeneity can be observed both between species and within a single cell population. Recent advances in genome editing (such as the development of the CRISPR/Cas9 platform) have further enabled researchers to carry out loss-of-function analysis of how disrupting key players in telomere maintenance affects telomere length regulation. Here we describe the steps to be carried out in order to analyze the average length of telomeres in CRISPR-engineered human knockout (KO) cells (TRF analysis).},
}
@article {pmid28324493,
year = {2017},
author = {Songyang, Z},
title = {Introduction to Telomeres and Telomerase.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1587},
number = {},
pages = {1-13},
doi = {10.1007/978-1-4939-6892-3_1},
pmid = {28324493},
issn = {1940-6029},
mesh = {Animals ; Cellular Senescence/physiology ; Humans ; Neoplasms/metabolism/pathology ; Proteomics/methods ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are ends of chromosomes that play an important part in the biology of eukaryotic cells. Continued optimization and development of technologies have enabled researchers to probe the mechanisms of telomere maintenance in ever expanding areas. A combination of molecular, genetic, proteomic, and biochemical approaches has revealed the complex and coordinated action of telomerase and telomere-associated proteins. The length and integrity of telomeres are maintained to prevent telomere dysfunction, which has been linked to senescence, aging, disease, and cancer. The tools and assays used to study telomeres today have helped assemble a more detailed, high-resolution picture of the various players and pathways at work at the telomeres.},
}
@article {pmid28322278,
year = {2018},
author = {Ridout, KK and Levandowski, M and Ridout, SJ and Gantz, L and Goonan, K and Palermo, D and Price, LH and Tyrka, AR},
title = {Early life adversity and telomere length: a meta-analysis.},
journal = {Molecular psychiatry},
volume = {23},
number = {4},
pages = {858-871},
pmid = {28322278},
issn = {1476-5578},
support = {R01 HD086487/HD/NICHD NIH HHS/United States ; R25 MH101076/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Adverse Childhood Experiences/classification/methods ; Cellular Senescence/genetics ; Child ; Female ; Humans ; Life Change Events ; Male ; Middle Aged ; Social Class ; Stress, Psychological/*genetics/psychology ; Telomere/genetics ; Telomere Shortening/*genetics ; },
abstract = {Early adversity, in the form of abuse, neglect, socioeconomic status and other adverse experiences, is associated with poor physical and mental health outcomes. To understand the biologic mechanisms underlying these associations, studies have evaluated the relationship between early adversity and telomere length, a marker of cellular senescence. Such results have varied in regard to the size and significance of this relationship. Using meta-analytic techniques, we aimed to clarify the relationship between early adversity and telomere length while exploring factors affecting the association, including adversity type, timing and study design. A comprehensive search in July 2016 of PubMed/MEDLINE, PsycINFO and Web of Science identified 2462 studies. Multiple reviewers appraised studies for inclusion or exclusion using a priori criteria; 3.9% met inclusion criteria. Data were extracted into a structured form; the Newcastle-Ottawa Scale assessed study quality, validity and bias. Forty-one studies (N=30 773) met inclusion criteria. Early adversity and telomere length were significantly associated (Cohen's d effect size=-0.35; 95% CI, -0.46 to -0.24; P<0.0001). Sensitivity analyses revealed no outlier effects. Adversity type and timing significantly impacted the association with telomere length (P<0.0001 and P=0.0025, respectively). Subgroup and meta-regression analyses revealed that medication use, medical or psychiatric conditions, case-control vs longitudinal study design, methodological factors, age and smoking significantly affected the relationship. Comprehensive evaluations of adversity demonstrated more extensive telomere length changes. These results suggest that early adversity may have long-lasting physiological consequences contributing to disease risk and biological aging.},
}
@article {pmid28318743,
year = {2017},
author = {Courtwright, A and El-Chemaly, S},
title = {Broadening the investigation-short telomeres and lung transplantation outcomes in pulmonary fibrosis.},
journal = {The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation},
volume = {36},
number = {8},
pages = {833-834},
doi = {10.1016/j.healun.2017.02.020},
pmid = {28318743},
issn = {1557-3117},
mesh = {Allografts ; Humans ; Lung ; *Lung Transplantation ; *Pulmonary Fibrosis ; Telomere ; },
}
@article {pmid28317975,
year = {2017},
author = {Cerón-Carrasco, JP and Jacquemin, D},
title = {Exposing the G-quadruplex to electric fields: the role played by telomeres in the propagation of DNA errors.},
journal = {Physical chemistry chemical physics : PCCP},
volume = {19},
number = {14},
pages = {9358-9365},
doi = {10.1039/c7cp01034f},
pmid = {28317975},
issn = {1463-9084},
mesh = {DNA/*chemistry ; *Electric Stimulation ; *G-Quadruplexes ; Genetic Techniques ; Mutation/*genetics ; Telomere/*genetics ; },
abstract = {To protect their core machinery from the attack of exogenous agents, cells locate DNA in their nucleus. Nevertheless, some reactive chemical species and physical agents might reach DNA and alter its natural double helix structure. For instance, pulsed electric fields can be used to selectively rewrite the stored genetic information. However, for such modification to be effective, one needs, as a prerequisite, that the replication mechanism is not stopped by the field, so that the changes propagate over the following generations. Here, we use theoretical calculations to demonstrate that while such fields lead to permanent noncanonical Watson-Crick guanine-cytosine (GC) base pairs, the G-quadruplex motifs present in telomeres can more effectively preserve their native forms. Indeed, G-quadruplexes "resist" the perturbations induced by field strengths going up to 60 × 10[-4] a.u., a figure constituting the upper limit before the complete destruction of the double helix architecture. Since the induced errors in the DNA base pairs are not transcribed into the telomeres, electric fields can indeed be used as a source of selective mutations in the genetic code.},
}
@article {pmid28303901,
year = {2017},
author = {Yang, TB and Chen, Q and Deng, JT and Jagannathan, G and Tobias, JW and Schultz, DC and Wang, S and Lengner, CJ and Rustgi, AK and Lynch, JP and Johnson, FB},
title = {Mutual reinforcement between telomere capping and canonical Wnt signalling in the intestinal stem cell niche.},
journal = {Nature communications},
volume = {8},
number = {},
pages = {14766},
pmid = {28303901},
issn = {2041-1723},
support = {P01 AG031862/AG/NIA NIH HHS/United States ; P30 DK050306/DK/NIDDK NIH HHS/United States ; R21 AG054209/AG/NIA NIH HHS/United States ; T32 DK007066/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Apoptosis/genetics ; Down-Regulation ; Dyskeratosis Congenita/genetics/metabolism ; *Feedback, Physiological ; Gene Expression ; Intestinal Mucosa/*cytology ; Mice ; Mice, Knockout ; Paneth Cells/metabolism ; RNA/genetics ; Stem Cell Niche/*genetics ; Stem Cells/*metabolism ; Telomerase/*genetics ; Telomere/*metabolism ; Telomere Shortening/*genetics ; Wnt Signaling Pathway/*genetics ; },
abstract = {Critical telomere shortening (for example, secondary to partial telomerase deficiency in the rare disease dyskeratosis congenita) causes tissue pathology, but underlying mechanisms are not fully understood. Mice lacking telomerase (for example, mTR[-/-] telomerase RNA template mutants) provide a model for investigating pathogenesis. In such mice, after several generations of telomerase deficiency telomeres shorten to the point of uncapping, causing defects most pronounced in high-turnover tissues including intestinal epithelium. Here we show that late-generation mTR[-/-] mutants experience marked downregulation of Wnt pathway genes in intestinal crypt epithelia, including crypt base columnar stem cells and Paneth cells, and in underlying stroma. The importance of these changes was revealed by rescue of crypt apoptosis and Wnt pathway gene expression upon treatment with Wnt pathway agonists. Rescue was associated with reduced telomere-dysfunction-induced foci and anaphase bridges, indicating improved telomere capping. Thus a mutually reinforcing feedback loop exists between telomere capping and Wnt signalling, and telomere capping can be impacted by extracellular cues in a fashion independent of telomerase.},
}
@article {pmid28301132,
year = {2017},
author = {Zhang, Z and Jiao, Y and Zhu, M and Zhang, S},
title = {Nuclear-Shell Biopolymers Initiated by Telomere Elongation for Individual Cancer Cell Imaging and Drug Delivery.},
journal = {Analytical chemistry},
volume = {89},
number = {7},
pages = {4320-4327},
doi = {10.1021/acs.analchem.7b00591},
pmid = {28301132},
issn = {1520-6882},
mesh = {Biopolymers/*chemistry ; Breast Neoplasms/*diagnostic imaging ; Cell Survival ; Cells, Cultured ; DNA, Neoplasm/genetics ; *Drug Delivery Systems ; Female ; Fluoresceins/*chemistry ; Fluorescence ; HeLa Cells ; Hep G2 Cells ; Hepatocytes/drug effects ; Humans ; Liver Neoplasms/*diagnostic imaging ; MCF-7 Cells ; *Molecular Imaging ; Nanoparticles/chemistry ; Nucleic Acid Amplification Techniques ; Particle Size ; Silicon Dioxide/chemistry ; Surface Properties ; Telomerase/metabolism ; Telomere/chemistry/*metabolism ; Uterine Cervical Neoplasms/*diagnostic imaging ; },
abstract = {Here, we propose a strategy for unique nuclear-shell biopolymers initiated by telomere elongation for telomerase activity detection and precise drug delivery to individual cancer cells. Telomerase-triggered DNA rolling-circle amplification (RCA) is used to assemble nuclear-shell biopolymers with signal molecules for selective cancer cell recognition and efficient drug delivery to targeted individual cells. This strategy not only should allow the creation of clustered 5-carboxyfluorescein (FAM)-fluorescence spots in response to human-telomerase activity in individual cancer cells but also could efficiently deliver drugs to reduce the undesired death of healthy cells. These findings offer new opportunities to improve the efficacy of cancer cell imaging and therapy.},
}
@article {pmid28299976,
year = {2017},
author = {Khalangot, M and Krasnienkov, D and Vaiserman, A and Avilov, I and Kovtun, V and Okhrimenko, N and Koliada, A and Kravchenko, V},
title = {Leukocyte telomere length is inversely associated with post-load but not with fasting plasma glucose levels.},
journal = {Experimental biology and medicine (Maywood, N.J.)},
volume = {242},
number = {7},
pages = {700-708},
pmid = {28299976},
issn = {1535-3699},
mesh = {Aged ; Blood Glucose/*analysis/physiology ; Diabetes Mellitus, Type 2/metabolism/physiopathology ; Fasting/*physiology ; Female ; Glucose Intolerance/metabolism/physiopathology ; Humans ; Leukocytes/metabolism/*physiology ; Male ; Middle Aged ; Multiplex Polymerase Chain Reaction ; *Telomere Shortening/physiology ; },
abstract = {Type 2 diabetes mellitus is characterized by shorter leukocyte telomere length, but the relationship between leukocyte telomere length and type 2 diabetes mellitus development is rather questioned. Fasting and post-load glycaemia associated with different types of insulin resistance and their relation with leukocyte telomere length remains unknown. We compared leukocyte telomere length and fasting or post-load glucose levels in persons who do not receive glucose lowering treatment. For 82 randomly selected rural residents of Ukraine, aged 45+, not previously diagnosed with type 2 diabetes mellitus, the WHO oral glucose tolerance test and anthropometric measurements were performed. Leukocyte telomere length was measured by standardized method of quantitative monochrome multiplex polymerase chain reaction in real time. Spearman's or Pearson's rank correlation was used for correlation analysis between fasting plasma glucose or 2-h post-load plasma glucose levels and leukocyte telomere length. Logistical regression models were used to evaluate risks of finding short or long telomeres associated with fasting plasma glucose or 2-h post-load plasma glucose levels. No association of fasting plasma glucose and leukocyte telomere length was revealed, whereas 2-h post-load plasma glucose levels demonstrated a negative correlation (P < 0.01) with leukocyte telomere length. Waist circumference and systolic blood pressure were negatively related (P = 0.03) with leukocyte telomere length in men. Oral glucose tolerance test result-based glycemic categories did not show differences between mean leukocyte telomere length in categories of normal fasting plasma glucose and 2-h post-load plasma glucose (NGT, n = 33); diabetes mellitus (DM), n = 18 and impaired fasting glucose/tolerance (IFG/IGT, n = 31) levels. A correlation relationship between leukocyte telomere length and 2-h post-load plasma glucose level in NGT; IFG/IGT and DM groups (P = 0.027; 0.029 and 0.049, respectively) was revealed; the association between leukocyte telomere length and fasting plasma glucose was confirmed in DM group only (P = 0.009). Increase of 2-h post-load plasma glucose (but not fasting plasma glucose) level improves the chances of revealing short telomeres: OR 1.52 (95% CI 1.04-2.22), P = 0.03. After the adjustment for age, gender, waist circumference, systolic blood pressure, and fasting plasma glucose, these phenomena remain significant. We conclude that 2-h post-load plasma glucose but not fasting plasma glucose is inversely associated with leukocyte telomere length. Impact statement • Contradictory epidemiologic data have been obtained about the link between the leucocyte telomere length (LTL) and diabetes. Type 2 diabetes (T2D) is likely to be pathophysiologically heterogeneous, but comparison of the association of LTL separately with fasting plasma glucose (FPG) and 2-h post-load plasma glucose (2hPG) levels has not been done before. Thus, the study of LTL changes associated with different types of hyperglycaemia, that largely determine the heterogenity of T2D is important. • In a population-based study of rural Ukrainians, we were the first to demonstrate that the increase of 2hPG (but not FPG) level increases the chances of revealing short telomeres. • The obtained data can help to clarify the relationship between the LTL shortening and different conditions of the insulin resistance (mainly liver resistance in high FPG and mostly muscle and adipose tissue resistance in high 2hPG).},
}
@article {pmid28297596,
year = {2017},
author = {Wignall, ND and Deschner, M and Evans, HM and Brown, ES},
title = {Relationship Between Current Depressive Symptoms and Telomere Length in a Large, Multiethnic Sample.},
journal = {The Journal of clinical psychiatry},
volume = {78},
number = {9},
pages = {1331-1336},
doi = {10.4088/JCP.15m10570},
pmid = {28297596},
issn = {1555-2101},
support = {UL1 TR001105/TR/NCATS NIH HHS/United States ; },
mesh = {Depression/*etiology/genetics ; Ethnicity/genetics/psychology/statistics &amp; numerical data ; Female ; Hispanic or Latino/genetics/psychology/statistics &amp; numerical data ; Humans ; Male ; Middle Aged ; Psychiatric Status Rating Scales ; Racial Groups/genetics/psychology/statistics &amp; numerical data ; *Telomere Shortening ; },
abstract = {OBJECTIVE: Previous research has suggested that depressive symptoms may be associated with telomere length; however, findings have been mixed, and few studies have sought to generalize the results beyond samples of white individuals. The present study, conducted from August 2013 through August 2015, sought to examine the relationship between depressive symptoms and leukocyte telomere length in a large (N = 2,710), multiethnic sample (African American, white, Hispanic) and to determine if this relationship differed across ethnic/racial groups. Analyses were based on data taken from the Dallas Heart Study, a recent epidemiologic-style, population-based study of adults from Dallas County, Texas.<br><br>METHODS: Depressive symptoms were measured using the Quick Inventory of Depressive Symptomatology, and leukocyte telomere length was measured using a quantitative polymerase chain reaction technique. Analyses of the relationship between depressive symptoms and telomere length were conducted using multiple linear regression models.<br><br>RESULTS: Among the whole sample, there was no significant relationship between depressive symptoms and telomere length in either a basic (&#x3b2; = -0.025, P = .190) or an adjusted (&#x3b2; = -0.015, P = .443) model. However, among non-Hispanic white participants, depressive symptoms were significantly associated with telomere length in both basic (&#x3b2; = -0.083, P = .014) and adjusted (&#x3b2; = -0.066, P = .049) models.<br><br>CONCLUSIONS: These findings suggest that ethnic/racial identification may be a factor in the relationship between depressive symptoms and telomere length and could impact the generalizability of previous research.},
}
@article {pmid28295518,
year = {2017},
author = {Mekontso Dessap, A and Cecchini, J and Chaar, V and Marcos, E and Habibi, A and Bartolucci, P and Ghaleh, B and Galacteros, F and Adnot, S},
title = {Telomere attrition in sickle cell anemia.},
journal = {American journal of hematology},
volume = {92},
number = {6},
pages = {E112-E114},
doi = {10.1002/ajh.24721},
pmid = {28295518},
issn = {1096-8652},
mesh = {Adolescent ; Adult ; Age Factors ; Anemia, Sickle Cell/blood/*genetics/mortality/therapy ; Arterial Occlusive Diseases/etiology ; Blood Viscosity ; Cellular Senescence ; Erythrocyte Indices ; Female ; Follow-Up Studies ; Gene Dosage ; Genotype ; Hemoglobins/analysis ; Humans ; Kaplan-Meier Estimate ; Leukocytes/ultrastructure ; Male ; Middle Aged ; Oxygen/blood ; Patient Selection ; Proportional Hazards Models ; *Telomere Shortening ; Young Adult ; },
}
@article {pmid28289249,
year = {2017},
author = {Roake, CM and Artandi, SE},
title = {Control of Cellular Aging, Tissue Function, and Cancer by p53 Downstream of Telomeres.},
journal = {Cold Spring Harbor perspectives in medicine},
volume = {7},
number = {5},
pages = {},
pmid = {28289249},
issn = {2157-1422},
support = {R35 CA197563/CA/NCI NIH HHS/United States ; T32 GM007365/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Apoptosis ; Cell Cycle Checkpoints ; Cellular Senescence/*genetics ; DNA Damage/physiology ; Humans ; Mice ; Mutation ; Neoplasms/*genetics/metabolism ; *Signal Transduction ; Telomerase/metabolism/*physiology ; Telomere/*genetics/physiology ; Telomere Shortening ; Tumor Suppressor Protein p53/metabolism/*physiology ; Up-Regulation ; },
abstract = {Telomeres, the nucleoprotein complex at the ends of eukaryotic chromosomes, perform an essential cellular role in part by preventing the chromosomal end from initiating a DNA-damage response. This function of telomeres can be compromised as telomeres erode either as a consequence of cell division in culture or as a normal part of cellular ageing in proliferative tissues. Telomere dysfunction in this context leads to DNA-damage signaling and activation of the tumor-suppressor protein p53, which then can prompt either cellular senescence or apoptosis. By culling cells with dysfunctional telomeres, p53 plays a critical role in protecting tissues against the effects of critically short telomeres. However, as telomere dysfunction worsens, p53 likely exacerbates short telomere-driven tissue failure diseases, including pulmonary fibrosis, aplastic anemia, and liver cirrhosis. In cells lacking p53, unchecked telomere shortening drives chromosomal end-to-end fusions and cycles of chromosome fusion-bridge-breakage. Incipient cancer cells confronting these telomere barriers must disable p53 signaling to avoid senescence and eventually up-regulate telomerase to achieve cellular immortality. The recent findings of highly recurrent activating mutations in the promoter for the telomerase reverse transcriptase (TERT) gene in diverse human cancers, together with the widespread mutations in p53 in cancer, provide support for the idea that circumvention of a telomere-p53 checkpoint is essential for malignant progression in human cancer.},
}
@article {pmid28288093,
year = {2017},
author = {Bertschi, NL and Toenhake, CG and Zou, A and Niederwieser, I and Henderson, R and Moes, S and Jenoe, P and Parkinson, J and Bartfai, R and Voss, TS},
title = {Malaria parasites possess a telomere repeat-binding protein that shares ancestry with transcription factor IIIA.},
journal = {Nature microbiology},
volume = {2},
number = {},
pages = {17033},
doi = {10.1038/nmicrobiol.2017.33},
pmid = {28288093},
issn = {2058-5276},
mesh = {*Evolution, Molecular ; Malaria, Falciparum/*genetics ; Protein Binding ; Telomere/metabolism ; Telomere-Binding Proteins/*genetics ; Transcription Factor TFIIIA/genetics ; Zinc Fingers ; },
abstract = {Telomere repeat-binding factors (TRFs) are essential components of the molecular machinery that regulates telomere function. TRFs are widely conserved across eukaryotes and bind duplex telomere repeats via a characteristic MYB-type domain. Here, we identified the telomere repeat-binding protein PfTRZ in the malaria parasite Plasmodium falciparum, a member of the Alveolate phylum for which TRFs have not been described so far. PfTRZ lacks an MYB domain and binds telomere repeats via a C2H2-type zinc finger domain instead. In vivo, PfTRZ binds with high specificity to the telomeric tract and to interstitial telomere repeats upstream of subtelomeric virulence genes. Conditional depletion experiments revealed that PfTRZ regulates telomere length homeostasis and is required for efficient cell cycle progression. Intriguingly, we found that PfTRZ also binds to and regulates the expression of 5S rDNA genes. Combined with detailed phylogenetic analyses, our findings identified PfTRZ as a remote functional homologue of the basic transcription factor TFIIIA, which acquired a new function in telomere maintenance early in the apicomplexan lineage. Our work sheds unexpected new light on the evolution of telomere repeat-binding proteins and paves the way for dissecting the presumably divergent mechanisms regulating telomere functionality in one of the most deadly human pathogens.},
}
@article {pmid28285024,
year = {2017},
author = {Galletly, C and Dhillon, VS and Liu, D and Balzan, RP and Hahn, LA and Fenech, MF},
title = {Shorter telomere length in people with schizophrenia: A preliminary study from Australia.},
journal = {Schizophrenia research},
volume = {190},
number = {},
pages = {46-51},
doi = {10.1016/j.schres.2017.03.007},
pmid = {28285024},
issn = {1573-2509},
mesh = {Adult ; Case-Control Studies ; Humans ; Male ; Preliminary Data ; Schizophrenia/genetics/*metabolism ; South Australia ; *Telomere/metabolism ; *Telomere Shortening ; },
abstract = {Schizophrenia is a complex mental illness affecting the normal functioning of the brain, interfering with the ability to think, feel and act. It can be conceptualised as a syndrome of accelerated ageing, with early onset of cardiovascular disease and high rates of premature mortality. Telomere attrition increases with oxidative stress and is considered a biomarker of ageing. Previous studies have assessed abnormalities in telomere length in schizophrenia, but the results are inconsistent. The present study used a case-control design to assess whether people with schizophrenia have shortened telomeres, indicative of accelerated ageing. Subjects were all male, aged 25-35years, living in the same urban region of Adelaide, South Australia. Telomere length was measured using a quantitative real-time polymerase chain reaction (PCR) method. We found significantly shorter telomeres in people with schizophrenia relative to healthy controls. This is the first study to show telomere attrition among people with schizophrenia in Australia. Shorter telomere length may indicate the common pathways that schizophrenia shares with other neuropsychiatric and neurodevelopmental disorders associated with increased cellular senescence. Further well-controlled larger studies in people with schizophrenia are required to fully understand (i) the role of variables that have the potential to modulate telomere length such as use of antipsychotic drugs, medical conditions, parental age, smoking, alcohol abuse and use of illicit drugs; (ii) effective treatments to slow telomere erosion and (iii) mechanisms responsible for accelerating and reducing telomere damage.},
}
@article {pmid28282748,
year = {2018},
author = {Loprinzi, PD and Loenneke, JP},
title = {Leukocyte telomere length and mortality among U.S. adults: Effect modification by physical activity behaviour.},
journal = {Journal of sports sciences},
volume = {36},
number = {2},
pages = {213-219},
doi = {10.1080/02640414.2017.1293280},
pmid = {28282748},
issn = {1466-447X},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/physiology ; Cardiovascular Diseases/mortality ; Exercise/*physiology ; Female ; Humans ; Leukocytes/*physiology ; Male ; Middle Aged ; *Mortality ; Nutrition Surveys ; *Telomere Homeostasis ; United States/epidemiology ; Young Adult ; },
abstract = {The purpose of this study was to examine the association between leukocyte telomere length (LTL) and mortality (outcome variable), with consideration by physical activity behaviour. Data from the 1999-2002 National Health and Nutrition Examination Survey were employed (N = 6,611; 20-85 yrs), with follow-up mortality assessment through 31 December 2006. DNA was extracted from whole blood to assess LTL via quantitative polymerase chain reaction. Compared to those in the first LTL tertile, the adjusted hazard ratio for all-cause mortality for those in the 2[nd] and 3[rd] LTL tertiles, respectively, was 0.82 (95% CI: 0.60-1.12; P = .22) and 0.76 (95% CI: 0.50-1.14; P = .18). However, after adjustments, LTL tertile 3 (vs. 1) was associated with all-cause mortality (HR = 0.37; 95% CI: 0.14-0.93; P = .03) for those who engaged in moderate-intensity exercise. Similarly, LTL was associated with CVD-specific mortality for those who engaged in moderate-intensity exercise (HR = 0.17; 95% CI: 0.04-0.73; P = .02). Longer telomeres are associated with increased survival, particularly among men and those who are active, underscoring the importance of promotion of physical activity behaviour.},
}
@article {pmid28281877,
year = {2017},
author = {Hou, C and Wang, F and Liu, X and Chang, G and Wang, F and Geng, X},
title = {Comprehensive Analysis of Interaction Networks of Telomerase Reverse Transcriptase with Multiple Bioinformatic Approaches: Deep Mining the Potential Functions of Telomere and Telomerase.},
journal = {Rejuvenation research},
volume = {20},
number = {4},
pages = {320-333},
doi = {10.1089/rej.2016.1909},
pmid = {28281877},
issn = {1557-8577},
mesh = {Computational Biology/*methods ; *Data Mining ; Databases as Topic ; Gene Ontology ; Gene Regulatory Networks ; Humans ; Molecular Sequence Annotation ; RNA/genetics/metabolism ; Software ; Telomerase/*genetics ; Telomere/*metabolism ; },
abstract = {Telomerase reverse transcriptase (TERT) is the protein component of telomerase complex. Evidence has accumulated showing that the nontelomeric functions of TERT are independent of telomere elongation. However, the mechanisms governing the interaction between TERT and its target genes are not clearly revealed. The biological functions of TERT are not fully elucidated and have thus far been underestimated. To further explore these functions, we investigated TERT interaction networks using multiple bioinformatic databases, including BioGRID, STRING, DAVID, GeneCards, GeneMANIA, PANTHER, miRWalk, mirTarBase, miRNet, miRDB, and TargetScan. In addition, network diagrams were built using Cytoscape software. As competing endogenous RNAs (ceRNAs) are endogenous transcripts that compete for the binding of microRNAs (miRNAs) by using shared miRNA recognition elements, they are involved in creating widespread regulatory networks. Therefore, the ceRNA regulatory networks of TERT were also investigated in this study. Interestingly, we found that the three genes PABPC1, SLC7A11, and TP53 were present in both TERT interaction networks and ceRNAs target genes. It was predicted that TERT might play nontelomeric roles in the generation or development of some rare diseases, such as Rift Valley fever and dyscalculia. Thus, our data will help to decipher the interaction networks of TERT and reveal the unknown functions of telomerase in cancer and aging-related diseases.},
}
@article {pmid28281015,
year = {2017},
author = {Dato, S and De Rango, F and Crocco, P and Passarino, G and Rose, G},
title = {Pleiotropic effects of UCP2-UCP3 variability on leucocyte telomere length and glucose homeostasis.},
journal = {Biogerontology},
volume = {18},
number = {3},
pages = {347-355},
doi = {10.1007/s10522-017-9690-z},
pmid = {28281015},
issn = {1573-6768},
mesh = {Aged ; Aged, 80 and over ; Case-Control Studies ; Cohort Studies ; Female ; Glucose/*metabolism ; *Homeostasis ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Real-Time Polymerase Chain Reaction ; *Telomere ; Uncoupling Protein 2/*genetics ; Uncoupling Protein 3/*genetics ; },
abstract = {The rate of telomere-shortening has been widely reported as a marker of risk for age-related conditions and mortality in human population. Genetic, environmental and stochastic factors have been shown to influence telomere attrition. In particular oxidative stress has been reported to play an important role on the process. Uncoupling proteins (UCPs) are among the most important regulators of cellular metabolism and oxidative stress. Several authors investigated the association of UCP genetic variants with leucocyte telomere length (LTL) in both healthy and unhealthy (affected by diabetes) subjects, reporting contrasting results. We tested the influence of four SNPs falling in UCP2-UCP3 genomic region on LTL and glucose metabolism by analyzing these polymorphisms in a cohort of 457 subjects, in an age range 64-105 years. Among subjects younger than 85 years, homozygotes for the minor alleles at two UCP2 variants (rs659366-A and rs660339-T) showed shorter LTL respect to the other genotypes (pmodel = 0.024). In the same samples, AA-rs659366 genotype was found associated with lower haematological levels of Glycosylate Haemoglobyn (p = 0.012 and p = 0.022, respectively). Furthermore, rs659366-AA at UCP2 and rs15673-TT at UCP3 were correlated to diabetes in a small sub-group of patients. Results here presented suggest that UCP variability has different pleiotropic effects, by affecting both telomere length and glucose homeostasis, likely through an influence on energy metabolism and stress response.},
}
@article {pmid28275103,
year = {2017},
author = {Nomura, SJ and Robien, K and Zota, AR},
title = {Serum Folate, Vitamin B-12, Vitamin A, γ-Tocopherol, α-Tocopherol, and Carotenoids Do Not Modify Associations between Cadmium Exposure and Leukocyte Telomere Length in the General US Adult Population.},
journal = {The Journal of nutrition},
volume = {147},
number = {4},
pages = {538-548},
pmid = {28275103},
issn = {1541-6100},
support = {R00 ES019881/ES/NIEHS NIH HHS/United States ; T32 CA009686/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Cadmium/*toxicity ; Carotenoids/*blood ; Cross-Sectional Studies ; Female ; Folic Acid/blood ; Humans ; Leukocytes/*drug effects ; Male ; Middle Aged ; Nutrition Surveys ; Telomere/*drug effects ; United States ; Vitamin A/blood ; Vitamin B 12/blood ; Vitamins/*blood ; Young Adult ; alpha-Tocopherol/blood ; gamma-Tocopherol/blood ; },
abstract = {Background: Leukocyte telomere length (LTL) is a biomarker of the aging process and is associated with the risk of chronic disease. Higher exposure to cadmium may be associated with shorter LTL, and adequate nutrient concentrations may be associated with longer LTL; however, the potential interaction between metals and nutrients on LTL has yet to be examined.Objectives: The objective of this study was to evaluate whether serum concentrations of vitamins and carotenoids were associated with LTL, and whether they modified the association between blood cadmium and LTL in the US NHANES (1999-2002).Methods: We evaluated cross-sectional associations between LTL and serum concentrations of vitamin A, γ-tocopherol, α-tocopherol, folate, and vitamin B-12 (1999-2002; n = 7458) and α-carotene, β-carotene, β-cryptoxanthin, lutein + zeaxanthin, and lycopene (2001-2002; n = 4018) in a nationally representative sample of US adults (≥20 y of age) with the use of multivariable linear regression. We further investigated whether vitamin and carotenoid concentrations modified associations between blood cadmium and LTL with models stratified by serum nutrient concentrations and the inclusion of an interaction term.Results: Blood cadmium was inversely associated with LTL (percentage of LTL difference per 1 μg/L = -3.74; 95% CI: -5.35, -2.10). Serum vitamin A was positively associated (percentage of LTL difference per 1 μg/L = 4.01; 95% CI: 0.26, 7.90) and γ-tocopherol was inversely associated (percentage of LTL difference per 1 μg/dL = -2.49; 95% CI: -4.21, -0.73) with LTL. Serum folate (P-trend = 0.06) and α-tocopherol (P-trend = 0.10) were marginally positively associated with LTL, whereas vitamin B-12 (P-trend = 0.78) was not associated with LTL. Serum carotenoids were generally positively associated with LTL. Serum vitamin and carotenoid concentrations did not modify blood cadmium and LTL associations (P-interaction > 0.10).Conclusions: Results from this cross-sectional study suggest that exposure to cadmium and certain nutrients may be associated with LTL in US adults, but the serum concentrations of the vitamins and carotenoids evaluated did not modify cross-sectional associations between cadmium exposure and LTL.},
}
@article {pmid28274506,
year = {2017},
author = {Maurya, PK and Rizzo, LB and Xavier, G and Tempaku, PF and Zeni-Graiff, M and Santoro, ML and Mazzotti, DR and Zugman, A and Pan, P and Noto, C and Maes, M and Asevedo, E and Mansur, RB and Cunha, GR and Gadelha, A and Bressan, RA and Belangero, SI and Brietzke, E},
title = {Shorter leukocyte telomere length in patients at ultra high risk for psychosis.},
journal = {European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology},
volume = {27},
number = {5},
pages = {538-542},
doi = {10.1016/j.euroneuro.2017.02.008},
pmid = {28274506},
issn = {1873-7862},
mesh = {Adolescent ; Adult ; Female ; Humans ; Leukocytes/*pathology ; Male ; Psychiatric Status Rating Scales ; Psychotic Disorders/*genetics/*pathology ; Telomere Shortening/*physiology ; Young Adult ; },
abstract = {Telomere length attrition has been demonstrated in schizophrenia but not in individuals in ultra high risk (UHR) for psychosis. The present study aimed to compare the leukocyte telomere length (TL) between patients at UHR for psychosis and healthy controls (HC). Twenty-two participants with UHR and 88 HC were enrolled in this study. Telomere lengths were determined using a multiplex qPCR assay. After adjustment for age, sex, ethnicity, and education, patients in UHR, compared with HC groups, had shorter telomere length (RR: 0.929, p=0.031). Shorter leukocyte telomere length in UHR could represent early signs of accelerated aging in this population.},
}
@article {pmid28264873,
year = {2017},
author = {Antwi, SO and Bamlet, WR and Broderick, BT and Chaffee, KG and Oberg, A and Jatoi, A and Boardman, LA and Petersen, GM},
title = {Genetically Predicted Telomere Length is not Associated with Pancreatic Cancer Risk.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {26},
number = {6},
pages = {971-974},
pmid = {28264873},
issn = {1538-7755},
support = {P30 CA015083/CA/NCI NIH HHS/United States ; P50 CA102701/CA/NCI NIH HHS/United States ; R01 CA204013/CA/NCI NIH HHS/United States ; R25 CA092049/CA/NCI NIH HHS/United States ; },
mesh = {Case-Control Studies ; Female ; Genotype ; Humans ; Male ; Pancreatic Neoplasms/*genetics/pathology ; Risk Factors ; Telomere/*genetics ; },
abstract = {Background: Epidemiologic associations of leukocyte telomere length (LTL) and pancreatic ductal adenocarcinoma (PDAC) have been inconsistent owing, in part, to variation in telomere length (TL) assessment across studies. To overcome this limitation and address concerns of potential reverse causation, we used carriage of telomere-related alleles to genetically predict TL and examined its association with PDAC.Methods: A case-control study of 1,500 PDAC cases and 1,500 controls, frequency-matched on age and sex was performed. Eight of nine polymorphisms previously associated with variation in LTL were analyzed. Genetic risk scores (GRS) consisting of the TL-related polymorphisms were computed as the number of long TL alleles carried by an individual scaled to published kilobase pairs of TL associated with each allele. Participants were further categorized on the basis of the number of short TL alleles they carry across all eight SNPs. Associations were examined in additive and dominant models using logistic regression to calculate ORs and 95% confidence intervals (CI).Results: In age- and sex-adjusted models, one short TL allele (rs10936599, T) was associated with reduced risk, whereas another short TL allele (rs2736100, A) was associated with increased risk, with per-allele ORs of 0.89 (95% CI, 0.79-0.99) and 1.13 (95% CI, 1.01-1.24), respectively. No association was observed with GRS or short TL allele counts, and no associations were observed in the dominant models.Conclusions: Findings suggest that genetically predicted short TL is not associated with PDAC risk.Impact: Common genetic determinants of short TL do not appear to influence PDAC risk. Cancer Epidemiol Biomarkers Prev; 26(6); 971-4. ©2017 AACR.},
}
@article {pmid28263285,
year = {2017},
author = {Ogawa, EF and Leveille, SG and Wright, JA and Shi, L and Camhi, SM and You, T},
title = {Physical Activity Domains/Recommendations and Leukocyte Telomere Length in U.S. Adults.},
journal = {Medicine and science in sports and exercise},
volume = {49},
number = {7},
pages = {1375-1382},
doi = {10.1249/MSS.0000000000001253},
pmid = {28263285},
issn = {1530-0315},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/physiology ; Exercise/*physiology ; Female ; Humans ; Leukocytes/*physiology ; Male ; Middle Aged ; Socioeconomic Factors ; Telomere/*physiology ; Telomere Shortening ; Young Adult ; },
abstract = {PURPOSE: The purpose of this study was to examine the associations between different physical activity (PA) domains, PA recommendations, and leukocyte telomere length (LTL) using data from a nationally representative sample of U.S. adults in the National Health and Nutrition Examination Survey, 1999-2002.<br><br>METHODS: A total of 6933 U.S. adults (3402 men, 3531 women; age range: 20-84 yr) who completed demographic, general health and PA questionnaires and provided a blood sample were included in the analyses. Multivariable-adjusted linear regression models were used to determine associations between PA (domain-specific PA [household/yard work PA, transportation PA, moderate leisure time PA (LTPA), and vigorous LTPA], total moderate PA and PA recommendation groups), and log-transformed LTL adjusting for age, gender, education, cigarette smoking, alcohol consumption, and body mass index.<br><br>RESULTS: On average, an increase of 1 h&#xb7;wk of vigorous LTPA was associated with a 0.31% (P < 0.001) longer LTL, and an increase of 1 h&#xb7;wk of household/yard work PA was associated with a 0.21% (P = 0.03) shorter LTL while adjusted for sociodemographic and health behavior covariates. Neither transportation PA nor moderate LTPA was significantly associated with LTL. In addition, compared with not meeting the PA recommendation (<150 min&#xb7;wk), exceeding the recommended PA levels (&#x2265;300 min&#xb7;wk) was positively associated with longer LTL (P = 0.04), whereas there was no difference in telomere length between those not meeting versus those meeting the PA recommendation (150-299 min&#xb7;wk).<br><br>CONCLUSION: Greater engagement in vigorous LTPA and exceeding the PA recommendation may have a protective effect against telomere shortening. Future studies should examine the association between PA and LTL by exploring potential mediators such as sedentary behavior, genetics, nutrition, and chronic diseases.},
}
@article {pmid28262705,
year = {2017},
author = {Cheng, R and Xu, J and Zhang, X and Shi, Z and Zhang, Q and Jin, Y},
title = {A selective and label-free strategy for rapid screening of telomere-binding Ligands via fluorescence regulation of DNA/silver nanocluster.},
journal = {Scientific reports},
volume = {7},
number = {},
pages = {42629},
pmid = {28262705},
issn = {2045-2322},
mesh = {Cell Line, Tumor ; Circular Dichroism ; DNA/*chemistry/*metabolism ; Drug Discovery ; Fluorescent Dyes ; G-Quadruplexes ; Humans ; *Ligands ; Luminescent Measurements ; *Metal Nanoparticles/chemistry ; *Silver/chemistry ; Telomere/*genetics/*metabolism ; },
abstract = {Herein, the conformational switch of G-rich oligonucleotide (GDNA) demonstrated the obvious functional switch of GDNA which was found to significantly affect the fluorescence of the in-situ synthesized DNA/silver nanocluster (DNA-AgNC) in homogeneous solution. We envisioned that the allosteric interaction between GDNA and DNA-AgNC would be possible to be used for screening telomere-binding ligands. A unimolecular probe (12C5TG) is ingeniously designed consisting of three contiguous DNA elements: G-rich telomeric DNA (GDNA) as molecular recognition sequence, T-rich DNA as linker and C-rich DNA as template of DNA-AgNC. The quantum yield and stability of 12C5TG-AgNC is greatly improved because the nearby deoxyguanosines tended to protect DNA/AgNC against oxidation. However, in the presence of ligands, the formation of G-quadruplex obviously quenched the fluorescence of DNA-AgNC. By taking full advantage of intramolecular allosteric effect, telomere-binding ligands were selectively and label-free screened by using deoxyguanines and G-quadruplex as natural fluorescence enhancer and quencher of DNA-AgNC respectively. Therefore, the functional switching of G-rich structure offers a cost-effective, facile and reliable way to screen drugs, which holds a great potential in bioanalysis as well.},
}
@article {pmid28262440,
year = {2017},
author = {Newton, CA and Kozlitina, J and Lines, JR and Kaza, V and Torres, F and Garcia, CK},
title = {Telomere length in patients with pulmonary fibrosis associated with chronic lung allograft dysfunction and post-lung transplantation survival.},
journal = {The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation},
volume = {36},
number = {8},
pages = {845-853},
pmid = {28262440},
issn = {1557-3117},
support = {R01 HL093096/HL/NHLBI NIH HHS/United States ; T32 HL098040/HL/NHLBI NIH HHS/United States ; UL1 TR001105/TR/NCATS NIH HHS/United States ; },
mesh = {Chronic Disease ; DNA/genetics ; Female ; Follow-Up Studies ; *Graft Survival ; Humans ; Incidence ; *Lung Transplantation ; Male ; Middle Aged ; Polymerase Chain Reaction ; *Postoperative Complications ; Postoperative Period ; Primary Graft Dysfunction/*complications/epidemiology/genetics ; Prospective Studies ; Pulmonary Fibrosis/epidemiology/etiology/*genetics ; Risk Factors ; Survival Rate/trends ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Texas/epidemiology ; },
abstract = {BACKGROUND: Prior studies have shown that patients with pulmonary fibrosis with mutations in the telomerase genes have a high rate of certain complications after lung transplantation. However, few studies have investigated clinical outcomes based on leukocyte telomere length.<br><br>METHODS: We conducted an observational cohort study of all patients with pulmonary fibrosis who underwent lung transplantation at a single center between January 1, 2007, and December 31, 2014. Leukocyte telomere length was measured from a blood sample collected before lung transplantation, and subjects were stratified into 2 groups (telomere length <10th percentile vs &#x2265;10th percentile). Primary outcome was post-lung transplant survival. Secondary outcomes included incidence of allograft dysfunction, non-pulmonary organ dysfunction, and infection.<br><br>RESULTS: Approximately 32% of subjects had a telomere length <10th percentile. Telomere length <10th percentile was independently associated with worse survival (hazard ratio 10.9, 95% confidence interval 2.7-44.8, p = 0.001). Telomere length <10th percentile was also independently associated with a shorter time to onset of chronic lung allograft dysfunction (hazard ratio 6.3, 95% confidence interval 2.0-20.0, p = 0.002). Grade 3 primary graft dysfunction occurred more frequently in the <10th percentile group compared with the &#x2265;10th percentile group (28% vs 7%; p = 0.034). There was no difference between the 2 groups in incidence of acute cellular rejection, cytopenias, infection, or renal dysfunction.<br><br>CONCLUSIONS: Telomere length <10th percentile was associated with worse survival and shorter time to onset of chronic lung allograft dysfunction and thus represents a biomarker that may aid in risk stratification of patients with pulmonary fibrosis before lung transplantation.},
}
@article {pmid28259884,
year = {2016},
author = {MacKinnon, RN and Duivenvoorden, HM and Campbell, LJ and Wall, M},
title = {The Dicentric Chromosome dic(20;22) Is a Recurrent Abnormality in Myelodysplastic Syndromes and Is a Product of Telomere Fusion.},
journal = {Cytogenetic and genome research},
volume = {150},
number = {3-4},
pages = {262-272},
doi = {10.1159/000456677},
pmid = {28259884},
issn = {1424-859X},
mesh = {*Chromosome Aberrations ; *Chromosomes, Human, Pair 20 ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Myelodysplastic Syndromes/*genetics ; Polymorphism, Single Nucleotide ; *Telomere ; },
abstract = {We describe a recurrent dicentric chromosome formed by telomere fusion between chromosome 20 and chromosome 22 in 4 cases of myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML). In particular, the presence of residual telomere sequences at the site of translocation in 3 of the 4 cases makes a compelling case for telomere fusion. This is the first description of a recurrent telomere fusion event in any malignant condition. The 20q subtelomeric region was retained in all 4 examples despite deletion of the 20q12 region closer to the centromere. The original dicentric chromosome in all 4 cases contained nucleolus organiser region material from the short arm of chromosome 22 and had also undergone secondary rearrangements that produced amplification of the common gained region on 20q. We propose that the sequence of events producing this chromosome abnormality is: degradation of the telomeres, formation of an unstable dicentric chromosome by 20q and 22p telomere fusion, breakage-fusion-bridge cycles causing copy number aberration between the centromeres, selection of cells with 20q12 deletion, and further selection of cells with 20q11.2 gain. The last 2 steps are driver events responsible for the abnormal chromosomes found in the malignant cells. Finding recurrent patterns in the complex genome reorganisation events that characterise poor-prognosis, complex-karyotype AML and MDS will help us understand the mechanisms and oncogenic driver mutations in these poorly understood malignancies.},
}
@article {pmid28254828,
year = {2017},
author = {Martínez, P and Blasco, MA},
title = {Telomere-driven diseases and telomere-targeting therapies.},
journal = {The Journal of cell biology},
volume = {216},
number = {4},
pages = {875-887},
pmid = {28254828},
issn = {1540-8140},
support = {232854/ERC_/European Research Council/International ; },
mesh = {Aging/genetics ; Animals ; Cell Transformation, Neoplastic/genetics ; Chromosomal Instability/genetics ; Dyskeratosis Congenita/genetics ; Fetal Growth Retardation/genetics ; Humans ; Intellectual Disability/genetics ; Microcephaly/genetics ; Molecular Targeted Therapy/methods ; Mutation/genetics ; Neoplasms/genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis/genetics ; Telomere Shortening/genetics ; },
abstract = {Telomeres, the protective ends of linear chromosomes, shorten throughout an individual's lifetime. Telomere shortening is proposed to be a primary molecular cause of aging. Short telomeres block the proliferative capacity of stem cells, affecting their potential to regenerate tissues, and trigger the development of age-associated diseases. Mutations in telomere maintenance genes are associated with pathologies referred to as telomere syndromes, including Hoyeraal-Hreidarsson syndrome, dyskeratosis congenita, pulmonary fibrosis, aplastic anemia, and liver fibrosis. Telomere shortening induces chromosomal instability that, in the absence of functional tumor suppressor genes, can contribute to tumorigenesis. In addition, mutations in telomere length maintenance genes and in shelterin components, the protein complex that protects telomeres, have been found to be associated with different types of cancer. These observations have encouraged the development of therapeutic strategies to treat and prevent telomere-associated diseases, namely aging-related diseases, including cancer. Here we review the molecular mechanisms underlying telomere-driven diseases and highlight recent advances in the preclinical development of telomere-targeted therapies using mouse models.},
}
@article {pmid28253088,
year = {2017},
author = {Ameh, OI and Okpechi, IG and Dandara, C and Kengne, AP},
title = {Association Between Telomere Length, Chronic Kidney Disease, and Renal Traits: A Systematic Review.},
journal = {Omics : a journal of integrative biology},
volume = {21},
number = {3},
pages = {143-155},
doi = {10.1089/omi.2016.0180},
pmid = {28253088},
issn = {1557-8100},
mesh = {Biomarkers/*metabolism ; Glomerulonephritis/genetics ; Humans ; Kidney/*metabolism ; Renal Insufficiency, Chronic/*genetics ; Telomere/*genetics ; },
abstract = {Telomere length (TL) is an important biological variable that can influence a variety of disease-related complex traits as well as host-environment interactions such as drug and nutritional responses. Chronic kidney disease (CKD) is a common global health challenge especially with the currently aging world population. We conducted a PubMed database search according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines for systematic reviews. Studies in adults (18 years and above) in which TL was determined and correlated with CKD, renal traits, and function were included, while animal model studies were excluded. Nine studies comprising 7829 participants, published between 2005 and 2016, met the inclusion criteria. These included eight observational studies (six being prospective), and one clinical trial. Participants in two studies were diabetic patients with varying stages of CKD, and nondialysis chronic glomerulonephritis CKD patients in two other studies. TL measurements used polymerase chain reaction in five studies, terminal restriction fragmentation in three studies, and quantitative fluorescence in situ hybridization in one study. Short TL was independently associated with increased risk of prevalent microalbuminuria in diabetic men with CKD (p = 0.007). Among CKD patients with heterogeneous etiologies, however, there was an unadjusted lower risk (p < 0.001). Short TL was significantly associated with CKD progression among smokers (p = 0.001) and diabetic patients (p = 0.03). On the other hand, long TL was paradoxically associated with longer diagnosed duration of moderate CKD. We postulate that shortening TL might be associated with CKD prevalence/occurrence or declining kidney function, but this association is likely offset by the cellular telomere reparative process in those surviving longer with CKD. This systematic review underscores the need for future omics and human genetics research to delineate the contribution of TL to CKD, renal dysfunction, and related health outcomes. Telomeres and telomerase activity hold great promise for CKD risk stratification and personalized medicine.},
}
@article {pmid28249683,
year = {2017},
author = {Zhou, Y and Jelinek, H and Hambly, BD and McLachlan, CS},
title = {Electrocardiogram QRS duration and associations with telomere length: A cross-sectional analysis in Australian rural diabetic and non-diabetic population.},
journal = {Journal of electrocardiology},
volume = {50},
number = {4},
pages = {450-456},
doi = {10.1016/j.jelectrocard.2017.02.010},
pmid = {28249683},
issn = {1532-8430},
mesh = {Adult ; Aged ; Australia ; Cross-Sectional Studies ; Diabetes Mellitus, Type 2/*physiopathology ; *Electrocardiography ; Female ; Humans ; Long QT Syndrome/*diagnosis/*physiopathology ; Male ; Middle Aged ; Polymerase Chain Reaction ; Retrospective Studies ; Risk Factors ; Rural Population ; Telomere/*pathology ; },
abstract = {Prolonged electrocardiogram QRS durations are often present in aging populations. Shorter telomere length is considered a biomarker of cellular aging. Decreased telomere length has been associated with coronary artery risk, and ventricular remodeling. However, the association between telomeres and cardiac conduction abnormalities, such as increased QRS duration are not well understood. A retrospective cross-sectional population was obtained from the CSU Diabetes Screening Research Initiative database where 273 participants had both ECG-derived QRS duration and DNA to permit leukocyte telomere length (LTL) determination. Telomere length was determined using the monochrome multiplex quantitative PCR method to measure mean relative LTL. Resting 12-lead electrocardiograms were obtained from each subject using a Welch Allyn PC-Based ECG system. Relative LTL was moderately negatively associated with QRS duration in type 2 diabetes mellitus (T2DM) patients (R[2]=0.055), compared to controls (R[2]=0.010). In general linear models with no adjustments a significant interaction between QRS duration and LTL is observed for a combined population of T2DM and non-diabetics. When we compared T2DM to non-diabetics, we found that T2DM increased the effect size for relative LTL on QRS duration in comparison to controls. Hence, for each 0.1 unit of relative LTL attrition, QRS duration in T2DM patients increased by 3.24ms (95% CI, -63.00 to -1.84), compared to 1.65ms in controls (95% CI, -40.44 to 7.40). In summary we have observed an association between LTL in a rural aging mixed population of T2DM and non-diabetes. We have observed an unadjusted association between QRS duration and LTL in T2DM. We noted that the control group demonstrated no such association. This highlights the complexity of T2DM when exploring disease phenotype-telomere interactions.},
}
@article {pmid28247509,
year = {2017},
author = {McDonnell, BJ and Yasmin, and Butcher, L and Cockcroft, JR and Wilkinson, IB and Erusalimsky, JD and McEniery, CM},
title = {The age-dependent association between aortic pulse wave velocity and telomere length.},
journal = {The Journal of physiology},
volume = {595},
number = {5},
pages = {1627-1635},
pmid = {28247509},
issn = {1469-7793},
support = {FS/12/8/29377/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Adolescent ; Adult ; Aged ; Aging/*physiology ; Aorta/*physiology ; Blood Pressure ; Cholesterol/blood ; Female ; Humans ; Male ; Middle Aged ; *Pulse Wave Analysis ; Telomere/*physiology ; Triglycerides/blood ; Young Adult ; },
abstract = {KEY POINTS: Age significantly modifies the relationship between aortic pulse wave velocity and telomere length. The differential relationships observed between aortic pulse wave velocity and telomere length in younger and older individuals suggest that the links between cellular and vascular ageing reflect a complex interaction between genetic and environmental factors acting over the life-course.<br><br>ABSTRACT: Ageing is associated with marked large artery stiffening. Telomere shortening, a marker of cellular ageing, is linked with arterial stiffening. However, the results of existing studies are inconsistent, possibly because of the confounding influence of variable exposure to cardiovascular risk factors. Therefore, we investigated the relationship between telomere length (TL) and aortic stiffness in well-characterized, younger and older healthy adults, who were pre-selected on the basis of having either low or high aortic pulse wave velocity (aPWV), a robust measure of aortic stiffness. Demographic, haemodynamic and biochemical data were drawn from participants in the Anglo-Cardiff Collaborative Trial. Two age groups with an equal sex ratio were examined: those aged <30&#xa0;years (younger) or >50&#xa0;years (older). Separately for each age group and sex, DNA samples representing the highest (n&#xa0;=&#xa0;125) and lowest (n&#xa0;=&#xa0;125) extremes of aPWV (adjusted for blood pressure) were selected for analysis of leukocyte TL. Ultimately, this yielded complete phenotypic data on 904 individuals. In younger subjects, TL was significantly shorter in those with high aPWV vs. those with low aPWV (P&#xa0;=&#xa0;0.017). By contrast, in older subjects, TL was significantly longer in those with high aPWV (P&#xa0;=&#xa0;0.001). Age significantly modified the relationship between aPWV and TL (P&#xa0;<&#xa0;0.001). Differential relationships are observed between aPWV and TL, with an inverse association in younger individuals and a positive association in older individuals. The links between cellular and vascular ageing reflect a complex interaction between genetic and environmental factors acting over the life-course.},
}
@article {pmid28244560,
year = {2017},
author = {Tucker, LA},
title = {Consumption of Nuts and Seeds and Telomere Length in 5,582 Men and Women of the National Health and Nutrition Examination Survey (NHANES).},
journal = {The journal of nutrition, health &amp; aging},
volume = {21},
number = {3},
pages = {233-240},
pmid = {28244560},
issn = {1760-4788},
mesh = {Adult ; Aging/*physiology ; Biomarkers/blood ; Cellular Senescence/*physiology ; Cross-Sectional Studies ; *Diet ; Female ; Humans ; Leukocytes ; Male ; Middle Aged ; Nutrition Policy ; Nutrition Surveys/*methods ; *Nuts ; Real-Time Polymerase Chain Reaction ; *Seeds ; Telomere/physiology ; Telomere Shortening/*physiology ; },
abstract = {OBJECTIVES: Consumption of nuts and seeds is associated favorably with all-cause mortality. Nuts and seeds could reduce disease and prolong life by influencing telomeres. Telomere length is a good indicator of the senescence of cells. The purpose of the present study was to determine the relationship between nuts and seeds intake and leukocyte telomere length, a biomarker of biologic aging.<br><br>DESIGN: Cross-sectional.<br><br>SETTING AND PARTICIPANTS: A total of 5,582 randomly selected men and women from the National Health and Nutrition Examination Survey (NHANES), 1999-2002, were studied.<br><br>MEASUREMENTS: DNA was obtained via blood samples. Telomere length was assessed using the quantitative polymerase chain reaction method. A validated, multi-pass, 24-h recall dietary assessment, administered by NHANES, was employed to quantify consumption of nuts and seeds.<br><br>RESULTS: Nuts and seeds intake was positively and linearly associated with telomere length. For each 1-percent of total energy derived from nuts and seeds, telomere length was 5 base pairs longer (F=8.6, P=0.0065). Given the age-related rate of telomere shortening was 15.4 base pairs per year (F=581.1, P<0.0001), adults of the same age had more than 1.5 years of reduced cell aging if they consumed 5% of their total energy from nuts and seeds.<br><br>CONCLUSIONS: Consumption of nuts and seeds accounts for meaningful decreases in biologic aging and cell senescence. The findings reinforce the recommendations of the 2015-2020 Dietary Guidelines for Americans, which encourage the consumption of nuts and seeds as part of a healthy diet.},
}
@article {pmid28241208,
year = {2017},
author = {, and Haycock, PC and Burgess, S and Nounu, A and Zheng, J and Okoli, GN and Bowden, J and Wade, KH and Timpson, NJ and Evans, DM and Willeit, P and Aviv, A and Gaunt, TR and Hemani, G and Mangino, M and Ellis, HP and Kurian, KM and Pooley, KA and Eeles, RA and Lee, JE and Fang, S and Chen, WV and Law, MH and Bowdler, LM and Iles, MM and Yang, Q and Worrall, BB and Markus, HS and Hung, RJ and Amos, CI and Spurdle, AB and Thompson, DJ and O'Mara, TA and Wolpin, B and Amundadottir, L and Stolzenberg-Solomon, R and Trichopoulou, A and Onland-Moret, NC and Lund, E and Duell, EJ and Canzian, F and Severi, G and Overvad, K and Gunter, MJ and Tumino, R and Svenson, U and van Rij, A and Baas, AF and Bown, MJ and Samani, NJ and van t'Hof, FNG and Tromp, G and Jones, GT and Kuivaniemi, H and Elmore, JR and Johansson, M and Mckay, J and Scelo, G and Carreras-Torres, R and Gaborieau, V and Brennan, P and Bracci, PM and Neale, RE and Olson, SH and Gallinger, S and Li, D and Petersen, GM and Risch, HA and Klein, AP and Han, J and Abnet, CC and Freedman, ND and Taylor, PR and Maris, JM and Aben, KK and Kiemeney, LA and Vermeulen, SH and Wiencke, JK and Walsh, KM and Wrensch, M and Rice, T and Turnbull, C and Litchfield, K and Paternoster, L and Standl, M and Abecasis, GR and SanGiovanni, JP and Li, Y and Mijatovic, V and Sapkota, Y and Low, SK and Zondervan, KT and Montgomery, GW and Nyholt, DR and van Heel, DA and Hunt, K and Arking, DE and Ashar, FN and Sotoodehnia, N and Woo, D and Rosand, J and Comeau, ME and Brown, WM and Silverman, EK and Hokanson, JE and Cho, MH and Hui, J and Ferreira, MA and Thompson, PJ and Morrison, AC and Felix, JF and Smith, NL and Christiano, AM and Petukhova, L and Betz, RC and Fan, X and Zhang, X and Zhu, C and Langefeld, CD and Thompson, SD and Wang, F and Lin, X and Schwartz, DA and Fingerlin, T and Rotter, JI and Cotch, MF and Jensen, RA and Munz, M and Dommisch, H and Schaefer, AS and Han, F and Ollila, HM and Hillary, RP and Albagha, O and Ralston, SH and Zeng, C and Zheng, W and Shu, XO and Reis, A and Uebe, S and Hüffmeier, U and Kawamura, Y and Otowa, T and Sasaki, T and Hibberd, ML and Davila, S and Xie, G and Siminovitch, K and Bei, JX and Zeng, YX and Försti, A and Chen, B and Landi, S and Franke, A and Fischer, A and Ellinghaus, D and Flores, C and Noth, I and Ma, SF and Foo, JN and Liu, J and Kim, JW and Cox, DG and Delattre, O and Mirabeau, O and Skibola, CF and Tang, CS and Garcia-Barcelo, M and Chang, KP and Su, WH and Chang, YS and Martin, NG and Gordon, S and Wade, TD and Lee, C and Kubo, M and Cha, PC and Nakamura, Y and Levy, D and Kimura, M and Hwang, SJ and Hunt, S and Spector, T and Soranzo, N and Manichaikul, AW and Barr, RG and Kahali, B and Speliotes, E and Yerges-Armstrong, LM and Cheng, CY and Jonas, JB and Wong, TY and Fogh, I and Lin, K and Powell, JF and Rice, K and Relton, CL and Martin, RM and Davey Smith, G},
title = {Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.},
journal = {JAMA oncology},
volume = {3},
number = {5},
pages = {636-651},
pmid = {28241208},
issn = {2374-2445},
support = {R01 DK106621/DK/NIDDK NIH HHS/United States ; ZIA EY000403-13/ImNIH/Intramural NIH HHS/United States ; ZIA EY000403-10/ImNIH/Intramural NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; P50 CA102701/CA/NCI NIH HHS/United States ; ZIA EY000403-08/ImNIH/Intramural NIH HHS/United States ; ZIA EY000403-12/ImNIH/Intramural NIH HHS/United States ; R01 CA052689/CA/NCI NIH HHS/United States ; 16563/CRUK_/Cancer Research UK/United Kingdom ; P20 GM103534/GM/NIGMS NIH HHS/United States ; P01 HL092870/HL/NHLBI NIH HHS/United States ; MR/L003120/1/MRC_/Medical Research Council/United Kingdom ; Z99 EY999999/ImNIH/Intramural NIH HHS/United States ; MC_UU_12013/2/MRC_/Medical Research Council/United Kingdom ; T32 NS047996/NS/NINDS NIH HHS/United States ; G1001158/MRC_/Medical Research Council/United Kingdom ; 19167/CRUK_/Cancer Research UK/United Kingdom ; U01 HG006382/HG/NHGRI NIH HHS/United States ; R01 HL077612/HL/NHLBI NIH HHS/United States ; ZIA EY000403-14/ImNIH/Intramural NIH HHS/United States ; ZIA EY000403-11/ImNIH/Intramural NIH HHS/United States ; UL1 TR000124/TR/NCATS NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; P30 CA023108/CA/NCI NIH HHS/United States ; 20138/CRUK_/Cancer Research UK/United Kingdom ; P50 CA097257/CA/NCI NIH HHS/United States ; ZIA EY000403-09/ImNIH/Intramural NIH HHS/United States ; Z01 EY000403-06/ImNIH/Intramural NIH HHS/United States ; RG/08/014/24067/BHF_/British Heart Foundation/United Kingdom ; P30 AR070549/AR/NIAMS NIH HHS/United States ; MC_UU_00002/7/MRC_/Medical Research Council/United Kingdom ; Z01 EY000403-07/ImNIH/Intramural NIH HHS/United States ; R01 DK107904/DK/NIDDK NIH HHS/United States ; 19169/CRUK_/Cancer Research UK/United Kingdom ; R01 HL064310/HL/NHLBI NIH HHS/United States ; R01 HL097163/HL/NHLBI NIH HHS/United States ; MC_UU_12013/8/MRC_/Medical Research Council/United Kingdom ; 204623/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; R33 HL120770/HL/NHLBI NIH HHS/United States ; MC_EX_MR/L012286/1/MRC_/Medical Research Council/United Kingdom ; MC_UU_12013/4/MRC_/Medical Research Council/United Kingdom ; G0700491/MRC_/Medical Research Council/United Kingdom ; ZIA EY000403-15/ImNIH/Intramural NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; 202802/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; UM1 CA182883/CA/NCI NIH HHS/United States ; MC_UU_12013/3/MRC_/Medical Research Council/United Kingdom ; P30 AR047363/AR/NIAMS NIH HHS/United States ; MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Cardiovascular Diseases/genetics ; Female ; Genetic Predisposition to Disease/*genetics ; Genome-Wide Association Study ; Germ-Line Mutation ; Humans ; Male ; Mendelian Randomization Analysis/*methods ; Middle Aged ; Neoplasms/*genetics ; Polymorphism, Single Nucleotide ; Risk Assessment/methods ; Telomere/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.<br><br>OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.<br><br>DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015.<br><br>STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.<br><br>DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.<br><br>MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.<br><br>RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420&#x202f;081 cases (median cases, 2526 per disease) and 1&#x202f;093&#x202f;105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).<br><br>CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.},
}
@article {pmid28239143,
year = {2017},
author = {Rossiello, F and Aguado, J and Sepe, S and Iannelli, F and Nguyen, Q and Pitchiaya, S and Carninci, P and d'Adda di Fagagna, F},
title = {DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs.},
journal = {Nature communications},
volume = {8},
number = {},
pages = {13980},
pmid = {28239143},
issn = {2041-1723},
support = {322726/ERC_/European Research Council/International ; },
mesh = {Animals ; *DNA Damage ; Mice, Inbred C57BL ; Mice, Knockout ; Oligonucleotides, Antisense/pharmacology ; RNA/genetics/*metabolism ; RNA Processing, Post-Transcriptional/drug effects/genetics ; Ribonuclease III/metabolism ; Telomere/*metabolism ; Transcription, Genetic/drug effects ; },
abstract = {The DNA damage response (DDR) is a set of cellular events that follows the generation of DNA damage. Recently, site-specific small non-coding RNAs, also termed DNA damage response RNAs (DDRNAs), have been shown to play a role in DDR signalling and DNA repair. Dysfunctional telomeres activate DDR in ageing, cancer and an increasing number of identified pathological conditions. Here we show that, in mammals, telomere dysfunction induces the transcription of telomeric DDRNAs (tDDRNAs) and their longer precursors from both DNA strands. DDR activation and maintenance at telomeres depend on the biogenesis and functions of tDDRNAs. Their functional inhibition by sequence-specific antisense oligonucleotides allows the unprecedented telomere-specific DDR inactivation in cultured cells and in vivo in mouse tissues. In summary, these results demonstrate that tDDRNAs are induced at dysfunctional telomeres and are necessary for DDR activation and they validate the viability of locus-specific DDR inhibition by targeting DDRNAs.},
}
@article {pmid28238220,
year = {2017},
author = {Chilton, WL and O'Brien, BJ and Grace, F and Charchar, FJ},
title = {Telomeres, exercise and cardiovascular disease: finding the means to justify the ends.},
journal = {Acta physiologica (Oxford, England)},
volume = {220},
number = {2},
pages = {186-188},
doi = {10.1111/apha.12862},
pmid = {28238220},
issn = {1748-1716},
mesh = {Cardiovascular Diseases ; *Exercise ; Humans ; *Telomere ; },
}
@article {pmid28235830,
year = {2017},
author = {Thorvaldsdottir, B and Aradottir, M and Stefansson, OA and Bodvarsdottir, SK and Eyfjörd, JE},
title = {Telomere Length Is Predictive of Breast Cancer Risk in BRCA2 Mutation Carriers.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {26},
number = {8},
pages = {1248-1254},
doi = {10.1158/1055-9965.EPI-16-0946},
pmid = {28235830},
issn = {1538-7755},
mesh = {Breast Neoplasms/*genetics/pathology ; Cohort Studies ; Female ; Genes, BRCA2/*physiology ; Germ-Line Mutation ; Humans ; Middle Aged ; Telomere/*pathology ; },
abstract = {Background: Germline BRCA2 mutations increase risk of breast cancer and other malignancies. BRCA2 has been shown to play a role in telomere protection and maintenance. Telomere length (TL) has been studied as a modifying factor for various diseases, including breast cancer. Previous research on TL in BRCA mutation carriers has produced contradicting results.Methods: We measured blood TL, using a high-throughput monochrome multiplex qPCR method, in a well-defined Icelandic cohort of female BRCA2 mutation carriers (n = 169), sporadic breast cancer patients (n = 561), and healthy controls (n = 537).Results: Breast cancer cases had significantly shorter TL than unaffected women (P < 0.0001), both BRCA2 mutation carriers (P = 0.0097) and noncarriers (P = 0.00006). Using exclusively samples acquired before breast cancer diagnosis, we found that shorter telomeres were significantly associated with increased breast cancer risk in BRCA2 mutation carriers [HR, 3.60; 95% confidence interval (CI), 1.17-11.28; P, 0.025] but not in non-carriers (HR,1.40; 95% CI, 0.89-2.22; P, 0.15). We found no association between TL and breast cancer-specific survival.Conclusions: Blood TL is predictive of breast cancer risk in BRCA2 mutation carriers. Breast cancer cases have significantly shorter TL than unaffected women, regardless of BRCA2 status, indicating that samples taken after breast cancer diagnosis should not be included in evaluations of TL and breast cancer risk.Impact: Our study is built on a well-defined cohort, highly accurate methods, and long follow-up and can therefore help to clarify some previously published, contradictory results. Our findings also suggest that BRCA2 has an important role in telomere maintenance, even in normal blood cells. Cancer Epidemiol Biomarkers Prev; 26(8); 1248-54. ©2017 AACR.},
}
@article {pmid28233473,
year = {2017},
author = {Sun, Y and Tao, W and Huang, M and Wu, X and Gu, J},
title = {Genetic variants in telomere-maintenance genes are associated with ovarian cancer risk and outcome.},
journal = {Journal of cellular and molecular medicine},
volume = {21},
number = {3},
pages = {510-518},
pmid = {28233473},
issn = {1582-4934},
mesh = {Alleles ; Case-Control Studies ; Female ; Genetic Predisposition to Disease/*genetics ; Genotype ; Humans ; Middle Aged ; Ovarian Neoplasms/*genetics ; Polymorphism, Single Nucleotide/*genetics ; Risk Factors ; Survival Analysis ; Telomere/*genetics ; },
abstract = {Most ovarian cancer patients present at an advanced stage with poor prognosis. Telomeres play a critical role in protecting chromosomes stability. The associations of genetic variants in telomere maintenance genes and ovarian cancer risk and outcome are unclear. We genotyped 137 single nucleotide polymorphisms (SNPs) in telomere-maintenance genes in 417 ovarian cancer cases and 417 matched healthy controls to evaluate their associations with cancer risk, survival and therapeutic response. False discovery rate Q-value was calculated to account for multiple testing. Eleven SNPs from two genes showed nominally significant associations with the risks of ovarian cancer. The most significant SNP was TEP1: rs2228026 with participants carrying at least one variant allele exhibiting a 3.28-fold (95% CI: 1.72-6.29; P < 0.001, Q = 0.028) increased ovarian cancer risk, which remained significant after multiple testing adjusting. There was also suggested evidence for the associations of SNPs with outcome, although none of the associations had a Q < 0.05. Seven SNPs from two genes showed associations with ovarian cancer survival (P < 0.05). The strongest association was found in TNKS gene (rs10093972, hazard ratio = 1.88; 95% CI: 1.20-2.92; P = 0.006, Q = 0.076). Five SNPs from four genes showed suggestive associations with therapeutic response (P < 0.05). In a survival tree analysis, TEP1:rs10143407 was the primary factor contributing to overall survival. Unfavourable genotype analysis showed a cumulative effect of significant SNPs on ovarian cancer risk, survival and therapeutic response. Genetic variations in telomere-maintenance genes may be associated with ovarian cancer risk and outcome.},
}
@article {pmid28226264,
year = {2017},
author = {Monroy-Jaramillo, N and Rodríguez-Agudelo, Y and Aviña-Cervantes, LC and Roberts, DL and Velligan, DI and Walss-Bass, C},
title = {Leukocyte telomere length in Hispanic schizophrenia patients under treatment with olanzapine.},
journal = {Journal of psychiatric research},
volume = {90},
number = {},
pages = {26-30},
doi = {10.1016/j.jpsychires.2017.02.007},
pmid = {28226264},
issn = {1879-1379},
mesh = {Adolescent ; Adult ; Antipsychotic Agents/*therapeutic use ; Benzodiazepines/*therapeutic use ; Female ; Hispanic or Latino ; Humans ; Leukocytes/*pathology ; Male ; Middle Aged ; Olanzapine ; Outpatients ; Schizophrenia/*drug therapy/ethnology/*genetics ; Telomere/*drug effects/genetics ; Young Adult ; },
abstract = {Different lines of evidence indicate that patients with schizophrenia (SZ) exhibit accelerated aging. Leukocyte telomere length (TL), an aging marker, is associated with age-related and chronic pathologies, including schizophrenia. We analyzed leukocyte TL in 170 SZ patients of Hispanic ancestry grouped based on antipsychotic treatment, compared to 126 matched controls. The group under treatment with atypical antipsychotics was further subdivided according to the risk of medication to cause metabolic syndrome (MetS). Our results show significant erosion in the TL of SZ patients under treatment with the atypical antipsychotics clozapine and olanzapine, which cause high-risk for MetS, compared to healthy controls and patients under treatment with medium and low-risk antipsychotics. However, when the analysis was done separately for clozapine and olanzapine, a significant difference remained only for olanzapine. These findings suggest that atypical antipsychotics that cause high-risk for MetS, particularly olanzapine, may modulate leukocyte TL in SZ patients. Future research is required to elucidate if in fact atypical antipsychotics are involved in TL maintenance in SZ subjects and the mechanism by which this occurs.},
}
@article {pmid28224765,
year = {2017},
author = {Park, HS and Choi, J and See, CJ and Kim, JA and Park, SN and Im, K and Kim, SM and Lee, DS and Hwang, SM},
title = {Dysregulation of Telomere Lengths and Telomerase Activity in Myelodysplastic Syndrome.},
journal = {Annals of laboratory medicine},
volume = {37},
number = {3},
pages = {195-203},
pmid = {28224765},
issn = {2234-3814},
mesh = {Adult ; Aged ; Aged, 80 and over ; Bone Marrow Cells/pathology ; Disease-Free Survival ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Interphase ; Kaplan-Meier Estimate ; Karyotyping ; Male ; Metaphase ; Middle Aged ; Myelodysplastic Syndromes/metabolism/mortality/*pathology ; Prognosis ; Proportional Hazards Models ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Shortening ; },
abstract = {BACKGROUND: Telomere shortening is thought to be involved in the pathophysiology of myeloid malignancies, but telomere lengths (TL) during interphase and metaphase in hematopoietic malignancies have not been analyzed. We aimed to assess the TLs of interphase and metaphase cells of MDS and telomerase activity (TA) and to find out prognostic significances of TL and TA.<br><br>METHODS: The prognostic significance of TA by quantitative PCR and TL by quantitative fluorescence in situ hybridization (QFISH) of interphase nuclei and metaphase chromosome arms of bone marrow cells from patients with MDS were evaluated.<br><br>RESULTS: MDS patients had shorter interphase TL than normal healthy donors (P<0.001). Average interphase and metaphase TL were inversely correlated (P=0.013, p arm; P=0.029, q arm), but there was no statistically significant correlation between TA and TL (P=0.258). The progression free survival was significantly shorter in patients with high TA, but the overall survival was not different according to average TA or interphase TL groups. Multivariable Cox analysis showed that old age, higher International Prognostic Scoring System (IPSS) subtypes, transformation to AML, no history of hematopoietic stem cell transplantation and short average interphase TL (<433 TL) as independent prognostic factors for poorer survival (P=0.003, 0.001, 0.005, 0.005, and 0.013, respectively).<br><br>CONCLUSIONS: The lack of correlation between age and TL, TA, and TL, and the inverse relationship between TL and TA in MDS patients reflect the dysregulation of telomere status and proliferation. As a prognostic marker for leukemia progression, TA may be considered, and since interphase TL has the advantage of automated measurement by QFISH, it may be used as a prognostic marker for survival in MDS.},
}
@article {pmid28222672,
year = {2017},
author = {Svenson, U and Roos, G and Wikström, P},
title = {Long leukocyte telomere length in prostate cancer patients at diagnosis is associated with poor metastasis-free and cancer-specific survival.},
journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine},
volume = {39},
number = {2},
pages = {1010428317692236},
doi = {10.1177/1010428317692236},
pmid = {28222672},
issn = {1423-0380},
mesh = {Aged ; Case-Control Studies ; Cohort Studies ; Humans ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Neoplasm Metastasis ; Prognosis ; Prostatic Neoplasms/*blood/*genetics/pathology ; Risk Factors ; Telomere/*ultrastructure ; },
abstract = {Previous studies have suggested that leukocyte telomere length is associated with risk of developing prostate cancer. Investigations of leukocyte telomere length as a prognostic factor in prostate cancer are, however, lacking. In this study, leukocyte telomere length was investigated both as a risk marker, comparing control subjects and patient risk groups (based on serum levels of prostate-specific antigen, tumor differentiation, and tumor stage), and as a prognostic marker for metastasis-free and cancer-specific survival. Relative telomere length was measured by a well-established quantitative polymerase chain reaction method in 415 consecutively sampled individuals. Statistical evaluation included 162 control subjects without cancer development during follow-up and 110 untreated patients with newly diagnosed localized prostate cancer at the time of blood draw. Leukocyte telomere length did not differ significantly between control subjects and patients, or between patient risk groups. Interestingly, however, and in line with our previous results in breast and kidney cancer patients, relative telomere length at diagnosis was an independent prognostic factor. Patients with long leukocyte telomeres (⩾median) had a significantly worse prostate cancer-specific and metastasis-free survival compared to patients with short telomere length. In contrast, for patients who died of other causes than prostate cancer, long relative telomere length was not coupled to shorter survival time. To our knowledge, these results are novel and give further strength to our hypothesis that leukocyte telomere length might be used as a prognostic marker in malignancy.},
}
@article {pmid28221367,
year = {2017},
author = {Lopizzo, N and Tosato, S and Begni, V and Tomassi, S and Cattane, N and Barcella, M and Turco, G and Ruggeri, M and Riva, MA and Pariante, CM and Cattaneo, A},
title = {Transcriptomic analyses and leukocyte telomere length measurement in subjects exposed to severe recent stressful life events.},
journal = {Translational psychiatry},
volume = {7},
number = {2},
pages = {e1042},
pmid = {28221367},
issn = {2158-3188},
support = {G108/603/MRC_/Medical Research Council/United Kingdom ; MR/J002739/1/MRC_/Medical Research Council/United Kingdom ; MR/N029488/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Case-Control Studies ; Female ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; Hydrocortisone/metabolism ; Immunity, Innate/genetics ; Inflammation/*genetics ; Interleukin-1/genetics ; Interleukin-6/metabolism ; Intramolecular Oxidoreductases/metabolism ; Leukocytes/*metabolism ; *Life Change Events ; Linear Models ; Macrophage Migration-Inhibitory Factors/metabolism ; Male ; Oxidative Stress/*genetics ; Real-Time Polymerase Chain Reaction ; Signal Transduction/genetics ; Telomere/*metabolism ; },
abstract = {Stressful life events occurring in adulthood have been found able to affect mood and behavior, thus increasing the vulnerability for several stress-related psychiatric disorders. However, although there is plenty of clinical data supporting an association between stressful life events in adulthood and an enhanced vulnerability for psychopathology, the underlying molecular mechanisms are still poorly investigated. Thus, in this study we performed peripheral/whole-genome transcriptomic analyses in blood samples obtained from 53 adult subjects characterized for recent stressful life events occurred within the previous 6 months. Transcriptomic data were analyzed using Partek Genomics Suite; pathway and network analyses were performed using Ingenuity Pathway Analysis and GeneMANIA Software. We found 207 genes significantly differentially expressed in adult subjects who reported recent stressful life experiences (n=21) compared with those without such experiences (n=32). Moreover, the same subjects exposed to such stressful experiences showed a reduction in leukocyte telomere length. A correlation analyses between telomere length and transcriptomic data indicated an association between the exposures to recent stressful life events and the modulation of several pathways, mainly involved in immune-inflammatory-related processes and oxidative stress, such as natural killer cell signaling, interleukin-1 (IL-1) signaling, MIF regulation of innate immunity and IL-6 signaling. Our data suggest an association between exposures to recent stressful life events in adulthood and alterations in the immune, inflammatory and oxidative stress pathways, which could be also involved in the negative effect of stressful life events on leukocyte telomere length. The modulation of these mechanisms may underlie the clinical association between the exposure to recent Stressful life events in adulthood and an enhanced vulnerability to develop psychiatric diseases in adulthood.},
}
@article {pmid28218725,
year = {2017},
author = {Ivancich, M and Schrank, Z and Wojdyla, L and Leviskas, B and Kuckovic, A and Sanjali, A and Puri, N},
title = {Treating Cancer by Targeting Telomeres and Telomerase.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {6},
number = {1},
pages = {},
pmid = {28218725},
issn = {2076-3921},
abstract = {Telomerase is expressed in more than 85% of cancer cells. Tumor cells with metastatic potential may have a high telomerase activity, allowing cells to escape from the inhibition of cell proliferation due to shortened telomeres. Human telomerase primarily consists of two main components: hTERT, a catalytic subunit, and hTR, an RNA template whose sequence is complimentary to the telomeric 5'-dTTAGGG-3' repeat. In humans, telomerase activity is typically restricted to renewing tissues, such as germ cells and stem cells, and is generally absent in normal cells. While hTR is constitutively expressed in most tissue types, hTERT expression levels are low enough that telomere length cannot be maintained, which sets a proliferative lifespan on normal cells. However, in the majority of cancers, telomerase maintains stable telomere length, thereby conferring cell immortality. Levels of hTERT mRNA are directly related to telomerase activity, thereby making it a more suitable therapeutic target than hTR. Recent data suggests that stabilization of telomeric G-quadruplexes may act to indirectly inhibit telomerase action by blocking hTR binding. Telomeric DNA has the propensity to spontaneously form intramolecular G-quadruplexes, four-stranded DNA secondary structures that are stabilized by the stacking of guanine residues in a planar arrangement. The functional roles of telomeric G-quadruplexes are not completely understood, but recent evidence suggests that they can stall the replication fork during DNA synthesis and inhibit telomere replication by preventing telomerase and related proteins from binding to the telomere. Long-term treatment with G-quadruplex stabilizers induces a gradual reduction in the length of the G-rich 3' end of the telomere without a reduction of the total telomere length, suggesting that telomerase activity is inhibited. However, inhibition of telomerase, either directly or indirectly, has shown only moderate success in cancer patients. Another promising approach of targeting the telomere is the use of guanine-rich oligonucleotides (GROs) homologous to the 3' telomere overhang sequence (T-oligos). T-oligos, particularly a specific 11-base oligonucleotide (5'-dGTTAGGGTTAG-3') called T11, have been shown to induce DNA damage responses (DDRs) such as senescence, apoptosis, and cell cycle arrest in numerous cancer cell types with minimal or no cytostatic effects in normal, non-transformed cells. As a result, T-oligos and other GROs are being investigated as prospective anticancer therapeutics. Interestingly, the DDRs induced by T-oligos in cancer cells are similar to the effects seen after progressive telomere degradation in normal cells. The loss of telomeres is an important tumor suppressor mechanism that is commonly absent in transformed malignant cells, and hence, T-oligos have garnered significant interest as a novel strategy to combat cancer. However, little is known about their mechanism of action. In this review, we discuss the current understanding of how T-oligos exert their antiproliferative effects in cancer cells and their role in inhibition of telomerase. We also discuss the current understanding of telomerase in cancer and various therapeutic targets related to the telomeres and telomerase.},
}
@article {pmid28216227,
year = {2017},
author = {Tan, R and Nakajima, S and Wang, Q and Sun, H and Xue, J and Wu, J and Hellwig, S and Zeng, X and Yates, NA and Smithgall, TE and Lei, M and Jiang, Y and Levine, AS and Su, B and Lan, L},
title = {Nek7 Protects Telomeres from Oxidative DNA Damage by Phosphorylation and Stabilization of TRF1.},
journal = {Molecular cell},
volume = {65},
number = {5},
pages = {818-831.e5},
pmid = {28216227},
issn = {1097-4164},
support = {P30 CA047904/CA/NCI NIH HHS/United States ; R01 GM118833/GM/NIGMS NIH HHS/United States ; R21 AG045545/AG/NIA NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins/genetics/metabolism ; Binding Sites ; *DNA Damage ; F-Box Proteins/genetics/metabolism ; HEK293 Cells ; HeLa Cells ; Histones/metabolism ; Humans ; NIMA-Related Kinases/genetics/*metabolism ; *Oxidative Stress ; Phosphorylation ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; Protein Stability ; RNA Interference ; Shelterin Complex ; Telomere/*enzymology/genetics/radiation effects ; Telomere-Binding Proteins/genetics/*metabolism ; Time Factors ; Transfection ; Tumor Suppressor p53-Binding Protein 1/genetics/metabolism ; Ubiquitination ; },
abstract = {Telomeric repeat binding factor 1 (TRF1) is essential to the maintenance of telomere chromatin structure and integrity. However, how telomere integrity is maintained, especially in response to damage, remains poorly understood. Here, we identify Nek7, a member of the Never in Mitosis Gene A (NIMA) kinase family, as a regulator of telomere integrity. Nek7 is recruited to telomeres and stabilizes TRF1 at telomeres after damage in an ATM activation-dependent manner. Nek7 deficiency leads to telomere aberrations, long-lasting γH2AX and 53BP1 foci, and augmented cell death upon oxidative telomeric DNA damage. Mechanistically, Nek7 interacts with and phosphorylates TRF1 on Ser114, which prevents TRF1 from binding to Fbx4, an Skp1-Cul1-F box E3 ligase subunit, thereby alleviating proteasomal degradation of TRF1, leading to a stable association of TRF1 with Tin2 to form a shelterin complex. Our data reveal a mechanism of efficient protection of telomeres from damage through Nek7-dependent stabilization of TRF1.},
}
@article {pmid28216226,
year = {2017},
author = {Rai, R and Hu, C and Broton, C and Chen, Y and Lei, M and Chang, S},
title = {NBS1 Phosphorylation Status Dictates Repair Choice of Dysfunctional Telomeres.},
journal = {Molecular cell},
volume = {65},
number = {5},
pages = {801-817.e4},
pmid = {28216226},
issn = {1097-4164},
support = {R01 AG028888/AG/NIA NIH HHS/United States ; R01 CA202816/CA/NCI NIH HHS/United States ; },
mesh = {Aminopeptidases/genetics/metabolism ; Ataxia Telangiectasia Mutated Proteins/genetics/metabolism ; Binding Sites ; Cell Cycle Proteins/chemistry/genetics/*metabolism ; Cyclin-Dependent Kinase 2/genetics/metabolism ; *DNA Breaks, Double-Stranded ; *DNA End-Joining Repair ; DNA Repair Enzymes/genetics/metabolism ; DNA-Binding Proteins ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics/metabolism ; Exodeoxyribonucleases ; G1 Phase ; G2 Phase ; HCT116 Cells ; Humans ; Inhibitor of Apoptosis Proteins/genetics/metabolism ; Models, Molecular ; Nuclear Proteins/chemistry/genetics/*metabolism ; Phosphorylation ; Protein Binding ; Protein Interaction Domains and Motifs ; S Phase ; Serine Proteases/genetics/metabolism ; Shelterin Complex ; Structure-Activity Relationship ; Telomere/genetics/*metabolism/pathology ; Telomere-Binding Proteins/genetics/metabolism ; Telomeric Repeat Binding Protein 2/chemistry/genetics/*metabolism ; },
abstract = {Telomeres employ TRF2 to protect chromosome ends from activating the DNA damage sensor MRE11-RAD50-NBS1 (MRN), thereby repressing ATM-dependent DNA damage checkpoint responses. How TRF2 prevents MRN activation at dysfunctional telomeres is unclear. Here, we show that the phosphorylation status of NBS1 determines the repair pathway choice of dysfunctional telomeres. The crystal structure of the TRF2-NBS1 complex at 3.0 Å resolution shows that the NBS1 429YQLSP433 motif interacts specifically with the TRF2[TRFH] domain. Phosphorylation of NBS1 serine 432 by CDK2 in S/G2 dissociates NBS1 from TRF2, promoting TRF2-Apollo/SNM1B complex formation and the protection of leading-strand telomeres. Classical-NHEJ-mediated repair of telomeres lacking TRF2 requires phosphorylated NBS1[S432] to activate ATM, while interaction of de-phosphorylated NBS1[S432] with TRF2 promotes alternative-NHEJ repair of telomeres lacking POT1-TPP1. Our work advances understanding of how the TRF2[TRFH] domain orchestrates telomere end protection and reveals how the phosphorylation status of the NBS1[S432] dictates repair pathway choice of dysfunctional telomeres.},
}
@article {pmid28209595,
year = {2017},
author = {Yang, M and Prescott, J and Poole, EM and Rice, MS and Kubzansky, LD and Idahl, A and Lundin, E and De Vivo, I and Tworoger, SS},
title = {Prediagnosis Leukocyte Telomere Length and Risk of Ovarian Cancer.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {26},
number = {3},
pages = {339-345},
pmid = {28209595},
issn = {1538-7755},
support = {P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA163451/CA/NCI NIH HHS/United States ; UM1 CA176726/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Case-Control Studies ; Female ; Genetic Markers ; Genetic Predisposition to Disease ; Humans ; *Leukocytes ; Middle Aged ; Ovarian Neoplasms/*genetics/mortality/pathology ; Prospective Studies ; Registries ; Risk Factors ; Telomere/*genetics ; Telomere Shortening ; },
abstract = {Background: The associations between telomere length and cancer risk are equivocal, and none have examined the association between prediagnosis leukocyte telomere length (LTL) and the risk of developing ovarian cancer.Methods: We prospectively measured LTL collected from 442 ovarian cancer cases and 727 controls in the Nurses' Health Studies and the Northern Sweden Health and Disease Study. Cases were matched to one or two controls on age, menopausal status, and date of blood collection. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression.Results: LTL was measured a median of 9.5 years before ovarian cancer diagnosis among cases. We observed a decreased risk of ovarian cancer with longer LTL. In multivariable models, women in the top quartile of LTL had an OR for ovarian cancer of 0.67 (95% CI, 0.46-0.97) compared with those in the bottom quartile. Inverse associations were stronger for nonserous cases (ORquartile 4 vs. quartile 1 of LTL = 0.55, 95% CI, 0.33-0.94) and rapidly fatal cases (i.e., cases who died within 3 years of diagnosis; ORquartile 4 vs. quartile 1 of LTL = 0.55, 95% CI, 0.32-0.95).Conclusions: Our prospective findings suggest that longer circulating LTL may be associated with a lower ovarian cancer risk, especially for nonserous and rapidly fatal cases. The evaluation of LTL in relation to ovarian cancer risk by tumor subtypes is warranted in larger prospective studies.Impact: Prediagnosis LTL may reflect an early event in the ovarian cancer development and could serve as a biomarker to predict future risk. Cancer Epidemiol Biomarkers Prev; 26(3); 339-45. ©2017 AACR.},
}
@article {pmid28205383,
year = {2018},
author = {Poonpet, T and Saetan, N and Tanavalee, A and Wilairatana, V and Yuktanandana, P and Honsawek, S},
title = {Association between leukocyte telomere length and angiogenic cytokines in knee osteoarthritis.},
journal = {International journal of rheumatic diseases},
volume = {21},
number = {1},
pages = {118-125},
doi = {10.1111/1756-185X.12988},
pmid = {28205383},
issn = {1756-185X},
mesh = {Aged ; Angiogenic Proteins/*blood ; Biomarkers/blood ; Case-Control Studies ; Cross-Sectional Studies ; Cytokines/*blood ; Female ; Granulocyte Colony-Stimulating Factor/blood ; Hepatocyte Growth Factor/blood ; Humans ; Immunoassay ; Male ; Middle Aged ; Osteoarthritis, Knee/*blood/diagnosis/genetics ; Real-Time Polymerase Chain Reaction ; Telomere/genetics/*metabolism ; *Telomere Shortening ; Vascular Endothelial Growth Factor A/blood ; },
abstract = {AIM: The aims of this study were to compare leukocyte relative telomere length (RTL) in knee osteoarthritis (OA) patients and healthy controls and to investigate associations between plasma angiogenic cytokine concentrations and leukocyte RTL.<br><br>METHOD: Eighty knee OA patients and 60 age-matched controls were enrolled. Leukocyte RTL was assessed using real-time quantitative polymerase chain reaction (qPCR). Angiogenic cytokines were measured by a multiplex immunoassay.<br><br>RESULTS: Leukocyte RTL in knee OA patients was significantly lower than that in healthy controls (1.1 &#xb1; 0.4 vs. 1.3 &#xb1; 0.6, P = 0.039). Plasma angiopoietin-2, follistatin, granulocyte-colony stimulating factor (G-CSF), hepatocyte growth factor (HGF), interleukin-8 (IL-8), platelet endothelial cell adhesion molecule-1 (PECAM-1), and vascular endothelial growth factor (VEGF) levels in knee OA patients were higher than those in controls (P < 0.01). Correlation analysis revealed significant negative correlations between leukocyte RTL and plasma levels of HGF (r = -0.377, P = 0.017), VEGF (r = -0.405, P = 0.009) and G-CSF (r = -0.347, P = 0.026). In contrast, plasma angiopoietin-2, follistatin, IL-8, leptin, platelet-derived growth factor-BB and PECAM-1 were not correlated with leukocyte RTL.<br><br>CONCLUSION: Telomere length was shortened in knee OA patients compared to healthy controls. Plasma HGF, VEGF and G-CSF were negatively correlated with leukocyte RTL, suggesting involvement of telomere shortening and these cytokines in knee OA.},
}
@article {pmid28197807,
year = {2018},
author = {Tahara, T and Tahara, S and Tuskamoto, T and Horiguchi, N and Kawamura, T and Okubo, M and Ishizuka, T and Nagasaka, M and Nakagawa, Y and Shibata, T and Kuroda, M and Ohmiya, N},
title = {Telomere length in the gastric mucosa after Helicobacter pylori eradication and its potential role in the gastric carcinogenesis.},
journal = {Clinical and experimental medicine},
volume = {18},
number = {1},
pages = {21-26},
pmid = {28197807},
issn = {1591-9528},
support = {JP26870685//JSPS KAKENHI Grant-in-Aid for Young Scientists (B)/ ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Biometry ; Biopsy ; *Carcinogenesis ; Female ; Gastric Mucosa/*pathology ; Helicobacter Infections/*complications/*drug therapy ; Helicobacter pylori/*drug effects ; Humans ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Stomach Neoplasms/*pathology ; *Telomere ; },
abstract = {The molecular mechanisms of gastric carcinogenesis after Helicobacter pylori (H. pylori) eradication remain unclear. We examined the telomere length of gastric mucosa samples after successful H. pylori eradication in patients without and those with gastric cancer. Telomere length was measured by the real-time PCR among four different groups of biopsies: gastric body from subjects without history of H. pylori infection (Hp-: n = 23), gastric body from cancer-free subjects after H. pylori eradication (cancer-free body: n = 24), gastric body from early gastric cancer patients diagnosed after H. pylori eradication (EGC body: n = 35) and its paired samples from adjacent mucosa of cancerous area (EGC ADJ: n = 35). The Hp-group presented the longest telomeres among the all groups (Hp- vs. all others, all P < 0.05). Samples from EGC body group showed shorter telomere length than the samples from cancer-free body groups (P < 0.05). Conversely, samples from EGC ADJ group showed rather longer telomere length compared to the EGC body group (P < 0.05), which was also confirmed by the comparison of 35 matched samples (P = 0.0007). Among the samples after H. pylori eradication, shorter telomere length was associated with higher expression of IL-1B and NF-kB (P < 0.0001, 0.0006, respectively). Longer telomere length was also associated with higher expression of TNF-A (P = 0.01). Telomere shortening seems to be important initial steps in gastric cancer predisposition after H. pylori eradication, while it might shift to lengthening to acquire more aggressive pathway to develop cancer.},
}
@article {pmid28196338,
year = {2017},
author = {Allegra, A and Innao, V and Penna, G and Gerace, D and Allegra, AG and Musolino, C},
title = {Telomerase and telomere biology in hematological diseases: A new therapeutic target.},
journal = {Leukemia research},
volume = {56},
number = {},
pages = {60-74},
doi = {10.1016/j.leukres.2017.02.002},
pmid = {28196338},
issn = {1873-5835},
mesh = {Hematologic Diseases/enzymology/*etiology/genetics/therapy ; Humans ; Molecular Targeted Therapy ; Mutation ; Telomerase/*genetics ; Telomere/*metabolism ; },
abstract = {Telomeres are structures confined at the ends of eukaryotic chromosomes. With each cell division, telomeric repeats are lost because DNA polymerases are incapable to fully duplicate the very ends of linear chromosomes. Loss of repeats causes cell senescence, and apoptosis. Telomerase neutralizes loss of telomeric sequences by adding telomere repeats at the 3' telomeric overhang. Telomere biology is frequently associated with human cancer and dysfunctional telomeres have been proved to participate to genetic instability. This review covers the information on telomerase expression and genetic alterations in the most relevant types of hematological diseases. Telomere erosion hampers the capability of hematopoietic stem cells to effectively replicate, clinically resulting in bone marrow failure. Furthermore, telomerase mutations are genetic risk factors for the occurrence of some hematologic cancers. New discoveries in telomere structure and telomerase functions have led to an increasing interest in targeting telomeres and telomerase in anti-cancer therapy.},
}
@article {pmid28194966,
year = {2017},
author = {Sieradzan, AK and Krupa, P and Wales, DJ},
title = {What Makes Telomeres Unique?.},
journal = {The journal of physical chemistry. B},
volume = {121},
number = {10},
pages = {2207-2219},
doi = {10.1021/acs.jpcb.6b08780},
pmid = {28194966},
issn = {1520-5207},
mesh = {Animals ; Base Sequence ; Biochemical Phenomena ; Candida ; DNA/*chemistry ; Humans ; Insecta ; Mechanical Phenomena ; Molecular Dynamics Simulation ; Plants ; Telomere/*chemistry ; },
abstract = {Telomeres are repetitive nucleotide sequences, which are essential for protecting the termini of chromosomes. Thousands of such repetitions are necessary to maintain the stability of the whole chromosome. Several similar repeated telomeric sequences have been found in different species, but why has nature chosen them? What features do telomeres have in common? In this article, we study the physical properties of human-like (TTAGGG), plant (TTTAGG), insect (TTAGG), and Candida guilermondi (GGTGTAC) telomeres in comparison with seven control, nontelomeric sequences. We used steered molecular dynamics with the nucleic acid united residue (NARES) coarse-grained force field, which we compared with the all-atom AMBER14 force field and experimental data. Our results reveal important features in all of the telomeric sequences, including their exceptionally high mechanical resistance and stability to untangling and stretching, compared to those of nontelomeric sequences. We find that the additional stability of the telomeres comes from their ability to form triplex structures and wrap around loose chains of linear DNA by regrabbing the chain. We find that, with slower pulling speed, regrabbing and triplex formation is more frequent. We also found that some of the sequences can form triplexes experimentally, such as TTTTTCCCC, and can mimic telomeric properties.},
}
@article {pmid28193312,
year = {2017},
author = {Sillanpää, E and Niskala, P and Laakkonen, EK and Ponsot, E and Alén, M and Kaprio, J and Kadi, F and Kovanen, V and Sipilä, S},
title = {Leukocyte and Skeletal Muscle Telomere Length and Body Composition in Monozygotic Twin Pairs Discordant for Long-term Hormone Replacement Therapy.},
journal = {Twin research and human genetics : the official journal of the International Society for Twin Studies},
volume = {20},
number = {2},
pages = {119-131},
doi = {10.1017/thg.2017.1},
pmid = {28193312},
issn = {1832-4274},
mesh = {*Body Composition ; Electric Impedance ; *Estrogen Replacement Therapy ; Exercise ; Female ; Hand Strength ; Humans ; Leukocytes/*drug effects ; Middle Aged ; Muscle, Skeletal/*drug effects ; Telomere/*drug effects/ultrastructure ; Twins, Monozygotic ; },
abstract = {Estrogen-based hormone replacement therapy (HRT) may be associated with deceleration of cellular aging. We investigated whether long-term HRT has effects on leukocyte (LTL) or mean and minimum skeletal muscle telomere length (SMTL) in a design that controls for genotype and childhood environment. Associations between telomeres, body composition, and physical performance were also examined. Eleven monozygotic twin pairs (age 57.6 ± 1.8 years) discordant for HRT were studied. Mean duration of HRT use was 7.3 ± 3.7 years in the user sister, while their co-twins had never used HRT. LTL was measured by qPCR and SMTLs by southern blot. Body and muscle composition were estimated by bioimpedance and computed tomography, respectively. Physical performance was measured by jumping height and grip strength. HRT users and non-users did not differ in LTL or mean or minimum SMTL. Within-pair correlations were high in LTL (r = 0.69, p = .020) and in mean (r = 0.74, p = .014) and minimum SMTL (r = 0.88, p = .001). Body composition and performance were better in users than non-users. In analyses of individuals, LTL was associated with BMI (r 2 = 0.30, p = .030), percentage total body (r 2 = 0.43, p = .014), and thigh (r 2 = 0.55, p = .004) fat, while minimum SMTL was associated with fat-free mass (r 2 = 0.27, p = .020) and thigh muscle area (r 2 = 0.42, p = .016). We found no associations between HRT use and telomere length. Longer LTLs were associated with lower total and regional fat, while longer minimum SMTLs were associated with higher fat-free mass and greater thigh muscle area. This suggests that telomeres measured from different tissues may have different associations with measures of body composition.},
}
@article {pmid28187293,
year = {2017},
author = {Vincent, J and Hovatta, I and Frissa, S and Goodwin, L and Hotopf, M and Hatch, SL and Breen, G and Powell, TR},
title = {Assessing the contributions of childhood maltreatment subtypes and depression case-control status on telomere length reveals a specific role of physical neglect.},
journal = {Journal of affective disorders},
volume = {213},
number = {},
pages = {16-22},
pmid = {28187293},
issn = {1573-2517},
support = {MR/N014863/1//Medical Research Council/United Kingdom ; },
mesh = {Adult ; *Adult Survivors of Child Abuse ; Aged ; Aged, 80 and over ; Child ; Child Abuse ; DNA/isolation &amp; purification ; Depression ; Depressive Disorder/*pathology ; Female ; Humans ; Male ; Middle Aged ; Polymerase Chain Reaction ; Risk Factors ; Surveys and Questionnaires ; Telomere/genetics/*ultrastructure ; *Telomere Shortening ; Young Adult ; },
abstract = {BACKGROUND: Studies have provided evidence that both childhood maltreatment and depressive disorders are associated with shortened telomere lengths. However, as childhood maltreatment is a risk factor for depression, it remains unclear whether this may be driving shortened telomere lengths observed amongst depressed patients. Furthermore, it's unclear if the effects of maltreatment on telomere length shortening are more pervasive amongst depressed patients relative to controls, and consequently whether biological ageing may contribute to depression's pathophysiology. The current study assesses the effects of childhood maltreatment, depression case/control status, and the interactive effect of both childhood maltreatment and depression case/control status on relative telomere length (RTL).<br><br>METHOD: DNA samples from 80 depressed subjects and 100 control subjects were utilized from a U.K. sample (ages 20-84), with childhood trauma questionnaire data available for all participants. RTL was quantified using quantitative polymerase chain reactions. Univariate linear regression analyses were used to assess the effects of depression status, childhood maltreatment and depression by childhood maltreatment interactions on RTL. The false discovery rate (q<0.05) was used for multiple testing correction.<br><br>RESULTS: Analysis of depression case/control status showed no significant main effect on RTL. Four subtypes of childhood maltreatment also demonstrated no significant main effect on RTL, however a history of physical neglect did significantly predict shorter RTL in adulthood (F(1, 174)=7.559, p=0.007, q=0.042, Variance Explained=4.2%), which was independent of case/control status. RTL was further predicted by severity of physical neglect, with the greatest differences observed in older maltreated individuals (>50 years old). There were no significant depression case/control status by childhood maltreatment interactions.<br><br>LIMITATIONS: A relatively small sample limited our power to detect interaction effects, and we were unable to consider depression chronicity or recurrence.<br><br>CONCLUSION: Shortened RTL was specifically associated with childhood physical neglect, but not the other subtypes of maltreatment or depression case/control status. Our results suggest that the telomere-eroding effects of physical neglect may represent a biological mechanism important in increasing risk for ageing-related disorders. As physical neglect is more frequent amongst depressed cases generally, it may also represent a confounding factor driving previous associations between shorter RTL and depression case status.},
}
@article {pmid28186493,
year = {2017},
author = {Cerchiara, JA and Risques, RA and Prunkard, D and Smith, JR and Kane, OJ and Boersma, PD},
title = {Telomeres shorten and then lengthen before fledging in Magellanic penguins (Spheniscus magellanicus).},
journal = {Aging},
volume = {9},
number = {2},
pages = {487-493},
pmid = {28186493},
issn = {1945-4589},
mesh = {Aging/*physiology ; Animals ; Spheniscidae ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; Telomere Shortening/*physiology ; },
abstract = {For all species, finite metabolic resources must be allocated toward three competing systems: maintenance, reproduction, and growth. Telomeres, the nucleoprotein tips of chromosomes, which shorten with age in most species, are correlated with increased survival. Chick growth is energetically costly and is associated with telomere shortening in most species. To assess the change in telomeres in penguin chicks, we quantified change in telomere length of wild known-age Magellanic penguin (Spheniscus magellanicus) chicks every 15 days during the species' growth period, from hatching to 60 days-of-age. Magellanic penguins continue to grow after fledging so we also sampled a set of 1-year-old juvenile penguins, and adults aged 5 years. Telomeres were significantly shorter on day 15 than on hatch day but returned to their initial length by 30 days old and remained at that length through 60 days of age. The length of telomeres of newly hatched chicks, chicks aged 30, 45 and 60 days, juveniles, and adults aged 5 years were similar. Chicks that fledged and those that died had similar telomere lengths. We show that while telomeres shorten during growth, Magellanic penguins elongate telomeres to their length at hatch, which may increase adult life span and reproductive opportunities.},
}
@article {pmid28186106,
year = {2017},
author = {Liu, H and Zhou, G and Chen, Q and Ouyang, F and Little, J and Zhang, J and Chen, D},
title = {Impact of Dehydroepiandrosterone Sulfate on Newborn Leukocyte Telomere Length.},
journal = {Scientific reports},
volume = {7},
number = {},
pages = {42160},
pmid = {28186106},
issn = {2045-2322},
mesh = {Dehydroepiandrosterone Sulfate/*blood ; Estradiol/blood ; Female ; Fetal Blood/*chemistry/metabolism ; Gestational Age ; Humans ; Hydrocortisone/blood ; Infant, Newborn ; Leukocytes/chemistry/metabolism ; Male ; Pregnancy ; Prospective Studies ; Reactive Oxygen Species/*blood ; Telomere/*ultrastructure ; *Telomere Homeostasis ; },
abstract = {The newborn setting of leukocyte telomere length (LTL) likely has important implications for telomere dynamics over the lifespan. However, its determinants are poorly understood. Hormones play an important role during pregnancy and delivery. We hypothesized that exposure to hormones may impact the fetal telomere biology system. To test this hypothesis, cortisol, estradiol, dehydroepiandrosterone sulfate (DHEAS) and reactive oxygen species (ROS) were measured in cord blood of 821 newborns from a prospective study. After accounting for the effects of potential determinants of newborn LTL, a 10-fold increase in DHEAS concentration was associated with a 0.021 increase in T/S ratio of newborn LTL (95% confidence interval: 0.009-0.034, P = 0.0008). For newborns who fell in the lowest quartile of DHEAS level, the mean newborn LTL was estimated to be approximately 2.0% shorter than the newborns in the highest DHEAS concentration quartile (P = 0.0014). However, no association was found between newborn LTL and cortisol or estradiol. As expected, newborns with higher ROS level (ROS > 260 mol/L) had lower LTL compared to that with lower ROS level (ROS ≤ 260 mol/L) (P = 0.007). There was also an inverse relationship between DHEAS and ROS (P < 1×10[-4]). Our findings suggest that exposure to DHEAS may exert a "programming" effect on the newborn telomere biology system.},
}
@article {pmid28183954,
year = {2017},
author = {Riddihough, G and Hurtley, SM},
title = {A protein to trim too-long telomeres.},
journal = {Science (New York, N.Y.)},
volume = {355},
number = {6325},
pages = {591-592},
doi = {10.1126/science.355.6325.591-i},
pmid = {28183954},
issn = {1095-9203},
}
@article {pmid28183935,
year = {2017},
author = {Lossaint, G and Lingner, J},
title = {TZAP or not to zap telomeres.},
journal = {Science (New York, N.Y.)},
volume = {355},
number = {6325},
pages = {578-579},
doi = {10.1126/science.aam7015},
pmid = {28183935},
issn = {1095-9203},
mesh = {Humans ; *Mutation ; Protein-Tyrosine Kinases ; *Telomere ; },
}
@article {pmid28183782,
year = {2017},
author = {Eastley, N and Ottolini, B and Garrido, C and Shaw, JA and McCulloch, TA and Ashford, RU and Royle, NJ},
title = {Telomere maintenance in soft tissue sarcomas.},
journal = {Journal of clinical pathology},
volume = {70},
number = {5},
pages = {371-377},
pmid = {28183782},
issn = {1472-4146},
support = {13462/CRUK_/Cancer Research UK/United Kingdom ; 2013 RIF - SHAW/PANCREATICCANUK_/Pancreatic Cancer UK/United Kingdom ; 23464/CRUK_/Cancer Research UK/United Kingdom ; MR/N02107X/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; Sarcoma/*genetics/pathology ; Soft Tissue Neoplasms/*genetics/pathology ; Telomerase/genetics/metabolism ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {Soft tissue sarcomas (STS) are a diverse group of heterogeneous malignant tumours derived from mesenchymal tissues. Over 50 different STS subtypes are recognised by WHO, which show a wide range of different biological behaviours and prognoses. At present, clinicians managing this complex group of tumours face several challenges. This is reflected by the relatively poor outcome of patients with STSs compared with many other solid malignant tumours. These include difficulties securing accurate diagnoses, a lack of effective systemic treatments and absence of any sensitive circulating biomarkers to monitor patients throughout their treatment and follow-up. In order to progress STS's cells must evade the usual cellular proliferative checkpoints, and then activate a telomere maintenance mechanism in order to achieve replicative immortality. The purpose of this review is to provide an overview of STS genetics focusing particularly on these mechanisms. We will also highlight some of the key barriers to improving outcome for patients with STS, and hypothesise how a better understanding of these genetic characteristics may impact on future STS management.},
}
@article {pmid28180323,
year = {2017},
author = {Huang, SH and Cozart, MR and Hart, MA and Kobryn, K},
title = {The Borrelia burgdorferi telomere resolvase, ResT, possesses ATP-dependent DNA unwinding activity.},
journal = {Nucleic acids research},
volume = {45},
number = {3},
pages = {1319-1329},
pmid = {28180323},
issn = {1362-4962},
mesh = {Adenosine Triphosphate/metabolism ; Amino Acid Substitution ; Bacterial Proteins/genetics/*metabolism ; Borrelia burgdorferi/genetics/*metabolism ; DNA Helicases/genetics/metabolism ; DNA Replication ; DNA, Bacterial/chemistry/genetics/metabolism ; Endodeoxyribonucleases/genetics/*metabolism ; Models, Biological ; Mutagenesis, Site-Directed ; Recombinant Proteins/genetics/metabolism ; Recombinases/genetics/*metabolism ; Telomere/metabolism ; },
abstract = {Spirochetes of the genus Borrelia possess unusual genomes harboring multiple linear and circular replicons. The linear replicons are terminated by covalently closed hairpin (hp) telomeres. Hairpin telomeres are formed from replicated intermediates by the telomere resolvase, ResT, in a phosphoryl transfer reaction with mechanistic similarities to those promoted by type 1B topoisomerases and tyrosine recombinases. There is growing evidence that ResT is multifunctional. Upon ResT depletion DNA replication unexpectedly ceases. Additionally, ResT possesses RecO-like biochemical activities being able to promote single-strand annealing on both free ssDNA and ssDNA complexed with cognate single-stranded DNA binding protein. We report here that ResT possesses DNA-dependent ATPase activity that promotes DNA unwinding with a 3΄-5΄ polarity. ResT can unwind a variety of substrates including synthetic replication forks and D-loops. We demonstrate that ResT's twin activities of DNA unwinding and annealing can drive regression of a model replication fork. These properties are similar to those of the RecQ helicase of the RecF pathway involved in DNA gap repair. We propose that ResT's combination of activities implicates it in replication and recombination processes operating on the linear chromosome and plasmids of Borrelia burgdorferi.},
}
@article {pmid28180297,
year = {2017},
author = {Takikawa, M and Tarumoto, Y and Ishikawa, F},
title = {Fission yeast Stn1 is crucial for semi-conservative replication at telomeres and subtelomeres.},
journal = {Nucleic acids research},
volume = {45},
number = {3},
pages = {1255-1269},
pmid = {28180297},
issn = {1362-4962},
mesh = {Cyclin B/genetics/metabolism ; DNA Damage ; DNA Replication/*genetics/*physiology ; DNA, Fungal/genetics/metabolism ; Genes, Fungal ; Mutagenesis ; Mutation ; Repressor Proteins/genetics/metabolism ; Schizosaccharomyces/*genetics/*metabolism ; Schizosaccharomyces pombe Proteins/*genetics/*metabolism ; Telomere/genetics/metabolism ; Telomere Shortening ; Telomere-Binding Proteins/*genetics/*metabolism ; Temperature ; },
abstract = {The CST complex is a phylogenetically conserved protein complex consisting of CTC1/Cdc13, Stn1 and Ten1 that protects telomeres on linear chromosomes. Deletion of the fission yeast homologs stn1 and ten1 results in complete telomere loss; however, the precise function of Stn1 is still largely unknown. Here, we have isolated a high-temperature sensitive stn1 allele (termed stn1-1). stn1-1 cells abruptly lost telomeric sequence almost completely at the restrictive temperature. The loss of chromosomal DNA happened without gradual telomere shortening, and extended to 30 kb from the ends of chromosomes. We found transient and modest single-stranded G-strand exposure, but did not find any evidence of checkpoint activation in stn1-1 at the restrictive temperature. When we probed neutral-neutral 2D gels for subtelomere regions, we found no Y-arc-shaped replication intermediates in cycling cells. We conclude that the loss of telomere and subtelomere DNAs in stn1-1 cells at the restrictive temperature is caused by very frequent replication fork collapses specifically in subtelomere regions. Furthermore, we identified two independent suppressor mutants of the high-temperature sensitivity of stn1-1: a multi-copy form of pmt3 and a deletion of rif1. Collectively, we propose that fission yeast Stn1 primarily safeguards the semi-conservative DNA replication at telomeres and subtelomeres.},
}
@article {pmid28180296,
year = {2017},
author = {Bao, HL and Ishizuka, T and Sakamoto, T and Fujimoto, K and Uechi, T and Kenmochi, N and Xu, Y},
title = {Characterization of human telomere RNA G-quadruplex structures in vitro and in living cells using 19F NMR spectroscopy.},
journal = {Nucleic acids research},
volume = {45},
number = {9},
pages = {5501-5511},
pmid = {28180296},
issn = {1362-4962},
mesh = {Animals ; Base Sequence ; Cell Survival ; Fluorine ; *G-Quadruplexes ; Humans ; Macromolecular Substances/metabolism ; *Magnetic Resonance Spectroscopy ; Nucleic Acid Conformation ; Nucleic Acid Denaturation ; RNA/*chemistry ; Telomere/*chemistry ; Temperature ; Thermodynamics ; Xenopus laevis ; },
abstract = {Human telomeric RNA has been identified as a key component of the telomere machinery. Recently, the growing evidence suggests that the telomeric RNA forms G-quadruplex structures to play an important role in telomere protection and regulation. In the present studies, we developed a 19F NMR spectroscopy method to investigate the telomeric RNA G-quadruplex structures in vitro and in living cells. We demonstrated that the simplicity and sensitivity of 19F NMR approach can be used to directly observe the dimeric and two-subunits stacked G-quadruplexes in vitro and in living cells and quantitatively characterize the thermodynamic properties of the G-quadruplexes. By employing the 19F NMR in living cell experiment, we confirmed for the first time that the higher-order G-quadruplex exists in cells. We further demonstrated that telomere RNA G-quadruplexes are converted to the higher-order G-quadruplex under molecular crowding condition, a cell-like environment. We also show that the higher-order G-quadruplex has high thermal stability in crowded solutions. The finding provides new insight into the structural behavior of telomere RNA G-quadruplex in living cells. These results open new avenues for the investigation of G-quadruplex structures in vitro and in living cells.},
}
@article {pmid28180293,
year = {2017},
author = {Wu, Z and Liu, J and Zhang, QD and Lv, DK and Wu, NF and Zhou, JQ},
title = {Rad6-Bre1-mediated H2B ubiquitination regulates telomere replication by promoting telomere-end resection.},
journal = {Nucleic acids research},
volume = {45},
number = {6},
pages = {3308-3322},
pmid = {28180293},
issn = {1362-4962},
mesh = {DNA, Single-Stranded/metabolism ; Endopeptidases/metabolism ; Gene Deletion ; Histones/*metabolism ; Microbial Viability ; Nuclear Proteins/metabolism ; Recombination, Genetic ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; Telomere Shortening ; Telomere-Binding Proteins/genetics ; Ubiquitin Thiolesterase/metabolism ; Ubiquitin-Conjugating Enzymes/antagonists &amp; inhibitors/genetics/*metabolism ; *Ubiquitination ; },
abstract = {Rad6 and Bre1, ubiquitin-conjugating E2 and E3 enzymes respectively, are responsible for histone H2B lysine 123 mono-ubiquitination (H2Bub1) in Saccharomyces cerevisiae. Previous studies have shown that Rad6 and Bre1 regulate telomere length and recombination. However, the underlying molecular mechanism remains largely unknown. Here we report that H2BK123 mutation results in telomere shortening, while inactivation of Ubp8 and/or Ubp10, deubiquitinases of H2Bub1, leads to telomere lengthening in Rad6-Bre1-dependent manner. In telomerase-deficient cells, inactivation of Rad6-Bre1 pathway retards telomere shortening rate and the onset of senescence, while deletion of UBP8 and/or UBP10 accelerates senescence. Thus, Rad6-Bre1 pathway regulates both telomere length and recombination through its role in H2Bub1. Additionally, inactivation of both Rad6-Bre1-H2Bub1 and Mre11-Rad50-Xrs2 (MRX) pathways causes synthetic growth defects and telomere shortening in telomerase-proficient cells, and significantly accelerates senescence and eliminates type II telomere recombination in telomerase-deficient cells. Furthermore, RAD6 or BRE1 deletion, or H2BK123R mutation decreases the accumulation of ssDNA at telomere ends. These results support the model that Rad6-Bre1-H2Bub1 cooperates with MRX to promote telomere-end resection and thus positively regulates both telomerase- and recombination-dependent telomere replication. This study provides a mechanistic link between histone H2B ubiquitination and telomere replication.},
}
@article {pmid28180280,
year = {2017},
author = {Young, E and Pastor, S and Rajagopalan, R and McCaffrey, J and Sibert, J and Mak, ACY and Kwok, PY and Riethman, H and Xiao, M},
title = {High-throughput single-molecule mapping links subtelomeric variants and long-range haplotypes with specific telomeres.},
journal = {Nucleic acids research},
volume = {45},
number = {9},
pages = {e73},
pmid = {28180280},
issn = {1362-4962},
support = {P30 CA010815/CA/NCI NIH HHS/United States ; R21 CA177395/CA/NCI NIH HHS/United States ; R21 HG007205/HG/NHGRI NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; R01 HG005946/HG/NHGRI NIH HHS/United States ; },
mesh = {Automation ; Chromosome Mapping/*methods ; DNA ; Feasibility Studies ; Genetic Variation ; *Haplotypes ; Humans ; Repetitive Sequences, Nucleic Acid ; Telomere/*genetics ; },
abstract = {Accurate maps and DNA sequences for human subtelomere regions, along with detailed knowledge of subtelomere variation and long-range telomere-terminal haplotypes in individuals, are critical for understanding telomere function and its roles in human biology. Here, we use a highly automated whole genome mapping technology in nano-channel arrays to analyze large terminal human chromosome segments extending from chromosome-specific subtelomere sequences through subtelomeric repeat regions to terminal (TTAGGG)n repeat tracts. We establish detailed maps for subtelomere gap regions in the human reference sequence, detect many new large subtelomeric variants and demonstrate the feasibility of long-range haplotyping through segmentally duplicated subtelomere regions. These features make the method a uniquely valuable new tool for improving the quality of genome assemblies in complex DNA regions. Based on single molecule mapping of telomere-terminal DNA fragments, we provide proof of principle for a novel method to estimate telomere lengths linked to distinguishable telomeric haplotypes; this single-telomere genotyping method may ultimately enable delineation of human cis elements involved in telomere length regulation.},
}
@article {pmid28179486,
year = {2017},
author = {Beilfuss, J and Camargo, CA and Kamycheva, E},
title = {Serum 25-Hydroxyvitamin D Has a Modest Positive Association with Leukocyte Telomere Length in Middle-Aged US Adults.},
journal = {The Journal of nutrition},
volume = {147},
number = {4},
pages = {514-520},
doi = {10.3945/jn.116.244137},
pmid = {28179486},
issn = {1541-6100},
mesh = {Adult ; Aging ; Body Mass Index ; Female ; Humans ; Leukocytes/*physiology ; Male ; Middle Aged ; Nutrition Surveys ; Surveys and Questionnaires ; Telomere/*physiology ; United States ; Vitamin D/*analogs &amp; derivatives/blood ; Young Adult ; },
abstract = {Background: Vitamin D deficiency has been linked to all-cause mortality and cancer. However, the biological plausibility of these associations is not well established. Leukocyte telomere length (LTL) shortening is associated with aging and is a hallmark of genomic instability and carcinogenesis.Objective: We aimed to investigate the association between serum 25-hydroxyvitamin D [25(OH)D] concentrations and LTL in the general US population.Methods: We analyzed data from the US NHANES 2001-2002. The study population comprised 1542 younger adults (aged 20-39 y), 1336 middle-aged adults (aged 40-59 y), and 1382 older adults (aged ≥60 y). LTL was measured by using quantitative polymerase chain reaction. Serum 25(OH)D concentrations ≥50 nmol/L were considered optimal. Linear regression, adjusted for age, sex, race/ethnicity, body mass index (BMI), total energy and sugar intakes, calcium intake, socioeconomic status, milk and dietary supplement consumption, and physical activity, was applied to investigate the association between serum 25(OH)D and LTL.Results: In the total population, age, sex, BMI, and non-Hispanic black race/ethnicity were significant predictors of LTL. In the participants aged 40-59 y, an increment in serum 25(OH)D of 10 nmol/L was associated with a 0.03- ± 0.01-kbp longer LTL, adjusted for age, sex, race/ethnicity, and other factors (P = 0.001). In the same age group, 25(OH)D concentrations ≥50 nmol/L were associated with a 0.13- ± 0.04-kbp longer LTL than those for 25(OH)D concentrations <50 nmol/L (P = 0.01). The association was independent of age, sex, race/ethnicity, BMI, and other factors.Conclusions: In a nationally representative population of adults, serum 25(OH)D was positively associated with LTL in middle-aged participants (aged 40-59 y), independently of other factors. These findings suggest that decreased 25(OH)D concentrations are associated with genomic instability, although the clinical impact of this observation remains unclear.},
}
@article {pmid28179311,
year = {2017},
author = {Zeng, H and Wu, HC and Wang, Q and Yang, HI and Chen, CJ and Santella, RM and Shen, J},
title = {Telomere Length and Risk of Hepatocellular Carcinoma: A Nested Case-control Study in Taiwan Cancer Screening Program Cohort.},
journal = {Anticancer research},
volume = {37},
number = {2},
pages = {637-644},
pmid = {28179311},
issn = {1791-7530},
support = {P30 CA013696/CA/NCI NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; R01 ES005116/ES/NIEHS NIH HHS/United States ; R03 CA156629/CA/NCI NIH HHS/United States ; },
mesh = {Analysis of Variance ; Asian People/genetics ; Carcinoma, Hepatocellular/diagnosis/ethnology/*genetics ; Case-Control Studies ; Cohort Studies ; Early Detection of Cancer/methods ; Female ; Humans ; Leukocytes, Mononuclear/metabolism ; Liver Neoplasms/diagnosis/ethnology/*genetics ; Male ; Middle Aged ; Polymerase Chain Reaction ; Risk Factors ; Taiwan ; Telomere/*genetics ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {BACKGROUND: Telomere length (TL) measured in peripheral blood leucocytes (PBL) might be a useful biomarker to identify elevated cancer risk.<br><br>PATIENTS AND METHODS: A case-control study which included 268 newly-diagnosed HCC cases and 536 matched controls, was conducted. Absolute TL in PBL was analyzed by quantitative real-time PCR.<br><br>RESULTS: The overall median length of TL was not statistically shorter in HCC cases compared to healthy controls. However, we found a significant synergistic effect of longer TL and HCV infection to increase HCC risk with a relative excess risk of 6.86 (95% CI: 2.14-11.58). Among HCC cases, significant shorter TLs were observed for <5 years (OR=3.93, 95% CI: 2.00-7.72); 5-10 years (OR=2.16, 95% CI: 1.10-4.24) compared to >10 years prior to diagnosis.<br><br>CONCLUSION: Shorter PBL TL alone was not significantly associated with increased HCC risk. Among HCC cases, significant shorter TLs were observed for <5 years prior to diagnosis.},
}
@article {pmid28178350,
year = {2017},
author = {Smeets, CC and Codd, V and Denniff, M and Samani, NJ and Hokken-Koelega, AC},
title = {Effects of size at birth, childhood growth patterns and growth hormone treatment on leukocyte telomere length.},
journal = {PloS one},
volume = {12},
number = {2},
pages = {e0171825},
pmid = {28178350},
issn = {1932-6203},
support = {MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adolescent ; Adult ; *Birth Weight ; *Body Size ; Female ; *Human Development ; Human Growth Hormone/*pharmacology ; Humans ; Leukocytes/*drug effects/*metabolism ; Male ; *Telomere ; Telomere Homeostasis/*drug effects ; Young Adult ; },
abstract = {BACKGROUND: Small size at birth and rapid growth in early life are associated with increased risk of cardiovascular disease in later life. Short children born small for gestational age (SGA) are treated with growth hormone (GH), inducing catch-up in length. Leukocyte telomere length (LTL) is a marker of biological age and shorter LTL is associated with increased risk of cardiovascular disease.<br><br>OBJECTIVES: To investigate whether LTL is influenced by birth size, childhood growth and long-term GH treatment.<br><br>METHODS: We analyzed LTL in 545 young adults with differences in birth size and childhood growth patterns. Previously GH-treated young adults born SGA (SGA-GH) were compared to untreated short SGA (SGA-S), SGA with spontaneous catch-up to a normal body size (SGA-CU), and appropriate for gestational age with a normal body size (AGA-NS). LTL was measured using a quantitative PCR assay.<br><br>RESULTS: We found a positive association between birth length and LTL (p = 0.04), and a trend towards a positive association between birth weight and LTL (p = 0.08), after adjustments for gender, age, gestational age and adult body size. Weight gain during infancy and childhood and fat mass percentage were not associated with LTL. Female gender and gestational age were positively associated with LTL, and smoking negatively. After adjustments for gender, age and gestational age, SGA-GH had a similar LTL as SGA-S (p = 0.11), SGA-CU (p = 0.80), and AGA-NS (p = 0.30).<br><br>CONCLUSIONS: Larger size at birth is positively associated with LTL in young adulthood. Growth patterns during infancy and childhood are not associated with LTL. Previously GH-treated young adults born SGA have similar LTL as untreated short SGA, SGA with spontaneous catch-up and AGA born controls, indicating no adverse effects of GH-induced catch-up in height on LTL.},
}
@article {pmid28177119,
year = {2017},
author = {Lewinska, A and Adamczyk-Grochala, J and Kwasniewicz, E and Wnuk, M},
title = {Downregulation of methyltransferase Dnmt2 results in condition-dependent telomere shortening and senescence or apoptosis in mouse fibroblasts.},
journal = {Journal of cellular physiology},
volume = {232},
number = {12},
pages = {3714-3726},
doi = {10.1002/jcp.25848},
pmid = {28177119},
issn = {1097-4652},
mesh = {Animals ; *Apoptosis/drug effects ; CRISPR-Cas Systems ; Cell Proliferation ; *Cellular Senescence/drug effects ; Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism ; DNA (Cytosine-5-)-Methyltransferase 1 ; DNA (Cytosine-5-)-Methyltransferases/genetics/*metabolism ; DNA Methylation ; DNA Methyltransferase 3A ; Down-Regulation ; Epigenesis, Genetic ; Fibroblasts/drug effects/*enzymology/pathology ; Gene Expression Regulation, Enzymologic ; Gene Knockdown Techniques ; Genomic Instability ; Hydrogen Peroxide/toxicity ; Mice ; NIH 3T3 Cells ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Telomerase/genetics/metabolism ; *Telomere Shortening/drug effects ; Transfection ; Tumor Suppressor Protein p53/genetics/metabolism ; DNA Methyltransferase 3B ; },
abstract = {Dnmt2 is a highly conserved methyltransferase of uncertain biological function(s). As Dnmt2 was considered as a driver of fruit fly longevity and a modulator of stress response, we decided to evaluate the role of Dnmt2 during stress-induced premature senescence in NIH3T3 mouse fibroblasts. Stable knockdown of Dnmt2 resulted in hydrogen peroxide-mediated sensitivity and apoptosis, whereas in the control conditions, senescence was induced. Cellular senescence was accompanied by elevated levels of p53 and p21, decreased telomere length and telomerase activity, increased production of reactive oxygen species and protein carbonylation, and DNA damage. Dnmt2 silencing also promoted global DNA and RNA hypermethylation, and upregulation of methyltransferases, namely Dnmt1, Dnmt3a, and Dnmt3b. Taken together, we show for the first time that Dnmt2 may promote lifespan in the control conditions and survival during stress conditions in mouse fibroblasts.},
}
@article {pmid28176031,
year = {2017},
author = {Lee, J and Solomon, DA and Tihan, T},
title = {Erratum to: The role of histone modifications and telomere alterations in the pathogenesis of diffuse gliomas in adults and children.},
journal = {Journal of neuro-oncology},
volume = {132},
number = {1},
pages = {13},
doi = {10.1007/s11060-017-2376-1},
pmid = {28176031},
issn = {1573-7373},
}
@article {pmid28166612,
year = {2017},
author = {Ludlow, AT and Gratidão, L and Ludlow, LW and Spangenburg, EE and Roth, SM},
title = {Acute exercise activates p38 MAPK and increases the expression of telomere-protective genes in cardiac muscle.},
journal = {Experimental physiology},
volume = {102},
number = {4},
pages = {397-410},
pmid = {28166612},
issn = {1469-445X},
support = {K99 CA197672/CA/NCI NIH HHS/United States ; R00 CA197672/CA/NCI NIH HHS/United States ; T32 AG000268/AG/NIA NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; },
mesh = {Aging/genetics/metabolism ; Animals ; DNA Repair/genetics ; Female ; Gene Expression/genetics ; Mice ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinases/metabolism ; Myocardium/*metabolism ; Phosphorylation/genetics ; Physical Conditioning, Animal/*physiology ; RNA, Messenger/genetics ; Running/physiology ; Telomere/*genetics ; p38 Mitogen-Activated Protein Kinases/*metabolism ; },
abstract = {What is the central question of this study? A positive association between telomere length and exercise training has been shown in cardiac tissue of mice. It is currently unknown how each bout of exercise influences telomere-length-regulating proteins. We sought to determine how a bout of exercise altered the expression of telomere-length-regulating genes and a related signalling pathway in cardiac tissue of mice. What is the main finding and its importance? Acute exercise altered the expression of telomere-length-regulating genes in cardiac tissue and might be related to altered mitogen-activated protein kinase signalling. These findings are important in understanding how exercise provides a cardioprotective phenotype with ageing. Age is the greatest risk factor for cardiovascular disease. Telomere length is shorter in the hearts of aged mice compared with young mice, and short telomere length has been associated with an increased risk of cardiovascular disease. One year of voluntary wheel-running exercise attenuates the age-associated loss of telomere length and results in altered gene expression of telomere-length-maintaining and genome-stabilizing proteins in heart tissue of mice. Understanding the early adaptive response of the heart to an endurance exercise bout is paramount to understanding the impact of endurance exercise on heart tissue and cells. To this end, we studied mice before (BL), immediately after (TP1) and 1 h after a treadmill running bout (TP2). We measured the changes in expression of telomere-related genes (shelterin components), DNA-damage-sensing (p53 and Chk2) and DNA-repair genes (Ku70 and Ku80) and mitogen-activated protein kinase (MAPK) signalling. The TP1 animals had increased TRF1 and TRF2 protein and mRNA levels, greater expression of DNA-repair and -response genes (Chk2 and Ku80) and greater protein content of phosphorylated p38 MAPK compared with both BL and TP2 animals. These data provide insights into how physiological stressors remodel the heart tissue and how an early adaptive response mediated by exercise may be maintaining telomere length and/or stabilizing the heart genome through the upregulation of telomere-protective genes.},
}
@article {pmid28162998,
year = {2017},
author = {Marión, RM and López de Silanes, I and Mosteiro, L and Gamache, B and Abad, M and Guerra, C and Megías, D and Serrano, M and Blasco, MA},
title = {Common Telomere Changes during In Vivo Reprogramming and Early Stages of Tumorigenesis.},
journal = {Stem cell reports},
volume = {8},
number = {2},
pages = {460-475},
pmid = {28162998},
issn = {2213-6711},
mesh = {Animals ; Cell Cycle Proteins/chemistry/genetics ; Cell Dedifferentiation/genetics ; Cell Transformation, Neoplastic/*genetics/metabolism ; Cellular Reprogramming/*genetics ; Chromatin Assembly and Disassembly/genetics ; Chromosomal Proteins, Non-Histone/chemistry/genetics ; Gene Expression Regulation ; Heterochromatin/genetics/metabolism ; Mice ; Mice, Transgenic ; Protein Subunits/genetics ; Stem Cells/cytology/metabolism ; Telomerase/metabolism ; Telomere/*genetics/metabolism ; Telomere Homeostasis ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Cohesins ; },
abstract = {Reprogramming of differentiated cells into induced pluripotent stem cells has been recently achieved in vivo in mice. Telomeres are essential for chromosomal stability and determine organismal life span as well as cancer growth. Here, we study whether tissue dedifferentiation induced by in vivo reprogramming involves changes at telomeres. We find telomerase-dependent telomere elongation in the reprogrammed areas. Notably, we found highly upregulated expression of the TRF1 telomere protein in the reprogrammed areas, which was independent of telomere length. Moreover, TRF1 inhibition reduced in vivo reprogramming efficiency. Importantly, we extend the finding of TRF1 upregulation to pathological tissue dedifferentiation associated with neoplasias, in particular during pancreatic acinar-to-ductal metaplasia, a process that involves transdifferentiation of adult acinar cells into ductal-like cells due to K-Ras oncogene expression. These findings place telomeres as important players in cellular plasticity both during in vivo reprogramming and in pathological conditions associated with increased plasticity, such as cancer.},
}
@article {pmid28161061,
year = {2017},
author = {Broady, AJ and Loichinger, MH and Ahn, HJ and Davy, PM and Allsopp, RC and Bryant-Greenwood, GD},
title = {Protective proteins and telomere length in placentas from patients with pre-eclampsia in the last trimester of gestation.},
journal = {Placenta},
volume = {50},
number = {},
pages = {44-52},
pmid = {28161061},
issn = {1532-3102},
support = {G12 MD007601/MD/NIMHD NIH HHS/United States ; P20 GM103457/GM/NIGMS NIH HHS/United States ; P20 GM103466/GM/NIGMS NIH HHS/United States ; U54 MD007584/MD/NIMHD NIH HHS/United States ; },
mesh = {Adult ; Biomarkers/metabolism ; Female ; Gestational Age ; Humans ; Nicotinamide Phosphoribosyltransferase/*metabolism ; Placenta/metabolism ; Pre-Eclampsia/*metabolism ; Pregnancy ; Pregnancy Trimester, Third ; Sirtuin 1/*metabolism ; Sirtuin 3/*metabolism ; *Telomere ; Trophoblasts/metabolism ; },
abstract = {INTRODUCTION: Visfatin/nicotinamide phosphoribosyltransferase (Nampt), an enzyme involved in energy metabolism and sirtuins, SIRT1 and SIRT3, which are NAD-dependent deacetylases, are critical for cellular function. All three either regulate or are regulated by intracellular NAD+ levels and therefore available cellular energy, important for placental cell survival and successful pregnancy. This study investigates whether these protective proteins are involved in the placental pathophysiology of pre-eclampsia (PE) and if they are associated with 8-oxo-deoxyguanosine (8OHdG), a marker of oxidative damage or with placental telomere length.<br><br>METHODS: Maternal blood and placental samples were collected from 31 patients with PE and 30 controls between 31 and 40 weeks gestation. Quantitative immunohistochemistry was performed on placental specimens for visfatin/Nampt, SIRT1, SIRT3, and nuclear 8OHdG. Plasma visfatin was measured by ELISA and telomere length by Southern blot analysis of telomere restriction fragments.<br><br>RESULTS: Visfatin/Nampt and SIRT1 in syncytiotrophoblast decreased in PE compared to controls (p&#xa0;<&#xa0;0.0001, p&#xa0;=&#xa0;0.004 respectively). SIRT3 decreased in PE most significantly at preterm (p&#xa0;=&#xa0;0.002). 8OHdG was only significantly lower in preterm controls compared to term controls (p&#xa0;=&#xa0;0.01) and correlated with SIRT1 in all samples (r&#xa0;=&#xa0;0.27). Telomere length was not different in PE and controls.<br><br>DISCUSSION: Decreased visfatin/Nampt, SIRT1 and SIRT3 in syncytiotrophoblast in PE suggests a lack of placental reserve in metabolic energy efficiency, increased inflammation, and lower resistance to environmental stressors. However, there was little effect on nuclear function, or evidence of genomic DNA damage, which would lead to cellular senescence and death.},
}
@article {pmid28160602,
year = {2017},
author = {Cesena, D and Cassani, C and Rizzo, E and Lisby, M and Bonetti, D and Longhese, MP},
title = {Regulation of telomere metabolism by the RNA processing protein Xrn1.},
journal = {Nucleic acids research},
volume = {45},
number = {7},
pages = {3860-3874},
pmid = {28160602},
issn = {1362-4962},
mesh = {DNA, Single-Stranded/metabolism ; Exoribonucleases/genetics/*metabolism/physiology ; Exosome Multienzyme Ribonuclease Complex/genetics/physiology ; Mutation ; RNA Processing, Post-Transcriptional ; Repressor Proteins/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism/physiology ; Telomere/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/genetics/metabolism ; Temperature ; },
abstract = {Telomeric DNA consists of repetitive G-rich sequences that terminate with a 3΄-ended single stranded overhang (G-tail), which is important for telomere extension by telomerase. Several proteins, including the CST complex, are necessary to maintain telomere structure and length in both yeast and mammals. Emerging evidence indicates that RNA processing factors play critical, yet poorly understood, roles in telomere metabolism. Here, we show that the lack of the RNA processing proteins Xrn1 or Rrp6 partially bypasses the requirement for the CST component Cdc13 in telomere protection by attenuating the activation of the DNA damage checkpoint. Xrn1 is necessary for checkpoint activation upon telomere uncapping because it promotes the generation of single-stranded DNA. Moreover, Xrn1 maintains telomere length by promoting the association of Cdc13 to telomeres independently of ssDNA generation and exerts this function by downregulating the transcript encoding the telomerase inhibitor Rif1. These findings reveal novel roles for RNA processing proteins in the regulation of telomere metabolism with implications for genome stability in eukaryotes.},
}
@article {pmid28158503,
year = {2017},
author = {Sun, L and Nakajima, S and Teng, Y and Chen, H and Yang, L and Chen, X and Gao, B and Levine, AS and Lan, L},
title = {WRN is recruited to damaged telomeres via its RQC domain and tankyrase1-mediated poly-ADP-ribosylation of TRF1.},
journal = {Nucleic acids research},
volume = {45},
number = {7},
pages = {3844-3859},
pmid = {28158503},
issn = {1362-4962},
support = {R01 GM118833/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Survival ; Cells, Cultured ; DNA Damage ; *DNA Repair ; Humans ; Oxidation-Reduction ; Protein Interaction Domains and Motifs ; Reactive Oxygen Species/metabolism ; Tankyrases/*metabolism ; Telomere/*enzymology/metabolism ; Telomeric Repeat Binding Protein 1/chemistry/*metabolism ; Werner Syndrome Helicase/chemistry/*metabolism ; },
abstract = {Werner syndrome (WS) is a progeroid-like syndrome caused by WRN gene mutations. WS cells exhibit shorter telomere length compared to normal cells, but it is not fully understood how WRN deficiency leads directly to telomere dysfunction. By generating localized telomere-specific DNA damage in a real-time fashion and a dose-dependent manner, we found that the damage response of WRN at telomeres relies on its RQC domain, which is different from the canonical damage response at genomic sites via its HRDC domain. We showed that in addition to steady state telomere erosion, WRN depleted cells are also sensitive to telomeric damage. WRN responds to site-specific telomeric damage via its RQC domain, interacting at Lysine 1016 and Phenylalanine1037 with the N-terminal acidic domain of the telomere shelterin protein TRF1 and demonstrating a novel mechanism for WRN's role in telomere protection. We also found that tankyrase1-mediated poly-ADP-ribosylation of TRF1 is important for both the interaction between WRN and TRF1 and the damage recruitment of WRN to telomeres. Mutations of potential tankyrase1 ADP-ribosylation sites within the RGCADG motif of TRF1 strongly diminish the interaction with WRN and the damage response of WRN only at telomeres. Taken together, our results reveal a novel mechanism as to how WRN protects telomere integrity from damage and telomere erosion.},
}
@article {pmid28158257,
year = {2017},
author = {Siland, JE and Geelhoed, B and van Gelder, IC and van der Harst, P and Rienstra, M},
title = {Telomere length and incident atrial fibrillation - data of the PREVEND cohort.},
journal = {PloS one},
volume = {12},
number = {2},
pages = {e0171545},
pmid = {28158257},
issn = {1932-6203},
mesh = {Age Factors ; Atrial Fibrillation/epidemiology/*genetics ; Cohort Studies ; Female ; Follow-Up Studies ; Humans ; Incidence ; Male ; Middle Aged ; Risk Factors ; Sex Factors ; *Telomere ; },
abstract = {BACKGROUND: The incidence of atrial fibrillation (AF) increases with age. Telomere length is considered a marker of biological ageing. We investigated the association between leukocyte telomere length and incident AF in the Dutch Prevention of Renal and Vascular End-stage Disease (PREVEND) study.<br><br>METHODS: We included 7775 individuals without prevalent AF, and with leukocyte telomere length measured. Mean telomere length was determined by a monochrome multiplex quantitative polymerase chain reaction-based assay.<br><br>RESULTS: Mean age of our cohort was 49&#xb1;13 years, and 50% were men. During a mean follow-up of 11.4&#xb1;2.9 years incident AF was detected in 367 (4.7%) individuals. Telomere length was shorter in individuals developing incident AF compared to those without AF (p = 0.013). Incident AF was inversely related to the telomere length. In the quartile with the longest telomere length 68 (3.5%) individuals developed AF, in the shortest telomere length quartile 100 (5.1%) individuals (p = 0.032). Telomere length was associated with incident AF in the second shortest telomere length quartile using the longest telomere length quartile as reference (hazard ratio 1.64; 95% CI 1.02-2.66; p = 0.043). After including age or AF risk factors, the relation between telomere length and incident AF was no longer significant. We found a significant interaction of age, male sex, systolic blood pressure, BMI, heart failure, and myocardial infarction with telomere length for the association with incident AF.<br><br>CONCLUSIONS: We found that shorter leukocyte telomere length is not independently associated with incident AF in a community-based cohort.},
}
@article {pmid28154163,
year = {2017},
author = {Gebreab, SY and Manna, ZG and Khan, RJ and Riestra, P and Xu, R and Davis, SK},
title = {Less Than Ideal Cardiovascular Health Is Associated With Shorter Leukocyte Telomere Length: The National Health and Nutrition Examination Surveys, 1999-2002.},
journal = {Journal of the American Heart Association},
volume = {6},
number = {2},
pages = {},
pmid = {28154163},
issn = {2047-9980},
mesh = {Adult ; Aged ; Aged, 80 and over ; Cardiovascular Diseases/ethnology/*genetics/physiopathology ; Cross-Sectional Studies ; *Ethnicity ; Exercise/*physiology ; Female ; Follow-Up Studies ; *Health Status ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Morbidity/trends ; *Nutrition Surveys ; Prevalence ; Retrospective Studies ; Risk Factors ; Social Class ; Telomere/*genetics ; Time Factors ; United States/epidemiology ; Young Adult ; },
abstract = {BACKGROUND: The associations between individual cardiovascular disease risk factors and leukocyte telomere length (LTL) have been inconclusive. We investigated the association between LTL and overall cardiovascular health (CVH) as defined by the American Heart Association and whether the association is modified by sex and race/ethnicity.<br><br>METHODS AND RESULTS: We included 5194 adults (aged &#x2265;20) from the National Health and Nutrition Examination Survey 1999-2002. CVH was defined as a composite score of the 7 metrics (smoking, physical activity, diet, body mass index, blood pressure, total cholesterol, and fasting blood glucose) and categorized as "poor," "intermediate," and "ideal." LTL was assayed from whole blood using the quantitative polymerase chain reaction method relative to standard reference DNA. Multivariable linear regression models were used to estimate the association between CVH and log-transformed LTL. We found strong graded association between CVH and LTL in the overall sample, with evidence of dose-response relationship (P for trend=0.013). Individuals with poor and intermediate CVH had significantly shorter LTL than individuals with ideal CVH (-3.4% [95% CI=-6.0%, -0.8%] and -2.4% [-4.4%, -0.3%], respectively), after adjustment for demographic variables, socioeconomic status, and C-reactive protein. The association was stronger in women (-6.6% [-10.2%, -2.9%] for poor vs ideal CVH) and non-Hispanic whites (-4.3% [-7.1%, -1.4%] for poor vs ideal CVH).<br><br>CONCLUSIONS: The findings suggest that less-than-ideal CVH is associated with shorter LTL, but this association varies by sex and race/ethnicity. Future longitudinal research is needed to elucidate the mechanisms that underlie the association between CVH and LTL.},
}
@article {pmid28152565,
year = {2017},
author = {Xu, N and Chen, Y and Dean, KC and Lu, X and Liu, X and Wang, W and Dean, DC and Kaplan, HJ and Gao, L and Dong, F and Liu, Y},
title = {Sphere-Induced Rejuvenation of Swine and Human Müller Glia Is Primarily Caused by Telomere Elongation.},
journal = {Stem cells (Dayton, Ohio)},
volume = {35},
number = {6},
pages = {1579-1591},
doi = {10.1002/stem.2585},
pmid = {28152565},
issn = {1549-4918},
mesh = {Animals ; Cells, Cultured ; Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor Proteins/genetics/metabolism ; Ependymoglial Cells/*metabolism ; Humans ; Models, Biological ; *Rejuvenation ; Spheroids, Cellular/*cytology ; Stem Cells/metabolism ; Sus scrofa ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Müller cells are the major supportive and protective glial cells in the retina with important functions in histogenesis and synaptogenesis during development, and in maintenance of mature neurons as they show to secrete various cytokines and manifest potentials of self-renewal and transdifferentiation into retinal neurons following injury in the vertebrate retinas. The swine retina has a visual streak structure similar to the human macular where cone photoreceptors are highly concentrated, thereby can serve as a better model for studying retinal diseases and for formulating cell-based therapeutics than the rodent retinas. Like most differentiated somatic mammalian cells, the isolated swine and human Müller glia become senescent over passages in culture, which restricts their potential application in basic and clinic researches. Here, we demonstrate that the senescence of swine and human Müller cells is caused by telomere attrition upon multiplications in vitro; and the senescent cells can be rejuvenated by sphere suspension culture. We also provide evidence that sphere-induced extension of telomeres in swine and human Müller glia is achieved by alternative lengthening of telomeres or/and by telomerase activation. Stem Cells 2017;35:1579-1591.},
}
@article {pmid28151853,
year = {2017},
author = {Lee, HW and Park, TI and Jang, SY and Park, SY and Park, WJ and Jung, SJ and Lee, JH},
title = {Clinicopathological characteristics of TERT promoter mutation and telomere length in hepatocellular carcinoma.},
journal = {Medicine},
volume = {96},
number = {5},
pages = {e5766},
pmid = {28151853},
issn = {1536-5964},
mesh = {Aged ; Carcinoma, Hepatocellular/*genetics/pathology ; Female ; Humans ; Liver Neoplasms/*genetics/pathology ; Male ; Middle Aged ; Mutation ; Prognosis ; Promoter Regions, Genetic ; Real-Time Polymerase Chain Reaction ; Retrospective Studies ; Sex Factors ; Telomerase/*genetics ; Telomere/*genetics/pathology ; },
abstract = {Promoter mutations in telomerase reverse transcriptase (TERT) and telomere length have been studied in various tumors. In the present study, the frequency and clinical characteristics of TERT promoter mutation and telomere length were studied in hepatocellular carcinoma (HCC). TERT promoter mutation and telomere length were analyzed in 162 tumor samples of the patients with HCC by sequencing and real-time PCR, respectively. The TERT promoter mutation rate was 28.8% (46/160) in HCC and was associated with males (P = 0.027). The telomere length was not significantly different in the presence of a TERT promoter mutation but was shorter in high-grade tumor stages (P = 0.048). Survival analyses showed that poor overall survival was associated with longer telomere length (P = 0.013). However, the TERT promoter mutation did not have a prognostic value for HCC. Multivariate survival analyses demonstrated that the telomere length was an independent prognostic marker for poor overall survival (hazard ratio = 1.75, 95% confidence interval: 1.046-2.913, P = 0.033). These data demonstrated that TERT promoter mutation is a frequent event in HCC; however, telomere length, but not the presence of a TERT promoter mutation, might have potential value as a prognostic indicator of HCC.},
}
@article {pmid28150695,
year = {2017},
author = {Fellows, CR and Williams, R and Davies, IR and Gohil, K and Baird, DM and Fairclough, J and Rooney, P and Archer, CW and Khan, IM},
title = {Characterisation of a divergent progenitor cell sub-populations in human osteoarthritic cartilage: the role of telomere erosion and replicative senescence.},
journal = {Scientific reports},
volume = {7},
number = {},
pages = {41421},
pmid = {28150695},
issn = {2045-2322},
support = {20069/VAC_/Versus Arthritis/United Kingdom ; MR/L02280X/1/MRC_/Medical Research Council/United Kingdom ; 20069/ARC_/Arthritis Research UK/United Kingdom ; },
mesh = {Adult ; Adult Stem Cells/pathology ; Aged ; Aged, 80 and over ; Bromodeoxyuridine/metabolism ; Cartilage, Articular/*pathology ; Cell Nucleus/metabolism ; Cell Separation ; *Cellular Senescence ; Chromosomes, Human/metabolism ; Clone Cells ; Humans ; Linear Models ; Middle Aged ; Osteoarthritis/*pathology ; Stem Cells/*pathology ; Telomere/*metabolism ; beta-Galactosidase/metabolism ; },
abstract = {In recent years it has become increasingly clear that articular cartilage harbours a viable pool of progenitor cells and interest has focussed on their role during development and disease. Analysis of progenitor numbers using fluorescence-activated sorting techniques has resulted in wide-ranging estimates, which may be the result of context-dependent expression of cell surface markers. We have used a colony-forming assay to reliably determine chondroprogenitor numbers in normal and osteoarthritic cartilage where we observed a 2-fold increase in diseased tissue (P < 0.0001). Intriguingly, cell kinetic analysis of clonal isolates derived from single and multiple donors of osteoarthritic cartilage revealed the presence of a divergent progenitor subpopulation characterised by an early senescent phenotype. Divergent sub-populations displayed increased senescence-associated β-galactosidase activity, lower average telomere lengths but retained the capacity to undergo multi-lineage differentiation. Osteoarthritis is an age-related disease and cellular senescence is predicted to be a significant component of the pathological process. This study shows that although early senescence is an inherent property of a subset of activated progenitors, there is also a pool of progenitors with extended viability and regenerative potential residing within osteoarthritic cartilage.},
}
@article {pmid28150689,
year = {2017},
author = {Mazidi, M and Kengne, AP and Banach, M},
title = {Mineral and vitamin consumption and telomere length among adults in the United States.},
journal = {Polish archives of internal medicine},
volume = {127},
number = {2},
pages = {87-90},
doi = {10.20452/pamw.3927},
pmid = {28150689},
issn = {1897-9483},
mesh = {Adult ; Aged ; Cross-Sectional Studies ; *Diet ; Female ; Humans ; Male ; Middle Aged ; *Minerals ; Nutrition Surveys ; *Telomere Homeostasis ; *Vitamins ; Young Adult ; },
abstract = {INTRODUCTION Shorter leukocyte telomere length (TL) is associated with several chronic diseases, but only a few studies have assessed the associations of dietary components and dietary patterns with TL in adults in the United States (US). OBJECTIVES This study was aimed to determine the relation of dietary components and dietary patterns with TL among adults in the US. PATIENTS AND METHODS National Health and Nutrition Examination Survey (NHANES) participants with data on dietary intake and TL measures from 1999 to 2001 were included. Daily intakes of 60 nutrients and bioactive compounds were calculated for each participant. Factor analysis, followed by a varimax rotation, was applied to derive the major nutrient patterns. All statistical analyses accounted for the survey design and sample weights. RESULTS Of the 10 568 eligible participants, 48.0% (n = 5020) were men; the mean age was 44.1 years. Mean (adjusted for sex, age, and race) dietary intakes of carbohydrate, dietary fiber, total folate, vitamin B6, magnesium, iron, copper, polyunsaturated fatty acids 22:5, and vitamin C monotonically increased across TL quarters (P <0.05 for all), while total fat and caffeine decreased across TL quarters (P <0.05 for all). Three food patterns together explaining 56.8% of the variance of the dietary nutrient consumption were identified. We found that the second food pattern, which was a representative of minerals and vitamins, monotonically increased across TL quarters and had a positive association with TL. CONCLUSIONS Higher mineral and vitamin consumption is associated with longer telomeres among adults in the US.},
}
@article {pmid28147207,
year = {2017},
author = {Liu, SY and Kawachi, I},
title = {Discrimination and Telomere Length Among Older Adults in the United States.},
journal = {Public health reports (Washington, D.C. : 1974)},
volume = {132},
number = {2},
pages = {220-230},
pmid = {28147207},
issn = {1468-2877},
mesh = {Black or African American/*psychology ; Aged ; Aged, 80 and over ; Ethnicity/*psychology ; Female ; Humans ; Leukocytes/*physiology ; Linear Models ; Male ; Middle Aged ; Racism/*psychology ; Surveys and Questionnaires ; Telomere/*genetics ; },
abstract = {OBJECTIVES: Chronic stress from experiencing discrimination can lead to long-term changes in psychological and physiologic responses, including shorter leukocyte telomere length. We examined the association between leukocyte telomere length and variations in the association by race or type of discrimination.<br><br>METHODS: Our study consisted of 3868 US-born non-Hispanic black (hereinafter, black) and non-Hispanic white (hereinafter, white) adult participants from the 2008 Health and Retirement Study biomarker sample with complete sociodemographic and discrimination information. We examined major lifetime unfair treatment and everyday discrimination. Coarsened exact matching matched exposed and unexposed participants on several sociodemographic factors. Coarsened exact matching creates analytic weights for the matched data sets. We applied weighted linear regression to the matched data sets. We conducted 2 subanalyses in which we matched on potential mediators-physical activity, smoking status, and obesity-and examined if racism was associated with shorter telomere length compared with other attributes. All analyses were stratified by race.<br><br>RESULTS: We found no difference in telomere length for black and white participants reporting major lifetime unfair treatment (&#x3b2; = 0.09; 95% CI, -0.33 to 0.15) or everyday discrimination (&#x3b2; = 0.04; 95% CI, -0.12 to 0.40). Everyday discrimination was associated with shorter leukocyte telomere length among black people (&#x3b2; = -0.23; 95% CI, -0.44 to -0.01) but not among white people (&#x3b2; = 0.05; 95% CI, -0.01 to 0.10). Matching on potential mediators generally decreased the effect estimate among black people.<br><br>CONCLUSIONS: Experiencing everyday discrimination was associated with shortened telomere length among older black adults. Further research is needed to understand the adverse physiologic effects of discrimination to create effective interventions.},
}
@article {pmid28146441,
year = {2017},
author = {Barger, SD and Cribbet, MR and Muldoon, MF},
title = {Leukocyte Telomere Length and Cardiovascular Risk Scores for Prediction of Cardiovascular Mortality.},
journal = {Epidemiology (Cambridge, Mass.)},
volume = {28},
number = {2},
pages = {e13-e15},
pmid = {28146441},
issn = {1531-5487},
support = {T32 HL082610/HL/NHLBI NIH HHS/United States ; },
mesh = {Cardiovascular Diseases/*mortality ; Humans ; Risk Factors ; Telomere ; *Telomere Shortening ; },
}
@article {pmid28146113,
year = {2017},
author = {Maestroni, L and Matmati, S and Coulon, S},
title = {Solving the Telomere Replication Problem.},
journal = {Genes},
volume = {8},
number = {2},
pages = {},
pmid = {28146113},
issn = {2073-4425},
abstract = {Telomeres are complex nucleoprotein structures that protect the extremities of linear chromosomes. Telomere replication is a major challenge because many obstacles to the progression of the replication fork are concentrated at the ends of the chromosomes. This is known as the telomere replication problem. In this article, different and new aspects of telomere replication, that can threaten the integrity of telomeres, will be reviewed. In particular, we will focus on the functions of shelterin and the replisome for the preservation of telomere integrity.},
}
@article {pmid28144256,
year = {2017},
author = {Mazidi, M and Michos, ED and Banach, M},
title = {The association of telomere length and serum 25-hydroxyvitamin D levels in US adults: the National Health and Nutrition Examination Survey.},
journal = {Archives of medical science : AMS},
volume = {13},
number = {1},
pages = {61-65},
pmid = {28144256},
issn = {1734-1922},
abstract = {INTRODUCTION: Higher vitamin D levels and longer telomere length (TL) have been associated with lower risk of several chronic diseases and all-cause mortality. However, direct relationships between 25-hydroxyvitamin D (25(OH)D) levels and TL are not well established. Vitamin D could influence TL through its anti-inflammatory properties. This study aimed to assess the relationship between vitamin D levels and TL in US adults.<br><br>MATERIAL AND METHODS: Participants of the National Health and Nutrition Examination Survey (NHANES) with data available on 25(OH)D and TL measures from 2001 to 2002 were included. 25(OH)D levels were measured by the DiaSorin Radioimmunoassay. We used multivariable-adjusted linear regression models, accounting for the survey design and sample weights.<br><br>RESULTS: Of the 4347 eligible participants, 47.0% (n = 2045) were men. The mean age was 42.7 years overall, 49.2 years in men and 42.5 years in women (p = 0.060). After adjustment for age, race, marital status, education, and C-reactive protein, each 1 ng/ml higher 25(OH)D level was associated with a 0.045 (95% confidence interval (CI): 0.032 to 0.059) longer telomere-to-single copy gene (T/S) ratio. This was driven by a significant association in women (0.054 (0.043 to 0.064)) and in men (0.036 (0.020 to 0.052)). However, after we further adjusted for smoking, body mass index, and physical activity, no significant relation was found in the overall sample (&#x3b2; coefficient -0.026, 95% CI: -3.16, 1.67), for men (-0.016 (-3.72, 2.64)), or for women (-0.052 (-6.85, 2.26)).<br><br>CONCLUSIONS: Our findings support a possible positive association between 25(OH)D levels and telomere length. The implications of this association deserve further investigation.},
}
@article {pmid28144163,
year = {2017},
author = {Murillo-Ortiz, B and Martínez-Garza, S and Suárez García, D and Castillo Valenzuela, RD and García Regalado, JF and Cano Velázquez, G},
title = {Association between telomere length and CYP19 TTTA repetition polymorphism in healthy and breast cancer-diagnosed women.},
journal = {Breast cancer (Dove Medical Press)},
volume = {9},
number = {},
pages = {21-27},
pmid = {28144163},
issn = {1179-1314},
abstract = {INTRODUCTION: Several studies have reported an increase in breast cancer (BC) risk when patients are carriers of the CYP19 TTA polymorphism with ≥10 repeats; moreover, it has been reported that telomere length is associated with a higher susceptibility of developing cancer.<br><br>OBJECTIVE: The objective of this study was to understand the relationship between CYP19 TTTA repetition polymorphism and telomere length and its effects on serum estradiol, estrone and follicle-stimulating hormone (FSH).<br><br>MATERIALS AND METHODS: A total of 180 postmenopausal healthy and 70 BC-diagnosed women were included. Telomere length was determined through real-time quantitative polymerase chain reaction, and aromatase polymorphism was analyzed through DNA; both samples were obtained from circulating leukocytes. Serum estrone, estradiol and FSH were determined by enzyme-linked immunosorbent assay.<br><br>RESULTS: Patients with a BC diagnosis showed >10 repetitions more frequently, compared with that of healthy women (50% vs 23%, &#x3c7;[2] = 11.44, p = 0.0007). A significant difference in telomere length between healthy and BC women was observed (5,042.7 vs 2,256.7 pb, Z = 4.88, p < 0.001). CYP19 TTTA repeat polymorphism was associated with serum levels of estradiol and estrone in both groups, being higher in those with >10 repeats. Moreover, telomere length showed an inverse relationship with the number of repeats of the aromatase polymorphism in healthy women (R[2] = 0.04, r = -0.24); in contrast, BC patients did not display this relationship. In addition, telomere length presented an inverse relationship with serum levels of estradiol and estrone in BC patients (p = 0.02).<br><br>CONCLUSION: Telomere length is shorter in BC patients than in healthy patients. The CYP19 TTTA repeat polymorphism is associated with serum levels of estradiol and estrone in both healthy women and BC patients, being higher in those with polymorphism carriers >10 repeats. Telomere length has an inverse correlation with the number of repeats of the aromatase polymorphism in healthy women but not in BC women. Estradiol and estrone levels in BC women have an inverse relationship with telomere length.},
}
@article {pmid28144030,
year = {2017},
author = {Zlotorynski, E},
title = {Chromosome biology: TZAP trims telomeres.},
journal = {Nature reviews. Molecular cell biology},
volume = {18},
number = {3},
pages = {140},
pmid = {28144030},
issn = {1471-0080},
mesh = {*Telomere ; },
}
@article {pmid28141967,
year = {2017},
author = {Wu, RA and Upton, HE and Vogan, JM and Collins, K},
title = {Telomerase Mechanism of Telomere Synthesis.},
journal = {Annual review of biochemistry},
volume = {86},
number = {},
pages = {439-460},
pmid = {28141967},
issn = {1545-4509},
support = {R01 GM054198/GM/NIGMS NIH HHS/United States ; R01 HL079585/HL/NHLBI NIH HHS/United States ; R56 HL079585/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Catalytic Domain ; *DNA Replication ; DNA, Single-Stranded/genetics/*metabolism ; Gene Expression Regulation ; Humans ; Microsatellite Repeats ; Nucleic Acid Conformation ; Oxytricha/genetics/metabolism ; RNA/genetics/*metabolism ; Ribonucleoproteins/genetics/*metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Telomerase/genetics/*metabolism ; Telomere/chemistry/*enzymology ; Tetrahymena thermophila/genetics/metabolism ; },
abstract = {Telomerase is the essential reverse transcriptase required for linear chromosome maintenance in most eukaryotes. Telomerase supplements the tandem array of simple-sequence repeats at chromosome ends to compensate for the DNA erosion inherent in genome replication. The template for telomerase reverse transcriptase is within the RNA subunit of the ribonucleoprotein complex, which in cells contains additional telomerase holoenzyme proteins that assemble the active ribonucleoprotein and promote its function at telomeres. Telomerase is distinct among polymerases in its reiterative reuse of an internal template. The template is precisely defined, processively copied, and regenerated by release of single-stranded product DNA. New specificities of nucleic acid handling that underlie the catalytic cycle of repeat synthesis derive from both active site specialization and new motif elaborations in protein and RNA subunits. Studies of telomerase provide unique insights into cellular requirements for genome stability, tissue renewal, and tumorigenesis as well as new perspectives on dynamic ribonucleoprotein machines.},
}
@article {pmid28139771,
year = {2017},
author = {Ioannou, D and Millan, NM and Jordan, E and Tempest, HG},
title = {A new model of sperm nuclear architecture following assessment of the organization of centromeres and telomeres in three-dimensions.},
journal = {Scientific reports},
volume = {7},
number = {},
pages = {41585},
pmid = {28139771},
issn = {2045-2322},
support = {R25 GM061347/GM/NIGMS NIH HHS/United States ; },
mesh = {Adult ; Cell Nucleus/*genetics/metabolism ; Centromere/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Models, Biological ; Spermatozoa/*metabolism ; Telomere/*genetics ; },
abstract = {The organization of chromosomes in sperm nuclei has been proposed to possess a unique "hairpin-loop" arrangement, which is hypothesized to aid in the ordered exodus of the paternal genome following fertilization. This study simultaneously assessed the 3D and 2D radial and longitudinal organization of telomeres, centromeres, and investigated whether chromosomes formed the same centromere clusters in sperm cells. Reproducible radial and longitudinal non-random organization was observed for all investigated loci using both 3D and 2D approaches in multiple subjects. We report novel findings, with telomeres and centromeres being localized throughout the nucleus but demonstrating roughly a 1:1 distribution in the nuclear periphery and the intermediate regions with <15% occupying the nuclear interior. Telomeres and centromeres were observed to aggregate in sperm nuclei, forming an average of 20 and 7 clusters, respectively. Reproducible longitudinal organization demonstrated preferential localization of telomeres and centromeres in the mid region of the sperm cell. Preliminary evidence is also provided to support the hypothesis that specific chromosomes preferentially form the same centromere clusters. The more segmental distribution of telomeres and centromeres as described in this study could more readily accommodate and facilitate the sequential exodus of paternal chromosomes following fertilization.},
}
@article {pmid28135248,
year = {2017},
author = {Barthel, FP and Wei, W and Tang, M and Martinez-Ledesma, E and Hu, X and Amin, SB and Akdemir, KC and Seth, S and Song, X and Wang, Q and Lichtenberg, T and Hu, J and Zhang, J and Zheng, S and Verhaak, RG},
title = {Systematic analysis of telomere length and somatic alterations in 31 cancer types.},
journal = {Nature genetics},
volume = {49},
number = {3},
pages = {349-357},
pmid = {28135248},
issn = {1546-1718},
support = {P01 CA085878/CA/NCI NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; P30 CA034196/CA/NCI NIH HHS/United States ; R01 CA190121/CA/NCI NIH HHS/United States ; },
mesh = {DNA Methylation/genetics ; Glioma/genetics ; Humans ; Neoplasms/*genetics ; Point Mutation/*genetics ; Promoter Regions, Genetic/genetics ; Retinoblastoma Binding Proteins/genetics ; Sarcoma/genetics ; Telomerase/genetics ; Telomere/*genetics ; Tumor Suppressor Protein p53/genetics ; Ubiquitin-Protein Ligases/genetics ; },
abstract = {Cancer cells survive cellular crisis through telomere maintenance mechanisms. We report telomere lengths in 18,430 samples, including tumors and non-neoplastic samples, across 31 cancer types. Telomeres were shorter in tumors than in normal tissues and longer in sarcomas and gliomas than in other cancers. Among 6,835 cancers, 73% expressed telomerase reverse transcriptase (TERT), which was associated with TERT point mutations, rearrangements, DNA amplifications and transcript fusions and predictive of telomerase activity. TERT promoter methylation provided an additional deregulatory TERT expression mechanism. Five percent of cases, characterized by undetectable TERT expression and alterations in ATRX or DAXX, demonstrated elongated telomeres and increased telomeric repeat-containing RNA (TERRA). The remaining 22% of tumors neither expressed TERT nor harbored alterations in ATRX or DAXX. In this group, telomere length positively correlated with TP53 and RB1 mutations. Our analysis integrates TERT abnormalities, telomerase activity and genomic alterations with telomere length in cancer.},
}
@article {pmid28129920,
year = {2017},
author = {Yip, BW and Mok, HO and Peterson, DR and Wan, MT and Taniguchi, Y and Ge, W and Au, DW},
title = {Sex-dependent telomere shortening, telomerase activity and oxidative damage in marine medaka Oryzias melastigma during aging.},
journal = {Marine pollution bulletin},
volume = {124},
number = {2},
pages = {701-709},
doi = {10.1016/j.marpolbul.2017.01.021},
pmid = {28129920},
issn = {1879-3363},
mesh = {*Aging ; Animals ; Estrogens/*metabolism ; Female ; Male ; Oryzias/*physiology ; *Oxidative Stress ; Sex Factors ; Telomerase/*metabolism ; *Telomere Shortening ; Testosterone/*metabolism ; },
abstract = {Marine medaka Oryzias melastigma at 4months (young), 8months (middle-aged) and 12months old (senior) were employed to determine age-associated change of sex ratios, sex hormones, telomere length (TL), telomerase activity (TA), telomerase transcription (omTERT) and oxidative damage in the liver. Overall, O. melastigma exhibited gradual senescence, sex differences in longevity (F>M), TL (F>M) and oxidative damage (F<M) during aging. In females, the plasma E2 level was positively correlated with TL (TRF>5kb), TA and omTERT expression (p≤0.01), and negatively correlated with liver DNA oxidation (p≤0.05). The results suggest high levels of E2 in female O. melastigma may retard TL shortening by enhancing TA via TERT transcription and/or reducing oxidative DNA damage. The findings support TL shortening as a biomarker of aging and further development of accelerated TL shortening, abnormal suppression of TA and excessive oxidative DNA damage as early molecular endpoints, indicative of advanced/premature aging in marine medaka/fish.},
}
@article {pmid28126377,
year = {2017},
author = {Aubert, G and Strauss, KA and Lansdorp, PM and Rider, NL},
title = {Defects in lymphocyte telomere homeostasis contribute to cellular immune phenotype in patients with cartilage-hair hypoplasia.},
journal = {The Journal of allergy and clinical immunology},
volume = {140},
number = {4},
pages = {1120-1129.e1},
doi = {10.1016/j.jaci.2016.11.051},
pmid = {28126377},
issn = {1097-6825},
mesh = {Adolescent ; Adult ; Cell Proliferation ; Cells, Cultured ; Child ; Child, Preschool ; Computational Biology ; Dyskeratosis Congenita/genetics ; Female ; Hair/*abnormalities/immunology ; Hirschsprung Disease/genetics/*immunology ; Humans ; Immunologic Deficiency Syndromes/genetics/*immunology ; Infant ; Lymphocyte Activation ; Lymphocytes/*physiology ; Male ; Middle Aged ; Mutation/*genetics ; Osteochondrodysplasias/*congenital/genetics/immunology ; Pedigree ; Primary Immunodeficiency Diseases ; RNA, Long Noncoding/*genetics ; Telomere/*genetics ; *Telomere Homeostasis ; Young Adult ; },
abstract = {BACKGROUND: Mutations in the long noncoding RNA RNase component of the mitochondrial RNA processing endoribonuclease (RMRP) give rise to the autosomal recessive condition cartilage-hair hypoplasia (CHH). The CHH disease phenotype has some overlap with dyskeratosis congenita, a well-known "telomere disorder." RMRP binds the telomerase reverse transcriptase (catalytic subunit) in some cell lines, raising the possibility that RMRP might play a role in telomere biology.<br><br>OBJECTIVE: We sought to determine whether a telomere phenotype is present in immune cells from patients with CHH and explore mechanisms underlying these observations.<br><br>METHODS: We assessed proliferative capacity and telomere length using flow-fluorescence in situ hybridization (in situ hybridization and flow cytometry) of primary lymphocytes from patients with CHH, carrier relatives, and control subjects. The role of telomerase holoenzyme components in gene expression and activity were assessed by using quantitative PCR and the telomere repeat amplification protocol from PBMCs and enriched lymphocyte cultures.<br><br>RESULTS: Lymphocyte cultures from patients with CHH display growth defects in&#xa0;vitro, which is consistent with an immune deficiency cellular phenotype. Here we show that telomere length and telomerase activity are impaired in primary lymphocyte subsets from patients with CHH. Notably, telomerase activity is affected in a gene dose-dependent manner when comparing heterozygote RMRP carriers with patients with CHH. Telomerase deficiency in patients with CHH is not mediated by abnormal telomerase gene transcript levels relative to those of endogenous genes.<br><br>CONCLUSION: These findings suggest that telomere deficiency is implicated in the CHH disease phenotype through an as yet unidentified mechanism.},
}
@article {pmid28125671,
year = {2017},
author = {Finnicum, CT and Dolan, CV and Willemsen, G and Weber, ZM and Petersen, JL and Beck, JJ and Codd, V and Boomsma, DI and Davies, GE and Ehli, EA},
title = {Relative Telomere Repeat Mass in Buccal and Leukocyte-Derived DNA.},
journal = {PloS one},
volume = {12},
number = {1},
pages = {e0170765},
pmid = {28125671},
issn = {1932-6203},
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Child ; DNA/*genetics/isolation &amp; purification ; DNA Primers/chemistry ; Female ; Humans ; K562 Cells ; Leukocytes, Mononuclear/chemistry/*metabolism ; Male ; Middle Aged ; Mouth Mucosa/chemistry/*metabolism ; Real-Time Polymerase Chain Reaction ; Reference Standards ; Sex Factors ; Siblings ; Telomere/*chemistry ; Twins, Dizygotic ; Twins, Monozygotic ; },
abstract = {Telomere length has garnered interest due to the potential role it may play as a biomarker for the cellular aging process. Telomere measurements obtained from blood-derived DNA are often used in epidemiological studies. However, the invasive nature of blood draws severely limits sample collection, particularly with children. Buccal cells are commonly sampled for DNA isolation and thus may present a non-invasive alternative for telomere measurement. Buccal and leukocyte derived DNA obtained from samples collected at the same time period were analyzed for telomere repeat mass (TRM). TRM was measured in buccal-derived DNA samples from individuals for whom previous TRM data from blood samples existed. TRM measurement was performed by qPCR and was normalized to the single copy 36B4 gene relative to a reference DNA sample (K562). Correlations between TRM from blood and buccal DNA were obtained and also between the same blood DNA samples measured in separate laboratories. Using the classical twin design, TRM heritability was estimated (N = 1892, MZ = 1044, DZ = 775). Buccal samples measured for TRM showed a significant correlation with the blood-1 (R = 0.39, p < 0.01) and blood-2 (R = 0.36, p < 0.01) samples. Sex and age effects were observed within the buccal samples as is the norm within blood-derived DNA. The buccal, blood-1, and blood-2 measurements generated heritability estimates of 23.3%, 47.6% and 22.2%, respectively. Buccal derived DNA provides a valid source for the determination of TRM, paving the way for non-invasive projects, such as longitudinal studies in children.},
}
@article {pmid28123685,
year = {2016},
author = {Kuznetsova, VG and Khabiev, GN and Anokhin, BA},
title = {Cytogenetic study on antlions (Neuroptera, Myrmeleontidae): first data on telomere structure and rDNA location.},
journal = {Comparative cytogenetics},
volume = {10},
number = {4},
pages = {647-656},
pmid = {28123685},
issn = {1993-0771},
abstract = {Myrmeleontidae, commonly known as "antlions", are the most diverse family of the insect order Neuroptera, with over 1700 described species (in 191 genera) of which 37 species (in 21 genera) have so far been studied in respect to standard karyotypes. In the present paper we provide first data on the occurrence of the "insect-type" telomeric repeat (TTAGG) n and location of 18S rDNA clusters in the antlion karyotypes studied using fluorescence in situ hybridization (FISH). We show that males of Palpares libelluloides (Linnaeus, 1764) (Palparinae), Acanthaclisis occitanica (Villers, 1789) (Acanthaclisinae) and Distoleon tetragrammicus (Fabricius, 1798) (Nemoleontinae) have rDNA clusters on a large bivalent, two last species having an additional rDNA cluster on one of the sex chromosomes, most probably the X. (TTAGG) n - containing telomeres are clearly characteristic of Palpares libelluloides and Acanthaclisis occitanica; the presence of this telomeric motif in Distoleon tetragrammicus is questionable. In addition, we detected the presence of the (TTAGG) n telomeric repeat in Libelloides macaronius (Scopoli, 1763) from the family Ascalaphidae (owlflies), a sister group to the Myrmeleontidae. We presume that the "insect" motif (TTAGG) n was present in a common ancestor of the families Ascalaphidae and Myrmeleontidae within the neuropteran suborder Myrmeleontiformia.},
}
@article {pmid28123684,
year = {2016},
author = {Monkheang, P and Chaveerach, A and Sudmoon, R and Tanee, T},
title = {Karyotypic features including organizations of the 5S, 45S rDNA loci and telomeres of Scadoxus multiflorus (Amaryllidaceae).},
journal = {Comparative cytogenetics},
volume = {10},
number = {4},
pages = {637-646},
pmid = {28123684},
issn = {1993-0771},
abstract = {Scadoxus multiflorus Martyn, 1795 is an ornamental plant with brilliantly colored flowers. Even though its chromosomes are rather large, there is no karyotype description reported so far. Therefore, conventional and molecular cytogenetic studies including fluorescence in situ hybridization (FISH) with 45S and 5S rDNA, and human telomere sequence (TTAGGG)n probes (Arabidopsis-type telomere probes yielded negative results) were carried out. The chromosome number is as reported previously, 2n = 18. The nine chromosome pairs include two large submetacentric, five large acrocentric, one medium acrocentric, two small metacentric and eight small submetacentric chromosomes. Hybridization sites of the 45S rDNA signals were on the short arm ends of chromosomes #1, #3 and #8, while 5S rDNA signals appeared on the long arm of chromosome 3, in one homologue as a double signal. The telomere signals were restricted to all chromosome ends. Three chromosome pairs could be newly identified, chromosome pair 3 by 5S rDNA and chromosomes #1, #3 and #8 by 45S rDNA loci. In addition to new information about rDNA locations we show that the ends of Scadoxus multiflorus chromosomes harbor human instead of Arabidopsis-type telomere sequences. Overall, the Scadoxus multiflorus karyotype presents chromosomal heteromorphy concerning size, shape and 45S and 5S rDNA positioning. As Scadoxus Rafinesque, 1838 and related species are poorly studied on chromosomal level the here presented data is important for better understanding of evolution in Amaryllidaceae.},
}
@article {pmid28122333,
year = {2017},
author = {Zou, Y and Leong, W and Yao, M and Hu, X and Lu, S and Zhu, X and Chen, L and Tong, J and Shi, J and Gilson, E and Ye, J and Lu, Y},
title = {Test anxiety and telomere length: Academic stress in adolescents may not cause rapid telomere erosion.},
journal = {Oncotarget},
volume = {8},
number = {7},
pages = {10836-10844},
pmid = {28122333},
issn = {1949-2553},
mesh = {Adolescent ; Anxiety/*psychology ; DNA/genetics/metabolism ; Educational Status ; Female ; Humans ; Male ; Saliva/cytology ; *Stress, Psychological ; Surveys and Questionnaires ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Academic stress (AS) is one of the most important health problems experienced by students, but no biomarker of the potential psychological or physical problems associated with AS has yet been identified. As several cross-sectional studies have shown that psychiatric conditions accelerate aging and shorten telomere length (TL), we explored whether AS affected TL.Between June 2014 and July 2014, we recruited 200 junior high school students with imminent final examinations for participation in this study. The students were divided into three subgroups (mild, moderate, and severe anxiety) using the Sarason Test Anxiety Scale (TAS). Saliva samples were collected for TL measurement via quantitative polymerase chain reaction (qPCR).Students from both a specialized and a general school suffered from anxiety (p > 0.05). A total 35% had severe anxiety (score: 26.09±3.87), 33% had moderate anxiety (16.98±2.64), and 32% had mild anxiety (7.89±1.92). The TAS values differed significantly (p < 0.05) among the three subgroups, but the TLs of saliva cells differed only slightly (p > 0.05): 1.14±0.46 for those with severe anxiety, 1.02±0.40 for those with moderate anxiety, and 1.12±0.45 for those with mild anxiety.Previous reports have found that AS is very common in Asian adolescents. We found no immediate telomere shortening in adolescents with AS. Longitudinal observations are required to determine if TL is affected by AS.},
}
@article {pmid28121388,
year = {2017},
author = {Eisenberg, DTA and Borja, JB and Hayes, MG and Kuzawa, CW},
title = {Early life infection, but not breastfeeding, predicts adult blood telomere lengths in the Philippines.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {29},
number = {4},
pages = {},
pmid = {28121388},
issn = {1520-6300},
support = {P30 ES010126/ES/NIEHS NIH HHS/United States ; P20 RR020649/RR/NCRR NIH HHS/United States ; R01 TW005596/TW/FIC NIH HHS/United States ; P30 DK056350/DK/NIDDK NIH HHS/United States ; R01 DK078150/DK/NIDDK NIH HHS/United States ; },
mesh = {Blood/*metabolism ; *Breast Feeding/statistics &amp; numerical data ; Diarrhea/*epidemiology ; Female ; Humans ; Male ; Morbidity ; Philippines/epidemiology ; Prospective Studies ; *Telomere Homeostasis ; *Telomere Shortening ; Time Factors ; Young Adult ; },
abstract = {OBJECTIVES: Telomeres are repetitive DNA at chromosomes ends that shorten with age due to cellular replication and oxidative stress. As telomeres shorten, this can eventually place limits on cell replication and contribute to senescence. Infections are common during early development and activate cellular immune responses that involve clonal expansion and oxidative stress. As such, a high infectious disease burden might shorten blood telomere length (BTL) and accelerate the pace of immune senescence.<br><br>METHODS: To test this, BTL measured in young adults (21.7&#x2009;&#xb1;&#x2009;0.3 years old) from the Philippines (N&#x2009;=&#x2009;1,759) were linked to prospectively collected early life data on infectious burden.<br><br>RESULTS: As predicted, increased early life diarrheal prevalence was associated with shorter adult BTL. The association was most marked for infections experienced from 6 to 12 months, which corresponds with weaning and maximal diarrheal burden. A standard deviation increase in infections at 6-12 m predicts a 45 bp decrease in BTL, equivalent to 3.3 years of adult telomeric aging in this population. Contrary to expectations, breastfeeding duration was not associated with BTL, nor did effects vary by sex.<br><br>CONCLUSIONS: These findings show that infancy diarrheal disease predicts a marker of cellular aging in adult immune cells. These findings suggest that early life infectious burden may influence late life health, or alternatively, that short TL in early life increases infectious disease susceptibility.},
}
@article {pmid28117327,
year = {2017},
author = {Sagie, S and Toubiana, S and Hartono, SR and Katzir, H and Tzur-Gilat, A and Havazelet, S and Francastel, C and Velasco, G and Chédin, F and Selig, S},
title = {Telomeres in ICF syndrome cells are vulnerable to DNA damage due to elevated DNA:RNA hybrids.},
journal = {Nature communications},
volume = {8},
number = {},
pages = {14015},
pmid = {28117327},
issn = {2041-1723},
support = {R01 GM094299/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line ; Chromosomal Instability/genetics ; DNA/genetics/*metabolism ; DNA Damage/*genetics ; Face/*abnormalities ; Humans ; Immunologic Deficiency Syndromes/blood/*genetics ; Lymphocytes ; Primary Cell Culture ; Primary Immunodeficiency Diseases ; RNA, Long Noncoding/genetics/*metabolism ; Repetitive Sequences, Nucleic Acid/genetics ; Ribonuclease H/metabolism ; Telomere/*genetics ; Telomere Shortening/genetics ; },
abstract = {DNA:RNA hybrids, nucleic acid structures with diverse physiological functions, can disrupt genome integrity when dysregulated. Human telomeres were shown to form hybrids with the lncRNA TERRA, yet the formation and distribution of these hybrids among telomeres, their regulation and their cellular effects remain elusive. Here we predict and confirm in several human cell types that DNA:RNA hybrids form at many subtelomeric and telomeric regions. We demonstrate that ICF syndrome cells, which exhibit short telomeres and elevated TERRA levels, are enriched for hybrids at telomeric regions throughout the cell cycle. Telomeric hybrids are associated with high levels of DNA damage at chromosome ends in ICF cells, which are significantly reduced with overexpression of RNase H1. Our findings suggest that abnormally high TERRA levels in ICF syndrome lead to accumulation of telomeric hybrids that, in turn, can result in telomeric dysfunction.},
}
@article {pmid28111257,
year = {2017},
author = {Barros, AV and Wolski, MA and Nogaroto, V and Almeida, MC and Moreira-Filho, O and Vicari, MR},
title = {Fragile sites, dysfunctional telomere and chromosome fusions: What is 5S rDNA role?.},
journal = {Gene},
volume = {608},
number = {},
pages = {20-27},
doi = {10.1016/j.gene.2017.01.013},
pmid = {28111257},
issn = {1879-0038},
mesh = {Animals ; Chromosomal Instability ; *Chromosome Fragile Sites ; Diploidy ; Evolution, Molecular ; Gene Fusion/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Nucleic Acid Conformation ; RNA, Ribosomal, 5S/*physiology ; Recombination, Genetic/*physiology ; Telomere/genetics/*metabolism ; },
abstract = {Repetitive DNA regions are known as fragile chromosomal sites which present a high flexibility and low stability. Our focus was characterize fragile sites in 5S rDNA regions. The Ancistrus sp. species shows a diploid number of 50 and an indicative Robertsonian fusion at chromosomal pair 1. Two sequences of 5S rDNA were identified: 5S.1 rDNA and 5S.2 rDNA. The first sequence gathers the necessary structures to gene expression and shows a functional secondary structure prediction. Otherwise, the 5S.2 rDNA sequence does not contain the upstream sequences that are required to expression, furthermore its structure prediction reveals a nonfunctional ribosomal RNA. The chromosomal mapping revealed several 5S.1 and 5S.2 rDNA clusters. In addition, the 5S.2 rDNA clusters were found in acrocentric and metacentric chromosomes proximal regions. The pair 1 5S.2 rDNA cluster is co-located with interstitial telomeric sites (ITS). Our results indicate that its clusters are hotspots to chromosomal breaks. During the meiotic prophase bouquet arrangement, double strand breaks (DSBs) at proximal 5S.2 rDNA of acrocentric chromosomes could lead to homologous and non-homologous repair mechanisms as Robertsonian fusions. Still, ITS sites provides chromosomal instability, resulting in telomeric recombination via TRF2 shelterin protein and a series of breakage-fusion-bridge cycles. Our proposal is that 5S rDNA derived sequences, act as chromosomal fragile sites in association with some chromosomal rearrangements of Loricariidae.},
}
@article {pmid28110603,
year = {2017},
author = {Barkovskaya, MS and Bogomolov, AG and Knauer, NY and Rubtsov, NB and Kozlov, VA},
title = {Development of software and modification of Q-FISH protocol for estimation of individual telomere length in immunopathology.},
journal = {Journal of bioinformatics and computational biology},
volume = {15},
number = {2},
pages = {1650041},
doi = {10.1142/S0219720016500414},
pmid = {28110603},
issn = {1757-6334},
mesh = {Arthritis, Rheumatoid/*genetics ; Humans ; Image Processing, Computer-Assisted/*methods ; In Situ Hybridization, Fluorescence/*methods ; *Software ; *Telomere ; Telomere Homeostasis ; },
abstract = {Telomere length is an important indicator of proliferative cell history and potential. Decreasing telomere length in the cells of an immune system can indicate immune aging in immune-mediated and chronic inflammatory diseases. Quantitative fluorescent in situ hybridization (Q-FISH) of a labeled (C3TA[Formula: see text] peptide nucleic acid probe onto fixed metaphase cells followed by digital image microscopy allows the evaluation of telomere length in the arms of individual chromosomes. Computer-assisted analysis of microscopic images can provide quantitative information on the number of telomeric repeats in individual telomeres. We developed new software to estimate telomere length. The MeTeLen software contains new options that can be used to solve some Q-FISH and microscopy problems, including correction of irregular light effects and elimination of background fluorescence. The identification and description of chromosomes and chromosome regions are essential to the Q-FISH technique. To improve the quality of cytogenetic analysis after Q-FISH, we optimized the temperature and time of DNA-denaturation to get better DAPI-banding of metaphase chromosomes. MeTeLen was tested by comparing telomere length estimations for sister chromatids, background fluorescence estimations, and correction of nonuniform light effects. The application of the developed software for analysis of telomere length in patients with rheumatoid arthritis was demonstrated.},
}
@article {pmid28108675,
year = {2017},
author = {Feng, W and Yu, D and Li, B and Luo, OY and Xu, T and Cao, Y and Ding, Y},
title = {Paired assessment of liver telomere lengths in hepatocellular cancer is a reliable predictor of disease persistence.},
journal = {Bioscience reports},
volume = {37},
number = {2},
pages = {},
pmid = {28108675},
issn = {1573-4935},
mesh = {Carcinoma, Hepatocellular/blood/diagnosis/*genetics ; Case-Control Studies ; Disease Progression ; Female ; Hepatitis B/blood/genetics/virology ; Hepatitis C/blood/genetics/virology ; Humans ; Leukocytes/metabolism ; Liver/*metabolism/pathology ; Liver Neoplasms/blood/diagnosis/*genetics ; Male ; Prognosis ; Prospective Studies ; Risk Factors ; Sensitivity and Specificity ; Telomere/*genetics ; Telomere Shortening/genetics ; },
abstract = {In the present study, we used a small series of highly defined patients, where we had matched timed peripheral blood samples (PBS), as well as paired liver biopsies obtained during collection of blood samples from patients with diagnosed hepatocellular carcinoma (HCC) and compared the correlation between the changes of telomere lengths in these defined samples. Patients included had either HCC alone or in conjunction with either pre-existing hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. PCR-based assay incorporating primers to the telomeric hexamer repeats to polymerize and detect telomeric DNA was used. The average telomere length for each independent assessment was measured by seeing the differences in the intensity of the sample's telomere signal (T) to the signal from a single-copy gene (S-, β-globin) to estimate the standard ratio. Our results provide the first convincing evidence that PBS may be utilized to assay telomere shortening as a predictor for disease persistence in HCC resulting after HBV or HCV infection, but not in non-infectious cause-stimulated HCC. These findings provide incipient opportunity to develop telomere length assessment as a biomarker tool for prediction of HCC in patients with HBV or HCV infection, as well as to gauge responses to chemotherapy and other treatment modalities.},
}
@article {pmid28107827,
year = {2017},
author = {},
title = {Telomeres and telomerase.},
journal = {Methods (San Diego, Calif.)},
volume = {114},
number = {},
pages = {1-3},
doi = {10.1016/j.ymeth.2017.01.001},
pmid = {28107827},
issn = {1095-9130},
mesh = {Animals ; Chromosome Structures/genetics ; Humans ; Telomerase/*genetics ; Telomere/*genetics ; Whole Genome Sequencing/methods/trends ; },
}
@article {pmid28104447,
year = {2017},
author = {Kamycheva, E and Goto, T and Camargo, CA},
title = {Celiac disease autoimmunity is associated with leukocyte telomere shortening in older adults: The U.S. National Health and Nutrition Examination Survey.},
journal = {Experimental gerontology},
volume = {89},
number = {},
pages = {64-68},
doi = {10.1016/j.exger.2017.01.003},
pmid = {28104447},
issn = {1873-6815},
mesh = {Aged ; Autoimmunity ; Case-Control Studies ; Celiac Disease/*genetics/*immunology ; Female ; *Genetic Predisposition to Disease ; Humans ; Leukocytes ; Linear Models ; Male ; Middle Aged ; Nutrition Surveys ; Social Class ; Telomere/ultrastructure ; *Telomere Shortening ; United States ; },
abstract = {PURPOSE: Telomeres are nucleotide sequences, and their function is to maintain cell surveillance. Exaggeration of the attrition rate of leukocyte telomere length (LTL) may result in genomic instability and tumorigenesis. Celiac disease (CD), an autoimmune inflammation of small intestine, has increasing prevalence in the elderly and may lead to lymphomas and gastrointestinal malignancies. We used nationally-representative datasets from the U.S. National Health and Nutrition Examination Survey (NHANES) to investigate if CD autoimmunity in older adults (age≥50years) is associated with shorter LTL.<br><br>RESULTS: Our study included 3939 subjects, where 25 subjects (mean age 65years) were CD seropositive and 3914 (mean age 64years) were CD seronegative. CD seropositive subjects had shorter LTL than CD seronegative subjects (P<0.001). In the linear regression model, CD seropositivity was significantly associated with 0.25kb pairs decrease in LTL length (P<0.001), adjusted for age, sex, race/ethnicity, serum ferritin and folate, and ratio of family income to poverty.<br><br>CONCLUSIONS: In a nationally-representative population of adults age&#x2265;50years, CD seropositivity is significantly associated with shorter LTL, independently of age, sex, race/ethnicity, serum ferritin and folate, and socioeconomic status. This supports the enhanced telomere attrition in of CD seropositive adults.},
}
@article {pmid28100466,
year = {2017},
author = {Shadyab, AH and Macera, CA and Shaffer, RA and Jain, S and Gallo, LC and LaMonte, MJ and Reiner, AP and Kooperberg, C and Carty, CL and Di, C and Manini, TM and Hou, L and LaCroix, AZ},
title = {Associations of Accelerometer-Measured and Self-Reported Sedentary Time With Leukocyte Telomere Length in Older Women.},
journal = {American journal of epidemiology},
volume = {185},
number = {3},
pages = {172-184},
pmid = {28100466},
issn = {1476-6256},
support = {HHSN268201100001I/HL/NHLBI NIH HHS/United States ; UL1 TR001412/TR/NCATS NIH HHS/United States ; R01 HL121023/HL/NHLBI NIH HHS/United States ; HHSN268201100004I/HL/NHLBI NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; T32 AR064194/AR/NIAMS NIH HHS/United States ; HHSN268201100003C/WH/WHI NIH HHS/United States ; HHSN268201300007C/HL/NHLBI NIH HHS/United States ; P30 AG028740/AG/NIA NIH HHS/United States ; HHSN271201100004C/AG/NIA NIH HHS/United States ; HHSN268201100002C/WH/WHI NIH HHS/United States ; HHSN268201100002I/HL/NHLBI NIH HHS/United States ; HHSN268201100001C/WH/WHI NIH HHS/United States ; HHSN268201100004C/WH/WHI NIH HHS/United States ; R01 HL105065/HL/NHLBI NIH HHS/United States ; },
mesh = {Accelerometry ; Black or African American ; Aged ; Aged, 80 and over ; Cross-Sectional Studies ; Exercise/*physiology ; Female ; Humans ; Leukocytes/*ultrastructure ; Middle Aged ; *Sedentary Behavior ; Self Report ; Telomere/*ultrastructure ; White People ; },
abstract = {Few studies have assessed the association of sedentary time with leukocyte telomere length (LTL). In a cross-sectional study conducted in 2012-2013, we examined associations of accelerometer-measured and self-reported sedentary time with LTL in a sample of 1,481 older white and African-American women from the Women's Health Initiative and determined whether associations varied by level of moderate- to vigorous-intensity physical activity (MVPA). The association between sedentary time and LTL was evaluated using multiple linear regression models. Women were aged 79.2 (standard deviation, 6.7) years, on average. Self-reported sedentary time was not associated with LTL. In a model adjusting for demographic characteristics, lifestyle behaviors, and health-related factors, among women at or below the median level of accelerometer-measured MVPA, those in the highest quartile of accelerometer-measured sedentary time had significantly shorter LTL than those in the lowest quartile, with an average difference of 170 base pairs (95% confidence interval: 4, 340). Accelerometer-measured sedentary time was not associated with LTL in women above the median level of MVPA. Findings suggest that, on the basis of accelerometer measurements, higher sedentary time may be associated with shorter LTL among less physically active women.},
}
@article {pmid28096526,
year = {2017},
author = {Maciejowski, J and de Lange, T},
title = {Telomeres in cancer: tumour suppression and genome instability.},
journal = {Nature reviews. Molecular cell biology},
volume = {18},
number = {3},
pages = {175-186},
pmid = {28096526},
issn = {1471-0080},
support = {R01 CA181090/CA/NCI NIH HHS/United States ; R56 AG016642/AG/NIA NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; K99 CA212290/CA/NCI NIH HHS/United States ; R00 CA212290/CA/NCI NIH HHS/United States ; },
mesh = {Chromothripsis ; *Genomic Instability ; Humans ; Neoplasms/*genetics/prevention &amp; control ; Telomerase/genetics/metabolism ; Telomere/*physiology ; Telomere Shortening ; },
abstract = {The shortening of human telomeres has two opposing effects during cancer development. On the one hand, telomere shortening can exert a tumour-suppressive effect through the proliferation arrest induced by activating the kinases ATM and ATR at unprotected chromosome ends. On the other hand, loss of telomere protection can lead to telomere crisis, which is a state of extensive genome instability that can promote cancer progression. Recent data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomere crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization.},
}
@article {pmid28088627,
year = {2017},
author = {Lee, WP and Lan, KH and Li, CP and Chao, Y and Hou, MC and Lin, HC and Lee, SD},
title = {The telomere-binding protein TRF2 is required for metronomic therapeutic effects of gemcitabine and capecitabine.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {1863},
number = {4},
pages = {917-928},
doi = {10.1016/j.bbadis.2017.01.008},
pmid = {28088627},
issn = {0925-4439},
mesh = {*Administration, Metronomic ; Animals ; Capecitabine/*pharmacology ; Cell Line, Tumor ; Deoxycytidine/*analogs &amp; derivatives/pharmacology ; Drug Resistance/*drug effects/genetics ; Female ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; Mice ; Mice, Nude ; Neoplasm Proteins ; Ovarian Neoplasms/*drug therapy/genetics/metabolism ; Telomere Homeostasis/*drug effects/genetics ; Telomeric Repeat Binding Protein 2/*biosynthesis/genetics ; Gemcitabine ; },
abstract = {Gemcitabine and capecitabine are two effective anticancer agents against solid tumors. The pharmacological mechanisms have been known as incorporation into DNA and thereby inhibition of DNA synthesis. When used as metronomic chemotherapy, they may inhibit angiogenesis and induce immunity. In our previous study, we showed that low-dose gemcitabine caused telomere shortening by stabilizing TRF2 that was required for XPF-dependent telomere loss. In this report, we established a SKOV3.ip1 ascites cell model. Tumor-bearing mice were treated with low-dose gemcitabine (GEM) or capecitabine (CAP). Both GEM and CAP caused telomere shortening and increased expression of TRF2 with improved ascites in nude mice and decreased in vitro clonogenic activity. TRF2 knockdown altered telomeres to a shortened but new status that may evade XPF-dependent telomere loss and conferred resistance of SKOV3.ip1 ascites cells to low-dose GEM and CAP. Our study provides a new mechanism of metronomic chemotherapy i.e. TRF2 is required for metronomic therapeutic effects of gemcitabine and capecitabine.},
}
@article {pmid28083855,
year = {2017},
author = {Riestra, P and Gebreab, SY and Xu, R and Khan, RJ and Quarels, R and Gibbons, G and Davis, SK},
title = {Obstructive sleep apnea risk and leukocyte telomere length in African Americans from the MH-GRID study.},
journal = {Sleep &amp; breathing = Schlaf &amp; Atmung},
volume = {21},
number = {3},
pages = {751-757},
pmid = {28083855},
issn = {1522-1709},
support = {1RC4MD005964-01//National Institute on Minority Health and Health Disparities/ ; },
mesh = {Adult ; Black or African American/*genetics ; Case-Control Studies ; Female ; Humans ; *Leukocytes ; Male ; Middle Aged ; Risk Assessment ; Sleep Apnea, Obstructive/*genetics ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {PURPOSE: Shorter telomere length and obstructive sleep apnea are associated with increased oxidative stress and chronic inflammation, which are both considered leading causes of age-related diseases. Different forms of sleep disordered breathing have been linked to telomere length although their relationship remains uncertain. The purpose of this study was to explore the associations between the risk of obstructive sleep apnea and telomere length in African Americans.<br><br>METHODS: The analysis included 184 women and 122 men aged 30-55&#xa0;years from the Morehouse School of Medicine Study. Relative TL (T/S ratio) was measured from peripheral blood leukocytes using quantitative real-time polymerase chain reaction. The Berlin questionnaire was used for OSA risk assessments. Multivariable linear regression models were used to examine the associations between OSA risk and LTL.<br><br>RESULTS: We observed that LTL varied by OSA risk in women (0.532&#xa0;&#xb1;&#xa0;0.006 vs. 0.569&#xa0;&#xb1;&#xa0;0.008) (p&#xa0;=&#xa0;0.04). Multiple linear regression analysis confirmed that women at higher risk for OSA presented shorter LTL compared to those at lower risk, independent of age, income, education, obesity, smoking, alcohol consumption, and hypertension. These differences were not observed in men.<br><br>CONCLUSIONS: Our findings suggest that OSA risk may contribute to the acceleration of cellular aging processes through telomere shortening.},
}
@article {pmid28082411,
year = {2017},
author = {Li, JS and Miralles Fusté, J and Simavorian, T and Bartocci, C and Tsai, J and Karlseder, J and Lazzerini Denchi, E},
title = {TZAP: A telomere-associated protein involved in telomere length control.},
journal = {Science (New York, N.Y.)},
volume = {355},
number = {6325},
pages = {638-641},
pmid = {28082411},
issn = {1095-9203},
support = {P30 CA014195/CA/NCI NIH HHS/United States ; R01 CA174942/CA/NCI NIH HHS/United States ; R01 GM087476/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; DNA-Binding Proteins/genetics/*metabolism ; Gene Knockout Techniques ; Humans ; Protein Binding ; Tandem Repeat Sequences ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; Transcription Factors/genetics/*metabolism ; *Zinc Fingers ; },
abstract = {Telomeres are found at the end of chromosomes and are important for chromosome stability. Here we describe a specific telomere-associated protein: TZAP (telomeric zinc finger-associated protein). TZAP binds preferentially to long telomeres that have a low concentration of shelterin complex, competing with the telomeric-repeat binding factors TRF1 and TRF2. When localized at telomeres, TZAP triggers a process known as telomere trimming, which results in the rapid deletion of telomeric repeats. On the basis of these results, we propose a model for telomere length regulation in mammalian cells: The reduced concentration of the shelterin complex at long telomeres results in TZAP binding and initiation of telomere trimming. Binding of TZAP to long telomeres represents the switch that triggers telomere trimming, setting the upper limit of telomere length.},
}
@article {pmid28082393,
year = {2017},
author = {Min, J and Wright, WE and Shay, JW},
title = {Alternative lengthening of telomeres can be maintained by preferential elongation of lagging strands.},
journal = {Nucleic acids research},
volume = {45},
number = {5},
pages = {2615-2628},
pmid = {28082393},
issn = {1362-4962},
support = {R01 AG001228/AG/NIA NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; },
mesh = {Cell Death ; Cell Line ; Cell Line, Tumor ; DNA Helicases/antagonists &amp; inhibitors ; Gene Knockout Techniques ; Humans ; Neoplasms/*genetics/metabolism ; Nuclear Proteins/antagonists &amp; inhibitors ; RNA/genetics ; S Phase/genetics ; Telomerase/genetics/metabolism ; Telomere/chemistry/*metabolism ; *Telomere Homeostasis ; X-linked Nuclear Protein ; },
abstract = {Alternative lengthening of telomeres (ALT) is a telomerase independent telomere maintenance mechanism that occurs in ∼15% of cancers. The potential mechanism of ALT is homology-directed telomere synthesis, but molecular mechanisms of how ALT maintains telomere length in human cancer is poorly understood. Here, we generated TERC (telomerase RNA) gene knockouts in telomerase positive cell lines that resulted in long-term surviving clones acquiring the ALT pathway but at a very low frequency. By comparing these ALT cells with parental telomerase positive cells, we observed that ALT cells possess excessively long telomeric overhangs derived from telomere elongation processes that mostly occur during S phase. ALT cells exhibited preferential elongation of the telomeric lagging strands, whereas telomerase positive cells exhibited similar elongation between leading and lagging strands. We propose that the ALT pathway preferentially occurs at telomeric lagging strands leading to heterogeneous telomere lengths observed in most ALT cancers.},
}
@article {pmid28076340,
year = {2017},
author = {Kłoda, K and Domański, L and Mierzecki, A},
title = {Telomere Length Assessment for Prediction of Organ Transplantation Outcome. Future or Failure: A Review of the Literature.},
journal = {Medical science monitor : international medical journal of experimental and clinical research},
volume = {23},
number = {},
pages = {158-162},
pmid = {28076340},
issn = {1643-3750},
mesh = {Graft Rejection/*etiology ; Humans ; Organ Transplantation/*adverse effects ; *Telomere Shortening ; Transplantation, Homologous ; Treatment Outcome ; },
abstract = {Telomeres are located at each end of eukaryotic chromosomes. Their functional role is genomic stability maintenance. The protective role of telomeres depends on various factors, including number of nucleotides repeats, telomere-binding proteins, and telomerase activity. Organ transplantation is the preferred replacement therapy in the case of chronic kidney disease and the only possibility of sustaining recipients' life in the case of advanced liver failure. While the prevalence of acute rejection is constantly decreasing, prevention of transplanted organ long-term function loss is still challenging. It has been demonstrated that post-transplant stressors accelerate aging of the allografts manifested through telomere shortening. The aim of this paper was to evaluate the importance of telomere length assessment for prediction of organ transplantation outcome. Literature review included the 10 most important studies regarding linkage between allograft function and telomere erosion, including 2 of our own reports. Telomere length assessment is useful to predict organ transplantation outcome. The importance of telomere length as a prediction marker depends on the analyzed material. To obtain reliable results, both graft cells (donor material) and lymphocytes (recipient material) should be examined. In the case of kidney transplantation, assessment of telomere length in the early post-transplant period allows prediction of the long-term function of the transplanted organ. To increase the accuracy of transplantation outcome prediction, telomere length assessment should be combined with evaluation of other aging biomarkers, like CDKN2A (p16). Large-scale clinical studies regarding telomere length measurement, including genome wide association analysis introducing relevant genetic factors, are needed for the future.},
}
@article {pmid28070423,
year = {2016},
author = {Weber, KA and Heaphy, CM and Rohrmann, S and Gonzalez, B and Bienstock, JL and Agurs-Collins, T and Platz, EA and Meeker, AK},
title = {Influence of In Utero Maternal and Neonate Factors on Cord Blood Leukocyte Telomere Length: Clues to the Racial Disparity in Prostate Cancer?.},
journal = {Prostate cancer},
volume = {2016},
number = {},
pages = {3691650},
pmid = {28070423},
issn = {2090-3111},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; F32 CA093140/CA/NCI NIH HHS/United States ; T32 CA009314/CA/NCI NIH HHS/United States ; U54 CA091409/CA/NCI NIH HHS/United States ; U54 CA091431/CA/NCI NIH HHS/United States ; },
abstract = {Background. Modifiable factors in adulthood that explain the racial disparity in prostate cancer have not been identified. Because racial differences in utero that may account for this disparity are understudied, we investigated the association of maternal and neonate factors with cord blood telomere length, as a cumulative marker of cell proliferation and oxidative damage, by race. Further, we evaluated whether cord blood telomere length differs by race. Methods. We measured venous umbilical cord blood leukocyte relative telomere length by qPCR in 38 black and 38 white full-term male neonates. Using linear regression, we estimated geometric mean relative telomere length and tested for differences by race. Results. Black mothers were younger and had higher parity and black neonates had lower birth and placental weights. These factors were not associated with relative telomere length, even after adjusting for or stratifying by race. Relative telomere length in black (2.72) and white (2.73) neonates did not differ, even after adjusting for maternal or neonate factors (all p > 0.9). Conclusions. Maternal and neonate factors were not associated with cord blood telomere length, and telomere length did not differ by race. These findings suggest that telomere length at birth does not explain the prostate cancer racial disparity.},
}
@article {pmid28070333,
year = {2017},
author = {Sebastiano, M and Eens, M and Angelier, F and Pineau, K and Chastel, O and Costantini, D},
title = {Corticosterone, inflammation, immune status and telomere length in frigatebird nestlings facing a severe herpesvirus infection.},
journal = {Conservation physiology},
volume = {5},
number = {1},
pages = {cow073},
pmid = {28070333},
issn = {2051-1434},
abstract = {Herpesvirus outbreaks are common in natural animal populations, but little is known about factors that favour the infection and its consequences for the organism. In this study, we examined the pathophysiological consequences of a disease probably attributable to herpesvirus infection for several markers of immune function, corticosterone, telomere length and inflammation. In addition, we assessed whether any markers used in this study might be associated with the occurrence of visible clinical signs of the disease and its impact on short-term survival perspectives. To address our questions, in spring 2015, we collected blood samples from nestlings of the magnificent frigatebird (Fregata magnificens) that were free of any clinical signs or showed visible signs of the disease. We found that the plasma concentration of haptoglobin was strongly associated with the infection status and could predict probabilities of survival. We also found that nestlings with clinical signs had lower baseline corticosterone concentrations and similar telomere length compared with healthy nestlings, whereas we did not find any association of the infection status with innate immune defenses or with nitric oxide concentration. Overall, our results suggest that the plasma concentration of haptoglobin might be a valuable tool to assess survival probabilities of frigatebird nestlings facing a herpesvirus outbreak.},
}
@article {pmid28064387,
year = {2017},
author = {Lee, J and Solomon, DA and Tihan, T},
title = {The role of histone modifications and telomere alterations in the pathogenesis of diffuse gliomas in adults and children.},
journal = {Journal of neuro-oncology},
volume = {132},
number = {1},
pages = {1-11},
pmid = {28064387},
issn = {1573-7373},
support = {DP5 OD021403/OD/NIH HHS/United States ; P50 CA097257/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Animals ; Brain Neoplasms/*genetics/pathology ; Child ; DNA Methylation ; Glioma/*genetics/pathology ; Histone Code ; Histones/*genetics ; Humans ; Telomere/*genetics ; X-linked Nuclear Protein/genetics ; },
abstract = {Genetic profiling is an increasingly useful tool for sub-classification of gliomas in adults and children. Specific gene mutations, structural rearrangements, DNA methylation patterns, and gene expression profiles are now recognized to define molecular subgroups of gliomas that arise in distinct anatomic locations and patient age groups, and also provide a better prediction of clinical outcomes for glioma patients compared to histologic assessment alone. Understanding the role of these distinctive genetic alterations in gliomagenesis is also important for the development of potential targeted therapeutic interventions. Mutations including K27M and G34R/V that affect critical amino acids within the N-terminal tail of the histone H3 variants, H3.3 and H3.1 (encoded by H3F3A and HIST1H3B genes), are prime examples of mutations in diffuse gliomas with characteristic clinical associations that can help diagnostic classification and guide effective patient management. These histone H3 mutations frequently co-occur with inactivating mutations in ATRX in association with alternative lengthening of telomeres. Telomere length can also be maintained through upregulation of telomerase reverse transcriptase (TERT) expression driven by mutation within the TERT gene promoter region, an alteration most commonly found in oligodendrogliomas and primary glioblastomas arising in adults. Interestingly, the genetic alterations perturbing histone and telomere function in pediatric gliomas tend to be different from those present in adult tumors. We present a review of these mutations affecting the histone code and telomere length, highlighting their importance in prognosis and as targets for novel therapeutics in the treatment of diffuse gliomas.},
}
@article {pmid28058238,
year = {2017},
author = {Edwards, MK and Loprinzi, PD},
title = {Sedentary behavior, physical activity and cardiorespiratory fitness on leukocyte telomere length.},
journal = {Health promotion perspectives},
volume = {7},
number = {1},
pages = {22-27},
pmid = {28058238},
issn = {2228-6497},
abstract = {Background: Emerging work is starting to investigate the cumulative effects of moderate-to-vigorous physical activity (MVPA), sedentary behavior and cardiorespiratory fitness on health. The objective of this study was to examine the cumulative and independent associations of MVPA, sedentary behavior and cardiorespiratory fitness on leukocyte telomere length (LTL). Methods: Data from the 1999-2002 National Health and Nutrition Examination Survey (NHANES) were used (N = 1868 adults 20+ years); analyzed in 2016. Sedentary behavior and MVPA were subjectively assessed with cardiorespiratory fitness determined from a submaximal treadmill-based test; participants were classified as above or below the median values for each of these three parameters. A blood sample was obtained from each participant to assess LTL via quantitative polymerase chain reaction, with participants grouped into LTL tertiles. Results: Participants who engaged in higher MVPA, sat less and had higher cardiorespiratory fitness had an increased odds (ranging from 85% to 105%) of being in LTL tertile 3 (vs. 1). In an extended adjusted multinomial logistic regression model, only MVPA was positively associated with LTL (odds ration [OR] = 1.37; 95% CI: 0.99-1.90; P = 0.05). Conclusion: All three behavior characteristics, but particularly MVPA, may be important in preserving LTLs.},
}
@article {pmid28057933,
year = {2017},
author = {Zhang, S and Ji, G and Liang, Y and Zhang, R and Shi, P and Guo, D and Li, C and Feng, J and Liu, F and Peng, R and Chen, M},
title = {Polymorphisms in Telomere Length Associated TERC and TERT predispose for Ischemic Stroke in a Chinese Han population.},
journal = {Scientific reports},
volume = {7},
number = {},
pages = {40151},
pmid = {28057933},
issn = {2045-2322},
mesh = {Asian People/genetics ; Brain Ischemia/complications/*genetics ; China ; DNA Helicases/genetics ; Humans ; Leukocytes/*metabolism ; *Polymorphism, Single Nucleotide ; RNA/*genetics ; Stroke/complications/*genetics ; Telomerase/*genetics ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {The role of telomere in genomic stability is an established fact. Variation in leukocyte telomere length (LTL) has been considered a crucial factor that associated with age-associated diseases. To elucidate the association between LTL variation and ischemic stroke (IS) risk, we selected ten single nucleotide polymorphisms (SNPs) in three genes (TERC, TERT and RTEL1) that previously reported link to LTL, and genotyped SNPs of these genes in a case-control study. The association between polymorphisms and IS risk were tested by Chi squared test and haplotype analysis. In allele association analysis, allele "C" in rs10936599 of TERC gene and allele "G" in rs2853677 of TERT gene were found to have an increased risk of IS when compared with allele "T" and "A", respectively. Model association analysis showed that genotype "G/A" in the overdominant model and genotypes "G/A" and "A/A" in the dominant model of rs2242652 presented a more likelihood to have IS. Another TERT locus (rs2853677) with genotype "G" was also found IS-related risky in the log-additive model. Taken together, our results suggest a potential association between LTL related TERC, TERT gene variants and ischemic stroke risk.},
}
@article {pmid28056862,
year = {2017},
author = {Naing, C and Aung, K and Lai, PK and Mak, JW},
title = {Association between telomere length and the risk of colorectal cancer: a meta-analysis of observational studies.},
journal = {BMC cancer},
volume = {17},
number = {1},
pages = {24},
pmid = {28056862},
issn = {1471-2407},
mesh = {Colorectal Neoplasms/*genetics ; Humans ; Observational Studies as Topic ; Odds Ratio ; Telomere/*pathology ; },
abstract = {BACKGROUND: Human chromosomes are capped and stabilized by telomeres. Telomere length regulates a 'cellular mitotic clock' that defines the number of cell divisions and hence, cellular life span. This study aimed to synthesize the evidence on the association between peripheral blood leucocytes (PBL) telomere length and the risk of colorectal cancer (CRC).<br><br>METHODS: We searched relevant studies in electronic databases. When two or more observational studies reported the same outcome measures, we performed pooled analysis. All the analyses were performed on PBL using PCR. The odds ratio (OR) and its 95% confidence interval (CI) were used to assess the strength of association.<br><br>RESULTS: Seven studies (with 8 datasets) were included in this meta-analysis; 3 prospective studies, 3 retrospective studies and 1 study with a separate prospective and retrospective designs. The pooled analysis of 4 prospective studies (summary OR 1.01, 95% CI: 0.77-1.34, I [2]:30%) and 4 retrospective studies (summary OR 1.65, 95% CI: 0.96-2.83, I [2]:96%) showed no relationship between PBL telomere length and the CRC risk. A subgroup analysis of 2 prospective studies exclusively on females also showed no association between PBL telomere length and the CRC risk (summary OR, 1.17, 95% CI:0.72-1.91, I [2]:57%).<br><br>CONCLUSION: The current analysis is insufficient to provide evidence on the relationship between PBL telomere length and the risk of CRC. Findings suggest that there may be a complex relationship between PBL telomere length and the CRC risk or discrepancy between genetics, age of patients and clinical studies. Future well powered, large prospective studies on the relationship between telomere length and the risk of CRC, and the investigations of the biologic mechanisms are recommended.},
}
@article {pmid28055115,
year = {2017},
author = {Henning, AL and Levitt, DE and Vingren, JL and McFarlin, BK},
title = {Measurement of T-Cell Telomere Length Using Amplified-Signal FISH Staining and Flow Cytometry.},
journal = {Current protocols in cytometry},
volume = {79},
number = {},
pages = {7.47.1-7.47.10},
doi = {10.1002/cpcy.11},
pmid = {28055115},
issn = {1934-9300},
mesh = {Cell Membrane/metabolism ; Flow Cytometry/*methods ; Humans ; In Situ Hybridization, Fluorescence/*methods ; *Staining and Labeling ; T-Lymphocytes/*metabolism ; Telomere/*metabolism ; },
abstract = {Exposure to pathogen-associated molecular patterns (PAMPS), damage-associated molecular patterns (DAMPS), and physiologically challenging stimuli either positively or negatively affect leukocyte maturity. Cellular maturity has implications for the effectiveness of host response to bacterial or viral infection and/or tissue injury. Thus, the ability to accurately assess cellular maturity and health is important to fully understand immune status and function. The most common technique for measuring cellular maturity is to measure telomere length; however, existing techniques are not optimized for single-cell measurements using flow cytometry. Specifically, existing methods used to measure telomere length are PCR-based, making it difficult for a researcher to measure maturity within specific leukocyte subsets (e.g., T cells). In this report, we describe a new approach for the measurement of telomere length within individual T cells using an amplified fluorescence in situ hybridization (FISH) technique (PrimeFlow RNA Assay). The unique aspect of this technique is that it amplifies the fluorescent signal rather than the target up to 3000-fold, resulting in the detection of as few as 1 copy of the target nucleic acid. While the current technique focuses on human T cells, this method can be broadly applied to a variety of cell types and disease models. © 2017 by John Wiley &amp; Sons, Inc.},
}
@article {pmid28055113,
year = {2017},
author = {Kelesidis, T and Schmid, I},
title = {Assessment of Telomere Length, Phenotype, and DNA Content.},
journal = {Current protocols in cytometry},
volume = {79},
number = {},
pages = {7.26.1-7.26.23},
pmid = {28055113},
issn = {1934-9300},
support = {R21 HL134444/HL/NHLBI NIH HHS/United States ; UL1 TR000124/TR/NCATS NIH HHS/United States ; K08 AI108272/AI/NIAID NIH HHS/United States ; P30 CA016042/CA/NCI NIH HHS/United States ; P30 AI028697/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; DNA/*analysis ; Flow Cytometry/*methods ; Fluorescent Antibody Technique ; Humans ; Immunophenotyping ; In Situ Hybridization, Fluorescence ; Phenotype ; Ploidies ; Telomere/*chemistry ; },
abstract = {Telomere sequences at the end of chromosomes control somatic cell division; therefore, telomere length in a given cell population provides information about its replication potential. This unit describes a method for flow cytometric measurement of telomere length in subpopulations using fluorescence in situ hybridization of fluorescently-labeled probes (Flow-FISH) without prior cell separation. After cells are stained for surface immunofluorescence, antigen-antibody complexes are covalently cross-linked onto cell membranes before FISH with a telomere-specific probe. Cells with long telomeres are included as internal standards. Addition of a DNA dye permits exclusion of proliferating cells during data analysis. DNA ploidy measurements of cells of interest and internal standard are performed on separate aliquots in parallel to Flow-FISH. Telomere fluorescence of G0/1 cells of subpopulations and internal standards obtained from Flow-FISH are normalized for DNA ploidy, and telomere length in subsets of interest is expressed as a fraction of the internal standard telomere length. © 2017 by John Wiley &amp; Sons, Inc.},
}
@article {pmid28052260,
year = {2017},
author = {Erdel, F and Kratz, K and Willcox, S and Griffith, JD and Greene, EC and de Lange, T},
title = {Telomere Recognition and Assembly Mechanism of Mammalian Shelterin.},
journal = {Cell reports},
volume = {18},
number = {1},
pages = {41-53},
pmid = {28052260},
issn = {2211-1247},
support = {P01 CA019014/CA/NCI NIH HHS/United States ; R01 GM082848/GM/NIGMS NIH HHS/United States ; P30 CA016086/CA/NCI NIH HHS/United States ; R01 GM031819/GM/NIGMS NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; R35 GM118026/GM/NIGMS NIH HHS/United States ; F30 ES013373/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; DNA/metabolism ; Diffusion ; HEK293 Cells ; Humans ; Kinetics ; Mammals/*metabolism ; Multiprotein Complexes/metabolism ; Protein Binding ; Repetitive Sequences, Nucleic Acid ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; rap1 GTP-Binding Proteins/metabolism ; },
abstract = {Shelterin is a six-subunit protein complex that plays crucial roles in telomere length regulation, protection, and maintenance. Although several shelterin subunits have been studied in vitro, the biochemical properties of the fully assembled shelterin complex are not well defined. Here, we characterize shelterin using ensemble biochemical methods, electron microscopy, and single-molecule imaging to determine how shelterin recognizes and assembles onto telomeric repeats. We show that shelterin complexes can exist in solution and primarily locate telomeric DNA through a three-dimensional diffusive search. Shelterin can diffuse along non-telomeric DNA but is impeded by nucleosomes, arguing against extensive one-dimensional diffusion as a viable assembly mechanism. Our work supports a model in which individual shelterin complexes rapidly bind to telomeric repeats as independent functional units, which do not alter the DNA-binding mode of neighboring complexes but, rather, occupy telomeric DNA in a "beads on a string" configuration.},
}
@article {pmid28050886,
year = {2017},
author = {Ramirez, J and Elmofty, M and Castillo, E and DeRouen, M and Shariff-Marco, S and Allen, L and Gomez, SL and Nápoles, AM and Márquez-Magaña, L},
title = {Evaluation of cortisol and telomere length measurements in ethnically diverse women with breast cancer using culturally sensitive methods.},
journal = {Journal of community genetics},
volume = {8},
number = {2},
pages = {75-86},
pmid = {28050886},
issn = {1868-310X},
support = {P30 AG015272/AG/NIA NIH HHS/United States ; RL5 GM118984/GM/NIGMS NIH HHS/United States ; TL4 GM118986/GM/NIGMS NIH HHS/United States ; UL1 GM118985/GM/NIGMS NIH HHS/United States ; },
abstract = {The under-representation of ethnic minority participants, who are more likely to be socially disadvantaged in biomedical research, limits generalizability of results and reductions in health disparities. To facilitate investigations of how social disadvantage "gets under the skin," this pilot study evaluated low-intensity methods for collecting hair and saliva samples from multiethnic breast cancer survivors (N = 70) and analysis of biomarkers of chronic stress (cortisol levels) and biological age (telomere length). Methods allowed for easy self-collection of hair (for cortisol) and saliva (for telomere lengths) samples that were highly stable for shipment and long-term storage. Measuring cortisol in hair as a biomarker of chronic stress was found to overcome many of the limitations of salivary cortisol measurements, and the coefficient of variation obtained using an ELISA-based approach to measure cortisol was within acceptable standards (16%). Telomere length measurements obtained using a qPCR approach had a coefficient of variation of <10% when the DNA extracted from the saliva biospecimens was of sufficient quantity and quality (84%). The overall response rate was 47%; rates were 32% for African-Americans, 39% for Latinas, 40% for Asians, and 82% for non-Latina Whites. Self-collection of hair and saliva overcame cultural and logistical barriers associated with collection of blood. Results support the use of these biospecimen collection and analysis methods among ethnically diverse and disadvantaged populations to identify biopsychosocial pathways of health disparities. Our tools should stimulate research to better understand how social disadvantage "gets under the skin" and increase participation of ethnic minorities in biomedical research.},
}
@article {pmid28049172,
year = {2017},
author = {de-Torres, JP and Sanchez-Salcedo, P and Bastarrika, G and Alcaide, AB and Pío, R and Pajares, MJ and Campo, A and Berto, J and Montuenga, L and Del Mar Ocon, M and Monente, C and Celli, BR and Zulueta, JJ},
title = {Telomere length, COPD and emphysema as risk factors for lung cancer.},
journal = {The European respiratory journal},
volume = {49},
number = {1},
pages = {},
doi = {10.1183/13993003.01521-2016},
pmid = {28049172},
issn = {1399-3003},
mesh = {Adult ; Aged ; Case-Control Studies ; Female ; Humans ; Lung Neoplasms/*complications/genetics ; Male ; Middle Aged ; Proportional Hazards Models ; Prospective Studies ; Pulmonary Disease, Chronic Obstructive/*complications/genetics ; Pulmonary Emphysema/*complications/genetics ; Risk Factors ; Smoking ; Spirometry ; Telomere/*ultrastructure ; *Telomere Shortening ; Vital Capacity ; },
}
@article {pmid28046023,
year = {2017},
author = {Crefcoeur, RP and Zgheib, O and Halazonetis, TD},
title = {A Model to Investigate Single-Strand DNA Responses in G1 Human Cells via a Telomere-Targeted, Nuclease-Deficient CRISPR-Cas9 System.},
journal = {PloS one},
volume = {12},
number = {1},
pages = {e0169126},
pmid = {28046023},
issn = {1932-6203},
mesh = {CRISPR-Cas Systems/*genetics ; Cell Line, Tumor ; Cell Separation ; Clustered Regularly Interspaced Short Palindromic Repeats ; DNA Repair ; *DNA Replication ; DNA, Single-Stranded/*genetics ; Deoxyribonucleases/metabolism ; Flow Cytometry ; G1 Phase ; Humans ; Plasmids/metabolism ; Telomere/*ultrastructure ; },
abstract = {DNA replication stress has the potential to compromise genomic stability and, therefore, cells have developed elaborate mechanisms to detect and resolve problems that may arise during DNA replication. The presence of single-stranded DNA (ssDNA) is often associated with DNA replication stress and serves as a signal for both checkpoint and repair responses. In this study, we exploited a CRISPR-Cas9 system to induce regions of ssDNA in the genome. Specifically, single-guide RNAs bearing sequence complementarity to human telomeric repeats, were used to target nuclease-deficient Cas9 (dCas9) to telomeres. Such targeting was associated with the formation of DNA-RNA hybrids, leaving one telomeric DNA strand single-stranded. This ssDNA then recruited DNA repair and checkpoint proteins, such as RPA, ATRIP, BLM and Rad51, at the telomeres. Interestingly, targeting of all these proteins to telomeric ssDNA was observed even in cells that were in the G1 phase of the cell cycle. Therefore, this system has the potential to serve as a platform for further investigation of DNA replication stress responses at specific loci in the human genome and in all phases of the cell cycle.},
}
@article {pmid28040793,
year = {2017},
author = {Brügger, F and Dettmer, MS and Neuenschwander, M and Perren, A and Marinoni, I and Hewer, E},
title = {TERT Promoter Mutations but not the Alternative Lengthening of Telomeres Phenotype Are Present in a Subset of Ependymomas and Are Associated With Adult Onset and Progression to Ependymosarcoma.},
journal = {Journal of neuropathology and experimental neurology},
volume = {76},
number = {1},
pages = {61-66},
doi = {10.1093/jnen/nlw106},
pmid = {28040793},
issn = {1554-6578},
mesh = {Adolescent ; Adult ; Age of Onset ; Aged ; Child ; Child, Preschool ; *Disease Progression ; Ependymoma/diagnosis/*genetics ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Mutation/*genetics ; *Phenotype ; Promoter Regions, Genetic/genetics ; Telomerase/*genetics ; Telomere/genetics ; Telomere Homeostasis/*genetics ; Young Adult ; },
abstract = {Genetic signatures related to telomere maintenance have emerged as powerful classifiers among CNS tumors. These include the alternative lengthening of telomeres (ALT) phenotype associated with mutations in the ATRX and DAXX genes and recurrent point mutations in the TERT gene promoter. We investigated a patient cohort covering the entire spectrum of childhood and adult ependymomas (n = 128), including subependymomas and myxopapillary ependymomas, for the presence of TERT promoter mutations, for loss of ATRX or DAXX expression by immunohistochemistry (as surrogates as underlying gene mutations), and for the ALT phenotype by fluorescence in situ hybridization (FISH). TERT promoter mutations were identified in 9/120 (7%) of tumors, all of which were conventional ependymomas occurring in adults. TERT promoter mutations were associated with older age and intracranial localization. Remarkably, 2 of these tumors progressed to ependymosarcoma upon recurrence. No tumors displayed an ALT phenotype by FISH or were ATRX or DAXX deficient by immunohistochemistry. In sum, TERT promoter mutations are present in a subset of mostly intracranial conventional ependymomas in adults and may be relevant for the uncommon progression to ependymosarcoma. Loss of ATRX immunoreactivity is a useful marker to rule out ependymoma in specific diagnostic settings.},
}
@article {pmid28039478,
year = {2017},
author = {Liu, F and Zhang, Z and Zhang, Y and Chen, Y and Yang, X and Li, J and Zhao, J},
title = {Genetic polymorphisms in the telomere length-related gene ACYP2 are associated with the risk of colorectal cancer in a Chinese Han population.},
journal = {Oncotarget},
volume = {8},
number = {6},
pages = {9849-9857},
pmid = {28039478},
issn = {1949-2553},
mesh = {Acid Anhydride Hydrolases/*genetics ; Adult ; Asian People/genetics ; Biomarkers, Tumor/*genetics ; Case-Control Studies ; Chi-Square Distribution ; China ; Colorectal Neoplasms/ethnology/*genetics/pathology ; Female ; Gene Frequency ; Genetic Association Studies ; Genetic Predisposition to Disease ; Haplotypes ; Heterozygote ; Homozygote ; Humans ; Logistic Models ; Male ; Middle Aged ; Odds Ratio ; Phenotype ; *Polymorphism, Single Nucleotide ; Risk Assessment ; Risk Factors ; Telomere/*pathology ; Telomere Homeostasis/*genetics ; },
abstract = {We investigated the association between single nucleotide polymorphisms (SNPs) in ACYP2, which has been associated with telomere length in several types of cancer, and the risk of CRC in a Chinese Han population. In a case-control study that included 247 cases and 300 healthy controls, 14 SNPs in ACYP2 were selected and genotyped using the Sequenom MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression after adjusting for age and gender. We determined that rs843711 and rs843706 were associated with an increased risk of CRC (rs843711: OR = 1.376, 95% CI = 1.082-1.749, p = 0.009; rs843706: OR = 1.361, 95% CI = 1.069-1.733, p = 0.012). Additionally, rs6713088, rs843645, rs843711, and rs843706 were associated with an increased risk of CRC under additive and recessive models (p < 0.05). Finally, the "TTCTCGCC" and "CG" haplotypes decreased the risk of CRC, while the "AG" haplotype increase the risk of CRC. The association between rs843711 and CRC remained significant after Bonferroni correction for multiple comparisons (p ≤ 0.00036). Our data shed new light on the associations between genetic variants in the ACYP2 gene and CRC susceptibility in a Chinese Han population.},
}
@article {pmid28038469,
year = {2017},
author = {Chen, J and Wei, Y and Chen, X and Jiao, J and Zhang, Y},
title = {Polyunsaturated fatty acids ameliorate aging via redox-telomere-antioncogene axis.},
journal = {Oncotarget},
volume = {8},
number = {5},
pages = {7301-7314},
pmid = {28038469},
issn = {1949-2553},
mesh = {Age Factors ; Aging/genetics/*metabolism/pathology ; Animals ; Arachidonic Acid/*administration &amp; dosage ; Brain/drug effects/enzymology/pathology ; Cellular Senescence/drug effects ; DNA Damage/drug effects ; Docosahexaenoic Acids/*administration &amp; dosage ; Down-Regulation ; *Genes, Tumor Suppressor ; Genes, p16 ; Genes, p53 ; Lipid Peroxidation/drug effects ; Liver/drug effects/enzymology/pathology ; Male ; Mice, Inbred ICR ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins c-myc/genetics/metabolism ; Signal Transduction/drug effects ; Telomerase/genetics/metabolism ; Telomere/*drug effects/genetics/metabolism ; Telomere Homeostasis/*drug effects ; Telomere Shortening/*drug effects ; Testis/drug effects/enzymology/pathology ; Time Factors ; },
abstract = {Polyunsaturated fatty acids (PUFA), a group of nourishing and health-promoting nutrients, ameliorate age-related chronic diseases. However, how PUFA especially n-3 PUFA exert anti-aging functions remains poorly understood. Here we link fish oil, docosahexaenoic acid (DHA) and arachidonic acid (AA) to the aging etiology via a redox-telomere-antioncogene axis based on D-galactose-induced aging mice. Both fish oil and PUFA enhanced hepatic superoxide dismutase (SOD) and catalase activities and cardiac SOD activities within the range of 18%-46%, 26%-65% and 19%-58%, respectively, whereas reduced cerebral monoamine oxidase activity, plasma F2-isoprostane level and cerebral lipid peroxidation level by 56%-90%, 20%-79% and 16%-54%, respectively. Thus, PUFA improve the in vivo redox and oxidative stress induced aging process, which however does not exhibit a dose-dependent manner. Notably, both PUFA and fish oil effectively inactivated testicular telomerase and inhibited c-Myc-mediated telomerase reverse transcriptase expression, whereas n-3 PUFA rather than n-6 PUFA protected liver and testes against telomere shortening within the range of 13%-25% and 25%-27%, respectively. Therefore, n-3 PUFA may be better at inhibiting the DNA damage induced aging process. Surprisingly, only DHA significantly suppressed cellular senescence pathway evidenced by testicular antioncogene p16 and p53 expression. This work provides evident support for the crosstalk between PUFA especially n-3 PUFA and the aging process via maintaining the in vivo redox homeostasis, rescuing age-related telomere attrition and down-regulating the antioncogene expression.},
}
@article {pmid28032863,
year = {2016},
author = {Celeghin, A and Giunco, S and Freguja, R and Zangrossi, M and Nalio, S and Dolcetti, R and De Rossi, A},
title = {Short-term inhibition of TERT induces telomere length-independent cell cycle arrest and apoptotic response in EBV-immortalized and transformed B cells.},
journal = {Cell death &amp; disease},
volume = {7},
number = {12},
pages = {e2562},
pmid = {28032863},
issn = {2041-4889},
mesh = {Aminobenzoates ; Apoptosis/*drug effects ; Ataxia Telangiectasia Mutated Proteins/metabolism ; B-Lymphocytes/drug effects/*metabolism/*virology ; Cell Cycle Checkpoints/*drug effects ; Cell Line, Transformed ; Cell Survival/drug effects ; Cyclophosphamide/pharmacology ; Herpesvirus 4, Human/*metabolism ; Histones/metabolism ; Humans ; Naphthalenes ; S Phase/drug effects ; Signal Transduction/drug effects ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/drug effects/*metabolism ; *Telomere Homeostasis/drug effects ; Vidarabine/analogs &amp; derivatives/pharmacology ; },
abstract = {Besides its canonical role in stabilizing telomeres, telomerase reverse transcriptase (TERT) may promote tumorigenesis through extra-telomeric functions. The possible therapeutic effects of BIBR1532 (BIBR), a powerful TERT inhibitor, have been evaluated in different cellular backgrounds, but no data are currently available regarding Epstein-Barr virus (EBV)-driven B-cell malignancies. Our aim was to characterize the biological effects of TERT inhibition by BIBR on EBV-immortalized lymphoblastoid cell lines (LCLs) and fully transformed Burkitt's lymphoma (BL) cell lines. We found that BIBR selectively inhibits telomerase activity in TERT-positive 4134/Late and 4134/TERT+ LCLs and EBV-negative BL41 and EBV-positive BL41/B95.8 BL cell lines. TERT inhibition led to decreased cell proliferation, accumulation of cells in the S-phase and ultimately to increased apoptosis, compared with mock-treated control cells. All these effects occurred within 72 h and were not observed in BIBR-treated TERT-negative 4134/TERT- and U2OS cells. The cell cycle arrest and apoptosis, consequent upon short-term TERT inhibition, were associated with and likely dependent on the activation of the DNA damage response (DDR), highlighted by the increased levels of γH2AX and activation of ATM and ATR pathways. Analyses of the mean and range of telomere lengths and telomere dysfunction-induced foci indicated that DDR after short-term TERT inhibition was not related to telomere dysfunction, thus suggesting that TERT, besides stabilizing telomere, may protect DNA via telomere-independent mechanisms. Notably, TERT-positive LCLs treated with BIBR in combination with fludarabine or cyclophosphamide showed a significant increase in the number of apoptotic cells with respect to those treated with chemotherapeutic agents alone. In conclusion, TERT inhibition impairs cell cycle progression and enhances the pro-apoptotic effects of chemotherapeutic agents in TERT-positive cells. These results support new therapeutic applications of TERT inhibitors in EBV-driven B-cell malignancies.},
}
@article {pmid28031483,
year = {2017},
author = {Tu, Z and Bayazit, MB and Liu, H and Zhang, J and Busayavalasa, K and Risal, S and Shao, J and Satyanarayana, A and Coppola, V and Tessarollo, L and Singh, M and Zheng, C and Han, C and Chen, Z and Kaldis, P and Gustafsson, J&#xc5; and Liu, K},
title = {Speedy A-Cdk2 binding mediates initial telomere-nuclear envelope attachment during meiotic prophase I independent of Cdk2 activation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {114},
number = {3},
pages = {592-597},
pmid = {28031483},
issn = {1091-6490},
support = {P30 CA016058/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle Proteins/deficiency/genetics/*metabolism ; Cyclin-Dependent Kinase 2/chemistry/*metabolism ; Enzyme Activation ; Female ; Male ; Meiotic Prophase I/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nuclear Envelope/metabolism ; Oocytes/cytology/metabolism ; Protein Interaction Domains and Motifs ; Spermatocytes/cytology/metabolism ; Telomere/metabolism ; },
abstract = {Telomere attachment to the nuclear envelope (NE) is a prerequisite for chromosome movement during meiotic prophase I that is required for pairing of homologous chromosomes, synapsis, and homologous recombination. Here we show that Speedy A, a noncanonical activator of cyclin-dependent kinases (Cdks), is specifically localized to telomeres in prophase I male and female germ cells in mice, and plays an essential role in the telomere-NE attachment. Deletion of Spdya in mice disrupts telomere-NE attachment, and this impairs homologous pairing and synapsis and leads to zygotene arrest in male and female germ cells. In addition, we have identified a telomere localization domain on Speedy A covering the distal N terminus and the Cdk2-binding Ringo domain, and this domain is essential for the localization of Speedy A to telomeres. Furthermore, we found that the binding of Cdk2 to Speedy A is indispensable for Cdk2's localization on telomeres, suggesting that Speedy A and Cdk2 might be the initial components that are recruited to the NE for forming the meiotic telomere complex. However, Speedy A-Cdk2-mediated telomere-NE attachment is independent of Cdk2 activation. Our results thus indicate that Speedy A and Cdk2 might mediate the initial telomere-NE attachment for the efficient assembly of the telomere complex that is essential for meiotic prophase I progression.},
}
@article {pmid28030839,
year = {2017},
author = {Pilyugin, M and André, PA and Ratajska, M and Kuzniacka, A and Limon, J and Tournier, BB and Colas, J and Laurent, G and Irminger-Finger, I},
title = {Antagonizing functions of BARD1 and its alternatively spliced variant BARD1δ in telomere stability.},
journal = {Oncotarget},
volume = {8},
number = {6},
pages = {9339-9353},
pmid = {28030839},
issn = {1949-2553},
mesh = {Alternative Splicing ; Animals ; Breast Neoplasms/genetics/*metabolism/pathology ; Cell Line, Tumor ; *Cell Proliferation ; Chromosomal Instability ; Female ; G2 Phase Cell Cycle Checkpoints ; Gene Expression Regulation, Neoplastic ; Germ-Line Mutation ; HEK293 Cells ; Humans ; Mice, Inbred C57BL ; Mice, Transgenic ; Ovarian Neoplasms/genetics/*metabolism/pathology ; Protein Binding ; Protein Isoforms ; Shelterin Complex ; Signal Transduction ; Telomere/genetics/*metabolism/pathology ; *Telomere Homeostasis ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; Time Factors ; Transfection ; Tumor Suppressor Proteins/genetics/*metabolism ; Ubiquitin-Protein Ligases/genetics/*metabolism ; Up-Regulation ; },
abstract = {Previous reports have shown that expression of BARD1δ, a deletion-bearing isoform of BARD1, correlates with tumor aggressiveness and progression. We show that expression of BARD1δ induces cell cycle arrest in vitro and in vivo in non-malignant cells. We investigated the mechanism that leads to proliferation arrest and found that BARD1δ overexpression induced mitotic arrest with chromosome and telomere aberrations in cell cultures, in transgenic mice, and in cells from human breast and ovarian cancer patients with BARD1 mutations. BARD1δ binds more efficiently than BARD1 to telomere binding proteins and causes their depletion from telomeres, leading to telomere and chromosomal instability. While this induces cell cycle arrest, cancer cells lacking G2/M checkpoint controls might continue to proliferate despite the BARD1δ-induced chromosomal instability. These features of BARD1δ may make it a genome permutator and a driver of continuous uncontrolled proliferation of cancer cells.},
}
@article {pmid28029664,
year = {2017},
author = {Whisman, MA and Richardson, ED},
title = {Depressive Symptoms and Salivary Telomere Length in a Probability Sample of Middle-Aged and Older Adults.},
journal = {Psychosomatic medicine},
volume = {79},
number = {2},
pages = {234-242},
pmid = {28029664},
issn = {1534-7796},
support = {R03 AG045301/AG/NIA NIH HHS/United States ; U01 AG009740/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Anxiety Disorders/*metabolism ; Body Mass Index ; Chronic Disease ; Depression/*metabolism ; Female ; Humans ; *Life Style ; Male ; Middle Aged ; Neuroticism ; Psychological Trauma/metabolism ; Saliva ; Sex Factors ; Smoking/metabolism ; Telomere Shortening/*physiology ; },
abstract = {OBJECTIVE: To examine the association between depressive symptoms and salivary telomere length in a probability sample of middle-aged and older adults, and to evaluate age and sex as potential moderators of this association and test whether this association was incremental to potential confounds.<br><br>METHODS: Participants were 3,609 individuals from the 2008 wave of the Health and Retirement Study. Telomere length assays were performed using quantitative real-time polymerase chain reaction on DNA extracted from saliva samples. Depressive symptoms were assessed via interview, and health and lifestyle factors, traumatic life events, and neuroticism were assessed via self-report. Regression analyses were conducted to examine the associations between predictor variables and salivary telomere length.<br><br>RESULTS: After adjusting for demographics, depressive symptoms were negatively associated with salivary telomere length (b = -.003; p = .014). Furthermore, this association was moderated by sex (b = .005; p = .011), such that depressive symptoms were significantly and negatively associated with salivary telomere length for men (b = - .006; p < .001) but not for women (b = - .001; p = .644). The negative association between depressive symptoms and salivary telomere length in men remained statistically significant after additionally adjusting for cigarette smoking, body mass index, chronic health conditions, childhood and lifetime exposure to traumatic life events, and neuroticism.<br><br>CONCLUSIONS: Higher levels of depressive symptoms were associated with shorter salivary telomeres in men, and this association was incremental to several potential confounds. Shortened telomeres may help account for the association between depression and poor physical health and mortality.},
}
@article {pmid28027815,
year = {2017},
author = {Lv, Y and Zhang, Y and Li, X and Ren, X and Wang, M and Tian, S and Hou, P and Shi, B and Yang, Q},
title = {Long telomere length predicts poor clinical outcome in esophageal cancer patients.},
journal = {Pathology, research and practice},
volume = {213},
number = {2},
pages = {113-118},
doi = {10.1016/j.prp.2016.11.010},
pmid = {28027815},
issn = {1618-0631},
mesh = {Aged ; Esophageal Neoplasms/*genetics/mortality/pathology ; Female ; Humans ; Male ; Middle Aged ; Prognosis ; Sex Factors ; Survival Rate ; *Telomere ; },
abstract = {BACKGROUND: Abnormal telomere length is widely reported in various human cancers, and it is considered to be an important hallmark of cancer. However, there is remarkably little consensus on the value of telomere length in the prognostic evaluation of esophageal cancers. Here, we attempted to determine the association of variable telomere length with clinical outcome of esophageal cancer patients.<br><br>MATERIALS AND METHODS: Using real-time quantitative PCR, we examined relative telomere lengths (RTL) in a cohort of esophageal cancer and normal esophageal tissues, and statistically investigated the association between RTL and clinical outcomes of esophageal cancer patients.<br><br>RESULTS: The majority of esophageal cancers in this study had longer RTLs as compared to adjacent non-tumor tissues. Enhanced tumor RTL was associated with smoking habit, poor differentiation, advanced tumor stage, lymph node metastasis and cancer related death. In particular, a close relationship between longer RTL and poor survival was fully demonstrated by using cox regression and Kaplan-Maier survival curves.<br><br>CONCLUSIONS: We found frequent telomere elongation in esophageal cancer tissues, and demonstrated longer RTL may be an independent poor prognostic factor for esophageal cancer patients.},
}
@article {pmid28027420,
year = {2017},
author = {Watson, RL and Bird, EJ and Underwood, S and Wilbourn, RV and Fairlie, J and Watt, K and Salvo-Chirnside, E and Pilkington, JG and Pemberton, JM and McNeilly, TN and Froy, H and Nussey, DH},
title = {Sex differences in leucocyte telomere length in a free-living mammal.},
journal = {Molecular ecology},
volume = {26},
number = {12},
pages = {3230-3240},
pmid = {28027420},
issn = {1365-294X},
support = {BB/H021868/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Cross-Sectional Studies ; Female ; *Leukocytes ; Male ; *Sex Characteristics ; Sheep/*genetics ; Telomere/*ultrastructure ; Telomere Shortening ; },
abstract = {Mounting evidence suggests that average telomere length reflects previous stress and predicts subsequent survival across vertebrate species. In humans, leucocyte telomere length (LTL) is consistently shorter during adulthood in males than in females, although the causes of this sex difference and its generality to other mammals remain unknown. Here, we measured LTL in a cross-sectional sample of free-living Soay sheep and found shorter telomeres in males than in females in later adulthood (>3 years of age), but not in early life. This observation was not related to sex differences in growth or parasite burden, but we did find evidence for reduced LTL associated with increased horn growth in early life in males. Variation in LTL was independent of variation in the proportions of different leucocyte cell types, which are known to differ in telomere length. Our results provide the first evidence of sex differences in LTL from a wild mammal, but longitudinal studies are now required to determine whether telomere attrition rates or selective disappearance are responsible for these observed differences.},
}
@article {pmid28025427,
year = {2016},
author = {Carkic, J and Nikolic, N and Radojevic-Skodric, S and Kuzmanovic-Pficer, J and Brajovic, G and Antunovic, M and Milasin, J and Popovic, B},
title = {The role of TERT-CLPTM1L SNPs, hTERT expression and telomere length in the pathogenesis of oral squamous cell carcinoma.},
journal = {Journal of oral science},
volume = {58},
number = {4},
pages = {449-458},
doi = {10.2334/josnusd.16-0108},
pmid = {28025427},
issn = {1880-4926},
mesh = {Aged ; Carcinoma, Squamous Cell/*genetics/pathology ; Female ; Humans ; Male ; Membrane Proteins/*physiology ; Middle Aged ; Mouth Neoplasms/*genetics/pathology ; *Polymorphism, Single Nucleotide ; Real-Time Polymerase Chain Reaction ; Telomerase/*physiology ; *Telomere ; },
abstract = {The aim of this study was to assess TERT-CLPTM1L single-nucleotide polymorphisms (SNPs) (rs402710 C/T in the CLPTM1L gene; rs2736100 A/C and rs2736098 G/A in the TERT gene) as risk factors for development of oral squamous cell carcinoma (OSCC), and to investigate the relationship between the analyzed polymorphisms, relative telomere length (RTL), telomerase expression and clinicopathologic characteristics of OSCC in a Serbian population. Paraffin-embedded tumor samples and buccal swabs from cancer-free controls were genotyped using PCR-RFLP, while tumor RTL values and telomerase expression were estimated by real-time PCR and immunohistochemistry, respectively. CLPTM1L rs402710 and TERT rs2736100 polymorphisms were associated with a significantly increased risk of OSCC, and TERT rs2736098 with a significantly decreased risk. No significant association was found between TERT-CLPTM1L polymorphisms, tumor RTL values, telomerase expression, and clinicopathologic features, although a trend towards longer telomeres was evident in telomerase-positive samples and less advanced tumors. Kaplan-Meier survival analysis showed that patients with longer telomeres in their tumors had significantly better overall survival than patients with shorter telomeres. Our research seems to provide strong evidence for an association between CLPTM1L rs402710C/T and TERT rs2736100A/C SNPs and the risk of OSSC, and suggests that higher tumor RTL values and positive hTERT expression may be applicable as early prognostic markers.(J Oral Sci 58, 449-458, 2016).},
}
@article {pmid28018213,
year = {2016},
author = {Rask, L and Bendix, L and Harbo, M and Fagerlund, B and Mortensen, EL and Lauritzen, MJ and Osler, M},
title = {Cognitive Change during the Life Course and Leukocyte Telomere Length in Late Middle-Aged Men.},
journal = {Frontiers in aging neuroscience},
volume = {8},
number = {},
pages = {300},
pmid = {28018213},
issn = {1663-4365},
abstract = {Importance: Cognitive skills are known to decline through the lifespan with large individual differences. The molecular mechanisms for this decline are incompletely understood. Although leukocyte telomere length provides an index of cellular age that predicts the incidence of age-related diseases, it is unclear whether there is an association between cognitive decline and leukocyte telomere length. Objective: To examine the association between changes in cognitive function during adult life and leukocyte telomere length after adjusting for confounding factors such as education, mental health and life style. Design, Setting, and Participants: Two groups of men with negative (n = 97) and positive (n = 93) change in cognitive performance were selected from a birth cohort of 1985 Danish men born in 1953. Cognitive performance of each individual was assessed at age ~20 and 56 years. Leukocyte telomere length at age ~58 was measured using qPCR. Linear regression models were used to investigate the association between cognitive function and leukocyte telomere length. Results: Men with negative change in cognitive performance during adult life had significantly shorter mean leukocyte telomere length than men with positive change in cognitive performance (unadjusted difference β = -0.09, 95% CI -0.16 to -0.02, p = 0.02). This association remained significant after adjusting for smoking, alcohol consumption, leisure time activity, body mass index (BMI) and cholesterol (adjusted difference β = -0.09, 95% CI -0.17 to -0.01, p = 0.02) but was non-significant after adjusting for smoking, alcohol consumption, leisure time activity, BMI, cholesterol, current cognitive function, depression and education (adjusted difference β = -0.07, 95% CI -0.16 to -0.01, p = 0.08). Conclusion and Relevance: Preclinical cognitive changes may be associated with leukocyte telomere length.},
}
@article {pmid28018048,
year = {2016},
author = {Edmonds, GW and Hampson, SE and Côté, HC and Hill, PL and Klest, B},
title = {Childhood Personality, Betrayal Trauma, and Leukocyte Telomere Length in Adulthood: A Lifespan Perspective on Conscientiousness and Betrayal Traumas as Predictors of a Biomarker of Cellular Aging.},
journal = {European journal of personality},
volume = {30},
number = {5},
pages = {426-437},
pmid = {28018048},
issn = {0890-2070},
support = {R01 AG020048/AG/NIA NIH HHS/United States ; R21 AG045015/AG/NIA NIH HHS/United States ; },
abstract = {Conscientiousness is associated with longevity. As such, identifying the biological pathways linking personality to mortality is important. This study employs longitudinal data spanning >40 years to test prospective associations with Leukocyte Telomere Length (LTL), a potential marker of cellular aging. Because telomeres shorten over time, and are sensitive to oxidative stress, shorter LTL may reflect cumulative damage associated with negative health behaviors and past stressful events. We investigated childhood conscientiousness as a protective factor, expecting an association with longer LTL in adulthood, possibly reflecting slower LTL shortening. Potential lifespan pathways involving childhood trauma, smoking behaviors, and Body Mass Index (BMI) were explored. Childhood conscientiousness showed a small raw association with LTL (r = .08, p = .04), although this effect did not persist when controlling for age and sex. Despite this lack of a direct effect on LTL, we detected an indirect effect operating jointly through BMI and smoking. Higher rates of childhood betrayal trauma were associated with shorter LTL. Contrary to our hypothesis that conscientiousness would buffer this effect, we found evidence for an interaction with childhood betrayal traumas where the association between childhood betrayal traumas and LTL was larger for those higher on conscientiousness in childhood.},
}
@article {pmid28009281,
year = {2016},
author = {Aeby, E and Ahmed, W and Redon, S and Simanis, V and Lingner, J},
title = {Peroxiredoxin 1 Protects Telomeres from Oxidative Damage and Preserves Telomeric DNA for Extension by Telomerase.},
journal = {Cell reports},
volume = {17},
number = {12},
pages = {3107-3114},
doi = {10.1016/j.celrep.2016.11.071},
pmid = {28009281},
issn = {2211-1247},
support = {166675/SNSF_/Swiss National Science Foundation/Switzerland ; },
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Cell Cycle ; Chromatin/genetics ; DNA/genetics ; DNA Damage/genetics ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Heterochromatin/*genetics ; Humans ; Oxidative Stress/*genetics ; Peroxiredoxins/*genetics/metabolism ; Reactive Oxygen Species/toxicity ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {Oxidative damage of telomeres can promote cancer, cardiac failure, and muscular dystrophy. Specific mechanisms protecting telomeres from oxidative damage have not been described. We analyzed telomeric chromatin composition during the cell cycle and show that the antioxidant enzyme peroxiredoxin 1 (PRDX1) is enriched at telomeres during S phase. Deletion of the PRDX1 gene leads to damage of telomeric DNA upon oxidative stress, revealing a protective function of PRDX1 against oxidative damage at telomeres. We also show that the oxidized nucleotide 8-oxo-2'deoxyguanosine-5'-triphosphate (8oxodGTP) causes premature chain termination when incorporated by telomerase and that some DNA substrates terminating in 8oxoG prevent extension by telomerase. Thus, PRDX1 safeguards telomeres from oxygen radicals to counteract telomere damage and preserve telomeric DNA for elongation by telomerase.},
}
@article {pmid28006764,
year = {2016},
author = {Laish, I and Mannasse-Green, B and Hadary, R and Biron-Shental, T and Konikoff, FM and Amiel, A and Kitay-Cohen, Y},
title = {Telomere Dysfunction in Nonalcoholic Fatty Liver Disease and Cryptogenic Cirrhosis.},
journal = {Cytogenetic and genome research},
volume = {150},
number = {2},
pages = {93-99},
doi = {10.1159/000454654},
pmid = {28006764},
issn = {1424-859X},
mesh = {Aged ; Case-Control Studies ; Cellular Senescence/genetics ; Disease Progression ; Female ; Genomic Instability ; Humans ; Liver Cirrhosis/*congenital/genetics ; Male ; Middle Aged ; Non-alcoholic Fatty Liver Disease/*genetics ; Prospective Studies ; RNA, Messenger/genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis/genetics ; Telomere Shortening/genetics ; },
abstract = {Nonalcoholic fatty liver disease (NAFLD) and cryptogenic cirrhosis (CC) are considered preneoplastic conditions that might progress to hepatocellular carcinoma. We evaluated parameters of telomere dysfunction in these patient groups to study the correlation between telomere length and the progression of NAFLD. We analyzed peripheral lymphocytes from 22 patients with NAFLD, 20 patients with CC, and 20 healthy, age-matched controls. Telomere length was analyzed using quantitative fluorescence in situ hybridization, and cellular senescence was evaluated by the percentage of cells with senescence-associated heterochromatin foci. The expression of telomerase reverse transcriptase (hTERT) mRNA was measured using polymerase chain reaction, and telomere capture (TC) was assessed with 2 Cytocell probes, 15qter and 13qter. Shorter telomere length and increased cellular senescence was demonstrated in patients with NAFLD, compared to the CC patients and healthy controls. While hTERT mRNA was significantly decreased, TC was increased in CC patients, compared to the NAFLD group and healthy individuals. Thus, there is a correlation between hTERT mRNA expression and telomere length in patients with NAFLD, which might be related to associated metabolic disorders and the risk of malignant transformation. Patients with CC, on the contrary, elongate their telomeres through the TC mechanism.},
}
@article {pmid28000540,
year = {2018},
author = {Monroy-Jaramillo, N and Dyukova, E and Walss-Bass, C},
title = {Telomere length in psychiatric disorders: Is it more than an ageing marker?.},
journal = {The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry},
volume = {19},
number = {sup2},
pages = {S2-S20},
doi = {10.1080/15622975.2016.1273550},
pmid = {28000540},
issn = {1814-1412},
mesh = {Aging/*genetics ; Biomarkers ; Humans ; Leukocytes ; Mental Disorders/*genetics ; *Mitochondria ; Substance-Related Disorders/genetics ; Telomere/*ultrastructure ; Telomere Shortening/*genetics ; },
abstract = {OBJECTIVES: Psychiatric and substance-use disorders have been associated with premature biological ageing. Telomere length (TL), considered an ageing marker, has been analysed in psychiatric disorders, and to a lesser extent in substance-use disorders, with recent findings suggesting TL may be related to disease pathology.<br><br>METHODS: We conducted a critical and non-systematic literature search of TL studies published up to June 2016 in psychiatric and substance-use disorders, focussing on studies describing mechanisms, including studies linking telomere biology with genetic factors, stress and mitochondrial alterations (104 studies selected).<br><br>RESULTS: Patients with major depressive disorder and anxiety appear to have shorter leukocyte telomeres compared to controls. Inconclusive results are found for other psychiatric disorders and for substance-use disorders. This may be due in part to differences in medication treatment and response, as studies suggest that some psychotropic medications may modulate TL. Importantly, some studies establish a relationship between telomere machinery, stress and mitochondria function in psychiatric and substance-use disorders.<br><br>CONCLUSIONS: While further longitudinal studies considering telomere genetics are needed to clarify the cause-effect link between telomeres and mitochondria function in psychiatric and substance-use disorders, the recent findings linking these biological processes suggest that telomeres may be more than ageing markers.},
}
@article {pmid27995640,
year = {2017},
author = {Finot, F and Kaddour, A and Morat, L and Mouche, I and Zaguia, N and Cuceu, C and Souverville, D and Négrault, S and Cariou, O and Essahli, A and Prigent, N and Saul, J and Paillard, F and Heidingsfelder, L and Lafouge, P and Al Jawhari, M and Hempel, WM and El May, M and Colicchio, B and Dieterlen, A and Jeandidier, E and Sabatier, L and Clements, J and M'Kacher, R},
title = {Genotoxic risk of ethyl-paraben could be related to telomere shortening.},
journal = {Journal of applied toxicology : JAT},
volume = {37},
number = {6},
pages = {758-771},
doi = {10.1002/jat.3425},
pmid = {27995640},
issn = {1099-1263},
mesh = {Activation, Metabolic ; Animals ; Cell Culture Techniques ; Cell Line, Tumor ; Humans ; Lymphocytes/drug effects/pathology ; Mice ; Micronuclei, Chromosome-Defective/*chemically induced/statistics &amp; numerical data ; Microsomes, Liver/metabolism ; Mutagens/*toxicity ; Parabens/*toxicity ; Rats, Sprague-Dawley ; Telomere Shortening/*drug effects ; },
abstract = {The ability of parabens to promote the appearance of multiple cancer hallmarks in breast epithelium cells provides grounds for regulatory review of the implication of the presence of parabens in human breast tissue. It is well documented that telomere dysfunction plays a significant role in the initiation of genomic instability during carcinogenesis in human breast cancer. In the present study, we evaluated the genotoxic effect of ethyl 4-hydroxybenzoate (ethyl-paraben), with and without metabolic activation (S9), in studies following OECD guidelines. We observed a significant increase in genotoxic damage using the Mouse Lymphoma Assay and in vitro micronucleus (MN) tests in the L5178Y cell line in the presence of S9 only after a short exposure. A high frequency of MN was observed in the TK6 cells after a short exposure (3 h) in the presence of S9 and a long exposure (26 h) without S9. We found significant increases in the MN frequency and induced chromosomal aberrations in the lymphocytes of only one donor after ethyl-paraben exposure in the presence of S9 after a short exposure. Cytogenetic characterization of the paraben-treated cells demonstrated telomere shortening associated with telomere loss and telomere deletions in L5178Y and TK6 cells and lymphocytes of the paraben sensitive-donor. In a control cohort of 68 human lymphocytes, telomere length and telomere aberrations were age-dependent and showed high inter-individual variation. This study is the first to link telomere shortening and the genotoxic effect of ethyl paraben in the presence of S9 and raises the possibility that telomere shortening may be a proxy for underlying inter-individual sensitivity to ethyl-paraben. Copyright © 2016 John Wiley &amp; Sons, Ltd.},
}
@article {pmid27993934,
year = {2017},
author = {Tripathi, E and Smith, S},
title = {Cell cycle-regulated ubiquitination of tankyrase 1 by RNF8 and ABRO1/BRCC36 controls the timing of sister telomere resolution.},
journal = {The EMBO journal},
volume = {36},
number = {4},
pages = {503-519},
pmid = {27993934},
issn = {1460-2075},
support = {R01 CA116352/CA/NCI NIH HHS/United States ; },
mesh = {*Cell Cycle ; DNA-Binding Proteins/*metabolism ; Deubiquitinating Enzymes ; HeLa Cells ; Humans ; Membrane Proteins/*metabolism ; Nuclear Matrix-Associated Proteins/*metabolism ; Tankyrases/*metabolism ; Telomere/enzymology/*metabolism ; Ubiquitin-Protein Ligases ; Ubiquitin-Specific Proteases/*metabolism ; *Ubiquitination ; },
abstract = {Timely resolution of sister chromatid cohesion in G2/M is essential for genome integrity. Resolution at telomeres requires the poly(ADP-ribose) polymerase tankyrase 1, but the mechanism that times its action is unknown. Here, we show that tankyrase 1 activity at telomeres is controlled by a ubiquitination/deubiquitination cycle depending on opposing ubiquitin ligase and deubiquitinase activities. In late S/G2 phase, the DNA damage-responsive E3 ligase RNF8 conjugates K63-linked ubiquitin chains to tankyrase 1, while in G1 phase such ubiquitin chains are removed by BRISC, an ABRO1/BRCC36-containing deubiquitinase complex. We show that K63-linked ubiquitin chains accumulate on tankyrase 1 in late S/G2 to promote its stabilization, association with telomeres, and resolution of cohesion. Timing of this posttranslational modification coincides with the ATM-mediated DNA damage response that occurs on functional telomeres following replication in G2. Removal of ubiquitin chains is controlled by ABRO1/BRCC36 and occurs as cells exit mitosis and enter G1, ensuring that telomere cohesion is not resolved prematurely in S phase. Our studies suggest that a cell cycle-regulated posttranslational mechanism couples resolution of telomere cohesion with completion of telomere replication to ensure genome integrity.},
}
@article {pmid27992608,
year = {2016},
author = {Goglin, SE and Farzaneh-Far, R and Epel, ES and Lin, J and Blackburn, EH and Whooley, MA},
title = {Correction: Change in Leukocyte Telomere Length Predicts Mortality in Patients with Stable Coronary Heart Disease from the Heart and Soul Study.},
journal = {PloS one},
volume = {11},
number = {12},
pages = {e0168868},
pmid = {27992608},
issn = {1932-6203},
abstract = {[This corrects the article DOI: 10.1371/journal.pone.0160748.].},
}
@article {pmid27990481,
year = {2016},
author = {Luttropp, K and Nordfors, L and McGuinness, D and Wennberg, L and Curley, H and Quasim, T and Genberg, H and Sandberg, J and Sönnerborg, I and Schalling, M and Qureshi, AR and Bárány, P and Shiels, PG and Stenvinkel, P},
title = {Increased Telomere Attrition After Renal Transplantation-Impact of Antimetabolite Therapy.},
journal = {Transplantation direct},
volume = {2},
number = {12},
pages = {e116},
pmid = {27990481},
issn = {2373-8731},
abstract = {BACKGROUND: The uremic milieu exposes chronic kidney disease (CKD) patients to premature ageing processes. The impact of renal replacement therapy (dialysis and renal transplantation [RTx]) or immunosuppressive treatment regimens on ageing biomarkers has scarcely been studied.<br><br>METHODS: In this study telomere length in whole blood cells was measured in 49 dialysis patients and 47 RTx patients close to therapy initiation and again after 12 months. Forty-three non-CKD patients were included as controls.<br><br>RESULTS: Non-CKD patients had significantly (P &#x2264; 0.01) longer telomeres than CKD patients. Telomere attrition after 12 months was significantly greater in RTx patients compared to dialysis patients (P = 0.008). RTx patients receiving mycophenolate mofetil (MMF) had a greater (P = 0.007) degree of telomere attrition compared to those treated with azathioprine. After 12 months, folate was significantly higher in RTx patients than in dialysis patients (P < 0.0001), whereas the opposite was true for homocysteine (P < 0.0001). The azathioprine group had lower levels of folate after 12 months than the MMF group (P = 0.003).<br><br>CONCLUSIONS: The associations between immunosuppressive therapy, telomere attrition, and changes in folate indicate a link between methyl donor potential, immunosuppressive drugs, and biological ageing. The hypothesis that the increased telomere attrition, observed in the MMF group after RTx, is driven by the immunosuppressive treatment, deserves further attention.},
}
@article {pmid27986801,
year = {2017},
author = {Kostjukovits, S and Degerman, S and Pekkinen, M and Klemetti, P and Landfors, M and Roos, G and Taskinen, M and Mäkitie, O},
title = {Decreased telomere length in children with cartilage-hair hypoplasia.},
journal = {Journal of medical genetics},
volume = {54},
number = {5},
pages = {365-370},
doi = {10.1136/jmedgenet-2016-104279},
pmid = {27986801},
issn = {1468-6244},
mesh = {Adolescent ; Adult ; Aged ; Case-Control Studies ; Child ; Endoribonucleases/genetics ; Female ; Hair/*abnormalities ; Heterozygote ; Hirschsprung Disease/*genetics ; Humans ; Immunologic Deficiency Syndromes/*genetics ; Male ; Middle Aged ; Morbidity ; Mutation/genetics ; Osteochondrodysplasias/*congenital/genetics ; Primary Immunodeficiency Diseases ; *Telomere Homeostasis ; Young Adult ; },
abstract = {BACKGROUND: Cartilage-hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia caused by RMRP (RNA component of mitochondrial RNA processing endoribonuclease) gene mutations. Manifestations include short stature, variable immunodeficiency, anaemia and increased risk of malignancies, all of which have been described also in telomere biology disorders. RMRP interacts with the telomerase RT (TERT) subunit, but the influence of RMRP mutations on telomere length is unknown. We measured relative telomere length (RTL) in patients with CHH, their first-degree relatives and healthy controls and correlated RTL with clinical and laboratory features.<br><br>METHODS: The study cohort included 48 patients with CHH with homozygous (n=36) or compound heterozygous RMRP mutations (median age 38.2&#x2005;years, range 6.0-70.8&#x2005;years), 86 relatives (74 with a heterozygous RMRP mutation) and 94 unrelated healthy controls. We extracted DNA from peripheral blood, sequenced the RMRP gene and measured RTL by qPCR.<br><br>RESULTS: Compared with age-matched and sex-matched healthy controls, median RTL was significantly shorter in patients with CHH (n=40 pairs, 1.05 vs 1.21, p=0.017), but not in mutation carriers (n=48 pairs, 1.16 vs 1.10, p=0.224). RTL correlated significantly with age in RMRP mutation carriers (r=-0.482, p<0.001) and non-carriers (r=-0.498, p<0.001), but not in patients (r=-0.236, p=0.107). In particular children (<18&#x2005;years) with CHH had shorter telomeres than controls (median RTL 1.12 vs 1.26, p=0.008). In patients with CHH, RTL showed no correlation with genotype, clinical or laboratory characteristics.<br><br>CONCLUSIONS: Telomere length was decreased in children with CHH. We found no correlation between RTL and clinical or laboratory parameters.},
}
@article {pmid27981152,
year = {2016},
author = {Law, E and Girgis, A and Lambert, S and Sylvie, L and Levesque, J and Pickett, H},
title = {Telomeres and Stress: Promising Avenues for Research in Psycho-Oncology.},
journal = {Asia-Pacific journal of oncology nursing},
volume = {3},
number = {2},
pages = {137-147},
pmid = {27981152},
issn = {2347-5625},
abstract = {A cancer diagnosis and subsequent treatment is a stressful experience with the potential for long-term health consequences for both patients and their caregivers. It is now well-established that psychological stress is associated with detrimental effects on physical health. Recent studies have investigated the link between telomeres, the protective cap at the end of chromosomes, and stress, suggesting that stress potentially impacts on cellular aging through telomere shortening, with subsequent consequences for health. This review aims to familiarize the reader with the pertinent literature exploring the relationship between telomeres and psychological and behavioral factors and propose future directions for telomere research in psycho-oncology.},
}
@article {pmid27979878,
year = {2017},
author = {Hapangama, DK and Kamal, A and Saretzki, G},
title = {Implications of telomeres and telomerase in endometrial pathology.},
journal = {Human reproduction update},
volume = {23},
number = {2},
pages = {166-187},
pmid = {27979878},
issn = {1460-2369},
mesh = {Endometrial Neoplasms/etiology ; Endometriosis/etiology ; Endometrium/*physiology ; Female ; Humans ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {BACKGROUND: Eukaryotic chromosomal ends are linear and are protected by nucleoprotein complexes known as telomeres. The complex structural anatomy and the diverse functions of telomeres as well as the unique reverse transcriptase enzyme, telomerase that maintains telomeres are under intensive scientific scrutiny. Both are involved in many human diseases including cancer, but also in ageing and chronic disease such as diabetes. Their intricate involvement in many cellular processes and pathways is being dynamically deciphered in many organs including the endometrium. This review summarizes our current knowledge on the topic of telomeres and telomerase and their potential role in providing plausible explanations for endometrial aberrations related to common gynaecological pathologies.<br><br>OBJECTIVE AND RATIONALE: This review outlines the recent major findings in telomere and telomerase functions in the context of endometrial biology. It highlights the contemporary discoveries in hormonal regulation, normal endometrial regeneration, stem cells and common gynaecological diseases such as endometriosis, infertility, recurrent reproductive failure and endometrial cancer (EC).<br><br>SEARCH METHODS: The authors carried out systematic PubMed (Medline) and Ovid searches using the key words: telomerase, telomeres, telomere length, human telomerase reverse transcriptase, telomeric RNA component, with endometrium, hormonal regulation, endometrial stem/progenitor cells, endometrial regeneration, endometriosis, recurrent miscarriage, infertility, endometrial hyperplasia, EC and uterine cancer. Publications used in this review date from 1995 until 31st June 2016.<br><br>OUTCOMES: The human endometrium is a unique somatic organ, which displays dynamic telomerase activity (TA) related to the menstrual cycle. Telomerase is implicated in almost all endometrial pathologies and appears to be crucial to endometrial stem cells. In particular, it is vital for normal endometrial regeneration, providing a distinct route to formulate possible curative, non-hormonal therapies to treat chronic endometrial conditions. Furthermore, our current understanding of telomere maintenance in EC is incomplete. Data derived from other malignancies on the role of telomerase in carcinogenesis cannot be extrapolated to EC because unlike in other cancers, TA is already present in proliferating healthy endometrial cells.<br><br>WIDER IMPLICATIONS: Since telomerase is pivotal to endometrial regeneration, further studies elucidating the role of telomeres, telomerase, their associated proteins and their regulation in normal endometrial regeneration as well as their role in endometrial pathologies are essential. This approach may allow future development of novel treatment strategies that are not only non-hormonal but also potentially curative.},
}
@article {pmid27978413,
year = {2016},
author = {Dlouhá, D and Vančura, V and Vymětalová, J and Hubáček, JA and Lánská, V and Málek, I},
title = {Can Leukocyte Telomere Length Predict Survival Time in Heart Transplant Recipients over a Minimal Follow-Up of 20 years?.},
journal = {Folia biologica},
volume = {62},
number = {5},
pages = {188-193},
pmid = {27978413},
issn = {0015-5500},
mesh = {Adult ; Cause of Death ; Follow-Up Studies ; Heart Failure/etiology/mortality ; Heart Transplantation/*mortality ; Humans ; Kaplan-Meier Estimate ; Leukocytes/*metabolism ; Male ; Survival Analysis ; *Telomere Homeostasis ; },
abstract = {In humans, leukocyte telomere length (LTL) reduces with age and is reported to be inversely associated with ageing-related diseases. We measured LTL in leukocyte DNA using a quantitative PCR-based method from 127 blood samples of heart recipients (107 males, 20 females, age 44.1 ± 10.5), followed for up to 30 years. Patients with coronary artery disease survived for a shorter time and also had shorter LTL (both P < 0.05 after adjustment for age and sex) than subjects with dilated cardiomyopathy. Patients with non-cardiac causes of death had shorter LTL than patients with cardiac causes (P < 0.05 after adjustment for age). An inverse correlation between LTL and age (P < 0.03) was observed in patients with non-cardiac causes of death only. Most importantly, LTL was not associated with general survival time in patients after heart transplantation. However, shorter LTL was a marker of non-cardiac causes of death. Different LTLs and survival times were determined in association with aetiology of heart failure (HF).},
}
@article {pmid27977688,
year = {2016},
author = {Kim, W and Ludlow, AT and Min, J and Robin, JD and Stadler, G and Mender, I and Lai, TP and Zhang, N and Wright, WE and Shay, JW},
title = {Regulation of the Human Telomerase Gene TERT by Telomere Position Effect-Over Long Distances (TPE-OLD): Implications for Aging and Cancer.},
journal = {PLoS biology},
volume = {14},
number = {12},
pages = {e2000016},
pmid = {27977688},
issn = {1545-7885},
support = {R00 CA197672/CA/NCI NIH HHS/United States ; K99 CA197672/CA/NCI NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; C06 RR030414/RR/NCRR NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; },
mesh = {Aging/*genetics ; Animals ; Chromosomes, Human, Pair 5 ; *Gene Expression Regulation, Enzymologic ; Humans ; Neoplasms/*genetics ; Primates/genetics ; Telomerase/*genetics ; *Telomere ; },
abstract = {Telomerase is expressed in early human development and then becomes silenced in most normal tissues. Because ~90% of primary human tumors express telomerase and generally maintain very short telomeres, telomerase is carefully regulated, particularly in large, long-lived mammals. In the current report, we provide substantial evidence for a new regulatory control mechanism of the rate limiting catalytic protein component of telomerase (hTERT) that is determined by the length of telomeres. We document that normal, young human cells with long telomeres have a repressed hTERT epigenetic status (chromatin and DNA methylation), but the epigenetic status is altered when telomeres become short. The change in epigenetic status correlates with altered expression of TERT and genes near to TERT, indicating a change in chromatin. Furthermore, we identified a chromosome 5p telomere loop to a region near TERT in human cells with long telomeres that is disengaged with increased cell divisions as telomeres progressively shorten. Finally, we provide support for a role of the TRF2 protein, and possibly TERRA, in the telomere looping maintenance mechanism through interactions with interstitial TTAGGG repeats. This provides new insights into how the changes in genome structure during replicative aging result in an increased susceptibility to age-related diseases and cancer prior to the initiation of a DNA damage signal.},
}
@article {pmid27974682,
year = {2016},
author = {Chen, N and Yang, X and Guo, W and You, J and Wu, Q and Zhang, G and Li, H and Geng, D and Jin, T and Fu, J and Zhang, Y},
title = {Association of polymorphisms in the telomere-related gene ACYP2 with lung cancer risk in the Chinese Han population.},
journal = {Oncotarget},
volume = {7},
number = {52},
pages = {87473-87478},
pmid = {27974682},
issn = {1949-2553},
mesh = {Acid Anhydride Hydrolases/*genetics ; Adult ; Aged ; Asian People/genetics ; Female ; *Genetic Predisposition to Disease ; Humans ; Logistic Models ; Lung Neoplasms/etiology/*genetics ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; Risk ; },
abstract = {Single nucleotide polymorphisms (SNPs) in the telomere-associated gene ACYP2 are associated with increased lung cancer risk. We explored the correlation between ACYP2 SNPs and lung cancer susceptibility in the Chinese Han population. A total of 554 lung cancer patients and 603 healthy controls were included in this study. Thirteen SNPs in ACYP2 were selected. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analysis. Multivariate logistic regression analysis was used assess the correlation between SNPs and lung cancer. We found that rs1682111 was associated with increased lung cancer risk in the recessive model (crude, OR=1.50, 95%CI: 1.04-2.16, p=0.029; adjusted for age, OR=1.55, 95%CI: 1.04-2.30, p=0.029), as was rs11896604 in the codominant model (crude, OR=0.65, 95%CI: 0.33-1.28, p=0.045; adjusted for age, OR=0.74, 95%CI: 0.36-1.53, p=0.049) and over-dominant model (crude, OR=1.30, 95%CI: 1.02-1.66, p=0.032; adjusted for age, OR=1.37, 95%CI: 1.05-1.78, p=0.020). Finally, rs843720 was associated with increased lung cancer risk in the recessive model (crude, OR=1.43, 95%CI: 1.02-2.02, p=0.040; adjusted for age, OR=1.48, 95%CI: 1.02-2.15, p=0.040). Thus three SNPs in ACYP2 (rs1682111, rs11896604 and rs843720) associate with lung cancer in the Chinese Han population.},
}
@article {pmid27967317,
year = {2017},
author = {Steptoe, A and Hamer, M and Lin, J and Blackburn, EH and Erusalimsky, JD},
title = {The Longitudinal Relationship Between Cortisol Responses to Mental Stress and Leukocyte Telomere Attrition.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {102},
number = {3},
pages = {962-969},
pmid = {27967317},
issn = {1945-7197},
support = {RG/10/005/28296/BHF_/British Heart Foundation/United Kingdom ; G0601647/MRC_/Medical Research Council/United Kingdom ; RG/05/006/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Aged ; Aging/*genetics/psychology ; Female ; Follow-Up Studies ; Humans ; Hydrocortisone/*metabolism ; Leukocytes/*metabolism ; Longitudinal Studies ; Male ; Middle Aged ; Saliva/chemistry ; Smoking ; Social Class ; Stress, Psychological/*genetics/metabolism/psychology ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {CONTEXT: Chronic psychological stress has been associated with shorter telomeres, but the underlying mechanisms are poorly understood. One possibility is that the neuroendocrine responses to stress exposure are involved.<br><br>OBJECTIVE: To test the hypothesis that greater cortisol responsivity to acute stressors predicts more rapid telomere attrition.<br><br>DESIGN: We measured salivary cortisol responses to 2 challenging behavioral tasks. Leukocyte telomere length was measured at the time of mental stress testing and 3 years later.<br><br>PARTICIPANTS: We studied 411 initially healthy men and women aged 54 to 76 years.<br><br>MAIN OUTCOME MEASURE: Leukocyte telomere length.<br><br>RESULTS: Cortisol responses to this protocol were small; we divided participants into cortisol responders (n = 156) and nonresponders (n = 255) using a criterion (&#x2265;20% increase in cortisol concentration) previously shown to predict increases in cardiovascular disease risk. There was no significant association between cortisol responsivity and baseline telomere length, although cortisol responders tended to have somewhat shorter telomeres (&#x3b2; = -0.061; standard error, 0.049). But cortisol responders had shorter telomeres and more rapid telomere attrition than nonresponders on follow-up, after controlling statistically for age, sex, socioeconomic status, smoking, time of day of stress , and baseline telomere length (&#x3b2; = -0.10; standard error, 0.046; P = 0.029). The association was maintained after additional control for cardiovascular risk factors (&#x3b2; = -0.11; P = 0.031). The difference between cortisol responders and nonresponders was equivalent to approximately 2 years in aging.<br><br>CONCLUSIONS: These findings suggest that cortisol responsivity may mediate, in part, the relationship between psychological stress and cellular aging.},
}
@article {pmid27959588,
year = {2017},
author = {Al-Mayah, AH and Bright, SJ and Bowler, DA and Slijepcevic, P and Goodwin, E and Kadhim, MA},
title = {Exosome-Mediated Telomere Instability in Human Breast Epithelial Cancer Cells after X Irradiation.},
journal = {Radiation research},
volume = {187},
number = {1},
pages = {98-106},
doi = {10.1667/RR14201.1},
pmid = {27959588},
issn = {1938-5404},
mesh = {Breast Neoplasms/*pathology ; Bystander Effect/radiation effects ; Exosomes/*genetics/*radiation effects ; Genomic Instability/*radiation effects ; Humans ; MCF-7 Cells ; Mammary Glands, Human/*pathology ; Telomere/*genetics/*radiation effects ; Time Factors ; X-Rays/adverse effects ; },
abstract = {In directly irradiating cells, telomere metabolism is altered and similar effects have been observed in nontargeted cells. Exosomes and their cargo play dominant roles in communicating radiation-induced bystander effects with end points related to DNA damage. Here we report novel evidence that exosomes are also responsible for inducing telomere-related bystander effects. Breast epithelial cancer cells were exposed to either 2 Gy X rays, or exposed to irradiated cell conditioned media (ICCM), or exosomes purified from ICCM. Compared to control cells, telomerase activity decreased in the 2 Gy irradiated cells and both bystander samples after one population doubling. At the first population doubling, telomere length was shorter in the 2 Gy irradiated sample but not in the bystander samples. By 24 population doublings telomerase activity recovered to control levels in all samples; however, the 2 Gy irradiated sample continued to demonstrate short telomeres and both bystander samples acquired shorter telomeres. RNase treatment of exosomes prevented the bystander effects on telomerase and telomere length that were observed at 1 population doubling and 24 population doublings, respectively. Thermal denaturation by boiling eliminated the reduction of telomere length in bystander samples, suggesting that the protein fraction of exosomes also contributes to the telomeric effect. RNase treatment plus boiling abrogated all telomere-related effects in directly irradiated and bystander cell populations. These findings suggest that both proteins and RNAs of exosomes can induce alterations in telomeric metabolism, which can instigate genomic instability in epithelial cancer cells after X-ray irradiation.},
}
@article {pmid27958374,
year = {2016},
author = {Yamada, T and Yoshimura, H and Shimada, R and Hattori, M and Eguchi, M and Fujiwara, TK and Kusumi, A and Ozawa, T},
title = {Spatiotemporal analysis with a genetically encoded fluorescent RNA probe reveals TERRA function around telomeres.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {38910},
pmid = {27958374},
issn = {2045-2322},
mesh = {Cell Line ; Fluorescent Dyes ; Heterogeneous Nuclear Ribonucleoprotein A1/*metabolism ; Humans ; Optical Imaging/*methods ; *RNA Probes ; RNA, Long Noncoding/*metabolism ; Spatio-Temporal Analysis ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomeric repeat-containing RNA (TERRA) controls the structure and length of telomeres through interactions with numerous telomere-binding proteins. However, little is known about the mechanism by which TERRA regulates the accessibility of the proteins to telomeres, mainly because of the lack of spatiotemporal information of TERRA and its-interacting proteins. We developed a fluorescent probe to visualize endogenous TERRA to investigate its dynamics in living cells. Single-particle fluorescence imaging revealed that TERRA accumulated in a telomere-neighboring region and trapped diffusive heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), thereby inhibiting hnRNPA1 localization to the telomere. These results suggest that TERRA regulates binding of hnRNPA1 to the telomere in a region surrounding the telomere, leading to a deeper understanding of the mechanism of TERRA function.},
}
@article {pmid27958357,
year = {2016},
author = {Zhao, F and Yang, Q and Shi, S and Luo, X and Sun, Y},
title = {Semen preparation methods and sperm telomere length: density gradient centrifugation versus the swim up procedure.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {39051},
pmid = {27958357},
issn = {2045-2322},
mesh = {Adult ; Centrifugation, Density Gradient ; DNA Fragmentation ; Humans ; Male ; Semen/*cytology ; Semen Analysis ; Sperm Motility/*physiology ; Spermatozoa/*cytology ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Previous studies have shown that both density gradient centrifugation (DGC) and swim up (SU) procedures can select spermatozoa with longer telomeres for assisted reproduction techniques (ART). However, it is unknown which approach is more effective. The aim of the present study was to compare the effects of these two methods on sperm telomere length (STL). A total of 150 normozoospermic subjects were recruited. STL, DNA fragmentation index (DFI), reactive oxygen species (ROS) content and progressive motility of semen samples were detected before and after the procedures of DGC and SU. When compared to raw semen, the average length of sperm telomeres was significantly longer after the two sperm preparation methods. However, no significant difference was found between the DGC and SU procedures. We also found that semen prepared by the two methods had lower DNA fragmentation, ROS content and sperm progressive motility. However, no significant difference was found in those parameters between the two procedures. This is the first study that compares the effects of the DGC and SU procedures on STL, and the results show that both methods can recover a sperm population with longer STL and better DNA integrity for ART.},
}
@article {pmid27956416,
year = {2017},
author = {Hammadah, M and Al Mheid, I and Wilmot, K and Ramadan, R and Abdelhadi, N and Alkhoder, A and Obideen, M and Pimple, PM and Levantsevych, O and Kelli, HM and Shah, A and Sun, YV and Pearce, B and Kutner, M and Long, Q and Ward, L and Ko, YA and Hosny Mohammed, K and Lin, J and Zhao, J and Bremner, JD and Kim, J and Waller, EK and Raggi, P and Sheps, D and Quyyumi, AA and Vaccarino, V},
title = {Telomere Shortening, Regenerative Capacity, and Cardiovascular Outcomes.},
journal = {Circulation research},
volume = {120},
number = {7},
pages = {1130-1138},
pmid = {27956416},
issn = {1524-4571},
support = {R56 HL126558/HL/NHLBI NIH HHS/United States ; R38 AI140299/AI/NIAID NIH HHS/United States ; R01 HL079115/HL/NHLBI NIH HHS/United States ; R01 MH056120/MH/NIMH NIH HHS/United States ; R01 DK091369/DK/NIDDK NIH HHS/United States ; P01 HL095070/HL/NHLBI NIH HHS/United States ; T32 HL130025/HL/NHLBI NIH HHS/United States ; K23 HL127251/HL/NHLBI NIH HHS/United States ; R01 HL129511/HL/NHLBI NIH HHS/United States ; KL2 TR000455/TR/NCATS NIH HHS/United States ; R01 HL109413/HL/NHLBI NIH HHS/United States ; R01 AG042127/AG/NIA NIH HHS/United States ; U54 AG062334/AG/NIA NIH HHS/United States ; K01 AG034259/AG/NIA NIH HHS/United States ; K24 HL077506/HL/NHLBI NIH HHS/United States ; R01 NS064162/NS/NINDS NIH HHS/United States ; R01 HL125246/HL/NHLBI NIH HHS/United States ; P01 HL086773/HL/NHLBI NIH HHS/United States ; DP3 DK108245/DK/NIDDK NIH HHS/United States ; UL1 TR000454/TR/NCATS NIH HHS/United States ; R01 HL068630/HL/NHLBI NIH HHS/United States ; R01 HL095479/HL/NHLBI NIH HHS/United States ; RF1 AG051633/AG/NIA NIH HHS/United States ; DP3 DK094346/DK/NIDDK NIH HHS/United States ; K24 MH076955/MH/NIMH NIH HHS/United States ; R01 HL088726/HL/NHLBI NIH HHS/United States ; U10 HL110302/HL/NHLBI NIH HHS/United States ; P20 HL113451/HL/NHLBI NIH HHS/United States ; P01 HL101398/HL/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Biomarkers/blood ; Bone Marrow Cells/cytology/metabolism ; Coronary Artery Disease/*blood/genetics ; Female ; Humans ; Male ; Middle Aged ; Regeneration ; *Telomere Shortening ; },
abstract = {RATIONALE: Leukocyte telomere length (LTL) is a biological marker of aging, and shorter LTL is associated with adverse cardiovascular outcomes. Reduced regenerative capacity has been proposed as a mechanism. Bone marrow-derived circulating progenitor cells are involved in tissue repair and regeneration.<br><br>OBJECTIVE: Main objective of this study was to examine the relationship between LTL and progenitor cells and their impact on adverse cardiovascular outcomes.<br><br>METHODS AND RESULTS: We measured LTL by quantitative polymerase chain reaction in 566 outpatients (age: 63&#xb1;9 years; 76% men) with coronary artery disease. Circulating progenitor cells were enumerated by flow cytometry. After adjustment for age, sex, race, body mass index, smoking status, and previous myocardial infarction, a shorter LTL was associated with a lower CD34[+] cell count: for each 10% shorter LTL, CD34[+] levels were 5.2% lower (P<0.001). After adjustment for the aforementioned factors, both short LTL (<Q1) and low CD34+ levels (<Q1) predicted adverse cardiovascular outcomes (death, myocardial infarction, coronary revascularization, or cerebrovascular events) independently of each other, with a hazard ratio of 1.8 and 95% confidence interval of 1.1 to 2.0, and a hazard ratio of 2.1 and 95% confidence interval of 1.3 to 3.0, respectively, comparing Q1 to Q2-4. Patients who had both short LTL (<Q1) and low CD34+ cell count (<Q1) had the greatest risk of adverse outcomes (hazard ratio =3.5; 95% confidence interval, 1.7-7.1).<br><br>CONCLUSIONS: Although shorter LTL is associated with decreased regenerative capacity, both LTL and circulating progenitor cell levels are independent and additive predictors of adverse cardiovascular outcomes in coronary artery disease patients. Our results suggest that both biological aging and reduced regenerative capacity contribute to cardiovascular events, independent of conventional risk factors.},
}
@article {pmid27956006,
year = {2017},
author = {Wark, L and Klonisch, T and Awe, J and LeClerc, C and Dyck, B and Quon, H and Mai, S},
title = {Dynamics of three-dimensional telomere profiles of circulating tumor cells in patients with high-risk prostate cancer who are undergoing androgen deprivation and radiation therapies.},
journal = {Urologic oncology},
volume = {35},
number = {3},
pages = {112.e1-112.e11},
doi = {10.1016/j.urolonc.2016.10.018},
pmid = {27956006},
issn = {1873-2496},
mesh = {Aged ; Androgen Antagonists/therapeutic use ; Antineoplastic Agents, Hormonal/*therapeutic use ; Cell Count/methods ; Cell Nucleus/metabolism ; Chemoradiotherapy/methods ; Female ; Genomic Instability/*drug effects/radiation effects ; Healthy Volunteers ; Humans ; Imaging, Three-Dimensional/methods ; Immunohistochemistry ; In Situ Hybridization, Fluorescence/methods ; Kallikreins/blood ; Male ; Microscopy, Fluorescence ; Middle Aged ; Neoplastic Cells, Circulating/*drug effects/metabolism/radiation effects ; Prostate/pathology ; Prostate-Specific Antigen/blood ; Prostatic Neoplasms/blood/genetics/pathology/*therapy ; Receptors, Androgen/metabolism ; Telomere/*drug effects/metabolism/radiation effects/ultrastructure ; Treatment Outcome ; },
abstract = {INTRODUCTION: Accurate assessment and monitoring of the therapeutic efficacy of locally advanced prostate cancer remains a major clinical challenge. Contrary to prostate biopsies, circulating tumor cells (CTCs) are a cellular source repeatedly obtainable by blood sampling and could serve as a surrogate marker for treatment efficacy. In this study, we used size-based filtration to isolate and enumerate CTCs from the blood of 20 patients with high-risk (any one of cT3, Gleason 8-10, or prostate-specific antigen>20ng/ml), nonmetastatic, and treatment-naive prostate cancer before and after androgen deprivation therapy (ADT) and radiation therapy (RT).<br><br>MATERIALS AND METHODS: We performed 3D telomere-specific quantitative fluorescence in situ hybridization on isolated CTCs to determine 3D telomere profiles for each patient before and throughout the course of both ADT and RT.<br><br>RESULTS: Based on the distinct 3D telomere signatures of CTC before treatment, patients were divided into 3 groups. ADT and RT resulted in distinct changes in 3D telomere signatures of CTCs, which were unique for each of the 3 patient groups.<br><br>CONCLUSION: The ability of 3D telomere analysis of CTCs to identify disease heterogeneity among a clinically homogeneous group of patients, which reveals differences in therapeutic responses, provides a new opportunity for better treatment monitoring and management of patients with high-risk prostate cancer.},
}
@article {pmid27943596,
year = {2017},
author = {Bateson, M and Nettle, D},
title = {The telomere lengthening conundrum - it could be biology.},
journal = {Aging cell},
volume = {16},
number = {2},
pages = {312-319},
pmid = {27943596},
issn = {1474-9726},
support = {666669/ERC_/European Research Council/International ; NC/K000802/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; },
mesh = {Computer Simulation ; Models, Biological ; *Telomere Homeostasis ; },
abstract = {Longitudinal studies of human leucocyte telomere length often report a percentage of individuals whose telomeres appear to lengthen. However, based on theoretical considerations and empirical data, Steenstrup et al. (Nucleic Acids Research, 2013, vol 41(13): e131) concluded that this lengthening is unlikely to be a real biological phenomenon and is more likely to be an artefact of measurement error. We dispute the logic underlying this claim. We argue that Steenstrup et al.'s analysis is incomplete because it failed to compare predictions derived from assuming a scenario with no true telomere lengthening with alternative scenarios in which true lengthening occurs. To address this deficit, we built a computational model of telomere dynamics that allowed us to compare the predicted percentage of observed telomere length gainers given differing assumptions about measurement error and the true underling dynamics. We modelled a set of scenarios, all assuming measurement error, but both with and without true telomere lengthening. We found a range of scenarios assuming some true telomere lengthening that yielded either similar or better quantitative fits to the empirical data on the percentage of individuals showing apparent telomere lengthening. We conclude that although measurement error contributes to the prevalence of apparent telomere lengthening, Steenstrup et al.'s conclusion was too strong, and current data do not allow us to reject the hypothesis that true telomere lengthening is a real biological phenomenon in epidemiological studies. Our analyses highlight the need for process-level models in the analysis of telomere dynamics.},
}
@article {pmid27940556,
year = {2017},
author = {Cicconi, A and Micheli, E and Vernì, F and Jackson, A and Gradilla, AC and Cipressa, F and Raimondo, D and Bosso, G and Wakefield, JG and Ciapponi, L and Cenci, G and Gatti, M and Cacchione, S and Raffa, GD},
title = {The Drosophila telomere-capping protein Verrocchio binds single-stranded DNA and protects telomeres from DNA damage response.},
journal = {Nucleic acids research},
volume = {45},
number = {6},
pages = {3068-3085},
pmid = {27940556},
issn = {1362-4962},
mesh = {Animals ; Chromosomal Proteins, Non-Histone/physiology ; *DNA Damage ; DNA Repair ; DNA, Single-Stranded/*metabolism/ultrastructure ; Drosophila/genetics ; Drosophila Proteins/chemistry/*metabolism/physiology/ultrastructure ; Microscopy, Atomic Force ; Protein Domains ; Protein Multimerization ; Replication Protein A/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/chemistry/*metabolism/ultrastructure ; },
abstract = {Drosophila telomeres are sequence-independent structures maintained by transposition to chromosome ends of three specialized retroelements rather than by telomerase activity. Fly telomeres are protected by the terminin complex that includes the HOAP, HipHop, Moi and Ver proteins. These are fast evolving, non-conserved proteins that localize and function exclusively at telomeres, protecting them from fusion events. We have previously suggested that terminin is the functional analogue of shelterin, the multi-protein complex that protects human telomeres. Here, we use electrophoretic mobility shift assay (EMSA) and atomic force microscopy (AFM) to show that Ver preferentially binds single-stranded DNA (ssDNA) with no sequence specificity. We also show that Moi and Ver form a complex in vivo. Although these two proteins are mutually dependent for their localization at telomeres, Moi neither binds ssDNA nor facilitates Ver binding to ssDNA. Consistent with these results, we found that Ver-depleted telomeres form RPA and γH2AX foci, like the human telomeres lacking the ssDNA-binding POT1 protein. Collectively, our findings suggest that Drosophila telomeres possess a ssDNA overhang like the other eukaryotes, and that the terminin complex is architecturally and functionally similar to shelterin.},
}
@article {pmid27936200,
year = {2016},
author = {Kong, PL and Looi, LM and Lau, TP and Cheah, PL},
title = {Correction: Assessment of Telomere Length in Archived Formalin-Fixed, Paraffinized Human Tissue Is Confounded by Chronological Age and Storage Duration.},
journal = {PloS one},
volume = {11},
number = {12},
pages = {e0168238},
pmid = {27936200},
issn = {1932-6203},
abstract = {[This corrects the article DOI: 10.1371/journal.pone.0161720.].},
}
@article {pmid27930670,
year = {2016},
author = {Larcher, MV and Pasquier, E and MacDonald, RS and Wellinger, RJ},
title = {Ku Binding on Telomeres Occurs at Sites Distal from the Physical Chromosome Ends.},
journal = {PLoS genetics},
volume = {12},
number = {12},
pages = {e1006479},
pmid = {27930670},
issn = {1553-7404},
mesh = {Chromosomes, Fungal/genetics ; DNA Breaks, Double-Stranded ; DNA End-Joining Repair/*genetics ; DNA Helicases/genetics ; DNA Replication/*genetics ; DNA-Binding Proteins/*genetics/metabolism ; Heterochromatin/genetics ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics ; Telomere ; Telomere-Binding Proteins/genetics ; rap1 GTP-Binding Proteins/*genetics ; },
abstract = {The Ku complex binds non-specifically to DNA breaks and ensures repair via NHEJ. However, Ku is also known to bind directly to telomeric DNA ends and its presence there is associated with telomere capping, but avoiding NHEJ. How the complex discriminates between a DNA break and a telomeric extremity remains unknown. Our results using a tagged Ku complex, or a chromosome end capturing method, in budding yeast show that yKu association with telomeres can occur at sites distant from the physical end, on sub-telomeric elements, as well as on interstitial telomeric repeats. Consistent with previous studies, our results also show that yKu associates with telomeres in two distinct and independent ways: either via protein-protein interactions between Yku80 and Sir4 or via direct DNA binding. Importantly, yKu associates with the new sites reported here via both modes. Therefore, in sir4Δ cells, telomere bound yKu molecules must have loaded from a DNA-end near the transition of non-telomeric to telomeric repeat sequences. Such ends may have been one sided DNA breaks that occur as a consequence of stalled replication forks on or near telomeric repeat DNA. Altogether, the results predict a new model for yKu function at telomeres that involves yKu binding at one-sided DNA breaks caused by replication stalling. On telomere proximal chromatin, this binding is not followed by initiation of non-homologous end-joining, but rather by break-induced replication or repeat elongation by telomerase. After repair, the yKu-distal portion of telomeres is bound by Rap1, which in turn reduces the potential for yKu to mediate NHEJ. These results thus propose a solution to a long-standing conundrum, namely how to accommodate the apparently conflicting functions of Ku on telomeres.},
}
@article {pmid27929092,
year = {2016},
author = {Weng, Q and Du, J and Yu, F and Huang, T and Chen, M and Lv, H and Ma, H and Hu, Z and Jin, G and Hu, Y and Shen, H},
title = {The known genetic loci for telomere length may be involved in the modification of telomeres length after birth.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {38729},
pmid = {27929092},
issn = {2045-2322},
mesh = {Adult ; Alleles ; China ; DNA/blood ; Female ; Genome-Wide Association Study ; Humans ; Infant, Newborn ; Pregnancy ; *Telomere ; Young Adult ; },
abstract = {Telomere length varies considerably among individuals. It is highly heritable and decreases with ageing or ageing related diseases. Recently, genome-wide association studies (GWAS) have identified several genetic loci associated with telomere length in adults. However, it is unclear whether these loci represent the genetic basis of telomere length or determine the individual susceptibility to shortening during growth process. Using DNA extracted from peripheral and cord blood of 444 mother-newborn pairs from a Chinese population, we measured relative telomere length (RTL) and genotyped eight known telomere length related variants that were initially identified in populations of European descent. We observed the T allele of rs10936599 and the T allele of rs2736100 were norminally associated with shorter RTL (P = 0.041 and 0.046, respectively) in maternal samples. Furthermore, the Weighted genetic score (WGS) of eight variants was significantly associated with RTL in maternal samples (R[2] = 0.012, P = 0.025). However, we didn't detect any significant associations for any individual variant or the combined WGS with RTL in newborns. These findings didn't support the hypothesis that telomere length related loci may affect telomere length at birth, and we suggested that these loci may play a role in telomere length modification during life course.},
}
@article {pmid27925632,
year = {2017},
author = {Oliveira, NM and Rios, ECS and de Lima, TM and Victorino, VJ and Barbeiro, H and Pinheiro da Silva, F and Szabo, C and Soriano, FG},
title = {Sepsis induces telomere shortening: a potential mechanism responsible for delayed pathophysiological events in sepsis survivors?.},
journal = {Molecular medicine (Cambridge, Mass.)},
volume = {22},
number = {},
pages = {886-891},
pmid = {27925632},
issn = {1528-3658},
support = {R01 GM107846/GM/NIGMS NIH HHS/United States ; },
abstract = {Sepsis survivors suffer from additional morbidities, including higher disk of readmissions, nervous system disturbances and cognitive dysfunction, and increased mortality, even several years after the initial episode of sepsis. In many ways, the phenotype of sepsis survivors resembles the phenotype associated with accelerated aging. Since telomere shortening is a hallmark of aging, we investigated whether sepsis also leads to telomere shortening. Male balb/c mice were divided into two groups: the control group received 100 μl of normal saline intraperitoneally; the sepsis group received 15 mg/kg of bacterial lipopolysaccharide i.p. After 48 hours, animals were sacrificed to collect blood, spleen and kidney. The human component of our study utilized blood samples obtained from patients in the Trauma Department and samples collected 7 days later in those patients who developed sepsis. Telomere length was measured by quantitative PCR. Since oxidative stress is a known inducer of telomere shortening, thiobarbituric acid reactive substances and superoxide dismutase (SOD) activity were analyzed in order to evaluate oxidative stress burden. Induction of endotoxemia in mice resulted in significant telomere shortening in spleen and kidney. Blood cells from patients that progressed to sepsis also exhibited a statistically significant reduction of telomere length. Endotoxemia in mice also induced an early-onset increase in oxidative stress markers, but was not associated with a downregulation of telomerase protein expression. We conclude that endotoxemia and sepsis induce telomere shortening in various tissues and hypothesize that this may contribute to the pathogenesis of the delayed pathophysiological events in sepsis survivors.},
}
@article {pmid27923931,
year = {2017},
author = {Popuri, V and Hsu, J and Khadka, P and Horvath, K and Liu, Y and Croteau, DL and Bohr, VA},
title = {Human RECQL1 participates in telomere maintenance.},
journal = {Nucleic acids research},
volume = {45},
number = {5},
pages = {2935},
doi = {10.1093/nar/gkw1217},
pmid = {27923931},
issn = {1362-4962},
}
@article {pmid27922939,
year = {2017},
author = {Fagan, E and Sun, F and Bae, H and Elo, I and Andersen, SL and Lee, J and Christensen, K and Thyagarajan, B and Sebastiani, P and Perls, T and Honig, LS and Schupf, N and , },
title = {Telomere length is longer in women with late maternal age.},
journal = {Menopause (New York, N.Y.)},
volume = {24},
number = {5},
pages = {497-501},
pmid = {27922939},
issn = {1530-0374},
support = {U01 AG023712/AG/NIA NIH HHS/United States ; U01 AG023744/AG/NIA NIH HHS/United States ; P30 AG034424/AG/NIA NIH HHS/United States ; P30 AG012836/AG/NIA NIH HHS/United States ; U01 AG023749/AG/NIA NIH HHS/United States ; U01 AG023755/AG/NIA NIH HHS/United States ; P01 AG008761/AG/NIA NIH HHS/United States ; U01 AG023746/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Denmark ; Female ; Humans ; *Leukocytes ; Longevity ; *Maternal Age ; Phenotype ; Pregnancy ; *Telomere ; United States ; },
abstract = {OBJECTIVE: Maternal age at birth of last child has been associated with maternal longevity. The aim of this study was to determine whether older women with a history of late maternal age at last childbirth had a longer leukocyte telomere length than those with maternal age at last childbirth of 29 years or less.<br><br>METHODS: A nested case control study was conducted using data from the Long Life Family Study. Three hundred eighty-seven women who gave birth to at least one child and lived to the top fifth percentile of their birth cohort, or died before the top fifth percentile of their birth cohort died, but were at least 70 years old, were studied. Logistic regression models using generalized estimating equations were used to determine the association between tertiles of telomere length and maternal age at last childbirth, adjusting for covariates.<br><br>RESULTS: Age at birth of the last child was significantly associated with leukocyte telomere length. Compared with women who gave birth to their last child before the age of 29, women who were past the age of 33 when they had their last child were two to three times more likely to have leukocyte telomere length in the second and third tertiles than in the first tertile.<br><br>CONCLUSIONS: These findings show an association between longer leukocyte telomere length and a later maternal age at birth of last child, suggesting that extended maternal age at last childbirth may be a marker for longevity.},
}
@article {pmid27922633,
year = {2016},
author = {Mamdani, F and Rollins, B and Morgan, L and Myers, RM and Barchas, JD and Schatzberg, AF and Watson, SJ and Akil, H and Potkin, SG and Bunney, WE and Vawter, MP and Sequeira, PA},
title = {Variable telomere length across post-mortem human brain regions and specific reduction in the hippocampus of major depressive disorder.},
journal = {Translational psychiatry},
volume = {6},
number = {12},
pages = {e969},
doi = {10.1038/tp.2015.164},
pmid = {27922633},
issn = {2158-3188},
support = {R01 MH097082/MH/NIMH NIH HHS/United States ; },
}
@article {pmid27922610,
year = {2016},
author = {Sarkar, J and Liu, Y},
title = {The origin of oxidized guanine resolves the puzzle of oxidation-induced telomere-length alterations.},
journal = {Nature structural &amp; molecular biology},
volume = {23},
number = {12},
pages = {1070-1071},
pmid = {27922610},
issn = {1545-9985},
support = {Z99 AG999999//Intramural NIH HHS/United States ; },
mesh = {DNA ; *Guanine ; Oxidation-Reduction ; *Telomere ; },
abstract = {Although oxidative stress has long been considered to be a major factor contributing to telomere shortening, recent work has established that oxidative stress and DNA damage are linked to telomere lengthening. Now, Opresko and colleagues resolve this apparent discrepancy by showing that differential modulation of telomerase activity depends on the origin of a common oxidative guanine lesion.},
}
@article {pmid27922187,
year = {2017},
author = {Merghoub, N and El Btaouri, H and Benbacer, L and Gmouh, S and Trentesaux, C and Brassart, B and Attaleb, M and Madoulet, C and Wenner, T and Amzazi, S and Morjani, H and El Mzibri, M},
title = {Tomentosin Induces Telomere Shortening and Caspase-Dependant Apoptosis in Cervical Cancer Cells.},
journal = {Journal of cellular biochemistry},
volume = {118},
number = {7},
pages = {1689-1698},
doi = {10.1002/jcb.25826},
pmid = {27922187},
issn = {1097-4644},
mesh = {Apoptosis/drug effects/genetics ; Blotting, Western ; Caspase 3/genetics/metabolism ; Cell Cycle Checkpoints/drug effects/genetics ; Cell Division/drug effects/genetics ; Cell Line, Tumor ; Cell Proliferation/drug effects/genetics ; Female ; G2 Phase/drug effects/genetics ; HeLa Cells ; Humans ; Lactones/*pharmacology ; Membrane Potential, Mitochondrial/drug effects/genetics ; Reactive Oxygen Species/metabolism ; Sesquiterpenes/*pharmacology ; Telomere/drug effects/*genetics ; Uterine Cervical Neoplasms/*genetics ; },
abstract = {Tomentosin, a natural sesquiterpene lactone purified from of Inula viscosa L., was investigated for its anti-proliferative, telomere shortening, and apoptotic effects on human cervical cancer HeLa and SiHa cell lines. Tomentosin was found to inhibit the growth of SiHa and HeLa cell lines in dose and time-dependent manner (IC50 values of 7.10 ± 0.78 μM and 5.87 ± 0.36 μM, respectively after 96 h of treatment). As evidenced by TTAGGG telomere length assay, tomentosin target specifically the telomeric overhang lengthening. This was confirmed by the evaluation of the cytotoxic effects of tomentosin in the foetal fibroblast Wi38 and JW10 cells which were derived from Wi38 and express hTERT, the telomerase catalytic subunit. We found that JW10 cells are 4.7-fold more sensitive to tomentosin which argues for telomere as its specific target. Furthermore, we found that tomentosin mediate this cytotoxic effect by inducing apoptosis and cell cycle arrest at G2/M phase. Morphological features of treated cells, as evidenced by Hoechst 33324 staining, revealed that the cytotoxic effect was due to induction of apoptosis. This was accompanied by pro-caspase-3 cleavage, an increase in caspase-3 activity and a cleavage of poly (ADP-ribose) polymerase (PARP). Moreover, tomentosin induced a decrease in mitochondrial membrane potential (ΔΨm) and an increase in reactive oxygen species (ROS), accompanied by a decrease in Bcl-2 expression. This indicates that tomentosin-induced apoptosis may involve a mitochondria-mediated signaling pathway. This study provides the first evidence that tomentosin targets telomere machinery and induces apoptosis in cervical cancer cells. The molecular mechanism underlying tomentosin-induced apoptosis may involve a mitochondria-mediated signaling pathway. J. Cell. Biochem. 118: 1689-1698, 2017. © 2016 Wiley Periodicals, Inc.},
}
@article {pmid27920200,
year = {2017},
author = {Duell, EJ},
title = {Telomere length and pancreatic cancer risk: breaking down the evidence.},
journal = {Gut},
volume = {66},
number = {6},
pages = {1},
doi = {10.1136/gutjnl-2016-313156},
pmid = {27920200},
issn = {1468-3288},
mesh = {Case-Control Studies ; Humans ; Pancreas ; *Pancreatic Neoplasms ; Risk ; Risk Factors ; *Telomere ; },
}
@article {pmid27918657,
year = {2017},
author = {Muniesa, CA and Verde, Z and Diaz-Ureña, G and Santiago, C and Gutiérrez, F and Díaz, E and Gómez-Gallego, F and Pareja-Galeano, H and Soares-Miranda, L and Lucia, A},
title = {Telomere Length in Elite Athletes.},
journal = {International journal of sports physiology and performance},
volume = {12},
number = {7},
pages = {994-996},
doi = {10.1123/ijspp.2016-0471},
pmid = {27918657},
issn = {1555-0273},
mesh = {Adult ; *Athletes ; Case-Control Studies ; *Exercise ; Female ; Humans ; Leukocytes/cytology ; Male ; Sedentary Behavior ; Telomere/*ultrastructure ; Young Adult ; },
abstract = {UNLABELLED: Growing evidence suggests that regular moderate-intensity physical activity is associated with an attenuation of leukocyte telomere length (LTL) shortening. However, more controversy exists regarding higher exercise loads such as those imposed by elite-sport participation.<br><br>METHODS: The authors investigated LTL differences between young elite athletes (n = 61, 54% men, age [mean &#xb1; SD] 27.2 &#xb1; 4.9 y) and healthy nonsmoker, physically inactive controls (n = 64, 52% men, 28.9 &#xb1; 6.3 y) using analysis of variance (ANOVA).<br><br>RESULTS: Elite athletes had, on average, higher LTL than control subjects, 0.89 &#xb1; 0.26 vs 0.78 &#xb1; 0.31, P = .013 for the group effect, with no significant sex (P = .995) or age effect (P = .114).<br><br>CONCLUSIONS: The results suggest that young elite athletes have longer telomeres than their inactive peers. Further research might assess the LTL of elite athletes of varying ages compared with both age-matched active and inactive individuals.},
}
@article {pmid27918544,
year = {2017},
author = {Rivera, T and Haggblom, C and Cosconati, S and Karlseder, J},
title = {A balance between elongation and trimming regulates telomere stability in stem cells.},
journal = {Nature structural &amp; molecular biology},
volume = {24},
number = {1},
pages = {30-39},
pmid = {27918544},
issn = {1545-9985},
support = {P30 CA014195/CA/NCI NIH HHS/United States ; R01 AG025837/AG/NIA NIH HHS/United States ; R01 CA174942/CA/NCI NIH HHS/United States ; R01 GM087476/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/metabolism ; Cells, Cultured ; Cellular Reprogramming ; DNA Replication ; DNA-Binding Proteins/metabolism ; Human Embryonic Stem Cells/*metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Nuclear Proteins/metabolism ; Repetitive Sequences, Nucleic Acid ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; },
abstract = {Telomere length maintenance ensures self-renewal of human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs); however, the mechanisms governing telomere length homeostasis in these cell types are unclear. Here, we report that telomere length is determined by the balance between telomere elongation, which is mediated by telomerase, and telomere trimming, which is controlled by XRCC3 and Nbs1, homologous recombination proteins that generate single-stranded C-rich telomeric DNA and double-stranded telomeric circular DNA (T-circles), respectively. We found that reprogramming of differentiated cells induces T-circle and single-stranded C-rich telomeric DNA accumulation, indicating the activation of telomere trimming pathways that compensate telomerase-dependent telomere elongation in hiPSCs. Excessive telomere elongation compromises telomere stability and promotes the formation of partially single-stranded telomeric DNA circles (C-circles) in hESCs, suggesting heightened sensitivity of stem cells to replication stress at overly long telomeres. Thus, tight control of telomere length homeostasis is essential to maintain telomere stability in hESCs.},
}
@article {pmid27911971,
year = {2016},
author = {Cardwell, MS},
title = {Commentary on "Association Between Maternal-Perceived Psychological Stress and Fetal Telomere Length".},
journal = {Southern medical journal},
volume = {109},
number = {12},
pages = {773},
doi = {10.14423/SMJ.0000000000000568},
pmid = {27911971},
issn = {1541-8243},
mesh = {Family ; Female ; Humans ; Perception ; Pregnancy ; Prenatal Care ; *Stress, Psychological ; *Telomere ; },
}
@article {pmid27911970,
year = {2016},
author = {Salihu, HM and King, LM and Nwoga, C and Paothong, A and Pradhan, A and Marty, PJ and Daas, R and Whiteman, VE},
title = {Association Between Maternal-Perceived Psychological Stress and Fetal Telomere Length.},
journal = {Southern medical journal},
volume = {109},
number = {12},
pages = {767-772},
doi = {10.14423/SMJ.0000000000000567},
pmid = {27911970},
issn = {1541-8243},
mesh = {Adult ; Diagnostic Self Evaluation ; Female ; Fetal Blood/*cytology ; Humans ; Infant, Newborn ; Labor, Obstetric/*psychology ; Obstetric Labor Complications/*psychology ; Pregnancy ; Stress, Psychological/*psychology ; Telomere/*genetics/physiology ; },
abstract = {OBJECTIVE: Our study aimed to investigate the association between maternal-perceived psychological stress and fetal telomere length.<br><br>METHODS: We recruited women in labor upon hospital delivery admission. Based on responses to the Perceived Stress Scale, we categorized participants as having "high," "normal," or "low" perceived stress. We collected umbilical cord blood samples (N = 71) and isolated genomic DNA from cord blood leukocytes using quantitative polymerase chain reaction. We used a ratio of relative telomere length derived by telomere-to-single-copy gene ratio (T/S ratio). We applied analysis of variance and bootstrapping statistical procedures.<br><br>RESULTS: Sixteen (22.5%) women were classified as having low perceived stress, 42 (59.2%) were classified as having normal perceived stress, and 13 (18.3%) were classified as having high perceived stress. Fetal telomere length differed significantly across the three stress groups in a dose-response pattern (T/S ratio of those with low perceived stress was greater than those with normal perceived stress, which was greater than those with high perceived stress [P < 0.05]).<br><br>CONCLUSIONS: Our findings support our hypothesis that maternal-perceived psychological stress during pregnancy is associated with shorter fetal telomere length and suggest maternal stress as a possible marker for early intrauterine programming for accelerated chromosomal aging.},
}
@article {pmid27911222,
year = {2017},
author = {Jezek, M and Gast, A and Choi, G and Kulkarni, R and Quijote, J and Graham-Yooll, A and Park, D and Green, EM},
title = {The histone methyltransferases Set5 and Set1 have overlapping functions in gene silencing and telomere maintenance.},
journal = {Epigenetics},
volume = {12},
number = {2},
pages = {93-104},
pmid = {27911222},
issn = {1559-2308},
support = {R03 AG052018/AG/NIA NIH HHS/United States ; },
mesh = {*Gene Silencing ; Histone-Lysine N-Methyltransferase/genetics/*metabolism ; Histones/metabolism ; Methylation ; Methyltransferases/genetics/*metabolism ; Protein Processing, Post-Translational ; Saccharomyces cerevisiae/enzymology/genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; *Telomere Homeostasis ; Transcriptome ; },
abstract = {Genes adjacent to telomeres are subject to transcriptional repression mediated by an integrated set of chromatin modifying and remodeling factors. The telomeres of Saccharomyces cerevisiae have served as a model for dissecting the function of diverse chromatin proteins in gene silencing, and their study has revealed overlapping roles for many chromatin proteins in either promoting or antagonizing gene repression. The H3K4 methyltransferase Set1, which is commonly linked to transcriptional activation, has been implicated in telomere silencing. Set5 is an H4 K5, K8, and K12 methyltransferase that functions with Set1 to promote repression at telomeres. Here, we analyzed the combined role for Set1 and Set5 in gene expression control at native yeast telomeres. Our data reveal that Set1 and Set5 promote a Sir protein-independent mechanism of repression that may primarily rely on regulation of H4K5ac and H4K8ac at telomeric regions. Furthermore, cells lacking both Set1 and Set5 have highly correlated transcriptomes to mutants in telomere maintenance pathways and display defects in telomere stability, linking their roles in silencing to protection of telomeres. Our data therefore provide insight into and clarify potential mechanisms by which Set1 contributes to telomere silencing and shed light on the function of Set5 at telomeres.},
}
@article {pmid27905522,
year = {2016},
author = {Tosevska, A and Franzke, B and Hofmann, M and Vierheilig, I and Schober-Halper, B and Oesen, S and Neubauer, O and Wessner, B and Wagner, KH},
title = {Circulating cell-free DNA, telomere length and bilirubin in the Vienna Active Ageing Study: exploratory analysis of a randomized, controlled trial.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {38084},
pmid = {27905522},
issn = {2045-2322},
mesh = {Aged ; Aged, 80 and over ; Aging/blood/*genetics/metabolism ; Bilirubin/*blood ; Biomarkers/blood ; Cell-Free Nucleic Acids/*blood ; Female ; Humans ; Institutionalization ; Male ; Resistance Training ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Telomere length (TL) in blood cells is widely used in human studies as a molecular marker of ageing. Circulating cell-free DNA (cfDNA) as well as unconjugated bilirubin (UCB) are dynamic blood constituents whose involvement in age-associated diseases is largely unexplored. To our knowledge, there are no published studies integrating all three parameters, especially in individuals of advanced age. Here we present a secondary analysis from the Vienna Active Aging Study (VAAS), a randomized controlled intervention trial in institutionalized elderly individuals (n = 101). Using an exploratory approach we combine three blood-based molecular markers (TL, UCB and cfDNA) with a range of primary and secondary outcomes from the intervention. We further look at the changes occurring in these parameters after 6-month resistance exercise training with or without supplementation. A correlation between UCB and TL was evident at baseline (p < 0.05), and both were associated with increased chromosomal anomalies such as nucleoplasmatic bridges and nuclear buds (p < 0.05). Of the three main markers explored in this paper, only cfDNA decreased significantly (p < 0.05) after 6-month training and dietary intervention. No clear relationship could be established between cfDNA and either UCB or TL. The trial was registered at ClinicalTrials.gov (NCT01775111).},
}
@article {pmid27903687,
year = {2016},
author = {Merck, SJ and Armanios, M},
title = {Shall we call them "telomere-mediated"? Renaming the idiopathic after the cause is found.},
journal = {The European respiratory journal},
volume = {48},
number = {6},
pages = {1556-1558},
doi = {10.1183/13993003.02115-2016},
pmid = {27903687},
issn = {1399-3003},
mesh = {Humans ; Idiopathic Pulmonary Fibrosis ; Telomerase/*genetics ; *Telomere ; },
}
@article {pmid27902754,
year = {2016},
author = {Mizutani, Y and Niizuma, Y and Yoda, K},
title = {How Do Growth and Sibling Competition Affect Telomere Dynamics in the First Month of Life of Long-Lived Seabird?.},
journal = {PloS one},
volume = {11},
number = {11},
pages = {e0167261},
pmid = {27902754},
issn = {1932-6203},
mesh = {Animals ; Charadriiformes/*genetics/*growth &amp; development/physiology ; Female ; Longevity/*genetics ; Male ; Nesting Behavior ; Oviposition ; *Siblings ; Telomere/*genetics ; },
abstract = {Telomeres are nucleotide sequences located at the ends of chromosomes that promote genome stability. Changes in telomere length (dynamics) are related to fitness or life expectancy, and telomere dynamics during the development phase are likely to be affected by growth and stress factors. Here, we examined telomere dynamics of black-tailed gull chicks (Larus crassirostris) in nests with and without siblings. We found that the initial telomere lengths of singletons at hatching were longer than those of siblings, indicating that singletons are higher-quality chicks than siblings in terms of telomere length. Other factors likely affecting individual quality (i.e., sex, laying date, laying order of eggs, and clutch size) were not related to telomere lengths. Within broods, initial telomere lengths were longer in older chicks than in younger chicks, suggesting that maternal effects, which vary with laying sequence, influence the initial lengths. Additionally, telomeres of chicks with a sibling showed more attrition between hatching and fledging than those of singleton chicks, suggesting that being raised with siblings can cause a sustained competitive environment that leads to telomere loss. High growth rates were associated with a low degree of telomere shortening observed in older siblings, perhaps because slower growth reflects higher food stress and/or higher aerobic metabolism from increased begging effort. Our results show that developmental telomere attrition was an inevitable consequence in two-chick nests in the pre- and post-hatching microenvironments due to the combination of social stress within the nest and maternal effects. The results of our study shed light on telomere dynamics in early life, which may represent an important physiological undercurrent of life-history traits.},
}
@article {pmid27898678,
year = {2016},
author = {Rehkopf, DH and Needham, BL and Lin, J and Blackburn, EH and Zota, AR and Wojcicki, JM and Epel, ES},
title = {Leukocyte Telomere Length in Relation to 17 Biomarkers of Cardiovascular Disease Risk: A Cross-Sectional Study of US Adults.},
journal = {PLoS medicine},
volume = {13},
number = {11},
pages = {e1002188},
pmid = {27898678},
issn = {1549-1676},
support = {K01 AG047280/AG/NIA NIH HHS/United States ; R01 AG033592/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Biomarkers/*analysis/blood ; Cardiovascular Diseases/blood/epidemiology/*genetics ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/*physiology ; Male ; Middle Aged ; Nutrition Surveys ; Risk Factors ; *Telomere Shortening ; United States/epidemiology ; Young Adult ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) is a putative biological marker of immune system age, and there are demonstrated associations between LTL and cardiovascular disease. This may be due in part to the relationship of LTL with other biomarkers associated with cardiovascular disease risk. However, the strength of associations between LTL and adiposity, metabolic, proinflammatory, and cardiovascular biomarkers has not been systematically evaluated in a United States nationally representative population.<br><br>METHODS AND FINDINGS: We examined associations between LTL and 17 cardiovascular biomarkers, including lipoproteins, blood sugar, circulatory pressure, proinflammatory markers, kidney function, and adiposity measures, in adults ages 20 to 84 from the cross-sectional US nationally representative 1999-2002 National Health and Nutrition Examination Survey (NHANES) (n = 7,252), statistically adjusting for immune cell type distributions. We also examine whether these associations differed systematically by age, race/ethnicity, gender, education, and income. We found that a one unit difference in the following biomarkers were associated with kilobase pair differences in LTL: BMI -0.00478 (95% CI -0.00749--0.00206), waist circumference -0.00211 (95% CI -0.00325--0.000969), percentage of body fat -0.00516 (95% CI -0.00761--0.0027), high density lipoprotein (HDL) cholesterol 0.00179 (95% CI 0.000571-0.00301), triglycerides -0.000285 (95% CI -0.000555--0.0000158), pulse rate -0.00194 (95% CI -0.00317--0.000705), C-reactive protein -0.0363 (95% CI 0.0601--0.0124), cystatin C -0.0391 (95% CI -0.0772--0.00107). When using clinical cut-points we additionally found associations between LTL and insulin resistance -0.0412 (95% CI -0.0685--0.0139), systolic blood pressure 0.0455 (95% CI 0.00137-0.0897), and diastolic blood pressure -0.0674 (95% CI -0.126--0.00889). These associations were 10%-15% greater without controlling for leukocyte cell types. There were very few differences in the associations by age, race/ethnicity, gender, education, or income. Our findings are relevant to the relationships between these cardiovascular biomarkers in the general population but not to cardiovascular disease as a clinical outcome.<br><br>CONCLUSIONS: LTL is most strongly associated with adiposity, but is also associated with biomarkers across several physiological systems. LTL may thus be a predictor of cardiovascular disease through its association with multiple risk factors that are physiologically correlated with risk for development of cardiovascular disease. Our results are consistent with LTL being a biomarker of cardiovascular aging through established physiological mechanisms.},
}
@article {pmid27896432,
year = {2017},
author = {Kronenberg, G and Uhlemann, R and Schöner, J and Wegner, S and Boujon, V and Deigendesch, N and Endres, M and Gertz, K},
title = {Repression of telomere-associated genes by microglia activation in neuropsychiatric disease.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {267},
number = {5},
pages = {473-477},
pmid = {27896432},
issn = {1433-8491},
mesh = {Animals ; CD11b Antigen/metabolism ; Cell Polarity/drug effects/genetics ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism ; Cytokines/genetics/metabolism ; Disease Models, Animal ; Gene Expression Regulation/drug effects/*genetics ; Infarction, Middle Cerebral Artery/*pathology ; Lipopolysaccharides/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/drug effects/*metabolism ; Mutation/genetics ; NF-E2-Related Factor 2/genetics/metabolism ; Presenilin-1/genetics ; RNA, Messenger/metabolism ; Telomerase/genetics/*metabolism ; },
abstract = {Microglia senescence may promote neuropsychiatric disease. This prompted us to examine the relationship between microglia activation states and telomere biology. A panel of candidate genes associated with telomere maintenance, mitochondrial biogenesis, and cell-cycle regulation were investigated in M1- and M2-polarized microglia in vitro as well as in MACS-purified CD11b+ microglia/brain macrophages from models of stroke, Alzheimer's disease, and chronic stress. M1 polarization, ischemia, and Alzheimer pathology elicited a strikingly similar transcriptomic profile with, in particular, reduced expression of murine Tert. Our results link classical microglia activation with repression of telomere-associated genes, suggesting a new mechanism underlying microglia dysfunction.},
}
@article {pmid27891759,
year = {2017},
author = {Flannagan, KS and Jansen, EC and Rozek, LS and Rentschler, KM and Roman, AV and Ramirez-Zea, M and Villamor, E and , },
title = {Sociodemographic correlates and family aggregation of leukocyte telomere length in adults and children from Mesoamerica.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {29},
number = {3},
pages = {},
doi = {10.1002/ajhb.22942},
pmid = {27891759},
issn = {1520-6300},
mesh = {Adult ; Age Factors ; Body Mass Index ; Central America ; Child ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/*physiology ; Male ; Mexico ; Middle Aged ; Sex Factors ; Smoking/physiopathology ; Social Class ; *Telomere Shortening ; },
abstract = {OBJECTIVE: Telomere length is a biomarker of cumulative stress and inflammation related to chronic disease risk. We examined the associations of leukocyte telomere length (LTL) with sociodemographic and anthropometric variables and estimated LTL family aggregation in Central America, a region with a high burden of chronic disease where LTL has not been studied.<br><br>METHODS: We conducted a cross-sectional study of 174 school age children and their parents in the capital cities of Belize, Honduras, Nicaragua, Costa Rica, Panama, and the city of Tuxtla-Gutierrez in Mexico. We measured LTL by quantitative PCR in DNA extracted from whole blood. We compared the distribution of LTL by categories of sociodemographic and anthropometric characteristics using linear regression. Family aggregation was estimated with correlation coefficients and intraclass correlations.<br><br>RESULTS: In mothers, LTL was inversely associated with age (P, trend&#x2009;<&#x2009;.0001) and positively associated with height (P&#x2009;=&#x2009;.0002). Among fathers, LTL was inversely associated with food insecurity (P, trend&#x2009;=&#x2009;.0004). In children, boys had 0.10 log units shorter LTL than girls (95% CI: -0.17, -0.03; P&#x2009;=&#x2009;.004). LTL was inversely associated with parental education (P, trend&#x2009;=&#x2009;.01) and positively associated with paternal age at birth (P, trend&#x2009;<&#x2009;.0001), maternal LTL (P, trend&#x2009;=&#x2009;.007), and paternal LTL (P, trend&#x2009;=&#x2009;.02). LTL varied significantly by country of origin among all family members. Aggregation was greatest between children and their mothers, and mostly occurred at the country, rather than family, level.<br><br>CONCLUSION: LTL is associated with age and height in women; food insecurity in men; and sex, parental education, parental LTL, and paternal age at birth among children.},
}
@article {pmid27891221,
year = {2016},
author = {Nettle, D and Andrews, C and Reichert, S and Bedford, T and Gott, A and Parker, C and Kolenda, C and Martin-Ruiz, C and Monaghan, P and Bateson, M},
title = {Brood size moderates associations between relative size, telomere length, and immune development in European starling nestlings.},
journal = {Ecology and evolution},
volume = {6},
number = {22},
pages = {8138-8148},
pmid = {27891221},
issn = {2045-7758},
abstract = {For young birds in a nest, body size may have implications for other aspects of development such as telomere length and immune function. However, it is possible to predict associations in either direction. On the one hand, there may be trade-offs between growth and telomere maintenance, and growth and investment in immune function, suggesting there will be negative correlations. On the other hand, relatively larger individuals might be advantaged in competition with their nest-mates, allowing them to garner more resources overall, leading to positive correlations. We studied development over the nestling period in 34 nests of wild European starlings, Sturnus vulgaris. Intrabrood competition is typically more intense in larger broods. Hence, we predicted that body size should become an increasingly positive predictor of telomere length and immune functioning as brood size increases. In partial support of our prediction, there were significant interactions between brood size and body size in predicting both erythrocyte telomere length change and plasma levels of the cytokine interleukin-6. The associations between body size and these outcomes went from negative in the smallest broods to positive in the largest. A further immune marker, high-sensitivity C-reactive protein, showed no systematic patterning with body size or brood size. Our results confirm that the size to which a nestling grows is important for telomere dynamics and the development of the immune system, but the phenotypic associations are moderated by the competitive context.},
}
@article {pmid27889357,
year = {2017},
author = {Dankel, SJ and Loenneke, JP and Loprinzi, PD},
title = {The impact of overweight/obesity duration and physical activity on telomere length: An application of the WATCH paradigm.},
journal = {Obesity research &amp; clinical practice},
volume = {11},
number = {2},
pages = {247-252},
doi = {10.1016/j.orcp.2016.11.002},
pmid = {27889357},
issn = {1871-403X},
mesh = {Adult ; Aged ; Aged, 80 and over ; Exercise/*physiology ; Female ; Health Behavior ; Humans ; *Leukocytes ; Male ; Middle Aged ; Nutrition Surveys ; Obesity/*etiology ; Overweight/*genetics ; *Telomere ; },
abstract = {INTRODUCTION: Physical activity may protect against health consequences associated with obesity, yet less is known on how the duration of obesity alters this association, specifically as it relates to leukocyte telomere length.<br><br>METHODS: The 1999-2002 NHANES was used to place individuals into 6 mutually exclusive groups based on physical activity status and weight status/duration.<br><br>RESULTS: All active individuals, except for those overweight/obese for longer durations, were associated with longer telomeres in comparison to sedentary individuals.<br><br>CONCLUSIONS: Physical activity may attenuate the decline in telomere length associated with obesity, but this protective effect may be negated by prolonged periods of overweight/obesity.},
}
@article {pmid27889084,
year = {2017},
author = {Liu, L},
title = {Linking Telomere Regulation to Stem Cell Pluripotency.},
journal = {Trends in genetics : TIG},
volume = {33},
number = {1},
pages = {16-33},
doi = {10.1016/j.tig.2016.10.007},
pmid = {27889084},
issn = {0168-9525},
mesh = {Animals ; Cell Differentiation/*genetics ; Cellular Reprogramming/genetics ; Embryonic Stem Cells/*cytology ; Induced Pluripotent Stem Cells/*cytology ; Mice ; Telomere/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Embryonic stem cells (ESCs), somatic cell nuclear transfer ESCs, and induced pluripotent stem cells (iPSCs) represent the most studied group of PSCs. Unlimited self-renewal without incurring chromosomal instability and pluripotency are essential for the potential use of PSCs in regenerative therapy. Telomere length maintenance is critical for the unlimited self-renewal, pluripotency, and chromosomal stability of PSCs. While telomerase has a primary role in telomere maintenance, alternative lengthening of telomere pathways involving recombination and epigenetic modifications are also required for telomere length regulation, notably in mouse PSCs. Telomere rejuvenation is part of epigenetic reprogramming to pluripotency. Insights into telomere reprogramming and maintenance in PSCs may have implications for understanding of aging and tumorigenesis. Here, I discuss the link between telomere elongation and homeostasis to the acquisition and maintenance of stem cell pluripotency, and their regulatory mechanisms by epigenetic modifications.},
}
@article {pmid27883035,
year = {2016},
author = {Hoelzl, F and Smith, S and Cornils, JS and Aydinonat, D and Bieber, C and Ruf, T},
title = {Telomeres are elongated in older individuals in a hibernating rodent, the edible dormouse (Glis glis).},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {36856},
pmid = {27883035},
issn = {2045-2322},
mesh = {Aging/genetics ; Animals ; Female ; Hibernation/*genetics ; Longevity/genetics ; Male ; Myoxidae/*genetics ; Reproduction/genetics ; Rodentia/*genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Telomere shortening is thought to be an important biomarker for life history traits such as lifespan and aging, and can be indicative of genome integrity, survival probability and the risk of cancer development. In humans and other animals, telomeres almost always shorten with age, with more rapid telomere attrition in short-lived species. Here, we show that in the edible dormouse (Glis glis) telomere length significantly increases from an age of 6 to an age of 9 years. While this finding could be due to higher survival of individuals with longer telomeres, we also found, using longitudinal measurements, a positive effect of age on the rate of telomere elongation within older individuals. To our knowledge, no previous study has reported such an effect of age on telomere lengthening. We attribute this exceptional pattern to the peculiar life-history of this species, which skips reproduction in years with low food availability. Further, we show that this "sit tight" strategy in the timing of reproduction is associated with an increasing likelihood for an individual to reproduce as it ages. As reproduction could facilitate telomere attrition, this life-history strategy may have led to the evolution of increased somatic maintenance and telomere elongation with increasing age.},
}
@article {pmid27881897,
year = {2016},
author = {Sudyka, J and Casasole, G and Rutkowska, J and Cichoń, M},
title = {Elevated reproduction does not affect telomere dynamics and oxidative stress.},
journal = {Behavioral ecology and sociobiology},
volume = {70},
number = {12},
pages = {2223-2233},
pmid = {27881897},
issn = {0340-5443},
abstract = {ABSTRACT: Oxidative stress and telomere dynamics are considered to be powerful biomarkers quantifying a potential trade-off between current reproduction and self-maintenance. Recent studies confirmed the negative impact of elevated reproduction on telomeres, but the evidence for the cost of reproduction in terms of oxidative stress remains equivocal. In order to induce reproductive costs, we experimentally manipulated reproductive effort by increasing brood size in captive zebra finches (Taeniopygia guttata) and additionally challenged all birds by a low ambient temperature to facilitate detection of these costs. We were not able to show any negative effects of elevated reproductive effort on telomere dynamics and oxidative stress among parents, although brood enlargement was effective in terms of total mass and number of fledged young. Interestingly, irrespective of brood size treatment, we found a significant increase in antioxidant capacity at peak breeding while oxidative damage did not change with time. Our results may suggest that reproduction, instead of generating costs, may stimulate physiological functions promoting self-maintenance in terms of higher protection against free radicals. Possibly, opportunistic breeders such as zebra finches may not impede their future performance for the sake of current reproduction.<br><br>SIGNIFICANCE STATEMENT: This study interrogates a molecular background behind one of the most intriguing trade-offs that potentially occurs between self-maintenance and reproduction. We manipulated breeding effort in zebra finches to understand if the cost of reproduction can be mediated by telomere dynamics and oxidative stress. In our study system, we did not detect the direct reproductive costs in terms of parental oxidative damage and telomere loss; instead, these costs were paid by the offspring in terms of their inhibited growth rate. Moreover, we found that entering into the reproductive state strongly stimulated self-maintenance by increasing antioxidant capacity in parents. Our results emphasize that current reproductive success is not always prioritized over investment in body maintenance preventing the oxidative cost of reproduction.},
}
@article {pmid27881392,
year = {2017},
author = {Eriksson, JG and Guzzardi, MA and Iozzo, P and Kajantie, E and Kautiainen, H and Salonen, MK},
title = {Higher serum phenylalanine concentration is associated with more rapid telomere shortening in men.},
journal = {The American journal of clinical nutrition},
volume = {105},
number = {1},
pages = {144-150},
doi = {10.3945/ajcn.116.130468},
pmid = {27881392},
issn = {1938-3207},
mesh = {Aged ; Aging/*blood ; Amino Acids/blood ; Cohort Studies ; Cross-Sectional Studies ; Female ; Finland ; Humans ; Leukocytes/metabolism ; Longitudinal Studies ; Male ; Middle Aged ; Phenylalanine/*blood ; Real-Time Polymerase Chain Reaction ; Risk Factors ; Sex Factors ; *Telomere ; *Telomere Shortening ; },
abstract = {BACKGROUND: Telomere length and telomere shortening are associated with age-related health outcomes. Only a few studies have been able to longitudinally report on factors that are associated with changes in telomere length in an aging population.<br><br>OBJECTIVE: We studied the longitudinal relation between telomere length, the change in telomere length, and circulating amino acids.<br><br>DESIGN: A total of 812 subjects from the Helsinki Birth Cohort Study (born from 1934 to 1944), who underwent 3 clinical visits during a 10-y interval that included measurements of cardiometabolic risk factors, were included in the study. Leukocyte telomere length (LTL) was measured with the use of quantitative real-time polymerase chain reaction. Circulating branched-chain and aromatic amino acids (alanine, glycine, histidine, phenylalanine, leucine, isoleucine, valine, and tyrosine) were assessed with the use of high-throughput nuclear magnetic resonance spectroscopy.<br><br>RESULTS: The relative &#xb1; SD LTL at a mean age of 71 y was 0.79 &#xb1; 0.27 in men and 0.89 &#xb1; 0.35 in women (P < 0.001). Of the studied amino acids, the strongest inverse association was observed between the phenylalanine concentration that was measured 5 y earlier and the LTL. This finding was significant in men (P = 0.021) and remained significant after adjustment for multiple comparisons, but it was not significant in women (P = 0.39). Longitudinally, the change in LTL over 10 y was inversely associated with the phenylalanine concentration in men (P = 0.007) but not in women (P = 0.58) after adjustment for baseline LTL, age, smoking, and percentage of body fat.<br><br>CONCLUSIONS: The serum phenylalanine concentration is associated with telomere length and, therefore, potentially with the aging process. Because the associations reported are observational, no conclusions can be made regarding causality. Our findings support the hypothesis that cellular pathways that regulate aging are sex specific.},
}
@article {pmid27880792,
year = {2016},
author = {Yang, B and Shebl, FM and Sternberg, LR and Warner, AC and Kleiner, DE and Edelman, DC and Gomez, A and Dagnall, CL and Hicks, BD and Altekruse, SF and Hernandez, BY and Lynch, CF and Meltzer, PS and McGlynn, KA},
title = {Telomere Length and Survival of Patients with Hepatocellular Carcinoma in the United States.},
journal = {PloS one},
volume = {11},
number = {11},
pages = {e0166828},
pmid = {27880792},
issn = {1932-6203},
support = {HHSN261200800001C/RC/CCR NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; P30 CA071789/CA/NCI NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Carcinoma, Hepatocellular/genetics/mortality/*pathology ; Demography ; Female ; Humans ; Liver Neoplasms/genetics/mortality/*pathology ; Male ; Middle Aged ; Multiplex Polymerase Chain Reaction ; Neoplasm Grading ; Neoplasm Staging ; Proportional Hazards Models ; Telomere/*metabolism ; Telomere Shortening ; },
abstract = {BACKGROUND: Telomere shortening is an important molecular event in hepatocellular carcinoma (HCC) initiation; however, its role in HCC progression and prognosis is less clear. Our study aimed to examine the association of telomere length with survival of patients with HCC.<br><br>METHODS: We measured telomere length in tumor and adjacent non-tumor tissues from 126 persons with HCC in the United States (U.S.) who were followed for mortality outcomes. Relative telomere length (RTL) was measured by a monochrome multiplex quantitative polymerase chain reaction assay. Multivariable Cox proportional hazards modeling was used to calculate hazard ratios (HRs) and 95% CIs for the association between telomere length and all-cause mortality. We also examined associations between telomere length and patient characteristics using multiple linear regression.<br><br>RESULTS: During a mean follow-up of 6.0 years, 79 deaths occurred among 114 individuals for whom survival data were available. The ratio of RTL in tumor relative to non-tumor tissue was greater for individuals with regional or distant stage tumors (0.97) than localized stage tumors (0.77), and for individuals with grade III or IV tumors (0.95) than grade II (0.88) or grade I (0.67) tumors. An RTL ratio &#x2265;1 was not associated with survival (HR 0.92, 95% CI 0.55, 1.55) compared to a ratio <1, after adjusting for age at diagnosis, sex, tumor stage and tumor size. Similarly, RTL in the tumor and non-tumor tissue, respectively, were not associated with survival.<br><br>CONCLUSIONS: This U.S. based study found that telomeres may be longer in more aggressive HCCs. There was no evidence, however, that telomere length was associated with survival of patients with HCC. Future investigations are warranted to clarify the role of telomere length in HCC prognosis.},
}
@article {pmid27880696,
year = {2016},
author = {Verhulst, S and Susser, E and Factor-Litvak, PR and Simons, M and Benetos, A and Steenstrup, T and Kark, JD and Aviv, A},
title = {Response to: Reliability and validity of telomere length measurements.},
journal = {International journal of epidemiology},
volume = {45},
number = {4},
pages = {1298-1301},
pmid = {27880696},
issn = {1464-3685},
support = {P30 ES009089/ES/NIEHS NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; },
mesh = {Humans ; Reproducibility of Results ; *Telomere ; },
}
@article {pmid27878970,
year = {2017},
author = {Shivappa, N and Wirth, MD and Hurley, TG and Hébert, JR},
title = {Association between the dietary inflammatory index (DII) and telomere length and C-reactive protein from the National Health and Nutrition Examination Survey-1999-2002.},
journal = {Molecular nutrition &amp; food research},
volume = {61},
number = {4},
pages = {},
pmid = {27878970},
issn = {1613-4133},
support = {R44 DK103377/DK/NIDDK NIH HHS/United States ; },
mesh = {Aging ; C-Reactive Protein/*metabolism ; *Diet ; Energy Intake ; Female ; Humans ; Inflammation/*metabolism ; Leukocytes/metabolism ; Linear Models ; Male ; *Nutrition Surveys ; *Telomere/drug effects/physiology ; },
abstract = {SCOPE: Leukocyte telomere length (LTL) is an important biomarker of aging. This study examined whether inflammatory potential of diet, as measured by the Dietary Inflammatory Index[TM] (DII) has an impact on telomere shortening in the National Health and Nutrition Examination Survey (NHANES). We also carried out validation of the DII with C-reactive protein (CRP).<br><br>METHODS AND RESULTS: Data came from NHANES 1999-2002. LTL and CRP were assayed from leukocyte DNA and serum specimens, respectively. The DII was calculated from food intakes assessed using 24-h dietary recalls and expressed per 1000 calories consumed. Associations were examined using survey-based multivariable linear regression for log-transformed LTL. After multivariable adjustment, higher DII scores (i.e. relatively more pro inflammatory) were associated with shorter LTL both when used as continuous (b&#x2009; = &#x2009;-0.003; 95% confidence interval [CI]&#x2009; = &#x2009;-0.005, -0.0002) and as quartiles (bDIIquartile4vs1 &#x2009; = &#x2009;-0.013; 95% CI&#x2009; = &#x2009;-0.025, -0.001; Ptrend &#x2009; = &#x2009;.03). In this same sample the DII also was associated with CRP &#x2265;3&#xa0;mg/L (ORDIIcontinuous = 1.10; 95% CI = 1.06, 1.16).<br><br>CONCLUSION: In these NHANES data there was an association between DII and LTL. This study also provided a successful construct validation of the DII using CRP in a nationally representative sample. These results are consistent with the hypothesis that diet-associated inflammation determines LTL.},
}
@article {pmid27876133,
year = {2016},
author = {Ribero, S and Mangino, M and Bataille, V},
title = {Skin phenotypes can offer some insight about the association between telomere length and cancer susceptibility.},
journal = {Medical hypotheses},
volume = {97},
number = {},
pages = {7-10},
doi = {10.1016/j.mehy.2016.10.010},
pmid = {27876133},
issn = {1532-2777},
mesh = {Carcinoma, Squamous Cell/genetics/pathology ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Keratosis/genetics/pathology ; Melanoma/genetics/pathology ; Mutation ; Nevus/genetics/pathology ; Phenotype ; Risk Factors ; Skin/*pathology ; Skin Aging ; Skin Neoplasms/*genetics/*pathology ; Telomere/*ultrastructure ; },
abstract = {The role of telomere biology in cancer has been studied for a wide variety of different cancers but the association with telomere length has been controversial. This is because some cancers have been found to be associated with longer telomeres in circulating white cells whilst other cancer types are more common in individuals with shorter telomeres. Hence, there has been some skepticism as to whether telomere length may be helpful in estimating cancer risk. For melanoma, however, results have been fairly consistent showing that longer telomeres are associated with an increased risk. This link was first discovered because of a link between longer telomeres and a high number of naevi. In contrast, for cutaneous squamous cell carcinomas, the relationship is reversed with higher risk in individuals with shorter telomeres. Differences in skin phenotypes with the presence of high number of naevi versus photoageing with solar elastosis and solar keratoses have already been valuable for dermatologists as the former phenotype is associated with melanoma whilst the latter is more common in patients with squamous cell carcinoma of the skin. The hypothesis is that the differences in cutaneous phenotypes already observed by dermatologists for skin cancers may, in fact, be useful as well for cancer prediction in general as it may reflect underlying telomere biology. This manuscript will address the evidence for links between telomere biology, skin phenotypes and cancer risk.},
}
@article {pmid27874106,
year = {2017},
author = {Karimi, B and Yunesian, M and Nabizadeh, R and Mehdipour, P and Aghaie, A},
title = {Is Leukocyte Telomere Length Related with Lung Cancer Risk?: A Meta-Analysis.},
journal = {Iranian biomedical journal},
volume = {21},
number = {3},
pages = {142-153},
pmid = {27874106},
issn = {2008-823X},
mesh = {Humans ; Leukocytes/*metabolism ; Lung Neoplasms/epidemiology/*genetics ; Publication Bias ; Risk Factors ; Sensitivity and Specificity ; Smoking/adverse effects ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Epidemiological studies have probed the correlation between telomere length and the risk of lung cancer, but their findings are inconsistent in this regard. The present meta-analysis study has been carried out to demonstrate the association between relative telomere length in peripheral blood leukocytes and the risk of lung cancer using an established Q-PCR technique.<br><br>METHODS: A systematic search was carried out using PubMed, EMBASE, and ISI before 2015. A total of 2925 cases of lung cancer and 2931 controls from 9 studies were employed to probe the relationship between lung cancer and telomere length .ORs were used at 95% CI. Random-effects models were used to investigate this relationship based on the heterogeneity test. Heterogeneity among studies was analyzed employing subgroup analysis based on type studies and the year of publication.<br><br>RESULTS: Random-effects meta-analysis revealed that patients with lung cancer were expected to have shorter telomere length than the control (1.13, 95% CI: 0.82-1.81, P=0.46). The summary of the pooled ORs of telomere length in adenocarcinoma lung cancer patients was 1 (95%CI=0.68-1.47, I2=93%) compared to patients with squamous cell lung cancer, which was 1.78 (95% CI=1.25-2.53, I2=3.9%). The meta-regression revealed that the effect of telomere length shortening, decreased and increased with the year of publication and the age of risks to lung cancer, was clearly related to short telomeres lengths.<br><br>CONCLUSION: Lung cancer risks clearly related with short telomeres lengths. In patients with breathing problems, lung cancer risk can be predicted by telomere length adjustment with age, sex, and smoking.},
}
@article {pmid27874017,
year = {2016},
author = {Vaquero-Sedas, MI and Vega-Palas, MA},
title = {Corrigendum: Determination of Arabidopsis thaliana telomere length by PCR.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {37380},
doi = {10.1038/srep37380},
pmid = {27874017},
issn = {2045-2322},
}
@article {pmid27873269,
year = {2017},
author = {Knecht, H and Mai, S},
title = {The Use of 3D Telomere FISH for the Characterization of the Nuclear Architecture in EBV-Positive Hodgkin's Lymphoma.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1532},
number = {},
pages = {93-104},
doi = {10.1007/978-1-4939-6655-4_6},
pmid = {27873269},
issn = {1940-6029},
mesh = {Antibodies/immunology ; Cell Nucleus/*genetics/metabolism/pathology ; Epstein-Barr Virus Infections/*complications/virology ; *Herpesvirus 4, Human ; Hodgkin Disease/diagnosis/*etiology/*pathology ; Humans ; Imaging, Three-Dimensional/*methods ; In Situ Hybridization, Fluorescence/*methods ; Reed-Sternberg Cells/metabolism/pathology ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/immunology ; Viral Matrix Proteins/genetics/metabolism ; },
abstract = {The 3D nuclear architecture is closely related to cellular functions and chromosomes are organized in distinct territories. Quantitative 3D telomere FISH analysis (3D Q-FISH) and 3D super-resolution imaging (3D-SIM) at a resolution up to 80 nm as well as the recently developed combined quantitative 3D TRF2-telomere immune FISH technique (3D TRF2/Telo-Q-FISH) have substantially contributed to elucidate molecular pathogenic mechanisms of hematological diseases. Here we report the methods we applied to uncover major molecular steps involved in the pathogenesis of EBV-associated Hodgkin's lymphoma. These methods allowed us to identify the EBV-encoded oncoprotein LMP1 as a key element in the formation of Hodgkin (H-cell) and multinucleated Reed-Sternberg cells (RS-cell), the diagnostic tumor cell of classical Hodgkin's lymphoma (cHL). LMP1 mediates multinuclearity through downregulation of shelterin proteins, in particular telomere repeat binding factor 2 (TRF2).},
}
@article {pmid27872149,
year = {2017},
author = {Chiba, K and Vogan, JM and Wu, RA and Gill, MS and Zhang, X and Collins, K and Hockemeyer, D},
title = {Endogenous Telomerase Reverse Transcriptase N-Terminal Tagging Affects Human Telomerase Function at Telomeres In Vivo.},
journal = {Molecular and cellular biology},
volume = {37},
number = {3},
pages = {},
pmid = {27872149},
issn = {1098-5549},
support = {R01 CA196884/CA/NCI NIH HHS/United States ; R01 GM054198/GM/NIGMS NIH HHS/United States ; R01 HL079585/HL/NHLBI NIH HHS/United States ; },
mesh = {Blotting, Southern ; Epitopes/*metabolism ; Gene Editing ; Genotype ; Human Embryonic Stem Cells/metabolism ; Humans ; Phenotype ; Repetitive Sequences, Nucleic Acid/genetics ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Telomerase action at telomeres is essential for the immortal phenotype of stem cells and the aberrant proliferative potential of cancer cells. Insufficient telomere maintenance can cause stem cell and tissue failure syndromes, while increased telomerase levels are associated with tumorigenesis. Both pathologies can arise from only small perturbation of telomerase function. To analyze telomerase at its low endogenous expression level, we genetically engineered human pluripotent stem cells (hPSCs) to express various N-terminal fusion proteins of the telomerase reverse transcriptase from its endogenous locus. Using this approach, we found that these modifications can perturb telomerase function in hPSCs and cancer cells, resulting in telomere length defects. Biochemical analysis suggests that this defect is multileveled, including changes in expression and activity. These findings highlight the unknown complexity of telomerase structural requirements for expression and function in vivo.},
}
@article {pmid27871926,
year = {2017},
author = {de Melo, AS and Reis, RM and Calado, RT and de Carvalho Cavalli, R and Bettiol, H and Cardoso, VC and Ferriani, RA and Barbieri, MA and Vieira, CS},
title = {The telomere attrition rate is not accelerated in women born small for gestational age: A birth cohort study.},
journal = {Gene},
volume = {600},
number = {},
pages = {16-20},
doi = {10.1016/j.gene.2016.11.030},
pmid = {27871926},
issn = {1879-0038},
mesh = {Adult ; Aging/genetics ; Birth Weight ; Cohort Studies ; Epigenesis, Genetic ; Female ; Gestational Age ; Humans ; Infant, Newborn ; *Infant, Small for Gestational Age ; Leukocytes/metabolism ; Prospective Studies ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {Physiologically, a reduction in telomere length (LTL) occurs with aging, but epigenetic changes may accelerate telomere shortening and also facilitate the onset of oxidative/inflammatory stress and the development of clinical/metabolic comorbidities in life spam. Although individuals born small for gestational age (SGA) may be related to those epigenetic changes, the assessment of LTL in individuals born SGA has yielded conflicting results (only cross-sectional studies) and has not been carried out in longitudinal studies. We performed a birth cohort study to evaluate the rate of telomere erosion in women born SGA in comparison to women born appropriate for gestational age (AGA) assessed at two different time points during the third decade of life. In our research, born SGA or AGA showed no difference in LTL shortening during a period of five years in the third decade of life. Our finding may have implications for understanding the natural history of diseases in lifespan because the same women (under the influence of similar environmental factors) may be accessed in different phases of life. Thus, the analysis of the present cohort population at a more advanced age may reveal a dynamics of telomere shortening different from here and its possible relation with onset of age-related diseases.},
}
@article {pmid27871469,
year = {2016},
author = {Wilson, SL and Liu, Y and Robinson, WP},
title = {Placental telomere length decline with gestational age differs by sex and TERT, DNMT1, and DNMT3A DNA methylation.},
journal = {Placenta},
volume = {48},
number = {},
pages = {26-33},
doi = {10.1016/j.placenta.2016.10.001},
pmid = {27871469},
issn = {1532-3102},
support = {49520//CIHR/Canada ; },
mesh = {DNA (Cytosine-5-)-Methyltransferase 1/genetics/*metabolism ; DNA (Cytosine-5-)-Methyltransferases/genetics/*metabolism ; *DNA Methylation ; DNA Methyltransferase 3A ; Female ; Fetal Growth Retardation/metabolism ; Gestational Age ; Humans ; Male ; Oxidative Stress/physiology ; Placenta/metabolism ; Pre-Eclampsia/metabolism ; Pregnancy ; Sex Factors ; Telomerase/genetics/*metabolism ; *Telomere ; Telomere Shortening/*physiology ; },
abstract = {INTRODUCTION: Telomere length (TL) has been suggested to be influenced by inherited genetic and epigenetic variation, hormonal effects, oxidative stress and age. However, the dynamics of TL during in utero development have not been well explored. This study investigates the relationship between placental TL and sex, gestational age (GA), and DNA methylation (DNAm). Placental TL is further evaluated in pregnancies complicated by preeclampsia (PE) and intrauterine growth restriction (IUGR), conditions hypothesized to lead to decreased placental TL due to increased oxidative stress.<br><br>METHODS: Average TL in 21 early-onset PE (EOPE), 18 late-onset PE (LOPE), 9 IUGR, 59 viable and 33 non-viable control placentas were measured by qPCR. Of these, 13 control, 20 EOPE, 17 LOPE, and 8 IUGR samples were also run on the Illumina 450K array. ANOVA was used to compare TL between controls and EOPE, LOPE, and IUGR. Linear regression correcting for GA and sex, assessed the association between TL and DNAm in biologically-relevant genes (TERC, TERT, DNMT1, DNMT3a, DNMT3b), and array-wide.<br><br>RESULTS: Male sex and increasing GA were associated with shorter placental TL. Correcting for these factors, no significant difference in TL was observed between EOPE, LOPE, and IUGR placentas compared to controls. Targeted analysis revealed TL was associated with DNAm at TERT, DNMT1, and DNMT3a. An array-wide approach found no additional sites associated with TL.<br><br>CONCLUSION: Variability in placental TL is associated with alterations in DNAm at TERT, DNMT1, and DNMT3a. Placental TL is not strongly influenced by EOPE, LOPE, or IUGR.},
}
@article {pmid27870638,
year = {2016},
author = {Zhao, Q and Zhu, Y and Yeh, F and Lin, J and Lee, ET and Cole, SA and Calhoun, D and Zhao, J},
title = {Depressive symptoms are associated with leukocyte telomere length in American Indians: findings from the Strong Heart Family Study.},
journal = {Aging},
volume = {8},
number = {11},
pages = {2961-2970},
pmid = {27870638},
issn = {1945-4589},
support = {U01 HL041642/HL/NHLBI NIH HHS/United States ; U01 HL041654/HL/NHLBI NIH HHS/United States ; K01 AG034259/AG/NIA NIH HHS/United States ; R01 DK091369/DK/NIDDK NIH HHS/United States ; R01 MH097018/MH/NIMH NIH HHS/United States ; U01 HL041652/HL/NHLBI NIH HHS/United States ; R21 HL092363/HL/NHLBI NIH HHS/United States ; R01 HL109284/HL/NHLBI NIH HHS/United States ; U01 HL065521/HL/NHLBI NIH HHS/United States ; R01 HL109301/HL/NHLBI NIH HHS/United States ; U01 HL065520/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Depression/*diagnosis/metabolism ; Female ; Humans ; Indians, North American ; Leukocytes/*metabolism ; Life Style ; Male ; Middle Aged ; Severity of Illness Index ; Symptom Assessment ; Telomere/*metabolism ; Young Adult ; },
abstract = {Patients with depression have an increased risk for many aging-related disorders, but the biological mechanisms underlying this link remain to be determined. Here we examined the association between depressive symptoms and leukocyte telomere length (LTL), a marker of biological aging, among 2,175 American Indians participating in the Strong Heart Family Study. Depressive symptoms were assessed by the Center for Epidemiologic Studies of Depression Scale (CES-D), which was categorized into four levels: none (< 10), mild (10-15), moderate (16 -24), and severe (> 24). LTL (T/S ratio) was quantified by qPCR. The association between depressive symptoms and LTL was examined by multivariate generalized estimating equation models, adjusting for sociodemographic factors, lifestyle factors, and chronic conditions. Results showed that individuals with a higher level of depressive symptoms had shorter LTL. Specifically, LTL in participants reporting none, mild, moderate, and severe depressive symptoms were 1.000, 0.999, 0.988, and 0.966, respectively (P for trend = 0.0278). Moreover, gender appears to modulate the effect of reported depressive symptoms that fall in the severe range (CES-D > 24) on LTL (P for interaction = 0.0346). Our results suggest that depressive symptoms may accelerate biological aging through pathways beyond traditional risk factors in American Indians.},
}
@article {pmid27869160,
year = {2017},
author = {Gu, P and Wang, Y and Bisht, KK and Wu, L and Kukova, L and Smith, EM and Xiao, Y and Bailey, SM and Lei, M and Nandakumar, J and Chang, S},
title = {Pot1 OB-fold mutations unleash telomere instability to initiate tumorigenesis.},
journal = {Oncogene},
volume = {36},
number = {14},
pages = {1939-1951},
pmid = {27869160},
issn = {1476-5594},
support = {T32 AG000114/AG/NIA NIH HHS/United States ; R01 CA202816/CA/NCI NIH HHS/United States ; R00 CA167644/CA/NCI NIH HHS/United States ; R21 CA200506/CA/NCI NIH HHS/United States ; R01 AG050509/AG/NIA NIH HHS/United States ; R21 CA182280/CA/NCI NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Carcinogenesis/*genetics/metabolism ; Cells, Cultured ; Chromosomal Instability/*genetics ; Chromosome Aberrations ; DNA End-Joining Repair/genetics ; HEK293 Cells ; HeLa Cells ; Humans ; Mice ; Mice, Knockout ; Mice, SCID ; *Mutation ; Oligonucleotides/genetics/metabolism ; Oligosaccharides/genetics/metabolism ; Shelterin Complex ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/*genetics ; },
abstract = {Chromosomal aberrations are a hallmark of human cancers, with complex cytogenetic rearrangements leading to genetic changes permissive for cancer initiation and progression. Protection of Telomere 1 (POT1) is an essential component of the shelterin complex and functions to maintain chromosome stability by repressing the activation of aberrant DNA damage and repair responses at telomeres. Sporadic and familial mutations in the oligosaccharide-oligonucleotide (OB) folds of POT1 have been identified in many human cancers, but the mechanism underlying how hPOT1 mutations initiate tumorigenesis has remained unclear. Here we show that the human POT1's OB-folds are essential for the protection of newly replicated telomeres. Oncogenic mutations in hPOT1 OB-fold fail to bind to single-stranded telomeric DNA, eliciting a DNA damage response at telomeres that promote inappropriate chromosome fusions via the mutagenic alternative non-homologous end joining (A-NHEJ) pathway. hPOT1 mutations also result in telomere elongation and the formation of transplantable hematopoietic malignancies. Strikingly, conditional deletion of both mPot1a and p53 in mouse mammary epithelium resulted in development of highly invasive breast carcinomas and the formation of whole chromosomes containing massive arrays of telomeric fusions indicative of multiple breakage-fusion-bridge cycles. Our results reveal that hPOT1 OB-folds are required to protect and prevent newly replicated telomeres from engaging in A-NHEJ mediated fusions that would otherwise promote genome instability to fuel tumorigenesis.},
}
@article {pmid27865975,
year = {2017},
author = {Jones, CW and Gambala, C and Esteves, KC and Wallace, M and Schlesinger, R and O'Quinn, M and Kidd, L and Theall, KP and Drury, SS},
title = {Differences in placental telomere length suggest a link between racial disparities in birth outcomes and cellular aging.},
journal = {American journal of obstetrics and gynecology},
volume = {216},
number = {3},
pages = {294.e1-294.e8},
pmid = {27865975},
issn = {1097-6868},
support = {K12 HD043451/HD/NICHD NIH HHS/United States ; R01 MH101533/MH/NIMH NIH HHS/United States ; U19 ES020677/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; *Black or African American ; *Cellular Senescence ; Female ; Health Status Disparities ; Humans ; Infant, Newborn ; Male ; *Placenta ; Pregnancy ; *Pregnancy Outcome ; Prospective Studies ; Telomere/*ultrastructure ; *Telomere Homeostasis ; *White People ; },
abstract = {BACKGROUND: Health disparities begin early in life and persist across the life course. Despite current efforts, black women exhibit greater risk for pregnancy complications and negative perinatal outcomes compared with white women. The placenta, which is a complex multi-tissue organ, serves as the primary transducer of bidirectional information between the mother and fetus. Altered placental function is linked to multiple racially disparate pregnancy complications; however, little is known about racial differences in molecular factors within the placenta. Several pregnancy complications, which include preeclampsia and fetal growth restriction, exhibit racial disparities and are associated with shorter placental telomere length, which is an indicator of cellular stress and aging. Cellular senescence and telomere dynamics are linked to the molecular mechanisms that are associated with the onset of labor and parturition. Further, racial differences in telomere length are found in a range of different peripheral tissues. Together these factors suggest that exploration of racial differences in telomere length of the placenta may provide novel mechanistic insight into racial disparities in birth outcomes.<br><br>OBJECTIVE: This study examined whether telomere length measured in 4 distinct fetally derived tissues were significantly different between black and white women. The study had 2 hypotheses: (1) that telomere length that is measured in different placental tissue types would be correlated and (2) that across all sampled tissues telomere length would differ by race.<br><br>STUDY DESIGN: In a prospective study, placental tissue samples were collected from the amnion, chorion, villus, and umbilical cord from black and white singleton pregnancies (N=46). Telomere length was determined with the use of monochrome multiplex quantitative real-time polymerase chain reaction in each placental tissue. Demographic and pregnancy-related data were also collected. Descriptive statistics characterized the sample overall and among black and white women separately. The overall impact of race was assessed by multilevel mixed-effects linear regression models that included empirically relevant covariates.<br><br>RESULTS: Telomere length was correlated significantly across all placental tissues. Pairwise analyses of placental tissue telomere length revealed significantly longer telomere length in the amnion compared with the chorion (t=-2.06; P=.043). Overall telomere length measured in placenta samples from black mothers were significantly shorter than those from white mothers (&#x3b2;=-0.09; P=.04). Controlling for relevant maternal and infant characteristics strengthened the significance of the observed racial differences (&#x3b2;=-0.12; P=.02). Within tissue analyses revealed that the greatest difference by race was found in chorionic telomere length (t=-2.81; P=.007).<br><br>CONCLUSION: These findings provide the first evidence of racial differences in placental telomere length. Telomere length was significantly shorter in placental samples from black mothers compared with white mothers. Given previous studies that have reported that telomere length, cellular senescence, and telomere dynamics are molecular factors that contribute to the rupture of the amniotic sac, onset of labor, and parturition, our findings of shorter telomere length in placentas from black mothers suggest that accelerated cellular aging across placental tissues may be relevant to the increased risk of preterm delivery in black pregnancies. Our results suggest that racial differences in cellular aging in the placenta contribute to the earliest roots of health disparities.},
}
@article {pmid27864096,
year = {2017},
author = {Eugène, S and Bourgeron, T and Xu, Z},
title = {Effects of initial telomere length distribution on senescence onset and heterogeneity.},
journal = {Journal of theoretical biology},
volume = {413},
number = {},
pages = {58-65},
pmid = {27864096},
issn = {1095-8541},
mesh = {*Cellular Senescence ; Computer Simulation ; DNA Replication ; Evolution, Molecular ; Numerical Analysis, Computer-Assisted ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Replicative senescence, induced by telomere shortening, exhibits considerable asynchrony and heterogeneity, the origins of which remain unclear. Here, we formally study how telomere shortening mechanisms impact on senescence kinetics and define two regimes of senescence, depending on the initial telomere length variance. We provide analytical solutions to the model, highlighting a non-linear relationship between senescence onset and initial telomere length distribution. This study reveals the complexity of the collective behavior of telomeres as they shorten, leading to senescence heterogeneity.},
}
@article {pmid27861975,
year = {2017},
author = {Fouquerel, E and Opresko, PL},
title = {Convergence of The Nobel Fields of Telomere Biology and DNA Repair.},
journal = {Photochemistry and photobiology},
volume = {93},
number = {1},
pages = {229-237},
pmid = {27861975},
issn = {1751-1097},
support = {R21 ES025606/ES/NIEHS NIH HHS/United States ; R44 GM108187/GM/NIGMS NIH HHS/United States ; R43 GM108187/GM/NIGMS NIH HHS/United States ; R01 ES022944/ES/NIEHS NIH HHS/United States ; R33 ES025606/ES/NIEHS NIH HHS/United States ; },
mesh = {Chromosome Aberrations ; DNA Damage ; *DNA Repair ; Deoxyribodipyrimidine Photo-Lyase/metabolism ; Humans ; Nobel Prize ; Pyrimidine Dimers/metabolism ; Telomerase/metabolism ; *Telomere ; Ultraviolet Rays ; },
abstract = {The fields of telomere biology and DNA repair have enjoyed a great deal of cross-fertilization and convergence in recent years. Telomeres function at chromosome ends to prevent them from being falsely recognized as chromosome breaks by the DNA damage response and repair machineries. Conversely, both canonical and nonconical functions of numerous DNA repair proteins have been found to be critical for preserving telomere structure and function. In 2009, Elizabeth Blackburn, Carol Greider and Jack Szostak were awarded the Nobel prize in Physiology or Medicine for the discovery of telomeres and telomerase. Four years later, pioneers in the field of DNA repair, Aziz Sancar, Tomas Lindahl and Paul Modrich were recognized for their seminal contributions by being awarded the Nobel Prize in Chemistry. This review is part of a special issue meant to celebrate this amazing achievement, and will focus in particular on the convergence of nucleotide excision repair and telomere biology, and will discuss the profound implications for human health.},
}
@article {pmid27858019,
year = {2016},
author = {Zheng, XH and Mu, G and Zhong, YF and Zhang, TP and Cao, Q and Ji, LN and Zhao, Y and Mao, ZW},
title = {Trigeminal star-like platinum complexes induce cancer cell senescence through quadruplex-mediated telomere dysfunction.},
journal = {Chemical communications (Cambridge, England)},
volume = {52},
number = {98},
pages = {14101-14104},
doi = {10.1039/c6cc08254h},
pmid = {27858019},
issn = {1364-548X},
mesh = {Cell Line, Tumor ; Cellular Senescence/*drug effects ; Dose-Response Relationship, Drug ; Fluorescence Resonance Energy Transfer ; G-Quadruplexes/*drug effects ; Humans ; Molecular Structure ; Organoplatinum Compounds/chemical synthesis/chemistry/*pharmacology ; Structure-Activity Relationship ; Telomere/*drug effects/metabolism ; },
abstract = {Two trigeminal star-like platinum complexes were synthesized to induce the formation of human telomere G-quadruplex (hTel G4) with extremely high selectivity and affinity. The induced hTel G4 activates strong telomeric DNA damage response (TDDR), resulting in telomere dysfunction and cell senescence.},
}
@article {pmid27856493,
year = {2017},
author = {Sillanpää, E and Sipilä, S and Törmäkangas, T and Kaprio, J and Rantanen, T},
title = {Genetic and Environmental Effects on Telomere Length and Lung Function: A Twin Study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {72},
number = {11},
pages = {1561-1568},
doi = {10.1093/gerona/glw178},
pmid = {27856493},
issn = {1758-535X},
mesh = {Aged ; Aging/*genetics ; *Environmental Exposure ; Female ; Forced Expiratory Volume/*physiology ; Humans ; Leukocytes/*ultrastructure ; Lung/*physiology ; Middle Aged ; Spirometry ; Telomere/*genetics ; Twins, Dizygotic ; Twins, Monozygotic ; },
abstract = {BACKGROUND: The purpose of the study was to estimate the heritability of leukocyte telomere length (LTL) and lung function and to examine whether LTL and lung function share genetic or environmental effects in common.<br><br>METHODS: 386 monozygotic and dizygotic Finnish twin sisters (age 68.4&#xb1;3.4 years) were included. Relative LTL was determined from peripheral blood DNA by qPCR. Lung function measures of FEV1, FVC, FEV1/FVC, and PEF were derived from spirometry. Genetic modeling was performed with MPlus statistical software.<br><br>RESULTS: Univariate analysis revealed that in LTL, 62% (95% confidence interval 50-72) of the variance was explained by additive genetic and 38% (28-50) by unique environmental factors. For FEV1, FVC, and PEF, the corresponding estimates were 65%-67% for additive genetic and 33%-35% for unique environmental factors. Across the sample, the phenotypic correlation between LTL and FEV1 was modest (r = .104, p = .041). Bivariate correlated factors model revealed that the genetic correlation between LTL and FEV1 was .18 (-0.19 to 0.64) and environmental correlation was -.10 (-0.84 to 0.55).<br><br>CONCLUSIONS: Both LTL and lung function variables are moderately to highly genetically determined. The associations between LTL and the lung function variables were weak. However, the positive genetic correlation point estimate gave minor suggestions that, in a larger sample, genetic factors in common might play a role in the phenotypic correlation between LTL and FEV1. Future studies with larger samples are needed to confirm these preliminary findings.},
}
@article {pmid27856448,
year = {2016},
author = {Zhang, C and Lauderdale, DS and Pierce, BL},
title = {Sex-Specific and Time-Varying Associations Between Cigarette Smoking and Telomere Length Among Older Adults.},
journal = {American journal of epidemiology},
volume = {184},
number = {12},
pages = {922-932},
pmid = {27856448},
issn = {1476-6256},
support = {P30 AG012857/AG/NIA NIH HHS/United States ; R01 ES020506/ES/NIEHS NIH HHS/United States ; T32 AG000243/AG/NIA NIH HHS/United States ; U01 HG007601/HG/NHGRI NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/blood/drug effects ; Biomarkers/blood ; DNA/analysis ; Female ; Health Status ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Oxidative Stress/drug effects ; Polymerase Chain Reaction ; Prospective Studies ; Saliva/*chemistry ; Sex Distribution ; Smoking/*adverse effects/blood/genetics ; Smoking Cessation/*statistics &amp; numerical data ; Telomere Shortening/*drug effects/genetics ; },
abstract = {Inconsistent associations between smoking and telomere length (TL) have been reported in epidemiologic studies, perhaps because of the time-varying nature of smoking behaviors. We estimated the associations of TL, which was measured by quantitative polymerase chain reaction using saliva DNA, with concurrent and past smoking status reported biennially for up to 16 years before TL measurement in 5,624 participants in the Health and Retirement Study (1992-2008). Smoking was associated with reduced TL when we used prospective data on smoking statuses among men and women, but the association was strongly attenuated among men in cross-sectional analyses. This attenuation was largely due to a higher rate of smoking cessation during the study period among men with shorter TL than among men with longer TL. Short TL was also associated with poorer overall health in men, which suggests that male smokers with short TL were more likely to quit smoking because of poor health. Analyses of years since cessation, smoking duration, and pack-years of smoking all support the hypothesis that increased cigarette use shortens TL. Our results provide a potential explanation for the inconsistent associations between smoking and TL reported in previous cross-sectional studies. Time-varying associations should be considered in future studies of smoking behavior, TL, aging, and disease risk.},
}
@article {pmid27855118,
year = {2016},
author = {Liu, J and He, MH and Peng, J and Duan, YM and Lu, YS and Wu, Z and Gong, T and Li, HT and Zhou, JQ},
title = {Tethering telomerase to telomeres increases genome instability and promotes chronological aging in yeast.},
journal = {Aging},
volume = {8},
number = {11},
pages = {2827-2847},
pmid = {27855118},
issn = {1945-4589},
mesh = {*Genomic Instability ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Chronological aging of the yeast Saccharomyces cerevisiae is attributed to multi-faceted traits especially those involving genome instability, and has been considered to be an aging model for post-mitotic cells in higher organisms. Telomeres are the physical ends of eukaryotic chromosomes, and are essential for genome integrity and stability. It remains elusive whether dysregulated telomerase activity affects chronological aging. We employed the CDC13-EST2 fusion gene, which tethers telomerase to telomeres, to examine the effect of constitutively active telomerase on chronological lifespan (CLS). The expression of Cdc13-Est2 fusion protein resulted in overlong telomeres (2 to 4 folds longer than normal telomeres), and long telomeres were stably maintained during long-term chronological aging. Accordingly, genome instability, manifested by accumulation of extra-chromosomal rDNA circle species, age-dependent CAN1 marker-gene mutation frequency and gross chromosomal rearrangement frequency, was significantly elevated. Importantly, inactivation of Sch9, a downstream kinase of the target of rapamycin complex 1 (TORC1), suppressed both the genome instability and accelerated chronological aging mediated by CDC13-EST2 expression. Interestingly, loss of the CDC13-EST2 fusion gene in the cells with overlong telomeres restored the regular CLS. Altogether, these data suggest that constitutively active telomerase is detrimental to the maintenance of genome stability, and promotes chronological aging in yeast.},
}
@article {pmid27847364,
year = {2017},
author = {Li, J and Yao, Y and Chen, Y and Xu, X and Lin, Y and Yang, Z and Qiao, W and Tan, J},
title = {Enterovirus 71 3C Promotes Apoptosis through Cleavage of PinX1, a Telomere Binding Protein.},
journal = {Journal of virology},
volume = {91},
number = {2},
pages = {},
pmid = {27847364},
issn = {1098-5514},
mesh = {3C Viral Proteases ; *Apoptosis/drug effects ; Cell Cycle Proteins ; Cell Line ; Coxsackievirus Infections/genetics/*metabolism/*virology ; Cysteine Endopeptidases/*metabolism ; Enterovirus A, Human/*physiology ; Etoposide/pharmacology ; Humans ; Protein Binding ; Proteolysis ; Telomere-Binding Proteins/genetics/metabolism ; Tumor Suppressor Proteins/genetics/*metabolism ; Viral Proteins/*metabolism ; Virus Release ; },
abstract = {UNLABELLED: Enterovirus 71 (EV71) is an emerging pathogen causing hand, foot, and mouth disease (HFMD) and fatal neurological diseases in infants and young children due to their underdeveloped immunocompetence. EV71 infection can induce cellular apoptosis through a variety of pathways, which promotes EV71 release. The viral protease 3C plays an important role in EV71-induced apoptosis. However, the molecular mechanism responsible for 3C-triggered apoptosis remains elusive. Here, we found that EV71 3C directly interacted with PinX1, a telomere binding protein. Furthermore, 3C cleaved PinX1 at the site of Q50-G51 pair through its protease activity. Overexpression of PinX1 reduced the level of EV71-induced apoptosis and EV71 release, whereas depletion of PinX1 by small interfering RNA promoted apoptosis induced by etoposide and increased EV71 release. Taken together, our study uncovered a mechanism that EV71 utilizes to promote host cell apoptosis through cleavage of cellular protein PinX1 by 3C.<br><br>IMPORTANCE: EV71 3C plays an important role in processing viral proteins and interacting with host cells. In this study, we showed that 3C promoted apoptosis through cleaving PinX1, a telomere binding protein, and that this cleavage facilitated EV71 release. Our study demonstrated that PinX1 plays an important role in EV71 release and revealed a novel mechanism that EV71 utilizes to induce apoptosis. This finding is important in understanding EV71-host cell interactions and has potential impact on understanding other enterovirus-host cell interactions.},
}
@article {pmid27844481,
year = {2017},
author = {Malouff, JM and Schutte, NS},
title = {A meta-analysis of the relationship between anxiety and telomere length.},
journal = {Anxiety, stress, and coping},
volume = {30},
number = {3},
pages = {264-272},
doi = {10.1080/10615806.2016.1261286},
pmid = {27844481},
issn = {1477-2205},
mesh = {Anxiety/*physiopathology ; Humans ; Stress, Psychological/*physiopathology ; *Telomere ; Telomere Shortening/*physiology ; },
abstract = {BACKGROUND AND OBJECTIVES: Telomeres are protective caps at the ends of chromosomes, and shorter telomeres are associated with poor physical health. The present study set out to consolidate the varying effect sizes found so far in studies of anxiety and telomere length.<br><br>DESIGN AND METHODS: A meta-analytic investigation of the relationship between anxiety and telomere length used information from 17 different samples comprising a total of 19,424 participants.<br><br>RESULTS: The results showed a small but significant association, r&#x2009;=&#x2009;-.06, between higher anxiety and shorter telomeres. Studies comparing individuals diagnosed with an anxiety disorder with other individuals had a significant effect size, and studies that did not use this comparison threshold did not have a significant effect size.<br><br>CONCLUSIONS: Anxiety is associated with an important biomarker related to health. Future experimental studies that examine the impact of interventions intended to reduce anxiety in conjunction with measurement of telomere length can further clarify the impact of anxiety on telomere length.},
}
@article {pmid27841304,
year = {2016},
author = {Ho, A and Wilson, FR and Peragine, SL and Jeyanthan, K and Mitchell, TR and Zhu, XD},
title = {TRF1 phosphorylation on T271 modulates telomerase-dependent telomere length maintenance as well as the formation of ALT-associated PML bodies.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {36913},
pmid = {27841304},
issn = {2045-2322},
support = {MOP-86620//CIHR/Canada ; },
mesh = {Cell Line, Tumor ; HeLa Cells ; Homeostasis ; Humans ; Intranuclear Inclusion Bodies/*metabolism ; Mutation ; Phosphorylation ; Promyelocytic Leukemia Protein/*metabolism ; Protein Binding ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; Telomeric Repeat Binding Protein 1/chemistry/genetics/*metabolism ; Tyrosine/*chemistry ; },
abstract = {TRF1, a component of the shelterin complex, plays a key role in both telomerase-dependent telomere maintenance and alternative lengthening of telomeres, the latter also known as ALT. Characteristics of ALT cells include C-circles and ALT-associated PML bodies, referred to as APBs. The function of TRF1 is tightly regulated by post-translational modification including phosphorylation, however TRF1 phosphorylation sites have yet to be fully characterized. Here we report a novel TRF1 phosphorylation site threonine 271. We show that a nonphosphorylatable mutation of T271A impairs TRF1 binding to telomeric DNA in vivo and renders TRF1 defective in inhibiting telomerase-dependent telomere elongation. On the other hand, TRF1 carrying a phosphomimic mutation of T271D is competent in not only binding to telomeric DNA but also inhibiting telomerase-mediated telomere lengthening. These results suggest that TRF1 phosphorylation on T271 negatively regulates telomerase-mediated telomere maintenance. We find that in telomerase-negative ALT cells, TRF1 carrying either a T271A or T271D mutation is able to promote C-circle production but fails to support APB formation. These results suggest that TRF1 phosphorylation on T271 is necessary for APB formation but dispensable for C-circle production. These results further imply that APB formation can be mechanistically separated from C-circle production.},
}
@article {pmid27836984,
year = {2017},
author = {Lee, YC and Leek, C and Levine, MT},
title = {Recurrent Innovation at Genes Required for Telomere Integrity in Drosophila.},
journal = {Molecular biology and evolution},
volume = {34},
number = {2},
pages = {467-482},
pmid = {27836984},
issn = {1537-1719},
support = {F32 GM109676/GM/NIGMS NIH HHS/United States ; K99 GM107351/GM/NIGMS NIH HHS/United States ; R00 GM107351/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; DNA Damage ; DNA Transposable Elements ; Drosophila Proteins/genetics ; Drosophila melanogaster/*genetics/metabolism ; Evolution, Molecular ; Female ; Gene Duplication ; Male ; Nuclear Proteins/genetics ; Phylogeny ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres are nucleoprotein complexes at the ends of linear chromosomes. These specialized structures ensure genome integrity and faithful chromosome inheritance. Recurrent addition of repetitive, telomere-specific DNA elements to chromosome ends combats end-attrition, while specialized telomere-associated proteins protect naked, double-stranded chromosome ends from promiscuous repair into end-to-end fusions. Although telomere length homeostasis and end-protection are ubiquitous across eukaryotes, there is sporadic but building evidence that the molecular machinery supporting these essential processes evolves rapidly. Nevertheless, no global analysis of the evolutionary forces that shape these fast-evolving proteins has been performed on any eukaryote. The abundant population and comparative genomic resources of Drosophila melanogaster and its close relatives offer us a unique opportunity to fill this gap. Here we leverage population genetics, molecular evolution, and phylogenomics to define the scope and evolutionary mechanisms driving fast evolution of genes required for telomere integrity. We uncover evidence of pervasive positive selection across multiple evolutionary timescales. We also document prolific expansion, turnover, and expression evolution in gene families founded by telomeric proteins. Motivated by the mutant phenotypes and molecular roles of these fast-evolving genes, we put forward four alternative, but not mutually exclusive, models of intra-genomic conflict that may play out at very termini of eukaryotic chromosomes. Our findings set the stage for investigating both the genetic causes and functional consequences of telomere protein evolution in Drosophila and beyond.},
}
@article {pmid27836977,
year = {2017},
author = {Xu, X and Chen, X and Zhang, X and Liu, Y and Wang, Z and Wang, P and Du, Y and Qin, Y and Chen, ZJ},
title = {Impaired telomere length and telomerase activity in peripheral blood leukocytes and granulosa cells in patients with biochemical primary ovarian insufficiency.},
journal = {Human reproduction (Oxford, England)},
volume = {32},
number = {1},
pages = {201-207},
doi = {10.1093/humrep/dew283},
pmid = {27836977},
issn = {1460-2350},
mesh = {Adult ; Cross-Sectional Studies ; Female ; Granulosa Cells/*metabolism ; Humans ; Leukocytes, Mononuclear/*metabolism ; Primary Ovarian Insufficiency/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {STUDY QUESTION: Are telomere length and telomerase activity associated with biochemical primary ovarian insufficiency (POI)?<br><br>SUMMARY ANSWER: Shortened telomere length and diminished telomerase activity were associated with biochemical POI.<br><br>WHAT IS KNOWN ALREADY: POI is a result of pathological reproductive aging and encompasses occult, biochemical and overt stages. Studies have indicated telomere length as a biomarker for biological aging.<br><br>STUDY DESIGN, SIZE, DURATION: A total of 120 patients with biochemical POI and 279 control women were recruited by the Center for Reproductive Medicine of Shandong University.<br><br>Telomere length in peripheral blood leukocytes (LTL) and granulosa cells (GTL) was measured using a modified Quantitative Polymerase Chain Reaction technique. The relative telomerase activity (RTA) in granulosa cells was detected using a modified quantitative-telomeric repeat amplification protocol assay.<br><br>After adjusting for age, patients with biochemical POI (n&#xa0;=&#xa0;120) exhibited significantly shorter LTLs (0.75&#xa0;&#xb1;&#xa0;0.09 vs 1.79&#xa0;&#xb1;&#xa0;0.12, P < 0.001; OR&#xa0;=&#xa0;0.54, 95% CI =&#xa0;0.43-0.68) and GTLs (0.78&#xa0;&#xb1;&#xa0;0.09 vs 1.90&#xa0;&#xb1;&#xa0;0.23, P < 0.001; OR&#xa0;=&#xa0;0.54, 95% CI&#xa0;=&#xa0;0.41-0.70) than the controls (n&#xa0;=&#xa0;279 for LTLs; n&#xa0;=&#xa0;90 for GTLs). Significantly diminished RTAs in granulosa cells were detected in patients with biochemical POI (n&#xa0;=&#xa0;31) compared with the controls (n&#xa0;=&#xa0;38) (1.57&#xa0;&#xb1;&#xa0;0.59 vs 4.63&#xa0;&#xb1;&#xa0;0.93, P&#xa0;=&#xa0;0.025; OR&#xa0;=&#xa0;0.84, 95% CI&#xa0;=&#xa0;0.72-0.98).<br><br>LARGE SCALE DATA: N/A.<br><br>The cross-sectional nature of this study might have its limit in telomere length as well as telomerase activity along with the progressing decline in ovarian function.<br><br>These findings suggest that telomere length and telomerase activity may be considered as indicators for progression of ovarian decline.<br><br>This research was supported by the National Basic Research Program of China (973 Program) (2012CB944700), Science research foundation item of no-earnings health vocation (201402004) and the National Natural Science Foundation of China (31471352, 81270662, 81471509, 81300461, 81522018). The authors have no potential conflict of interest to declare.},
}
@article {pmid27836509,
year = {2017},
author = {da Silva, MS and Segatto, M and Pavani, RS and Gutierrez-Rodrigues, F and Bispo, VD and de Medeiros, MH and Calado, RT and Elias, MC and Cano, MI},
title = {Consequences of acute oxidative stress in Leishmania amazonensis: From telomere shortening to the selection of the fittest parasites.},
journal = {Biochimica et biophysica acta. Molecular cell research},
volume = {1864},
number = {1},
pages = {138-150},
doi = {10.1016/j.bbamcr.2016.11.001},
pmid = {27836509},
issn = {0167-4889},
mesh = {Adaptation, Physiological/*genetics ; Base Sequence ; DNA Damage ; *DNA Repair ; DNA, Protozoan/*genetics/metabolism ; DNA, Single-Stranded/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; G2 Phase Cell Cycle Checkpoints ; Gene Expression ; Genetic Fitness ; Hydrogen Peroxide/*pharmacology ; Leishmania mexicana/*drug effects/genetics/growth &amp; development/metabolism ; Oxidative Stress ; Protozoan Proteins/genetics/metabolism ; Reactive Oxygen Species/agonists/metabolism ; Selection, Genetic ; Stress, Physiological ; Telomere/chemistry ; Telomere Shortening/*drug effects ; },
abstract = {Leishmaniasis is a spectrum of diseases caused by parasites of the genus Leishmania that affects millions of people around the world. During infection, the parasites use different strategies to survive the host's defenses, including overcoming exposure to reactive oxidant species (ROS), responsible for causing damage to lipids, proteins and DNA. This damage especially affects telomeres, which frequently results in genome instability, senescence and cell death. Telomeres are the physical ends of the chromosomes composed of repetitive DNA coupled with proteins, whose function is to protect the chromosomes termini and avoid end-fusion and nucleolytic degradation. In this work, we induced acute oxidative stress in promastigote forms of Leishmania amazonensis by treating parasites with 2mM hydrogen peroxide (H2O2) for 1h, which was able to increase intracellular ROS levels. In addition, oxidative stress induced DNA damage, as confirmed by 8-oxodGuo quantification and TUNEL assays and the dissociation of LaRPA-1 from the 3' G-overhang, leading to telomere shortening. Moreover, LaRPA-1 was observed to interact with newly formed C-rich single-stranded telomeric DNA, probably as a consequence of the DNA damage response. Nonetheless, acute oxidative stress caused the death of some of the L. amazonensis population and induced cell cycle arrest at the G2/M phase in survivor parasites, which were able to continue proliferating and replicating DNA and became more resistant to oxidative stress. Taken together, these results suggest that adaptation occurs through the selection of the fittest parasites in terms of repairing oxidative DNA damage at telomeres and maintaining genome stability in a stressful environment.},
}
@article {pmid27835738,
year = {2017},
author = {Wolkowitz, OM and Jeste, DV and Martin, AS and Lin, J and Daly, RE and Reuter, C and Kraemer, H},
title = {Leukocyte telomere length: Effects of schizophrenia, age, and gender.},
journal = {Journal of psychiatric research},
volume = {85},
number = {},
pages = {42-48},
doi = {10.1016/j.jpsychires.2016.10.015},
pmid = {27835738},
issn = {1879-1379},
support = {R01 MH094151/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging/genetics/*metabolism ; Female ; Humans ; Interview, Psychological ; Leukocytes/*metabolism ; Linear Models ; Longitudinal Studies ; Male ; Middle Aged ; Outpatients ; Psychotic Disorders/genetics/*metabolism ; Schizophrenia/genetics/*metabolism ; *Sex Characteristics ; Telomere/*metabolism ; Telomere Shortening/physiology ; },
abstract = {BACKGROUND: Schizophrenia is linked with early medical comorbidity and mortality. These observations indicate possible "accelerated biological aging" in schizophrenia, although prior findings are mixed, and few such studies have examined the role of gender. One putative marker of biological aging is leukocyte telomere length (LTL), which typically shortens with age.<br><br>METHODS: We assessed LTL in phenotypically well characterized 134 individuals with schizophrenia (60 women and 74 men) and 123 healthy comparison subjects (HCs) (66 women and 57 men), aged 26 to 65 years.<br><br>RESULTS: Overall, LTL was inversely associated with age (t(249)&#xa0;=&#xa0;-6.2, p&#xa0;<&#xa0;0.001), and a gender effect on the rate of LTL decrease with age was found (t(249)&#xa0;=&#xa0;2.20, p&#xa0;=&#xa0;0.029), with men declining more rapidly than women. No significant overall effect of diagnosis on the rate of decline was detected. However, at the average sample age (48 years), there was a significant gender effect in both schizophrenia and HC groups (t(249)&#xa0;=&#xa0;2.48, p&#xa0;=&#xa0;0.014), with women having longer LTL than men, and a significant gender X diagnosis effect (t(249)&#xa0;=&#xa0;2.43, p&#xa0;=&#xa0;0.016) - at the average sample age, women with schizophrenia had shorter LTL than HC women.<br><br>DISCUSSION: Gender, not the diagnosis of schizophrenia, was the major factor involved with LTL shortening across the age range studied. We discuss the constraints of a cross-sectional design and other methodological issues, and indicate future directions. Understanding the impact of schizophrenia on biological aging will require separate evaluations in men and women.},
}
@article {pmid27835648,
year = {2016},
author = {Zhang, Y and Zhang, L and Tang, X and Bhardwaj, SR and Ji, J and Rong, YS},
title = {MTV, an ssDNA Protecting Complex Essential for Transposon-Based Telomere Maintenance in Drosophila.},
journal = {PLoS genetics},
volume = {12},
number = {11},
pages = {e1006435},
pmid = {27835648},
issn = {1553-7404},
mesh = {Animals ; Carrier Proteins/genetics ; Chromosomal Proteins, Non-Histone/*genetics ; DNA Transposable Elements/genetics ; DNA, Single-Stranded/*genetics ; Drosophila Proteins/*genetics ; Drosophila melanogaster/genetics ; Nerve Growth Factors/*genetics ; Point Mutation/genetics ; Protein Binding/genetics ; Protein Serine-Threonine Kinases/genetics ; Telomerase/genetics ; Telomere/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Multiple complexes protect telomeres. In telomerase-maintained organisms, Shelterin related complexes occupy the duplex region while the CST and Tpp1-Pot1 complexes bind the single stranded overhang of telomeres. Drosophila uses a transposon-based mechanism for end protection. We showed that the HOAP-HipHop complex occupies the duplex region. Whether an ssDNA-binding complex exists is not known. Here we discover a novel protein, Tea, that is specifically enriched at telomeres to prevent telomere fusion. We also identify a complex consisting of Tea and two known capping proteins, Ver and Moi. The Moi-Tea-Ver (MTV) complex purified in vitro binds and protects ssDNA in a sequence-independent manner. Tea recruits Ver and Moi to telomeres, and point mutations disrupting MTV interaction in vitro result in telomere uncapping, consistent with these proteins functioning as a complex in vivo. MTV thus shares functional similarities with CST or TPP1-POT1 in protecting ssDNA, highlighting a conserved feature in end protecting mechanisms.},
}
@article {pmid27834202,
year = {2016},
author = {Dieckmann, AK and Babin, V and Harari, Y and Eils, R and König, R and Luke, B and Kupiec, M},
title = {Role of the ESCRT Complexes in Telomere Biology.},
journal = {mBio},
volume = {7},
number = {6},
pages = {},
pmid = {27834202},
issn = {2150-7511},
mesh = {DNA Repair ; DNA Replication ; DNA-Binding Proteins/metabolism ; Endosomal Sorting Complexes Required for Transport/genetics/*metabolism ; *Genome, Fungal ; Humans ; Mutation ; Saccharomyces cerevisiae/*genetics ; Telomerase/metabolism ; Telomere/genetics/metabolism/*physiology ; Telomere Homeostasis/*genetics/physiology ; Telomere Shortening/*genetics/physiology ; },
abstract = {UNLABELLED: Eukaryotic chromosomal ends are protected by telomeres from fusion, degradation, and unwanted double-strand break repair events. Therefore, telomeres preserve genome stability and integrity. Telomere length can be maintained by telomerase, which is expressed in most human primary tumors but is not expressed in the majority of somatic cells. Thus, telomerase may be a highly relevant anticancer drug target. Genome-wide studies in the yeast Saccharomyces cerevisiae identified a set of genes associated with telomere length maintenance (TLM genes). Among the tlm mutants with short telomeres, we found a strong enrichment for those affecting vacuolar and endosomal traffic (particularly the endosomal sorting complex required for transport [ESCRT] pathway). Here, we present our results from investigating the surprising link between telomere shortening and the ESCRT machinery. Our data show that the whole ESCRT system is required to safeguard proper telomere length maintenance. We propose a model of impaired end resection resulting in too little telomeric overhang, such that Cdc13 binding is prevented, precluding either telomerase recruitment or telomeric overhang protection.<br><br>IMPORTANCE: Telomeres are the ends of eukaryotic chromosomes. They are necessary for the proper replication of the genome and protect the chromosomes from degradation. In a large-scale systematic screen for mutants that affect telomere length in yeast, we found that mutations in any of the genes encoding the ESCRT complexes, required for the formation of transport vesicles within the cell, cause telomere shortening. We carried out an analysis of the mechanisms disrupted in these mutants and found that they are defective for the ability to elongate short telomeres, probably due to faulty end processing. We discuss the significance of these findings and how they could be relevant to anticancer therapies.},
}
@article {pmid27833022,
year = {2016},
author = {Jamiruddin, MR and Kaitsuka, T and Hakim, F and Fujimura, A and Wei, FY and Saitoh, H and Tomizawa, K},
title = {HDAC9 regulates the alternative lengthening of telomere (ALT) pathway via the formation of ALT-associated PML bodies.},
journal = {Biochemical and biophysical research communications},
volume = {481},
number = {1-2},
pages = {25-30},
doi = {10.1016/j.bbrc.2016.11.026},
pmid = {27833022},
issn = {1090-2104},
mesh = {Cell Line, Tumor ; HeLa Cells ; Histone Deacetylases/*metabolism ; Humans ; Neoplasms, Experimental/*metabolism/*pathology ; Repressor Proteins/*metabolism ; Telomere/*pathology ; *Telomere Homeostasis ; },
abstract = {Cancer cells overcome cellular senescence by activating the telomere maintenance mechanism, which can be either through telomerase or the alternative lengthening of telomeres (ALT). Being exclusive to cancer cells, targeting ALT is a more promising route for the development of drugs against cancer. The histone deacetylase (HDAC) family plays significant roles in various cellular processes. In addition to the regulation of gene expression, HDACs are also known to directly interact with many proteins. We focused on this family, and found that HDAC9 was up-regulated in ALT-positive cells. In ALT-positive cells treated with HDAC9 siRNA, there was a decrease in the telomere replicative capacity, which was evident from the C-circles assay. Furthermore, the formation of ALT-associated promyelocytic leukemia (PML) nuclear bodies (APBs) was inhibited by HDAC9 knockdown. Based on this study, it is suggested that HDAC9 regulates the formation of APBs and could be a candidate for the target of ALT-cancer therapy.},
}
@article {pmid27832427,
year = {2016},
author = {Gao, X and Mons, U and Zhang, Y and Breitling, LP and Brenner, H},
title = {DNA methylation changes in response to active smoking exposure are associated with leukocyte telomere length among older adults.},
journal = {European journal of epidemiology},
volume = {31},
number = {12},
pages = {1231-1241},
pmid = {27832427},
issn = {1573-7284},
mesh = {Aged ; DNA Methylation/*physiology ; Female ; Germany ; Humans ; *Leukocytes ; Male ; Middle Aged ; Polymerase Chain Reaction ; Smoking/*physiopathology ; Telomere ; Telomere Shortening/*physiology ; },
abstract = {Telomere length (TL) is associated with an increased risk of aging-related diseases. As a preventable environmental hazard of morbidity and mortality, smoking has been reported to promote TL attrition by producing a variety of oxidants and free radicals. Since DNA methylation has been demonstrated to play an important role in the pathways of smoking and smoking-induced diseases, this study aimed to address whether the smoking-associated DNA methylation changes could be associated with accelerated TL shortening. We obtained DNA methylation profiles in whole blood samples by Illumina Infinium Human Methylation 450 Beadchip array in two independent subsamples of the ESTHER study and measured their relative TL by quantitative PCR. Terminal Restriction Fragment analysis was additionally performed in a subsample to obtain absolute TL in base pairs. TL measurements across panels were standardized by z-transformation. After correction for multiple testing, we successfully confirmed that seven out of 151 smoking-related CpG sites were associated with TL (FDR <0.05). A smoking index based on the seven loci showed monotonic associations with TL, cumulative smoking exposure and time after smoking cessation. In conclusion, our study supports suggestions that epigenetic alterations could play a role in smoking-associated disproportionate aging as reflected by TL. Further research is required to examine whether the identified epigenetic signatures of smoking can be of value in clinical practice to assess individual aging across the lifespan.},
}
@article {pmid27831704,
year = {2017},
author = {Brody, GH and Yu, T and Shalev, I},
title = {Risky family processes prospectively forecast shorter telomere length mediated through negative emotions.},
journal = {Health psychology : official journal of the Division of Health Psychology, American Psychological Association},
volume = {36},
number = {5},
pages = {438-444},
pmid = {27831704},
issn = {1930-7810},
support = {P30 DA027827/DA/NIDA NIH HHS/United States ; R01 DA019230/DA/NIDA NIH HHS/United States ; R01 HD030588/HD/NICHD NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Emotions/*physiology ; Female ; Humans ; Male ; Prospective Studies ; Risk ; Telomere Shortening/*physiology ; Young Adult ; },
abstract = {OBJECTIVE: This study was designed to examine prospective associations of risky family environments with subsequent levels of negative emotions and peripheral blood mononuclear cell telomere length (TL), a marker of cellular aging. A second purpose was to determine whether negative emotions mediate the hypothesized link between risky family processes and diminished telomere length.<br><br>METHOD: Participants were 293 adolescents (age 17 years at the first assessment) and their primary caregivers. Caregivers provided data on risky family processes when the youths were age 17 years, youths reported their negative emotions at age 18 years, and youths' TL was assayed from a blood sample at age 22 years.<br><br>RESULTS: The results revealed that (a) risky family processes forecast heightened negative emotions (&#x3b2; = .316, p < .001) and diminished TL (&#x3b2; = -.199, p = .003) among youths, (b) higher levels of negative emotions forecast shorter TL (&#x3b2; = -.187, p = .012), and (c) negative emotions served as a mediator connecting risky family processes with diminished TL (indirect effect = -0.012, 95% CI [-0.036, -0.002]).<br><br>CONCLUSIONS: These findings are consistent with the hypothesis that risky family processes presage premature cellular aging through effects on negative emotions, with potential implications for lifelong health. (PsycINFO Database Record},
}
@article {pmid27829156,
year = {2016},
author = {Garcia-Exposito, L and Bournique, E and Bergoglio, V and Bose, A and Barroso-Gonzalez, J and Zhang, S and Roncaioli, JL and Lee, M and Wallace, CT and Watkins, SC and Opresko, PL and Hoffmann, JS and O'Sullivan, RJ},
title = {Proteomic Profiling Reveals a Specific Role for Translesion DNA Polymerase η in the Alternative Lengthening of Telomeres.},
journal = {Cell reports},
volume = {17},
number = {7},
pages = {1858-1871},
pmid = {27829156},
issn = {2211-1247},
support = {P30 CA047904/CA/NCI NIH HHS/United States ; R01 CA207209/CA/NCI NIH HHS/United States ; R01 ES022944/ES/NIEHS NIH HHS/United States ; S10 OD019973/OD/NIH HHS/United States ; },
mesh = {Biotinylation ; DNA/biosynthesis ; DNA Polymerase III/metabolism ; DNA Replication ; DNA-Directed DNA Polymerase/*metabolism ; HeLa Cells ; Humans ; Mitosis ; Proteomics/*methods ; Recombinational DNA Repair ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Cancer cells rely on the activation of telomerase or the alternative lengthening of telomeres (ALT) pathways for telomere maintenance and survival. ALT involves homologous recombination (HR)-dependent exchange and/or HR-associated synthesis of telomeric DNA. Utilizing proximity-dependent biotinylation (BioID), we sought to determine the proteome of telomeres in cancer cells that employ these distinct telomere elongation mechanisms. Our analysis reveals that multiple DNA repair networks converge at ALT telomeres. These include the specialized translesion DNA synthesis (TLS) proteins FANCJ-RAD18-PCNA and, most notably, DNA polymerase eta (Polη). We observe that the depletion of Polη leads to increased ALT activity and late DNA polymerase δ (Polδ)-dependent synthesis of telomeric DNA in mitosis. We propose that Polη fulfills an important role in managing replicative stress at ALT telomeres, maintaining telomere recombination at tolerable levels and stimulating DNA synthesis by Polδ.},
}
@article {pmid27824607,
year = {2017},
author = {Khincha, PP and Bertuch, AA and Agarwal, S and Townsley, DM and Young, NS and Keel, S and Shimamura, A and Boulad, F and Simoneau, T and Justino, H and Kuo, C and Artandi, S and McCaslin, C and Cox, DW and Chaffee, S and Collins, BF and Giri, N and Alter, BP and Raghu, G and Savage, SA},
title = {Pulmonary arteriovenous malformations: an uncharacterised phenotype of dyskeratosis congenita and related telomere biology disorders.},
journal = {The European respiratory journal},
volume = {49},
number = {1},
pages = {},
pmid = {27824607},
issn = {1399-3003},
support = {R01 DK107716/DK/NIDDK NIH HHS/United States ; R24 DK099808/DK/NIDDK NIH HHS/United States ; R35 CA197563/CA/NCI NIH HHS/United States ; Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Arteriovenous Fistula/*genetics/physiopathology ; Bone Marrow ; Child ; Child, Preschool ; Dyskeratosis Congenita/*genetics/physiopathology ; Female ; Genotype ; Germ-Line Mutation ; Humans ; Hypoxia ; Infant ; Leukocytes/cytology ; Lung/pathology ; Male ; *Mutation ; Perfusion ; Phenotype ; Pulmonary Artery/*abnormalities/physiopathology ; Pulmonary Veins/*abnormalities/physiopathology ; Retrospective Studies ; Telomerase/*genetics ; Telomere/genetics ; Young Adult ; },
abstract = {Pulmonary arteriovenous malformations are under-recognized in telomere biology disorders and present diagnostic and therapeutic challenges.},
}
@article {pmid27821557,
year = {2016},
author = {Keefe, DL},
title = {Telomeres, Reproductive Aging, and Genomic Instability During Early Development.},
journal = {Reproductive sciences (Thousand Oaks, Calif.)},
volume = {23},
number = {12},
pages = {1612-1615},
doi = {10.1177/1933719116676397},
pmid = {27821557},
issn = {1933-7205},
mesh = {*Aging ; Animals ; Female ; Humans ; Mice ; Oocytes/*physiology ; *Reproduction ; Telomere/*physiology ; },
abstract = {Implantation rate decreases and miscarriage rate increases with advancing maternal age. The oocyte must be the locus of reproductive aging because donation of oocytes from younger to older women abrogates the effects of aging on fecundity. Nuclear transfer experiments in a mouse model of reproductive aging show that the reproductive aging phenotype segregates with the nucleus rather than the cytoplasm. A number of factors within the nucleus have been hypothesized to mediate reproductive aging, including disruption of cohesions, reduced chiasma, aneuploidy, disrupted meiotic spindles, and DNA damage caused by chronic exposure to reactive oxygen species. We have proposed telomere attrition as a parsimonious way to explain these diverse effects of aging on oocyte function. Telomeres are repetitive sequences of DNA and associated proteins, which form a loop (t loop) at chromosome ends. Telomeres prevent the blunt end of DNA from triggering a DNA damage response. Previously, we showed that experimental telomere shortening phenocopies reproductive aging in mice. Telomere shortening causes reduced synapsis and chiasma, chromosome fusions, embryo arrest and fragmentation, and abnormal meiotic spindles. Telomere length of polar bodies predicts the fragmentation of human embryos. Telomerase, the reverse transcriptase capable of reconstituting shortened telomeres, is only minimally active in oocytes and preimplantation embryos. Intriguingly, during the first cell cycles following activation, telomeres robustly elongate via a DNA double-strand break mechanism called alternative lengthening of telomeres (ALTs). Alternative lengthening of telomere takes place even in telomerase-null mice. This mechanism of telomere elongation previously had been found only in cancer cells lacking telomerase activity. We propose that ALT elongates telomeres across generations but does so at the cost of extensive genomic instability in preimplantation embryos.},
}
@article {pmid27819056,
year = {2016},
author = {Diman, A and Boros, J and Poulain, F and Rodriguez, J and Purnelle, M and Episkopou, H and Bertrand, L and Francaux, M and Deldicque, L and Decottignies, A},
title = {Nuclear respiratory factor 1 and endurance exercise promote human telomere transcription.},
journal = {Science advances},
volume = {2},
number = {7},
pages = {e1600031},
pmid = {27819056},
issn = {2375-2548},
mesh = {AMP-Activated Protein Kinases/metabolism ; Cell Line, Tumor ; Chromatin Immunoprecipitation ; *Exercise ; Genes, Reporter ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Muscle, Skeletal/metabolism ; Nuclear Respiratory Factor 1/chemistry/*metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Protein Binding ; Telomere/chemistry/*metabolism ; Transcription, Genetic ; Up-Regulation ; Young Adult ; },
abstract = {DNA breaks activate the DNA damage response and, if left unrepaired, trigger cellular senescence. Telomeres are specialized nucleoprotein structures that protect chromosome ends from persistent DNA damage response activation. Whether protection can be enhanced to counteract the age-dependent decline in telomere integrity is a challenging question. Telomeric repeat-containing RNA (TERRA), which is transcribed from telomeres, emerged as important player in telomere integrity. However, how human telomere transcription is regulated is still largely unknown. We identify nuclear respiratory factor 1 and peroxisome proliferator-activated receptor γ coactivator 1α as regulators of human telomere transcription. In agreement with an upstream regulation of these factors by adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), pharmacological activation of AMPK in cancer cell lines or in normal nonproliferating myotubes up-regulated TERRA, thereby linking metabolism to telomere fitness. Cycling endurance exercise, which is associated with AMPK activation, increased TERRA levels in skeletal muscle biopsies obtained from 10 healthy young volunteers. The data support the idea that exercise may protect against aging.},
}
@article {pmid27816684,
year = {2016},
author = {Sethi, I and Bhat, GR and Singh, V and Kumar, R and Bhanwer, AJ and Bamezai, RN and Sharma, S and Rai, E},
title = {Role of telomeres and associated maintenance genes in Type 2 Diabetes Mellitus: A review.},
journal = {Diabetes research and clinical practice},
volume = {122},
number = {},
pages = {92-100},
doi = {10.1016/j.diabres.2016.10.015},
pmid = {27816684},
issn = {1872-8227},
mesh = {Diabetes Mellitus, Type 2/*genetics/metabolism ; *Genetic Predisposition to Disease ; *Genome-Wide Association Study ; Humans ; *Polymorphism, Single Nucleotide ; Telomere/*physiology ; },
abstract = {Type 2 Diabetes Mellitus (T2DM), a multifactorial complex disorder, is emerging as a major cause of morbidity, mortality and socio-economic burden across the world. Despite huge efforts in understanding genetics of T2DM, only ∼10% of the genetic factors have been identified so far. Telomere attrition, a natural phenomenon has recently emerged in understanding the pathophysiology of T2DM. It has been indicated that Telomeres and associated pathways might be the critical components in the disease etiology, though the mechanism(s) involved are not clear. Recent Genome Wide (GWAS) and Candidate Gene Case-Control Association Studies have also indicated an association of Telomere and associated pathways related genes with T2DM. Single Nucleotide Polymorphisms (SNPs) in the telomere maintenance genes: TERT, TERC, TNKS, CSNK2A2, TEP1, ACD, TRF1 and TRF2, have shown strong association with telomere attrition in T2DM and its pathophysiology, in these studies. However, the assessment has been made within limited ethnicities (Caucasians, Han Chinese cohort and Punjabi Sikhs from South Asia), warranting the study of such associations in different ethnic groups. Here, we propose the possible mechanisms, in the light of existing knowledge, to understand the association of T2DM with telomeres and associated pathways.},
}
@article {pmid27814605,
year = {2017},
author = {Gonzales-Ebsen, AC and Gregersen, N and Olsen, RK},
title = {Linking telomere loss and mitochondrial dysfunction in chronic disease.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {22},
number = {1},
pages = {117-127},
doi = {10.2741/4475},
pmid = {27814605},
issn = {2768-6698},
mesh = {Aging/genetics/metabolism ; Animals ; Chronic Disease ; Humans ; Mitochondria/*metabolism ; Models, Biological ; Organelle Biogenesis ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Telomere/metabolism ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Telomeres and mitochondria are known to deteriorate over time. Telomere shortening is associated with aging, early senescence, and premature cell death. Mitochondrial dysfunction produces indiscriminate amounts of reactive oxygen species that may lead to oxidative damage to cellular constituents, including telomeric DNA, causing telomere shortening. In fact, primary mitochondrial dysfunction (for example respiratory chain disorders) and secondary mitochondrial dysfunction (such as metabolic diseases, neurodegenerative diseases, cardiovascular diseases, and mood disorders, among others) have been shown to have shorter telomeres than healthy individuals. Drawing a mechanistic connection between telomere function and mitochondria biology will provide a broader perspective for understanding the pathophysiology of diseases and their relation to the aging process, and may provide opportunities for new possible treatments.},
}
@article {pmid27814571,
year = {2017},
author = {Panero, J and Santos, PD and Slavutsky, I},
title = {Telomere protein complexes and their role in lymphoid malignancies.},
journal = {Frontiers in bioscience (Scholar edition)},
volume = {9},
number = {1},
pages = {17-30},
doi = {10.2741/s469},
pmid = {27814571},
issn = {1945-0524},
mesh = {Animals ; Cellular Senescence/genetics ; Hematologic Neoplasms/*genetics/*metabolism/pathology ; Humans ; Telomerase/genetics/metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {Telomeres are highly regulated and dynamic complexes that protect the genomic DNA and prevent the end of linear chromosomes from being misrecognized as a broken DNA. Due to the end replication problem, telomeres of somatic cells shorten with each cell division, inducing cell senescence. Telomerase is a reverse transcriptase capable of compensating telomere attrition by adding telomere repeats to the ends of chromosomes. Human telomeres are associated with the shelterin complex which consists of six telomere-associated proteins that specifically bind to telomeric DNA. Alterations or removal of individual shelterin components would lead to telomere uncapping and telomere dysfunction, resulting in cellular senescence and transformation to a malignant state. Another complex of multifunctional proteins, named non-shelterin complex, is thought to prevent telomere degradation and facilitate telomerase-based telomere elongation. As telomerase is highly expressed in most human tumor cells, it is considered an attractive target for new therapeutic strategies. In this review, we will summarize the characteristics of telomeres and telomerase in lymphoid malignancies and discuss the role of telomere-associated proteins in these entities.},
}
@article {pmid27812868,
year = {2017},
author = {Patel, PL and Herbig, U},
title = {Detection of Dysfunctional Telomeres in Oncogene-Induced Senescence.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1534},
number = {},
pages = {69-78},
doi = {10.1007/978-1-4939-6670-7_6},
pmid = {27812868},
issn = {1940-6029},
support = {R01 CA136533/CA/NCI NIH HHS/United States ; R01 CA184572/CA/NCI NIH HHS/United States ; },
mesh = {Biomarkers ; Cell Line, Tumor ; Cellular Senescence/*genetics ; DNA Damage ; Fibroblasts/metabolism ; Fluorescent Antibody Technique ; Gene Expression ; Genetic Vectors/genetics ; Humans ; In Situ Hybridization, Fluorescence ; Oncogenes/*genetics ; Retroviridae/genetics ; Telomere/*genetics ; Transduction, Genetic ; },
abstract = {Expressing oncogenes in normal somatic human cells leads to cellular senescence after just a few cell division cycles. In cells that are more resistant to culture stresses, such as human dermal fibroblasts, this oncogene-induced senescence (OIS) is a result of a DNA damage response (DDR) that is activated due to the formation of DNA lesions at both non-telomeric and telomeric DNA sequences. DNA lesions can be visualized as DDR foci by immunofluorescence microscopy using antibodies against a number of DDR factors, including ϒ-H2AX and 53BP1. Over time and as cells remain arrested in OIS, non-telomeric DDR foci progressively become resolved, while telomeric DDR foci, also called dysfunctional telomeres, persist. Here we describe a protocol to detect dysfunctional telomeres in cultured human cells, to monitor a temporal enrichment of dysfunctional telomeres in cells that had undergone OIS, and to detect dysfunctional telomeres in paraffin-embedded and formalin-fixed human tissue.},
}
@article {pmid27812514,
year = {2016},
author = {Paik, JK and Kang, R and Cho, Y and Shin, MJ},
title = {Association between Genetic Variations Affecting Mean Telomere Length and the Prevalence of Hypertension and Coronary Heart Disease in Koreans.},
journal = {Clinical nutrition research},
volume = {5},
number = {4},
pages = {249-260},
pmid = {27812514},
issn = {2287-3732},
abstract = {In this study, we investigated whether the single nucleotide polymorphisms (SNPs) associated with telomere length (TL) were associated with the incidence of hypertension (HTN)/coronary heart disease (CHD) and cardiovascular risk factors in the Korean population. Data from 5,705 (ages 39-70) participants in the Korean Genome Epidemiology Study (rural Ansung and urban Ansan cohorts) were studied. Twelve SNPs known to be associated with telomere biology were tested for an association with HTN/CHD. As results, no significant associations were found between the selected TL-related SNPs and prevalence of HTN and CHD. Among non-alcohol users, subjects with minor alleles in rs1269304 and rs10936601 (TERC and LRRC34, respectively) exhibited a higher rate of CHD occurrence (odds ratio [OR], 1.862; 95% confidence intervals [CIs], 1.137, 3.049; OR, 1.855; 95% CIs, 1.111, 2.985; respectively). However, alcohol users with minor alleles in rs398652 (PELI2) were significantly associated with higher HTN prevalence (OR, 1.179; 95% CIs, 1.040, 1.336). Of the 3 SNPs related to disease outcomes, rs1296304 was significantly associated with increased levels of diastolic blood pressure (β estimate, 0.470; 95% CIs, 0.013, 0.926). The minor allele in rs398652 was significantly associated with higher levels of body mass index (OR, 0.128; 95% CIs, 0.010, 0.246) and γ-glutamyl transpeptidase (OR, 0.013; 95% CIs, 0.001, 0.024). In conclusion, there were no significant associations between the selected TL-related SNPs and the occurrence of HTN/CHD in Koreans. However, the results suggest the presence of a possible interaction between related SNPs and alcohol behavior associated with HTN/CHD occurrence.},
}
@article {pmid27810892,
year = {2017},
author = {Wium-Andersen, MK and Ørsted, DD and Rode, L and Bojesen, SE and Nordestgaard, BG},
title = {Telomere length and depression: prospective cohort study and Mendelian randomisation study in 67 306 individuals.},
journal = {The British journal of psychiatry : the journal of mental science},
volume = {210},
number = {1},
pages = {31-38},
doi = {10.1192/bjp.bp.115.178798},
pmid = {27810892},
issn = {1472-1465},
mesh = {Adult ; Aged ; Aged, 80 and over ; Cross-Sectional Studies ; Denmark ; Depression/*genetics ; Depressive Disorder/*genetics ; Female ; Humans ; Male ; Mendelian Randomization Analysis/*methods ; Middle Aged ; Prospective Studies ; *Registries ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {BACKGROUND: Depression has been cross-sectionally associated with short telomeres as a measure of biological age. However, the direction and nature of the association is currently unclear.<br><br>AIMS: We examined whether short telomere length is associated with depression cross-sectionally as well as prospectively and genetically.<br><br>METHOD: Telomere length and three polymorphisms, TERT, TERC and OBFC1, were measured in 67 306 individuals aged 20-100 years from the Danish general population and associated with register-based attendance at hospital for depression and purchase of antidepressant medication.<br><br>RESULTS: Attendance at hospital for depression was associated with short telomere length cross-sectionally, but not prospectively. Further, purchase of antidepressant medication was not associated with short telomere length cross-sectionally or prospectively. Mean follow-up was 7.6 years (range 0.0-21.5). The genetic analyses suggested that telomere length was not causally associated with attendance at hospital for depression or with purchase of antidepressant medication.<br><br>CONCLUSIONS: Short telomeres were not associated with depression in prospective or in causal, genetic analyses.},
}
@article {pmid27763985,
year = {2016},
author = {Schneper, LM and Brooks-Gunn, J and Notterman, DA and Suomi, SJ},
title = {Early-Life Experiences and Telomere Length in Adult Rhesus Monkeys: An Exploratory Study.},
journal = {Psychosomatic medicine},
volume = {78},
number = {9},
pages = {1066-1071},
pmid = {27763985},
issn = {1534-7796},
support = {P2C HD047879/HD/NICHD NIH HHS/United States ; R01 HD076592/HD/NICHD NIH HHS/United States ; },
mesh = {Age Factors ; Animals ; Female ; Leukocytes ; Macaca mulatta/genetics/*physiology ; *Social Environment ; *Telomere/genetics ; },
abstract = {OBJECTIVE: Child-rearing environments have been associated with morbidity in adult rhesus monkeys. We examine whether such links are also seen with leukocyte telomere length.<br><br>METHODS: To determine telomere length in leukocytes, blood was collected from 11 adult female monkeys aged 7 to 10 years who had been exposed to different rearing environments between birth and 7 months. Four had been reared with their mothers in typical social groups composed of other female monkeys, their offspring, and 1 to 2 adult male monkeys. The other 7 had been reared in either small groups of peers or individual cages with extensive peer interaction daily. After 7 months, all shared a common environment.<br><br>RESULTS: Telomere lengths were longer for those adults who had been reared with their mothers in social groups (median = 16.0 kb, interquartile range = 16.5-15.4) than for those who were reared without their mothers (median = 14.0 kb, interquartile range = 14.3-12.7; 2.2 kb/telomere difference, p < .027).<br><br>CONCLUSIONS: This observation adds to emerging knowledge about early adverse child-rearing conditions and their potential for influencing later morbidity. Because newborns were randomly assigned to the mother or other rearing conditions, the findings are not confounded by other conditions that co-occur with adverse child-rearing environments in humans (e.g., prenatal stress, nutrition and health as well as postnatal nutrition and negative life experiences over and above rearing conditions).},
}
@article {pmid27697833,
year = {2016},
author = {Cortizas, EM and Zahn, A and Safavi, S and Reed, JA and Vega, F and Di Noia, JM and Verdun, RE},
title = {UNG protects B cells from AID-induced telomere loss.},
journal = {The Journal of experimental medicine},
volume = {213},
number = {11},
pages = {2459-2472},
pmid = {27697833},
issn = {1540-9538},
support = {P30 AI073961/AI/NIAID NIH HHS/United States ; R56 AI106894/AI/NIAID NIH HHS/United States ; MOP130535//CIHR/Canada ; },
mesh = {Animals ; B-Lymphocytes/*metabolism ; Base Sequence ; Cell Proliferation ; Clone Cells ; Cytidine Deaminase/*metabolism ; *Cytoprotection ; DNA Damage/genetics ; DNA Mismatch Repair/genetics ; Germinal Center/metabolism ; Immunoglobulin Class Switching ; Lymphocyte Activation/immunology ; Lymphoma, B-Cell/pathology ; Mice, Inbred C57BL ; Models, Biological ; Protein Binding ; Recombination, Genetic/genetics ; Telomere/*metabolism ; Uracil-DNA Glycosidase/deficiency/*metabolism ; },
abstract = {Activation-induced deaminase (AID) initiates antibody gene diversification by creating G:U mismatches in the immunoglobulin loci. However, AID also deaminates nonimmunoglobulin genes, and failure to faithfully repair these off-target lesions can cause B cell lymphoma. In this study, we identify a mechanism by which processing of G:U produced by AID at the telomeres can eliminate B cells at risk of genomic instability. We show that telomeres are off-target substrates of AID and that B cell proliferation depends on protective repair by uracil-DNA glycosylase (UNG). In contrast, in the absence of UNG activity, deleterious processing by mismatch repair leads to telomere loss and defective cell proliferation. Indeed, we show that UNG deficiency reduces B cell clonal expansion in the germinal center in mice and blocks the proliferation of tumor B cells expressing AID. We propose that AID-induced damage at telomeres acts as a fail-safe mechanism to limit the tumor promoting activity of AID when it overwhelms uracil excision repair.},
}
@article {pmid27645931,
year = {2016},
author = {Zubko, EI and Shackleton, JL and Zubko, MK},
title = {ATLAS: An advanced PCR-method for routine visualization of telomere length in Saccharomyces cerevisiae.},
journal = {International journal of biological macromolecules},
volume = {93},
number = {Pt A},
pages = {1285-1294},
doi = {10.1016/j.ijbiomac.2016.09.006},
pmid = {27645931},
issn = {1879-0003},
mesh = {Base Sequence ; Chromosomes, Fungal/genetics ; DNA Primers/genetics ; Polymerase Chain Reaction/*methods ; Saccharomyces cerevisiae/*genetics ; Telomere/*genetics ; Temperature ; },
abstract = {Measuring telomere length is essential in telomere biology. Southern blot hybridization is the predominant method for measuring telomere length in the genetic model Saccharomyces cerevisiae. We have further developed and refined a telomere PCR approach, which was rarely used previously (mainly in specific telomeric projects), into a robust method allowing direct visualisation of telomere length differences in routine experiments with S. cerevisiae, and showing a strong correlation of results with data obtained by Southern blot hybridization. In this expanded method denoted as ATLAS (A-dvanced T-elomere L-ength A-nalysis in S. cerevisiae), we have introduced: 1) set of new primers annealing with high specificity to telomeric regions on five different chromosomes; 2) new approach for designing reverse telomere primers that is based on the ligation of an adaptor of a fixed size to telomeric ends. ATLAS can be used at the scale of individual assays and high-throughput approaches. This simple, time/cost-effective and reproducible methodology will complement Southern blot hybridization and facilitate further progress in telomere research.},
}
@article {pmid27604461,
year = {2016},
author = {Novakovic, B and Napier, CE and Vryer, R and Dimitriadis, E and Manuelpillai, U and Sharkey, A and Craig, JM and Reddel, RR and Saffery, R},
title = {DNA methylation mediated up-regulation of TERRA non-coding RNA is coincident with elongated telomeres in the human placenta.},
journal = {Molecular human reproduction},
volume = {22},
number = {11},
pages = {791-799},
doi = {10.1093/molehr/gaw053},
pmid = {27604461},
issn = {1460-2407},
mesh = {Cell Line ; DNA Methylation/genetics/*physiology ; Female ; Humans ; Placenta/*metabolism ; Pregnancy ; Promoter Regions, Genetic/genetics ; RNA, Untranslated/*genetics ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomere Homeostasis/genetics/physiology ; Trophoblasts/metabolism ; },
abstract = {STUDY QUESTION: What factors regulate elongated telomere length in the human placenta?<br><br>SUMMARY ANSWER: Hypomethylation of TERRA promoters in the human placenta is associated with high TERRA expression, however, no clear mechanistic link between these phenomena and elongated telomere length in the human placenta was found.<br><br>WHAT IS KNOWN ALREADY: Human placenta tissue and trophoblasts show longer telomere lengths compared to gestational age-matched somatic cells. However, telomerase (hTERT) expression and activity in the placenta is low, suggesting a role for an alternative lengthening of telomeres (ALT). While ALT is observed in 10-15% of human cancers and in some mouse stem cells, ALT has never been reported in non-cancerous human tissues.<br><br>Human term placental tissue and matched cord blood mononuclear cells (CBMCs) were collected as part of the Peri/Postnatal Epigenetic Twins study (PETS). In addition, first trimester placental villi, purified cytotrophoblasts, choriocarcinoma cell lines and a panel of ALT-positive cancer cell lines were tested. Telomere length was determined using the Terminal Restriction Fragment (TRF) assay and a relative quantitative PCR method. DNA methylation levels at several CpG rich subtelomeric TERRA promoters were determined using bisulfite conversion and the SEQUENOM EpiTYPER platform. Expression of TERRA and hTERT was determined using quantitative RT-PCR. ALT was assessed using the C-circle assay (CCA).<br><br>The human placenta tissue and purified first trimester trophoblasts showed low subtelomeric (TERRA) DNA methylation compared to matched CBMCs and other somatic cells. Interestingly placental TERRA methylation was lower than ALT-cancer cell lines, previously reported to be hypomethylated at these loci. Low TERRA methylation was associated with higher expression of TERRA RNA in placenta compared to matched CBMCs. Detectable levels of C-circles were observed in first trimester placental villi, but not term placenta, suggesting that the ALT mechanism may be active in specific placental cells in early gestation. C-circle analysis of purified first trimester trophoblasts and ALT-associated PML bodies (APB) staining of first trimester villi cross-sections failed to identify this specific cell type population.<br><br>While first trimester villi showed detectable levels of C-circles, these levels were very low compared with those observed in ALT-positive tumours and cell lines. This is consistent with a small sub-population of ALT-positive cells but this requires further investigation. Finally, no mechanistic link was established between TERRA DNA methylation, the presence of C-circles and longer telomere length.<br><br>Given the previously described role of TERRA ncRNA as a negative regulator of telomerase, the finding of elevated TERRA and long telomeres is counterintutive. ALT as a mechanism for telomere length maintenance has only been reported in certain human cancers, and recently in mouse embryonic stem cells and embryos. As with many aspects of cancer, it appears that ALT activity in tumours may be the inappropriate activation of a pathway found in very specific cell types in human development. Our data are the first supportive evidence for ALT in a non-cancerous human tissue, a result that requires further investigation and replication. The level of TERRA methylation in the human placenta is significantly lower than found in ALT cancer cell lines and somatic cells, raising the possibility of a novel mechanism in maintaining low methylation at subtelomeric regions.<br><br>LARGE SCALE DATA: Not applicable.<br><br>This study was supported by NHMRC early career fellowship (B.N.), NHMRC Senior Research Fellowship (R.S.) and the Victoria Government Infrastructure Grant. R.R. holds a patent for the C-circle assay. No other conflicts declared.},
}
@article {pmid27807141,
year = {2016},
author = {Bisht, K and Smith, EM and Tesmer, VM and Nandakumar, J},
title = {Structural and functional consequences of a disease mutation in the telomere protein TPP1.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {113},
number = {46},
pages = {13021-13026},
pmid = {27807141},
issn = {1091-6490},
support = {R00 CA167644/CA/NCI NIH HHS/United States ; R01 AG050509/AG/NIA NIH HHS/United States ; R01 GM120094/GM/NIGMS NIH HHS/United States ; T32 AG000114/AG/NIA NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Crystallography, X-Ray ; Dyskeratosis Congenita/*genetics ; HEK293 Cells ; Humans ; Mutagenesis, Site-Directed ; Mutation ; Protein Conformation ; Shelterin Complex ; Telomerase/metabolism ; Telomere/metabolism ; Telomere-Binding Proteins/*chemistry/*genetics ; },
abstract = {Telomerase replicates chromosome ends to facilitate continued cell division. Mutations that compromise telomerase function result in stem cell failure diseases, such as dyskeratosis congenita (DC). One such mutation (K170Δ), residing in the telomerase-recruitment factor TPP1, provides an excellent opportunity to structurally, biochemically, and genetically dissect the mechanism of such diseases. We show through site-directed mutagenesis and X-ray crystallography that this TPP1 disease mutation deforms the conformation of two critical amino acids of the TEL [TPP1's glutamate (E) and leucine-rich (L)] patch, the surface of TPP1 that binds telomerase. Using CRISPR-Cas9 technology, we demonstrate that introduction of this mutation in a heterozygous manner is sufficient to shorten telomeres in human cells. Our findings rule out dominant-negative effects of the mutation. Instead, these findings implicate reduced TEL patch dosage in causing telomere shortening. Our studies provide mechanistic insight into telomerase-deficiency diseases and encourage the development of gene therapies to counter such diseases.},
}
@article {pmid27760120,
year = {2016},
author = {Dilley, RL and Verma, P and Cho, NW and Winters, HD and Wondisford, AR and Greenberg, RA},
title = {Break-induced telomere synthesis underlies alternative telomere maintenance.},
journal = {Nature},
volume = {539},
number = {7627},
pages = {54-58},
pmid = {27760120},
issn = {1476-4687},
support = {R01 CA174904/CA/NCI NIH HHS/United States ; T32 GM007170/GM/NIGMS NIH HHS/United States ; R01 GM101149/GM/NIGMS NIH HHS/United States ; T32 GM008216/GM/NIGMS NIH HHS/United States ; R01 CA138835/CA/NCI NIH HHS/United States ; R21 CA194973/CA/NCI NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins/metabolism ; Cell Line, Tumor ; *DNA Breaks, Double-Stranded ; DNA Damage ; DNA Polymerase III/metabolism ; DNA Repair ; *DNA Replication ; DNA-Directed DNA Polymerase/metabolism ; Humans ; Multienzyme Complexes/metabolism ; Neoplasms/enzymology/*genetics/metabolism/pathology ; Proliferating Cell Nuclear Antigen/metabolism ; Replication Protein C/metabolism ; Sequence Homology ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Homology-directed DNA repair is essential for genome maintenance through templated DNA synthesis. Alternative lengthening of telomeres (ALT) necessitates homology-directed DNA repair to maintain telomeres in about 10-15% of human cancers. How DNA damage induces assembly and execution of a DNA replication complex (break-induced replisome) at telomeres or elsewhere in the mammalian genome is poorly understood. Here we define break-induced telomere synthesis and demonstrate that it utilizes a specialized replisome, which underlies ALT telomere maintenance. DNA double-strand breaks enact nascent telomere synthesis by long-tract unidirectional replication. Proliferating cell nuclear antigen (PCNA) loading by replication factor C (RFC) acts as the initial sensor of telomere damage to establish predominance of DNA polymerase δ (Pol δ) through its POLD3 subunit. Break-induced telomere synthesis requires the RFC-PCNA-Pol δ axis, but is independent of other canonical replisome components, ATM and ATR, or the homologous recombination protein Rad51. Thus, the inception of telomere damage recognition by the break-induced replisome orchestrates homology-directed telomere maintenance.},
}
@article {pmid27760112,
year = {2016},
author = {Roake, CM and Artandi, SE},
title = {DNA repair: Telomere-lengthening mechanism revealed.},
journal = {Nature},
volume = {539},
number = {7627},
pages = {35-36},
pmid = {27760112},
issn = {1476-4687},
support = {R35 CA197563/CA/NCI NIH HHS/United States ; },
mesh = {DNA Repair ; Telomerase/genetics ; Telomere/*metabolism ; *Telomere Homeostasis ; },
}
@article {pmid27806302,
year = {2016},
author = {Doksani, Y and de Lange, T},
title = {Telomere-Internal Double-Strand Breaks Are Repaired by Homologous Recombination and PARP1/Lig3-Dependent End-Joining.},
journal = {Cell reports},
volume = {17},
number = {6},
pages = {1646-1656},
pmid = {27806302},
issn = {2211-1247},
support = {R01 AG016642/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *DNA Breaks, Double-Stranded ; *DNA End-Joining Repair ; DNA Ligase ATP/*metabolism ; Mice ; Models, Biological ; Poly(ADP-ribose) Polymerases/*metabolism ; Poly-ADP-Ribose Binding Proteins/*metabolism ; *Recombinational DNA Repair ; S Phase ; Signal Transduction ; Telomere/*metabolism ; },
abstract = {Shelterin protects chromosome ends from the DNA damage response. Although the mechanism of telomere protection has been studied extensively, the fate of double-strand breaks (DSBs) inside telomeres is not known. Here, we report that telomere-internal FokI-induced DSBs activate ATM kinase-dependent signaling in S-phase but are well tolerated and repaired efficiently. Homologous recombination contributes to repair, leading to increased telomere length heterogeneity typical of the alternative lengthening of telomeres (ALT) pathway. Furthermore, cells accumulate extra chromosomal telomeric signals (ECTS), a second hallmark of ALT. Telomere-internal DSBs are also repaired by a PARP1- and Ligase3-dependent reaction, suggesting alternative non-homologous end-joining (alt-NHEJ), which relies on microhomology at DSBs. However, as resected telomere-internal DSBs have perfect homology, their PARP1/Lig3-dependent end-joining may be more akin to single strand break repair. We conclude that shelterin does not repress ATM kinase signaling or DSB repair at telomere-internal sites, thereby allowing DNA repair to maintain telomere integrity.},
}
@article {pmid27797826,
year = {2017},
author = {Pan, W and Du, J and Shi, M and Jin, G and Yang, M},
title = {Short leukocyte telomere length, alone and in combination with smoking, contributes to increased risk of gastric cancer or esophageal squamous cell carcinoma.},
journal = {Carcinogenesis},
volume = {38},
number = {1},
pages = {12-18},
doi = {10.1093/carcin/bgw111},
pmid = {27797826},
issn = {1460-2180},
mesh = {Adult ; Aged ; Aged, 80 and over ; Alcohol Drinking/adverse effects ; Biomarkers, Tumor/analysis ; Carcinoma, Squamous Cell/*etiology/pathology ; Case-Control Studies ; Esophageal Neoplasms/*etiology/pathology ; Female ; Follow-Up Studies ; Gene-Environment Interaction ; Humans ; Leukocytes/*metabolism/pathology ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis ; Risk Factors ; Smoking/*adverse effects ; Stomach Neoplasms/*etiology/pathology ; Telomere/*genetics ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {In humans, telomeres shorten along with division of somatic cells. Shortened telomere length might result in genomic instability and has been associated with several malignancies. However, the findings in different populations remain conflicting. Therefore, we assessed the association of telomere length in peripheral blood leukocytes with risk of gastric cancer (GC) or esophageal squamous cell carcinoma (ESCC) in a Chinese Han population. A total of 574 GC cases, 740 ESCC cases and 774 age- and sex-matched healthy controls were included in this analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. The GC or ESCC patients had significantly shorter relative telomere length (RTL) (median ± SD: GC: 1.20 ± 0.42; ESCC: 1.27 ± 0.48) than controls (1.41 ± 0.58). Four-fold increased GC risk (OR = 4.10, 95% CI = 2.78-6.05, P = 1.10 × 10[-12]) or 1.56-fold increased ESCC risk (95% CI = 1.12-2.18, P = 0.009) among subjects in the shortest quartile of telomere length was found compared with the highest quartile. We also observed a cumulative effect between short RTL and smoking in intensifying risk of GC (P = 4.50 × 10[-9]) or ESCC (P = 5.92 × 10[-33]). Moreover, there were cumulative effects between RTL, smoking and drinking in elevating risk of GC (Ptrend = 0.001) or ESCC (Ptrend = 1.57 × 10[-32]). Interestingly, RTL-related rs621559 and rs398652 genetic variants are significantly associated with GC risk. These results indicate that short RTL is involved in susceptibility to developing GC or ESCC, alone and in a gene-environment interaction manner. Short telomere length might be a potential molecular marker, in combination with lifestyle risk factors, to identify high-risk individuals.},
}
@article {pmid27744391,
year = {2016},
author = {Tempaku, PF and de Oliveira, DL and Hirotsu, C and Andersen, ML and Tufik, S},
title = {RE: "25-HYDROXYVITAMIN D CONCENTRATION AND LEUKOCYTE TELOMERE LENGTH IN YOUNG ADULTS: FINDINGS FROM THE NORTHERN FINLAND BIRTH COHORT 1966".},
journal = {American journal of epidemiology},
volume = {184},
number = {9},
pages = {701-702},
doi = {10.1093/aje/kww132},
pmid = {27744391},
issn = {1476-6256},
support = {G0600705/MRC_/Medical Research Council/United Kingdom ; G0601653/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; *Calcifediol ; Finland ; Humans ; Leukocytes ; *Telomere ; Vitamin D/analogs &amp; derivatives ; Young Adult ; },
}
@article {pmid27733399,
year = {2016},
author = {Kobyliansky, E and Torchinsky, D and Kalichman, L and Karasik, D},
title = {Leukocyte telomere length pattern in a Chuvash population that experienced mass famine in 1922-1923: a retrospective cohort study.},
journal = {The American journal of clinical nutrition},
volume = {104},
number = {5},
pages = {1410-1415},
doi = {10.3945/ajcn.116.138040},
pmid = {27733399},
issn = {1938-3207},
mesh = {Databases, Factual ; Female ; Humans ; Leukocytes/*metabolism ; Linear Models ; Male ; Middle Aged ; Retrospective Studies ; Russia ; *Starvation ; Telomere/*ultrastructure ; *Telomere Shortening ; },
abstract = {BACKGROUND: To our knowledge, there are no experimental studies that have addressed the effects of starvation on the maintenance of telomere length. Two epidemiologic studies that have addressed this topic gave controversial results.<br><br>OBJECTIVE: We characterized leukocyte telomere length (LTL) in a Chuvash population that was comprised of survivors of the mass famine of 1922-1923 and in these survivors' descendants.<br><br>DESIGN: The tested cohort consisted of native Chuvash men (n = 687) and women (n = 647) who were born between 1909 and 1980 and who resided in small villages in the Chuvash Republic of the Russian Federation. Data were gathered during 3 expeditions undertaken in 1994, 1999, and 2002. With the use of this method of gathering the study cohort, we were able to treat age and birth year as independent variables (i.e., after adjustment for age, we were able to analyze how LTL correlates with a birth year in the interval between 1909 and 1980). The DNA of peripheral blood leukocytes was used to measure the telomere length with a quantitative polymerase chain reaction technique.<br><br>RESULTS: The main observations were as follows: 1) there were shorter leukocyte telomeres in men born after 1923 (i.e., after the mass famine) than in men born before 1922 (i.e., before the mass famine); 2) there was a stable inheritance of shorter telomeres by men of ensuing generations; and 3) there was an absence of a correlation between LTL and birth year in women.<br><br>CONCLUSIONS: Our study does not provide direct evidence for leukocyte telomere shortening in famine survivors. However, the comparative analysis of LTL in the survivors and their descendants suggests that such an effect did take place. The study also implies that mass famine may be associated with telomere shortening in male descendants of famine survivors. This observation is in agreement with the "thrifty telomere hypothesis" predicting that longer telomeres are disadvantageous in nutritionally marginal environments.},
}
@article {pmid27802523,
year = {2016},
author = {Gendron, SP and Thériault, M and Proulx, S and Brunette, I and Rochette, PJ},
title = {Restoration of Mitochondrial Integrity, Telomere Length, and Sensitivity to Oxidation by In Vitro Culture of Fuchs' Endothelial Corneal Dystrophy Cells.},
journal = {Investigative ophthalmology &amp; visual science},
volume = {57},
number = {14},
pages = {5926-5934},
doi = {10.1167/iovs.16-20551},
pmid = {27802523},
issn = {1552-5783},
mesh = {Antioxidants/pharmacology ; Cells, Cultured ; DNA Damage/genetics ; DNA, Mitochondrial/*genetics ; Descemet Membrane/cytology/metabolism ; Endothelial Cells/*drug effects/radiation effects ; Endothelium, Corneal/cytology/metabolism ; Female ; Fuchs' Endothelial Dystrophy/*genetics/physiopathology ; Humans ; Hydrogen Peroxide/pharmacology ; Male ; Mitochondria/*genetics/pathology ; Oxidants/*pharmacology ; Oxidative Stress/*physiology ; Sequence Deletion ; Telomere/*physiology ; Ultraviolet Rays ; },
abstract = {PURPOSE: Fuchs' endothelial corneal dystrophy (FECD), a degenerative disease of the corneal endothelium that leads to vision loss, is a leading cause of corneal transplantation. The cause of this disease is still unknown, but the implication of oxidative stress is strongly suggested. In this study, we analyzed the impact of FECD on mitochondrial DNA (mtDNA) integrity and telomere length, both of which are affected by the oxidative status of the cell.<br><br>METHODS: We compared the levels of total mtDNA, mtDNA common deletion (4977 bp), and relative telomere length in the corneal endothelial cells of fresh Descemet's membrane-endothelium explants and cultured cells from healthy and late stage FECD subjects. Oxidant-antioxidant gene expression and sensitivity to ultraviolet A (UVA)- and H2O2-induced cell death were assessed in cultured cells.<br><br>RESULTS: Our results revealed increased mtDNA levels and telomere shortening in FECD explants. We also found that cell culture restores a normal phenotype in terms of mtDNA levels, telomere length, oxidant-antioxidant gene expression balance, and sensitivity to oxidative stress-induced cell death in the FECD cells compared with the healthy cells.<br><br>CONCLUSIONS: Taken together, these results bring new evidence of the implication of oxidative stress in FECD. They also show that FECD does not evenly affect the integrity of corneal endothelial cells and that cell culture can rehabilitate the molecular phenotypes related to oxidative stress by selecting the more functional FECD cells.},
}
@article {pmid27799523,
year = {2016},
author = {Chang, AC and Ong, SG and LaGory, EL and Kraft, PE and Giaccia, AJ and Wu, JC and Blau, HM},
title = {Telomere shortening and metabolic compromise underlie dystrophic cardiomyopathy.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {113},
number = {46},
pages = {13120-13125},
pmid = {27799523},
issn = {1091-6490},
support = {R37 AG009521/AG/NIA NIH HHS/United States ; R01 NS089533/NS/NINDS NIH HHS/United States ; R21 AG044815/AG/NIA NIH HHS/United States ; R01 AG020961/AG/NIA NIH HHS/United States ; R01 AG009521/AG/NIA NIH HHS/United States ; P30 CA124435/CA/NCI NIH HHS/United States ; R01 AR063963/AR/NIAMS NIH HHS/United States ; 201411MFE-338745-169197//CIHR/Canada ; },
mesh = {Animals ; *Cardiomyopathy, Dilated/genetics/metabolism/physiopathology ; Cell Cycle ; Cell Proliferation ; DNA Damage ; Male ; Membrane Potential, Mitochondrial ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria, Heart/metabolism/physiology ; Mitosis ; *Muscular Dystrophy, Animal/genetics/metabolism/physiopathology ; Muscular Dystrophy, Duchenne ; Myocytes, Cardiac/*physiology ; Reactive Oxygen Species/metabolism ; *Telomere Shortening ; },
abstract = {Duchenne muscular dystrophy (DMD) is an incurable X-linked genetic disease that is caused by a mutation in the dystrophin gene and affects one in every 3,600 boys. We previously showed that long telomeres protect mice from the lethal cardiac disease seen in humans with the same genetic defect, dystrophin deficiency. By generating the mdx[4cv]/mTR[G2] mouse model with "humanized" telomere lengths, the devastating dilated cardiomyopathy phenotype seen in patients with DMD was recapitulated. Here, we analyze the degenerative sequelae that culminate in heart failure and death in this mouse model. We report progressive telomere shortening in developing mouse cardiomyocytes after postnatal week 1, a time when the cells are no longer dividing. This proliferation-independent telomere shortening is accompanied by an induction of a DNA damage response, evident by p53 activation and increased expression of its target gene p21 in isolated cardiomyocytes. The consequent repression of Pgc1α/β leads to impaired mitochondrial biogenesis, which, in conjunction with the high demands of contraction, leads to increased oxidative stress and decreased mitochondrial membrane potential. As a result, cardiomyocyte respiration and ATP output are severely compromised. Importantly, treatment with a mitochondrial-specific antioxidant before the onset of cardiac dysfunction rescues the metabolic defects. These findings provide evidence for a link between short telomere length and metabolic compromise in the etiology of dilated cardiomyopathy in DMD and identify a window of opportunity for preventive interventions.},
}
@article {pmid27798998,
year = {2016},
author = {Verhoeven, JE and Lin, J and Révész, D and Wolkowitz, OM and Penninx, BW},
title = {Unresolved Issues in Longitudinal Telomere Length Research: Response to Susser et al.},
journal = {The American journal of psychiatry},
volume = {173},
number = {11},
pages = {1147-1149},
doi = {10.1176/appi.ajp.2016.16060747r},
pmid = {27798998},
issn = {1535-7228},
mesh = {Humans ; *Research ; *Telomere ; },
}
@article {pmid27798991,
year = {2016},
author = {Susser, E and Verhulst, S and Kark, JD and Factor-Litvak, PR and Keyes, K and Magnus, P and Aviv, A},
title = {Non-Dynamic Association of Depressive and Anxiety Disorders With Leukocyte Telomere Length?.},
journal = {The American journal of psychiatry},
volume = {173},
number = {11},
pages = {1147},
pmid = {27798991},
issn = {1535-7228},
support = {P30 ES009089/ES/NIEHS NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; },
mesh = {*Anxiety Disorders ; Humans ; Leukocytes ; *Telomere ; },
}
@article {pmid27798713,
year = {2016},
author = {Barbé-Tuana, FM and Parisi, MM and Panizzutti, BS and Fries, GR and Grun, LK and Guma, FT and Kapczinski, F and Berk, M and Gama, CS and Rosa, AR},
title = {Shortened telomere length in bipolar disorder: a comparison of the early and late stages of disease.},
journal = {Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)},
volume = {38},
number = {4},
pages = {281-286},
pmid = {27798713},
issn = {1809-452X},
mesh = {Adult ; Aged ; Aging/*genetics ; Bipolar Disorder/*genetics/physiopathology ; Case-Control Studies ; Cellular Senescence/genetics ; DNA/blood ; Female ; Humans ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {OBJECTIVE:: Bipolar disorder (BD) has been associated with increased rates of age-related diseases, such as type II diabetes, metabolic syndrome, osteoporosis, and cardiovascular disorders. Several biological findings have been associated with age-related disorders, including increased oxidative stress, inflammation, and telomere shortening. The objective of this study was to compare telomere length among participants with BD at early and late stages and age- and gender-matched healthy controls.<br><br>METHODS:: Twenty-six euthymic subjects with BD and 34 healthy controls were recruited. Genomic DNA was extracted from peripheral blood and mean telomere length was measured using real-time quantitative polymerase chain reaction.<br><br>RESULTS:: Telomere length was significantly shorter in both the early and late subgroups of BD subjects when compared to the respective controls (p = 0.002 and p = 0.005, respectively). The sample size prevented additional subgroup analyses, including potential effects of medication, smoking status, and lifestyle.<br><br>CONCLUSION:: This study is concordant with previous evidence of telomere shortening in BD, in both early and late stages of the disorder, and supports the notion of accelerated aging in BD.},
}
@article {pmid27797938,
year = {2017},
author = {Bao, Y and Prescott, J and Yuan, C and Zhang, M and Kraft, P and Babic, A and Morales-Oyarvide, V and Qian, ZR and Buring, JE and Cochrane, BB and Gaziano, JM and Giovannucci, EL and Manson, JE and Ng, K and Ogino, S and Rohan, TE and Sesso, HD and Stampfer, MJ and Fuchs, CS and De Vivo, I and Amundadottir, LT and Wolpin, BM},
title = {Leucocyte telomere length, genetic variants at the TERT gene region and risk of pancreatic cancer.},
journal = {Gut},
volume = {66},
number = {6},
pages = {1116-1122},
pmid = {27797938},
issn = {1468-3288},
support = {N01WH32122/WH/WHI NIH HHS/United States ; N01WH44221/WH/WHI NIH HHS/United States ; U01 CA210171/CA/NCI NIH HHS/United States ; R01 HL034595/HL/NHLBI NIH HHS/United States ; N01WH42107/HL/NHLBI NIH HHS/United States ; R01 CA124908/CA/NCI NIH HHS/United States ; N01WH32115/WH/WHI NIH HHS/United States ; R01 CA034944-03/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; UM1 CA182913/CA/NCI NIH HHS/United States ; R01 HL026490/HL/NHLBI NIH HHS/United States ; R01 CA047988/CA/NCI NIH HHS/United States ; R01 HL034595-07/HL/NHLBI NIH HHS/United States ; N01WH32118/HL/NHLBI NIH HHS/United States ; KL2 TR001100/TR/NCATS NIH HHS/United States ; N01WH42129/WH/WHI NIH HHS/United States ; N01WH32111/WH/WHI NIH HHS/United States ; N01WH32100/WH/WHI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; N01WH24152/WH/WHI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; R01 HL043851/HL/NHLBI NIH HHS/United States ; R01 HL080467/HL/NHLBI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; K07 CA140790/CA/NCI NIH HHS/United States ; UH2 CA191284/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; R01 CA040360/CA/NCI NIH HHS/United States ; R01 HL026490-03/HL/NHLBI NIH HHS/United States ; P50 CA127003/CA/NCI NIH HHS/United States ; N01WH32119/WH/WHI NIH HHS/United States ; R01 CA097193/CA/NCI NIH HHS/United States ; N01WH32108/WH/WHI NIH HHS/United States ; R01 CA034944/CA/NCI NIH HHS/United States ; N01WH22110/WH/WHI NIH HHS/United States ; N01WH32105/HL/NHLBI NIH HHS/United States ; },
mesh = {Adenocarcinoma/*epidemiology/*genetics ; Adult ; Aged ; Aged, 80 and over ; Alleles ; Case-Control Studies ; Female ; Follow-Up Studies ; Humans ; Leukocytes ; Male ; Middle Aged ; Odds Ratio ; Pancreatic Neoplasms/*epidemiology/*genetics ; Polymorphism, Single Nucleotide ; Prospective Studies ; Randomized Controlled Trials as Topic ; Risk Factors ; Telomerase/*genetics ; *Telomere Shortening ; United States/epidemiology ; },
abstract = {OBJECTIVE: Telomere shortening occurs as an early event in pancreatic tumorigenesis, and genetic variants at the telomerase reverse transcriptase (TERT) gene region have been associated with pancreatic cancer risk. However, it is unknown whether prediagnostic leucocyte telomere length is associated with subsequent risk of pancreatic cancer.<br><br>DESIGN: We measured prediagnostic leucocyte telomere length in 386 pancreatic cancer cases and 896 matched controls from five prospective US cohorts. ORs and 95% CIs were calculated using conditional logistic regression. Matching factors included year of birth, cohort (which also matches on sex), smoking status, fasting status and month/year of blood collection. We additionally examined single-nucleotide polymorphisms (SNPs) at the TERT region in relation to pancreatic cancer risk and leucocyte telomere length using logistic and linear regression, respectively.<br><br>RESULTS: Shorter prediagnostic leucocyte telomere length was associated with higher risk of pancreatic cancer (comparing extreme quintiles of telomere length, OR 1.72; 95% CI 1.07 to 2.78; ptrend=0.048). Results remained unchanged after adjustment for diabetes, body mass index and physical activity. Three SNPs at TERT (linkage disequilibrium r[2]<0.25) were associated with pancreatic cancer risk, including rs401681 (per minor allele OR 1.33; 95% CI 1.12 to 1.59; p=0.002), rs2736100 (per minor allele OR 1.36; 95% CI 1.13 to 1.63; p=0.001) and rs2736098 (per minor allele OR 0.75; 95% CI 0.63 to 0.90; p=0.002). The minor allele for rs401681 was associated with shorter telomere length (p=0.023).<br><br>CONCLUSIONS: Prediagnostic leucocyte telomere length and genetic variants at the TERT gene region were associated with risk of pancreatic cancer.},
}
@article {pmid27760777,
year = {2016},
author = {Roumelioti, FM and Sotiriou, SK and Katsini, V and Chiourea, M and Halazonetis, TD and Gagos, S},
title = {Alternative lengthening of human telomeres is a conservative DNA replication process with features of break-induced replication.},
journal = {EMBO reports},
volume = {17},
number = {12},
pages = {1731-1737},
pmid = {27760777},
issn = {1469-3178},
mesh = {DNA Breaks, Double-Stranded ; DNA Polymerase III/deficiency/genetics/metabolism ; *DNA Repair/genetics ; *DNA Replication/genetics ; DNA-Directed DNA Polymerase/genetics ; Homologous Recombination/genetics ; Humans ; In Situ Hybridization, Fluorescence ; Neoplasms/*genetics ; Saccharomyces cerevisiae Proteins/genetics ; Telomerase/genetics/metabolism ; *Telomere Homeostasis/genetics ; Telomere Shortening/genetics ; Yeasts/genetics/physiology ; },
abstract = {Human malignancies overcome replicative senescence either by activating the reverse-transcriptase telomerase or by utilizing a homologous recombination-based mechanism, referred to as alternative lengthening of telomeres (ALT). In budding yeast, ALT exhibits features of break-induced replication (BIR), a repair pathway for one-ended DNA double-strand breaks (DSBs) that requires the non-essential subunit Pol32 of DNA polymerase delta and leads to conservative DNA replication. Here, we examined whether ALT in human cancers also exhibits features of BIR A telomeric fluorescence in situ hybridization protocol involving three consecutive staining steps revealed the presence of conservatively replicated telomeric DNA in telomerase-negative cancer cells. Furthermore, depletion of PolD3 or PolD4, two subunits of human DNA polymerase delta that are essential for BIR, reduced the frequency of conservatively replicated telomeric DNA ends and led to shorter telomeres and chromosome end-to-end fusions. Taken together, these results suggest that BIR is associated with conservative DNA replication in human cells and mediates ALT in cancer.},
}
@article {pmid27793328,
year = {2016},
author = {Kawashima, M and Kojima, M and Ueda, Y and Kurihara, S and Hiyama, E},
title = {Telomere biology including TERT rearrangements in neuroblastoma: a useful indicator for surgical treatments.},
journal = {Journal of pediatric surgery},
volume = {51},
number = {12},
pages = {2080-2085},
doi = {10.1016/j.jpedsurg.2016.09.042},
pmid = {27793328},
issn = {1531-5037},
mesh = {Child ; Child, Preschool ; DNA Helicases/genetics ; DNA Mutational Analysis ; DNA, Neoplasm/*genetics ; Disease Progression ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; *Mutation ; Neuroblastoma/*genetics/pathology/*surgery ; Prognosis ; Telomerase/*genetics/metabolism ; Telomere/*physiology ; },
abstract = {PURPOSE: Our telomere biology study of neuroblastomas (NBLs) has revealed that unfavorable NBLs acquired telomere stabilization by telomerase activation or ALT (alternative lengthening of telomeres). Recently, genomic rearrangements in a region proximal to the telomerase reverse transcriptase (TERT) gene have been discovered in NBLs. In this study, TERT rearrangements were examined in NBLs along with their relationship to other aspects of telomere biology.<br><br>METHODS: In 121 NBLs, including 67 cases detected by mass-screening whose telomere length, telomerase activity, ALT with ATRX/DAXX alterations, and MYCN amplification were already known, TERT rearrangements were examined using GeneChip SNP arrays.<br><br>RESULTS: The 11 ATRX/DAXX mutated ALT cases and 29 cases with high telomerase activity showed poor prognosis. MYCN amplification and TERT rearrangements were independently detected in 16 and 13 cases, respectively, and these alterations were significantly correlated with high telomerase activity. In 81 infant cases, MYCN amplification, TERT rearrangements and ATRX mutations were detected in 3, 4, and 3 cases, respectively. Among them, 6 cases showed progression or recurrences.<br><br>CONCLUSIONS: Telomere stabilization in NBLs is acquired by telomerase activation through MYCN amplification, TERT rearrangements or by ALT. Since these tumors usually show progression and recurrence, complete resection should be considered, even in infant cases.<br><br>LEVEL OF EVIDENCE: Prognosis study, level III.},
}
@article {pmid27790683,
year = {2016},
author = {Barrett, JH},
title = {Telomere length and melanoma - is there a straightforward relationship?.},
journal = {The British journal of dermatology},
volume = {175},
number = {5},
pages = {865-866},
doi = {10.1111/bjd.14892},
pmid = {27790683},
issn = {1365-2133},
mesh = {Humans ; *Melanoma ; Skin Neoplasms ; *Telomere ; },
}
@article {pmid27716889,
year = {2017},
author = {Wang, W and Feng, X and Duan, X and Tan, S and Wang, S and Wang, T and Feng, F and Wu, Y and Wu, Y},
title = {Establishment of two data mining models of lung cancer screening based on three gene promoter methylations combined with telomere damage.},
journal = {The International journal of biological markers},
volume = {32},
number = {1},
pages = {e141-e146},
doi = {10.5301/jbm.5000232},
pmid = {27716889},
issn = {1724-6008},
mesh = {Acid Anhydride Hydrolases/*genetics ; Biomarkers, Tumor/*genetics ; Case-Control Studies ; Cyclin-Dependent Kinase Inhibitor p16/*genetics ; *DNA Methylation ; Data Mining ; Early Detection of Cancer ; Female ; Follow-Up Studies ; Humans ; Lung Neoplasms/*diagnosis/genetics ; Male ; Middle Aged ; Models, Statistical ; Neoplasm Proteins/*genetics ; Neoplasm Staging ; Prognosis ; Promoter Regions, Genetic/*genetics ; Real-Time Polymerase Chain Reaction ; Telomere/*genetics ; Tumor Suppressor Proteins/*genetics ; },
abstract = {OBJECTIVE: To identify the significance of a support vector machine (SVM) model and a decision tree (DT) model for the diagnosis of lung cancer combined with the detection of fragile histidine triad (FHIT), RAS association domain family 1 (RASSF1A) and cyclin-dependent kinase inhibitor 2A (p16) promoter methylation levels and relative telomere length (RTL) of white blood cells from peripheral blood DNA.<br><br>METHODS: The levels of p16, RASSF1A and FHIT promoter methylation and the RTL of white blood cells in peripheral blood DNA of 200 healthy individuals and 200 lung cancer patients were analyzed by SYBR Green-based quantitative methylation-specific PCR and quantitative PCR. Based on the 4 biomarkers, SVM and DT models were developed.<br><br>RESULTS: The levels of FHIT, RASSF1A and p16 promoter methylation were 3.33 (1.86-6.40) and 2.85 (1.39-5.44) (p = 0.002); 27.62 (9.09-52.86) and 17.17 (3.86-50.87) (p = 0.038); and 0.59 (0.16-4.50) and 0.36 (0.06-4.00) (p = 0.008) in cases and controls, respectively. RTL was 0.93 &#xb1; 0.32 and 1.16 &#xb1; 0.57 (p<0.001). The areas under the receiver operating characteristic (ROC) curves of the Fisher discriminant analysis, SVM and DT models were 0.670 (0.569-0.761), 0.810 (0.719-0.882) and 0.810 (0.719-0.882), respectively.<br><br>CONCLUSIONS: The SVM and DT models for diagnosing lung cancer were successfully developed through the combined detection of p16, RASSF1A and FHIT promoter methylation and RTL, which provided useful tools for screening lung cancer.},
}
@article {pmid27698131,
year = {2016},
author = {Puterman, E and Gemmill, A and Karasek, D and Weir, D and Adler, NE and Prather, AA and Epel, ES},
title = {Lifespan adversity and later adulthood telomere length in the nationally representative US Health and Retirement Study.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {113},
number = {42},
pages = {E6335-E6342},
pmid = {27698131},
issn = {1091-6490},
support = {U01 AG009740/AG/NIA NIH HHS/United States ; R00 HL109247/HL/NHLBI NIH HHS/United States ; T32 AG000246/AG/NIA NIH HHS/United States ; R24 AG048024/AG/NIA NIH HHS/United States ; K08 HL112961/HL/NHLBI NIH HHS/United States ; T32 HD007275/HD/NICHD NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Cellular Senescence ; Female ; Humans ; Longevity/*genetics ; Male ; Middle Aged ; Multivariate Analysis ; Odds Ratio ; Public Health Surveillance ; Risk Factors ; Stress, Psychological ; Telomere/*genetics ; Telomere Shortening ; United States ; },
abstract = {Stress over the lifespan is thought to promote accelerated aging and early disease. Telomere length is a marker of cell aging that appears to be one mediator of this relationship. Telomere length is associated with early adversity and with chronic stressors in adulthood in many studies. Although cumulative lifespan adversity should have bigger impacts than single events, it is also possible that adversity in childhood has larger effects on later life health than adult stressors, as suggested by models of biological embedding in early life. No studies have examined the individual vs. cumulative effects of childhood and adulthood adversities on adult telomere length. Here, we examined the relationship between cumulative childhood and adulthood adversity, adding up a range of severe financial, traumatic, and social exposures, as well as comparing them to each other, in relation to salivary telomere length. We examined 4,598 men and women from the US Health and Retirement Study. Single adversities tended to have nonsignificant relations with telomere length. In adjusted models, lifetime cumulative adversity predicted 6% greater odds of shorter telomere length. This result was mainly due to childhood adversity. In adjusted models for cumulative childhood adversity, the occurrence of each additional childhood event predicted 11% increased odds of having short telomeres. This result appeared mainly because of social/traumatic exposures rather than financial exposures. This study suggests that the shadow of childhood adversity may reach far into later adulthood in part through cellular aging.},
}
@article {pmid27683094,
year = {2016},
author = {Simon, MN and Churikov, D and Géli, V},
title = {Replication stress as a source of telomere recombination during replicative senescence in Saccharomyces cerevisiae.},
journal = {FEMS yeast research},
volume = {16},
number = {7},
pages = {},
doi = {10.1093/femsyr/fow085},
pmid = {27683094},
issn = {1567-1364},
mesh = {Cellular Senescence ; *DNA Replication ; DNA, Fungal/*genetics/*metabolism ; *Recombination, Genetic ; Saccharomyces cerevisiae/*genetics/*metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {Replicative senescence is triggered by short unprotected telomeres that arise in the absence of telomerase. In addition, telomeres are known as difficult regions to replicate due to their repetitive G-rich sequence prone to secondary structures and tightly bound non-histone proteins. Here we review accumulating evidence that telomerase inactivation in yeast immediately unmasks the problems associated with replication stress at telomeres. Early after telomerase inactivation, yeast cells undergo successive rounds of stochastic DNA damages and become dependent on recombination for viability long before the bulk of telomeres are getting critically short. The switch from telomerase to recombination to repair replication stress-induced damage at telomeres creates telomere instability, which may drive further genomic alterations and prepare the ground for telomerase-independent immortalization observed in yeast survivors and in 15% of human cancer.},
}
@article {pmid27633529,
year = {2016},
author = {Schmidt, JE and Sirman, AE and Kittilson, JD and Clark, ME and Reed, WL and Heidinger, BJ},
title = {Telomere correlations during early life in a long-lived seabird.},
journal = {Experimental gerontology},
volume = {85},
number = {},
pages = {28-32},
doi = {10.1016/j.exger.2016.09.011},
pmid = {27633529},
issn = {1873-6815},
mesh = {Aging/*physiology ; Animals ; Charadriiformes/*physiology ; Female ; Longevity/*physiology ; Male ; Telomere/genetics/*physiology ; },
abstract = {Telomere dynamics in blood cells have been linked to aging in a variety of organisms. However, whether blood telomeres are correlated with telomeres in other parts of the body is not well known, especially during early life when telomere loss is expected to be most rapid. We investigated this question in Franklin's gulls (Leucophaeus pipixcan) by measuring telomere lengths in blood and several other tissues including: heart, liver, and skeletal muscle at the end of embryonic (n=31) and post-natal development (n=20). In late-stage embryos, blood telomeres were significantly positively correlated with heart and skeletal muscle, but not liver telomeres. However, at the end of post-natal development, there were no significant correlations among blood telomeres and telomeres in any other tissues. In late-stage embryos, heart telomeres were significantly longer than blood, liver, and skeletal muscle telomeres, but at the end of post-natal development telomere lengths did not significantly differ among tissues. These results suggest that blood telomere length is not necessarily indicative of other tissues at all stages of development and highlights the importance of understanding any functional consequences of tissue specific telomere dynamics in early life.},
}
@article {pmid27788238,
year = {2016},
author = {Starnino, L and Busque, L and Tardif, JC and D'Antono, B},
title = {Psychological Profiles in the Prediction of Leukocyte Telomere Length in Healthy Individuals.},
journal = {PloS one},
volume = {11},
number = {10},
pages = {e0165482},
pmid = {27788238},
issn = {1932-6203},
mesh = {Adult ; Anxiety/genetics ; Depression/genetics ; Female ; Healthy Volunteers/*psychology ; Humans ; Leukocytes/*metabolism ; Male ; Risk Factors ; Telomere/*genetics ; Telomere Shortening ; },
abstract = {BACKGROUND: Shorter telomere length (TL) may signal premature cellular aging and increased risk for disease. While depression and psychosocial stress have been associated with shorter telomeres, other psychological risk factors for cardiovascular disease have received less attention.<br><br>PURPOSE: To evaluate the association between TL and psychological risk factors (symptoms of anxiety and depression, hostility and defensiveness traits) for heart disease, and to examine whether chronological age and sex moderate the associations observed.<br><br>METHODS: 132 healthy men and women (Mage = 45.34 years) completed the Marlowe-Crowne Social Desirability Scale, the Beck Depression Inventory II, The Beck Anxiety Inventory and the Cook-Medley Hostility Scale. Relative TL was measured by quantitative polymerase chain reaction (PCR) of total genomic DNA samples. A series of hierarchical linear regressions were performed controlling for pertinent covariates.<br><br>RESULTS: Shorter TL was observed among individuals high in defensiveness (&#x3b2; = -.221) and depressive symptoms (&#x3b2; = -.213), as well as in those with less hostility (&#x3b2; =.256) and anxiety (&#x3b2; =.220)(all Ps<.05). Psychological variables explained 19% of the variance over and above that explained by covariates (age, sex, exercise, alcohol consumption, systemic inflammation, and 24-hr mean arterial pressure). Age moderated the relation between TL and defensiveness (&#x3b2; =.179, p =.03). Sex did not influence any of the relations.<br><br>CONCLUSIONS: Telomere length is associated with psychological burden though the direction of effect differs depending on the psychological variables under study. Further research is needed to determine the reasons for and implications of these seemingly contradictory findings.},
}
@article {pmid27785566,
year = {2018},
author = {Milte, CM and Russell, AP and Ball, K and Crawford, D and Salmon, J and McNaughton, SA},
title = {Diet quality and telomere length in older Australian men and women.},
journal = {European journal of nutrition},
volume = {57},
number = {1},
pages = {363-372},
pmid = {27785566},
issn = {1436-6215},
support = {FT100100581//Australian Research Council/ ; DP1095595//Australian Research Council/ ; 1042442//National Health and Medical Research Council/ ; 1104636//National Health and Medical Research Council/ ; APP1026216//National Health and Medical Research Council/ ; },
mesh = {Aged ; Aging/*physiology ; Body Mass Index ; Cell Survival ; Cross-Sectional Studies ; Diet ; Diet Surveys ; *Diet, Healthy ; Exercise ; Female ; Humans ; Longevity/physiology ; Longitudinal Studies ; Male ; Middle Aged ; Telomere Homeostasis/*physiology ; Victoria ; },
abstract = {PURPOSE: Telomere length is a biomarker of cellular ageing, with longer telomeres associated with longevity and reduced risk of chronic disease in older age. Consumption of a healthy diet may contribute to longevity via its impact on cellular ageing, but studies on diet and telomere length to date have been limited and their findings equivocal. The aim of this study was to examine associations between three indices of diet quality and telomere length in older men and women.<br><br>METHODS: Adults aged 57-68&#xa0;years participating in the Wellbeing, Eating and Exercise for a Long Life (WELL) study in Victoria, Australia (n&#xa0;=&#xa0;679), completed a postal survey including an 111-item food frequency questionnaire in 2012. Diet quality was assessed via three indices: the Dietary Guideline Index, the Recommended Food Score, and the Mediterranean Diet Score. Relative telomere length was measured by quantitative polymerase chain reaction. Associations between diet quality and telomere length were assessed using linear regression adjusted for covariates.<br><br>RESULTS: After adjustment for age, sex, education, smoking, physical activity, and body mass index (BMI), there were no significant associations between diet quality and relative telomere length.<br><br>CONCLUSIONS: In a sample of older adults residing in Victoria, Australia, men and women aged 57-68&#xa0;years with better-quality diets did not have longer telomeres. Further investigation in longitudinal studies will determine whether diet can influence telomere length over time in an ageing population.},
}
@article {pmid27785368,
year = {2016},
author = {Gay-Bellile, M and Romero, P and Cayre, A and Véronèse, L and Privat, M and Singh, S and Combes, P and Kwiatkowski, F and Abrial, C and Bignon, YJ and Vago, P and Penault-Llorca, F and Tchirkov, A},
title = {ERCC1 and telomere status in breast tumours treated with neoadjuvant chemotherapy and their association with patient prognosis.},
journal = {The journal of pathology. Clinical research},
volume = {2},
number = {4},
pages = {234-246},
pmid = {27785368},
issn = {2056-4538},
abstract = {Dysfunctional telomeres and DNA damage repair (DDR) play important roles in cancer progression. Studies have reported correlations between these factors and tumour aggressiveness and clinical outcome in breast cancer. We studied the characteristics of telomeres and expression of ERCC1, a protein involved in a number of DNA repair pathways and in telomere homeostasis, to assess their prognostic value, alone or in combination, in 90 residual breast tumours after treatment with neoadjuvant chemotherapy (NCT). ERCC1 status was investigated at different molecular levels (protein and gene expression and gene copy-number variations) by immunohistochemistry, qRT-PCR and quantitative multiplex fluorescent-PCR (QMF-PCR). A comprehensive analysis of telomere characteristics was performed using qPCR for telomere length and qRT-PCR for telomerase (hTERT), tankyrase 1 (TNKS) and shelterin complex (TRF1, TRF2, POT1, TPP1, RAP1 and TIN2) gene expression. Short telomeres, high hTERT and TNKS expression and low ERCC1 protein expression were independently associated with worse survival outcome. Interestingly, ERCC1 gains and losses correlated with worse disease-free (p = 0.026) and overall (p = 0.043) survival as compared to survival of patients with normal gene copy-numbers. Unsupervised hierarchical clustering of all ERCC1 and telomere parameters identified four subgroups with distinct prognosis. In particular, a cluster combining low ERCC1, ERCC1 gene alterations, dysfunctional telomeres and high hTERT and a cluster with high TNKS and shelterin expression correlated with poor disease-free (HR= 5.41, p= 0.0044) and overall survival (HR= 6.01, p= 0.0023) irrespective of tumour stage and grade. This comprehensive study demonstrates that telomere dysfunction and DDR can contribute synergistically to tumour progression and chemoresistance. These parameters are predictors of clinical outcome in breast cancer patients treated with NCT and could be useful clinically as prognostic biomarkers to tailor adjuvant chemotherapy post-NCT.},
}
@article {pmid27662635,
year = {2016},
author = {McLennan, D and Armstrong, JD and Stewart, DC and Mckelvey, S and Boner, W and Monaghan, P and Metcalfe, NB},
title = {Interactions between parental traits, environmental harshness and growth rate in determining telomere length in wild juvenile salmon.},
journal = {Molecular ecology},
volume = {25},
number = {21},
pages = {5425-5438},
pmid = {27662635},
issn = {1365-294X},
support = {268926/ERC_/European Research Council/International ; },
mesh = {Animals ; Body Size ; Environment ; Female ; Longevity ; Male ; Salmo salar/*genetics/*growth &amp; development ; Scotland ; Telomere/*ultrastructure ; *Telomere Shortening ; },
abstract = {A larger body size confers many benefits, such as increased reproductive success, ability to evade predators and increased competitive ability and social status. However, individuals rarely maximize their growth rates, suggesting that this carries costs. One such cost could be faster attrition of the telomeres that cap the ends of eukaryotic chromosomes and play an important role in chromosome protection. A relatively short telomere length is indicative of poor biological state, including poorer tissue and organ performance, reduced potential longevity and increased disease susceptibility. Telomere loss during growth may also be accelerated by environmental factors, but these have rarely been subjected to experimental manipulation in the natural environment. Using a wild system involving experimental manipulations of juvenile Atlantic salmon Salmo salar in Scottish streams, we found that telomere length in juvenile fish was influenced by parental traits and by direct environmental effects. We found that faster-growing fish had shorter telomeres and there was a greater cost (in terms of reduced telomere length) if the growth occurred in a harsher environment. We also found a positive association between offspring telomere length and the growth history of their fathers (but not mothers), represented by the number of years fathers had spent at sea. This suggests that there may be long-term consequences of growth conditions and parental life history for individual longevity.},
}
@article {pmid27662607,
year = {2016},
author = {Debes, PV and Visse, M and Panda, B and Ilmonen, P and Vasemägi, A},
title = {Is telomere length a molecular marker of past thermal stress in wild fish?.},
journal = {Molecular ecology},
volume = {25},
number = {21},
pages = {5412-5424},
doi = {10.1111/mec.13856},
pmid = {27662607},
issn = {1365-294X},
mesh = {Animals ; Biomarkers ; Body Size ; *Stress, Physiological ; Telomere/*ultrastructure ; *Telomere Shortening ; *Temperature ; Trout/*genetics/growth &amp; development ; },
abstract = {Telomeres protect eukaryotic chromosomes; variation in telomere length has been linked (primarily in homoeothermic animals) to variation in stress, cellular ageing and disease risk. Moreover, telomeres have been suggested to function as biomarker for quantifying past environmental stress, but studies in wild animals remain rare. Environmental stress, such as extreme environmental temperatures in poikilothermic animals, may result in oxidative stress that accelerates telomere attrition. However, growth, which may depend on temperature, can also contribute to telomere attrition. To test for associations between multitissue telomere length and past water temperature while accounting for the previous individual growth, we used quantitative PCR to analyse samples from 112 young-of-the-year brown trout from 10 natural rivers with average water temperature differences of up to 6°C (and an absolute maximum of 23°C). We found negative associations between relative telomere length (RTL) and both average river temperature and individual body size. We found no indication of RTL-temperature association differences among six tissues, but we did find indications for differences among the tissues for associations between RTL and body size; size trends, albeit nonsignificant in their differences, were strongest in muscle and weakest in fin. Although causal relationships among temperature, growth, oxidative stress, and cross-sectional telomere length remain largely unknown, our results indicate that telomere-length variation in a poikilothermic wild animal is associated with both past temperature and growth.},
}
@article {pmid27783614,
year = {2016},
author = {Goglin, SE and Farzaneh-Far, R and Epel, ES and Lin, J and Blackburn, EH and Whooley, MA},
title = {Change in Leukocyte Telomere Length Predicts Mortality in Patients with Stable Coronary Heart Disease from the Heart and Soul Study.},
journal = {PloS one},
volume = {11},
number = {10},
pages = {e0160748},
pmid = {27783614},
issn = {1932-6203},
support = {R01 HL079235/HL/NHLBI NIH HHS/United States ; },
mesh = {Age Factors ; Aged ; Cohort Studies ; Coronary Artery Disease/*mortality/psychology ; Creatinine/blood ; Exercise ; Female ; Follow-Up Studies ; Humans ; Interviews as Topic ; Kaplan-Meier Estimate ; Leukocytes/*metabolism ; Male ; Middle Aged ; Proportional Hazards Models ; Prospective Studies ; Sex Factors ; Telomere/*metabolism ; Telomere Shortening ; Ventricular Function, Left ; Waist-Hip Ratio ; },
abstract = {BACKGROUND: Short telomere length independently predicts mortality in patients with coronary heart disease. Whether 5-year change in telomere length predicts subsequent mortality in patients with coronary heart disease has not been evaluated.<br><br>METHODS: In a prospective cohort study of 608 individuals with stable coronary artery disease, we measured leukocyte telomere length at baseline and after five years of follow-up. We divided the sample into tertiles of telomere change: shortened, maintained or lengthened. We used Cox survival models to evaluate 5-year change in telomere length as a predictor of mortality.<br><br>RESULTS: During an average of 4.2 years follow-up, there were 149 deaths. Change in telomere length was inversely predictive of all-cause mortality. Using the continuous variable of telomere length change, each standard deviation (325 base pair) greater increase in telomere length was associated with a 24% reduction in mortality (HR 0.76, 95% CI 0.61-0.94; p = 0.01), adjusted for age, sex, waist to hip ratio, exercise capacity, LV ejection fraction, serum creatinine, and year 5 telomere length. Mortality occurred in 39% (79/203) of patients who experienced telomere shortening, 22% (45/203) of patients whose telomere length was maintained, and 12% (25/202) of patients who experienced telomere lengthening (p<0.001). As compared with patients whose telomere length was maintained, those who experienced telomere lengthening were 56% less likely to die (HR 0.44, 95% CI, 0.23-0.87).<br><br>CONCLUSIONS: In patients with coronary heart disease, an increase in leukocyte telomere length over 5 years is associated with decreased mortality.},
}
@article {pmid27782152,
year = {2016},
author = {Wu, M and Lin, Z and Li, X and Xin, X and An, J and Zheng, Q and Yang, Y and Lu, D},
title = {HULC cooperates with MALAT1 to aggravate liver cancer stem cells growth through telomere repeat-binding factor 2.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {36045},
pmid = {27782152},
issn = {2045-2322},
mesh = {Cell Line, Tumor ; Female ; *Gene Expression Regulation, Neoplastic ; Humans ; Liver Neoplasms/genetics/*metabolism/pathology ; Male ; Neoplasm Proteins/*biosynthesis/genetics ; Neoplastic Stem Cells/*metabolism/pathology ; RNA, Long Noncoding/*biosynthesis/genetics ; RNA, Neoplasm/*biosynthesis/genetics ; Telomeric Repeat Binding Protein 2/*biosynthesis/genetics ; },
abstract = {The dysregulation of lncRNAs has increasingly been linked to many human diseases, especially in cancers. Our results demonstrate HULC, MALAT1 and TRF2 are highly expressed in human hepatocellular carcinoma tissues, and HULC plus MALAT1 overexpression drastically promotes the growth of liver cancer stem cells. Mechanistically, both HULC and MALAT1 overexpression enhanced RNA polII, P300, CREPT to load on the promoter region of telomere repeat-binding factor 2(TRF2), triggering the overexpression, phosphorylation and SUMOylation of TRF2. Strikingly, the excessive TRF2 interacts with HULC or MALAT1 to form the complex that loads on the telomeric region, replacing the CST/AAF and recruiting POT1, pPOT1, ExoI, SNM1B, HP1 α. Accordingly, the telomere is greatly protected and enlonged. Furthermore, the excessive HULC plus MALAT1 reduced the methylation of the TERC promoter dependent on TRF2, increasing the TERC expression that causes the increase of interplay between TRET and TERC. Ultimately, the interaction between RFC and PCNA or between CDK2 and CyclinE, the telomerase activity and the microsatellite instability (MSI) are significantly increased in the liver cancer stem cells. Our demonstrations suggest that haploinsufficiency of HULC/MALAT1 plays an important role in malignant growth of liver cancer stem cell.},
}
@article {pmid27688015,
year = {2016},
author = {Belsky, J and Shalev, I},
title = {Contextual adversity, telomere erosion, pubertal development, and health: Two models of accelerated aging, or one?.},
journal = {Development and psychopathology},
volume = {28},
number = {4pt2},
pages = {1367-1383},
doi = {10.1017/S0954579416000900},
pmid = {27688015},
issn = {1469-2198},
mesh = {Aging/*physiology ; Biological Evolution ; Female ; Humans ; Reproduction/physiology ; Stress, Psychological/*physiopathology ; *Telomere Shortening ; },
abstract = {Two independent lines of inquiry suggest that growing up under conditions of contextual adversity (e.g., poverty and household chaos) accelerates aging and undermines long-term health. Whereas work addressing the developmental origins of health and disease highlights accelerated-aging effects of contextual adversity on telomere erosion, that informed by an evolutionary analysis of reproductive strategies highlights such effects with regard to pubertal development (in females). That both shorter telomeres early in life and earlier age of menarche are associated with poor health later in life raises the prospect, consistent with evolutionary life-history theory, that these two bodies of theory and research are tapping into the same evolutionary-developmental process whereby longer term health costs are traded off for increased probability of reproducing before dying via a process of accelerated aging. Here we make the case for such a claim, while highlighting biological processes responsible for these effects, as well as unknowns in the epigenetic equation that might instantiate these contextually regulated developmental processes.},
}
@article {pmid27617397,
year = {2016},
author = {Roura, S and Fernández, MA and Elchinova, E and Teubel, I and Requena, G and Cabanes, R and Lupón, J and Bayes-Genis, A},
title = {Brilliant violet fluorochromes in simultaneous multicolor flow cytometry-fluorescence in situ hybridization measurement of monocyte subsets and telomere length in heart failure.},
journal = {Laboratory investigation; a journal of technical methods and pathology},
volume = {96},
number = {11},
pages = {1223-1230},
pmid = {27617397},
issn = {1530-0307},
mesh = {Aged ; Female ; Flow Cytometry/*methods ; *Fluorescent Dyes ; Heart Failure/*pathology ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Male ; Middle Aged ; Monocytes/*pathology ; *Telomere Homeostasis ; },
abstract = {Conventional analytical methods to determine telomere length (TL) have been replaced by more precise and reproducible procedures, such as fluorescence in situ hybridization coupled with flow cytometry (flow-FISH). However, simultaneous measurement of TL and cell phenotype remains difficult. Relatively expensive and time-consuming cell-sorting purification is needed to counteract the loss, due to stringent FISH conditions, of prehybridization fluorescence by the organic fluorochromes conventionally used in the phenotyping step. Here, we sought to assess whether the newly developed Brilliant Violet (BV) dyes are valuable to specifically and simultaneously assess the distribution and telomere attrition of monocyte subsets circulating in the blood of a cohort of patients with heart failure. We performed flow-FISH on blood samples from 28 patients with heart failure. To differentiate among monocyte subsets, we used BV and conventional fluorochromes conjugated to antibodies against CD86, CD14, CD16, and CD15. We simultaneously assessed the TLs of the monocyte subsets with a telomere-specific peptide nucleic acid probe labeled with fluorescein isothiocyanate. The BV dyes completely tolerated the harsh conditions required for adequate DNA denaturation and simultaneously provided accurate identification of monocyte subpopulations and respective TLs. The presented protocol may be faster and less expensive than those used currently for purposes such as establishing associations among patient categories, disease progression, monocyte heterogeneity, and aging in the context of heart failure.},
}
@article {pmid27775641,
year = {2016},
author = {Caria, P and Cantara, S and Frau, DV and Pacini, F and Vanni, R and Dettori, T},
title = {Genetic Heterogeneity of HER2 Amplification and Telomere Shortening in Papillary Thyroid Carcinoma.},
journal = {International journal of molecular sciences},
volume = {17},
number = {10},
pages = {},
pmid = {27775641},
issn = {1422-0067},
mesh = {Adult ; Aged ; Aged, 80 and over ; Anaplastic Lymphoma Kinase ; Carcinoma, Papillary/*genetics/pathology ; Female ; *Gene Amplification ; Gene Rearrangement ; *Genetic Heterogeneity ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Mutation ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins c-ets/genetics ; Proto-Oncogene Proteins c-ret/genetics ; Receptor Protein-Tyrosine Kinases/genetics ; Receptor, ErbB-2/*genetics ; Repressor Proteins/genetics ; Telomere Shortening/*genetics ; Thyroid Neoplasms/*genetics/pathology ; Young Adult ; ETS Translocation Variant 6 Protein ; },
abstract = {Extensive research is dedicated to understanding if sporadic and familial papillary thyroid carcinoma are distinct biological entities. We have previously demonstrated that familial papillary thyroid cancer (fPTC) cells exhibit short relative telomere length (RTL) in both blood and tissues and that these features may be associated with chromosome instability. Here, we investigated the frequency of HER2 (Human Epidermal Growth Factor Receptor 2) amplification, and other recently reported genetic alterations in sporadic PTC (sPTC) and fPTC, and assessed correlations with RTL and BRAF mutational status. We analyzed HER2 gene amplification and the integrity of ALK, ETV6, RET, and BRAF genes by fluorescence in situ hybridization in isolated nuclei and paraffin-embedded formalin-fixed sections of 13 fPTC and 18 sPTC patients. We analyzed BRAF[V600E] mutation and RTL by qRT-PCR. Significant HER2 amplification (p = 0.0076), which was restricted to scattered groups of cells, was found in fPTC samples. HER2 amplification in fPTCs was invariably associated with BRAF[V600E] mutation. RTL was shorter in fPTCs than sPTCs (p < 0.001). No rearrangements of other tested genes were observed. These findings suggest that the association of HER2 amplification with BRAF[V600E] mutation and telomere shortening may represent a marker of tumor aggressiveness, and, in refractory thyroid cancer, may warrant exploration as a site for targeted therapy.},
}
@article {pmid27775181,
year = {2017},
author = {Kaya, Z and Akkiprik, M and Karabulut, S and Peker, I and Gullu Amuran, G and Ozmen, T and Gulluoglu, BM and Kaya, H and Ozer, A},
title = {Comparison of telomere length and insulin-like growth factor-binding protein 7 promoter methylation between breast cancer tissues and adjacent normal tissues in Turkish women.},
journal = {Journal of clinical laboratory analysis},
volume = {31},
number = {5},
pages = {},
pmid = {27775181},
issn = {1098-2825},
mesh = {Breast/*chemistry ; Breast Neoplasms/chemistry/*epidemiology/*genetics/mortality ; Cohort Studies ; DNA Methylation ; Female ; Humans ; Insulin-Like Growth Factor Binding Proteins/*genetics ; Middle Aged ; Survival Analysis ; Telomere/chemistry/*genetics ; Turkey ; },
abstract = {BACKGROUND: Both insulin-like growth factor-binding protein 7 (IGFBP7) and telomere length (TL) are associated with proliferation and senescence of human breast cancer. This study assessed the clinical significance of both TL and IGFBP7 methylation status in breast cancer tissues compared with adjacent normal tissues. We also investigated whether IGFBP7 methylation status could be affecting TL.<br><br>METHODS: Telomere length was measured by quantitative PCR to compare tumors with their adjacent normal tissues. The IGFBP7 promoter methylation status was evaluated by methylation-specific PCR and its expression levels were determined by western blotting.<br><br>RESULTS: Telomeres were shorter in tumor tissues compared to controls (P<.0001). The mean TL was higher in breast cancer with invasive ductal carcinoma (IDC; n=72; P=.014) compared with other histological type (n=29), and TL in IDC with HER2 negative (n=53; P=.017) was higher than TL in IDC with HER2 positive (n=19). However, telomeres were shortened in advanced stages and growing tumors. IGFBP7 methylation was observed in 90% of tumor tissues and 59% of controls (P=.0002). Its frequency was significantly higher in IDC compared with invasive mixed carcinoma (IMC; P=.002) and it was not correlated either with protein expression or the other clinicopathological parameters.<br><br>CONCLUSION: These results suggest that IGFBP7 promoter methylation and shorter TL in tumor compared with adjacent tissues may be predictive biomarkers for breast cancer. Telomere maintenance may be indicative of IDC and IDC with HER2 (-) of breast cancer. Further studies with larger number of cases are necessary to verify this association.},
}
@article {pmid27626826,
year = {2016},
author = {Yoshida, K and Misumi, M and Kubo, Y and Yamaoka, M and Kyoizumi, S and Ohishi, W and Hayashi, T and Kusunoki, Y},
title = {Long-Term Effects of Radiation Exposure and Metabolic Status on Telomere Length of Peripheral Blood T Cells in Atomic Bomb Survivors.},
journal = {Radiation research},
volume = {186},
number = {4},
pages = {367-376},
doi = {10.1667/RR14389.1},
pmid = {27626826},
issn = {1938-5404},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/genetics/metabolism/radiation effects ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; Middle Aged ; *Nuclear Weapons ; Radiation Exposure/*adverse effects ; *Survivors ; T-Lymphocytes/cytology/metabolism/*radiation effects ; Telomere/*genetics/*radiation effects ; Young Adult ; },
abstract = {In a series of studies of atomic bomb survivors, radiation-dose-dependent alterations in peripheral T-cell populations have been reported. For example, reduced size in naïve T-cell pools and impaired proliferation ability of T cells were observed. Because these alterations are also generally observed with human aging, we hypothesized that radiation exposure may accelerate the aging process of the T-cell immune system. To further test this hypothesis, we conducted cross-sectional analyses of telomere length, a hallmark of cellular aging, of naïve and memory CD4 T cells and total CD8 T cells in the peripheral blood of 620 atomic bomb survivors as it relates to age and radiation dose, using fluorescence in situ hybridization with flow cytometry. Since telomere shortening has been recently demonstrated in obesity-related metabolic abnormalities and diseases, the modifying effects of metabolic status were also examined. Our results indicated nonlinear relationships between T-cell telomere length and prior radiation exposure, i.e., longer telomeres with lower dose exposure and a decreasing trend of telomere length with individuals exposed to doses higher than 0.5 Gy. There were associations between shorter T-cell telomeres and higher hemoglobin Alc levels or fatty liver development. In naïve and memory CD4 T cells, radiation dose and high-density lipoprotein (HDL) cholesterol were found to positively interact with telomere length, suggesting that the decreasing trend of telomere length from a higher radiation dose was less conspicuous in individuals with a higher HDL cholesterol. It is therefore likely that radiation exposure perturbs T-cell homeostasis involving telomere length maintenance by multiple biological mechanisms, depending on dose, and that long-term-radiation-induced effects on the maintenance of T-cell telomeres may be modified by the subsequent metabolic conditions of individuals.},
}
@article {pmid27714790,
year = {2016},
author = {Bennett, HW and Liu, N and Hu, Y and King, MC},
title = {TeloPCR-seq: a high-throughput sequencing approach for telomeres.},
journal = {FEBS letters},
volume = {590},
number = {23},
pages = {4159-4170},
pmid = {27714790},
issn = {1873-3468},
support = {DP2 OD008429/OD/NIH HHS/United States ; R21 HG006742/HG/NHGRI NIH HHS/United States ; },
mesh = {Base Sequence ; High-Throughput Nucleotide Sequencing/*methods ; Polymerase Chain Reaction ; Repetitive Sequences, Nucleic Acid/genetics ; Schizosaccharomyces/enzymology/genetics ; Telomerase/metabolism ; Telomere/*genetics ; },
abstract = {We have developed a high-throughput sequencing approach that enables us to determine terminal telomere sequences from tens of thousands of individual Schizosaccharomyces pombe telomeres. This method provides unprecedented coverage of telomeric sequence complexity in fission yeast. S. pombe telomeres are composed of modular degenerate repeats that can be explained by variation in usage of the TER1 RNA template during reverse transcription. Taking advantage of this deep sequencing approach, we find that 'like' repeat modules are highly correlated within individual telomeres. Moreover, repeat module preference varies with telomere length, suggesting that existing repeats promote the incorporation of like repeats and/or that specific conformations of the telomerase holoenzyme efficiently and/or processively add repeats of like nature. After the loss of telomerase activity, this sequencing and analysis pipeline defines a population of telomeres with altered sequence content. This approach will be adaptable to study telomeric repeats in other organisms and also to interrogate repetitive sequences throughout the genome that are inaccessible to other sequencing methods.},
}
@article {pmid27591803,
year = {2016},
author = {Walton, RT and Mudway, IS and Dundas, I and Marlin, N and Koh, LC and Aitlhadj, L and Vulliamy, T and Jamaludin, JB and Wood, HE and Barratt, BM and Beevers, S and Dajnak, D and Sheikh, A and Kelly, FJ and Griffiths, CJ and Grigg, J},
title = {Air pollution, ethnicity and telomere length in east London schoolchildren: An observational study.},
journal = {Environment international},
volume = {96},
number = {},
pages = {41-47},
doi = {10.1016/j.envint.2016.08.021},
pmid = {27591803},
issn = {1873-6750},
support = {G0801056/MRC_/Medical Research Council/United Kingdom ; G1000758/MRC_/Medical Research Council/United Kingdom ; MR/L01341X/1/MRC_/Medical Research Council/United Kingdom ; RP-PG-0609-10181/DH_/Department of Health/United Kingdom ; MR/K007017/1/MRC_/Medical Research Council/United Kingdom ; MC_PC_13040/MRC_/Medical Research Council/United Kingdom ; MC_U190081977/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Air Pollutants/analysis/toxicity ; Air Pollution/*adverse effects/analysis ; Child ; Ethnicity/*statistics &amp; numerical data ; Female ; Humans ; Linear Models ; London ; Male ; Nitrogen Oxides/adverse effects ; Particulate Matter/adverse effects ; Telomere/*drug effects ; Telomere Homeostasis/*drug effects/genetics ; Tobacco Smoke Pollution/adverse effects/analysis ; Vehicle Emissions/analysis/*toxicity ; },
abstract = {BACKGROUND: Short telomeres are associated with chronic disease and early mortality. Recent studies in adults suggest an association between telomere length and exposure to particulate matter, and that ethnicity may modify the relationship. However associations in children are unknown.<br><br>OBJECTIVES: We examined associations between air pollution and telomere length in an ethnically diverse group of children exposed to high levels of traffic derived pollutants, particularly diesel exhaust, and to environmental tobacco smoke.<br><br>METHODS: Oral DNA from 333 children (8-9years) participating in a study on air quality and respiratory health in 23 inner city London schools was analysed for relative telomere length using monochrome multiplex qPCR. Annual, weekly and daily exposures to nitrogen oxides and particulate matter were obtained from urban dispersion models (2008-10) and tobacco smoke by urinary cotinine. Ethnicity was assessed by self-report and continental ancestry by analysis of 28 random genomic markers. We used linear mixed effects models to examine associations with telomere length.<br><br>RESULTS: Telomere length increased with increasing annual exposure to NOx (model coefficient 0.003, [0.001, 0.005], p<0.001), NO2 (0.009 [0.004, 0.015], p<0.001), PM2.5 (0.041, [0.020, 0.063], p<0.001) and PM10 (0.096, [0.044, 0.149], p<0.001). There was no association with environmental tobacco smoke. Telomere length was increased in children reporting black ethnicity (22% [95% CI 10%, 36%], p<0.001) CONCLUSIONS: Pollution exposure is associated with longer telomeres in children and genetic ancestry is an important determinant of telomere length. Further studies should investigate both short and long-term associations between pollutant exposure and telomeres in childhood and assess underlying mechanisms.},
}
@article {pmid27768860,
year = {2016},
author = {Robinson, NJ and Schiemann, WP},
title = {Means to the ends: The role of telomeres and telomere processing machinery in metastasis.},
journal = {Biochimica et biophysica acta},
volume = {1866},
number = {2},
pages = {320-329},
pmid = {27768860},
issn = {0006-3002},
support = {R01 CA177069/CA/NCI NIH HHS/United States ; TL1 TR002549/TR/NCATS NIH HHS/United States ; TL1 TR000441/TR/NCATS NIH HHS/United States ; R01 CA129359/CA/NCI NIH HHS/United States ; R01 CA194518/CA/NCI NIH HHS/United States ; T32 GM007250/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Homologous Recombination ; Humans ; *Neoplasm Metastasis ; Telomerase/physiology ; Telomere/*physiology ; Telomere Homeostasis ; },
abstract = {Despite significant clinical advancements, cancer remains a leading cause of mortality throughout the world due largely to the process of metastasis and the dissemination of cancer cells from their primary tumor of origin to distant secondary sites. The clinical burden imposed by metastasis is further compounded by a paucity of information regarding the factors that mediate metastatic progression. Linear chromosomes are capped by structures known as telomeres, which dictate cellular lifespan in humans by shortening progressively during successive cell divisions. Although telomere shortening occurs in nearly all somatic cells, telomeres may be elongated via two seemingly disjoint pathways: (i) telomerase-mediated extension, and (ii) homologous recombination-based alternative lengthening of telomeres (ALT). Both telomerase and ALT are activated in various human cancers, with more recent evidence implicating both pathways as potential mediators of metastasis. Here we review the known roles of telomere homeostasis in metastasis and posit a mechanism whereby metastatic activity is determined by a dynamic fluctuation between ALT and telomerase, as opposed to the mere activation of a generic telomere elongation program. Additionally, the pleiotropic nature of the telomere processing machinery makes it an attractive therapeutic target for metastasis, and as such, we also explore the therapeutic implications of our proposed mechanism.},
}
@article {pmid27768793,
year = {2016},
author = {Drigeard Desgarnier, MC and Zinflou, C and Mallet, JD and Gendron, SP and Méthot, SJ and Rochette, PJ},
title = {Telomere Length Measurement in Different Ocular Structures: A Potential Implication in Corneal Endothelium Pathogenesis.},
journal = {Investigative ophthalmology &amp; visual science},
volume = {57},
number = {13},
pages = {5547-5555},
doi = {10.1167/iovs.16-19878},
pmid = {27768793},
issn = {1552-5783},
mesh = {Aged ; Aged, 80 and over ; Aging/*genetics ; Cadaver ; Child ; Corneal Diseases/diagnosis/*genetics/metabolism ; DNA/*genetics ; Endothelium, Corneal/*metabolism/pathology ; Female ; Humans ; Male ; Middle Aged ; *Oxidative Stress ; Real-Time Polymerase Chain Reaction ; Telomere/*genetics/metabolism ; },
abstract = {PURPOSE: Human chromosomes are protected at their end by a long portion of hexameric tandem repeats, the telomere. In somatic cells, telomere attrition caused by endogenous and exogenous oxidative stress as well as DNA replication can threaten genomic integrity and lead to the deterioration of tissue functions and an age-related physiological decline. The human eye is a complex organ in which cells of different ocular tissues are exposed to photo-oxidation, high mitochondrial metabolic activity, and/or replicative pressure.<br><br>METHODS: We employed a highly sensitive quantitative PCR technique to determine relative telomere length in different human ocular structures.<br><br>RESULTS: The longest telomeres in all ocular structures analyzed are found in neural retina, and the shortest are in the cornea. Within the retina, retinal pigment epithelium has four times shorter telomeres when compared to neural retina. However, no age-dependent telomere attrition in the retina and no difference between telomere lengths in the macular region and the rest of the retina have been found. In the cornea, stroma has the longer telomeres. In the corneal endothelium, we found a clear age-dependent telomere shortening. Since the endothelium is one of the most metabolically active ocular structure, this result suggests that endogenous oxidative stress from high mitochondrial activity is a major determinant of telomere loss in this structure.<br><br>CONCLUSIONS: Taken together, our results imply that the aging process and telomere attrition in the different ocular structures are the result of multiple factors and could not be attributed to solely exogenous or endogenous oxidation or DNA replication.},
}
@article {pmid27766953,
year = {2016},
author = {Holohan, B and Kim, W and Lai, TP and Hoshiyama, H and Zhang, N and Alazami, AM and Wright, WE and Meyn, MS and Alkuraya, FS and Shay, JW},
title = {Impaired telomere maintenance in Alazami syndrome patients with LARP7 deficiency.},
journal = {BMC genomics},
volume = {17},
number = {Suppl 9},
pages = {749},
pmid = {27766953},
issn = {1471-2164},
support = {C06 RR030414/RR/NCRR NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Cell Line ; Child ; Cohort Studies ; Consanguinity ; Female ; Gene Knockdown Techniques ; *Genetic Association Studies ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Models, Genetic ; Mutation ; Pedigree ; Phenotype ; Ribonucleoproteins/*deficiency ; Telomere/*genetics ; Telomere Homeostasis/genetics ; },
abstract = {BACKGROUND: Loss of function in genes required for telomere maintenance result in disorders known as telomeropathies, which are characterized by a pattern of symptoms including generalized and specific lymphocytopenias as well as very short telomere length and disease anticipation.<br><br>METHODS: Because human LARP7 is the most likely ortholog of the Tetrahymena p65 protein, which is required for telomerase activity in that organism, we investigated the effects of LARP7 silencing in human cells as well as in two distinct families with Alazami syndrome (loss of function of LARP7).<br><br>RESULTS: Depletion of LARP7 caused a reduction in telomerase enzymatic activity and progressively shorter telomeres in human cancer cell lines. Alazami syndrome patients from two separate cohorts exhibited very short lymphocyte telomeres. Further, wild-type offspring of LARP7 mutant individuals also had very short telomeres, comparable to what is observed in telomerase (hTERT) mutant cohorts.<br><br>CONCLUSIONS: Together, these experiments demonstrate that in addition to the readily apparent developmental disorder associated with LARP7 deficiency, an underlying telomeropathy exists even in unaffected siblings of these individuals.},
}
@article {pmid27717244,
year = {2016},
author = {Wand, T and Fang, M and Chen, C and Hardy, N and McCoy, JP and Dumitriu, B and Young, NS and Biancotto, A},
title = {Telomere content measurement in human hematopoietic cells: Comparative analysis of qPCR and Flow-FISH techniques.},
journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology},
volume = {89},
number = {10},
pages = {914-921},
pmid = {27717244},
issn = {1552-4930},
support = {ZIC HL005905-03//Intramural NIH HHS/United States ; },
mesh = {Adult ; Aged ; Cell Line ; DNA/chemistry ; Female ; Flow Cytometry/*methods ; Fluorescein/chemistry ; Fluorescence ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Leukocytes, Mononuclear/*chemistry ; Male ; Middle Aged ; Peptide Nucleic Acids/chemistry ; Propidium/chemistry ; Real-Time Polymerase Chain Reaction/*methods ; Single-Cell Analysis/methods ; Telomere/*chemistry ; Young Adult ; },
abstract = {Abnormal telomere lengths have been linked to cancer and other hematologic disorders. Determination of mean telomere content (MTC) is traditionally performed by Southern blotting and densitometry, giving a mean telomere restriction fragment (TRF) value for the total cell population studied. Here, we compared a quantitative Polymerase Chain Reaction approach (qPCR) and a flow cytometric approach, fluorescence in situ hybridization (Flow-FISH), to evaluate telomere content distribution in total patient peripheral blood mononuclear cells or specific cell populations. Flow-FISH is based on in situ hybridization using a fluorescein-labeled peptide nucleic acid (PNA) (CCCTAA)3 probe and DNA staining with propidium iodide. We showed that both qPCR and Flow-FISH provide a robust measurement, with Flow-FISH measuring a relative content longer than qPCR at a single cell approach and that TRF2 fluorescence intensity did not correlate with MTC. Both methods showed comparable telomere content reduction with age, and the rate of relative telomere loss was similar. Published 2016 Wiley Periodicals Inc. This article is a US government work and, as such, is in the public domain in the United States of America.},
}
@article {pmid27693060,
year = {2016},
author = {Liu, HY and Zhao, Q and Zhang, TP and Wu, Y and Xiong, YX and Wang, SK and Ge, YL and He, JH and Lv, P and Ou, TM and Tan, JH and Li, D and Gu, LQ and Ren, J and Zhao, Y and Huang, ZS},
title = {Conformation Selective Antibody Enables Genome Profiling and Leads to Discovery of Parallel G-Quadruplex in Human Telomeres.},
journal = {Cell chemical biology},
volume = {23},
number = {10},
pages = {1261-1270},
doi = {10.1016/j.chembiol.2016.08.013},
pmid = {27693060},
issn = {2451-9448},
mesh = {Base Sequence ; Cell Line ; Consensus Sequence ; *G-Quadruplexes ; Genome, Human ; HeLa Cells ; Humans ; Ligands ; Models, Molecular ; Single-Chain Antibodies/*chemistry/immunology ; Telomere/*chemistry/genetics/immunology ; },
abstract = {G-quadruplexes are specialized secondary structures in nucleic acids that possess significant conformational polymorphisms. The precise G-quadruplex conformations in vivo and their relevance to biological functions remain controversial and unclear, especially for telomeric G-quadruplexes. Here, we report a novel single-chain variable fragment (scFv) antibody, D1, with high binding selectivity for parallel G-quadruplexes in vitro and in vivo. Genome-wide chromatin immunoprecipitation using D1 and deep-sequencing revealed the consensus sequence for parallel G-quadruplex formation, which is characterized by G-rich sequence with a short loop size (<3 nt). By using D1, telomeric parallel G-quadruplex was identified and its formation was regulated by small molecular ligands targeting and telomere replication. Together, parallel G-quadruplex specific antibody D1 was found to be a valuable tool for determination of G-quadruplex and its conformation, which will prompt further studies on the structure of G-quadruplex and its biological implication in vivo.},
}
@article {pmid27650176,
year = {2016},
author = {Rodriguez, FJ and Vizcaino, MA and Blakeley, J and Heaphy, CM},
title = {Frequent alternative lengthening of telomeres and ATRX loss in adult NF1-associated diffuse and high-grade astrocytomas.},
journal = {Acta neuropathologica},
volume = {132},
number = {5},
pages = {761-763},
doi = {10.1007/s00401-016-1619-0},
pmid = {27650176},
issn = {1432-0533},
mesh = {Adaptor Proteins, Signal Transducing/genetics ; Adolescent ; Adult ; Brain Neoplasms/*genetics/*metabolism/pathology ; Child ; Child, Preschool ; Co-Repressor Proteins ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Isocitrate Dehydrogenase/genetics ; Male ; Middle Aged ; Molecular Chaperones ; Neoplasms, Neuroepithelial/*genetics/metabolism/pathology ; Neurofibromatosis 1/complications/*genetics ; Nuclear Proteins/genetics ; Telomere/*pathology ; Telomere Homeostasis/*genetics ; X-linked Nuclear Protein/genetics/*metabolism ; Young Adult ; },
}
@article {pmid27597395,
year = {2017},
author = {Lu, Y and Yan, C and Du, J and Ji, Y and Gao, Y and Zhu, X and Yu, F and Huang, T and Dai, J and Ma, H and Jiang, Y and Chen, J and Shen, H and Jin, G and Yin, Y and Hu, Z},
title = {Genetic variants affecting telomere length are associated with the prognosis of esophageal squamous cell carcinoma in a Chinese population.},
journal = {Molecular carcinogenesis},
volume = {56},
number = {3},
pages = {1021-1029},
doi = {10.1002/mc.22567},
pmid = {27597395},
issn = {1098-2744},
mesh = {Adult ; Aged ; Aged, 80 and over ; Asian People/*genetics ; Carcinoma, Squamous Cell/genetics/*pathology ; China ; Cohort Studies ; Esophageal Neoplasms/genetics/*pathology ; Esophageal Squamous Cell Carcinoma ; Female ; Genetic Association Studies ; Humans ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; Prognosis ; Survival Analysis ; Telomere/*genetics ; Telomere Homeostasis ; },
abstract = {Telomeres are essential for maintaining chromosomal stability and are crucial in tumor progression. Previous studies have explored the associations between telomere length and cancer prognosis, but the findings are inconclusive. Genome-wide association studies have identified several genetic variants associated with telomere length in Caucasians. However, the roles of telomere length and related genetic variants on esophageal squamous cell carcinoma (ESCC) prognosis are largely unknown. Therefore, we conducted a case-cohort study with 431 ESCC patients to assess the associations between relative telomere length (RTL), eight known telomere length related variants and the overall survival of ESCC in Chinese population. We found that as compared with the reference group, patients in the fifth (the longest) quintile had a significantly better prognosis [(adjusted hazard ratio (HR) = 0.58, 95% confidence interval (CI) = 0.34-0.98, P = 0.041]. Furthermore, A allele of rs2736108 was significantly associated with both the increased RTL (P = 0.048) and the better prognosis of ESCC (adjusted HR = 0.55, 95%CI = 0.38-0.79, P = 1.31 × 10[-3]). Mediation analysis indicated that the effect of rs2736108 on ESCC prognosis was partly explained by RTL (1.99%). Stepwise Cox proportional hazard analysis suggested that rs2736108 played an important protective role in ESCC prognosis (HR = 0.57, 95%CI = 0.40-0.81, P = 1.97 × 10[-][3]). Our findings provide evidence that prolonged telomere length is a protective factor for ESCC patients' survival and the known telomere length related genetic variant rs2736108 can contribute to the prognosis of ESCC as well in Chinese population. © 2016 Wiley Periodicals, Inc.},
}
@article {pmid27761787,
year = {2017},
author = {Piñol-Felis, C and Fernández-Marcelo, T and Viñas-Salas, J and Valls-Bautista, C},
title = {Telomeres and telomerase in the clinical management of colorectal cancer.},
journal = {Clinical &amp; translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico},
volume = {19},
number = {4},
pages = {399-408},
pmid = {27761787},
issn = {1699-3055},
mesh = {Biomarkers, Tumor/*analysis ; Colorectal Neoplasms/*diagnosis/enzymology/genetics/*therapy ; Humans ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {Colorectal cancer (CRC) is the third most common cancer worldwide. Our aim is to describe the state of the art about the role of telomeres and telomerase in the clinical management of CRC and its potential utility as prognostic and diagnostic biomarkers and targets of new treatments. Telomere length could be a new diagnostic marker as an anomalous behavior is observed in peripheral blood cells when CRC patients and healthy people are compared. Moreover, telomeres and telomerase may be used as diagnostic markers considering that universal changes appear along the CRC process. Currently, new therapeutic cancer approaches are focused on inhibiting the maintenance of telomere length, choosing as targets telomerase -or its subunits- or the Shelterin complex. The goal of these therapies is the shortening of telomeres and the induction of cell senescence. Telomeres and telomerase emerge as useful molecular tools in the clinical management of CRC.},
}
@article {pmid27757766,
year = {2017},
author = {Zou, Y and Tong, HJ and Li, M and Tan, KS and Cao, T},
title = {Telomere length is regulated by FGF-2 in human embryonic stem cells and affects the life span of its differentiated progenies.},
journal = {Biogerontology},
volume = {18},
number = {1},
pages = {69-84},
doi = {10.1007/s10522-016-9662-8},
pmid = {27757766},
issn = {1573-6768},
mesh = {Cell Differentiation/physiology ; Cells, Cultured ; Cellular Senescence/*physiology ; Fibroblast Growth Factor 2/*metabolism ; Human Embryonic Stem Cells/*cytology/*physiology ; Humans ; Longevity/physiology ; Telomere Homeostasis/*physiology ; },
abstract = {The ability of human embryonic stem cells (hESCs) to proliferate indefinitely is attributed to its high telomerase activity and associated long telomere. However, factors regulating telomere length in hESCs remain largely uncharacterized. The aims of this study were, to identify factors which modulate telomere length of hESCs, and to determine if the telomere length of hESCs influences cellular senescence of its differentiated progeny cells. Telomerase reverse transcriptase (TERT) gene expression, telomerase activity and telomere length of hESCs cultured in different culture systems were compared. Genetically identical hESCs of different telomere lengths were differentiated into fibroblasts simultaneously, and the population doubling and cellular senescence levels were determined. We found that telomere lengths were significantly different in different culture systems and Fibroblast growth factor-2 (FGF-2) upregulated TERT expression, telomerase activity and telomere length via Wnt/β-catenin signaling pathway in hESCs in a significant manner. We also provide evidence that fibroblast differentiated from hESCs with longer telomere exhibited significant more population doublings and longer life span than those derived from hESCs with shorter telomeres. Thus, FGF-2 levels in hESCs culture systems can be manipulated to generate cells with longer telomere which would be advantageous in the applications of hESCs in regenerative medicine.},
}
@article {pmid27696588,
year = {2016},
author = {Bauch, C and Riechert, J and Verhulst, S and Becker, PH},
title = {Telomere length reflects reproductive effort indicated by corticosterone levels in a long-lived seabird.},
journal = {Molecular ecology},
volume = {25},
number = {22},
pages = {5785-5794},
doi = {10.1111/mec.13874},
pmid = {27696588},
issn = {1365-294X},
mesh = {Aging ; Animals ; Charadriiformes/*physiology ; Corticosterone/*blood ; Female ; Male ; *Reproduction ; Telomere/*ultrastructure ; Telomere Shortening ; },
abstract = {Telomere length (TL) is a candidate biomarker of ageing and phenotypic quality, but little is known of the (physiological) causes of TL variation. We previously showed that individual common terns Sterna hirundo with high reproductive success had short telomeres independent of age, and this pattern was particularly strong in the longer telomeres of the within-individual TL distribution. To test whether this relation can be attributed to effects of reproductive effort, we investigated baseline corticosterone in relation to reproductive success (number of fledglings) and TL. In this context, we assume that variation in baseline corticosterone can be interpreted as index of energy expenditure and allostatic load. Males with higher corticosterone levels during incubation, compared between and within individuals, achieved higher reproductive success and had shorter telomeres. The effect on telomeres was more pronounced in corticosterone measured later in incubation and in the longer telomeres of the within-individual TL distribution. Female corticosterone level during incubation was neither related to reproductive success nor to TL. That we observed these effects only in males mirrors different parental roles during reproduction in the common tern, where males do most of the chick provisioning. The negative association between reproductive success and TL suggests individual differences in reproductive effort as reflected in, or mediated by, baseline corticosterone. We see this result as a promising step towards unravelling the physiological causes of variation in TL and the costs of reproduction.},
}
@article {pmid27751173,
year = {2016},
author = {Martens, DS and Plusquin, M and Gyselaers, W and De Vivo, I and Nawrot, TS},
title = {Maternal pre-pregnancy body mass index and newborn telomere length.},
journal = {BMC medicine},
volume = {14},
number = {1},
pages = {148},
pmid = {27751173},
issn = {1741-7015},
mesh = {Adolescent ; Adult ; *Body Mass Index ; Female ; Fetal Blood/physiology ; Humans ; Infant, Newborn ; Male ; Obesity/genetics/metabolism ; Placenta/physiology ; Pregnancy ; Pregnancy Complications/genetics/metabolism ; Real-Time Polymerase Chain Reaction ; Telomere/*genetics/metabolism ; Young Adult ; },
abstract = {BACKGROUND: Newborn telomere length sets telomere length for later life. At birth, telomere length is highly variable among newborns and the environmental factors during in utero life for this observation remain largely unidentified. Obesity during pregnancy might reflect an adverse nutritional status affecting pregnancy and offspring outcomes, but the association of maternal pre-pregnancy body mass index (BMI) with newborn telomere length, as a mechanism of maternal obesity, on the next generation has not been addressed.<br><br>METHODS: Average relative telomere lengths were measured in cord blood (n&#x2009;=&#x2009;743) and placental tissue (n&#x2009;=&#x2009;702) samples using a quantitative real-time PCR method from newborns from the ENVIRONAGE birth cohort in Belgium. By using univariate and multivariable adjusted linear regression models we addressed the associations between pre-pregnancy BMI and cord blood and placental telomere lengths.<br><br>RESULTS: Maternal age was 29.1&#xa0;years (range, 17-44) and mean (SD) pre-pregnancy BMI was 24.1 (4.1) kg/m[2]. Decline in newborn telomere length occurred in parallel with higher maternal pre-pregnancy BMI. Independent of maternal and paternal age at birth, maternal education, gestational age, newborn gender, ethnicity, birthweight, maternal smoking status, parity, cesarean section, and pregnancy complications, each kg/m[2] increase in pre-pregnancy BMI was associated with a -0.50&#xa0;% (95&#xa0;% CI, -0.83 to -0.17&#xa0;%; P&#x2009;=&#x2009;0.003) shorter cord blood telomere length and a -0.66&#xa0;% (95&#xa0;% CI, -1.06 to -0.25&#xa0;%; P&#x2009;=&#x2009;0.002) shorter placental telomere length.<br><br>CONCLUSIONS: Maternal pre-pregnancy BMI is associated with shorter newborn telomere lengths as reflected by cord blood and placental telomeres. These findings support the benefits of a pre-pregnancy healthy weight for promoting molecular longevity from early life onwards.},
}
@article {pmid27725304,
year = {2017},
author = {Gunkel, M and Chung, I and Wörz, S and Deeg, KI and Simon, R and Sauter, G and Jones, DTW and Korshunov, A and Rohr, K and Erfle, H and Rippe, K},
title = {Quantification of telomere features in tumor tissue sections by an automated 3D imaging-based workflow.},
journal = {Methods (San Diego, Calif.)},
volume = {114},
number = {},
pages = {60-73},
doi = {10.1016/j.ymeth.2016.09.014},
pmid = {27725304},
issn = {1095-9130},
mesh = {Automation ; Child ; Fluorescent Antibody Technique ; Glioblastoma/*genetics/pathology ; Humans ; Image Processing, Computer-Assisted/*methods ; Imaging, Three-Dimensional/*methods ; In Situ Hybridization, Fluorescence ; Male ; Microscopy, Confocal ; Paraffin Embedding ; Prostatic Neoplasms/*genetics/pathology ; *Telomere ; Workflow ; },
abstract = {The microscopic analysis of telomere features provides a wealth of information on the mechanism by which tumor cells maintain their unlimited proliferative potential. Accordingly, the analysis of telomeres in tissue sections of patient tumor samples can be exploited to obtain diagnostic information and to define tumor subgroups. In many instances, however, analysis of the image data is conducted by manual inspection of 2D images at relatively low resolution for only a small part of the sample. As the telomere feature signal distribution is frequently heterogeneous, this approach is prone to a biased selection of the information present in the image and lacks subcellular details. Here we address these issues by using an automated high-resolution imaging and analysis workflow that quantifies individual telomere features on tissue sections for a large number of cells. The approach is particularly suited to assess telomere heterogeneity and low abundant cellular subpopulations with distinct telomere characteristics in a reproducible manner. It comprises the integration of multi-color fluorescence in situ hybridization, immunofluorescence and DNA staining with targeted automated 3D fluorescence microscopy and image analysis. We apply our method to telomeres in glioblastoma and prostate cancer samples, and describe how the imaging data can be used to derive statistically reliable information on telomere length distribution or colocalization with PML nuclear bodies. We anticipate that relating this approach to clinical outcome data will prove to be valuable for pretherapeutic patient stratification.},
}
@article {pmid27377564,
year = {2016},
author = {Pavlištová, V and Dvořáčková, M and Jež, M and Mozgová, I and Mokroš, P and Fajkus, J},
title = {Phenotypic reversion in fas mutants of Arabidopsis thaliana by reintroduction of FAS genes: variable recovery of telomeres with major spatial rearrangements and transcriptional reprogramming of 45S rDNA genes.},
journal = {The Plant journal : for cell and molecular biology},
volume = {88},
number = {3},
pages = {411-424},
doi = {10.1111/tpj.13257},
pmid = {27377564},
issn = {1365-313X},
mesh = {Arabidopsis/genetics/*metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Chromatin/genetics/metabolism ; DNA, Ribosomal/genetics/metabolism ; Genome, Plant/genetics ; Telomere/genetics/metabolism ; },
abstract = {Arabidopsis thaliana mutants dysfunctional in the evolutionarily conserved protein complex chromatin assembly factor-1 (CAF-1), which deposits the canonical histone H3 variant H3.1 during DNA synthesis-dependent chromatin assembly, display complex phenotypic changes including meristem and growth alterations, sensitivity to DNA-damaging agents, and reduced fertility. We reported previously that mutants in the FAS1 subunit of CAF-1 progressively lose telomere and 45S rDNA repeats. Here we show that multiple aspects of the fas phenotype are recovered immediately on expression of a reintroduced FAS1 allele, and are clearly independent of the recovery of rDNA copy-numbers and telomeres. In reverted lines, 45S rDNA genes are recovered to diverse levels with a strikingly different representation of their variants, and the typical association of nucleolar organizing region 4 with the nucleolus is perturbed. One of 45S rDNA variants (VAR1), which is silenced in wild-type (WT) plants without mutation history (Col-0 WT), dominates the expression pattern, whereas VAR2 is dominant in Col-0 WT plants. We propose an explanation for the variability of telomere and 45S rDNA repeats associated with CAF-1 function, suggesting that the differences in nuclear partitioning and expression of the rDNA variants in fas mutants and their revertants provide a useful experimental system to study genetic and epigenetic factors in gene dosage compensation.},
}
@article {pmid27736899,
year = {2016},
author = {Gilfillan, C and Naidu, P and Gunawan, F and Hassan, F and Tian, P and Elwood, N},
title = {Leukocyte Telomere Length in the Neonatal Offspring of Mothers with Gestational and Pre-Gestational Diabetes.},
journal = {PloS one},
volume = {11},
number = {10},
pages = {e0163824},
pmid = {27736899},
issn = {1932-6203},
mesh = {Biomarkers/blood ; Blood Glucose/analysis ; DNA/genetics ; Diabetes, Gestational/*blood ; Female ; *Fetal Blood/chemistry ; Glutathione Peroxidase/blood ; Glycated Hemoglobin/analysis ; Humans ; Infant, Newborn/*blood ; Leukocytes/*cytology ; Lipid Peroxidation ; Male ; Oxidative Stress ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Pregnancy ; Superoxide Dismutase/blood ; *Telomere Shortening ; },
abstract = {AIMS: Telomeres undergo shortening with cell division, accelerated by increased oxidative stress. We aimed to demonstrate shortened telomeres in the offspring of mothers who have diabetes as a consequence of exposure to increased oxidative stress during intrauterine development.<br><br>METHODS: We examined the level of glycaemia (glucose, HbA1c, fructosamine), oxidative stress (lipid peroxidation) and the levels of antioxidant enzymes (Superoxide dismutase (SOD) and Selenium dependent glutathione peroxidase) and correlate these findings with mean telomere length (TL) in maternal and foetal blood in groups of pregnant women with pre-gestational diabetes (PGD), gestational diabetes (GD) and a euglycaemic control group.<br><br>RESULTS: Foetal and maternal glucose, maternal HbA1c, and foetal insulin and C-peptide were higher in the PGD group with the GD group being intermediate. Markers of oxidative stress did not vary between groups with the exception of foetal SOD activity that was highest in the GD group. There were no detectable differences in maternal or foetal TL between study groups. An exploratory analysis looking at correlations between glycaemic and oxidative stress parameters and TL revealed a negative correlation between maternal and foetal glucose and TL across the whole study population. This relationship held for the short-term marker of glycaemic control, fructosamine.<br><br>CONCLUSIONS: We were unable to show significant telomere shortening in the offspring of mothers with PGD or GD. Exploratory analysis revealed a relationship between foetal TL and short-term glycaemia particularly in PGD. It is possible that increased telomerase activity can compensate for long-term increased oxidative stress but not for short-term dysglycaemia.},
}
@article {pmid27733476,
year = {2017},
author = {Ruiz, RJ and Trzeciakowski, J and Moore, T and Ayers, KS and Pickler, RH},
title = {Acculturation Predicts Negative Affect and Shortened Telomere Length.},
journal = {Biological research for nursing},
volume = {19},
number = {1},
pages = {28-35},
pmid = {27733476},
issn = {1552-4175},
support = {R01 NR007891/NR/NINR NIH HHS/United States ; },
abstract = {Chronic stress may accelerate cellular aging. Telomeres, protective "caps" at the end of chromosomes, modulate cellular aging and may be good biomarkers for the effects of chronic stress, including that associated with acculturation. The purpose of this analysis was to examine telomere length (TL) in acculturating Hispanic Mexican American women and to determine the associations among TL, acculturation, and psychological factors. As part of a larger cross-sectional study of 516 pregnant Hispanic Mexican American women, we analyzed DNA in blood samples (N = 56) collected at 22-24 weeks gestation for TL as an exploratory measure using monochrome multiplex quantitative telomere polymerase chain reaction (PCR). We measured acculturation with the Acculturation Rating Scale for Mexican Americans, depression with the Beck Depression Inventory, discrimination with the Experiences of Discrimination Scale, and stress with the Perceived Stress Scale. TL was negatively moderately correlated with two variables of acculturation: Anglo orientation and greater acculturation-level scores. We combined these scores for a latent variable, acculturation, and we combined depression, stress, and discrimination scores in another latent variable, "negative affectivity." Acculturation and negative affectivity were bidirectionally correlated. Acculturation significantly negatively predicted TL. Using structural equation modeling, we found the model had an excellent fit with the root mean square error of approximation estimate = .0001, comparative fit index = 1.0, Tucker-Lewis index = 1.0, and standardized root mean square residual = .05. The negative effects of acculturation on the health of Hispanic women have been previously demonstrated. Findings from this analysis suggest a link between acculturation and TL, which may indicate accelerated cellular aging associated with overall poor health outcomes.},
}
@article {pmid27731903,
year = {2017},
author = {Eisenberg, DT and Tackney, J and Cawthon, RM and Cloutier, CT and Hawkes, K},
title = {Paternal and grandpaternal ages at conception and descendant telomere lengths in chimpanzees and humans.},
journal = {American journal of physical anthropology},
volume = {162},
number = {2},
pages = {201-207},
pmid = {27731903},
issn = {1096-8644},
support = {P51 OD011133/OD/NIH HHS/United States ; P51 RR000165/RR/NCRR NIH HHS/United States ; R24 HD042828/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Animals ; Anthropology, Physical ; Biological Evolution ; Epigenomics ; Humans ; Linear Models ; Male ; Pan troglodytes/*genetics ; *Paternal Age ; Telomere/*chemistry/*genetics ; Young Adult ; },
abstract = {UNLABELLED: Telomeres are repeating DNA at chromosome ends. Telomere length (TL) declines with age in most human tissues, and shorter TL is thought to accelerate senescence. In contrast, older men have sperm with longer TL; correspondingly, older paternal age at conception (PAC) predicts longer TL in offspring. This PAC-effect could be a unique form of transgenerational genetic plasticity that modifies somatic maintenance in response to cues of recent ancestral experience. The PAC-effect has not been examined in any non-human mammals.<br><br>OBJECTIVES: Here, we examine the PAC-effect in chimpanzees (Pan troglodytes). The PAC-effect on TL is thought to be driven by continual production of sperm-the same process that drives increased de novo mutations with PAC. As chimpanzees have both greater sperm production and greater sperm mutation rates with PAC than humans, we predict that the PAC-effect on TL will be more pronounced in chimpanzees. Additionally we examine whether PAC predicts TL of grandchildren.<br><br>MATERIALS AND METHODS: TL were measured using qPCR from DNA from blood samples from 40 captive chimpanzees and 144 humans.<br><br>RESULTS: Analyses showed increasing TL with PAC in chimpanzees (p&#x2009;=&#x2009;.009) with a slope six times that in humans (p&#x2009;=&#x2009;.026). No associations between TL and grandpaternal ages were found in humans or chimpanzees-although statistical power was low.<br><br>DISCUSSION: These results suggest that sperm production rates across species may be a determinant of the PAC-effect on offspring TL. This raises the possibility that sperm production rates within species may influence the TL passed on to offspring.},
}
@article {pmid27726944,
year = {2016},
author = {Xu, Y and Wang, X and Chen, SM and Chen, C and Wang, Y and Xiao, BK and Tao, ZZ},
title = {Effect of silencing key proteins in telomerase mechanism and alternative lengthening of telomeres mechanism in laryngeal cancer cells.},
journal = {American journal of otolaryngology},
volume = {37},
number = {6},
pages = {552-558},
doi = {10.1016/j.amjoto.2016.07.009},
pmid = {27726944},
issn = {1532-818X},
mesh = {Carcinoma, Squamous Cell/*pathology ; Cell Culture Techniques ; Cell Cycle Proteins/genetics/metabolism ; Cell Line, Tumor ; Cell Survival ; Humans ; Laryngeal Neoplasms/metabolism/*pathology ; Nuclear Proteins/genetics/metabolism ; RNA, Messenger ; RNA, Small Interfering ; Rad51 Recombinase/genetics/metabolism ; Telomerase/genetics/metabolism/*physiology ; Telomere ; Telomere Homeostasis/*physiology ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Transfection ; },
abstract = {PURPOSE: To explore the influences of telomerase and alternative lengthening of telomeres mechanism on telomere length and laryngeal squamous cell carcinoma in vitro and in vivo.<br><br>MATERIALS AND METHODS: Short hairpin RNA expression vectors targeting the messenger TERT, TRF2, RAD51 and NBS1 were constructed. The mRNA and protein expression of targeted genes in human laryngeal squamous carcinoma cell line HEp-2 was evaluated by reverse transcription polymerase chain reaction and Western blotting separately. The length of telomere was analyzed by fluorescent in-situ hybridization. Cell viability was examined by cell counting Kit-8. Effects on tumor growth were also investigated in vivo.<br><br>RESULTS: The transfection of multiple short hairpin RNAs expression plasmid significantly inhibited the mRNA and protein expression of related genes. Silence of alternative lengthening of telomeres mechanism and telomerase mechanism related genes resulted in the shortening of telomere length in HEp-2 cell. However, silence of alternative lengthening of telomeres mechanism related genes could shorten the telomere length but had no significant difference. Both simultaneously and separately blocking telomerase mechanism and alternative lengthening of telomeres mechanism resulted in reduction of tumor cell viability. Silence of alternative lengthening of telomeres mechanism and telomerase mechanism related genes inhibited the tumor growth in vivo.<br><br>CONCLUSIONS: The inhibition of telomere related gene may be a promising strategy for the treatment of laryngeal squamous cell carcinoma.},
}
@article {pmid27726484,
year = {2016},
author = {Agrawal, RK and Wang, HW and Belfort, M},
title = {Forks in the tracks: Group II introns, spliceosomes, telomeres and beyond.},
journal = {RNA biology},
volume = {13},
number = {12},
pages = {1218-1222},
pmid = {27726484},
issn = {1555-8584},
support = {R01 GM039422/GM/NIGMS NIH HHS/United States ; R01 GM044844/GM/NIGMS NIH HHS/United States ; R01 GM061576/GM/NIGMS NIH HHS/United States ; },
mesh = {Evolution, Molecular ; Models, Molecular ; Molecular Conformation ; Phylogeny ; RNA, Catalytic/chemistry/*metabolism ; Ribonucleoproteins/chemistry/metabolism ; Spliceosomes/chemistry/*metabolism ; Telomere/*metabolism ; },
abstract = {Group II introns are large catalytic RNAs that form a ribonucleoprotein (RNP) complex by binding to an intron-encoded protein (IEP). The IEP, which facilitates both RNA splicing and intron mobility, has multiple activities including reverse transcriptase. Recent structures of a group II intron RNP complex and of IEPs from diverse bacteria fuel arguments that group II introns are ancestrally related to eukaryotic spliceosomes as well as to telomerase and viruses. Furthermore, recent structural studies of various functional states of the spliceosome allow us to draw parallels between the group II intron RNP and the spliceosome. Here we present an overview of these studies, with an emphasis on the structure of the IEPs in their isolated and RNA-bound states and on their evolutionary relatedness. In addition, we address the conundrum of the free, albeit truncated IEPs forming dimers, whereas the IEP bound to the intron ribozyme is a monomer in the mature RNP. Future studies needed to resolve some of the outstanding issues related to group II intron RNP function and dynamics are also discussed.},
}
@article {pmid27723841,
year = {2016},
author = {Seeker, LA and Holland, R and Underwood, S and Fairlie, J and Psifidi, A and Ilska, JJ and Bagnall, A and Whitelaw, B and Coffey, M and Banos, G and Nussey, DH},
title = {Method Specific Calibration Corrects for DNA Extraction Method Effects on Relative Telomere Length Measurements by Quantitative PCR.},
journal = {PloS one},
volume = {11},
number = {10},
pages = {e0164046},
pmid = {27723841},
issn = {1932-6203},
mesh = {Animals ; Calibration ; Cattle ; *DNA/chemistry/genetics/isolation &amp; purification ; Female ; Male ; *Real-Time Polymerase Chain Reaction/methods/standards ; Sheep ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {Telomere length (TL) is increasingly being used as a biomarker in epidemiological, biomedical and ecological studies. A wide range of DNA extraction techniques have been used in telomere experiments and recent quantitative PCR (qPCR) based studies suggest that the choice of DNA extraction method may influence average relative TL (RTL) measurements. Such extraction method effects may limit the use of historically collected DNA samples extracted with different methods. However, if extraction method effects are systematic an extraction method specific (MS) calibrator might be able to correct for them, because systematic effects would influence the calibrator sample in the same way as all other samples. In the present study we tested whether leukocyte RTL in blood samples from Holstein Friesian cattle and Soay sheep measured by qPCR was influenced by DNA extraction method and whether MS calibration could account for any observed differences. We compared two silica membrane-based DNA extraction kits and a salting out method. All extraction methods were optimized to yield enough high quality DNA for TL measurement. In both species we found that silica membrane-based DNA extraction methods produced shorter RTL measurements than the non-membrane-based method when calibrated against an identical calibrator. However, these differences were not statistically detectable when a MS calibrator was used to calculate RTL. This approach produced RTL measurements that were highly correlated across extraction methods (r > 0.76) and had coefficients of variation lower than 10% across plates of identical samples extracted by different methods. Our results are consistent with previous findings that popular membrane-based DNA extraction methods may lead to shorter RTL measurements than non-membrane-based methods. However, we also demonstrate that these differences can be accounted for by using an extraction method-specific calibrator, offering researchers a simple means of accounting for differences in RTL measurements from samples extracted by different DNA extraction methods within a study.},
}
@article {pmid27716774,
year = {2016},
author = {Beyer, T and Weinert, T},
title = {Ontogeny of Unstable Chromosomes Generated by Telomere Error in Budding Yeast.},
journal = {PLoS genetics},
volume = {12},
number = {10},
pages = {e1006345},
pmid = {27716774},
issn = {1553-7404},
support = {R01 GM076186/GM/NIGMS NIH HHS/United States ; T32 GM008659/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/chemistry/*genetics ; Chromosomal Instability/*genetics ; Chromosomes, Fungal/*genetics ; DNA Damage/genetics ; DNA Helicases/chemistry/*genetics ; DNA Replication/genetics ; Homologous Recombination/genetics ; Intracellular Signaling Peptides and Proteins/chemistry/*genetics ; Protein Serine-Threonine Kinases/chemistry/*genetics ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/chemistry/*genetics ; Telomerase/chemistry/genetics ; Telomere/genetics ; },
abstract = {DNA replication errors at certain sites in the genome initiate chromosome instability that ultimately leads to stable genomic rearrangements. Where instability begins is often unclear. And, early instability may form unstable chromosome intermediates whose transient nature also hinders mechanistic understanding. We report here a budding yeast model that reveals the genetic ontogeny of genome rearrangements, from initial replication error to unstable chromosome formation to their resolution. Remarkably, the initial error often arises in or near the telomere, and frequently forms unstable chromosomes. Early unstable chromosomes may then resolve to an internal "collection site" where a dicentric forms and resolves to an isochromosome (other outcomes are possible at each step). The initial telomere-proximal unstable chromosome is increased in mutants in telomerase subunits, Tel1, and even Rad9, with no known telomere-specific function. Defects in Tel1 and in Rrm3, a checkpoint protein kinase with a role in telomere maintenance and a DNA helicase, respectively, synergize dramatically to generate unstable chromosomes, further illustrating the consequence of replication error in the telomere. Collectively, our results suggest telomeric replication errors may be a common cause of seemingly unrelated genomic rearrangements located hundreds of kilobases away.},
}
@article {pmid27716743,
year = {2016},
author = {Caocci, G and Greco, M and Delogu, G and Secchi, C and Perra, A and Ghiani, S and Orru, F and Vacca, A and Galimi, F and La Nasa, G},
title = {Ruxolitinib therapy and telomere length in myelofibrosis.},
journal = {Blood cancer journal},
volume = {6},
number = {10},
pages = {e479},
pmid = {27716743},
issn = {2044-5385},
mesh = {Aged ; Aged, 80 and over ; Case-Control Studies ; Female ; Humans ; K562 Cells ; Male ; Middle Aged ; Nitriles ; Primary Myelofibrosis/*drug therapy/genetics/pathology ; Pyrazoles/*therapeutic use ; Pyrimidines ; Telomere/*drug effects/metabolism ; Telomere Homeostasis/*drug effects ; Treatment Outcome ; },
}
@article {pmid27699234,
year = {2016},
author = {Naikawadi, RP and Disayabutr, S and Mallavia, B and Donne, ML and Green, G and La, JL and Rock, JR and Looney, MR and Wolters, PJ},
title = {Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis.},
journal = {JCI insight},
volume = {1},
number = {14},
pages = {e86704},
pmid = {27699234},
issn = {2379-3708},
support = {T32 HD007470/HD/NICHD NIH HHS/United States ; },
mesh = {Alveolar Epithelial Cells/*cytology ; Animals ; Cells, Cultured ; Epithelial Cells ; Idiopathic Pulmonary Fibrosis ; Lung/*pathology ; Mice ; Pulmonary Fibrosis/*pathology ; Telomere/*pathology ; Telomere Shortening ; },
abstract = {Telomeres are short in type II alveolar epithelial cells (AECs) of patients with idiopathic pulmonary fibrosis (IPF). Whether dysfunctional telomeres contribute directly to development of lung fibrosis remains unknown. The objective of this study was to investigate whether telomere dysfunction in type II AECs, mediated by deletion of the telomere shelterin protein TRF1, leads to pulmonary fibrosis in mice (SPC-Cre TRF1[fl/fl] mice). Deletion of TRF1 in type II AECs for 2 weeks increased γH2AX DNA damage foci, but not histopathologic changes in the lung. Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling characterized by increased numbers of type II AECs, α-smooth muscle actin[+] mesenchymal cells, collagen deposition, and accumulation of senescence-associated β-galactosidase[+] lung epithelial cells. Deletion of TRF1 in collagen-expressing cells caused pulmonary edema, but not fibrosis. These results demonstrate that prolonged telomere dysfunction in type II AECs, but not collagen-expressing cells, leads to age-dependent lung remodeling and fibrosis. We conclude that telomere dysfunction in type II AECs is sufficient to cause lung fibrosis, and may be a dominant molecular defect causing IPF. SPC-Cre TRF1[fl/fl] mice will be useful for assessing cellular and molecular mechanisms of lung fibrosis mediated by telomere dysfunction.},
}
@article {pmid27699083,
year = {2016},
author = {Kim, KS and Kwak, JW and Lim, SJ and Park, YK and Yang, HS and Kim, HJ},
title = {Oxidative Stress-induced Telomere Length Shortening of Circulating Leukocyte in Patients with Obstructive Sleep Apnea.},
journal = {Aging and disease},
volume = {7},
number = {5},
pages = {604-613},
pmid = {27699083},
issn = {2152-5250},
abstract = {The main mechanism of pathogenesis which causes systemic complications in obstructive sleep apnea (OSA) patients is believed to be intermittent hypoxia-induced intermediary effect and it depends on the burden of oxidative stress during sleep. We aimed to search the predictive markers which reflect the burden of systemic oxidative stress in patients with OSA and whether excessive telomere length shortening is a characteristic feature that can assess oxidative stress levels. We used quantitative PCR to measure telomere length using peripheral blood genomic DNA. Telomere lengths were compared in an age- and body mass index (BMI)-dependent manner in 34 healthy volunteers and 43 OSA subjects. We also performed reactive oxygen species assay to measure the concentration of hydrogen peroxide in the peripheral blood of healthy volunteers and OSA subjects. We found that the serum concentration of hydrogen peroxide was considerably higher in OSA patients, and that this was closely related with the severity of OSA. Significantly shortened telomere length was observed in the circulating leukocytes of the peripheral blood of OSA patients, and telomere length shortening was aggravated more acutely in an age- and BMI-dependent manner. An inverse correlation was observed between the concentration of hydrogen peroxide and the telomere length of OSA patients and excessive telomere length shortening was also linked to severity of OSA. The results provided evidence that telomere length shortening or excessive cellular aging might be distinctive in circulating leukocyte of OSA patients and may be an predictive biomarker for reflect the burden of oxidative stress in the peripheral blood of OSA patients.},
}
@article {pmid27699078,
year = {2016},
author = {Guzzardi, MA and Iozzo, P and Salonen, MK and Kajantie, E and Airaksinen, R and Kiviranta, H and Rantakokko, P and Eriksson, JG},
title = {Exposure to Persistent Organic Pollutants Predicts Telomere Length in Older Age: Results from the Helsinki Birth Cohort Study.},
journal = {Aging and disease},
volume = {7},
number = {5},
pages = {540-552},
pmid = {27699078},
issn = {2152-5250},
abstract = {As the population ages, the occurrence of chronic pathologies becomes more common. Leukocyte telomere shortening associates to ageing and age-related diseases. Recent studies suggest that environmental chemicals can affect telomere length. Persistent organic pollutants (POPs) are most relevant, since they are ingested with foods, and accumulate in the body for a long time. This longitudinal study was undertaken to test if circulating POPs predict telomere length and shortening in elderly people. We studied 1082 subjects belonging to the Helsinki Birth Cohort Study (born 1934-1944), undergoing two visits (2001-2004 and 2011-2014). POPs (oxychlordane, trans-nonachlor, p, p'-DDE, PCB 153, BDE 47, BDE 153) were analysed at baseline. Relative telomere length was measured twice, '10 years apart, by quantitative real-time PCR. Oxychlordane, trans-nonachlor and PCB-153 levels were significant predictors of telomere length and shortening. In men, we did not find a linear relationship between POPs exposure and telomere shortening. In women, a significant reduction across quartiles categories of oxychlordane and trans-nonachlor exposure was observed. Baseline characteristics of subjects in the highest POPs categories included higher levels of C-reactive protein and fasting glucose, and lower body fat percentage. This is one of few studies combining POPs and telomere length. Our results indicate that exposure to oxychlordane, trans-nonachlor and PCB 153 predicts telomere attrition. This finding is important because concentrations of POPs observed here occur in contemporary younger people, and may contribute to an accelerated ageing.},
}
@article {pmid27696331,
year = {2017},
author = {Cassar, L and Nicholls, C and Pinto, AR and Chen, R and Wang, L and Li, H and Liu, JP},
title = {TGF-beta receptor mediated telomerase inhibition, telomere shortening and breast cancer cell senescence.},
journal = {Protein &amp; cell},
volume = {8},
number = {1},
pages = {39-54},
pmid = {27696331},
issn = {1674-8018},
mesh = {Actin-Related Protein 2/genetics/*metabolism ; Activin Receptors, Type II/genetics/*metabolism ; Bone Morphogenetic Protein 7/genetics/*metabolism ; Bone Morphogenetic Protein Receptors, Type II/genetics/metabolism ; Breast Neoplasms/genetics/*metabolism ; *Cellular Senescence ; Female ; HeLa Cells ; Humans ; MCF-7 Cells ; Neoplasm Proteins/genetics/*metabolism ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Receptor, Transforming Growth Factor-beta Type II ; Receptors, Transforming Growth Factor beta/genetics/*metabolism ; Smad3 Protein/genetics/metabolism ; Telomerase/genetics/*metabolism ; *Telomere Homeostasis ; },
abstract = {Human telomerase reverse transcriptase (hTERT) plays a central role in telomere lengthening for continuous cell proliferation, but it remains unclear how extracellular cues regulate telomerase lengthening of telomeres. Here we report that the cytokine bone morphogenetic protein-7 (BMP7) induces the hTERT gene repression in a BMPRII receptor- and Smad3-dependent manner in human breast cancer cells. Chonic exposure of human breast cancer cells to BMP7 results in short telomeres, cell senescence and apoptosis. Mutation of the BMPRII receptor, but not TGFbRII, ACTRIIA or ACTRIIB receptor, inhibits BMP7-induced repression of the hTERT gene promoter activity, leading to increased telomerase activity, lengthened telomeres and continued cell proliferation. Expression of hTERT prevents BMP7-induced breast cancer cell senescence and apoptosis. Thus, our data suggest that BMP7 induces breast cancer cell aging by a mechanism involving BMPRII receptor- and Smad3-mediated repression of the hTERT gene.},
}
@article {pmid27693374,
year = {2017},
author = {Ribero, S and Sanna, M and Visconti, A and Navarini, A and Aviv, A and Glass, D and Spector, TD and Smith, C and Simpson, M and Barker, J and Mangino, M and Falchi, M and Bataille, V},
title = {Acne and Telomere Length: A New Spectrum between Senescence and Apoptosis Pathways.},
journal = {The Journal of investigative dermatology},
volume = {137},
number = {2},
pages = {513-515},
doi = {10.1016/j.jid.2016.09.014},
pmid = {27693374},
issn = {1523-1747},
support = {//Medical Research Council/United Kingdom ; //Wellcome Trust/United Kingdom ; },
mesh = {Acne Vulgaris/*genetics ; Case-Control Studies ; Female ; *Gene Expression Regulation ; Genes, p53/genetics ; Humans ; Logistic Models ; Male ; Reference Values ; Telomere/*genetics ; Telomere Shortening/*genetics ; Up-Regulation ; },
}
@article {pmid27693158,
year = {2017},
author = {Stauffer, J and Panda, B and Eeva, T and Rainio, M and Ilmonen, P},
title = {Telomere damage and redox status alterations in free-living passerines exposed to metals.},
journal = {The Science of the total environment},
volume = {575},
number = {},
pages = {841-848},
doi = {10.1016/j.scitotenv.2016.09.131},
pmid = {27693158},
issn = {1879-1026},
mesh = {Animals ; Environmental Pollutants/*toxicity ; Female ; Metals, Heavy/*toxicity ; Oxidation-Reduction ; *Oxidative Stress ; *Passeriformes ; Telomere Shortening/*drug effects ; },
abstract = {Telomere length may reflect the expected life span and possibly individual quality. Environmental stressors are known to increase oxidative stress and accelerate telomere attrition: however the interactions between redox status and telomere dynamics are not fully understood. We investigated whether exposure to heavy metal pollution is associated with oxidative stress and telomere damage in two insectivorous passerines, the Great tit (Parus major) and the Pied flycatcher (Ficedula hypoleuca). We were also interested to know whether within-brood competition could influence the nestling redox status or telomere length. Breeding females and nestlings were sampled near the point pollution source and compared to birds in non-polluted control zone. We measured heavy metal concentrations, calcium, metallothioneins, telomere lengths and redox status (oxidative damage, and enzymatic and non-enzymatic antioxidants) in liver samples. Great tit nestlings in the polluted zone had significantly shorter telomeres compared to those in the unpolluted control zone. In addition, those great tit nestlings that were lighter than their average siblings, had shorter telomeres compared to the heavier ones. In pied flycatchers neither pollution nor growth stress were associated with telomere length, but adult females had significantly shorter telomeres compared to the nestlings. All the results related to redox status varied remarkably among the species and the age groups. In both species antioxidants were related to pollution. There were no significant associations between redox status and telomere length. Our results suggest that wild birds at a young age are vulnerable to pollution and growth stress induced telomere damage. Redox status seems to interact with pollution and growth, but more studies are needed to clarify the underlying physiological mechanisms of telomere attrition. Our study highlights that all the observed associations and differences between the sampling zones varied depending on the species, age, and degree of exposure to pollution.},
}
@article {pmid27690451,
year = {2016},
author = {Kawamoto, Y and Sasaki, A and Chandran, A and Hashiya, K and Ide, S and Bando, T and Maeshima, K and Sugiyama, H},
title = {Targeting 24 bp within Telomere Repeat Sequences with Tandem Tetramer Pyrrole-Imidazole Polyamide Probes.},
journal = {Journal of the American Chemical Society},
volume = {138},
number = {42},
pages = {14100-14107},
doi = {10.1021/jacs.6b09023},
pmid = {27690451},
issn = {1520-5126},
abstract = {Synthetic molecules that bind sequence-specifically to DNA have been developed for varied biological applications, including anticancer activity, regulation of gene expression, and visualization of specific genomic regions. Increasing the number of base pairs targeted by synthetic molecules strengthens their sequence specificity. Our group has been working on the development of pyrrole-imidazole polyamides that bind to the minor groove of DNA in a sequence-specific manner without causing denaturation. Recently, we reported a simple synthetic method of fluorescent tandem dimer polyamide probes composed of two hairpin moieties with a linking hinge, which bound to 12 bp in human telomeric repeats (5'-(TTAGGG)n-3') and could be used to specifically visualize telomeres in chemically fixed cells under mild conditions. We also performed structural optimization and extension of the target base pairs to allow more specific staining of telomeres. In the present study, we synthesized tandem tetramer polyamides composed of four hairpin moieties, targeting 24 bp in telomeric repeats, the longest reported binding site for synthetic, non-nucleic-acid-based, sequence-specific DNA-binding molecules. The novel tandem tetramers bound with a nanomolar dissociation constant to 24 bp sequences made up of four telomeric repeats. Fluorescently labeled tandem tetramer polyamide probes could visualize human telomeres in chemically fixed cells with lower background signals than polyamide probes reported previously, suggesting that they had higher specificity for telomeres. Furthermore, high-throughput sequencing of human genomic DNA pulled down by the biotin-labeled tandem tetramer polyamide probe confirmed its effective binding to telomeric repeats in the complex chromatinized genome.},
}
@article {pmid27690344,
year = {2016},
author = {Tempaku, PF and Mazzotti, DR and Hirotsu, C and Andersen, ML and Xavier, G and Maurya, PK and Rizzo, LB and Brietzke, E and Belangero, SI and Bittencourt, L and Tufik, S},
title = {The effect of the severity of obstructive sleep apnea syndrome on telomere length.},
journal = {Oncotarget},
volume = {7},
number = {43},
pages = {69216-69224},
pmid = {27690344},
issn = {1949-2553},
mesh = {Adult ; Cross-Sectional Studies ; DNA/analysis/genetics ; Female ; Humans ; Leukocytes/metabolism ; Male ; Middle Aged ; Polysomnography ; Real-Time Polymerase Chain Reaction ; *Severity of Illness Index ; Sleep Apnea, Obstructive/blood/pathology/*physiopathology ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Aging is associated with an increase in the prevalence of obstructive sleep apnea syndrome (OSAS) as well as the shortening of telomeres. It is known that OSAS-related factors are stimuli that can contribute to the acceleration of cellular senescence. Thus, the present study aimed to compare the leukocyte telomere length (LTL) between OSAS patients and controls, as well as to verify the correlation between LTL and sleep parameters. We used DNA extracted of 928 individuals from EPISONO to measure the LTL by the quantitative real-time polymerase chain reaction. All individuals were subjected to one full-night polysomnography. LTL was significantly shorter in OSAS patients compared to controls. The results showed negative correlations between LTL and the following variables: apnea-hypopnea index, respiratory disturbance index, desaturation index and wake after sleep onset. LTL was positively correlated with sleep efficiency, total sleep time, basal, minimum and maximum oxygen saturation. Lastly, it was observed that OSAS severity was associated with shorter LTL even after adjusting for sex, age, years of schooling, body mass index, diabetes, stroke and heart attack. In conclusion, our study indicates the presence of an association between LTL and OSAS and a significant impact of severity of OSAS in telomeres shortening.},
}
@article {pmid27689898,
year = {2016},
author = {Watkins, LE and Harpaz-Rotem, I and Sippel, LM and Krystal, JH and Southwick, SM and Pietrzak, RH},
title = {Hostility and telomere shortening among U.S. military veterans: Results from the National Health and Resilience in Veterans Study.},
journal = {Psychoneuroendocrinology},
volume = {74},
number = {},
pages = {251-257},
doi = {10.1016/j.psyneuen.2016.09.006},
pmid = {27689898},
issn = {1873-3360},
support = {P50 AA012870/AA/NIAAA NIH HHS/United States ; UL1 RR024139/RR/NCRR NIH HHS/United States ; UH2 TR000960/TR/NCATS NIH HHS/United States ; },
mesh = {Adult ; Aged ; Anger/*physiology ; Female ; Health Surveys ; *Hostility ; Humans ; Male ; Middle Aged ; Resilience, Psychological ; Telomere Shortening/*physiology ; United States ; Veterans/*statistics &amp; numerical data ; },
abstract = {Chronic disorders of aging are critical concerns for the U.S. veteran population, which is, on average, two decades older than the non-veteran population. Characterization of risk factors that may accelerate biological aging is important in identifying targets for prevention and intervention. In the current study, we analyzed data from a contemporary, and nationally representative sample of U.S. veterans to evaluate the relationship between a broad range of sociodemographic, military, and clinical variables, and peripheral telomere length, which is an indicator of biological age and linked to risk for aging-related disorders and mortality. Data from 468U.S. military veterans who participated in the National Health and Resilience in Veterans Study were analyzed. Telomere length was assessed from cells isolated from saliva using quantitative polymerase chain reaction methods. A multivariable binary logistic regression analysis was conducted to evaluate the relations between hostility and telomere length, while controlling for sociodemographic, military, and clinical variables. Greater scores on a measure of hostility were independently associated with telomere shortening, even after adjustment for a broad range of other variables (odds ratio [OR]=1.58, 95% confidence interval [CI]=1.15-2.18). Secondary analyses revealed that this association was driven by difficulties controlling anger (OR=1.72, 95%CI=1.14-2.61), which reflect the external manifestation of hostility, rather than aggressive urges or impulses. Hostility, particularly difficulties controlling anger, is associated with peripheral telomere shortening in U.S. military veterans. Prevention and treatment efforts designed to reduce hostility may help mitigate risk for accelerated cellular aging in this growing segment of the U.S.},
}
@article {pmid27685813,
year = {2016},
author = {Phipps, ML and Goodwin, PM and Martinez, JS and Goodwin, EH},
title = {Super-resolution optical microscopy study of telomere structure.},
journal = {Journal of biomedical optics},
volume = {21},
number = {9},
pages = {94003},
doi = {10.1117/1.JBO.21.9.094003},
pmid = {27685813},
issn = {1560-2281},
abstract = {Chromosome ends are shielded from exonucleolytic attack and inappropriate end-joining by terminal structures called telomeres; these structures are potential targets for anticancer drugs. Telomeres are composed of a simple DNA sequence (5?-TTAGGG-3? in humans) repeated more than a thousand times, a short 3? single-stranded overhang, and numerous proteins. Electron microscopy has shown that the 3? overhang pairs with the complementary strand at an internal site creating a small displacement loop and a large double-stranded “t-loop.” Our goal is to determine whether all telomeres adopt the t-loop configuration, or whether there are two or more distinct configurations. Progress in optimizing super-resolution (SR) microscopy for this ongoing investigation is reported here. Results suggest that under certain conditions sample preparation procedures may disrupt chromatin by causing loss of nucleosomes. This finding may limit the use of SR microscopy in telomere studies.},
}
@article {pmid27684844,
year = {2016},
author = {Ma, Q and Cai, J and Cai, Y and Xu, Y and Chang, F and Xu, L and Zhang, G and Guo, X},
title = {Association of telomere length in peripheral leukocytes with chronic hepatitis B and hepatocellular carcinoma.},
journal = {Medicine},
volume = {95},
number = {39},
pages = {e4970},
pmid = {27684844},
issn = {1536-5964},
mesh = {Adult ; Carcinoma, Hepatocellular/blood/epidemiology/*genetics ; Case-Control Studies ; DNA/blood ; Female ; Hepatitis B, Chronic/blood/complications/*genetics ; Humans ; Incidence ; *Leukocytes ; Liver Neoplasms/blood/epidemiology/*genetics ; Male ; Middle Aged ; Odds Ratio ; Risk Factors ; Telomere/*genetics ; },
abstract = {BACKGROUND &amp; OBJECTIVES: Telomere plays a critical role in the maintenance of genomic stability in eukaryotic chromosomes. More and more findings have shown that alteration in telomere length may involve in normal somatic cells and some diseases, however, whether the telomere length is associated with the development and/or progression of hepatic diseases remains poorly understood.<br><br>METHODS: A case-control study was employed to illustrate the correlation of relative telomere length (RTL) with chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC). In this study, 152 patients with HCC, 212 patients with CHB, and 184 healthy controls were recruited. Genomic deoxyribonucleic acid (DNA) was extracted from the peripheral blood leukocytes, and fluorescence quantitative polymerase chain reaction (FQ-PCR) was used to detect telomere repeated numbers and 36B4 copy numbers. The RTL was calculated by telomere repeat copy number to single-copy gene number ratio in each sample compared with a reference DNA sample.<br><br>RESULTS: We found that the RTL in HCC group was the longest, followed by CHB group, and healthy control group was the shortest, showing significant statistical differences. When participants were categorized into longer and shorter group according to medium value in healthy controls, individuals who had longer RTL had a significant increased risk of CHB (odds ratio [OR]: 1.83, 95% confidence interval [CI]: 1.22-2.73) when the healthy control was used as the reference groups; furthermore, longer RTL also showed higher incidence of HCC (OR: 3.22, 95% CI: 2.01-5.17; OR: 1.58, 95% CI:1.03-2.41) when healthy control and CHB were used as the reference groups, respectively. When participants were categorized further into 4 groups according to quartile values of RTL in healthy controls, it showed that the longest RTL was also associated with an increased risk of CHB (OR: 2.09, 95% CI: 1.17-3.74) and HCC (OR: 4.31, 95% CI: 2.18-8.52; OR: 2.86, 95% CI: 1.53-5.34) when control and control/CHB group were used as the reference groups, respectively.<br><br>CONCLUSION: Our results suggest that the alteration of telomere length in peripheral leukocytes might be involved in the hepatitis B virus infection and HCC events, and RTL might be a potential useful predictor of CHB and HCC.},
}
@article {pmid27677729,
year = {2017},
author = {Ennour-Idrissi, K and Maunsell, E and Diorio, C},
title = {Telomere Length and Breast Cancer Prognosis: A Systematic Review.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {26},
number = {1},
pages = {3-10},
doi = {10.1158/1055-9965.EPI-16-0343},
pmid = {27677729},
issn = {1538-7755},
mesh = {Breast Neoplasms/*genetics/*mortality/therapy ; Female ; Genetic Markers ; Humans ; Observational Studies as Topic ; Predictive Value of Tests ; Prognosis ; Retrospective Studies ; Telomere/*genetics/pathology ; Telomere Shortening/*genetics ; Treatment Outcome ; },
abstract = {Telomeres ensure genome integrity during replication. Loss of telomeric function leads to cell immortalization and accumulation of genetic alterations. The association of telomere length (TL) with breast cancer prognosis is examined through a systematic review. Electronic databases (MEDLINE, EMBASE, CENTRAL), from inception to December 2015, and relevant reviews were searched. Studies that evaluated TL (blood and/or tumor) in association with breast cancer survival or prognostic factor were included. Thirty-six studies met inclusion criteria. Overall risk of bias was critical. Eight studies reported survival outcomes. Overall, there was a trend toward an association of longer telomeres with better outcomes (tumor, not blood). Of the 33 studies reporting associations with prognostic factors, nine adjusted for potential confounders. Among the latter, shorter telomeres were associated with older age (blood, not tumor), higher local recurrence rates (normal tissue), higher tumor grade (tumor), and lower physical activity (blood), which were reported in one study each. TL was not associated with molecular subtype (blood, one study), family history (tumor, one study), chemotherapy (blood, three of four studies), and stress reduction interventions (blood, two of two studies). Although major methodologic differences preclude from drawing conclusive results, TL could be a valuable breast cancer prognostic marker. Cancer Epidemiol Biomarkers Prev; 26(1); 3-10. ©2016 AACR.},
}
@article {pmid27677058,
year = {2016},
author = {Humphreys, KL and Esteves, K and Zeanah, CH and Fox, NA and Nelson, CA and Drury, SS},
title = {Accelerated telomere shortening: Tracking the lasting impact of early institutional care at the cellular level.},
journal = {Psychiatry research},
volume = {246},
number = {},
pages = {95-100},
pmid = {27677058},
issn = {1872-7123},
support = {K12 HD043451/HD/NICHD NIH HHS/United States ; R01 MH091363/MH/NIMH NIH HHS/United States ; R21 MH094688/MH/NIMH NIH HHS/United States ; U54 HD090255/HD/NICHD NIH HHS/United States ; },
mesh = {Adolescent ; Child ; *Child, Institutionalized ; Child, Preschool ; Female ; Humans ; Infant ; Longitudinal Studies ; Male ; *Orphanages ; *Psychosocial Deprivation ; Romania ; Telomere Shortening/*physiology ; },
abstract = {Studies examining the association between early adversity and longitudinal changes in telomere length within the same individual are rare, yet are likely to provide novel insight into the subsequent lasting effects of negative early experiences. We sought to examine the association between institutional care history and telomere shortening longitudinally across middle childhood and into adolescence. Buccal DNA was collected 2-4 times, between the ages of 6 and 15 years, in 79 children enrolled in the Bucharest Early Intervention Project (BEIP), a longitudinal study exploring the impact of early institutional rearing on child health and development. Children with a history of early institutional care (n=50) demonstrated significantly greater telomere shortening across middle childhood and adolescence compared to never institutionalized children (n=29). Among children with a history of institutional care, randomization to high quality foster care was not associated with differential telomere attrition across development. Cross-sectional analysis of children randomized to the care as usual group indicated shorter telomere length was associated with greater percent of the child's life spent in institutional care up to age 8. These results suggest that early adverse care from severe psychosocial deprivation may be embedded at the molecular genetic level through accelerated telomere shortening.},
}
@article {pmid27671173,
year = {2016},
author = {Baig, S},
title = {Telomeres and Pace of Aging in the Developing World.},
journal = {Journal of the College of Physicians and Surgeons--Pakistan : JCPSP},
volume = {26},
number = {9},
pages = {729-730},
pmid = {27671173},
issn = {1681-7168},
mesh = {Aging/*physiology ; Developing Countries ; Humans ; Social Environment ; Socioeconomic Factors ; *Telomere/genetics/physiology ; },
}
@article {pmid27666406,
year = {2017},
author = {Lue, NF and Yu, EY},
title = {Telomere recombination pathways: tales of several unhappy marriages.},
journal = {Current genetics},
volume = {63},
number = {3},
pages = {401-409},
pmid = {27666406},
issn = {1432-0983},
support = {R01 GM107287/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; *Recombination, Genetic ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Homeostasis/genetics ; Ustilago/*genetics ; },
abstract = {All happy families are alike; each unhappy family is unhappy in its own way.-Leo Tolstoy, Anna Karenina.},
}
@article {pmid27664411,
year = {2017},
author = {Yang, L and Wang, Y and Li, B and Jin, Y},
title = {High-throughput identification of telomere-binding ligands based on the fluorescence regulation of DNA-copper nanoparticles.},
journal = {Biosensors &amp; bioelectronics},
volume = {87},
number = {},
pages = {915-920},
doi = {10.1016/j.bios.2016.09.055},
pmid = {27664411},
issn = {1873-4235},
mesh = {Binding Sites ; Copper/chemistry/*metabolism ; DNA/chemistry/*metabolism ; G-Quadruplexes ; HeLa Cells ; High-Throughput Screening Assays ; Humans ; Ligands ; Nanoparticles/chemistry/*metabolism/ultrastructure ; Telomere/chemistry/*metabolism ; },
abstract = {Formation of the G-quadruplex in the human telomeric DNA is an effective way to inhibit telomerase activity. Therefore, screening ligands of G-quadruplex has potential applications in the treatment of cancer by inhibit telomerase activity. Although several techniques have been explored for screening of telomeric G-quadruplexes ligands, high-throughput screening method for fast screening telomere-binding ligands from the large compound library is still urgently needed. Herein, a label-free fluorescence strategy has been proposed for high-throughput screening telomere-binding ligands by using DNA-copper nanoparticles (DNA-CuNPs) as a signal probe. In the absence of ligands, human telomeric DNA (GDNA) hybridized with its complementary DNA (cDNA) to form double stranded DNA (dsDNA) which can act as an efficient template for the formation of DNA-CuNPs, leading to the high fluorescence of DNA-CuNPs. In the presence of ligands, GDNA folded into G-quadruplex. Single-strdanded cDNA does not support the formation of DNA-CuNP, resulting in low fluorescence of DNA-CuNPs. Therefore, telomere-binding ligands can be high-throughput screened by monitoring the change in the fluorescence of DNA-CuNPs. Thirteen traditional chinese medicines were screened. Circular dichroism (CD) measurements demonstrated that the selected ligands could induce single-stranded telomeric DNA to form G-quadruplex. The telomere repeat amplification protocol (TRAP) assay demonstrated that the selected ligands can effectively inhibit telomerase activity. Therefore, it offers a cost-effective, label-free and reliable high-throughput way to identify G-quadruplex ligands, which holds great potential in discovering telomerase-targeted anticancer drugs.},
}
@article {pmid27663587,
year = {2017},
author = {Kim, JY and Brosnan-Cashman, JA and An, S and Kim, SJ and Song, KB and Kim, MS and Kim, MJ and Hwang, DW and Meeker, AK and Yu, E and Kim, SC and Hruban, RH and Heaphy, CM and Hong, SM},
title = {Alternative Lengthening of Telomeres in Primary Pancreatic Neuroendocrine Tumors Is Associated with Aggressive Clinical Behavior and Poor Survival.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {23},
number = {6},
pages = {1598-1606},
pmid = {27663587},
issn = {1557-3265},
support = {R01 CA172380/CA/NCI NIH HHS/United States ; T32 CA009110/CA/NCI NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing/*genetics ; Aged ; Biomarkers, Tumor/genetics ; Co-Repressor Proteins ; Disease-Free Survival ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Molecular Chaperones ; Mutation ; Neuroendocrine Tumors/*genetics/pathology ; Nuclear Proteins/*genetics ; Pancreatic Neoplasms/*genetics/pathology ; Prognosis ; Telomere Homeostasis/*genetics ; X-linked Nuclear Protein/*genetics ; },
abstract = {Purpose: Alternative lengthening of telomeres (ALT), a telomerase-independent telomere maintenance mechanism, is strongly associated with ATRX and DAXX alterations and occurs frequently in pancreatic neuroendocrine tumors (PanNET).Experimental Design: In a Korean cohort of 269 surgically resected primary PanNETs and 19 sporadic microadenomas, ALT status and nuclear ATRX and DAXX protein expression were assessed and compared with clinicopathologic factors.Results: In PanNETs, ALT or loss of ATRX/DAXX nuclear expression was observed in 20.8% and 19.3%, respectively, whereas microadenomas were not altered. ALT-positive PanNETs displayed a significantly higher grade, size, and pT classification (all, P < 0.001). ALT also strongly correlated with lymphovascular (P < 0.001) and perineural invasion (P = 0.001) and the presence of lymph node (P < 0.001) and distant metastases (P = 0.002). Furthermore, patients with ALT-positive primary PanNETs had a shorter recurrence-free survival [HR = 3.38; 95% confidence interval (CI), 1.83-6.27; P < 0.001]. Interestingly, when limiting to patients with distant metastases, those with ALT-positive primary tumors had significantly better overall survival (HR = 0.23; 95% CI, 0.08-0.68; P = 0.008). Similarly, tumors with loss of ATRX/DAXX expression were significantly associated with ALT (P < 0.001), aggressive clinical behavior, and reduced recurrence-free survival (P < 0.001). However, similar to ALT, when limiting to patients with distant metastases, loss of ATRX/DAXX expression was associated with better overall survival (P = 0.003).Conclusions: Both primary ALT-positive and ATRX/DAXX-negative PanNETs are independently associated with aggressive clinicopathologic behavior and displayed reduced recurrence-free survival. In contrast, ALT activation and loss of ATRX/DAXX are both associated with better overall survival in patients with metastases. Therefore, these biomarkers may be used as prognostic markers depending on the context of the disease. Clin Cancer Res; 23(6); 1598-606. ©2016 AACR.},
}
@article {pmid27660162,
year = {2017},
author = {Peng, H and Mete, M and Desale, S and Fretts, AM and Cole, SA and Best, LG and Lin, J and Blackburn, E and Lee, ET and Howard, BV and Zhao, J},
title = {Leukocyte telomere length and ideal cardiovascular health in American Indians: the Strong Heart Family Study.},
journal = {European journal of epidemiology},
volume = {32},
number = {1},
pages = {67-75},
pmid = {27660162},
issn = {1573-7284},
support = {U01 HL041642/HL/NHLBI NIH HHS/United States ; U01 HL041654/HL/NHLBI NIH HHS/United States ; K01 AG034259/AG/NIA NIH HHS/United States ; R01 DK091369/DK/NIDDK NIH HHS/United States ; UL1 TR001409/TR/NCATS NIH HHS/United States ; U01 HL041652/HL/NHLBI NIH HHS/United States ; R21 HL092363/HL/NHLBI NIH HHS/United States ; R01 HL109284/HL/NHLBI NIH HHS/United States ; U01 HL065521/HL/NHLBI NIH HHS/United States ; U01 HL065520/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Blood Pressure/physiology ; Body Mass Index ; Cardiovascular Diseases/*epidemiology ; Cholesterol/blood ; Diet ; Exercise ; Female ; *Health Status ; Humans ; *Indians, North American ; *Leukocytes/metabolism ; Longitudinal Studies ; Male ; Middle Aged ; Polymerase Chain Reaction ; Risk Factors ; Smoking/epidemiology ; Telomere/*genetics ; United States/epidemiology ; Young Adult ; },
abstract = {Telomere length, a marker of biological aging, has been associated with cardiovascular disease (CVD) and its risk factors. Ideal cardiovascular health (CVH), defined by the American Heart Association (AHA), has also been associated with a reduced risk of CVD, but the relationship between telomere length and ideal CVH is unclear. We measured leukocyte telomere length (LTL) by qPCR in 2568 American Indians in the Strong Heart Family Study (SHFS). All participants were free of overt CVD at enrollment (2001-2003). CVH indices included four behavioral factors (smoking, physical activity, diet, BMI) and three health factors (blood pressure, cholesterol, fasting glucose). Each index was categorized as poor, intermediate, or ideal according to the AHA's guideline. CVH was further categorized into below average (0-1), average (2-3) and above average (≥4) based on the total number of ideal indices. Results showed that, 29, 50 and 21 % of study participants had below average, average, and above average CVH, respectively. Participants with above average CVH had significantly longer LTL than those with below average CVH (β = 0.034, P = 0.042) after adjusting for age, sex, education level, marital status, processed meat consumption, alcohol consumption, and study site. Compared to the U.S. general population, American Indians achieved lower rates for five out of the seven ideal CVH metrics, including smoking, BMI, physical activity, diet, and blood pressure. Achieving four or more ideal CVH metrics was significantly associated with longer LTL. This finding suggests that achieving an ideal CVH may prevent or delay CVD, probably through promoting healthy aging.},
}
@article {pmid27657132,
year = {2016},
author = {Amorim, JP and Santos, G and Vinagre, J and Soares, P},
title = {The Role of ATRX in the Alternative Lengthening of Telomeres (ALT) Phenotype.},
journal = {Genes},
volume = {7},
number = {9},
pages = {},
pmid = {27657132},
issn = {2073-4425},
abstract = {Telomeres are responsible for protecting chromosome ends in order to prevent the loss of coding DNA. Their maintenance is required for achieving immortality by neoplastic cells and can occur by upregulation of the telomerase enzyme or through a homologous recombination-associated process, the alternative lengthening of telomeres (ALT). The precise mechanisms that govern the activation of ALT or telomerase in tumor cells are not fully understood, although cellular origin may favor one of the other mechanisms that have been found thus far in mutual exclusivity. Specific mutational events influence ALT activation and maintenance: a unifying frequent feature of tumors that acquire this phenotype are the recurrent mutations of the Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) or Death-Domain Associated Protein (DAXX) genes. This review summarizes the established criteria about this phenotype: its prevalence, theoretical molecular mechanisms and relation with ATRX, DAXX and other proteins (directly or indirectly interacting and resulting in the ALT phenotype).},
}
@article {pmid27655633,
year = {2016},
author = {Rajavel, M and Orban, T and Xu, M and Hernandez-Sanchez, W and de la Fuente, M and Palczewski, K and Taylor, DJ},
title = {Dynamic peptides of human TPP1 fulfill diverse functions in telomere maintenance.},
journal = {Nucleic acids research},
volume = {44},
number = {21},
pages = {10467-10479},
pmid = {27655633},
issn = {1362-4962},
support = {DP2 CA186571/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Aminopeptidases/chemistry/genetics/*metabolism ; Animals ; Circular Dichroism ; DNA/chemistry/metabolism ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/chemistry/genetics/*metabolism ; Humans ; Mass Spectrometry ; Models, Molecular ; Mutation ; Peptides/chemistry/genetics/*metabolism/pharmacology ; Protein Binding ; Protein Conformation ; Protein Multimerization ; Recombinant Fusion Proteins ; Serine Proteases/chemistry/genetics/*metabolism ; *Shelterin Complex/chemistry ; Structure-Activity Relationship ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis/drug effects ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {Telomeres are specialized nucleoprotein complexes that comprise the ends of linear chromosomes. Human telomeres end in a short, single-stranded DNA (ssDNA) overhang that is recognized and bound by two telomere proteins, POT1 and TPP1. Whereas POT1 binds directly to telomere ssDNA, its interaction with TPP1 is essential for localization of POT1 to the telomere. TPP1 also provides enhanced binding and sequence discrimination that regulates POT1-TPP1 interactions exclusively with telomere ssDNA. Finally, TPP1 recruits telomerase, the enzyme responsible for synthesis of telomere DNA, to the telomere. While the oligosaccharide-oligonucleotide-binding (OB)-fold domain of TPP1 has been solved by X-ray crystallography, the molecular interactions within the POT1-TPP1-ssDNA ternary complex and the conformational changes that contribute to its diverse functions remain ambiguous. We employed hydrogen/deuterium exchange combined with mass spectrometry to identify three peptides, all residing within the OB-fold of TPP1, that exhibit altered exchange rates upon complex formation or ssDNA binding. Mutation of these regions combined with functional assays revealed the diverse contributions of each moiety in protein-protein interactions, regulating telomerase activity or DNA-binding. Together, these functional data combined with biophysical analyses and homology modeling provide a molecular understanding of the diverse contributions of TPP1 in telomere maintenance.},
}
@article {pmid27655116,
year = {2016},
author = {Auld, E and Lin, J and Chang, E and Byanyima, P and Ayakaka, I and Musisi, E and Worodria, W and Davis, JL and Segal, M and Blackburn, E and Huang, L},
title = {HIV Infection Is Associated with Shortened Telomere Length in Ugandans with Suspected Tuberculosis.},
journal = {PloS one},
volume = {11},
number = {9},
pages = {e0163153},
pmid = {27655116},
issn = {1932-6203},
support = {K24 HL087713/HL/NHLBI NIH HHS/United States ; R01 HL090335/HL/NHLBI NIH HHS/United States ; R01 HL128156/HL/NHLBI NIH HHS/United States ; },
abstract = {INTRODUCTION: HIV infection is a risk factor for opportunistic pneumonias such as tuberculosis (TB) and for age-associated health complications. Short telomeres, markers of biological aging, are also associated with an increased risk of age-associated diseases and mortality. Our goals were to use a single cohort of HIV-infected and HIV-uninfected individuals hospitalized with pneumonia to assess whether shortened telomere length was associated with HIV infection, TB diagnosis, and 2-month mortality.<br><br>METHODS: This was a sub-study of the IHOP Study, a prospective observational study. Participants consisted of 184 adults admitted to Mulago Hospital in Kampala, Uganda who underwent evaluation for suspected TB and were followed for 2 months. Standardized questionnaires were administered to collect demographic and clinical data. PBMCs were isolated and analyzed using quantitative PCR to determine telomere length. The association between HIV infection, demographic and clinical characteristics, and telomere length was assessed, as were the associations between telomere length, TB diagnosis and 2-month mortality. Variables with a P&#x2264;0.2 in bivariate analysis were included in multivariate models.<br><br>RESULTS: No significant demographic or clinical differences were observed between the HIV-infected and HIV-uninfected subjects. Older age (P<0.0001), male gender (P = 0.04), total pack-years smoked (P<0.001), alcohol consumption in the past year (P = 0.12), and asthma (P = 0.08) were all associated (P&#x2264;0.2) with shorter telomere length in bivariate analysis. In multivariate analysis adjusting for these five variables, HIV-positive participants had significantly shorter telomeres than HIV-negative participants (&#x3b2; = -0.0621, 95% CI -0.113 to -0.011, P = 0.02). Shortened telomeres were not associated with TB or short-term mortality.<br><br>CONCLUSIONS: The association between HIV infection and shorter telomeres suggests that HIV may play a role in cellular senescence and biological aging and that shorter telomeres may be involved in age-associated health complications seen in this population. The findings indicate a need to further research the impact of HIV on aging.},
}
@article {pmid27653523,
year = {2017},
author = {Wu, RT and Cao, L and Mattson, E and Witwer, KW and Cao, J and Zeng, H and He, X and Combs, GF and Cheng, WH},
title = {Opposing impacts on healthspan and longevity by limiting dietary selenium in telomere dysfunctional mice.},
journal = {Aging cell},
volume = {16},
number = {1},
pages = {125-135},
pmid = {27653523},
issn = {1474-9726},
mesh = {Animals ; Body Weight/drug effects ; *Diet ; Down-Regulation/drug effects ; Gene Expression Profiling ; Genomic Instability/drug effects ; Glucose/metabolism ; *Health ; Histones/metabolism ; Insulin/metabolism ; Longevity/*drug effects ; Male ; Mice ; Mice, Inbred C57BL ; MicroRNAs/genetics/metabolism ; Pancreas/drug effects/metabolism ; Phenotype ; RNA/metabolism ; RNA, Messenger/genetics/metabolism ; Selenium/blood/*pharmacology ; Survival Analysis ; Telomerase/metabolism ; Telomere/drug effects/*metabolism ; },
abstract = {Selenium (Se) is a trace metalloid essential for life, but its nutritional and physiological roles during the aging process remain elusive. While telomere attrition contributes to replicative senescence mainly through persistent DNA damage response, such an aging process is mitigated in mice with inherently long telomeres. Here, weanling third generation telomerase RNA component knockout mice carrying short telomeres were fed a Se-deficient basal diet or the diet supplemented with 0.15 ppm Se as sodium selenate to be nutritionally sufficient throughout their life. Dietary Se deprivation delayed wound healing and accelerated incidence of osteoporosis, gray hair, alopecia, and cataract, but surprisingly promoted longevity. Plasma microRNA profiling revealed a circulating signature of Se deprivation, and subsequent ontological analyses predicted dominant changes in metabolism. Consistent with this observation, dietary Se deprivation accelerated age-dependent declines in glucose tolerance, insulin sensitivity, and glucose-stimulated insulin production in the mice. Moreover, DNA damage and senescence responses were enhanced and Pdx1 and MafA mRNA expression were reduced in pancreas of the Se-deficient mice. Altogether, these results suggest a novel model of aging with conceptual advances, whereby Se at low levels may be considered a hormetic chemical and decouple healthspan and longevity.},
}
@article {pmid27651456,
year = {2016},
author = {Arora, A and Beilstein, MA and Shippen, DE},
title = {Evolution of Arabidopsis protection of telomeres 1 alters nucleic acid recognition and telomerase regulation.},
journal = {Nucleic acids research},
volume = {44},
number = {20},
pages = {9821-9830},
pmid = {27651456},
issn = {1362-4962},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; },
mesh = {Arabidopsis/*genetics/*metabolism ; Arabidopsis Proteins/metabolism ; Binding Sites ; *Biological Evolution ; Conserved Sequence ; Models, Molecular ; Phenylalanine/chemistry ; Protein Binding ; Protein Conformation ; RNA, Plant/genetics/metabolism ; Shelterin Complex ; Telomerase/chemistry/*metabolism ; Telomere/chemistry/*genetics/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Protection of telomeres (POT1) binds chromosome ends, recognizing single-strand telomeric DNA via two oligonucleotide/oligosaccharide binding folds (OB-folds). The Arabidopsis thaliana POT1a and POT1b paralogs are atypical: they do not exhibit telomeric DNA binding, and they have opposing roles in regulating telomerase activity. AtPOT1a stimulates repeat addition processivity of the canonical telomerase enzyme, while AtPOT1b interacts with a regulatory lncRNA that represses telomerase activity. Here, we show that OB1 of POT1a, but not POT1b, has an intrinsic affinity for telomeric DNA. DNA binding was dependent upon a highly conserved Phe residue (F65) that in human POT1 directly contacts telomeric DNA. F65A mutation of POT1aOB1 abolished DNA binding and diminished telomerase repeat addition processivity. Conversely, AtPOT1b and other POT1b homologs from Brassicaceae and its sister family, Cleomaceae, naturally bear a non-aromatic amino acid at this position. By swapping Val (V63) with Phe, AtPOT1bOB1 gained the capacity to bind telomeric DNA and to stimulate telomerase repeat addition processivity. We conclude that, in the context of DNA binding, variation at a single amino acid position promotes divergence of the AtPOT1b paralog from the ancestral POT1 protein.},
}
@article {pmid27650676,
year = {2016},
author = {Wulaningsih, W and Watkins, J and Matsuguchi, T and Hardy, R},
title = {Investigating the associations between adiposity, life course overweight trajectories, and telomere length.},
journal = {Aging},
volume = {8},
number = {11},
pages = {2689-2701},
pmid = {27650676},
issn = {1945-4589},
support = {MC_UU_12019/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adiposity/*genetics ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Body Mass Index ; Female ; Humans ; Male ; Middle Aged ; Obesity/*genetics ; Risk Factors ; Telomere/*genetics ; },
abstract = {Obesity may accelerate ageing through chronic inflammation. To further examine this association, we assessed current adiposity, adiposity at early adulthood and life course overweight trajectories in relation to leukocyte telomere length (LTL). We included a total of 7,008 nationally representative U.S. residents and collected information on objectively measured body mass index (BMI), waist circumference and percent body fat. BMI at age 25 and overweight trajectories were assessed using self-reported history. Leukocyte telomere length (LTL) relative to a standard DNA reference (T/S ratio) was quantified by polymerase chain reaction (PCR). Linear regression models were used to examine the difference in LTL across adiposity measures at examination, BMI at age 25, and overweight trajectories. A 0.2% decrease in telomere length (95% CI: -0.3 to -0.07%) was observed for every kg/m2 increase in BMI, whereas a unit increase in waist circumference (cm) and percent body fat contributed to a 0.09% and 0.01% decrease in LTL, respectively. Higher BMI and being obese at age 25 contributed to lower LTL at older ages. Associations between weight loss through life course and LTL were observed, which further marked the importance of life course adiposity dynamics as a determinant of ageing.},
}
@article {pmid27644953,
year = {2018},
author = {Lee, YH and Bae, SC},
title = {Association between shortened telomere length and rheumatoid arthritis : A meta-analysis.},
journal = {Zeitschrift fur Rheumatologie},
volume = {77},
number = {2},
pages = {160-167},
pmid = {27644953},
issn = {1435-1250},
mesh = {*Arthritis, Rheumatoid/genetics ; Cross-Sectional Studies ; Genetic Predisposition to Disease ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes, Mononuclear ; *Telomere ; *Telomere Shortening ; },
abstract = {OBJECTIVE: This study aimed to evaluate the relationship between telomere length and rheumatoid arthritis (RA).<br><br>METHODS: We performed a&#xa0;meta-analysis of studies comparing the telomere length in RA patients and healthy controls, and conducted subgroup analysis based on ethnicity, age-matched status, study quality, sample type, assay method, subject number, and shared epitope (SE) status.<br><br>RESULTS: Nine studies from seven articles, with 388 RA patients and 362 controls, were included. Meta-analysis showed that the telomere length was significantly shorter in all individuals of the RA group than in those of the control group (SMD&#xa0;= -0.833, 95&#x2009;% CI&#xa0;= -1.332 to -0.334, p&#xa0;= 0.001). Stratification by ethnicity showed significantly shortened telomere lengths in both mixed and age-matched Caucasian populations with RA (SMD&#xa0;= -1.415, 95&#x2009;% CI&#xa0;= -1.709 to -1.120, p&#xa0;< 1.0&#xa0;&#xd7; 10[-8]; SMD&#xa0;= -0.658, 95&#x2009;% CI&#xa0;= -1.187 to -0.0.128, p&#xa0;= 0.015). The telomere length was significantly shorter in the RA group than in the age-matched control group; however, this was not the case in the RA group that was not age-matched (SMD&#xa0;= -1.070, 95&#x2009;% CI&#xa0;= -1.489 to -0.650, p&#xa0;= 5.7&#xa0;&#xd7; 10[-7]; SMD&#xa0;= 0.155, 95&#x2009;% CI&#xa0;= -0.119 to 0.429, p&#xa0;= 0.267). Stratification by SE status revealed a&#xa0;significantly shortened telomere length in the SE-positive group, but not in the SE-negative group (SMD&#xa0;= -1.033, 95&#x2009;% CI&#xa0;= -1.398 to -0.768, p&#xa0;< 1.0&#xa0;&#xd7; 10[-8]; SMD&#xa0;= -0.967, 95&#x2009;% CI&#xa0;= -2.382 to 0.449, p&#xa0;= 0.181). In addition, the telomere length was significantly shorter in the SE-positive RA group than in the SE-negative RA group (SMD&#xa0;= -0.415, 95&#x2009;% CI&#xa0;= -0.699 to -0.131, p&#xa0;= 0.004).<br><br>CONCLUSIONS: Our meta-analysis demonstrated that the telomere length was significantly shorter in patients with RA, and was significantly more so in the SE-positive group than in the SE-negative group.},
}
@article {pmid27641680,
year = {2016},
author = {Gadalla, SM and Wang, T and Dagnall, C and Haagenson, M and Spellman, SR and Hicks, B and Jones, K and Katki, HA and Lee, SJ and Savage, SA},
title = {Effect of Recipient Age and Stem Cell Source on the Association between Donor Telomere Length and Survival after Allogeneic Unrelated Hematopoietic Cell Transplantation for Severe Aplastic Anemia.},
journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation},
volume = {22},
number = {12},
pages = {2276-2282},
pmid = {27641680},
issn = {1523-6536},
support = {U24 CA076518/CA/NCI NIH HHS/United States ; ZIA CP010144-17//Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Anemia, Aplastic/diagnosis/mortality/*therapy ; Bone Marrow Transplantation/methods/mortality ; Child ; Child, Preschool ; Hematopoietic Stem Cell Transplantation/*methods/mortality ; Humans ; Infant ; Middle Aged ; Prognosis ; Real-Time Polymerase Chain Reaction ; Stem Cells/*immunology ; *Survival ; Telomere/*ultrastructure ; *Transplant Recipients ; *Unrelated Donors ; Young Adult ; },
abstract = {We previously showed an association between donor leukocyte relative telomere length (RTL) and post-hematopoietic cell transplantation (HCT) survival in patients with severe aplastic anemia (SAA) who received bone marrow grafts at ages <40 years. Here, we tested the generalizability of the prior findings in an independent validation cohort and by recipient age and stem cell source in the combined discovery and validation cohorts. We used monoplex quantitative real-time PCR to measure RTL in: (1) a new SAA validation cohort of 428 patients (age range, .2 to 77 years) with available pretransplantation donor blood samples in the Center for International Blood and Marrow Transplant Research repository, and (2) 278 patients from the original cohort who had sufficient DNA to repeat RTL testing. We used Cox proportional hazard models to calculate hazard ratios (HRs), and 95% confidence intervals (CIs) across categories of donor RTL. Data from the validation cohort showed no association between donor RTL and patient survival, but further analysis identified differences by recipient age and stem cell source as the likely explanation. In patients <40 years, the HR comparing longest with shortest and middle RTL tertiles = .75; 95% CI, .44 to 1.30 versus HR = 1.05; 95% CI, .59 to 1.89 for patients ≥40 years, P interaction = .37. In bone marrow recipients, the HR = .68; 95% CI, .72 to 1.10 versus HR = 1.29; 95% CI, .64 to 2.62 for peripheral blood stem cell grafts; P interaction = .88. Analyses using data from the 2 cohorts showed a statistically significant survival benefit only in <40-year-old patients receiving bone marrow graft (HR comparing longest and middle RTL tertiles with shortest = .69; 95% CI, .50 to .95, P = .02). The study suggested that the association between donor RTL and post-HCT outcomes in recipients with SAA may vary by recipient age and stem cell source. A larger study is needed to account for multiple comparisons and to further test the generalizability of our findings.},
}
@article {pmid27638151,
year = {2017},
author = {Uzlíková, M and Fulnečková, J and Weisz, F and Sýkorová, E and Nohýnková, E and Tůmová, P},
title = {Characterization of telomeres and telomerase from the single-celled eukaryote Giardia intestinalis.},
journal = {Molecular and biochemical parasitology},
volume = {211},
number = {},
pages = {31-38},
doi = {10.1016/j.molbiopara.2016.09.003},
pmid = {27638151},
issn = {1872-9428},
mesh = {Cell Line ; Enzyme Activation ; Giardia lamblia/*enzymology/*genetics ; Giardiasis/parasitology ; Humans ; In Situ Hybridization, Fluorescence ; Mitosis/genetics ; Protein Subunits/metabolism ; Protein Transport ; Repetitive Sequences, Nucleic Acid ; Telomerase/chemistry/*metabolism ; Telomere/*genetics ; Telomere Homeostasis ; },
abstract = {The ends of linear chromosomes, telomeres, are most commonly maintained by the enzyme telomerase. Our study presents the characteristics of telomeres and telomerase from the single-celled parasitic eukaryote Giardia intestinalis. Using fluorescence in situ hybridization, we localized telomeres during all stages of the trophozoite cell cycle and demonstrated differences in the observed number of telomeric foci, indicating telomere clustering. The length of Giardia telomeres was determined in different cell lines derived from WB clinical isolate using terminal restriction fragment analysis and ranged from 0.5 to 2.5kb; moreover, a BAL-31 digestion experiment did not reveal any long interstitial telomeric sequences in the genome. Despite the absence of the specific T motif in the telomerase catalytic subunit, the presence of an active telomerase enzyme synthesising telomeric repeats in Giardia was proved by a Telomere repeat amplification protocol assay, and its localization in nuclei was determined by the expression of recombinant GiTERT. Except for the Giardia-type TAGGG telomeric repeat, Giardia telomerase was proved to synthesize in vitro also other repeat variants, TAAGG and TAAGGG. In summary, despite its unusual characteristics, including a structurally divergent but active telomerase, unique terminal sequences and relatively short telomeres, the present data support the view that the chromosomal termini in Giardia are maintained in a conservative manner that is common to other eukaryotes.},
}
@article {pmid27637341,
year = {2016},
author = {See, VH and Mas, E and Burrows, S and O'Callaghan, NJ and Fenech, M and Prescott, SL and Beilin, LJ and Huang, RC and Mori, TA},
title = {Prenatal omega-3 fatty acid supplementation does not affect offspring telomere length and F2-isoprostanes at 12 years: A double blind, randomized controlled trial.},
journal = {Prostaglandins, leukotrienes, and essential fatty acids},
volume = {112},
number = {},
pages = {50-55},
doi = {10.1016/j.plefa.2016.08.006},
pmid = {27637341},
issn = {1532-2823},
mesh = {Child ; Dietary Supplements ; Double-Blind Method ; Erythrocytes/chemistry ; F2-Isoprostanes/*blood/*urine ; Fatty Acids, Omega-3/*administration &amp; dosage/pharmacology ; Female ; Humans ; Oxidative Stress/drug effects ; Pregnancy ; Prenatal Care ; Telomere/*drug effects ; },
abstract = {BACKGROUND: Oxidative stress and nutritional deficiency may influence the excessive shortening of the telomeric ends of chromosomes. It is known that stress exposure in intrauterine life can produce variations in telomere length (TL), thereby potentially setting up a long-term trajectory for disease susceptibility.<br><br>OBJECTIVE: To assess the effect of omega-3 long chain polyunsaturated fatty acid (n-3 LCPUFA) supplementation during pregnancy on telomere length and oxidative stress in offspring at birth and 12 years of age (12y).<br><br>DESIGN: In a double-blind, placebo-controlled, parallel-group study, 98 pregnant atopic women were randomised to 4g/day of n-3 LCPUFA or control (olive oil [OO]), from 20 weeks gestation until delivery. Telomere length as a marker of cell senescence and plasma and urinary F2-isoprostanes as a marker of oxidative stress were measured in the offspring at birth and 12y.<br><br>RESULTS: Maternal n-3 LCPUFA supplementation did not influence offspring telomere length at birth or at 12y with no changes over time. Telomere length was not associated with F2-isoprostanes or erythrocyte total n-3 fatty acids. Supplementation significantly reduced cord plasma F2-isoprostanes (P<0.001), with a difference in the change over time between groups (P=0.05). However, the differences were no longer apparent at 12y. Between-group differences for urinary F2-isoprostanes at birth and at 12y were non-significant with no changes over time.<br><br>CONCLUSIONS: This study does not support the hypothesis that n-3 LCPUFA during pregnancy provides sustained effects on postnatal oxidative stress and telomere length as observed in the offspring.},
}
@article {pmid27637081,
year = {2016},
author = {Li, X and Liang, G and Du, M and De Vivo, I and Nan, H},
title = {No association between telomere length-related loci and number of cutaneous nevi.},
journal = {Oncotarget},
volume = {7},
number = {50},
pages = {82396-82399},
pmid = {27637081},
issn = {1949-2553},
support = {P01 CA087969/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; },
mesh = {Genetic Association Studies ; *Genetic Loci ; Genetic Predisposition to Disease ; Humans ; Nevus/epidemiology/*genetics/pathology ; Phenotype ; *Polymorphism, Single Nucleotide ; Risk Factors ; Skin Neoplasms/epidemiology/*genetics/pathology ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; United States/epidemiology ; },
abstract = {BACKGROUND: Longer telomeres have been associated both with increased melanoma risk and increased nevus counts. Nevus count is one of the strongest risk factors for melanoma. Recent data showed that a genetic score derived by telomere length-related single nucleotide polymorphisms (SNPs) was strongly associated with melanoma risk; however, the relationships between these SNPs and number of cutaneous nevi have not been investigated.<br><br>METHODS: We evaluated the associations between telomere length-related SNPs reported by previous genome-wide association study (GWAS) and nevus counts among 15,955 participants of European Ancestry in the Nurses' Health Study and Health Professionals Follow-up Study.<br><br>RESULTS: None of the SNPs was associated with nevus counts, nor was the genetic score combining the dosage of alleles related to increased telomere length.<br><br>CONCLUSIONS: The telomere length-related SNPs identified by published GWAS do not appear to play an important role in nevus formation. Genetic determinants of telomere length reported by GWAS do not explain the observed epidemiologic association between telomere length and nevus counts.},
}
@article {pmid27632567,
year = {2016},
author = {Baljevic, M and Dumitriu, B and Lee, JW and Paietta, EM and Wiernik, PH and Racevskis, J and Chen, C and Stein, EM and Gallagher, RE and Rowe, JM and Appelbaum, FR and Powell, BL and Larson, RA and Coutré, SE and Lancet, J and Litzow, MR and Luger, SM and Young, NS and Tallman, MS},
title = {Telomere Length Recovery: A Strong Predictor of Overall Survival in Acute Promyelocytic Leukemia.},
journal = {Acta haematologica},
volume = {136},
number = {4},
pages = {210-218},
pmid = {27632567},
issn = {1421-9662},
support = {UG1 CA189859/CA/NCI NIH HHS/United States ; U24 CA196172/CA/NCI NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; U10 CA180790/CA/NCI NIH HHS/United States ; U10 CA180820/CA/NCI NIH HHS/United States ; U10 CA180794/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180816/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; U10 CA180791/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; *Codon ; Disease-Free Survival ; Female ; Follow-Up Studies ; Humans ; Leukemia, Promyelocytic, Acute/drug therapy/*genetics/*mortality ; Male ; Middle Aged ; Oncogene Proteins, Fusion/genetics ; *Polymorphism, Genetic ; RNA/genetics ; Survival Rate ; Telomerase/*genetics ; Telomere Homeostasis/drug effects/*genetics ; },
abstract = {Telomeres are the capping ends of chromosomes that protect the loss of genetic material and prevent chromosomal instability. In human tissue-specific stem/progenitor cells, telomere length (TL) is maintained by the telomerase complex, which consists of a reverse transcriptase catalytic subunit (TERT) and an RNA template (TERC). Very short telomeres and loss-of-function mutations in the TERT and TERC genes have been reported in acute myeloid leukemia, but the role of telomeres in acute promyelocytic leukemia (APL) has not been well established. We report the results for a large cohort of 187 PML/RARα-positive APL patients. No germline mutations in the TERT or TERC genes were identified. Codon 279 and 1062 TERT polymorphisms were present at a frequency similar to that in the general population. TL measured in blood or marrow mononuclear cells at diagnosis was significantly shorter in the APL patients than in healthy volunteers, and shorter telomeres at diagnosis were significantly associated with high-risk disease. For patients who achieved complete remission, the median increase in TL from diagnosis to remission (delta TL) was 2.0 kilobase (kb), and we found delta TL to be the most powerful predictor of overall survival when compared with well-established risk factors for poor outcomes in APL.},
}
@article {pmid27630582,
year = {2016},
author = {Küffer, AL and O'Donovan, A and Burri, A and Maercker, A},
title = {Posttraumatic Stress Disorder, Adverse Childhood Events, and Buccal Cell Telomere Length in Elderly Swiss Former Indentured Child Laborers.},
journal = {Frontiers in psychiatry},
volume = {7},
number = {},
pages = {147},
pmid = {27630582},
issn = {1664-0640},
support = {K01 MH109871/MH/NIMH NIH HHS/United States ; KL2 TR000143/TR/NCATS NIH HHS/United States ; },
abstract = {Posttraumatic stress disorder (PTSD) is associated with increased risk for age-related diseases and early mortality. Accelerated biological aging could contribute to this elevated risk. The aim of the present study was to assess buccal cell telomere length (BTL) - a proposed marker of biological age - in men and women with and without PTSD. The role of childhood trauma was assessed as a potential additional risk factor for shorter telomere length. The sample included 62 former indentured Swiss child laborers (age: M = 76.19, SD = 6.18) and 58 healthy controls (age: M = 71.85, SD = 5.97). Structured clinical interviews were conducted to screen for PTSD and other psychiatric disorders. The Childhood Trauma Questionnaire (CTQ) was used to assess childhood trauma exposure. Quantitative polymerase chain reaction was used to measure BTL. Covariates include age, sex, years of education, self-evaluated financial situation, depression, and mental and physical functioning. Forty-eight (77.42%) of the former indentured child laborers screened positive for childhood trauma, and 21 (33.87%) had partial or full-blown PTSD. Results did not support our hypotheses that PTSD and childhood trauma would be associated with shorter BTL. In fact, results revealed a trend toward longer BTL in participants with partial or full PTSD [F(2,109) = 3.27, p = 0.04, η(2) = 0.06], and longer BTL was marginally associated with higher CTQ scores (age adjusted: β = 0.17 [95% CI: -0.01 to 0.35], t = 1.90, p = 0.06). Furthermore, within-group analyses indicated no significant association between BTL and CTQ scores. To the best of our knowledge, this is the first study exploring the association between childhood trauma and BTL in older individuals with and without PTSD. Contrary to predictions, there were no significant differences in BTL between participants with and without PTSD in our adjusted analyses, and childhood adversity was not associated with BTL. Possible explanations and future research possibilities are discussed.},
}
@article {pmid27627813,
year = {2016},
author = {Slattery, ML and Herrick, JS and Pellatt, AJ and Wolff, RK and Mullany, LE},
title = {Telomere Length, TERT, and miRNA Expression.},
journal = {PloS one},
volume = {11},
number = {9},
pages = {e0162077},
pmid = {27627813},
issn = {1932-6203},
support = {R01 CA048998/CA/NCI NIH HHS/United States ; R01 CA061757/CA/NCI NIH HHS/United States ; R01 CA163683/CA/NCI NIH HHS/United States ; U01 CA048998/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Colonic Neoplasms/genetics ; Colorectal Neoplasms/*genetics ; Female ; Gene Library ; Genetic Association Studies ; Humans ; Male ; MicroRNAs/*physiology ; Middle Aged ; Multiplex Polymerase Chain Reaction ; Polymorphism, Single Nucleotide/genetics/physiology ; Rectal Neoplasms/genetics ; Telomerase/*genetics/physiology ; Telomere Homeostasis/genetics/*physiology ; Telomere Shortening/genetics/physiology ; },
abstract = {It has been proposed that miRNAs are involved in the control of telomeres. We test that hypothesis by examining the association between miRNAs and telomere length (TL). Additionally, we evaluate if genetic variation in telomerase reverse transcriptase (TERT) is associated with miRNA expression levels. We use data from a population-based study of colorectal cancer (CRC), where we have previously shown associations between TL and TERT and CRC, to test associations between TL and miRNA expression and TERT and miRNA expression. To gain insight into functions of miRNAs associated with TERT we tested linear associations between miRNAs and their targeted gene mRNAs. An Agilent platform that contained information on over 2000 miRNAs was used. TL was measured using a multiplexed quantitative PCR (qPCR). RNAseq was used to assess gene expression. Our sample consisted of 1152 individuals with SNP data and miRNA expression data; 363 individuals with both TL and miRNA; and 148 individuals with miRNA and mRNA data. Thirty-three miRNAs were directly associated with TL after adjusting for age and sex (false discovery rate (FDR) of 0.05). TERT rs2736118 was associated with differences in miRNA expression between carcinoma and normal colonic mucosa for 75 miRNAs (FDR <0.05). Genes regulated by these miRNAs, as indicated by mRNA/miRNA associations, were associated with major signaling pathways beyond their TL-related functions, including PTEN, and PI3K/AKT signaling. Our data support a direct association between miRNAs and TL; differences in miRNA expression levels by TERT genotype were observed. Based on miRNA and targeted mRNA associations our data suggest that TERT is involved in non-TL-related functions by acting through altered miRNA expression.},
}
@article {pmid27626530,
year = {2016},
author = {Jouneau, S and Kerjouan, M and Ricordel, C},
title = {Danazol Treatment for Telomere Diseases.},
journal = {The New England journal of medicine},
volume = {375},
number = {11},
pages = {1095},
doi = {10.1056/NEJMc1607752},
pmid = {27626530},
issn = {1533-4406},
mesh = {*Danazol ; Estrogen Antagonists/therapeutic use ; Humans ; *Telomere ; },
}
@article {pmid27626529,
year = {2016},
author = {Grossmann, M},
title = {Danazol Treatment for Telomere Diseases.},
journal = {The New England journal of medicine},
volume = {375},
number = {11},
pages = {1095},
doi = {10.1056/NEJMc1607752},
pmid = {27626529},
issn = {1533-4406},
mesh = {*Danazol ; Estrogen Antagonists/therapeutic use ; Humans ; *Telomere ; },
}
@article {pmid27626528,
year = {2016},
author = {Townsley, DM and Dumitriu, B and Young, NS},
title = {Danazol Treatment for Telomere Diseases.},
journal = {The New England journal of medicine},
volume = {375},
number = {11},
pages = {1095-1096},
doi = {10.1056/NEJMc1607752},
pmid = {27626528},
issn = {1533-4406},
mesh = {*Danazol ; Estrogen Antagonists/therapeutic use ; Humans ; *Telomere ; },
}
@article {pmid27622310,
year = {2016},
author = {Alegría-Torres, JA and Velázquez-Villafaña, M and López-Gutiérrez, JM and Chagoyán-Martínez, MM and Rocha-Amador, DO and Costilla-Salazar, R and García-Torres, L},
title = {Association of Leukocyte Telomere Length and Mitochondrial DNA Copy Number in Children from Salamanca, Mexico.},
journal = {Genetic testing and molecular biomarkers},
volume = {20},
number = {11},
pages = {654-659},
doi = {10.1089/gtmb.2016.0176},
pmid = {27622310},
issn = {1945-0257},
mesh = {Biomarkers/metabolism ; Child ; DNA Copy Number Variations ; DNA, Mitochondrial/*genetics/metabolism ; Female ; Gene Dosage ; Humans ; Leukocytes/cytology/metabolism/*ultrastructure ; Male ; Mexico ; Mitochondria/genetics ; Real-Time Polymerase Chain Reaction ; Telomere/genetics/*metabolism ; Telomere Shortening/genetics ; },
abstract = {AIM: The purpose of this study was to determine if there is a correlation between telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) in children.<br><br>METHODS: Leukocyte TL and mtDNAcn were measured by real-time PCR in 98 Mexican children 6-12 years of age from Salamanca, M&#xe9;xico.<br><br>RESULTS: A positive association was found between TL and mtDNAcn after a natural log transformation (Pearson correlation r&#x2009;=&#x2009;0.72; p&#x2009;<&#x2009;0.0001). No correlation between age and body mass index (BMI) biomarkers was found, and no differences according to sex were observed. After adjustment for these variables, a linear regression model showed an association between TL and mtDNAcn (&#x3b2;&#x2009;=&#x2009;0.739, 95% confidence interval 0.594; 0.885, p&#x2009;<&#x2009;0.0001).<br><br>CONCLUSIONS: A strong positive correlation between TL and mtDNAcn was found in the study population; age, sex, and BMI seemed to have no effect on this correlation.},
}
@article {pmid27617363,
year = {2016},
author = {Simide, R and Angelier, F and Gaillard, S and Stier, A},
title = {Age and Heat Stress as Determinants of Telomere Length in a Long-Lived Fish, the Siberian Sturgeon.},
journal = {Physiological and biochemical zoology : PBZ},
volume = {89},
number = {5},
pages = {441-447},
doi = {10.1086/687378},
pmid = {27617363},
issn = {1537-5293},
mesh = {Aging/*physiology ; Animals ; Erythrocytes ; Fishes/*physiology ; Hot Temperature/*adverse effects ; Stress, Physiological/*physiology ; Telomere/*physiology ; },
abstract = {Telomeres shorten at each cell division due to the end-replication problem but also in response to oxidative stress. Consequently, telomeres shorten with age in many endotherms, and this shortening is accelerated under stressful environmental conditions. Data in ectotherm vertebrates remain scarce so far, so our goal was to review existing data for fish and to test the influence of age and stress on telomere length in a very long-lived fish, the Siberian sturgeon (Acipenser baerii). Our review of the literature revealed age-related telomere shortening in approximately half of the published studies. In the Siberian sturgeon, we found a significant telomere shortening with age, both at the intraindividual level using red blood cells (-12.5% in 16 mo) and at the interindividual level using cross-sectional samples of fin over an age range of 8 yr. We also found that heat stress (30°C) significantly reduced telomere length by 15.0% after only 1 mo of exposure. Our results highlight that both age and stressful environmental conditions might be important determinants of telomere length in fish.},
}
@article {pmid27616348,
year = {2016},
author = {Schutte, NS and Palanisamy, SK and McFarlane, JR},
title = {The relationship between positive psychological characteristics and longer telomeres.},
journal = {Psychology &amp; health},
volume = {31},
number = {12},
pages = {1466-1480},
doi = {10.1080/08870446.2016.1226308},
pmid = {27616348},
issn = {1476-8321},
mesh = {Adult ; Female ; Humans ; Male ; *Mental Health ; Middle Aged ; *Personality ; Telomere/*genetics ; },
abstract = {OBJECTIVE: Longer telomeres are associated with better health and longevity. This research investigated the relationship between positive psychological dispositional traits and telomere length. Positive traits examined were typical high positive affect, typical low negative affect, life satisfaction, trait mindfulness, trait emotional intelligence, general self-efficacy and optimism.<br><br>DESIGN AND MEASURES: One hundred and twenty women and men, with a mean age of 40.92, completed measures of positive characteristics and provided samples for telomere length analysis.<br><br>RESULTS: Together the positive dispositional characteristics explained significant variance in telomere length, R&#xa0;=&#xa0;.40. Among the individual characteristics, greater optimism and higher emotional intelligence were associated with longer telomeres after adjustment for age and gender and the association between optimism and telomere length remained significant after adjusting for age and gender as well as the other positive characteristics, with a partial correlation r of .30.<br><br>CONCLUSION: These results in conjunction with previous research findings provide a platform for further exploration of biological pathways connecting positive characteristics such as optimism to telomere length and investigation of the impact of increasing a characteristic such as optimism on telomere functioning.},
}
@article {pmid27615599,
year = {2016},
author = {Zhou, Y and Simmons, D and Hambly, BD and McLachlan, CS},
title = {Interactions between UCP2 SNPs and telomere length exist in the absence of diabetes or pre-diabetes.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {33147},
pmid = {27615599},
issn = {2045-2322},
mesh = {Alleles ; Cardiovascular Diseases/complications ; Diabetes Mellitus, Type 2/complications/*genetics ; Female ; Genotype ; Humans ; Leukocytes/metabolism ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Prediabetic State/complications/*genetics ; Risk Factors ; Telomere/*genetics ; Uncoupling Protein 2/*genetics ; },
abstract = {Mitochondrial uncoupling protein 2 (UCP2) can affect oxidative stress levels. UCP2 polymorphisms are associated with leukocyte telomere length (LTL) in Type 2 Diabetes, which also induces considerable background oxidative stress. The effects of UCP2 polymorphisms on LTL in populations without diabetes have not been well described. Our aims are to evaluate the interaction between LTL and UCP2 polymorphisms in 950 subjects without diabetes. The monochrome multiplex quantitative PCR method was used to measure relative LTL. Taqman SNP genotyping assay was applied to genotypes for UCP2 rs659366 and rs660339. We found shorter LTL associated with increased age (P < 0.001) and triglyceride levels (P = 0.041). After adjustment for cardiovascular risk factors, rs659336 GG genotype carriers demonstrated a shorter LTL (1.257 ± 0.186), compared to GA carriers (1.288 ± 0.230, P = 0.022) and AA carriers (1.314 ± 0.253, P = 0.002). LTL was shorter in the CC rs660339 genotype (1.254 ± 0.187) compared to TT (1.297 ± 0.242, P = 0.007) and CT carriers (1.292 ± 0.229, P = 0.016). The T allele of rs660339 is associated with a longer LTL of approximately 0.04 compared to CC homozygotes. Thus, UCP2 rs659366 A allele and rs660339 T allele are both related to longer LTL in subjects without diabetes, independent of cardiovascular risk factors.},
}
@article {pmid27612935,
year = {2017},
author = {Aguado, T and Gutiérrez, FJ and Aix, E and Schneider, RP and Giovinazzo, G and Blasco, MA and Flores, I},
title = {Telomere Length Defines the Cardiomyocyte Differentiation Potency of Mouse Induced Pluripotent Stem Cells.},
journal = {Stem cells (Dayton, Ohio)},
volume = {35},
number = {2},
pages = {362-373},
doi = {10.1002/stem.2497},
pmid = {27612935},
issn = {1549-4918},
mesh = {Animals ; Ascorbic Acid/pharmacology ; *Cell Differentiation/drug effects ; Cell Lineage/drug effects ; Cell Proliferation/drug effects ; Cell Size/drug effects ; Collagen/metabolism ; Embryoid Bodies/cytology/metabolism ; Induced Pluripotent Stem Cells/*cytology/*metabolism ; Mice ; Myocytes, Cardiac/*cytology/drug effects/*metabolism ; *Telomere Homeostasis/drug effects ; },
abstract = {Induced pluripotent stem cells (iPSCs) can be differentiated in vitro and in vivo to all cardiovascular lineages and are therefore a promising cell source for cardiac regenerative therapy. However, iPSC lines do not all differentiate into cardiomyocytes (CMs) with the same efficiency. Here, we show that telomerase-competent iPSCs with relatively long telomeres and high expression of the shelterin-complex protein TRF1 (iPSC[highT]) differentiate sooner and more efficiently into CMs than those with relatively short telomeres and low TRF1 expression (iPSC[lowT]). Ascorbic acid, an enhancer of cardiomyocyte differentiation, further increases the cardiomyocyte yield from iPSC[highT] but does not rescue the cardiomyogenic potential of iPSC[lowT] . Interestingly, although iPSCs[lowT] differentiate very poorly to the mesoderm and endoderm lineages, they differentiate very efficiently to the ectoderm lineage, indicating that cell fate can be determined by in vitro selection of iPSCs with different telomere content. Our findings highlight the importance of selecting iPSCs with ample telomere reserves in order to generate high numbers of CMs in a fast, reliable, and efficient way. Stem Cells 2017;35:362-373.},
}
@article {pmid27611693,
year = {2016},
author = {Katsumata, K and Hirayasu, A and Miyoshi, J and Nishi, E and Ichikawa, K and Tateho, K and Wakuda, A and Matsuhara, H and Yamamoto, A},
title = {A Taz1- and Microtubule-Dependent Regulatory Relationship between Telomere and Centromere Positions in Bouquet Formation Secures Proper Meiotic Divisions.},
journal = {PLoS genetics},
volume = {12},
number = {9},
pages = {e1006304},
pmid = {27611693},
issn = {1553-7404},
mesh = {Centromere/*genetics ; *Prophase ; Protein Binding ; Schizosaccharomyces/genetics ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Spindle Pole Bodies/genetics/*metabolism ; Telomere/*genetics ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {During meiotic prophase, telomeres cluster, forming the bouquet chromosome arrangement, and facilitate homologous chromosome pairing. In fission yeast, bouquet formation requires switching of telomere and centromere positions. Centromeres are located at the spindle pole body (SPB) during mitotic interphase, and upon entering meiosis, telomeres cluster at the SPB, followed by centromere detachment from the SPB. Telomere clustering depends on the formation of the microtubule-organizing center at telomeres by the linker of nucleoskeleton and cytoskeleton complex (LINC), while centromere detachment depends on disassembly of kinetochores, which induces meiotic centromere formation. However, how the switching of telomere and centromere positions occurs during bouquet formation is not fully understood. Here, we show that, when impaired telomere interaction with the LINC or microtubule disruption inhibited telomere clustering, kinetochore disassembly-dependent centromere detachment and accompanying meiotic centromere formation were also inhibited. Efficient centromere detachment required telomere clustering-dependent SPB recruitment of a conserved telomere component, Taz1, and microtubules. Furthermore, when artificial SPB recruitment of Taz1 induced centromere detachment in telomere clustering-defective cells, spindle formation was impaired. Thus, detachment of centromeres from the SPB without telomere clustering causes spindle impairment. These findings establish novel regulatory mechanisms, which prevent concurrent detachment of telomeres and centromeres from the SPB during bouquet formation and secure proper meiotic divisions.},
}
@article {pmid27609839,
year = {2016},
author = {Lee, JR and Xie, X and Yang, K and Zhang, J and Lee, SY and Shippen, DE},
title = {Dynamic Interactions of Arabidopsis TEN1: Stabilizing Telomeres in Response to Heat Stress.},
journal = {The Plant cell},
volume = {28},
number = {9},
pages = {2212-2224},
pmid = {27609839},
issn = {1532-298X},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; },
abstract = {Telomeres are the essential nucleoprotein structures that provide a physical cap for the ends of linear chromosomes. The highly conserved CST (CTC1/STN1/TEN1) protein complex facilitates telomeric DNA replication and promotes telomere stability. Here we report three unexpected properties of Arabidopsis thaliana TEN1 that indicate it possesses functions distinct from other previously characterized telomere proteins. First, we show that telomeres in ten1 mutants are highly sensitive to thermal stress. Heat shock causes abrupt and dramatic loss of telomeric DNA in ten1 plants, likely via deletional recombination. Second, we show that AtTEN1 has the properties of a heat-shock induced molecular chaperone. At elevated temperature, AtTEN1 rapidly assembles into high molecular weight homo-oligomeric complexes that efficiently suppress heat-induced aggregation of model protein substrates in vitro. Finally, we report that AtTEN1 specifically protects CTC1 from heat-induced aggregation in vitro, and from heat-induced protein degradation and loss of telomere association in vivo. Collectively, these observations define Arabidopsis TEN1 as a highly dynamic protein that works in concert with CTC1 to preserve telomere integrity in response to environmental stress.},
}
@article {pmid27607141,
year = {2016},
author = {Hammerl, JA and Jäckel, C and Funk, E and Pinnau, S and Mache, C and Hertwig, S},
title = {The diverse genetic switch of enterobacterial and marine telomere phages.},
journal = {Bacteriophage},
volume = {6},
number = {2},
pages = {e1148805},
pmid = {27607141},
issn = {2159-7073},
abstract = {Temperate bacteriophages possess a genetic switch which regulates the lytic and lysogenic cycle. The genomes of the enterobacterial telomere phages N15, PY54 and ϕKO2 harbor a primary immunity region (immB) comprising genes for the prophage repressor, the lytic repressor and a putative antiterminator, similar to CI, Cro and Q of lambda, respectively. Moreover, N15 and ϕKO2 contain 3 related operator (OR) sites between cI and cro, while only one site (OR3) has been detected in PY54. Marine telomere phages possess a putative cI gene but not a cro-like gene. Instead, a gene is located at the position of cro, whose product shows some similarity to the PY54 ORF42 product, the function of which is unknown. We have determined the transcription start sites of the predicted repressor genes of N15, PY54, ϕKO2 and of the marine telomere phage VP58.5. The influence of the genes on phage propagation was analyzed in E. coli, Y. enterocolitica and V.parahaemolyticus. We show that the repressors and antiterminators of N15, ϕKO2 and PY54 exerted their predicted activities. However, while the proteins of both N15 and ϕKO2 affected lysis and lysogeny by N15, they did not affect PY54 propagation. On the other hand, the respective PY54 proteins exclusively influenced the propagation of this phage. The immB region of VP58.5 contains 2 genes that revealed prophage repressor activity, while a lytic repressor gene could not be identified. The results indicate an unexpected diversity of the growth regulation mechanisms in these temperate phages.},
}
@article {pmid27602331,
year = {2016},
author = {Deeg, KI and Chung, I and Bauer, C and Rippe, K},
title = {Cancer Cells with Alternative Lengthening of Telomeres Do Not Display a General Hypersensitivity to ATR Inhibition.},
journal = {Frontiers in oncology},
volume = {6},
number = {},
pages = {186},
pmid = {27602331},
issn = {2234-943X},
abstract = {Telomere maintenance is a hallmark of cancer as it provides cancer cells with cellular immortality. A significant fraction of tumors uses the alternative lengthening of telomeres (ALT) pathway to elongate their telomeres and to gain an unlimited proliferation potential. Since the ALT pathway is unique to cancer cells, it represents a potentially valuable, currently unexploited target for anti-cancer therapies. Recently, it was proposed that ALT renders cells hypersensitive to ataxia telangiectasia- and RAD3-related (ATR) protein inhibitors (Flynn et al., Science 347, 273). Here, we measured the response of various ALT- or telomerase-positive cell lines to the ATR inhibitor VE-821. In addition, we compared the effect of the inhibitor on cell viability in isogenic cell lines, in which ALT was active or suppressed. In these experiments, a general ATR inhibitor sensitivity of cells with ALT could not be confirmed. We rather propose that the observed variations in sensitivity reflect differences between cell lines that are unrelated to ALT.},
}
@article {pmid27598341,
year = {2016},
author = {Kong, PL and Looi, LM and Lau, TP and Cheah, PL},
title = {Assessment of Telomere Length in Archived Formalin-Fixed, Paraffinized Human Tissue Is Confounded by Chronological Age and Storage Duration.},
journal = {PloS one},
volume = {11},
number = {9},
pages = {e0161720},
pmid = {27598341},
issn = {1932-6203},
mesh = {Adult ; Aged ; Aging/*genetics/pathology ; DNA/genetics ; Female ; Formaldehyde ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Paraffin Embedding ; Specimen Handling ; Telomere ; Telomere Homeostasis/*genetics ; },
abstract = {Telomeres shorten with physiological aging but undergo substantial restoration during cancer immortalization. Increasingly, cancer studies utilize the archive of formalin-fixed, paraffin-embedded (FFPE) tissues in diagnostic pathology departments. Conceptually, such studies would be confounded by physiological telomere attrition and loss of DNA integrity from prolonged tissue storage. Our study aimed to investigate these two confounding factors. 145 FFPE tissues of surgically-resected, non-diseased appendixes were retrieved from our pathology archive, from years 2008 to 2014. Cases from 2013 to 2014 were categorized by patient chronological age (0-20 years, 21-40 years, 41-60 years, > 60 years). Telomere lengths of age categories were depicted by telomere/chromosome 2 centromere intensity ratio (TCR) revealed by quantitative fluorescence in situ hybridization. Material from individuals aged 0-20 years from years 2013/2014, 2011/2012, 2009/2010, and 2008 were compared for storage effect. Telomere integrity was assessed by telomere fluorescence intensity (TFI). Epithelial TCRs (mean ± SD) for the respective age groups were 4.84 ± 2.08, 3.64 ± 1.21, 2.03 ± 0.37, and 1.93 ± 0.45, whereas corresponding stromal TCRs were 5.16 ± 2.55, 3.84 ± 1.36, 2.49 ± 1.20, and 2.93 ± 1.24. A trend of inverse correlation with age in both epithelial and stromal tissues is supported by r = -0.69, p < 0.001 and r = -0.42, p < 0.001 respectively. Epithelial TFIs (mean ± SD) of years 2013/2014, 2011/2012, 2009/2010 and 2008 were 852.60 ± 432.46, 353.04 ± 127.12, 209.24 ± 55.57 and 429.22 ± 188.75 respectively. Generally, TFIs reduced with storage duration (r = -0.42, p < 0.001). Our findings agree that age-related telomere attrition occurs in normal somatic tissues, and suggest that an age-based reference can be established for telomere studies on FFPE tissues. We also showed that FFPE tissues archived beyond 2 years are suboptimal for telomere analysis.},
}
@article {pmid27598205,
year = {2016},
author = {Kordinas, V and Ioannidis, A and Chatzipanagiotou, S},
title = {The Telomere/Telomerase System in Chronic Inflammatory Diseases. Cause or Effect?.},
journal = {Genes},
volume = {7},
number = {9},
pages = {},
pmid = {27598205},
issn = {2073-4425},
abstract = {Telomeres are specialized nucleoprotein structures located at the end of linear chromosomes and telomerase is the enzyme responsible for telomere elongation. Telomerase activity is a key component of many cancer cells responsible for rapid cell division but it has also been found by many laboratories around the world that telomere/telomerase biology is dysfunctional in many other chronic conditions as well. These conditions are characterized by chronic inflammation, a situation mostly overlooked by physicians regarding patient treatment. Among others, these conditions include diabetes, renal failure, chronic obstructive pulmonary disease, etc. Since researchers have in many cases identified the association between telomerase and inflammation but there are still many missing links regarding this correlation, the latest findings about this phenomenon will be discussed by reviewing the literature. Our focus will be describing telomere/telomerase status in chronic diseases under the prism of inflammation, reporting molecular findings where available and proposing possible future approaches.},
}
@article {pmid27598203,
year = {2016},
author = {Yeh, JK and Wang, CY},
title = {Telomeres and Telomerase in Cardiovascular Diseases.},
journal = {Genes},
volume = {7},
number = {9},
pages = {},
pmid = {27598203},
issn = {2073-4425},
abstract = {Telomeres are tandem repeat DNA sequences present at the ends of each eukaryotic chromosome to stabilize the genome structure integrity. Telomere lengths progressively shorten with each cell division. Inflammation and oxidative stress, which are implicated as major mechanisms underlying cardiovascular diseases, increase the rate of telomere shortening and lead to cellular senescence. In clinical studies, cardiovascular risk factors such as smoking, obesity, sedentary lifestyle, and hypertension have been associated with short leukocyte telomere length. In addition, low telomerase activity and short leukocyte telomere length have been observed in atherosclerotic plaque and associated with plaque instability, thus stroke or acute myocardial infarction. The aging myocardium with telomere shortening and accumulation of senescent cells limits the tissue regenerative capacity, contributing to systolic or diastolic heart failure. In addition, patients with ion-channel defects might have genetic imbalance caused by oxidative stress-related accelerated telomere shortening, which may subsequently cause sudden cardiac death. Telomere length can serve as a marker for the biological status of previous cell divisions and DNA damage with inflammation and oxidative stress. It can be integrated into current risk prediction and stratification models for cardiovascular diseases and can be used in precise personalized treatments. In this review, we summarize the current understanding of telomeres and telomerase in the aging process and their association with cardiovascular diseases. In addition, we discuss therapeutic interventions targeting the telomere system in cardiovascular disease treatments.},
}
@article {pmid27597942,
year = {2016},
author = {Ameer, SS and Xu, Y and Engström, K and Li, H and Tallving, P and Nermell, B and Boemo, A and Parada, LA and Peñaloza, LG and Concha, G and Harari, F and Vahter, M and Broberg, K},
title = {Exposure to Inorganic Arsenic Is Associated with Increased Mitochondrial DNA Copy Number and Longer Telomere Length in Peripheral Blood.},
journal = {Frontiers in cell and developmental biology},
volume = {4},
number = {},
pages = {87},
pmid = {27597942},
issn = {2296-634X},
abstract = {BACKGROUND: Exposure to inorganic arsenic (iAs) through drinking water causes cancer. Alterations in mitochondrial DNA copy number (mtDNAcn) and telomere length in blood have been associated with cancer risk. We elucidated if arsenic exposure alters mtDNAcn and telomere length in individuals with different arsenic metabolizing capacity.<br><br>METHODS: We studied two groups in the Salta province, Argentina, one in the Puna area of the Andes (N = 264, 89% females) and one in Chaco (N = 169, 75% females). We assessed arsenic exposure as the sum of arsenic metabolites [iAs, methylarsonic acid (MMA), dimethylarsinic acid (DMA)] in urine (U-As) using high-performance liquid chromatography coupled with hydride generation and inductively coupled plasma mass spectrometry. Efficiency of arsenic metabolism was expressed as percentage of urinary metabolites. MtDNAcn and telomere length were determined in blood by real-time PCR.<br><br>RESULTS: Median U-As was 196 (5-95 percentile: 21-537) &#x3bc;g/L in Andes and 80 (5-95 percentile: 15-1637) &#x3bc;g/L in Chaco. The latter study group had less-efficient metabolism, with higher %iAs and %MMA in urine compared with the Andean group. U-As was significantly associated with increased mtDNAcn (log2 transformed to improve linearity) in Chaco (&#x3b2; = 0.027 per 100 &#x3bc;g/L, p = 0.0085; adjusted for age and sex), but not in Andes (&#x3b2; = 0.025, p = 0.24). U-As was also associated with longer telomere length in Chaco (&#x3b2; = 0.016, p = 0.0066) and Andes (&#x3b2; = 0.0075, p = 0.029). In both populations, individuals with above median %iAs showed significantly higher mtDNAcn and telomere length compared with individuals with below median %iAs.<br><br>CONCLUSIONS: Arsenic was associated with increased mtDNAcn and telomere length, particularly in individuals with less-efficient arsenic metabolism, a group who may have increased risk for arsenic-related cancer.},
}
@article {pmid27595912,
year = {2017},
author = {Peška, V and Sitová, Z and Fajkus, P and Fajkus, J},
title = {BAL31-NGS approach for identification of telomeres de novo in large genomes.},
journal = {Methods (San Diego, Calif.)},
volume = {114},
number = {},
pages = {16-27},
doi = {10.1016/j.ymeth.2016.08.017},
pmid = {27595912},
issn = {1095-9130},
mesh = {Allium/*genetics ; Cestrum/*genetics ; Chromosomes, Plant ; Endodeoxyribonucleases/*metabolism ; *Genome, Plant ; Genomics ; High-Throughput Nucleotide Sequencing/*methods ; Sequence Analysis, DNA/*methods ; Telomere/*genetics ; },
abstract = {This article describes a novel method to identify as yet undiscovered telomere sequences, which combines next generation sequencing (NGS) with BAL31 digestion of high molecular weight DNA. The method was applied to two groups of plants: i) dicots, genus Cestrum, and ii) monocots, Allium species (e.g. A. ursinum and A. cepa). Both groups consist of species with large genomes (tens of Gb) and a low number of chromosomes (2n=14-16), full of repeat elements. Both genera lack typical telomeric repeats and multiple studies have attempted to characterize alternative telomeric sequences. However, despite interesting hypotheses and suggestions of alternative candidate telomeres (retrotransposons, rDNA, satellite repeats) these studies have not resolved the question. In a novel approach based on the two most general features of eukaryotic telomeres, their repetitive character and sensitivity to BAL31 nuclease digestion, we have taken advantage of the capacity and current affordability of NGS in combination with the robustness of classical BAL31 nuclease digestion of chromosomal termini. While representative samples of most repeat elements were ensured by low-coverage (less than 5%) genomic shot-gun NGS, candidate telomeres were identified as under-represented sequences in BAL31-treated samples.},
}
@article {pmid27595911,
year = {2017},
author = {Henson, JD and Lau, LM and Koch, S and Martin La Rotta, N and Dagg, RA and Reddel, RR},
title = {The C-Circle Assay for alternative-lengthening-of-telomeres activity.},
journal = {Methods (San Diego, Calif.)},
volume = {114},
number = {},
pages = {74-84},
doi = {10.1016/j.ymeth.2016.08.016},
pmid = {27595911},
issn = {1095-9130},
mesh = {Biomarkers, Tumor/*genetics ; DNA, Circular/*analysis ; DNA, Neoplasm/*genetics ; Humans ; Neoplasms/*diagnosis/genetics ; *Telomere ; },
abstract = {The C-Circle Assay has satisfied the need for a rapid, robust and quantitative ALT assay that responds quickly to changes in ALT activity. The C-Circle Assay involves (i) extraction or simple preparation (Quick C-Circle Preparation) of the cell's DNA, which includes C-Circles (ii) amplification of the self-primed C-Circles with a rolling circle amplification reaction and (iii) sequence specific detection of the amplification products by native telomeric DNA dot blot or telomeric qPCR. Here we detail the protocols and considerations required to perform the C-Circle Assay and its controls, which include exonuclease removal of linear telomeric DNA, production of the synthetic C-Circle C96 and modulation of ALT activity by γ-irradiation.},
}
@article {pmid27589328,
year = {2016},
author = {Courtwright, AM and Fried, S and Villalba, JA and Moniodis, A and Guleria, I and Wood, I and Milford, E and Mallidi, HH and Hunninghake, GM and Raby, BA and Agarwal, S and Camp, PC and Rosas, IO and Goldberg, HJ and El-Chemaly, S},
title = {Association of Donor and Recipient Telomere Length with Clinical Outcomes following Lung Transplantation.},
journal = {PloS one},
volume = {11},
number = {9},
pages = {e0162409},
pmid = {27589328},
issn = {1932-6203},
support = {R01 HL111024/HL/NHLBI NIH HHS/United States ; R01 HL130275/HL/NHLBI NIH HHS/United States ; R01 HL130974/HL/NHLBI NIH HHS/United States ; T32 HL007633/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Female ; Graft Rejection/genetics ; Humans ; *Lung Transplantation ; Male ; Middle Aged ; Prognosis ; *Telomere ; Telomere Shortening/genetics ; *Tissue Donors ; *Transplant Recipients ; *Treatment Outcome ; Young Adult ; },
abstract = {BACKGROUND: Patients with short telomere syndromes and pulmonary fibrosis have increased complications after lung transplant. However, the more general impact of donor and recipient telomere length in lung transplant has not been well characterized.<br><br>METHODS: This was an observational cohort study of patients who received lung transplant at a single center between January 1st 2012 and January 31st 2015. Relative donor lymphocyte telomere length was measured and classified into long (third tertile) and short (other tertiles). Relative recipient lung telomere length was measured and classified into short (first tertile) and long (other tertiles). Outcome data included survival, need for modification of immunosuppression, liver or kidney injury, cytomegalovirus reactivation, and acute rejection.<br><br>RESULTS: Recipient lung tissue telomere lengths were measured for 54 of the 79 patients (68.3%) who underwent transplant during the study period. Donor lymphocyte telomeres were measured for 45 (83.3%) of these recipients. Neither long donor telomere length (hazard ratio [HR] = 0.58, 95% confidence interval [CI], 0.12-2.85, p = 0.50) nor short recipient telomere length (HR = 1.01, 95% CI = 0.50-2.05, p = 0.96) were associated with adjusted survival following lung transplant. Recipients with short telomeres were less likely to have acute cellular rejection (23.5% vs. 58.8%, p = 0.02) but were not more likely to have other organ dysfunction.<br><br>CONCLUSIONS: In this small cohort, neither long donor lymphocyte telomeres nor short recipient lung tissue telomeres were associated with adjusted survival after lung transplantation. Larger studies are needed to confirm these findings.},
}
@article {pmid27587879,
year = {2016},
author = {Boyraz, B and Bellomo, CM and Fleming, MD and Cutler, CS and Agarwal, S},
title = {A novel TERC CR4/CR5 domain mutation causes telomere disease via decreased TERT binding.},
journal = {Blood},
volume = {128},
number = {16},
pages = {2089-2092},
pmid = {27587879},
issn = {1528-0020},
support = {R01 DK107716/DK/NIDDK NIH HHS/United States ; },
mesh = {Adult ; Female ; Humans ; Male ; *Mutation ; Nucleic Acid Conformation ; Protein Binding ; RNA/chemistry/*genetics/metabolism ; Siblings ; Telomerase/chemistry/*genetics/*metabolism ; Telomere/*metabolism ; Thrombocytopenia/*genetics/metabolism ; },
}
@article {pmid27587191,
year = {2016},
author = {Piqueret-Stephan, L and Ricoul, M and Hempel, WM and Sabatier, L},
title = {Replication Timing of Human Telomeres is Conserved during Immortalization and Influenced by Respective Subtelomeres.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {32510},
pmid = {27587191},
issn = {2045-2322},
mesh = {Cell Line, Transformed ; Chromosomes, Human/genetics ; *DNA Replication Timing ; Fibroblasts/metabolism ; Humans ; Models, Biological ; S Phase ; Telomere/*metabolism ; Transfection ; },
abstract = {Telomeres are specific structures that protect chromosome ends and act as a biological clock, preventing normal cells from replicating indefinitely. Mammalian telomeres are replicated throughout S-phase in a predetermined order. However, the mechanism of this regulation is still unknown. We wished to investigate this phenomenon under physiological conditions in a changing environment, such as the immortalization process to better understand the mechanism for its control. We thus examined the timing of human telomere replication in normal and SV40 immortalized cells, which are cytogenetically very similar to cancer cells. We found that the timing of telomere replication was globally conserved under different conditions during the immortalization process. The timing of telomere replication was conserved despite changes in telomere length due to endogenous telomerase reactivation, in duplicated homologous chromosomes, and in rearranged chromosomes. Importantly, translocated telomeres, possessing their initial subtelomere, retained the replication timing of their homolog, independently of the proportion of the translocated arm, even when the remaining flanking DNA is restricted to its subtelomere, the closest chromosome-specific sequences (inferior to 500 kb). Our observations support the notion that subtelomere regions strongly influence the replication timing of the associated telomere.},
}
@article {pmid27586969,
year = {2016},
author = {Martínez, P and Gómez-López, G and Pisano, DG and Flores, JM and Blasco, MA},
title = {A genetic interaction between RAP1 and telomerase reveals an unanticipated role for RAP1 in telomere maintenance.},
journal = {Aging cell},
volume = {15},
number = {6},
pages = {1113-1125},
pmid = {27586969},
issn = {1474-9726},
support = {SAF2013-45111-R//Spanish Ministry of Economy and Competitiveness (MINECO and FEDER) Project RETOS/ ; ERC-2008-AdG/232854//European Research Council (ERC) Project TEL STEM CELL/ ; //Fundaci&#xf3;n Bot&#xed;n/ ; },
abstract = {RAP1 is one of the components of shelterin, the capping complex at chromosome ends or telomeres, although its role in telomere length maintenance and protection has remained elusive. RAP1 also binds subtelomeric repeats and along chromosome arms, where it regulates gene expression and has been shown to function in metabolism control. Telomerase is the enzyme that elongates telomeres, and its deficiency causes a premature aging in humans and mice. We describe an unanticipated genetic interaction between RAP1 and telomerase. While RAP1 deficiency alone does not impact on mouse survival, mice lacking both RAP1 and telomerase show a progressively decreased survival with increasing mouse generations compared to telomerase single mutants. Telomere shortening is more pronounced in Rap1[-/-] Terc[-/-] doubly deficient mice than in the single-mutant Terc[-/-] counterparts, leading to an earlier onset of telomere-induced DNA damage and degenerative pathologies. Telomerase deficiency abolishes obesity and liver steatohepatitis provoked by RAP1 deficiency. Using genomewide ChIP sequencing, we find that progressive telomere shortening owing to telomerase deficiency leads to re-localization of RAP1 from telomeres and subtelomeric regions to extratelomeric sites in a genomewide manner. These findings suggest that although in the presence of sufficient telomere reserve RAP1 is not a key factor for telomere maintenance and protection, it plays a crucial role in the context of telomerase deficiency, thus in agreement with its evolutionary conservation as a telomere component from yeast to humans.},
}
@article {pmid27585244,
year = {2017},
author = {Kreilmeier, T and Sampl, S and Deloria, AJ and Walter, I and Reifinger, M and Hauck, M and Borst, LB and Holzmann, K and Kleiter, M},
title = {Alternative lengthening of telomeres does exist in various canine sarcomas.},
journal = {Molecular carcinogenesis},
volume = {56},
number = {3},
pages = {923-935},
doi = {10.1002/mc.22546},
pmid = {27585244},
issn = {1098-2744},
mesh = {Animals ; Cell Line, Tumor ; DNA Helicases/genetics ; Dog Diseases/*genetics/pathology ; Dogs ; Gene Expression Regulation, Neoplastic ; Humans ; Neuroblastoma/*genetics/pathology ; Nuclear Proteins/genetics ; Sarcoma/genetics/pathology/*veterinary ; Telomere/*genetics ; *Telomere Homeostasis ; Tumor Suppressor Protein p53/genetics ; X-linked Nuclear Protein ; },
abstract = {Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism (TMM) found in some human tumors such as sarcomas. Canine tumors are not characterized for ALT and the study aim was to identify if the ALT phenotype exists in canine sarcomas. Sixty-four canine sarcoma samples (20 snap-frozen, 44 FFPE) as well as six canine sarcoma cell lines were screened for ALT by C-circle assay. ALT was further evaluated by measuring telomere length via qPCR and telomere restriction-fragments including pulsed-field electrophoresis. ALT-associated proteins were validated by immunohistochemistry. Further, telomerase activity (TA) and gene expression were analyzed by TRAP and qPCR. DNA from 20 human neuroblastomas and 8 sarcoma cell lines served as comparative controls. ALT was detected in 9.4% (6/64) canine sarcomas including aggressive subtypes as hemangiosarcoma, osteosarcoma, and histiocytic sarcoma. C-circle levels were comparable with human ALT-positive controls. All ALT tumors demonstrated loss of ATRX expression and 5/6 showed strong p53 expression. TA was detected in 93% (14/15) snap-frozen samples including a sarcoma with ALT activity. This tumor showed long heterogeneous telomeres, and a high level of colocalization of DAXX with telomeres. One sarcoma was ALT and TA negative. All canine and human sarcoma cell lines were ALT negative. In this study, we demonstrated that canine sarcomas use ALT. As in humans, ALT was identified in aggressive sarcomas subtypes and coexisted with TA in one tumor. Overall, canine sarcomas seem to share many similarities with their human counterparts and appear an attractive model for comparative telomere research. © 2016 Wiley Periodicals, Inc.},
}
@article {pmid27584834,
year = {2016},
author = {Druliner, BR and Ruan, X and Johnson, R and Grill, D and O'Brien, D and Lai, TP and Rashtak, S and Felmlee-Devine, D and Washechek-Aletto, J and Malykh, A and Smyrk, T and Oberg, A and Liu, H and Shay, JW and Ahlquist, DA and Boardman, LA},
title = {Time Lapse to Colorectal Cancer: Telomere Dynamics Define the Malignant Potential of Polyps.},
journal = {Clinical and translational gastroenterology},
volume = {7},
number = {9},
pages = {e188},
pmid = {27584834},
issn = {2155-384X},
support = {P30 DK084567/DK/NIDDK NIH HHS/United States ; R01 CA170357/CA/NCI NIH HHS/United States ; R01 CA204013/CA/NCI NIH HHS/United States ; },
abstract = {OBJECTIVE: Whereas few adenomas become cancer, most colorectal cancers arise from adenomas. Telomere length is a recognized biomarker in multiple cancers, and telomere maintenance mechanisms (TMM) are exploited by malignant cells. We sought to determine whether telomere length and TMM distinguish cancer-associated adenomas from those that are cancer-free.<br><br>METHODS: Tissues were identified as cancer-adjacent polyp (CAP)-residual adenoma contiguous with cancer-and cancer-free polyp (CFP)-adenomas without malignancy. Telomere length, TMM, and expression were measured in 102 tissues including peripheral blood leukocytes (PBLs), normal colon epithelium, adenoma, and cancer (in CAP cases) from 31 patients. Telomere length was measured in a separate cohort of 342 PBL from CAP and CFP patients.<br><br>RESULTS: The mean differences in telomere length between normal and adenoma were greater in CAP than in CFP cases, P=0.001; telomere length in PBL was 91.7&#x2009;bp greater in CAP than in CFP, P=0.007. Each 100&#x2009;bp telomere increase was associated with a 1.14 (1.04-1.26) increased odds of being a CAP, P=0.0063. The polyp tissue from CAP patients had shorter telomeres and higher Telomerase reverse transcriptase (hTERT) expression compared with polyps from CFP patients, P=0.05. There was a greater degree of alternative lengthening of telomere (ALT) level difference in CFP polyps than in CAP polyps. The polyp telomere lengths of aggressive CAPs were significantly different from the polyps of non-aggressive CAPs, P=0.01.<br><br>CONCLUSIONS: Adenomas that progress to cancer exhibit distinct telomere length and TMM profiles. We report for the first time that PBL telomeres differ in patients with polyps that become malignant, and therefore may have clinical value in adenoma risk assessment and management.},
}
@article {pmid27583462,
year = {2016},
author = {Seo, B and Lee, J},
title = {Observation and Quantification of Telomere and Repetitive Sequences Using Fluorescence In Situ Hybridization (FISH) with PNA Probes in Caenorhabditis elegans.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {114},
pages = {},
pmid = {27583462},
issn = {1940-087X},
mesh = {Animals ; Caenorhabditis elegans/*genetics/metabolism ; DNA Probes/chemistry/genetics ; In Situ Hybridization, Fluorescence/*methods ; Peptide Nucleic Acids/chemistry/genetics ; Repetitive Sequences, Nucleic Acid ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomere is a ribonucleoprotein structure that protects chromosomal ends from aberrant fusion and degradation. Telomere length is maintained by telomerase or an alternative pathway, known as alternative lengthening of telomeres (ALT)(1). Recently, C. elegans has emerged as a multicellular model organism for the study of telomere and ALT(2). Visualization of repetitive sequences in the genome is critical in understanding the biology of telomeres. While telomere length can be measured by telomere restriction fragment assay or quantitative PCR, these methods only provide the averaged telomere length. On the contrary, fluorescence in situ hybridization (FISH) can provide the information of the individual telomeres in cells. Here, we provide protocols and representative results of the method to determine telomere length of C. elegans by fluorescent in situ hybridization. This method provides a simple, but powerful, in situ procedure that does not cause noticeable damage to morphology. By using fluorescently labeled peptide nucleic acid (PNA) and digoxigenin-dUTP-labeled probe, we were able to visualize two different repetitive sequences: telomere repeats and template of ALT (TALT) in C. elegans embryos and gonads.},
}
@article {pmid27581804,
year = {2016},
author = {Eisenberg, DT},
title = {Telomere length measurement validity: the coefficient of variation is invalid and cannot be used to compare quantitative polymerase chain reaction and Southern blot telomere length measurement techniques.},
journal = {International journal of epidemiology},
volume = {45},
number = {4},
pages = {1295-1298},
doi = {10.1093/ije/dyw191},
pmid = {27581804},
issn = {1464-3685},
mesh = {*Blotting, Southern ; Humans ; Leukocytes ; Polymerase Chain Reaction ; *Telomere ; },
}
@article {pmid27581250,
year = {2016},
author = {Luu, HN and Long, J and Wen, W and Zheng, Y and Cai, Q and Gao, YT and Zheng, W and Shu, XO},
title = {Association between genetic risk score for telomere length and risk of breast cancer.},
journal = {Cancer causes &amp; control : CCC},
volume = {27},
number = {10},
pages = {1219-1228},
pmid = {27581250},
issn = {1573-7225},
support = {R37 CA070867/CA/NCI NIH HHS/United States ; R25 CA160056/CA/NCI NIH HHS/United States ; R01 CA090899/CA/NCI NIH HHS/United States ; R01 CA064277/CA/NCI NIH HHS/United States ; R01 CA148667/CA/NCI NIH HHS/United States ; R01 CA118229/CA/NCI NIH HHS/United States ; UM1 CA182910/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Alleles ; Asian People/genetics/statistics &amp; numerical data ; Breast Neoplasms/epidemiology/*genetics ; Case-Control Studies ; China/epidemiology ; Ethnicity ; Female ; Genetic Predisposition to Disease ; Genetic Variation ; Genome-Wide Association Study ; Humans ; Middle Aged ; Polymorphism, Single Nucleotide ; Telomere/*genetics ; White People/genetics/statistics &amp; numerical data ; },
abstract = {PURPOSE: While leukocyte telomere length (TL) has been associated with breast cancer risk, limited information is available regarding the role of genetically-determined TL on breast cancer risk. We investigated whether aggregated TL-associated variants are associated with the risk of breast cancer in 2,865 breast cancer cases and 2,285 controls from the Shanghai Breast Cancer Genetics Study.<br><br>METHODS: Six genetic variants, identified through a genome-wide association study (GWAS) of TL in European-ancestry participants, were included in the study. A separate sample [n&#xa0;=&#xa0;1,536, from the Shanghai Women's Health Study (SWHS), for whom information on both phenotypical leukocyte TL and genetic information was collected] was used to evaluate the association of six variants with TL in Asians. Three genetic risk scores (GRSs), based on the number of alleles associated with shorter TL that each individual carries for the six variants, were derived for the study: un-weighted, internally weighted (from the SWHS), and externally weighted (from the European-ancestry GWAS study), and evaluated for their association with breast cancer risk by applying logistic regression analysis.<br><br>RESULTS: Both internally and externally weighted GRSs were significantly associated with a decreased risk of breast cancer (OR 0.83, 95&#xa0;% CI 0.72-0.95 and OR 0.84, 95&#xa0;% CI 0.74-0.96, respectively, for tertile 3 vs. tertile 1). Non-genetic risk factors for breast cancer (i.e., age, years of menstruation/reproduction, oral contraceptive usage, and BMI) did not modify the association between GRSs and the risk of breast cancer.<br><br>CONCLUSION: Our results suggest that short TL, determined by genetic factors, may be associated with a reduced susceptibility to breast cancer.},
}
@article {pmid27575340,
year = {2016},
author = {Lloyd, NR and Dickey, TH and Hom, RA and Wuttke, DS},
title = {Tying up the Ends: Plasticity in the Recognition of Single-Stranded DNA at Telomeres.},
journal = {Biochemistry},
volume = {55},
number = {38},
pages = {5326-5340},
pmid = {27575340},
issn = {1520-4995},
support = {R01 GM059414/GM/NIGMS NIH HHS/United States ; T32 GM065103/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA, Single-Stranded/*chemistry ; Schizosaccharomyces/*chemistry ; Schizosaccharomyces pombe Proteins/*chemistry ; *Telomere ; },
abstract = {Telomeres terminate nearly exclusively in single-stranded DNA (ssDNA) overhangs comprised of the G-rich 3' end. This overhang varies widely in length from species to species, ranging from just a few bases to several hundred nucleotides. These overhangs are not merely a remnant of DNA replication but rather are the result of complex further processing. Proper management of the telomeric overhang is required both to deter the action of the DNA damage machinery and to present the ends properly to the replicative enzyme telomerase. This Current Topic addresses the biochemical and structural features used by the proteins that manage these variable telomeric overhangs. The Pot1 protein tightly binds the single-stranded overhang, preventing DNA damage sensors from binding. Pot1 also orchestrates the access of telomerase to that same substrate. The remarkable plasticity of the binding interface exhibited by the Schizosaccharomyces pombe Pot1 provides mechanistic insight into how these roles may be accomplished, and disease-associated mutations clustered around the DNA-binding interface in the hPOT1 highlight the importance of this function. The budding yeast Cdc13-Stn1-Ten1, a telomeric RPA complex closely associated with telomere function, also interacts with ssDNA in a fashion that allows degenerate sequences to be recognized. A related human complex composed of hCTC1, hSTN1, and hTEN1 has recently emerged with links to both telomere maintenance and general DNA replication and also exhibits mutations associated with telomere pathologies. Overall, these sequence-specific ssDNA binders exhibit a range of recognition properties that allow them to perform their unique biological functions.},
}
@article {pmid27571273,
year = {2016},
author = {Ennour-Idrissi, K and Têtu, B and Maunsell, E and Poirier, B and Montoni, A and Rochette, PJ and Diorio, C},
title = {Association of Telomere Length with Breast Cancer Prognostic Factors.},
journal = {PloS one},
volume = {11},
number = {8},
pages = {e0161903},
pmid = {27571273},
issn = {1932-6203},
mesh = {Adult ; Age Factors ; Aged ; Breast Neoplasms/*genetics/*pathology ; Cross-Sectional Studies ; Female ; Humans ; Middle Aged ; Polymerase Chain Reaction ; Prognosis ; Telomere/*genetics ; },
abstract = {INTRODUCTION: Telomere length, a marker of cell aging, seems to be affected by the same factors thought to be associated with breast cancer prognosis.<br><br>OBJECTIVE: To examine associations of peripheral blood cell-measured telomere length with traditional and potential prognostic factors in breast cancer patients.<br><br>METHODS: We conducted a cross-sectional analysis of data collected before surgery from 162 breast cancer patients recruited consecutively between 01/2011 and 05/2012, at a breast cancer reference center. Data on the main lifestyle factors (smoking, alcohol consumption, physical activity) were collected using standardized questionnaires. Anthropometric factors were measured. Tumor biological characteristics were extracted from pathology reports. Telomere length was measured using a highly reproducible quantitative PCR method in peripheral white blood cells. Spearman partial rank-order correlations and multivariate general linear models were used to evaluate relationships between telomere length and prognostic factors.<br><br>RESULTS: Telomere length was positively associated with total physical activity (rs = 0.17, P = 0.033; Ptrend = 0.069), occupational physical activity (rs = 0.15, P = 0.054; Ptrend = 0.054) and transportation-related physical activity (rs = 0.19, P = 0.019; P = 0.005). Among post-menopausal women, telomere length remained positively associated with total physical activity (rs = 0.27, P = 0.016; Ptrend = 0.054) and occupational physical activity (rs = 0.26, P = 0.021; Ptrend = 0.056) and was only associated with transportation-related physical activity among pre-menopausal women (rs = 0.27, P = 0.015; P = 0.004). No association was observed between telomere length and recreational or household activities, other lifestyle factors or traditional prognostic factors.<br><br>CONCLUSIONS: Telomeres are longer in more active breast cancer patients. Since white blood cells are involved in anticancer immune responses, these findings suggest that even regular low-intensity physical activity, such as that related to transportation or occupation, could be recommended to breast cancer patients.},
}
@article {pmid27568819,
year = {2016},
author = {Watts, JM and Dumitriu, B and Hilden, P and Kishtagari, A and Rapaport, F and Chen, C and Ahn, J and Devlin, SM and Stein, EM and Rampal, R and Levine, RL and Young, N and Tallman, MS},
title = {Telomere length and associations with somatic mutations and clinical outcomes in acute myeloid leukemia.},
journal = {Leukemia research},
volume = {49},
number = {},
pages = {62-65},
pmid = {27568819},
issn = {1873-5835},
support = {K08 CA188529/CA/NCI NIH HHS/United States ; KL2 TR000461/TR/NCATS NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; Female ; Humans ; Isocitrate Dehydrogenase/genetics ; Leukemia, Myeloid, Acute/diagnosis/*genetics/mortality ; Male ; Middle Aged ; *Mutation ; Prognosis ; Survival Analysis ; Telomere/*ultrastructure ; Treatment Outcome ; fms-Like Tyrosine Kinase 3/genetics ; },
abstract = {We examined the genetic implications and clinical impact of telomere length (TL) in 67 patients with acute myeloid leukemia (AML). There was a trend toward improved survival at 6 months in patients with longer TL. We found that patients with activating mutations, such as FLT3-ITD, had shorter TL, while those with mutations in epigenetic modifying enzymes, particularly IDH1 and IDH2, had longer TL. These are intriguing findings that warrant further investigation in larger cohorts. Our data show the potential of TL as a predictive biomarker in AML and identify genetic subsets that may be particularly vulnerable to telomere-targeted therapies.},
}
@article {pmid27567959,
year = {2016},
author = {Kuzyk, A and Gartner, J and Mai, S},
title = {Identification of Neuroblastoma Subgroups Based on Three-Dimensional Telomere Organization.},
journal = {Translational oncology},
volume = {9},
number = {4},
pages = {348-356},
pmid = {27567959},
issn = {1936-5233},
abstract = {Using 3D telomere quantitative fluorescence in situ hybridization, we determined the 3D telomere organization of 74 neuroblastoma tissue samples. Hierarchical cluster analysis of the measured telomere parameters identified three subgroups from our patient cohort. These subgroups have unique telomere profiles based on telomere length and nuclear architecture. Subgroups with higher levels of telomere dysfunction were comprised of tumors with greater numbers of telomeres, telomeric aggregates, and short telomeres (P<.0001). Tumors with greater telomere dysfunction were associated with unfavorable tumor characteristics (greater age at diagnosis, unfavorable histology, higher stage of disease, MYCN amplification, and higher MYCN expression) and poor prognostic risk (P<.001). Subgroups with greater telomere dysfunction also had higher intratumor heterogeneity. MYCN overexpression in two neuroblastoma cell lines with constitutively low MYCN expression induced changes in their telomere profile that were consistent with increased telomere dysfunction; this illustrates a functional relationship between MYCN and 3D telomere organization. This study demonstrates the ability to classify neuroblastomas based on the level of telomere dysfunction, which is a novel approach for this cancer.},
}
@article {pmid27566956,
year = {2016},
author = {Hamad, R and Tuljapurkar, S and Rehkopf, DH},
title = {Racial and Socioeconomic Variation in Genetic Markers of Telomere Length: A Cross-Sectional Study of U.S. Older Adults.},
journal = {EBioMedicine},
volume = {11},
number = {},
pages = {296-301},
pmid = {27566956},
issn = {2352-3964},
support = {K01 AG047280/AG/NIA NIH HHS/United States ; KL2 TR001083/TR/NCATS NIH HHS/United States ; R24 AG039345/AG/NIA NIH HHS/United States ; },
mesh = {Age Factors ; Aged ; Aged, 80 and over ; Alleles ; Cross-Sectional Studies ; Ethnicity/*genetics ; Female ; Gene Frequency ; *Genetic Markers ; Genome-Wide Association Study ; Geriatric Assessment ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; *Population Surveillance ; Socioeconomic Factors ; Telomere Homeostasis/*genetics ; United States/epidemiology ; },
abstract = {BACKGROUND: Shorter telomere length (TL) has been associated with stress and adverse socioeconomic conditions, yet U.S. blacks have longer TL than whites. The role of genetic versus environmental factors in explaining TL by race and socioeconomic position (SEP) remains unclear.<br><br>METHODS: We used data from the U.S. Health and Retirement Study (N=11,934) to test the hypothesis that there are differences in TL-associated SNPs by race and SEP. We constructed a TL polygenic risk score (PRS) and examined its association with race/ethnicity, educational attainment, assets, gender, and age.<br><br>RESULTS: U.S. blacks were more likely to have a lower PRS for TL, as were older individuals and men. Racial differences in TL were statistically accounted for when controlling for population structure using genetic principal components. The GWAS-derived SNPs for TL, however, may not have consistent associations with TL across different racial/ethnic groups.<br><br>CONCLUSIONS: This study showed that associations of race/ethnicity with TL differed when accounting for population stratification. The role of race/ethnicity for TL remains uncertain, however, as the genetic determinants of TL may differ by race/ethnicity. Future GWAS samples should include racially diverse participants to allow for better characterization of the determinants of TL in human populations.},
}
@article {pmid27566420,
year = {2016},
author = {Kachuri, L and Latifovic, L and Liu, G and Hung, RJ},
title = {Systematic Review of Genetic Variation in Chromosome 5p15.33 and Telomere Length as Predictive and Prognostic Biomarkers for Lung Cancer.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {25},
number = {12},
pages = {1537-1549},
doi = {10.1158/1055-9965.EPI-16-0200},
pmid = {27566420},
issn = {1538-7755},
support = {//CIHR/Canada ; },
mesh = {*Chromosomes, Human, Pair 5 ; Humans ; Lung Neoplasms/diagnosis/*genetics/metabolism ; Membrane Proteins/genetics ; Neoplasm Proteins/genetics ; *Polymorphism, Single Nucleotide ; Prognosis ; Telomerase/genetics ; *Telomere Homeostasis ; },
abstract = {Lung cancer remains the leading cause of cancer mortality worldwide. Known histomolecular characteristics and genomic profiles provide limited insight into factors influencing patient outcomes. Telomere length (TL) is important for genomic integrity and has been a growing area of interest as agents targeting telomerase are being evaluated. Chromosome 5p15.33, an established cancer susceptibility locus, contains a telomerase-regulatory gene, TERT, and CLPTM1L, a gene associated with cisplatin-induced apoptosis. This review offers a summary of the clinical utility of 5p15.33 polymorphisms and TL. A total of 621 abstracts were screened, and 14 studies (7 for 5p15.33, 7 for TL) were reviewed. Endpoints included overall survival (OS), progression-free survival (PFS), therapy response, and toxicity. Of the 23 genetic variants identified, significant associations with OS and/or PFS were reported for rs401681 (CLPTM1L), rs4975616 (TERT-CLPTM1L), and rs2736109 (TERT). Both shorter and longer TL, in tumor and blood, was linked to OS and PFS. Overall, consistent evidence across multiple studies of 5p15.33 polymorphisms and TL was lacking. Despite the potential to become useful prognostic biomarkers in lung cancer, the limited number of reports and their methodologic limitations highlight the need for larger, carefully designed studies with clinically defined subpopulations and higher resolution genetic analyses. Cancer Epidemiol Biomarkers Prev; 25(12); 1537-49. ©2016 AACR.},
}
@article {pmid27566293,
year = {2016},
author = {Kahl, VFS and da Silva, J and da Silva, FR},
title = {Influence of exposure to pesticides on telomere length in tobacco farmers: A biology system approach.},
journal = {Mutation research},
volume = {791-792},
number = {},
pages = {19-26},
doi = {10.1016/j.mrfmmm.2016.08.003},
pmid = {27566293},
issn = {1873-135X},
mesh = {Brazil ; DNA-Binding Proteins/*metabolism ; *Farmers ; Humans ; Nicotine/*toxicity ; Occupational Exposure/*adverse effects ; Pesticides/*toxicity ; *Protein Interaction Maps ; Systems Biology ; Telomere/drug effects/metabolism ; Telomere Shortening/*drug effects ; Nicotiana/adverse effects/chemistry/growth &amp; development ; },
abstract = {Various pesticides in the form of mixtures must be used to keep tobacco crops pest-free. Recent studies have shown a link between occupational exposure to pesticides in tobacco crops and increased damage to the DNA, mononuclei, nuclear buds and binucleated cells in buccal cells as well as micronuclei in lymphocytes. Furthermore, pesticides used specifically for tobacco crops shorten telomere length (TL) significantly. However, the molecular mechanism of pesticide action on telomere length is not fully understood. Our study evaluated the interaction between a complex mixture of chemical compounds (tobacco cultivation pesticides plus nicotine) and proteins associated with maintaining TL, as well as the biological processes involved in this exposure by System Biology tools to provide insight regarding the influence of pesticide exposure on TL maintenance in tobacco farmers. Our analysis showed that one cluster was associated with TL proteins that act in bioprocesses such as (i) telomere maintenance via telomere lengthening; (ii) senescence; (iii) age-dependent telomere shortening; (iv) DNA repair (v) cellular response to stress and (vi) regulation of proteasome ubiquitin-dependent protein catabolic process. We also describe how pesticides and nicotine regulate telomere length. In addition, pesticides inhibit the ubiquitin proteasome system (UPS) and consequently increase proteins of the shelterin complex, avoiding the access of telomerase in telomere and, nicotine activates UPS mechanisms and promotes the degradation of human telomerase reverse transcriptase (hTERT), decreasing telomerase activity.},
}
@article {pmid27566127,
year = {2017},
author = {Wulaningsih, W and Astuti, Y and Matsuguchi, T and Anggrandariyanny, P and Watkins, J and , },
title = {Circulating Prostate-Specific Antigen and Telomere Length in a Nationally Representative Sample of Men Without History of Prostate Cancer.},
journal = {The Prostate},
volume = {77},
number = {1},
pages = {22-32},
doi = {10.1002/pros.23245},
pmid = {27566127},
issn = {1097-0045},
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/*blood ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Nutrition Surveys/methods ; Prostate-Specific Antigen/*blood ; Prostatic Neoplasms/*blood/epidemiology ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {BACKGROUND: We investigated the association of prostate-specific antigen (PSA) with leukocyte telomere length, which may be altered in preclinical prostate malignancies.<br><br>METHODS: This study was based on the 2001-2002&#x2009;U.S. National Health and Nutrition Examination Survey (NHANES). A subsample of 1,127 men aged 40-85 years without prior history of prostate cancer who provided informed consent and blood samples were selected. Leukocyte telomere length (LTL) relative to standard DNA reference (T/S ratio) was quantified by polymerase chain reaction (PCR). Survey-weighted multivariable linear regression was performed to examine T/S ratio across quintiles of total and free PSA and free-to-total PSA ratio (%fPSA). A sensitivity analysis was performed by excluding men dying from prostate cancer during follow-up through to December 31, 2006. Stratification analyses were carried out to assess any effect modification by age group, race, body mass index (BMI), and levels of C-reactive protein (CRP), a marker of inflammation.<br><br>RESULTS: Higher total PSA levels were associated to longer LTL, with approximately 8% increase in log-transformed T/S ratio (95% confidence interval [CI]: 2-13%) among men in the highest quintile of total PSA compared to the lowest in the fully adjusted model (Ptrend &#x2009;=&#x2009;0.01). No significant association was found for free PSA or %fPSA, although nonlinearity between all PSA measures and T/S ratio was indicated. Similar results were found after excluding men who died from prostate cancer during follow-up. We also found the associations between total PSA and T/S ratio to be strongest among non-Hispanic blacks, non-obese men (BMI <30&#x2009;kg/m[2]), and those with low CRP. However, a significant interaction was only found between total PSA and race/ethnicity (Pinteraction &#x2009;=&#x2009;0.01).<br><br>CONCLUSION: Total PSA levels were strongly associated to LTL, particularly among non-Hispanic blacks. Our findings support a potential link between PSA and specific mechanisms contributing to prostate cancer development. Prostate 77:22-32, 2017. &#xa9; 2016 Wiley Periodicals, Inc.},
}
@article {pmid27565742,
year = {2017},
author = {Lee, M and Napier, CE and Yang, SF and Arthur, JW and Reddel, RR and Pickett, HA},
title = {Comparative analysis of whole genome sequencing-based telomere length measurement techniques.},
journal = {Methods (San Diego, Calif.)},
volume = {114},
number = {},
pages = {4-15},
doi = {10.1016/j.ymeth.2016.08.008},
pmid = {27565742},
issn = {1095-9130},
mesh = {*Cellular Senescence ; Computational Biology/methods ; *Genome, Human ; Humans ; *Software ; *Telomere Homeostasis ; Whole Genome Sequencing/*methods ; },
abstract = {Telomeres are regions of repetitive DNA at the ends of human chromosomes that function to maintain the integrity of the genome. Telomere attrition is associated with cellular ageing, whilst telomere maintenance is a prerequisite for malignant transformation. Whole genome sequencing (WGS) captures sequence information from the entire genome, including the telomeres, and is increasingly being applied in research and in the clinic. Several bioinformatics tools have been designed to determine telomere content and length from WGS data, and include Motif_counter, TelSeq, Computel, qMotif, and Telomerecat. These tools utilise different approaches to identify, quantify and normalise telomeric reads; however, it is not known how they compare to one another. Here we describe the details and utility of each tool, and directly compare WGS telomere length output with laboratory-based telomere length measurements. In addition, we evaluate the accessibility, practicality, speed, and additional features of each tool. Each tool was tested using a range of telomere read extraction criteria, to determine the optimal parameters for the specific WGS read length. The aim of this article is to improve the accessibility of WGS telomere length measurement tools, which have the potential to be applied to WGS cohorts for clinical as well as research benefit.},
}
@article {pmid27564449,
year = {2016},
author = {Moradi-Fard, S and Sarthi, J and Tittel-Elmer, M and Lalonde, M and Cusanelli, E and Chartrand, P and Cobb, JA},
title = {Smc5/6 Is a Telomere-Associated Complex that Regulates Sir4 Binding and TPE.},
journal = {PLoS genetics},
volume = {12},
number = {8},
pages = {e1006268},
pmid = {27564449},
issn = {1553-7404},
support = {MOP-82736//CIHR/Canada ; MOP-137062//CIHR/Canada ; MOP-89768//CIHR/Canada ; },
mesh = {Adenosine Triphosphatases/genetics/metabolism ; Cell Cycle Proteins/*genetics/metabolism ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; Chromosomes/genetics ; DNA Replication/genetics ; DNA-Binding Proteins/genetics/metabolism ; Multiprotein Complexes/genetics/metabolism ; Mutation ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/*genetics/metabolism ; Sumoylation/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; *Transcription, Genetic ; Cohesins ; },
abstract = {SMC proteins constitute the core members of the Smc5/6, cohesin and condensin complexes. We demonstrate that Smc5/6 is present at telomeres throughout the cell cycle and its association with chromosome ends is dependent on Nse3, a subcomponent of the complex. Cells harboring a temperature sensitive mutant, nse3-1, are defective in Smc5/6 localization to telomeres and have slightly shorter telomeres. Nse3 interacts physically and genetically with two Rap1-binding factors, Rif2 and Sir4. Reduction in telomere-associated Smc5/6 leads to defects in telomere clustering, dispersion of the silencing factor, Sir4, and a loss in transcriptional repression for sub-telomeric genes and non-coding telomeric repeat-containing RNA (TERRA). SIR4 recovery at telomeres is reduced in cells lacking Smc5/6 functionality and vice versa. However, nse3-1/ sir4 Δ double mutants show additive defects for telomere shortening and TPE indicating the contribution of Smc5/6 to telomere homeostasis is only in partial overlap with SIR factor silencing. These findings support a role for Smc5/6 in telomere maintenance that is separate from its canonical role(s) in HR-mediated events during replication and telomere elongation.},
}
@article {pmid27562613,
year = {2017},
author = {Appleby, S and Pearson, JF and Aitchison, A and Spittlehouse, JK and Joyce, PR and Kennedy, MA},
title = {Mean telomere length is not associated with current health status in a 50-year-old population sample.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {29},
number = {1},
pages = {},
doi = {10.1002/ajhb.22906},
pmid = {27562613},
issn = {1520-6300},
mesh = {Biomarkers/analysis ; Female ; Health Status ; *Health Status Indicators ; Humans ; Male ; Middle Aged ; New Zealand ; Obesity/physiopathology ; Phenotype ; Sex Factors ; Telomere/*physiology ; },
abstract = {OBJECTIVES: Telomeres are nucleoprotein complexes that cap the ends of linear chromosomes. Telomeric DNA decreases with age and shows considerable heterogeneity in the wider population. There is interest in the application of telomere length measures as a biomarker of general health or "biological age," and the possibility of using mean telomere length to gauge individual disease risk, and to promote lifestyle changes to improve health. This study examined the effectiveness of telomere length as a biomarker for an individual's current overall health status by assessing several measures of general health including SF-36v2 score, current smoking status and a comprehensive obesity phenotype.<br><br>METHODS: Participants were from the Canterbury Health, Ageing and Lifecourse (CHALICE) cohort, a New Zealand population based multidisciplinary study of aging. Telomere length measurements were obtained on DNA from peripheral blood samples at age 49-51 (n&#x2009;=&#x2009;351), using a quantitative polymerase chain reaction assay.<br><br>RESULTS: No associations were found between telomere length measured at age 49-51 and any measures of current health status. The only significant association observed was between telomere length and gender, with females having longer telomere length than men.<br><br>CONCLUSIONS: Our results suggest that telomere length measurements are unlikely to provide information of much predictive significance for an individual's health status.},
}
@article {pmid27562105,
year = {2016},
author = {Joyce, BT and Hou, L},
title = {Telomere Length: The Intersection of Sociology, Molecular Biology, and Human Disease.},
journal = {EBioMedicine},
volume = {11},
number = {},
pages = {27-28},
pmid = {27562105},
issn = {2352-3964},
support = {P30 CA060553/CA/NCI NIH HHS/United States ; },
mesh = {Ethnicity/*genetics ; *Genetic Predisposition to Disease ; Humans ; Telomere/*genetics ; *Telomere Homeostasis ; United States ; },
}
@article {pmid27559927,
year = {2017},
author = {Ahmad, T and Sundar, IK and Tormos, AM and Lerner, CA and Gerloff, J and Yao, H and Rahman, I},
title = {Shelterin Telomere Protection Protein 1 Reduction Causes Telomere Attrition and Cellular Senescence via Sirtuin 1 Deacetylase in Chronic Obstructive Pulmonary Disease.},
journal = {American journal of respiratory cell and molecular biology},
volume = {56},
number = {1},
pages = {38-49},
pmid = {27559927},
issn = {1535-4989},
support = {P20 GM103652/GM/NIGMS NIH HHS/United States ; P30 ES001247/ES/NIEHS NIH HHS/United States ; R01 HL085613/HL/NHLBI NIH HHS/United States ; },
mesh = {Acetylation ; Animals ; Cells, Cultured ; *Cellular Senescence ; DNA Damage ; DNA-Binding Proteins/*metabolism ; Epithelial Cells/metabolism/pathology ; Fibroblasts/metabolism/pathology ; Humans ; Lung/metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Protein Binding ; Pulmonary Disease, Chronic Obstructive/*metabolism/*pathology ; Pulmonary Emphysema/metabolism/pathology ; Shelterin Complex/*metabolism ; Sirtuin 1/*metabolism ; Smoking/adverse effects ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Lung cellular senescence and inflammatory response are the key events in the pathogenesis of chronic obstructive pulmonary disease (COPD) when cigarette smoke (CS) is the main etiological factor. Telomere dysfunction is induced by either critical shortening or disruption of the shelterin complex, leading to cellular senescence. However, it remains unknown whether disruption of the shelterin complex is responsible for CS-induced lung cellular senescence. Here we show that telomere protection protein 1 (TPP1) levels are reduced on telomeres in lungs from mice with emphysema, as well as in lungs from smokers and from patients with COPD. This is associated with persistent telomeric DNA damage, leading to cellular senescence. CS disrupts the interaction of TPP1 with the Sirtuin 1 (Sirt1) complex, leading to increased TPP1 acetylation and degradation. Lung fibroblasts deficient in Sirt1 or treated with a selective Sirt1 inhibitor exhibit increased cellular senescence and decreased TPP1 levels, whereas Sirt1 overexpression and pharmacological activation protect against CS-induced TPP1 reduction and telomeric DNA damage. Our findings support an essential role of TPP1 in protecting CS-induced telomeric DNA damage and cellular senescence, and therefore provide a rationale for a potential therapy for COPD, on the basis of the shelterin complex, in attenuating cellular senescence.},
}
@article {pmid27558653,
year = {2016},
author = {Liu, HJ and Peng, H and Hu, CC and Li, XY and Zhang, JL and Zheng, Z and Zhang, WC},
title = {Effects of donor cells' sex on nuclear transfer efficiency and telomere lengths of cloned goats.},
journal = {Reproduction in domestic animals = Zuchthygiene},
volume = {51},
number = {5},
pages = {789-794},
doi = {10.1111/rda.12752},
pmid = {27558653},
issn = {1439-0531},
mesh = {Animals ; *Cloning, Organism ; DNA/genetics ; Embryo Transfer/veterinary ; Embryo, Mammalian ; Female ; Goats/*genetics ; Male ; Microsatellite Repeats ; Nuclear Transfer Techniques/*veterinary ; Sequence Analysis, DNA/methods ; *Telomere/genetics ; },
abstract = {The aim of this study was to investigate the effects of donor cells' sex on nuclear transfer efficiency and telomere length of cloned goats from adult skin fibroblast cells. The telomere length of somatic cell cloned goats and their offspring was determined by measuring their mean terminal restriction fragment (TRF) length. The result showed that (i) reconstructed embryos with fibroblast cells from males Boer goats obtained significantly higher kids rate and rate of live kids than those of female embryos and (ii) the telomere lengths of four female cloned goats were shorter compared to their donor cells, but five male cloned goats had the same telomere length with their donor cells, mainly due to great variation existed among them. The offspring from female cloned goats had the same telomere length with their age-matched counterparts. In conclusion, the donor cells' sex had significant effects on nuclear transfer efficiency and telomere lengths of cloned goats.},
}
@article {pmid27558579,
year = {2016},
author = {Fretts, AM and Howard, BV and Siscovick, DS and Best, LG and Beresford, SA and Mete, M and Eilat-Adar, S and Sotoodehnia, N and Zhao, J},
title = {Processed Meat, but Not Unprocessed Red Meat, Is Inversely Associated with Leukocyte Telomere Length in the Strong Heart Family Study.},
journal = {The Journal of nutrition},
volume = {146},
number = {10},
pages = {2013-2018},
pmid = {27558579},
issn = {1541-6100},
support = {R01 DK091369/DK/NIDDK NIH HHS/United States ; UL1 TR001409/TR/NCATS NIH HHS/United States ; R01 HL109284/HL/NHLBI NIH HHS/United States ; KL2 TR002317/TR/NCATS NIH HHS/United States ; KL2 TR000421/TR/NCATS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Biomarkers/blood ; Body Mass Index ; Cardiovascular Diseases/prevention &amp; control ; Cohort Studies ; Cross-Sectional Studies ; Diet ; Exercise ; Female ; Humans ; Leukocytes/*chemistry ; Life Style ; Lipids/blood ; Male ; *Meat Products ; Middle Aged ; Nutrition Assessment ; *Red Meat ; Risk Factors ; Surveys and Questionnaires ; Telomere/*ultrastructure ; Waist Circumference ; Young Adult ; },
abstract = {BACKGROUND: Telomeres are repetitive nucleotide sequences (TTAGGG) and their associated proteins at the end of eukaryote chromosomes. Telomere length shortens throughout the lifespan with each cell division, and leukocyte telomere length (LTL) is often used as a biomarker of cellular aging. LTL is related to many chronic diseases, including cardiovascular disease and diabetes. However, to our knowledge, the relation between LTL and risk factors for cardiovascular disease and diabetes, such as dietary intake of processed meat and unprocessed red meat, is largely unknown.<br><br>OBJECTIVE: We examined the associations of processed meat intake and unprocessed red meat intake with LTL.<br><br>METHODS: This cross-sectional study comprised 2846 American Indians from the Strong Heart Family Study who participated in the 2001-2003 examination. Dietary factors, including past-year consumption of processed meat and unprocessed red meat, were assessed with the use of a 119-item Block Food-Frequency Questionnaire. LTL was measured with the use of quantitative polymerase chain reaction. Generalized estimating equations were used to examine the associations of intake of processed meat and unprocessed red meat with LTL.<br><br>RESULTS: Consumption of processed meat was negatively associated with LTL after adjustment for age, sex, site, education, smoking, alcohol use, physical activity, and other dietary factors. For every additional daily serving of processed meat, LTL was 0.021 units (telomeric product-to-single-copy gene ratio) shorter (&#x3b2; &#xb1; SE = -0.021 &#xb1; 0.008, P = 0.009). No association was observed between the intake of unprocessed red meat and LTL (&#x3b2; &#xb1; SE = 0.008 &#xb1; 0.011, P = 0.46).<br><br>CONCLUSIONS: In the Strong Heart Family Study, consumption of processed meat, but not unprocessed red meat, was associated with shorter LTL, a potential mediator for several age-related diseases. Further studies are needed to better understand the biological mechanism by which processed meat intake influences cellular aging.},
}
@article {pmid27558242,
year = {2016},
author = {Bao, D and Ba, Y and Zhou, F and Zhao, J and Yang, Q and Ge, N and Guo, X and Wu, Z and Zhang, H and Yang, H and Wan, S and Xing, J},
title = {Alterations of telomere length and mtDNA copy number are associated with overall survival in hepatocellular carcinoma patients treated with transarterial chemoembolization.},
journal = {Cancer chemotherapy and pharmacology},
volume = {78},
number = {4},
pages = {791-799},
doi = {10.1007/s00280-016-3128-1},
pmid = {27558242},
issn = {1432-0843},
mesh = {Adult ; Aged ; Carcinoma, Hepatocellular/*genetics/*therapy ; DNA, Mitochondrial/*genetics ; Disease-Free Survival ; Embolization, Therapeutic ; Female ; Gene Dosage/*genetics ; Humans ; Kaplan-Meier Estimate ; Leukocytes/ultrastructure ; Liver Neoplasms/*genetics/*therapy ; Male ; Middle Aged ; Prognosis ; Survival ; Survival Analysis ; Telomere Shortening/*genetics ; },
abstract = {PURPOSE: Increasing evidence suggests that alterations in mitochondrial DNA (mtDNA) copy number (mtDNAcn) and relative telomere length (RTL) may be implicated in the tumorigenesis of several malignancies. Alterations of both RTL and mtDNAcn are generally accepted as independent biomarkers for predicting risk and prognosis in various cancers. The aim of this study was to evaluate the prognostic value of combining leukocyte RTL with mtDNAcn (RTL-mtDNAcn) in hepatocellular carcinoma (HCC).<br><br>METHODS: RTL and mtDNAcn in peripheral blood leukocytes (PBLs) were measured using a real-time PCR-based method in a total of 250 HCC patients treated with transcatheter arterial chemoembolization (TACE). We evaluated the associations between RTL and/or mtDNAcn and HCC overall survival using Kaplan-Meier curve analysis and Cox proportional hazards regression model.<br><br>RESULTS: We found that patients with longer leukocyte RTL or lower mtDNAcn had shorter overall survival time. The univariate analysis (HR&#xa0;1.63, 95&#xa0;% CI 1.23-2.17, P&#xa0;=&#xa0;7.7&#xa0;&#xd7;&#xa0;10(-4)) and multivariate analysis (HR&#xa0;1.78, 95&#xa0;% CI 1.31-2.42, P&#xa0;=&#xa0;2.4&#xa0;&#xd7;&#xa0;10(-4)) indicated that longer leukocyte RTL was significantly associated with poorer OS in HCC patients. Kaplan-Meier curve analysis showed that patients with longer RTL had shorter overall survival time than those with shorter RTL (log-rank P&#xa0;=&#xa0;0.001). Patients with lower mtDNA copy number was significantly associated with poorer OS by Cox proportional hazards model using both univariate (HR&#xa0;1.60, 95&#xa0;% CI 1.21-2.13, P&#xa0;=&#xa0;0.001) and multivariate analyses (HR&#xa0;1.77, 95&#xa0;% CI 1.30-2.41, P&#xa0;=&#xa0;2.8&#xa0;&#xd7;&#xa0;10(-4)). Kaplan-Meier curve analysis showed that patients with lower mtDNA content had significantly shorter overall survival time than those with higher mtDNA content (log-rank P&#xa0;=&#xa0;0.001). Furthermore, combination of leukocyte RTL and mtDNAcn significantly improved the efficacy of predicting HCC prognosis. Patients with longer RTL and lower mtDNAcn exhibited a significantly poorer overall survival in both the univariate analysis (HR&#xa0;2.21, 95&#xa0;% CI 1.52-3.22, P&#xa0;=&#xa0;3.5&#xa0;&#xd7;&#xa0;10(-5)) and multivariate analysis (HR&#xa0;2.60, 95&#xa0;% CI 1.73-3.90, P&#xa0;=&#xa0;4.3&#xa0;&#xd7;&#xa0;10(-6)). The effect on patient prognosis was more evident in patients with longer RTL and lower mtDNAcn than in those with shorter RTL and lower mtDNA (HR&#xa0;2.11, 95&#xa0;% CI 1.34-3.32, P&#xa0;=&#xa0;0.001) or in those with longer RTL and higher mtDNA (HR&#xa0;2.10, 95&#xa0;% CI 1.34-3.27, P&#xa0;=&#xa0;0.001).<br><br>CONCLUSIONS: Our data suggest that combination of leukocyte RTL-mtDNAcn may be a potential efficient prognostic marker for HCC patients receiving the TACE treatment.},
}
@article {pmid27557682,
year = {2016},
author = {Graham, N and Swyers, N and Cody, J and McCaw, M and Zhao, C and Birchler, JA},
title = {Production of Engineered Minichromosome Vectors via the Introduction of Telomere Sequences.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1469},
number = {},
pages = {1-13},
doi = {10.1007/978-1-4939-4931-1_1},
pmid = {27557682},
issn = {1940-6029},
mesh = {Agrobacterium tumefaciens/genetics ; *Chromosomes, Artificial ; Genetic Engineering/*methods ; Genetic Vectors/*genetics ; Plants, Genetically Modified/genetics ; Polymerase Chain Reaction/methods ; *Telomere ; Transgenes ; },
abstract = {Artificial minichromosomes are non-integrating vectors capable of stably maintaining transgenes outside of the main chromosome set. The production of minichromosomes relies on telomere-mediated chromosomal truncation, which involves introducing transgenes and telomere sequences concurrently to the cell to truncate an endogenous chromosomal target. Two methods can be utilized; either the telomere sequences can be incorporated into a binary vector for transformation with Agrobacterium tumefaciens, or the telomere sequences can be co-introduced with transgenes during particle bombardment. In this protocol, the methods required to isolate and introduce telomere sequences are presented. Following the methods presented, standard transformation procedures can be followed to produce minichromosome containing plants.},
}
@article {pmid27552709,
year = {2016},
author = {He, Y and Zhang, X and Li, X and Du, J and He, X and Zhang, Z and Zhang, Y and Kang, L and Jin, T and Yuan, D},
title = {Telomere length-related gene ACYP2 polymorphism is associated with the risk of HAPE in Chinese Han population.},
journal = {The journal of gene medicine},
volume = {18},
number = {9},
pages = {244-249},
doi = {10.1002/jgm.2896},
pmid = {27552709},
issn = {1521-2254},
mesh = {Acid Anhydride Hydrolases/*genetics ; Adult ; Alleles ; Altitude Sickness/ethnology/*genetics ; Asian People/genetics ; Case-Control Studies ; Chi-Square Distribution ; China ; Female ; Gene Frequency ; Genetic Predisposition to Disease/ethnology/*genetics ; Genotype ; Humans ; Hypertension, Pulmonary/ethnology/*genetics ; Male ; *Polymorphism, Single Nucleotide ; Risk Factors ; Telomere/*genetics ; Young Adult ; },
abstract = {BACKGROUND: High altitude pulmonary edema (HAPE) is a type of pneumonedema that mostly occurs under conditions such as high altitude, rapid ascent and hypoxia, amongst others. The ACYP2 polymorphism is suggested to be associated with mean telomere length, and telomere length is significantly longer at a moderate attitude than at sea-level or at simulated high attitude. The present study aimed to determine whethher there is any association between ACYP2 polymorphism and the risk of HAPE.<br><br>METHODS: A total of 265 patients and 303 healthy controls were enrolled in our case-control study. Six SNPs were selected and genotyped using the Sequenom MassARRAY method. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by unconditional logistic regression with adjustment for gender and age.<br><br>RESULTS: Using chi-squared tests, we found that the minor allele G of rs11896604 is significantly associated with a decreased risk of HAPE [odds ratio (OR)&#x2009;=&#x2009;0.87, 95% confidence interval (CI)&#x2009;=&#x2009;0.65-1.16, p&#x2009;=&#x2009;0.048]. We also found that the 'A/A' genotype of rs12615793 is associated with a decreased risk of HAPE based on the recessive model (OR =0.28; 95% CI&#x2009;=&#x2009;0.09-0.88; p&#x2009;=&#x2009;0.017). Additionally, the 'G/G' genotype of rs11896604 was found to be associated with a decreased risk of HAPE based on the codominant model (OR =0.26; 95% CI&#x2009;=&#x2009;0.08-0.79; p&#x2009;=&#x2009;0.025) and recessive model (OR =0.25; 95% CI&#x2009;=&#x2009;0.08-0.77; p&#x2009;=&#x2009;0.007). However, only rs11896604 remained significant after Bonferroni correction (p&#x2009;<&#x2009;0.0083).<br><br>CONCLUSIONS: The present study found that the ACYP2 gene polymorphism significantly decreased the risk of HAPE. Copyright &#xa9; 2016 John Wiley &amp; Sons, Ltd. Copyright &#xa9; 2016 John Wiley &amp; Sons, Ltd.},
}
@article {pmid27550625,
year = {2017},
author = {Lee, JY and Shin, C and Baik, I},
title = {Longitudinal associations between micronutrient consumption and leukocyte telomere length.},
journal = {Journal of human nutrition and dietetics : the official journal of the British Dietetic Association},
volume = {30},
number = {2},
pages = {236-243},
doi = {10.1111/jhn.12403},
pmid = {27550625},
issn = {1365-277X},
mesh = {Adult ; Aged ; *Aging ; Body Mass Index ; Diet ; Female ; Follow-Up Studies ; Health Behavior ; Humans ; Leukocytes/*physiology ; Longitudinal Studies ; Male ; Micronutrients/*administration &amp; dosage ; Middle Aged ; Nutrition Assessment ; Surveys and Questionnaires ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: There are few studies on the association between nutrient intake and telomere length, which may reflect cumulative oxidative stress and indicate biological ageing. In the present study, we evaluated longitudinal associations between the consumption of micronutrients, including antioxidant nutrients and B vitamins involved in one-carbon transfer pathways, and leukocyte telomere length (LTL).<br><br>METHODS: The study included 1958 middle-aged and older Korean men and women (age range at baseline: 40-69 years) from a population-based cohort. We collected dietary information at baseline using a semiquantitative food frequency questionnaire (June 2001 to January 2003) and assessed the consumption of micronutrients, including vitamins A, B1 , B2 , B3 , B6 , B9 (folate), C and E, as well as calcium, phosphorus, potassium, iron and zinc. We measured LTL using a real-time polymerase chain reaction at the 10-year follow-up examination (February 2011 to November 2012).<br><br>RESULTS: In the multiple regression model adjusted for potential confounders, LTL was positively associated with the consumption of vitamin C (P < 0.05), folate (P = 0.05) and potassium (P = 0.05) in all participants. In the age-stratified analysis, the association between the consumption of vitamin C (P < 0.01), folate (P < 0.05) and potassium (P < 0.05) with LTL was significant only among participants aged <50 years.<br><br>CONCLUSIONS: Our findings suggest that the earlier consumption of vitamin C, folate and potassium, which are abundant in fruits and vegetables, can delay biological ageing in middle-aged and older adults.},
}
@article {pmid27550225,
year = {2016},
author = {Scheffold, A and Holtman, IR and Dieni, S and Brouwer, N and Katz, SF and Jebaraj, BM and Kahle, PJ and Hengerer, B and Lechel, A and Stilgenbauer, S and Boddeke, EW and Eggen, BJ and Rudolph, KL and Biber, K},
title = {Telomere shortening leads to an acceleration of synucleinopathy and impaired microglia response in a genetic mouse model.},
journal = {Acta neuropathologica communications},
volume = {4},
number = {1},
pages = {87},
pmid = {27550225},
issn = {2051-5960},
mesh = {Animals ; Brain Stem/*metabolism/pathology ; Disease Progression ; Humans ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/*metabolism/pathology ; Motor Activity/physiology ; Parkinsonian Disorders/*metabolism/pathology ; Phenotype ; Postural Balance/physiology ; Protein Aggregation, Pathological/metabolism/pathology ; RNA, Messenger/metabolism ; Telomere Shortening/*physiology ; Time Factors ; alpha-Synuclein/*metabolism ; },
abstract = {Parkinson's disease is one of the most common neurodegenerative disorders of the elderly and ageing hence described to be a major risk factor. Telomere shortening as a result of the inability to fully replicate the ends of linear chromosomes is one of the hallmarks of ageing. The role of telomere dysfunction in neurological diseases and the ageing brain is not clarified and there is an ongoing discussion whether telomere shortening is linked to Parkinson's disease. Here we studied a mouse model of Parkinson's disease (Thy-1 [A30P] α-synuclein transgenic mouse model) in the background of telomere shortening (Terc knockout mouse model). α-synuclein transgenic mice with short telomeres (αSYN(tg/tg) G3Terc(-/-)) developed an accelerated disease with significantly decreased survival. This accelerated phenotype of mice with short telomeres was characterized by a declined motor performance and an increased formation of α-synuclein aggregates. Immunohistochemical analysis and mRNA expression studies revealed that the disease end-stage brain stem microglia showed an impaired response in αSYN(tg/tg) G3Terc(-/-) microglia animals. These results provide the first experimental data that telomere shortening accelerates α-synuclein pathology that is linked to limited microglia function in the brainstem.},
}
@article {pmid27545506,
year = {2016},
author = {Woo, DH and Chen, Q and Yang, TL and Glineburg, MR and Hoge, C and Leu, NA and Johnson, FB and Lengner, CJ},
title = {Enhancing a Wnt-Telomere Feedback Loop Restores Intestinal Stem Cell Function in a Human Organotypic Model of Dyskeratosis Congenita.},
journal = {Cell stem cell},
volume = {19},
number = {3},
pages = {397-405},
pmid = {27545506},
issn = {1875-9777},
support = {P01 AG031862/AG/NIA NIH HHS/United States ; P30 DK050306/DK/NIDDK NIH HHS/United States ; R21 AG054209/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cell Differentiation/drug effects ; Dyskeratosis Congenita/metabolism/*pathology ; *Feedback, Physiological/drug effects ; HEK293 Cells ; Humans ; Intestines/*cytology ; Lithium/pharmacology ; Mice ; *Models, Biological ; Organoids/drug effects/*metabolism ; Phenotype ; Stem Cells/drug effects/*metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; *Wnt Signaling Pathway/drug effects ; },
abstract = {Patients with dyskeratosis congenita (DC) suffer from stem cell failure in highly proliferative tissues, including the intestinal epithelium. Few therapeutic options exist for this disorder, and patients are treated primarily with bone marrow transplantation to restore hematopoietic function. Here, we generate isogenic DC patient and disease allele-corrected intestinal tissue using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated gene correction in induced pluripotent stem cells and directed differentiation. We show that DC tissue has suboptimal Wnt pathway activity causing intestinal stem cell failure and that enhanced expression of the telomere-capping protein TRF2, a Wnt target gene, can alleviate DC phenotypes. Treatment with the clinically relevant Wnt agonists LiCl or CHIR99021 restored TRF2 expression and reversed gastrointestinal DC phenotypes, including organoid formation in vitro, and maturation of intestinal tissue and xenografted organoids in vivo. Thus, the isogenic DC cell model provides a platform for therapeutic discovery and identifies Wnt modulation as a potential strategy for treatment of DC patients.},
}
@article {pmid27540018,
year = {2016},
author = {Newton, CA and Batra, K and Torrealba, J and Kozlitina, J and Glazer, CS and Aravena, C and Meyer, K and Raghu, G and Collard, HR and Garcia, CK},
title = {Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive.},
journal = {The European respiratory journal},
volume = {48},
number = {6},
pages = {1710-1720},
pmid = {27540018},
issn = {1399-3003},
support = {R01 HL093096/HL/NHLBI NIH HHS/United States ; T32 HL098040/HL/NHLBI NIH HHS/United States ; UL1 TR001105/TR/NCATS NIH HHS/United States ; },
mesh = {Aged ; DNA Helicases/genetics ; Exoribonucleases/genetics ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/*diagnosis/*genetics/surgery ; Linear Models ; Lung Transplantation ; Male ; Middle Aged ; Mutation ; RNA/genetics ; Telomerase/genetics ; Telomere/*genetics ; Texas ; Tomography, X-Ray Computed ; },
abstract = {Heterozygous mutations in four telomere-related genes have been linked to pulmonary fibrosis, but little is known about similarities or differences of affected individuals.115 patients with mutations in telomerase reverse transcriptase (TERT) (n=75), telomerase RNA component (TERC) (n=7), regulator of telomere elongation helicase 1 (RTEL1) (n=14) and poly(A)-specific ribonuclease (PARN) (n=19) were identified and clinical data were analysed.Approximately one-half (46%) had a multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF); others had unclassifiable lung fibrosis (20%), chronic hypersensitivity pneumonitis (12%), pleuroparenchymal fibroelastosis (10%), interstitial pneumonia with autoimmune features (7%), an idiopathic interstitial pneumonia (4%) and connective tissue disease-related interstitial fibrosis (3%). Discordant interstitial lung disease diagnoses were found in affected individuals from 80% of families. Patients with TERC mutations were diagnosed at an earlier age than those with PARN mutations (51±11 years versus 64±8 years; p=0.03) and had a higher incidence of haematological comorbidities. The mean rate of forced vital capacity decline was 300 mL·year[-1] and the median time to death or transplant was 2.87 years. There was no significant difference in time to death or transplant for patients across gene mutation groups or for patients with a diagnosis of IPF versus a non-IPF diagnosis.Genetic mutations in telomere related genes lead to a variety of interstitial lung disease (ILD) diagnoses that are universally progressive.},
}
@article {pmid27539745,
year = {2016},
author = {Lieberman, PM},
title = {Retrotransposon-derived p53 binding sites enhance telomere maintenance and genome protection.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {38},
number = {10},
pages = {943-949},
pmid = {27539745},
issn = {1521-1878},
support = {P30 CA010815/CA/NCI NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; *Genomic Instability ; Humans ; Mice ; *Retroelements ; Telomere/genetics/*metabolism ; Telomere Homeostasis ; Tumor Suppressor Protein p53/*metabolism ; },
abstract = {Tumor suppressor protein 53 (p53) plays a central role in the control of genome stability, acting primarily through the transcriptional activation of stress-response genes. However, many p53 binding sites are located at genomic locations with no obvious regulatory-link to known stress-response genes. We recently discovered p53 binding sites within retrotransposon-derived elements in human and mouse subtelomeres. These retrotransposon-derived p53 binding sites protected chromosome ends through transcription activation of telomere repeat RNA, as well as through the direct modification of local chromatin structure in response to DNA damage. Based on these findings, I hypothesize that a class of p53 binding sites, including the retrotransposon-derived p53-sites found in subtlomeres, provide a primary function in genome stability by mounting a direct and local protective chromatin-response to DNA damage. I speculate that retrotransposon-derived p53 binding sites share features with telomere-repeats through an evolutionary drive to monitor and maintain genome integrity.},
}
@article {pmid27538365,
year = {2016},
author = {Toledo, F},
title = {p53: A two-faced regulator of telomere metabolism? (comment on DOI 10.1002/bies.201600078).},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {38},
number = {10},
pages = {938},
doi = {10.1002/bies.201600149},
pmid = {27538365},
issn = {1521-1878},
mesh = {Humans ; *Telomere ; *Tumor Suppressor Protein p53 ; },
}
@article {pmid27537914,
year = {2016},
author = {Kreilmeier, T and Mejri, D and Hauck, M and Kleiter, M and Holzmann, K},
title = {Telomere Transcripts Target Telomerase in Human Cancer Cells.},
journal = {Genes},
volume = {7},
number = {8},
pages = {},
pmid = {27537914},
issn = {2073-4425},
abstract = {Long non-coding transcripts from telomeres, called telomeric repeat-containing RNA (TERRA), were identified as blocking telomerase activity (TA), a telomere maintenance mechanism (TMM), in tumors. We expressed recombinant TERRA transcripts in tumor cell lines with TA and with alternative lengthening of telomeres (ALT) to study effects on TMM and cell growth. Adeno- and lentivirus constructs (AV and LV) were established for transient and stable expression of approximately 130 units of telomere hexanucleotide repeats under control of cytomegalovirus (CMV) and human RNase P RNA H1 (hH1) promoters with and without polyadenylation, respectively. Six human tumor cell lines either using telomerase or ALT were infected and analyzed for TA levels. Pre-infection cells using telomerase had 1%-3% of the TERRA expression levels of ALT cells. AV and LV expression of recombinant TERRA in telomerase positive cells showed a 1.3-2.6 fold increase in TERRA levels, and a decrease in TA of 25%-58%. Dominant-negative or small hairpin RNA (shRNA) viral expression against human telomerase reverse transcriptase (hTERT) results in senescence, not induced by TERRA expression. Population doubling time, cell viability and TL (telomere length) were not impacted by ectopic TERRA expression. Clonal growth was reduced by TERRA expression in TA but not ALT cell lines. ALT cells were not affected by treatments applied. Established cell models and tools may be used to better understand the role of TERRA in the cell, especially for targeting telomerase.},
}
@article {pmid27536146,
year = {2016},
author = {Qian, D and Cheng, J and Ding, X and Chen, X and Chen, X and Guan, Y and Zhang, B and Wang, J and Er, P and Qiu, M and Zeng, X and Guo, Y and Wang, H and Zhao, L and Xie, D and Yuan, Z and Wang, P and Pang, Q},
title = {PinX1 suppresses tumorigenesis by negatively regulating telomerase/telomeres in colorectal carcinoma cells and is a promising molecular marker for patient prognosis.},
journal = {OncoTargets and therapy},
volume = {9},
number = {},
pages = {4821-4831},
pmid = {27536146},
issn = {1178-6930},
abstract = {PinX1 plays positive and negative roles in the maintenance of telomerase and telomeres, as well as in tumorigenesis. The aim of the present study was to investigate the expression and clinical significance of PinX1 in colorectal carcinoma (CRC) and to determine the effect of PinX1 on CRC cell proliferation and apoptosis. A total of 86 CRC patients treated with radical resection and 5-fluorouracil-based adjuvant chemotherapy were enrolled in this study. The expression dynamics of PinX1 was detected by immunohistochemistry in the CRC patients and 25 normal colonic mucosa controls. PinX1 expression was significantly reduced in tumor tissues as compared to normal tissues, and the rate of PinX1 protein low/negative expression in CRC and normal tissues was 60% (52/86) and 24% (6/25), respectively (P=0.037). In addition, PinX1 downregulation was significantly associated with short overall survival (P=0.016) and disease-free survival (P=0.042) in CRC patients. Cox proportional hazards model further revealed that PinX1 expression was an independent factor in predicting overall survival and disease-free survival for CRC patients. Furthermore, we demonstrated that ectopic overexpression of PinX1 in CRC cells inhibited their proliferation, promoted apoptosis, repressed telomerase activity, and induced telomere shortening. These findings suggest that PinX1 may be a prognostic biomarker for CRC patients' survival and that it inhibits cell proliferation and promotes apoptosis by repressing telomerase activity and inducing telomere shortening. Targeting PinX1 may therefore provide a novel therapeutic strategy for CRC patients.},
}
@article {pmid27535986,
year = {2016},
author = {Hoelzl, F and Cornils, JS and Smith, S and Moodley, Y and Ruf, T},
title = {Telomere dynamics in free-living edible dormice (Glis glis): the impact of hibernation and food supply.},
journal = {The Journal of experimental biology},
volume = {219},
number = {Pt 16},
pages = {2469-2474},
pmid = {27535986},
issn = {1477-9145},
mesh = {Animals ; Body Temperature/physiology ; Feeding Behavior/physiology ; *Food Supply ; Hibernation/*physiology ; Myoxidae/*physiology ; Seasons ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {We studied the impact of hibernation and food supply on relative telomere length (RTL), an indicator for aging and somatic maintenance, in free-living edible dormice. Small hibernators such as dormice have ∼50% higher maximum longevity than non-hibernators. Increased longevity could theoretically be due to prolonged torpor directly slowing cellular damage and RTL shortening. However, although mitosis is arrested in mammals at low body temperatures, recent evidence points to accelerated RTL shortening during periodic re-warming (arousal) from torpor. Therefore, we hypothesized that these arousals during hibernation should have a negative effect on RTL. Here, we show that RTL was shortened in all animals over the course of ∼1 year, during which dormice hibernated for 7.5-11.4 months. The rate of periodic arousals, rather than the time spent euthermic during the hibernation season, was the best predictor of RTL shortening. This finding points to negative effects on RTL of the transition from low torpor to high euthermic body temperature and metabolic rate during arousals, possibly because of increased oxidative stress. The animals were, however, able to elongate their telomeres during the active season, when food availability was increased by supplemental feeding in a year of low natural food abundance. We conclude that in addition to their energetic costs, periodic arousals also lead to accelerated cellular damage in terms of RTL shortening. Although dormice are able to counteract and even over-compensate for the negative effects of hibernation, restoration of RTL appears to be energetically costly.},
}
@article {pmid27532233,
year = {2016},
author = {Baragetti, A and Palmen, J and Garlaschelli, K and Grigore, L and Humphries, SE and Talmud, PJ and Catapano, AL and Norata, GD},
title = {Genetically determined telomeres shortening is associated with carotid atherosclerosis progression and increased incidence of cardiovascular events.},
journal = {International journal of cardiology},
volume = {223},
number = {},
pages = {43-45},
doi = {10.1016/j.ijcard.2016.08.164},
pmid = {27532233},
issn = {1874-1754},
support = {RG/08/008/25291/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Asymptomatic Diseases ; *Cardiovascular Diseases/epidemiology/etiology ; *Carotid Artery Diseases/complications/diagnosis/genetics ; Carotid Intima-Media Thickness ; Disease Progression ; Humans ; Incidence ; Membrane Proteins/*genetics ; Neoplasm Proteins/*genetics ; Polymorphism, Single Nucleotide ; RNA/*genetics ; Risk Factors ; Statistics as Topic ; Telomerase/*genetics ; Telomere Shortening/*genetics ; },
}
@article {pmid27531349,
year = {2016},
author = {Montero, JJ and López de Silanes, I and Graña, O and Blasco, MA},
title = {Telomeric RNAs are essential to maintain telomeres.},
journal = {Nature communications},
volume = {7},
number = {},
pages = {12534},
pmid = {27531349},
issn = {2041-1723},
mesh = {Base Sequence ; CRISPR-Cas Systems/genetics ; Cell Line ; Chromosomes, Human, Pair 20/genetics ; Chromosomes, Human, X/genetics ; Genetic Loci ; Genotype ; Humans ; RNA/*metabolism ; RNA, Long Noncoding ; RNA, Messenger/genetics/metabolism ; Sequence Deletion ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Telomeres are transcribed generating long non-coding RNAs known as TERRA. Deciphering the role of TERRA has been one of the unsolved issues of telomere biology in the past decade. This has been, in part, due to lack of knowledge on the TERRA loci, thus preventing functional genetic studies. Here, we describe that long non-coding RNAs with TERRA features are transcribed from the human 20q and Xp subtelomeres. Deletion of the 20q locus by using the CRISPR-Cas9 technology causes a dramatic decrease in TERRA levels, while deletion of the Xp locus does not result in decreased TERRA levels. Strikingly, 20q-TERRA ablation leads to dramatic loss of telomere sequences and the induction of a massive DNA damage response. These findings identify chromosome 20q as a main TERRA locus in human cells and represent the first demonstration in any organism of the essential role of TERRA in the maintenance of telomeres.},
}
@article {pmid27530475,
year = {2017},
author = {Rafie, N and Golpour Hamedani, S and Barak, F and Safavi, SM and Miraghajani, M},
title = {Dietary patterns, food groups and telomere length: a systematic review of current studies.},
journal = {European journal of clinical nutrition},
volume = {71},
number = {2},
pages = {151-158},
pmid = {27530475},
issn = {1476-5640},
mesh = {Aging/*genetics ; Diet, Mediterranean ; Eating/*genetics ; Feeding Behavior/*physiology ; Humans ; Telomere/*physiology ; *Telomere Homeostasis ; },
abstract = {UNLABELLED: Telomere length (TL) is recognized as a biomarker of aging and shorter telomeres are linked with shorter lifespan. Inter-individual variability in telomere length is highly heritable. However, there has been a resurgence of interest in the controversial relationship between diet and TL. Evaluating the impact of diet at the food group and dietary pattern level will provide greater insight into the effect of diet on TL dynamics, which are of significant importance in health and longevity. This article reports the first systematic review of the relation between food groups, dietary patterns and TL in human populations based on PRISMA guidelines.<br><br>DESIGN: PubMed, Science Direct, The Cochrane Library and Google Scholar databases were electronically searched for all relevant studies, up to November 2015. Among the 17 included studies, 3 and 10 of them were regarding the effect of dietary patterns and various food groups on TL, respectively. Also, in 4 studies, both dietary patterns and different food groups were assessed in relation to TL. Mediterranean dietary pattern was related to longer TL in 3 studies. Five studies indicated beneficial effect of fruits or vegetables on TL. In 7 studies, a reverse association between TL and intake of cereals, processed meat, and fats and oils was reported. Our systematic review supports the health benefits of adherence to Mediterranean diet on TL. Except for the fruits and vegetables, which showed positive association with TL, results were inconsistent for other dietary factors. Also, certain food categories including processed meat, cereals and sugar-sweetened beverages may be associated with shorter TLs. However, additional epidemiological evidence and clinical trials should be considered in future research in order to develop firm conclusions in this regard.},
}
@article {pmid27530331,
year = {2017},
author = {Borghini, A and Roursgaard, M and Andreassi, MG and Kermanizadeh, A and Møller, P},
title = {Repair activity of oxidatively damaged DNA and telomere length in human lung epithelial cells after exposure to multi-walled carbon nanotubes.},
journal = {Mutagenesis},
volume = {32},
number = {1},
pages = {173-180},
doi = {10.1093/mutage/gew036},
pmid = {27530331},
issn = {1464-3804},
mesh = {A549 Cells ; DNA/metabolism ; DNA Damage ; DNA Repair/*drug effects ; Epithelial Cells/*drug effects/metabolism ; Humans ; Lung ; Nanotubes, Carbon/*toxicity ; Oxidative Stress ; Telomere/*drug effects ; },
abstract = {One type of carbon nanotubes (CNTs) (MWCNT-7, from Mitsui) has been classified as probably carcinogenic to humans, however insufficient data does not warrant the same classification for other types of CNTs. Experimental data indicate that CNT exposure can result in oxidative stress and DNA damage in cultured cells, whereas these materials appear to induce low or no mutagenicity. Therefore, the present study aimed to investigate whether in vitro exposure of cultured airway epithelial cells (A549) to multi-walled CNTs (MWCNTs) could increase the DNA repair activity of oxidatively damaged DNA and drive the cells toward replicative senescence, assessed by attrition of telomeres. To investigate this, H2O2 and KBrO3 were used to induce DNA damage in the cells and the effect of pre-exposure to MWCNT tested for a change in repair activity inside the cells or in the extract of treated cells. The effect of MWCNT exposure on telomere length was investigated for concentration and time response. We report a significantly increased repair activity in A549 cells exposed to MWCNTs compared to non-exposed cells, suggesting that DNA repair activity may be influenced by exposure to MWCNTs. The telomere length was decreased at times longer than 24h, but this decrease was not concentration dependent. The results suggest that the seemingly low mutagenicity of CNTs in cultured cells may be associated with an increased DNA repair activity and a replicative senescence, which may counteract the manifestation of DNA lesions to mutations.},
}
@article {pmid27529270,
year = {2016},
author = {Usadi, B and Bruhn, R and Lin, J and Lee, TH and Blackburn, E and Murphy, EL},
title = {Telomere Length, Proviral Load and Neurologic Impairment in HTLV-1 and HTLV-2-Infected Subjects.},
journal = {Viruses},
volume = {8},
number = {8},
pages = {},
pmid = {27529270},
issn = {1999-4915},
support = {K24 HL075036/HL/NHLBI NIH HHS/United States ; R01 HL062235/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; HTLV-I Infections/*pathology/virology ; HTLV-II Infections/*pathology/virology ; Human T-lymphotropic virus 1/genetics/*isolation &amp; purification ; Human T-lymphotropic virus 2/genetics/*isolation &amp; purification ; Humans ; Male ; Middle Aged ; Proviruses/genetics/*isolation &amp; purification ; *Telomere ; *Viral Load ; },
abstract = {Short or damaged telomeres have been implicated in degenerative conditions. We hypothesized that analysis of telomere length (TL) in human T-cell lymphotropic virus (HTLV) infection and HTLV-associated neuropathy might provide clues to the etiology of HTLV-associated disease and viral dynamics. A subset of 45 human T-cell lymphotropic virus type 1 (HTLV-1), 45 human T-cell lymphotropic virus type 2 (HTLV-2), and 45 seronegative subjects was selected from the larger HTLV Outcomes Study (HOST) cohort, matched on age, sex and race/ethnicity. Telomere-to-single-copy gene (T/S) ratio (a measure of TL) and HTLV-1 and HTLV-2 proviral loads were measured in peripheral blood mononuclear cells (PBMCs) using quantitative PCR (qPCR). Vibration sensation measured by tuning fork during neurologic examinations performed as part of the HOST study allowed for an assessment of peripheral neuropathy. TL was compared between groups using t-tests, linear and logistic regression. Mean T/S ratio was 1.02 ± 0.16 in HTLV-1, 1.03 ± 0.17 in HTLV-2 and 0.99 ± 0.18 in HTLV seronegative subjects (p = 0.322). TL was not associated with HTLV-1 or -2 proviral load. Shorter TL was significantly associated with impaired vibration sense in the HTLV-2 positive group only. Overall, we found no evidence that telomere length was affected by chronic HTLV-1 and HTLV-2 infection. That TL was only associated with peripheral neuropathy in the HTLV-2-positive group is intriguing, but should be interpreted cautiously. Studies with larger sample size and telomere length measurement in lymphocyte subsets may clarify the relationship between TL and HTLV-infection.},
}
@article {pmid27527206,
year = {2016},
author = {Hammerl, JA and Jäckel, C and Lanka, E and Roschanski, N and Hertwig, S},
title = {Binding Specificities of the Telomere Phage ϕKO2 Prophage Repressor CB and Lytic Repressor Cro.},
journal = {Viruses},
volume = {8},
number = {8},
pages = {},
pmid = {27527206},
issn = {1999-4915},
mesh = {Bacteriophages/*enzymology/genetics ; Binding Sites ; DNA, Viral/*metabolism ; Electrophoretic Mobility Shift Assay ; Gene Order ; Genes, Viral ; Operator Regions, Genetic ; Promoter Regions, Genetic ; Protein Binding ; Repressor Proteins/*metabolism ; Substrate Specificity ; Synteny ; Viral Proteins/*metabolism ; },
abstract = {Temperate bacteriophages possess a genetic switch which regulates the lytic and lysogenic cycle. The genomes of the temperate telomere phages N15, PY54, and ϕKO2 harbor a primary immunity region (immB) comprising genes for the prophage repressor (cI or cB), the lytic repressor (cro) and a putative antiterminator (q). The roles of these products are thought to be similar to those of the lambda proteins CI (CI prophage repressor), Cro (Cro repressor), and Q (antiterminator Q), respectively. Moreover, the gene order and the location of several operator sites in the prototype telomere phage N15 and in ϕKO2 are reminiscent of lambda-like phages. We determined binding sites of the ϕKO2 prophage repressor CB and lytic repressor Cro on the ϕKO2 genome in detail by electrophoretic mobility shift assay (EMSA) studies. Unexpectedly, ϕKO2 CB and Cro revealed different binding specificities. CB was bound to three OR operators in the intergenic region between cB and cro, two OL operators between cB and the replication gene repA and even to operators of N15. Cro bound exclusively to the 16 bp operator site OR3 upstream of the ϕKO2 prophage repressor gene. The ϕKO2 genes cB and cro are regulated by several strong promoters overlapping with the OR operators. The data suggest that Cro represses cB transcription but not its own synthesis, as already reported for PY54 Cro. Thus, not only PY54, but also phage ϕKO2 possesses a genetic switch that diverges significantly from the switch of lambda-like phages.},
}
@article {pmid27525486,
year = {2016},
author = {Vogan, JM and Zhang, X and Youmans, DT and Regalado, SG and Johnson, JZ and Hockemeyer, D and Collins, K},
title = {Minimized human telomerase maintains telomeres and resolves endogenous roles of H/ACA proteins, TCAB1, and Cajal bodies.},
journal = {eLife},
volume = {5},
number = {},
pages = {},
pmid = {27525486},
issn = {2050-084X},
support = {R01 CA196884/CA/NCI NIH HHS/United States ; R01 HL079585/HL/NHLBI NIH HHS/United States ; T32 GM007266/GM/NIGMS NIH HHS/United States ; },
mesh = {Coiled Bodies/*metabolism ; Humans ; Molecular Chaperones ; Ribonucleoproteins, Small Nuclear/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {We dissected the importance of human telomerase biogenesis and trafficking pathways for telomere maintenance. Biological stability of human telomerase RNA (hTR) relies on H/ACA proteins, but other eukaryotes use other RNP assembly pathways. To investigate additional rationale for human telomerase assembly as H/ACA RNP, we developed a minimized cellular hTR. Remarkably, with only binding sites for telomerase reverse transcriptase (TERT), minimized hTR assembled biologically active enzyme. TERT overexpression was required for cellular interaction with minimized hTR, indicating that H/ACA RNP assembly enhances endogenous hTR-TERT interaction. Telomere maintenance by minimized telomerase was unaffected by the elimination of the telomerase holoenzyme Cajal body chaperone TCAB1 or the Cajal body scaffold protein Coilin. Surprisingly, wild-type hTR also maintained and elongated telomeres in TCAB1 or Coilin knockout cells, with distinct changes in telomerase action. Overall, we elucidate trafficking requirements for telomerase biogenesis and function and expand mechanisms by which altered telomere maintenance engenders human disease.},
}
@article {pmid27523609,
year = {2016},
author = {Schmidt, JC and Zaug, AJ and Cech, TR},
title = {Live Cell Imaging Reveals the Dynamics of Telomerase Recruitment to Telomeres.},
journal = {Cell},
volume = {166},
number = {5},
pages = {1188-1197.e9},
pmid = {27523609},
issn = {1097-4172},
support = {K99 GM120386/GM/NIGMS NIH HHS/United States ; R01 GM099705/GM/NIGMS NIH HHS/United States ; /HHMI/HHMI/United States ; },
mesh = {Active Transport, Cell Nucleus ; Bacterial Proteins ; CRISPR-Associated Protein 9 ; Cell Line ; Cell Nucleus/enzymology ; Clustered Regularly Interspaced Short Palindromic Repeats ; Coiled Bodies/enzymology ; Endonucleases ; Gene Editing ; Genome, Human ; HeLa Cells ; Humans ; Imaging, Three-Dimensional ; Protein Domains ; S Phase ; Saccharomyces cerevisiae/enzymology/genetics ; Shelterin Complex ; Telomerase/chemistry/*metabolism ; Telomere/chemistry/*enzymology ; Telomere Homeostasis ; Telomere-Binding Proteins/chemistry/metabolism ; },
abstract = {Telomerase maintains genome integrity by adding repetitive DNA sequences to the chromosome ends in actively dividing cells, including 90% of all cancer cells. Recruitment of human telomerase to telomeres occurs during S-phase of the cell cycle, but the molecular mechanism of the process is only partially understood. Here, we use CRISPR genome editing and single-molecule imaging to track telomerase trafficking in nuclei of living human cells. We demonstrate that telomerase uses three-dimensional diffusion to search for telomeres, probing each telomere thousands of times each S-phase but only rarely forming a stable association. Both the transient and stable association events depend on the direct interaction of the telomerase protein TERT with the telomeric protein TPP1. Our results reveal that telomerase recruitment to telomeres is driven by dynamic interactions between the rapidly diffusing telomerase and the chromosome end.},
}
@article {pmid27522147,
year = {2016},
author = {Ling, X and Zhang, G and Chen, Q and Yang, H and Sun, L and Zhou, N and Wang, Z and Zou, P and Wang, X and Cui, Z and Liu, J and Ao, L and Cao, J},
title = {Shorter sperm telomere length in association with exposure to polycyclic aromatic hydrocarbons: Results from the MARHCS cohort study in Chongqing, China and in vivo animal experiments.},
journal = {Environment international},
volume = {95},
number = {},
pages = {79-85},
doi = {10.1016/j.envint.2016.08.001},
pmid = {27522147},
issn = {1873-6750},
mesh = {Animal Experimentation ; Animals ; Apoptosis/drug effects ; Benzo(a)pyrene ; China ; Cohort Studies ; Environmental Exposure ; Humans ; Infertility, Male ; Male ; Polycyclic Aromatic Hydrocarbons/*toxicity/urine ; Pyrenes ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reproductive Health ; Semen ; Semen Analysis ; Spermatozoa/*drug effects ; Students ; Telomere/*drug effects ; Telomere Homeostasis/*drug effects ; Toxicity Tests ; Young Adult ; },
abstract = {It has been well demonstrated that polycyclic aromatic hydrocarbons (PAHs) can cause reproductive toxicity, and shorter telomere length in sperm may be one of the factors causing male infertility. However, whether exposure to PAHs is associated with sperm telomere length (STL) has never been evaluated. The present study aimed to assess the potential association between PAHs exposure and STL, and to explore potential biomarkers that may predict the effects of low-level exposure to PAHs on human sperm. Questionnaires and biological samples were collected from 666 volunteers participating in the Male Reproductive Health in Chongqing College Students (MARHCS) cohort study in 2014. Semen parameters were measured for 656 participants, while urinary PAH metabolites, STL and sperm apoptosis were successfully measured for 492, 444 and 628 participants, respectively. The linear regression analysis revealed that increased levels of urinary 1-hydroxypyrene (1-OHPyr) and 1-hydroxynapthalene (1-OHNap) were associated with decreased STL (-0.385; 95% CI, -0.749, -0.021 for 1-OHPyr; and -0.079; 95% CI, -0.146, -0.011 for 1-OHNap). The significant negative associations remained after adjusting for potential confounders. However, no significant associations were observed between urinary PAH metabolites and semen quality or sperm apoptosis. We also administrated rats with benzo[a]pyrene (B[a]P; 0, 1, 5, and 10mg/kg) for 4weeks and found shorter STL and decreased telomerase expression in germ cells in a dose-dependent manner. In conclusion, environmental exposure to some PAHs may be associated with decreased human STL, and the in vivo animal results also demonstrate the adverse effects of B[a]P on telomere of male germ cells.},
}
@article {pmid27515444,
year = {2016},
author = {Liu, JJ and Cahoon, EK and Linet, MS and Little, MP and Dagnall, CL and Higson, H and Savage, SA and Freedman, DM},
title = {Relationship between plasma 25-hydroxyvitamin D and leucocyte telomere length by sex and race in a US study.},
journal = {The British journal of nutrition},
volume = {116},
number = {6},
pages = {953-960},
pmid = {27515444},
issn = {1475-2662},
support = {ZIA CP010135/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; *Leukocytes ; Logistic Models ; Male ; Middle Aged ; *Racial Groups ; Sex Factors ; Telomere Homeostasis/*physiology ; United States ; Vitamin D/*analogs &amp; derivatives/blood ; },
abstract = {A few studies have examined the association between vitamin D and telomere length, and fewer still have examined the relationship in black or male populations. We investigated the cross-sectional association between the vitamin D metabolite 25-hydroxyvitamin D (25(OH)D) concentration in plasma and relative leucocyte telomere length (LTL) in 1154 US radiologic technologists who were 48-93 years old (373 white females, 278 white males, 338 black females, 165 black males). Plasma 25(OH)D concentration was measured by the chemiluminescence immunoassay, and relative LTL was measured by quantitative PCR. Logistic regression was used to obtain OR and 95 % CI for long v. short (based on median) LTL in relation to continuous 25(OH)D, quartiles of 25(OH)D and 25(OH)D deficiency. We found no significant association between continuous 25(OH)D and long LTL in all participants (P trend=0·440), nor in white females (P trend=0·845), white males (P trend=0·636), black females (P trend=0·967) or black males (P trend=0·484). Vitamin D deficiency (defined as 25(OH)D<30 nmol/l), however, was significantly associated with short LTL in whites (P=0·024), but not in other groups. In this population, we found little evidence to support associations between 25(OH)D and long LTL over the entire range of 25(OH)D in the overall study population or by sex and race.},
}
@article {pmid27515284,
year = {2016},
author = {Chiu, CL and Hearn, NL and Paine, D and Steiner, N and Lind, JM},
title = {Does Telomere Shortening Precede the Onset of Hypertension in Spontaneously Hypertensive Mice?.},
journal = {Twin research and human genetics : the official journal of the International Society for Twin Studies},
volume = {19},
number = {5},
pages = {422-429},
doi = {10.1017/thg.2016.63},
pmid = {27515284},
issn = {1832-4274},
mesh = {*Aging/genetics/metabolism ; Animals ; *Hypertension/genetics/metabolism/physiopathology ; *Kidney/metabolism/physiopathology ; Male ; Mice ; Myocardium/*metabolism ; Species Specificity ; *Telomere/genetics/metabolism ; *Telomere Shortening ; },
abstract = {Telomere length is widely considered as a marker of biological aging. Clinical studies have reported associations between reduced telomere length and hypertension. The aim of this study was to compare telomere length in hypertensive and normotensive mice at pre-disease and established disease time points to determine whether telomere length differs between the strains before and after the onset of disease. Genomic DNA was extracted from kidney and heart tissues of 4-, 12-, and 20-week-old male hypertensive (BPH/2J) and normotensive (BPN/3J) mice. Relative telomere length (T/S) was measured using quantitative PCR. Age was inversely correlated with telomere length in both strains. In 4-week-old pre-hypertensive animals, no difference in T/S was observed between BPH/2J and BPN/3J animals in kidney or heart tissue (kidney p = 0.14, heart p = 0.06). Once the animals had established disease, at 12 and 20 weeks, BPH/2J mice had significantly shorter telomeres when compared to their age-matched controls in both kidney (12 weeks p < 0.001 and 20 weeks p = 0.004) and heart tissues (12 weeks p < 0.001 and 20 weeks p < 0.001). This is the first study to show that differences in telomere lengths between BPH/2J and BPN/3J mice occur after the development of hypertension and do not cause hypertension in the BPH/2J mice.},
}
@article {pmid27510600,
year = {2017},
author = {Lee, YH and Jung, JH and Seo, YH and Kim, JH and Choi, SJ and Ji, JD and Song, GG},
title = {Association between shortened telomere length and systemic lupus erythematosus: a meta-analysis.},
journal = {Lupus},
volume = {26},
number = {3},
pages = {282-288},
doi = {10.1177/0961203316662721},
pmid = {27510600},
issn = {1477-0962},
mesh = {Genetic Predisposition to Disease ; Humans ; Lupus Erythematosus, Systemic/*genetics ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Objective We aimed to evaluate the relationship between telomere length and systemic lupus erythematosus (SLE). Methods PUBMED and EMBASE databases were searched; meta-analyses were performed comparing telomere length in SLE patients and healthy controls, and on SLE patients in subgroups based on ethnicity, sample type, assay method and data type. Results Eight studies including 472 SLE patients and 365 controls were ultimately selected which showed that telomere length was significantly shorter in the SLE group than in the control group (standardized mean difference (SMD) = -0.835, 95% confidence interval (CI) = -1.291 to -0.380, p = 3.3 × 10[-4]). Stratification by ethnicity showed significantly shortened telomere length in the SLE group in Caucasian, Asian and mixed populations (SMD = -0.455, 95% CI = -0.763 to -0.147, p = 0.004; SMD = -0.887, 95% CI = -1.261 to -0.513, p = 3.4 × 10[-4]; SMD = -0.535, 95% CI = -0.923 to -0.147, p = 0.007; respectively). Furthermore, telomere length was significantly shorter in the SLE group than in the control group in whole blood and peripheral blood mononuclear cell groups (SMD = -0.361, 95% CI = -0.553 to -0.169, p = 2.3 × 10[-4]; SMD = -1.546, 95% CI = -2.583 to -0.510, p = 0.003; respectively); a similar trend was observed in leukocyte groups (SMD = -0.699, 95% CI = -1.511 to -0.114, p = 0.092). Meta-analyses based on assay method or data type revealed similar associations. Conclusions Our meta-analysis demonstrated that telomere length was significantly shorter in patients with SLE, regardless of ethnicity, sample type or assay method evaluated.},
}
@article {pmid27509261,
year = {2016},
author = {Zhang, R and Zhao, J and Xu, J and Liu, F},
title = {Association of peripheral leukocyte telomere length and its variation with pancreatic cancer and colorectal cancer risk in Chinese population.},
journal = {Oncotarget},
volume = {7},
number = {25},
pages = {38579-38585},
pmid = {27509261},
issn = {1949-2553},
mesh = {Asian People ; Case-Control Studies ; Colorectal Neoplasms/*genetics/pathology ; Female ; Humans ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Pancreatic Neoplasms/*genetics/metabolism/pathology ; Risk Factors ; Telomere/genetics/*metabolism ; },
abstract = {There is increasing evidence supporting the role of telomeres in cancer pathogenesis. However, limited studies have investigated the association between telomere length features and risk of pancreatic cancer and colorectal cancer (CRC), and little was conducted in Asians. To help clarify this issue, We measured relative peripheral leukocytes telomere length (LTL) and telomere length variation (TLV) in a prospective study of 900 pancreatic cancer cases, 300 CRC cases, and 900 controls. Both subjects with longer LTL (quartile 4: adjusted OR=1.51, 95% CI: 1.14-1.99, P=0.004) and shorter LTL (quartile 1: adjusted OR=3.12, 95% CI: 1.89-5.14, P=8.50x10-6) showed increased risk of pancreatic cancer. A linear increased risk was detected For TLV (adjusted OR=1.60, 95% CI: 1.14-2.24, P=0.006). We also identified significant interaction for relative LTL, TLV on pancreatic cancer risk (P interaction =0.009). Significant relationship between shorter RTL and increased CRC risk were also detected. This findings provide insights into telomere dynamics and highlight the complex relationship between relative LTL, TLV and cancer risk.},
}
@article {pmid27509177,
year = {2016},
author = {Wulaningsih, W and Serrano, FE and Utarini, A and Matsuguchi, T and Watkins, J and , },
title = {Smoking, second-hand smoke exposure and smoking cessation in relation to leukocyte telomere length and mortality.},
journal = {Oncotarget},
volume = {7},
number = {37},
pages = {60419-60431},
pmid = {27509177},
issn = {1949-2553},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging, Premature/*epidemiology/mortality ; Cigarette Smoking/*epidemiology/genetics ; Environmental Exposure/adverse effects ; Female ; Follow-Up Studies ; Humans ; Leukocytes/*physiology ; Male ; Middle Aged ; Smoking Cessation ; Survival Analysis ; *Telomere Homeostasis ; Tobacco Smoke Pollution/*statistics &amp; numerical data ; United Kingdom/epidemiology ; Young Adult ; },
abstract = {OBJECTIVES: To investigate the link between smoking exposure, telomere length and mortality, with emphasis on second-hand smoke (SHS) exposure and the duration of smoking cessation.<br><br>RESULTS: A total of 1,018 participants died during follow-up (mean: 10.3 years). A 50 base-pair decrease in LTL was shown among cotinine-confirmed current versus never smokers. The 90th quantile of LTL decreased with increasing cotinine among never smokers, indicating a role of SHS. Longer telomeres with smoking cessation were indicated but limited to a 3-16 year period of abstaining smoking. When assessing mortality, we observed a lower risk of all-cause death for the second quintile compared to the first among never smokers (HR: 0.67, 95% CI: 0.52-0.87), and a higher risk was found among current smokers (HR: 1.89, 1.19-2.92).<br><br>MATERIALS AND METHODS: We studied 6,456 nationally representative U.S. respondents with mortality follow-up through to 31 December 2011. Smoking status was assessed by interviews and cotinine levels. Relative leukocyte telomere length (LTL) was quantified by polymerase chain reaction (PCR). Multivariable linear regression was performed to examine LTL by smoking exposure, adjusted for age, sex, race/ethnicity, socioeconomic status, education, body mass index, alcohol consumption, and physical activity. We further estimated the association of LTL with cotinine levels using quantile regression, and with smoking cessation dynamics. Cox regression was used to estimate mortality by smoking status and LTL.<br><br>CONCLUSION: Our findings indicated a complex association between smoking, telomere length, and mortality. LTL alterations with SHS and smoking cessation warrant further investigation for translation to public health measures.},
}
@article {pmid27501725,
year = {2016},
author = {Boscolo-Rizzo, P and Da Mosto, MC and Rampazzo, E and Giunco, S and Del Mistro, A and Menegaldo, A and Baboci, L and Mantovani, M and Tirelli, G and De Rossi, A},
title = {Telomeres and telomerase in head and neck squamous cell carcinoma: from pathogenesis to clinical implications.},
journal = {Cancer metastasis reviews},
volume = {35},
number = {3},
pages = {457-474},
pmid = {27501725},
issn = {1573-7233},
mesh = {Animals ; Biomarkers, Tumor ; Carcinoma, Squamous Cell/*genetics/*metabolism/mortality/pathology ; Cell Transformation, Neoplastic/genetics/metabolism ; Gene Expression Regulation, Neoplastic ; Genetic Predisposition to Disease ; Genetic Variation ; Genomic Instability ; Head and Neck Neoplasms/*genetics/*metabolism/mortality/pathology ; Humans ; Leukocytes, Mononuclear/metabolism/pathology ; Mice ; Prognosis ; Squamous Cell Carcinoma of Head and Neck ; Telomerase/*metabolism ; Telomere/*genetics ; Telomere Homeostasis ; },
abstract = {Strongly associated with tobacco use, heavy alcohol consumption, and with high-risk human papillomavirus (HPV) infection, head and neck squamous cell carcinoma (HNSCC) is a frequently lethal, heterogeneous disease whose pathogenesis is a multistep and multifactorial process involving genetic and epigenetic events. The majority of HNSCC patients present with locoregional advanced stage disease and are treated with combined modality strategies that can markedly impair quality of life and elicit unpredictable results. A large fraction of those who undergo locoregional treatment and achieve a complete response later develop locoregional recurrences or second field tumors. Biomarkers that are thus able to stratify risk and enable clinicians to tailor treatment plans and to personalize post-therapeutic surveillance strategies are highly desirable. To date, only HPV status is considered a reliable independent predictor of treatment response and survival in patients with HNSCC arising from the oropharyngeal site. Recent studies suggest that telomere attrition, which may be an early event in human carcinogenesis, and telomerase activation, which is detected in up to 90 % of malignancies, could be potential markers of cancer risk and disease outcome. This review examines the current state of knowledge on and discusses the implications linked to telomere dysfunction and telomerase activation in the development and clinical outcome of HNSCC.},
}
@article {pmid27500189,
year = {2015},
author = {Mender, I and Shay, JW},
title = {Telomere Restriction Fragment (TRF) Analysis.},
journal = {Bio-protocol},
volume = {5},
number = {22},
pages = {},
pmid = {27500189},
issn = {2331-8325},
support = {P50 CA070907/CA/NCI NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; },
abstract = {While telomerase is expressed in ~90% of primary human tumors, most somatic tissue cells except transiently proliferating stem-like cells do not have detectable telomerase activity (Shay and Wright, 1996; Shay and Wright, 2001). Telomeres progressively shorten with each cell division in normal cells, including proliferating stem-like cells, due to the end replication (lagging strand synthesis) problem and other causes such as oxidative damage, therefore all somatic cells have limited cell proliferation capacity (Hayflick limit) (Hayflick and Moorhead, 1961; Olovnikov, 1973). The progressive telomere shortening eventually leads to growth arrest in normal cells, which is known as replicative senescence (Shay et al., 1991). Once telomerase is activated in cancer cells, telomere length is stabilized by the addition of TTAGGG repeats to the end of chromosomes, thus enabling the limitless continuation of cell division (Shay and Wright, 1996; Shay and Wright, 2001). Therefore, the link between aging and cancer can be partially explained by telomere biology. There are many rapid and convenient methods to study telomere biology such as Telomere Restriction Fragment (TRF), Telomere Repeat Amplification Protocol (TRAP) (Mender and Shay, 2015b) and Telomere dysfunction Induced Foci (TIF) analysis (Mender and Shay, 2015a). In this protocol paper we describe Telomere Restriction Fragment (TRF) analysis to determine average telomeric length of cells. Telomeric length can be indirectly measured by a technique called Telomere Restriction Fragment analysis (TRF). This technique is a modified Southern blot, which measures the heterogeneous range of telomere lengths in a cell population using the length distribution of the terminal restriction fragments (Harley et al., 1990; Ouellette et al., 2000). This method can be used in eukaryotic cells. The description below focuses on the measurement of human cancer cells telomere length. The principle of this method relies on the lack of restriction enzyme recognition sites within TTAGGG tandem telomeric repeats, therefore digestion of genomic DNA, not telomeric DNA, with a combination of 6 base restriction endonucleases reduces genomic DNA size to less than 800 bp.},
}
@article {pmid27500188,
year = {2015},
author = {Mender, I and Shay, JW},
title = {Telomere Dysfunction Induced Foci (TIF) Analysis.},
journal = {Bio-protocol},
volume = {5},
number = {22},
pages = {},
pmid = {27500188},
issn = {2331-8325},
support = {P50 CA070907/CA/NCI NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; },
abstract = {Telomerase maintains telomeric DNA in eukaryotes during early developments, ~90% of cancer cells and some proliferative stem like cells. Telomeric repeats at the end of chromosomes are associated with the shelterin complex. This complex consists of TRF1, TRF2, Rap1, TIN2, TPP1, POT1 which protect DNA from being recognized as DNA double-stranded breaks. Critically short telomeres or impaired shelterin proteins can cause telomere dysfunction, which eventually induces DNA damage responses at the telomeres. DNA damage responses can be identified by antibodies to 53BP1, gammaH2AX, Rad17, ATM, and Mre11. DNA damage foci at uncapped telomeres are referred to as Telomere dysfunction-Induced Foci (TIFs) (de Lange, 2005; Takai et al., 2003). The TIF assay is based on the co-localization detection of DNA damage by an antibody against DNA damage markers, such as gamma-H2AX, and telomeres using an antibody against one of the shelterin proteins such as TRF2 (Takai et al., 2003; de Lange, 2002; Karlseder et al., 1999). The method we describe here can be used in normal human and cancer cells. Other commonly used methods-Telomere Restriction Fragment (TRF) Analysis (Mender and Shay, 2015b) and Telomere Repeat Amplification Protocol (TRAP) (Mender and Shay, 2015a)- in telomere biology can be found by clicking on the indicated links.},
}
@article {pmid27498151,
year = {2016},
author = {Rode, L and Nordestgaard, BG and Bojesen, SE},
title = {Long telomeres and cancer risk among 95 568 individuals from the general population.},
journal = {International journal of epidemiology},
volume = {45},
number = {5},
pages = {1634-1643},
doi = {10.1093/ije/dyw179},
pmid = {27498151},
issn = {1464-3685},
mesh = {Adult ; Aged ; Denmark ; Female ; Genetic Predisposition to Disease ; Genetic Testing ; Humans ; Logistic Models ; Lung Neoplasms/*genetics ; Male ; Melanoma/*genetics ; Middle Aged ; Multivariate Analysis ; Odds Ratio ; Proportional Hazards Models ; Risk Factors ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Results regarding telomere length and cancer risk are conflicting. We tested the hypothesis that long telomeres are associated with increased risk of any cancer and specific cancer types in genetic and observational analyses.<br><br>METHODS: Individuals (N&#x2009;=&#x2009;95&#x2009;568) from the Copenhagen City Heart Study and the Copenhagen General Population Study had the telomere length-associated genotypes rs7726159 (TERT), rs1317082 (TERC), and rs2487999 (OBFC1) determined, and 65&#x2009;176 had telomere length measured. A total of 10&#x2009;895 individuals had had a cancer diagnosis. Endpoints were any cancer and 25 specific cancer types. We conducted Cox regression analyses and logistic regression analyses. The three genotypes were combined as an allele sum.<br><br>RESULTS: Telomere length increased 67 base-pairs [95% confidence interval (CI) 61-74] per allele. In logistic regression models, the per-allele odds ratio (OR) for cancer was 1.05 (95% CI 1.03-1.07) for the allele sum, 1.05 (1.02-1.09) for rs7726159, 1.05 (1.02-1.08) for rs1317082 and 1.07 (1.02-1.12) for rs2487999. In contrast, the hazard ratio for any cancer was 1.01 (1.00-1.01) per 200-base-pair increase in telomere length in multivariable adjusted observational analysis. In genetic analyses according to specific cancer types, the per-allele odds ratio was 1.19 (1.12-1.27) for melanoma and 1.14 (1.06-1.22) for lung cancer.<br><br>CONCLUSIONS: Genetic determinants of long telomeres are associated with increased cancer risk, particularly melanoma and lung cancer. This genetic predisposition to enhanced telomere maintenance may represent a survival advantage for pre-cancerous cells, allowing for multiple cell divisions leading to cancer development.},
}
@article {pmid27496426,
year = {2016},
author = {Kłoda, K and Domański, L and Kwiatkowska, E and Safranow, K and Drozd, A and Ciechanowicz, A and Ciechanowski, K},
title = {BICD1 and Chromosome 18 Polymorphisms Associated With Recipients' Telomere Length Affect Kidney Allograft Function After Transplantation.},
journal = {Transplantation proceedings},
volume = {48},
number = {5},
pages = {1451-1455},
doi = {10.1016/j.transproceed.2015.10.086},
pmid = {27496426},
issn = {1873-2623},
mesh = {Adaptor Proteins, Signal Transducing/*genetics ; Adult ; Alleles ; Allografts/*physiopathology ; Chromosomes, Human, Pair 18/*genetics ; Creatinine/blood ; Cytoskeletal Proteins/*genetics ; Delayed Graft Function/*genetics ; Female ; Genotype ; Humans ; *Kidney Transplantation ; Male ; Middle Aged ; Poland ; Polymorphism, Genetic ; Real-Time Polymerase Chain Reaction ; Telomerase/genetics ; Telomere ; },
abstract = {BACKGROUND: Reports regarding recipient's nonmodifiable genetic factors affecting telomerase activity and thus allograft function are lacking. Therefore the aim of this study was to analyze the associations between recipients' rs2735940 hTERT, rs2630578 BICD1, and rs7235755 chromosome 18 polymorphisms and kidney function after transplantation.<br><br>METHODS: The study enrolled 119 white Polish kidney allograft recipients (64 men, 55 women; overall mean age, 47.3 &#xb1; 14.0&#xa0;y). To identify genotypes of the studied polymorphisms, real-time polymerase chain reaction was performed.<br><br>RESULTS: There were statistically significant differences in distribution of rs7235755 chromosome 18 polymorphism genotypes and alleles between recipients with delayed graft function (DGF) and without DGF (P&#xa0;= .03). The presence of A allele was significantly associated with higher risk of DGF occurrence (AA&#xa0;+ GA vs GG: OR, 3.25 [95% CI, 1.16-9.14]; P&#xa0;= .02; GA vs GG: OR, 4.00 [1.35-11.82]; P&#xa0;= .01). Analysis of the rs2630578 BICD1 gene polymorphism genotypes revealed statistically significant differences in long-term creatinine concentrations. The presence of C allele of this polymorphism was significantly associated with higher creatinine concentrations 24, 36, and 18-48 months after transplantation (GC&#xa0;+ CC vs GG: P&#xa0;= .008, P&#xa0;= .008, and P&#xa0;= .01, respectively).<br><br>CONCLUSIONS: Recipients' polymorphisms of genes associated with telomere length, BICD1 and chromosome 18, but not hTERT, affect kidney allograft early and long-term function after transplantation. There is an urgent need for explanation of these observations in genome-wide association studies.},
}
@article {pmid27491801,
year = {2017},
author = {Cho, NW and Lampson, MA and Greenberg, RA},
title = {In vivo imaging of DNA double-strand break induced telomere mobility during alternative lengthening of telomeres.},
journal = {Methods (San Diego, Calif.)},
volume = {114},
number = {},
pages = {54-59},
pmid = {27491801},
issn = {1095-9130},
support = {R01 GM083988/GM/NIGMS NIH HHS/United States ; R01 CA174904/CA/NCI NIH HHS/United States ; R01 GM101149/GM/NIGMS NIH HHS/United States ; R01 CA138835/CA/NCI NIH HHS/United States ; R21 CA194973/CA/NCI NIH HHS/United States ; },
mesh = {*DNA Breaks, Double-Stranded ; DNA Repair ; Genes, Reporter/*genetics ; Homologous Recombination ; Humans ; Molecular Imaging/*methods ; *Telomere Homeostasis ; },
abstract = {Repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) requires mobilization of chromatin for homology searches that allow interaction of the sequence to be repaired and its template DNA. Here we describe a system to rapidly induce DSBs at telomeres and track their movement, as well as a semi-automated workflow for quantitative analysis. We have successfully used this approach to show that DSBs targeted to telomeres in cells utilizing the alternative lengthening of telomeres (ALT) mechanism increase their diffusion and subsequent long-range directional movement to merge with telomeres on other chromosomes. These methods are simple to implement and are compatible with almost any cell line or in vivo microscopy setup. The magnitude of DSB-induced telomere mobility allows the investigator to easily test for factors regulating telomere mobility during ALT.},
}
@article {pmid27488651,
year = {2016},
author = {Asghar, M and Palinauskas, V and Zaghdoudi-Allan, N and Valkiūnas, G and Mukhin, A and Platonova, E and Färnert, A and Bensch, S and Hasselquist, D},
title = {Parallel telomere shortening in multiple body tissues owing to malaria infection.},
journal = {Proceedings. Biological sciences},
volume = {283},
number = {1836},
pages = {},
pmid = {27488651},
issn = {1471-2954},
mesh = {Animals ; Malaria, Avian/*pathology ; Passeriformes/*parasitology ; Plasmodium ; Telomere/*ultrastructure ; *Telomere Shortening ; },
abstract = {Several studies have shown associations between shorter telomere length in blood and weakened immune function, susceptibility to infections, and increased risk of morbidity and mortality. Recently, we have shown that malaria accelerates telomere attrition in blood cells and shortens lifespan in birds. However, the impact of infections on telomere attrition in different body tissues within an individual is unknown. Here, we tested whether malarial infection leads to parallel telomere shortening in blood and tissue samples from different organs. We experimentally infected siskins (Spinus spinus) with the avian malaria parasite Plasmodium ashfordi, and used real-time quantitative polymerase chain reaction (PCR) to measure telomere length in control and experimentally infected siskins. We found that experimentally infected birds showed faster telomere attrition in blood over the course of infection compared with control individuals (repeatedly measured over 105 days post-infection (DPI)). Shorter telomeres were also found in the tissue of all six major organs investigated (liver, lungs, spleen, heart, kidney, and brain) in infected birds compared with controls at 105 DPI. To the best of our knowledge, this is the first study showing that an infectious disease results in synchronous telomere shortening in the blood and tissue cells of internal organs within individuals, implying that the infection induces systemic stress. Our results have far-reaching implications for understanding how the short-term effects of an infection can translate into long-term costs, such as organ dysfunction, degenerative diseases, and ageing.},
}
@article {pmid27486974,
year = {2016},
author = {Guièze, R and Pages, M and Véronèse, L and Combes, P and Lemal, R and Gay-Bellile, M and Chauvet, M and Callanan, M and Kwiatkowski, F and Pereira, B and Vago, P and Bay, JO and Tournilhac, O and Tchirkov, A},
title = {Telomere status in chronic lymphocytic leukemia with TP53 disruption.},
journal = {Oncotarget},
volume = {7},
number = {35},
pages = {56976-56985},
pmid = {27486974},
issn = {1949-2553},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aminopeptidases/metabolism ; Biomarkers, Tumor ; DNA Mutational Analysis ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism ; Disease-Free Survival ; Female ; Follow-Up Studies ; Gene Deletion ; Gene Expression Profiling ; Gene Expression Regulation, Leukemic ; Genomics ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics/*metabolism ; Male ; Middle Aged ; Mutation ; Prognosis ; Serine Proteases/metabolism ; Shelterin Complex ; Telomerase/genetics ; Telomere/*ultrastructure ; Telomere-Binding Proteins/metabolism ; Tumor Suppressor Protein p53/*genetics ; },
abstract = {In chronic lymphocytic leukemia (CLL), telomere dysfunction is associated with poor outcomes. TP53 is involved in cellular responses to dysfunctional telomeres, and its inactivation is the strongest adverse prognostic factor for CLL. Given the biological relationship between TP53 and telomeres, and their prognostic value, it is important to improve our understanding of the impact of TP53 alterations on telomeres. We performed a comprehensive study of the deletions and mutations of the TP53 gene and telomere parameters, including hTERT and the shelterin complex, in 115 CLL patients. We found that any type of TP53 alteration was associated with very short telomeres and high hTERT expression, independently of other biological CLL features. Patients with disrupted TP53 showed telomere deletions and chromosomal end-to-end fusions in cells with complex karyotypes. TP53 disruption was characterized by downregulation of shelterin genes. Interestingly, low expression of POT1, TPP1 and TIN2 was also found in some patients with wild-type TP53 and had an adverse impact on progression-free survival after standard genotoxic therapy. In conclusion, we have demonstrated that patients with disrupted TP53 have severe telomere dysfunction and high genomic instability. Thus, the telomeric profile could be tested as a biomarker in CLL patients treated with new therapeutic agents.},
}
@article {pmid27484724,
year = {2016},
author = {Bončina, M and Vesnaver, G and Chaires, JB and Lah, J},
title = {Unraveling the Thermodynamics of the Folding and Interconversion of Human Telomere G-Quadruplexes.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {55},
number = {35},
pages = {10340-10344},
pmid = {27484724},
issn = {1521-3773},
support = {R01 CA035635/CA/NCI NIH HHS/United States ; R01 GM077422/GM/NIGMS NIH HHS/United States ; },
mesh = {Calorimetry, Differential Scanning ; Circular Dichroism ; DNA/*chemistry ; *G-Quadruplexes ; Humans ; *Telomere ; *Thermodynamics ; },
abstract = {Why human telomere DNA fragments fold into different G-quadruplex structures with parallel, hybrid, and antiparallel strand orientations depending on the temperature and concentration of co-solutes remains poorly understood. Similarly, the formation of intermediate structures along the folding or interconversion pathways is not well understood. Herein, we address these questions by introducing a conceptual framework, based on the global thermodynamic analysis of DSC and CD spectroscopy data, which led to a detailed description of the topological phase space (phase diagram) of the stability of the human telomere fragment 5'-AGGG(TTAGGG)3 -3' (Tel22). This framework clarifies the driving forces of quadruplex folding and interconversion processes over a wide range of temperatures and ion (K(+) , Na(+)) and polyethylene glycol (PEG) concentrations and demonstrates their linkage to the human telomere DNA structural features.},
}
@article {pmid27482890,
year = {2016},
author = {Boyraz, B and Moon, DH and Segal, M and Muosieyiri, MZ and Aykanat, A and Tai, AK and Cahan, P and Agarwal, S},
title = {Posttranscriptional manipulation of TERC reverses molecular hallmarks of telomere disease.},
journal = {The Journal of clinical investigation},
volume = {126},
number = {9},
pages = {3377-3382},
pmid = {27482890},
issn = {1558-8238},
support = {R01 DK107716/DK/NIDDK NIH HHS/United States ; T32 HL007574/HL/NHLBI NIH HHS/United States ; },
mesh = {DNA, Complementary/metabolism ; Dyskeratosis Congenita/genetics ; Exoribonucleases/*genetics ; Fibroblasts/metabolism ; Gene Deletion ; *Gene Expression Regulation ; HEK293 Cells ; Humans ; Lentivirus/genetics ; Mutation ; Phenotype ; *Protein Processing, Post-Translational ; RNA/*genetics ; RNA Interference ; RNA Nucleotidyltransferases/metabolism ; RNA, Small Interfering/genetics ; Skin/metabolism ; Telomerase/*genetics/metabolism ; Telomere/ultrastructure ; },
abstract = {The telomerase RNA component (TERC) is a critical determinant of cellular self-renewal. Poly(A)-specific ribonuclease (PARN) is required for posttranscriptional maturation of TERC. PARN mutations lead to incomplete 3' end processing and increased destruction of nascent TERC RNA transcripts, resulting in telomerase deficiency and telomere diseases. Here, we determined that overexpression of TERC increased telomere length in PARN-deficient cells and hypothesized that decreasing posttranscriptional 3' oligo-adenylation of TERC would counteract the deleterious effects of PARN mutations. Inhibition of the noncanonical poly(A) polymerase PAP-associated domain-containing 5 (PAPD5) increased TERC levels in PARN-mutant patient cells. PAPD5 inhibition was also associated with increases in TERC stability, telomerase activity, and telomere elongation. Our results demonstrate that manipulating posttranscriptional regulatory pathways may be a potential strategy to reverse the molecular hallmarks of telomere disease.},
}
@article {pmid27482813,
year = {2016},
author = {Carneiro, MC and de Castro, IP and Ferreira, MG},
title = {Telomeres in aging and disease: lessons from zebrafish.},
journal = {Disease models &amp; mechanisms},
volume = {9},
number = {7},
pages = {737-748},
pmid = {27482813},
issn = {1754-8411},
mesh = {Aging/*metabolism ; Animals ; *Disease ; Humans ; Models, Biological ; Telomerase/metabolism ; Telomere/*metabolism ; Zebrafish/*physiology ; },
abstract = {Age is the highest risk factor for some of the most prevalent human diseases, including cancer. Telomere shortening is thought to play a central role in the aging process in humans. The link between telomeres and aging is highlighted by the fact that genetic diseases causing telomerase deficiency are associated with premature aging and increased risk of cancer. For the last two decades, this link has been mostly investigated using mice that have long telomeres. However, zebrafish has recently emerged as a powerful and complementary model system to study telomere biology. Zebrafish possess human-like short telomeres that progressively decline with age, reaching lengths in old age that are observed when telomerase is mutated. The extensive characterization of its well-conserved molecular and cellular physiology makes this vertebrate an excellent model to unravel the underlying relationship between telomere shortening, tissue regeneration, aging and disease. In this Review, we explore the advantages of using zebrafish in telomere research and discuss the primary discoveries made in this model that have contributed to expanding our knowledge of how telomere attrition contributes to cellular senescence, organ dysfunction and disease.},
}
@article {pmid27479817,
year = {2016},
author = {Navrkalova, V and Young, E and Baliakas, P and Radova, L and Sutton, LA and Plevova, K and Mansouri, L and Ljungström, V and Ntoufa, S and Davis, Z and Juliusson, G and Smedby, KE and Belessi, C and Panagiotidis, P and Touloumenidou, T and Davi, F and Langerak, AW and Ghia, P and Strefford, JC and Oscier, D and Mayer, J and Stamatopoulos, K and Pospisilova, S and Rosenquist, R and Trbusek, M},
title = {ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset #2 is associated with markedly short telomeres.},
journal = {Haematologica},
volume = {101},
number = {9},
pages = {e369-73},
pmid = {27479817},
issn = {1592-8721},
mesh = {Ataxia Telangiectasia Mutated Proteins/*genetics ; Cohort Studies ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*classification/genetics/mortality ; *Mutation ; Sequence Analysis, DNA ; Survival Analysis ; Telomere/ultrastructure ; *Telomere Shortening ; },
}
@article {pmid27478776,
year = {2016},
author = {Brazvan, B and Farahzadi, R and Mohammadi, SM and Montazer Saheb, S and Shanehbandi, D and Schmied, L and Soleimani Rad, J and Darabi, M and Nozad Charoudeh, H},
title = {Key Immune Cell Cytokines Affects the Telomere Activity of Cord Blood Cells In vitro.},
journal = {Advanced pharmaceutical bulletin},
volume = {6},
number = {2},
pages = {153-161},
pmid = {27478776},
issn = {2228-5881},
abstract = {PURPOSE: Telomere is a nucleoprotein complex at the end of eukaryotic chromosomes and its length is regulated by telomerase. The number of DNA repeat sequence (TTAGGG)n is reduced with each cell division in differentiated cells. The aim of this study was to evaluate the effect of SCF (Stem Cell Factor), Flt3 (Fms- Like tyrosine kinase-3), Interleukin-2, 7 and 15 on telomere length and hTERT gene expression in mononuclear and umbilical cord blood stem cells (CD34+ cells) during development to lymphoid cells.<br><br>METHODS: The mononuclear cells were isolated from umbilical cord blood by Ficoll-Paque density gradient. Then cells were cultured for 21 days in the presence of different cytokines. Telomere length and hTERT gene expression were evaluated in freshly isolated cells, 7, 14 and 21 days of culture by real-time PCR. The same condition had been done for CD34+ cells but telomere length and hTERT gene expression were measured at initial and day 21 of the experiment.<br><br>RESULTS: Highest hTERT gene expression and maximum telomere length were measured at day14 of MNCs in the presence of IL-7 and IL-15. Also, there was a significant correlation between telomere length and telomerase gene expression in MNCs at 14 days in a combination of IL-7 and IL-15 (r = 0.998, p =0.04). In contrast, IL-2 showed no distinct effect on telomere length and hTERT gene expression in cells.<br><br>CONCLUSION: Taken together, IL-7 and IL-15 increased telomere length and hTERT gene expression at 14 day of the experiment. In conclusion, it seems likely that cells maintain na&#xef;ve phenotype due to prolonged exposure of IL-7 and IL-15.},
}
@article {pmid27477026,
year = {2016},
author = {Duan, YM and Zhou, BO and Peng, J and Tong, XJ and Zhang, QD and Zhou, JQ},
title = {Molecular dynamics of de novo telomere heterochromatin formation in budding yeast.},
journal = {Journal of genetics and genomics = Yi chuan xue bao},
volume = {43},
number = {7},
pages = {451-465},
doi = {10.1016/j.jgg.2016.03.009},
pmid = {27477026},
issn = {1673-8527},
mesh = {Aldose-Ketose Isomerases/deficiency/genetics ; Base Sequence ; Gene Silencing ; Genetic Loci/genetics ; Heterochromatin/*genetics ; Repressor Proteins/deficiency/genetics ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Telomerase/metabolism ; Telomere/*genetics ; Telomere-Binding Proteins/deficiency/genetics ; },
abstract = {In the budding yeast Saccharomyces cerevisiae, heterochromatin structure is found at three chromosome regions, which are homothallic mating-type loci, rDNA regions and telomeres. To address how telomere heterochromatin is assembled under physiological conditions, we employed a de novo telomere addition system, and analyzed the dynamic chromatin changes of the TRP1 reporter gene during telomere elongation. We found that integrating a 255-bp, but not an 81-bp telomeric sequence near the TRP1 promoter could trigger Sir2 recruitment, active chromatin mark(s)' removal, chromatin compaction and TRP1 gene silencing, indicating that the length of the telomeric sequence inserted in the internal region of a chromosome is critical for determining the chromatin state at the proximal region. Interestingly, Rif1 but not Rif2 or yKu is indispensable for the formation of intra-chromosomal silent chromatin initiated by telomeric sequence. When an internal short telomeric sequence (e.g., 81 bp) gets exposed to become a de novo telomere, the herterochromatin features, such as Sir recruitment, active chromatin mark(s)' removal and chromatin compaction, are detected within a few hours before the de novo telomere reaches a stable length. Our results recapitulate the molecular dynamics and reveal a coherent picture of telomere heterochromatin formation.},
}
@article {pmid27473052,
year = {2016},
author = {Caocci, G and Greco, M and Delogu, G and Secchi, C and Martino, B and Labate, C and Abruzzese, E and Trawinska, MM and Galimberti, S and Orru, F and Fozza, C and Gambacorti Passerini, C and Galimi, F and La Nasa, G},
title = {Telomere length shortening is associated with treatment-free remission in chronic myeloid leukemia patients.},
journal = {Journal of hematology &amp; oncology},
volume = {9},
number = {1},
pages = {63},
pmid = {27473052},
issn = {1756-8722},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Case-Control Studies ; Female ; Humans ; Imatinib Mesylate/therapeutic use ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/*pathology ; Male ; Middle Aged ; Polymerase Chain Reaction ; Remission Induction ; Telomere/ultrastructure ; *Telomere Shortening/genetics ; *Withholding Treatment ; },
abstract = {We studied telomere length in 32 CML patients who discontinued imatinib after achieving complete molecular remission and 32 age-sex-matched controls. The relative telomere length (RTL) was determined by q-PCR as the telomere to single copy gene (36B4) ratio normalized to a reference sample (K-562 DNA). Age-corrected RTL (acRTL) was also obtained. The 36-month probability of treatment-free remission (TFR) was 59.4 %. TFR patients showed shorter acRTL compared to relapsed (mean ± SD = 0.01 ± 0.14 vs 0.20 ± 0.21; p = 0.01). TFR was significantly higher in CML patients with acRTL ≤0.09 (78.9 vs 30.8 %, p = 0.002). CML stem cells harboring longer telomeres possibly maintain a proliferative potential after treatment discontinuation.},
}
@article {pmid27470362,
year = {2016},
author = {Sameni, S and Hande, MP},
title = {Plumbagin triggers DNA damage response, telomere dysfunction and genome instability of human breast cancer cells.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {82},
number = {},
pages = {256-268},
doi = {10.1016/j.biopha.2016.05.007},
pmid = {27470362},
issn = {1950-6007},
mesh = {Apoptosis/drug effects/genetics ; Breast Neoplasms/*genetics/*pathology ; Cell Cycle Checkpoints/drug effects/genetics ; Cell Line, Tumor ; Cell Movement/drug effects/genetics ; Chromosome Aberrations ; Clone Cells ; DNA Breaks, Double-Stranded ; *DNA Damage/genetics ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Genomic Instability/*drug effects ; Humans ; In Situ Hybridization, Fluorescence ; Naphthoquinones/*pharmacology ; Oligonucleotide Array Sequence Analysis ; Telomerase/metabolism ; Telomere/drug effects/*metabolism ; Telomere Homeostasis/drug effects ; Wound Healing/drug effects ; },
abstract = {AIM: Natural plant products are increasingly being used in cancer therapeutic studies due to their reduced normal cell toxicity. In this study, the anti-cancer properties of plumbagin, a naphthoquinone derivative extracted from the roots of Plumbago, were evaluated in breast cancer cells.<br><br>METHODS: To evaluate the effects of plumbagin on breast cancer cell types, we employed a variety of techniques comprising cell viability, cell cycle assay, comet assay, western blotting, immunocytochemistry, measurement of telomerase activity, telomere restriction fragment length, quantitative fluorescence in situ hybridisation, along with gene expression analysis of untreated cells.<br><br>RESULTS: Plumbagin treatment induced cytotoxicity in human breast cancer cells along with cell cycle arrest, DNA damage and cell death leading to apoptosis. Plumbagin was also found to suppress the telomerase activity in cancer cells accompanied by telomere attrition. Telomere shortening was corroborated by reduced telomere fluorescence on chromosome ends and genome instability.<br><br>CONCLUSION: Together, these findings may suggest the application of plumbagin as adjuvant modality in breast cancer therapeutics.},
}
@article {pmid27470228,
year = {2016},
author = {Osler, M and Bendix, L and Rask, L and Rod, NH},
title = {Stressful life events and leucocyte telomere length: Do lifestyle factors, somatic and mental health, or low grade inflammation mediate this relationship? Results from a cohort of Danish men born in 1953.},
journal = {Brain, behavior, and immunity},
volume = {58},
number = {},
pages = {248-253},
doi = {10.1016/j.bbi.2016.07.154},
pmid = {27470228},
issn = {1090-2139},
mesh = {Biomarkers/blood ; Cardiovascular Diseases/complications/physiopathology ; Cohort Studies ; Denmark ; Depressive Disorder, Major/complications/physiopathology ; Humans ; Inflammation/complications/*physiopathology ; Leukocytes/*physiology ; Life Style ; Male ; Mental Health ; Stress, Psychological/complications/*physiopathology/*psychology ; Telomere/*physiology ; *Telomere Shortening ; },
abstract = {Exposure to psychosocial stress is associated with increased risk of a number of somatic and mental disorders with relation to immune system functioning. We aimed to explore whether stressful events in early and recent life was associated with leucocyte telomere length (TL), which is assumed to reflect the accumulated burden of inflammation and oxidative stress occurring during the life course. We specifically aimed to address whether childhood constitutes a sensitive period and how much of the relation between stressful life events and TL is mediated through somatic and mental health, lifestyle, and markers of low-grade inflammation. A cohort of Danish men born in 1953 has been followed since birth in the Metropolit Cohort. These men underwent a health examination including blood sampling in 2010 and a subset of 324 also had a quantitative PCR-based measurement of TL. The relation between stressful life events and TL was analysed using structural equation modelling, which also provided an estimate of the proportion of the total effect mediated by somatic and mental health (cardiovascular disease, body mass and depressive mood), lifestyle factors, and low grade inflammation (C-reactive protein (CRP), interleukin (IL)-6 and IL-10). Total number of stressful events experienced during the life course was not associated with TL. In terms of sensitive periods, we found that number of stressful events in childhood was associated with shorter TL (βper number stressful events in childhood=-0.02(SE=-0.02); P=0.05). This relation was particularly strong for being placed away from home (β=-0.16; P<0.000). Thirty percent of the total effect of stressful events in childhood on TL was mediated by the included variables, with the largest proportion being mediated through depressive mood (16%) and CRP (9%). This study suggests that stressful events in childhood are associated with shorter TL in middle-aged men and that part of this relation is explained by depressive mood and low grade inflammation.},
}
@article {pmid27470185,
year = {2016},
author = {Adriaenssens, B and Pauliny, A and Blomqvist, D and Johnsson, JI},
title = {Telomere length covaries with personality in wild brown trout.},
journal = {Physiology &amp; behavior},
volume = {165},
number = {},
pages = {217-222},
doi = {10.1016/j.physbeh.2016.07.005},
pmid = {27470185},
issn = {1873-507X},
mesh = {Aggression ; Animals ; Body Size/genetics ; Exploratory Behavior/physiology ; Longevity/*genetics/physiology ; *Personality ; Phenotype ; Principal Component Analysis ; Telomere/*physiology ; *Telomere Shortening ; Trout ; },
abstract = {The prevalence of consistent among-individual differences in behaviour, or personality, makes adaptive sense if individuals differ in stable state variables that shift the balance between the costs and benefits of their behavioural decisions. These differences may give rise to both individual differences in, and covariance among, behaviours that influence an individual's exposure to risks. We here study the link between behaviour and a candidate state variable previously overlooked in the study of state-dependent personality variation: telomere length. Telomeres are the protective endcaps of chromosomes and their erosion with age is thought to play a crucial role in regulating organismal senescence and intrinsic lifespan. Following evidence that shorter telomeres may reduce the lifespan of animals in a wide range of taxa, we predict individuals with shorter telomeres to behave more boldly and aggressively. In order to test this, we measured telomere length and behaviour in wild juvenile brown trout (Salmo trutta). We found individuals with shorter fin telomeres to behave consistently more boldly and aggressively under controlled conditions in the laboratory. No such relationship was found with muscle telomere length 3-4months after the behavioural assays. We suggest that telomere dynamics are an important factor integrating personality traits with other state variables thought to be important in the regulation of behaviour, such as metabolism, disease resistance and growth.},
}
@article {pmid27469599,
year = {2017},
author = {Brown, L and Needham, B and Ailshire, J},
title = {Telomere Length Among Older U.S. Adults: Differences by Race/Ethnicity, Gender, and Age.},
journal = {Journal of aging and health},
volume = {29},
number = {8},
pages = {1350-1366},
pmid = {27469599},
issn = {1552-6887},
support = {P30 AG043073/AG/NIA NIH HHS/United States ; R00 AG039528/AG/NIA NIH HHS/United States ; T32 AG000037/AG/NIA NIH HHS/United States ; U01 AG009740/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; *Aging ; Biomarkers ; Female ; Health Status Disparities ; Humans ; Interviews as Topic ; Male ; Minority Groups ; Qualitative Research ; Telomere/*genetics ; United States ; },
abstract = {OBJECTIVE: We examine race/ethnic, gender, and age differences in telomere length (TL) within a diverse, nationally representative sample of older adults.<br><br>METHOD: Data come from 5,228 White, Black, and Hispanic respondents aged 54+ in the 2008 Health and Retirement Study. TL was assayed from saliva using quantitative polymerase chain reaction (qPCR) by comparing telomere sequence copy number with a single gene copy number (T/S ratio). Linear regression was used to examine TL by race/ethnicity, gender, and age adjusting for social, economic, and health characteristics.<br><br>RESULTS: Women had longer TL than men (p < .05). Blacks (p < .05) and Hispanics (p < .10) had longer TL than Whites. Black women and men had the longest TL relative to other groups (p < .05), while White men had the shortest TL (p < .05). Black women and Hispanic men showed greater differences in TL with age.<br><br>DISCUSSION: Findings indicate social patterns in TL by race/ethnicity, gender, and age among older adults do not reflect differences observed in most population health outcomes.},
}
@article {pmid27468421,
year = {2016},
author = {Gadalla, SM and Khincha, PP and Katki, HA and Giri, N and Wong, JY and Spellman, S and Yanovski, JA and Han, JC and De Vivo, I and Alter, BP and Savage, SA},
title = {The limitations of qPCR telomere length measurement in diagnosing dyskeratosis congenita.},
journal = {Molecular genetics &amp; genomic medicine},
volume = {4},
number = {4},
pages = {475-479},
pmid = {27468421},
issn = {2324-9269},
support = {R01 CA082838/CA/NCI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; },
abstract = {BACKGROUND: Telomere length <1st percentile-for-age in leukocyte subsets by flow cytometry with fluorescence in situ hybridization (flow FISH) is highly sensitive and specific in diagnosing patients with dyskeratosis congenita (DC), a telomere biology disorder.<br><br>METHODS: We evaluated the clinical utility of the high-throughput quantitative real-time PCR (qPCR) relative telomere length (RTL) measurement as a diagnostic test for DC in patients with a priori clinical and/or genetic DC diagnoses. We calculated the sensitivity and specificity of RTL at different age-specific percentile cutoffs in 31 patients with DC and 51 mutation-negative relatives, and evaluated RTL difference by disease genotype.<br><br>RESULTS: qPCR RTL <1st percentile-for-age failed to identify more than 60% of the patients already known to have DC (sensitivity&#xa0;=&#xa0;39%, specificity&#xa0;=&#xa0;98%). Three-quarters of DC patients had RTL below the 10th percentile-for-age (sensitivity&#xa0;=&#xa0;74%), as did 12% of the unaffected relatives (specificity&#xa0;=&#xa0;88%).<br><br>CONCLUSIONS: Our findings suggest that the qPCR RTL method is not optimal for diagnosing DC. In light of these limitations, leukocyte flow FISH telomere length remains the recommended molecular test for diagnosing DC.},
}
@article {pmid27465399,
year = {2016},
author = {Hwang, SM and Kim, SY and Kim, JA and Park, HS and Park, SN and Im, K and Kim, K and Kim, SM and Lee, DS},
title = {Short telomere length and its correlation with gene mutations in myelodysplastic syndrome.},
journal = {Journal of hematology &amp; oncology},
volume = {9},
number = {1},
pages = {62},
pmid = {27465399},
issn = {1756-8722},
mesh = {Adolescent ; Adult ; Aged ; Bone Marrow Cells ; Chromosome Aberrations ; Female ; Genomic Instability ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; *Mutation ; Myelodysplastic Syndromes/*genetics/*pathology ; Survival Rate ; Telomere/*pathology ; Telomere Shortening ; Young Adult ; },
abstract = {BACKGROUND: Telomere erosion can lead to genomic instability and cancer progression. It has been suggested that the shortest telomere, not the average telomere length (TL), is critical for cell viability. Some studies have shown shorter TL in myelodysplastic syndrome (MDS) patients but the critically short telomeres, the variability of TL within individual patient has not been evaluated. Thus, we aimed to investigate the TL of MDS patients and assessed the association of TL with recurrent genetic mutations in MDS.<br><br>METHODS: We measured the TL of bone marrow nucleated cells for diagnostic samples at a single-cell level by quantitative fluorescence in situ hybridization (Q-FISH) for 58 MDS patients and analyzed the minimum, median, average, standard deviation, average of the 0th to 10th percentile TL within a patient, and the proportion of cells with TL that is shorter than the lowest 10th percentile of the normal control (NC). The correlations of TL to clinical parameters, cytogenetic results, and genetic mutations were assessed.<br><br>RESULTS: MDS patients showed eroded telomeres and narrow distribution compared to the NC (P&#x2009;<&#x2009;0.001, P&#x2009;=&#x2009;0.018, respectively). Patients with mutation showed significantly lesser cells with short TL, below the lowest 10th percentile of the NC (P&#x2009;=&#x2009;0.017), but no differences in TL were found according to mutations/cytogenetic abnormalities except for CSF3R mutation. However, those patients with a high percentage (&#x2265;80&#xa0;%) of cells with short TL showed poorer overall survival (P&#x2009;=&#x2009;0.021), and this was an independent prognostic factor, along with TP53, U2AF1 mutation, and high BM blast count (P&#x2009;=&#x2009;0.044, 0.001, 0.004, 0.012, respectively).<br><br>CONCLUSIONS: The shortest TL, which determines the fate of the cell, was significantly shorter, and higher burden of cells with short TL were found in MDS, which correlated with poor survival, suggesting the need to measure TL in single cells by Q-FISH.},
}
@article {pmid27459707,
year = {2016},
author = {Karami, S and Han, Y and Pande, M and Cheng, I and Rudd, J and Pierce, BL and Nutter, EL and Schumacher, FR and Kote-Jarai, Z and Lindstrom, S and Witte, JS and Fang, S and Han, J and Kraft, P and Hunter, DJ and Song, F and Hung, RJ and McKay, J and Gruber, SB and Chanock, SJ and Risch, A and Shen, H and Haiman, CA and Boardman, L and Ulrich, CM and Casey, G and Peters, U and Amin Al Olama, A and Berchuck, A and Berndt, SI and Bezieau, S and Brennan, P and Brenner, H and Brinton, L and Caporaso, N and Chan, AT and Chang-Claude, J and Christiani, DC and Cunningham, JM and Easton, D and Eeles, RA and Eisen, T and Gala, M and Gallinger, SJ and Gayther, SA and Goode, EL and Grönberg, H and Henderson, BE and Houlston, R and Joshi, AD and Küry, S and Landi, MT and Le Marchand, L and Muir, K and Newcomb, PA and Permuth-Wey, J and Pharoah, P and Phelan, C and Potter, JD and Ramus, SJ and Risch, H and Schildkraut, J and Slattery, ML and Song, H and Wentzensen, N and White, E and Wiklund, F and Zanke, BW and Sellers, TA and Zheng, W and Chatterjee, N and Amos, CI and Doherty, JA and , },
title = {Telomere structure and maintenance gene variants and risk of five cancer types.},
journal = {International journal of cancer},
volume = {139},
number = {12},
pages = {2655-2670},
pmid = {27459707},
issn = {1097-0215},
support = {P01 CA087969/CA/NCI NIH HHS/United States ; HHSN268201100004I/HL/NHLBI NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; U01 CA164930/CA/NCI NIH HHS/United States ; UL1 TR001108/TR/NCATS NIH HHS/United States ; HHSN271201100004C/AG/NIA NIH HHS/United States ; R01 CA042182/CA/NCI NIH HHS/United States ; R01 CA060987/CA/NCI NIH HHS/United States ; UM1 CA167551/CA/NCI NIH HHS/United States ; P50 CA127003/CA/NCI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; HHSN268201100001I/HL/NHLBI NIH HHS/United States ; U19 CA148127/CA/NCI NIH HHS/United States ; 10124/CRUK_/Cancer Research UK/United Kingdom ; R01 CA076366/CA/NCI NIH HHS/United States ; R35 CA197449/CA/NCI NIH HHS/United States ; U01 HG004438/HG/NHGRI NIH HHS/United States ; U01 HG004446/HG/NHGRI NIH HHS/United States ; P50 CA180995/CA/NCI NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; R01 CA048998/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; HHSN268201100003C/WH/WHI NIH HHS/United States ; Z01 CP010200/ImNIH/Intramural NIH HHS/United States ; P30 CA023108/CA/NCI NIH HHS/United States ; 17528/CRUK_/Cancer Research UK/United Kingdom ; R01 CA137178/CA/NCI NIH HHS/United States ; R01 CA128978/CA/NCI NIH HHS/United States ; R01 ES020506/ES/NIEHS NIH HHS/United States ; K07 CA160753/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; U19 CA148537/CA/NCI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; Z01 CP010200-03/ImNIH/Intramural NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; HHSN268201100002C/WH/WHI NIH HHS/United States ; R01 CA122443/CA/NCI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; 16561/CRUK_/Cancer Research UK/United Kingdom ; U19 CA148112/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; U19 CA148065/CA/NCI NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; HHSN268201100002I/HL/NHLBI NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; R01 CA151989/CA/NCI NIH HHS/United States ; 15007/CRUK_/Cancer Research UK/United Kingdom ; U01 CA164973/CA/NCI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; P50 CA136393/CA/NCI NIH HHS/United States ; HHSN268201100001C/WH/WHI NIH HHS/United States ; HHSN268201100004C/WH/WHI NIH HHS/United States ; 10119/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Alleles ; Case-Control Studies ; Genetic Association Studies ; Genetic Predisposition to Disease ; *Genetic Variation ; Genome-Wide Association Study ; Humans ; Linkage Disequilibrium ; Neoplasms/*epidemiology/*genetics ; Odds Ratio ; Polymorphism, Single Nucleotide ; Risk ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; White People ; },
abstract = {Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs ≤3.08 × 10[-5]). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk.},
}
@article {pmid27459442,
year = {2016},
author = {Townsend, MK and Aschard, H and De Vivo, I and Michels, KB and Kraft, P},
title = {Genomics, Telomere Length, Epigenetics, and Metabolomics in the Nurses' Health Studies.},
journal = {American journal of public health},
volume = {106},
number = {9},
pages = {1663-1668},
pmid = {27459442},
issn = {1541-0048},
support = {P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA067262/CA/NCI NIH HHS/United States ; UM1 CA176726/CA/NCI NIH HHS/United States ; K01 HL125698/HL/NHLBI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Biomarkers ; Epidemiologic Studies ; *Epigenomics ; Female ; Gene-Environment Interaction ; *Genomics ; Genotype ; Humans ; Life Style ; Longitudinal Studies ; *Metabolomics ; Middle Aged ; *Nurses ; Phenotype ; Prospective Studies ; Risk Factors ; *Telomere ; United States/epidemiology ; Women's Health ; },
abstract = {OBJECTIVES: To review the contribution of the Nurses' Health Study (NHS) and NHS II to genomics, epigenetics, and metabolomics research.<br><br>METHODS: We performed a narrative review of the publications of the NHS and NHS II between 1990 and 2016 based on biospecimens, including blood and tumor tissue, collected from participants.<br><br>RESULTS: The NHS has contributed to the discovery of genetic loci influencing more than 45 complex human phenotypes, including cancers, diabetes, cardiovascular disease, reproductive characteristics, and anthropometric traits. The combination of genomewide genotype data with extensive exposure and lifestyle data has enabled the evaluation of gene-environment interactions. Furthermore, data suggest that longer telomere length increases risk of cancers not related to smoking, and that modifiable factors (e.g., diet) may have an impact on telomere length. "Omics" research in the NHS continues to expand, with epigenetics and metabolomics becoming greater areas of focus.<br><br>CONCLUSIONS: The combination of prospective biomarker data and broad exposure information has enabled the NHS to participate in a variety of "omics" research, contributing to understanding of the epidemiology and biology of multiple complex diseases.},
}
@article {pmid27452433,
year = {2016},
author = {Biron-Shental, T and Liberman, M and Elbaz, M and Laish, I and Sharony, R and Amiel, A},
title = {Telomere homeostasis in placentas from pregnancies with uncontrolled diabetes.},
journal = {Placenta},
volume = {44},
number = {},
pages = {13-18},
doi = {10.1016/j.placenta.2016.05.009},
pmid = {27452433},
issn = {1532-3102},
mesh = {Adult ; Diabetes, Gestational/*metabolism ; Female ; Fetal Blood/metabolism ; Humans ; Placenta/*metabolism ; Pregnancy ; Telomerase/*metabolism ; Telomere/metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {OBJECTIVE: Diabetes during pregnancy causes an intrauterine environment that influences lifetime sickness of the mother and the fetus. There is a correlation between diabetes and telomere shortening; however, very little is known about telomere homeostasis in the placenta. We aimed to study the telomerase complex in placentas and in cord blood leukocytes from patients with poorly controlled diabetes.<br><br>METHODS: Biopsies from 16 third-trimester placentas and cord blood samples from pregnancies complicated with uncontrolled diabetes and from 16 gestational age-matched controls from uncomplicated pregnancies were examined. The expression of hTERT (human telomerase reverse transcriptase) was evaluated by immunohistochemistry and by RT-RCR. TERC gene copy number and telomere capture were evaluated by FISH.<br><br>RESULTS: Telomerase expression was significantly lower in the diabetic placentas, both the protein (17.8&#xa0;&#xb1;&#xa0;2.8% cellular staining vs. 37&#xa0;&#xb1;&#xa0;5.32%, P&#xa0;=&#xa0;0.012) and the mRNA levels (0.42&#xa0;&#xb1;&#xa0;0.03 folds, P&#xa0;=&#xa0;0.022). Lower expression of TERC gene copy number were shown in the diabetic placentas compared to the healthy controls (1.7&#xa0;&#xb1;&#xa0;0.8% vs. 3.7&#xa0;&#xb1;&#xa0;1.6%, P&#xa0;=&#xa0;0.035). We also detected higher percentage of cells with telomere capture among the diabetic trophoblasts compared to the healthy controls (19.8&#xa0;&#xb1;&#xa0;5.12% vs. 9.6&#xa0;&#xb1;&#xa0;3.65%, P&#xa0;=&#xa0;0.038). Those differences were not observed in cord blood leukocytes from the same samples.<br><br>CONCLUSIONS: Uncontrolled diabetes during pregnancy disrupts telomere-telomerase homeostasis in the trophoblasts. These changes may increase the risk for metabolic diseases in adulthood among offspring of pregnancies complicated by gestational diabetes mellitus as part of intrauterine programming. These variations were not observed in cord blood leukocytes, which imply different telomere homeostasis mechanisms in fetal cord blood.},
}
@article {pmid27451965,
year = {2017},
author = {Ping, F and Li, ZY and Lv, K and Zhou, MC and Dong, YX and Sun, Q and Li, YX},
title = {Deoxyribonucleic acid telomere length shortening can predict the incidence of non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus.},
journal = {Journal of diabetes investigation},
volume = {8},
number = {2},
pages = {174-180},
pmid = {27451965},
issn = {2040-1124},
mesh = {Aged ; DNA/*genetics ; Diabetes Mellitus, Type 2/*complications ; Humans ; Incidence ; Insulin Resistance/genetics ; Insulin-Secreting Cells/metabolism ; Lipids/blood ; Middle Aged ; Non-alcoholic Fatty Liver Disease/complications/epidemiology/*genetics ; Prospective Studies ; Risk Factors ; Telomere/*genetics ; },
abstract = {AIMS/INTRODUCTION: To investigate the effect of telomere shortening and other predictive factors of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus patients in a 6-year prospective cohort study.<br><br>MATERIALS AND METHODS: A total of 70 type 2 diabetes mellitus (mean age 57.8 &#xb1; 6.7 years) patients without NAFLD were included in the study, and 64 of them were successfully followed up 6 years later, excluding four cases with significant alcohol consumption. NAFLD was diagnosed by the hepatorenal ratio obtained by a quantitative ultrasound method using NIH image analysis software. The 39 individuals that developed NAFLD were allocated to group A, and the 21 individuals that did not develop NAFLD were allocated to group B. Fluorescent real-time quantitative polymerase chain reaction was used to measure telomere length.<br><br>RESULTS: There was no significant difference between the two groups in baseline telomere length; however, at the end of the 6th year, telomere length had become shorter in group A compared with group B. There were significant differences between these two groups in baseline body mass index, waistline, systolic blood pressure, glycated hemoglobin and fasting C-peptide level. In addition, the estimated indices of baseline insulin resistance increased in group A. Fasting insulin level, body mass index, systolic blood pressure at baseline and the shortening of telomere length were independent risk factors of NAFLD in type 2 diabetes mellitus patients.<br><br>CONCLUSIONS: Telomere length became shorter in type 2 diabetes mellitus patients who developed NAFLD over the course of 6 years. Type 2 diabetes mellitus patients who developed NAFLD had more serious insulin resistance compared with those who did not develop NAFLD a long time ago.},
}
@article {pmid27450718,
year = {2016},
author = {Lee, WP and Hou, MC and Lan, KH and Li, CP and Chao, Y and Lin, HC and Lee, SD},
title = {Helicobacter pylori-induced chronic inflammation causes telomere shortening of gastric mucosa by promoting PARP-1-mediated non-homologous end joining of DNA.},
journal = {Archives of biochemistry and biophysics},
volume = {606},
number = {},
pages = {90-98},
doi = {10.1016/j.abb.2016.07.014},
pmid = {27450718},
issn = {1096-0384},
mesh = {Adult ; Chronic Disease ; DNA/chemistry ; DNA Damage ; *DNA End-Joining Repair ; Female ; Gastric Mucosa/*metabolism ; Gastritis/metabolism ; Helicobacter Infections/drug therapy ; Helicobacter pylori/*pathogenicity ; Histones/chemistry ; Humans ; Hydrogen Peroxide/chemistry ; Inflammation/*microbiology ; Male ; Middle Aged ; NF-kappa B/metabolism ; Oxidative Stress ; Oxygen/chemistry ; Poly (ADP-Ribose) Polymerase-1/*metabolism ; RNA, Small Interfering/metabolism ; Telomere/chemistry/*ultrastructure ; },
abstract = {Helicobacter pylori infection leads to chronic gastritis and increased risk of gastric cancer. The mechanism involves chronic inflammation. We aimed to determine the mechanism by which H. pylori infection causes telomere shortening in inflammatory gastric mucosa. Gastric biopsy specimens were obtained from 20 patients with chronic gastritis or peptic ulcer caused by H. pylori infection. The specimens showed increased NF-κB and superoxide dismutase activities and elevated expressions of PARP-1 and γ-H2AX, all of which returned to normal levels after anti-H. pylori treatment, suggesting that oxidative DNA damage and PARP-1 overexpression might cause telomere shortening. In this report, we adopted DNA end joining assay and showed that H. pylori-infected gastric mucosa had increased alternative NHEJ (non-homologous end joining), implicating that telomere shortening was caused by inflammation-mediated overproduction of reactive oxygen species and PARP-1, leading to telomere shortening.},
}
@article {pmid27449056,
year = {2016},
author = {Cook, DE and Zdraljevic, S and Tanny, RE and Seo, B and Riccardi, DD and Noble, LM and Rockman, MV and Alkema, MJ and Braendle, C and Kammenga, JE and Wang, J and Kruglyak, L and Félix, MA and Lee, J and Andersen, EC},
title = {The Genetic Basis of Natural Variation in Caenorhabditis elegans Telomere Length.},
journal = {Genetics},
volume = {204},
number = {1},
pages = {371-383},
pmid = {27449056},
issn = {1943-2631},
support = {R01 GM107227/GM/NIGMS NIH HHS/United States ; R01 HG004321/HG/NHGRI NIH HHS/United States ; T32 GM008061/GM/NIGMS NIH HHS/United States ; R01 GM089972/GM/NIGMS NIH HHS/United States ; P30 CA060553/CA/NCI NIH HHS/United States ; R01 GM084491/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Caenorhabditis elegans/*genetics/metabolism ; Caenorhabditis elegans Proteins/genetics/metabolism ; DNA/metabolism ; Genetic Variation ; Genome-Wide Association Study ; Longevity/genetics ; Mutation ; Sequence Analysis, DNA ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomeres are involved in the maintenance of chromosomes and the prevention of genome instability. Despite this central importance, significant variation in telomere length has been observed in a variety of organisms. The genetic determinants of telomere-length variation and their effects on organismal fitness are largely unexplored. Here, we describe natural variation in telomere length across the Caenorhabditis elegans species. We identify a large-effect variant that contributes to differences in telomere length. The variant alters the conserved oligonucleotide/oligosaccharide-binding fold of protection of telomeres 2 (POT-2), a homolog of a human telomere-capping shelterin complex subunit. Mutations within this domain likely reduce the ability of POT-2 to bind telomeric DNA, thereby increasing telomere length. We find that telomere-length variation does not correlate with offspring production or longevity in C. elegans wild isolates, suggesting that naturally long telomeres play a limited role in modifying fitness phenotypes in C. elegans.},
}
@article {pmid27446538,
year = {2016},
author = {Swanson, MJ and Baribault, ME and Israel, JN and Bae, NS},
title = {Telomere protein RAP1 levels are affected by cellular aging and oxidative stress.},
journal = {Biomedical reports},
volume = {5},
number = {2},
pages = {181-187},
pmid = {27446538},
issn = {2049-9434},
abstract = {Telomeres are important for maintaining the integrity of the genome through the action of the shelterin complex. Previous studies indicted that the length of the telomere did not have an effect on the amount of the shelterin subunits; however, those experiments were performed using immortalized cells with stable telomere lengths. The interest of the present study was to observe how decreasing telomere lengths over successive generations would affect the shelterin subunits. As neonatal human dermal fibroblasts aged and their telomeres became shorter, the levels of the telomere-binding protein telomeric repeat factor 2 (TRF2) decreased significantly. By contrast, the levels of one of its binding partners, repressor/activator protein 1 (RAP1), decreased to a lesser extent than would be expected from the decrease in TRF2. Other subunits, TERF1-interacting nuclear factor 2 and protection of telomeres protein 1, remained stable. The decrease in RAP1 in the older cells occurred in the nuclear and cytoplasmic fractions. Hydrogen peroxide (H2O2) stress was used as an artificial means of aging in the cells, and this resulted in RAP1 levels decreasing, but the effect was only observed in the nuclear portion. Similar results were obtained using U251 glioblastoma cells treated with H2O2 or grown in serum-depleted medium. The present findings indicate that TRF2 and RAP1 levels decrease as fibroblasts naturally age. RAP1 remains more stable compared to TRF2. RAP1 also responds to oxidative stress, but the response is different to that observed in aging.},
}
@article {pmid27446102,
year = {2016},
author = {Procházková Schrumpfová, P and Schořová, &#x160; and Fajkus, J},
title = {Telomere- and Telomerase-Associated Proteins and Their Functions in the Plant Cell.},
journal = {Frontiers in plant science},
volume = {7},
number = {},
pages = {851},
pmid = {27446102},
issn = {1664-462X},
abstract = {Telomeres, as physical ends of linear chromosomes, are targets of a number of specific proteins, including primarily telomerase reverse transcriptase. Access of proteins to the telomere may be affected by a number of diverse factors, e.g., protein interaction partners, local DNA or chromatin structures, subcellular localization/trafficking, or simply protein modification. Knowledge of composition of the functional nucleoprotein complex of plant telomeres is only fragmentary. Moreover, the plant telomeric repeat binding proteins that were characterized recently appear to also be involved in non-telomeric processes, e.g., ribosome biogenesis. This interesting finding was not totally unexpected since non-telomeric functions of yeast or animal telomeric proteins, as well as of telomerase subunits, have been reported for almost a decade. Here we summarize known facts about the architecture of plant telomeres and compare them with the well-described composition of telomeres in other organisms.},
}
@article {pmid27440083,
year = {2016},
author = {Wojcicki, JM and Heyman, MB and Elwan, D and Lin, J and Blackburn, E and Epel, E},
title = {Early exclusive breastfeeding is associated with longer telomeres in Latino preschool children.},
journal = {The American journal of clinical nutrition},
volume = {104},
number = {2},
pages = {397-405},
pmid = {27440083},
issn = {1938-3207},
support = {UL1 RR024131/RR/NCRR NIH HHS/United States ; },
mesh = {Age Factors ; Beverages ; *Breast Feeding ; Child, Preschool ; Cohort Studies ; *Diet ; Dietary Sucrose/pharmacology ; Fathers ; Female ; *Hispanic or Latino ; Humans ; Infant ; Infant, Newborn ; Male ; Milk, Human ; Mothers ; Pediatric Obesity/complications ; Risk Factors ; *Telomere ; *Telomere Shortening ; Urban Population ; },
abstract = {BACKGROUND: Telomere length (TL) is a marker of cellular aging, with the majority of lifetime attrition occurring during the first 4 y. Little is known about risk factors for telomere shortening in childhood.<br><br>OBJECTIVE: We evaluated the relation between early life feeding variables and preschool TL.<br><br>DESIGN: We assessed the relation between dietary, feeding, and weight-associated risk factors measured from birth and TL from blood samples taken at 4 y of age (n = 108) and 5 y of age (n = 92) in a cohort of urban, Latino children (n = 121 individual children). Feeding variables were evaluated in children with repeat measurements (n = 77).<br><br>RESULTS: Mean TL (in bp) was associated with exclusive breastfeeding at 4-6 wk of age (adjusted coefficient: 353.85; 95% CI: 72.81, 634.89; P = 0.01), maternal TL (adjusted coefficient: 0.32; 95% CI: 0.11, 0.54; P < 0.01), and older paternal age (adjusted coefficient: 33.27; 95% CI: 4.10, 62.44; P = 0.03). The introduction of other foods or drinks in addition to breast-milk or replacement-milk substitutes before 4-6 wk of age was associated with mean TL at 4 and 5 y of age (adjusted coefficient: -457.01; 95% CI: -720.50, -193.51; P < 0.01). Infant obesity at 6 mo of age and soda consumption at 4 y of age mediated the relation in part between exclusive breastfeeding at 4-6 wk of age and mean TL at 4 and 5 y of age. High soda consumption at 3 y of age was associated with an accelerated attrition from 4 to 5 y of age (adjusted coefficient: -515.14; 95% CI: -986.06, -41.22; P = 0.03).<br><br>CONCLUSION: Exclusive breastfeeding at 4-6 wk of age may have long-term effects on child health as evidenced by longer TL at 4 and 5 y of age.},
}
@article {pmid27439449,
year = {2016},
author = {Andreassi, MG and Borghini, A and Pulignani, S and Baffigi, F and Fulgentini, L and Koester, P and Cresci, M and Vecoli, C and Lamia, D and Russo, G and Panetta, D and Tripodi, M and Gizzi, LA and Labate, L},
title = {Radiobiological Effectiveness of Ultrashort Laser-Driven Electron Bunches: Micronucleus Frequency, Telomere Shortening and Cell Viability.},
journal = {Radiation research},
volume = {186},
number = {3},
pages = {245-253},
doi = {10.1667/RR14266.1},
pmid = {27439449},
issn = {1938-5404},
mesh = {Cell Line, Tumor ; Cell Survival/*radiation effects ; Dose-Response Relationship, Radiation ; *Electrons ; Humans ; *Lasers ; Lymphocytes/cytology/metabolism/radiation effects ; *Micronucleus Tests ; Particle Accelerators ; Relative Biological Effectiveness ; Telomere Shortening/*radiation effects ; X-Rays/adverse effects ; },
abstract = {Laser-driven electron accelerators are capable of producing high-energy electron bunches in shorter distances than conventional radiofrequency accelerators. To date, our knowledge of the radiobiological effects in cells exposed to electrons using a laser-plasma accelerator is still very limited. In this study, we compared the dose-response curves for micronucleus (MN) frequency and telomere length in peripheral blood lymphocytes exposed to laser-driven electron pulse and X-ray radiations. Additionally, we evaluated the effects on cell survival of in vitro tumor cells after exposure to laser-driven electron pulse compared to electron beams produced by a conventional radiofrequency accelerator used for intraoperative radiation therapy. Blood samples from two different donors were exposed to six radiation doses ranging from 0 to 2 Gy. Relative biological effectiveness (RBE) for micronucleus induction was calculated from the alpha coefficients for electrons compared to X rays (RBE = alpha laser/alpha X rays). Cell viability was monitored in the OVCAR-3 ovarian cancer cell line using trypan blue exclusion assay at day 3, 5 and 7 postirradiation (2, 4, 6, 8 and 10 Gy). The RBE values obtained by comparing the alpha values were 1.3 and 1.2 for the two donors. Mean telomere length was also found to be reduced in a significant dose-dependent manner after irradiation with both electrons and X rays in both donors studied. Our findings showed a radiobiological response as mirrored by the induction of micronuclei and shortening of telomere as well as by the reduction of cell survival in blood samples and cancer cells exposed in vitro to laser-generated electron bunches. Additional studies are needed to improve preclinical validation of the radiobiological characteristics and efficacy of laser-driven electron accelerators in the future.},
}
@article {pmid27437767,
year = {2016},
author = {Bonfigli, AR and Spazzafumo, L and Prattichizzo, F and Bonafè, M and Mensà, E and Micolucci, L and Giuliani, A and Fabbietti, P and Testa, R and Boemi, M and Lattanzio, F and Olivieri, F},
title = {Leukocyte telomere length and mortality risk in patients with type 2 diabetes.},
journal = {Oncotarget},
volume = {7},
number = {32},
pages = {50835-50844},
pmid = {27437767},
issn = {1949-2553},
mesh = {Adult ; Aged ; Diabetes Mellitus, Type 2/*genetics/*mortality ; Female ; Genetic Markers/genetics ; Humans ; Kaplan-Meier Estimate ; Leukocytes/*pathology ; Male ; Middle Aged ; Prognosis ; Telomere/*pathology ; },
abstract = {Leukocyte telomere length (LTL) shortening is found in a number of age-related diseases, including type 2 diabetes (T2DM). In this study its possible association with mortality was analyzed in a sample of 568 T2DM patients (mean age 65.9 ± 9 years), who were followed for a median of 10.2 years (interquartile range 2.2). A number of demographic, laboratory and clinical parameters determined at baseline were evaluated as mortality risk factors. LTL was measured by quantitative real-time PCR and reported as T/S (telomere-to-single copy gene ratio). Age, gender, creatinine, diabetes duration at baseline, and LTL were significantly different between T2DM patients who were dead and alive at follow-up. In the Cox regression analysis adjusted for the confounding variables, shorter LTL, older age, and longer disease duration significantly increased the risk of all-cause mortality (HR = 3.45, 95%CI 1.02-12.5, p = 0.004). Kaplan-Maier analysis also found a different cumulative mortality risk for patients having an LTL shorter than the median (T/S ≤0.04) and disease duration longer than the median (>10 years) (log-rank = 11.02, p = 0.011). Time-dependent mortality risk stratification showed that T2DM duration and LTL combined was a fairly good predictor of mortality over the first 76 months of follow-up.In conclusion, LTL combined with clinical parameters can provide additive prognostic information on mortality risk in T2DM patients.},
}
@article {pmid27432940,
year = {2016},
author = {Simon, AJ and Lev, A and Zhang, Y and Weiss, B and Rylova, A and Eyal, E and Kol, N and Barel, O and Cesarkas, K and Soudack, M and Greenberg-Kushnir, N and Rhodes, M and Wiest, DL and Schiby, G and Barshack, I and Katz, S and Pras, E and Poran, H and Reznik-Wolf, H and Ribakovsky, E and Simon, C and Hazou, W and Sidi, Y and Lahad, A and Katzir, H and Sagie, S and Aqeilan, HA and Glousker, G and Amariglio, N and Tzfati, Y and Selig, S and Rechavi, G and Somech, R},
title = {Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects.},
journal = {The Journal of experimental medicine},
volume = {213},
number = {8},
pages = {1429-1440},
pmid = {27432940},
issn = {1540-9538},
support = {15-0338/AICR_/Worldwide Cancer Research/United Kingdom ; P30 CA006927/CA/NCI NIH HHS/United States ; R21 AI111208/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; *Ataxia/drug therapy/genetics/metabolism/pathology ; *Brain Neoplasms/drug therapy/genetics/metabolism/pathology ; *Calcinosis/drug therapy/genetics/metabolism/pathology ; *Central Nervous System Cysts/drug therapy/genetics/metabolism/pathology ; Disease Models, Animal ; Female ; Gene Expression Regulation/*drug effects ; Humans ; *Leukoencephalopathies/drug therapy/genetics/metabolism/pathology ; Male ; *Muscle Spasticity/drug therapy/genetics/metabolism/pathology ; *Mutation ; *Retinal Diseases/drug therapy/genetics/metabolism/pathology ; *Seizures/drug therapy/genetics/metabolism/pathology ; *Telomere/genetics/metabolism/pathology ; *Telomere-Binding Proteins/biosynthesis/genetics ; Thalidomide/*administration &amp; dosage/adverse effects ; Zebrafish ; },
abstract = {The analysis of individuals with telomere defects may shed light on the delicate interplay of factors controlling genome stability, premature aging, and cancer. We herein describe two Coats plus patients with telomere and genomic defects; both harbor distinct, novel mutations in STN1, a member of the human CTC1-STN1-TEN1 (CST) complex, thus linking this gene for the first time to a human telomeropathy. We characterized the patients' phenotype, recapitulated it in a zebrafish model and rescued cellular and clinical aspects by the ectopic expression of wild-type STN1 or by thalidomide treatment. Interestingly, a significant lengthy control of the gastrointestinal bleeding in one of our patients was achieved by thalidomide treatment, exemplifying a successful bed-to-bench-and-back approach.},
}
@article {pmid27428329,
year = {2016},
author = {Claussin, C and Chang, M},
title = {Multiple Rad52-Mediated Homology-Directed Repair Mechanisms Are Required to Prevent Telomere Attrition-Induced Senescence in Saccharomyces cerevisiae.},
journal = {PLoS genetics},
volume = {12},
number = {7},
pages = {e1006176},
pmid = {27428329},
issn = {1553-7404},
mesh = {Chromatids/metabolism ; *DNA Repair ; Gene Expression Regulation, Fungal ; Histones/chemistry ; Lysine/chemistry ; Microscopy, Fluorescence ; Mutation ; Plasmids/metabolism ; Polymerase Chain Reaction ; Rad52 DNA Repair and Recombination Protein/*genetics/metabolism ; Recombination, Genetic ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Sister Chromatid Exchange ; Telomerase/genetics ; Telomere/*ultrastructure ; },
abstract = {Most human somatic cells express insufficient levels of telomerase, which can result in telomere shortening and eventually senescence, both of which are hallmarks of ageing. Homology-directed repair (HDR) is important for maintaining proper telomere function in yeast and mammals. In Saccharomyces cerevisiae, Rad52 is required for almost all HDR mechanisms, and telomerase-null cells senesce faster in the absence of Rad52. However, its role in preventing accelerated senescence has been unclear. In this study, we make use of rad52 separation-of-function mutants to find that multiple Rad52-mediated HDR mechanisms are required to delay senescence, including break-induced replication and sister chromatid recombination. In addition, we show that misregulation of histone 3 lysine 56 acetylation, which is known to be defective in sister chromatid recombination, also causes accelerated senescence. We propose a model where Rad52 is needed to repair telomere attrition-induced replication stress.},
}
@article {pmid27429957,
year = {2016},
author = {Hough, CM and Bersani, FS and Mellon, SH and Epel, ES and Reus, VI and Lindqvist, D and Lin, J and Mahan, L and Rosser, R and Burke, H and Coetzee, J and Nelson, JC and Blackburn, EH and Wolkowitz, OM},
title = {Leukocyte telomere length predicts SSRI response in major depressive disorder: A preliminary report.},
journal = {Molecular neuropsychiatry},
volume = {2},
number = {2},
pages = {88-96},
pmid = {27429957},
issn = {2296-9209},
support = {R01 MH083784/MH/NIMH NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; },
abstract = {Short leukocyte telomere length (LTL) may be associated with several psychiatric disorders, including major depressive disorder (MDD). Short LTL has previously been associated with poor response to psychiatric medications in bipolar disorder and schizophrenia, but no studies have prospectively assessed the relationship of LTL to SSRI response in MDD. We assessed pre-treatment LTL, depression severity (using the Hamilton Depression Rating Scale [HDRS]), and self-reported positive and negative affect in 27 healthy, unmedicated adults with MDD. Subjects then underwent open-label treatment with a selective serotonin reuptake inhibitor (SSRI) antidepressant for eight weeks, after which clinical ratings were repeated. Analyses were corrected for age, sex and BMI. "Non-responders" to treatment (HDRS improvement <50%) had significantly shorter pre-treatment LTL, compared to "Responders" (p=0.037). Further, shorter pre-treatment LTL was associated with less improvement in negative affect (p<0.010) but not with changes in positive affect (p=0.356). This preliminary study is the first to assess the relationship between LTL and SSRI response in MDD and among the first to prospectively assess its relationship to treatment outcome in any psychiatric illness. Our data suggest that short LTL may serve as a vulnerability index of poorer response to SSRI treatment, but this needs examination in larger samples.},
}
@article {pmid27427384,
year = {2016},
author = {Root, H and Larsen, A and Komosa, M and Al-Azri, F and Li, R and Bazett-Jones, DP and Stephen Meyn, M},
title = {FANCD2 limits BLM-dependent telomere instability in the alternative lengthening of telomeres pathway.},
journal = {Human molecular genetics},
volume = {25},
number = {15},
pages = {3255-3268},
doi = {10.1093/hmg/ddw175},
pmid = {27427384},
issn = {1460-2083},
mesh = {Cell Line ; Fanconi Anemia Complementation Group D2 Protein/genetics/*metabolism ; Humans ; Rad51 Recombinase/genetics/metabolism ; RecQ Helicases/genetics/*metabolism ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; },
abstract = {Fanconi anemia and Bloom syndrome are genomic instability syndromes caused by mutations in proteins that participate in overlapping DNA repair and replication pathways. Here, we show that the monoubiquitinated form of the Fanconi Anemia protein FANCD2 acts in opposition to the BLM DNA helicase to restrain telomere replication and recombination in human cells that utilize the Alternative Lengthening of Telomeres (ALT) pathway. ALT relies on exchanges of telomeric DNA to maintain telomeres, a process that we show FANCD2 suppresses. Depletion of FANCD2 results in a hyper-ALT phenotype, including an increase in extrachromosomal telomeric repeat DNAs, putative recombinational byproducts that we show exist as intertwined complexes forming the nucleic acid component of ALT-associated PML bodies. Increases in telomeric DNA are suppressed by loss of BLM but not RAD51, occur without parallel upregulation of shelterin proteins TRF1 and TRF2, and are associated with increased frequencies of deprotected and fragile telomeres. Inactivation of the FA pathway does not trigger ALT, as FANCD2 depleted telomerase positive cells do not acquire ALT-like phenotypes. We observe frequent fragile telomeres in ALT cells, suggesting that telomere sequences are prone to replication problems. We propose that, in ALT cells, FANCD2 promotes intramolecular resolution of stalled replication forks in telomeric DNA while BLM facilitates their resection and subsequent involvement in the intermolecular exchanges that drive ALT.},
}
@article {pmid27423705,
year = {2016},
author = {Scinicariello, F and Buser, MC},
title = {Urinary antimony and leukocyte telomere length: An analysis of NHANES 1999-2002.},
journal = {Environmental research},
volume = {150},
number = {},
pages = {513-518},
pmid = {27423705},
issn = {1096-0953},
support = {CC999999//Intramural CDC HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Antimony/*urine ; Creatinine/urine ; Environmental Monitoring ; Environmental Pollutants/*urine ; Female ; Humans ; Lead/urine ; Leukocytes/*metabolism ; Male ; Middle Aged ; Nutrition Surveys ; Telomere/*metabolism ; Young Adult ; },
abstract = {Telomeres are repetitive DNA sequences (TTAGGG) at the end of chromosomes. Cells with critically short telomeres enter replicative senescence and apoptosis. Several in vitro studies report that antimony causes cell apoptosis in human leukocyte cell lines. The goal of this analysis was to investigate whether there is an association between antimony exposure and leukocyte telomere length (LTL) among US adults aged 20 and older based on the National Health and Nutrition Examination Survey (NHANES) 1999-2002. We used multivariate linear regression to analyze the association of urinary antimony with LTL. LTL was log-natural transformed and the results were re-transformed and presented as percent differences. After adjustment for potential confounders, individuals in the 3rd and 4th quartiles of urinary antimony had statistically significantly shorter LTL (-4.78%, 95% CI: -8.42,-0.90; and -6.11%, 95% CI: -11.04,-1.00, respectively) compared to the lowest referent quartile, with evidence of a dose-response relationship (p-value for trend =0.03). Shorter LTL with antimony was driven by middle aged (40-59 years) and older (60-85 years) adult groups. The association may be biologically plausible because of reported oxidative stress and apoptosis effects of antimony on blood cells, effects known to shorten telomere length.},
}
@article {pmid27422587,
year = {2016},
author = {Hill, TD and Ellison, CG and Taylor, J and Burdette, AM},
title = {A response to a commentary on "Dimensions of religious involvement and leukocyte telomere length".},
journal = {Social science &amp; medicine (1982)},
volume = {163},
number = {},
pages = {179-180},
doi = {10.1016/j.socscimed.2016.06.050},
pmid = {27422587},
issn = {1873-5347},
mesh = {*Leukocytes ; *Telomere ; },
}
@article {pmid27419638,
year = {2016},
author = {Sfeir, A and Denchi, EL},
title = {Stressed telomeres without POT1 enhance tumorigenesis.},
journal = {Oncotarget},
volume = {7},
number = {30},
pages = {46833-46834},
pmid = {27419638},
issn = {1949-2553},
mesh = {Animals ; Carcinogenesis/*genetics ; DNA Replication ; DNA-Binding Proteins/*deficiency/genetics/metabolism ; Mice ; *Mutation ; Neoplasms/*genetics/metabolism/*pathology ; Shelterin Complex ; Telomere/genetics/*metabolism/*pathology ; Telomere-Binding Proteins ; },
}
@article {pmid27419529,
year = {2016},
author = {Chartrand, P},
title = {Special focus on telomeres and telomerase.},
journal = {RNA biology},
volume = {13},
number = {8},
pages = {681-682},
pmid = {27419529},
issn = {1555-8584},
mesh = {Humans ; Neoplasms/genetics/metabolism ; Pluripotent Stem Cells/metabolism ; RNA/genetics/*metabolism ; Shelterin Complex ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
}
@article {pmid27419121,
year = {2016},
author = {Shin, YA and Lee, KY},
title = {Low estrogen levels and obesity are associated with shorter telomere lengths in pre- and postmenopausal women.},
journal = {Journal of exercise rehabilitation},
volume = {12},
number = {3},
pages = {238-246},
pmid = {27419121},
issn = {2288-176X},
abstract = {The aim of this study was to determine whether there is an association between leukocyte telomere length (LTL), and estrogen level, oxidative stress, cardiovascular disease (CVD) risk factors, and cardiorespiratory fitness (CRF) in pre- and postmenopausal obese women. Fifty-four obese women (premenopausal, n=25; postmenopausal, n=29) were selected to participate in this study. The outcome measurements in the pre- and postmenopausal groups were compared using independent t-tests and Pearson correlation analysis. The estrogen level (P<0.001), LTL (P<0.05), high-density lipoprotein level (P<0.05), and CRF (P<0.001) were higher in premenopausal women than in postmenopausal women. The body fat percentage (P<0.05) and triglyceride concentration (P<0.05) were lower in premenopausal women than in postmenopausal women. There were no significant associations between LTL, CVD risk, CRF, and oxidative stress and antioxidant enzyme activity in pre-menopausal women. The body mass index (BMI) and body fat percent-age in postmenopausal women were negatively associated with LTL (P<0.05). When all women were considered (i.e., both pre- and post-menopause), the BMI, percentage of fat, and waist circumference had a negative association with LTL (P<0.05), and estrogen levels were positively associated with LTL (P<0.05). Decreased estrogen levels after menopause, a pivotal factor in the biology of aging, and obesity were more associated with shorter telomere lengths in pre- and postmenopausal women than aerobic capacity and other CVD risk factors.},
}
@article {pmid27418163,
year = {2016},
author = {Kasielski, M and Eusebio, MO and Pietruczuk, M and Nowak, D},
title = {The relationship between peripheral blood mononuclear cells telomere length and diet - unexpected effect of red meat.},
journal = {Nutrition journal},
volume = {15},
number = {1},
pages = {68},
pmid = {27418163},
issn = {1475-2891},
mesh = {Adolescent ; Adult ; Aged ; Beverages ; Cholesterol, HDL/blood ; Cholesterol, LDL/blood ; Cross-Sectional Studies ; Dairy Products ; *Diet ; Edible Grain ; Exercise ; Female ; Fruit ; Humans ; Leukocytes, Mononuclear/*metabolism ; Male ; Middle Aged ; Prospective Studies ; Red Meat/*adverse effects ; Smoking/adverse effects ; Socioeconomic Factors ; Surveys and Questionnaires ; Telomere/*ultrastructure ; Vegetables ; Young Adult ; },
abstract = {BACKGROUND: Repeated nucleotide sequences combined with proteins called telomeres cover chromosome ends and dictate cells lifespan. Many factors can modify telomere length, among them are: nutrition and smoking habits, physical activities and socioeconomic status measured by education level. The aim of the study was to determine the influence of above mentioned factors on peripheral blood mononuclear cells telomere length.<br><br>METHODS: Study included 28 subjects (seven male and 21 female, age 18-65&#xa0;years.), smokers and non-smokers without any serious health problems in past and present. Following a basic medical examination, patients completed the food frequency questionnaire with 17 foods and beverages most common groups and gave blood for testing. PBMC telomere length were measured with qualitative real-time Polymerase Chain Reaction (rtPCR) method and expressed as a T/S ratio.<br><br>RESULTS: Among nine food types (cereal, fruits, vegetables, diary, red meat, poultry, fish, sweets and salty snacks) and eight beverages (juices, coffee, tea, mineral water, alcoholic- and sweetened carbonated beverages) only intake of red meat was related to T/S ratio. Individuals with increased consumption of red meat have had higher T/S ratio and the strongest significant differences were observed between consumer groups: "never" and "1-2 daily" (p&#x2009;=&#x2009;0.02). Smoking habits, physical activity, LDL and HDL concentrations, and education level were not related to telomere length, directly or as a covariates.<br><br>CONCLUSIONS: Unexpected correlation of telomere length with the frequency of consumption of red meat indicates the need for further in-depth research and may undermine some accepted concepts of adverse effects of this diet on the health status and life longevity.},
}
@article {pmid27407094,
year = {2017},
author = {Singhi, AD and Liu, TC and Roncaioli, JL and Cao, D and Zeh, HJ and Zureikat, AH and Tsung, A and Marsh, JW and Lee, KK and Hogg, ME and Bahary, N and Brand, RE and McGrath, KM and Slivka, A and Cressman, KL and Fuhrer, K and O'Sullivan, RJ},
title = {Alternative Lengthening of Telomeres and Loss of DAXX/ATRX Expression Predicts Metastatic Disease and Poor Survival in Patients with Pancreatic Neuroendocrine Tumors.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {23},
number = {2},
pages = {600-609},
pmid = {27407094},
issn = {1557-3265},
support = {P30 CA047904/CA/NCI NIH HHS/United States ; R01 CA207209/CA/NCI NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing/*genetics ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Neuroendocrine/*genetics/pathology ; Co-Repressor Proteins ; Disease-Free Survival ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; In Situ Hybridization, Fluorescence ; Lymphatic Metastasis/genetics ; Male ; Middle Aged ; Molecular Chaperones ; Neoplasm Metastasis ; Nuclear Proteins/*genetics ; Pancreatic Neoplasms/*genetics/pathology ; Telomere ; Telomere Homeostasis/*genetics ; Exome Sequencing ; X-linked Nuclear Protein/*genetics ; },
abstract = {PURPOSE: Pancreatic neuroendocrine tumors (PanNET) are a heterogeneous group of neoplasms with increasing incidence and unpredictable behavior. Whole-exome sequencing has identified recurrent mutations in the genes DAXX and ATRX, which correlate with loss of protein expression and alternative lengthening of telomeres (ALT). Both ALT and DAXX/ATRX loss were initially reported to be associated with a favorable prognosis; however, recent studies suggest the contrary. Our aims were to assess the prevalence and prognostic significance of ALT and DAXX/ATRX in both primary and metastatic PanNETs.<br><br>EXPERIMENTAL DESIGN: Telomere-specific FISH and DAXX/ATRX IHC was performed on a multi-institutional cohort of 321 patients with resected PanNET and 191 distant metastases from 52 patients. These results were correlated with clinicopathologic features, including disease-free survival (DFS) and disease-specific survival (DSS).<br><br>RESULTS: The prevalence of ALT and DAXX/ATRX loss in resected PanNETs was 31% and 26%, respectively, and associated with larger tumor size, higher WHO grade, lymph node metastasis, and distant metastasis (P < 0.001). The 5-year DFS and 10-year DSS of patients with ALT-positive and DAXX/ATRX-negative PanNETs were 40% and 50%, respectively, as compared with 96% and 89%, respectively, for wild-type PanNETs. Among distant metastases, ALT and DAXX/ATRX loss was 67% and 52%, respectively, and only occurred in the setting of an ALT-positive and DAXX/ATRX-negative primary PanNET. By multivariate analysis, both ALT and DAXX/ATRX loss were negative, independent prognostic factors for DFS.<br><br>CONCLUSIONS: ALT and DAXX/ATRX loss in PanNETs was associated with shorter DFS and DSS and likely plays a significant role in driving metastatic disease. Clin Cancer Res; 23(2); 600-9. &#xa9;2016 AACR.},
}
@article {pmid27405804,
year = {2016},
author = {Vega-Vaquero, A and Bonora, G and Morselli, M and Vaquero-Sedas, MI and Rubbi, L and Pellegrini, M and Vega-Palas, MA},
title = {Novel features of telomere biology revealed by the absence of telomeric DNA methylation.},
journal = {Genome research},
volume = {26},
number = {8},
pages = {1047-1056},
pmid = {27405804},
issn = {1549-5469},
support = {P30 CA016042/CA/NCI NIH HHS/United States ; },
mesh = {Arabidopsis/*genetics/growth &amp; development ; Cytosine/metabolism ; DNA Methylation/*genetics ; DNA, Mitochondrial/genetics ; RNA/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Cytosine methylation regulates the length and stability of telomeres, which can affect a wide variety of biological features, including cell differentiation, development, or illness. Although it is well established that subtelomeric regions are methylated, the presence of methylated cytosines at telomeres has remained controversial. Here, we have analyzed multiple bisulfite sequencing studies to address the methylation status of Arabidopsis thaliana telomeres. We found that the levels of estimated telomeric DNA methylation varied among studies. Interestingly, we estimated higher levels of telomeric DNA methylation in studies that produced C-rich telomeric strands with lower efficiency. However, these high methylation estimates arose due to experimental limitations of the bisulfite technique. We found a similar phenomenon for mitochondrial DNA: The levels of mitochondrial DNA methylation detected were higher in experiments with lower mitochondrial read production efficiencies. Based on experiments with high telomeric C-rich strand production efficiencies, we concluded that Arabidopsis telomeres are not methylated, which was confirmed by methylation-dependent restriction enzyme analyses. Thus, our studies indicate that telomeres are refractory to de novo DNA methylation by the RNA-directed DNA methylation machinery. This result, together with previously reported data, reveals that subtelomeric DNA methylation controls the homeostasis of telomere length.},
}
@article {pmid27401551,
year = {2016},
author = {Greider, CW},
title = {Regulating telomere length from the inside out: the replication fork model.},
journal = {Genes &amp; development},
volume = {30},
number = {13},
pages = {1483-1491},
pmid = {27401551},
issn = {1549-5477},
support = {R01 CA160300/CA/NCI NIH HHS/United States ; R35 CA209974/CA/NCI NIH HHS/United States ; R37 AG009383/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; DNA/metabolism ; DNA Replication/*physiology ; DNA-Directed DNA Polymerase/metabolism ; DNA-Directed RNA Polymerases/metabolism ; Feedback, Physiological/physiology ; Humans ; *Models, Biological ; Saccharomyces cerevisiae/genetics ; Telomere Homeostasis/*physiology ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomere length is regulated around an equilibrium set point. Telomeres shorten during replication and are lengthened by telomerase. Disruption of the length equilibrium leads to disease; thus, it is important to understand the mechanisms that regulate length at the molecular level. The prevailing protein-counting model for regulating telomerase access to elongate the telomere does not explain accumulating evidence of a role of DNA replication in telomere length regulation. Here I present an alternative model: the replication fork model that can explain how passage of a replication fork and regulation of origin firing affect telomere length.},
}
@article {pmid27398800,
year = {2016},
author = {Slijepcevic, P},
title = {Mechanisms of the Evolutionary Chromosome Plasticity: Integrating the 'Centromere-from-Telomere' Hypothesis with Telomere Length Regulation.},
journal = {Cytogenetic and genome research},
volume = {148},
number = {4},
pages = {268-278},
doi = {10.1159/000447415},
pmid = {27398800},
issn = {1424-859X},
mesh = {Animals ; Centromere/*genetics ; *Evolution, Molecular ; Genomic Instability/*genetics ; Humans ; Karyotype ; *Models, Genetic ; Symbiosis/genetics ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {The 'centromere-from-telomere' hypothesis proposed by Villasante et al. [2007a] aims to explain the evolutionary origin of the eukaryotic chromosome. The hypothesis is based on the notion that the process of eukaryogenesis was initiated by adaptive responses of the symbiont eubacterium and its archaeal host to their new conditions. The adaptive responses included fragmentation of the circular genome of the host into multiple linear fragments with free DNA ends. The action of mobile genetic elements stabilized the free DNA ends resulting in the formation of proto-telomeres. Sequences next to the proto-telomeres, the subtelomeric sequences, were immediately targeted as the new cargo by the tubulin-based cytoskeleton, thus becoming proto-centromeres. A period of genomic instability followed. Eventually, functioning centromeres and telomeres emerged heralding the arrival of the eukaryotic chromosome in the evolution. This paper expands the 'centromere-from-telomere' hypothesis by integrating it with 2 sets of data: chromosome-specific telomere length distribution and chromomere size gradient. The integration adds a new dimension to the hypothesis but also provides an insight into the mechanisms of chromosome plasticity underlying karyotype evolution.},
}
@article {pmid27397571,
year = {2016},
author = {Choi, KM and Thomas, RJ and Yoon, DW and Lee, SK and Baik, I and Shin, C},
title = {Interaction between Obstructive Sleep Apnea and Shortened Telomere Length on Brain White Matter Abnormality.},
journal = {Sleep},
volume = {39},
number = {9},
pages = {1639-1645},
pmid = {27397571},
issn = {1550-9109},
mesh = {Adult ; Aged ; Cross-Sectional Studies ; Female ; Genetic Markers ; Humans ; Logistic Models ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Odds Ratio ; Polysomnography ; Prospective Studies ; Sleep Apnea, Obstructive/*genetics/*pathology/physiopathology ; Telomere/*pathology ; White Matter/*pathology ; },
abstract = {STUDY OBJECTIVES: Age-related brain white matter changes (WMC) have been associated separately with obstructive sleep apnea (OSA) and short telomere length (TL). No studies have examined their interaction effect on WMC.<br><br>METHODS: This is a cross-sectional study with a community-based sample of 420 participants (mean age, 61.3 &#xb1; 7.2) from the Korean Genome and Epidemiology Study during 2011-2012. An overnight fasted blood sample was taken to determine glucose and blood lipid levels at the sleep laboratory of Korea University Ansan Hospital. The status of brain WMC was determined using structural magnetic resonance imaging at 1.5 Tesla. Overnight polysomnography was performed, and leukocyte TL was measured. OSA was determined based on apnea-hypopnea index, and short TL was defined as the lowest quartile of the study participants.<br><br>RESULTS: Adjusting for age, sex, BMI, smoking, drinking, snoring, and hypertension, odds ratio (OR) of brain WMC was estimated using multivariate logistic regression. The odds ratio was significant for cardiovascular disease (OR, 4.5; 95% CI, 1.2-16.3) and OSA (OR, 4.0; 95% CI, 1.0-15.2) among those with short TL; and for diabetes (OR, 3.0; 95% CI, 1.3-13.0) and age (OR, 1.1; 95% CI, 1.0-1.1) among those with longer TL. Interaction effect of OSA and short TL (OR, 4.3; 95% CI, 1.4-13.8) was significant, compared to those with neither OSA nor short TL.<br><br>CONCLUSIONS: This study provides a first evidence of mediated interaction of short TL with OSA on brain WMC in a community-based sample. The results generate new hypotheses regarding mechanisms of impaired brain health in sleep apnea.},
}
@article {pmid27396673,
year = {2016},
author = {Cariati, F and Jaroudi, S and Alfarawati, S and Raberi, A and Alviggi, C and Pivonello, R and Wells, D},
title = {Investigation of sperm telomere length as a potential marker of paternal genome integrity and semen quality.},
journal = {Reproductive biomedicine online},
volume = {33},
number = {3},
pages = {404-411},
doi = {10.1016/j.rbmo.2016.06.006},
pmid = {27396673},
issn = {1472-6491},
mesh = {Adult ; Aneuploidy ; DNA Fragmentation ; *Genome, Human ; Humans ; Infertility, Male/genetics ; Male ; Middle Aged ; Semen Analysis/*methods ; *Spermatozoa ; Telomere/*chemistry ; },
abstract = {Recent studies have reported shorter sperm telomere length (STL) in men with idiopathic infertility. The aim of this study was to measure STL in semen samples from men to evaluate whether STL variation is associated with chromosomal abnormality, DNA fragmentation, traditional semen parameters, IVF outcome, or all four factors. A significant correlation between telomere length and diploidy was observed (P = 0.037). Additionally, STL was found to be positively associated with sperm count (P = 0.006); oligospermic samples had particularly short telomeres (0.9 ± 0.1 versus 1.4 ± 0.1; P = 0.0019). The results confirmed a link between sperm DNA fragmentation and aneuploidy, previously proposed (P = 0.009). A negative relationship was demonstrated between sperm concentration and aneuploidy and Sperm DNA framentation (P = 0.03, P < 0.0001, respectively). For a subset of 51 of the 73 sperm samples used for fertilization, IVF outcomes were known. A total of 17.6% of these samples had atypical STLs. None of these samples produced an ongoing pregnancy. In contrast, the pregnancy rate for samples that had STLs in the normal range was 35.7% (P = 0.044). In conclusion, STL has potential as a fast and inexpensive form of sperm quality assessment.},
}
@article {pmid27396482,
year = {2016},
author = {Hirai, Y and Tamura, M and Otani, J and Ishikawa, F},
title = {NEK6-mediated phosphorylation of human TPP1 regulates telomere length through telomerase recruitment.},
journal = {Genes to cells : devoted to molecular &amp; cellular mechanisms},
volume = {21},
number = {8},
pages = {874-889},
doi = {10.1111/gtc.12391},
pmid = {27396482},
issn = {1365-2443},
mesh = {Aminopeptidases/*genetics/metabolism ; Cell Line ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/*genetics/metabolism ; Humans ; NIMA-Related Kinases/genetics/metabolism ; Phosphorylation ; Protein Binding ; Protein Domains ; Serine Proteases/*genetics/metabolism ; Shelterin Complex/*genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis/genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {Shelterin component TPP1 plays critical roles in chromosome end protection and telomere length regulation. Specifically, TPP1 contains an OB-fold domain that provides an interface to recruit telomerase. However, it remains largely unknown how telomerase recruitment is regulated by cell cycle regulators. We show that TPP1 interacts with the cell cycle regulator kinase NEK6 in human cells. We found that NEK6-mediated phosphorylation of TPP1 Ser255 in G2/M phase regulates the association between telomerase activity and TPP1. Furthermore, we found evidence that POT1 negatively regulates TPP1 phosphorylation because the level of Ser255 phosphorylation was elevated when telomeres were elongated by a POT1 mutant lacking its OB-fold domains. Ser255 is located in the intervening region between the telomerase-recruiting OB-fold and the POT1 recruitment domains. Ser255 and the surrounding amino acids are conserved among vertebrates. These observations suggest that a region adjacent to the OB-fold domain of TPP1 is involved in telomere length regulation via telomerase recruitment.},
}
@article {pmid27391907,
year = {2017},
author = {Scheffold, A and Jebaraj, BMC and Jaramillo, S and Tausch, E and Steinbrecher, D and Hahn, M and Böttcher, S and Ritgen, M and Bunjes, D and Zeis, M and Stadler, M and Uharek, L and Scheid, C and Hegenbart, U and Hallek, M and Kneba, M and Schmitz, N and Döhner, H and Dreger, P and Stilgenbauer, S},
title = {Impact of telomere length on the outcome of allogeneic stem cell transplantation for poor-risk chronic lymphocytic leukaemia: results from the GCLLSG CLL3X trial.},
journal = {British journal of haematology},
volume = {179},
number = {2},
pages = {342-346},
doi = {10.1111/bjh.14219},
pmid = {27391907},
issn = {1365-2141},
mesh = {Chromosome Aberrations ; Clinical Trials, Phase II as Topic ; Follow-Up Studies ; Hematopoietic Stem Cell Transplantation/methods ; Humans ; Immunoglobulin Heavy Chains/genetics ; Immunoglobulin Variable Region/genetics ; In Situ Hybridization, Fluorescence ; Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis/*genetics/*mortality/therapy ; Multicenter Studies as Topic ; Mutation ; Prognosis ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere Shortening ; Transplantation, Homologous ; Treatment Outcome ; },
}
@article {pmid27391763,
year = {2016},
author = {Berglund, K and Reynolds, CA and Ploner, A and Gerritsen, L and Hovatta, I and Pedersen, NL and Hägg, S},
title = {Longitudinal decline of leukocyte telomere length in old age and the association with sex and genetic risk.},
journal = {Aging},
volume = {8},
number = {7},
pages = {1398-1415},
pmid = {27391763},
issn = {1945-4589},
support = {R01 AG010175/AG/NIA NIH HHS/United States ; R01 AG028555/AG/NIA NIH HHS/United States ; },
mesh = {Age Factors ; Aged ; Aging/genetics/*metabolism ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Risk Factors ; Sex Factors ; *Telomere ; },
abstract = {Telomeres are DNA-protein structures at the ends of chromosomes. Leukocyte telomere length (LTL) shortening has been associated with advanced age. However, most studies use cross-sectional data, hence, the aim of our study was to model longitudinal trajectories of LTL attrition across 20 years at old age. Assessments of LTL were done by qPCR in SATSA (Swedish Adoption/Twin Study of Aging; N=636 individuals). Cross-sectional and longitudinal associations with age were estimated, the latter using latent growth curve analysis. A genetic risk score (GRS) for LTL was further assessed and included in the models. We confirmed an inverse cross-sectional association of LTL with age (B=-0.0022 T/S-ratio; 95% CI: -0.0035, -0.0009, p-value=0.0008). Longitudinal LTL analyses adjusted for sex (1598 samples; ≤5 measurements) suggested modest average decline until 69 years of age but accelerating decline after 69 years, with significant inter-individual variation. Women had on average ~6% T/S-ratio units longer LTL at baseline, and inclusion of the GRS improved the model where four risk alleles was equivalent to the effect size difference between the sexes. In this cohort of old individuals, baseline LTL varied with age, sex and genetic background. The rate of change of LTL accelerated with age and varied considerably between individuals.},
}
@article {pmid27390278,
year = {2016},
author = {Escribano, A and Pastor, S and Reula, A and Castillo, S and Vicente, S and Sanz, F and Casas, F and Torres, M and Fernández-Fabrellas, E and Codoñer-Franch, P and Dasí, F},
title = {Accelerated telomere attrition in children and teenagers with α1-antitrypsin deficiency.},
journal = {The European respiratory journal},
volume = {48},
number = {2},
pages = {350-358},
doi = {10.1183/13993003.00176-2016},
pmid = {27390278},
issn = {1399-3003},
mesh = {Adolescent ; Body Mass Index ; Case-Control Studies ; Child ; Child, Preschool ; Female ; Humans ; Lung/metabolism ; Male ; Oxidative Stress ; Phenotype ; Spirometry ; Telomerase/genetics ; Telomere/*ultrastructure ; *Telomere Shortening ; alpha 1-Antitrypsin Deficiency/*genetics/metabolism ; },
abstract = {Numerous studies have shown that oxidative stress accelerates telomere shortening in several lung pathologies. Since oxidative stress is involved in the pathophysiology of α1-antitrypsin deficiency (AATD), we hypothesised that telomere shortening would be accelerated in AATD patients. This study aimed to assess telomere length in AATD patients and to study its association with α1-antitrypsin phenotypes.Telomere length, telomerase activity, telomerase reverse transcriptase (hTERT) expression and biomarkers of oxidative stress were measured in 62 children and teenagers (aged 2-18 years) diagnosed with AATD and 18 controls (aged 3-16 years).Our results show that intermediate-risk (MZ; SZ) and high-risk (ZZ) AATD patients have significantly shorter telomeres and increased oxidative stress than controls. Correlation studies indicate that telomere length was related to oxidative stress markers in AATD patients. Multiple hypothesis testing revealed an association between telomere length, telomerase activity, hTERT expression and AATD phenotypes; high-risk patients showed shorter telomeres, lower hTERT expression and decreased telomerase activity than intermediate-risk and low-risk patients.AATD patients show evidence of increased oxidative stress leading to telomere attrition. An association between telomere and α1-antitrypsin phenotypes is observed suggesting that telomere length could be a promising biomarker for AATD disease progression.},
}
@article {pmid27386863,
year = {2016},
author = {Stone, RC and Horvath, K and Kark, JD and Susser, E and Tishkoff, SA and Aviv, A},
title = {Telomere Length and the Cancer-Atherosclerosis Trade-Off.},
journal = {PLoS genetics},
volume = {12},
number = {7},
pages = {e1006144},
pmid = {27386863},
issn = {1553-7404},
support = {R01 DK104339/DK/NIDDK NIH HHS/United States ; R01 GM113657/GM/NIGMS NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; R01 HL116446/HL/NHLBI NIH HHS/United States ; },
mesh = {Aging/genetics ; Atherosclerosis/*genetics/pathology ; Humans ; Longevity/genetics ; Neoplasms/*genetics/pathology ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere Shortening ; },
abstract = {Modern humans, the longest-living terrestrial mammals, display short telomeres and repressed telomerase activity in somatic tissues compared with most short-living small mammals. The dual trait of short telomeres and repressed telomerase might render humans relatively resistant to cancer compared with short-living small mammals. However, the trade-off for cancer resistance is ostensibly increased age-related degenerative diseases, principally in the form of atherosclerosis. In this communication, we discuss (a) the genetics of human telomere length, a highly heritable complex trait that is influenced by genetic ancestry, sex, and paternal age at conception, (b) how cancer might have played a role in the evolution of telomere biology across mammals, (c) evidence that in modern humans telomere length is a determinant (rather than only a biomarker) of cancer and atherosclerosis, and (d) the potential influence of relatively recent evolutionary forces in fashioning the variation in telomere length across and within populations, and their likely lasting impact on major diseases in humans. Finally, we propose venues for future research on human telomere genetics in the context of its potential role in shaping the modern human lifespan.},
}
@article {pmid27384379,
year = {2016},
author = {Wennerström, EC and Risques, RA and Prunkard, D and Giffen, C and Corley, DA and Murray, LJ and Whiteman, DC and Wu, AH and Bernstein, L and Ye, W and Chow, WH and Vaughan, TL and Liao, LM},
title = {Leukocyte telomere length in relation to the risk of Barrett's esophagus and esophageal adenocarcinoma.},
journal = {Cancer medicine},
volume = {5},
number = {9},
pages = {2657-2665},
pmid = {27384379},
issn = {2045-7634},
support = {K05 CA124911/CA/NCI NIH HHS/United States ; R01 CA072866/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma/*epidemiology/*etiology ; Barrett Esophagus/*epidemiology/*etiology ; Esophageal Neoplasms/*epidemiology/*etiology ; Female ; Gastroesophageal Reflux/complications/epidemiology/etiology ; Humans ; Leukocytes/*metabolism ; Male ; Odds Ratio ; Population Surveillance ; Prevalence ; Risk ; Telomere/*genetics ; },
abstract = {Chronic inflammation and oxidative damage caused by obesity, cigarette smoking, and chronic gastroesophageal reflux disease (GERD) are major risk factors associated with Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). EAC has been increasing the past few decades, and early discovery and treatment are crucial for survival. Telomere shortening due to cell division and oxidative damage may reflect the impact of chronic inflammation and could possibly be used as predictor for disease development. We examined the prevalence of shorter leukocyte telomere length (LTL) among individuals with GERD, BE, or EAC using a pooled analysis of studies from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON). Telomere length was measured in leukocyte DNA samples by Q-PCR. Participants included 1173 patients (386 with GERD, 384 with EAC, 403 with BE) and 736 population-based controls. The association of LTL (in tertiles) along the continuum of disease progression from GERD to BE to EAC was calculated using study-specific odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models adjusted for potential confounders. Shorter LTL were less prevalent among GERD patients (OR 0.57; 95% CI: 0.35-0.93), compared to population-based controls. No statistically significant increased prevalence of short/long LTL among individuals with BE or EAC was observed. In contrast to some earlier reports, our findings add to the evidence that leukocyte telomere length is not a biomarker of risk related to the etiology of EAC. The findings do not suggest a relationship between LTL and BE or EAC.},
}
@article {pmid27380936,
year = {2016},
author = {Sasaki, A and Ide, S and Kawamoto, Y and Bando, T and Murata, Y and Shimura, M and Yamada, K and Hirata, A and Nokihara, K and Hirata, T and Sugiyama, H and Maeshima, K},
title = {Telomere Visualization in Tissue Sections using Pyrrole-Imidazole Polyamide Probes.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {29261},
pmid = {27380936},
issn = {2045-2322},
mesh = {Animals ; Cytological Techniques/methods ; DNA/*metabolism ; Histocytochemistry/methods ; Humans ; Imidazoles/*metabolism ; Mice ; Nylons/*metabolism ; Optical Imaging/*methods ; Pyrroles/*metabolism ; Staining and Labeling/*methods ; Telomere/*metabolism ; },
abstract = {Pyrrole-Imidazole (PI) polyamides bind to specific DNA sequences in the minor groove with high affinity. Specific DNA labeling by PI polyamides does not require DNA denaturation with harsh treatments of heat and formamide and has the advantages of rapid and less disruptive processing. Previously, we developed tandem hairpin PI polyamide probes (TH59 series), which label telomeres in cultured cell lines more efficiently than conventional methods, such as fluorescence in situ hybridization (FISH). Here, we demonstrate that a TH59 derivative, HPTH59-b, along with immunostaining for specifying cell types in the tissues, visualizes telomeres in mouse and human tissue sections. Quantitative measurements of telomere length with single-cell resolution suggested shorter telomeres in the proliferating cell fractions of tumor than in non-tumor tissues. Thus, PI polyamides are a promising alternative for telomere labeling in clinical research, as well as in cell biology.},
}
@article {pmid27379829,
year = {2017},
author = {Pusceddu, I and Herrmann, M and Kirsch, SH and Werner, C and Hübner, U and Bodis, M and Laufs, U and Widmann, T and Wagenpfeil, S and Geisel, J and Herrmann, W},
title = {One-carbon metabolites and telomere length in a prospective and randomized study of B- and/or D-vitamin supplementation.},
journal = {European journal of nutrition},
volume = {56},
number = {5},
pages = {1887-1898},
pmid = {27379829},
issn = {1436-6215},
mesh = {Aged ; Biomarkers/blood ; Body Mass Index ; Calcium Carbonate/administration &amp; dosage ; Carbon/*metabolism ; Choline/blood ; Cross-Sectional Studies ; *Dietary Supplements ; Double-Blind Method ; Female ; Folic Acid/administration &amp; dosage/blood ; Humans ; Male ; Methylenetetrahydrofolate Reductase (NADPH2)/blood/genetics ; Methylmalonic Acid/blood ; Middle Aged ; Pilot Projects ; Prospective Studies ; Sarcosine/analogs &amp; derivatives/blood ; Telomere/*ultrastructure ; *Telomere Homeostasis ; Tetrahydrofolates/blood ; Vitamin B 12/administration &amp; dosage/blood ; Vitamin B 6/administration &amp; dosage/blood ; Vitamin B Complex/*administration &amp; dosage/blood ; Vitamin D/*administration &amp; dosage/blood ; },
abstract = {BACKGROUND: Vitamin B deficiency is common in elderly people and has been associated with an increased risk of developing age-related diseases. B-vitamins are essential for the synthesis and stability of DNA. Telomers are the end caps of chromosomes that shorten progressively with age, and short telomers are associated with DNA instability.<br><br>OBJECTIVE: In the present randomized intervention study, we investigated whether the one-carbon metabolism is related to telomere length, a surrogate marker for cellular aging.<br><br>DESIGN: Sixty-five subjects (>54&#xa0;years) were randomly assigned to receive either a daily combination of vitamin D3 (1200&#xa0;IU), folic acid (0.5&#xa0;mg), vitamin B12 (0.5&#xa0;mg), vitamin B6 (50&#xa0;mg) and calcium carbonate (456&#xa0;mg) (group A) or vitamin D3 and calcium carbonate alone (group B). Blood testing was performed at baseline and after 1&#xa0;year of supplementation. The concentrations of several metabolites of the one-carbon pathway, as well as relative telomere length (RTL) and 5,10-methylenetetrahydrofolate reductase C677T genotype, were analyzed.<br><br>RESULTS: At baseline, age- and gender-adjusted RTL correlated with total folate and 5-methyltetrahydrofolate (5-methylTHF). Subjects with RTL above the median had higher concentrations of total folate and 5-methylTHF compared to subjects below the median. At study end, gender- and age-adjusted RTL correlated in group A with methylmalonic acid (MMA; r&#xa0;=&#xa0;-0.460, p&#xa0;=&#xa0;0.0012) and choline (r&#xa0;=&#xa0;0.434, p&#xa0;=&#xa0;0.0021) and in group B with 5,10-methenyltetrahydrofolate (r&#xa0;=&#xa0;0.455, p&#xa0;=&#xa0;0.026) and dimethylglycine (DMG; r&#xa0;=&#xa0;-0.386, p&#xa0;=&#xa0;0.047). Subjects in the group A with RTL above the median had lower MMA and higher choline compared to subjects below the median.<br><br>CONCLUSIONS: The present pilot study suggests a functional relationship between one-carbon metabolism and telomere length. This conclusion is supported by several correlations that were modified by B-vitamin supplementation. In agreement with our hypothesis, the availability of nucleotides and methylation groups seems to impact telomere length. Due to the small sample size and the limitations of the study, further studies should confirm the present results in a larger cohort.},
}
@article {pmid27378050,
year = {2016},
author = {Steensma, DP and Kyle, RA and Shampo, MA},
title = {Elizabeth Blackburn and Maintenance of Telomeres.},
journal = {Mayo Clinic proceedings},
volume = {91},
number = {7},
pages = {e105},
doi = {10.1016/j.mayocp.2016.01.026},
pmid = {27378050},
issn = {1942-5546},
mesh = {Biomedical Research/history ; History, 20th Century ; History, 21st Century ; Humans ; Nobel Prize ; Telomerase/*history ; *Telomere ; },
}
@article {pmid27376021,
year = {2016},
author = {Mishra, S and Kumar, R and Malhotra, N and Singh, N and Dada, R},
title = {Mild oxidative stress is beneficial for sperm telomere length maintenance.},
journal = {World journal of methodology},
volume = {6},
number = {2},
pages = {163-170},
pmid = {27376021},
issn = {2222-0682},
abstract = {AIM: To evaluate telomere length in sperm DNA and its correlation with oxidative stress (normal, mild, severe).<br><br>METHODS: The study included infertile men (n = 112) and age matched fertile controls (n = 102). The average telomere length from the sperm DNA was measured using a quantitative real time PCR based assay. Seminal reactive oxygen species (ROS) and 8-Isoprostane (8-IP) levels were measured by chemiluminescence assay and ELISA respectively.<br><br>RESULTS: Average sperm telomere length in infertile men and controls was 0.609 &#xb1; 0.15 and 0.789 &#xb1; 0.060, respectively (P < 0.0001). Seminal ROS levels in infertile was higher [66.61 &#xb1; 28.32 relative light units (RLU)/s/million sperm] than in controls (14.04 &#xb1; 10.67 RLU/s/million sperm) (P < 0.0001). The 8-IP level in infertile men was significantly higher (421.55 &#xb1; 131.29 pg/mL) than in controls (275.94 &#xb1; 48.13 pg/mL) (P < 0.001). When correlated to oxidative stress, in normal range of oxidative stress (ROS, 0-21.3 RLU/s/million sperm) the average telomere length in cases was 0.663 &#xb1; 0.14, in mild oxidative stress (ROS, 21.3-35 RLU/s/million sperm) it was elevated (0.684 &#xb1; 0.12) and in severe oxidative stress (ROS > 35 RLU/s/million sperm) average telomere length was decreased to 0.595 &#xb1; 0.15.<br><br>CONCLUSION: Mild oxidative stress results in lengthening of telomere length, but severe oxidative stress results in shorter telomeres. Although telomere maintenance is a complex trait, the study shows that mild oxidative stress is beneficial in telomere length maintenance and thus a delicate balance needs to be established to maximize the beneficial effects of free radicals and prevent harmful effects of supra physiological levels. Detailed molecular evaluation of telomere structure, its correlation with oxidative stress would aid in elucidating the cause of accelerated telomere length attrition.},
}
@article {pmid27373959,
year = {2016},
author = {VanderWeele, TJ and Shields, AE},
title = {Religiosity and telomere length: One step forward, one step back.},
journal = {Social science &amp; medicine (1982)},
volume = {163},
number = {},
pages = {176-178},
doi = {10.1016/j.socscimed.2016.06.038},
pmid = {27373959},
issn = {1873-5347},
mesh = {*Leukocytes ; Religion ; *Telomere ; },
}
@article {pmid27367027,
year = {2016},
author = {An, J and Wu, M and Xin, X and Lin, Z and Li, X and Zheng, Q and Gui, X and Li, T and Pu, H and Li, H and Lu, D},
title = {Inflammatory related gene IKKα, IKKβ, IKKγ cooperates to determine liver cancer stem cells progression by altering telomere via heterochromatin protein 1-HOTAIR axis.},
journal = {Oncotarget},
volume = {7},
number = {31},
pages = {50131-50149},
pmid = {27367027},
issn = {1949-2553},
mesh = {Animals ; Cell Movement ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/*metabolism ; DNA Methylation ; Disease Progression ; Gene Expression Regulation, Neoplastic ; Histones/metabolism ; Humans ; I-kappa B Kinase/*metabolism ; Inflammation ; Liver Neoplasms/*metabolism ; Mice ; Mice, Inbred BALB C ; Neoplasm Recurrence, Local ; Neoplasm Transplantation ; Neoplastic Stem Cells/*metabolism ; RNA, Long Noncoding/*metabolism ; Signal Transduction ; Telomere/*ultrastructure ; },
abstract = {Cancer stem cells are associated with tumor recurrence. IKK is a protein kinase that is composed of IKKα, IKKβ, IKKγ. Herein, we demonstrate that IKKα plus IKKβ promoted and IKKγ inhibited liver cancer stem cell growth in vitro and in vivo. Mechanistically, IKKα plus IKKβ enhanced and IKKγ inhibited the interplay among HP1α, HP1β and HP1γ that competes for the interaction among HP1α, SUZ12, HEZ2. Therefore, IKKα plus IKKβ inhibited and IKKγ enhanced the activity of H3K27 methyltransferase SUZ12 and EZH2, which methylates H3K27 immediately sites on HOTAIR promoter region. Therefore, IKKα plus IKKβ increased and IKKγ decreased the HOTAIR expression. Strikingly, IKKα plus IKKβ decreases and IKKγ increases the HP1α interplays with DNA methyltransferase DNMT3b, which increases or decreases TERRA promoter DNA methylation. Thus IKKα plus IKKβ reduces and IKKγ increases to recruit TRF1 and RNA polymerase II deposition and elongation on the TERRA promoter locus, which increases or decreases TERRA expression. Furthermore, IKKα plus IKKβ decreases/increases and IKKγ increases/decreases the interplay between TERT and TRRRA/between TERT and TREC. Ultimately, IKKα plus IKKβ increases and IKKγ decreases the telomerase activity. On the other hand, at the telomere locus, IKKα plus IKKβ increases/drcreases and IKKγ decreases/increases TRF2, POT1, pPOT1, Exo1, pExo1, SNM1B, pSNM1B/CST-AAF binding, which keep active telomere regulatory genes and poised for telomere length. Strikingly, HOTAIR is required for IKKα plus IKKβ and IKKγ to control telomerase activity and telomere length. These observations suggest that HOTAIR operates the action of IKKα, IKKβ, IKKγ in liver cancer stem cells. This study provides a novel basis to elucidate the oncogenic action of IKKα, IKKβ, IKKγ and prompts that IKKα, IKKβ, IKKγ cooperate to HOTAR to be used as a novel therapeutic targets for liver cancer.},
}
@article {pmid27359174,
year = {2016},
author = {Darrow, SM and Verhoeven, JE and Révész, D and Lindqvist, D and Penninx, BW and Delucchi, KL and Wolkowitz, OM and Mathews, CA},
title = {The Association Between Psychiatric Disorders and Telomere Length: A Meta-Analysis Involving 14,827 Persons.},
journal = {Psychosomatic medicine},
volume = {78},
number = {7},
pages = {776-787},
pmid = {27359174},
issn = {1534-7796},
support = {R01 MH083784/MH/NIMH NIH HHS/United States ; R01 MH096767/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Humans ; Mental Disorders/*metabolism ; Middle Aged ; Telomere Shortening/*physiology ; Young Adult ; },
abstract = {OBJECTIVE: This study examined the relationship between leukocyte telomere length (LTL), a marker of cell aging, and psychiatric disorders in adults compared with controls using meta-analytic methods.<br><br>METHODS: Data were abstracted from studies examining the relationship between LTL and adult psychiatric disorders. In addition to an overall estimate of effect size, subgroup analyses and meta-regression were performed to examine whether covariates (including psychiatric diagnoses) moderated the estimate.<br><br>RESULTS: A significant overall effect size showing LTL shortening was found across all psychiatric disorders (Hedge g = -0.50, p < .001). Subgroup analyses did not demonstrate significant differences in effect size based on individual covariates (psychiatric disorder, sex, age, or assay method). The meta-regression indicated that although type of disorder and, likely, age moderate the overall effect size, the heterogeneity between studies could not be explained by a model that included these variables as well as sex and assay method. Although not significantly different, posttraumatic stress disorder, anxiety disorders, and depressive disorders had comparatively larger effect sizes (-1.27, -0.53, and -0.55), and psychotic and bipolar disorders had comparatively smaller ones (-0.23 and -0.26).<br><br>CONCLUSIONS: We observed a robust effect size of LTL shortening for psychiatric disorders as a whole compared with controls. The results were less straightforward regarding relative differences in the strength of this association by specific disorder. Future studies should focus on mechanisms explaining accelerated cell aging with psychiatric illness, defining directions (if any) of causality and elucidating possible differences in this association between disorders.},
}
@article {pmid27357566,
year = {2016},
author = {Martens, DS and Nawrot, TS},
title = {Air Pollution Stress and the Aging Phenotype: The Telomere Connection.},
journal = {Current environmental health reports},
volume = {3},
number = {3},
pages = {258-269},
pmid = {27357566},
issn = {2196-5412},
mesh = {*Aging ; Air Pollutants/*adverse effects ; Environmental Exposure ; Humans ; Particulate Matter/adverse effects ; *Phenotype ; Risk Factors ; *Telomere ; },
abstract = {Aging is a complex physiological phenomenon. The question why some subjects grow old while remaining free from disease whereas others prematurely die remains largely unanswered. We focus here on the role of air pollution in biological aging. Hallmarks of aging can be grouped into three main categories: genomic instability, telomere attrition, and epigenetic alterations leading to altered mitochondrial function and cellular senescence. At birth, the initial telomere length of a person is largely determined by environmental factors. Telomere length shortens with each cell division and exposure to air pollution as well as low residential greens space exposure is associated with shorter telomere length. Recent studies show that the estimated effects of particulate air pollution exposure on the telomere mitochondrial axis of aging may play an important role in chronic health effects of air pollution. The exposome encompasses all exposures over an entire life. As telomeres can be considered as the cellular memories of exposure to oxidative stress and inflammation, telomere maintenance may be a proxy for assessing the "exposome". If telomeres are causally related to the aging phenotype and environmental air pollution is an important determinant of telomere length, this might provide new avenues for future preventive strategies.},
}
@article {pmid27357526,
year = {2017},
author = {Tellechea, ML and Pirola, CJ},
title = {The impact of hypertension on leukocyte telomere length: a systematic review and meta-analysis of human studies.},
journal = {Journal of human hypertension},
volume = {31},
number = {2},
pages = {99-105},
pmid = {27357526},
issn = {1476-5527},
mesh = {Humans ; Hypertension/*physiopathology ; Leukocytes ; *Telomere Homeostasis ; },
abstract = {Shortened leukocyte telomere length (LTL) is a novel biomarker for age and age-related diseases. Several epidemiological studies have examined the association between telomere length in surrogate tissues (for example, blood cells) and hypertension, and meanwhile the majority of studies reported an association some individual studies do not. We carried out a systematic review and meta-analysis to address the hypothesis that, in humans, telomere length is related with hypertension. Searches were conducted in Pubmed by September 2015 and reference lists of retrieved citations were hand searched. Eligible studies measured telomeres for both hypertensive and normotensive subjects. No restrictions were placed on sample size, publication type, age or gender. We calculated summary estimates using fixed and random effects meta-analysis. Publication bias and heterogeneity among studies were further tested. Meta-analyses from 3097 participants (1415 patients with hypertension and 1682 control subjects) showed a significant standardized mean difference between LTL in hypertensive patients and controls, either in the fixed (P<5 × 10[-6]) or the random model (P<0.005). Heterogeneity among studies was substantial (Q-statistic P-value <0.001, I[2] 97.73%). Sensitivity analysis indicated that no single study changed the standardized mean difference qualitatively (0.022> random model P-value >0.002). Egger's test for asymmetry of effect sizes (intercept±s.e.=-7.278±3.574; P=0.072) did not show evidence for strong study publication bias. Leukocyte telomeres may be shorter in hypertensive than in normotensive individuals. Larger studies controlling for confounder effects are needed to confirm these findings and further explore sources of heterogeneity.},
}
@article {pmid27355316,
year = {2016},
author = {Poole, LA and Cortez, D},
title = {SMARCAL1 and telomeres: Replicating the troublesome ends.},
journal = {Nucleus (Austin, Tex.)},
volume = {7},
number = {3},
pages = {270-274},
pmid = {27355316},
issn = {1949-1042},
support = {R01 GM116616/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA Helicases/*metabolism ; *DNA Replication ; Genomic Instability ; Humans ; Telomere/*genetics ; Telomere Homeostasis ; },
abstract = {DNA replication is constantly challenged by both endogenous and exogenous sources of replication stress. SMARCAL1, an SNF2 family DNA translocase, functions in the DNA damage response to address these obstacles and promote the completion of replication. Most studies examining the function of SMARCAL1 and related enzymes have relied on the addition of exogenous genotoxic agents, but SMARCAL1 is needed even in the absence of these drugs to maintain genome stability during DNA replication. We recently determined that SMARCAL1 functions to limit DNA damage during replication of difficult-to-replicate telomere sequences. SMARCAL1-deficient cells display several markers of telomere instability including extrachromosomal telomere circles and co-localization with DNA damage markers. Furthermore, cells lacking the highly related proteins ZRANB3 and HLTF do not exhibit similar problems suggesting a unique function for SMARCAL1. These studies identified the first source of endogenous replication stress that SMARCAL1 resolves and provide insight into the mechanism of SMARCAL1 function in maintaining genome stability.},
}
@article {pmid27354474,
year = {2016},
author = {Gerbing, RB and Alonzo, TA and Sung, L and Gamis, AS and Meshinchi, S and Plon, SE and Bertuch, AA and Gramatges, MM},
title = {Shorter Remission Telomere Length Predicts Delayed Neutrophil Recovery After Acute Myeloid Leukemia Therapy: A Report From the Children's Oncology Group.},
journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology},
volume = {34},
number = {31},
pages = {3766-3772},
pmid = {27354474},
issn = {1527-7755},
support = {K23 CA158148/CA/NCI NIH HHS/United States ; L40 CA153043/CA/NCI NIH HHS/United States ; U10 CA098413/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; R01 CA114563/CA/NCI NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; },
mesh = {Acute Disease ; Adolescent ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Child ; Child, Preschool ; Cohort Studies ; Female ; Humans ; Infant ; Kaplan-Meier Estimate ; Leukemia, Myeloid/*drug therapy/genetics/pathology ; Male ; Neutrophils/*drug effects/metabolism ; Outcome Assessment, Health Care/methods/statistics &amp; numerical data ; Prognosis ; Proportional Hazards Models ; Remission Induction ; Telomere/*drug effects/genetics ; },
abstract = {Purpose Suboptimal outcomes for children with acute myeloid leukemia (AML) necessitate maximally intensive therapy. Consequently, serious adverse events, such as prolonged periods of profound myelosuppression, contribute to AML treatment-related mortality. Telomeres, the repetitive DNA-protein structures at chromosome ends, influence cellular replicative capacity in that critically short telomeres can induce cell senescence or apoptosis. Our objective was to evaluate the impact of telomere length on duration of post-therapy neutropenia in a pediatric AML cohort. Patients and Methods Patients were diagnosed with de novo AML, enrolled in Children's Oncology Group study AAML0531, and included those with (n = 53) and without (n = 62) significantly delayed neutrophil recovery after chemotherapy. We used quantitative polymerase chain reaction to measure telomere content (TC), a validated proxy for telomere length, from remission bone marrow samples obtained after the second induction chemotherapy course. Results Less TC was significantly associated with prolonged neutropenia after the fourth (P < .001) and fifth chemotherapy courses (P = .002). Cox regression adjusting for age at diagnosis confirmed that TC remained independently predictive of time to recovery of absolute neutrophil count for both the fourth and fifth courses (P = .002 and .009, respectively). DNA from patients was analyzed for germline mutations in four telomere maintenance genes associated with telomere biology disorders. Sequence analysis revealed no enrichment of rare or novel variants in the delayed recovery group. Conclusion Our results suggest that TC at end of AML induction is associated with hematopoietic reconstitution capacity independently of age and may identify those at highest risk for markedly delayed bone marrow recovery after AML therapy.},
}
@article {pmid27351774,
year = {2016},
author = {Wang, Z and Lieberman, PM},
title = {The crosstalk of telomere dysfunction and inflammation through cell-free TERRA containing exosomes.},
journal = {RNA biology},
volume = {13},
number = {8},
pages = {690-695},
pmid = {27351774},
issn = {1555-8584},
support = {P30 CA010815/CA/NCI NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; },
mesh = {Alarmins/metabolism ; Animals ; Biomarkers ; Cytokines/metabolism ; Disease Susceptibility ; Exosomes/*metabolism ; Humans ; Inflammation/*genetics/*metabolism ; Inflammation Mediators ; Pathogen-Associated Molecular Pattern Molecules/metabolism ; RNA, Untranslated/*genetics ; Telomere/*genetics/*metabolism ; },
abstract = {Telomeric repeats-containing RNA (TERRA) are telomere-derived non-coding RNAs that contribute to telomere function in protecting chromosome ends. We recently identified a cell-free form of TERRA (cfTERRA) enriched in extracellular exosomes. These cfTERRA-containing exosomes stimulate inflammatory cytokines when incubated with immune responsive cells. Here, we report that cfTERRA levels were increased in exosomes during telomere dysfunction induced by the expression of the dominant negative TRF2. The exosomes from these damaged cells also enriched with DNA damage marker γH2AX and fragmented telomere repeat DNA. Purified cfTERRA stimulated inflammatory cytokines, but the intact membrane-associated nucleoprotein complexes produced a more robust cytokine activation. Therefore, we propose cfTERRA-containing exosomes transport a telomere-associated molecular pattern (TAMP) and telomere-specific alarmin from dysfunctional telomeres to the extracellular environment to elicit an inflammatory response. Since cfTERRA can be readily detected in human serum it may provide a useful biomarker for the detection of telomere dysfunction in the early stage of cancers and aging-associated inflammatory disease.},
}
@article {pmid27350315,
year = {2016},
author = {Kłoda, K and Domański, L and Kwiatkowska, E and Safranow, K and Drozd, A and Ciechanowicz, A and Ciechanowski, K},
title = {Kidney Allograft Telomere Length Is Not Associated with Sex, Recipient Comorbid Conditions, Post-Transplant Infections, or CMV Reactivation.},
journal = {Annals of transplantation},
volume = {21},
number = {},
pages = {392-399},
doi = {10.12659/aot.898007},
pmid = {27350315},
issn = {2329-0358},
mesh = {Adaptor Proteins, Signal Transducing/genetics ; Adult ; *Allografts ; Cytomegalovirus Infections/*immunology ; Cytoskeletal Proteins/genetics ; Female ; Humans ; *Immunosenescence ; *Kidney Transplantation ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Sex Factors ; Telomerase/genetics ; *Telomere ; Virus Activation/immunology ; },
abstract = {BACKGROUND Immunosenescence is closely linked to chromosome telomere erosion and telomerase activity alterations. The aim of this study was to analyze the associations of relative telomere length (RTL) of a graft with sex, comorbid conditions, post-transplant infections, and CMV reactivation among transplanted kidney recipients. Additionally, the associations of donor and recipient hTERT, BICD1 genes and chromosome 18 polymorphisms with post-transplant infections were analyzed, including the analysis of donor-recipient genotype pairs. MATERIAL AND METHODS The study enrolled 119 white Polish kidney allograft recipients (64M/55F, mean age 47.3±14.0). The RTL was assessed by modification of a method developed by Cawthon, using a qPCR system. To identify genotypes of the studied polymorphisms, real-time PCR was performed. RESULTS There were no significant associations between graft RTL and sex of donor and recipient, comorbid DM and AH, as well as post-transplant infections and CMV reactivation. There were no statistically significant differences in distribution of hTERT, BICD1 genes and chromosome 18 graft and recipient polymorphisms genotypes between individuals with post-transplant infection and those without infection. The rs2735940 CX-TT hTERT gene donor-recipient genotypes combination was associated with higher risk of post-transplant infection on the border of statistical significance (OR=4.632, 95%CI (0.853-25.14); p=0.067). CONCLUSIONS Assessment of kidney allograft RTL does not show its association with sex, DM, AH, post-transplant infection, or CMV reactivation in the recipients, suggesting that other factors, probably directly related to the transplantation procedure, have a greater effect on telomere length.},
}
@article {pmid27346946,
year = {2016},
author = {Nersisyan, L},
title = {Integration of Telomere Length Dynamics into Systems Biology Framework: A Review.},
journal = {Gene regulation and systems biology},
volume = {10},
number = {},
pages = {35-42},
pmid = {27346946},
issn = {1177-6250},
abstract = {Telomere length dynamics plays a crucial role in regulation of cellular processes and cell fate. In contrast to epidemiological studies revealing the association of telomere length with age, age-related diseases, and cancers, the role of telomeres in regulation of transcriptome and epigenome and the role of genomic variations in telomere lengthening are not extensively analyzed. This is explained by the fact that experimental assays for telomere length measurement are resource consuming, and there are very few studies where high-throughput genomics, transcriptomics, and/or epigenomics experiments have been coupled with telomere length measurements. Recent development of computational approaches for assessment of telomere length from whole genome sequencing data pave a new perspective on integration of telomeres into high-throughput systems biology analysis framework. Herein, we review existing methodologies for telomere length measurement and compare them to computational approaches, as well as discuss their applications in large-scale studies on telomere length dynamics.},
}
@article {pmid27345719,
year = {2016},
author = {Vembar, SS and Seetin, M and Lambert, C and Nattestad, M and Schatz, MC and Baybayan, P and Scherf, A and Smith, ML},
title = {Complete telomere-to-telomere de novo assembly of the Plasmodium falciparum genome through long-read (&gt;11 kb), single molecule, real-time sequencing.},
journal = {DNA research : an international journal for rapid publication of reports on genes and genomes},
volume = {23},
number = {4},
pages = {339-351},
pmid = {27345719},
issn = {1756-1663},
mesh = {Contig Mapping ; *Genome, Protozoan ; Plasmodium falciparum/*genetics ; Polymorphism, Genetic ; Sequence Analysis, DNA ; Telomere/*genetics ; },
abstract = {The application of next-generation sequencing to estimate genetic diversity of Plasmodium falciparum, the most lethal malaria parasite, has proved challenging due to the skewed AT-richness [∼80.6% (A + T)] of its genome and the lack of technology to assemble highly polymorphic subtelomeric regions that contain clonally variant, multigene virulence families (Ex: var and rifin). To address this, we performed amplification-free, single molecule, real-time sequencing of P. falciparum genomic DNA and generated reads of average length 12 kb, with 50% of the reads between 15.5 and 50 kb in length. Next, using the Hierarchical Genome Assembly Process, we assembled the P. falciparum genome de novo and successfully compiled all 14 nuclear chromosomes telomere-to-telomere. We also accurately resolved centromeres [∼90-99% (A + T)] and subtelomeric regions and identified large insertions and duplications that add extra var and rifin genes to the genome, along with smaller structural variants such as homopolymer tract expansions. Overall, we show that amplification-free, long-read sequencing combined with de novo assembly overcomes major challenges inherent to studying the P. falciparum genome. Indeed, this technology may not only identify the polymorphic and repetitive subtelomeric sequences of parasite populations from endemic areas but may also evaluate structural variation linked to virulence, drug resistance and disease transmission.},
}
@article {pmid27340887,
year = {2016},
author = {Scherthan, H and Sotnik, N and Peper, M and Schrock, G and Azizova, T and Abend, M},
title = {Telomere Length in Aged Mayak PA Nuclear Workers Chronically Exposed to Internal Alpha and External Gamma Radiation.},
journal = {Radiation research},
volume = {185},
number = {6},
pages = {658-667},
doi = {10.1667/RR14271.1},
pmid = {27340887},
issn = {1938-5404},
mesh = {Aged ; Aged, 80 and over ; Aging/genetics ; Alpha Particles/*adverse effects ; Dose-Response Relationship, Radiation ; Female ; Gamma Rays/*adverse effects ; Humans ; Male ; Middle Aged ; *Nuclear Reactors ; Occupational Exposure/*adverse effects ; Russia ; Telomere/*genetics/*radiation effects ; Time Factors ; },
abstract = {Telomeres consist of GC-rich DNA repeats and the "shelterin" protein complex that together protect chromosome ends from fusion and degradation. Telomeres shorten with age due to incomplete end replication and upon exposure to environmental and intrinsic stressors. Exposure to ionizing radiation is known to modulate telomere length. However, the response of telomere length in humans chronically exposed to radiation is poorly understood. Here, we studied relative telomere length (RTL) by IQ-FISH to leukocyte nuclei in a group of 100 workers from the plutonium production facility at the Mayak Production Association (PA) who were chronically exposed to alpha-emitting ((239)Pu) radiation and/or gamma (photon) radiation, and 51 local residents serving as controls, with a similar mean age of about 80 years. We applied generalized linear statistical models adjusted for age at biosampling and the second exposure type on a linear scale and observed an age-dependent telomere length reduction. In those individuals with the lowest exposure, a significant reduction of about 20% RTL was observed, both for external gamma radiation (≤1 Gy) and internal alpha radiation (≤0.05-0.1 Gy to the red bone marrow). In highly exposed individuals (>0.1 Gy alpha, 1-1.5 Gy gamma), the RTL was similar to control. Stratification by gender revealed a significant (∼30%) telomere reduction in low-dose-exposed males, which was absent in females. While the gender differences in RTL may reflect different working conditions, lifestyle and/or telomere biology, absence of a dose response in the highly exposed individuals may reflect selection against cells with short telomeres or induction of telomere-protective effects. Our observations suggest that chronic systemic exposure to radiation leads to variable dose-dependent effects on telomere length.},
}
@article {pmid27339602,
year = {2016},
author = {Arndt, GM and MacKenzie, KL},
title = {New prospects for targeting telomerase beyond the telomere.},
journal = {Nature reviews. Cancer},
volume = {16},
number = {8},
pages = {508-524},
pmid = {27339602},
issn = {1474-1768},
mesh = {Drug Design ; Enzyme Inhibitors/chemical synthesis/pharmacology ; High-Throughput Screening Assays ; Humans ; Neoplasms/*drug therapy/enzymology/pathology ; RNA/genetics ; Telomerase/*antagonists &amp; inhibitors/genetics/metabolism ; *Telomere ; },
abstract = {Telomerase activity is responsible for the maintenance of chromosome end structures (telomeres) and cancer cell immortality in most human malignancies, making telomerase an attractive therapeutic target. The rationale for targeting components of the telomerase holoenzyme has been strengthened by accumulating evidence indicating that these molecules have extra-telomeric functions in tumour cell survival and proliferation. This Review discusses current knowledge of the biogenesis, structure and multiple functions of telomerase-associated molecules intertwined with recent advances in drug discovery approaches. We also describe the fertile ground available for the pursuit of next-generation small-molecule inhibitors of telomerase.},
}
@article {pmid27334270,
year = {2016},
author = {Raykov, V and Marvin, ME and Louis, EJ and Maringele, L},
title = {Telomere Dysfunction Triggers Palindrome Formation Independently of Double-Strand Break Repair Mechanisms.},
journal = {Genetics},
volume = {203},
number = {4},
pages = {1659-1668},
pmid = {27334270},
issn = {1943-2631},
support = {81164//Wellcome Trust/United Kingdom ; },
mesh = {DNA End-Joining Repair/genetics ; DNA Ligase ATP/*genetics ; DNA-Directed DNA Polymerase/*genetics ; Homologous Recombination/genetics ; Inverted Repeat Sequences/*genetics ; Rad51 Recombinase/genetics ; Rad52 DNA Repair and Recombination Protein/genetics ; Recombinational DNA Repair/genetics ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/*genetics ; Telomerase/*genetics ; Telomere ; Telomere Homeostasis ; },
abstract = {Inverted chromosome duplications or palindromes are linked with genetic disorders and malignant transformation. They are considered by-products of DNA double-strand break (DSB) repair: the homologous recombination (HR) and the nonhomologous end joining (NHEJ). Palindromes near chromosome ends are often triggered by telomere losses. An important question is to what extent their formation depends upon DSB repair mechanisms. Here we addressed this question using yeast genetics and comparative genomic hybridization. We induced palindrome formation by passaging cells lacking any form of telomere maintenance (telomerase and telomere recombination). Surprisingly, we found that DNA ligase 4, essential for NHEJ, did not make a significant contribution to palindrome formation induced by telomere losses. Moreover RAD51, important for certain HR-derived mechanisms, had little effect. Furthermore RAD52, which is essential for HR in yeast, appeared to decrease the number of palindromes in cells proliferating without telomeres. This study also uncovered an important role for Rev3 and Rev7 (but not for Pol32) subunits of polymerase ζ in the survival of cells undergoing telomere losses and forming palindromes. We propose a model called short-inverted repeat-induced synthesis in which DNA synthesis, rather than DSB repair, drives the inverted duplication triggered by telomere dysfunction.},
}
@article {pmid27329676,
year = {2016},
author = {Gao, Y and Wu, S and Ye, X},
title = {The effects of monovalent metal ions on the conformation of human telomere DNA using analytical ultracentrifugation.},
journal = {Soft matter},
volume = {12},
number = {27},
pages = {5959-5967},
doi = {10.1039/c6sm01010e},
pmid = {27329676},
issn = {1744-6848},
mesh = {Cesium/chemistry ; Circular Dichroism ; DNA/*ultrastructure ; *G-Quadruplexes ; Humans ; Lithium/chemistry ; Nucleic Acid Conformation ; Potassium/*chemistry ; Sodium/chemistry ; Telomere/*ultrastructure ; Ultracentrifugation ; },
abstract = {A human telomere DNA segment (HT-DNA) can fold into a G-quadruplex in the presence of some monovalent cations. These cations can interact with the phosphate groups of the DNA segment and/or with the O6 oxygen atom of guanines, which are called non-specific interactions and specific interactions, respectively. However, until now how these two interactions affect the structure of HT-DNA has not been well understood. In this study, a combination of analytical ultracentrifugation (AUC) and circular dichroism (CD) was used to explore the effects of these two interactions on the structure of a 22-mer single-stranded DNA with a sequence of 5'-AGGG(TTAGGG)3-3'. The results showed that the standard sedimentation coefficient (s20,w) of HT-DNA starts to increase when the concentration of potassium ions (CK(+)) is higher than 10.0 µM due to the formation of a G-quadruplex through specific interactions. Whereas, for a control DNA, a higher CK(+) value of 1.0 mM was needed for increasing s20,w due to non-specific interactions. Moreover, potassium ions could promote the formation of the G-quadruplex much more easily than lithium, sodium and cesium ions, presumably due to its appropriate size in the dehydrated state and easier dehydration. The molar mass of DNA at different cation concentrations was nearly a constant and close to the theoretical value of the molar mass of monomeric HT-DNA, indicating that what we observed is the structural change of individual DNA chains.},
}
@article {pmid27329016,
year = {2016},
author = {Januszewski, AS and Sutanto, SS and McLennan, S and O'Neal, DN and Keech, AC and Twigg, SM and Jenkins, AJ},
title = {Shorter telomeres in adults with Type 1 diabetes correlate with diabetes duration, but only weakly with vascular function and risk factors.},
journal = {Diabetes research and clinical practice},
volume = {117},
number = {},
pages = {4-11},
doi = {10.1016/j.diabres.2016.04.040},
pmid = {27329016},
issn = {1872-8227},
mesh = {Adult ; Biomarkers/blood ; Blood Pressure ; Case-Control Studies ; Cross-Sectional Studies ; Diabetes Mellitus, Type 1/blood/*complications/genetics ; Diabetic Angiopathies/diagnosis/*etiology ; Female ; Humans ; Inflammation/diagnosis/*etiology ; Insulin Resistance ; Male ; *Oxidative Stress ; Real-Time Polymerase Chain Reaction ; Risk Factors ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {OBJECTIVE: To determine if white blood cell (WBC) telomeres are shorter in Type 1 diabetes (T1D) than in subjects without diabetes (non-DB), and shorter in T1D subjects with vs. without vascular complications; and to determine associations with vascular biomarkers.<br><br>RESEARCH DESIGN AND METHODS: WBC relative telomere length (RTL) was determined by quantitative PCR in a cross-sectional study of 140 non-DB and 199 T1D adults, including 128 subjects without vascular complications (T1DNoCx) and 71 subjects with vascular complications (T1DCx). Relationships of RTL with age, T1D duration, arterial elasticity, pulse pressure and vascular risk factors were determined.<br><br>RESULTS: RTL did not differ by gender within T1D and non-DB groups. Age-adjusted RTL was shorter in T1D vs. non-DB subjects (1.48&#xb1;0.03 AU vs. 1.64&#xb1;0.04 AU, p=0.002), but did not differ by T1D complication status (T1DNoCX 1.50&#xb1;0.04 vs. T1DCX 1.46&#xb1;0.05, p=0.50), nor correlate with arterial elasticity. Univariate analysis in T1D showed RTL correlated (inversely) with age r=-0.27, p=0.0001, T1D duration r=-0.16, p=0.03, and pulse pressure (r=-0.15, p=0.04), but not with HbA1c, BP, renal function (serum creatinine, ACR, eGFR), lipids, insulin sensitivity, inflammation (CRP, CAMs) or oxidative stress (OxLDL, OxLDL/LDL-C, MPO, PON-1). Multiple regression analysis showed independent determinants of RTL were age and T1D presence (r=0.29, p<0.0001).<br><br>CONCLUSIONS: In this cross-sectional study telomeres were shorter in T1D. RTL correlated inversely with T1D duration, but did not differ by complication status and weakly correlated with pulse pressure and vascular risk factors. Only age and T1D were independent determinants of RTL. Longitudinal studies are merited.},
}
@article {pmid27326259,
year = {2016},
author = {Yang, H and Wu, L and Ke, S and Wang, W and Yang, L and Gao, X and Fang, H and Yu, H and Zhong, Y and Xie, C and Zhou, F and Zhou, Y},
title = {Downregulation of Ubiquitin-conjugating Enzyme UBE2D3 Promotes Telomere Maintenance and Radioresistance of Eca-109 Human Esophageal Carcinoma Cells.},
journal = {Journal of Cancer},
volume = {7},
number = {9},
pages = {1152-1162},
pmid = {27326259},
issn = {1837-9664},
abstract = {Ubiquitin-conjugating enzyme UBE2D3 is an important member of the ubiquitin-proteasome pathways. Our previous study showed that the expression of UBE2D3 was negatively related to human telomerase reverse transcriptase (hTERT) and radioresistance in human breast cancer cells. However, in esophageal carcinoma, the exact effects and mechanisms of UBE2D3 in radioresistance remain unclear. This study shows that UBE2D3 knockdown was associated with significant increases in radioresistance to X-rays, telomerase activity, telomere length, and telomere shelterins. UBE2D3 knockdown-mediated radioresistance was related to a decrease in the spontaneous and ionizing radiation-induced apoptosis, resulting from a decrease in the Bax/Bcl-2 ratio. Furthermore, UBE2D3 downregulation was associated with increased G1-S phase transition and prolonged IR-induced G2/M arrest through over expression of cyclin D1, decrease of CDC25A expression and promotion of the ATM/ATR-Chk1-CDC25C pathway. Moreover, UBE2D3 downregulation reduced spontaneous DNA double-strand breaks and accelerated the repair of DNA damage induced by IR. The current data thus demonstrate that UBE2D3 downregulation enhances radioresistance by increased telomere homeostasis and prolonged IR-induced G2/M arrest, but decreases the IR-induced apoptosis and the number of DNA damage foci. These results suggest that UBE2D3 might be a potential molecular target to improve radiotherapy effects in esophageal carcinoma.},
}
@article {pmid27323951,
year = {2016},
author = {Jafri, MA and Ansari, SA and Alqahtani, MH and Shay, JW},
title = {Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies.},
journal = {Genome medicine},
volume = {8},
number = {1},
pages = {69},
pmid = {27323951},
issn = {1756-994X},
support = {C06 RR030414/RR/NCRR NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing/genetics ; Antineoplastic Agents/pharmacology/*therapeutic use ; Co-Repressor Proteins ; DNA Helicases/genetics ; Enzyme Inhibitors/pharmacology/*therapeutic use ; Humans ; Molecular Chaperones ; Mutation ; Neoplasms/diagnosis/*drug therapy/*genetics ; Nuclear Proteins/genetics ; Promoter Regions, Genetic ; Telomerase/antagonists &amp; inhibitors/genetics ; Telomere/drug effects/*physiology ; Telomere Homeostasis ; X-linked Nuclear Protein ; },
abstract = {Telomeres maintain genomic integrity in normal cells, and their progressive shortening during successive cell divisions induces chromosomal instability. In the large majority of cancer cells, telomere length is maintained by telomerase. Thus, telomere length and telomerase activity are crucial for cancer initiation and the survival of tumors. Several pathways that regulate telomere length have been identified, and genome-scale studies have helped in mapping genes that are involved in telomere length control. Additionally, genomic screening for recurrent human telomerase gene hTERT promoter mutations and mutations in genes involved in the alternative lengthening of telomeres pathway, such as ATRX and DAXX, has elucidated how these genomic changes contribute to the activation of telomere maintenance mechanisms in cancer cells. Attempts have also been made to develop telomere length- and telomerase-based diagnostic tools and anticancer therapeutics. Recent efforts have revealed key aspects of telomerase assembly, intracellular trafficking and recruitment to telomeres for completing DNA synthesis, which may provide novel targets for the development of anticancer agents. Here, we summarize telomere organization and function and its role in oncogenesis. We also highlight genomic mutations that lead to reactivation of telomerase, and mechanisms of telomerase reconstitution and trafficking that shed light on its function in cancer initiation and tumor development. Additionally, recent advances in the clinical development of telomerase inhibitors, as well as potential novel targets, will be summarized.},
}
@article {pmid27321645,
year = {2016},
author = {Hamad, R and Walter, S and Rehkopf, DH},
title = {Telomere length and health outcomes: A two-sample genetic instrumental variables analysis.},
journal = {Experimental gerontology},
volume = {82},
number = {},
pages = {88-94},
pmid = {27321645},
issn = {1873-6815},
support = {K01 AG047280/AG/NIA NIH HHS/United States ; KL2 TR001083/TR/NCATS NIH HHS/United States ; U01 AG009740/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aging/*genetics/*physiology ; Coronary Artery Disease/*epidemiology/genetics ; Databases, Factual ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Molecular Epidemiology ; Polymorphism, Single Nucleotide ; Self Report ; Telomere/*ultrastructure ; Telomere Homeostasis/*physiology ; United States ; },
abstract = {OBJECTIVE: Previous studies linking telomere length (TL) and health have been largely associational. We apply genetic instrumental variables (IV) analysis, also known as Mendelian randomization, to test the hypothesis that shorter TL leads to poorer health. This method reduces bias from reverse causation or confounding.<br><br>METHODS: We used two approaches in this study that rely on two separate data sources: (1) individual-level data from the Health and Retirement Study (HRS) (N=3734), and (2) coefficients from genome-wide association studies (GWAS). We employed two-sample genetic IV analyses, constructing a polygenic risk score (PRS) of TL-associated single nucleotide polymorphisms. The first approach examined the association of the PRS with nine individual health outcomes in HRS. The second approach took advantage of estimates available in GWAS databases to estimate the impact of TL on five health outcomes using an inverse variance-weighted meta-analytic technique.<br><br>RESULTS: Using individual-level data, shorter TL was marginally statistically significantly associated with decreased risk of stroke and increased risk of heart disease. Using the meta-analytic approach, shorter TL was associated with increased risk of coronary artery disease (OR 1.02 per 100 base pairs, 95%CI: 1.00, 1.03).<br><br>DISCUSSION: With the exception of a small contribution to heart disease, our findings suggest that TL may be a marker of disease rather than a cause. They also demonstrate the utility of the inverse variance-weighted meta-analytic approach when examining small effect sizes.},
}
@article {pmid27314101,
year = {2016},
author = {Koschmann, C and Lowenstein, PR and Castro, MG},
title = {ATRX mutations and glioblastoma: Impaired DNA damage repair, alternative lengthening of telomeres, and genetic instability.},
journal = {Molecular &amp; cellular oncology},
volume = {3},
number = {3},
pages = {e1167158},
pmid = {27314101},
issn = {2372-3556},
support = {R01 NS082311/NS/NINDS NIH HHS/United States ; R01 NS096756/NS/NINDS NIH HHS/United States ; },
abstract = {Alpha thalassemia/mental retardation syndrome X-linked (ATRX) is mutated in nearly a third of pediatric glioblastoma (GBM) patients. We developed an animal model of ATRX-deficient GBM. Using this model combined with analysis of multiple human glioma genome-wide datasets, we determined that ATRX mutation leads to genetic instability, impaired non-homologous end joining, and alternate lengthening of telomeres (ALT).},
}
@article {pmid27312549,
year = {2016},
author = {Liu, M and Huo, YR and Wang, J and Wang, C and Liu, S and Liu, S and Wang, J and Ji, Y},
title = {Telomere Shortening in Alzheimer's Disease Patients.},
journal = {Annals of clinical and laboratory science},
volume = {46},
number = {3},
pages = {260-265},
pmid = {27312549},
issn = {1550-8080},
mesh = {Aged ; Alzheimer Disease/*pathology ; Case-Control Studies ; Female ; Humans ; Male ; *Telomere Shortening ; },
abstract = {BACKGROUND AND AIMS: Sporadic Alzheimer's Disease (AD) is considered an age-related disease, and telomere length has been shown to decrease with age in animal and human studies. Shortening of telomere length has also been reported to beis associated with numerous neurodegenerative diseases, including AD. The aim of this study is to confirm and further elucidate the relationship between peripheral telomere length and Alzheimer's disease, cognitive function, and duration of Alzheimer's disease.<br><br>METHODS: In this study, we recruited 165 Han Chinese subjects, consisting of 79 normal controls and 86 patients with AD without family history of AD or vascular dementia cases. We measured telomere length (T/S ratio) at baseline using quantitative PCR.<br><br>RESULTS: Our data showed that the negative correlation between telomere length and age become much stronger in AD patients (n=86, r=-0.382, p<0.001) compared to the control group (n=79, r=-0.024, p=0.833), presenting an estimated telomere loss rate of 0.003 T/S ratio/year (p<0.001). Moreover, we observed that the duration of AD is significantly negatively correlated with telomere length (n=86, r=-0.224, p=0.039), especially in female patients (n=43, r=-0.375, p=0.013) and ApoE4-noncarrier patients (n=52, r=-0.368, p=0.007). We also had some unexpected results, namely that in AD patients, higher Minimum Mental State Examination (MMSE) score were associated with shorter telomere length (n=76, r=-0.281, p=0.014).<br><br>CONCLUSIONS: This study revealed an accelerated rate of telomere shortening in AD, as well as strong influence of gender and ApoE status on telomere length in the context of this disease.},
}
@article {pmid27303051,
year = {2016},
author = {Salmón, P and Nilsson, JF and Nord, A and Bensch, S and Isaksson, C},
title = {Urban environment shortens telomere length in nestling great tits, Parus major.},
journal = {Biology letters},
volume = {12},
number = {6},
pages = {},
pmid = {27303051},
issn = {1744-957X},
mesh = {Animals ; *Ecosystem ; Female ; Male ; Passeriformes/*physiology ; Sweden ; Telomere/*physiology ; *Telomere Shortening ; },
abstract = {Urban environments are expanding rapidly, and with urbanization come both challenges and opportunities for wildlife. Challenges include combating the anthropogenic disturbances such as light, noise and air pollution and lower availability of natural food sources. The benefits are many, including the availability of anthropogenic food sources, breeding boxes and warmer temperatures. Thus, depending on the context, urbanization can have both positive and negative effects on fitness related traits. It is well known that early-life conditions can have lifelong implications on fitness; little is however known about development in urban environments. We reciprocally cross-fostered urban and rural nestling great tits (Parus major L.) to study how growing up in an urban versus rural habitat affected telomere length (TL)-a suggested biomarker of longevity. We show, for the first time, that growing up in an urban environment significantly shortens TL, independently of natal origin (i.e. urban or rural). This implies that the urban environment imposes a challenge to developing birds, with potentially irreversible effects on lifespan.},
}
@article {pmid27302823,
year = {2016},
author = {Atala, A},
title = {Re: Mutations in TERT Promoter and FGFR3 and Telomere Length in Bladder Cancer.},
journal = {The Journal of urology},
volume = {195},
number = {4 Pt 1},
pages = {1168-1169},
doi = {10.1016/j.juro.2016.01.020},
pmid = {27302823},
issn = {1527-3792},
mesh = {Humans ; Mutation ; Promoter Regions, Genetic ; Receptor, Fibroblast Growth Factor, Type 3/genetics ; *Telomere ; Urinary Bladder Neoplasms/*genetics ; },
}
@article {pmid27302811,
year = {2016},
author = {Niederberger, C},
title = {Re: Sperm Telomere Length is Positively Associated with the Quality of Early Embryonic Development.},
journal = {The Journal of urology},
volume = {195},
number = {4 Pt 1},
pages = {1076-1077},
doi = {10.1016/j.juro.2016.01.031},
pmid = {27302811},
issn = {1527-3792},
mesh = {Female ; Pregnancy ; *Spermatozoa ; *Telomere ; },
}
@article {pmid27302671,
year = {2016},
author = {Leung, CW and Laraia, BA and Coleman-Phox, K and Bush, NR and Lin, J and Blackburn, EH and Adler, NE and Epel, ES},
title = {Sugary beverage and food consumption, and leukocyte telomere length maintenance in pregnant women.},
journal = {European journal of clinical nutrition},
volume = {70},
number = {9},
pages = {1086-1088},
pmid = {27302671},
issn = {1476-5640},
support = {K99 HD084758/HD/NICHD NIH HHS/United States ; P30 DK098722/DK/NIDDK NIH HHS/United States ; R00 HD084758/HD/NICHD NIH HHS/United States ; U01 HL097973/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; *Beverages ; *Diet ; Dietary Sugars/*adverse effects ; Energy Intake ; *Feeding Behavior ; Female ; Humans ; *Leukocytes ; Middle Aged ; Mindfulness ; Obesity/complications ; Pregnancy ; Pregnancy Complications ; Telomere/*drug effects ; *Telomere Homeostasis ; Telomere Shortening ; Young Adult ; },
abstract = {Leukocyte telomere length (LTL) has been inversely associated with sugar-sweetened beverage (SSB) consumption in cross-sectional studies, but no studies have examined whether dietary intake influences LTL over time. This study examined longitudinal associations between sugary foods and beverages and LTL. Participants were 65 overweight and obese pregnant women, aged 18-45 years, from a mindfulness intervention study conducted from early pregnancy (⩽16 weeks gestation) and followed through 9 months postpartum. During pregnancy and postpartum, dietary intake was measured with 24-h diet recalls, and LTL was assessed using quantitative PCR. Adjusting for sociodemographic and health characteristics, decreased SSB consumption from baseline to 9 months postpartum was associated with greater concurrent LTL lengthening (β=-0.102, 95% confidence interval (CI) -0.192, -0.013). No associations between sugary foods and LTL were found in either period. The finding that reduced SSB consumption is associated with increased LTL warrants investigation in large cohort studies.},
}
@article {pmid27299710,
year = {2016},
author = {Liu, CC and Ma, DL and Yan, TD and Fan, X and Poon, Z and Poon, LF and Goh, SA and Rozen, SG and Hwang, WY and Tergaonkar, V and Tan, P and Ghosh, S and Virshup, DM and Goh, EL and Li, S},
title = {Distinct Responses of Stem Cells to Telomere Uncapping-A Potential Strategy to Improve the Safety of Cell Therapy.},
journal = {Stem cells (Dayton, Ohio)},
volume = {34},
number = {10},
pages = {2471-2484},
doi = {10.1002/stem.2431},
pmid = {27299710},
issn = {1549-4918},
mesh = {Animals ; Biomarkers/metabolism ; Cell Death/drug effects ; Cell Differentiation/drug effects ; Cell Proliferation/drug effects ; Cell- and Tissue-Based Therapy/*adverse effects ; Etoposide/pharmacology ; Gene Expression Profiling ; Gene Knockout Techniques ; Genetic Engineering ; Genome, Human ; Human Embryonic Stem Cells/*cytology/drug effects/*metabolism/transplantation ; Humans ; Mice, SCID ; Neurons/cytology/drug effects/metabolism ; Stem Cell Transplantation ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere Shortening/drug effects ; Teratoma/genetics/pathology ; },
abstract = {In most human somatic cells, the lack of telomerase activity results in progressive telomere shortening during each cell division. Eventually, DNA damage responses triggered by critically short telomeres induce an irreversible cell cycle arrest termed replicative senescence. However, the cellular responses of human pluripotent stem cells to telomere uncapping remain unknown. We generated telomerase knockout human embryonic stem (ES) cells through gene targeting. Telomerase inactivation in ES cells results in progressive telomere shortening. Telomere DNA damage in ES cells and neural progenitor cells induces rapid apoptosis when telomeres are uncapped, in contrast to fibroblast cells that enter a state of replicative senescence. Significantly, telomerase inactivation limits the proliferation capacity of human ES cells without affecting their pluripotency. By targeting telomerase activity, we can functionally separate the two unique properties of human pluripotent stem cells, namely unlimited self-renewal and pluripotency. We show that the potential of ES cells to form teratomas in vivo is dictated by their telomere length. By controlling telomere length of ES cells through telomerase inactivation, we can inhibit teratoma formation and potentially improve the safety of cell therapies involving terminally differentiated cells as well as specific progenitor cells that do not require sustained cellular proliferation in vivo, and thus sustained telomerase activity. Stem Cells 2016;34:2471-2484.},
}
@article {pmid27295426,
year = {2016},
author = {Kargaran, PK and Yasaei, H and Anjomani-Virmouni, S and Mangiapane, G and Slijepcevic, P},
title = {Analysis of alternative lengthening of telomere markers in BRCA1 defective cells.},
journal = {Genes, chromosomes &amp; cancer},
volume = {55},
number = {11},
pages = {864-876},
pmid = {27295426},
issn = {1098-2264},
mesh = {Animals ; BRCA1 Protein/*genetics ; Cell Line, Tumor ; Humans ; Leukemia, Promyelocytic, Acute/*genetics/pathology ; Mice ; Mouse Embryonic Stem Cells/pathology ; Mutation ; Recombination, Genetic ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Telomeres are specialized structures responsible for the chromosome end protection. Previous studies have revealed that defective BRCA1 may lead to elevated telomere fusions and accelerated telomere shortening. In addition, BRCA1 associates with promyelocytic leukemia (PML) bodies in alternative lengthening of telomeres (ALTs) positive cells. We report here elevated recombination rates at telomeres in cells from human BRCA1 mutation carriers and in mouse embryonic stem cells lacking both copies of functional Brca1. An increased recombination rate at telomeres is one of the signs of ALT. To investigate this possibility further we employed the C-circle assay that identifies ALT unequivocally. Our results revealed elevated levels of ALT activity in Brca1 defective mouse cells. Similar results were obtained when the same cells were assayed for the presence of another ALT marker, namely the frequency of PML bodies. These results suggest that BRCA1 may act as a repressor of ALT. © 2016 The Authors Genes, Chromosomes &amp; Cancer Published by Wiley Periodicals, Inc.},
}
@article {pmid27288716,
year = {2016},
author = {Zubakov, D and Liu, F and Kokmeijer, I and Choi, Y and van Meurs, JBJ and van IJcken, WFJ and Uitterlinden, AG and Hofman, A and Broer, L and van Duijn, CM and Lewin, J and Kayser, M},
title = {Human age estimation from blood using mRNA, DNA methylation, DNA rearrangement, and telomere length.},
journal = {Forensic science international. Genetics},
volume = {24},
number = {},
pages = {33-43},
doi = {10.1016/j.fsigen.2016.05.014},
pmid = {27288716},
issn = {1878-0326},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Biomarkers/blood ; *Blood Chemical Analysis ; CpG Islands/genetics ; *DNA Methylation ; Gene Expression Profiling ; *Gene Rearrangement ; Humans ; Male ; Microarray Analysis ; Middle Aged ; Polymerase Chain Reaction ; RNA, Messenger/*genetics ; Telomere/*genetics ; Young Adult ; },
abstract = {Establishing the age of unknown persons, or persons with unknown age, can provide important leads in police investigations, disaster victim identification, fraud cases, and in other legal affairs. Previous methods mostly relied on morphological features available from teeth or skeletal parts. The development of molecular methods for age estimation allowing to use human specimens that possess no morphological age information, such as bloodstains, is extremely valuable as this type of samples is commonly found at crime scenes. Recently, we introduced a DNA-based approach for human age estimation from blood based on the quantification of T-cell specific DNA rearrangements (sjTRECs), which achieves accurate assignment of blood DNA samples to one of four 20-year-interval age categories. Aiming at improving the accuracy of molecular age estimation from blood, we investigated different types of biomarkers. We started out by systematic genome-wide surveys for new age-informative mRNA and DNA methylation markers in blood from the same young and old individuals using microarray technologies. The obtained candidate markers were validated in independent samples covering a wide age range using alternative technologies together with previously proposed DNA methylation, sjTREC, and telomere length markers. Cross-validated multiple regression analysis was applied for estimating and validating the age predictive power of various sets of biomarkers within and across different marker types. We found that DNA methylation markers outperformed mRNA, sjTREC, and telomere length in age predictive power. The best performing model included 8 DNA methylation markers derived from 3 CpG islands reaching a high level of accuracy (cross-validated R(2)=0.88, SE±6.97 years, mean absolute deviation 5.07 years). However, our data also suggest that mRNA markers can provide independent age information: a model using a combined set of 5 DNA methylation markers and one mRNA marker could provide similarly high accuracy (cross-validated R(2)=0.86, SE±7.62 years, mean absolute deviation 4.60 years). Overall, our study provides new and confirms previously suggested molecular biomarkers for age estimation from blood. Moreover, our comparative study design revealed that DNA methylation markers are superior for this purpose over other types of molecular biomarkers tested. While the new and some previous findings are highly promising, before molecular age estimation can eventually meet forensic practice, the proposed biomarkers should be tested further in larger sets of blood samples from both healthy and unhealthy individuals, and markers and genotyping methods shall be validated to meet forensic standards.},
}
@article {pmid27281805,
year = {2016},
author = {Liu, JJ and Crous-Bou, M and Giovannucci, E and De Vivo, I},
title = {Coffee Consumption Is Positively Associated with Longer Leukocyte Telomere Length in the Nurses' Health Study.},
journal = {The Journal of nutrition},
volume = {146},
number = {7},
pages = {1373-1378},
pmid = {27281805},
issn = {1541-6100},
support = {R01 CA163451/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA134958/CA/NCI NIH HHS/United States ; R01 CA082838/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; R01 CA065725/CA/NCI NIH HHS/United States ; R03 CA132190/CA/NCI NIH HHS/United States ; R03 CA139586/CA/NCI NIH HHS/United States ; R03 CA139586/CA/NCI NIH HHS/United States ; K07 CA140790/CA/NCI NIH HHS/United States ; R03 CA133914/CA/NCI NIH HHS/United States ; R03 CA132175/CA/NCI NIH HHS/United States ; R01 HL088521/HL/NHLBI NIH HHS/United States ; R01 HL060712/HL/NHLBI NIH HHS/United States ; U54 CA155626/CA/NCI NIH HHS/United States ; R01 AR059073/AR/NIAMS NIH HHS/United States ; R01 HL034594/HL/NHLBI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 HL034594/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Caffeine/administration &amp; dosage/chemistry ; Coffee/*chemistry ; Cross-Sectional Studies ; Diet ; Diet Records ; Diet Surveys ; Female ; Humans ; Leukocytes/*ultrastructure ; Middle Aged ; Telomere/ultrastructure ; },
abstract = {BACKGROUND: Coffee is an important source of antioxidants, and consumption of this beverage is associated with many health conditions and a lower mortality risk. However, no study, to our knowledge, has examined whether varying coffee or caffeine consumption levels are associated with telomere length, a biomarker of aging whose shortening can be accelerated by oxidative stress.<br><br>OBJECTIVE: We performed a large comprehensive study on how coffee consumption is associated with telomere length.<br><br>METHODS: We used data from the Nurses' Health Study (NHS), a prospective cohort study of female nurses that began in 1976. We examined the cross-sectional association between coffee consumption and telomere length in 4780 women from the NHS. Coffee consumption information was obtained from validated food-frequency questionnaires, and relative telomere length was measured in peripheral blood leukocytes by the quantitative real-time polymerase chain reaction. Unconditional logistic regression was used to obtain ORs when the telomere length outcome was dichotomized at the median. Linear regression was used for tests of trend with coffee consumption and telomere length as continuous variables.<br><br>RESULTS: Higher total coffee consumption was significantly associated with longer telomeres after potential confounding adjustment. Compared with non-coffee drinkers, multivariable ORs for those drinking 2 to <3 and &#x2265;3 cups of coffee/d were, respectively, 1.29 (95% CI: 0.99, 1.68) and 1.36 (95% CI: 1.04, 1.78) (P-trend = 0.02). We found a significant linear association between caffeine consumption from all dietary sources and telomere length (P-trend = 0.02) after adjusting for potential confounders, but not after additionally adjusting for total coffee consumption (P-trend = 0.37).<br><br>CONCLUSIONS: We found that higher coffee consumption is associated with longer telomeres among female nurses. Future studies are needed to better understand the influence of coffee consumption on telomeres, which may uncover new knowledge of how coffee consumption affects health and longevity.},
}
@article {pmid27266474,
year = {2016},
author = {Révész, D and Verhoeven, JE and Milaneschi, Y and Penninx, BW},
title = {Depressive and anxiety disorders and short leukocyte telomere length: mediating effects of metabolic stress and lifestyle factors.},
journal = {Psychological medicine},
volume = {46},
number = {11},
pages = {2337-2349},
doi = {10.1017/S0033291716000891},
pmid = {27266474},
issn = {1469-8978},
mesh = {Adult ; *Anxiety Disorders/immunology/metabolism/physiopathology ; *Depressive Disorder/immunology/metabolism/physiopathology ; Female ; Humans ; *Leukocytes ; *Life Style ; Male ; *Metabolic Syndrome/immunology/metabolism/physiopathology ; Middle Aged ; Netherlands ; *Smoking/immunology/metabolism/physiopathology ; *Stress, Psychological/immunology/metabolism/physiopathology ; *Telomere ; },
abstract = {BACKGROUND: Depressive and anxiety disorders are associated with shorter leukocyte telomere length (LTL), an indicator of cellular aging. It is, however, unknown which pathways underlie this association. This study examined the extent to which lifestyle factors and physiological changes such as inflammatory or metabolic alterations mediate the relationship.<br><br>METHOD: We applied mediation analysis techniques to data from 2750 participants of the Netherlands Study of Depression and Anxiety. LTL was assessed using quantitative polymerase chain reaction. Independent variables were current depressive (30-item Inventory of Depressive Symptoms - Self Report) and anxiety (21-item Beck's Anxiety Inventory) symptoms and presence of a depressive or anxiety disorder diagnosis based on DSM-IV; mediator variables included physiological stress systems, metabolic syndrome components and lifestyle factors.<br><br>RESULTS: Short LTL was associated with higher symptom severity (B = -2.4, p = 0.002) and current psychiatric diagnosis (B = -63.3, p = 0.024). C-reactive protein, interleukin-6, waist circumference, triglycerides, high-density lipoprotein cholesterol and cigarette smoking were significant mediators in the relationship between psychopathology and LTL. When all significant mediators were included in one model, the effect sizes of the relationships between LTL and symptom severity and current diagnosis were reduced by 36.7 and 32.7%, respectively, and the remaining direct effects were no longer significant.<br><br>CONCLUSIONS: Pro-inflammatory cytokines, metabolic alterations and cigarette smoking are important mediators of the association between depressive and anxiety disorders and LTL. This calls for future research on intervention programs that take into account lifestyle changes in mental health care settings.},
}
@article {pmid27259814,
year = {2016},
author = {Scheller Madrid, A and Rode, L and Nordestgaard, BG and Bojesen, SE},
title = {Short Telomere Length and Ischemic Heart Disease: Observational and Genetic Studies in 290 022 Individuals.},
journal = {Clinical chemistry},
volume = {62},
number = {8},
pages = {1140-1149},
doi = {10.1373/clinchem.2016.258566},
pmid = {27259814},
issn = {1530-8561},
mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Myocardial Ischemia/*genetics ; Prospective Studies ; RNA/genetics ; Telomerase/genetics ; Telomere Shortening/*genetics ; Telomere-Binding Proteins/genetics ; Young Adult ; },
abstract = {BACKGROUND: Short telomeres are associated with aging and have been associated with a high risk of ischemic heart disease in observational studies; however, the latter association could be due to residual confounding and/or reverse causation. We wanted to test the hypothesis that short telomeres are associated with high risk of ischemic heart disease using a Mendelian randomization approach free of reverse causation and of most confounding.<br><br>METHODS: We genotyped 3 genetic variants in OBFC1 (oligonucleotide/oligosaccharide binding fold containing 1), TERT (telomerase reverse transcriptase), and TERC (telomerase RNA component), which code for proteins and RNA involved in telomere maintenance. We studied 105 055 individuals from Copenhagen; 17 235 of these individuals were diagnosed with ischemic heart disease between 1977 and 2013, and 66 618 had telomere length measured. For genetic studies, we further included the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) consortium dataset, which included up to 184 967 participants and 60 837 cases of ischemic heart disease. We conducted multivariable adjusted Cox proportional hazard models for observational estimates, using logistic and instrumental variable analysis for genetic estimates.<br><br>RESULTS: Observationally, a 200-bp-shorter telomere length was associated with a multivariable adjusted hazard ratio for ischemic heart disease of 1.02 (95% CI, 1.01-1.03). Per allele, telomeres were shorter by 67 bp (73-60). In meta-analyses of all 4 studies combined, odds ratios for ischemic heart disease were 1.05 (1.03-1.08) for OBCF1, 1.04 (1.02-1.06) for TERT, and 1.01 (0.99-1.03) for TERC. A genetically determined 200-bp-shorter telomere length was associated with an odds ratio for ischemic heart disease of 1.10 (1.06-1.14).<br><br>CONCLUSIONS: Shorter telomeres were associated with a higher risk of ischemic heart disease, both observationally and genetically.},
}
@article {pmid27259265,
year = {2016},
author = {Tahara, T and Shibata, T and Okubo, M and Kawamura, T and Horiguchi, N and Ishizuka, T and Nakano, N and Nagasaka, M and Nakagawa, Y and Ohmiya, N},
title = {Demonstration of potential link between Helicobacter pylori related promoter CpG island methylation and telomere shortening in human gastric mucosa.},
journal = {Oncotarget},
volume = {7},
number = {28},
pages = {43989-43996},
pmid = {27259265},
issn = {1949-2553},
mesh = {Aged ; CpG Islands/*genetics ; *DNA Methylation ; Female ; Gastric Mucosa/*metabolism/microbiology ; Genetic Predisposition to Disease/genetics ; Helicobacter Infections/*genetics/microbiology ; Helicobacter pylori/*isolation &amp; purification/physiology ; Host-Pathogen Interactions ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Promoter Regions, Genetic/*genetics ; Risk Factors ; Sequence Analysis, DNA/methods ; Stomach Diseases/genetics/microbiology ; Telomere Shortening/*genetics ; },
abstract = {BACKGROUND: Telomere length shortening in Helicobacter pylori (H. pylori) infected gastric mucosa constitutes the earliest steps toward neoplastic transformation. In addition to this genotoxic changes, epigenetic changes such as promoter CpG island (PCGI) methylation are frequently occurred in H. pylori infected gastric mucosa. The aim of this study was to investigate a potential link between H. pylori related PCGI methylation and telomere length shortening in the human gastric mucosa.<br><br>METHODS: Telomere length was measured in non-neoplastic gastric mucosa from 106 cancer-free subjects. To identify H. pylori related PCGI methylation, bisulfite pyrosequencing was used to quantify the methylation of 49 PCGIs from 47 genes and LINE1 repetitive elementResults: We identified five PCGIs (IGF2, SLC16A12, SOX11, P2RX7 and MYOD1), which the methylation is closely associated with H. pylori infection. Hypermethylation of all these PCGIs was associated with development of pathological state from normal to mild, active, and atrophic gastritis (P<0.001) and lower pepsinogen I/II ratio (P<0.05), an indicator for gastric mucosal atrophy. Telomere shortening was significantly associated with mean Z score methylation of five PCGIs (R=-0.39, P<0.0001) and four of these locus (IGF2: R=-0.35, P=0.0003, SLC16A12: R=-0.35, P=0.0002, P2RX7: R=-0.29, P=0.003, and MYOD1: R=-0.33, P=0.0005). Multivariate analysis revealed that telomere shortening held an increased risk for hypermethylation (odds ratio: 1.71, 95% confidence interval: 1.11-2.63, P=0.016).<br><br>CONCLUSION: Potential link between H. pylori related PCGI methylation and telomere shortening emphasize the importance of genotoxic-epigenetic interaction in the pathological state of H. pylori infected gastric mucosa.},
}
@article {pmid27259001,
year = {2017},
author = {Colicino, E and Wilson, A and Frisardi, MC and Prada, D and Power, MC and Hoxha, M and Dioni, L and Spiro, A and Vokonas, PS and Weisskopf, MG and Schwartz, JD and Baccarelli, AA},
title = {Telomere Length, Long-Term Black Carbon Exposure, and Cognitive Function in a Cohort of Older Men: The VA Normative Aging Study.},
journal = {Environmental health perspectives},
volume = {125},
number = {1},
pages = {76-81},
pmid = {27259001},
issn = {1552-9924},
support = {R01 ES015172/ES/NIEHS NIH HHS/United States ; T32 AG027668/AG/NIA NIH HHS/United States ; T32 ES007142/ES/NIEHS NIH HHS/United States ; P30 ES000002/ES/NIEHS NIH HHS/United States ; R01 ES021733/ES/NIEHS NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; },
mesh = {Aged ; Aging ; Air Pollutants/*analysis ; Air Pollution/*statistics &amp; numerical data ; Biomarkers ; C-Reactive Protein/metabolism ; Carbon ; Cognition ; Cognition Disorders ; Environmental Exposure/*statistics &amp; numerical data ; Humans ; Male ; Neuropsychological Tests ; Soot/*analysis ; Telomere/*physiology ; Veterans ; },
abstract = {BACKGROUND: Long-term air pollution exposure has been associated with age-related cognitive impairment, possibly because of enhanced inflammation. Leukocytes with longer telomere length (TL) are more responsive to inflammatory stimuli, yet TL has not been evaluated in relation to air pollution and cognition.<br><br>OBJECTIVES: We assessed whether TL modifies the association of 1-year exposure to black carbon (BC), a marker of traffic-related air pollution, with cognitive function in older men, and we examined whether this modification is independent of age and of C-reactive protein (CRP), a marker of inflammation.<br><br>METHODS: Between 1999 and 2007, we conducted 1-3 cognitive examinations of 428 older men in the Veterans Affairs (VA) Normative Aging Study. We used covariate-adjusted repeated-measure logistic regression to estimate associations of 1-year BC exposure with relative odds of being a low scorer (&#x2264; 25) on the Mini-Mental State Examination (MMSE), which is a proxy of poor cognition. Confounders included age, CRP, and lifestyle and sociodemographic factors.<br><br>RESULTS: Each doubling in BC level was associated with 1.57 (95% CI: 1.20, 2.05) times higher odds of low MMSE scores. The BC-MMSE association was greater only among individuals with longer blood TL (5th quintile) (OR = 3.23; 95% CI: 1.37, 7.59; p = 0.04 for BC-by-TL-interaction). TL and CRP were associated neither with each other nor with MMSE. However, CRP modified the BC-MMSE relationship, with stronger associations only at higher CRP (5th quintile) and reference TL level (1st quintile) (OR = 2.68; 95% CI: 1.06, 6.79; p = 0.04 for BC-by-CRP-interaction).<br><br>CONCLUSIONS: TL and CRP levels may help predict the impact of BC exposure on cognitive function in older men. Citation: Colicino E, Wilson A, Frisardi MC, Prada D, Power MC, Hoxha M, Dioni L, Spiro A III, Vokonas PS, Weisskopf MG, Schwartz JD, Baccarelli AA. 2017. Telomere length, long-term black carbon exposure, and cognitive function in a cohort of older men: the VA Normative Aging Study. Environ Health Perspect 125:76-81;&#x2002;http://dx.doi.org/10.1289/EHP241.},
}
@article {pmid27253066,
year = {2016},
author = {Hu, X and Liu, J and Jun, HI and Kim, JK and Qiao, F},
title = {Multi-step coordination of telomerase recruitment in fission yeast through two coupled telomere-telomerase interfaces.},
journal = {eLife},
volume = {5},
number = {},
pages = {},
pmid = {27253066},
issn = {2050-084X},
support = {R01 GM098943/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Cell Cycle ; Checkpoint Kinase 2/genetics/metabolism ; Mutation ; Nucleotidases/genetics/*metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases/genetics/metabolism ; Schizosaccharomyces/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Sequence Homology ; Shelterin Complex ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins ; },
abstract = {Tightly controlled recruitment of telomerase, a low-abundance enzyme, to telomeres is essential for regulated telomere synthesis. Recent studies in human cells revealed that a patch of amino acids in the shelterin component TPP1, called the TEL-patch, is essential for recruiting telomerase to telomeres. However, how TEL-patch-telomerase interaction integrates into the overall orchestration of telomerase regulation at telomeres is unclear. In fission yeast, Tel1(ATM)/Rad3(ATR)-mediated phosphorylation of shelterin component Ccq1 during late S phase is involved in telomerase recruitment through promoting the binding of Ccq1 to a telomerase accessory protein Est1. Here, we identify the TEL-patch in Tpz1(TPP1), mutations of which lead to decreased telomeric association of telomerase, similar to the phosphorylation-defective Ccq1. Furthermore, we find that telomerase action at telomeres requires formation and resolution of an intermediate state, in which the cell cycle-dependent Ccq1-Est1 interaction is coupled to the TEL-patch-Trt1 interaction, to achieve temporally regulated telomerase elongation of telomeres.},
}
@article {pmid27252422,
year = {2016},
author = {Ormseth, MJ and Solus, JF and Oeser, AM and Bian, A and Gebretsadik, T and Shintani, A and Raggi, P and Stein, CM},
title = {Telomere Length and Coronary Atherosclerosis in Rheumatoid Arthritis.},
journal = {The Journal of rheumatology},
volume = {43},
number = {8},
pages = {1469-1474},
pmid = {27252422},
issn = {1499-2752},
support = {P60 AR056116/AR/NIAMS NIH HHS/United States ; UL1 TR000445/TR/NCATS NIH HHS/United States ; K23 AR068443/AR/NIAMS NIH HHS/United States ; KL2 TR000446/TR/NCATS NIH HHS/United States ; T32 AR059039/AR/NIAMS NIH HHS/United States ; },
mesh = {Aging/genetics/metabolism ; Arthritis, Rheumatoid/*complications/genetics/metabolism ; Atherosclerosis/*etiology/genetics/metabolism ; Biomarkers ; Coronary Artery Disease/*etiology/genetics/metabolism ; Cross-Sectional Studies ; Female ; Humans ; Male ; Middle Aged ; *Telomere ; Telomere Shortening/*physiology ; },
abstract = {OBJECTIVE: Telomeres protect against chromosomal end damage and shorten with each cell division; their length may be a marker of cardiovascular and overall biological aging. We examined the hypothesis that reduced telomere length is associated with increased coronary atherosclerosis in rheumatoid arthritis (RA).<br><br>METHODS: We performed a cross-sectional study in 145 patients with RA and 87 control subjects frequency-matched for age, race, and sex. Coronary artery calcium score was determined by noncontrast cardiac computed tomography. Telomere length was measured from whole blood DNA, using real-time quantitative polymerase chain reaction and expressed as telomeric product to a single-copy gene product ratio (T/S ratio). Associations between telomere length, coronary artery calcium score, and 28-joint Disease Activity Score (DAS28) were assessed with Spearman correlation, proportional odds logistic regression, and linear regression, adjusting for age, race, and sex.<br><br>RESULTS: Telomere length was significantly inversely correlated with age in patients with RA (&#x3c1; = -0.37, p < 0.001) and control subjects (&#x3c1; = -0.39, p = 0.001). Among patients with RA, for every interquartile range (IQR) decrease in telomere length (T/S ratio), the odds of higher coronary artery calcium score increased by 38% (95% CI: 4-60) after adjusting for age, race, and sex (p adjusted = 0.03). Telomere length was not associated with DAS28 (p adjusted = 0.17). Telomere length was not significantly different in patients with RA [median (IQR): 1.02 units (0.9-1.11)] compared to control subjects [1.05 units (0.95-1.17); p = 0.10].<br><br>CONCLUSION: Telomere length is inversely associated with coronary artery calcium score, independent of age, race, and sex in patients with RA.},
}
@article {pmid27252220,
year = {2016},
author = {Ouyang, JQ and Lendvai, &#xc1;Z and Moore, IT and Bonier, F and Haussmann, MF},
title = {Do Hormones, Telomere Lengths, and Oxidative Stress form an Integrated Phenotype? A Case Study in Free-Living Tree Swallows.},
journal = {Integrative and comparative biology},
volume = {56},
number = {2},
pages = {138-145},
pmid = {27252220},
issn = {1557-7023},
support = {P20 GM103650/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Female ; Glucocorticoids/*metabolism ; *Life History Traits ; Male ; Ontario ; *Oxidative Stress ; Phenotype ; Swallows/genetics/*physiology ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Synopsis All organisms must anticipate and balance energetic demands and available resources in order to maximize fitness. As hormones coordinate many interactions between an organism's internal condition and the external environment, they may be key in mediating the allocation of resources to meet these demands. However, given that individuals differ considerably in how they react to changes in energetic demand, we asked whether variations in endocrine traits also correspond with life history variation. We tested whether natural variation in glucocorticoid hormone levels, oxidative stress measurements, and condition related to reproductive effort in a free-living songbird, the tree swallow, Tachycineta bicolor We then tested whether any of these traits predicted the probability of a particular individual's return to the local population in the following two years, an indicator of survival in this philopatric species. We found that males and females with longer telomeres had lighter nestlings. Moreover, individuals with lower plasma antioxidant capacity and higher reactive oxygen metabolites (i.e., greater oxidative stress) were less likely to return to the population. However, none of these traits were related to glucocorticoid levels. Our findings suggest a trade-off between reproduction and survival, with individuals with shorter telomeres having heavier nestlings but potentially paying a cost in terms of higher oxidative stress and lower survival. Interestingly, the evidence of this trade-off was unrelated to natural variation in glucocorticoids.},
}
@article {pmid27252083,
year = {2016},
author = {Varela, E and Muñoz-Lorente, MA and Tejera, AM and Ortega, S and Blasco, MA},
title = {Generation of mice with longer and better preserved telomeres in the absence of genetic manipulations.},
journal = {Nature communications},
volume = {7},
number = {},
pages = {11739},
pmid = {27252083},
issn = {2041-1723},
mesh = {Aging/*genetics/metabolism ; Animals ; Brain/cytology/growth &amp; development/metabolism ; DNA Damage ; Embryonic Stem Cells/cytology/*metabolism ; Female ; Gene Expression ; Genes, Reporter ; Green Fluorescent Proteins/genetics/metabolism ; Intestinal Mucosa/metabolism ; Intestines/cytology/growth &amp; development ; Longevity/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Primary Cell Culture ; Skin/cytology/growth &amp; development/metabolism ; Surgical Wound ; Telomere/*chemistry/metabolism ; *Telomere Homeostasis ; Telomere Shortening ; Wound Healing/*genetics ; },
abstract = {Although telomere length is genetically determined, mouse embryonic stem (ES) cells with telomeres of twice the normal size have been generated. Here, we use such ES cells with 'hyper-long' telomeres, which also express green fluorescent protein (GFP), to generate chimaeric mice containing cells with both hyper-long and normal telomeres. We show that chimaeric mice contain GFP-positive cells in all mouse tissues, display normal tissue histology and normal survival. Both hyper-long and normal telomeres shorten with age, but GFP-positive cells retain longer telomeres as mice age. Chimaeric mice with hyper-long telomeres also accumulate fewer cells with short telomeres and less DNA damage with age, and express lower levels of p53. In highly renewing compartments, such as the blood, cells with hyper-long telomeres are longitudinally maintained or enriched with age. We further show that wound-healing rates in the skin are increased in chimaeric mice. Our work demonstrates that mice with functional, longer and better preserved telomeres can be generated without the need for genetic manipulations, such as TERT overexpression.},
}
@article {pmid27247888,
year = {2016},
author = {Wang, S and Duan, X and Wang, T and Feng, X and Wang, P and Yao, W and Wu, Y and Wu, Y and Yan, Z and Feng, F and Yu, S and Wang, W},
title = {Detection of the rs10250202 polymorphism in protection of telomeres 1 gene through introducing a new restriction enzyme site for PCR-RFLP assay.},
journal = {SpringerPlus},
volume = {5},
number = {},
pages = {592},
pmid = {27247888},
issn = {2193-1801},
abstract = {Human protection of telomeres 1 (POT1) gene is a single stranded telomere binding proteins with a critical role in ensuring chromosome stability. There have been variants of POT1 gene, and the polymorphisms of POT1 gene were associated with some diseases. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) is a traditional method to detect the single nucleotide polymorphism (SNP), and it can be used to detect the polymorphism of rs10250202. But the restriction enzymes required for the detection of the polymorphism of rs10250202 are expensive. So we designed a novel PCR-RFLP assay for genotyping the POT1 rs10250202 SNP. In the study, a new restriction enzyme cutting site was created by created restriction site PCR (CRS-PCR), and the restriction enzyme BclI for CRS-PCR was cheaper than other enzymes. After detecting Han Chinese workers, Allele frequencies were found to be 51.54 % for allele A and 48.46 % for allele C respectively. The PCR results were confirmed by DNA sequencing. CRS-PCR provides a simple, low-cost, practical, and reproducible method.},
}
@article {pmid27245263,
year = {2016},
author = {Stindl, R},
title = {The Paradoxical Lengthening of Telomeres in Somatic Tissues of the Very Old: Aging Effect Meets Birth-Cohort Effect.},
journal = {Journal of experimental zoology. Part B, Molecular and developmental evolution},
volume = {326},
number = {4},
pages = {213-214},
doi = {10.1002/jez.b.22677},
pmid = {27245263},
issn = {1552-5015},
mesh = {Animals ; *Cohort Effect ; *Telomere ; },
}
@article {pmid27245186,
year = {2016},
author = {Reynolds, CF},
title = {Telomere Attrition: A Window Into Common Mental Disorders and Cellular Aging.},
journal = {The American journal of psychiatry},
volume = {173},
number = {6},
pages = {556-558},
doi = {10.1176/appi.ajp.2016.16020164},
pmid = {27245186},
issn = {1535-7228},
support = {P60 MD000207/MD/NIMHD NIH HHS/United States ; P30 MH090333/MH/NIMH NIH HHS/United States ; UL1 RR024153/RR/NCRR NIH HHS/United States ; UL1 TR000005/TR/NCATS NIH HHS/United States ; },
mesh = {Aging ; *Cellular Senescence ; Humans ; Mental Disorders ; *Telomere ; },
}
@article {pmid27243754,
year = {2016},
author = {Udomsinprasert, W and Kitkumthorn, N and Mutirangura, A and Chongsrisawat, V and Poovorawan, Y and Honsawek, S},
title = {Global methylation, oxidative stress, and relative telomere length in biliary atresia patients.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {26969},
pmid = {27243754},
issn = {2045-2322},
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Adult ; *Alu Elements ; Bile Ducts, Extrahepatic/metabolism/pathology ; Biliary Atresia/*genetics/metabolism/pathology ; Case-Control Studies ; Child ; DNA Damage ; DNA Methylation ; Deoxyguanosine/analogs &amp; derivatives/blood/genetics ; *Epigenesis, Genetic ; Female ; Genome-Wide Association Study ; Humans ; Liver/metabolism/pathology ; *Long Interspersed Nucleotide Elements ; Male ; Oxidative Stress ; Risk ; Telomere/*chemistry ; *Telomere Homeostasis ; Twins, Monozygotic ; },
abstract = {Alu and LINE-1 elements are retrotransposons with a ubiquitous presence in the human genome that can cause genomic instability, specifically relating to telomere length. Genotoxic agents may induce methylation of retrotransposons, in addition to oxidative DNA damage in the form of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Methylation of retrotransposons induced by these agents may contribute to biliary atresia (BA) etiology. Here, we investigated correlations between global methylation, 8-OHdG, and relative telomere length, as well as reporting on Alu and LINE-1 hypomethylation in BA patients. Alu and LINE-1 hypomethylation were found to be associated with elevated risk of BA (OR = 4.07; 95% CI: 2.27-7.32; P < 0.0001 and OR = 3.51; 95% CI: 1.87-6.59; P < 0.0001, respectively). Furthermore, LINE-1 methylation was associated with liver stiffness in BA patients (β coefficient = -0.17; 95% CI: -0.24 to -0.10; P < 0.0001). Stratified analysis revealed negative correlations between Alu and LINE-1 methylation and 8-OHdG in BA patients (P < 0.0001). In contrast, positive relationships were identified between Alu and LINE-1 methylation and relative telomere length in BA patients (P < 0.0001). These findings suggest that retrotransposon hypomethylation is associated with plasma 8-OHdG and telomere length in BA patients.},
}
@article {pmid27241915,
year = {2016},
author = {Aix, E and Gutiérrez-Gutiérrez, &#xd3; and Sánchez-Ferrer, C and Aguado, T and Flores, I},
title = {Postnatal telomere dysfunction induces cardiomyocyte cell-cycle arrest through p21 activation.},
journal = {The Journal of cell biology},
volume = {213},
number = {5},
pages = {571-583},
pmid = {27241915},
issn = {1540-8140},
mesh = {Anaphase ; Animals ; Animals, Newborn ; *Cell Cycle Checkpoints ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor p21/*metabolism ; DNA Damage ; DNA Repair ; Mice, Inbred C57BL ; Models, Biological ; Myocytes, Cardiac/*cytology/*metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {The molecular mechanisms that drive mammalian cardiomyocytes out of the cell cycle soon after birth remain largely unknown. Here, we identify telomere dysfunction as a critical physiological signal for cardiomyocyte cell-cycle arrest. We show that telomerase activity and cardiomyocyte telomere length decrease sharply in wild-type mouse hearts after birth, resulting in cardiomyocytes with dysfunctional telomeres and anaphase bridges and positive for the cell-cycle arrest protein p21. We further show that premature telomere dysfunction pushes cardiomyocytes out of the cell cycle. Cardiomyocytes from telomerase-deficient mice with dysfunctional telomeres (G3 Terc(-/-)) show precocious development of anaphase-bridge formation, p21 up-regulation, and binucleation. In line with these findings, the cardiomyocyte proliferative response after cardiac injury was lost in G3 Terc(-/-) newborns but rescued in G3 Terc(-/-)/p21(-/-) mice. These results reveal telomere dysfunction as a crucial signal for cardiomyocyte cell-cycle arrest after birth and suggest interventions to augment the regeneration capacity of mammalian hearts.},
}
@article {pmid27240403,
year = {2016},
author = {Xu, Y and Goldkorn, A},
title = {Telomere and Telomerase Therapeutics in Cancer.},
journal = {Genes},
volume = {7},
number = {6},
pages = {},
pmid = {27240403},
issn = {2073-4425},
support = {P30 CA014089/CA/NCI NIH HHS/United States ; },
abstract = {Telomerase is a reverse transcriptase capable of utilizing an integrated RNA component as a template to add protective tandem telomeric single strand DNA repeats, TTAGGG, to the ends of chromosomes. Telomere dysfunction and telomerase reactivation are observed in approximately 90% of human cancers; hence, telomerase activation plays a unique role as a nearly universal step on the path to malignancy. In the past two decades, multiple telomerase targeting therapeutic strategies have been pursued, including direct telomerase inhibition, telomerase interference, hTERT or hTERC promoter driven therapy, telomere-based approaches, and telomerase vaccines. Many of these strategies have entered clinical development, and some have now advanced to phase III clinical trials. In the coming years, one or more of these new telomerase-targeting drugs may be expected to enter the pharmacopeia of standard care. Here, we briefly review the molecular functions of telomerase in cancer and provide an update about the preclinical and clinical development of telomerase targeting therapeutics.},
}
@article {pmid27239034,
year = {2016},
author = {Pinzaru, AM and Hom, RA and Beal, A and Phillips, AF and Ni, E and Cardozo, T and Nair, N and Choi, J and Wuttke, DS and Sfeir, A and Denchi, EL},
title = {Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis.},
journal = {Cell reports},
volume = {15},
number = {10},
pages = {2170-2184},
pmid = {27239034},
issn = {2211-1247},
support = {DP2 CA195767/CA/NCI NIH HHS/United States ; F32 GM100532/GM/NIGMS NIH HHS/United States ; R01 AG038677/AG/NIA NIH HHS/United States ; R01 GM059414/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Carcinogenesis/*metabolism/*pathology ; DNA Damage/genetics ; DNA Repair/genetics ; *DNA Replication ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Genetic Predisposition to Disease ; Genomic Instability ; Lymphoid Progenitor Cells/metabolism ; Lymphoma, T-Cell, Cutaneous/genetics/immunology/pathology ; Mice ; Mutant Proteins/metabolism ; Mutation/genetics ; Protein Binding ; Shelterin Complex ; *Stress, Physiological ; Telomere/*metabolism ; Telomere-Binding Proteins ; Thymus Gland/pathology ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Genome sequencing studies have revealed a number of cancer-associated mutations in the telomere-binding factor POT1. Here, we show that when combined with p53 deficiency, depletion of murine POT1a in common lymphoid progenitor cells fosters genetic instability, accelerates the onset, and increases the severity of T cell lymphomas. In parallel, we examined human and mouse cells carrying POT1 mutations found in cutaneous T cell lymphoma (CTCL) patients. Inhibition of POT1 activates ATR-dependent DNA damage signaling and induces telomere fragility, replication fork stalling, and telomere elongation. Our data suggest that these phenotypes are linked to impaired CST (CTC1-STN1-TEN1) function at telomeres. Lastly, we show that proliferation of cancer cells lacking POT1 is enabled by the attenuation of the ATR kinase pathway. These results uncover a role for defective telomere replication during tumorigenesis.},
}
@article {pmid27233114,
year = {2016},
author = {Geronimo, CL and Zakian, VA},
title = {Getting it done at the ends: Pif1 family DNA helicases and telomeres.},
journal = {DNA repair},
volume = {44},
number = {},
pages = {151-158},
pmid = {27233114},
issn = {1568-7856},
support = {R01 GM026938/GM/NIGMS NIH HHS/United States ; R35 GM118279/GM/NIGMS NIH HHS/United States ; R37 GM026938/GM/NIGMS NIH HHS/United States ; T32 GM007388/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Pairing ; Chromatin/metabolism/ultrastructure ; DNA/genetics/*metabolism ; DNA Helicases/genetics/*metabolism ; *DNA Replication ; Humans ; Multigene Family ; Nucleic Acid Conformation ; RNA, Messenger/genetics/*metabolism ; Recombination, Genetic ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Schizosaccharomyces/genetics/metabolism ; Telomere/*metabolism/ultrastructure ; Telomere Homeostasis ; },
abstract = {It is widely appreciated that the ends of linear DNA molecules cannot be fully replicated by the conventional replication apparatus. Less well known is that semi-conservative replication of telomeric DNA also presents problems for DNA replication. These problems likely arise from the atypical chromatin structure of telomeres, the GC-richness of telomeric DNA that makes it prone to forming DNA secondary structures, and from RNA-DNA hybrids, formed by transcripts of one or both DNA strands. Given the different aspects of telomeres that complicate their replication, it is not surprising that multiple DNA helicases promote replication of telomeric DNA. This review focuses on one such class of DNA helicases, the Pif1 family of 5'-3' DNA helicases. In budding and fission yeasts, Pif1 family helicases impact both telomerase-mediated and semi-conservative replication of telomeric DNA as well as recombination-mediated telomere lengthening.},
}
@article {pmid27233113,
year = {2016},
author = {Fouquerel, E and Parikh, D and Opresko, P},
title = {DNA damage processing at telomeres: The ends justify the means.},
journal = {DNA repair},
volume = {44},
number = {},
pages = {159-168},
pmid = {27233113},
issn = {1568-7856},
support = {R01 ES022944/ES/NIEHS NIH HHS/United States ; R21 AG045545/AG/NIA NIH HHS/United States ; R33 ES025606/ES/NIEHS NIH HHS/United States ; R43 GM108187/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; DNA/*genetics/metabolism ; DNA Breaks, Double-Stranded ; DNA Glycosylases/genetics/metabolism ; *DNA Repair ; *DNA Replication ; G-Quadruplexes ; Humans ; Protein Subunits/*genetics/metabolism ; Shelterin Complex ; Telomere/*metabolism/ultrastructure ; Telomere Homeostasis ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {Telomeres at chromosome ends are nucleoprotein structures consisting of tandem TTAGGG repeats and a complex of proteins termed shelterin. DNA damage and repair at telomeres is uniquely influenced by the ability of telomeric DNA to form alternate structures including loops and G-quadruplexes, coupled with the ability of shelterin proteins to interact with and regulate enzymes in every known DNA repair pathway. The role of shelterin proteins in preventing telomeric ends from being falsely recognized and processed as DNA double strand breaks is well established. Here we focus instead on recent developments in understanding the roles of shelterin proteins and telomeric DNA sequence and structure in processing genuine damage at telomeres induced by endogenous and exogenous DNA damage agents. We will highlight advances in double strand break repair, base excision repair and nucleotide excision repair at telomeres, and will discuss important questions remaining in the field.},
}
@article {pmid27230693,
year = {2016},
author = {Hain, KO and Colin, DJ and Rastogi, S and Allan, LA and Clarke, PR},
title = {Prolonged mitotic arrest induces a caspase-dependent DNA damage response at telomeres that determines cell survival.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {26766},
pmid = {27230693},
issn = {2045-2322},
support = {12-0105/AICR_/Worldwide Cancer Research/United Kingdom ; 13424/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {*Apoptosis ; Caspase 3/metabolism ; Caspase 7/metabolism ; Caspase 9/metabolism ; Caspases/*metabolism ; Cell Line ; Cell Survival ; *DNA Damage ; Humans ; *M Phase Cell Cycle Checkpoints ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Signal Transduction ; Stress, Physiological ; Telomere/*metabolism ; },
abstract = {A delay in the completion of metaphase induces a stress response that inhibits further cell proliferation or induces apoptosis. This response is thought to protect against genomic instability and is important for the effects of anti-mitotic cancer drugs. Here, we show that mitotic arrest induces a caspase-dependent DNA damage response (DDR) at telomeres in non-apoptotic cells. This pathway is under the control of Mcl-1 and other Bcl-2 family proteins and requires caspase-9, caspase-3/7 and the endonuclease CAD/DFF40. The gradual caspase-dependent loss of the shelterin complex protein TRF2 from telomeres promotes a DDR that involves DNA-dependent protein kinase (DNA-PK). Suppression of mitotic telomere damage by enhanced expression of TRF2, or the inhibition of either caspase-3/7 or DNA-PK during mitotic arrest, promotes subsequent cell survival. Thus, we demonstrate that mitotic stress is characterised by the sub-apoptotic activation of a classical caspase pathway, which promotes telomere deprotection, activates DNA damage signalling, and determines cell fate in response to a prolonged delay in mitosis.},
}
@article {pmid27230042,
year = {2016},
author = {Rietzschel, ER and Bekaert, S and De Meyer, T},
title = {Telomeres and Atherosclerosis: The Attrition of an Attractive Hypothesis.},
journal = {Journal of the American College of Cardiology},
volume = {67},
number = {21},
pages = {2477-2479},
doi = {10.1016/j.jacc.2016.03.541},
pmid = {27230042},
issn = {1558-3597},
mesh = {*Atherosclerosis ; Humans ; *Telomere ; },
}
@article {pmid27230041,
year = {2016},
author = {Fernández-Alvira, JM and Fuster, V and Dorado, B and Soberón, N and Flores, I and Gallardo, M and Pocock, S and Blasco, MA and Andrés, V},
title = {Short Telomere Load, Telomere Length, and Subclinical Atherosclerosis: The PESA Study.},
journal = {Journal of the American College of Cardiology},
volume = {67},
number = {21},
pages = {2467-2476},
doi = {10.1016/j.jacc.2016.03.530},
pmid = {27230041},
issn = {1558-3597},
mesh = {Adult ; Age Factors ; Atherosclerosis/diagnostic imaging/*genetics ; Carotid Arteries/diagnostic imaging/metabolism ; Cross-Sectional Studies ; Female ; Femoral Artery/diagnostic imaging/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes/*metabolism ; Lipoproteins, LDL/blood ; Male ; Middle Aged ; Plaque, Atherosclerotic/diagnostic imaging/genetics ; *Telomere ; *Telomere Shortening ; Ultrasonography ; },
abstract = {BACKGROUND: Leucocyte telomere length (LTL) shortening is associated with cardiovascular ischemic events and mortality in humans, but data on its association with subclinical atherosclerosis are scarce. Whether the incidence and severity of subclinical atherosclerosis are associated with the abundance of critically short telomeres, a major trigger of cellular senescence, remains unknown.<br><br>OBJECTIVES: The authors conducted a cross-sectional exploration of the association between subclinical atherosclerosis burden and both average LTL and the abundance of short telomeres (%LTL<3 kb).<br><br>METHODS: Telomere length was assessed by high-throughput quantitative fluorescence in situ hybridization in circulating leukocytes from 1,459 volunteers without established cardiovascular disease (58% men, 40 to 54 years of age) from the PESA (Progression of Early Subclinical Atherosclerosis) study. Subclinical atherosclerosis was evaluated by coronary artery calcium scan and 2-dimensional/3-dimensional ultrasound in different aortic territories. Statistical significance of differences among multiple covariates was assessed with linear regression models. Independent associations of telomere parameters with plaque presence were evaluated using general linear models.<br><br>RESULTS: In men and women, age was inversely associated with LTL (Pearson's r&#xa0;=&#xa0;-0.127, p&#xa0;< 0.001) and directly with&#xa0;%LTL<3 kb (Pearson's r&#xa0;= 0.085; p&#xa0;= 0.001). Short LTL reached statistical significance as a determinant of total&#xa0;and&#xa0;femoral plaque in men, but not in women. However, this association was not sustained after adjustment for age or additional adjustment for cardiovascular risk factors. No significant independent association was found between %LTL<3&#xa0;kb and plaque burden. Serum-oxidized low-density lipoprotein levels were directly associated with %LTL<3 kb in men (p&#xa0;= 0.008) and women (p&#xa0;< 0.001).<br><br>CONCLUSIONS: In a cross-sectional study of a middle-aged population, average LTL and short telomere load are not significant independent determinants of subclinical atherosclerosis. Longitudinal follow-up of PESA participants will assess long-term associations between telomere length and progression of subclinical atherosclerosis.},
}
@article {pmid27228173,
year = {2016},
author = {Su, CH and Cheng, C and Tzeng, TY and Lin, IH and Hsu, MT},
title = {An H2A Histone Isotype, H2ac, Associates with Telomere and Maintains Telomere Integrity.},
journal = {PloS one},
volume = {11},
number = {5},
pages = {e0156378},
pmid = {27228173},
issn = {1932-6203},
mesh = {Ataxia Telangiectasia Mutated Proteins/genetics/metabolism ; Chromosomal Instability/physiology ; *DNA Damage ; Histones/genetics/*metabolism ; Humans ; MCF-7 Cells ; Protein Isoforms/genetics/metabolism ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere Homeostasis/*physiology ; Telomere-Binding Proteins/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; },
abstract = {Telomeres are capped at the ends of eukaryotic chromosomes and are composed of TTAGGG repeats bound to the shelterin complex. Here we report that a replication-dependent histone H2A isotype, H2ac, was associated with telomeres in human cells and co-immunoprecipitates with telomere repeat factor 2 (TRF2) and protection of telomeres protein 1 (POT1), whereas other histone H2A isotypes and mutations of H2ac did not bind to telomeres or these two proteins. The amino terminal basic domain of TRF2 was necessary for the association with H2ac and for the recruitment of H2ac to telomeres. Depletion of H2ac led to loss of telomeric repeat sequences, the appearance of dysfunctional telomeres, and chromosomal instability, including chromosomal breaks and anaphase bridges, as well as accumulation of telomere-associated DNA damage factors in H2ac depleted cells. Additionally, knockdown of H2ac elicits an ATM-dependent DNA damage response at telomeres and depletion of XPF protects telomeres against H2ac-deficiency-induced G-strand overhangs loss and DNA damage response, and prevents chromosomal instability. These findings suggest that the H2A isotype, H2ac, plays an essential role in maintaining telomere functional integrity.},
}
@article {pmid27228154,
year = {2016},
author = {Devlin, R and Marques, CA and Paape, D and Prorocic, M and Zurita-Leal, AC and Campbell, SJ and Lapsley, C and Dickens, N and McCulloch, R},
title = {Mapping replication dynamics in Trypanosoma brucei reveals a link with telomere transcription and antigenic variation.},
journal = {eLife},
volume = {5},
number = {},
pages = {},
pmid = {27228154},
issn = {2050-084X},
support = {093589//Wellcome Trust/United Kingdom ; BB/K006495/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {*Antigenic Variation ; DNA Breaks ; DNA Repair ; *DNA Replication ; RecQ Helicases/metabolism ; Telomere/*metabolism ; *Transcription, Genetic ; Trypanosoma brucei brucei/*genetics/*metabolism ; Variant Surface Glycoproteins, Trypanosoma/*biosynthesis ; },
abstract = {Survival of Trypanosoma brucei depends upon switches in its protective Variant Surface Glycoprotein (VSG) coat by antigenic variation. VSG switching occurs by frequent homologous recombination, which is thought to require locus-specific initiation. Here, we show that a RecQ helicase, RECQ2, acts to repair DNA breaks, including in the telomeric site of VSG expression. Despite this, RECQ2 loss does not impair antigenic variation, but causes increased VSG switching by recombination, arguing against models for VSG switch initiation through direct generation of a DNA double strand break (DSB). Indeed, we show DSBs inefficiently direct recombination in the VSG expression site. By mapping genome replication dynamics, we reveal that the transcribed VSG expression site is the only telomeric site that is early replicating - a differential timing only seen in mammal-infective parasites. Specific association between VSG transcription and replication timing reveals a model for antigenic variation based on replication-derived DNA fragility.},
}
@article {pmid27226730,
year = {2016},
author = {Qian, Y and Ding, T and Wei, L and Cao, S and Yang, L},
title = {Shorter telomere length of T-cells in peripheral blood of patients with lung cancer.},
journal = {OncoTargets and therapy},
volume = {9},
number = {},
pages = {2675-2682},
pmid = {27226730},
issn = {1178-6930},
abstract = {PURPOSE: Telomere shortening occurs in tumor tissues and peripheral blood lymphocytes of many common human malignancies, including lung cancer, but its variation in T-cells has never been investigated. Thus, the aim of this study was to assess telomere length in T-cells and its correlation with the clinical characteristics of patients with lung cancer.<br><br>PATIENTS AND METHODS: A total of 40 patients with lung cancer but without prior cancer history and 25 healthy individuals were selected. T-cells were isolated and their telomere lengths were measured using quantitative real-time polymerase chain reaction methods.<br><br>RESULTS: Telomere length in T-cells was significantly shorter in patients with lung cancer than in controls (P<0.001). Shorter telomere length was significantly associated with increased clinical stage (P=0.008) and distant metastasis (P=0.028). Na&#xef;ve T-cells from patients with lung cancer had significantly decreased telomere length when compared with those from controls (P=0.012).<br><br>CONCLUSION: The shortened telomere length in T-cells occurred in na&#xef;ve T-cells and might be related to lung cancer progression.},
}
@article {pmid27221886,
year = {2016},
author = {Miao, GY and Zhou, X and Zhang, X and Xie, Y and Sun, C and Liu, Y and Gan, L and Zhang, H},
title = {Telomere-Mitochondrion Links Contribute to Induction of Senescence in MCF-7 Cells after Carbon-Ion Irradiation.},
journal = {Asian Pacific journal of cancer prevention : APJCP},
volume = {17},
number = {4},
pages = {1993-1998},
doi = {10.7314/apjcp.2016.17.4.1993},
pmid = {27221886},
issn = {2476-762X},
mesh = {Blotting, Western ; Breast Neoplasms/metabolism/*pathology/radiotherapy ; Cell Proliferation ; Cellular Senescence/*radiation effects ; DNA Damage/radiation effects ; Female ; *Heavy Ion Radiotherapy ; Humans ; Immunoenzyme Techniques ; MCF-7 Cells ; Membrane Potential, Mitochondrial/*radiation effects ; Mitochondria/*radiation effects ; RNA, Messenger/genetics ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/genetics/metabolism ; Telomere Shortening/*radiation effects ; },
abstract = {The effects of carbon-ion irradiation on cancer cell telomere function have not been comprehensively studied. In our previous report cancer cells with telomere dysfunction were more sensitive to carbon-ion irradiation, but the underlying mechanisms remained unclear. Here we found that telomerase activity was suppressed by carbon-ion irradiation via hTERT down-regulation. Inhibition of telomere activity by MST-312 further increased cancer cell radiosensitivity to carbon-ion radiation. hTERT suppression caused by either carbon-ion irradiation or MST-312 impaired mitochondrial function, as indicated by decreased membrane potential, mtDNA copy number, mitochondrial mass, total ATP levels and elevated reactive oxygen species (ROS). PGC-1α expression was repressed after carbion-ion irradiation, and hTERT inhibition by MST-312 could further exacerbate this effect. Lowering the mitochondrial ROS level by MitoTEMPO could partially counteract the induction of cellular senescence induced by carbon-ion radiation and MST-312 incubation. Taken together, the current data suggest that telomere-mitochondrion links play a role in the induction of senescence in MCF-7 cells after carbon-ion irradiation.},
}
@article {pmid27221260,
year = {2016},
author = {Dismukes, AR and Meyer, VJ and Shirtcliff, EA and Theall, KP and Esteves, KC and Drury, SS},
title = {Diurnal and stress-reactive dehydroepiandrosterone levels and telomere length in youth.},
journal = {Endocrine connections},
volume = {5},
number = {3},
pages = {107-114},
pmid = {27221260},
issn = {2049-3614},
support = {R21 MH094688/MH/NIMH NIH HHS/United States ; },
abstract = {The current investigation examined the association between the aging-related biomarkers dehydroepiandrosterone (DHEA) and telomere length (TL) in community-recruited African-American youth. The examination of DHEA included stress reactive, basal and diurnal sampling, in order to elucidate the underlying physiological process that may overlap with TL. One hundred and two participants completed the Trier Social Stressor Test for children (TSST-C). TL was obtained from all youth from buccal swabs on the same day as the TSST-C. Saliva samples from 83 participants were obtained over the course of two additional days to measure waking and diurnal levels of DHEA. DHEA diurnal slope was a robust predictor of TL (B=0.516, P<0.05), while other DHEA values were not significantly associated with TL. This study is one of the first studies to examine basal, diurnal and reactivity measurements of DHEA in youth. Furthermore, this is the first study, to our knowledge, to demonstrate a positive association between DHEA, a putative anti-aging hormone, and TL, an indicator of cellular aging.},
}
@article {pmid27220467,
year = {2016},
author = {Ge, Y and Wu, S and Xue, Y and Tao, J and Li, F and Chen, Y and Liu, H and Ma, W and Huang, J and Zhao, Y},
title = {Preferential extension of short telomeres induced by low extracellular pH.},
journal = {Nucleic acids research},
volume = {44},
number = {17},
pages = {8086-8096},
pmid = {27220467},
issn = {1362-4962},
mesh = {Acetylation ; Chromatin/metabolism ; DNA/metabolism ; Extracellular Space/*metabolism ; HeLa Cells ; Histones/metabolism ; Humans ; Hydrogen-Ion Concentration ; Shelterin Complex ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere Shortening ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {The majority of tumor cells overcome proliferative limit by expressing telomerase. Whether or not telomerase preferentially extends the shortest telomeres is still under debate. When human cancer cells are cultured at neutral pH, telomerase extends telomeres in telomere length-independent manner. However, the microenvironment of tumor is slightly acidic, and it is not yet known how this influences telomerase action. Here, we examine telomere length homeostasis in tumor cells cultured at pHe 6.8. The results indicate that telomerase preferentially extends short telomeres, such that telomere length distribution narrows and telomeres become nearly uniform in size. After growth at pHe 6.8, the expression of telomerase, TRF1, TRF2 and TIN2 decreases, and the abundance of Cajal bodies decreases. Therefore, telomerase are insufficient for extending every telomere and shorter telomeres bearing less shelterin proteins are more accessible for telomerase recruitment. The findings support the 'protein-counting mechanism' in which extended and unextended state of telomere is determined by the number of associated shelterin proteins and the abundance of telomerase. Decreased expression of telomerase and preferential extension of short telomeres have important implications for tumor cell viability, and generate a strong rationale for research on telomerase-targeted anti-cancer therapeutics.},
}
@article {pmid27217844,
year = {2016},
author = {Alda, M and Puebla-Guedea, M and Rodero, B and Demarzo, M and Montero-Marin, J and Roca, M and Garcia-Campayo, J},
title = {Zen meditation, Length of Telomeres, and the Role of Experiential Avoidance and Compassion.},
journal = {Mindfulness},
volume = {7},
number = {},
pages = {651-659},
pmid = {27217844},
issn = {1868-8527},
abstract = {Mindfulness refers to an awareness that emerges by intentionally focusing on the present experience in a nonjudgmental or evaluative manner. Evidence regarding its efficacy has been increasing exponentially, and recent research suggests that the practice of meditation is associated with longer leukocyte telomere length. However, the psychological mechanisms underlying this potential relationship are unknown. We examined the telomere lengths of a group of 20 Zen meditation experts and another 20 healthy matched comparison participants who had not previously meditated. We also measured multiple psychological variables related to meditation practice. Genomic DNA was extracted for telomere measurement using a Life Length proprietary program. High-throughput quantitative fluorescence in situ hybridization (HT-Q-FISH) was used to measure the telomere length distribution and the median telomere length (MTL). The meditators group had a longer MTL (p = 0.005) and a lower percentage of short telomeres in individual cells (p = 0.007) than those in the comparison group. To determine which of the psychological variables contributed more to telomere maintenance, two regression analyses were conducted. In the first model, which applied to the MTL, the following three factors were significant: age, absence of experiential avoidance, and Common Humanity subscale of the Self Compassion Scale. Similarly, in the model that examined the percentage of short telomeres, the same factors were significant: age, absence of experiential avoidance, and Common Humanity subscale of the Self Compassion Scale. Although limited by a small sample size, these results suggest that the absence of experiential avoidance of negative emotions and thoughts is integral to the connection between meditation and telomeres.},
}
@article {pmid27216158,
year = {2016},
author = {Tamura, Y and Izumiyama-Shimomura, N and Kimbara, Y and Nakamura, K and Ishikawa, N and Aida, J and Chiba, Y and Matsuda, Y and Mori, S and Arai, T and Fujiwara, M and Poon, SS and Ishizaki, T and Araki, A and Takubo, K and Ito, H},
title = {Telomere attrition in beta and alpha cells with age.},
journal = {Age (Dordrecht, Netherlands)},
volume = {38},
number = {3},
pages = {61},
pmid = {27216158},
issn = {1574-4647},
mesh = {Adult ; Aged ; Aging/*genetics ; Diabetes Mellitus, Type 2/*genetics/metabolism/pathology ; Female ; Follow-Up Studies ; Glucagon-Secreting Cells/*metabolism/pathology ; Humans ; In Situ Hybridization, Fluorescence ; Insulin-Secreting Cells/*metabolism/pathology ; Male ; Middle Aged ; Retrospective Studies ; Telomere/*genetics ; },
abstract = {We have reported telomere attrition in β and α cells of the pancreas in elderly patients with type 2 diabetes, but it has not been explored how the telomere lengths of these islet cells change according to age in normal subjects. To examine the telomere lengths of β and α cells in individuals without diabetes across a wide range of ages, we conducted measurement of the telomere lengths of human pancreatic β and α cells obtained from 104 autopsied subjects without diabetes ranging in age from 0 to 100 years. As an index of telomere lengths, the normalized telomere-centromere ratio (NTCR) was determined for β (NTCRβ) and α (NTCRα) cells by quantitative fluorescence in situ hybridization (Q-FISH). We found NTCRβ and NTCRα showed almost the same levels and both decreased according to age (p < 0.001 for both). NTCRs decreased more rapidly with age and were more widely distributed (p = 0.036 for NTCRβ, p < 0.001 for NTCRα) in subjects under 18 years of age than in subjects over 18 years. There was a positive correlation between NTCRβ and NTCRα only among adult subjects (p < 0.001). In conclusion, the telomeres of β and α cells become shortened with normal aging process.},
}
@article {pmid27215853,
year = {2017},
author = {Opresko, PL and Shay, JW},
title = {Telomere-associated aging disorders.},
journal = {Ageing research reviews},
volume = {33},
number = {},
pages = {52-66},
pmid = {27215853},
issn = {1872-9649},
support = {R21 ES025606/ES/NIEHS NIH HHS/United States ; R43 GM108187/GM/NIGMS NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; R01 ES022944/ES/NIEHS NIH HHS/United States ; R33 ES025606/ES/NIEHS NIH HHS/United States ; R21 AG045545/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*physiology ; *Aging, Premature/genetics/physiopathology ; Animals ; DNA Repair/genetics ; *Genetic Diseases, Inborn/diagnosis/genetics/physiopathology ; Humans ; Mutation ; Symptom Assessment ; Telomerase/*genetics ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; Telomere Shortening ; },
abstract = {Telomeres are dynamic nucleoprotein-DNA structures that cap and protect linear chromosome ends. Several monogenic inherited diseases that display features of human premature aging correlate with shortened telomeres, and are referred to collectively as telomeropathies. These disorders have overlapping symptoms and a common underlying mechanism of telomere dysfunction, but also exhibit variable symptoms and age of onset, suggesting they fall along a spectrum of disorders. Primary telomeropathies are caused by defects in the telomere maintenance machinery, whereas secondary telomeropathies have some overlapping symptoms with primary telomeropathies, but are generally caused by mutations in DNA repair proteins that contribute to telomere preservation. Here we review both the primary and secondary telomeropathies, discuss potential mechanisms for tissue specificity and age of onset, and highlight outstanding questions in the field and future directions toward elucidating disease etiology and developing therapeutic strategies.},
}
@article {pmid27214791,
year = {2016},
author = {Jeong, YY and Her, J and Chung, IK},
title = {NEDD8 ultimate buster-1 regulates the abundance of TRF1 at telomeres by promoting its proteasomal degradation.},
journal = {FEBS letters},
volume = {590},
number = {12},
pages = {1776-1790},
doi = {10.1002/1873-3468.12221},
pmid = {27214791},
issn = {1873-3468},
mesh = {Adaptor Proteins, Signal Transducing ; HEK293 Cells ; HeLa Cells ; Humans ; NEDD8 Protein ; Proteasome Endopeptidase Complex/genetics/*metabolism ; Protein Processing, Post-Translational/physiology ; *Proteolysis ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/*metabolism ; Transcription Factors/genetics/*metabolism ; Ubiquitins/genetics/metabolism ; },
abstract = {The human telomeric protein TRF1 negatively regulates telomere length by inhibiting the access of telomerase to telomeres. Here, we describe a novel function of NEDD8 ultimate buster-1 (NUB1) for regulating the levels of TRF1 at telomeres. NUB1 is a NEDD8-interacting protein, which down-regulates the NEDD8 conjugation system. We showed that NUB1 physically interacts with TRF1 and promotes its degradation by the proteasome in the absence of NEDD8 conjugation. We also demonstrated that TRF1 is conjugated to NEDD8, and that neddylated TRF1 is targeted to the proteasome for degradation in a NUB1-dependent manner. These data suggest that NUB1 participates in telomere maintenance by regulating the levels of TRF1 at telomeres through both NEDD8-dependent and NEDD8-independent pathways.},
}
@article {pmid27211552,
year = {2016},
author = {Scinicariello, F and Feroe, AG and Attanasio, R},
title = {Urinary Phthalates and Leukocyte Telomere Length: An Analysis of NHANES 1999-2002.},
journal = {EBioMedicine},
volume = {6},
number = {},
pages = {96-102},
pmid = {27211552},
issn = {2352-3964},
mesh = {Adult ; Cross-Sectional Studies ; Dose-Response Relationship, Drug ; Environmental Exposure/adverse effects ; Female ; Humans ; Male ; Middle Aged ; Neoplasms/chemically induced/*genetics/urine ; Phthalic Acids/adverse effects/*urine ; Surveys and Questionnaires ; Telomere Homeostasis/*drug effects ; Young Adult ; },
abstract = {The International Agency for Research on Cancer classified the di-2-ethylhexyl phthalate (DEHP) as "possibly carcinogenic to humans". In vitro studies reported that phthalate exposure resulted in induction of several nuclear transcription factors that are activators of telomerase reverse transcriptase (TERT) and telomerase activity of the human telomerase complex. The objective of this study was to determine whether there is an association between urinary phthalate metabolites [mono-ethyl phthalate (MEP), mono-butyl phthalate (MBP), mono-(2-ethyl)-hexyl phthalate (MEHP), and mono-benzyl phthalate (MBzP) and leukocyte telomere length (LTL) in the adult population of the National Health and Nutrition Examination Survey (NHANES) 1999-2002 (n=2472). After adjustment for potential confounders, participants in the 3rd and 4th quartiles of urinary MEHP had statistically significantly longer LTL (5.34%, 95% CI: 1.31, 9.53; and 7.14%, 95% CI: 2.94, 11.63; respectively) compared to the lowest quartile, with evidence of a dose-response relationship (p-trend=0.01). The association remained when the analyses were stratified by age groups (20-39years, 40-59years, and 60years and older), and sex. Furthermore, MBP and MBzP were associated with higher LTL in older participants. The age independent association between longer LTL and MEHP (a metabolite of DEHP) might suggest a possible role of MEHP as tumor promoter.},
}
@article {pmid27211533,
year = {2016},
author = {Cai, Q},
title = {Telomere length: A possible link between phthalate exposure and cancer development?.},
journal = {EBioMedicine},
volume = {6},
number = {},
pages = {6-7},
pmid = {27211533},
issn = {2352-3964},
mesh = {Humans ; *Neoplasms ; *Telomere ; Telomere Shortening ; },
}
@article {pmid27208844,
year = {2016},
author = {Benhamou, Y and Picco, V and Pagès, G},
title = {The telomere proteins in tumorigenesis and clinical outcomes of oral squamous cell carcinoma.},
journal = {Oral oncology},
volume = {57},
number = {},
pages = {46-53},
doi = {10.1016/j.oraloncology.2016.04.006},
pmid = {27208844},
issn = {1879-0593},
mesh = {Animals ; *Carcinogenesis ; Carcinoma, Squamous Cell/*pathology ; Humans ; Mouth Neoplasms/*pathology ; Shelterin Complex ; Telomerase/*metabolism ; Telomere ; Telomere-Binding Proteins/*metabolism ; },
abstract = {The "Hallmarks of Cancer" describe the ways by which cancer cells bypass homeostasis. Escape from replicative senescence is one of the earliest features of cancer cells. Maintenance of the telomeres through reactivation of telomerase was initially associated with replicative immortality in various cancers. The shelterin complex, a telomeric hexaprotein association, plays a key role in telomere maintenance and in the hallmarks of cancer. Some shelterin proteins are overexpressed in diverse cancers and can promote tumorigenesis in animal models. Shelterin can also have an impact on tumor size, tumor growth and resistance to treatment. Studies into the expression level of shelterin in oral squamous cell carcinoma (OSCC) report contradictory results. Moreover, the exact role of these proteins in OSCC tumorigenesis remains uncertain. In this review, we examined the data linking telomeres and hallmarks of OSCC. Furthermore, we examined the literature concerning telomeres and the clinical outcome of OSCC. Finally, we propose a model encompassing the role of shelterin proteins in oral tumorigenesis and treatment outcome.},
}
@article {pmid27207662,
year = {2016},
author = {Walsh, KM and Whitehead, TP and de Smith, AJ and Smirnov, IV and Park, M and Endicott, AA and Francis, SS and Codd, V and , and Samani, NJ and Metayer, C and Wiemels, JL},
title = {Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers.},
journal = {Carcinogenesis},
volume = {37},
number = {6},
pages = {576-582},
pmid = {27207662},
issn = {1460-2180},
support = {R21 CA158568/CA/NCI NIH HHS/United States ; T32 CA151022/CA/NCI NIH HHS/United States ; R01 CA124709/CA/NCI NIH HHS/United States ; R37 CA036401/CA/NCI NIH HHS/United States ; U24 CA114766/CA/NCI NIH HHS/United States ; RC4 CA156449/CA/NCI NIH HHS/United States ; R01 CA140729/CA/NCI NIH HHS/United States ; P01 ES018172/ES/NIEHS NIH HHS/United States ; MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; U01 GM092666/GM/NIGMS NIH HHS/United States ; R01 CA142665/CA/NCI NIH HHS/United States ; R01 CA155461/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; P50 ES018172/ES/NIEHS NIH HHS/United States ; R01 CA194189/CA/NCI NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; R01 CA036401/CA/NCI NIH HHS/United States ; //Wellcome Trust/United Kingdom ; },
mesh = {Adolescent ; Bone Neoplasms/genetics ; Case-Control Studies ; Child ; *Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Leukocytes/physiology ; Neuroblastoma/*genetics ; Osteosarcoma/genetics ; *Polymorphism, Single Nucleotide ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Proteins/*genetics ; *Telomere Homeostasis ; Young Adult ; },
abstract = {Aberrant telomere lengthening is an important feature of cancer cells in adults and children. In addition to somatic mutations, germline polymorphisms in telomere maintenance genes impact telomere length. Whether these telomere-associated polymorphisms affect risk of childhood malignancies remains largely unexplored. We collected genome-wide data from three groups with pediatric malignancies [neuroblastoma (N = 1516), acute lymphoblastic leukemia (ALL) (N = 958) and osteosarcoma (N = 660)] and three control populations (N = 6892). Using case-control comparisons, we analyzed eight single nucleotide polymorphisms (SNPs) in genes definitively associated with interindividual variation in leukocyte telomere length (LTL) in prior genome-wide association studies: ACYP2, TERC, NAF1, TERT, OBFC1, CTC1, ZNF208 and RTEL1 Six of these SNPs were associated (P < 0.05) with neuroblastoma risk, one with leukemia risk and one with osteosarcoma risk. The allele associated with longer LTL increased cancer risk for all these significantly associated SNPs. Using a weighted linear combination of the eight LTL-associated SNPs, we observed that neuroblastoma patients were predisposed to longer LTL than controls, with each standard deviation increase in genotypically estimated LTL associated with a 1.15-fold increased odds of neuroblastoma (95%CI = 1.09-1.22; P = 7.9×10(-7)). This effect was more pronounced in adolescent-onset neuroblastoma patients (OR = 1.46; 95%CI = 1.03-2.08). A one standard deviation increase in genotypically estimated LTL was more weakly associated with osteosarcoma risk (OR = 1.10; 95%CI = 1.01-1.19; P = 0.017) and leukemia risk (OR = 1.07; 95%CI = 1.00-1.14; P = 0.044), specifically for leukemia patients who relapsed (OR = 1.19; 95%CI = 1.01-1.40; P = 0.043). These results indicate that genetic predisposition to longer LTL is a newly identified risk factor for neuroblastoma and potentially for other cancers of childhood.},
}
@article {pmid27203556,
year = {2016},
author = {Santos-Serejo, JA and Aguiar-Perecin, ML},
title = {Breakage-fusion-bridge cycles and de novo telomere formation on broken chromosomes in maize callus cultures.},
journal = {Genome},
volume = {59},
number = {6},
pages = {367-378},
doi = {10.1139/gen-2015-0211},
pmid = {27203556},
issn = {1480-3321},
mesh = {Cell Cycle/genetics ; Cells, Cultured ; Chromosomal Instability ; Chromosome Banding ; *Chromosome Breakage ; Chromosomes/*genetics/physiology ; Heterochromatin/genetics ; In Situ Hybridization, Fluorescence ; Meiosis/genetics ; Mitosis/genetics ; Telomere/*genetics ; Zea mays/*genetics ; },
abstract = {Breakpoints involved in chromosome alterations associated with heterochromatin have been detected in maize plants regenerated from callus culture. A cytogenetic analysis of plants regenerated from a maize callus was performed aiming to analyze the stability of a chromosome 7 bearing a deficiency-duplication (Df-Dp), which was interpreted as derived from a chromatid type breakage-fusion-bridge (BFB) cycle. The Df-Dp chromosome 7 was stable in mitotic and meiotic cells of the regenerated plants. Fluorescence in situ hybridization showed signals of telomeric sequences on the broken chromosome arm and provided evidence of de novo telomere formation. The stability of two types of altered chromosome 7 was investigated in C-banded metaphases from samples of the original callus that were collected during a period of 30-42 months after culture initiation. New alterations involving heterochromatic knobs of chromosomes 7 and 9 were observed. The aberrant chromosomes were stable in the subcultures, thus providing evidence of broken chromosome healing. The examination of anaphases showed the presence of bridges, which was consistent with the occurrence of BFB cycles. De novo telomere formation occurred in euchromatic and heterochromatic chromosome termini. The results point to events of chromosomal evolution that might occur in plants.},
}
@article {pmid27197291,
year = {2016},
author = {Ojha, J and Codd, V and Nelson, CP and Samani, NJ and Smirnov, IV and Madsen, NR and Hansen, HM and de Smith, AJ and Bracci, PM and Wiencke, JK and Wrensch, MR and Wiemels, JL and Walsh, KM and , },
title = {Genetic Variation Associated with Longer Telomere Length Increases Risk of Chronic Lymphocytic Leukemia.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {25},
number = {7},
pages = {1043-1049},
pmid = {27197291},
issn = {1538-7755},
support = {R01 CA139020/CA/NCI NIH HHS/United States ; /BHF_/British Heart Foundation/United Kingdom ; U54 HG003067/HG/NHGRI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; R01 CA126831/CA/NCI NIH HHS/United States ; 085475/WT_/Wellcome Trust/United Kingdom ; P50 CA097257/CA/NCI NIH HHS/United States ; R21 CA115043/CA/NCI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; R01 CA052689/CA/NCI NIH HHS/United States ; 076113/WT_/Wellcome Trust/United Kingdom ; R01 CA132780/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Biomarkers, Tumor/*genetics ; Case-Control Studies ; Female ; *Genetic Predisposition to Disease ; *Genetic Variation ; Genome-Wide Association Study ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics ; Leukocytes/metabolism ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Risk Factors ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Shorter mean telomere length in leukemic cells has been associated with more aggressive disease. Germline polymorphisms in telomere maintenance genes affect telomere length and may contribute to CLL susceptibility.<br><br>METHODS: We collected genome-wide data from two groups of patients with CLL (N = 273) and two control populations (N = 5,725). In ancestry-adjusted case-control comparisons, we analyzed eight SNPs in genes definitively associated with inter-individual variation in leukocyte telomere length (LTL) in prior genome-wide association studies: ACYP2, TERC, NAF1, TERT, OBFC1, CTC1, ZNF208, and RTEL1 RESULTS: Three of the eight LTL-associated SNPs were associated with CLL risk at P < 0.05, including those near: TERC [OR, 1.46; 95% confidence interval (CI), 1.15-1.86; P = 1.8 &#xd7; 10(-3)], TERT (OR = 1.23; 95% CI, 1.02-1.48; P = 0.030), and OBFC1 (OR, 1.36; 95% CI, 1.08-1.71; P = 9.6 &#xd7; 10(-3)). Using a weighted linear combination of the eight LTL-associated SNPs, we observed that CLL patients were predisposed to longer LTL than controls in both case-control sets (P = 9.4 &#xd7; 10(-4) and 0.032, respectively). CLL risk increased monotonically with increasing quintiles of the weighted linear combination.<br><br>CONCLUSIONS: Genetic variants in TERC, TERT, and OBFC1 are associated with both longer LTL and increased CLL risk. Because the human CST complex competes with shelterin for telomeric DNA, future work should explore the role of OBFC1 and other CST complex genes in leukemogenesis.<br><br>IMPACT: A genetic predisposition to longer telomere length is associated with an increased risk of CLL, suggesting that the role of telomere length in CLL etiology may be distinct from its role in disease progression. Cancer Epidemiol Biomarkers Prev; 25(7); 1043-9. &#xa9;2016 AACR.},
}
@article {pmid27194546,
year = {2017},
author = {Ip, P and Chung, BH and Ho, FK and Chan, GC and Deng, W and Wong, WH and Lee, SL and Chan, PY and Ying, D and Wong, WL and Tung, KT and Lau, YL},
title = {Prenatal Tobacco Exposure Shortens Telomere Length in Children.},
journal = {Nicotine &amp; tobacco research : official journal of the Society for Research on Nicotine and Tobacco},
volume = {19},
number = {1},
pages = {111-118},
doi = {10.1093/ntr/ntw139},
pmid = {27194546},
issn = {1469-994X},
mesh = {Adult ; Case-Control Studies ; Child ; Female ; Hong Kong/epidemiology ; Humans ; Male ; Pregnancy ; Prenatal Exposure Delayed Effects/*genetics ; Smoking/epidemiology ; Social Class ; Telomere ; *Telomere Homeostasis ; *Tobacco Smoke Pollution/analysis ; Young Adult ; },
abstract = {INTRODUCTION: Preliminary evidence suggests a possible association between prenatal tobacco exposure and telomere length in children. This study was conducted to investigate whether maternal smoking during pregnancy was associated with telomere shortening in their children and whether prenatal and childhood exposure to environmental tobacco had any impact on this association.<br><br>METHODS: This is a population-representative study on the association between prenatal tobacco exposure and telomere length in children. Ninety-eight Hong Kong Chinese children aged under 15 years with prenatal tobacco exposure and 98 age- and gender-matched controls were recruited from a population health study with stratified random sampling.<br><br>RESULTS: Telomere length in children with prenatal tobacco exposure was significantly shorter than in those with no exposure (mean T/S ratio = 24.9 [SD = 8.58] in exposed vs. 28.97 [14.15] in control groups; P = 0.02). A negative dose-response relationship was observed between the T/S ratio and tobacco exposure duration: the longer the duration of maternal smoking in pregnancy, the shorter the child's telomere length. The association between the child's telomere length and prenatal tobacco exposure remained significant after considering the influence of family socioeconomic status and exposure to environmental tobacco smoke during pregnancy and childhood.<br><br>CONCLUSIONS: Prenatal tobacco exposure was associated with telomere shortening in children. As this may impose significant health impacts through fetal genetic programming, more efforts should be made to reduce fetal tobacco exposure by educating pregnant women to not smoke and motivating smokers to quit in early pregnancy.<br><br>IMPLICATIONS: As reflected by telomere shortening, prenatal tobacco exposure in children can cause premature aging and increased health risks, which we suggest is entirely preventable. Not smoking during pregnancy or quitting smoking is critical to improving the health outcome of our future generations as prenatal tobacco exposure may affect children's biological programming.},
}
@article {pmid27192677,
year = {2016},
author = {Lansdorp, PM},
title = {Telomeres on Steroids--Turning Back the Mitotic Clock?.},
journal = {The New England journal of medicine},
volume = {374},
number = {20},
pages = {1978-1980},
doi = {10.1056/NEJMe1602822},
pmid = {27192677},
issn = {1533-4406},
mesh = {Bone Marrow Diseases/*drug therapy ; Danazol/*therapeutic use ; Estrogen Antagonists/*therapeutic use ; Female ; Humans ; Liver Cirrhosis/*drug therapy ; Male ; Pulmonary Fibrosis/*drug therapy ; Telomere/*drug effects ; },
}
@article {pmid27192671,
year = {2016},
author = {Townsley, DM and Dumitriu, B and Liu, D and Biancotto, A and Weinstein, B and Chen, C and Hardy, N and Mihalek, AD and Lingala, S and Kim, YJ and Yao, J and Jones, E and Gochuico, BR and Heller, T and Wu, CO and Calado, RT and Scheinberg, P and Young, NS},
title = {Danazol Treatment for Telomere Diseases.},
journal = {The New England journal of medicine},
volume = {374},
number = {20},
pages = {1922-1931},
pmid = {27192671},
issn = {1533-4406},
support = {Z99 HL999999//Intramural NIH HHS/United States ; },
mesh = {Administration, Oral ; Adolescent ; Adult ; Aged ; Bone Marrow Diseases/*drug therapy ; Danazol/*therapeutic use ; Estrogen Antagonists/*therapeutic use ; Female ; Hair Color/genetics ; Humans ; Liver Cirrhosis/*drug therapy ; Male ; Middle Aged ; Mutation ; Prospective Studies ; Pulmonary Fibrosis/*drug therapy ; Telomerase/genetics/metabolism ; Telomere/*drug effects/ultrastructure ; Up-Regulation ; Young Adult ; },
abstract = {BACKGROUND: Genetic defects in telomere maintenance and repair cause bone marrow failure, liver cirrhosis, and pulmonary fibrosis, and they increase susceptibility to cancer. Historically, androgens have been useful as treatment for marrow failure syndromes. In tissue culture and animal models, sex hormones regulate expression of the telomerase gene.<br><br>METHODS: In a phase 1-2 prospective study involving patients with telomere diseases, we administered the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months. The goal of treatment was the attenuation of accelerated telomere attrition, and the primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months. The occurrence of toxic effects of treatment was the primary safety end point. Hematologic response to treatment at various time points was the secondary efficacy end point.<br><br>RESULTS: After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval [CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months. Known adverse effects of danazol--elevated liver-enzyme levels and muscle cramps--of grade 2 or less occurred in 41% and 33% of the patients, respectively.<br><br>CONCLUSIONS: In our study, treatment with danazol led to telomere elongation in patients with telomere diseases. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01441037.).},
}
@article {pmid27192120,
year = {2016},
author = {Frink, RE and Peyton, M and Schiller, JH and Gazdar, AF and Shay, JW and Minna, JD},
title = {Telomerase inhibitor imetelstat has preclinical activity across the spectrum of non-small cell lung cancer oncogenotypes in a telomere length dependent manner.},
journal = {Oncotarget},
volume = {7},
number = {22},
pages = {31639-31651},
pmid = {27192120},
issn = {1949-2553},
support = {P30 CA142543/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; },
mesh = {A549 Cells ; Animals ; Antineoplastic Agents/*pharmacology ; Carcinoma, Non-Small-Cell Lung/*drug therapy/enzymology/genetics/pathology ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/*pharmacology ; Female ; Genotype ; Humans ; Indoles/*pharmacology ; Lung Neoplasms/*drug therapy/enzymology/genetics/pathology ; Mice, Inbred NOD ; Mice, SCID ; Niacinamide/*analogs &amp; derivatives/pharmacology ; Oligonucleotides ; Phenotype ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/*drug effects/metabolism ; Telomere Homeostasis/*drug effects ; Telomere Shortening/*drug effects ; Time Factors ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays ; },
abstract = {Telomerase was evaluated as a therapeutic oncotarget by studying the efficacy of the telomerase inhibitor imetelstat in non-small cell lung cancer (NSCLC) cell lines to determine the range of response phenotypes and identify potential biomarkers of response. A panel of 63 NSCLC cell lines was studied for telomere length and imetelstat efficacy in inhibiting colony formation and no correlation was found with patient characteristics, tumor histology, and oncogenotypes. While there was no overall correlation between imetelstat efficacy with initial telomere length (ranging from 1.5 to 20 kb), the quartile of NSCLC lines with the shortest telomeres was more sensitive than the quartile with the longest telomeres. Continuous long-term treatment with imetelstat resulted in sustained telomerase inhibition, progressive telomere shortening and eventual growth inhibition in a telomere-length dependent manner. Cessation of imetelstat therapy before growth inhibition was followed by telomere regrowth. Likewise, in vivo imetelstat treatment caused tumor xenograft growth inhibition in a telomere-length dependent manner. We conclude from these preclinical studies of telomerase as an oncotarget tested by imetelstat response that imetelstat has efficacy across the entire oncogenotype spectrum of NSCLC, continuous therapy is necessary to prevent telomere regrowth, and short telomeres appears to be the best treatment biomarker.},
}
@article {pmid27186324,
year = {2016},
author = {Pierce, BL and Jasmine, F and Roy, S and Zhang, C and Aviv, A and Hunt, SC and Ahsan, H and Kibriya, MG},
title = {Telomere length measurement by a novel Luminex-based assay: a blinded comparison to Southern blot.},
journal = {International journal of molecular epidemiology and genetics},
volume = {7},
number = {1},
pages = {18-23},
pmid = {27186324},
issn = {1948-1756},
support = {R01 ES020506/ES/NIEHS NIH HHS/United States ; T32 AG000243/AG/NIA NIH HHS/United States ; U01 HG007601/HG/NHGRI NIH HHS/United States ; },
abstract = {Telomere length (TL) is a potential biomarker of aging and age-related disease risk. We recently published a novel Luminex-based method for high-throughput, low-cost TL measurement. Here we describe a blinded comparison of the Luminex method to Southern blot, the most precise TL measurement method. Luminex and Southern blot measurements for the same 50 DNA samples were taken in two independent laboratories; each sample was measured twice, several months apart. The inter-assay CV for Luminex ranged from 5.5 to 9.1 (depending on CV estimation method), and Southern blot CV from 1.0 to 1.7. Both measures were inversely associated with age. The correlation between the repeated measurements was 0.66 for Luminex and 0.97 for Southern blot. The correlation between Southern blot and Luminex was 0.65 in round 1 and 0.75 in round 2, and the relationship showed no evidence of non-linearity. Our results demonstrate that the Luminex assay is a valid and reproducible method for high-throughput TL measurement. The Luminex assay involves no DNA amplification, which may make Luminex an attractive alternative to PCR-based TL measurement.},
}
@article {pmid27185042,
year = {2016},
author = {Xu, X and Qu, K and Pang, Q and Wang, Z and Zhou, Y and Liu, C},
title = {Association between telomere length and survival in cancer patients: a meta-analysis and review of literature.},
journal = {Frontiers of medicine},
volume = {10},
number = {2},
pages = {191-203},
pmid = {27185042},
issn = {2095-0225},
mesh = {*Disease Progression ; Humans ; Neoplasms/*genetics/*mortality ; Proportional Hazards Models ; Survival Rate ; *Telomere Shortening ; },
abstract = {The relationship between telomere length and cancer survival has been widely studied. To gain a deeper insight, we reviewed the published studies. A total of 29 studies evaluated telomere length in the peripheral blood; 22 studies evaluated telomere length in the tumor tissue. First, in the peripheral blood studies, for solid tumor patients with shortened telomere length, the combined hazard ratios (HRs) for mortality and tumor progression were 1.21 (95%CI, 1.10-1.32) and 1.71 (95%CI, 1.37-2.13), respectively. Meanwhile, in hematology malignancy, the combined HRs for mortality and tumor progression were 2.83 (95%CI, 2.14-3.74) and 2.65 (95%CI, 2.18-3.22), respectively. Second, in the studies that use tumor tissue, for patients with shortened telomeres, the combined HRs for mortality and tumor progression were 1.26 (95%CI, 0.95-1.66) and 1.65 (95%CI, 1.26-2.15), respectively. In the studies that calculate the telomere length ratios of tumor tissue to adjacent normal mucosa, for patients with lower telomere length ratios, the combined HRs were 0.66 (95%CI, 0.53-0.83) and 0.74 (95%CI, 0.41-1.32) for mortality and tumor progression, respectively. In conclusion, shortened telomere in peripheral blood and tumor tissue might indicate poor survival for cancer patients. However, by calculating the telomere length ratios of tumor tissue to adjacent normal mucosa, the lower ratio might indicate better survival.},
}
@article {pmid27184841,
year = {2016},
author = {Yang, J and Guo, R and Wang, H and Ye, X and Zhou, Z and Dan, J and Wang, H and Gong, P and Deng, W and Yin, Y and Mao, S and Wang, L and Ding, J and Li, J and Keefe, DL and Dawlaty, MM and Wang, J and Xu, G and Liu, L},
title = {Tet Enzymes Regulate Telomere Maintenance and Chromosomal Stability of Mouse ESCs.},
journal = {Cell reports},
volume = {15},
number = {8},
pages = {1809-1821},
doi = {10.1016/j.celrep.2016.04.058},
pmid = {27184841},
issn = {2211-1247},
mesh = {Animals ; Chromosomal Instability/*genetics ; Chromosomes, Mammalian/genetics ; DNA (Cytosine-5-)-Methyltransferases/metabolism ; DNA Methylation/genetics ; DNA-Binding Proteins/*metabolism ; Gene Deletion ; Mice ; Mice, Knockout ; Mouse Embryonic Stem Cells/*metabolism ; Recombination, Genetic/genetics ; Telomere/*metabolism ; Telomere Shortening ; DNA Methyltransferase 3B ; },
abstract = {Ten-eleven translocation (Tet) family proteins convert 5-methylcytosine to 5-hydroxymethylcytosine. We show that mouse embryonic stem cells (ESCs) depleted of Tet1 and/or Tet2 by RNAi exhibit short telomeres and chromosomal instability, concomitant with reduced telomere recombination. Tet1 and Tet2 double-knockout ESCs also display short telomeres but to a lesser extent. Notably, Tet1/2/3 triple-knockout ESCs show heterogeneous telomere lengths and increased frequency of telomere loss and chromosomal fusion. Mechanistically, Tets depletion or deficiency increases Dnmt3b and decreases 5hmC levels, resulting in elevated methylation levels at sub-telomeres. Consistently, knockdown of Dnmt3b or addition of 2i (MAPK and GSK3β inhibitors), which also inhibits Dnmt3b, reduces telomere shortening, partially rescuing Tet1/2 deficiency. Interestingly, Tet1/2 double or Tet1/2/3 triple knockout in ESCs consistently upregulates Zscan4, which may counteract telomere shortening. Together, Tet enzymes play important roles in telomere maintenance and chromosomal stability of ESCs by modulating sub-telomeric methylation levels.},
}
@article {pmid27184206,
year = {2016},
author = {Bebbington, K and Spurgin, LG and Fairfield, EA and Dugdale, HL and Komdeur, J and Burke, T and Richardson, DS},
title = {Telomere length reveals cumulative individual and transgenerational inbreeding effects in a passerine bird.},
journal = {Molecular ecology},
volume = {25},
number = {12},
pages = {2949-2960},
pmid = {27184206},
issn = {1365-294X},
mesh = {Animals ; Female ; Genetic Fitness ; *Genetics, Population ; Homozygote ; *Inbreeding ; Male ; Models, Genetic ; Seychelles ; Songbirds/*genetics ; Telomere/*ultrastructure ; },
abstract = {Inbreeding results in more homozygous offspring that should suffer reduced fitness, but it can be difficult to quantify these costs for several reasons. First, inbreeding depression may vary with ecological or physiological stress and only be detectable over long time periods. Second, parental homozygosity may indirectly affect offspring fitness, thus confounding analyses that consider offspring homozygosity alone. Finally, measurement of inbreeding coefficients, survival and reproductive success may often be too crude to detect inbreeding costs in wild populations. Telomere length provides a more precise measure of somatic costs, predicts survival in many species and should reflect differences in somatic condition that result from varying ability to cope with environmental stressors. We studied relative telomere length in a wild population of Seychelles warblers (Acrocephalus sechellensis) to assess the lifelong relationship between individual homozygosity, which reflects genome-wide inbreeding in this species, and telomere length. In juveniles, individual homozygosity was negatively associated with telomere length in poor seasons. In adults, individual homozygosity was consistently negatively related to telomere length, suggesting the accumulation of inbreeding depression during life. Maternal homozygosity also negatively predicted offspring telomere length. Our results show that somatic inbreeding costs are environmentally dependent at certain life stages but may accumulate throughout life.},
}
@article {pmid27183912,
year = {2016},
author = {Gomez-Escobar, N and Almobadel, N and Alzahrani, O and Feichtinger, J and Planells-Palop, V and Alshehri, Z and Thallinger, GG and Wakeman, JA and McFarlane, RJ},
title = {Translin and Trax differentially regulate telomere-associated transcript homeostasis.},
journal = {Oncotarget},
volume = {7},
number = {23},
pages = {33809-33820},
pmid = {27183912},
issn = {1949-2553},
mesh = {Argonaute Proteins/genetics/metabolism ; Carrier Proteins/genetics/*metabolism ; Cell Line, Tumor ; DNA-Binding Proteins/genetics/*metabolism ; Gene Expression Regulation, Fungal ; Humans ; Mutation ; Neoplasms/genetics/*metabolism ; RNA Interference ; RNA, Fungal/genetics/*metabolism ; RNA, Long Noncoding/genetics/*metabolism ; RNA, Messenger/genetics/*metabolism ; RNA-Binding Proteins/genetics/*metabolism ; Schizosaccharomyces/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; Transcriptome ; Transfection ; },
abstract = {Translin and Trax proteins are highly conserved nucleic acid binding proteins that have been implicated in RNA regulation in a range of biological processes including tRNA processing, RNA interference, microRNA degradation during oncogenesis, spermatogenesis and neuronal regulation. Here, we explore the function of this paralogue pair of proteins in the fission yeast. Using transcript analysis we demonstrate a reciprocal mechanism for control of telomere-associated transcripts. Mutation of tfx1+ (Trax) elevates transcript levels from silenced sub-telomeric regions of the genome, but not other silenced regions, such as the peri-centromeric heterochromatin. In the case of some sub-telomeric transcripts, but not all, this elevation is dependent on the Trax paralogue, Tsn1 (Translin). In a reciprocal fashion, Tsn1 (Translin) serves to repress levels of transcripts (TERRAs) from the telomeric repeats, whereas Tfx1 serves to maintain these elevated levels. This reveals a novel mechanism for the regulation of telomeric transcripts. We extend this to demonstrate that human Translin and Trax also control telomere-associated transcript levels in human cells in a telomere-specific fashion.},
}
@article {pmid27183789,
year = {2016},
author = {Zhdanova, NS and Rubtsov, NB},
title = {[Telomere Recombination in Normal Mammalian Cells].},
journal = {Genetika},
volume = {52},
number = {1},
pages = {14-23},
pmid = {27183789},
issn = {0016-6758},
mesh = {Animals ; DNA/*genetics ; DNA Replication/genetics ; Homologous Recombination/genetics ; Humans ; Neoplasms/*genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Two mechanisms of telomere length maintenance are known to date. The first includes the use of a special enzymatic telomerase complex to solve the problems that arise during the replication of linear DNA in a normal diploid and part of tumor cells. Alternative lengthening of telomeres (ALT), which is based on the homologous recombination of telomere DNA, represents the second mechanism. Until recently, ALT was assumed to be expressed only in 15-20% of tumors lacking active telomerase and, together with telomerase reactivation represented one of two possibilities to overcome the replicative senescence observed in somatic mammalian cells due to aging or during cell culturing in vitro. Previously described sporadic cases of combinations of the two mechanisms of telomere length maintenance in several cell lines in vitro were attributed to the experimental design rather than to a real biological phenomenon, since active cellular division without active telomerase was considered to be the "gold standard" of ALT. The present review describes the morphological and functional reorganizations of mammalian telomeres observed with ALT activation, as well as recently observed,and well-documented cases of combinations between ALT-like and telomerase-dependent mechanisms in mammalian cells. The possible role of telomere recombination in telomerase-dependent cells is discussed.},
}
@article {pmid27182778,
year = {2016},
author = {Kibriya, MG and Jasmine, F and Roy, S and Ahsan, H and Pierce, BL},
title = {Novel Luminex Assay for Telomere Repeat Mass Does Not Show Well Position Effects Like qPCR.},
journal = {PloS one},
volume = {11},
number = {5},
pages = {e0155548},
pmid = {27182778},
issn = {1932-6203},
support = {R01 CA107431/CA/NCI NIH HHS/United States ; R01 ES020506/ES/NIEHS NIH HHS/United States ; U01 HG007601/HG/NHGRI NIH HHS/United States ; },
mesh = {Humans ; Real-Time Polymerase Chain Reaction/methods/standards ; *Repetitive Sequences, Nucleic Acid ; Reproducibility of Results ; Telomere/*genetics ; },
abstract = {Telomere length is a potential biomarker of aging and risk for age-related diseases. For measurement of relative telomere repeat mass (TRM), qPCR is typically used primarily due to its low cost and low DNA input. But the position of the sample on a plate often impacts the qPCR-based TRM measurement. Recently we developed a novel, probe-based Luminex assay for TRM that requires ~50ng DNA and involves no DNA amplification. Here we report, for the first time, a comparison among TRM measurements obtained from (a) two singleplex qPCR assays (using two different primer sets), (b) a multiplex qPCR assay, and (c) our novel Luminex assay. Our comparison is focused on characterizing the effects of sample positioning on TRM measurement. For qPCR, DNA samples from two individuals (K and F) were placed in 48 wells of a 96-well plate. For each singleplex qPCR assay, we used two plates (one for Telomere and one for Reference gene). For the multiplex qPCR and the Luminex assay, the telomere and the reference genes were assayed from the same well. The coefficient of variation (CV) of the TRM for Luminex (7.2 to 8.4%) was consistently lower than singleplex qPCR (11.4 to 14.9%) and multiplex qPCR (19.7 to 24.3%). In all three qPCR assays the DNA samples in the left- and right-most columns showed significantly lower TRM than the samples towards the center, which was not the case for the Luminex assay (p = 0.83). For singleplex qPCR, 30.5% of the variation in TL was explained by column-to-column variation and 0.82 to 27.9% was explained by sample-to-sample variation. In contrast, only 5.8% of the variation in TRM for the Luminex assay was explained by column-to column variation and 50.4% was explained by sample-to-sample variation. Our novel Luminex assay for TRM had good precision and did not show the well position effects of the sample that were seen in all three of the qPCR assays that were tested.},
}
@article {pmid27179575,
year = {2016},
author = {Dlouha, D and Vymetalova, J and Malek, I and Hubacek, JA},
title = {Comparison of relative telomere length measured in aortic tissue and leukocytes in patients with end stage heart failure.},
journal = {Neuro endocrinology letters},
volume = {37},
number = {2},
pages = {124-128},
pmid = {27179575},
issn = {0172-780X},
mesh = {Biomarkers, Tumor/genetics ; DNA ; Female ; Heart Failure/*genetics ; Humans ; Leukocytes/*metabolism ; Male ; Real-Time Polymerase Chain Reaction ; Telomere/genetics/*pathology ; },
abstract = {OBJECTIVES: Telomeres are repetitive non-coding DNA sequences on the ends of eukaryotic chromosomes. Relative leukocyte telomere length (LrTL) is considered to reflect biological ageing and fitness. Therefore, we examined whether LrTL would reflect rTL in aortic tissue (ArTL) and whether it could be used as a marker of biological heart age.<br><br>DESIGN: We analysed telomere length in aortic and leukocyte samples from 73 heart recipients (63 males, 10 females; age 52.2&#xb1;11.7 years). Relative telomere length was measured using a quantitative PCR-based method.<br><br>RESULTS: Neither LrTL nor ArTL correlated significantly with the age of heart recipients. Mean ArTL was slightly shorter than LrTL (p=0.06) and there was a slight but significant inverse correlation between LrTL and ArTL (p=0.019).<br><br>CONCLUSIONS: The age of patients with end stage heart failure was not associated with leukocyte or aortic telomere length. An inverse correlation between LrTL and ArTL suggests that LrTL is unlikely to be an important predictor of biological ageing in these patients.},
}
@article {pmid27177656,
year = {2016},
author = {Maiti, SN},
title = {Measurement of Average Telomere Length in Ex Vivo Expanded Natural Killer Cells by Fluorescence In Situ Hybridization (FISH) and Flow Cytometry.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1441},
number = {},
pages = {57-63},
doi = {10.1007/978-1-4939-3684-7_5},
pmid = {27177656},
issn = {1940-6029},
mesh = {Cell Proliferation ; Cells, Cultured ; Flow Cytometry ; Humans ; In Situ Hybridization, Fluorescence ; K562 Cells ; Killer Cells, Natural/*cytology ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Natural killer (NK) cells are a subset of cytotoxic lymphocytes that play a critical role in innate immune surveillance against infections and tumors through cytokine secretion and target cell lysis. NK cells function without any need for prior antigen exposure. Thus, more recently NK cells are considered a promising source of lymphocytes for adoptive tumor therapy. However, because NK cells represent only a small lymphocyte fraction, expand poorly ex vivo, and have limited life spans, clinical scale generation of NK cells for tumor immunotherapy was a challenging issue. To overcome this challenge, numerous expansion platforms have been developed. However, ex vivo expansion of NK cells could lead to proliferation-induced senescence. Telomeres at the end of chromosomes play a crucial role in maintaining the integrity of the chromosome and are lost at each cell division in somatic cells and have emerged as important cellular elements in aging and cancer. Because telomere length is known to decrease in adult human NK cells and is associated with proliferation-induced senescence, it is important to determine the effect of NK cell expansion systems on telomere length. In this chapter, a detailed protocol is provided to analyze the telomere length of expanded NK cells using a commercially available Flow FISH kit.},
}
@article {pmid27174767,
year = {2016},
author = {Noguera, JC and Metcalfe, NB and Reichert, S and Monaghan, P},
title = {Embryonic and postnatal telomere length decrease with ovulation order within clutches.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {25915},
pmid = {27174767},
issn = {2045-2322},
support = {268926/ERC_/European Research Council/International ; },
mesh = {Animals ; Animals, Newborn ; Female ; Finches/embryology/metabolism/*physiology ; Male ; *Ovulation ; Telomere/*metabolism ; Telomere Shortening ; },
abstract = {Telomere length (TL) in early life has been found to be predictive of subsequent lifespan. Factors such as parental TL, parental age and environmental conditions during development have been shown to contribute to the observed variation in TL among individuals. One factor that has not hitherto been considered is ovulation order, although it is well established that the last hatched/born offspring in a brood or litter often show relatively poor subsequent performance. We examined the within- and across-clutch effect of ovulation order on TL in embryos of zebra finches experiencing the same controlled incubation conditions (N = 151), and tested whether any such ovulation order effects remained detectable in adults (N = 122). Irrespective of clutch and egg size, TL in early-stage embryos (72 h incubation) markedly decreased with within-clutch ovulation order; the difference in TL of first and last-laid embryos was equivalent to the average within-individual telomere loss over the entire period of nestling and juvenile life. This ovulation-order effect occurred only within but not across clutches, and was still evident in adults. Given that TL in early life predicts lifespan, our results suggest that parental effects on telomere length could contribute to the known poor performance of later-ovulated family members.},
}
@article {pmid27174400,
year = {2016},
author = {Rao, S and Kota, LN and Li, Z and Yao, Y and Tang, J and Mao, C and Jain, S and Xu, Y and Xu, Q},
title = {Accelerated leukocyte telomere erosion in schizophrenia: Evidence from the present study and a meta-analysis.},
journal = {Journal of psychiatric research},
volume = {79},
number = {},
pages = {50-56},
doi = {10.1016/j.jpsychires.2016.04.010},
pmid = {27174400},
issn = {1879-1379},
mesh = {Humans ; Leukocytes/*metabolism ; Schizophrenia/*genetics/*metabolism ; *Telomere Shortening ; },
abstract = {Human telomeres consist of tandem nucleotide repeats (TTAGGG) and associated proteins, and telomere length (TL) is reduced progressively with cell division over the lifespan. Telomere erosion might be accelerated or prevented to varying degrees when exposure to serious medical illnesses. In previous studies, an association between TL decrease and schizophrenia has been extensively reported; however, the results remain largely controversial. To further investigate TL in schizophrenia patients and reconcile this controversy, we first measured leucocyte TL (LTL) in our samples (52 paranoid schizophrenia, 89 non-paranoid patients and 120 controls), and then conducted a comprehensive meta-analysis of the existing results of LTL in patients of schizophrenia compared to healthy subjects. Totally, 11 studies encompassing 1243 patients of schizophrenia and 1274 controls were included in the final meta-analysis model. In our samples, significant reduction of LTL in paranoid schizophrenia was observed compared to controls (F = 50.88, P < 0.001); whereas there was no significant difference in LTL between non-paranoid schizophrenia and controls (F = 0.842, P = 0.360). For meta-analysis, random-effects model showed significant LTL decrease in patients of schizophrenia when compared to controls (Z = 2.07, P = 0.039, SMD = -0.48, 95% CI = -0.94 to -0.03). Moreover, a marginal decrease in LTL was observed in medicated patients (Z = 1.92, P = 0.055, SMD = -0.58, 95% CI = -1.18-0.01) and those patients with poor response to antipsychotics (Z = 1.76, P = 0.078, SMD = -0.60, 95% CI = -1.27-0.07). In conclusion, we observed significant reduction of LTL in individuals with schizophrenia compared with controls. However, all the studies included in the meta-analysis were cross-sectional, and better controlled long-term studies are needed to replicate this result.},
}
@article {pmid27174242,
year = {2016},
author = {Hill, TD and Ellison, CG and Burdette, AM and Taylor, J and Friedman, KL},
title = {Dimensions of religious involvement and leukocyte telomere length.},
journal = {Social science &amp; medicine (1982)},
volume = {163},
number = {},
pages = {168-175},
doi = {10.1016/j.socscimed.2016.04.032},
pmid = {27174242},
issn = {1873-5347},
support = {R01 AG034067/AG/NIA NIH HHS/United States ; },
mesh = {Adaptation, Psychological ; Adult ; Aged ; Aging ; Alcoholics/psychology ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/classification ; Male ; Middle Aged ; Regression Analysis ; *Religion ; Smokers/psychology ; Social Support ; Stress, Psychological/complications/epidemiology ; Telomere/*classification ; Tennessee ; },
abstract = {Although numerous studies suggest that religious involvement is associated with a wide range of favorable health outcomes, it is unclear whether this general pattern extends to cellular aging. In this paper, we tested whether leukocyte telomere length varies according to several dimensions of religious involvement. We used cross-sectional data from the Nashville Stress and Health Study (2011-2014), a large probability sample of 1252 black and white adults aged 22 to 69 living in Davidson County, TN, USA. Leukocyte telomere length was measured using the monochrome multiplex quantitative polymerase chain reaction method with albumin as the single-copy reference sequence. Dimensions of religious involvement included religiosity, religious support, and religious coping. Our multivariate analyses showed that religiosity (an index of religious attendance, prayer frequency, and religious identity) was positively associated with leukocyte telomere length, even with adjustments for religious support, religious coping, age, gender, race, education, employment status, income, financial strain, stressful life events, marital status, family support, friend support, depressive symptoms, smoking, heavy drinking, and allostatic load. Unlike religiosity, religious support and religious coping were unrelated to leukocyte telomere length across models. Depressive symptoms, smoking, heavy drinking, and allostatic load failed to explain any of the association between religiosity and telomere length. To our knowledge, this is the first population-based study to link religious involvement and cellular aging. Although our data suggest that adults who frequently attend religious services, pray with regularity, and consider themselves to be religious tend to exhibit longer telomeres than those who attend and pray less frequently and do not consider themselves to be religious, additional research is needed to establish the mechanisms underlying this association.},
}
@article {pmid28843281,
year = {2016},
author = {Sarek, G and Vannier, JB and Panier, S and Petrini, JHJ and Boulton, SJ},
title = {TRF2 Recruits RTEL1 to Telomeres in S Phase to Promote T-Loop Unwinding.},
journal = {Molecular cell},
volume = {61},
number = {5},
pages = {788-789},
doi = {10.1016/j.molcel.2016.02.016},
pmid = {28843281},
issn = {1097-4164},
}
@article {pmid28875649,
year = {2016},
author = {Yang, F and Zhao, PW and Sun, P and Ma, LJ and Zhao, PW},
title = {[Effect of Cynomorium songaricum polysaccharide on telomere of lung cancer A549 cells].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {41},
number = {5},
pages = {917-921},
doi = {10.4268/cjcmm20160526},
pmid = {28875649},
issn = {1001-5302},
mesh = {A549 Cells ; Apoptosis/drug effects ; Carcinoma, Non-Small-Cell Lung/genetics/*metabolism/physiopathology ; Cell Proliferation/drug effects ; Cynomorium/*chemistry ; Drugs, Chinese Herbal/*pharmacology ; Humans ; Lung Neoplasms/genetics/*metabolism/physiopathology ; Polysaccharides/*pharmacology ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {To study the effect of Cynomorium songaricum polysaccharide (CSRP) on A549 cells telomere of human non-small cell lung cancer, the mice were intragastric administrated with CSRP (0.08 g•kg[-1]) once daily for 4 days. Then their serum was taken for preparing CSRP drug serum. A549 cells were treated by the drug serum, and the effect of drug serum with different concentrations and different treating time on the proliferation of non-small cell lung cancer A549 cells was determined by MTT test. After treating for 48 hours by the drug serum of different concentrations, the telomere length of the cells was determined by fluorescence quantitative polymerase chain reaction (qPCR); the mRNA expression of telomerase reverse transcriptase (TERT) was determined by RT-qPCR; the cells apoptosis was determined by TUNEL assay. The results demonstrated that CSRP of various concentrations could inhibit the proliferation of the lung cancer A549 cells significantly, and the inhibition effect was strongest at 48 hours with the concentration of 6.0 mL•L[-1]. At 48 h, that CSRP of the concentrations from 1.5 to 12.0 mL•L[-1] could significantly shorten the telomere length of A549 cells, and the effect was strongest with the concentration of 1.5 mg•L[-1]. CSRP of various concentrations could significantly inhibit the mRNA expression of TERT in A549 cells, and the inhibition effect was stronger when the concentration was ≥6.0 mL•L[-1]. CSRP of various concentrations could promote A549 cells apoptosis, and the effect was stronger when the concentration was ≥6.0 mL•L[-1]. In conclusion, CSRP has the anti-cancer effect, and the action mechanism may be associated with inhibiting TERT mRNA expression, shortening telomere length, inhibiting cells proliferation and promoting cells apoptosis.},
}
@article {pmid28741530,
year = {2016},
author = {Voon, HPJ and Collas, P and Wong, LH},
title = {Compromised Telomeric Heterochromatin Promotes ALTernative Lengthening of Telomeres.},
journal = {Trends in cancer},
volume = {2},
number = {3},
pages = {114-116},
doi = {10.1016/j.trecan.2016.02.003},
pmid = {28741530},
issn = {2405-8025},
mesh = {Adaptor Proteins, Signal Transducing/*genetics ; Co-Repressor Proteins ; Heterochromatin/*metabolism ; Humans ; Molecular Chaperones ; Mutation ; Neoplasms/*genetics ; Nuclear Proteins/*genetics ; Telomere ; *Telomere Homeostasis ; X-linked Nuclear Protein/*genetics ; },
abstract = {Alternative lengthening of telomeres (ALT) is an enigmatic process that allows certain cancers to maintain telomeres in the absence of telomerase. ALT cancers are frequently defective for ATRX/DAXX, a chaperone complex that deposits histone variant H3.3 at telomeres. We propose that mutations in alpha thalassemia-mental retardation syndrome X-linked (ATRX)/death-domain associated protein (DAXX) prime ALT activation by disrupting telomeric heterochromatin.},
}
@article {pmid29209637,
year = {2017},
author = {Tutton, S and Lieberman, PM},
title = {A role for p53 in telomere protection.},
journal = {Molecular &amp; cellular oncology},
volume = {4},
number = {6},
pages = {e1143078},
pmid = {29209637},
issn = {2372-3556},
support = {R01 CA140652/CA/NCI NIH HHS/United States ; },
abstract = {Telomeres cap the ends of chromosomes and are crucial for genome stability. The p53 protein (TP53) is a vital tumor suppressor, activating the transcription of numerous genes in response to cell stress. We reported that direct binding of p53 at human subtelomeres corresponds with local transcription activation and enhanced telomere stability in the presence of DNA damage.},
}
@article {pmid28556637,
year = {2016},
author = {Maximov, VN and Malyutina, SK and Orlov, PS and Ivanoschuk, DE and Voropaeva, EN and Bobak, M and Voevoda, MI},
title = {[Length telomere leukocytes as ageing markers and risk factors for age-related diseases in humans].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {29},
number = {5},
pages = {702-708},
pmid = {28556637},
issn = {1561-9125},
mesh = {Aged ; Aging/*genetics ; Female ; Humans ; Leukocytes/*physiology ; Male ; Middle Aged ; Risk Factors ; Russia ; Sex Factors ; Telomere Homeostasis/*physiology ; },
abstract = {The purpose of the research was studying of leukocyte telomere length association with age, sex, risk factors for age-related diseases in Russian people of pre-retirement and retirement age. By quantitative real-time PCR method we studied the leukocyte telomere length in 398 men (56,3±7,2 years) and 365 women (56,6±7,1 years) selected from a population sample of 45-69 year-old residents of the Oktyabrsky and Kirovsky districts of Novosibirsk (9 400 people). The selection was formed in the course of work on the international project HAPIEE. As a result, an inverse correlation of telomere length with age (r=-0,159, р<0,001), with the ratio waist / hips (r=-0,107, p=0,003) was found out. The average length of telomeres in women significantly more than in men, p=0,031.The correlation of telomere length in males with weight (r=0,140, p=0,005), waist size (r=0,111, p=0,027) was found out. In women, there is an inverse correlation of telomere length with a waist size (r=-0,127, p=0,015), the ratio of waist / hips (r=-0,141, p=0,007). The length of telomeres is an inverse correlation with correlation with quantity of the cigarettes smoked (r=-0,121, р=0,024). The length of telomeres leukocytes correlates with age, smoking, and a number of phenotypical signs. In men with the family anamnesis burdened by malignancies leucocytes telomere length was found to be greater than in men without such anamnesis.},
}
@article {pmid28525700,
year = {2016},
author = {Streltsova, LI and Plokhova, EV and Kruglikova, AS and Pykhtina, VS and Akasheva, DU and Tkacheva, ON and Boitsov, SA},
title = {[The age-related changes of the heart rate variability measurements: the role of the inflammation, oxidative stress and telomeres biology].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {29},
number = {3},
pages = {495-501},
pmid = {28525700},
issn = {1561-9125},
mesh = {Aging/*physiology ; Arrhythmias, Cardiac/physiopathology ; Autonomic Nervous System/physiology ; Heart Rate/*physiology ; Humans ; Inflammation/physiopathology ; Oxidative Stress/physiology ; Telomere Homeostasis/*physiology ; },
abstract = {The autonomic and central nervous system, a number of humoral and reflex effects regulate the heart rate. The main role in the heart rate regulation belongs to the autonomic nervous system. A common method for studying the autonomic influences on the heart rate is the analysis of heart rate variability (HRV), which allows to evaluate the neuro-vegetative status of the organism, determine its adaptive capacity, to evaluate the level of stress and the degree of tension of regulatory systems. An age-related decrease of HRV measurements in healthy people reflects the weakening of the autonomic regulation of cardiac activity. The most pronounced changes are found in patients older than 60 years. The HRV depression is preceded by hemodynamic and metabolic disorders is associated with high cardiovascular risk and is a predictor of life-threatening arrhythmias and sudden death in the elderly.The reasons for HRV changes with age stay unclear. In the light of modern ideas about the mechanisms of aging, several complementary theories proposed. Telomere shortening, the role of oxidative stress and inflammation as possible mechanisms of age-related changes in the autonomic regulation of the heart rhythm, will be discussed in this article.},
}
@article {pmid28514537,
year = {2016},
author = {Bondarev, IE and Khavinson, VK},
title = {[Suppression of alternative telomere lengthening in cancer cells with reverse transcriptase inhibitors].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {29},
number = {2},
pages = {218-221},
pmid = {28514537},
issn = {1561-9125},
mesh = {Cell Line, Tumor ; Drug Screening Assays, Antitumor ; Humans ; *Neoplasms/drug therapy/genetics ; Reverse Transcriptase Inhibitors/pharmacology ; Telomerase/genetics ; *Telomere Homeostasis/drug effects/genetics ; Zidovudine/*pharmacology ; },
abstract = {Telomerase is a ribonucleoprotein enzyme that elongates telomeres and therefore maintains chromosomal stability in germline, and in the majority of cancer cells, during cell doubling. However, up to 30 % of human tumors of different types do not express telomerase, but instead use an alternative lengthening of telomeres (ALT). Here authors show that human tumor-derived ALT cell lines express a LINE-1 (L1) retrotransposon, which suggests its participation in telomere maintenance, possibly by a «slippage» mechanism of telomeric DNA synthesis. Moreover, suppression of the L1 encoded reverse transcriptase activity using an antisense strategy, or treatment of the ALT cells with the reverse transcriptase inhibitor 3'-azido-2',3'-dideoxythymidine (AZT), induces progressive telomere loss, arrest in G2-phase of the cell cycle, and, eventually, in cancer cell death. This finding suggests an exciting opportunity for the cure of up to 30 % of cancer cases.},
}
@article {pmid28423253,
year = {2016},
author = {Kireev, KA and Fokin, AA and Kireeva, TS},
title = {[Association of renal function, telomere length and markers of chronic inflammation for patients without chronic kidney and cardiovascular diseases].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {29},
number = {1},
pages = {97-101},
pmid = {28423253},
issn = {1561-9125},
mesh = {Aged, 80 and over ; Angioplasty, Balloon, Coronary ; *Cardiovascular Diseases ; Humans ; Inflammation ; Myocardial Infarction ; Retrospective Studies ; *Telomere ; Thrombolytic Therapy ; },
abstract = {The retrospective analysis of 50 cases of acute myocardial infarction's treatment in patients older than 90 years old was held. Patients' age ranged from 90 to 101 years old. The average age was 92,1±0,7 years. 20 (40 %) patients have had reperfusion therapy: thrombolytic therapy - 2 (4 %), emergency coronary stenting - 18 (36%). The mortality rate was 26 %. Mortality in groups with/without reperfusion therapy was 20 % and 30 %, respectively. In the subgroup of coronary stenting, 4 patients died (the mortality rate was 22,2 %). The specialized medical care for patients over 90 years old with acute myocardial infarction associated with high mortality (26 %). It was proved statistically that the reduction (p < 0,05) of mortality is connected with coronary stenting. In cases with endovascular technical possibilities' presence, even with multivessel lesions, it is necessary to perform coronary stenting of the infarct/ischemia-responsible coronary artery. It is particularly important in cases complicated by acute heart failure.},
}
@article {pmid28423250,
year = {2016},
author = {Pykhtina, VS and Strazhesko, ID and Tkacheva, ON and Akasheva, DU and Dudinskaya, EN and Vygodin, VA and Plokhova, EV and Kruglikova, AS and Boitsov, SA},
title = {[Association of renal function, telomere length and markers of chronic inflammation for patients without chronic kidney and cardiovascular diseases].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {29},
number = {1},
pages = {79-85},
pmid = {28423250},
issn = {1561-9125},
mesh = {Cardiovascular Diseases ; Female ; Glomerular Filtration Rate ; Humans ; Inflammation ; Kidney Diseases ; Male ; Middle Aged ; *Telomere ; },
abstract = {UNLABELLED: Most of people over 60 years of age have decreased renal function and the velocity of glomerular filtration rate reduction varies greatly. Presumably, one of the probable mechanisms of accelerated decline of renal function may be a shortening of telomere length due to chronic inflammation. The main purpose of research was to appreciate the association of renal function, leukocytes telomeres length and markers of chronic inflammation in patients without chronic kidney disease and cardiovascular disease. 253 patients without chronic kidney diseases and cardiovascular diseases were included in the study. The average age of patients was 51,5±13,3 years. There were 172 women and 81 men. 55 patients had hypertension of 1-2 degree, 46 patients had normal renal function, 207 had mild failure of kidney function. Albuminuria was < 30 mg/day in all patients. Multivariate linear regression analysis revealed statistically significant correlation between albuminuria level and telomere length (p=0,023), C reactive protein (p=0,047) and fibrinogen (p=0,001). Glomerular filtration rate, urea and creatinine were not associated with telomere length and markers of inflammation but were correlated well with age, p < 0,001.<br><br>CONCLUSIONS: Albuminuria is mainly associated with chronic inflammation and telomere length (from all studied indices of renal function). Albuminuria may be regarded as a marker of replicative cell senescence and a therapeutic target for the prevention of renal function reduction.},
}
@article {pmid28322101,
year = {2016},
author = {Wang, J and Dong, X and Cao, L and Sun, Y and Qiu, Y and Zhang, Y and Cao, R and Covasa, M and Zhong, L},
title = {Association between telomere length and diabetes mellitus: A meta-analysis.},
journal = {The Journal of international medical research},
volume = {44},
number = {6},
pages = {1156-1173},
pmid = {28322101},
issn = {1473-2300},
mesh = {Adult ; Age Factors ; Body Mass Index ; Case-Control Studies ; Diabetes Mellitus, Type 1/diagnosis/*genetics ; Diabetes Mellitus, Type 2/diagnosis/*genetics ; Female ; Humans ; Male ; Middle Aged ; Sex Factors ; Telomere/*chemistry ; *Telomere Shortening ; },
abstract = {Objective We investigated the relationship between diabetes and telomere length by meta-analysis. Methods We searched five popular databases for articles published between 1990 and 2015 using "diabetes" and "telomere" as search terms. Data were processed with RevMan5, and random- or fixed-effects meta-analysis was applied. The effects of geographical region, diabetes type, body mass index (BMI), age and sex were examined. Funnel plots were applied to evaluate publication bias. Results Seventeen articles were obtained from 571 references. We identified a significant association between telomere length and diabetes mellitus (standardized mean difference [SMD]: -3.41; 95% confidence interval [CI]: -4.01, -2.80; heterogeneity, I[2 ]= 99%) by comparing 5575 patients with diabetes and 6349 healthy individuals. The pooled SMD by geographic region indicated a significant association between shortened telomere length and diabetes mellitus (SMD: -3.41; 95% CI: -4.01, -2.80; heterogeneity, I[2 ]= 99%). In addition, telomere length was significantly associated with age (SMD: -3.41; 95% CI: -4.01, -2.80), diabetes type (SMD: -3.41; 95% CI: -4.01, -2.80), BMI (SMD: -1.61; 95% CI: -1.98, -1.23) and sex (SMD: -4.94; 95% CI: -9.47, -0.40). Conclusions The study demonstrated a close relationship between diabetes mellitus and telomere length, which was influenced by region, age, diabetes type, BMI and sex.},
}
@article {pmid28294800,
year = {2015},
author = {Drapkina, OM and Shepel, RN},
title = {[Smoking, Telomere Length and Cardiovascular Diseases].},
journal = {Kardiologiia},
volume = {55},
number = {10},
pages = {85-89},
doi = {10.18565/cardio.2015.10.85-89},
pmid = {28294800},
issn = {0022-9040},
abstract = {The role of smoking in the development of various diseases, including cardiovascular system is widely known and proven. At the same time, given the multi-component composition of tobacco smoke, many mechanisms of its damaging effect on the target organs remain unknown. Effect of smoking on duration of life and risk of cardiovascular diseases mediated by changes of rate of telomere shortening in chromosomes of eukaryotic cells has been actively studied in recent years. This article describes main damaging mechanisms of tobacco smoke on the cardiovascular system including changes at the molecular- genetic level.},
}
@article {pmid28357265,
year = {2015},
author = {Mersaoui, SY and Gravel, S and Karpov, V and Wellinger, RJ},
title = {DNA damage checkpoint adaptation genes are required for division of cells harbouring eroded telomeres.},
journal = {Microbial cell (Graz, Austria)},
volume = {2},
number = {10},
pages = {394-405},
pmid = {28357265},
issn = {2311-2638},
abstract = {In budding yeast, telomerase and the Cdc13p protein are two key players acting to ensure telomere stability. In the absence of telomerase, cells eventually enter a growth arrest which only few can overcome via a conserved process; such cells are called survivors. Survivors rely on homologous recombination-dependent mechanisms for telomeric repeat addition. Previously, we showed that such survivor cells also manage to bypass the loss of the essential Cdc13p protein to give rise to Cdc13-independent (or cap-independent) strains. Here we show that Cdc13-independent cells grow with persistently recognized DNA damage, which does not however result in a checkpoint activation; thus no defect in cell cycle progression is detectable. The absence of checkpoint signalling rather is due to the accumulation of mutations in checkpoint genes such as RAD24 or MEC1. Importantly, our results also show that cells that have lost the ability to adapt to persistent DNA damage, also are very much impaired in generating cap-independent cells. Altogether, these results show that while the capping process can be flexible, it takes a very specific genetic setup to allow a change from canonical capping to alternative capping. We hypothesize that in the alternative capping mode, genome integrity mechanisms are abrogated, which could cause increased mutation frequencies. These results from yeast have clear parallels in transformed human cancer cells and offer deeper insights into processes operating in pre-cancerous human cells that harbour eroded telomeres.},
}
@article {pmid28357308,
year = {2015},
author = {Claussin, C and Chang, M},
title = {The many facets of homologous recombination at telomeres.},
journal = {Microbial cell (Graz, Austria)},
volume = {2},
number = {9},
pages = {308-321},
pmid = {28357308},
issn = {2311-2638},
abstract = {The ends of linear chromosomes are capped by nucleoprotein structures called telomeres. A dysfunctional telomere may resemble a DNA double-strand break (DSB), which is a severe form of DNA damage. The presence of one DSB is sufficient to drive cell cycle arrest and cell death. Therefore cells have evolved mechanisms to repair DSBs such as homologous recombination (HR). HR-mediated repair of telomeres can lead to genome instability, a hallmark of cancer cells, which is why such repair is normally inhibited. However, some HR-mediated processes are required for proper telomere function. The need for some recombination activities at telomeres but not others necessitates careful and complex regulation, defects in which can lead to catastrophic consequences. Furthermore, some cell types can maintain telomeres via telomerase-independent, recombination-mediated mechanisms. In humans, these mechanisms are called alternative lengthening of telomeres (ALT) and are used in a subset of human cancer cells. In this review, we summarize the different recombination activities occurring at telomeres and discuss how they are regulated. Much of the current knowledge is derived from work using yeast models, which is the focus of this review, but relevant studies in mammals are also included.},
}
@article {pmid27646911,
year = {2015},
author = {Tesovnik, T and Kovac, J and Hovnik, T and Kotnik, P and Battelino, T and Trebusak Podkrajsek, K},
title = {Association of Average Telomere Length with Body-Mass Index and Vitamin D Status in Juvenile Population with Type 1 Diabetes.},
journal = {Zdravstveno varstvo},
volume = {54},
number = {2},
pages = {74-78},
pmid = {27646911},
issn = {0351-0026},
abstract = {BACKGROUND: Type 1 diabetes (T1D) is an autoimmune chronic disease where hyperglycemia, increased risk of oxidative stress, advanced glycation end-products and other genetic and environmental factors lead to T1D complications. Shorter telomeres are associated with hyperglycemic levels and lower serum vitamin D levels.<br><br>METHODS: Average telomere length (ATL) in whole blood DNA samples was assessed with qPCR method in 53 Slovenian T1D children/adolescents (median age 8.7 years, 1:1.3 male/female ratio). Body mass index standard deviation score (BMI-SDS), glycated haemoglobin and serum level of vitamin D metabolite (25-(OH)-D3) and the age at the onset of T1D were collected from the available medical documentation.<br><br>RESULTS: Results indicate shorter ATL in subjects with higher BMI-SDS when compared to those with longer ATL (0.455 &#xb1; 0.438, -0.63 &#xb1; 0.295; p=0.049). Subjects with higher BMI-SDS had lower serum vitamin D levels when compared to those with lower BMI-SDS (40.66 &#xb1; 3.07 vs. 52.86 &#xb1; 4.85 nmol/L; p=0.045). Vitamin D serum levels did not significantly differ between subjects with longer/shorter ATL.<br><br>CONCLUSION: T1D children/adolescents with shorter ATL tend to have higher BMI-SDS. Lower serum vitamin D levels were associated with higher BMI-SDS, while associations between vitamin D serum levels, age at the onset of T1D, glycated haemoglobin and ATL were not observed. Additional studies with more participants are required to clarify the role of the telomere dynamics in T1D aetiology and development of complications.},
}
@article {pmid28352708,
year = {2015},
author = {Polansky, H and Javaherian, A},
title = {The latent cytomegalovirus decreases telomere length by microcompetition.},
journal = {Open medicine (Warsaw, Poland)},
volume = {10},
number = {1},
pages = {294-296},
pmid = {28352708},
issn = {2391-5463},
abstract = {Reduced telomere length has been associated with aging and age-related diseases. Latent infection with the Cytomegalovirus (CMV) induces telomere shortening in the infected cells. Latent CMV infection may cause reduced telomere length via GABP transcription factor deficiency, according to the Microcompetition Theory. Microcompetition and viral-induced transcription factor deficiency is important since most people harbor a latent viral infection.},
}
@article {pmid28294907,
year = {2015},
author = {Akasheva, DU and Plokhova, EV and Tkacheva, ON and Strazhesko, ID and Kruglikova, AS and Pykhtina, VS and Dudinskaya, EN and Skvortsov, DA and Egshatyan, LV and Brailova, NV and Agaltsov, MV and Ozerova, IN and Vigodin, VA and Boytsov, SA},
title = {[Age-related Changes of Left Ventricular Diastolic Function, NT-proBNP Level and Their Association with Leukocyte Telomere Length].},
journal = {Kardiologiia},
volume = {55},
number = {5},
pages = {59-65},
pmid = {28294907},
issn = {0022-9040},
abstract = {UNLABELLED: With advancing age the left ventricle (LV) undergoes structural and functional changes, thereby creating the substrate for the development of diseases. One possible mechanism of the ageing of the heart is cellular senescence. Leukocyte telomere length (LTL) is a marker of replicative ageing. The purpose of this study was to evaluate the diastolic function of LV and level of NT-proBNP in people of different ages free of cardiovascular diseases and to assess their relationship with LTL. Our data showed that old age is associated with diastolic dysfunction and increase in the levels of NT-proBNP. The group of older subjects had lower values of E/A (0.96+/-0.036 vs 1.27+/-0.03, p<0.001), Em/Am (0.9+/-0.035 vs 1.5+/-0.066) and higher values of IVRT (81+/-1.56 vs 70+/-1.23 s, p<0.001), DT (198+/-3.98 vs 175+/-2.82 s, p<0.001), that reflected impairment of LV relaxation. NT-proBNP level was higher in the elderly (100.82+/-7.1 vs 48.47+/-6.7 g/ml, p<0.01), but it did not correlate with LTL. The most sensitive to the age parameters of LV diastolic function (E/A and Em/Am ratio) were positively and independently of age associated with LTL (p<0.001). Older individuals with shorter LTL had significantly lower values of E/A ratio.<br><br>CONCLUSION: Telomere length appears to be a biomarker of myocardium ageing.},
}
@article {pmid28509478,
year = {2015},
author = {Spivak, IM and Mikhelson, VM and Spivak, DL},
title = {[Telomere length, telomerase activity, stress and aging].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {28},
number = {3},
pages = {441-448},
pmid = {28509478},
issn = {1561-9125},
mesh = {Adaptation, Psychological/*physiology ; *Aging/physiology/psychology ; *Healthy Aging/physiology/psychology ; Humans ; Life Expectancy ; Longevity/*physiology ; Telomerase/physiology ; Telomere/physiology ; *Telomere Homeostasis ; Telomere Shortening ; },
abstract = {The review is dedicated to analysis of data available at present time concerning possible influence of stress upon telomere lengths and telomerase activity, as well as various ways of counteracting it. Present-day telomerase theory of aging gains a new impetus, shedding light upon the influence of psychological state of humans and their ability to counteract stress, upon the process of aging. It also tends to regard telomere shortening and the decrease in the activity of telomerase as a marker of level of the ability to adapt to both inner and outer influences. Both aging and age-dependent diseases are proved to be substantially retarded not only by the administration of drugs, but also by psychological means, which forms a good way towards healthy longevity. With complete understanding of the impossibility to prevent or even to slow down natural senescence itself, these methods allow to remove causes, which accelerate senescence, and to increase the average human longevity.},
}
@article {pmid27308409,
year = {2015},
author = {Hendrickson, EA and Baird, DM},
title = {Alternative end joining, clonal evolution, and escape from a telomere-driven crisis.},
journal = {Molecular &amp; cellular oncology},
volume = {2},
number = {1},
pages = {e975623},
pmid = {27308409},
issn = {2372-3556},
support = {R01 CA154461/CA/NCI NIH HHS/United States ; R01 GM088351/GM/NIGMS NIH HHS/United States ; },
abstract = {Telomere dysfunction and fusion play key roles in driving genomic instability and clonal evolution in many tumor types. We have recently described a role for DNA ligase III (LIG3) in facilitating the escape of cells from crisis induced by telomere dysfunction. Our data indicate that LIG3-mediated telomere fusion is important in facilitating clonal evolution.},
}
@article {pmid28348703,
year = {2014},
author = {Sameer, AS and Nissar, S and Aziz, R},
title = {Telomeres and Estrogens: The Unholy Nexus in Pathogenesis of Atherosclerosis.},
journal = {Cardiology research},
volume = {5},
number = {3-4},
pages = {85-90},
pmid = {28348703},
issn = {1923-2829},
abstract = {Atherosclerosis (AS) is a complex inflammatory process and is categorized as a multifactorial disease involving the interplay of genetic and environmental factors. There are many factors which play role in predisposition and development of AS. In this review we have tried to address the basic pathophysiology of AS lesions and the role played by two important factors - telomeres and estrogens in the development of this disease.},
}
@article {pmid27308342,
year = {2014},
author = {Marcand, S},
title = {How do telomeres and NHEJ coexist?.},
journal = {Molecular &amp; cellular oncology},
volume = {1},
number = {3},
pages = {e963438},
pmid = {27308342},
issn = {2372-3556},
abstract = {The telomeres of eukaryotes are stable open double-strand ends that coexist with nonhomologous end joining (NHEJ), the repair pathway that directly ligates DNA ends generated by double-strand breaks. Since a single end-joining event between 2 telomeres generates a circular chromosome or an unstable dicentric chromosome, NHEJ must be prevented from acting on telomeres. Multiple mechanisms mediated by telomere factors act in synergy to achieve this inhibition.},
}
@article {pmid28357225,
year = {2014},
author = {Harari, Y and Kupiec, M},
title = {Genome-wide studies of telomere biology in budding yeast.},
journal = {Microbial cell (Graz, Austria)},
volume = {1},
number = {3},
pages = {70-80},
pmid = {28357225},
issn = {2311-2638},
abstract = {Telomeres are specialized DNA-protein structures at the ends of eukaryotic chromosomes. Telomeres are essential for chromosomal stability and integrity, as they prevent chromosome ends from being recognized as double strand breaks. In rapidly proliferating cells, telomeric DNA is synthesized by the enzyme telomerase, which copies a short template sequence within its own RNA moiety, thus helping to solve the "end-replication problem", in which information is lost at the ends of chromosomes with each DNA replication cycle. The basic mechanisms of telomere length, structure and function maintenance are conserved among eukaryotes. Studies in the yeast Saccharomyces cerevisiae have been instrumental in deciphering the basic aspects of telomere biology. In the last decade, technical advances, such as the availability of mutant collections, have allowed carrying out systematic genome-wide screens for mutants affecting various aspects of telomere biology. In this review we summarize these efforts, and the insights that this Systems Biology approach has produced so far.},
}
@article {pmid27308311,
year = {2014},
author = {Gobbini, E and Trovesi, C and Cassani, C and Longhese, MP},
title = {Telomere uncapping at the crossroad between cell cycle arrest and carcinogenesis.},
journal = {Molecular &amp; cellular oncology},
volume = {1},
number = {1},
pages = {e29901},
pmid = {27308311},
issn = {2372-3556},
abstract = {Telomeres are nucleoprotein complexes that protect the natural ends of chromosomes from fusion and degradation and prevent them eliciting a checkpoint response. This protective function, which is called telomere capping, is largely mediated by telomere-binding proteins that suppress checkpoint activation and DNA repair activities. Telomere dysfunction through progressive shortening or removal of capping proteins leads to a checkpoint-mediated block of cell proliferation, which acts as a cancer-suppressor mechanism. However, genetic alterations that inactivate the checkpoint can lead to further telomere erosion and increased genomic instability that, coupled with the activation of mechanisms to restabilize telomeres, can drive the oncogenic process.},
}
@article {pmid27265287,
year = {2006},
author = {Tükün, A and Akay, GG and Yürür Kutlay, N},
title = {Telomere and telomerase in hematologicalmalignancies.},
journal = {Turkish journal of haematology : official journal of Turkish Society of Haematology},
volume = {23},
number = {2},
pages = {77-83},
pmid = {27265287},
issn = {1300-7777},
}
@article {pmid28547037,
year = {2002},
author = {Haussmann, MF and Vleck, CM},
title = {Telomere length provides a new technique for aging animals.},
journal = {Oecologia},
volume = {130},
number = {3},
pages = {325-328},
doi = {10.1007/s00442-001-0827-y},
pmid = {28547037},
issn = {1432-1939},
abstract = {Field biologists often work with animals for which there is no prior history. A marker of an animal's age would offer insight into how age and experience affect reproductive success and other life history parameters. Telomere length shortens with age in cultured cells and mouse and human tissues. We found that lengths of telomere restriction fragments cleaved from blood cell DNA shorten predictably with age in the zebra finch (Taeniopygia guttata). If this relationship holds in other species, it should be possible, once the relationship between telomere length and age has been determined for a given species, to use blood samples to estimate ages of free-living animals. This will allow the incorporation of age into estimates of factors affecting life history parameters in cases where previous histories of animals are unknown.},
}
@article {pmid27406800,
year = {1997},
author = {Jiang, XR and Kelsey, SM and Newland, AC},
title = {Telomeres, Telomerase and Leukaemia.},
journal = {Hematology (Amsterdam, Netherlands)},
volume = {2},
number = {2},
pages = {101-111},
doi = {10.1080/10245332.1997.11746325},
pmid = {27406800},
issn = {1024-5332},
abstract = {There is increasing evidence supporting the hypothesis that telomere shortening both in vitro and in vivo is the clock that counts cell divisions and determines the onset of cellular senescence. Cells overcome the senescence mechanisms by stabilising telomere length, probably due to the activity of telomerase that specifically elongates telomeres. The striking observation that almost all malignant cancers have telomerase activity indicate that there is intensive selective pressure of telomerase activation with the progression of malignancy. Indirect support for this view is that benign or pre-cancerous lesions are telomerase silent. The fact that telomerase activity is observed in over 85% of human primary malignancies raises the possibilities that it may be a new marker of cancer with diagnostic and therapeutic potentials. Can such ideas be applied to leukaemias and preleukaemias? Since normal haematopoietic stem cells and their progeny express telomerase activity, it is important to consider whether or not telomere shortening and telomerase activity play any role in leukaemic progression. Telomere reduction has been observed in various leukaemias including in ALL, AML, transformed leukaemias from MDS and late stage of CML and CLL and might be indicative of the length of the disease. Elevated telomerase activity has also been found in ALL, AML, CML and CLL. In AML, patients with chromosomal abnormalities 11q, -5, -7 had higher telomerase activity and unfavourable prognosis; while those with favourable cytogenetics such as t(8:21), inversion 16 showed low levels of telomerase. This suggests that telomerase activity may be a marker for poor prognosis of AML. Unanswered at present is the potential role of telomeres and telomerase in the progression of benign to malignant tumours. Further studies on the expression and regulation of the individual components of telomerase may enable us to clarify the diagnostic and therapeutic potential of telomerase in leukaemias.},
}
@article {pmid27061190,
year = {2016},
author = {Menin, C and Bojnik, E and Del Bianco, P and Elefanti, L and Gianesin, K and Keppel, S and Stagni, C and Mocellin, S and Vecchiato, A and De Rossi, A},
title = {Differences in telomere length between sporadic and familial cutaneous melanoma.},
journal = {The British journal of dermatology},
volume = {175},
number = {5},
pages = {937-943},
doi = {10.1111/bjd.14652},
pmid = {27061190},
issn = {1365-2133},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Case-Control Studies ; Cyclin-Dependent Kinase Inhibitor p16 ; Cyclin-Dependent Kinase Inhibitor p18/genetics ; Female ; Genetic Predisposition to Disease/genetics ; Humans ; Male ; Melanoma/genetics/*pathology ; Middle Aged ; Risk Factors ; Skin Neoplasms/genetics/*pathology ; Telomere/*pathology ; Young Adult ; },
abstract = {BACKGROUND: Several pieces of evidence indicate that a complex relationship exists between constitutional telomere length (TL) and the risk of cutaneous melanoma. Although the general perception is that longer telomeres increase melanoma risk, some studies do not support this association. We hypothesize that discordant data are due to the characteristics of the studied populations.<br><br>OBJECTIVES: To evaluate the association of TL with familial and sporadic melanoma.<br><br>MATERIALS AND METHODS: TL was measured by multiplex quantitative polymerase chain reaction in leukocytes from 310 patients with melanoma according to familial/sporadic and single/multiple cancers and 216 age-matched controls.<br><br>RESULTS: Patients with sporadic melanoma were found to have shorter telomeres compared with those with familial melanoma. In addition, shorter telomeres, while tending to reduce the risk of familial melanoma regardless of single or multiple tumours, nearly trebled the risk of single sporadic melanoma.<br><br>CONCLUSIONS: This is the first time that TL has been correlated to opposite effects on melanoma risk according to the presence or absence of familial predisposition. Individual susceptibility to melanoma should be taken into account when assessing the role of TL as a risk factor.},
}
@article {pmid26936823,
year = {2016},
author = {Hansen, ME and Hunt, SC and Stone, RC and Horvath, K and Herbig, U and Ranciaro, A and Hirbo, J and Beggs, W and Reiner, AP and Wilson, JG and Kimura, M and De Vivo, I and Chen, MM and Kark, JD and Levy, D and Nyambo, T and Tishkoff, SA and Aviv, A},
title = {Shorter telomere length in Europeans than in Africans due to polygenetic adaptation.},
journal = {Human molecular genetics},
volume = {25},
number = {11},
pages = {2324-2330},
pmid = {26936823},
issn = {1460-2083},
support = {R01 AG018734/AG/NIA NIH HHS/United States ; R01 HL116446/HL/NHLBI NIH HHS/United States ; DP1 ES022577/ES/NIEHS NIH HHS/United States ; R01 CA184572/CA/NCI NIH HHS/United States ; P30 ES013508/ES/NIEHS NIH HHS/United States ; R01 DK104339/DK/NIDDK NIH HHS/United States ; R01 GM113657/GM/NIGMS NIH HHS/United States ; T32 ES019851/ES/NIEHS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Black or African American/genetics ; Aged ; Aged, 80 and over ; Alleles ; Black People/genetics ; Child ; Female ; Genetic Drift ; Humans ; Leukocytes/*cytology ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere Shortening/*genetics ; White People/genetics ; },
abstract = {Leukocyte telomere length (LTL), which reflects telomere length in other somatic tissues, is a complex genetic trait. Eleven SNPs have been shown in genome-wide association studies to be associated with LTL at a genome-wide level of significance within cohorts of European ancestry. It has been observed that LTL is longer in African Americans than in Europeans. The underlying reason for this difference is unknown. Here we show that LTL is significantly longer in sub-Saharan Africans than in both Europeans and African Americans. Based on the 11 LTL-associated alleles and genetic data in phase 3 of the 1000 Genomes Project, we show that the shifts in allele frequency within Europe and between Europe and Africa do not fit the pattern expected by neutral genetic drift. Our findings suggest that differences in LTL within Europeans and between Europeans and Africans is influenced by polygenic adaptation and that differences in LTL between Europeans and Africans might explain, in part, ethnic differences in risks for human diseases that have been linked to LTL.},
}
@article {pmid27072825,
year = {2016},
author = {Ceja-Rangel, HA and Sánchez-Suárez, P and Castellanos-Juárez, E and Peñaroja-Flores, R and Arenas-Aranda, DJ and Gariglio, P and Benítez-Bribiesca, L},
title = {Shorter telomeres and high telomerase activity correlate with a highly aggressive phenotype in breast cancer cell lines.},
journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine},
volume = {37},
number = {9},
pages = {11917-11926},
pmid = {27072825},
issn = {1423-0380},
mesh = {Animals ; Biomarkers, Tumor/*metabolism ; Blotting, Western ; Breast Neoplasms/enzymology/genetics/pathology ; Cell Line, Tumor ; HeLa Cells ; Humans ; MCF-7 Cells ; Matrix Metalloproteinases/metabolism ; Mice ; Microscopy, Fluorescence ; NIH 3T3 Cells ; Neoplasm Invasiveness ; Phenotype ; Polymerase Chain Reaction/methods ; Telomerase/*metabolism ; Telomere/*genetics ; *Telomere Shortening ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Maintenance of telomere length is one function of human telomerase that is crucial for the survival of cancer cells and cancer progression. Both telomeres and telomerase have been proposed as possible biomarkers of cancer risk and cancer invasiveness; however, their clinical relevance is still under discussion. In order to improve our understanding of the relationship between telomere length and telomerase activity with cancer invasiveness, we studied telomere length as well as telomerase levels, activity, and intracellular localization in breast cancer cell lines with diverse invasive phenotypes. We found an apparently paradoxical coincidence of short telomeres and enhanced telomerase activity in the most invasive breast cancer cell lines. We also observed that hTERT intracellular localization could be correlated with its level of activity. There was no association between human telomerase reverse transcriptase (hTERT) protein expression levels and invasiveness. We propose that simultaneous evaluation of these two biomarkers-telomere length and telomerase activity-could be useful for the assessment of the invasive capacity and aggressiveness of tumor cells from breast cancer patients.},
}
@article {pmid27102155,
year = {2016},
author = {Lustig, A and Shterev, I and Geyer, S and Shi, A and Hu, Y and Morishita, Y and Nagamura, H and Sasaki, K and Maki, M and Hayashi, I and Furukawa, K and Yoshida, K and Kajimura, J and Kyoizumi, S and Kusunoki, Y and Ohishi, W and Nakachi, K and Weng, NP and Hayashi, T},
title = {Long term effects of radiation exposure on telomere lengths of leukocytes and its associated biomarkers among atomic-bomb survivors.},
journal = {Oncotarget},
volume = {7},
number = {26},
pages = {38988-38998},
pmid = {27102155},
issn = {1949-2553},
support = {ZIA AG000756-18//Intramural NIH HHS/United States ; ZIA AG000756-19//Intramural NIH HHS/United States ; },
mesh = {Age Factors ; Aged ; Aged, 80 and over ; Aging ; Biomarkers/*metabolism ; Biomarkers, Tumor ; Cross-Sectional Studies ; Female ; Follow-Up Studies ; Humans ; Japan ; Leukocytes/*metabolism/*radiation effects ; Longitudinal Studies ; Male ; Middle Aged ; *Nuclear Weapons ; *Radiation Exposure ; Radiation, Ionizing ; Survivors ; Telomere/radiation effects/*ultrastructure ; Telomere Shortening ; },
abstract = {Ionizing radiation (IR) is a major source of cellular damage and the immediate cellular response to IR has been well characterized. But the long-term impact of IR on cell function and its relationship with aging are not known. Here, we examined the IR effects on telomere length and other biomarkers 50 to 68 years post-exposure (two time points per person) in survivors of the atomic bombing at Hiroshima during WWII. We found that telomere length of leukocytes was inversely correlated with the dose of IR (p=0.008), and this effect was primarily found in survivors who were exposed at younger ages; specifically those <12 years old (p=0.0004). Although a dose-related retardation of telomere shortening with age was observed in the cross-sectional data, longitudinal follow-up after 11 years did not show IR exposure-related alteration of the rate of telomere shortening with age. In addition, IR diminished the associations between telomere length and selected aging biomarkers that were observed in survivors with no dose. These included uric acid metabolism, cytokines, and blood T cell counts. These findings showed long-lasting detrimental effects of IR on telomere length of leukocytes in both dose- and age-at-exposure dependent manner, and on alterations of biomarkers with aging.},
}
@article {pmid27173780,
year = {2016},
author = {Tahara, T and Shibata, T and Kawamura, T and Horiguchi, N and Okubo, M and Nakano, N and Ishizuka, T and Nagasaka, M and Nakagawa, Y and Ohmiya, N},
title = {Telomere length shortening in gastric mucosa is a field effect associated with increased risk of gastric cancer.},
journal = {Virchows Archiv : an international journal of pathology},
volume = {469},
number = {1},
pages = {19-24},
pmid = {27173780},
issn = {1432-2307},
mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Gastric Mucosa/*pathology ; Helicobacter Infections/complications/diagnosis/pathology ; Helicobacter pylori ; Humans ; Male ; Metaplasia/diagnosis/*pathology ; Middle Aged ; Prognosis ; Risk ; Stomach/pathology ; Stomach Neoplasms/*diagnosis/*pathology ; Telomere/*pathology ; },
abstract = {Telomere shortening occurs in many organs and tissues and is accelerated by oxidative injury and rapid cell turnover. Short telomeres initiate chromosomal instability and may eventually contribute to tumorigenesis. To evaluate telomere length as potential biomarker for gastric cancer (GC) risk, we measured average telomere length using quantitative real-time PCR in GC tissues and in non-neoplastic mucosa from patients with GC and without GC. We obtained of 217 GC patients matched biopsies from the GC and adjacent tissues as well as gastric biopsies of 102 subjects without GC. Relative telomere length was measured in genomic DNA by real-time PCR. Relative telomere length decreased gradually in Helicobacter pylori (H. pylori) negative and positive gastric mucosa of GC free subjects compared with adjacent mucosa and cancer tissue from GC patients (4.03 ± 0.3 vs. 2.82 ± 0.19 vs. 0.82 ± 0.07 vs. 0.29 ± 0.09, P < 0.0001). In non-neoplastic mucosa of GC patients, shorter telomeres were found significantly more often than in that of GC free subjects (age, sex, and H. pylori adjusted odds ratio = 7.81, 95 % confidence interval = 4.71-12.9, P < 0.0001). Telomere shortening in non-neoplastic mucosa was associated with chronic inflammation (P = 0.0018) and intestinal metaplasia (P < 0.0001). No significant associations were found between relative telomere length and clinicopathological features of GC and overall survival. Telomere shortening in gastric mucosa reflects a field effect in an early stage of carcinogenesis and is associated with an increased risk of GC. Telomere length in GC is not associated with clinicopathological features or prognosis.},
}
@article {pmid27173378,
year = {2016},
author = {Mullins, MR and Rajavel, M and Hernandez-Sanchez, W and de la Fuente, M and Biendarra, SM and Harris, ME and Taylor, DJ},
title = {POT1-TPP1 Binding and Unfolding of Telomere DNA Discriminates against Structural Polymorphism.},
journal = {Journal of molecular biology},
volume = {428},
number = {13},
pages = {2695-2708},
pmid = {27173378},
issn = {1089-8638},
support = {DP2 CA186571/CA/NCI NIH HHS/United States ; R01 GM056740/GM/NIGMS NIH HHS/United States ; T32 GM072474/GM/NIGMS NIH HHS/United States ; },
mesh = {Aminopeptidases/*metabolism ; DNA, Single-Stranded/*genetics ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/*metabolism ; G-Quadruplexes ; Humans ; Polymorphism, Genetic/*genetics ; Protein Binding ; Serine Proteases/*metabolism ; Shelterin Complex/*metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomeres are nucleoprotein complexes that reside at the ends of linear chromosomes and help maintain genomic integrity. Protection of telomeres 1 (POT1) and TPP1 are telomere-specific proteins that bind as a heterodimer to single-stranded telomere DNA to prevent illicit DNA damage responses and to enhance telomerase-mediated telomere extension. Telomere DNA is guanosine rich and, as such, can form highly stable secondary structures including G-quadruplexes. G-quadruplex DNA folds into different topologies that are determined by several factors including monovalent ion composition and the precise sequence and length of the DNA. Here, we explore the influence of DNA secondary structure on POT1-TPP1 binding. Equilibrium binding assays reveal that the POT1-TPP1 complex binds G-quadruplex structures formed in buffers containing Na(+) with an affinity that is fivefold higher than for G-quadruplex structures formed in the presence of K(+). However, the binding of the second heterodimer is insensitive to DNA secondary structure, presumably due to unfolding resulting from binding of the first POT1-TPP1. We further show that the rate constant for POT1-TPP1-induced unfolding of DNA secondary structure is substantially faster for G-quadruplex topologies formed in the presence of Na(+) ions. When bound to DNA, POT1-TPP1 forms complexes with similar CD spectra and enhances telomerase activity for all DNA substrates tested, regardless of the substrate secondary structure or solution monovalent ion composition. Together, these data indicate that binding of POT1-TPP1 unfolds telomere secondary structure to assist loading of additional heterodimers and to ensure efficient promotion of telomerase-mediated extension.},
}
@article {pmid27167335,
year = {2016},
author = {Suraweera, N and Mouradov, D and Li, S and Jorissen, RN and Hampson, D and Ghosh, A and Sengupta, N and Thaha, M and Ahmed, S and Kirwan, M and Aleva, F and Propper, D and Feakins, RM and Vulliamy, T and Elwood, NJ and Tian, P and Ward, RL and Hawkins, NJ and Xu, ZZ and Molloy, PL and Jones, IT and Croxford, M and Gibbs, P and Silver, A and Sieber, OM},
title = {Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer.},
journal = {Oncotarget},
volume = {7},
number = {24},
pages = {36474-36488},
pmid = {27167335},
issn = {1949-2553},
mesh = {Adult ; Aged ; Aged, 80 and over ; Chromosomal Instability/*genetics ; Colorectal Neoplasms/*genetics/pathology ; Disease Progression ; Disease-Free Survival ; Female ; Humans ; Male ; Middle Aged ; Mucous Membrane/*metabolism ; Multivariate Analysis ; Mutation/genetics ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins p21(ras)/genetics ; Telomere/*genetics ; Tumor Suppressor Protein p53/genetics ; },
abstract = {Telomeric dysfunction is linked to colorectal cancer (CRC) initiation. However, the relationship of normal tissue and tumor telomere lengths with CRC progression, molecular features and prognosis is unclear. Here, we measured relative telomere length (RTL) by real-time quantitative PCR in 90 adenomas (aRTL), 419 stage I-IV CRCs (cRTL) and adjacent normal mucosa (nRTL). Age-adjusted RTL was analyzed against germline variants in telomere biology genes, chromosome instability (CIN), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), TP53, KRAS, BRAF mutations and clinical outcomes. In 509 adenoma or CRC patients, nRTL decreased with advancing age. Female gender, proximal location and the TERT rs2736100 G allele were independently associated with longer age-adjusted nRTL. Adenomas and carcinomas exhibited telomere shortening in 79% and 67% and lengthening in 7% and 15% of cases. Age-adjusted nRTL and cRTL were independently associated with tumor stage, decreasing from adenoma to stage III and leveling out or increasing from stage III to IV, respectively. Cancer MSI, CIMP, TP53, KRAS and BRAF status were not related to nRTL or cRTL. Near-tetraploid CRCs exhibited significantly longer cRTLs than CIN- and aneuploidy CRCs, while cRTL was significantly shorter in CRCs with larger numbers of chromosome breaks. Age-adjusted nRTL, cRTL or cRTL:nRTL ratios were not associated with disease-free or overall survival in stage II/III CRC. Taken together, our data show that both normal mucosa and tumor RTL are independently associated with CRC progression, and highlight divergent associations of CRC telomere length with tumor CIN profiles.},
}
@article {pmid27165790,
year = {2016},
author = {Lazzerini-Denchi, E and Sfeir, A},
title = {Stop pulling my strings - what telomeres taught us about the DNA damage response.},
journal = {Nature reviews. Molecular cell biology},
volume = {17},
number = {6},
pages = {364-378},
pmid = {27165790},
issn = {1471-0080},
support = {DP2 CA195767/CA/NCI NIH HHS/United States ; R01 AG038677/AG/NIA NIH HHS/United States ; R01 DK102562/DK/NIDDK NIH HHS/United States ; R21 CA195012/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; DNA Breaks, Double-Stranded ; *DNA Repair ; Genomic Instability ; Humans ; Signal Transduction ; Telomere/*genetics ; Telomere Homeostasis ; },
abstract = {Mammalian cells have evolved specialized mechanisms to sense and repair double-strand breaks (DSBs) to maintain genomic stability. However, in certain cases, the activity of these pathways can lead to aberrant DNA repair, genomic instability and tumorigenesis. One such case is DNA repair at the natural ends of linear chromosomes, known as telomeres, which can lead to chromosome-end fusions. Here, we review data obtained over the past decade and discuss the mechanisms that protect mammalian chromosome ends from the DNA damage response. We also discuss how telomere research has helped to uncover key steps in DSB repair. Last, we summarize how dysfunctional telomeres and the ensuing genomic instability drive the progression of cancer.},
}
@article {pmid27165085,
year = {2016},
author = {Blinova, EA and Zinnatova, EV and Barkovskaya, MSh and Borisov, VI and Sizikov, AE and Kozhevnikov, VS and Rubtsov, NB and Kozlov, VA},
title = {Telomere Length of Individual Chromosomes in Patients with Rheumatoid Arthritis.},
journal = {Bulletin of experimental biology and medicine},
volume = {160},
number = {6},
pages = {779-782},
doi = {10.1007/s10517-016-3308-3},
pmid = {27165085},
issn = {1573-8221},
mesh = {Adult ; Arthritis, Rheumatoid/genetics/*pathology ; Case-Control Studies ; Chromosomes, Human/*genetics ; Female ; Humans ; Male ; Middle Aged ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {We analyzed telomere length of individual chromosomes in peripheral blood lymphocytes of healthy individuals and patients with rheumatoid arthritis. Quantitative fluorescent in situ hybridization and subsequent computer analysis of metaphase chromosomes showed that distribution of telomere length on individual chromosomes is different under normal and pathological conditions. Patients with rheumatoid arthritis had significantly shorter chromosome 4p telomeres, which can be essential for pathogenesis of this multifactorial disease. Additionally, disease activity inversely correlated with telomere length on chromosome 10p carrying genes involved in T cell differentiation and proliferation.},
}
@article {pmid27163410,
year = {2016},
author = {Boyer, L and Audureau, E and Margarit, L and Marcos, E and Bizard, E and Le Corvoisier, P and Macquin-Mavier, I and Derumeaux, G and Damy, T and Drouot, X and Covali-Noroc, A and Boczkowski, J and Bastuji-Garin, S and Adnot, S},
title = {Telomere Shortening in Middle-Aged Men with Sleep-disordered Breathing.},
journal = {Annals of the American Thoracic Society},
volume = {13},
number = {7},
pages = {1136-1143},
doi = {10.1513/AnnalsATS.201510-718OC},
pmid = {27163410},
issn = {2325-6621},
mesh = {Adult ; Aging/*genetics ; Comorbidity ; Cross-Sectional Studies ; France ; Humans ; Linear Models ; Male ; Middle Aged ; Models, Genetic ; Multivariate Analysis ; Polysomnography ; Prospective Studies ; Pulse Wave Analysis ; Severity of Illness Index ; Sleep Apnea Syndromes/*genetics/*physiopathology ; *Telomere Shortening ; },
abstract = {RATIONALE: Sleep disorders may lead to stress-induced premature aging and telomere shortening.<br><br>OBJECTIVES: To determine whether obstructive sleep apnea syndrome causing intermittent hypoxemic episodes was associated with telomere shortening independently from the comorbidities associated with this syndrome.<br><br>METHODS: We conducted a cross-sectional study in 161prospectivelly enrolled, untreated, middle-aged men free of known comorbidities related or unrelated to sleep apnea. Each participant underwent full standard overnight polysomnography. Patients with apnea sleep syndrome were naive to treatment.<br><br>MEASUREMENTS AND MAIN RESULTS: In univariate analysis, we found that telomere shortening was associated with older age, apnea-hypopnea index, oxygen desaturation index, waist circumference, and fat mass. After adjustment for age, only apnea-hypopnea index and oxygen desaturation index were significantly related to telomere shortening. The mean telomere length ratio was 0.70&#x2009;&#xb1;&#x2009;0.37 in the participants without sleep apnea, compared with 0.61&#x2009;&#xb1;&#x2009;0.22 and 0.53&#x2009;&#xb1;&#x2009;0.16 in those with mild to moderate and severe sleep apnea, respectively (P&#x2009;=&#x2009;0.01). In multivariate analysis, we found that oxygen desaturation index was the only factor independently associated with telomere length. Arterial stiffness assessed by carotid-femoral pulse wave velocity correlated negatively with telomere length.<br><br>CONCLUSIONS: Intermittent hypoxemia due to obstructive sleep apnea syndrome is a major contributor to telomere shortening in middle-aged men. Oxidative stress may explain this finding.},
}
@article {pmid27157420,
year = {2016},
author = {Carulli, L and Anzivino, C and Baldelli, E and Zenobii, MF and Rocchi, MB and Bertolotti, M},
title = {Telomere length elongation after weight loss intervention in obese adults.},
journal = {Molecular genetics and metabolism},
volume = {118},
number = {2},
pages = {138-142},
doi = {10.1016/j.ymgme.2016.04.003},
pmid = {27157420},
issn = {1096-7206},
mesh = {Adolescent ; Adult ; Aging/genetics ; Female ; Gastric Balloon ; Genetic Markers ; Humans ; Male ; Middle Aged ; Obesity/*genetics/*therapy ; Statistics, Nonparametric ; Telomere/*genetics ; *Telomere Homeostasis ; Time Factors ; Weight Loss/*genetics ; },
abstract = {INTRODUCTION: Telomeres may be considered markers of biological aging, shorter telomere length is associated with some age-related diseases; in several studies short telomere length has also been associated to obesity in adults and adolescents. However the relationship between telomere complex functions and obesity is still not clear. Aim of the study was to assess telomere length (TL) in adults' obese subjects before and after weight loss obtained by placement of bioenteric intragastric balloon (BIB) for 6months.<br><br>METHODS: We enrolled 42 obese subjects before and after BIB placement as weight loss intervention. Blood samples were collected in order to obtain DNA from leukocyte to measure TL by quantitative PCR.<br><br>RESULTS: Data were analyzed only in 37 subjects with complete data; all presented important body weight loss (124.06&#xb1;26.7 vs 105.40&#xb1;23.14, p<0.001) and more interesting they presented a significant increase in TL (3.58&#xb1;0.83 vs 5.61&#xb1;3.29, p<0.001). Moreover we observed a significant positive correlation between TL elongation and weight loss (r=0.44, p=0.007) as well as an inverse correlation between TL at baseline and TL elongation (r=-0.35, p=0.03).The predictors of TL elongation were once again weight loss and short TL at baseline (respectively p=0.007 and p=0.003).<br><br>CONCLUSIONS: Our study shows that weight loss is associated to telomere lengthening in a positive correlation: the greater weight loss the greater telomere lengthening; moreover telomere lengthening is more significant in those subjects with shortest telomeres at baseline.},
}
@article {pmid27157144,
year = {2016},
author = {Raymond, AR and Brooksbank, RL and Millen, AM and Norton, GR and Solomon, A and Woodiwiss, AJ and Tsang, L and Dessein, PH and Gonzalez-Gay, MA},
title = {Telomere length, endothelial activation and carotid atherosclerosis in black and white African patients with rheumatoid arthritis.},
journal = {Clinical and experimental rheumatology},
volume = {34},
number = {5},
pages = {864-871},
pmid = {27157144},
issn = {0392-856X},
mesh = {Aged ; Antirheumatic Agents/therapeutic use ; Arthritis, Rheumatoid/blood/drug therapy/*ethnology/genetics ; Biomarkers/blood ; *Black People/genetics ; Cardiovascular Agents/therapeutic use ; Carotid Artery Diseases/blood/drug therapy/*ethnology/genetics ; Comorbidity ; Confounding Factors, Epidemiologic ; Cross-Sectional Studies ; Endothelium, Vascular/drug effects/*metabolism ; Female ; Health Status ; Health Status Indicators ; Humans ; Linear Models ; Male ; Middle Aged ; Odds Ratio ; Predictive Value of Tests ; Prognosis ; Risk Factors ; South Africa/epidemiology ; Telomere/drug effects/genetics/*metabolism ; *Telomere Homeostasis/drug effects ; Vascular Cell Adhesion Molecule-1/blood ; *White People/genetics ; },
abstract = {OBJECTIVES: Our objective was to examine associations of traditional and non-traditional cardiovascular risk factors with relative leukocyte telomere length and confounder adjusted relationships of relative telomere length with endothelial activation and carotid atherosclerosis in black and white African patients with rheumatoid arthritis (RA).<br><br>METHODS: Relative telomere length of leukocyte DNA in whole blood was determined using quantitative RT-PCR in 205 (101 black) African patients with RA.<br><br>RESULTS: In demographic characteristic adjusted analysis, relative telomere length tended to be larger in black compared to white patients (median (IQR)=0.54 (0.42-0.54) and 0.48 (0.37-0.60) (p=0.07), respectively). In black patients, waist circumference, systolic, diastolic and mean blood pressure were associated with relative telomere length (&#x3b2; (SE)=-0.00270 (0.00114) (p=0.02), -0.00185 (0.00060) (p=0.003), -0.00243 (0.00112) (p=0.03) and -0.00225 (0.00075) (p=0.003), respectively); in white patients, age, anti-cyclic citrullinated antibody positivity, biologic agent use, a cholesterol-HDL cholesterol ratio of >4 and the number of major traditional risk factors were related to relative telomere length (&#x3b2; (SE) =-0.00242 (0.00113) (p=0.03), 0.06629 (0.03374) (p=0.05), -0.09321 (0.04310) (p=0.03), 0.08225 (0.03420) (p=0.02) and 0.04046 (0.01719) (p=0.02), respectively). One SD increase in relative telomere length was associated with carotid plaque (OR (95% CI)=1.65 (0.99-2.75) (p=0.05)) and vascular cell adhesion molecule-1 concentrations (&#x3b2; (SE)=-0.05031 (0.02480) (p=0.04)) in black and white patients, respectively.<br><br>CONCLUSIONS: This study disclosed paradoxically direct relationships between relative telomere length and cardiovascular risk factors in white and atherosclerosis in black African RA patients. The role of relative telomere length in cardiovascular risk and its stratification in RA requires longitudinal investigation.},
}
@article {pmid27156058,
year = {2016},
author = {Masi, S and D'Aiuto, F and Cooper, J and Salpea, K and Stephens, JW and Hurel, SJ and Deanfield, JE and Humphries, SE},
title = {Telomere length, antioxidant status and incidence of ischaemic heart disease in type 2 diabetes.},
journal = {International journal of cardiology},
volume = {216},
number = {},
pages = {159-164},
pmid = {27156058},
issn = {1874-1754},
support = {MR/K006584/1/MRC_/Medical Research Council/United Kingdom ; RG/08/008/25291/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Antioxidants/*metabolism ; Cellular Senescence ; Diabetes Mellitus, Type 2/*complications ; Female ; Humans ; Incidence ; Male ; Middle Aged ; Myocardial Ischemia/*epidemiology/genetics/metabolism ; Oxidative Stress ; Plasma/chemistry ; Risk Factors ; Telomere/*genetics ; Telomere Homeostasis ; },
abstract = {BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of ischaemic heart disease (IHD). An accelerated process of vascular ageing induced by an increased oxidative stress exposure is suggested as potential pathway accounting for this association. However, no studies have explored the relationship between markers of vascular ageing, measures of oxidative stress and risk of IHD in T2D.<br><br>OBJECTIVES: To explore the association between plasma antioxidant status, marker of cellular ageing (leukocyte telomere length, LTL) and 10years risk of IHD in patients with T2D.<br><br>METHODS: Between 2001 and 2002, 489 Caucasians subjects with T2D were enrolled at the diabetic clinic, University College London Hospital. Plasma total anti-oxidant status (TAOS) and LTL were measured by photometric microassay and RT-PCR, respectively. The incidence of IHD over 10years was determined through linkage with the national clinical audit of acute coronary syndrome in UK.<br><br>RESULTS: At baseline, TAOS was associated with LTL (age adjusted: r=0.106, p=0.024). After 10years, 61 patients developed IHD. Lower TAOS and shorter LTL at baseline predicted an increased IHD risk at follow-up (age adjusted: p=0.033 and p=0.040, respectively). These associations were independent of age, gender, cardiovascular risk factors, circulating levels of CRP and medication differences.<br><br>CONCLUSIONS: Reduced TAOS and short LTL are interrelated pathways which predict risk of IHD in patients with T2D. Our findings suggest that antioxidant defences are important to maintain telomere integrity, potentially reducing the progression of vascular ageing in patients with T2D.},
}
@article {pmid27155138,
year = {2016},
author = {Fillman, T and Shimizu-Furusawa, H and Ng, CFS and Parajuli, RP and Watanabe, C},
title = {Association of cadmium and arsenic exposure with salivary telomere length in adolescents in Terai, Nepal.},
journal = {Environmental research},
volume = {149},
number = {},
pages = {8-14},
doi = {10.1016/j.envres.2016.04.037},
pmid = {27155138},
issn = {1096-0953},
mesh = {Adolescent ; Arsenic/*urine ; Cadmium/*urine ; Child ; *Environmental Exposure ; Female ; Groundwater/analysis ; Humans ; Male ; Nepal ; Saliva/cytology ; Telomere/*drug effects/physiology ; Water Pollutants, Chemical/*toxicity/*urine ; },
abstract = {BACKGROUND: Cadmium and arsenic are ubiquitous metals commonly found in the environment which can harm human health. A growing body of research shows telomere length as a potential biomarker of future disease risk. Few studies have examined the effects of metals on telomere length and none have focused on adolescents.<br><br>OBJECTIVES: In this study, the impact of cadmium and arsenic on salivary telomere length was studied in adolescents in Terai, Nepal.<br><br>METHODS: Adolescents aged 12-16 years old (n=351)were recruited where questionnaire interviews and both saliva and urine collection took place. Telomere length was determined by quantitative polymerase chain reaction using DNA extracted from saliva. Urinary cadmium and arsenic concentration were measured by inductively coupled plasma mass spectrometry. Multivariable linear regression was used to examine associations between urinary metals and salivary telomere length.<br><br>RESULTS: The geometric means and standard deviations of cadmium and arsenic were 0.33&#xb1;0.33&#x3bc;g/g creatinine and 196.0&#xb1;301.1&#x3bc;g/g creatinine, respectively. Urinary cadmium concentration was negatively associated with salivary telomere length after adjustment for confounders (&#x3b2;=-0.24, 95% CI -0.42,-0.07). Arsenic showed positive associations with telomere length but did not reach statistical significance.<br><br>CONCLUSIONS: This is the first study to demonstrate that cadmium may shorten adolescent telomeres, even at exposure levels that may be considered low. These results agree with prior experimental and adult epidemiological studies, and also help identify the mechanism of DNA damage by cadmium. This study expanded current evidence on the harmful effects of cadmium exposure on telomere length even to adolescents.},
}
@article {pmid27154402,
year = {2016},
author = {Moravec, M and Wischnewski, H and Bah, A and Hu, Y and Liu, N and Lafranchi, L and King, MC and Azzalin, CM},
title = {TERRA promotes telomerase-mediated telomere elongation in Schizosaccharomyces pombe.},
journal = {EMBO reports},
volume = {17},
number = {7},
pages = {999-1012},
pmid = {27154402},
issn = {1469-3178},
support = {DP2 OD008429/OD/NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; },
mesh = {DNA-Binding Proteins/genetics/*metabolism ; Gene Expression Regulation, Fungal ; Genome, Fungal ; Poly A ; Protein Binding ; Schizosaccharomyces/*genetics/*metabolism ; Telomerase/*metabolism ; Telomere/*genetics/*metabolism ; *Telomere Homeostasis ; Telomere Shortening ; Transcription, Genetic ; },
abstract = {Telomerase-mediated telomere elongation provides cell populations with the ability to proliferate indefinitely. Telomerase is capable of recognizing and extending the shortest telomeres in cells; nevertheless, how this mechanism is executed remains unclear. Here, we show that, in the fission yeast Schizosaccharomyces pombe, shortened telomeres are highly transcribed into the evolutionarily conserved long noncoding RNA TERRA A fraction of TERRA produced upon telomere shortening is polyadenylated and largely devoid of telomeric repeats, and furthermore, telomerase physically interacts with this polyadenylated TERRA in vivo We also show that experimentally enhanced transcription of a manipulated telomere promotes its association with telomerase and concomitant elongation. Our data represent the first direct evidence that TERRA stimulates telomerase recruitment and activity at chromosome ends in an organism with human-like telomeres.},
}
@article {pmid27147043,
year = {2016},
author = {Link, J and Benavente, R and Alsheimer, M},
title = {Analysis of Meiotic Telomere Behavior in the Mouse.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1411},
number = {},
pages = {195-208},
doi = {10.1007/978-1-4939-3530-7_12},
pmid = {27147043},
issn = {1940-6029},
mesh = {Animals ; Chromosomes, Mammalian ; Female ; In Situ Hybridization, Fluorescence ; Male ; Meiosis/*genetics ; Mice ; Microscopy, Electron ; Nuclear Envelope/metabolism ; Oocytes/metabolism ; Ovary/metabolism ; Spermatocytes/metabolism ; Telomere/*genetics ; *Telomere Homeostasis ; Testis/metabolism ; },
abstract = {Linear eukaryotic chromosomes are capped by the telomeres, which consist of highly repetitive nucleotide sequences bound by several telomere-specific proteins. While the general role of telomeres is to protect chromosomes from degradation and end-to-end fusion, during meiosis they are assigned with a distinct and without doubt highly fascinating function. During meiosis, telomeres attach to the nuclear envelope and mediate characteristic chromosome movements, essential for correct haploidization of the genome. Here, we provide elaborate tools to study telomeres in mammalian meiotic germ cells, which include (co-)immunofluorescence staining procedures on cell spreads and paraffin-embedded tissues. We provide detailed procedures for fluorescence labeling of telomeric DNA (Telo-FISH) to visualize telomeres at the light microscopic level, which we often use in combination with immunofluorescence staining of meiotic proteins. We also present a protocol for detection of telomeric DNA at the electron microscopic level (EM-ISH). We finally describe how meiotic telomeres can be visualized by common electron microscopic methods and how they can be analyzed at the ultrastructural level by immunogold labeling of telomere components or associated structures.},
}
@article {pmid27146145,
year = {2017},
author = {Ziegler, S and Schettgen, T and Beier, F and Wilop, S and Quinete, N and Esser, A and Masouleh, BK and Ferreira, MS and Vankann, L and Uciechowski, P and Rink, L and Kraus, T and Brümmendorf, TH and Ziegler, P},
title = {Accelerated telomere shortening in peripheral blood lymphocytes after occupational polychlorinated biphenyls exposure.},
journal = {Archives of toxicology},
volume = {91},
number = {1},
pages = {289-300},
pmid = {27146145},
issn = {1432-0738},
mesh = {Biotransformation ; Carcinogens, Environmental/analysis/*toxicity ; Cell Proliferation/drug effects ; Cells, Cultured ; Cohort Studies ; Drug Residues/analysis ; Female ; Gene Expression Regulation, Enzymologic/drug effects ; Germany ; Humans ; Immunologic Surveillance/drug effects ; Kinetics ; Lymphocytes/cytology/*drug effects/metabolism/pathology ; Male ; Occupational Exposure/*adverse effects ; Polychlorinated Biphenyls/blood/metabolism/*toxicity ; Population Surveillance ; Recycling ; Telomerase/antagonists &amp; inhibitors/blood/metabolism ; Telomere Shortening/*drug effects ; Toxicokinetics ; },
abstract = {Polychlorinated biphenyls (PCBs) are organochlorine pollutants with a worldwide dissemination. We examined telomere length (TL) in peripheral blood cells of 207 individuals with a high body burden of PCBs due to occupational exposure in a transformer recycling company. Whereas TL in granulocytes was not affected, the age-adjusted TL in lymphocytes (∆TLLymph) of exposed individuals was significantly shorter than expected [-0.77 kb; 95 % confidence interval (CI) -0.9316; -0.6052; p = 0.0001]. PCB exposure did not affect lymphocyte numbers or T cell receptor excision circle (TREC) levels in T cells, suggesting that PCBs cause loss of telomeric DNA in T cells due to their metabolic activation and antigen-stimulated proliferation. In support of this hypothesis, blood plasma levels of PCB-exposed individuals inhibited expression of telomerase, the telomere elongating enzyme in vitro in antigen-specific T cell proliferation assays. 3-OH-CB28, a downstream metabolite of the lower chlorinated PCB-28 in PCB-exposed individuals (mean blood plasma concentration: 0.185 ± 0.68 ng/mL), inhibited telomerase gene expression within 48 h of incubation in lymphoproliferative assays starting at a concentration of 0.27-6.75 µg/mL and accelerated telomere shortening in long-term cell culture experiments. Accelerated telomere shortening due to PCB exposure may lead to limitations of cell renewal and clonal expansion of lymphocyte populations. As PCB-related immune dysfunctions have been linked to increased susceptibility to infectious diseases and increased risk of cancer, our data provide a possible explanation, for how PCBs could promote infections and cancer through limiting immune surveillance.},
}
@article {pmid27138987,
year = {2016},
author = {Raschenberger, J and Lamina, C and Haun, M and Kollerits, B and Coassin, S and Boes, E and Kedenko, L and Köttgen, A and Kronenberg, F},
title = {Influence of DNA extraction methods on relative telomere length measurements and its impact on epidemiological studies.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {25398},
pmid = {27138987},
issn = {2045-2322},
mesh = {Adult ; DNA/chemistry/*genetics/*isolation &amp; purification ; DNA Fingerprinting/methods ; Epidemiologic Studies ; Female ; Humans ; Male ; Telomere/chemistry/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Measurement of telomere length is widely used in epidemiologic studies. Insufficient standardization of the measurements processes has, however, complicated the comparison of results between studies. We aimed to investigate whether DNA extraction methods have an influence on measured values of relative telomere length (RTL) and whether this has consequences for epidemiological studies. We performed four experiments with RTL measurement in quadruplicate by qPCR using DNA extracted with different methods: 1) a standardized validation experiment including three extraction methods (magnetic-particle-method EZ1, salting-out-method INV, phenol-chloroform-isoamyl-alcohol PCI) each in the same 20 samples demonstrated pronounced differences in RTL with lowest values with EZ1 followed by INV and PCI-isolated DNA; 2) a comparison of 307 samples from an epidemiological study showing EZ1-measurements 40% lower than INV-measurements; 3) a matching-approach of two similar non-diseased control groups including 143 pairs of subjects revealed significantly shorter RTL in EZ1 than INV-extracted DNA (0.844 ± 0.157 vs. 1.357 ± 0.242); 4) an association analysis of RTL with prevalent cardiovascular disease detected a stronger association with INV than with EZ1-extracted DNA. In summary, DNA extraction methods have a pronounced influence on the measured RTL-values. This might result in spurious or lost associations in epidemiological studies under certain circumstances.},
}
@article {pmid27135574,
year = {2016},
author = {Blévin, P and Angelier, F and Tartu, S and Ruault, S and Bustamante, P and Herzke, D and Moe, B and Bech, C and Gabrielsen, GW and Bustnes, JO and Chastel, O},
title = {Exposure to oxychlordane is associated with shorter telomeres in arctic breeding kittiwakes.},
journal = {The Science of the total environment},
volume = {563-564},
number = {},
pages = {125-130},
doi = {10.1016/j.scitotenv.2016.04.096},
pmid = {27135574},
issn = {1879-1026},
mesh = {Animals ; Arctic Regions ; Charadriiformes/*genetics/metabolism ; Chlordan/*analogs &amp; derivatives/toxicity ; Female ; Insecticides/toxicity ; Male ; Polychlorinated Biphenyls/*toxicity ; Svalbard ; Telomere Shortening/*drug effects ; Water Pollutants, Chemical/*toxicity ; },
abstract = {Telomeres are DNA-protein complexes located at the end of chromosomes, which play an important role in maintaining the genomic integrity. Telomeres shorten at each cell division and previous studies have shown that telomere length is related to health and lifespan and can be affected by a wide range of environmental factors. Among them, some persistent organic pollutants (POPs) have the potential to damage DNA. However, the effect of POPs on telomeres is poorly known for wildlife. Here, we investigated the relationships between some legacy POPs (organochlorine pesticides and polychlorobiphenyls) and telomere length in breeding adult black-legged kittiwakes (Rissa tridactyla), an arctic seabird species. Our results show that among legacy POPs, only blood concentration of oxychlordane, the major metabolite of chlordane mixture, is associated with shorter telomere length in females but not in males. This suggests that female kittiwakes could be more sensitive to oxychlordane, potentially explaining the previously reported lower survival rate in most oxychlordane-contaminated kittiwakes from the same population. This study is the first to report a significant and negative relationship between POPs and telomere length in a free-living bird and highlights sex-related susceptibility to banned pesticides.},
}
@article {pmid27134164,
year = {2016},
author = {Churikov, D and Charifi, F and Eckert-Boulet, N and Silva, S and Simon, MN and Lisby, M and Géli, V},
title = {SUMO-Dependent Relocalization of Eroded Telomeres to Nuclear Pore Complexes Controls Telomere Recombination.},
journal = {Cell reports},
volume = {15},
number = {6},
pages = {1242-1253},
doi = {10.1016/j.celrep.2016.04.008},
pmid = {27134164},
issn = {2211-1247},
mesh = {Nuclear Pore/*metabolism ; Protein Binding ; *Recombination, Genetic ; Saccharomyces cerevisiae/growth &amp; development/*metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Small Ubiquitin-Related Modifier Proteins/*metabolism ; Sumoylation ; Telomerase/metabolism ; Telomere/*metabolism ; Ubiquitin-Protein Ligases/metabolism ; },
abstract = {In budding yeast, inactivation of telomerase and ensuing telomere erosion cause relocalization of telomeres to nuclear pore complexes (NPCs). However, neither the mechanism of such relocalization nor its significance are understood. We report that proteins bound to eroded telomeres are recognized by the SUMO (small ubiquitin-like modifier)-targeted ubiquitin ligase (STUbL) Slx5-Slx8 and become increasingly SUMOylated. Recruitment of Slx5-Slx8 to eroded telomeres facilitates telomere relocalization to NPCs and type II telomere recombination, a counterpart of mammalian alternative lengthening of telomeres (ALT). Moreover, artificial tethering of a telomere to a NPC promotes type II telomere recombination but cannot bypass the lack of Slx5-Slx8 in this process. Together, our results indicate that SUMOylation positively contributes to telomere relocalization to the NPC, where poly-SUMOylated proteins that accumulated over time have to be removed. We propose that STUbL-dependent relocalization of telomeres to NPCs constitutes a pathway in which excessively SUMOylated proteins are removed from "congested" intermediates to ensure unconventional recombination.},
}
@article {pmid27131910,
year = {2016},
author = {Czepielewski, LS and Massuda, R and Panizzutti, B and da Rosa, ED and de Lucena, D and Macêdo, D and Grun, LK and Barbé-Tuana, FM and Gama, CS},
title = {Telomere length in subjects with schizophrenia, their unaffected siblings and healthy controls: Evidence of accelerated aging.},
journal = {Schizophrenia research},
volume = {174},
number = {1-3},
pages = {39-42},
doi = {10.1016/j.schres.2016.04.004},
pmid = {27131910},
issn = {1573-2509},
mesh = {Adolescent ; Adult ; Aging/metabolism ; Analysis of Variance ; Antipsychotic Agents/therapeutic use ; Body Mass Index ; Educational Status ; Endophenotypes ; Female ; Humans ; Interview, Psychological ; Male ; Middle Aged ; Psychiatric Status Rating Scales ; Schizophrenia/diagnosis/drug therapy/*metabolism ; *Siblings ; Telomere/metabolism ; *Telomere Shortening ; Young Adult ; },
abstract = {Schizophrenia (SZ) is associated with broad burden. The clinical manifestations of SZ are related to pathophysiological alterations similar to what is seen in normal aging. Our aim was to evaluate the differences in telomere length (TL), a biomarker of cellular aging, in subjects with SZ (n=36), unaffected siblings (SB, n=36) and healthy controls (HC, n=47). SZ had shorter TL compared to HC, but no difference was found in SB comparing to SZ. These findings indicate that a pathological accelerated aging profile could be present in the course of SZ and further studies are needed to confirm TL as potential endophenotype, especially in at risk populations.},
}
@article {pmid27131360,
year = {2016},
author = {Huang, SH and Kobryn, K},
title = {The Borrelia burgdorferi telomere resolvase, ResT, anneals ssDNA complexed with its cognate ssDNA-binding protein.},
journal = {Nucleic acids research},
volume = {44},
number = {11},
pages = {5288-5298},
pmid = {27131360},
issn = {1362-4962},
mesh = {Bacterial Proteins/chemistry/*metabolism ; Borrelia burgdorferi/*physiology ; DNA, Bacterial/*metabolism ; DNA, Single-Stranded/*metabolism ; DNA-Binding Proteins/chemistry/*metabolism ; Endodeoxyribonucleases/chemistry/*metabolism ; Protein Binding ; Protein Interaction Domains and Motifs ; },
abstract = {Spirochetes of the genus Borrelia possess unusual genomes that consist in a linear chromosome and multiple linear and circular plasmids. The linear replicons are terminated by covalently closed hairpin ends, referred to as hairpin telomeres. The hairpin telomeres represent a simple solution to the end-replication problem. Deoxyribonucleic acid replication initiates internally and proceeds bidirectionally toward the hairpin telomeres. The telomere resolvase, ResT, forms the hairpin telomeres from replicated telomere intermediates in a reaction with similarities to those promoted by type IB topoisomerases and tyrosine recombinases. ResT has also been shown to possess DNA single-strand annealing activity. We report here that ResT promotes single-strand annealing of both free DNA strands and ssDNA complexed with single-stranded DNA binding protein (SSB). The annealing of complementary strands bound by SSB requires a ResT-SSB interaction that is mediated by the conserved amphipathic C-terminal tail of SSB. These properties of ResT are similar to those demonstrated for the recombination mediator protein, RecO, of the RecF pathway. Borrelia burgdorferi is unusual in lacking identifiable homologs of the RecFOR proteins. We propose that ResT may provide missing RecFOR functions.},
}
@article {pmid27122604,
year = {2016},
author = {Laporte, D and Courtout, F and Tollis, S and Sagot, I},
title = {Quiescent Saccharomyces cerevisiae forms telomere hyperclusters at the nuclear membrane vicinity through a multifaceted mechanism involving Esc1, the Sir complex, and chromatin condensation.},
journal = {Molecular biology of the cell},
volume = {27},
number = {12},
pages = {1875-1884},
pmid = {27122604},
issn = {1939-4586},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Adenosine Triphosphatases/metabolism ; Chromatin/metabolism/physiology ; Chromatin Assembly and Disassembly/physiology ; DNA-Binding Proteins/metabolism ; G1 Phase ; Heterochromatin/metabolism ; Histones/metabolism ; Multiprotein Complexes/metabolism ; Nuclear Envelope/metabolism/physiology ; Nuclear Proteins/genetics/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Telomere/*metabolism/*physiology ; },
abstract = {Like other eukaryotes, Saccharomyces cerevisiae spatially organizes its chromosomes within the nucleus. In G1 phase, the yeast's 32 telomeres are clustered into 6-10 foci that dynamically interact with the nuclear membrane. Here we show that, when cells leave the division cycle and enter quiescence, telomeres gather into two to three hyperclusters at the nuclear membrane vicinity. This localization depends on Esc1 but not on the Ku proteins. Telomere hypercluster formation requires the Sir complex but is independent of the nuclear microtubule bundle that specifically assembles in quiescent cells. Importantly, mutants deleted for the linker histone H1 Hho1 or defective in condensin activity or affected for histone H4 Lys-16 deacetylation are impaired, at least in part, for telomere hypercluster formation in quiescence, suggesting that this process involves chromosome condensation. Finally, we establish that telomere hypercluster formation is not necessary for quiescence establishment, maintenance, and exit, raising the question of the physiological raison d'être of this nuclear reorganization.},
}
@article {pmid27118469,
year = {2016},
author = {Sarkar, J and Liu, Y},
title = {Fanconi anemia proteins in telomere maintenance.},
journal = {DNA repair},
volume = {43},
number = {},
pages = {107-112},
pmid = {27118469},
issn = {1568-7856},
support = {Z01 AG000744-01//Intramural NIH HHS/United States ; },
mesh = {Animals ; Chromosomes, Human/chemistry/metabolism ; DNA/*genetics/metabolism ; DNA Breaks, Double-Stranded ; DNA Repair ; DNA Replication ; Fanconi Anemia/*genetics/metabolism/pathology ; Fanconi Anemia Complementation Group Proteins/*genetics/metabolism ; Genomic Instability ; Humans ; Nucleic Acid Conformation ; Shelterin Complex ; Telomere/chemistry/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {Mammalian chromosome ends are protected by nucleoprotein structures called telomeres. Telomeres ensure genome stability by preventing chromosome termini from being recognized as DNA damage. Telomere length homeostasis is inevitable for telomere maintenance because critical shortening or over-lengthening of telomeres may lead to DNA damage response or delay in DNA replication, and hence genome instability. Due to their repetitive DNA sequence, unique architecture, bound shelterin proteins, and high propensity to form alternate/secondary DNA structures, telomeres are like common fragile sites and pose an inherent challenge to the progression of DNA replication, repair, and recombination apparatus. It is conceivable that longer the telomeres are, greater is the severity of such challenges. Recent studies have linked excessively long telomeres with increased tumorigenesis. Here we discuss telomere abnormalities in a rare recessive chromosomal instability disorder called Fanconi Anemia and the role of the Fanconi Anemia pathway in telomere biology. Reports suggest that Fanconi Anemia proteins play a role in maintaining long telomeres, including processing telomeric joint molecule intermediates. We speculate that ablation of the Fanconi Anemia pathway would lead to inadequate aberrant structural barrier resolution at excessively long telomeres, thereby causing replicative burden on the cell.},
}
@article {pmid27116558,
year = {2016},
author = {Burla, R and La Torre, M and Saggio, I},
title = {Mammalian telomeres and their partnership with lamins.},
journal = {Nucleus (Austin, Tex.)},
volume = {7},
number = {2},
pages = {187-202},
pmid = {27116558},
issn = {1949-1042},
mesh = {Animals ; DNA Damage ; DNA Replication ; Disease/genetics ; Humans ; Lamins/*metabolism ; Phenotype ; Telomere/*genetics/*metabolism ; },
abstract = {Chromosome ends are complex structures, which require a panel of factors for their elongation, replication, and protection. We describe here the mechanics of mammalian telomeres, dynamics and maintainance in relation to lamins. Multiple biochemical connections, including association of telomeres to the nuclear envelope and matrix, of telomeric proteins to lamins, and of lamin-associated proteins to chromosome ends, underline the interplay between lamins and telomeres. Paths toward senescence, such as defective telomere replication, altered heterochromatin organization, and impaired DNA repair, are common to lamins' and telomeres' dysfunction. The convergence of phenotypes can be interpreted through a model of dynamic, lamin-controlled functional platforms dedicated to the function of telomeres as fragile sites. The features of telomeropathies and laminopathies, and of animal models underline further overlapping aspects, including the alteration of stem cell compartments. We expect that future studies of basic biology and on aging will benefit from the analysis of this telomere-lamina interplay.},
}
@article {pmid27113195,
year = {2016},
author = {Wang, Y and Wang, X and Flores, ER and Yu, J and Chang, S},
title = {Dysfunctional telomeres induce p53-dependent and independent apoptosis to compromise cellular proliferation and inhibit tumor formation.},
journal = {Aging cell},
volume = {15},
number = {4},
pages = {646-660},
pmid = {27113195},
issn = {1474-9726},
support = {R01 CA160394/CA/NCI NIH HHS/United States ; R01 CA202816/CA/NCI NIH HHS/United States ; U24 DK085532/DK/NIDDK NIH HHS/United States ; R21 CA200506/CA/NCI NIH HHS/United States ; R01 CA134796/CA/NCI NIH HHS/United States ; U01 DK085532/DK/NIDDK NIH HHS/United States ; P30 CA016359/CA/NCI NIH HHS/United States ; R21 CA182280/CA/NCI NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; R01 AG028888/AG/NIA NIH HHS/United States ; U01 DK085570/DK/NIDDK NIH HHS/United States ; },
mesh = {3T3 Cells ; Animals ; *Apoptosis ; B-Lymphocytes/cytology ; Carcinogenesis/*metabolism/*pathology ; *Cell Cycle Checkpoints ; Cell Differentiation ; Cell Proliferation ; Cellular Senescence ; DNA Damage ; DNA-Binding Proteins/metabolism ; Gene Deletion ; Longevity ; Mice ; Sequence Analysis, DNA ; Telomere/*metabolism ; Tumor Protein p73/metabolism ; Tumor Suppressor Protein p53/*metabolism ; },
abstract = {Aging is associated with progressive telomere shortening, resulting in the formation of dysfunctional telomeres that compromise tissue proliferation. However, dysfunctional telomeres can limit tumorigenesis by activating p53-dependent cellular senescence and apoptosis. While activation of both senescence and apoptosis is required for repress tumor formation, it is not clear which pathway is the major tumor suppressive pathway in vivo. In this study, we generated Eμ-myc; Pot1b(∆/∆) mouse to directly compare tumor formation under conditions in which either p53-dependent apoptosis or senescence is activated by telomeres devoid of the shelterin component Pot1b. We found that activation of p53-dependent apoptosis plays a more critical role in suppressing lymphoma formation than p53-dependent senescence. In addition, we found that telomeres in Pot1b(∆/∆) ; p53(-/-) mice activate an ATR-Chk1-dependent DNA damage response to initiate a robust p53-independent, p73-dependent apoptotic pathway that limited stem cell proliferation but suppressed B-cell lymphomagenesis. Our results demonstrate that in mouse models, both p53-dependent and p53-independent apoptosis are important to suppressing tumor formation.},
}
@article {pmid27112383,
year = {2016},
author = {Tempaku, PF and Hirotsu, C and Tufik, S},
title = {The importance of sleep in the association between perceived stress and telomere length.},
journal = {Brain, behavior, and immunity},
volume = {56},
number = {},
pages = {412},
doi = {10.1016/j.bbi.2016.04.010},
pmid = {27112383},
issn = {1090-2139},
mesh = {Perception ; *Sleep ; Stress, Psychological ; *Telomere ; Telomere Shortening ; },
}
@article {pmid27112382,
year = {2016},
author = {Mathur, MB and Epel, E and Kind, S and Desai, M and Parks, CG and Sandler, DP and Khazeni, N},
title = {Toward a mechanistic understanding of psychosocial factors in telomere degradation.},
journal = {Brain, behavior, and immunity},
volume = {56},
number = {},
pages = {413},
doi = {10.1016/j.bbi.2016.04.011},
pmid = {27112382},
issn = {1090-2139},
mesh = {*Telomere ; *Telomere Homeostasis ; Telomere Shortening ; },
}
@article {pmid27110446,
year = {2016},
author = {Smearman, EL and Yu, T and Brody, GH},
title = {Variation in the oxytocin receptor gene moderates the protective effects of a family-based prevention program on telomere length.},
journal = {Brain and behavior},
volume = {6},
number = {2},
pages = {e00423},
pmid = {27110446},
issn = {2162-3279},
support = {P30 DA027827/DA/NIDA NIH HHS/United States ; T32 GM008169/GM/NIGMS NIH HHS/United States ; },
mesh = {Adolescent ; Black or African American/genetics ; Anger ; Female ; Follow-Up Studies ; *Gene-Environment Interaction ; Genetic Variation ; Humans ; Male ; *Parent-Child Relations ; Parenting ; Receptors, Oxytocin/*genetics ; Stress, Psychological/*genetics/*therapy ; Telomere/metabolism ; *Telomere Shortening ; Treatment Outcome ; Young Adult ; },
abstract = {INTRODUCTION: Parent-child relationships with high conflict and low warmth and support are associated with later adverse behavioral and physiological child outcomes. These outcomes include shorter telomere lengths, the repetitive sequences at the ends of chromosomes that have been utilized as a biomarker for chronic stress. Our research group furthered this by exploring telomere length outcomes following a family-based prevention program and identified reduced telomere shortening 5 years post intervention among those originally exposed to nonsupportive parenting and randomized to the intervention condition. However, not all individuals respond equally, and a growing literature suggests genetic sensitivity to one's environment, with variations in the oxytocin receptor gene (OXTR) potentially influencing this sensitivity.<br><br>METHODS: We utilized data from African American youths (mean age 17) randomized to intervention (n&#xa0;=&#xa0;100) or control condition (n&#xa0;=&#xa0;91) with baseline assessments of genetic status and nonsupportive parenting, and 5-year follow-up assessments of telomere length.<br><br>RESULTS: We found a significant three-way interaction between nonsupportive parenting, intervention condition, and OXTR rs53576 genotype. OXTR GG individuals, who are suggested to be more sensitive to their social environment, exhibited significantly more variability, evidencing the shortest telomeres when exposed to nonsupportive parenting and randomized to the control condition, and similar telomere lengths to non at-risk groups when randomized to the intervention. In contrast, those with the A allele showed no statistical difference in telomere lengths across parental and intervention conditions. Subsequent analyses suggest that these findings may be mediated through chronic anger, whereby GG individuals exposed to nonsupportive parenting and randomized to the control condition had a greater increase in chronic anger by study follow-up, compared to those in the intervention, and this change associated with greater telomere shortening.<br><br>CONCLUSIONS: These findings highlight the importance of individual differences and potential role of genetic status in moderating the relationship between environmental contexts and biological outcomes.},
}
@article {pmid27102052,
year = {2016},
author = {Guzzardi, MA and Iozzo, P and Salonen, MK and Kajantie, E and Eriksson, JG},
title = {Maternal adiposity and infancy growth predict later telomere length: a longitudinal cohort study.},
journal = {International journal of obesity (2005)},
volume = {40},
number = {7},
pages = {1063-1069},
pmid = {27102052},
issn = {1476-5497},
mesh = {Adiposity/*genetics ; Age Factors ; Aged ; Aging ; Body Mass Index ; Female ; Finland/epidemiology ; Humans ; Infant ; Leukocytes/*metabolism ; Longitudinal Studies ; Male ; Obesity/*epidemiology/genetics ; Real-Time Polymerase Chain Reaction ; Risk Factors ; Telomere/*genetics ; Telomere Shortening ; Time Factors ; Weight Gain/*genetics ; },
abstract = {BACKGROUND/OBJECTIVES: Maternal overweight and obesity during pregnancy, and childhood growth patterns are risk factors influencing long-term health outcomes among the offspring. Furthermore, poor health condition has been associated with shorter leukocyte telomere length in adult subjects. We aimed to assess whether maternal adiposity during pregnancy and growth trajectory during infancy predict leukocyte telomere length (LTL) in later life.<br><br>SUBJECTS/METHODS: We studied a cohort of 1082 subjects belonging to the Helsinki Birth Cohort Study, born between 1934 and 1944. They underwent two clinical visits 10 years apart (2001-2004 and 2011-2013), during which LTL and anthropometrics were assessed. Birth records included birth weight, length, maternal body mass index (BMI) at the end of pregnancy. Serial measurements of height and weight from birth to 11 years were available.<br><br>RESULTS: Higher maternal BMI was associated with shorter LTL in elderly women (r=-0.102, P=0.024) but not in men. Also, in women but not in men shorter LTL and greater telomere shortening over a 10-year interval were predicted by higher weight at 12 months of age (P=0.008 and P=0.029, respectively), and higher weight gain during the first 12 months of life (P=0.008 and P=0.006, respectively), particularly between 6 and 9 months of age (P=0.002 for both LTL and LTL shortening rate). A correlation between younger age at adiposity rebound and shorter LTL at 60 years (P=0.022) was also found.<br><br>CONCLUSIONS: High maternal adiposity during pregnancy is associated with shorter LTL in elderly female offspring, but not in men. Moreover, higher weight and weight gain during the first year of life and younger age at adiposity rebound predict shorter LTL in older age in women, suggesting that rapid growth during the perinatal period accelerates cellular aging in late adulthood.},
}
@article {pmid27101289,
year = {2016},
author = {Sepsiova, R and Necasova, I and Willcox, S and Prochazkova, K and Gorilak, P and Nosek, J and Hofr, C and Griffith, JD and Tomaska, L},
title = {Evolution of Telomeres in Schizosaccharomyces pombe and Its Possible Relationship to the Diversification of Telomere Binding Proteins.},
journal = {PloS one},
volume = {11},
number = {4},
pages = {e0154225},
pmid = {27101289},
issn = {1932-6203},
support = {P01 CA019014/CA/NCI NIH HHS/United States ; R01 ES013773/ES/NIEHS NIH HHS/United States ; R01 GM031819/GM/NIGMS NIH HHS/United States ; R56 ES013773/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA-Binding Proteins/genetics/metabolism/ultrastructure ; Electrophoretic Mobility Shift Assay ; Evolution, Molecular ; Fluorescence Polarization ; Genetic Variation ; Humans ; Microscopy, Electron ; Oligonucleotides/genetics/metabolism ; Phylogeny ; Protein Binding ; Schizosaccharomyces/*genetics ; Schizosaccharomyces pombe Proteins/*genetics/metabolism/ultrastructure ; Telomere/*genetics/metabolism/ultrastructure ; Telomere-Binding Proteins/classification/*genetics/metabolism/ultrastructure ; Transcription Factors/genetics/metabolism/ultrastructure ; },
abstract = {Telomeres of nuclear chromosomes are usually composed of an array of tandemly repeated sequences that are recognized by specific Myb domain containing DNA-binding proteins (telomere-binding proteins, TBPs). Whereas in many eukaryotes the length and sequence of the telomeric repeat is relatively conserved, telomeric sequences in various yeasts are highly variable. Schizosaccharomyces pombe provides an excellent model for investigation of co-evolution of telomeres and TBPs. First, telomeric repeats of S. pombe differ from the canonical mammalian type TTAGGG sequence. Second, S. pombe telomeres exhibit a high degree of intratelomeric heterogeneity. Third, S. pombe contains all types of known TBPs (Rap1p [a version unable to bind DNA], Tay1p/Teb1p, and Taz1p) that are employed by various yeast species to protect their telomeres. With the aim of reconstructing evolutionary paths leading to a separation of roles between Teb1p and Taz1p, we performed a comparative analysis of the DNA-binding properties of both proteins using combined qualitative and quantitative biochemical approaches. Visualization of DNA-protein complexes by electron microscopy revealed qualitative differences of binding of Teb1p and Taz1p to mammalian type and fission yeast telomeres. Fluorescence anisotropy analysis quantified the binding affinity of Teb1p and Taz1p to three different DNA substrates. Additionally, we carried out electrophoretic mobility shift assays using mammalian type telomeres and native substrates (telomeric repeats, histone-box sequences) as well as their mutated versions. We observed relative DNA sequence binding flexibility of Taz1p and higher binding stringency of Teb1p when both proteins were compared directly to each other. These properties may have driven replacement of Teb1p by Taz1p as the TBP in fission yeast.},
}
@article {pmid27092174,
year = {2016},
author = {Runge, KW and Lustig, AJ},
title = {Editorial: The Evolving Telomeres.},
journal = {Frontiers in genetics},
volume = {7},
number = {},
pages = {50},
pmid = {27092174},
issn = {1664-8021},
support = {R01 AG051601/AG/NIA NIH HHS/United States ; R01 GM069943/GM/NIGMS NIH HHS/United States ; R56 GM069943/GM/NIGMS NIH HHS/United States ; },
}
@article {pmid27091133,
year = {2016},
author = {Forero, DA and González-Giraldo, Y and López-Quintero, C and Castro-Vega, LJ and Barreto, GE and Perry, G},
title = {Meta-analysis of Telomere Length in Alzheimer's Disease.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {71},
number = {8},
pages = {1069-1073},
pmid = {27091133},
issn = {1758-535X},
support = {G12 MD007591/MD/NIMHD NIH HHS/United States ; T32 DA021129/DA/NIDA NIH HHS/United States ; },
mesh = {*Aging ; Alzheimer Disease/*genetics ; Evidence-Based Medicine ; Humans ; Risk Factors ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a common and severe neurodegenerative disorder. Human telomeres are fundamental for the maintenance of genomic stability and play prominent roles in both cellular senescence and organismal aging. Regulation of telomere length (TL) is the result of the complex interplay between environmental and genetic factors. Alterations in TL are increasingly being studied as a possible risk factor for AD, and published studies on TL in AD show discrepant results, highlighting the need for a meta-analysis.<br><br>METHODS: In the current study, we carried out a meta-analysis of published studies of TL in AD patients and healthy controls. PubMed, Web of Science and Google Scholar databases (from inception to September 2015) were used to identify relevant articles reporting TL in humans with AD, from which we retrieved data such as sample size, experimental methods, and mean TL for cases and controls. A random-effects model was used for meta-analytical procedures.<br><br>RESULTS: The meta-analysis included 13 primary studies and demonstrated a significant difference in TL between 860 AD patients and 2,022 controls, with a standardized mean difference of -0.984 (confidence interval: -1.433 to -0.535; p value: <.001).<br><br>CONCLUSIONS: Our results show a consistent evidence of shorter telomeres in AD patients and highlight the importance of the analysis of epigenomic markers associated with neurodegeneration and with the risk for common and severe neurological diseases, such as AD.},
}
@article {pmid27085557,
year = {2016},
author = {Shekhani, MT and Barber, JR and Bezerra, SM and Heaphy, CM and Gonzalez Roibon, ND and Taheri, D and Reis, LO and Guner, G and Joshu, CE and Netto, GJ and Meeker, AK},
title = {High-resolution telomere fluorescence in situ hybridization reveals intriguing anomalies in germ cell tumors.},
journal = {Human pathology},
volume = {54},
number = {},
pages = {106-112},
doi = {10.1016/j.humpath.2016.03.015},
pmid = {27085557},
issn = {1532-8392},
support = {R01 CA172380/CA/NCI NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing/analysis ; Adult ; Biomarkers, Tumor/analysis/*genetics ; Carcinoma in Situ/chemistry/*genetics/pathology/surgery ; Co-Repressor Proteins ; DNA Helicases/analysis ; Fluorescent Antibody Technique ; Humans ; *In Situ Hybridization, Fluorescence ; Male ; Molecular Chaperones ; Neoplasms, Germ Cell and Embryonal/chemistry/*genetics/pathology/surgery ; Nuclear Proteins/analysis ; Octamer Transcription Factor-3/analysis ; Seminoma/chemistry/*genetics/pathology/surgery ; Telomere/chemistry/*genetics ; Telomere Homeostasis ; Telomere Shortening ; Testicular Neoplasms/chemistry/*genetics/pathology/surgery ; X-linked Nuclear Protein ; Young Adult ; },
abstract = {Testicular germ cell tumor (TGCT) is the most common malignancy of young men. Most patients are completely cured, which distinguishes these from most other malignancies. Orchiectomy specimens (n=76) were evaluated using high-resolution (single-cell discriminative) telomere-specific fluorescence in situ hybridization (FISH) with simultaneous Oct4 immunofluorescence to describe telomere length phenotype in TGCT neoplastic cells. For the first time, the TGCT precursor lesion, germ cell neoplasia in situ (GCNIS) is also evaluated in depth. The intensity of the signals from cancerous cells was compared to the same patient's reference cells-namely, healthy germ cells (defined as "medium" length) and interstitial/somatic cells (defined as "short" telomere length). We observed short telomeres in most GCNIS and pure seminomas (P=.006 and P=.0005, respectively). In contrast, nonseminomas displayed longer telomeres. Lesion-specific telomere lengths were documented in mixed tumor cases. Embryonal carcinoma (EC) demonstrated the longest telomeres. A fraction of EC displays the telomerase-independent alternative lengthening of telomeres (ALT) phenotype (24% of cases). Loss of ATRX or DAXX nuclear expression was strongly associated with ALT; however, nuclear expression of both proteins was retained in half of ALT-positive ECs. The particular distribution of telomere lengths among TGCT and GCNIS precursors implicate telomeres anomalies in pathogenesis. These results may advise management decisions as well.},
}
@article {pmid27084675,
year = {2016},
author = {Borghini, A and Faita, F and Mercuri, A and Minichilli, F and Bustaffa, E and Bianchi, F and Andreassi, MG},
title = {Arsenic exposure, genetic susceptibility and leukocyte telomere length in an Italian young adult population.},
journal = {Mutagenesis},
volume = {31},
number = {5},
pages = {539-546},
doi = {10.1093/mutage/gew017},
pmid = {27084675},
issn = {1464-3804},
mesh = {Adult ; Arsenic/metabolism/*toxicity/urine ; DNA/drug effects/metabolism ; DNA Damage ; DNA Glycosylases/*genetics/metabolism ; DNA Repair ; DNA-Binding Proteins/*genetics/metabolism ; Drug Tolerance/genetics ; Environmental Exposure ; Female ; *Gene-Environment Interaction ; Glutathione Transferase/genetics/metabolism ; Humans ; Italy ; Leukocytes/metabolism/*physiology ; Male ; *Polymorphism, Single Nucleotide ; Telomere/*drug effects/metabolism ; X-ray Repair Cross Complementing Protein 1 ; },
abstract = {Arsenic-induced health effects may be associated with critically shortened telomeres. However, few data are available on the effects of arsenic exposure on telomere length. The aim of this study was to investigate the effects of chronic arsenic exposure on leukocyte telomere length (LTL) as well as the contribution of common polymorphisms in genes implicated in arsenic metabolism (GSTT1 and GSTM1) and DNA repair (hOGG1 and XRCC1). A group of 241 healthy subjects was enrolled from four areas of Italy known to be affected by natural or anthropogenic arsenic pollution. Urine samples were tested for inorganic As (iAs), monomethylarsinic (MMA) and dimethylarsinic acid (DMA). LTL was evaluated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Genotyping was carried out by PCR-RFLP on leukocyte DNA. In multiple linear regression analysis, LTL was significantly and inversely correlated with age (β = -0.231, P = 0.006) and showed a certain trend toward significance with iAs urinary concentration (log10 iAs, β = -0.106, P = 0.08). The genotype distribution showed significant associations between GSTT1 and the As concentration (log10 iAs, P = 0.01) and metabolite patterns (log10 DMA, P = 0.05) in the urine. However, GST genes did not interact with arsenic exposure in the modulation of LTL. Conversely, the combined presence of a higher level of iAs + MMA + DMA ≥ 19.3 μg/l (F = 6.0, P interaction = 0.01), Asi ≥ 3.86 (F = 3.9, P interaction = 0.04) μg/l, iAs + MMA + DMA ≥ 15 μg/l (F = 4.2, P interaction = 0.04) and hOGG1 Cys allele was associated with a significantly lower LTL. An interaction between XRCC1 Arg399Gln and arsenic exposure was also observed (all P interaction = 0.04). These findings suggest that telomere shortening may represent a mechanism that contributes to arsenic-related disease. The interaction of hOGG1 and XRCC1 DNA repair polymorphisms and exposure enhances telomeric DNA damage. Future studies are warranted to understand better the epidemiologic impact of arsenic on telomere function as well as to identify the subgroups of exposed subjects who need better health surveillance.},
}
@article {pmid27084304,
year = {2016},
author = {Squassina, A and Pisanu, C and Congiu, D and Caria, P and Frau, D and Niola, P and Melis, C and Baggiani, G and Lopez, JP and Cruceanu, C and Turecki, G and Severino, G and Bocchetta, A and Vanni, R and Chillotti, C and Del Zompo, M},
title = {Leukocyte telomere length positively correlates with duration of lithium treatment in bipolar disorder patients.},
journal = {European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology},
volume = {26},
number = {7},
pages = {1241-1247},
doi = {10.1016/j.euroneuro.2016.03.020},
pmid = {27084304},
issn = {1873-7862},
mesh = {Adult ; Age Factors ; Antimanic Agents/*therapeutic use ; Bipolar Disorder/*drug therapy/genetics/*metabolism ; Cell Line ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes/drug effects/metabolism ; Lithium Compounds/*therapeutic use ; Male ; Middle Aged ; Neural Stem Cells/drug effects/metabolism ; Polymerase Chain Reaction ; Sex Factors ; Telomerase/metabolism ; Telomere/*drug effects/*metabolism ; Telomere Shortening/drug effects ; Time Factors ; },
abstract = {Bipolar disorder (BD) has been suggested to be associated with accelerated aging and premature cell senescence. While findings on shorter telomeres in BD are controversial, a recent study showed that long-term lithium treatment correlates with longer telomeres in BD. In our study, we sought to investigate the correlation between leukocyte telomere length (LTL) and long-term lithium treatment in a sample of 200 BD patients characterized for lithium response. We also compared data from two different methods commonly used to measure telomere length, quantitative PCR (qPCR) and quantitative fluorescence in situ hybridization (Q-FISH). We also measured, for the first time, the effect of lithium in vitro on the expression of the telomerase gene in human-derived neural progenitor cells (NPCs). Our findings showed that LTL correlated negatively with age (p=0.0002) and was independent of sex, diagnosis, age at onset, suicidal behavior, number of mood episodes, response to lithium and use of other psychotropic medications. After correcting for age, LTL was positively correlated with lithium treatment duration in patients treated for more than two years (n=150, R=0.17, p=0.037). There was a significant correlation between data measured with qPCR and Q-FISH (p=0.012, R=0.826). Lithium treatment increased telomerase expression in NPCs, though this effect was not statistically significant. Our data support previous findings showing that long-term lithium treatment associates with longer telomeres in BD, though this effect appeared to be independent from clinical response to the treatment. Moreover, we suggested for the first time that lithium increases the expression of telomerase gene in human neural progenitor cells.},
}
@article {pmid27083496,
year = {2016},
author = {García-Calzón, S and Martínez-González, MA and Razquin, C and Arós, F and Lapetra, J and Martínez, JA and Zalba, G and Marti, A},
title = {Mediterranean diet and telomere length in high cardiovascular risk subjects from the PREDIMED-NAVARRA study.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {35},
number = {6},
pages = {1399-1405},
doi = {10.1016/j.clnu.2016.03.013},
pmid = {27083496},
issn = {1532-1983},
mesh = {Aged ; Aged, 80 and over ; Body Mass Index ; Cardiovascular Diseases/*epidemiology ; Cross-Sectional Studies ; Diet, Fat-Restricted ; *Diet, Mediterranean ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Nuts ; Olive Oil ; Risk Factors ; Telomere/*metabolism/*ultrastructure ; Telomere Shortening ; },
abstract = {BACKGROUND &amp; AIMS: A healthy lifestyle has been associated with longer telomeres, but whether Mediterranean Diet (MeDiet) affect telomere length (TL) has not been fully elucidated yet. Our aim was to assess the relationship between MeDiet and TL in high cardiovascular risk subjects in the context of a randomized nutritional intervention trial.<br><br>METHODS: We assessed 520 participants (55-80 years, 55% women) from the PREDIMED-NAVARRA trial. Leukocyte TL was measured by qPCR at baseline and after 5 years of a dietary intervention program where subjects were randomly assigned to a low-fat control diet or to two MeDiets, one supplemented with extra virgin olive oil (MeDiet-EVOO) and the other with mixed nuts (MeDiet-nuts). A validated 14-item questionnaire was used to appraise baseline adherence of participants to the MeDiet.<br><br>RESULTS: Better adherence to MeDiet (as appraised by the 14-item score) was associated with longer basal telomeres in women in the baseline cross-sectional analysis, whereas the opposite was observed in men (P interaction&#xa0;=&#xa0;0.036). Female subjects who scored 10 points had longer basal telomeres (0.27, 95% CI: 0.03-0.52) than women scoring &#x2264;6 points at the beginning of the study (-0.46, 95% CI:&#xa0;-0.85 to&#xa0;-0.7) (P&#xa0;=&#xa0;0.003). However, allocation to the MeDiet-nuts group (-0.24, 95% CI:&#xa0;-0.38 to&#xa0;-0.01) was associated with a higher risk of telomere shortening after 5 years of intervention, whereas no differences were found for the MeDiet-EVOO group (0.14, 95% CI: 0.02-0.27), in comparison with the Control group (0.07, 95% CI:&#xa0;-0.08 to 0.23) (P&#xa0;=&#xa0;0.003 and P&#xa0;=&#xa0;0.537, respectively).<br><br>CONCLUSION: A greater baseline adherence to a Mediterranean dietary pattern was associated with longer telomeres only in women. No beneficial effect of the intervention with the MeDiet for the prevention of telomere shortening in comparison with a low-fat diet was observed.},
}
@article {pmid27082536,
year = {2016},
author = {Birch, J and Victorelli, S and Rahmatika, D and Anderson, RK and Jiwa, K and Moisey, E and Ward, C and Fisher, AJ and De Soyza, A and Passos, JF},
title = {Telomere Dysfunction and Senescence-associated Pathways in Bronchiectasis.},
journal = {American journal of respiratory and critical care medicine},
volume = {193},
number = {8},
pages = {929-932},
pmid = {27082536},
issn = {1535-4970},
support = {BB/H022384/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MR/K006312/1/MRC_/Medical Research Council/United Kingdom ; MR/L011263/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Bronchiectasis/*pathology ; *Cellular Senescence ; Female ; Humans ; Male ; Middle Aged ; Telomere/*pathology ; },
}
@article {pmid27081482,
year = {2016},
author = {Bär, C and Blasco, MA},
title = {Telomeres and telomerase as therapeutic targets to prevent and treat age-related diseases.},
journal = {F1000Research},
volume = {5},
number = {},
pages = {},
pmid = {27081482},
issn = {2046-1402},
abstract = {Telomeres, the protective ends of linear chromosomes, shorten throughout an individual's lifetime. Telomere shortening is a hallmark of molecular aging and is associated with premature appearance of diseases associated with aging. Here, we discuss the role of telomere shortening as a direct cause for aging and age-related diseases. In particular, we draw attention to the fact that telomere length influences longevity. Furthermore, we discuss intrinsic and environmental factors that can impact on human telomere erosion. Finally, we highlight recent advances in telomerase-based therapeutic strategies for the treatment of diseases associated with extremely short telomeres owing to mutations in telomerase, as well as age-related diseases, and ultimately aging itself.},
}
@article {pmid27081027,
year = {2016},
author = {D'Mello, MJJ and Ross, SA and Anand, SS and Gerstein, H and McQueen, M and Yusuf, S and Paré, G},
title = {Telomere Length and Risk of Myocardial Infarction in a MultiEthnic Population: The INTERHEART Study.},
journal = {Journal of the American College of Cardiology},
volume = {67},
number = {15},
pages = {1863-1865},
doi = {10.1016/j.jacc.2016.01.061},
pmid = {27081027},
issn = {1558-3597},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Case-Control Studies ; Humans ; Internationality ; *Myocardial Infarction/ethnology/genetics ; Risk Factors ; Telomere/*pathology ; },
}
@article {pmid27075770,
year = {2018},
author = {Marioni, RE and Harris, SE and Shah, S and McRae, AF and von Zglinicki, T and Martin-Ruiz, C and Wray, NR and Visscher, PM and Deary, IJ},
title = {The epigenetic clock and telomere length are independently associated with chronological age and mortality.},
journal = {International journal of epidemiology},
volume = {45},
number = {2},
pages = {424-432},
pmid = {27075770},
issn = {1464-3685},
support = {MR/J50001X/1/MRC_/Medical Research Council/United Kingdom ; G0500997/MRC_/Medical Research Council/United Kingdom ; G0601333/MRC_/Medical Research Council/United Kingdom ; MR/K026992/1/MRC_/Medical Research Council/United Kingdom ; BB/F019394/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
abstract = {BACKGROUND: Telomere length and DNA methylation have been proposed as biological clock measures that track chronological age. Whether they change in tandem, or contribute independently to the prediction of chronological age, is not known.<br><br>METHODS: We address these points using data from two Scottish cohorts: the Lothian Birth Cohorts of 1921 (LBC1921) and 1936 (LBC1936). Telomere length and epigenetic clock estimates from DNA methylation were measured in 920 LBC1936 participants (ages 70, 73 and 76 years) and in 414 LBC1921 participants (ages 79, 87 and 90 years).<br><br>RESULTS: The epigenetic clock changed over time at roughly the same rate as chronological age in both cohorts. Telomere length decreased at 48-67 base pairs per year on average. Weak, non-significant correlations were found between epigenetic clock estimates and telomere length. Telomere length explained 6.6% of the variance in age in LBC1921, the epigenetic clock explained 10.0%, and combined they explained 17.3% (allP< 1 &#xd7; 10[-7]). Corresponding figures for the LBC1936 cohort were 14.3%, 11.7% and 19.5% (allP< 1 &#xd7; 10[-12]). In a combined cohorts analysis, the respective estimates were 2.8%, 28.5% and 29.5%. Also in a combined cohorts analysis, a one standard deviation increase in baseline epigenetic age was linked to a 22% increased mortality risk (P= 2.6 &#xd7; 10[-4]) whereas, in the same model, a one standard deviation increase in baseline telomere length was independently linked to an 11% decreased mortality risk (P= 0.06).<br><br>CONCLUSIONS: These results suggest that telomere length and epigenetic clock estimates are independent predictors of chronological age and mortality risk.},
}
@article {pmid27074439,
year = {2017},
author = {von Känel, R and Bruwer, EJ and Hamer, M and de Ridder, JH and Malan, L},
title = {Association between objectively measured physical activity, chronic stress and leukocyte telomere length.},
journal = {The Journal of sports medicine and physical fitness},
volume = {57},
number = {10},
pages = {1349-1358},
doi = {10.23736/S0022-4707.16.06426-4},
pmid = {27074439},
issn = {1827-1928},
mesh = {Adult ; Biomarkers/blood ; Black People/psychology ; Exercise/*physiology ; Female ; Humans ; *Leukocytes ; Male ; Middle Aged ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; *Stress, Psychological ; Surveys and Questionnaires ; Telomere Homeostasis/*physiology ; Waist Circumference ; White People/psychology ; },
abstract = {BACKGROUND: Physical activity (PA) attenuates chronic stress and age-related and cardiovascular disease risks, whereby potentially slowing telomere shortening. We aimed to study the association between seven-day objectively measured habitual PA, chronic stress and leukocyte telomere length.<br><br>METHODS: Study participants were African (N.=96) and Caucasian (N.=107) school teachers of the Sympathetic activity and Ambulatory Blood Pressure in Africans study. All lifestyle characteristics (including PA) were objectively measured. The general health questionnaire and serum cortisol were assessed as psychological and physical measures of chronic stress. Leukocyte telomere length was measured using the quantitative real-time polymerase chain reaction.<br><br>RESULTS: Africans had significantly shorter telomeres (P<.0001) and greater psychological distress (P=0.001) than Caucasians, whereas no group difference was seen for cortisol levels. Higher age (&#xdf;=-0.28 [-0.40, -0.16, P&#x2264;0.000), higher alcohol consumption (&#xdf;=-0.21 [-0.36, -0.08], P=0.003) and increased central obesity (&#xdf;=-0.17 [-0.30, -0.03], P=0.017) were all significantly associated with shorter telomeres. Habitual PA of different intensity was not significantly associated with markers of chronic stress or telomere length. However, more time spent with light intensity PA time was significantly and independently correlated with lower waist circumference (r=-0.21, P=0.004); in turn, greater waist circumference was significantly associated shorter telomeres (&#x3b2;=-0.17 [-0.30, -0.03], P=0.017).<br><br>CONCLUSIONS: Habitual PA of different intensity was not directly associated with markers of chronic stress and leukocyte telomere length in this biethnic cohort. However, our findings suggest that light intensity PA could contribute to lowered age-related disease risk and healthy ageing by facilitating maintenance of a normal waist circumference.},
}
@article {pmid27073737,
year = {2016},
author = {Kim, C and Sung, S and Lee, J},
title = {Internal genomic regions mobilized for telomere maintenance in C. elegans.},
journal = {Worm},
volume = {5},
number = {1},
pages = {e1146856},
pmid = {27073737},
issn = {2162-4046},
abstract = {Because DNA polymerase cannot replicate telomeric DNA at linear chromosomal ends, eukaryotes have developed specific telomere maintenance mechanisms (TMMs). A major TMM involves specialized reverse transcriptase, telomerase. However, there also exist various telomerase-independent TMMs (TI-TMMs), which can arise both in pathological conditions (such as cancers) and during evolution. The TI-TMM in cancer cells is called alternative lengthening of telomeres (ALT), whose mechanism is not fully understood. We generated stably maintained telomerase-independent survivors from C. elegans telomerase mutants and found that, unlike previously described survivors in worms, these survivors "mobilize" specific internal sequence blocks for telomere lengthening, which we named TALTs (templates for ALT). The cis-duplication of internal genomic TALTs produces "reservoirs" of TALTs, whose trans-duplication occurs at all chromosome ends in the ALT survivors. Our discovery that different TALTs are utilized in different wild isolates provides insight into the molecular events leading to telomere evolution.},
}
@article {pmid27071945,
year = {2017},
author = {de Zegher, F and Díaz, M and Lopez-Bermejo, A and Ibáñez, L},
title = {Recognition of a sequence: more growth before birth, longer telomeres at birth, more lean mass after birth.},
journal = {Pediatric obesity},
volume = {12},
number = {4},
pages = {274-279},
doi = {10.1111/ijpo.12137},
pmid = {27071945},
issn = {2047-6310},
mesh = {Absorptiometry, Photon ; Birth Weight/*genetics/physiology ; Body Composition/*genetics/physiology ; Body Mass Index ; Female ; Fetal Development/*genetics ; Gestational Age ; Humans ; Infant ; Infant, Newborn ; Infant, Small for Gestational Age ; Male ; Real-Time Polymerase Chain Reaction ; Telomere/*metabolism ; Weight Gain ; },
abstract = {BACKGROUND: Telomere length at birth is a major determinant of telomere length in late adulthood. However, the prenatal setting of telomere length is poorly understood. Individuals born large from non-diabetic mothers are at lower risk for later-life disorders than those born small, a feature of their longer health span being a higher lean mass that provides more muscle strength and that is already present in infancy.<br><br>METHODS: At birth, we studied leukocyte telomere length (by quantitative polymerase chain reaction) in 103 small-for-gestational-age, appropriate-for-gestational-age or large-for-gestational-age (SGA, AGA or LGA) infants born after uncomplicated, term, singleton pregnancies. All infants were breastfed for &#x2265;4&#x2009;months. At 2&#x2009;weeks and 12&#x2009;months, body composition was assessed by dual X-ray absorptiometry.<br><br>RESULTS: Telomere lengths were shorter in SGA newborns and longer in LGA newborns than in AGA newborns (P&#x2009;<&#x2009;0.001), also after adjustment for maternal age, pre-gestational body mass index, gestational weight gain and gestational age. Telomere length at birth associated (all P&#x2009;&#x2264;&#x2009;0.001) to birthweight (r&#x2009;=&#x2009;0.50) and to both lean mass (r&#x2009;=&#x2009;0.43) and fat mass (r&#x2009;=&#x2009;0.48) at age 2&#x2009;weeks, but only to lean mass at 12&#x2009;months (r&#x2009;=&#x2009;0.51).<br><br>CONCLUSION: Higher weight and longer telomeres at birth are followed by more lean mass in late infancy. Relatively large, breastfed infants from non-diabetic mothers may become models of how to make a healthy start.},
}
@article {pmid27071798,
year = {2017},
author = {García-Calzón, S and Moleres, A and Gómez-Martinez, S and Diaz, LE and Bueno, G and Campoy, C and Martinez, JA and Marcos, A and Azcona-Sanjulián, MC and Zalba, G and Marti, A and , },
title = {Association of telomere length with IL-6 levels during an obesity treatment in adolescents: interaction with the-174G/C polymorphism in the IL-6gene.},
journal = {Pediatric obesity},
volume = {12},
number = {3},
pages = {257-263},
doi = {10.1111/ijpo.12136},
pmid = {27071798},
issn = {2047-6310},
mesh = {Adolescent ; Anthropometry ; Biomarkers ; Blood Glucose/genetics ; Child ; Female ; Genotype ; Humans ; Inflammation/genetics ; Interleukin-6/*genetics ; Male ; Pediatric Obesity/*genetics/physiopathology/therapy ; Polymorphism, Genetic ; Real-Time Polymerase Chain Reaction ; Telomere/*genetics ; Weight Reduction Programs/*methods ; },
abstract = {BACKGROUND: Shorter telomeres have been associated with elevated risk for age-related diseases. However, little is known about the biomarker role of telomere length (TL) for predicting inflammation and glucose alterations.<br><br>OBJECTIVE: The objective of this research is to evaluate the association between TL, inflammatory markers and glucose levels after a 2-month weight-loss programme in obese adolescents.<br><br>METHODS: Telomere length was measured using a quantitative polymerase chain reaction in 66 obese adolescents aged 12-17 years (51% men) from the EVASYON programme. The adolescents were genotyped for the polymorphism -174G/C (rs1800795) in the IL-6gene, and anthropometric and biochemical markers as well as inflammatory cytokines were analysed.<br><br>RESULTS: Multiple-adjusted models showed that longer telomeres at baseline were associated with a higher reduction in glucose (B&#x2009;=&#x2009;-4.08, 95% confidence interval: -6.66 to -1.50) and IL-6 (B&#x2009;=&#x2009;-1.03, 95% confidence interval: -2.01 to -0.05) serum levels after 2&#x2009;months of the weight-loss treatment. The -174G/C polymorphism modulated the association between basal TL and changes in IL-6 (P interaction&#x2009;=&#x2009;0.029). Thus, subjects with the GG&#x2009;+&#x2009;GC genotype and with longer telomeres showed a higher decrease in IL-6 levels than CC homozygotes.<br><br>CONCLUSION: Longer telomeres are associated with an improvement in glucose tolerance and inflammation after a weight-loss programme in obese adolescents. Moreover, the -174G/C polymorphism may influence the relationship between TL and IL-6 changes.},
}
@article {pmid27071648,
year = {2016},
author = {Zhou, M and Zhu, L and Cui, X and Feng, L and Zhao, X and He, S and Ping, F and Li, W and Li, Y},
title = {Influence of diet on leukocyte telomere length, markers of inflammation and oxidative stress in individuals with varied glucose tolerance: a Chinese population study.},
journal = {Nutrition journal},
volume = {15},
number = {},
pages = {39},
pmid = {27071648},
issn = {1475-2891},
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Aged ; Asian People ; Biomarkers/*blood ; Blood Glucose/metabolism ; China ; Cross-Sectional Studies ; Deoxyguanosine/analogs &amp; derivatives/blood ; *Diet ; Female ; Glucose Intolerance/*blood ; Glutathione Reductase/blood ; Humans ; Inflammation/blood/diagnosis ; Insulin/blood ; Insulin Resistance ; Interleukin-6/blood ; Leukocytes/*metabolism ; Male ; Middle Aged ; Nutrition Surveys ; *Oxidative Stress ; Superoxide Dismutase/blood ; Telomere/*ultrastructure ; Tumor Necrosis Factor-alpha/blood ; },
abstract = {OBJECTIVES: To explore influence of carbohydrates/fat proportions, dietary ingredients on telomere length shortening, oxidative stress and inflammation in a Chinese population with different glucose tolerance status.<br><br>METHODS: Five hundred and fifty-six Chinese subjects without diabetes history underwent a 75 g, 2 h Oral Glucose Tolerance Test (OGTT). Subjects with diabetes (n = 159), pre-diabetes (n = 197), and normal glucose tolerance (n = 200) were screened. Dietary intakes were evaluated using a semi-quantitative food frequency questionnaire (FFQ). Peripheral blood leukocyte telomere length (LTL) was assessed using a real-time PCR assay. Blood lipid profile, levels of the oxidative stress indicators superoxide dismutase (SOD), glutathione reductase (GR), 8-oxo-2'-deoxyguanosine (8-oxo-dG) and inflammation indicators tumor necrosis factor (TNF-&#x251;), interleukine-6 (IL-6) were measured. Levels of HbA1c, plasma glucose, insulin, and C peptide were also determined. Measurements were taken at 0 min, 30 min, 60 min, and 120 min after 75 g OGTT. Insulin sensitivity was evaluated by HOMA-IR. Basal insulin secretion index (HOMA-&#x3b2;), early phase disposition index (DI30) and total phase disposition index (DI120) indicate insulin levels at different phases of insulin secretion.<br><br>RESULTS: In patients with newly diagnosed diabetes, LTL adjusted by age was longer in HbA1c < 7 % group (log (LTL):1.93 &#xb1; 0.25) than in HbA1c &#x2265; 7 % group (log (LTL):1.82 &#xb1; 0.29). LTL was not associated with daily energy intake, diet fat, carbohydrates and protein proportions. Multiple linear regression analysis indicated that legumes, nuts, fish and seaweeds were protective factors for LTL shortening, and sweetened carbonated beverage was a risk factor for LTL shortening (legumes: &#x3b2; = 0.105, p = 0.018; nuts: &#x3b2; = 0.110, p = 0.011; fish: &#x3b2; = 0.118, p = 0.007; seaweeds: &#x3b2; = 0.116, p = 0.009; sweetened carbonated beverage: &#x3b2; = -0.120, p = 0.004). Daily energy intake was positively associated with TNF-&#x251;, IL-6 (TNF-&#x251;: r = 0.125, p = 0.006;IL-6: r = 0.092, p =0.04). Fat, carbohydrate proportions were positively associated with TNF-&#x251; (fat: r = 0.119, p = 0.008 ; carbohydrate: r = 0.094, p = 0.043). Seaweeds and dairy intake were negatively associated with 8-oxo-dG (seaweed: r = -0.496, p = 0.001;dairy: r = -0.246, p = 0.046), vegetables and fruits were positively associated with GR (vegetables: r = 0.101, p = 0.034;fruits: r = 0.125, p = 0.045). Cereal, meat were positively associated with TNF-&#x251; (cereal: r = 0.091, p = 0.048 ; meat: r = 0.405, p = 0.009).<br><br>CONCLUSION: Diabetes patients with better plasma glucose (HbA1c < 7 %) had longer LTL, LTL could reflect plasma glucose status in diabetes patients. LTL were probably not influenced by diet carbohydrates/fat proportions but was associated with diet ingredients. Diet ingredients significantly impacted on markers of inflammation and oxidative stress, which probably had an effect on LTL.},
}
@article {pmid27070760,
year = {2016},
author = {Gebreab, SY and Riestra, P and Gaye, A and Khan, RJ and Xu, R and Davis, AR and Quarells, RC and Davis, SK and Gibbons, GH},
title = {Perceived neighborhood problems are associated with shorter telomere length in African American women.},
journal = {Psychoneuroendocrinology},
volume = {69},
number = {},
pages = {90-97},
pmid = {27070760},
issn = {1873-3360},
support = {RC4 MD005964/MD/NIMHD NIH HHS/United States ; Z99 HG999999//Intramural NIH HHS/United States ; },
mesh = {Adult ; Black or African American/psychology ; Aging ; Cellular Senescence ; Female ; Humans ; Male ; Middle Aged ; Perception/physiology ; Residence Characteristics ; Risk Factors ; Stress, Psychological/*physiopathology/psychology ; Telomere/pathology/*physiology ; Telomere Shortening/*physiology ; },
abstract = {OBJECTIVES: African Americans (AA) experience higher levels of stress related to living in racially segregated and poor neighborhoods. However, little is known about the associations between perceived neighborhood environments and cellular aging among adult AA. This study examined whether perceived neighborhood environments were associated with telomere length (TL) in AA after adjustment for individual-level risk factors.<br><br>METHODS: The analysis included 158 women and 75 men AA aged 30-55 years from the Morehouse School of Medicine Study. Relative TL (T/S ratio) was measured from peripheral blood leukocytes using quantitative real-time polymerase chain reaction. Multivariable linear regression models were used to examine the associations of perceived neighborhood social cohesion, problems, and overall unfavorable perceptions with log-TL.<br><br>RESULTS: Women had significantly longer TL than men (0.59 vs. 0.54, p=0.012). After controlling for sociodemographic, and biomedical and psychosocial factors, a 1-SD increase in perceived neighborhood problems was associated with 7.3% shorter TL in women (Mean Difference [MD]=-0.073 (Standard Error=0.03), p=0.012). Overall unfavorable perception of neighborhood was also associated with 5.9% shorter TL among women (MD=-0.059(0.03), p=0.023). Better perceived social cohesion were associated with 2.4% longer TL, but did not reach statistical significance (MD=0.024(0.02), p=0.218). No association was observed between perceived neighborhood environments and TL in men.<br><br>CONCLUSIONS: Our findings suggest that perceived neighborhood environments may be predictive of cellular aging in AA women even after accounting for individual-level risk factors. Additional research with a larger sample is needed to determine whether perceived neighborhood environments are causally related to TL.},
}
@article {pmid27069984,
year = {2016},
author = {Fan, X and Yue, Q and Li, Y and Liu, Y and Qu, LL and Cao, Y and Li, H},
title = {A single-bead telomere sensor based on fluorescence resonance energy transfer.},
journal = {The Analyst},
volume = {141},
number = {10},
pages = {3033-3040},
doi = {10.1039/c5an02543e},
pmid = {27069984},
issn = {1364-5528},
mesh = {*Biosensing Techniques ; *DNA ; Fluorescence ; *Fluorescence Resonance Energy Transfer ; *G-Quadruplexes ; Telomere/*chemistry ; },
abstract = {We present a 200 nm in-diameter single-bead sensor for the detection of single, unlabeled DNA molecules in solution using fluorescence resonance energy transfer technology. DNA-bound Alexa 488 and Crimson 625 loaded on commercial beads served as the donor and acceptor, respectively. Binding of the target DNA to the single bead sensor induces G-quadruplex stretching, resulting in a decrease in fluorescence energy transfer. G-rich telomere sequences formed a G-quadruplex structure in the presence of ZnTCPP, as demonstrated by the detection of two strong donor and acceptor signals. The sensitivity of the sensor was 1 fM. Under optimized conditions using a polydimethylsiloxane microfluidic device, we measured the number of sensor beads by direct counting. By controlling the flow rate via the probe volume, one sensing experiment can be completed in 5 minutes. Based on these results, we propose a new parameter-dependability (RS)-as a quantitative measure to judge the quality of a bio-sensor. This parameter is based on the ratio of the sensor and sensing sample fluorescence signals. This parameter can range from 0.1 to 100, where a value of 10 represents an optimized bio-sensor.},
}
@article {pmid27068713,
year = {2016},
author = {Gadaleta, MC and González-Medina, A and Noguchi, E},
title = {Timeless protection of telomeres.},
journal = {Current genetics},
volume = {62},
number = {4},
pages = {725-730},
pmid = {27068713},
issn = {1432-0983},
support = {R01 GM077604/GM/NIGMS NIH HHS/United States ; },
mesh = {Carrier Proteins ; Chromosomal Proteins, Non-Histone/metabolism ; DNA Damage ; DNA Replication ; DNA-Directed DNA Polymerase/metabolism ; Genome ; Genomics ; Protein Binding ; Recombinases/antagonists &amp; inhibitors/metabolism ; Recombination, Genetic ; Repetitive Sequences, Nucleic Acid ; Telomerase/metabolism ; Telomere/*genetics/*metabolism ; Telomere Homeostasis ; },
abstract = {The DNA replication machinery encounters problems at numerous genomic regions that are inherently difficult to replicate. These genomic regions include telomeres, which contain repetitive DNA and telomere-binding proteins. If not properly regulated, replication of such genomic regions can result in DNA damage, leading to genomic instability. Studies implicated a role of Timeless-related proteins at difficult-to-replicate genomic regions, including telomeres. However, how these proteins maintain telomeres was elusive. In a recent report, we described the role of Swi1, a Timeless-related protein, in telomere maintenance in fission yeast. We demonstrated that Swi1 is required for proper replication of repeat DNA sequences at telomeres. We also showed that Swi1-deficient cells utilize recombination-based ALT (alternative lengthening of telomeres)-like mechanisms to maintain telomeres in the absence of telomerase. Here, we highlight these findings and present additional data to discuss the role of Swi1[Timeless] in telomere protection and ALT prevention.},
}
@article {pmid27066066,
year = {2016},
author = {Mattarocci, S and Hafner, L and Lezaja, A and Shyian, M and Shore, D},
title = {Rif1: A Conserved Regulator of DNA Replication and Repair Hijacked by Telomeres in Yeasts.},
journal = {Frontiers in genetics},
volume = {7},
number = {},
pages = {45},
pmid = {27066066},
issn = {1664-8021},
abstract = {Rap1-interacting factor 1 (Rif1) was originally identified in the budding yeast Saccharomyces cerevisiae as a telomere-binding protein that negatively regulates telomerase-mediated telomere elongation. Although this function is conserved in the distantly related fission yeast Schizosaccharomyces pombe, recent studies, both in yeasts and in metazoans, reveal that Rif1 also functions more globally, both in the temporal control of DNA replication and in DNA repair. Rif1 proteins are large and characterized by N-terminal HEAT repeats, predicted to form an elongated alpha-helical structure. In addition, all Rif1 homologs contain two short motifs, abbreviated RVxF/SILK, that are implicated in recruitment of the PP1 (yeast Glc7) phosphatase. In yeasts the RVxF/SILK domains have been shown to play a role in control of DNA replication initiation, at least in part through targeted de-phosphorylation of proteins in the pre-Replication Complex. In human cells Rif1 is recruited to DNA double-strand breaks through an interaction with 53BP1 where it counteracts DNA resection, thus promoting repair by non-homologous end-joining. This function requires the N-terminal HEAT repeat-containing domain. Interestingly, this domain is also implicated in DNA end protection at un-capped telomeres in yeast. We conclude by discussing the deployment of Rif1 at telomeres in yeasts from both an evolutionary perspective and in light of its recently discovered global functions.},
}
@article {pmid27064212,
year = {2016},
author = {Ebrahimi, H and Cooper, JP},
title = {Finding a place in the SUN: telomere maintenance in a diverse nuclear landscape.},
journal = {Current opinion in cell biology},
volume = {40},
number = {},
pages = {145-152},
pmid = {27064212},
issn = {1879-0410},
support = {Z99 CA999999//Intramural NIH HHS/United States ; ZIA BC011519-01//Intramural NIH HHS/United States ; ZIA BC011519-02//Intramural NIH HHS/United States ; },
mesh = {Animals ; Cell Nucleus/*chemistry/metabolism ; Chromosomes/metabolism ; Eukaryotic Cells/classification/*cytology/metabolism ; Humans ; Nuclear Envelope/metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres function in the context of a complex nuclear milieu in which telomeres tend to occupy distinct subnuclear regions. Indeed, regulation of the subnuclear positioning of telomeres is conserved from yeast to human, raising the age-old question: to what extent is location important for function? In mitotically dividing cells, the positioning of telomeres affects their epigenetic state and influences telomere processing and synthesis. In meiotic cells, telomere location is important for homologue pairing, centromere assembly and spindle formation. Here we focus on recent insights into the functions of telomere positioning in maintaining genome integrity.},
}
@article {pmid27062452,
year = {2016},
author = {Whisman, MA and Robustelli, BL and Sbarra, DA},
title = {Marital disruption is associated with shorter salivary telomere length in a probability sample of older adults.},
journal = {Social science &amp; medicine (1982)},
volume = {157},
number = {},
pages = {60-67},
pmid = {27062452},
issn = {1873-5347},
support = {R03 AG045301/AG/NIA NIH HHS/United States ; U01 AG009740/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Body Mass Index ; Cellular Senescence/physiology ; Cohort Studies ; *Family Conflict ; Female ; Humans ; Male ; Marital Status/*statistics &amp; numerical data ; Middle Aged ; Neuroticism ; Polymerase Chain Reaction/methods ; Saliva/*physiology ; Social Class ; Stress, Psychological/complications/etiology ; Telomere/*pathology ; United States ; },
abstract = {RATIONALE: Marital disruption (i.e., marital separation, divorce) is associated with a wide range of poor mental and physical health outcomes, including increased risk for all-cause mortality. One biological intermediary that may help explain the association between marital disruption and poor health is accelerated cellular aging.<br><br>OBJECTIVE: This study examines the association between marital disruption and salivary telomere length in a United States probability sample of adults &#x2265;50 years of age.<br><br>METHOD: Participants were 3526 individuals who participated in the 2008 wave of the Health and Retirement Study. Telomere length assays were performed using quantitative real-time polymerase chain reaction (qPCR) on DNA extracted from saliva samples. Health and lifestyle factors, traumatic and stressful life events, and neuroticism were assessed via self-report. Linear regression analyses were conducted to examine the associations between predictor variables and salivary telomere length.<br><br>RESULTS: Based on their marital status data in the 2006 wave, people who were separated or divorced had shorter salivary telomeres than people who were continuously married or had never been married, and the association between marital disruption and salivary telomere length was not moderated by gender or neuroticism. Furthermore, the association between marital disruption and salivary telomere length remained statistically significant after adjusting for demographic and socioeconomic variables, neuroticism, cigarette use, body mass, traumatic life events, and other stressful life events. Additionally, results revealed that currently married adults with a history of divorce evidenced shorter salivary telomeres than people who were continuously married or never married.<br><br>CONCLUSION: Accelerated cellular aging, as indexed by telomere shortening, may be one pathway through which marital disruption is associated with morbidity and mortality.},
}
@article {pmid27059547,
year = {2017},
author = {Patel, CJ and Manrai, AK and Corona, E and Kohane, IS},
title = {Systematic correlation of environmental exposure and physiological and self-reported behaviour factors with leukocyte telomere length.},
journal = {International journal of epidemiology},
volume = {46},
number = {1},
pages = {44-56},
pmid = {27059547},
issn = {1464-3685},
support = {K99 ES023504/ES/NIEHS NIH HHS/United States ; R00 ES023504/ES/NIEHS NIH HHS/United States ; R21 ES025052/ES/NIEHS NIH HHS/United States ; U54 HG007963/HG/NHGRI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging/*physiology ; Biomarkers/*metabolism ; C-Reactive Protein/metabolism ; Environmental Exposure/*adverse effects ; Female ; Gene Expression ; *Gene-Environment Interaction ; Genome-Wide Association Study ; Humans ; Leukocytes/metabolism ; Linear Models ; Male ; Middle Aged ; Multivariate Analysis ; Nutrition Surveys ; Risk Factors ; Self Report ; Telomere/*ultrastructure ; Telomere Shortening ; United States ; },
abstract = {BACKGROUND: It is hypothesized that environmental exposures and behaviour influence telomere length, an indicator of cellular ageing. We systematically associated 461 indicators of environmental exposures, physiology and self-reported behaviour with telomere length in data from the US National Health and Nutrition Examination Survey (NHANES) in 1999-2002. Further, we tested whether factors identified in the NHANES participants are also correlated with gene expression of telomere length modifying genes.<br><br>METHODS: We correlated 461 environmental exposures, behaviours and clinical variables with telomere length, using survey-weighted linear regression, adjusting for sex, age, age squared, race/ethnicity, poverty level, education and born outside the USA, and estimated the false discovery rate to adjust for multiple hypotheses. We conducted a secondary analysis to investigate the correlation between identified environmental variables and gene expression levels of telomere-associated genes in publicly available gene expression samples.<br><br>RESULTS: After correlating 461 variables with telomere length, we found 22 variables significantly associated with telomere length after adjustment for multiple hypotheses. Of these varaibales, 14 were associated with longer telomeres, including biomarkers of polychlorinated biphenyls([PCBs; 0.1 to 0.2 standard deviation (SD) increase for 1 SD increase in PCB level, P &#x2009;<&#x2009;0.002] and a form of vitamin A, retinyl stearate. Eight variables associated with shorter telomeres, including biomarkers of cadmium, C-reactive protein and lack of physical activity. We could not conclude that PCBs are correlated with gene expression of telomere-associated genes.<br><br>CONCLUSIONS: Both environmental exposures and chronic disease-related risk factors may play a role in telomere length. Our secondary analysis found no evidence of association between PCBs/smoking and gene expression of telomere-associated genes. All correlations between exposures, behaviours and clinical factors and changes in telomere length will require further investigation regarding biological influence of exposure.},
}
@article {pmid27053148,
year = {2016},
author = {To-Miles, FYL and Backman, CL},
title = {What telomeres say about activity and health: A rapid review: Ce que les télomères révèlent au sujet de l'activité et de la santé : revue rapide.},
journal = {Canadian journal of occupational therapy. Revue canadienne d'ergotherapie},
volume = {83},
number = {3},
pages = {143-153},
doi = {10.1177/0008417415627345},
pmid = {27053148},
issn = {1911-9828},
abstract = {BACKGROUND.: Empirical studies on occupation as a determinant of health could be advanced with research incorporating biological measures of health. Telomere length and telomerase function are promising biomarkers of the interaction of genetics, lifestyle, and behaviour; however, they have not been used in occupational therapy research.<br><br>PURPOSE.: This paper reviews current evidence on the role of physical and mindfulness activities in sustaining telomeres. The findings are applied to the study of occupation, health, and aging.<br><br>METHOD.: A rapid review was conducted with an evidence synthesis of 23 studies published from 2008 to 2014.<br><br>FINDINGS.: Mindfulness activities may preserve telomeres, slow cell senescence and death, and sustain health through mediating life stressors. Inconsistencies exist for the effect of physical activities on telomeres.<br><br>IMPLICATIONS.: Similar research examining a range of occupations may help to identify the health-promoting benefits of occupation and inform lifestyle interventions.},
}
@article {pmid27052595,
year = {2016},
author = {Marchesini, M and Matocci, R and Tasselli, L and Cambiaghi, V and Orleth, A and Furia, L and Marinelli, C and Lombardi, S and Sammarelli, G and Aversa, F and Minucci, S and Faretta, M and Pelicci, PG and Grignani, F},
title = {PML is required for telomere stability in non-neoplastic human cells.},
journal = {Oncogene},
volume = {35},
number = {14},
pages = {1876},
doi = {10.1038/onc.2015.312},
pmid = {27052595},
issn = {1476-5594},
}
@article {pmid27052502,
year = {2016},
author = {Rocca, MS and Speltra, E and Menegazzo, M and Garolla, A and Foresta, C and Ferlin, A},
title = {Sperm telomere length as a parameter of sperm quality in normozoospermic men.},
journal = {Human reproduction (Oxford, England)},
volume = {31},
number = {6},
pages = {1158-1163},
doi = {10.1093/humrep/dew061},
pmid = {27052502},
issn = {1460-2350},
mesh = {Adult ; Biomarkers ; Cohort Studies ; DNA Fragmentation ; Humans ; In Situ Nick-End Labeling ; Infertility, Male/*genetics ; Male ; *Semen Analysis ; Telomere/chemistry/*metabolism ; *Telomere Homeostasis ; },
abstract = {STUDY QUESTION: Could sperm telomere length (STL) represent a novel parameter and biomarker of sperm quality?<br><br>SUMMARY ANSWER: STL is associated with standard semen quality parameters and, more importantly, it is significantly associated with levels of DNA fragmentation and sperm protamination.<br><br>WHAT IS KNOWN ALREADY: Telomeres are fundamental for genome integrity. Recent studies have demonstrated that STL increases with age and men with oligozoospermia have shorter sperm telomeres than normozoospermic men.<br><br>STUDY DESIGN, SIZE, DURATION: Cohort study conducted from September 2014 to June 2015 on 100 subjects with normal standard semen parameters.<br><br>STL was measured indirectly by quantitative polymerase chain reaction using telomere/single-copy gene ratio, sperm DNA fragmentation by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling assay and protamination by aniline blue staining. Data were analyzed for determining the relationships between STL, standard semen parameters and DNA fragmentation and protamination.<br><br>Among standard semen parameters, STL was positively associated with progressive motility (P = 0.004) and vitality (P = 0.007). STL was significantly and negatively associated with sperm DNA fragmentation (P = 0.001) and significantly and positively associated with protamination (P = 0.002). The role of chance was limited and the findings have biological relevance and a pathophysiological explanation.<br><br>For the present study, we deliberately selected only men with normozoospermia to better analyze whether STL might represent a biomarker of sperm quality beyond traditional sperm parameters. Additional studies in proven fertile men with normal sperm parameters are needed.<br><br>The measurement of STL is a simple and rapid method that offers further information about the quality of sperm. The results of this study demonstrate that STL could be considered as an additional sperm parameter and opens new perspectives in the evaluation of the infertile male. Additional studies will clarify the significance of this parameter also as a prognostic biomarker in assisted reproduction.<br><br>No external funding was either sought or obtained for this study. There are no conflicts of interest to be declared.},
}
@article {pmid27050267,
year = {2016},
author = {Li, B and Qiao, R and Wang, Z and Zhou, W and Li, X and Xu, W and Rao, Z},
title = {Crystal structure of a tankyrase 1-telomere repeat factor 1 complex.},
journal = {Acta crystallographica. Section F, Structural biology communications},
volume = {72},
number = {Pt 4},
pages = {320-327},
pmid = {27050267},
issn = {2053-230X},
mesh = {Amino Acid Sequence ; Crystallography, X-Ray ; Protein Conformation ; Sequence Homology, Amino Acid ; Tankyrases/*chemistry ; *Telomere ; },
abstract = {Telomere repeat factor 1 (TRF1) is a subunit of shelterin (also known as the telosome) and plays a critical role in inhibiting telomere elongation by telomerase. Tankyrase 1 (TNKS1) is a poly(ADP-ribose) polymerase that regulates the activity of TRF1 through poly(ADP-ribosyl)ation (PARylation). PARylation of TRF1 by TNKS1 leads to the release of TRF1 from telomeres and allows telomerase to access telomeres. The interaction between TRF1 and TNKS1 is thus important for telomere stability and the mitotic cell cycle. Here, the crystal structure of a complex between the N-terminal acidic domain of TRF1 (residues 1-55) and a fragment of TNKS1 covering the second and third ankyrin-repeat clusters (ARC2-3) is presented at 2.2 Å resolution. The TNKS1-TRF1 complex crystals were optimized using an `oriented rescreening' strategy, in which the initial crystallization condition was used as a guide for a second round of large-scale sparse-matrix screening. This crystallographic and biochemical analysis provides a better understanding of the TRF1-TNKS1 interaction and the three-dimensional structure of the ankyrin-repeat domain of TNKS.},
}
@article {pmid27050034,
year = {2016},
author = {Faul, JD and Mitchell, CM and Smith, JA and Zhao, W},
title = {Estimating Telomere Length Heritability in an Unrelated Sample of Adults: Is Heritability of Telomere Length Modified by Life Course Socioeconomic Status?.},
journal = {Biodemography and social biology},
volume = {62},
number = {1},
pages = {73-86},
pmid = {27050034},
issn = {1948-5573},
support = {U01 AG009740/AG/NIA NIH HHS/United States ; P30 AG012846/AG/NIA NIH HHS/United States ; R24 HD041028/HD/NICHD NIH HHS/United States ; P2C HD041028/HD/NICHD NIH HHS/United States ; RC2 AG036495/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; *Aging/genetics/physiology ; Educational Status ; Female ; Genotype ; Humans ; Income ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/genetics ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; *Social Class ; Telomere/*genetics ; United States ; },
abstract = {Telomere length (TL) is a widely used marker of biological aging and is associated with an increased risk of morbidity and mortality. Recently, there has been evidence for an association between TL and socioeconomic status (SES), particularly for measures of education and childhood SES. Individual differences in TL are also influenced by genetic factors, with heritability estimates from twin and sibling studies ranging from 34 to 82 percent. Yet the additive heritability of TL as a result of measured genetic variations and the extent to which heritability is modified by SES is still unknown. Data from the Health and Retirement Study, a nationally representative cohort of older adults (mean age 69 years), were used to provide the first estimates of molecular-based heritability of TL using genome-wide complex trait analysis (GCTA). We found that additive genetic variance contributed 28 percent (p = .012) of total phenotypic variance of TL in the European American sample (n = 3,290). Estimation using the GCTA and KING Robust relationship inference methods did not differ significantly in this sample. None of the variance from the gene-by-SES interactions examined contributed significantly to the total TL variance. Estimation of heritability and genetic interaction with SES in the African American sample (n = 442) was too unstable to provide reliable estimates.},
}
@article {pmid27049651,
year = {2016},
author = {Glei, DA and Goldman, N and Risques, RA and Rehkopf, DH and Dow, WH and Rosero-Bixby, L and Weinstein, M},
title = {Predicting Survival from Telomere Length versus Conventional Predictors: A Multinational Population-Based Cohort Study.},
journal = {PloS one},
volume = {11},
number = {4},
pages = {e0152486},
pmid = {27049651},
issn = {1932-6203},
support = {R01 AG031716/AG/NIA NIH HHS/United States ; R01AG16790/AG/NIA NIH HHS/United States ; P30 AG012839/AG/NIA NIH HHS/United States ; R01AG16661/AG/NIA NIH HHS/United States ; P2C HD047879/HD/NICHD NIH HHS/United States ; R01 AG016790/AG/NIA NIH HHS/United States ; K01AG047280/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 AG016661/AG/NIA NIH HHS/United States ; K01 AG047280/AG/NIA NIH HHS/United States ; 072406/Z/03/Z/WT_/Wellcome Trust/United Kingdom ; P30AG012839/AG/NIA NIH HHS/United States ; R01AG031716/AG/NIA NIH HHS/United States ; },
mesh = {Cohort Studies ; Costa Rica ; Female ; Humans ; Male ; Middle Aged ; Taiwan ; *Telomere ; United States ; },
abstract = {Telomere length has generated substantial interest as a potential predictor of aging-related diseases and mortality. Some studies have reported significant associations, but few have tested its ability to discriminate between decedents and survivors compared with a broad range of well-established predictors that include both biomarkers and commonly collected self-reported data. Our aim here was to quantify the prognostic value of leukocyte telomere length relative to age, sex, and 19 other variables for predicting five-year mortality among older persons in three countries. We used data from nationally representative surveys in Costa Rica (N = 923, aged 61+), Taiwan (N = 976, aged 54+), and the U.S. (N = 2672, aged 60+). Our study used a prospective cohort design with all-cause mortality during five years post-exam as the outcome. We fit Cox hazards models separately by country, and assessed the discriminatory ability of each predictor. Age was, by far, the single best predictor of all-cause mortality, whereas leukocyte telomere length was only somewhat better than random chance in terms of discriminating between decedents and survivors. After adjustment for age and sex, telomere length ranked between 15th and 17th (out of 20), and its incremental contribution was small; nine self-reported variables (e.g., mobility, global self-assessed health status, limitations with activities of daily living, smoking status), a cognitive assessment, and three biological markers (C-reactive protein, serum creatinine, and glycosylated hemoglobin) were more powerful predictors of mortality in all three countries. Results were similar for cause-specific models (i.e., mortality from cardiovascular disease, cancer, and all other causes combined). Leukocyte telomere length had a statistically discernible, but weak, association with mortality, but it did not predict survival as well as age or many other self-reported variables. Although telomere length may eventually help scientists understand aging, more powerful and more easily obtained tools are available for predicting survival.},
}
@article {pmid27047742,
year = {2016},
author = {Liu, B and Maekawa, T and Chatton, B and Ishii, S},
title = {In utero TNF-α treatment induces telomere shortening in young adult mice in an ATF7-dependent manner.},
journal = {FEBS open bio},
volume = {6},
number = {1},
pages = {56-63},
pmid = {27047742},
issn = {2211-5463},
abstract = {Epidemiological studies indicate that exposure to stress during intrauterine life is associated with shorter telomeres in young adulthood, and a correlation between telomere length in early life and lifespan has been suggested. However, empirical studies evaluating these phenomena have not been performed, and the mechanism of stress-induced telomere shortening remains unknown. Since the level of tumour necrosis factor α (TNF-α) in peripheral blood cells is increased by various psychological stresses, the effect of TNF-α administration to pregnant mice on telomere length in adulthood was examined in the present study. In utero TNF-α treatment-induced telomere shortening in adult mice. Telomere shortening was observed in certain tissues such as the bone marrow, spleen, and lung, and was detected at specific age ranges during adulthood. Telomere shortening was not observed in mice lacking the stress-responsive transcription factor ATF7, which contributes to heterochromatin formation in the absence of stress. The present study identified the conditions under which in utero TNF-α treatment induces telomere shortening in adulthood.},
}
@article {pmid27046097,
year = {2016},
author = {Marshall, WF and Fung, JC},
title = {Modeling meiotic chromosome pairing: nuclear envelope attachment, telomere-led active random motion, and anomalous diffusion.},
journal = {Physical biology},
volume = {13},
number = {2},
pages = {026003},
pmid = {27046097},
issn = {1478-3975},
support = {R01 GM097213/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromatin/metabolism ; *Chromosome Pairing ; Chromosomes/metabolism ; Diffusion ; Humans ; *Meiosis ; Models, Biological ; Molecular Dynamics Simulation ; Motion ; Nuclear Envelope/*metabolism ; Telomere/*metabolism ; },
abstract = {The recognition and pairing of homologous chromosomes during meiosis is a complex physical and molecular process involving a combination of polymer dynamics and molecular recognition events. Two highly conserved features of meiotic chromosome behavior are the attachment of telomeres to the nuclear envelope and the active random motion of telomeres driven by their interaction with cytoskeletal motor proteins. Both of these features have been proposed to facilitate the process of homolog pairing, but exactly what role these features play in meiosis remains poorly understood. Here we investigate the roles of active motion and nuclear envelope tethering using a Brownian dynamics simulation in which meiotic chromosomes are represented by a Rouse polymer model subjected to tethering and active forces at the telomeres. We find that tethering telomeres to the nuclear envelope slows down pairing relative to the rates achieved by unattached chromosomes, but that randomly directed active forces applied to the telomeres speed up pairing dramatically in a manner that depends on the statistical properties of the telomere force fluctuations. The increased rate of initial pairing cannot be explained by stretching out of the chromosome conformation but instead seems to correlate with anomalous diffusion of sub-telomeric regions.},
}
@article {pmid27044869,
year = {2016},
author = {Obodo, UC and Epum, EA and Platts, MH and Seloff, J and Dahlson, NA and Velkovsky, SM and Paul, SR and Friedman, KL},
title = {Endogenous Hot Spots of De Novo Telomere Addition in the Yeast Genome Contain Proximal Enhancers That Bind Cdc13.},
journal = {Molecular and cellular biology},
volume = {36},
number = {12},
pages = {1750-1763},
pmid = {27044869},
issn = {1098-5549},
mesh = {Binding Sites ; DNA Breaks, Double-Stranded ; DNA Repair ; DNA, Fungal/chemistry/metabolism ; *Enhancer Elements, Genetic ; Genome, Fungal ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomerase/metabolism ; Telomere/*genetics ; Telomere-Binding Proteins/*metabolism ; },
abstract = {DNA double-strand breaks (DSBs) pose a threat to genome stability and are repaired through multiple mechanisms. Rarely, telomerase, the enzyme that maintains telomeres, acts upon a DSB in a mutagenic process termed telomere healing. The probability of telomere addition is increased at specific genomic sequences termed sites of repair-associated telomere addition (SiRTAs). By monitoring repair of an induced DSB, we show that SiRTAs on chromosomes V and IX share a bipartite structure in which a core sequence (Core) is directly targeted by telomerase, while a proximal sequence (Stim) enhances the probability of de novo telomere formation. The Stim and Core sequences are sufficient to confer a high frequency of telomere addition to an ectopic site. Cdc13, a single-stranded DNA binding protein that recruits telomerase to endogenous telomeres, is known to stimulate de novo telomere addition when artificially recruited to an induced DSB. Here we show that the ability of the Stim sequence to enhance de novo telomere addition correlates with its ability to bind Cdc13, indicating that natural sites at which telomere addition occurs at high frequency require binding by Cdc13 to a sequence 20 to 100 bp internal from the site at which telomerase acts to initiate de novo telomere addition.},
}
@article {pmid27035147,
year = {2016},
author = {Gavaldá, S and Santos-Pereira, JM and García-Rubio, ML and Luna, R and Aguilera, A},
title = {Excess of Yra1 RNA-Binding Factor Causes Transcription-Dependent Genome Instability, Replication Impairment and Telomere Shortening.},
journal = {PLoS genetics},
volume = {12},
number = {4},
pages = {e1005966},
pmid = {27035147},
issn = {1553-7404},
mesh = {*DNA Replication ; Genes, Fungal ; *Genomic Instability ; Nuclear Proteins/*physiology ; Nucleic Acid Hybridization ; RNA-Binding Proteins/*physiology ; Recombination, Genetic ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/*physiology ; *Telomere Shortening ; *Transcription, Genetic ; },
abstract = {Yra1 is an essential nuclear factor of the evolutionarily conserved family of hnRNP-like export factors that when overexpressed impairs mRNA export and cell growth. To investigate further the relevance of proper Yra1 stoichiometry in the cell, we overexpressed Yra1 by transforming yeast cells with YRA1 intron-less constructs and analyzed its effect on gene expression and genome integrity. We found that YRA1 overexpression induces DNA damage and leads to a transcription-associated hyperrecombination phenotype that is mediated by RNA:DNA hybrids. In addition, it confers a genome-wide replication retardation as seen by reduced BrdU incorporation and accumulation of the Rrm3 helicase. In addition, YRA1 overexpression causes a cell senescence-like phenotype and telomere shortening. ChIP-chip analysis shows that overexpressed Yra1 is loaded to transcribed chromatin along the genome and to Y' telomeric regions, where Rrm3 is also accumulated, suggesting an impairment of telomere replication. Our work not only demonstrates that a proper stoichiometry of the Yra1 mRNA binding and export factor is required to maintain genome integrity and telomere homeostasis, but suggests that the cellular imbalance between transcribed RNA and specific RNA-binding factors may become a major cause of genome instability mediated by co-transcriptional replication impairment.},
}
@article {pmid27029895,
year = {2016},
author = {Shay, JW},
title = {Role of Telomeres and Telomerase in Aging and Cancer.},
journal = {Cancer discovery},
volume = {6},
number = {6},
pages = {584-593},
pmid = {27029895},
issn = {2159-8290},
support = {C06 RR030414/RR/NCRR NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*genetics/*metabolism ; Animals ; Apoptosis ; Cell Proliferation ; Cell Transformation, Neoplastic/genetics/metabolism ; Humans ; Neoplasms/*genetics/*metabolism ; Telomerase/*metabolism ; Telomere/*genetics/metabolism ; Telomere Homeostasis ; Telomere Shortening ; },
abstract = {UNLABELLED: Telomeres progressively shorten throughout life. A hallmark of advanced malignancies is the ability for continuous cell divisions that almost universally correlates with the stabilization of telomere length by the reactivation of telomerase. The repression of telomerase and shorter telomeres in humans may have evolved, in part, as an anticancer protection mechanism. Although there is still much we do not understand about the regulation of telomerase, it remains a very attractive and novel target for cancer therapeutics. This review focuses on the current state of advances in the telomerase area, identifies outstanding questions, and addresses areas and methods that need refinement.<br><br>SIGNIFICANCE: Despite many recent advances, telomerase remains a challenging target for cancer therapy. There are few telomerase-directed therapies, and many of the assays used to measure telomeres and telomerase have serious limitations. This review provides an overview of the current state of the field and how recent advances could affect future research and treatment approaches. Cancer Discov; 6(6); 584-93. &#xa9;2016 AACR.},
}
@article {pmid27029731,
year = {2016},
author = {Yamaki, T and Yasuda, GK and Wakimoto, BT},
title = {The Deadbeat Paternal Effect of Uncapped Sperm Telomeres on Cell Cycle Progression and Chromosome Behavior in Drosophila melanogaster.},
journal = {Genetics},
volume = {203},
number = {2},
pages = {799-816},
pmid = {27029731},
issn = {1943-2631},
mesh = {Animals ; *Cell Cycle ; Checkpoint Kinase 2/genetics/metabolism ; Chimera ; Chromatin Assembly and Disassembly ; Chromosomes, Insect/*genetics ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/genetics/growth &amp; development ; Female ; Male ; Nuclear Proteins/*genetics/metabolism ; *Paternal Inheritance ; Spermatozoa/cytology/metabolism ; Telomere/*genetics ; Telomere Homeostasis ; },
abstract = {Telomere-capping complexes (TCCs) protect the ends of linear chromosomes from illegitimate repair and end-to-end fusions and are required for genome stability. The identity and assembly of TCC components have been extensively studied, but whether TCCs require active maintenance in nondividing cells remains an open question. Here we show that Drosophila melanogaster requires Deadbeat (Ddbt), a sperm nuclear basic protein (SNBP) that is recruited to the telomere by the TCC and is required for TCC maintenance during genome-wide chromatin remodeling, which transforms spermatids to mature sperm. Ddbt-deficient males produce sperm lacking TCCs. Their offspring delay the initiation of anaphase as early as cycle 1 but progress through the first two cycles. Persistence of uncapped paternal chromosomes induces arrest at or around cycle 3. This early arrest can be rescued by selective elimination of paternal chromosomes and production of gynogenetic haploid or haploid mosaics. Progression past cycle 3 can also occur if embryos have reduced levels of the maternally provided checkpoint kinase Chk2. The findings provide insights into how telomere integrity affects the regulation of the earliest embryonic cell cycles. They also suggest that other SNBPs, including those in humans, may have analogous roles and manifest as paternal effects on embryo quality.},
}
@article {pmid27029497,
year = {2016},
author = {Endicott, AA and Taylor, JW and Walsh, KM},
title = {Telomere length connects melanoma and glioma predispositions.},
journal = {Aging},
volume = {8},
number = {3},
pages = {423-424},
pmid = {27029497},
issn = {1945-4589},
mesh = {Genetic Predisposition to Disease ; Glioma/*genetics ; Humans ; Melanoma/*genetics ; Telomere Homeostasis/*genetics ; },
}
@article {pmid27025256,
year = {2016},
author = {Mikolcevic, P and Isoda, M and Shibuya, H and del Barco Barrantes, I and Igea, A and Suja, JA and Shackleton, S and Watanabe, Y and Nebreda, AR},
title = {Essential role of the Cdk2 activator RingoA in meiotic telomere tethering to the nuclear envelope.},
journal = {Nature communications},
volume = {7},
number = {},
pages = {11084},
pmid = {27025256},
issn = {2041-1723},
mesh = {Animals ; Cell Cycle Checkpoints ; Cell Cycle Proteins/*metabolism ; Chromosome Pairing ; Cyclin-Dependent Kinase 2/*metabolism ; DNA Breaks, Double-Stranded ; DNA Repair ; Humans ; Infertility, Male/metabolism/pathology ; Male ; *Meiosis ; Meiotic Prophase I ; Membrane Proteins/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Microtubule-Associated Proteins/metabolism ; Nuclear Envelope/*metabolism ; Nuclear Proteins/metabolism ; Pachytene Stage ; Protein Binding ; Spermatocytes/pathology ; Telomere/*metabolism ; },
abstract = {Cyclin-dependent kinases (CDKs) play key roles in cell cycle regulation. Genetic analysis in mice has revealed an essential role for Cdk2 in meiosis, which renders Cdk2 knockout (KO) mice sterile. Here we show that mice deficient in RingoA, an atypical activator of Cdk1 and Cdk2 that has no amino acid sequence homology to cyclins, are sterile and display meiotic defects virtually identical to those observed in Cdk2 KO mice including non-homologous chromosome pairing, unrepaired double-strand breaks, undetectable sex-body and pachytene arrest. Interestingly, RingoA is required for Cdk2 targeting to telomeres and RingoA KO spermatocytes display severely affected telomere tethering as well as impaired distribution of Sun1, a protein essential for the attachment of telomeres to the nuclear envelope. Our results identify RingoA as an important activator of Cdk2 at meiotic telomeres, and provide genetic evidence for a physiological function of mammalian Cdk2 that is not dependent on cyclins.},
}
@article {pmid27022325,
year = {2016},
author = {Poot, M},
title = {From Telomere Crisis via Dicentric Chromosomes to Kataegis and Chromothripsis.},
journal = {Molecular syndromology},
volume = {6},
number = {6},
pages = {259-260},
pmid = {27022325},
issn = {1661-8769},
}
@article {pmid27020448,
year = {2016},
author = {Verhulst, S and Dalgård, C and Labat, C and Kark, JD and Kimura, M and Christensen, K and Toupance, S and Aviv, A and Kyvik, KO and Benetos, A},
title = {A short leucocyte telomere length is associated with development of insulin resistance.},
journal = {Diabetologia},
volume = {59},
number = {6},
pages = {1258-1265},
pmid = {27020448},
issn = {1432-0428},
support = {R01 AG030678/AG/NIA NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Body Mass Index ; Cardiovascular Diseases/genetics/*physiopathology ; Female ; Humans ; Insulin Resistance/genetics/*physiology ; Leukocytes/*metabolism ; Male ; Middle Aged ; Risk Factors ; Sex Factors ; Telomere/*genetics ; },
abstract = {AIMS/HYPOTHESIS: A number of studies have shown that leucocyte telomere length (LTL) is inversely associated with insulin resistance and type 2 diabetes mellitus. The aim of the present longitudinal cohort study, utilising a twin design, was to assess whether shorter LTL predicts insulin resistance or is a consequence thereof.<br><br>METHODS: Participants were recruited between 1997 and 2000 through the population-based national Danish Twin Registry to participate in the GEMINAKAR study, a longitudinal evaluation of metabolic disorders and cardiovascular risk factors. Baseline and follow-up measurements of LTL and insulin resistance over an average of 12&#xa0;years were performed in a subset of the Registry consisting of 338 (184 monozygotic and 154 dizygotic) same-sex twin pairs.<br><br>RESULTS: Age at baseline examination was 37.4&#x2009;&#xb1;&#x2009;9.6 (mean&#x2009;&#xb1;&#x2009;SD) years. Baseline insulin resistance was not associated with age-dependent changes in LTL (attrition) over the follow-up period, whereas baseline LTL was associated with changes in insulin resistance during this period. The shorter the LTL at baseline, the more pronounced was the increase in insulin resistance over the follow-up period (p&#x2009;<&#x2009;0.001); this effect was additive to that of BMI. The co-twin with the shorter baseline LTL displayed higher insulin resistance at follow-up than the co-twin with the longer LTL.<br><br>CONCLUSIONS/INTERPRETATION: These findings suggest that individuals with short LTL are more likely to develop insulin resistance later in life. By contrast, presence of insulin resistance does not accelerate LTL attrition.},
}
@article {pmid27020053,
year = {2016},
author = {Spigoni, V and Aldigeri, R and Picconi, A and Derlindati, E and Franzini, L and Haddoub, S and Prampolini, G and Vigna, GB and Zavaroni, I and Bonadonna, RC and Dei Cas, A},
title = {Telomere length is independently associated with subclinical atherosclerosis in subjects with type 2 diabetes: a cross-sectional study.},
journal = {Acta diabetologica},
volume = {53},
number = {4},
pages = {661-667},
doi = {10.1007/s00592-016-0857-x},
pmid = {27020053},
issn = {1432-5233},
mesh = {Aged ; Atherosclerosis/complications/*genetics ; Biomarkers/blood ; Carotid Intima-Media Thickness ; Cross-Sectional Studies ; Diabetes Mellitus, Type 2/complications/*genetics ; Diabetic Angiopathies/*genetics ; Female ; Humans ; Leukocytes/cytology ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; *Telomere Shortening ; },
abstract = {AIMS: Individuals with type 2 diabetes show shorter leukocyte telomere length (LTL) compared to people without diabetes. Reduced LTL is associated with increased carotid intima-media thickness (IMT) in healthy subjects. The aim of the study is to assess whether LTL also correlates with IMT in patients with diabetes.<br><br>METHODS: In a cohort of 104 subjects with type 2 diabetes and atherogenic dyslipidemia, we assessed anthropometric, hemodynamic and metabolic parameters. Common carotid IMT was expressed as the maximum IMT. LTL was assessed by a specific real-time PCR reaction.<br><br>RESULTS: At univariate analysis, IMT values were positively correlated with age (p&#xa0;<&#xa0;0.001), previous history of cardiovascular events (p&#xa0;<&#xa0;0.005), fasting plasma glucose (p&#xa0;<&#xa0;0.01), HbA1c (p&#xa0;<&#xa0;0.05) and negatively correlated with LTL (p&#xa0;<&#xa0;0.05). In a multivariate model, age (p&#xa0;<&#xa0;0.001) and LTL (p&#xa0;<&#xa0;0.05) were the only independent predictors of maximum IMT, with an adjusted R (2) of 0.22.<br><br>CONCLUSIONS: LTL is an independent predictor of subclinical atherosclerosis pointing to a role of LTL as an early marker of vascular burden and cardiovascular disease also in type 2 diabetes.},
}
@article {pmid27018285,
year = {2016},
author = {Tamura, Y and Takubo, K and Aida, J and Araki, A and Ito, H},
title = {Telomere attrition and diabetes mellitus.},
journal = {Geriatrics &amp; gerontology international},
volume = {16 Suppl 1},
number = {},
pages = {66-74},
doi = {10.1111/ggi.12738},
pmid = {27018285},
issn = {1447-0594},
mesh = {Diabetes Mellitus/*genetics/metabolism ; Humans ; *Insulin Resistance ; *Oxidative Stress ; Telomere/*genetics/metabolism ; },
abstract = {Type 2 diabetes mellitus (DM) is a disease characterized by dysfunction of various organs. Recent studies have shown a close relationship between DM and telomere attrition in leukocytes. In patients with DM or impaired glucose tolerance, excessive oxidative stress induces damage to telomeres and shortens their length. Furthermore, it is suggested that telomere length is a good surrogate marker for mortality and diabetic complications in DM patients. We recently found that telomere length in pancreatic β-cells is also shortened in DM patients, potentially leading to an impaired capacity for proliferation and insulin secretion, and accelerated cell death. In contrast, leukocyte telomere length has also been reported in patients with obesity or insulin resistance, both of which are frequently associated with type 2 DM. In an animal model, it has been shown that telomere attrition in adipose tissue induces insulin resistance. Taken together, the available data suggest that hyperglycemia, oxidative stress, and telomere attrition in pancreatic β-cells and adipocytes create a vicious cycle that underlies the pathophysiology of type 2 DM. Inhibition of telomere attrition in various organs, including pancreatic β-cells, could be a new approach for preventing the progression of DM and its complications.},
}
@article {pmid27018281,
year = {2016},
author = {Ishikawa, N and Nakamura, K and Izumiyama-Shimomura, N and Aida, J and Matsuda, Y and Arai, T and Takubo, K},
title = {Changes of telomere status with aging: An update.},
journal = {Geriatrics &amp; gerontology international},
volume = {16 Suppl 1},
number = {},
pages = {30-42},
doi = {10.1111/ggi.12772},
pmid = {27018281},
issn = {1447-0594},
mesh = {Aging/*genetics ; Blotting, Southern ; Humans ; In Situ Hybridization, Fluorescence ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; },
abstract = {Accumulated data have shown that most human somatic cells or tissues show irreversible telomere shortening with age, and that there are strong associations between telomere attrition and aging-related diseases, including cancers, diabetes and cognitive disorders. Although it has been largely accepted that telomere attrition is one of the major causes of aging-related disorders, critical aspects of telomere biology remain unresolved, especially the lack of standardized methodology for quantification of telomere length. Another frustrating issue is that no potentially promising methods for safe prevention of telomere erosion, or for telomere elongation, have been devised. Here, we review several methods for quantification of telomere length currently utilized worldwide, considering their advantages and drawbacks. We also summarize the results of our recent studies of human cells and tissues, mainly using quantitative fluorescence in situ hybridization and Southern blotting, including those derived from patients with progeria-prone Werner syndrome and trisomy 21, and several strains of induced pluripotent stem cells. We discuss the possible merits of using telomere shortness as an indicator, or a new marker, for diagnosis of precancerous states and aging-related disorders. In addition, we describe newly found factors that are thought to impact telomere dynamics, providing a new avenue for examining the unsolved issues related to telomere restoration and maintenance.},
}
@article {pmid27013236,
year = {2016},
author = {Takai, H and Jenkinson, E and Kabir, S and Babul-Hirji, R and Najm-Tehrani, N and Chitayat, DA and Crow, YJ and de Lange, T},
title = {A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus.},
journal = {Genes &amp; development},
volume = {30},
number = {7},
pages = {812-826},
pmid = {27013236},
issn = {1549-5477},
support = {R01 CA181090/CA/NCI NIH HHS/United States ; R56 AG016642/AG/NIA NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; AG16642//National Institute of Aging/International ; 1R01CA181090/CA/NCI NIH HHS/United States ; },
mesh = {Aminopeptidases/metabolism ; Ataxia/*genetics ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Brain Neoplasms/*genetics ; Calcinosis/*genetics ; Cells, Cultured ; Central Nervous System Cysts/*genetics ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism ; Female ; Humans ; Leukoencephalopathies/*genetics ; Metaphase ; Muscle Spasticity/*genetics ; Mutation/*genetics ; Protein Binding ; Retinal Diseases/*genetics ; Seizures/*genetics ; Serine Proteases/metabolism ; Shelterin Complex ; Signal Transduction ; Telomere/*genetics/metabolism/*pathology ; Telomere Homeostasis/genetics ; Telomere Shortening/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {Coats plus (CP) can be caused by mutations in the CTC1 component of CST, which promotes polymerase α (polα)/primase-dependent fill-in throughout the genome and at telomeres. The cellular pathology relating to CP has not been established. We identified a homozygous POT1 S322L substitution (POT1(CP)) in two siblings with CP. POT1(CP)induced a proliferative arrest that could be bypassed by telomerase. POT1(CP)was expressed at normal levels, bound TPP1 and telomeres, and blocked ATR signaling. POT1(CP)was defective in regulating telomerase, leading to telomere elongation rather than the telomere shortening observed in other telomeropathies. POT1(CP)was also defective in the maintenance of the telomeric C strand, causing extended 3' overhangs and stochastic telomere truncations that could be healed by telomerase. Consistent with shortening of the telomeric C strand, metaphase chromosomes showed loss of telomeres synthesized by leading strand DNA synthesis. We propose that CP is caused by a defect in POT1/CST-dependent telomere fill-in. We further propose that deficiency in the fill-in step generates truncated telomeres that halt proliferation in cells lacking telomerase, whereas, in tissues expressing telomerase (e.g., bone marrow), the truncations are healed. The proposed etiology can explain why CP presents with features distinct from those associated with telomerase defects (e.g., dyskeratosis congenita).},
}
@article {pmid27012789,
year = {2016},
author = {Zhang, L and Zhang, K and Rauf, S and Dong, D and Liu, Y and Li, J},
title = {Single-Molecule Analysis of Human Telomere Sequence Interactions with G-quadruplex Ligand.},
journal = {Analytical chemistry},
volume = {88},
number = {8},
pages = {4533-4540},
doi = {10.1021/acs.analchem.6b00555},
pmid = {27012789},
issn = {1520-6882},
mesh = {Aminoquinolines/*chemistry ; Base Sequence ; *G-Quadruplexes ; Hemolysin Proteins/*chemistry ; Humans ; Ligands ; Nanopores ; Picolinic Acids/*chemistry ; Potassium/chemistry ; *Single Molecule Imaging ; Telomere/*chemistry ; Thermodynamics ; },
abstract = {Ligands that selectively promote the formation of G-quadruplexes in human telomeres have great potential for cancer treatment by inhibiting the telomere extension by telomerase. Thus, understanding the interactions of the G-quadruplex ligands with the telomere sequence at the single-molecule level is of significant importance. Here, human telomere sequence interactions with a small molecule ligand pyridostatin (PDS) were analyzed via α-hemolysin protein nanopore, and a nanopore thermodynamic analytical method was proposed. The prolonged unraveling time of the telomeric DNA G-quadruplex after PDS binding demonstrated the potent stabilization effect of ligand on G-quadruplex structure. The signature two-level electronic blocks generated by K(+)-PDS-G-quadruplex complexes suggested a two-state unraveling process, including the dissociation of the interquartet cation and the unraveling of the cation-free ligand-bound G-quadruplex. The translocation studies and the analysis of free-energy changes demonstrated a ligand-binding mode in which PDS molecule and K(+) were simultaneously bound to one G-quadruplex structure with the coordinated effect on G-quadruplex stabilization. The single-molecular nanopore platform permits the efficient and accurate determination of ligand affinity constants without the requirement for labeling, amplification, or ligand/receptor titration, which provides a general analytical tool for effectively monitoring and quantifying the G-quadruplex/ligand interactions, possessing important implications for the design and screen of anticancer drugs.},
}
@article {pmid27010504,
year = {2016},
author = {Gonzalo, S and Eissenberg, JC},
title = {Tying up loose ends: telomeres, genomic instability and lamins.},
journal = {Current opinion in genetics &amp; development},
volume = {37},
number = {},
pages = {109-118},
pmid = {27010504},
issn = {1879-0380},
support = {R01 GM094513/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Nucleus/genetics ; Chromatin/genetics ; Chromosomes/genetics ; DNA Damage/genetics ; DNA Repair/genetics ; *Genomic Instability ; Humans ; Lamins/*genetics ; Telomere/*genetics ; },
abstract = {On casual inspection, the eukaryotic nucleus is a deceptively simple organelle. Far from being a bag of chromatin, the nucleus is, in some ways, a structural and functional extension of the chromosomes it contains. Recently, interest has intensified in how chromosome compartmentalization and dynamics affect nuclear function. Different studies uncovered functional interactions between chromosomes and the filamentous nuclear meshwork comprised of lamin proteins. Here, we summarize recent research suggesting that telomeres, the capping structures that protect chromosome ends, are stabilized by lamin-binding and that alterations in nuclear lamins lead to defects in telomere compartmentalization, homeostasis and function. Telomere dysfunction contributes to the genomic instability that characterizes aging-related diseases, and might be an important factor in the pathophysiology of lamin-related diseases.},
}
@article {pmid27008888,
year = {2016},
author = {Machiela, MJ and Lan, Q and Slager, SL and Vermeulen, RC and Teras, LR and Camp, NJ and Cerhan, JR and Spinelli, JJ and Wang, SS and Nieters, A and Vijai, J and Yeager, M and Wang, Z and Ghesquières, H and McKay, J and Conde, L and de Bakker, PI and Cox, DG and Burdett, L and Monnereau, A and Flowers, CR and De Roos, AJ and Brooks-Wilson, AR and Giles, GG and Melbye, M and Gu, J and Jackson, RD and Kane, E and Purdue, MP and Vajdic, CM and Albanes, D and Kelly, RS and Zucca, M and Bertrand, KA and Zeleniuch-Jacquotte, A and Lawrence, C and Hutchinson, A and Zhi, D and Habermann, TM and Link, BK and Novak, AJ and Dogan, A and Asmann, YW and Liebow, M and Thompson, CA and Ansell, SM and Witzig, TE and Tilly, H and Haioun, C and Molina, TJ and Hjalgrim, H and Glimelius, B and Adami, HO and Roos, G and Bracci, PM and Riby, J and Smith, MT and Holly, EA and Cozen, W and Hartge, P and Morton, LM and Severson, RK and Tinker, LF and North, KE and Becker, N and Benavente, Y and Boffetta, P and Brennan, P and Foretova, L and Maynadie, M and Staines, A and Lightfoot, T and Crouch, S and Smith, A and Roman, E and Diver, WR and Offit, K and Zelenetz, A and Klein, RJ and Villano, DJ and Zheng, T and Zhang, Y and Holford, TR and Turner, J and Southey, MC and Clavel, J and Virtamo, J and Weinstein, S and Riboli, E and Vineis, P and Kaaks, R and Boeing, H and Tjønneland, A and Angelucci, E and Di Lollo, S and Rais, M and De Vivo, I and Giovannucci, E and Kraft, P and Huang, J and Ma, B and Ye, Y and Chiu, BC and Liang, L and Park, JH and Chung, CC and Weisenburger, DD and Fraumeni, JF and Salles, G and Glenn, M and Cannon-Albright, L and Curtin, K and Wu, X and Smedby, KE and de Sanjose, S and Skibola, CF and Berndt, SI and Birmann, BM and Chanock, SJ and Rothman, N},
title = {Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes.},
journal = {Human molecular genetics},
volume = {25},
number = {8},
pages = {1663-1676},
pmid = {27008888},
issn = {1460-2083},
support = {UL1 TR001863/TR/NCATS NIH HHS/United States ; CA098122/CA/NCI NIH HHS/United States ; N01RC37004/RC/CCR NIH HHS/United States ; P50 CA097274/CA/NCI NIH HHS/United States ; R01 CA134674/CA/NCI NIH HHS/United States ; CA1046282/CA/NCI NIH HHS/United States ; UL1 TR001070/TR/NCATS NIH HHS/United States ; CA167552/CA/NCI NIH HHS/United States ; CA118444/CA/NCI NIH HHS/United States ; N01 PC067009/CN/NCI NIH HHS/United States ; CA134674/CA/NCI NIH HHS/United States ; N02-PC-71105/PC/NCI NIH HHS/United States ; HHSN268201100001I/HL/NHLBI NIH HHS/United States ; R35 CA197449/CA/NCI NIH HHS/United States ; N01-RC-45035/RC/CCR NIH HHS/United States ; P30 CA016087/CA/NCI NIH HHS/United States ; HHSN261201000140C/CA/NCI NIH HHS/United States ; N01 PC067010/PC/NCI NIH HHS/United States ; R01 CA098122/CA/NCI NIH HHS/United States ; P30 CA42014/CA/NCI NIH HHS/United States ; U01 HG007033/HG/NHGRI NIH HHS/United States ; HHSN261201000035C/CA/NCI NIH HHS/United States ; K08CA134919/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; HHSN261201000006C/CP/NCI NIH HHS/United States ; R21 CA165923/CA/NCI NIH HHS/United States ; HHSN268201100004I/HL/NHLBI NIH HHS/United States ; CA154643/CA/NCI NIH HHS/United States ; K07 CA115687/CA/NCI NIH HHS/United States ; CA098566/CA/NCI NIH HHS/United States ; CA148690/CA/NCI NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; /CAPMC/CIHR/Canada ; P30 CA086862/CA/NCI NIH HHS/United States ; CA87969/CA/NCI NIH HHS/United States ; N01 PC067008/PC/NCI NIH HHS/United States ; HHSN268201100003C/WH/WHI NIH HHS/United States ; R01 CA148690/CA/NCI NIH HHS/United States ; P30 ES000260/ES/NIEHS NIH HHS/United States ; CA49449/CA/NCI NIH HHS/United States ; CA92153/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R25 CA098566/CA/NCI NIH HHS/United States ; U58 DP000807/DP/NCCDPHP CDC HHS/United States ; N01-PC-67009/PC/NCI NIH HHS/United States ; CA149445/CA/NCI NIH HHS/United States ; R01 CA154643/CA/NCI NIH HHS/United States ; R01 CA062006/CA/NCI NIH HHS/United States ; N01 PC065064/PC/NCI NIH HHS/United States ; K08 CA134919/CA/NCI NIH HHS/United States ; UL1 TR000135/TR/NCATS NIH HHS/United States ; HHSN271201100004C/AG/NIA NIH HHS/United States ; R01 CA098661/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; HHSN268201100002C/WH/WHI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; R01 CA092153/CA/NCI NIH HHS/United States ; HHSN261201000035I/CA/NCI NIH HHS/United States ; CA165923/CA/NCI NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; 5R01 CA69669-02/CA/NCI NIH HHS/United States ; HHSN261201000034C/CA/NCI NIH HHS/United States ; R01 CA92153/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; HHSN268201100002I/HL/NHLBI NIH HHS/United States ; P30 CA016359/CA/NCI NIH HHS/United States ; CA186107/CA/NCI NIH HHS/United States ; N01CO12400/CA/NCI NIH HHS/United States ; N01 CN045165/CN/NCI NIH HHS/United States ; U01 CA049449/CA/NCI NIH HHS/United States ; R01 CA149445/CA/NCI NIH HHS/United States ; #1U58 DP000807-01/DP/NCCDPHP CDC HHS/United States ; HHSN268201100001C/WH/WHI NIH HHS/United States ; HHSN261201000026C/CA/NCI NIH HHS/United States ; P50 CA97274/CA/NCI NIH HHS/United States ; N01-CO-12400/CO/NCI NIH HHS/United States ; HHSN268201100004C/WH/WHI NIH HHS/United States ; /CRUK_/Cancer Research UK/United Kingdom ; U01 CA118444/CA/NCI NIH HHS/United States ; P30 CA042014/CA/NCI NIH HHS/United States ; ES000260/ES/NIEHS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Female ; Genetic Association Studies/*methods ; *Genetic Predisposition to Disease ; Humans ; Lymphoma, B-Cell/*genetics/*pathology ; Male ; Middle Aged ; Prospective Studies ; Telomere/*pathology ; },
abstract = {Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 × 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 × 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.},
}
@article {pmid27007392,
year = {2016},
author = {Barden, A and O'Callaghan, N and Burke, V and Mas, E and Beilin, LJ and Fenech, M and Irish, AB and Watts, GF and Puddey, IB and Huang, RC and Mori, TA},
title = {n-3 Fatty Acid Supplementation and Leukocyte Telomere Length in Patients with Chronic Kidney Disease.},
journal = {Nutrients},
volume = {8},
number = {3},
pages = {175},
pmid = {27007392},
issn = {2072-6643},
mesh = {Adult ; Aged ; Antioxidants/adverse effects/*therapeutic use ; Biomarkers/blood ; *Dietary Supplements/adverse effects ; Docosahexaenoic Acids/adverse effects/*therapeutic use ; Double-Blind Method ; Drug Combinations ; Eicosapentaenoic Acid/adverse effects/*therapeutic use ; F2-Isoprostanes/blood ; Female ; Humans ; Leukocytes, Mononuclear/*drug effects/metabolism ; Male ; Middle Aged ; Neutrophils/*drug effects/metabolism ; Oxidative Stress/drug effects ; Renal Insufficiency, Chronic/diagnosis/*drug therapy/genetics ; Telomere/*drug effects/metabolism ; Telomere Homeostasis/*drug effects ; Time Factors ; Treatment Outcome ; Ubiquinone/adverse effects/*analogs &amp; derivatives/therapeutic use ; Western Australia ; },
abstract = {DNA telomere shortening associates with the age-related increase cardiovascular disease (CVD) risk. Reducing oxidative stress, could modify telomere erosion during cell replication, and CVD risk in patients with chronic kidney disease (CKD). The effect of n-3 fatty acids and coenzyme Q10 (CoQ) on telomere length was studied in a double-blind placebo-controlled trial in CKD. Eighty-five CKD patients were randomized to: n-3 fatty acids (4 g); CoQ (200 mg); both supplements; or control (4 g olive oil), daily for 8 weeks. Telomere length was measured in neutrophils and peripheral blood mononuclear cells (PBMC) at baseline and 8 weeks, with and without correction for cell counts. Main and interactive effects of n-3 fatty acids and CoQ on telomere length were assessed adjusting for baseline values. F2-isoprostanes were measured as markers of oxidative stress. There was no effect of n-3 fatty acids or CoQ on neutrophil or PBMC telomere length. However, telomere length corrected for neutrophil count was increased after n-3 fatty acids (p = 0.015). Post-intervention plasma F2-isoprostanes were negative predictors of post-intervention telomere length corrected for neutrophil count (p = 0.025).The effect of n-3 fatty acids to increased telomere length corrected for neutrophil count may relate to reduced oxidative stress and increased clearance of neutrophils with shorter telomeres from the circulation. This may be a novel mechanism of modifying CVD risk in CKD patients.},
}
@article {pmid27004475,
year = {2016},
author = {Xue, Y and Marvin, ME and Ivanova, IG and Lydall, D and Louis, EJ and Maringele, L},
title = {Rif1 and Exo1 regulate the genomic instability following telomere losses.},
journal = {Aging cell},
volume = {15},
number = {3},
pages = {553-562},
pmid = {27004475},
issn = {1474-9726},
support = {/WT_/Wellcome Trust/United Kingdom ; 13314/CRUK_/Cancer Research UK/United Kingdom ; MR/L001284/1/MRC_/Medical Research Council/United Kingdom ; 81164/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Cell Cycle Checkpoints/genetics ; Cell Proliferation/genetics ; Cellular Senescence/genetics ; Chromosomes, Fungal/metabolism ; DNA Breaks, Double-Stranded ; Endonucleases/metabolism ; Exodeoxyribonucleases/*metabolism ; Gene Deletion ; *Genomic Instability ; Microbial Viability/genetics ; Models, Biological ; Phenotype ; Repressor Proteins/*metabolism ; Saccharomyces cerevisiae/cytology/*genetics/growth &amp; development ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomere attrition is linked to cancer, diabetes, cardiovascular disease and aging. This is because telomere losses trigger further genomic modifications, culminating with loss of cell function and malignant transformation. However, factors regulating the transition from cells with short telomeres, to cells with profoundly altered genomes, are little understood. Here, we use budding yeast engineered to lack telomerase and other forms of telomere maintenance, to screen for such factors. We show that initially, different DNA damage checkpoint proteins act together with Exo1 and Mre11 nucleases, to inhibit proliferation of cells undergoing telomere attrition. However, this situation changes when survivors lacking telomeres emerge. Intriguingly, checkpoint pathways become tolerant to loss of telomeres in survivors, yet still alert to new DNA damage. We show that Rif1 is responsible for the checkpoint tolerance and proliferation of these survivors, and that is also important for proliferation of cells with a broken chromosome. In contrast, Exo1 drives extensive genomic modifications in survivors. Thus, the conserved proteins Rif1 and Exo1 are critical for survival and evolution of cells with lost telomeres.},
}
@article {pmid26999107,
year = {2016},
author = {Donati, B and Valenti, L},
title = {Telomeres, NAFLD and Chronic Liver Disease.},
journal = {International journal of molecular sciences},
volume = {17},
number = {3},
pages = {383},
pmid = {26999107},
issn = {1422-0067},
mesh = {Disease Progression ; Humans ; Liver Diseases/genetics/metabolism/*pathology ; Mutation ; Non-alcoholic Fatty Liver Disease/genetics/metabolism/*pathology ; RNA/metabolism ; Shelterin Complex ; Telomerase/metabolism ; Telomere/*genetics/metabolism ; Telomere Shortening ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomeres consist of repeat DNA sequences located at the terminal portion of chromosomes that shorten during mitosis, protecting the tips of chromosomes. During chronic degenerative conditions associated with high cell replication rate, progressive telomere attrition is accentuated, favoring senescence and genomic instability. Several lines of evidence suggest that this process is involved in liver disease progression: (a) telomere shortening and alterations in the expression of proteins protecting the telomere are associated with cirrhosis and hepatocellular carcinoma; (b) advanced liver damage is a feature of a spectrum of genetic diseases impairing telomere function, and inactivating germline mutations in the telomerase complex (including human Telomerase Reverse Transcriptase (hTERT) and human Telomerase RNA Component (hTERC)) are enriched in cirrhotic patients independently of the etiology; and (c) experimental models suggest that telomerase protects from liver fibrosis progression. Conversely, reactivation of telomerase occurs during hepatocarcinogenesis, allowing the immortalization of the neoplastic clone. The role of telomere attrition may be particularly relevant in the progression of nonalcoholic fatty liver, an emerging cause of advanced liver disease. Modulation of telomerase or shelterins may be exploited to prevent liver disease progression, and to define specific treatments for different stages of liver disease.},
}
@article {pmid26998167,
year = {2016},
author = {Barczak, W and Rozwadowska, N and Romaniuk, A and Lipińska, N and Lisiak, N and Grodecka-Gazdecka, S and Książek, K and Rubiś, B},
title = {Telomere length assessment in leukocytes presents potential diagnostic value in patients with breast cancer.},
journal = {Oncology letters},
volume = {11},
number = {3},
pages = {2305-2309},
pmid = {26998167},
issn = {1792-1074},
abstract = {Telomere shortening is associated with cancer development, primarily through the induction of genomic instability. The majority of studies have indicated that individuals with shorter blood telomeres may be at a higher risk of developing various types of cancer. There is increasing evidence that the study of the alterations in telomere length may improve cancer prognosis. The aim of the present study was to verify the use of telomere length parameters in the diagnostics of breast cancer stage. Telomere length was analyzed in the blood leukocytes of 52 patients with breast cancer relative to 47 control subjects using quantitative polymerase chain reaction. The effects of stage, grade, estrogen receptor, progesterone receptor and human epidermal growth factor 2 (HER2) status were assessed. The current study demonstrated that the average telomeric sequence length was significantly shorter in leukocytes from individuals diagnosed with a more severe stage of breast cancer (T2N1M0) than in leukocytes in the early stages of the disease (T1N0M0) (P=0.0207). Furthermore, the data indicated that telomeres in leukocytes derived from patients with HER2[+] breast cancer were significantly longer compared with those with the HER2[-] type (P=0.0347). These results suggest that the assessment of telomeres in blood leukocytes may, at least partially, correspond with breast cancer staging and HER2 receptor status.},
}
@article {pmid26997646,
year = {2016},
author = {Nakai-Futatsugi, Y and Niwa, H},
title = {Zscan4 Is Activated after Telomere Shortening in Mouse Embryonic Stem Cells.},
journal = {Stem cell reports},
volume = {6},
number = {4},
pages = {483-495},
pmid = {26997646},
issn = {2213-6711},
mesh = {Animals ; Cell Cycle/genetics ; Green Fluorescent Proteins/genetics/metabolism ; In Situ Hybridization, Fluorescence ; Luciferases/genetics/metabolism ; Mice ; Microscopy, Fluorescence ; Models, Genetic ; Mouse Embryonic Stem Cells/cytology/*metabolism ; RNA Interference ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*genetics/metabolism ; Telomere Shortening/*genetics ; Time Factors ; Time-Lapse Imaging/methods ; Transcription Factors/*genetics/metabolism ; },
abstract = {ZSCAN4 is a DNA-binding protein that functions for telomere elongation and genomic stability. In vivo, it is specifically expressed at the two-cell stage during mouse development. In vitro, it is transiently expressed in mouse embryonic stem cells (ESCs), only in 5% of the population at one time. Here we attempted to elucidate when, under what circumstances, Zscan4 is activated in ESCs. Using live cell imaging, we monitored the activity of Zscan4 together with the pluripotency marker Rex1. The lengths of the cell cycles in ESCs were diverse. Longer cell cycles were accompanied by shorter telomeres and higher activation of Zscan4. Since activation of Zscan4 is involved in telomere elongation, we speculate that the extended cell cycles accompanied by Zscan4 activation reflect the time for telomere recovery. Rex1 and Zscan4 did not show any correlation. Taken together, we propose that Zscan4 is activated to recover shortened telomeres during extended cell cycles, irrespective of the pluripotent status.},
}
@article {pmid26995138,
year = {2016},
author = {Laubenthal, L and Hoelker, M and Frahm, J and Dänicke, S and Gerlach, K and Südekum, KH and Sauerwein, H and Häussler, S},
title = {Short communication: Telomere lengths in different tissues of dairy cows during early and late lactation.},
journal = {Journal of dairy science},
volume = {99},
number = {6},
pages = {4881-4885},
doi = {10.3168/jds.2015-10095},
pmid = {26995138},
issn = {1525-3198},
mesh = {Animals ; Cattle/genetics ; Female ; Genomics ; *Lactation ; Liver/metabolism ; Mammary Glands, Animal/metabolism ; Sequence Analysis, DNA ; Subcutaneous Fat/metabolism ; Telomere/*chemistry/genetics ; },
abstract = {Telomeres create a protective cap on the ends of chromosomes that shorten with cell division and are influenced by stressful conditions. With the onset of lactation, high-yielding dairy cows are exposed to metabolic stress. In the present study, we aimed to analyze telomere length (TL) in key metabolic organs, such as liver, subcutaneous (sc) adipose tissue (AT), and mammary gland, as well as in peripheral blood cells during early and late lactation in German Holstein cows (n=21). Animals were fed according to their requirement, and biopsies from scAT, liver, and mammary gland as well as blood cells were collected in early and late lactation. The relative quantity of telomere products (qT), which is proportional to the average TL, was determined in genomic DNA by multiplex quantitative PCR. In this study, relative qT varied widely in the investigated tissues and blood. In late lactation, slowly proliferating tissues, such as liver and scAT, had the highest qT, whereas peripheral blood cells and in the mammary gland had the lowest qT. Comparing early with late lactation, relative qT attrition was limited to blood and mammary gland. Relationships between relative qT in blood, mammary gland, scAT, and liver suggest that blood qT might serve as a surrogate marker for tissue-specific qT. Cows with high initial qT in tissues and blood in early lactation had greater qT attrition during the course of lactation than cows with lower qT. The determination of qT could be included when phenotyping dairy cattle to test for associations with performance and fitness traits.},
}
@article {pmid26992670,
year = {2016},
author = {Biron-Shental, T and Sadeh-Mestechkin, D and Amiel, A},
title = {Telomere homeostasis in IUGR placentas - A review.},
journal = {Placenta},
volume = {39},
number = {},
pages = {21-23},
doi = {10.1016/j.placenta.2015.11.006},
pmid = {26992670},
issn = {1532-3102},
mesh = {Animals ; Female ; Fetal Growth Retardation/*genetics/metabolism/pathology ; Humans ; Placenta/*metabolism/pathology ; Pregnancy ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {Telomeres are nucleoprotein structures located at the termini of chromosomes. They are essential for chromosome stability. Telomeres become shorter due to mitotic cycles and environmental factors. When telomeres are shortened and therefore dysfunctional, cellular senescence occurs and organ dysfunction might develop. During pregnancy, fetal growth restriction secondary to placental insufficiency has been linked to impaired telomere homeostasis in which telomeres are shorter, telomerase is decreased, and compensatory mechanisms of telomere capture are enhanced. These characteristics, along with increased signs of senescence, indicate telomere dysfunction in trophoblasts from placentas affected by intrauterine growth restriction (IUGR). This review summarizes the information currently available regarding telomere homeostasis in trophoblasts from human pregnancies affected by IUGR. Improved understanding of placental physiology might help in the development of treatment options for fetuses with IUGR.},
}
@article {pmid26991404,
year = {2016},
author = {Taylor-Kashton, C and Lichtensztejn, D and Baloglu, E and Senapedis, W and Shacham, S and Kauffman, MG and Kotb, R and Mai, S},
title = {XPO1 Inhibition Preferentially Disrupts the 3D Nuclear Organization of Telomeres in Tumor Cells.},
journal = {Journal of cellular physiology},
volume = {231},
number = {12},
pages = {2711-2719},
pmid = {26991404},
issn = {1097-4652},
mesh = {Aged ; Cell Line, Tumor ; Cell Nucleus/*metabolism ; Female ; Fibroblasts/metabolism ; Humans ; *Imaging, Three-Dimensional ; Karyopherins/*metabolism ; Male ; Middle Aged ; Multiple Myeloma/pathology ; Receptors, Cytoplasmic and Nuclear/*metabolism ; Telomere/*metabolism ; Exportin 1 Protein ; },
abstract = {Previous work has shown that the three-dimensional (3D) nuclear organization of telomeres is altered in cancer cells and the degree of alterations coincides with aggressiveness of disease. Nuclear pores are essential for spatial genome organization and gene regulation and XPO1 (exportin 1/CRM1) is the key nuclear export protein. The Selective Inhibitor of Nuclear Export (SINE) compounds developed by Karyopharm Therapeutics (KPT-185, KPT-330/selinexor, and KPT-8602) inhibit XPO1 nuclear export function. In this study, we investigated whether XPO1 inhibition has downstream effects on the 3D nuclear organization of the genome. This was assessed by measuring the 3D telomeric architecture of normal and tumor cells in vitro and ex vivo. Our data demonstrate for the first time a rapid and preferential disruption of the 3D nuclear organization of telomeres in tumor cell lines and in primary cells ex vivo derived from treatment-naïve newly diagnosed multiple myeloma patients. Normal primary cells in culture as well as healthy lymphocyte control cells from the same patients were minimally affected. Using both lymphoid and non-lymphoid tumor cell lines, we found that the downstream effects on the 3D nuclear telomere structure are independent of tumor type. We conclude that the 3D nuclear organization of telomeres is a sensitive indicator of cellular response when treated with XPO1 inhibitors. J. Cell. Physiol. 231: 2711-2719, 2016. © 2016 Wiley Periodicals, Inc.},
}
@article {pmid26990647,
year = {2016},
author = {Gadaleta, MC and Das, MM and Tanizawa, H and Chang, YT and Noma, K and Nakamura, TM and Noguchi, E},
title = {Swi1Timeless Prevents Repeat Instability at Fission Yeast Telomeres.},
journal = {PLoS genetics},
volume = {12},
number = {3},
pages = {e1005943},
pmid = {26990647},
issn = {1553-7404},
support = {GM078253/GM/NIGMS NIH HHS/United States ; DP2 OD004348/OD/NIH HHS/United States ; GM077604/GM/NIGMS NIH HHS/United States ; R01 GM078253/GM/NIGMS NIH HHS/United States ; R01 GM077604/GM/NIGMS NIH HHS/United States ; DP2-OD004348/OD/NIH HHS/United States ; P30CA010815/CA/NCI NIH HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/*genetics ; DNA Replication/genetics ; DNA-Binding Proteins/*genetics ; Genomic Instability ; Heterochromatin/genetics ; Humans ; *Microsatellite Instability ; Rad52 DNA Repair and Recombination Protein/genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; Schizosaccharomyces/genetics ; Schizosaccharomyces pombe Proteins/*genetics ; Telomere/genetics ; Telomere Homeostasis ; Telomere Shortening/genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {Genomic instability associated with DNA replication stress is linked to cancer and genetic pathologies in humans. If not properly regulated, replication stress, such as fork stalling and collapse, can be induced at natural replication impediments present throughout the genome. The fork protection complex (FPC) is thought to play a critical role in stabilizing stalled replication forks at several known replication barriers including eukaryotic rDNA genes and the fission yeast mating-type locus. However, little is known about the role of the FPC at other natural impediments including telomeres. Telomeres are considered to be difficult to replicate due to the presence of repetitive GT-rich sequences and telomere-binding proteins. However, the regulatory mechanism that ensures telomere replication is not fully understood. Here, we report the role of the fission yeast Swi1(Timeless), a subunit of the FPC, in telomere replication. Loss of Swi1 causes telomere shortening in a telomerase-independent manner. Our epistasis analyses suggest that heterochromatin and telomere-binding proteins are not major impediments for telomere replication in the absence of Swi1. Instead, repetitive DNA sequences impair telomere integrity in swi1Δ mutant cells, leading to the loss of repeat DNA. In the absence of Swi1, telomere shortening is accompanied with an increased recruitment of Rad52 recombinase and more frequent amplification of telomere/subtelomeres, reminiscent of tumor cells that utilize the alternative lengthening of telomeres pathway (ALT) to maintain telomeres. These results suggest that Swi1 ensures telomere replication by suppressing recombination and repeat instability at telomeres. Our studies may also be relevant in understanding the potential role of Swi1(Timeless) in regulation of telomere stability in cancer cells.},
}
@article {pmid26978042,
year = {2016},
author = {Linkus, B and Wiesner, D and Meßner, M and Karabatsiakis, A and Scheffold, A and Rudolph, KL and Thal, DR and Weishaupt, JH and Ludolph, AC and Danzer, KM},
title = {Telomere shortening leads to earlier age of onset in ALS mice.},
journal = {Aging},
volume = {8},
number = {2},
pages = {382-393},
pmid = {26978042},
issn = {1945-4589},
mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Astrocytes/pathology ; Brain/*pathology ; Disease Models, Animal ; Female ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Mice, Knockout ; Mice, Transgenic ; Microglia/pathology ; Neurons/pathology ; Telomere/*pathology ; Telomere Shortening/*physiology ; },
abstract = {Telomere shortening has been linked to a variety of neurodegenerative diseases. Recent evidence suggests that reduced telomerase expression results in shorter telomeres in leukocytes from sporadic patients with amyotrophic lateral sclerosis (ALS) compared with healthy controls. Here, we have characterized telomere length in microglia, astroglia and neurons in human post mortem brain tissue from ALS patients and healthy controls. Moreover, we studied the consequences of telomerase deletion in a genetic mouse model for ALS. We found a trend towards longer telomeres in microglia in the brains of ALS patients compared to non-neurologic controls. Knockout of telomerase leading to telomere shortening accelerated the ALS phenotype inSOD1G93A-transgenic mice. Our results suggest that telomerase dysfunction might contribute to the age-related risk for ALS.},
}
@article {pmid26977417,
year = {2016},
author = {Lin, J and Cheon, J and Brown, R and Coccia, M and Puterman, E and Aschbacher, K and Sinclair, E and Epel, E and Blackburn, EH},
title = {Systematic and Cell Type-Specific Telomere Length Changes in Subsets of Lymphocytes.},
journal = {Journal of immunology research},
volume = {2016},
number = {},
pages = {5371050},
pmid = {26977417},
issn = {2314-7156},
support = {R01 AG030424-01A2/AG/NIA NIH HHS/United States ; P30AI027763/AI/NIAID NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; UL1RR024131/RR/NCRR NIH HHS/United States ; P30 AI027763/AI/NIAID NIH HHS/United States ; R01 AG030424/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Antigens, CD/genetics/immunology ; B-Lymphocytes/*immunology/pathology ; CD4-Positive T-Lymphocytes/*immunology/pathology ; CD8-Positive T-Lymphocytes/*immunology/pathology ; Case-Control Studies ; Female ; Gene Expression ; Humans ; Immunophenotyping ; Middle Aged ; Organ Specificity ; Premenopause/immunology ; Stress, Psychological/genetics/*immunology/pathology ; Telomere/*immunology ; Telomere Homeostasis/*immunology ; },
abstract = {Telomeres, the protective DNA-protein complexes at the ends of linear chromosomes, are important for genome stability. Leukocyte or peripheral blood mononuclear cell (PBMC) telomere length is a potential biomarker for human aging that integrates genetic, environmental, and lifestyle factors and is associated with mortality and risks for major diseases. However, only a limited number of studies have examined longitudinal changes of telomere length and few have reported data on sorted circulating immune cells. We examined the average telomere length (TL) in CD4+, CD8+CD28+, and CD8+CD28- T cells, B cells, and PBMCs, cross-sectionally and longitudinally, in a cohort of premenopausal women. We report that TL changes over 18 months were correlated among these three T cell types within the same participant. Additionally, PBMC TL change was also correlated with those of all three T cell types, and B cells. The rate of shortening for B cells was significantly greater than for the three T cell types. CD8+CD28- cells, despite having the shortest TL, showed significantly more rapid attrition when compared to CD8+CD28+ T cells. These results suggest systematically coordinated, yet cell type-specific responses to factors and pathways contribute to telomere length regulation.},
}
@article {pmid26975532,
year = {2016},
author = {Freitas-Simoes, TM and Ros, E and Sala-Vila, A},
title = {Nutrients, foods, dietary patterns and telomere length: Update of epidemiological studies and randomized trials.},
journal = {Metabolism: clinical and experimental},
volume = {65},
number = {4},
pages = {406-415},
doi = {10.1016/j.metabol.2015.11.004},
pmid = {26975532},
issn = {1532-8600},
mesh = {Animals ; *Diet ; Diet, Mediterranean ; *Epidemiologic Factors ; Food ; Humans ; *Nutritional Status ; Randomized Controlled Trials as Topic ; Telomere/*physiology/*ultrastructure ; *Telomere Shortening ; },
abstract = {Identifying simple strategies to prevent or delay age-associated pathologies is a major public health concern. Attrition of telomeres, chromatin structures that help maintain genome stability, leads to cell death or senescence. Thus telomere length is a reliable hallmark of biological aging and the risk of developing age-related chronic diseases through common oxidation and inflammation mechanisms. Variability in telomere shortening that is independent of chronological age suggests that it is a modifiable factor, which may be explained in part by lifestyle variables such as smoking, adiposity, physical exercise, and diet. Here we summarize data from published studies focused on nutrition (nutrients, foods, and dietary patterns) and telomere length. Research on the topic is incipient and most data comes from epidemiologic studies, often cross-sectional in design. Consistent with well-known evidence of benefit or harm for chronic age-related diseases, dietary antioxidants and consumption of antioxidant-rich, plant-derived foods help maintain telomere length. In contrast, total and saturated fat intake and consumption of refined flour cereals, meat and meat products, and sugar-sweetened beverages relate to shorter telomeres. Data on alcohol and dairy products is controversial. There is evidence that adherence to the Mediterranean diet is associated with longer telomeres. Randomized clinical trials are limited to seafood-derived long-chain n-3 polyunsaturated fatty acids, with promising results. To fill the many gaps in our knowledge of the aging process and confirm nutrition as a useful tool to counteract biological aging more research is warranted, particularly observational studies using repeated measurements of telomere length and randomized trials of foods and dietary patterns with sequential telomere analyses.},
}
@article {pmid26974669,
year = {2016},
author = {van Mourik, PM and de Jong, J and Agpalo, D and Claussin, C and Rothstein, R and Chang, M},
title = {Recombination-Mediated Telomere Maintenance in Saccharomyces cerevisiae Is Not Dependent on the Shu Complex.},
journal = {PloS one},
volume = {11},
number = {3},
pages = {e0151314},
pmid = {26974669},
issn = {1932-6203},
support = {R01 GM050237/GM/NIGMS NIH HHS/United States ; R37 GM050237/GM/NIGMS NIH HHS/United States ; GM50237/GM/NIGMS NIH HHS/United States ; },
mesh = {Gene Deletion ; Microbial Viability/genetics ; Multiprotein Complexes/*metabolism ; *Recombination, Genetic ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {In cells lacking telomerase, telomeres shorten progressively during each cell division due to incomplete end-replication. When the telomeres become very short, cells enter a state that blocks cell division, termed senescence. A subset of these cells can overcome senescence and maintain their telomeres using telomerase-independent mechanisms. In Saccharomyces cerevisiae, these cells are called 'survivors' and are dependent on Rad52-dependent homologous recombination and Pol32-dependent break-induced replication. There are two main types of survivors: type I and type II. The type I survivors require Rad51 and maintain telomeres by amplification of subtelomeric elements, while the type II survivors are Rad51-independent, but require the MRX complex and Sgs1 to amplify the C1-3A/TG1-3 telomeric sequences. Rad52, Pol32, Rad51, and Sgs1 are also important to prevent accelerated senescence, indicating that recombination processes are important at telomeres even before the formation of survivors. The Shu complex, which consists of Shu1, Shu2, Psy3, and Csm2, promotes Rad51-dependent homologous recombination and has been suggested to be important for break-induced replication. It also promotes the formation of recombination intermediates that are processed by the Sgs1-Top3-Rmi1 complex, as mutations in the SHU genes can suppress various sgs1, top3, and rmi1 mutant phenotypes. Given the importance of recombination processes during senescence and survivor formation, and the involvement of the Shu complex in many of the same processes during DNA repair, we hypothesized that the Shu complex may also have functions at telomeres. Surprisingly, we find that this is not the case: the Shu complex does not affect the rate of senescence, does not influence survivor formation, and deletion of SHU1 does not suppress the rapid senescence and type II survivor formation defect of a telomerase-negative sgs1 mutant. Altogether, our data suggest that the Shu complex is not important for recombination processes at telomeres.},
}
@article {pmid26972231,
year = {2016},
author = {Shin, C and Baik, I},
title = {Associations Between Alcohol Consumption and Leukocyte Telomere Length Modified by a Common Polymorphism of ALDH2.},
journal = {Alcoholism, clinical and experimental research},
volume = {40},
number = {4},
pages = {765-771},
doi = {10.1111/acer.13005},
pmid = {26972231},
issn = {1530-0277},
mesh = {Adult ; Aged ; Aging/genetics ; Alcohol Drinking/adverse effects/epidemiology/*genetics ; Aldehyde Dehydrogenase, Mitochondrial/*genetics ; Cohort Studies ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/*physiology ; Male ; Middle Aged ; Polymorphism, Genetic/*genetics ; Population Surveillance ; Republic of Korea/epidemiology ; Telomere Homeostasis/*genetics ; Telomere Shortening/*genetics ; },
abstract = {BACKGROUND: Data on the association between alcohol consumption and telomere length, a marker of biological aging, are inconsistent. Moreover, the genetic modification of this association has been reported only rarely. To evaluate the association between alcohol consumption and leukocyte telomere length (LTL), and the effect modification of this association by a common polymorphism of the aldehyde dehydrogenase 2 (ALDH2) gene, we conducted a cross-sectional study in a general population including 1,771 middle-aged and elderly Koreans, aged 49 to 79 years.<br><br>METHODS: Study participants provided blood samples between 2011 and 2012 for the LTL assay, and between 2001 and 2002 for genomewide genotyping. Between 2011 and 2012, they also completed a questionnaire-based interview regarding their alcohol consumption. We examined effect modification by rs2074356, a surrogate marker of the ALDH2 polymorphism.<br><br>RESULTS: Heavy alcohol consumption (average daily alcohol consumption of >30 g) was inversely associated with LTL only among carriers of the mutant alleles (CT and TT) of rs2074356 (p < 0.01). Among these subjects, elderly drinkers in particular showed the strongest association (p < 0.001). Light-to-moderate alcohol consumption on an almost daily basis was positively associated with LTL (p < 0.001), and this association was significant among carriers of the wild-type allele (CC) of rs2074356 (p < 0.01) but not among those with the mutant alleles.<br><br>CONCLUSIONS: Our findings suggest that the potential benefit of light-to-moderate alcohol consumption and the detriment of heavy alcohol consumption on biological aging may depend on ALDH2 polymorphism.},
}
@article {pmid26972047,
year = {2016},
author = {Hsieh, AYY and Saberi, S and Ajaykumar, A and Hukezalie, K and Gadawski, I and Sattha, B and Côté, HCF},
title = {Optimization of a Relative Telomere Length Assay by Monochromatic Multiplex Real-Time Quantitative PCR on the LightCycler 480: Sources of Variability and Quality Control Considerations.},
journal = {The Journal of molecular diagnostics : JMD},
volume = {18},
number = {3},
pages = {425-437},
pmid = {26972047},
issn = {1943-7811},
support = {R21 AG045015/AG/NIA NIH HHS/United States ; TCO-125269//CIHR/Canada ; },
mesh = {Cell Line, Tumor ; Humans ; Quality Control ; *Real-Time Polymerase Chain Reaction/instrumentation/methods/standards ; Reproducibility of Results ; Sensitivity and Specificity ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Telomere length (TL) measurement is central to many biomedical research, population, and epidemiology studies, with promising potential as a clinical tool. Various assays are used to determine TL, depending on the type and size of the sample. We describe the detailed optimization of a monochromatic multiplex real-time quantitative PCR (MMqPCR) assay for relative TL using the LightCycler 480. MMqPCR was initially developed using a different instrument with many separate reagents. Differences in instrument performance, reagents, and workflow required substantial optimization for the assay to be compatible with the LightCycler 480. We optimized the chemistry of the assay using a purchased one-component reaction mix and herein describe sources of variability and quality control relevant to the MMqPCR TL assay on any instrument. Finally, the assay was validated against other TL assays, such as terminal restriction fragment, Southern blot, and flow fluorescent in situ hybridization. The correlations obtained between data from MMqPCR and these assays (R(2) = 0.88 and 0.81) were comparable to those seen with the monoplex version (R(2) = 0.85 and 0.82) when the same samples were assayed. The intrarun and interrun CV ranged from 4.2% to 6.2% and 3.2% to 4.9%, respectively. We describe a protocol for measuring TL on the LightCycler platform that provides a robust high-throughput method applicable to clinical diagnostics or large-scale studies of archived specimens.},
}
@article {pmid26969272,
year = {2016},
author = {Factor-Litvak, P and Susser, E and Kezios, K and McKeague, I and Kark, JD and Hoffman, M and Kimura, M and Wapner, R and Aviv, A},
title = {Leukocyte Telomere Length in Newborns: Implications for the Role of Telomeres in Human Disease.},
journal = {Pediatrics},
volume = {137},
number = {4},
pages = {},
pmid = {26969272},
issn = {1098-4275},
support = {P30 ES009089/ES/NIEHS NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; R21 ES023582/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; Biological Clocks ; Fathers ; Female ; Humans ; Infant, Newborn ; *Leukocytes ; Male ; Mothers ; Sex Factors ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND AND OBJECTIVE: In adults, leukocyte telomere length (LTL) is variable, familial, and longer in women and in offspring conceived by older fathers. Although short LTL is associated with atherosclerotic cardiovascular disease, long LTL is associated with major cancers. The prevailing notion is that LTL is a "telomeric clock," whose movement (expressed in LTL attrition) reflects the pace of aging. Accordingly, individuals with short LTL are considered to be biologically older than their peers. Recent studies suggest that LTL is largely determined before adulthood. We examined whether factors that largely characterize LTL in adults also influence LTL in newborns.<br><br>METHODS: LTL was measured in blood samples from 490 newborns and their parents.<br><br>RESULTS: LTL (mean &#xb1; SD) was longer (9.50 &#xb1; 0.70 kb) in newborns than in their mothers (7.92 &#xb1; 0.67 kb) and fathers (7.70 &#xb1; 0.71 kb) (both P < .0001); there was no difference in the variance of LTL among the 3 groups. Newborn LTL correlated more strongly with age-adjusted LTL in mothers (r = 0.47; P < .01) than in fathers (r = 0.36; P < .01) (P for interaction = .02). Newborn LTL was longer by 0.144 kb in girls than in boys (P = .02), and LTL was longer by 0.175 kb in mothers than in fathers (P < .0001). For each 1-year increase in father's age, newborn LTL increased by 0.016 kb (95% confidence interval: 0.04 to 0.28) (P = .0086).<br><br>CONCLUSIONS: The large LTL variation across newborns challenges the telomeric clock model. Having inherently short or long LTL may be largely determined at birth, anteceding by decades disease manifestation in adults.},
}
@article {pmid26966248,
year = {2016},
author = {Silva, S and Altmannova, V and Luke-Glaser, S and Henriksen, P and Gallina, I and Yang, X and Choudhary, C and Luke, B and Krejci, L and Lisby, M},
title = {Mte1 interacts with Mph1 and promotes crossover recombination and telomere maintenance.},
journal = {Genes &amp; development},
volume = {30},
number = {6},
pages = {700-717},
pmid = {26966248},
issn = {1549-5477},
mesh = {Crossing Over, Genetic/*genetics ; DEAD-box RNA Helicases/genetics/*metabolism ; Gene Deletion ; Protein Transport ; Saccharomyces cerevisiae/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Stress, Physiological/genetics ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Mph1 is a member of the conserved FANCM family of DNA motor proteins that play key roles in genome maintenance processes underlying Fanconi anemia, a cancer predisposition syndrome in humans. Here, we identify Mte1 as a novel interactor of the Mph1 helicase in Saccharomyces cerevisiae. In vitro, Mte1 (Mph1-associated telomere maintenance protein 1) binds directly to DNA with a preference for branched molecules such as D loops and fork structures. In addition, Mte1 stimulates the helicase and fork regression activities of Mph1 while inhibiting the ability of Mph1 to dissociate recombination intermediates. Deletion of MTE1 reduces crossover recombination and suppresses the sensitivity of mph1Δ mutant cells to replication stress. Mph1 and Mte1 interdependently colocalize at DNA damage-induced foci and dysfunctional telomeres, and MTE1 deletion results in elongated telomeres. Taken together, our data indicate that Mte1 plays a role in regulation of crossover recombination, response to replication stress, and telomere maintenance.},
}
@article {pmid26965507,
year = {2016},
author = {Wojcicki, JM and Shiboski, S and Heyman, MB and Elwan, D and Lin, J and Blackburn, E and Epel, E},
title = {Telomere length change plateaus at 4 years of age in Latino children: associations with baseline length and maternal change.},
journal = {Molecular genetics and genomics : MGG},
volume = {291},
number = {3},
pages = {1379-1389},
pmid = {26965507},
issn = {1617-4623},
mesh = {Adult ; Child, Preschool ; Female ; Hispanic or Latino/*genetics ; Humans ; Male ; Mother-Child Relations ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Telomeres are the protective complexes at the end of chromosomes, required for genomic stability. Little is known about predictors of attrition in young children or the relationship between parental and child patterns of telomere change. Telomere length was assessed twice over one year, at 4 and at 5 years of age, in Latino preschool children (n = 77) and their mothers (n = 70) in whole blood leukocytes. Maternal and child rates of attrition during the same time period were compared in 70 mother-child pairs. More children showed lengthened telomeres over one year compared to their mothers and very few children showed attrition (2.6 %). Approximately 31 % of children and 16 % of mothers displayed lengthening over one year while 66 % of children showed maintenance in contrast with 74 % of mothers. The strongest predictor for child telomere length change was child's baseline telomere length (r = -0.61, p < 0.01). Maternal rate of change was associated with child rate of change (r = 0.33, p < 0.01). After controlling for child baseline telomere length, the relationship between child and maternal rate of change trended towards significance (Coeff = 0.20, 95 % CI -0.03 to 0.43; p = 0.08). We found primarily maintenance and lengthening from 4 to 5 years of age in children, with minimal telomere attrition, indicating that most of the telomere loss happens in the first 4 years, plateauing by age 4. Lastly, we found close to 10 % of the variance in rate of change in children shared by mothers. While some of this shared variance is genetic, there are likely environmental factors that need to be further identified that impact rate of telomere length change.},
}
@article {pmid26960211,
year = {2016},
author = {Kato, S and Shiels, PG and McGuinness, D and Lindholm, B and Stenvinkel, P and Nordfors, L and Qureshi, AR and Yuzawa, Y and Matsuo, S and Maruyama, S},
title = {Telomere Attrition and Elongation after Chronic Dialysis Initiation in Patients with End-Stage Renal Disease.},
journal = {Blood purification},
volume = {41},
number = {1-3},
pages = {25-33},
doi = {10.1159/000440971},
pmid = {26960211},
issn = {1421-9735},
mesh = {Aged ; Biomarkers/blood ; Cellular Senescence ; Female ; Humans ; Kidney Failure, Chronic/blood/*genetics/pathology/*therapy ; Leukocyte Count ; Leukocytes, Mononuclear/metabolism/*pathology ; Logistic Models ; Male ; Middle Aged ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; *Renal Dialysis ; Telomere/*chemistry/metabolism ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {AIMS: To analyze changes in telomere length (TL) after dialysis initiation.<br><br>METHODS: In 59 Japanese incident dialysis patients, associations between TL in peripheral blood leukocytes, inflammatory biomarkers and nutritional status at baseline and changes in TL during 1 year of dialysis, were investigated.<br><br>RESULTS: Whereas relative TL decreased by 8.6% (median 14.4%), TL elongation occurred in 16 patients (27%). Change in TL (x0394;TL), defined as TL at 1 year minus TL at baseline, was associated with baseline TL (x03C1; = -0.70, p < 0.0001) and leukocyte count (x03C1; = 0.26, p = 0.044). In a logistic regression model, baseline TL (p < 0.0001) and leukocyte count (p = 0.047) were associated with x0394;TL.<br><br>CONCLUSIONS: TL shortening was observed in most incident dialysis patients. In 16 of the 59 patients, TL elongation occurred, possibly reflecting a more robust biological aging in patients whose na&#xef;ve leukocytes may have undergone less proliferation to replace lost leukocytes.},
}
@article {pmid26953344,
year = {2016},
author = {Suryo Rahmanto, Y and Jung, JG and Wu, RC and Kobayashi, Y and Heaphy, CM and Meeker, AK and Wang, TL and Shih, IeM},
title = {Inactivating ARID1A Tumor Suppressor Enhances TERT Transcription and Maintains Telomere Length in Cancer Cells.},
journal = {The Journal of biological chemistry},
volume = {291},
number = {18},
pages = {9690-9699},
pmid = {26953344},
issn = {1083-351X},
support = {R01 CA129080/CA/NCI NIH HHS/United States ; R01 CA148826/CA/NCI NIH HHS/United States ; R21 CA165807/CA/NCI NIH HHS/United States ; R21 CA187512/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; DNA-Binding Proteins ; *Gene Expression Regulation, Enzymologic ; *Gene Expression Regulation, Neoplastic ; Histones/genetics/metabolism ; Humans ; *Mutation ; Neoplasms/genetics/*metabolism/pathology ; Nuclear Proteins/genetics/*metabolism ; Repressor Proteins/genetics/metabolism ; Sin3 Histone Deacetylase and Corepressor Complex ; Telomerase/*biosynthesis/genetics ; *Telomere Homeostasis ; Transcription Factors/genetics/*metabolism ; *Transcription, Genetic ; Tumor Suppressor Proteins/genetics/*metabolism ; },
abstract = {ARID1A is a tumor suppressor gene that belongs to the switch/sucrose non-fermentable chromatin remodeling gene family. It is mutated in many types of human cancer with the highest frequency in endometrium-related ovarian and uterine neoplasms including ovarian clear cell, ovarian endometrioid, and uterine endometrioid carcinomas. We have previously reported that mutations in the promoter of human telomerase reverse transcriptase (TERT) rarely co-occur with the loss of ARID1A protein expression, suggesting a potential role of ARID1A in telomere biology. In this study, we demonstrate that ARID1A negatively regulates TERT transcriptional regulation and activity via binding to the regulatory element of TERT and promotes a repressive histone mode. Induction of ARID1A expression was associated with increased occupancy of SIN3A and H3K9me3, known transcription repressor and histone repressor marks, respectively. Thus, loss of ARID1A protein expression caused by inactivating mutations reactivates TERT transcriptional activity and confers a survival advantage of tumor cells by maintaining their telomeres.},
}
@article {pmid26951191,
year = {2016},
author = {Zhou, Y and Ning, Z and Lee, Y and Hambly, BD and McLachlan, CS},
title = {Shortened leukocyte telomere length in type 2 diabetes mellitus: genetic polymorphisms in mitochondrial uncoupling proteins and telomeric pathways.},
journal = {Clinical and translational medicine},
volume = {5},
number = {1},
pages = {8},
pmid = {26951191},
issn = {2001-1326},
abstract = {Current debate in type 2 diabetes (T2DM) has focused on shortened leukocyte telomere length (LTL) as the result of a number of possible causes, including polymorphisms in mitochondrial uncoupling proteins (UCPs) leading to oxidative stress, telomere regulatory pathway gene polymorphisms, or as a direct result of associated cardiovascular complications inducing tissue organ inflammation and oxidative stress. There is evidence that a heritable shorter telomere trait is a risk factor for development of T2DM. This review discusses the contribution and balance of genetic regulation of UCPs and telomere pathways in the context of T2DM. We discuss genotypes that are well known to influence the shortening of LTL, in particular OBFC1 and telomerase genotypes such as TERC. Interestingly, the interaction between short telomeres and T2DM risk appears to involve mitochondrial dysfunction as an intermediate process. A hypothesis is presented that genetic heterogeneity within UCPs may directly affect oxidative stress that feeds back to influence the fine balance of telomere regulation, cell cycle regulation and diabetes risk and/or metabolic disease progression.},
}
@article {pmid26950204,
year = {2016},
author = {Salvador, L and Singaravelu, G and Harley, CB and Flom, P and Suram, A and Raffaele, JM},
title = {A Natural Product Telomerase Activator Lengthens Telomeres in Humans: A Randomized, Double Blind, and Placebo Controlled Study.},
journal = {Rejuvenation research},
volume = {19},
number = {6},
pages = {478-484},
pmid = {26950204},
issn = {1557-8577},
mesh = {Aged ; Aged, 80 and over ; Biological Products/*pharmacology ; Cross-Sectional Studies ; Dose-Response Relationship, Drug ; Double-Blind Method ; Enzyme Activation/drug effects ; Humans ; *Medicine, Chinese Traditional ; Middle Aged ; Telomerase/*physiology ; Telomere/*drug effects ; },
abstract = {TA-65 is a dietary supplement based on an improved formulation of a small molecule telomerase activator that was discovered in a systematic screening of natural product extracts from traditional Chinese medicines. This study summarizes the findings on telomere length (TL) changes from a randomized, double blind, placebo controlled study of TA-65 over a 1 year period. The study was conducted on 117 relatively healthy cytomegalovirus-positive subjects aged 53-87 years old. Subjects taking the low dose of TA-65 (250 U) significantly increased TL over the 12 months period (530 ± 180 bp; p = 0.005), whereas subjects in the placebo group significantly lost TL (290 ± 100 bp; p = 0.01). The high dose of TA-65 (1000 U) showed a trend of improvements in TL compared with that of the placebo group; however, the improvements did not reach statistical significance. TL changes in the low-dose group were similar for both median and 20th percentile TLs. The findings suggest that TA-65 can lengthen telomeres in a statistically and possibly clinically significant manner.},
}
@article {pmid26947392,
year = {2016},
author = {Zhang, E and Cotton, VE and Hidalgo-Bravo, A and Huang, Y and Bell, AJ and Jarrett, RF and Wilkie, GS and Davison, AJ and Nacheva, EP and Siebert, R and Majid, A and Kelpanides, I and Jayne, S and Dyer, MJ and Royle, NJ},
title = {HHV-8-unrelated primary effusion-like lymphoma associated with clonal loss of inherited chromosomally-integrated human herpesvirus-6A from the telomere of chromosome 19q.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {22730},
pmid = {26947392},
issn = {2045-2322},
support = {G0801822/MRC_/Medical Research Council/United Kingdom ; MC_U132670597/MRC_/Medical Research Council/United Kingdom ; MC_UU_12014/12/MRC_/Medical Research Council/United Kingdom ; WT097828MF/WT_/Wellcome Trust/United Kingdom ; MC_UU_12014/3/MRC_/Medical Research Council/United Kingdom ; G0901657/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aged ; *Chromosomes, Human, Pair 19 ; Female ; Herpesvirus 6, Human/*genetics ; Humans ; Lymphoma, Primary Effusion/*diagnosis/pathology/virology ; Male ; Proviruses/*genetics ; Roseolovirus Infections/*complications ; Sequence Analysis, DNA ; *Sequence Deletion ; *Telomere ; Virus Integration ; },
abstract = {Primary effusion lymphomas (PEL) are associated with human herpesvirus-8 (HHV-8) and usually occur in immunocompromised individuals. However, there are numerous reports of HHV-8-unrelated PEL-like lymphomas with unknown aetiology. Here we characterize an HHV-8-unrelated PEL-like lymphoma in an elderly woman who was negative for human immunodeficiency viruses 1 and 2, and hepatitis B and C. The woman was, however, a carrier of an inherited-chromosomally-integrated human herpesvirus-6A (iciHHV-6A) genome in one 19q telomere. The iciHHV-6A genome was complete in blood DNA, encoding a full set of protein-coding genes. Interestingly, the entire iciHHV-6A genome was absent from the HHV-8-unrelated-PEL-like lymphoma cells despite retention of both copies of chromosome 19. The somatic loss of the 19q-iciHHV-6A genome occurred very early during lymphoma development and we propose it occurred via telomere-loop formation and excision to release a circular viral genome that was subsequently lost. Whether release of the HHV-6A genome from the telomere contributed to lymphomagenesis, or was coincidental, remains unclear but this event may have deregulated the expression of HHV-6A or 19q genes or else disrupted telomere function. To establish the frequency and importance of iciHHV-6 loss from telomeres, the HHV-6 copy number should be assessed in tumours that arise in iciHHV-6 carriers.},
}
@article {pmid26941250,
year = {2016},
author = {Liddiard, K and Ruis, B and Takasugi, T and Harvey, A and Ashelford, KE and Hendrickson, EA and Baird, DM},
title = {Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4.},
journal = {Genome research},
volume = {26},
number = {5},
pages = {588-600},
pmid = {26941250},
issn = {1549-5469},
support = {18246/CRUK_/Cancer Research UK/United Kingdom ; R01 CA154461/CA/NCI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 GM088351/GM/NIGMS NIH HHS/United States ; R01 CA190492/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; *Chromatids/genetics/metabolism ; *Chromosomes, Human/genetics/metabolism ; *DNA Breaks, Double-Stranded ; *DNA End-Joining Repair ; *DNA Ligase ATP ; Gene Deletion ; Humans ; *Neoplasms/genetics/metabolism ; *Telomere/genetics/metabolism ; Tumor Suppressor Protein p53 ; },
abstract = {Telomeres shorten with each cell division and can ultimately become substrates for nonhomologous end-joining repair, leading to large-scale genomic rearrangements of the kind frequently observed in human cancers. We have characterized more than 1400 telomere fusion events at the single-molecule level, using a combination of high-throughput sequence analysis together with experimentally induced telomeric double-stranded DNA breaks. We show that a single chromosomal dysfunctional telomere can fuse with diverse nontelomeric genomic loci, even in the presence of an otherwise stable genome, and that fusion predominates in coding regions. Fusion frequency was markedly increased in the absence of TP53 checkpoint control and significantly modulated by the cellular capacity for classical, versus alternative, nonhomologous end joining (NHEJ). We observed a striking reduction in inter-chromosomal fusion events in cells lacking DNA ligase 4, in contrast to a remarkably consistent profile of intra-chromosomal fusion in the context of multiple genetic knockouts, including DNA ligase 3 and 4 double-knockouts. We reveal distinct mutational signatures associated with classical NHEJ-mediated inter-chromosomal, as opposed to alternative NHEJ-mediated intra-chromosomal, telomere fusions and evidence for an unanticipated sufficiency of DNA ligase 1 for these intra-chromosomal events. Our findings have implications for mechanisms driving cancer genome evolution.},
}
@article {pmid26941064,
year = {2016},
author = {Rai, R and Chen, Y and Lei, M and Chang, S},
title = {TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions.},
journal = {Nature communications},
volume = {7},
number = {},
pages = {10881},
pmid = {26941064},
issn = {2041-1723},
support = {R21 AG043747/AG/NIA NIH HHS/United States ; R01 CA202816/CA/NCI NIH HHS/United States ; R21 CA200506/CA/NCI NIH HHS/United States ; R21CA182280/CA/NCI NIH HHS/United States ; P30 CA016359/CA/NCI NIH HHS/United States ; R21 CA182280/CA/NCI NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; DNA Repair ; DNA-Binding Proteins ; Fibroblasts/metabolism ; *Gene Deletion ; Gene Expression Regulation/*physiology ; Genomic Instability ; Humans ; Mice ; Protein Transport ; Recombinant Proteins/genetics/*metabolism ; Shelterin Complex ; Telomere/physiology ; Telomere-Binding Proteins/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/*metabolism/*physiology ; },
abstract = {Repressor/activator protein 1 (RAP1) is a highly conserved telomere-interacting protein. Yeast Rap1 protects telomeres from non-homologous end joining (NHEJ), plays important roles in telomere length control and is involved in transcriptional gene regulation. However, a role for mammalian RAP1 in telomere end protection remains controversial. Here we present evidence that mammalian RAP1 is essential to protect telomere from homology directed repair (HDR) of telomeres. RAP1 cooperates with the basic domain of TRF2 (TRF2(B)) to repress PARP1 and SLX4 localization to telomeres. Without RAP1 and TRF2(B), PARP1 and SLX4 HR factors promote rapid telomere resection, resulting in catastrophic telomere loss and the generation of telomere-free chromosome fusions in both mouse and human cells. The RAP1 Myb domain is required to repress both telomere loss and formation of telomere-free fusions. Our results highlight the importance of the RAP1-TRF2 heterodimer in protecting telomeres from inappropriate processing by the HDR pathway.},
}
@article {pmid26940806,
year = {2016},
author = {Verhoeven, JE and van Oppen, P and Révész, D and Wolkowitz, OM and Penninx, BW},
title = {Depressive and Anxiety Disorders Showing Robust, but Non-Dynamic, 6-Year Longitudinal Association With Short Leukocyte Telomere Length.},
journal = {The American journal of psychiatry},
volume = {173},
number = {6},
pages = {617-624},
doi = {10.1176/appi.ajp.2015.15070887},
pmid = {26940806},
issn = {1535-7228},
mesh = {Adult ; Anxiety Disorders/diagnosis/*genetics ; Case-Control Studies ; Depressive Disorder/diagnosis/*genetics ; Female ; Humans ; Leukocytes/metabolism ; Longitudinal Studies ; Male ; *Telomere Shortening ; },
abstract = {OBJECTIVE: Several cross-sectional studies have related depressive and anxiety disorders to shorter leukocyte telomere length (LTL) as an indicator of cellular aging. However, these studies have left many unresolved questions about underlying causality and ordering of associations. The objective of the present large, longitudinal study was to examine the relationship between depressive and anxiety disorders and LTL over a 6-year time period.<br><br>METHOD: Data are from the Netherlands Study of Depression and Anxiety, including 2,292 patients with remitted and current diagnoses of depressive or anxiety disorders and 644 healthy control subjects. LTL was assessed using quantitative PCR and measured at baseline and after 6 years; depressive and anxiety disorder diagnoses and characteristics (course, duration, and severity) were determined at baseline and after 2, 4, and 6 years.<br><br>RESULTS: Results showed that persons with remitted (B=-52.6) and current (B=-60.8) depressive or anxiety disorder had consistently shorter LTL compared with healthy control subjects across baseline and at the 6-year follow-up, remaining significant when controlling for lifestyle and somatic health variables. Changes in the course of depressive or anxiety disorder characteristics over 6 years, however, were not associated with different LTL attrition rates.<br><br>CONCLUSIONS: This study confirmed robust associations of depressive and anxiety disorders with shorter telomeres, but interestingly, it did not demonstrate that depressive and anxiety disorders and LTL change together over time, suggesting the absence of a direct within-person relationship. Short LTL is suggested to be either a long-term consequence or an underlying vulnerability factor for depressive or anxiety disorders.},
}
@article {pmid26940017,
year = {2016},
author = {Sillanpää, E and Törmäkangas, T and Rantanen, T and Kaprio, J and Sipilä, S},
title = {Does telomere length predict decline in physical functioning in older twin sisters during an 11-year follow-up?.},
journal = {Age (Dordrecht, Netherlands)},
volume = {38},
number = {2},
pages = {34},
pmid = {26940017},
issn = {1574-4647},
mesh = {Aged ; *Aging ; Disease Progression ; Diseases in Twins/metabolism/*mortality/physiopathology ; Female ; Finland/epidemiology ; *Forecasting ; Humans ; Leukocytes/*metabolism ; Middle Aged ; *Mobility Limitation ; Motor Activity ; Survival Rate/trends ; Telomere/*physiology ; *Twins ; },
abstract = {Leukocyte telomere length (LTL) is known to be associated with mortality, but its association with age-related decline in physical functioning and the development of disability is less clear. This study examined the associations between LTL and physical functioning, and investigated whether LTL predicts level of physical functioning over an 11-year follow-up. Older mono- (MZ) and dizygotic (DZ) twin sisters (n = 386) participated in the study. Relative LTL was measured by qPCR at baseline. Physical functioning was measured by 6-min walking distance and level of physical activity (PA). Walking distance was measured at baseline and at 3-year follow-up. PA was assessed by questionnaire at baseline and at 3- and 11-year follow-ups. The baseline analysis was performed with path models, adjusted with age and within-pair dependence of twin pairs. The longitudinal analysis was performed with a repeated measures linear model adjusted for age and longitudinal within-pair dependence. A nonrandom missing data analysis was utilized. At baseline, in all individuals, LTL was associated with PA (est. 0.14, SE 0.06, p = 0.011), but not with walking distance. Over the follow-up, a borderline significant association was observed between LTL and walking distance (est. 0.14, SE 0.07, p = 0.060) and a significant association between LTL and PA (est. 0.19, SE 0.06, p = 0.001). The results suggest that LTL is associated with PA and may, therefore, serve as a biomarker predicting the development of disability. Longitudinal associations between LTL and PA were observed only when nonrandom data missingness was taken into account in the analysis.},
}
@article {pmid26926838,
year = {2016},
author = {Tosevska, A and Moelzer, C and Wallner, M and Janosec, M and Schwarz, U and Kern, C and Marculescu, R and Doberer, D and Weckwerth, W and Wagner, KH},
title = {Longer telomeres in chronic, moderate, unconjugated hyperbilirubinaemia: insights from a human study on Gilbert's Syndrome.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {22300},
pmid = {26926838},
issn = {2045-2322},
mesh = {Animals ; Bilirubin/*metabolism ; Gilbert Disease/*genetics ; Humans ; Hyperbilirubinemia/*genetics ; Immunomodulation ; Interleukin-1beta/metabolism ; Interleukin-6/metabolism ; Leukocytes, Mononuclear/*physiology ; Male ; Oxidation-Reduction ; Rats ; Rats, Gunn ; Telomere/*genetics ; Telomere Homeostasis/genetics ; },
abstract = {Bilirubin (BR) is a natural endogenous compound with a potent bioactivity. Gilbert's Syndrome (GS) is a benign hereditary condition of increased unconjugated bilirubin (UCB) in serum and serves as a convenient model for studying the effects of BR in humans. In absence of liver disease, increased UCB levels are inversely associated to all-cause mortality risk, especially from cardiovascular diseases (CVDs). On the other hand, telomere malfunction is linked to a higher risk of CVDs. To our knowledge, there is no data on whether UCB is linked to telomere length in healthy or diseased individuals In the present study we have observed a relationship between mildly increased serum UCB and telomere length. We used an in vivo approach, assessing telomere length in PBMCs from individuals with GS (n = 60) and matched healthy controls (n = 60). An occurrence of longer telomeres was observed in male individuals chronically exposed to increased UCB, as well as in Gunn rats, an animal model of unconjugated hyperbilirubinaemia. Previously identified differences in immunomodulation and redox parameters in individuals with GS, such as IL-6, IL-1β and ferric reducing ability of plasma, were confirmed and proposed as possible contributors to the occurrence of longer telomeres in GS.},
}
@article {pmid26925173,
year = {2016},
author = {Breitling, LP and Saum, KU and Perna, L and Schöttker, B and Holleczek, B and Brenner, H},
title = {Frailty is associated with the epigenetic clock but not with telomere length in a German cohort.},
journal = {Clinical epigenetics},
volume = {8},
number = {},
pages = {21},
pmid = {26925173},
issn = {1868-7075},
mesh = {Aged ; Aging/genetics ; Aging, Premature/genetics ; Cross-Sectional Studies ; DNA Methylation ; *Epigenesis, Genetic ; Female ; *Frail Elderly/statistics &amp; numerical data ; Germany/epidemiology ; Humans ; Male ; Middle Aged ; *Telomere Shortening ; },
abstract = {BACKGROUND: The epigenetic clock, in particular epigenetic pre-aging quantified by the so-called DNA methylation age acceleration, has recently been suggested to closely correlate with a variety of disease phenotypes. There remains a dearth of data, however, on its association with telomere length and frailty, which can be considered major correlates of age on the genomic and clinical level, respectively.<br><br>RESULTS: In this cross-sectional observational study on altogether 1820 subjects from two subsets (n&#x2009;=&#x2009;969 and n&#x2009;=&#x2009;851; mean&#x2009;&#xb1;&#x2009;standard deviation age 62.1&#x2009;&#xb1;&#x2009;6.5 and 63.0&#x2009;&#xb1;&#x2009;6.7&#xa0;years, respectively) of the ESTHER cohort study of the elderly general population in Germany, DNA methylation age was calculated based on a 353 loci predictor previously developed in a large meta-study, and the difference-based epigenetic age acceleration was calculated as predicted methylation age minus chronological age. No correlation of epigenetic age acceleration with telomere length was found in our study (p&#x2009;=&#x2009;0.63). However, there was an association of DNA methylation age acceleration with a comprehensive frailty measure, such that the accumulated deficits significantly increased with increasing age acceleration. Quantitatively, about half an additional deficit was added per 6&#xa0;years of methylation age acceleration (p&#x2009;=&#x2009;0.0004). This association was independent from age, sex, and estimated leukocyte distribution, as well as from a variety of other confounding variables considered.<br><br>CONCLUSIONS: The results of the present study suggest that epigenetic age acceleration is correlated with clinically relevant aging-related phenotypes through pathways unrelated to cellular senescence as assessed by telomere length. Innovative approaches like Mendelian randomization will be needed to elucidate whether epigenetic age acceleration indeed plays a causal role for the development of clinical phenotypes.},
}
@article {pmid26922833,
year = {2016},
author = {Scaglioni, L and Mondelli, R and Artali, R and Sirtori, FR and Mazzini, S},
title = {Nemorubicin and doxorubicin bind the G-quadruplex sequences of the human telomeres and of the c-MYC promoter element Pu22.},
journal = {Biochimica et biophysica acta},
volume = {1860},
number = {6},
pages = {1129-1138},
doi = {10.1016/j.bbagen.2016.02.011},
pmid = {26922833},
issn = {0006-3002},
mesh = {Antineoplastic Agents/*chemistry ; Doxorubicin/*analogs &amp; derivatives/*chemistry ; *G-Quadruplexes ; *Genes, myc ; Magnetic Resonance Spectroscopy ; Models, Molecular ; *Promoter Regions, Genetic ; Spectrometry, Mass, Electrospray Ionization ; *Telomere ; },
abstract = {BACKGROUND: Intra-molecular G-quadruplex structures are present in the guanine rich regions of human telomeres and were found to be prevalent in gene promoters. More recently, the targeting of c-MYC transcriptional control has been suggested, because the over expression of the c-MYC oncogene is one of the most common aberration found in a wide range of human tumors.<br><br>METHODS: The interaction of nemorubicin and doxorubicin with DNA G-quadruplex structures has been studied by NMR, ESI-MS and molecular modelling, in order to obtain further information about the complex and the multiple mechanisms of action of these drugs.<br><br>RESULTS AND CONCLUSIONS: Nemorubicin intercalates between A3 and G4 of d(TTAGGGT)4 and form cap-complex at the G6pT7 site. The presence of the adenine in this sequence is important for the stabilization of the complex, as was shown by the interaction with d(TTGGGTT)4 and d(TTTGGGT)4, which form only a 1:1 complex. The interaction of doxorubicin with d(TTAGGGT)4 is similar, but the complex appears less stable. Nemorubicin also binds with high efficiency the c-MYC G-quadruplex sequence Pu22, to form a very well defined complex. Two nemorubicin molecules bind to the 3'-end and to the 5'-end, forming an additional plane of stacking over each external G-tetrad. The wild type c-MYCPu22 sequence forms with nemorubicin the same complex.<br><br>GENERAL SIGNIFICANCE: Nemorubicin and doxorubicin, not only intercalate into the duplex DNA, but also result in significant ligands for G-quadruplex DNA segments, stabilizing their structure; this may in part explain the multiple mechanisms of action of their antitumor activity.},
}
@article {pmid26919486,
year = {2016},
author = {Lin, PY and Huang, YC and Hung, CF},
title = {Shortened telomere length in patients with depression: A meta-analytic study.},
journal = {Journal of psychiatric research},
volume = {76},
number = {},
pages = {84-93},
doi = {10.1016/j.jpsychires.2016.01.015},
pmid = {26919486},
issn = {1879-1379},
mesh = {Aging/*genetics ; Case-Control Studies ; Cross-Sectional Studies ; Depression/*genetics ; Female ; Humans ; Male ; PubMed/statistics &amp; numerical data ; Sex Factors ; Telomere ; Telomere Shortening/*genetics ; },
abstract = {BACKGROUND: Accelerated telomere shortening is associated with stress-related cell damage and aging. Patients with depression have been shown to have shortened life expectancy and to be associated with multiple age-related systemic diseases. Previous studies have examined leukocyte telomere length (LTL) in patients with depression, but have shown inconsistent results.<br><br>METHODS: We conducted meta-analyses by pooling relevant results strictly from all eligible case-control studies for cross-sectional comparison of LTL between depressive patients and control subjects (16 studies involving 7207 subjects). The effect sizes (shown as Hedges' g) of each individual study were synthesized by using a random effects model.<br><br>RESULTS: Our analysis revealed telomere length is significantly shorter in subjects with depression in comparison to healthy controls (Hedges' g&#xa0;=&#xa0;-0.42, p&#xa0;=&#xa0;1&#xa0;&#xd7;&#xa0;10(-5), corresponding to r&#xa0;=&#xa0;-0.21). Significant heterogeneity among studies examining LTL in subjects with depression was found (Q&#xa0;=&#xa0;116.07, df&#xa0;=&#xa0;16, I(2)&#xa0;=&#xa0;86.21%, p&#xa0;<&#xa0;1&#xa0;&#xd7;&#xa0;10(-8)), which can possibly be explained by methods used in measuring telomere length (Q&#xa0;=&#xa0;18.42, df&#xa0;=&#xa0;2, p&#xa0;=&#xa0;1&#xa0;&#xd7;&#xa0;10(-4)). There was no significant publication bias, nor moderating effect of age, female percentage, or illness duration of depression on synthesized results.<br><br>CONCLUSIONS: Our results support the hypothesis that depression is associated with accelerated cell aging. Future studies are required to clarify whether the association is mediated through environmental stress, and whether effective treatment can halt cell aging.},
}
@article {pmid26918633,
year = {2016},
author = {Feigon, J and Chan, H and Jiang, J},
title = {Integrative structural biology of Tetrahymena telomerase - insights into catalytic mechanism and interaction at telomeres.},
journal = {The FEBS journal},
volume = {283},
number = {11},
pages = {2044-2050},
pmid = {26918633},
issn = {1742-4658},
support = {R01 GM048123/GM/NIGMS NIH HHS/United States ; T32 GM007185/GM/NIGMS NIH HHS/United States ; },
mesh = {Cryoelectron Microscopy ; Crystallography, X-Ray ; Holoenzymes/*chemistry ; Magnetic Resonance Spectroscopy ; Protein Binding ; Telomerase/*chemistry ; Telomere/chemistry/genetics ; Tetrahymena thermophila/*enzymology ; },
abstract = {Telomerase is a ribonucleoprotein complex that helps maintain telomeres, the physical ends of linear chromosomes. The low cellular levels of telomerase, propensity for telomerase reverse transcriptase and other telomerase proteins to aggregate, and cell cycle regulation of telomerase assembly in most organisms has made it a challenging complex for structural biology. Here we review recent progress in determining the structural basis of Tetrahymena telomerase holoenzyme function and interaction at telomeres from solution NMR, X-ray crystallography and electron microscopy studies, including the first cryoelectron microscopy structure of a telomerase holoenzyme (Science, 350, 2015, aab4070).},
}
@article {pmid26915412,
year = {2016},
author = {Zhu, X and Han, W and Xue, W and Zou, Y and Xie, C and Du, J and Jin, G},
title = {The association between telomere length and cancer risk in population studies.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {22243},
pmid = {26915412},
issn = {2045-2322},
mesh = {Gastrointestinal Neoplasms/*genetics ; Head and Neck Neoplasms/*genetics ; Humans ; Risk Assessment ; Risk Factors ; Telomere/*genetics ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Telomeres are crucial in the maintenance of chromosome integrity and genomic stability. A series of epidemiological studies have examined the association between telomere length and the risk of cancers, but the findings remain conflicting. We performed literature review and meta-analysis to demonstrate the relationship between telomere length and cancer risk. A total of 23,379 cases and 68,792 controls from 51 publications with 62 population studies were included in this meta-analysis to assess the association between overall cancer or cancer-specific risk and telomere length. General association and dose-response relationship were evaluated based on two and three groups, respectively. The estimates of association were evaluated with odds ratios and 95% confidence intervals by the random-effects or fixed-effects model based on heterogeneity test. We observed a non-significant association between short telomeres and overall risk of cancer. Convincing evidence was observed for the association of short telomeres with an increased risk of gastrointestinal tumor and head and neck cancer. Significant dose-response associations were also observed for gastrointestinal tumor and head and neck cancer. Our findings indicate that telomeres may play diverse roles in different cancers, and short telomeres may be risk factors for the tumors of digestive system.},
}
@article {pmid26914269,
year = {2016},
author = {Denham, J and O'Brien, BJ and Charchar, FJ},
title = {Telomere Length Maintenance and Cardio-Metabolic Disease Prevention Through Exercise Training.},
journal = {Sports medicine (Auckland, N.Z.)},
volume = {46},
number = {9},
pages = {1213-1237},
pmid = {26914269},
issn = {1179-2035},
mesh = {Aging/physiology ; *Cardiorespiratory Fitness ; Cardiovascular Diseases/*prevention &amp; control ; Exercise/*physiology ; Humans ; Metabolic Diseases/*prevention &amp; control ; Physical Endurance/physiology ; Shelterin Complex ; Telomerase/metabolism ; Telomere Homeostasis/*physiology ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomeres are tandem repeat DNA sequences located at distal ends of chromosomes that protect against genomic DNA degradation and chromosomal instability. Excessive telomere shortening leads to cellular senescence and for this reason telomere length is a marker of biological age. Abnormally short telomeres may culminate in the manifestation of a number of cardio-metabolic diseases. Age-related cardio-metabolic diseases attributable to an inactive lifestyle, such as obesity, type 2 diabetes mellitus and cardiovascular disease, are associated with short leukocyte telomeres. Exercise training prevents and manages the symptoms of many cardio-metabolic diseases whilst concurrently maintaining telomere length. The positive relationship between exercise training, physical fitness and telomere length raises the possibility of a mediating role of telomeres in chronic disease prevention via exercise. Further elucidation of the underpinning molecular mechanisms of how exercise maintains telomere length should provide crucial information on how physical activity can be best structured to combat the chronic disease epidemic and improve the human health span. Here, we synthesise and discuss the current evidence on the impact of physical activity and cardiorespiratory fitness on telomere dynamics. We provide the molecular mechanisms with a known role in exercise-induced telomere length maintenance and highlight unexplored, alternative pathways ripe for future investigations.},
}
@article {pmid26913901,
year = {2016},
author = {Fernández-Marcelo, T and Sánchez-Pernaute, A and Pascua, I and De Juan, C and Head, J and Torres-García, AJ and Iniesta, P},
title = {Clinical Relevance of Telomere Status and Telomerase Activity in Colorectal Cancer.},
journal = {PloS one},
volume = {11},
number = {2},
pages = {e0149626},
pmid = {26913901},
issn = {1932-6203},
mesh = {Aged ; Biomarkers, Tumor/genetics/metabolism ; Colorectal Neoplasms/diagnosis/*enzymology/*genetics/pathology ; Female ; Humans ; Male ; Neoplasm Staging ; Prognosis ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {The role of telomeres and telomerase in colorectal cancer (CRC) is well established as the major driving force in generating chromosomal instability. However, their potential as prognostic markers remains unclear. We investigated the outcome implications of telomeres and telomerase in this tumour type. We considered telomere length (TL), ratio of telomere length in cancer to non-cancer tissue (T/N ratio), telomerase activity and TERT levels; their relation with clinical variables and their role as prognostic markers. We analyzed 132 CRCs and paired non-cancer tissues. Kaplan-Meier curves for disease-free survival were calculated for TL, T/N ratio, telomerase activity and TERT levels. Overall, tumours had shorter telomeres than non-tumour tissues (P < 0.001) and more than 80% of CRCs displayed telomerase activity. Telomere lengths of non-tumour tissues and CRCs were positively correlated (P < 0.001). Considering telomere status and clinical variables, the lowest degree of telomere shortening was shown by tumours located in the rectum (P = 0.021). Regarding prognosis studies, patients with tumours showing a mean TL < 6.35 Kb experienced a significantly better clinical evolution (P < 0.001) and none of them with the highest degree of tumour telomere shortening relapsed during the follow-up period (P = 0.043). The mean TL in CRCs emerged as an independent prognostic factor in the Cox analysis (P = 0.017). Telomerase-positive activity was identified as a marker that confers a trend toward a poor prognosis. In CRC, our results support the use of telomere status as an independent prognostic factor. Telomere status may contribute to explaining the different molecular identities of this tumour type.},
}
@article {pmid26908837,
year = {2016},
author = {Xing, C and Garcia, CK},
title = {Epigenetic inheritance of telomere length obscures identification of causative PARN locus.},
journal = {Journal of medical genetics},
volume = {53},
number = {5},
pages = {356-358},
pmid = {26908837},
issn = {1468-6244},
support = {R01 HL093096/HL/NHLBI NIH HHS/United States ; UL1 TR001105/TR/NCATS NIH HHS/United States ; },
mesh = {*Epigenesis, Genetic ; Exoribonucleases/*genetics ; Family Health ; Female ; Humans ; Male ; *Mutation ; Pedigree ; Polymorphism, Single Nucleotide ; Pulmonary Fibrosis/genetics ; Telomere Homeostasis/*genetics ; Telomere Shortening/*genetics ; },
}
@article {pmid26908447,
year = {2016},
author = {Zhou, G and Liu, X and Li, Y and Xu, S and Ma, C and Wu, X and Cheng, Y and Yu, Z and Zhao, G and Chen, Y},
title = {Telomere targeting with a novel G-quadruplex-interactive ligand BRACO-19 induces T-loop disassembly and telomerase displacement in human glioblastoma cells.},
journal = {Oncotarget},
volume = {7},
number = {12},
pages = {14925-14939},
pmid = {26908447},
issn = {1949-2553},
mesh = {Acridines/*pharmacology ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; Cytostatic Agents/*pharmacology ; DNA Damage/drug effects ; G-Quadruplexes/*drug effects ; Glioblastoma/drug therapy/enzymology/*genetics/*pathology ; Humans ; Telomerase/*antagonists &amp; inhibitors/genetics ; Telomere/*chemistry/genetics ; Tumor Cells, Cultured ; },
abstract = {Interference with telomerase and telomere maintenance is emerging as an attractive target for anticancer therapies. Ligand-induced stabilization of G-quadruplex formation by the telomeric DNA 3'-overhang inhibits telomerase from catalyzing telomeric DNA synthesis and from capping telomeric ends, making these ligands good candidates for chemotherapeutic purposes. BRACO-19 is one of the most effective and specific ligand for telomeric G4. It is shown here that BRACO-19 suppresses proliferation and reduces telomerase activity in human glioblastoma cells, paralleled by the displacement of telomerase from nuclear to cytoplasm. Meanwhile, BRACO-19 triggers extensive DNA damage response at telomere, which may result from uncapping and disassembly of telomeric T-loop structure, characterized by the formation of anaphase bridge and telomere fusion, as well as the release of telomere-binding protein from telomere. The resulting dysfunctional telomere ultimately provokes p53 and p21-mediated cell cycle arrest, apoptosis and senescence. Notably, normal primary astrocytes do not respond to the treatment of BRACO-19, suggesting the agent's good selectivity for cancer cells. These results reinforce the notion that G-quadruplex binding compounds can act as broad inhibitors of telomere-related processes and have potential as selective antineoplastic drugs for various tumors including malignant gliomas.},
}
@article {pmid26904098,
year = {2016},
author = {Lustig, AJ},
title = {Hypothesis: Paralog Formation from Progenitor Proteins and Paralog Mutagenesis Spur the Rapid Evolution of Telomere Binding Proteins.},
journal = {Frontiers in genetics},
volume = {7},
number = {},
pages = {10},
pmid = {26904098},
issn = {1664-8021},
support = {R01 GM069943/GM/NIGMS NIH HHS/United States ; R56 GM069943/GM/NIGMS NIH HHS/United States ; },
abstract = {Through elegant studies in fungal cells and complex organisms, we propose a unifying paradigm for the rapid evolution of telomere binding proteins (TBPs) that associate with either (or both) telomeric DNA and telomeric proteins. TBPs protect and regulate telomere structure and function. Four critical factors are involved. First, TBPs that commonly bind to telomeric DNA include the c-Myb binding proteins, OB-fold single-stranded binding proteins, and G-G base paired Hoogsteen structure (G4) binding proteins. Each contributes independently or, in some cases, cooperatively, to provide a minimum level of telomere function. As a result of these minimal requirements and the great abundance of homologs of these motifs in the proteome, DNA telomere-binding activity may be generated more easily than expected. Second, telomere dysfunction gives rise to genome instability, through the elevation of recombination rates, genome ploidy, and the frequency of gene mutations. The formation of paralogs that diverge from their progenitor proteins ultimately can form a high frequency of altered TBPs with altered functions. Third, TBPs that assemble into complexes (e.g., mammalian shelterin) derive benefits from the novel emergent functions. Fourth, a limiting factor in the evolution of TBP complexes is the formation of mutually compatible interaction surfaces amongst the TBPs. These factors may have different degrees of importance in the evolution of different phyla, illustrated by the apparently simpler telomeres in complex plants. Selective pressures that can utilize the mechanisms of paralog formation and mutagenesis to drive TBP evolution along routes dependent on the requisite physiologic changes.},
}
@article {pmid26903639,
year = {2016},
author = {Yim, OS and Zhang, X and Shalev, I and Monakhov, M and Zhong, S and Hsu, M and Chew, SH and Lai, PS and Ebstein, RP},
title = {Delay discounting, genetic sensitivity, and leukocyte telomere length.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {113},
number = {10},
pages = {2780-2785},
pmid = {26903639},
issn = {1091-6490},
support = {R01 MH098023/MH/NIMH NIH HHS/United States ; },
mesh = {Algorithms ; Cellular Senescence/genetics ; *Delay Discounting ; Estrogen Receptor beta/genetics ; Female ; Gene Frequency ; Genotype ; Humans ; Leukocytes/cytology/*metabolism ; Male ; *Polymorphism, Single Nucleotide ; Receptors, Oxytocin/genetics ; Regression Analysis ; Sex Factors ; Telomere/*genetics ; Time Factors ; Young Adult ; },
abstract = {In a graying world, there is an increasing interest in correlates of aging, especially those found in early life. Leukocyte telomere length (LTL) is an emerging marker of aging at the cellular level, but little is known regarding its link with poor decision making that often entails being overly impatient. Here we investigate the relationship between LTL and the degree of impatience, which is measured in the laboratory using an incentivized delay discounting task. In a sample of 1,158 Han Chinese undergraduates, we observe that steeper delay discounting, indexing higher degree of impatience, is negatively associated with LTL. The relationship is robust after controlling for health-related variables, as well as risk attitude-another important determinant of decision making. LTL in females is more sensitive to impatience than in males. We then asked if genes possibly modulate the effect of impatient behavior on LTL. The oxytocin receptor gene (OXTR) polymorphism rs53576, which has figured prominently in investigations of social cognition and psychological resources, and the estrogen receptor β gene (ESR2) polymorphism rs2978381, one of two gonadal sex hormone genes, significantly mitigate the negative effect of impatience on cellular aging in females. The current results contribute to understanding the relationship between preferences in decision making, particularly impatience, and cellular aging, for the first time to our knowledge. Notably, oxytocin and estrogen receptor polymorphisms temper accelerated cellular aging in young females who tend to make impatient choices.},
}
@article {pmid26903545,
year = {2016},
author = {Bär, C and Povedano, JM and Serrano, R and Benitez-Buelga, C and Popkes, M and Formentini, I and Bobadilla, M and Bosch, F and Blasco, MA},
title = {Telomerase gene therapy rescues telomere length, bone marrow aplasia, and survival in mice with aplastic anemia.},
journal = {Blood},
volume = {127},
number = {14},
pages = {1770-1779},
doi = {10.1182/blood-2015-08-667485},
pmid = {26903545},
issn = {1528-0020},
mesh = {Anemia, Aplastic/genetics/metabolism/pathology/*therapy ; Animals ; *Dependovirus ; Disease Models, Animal ; Genetic Therapy/*methods ; Hematopoietic Stem Cells/metabolism/pathology ; Mice ; Mice, Knockout ; Telomerase/*biosynthesis/genetics ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; *Transduction, Genetic ; },
abstract = {Aplastic anemia is a fatal bone marrow disorder characterized by peripheral pancytopenia and marrow hypoplasia. The disease can be hereditary or acquired and develops at any stage of life. A subgroup of the inherited form is caused by replicative impairment of hematopoietic stem and progenitor cells due to very short telomeres as a result of mutations in telomerase and other telomere components. Abnormal telomere shortening is also described in cases of acquired aplastic anemia, most likely secondary to increased turnover of bone marrow stem and progenitor cells. Here, we test the therapeutic efficacy of telomerase activation by using adeno-associated virus (AAV)9 gene therapy vectors carrying the telomerase Tert gene in 2 independent mouse models of aplastic anemia due to short telomeres (Trf1- and Tert-deficient mice). We find that a high dose of AAV9-Tert targets the bone marrow compartment, including hematopoietic stem cells. AAV9-Tert treatment after telomere attrition in bone marrow cells rescues aplastic anemia and mouse survival compared with mice treated with the empty vector. Improved survival is associated with a significant increase in telomere length in peripheral blood and bone marrow cells, as well as improved blood counts. These findings indicate that telomerase gene therapy represents a novel therapeutic strategy to treat aplastic anemia provoked or associated with short telomeres.},
}
@article {pmid26897704,
year = {2016},
author = {Révész, D and Milaneschi, Y and Terpstra, EM and Penninx, BW},
title = {Baseline biopsychosocial determinants of telomere length and 6-year attrition rate.},
journal = {Psychoneuroendocrinology},
volume = {67},
number = {},
pages = {153-162},
doi = {10.1016/j.psyneuen.2016.02.007},
pmid = {26897704},
issn = {1873-3360},
mesh = {Adolescent ; Adult ; Aged ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/physiology ; *Life Style ; Longitudinal Studies ; Male ; Middle Aged ; *Socioeconomic Factors ; Stress, Physiological/*physiology ; Stress, Psychological/*physiopathology ; Telomere Homeostasis/*physiology ; Telomere Shortening/*physiology ; Time Factors ; Young Adult ; },
abstract = {BACKGROUND: Short leukocyte telomere length (TL) and accelerated telomere attrition have been associated with various deleterious health outcomes, although their determinants have not been explored collectively in a large-scale study.<br><br>MATERIAL AND METHODS: Leukocyte TL was measured (baseline N=2936; 6-year follow-up N=1860) in participants (18-65 years) from the NESDA study. Baseline determinants of TL included sociodemographics, lifestyle, chronic diseases, psychosocial stressors, and metabolic and physiological stress markers. Multivariate linear regression models were used to examine the associations between these determinants and (1) baseline TL, and (2) 6-year TL change. Multinomial logistic regression analyses were used to examine the predictors of telomere attrition and lengthening, as compared to stable TL.<br><br>RESULTS: Short baseline TL was associated with older age, male sex, non-European ethnicity, cigarette smoking, recent life events, and higher triglycerides, glucose and pre-ejection period (R(2)=11.3%). The 6-year telomere attrition was inversely associated with baseline TL (R(2)=51.6%); also older age, long sleep, not having a partner, high childhood trauma index, and gastrointestinal disease were associated with 6-year TL attrition (additional R(2)=3.7%). Telomere attrition seemed to have slightly more predictors than lengthening.<br><br>CONCLUSIONS: Sociodemographic, lifestyle, psychosocial stress and metabolic and physiological stress factors are cross-sectionally linked with TL. Telomere attrition over six years was strongly associated with baseline TL, suggesting an internal homeostatic influence. Modulation of the identified determinants may become target of future studies to promote telomere maintenance and healthy aging.},
}
@article {pmid26896808,
year = {2016},
author = {Dong, Y and Zhang, G and Yuan, X and Zhang, Y and Hu, M},
title = {Telomere length and telomere repeating factors: Cellular markers for post-traumatic stress disorder-like model.},
journal = {Journal of affective disorders},
volume = {195},
number = {},
pages = {156-162},
doi = {10.1016/j.jad.2016.02.032},
pmid = {26896808},
issn = {1573-2517},
mesh = {Animals ; CA1 Region, Hippocampal/chemistry/metabolism ; Disease Models, Animal ; Genetic Markers ; Leukocytes/ultrastructure ; Male ; Rats ; Rats, Wistar ; Stress Disorders, Post-Traumatic/*genetics ; Stress, Psychological/psychology ; Swimming/psychology ; TATA Box Binding Protein-Like Proteins/genetics/metabolism ; Telomere/*genetics/ultrastructure ; Telomere Shortening/*genetics ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; },
abstract = {OBJECTIVE: The aim of the present study was to explore the telomere length of peripheral blood leukocytes from a rat model of post-traumatic stress disorder (PTSD), as well as the expression level of telomere-binding protein in the hippocampal CA1 region.<br><br>METHODS: The PTSD model was established with 42 adult male Wistar rats. The relative telomere length of the leukocytes was measured by real-time fluorescence quantitative polymerase chain reaction, and the expression levels of telomere repeating factor 1 (TRF1) and telomere repeating factor 2 (TRF2) in the hippocampal CA1 region of the PTSD rat model were determined by immunofluorescence technology. The covariance analysis of repeated measurements by the mixed model approach was used for the telomere length analysis. The comparison of averaged data among groups was performed using least significant difference and analysis of variance. The Student's t test or the Mann-Whitney U test was used for intragroup comparison. The association study among groups was conducted using the Spearman test.<br><br>RESULTS: The shortening speed of telomere length significantly accelerated in rats after Single Prolonged Stress (SPS) stimulation (P<0.05). The expression levels of TRF1 and TRF2 increased with the progress of PTSD, and the expression peak was shown in day 14, which was significantly different from the control group (P<0.05).<br><br>CONCLUSION: The shortening speed of the telomere length of peripheral blood leukocytes accelerated in PTSD rats, and the expression levels of TRF1 and TRF2 increased in hippocampus, both of which were closely associated with the pathological progress of the PTSD-like model and unfavorable prognosis.},
}
@article {pmid26895795,
year = {2017},
author = {An, R and Yan, H},
title = {Body weight status and telomere length in U.S. middle-aged and older adults.},
journal = {Obesity research &amp; clinical practice},
volume = {11},
number = {1},
pages = {51-62},
doi = {10.1016/j.orcp.2016.01.003},
pmid = {26895795},
issn = {1871-403X},
mesh = {Aged ; *Aging ; *Body Mass Index ; *Body Weight ; Ethnicity ; Female ; Humans ; Linear Models ; Male ; Middle Aged ; *Obesity ; Overweight ; Racial Groups ; Risk Factors ; Sex Factors ; *Telomere ; *Telomere Shortening ; United States ; White People ; },
abstract = {OBJECTIVE: Telomere length has been proposed as a biomarker of biological aging. This study examined the relationship between body weight status and telomere length in U.S. middle-aged and older adults.<br><br>METHODS: Nationally representative data (N=2749) came from the Health and Retirement Study. Linear regressions were performed to examine the relationship between baseline body weight status reported in 1992 and telomere length measured in 2008 in the overall sample and by sex and racial/ethnic groups, adjusted for individual characteristics.<br><br>RESULTS: Baseline overweight (25kg/m[2]&#x2264;body mass index [BMI]<30kg/m[2]) and obesity (BMI&#x2265;30kg/m[2]) status positively predicted telomere length 17 years later. Compared with their normal weight counterparts, telomere length ratio was on average 0.062 (95% confidence interval=0.016, 0.109) and 0.125 (0.048, 0.202) larger among overweight and obese adults, respectively. In comparison to women and racial/ethnic minorities, the estimated positive associations between overweight and obesity status and telomere length were more salient among men and non-Hispanic whites, respectively.<br><br>CONCLUSIONS: The positive association between body weight status and telomere length found in this study was opposite to what existing biological model predicts, and could partially relate to the nonlinear relationship between body weight status and telomere length across age cohorts, and/or the lack of reliability of BMI as an indicator for adiposity in the older population. Large-scale longitudinal studies with baseline telomere length measures are warranted to replicate this study finding and explore the potential heterogeneous relationship between body weight status and telomere length.},
}
@article {pmid26892575,
year = {2016},
author = {Yabuta, S and Masaki, M and Shidoji, Y},
title = {Associations of Buccal Cell Telomere Length with Daily Intake of β-Carotene or α-Tocopherol Are Dependent on Carotenoid Metabolism-related Gene Polymorphisms in Healthy Japanese Adults.},
journal = {The journal of nutrition, health &amp; aging},
volume = {20},
number = {3},
pages = {267-274},
pmid = {26892575},
issn = {1760-4788},
mesh = {Adult ; Antioxidants/administration &amp; dosage/pharmacology ; Asian People ; Diet ; *Feeding Behavior ; Female ; Genotype ; *Healthy Volunteers ; Humans ; Japan ; Lipid Metabolism ; Male ; Middle Aged ; Mouth Mucosa/*cytology/drug effects/metabolism ; Polymorphism, Single Nucleotide/*genetics ; Telomere/drug effects/metabolism ; Telomere Shortening/*drug effects/genetics ; Young Adult ; alpha-Tocopherol/administration &amp; dosage/*pharmacology ; beta Carotene/administration &amp; dosage/*metabolism/*pharmacology ; },
abstract = {OBJECTIVE: Telomere length shortening is modulated not only by aging, but also by both genetic and environmental factors. The aim of this study was to investigate the interactions between antioxidant nutrient metabolism-related gene single nucleotide polymorphisms (the genetic factors) and nutrient intake (the environmental factors) in their effects on telomere length shortening.<br><br>SETTING AND PARTICIPANTS: Data were collected on the relative telomere lengths (RTLs) of buccal cells and the habitual food intake of 70 healthy Japanese adults.<br><br>MEASUREMENTS: All subjects were genotyped for two common single nucleotide polymorphisms: rs6564851 in the &#x3b2;-carotene-15,15'-mono-oxygenase 1 (BCMO1) gene and rs362090 in the intestine-specific homeobox (ISX) gene.<br><br>RESULTS: Univariate analysis revealed that buccal RTL was not significantly modulated by either age or gender. Then, we subdivided the study population into four groups based on combinations of the rs6564851 and rs362090 genotypes. After this subdivision, we showed a positive effect of daily &#x3b1;- or &#x3b2;-carotene intake on buccal RTL in the ISX rs362090 G-allele carrier + BCMO1 rs6564851 GG-genotype group (p = 0.026). Additionally, daily intake of another antioxidative fat-soluble vitamin, &#x3b1;-tocopherol, was positively associated with buccal RTL in the ISX rs362090 AA-homozygote + BCMO1 rs6564851 T-allele carrier group (p = 0.037).<br><br>CONCLUSION: Our study clearly indicates that high dietary intake of the antioxidants &#x3b1;, &#x3b2;-carotene and &#x3b1;-tocopherol protects buccal cells from RTL shortening, depending on the genetic background of antioxidant vitamin-related genes.},
}
@article {pmid26888036,
year = {2016},
author = {Beirne, C and Waring, L and McDonald, RA and Delahay, R and Young, A},
title = {Age-related declines in immune response in a wild mammal are unrelated to immune cell telomere length.},
journal = {Proceedings. Biological sciences},
volume = {283},
number = {1825},
pages = {20152949},
pmid = {26888036},
issn = {1471-2954},
support = {BB/H022716/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {*Aging ; Animals ; England ; Female ; *Immunity, Innate ; Interferon-gamma/*genetics/metabolism ; Male ; *Mustelidae/genetics/immunology/physiology ; *Telomere ; Tuberculosis/*immunology ; },
abstract = {Senescence has been hypothesized to arise in part from age-related declines in immune performance, but the patterns and drivers of within-individual age-related changes in immunity remain virtually unexplored in natural populations. Here, using a long-term epidemiological study of wild European badgers (Meles meles), we (i) present evidence of a within-individual age-related decline in the response of a key immune-signalling cytokine, interferon-gamma (IFNγ), to ex vivo lymphocyte stimulation, and (ii) investigate three putative drivers of individual variation in the rate of this decline (sex, disease and immune cell telomere length; ICTL). That the within-individual rate of age-related decline markedly exceeded that at the population level suggests that individuals with weaker IFNγ responses are selectively lost from this population. IFNγ responses appeared to decrease with the progression of bovine tuberculosis infection (independent of age) and were weaker among males than females. However, neither sex nor disease influenced the rate of age-related decline in IFNγ response. Similarly, while ICTL also declines with age, variation in ICTL predicted neither among- nor within-individual variation in IFNγ response. Our findings provide evidence of within-individual age-related declines in immune performance in a wild mammal and highlight the likely complexity of the mechanisms that generate them.},
}
@article {pmid26883631,
year = {2016},
author = {Ivanova, IG and Maringele, L},
title = {Polymerases ε and ∂ repair dysfunctional telomeres facilitated by salt.},
journal = {Nucleic acids research},
volume = {44},
number = {8},
pages = {3728-3738},
pmid = {26883631},
issn = {1362-4962},
support = {81164//Wellcome Trust/United Kingdom ; },
mesh = {Cell Proliferation/drug effects ; Chromosomes, Fungal/drug effects/enzymology/metabolism ; DNA Polymerase I/physiology ; DNA Polymerase II/*metabolism ; DNA Polymerase III/*metabolism ; *DNA Repair ; DNA, Fungal/biosynthesis ; DNA-Binding Proteins/metabolism ; DNA-Directed DNA Polymerase/metabolism/physiology ; Mitogen-Activated Protein Kinases/metabolism ; Phleomycins/pharmacology ; Saccharomyces cerevisiae/drug effects/enzymology/genetics ; Saccharomyces cerevisiae Proteins/metabolism/physiology ; Sodium Chloride/*pharmacology ; Telomere/drug effects/*enzymology/metabolism ; Telomere Homeostasis ; Transcription Factors/metabolism ; },
abstract = {Damaged DNA can be repaired by removal and re-synthesis of up to 30 nucleotides during base or nucleotide excision repair. An important question is what happens when many more nucleotides are removed, resulting in long single-stranded DNA (ssDNA) lesions. Such lesions appear on chromosomes during telomere damage, double strand break repair or after the UV damage of stationary phase cells. Here, we show that long single-stranded lesions, formed at dysfunctional telomeres in budding yeast, are re-synthesized when cells are removed from the telomere-damaging environment. This process requires Pol32, an accessory factor of Polymerase δ. However, re-synthesis takes place even when the telomere-damaging conditions persist, in which case the accessory factors of both polymerases δ and ε are required, and surprisingly, salt. Salt added to the medium facilitates the DNA synthesis, independently of the osmotic stress responses. These results provide unexpected insights into the DNA metabolism and challenge the current view on cellular responses to telomere dysfunction.},
}
@article {pmid26883253,
year = {2016},
author = {Svenson, U and Öberg, &#xc5; and Stenling, R and Palmqvist, R and Roos, G},
title = {Telomere length in peripheral leukocytes is associated with immune cell tumor infiltration and prognosis in colorectal cancer patients.},
journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine},
volume = {37},
number = {8},
pages = {10877-10882},
pmid = {26883253},
issn = {1423-0380},
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/*genetics ; Colorectal Neoplasms/immunology/mortality/*pathology ; Female ; Humans ; Kaplan-Meier Estimate ; Leukocytes/*metabolism ; Lymphocytes, Tumor-Infiltrating/*immunology ; Male ; Middle Aged ; Prognosis ; Proportional Hazards Models ; Real-Time Polymerase Chain Reaction ; Telomere/*metabolism ; },
abstract = {Telomeres are protective structures at the end of chromosomes, essential for chromosomal integrity. A large number of studies have investigated leukocyte telomere length as a possible risk marker for various cancers, colorectal cancer (CRC) included. In contrast, studies investigating leukocyte telomere length in relation to CRC survival are lacking. We previously reported that relative telomere length (RTL) of leukocytes collected at diagnosis predicted survival in patients with breast and kidney cancer. We suggested that these findings might reflect various immunological mechanisms, affected by the presence of a tumor. In the present study, leukocyte RTL was examined in relation to immune cell tumor infiltration and prognosis in 130 patients with CRC diagnosis. RTL was measured with a well-established qPCR method. We found that patients with the highest degree of lymphocyte tumor infiltration had shorter leukocyte RTL. Consistent with our previous findings, short RTL was a favorable prognostic marker in univariate survival analysis. In the current study, RTL did not remain as an independent predictor in multivariate survival analysis, when including metastatic status in the model. However, a non-significant trend towards a similar telomere-associated survival pattern was observed in patients with limited disease. In contrast, for patients who died of other causes than CRC, short RTL was associated with significantly shorter survival time. To our knowledge, this is the first study to investigate an association between leukocyte RTL, immune cell tumor infiltration, and cancer-specific survival in CRC patients. Larger studies are warranted to verify these findings.},
}
@article {pmid26876762,
year = {2016},
author = {Harris, SE and Marioni, RE and Martin-Ruiz, C and Pattie, A and Gow, AJ and Cox, SR and Corley, J and von Zglinicki, T and Starr, JM and Deary, IJ},
title = {Longitudinal telomere length shortening and cognitive and physical decline in later life: The Lothian Birth Cohorts 1936 and 1921.},
journal = {Mechanisms of ageing and development},
volume = {154},
number = {},
pages = {43-48},
pmid = {26876762},
issn = {1872-6216},
support = {G0500997/MRC_/Medical Research Council/United Kingdom ; MR/K026992/1/MRC_/Medical Research Council/United Kingdom ; BB/F019394/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MR/M013111/1/MRC_/Medical Research Council/United Kingdom ; G0601333/MRC_/Medical Research Council/United Kingdom ; G1001245/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*metabolism ; Cognition/*physiology ; Female ; Humans ; Longitudinal Studies ; Male ; Scotland ; Telomere Homeostasis/*physiology ; },
abstract = {Telomere length is hypothesised to be a biological marker of both cognitive and physical ageing. Here we measure telomere length, and cognitive and physical abilities at mean ages 70, 73 and 76 years in the Lothian Birth Cohort 1936 (LBC1936), and at mean ages 79, 87, 90 and 92 years in the Lothian Birth Cohort 1921 (LBC1921). We investigate whether telomere length change predicts change in cognitive and physical abilities. In LBC1936 telomere length decreased by an average of 65 base pairs per year and in LBC1921 by 69 base pairs per year. However, change in telomere length did not predict change in cognitive or physical abilities. This study shows that, although cognitive ability, walking speed, lung function and grip strength all decline with age, they do so independently of telomere length shortening.},
}
@article {pmid26871293,
year = {2016},
author = {Cheng, Y and Li, Y and Ma, C and Song, Y and Xu, H and Yu, H and Xu, S and Mu, Q and Li, H and Chen, Y and Zhao, G},
title = {Arsenic trioxide inhibits glioma cell growth through induction of telomerase displacement and telomere dysfunction.},
journal = {Oncotarget},
volume = {7},
number = {11},
pages = {12682-12692},
pmid = {26871293},
issn = {1949-2553},
mesh = {Antineoplastic Agents/*pharmacology ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Damage/drug effects ; Glioma/*pathology ; Humans ; Oxides/*pharmacology ; Protein Transport/drug effects ; Telomerase/*drug effects/metabolism ; Telomere/*drug effects/pathology ; },
abstract = {Glioblastomas are resistant to many kinds of treatment, including chemotherapy, radiation and other adjuvant therapies. As2O3 reportedly induces ROS generation in cells, suggesting it may be able to induce telomerase suppression and telomere dysfunction in glioblastoma cells. We show here that As2O3 induces ROS generation as well as telomerase phosphorylation in U87, U251, SHG4 and C6 glioma cells. It also induces translocation of telomerase from the nucleus to the cytoplasm, thereby decreasing total telomerase activity. These effects of As2O3 trigger an extensive DNA damage response at the telomere, which includes up-regulation of ATM, ATR, 53BP1, γ-H2AX and Mer11, in parallel with telomere fusion and 3'-overhang degradation. This ultimately results in induction of p53- and p21-mediated cell apoptosis, G2/M cell cycle arrest and cellular senescence. These results provide new insight into the antitumor effects of As2O3 and can perhaps contribute to solving the problem of glioblastoma treatment resistance.},
}
@article {pmid26863877,
year = {2016},
author = {Silva, LC and de Araújo, AL and Fernandes, JR and Matias, Mde S and Silva, PR and Duarte, AJ and Garcez Leme, LE and Benard, G},
title = {Moderate and intense exercise lifestyles attenuate the effects of aging on telomere length and the survival and composition of T cell subpopulations.},
journal = {Age (Dordrecht, Netherlands)},
volume = {38},
number = {1},
pages = {24},
pmid = {26863877},
issn = {1574-4647},
mesh = {Aged ; Aged, 80 and over ; Aging/*immunology/pathology ; Cell Differentiation ; Cytokines/metabolism ; Exercise/*physiology ; Female ; Humans ; *Life Style ; Male ; T-Lymphocyte Subsets/*immunology/pathology ; Telomere ; },
abstract = {Studies indicate that exercise might delay human biological aging, but the effects of long-term exercise on T cell function are not well known. We tested the hypothesis that moderate or intense exercise lifestyle may attenuate the effects of aging on the telomere length and the survival and composition of T cell subpopulations. Elderly (65-85 years) with intense training lifestyle (IT, n = 15), moderate training lifestyle (MT, n = 16), and who never trained (NT, n = 15) were studied. Although the three groups presented the age-associated contraction of the TCD4(+)/TCD8(+) naïve compartments and expansion of the memory compartments, both training modalities were associated with lower proportion of terminally differentiated (CD45RA(+)CCR7(neg)) TCD4(+) and TCD8(+) cells, although among the latter cells, the reduction reached statistical significance only with IT. MT was associated with higher proportion of central memory TCD4(+) cells, while IT was associated with higher proportion of effector memory TCD8(+) cells. However, both training lifestyles were unable to modify the proportion of senescent (CD28(neg)) TCD8(+) cells. Telomeres were longer in T cells in both training groups; with IT, telomere length increased mainly in TCD8(+) cells, whereas with MT, a modest increase in telomere length was observed in both TCD8(+) and TCD4(+) cells. Reduced commitment to apoptosis of resting T cells, as assessed by caspase-3 and Bcl-2 expression, was seen predominantly with IT. Measurement of pro-inflammatory cytokines in serum and peripheral blood mononuclear cell (PBMC)'s supernatants did not show chronic low-grade inflammation in any of the groups. In conclusion, MT and IT lifestyles attenuated some of the effects of aging on the immune system.},
}
@article {pmid26858775,
year = {2016},
author = {Stindl, R},
title = {The paradox of longer sperm telomeres in older men's testes: a birth-cohort effect caused by transgenerational telomere erosion in the female germline.},
journal = {Molecular cytogenetics},
volume = {9},
number = {},
pages = {12},
pmid = {26858775},
issn = {1755-8166},
abstract = {Longer telomeres in the somatic cells of an individual have been regarded as a marker of youth and biological fitness within a population. Yet, several research groups have reported the surprising findings of longer telomeres in the germ cells of older men, which translated into longer leukocyte telomere length in their offspring. Although all these studies were purely cross-sectional, a longitudinal trend in the aging testes of individual males was taken for granted. Recently, a high-profile study reported a negative birth-cohort effect on leukocyte mean telomere length in human populations, namely the progressive loss of telomeric sequence between healthy human generations. This is what I based my theory of telomere-driven macroevolution on, 12 years ago. On the basis of published data on telomere length inheritance, I identified the source of human intergenerational telomere erosion in the female germline. Accordingly, because of the resulting birth-cohort effect, there is no need for any paradoxical telomere lengthening in older men's gonads to interpret the old-father-long-telomered-offspring data.},
}
@article {pmid26857734,
year = {2016},
author = {Gu, Y and Yu, C and Miao, L and Wang, L and Xu, C and Xue, W and Du, J and Yuan, H and Dai, J and Jin, G and Hu, Z and Ma, H and Shen, H},
title = {Telomere length, genetic variants and risk of squamous cell carcinoma of the head and neck in Southeast Chinese.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {20675},
pmid = {26857734},
issn = {2045-2322},
mesh = {Aged ; *Alleles ; Asian People ; Carcinoma, Squamous Cell/*genetics ; China ; Genome-Wide Association Study ; Head and Neck Neoplasms/*genetics ; Humans ; Middle Aged ; *Polymorphism, Single Nucleotide ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {Telomere dysfunction participates in malignant transformation and tumorigenesis. Previous studies have explored the associations between telomere length (TL) and cancer susceptibility; however, the findings are inconclusive. The associations between genetic variants and TL have been verified by quite a few genome-wide association studies (GWAS). Yet, to date, there was no published study on the relationship between TL, related genetic variants and susceptibility to squamous cell carcinoma of the head and neck (SCCHN) in Chinese. Hence, we detected relative telomere length (RTL) by using quantitative PCR and genotyped seven selected single nucleotide polymorphisms by TaqMan allelic discrimination assay in 510 SCCHN cases and 913 controls in southeast Chinese. The results showed that RTL was significantly associated with SCCHN risk [(adjusted odds ratio (OR) = 1.19, 95% confidence interval (CI) = 1.08-1.32, P = 0.001]. Furthermore, among seven selected SNPs, only G allele of rs2736100 related to RTL in Caucasians was significantly associated with both the decreased RTL (P = 0.002) and the increased susceptibility to SCCHN in Chinese (additive model: adjusted OR = 1.17, 95%CI = 1.00-1.38, P = 0.049). These findings provide evidence that shortened TL is a risk factor for SCCHN, and genetic variants can contribute to both TL and the susceptibility to SCCHN in southeast Chinese population.},
}
@article {pmid26857545,
year = {2016},
author = {Lee, WK and Cho, MH},
title = {Telomere-binding protein regulates the chromosome ends through the interaction with histone deacetylases in Arabidopsis thaliana.},
journal = {Nucleic acids research},
volume = {44},
number = {10},
pages = {4610-4624},
pmid = {26857545},
issn = {1362-4962},
mesh = {Arabidopsis/*genetics ; Arabidopsis Proteins/genetics/*metabolism ; *Chromosomes, Plant ; DNA Methylation ; Epigenesis, Genetic ; Histone Deacetylases/genetics/*metabolism ; Lysine/metabolism ; Mutation ; Plants, Genetically Modified ; Telomere/genetics/metabolism ; Telomere Homeostasis/genetics ; Telomere-Binding Proteins/genetics/*metabolism ; Nicotiana/genetics ; },
abstract = {Telomeres are nucleoprotein complexes at the end of eukaryotic chromosomes. Many telomere-binding proteins bind to telomeric repeat sequences and further generate T-loops in animals. However, it is not clear if they regulate telomere organization using epigenetic mechanisms and how the epigenetic molecules are involved in regulating the telomeres. Here, we show direct interactions between the telomere-binding protein, AtTRB2 and histone deacetylases, HDT4 and HDA6, in vitro and in vivo AtTRB2 mediates the associations of HDT4 and HDA6 with telomeric repeats. Telomere elongation is found in AtTRB2, HDT4 and HDA6 mutants over generations, but also in met1 and cmt3 DNA methyltransferases mutants. We also characterized HDT4 as an Arabidopsis H3K27 histone deacetylase. HDT4 binds to acetylated peptides at residue K27 of histone H3 in vitro, and deacetylates this residue in vivo Our results suggest that AtTRB2 also has a role in the regulation of telomeric chromatin as a possible scaffold protein for recruiting the epigenetic regulators in Arabidopsis, in addition to its telomere binding and length regulation activity. Our data provide evidences that epigenetic molecules associate with telomeres by direct physical interaction with telomere-binding proteins and further regulate homeostasis of telomeres in Arabidopsis thaliana.},
}
@article {pmid26856965,
year = {2016},
author = {Poojary, SS and Mishra, G and Gupta, S and Shrivastav, BR and Tiwari, PK},
title = {Dysfunction of subtelomeric methylation and telomere length in gallstone disease and gallbladder cancer patients of North Central India.},
journal = {Journal of hepato-biliary-pancreatic sciences},
volume = {23},
number = {5},
pages = {276-282},
doi = {10.1002/jhbp.332},
pmid = {26856965},
issn = {1868-6982},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; DNA Methylation ; DNA, Neoplasm/*genetics ; Female ; Gallbladder Neoplasms/epidemiology/*genetics/metabolism ; Gallstones/epidemiology/*genetics/metabolism ; *Genetic Predisposition to Disease ; Humans ; Immunohistochemistry ; India/epidemiology ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Telomere ; Young Adult ; },
abstract = {BACKGROUND: Telomeres play an important role in cancer progression. Recently it has been shown that subtelomeric methylation negatively regulates telomere length in various diseases, including cancers. Here, we evaluated the influence of subtelomeric methylation in telomere dysfunction in gallbladder cancer (GBC), and whether this dysfunction is affected by the presence of gallstones.<br><br>METHODS: Relative telomere length and subtelomeric methylation levels were assessed using monochrome multiplex quantitative polymerase chain reaction and bisulfite sequencing, respectively, in different gallbladder tissue types including different grades of GBC, gallstones and adjacent non-tumor.<br><br>RESULTS: We found telomere length to shorten significantly in overall GBC, but specifically in early grade cancer. We also found D4Z4 and DNF92 subtelomeric sequences to be hypermethylated and hypomethylated, respectively, in GBC; however, their methylation levels differed significantly, only in early grade cancer. We could not find any specific correlation between subtelomeric methylation and telomere length in GBC. Interestingly, telomere length and subtelomeric methylation differed significantly in GBC without gallstones but not in GBC with gallstones.<br><br>CONCLUSIONS: This study, thus, suggests that telomere dysfunction and changes in methylation levels may occur earlier in the progression of GBC, while the presence of gallstones may have no influence on telomere length as well as on methylation levels.},
}
@article {pmid26856307,
year = {2016},
author = {Ernst, A and Jones, DT and Maass, KK and Rode, A and Deeg, KI and Jebaraj, BM and Korshunov, A and Hovestadt, V and Tainsky, MA and Pajtler, KW and Bender, S and Brabetz, S and Gröbner, S and Kool, M and Devens, F and Edelmann, J and Zhang, C and Castelo-Branco, P and Tabori, U and Malkin, D and Rippe, K and Stilgenbauer, S and Pfister, SM and Zapatka, M and Lichter, P},
title = {Telomere dysfunction and chromothripsis.},
journal = {International journal of cancer},
volume = {138},
number = {12},
pages = {2905-2914},
doi = {10.1002/ijc.30033},
pmid = {26856307},
issn = {1097-0215},
mesh = {Case-Control Studies ; Cerebellar Neoplasms/enzymology/*genetics ; Chromosome Disorders/enzymology/genetics ; Ependymoma/enzymology/genetics ; Gene Expression ; *Genomic Instability ; Humans ; Medulloblastoma/enzymology/*genetics ; Telomerase/genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {Chromothripsis is a recently discovered form of genomic instability, characterized by tens to hundreds of clustered DNA rearrangements resulting from a single dramatic event. Telomere dysfunction has been suggested to play a role in the initiation of this phenomenon, which occurs in a large number of tumor entities. Here, we show that telomere attrition can indeed lead to catastrophic genomic events, and that telomere patterns differ between cells analyzed before and after such genomic catastrophes. Telomere length and telomere stabilization mechanisms diverge between samples with and without chromothripsis in a given tumor subtype. Longitudinal analyses of the evolution of chromothriptic patterns identify either stable patterns between matched primary and relapsed tumors, or loss of the chromothriptic clone in the relapsed specimen. The absence of additional chromothriptic events occurring between the initial tumor and the relapsed tumor sample points to telomere stabilization after the initial chromothriptic event which prevents further shattering of the genome.},
}
@article {pmid26854139,
year = {2016},
author = {Ahrens, KA and Rossen, LM and Simon, AE},
title = {Relationship Between Mean Leucocyte Telomere Length and Measures of Allostatic Load in US Reproductive-Aged Women, NHANES 1999-2002.},
journal = {Paediatric and perinatal epidemiology},
volume = {30},
number = {4},
pages = {325-335},
pmid = {26854139},
issn = {1365-3016},
support = {CC999999//Intramural CDC HHS/United States ; },
mesh = {Adult ; Black or African American/statistics &amp; numerical data ; Allostasis/*physiology ; Biomarkers/metabolism ; C-Reactive Protein/metabolism ; Creatinine/metabolism ; Cross-Sectional Studies ; Ethnicity ; Female ; Health Status Disparities ; Humans ; Leukocytes/metabolism/*physiology ; *Nutrition Surveys ; Reproductive Health/ethnology ; Socioeconomic Factors ; Stress, Psychological/metabolism/physiopathology ; Telomere/*physiology ; *Telomere Shortening ; United States/epidemiology ; White People/statistics &amp; numerical data ; },
abstract = {BACKGROUND: Reproductive health disparities may be partly explained by the cumulative effects of chronic stress experienced by socially disadvantaged groups. Although, telomere length (TL) and allostatic load score have each been used as biological markers of stress, the relationship between these two measures is unknown.<br><br>METHODS: We investigated the association between leucocyte TL and allostatic load score in 1503 non-pregnant women (20-44&#xa0;years) participating in the National Health and Nutrition Examination Survey, 1999-2002. We constructed six different allostatic load scores using either quartile- or clinical-based cut-points for 14 biomarkers based on previously published methods. We estimated associations between TL and allostatic load scores and component biomarkers using linear regression, also assessing interactions by race/ethnicity.<br><br>RESULTS: After adjustment for age, longer TL was associated with higher HDL cholesterol and lower C-reactive protein and creatinine clearance; TL was not associated with the other component biomarkers. Shorter TL was associated with higher allostatic load scores for the two clinical cut-point-based scores after adjustment for age, but not the four scores based on quartile cut-points. Significant interactions by race/ethnicity were observed for TL and HbA1c and triglycerides, but not for other component biomarkers or allostatic load scores.<br><br>CONCLUSIONS: Although TL and allostatic load score are both considered measures of cumulative stress, most component biomarkers and scores using quartile-based cut-points were not associated with TL. In reproductive-aged women, allostatic load scores using clinical-based cut-points were more strongly associated with TL compared with quartile-based scores.},
}
@article {pmid26853993,
year = {2016},
author = {Mathur, MB and Epel, E and Kind, S and Desai, M and Parks, CG and Sandler, DP and Khazeni, N},
title = {Perceived stress and telomere length: A systematic review, meta-analysis, and methodologic considerations for advancing the field.},
journal = {Brain, behavior, and immunity},
volume = {54},
number = {},
pages = {158-169},
pmid = {26853993},
issn = {1090-2139},
support = {K08 HS019816/HS/AHRQ HHS/United States ; UL1 TR000427/TR/NCATS NIH HHS/United States ; Z01 ES044005-09/ImNIH/Intramural NIH HHS/United States ; UL1 RR025011/RR/NCRR NIH HHS/United States ; 1 RC2 HL101468/HL/NHLBI NIH HHS/United States ; Z01 ES044005/ImNIH/Intramural NIH HHS/United States ; 5UL1RR025011/RR/NCRR NIH HHS/United States ; 1 K08 HS019816/HS/AHRQ HHS/United States ; BC045286/BC/NCI NIH HHS/United States ; RC2 HL101468/HL/NHLBI NIH HHS/United States ; ZO1ES044005/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; Humans ; Publication Bias ; Statistics as Topic ; Stress, Psychological/genetics/metabolism/*pathology ; Telomere/genetics/metabolism/*physiology ; Telomere Shortening/*physiology ; },
abstract = {IMPORTANCE: Psychological stress contributes to numerous diseases and may do so in part through damage to telomeres, protective non-coding segments on the ends of chromosomes.<br><br>OBJECTIVE: We conducted a systematic review and meta-analysis to determine the association between self-reported, perceived psychological stress (PS) and telomere length (TL).<br><br>DATA SOURCES: We searched 3 databases (PubMed, PsycInfo, and Scopus), completed manual searches of published and unpublished studies, and contacted all study authors to obtain potentially relevant data.<br><br>STUDY SELECTION: Two independent reviewers assessed studies for original research measuring (but not necessarily reporting the correlation between) PS and TL in human subjects. 23 studies met inclusion criteria; 22 (totaling 8948 subjects) could be meta-analyzed.<br><br>DATA EXTRACTION AND SYNTHESIS: We assessed study quality using modified MINORS criteria. Since not all included studies reported PS-TL correlations, we obtained them via direct calculation from author-provided data (7 studies), contact with authors (14 studies), or extraction from the published article (1 study).<br><br>MAIN OUTCOMES AND MEASURES: We conducted random-effects meta-analysis on our primary outcome, the age-adjusted PS-TL correlation. We investigated potential confounders and moderators (sex, life stress exposure, and PS measure validation) via post hoc subset analyses and meta-regression.<br><br>RESULTS: Increased PS was associated with a very small decrease in TL (n=8724 total; r=-0.06; 95% CI: -0.10, -0.008; p=0.01; &#x3b1;=0.025), adjusting for age. This relationship was similar between sexes and within studies using validated measures of PS, and marginally (nonsignificantly) stronger among samples recruited for stress exposure (r=-0.13; vs. general samples: b=-0.11; 95% CI: -0.27, 0.01; p=0.05; &#x3b1;=0.013). Publication bias may exist; correcting for its effects attenuated the relationship.<br><br>CONCLUSIONS AND RELEVANCE: Our analysis finds a very small, statistically significant relationship between increased PS (as measured over the past month) and decreased TL that may reflect publication bias, although fully parsing the effects of publication bias from other sample-size correlates is challenging, as discussed. The association may be stronger with known major stressors and is similar in magnitude to that noted between obesity and TL. All included studies used single measures of short-term stress; the literature suggests long-term chronic stress may have a larger cumulative effect. Future research should assess for potential confounders and use longitudinal, multidimensional models of stress.},
}
@article {pmid26853349,
year = {2016},
author = {Stanley, SE and Rao, AD and Gable, DL},
title = {Erratum. Radiation sensitivity and radiation necrosis in the short telomere syndromes.},
journal = {International journal of radiation oncology, biology, physics},
volume = {94},
number = {2},
pages = {423},
doi = {10.1016/j.ijrobp.2015.11.021},
pmid = {26853349},
issn = {1879-355X},
}
@article {pmid26851133,
year = {2016},
author = {Prather, AA and Hecht, FM and Epel, ES},
title = {Factors related to telomere length.},
journal = {Brain, behavior, and immunity},
volume = {53},
number = {},
pages = {279},
pmid = {26851133},
issn = {1090-2139},
support = {K08 HL112961/HL/NHLBI NIH HHS/United States ; K24 AT007827/AT/NCCIH NIH HHS/United States ; },
mesh = {Female ; Humans ; Leukocytes/*metabolism ; Male ; Obesity/*metabolism ; Sleep/*physiology ; Stress, Psychological/*metabolism ; Telomere/*metabolism ; },
}
@article {pmid26845351,
year = {2016},
author = {Hasegawa, D and Okabe, S and Okamoto, K and Nakano, I and Shin-ya, K and Seimiya, H},
title = {G-quadruplex ligand-induced DNA damage response coupled with telomere dysfunction and replication stress in glioma stem cells.},
journal = {Biochemical and biophysical research communications},
volume = {471},
number = {1},
pages = {75-81},
pmid = {26845351},
issn = {1090-2104},
support = {R01 CA183991/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; *DNA Damage ; DNA Replication/*genetics ; *G-Quadruplexes ; Glioblastoma/*genetics ; Humans ; Neoplastic Stem Cells/*physiology ; Telomere/*genetics ; Telomere Homeostasis/genetics ; },
abstract = {Glioblastoma (GBM) is an invariably fatal brain tumor in which a small subpopulation of self-renewable glioma stem cells (GSCs) contributes to tumor propagation and relapse. Targeting GSCs could therefore have a significant clinical impact for GBM. Telomestatin is a naturally-occurring compound that preferentially impairs GSC growth by perturbing transcription and inducing a DNA damage response. Telomestatin stabilizes G-quadruplexes (G4s), which are guanine-rich four-strand nucleic acid structures observed in vitro and in vivo. However, the mechanism underlying the GSC-selective nature of the DNA damage response remains unknown. Here we demonstrate that GSCs are more susceptible to telomestatin-induced telomere dysfunction and replication stress when compared with GSC-derived non-stem glioma cells (NSGCs). Telomestatin induced dissociation of the telomere-capping protein TRF2 from telomeres, leading to telomeric DNA damage in GSCs-but not in NSGCs. BIBR1532, a telomerase catalytic inhibitor, did not preferentially inhibit GSC growth, suggesting that telomestatin promotes telomere dysfunction in a telomerase-independent manner. GSCs and NSGCs had comparable levels of G4s in their nuclei, and both responded to telomestatin with phosphorylation of RPA2 at Ser33-a hallmark of replication stress. However, activation of the checkpoint kinase Chk1, induction of a DNA damage response, and subsequent growth inhibition occurred only in telomestatin-treated GSCs. These observations suggest that telomestatin impairs GSC growth through removal of TRF2 from telomeres and potent activation of the replication stress response pathway. Therefore, a novel G4-directed therapeutic strategy could specifically target cancer stem cells in GBM.},
}
@article {pmid26844276,
year = {2015},
author = {Scinicariello, F and Buser, MC},
title = {Polychlorinated Biphenyls and Leukocyte Telomere Length: An Analysis of NHANES 1999-2002.},
journal = {EBioMedicine},
volume = {2},
number = {12},
pages = {1974-1979},
pmid = {26844276},
issn = {2352-3964},
mesh = {Adult ; Biomarkers/blood ; Cross-Sectional Studies ; Environmental Exposure/*adverse effects ; Environmental Pollutants/*toxicity ; Female ; Humans ; Leukocytes/*drug effects/*metabolism ; Male ; Middle Aged ; Polychlorinated Biphenyls/*toxicity ; Proto-Oncogene Mas ; *Public Health Surveillance ; Telomere/*genetics ; United States/epidemiology ; Young Adult ; },
abstract = {Polychlorinated biphenyls (PCBs) induce the expression of the proto-oncogene c-myc which has a role in cellular growth and proliferation programs. The c-myc up-regulates the telomerase reverse transcriptase which adds the telomeres repeating sequences to the chromosomal ends to compensate for the progressive loss of telomeric sequence. We performed multivariate linear regression to analyze the association of PCBs, polychlorinated dibenzo-p-dioxins, and 1,2,3,4,6,7,8-heptachlorodibenzofuran with leukocyte telomere length (LTL) in the adult population (n = 2413) of the National Health and Nutrition Examination Survey 1999-2002. LTL was natural log-transformed and the results were re-transformed and presented as percent differences. Individuals in the 3rd and 4th quartiles of the sum of PCBs were associated with 8.33% (95% CI: 4.08-13.88) and 11.63% (95% CI: 6.18-17.35) longer LTLs, respectively, compared with the lowest quartile, with evidence of a dose-response relationship (p-trend < 0.01). The association of the sum PCBs with longer LTL was found in both sexes. Additionally, 1,2,3,4,6,7,8-heptachlorodibenzofuran and 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin were associated with longer LTL. The age independent association between longer LTL and environmental exposures to PCBs, 1,2,3,4,6,7,8-heptachlorodibenzofuran and 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin may support a role as tumor promoter of these compounds. Further studies to evaluate the effect of these compounds on LTL are needed to more fully understand the implications of our finding.},
}
@article {pmid26844258,
year = {2015},
author = {Gadalla, SM and Andreotti, G},
title = {Polychlorinated Biphenyls and Cancer: Are Telomeres to Blame?.},
journal = {EBioMedicine},
volume = {2},
number = {12},
pages = {1856-1857},
pmid = {26844258},
issn = {2352-3964},
mesh = {Humans ; Neoplasms ; *Polychlorinated Biphenyls ; *Telomere ; },
}
@article {pmid26844257,
year = {2015},
author = {Joyce, BT and Hou, L},
title = {Organic Pollutants and Telomere Length: A New Facet of Carcinogenesis.},
journal = {EBioMedicine},
volume = {2},
number = {12},
pages = {1854-1855},
pmid = {26844257},
issn = {2352-3964},
support = {P30 CA060553/CA/NCI NIH HHS/United States ; },
mesh = {Carcinogenesis ; Telomerase/*metabolism ; Telomere/*metabolism ; },
}
@article {pmid26839872,
year = {2016},
author = {Shin, C and Baik, I},
title = {Leukocyte Telomere Length is Associated With Serum Vitamin B12 and Homocysteine Levels in Older Adults With the Presence of Systemic Inflammation.},
journal = {Clinical nutrition research},
volume = {5},
number = {1},
pages = {7-14},
pmid = {26839872},
issn = {2287-3732},
abstract = {Folate, vitamin B12, and homocysteine (HCY) are involved in the metabolism of nucleic acid precursors and it has been hypothesized that they also influence telomere length, a biomarker of aging. However, previous studies have reported inconsistent findings, and data for older adults are limited. Our study aimed to evaluate associations between leukocyte telomere length (LTL) and serum folate, vitamin B12, and HCY levels among adults aged 55 years and over. In a cross-sectional study in 798 men and women aged 55-79 years, serum folate, vitamin B12, and HCY levels were measured using chemiluminescent immunometric assays, and relative LTL was assessed using quantitative real-time polymerase chain reaction. To evaluate associations between LTL and serum folate, vitamin B12, and HCY levels, multiple linear regression models were used. In multiple models adjusted for age, sex, serum high sensitive C-reactive protein (hs-CRP) levels, and other potential confounding factors, we found no association between LTL and serum folate, vitamin B12, and HCY levels. However, we did find a significant inverse association between HCY levels and LTL in participants with serum hs-CRP levels of ≥ 2 mg/L (p < 0.05). Moreover, there was a trend toward an association between HCY and vitamin B12 levels in these individuals (p = 0.08). In those with serum hs-CRP levels of < 2 mg/L, HCY was inversely associated with vitamin B12 levels (p < 0.001) and had no association with LTL. Our findings suggest that increased serum HCY levels, when combined with the presence of systemic inflammation, may play a role in accelerating biological aging.},
}
@article {pmid26836334,
year = {2016},
author = {Galer, P and Wang, B and Šket, P and Plavec, J},
title = {Reversible pH Switch of Two-Quartet G-Quadruplexes Formed by Human Telomere.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {55},
number = {6},
pages = {1993-1997},
doi = {10.1002/anie.201507569},
pmid = {26836334},
issn = {1521-3773},
mesh = {Base Sequence ; DNA/*chemistry/genetics ; *G-Quadruplexes ; Humans ; Hydrogen-Ion Concentration ; Telomere/*chemistry/genetics ; },
abstract = {A four-repeat human telomere DNA sequence without the 3'-end guanine, d[TAGGG(TTAGGG)2 TTAGG] (htel1-ΔG23) has been found to adopt two distinct two G-quartet antiparallel basket-type G-quadruplexes, TD and KDH(+) in presence of KCl. NMR, CD, and UV spectroscopy have demonstrated that topology of KDH(+) form is distinctive with unique protonated T18⋅A20(+) ⋅G5 base triple and other capping structural elements that provide novel insight into structural polymorphism and heterogeneity of G-quadruplexes in general. Specific stacking interactions amongst two G-quartets flanking base triples and base pairs in TD and KDH(+) forms are reflected in 10 K higher thermal stability of KDH(+) . Populations of TD and KDH(+) forms are controlled by pH. The (de)protonation of A20 is the key for pH driven structural transformation of htel1-ΔG23. Reversibility offers possibilities for its utilization as a conformational switch within different compartments of living cell enabling specific ligand and protein interactions.},
}
@article {pmid26835596,
year = {2016},
author = {Coussens, E and Grine, L and Bostoen, J and Mielants, H and Lambert, J},
title = {Analysis of telomere length as predictive marker in psoriasis for comorbidities.},
journal = {Experimental dermatology},
volume = {25},
number = {5},
pages = {388-390},
doi = {10.1111/exd.12959},
pmid = {26835596},
issn = {1600-0625},
mesh = {Adult ; Arthritis, Psoriatic/*complications/physiopathology ; Cardiovascular Diseases/*complications/physiopathology ; Female ; Humans ; Male ; Metabolic Syndrome/*complications/physiopathology ; Middle Aged ; *Telomere Homeostasis ; },
}
@article {pmid26832416,
year = {2016},
author = {Cox, KE and Maréchal, A and Flynn, RL},
title = {SMARCAL1 Resolves Replication Stress at ALT Telomeres.},
journal = {Cell reports},
volume = {14},
number = {5},
pages = {1032-1040},
pmid = {26832416},
issn = {2211-1247},
support = {K99 CA166729/CA/NCI NIH HHS/United States ; R00 CA166729/CA/NCI NIH HHS/United States ; T32 GM008541/GM/NIGMS NIH HHS/United States ; CA166729/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; *Cellular Senescence ; Chromosome Aberrations ; DNA Breaks, Double-Stranded ; DNA Helicases/*metabolism ; Humans ; Rad51 Recombinase/metabolism ; *Stress, Physiological ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Cancer cells overcome replicative senescence by exploiting mechanisms of telomere elongation, a process often accomplished by reactivation of the enzyme telomerase. However, a subset of cancer cells lack telomerase activity and rely on the alternative lengthening of telomeres (ALT) pathway, a recombination-based mechanism of telomere elongation. Although the mechanisms regulating ALT are not fully defined, chronic replication stress at telomeres might prime these fragile regions for recombination. Here, we demonstrate that the replication stress response protein SMARCAL1 is a critical regulator of ALT activity. SMARCAL1 associates with ALT telomeres to resolve replication stress and ensure telomere stability. In the absence of SMARCAL1, persistently stalled replication forks at ALT telomeres deteriorate into DNA double-strand breaks promoting the formation of chromosome fusions. Our studies not only define a role for SMARCAL1 in ALT telomere maintenance, but also demonstrate that resolution of replication stress is a crucial step in the ALT mechanism.},
}
@article {pmid26829506,
year = {2016},
author = {Marchetto, NM and Glynn, RA and Ferry, ML and Ostojic, M and Wolff, SM and Yao, R and Haussmann, MF},
title = {Prenatal stress and newborn telomere length.},
journal = {American journal of obstetrics and gynecology},
volume = {215},
number = {1},
pages = {94.e1-8},
doi = {10.1016/j.ajog.2016.01.177},
pmid = {26829506},
issn = {1097-6868},
mesh = {Adult ; Female ; Fetal Blood ; Fetal Development/physiology ; Hospitals, Teaching ; Humans ; Infant, Newborn ; Pregnancy/*psychology ; Pregnancy Complications/blood/etiology/*physiopathology ; Pregnancy Trimester, Third/*blood ; Prenatal Exposure Delayed Effects/blood/*physiopathology ; Prospective Studies ; Stress, Psychological/blood/complications/*physiopathology ; *Telomere Shortening ; Urban Population ; Young Adult ; },
abstract = {BACKGROUND: The developmental origin of the health and disease hypothesis is based on the premise that many chronic diseases have their roots in fetal development. Specifically, maternal stress during pregnancy is associated with altered fetal development and many adverse long-term health outcomes. Although the mechanisms underlying this effect are currently unclear, at the cellular level 1 possible mediator is the regulation of telomere length. Telomere dynamics appear to play a role in disease progression, and an adverse intrauterine environment may contribute in the establishment of short telomeres in newborns. In accordance with this, it was recently reported that prenatal stress is significantly associated with shorter mean newborn telomere length. However, this finding has yet to be replicated, and currently we know nothing about whether different size classes of telomeres within the telomere length distribution are differentially affected by prenatal stress. Examining telomere length frequency distributions is important, because the shortest telomeres in the distribution appear to be the most indicative of telomere dysfunction and thus the best predictors of mortality and morbidity in humans.<br><br>OBJECTIVE: We investigated the effects of intrauterine exposure to maternal stress over the whole course of gestation on newborn mean telomere length and telomere length frequency distributions.<br><br>STUDY DESIGN: We conducted a prospective cohort study of 24 mother-newborn dyads at an urban teaching hospital. Pregnant women with nonanomalous, uncomplicated pregnancies were recruited and assessed in the third trimester of gestation. Maternal psychosocial stress was quantified using the Holmes and Rahe Stress Scale and categorized as high stress (&#x2265;300 points) or low stress (&#x2264;299 points) exposure. Newborn telomere length was measured from cord blood at delivery using the Telomere Restriction Fragment assay.<br><br>RESULTS: We found a significant negative association between maternal stress and newborn telomere length (&#x3b2;&#xa0;=&#xa0;-0.463, P&#xa0;= 0.04). Newborns whose mothers experienced a high level of stress during pregnancy had significantly shorter telomere length (6.98 &#xb1; 0.41 kb) compared to newborns of mothers with low stress (8.74 &#xb1; 0.24 kb; t&#xa0;=&#xa0;-3.99, P&#xa0;= .003). Moreover, the difference in newborn telomere length between high-stress and low-stress mothers was due to a shift in the telomere length distribution, with the high-stress group showing an underrepresentation of longer telomeres and an over-representation of shorter telomeres.<br><br>CONCLUSION: Our findings replicate those of other recent studies and also show, for the first time, that the prenatal stress-associated difference in newborn mean telomere length is due to a shift in the overall telomere distribution.},
}
@article {pmid26820977,
year = {2016},
author = {Meyer, A and Salewsky, B and Buchmann, N and Steinhagen-Thiessen, E and Demuth, I},
title = {Relative Leukocyte Telomere Length, Hematological Parameters and Anemia - Data from the Berlin Aging Study II (BASE-II).},
journal = {Gerontology},
volume = {62},
number = {3},
pages = {330-336},
doi = {10.1159/000430950},
pmid = {26820977},
issn = {1423-0003},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*genetics/metabolism ; Anemia/*metabolism ; Erythrocyte Count ; Erythrocyte Indices ; Female ; Hematocrit ; Hemoglobins/*metabolism ; Humans ; Leukocytes/*metabolism ; Lymphocyte Count ; Male ; Middle Aged ; Platelet Count ; Polymerase Chain Reaction ; Telomere/*metabolism ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {BACKGROUND: The length of the chromosome ends, telomeres, is widely accepted as a biomarker of aging. However, the dynamic of the relationship between telomere length and hematopoietic parameters in the normal aging process, which is of particular interest with respect to age-related anemia, is not well understood.<br><br>OBJECTIVE: We have analyzed the relationship between relative leukocyte telomere length (rLTL) and several hematological parameters in the older group of the Berlin Aging Study II (BASE-II) participants. This paper also compares rLTL between both BASE-II age groups (22-37 and 60-83 years).<br><br>METHODS: Genomic DNA was extracted from peripheral blood leukocytes of BASE-II participants and used to determine rLTL by a quantitative PCR protocol. Standard methods were used to determine blood parameters, and the WHO criteria were used to identify anemic participants.<br><br>RESULTS: Telomere length data were available for 444 younger participants (28.4 &#xb1; 3.1 years old; 52% women) and 1,460 older participants (68.2 &#xb1; 3.7 years old; 49.4% women). rLTL was significantly shorter in BASE-II participants of the older group (p = 3.7 &#xd7; 10-12) and in women (p = 4.2 &#xd7; 10-31). rLTL of older men exhibited a statistically significant, positive partial correlation with mean corpuscular hemoglobin (MCH; p = 0.012) and MCH concentration (p = 0.002). While these correlations were only observed in men, the rLTL of older women was negatively correlated with the number of thrombocytes (p = 0.015) in the same type of analysis. Among all older participants, 6% met the criteria to be categorized as 'anemic'; however, there was no association between anemia and rLTL.<br><br>CONCLUSION: In the present study, we have detected isolated correlations between rLTL and hematological parameters; however, in all cases, rLTL explained only a small part of the variation of the analyzed parameters. In disagreement with some other studies showing similar data, we interpret the association between rLTL and some of the hematological parameters studied here to be at most marginal. This applies also to the role of rLTL in anemia, at least in the age group investigated here. Since BASE-II is yet another large cohort in which women have on average shorter telomeres than men, this finding will be addressed in the discussion with respect to the ongoing debate on gender differences in telomere length.},
}
@article {pmid26818530,
year = {2017},
author = {Min, KB and Min, JY},
title = {Association between leukocyte telomere length and serum carotenoid in US adults.},
journal = {European journal of nutrition},
volume = {56},
number = {3},
pages = {1045-1052},
pmid = {26818530},
issn = {1436-6215},
mesh = {Adult ; Aged ; Aged, 80 and over ; *Aging ; Biomarkers/metabolism ; Body Mass Index ; Carotenoids/administration &amp; dosage/*blood ; Chromatography, High Pressure Liquid ; Cross-Sectional Studies ; Docosahexaenoic Acids/administration &amp; dosage/blood ; Eicosapentaenoic Acid/administration &amp; dosage/blood ; Female ; Folic Acid/blood ; Homocysteine/blood ; Humans ; Leukocytes/*metabolism ; Logistic Models ; Male ; Middle Aged ; Nutrition Surveys ; Socioeconomic Factors ; Telomere/*ultrastructure ; Young Adult ; },
abstract = {PURPOSE: Telomere length is a biomarker for aging. It is known that oxidative stress can accelerate telomere shortening, whereas antioxidants can delay their shortening. Carotenoids as antioxidants are favorably associated with health- and aging-related diseases caused by oxidative stress, but their association with telomere length is less certain. We investigated the association between blood carotenoid levels and leukocyte telomere length in a representative sample of US adults.<br><br>METHODS: We analyzed 3660 participants aged 20&#xa0;years and older in the 1999-2002 National Health and Nutrition Examination Survey. The levels of carotenoids-alpha-carotene, beta-carotene (trans&#xa0;+&#xa0;cis), beta-cryptoxanthin, combined lutein/zeaxanthin, and trans-lycopene-were measured using high-performance liquid chromatography. The leukocyte telomere length (T/S ratio) was assayed using the quantitative polymerase chain reaction method.<br><br>RESULTS: A doubling of blood alpha-carotene, beta-carotene (trans&#xa0;+&#xa0;cis), and beta-cryptoxanthin was associated with approximately 2&#xa0;% longer telomeres. Compared with the lowest carotenoid quartile of alpha-carotene, beta-carotene (trans&#xa0;+&#xa0;cis), and beta-cryptoxanthin, telomere length for adults with the highest quartiles was significantly increased by 5-8&#xa0;%.<br><br>CONCLUSION: We found that increasing levels of blood carotenoid were significantly associated with longer leukocyte telomeres in US adults. High intake of carotenoid-rich food may play a role in protecting telomeres and regulating telomere length.},
}
@article {pmid26816107,
year = {2016},
author = {Zhang, Q and Dan, J and Wang, H and Guo, R and Mao, J and Fu, H and Wei, X and Liu, L},
title = {Tcstv1 and Tcstv3 elongate telomeres of mouse ES cells.},
journal = {Scientific reports},
volume = {6},
number = {},
pages = {19852},
pmid = {26816107},
issn = {2045-2322},
mesh = {Animals ; Cell Differentiation/physiology ; Cell Proliferation/*physiology ; Gene Knockdown Techniques ; Mice ; Mouse Embryonic Stem Cells/cytology/*metabolism ; Telomere/genetics/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {Mouse embryonic stem cell (ESC) cultures exhibit a heterogeneous mixture of metastable cells sporadically entering the 2-cell (2C)-embryo-like state, critical for ESC potency. One of 2-cell genes, Zscan4, has been shown to be responsible for telomere maintenance, genomic stability and pluripotency of mouse ESCs. Functions of other 2C-genes in ESCs remain elusive. Here we show that 2C-genes Tcstv1 and Tcstv3 play a role in regulation of telomere lengths. Overexpression or knockdown Tcstv1 and Tcstv3 does not immediately affect proliferation, pluripotency and differentiation in vitro of ESCs. However, ectopic expression of Tcstv1 or Tcstv3 results in telomere elongation, whereas Tcstv1/3 knockdown shortens telomeres of ESCs. Overexpression of Tcstv1 or Tcstv3 does not alter telomere stability. Furthermore, Tcstv1 can increase Zscan4 protein levels and telomere recombination by telomere sister chromatid exchange (T-SCE). Depletion of Tcstv1/3 reduces Zscan4 protein levels. Together, Tcstv1 and Tcstv3 are involved in telomere maintenance that is required for long-term self-renewal of mouse ESCs. Our data also suggests that Tcstv1/3 may co-operate and stabilize Zscan4 protein but the molecular bases remain to be determined.},
}
@article {pmid26813775,
year = {2016},
author = {Fulnečková, J and Ševčíková, T and Lukešová, A and Sýkorová, E},
title = {Erratum to: Transitions between the Arabidopsis-type and the human-type telomere sequence in green algae (clade Caudivolvoxa, Chlamydomonadales).},
journal = {Chromosoma},
volume = {125},
number = {3},
pages = {453},
doi = {10.1007/s00412-016-0575-8},
pmid = {26813775},
issn = {1432-0886},
}
@article {pmid26812475,
year = {2016},
author = {Zong, S and Chen, C and Wang, Z and Zhang, Y and Cui, Y},
title = {Surface Enhanced Raman Scattering Based in Situ Hybridization Strategy for Telomere Length Assessment.},
journal = {ACS nano},
volume = {10},
number = {2},
pages = {2950-2959},
doi = {10.1021/acsnano.6b00198},
pmid = {26812475},
issn = {1936-086X},
mesh = {DNA Probes/chemistry ; Gold/chemistry ; HeLa Cells ; Humans ; In Situ Hybridization/*methods ; Metal Nanoparticles/chemistry ; Spectrum Analysis, Raman/*methods ; Telomere/*chemistry/genetics ; Telomere Homeostasis ; },
abstract = {Assessing telomere length is of vital importance since telomere length is closely related with several fatal diseases such as atherosclerosis and cancer. Here, we present a strategy to assess/measure telomere length, that is, surface enhanced Raman scattering (SERS) based in situ hybridization (SISH). The SISH method uses two kinds of SERS nanoprobes to hybridize in situ with telomeres and centromeres, respectively. The telomere specific SERS nanoprobe is called the Telo-probe, while the centromere specific SERS nanoprobe is called the Centro-probe. They are composed of metal nanoparticles (NPs), Raman reporter molecules and specially designed DNA strands. With longer telomeres, more Telo-probes will hybridize with them, resulting in a stronger SERS signal. To exclude possible influence of the SERS intensity by external factors (such as the nanoprobe concentration, the cell number or different batches of nanoprobes), centromeres are used as the inner control, which can be recognized by Centro-probes. Telomere length is evaluated using a redefined telomere-to-centromere ratio (T/C ratio). The calculation method for T/C ratio in SISH method is more reliable than that in fluorescent in situ hybridization (FISH). In addition, unlike FISH method, the SISH method is insensitive to autofluorescence. Moreover, SISH method can be used to analyze single telomeres. These features make SISH an excellent alternative strategy for telomere length measurement.},
}
@article {pmid26807592,
year = {2016},
author = {Rodriguez-Brenes, IA and Wodarz, D},
title = {Telomeres open a window on stem cell division.},
journal = {eLife},
volume = {5},
number = {},
pages = {e12481},
pmid = {26807592},
issn = {2050-084X},
mesh = {*Cell Division ; *Models, Biological ; Stem Cells/*physiology ; Telomere/*metabolism/ultrastructure ; },
abstract = {Measuring the length distribution of telomeres can reveal information about biological processes that are otherwise difficult to analyze experimentally.},
}
@article {pmid26805999,
year = {2016},
author = {Yip, L and Oh, SY and Li, Z and You, Q and Quinton, VM and Gilchrist, GC and Karrow, NA},
title = {Short communication: Ovine leukocyte telomere length is associated with variation in the cortisol response to systemic bacterial endotoxin challenge.},
journal = {Journal of dairy science},
volume = {99},
number = {4},
pages = {3157-3161},
doi = {10.3168/jds.2015-10363},
pmid = {26805999},
issn = {1525-3198},
mesh = {Aging/physiology ; Animals ; Endotoxins/*pharmacology ; Hydrocortisone/*blood ; Hypothalamo-Hypophyseal System/physiology ; Leukocytes/*ultrastructure ; Longevity ; Pituitary-Adrenal System/physiology ; Sheep/*blood ; Sheep, Domestic ; Stress, Physiological ; Telomere/drug effects/*ultrastructure ; *Telomere Shortening ; },
abstract = {Stress has been associated with biological aging and numerous age-related diseases. This may be due, in part, to accelerated shortening of telomeres, which are critical genomic structures that cap and protect chromosomal ends. Dysfunction of the hypothalamic-pituitary-adrenal axis may indirectly contribute to telomere shortening if an animal reacts too strongly or weakly to a stressor, leading to accelerated biological aging. In this study, outbred Rideau-Arcott sheep were stress challenged with Escherichia coli endotoxin and classified as high, middle, or low cortisol responders to investigate a potential relationship between cortisol response and age, and telomere length. In the present study, no association was found between age and telomere length. The study, however, revealed shorter telomeres in high and low cortisol responders compared with the middle cortisol responders, which suggests that health and longevity may be compromised in extreme high- and low-stress-responding sheep.},
}
@article {pmid26805432,
year = {2016},
author = {Bernadotte, A and Mikhelson, VM and Spivak, IM},
title = {Markers of cellular senescence. Telomere shortening as a marker of cellular senescence.},
journal = {Aging},
volume = {8},
number = {1},
pages = {3-11},
pmid = {26805432},
issn = {1945-4589},
mesh = {Age Factors ; Aging/genetics/*metabolism/pathology ; Animals ; Cell Cycle Checkpoints ; Cell Proliferation ; *Cellular Senescence ; Chromatin Assembly and Disassembly ; Genetic Markers ; Genetic Predisposition to Disease ; Heterochromatin/metabolism ; Histones/metabolism ; Humans ; Phenotype ; Reproducibility of Results ; Telomere/genetics/*metabolism ; *Telomere Shortening ; },
abstract = {The cellular senescence definition comes to the fact of cells irreversible proliferation disability. Besides the cell cycle arrest, senescent cells go through some morphological, biochemical, and functional changes which are the signs of cellular senescence. The senescent cells (including replicative senescence and stress-induced premature senescence) of all the tissues look alike. They are metabolically active and possess the set of characteristics in vitro and in vivo, which are known as biomarkers of aging and cellular senescence. Among biomarkers of cellular senescence telomere shortening is a rather elegant frequently used biomarker. Validity of telomere shortening as a marker for cellular senescence is based on theoretical and experimental data.},
}
@article {pmid26803233,
year = {2016},
author = {Sawhney, V and Campbell, NG and Brouilette, SW and Coppen, SR and Harbo, M and Baker, V and Ikebe, C and Shintani, Y and Hunter, RJ and Dhinoja, M and Johnston, A and Earley, MJ and Sporton, S and Bendix, L and Suzuki, K and Schilling, RJ},
title = {Telomere shortening and telomerase activity in ischaemic cardiomyopathy patients - Potential markers of ventricular arrhythmia.},
journal = {International journal of cardiology},
volume = {207},
number = {},
pages = {157-163},
doi = {10.1016/j.ijcard.2016.01.066},
pmid = {26803233},
issn = {1874-1754},
support = {PG/12/10/29389/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Aged ; Aged, 80 and over ; Biomarkers/blood/metabolism ; Cardiomyopathies/diagnosis/*metabolism/therapy ; Case-Control Studies ; Cross-Sectional Studies ; *Defibrillators, Implantable ; Enzyme Activation/physiology ; Female ; Humans ; Male ; Middle Aged ; Myocardial Ischemia/diagnosis/*metabolism/therapy ; Retrospective Studies ; Tachycardia, Ventricular/diagnosis/*metabolism/therapy ; Telomerase/blood/*metabolism ; Telomere Shortening/*physiology ; },
abstract = {BACKGROUND: Implantable cardioverter defibrillators (ICDs) reduce mortality in patients with ischaemic cardiomyopathy at high risk of ventricular arrhythmias (VA). However, the current indication for ICD prescription needs improvement. Telomere and telomerase in leucocytes have been shown to associate with biological ageing and pathogenesis of cardiovascular diseases. We hypothesised that leucocyte telomere length, load-of-short telomeres and/or telomerase activity are associated with VA occurrence in ischaemic cardiomyopathy patients.<br><br>METHODS AND RESULTS: 90 ischaemic cardiomyopathy patients with primary prevention ICDs were recruited. 35 had received appropriate therapy from the ICD for potentially-fatal VA while the remaining 55 patients had not. No significant differences in baseline demographic data relevant to telomere biology were seen between the two groups. There was no significant difference in the age and sex adjusted mean telomere length analysed by qPCR between the groups (p=0.88). In contrast, the load-of-short telomeres assessed by Universal-STELA method and telomerase activity by TRAP assay were both higher in patients who had appropriate ICD therapy and were significantly associated with incidence of ICD therapy (p=0.02, p=0.02). ROC analyses demonstrated that the sensitivity and specificity of these telomere dynamics in predicting potentially-fatal VA was higher than the current gold-standard - left ventricular ejection fraction (AUC 0.82 versus 0.47).<br><br>CONCLUSION: The load-of-short telomeres and telomerase activity had a significant association with ICD therapy (for VA) in ischaemic cardiomyopathy patients. These biomarkers should be tested in prospective studies to assess their clinical utility in predicting VA after myocardial infarction and guiding primary prevention ICD prescription.},
}
@article {pmid26803156,
year = {2016},
author = {Hakobyan, A and Nersisyan, L and Arakelyan, A},
title = {Quantitative trait association study for mean telomere length in the South Asian genomes.},
journal = {Bioinformatics (Oxford, England)},
volume = {32},
number = {11},
pages = {1697-1700},
doi = {10.1093/bioinformatics/btw027},
pmid = {26803156},
issn = {1367-4811},
mesh = {Asian People ; *Genome, Human ; Genome-Wide Association Study ; Genotype ; Humans ; Polymorphism, Single Nucleotide ; *Telomere ; },
abstract = {MOTIVATION: Mean telomere length (MTL) is associated with cancers and age-related diseases, which necessitates identification of genomic and environmental factors that impact telomere length dynamics. Here, we present a pilot genome wide association (GWA) study for MTL in South Asian population using publicly available next generation whole genome sequences (WGS), both for MTL and genotype calculations.<br><br>RESULTS: MTL in the studied population was not correlated with age, which is in accordance with previous reports. Further, we identified that individuals with Sikh religion had longer telomeres, which may be the result of complex interaction between genetic background and environmental factors. Finally, we identified 51 MTL-associated SNPs residing in five loci. The top ones were located in ADARB2 gene, which has previously been implicated with extreme old age.<br><br>CONCLUSION: Our results show that WGS data can be used in telomere length studies. In addition, we introduce novel loci implicated in MTL that may be worth considering in further telomere studies.<br><br>CONTACT: aarakelyan@sci.am<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid26799699,
year = {2016},
author = {Rao, S and Ye, N and Hu, H and Shen, Y and Xu, Q},
title = {Variants in TERT influencing telomere length are associated with paranoid schizophrenia risk.},
journal = {American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics},
volume = {171B},
number = {3},
pages = {317-324},
doi = {10.1002/ajmg.b.32403},
pmid = {26799699},
issn = {1552-485X},
mesh = {Adult ; Alleles ; Case-Control Studies ; Female ; *Genetic Association Studies ; *Genetic Predisposition to Disease ; Haplotypes/genetics ; Humans ; Linkage Disequilibrium/genetics ; Lymphocytes/metabolism ; Male ; Polymorphism, Single Nucleotide/*genetics ; Risk Factors ; Schizophrenia, Paranoid/*genetics ; Telomerase/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Schizophrenia is one of the most severe psychiatric disorders, with a high heritability of up to 80%. Several studies have reported telomere dysfunction in schizophrenia, and common variants in the telomerase reverse transcriptase (TERT) gene. TERT is a key component of the telomerase complex that maintains telomere length by addition of telomere repeats to telomere ends, and has repeatedly shown association with mean lymphocyte telomere length (LTL). Thus, we hypothesized that TERT may be a novel susceptibility gene for schizophrenia. Using a Taqman protocol, we genotyped eight tag SNPs from the TERT locus in 1,072 patients with paranoid schizophrenia and 1,284 control subjects from a Chinese Han population. We also measured mean LTL in 98 cases and 109 controls using a quantitative PCR-based technique. Chi-square tests showed that two SNPs, rs2075786 (P = 0.0009, OR = 0.76, 95%CI = 0.65-0.90) and rs4975605 (P = 0.0026, OR = 0.73, 95%CI = 0.60-0.90), were associated with a protective effect, while rs10069690 was associated with risk of paranoid schizophrenia (P = 0.0044, OR = 1.23, 95%CI = 1.07-1.42). Additionally, the rs2736118-rs2075786 haplotype showed significant association with paranoid schizophrenia (P = 0.0013). Moreover, mean LTL correlated with rs2075786 genotypes was significantly shorter in the patient group than the control group. The present results suggest that the TERT gene may be a novel candidate involved in the development of paranoid schizophrenia.},
}
@article {pmid26799419,
year = {2016},
author = {Natarajan, S and Begum, F and Gim, J and Wark, L and Henderson, D and Davie, JR and Hombach-Klonisch, S and Klonisch, T},
title = {High Mobility Group A2 protects cancer cells against telomere dysfunction.},
journal = {Oncotarget},
volume = {7},
number = {11},
pages = {12761-12782},
pmid = {26799419},
issn = {1949-2553},
mesh = {Cell Line, Tumor ; HMGA2 Protein/*metabolism ; Humans ; Neoplasms/*metabolism/*pathology ; Protein Stability ; Signal Transduction/physiology ; Telomere/metabolism/*pathology ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {The non-histone chromatin binding protein High Mobility Group AT-hook protein 2 (HMGA2) plays important roles in the repair and protection of genomic DNA in embryonic stem cells and cancer cells. Here we show that HMGA2 localizes to mammalian telomeres and enhances telomere stability in cancer cells. We present a novel interaction of HMGA2 with the key shelterin protein TRF2. We found that the linker (L1) region of HMGA2 contributes to this interaction but the ATI-L1-ATII molecular region of HMGA2 is required for strong interaction with TRF2. This interaction was independent of HMGA2 DNA-binding and did not require the TRF2 interacting partner RAP1 but involved the homodimerization and hinge regions of TRF2. HMGA2 retained TRF2 at telomeres and reduced telomere-dysfunction despite induced telomere stress. Silencing of HMGA2 resulted in (i) reduced binding of TRF2 to telomere DNA as observed by ChIP, (ii) increased telomere instability and (iii) the formation of telomere dysfunction-induced foci (TIF). This resulted in increased telomere aggregation, anaphase bridges and micronuclei. HMGA2 prevented ATM-dependent pTRF2T188 phosphorylation and attenuated signaling via the telomere specific ATM-CHK2-CDC25C DNA damage signaling axis. In summary, our data demonstrate a unique and novel role of HMGA2 in telomere protection and promoting telomere stability in cancer cells. This identifies HMGA2 as a new therapeutic target for the destabilization of telomeres in HMGA2+ cancer cells.},
}
@article {pmid26797767,
year = {2016},
author = {Zierer, J and Kastenmüller, G and Suhre, K and Gieger, C and Codd, V and Tsai, PC and Bell, J and Peters, A and Strauch, K and Schulz, H and Weidinger, S and Mohney, RP and Samani, NJ and Spector, T and Mangino, M and Menni, C},
title = {Metabolomics profiling reveals novel markers for leukocyte telomere length.},
journal = {Aging},
volume = {8},
number = {1},
pages = {77-94},
pmid = {26797767},
issn = {1945-4589},
support = {MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Age Factors ; Aged ; Aging/blood/genetics ; Biomarkers/blood ; Energy Metabolism ; Fatty Acids/metabolism ; Female ; Germany ; Humans ; Leukocytes/*metabolism ; Metabolomics/methods ; Middle Aged ; Oxidative Stress ; Phenotype ; Registries ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; Twins/genetics ; United Kingdom ; },
abstract = {Leukocyte telomere length (LTL) is considered one of the most predictive markers of biological aging. The aim of this study was to identify novel pathways regulating LTL using a metabolomics approach. To this end, we tested associations between 280 blood metabolites and LTL in 3511 females from TwinsUK and replicated our results in the KORA cohort. We furthermore tested significant metabolites for associations with several aging-related phenotypes, gene expression markers and epigenetic markers to investigate potential underlying pathways. Five metabolites were associated with LTL: Two lysolipids, 1-stearoylglycerophosphoinositol (P=1.6×10(-5)) and 1-palmitoylglycerophosphoinositol (P=1.6×10(-5)), were found to be negatively associated with LTL and positively associated with phospholipase A2 expression levels suggesting an involvement of fatty acid metabolism and particularly membrane composition in biological aging. Moreover, two gamma-glutamyl amino acids, gamma-glutamyltyrosine (P=2.5×10(-6)) and gamma-glutamylphenylalanine (P=1.7×10(-5)), were negatively correlated with LTL. Both are products of the glutathione cycle and markers for increased oxidative stress. Metabolites were also correlated with functional measures of aging, i.e. higher blood pressure and HDL cholesterol levels and poorer lung, liver and kidney function. Our results suggest an involvement of altered fatty acid metabolism and increased oxidative stress in human biological aging, reflected by LTL and age-related phenotypes of vital organ systems.},
}
@article {pmid26797572,
year = {2016},
author = {Williams, DM and Palaniswamy, S and Sebert, S and Buxton, JL and Blakemore, AI and Hyppönen, E and Jarvelin, MR},
title = {25-Hydroxyvitamin D Concentration and Leukocyte Telomere Length in Young Adults: Findings From the Northern Finland Birth Cohort 1966.},
journal = {American journal of epidemiology},
volume = {183},
number = {3},
pages = {191-198},
pmid = {26797572},
issn = {1476-6256},
support = {R01 MH063706/MH/NIMH NIH HHS/United States ; 5R01MH63706:02/MH/NIMH NIH HHS/United States ; WT088431MA/WT_/Wellcome Trust/United Kingdom ; 08/0003775/DUK_/Diabetes UK/United Kingdom ; G0600705/MRC_/Medical Research Council/United Kingdom ; G0601653/MRC_/Medical Research Council/United Kingdom ; 5R01HL087679-02/HL/NHLBI NIH HHS/United States ; 08/0003775/WT_/Wellcome Trust/United Kingdom ; K014536/MRC_/Medical Research Council/United Kingdom ; R01 HL087679/HL/NHLBI NIH HHS/United States ; G0500539/MRC_/Medical Research Council/United Kingdom ; GR069224/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adiposity ; Adult ; *Body Mass Index ; C-Reactive Protein/metabolism ; Cross-Sectional Studies ; Female ; Finland ; Humans ; Leukocytes ; Male ; Prospective Studies ; *Telomere Homeostasis ; Vitamin D/*analogs &amp; derivatives/blood ; },
abstract = {Higher vitamin D status, lower adiposity, and longer telomere length are each reportedly associated with lower risk of several chronic diseases and all-cause mortality. However, direct relationships between vitamin D status (measured by circulating 25-hydroxyvitamin D (25(OH)D) concentration), adiposity, and telomere length are not well established. We conducted a cross-sectional analysis of associations of 25(OH)D and body mass index (BMI; weight (kg)/height (m)(2)) with mean relative leukocyte telomere length (LTL) using data gathered on 5,096 participants from Northern Finland Birth Cohort 1966 at age 31 years (1997). 25(OH)D was not associated with LTL in either basic or confounder/mediator-adjusted models. BMI was inversely associated with LTL after adjustment for potential confounding by age, sex, socioeconomic position, physical activity, diet, smoking, alcohol intake, and use of oral contraceptives (per 1-unit increase in BMI, mean difference in LTL = -0.4%, 95% confidence interval: -0.6, -0.2). The BMI-LTL association was also independent of 25(OH)D and was attenuated slightly, but remained, after adjustment for C-reactive protein, a marker of low-grade inflammation (mean difference in LTL = -0.3%, 95% confidence interval -0.6, -0.1). These findings suggest that vitamin D status is unlikely to be an important determinant of LTL, at least by young adulthood. Inflammation may partly mediate associations of adiposity with LTL.},
}
@article {pmid26794045,
year = {2016},
author = {Loprinzi, PD and Sng, E},
title = {Mode-specific physical activity and leukocyte telomere length among U.S. adults: Implications of running on cellular aging.},
journal = {Preventive medicine},
volume = {85},
number = {},
pages = {17-19},
doi = {10.1016/j.ypmed.2016.01.002},
pmid = {26794045},
issn = {1096-0260},
mesh = {Adult ; Cellular Senescence/*genetics ; Female ; Humans ; Leukocytes/*metabolism ; Linear Models ; Male ; Nutrition Surveys ; Running/*physiology ; Telomere/*genetics ; United States ; },
abstract = {BACKGROUND: Previous research demonstrates that physical activity participation is associated with longer leukocyte telomere length, with shorter leukocyte telomere length being a hallmark characteristic of cellular aging. What remains under-investigated, however, is whether there is a mode-specific association of physical activity on leukocyte telomere length, which was this study's purpose.<br><br>METHODS: Data from the 1999-2002 National Health and Nutrition Examination Survey were used (N=6474 adults analyzed). Leukocyte telomere length was assessed using quantitative polymerase chain reaction. Physical activity was assessed via self-report, with participants classified as meeting physical activity guidelines (&#x2265;2000 metabolic equivalent of task-min-month) for 9 separate physical activities, including aerobics (unweighted percent meeting guidelines: 2.98%; n=193), basketball (2.0%; n=129), bicycling (3.71%; n=240), dance (2.30%; n=149), running (3.09%; n=200), stair climbing (1.33%, n=86), swimming (1.85%, n=120), walking (13.53%; n=876), and weight lifting (2.61%; n=169).<br><br>RESULTS: In a single multivariable linear regression model including the independent variables of age, gender, race-ethnicity, weight status, total cholesterol, C-reactive protein, total metabolic equivalent of task-min-month of physical activity and the 9 binary meeting physical activity guideline variables, the only mode of physical activity that was significantly associated with leukocyte telomere length was meeting physical activity guidelines from running (&#x3b2;=0.06; 95% CI: 0.01-0.11; P=0.03).<br><br>CONCLUSION: Running-specific physical activity was the only evaluated physical activity associated with leukocyte telomere length, which may provide one potential mechanism (i.e., leukocyte telomere length) through which running-based physical activity may help to prevent cardiovascular disease and premature mortality.},
}
@article {pmid26789780,
year = {2016},
author = {Yeap, BB and Knuiman, MW and Divitini, ML and Hui, J and Arscott, GM and Handelsman, DJ and McLennan, SV and Twigg, SM and McQuillan, B and Hung, J and Beilby, JP},
title = {Epidemiological and Mendelian Randomization Studies of Dihydrotestosterone and Estradiol and Leukocyte Telomere Length in Men.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {101},
number = {3},
pages = {1299-1306},
doi = {10.1210/jc.2015-4139},
pmid = {26789780},
issn = {1945-7197},
mesh = {3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/genetics ; Aromatase/genetics ; Dihydrotestosterone/*blood ; Estradiol/*blood ; Genetic Association Studies/statistics &amp; numerical data ; Humans ; Leukocytes/*metabolism ; Male ; Membrane Proteins/genetics ; Mendelian Randomization Analysis ; Middle Aged ; *Polymorphism, Single Nucleotide ; Telomere/metabolism ; Telomere Homeostasis/*genetics ; Western Australia/epidemiology ; Young Adult ; },
abstract = {CONTEXT: Advancing age is accompanied by an accumulation of ill health and shortening of chromosomal telomeres signifying biological aging. T is metabolized to DHT by 5α-reductase (SRD5A2) and to estradiol (E2) by aromatase (CYP19A1). Telomerase preserves telomeres, and T and E2 regulate telomerase expression and activity in vitro.<br><br>OBJECTIVE: The objective of the study was to establish whether circulating T or its metabolites, DHT or E2, and single-nucleotide polymorphisms in SRD5A2 or CYP19A1 associate with leucocyte telomere length (LTL) in men.<br><br>PARTICIPANTS AND METHODS: Early-morning serum T, DHT, and E2 were assayed using mass spectrometry, and SRD5A2 and CYP19A1 single-nucleotide polymorphisms and LTL analyzed by PCR in 980 men from the Western Australian Busselton Health Survey who participated in the study. LTL was expressed as the T/S ratio.<br><br>RESULTS: Men were aged (mean &#xb1; SD) 53.7 &#xb1; 15.6 years. LTL decreased linearly with age, from the T/S ratio of 1.89 &#xb1; 0.41 at younger than 30 years to 1.50 &#xb1; 0.49 at 70 to younger than 80 years (r = -0.225, P < .0001). After adjustment for age, DHT and E2 were positively correlated with LTL (DHT, r = 0.069, P = .030; E2, r = 0.068, P = .034). The SRD5A2 rs9282858 polymorphism was associated with serum DHT but not with LTL. Three dominant alleles of CYP19A1 were each associated with lower serum E2 and shorter LTL: rs2899470 T (E2, 59.3 vs 68.6 pmol/L, P < .0001; T/S ratio, 1.54 vs 1.62, P = .045), rs10046 C (60.5 vs 68.1 pmol/L, P = .0005, 1.54 vs 1.62, P = .035), and rs700518 A (59.9 vs 68.9 pmol/L, P < .0001, 1.54 vs 1.63, P = .020). A single-copy haplotype C/T/I/A/T rs10046/rs2899470/rs11575899/rs700518/rs17703883 (52% prevalence) was associated with both lower E2 and shorter LTL.<br><br>CONCLUSIONS: In men, serum DHT and E2 correlate with LTL independently of age. Aromatase gene polymorphisms include three dominant alleles that are associated with both lower serum E2 and shorter LTL. E2 influences telomere length in vivo, thus warranting further studies to examine whether hormonal interventions might slow biological aging in men.},
}
@article {pmid26789415,
year = {2016},
author = {Carneiro, MC and Henriques, CM and Nabais, J and Ferreira, T and Carvalho, T and Ferreira, MG},
title = {Short Telomeres in Key Tissues Initiate Local and Systemic Aging in Zebrafish.},
journal = {PLoS genetics},
volume = {12},
number = {1},
pages = {e1005798},
pmid = {26789415},
issn = {1553-7404},
mesh = {Aging/*genetics/pathology ; Animals ; Apoptosis/*genetics ; Blood Cells ; Cell Division/genetics ; DNA Damage/genetics ; Humans ; Kidney/metabolism ; Neoplasms/etiology/*genetics ; Organ Specificity ; Telomere/*genetics ; Telomere Shortening/*genetics ; Zebrafish ; },
abstract = {Telomeres shorten with each cell division and telomere dysfunction is a recognized hallmark of aging. Tissue proliferation is expected to dictate the rate at which telomeres shorten. We set out to test whether proliferative tissues age faster than non-proliferative due to telomere shortening during zebrafish aging. We performed a prospective study linking telomere length to tissue pathology and disease. Contrary to expectations, we show that telomeres shorten to critical lengths only in specific tissues and independently of their proliferation rate. Short telomeres accumulate in the gut but not in other highly proliferative tissues such as the blood and gonads. Notably, the muscle, a low proliferative tissue, accumulates short telomeres and DNA damage at the same rate as the gut. Together, our work shows that telomere shortening and DNA damage in key tissues triggers not only local dysfunction but also anticipates the onset of age-associated diseases in other tissues, including cancer.},
}
@article {pmid26789258,
year = {2016},
author = {Hatakeyama, H and Yamazaki, H and Nakamura, K and Izumiyama-Shimomura, N and Aida, J and Suzuki, H and Tsuchida, S and Matsuura, M and Takubo, K and Ishikawa, N},
title = {Telomere attrition and restoration in the normal teleost Oryzias latipes are linked to growth rate and telomerase activity at each life stage.},
journal = {Aging},
volume = {8},
number = {1},
pages = {62-76},
pmid = {26789258},
issn = {1945-4589},
mesh = {Age Factors ; Animals ; Fish Proteins/*metabolism ; Kinetics ; Life Cycle Stages ; Oryzias/genetics/growth &amp; development/*metabolism ; Telomerase/*metabolism ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Telomere shortening occurs when cells divide, both in vitro and in vivo. On the other hand, telomerase is able to maintain telomere length in cells by adding TTAGGG repeats to the ends of telomeres. However, the interrelationships existing among telomere length, telomerase activity and growth in vertebrates remain to be clarified. In the present study we measured telomere length (terminal restriction fragment length), telomerase activity and body growth of Oryzias latipes from the embryo stage until senescence. During the rapid growth stage (age 0-7 months), telomeres shortened in parallel with decreasing telomerase activity. Then, during adolescence (age 7 months - 1 year), telomeres lengthened quickly as growth slowed and telomerase activity increased. In the adult stage (age 1-4 years) characterized by little growth, telomerase activity decreased gradually and telomeres shortened. Our data indicate that telomere attrition and restoration are linked to growth and telomerase activity, and suggest that critical loss of telomere homeostasis is associated with mortality in this animal.},
}
@article {pmid26787169,
year = {2016},
author = {Rousseau, P and Khondaker, S and Zhu, S and Lauzon, C and Mai, S and Autexier, C},
title = {An intact putative mouse telomerase essential N-terminal domain is necessary for proper telomere maintenance.},
journal = {Biology of the cell},
volume = {108},
number = {4},
pages = {96-112},
doi = {10.1111/boc.201500089},
pmid = {26787169},
issn = {1768-322X},
support = {MOP-123379//Canadian Institutes of Health Research/Canada ; MOP-133449//Canadian Institutes of Health Research/Canada ; },
mesh = {Alternative Splicing ; Animals ; Cell Line ; Mice ; Protein Biosynthesis ; Protein Isoforms/analysis/genetics/metabolism ; RNA/metabolism ; Telomerase/analysis/*genetics/*metabolism ; Telomere/*metabolism ; Transcription, Genetic ; },
abstract = {BACKGROUND INFORMATION: Naturally occurring telomerase reverse transcriptase (TERT) isoforms may regulate telomerase activity, and possibly function independently of telomeres to modulate embryonic stem (ES) cell self-renewal and differentiation.<br><br>RESULTS: We report the characterisation of two novel mouse TERT (mTERT) splice variants, Ins-i1[1-102] (Insi1 for short) and Del-e12[1-40] (Dele12 for short) that have not been previously described. Insi1 represents an in-frame insertion of nucleotides 1-102 from intron 1, encoding a 34 amino acid insertion at amino acid 73. Based on known functions of this region in human and Tetrahymena TERTs, the insertion interrupts the RNA interaction domain 1 implicated in low-affinity RNA binding and the telomerase essential N-terminal domain implicated in DNA substrate interactions. Dele12 contains a 40 nucleotide deletion of exon 12 which generates a premature stop codon, and possible protein lacking the C-terminus. We found Insi1 expressed in adult mouse brain and kidney and Dele12 expressed in adult mouse ovary. Dele12 was inactive in vitro and in mTERT(-/-) ES cells and Insi1 retained 26-48% of telomerase activity reconstituted by wild-type mTERT in vitro and in mTERT(-/-) ES cells. The Insi1 variant exhibited reduced DNA substrate binding in vitro and both variants exhibited a reduction in binding the telomerase RNA, mTR, when expressed in mTERT(-/-) ES cells. Stable expression of Dele12 in the mouse fibroblast CB17 cell line inhibited telomerase activity and slowed cell growth, suggesting a potential dominant-negative effect. Levels of signal-free ends, representing short telomeres, and end-to-end fusions were higher in mTERT(-/-) ES cells expressing mTERT-Insi1 and mTERT-Dele12, compared with levels observed in mTERT(-/-) ES cells expressing wild-type mTERT. In addition, in mTERT(-/-) cells expressing mTERT-Insi1, we observed chromosomes that were products of repeated breakage-bridge-fusion cycles and other telomere dysfunction-related aberrations.<br><br>CONCLUSION AND SIGNIFICANCE: An intact mTERT N-terminus which contributes to mTR binding, DNA binding and telomerase activity is necessary for elongation of short telomeres and the maintenance of functional telomeres. It is reasonable to speculate that relative levels of mTERT-Insi1 may regulate telomere function in specific tissues.},
}
@article {pmid26786804,
year = {2015},
author = {Marzullo, M and Gatti, M},
title = {Telomere fusion in Drosophila: The role of subtelomeric chromatin.},
journal = {Fly},
volume = {9},
number = {3},
pages = {121-125},
pmid = {26786804},
issn = {1933-6942},
mesh = {Animals ; Brain/metabolism/ultrastructure ; Chromatin/metabolism/*physiology ; DNA Replication ; Drosophila/*genetics ; Drosophila Proteins/genetics/metabolism/*physiology ; Female ; Male ; Mutation ; Nuclear Proteins/genetics/metabolism/*physiology ; Retroelements/physiology ; Telomere/*metabolism/ultrastructure ; },
abstract = {Drosophila telomeres are maintained by transposition to chromosome ends of the HeT-A, TART and TAHRE retrotransposons, collectively designated as HTT. Although all Drosophila telomeres terminate with HTT arrays and are capped by the terminin complex, they differ in the type of subtelomeric chromatin. The HTT sequences of YS, YL, XR, and 4L are juxtaposed to constitutive heterochromatin, while the HTTs of the other telomeres are linked to either the TAS repeat-associated chromatin (XL, 2L, 2R, 3L, 3R) or to the specialized 4R chromatin. We found that mutations in pendolino (peo) cause (telomeric fusions) that preferentially involve the heterochromatin-associated telomeres (Ha-telomeres), a telomeric fusion pattern never observed in the other 10 telomere-capping mutants characterized so far. Peo, is homologous to the E2 variant ubiquitin-conjugating enzymes and is required for DNA replication. Our analyses lead us to hypothesize that DNA replication in Peo-depleted cells results in specific fusigenic lesions concentrated in Ha-telomeres. These data provide the first demonstration that subtelomeres can affect telomere fusion.},
}
@article {pmid26786510,
year = {2016},
author = {Fuhrmann, G and Jönsson, F and Weil, PP and Postberg, J and Lipps, HJ},
title = {RNA-template dependent de novo telomere addition.},
journal = {RNA biology},
volume = {13},
number = {8},
pages = {733-739},
pmid = {26786510},
issn = {1555-8584},
mesh = {Cell Nucleolus/genetics/metabolism ; Ciliophora/genetics/metabolism ; *DNA Replication ; Gene Amplification ; Genetic Variation ; Models, Biological ; RNA/*genetics ; RNA, Double-Stranded/genetics ; RNA, Untranslated/genetics ; Telomere/*genetics/metabolism ; *Templates, Genetic ; },
abstract = {De novo addition of telomeric sequences can occur at broken chromosomes and must be well controlled, which is essential during programmed DNA reorganization processes. In ciliated protozoa an extreme form of DNA-reorganization is observed during macronuclear differentiation after sexual reproduction leading to the elimination of specific parts of the germline genome. Regulating these processes involves small noncoding RNAs, but in addition DNA-reordering, excision and amplification require RNA templates deriving from the parental macronucleus. We show that these putative RNA templates can carry telomeric repeats. Microinjection of RNA templates carrying modified telomeres into the developing macronucleus leads to modified telomeres in vegetative cells, providing strong evidence, that de novo addition of telomeres depends on a telomere-containing transcript from the parental macronucleus.},
}
@article {pmid26786236,
year = {2016},
author = {Teichroeb, JH and Kim, J and Betts, DH},
title = {The role of telomeres and telomerase reverse transcriptase isoforms in pluripotency induction and maintenance.},
journal = {RNA biology},
volume = {13},
number = {8},
pages = {707-719},
pmid = {26786236},
issn = {1555-8584},
support = {//CIHR/Canada ; },
mesh = {Alternative Splicing ; Animals ; Biomarkers ; Cell Self Renewal/*genetics ; Embryonic Stem Cells/cytology/metabolism ; Gene Expression Regulation ; Humans ; Isoenzymes ; Mitochondria/genetics/metabolism ; Pluripotent Stem Cells/*cytology/*metabolism ; Protein Binding ; Telomerase/genetics/*metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {Telomeres are linear guanine-rich DNA structures at the ends of chromosomes. The length of telomeric DNA is actively regulated by a number of mechanisms in highly proliferative cells such as germ cells, cancer cells, and pluripotent stem cells. Telomeric DNA is synthesized by way of the ribonucleoprotein called telomerase containing a reverse transcriptase (TERT) subunit and RNA component (TERC). TERT is highly conserved across species and ubiquitously present in their respective pluripotent cells. Recent studies have uncovered intricate associations between telomeres and the self-renewal and differentiation properties of pluripotent stem cells. Interestingly, the past decade's work indicates that the TERT subunit also has the capacity to modulate mitochondrial function, to remodel chromatin structure, and to participate in key signaling pathways such as the Wnt/β-catenin pathway. Many of these non-canonical functions do not require TERT's catalytic activity, which hints at possible functions for the extensive number of alternatively spliced TERT isoforms that are highly expressed in pluripotent stem cells. In this review, some of the established and potential routes of pluripotency induction and maintenance are highlighted from the perspectives of telomere maintenance, known TERT isoform functions and their complex regulation.},
}
@article {pmid26786116,
year = {2016},
author = {Allende, M and Molina, E and González-Porras, JR and Toledo, E and Lecumberri, R and Hermida, J},
title = {Short Leukocyte Telomere Length Is Associated With Cardioembolic Stroke Risk in Patients With Atrial Fibrillation.},
journal = {Stroke},
volume = {47},
number = {3},
pages = {863-865},
doi = {10.1161/STROKEAHA.115.011837},
pmid = {26786116},
issn = {1524-4628},
mesh = {Aged ; Aged, 80 and over ; Atrial Fibrillation/*diagnosis/epidemiology ; Embolism/*diagnosis/epidemiology ; Female ; Humans ; Leukocytes/*physiology ; Male ; Prospective Studies ; Risk Factors ; Stroke/*diagnosis/epidemiology ; Telomere Shortening/*physiology ; },
abstract = {BACKGROUND AND PURPOSE: The risk of cardioembolic stroke in patients with atrial fibrillation (AF) cannot be accurately assessed and novel tools are needed to improve prediction. We hypothesize that telomere shortening constitutes a novel risk factor for cardioembolic stroke in patients with AF.<br><br>METHODS: The peripheral blood leukocyte telomere length (LTL) was determined by real-time polymerase chain reaction in 187 patients with AF, 93 of them without stroke history and 94 of them having suffered 1 cardioembolic stroke. Percentiles were calculated according to LTL values in the nonstroke group to estimate the cardioembolic stroke risk associated with LTL using logistic regression models.<br><br>RESULTS: Short LTL values were independently and dose-dependently associated with an increased risk of cardioembolic stroke, with an odds ratio (95% confidence interval) of 2.93 (1.24-6.94) and 6.26 (2.01-19.52), respectively, for sex, hypertension, diabetes mellitus, heart failure, and age-adjusted models using the LTL 10th and 5th percentile cut-offs, respectively.<br><br>CONCLUSIONS: Telomere shortening is associated with cardioembolic stroke risk in patients with AF. Prospective studies are encouraged to establish the value of LTL to improve prediction tools to categorize cardioembolic stroke risk in AF.},
}
@article {pmid26785477,
year = {2015},
author = {Blackburn, EH and Epel, ES and Lin, J},
title = {Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection.},
journal = {Science (New York, N.Y.)},
volume = {350},
number = {6265},
pages = {1193-1198},
doi = {10.1126/science.aab3389},
pmid = {26785477},
issn = {1095-9203},
support = {CA096840/CA/NCI NIH HHS/United States ; GM026259/GM/NIGMS NIH HHS/United States ; },
mesh = {Aging/*genetics ; Cell Division/genetics ; Disease/*genetics ; *Genetic Predisposition to Disease ; Humans ; Life Style ; Neoplasms/genetics ; Stress, Physiological ; Telomerase/metabolism ; Telomere/chemistry/*physiology/ultrastructure ; Telomere Homeostasis/*genetics ; },
abstract = {Telomeres are the protective end-complexes at the termini of eukaryotic chromosomes. Telomere attrition can lead to potentially maladaptive cellular changes, block cell division, and interfere with tissue replenishment. Recent advances in the understanding of human disease processes have clarified the roles of telomere biology, especially in diseases of human aging and in some aging-related processes. Greater overall telomere attrition predicts mortality and aging-related diseases in inherited telomere syndrome patients, and also in general human cohorts. However, genetically caused variations in telomere maintenance either raise or lower risks and progression of cancers, in a highly cancer type-specific fashion. Telomere maintenance is determined by genetic factors and is also cumulatively shaped by nongenetic influences throughout human life; both can interact. These and other recent findings highlight both causal and potentiating roles for telomere attrition in human diseases.},
}
@article {pmid26779251,
year = {2015},
author = {Fulcher, N and Riha, K},
title = {Using Centromere Mediated Genome Elimination to Elucidate the Functional Redundancy of Candidate Telomere Binding Proteins in Arabidopsis thaliana.},
journal = {Frontiers in genetics},
volume = {6},
number = {},
pages = {349},
pmid = {26779251},
issn = {1664-8021},
abstract = {Proteins that bind to telomeric DNA form the key structural and functional constituents of telomeres. While telomere binding proteins have been described in the majority of organisms, their identity in plants remains unknown. Several protein families containing a telomere binding motif known as the telobox have been previously described in Arabidopsis thaliana. Nonetheless, functional evidence for their involvement at telomeres has not been obtained, likely due to functional redundancy. Here we performed genetic analysis on the TRF-like family consisting of six proteins (TRB1, TRP1, TRFL1, TRFL2, TRFL4, and TRF9) which have previously shown to bind telomeric DNA in vitro. We used haploid genetics to create multiple knock-out plants deficient for all six proteins of this gene family. These plants did not exhibit changes in telomere length, or phenotypes associated with telomere dysfunction. This data demonstrates that this telobox protein family is not involved in telomere maintenance in Arabidopsis. Phylogenetic analysis in major plant lineages revealed early diversification of telobox proteins families indicating that telomere function may be associated with other telobox proteins.},
}
@article {pmid26778495,
year = {2016},
author = {Cipressa, F and Morciano, P and Bosso, G and Mannini, L and Galati, A and Raffa, GD and Cacchione, S and Musio, A and Cenci, G},
title = {A role for Separase in telomere protection.},
journal = {Nature communications},
volume = {7},
number = {},
pages = {10405},
pmid = {26778495},
issn = {2041-1723},
mesh = {Animals ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; Drosophila ; Drosophila Proteins/genetics/*metabolism ; Humans ; Nuclear Proteins/genetics/metabolism ; Separase/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Drosophila telomeres are elongated by transposition of specialized retroelements rather than telomerase activity and are assembled independently of the sequence. Fly telomeres are protected by the terminin complex that localizes and functions exclusively at telomeres and by non-terminin proteins that do not serve telomere-specific functions. We show that mutations in the Drosophila Separase encoding gene Sse lead not only to endoreduplication but also telomeric fusions (TFs), suggesting a role for Sse in telomere capping. We demonstrate that Separase binds terminin proteins and HP1, and that it is enriched at telomeres. Furthermore, we show that loss of Sse strongly reduces HP1 levels, and that HP1 overexpression in Sse mutants suppresses TFs, suggesting that TFs are caused by a HP1 diminution. Finally, we find that siRNA-induced depletion of ESPL1, the Sse human orthologue, causes telomere dysfunction and HP1 level reduction in primary fibroblasts, highlighting a conserved role of Separase in telomere protection.},
}
@article {pmid26778124,
year = {2016},
author = {Kibe, T and Zimmermann, M and de Lange, T},
title = {TPP1 Blocks an ATR-Mediated Resection Mechanism at Telomeres.},
journal = {Molecular cell},
volume = {61},
number = {2},
pages = {236-246},
pmid = {26778124},
issn = {1097-4164},
support = {R01 GM049046/GM/NIGMS NIH HHS/United States ; R01 CA181090/CA/NCI NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; CA181090/CA/NCI NIH HHS/United States ; GM049046/GM/NIGMS NIH HHS/United States ; },
mesh = {Aminopeptidases/*metabolism ; Animals ; Ataxia Telangiectasia Mutated Proteins/genetics/metabolism ; Carrier Proteins/metabolism ; Cell Cycle Proteins/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; DNA Repair Enzymes/metabolism ; DNA-Binding Proteins/metabolism ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/*metabolism ; Exodeoxyribonucleases/metabolism ; Mice ; Models, Biological ; Protein Structure, Tertiary ; RecQ Helicases/metabolism ; Serine Proteases/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; Telomeric Repeat Binding Protein 2/chemistry/metabolism ; Tumor Suppressor p53-Binding Protein 1 ; },
abstract = {The regulation of 5' end resection at DSBs and telomeres prevents genome instability. DSB resection is positively and negatively regulated by ATM signaling through CtIP/MRN and 53BP1-bound Rif1, respectively. Similarly, telomeres lacking TRF2 undergo ATM-controlled CtIP-dependent hyper-resection when the repression by 53BP1/Rif1 is alleviated. However, telomere resection in the absence of 53BP1/Rif1 is more extensive upon complete removal of shelterin, indicating additional protection against resection by shelterin. Here we show that TPP1 and POT1a/b in shelterin block a resection pathway distinct from that repressed by TRF2. This second pathway is regulated by ATR signaling, involves Exo1 and BLM, and is inhibited by 53BP1/Rif1. Thus, mammalian cells have two distinct 5' end-resection pathways that are regulated by DNA damage signaling, in part through Rif1-mediated inhibition. The data show that telomeres are protected from hyper-resection through the repression of the ATM and ATR kinases by TRF2 and TPP1-bound POT1a/b, respectively.},
}
@article {pmid26774283,
year = {2016},
author = {Benarroch-Popivker, D and Pisano, S and Mendez-Bermudez, A and Lototska, L and Kaur, P and Bauwens, S and Djerbi, N and Latrick, CM and Fraisier, V and Pei, B and Gay, A and Jaune, E and Foucher, K and Cherfils-Vicini, J and Aeby, E and Miron, S and Londoño-Vallejo, A and Ye, J and Le Du, MH and Wang, H and Gilson, E and Giraud-Panis, MJ},
title = {TRF2-Mediated Control of Telomere DNA Topology as a Mechanism for Chromosome-End Protection.},
journal = {Molecular cell},
volume = {61},
number = {2},
pages = {274-286},
pmid = {26774283},
issn = {1097-4164},
support = {P30 ES025128/ES/NIEHS NIH HHS/United States ; R00 ES016758/ES/NIEHS NIH HHS/United States ; R01 GM107559/GM/NIGMS NIH HHS/United States ; R01GM107559/GM/NIGMS NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins/metabolism ; Base Pairing ; DNA/*chemistry/metabolism ; DNA Damage ; DNA End-Joining Repair ; HeLa Cells ; Humans ; Lysine/metabolism ; Models, Molecular ; Mutation ; *Nucleic Acid Conformation ; Protein Structure, Tertiary ; Shelterin Complex ; Signal Transduction ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 2/chemistry/*metabolism ; },
abstract = {The shelterin proteins protect telomeres against activation of the DNA damage checkpoints and recombinational repair. We show here that a dimer of the shelterin subunit TRF2 wraps ∼ 90 bp of DNA through several lysine and arginine residues localized around its homodimerization domain. The expression of a wrapping-deficient TRF2 mutant, named Top-less, alters telomeric DNA topology, decreases the number of terminal loops (t-loops), and triggers the ATM checkpoint, while still protecting telomeres against non-homologous end joining (NHEJ). In Top-less cells, the protection against NHEJ is alleviated if the expression of the TRF2-interacting protein RAP1 is reduced. We conclude that a distinctive topological state of telomeric DNA, controlled by the TRF2-dependent DNA wrapping and linked to t-loop formation, inhibits both ATM activation and NHEJ. The presence of RAP1 at telomeres appears as a backup mechanism to prevent NHEJ when topology-mediated telomere protection is impaired.},
}
@article {pmid26773113,
year = {2016},
author = {Prescott, J and Karlson, EW and Orr, EH and Zee, RY and De Vivo, I and Costenbader, KH},
title = {A Prospective Study Investigating Prediagnostic Leukocyte Telomere Length and Risk of Developing Rheumatoid Arthritis in Women.},
journal = {The Journal of rheumatology},
volume = {43},
number = {2},
pages = {282-288},
pmid = {26773113},
issn = {1499-2752},
support = {HL099355/HL/NHLBI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA67262/CA/NCI NIH HHS/United States ; R01 CA067262/CA/NCI NIH HHS/United States ; R01 HL043851/HL/NHLBI NIH HHS/United States ; UM1 CA176726/CA/NCI NIH HHS/United States ; K24 AR066109/AR/NIAMS NIH HHS/United States ; R01 AR059073/AR/NIAMS NIH HHS/United States ; R01 CA49449/CA/NCI NIH HHS/United States ; U01 CA067262/CA/NCI NIH HHS/United States ; P60 AR047782/AR/NIAMS NIH HHS/United States ; K24 AR052403/AR/NIAMS NIH HHS/United States ; P01 CA87969/CA/NCI NIH HHS/United States ; R01 AR049880/AR/NIAMS NIH HHS/United States ; R01 CA047988/CA/NCI NIH HHS/United States ; R01 HL080467/HL/NHLBI NIH HHS/United States ; HL080467/HL/NHLBI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; RC1 HL099355/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Arthritis, Rheumatoid/diagnosis/*genetics ; Case-Control Studies ; Female ; Humans ; Middle Aged ; Prospective Studies ; Risk Factors ; *Telomere ; },
abstract = {OBJECTIVE: To prospectively examine the association between leukocyte telomere length (LTL) and subsequent rheumatoid arthritis (RA) development in women.<br><br>METHODS: Using a case-control design nested within the prospective Nurses' Health Study (NHS), NHS II (NHSII), and Women's Health Study (WHS), each validated case of RA with a prediagnostic blood sample was matched to 3 controls by cohort, age, menopausal status, postmenopausal hormone therapy, and blood collection covariates. We measured telomere length in genomic DNA extracted from stored buffy coat samples using quantitative PCR. We used unconditional logistic regression to determine OR and 95% CI, and random-effects metaanalysis to combine study results.<br><br>RESULTS: In total, we analyzed 296 incident RA cases and 827 matched controls. Mean age of diagnosis among women who developed RA was 60.5 in NHS/NHSII and 61.3 in WHS. Metaanalysis demonstrated that longer prediagnostic LTL was associated with increased RA risk when women in the longest versus shortest LTL tertile were compared (OR 1.51, 95% CI 1.03-2.23, Pheterogeneity = 0.27). However, statistically significant between-study heterogeneity was observed for the intermediate tertile category (Pheterogeneity = 0.008). We did not observe heterogeneity by menopausal status, inflammatory cytokine levels, age at diagnosis, age at blood collection, body mass index, seropositivity, or HLA-DR&#x3b2;1 shared epitope status.<br><br>CONCLUSION: Our results do not support an involvement for short LTL preceding RA development.},
}
@article {pmid26772888,
year = {2016},
author = {Forero, DA and González-Giraldo, Y and López-Quintero, C and Castro-Vega, LJ and Barreto, GE and Perry, G},
title = {Telomere length in Parkinson's disease: A meta-analysis.},
journal = {Experimental gerontology},
volume = {75},
number = {},
pages = {53-55},
pmid = {26772888},
issn = {1873-6815},
support = {G12 MD007591/MD/NIMHD NIH HHS/United States ; T32DA021129/DA/NIDA NIH HHS/United States ; G12-MD007591/MD/NIMHD NIH HHS/United States ; K05 DA015799/DA/NIDA NIH HHS/United States ; T32 DA021129/DA/NIDA NIH HHS/United States ; },
mesh = {Case-Control Studies ; Humans ; Parkinson Disease/*genetics ; Risk Factors ; Telomere/*pathology ; *Telomere Shortening ; },
abstract = {Parkinson's disease (PD) is a common and severe movement disorder. Differences in telomere length (TL) have been reported as possible risk factors for several neuropsychiatric disorders, including PD. Results from published studies for TL in PD are inconsistent, highlighting the need for a meta-analysis. In the current work, a meta-analysis of published studies for TL in PD was carried out. PubMed, Web of Science and Google Scholar databases were used to identify relevant articles that reported TL in groups of PD patients and controls. A random-effects model was used for meta-analytical procedures. The meta-analysis included eight primary studies, derived from populations of European and Asian descent, and did not show a significant difference in TL between 956 PD patients and 1284 controls (p value: 0.246). Our results show that there is no consistent evidence of shorter telomeres in PD patients and suggest the importance of future studies on TL and PD that analyze other populations and also include assessment of TL from different brain regions.},
}
@article {pmid26771897,
year = {2016},
author = {Merghoub, N and El Btaouri, H and Benbacer, L and Gmouh, S and Trentesaux, C and Brassart, B and Terryn, C and Attaleb, M and Madoulet, C and Benjouad, A and Amzazi, S and El Mzibri, M and Morjani, H},
title = {Inula Viscosa Extracts Induces Telomere Shortening and Apoptosis in Cancer Cells and Overcome Drug Resistance.},
journal = {Nutrition and cancer},
volume = {68},
number = {1},
pages = {131-143},
doi = {10.1080/01635581.2016.1115105},
pmid = {26771897},
issn = {1532-7914},
mesh = {Annexin A5/analysis ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Humans ; *Inula ; Plant Extracts/*pharmacology ; Telomerase/metabolism ; Telomere Shortening/*drug effects ; },
abstract = {Telomerase is activated in human papillomavirus (HPV) positive cervical cancer and targeting telomeres offers a novel anticancer therapeutic strategy. In this study, the telomere targeting properties, the cytotoxic as well as the pro-apoptotic effects of hexane (IV-HE) and dichloromethane (IV-DF) fractions from Inula viscosa L. extracts were investigated on human cervical HeLa and SiHa cancer cells. Our data demonstrate that IV-HE and IV-DF extracts were able to inhibit cell growth in HeLa and SiHa cells in a dose-dependent manner and studied resistant cell lines exhibited a resistance factor less than 2 when treated with the extracts. IV-HE and IV-DF extracts were able to inhibit telomerase activity and to induce telomere shortening as shown by telomeric repeat amplification protocol and TTAGGG telomere length assay, respectively. The sensitivity of fibroblasts to the extracts was increased when telomerase was expressed. Finally, IV-HE and IV-DF were able to induce apoptosis as evidenced by an increase in annexin-V labeling and caspase-3 activity. This study provides the first evidence that the IV-HE and IV-DF extracts from Inula viscosa L. target telomeres induce apoptosis and overcome drug resistance in tumor cells. Future studies will focus on the identification of the molecules involved in the anticancer activity.},
}
@article {pmid26769142,
year = {2016},
author = {Hung, NA and Eiholzer, RA and Kirs, S and Zhou, J and Ward-Hartstonge, K and Wiles, AK and Frampton, CM and Taha, A and Royds, JA and Slatter, TL},
title = {Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma.},
journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},
volume = {29},
number = {3},
pages = {212-226},
pmid = {26769142},
issn = {1530-0285},
mesh = {Adult ; Aged ; Blotting, Western ; Brain Neoplasms/immunology/mortality/*pathology ; Female ; Glioblastoma/immunology/mortality/*pathology ; Humans ; Immunohistochemistry ; Kaplan-Meier Estimate ; Macrophages/*immunology ; Male ; Middle Aged ; Polymerase Chain Reaction ; Prognosis ; Telomere/*physiology ; },
abstract = {Telomere maintenance is a hallmark of cancer and likely to be targeted in future treatments. In glioblastoma established methods of identifying telomerase and alternative lengthening of telomeres leave a significant proportion of tumors with no defined telomere maintenance mechanism. This study investigated the composition of these tumors using RNA-Seq. Glioblastomas with an indeterminate telomere maintenance mechanism had an increased immune signature compared with alternative lengthening of telomeres and telomerase-positive tumors. Immunohistochemistry for CD163 confirmed that the majority (80%) of tumors with an indeterminate telomere maintenance mechanism had a high presence of tumor-associated macrophages. The RNA-Seq and immunostaining data separated tumors with no defined telomere maintenance mechanism into three subgroups: alternative lengthening of telomeres like tumors with a high presence of tumor-associated macrophages and telomerase like tumors with a high presence of tumor-associated macrophages. The third subgroup had no increase in tumor-associated macrophages and may represent a distinct category. The presence of tumor-associated macrophages conferred a worse prognosis with reduced patient survival times (alternative lengthening of telomeres with and without macrophages P=0.0004, and telomerase with and without macrophages P=0.013). The immune signatures obtained from RNA-Seq were significantly different between telomere maintenance mechanisms. Alternative lengthening of telomeres like tumors with macrophages had increased expression of interferon-induced proteins with tetratricopeptide repeats (IFIT1-3). Telomerase-positive tumors with macrophages had increased expression of macrophage receptor with collagenous structure (MARCO), CXCL12 and sushi-repeat containing protein x-linked 2 (SRPX2). Telomerase-positive tumors with macrophages were also associated with a reduced frequency of total/near total resections (44% vs >76% for all other subtypes, P=0.014). In summary, different immune signatures are found among telomere maintenance mechanism-based subgroups in glioblastoma. The reduced extent of surgical resection of telomerase-positive tumors with macrophages suggests that some tumor-associated macrophages are more unfavorable.},
}
@article {pmid26765095,
year = {2016},
author = {Dlouha, D and Pitha, J and Mesanyova, J and Mrazkova, J and Fellnerova, A and Stanek, V and Lanska, V and Hubacek, JA},
title = {Genetic variants within telomere-associated genes, leukocyte telomere length and the risk of acute coronary syndrome in Czech women.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {454},
number = {},
pages = {62-65},
doi = {10.1016/j.cca.2015.12.041},
pmid = {26765095},
issn = {1873-3492},
mesh = {Acute Coronary Syndrome/*genetics ; Czech Republic ; Female ; Genetic Variation/*genetics ; Humans ; Leukocytes/*metabolism ; Middle Aged ; Risk Factors ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {The association between leukocyte telomere length (LTL) and cardiovascular disease (CVD) has been published in many reports, although almost exclusively in men. In our study we analysed the association between LTL and five selected variants within three candidate genes (TERC rs12696304; TERF2IP rs3784929 and rs8053257; UCP2 rs659366 and rs622064), which are not only involved in telomere-length maintenance but also potentially associated with higher risk of acute coronary syndrome (ACS) in Czech women (505 cases and 642 controls). We detected significantly shorter LTL in women with ACS (P<0.001), but the difference disappeared after multiple adjustments. We did not find any significant associations between analysed variants and LTL, except for rs622064 within the UCP2 gene, in which case AA homozygotes had a higher LTL (P<0.04). Genotype frequencies of the analysed SNPs did not differ between controls and women with ACS. Variants within UCP2 (rs622064; CC vs. A allele carriers OR=1.61; 95% CI: 1.21-2.15, P<0.002) and within TERF2IP (rs8053257; A allele carriers vs. GG, OR=1.78; 95% CI: 1.07-3.18, P<0.03) were associated with increased risk of type 2 diabetes mellitus (T2DM). Analysed polymorphisms were not major determinants of telomere length or ACS risk in Czech females.},
}
@article {pmid26759601,
year = {2016},
author = {Quirici, V and Guerrero, CJ and Krause, JS and Wingfield, JC and Vásquez, RA},
title = {The relationship of telomere length to baseline corticosterone levels in nestlings of an altricial passerine bird in natural populations.},
journal = {Frontiers in zoology},
volume = {13},
number = {},
pages = {1},
pmid = {26759601},
issn = {1742-9994},
abstract = {BACKGROUND: Environmental stressors increase the secretion of glucocorticoids that in turn can shorten telomeres via oxidative damage. Modification of telomere length, as a result of adversity faced early in life, can modify an individual's phenotype. Studies in captivity have suggested a relationship between glucocorticoids and telomere length in developing individuals, however less is known about that relationship in natural populations.<br><br>METHODS: In order to evaluate the effect of early environmental stressors on telomere length in natural populations, we compared baseline corticosterone (CORT) levels and telomere length in nestlings of the same age. We collected blood samples for hormone assay and telomere determination from two geographically distinct populations of the Thorn-tailed Rayadito (Aphrastura spinicauda) that differed in brood size; nestlings body mass and primary productivity. Within each population we used path analysis to evaluate the relationship between brood size, body mass, baseline CORT and telomere length.<br><br>RESULTS: Within each distinct population, path coefficients showed a positive relationship between brood size and baseline CORT and a strong and negative correlation between baseline CORT and telomere length. In general, nestlings that presented higher baseline CORT levels tended to present shorter telomeres. When comparing populations it was the low latitude population that presented higher levels of baseline CORT and shorter telomere length.<br><br>CONCLUSIONS: Taken together our results reveal the importance of the condition experienced early in life in affecting telomere length, and the relevance of integrative studies carried out in natural conditions.},
}
@article {pmid26758019,
year = {2016},
author = {Feijoo, P and Terradas, M and Soler, D and Domínguez, D and Tusell, L and Genescà, A},
title = {Breast primary epithelial cells that escape p16-dependent stasis enter a telomere-driven crisis state.},
journal = {Breast cancer research : BCR},
volume = {18},
number = {1},
pages = {7},
pmid = {26758019},
issn = {1465-542X},
mesh = {Animals ; Breast Neoplasms/*genetics/pathology ; Cell Culture Techniques ; Cell Proliferation/genetics ; Cellular Senescence/genetics ; Chromosomal Instability/*genetics ; Cyclin-Dependent Kinase Inhibitor p16/*genetics ; DNA Damage/genetics ; DNA Methylation/*genetics ; Epithelial Cells/pathology ; Female ; High-Throughput Nucleotide Sequencing ; Humans ; Mice ; Promoter Regions, Genetic/genetics ; Telomerase/*genetics ; Telomere/genetics ; },
abstract = {Breast cancer is the most common malignant disease in women, but some basic questions remain in breast cancer biology. To answer these, several cell models were developed. Recently, the use of improved cell-culture conditions has enabled the development of a new primary cell model with certain luminal characteristics. This model is relevant because, after the introduction of a specific set of genetic elements, the transformed cells yielded tumors resembling human adenocarcinomas in mice. The use of improved cell-culture conditions supporting the growth of these breast primary epithelial cells was expected to delay or eliminate stress-induced senescence and lead to the propagation of normal cells. However, no studies have been carried out to investigate these points. Propagation of breast primary epithelial cells was performed in WIT medium on Primaria plates. Immunofluorescence, western blot and qRT-PCR were used to detect molecular markers, and to determine the integrity of DNA damage-response pathways. Promoter methylation of p16 (INK4a) was assessed by pyrosequencing. In order to obtain a dynamic picture of chromosome instability over time in culture, we applied FISH methodologies. To better link chromosome instability with excessive telomere attrition, we introduced the telomerase reverse transcriptase human gene using a lentiviral vector. We report here that breast primary epithelial cells propagated in vitro with WIT medium on Primaria plates express some luminal characteristics, but not a complete luminal lineage phenotype. They undergo a p16-dependent stress-induced senescence (stasis), and the cells that escape stasis finally enter a crisis state with rampant chromosome instability. Chromosome instability in these cells is driven by excessive telomere attrition, as distributions of chromosomes involved in aberrations correlate with the profiles of telomere signal-free ends. Importantly, ectopic expression of the human TERT gene rescued their chromosomal instability phenotype. Essentially, our data show that contrary to what was previously suggested, improved culture conditions to propagate in vitro mammary epithelial cells with some luminal characteristics do not prevent stress-induced senescence. This barrier is overcome by spontaneous methylation of the p16 (INK4a) promoter, allowing the proliferation of cells with telomere dysfunction and ensuing chromosome instability.},
}
@article {pmid26752285,
year = {2016},
author = {Lynch, SM and Peek, MK and Mitra, N and Ravichandran, K and Branas, C and Spangler, E and Zhou, W and Paskett, ED and Gehlert, S and DeGraffinreid, C and Rebbeck, TR and Riethman, H},
title = {Race, Ethnicity, Psychosocial Factors, and Telomere Length in a Multicenter Setting.},
journal = {PloS one},
volume = {11},
number = {1},
pages = {e0146723},
pmid = {26752285},
issn = {1932-6203},
support = {F31-AG039986/AG/NIA NIH HHS/United States ; P60-NM006900//PHS HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; P50-CA105641/CA/NCI NIH HHS/United States ; R01 CA085074/CA/NCI NIH HHS/United States ; P50 CA105641/CA/NCI NIH HHS/United States ; P30 CA016520/CA/NCI NIH HHS/United States ; F31 AG039986/AG/NIA NIH HHS/United States ; R01-CA85074/CA/NCI NIH HHS/United States ; P30 CA006927/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; *Ethnicity ; Female ; Humans ; Male ; Middle Aged ; *Psychology ; *Racial Groups ; Regression Analysis ; Socioeconomic Factors ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Leukocyte telomere length(LTL) has been associated with age, self-reported race/ethnicity, gender, education, and psychosocial factors, including perceived stress, and depression. However, inconsistencies in associations of LTL with disease and other phenotypes exist across studies. Population characteristics, including race/ethnicity, laboratory methods, and statistical approaches in LTL have not been comprehensively studied and could explain inconsistent LTL associations.<br><br>METHODS: LTL was measured using Southern Blot in 1510 participants from a multi-ethnic, multi-center study combining data from 3 centers with different population characteristics and laboratory processing methods. Main associations between LTL and psychosocial factors and LTL and race/ethnicity were evaluated and then compared across generalized estimating equations(GEE) and linear regression models. Statistical models were adjusted for factors typically associated with LTL(age, gender, cancer status) and also accounted for factors related to center differences, including laboratory methods(i.e., DNA extraction). Associations between LTL and psychosocial factors were also evaluated within race/ethnicity subgroups (Non-hispanic Whites, African Americans, and Hispanics).<br><br>RESULTS: Beyond adjustment for age, gender, and cancer status, additional adjustments for DNA extraction and clustering by center were needed given their effects on LTL measurements. In adjusted GEE models, longer LTL was associated with African American race (Beta(&#x3b2;)(standard error(SE)) = 0.09(0.04), p-value = 0.04) and Hispanic ethnicity (&#x3b2;(SE) = 0.06(0.01), p-value = 0.02) compared to Non-Hispanic Whites. Longer LTL was also associated with less than a high school education compared to having greater than a high school education (&#x3b2;(SE) = 0.06(0.02), p-value = 0.04). LTL was inversely related to perceived stress (&#x3b2;(SE) = -0.02(0.003), p<0.001). In subgroup analyses, there was a negative association with LTL in African Americans with a high school education versus those with greater than a high school education(&#x3b2;(SE) = -0.11(0.03), p-value<0.001).<br><br>CONCLUSIONS: Laboratory methods and population characteristics that differ by center can influence telomere length associations in multicenter settings, but these effects could be addressed through statistical adjustments. Proper evaluation of potential sources of bias can allow for combined multicenter analyses and may resolve some inconsistencies in reporting of LTL associations. Further, biologic effects on LTL may differ under certain psychosocial and racial/ethnic circumstances and could impact future health disparity studies.},
}
@article {pmid26745135,
year = {2015},
author = {Sasidharan, S and Jothy, SL and Kavitha, N and Chen, Y and Kanwar, JR},
title = {Deactivation of Telomerase Enzyme and Telomere Destabilization by Natural Products: a Potential Target for Cancer Green Therapy.},
journal = {Asian Pacific journal of cancer prevention : APJCP},
volume = {16},
number = {18},
pages = {8671},
doi = {10.7314/apjcp.2015.16.18.8671},
pmid = {26745135},
issn = {2476-762X},
mesh = {Biological Products/*therapeutic use ; Humans ; Neoplasms/*drug therapy/enzymology/genetics ; Prognosis ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*chemistry/genetics ; },
}
@article {pmid26742748,
year = {2016},
author = {Khavinson, VKh and Kuznik, BI and Tarnovskaya, SI and Lin'kova, NS},
title = {Short Peptides and Telomere Length Regulator Hormone Irisin.},
journal = {Bulletin of experimental biology and medicine},
volume = {160},
number = {3},
pages = {347-349},
doi = {10.1007/s10517-016-3167-y},
pmid = {26742748},
issn = {1573-8221},
mesh = {Animals ; Epigenesis, Genetic/genetics ; Fibronectins/genetics/*metabolism ; Humans ; Mice ; Peptides/genetics/metabolism ; Telomere/*genetics ; },
abstract = {Irisin produced by muscles during exercise and promoting fat burning also exhibits geroprotective effect and induces telomere elongation in normal somatic cells. Special attention is paid to studies of the role of peptides Lys-Glu, Glu-Asp-Arg, and Ala-Glu-Asp-Gly in epigenetic regulation of irisin content. The data suggest that the immunomodulatory peptide Lys-Glu and neuroprotective peptide Glu-Asp-Arg modulate the life span by modulating irisin gene expression.},
}
@article {pmid26742602,
year = {2016},
author = {López-Panadès, E and Casacuberta, E},
title = {NAP-1, Nucleosome assembly protein 1, a histone chaperone involved in Drosophila telomeres.},
journal = {Insect biochemistry and molecular biology},
volume = {70},
number = {},
pages = {111-115},
doi = {10.1016/j.ibmb.2015.11.011},
pmid = {26742602},
issn = {1879-0240},
mesh = {Animals ; Drosophila/*genetics ; Drosophila Proteins/*physiology ; Female ; Nucleosome Assembly Protein 1/*physiology ; *Telomere ; Transcription, Genetic/physiology ; },
abstract = {Telomere elongation is a function that all eukaryote cells must accomplish in order to guarantee, first, the stability of the end of the chromosomes and second, to protect the genetic information from the inevitable terminal erosion. The targeted transposition of the telomere transposons HeT-A, TART and TAHRE perform this function in Drosophila, while the telomerase mechanism elongates the telomeres in most eukaryotes. In order to integrate telomere maintenance together with cell cycle and metabolism, different components of the cell interact, regulate, and control the proteins involved in telomere elongation. Different partners of the telomerase mechanism have already been described, but in contrast, very few proteins have been related with assisting the telomere transposons of Drosophila. Here, we describe for the first time, the implication of NAP-1 (Nucleosome assembly protein 1), a histone chaperone that has been involved in nuclear transport, transcription regulation, and chromatin remodeling, in telomere biology. We find that Nap-1 and HeT-A Gag, one of the major components of the Drosophila telomeres, are part of the same protein complex. We also demonstrate that their close interaction is necessary to guarantee telomere stability in dividing cells. We further show that NAP-1 regulates the transcription of the HeT-A retrotransposon, pointing to a positive regulatory role of NAP-1 in telomere expression. All these results facilitate the understanding of the transposon telomere maintenance mechanism, as well as the integration of telomere biology with the rest of the cell metabolism.},
}
@article {pmid26741140,
year = {2016},
author = {Jia, H and Wang, Z},
title = {Telomere Length as a Prognostic Factor for Overall Survival in Colorectal Cancer Patients.},
journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology},
volume = {38},
number = {1},
pages = {122-128},
doi = {10.1159/000438614},
pmid = {26741140},
issn = {1421-9778},
mesh = {Colorectal Neoplasms/genetics/mortality/*pathology ; Databases, Factual ; Humans ; Leukocytes/metabolism ; Prognosis ; Survival Analysis ; Telomere/*metabolism ; Telomere Shortening ; },
abstract = {BACKGROUND/AIMS: The stabilization of telomere length has important roles in the carcinogenesis of colorectal cancer. A systemic review and meta-analysis of published studies was performed to assess the prognostic role of telomere length in colorectal cancer.<br><br>METHODS: Pubmed and Embase were searched for eligible studies on the association between telomere length and overall survival in colorectal cancer patients. The pooled hazard ratio (HR) and corresponding 95% confidence intervals (95%CI) was calculated using fixed-effects or random-effects model according to the magnitude of between-study heterogeneity.<br><br>RESULTS: Seven individual studies with a total of 956 colorectal cancer patients were included. Long telomere length in cancer tissues was marginally associated with poorer overall survival (Random-effects HR = 1.85, 95% 0.90 to 3.83, P = 0.09). When using studies with adjusted estimates, long telomere length in cancer tissues was independently and significantly associated with poorer overall survival (Fixed-effects HR = 2.70, 95% 1.51 to 4.84, P = 0.001). However, short telomere length in peripheral blood leukocytes was independently and significantly associated with poorer overall survival (Fixed-effects HR = 2.01, 95% 1.46 to 2.77, P < 0.001).<br><br>CONCLUSIONS: There is some evidence for telomere length as a prognostic factor for overall survival in colorectal cancer patients. More studies with large number of participants are needed to further assess the prognostic significance of telomere length in colorectal cancer patients.},
}
@article {pmid26732034,
year = {2016},
author = {Oliveira, BS and Zunzunegui, MV and Quinlan, J and Fahmi, H and Tu, MT and Guerra, RO},
title = {Systematic review of the association between chronic social stress and telomere length: A life course perspective.},
journal = {Ageing research reviews},
volume = {26},
number = {},
pages = {37-52},
doi = {10.1016/j.arr.2015.12.006},
pmid = {26732034},
issn = {1872-9649},
mesh = {Adult ; Child ; *Family Health ; Humans ; Poverty/*psychology ; Social Environment ; Social Support ; *Stress, Psychological/etiology/physiopathology ; Telomere Homeostasis/physiology ; *Telomere Shortening ; Violence/*psychology ; },
abstract = {Our aim was to examine whether chronic social stress is associated with telomere length throughout the life course, following our protocol published in 2014. Structured searches were conducted in MEDLINE (PubMed interface), EMBASE (OVID interface), Cochrane Central (OVID interface) and grey from their start date onwards. Reference lists of retrieved citations were hand searched for relevant studies. Eighteen studies published until May 1, 2015 investigating the association between chronic social stress (as defined by poverty, exposure to violence, or family caregiving) and telomere length in healthy or diseased adults and children were independently selected by 2 reviewers. Sixteen of those studies were cross-sectional and two had a longitudinal design. Studies differed in type of stress exposure, method to measure telomere length and cell type. As meta-analysis could not be conducted, the data were synthesized as a narrative review. Based on this comprehensive review, chronic social stress accompanies telomere shortening in both early and adult exposures, with most eligible studies showing a significant relationship. We discuss the significance of chronic stress of social origin and the potential for social interventions through public policies and we recommend methodological improvements that would allow for future meta-analysis.},
}
@article {pmid26731744,
year = {2016},
author = {Barha, CK and Hanna, CW and Salvante, KG and Wilson, SL and Robinson, WP and Altman, RM and Nepomnaschy, PA},
title = {Number of Children and Telomere Length in Women: A Prospective, Longitudinal Evaluation.},
journal = {PloS one},
volume = {11},
number = {1},
pages = {e0146424},
pmid = {26731744},
issn = {1932-6203},
support = {106705//Canadian Institutes of Health Research/Canada ; },
mesh = {Adult ; Aging/*metabolism ; Cellular Senescence/*genetics ; Female ; Humans ; Longitudinal Studies ; Middle Aged ; Oxidative Stress/genetics ; Parity/*physiology ; Pregnancy ; Prospective Studies ; Telomere/*metabolism ; },
abstract = {Life history theory (LHT) predicts a trade-off between reproductive effort and the pace of biological aging. Energy invested in reproduction is not available for tissue maintenance, thus having more offspring is expected to lead to accelerated senescence. Studies conducted in a variety of non-human species are consistent with this LHT prediction. Here we investigate the relationship between the number of surviving children born to a woman and telomere length (TL, a marker of cellular aging) over 13 years in a group of 75 Kaqchikel Mayan women. Contrary to LHT's prediction, women who had fewer children exhibited shorter TLs than those who had more children (p = 0.045) after controlling for TL at the onset of the 13-year study period. An "ultimate" explanation for this apparently protective effect of having more children may lay with human's cooperative-breeding strategy. In a number of socio-economic and cultural contexts, having more chilren appears to be linked to an increase in social support for mothers (e.g., allomaternal care). Higher social support, has been argued to reduce the costs of further reproduction. Lower reproductive costs may make more metabolic energy available for tissue maintenance, resulting in a slower pace of cellular aging. At a "proximate" level, mechanisms involved may include the actions of the gonadal steroid estradiol, which increases dramatically during pregnancy. Estradiol is known to protect TL from the effects of oxidative stress as well as increase telomerase activity, an enzyme that maintains TL. Future research should explore the potential role of social support as well as that of estradiol and other potential biological pathways in the trade-offs between reproductive effort and the pace of cellular aging within and among human as well as in non-human populations.},
}
@article {pmid26731446,
year = {2016},
author = {Rasgon, N and Lin, KW and Lin, J and Epel, E and Blackburn, E},
title = {Telomere length as a predictor of response to Pioglitazone in patients with unremitted depression: a preliminary study.},
journal = {Translational psychiatry},
volume = {6},
number = {1},
pages = {e709},
pmid = {26731446},
issn = {2158-3188},
support = {R01 AG022008/AG/NIA NIH HHS/United States ; R21 AG22008/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Depressive Disorder/*drug therapy ; Double-Blind Method ; Female ; Humans ; Hypoglycemic Agents/*therapeutic use ; Insulin Resistance ; Male ; Middle Aged ; Pioglitazone ; Predictive Value of Tests ; Severity of Illness Index ; *Telomere ; Thiazolidinediones/*therapeutic use ; Treatment Outcome ; Young Adult ; },
abstract = {We studied peripheral leukocyte telomere length (LTL) as a predictor of antidepressant response to PPAR-γ agonist in patients with unremitted depression. In addition we examined correlation between LTL and the insulin resistance (IR) status in these subjects. Forty-two medically stable men and women ages 23-71 with non-remitted depression participated in double-blind placebo-controlled add-on of Pioglitazone to treatment-as-usual. Oral glucose tolerance tests were administered at baseline and at 12 weeks. Diagnostic evaluation of psychiatric disorders was performed at baseline and mood severity was followed weekly throughout the duration of the trial. At baseline, no differences in LTL were detected by depression severity, duration or chronicity. LTL was also not significantly different between insulin-resistant and insulin-sensitive subjects at baseline. Subjects with longer telomeres exhibited greater declines in depression severity in the active arm, but not in a placebo arm, P=0.005, r=-0.63, 95% confidence interval (95% CI)=(-0.84,-0.21). In addition, LTL predicted improvement in insulin sensitivity in the group overall and did not differ between intervention arms, P=0.036, r=-0.44, 95% CI=(-0.74,0.02) for the active arm, and P=0.026, r=-0.50, 95% CI=(-0.78,-0.03) for the placebo arm. LTL may emerge as a viable predictor of antidepressant response. An association between insulin sensitization and LTL regardless of the baseline IR status points to potential role of LTL as a non-specific moderator of metabolic improvement in these patients.},
}
@article {pmid26724375,
year = {2016},
author = {Mancini, J and Rousseau, P and Castor, KJ and Sleiman, HF and Autexier, C},
title = {Platinum(II) phenanthroimidazole G-quadruplex ligand induces selective telomere shortening in A549 cancer cells.},
journal = {Biochimie},
volume = {121},
number = {},
pages = {287-297},
doi = {10.1016/j.biochi.2015.12.015},
pmid = {26724375},
issn = {1638-6183},
support = {MOP-89978//Canadian Institutes of Health Research/Canada ; },
mesh = {Cell Line ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cellular Senescence/drug effects ; Humans ; Platinum Compounds/chemistry/*pharmacology ; Telomere/drug effects ; Telomere Shortening/*drug effects ; },
abstract = {Telomere maintenance, achieved by the binding of protective shelterin capping proteins to telomeres and by either telomerase or a recombination-based alternative lengthening of telomere (ALT) mechanism, is critical for cell proliferation and survival. Extensive telomere shortening or loss of telomere integrity activates DNA damage checkpoints, leading to cell senescence or death. Although telomerase upregulation is an attractive target for anti-cancer therapy, the lag associated with telomere shortening and the potential activation of ALT pose a challenge. An alternative approach is to modify telomere interactions with binding proteins (telomere uncapping). G-quadruplex ligands stabilize structures generated from single-stranded G-rich 3'-telomere end (G-quadruplex) folding, which in principle, cannot be elongated by telomerase, thus leading to telomere shortening. Ligands can also mediate rapid anti-proliferative effects by telomere uncapping. We previously reported that the G-quadruplex ligand, phenylphenanthroimidazole ethylenediamine platinum(II) (PIP), inhibits telomerase activity in vitro[47]. In the current study, a long-term seeding assay showed that PIP significantly inhibited the seeding capacity of A549 lung cancer cells and to a lesser extent primary MRC5 fibroblast cells. Importantly, treatment with PIP caused a significant dose- and time-dependent decrease in average telomere length of A549 but not MRC5 cells. Moreover, cell cycle analysis revealed a significant increase in G1 arrest upon treatment of A549 cells, but not MRC5 cells. Both apoptosis and cellular senescence may contribute to the anti-proliferative effects of PIP. Our studies validate the development of novel and specific therapeutic ligands targeting telomeric G-quadruplex structures in cancer cells.},
}
@article {pmid26721861,
year = {2016},
author = {Zhou, Y and Hartwig, B and James, GV and Schneeberger, K and Turck, F},
title = {Complementary Activities of TELOMERE REPEAT BINDING Proteins and Polycomb Group Complexes in Transcriptional Regulation of Target Genes.},
journal = {The Plant cell},
volume = {28},
number = {1},
pages = {87-101},
pmid = {26721861},
issn = {1532-298X},
mesh = {Alleles ; Amino Acid Motifs ; Arabidopsis/*genetics ; Arabidopsis Proteins/genetics/*metabolism ; Binding Sites ; *Gene Expression Regulation, Plant ; Genes, Developmental ; *Genes, Plant ; Meristem/genetics ; Models, Biological ; Multigene Family ; Mutation/genetics ; Phenotype ; Photosynthesis/genetics ; Polycomb-Group Proteins/*metabolism ; Protein Binding/genetics ; Seedlings/genetics ; Telomere/metabolism ; Telomere-Binding Proteins/*metabolism ; *Transcription, Genetic ; },
abstract = {In multicellular organisms, Polycomb Repressive Complex 1 (PRC1) and PRC2 repress target genes through histone modification and chromatin compaction. Arabidopsis thaliana mutants strongly compromised in the pathway cannot develop differentiated organs. LIKE HETEROCHROMATIN PROTEIN1 (LHP1) is so far the only known plant PRC1 component that directly binds to H3K27me3, the histone modification set by PRC2, and also associates genome-wide with trimethylation of lysine 27 of histone H3 (H3K27me3). Surprisingly, lhp1 mutants show relatively mild phenotypic alterations. To explain this paradox, we screened for genetic enhancers of lhp1 mutants to identify novel components repressing target genes together with, or in parallel to, LHP1. Two enhancing mutations were mapped to TELOMERE REPEAT BINDING PROTEIN1 (TRB1) and its paralog TRB3. We show that TRB1 binds to thousands of genomic sites containing telobox or related cis-elements with a significant increase of sites and strength of binding in the lhp1 background. Furthermore, in combination with lhp1, but not alone, trb1 mutants show increased transcription of LHP1 targets, such as floral meristem identity genes, which are more likely to be bound by TRB1 in the lhp1 background. By contrast, expression of a subset of LHP1-independent TRB1 target genes, many involved in primary metabolism, is decreased in the absence of TRB1 alone. Thus, TRB1 is a bivalent transcriptional modulator that maintains downregulation of Polycomb Group (PcG) target genes in lhp1 mutants, while it sustains high expression of targets that are regulated independently of PcG.},
}
@article {pmid26720590,
year = {2015},
author = {Al Khaldi, R and Mojiminiyi, O and AlMulla, F and Abdella, N},
title = {Associations of TERC Single Nucleotide Polymorphisms with Human Leukocyte Telomere Length and the Risk of Type 2 Diabetes Mellitus.},
journal = {PloS one},
volume = {10},
number = {12},
pages = {e0145721},
pmid = {26720590},
issn = {1932-6203},
mesh = {Alleles ; Case-Control Studies ; Diabetes Mellitus, Type 2/*genetics ; Female ; Genetic Predisposition to Disease/*genetics ; Genome-Wide Association Study/methods ; Genotype ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/*genetics ; RNA/*genetics ; Risk ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Homeostasis/genetics ; },
abstract = {Previous Studies have mapped putative loci that may probably regulate leukocyte telomere length (LTL). The strongest associations with LTL were reported for SNP rs12696304 and rs16847897 near the non-coding Ribose Nucleic Acid (RNA) molecule component (TERC) of telomerase enzyme on 3q26. It is unclear whether these identified loci coding functional components of telomerase, exert a similar effect on LTL in other populations or influence risk factors of Type 2 Diabetes Mellitus (T2DM). The present study was performed to: study the influence of TERC polymorphisms on LTL, human telomerase reverse transcriptase (hTERT), indices of obesity and explore the potential associations with T2DM. 225 T2DM patients and 245 age and sex matched controls were studied. Allelic Discrimination (AD) genotyping was utilized to determine TERC SNPs [rs12696304 and rs16847897]. hTERT, adiponectin, Insulin, Homeostasis Model Assessment (HOMA-IR), and LTL were measured. Body Mass Index (BMI) and waist circumference (WC) were recorded. [CC] genotype of rs16847897 was significantly associated with shorter LTL [OR = 1.6, p = 0.004], lower hTERT levels [OR = 0.4, p = 0.006], higher BMI [OR = 2.2, p = 0.006], larger WC [OR = 23.4, p = 0.007] and hypo-adiponectemia [OR = 0.6, p = 0.006]. [GG] genotype of rs12696304 was also significantly associated with shorter LTL [OR = 1.5, p = 0.004], lower hTERT [OR = 0.7, p = 0.006] but with larger WC[OR = 5.3, p = 0.004]. [CC] genotype of rs16847897 and [GG] genotype of rs12696304 together increased the risk of T2DM significantly [OR = 1.7, p = 0.004]. We provide insights connecting a structure that is critically involved in maintaining genomic stability with obesity and T2DM. Given the central role of telomere length in determining telomere function our findings may expand our understanding of the pathological mechanisms underlying age associated conditions such as T2DM.},
}
@article {pmid26716914,
year = {2016},
author = {Fajkus, P and Peška, V and Sitová, Z and Fulnečková, J and Dvořáčková, M and Gogela, R and Sýkorová, E and Hapala, J and Fajkus, J},
title = {Allium telomeres unmasked: the unusual telomeric sequence (CTCGGTTATGGG)n is synthesized by telomerase.},
journal = {The Plant journal : for cell and molecular biology},
volume = {85},
number = {3},
pages = {337-347},
doi = {10.1111/tpj.13115},
pmid = {26716914},
issn = {1365-313X},
mesh = {Allium/enzymology/*genetics ; Base Sequence ; Chromosomes, Plant/*genetics ; Computational Biology ; *Evolution, Molecular ; Genomics ; In Situ Hybridization, Fluorescence ; Phylogeny ; Sequence Analysis, DNA ; Telomerase/genetics/*metabolism ; Telomere/*genetics ; Transcriptome ; },
abstract = {Phylogenetic divergence in Asparagales plants is associated with switches in telomere sequences. The last switch occurred with divergence of the genus Allium (Amaryllidaceae) from the other Allioideae (formerly Alliaceae) genera, resulting in uncharacterized telomeres maintained by an unknown mechanism. To characterize the unknown Allium telomeres, we applied a combination of bioinformatic processing of transcriptomic and genomic data with standard approaches in telomere biology such as BAL31 sensitivity tests, terminal restriction fragment analysis, the telomere repeat amplification protocol (TRAP), and fluorescence in situ hybridization (FISH). Using these methods, we characterize the unusual telomeric sequence (CTCGGTTATGGG)n present in Allium species, demonstrate its synthesis by telomerase, and characterize the telomerase reverse transcriptase (TERT) subunit of Allium cepa. Our findings open up the possibility of studying the molecular details of the evolutionary genetic change in Allium telomeres and its possible role in speciation. Experimental studies addressing the implications of this change in terms of the interplay of telomere components may now be designed to shed more light on telomere functions and evolution in general.},
}
@article {pmid26715231,
year = {2016},
author = {Carroll, JE and Esquivel, S and Goldberg, A and Seeman, TE and Effros, RB and Dock, J and Olmstead, R and Breen, EC and Irwin, MR},
title = {Insomnia and Telomere Length in Older Adults.},
journal = {Sleep},
volume = {39},
number = {3},
pages = {559-564},
pmid = {26715231},
issn = {1550-9109},
support = {UL1TR000124/TR/NCATS NIH HHS/United States ; K01AG044462/AG/NIA NIH HHS/United States ; UL1 TR000124/TR/NCATS NIH HHS/United States ; T32 MH019925/MH/NIMH NIH HHS/United States ; R01 AG026364/AG/NIA NIH HHS/United States ; P30 AG028748/AG/NIA NIH HHS/United States ; R01-AG034588/AG/NIA NIH HHS/United States ; R01 AG034588/AG/NIA NIH HHS/United States ; K01 AG044462/AG/NIA NIH HHS/United States ; AG028748/AG/NIA NIH HHS/United States ; R01AG032422/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*genetics/*pathology ; Case-Control Studies ; Cellular Senescence/*genetics ; Chronic Disease ; Female ; Humans ; Leukocytes, Mononuclear/metabolism ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Risk ; Sleep Initiation and Maintenance Disorders/diagnosis/*genetics/*pathology ; Telomere/genetics/*metabolism ; },
abstract = {STUDY OBJECTIVES: Insomnia, particularly in later life, may raise the risk for chronic diseases of aging and mortality through its effect on cellular aging. The current study examines the effects of insomnia on telomere length, a measure of cellular aging, and tests whether insomnia interacts with chronological age to increase cellular aging.<br><br>METHODS: A total of 126 males and females (60-88 y) were assessed for insomnia using the Diagnostic and Statistical Manual IV criterion for primary insomnia and the International Classification of Sleep Disorders, Second Edition for general insomnia (45 insomnia cases; 81 controls). Telomere length in peripheral blood mononuclear cells (PBMC) was determined using real-time quantitative polymerase chain reaction (qPCR) methodology.<br><br>RESULTS: In the analysis of covariance model adjusting for body mass index and sex, age (60-69 y versus 70-88 y) and insomnia diagnosis interacted to predict shorter PBMC telomere length (P = 0.04). In the oldest age group (70-88 y), PBMC telomere length was significantly shorter in those with insomnia, mean (standard deviation) M(SD) = 0.59(0.2) compared to controls with no insomnia M(SD) = 0.78(0.4), P = 0.04. In the adults aged 60-69 y, PBMC telomere length was not different between insomnia cases and controls, P = 0.44.<br><br>CONCLUSIONS: Insomnia is associated with shorter PBMC telomere length in adults aged 70-88 y, but not in those younger than 70 y, suggesting that clinically severe sleep disturbances may increase cellular aging, especially in the later years of life. These findings highlight insomnia as a vulnerability factor in later life, with implications for risk for diseases of aging.},
}
@article {pmid26715224,
year = {2016},
author = {Shin, C and Yun, CH and Yoon, DW and Baik, I},
title = {Association between Snoring and Leukocyte Telomere Length.},
journal = {Sleep},
volume = {39},
number = {4},
pages = {767-772},
pmid = {26715224},
issn = {1550-9109},
mesh = {Adult ; Aged ; *Aging/genetics/pathology ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/metabolism/*pathology ; Male ; Middle Aged ; Polysomnography ; Republic of Korea ; Risk Factors ; Sleep ; Sleep Apnea Syndromes/complications/genetics/pathology ; Snoring/complications/genetics/*pathology ; Surveys and Questionnaires ; Telomere/genetics/*physiology ; Telomere Homeostasis/genetics/*physiology ; },
abstract = {STUDY OBJECTIVES: Data on the association between snoring and telomere length, an indicator of biological aging, are very limited. Moreover, no polysomnography (PSG) studies on this association in a general population have been conducted. Our study aimed to evaluate the association between snoring and leukocyte telomere length (LTL) using PSG and a questionnaire.<br><br>METHODS: A cross-sectional PSG study embedded in a population-based cohort from the Korean Genome Epidemiology Study was conducted in 2010-2013. During the same period, questionnaire-based interviews, blood collection, and relative LTL assays were conducted. A total of 887 Korean men and women aged 50-79 y with an apnea-hypopnea index (AHI) < 15 determined in the PSG study were included in the study.<br><br>RESULTS: We observed that the percentage of time spent snoring during sleep (% time spent snoring) assessed by PSG was inversely associated with LTL even after adjusting for potential risk factors and AHI. In the linear regression association between tertiles of percentage of time spent snoring and log-transformed LTL, coefficient estimates (P value) were -0.076 (< 0.05) for the second tertile and -0.084 (< 0.01) for the third tertile compared with the bottom tertile. When LTL was compared according to snoring status determined using PSG and questionnaire information, both primary snorers and those with mild sleep apnea (5 &#x2264; AHI < 15) had shorter LTL than nonsnorers.<br><br>CONCLUSIONS: Our findings suggest that snoring may influence telomere attrition independent of sleep apnea.},
}
@article {pmid26713854,
year = {2016},
author = {Thomson, WM and Zeng, J and Broadbent, JM and Foster Page, LA and Shalev, I and Moffitt, TE and Caspi, A and Williams, SM and Braithwaite, AW and Robertson, SP and Poulton, R},
title = {Telomere length and periodontal attachment loss: a prospective cohort study.},
journal = {Journal of clinical periodontology},
volume = {43},
number = {2},
pages = {121-127},
pmid = {26713854},
issn = {1600-051X},
support = {AG032282/AG/NIA NIH HHS/United States ; R01 DE015260/DE/NIDCR NIH HHS/United States ; R01 DE-015260-01A1/DE/NIDCR NIH HHS/United States ; MR/K00381X//Medical Research Council/United Kingdom ; MR/K00381X/1/MRC_/Medical Research Council/United Kingdom ; R01 AG032282/AG/NIA NIH HHS/United States ; P30 AG034424/AG/NIA NIH HHS/United States ; R01 AG048895/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Cohort Studies ; Female ; Humans ; Male ; New Zealand ; *Periodontal Attachment Loss ; Periodontitis ; Prospective Studies ; Smoking ; *Telomere ; Telomere Shortening ; },
abstract = {AIM: The aim of the study was to examine the association between telomere erosion and periodontitis in a long-standing prospective cohort study of New Zealand adults. Specific hypotheses tested were as follows: (i) that exposure to periodontitis at ages 26 and 38 was associated with accelerated leucocyte telomere erosion and (ii) that accelerated leucocyte telomere erosion was associated with higher rates of periodontitis by ages 26 and 38.<br><br>MATERIALS AND METHODS: Periodontal attachment loss data were collected at ages 26 and 38. Blood samples taken at the same ages were analysed to obtain estimates of leucocyte telomere length and erosion over a 12-year period.<br><br>RESULTS: Overall, the mean telomere length was reduced by 0.15 T/S ratio (adjusted) from age 26 to 38 among the 661 participants reported on here. During the same period, the mean attachment loss increased by 10%, after adjusting for sex, socio-economic status and smoking. Regression models showed that attachment loss did not predict telomere length, and that telomere erosion did not predict attachment loss.<br><br>CONCLUSIONS: Although both periodontitis and telomere length are age-dependent, they do not appear to be linked, suggesting that determination of leucocyte telomere length may not be a promising clinical approach at this age for identifying people who are at risk for periodontitis.},
}
@article {pmid26712234,
year = {2016},
author = {Manterola, M and Sicinski, P and Wolgemuth, DJ},
title = {E-type cyclins modulate telomere integrity in mammalian male meiosis.},
journal = {Chromosoma},
volume = {125},
number = {2},
pages = {253-264},
pmid = {26712234},
issn = {1432-0886},
support = {R01 CA083688/CA/NCI NIH HHS/United States ; R01 HD034915/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Cyclin E/genetics/*metabolism ; Cyclins/genetics/*metabolism ; DNA Damage ; DNA Repair ; Female ; Male ; *Meiosis ; Mice ; Oncogene Proteins/genetics/*metabolism ; Pachytene Stage ; Spermatocytes/*cytology/metabolism ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; rap GTP-Binding Proteins/genetics/metabolism ; },
abstract = {We have shown that E-type cyclins are key regulators of mammalian male meiosis. Depletion of cyclin E2 reduced fertility in male mice due to meiotic defects, involving abnormal pairing and synapsis, unrepaired DNA, and loss of telomere structure. These defects were exacerbated by additional loss of cyclin E1, and complete absence of both E-type cyclins produces a meiotic catastrophe. Here, we investigated the involvement of E-type cyclins in maintaining telomere integrity in male meiosis. Spermatocytes lacking cyclin E2 and one E1 allele (E1+/-E2-/-) displayed a high rate of telomere abnormalities but can progress to pachytene and diplotene stages. We show that their telomeres exhibited an aberrant DNA damage repair response during pachynema and that the shelterin complex proteins TRF2 and RAP2 were significantly decreased in the proximal telomeres. Moreover, the insufficient level of these proteins correlated with an increase of γ-H2AX foci in the affected telomeres and resulted in telomere associations involving TRF1 and telomere detachment in later prophase-I stages. These results suggest that E-type cyclins are key modulators of telomere integrity during meiosis by, at least in part, maintaining the balance of shelterin complex proteins, and uncover a novel role of E-type cyclins in regulating chromosome structure during male meiosis.},
}
@article {pmid26709770,
year = {2016},
author = {Chiodi, I and Mondello, C},
title = {Telomere and telomerase stability in human diseases and cancer.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {21},
number = {1},
pages = {203-224},
doi = {10.2741/4385},
pmid = {26709770},
issn = {2768-6698},
mesh = {Disease/*genetics ; Humans ; Neoplasms/enzymology/*genetics ; Telomerase/*metabolism ; *Telomere ; },
abstract = {Telomeres are the nucleoprotein structures at the end of linear eukaryotic chromosomes required for genome stability. Telomerase is the specialized enzyme deputed to their elongation. Maintenance of a proper telomere structure, an accurate regulation of telomerase biogenesis and activity, as well as a correct telomere-telomerase interaction and a faithful telomeric DNA replication are all processes that a cell has to precisely control to safeguard its functionality. Here, we review key factors that play a role in the development of these processes and their relationship with human health.},
}
@article {pmid26709201,
year = {2016},
author = {Hehar, H and Mychasiuk, R},
title = {The use of telomere length as a predictive biomarker for injury prognosis in juvenile rats following a concussion/mild traumatic brain injury.},
journal = {Neurobiology of disease},
volume = {87},
number = {},
pages = {11-18},
doi = {10.1016/j.nbd.2015.12.007},
pmid = {26709201},
issn = {1095-953X},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Animals ; Brain Concussion/*diagnosis/*physiopathology ; Cohort Studies ; *Diet, High-Fat ; *Diet, Reducing ; Disease Models, Animal ; Ear ; Female ; Linear Models ; Male ; Maze Learning/physiology ; Motor Activity/*physiology ; Prognosis ; Random Allocation ; Rats, Sprague-Dawley ; Recovery of Function/physiology ; Severity of Illness Index ; Skin/metabolism ; Telomere/*metabolism ; Telomere Shortening/physiology ; },
abstract = {Telomeres were originally believed to be passive players in cellular replication, but recent research has highlighted their more active role in epigenetic patterning and promotion of cellular growth and survival. Furthermore, literature demonstrates that telomere length (TL) is responsive to environmental manipulations such as prenatal stress and dietary programming. As the search for a prognostic biomarker of concussion has had limited success, this study sought to examine whether or not telomere length (TL) could be an efficacious predictor of symptom severity in juvenile rats following concussion. Rats from four distinct experimental groups (caloric restriction (CR), high fat diet (HFD), exercise (EX), and standard controls (STD)) received a mild traumatic brain injury (mTBI)/concussion and were then subjected to a behavioural test battery. The test battery was scored and the animals were categorized as poor, average, or good, based on their performance on the 6 tests examined. Skin cells (from ear notch samples) were taken 17days post-injury and DNA was extracted for telomere length analysis. Ear notch skin cell TL was highly correlated with brain tissue TL for a given individual. Animals in the CR and EX cohorts had significantly longer telomeres, while animals in the HFD cohort had significantly shorter telomeres, when compared to controls. The mTBI/concussion reduced TL in all cohorts except the EX group. A significant linear relationship was found between TL and performance on the behavioural test battery, whereby shorter telomeres were associated with poorer performance and longer telomeres with better performance. As performance on the test battery is linked to symptom severity, this study found TL to be a reasonable tool for concussion prognosis. Future studies with human populations should examine the validity of TL in peripheral cells, as a predictor of concussion pathology.},
}
@article {pmid26708219,
year = {2016},
author = {Makino, N and Oyama, J and Maeda, T and Koyanagi, M and Higuchi, Y and Shimokawa, I and Mori, N and Furuyama, T},
title = {FoxO1 signaling plays a pivotal role in the cardiac telomere biology responses to calorie restriction.},
journal = {Molecular and cellular biochemistry},
volume = {412},
number = {1-2},
pages = {119-130},
pmid = {26708219},
issn = {1573-4919},
mesh = {Animals ; Body Weight ; *Caloric Restriction ; Caspase 3/metabolism ; DNA Damage ; Forkhead Box Protein O1 ; Forkhead Transcription Factors/*metabolism ; Mice ; Mice, Knockout ; Myocardium/*metabolism ; Nitric Oxide Synthase Type III/metabolism ; Organ Size ; Oxidative Stress ; *Signal Transduction ; Superoxide Dismutase/metabolism ; *Telomere ; },
abstract = {This study examined whether the forkhead transcription factors of O group 1 (FoxO1) might be involved in telomere biology during calorie restriction (CR). We used FoxO1-knockout heterozygous mice (FoxO1(+/-)) and wild-type mice (WT) as a control. Both WT and FoxO1(+/-) were subjected to ad libitum (AL) feeding or 30% CR compared to AL for 20 weeks from 15 weeks of age. The heart-to-body weight ratio, blood glucose, and serum lipid profiles were not different among all groups of mice at the end of the study. Telomere size was significantly lower in the FoxO1(+/-)-AL than the WT-AL, and telomere attrition was not observed in either WT-CR or FoxO1(+/-)-CR. Telomerase activity was elevated in the heart and liver of WT-CR, but not in those of FoxO1(+/-)-CR. The phosphorylation of Akt was inhibited and Sirt 1 was activated in heart tissues of WT-CR and FoxO1(+/-)-CR. However, the ratio of conjugated to cytosolic light chain 3 increased and the level of p62 decreased in WT-CR, but not in FoxO1(+/-)-CR. A marker of oxidative DNA damage, 8-OhdG, was significantly lower in WT-CR only. The level of MnSOD and eNOS increased, and the level of cleaved caspase-3 decreased in WT-CR, but not FoxO1(+/-)-CR. Echocardiography showed that the left ventricular end-diastolic and systolic dimensions were significantly lower in WT-CR or FoxO1(+/-)-CR than WT-AL or FoxO1(+/-)-AL, respectively. The present studies suggest that FoxO1 plays beneficial roles by inducing genes involved in telomerase activity, as well as anti-oxidant, autophagic, and anti-apoptotic genes under conditions of CR, and suggest that FoxO1 signaling may be an important mediator of metabolic equilibrium during CR.},
}
@article {pmid26704385,
year = {2016},
author = {Olivier, M and Da Ines, O and Amiard, S and Serra, H and Goubely, C and White, CI and Gallego, ME},
title = {The Structure-Specific Endonucleases MUS81 and SEND1 Are Essential for Telomere Stability in Arabidopsis.},
journal = {The Plant cell},
volume = {28},
number = {1},
pages = {74-86},
pmid = {26704385},
issn = {1532-298X},
mesh = {Arabidopsis/cytology/growth &amp; development/*metabolism ; Arabidopsis Proteins/*metabolism ; Cell Cycle ; Chromosomes, Plant/genetics ; DNA Repair ; DNA Replication ; DNA, Bacterial/genetics ; Endonucleases/*metabolism ; Genomic Instability ; Holliday Junction Resolvases/*metabolism ; Meiosis ; Mutagenesis, Insertional/genetics ; Mutation/genetics ; Phenotype ; Rad51 Recombinase/metabolism ; Telomere/*metabolism ; },
abstract = {Structure-specific endonucleases act to repair potentially toxic structures produced by recombination and DNA replication, ensuring proper segregation of the genetic material to daughter cells during mitosis and meiosis. Arabidopsis thaliana has two putative homologs of the resolvase (structure-specific endonuclease): GEN1/Yen1. Knockout of resolvase genes GEN1 and SEND1, individually or together, has no detectable effect on growth, fertility, or sensitivity to DNA damage. However, combined absence of the endonucleases MUS81 and SEND1 results in severe developmental defects, spontaneous cell death, and genome instability. A similar effect is not seen in mus81 gen1 plants, which develop normally and are fertile. Absence of RAD51 does not rescue mus81 send1, pointing to roles of these proteins in DNA replication rather than DNA break repair. The enrichment of S-phase histone γ-H2AX foci and a striking loss of telomeric DNA in mus81 send1 further support this interpretation. SEND1 has at most a minor role in resolution of the Holliday junction but acts as an essential backup to MUS81 for resolution of toxic replication structures to ensure genome stability and to maintain telomere integrity.},
}
@article {pmid26699462,
year = {2016},
author = {Makhija, E and Jokhun, DS and Shivashankar, GV},
title = {Nuclear deformability and telomere dynamics are regulated by cell geometric constraints.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {113},
number = {1},
pages = {E32-40},
pmid = {26699462},
issn = {1091-6490},
mesh = {Animals ; *Chromatin Assembly and Disassembly ; *Gene Expression Regulation ; Heterochromatin/metabolism ; Lamin Type A/metabolism ; Mice ; NIH 3T3 Cells ; Nuclear Envelope/metabolism/*ultrastructure ; Stress Fibers/chemistry/metabolism ; Telomere/chemistry/*metabolism ; },
abstract = {Forces generated by the cytoskeleton can be transmitted to the nucleus and chromatin via physical links on the nuclear envelope and the lamin meshwork. Although the role of these active forces in modulating prestressed nuclear morphology has been well studied, the effect on nuclear and chromatin dynamics remains to be explored. To understand the regulation of nuclear deformability by these active forces, we created different cytoskeletal states in mouse fibroblasts using micropatterned substrates. We observed that constrained and isotropic cells, which lack long actin stress fibers, have more deformable nuclei than elongated and polarized cells. This nuclear deformability altered in response to actin, myosin, formin perturbations, or a transcriptional down-regulation of lamin A/C levels in the constrained and isotropic geometry. Furthermore, to probe the effect of active cytoskeletal forces on chromatin dynamics, we tracked the spatiotemporal dynamics of heterochromatin foci and telomeres. We observed increased dynamics and decreased correlation of the heterochromatin foci and telomere trajectories in constrained and isotropic cell geometry. The observed enhanced dynamics upon treatment with actin depolymerizing reagents in elongated and polarized geometry were regained once the reagent was washed off, suggesting an inherent structural memory in chromatin organization. We conclude that active forces from the cytoskeleton and rigidity from lamin A/C nucleoskeleton can together regulate nuclear and chromatin dynamics. Because chromatin remodeling is a necessary step in transcription control and its memory, genome integrity, and cellular deformability during migration, our results highlight the importance of cell geometric constraints as critical regulators in cell behavior.},
}
@article {pmid26697827,
year = {2015},
author = {Webb, CJ and Zakian, VA},
title = {Telomere les(i/s)ons from a telomerase RNA mutant.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {14},
number = {24},
pages = {3769-3770},
pmid = {26697827},
issn = {1551-4005},
support = {R35 GM118279/GM/NIGMS NIH HHS/United States ; R37 GM026938/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Humans ; Mutation/genetics ; RNA/*genetics ; Telomerase/*genetics ; Telomere/*genetics/*pathology ; },
}
@article {pmid26695909,
year = {2015},
author = {Bazyka, DA and Loganovsky, KM and Ilyenko, IM and Chumak, SA and Bomko, MO},
title = {Gene expression, telomere and cognitive deficit analysis as a function of Chornobyl radiation dose and age: from in utero to adulthood.},
journal = {Problemy radiatsiinoi medytsyny ta radiobiolohii},
volume = {20},
number = {},
pages = {283-310},
pmid = {26695909},
issn = {2304-8336},
abstract = {UNLABELLED: Objective - to estimate the possible effects of low dose ionizing radiation on human cognitive function in adult hood and in utero.<br><br>MATERIALS AND METHODS: Cognitive tests, telomere length and expression of genes regulating telomere function were studied in Chornobyl cleanup workers who were exposed to doses under 500 mSv (n = 326) and subjects exposed in utero during the first days after the accident Prypiat town (n = 104). The neurocognitive assessment covered mem ory, attention, language, executive and visiospatial functions. In young adults after prenatal exposure a relation ship was analyzed between a cognitive function and radiation dose to foetus, brain and thyroid gland. Internal con trols were used for both groups - the group of Chornobyl cleanup workers exposed in doses less than 20 mSv and an age matched comparison group from radioactively contaminated areas for subjects exposed in utero.<br><br>RESULTS: Cognitive functions in cleanup workers exposed to ionizing radiation at adulthood are characterized by symptoms of a mild cognitive impairment according to the MMSE (mean group score 25,58 &#xb1; 2,95) and a significant ly higher level of mental disorders according to the BPRS in a dose related manner. Cleanup workers exposed to doses over 500 mSv demonstrate a significant cognitive deficit in comparison with those exposed below 500 mSv and espe cially non exposed patients. Subjects exposed in utero during the check at age of 25-27 years exhibit an excess of the disorders of autonomic nervous system (ICD 10: G90). Neurological microsymptoms as well as neurotic, stress relat ed and somatoform disorders (F40-F48) dominate. Relationship were revealed between the TERT, TERF1, TERF2 genes expression, relative telomere length (RTL),cognitive deficit and cerebrovascular pathology, radiation dose and age. Telomere length in cleanup workers is sreduced after 50 years (6.1 %). The most significant reduction in telomere length is shown after 70 years (11.7 %). Negative correlation was found between telomere length and degree of cog nitive deficit (MMSE scale) and between age and degree of cognitive deficit. The RTL is significantly decreased in groups of persons with cognitive deficit compared to a comparison group. Telomere length at the late period after low dose radiation exposure is downregulated by the high TERF2 gene expression combined with low expression of TERT gene. After exposure to doses over 250-500 mSv a cognitive deficit and dementia were associated with a substantial increase in TERT gene expression, overexpression of TERF1 and decrease in expression of TERF2 gene. A relationship was revealed between the TERF2 gene expression and CD95+ cell fraction susceptible to apoptosis.<br><br>CONCLUSIONS: This study shows that cognitive deficit in humans at a late period after radiation exposure is influ enced by dose, age at exposure and gene regulation of telomere function.},
}
@article {pmid26692203,
year = {2016},
author = {Sinkey, RG and Salihu, HM and King, LM and Paothong, A and Louis-Jacques, A and Pradhan, A and Bruder, KL and Zoorob, R and Siegel, E and Riggs, B and Whiteman, VE},
title = {Homocysteine Levels Are not Related to Telomere Length in Cord Blood Leukocytes of Newborns.},
journal = {American journal of perinatology},
volume = {33},
number = {6},
pages = {552-559},
doi = {10.1055/s-0035-1570318},
pmid = {26692203},
issn = {1098-8785},
mesh = {Adolescent ; Adult ; DNA/*analysis ; Female ; Fetal Blood/cytology ; Florida ; Gestational Age ; Homocysteine/*blood ; Humans ; *Infant, Newborn ; Leukocytes/*physiology ; Linear Models ; Pregnancy ; Prospective Studies ; Statistics as Topic ; Telomere/metabolism/*ultrastructure ; Young Adult ; },
abstract = {Objective Elevated homocysteine (HC) levels and/or shortened telomere length (TL) are associated with adverse medical conditions. Our objective is to investigate the relationship between HC and TL in cord blood leukocytes of newborns. Study Design This is a nested study from a prospective cohort from 2011 to 2012 in pregnant women admitted for delivery at a university-affiliated hospital. Cord blood was collected at delivery and genomic DNA was analyzed using quantitative PCR. The telomere-to-single copy gene ratio method was employed to quantify TL. Newborn HC levels were measured. generalized linear regression modeling (GLM) and bootstrap statistical analyses were performed. Results Seventy-seven maternal-fetal dyads with a mean gestational age of 39 weeks were included. The distribution of the coefficient of homocysteine showed most values greater than zero demonstrating that homocysteine had a positive relationship with TL. In 915 of 10,000 (9.15%) iterations, the p-value was < 0.05 demonstrating a positive effect. Conclusion Increasing newborn concentrations of HC are not associated with decreasing TL. Larger, prospective studies are needed to confirm these findings and long-term implications.},
}
@article {pmid26688493,
year = {2016},
author = {Ridout, KK and Ridout, SJ and Price, LH and Sen, S and Tyrka, AR},
title = {Depression and telomere length: A meta-analysis.},
journal = {Journal of affective disorders},
volume = {191},
number = {},
pages = {237-247},
pmid = {26688493},
issn = {1573-2517},
support = {R01 MH083704/MH/NIMH NIH HHS/United States ; R01 MH101459/MH/NIMH NIH HHS/United States ; R25 MH101076/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Depression/*genetics ; Depressive Disorder/*genetics ; Female ; Genetic Techniques ; Humans ; Male ; Middle Aged ; Telomere/*pathology ; Young Adult ; },
abstract = {BACKGROUND: Several recent studies have investigated the relationship between telomere length and depression with inconsistent results. This meta-analysis examined whether telomere length and depression are associated and explored factors that might affect this association.<br><br>METHODS: Studies measuring telomere length in subjects with clinically significant unipolar depression were included. A comprehensive search strategy identified studies in PubMed, MEDLINE, PsycINFO, Global Health, The Cochrane Library, and Web of Science. A structured data abstraction form was used and studies were appraised for inclusion or exclusion using a priori conditions. Analyses were conducted using standardized mean differences in a continuous random effects model.<br><br>RESULTS: Thirty-eight studies (N=34,347) met the inclusion criteria. The association between depression and telomere length was significant, with a Cohen's d effect size of -0.205 (p<0.0001, I(2)=42%). Depression severity significantly associated with telomere length (p=0.03). Trim and fill analysis indicated the presence of publication bias (p=0.003), but that the association remained highly significant after accounting for the bias. Subgroup analysis revealed depression assessment tools, telomere measurement techniques, source tissue and comorbid medical conditions significantly affected the relationship.<br><br>LIMITATIONS: Other potentially important sub-groups, including antidepressant use, have not been investigated in sufficient detail or number yet and thus were not addressed in this meta-analysis.<br><br>CONCLUSIONS: There is a negative association between depression and telomere length. Further studies are needed to clarify potential causality underlying this association and to elucidate the biology linking depression and this cellular marker of stress exposure and aging.},
}
@article {pmid26687355,
year = {2015},
author = {Maciejowski, J and Li, Y and Bosco, N and Campbell, PJ and de Lange, T},
title = {Chromothripsis and Kataegis Induced by Telomere Crisis.},
journal = {Cell},
volume = {163},
number = {7},
pages = {1641-1654},
pmid = {26687355},
issn = {1097-4172},
support = {WT088340MA//Wellcome Trust/United Kingdom ; 077012/Z/05/Z//Wellcome Trust/United Kingdom ; 5R01CA181090/CA/NCI NIH HHS/United States ; R01 CA181090/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; 103858//Wellcome Trust/United Kingdom ; },
mesh = {*Chromosomal Instability ; Chromosome Aberrations ; *Chromosomes, Human ; Cytokinesis ; DNA, Single-Stranded/metabolism ; Exodeoxyribonucleases/metabolism ; *Genomic Instability ; Humans ; Mitosis ; Neoplasms/*genetics ; Nuclear Envelope/metabolism ; Phosphoproteins/metabolism ; *Telomere ; },
abstract = {Telomere crisis occurs during tumorigenesis when depletion of the telomere reserve leads to frequent telomere fusions. The resulting dicentric chromosomes have been proposed to drive genome instability. Here, we examine the fate of dicentric human chromosomes in telomere crisis. We observed that dicentric chromosomes invariably persisted through mitosis and developed into 50-200 μm chromatin bridges connecting the daughter cells. Before their resolution at 3-20 hr after anaphase, the chromatin bridges induced nuclear envelope rupture in interphase, accumulated the cytoplasmic 3' nuclease TREX1, and developed RPA-coated single stranded (ss) DNA. CRISPR knockouts showed that TREX1 contributed to the generation of the ssDNA and the resolution of the chromatin bridges. Post-crisis clones showed chromothripsis and kataegis, presumably resulting from DNA repair and APOBEC editing of the fragmented chromatin bridge DNA. We propose that chromothripsis in human cancer may arise through TREX1-mediated fragmentation of dicentric chromosomes formed in telomere crisis.},
}
@article {pmid26686913,
year = {2016},
author = {An, N and Fleming, AM and Burrows, CJ},
title = {Human Telomere G-Quadruplexes with Five Repeats Accommodate 8-Oxo-7,8-dihydroguanine by Looping out the DNA Damage.},
journal = {ACS chemical biology},
volume = {11},
number = {2},
pages = {500-507},
pmid = {26686913},
issn = {1554-8937},
support = {P30 CA042014/CA/NCI NIH HHS/United States ; R01 CA090689/CA/NCI NIH HHS/United States ; R01 GM093099/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; DNA Damage ; *G-Quadruplexes ; Guanine/*analogs &amp; derivatives/chemistry ; Humans ; Models, Molecular ; Telomere/*chemistry ; },
abstract = {Inflammation and oxidative stress generate free radicals that oxidize guanine (G) in DNA to 8-oxo-7,8-dihydroguanine (OG), and this reaction is prominent in the G-rich telomere sequence. In telomeres, OG is not efficiently removed by repair pathways allowing its concentration to build, surprisingly without any immediate negative consequences to stability. Herein, OG was synthesized in five repeats of the human telomere sequence (TTAGGG)n, at the 5'-G of the 5'-most, middle, and 3'-most G tracks, representing hotspots for oxidation. These synthetic oligomers were folded in relevant amounts of K(+)/Na(+) to adopt hybrid G-quadruplex folds. The structural impact of OG was assayed by circular dichroism, thermal melting, (1)H NMR, and single-molecule profiling by the α-hemolysin nanopore. On the basis of these results, OG was well accommodated in the five-repeat sequences by looping out the damaged G track to allow the other four tracks to adopt a hybrid G-quadruplex. These results run counter to previous studies with OG in four-repeat telomere sequences that found OG to be highly destabilizing and causing significant reorientation of the fold. When taking a wider view of the human telomere sequence and considering additional repeats, we found OG to cause minimal impact on the structure. The plasticity of this repeat sequence addresses how OG concentrations can increase in telomeres without immediate telomere instability or attrition.},
}
@article {pmid26680692,
year = {2015},
author = {Li, Z and Hu, M and Zong, X and He, Y and Wang, D and Dai, L and Dong, M and Zhou, J and Cao, H and Lv, L and Chen, X and Tang, J},
title = {Association of telomere length and mitochondrial DNA copy number with risperidone treatment response in first-episode antipsychotic-naïve schizophrenia.},
journal = {Scientific reports},
volume = {5},
number = {},
pages = {18553},
pmid = {26680692},
issn = {2045-2322},
mesh = {Adult ; Antipsychotic Agents/*therapeutic use ; DNA, Mitochondrial/*metabolism ; Drug Administration Schedule ; Female ; Follow-Up Studies ; Gene Dosage ; Humans ; Linear Models ; Longitudinal Studies ; Male ; Mitochondria/genetics ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; Risperidone/*therapeutic use ; Schizophrenia/*drug therapy ; Telomere/*metabolism ; Telomere Shortening ; Young Adult ; },
abstract = {Accumulating evidence indicates a putative association of telomere length and mitochondrial function with antipsychotics response in schizophrenia (SCZ). However, pharmacological findings were limited and no previous work has assessed this in a prospective longitudinal study. This study assessed telomere length and mitochondrial DNA copy number in first-episode antipsychotic-naïve SCZ patients with 8-week risperidone treatment to evaluate the association between these biomarkers and clinical treatment response. We recruited 137 first-episode antipsychotic-naive SCZ patients (and 144 controls) at baseline and 89 patients completed the 8-week follow-up. Patients, completed follow-up, were divided into Responders (N = 46) and Non-Responders (N = 43) according to the percentage of symptoms improvement. Linear regression analyses show that SCZ patients had significantly lower mtDNA copy number (β = -0.108, p = 0.002), and no alteration of telomere length when compared with healthy controls. In addition, compared with Non-Responders, Responders had significantly lower mtDNA copy number (β = -0.178, p = 0.001), and longer telomere length (β = 0.111, p = 0.071) before the 8-week treatment. After treatment, Responders persisted lower mtDNA copy number comparing with No-Responders (partial η(2) = 0.125, p = 0.001). These findings suggest that telomere length and mtDNA copy number may hold the potential to serve as predictors of antipsychotic response of SCZ patients.},
}
@article {pmid26675777,
year = {2016},
author = {Meyer, A and Salewsky, B and Spira, D and Steinhagen-Thiessen, E and Norman, K and Demuth, I},
title = {Leukocyte telomere length is related to appendicular lean mass: cross-sectional data from the Berlin Aging Study II (BASE-II).},
journal = {The American journal of clinical nutrition},
volume = {103},
number = {1},
pages = {178-183},
doi = {10.3945/ajcn.115.116806},
pmid = {26675777},
issn = {1938-3207},
mesh = {Absorptiometry, Photon ; Adult ; Aged ; Aged, 80 and over ; Aging/*physiology ; Berlin ; Body Mass Index ; Cross-Sectional Studies ; Female ; Humans ; Leg ; *Leukocytes ; Male ; Middle Aged ; Muscle, Skeletal/*pathology ; Polymerase Chain Reaction ; Risk Factors ; Sarcopenia/*etiology ; Telomere/*physiology ; *Telomere Shortening ; Young Adult ; },
abstract = {BACKGROUND: Age-related progressive loss of muscle mass is an increasing problem in our aging society, affecting physical ability, risk of falls, and need for health care. Telomere length has been recognized as a marker of biological age on the population level. The relation between muscle mass in advanced age and telomere length, however, has rarely been examined.<br><br>OBJECTIVE: We evaluated the relation between appendicular lean mass (ALM) and relative leukocyte telomere length (rLTL) in 1398 participants of the Berlin Aging Study II (mean &#xb1; SD age: 68.2 &#xb1; 3.7 y; 49.6% men).<br><br>DESIGN: rLTL was determined by real-time polymerase chain reaction. Lean mass was estimated by dual X-ray absorptiometry and examined as leg lean mass (LLM), ALM, and the ratio of ALM to body mass index (ALMBMI).<br><br>RESULTS: Weak, but highly significant (P < 0.001), correlations of rLTL with ALM (r = 0.248), ALMBMI (r = 0.254), and LLM (r = 0.263) were found. In the fully adjusted model that included age, BMI, low-grade inflammation, lifestyle factors, and morbidities as potential confounders, rLTL was associated with ALM (&#x3b2; = 1.11, SEM = 0.46, P = 0.017), LLM (&#x3b2; = 1.20, SEM = 0.36, P = 0.001), and ALMBMI (&#x3b2; = 0.04, SEM = 0.02, P = 0.013) in men and with LLM in women (&#x3b2; = 0.78, SEM = 0.35, P = 0.026).<br><br>CONCLUSIONS: Our results suggest that short telomeres may be a risk factor for lower ALM, particularly for low LLM. To confirm the association between telomere attrition and loss of LLM and ALMBMI, which are highly relevant for physical ability, further research in a longitudinal context is needed. The medical portion of this trial was registered in the German Clinical Trials Registry (http://drks-neu.uniklinik-freiburg.de/drks_web/navigate.do?navigationId=start) as DRKS00009277.},
}
@article {pmid26675332,
year = {2015},
author = {Heeg, S},
title = {Variations in telomere maintenance and the role of telomerase inhibition in gastrointestinal cancer.},
journal = {Pharmacogenomics and personalized medicine},
volume = {8},
number = {},
pages = {171-180},
pmid = {26675332},
issn = {1178-7066},
abstract = {Immortalization is an important step toward the malignant transformation of human cells and is critically dependent upon telomere maintenance. There are two known mechanisms to maintain human telomeres. The process of telomere maintenance is either mediated through activation of the enzyme telomerase or through an alternative mechanism of telomere lengthening called ALT. While 85% of all human tumors show reactivation of telomerase, the remaining 15% are able to maintain telomeres via ALT. The therapeutic potential of telomerase inhibitors is currently investigated in a variety of human cancers. Gastrointestinal tumors are highly dependent on telomerase as a mechanism of telomere maintenance, rendering telomeres as well as telomerase potential targets for cancer therapy. This article focuses on the molecular mechanisms of telomere biology and telomerase activation in gastrointestinal cancers and reviews strategies of telomerase inhibition and their potential therapeutic use in these tumor entities.},
}
@article {pmid26674112,
year = {2015},
author = {Nilsonne, G and Tamm, S and Månsson, KN and Åkerstedt, T and Lekander, M},
title = {Leukocyte telomere length and hippocampus volume: a meta-analysis.},
journal = {F1000Research},
volume = {4},
number = {},
pages = {1073},
pmid = {26674112},
issn = {2046-1402},
abstract = {Leukocyte telomere length has been shown to correlate to hippocampus volume, but effect estimates differ in magnitude and are not uniformly positive. This study aimed primarily to investigate the relationship between leukocyte telomere length and hippocampus gray matter volume by meta-analysis and secondarily to investigate possible effect moderators. Five studies were included with a total of 2107 participants, of which 1960 were contributed by one single influential study. A random-effects meta-analysis estimated the effect to r = 0.12 [95% CI -0.13, 0.37] in the presence of heterogeneity and a subjectively estimated moderate to high risk of bias. There was no evidence that apolipoprotein E (APOE) genotype was an effect moderator, nor that the ratio of leukocyte telomerase activity to telomere length was a better predictor than leukocyte telomere length for hippocampus volume. This meta-analysis, while not proving a positive relationship, also is not able to disprove the earlier finding of a positive correlation in the one large study included in analyses. We propose that a relationship between leukocyte telomere length and hippocamus volume may be mediated by transmigrating monocytes which differentiate into microglia in the brain parenchyma.},
}
@article {pmid26673900,
year = {2016},
author = {Zhao, A and Zhao, C and Tateishi-Karimata, H and Ren, J and Sugimoto, N and Qu, X},
title = {Incorporation of O(6)-methylguanine restricts the conformational conversion of the human telomere G-quadruplex under molecular crowding conditions.},
journal = {Chemical communications (Cambridge, England)},
volume = {52},
number = {9},
pages = {1903-1906},
doi = {10.1039/c5cc09728b},
pmid = {26673900},
issn = {1364-548X},
abstract = {Here we systematically studied the incorporation of O(6)-methylguanine (6mG) into different positions of the human telomere G-quadruplex. In contrast to the natural G-quadruplex, the 6mG incorporated G-quadruplexes impeded the conformational conversion of the G-quadruplex from a hybrid to a parallel structure under molecular crowding conditions in a K(+) containing buffer.},
}
@article {pmid26670612,
year = {2015},
author = {Sharma, R and Gupta, A and Thungapathra, M and Bansal, R},
title = {Telomere mean length in patients with diabetic retinopathy.},
journal = {Scientific reports},
volume = {5},
number = {},
pages = {18368},
pmid = {26670612},
issn = {2045-2322},
mesh = {Adult ; Aged ; Diabetes Mellitus, Type 2/*metabolism ; Diabetic Retinopathy/*metabolism ; Female ; Humans ; Male ; Middle Aged ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Telomere regression has been shown to be associated with several complex disorders like diabetes mellitus, cancer, cataract etc. Diabetic retinopathy develops as a complication of chronic hyperglycemia leading to increased oxidative stress that may potentially lead to shortening of telomeres. We sought to determine whether there is any association between telomere mean length (TML) of peripheral blood monocytes with the presence and severity of diabetic retinopathy. The study involved 120 subjects, comprising 27 non-insulin dependent diabetes mellitus (NIDDM) without any diabetic retinopathy (NDR), 45 NIDDM subjects with non-proliferative diabetic retinopathy (NPDR), 12 NIDDM subjects with proliferative diabetic retinopathy (PDR) and 36 healthy controls. Determination of TML of the study subjects was performed by Southern hybridization using telomere probe. Among the biochemical parameters, HBA1c showed a negative correlation with shortened telomeres in the PDR subjects. However, telomere length was positively correlated with high density lipo protein (HDL) in the control subjects. The control group had significantly greater TML as compared to the rest of the groups and the NDR subjects with NPDR and PDR had substantially decreased TML than the NIDDM subjects without retinopathy.},
}
@article {pmid26669979,
year = {2016},
author = {Koenig, HG and Nelson, B and Shaw, SF and Saxena, S and Cohen, HJ},
title = {Religious Involvement and Telomere Length in Women Family Caregivers.},
journal = {The Journal of nervous and mental disease},
volume = {204},
number = {1},
pages = {36-42},
doi = {10.1097/NMD.0000000000000443},
pmid = {26669979},
issn = {1539-736X},
mesh = {Adult ; Aged ; Caregivers/*psychology ; Female ; Humans ; Los Angeles ; Middle Aged ; North Carolina ; Real-Time Polymerase Chain Reaction ; *Religion and Psychology ; Stress, Psychological/genetics/*psychology ; Telomere/*genetics ; Telomere Shortening/genetics/physiology ; },
abstract = {Telomere length (TL) is an indicator of cellular aging associated with longevity and psychosocial stress. We examine here the relationship between religious involvement and TL in 251 stressed female family caregivers recruited into a 2-site study. Religious involvement, perceived stress, caregiver burden, depressive symptoms, and social support were measured and correlated with TL in whole blood leukocytes. Results indicated a U-shaped relationship between religiosity and TL. Those scoring in the lowest 10% on religiosity tended to have the longest telomeres (5743 bp ± 367 vs. 5595 ± 383, p = 0.069). However, among the 90% of caregivers who were at least somewhat religious, religiosity was significantly and positively related to TL after controlling for covariates (B = 1.74, SE = 0.82, p = 0.034). Whereas nonreligious caregivers have relatively long telomeres, we found a positive relationship between religiosity and TL among those who are at least somewhat religious.},
}
@article {pmid26666879,
year = {2016},
author = {Ellehoj, H and Bendix, L and Osler, M},
title = {Leucocyte Telomere Length and Risk of Cardiovascular Disease in a Cohort of 1,397 Danish Men and Women.},
journal = {Cardiology},
volume = {133},
number = {3},
pages = {173-177},
doi = {10.1159/000441819},
pmid = {26666879},
issn = {1421-9751},
mesh = {Adult ; Aged ; Cardiovascular Diseases/blood/*epidemiology/*etiology ; Cohort Studies ; Denmark/epidemiology ; Female ; Follow-Up Studies ; Humans ; Leukocytes ; Male ; Medical Record Linkage ; Middle Aged ; Myocardial Ischemia/epidemiology/etiology ; Proportional Hazards Models ; Registries ; Risk Factors ; Stroke ; Surveys and Questionnaires ; *Telomere Homeostasis/physiology ; },
abstract = {OBJECTIVES: Short leucocyte telomere length (LTL) might be a risk factor for cardiovascular diseases (CVD). The present study examines the relation between LTL and incident fatal or non-fatal CVD, ischaemic heart disease (IHD) and stroke in a Danish cohort followed for 29 years.<br><br>METHODS: In total, 1,397 men and women who participated in health examinations with blood sampling in 1981-1984 were followed for CVD outcomes until the end of 2012 by linkage to national registers. Cox proportional hazard regression models were used to analyse the relation between LTL and CVD adjusting for potential confounding CVD risk factors.<br><br>RESULTS: During the follow-up, 603 participants experienced an incident fatal or non-fatal CVD. The survival analysis showed that baseline LTL was not associated with CVD outcomes. In the subanalysis with IHD as outcome, those with middle and short LTL had an increased hazard rate ratio of 1.97 (95% CI 1.31-2.93) and 1.55 (95% CI 1.02-2.35), respectively, which was attenuated when confounding factors were adjusted for. For stroke, the pattern of associations was similar but less precisely estimated.<br><br>CONCLUSIONS: In this study short, LTL was not associated with an increased risk of CVD, but modestly associated with an increased risk of IHD.},
}
@article {pmid26658719,
year = {2016},
author = {Hohensinner, PJ and Kaun, C and Buchberger, E and Ebenbauer, B and Demyanets, S and Huk, I and Eppel, W and Maurer, G and Huber, K and Wojta, J},
title = {Age intrinsic loss of telomere protection via TRF1 reduction in endothelial cells.},
journal = {Biochimica et biophysica acta},
volume = {1863},
number = {2},
pages = {360-367},
doi = {10.1016/j.bbamcr.2015.11.034},
pmid = {26658719},
issn = {0006-3002},
support = {J 3064/FWF_/Austrian Science Fund FWF/Austria ; },
mesh = {Blotting, Western ; Cells, Cultured ; Cellular Senescence/*genetics ; Chemokine CCL2/genetics/metabolism ; DNA Damage ; Gene Expression ; Granulocyte-Macrophage Colony-Stimulating Factor/genetics/metabolism ; Human Umbilical Vein Endothelial Cells/*metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Microscopy, Confocal ; Plasminogen Activator Inhibitor 1/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 1/*genetics/metabolism ; },
abstract = {Aging is a major factor predisposing for multiple diseases. Telomeres at the ends of chromosomes protect the integrity of chromosomal DNA. A specialized six-protein complex termed shelterin protects the telomere from unwanted interaction with DNA damage pathways. The aim of our study was to evaluate the integrity of telomeres and the stability of telomere protection during aging in endothelial cells (EC). We describe that aging EC can be characterized by an increased cell size (40%, p=0.02) and increased expression of PAI 1 (4 fold, p=0.02), MCP1 (10 fold, p=0.001) and GMCSF (15 fold, p=0.004). Telomeric state in aging cells is defined by an increased telomere oxidation (27%, p=0.01), reduced telomere length (62%, p=0.02), and increased DNA damage foci formation (5% in young EC versus 16% in aged EC, p=0.003). This telomeric dysfunction is accompanied by a reduction in the shelterin component TRF1 (33% mRNA, p=0.001; 24% protein, p=0.007). Overexpression of TRF1 in aging EC reduced telomere-associated DNA damage foci to 5% (p=0.02) and reduced expression levels of MCP1 (18% reduction, p=0.008). Aged EC have increased telomere damage and an intrinsic loss of telomere protection. Reestablishing telomere integrity could therefore be a target for rejuvenating endothelial cell function.},
}
@article {pmid26658110,
year = {2016},
author = {Tutton, S and Azzam, GA and Stong, N and Vladimirova, O and Wiedmer, A and Monteith, JA and Beishline, K and Wang, Z and Deng, Z and Riethman, H and McMahon, SB and Murphy, M and Lieberman, PM},
title = {Subtelomeric p53 binding prevents accumulation of DNA damage at human telomeres.},
journal = {The EMBO journal},
volume = {35},
number = {2},
pages = {193-207},
pmid = {26658110},
issn = {1460-2075},
support = {R01CA102184/CA/NCI NIH HHS/United States ; F31 CA174199/CA/NCI NIH HHS/United States ; R21 CA 177395-01/CA/NCI NIH HHS/United States ; F31HG006395/HG/NHGRI NIH HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; R21 CA177395/CA/NCI NIH HHS/United States ; R21HG007205/HG/NHGRI NIH HHS/United States ; R21 HG007205/HG/NHGRI NIH HHS/United States ; R01CA164864/CA/NCI NIH HHS/United States ; F31 HG006395/HG/NHGRI NIH HHS/United States ; R01 CA102184/CA/NCI NIH HHS/United States ; R01 CA164834/CA/NCI NIH HHS/United States ; R01CA140652/CA/NCI NIH HHS/United States ; P30 CA10815/CA/NCI NIH HHS/United States ; T32 CA009171/CA/NCI NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; F31CA174199/CA/NCI NIH HHS/United States ; T32 CA115299/CA/NCI NIH HHS/United States ; },
mesh = {Carrier Proteins/genetics/*metabolism ; DNA Damage/*genetics ; HCT116 Cells ; Humans ; Protein Binding ; Telomere/genetics/*metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; },
abstract = {Telomeres and tumor suppressor protein TP53 (p53) function in genome protection, but a direct role of p53 at telomeres has not yet been described. Here, we have identified non-canonical p53-binding sites within the human subtelomeres that suppress the accumulation of DNA damage at telomeric repeat DNA. These non-canonical subtelomeric p53-binding sites conferred transcription enhancer-like functions that include an increase in local histone H3K9 and H3K27 acetylation and stimulation of subtelomeric transcripts, including telomere repeat-containing RNA (TERRA). p53 suppressed formation of telomere-associated γH2AX and prevented telomere DNA degradation in response to DNA damage stress. Our findings indicate that p53 provides a direct chromatin-associated protection to human telomeres, as well as other fragile genomic sites. We propose that p53-associated chromatin modifications enhance local DNA repair or protection to provide a previously unrecognized tumor suppressor function of p53.},
}
@article {pmid26657493,
year = {2016},
author = {Müezzinler, A and Mons, U and Dieffenbach, AK and Butterbach, K and Saum, KU and Schick, M and Stammer, H and Boukamp, P and Holleczek, B and Stegmaier, C and Brenner, H},
title = {Body mass index and leukocyte telomere length dynamics among older adults: Results from the ESTHER cohort.},
journal = {Experimental gerontology},
volume = {74},
number = {},
pages = {1-8},
doi = {10.1016/j.exger.2015.11.019},
pmid = {26657493},
issn = {1873-6815},
mesh = {Adiposity ; Age Factors ; Aged ; Aging/blood/*genetics ; *Body Mass Index ; Cross-Sectional Studies ; Female ; Germany ; Humans ; Leukocytes/metabolism ; Longitudinal Studies ; Male ; Middle Aged ; Obesity/blood/diagnosis/*genetics/*physiopathology ; Polymerase Chain Reaction ; Risk Factors ; Telomere/*genetics/metabolism ; *Telomere Shortening ; Time Factors ; Weight Gain ; },
abstract = {OBJECTIVE: Telomere length (TL) has been proposed as a biomarker of ageing, which might be used to identify individuals at higher risk of age-related diseases. Obesity is a well-known risk factor for several diseases. This study aims to analyse the associations of BMI with TL and the rate of TL change in older adults.<br><br>METHODS: Leukocyte TL (LTL) was measured by quantitative PCR in blood samples of 3600 older adults aged 50-75 years obtained at the baseline examination of a population-based cohort study in Germany. For longitudinal analyses, measurements were repeated in blood samples obtained at 8-year follow-up from 1000 participants. Multivariate linear regression models were used to estimate associations of BMI with LTL and changes in LTL over time.<br><br>RESULTS: LTL was inversely associated with age (r = -0.090, p < 0.0001). BMI and LTL associations varied according to age (p for interaction = 0.021). BMI was significantly inversely associated with LTL in those younger than 60 years (-6 basepairs per 1 kg/m(2) difference in BMI). In particular, weight gain during adulthood was inversely associated with LTL in a dose-response manner in this age group, with those having gained &#x2265; 30 kg having significantly shorter telomeres (-209 basepairs) than those who maintained their weight. No clear patterns were observed between any of BMI-related variables and the rate of LTL change.<br><br>CONCLUSIONS: Our cross-sectional analysis supports suggestions that weight gain during adulthood and obesity may contribute to shorter telomere length below 60 years of age, but this relationship could not be shown longitudinally.},
}
@article {pmid26656293,
year = {2016},
author = {Latifovic, L and Peacock, SD and Massey, TE and King, WD},
title = {The Influence of Alcohol Consumption, Cigarette Smoking, and Physical Activity on Leukocyte Telomere Length.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {25},
number = {2},
pages = {374-380},
doi = {10.1158/1055-9965.EPI-14-1364},
pmid = {26656293},
issn = {1538-7755},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Adult ; Alcohol Drinking/*adverse effects ; Cross-Sectional Studies ; Humans ; Leukocytes/cytology/*metabolism ; Male ; Middle Aged ; Motor Activity/*physiology ; Risk Factors ; Smoking/*adverse effects ; Telomere Shortening ; Young Adult ; },
abstract = {BACKGROUND: Telomeres protect from DNA degradation and maintain chromosomal stability. Short telomeres have been associated with an increased risk of cancer at several sites. However, there is limited knowledge about the lifestyle determinants of telomere length. We aimed to determine the effect of three factors, known to be important in cancer etiology, on relative leukocyte telomere length (rLTL): alcohol consumption, smoking, and physical activity.<br><br>METHODS: This cross-sectional study included 477 healthy volunteers ages 20 to 50 years who completed a questionnaire and provided a fasting blood sample. Multiplex quantitative real-time PCR (qPCR) was used to measure rLTL. Regression coefficients were calculated using multiple linear regression while controlling for important covariates.<br><br>RESULTS: There was no association between alcohol consumption and rLTL. Daily smokers and those in the middle and lower tertile of pack-years smoking had shorter rLTL than never daily smokers (P = 0.02). Data were suggestive of a linear trend with total physical activity (P = 0.06). Compared with the lowest quartile, the highest quartile of vigorous physical activity was associated with longer rLTL. A significant linear trend of increasing rLTL with increasing vigorous physical activity was observed (P = 0.02).<br><br>CONCLUSIONS: Cigarette smoking and vigorous physical activity have an impact on telomere length. Smoking was related to shorter telomere length while vigorous physical activity was related to longer telomeres.<br><br>IMPACT: The findings from this study suggest that lifestyle may play an important role in telomere dynamics and also suggest that engaging in healthy behaviors may mitigate the effect of harmful behaviors on telomere length.},
}
@article {pmid26655528,
year = {2016},
author = {Vecoli, C and Borghini, A and Foffa, I and Ait-Ali, L and Picano, E and Andreassi, MG},
title = {Leukocyte telomere shortening in grown-up patients with congenital heart disease.},
journal = {International journal of cardiology},
volume = {204},
number = {},
pages = {17-22},
doi = {10.1016/j.ijcard.2015.11.133},
pmid = {26655528},
issn = {1874-1754},
mesh = {Adolescent ; Adult ; Female ; Heart Defects, Congenital/*diagnosis/genetics/therapy ; Humans ; Leukocytes/*physiology/*radiation effects ; Male ; Radiation Exposure/*adverse effects ; Telomere Shortening/*physiology/*radiation effects ; Young Adult ; },
abstract = {BACKGROUND/OBJECTIVES: Children with congenital heart disease are exposed by repeated imaging to ionizing radiation, which may have important implications for lifetime health risks. Leukocyte telomere length (LTL), a reliable biomarker of genomic instability, is associated with increased risk of cancer and cardiovascular disease. We investigated LTL in grown-up patients with CHD (GUCHs) and a positive history of medical radiation exposure as well as the influence of functional polymorphisms of genes involved in DNA repair.<br><br>METHODS: A group of 50 GUCH patients (26 males; age 25.2 &#xb1; 9.0 years) and 50 healthy age/gender-matched subjects (20 males; 27.0 &#xb1; 3.1 years) were enrolled. In GUCH patients, the cumulative exposure was estimated as effective dose (ED) in milliSievert. LTL was measured by quantitative RT-PCR. X-ray repair cross complementing-1 (XRCC1) and X-ray repair cross complementing-3 (XRCC3) SNPs (XRCC1Arg399Gln, XRCC1Arg194Tr and XRCC3 Thr241Met) were evaluated.<br><br>RESULTS: GUCHs showed significantly shorter LTL compared with controls (1.0 &#xb1; 0.3 vs 1.3 &#xb1; 0.4, p = 0.001). A significant inverse correlation between LTL and cumulative radiological ED was observed (r = -0.34, p = 0.03). Patients with Thr/Met XRCC3 or Met/Met XRCC3 genotypes were significantly associated with a significantly shorter LTL compared with wild-type genotype (p = 0.01 for Thr/Met and p = 0.008 for Met/Met). Carriers of XRCC1 194Trp and XRCC3 241Met alleles presented a significant interaction with cumulative radiation dose exposure for LTL (both p interaction = 0.02).<br><br>CONCLUSIONS: GUCH patients have LTL shortening, suggesting evidence of early biological aging. Common SNPs in DNA repair genes modify the effects of medical exposure to radiation LTL-related degenerative diseases.},
}
@article {pmid26653979,
year = {2015},
author = {Paviolo, NS and Santiñaque, FF and Castrogiovanni, DC and Folle, GA and Bolzán, AD},
title = {The methylating agent streptozotocin induces persistent telomere dysfunction in mammalian cells.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {794},
number = {},
pages = {17-24},
doi = {10.1016/j.mrgentox.2015.09.007},
pmid = {26653979},
issn = {1879-3592},
mesh = {Adipose Tissue/cytology/drug effects ; Animals ; Cell Line ; Chromosome Aberrations/*chemically induced ; Cytogenetic Analysis ; Genomic Instability/drug effects ; Humans ; In Situ Hybridization, Fluorescence ; Jurkat Cells ; Male ; Mice ; Mice, Inbred C57BL ; Rats ; Rats, Sprague-Dawley ; Streptozocin/*adverse effects ; Telomere/*drug effects/pathology ; },
abstract = {We analyzed chromosomal aberrations involving telomeres in the progeny of mammalian cells exposed to the methylating agent and antineoplastic/diabetogenic drug streptozotocin (STZ), to test whether it induces long-term telomere instability (by chromosome end loss and/or telomere dysfunction). Rat cells (ADIPO-P2 cell line, derived from Sprague-Dawley rat adipose cells) were treated with a single concentration of STZ (2mM). Chromosomal aberrations were analyzed 18h, 10 days, and 15 days after treatment, using PNA-FISH with a pan-telomeric probe [Cy3-(CCCTAA)3] to detect (TTAGGG)n repeats. Cytogenetic analysis revealed a higher frequency of chromosomal aberrations in STZ-exposed cultures vs. untreated cultures at each time point analyzed. The yield of induced aberrations was very similar at each time point. Induction of aberrations not involving telomere dysfunction was only observed 18h and 15 days after treatment, whereas induction of telomere dysfunction-related aberrations by STZ (mainly in the form of telomere FISH signal loss and duplications, most of them chromatid-type aberrations) was observed at each time point. Our results show that STZ induces persistent telomere instability in mammalian cells, cytogenetically manifested as telomere dysfunction-related chromosomal aberrations. Neither telomere length nor telomerase activity is related to the telomere dysfunction.},
}
@article {pmid26653646,
year = {2015},
author = {Wang, Y and Duan, X and Zhang, Y and Wang, S and Yao, W and Wang, S and Wang, W and Wu, Y},
title = {[DNA methylation and telomere damage in occupational people exposed to coal tar pitch].},
journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases},
volume = {33},
number = {7},
pages = {507-511},
pmid = {26653646},
issn = {1001-9391},
mesh = {Acid Anhydride Hydrolases/genetics ; Coal Tar/*adverse effects ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; *DNA Methylation ; Humans ; Leukocytes/drug effects ; Neoplasm Proteins/genetics ; Occupational Exposure/*adverse effects ; *Promoter Regions, Genetic ; Telomere/*drug effects/ultrastructure ; Tumor Suppressor Proteins/genetics ; },
abstract = {OBJECTIVE: To investigate the promoter methylation of p16, FHIT and RASSF1A gene and telomere damage in the workers exposed to coal tar pitch, and to explore the effective biomarker of occupational exposure to coal tar pitch.<br><br>METHODS: 180 cases of workers exposed to coal tar pitch in a certain carbon plant named as exposure group, and 145 healthy cases with a medical examination in the first affiliated hospital of Zhengzhou University were selected as control group. Relative telomere length in peripheral blood DNA was detected using real-time quantitative PCR, and the promoter methylation rate of p16, RASSF1A and FHIT gene in peripheral blood DNA were determined by real-time quantitative methylation specific PCR. The relative telomere length and gene promoter methylation in two groups were compared, and influencing factors were analyzed.<br><br>RESULTS: Relative telomere length in exposed group was lower than that in the control group, and the difference was statistically significant (Z = -5.395, P < 0.001). There was no significant difference in the promoter methylation rate of p16, FHIT and RASSF1A gene between the two groups (P > 0.05). Stratification analysis by gender, age, and smoking, we found that when the age was less than or equal to 40, the promoter methylation rate of p16 in exposed group was more than that in control group, and the difference was statistically significant (Z = -1.914, P = 0.011).<br><br>CONCLUSION: Occupational exposure to coal tar pitch may induce leukocyte DNA telomere length of human peripheral blood shortened, and may not change the promoter methylation rates of p16, FHIT and RASSF1A gene.},
}
@article {pmid26653081,
year = {2016},
author = {Hertwig, F and Peifer, M and Fischer, M},
title = {Telomere maintenance is pivotal for high-risk neuroblastoma.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {15},
number = {3},
pages = {311-312},
pmid = {26653081},
issn = {1551-4005},
mesh = {DNA Helicases/genetics/metabolism ; Humans ; N-Myc Proto-Oncogene Protein/metabolism ; Neuroblastoma/metabolism/*pathology ; Nuclear Proteins/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Telomere Shortening ; X-linked Nuclear Protein ; },
}
@article {pmid26646793,
year = {2015},
author = {Walsh, KM and Codd, V and Rice, T and Nelson, CP and Smirnov, IV and McCoy, LS and Hansen, HM and Elhauge, E and Ojha, J and Francis, SS and Madsen, NR and Bracci, PM and Pico, AR and Molinaro, AM and Tihan, T and Berger, MS and Chang, SM and Prados, MD and Jenkins, RB and Wiemels, JL and , and Samani, NJ and Wiencke, JK and Wrensch, MR},
title = {Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk.},
journal = {Oncotarget},
volume = {6},
number = {40},
pages = {42468-42477},
pmid = {26646793},
issn = {1949-2553},
support = {R01 CA139020/CA/NCI NIH HHS/United States ; R01CA126831/CA/NCI NIH HHS/United States ; U58DP003862-01/DP/NCCDPHP CDC HHS/United States ; HHSN261201000140C/CA/NCI NIH HHS/United States ; P50 CA108961/CA/NCI NIH HHS/United States ; HHSN261201000035C/CA/NCI NIH HHS/United States ; RC1NS068222Z/NS/NINDS NIH HHS/United States ; R25 CA112355/CA/NCI NIH HHS/United States ; R01 CA126831/CA/NCI NIH HHS/United States ; P50 CA097257/CA/NCI NIH HHS/United States ; P30CA15083/CA/NCI NIH HHS/United States ; MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; R01 CA052689/CA/NCI NIH HHS/United States ; T32 CA151022/CA/NCI NIH HHS/United States ; /BHF_/British Heart Foundation/United Kingdom ; RC1 NS068222/NS/NINDS NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; 076113/WT_/Wellcome Trust/United Kingdom ; R25CA112355/CA/NCI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; HHSN261201000035I/CA/NCI NIH HHS/United States ; P50CA097257/CA/NCI NIH HHS/United States ; HHSN261201000034C/CA/NCI NIH HHS/United States ; P50CA108961/CA/NCI NIH HHS/United States ; R01CA139020/CA/NCI NIH HHS/United States ; R01CA52689/CA/NCI NIH HHS/United States ; U58 DP003862/DP/NCCDPHP CDC HHS/United States ; 085475/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Adult ; Brain Neoplasms/*genetics ; Case-Control Studies ; Female ; Genetic Predisposition to Disease/*genetics ; Genome-Wide Association Study ; Genotype ; Glioma/*genetics ; Humans ; Leukocytes/*metabolism ; Male ; Models, Statistical ; Polymorphism, Single Nucleotide ; Risk Factors ; Telomere/*genetics ; },
abstract = {Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82x10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48x10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83x10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis.},
}
@article {pmid26645576,
year = {2016},
author = {Bateson, M},
title = {Cumulative stress in research animals: Telomere attrition as a biomarker in a welfare context?.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {38},
number = {2},
pages = {201-212},
pmid = {26645576},
issn = {1521-1878},
support = {NC/K000802/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; BB/JJ016446/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Biomarkers/*metabolism ; Humans ; Stress, Physiological/*genetics/*physiology ; Telomere/*genetics ; },
abstract = {Progress in improving animal welfare is currently limited by the lack of objective methods for assessing lifetime experience. I propose that telomere attrition, a cellular biomarker of biological age, provides a molecular measure of cumulative experience that could be used to assess the welfare impact of husbandry regimes and/or experimental procedures on non-human animals. I review evidence from humans that telomere attrition is accelerated by negative experiences in a cumulative and dose-dependent manner, but that this attrition can be mitigated or even reversed by positive life-style interventions. Evidence from non-human animals suggests that despite some specific differences in telomere biology, stress-induced telomere attrition is a robust phenomenon, occurring in a range of species including mice and chickens. I conclude that telomere attrition apparently integrates positive and negative experience in an accessible common currency that translates readily to novel species--the Holy Grail of a cumulative welfare indicator.},
}
@article {pmid26645051,
year = {2015},
author = {Dilley, RL and Greenberg, RA},
title = {ALTernative Telomere Maintenance and Cancer.},
journal = {Trends in cancer},
volume = {1},
number = {2},
pages = {145-156},
pmid = {26645051},
issn = {2405-8033},
support = {R01 CA174904/CA/NCI NIH HHS/United States ; T32 GM007170/GM/NIGMS NIH HHS/United States ; R01 GM101149/GM/NIGMS NIH HHS/United States ; T32 GM008216/GM/NIGMS NIH HHS/United States ; R01 CA138835/CA/NCI NIH HHS/United States ; },
abstract = {Activation of a telomere maintenance mechanism (TMM) is permissive for replicative immortality and a hallmark of human cancer. While most cancers rely on reactivation of telomerase, a significant fraction utilizes the recombination dependent alternative lengthening of telomeres (ALT) pathway. ALT is enriched in tumors of mesenchymal origin, including those arising from bone, soft tissue, and the nervous system, and usually portends a poor prognosis. Recent insights into the mechanisms of ALT are uncovering novel avenues to exploit vulnerabilities and may facilitate clinical development of ALT detection assays and personalized treatment decisions based on TMM status. Treatments targeting ALT may hold promise for a broadly applicable therapeutic modality specific to mesenchymal lineage tumors, something that has thus far remained elusive.},
}
@article {pmid26640565,
year = {2015},
author = {Wang, Y and Zhao, Z and Yang, Y and Zhao, Y and Ge, RL},
title = {Thymocytes maintain immune activity through telomere elongation in rats under hypoxic conditions.},
journal = {Experimental and therapeutic medicine},
volume = {10},
number = {5},
pages = {1877-1882},
pmid = {26640565},
issn = {1792-0981},
abstract = {The main purpose of the present study was to investigate the change in thymocyte telomere length of rats exposed to different hypoxic conditions for different periods of time, as well as its effect on the immune system. A total of 110 male Wistar rats were randomly assigned to one of the three following groups: i) Sea level (SL) group, in which 10 rats were maintained at an altitude of 10 m; ii) moderate altitude (MA) group, in which 50 rats were maintained at an altitude of 2,260 m and then randomly sacrificed on days 1, 3, 7, 15 and 30 (n=10 each); and iii) simulated high altitude (SHA) group, in which 50 rats were maintained at a simulated altitude of 5,000 m, and then randomly sacrificed on days 1, 3, 7, 15 and 30 (n=10 each). The morphological changes of the thymus were observed, while the telomere length, the mRNA and protein expression levels of telomerase reverse transcriptase (TERT), and the peripheral blood lymphocyte count were measured. The results indicated that hypoxia induced morphological changes and apoptosis in thymocytes, as well as atrophy of the thymus tissue, and resulted in a significant increase in telomere length and TERT mRNA and protein expression levels. This effect appeared to be more pronounced in the SHA group compared with that in the MA group; however, no statistically significant changes were observed in the peripheral blood lymphocyte count. Based on these findings, the hypoxia-associated loss of thymic function appears to be only quantitative and not qualitative, and the thymus may be able to maintain its immune function even under hypoxic conditions.},
}
@article {pmid26640040,
year = {2015},
author = {Nera, B and Huang, HS and Lai, T and Xu, L},
title = {Elevated levels of TRF2 induce telomeric ultrafine anaphase bridges and rapid telomere deletions.},
journal = {Nature communications},
volume = {6},
number = {},
pages = {10132},
pmid = {26640040},
issn = {2041-1723},
mesh = {Anaphase ; *Base Sequence ; Cell Line, Tumor ; DNA Replication/genetics ; Gene Knock-In Techniques ; Genomic Instability ; HeLa Cells ; Humans ; Immunoblotting ; In Situ Hybridization, Fluorescence ; MCF-7 Cells ; Metaphase ; Neoplasms/*genetics/metabolism ; Real-Time Polymerase Chain Reaction ; Sequence Deletion/*genetics ; Telomere/*genetics/metabolism ; Telomere Shortening/genetics ; Telomeric Repeat Binding Protein 2/*genetics/metabolism ; },
abstract = {The shelterin protein TRF2 is essential for chromosome-end protection. Depletion of TRF2 causes chromosome end-to-end fusions, initiating genomic instability that can be cancer promoting. Paradoxically, significant increased levels of TRF2 are observed in a subset of human cancers. Experimental overexpression of TRF2 has also been shown to induce telomere shortening, through an unknown mechanism. Here we report that TRF2 overexpression results in replication stalling in duplex telomeric repeat tracts and the subsequent formation of telomeric ultrafine anaphase bridges (UFBs), ultimately leading to stochastic loss of telomeric sequences. These TRF2 overexpression-induced telomere deletions generate chromosome fusions resembling those detected in human cancers and in mammalian cells containing critically shortened telomeres. Therefore, our findings have uncovered a second pathway by which altered TRF2 protein levels can induce end-to-end fusions. The observations also provide mechanistic insight into the molecular basis of genomic instability in tumour cells containing significantly increased TRF2 levels.},
}
@article {pmid26638179,
year = {2015},
author = {Falandry, C and Horard, B and Bruyas, A and Legouffe, E and Cretin, J and Meunier, J and Alexandre, J and Delecroix, V and Fabbro, M and Certain, MN and Maraval-Gaget, R and Pujade-Lauraine, E and Gilson, E and Freyer, G},
title = {Telomere length is a prognostic biomarker in elderly advanced ovarian cancer patients: a multicenter GINECO study.},
journal = {Aging},
volume = {7},
number = {12},
pages = {1066-1076},
pmid = {26638179},
issn = {1945-4589},
mesh = {Aged ; Aged, 80 and over ; *Aging ; Antineoplastic Agents/*therapeutic use ; Biomarkers ; Carboplatin/*therapeutic use ; Female ; Humans ; Neoplasm Staging ; Ovarian Neoplasms/drug therapy/*metabolism ; Pregnancy ; Telomere Homeostasis/*physiology ; Time Factors ; },
abstract = {PURPOSE: Age induces a progressive decline in functional reserve and impacts cancer treatments. Telomere attrition leads to tissue senescence. We tested the hypothesis that telomere length (TL) could predict patient vulnerability and outcome with cancer treatment.<br><br>PATIENTS AND METHODS: An ancillary study in the Elderly Women GINECO Trial 3 was performed to evaluate the impact of geriatric covariates on survival in elderly advanced ovarian cancer patients receiving six cycles of carboplatin. TL was estimated from peripheral blood at inclusion using standard procedures.<br><br>RESULTS: TL (in base pairs) was estimated for 109/111 patients (median 6.1 kb; range [4.5-8.3 kb]). With a cut-off of 5.77 kb, TL discriminated two patient groups, long telomere (LT) and short telomeres (ST), with significantly different treatment completion rates of 0.80 (95% CI [0.71-0.89]) and 0.59 (95% CI [0.41-0.76]), respectively (odds ratio [OR]=2.8, p=0.02). ST patients were at higher risk of serious adverse events (SAE, OR=2.7; p=0.02) and had more unplanned hospital admissions (OR=2.1; p=0.08). After adjustment on FIGO stage, TL shorter than 6 kb was a risk factor of premature death (HR=1.57; p=0.06).<br><br>CONCLUSION: This exploratory study identifies TL as predictive factor of decreased treatment completion, SAE risk, unplanned hospital admissions and OS after adjustment on FIGO stage.},
}
@article {pmid26637967,
year = {2016},
author = {Li, H and Åkerman, G and Lidén, C and Alhamdow, A and Wojdacz, TK and Broberg, K and Albin, M},
title = {Alterations of telomere length and DNA methylation in hairdressers: A cross-sectional study.},
journal = {Environmental and molecular mutagenesis},
volume = {57},
number = {2},
pages = {159-167},
doi = {10.1002/em.21991},
pmid = {26637967},
issn = {1098-2280},
mesh = {Adult ; Aging/genetics ; Case-Control Studies ; Cross-Sectional Studies ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; *DNA Methylation ; DNA Modification Methylases/genetics ; DNA Repair Enzymes/genetics ; Female ; Glutathione S-Transferase pi/genetics ; Humans ; Middle Aged ; Nuclear Proteins/genetics ; Occupational Diseases/etiology ; Occupational Exposure/*adverse effects ; Sweden ; *Telomere ; Time Factors ; Tumor Suppressor Proteins/genetics ; Twist-Related Protein 1/genetics ; Young Adult ; },
abstract = {Working as hairdressers has been associated with increased risk for cancer, particularly bladder cancer. To evaluate if current hairdressers have elevated risks of adverse health effects, we measured several biomarkers related to cancer-related DNA alterations. We enrolled 295 hairdressers and 92 non-hairdressers (all female non-smokers) from Stockholm and southern Sweden. Questionnaire data were collected for each participant, including work tasks for the hairdressers. We measured telomere length in peripheral blood leucocytes using quantitative PCR and DNA methylation status of genes relevant for bladder cancer using methylation sensitive high resolution melting analysis. The hairdressers had shorter telomeres (β = -0.069, P = 0.019) compared with non-hairdressers. Shorter telomeres were found in hairdressers up to 32 years old performing hair waving more than once per week as compared with hairdressers in the same age group performing hair waving less often (β = -0.12, P = 0.037). Hair waving was associated with less frequent CDKN2A methylation (odds ratio, OR = 0.19, P = 0.033). Shorter telomeres in hairdressers may indicate a genotoxic effect. Performing hair waving was associated with short telomere length, although the effect was only observed in young hairdressers. No clear patterns were discerned with regard to DNA methylation of bladder cancer-related genes. The observed changes of methylation were not all in the expected direction and warrant further investigation.},
}
@article {pmid26636575,
year = {2015},
author = {Tolios, A and Teupser, D and Holdt, LM},
title = {Preanalytical Conditions and DNA Isolation Methods Affect Telomere Length Quantification in Whole Blood.},
journal = {PloS one},
volume = {10},
number = {12},
pages = {e0143889},
pmid = {26636575},
issn = {1932-6203},
mesh = {DNA, Neoplasm/chemistry/genetics/*isolation &amp; purification ; Female ; Humans ; Male ; Neoplasms/*chemistry/genetics ; Telomere/*chemistry/genetics ; *Telomere Homeostasis ; },
abstract = {Telomeres are located at chromosome ends and their length (TL) has been associated with aging and human diseases such as cancer. Whole blood DNA is frequently used for TL measurements but the influence of preanalytical conditions and DNA isolation methods on TL quantification has not been thoroughly investigated. To evaluate potential preanalytical as well as methodological bias on TL, anonymized leftover EDTA-whole blood samples were pooled according to leukocyte counts and were incubated with and without actinomycin D to induce apoptosis as a prototype of sample degradation. DNA was isolated from fresh blood pools and after freezing at -80°C. Commercially available kits using beads (Invitrogen), spin columns (Qiagen, Macherey-Nagel and 5prime) or precipitation (Stratec/Invisorb) and a published isopropanol precipitation protocol (IPP) were used for DNA isolation. TL was assessed by qPCR, and normalized to the single copy reference gene 36B4 using two established single-plex and a new multiplex protocol. We show that the method of DNA isolation significantly affected TL (e.g. 1.86-fold longer TL when comparing IPP vs. Invitrogen). Sample degradation led to an average TL decrease of 22% when using all except for one DNA isolation method (5prime). Preanalytical storage conditions did not affect TL with exception of samples that were isolated with the 5prime kit, where a 27% increase in TL was observed after freezing. Finally, performance of the multiplex qPCR protocol was comparable to the single-plex assays, but showed superior time- and cost-effectiveness and required > 80% less DNA. Findings of the current study highlight the need for standardization of whole blood processing and DNA isolation in clinical study settings to avoid preanalytical bias of TL quantification and show that multiplex assays may improve TL/SCG measurements.},
}
@article {pmid26636039,
year = {2015},
author = {Sishc, BJ and Nelson, CB and McKenna, MJ and Battaglia, CL and Herndon, A and Idate, R and Liber, HL and Bailey, SM},
title = {Telomeres and Telomerase in the Radiation Response: Implications for Instability, Reprograming, and Carcinogenesis.},
journal = {Frontiers in oncology},
volume = {5},
number = {},
pages = {257},
pmid = {26636039},
issn = {2234-943X},
abstract = {Telomeres are nucleoprotein complexes comprised of tandem arrays of repetitive DNA sequence that serve to protect chromosomal termini from inappropriate degradation, as well as to prevent these natural DNA ends from being recognized as broken DNA (double-strand breaks) and triggering of inappropriate DNA damage responses. Preservation of telomere length requires telomerase, the specialized reverse transcriptase capable of maintaining telomere length via template-mediated addition of telomeric repeats onto the ends of newly synthesized chromosomes. Loss of either end-capping function or telomere length maintenance has been associated with genomic instability or senescence in a variety of settings; therefore, telomeres and telomerase have well-established connections to cancer and aging. It has long been recognized that oxidative stress promotes shortening of telomeres, and that telomerase activity is a radiation-inducible function. However, the effects of ionizing radiation (IR) exposure on telomeres per se are much less well understood and appreciated. To gain a deeper understanding of the roles, telomeres and telomerase play in the response of human cells to IRs of different qualities, we tracked changes in telomeric end-capping function, telomere length, and telomerase activity in panels of mammary epithelial and hematopoietic cell lines exposed to low linear energy transfer (LET) gamma(γ)-rays or high LET, high charge, high energy (HZE) particles, delivered either acutely or at low dose rates. In addition to demonstrating that dysfunctional telomeres contribute to IR-induced mutation frequencies and genome instability, we reveal non-canonical roles for telomerase, in that telomerase activity was required for IR-induced enrichment of mammary epithelial putative stem/progenitor cell populations, a finding also suggestive of cellular reprograming. Taken together, the results reported here establish the critical importance of telomeres and telomerase in the radiation response and, as such, have compelling implications not only for accelerated tumor repopulation following radiation therapy but also for carcinogenic potential following low dose exposures as well, including those of relevance to spaceflight-associated galactic cosmic radiations.},
}
@article {pmid26633809,
year = {2015},
author = {Lee, JS and Jeong, SW and Cho, SW and Juhn, JP and Kim, KW},
title = {Relationship between Initial Telomere Length, Initial Telomerase Activity, Age, and Replicative Capacity of Nucleus Pulposus Chondrocytes in Human Intervertebral Discs: What Is a Predictor of Replicative Potential?.},
journal = {PloS one},
volume = {10},
number = {12},
pages = {e0144177},
pmid = {26633809},
issn = {1932-6203},
mesh = {Adult ; Aged ; Cell Division ; Chondrocytes/cytology/*metabolism ; Female ; Humans ; Intervertebral Disc/cytology/*metabolism ; Male ; Middle Aged ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {There is evidence that telomere length (TL), telomerase activity (TA), and age are related to the replicative potential of human nucleus pulposus chondrocytes (NPCs). However, it has not yet been established if any of these factors can serve as predictors of the replicative potential of NPCs. To establish predictors of the replicative potential of NPCs, we evaluated potential relationships between replicative capacity of NPCs, initial TL (telomere length at the first passage), initial TA (telomerase activity at the first passage), and age. Nucleus pulposus specimens were obtained from 14 patients of various ages undergoing discectomy. NPCs were serially cultivated until the end of their replicative lifespans. Relationships among cumulative population doubling level (PDL), initial TL, initial TA, and age were analyzed. Initial TA was negatively correlated with age (r = -0.674, P = 0.008). However, no correlation between initial TL and age was observed. Cumulative PDL was also negatively correlated with age (r = -0.585, P = 0.028). Although the cumulative PDL appeared to increase with initial TL or initial TA, this trend was not statistically significant. In conclusion, age is the sole predictor of the replicative potential of human NPCs, and replicative potential decreases with age. Initial TL and initial TA are not predictors of replicative potential, and can serve only as reference values.},
}
@article {pmid26633142,
year = {2016},
author = {Wojcicki, JM and Olveda, R and Heyman, MB and Elwan, D and Lin, J and Blackburn, E and Epel, E},
title = {Cord blood telomere length in Latino infants: relation with maternal education and infant sex.},
journal = {Journal of perinatology : official journal of the California Perinatal Association},
volume = {36},
number = {3},
pages = {235-241},
pmid = {26633142},
issn = {1476-5543},
support = {K01 DK080825/DK/NIDDK NIH HHS/United States ; 097458//PHS HHS/United States ; NIDDK 080825//PHS HHS/United States ; R25MD006832/MD/NIMHD NIH HHS/United States ; },
mesh = {*Birth Weight ; Female ; *Fetal Blood ; Hispanic or Latino ; Humans ; Infant ; Infant, Newborn ; Linear Models ; Male ; Mothers/*education ; Multivariate Analysis ; Pregnancy ; *Sex Factors ; Telomere/*ultrastructure ; *Telomere Shortening ; United States ; },
abstract = {OBJECTIVE: Telomere length (TL) has important consequences for early disease and lifelong health. However, few studies have examined determinants of TL at birth.<br><br>STUDY DESIGN: Here we test associations between cord blood TL and parental and birth factors associated with exposure to stress and indicative of healthy intrauterine life in Latino infants. We tested associations that were significant in bivariate analysis in a multivariate regression model to identify independent predictors for shorter TL at birth.<br><br>RESULT: Two novel and independent predictors emerged in our analysis of 54 infants. Female gender was associated with longer TL by ~350 base pairs (adjusted &#x3b2;-coefficient for male gender=-369.57, (95% confidence interval, -718.21 to (-)20.92), P=0.02); rho=-0.26, P=0.057). Increased maternal high-school education, as indicated by a high-school diploma or additional education beyond high school, was also associated with longer TL, by ~500 base pairs (adjusted &#x3b2;-coefficient for high-school diploma or greater=505.68 (95% confidence interval, 151.69 to 859.68), P<0.01); rho=0.36, P<0.01). Increasing head circumference trended towards statistical significance in association with longer TL (adjusted &#x3b2;-coefficient = 7.33; 95% confidence interval -0.52 to 15.18; P=0.07). When we removed all infants who had been exposed to high oxidative stress in pregnancy including those exposed to maternal hypertension, preeclampsia, gestational diabetes, and those who were low birth weight or preterm birth (n=7), increasing birth weight percentile was associated with longer TL (adjusted &#x3b2;-coefficient=8.04 (95% confidence interval 0.07 to 16.00), P=0.048).<br><br>CONCLUSION: Shorter TL at birth is associated with being male, low maternal education (less than a high school degree), and a trend towards lower birth weight and head circumference. Given the critical role of long TL in predicting health and disease, these findings contribute to the growing literature attempting to understand determinants of TL.},
}
@article {pmid26631569,
year = {2015},
author = {Ringsby, TH and Jensen, H and Pärn, H and Kvalnes, T and Boner, W and Gillespie, R and Holand, H and Hagen, IJ and Rønning, B and Sæther, BE and Monaghan, P},
title = {On being the right size: increased body size is associated with reduced telomere length under natural conditions.},
journal = {Proceedings. Biological sciences},
volume = {282},
number = {1820},
pages = {20152331},
pmid = {26631569},
issn = {1471-2954},
support = {268926/ERC_/European Research Council/International ; },
mesh = {Animals ; Body Size/*genetics ; Male ; Selection, Genetic ; Sparrows/*genetics ; *Telomere ; },
abstract = {Evolution of body size is likely to involve trade-offs between body size, growth rate and longevity. Within species, larger body size is associated with faster growth and ageing, and reduced longevity, but the cellular processes driving these relationships are poorly understood. One mechanism that might play a key role in determining optimal body size is the relationship between body size and telomere dynamics. However, we know little about how telomere length is affected when selection for larger size is imposed in natural populations. We report here on the relationship between structural body size and telomere length in wild house sparrows at the beginning and end of a selection regime for larger parent size that was imposed for 4 years in an isolated population of house sparrows. A negative relationship between fledgling size and telomere length was present at the start of the selection; this was extended when fledgling size increased under the selection regime, demonstrating a persistent covariance between structural size and telomere length. Changes in telomere dynamics, either as a correlated trait or a consequence of larger size, could reduce potential longevity and the consequent trade-offs could thereby play an important role in the evolution of optimal body size.},
}
@article {pmid26630493,
year = {2015},
author = {Saßenroth, D and Meyer, A and Salewsky, B and Kroh, M and Norman, K and Steinhagen-Thiessen, E and Demuth, I},
title = {Sports and Exercise at Different Ages and Leukocyte Telomere Length in Later Life--Data from the Berlin Aging Study II (BASE-II).},
journal = {PloS one},
volume = {10},
number = {12},
pages = {e0142131},
pmid = {26630493},
issn = {1932-6203},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Aging/*physiology ; Berlin ; Cohort Studies ; Exercise/*physiology ; Female ; Humans ; Leukocytes/*physiology ; Male ; Middle Aged ; Polymerase Chain Reaction ; *Sports ; Surveys and Questionnaires ; Telomere Homeostasis/*genetics ; Time Factors ; Young Adult ; },
abstract = {Physical activity and sports have repeatedly been reported to be associated with telomere length. We studied the association of different types of sports across different stages of life on relative leukocyte telomere length (rLTL) in advanced age.815 participants (397 men) from the Berlin Aging Study II aged over 61 years were included in the analysis. rLTL was measured by real time PCR and physical activity was determined retrospectively by questionnaire, assessing type and duration of sports in the past as well as currently. Five separate multiple linear regression models adjusted for various control variables were performed. 67.3% of participants exercised currently, whereas 19.4% performed sports only between the age of 20 and 30. rLTL was higher in subjects who stated to exercise currently (N = 456), and in subjects who engaged in endurance (N = 138) or intensive activity sports (N = 32). Current physical activity was positively associated with rLTL in the risk factor adjusted regression model (β = 0.26, p < 0.001) and practicing sports for a minimum of 10 years preceding the assessment had a significant effect on rLTL (β = 0.39, p = 0.011). The highest impact was seen for intensive activity sports (β = 0.79, p < 0.001) and physical activity since at least 42 years (β = 0.47, p = 0.001). However, physical activity only between 20 and 30 years of age did not affect rLTL in old age when compared to no sports at all (β = -0.16, p = 0.21). Physical activity is clearly associated with longer rLTL. The effect is seen with longer periods of physical activity (at least 10 years), with intensive sports activities having the greatest impact on rLTL. Our data suggest that regular physical activity for at least 10 years is necessary to achieve a sustained effect on rLTL.},
}
@article {pmid26629734,
year = {2015},
author = {Kalmbach, KH and Antunes, DM and Kohlrausch, F and Keefe, DL},
title = {Telomeres and Female Reproductive Aging.},
journal = {Seminars in reproductive medicine},
volume = {33},
number = {6},
pages = {389-395},
doi = {10.1055/s-0035-1567823},
pmid = {26629734},
issn = {1526-4564},
mesh = {Adult ; Age Factors ; Aging/*genetics/metabolism/pathology ; Animals ; Cellular Senescence/*genetics ; Female ; Fertility/genetics ; Humans ; Infertility, Female/genetics/metabolism/physiopathology/therapy ; Middle Aged ; Oocytes/*metabolism/pathology ; Pregnancy ; Reproduction/*genetics ; Reproductive Techniques, Assisted ; Telomere/*genetics/metabolism ; *Telomere Shortening ; Young Adult ; },
abstract = {Reproductive aging involves declines both in oocyte number and developmental capacity. Declining oocyte number alone cannot explain the manifestations of reproductive aging in women. We have proposed the Telomere Theory of Reproductive Aging to explain the complex phenotype found in oocytes from older women. Telomeres are TTAGGG repeats and associated proteins, which form loops at the ends of chromosomes to provide structural and genomic stability. Studies in mice and women show that telomere shortening in oocytes provides a parsimonious explanation for the effects of reproductive aging on oocyte quality. Measurement of polar body telomere length may predict oocyte quality in women undergoing ART.},
}
@article {pmid26629551,
year = {2015},
author = {Arai, Y and Martin-Ruiz, CM and Takayama, M and Abe, Y and Takebayashi, T and Koyasu, S and Suematsu, M and Hirose, N and von Zglinicki, T},
title = {Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians.},
journal = {EBioMedicine},
volume = {2},
number = {10},
pages = {1549-1558},
pmid = {26629551},
issn = {2352-3964},
support = {BB/I020748/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; G0601333/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*genetics/metabolism ; Biomarkers ; Cause of Death ; Cellular Senescence/genetics ; Female ; Humans ; Immunosenescence/genetics ; Inflammation/epidemiology/*genetics/metabolism/*mortality ; Kaplan-Meier Estimate ; Longevity/genetics ; Longitudinal Studies ; Male ; Morbidity ; Telomere/*genetics ; },
abstract = {To determine the most important drivers of successful ageing at extreme old age, we combined community-based prospective cohorts: Tokyo Oldest Old Survey on Total Health (TOOTH), Tokyo Centenarians Study (TCS) and Japanese Semi-Supercentenarians Study (JSS) comprising 1554 individuals including 684 centenarians and (semi-)supercentenarians, 167 pairs of centenarian offspring and spouses, and 536 community-living very old (85 to 99 years). We combined z scores from multiple biomarkers to describe haematopoiesis, inflammation, lipid and glucose metabolism, liver function, renal function, and cellular senescence domains. In Cox proportional hazard models, inflammation predicted all-cause mortality with hazard ratios (95% CI) 1.89 (1.21 to 2.95) and 1.36 (1.05 to 1.78) in the very old and (semi-)supercentenarians, respectively. In linear forward stepwise models, inflammation predicted capability (10.8% variance explained) and cognition (8(.)6% variance explained) in (semi-)supercentenarians better than chronologic age or gender. The inflammation score was also lower in centenarian offspring compared to age-matched controls with Δ (95% CI) = - 0.795 (- 1.436 to - 0.154). Centenarians and their offspring were able to maintain long telomeres, but telomere length was not a predictor of successful ageing in centenarians and semi-supercentenarians. We conclude that inflammation is an important malleable driver of ageing up to extreme old age in humans.},
}
@article {pmid26622642,
year = {2015},
author = {Lei, H and Feng, D and Zhou, F and Xu, H and Tang, T and Yu, H and Xie, C and Zhou, Y},
title = {Expression of human protection of telomere 1 correlates with telomere length and radiosensitivity in the human laryngeal cancer Hep-2 cell line.},
journal = {Oncology letters},
volume = {10},
number = {2},
pages = {1149-1154},
pmid = {26622642},
issn = {1792-1074},
abstract = {The close association between telomere length and radiosensitivity has been established by several studies. There is also a hypothesis that telomere length may be regulated by human protection of telomere 1 (hPOT1) in human carcinoma cells. In the present study, the hPOT1 level between the radioresistant Hep-2R cells and the wild-type were compared, and the results showed that the hPOT1 gene was upregulated in the radioresistant Hep-2R cell lines compared with the wild-type. This suggested that the expression level of hPOT1 correlates with radiosensitivity. Additionally, an hPOT1-directed short hairpin (sh)RNA plasmid was constructed and transferred into the Hep-2R cells, which lead to telomere shortening, an increase in apoptosis and markedly decreased growth of the RNAi-Hep-2R cell line. These results demonstrate that hPOT1-directed shRNAs are associated with telomere length and radiosensitivity, and maybe a potent sensitizer for laryngeal cancer radiotherapy.},
}
@article {pmid26621262,
year = {2017},
author = {Squassina, A and Pisanu, C and Corbett, N and Alda, M},
title = {Telomere length in bipolar disorder and lithium response.},
journal = {European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology},
volume = {27},
number = {6},
pages = {560-567},
doi = {10.1016/j.euroneuro.2015.10.008},
pmid = {26621262},
issn = {1873-7862},
support = {64410//CIHR/Canada ; },
mesh = {Bipolar Disorder/*blood/diagnosis/*drug therapy ; Humans ; Lithium/pharmacology/*therapeutic use ; Telomere/drug effects/physiology ; Telomere Homeostasis/*drug effects/*physiology ; Telomere Shortening/drug effects/physiology ; Treatment Outcome ; },
abstract = {Telomeres consist of exanucleotide tandem repeats and proteins complexes at the end of chromosome ends. Telomeres shorten at each cell division, and as such telomere length is a marker of cellular age. Accelerated telomere shortening and cell senescence have been associated with a number of chronic medical conditions, including psychiatric disorders, where increased prevalence of age-related disorders and shorter telomere length have been reported. Shorter telomeres in psychiatric patients are thought to be the consequence of allostatic load, consisting in the overactivation of allostatic systems due to chronic exposure to severe medical conditions and failure to adapt to chronic stressful stimuli. Most of the studies on telomere length in psychiatry have focused on major depressive disorder, but recent findings have shown shorter leukocyte telomere length in bipolar disorder patients and suggested that lithium may counteract telomeres shortening. These findings provided new insights into the pathophysiology of bipolar disorder and the mechanism of action of lithium. In this review we will present findings from the literature on telomere length in bipolar disorder, with a specific focus on lithium. We will also discuss advances and limitations of published work as well as methodological issues and potential confounding factors that should be taken into account when designing research protocols to study telomere length.},
}
@article {pmid26621152,
year = {2016},
author = {Sunpaweravong, P and Thu, KL and Lam, WL and Mai, S},
title = {Assessment of the clinical relevance of 17q25.3 copy number and three-dimensional telomere organization in non-small lung cancer patients.},
journal = {Journal of cancer research and clinical oncology},
volume = {142},
number = {4},
pages = {749-756},
pmid = {26621152},
issn = {1432-1335},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Adenocarcinoma/genetics ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Non-Small-Cell Lung/*genetics/pathology ; *Chromosomes, Human, Pair 17 ; Comparative Genomic Hybridization ; *DNA Copy Number Variations ; ErbB Receptors/*genetics ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Lung Neoplasms/*genetics/pathology ; Male ; Middle Aged ; Neoplasm Staging ; *Polymorphism, Single Nucleotide ; Smoking/*adverse effects ; Survival Analysis ; Telomere/genetics/*metabolism ; },
abstract = {PURPOSE: To identify potential biomarkers that may provide new therapeutic targets or prognostic indicators for non-small cell lung cancer (NSCLC), we investigated the three-dimensional (3D) organization of telomeres and cytoband 17q25.3 copy number in NSCLC tissues.<br><br>METHODS: NSCLC paraffin-embedded tissue specimens from 18 patients were assessed for 3D telomere organization by 3D nuclear telomere imaging followed by quantitative analysis. Patients were stratified by smoking, histology, and EGFR status. Cytoband 17q25.3 was examined by fluorescent in situ hybridization. Data from comparative genomic hybridization and/or single nucleotide polymorphism arrays for cytoband 17q25.3 were obtained and correlated with Q-FISH and 3D telomere results.<br><br>RESULTS: 3D telomeric profiling demonstrated that the smokers, EGFR-negative, and squamous cell carcinoma subgroups tended to have higher numbers of lower-intensity telomeres, indicative of shorter telomeres, as well as higher numbers of telomeric aggregations compared to non-smokers, EGFR-positive, and adenocarcinomas, respectively. Gains of cytoband 17q25.3 in conjunction with an increase in the control region 17p11.2 were observed in 7 of 18 (38.9 %) patients, reflecting a gain of chromosome 17. Clonal gains of cytoband 17q25.3 were observed in 11 of 18 (61 %) patients, highlighting a potential biological significance for the genes in this region in NSCLC tumourigenesis.<br><br>CONCLUSIONS: The 3D telomere profiles may differentiate NSCLC patients with different histologies, EGFR, and smoking statuses, rendering them a potential biomarker for distinguishing these clinically relevant histological and molecular subtypes of lung cancer. Highly frequent clonal gain of cytoband 17q25.3 was also demonstrated, suggesting an important biological role for the genes in this region.},
}
@article {pmid26619005,
year = {2015},
author = {Smeets, CC and Codd, V and Samani, NJ and Hokken-Koelega, AC},
title = {Leukocyte Telomere Length in Young Adults Born Preterm: Support for Accelerated Biological Ageing.},
journal = {PloS one},
volume = {10},
number = {11},
pages = {e0143951},
pmid = {26619005},
issn = {1932-6203},
support = {MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; /BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Adult ; Aging/*genetics ; Cardiovascular Diseases/*genetics ; Female ; Humans ; Infant, Newborn ; Infant, Premature ; Leukocytes/*cytology ; Male ; Telomere/*genetics ; Young Adult ; },
abstract = {BACKGROUND: Subjects born preterm have an increased risk for age-associated diseases, such as cardiovascular disease in later life, but the underlying causes are largely unknown. Shorter leukocyte telomere length (LTL), a marker of biological age, is associated with increased risk of cardiovascular disease.<br><br>OBJECTIVES: To compare LTL between subjects born preterm and at term and to assess if LTL is associated with other putative cardiovascular risk factors at young adult age.<br><br>METHODS: We measured mean LTL in 470 young adults. LTL was measured using a quantitative PCR assay and expressed as T/S ratio. We analyzed the influence of gestational age on LTL and compared LTL between subjects born preterm (n = 186) and at term (n = 284). Additionally, we analyzed the correlation between LTL and potential risk factors of cardiovascular disease.<br><br>RESULTS: Gestational age was positively associated with LTL (r = 0.11, p = 0.02). Subjects born preterm had shorter LTL (mean (SD) T/S ratio = 3.12 (0.44)) than subjects born at term (mean (SD) T/S ratio = 3.25 (0.46)), p = 0.003). The difference remained significant after adjustment for gender and size at birth (p = 0.001). There was no association of LTL with any one of the putative risk factors analyzed.<br><br>CONCLUSIONS: Young adults born preterm have shorter LTL than young adults born at term. Although we found no correlation between LTL and risk for CVD at this young adult age, this biological ageing indicator may contribute to CVD and other adult onset diseases at a later age in those born preterm.},
}
@article {pmid26616856,
year = {2016},
author = {Zhang, S and Matsunaga, S and Lin, YF and Sishc, B and Shang, Z and Sui, J and Shih, HY and Zhao, Y and Foreman, O and Story, MD and Chen, DJ and Chen, BP},
title = {Spontaneous tumor development in bone marrow-rescued DNA-PKcs(3A/3A) mice due to dysfunction of telomere leading strand deprotection.},
journal = {Oncogene},
volume = {35},
number = {30},
pages = {3909-3918},
pmid = {26616856},
issn = {1476-5594},
support = {R01 CA166677/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; *Bone Marrow Transplantation ; Cells, Cultured ; DNA Damage ; DNA-Activated Protein Kinase/*physiology ; DNA-Binding Proteins/*physiology ; Genomic Instability ; Histones/analysis ; Keratinocytes/metabolism ; Mice ; Neoplasms/*etiology ; Nuclear Proteins/*physiology ; Telomere/*physiology ; },
abstract = {Phosphorylation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) at the Thr2609 cluster is essential for its complete function in DNA repair and tissue stem cell homeostasis. This phenomenon is demonstrated by congenital bone marrow failure occurring in DNA-PKcs(3A/3A) mutant mice, which require bone marrow transplantation (BMT) to prevent early mortality. Surprisingly, an increased incidence of spontaneous tumors, especially skin cancer, was observed in adult BMT-rescued DNA-PKcs(3A/3A) mice. Upon further investigation, we found that spontaneous γH2AX foci occurred in DNA-PKcs(3A/3A) skin biopsies and primary keratinocytes and that these foci overlapped with telomeres during mitosis, indicating impairment of telomere replication and maturation. Consistently, we observed significantly elevated frequencies of telomere fusion events in DNA-PKcs(3A/3A) cells as compared with wild-type and DNA-PKcs-knockout cells. In addition, a previously identified DNA-PKcs Thr2609Pro mutation, found in breast cancer, also induces a similar impairment of telomere leading-end maturation. Taken together, our current analyses indicate that the functional DNA-PKcs T2609 cluster is required to facilitate telomere leading strand maturation and prevention of genomic instability and cancer development.},
}
@article {pmid26616852,
year = {2016},
author = {Zhang, J and Rane, G and Dai, X and Shanmugam, MK and Arfuso, F and Samy, RP and Lai, MK and Kappei, D and Kumar, AP and Sethi, G},
title = {Ageing and the telomere connection: An intimate relationship with inflammation.},
journal = {Ageing research reviews},
volume = {25},
number = {},
pages = {55-69},
doi = {10.1016/j.arr.2015.11.006},
pmid = {26616852},
issn = {1872-9649},
mesh = {Aging/*genetics/*pathology ; Animals ; Humans ; Inflammation/*genetics/*pathology ; Telomere/metabolism/*pathology ; },
abstract = {Telomeres are the heterochromatic repeat regions at the ends of eukaryotic chromosomes, whose length is considered to be a determinant of biological ageing. Normal ageing itself is associated with telomere shortening. Here, critically short telomeres trigger senescence and eventually cell death. This shortening rate may be further increased by inflammation and oxidative stress and thus affect the ageing process. Apart from shortened or dysfunctional telomeres, cells undergoing senescence are also associated with hyperactivity of the transcription factor NF-κB and overexpression of inflammatory cytokines such as TNF-α, IL-6, and IFN-γ in circulating macrophages. Interestingly, telomerase, a reverse transcriptase that elongates telomeres, is involved in modulating NF-κB activity. Furthermore, inflammation and oxidative stress are implicated as pre-disease mechanisms for chronic diseases of ageing such as neurodegenerative diseases, cardiovascular disease, and cancer. To date, inflammation and telomere shortening have mostly been studied individually in terms of ageing and the associated disease phenotype. However, the interdependent nature of the two demands a more synergistic approach in understanding the ageing process itself and for developing new therapeutic approaches. In this review, we aim to summarize the intricate association between the various inflammatory molecules and telomeres that together contribute to the ageing process and related diseases.},
}
@article {pmid26615915,
year = {2016},
author = {Babushok, DV and Grignon, AL and Li, Y and Atienza, J and Xie, HM and Lam, HS and Hartung, H and Bessler, M and Olson, TS},
title = {Disrupted lymphocyte homeostasis in hepatitis-associated acquired aplastic anemia is associated with short telomeres.},
journal = {American journal of hematology},
volume = {91},
number = {2},
pages = {243-247},
pmid = {26615915},
issn = {1096-8652},
support = {R24DK103001/DK/NIDDK NIH HHS/United States ; R01 HL097064/HL/NHLBI NIH HHS/United States ; K08 HL122306/HL/NHLBI NIH HHS/United States ; R01 CA105312/CA/NCI NIH HHS/United States ; P30 CA016520/CA/NCI NIH HHS/United States ; K12 HL087064/HL/NHLBI NIH HHS/United States ; K12 HL097064/HL/NHLBI NIH HHS/United States ; R24 DK103001/DK/NIDDK NIH HHS/United States ; },
mesh = {Adolescent ; Anemia, Aplastic/*blood/complications/genetics ; Child ; Child, Preschool ; Cytogenetic Analysis ; Female ; Flow Cytometry ; Hepatitis/*blood/complications/genetics ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; Lymphocyte Subsets/*ultrastructure ; Male ; Telomere Homeostasis/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Hepatitis-associated aplastic anemia (HAA) is a variant of acquired aplastic anemia (AA) in which immune-mediated bone marrow failure (BMF) develops following an acute episode of seronegative hepatitis. Dyskeratosis congenita (DC) is an inherited BMF syndrome characterized by the presence of short telomeres, mucocutaneous abnormalities, and cancer predisposition. While both conditions may cause BMF and hepatic impairment, therapeutic approaches are distinct, making it imperative to establish the correct diagnosis. In clinical practice, lymphocyte telomere lengths (TL) are used as a first-line screen to rule out inherited telomeropathies before initiating treatment for AA. To evaluate the reliability of TL in the HAA population, we performed a retrospective analysis of TL in 10 consecutively enrolled HAA patients compared to 19 patients with idiopathic AA (IAA). HAA patients had significantly shorter telomeres than IAA patients (P = 0.009), including four patients with TL at or below the 1st percentile for age-matched controls. HAA patients had no clinical features of DC and did not carry disease-causing mutations in known genes associated with inherited telomere disorders. Instead, short TLs were significantly correlated with severe lymphopenia and skewed lymphocyte subsets, features characteristic of HAA. Our results indicate the importance of caution in the interpretation of TL measurements in HAA, because, in this patient population, short telomeres have limited specificity.},
}
@article {pmid26615626,
year = {2015},
author = {Akasheva, DU and Plokhova, EV and Tkacheva, ON and Strazhesko, ID and Kruglikova, AS and Pykhtina, VS and Dudinskaya, EN and Skvortsov, DA and Egshatyan, LV and Brailova, NV and Agaltsov, MV and Ozerova, IN and Vygodin, VA and Boytsov, SA},
title = {[Age-related Changes of Left Ventricular Diastolic Function, NT-proBNP Level and Their Association With Leukocyte Telomere Length].},
journal = {Kardiologiia},
volume = {55},
number = {5},
pages = {59-65},
pmid = {26615626},
issn = {0022-9040},
mesh = {Adult ; Aged ; Aging/*physiology ; Diastole ; Female ; Humans ; Leukocytes/*physiology ; Male ; Middle Aged ; Natriuretic Peptide, Brain/*blood ; Peptide Fragments/*blood ; Telomere/*physiology ; Ventricular Function, Left/*physiology ; },
abstract = {UNLABELLED: With advancing age the left ventricle (LV) undergoes structural and functional changes, thereby creating the substrate for the development of diseases. One possible mechanism of the ageing of the heart is cellular senescence. Leukocyte telomere length (LTL) is a marker of replicative ageing. The purpose of this study was to evaluate the diastolic function of LV and level of NT-proBNP in people of different ages free of cardiovascular diseases and to assess their relationship with LTL. Our data showed that old age is associated with diastolic dysfunction and increase in the levels of NT-proBNP. The group of older subjects had lower values of E/A (0.96 ± 0.036 vs 1.27 ± 0.03, p < 0.001), Em/Am (0.9 ± 0.035 vs 1.5 ± 0.066) and higher values of IVRT (81 ± 1.56 vs 70 ± 1.23 MS, p < 0.001), DT (198 ± 3.98 vs 175 ± 2.82 MS, p < 0.001), that reflected impairment of LV relaxation. NT-proBNP level was higher in the elderly (100.82 ± 7.1 vs 48.47 ± 6.7 ωg/ml, p < 0.01), but it did not correlate with LTL. The most sensitive to the age parameters of LV diastolic function (E/A and Em/Am ratio) were positively and independently of age associated with LTL (p < 0.001). Older individuals with shorter LTL had significantly lower values of E/A ratio.<br><br>CONCLUSION: Telomere length appears to be a biomarker of myocardium ageing.},
}
@article {pmid26611732,
year = {2016},
author = {Workalemahu, T and Enquobahrie, DA and Yohannes, E and Sanchez, SE and Gelaye, B and Qiu, C and Williams, MA},
title = {Placental telomere length and risk of placental abruption.},
journal = {The journal of maternal-fetal &amp; neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians},
volume = {29},
number = {17},
pages = {2767-2772},
pmid = {26611732},
issn = {1476-4954},
support = {F32 HL010374/HL/NHLBI NIH HHS/United States ; P30 CA016056/CA/NCI NIH HHS/United States ; R01 HD059827/HD/NICHD NIH HHS/United States ; T32 HD052462/HD/NICHD NIH HHS/United States ; },
mesh = {Abruptio Placentae/*etiology ; Adult ; Case-Control Studies ; DNA, Mitochondrial/*chemistry ; Female ; Gene Dosage ; Humans ; Placenta/chemistry ; Pregnancy ; *Telomere Homeostasis ; Young Adult ; },
abstract = {OBJECTIVE: To investigate the associations of placental telomere length with placental abruption (PA) risk and interactions between placental telomere length and placental mitochondrial DNA (mtDNA) copy number on PA risk.<br><br>MATERIALS AND METHODS: Relative telomere length and mtDNA copy number in placental samples collected from 105 cases and 73 controls were measured in two batches using qRT-PCR. Mean differences in relative telomere length between PA cases and controls were examined. After creating batch-specific median cutoffs for relative telomere length (84.92 and 102.53) and mtDNA copy number (2.32 and 1.42), interaction between the two variables was examined using stratified logistic regression models.<br><br>RESULTS: Adjusted mean difference in relative telomere length between PA cases and controls was -0.07 (p&#x2009;>&#x2009;0.05). Among participants with low mtDNA copy number, participants with short relative telomere length had a 3.07-fold higher odds (95% CI: 1.13-8.38) of PA as compared with participants with long relative telomere length (the reference group). Among participants with high mtDNA copy number, participants with short relative telomere length had a 0.71-fold lower odds (95% CI: 0.28-1.83) of PA as compared with the reference group (interaction p values&#x2009;=&#x2009;0.03).<br><br>CONCLUSION: Findings suggest complex relationships between placental telomere length, mtDNA copy number and PA risk which warrant further larger studies.},
}
@article {pmid26608986,
year = {2015},
author = {Chang, HB and Zou, JZ and He, C and Zeng, R and Li, YY and Ma, FF and Liu, Z and Ye, H and Wu, JX},
title = {Association between Long Interspersed Nuclear Element-1 Methylation and Relative Telomere Length in Wilms Tumor.},
journal = {Chinese medical journal},
volume = {128},
number = {22},
pages = {3055-3061},
pmid = {26608986},
issn = {2542-5641},
mesh = {Cell Line, Tumor ; Child ; Child, Preschool ; DNA Methylation/genetics ; Female ; Humans ; Long Interspersed Nucleotide Elements/*genetics ; Male ; Polymerase Chain Reaction ; Telomere/*genetics ; Wilms Tumor/*genetics ; },
abstract = {BACKGROUND: DNA hypomethylation of long interspersed nuclear elements-1 (LINEs-1) occurs during carcinogenesis, whereas information addressing LINE-1 methylation in Wilms tumor (WT) is limited. The main purpose of our study was to quantify LINE-1 methylation levels and evaluate their relationship with relative telomere length (TL) in WT.<br><br>METHODS: We investigated LINE-1 methylation and relative TL using bisulfite-polymerase chain reaction (PCR) pyrosequencing and quantitative PCR, respectively, in 20 WT tissues, 10 normal kidney tissues and a WT cell line. Significant changes were analyzed by t-tests.<br><br>RESULTS: LINE-1 methylation levels were significantly lower (P < 0.05) and relative TLs were significantly shorter (P < 0.05) in WT compared with normal kidney. There was a significant positive relationship between LINE-1 methylation and relative TL in WT (r = 0.671, P = 0.001). LINE-1 Methylation levels were significantly associated with global DNA methylation (r = 0.332, P < 0.01). In addition, relative TL was shortened and LINE-1 methylation was decreased in a WT cell line treated with the hypomethylating agent 5-aza-2'-deoxycytidine compared with untreated WT cell line.<br><br>CONCLUSION: These results suggest that LINE-1 hypomethylation is common and may be linked to telomere shortening in WT.},
}
@article {pmid26607038,
year = {2016},
author = {Laimer, M and Melmer, A and Lamina, C and Raschenberger, J and Adamovski, P and Engl, J and Ress, C and Tschoner, A and Gelsinger, C and Mair, L and Kiechl, S and Willeit, J and Willeit, P and Stettler, C and Tilg, H and Kronenberg, F and Ebenbichler, C},
title = {Telomere length increase after weight loss induced by bariatric surgery: results from a 10 year prospective study.},
journal = {International journal of obesity (2005)},
volume = {40},
number = {5},
pages = {773-778},
pmid = {26607038},
issn = {1476-5497},
support = {KLI 348/FWF_/Austrian Science Fund FWF/Austria ; P 26673/FWF_/Austrian Science Fund FWF/Austria ; },
mesh = {Adult ; Aged ; Austria ; *Bariatric Surgery ; Body Mass Index ; Comorbidity ; Female ; Humans ; Lipoproteins, HDL/*metabolism ; Male ; Middle Aged ; Obesity, Morbid/*surgery ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; Telomere/*physiology ; Telomere Shortening/*physiology ; Time Factors ; Weight Loss/*physiology ; },
abstract = {BACKGROUND/OBJECTIVES: Obesity contributes to telomere attrition. Studies focusing on short-term effects of weight loss have been unable to identify protection of telomere length. This study investigates long-term effects of pronounced weight loss induced by bariatric surgery on telomere length.<br><br>SUBJECTS/METHODS: One hundred forty-two patients were recruited in a prospective, controlled intervention study, follow-up investigations were done after 10.46&#xb1;1.48 years. A control group of normal weight participants was recruited and followed from 1995 to 2005 in the Bruneck Study. A total of 110 participants from each study was matched by age and sex to compare changes in telomere length. Quantitative PCR was used to determine telomere length.<br><br>RESULTS: Telomere length increased significantly by 0.024&#xb1;0.14 (P=0.047) in 142 bariatric patients within 10 years after surgery. The increase was different from telomere attrition in an age- and sex-matched cohort population of the Bruneck Study (-0.057&#xb1;0.18; &#x3b2;=0.08; P=0.003). Significant changes in telomere length disappeared after adjusting for baseline body mass index (BMI) because of general differences in BMI and telomere length between the two study populations (&#x3b2;=0.07; P=0.06). Age was proportional to telomere length in matched bariatric patients (r=0.188; P=0.049) but inversely correlated with telomere length in participants of the Bruneck Study (r=-0.197; P=0.039). There was no association between percent BMI/excess weight loss and telomere attrition in bariatric patients. Baseline telomere length in bariatric patients was inversely associated with baseline plasma cholesterol and triglyceride concentrations. Telomere shortening was associated with lower high-density lipoprotein cholesterol and higher fasting glucose concentration at baseline in bariatric patients.<br><br>CONCLUSIONS: Increases in relative telomere length were found after bariatric surgery in the long term, presumably due to amelioration of metabolic traits. This may overrule the influence of age and baseline telomere length and facilitate telomere protection in patients experiencing pronounced weight loss.},
}
@article {pmid26603336,
year = {2015},
author = {Ramin, C and Wang, W and Prescott, J and Rosner, B and Simon, NM and De Vivo, I and Okereke, OI},
title = {A prospective study of leukocyte telomere length and risk of phobic anxiety among women.},
journal = {Psychiatry research},
volume = {230},
number = {2},
pages = {545-552},
pmid = {26603336},
issn = {1872-7123},
support = {R03 CA139586/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA163451/CA/NCI NIH HHS/United States ; R01 AR059073/AR/NIAMS NIH HHS/United States ; R01 CA49449/CA/NCI NIH HHS/United States ; R01 CA065725/CA/NCI NIH HHS/United States ; R01 CA082838/CA/NCI NIH HHS/United States ; P01 CA87969/CA/NCI NIH HHS/United States ; R01 HL034594/HL/NHLBI NIH HHS/United States ; R01 MH096776/MH/NIMH NIH HHS/United States ; R03 CA132190/CA/NCI NIH HHS/United States ; K07 CA140790/CA/NCI NIH HHS/United States ; R01 HL088521/HL/NHLBI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; U01 CA049449/CA/NCI NIH HHS/United States ; R03 CA1321905/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Biomarkers/metabolism ; Female ; Humans ; Leukocytes/*metabolism ; Middle Aged ; Models, Statistical ; Phobic Disorders/epidemiology/*metabolism ; Prospective Studies ; Risk ; Telomere/*metabolism ; United States ; },
abstract = {We prospectively examined the relation of relative telomere lengths (RTLs), a marker of biological aging, to phobic anxiety in later-life. RTLs in peripheral blood leukocytes were measured among 3194 women in the Nurses' Health Study who provided blood samples in 1989/90. The Crown-Crisp Phobic Index (CCI, range=0–16) was assessed in 1988 and 2004. Only participants with CCI≤3 (consistent with no meaningful anxiety symptoms) in 1988 were included. We related baseline RTLs to odds ratios (ORs) of incident high phobic anxiety symptoms (CCI≥6). To enhance clinical relevance, we used finite mixture modeling (FMM) to relate baseline RTLs to latent classes of CCI in 2004. RTLs were not significantly associated with high phobic anxiety symptoms after 16 years of follow-up. However, FMM identified 3 groups of phobic symptoms in later-life: severe, minimal/intermediate, and non-anxious. The severe group had non-significantly shorter multivariable-adjusted mean RTLs than the minimal/intermediate and non-anxious groups. Women with shorter telomeres vs. longest telomeres had non-significantly higher likelihood of being in the severe vs. non-anxious group. Overall, there was no significant association between RTLs and incident phobic anxiety symptoms. Further work is required to explore potential connections of telomere length and emergence of severe phobic anxiety symptoms during later-life.},
}
@article {pmid26602606,
year = {2016},
author = {Walker, AE and Morgan, RG and Ives, SJ and Cawthon, RM and Andtbacka, RH and Noyes, D and Lesniewski, LA and Richardson, RS and Donato, AJ},
title = {Age-related arterial telomere uncapping and senescence is greater in women compared with men.},
journal = {Experimental gerontology},
volume = {73},
number = {},
pages = {65-71},
pmid = {26602606},
issn = {1873-6815},
support = {AG043952/AG/NIA NIH HHS/United States ; K01 AG046326/AG/NIA NIH HHS/United States ; T32 ES007032/ES/NIEHS NIH HHS/United States ; K02 AG045339/AG/NIA NIH HHS/United States ; AG040297/AG/NIA NIH HHS/United States ; I01 BX002151/BX/BLRD VA/United States ; AG046326/AG/NIA NIH HHS/United States ; HL091830/HL/NHLBI NIH HHS/United States ; R21 AG043952/AG/NIA NIH HHS/United States ; ES007032/ES/NIEHS NIH HHS/United States ; R01 AG050238/AG/NIA NIH HHS/United States ; P01 HL091830/HL/NHLBI NIH HHS/United States ; R01 AG040297/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*genetics/physiology ; Arteries/physiopathology/*ultrastructure ; Blood Glucose/metabolism ; Female ; Histones/metabolism ; Humans ; Male ; Middle Aged ; Phosphorylation ; Postmenopause/genetics/physiology ; Premenopause/genetics/physiology ; *Sex Characteristics ; Telomerase/metabolism ; Telomere/metabolism/*physiology ; Telomere Shortening/physiology ; Young Adult ; },
abstract = {Telomere uncapping increases with advancing age in human arteries and this telomere uncapping is associated with increased markers of senescence, independent of mean telomere length. However, whether there are sex specific differences in arterial telomere uncapping is unknown. We found that telomere uncapping (serine 139 phosphorylated histone γ-H2A.X in telomeres) in arteries was ~2.5 fold greater in post-menopausal women (n=17, 63±2 years) compared with pre-menopausal women (n=11, 30±2 years, p=0.02), while there was only a trend towards greater telomere uncapping in older men (n=26, 66±2 years) compared with young men (n=11, 31±2, p=0.11). Senescence markers, p53 bound to the p21 gene promoter and p21 gene expression, were 3-4 fold greater in post-menopausal compared with pre-menopausal women (p=0.01-0.02), but only 1.5-2 fold greater in older compared with young men (p=0.02-0.08). Blood glucose was related to telomere uncapping in women, while systolic blood pressure, pulse pressure and serum creatinine were related to telomere uncapping in men. Mean arterial telomere length decreased similarly in women and men with age (p<0.01). Thus, the age-related increase in arterial telomere uncapping and senescence is greater in women than men, despite similar age-related reductions in mean telomere length in both sexes.},
}
@article {pmid26597966,
year = {2016},
author = {Schrumpfová, PP and Vychodilová, I and Hapala, J and Schořová, &#x160; and Dvořáček, V and Fajkus, J},
title = {Telomere binding protein TRB1 is associated with promoters of translation machinery genes in vivo.},
journal = {Plant molecular biology},
volume = {90},
number = {1-2},
pages = {189-206},
pmid = {26597966},
issn = {1573-5028},
mesh = {Arabidopsis/*genetics/metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Base Sequence ; Computational Biology ; Gene Library ; Histones/metabolism ; Molecular Sequence Data ; Nucleotide Motifs ; Oligonucleotide Array Sequence Analysis ; Promoter Regions, Genetic/genetics ; Protein Binding ; Protein Biosynthesis ; Ribosomes/genetics ; Sequence Analysis, DNA ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Recently we characterised TRB1, a protein from a single-myb-histone family, as a structural and functional component of telomeres in Arabidopsis thaliana. TRB proteins, besides their ability to bind specifically to telomeric DNA using their N-terminally positioned myb-like domain of the same type as in human shelterin proteins TRF1 or TRF2, also possess a histone-like domain which is involved in protein-protein interactions e.g., with POT1b. Here we set out to investigate the genome-wide localization pattern of TRB1 to reveal its preferential sites of binding to chromatin in vivo and its potential functional roles in the genome-wide context. Our results demonstrate that TRB1 is preferentially associated with promoter regions of genes involved in ribosome biogenesis, in addition to its roles at telomeres. This preference coincides with the frequent occurrence of telobox motifs in the upstream regions of genes in this category, but it is not restricted to the presence of a telobox. We conclude that TRB1 shows a specific genome-wide distribution pattern which suggests its role in regulation of genes involved in biogenesis of the translational machinery, in addition to its preferential telomeric localization.},
}
@article {pmid26596989,
year = {2016},
author = {Fulnečková, J and Ševčíková, T and Lukešová, A and Sýkorová, E},
title = {Transitions between the Arabidopsis-type and the human-type telomere sequence in green algae (clade Caudivolvoxa, Chlamydomonadales).},
journal = {Chromosoma},
volume = {125},
number = {3},
pages = {437-451},
pmid = {26596989},
issn = {1432-0886},
mesh = {Amino Acid Motifs/*genetics ; Base Sequence ; DNA, Ribosomal/genetics ; Phylogeny ; RNA, Ribosomal, 18S/genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; Sequence Analysis, DNA ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Shortening/genetics ; Volvocida/*genetics ; },
abstract = {Telomeres are nucleoprotein structures that distinguish native chromosomal ends from double-stranded breaks. They are maintained by telomerase that adds short G-rich telomeric repeats at chromosomal ends in most eukaryotes and determines the TnAmGo sequence of canonical telomeres. We employed an experimental approach that was based on detection of repeats added by telomerase to identify the telomere sequence type forming the very ends of chromosomes. Our previous studies that focused on the algal order Chlamydomonadales revealed several changes in telomere motifs that were consistent with the phylogeny and supported the concept of the Arabidopsis-type sequence being the ancestral telomeric motif for green algae. In addition to previously described independent transitions to the Chlamydomonas-type sequence, we report that the ancestral telomeric motif was replaced by the human-type sequence in the majority of algal species grouped within a higher order clade, Caudivolvoxa. The Arabidopsis-type sequence was apparently retained in the Polytominia clade. Regarding the telomere sequence, the Chlorogonia clade within Caudivolvoxa bifurcates into two groups, one with the human-type sequence and the other group with the Arabidopsis-type sequence that is solely formed by the Chlorogonium species. This suggests that reversion to the Arabidopsis-type telomeric motif occurred in the common ancestral Chlorogonium species. The human-type sequence is also synthesized by telomerases of algal strains from Arenicolinia, Dunaliellinia and Stephanosphaerinia, except a distinct subclade within Stephanosphaerinia, where telomerase activity was not detected and a change to an unidentified telomeric motif might arise. We discuss plausible reasons why changes in telomeric motifs were tolerated during evolution of green algae.},
}
@article {pmid26596548,
year = {2015},
author = {Franzke, B and Neubauer, O and Wagner, KH},
title = {Super DNAging-New insights into DNA integrity, genome stability and telomeres in the oldest old.},
journal = {Mutation research. Reviews in mutation research},
volume = {766},
number = {},
pages = {48-57},
doi = {10.1016/j.mrrev.2015.08.001},
pmid = {26596548},
issn = {1388-2139},
mesh = {Aged, 80 and over ; Aging/*genetics ; DNA Damage/*genetics ; *Genomic Instability ; Humans ; Telomere/*genetics ; },
abstract = {Reductions in DNA integrity, genome stability, and telomere length are strongly associated with the aging process, age-related diseases as well as the age-related loss of muscle mass. However, in people reaching an age far beyond their statistical life expectancy the prevalence of diseases, such as cancer, cardiovascular disease, diabetes or dementia, is much lower compared to "averagely" aged humans. These inverse observations in nonagenarians (90-99 years), centenarians (100-109 years) and super-centenarians (110 years and older) require a closer look into dynamics underlying DNA damage within the oldest old of our society. Available data indicate improved DNA repair and antioxidant defense mechanisms in "super old" humans, which are comparable with much younger cohorts. Partly as a result of these enhanced endogenous repair and protective mechanisms, the oldest old humans appear to cope better with risk factors for DNA damage over their lifetime compared to subjects whose lifespan coincides with the statistical life expectancy. This model is supported by study results demonstrating superior chromosomal stability, telomere dynamics and DNA integrity in "successful agers". There is also compelling evidence suggesting that life-style related factors including regular physical activity, a well-balanced diet and minimized psycho-social stress can reduce DNA damage and improve chromosomal stability. The most conclusive picture that emerges from reviewing the literature is that reaching "super old" age appears to be primarily determined by hereditary/genetic factors, while a healthy lifestyle additionally contributes to achieving the individual maximum lifespan in humans. More research is required in this rapidly growing population of super old people. In particular, there is need for more comprehensive investigations including short- and long-term lifestyle interventions as well as investigations focusing on the mechanisms causing DNA damage, mutations, and telomere shortening.},
}
@article {pmid26593971,
year = {2016},
author = {Jenkins, EC and Ye, L and Krinsky-McHale, SJ and Zigman, WB and Schupf, N and Silverman, WP},
title = {Telomere longitudinal shortening as a biomarker for dementia status of adults with Down syndrome.},
journal = {American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics},
volume = {171B},
number = {2},
pages = {169-174},
doi = {10.1002/ajmg.b.32389},
pmid = {26593971},
issn = {1552-485X},
support = {P01-HD35897/HD/NICHD NIH HHS/United States ; P30-HD024061/HD/NICHD NIH HHS/United States ; R01-AG-14673/AG/NIA NIH HHS/United States ; R01-HD37425/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Biomarkers/metabolism ; Dementia/*complications/*genetics ; Down Syndrome/*complications/*genetics ; Female ; Humans ; Male ; Metaphase/genetics ; Middle Aged ; T-Lymphocytes/metabolism ; Telomere Shortening/*genetics ; },
abstract = {Previous studies have suggested that Alzheimer's disease (AD) causes an accelerated shortening of telomeres, the ends of chromosomes consisting of highly conserved TTAGGG repeats that, because of unidirectional 5'-3' DNA synthesis, lose end point material with each cell division. Our own previous work suggested that telomere length of T-lymphocytes might be a remarkably accurate biomarker for "mild cognitive impairment" in adults with Down syndrome (MCI-DS), a population at dramatically high risk for AD. To verify that the progression of cognitive and functional losses due to AD produced this observed telomere shortening, we have now examined sequential changes in telomere length in five individuals with Down syndrome (3F, 2M) as they transitioned from preclinical AD to MCI-DS (N = 4) or dementia (N = 1). As in our previous studies, we used PNA (peptide nucleic acid) probes for telomeres and the chromosome 2 centromere (as an "internal standard" expected to be unaffected by aging or dementia status), with samples from the same individuals now collected prior to and following development of MCI-DS or dementia. Consistent shortening of telomere length was observed over time. Further comparisons with our previous cross-sectional findings indicated that telomere lengths prior to clinical decline were similar to those of other adults with Down syndrome (DS) who have not experienced clinical decline while telomere lengths following transition to MCI-DS or dementia in the current study were comparable to those of other adults with DS who have developed MCI-DS or dementia. Taken together, findings indicate that telomere length has significant promise as a biomarker of clinical progression of AD for adults with DS, and further longitudinal studies of a larger sample of individuals with DS are clearly warranted to validate these findings and determine if and how factors affecting AD risk also influence these measures of telomere length.},
}
@article {pmid26590017,
year = {2015},
author = {Byun, MY and Cui, LH and Kim, WT},
title = {Suppression of OsKu80 results in defects in developmental growth and increased telomere length in rice (Oryza sativa L.).},
journal = {Biochemical and biophysical research communications},
volume = {468},
number = {4},
pages = {857-862},
doi = {10.1016/j.bbrc.2015.11.044},
pmid = {26590017},
issn = {1090-2104},
mesh = {Arabidopsis Proteins/*genetics ; DNA Helicases/*genetics ; Gene Expression Regulation, Developmental/*physiology ; Gene Expression Regulation, Plant/*physiology ; Genomic Instability/physiology ; Oryza/*genetics/*growth &amp; development ; Plants, Genetically Modified/physiology ; Telomere Homeostasis/*genetics ; },
abstract = {The Ku70-Ku80 heterodimer plays a critical role in the maintenance of genomic stability in humans and yeasts. In this report, we identified and characterized OsKu80 in rice, a model monocot crop. OsKu80 forms a heterodimer with OsKu70 in yeast and plant cells, as demonstrated by yeast two-hybrid, in vivo co-immunoprecipitation, and bimolecular fluorescence complementation assays. RNAi-mediated knock-down T3 transgenic rice plants (Ubi:RNAi-OsKu80) displayed a retarded growth phenotype at the post-germination stage. In addition, the Ubi:RNAi-OsKu80 knock-down progeny exhibited noticeably increased telomere length as compared to wild-type rice. These results are discussed with the idea that OsKu80 plays a role in developmental growth and telomere length regulation in rice plants.},
}
@article {pmid26586905,
year = {2016},
author = {Denham, J and O'Brien, BJ and Prestes, PR and Brown, NJ and Charchar, FJ},
title = {Increased expression of telomere-regulating genes in endurance athletes with long leukocyte telomeres.},
journal = {Journal of applied physiology (Bethesda, Md. : 1985)},
volume = {120},
number = {2},
pages = {148-158},
doi = {10.1152/japplphysiol.00587.2015},
pmid = {26586905},
issn = {1522-1601},
mesh = {Adult ; Aging/genetics ; Athletes ; Exercise/*physiology ; Female ; Gene Expression/*genetics ; Humans ; Leukocytes/*metabolism ; Male ; Physical Endurance/*genetics/physiology ; RNA, Messenger/genetics ; Running/physiology ; Shelterin Complex/*genetics ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics ; Up-Regulation/genetics ; },
abstract = {Leukocyte telomeres shorten with age, and excessive shortening is associated with age-related cardiometabolic diseases. Exercise training may prevent disease through telomere length maintenance although the optimal amount of exercise that attenuates telomere attrition is unknown. Furthermore, the underlying molecular mechanisms responsible for the enhanced telomere maintenance observed in endurance athletes is poorly understood. We quantified the leukocyte telomere length and analyzed the expression of telomere-regulating genes in endurance athletes and healthy controls (both n = 61), using quantitative PCR. We found endurance athletes have significantly longer (7.1%, 208-416 nt) leukocyte telomeres and upregulated TERT (2.0-fold) and TPP1 (1.3-fold) mRNA expression compared with controls in age-adjusted analysis. The telomere length and telomere-regulating gene expression differences were no longer statistically significant after adjustment for resting heart rate and relative V̇O(2 max) (all P > 0.05). Resting heart rate emerged as an independent predictor of leukocyte telomere length and TERT and TPP1 mRNA expression in stepwise regression models. To gauge whether volume of exercise was associated with leukocyte telomere length, we divided subjects into running and cycling tertiles (distance covered per week) and found individuals in the middle and highest tertiles had longer telomeres than individuals in the lowest tertile. These data emphasize the importance of cardiorespiratory fitness and exercise training in the prevention of biological aging. They also support the concept that moderate amounts of exercise training protects against biological aging, while higher amounts may not elicit additional benefits.},
}
@article {pmid26586671,
year = {2016},
author = {Miranda-Furtado, CL and Ramos, FK and Kogure, GS and Santana-Lemos, BA and Ferriani, RA and Calado, RT and Dos Reis, RM},
title = {A Nonrandomized Trial of Progressive Resistance Training Intervention in Women With Polycystic Ovary Syndrome and Its Implications in Telomere Content.},
journal = {Reproductive sciences (Thousand Oaks, Calif.)},
volume = {23},
number = {5},
pages = {644-654},
doi = {10.1177/1933719115611753},
pmid = {26586671},
issn = {1933-7205},
mesh = {Adipose Tissue/physiology ; Adolescent ; Adult ; Blood Glucose/metabolism ; Female ; Humans ; Insulin Resistance/physiology ; Obesity/blood/diagnosis/therapy ; Polycystic Ovary Syndrome/*blood/diagnosis/*therapy ; Resistance Training/*methods ; Telomere/*physiology ; Waist Circumference/physiology ; Young Adult ; },
abstract = {BACKGROUND: Physical activity is known to relieve the metabolic complications of polycystic ovary syndrome (PCOS), and exercise is also associated with telomere biology. We investigated the changes induced by progressive resistance training (PRT) in telomere content and metabolic disorder in women with PCOS and controls.<br><br>PARTICIPANTS AND METHODS: Forty-five women with PCOS and 52 healthy women aged 18 to 37 years were submitted to PRT. A linear periodization of PRT was prepared based on a trend of decreasing volume and intensity throughout the training period. The volunteers performed PRT 3 times a week for 4 months. The participants' physical characteristics and hormonal concentrations were measured before and after PRT, as telomere content that was measured using quantitative real-time polymerase chain reaction.<br><br>RESULTS: Briefly, Progressive resistance training reduced waist circumference, body fat percentage, plasma testosterone and sex hormone-binding globulin concentrations, glycemia, and free androgen index. Fasting insulin and insulin resistance index were greater in women with PCOS. Androstenedione and homocysteine increased after PRT. There were no differences in telomere content between controls (0.96 &#xb1; 0.3 before vs 0.85 &#xb1; 0.21 after) and women with PCOS (0.94 &#xb1; 0.33 before vs 0.88 &#xb1; 0.39 after). Adjusted analysis showed telomere shortening after PRT in all women (0.95 &#xb1; 0.31 before vs 0.86 &#xb1; 0.31 after; P = .03). In women with PCOS, increased homocysteine levels were related to telomere reduction and increased androstenedione was positively correlated with telomere content after PRT.<br><br>CONCLUSIONS: Progressive resistance training had positive effects on the hormonal and physical characteristics of women with PCOS and controls, but telomere content was reduced and homocysteine level increased in all participants.},
}
@article {pmid26586433,
year = {2015},
author = {Tong, AS and Stern, JL and Sfeir, A and Kartawinata, M and de Lange, T and Zhu, XD and Bryan, TM},
title = {ATM and ATR Signaling Regulate the Recruitment of Human Telomerase to Telomeres.},
journal = {Cell reports},
volume = {13},
number = {8},
pages = {1633-1646},
pmid = {26586433},
issn = {2211-1247},
support = {R01 AG016642/AG/NIA NIH HHS/United States ; MOP-86620//Canadian Institutes of Health Research/Canada ; },
mesh = {Ataxia Telangiectasia Mutated Proteins/*metabolism ; Cell Cycle Proteins/metabolism ; Cell Line ; Cell Line, Tumor ; DNA Damage/genetics ; DNA Replication/genetics ; HEK293 Cells ; HeLa Cells ; Humans ; Phosphorylation/genetics ; Protein Kinases/metabolism ; Signal Transduction/genetics ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/genetics ; Yeasts/metabolism ; },
abstract = {The yeast homologs of the ATM and ATR DNA damage response kinases play key roles in telomerase-mediated telomere maintenance, but the role of ATM/ATR in the mammalian telomerase pathway has been less clear. Here, we demonstrate the requirement for ATM and ATR in the localization of telomerase to telomeres and telomere elongation in immortal human cells. Stalled replication forks increased telomerase recruitment in an ATR-dependent manner. Furthermore, increased telomerase recruitment was observed upon phosphorylation of the shelterin component TRF1 at an ATM/ATR target site (S367). This phosphorylation leads to loss of TRF1 from telomeres and may therefore increase replication fork stalling. ATM and ATR depletion reduced assembly of the telomerase complex, and ATM was required for telomere elongation in cells expressing POT1ΔOB, an allele of POT1 that disrupts telomere-length homeostasis. These data establish that human telomerase recruitment and telomere elongation are modulated by DNA-damage-transducing kinases.},
}
@article {pmid26586427,
year = {2015},
author = {Lee, SS and Bohrson, C and Pike, AM and Wheelan, SJ and Greider, CW},
title = {ATM Kinase Is Required for Telomere Elongation in Mouse and Human Cells.},
journal = {Cell reports},
volume = {13},
number = {8},
pages = {1623-1632},
pmid = {26586427},
issn = {2211-1247},
support = {T32 GM007814/GM/NIGMS NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; R01 CA160300/CA/NCI NIH HHS/United States ; R37 AG009383/AG/NIA NIH HHS/United States ; R37AG009383/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins/*metabolism ; Cell Cycle Proteins/metabolism ; Cell Line ; DNA-Binding Proteins/metabolism ; Humans ; Mice ; Poly(ADP-ribose) Polymerases/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {Short telomeres induce a DNA damage response, senescence, and apoptosis, thus maintaining telomere length equilibrium is essential for cell viability. Telomerase addition of telomere repeats is tightly regulated in cells. To probe pathways that regulate telomere addition, we developed the ADDIT assay to measure new telomere addition at a single telomere in vivo. Sequence analysis showed telomerase-specific addition of repeats onto a new telomere occurred in just 48 hr. Using the ADDIT assay, we found that ATM is required for addition of new repeats onto telomeres in mouse cells. Evaluation of bulk telomeres, in both human and mouse cells, showed that blocking ATM inhibited telomere elongation. Finally, the activation of ATM through the inhibition of PARP1 resulted in increased telomere elongation, supporting the central role of the ATM pathway in regulating telomere addition. Understanding this role of ATM may yield new areas for possible therapeutic intervention in telomere-mediated disease.},
}
@article {pmid26582527,
year = {2015},
author = {Liu, SY and Zhang, CJ and Peng, HY and Huang, XQ and Sun, H and Lin, KQ and Huang, K and Chu, JY and Yang, ZQ},
title = {[Association study of telomere length with idiopathic male infertility].},
journal = {Yi chuan = Hereditas},
volume = {37},
number = {11},
pages = {1137-1142},
doi = {10.16288/j.yczz.15-267},
pmid = {26582527},
issn = {0253-9772},
mesh = {Adult ; Humans ; Infertility, Male/*genetics ; Male ; Middle Aged ; Sperm Count ; Sperm Motility ; *Telomere ; },
abstract = {Telomeres are evolutionary conserved, multifunctional DNA-protein complexes located at the ends of eukaryotic chromosomes. Telomeres maintain chromosome stability and genome integrity and also play an important role in meiosis which aid in synapsis, homologous recombination, and segregation. Sperm telomere has been reported to play an important role in fertilization and embryo development. Nowadays, the association between telomere and reproduction is one of the major areas of interest, however whether sperm telomere associated with male infertility is not clear. In this study, in order to find out the association between Chinese idiopathic infertility and sperm telomere length, we analyzed the difference of sperm telomere length between idiopathic infertile men and normal fertile men, as well as the correlations between sperm telomere length and human semen characteristics. We analyzed 126 Chinese idiopathic infertile men and 138 normal fertile men for sperm telomere length by using quantitative PCR. We found that the relative sperm mean telomere length of infertile men was significantly shorter than that of fertile men (2.894 ± 0.115 vs. 4.016 ± 0.603, P=5.097 x 10[-5]). Both sperm count and semen progressive motility are related with telomere length. Our results suggest that sperm telomere length is associated with idiopathic male infertility of China and we proposed the possibility that shorter telomeres in sperm chromosome will reduce spermatogenesis and sperm functions, which finally affected the fertility of male.},
}
@article {pmid26581522,
year = {2015},
author = {Pickett, HA and Reddel, RR},
title = {Molecular mechanisms of activity and derepression of alternative lengthening of telomeres.},
journal = {Nature structural &amp; molecular biology},
volume = {22},
number = {11},
pages = {875-880},
pmid = {26581522},
issn = {1545-9985},
mesh = {DNA Helicases/metabolism ; Homologous Recombination ; Nuclear Proteins/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Alternative lengthening of telomeres (ALT) involves homology-directed telomere synthesis. This multistep process is facilitated by loss of the ATRX or DAXX chromatin-remodeling factors and by abnormalities of the telomere nucleoprotein architecture, including altered DNA sequence and decreased TRF2 saturation. Induction of telomere-specific DNA damage triggers homology-directed searches, and NuRD-ZNF827 protein-protein interactions provide a platform for the telomeric recruitment of homologous recombination (HR) proteins. Telomere lengthening proceeds by strand exchange and template-driven DNA synthesis, which culminates in dissolution of HR intermediates.},
}
@article {pmid26581521,
year = {2015},
author = {Sarek, G and Marzec, P and Margalef, P and Boulton, SJ},
title = {Molecular basis of telomere dysfunction in human genetic diseases.},
journal = {Nature structural &amp; molecular biology},
volume = {22},
number = {11},
pages = {867-874},
pmid = {26581521},
issn = {1545-9985},
support = {104558/WT_/Wellcome Trust/United Kingdom ; 11581/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Genetic Diseases, Inborn/*genetics ; Genetics, Medical ; Genomic Instability ; Humans ; Mutation ; Telomere/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/*genetics/*metabolism ; },
abstract = {Mutations in genes encoding proteins required for telomere structure, replication, repair and length maintenance are associated with several debilitating human genetic disorders. These complex telomere biology disorders (TBDs) give rise to critically short telomeres that affect the homeostasis of multiple organs. Furthermore, genome instability is often a hallmark of telomere syndromes, which are associated with increased cancer risk. Here, we summarize the molecular causes and cellular consequences of disease-causing mutations associated with telomere dysfunction.},
}
@article {pmid26581520,
year = {2015},
author = {Arnoult, N and Karlseder, J},
title = {Complex interactions between the DNA-damage response and mammalian telomeres.},
journal = {Nature structural &amp; molecular biology},
volume = {22},
number = {11},
pages = {859-866},
pmid = {26581520},
issn = {1545-9985},
support = {R01CA174942/CA/NCI NIH HHS/United States ; R01 CA174942/CA/NCI NIH HHS/United States ; R01GM087476/GM/NIGMS NIH HHS/United States ; P30CA014195/CA/NCI NIH HHS/United States ; R01 GM087476/GM/NIGMS NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; DNA/*metabolism ; DNA Repair Enzymes/*antagonists &amp; inhibitors ; DNA Replication ; Humans ; Mammals/*genetics ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Natural chromosome ends resemble double-stranded DNA breaks, but they do not activate a damage response in healthy cells. Telomeres therefore have evolved to solve the 'end-protection problem' by inhibiting multiple DNA damage-response pathways. During the past decade, the view of telomeres has progressed from simple caps that hide chromosome ends to complex machineries that have an active role in organizing the genome. Here we focus on mammalian telomeres and summarize and interpret recent discoveries in detail, focusing on how repair pathways are inhibited, how resection and replication are controlled and how these mechanisms govern cell fate during senescence, crisis and transformation.},
}
@article {pmid26581519,
year = {2015},
author = {Rippe, K and Luke, B},
title = {TERRA and the state of the telomere.},
journal = {Nature structural &amp; molecular biology},
volume = {22},
number = {11},
pages = {853-858},
pmid = {26581519},
issn = {1545-9985},
mesh = {Eukaryota/*physiology ; Models, Biological ; RNA, Untranslated/*metabolism ; Telomerase/*metabolism ; *Telomere Homeostasis ; },
abstract = {Long noncoding telomeric repeat-containing RNA (TERRA) has been implicated in telomere maintenance in a telomerase-dependent and a telomerase-independent manner during replicative senescence and cancer. TERRA's proposed activities are diverse, thus making it difficult to pinpoint the critical roles that TERRA may have. We propose that TERRA orchestrates different activities at chromosome ends in a manner that depends on the state of the telomere.},
}
@article {pmid26581518,
year = {2015},
author = {Hockemeyer, D and Collins, K},
title = {Control of telomerase action at human telomeres.},
journal = {Nature structural &amp; molecular biology},
volume = {22},
number = {11},
pages = {848-852},
pmid = {26581518},
issn = {1545-9985},
support = {R01 CA196884/CA/NCI NIH HHS/United States ; R01 HL079585/HL/NHLBI NIH HHS/United States ; HL0795985/HL/NHLBI NIH HHS/United States ; RCA196884A//PHS HHS/United States ; },
mesh = {DNA/*metabolism ; Humans ; Models, Biological ; Protein Binding ; Shelterin Complex ; Telomerase/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Recent progress has greatly increased the understanding of telomere-bound shelterin proteins and the telomerase holoenzyme, predominantly as separate complexes. Pioneering studies have begun to investigate the requirements for shelterin-telomerase interaction. From this vantage point, focusing on human cells, we review and discuss models for how telomerase and shelterin subunits coordinate to achieve balanced telomere-length homeostasis.},
}
@article {pmid26581517,
year = {2015},
author = {Yang, W and Lee, YS},
title = {A DNA-hairpin model for repeat-addition processivity in telomere synthesis.},
journal = {Nature structural &amp; molecular biology},
volume = {22},
number = {11},
pages = {844-847},
pmid = {26581517},
issn = {1545-9985},
support = {ZIA DK036146-09//Intramural NIH HHS/United States ; DK036146-08/DK/NIDDK NIH HHS/United States ; },
mesh = {DNA/*metabolism ; Inverted Repeat Sequences ; *Models, Biological ; *Repetitive Sequences, Nucleic Acid ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {We propose a DNA-hairpin model for the processivity of telomeric-repeat addition. Concomitantly with template-RNA translocation after each repeat synthesis, the complementary DNA repeat, for example, AGGGTT, loops out in a noncanonical base-paired hairpin, thus freeing the RNA template for the next round of repeat synthesis. The DNA hairpin is temporarily stabilized by telomerase and the incoming dGTP but becomes realigned for processive telomere synthesis.},
}
@article {pmid26581417,
year = {2015},
author = {Du, J and Xue, W and Ji, Y and Zhu, X and Gu, Y and Zhu, M and Wang, C and Gao, Y and Dai, J and Ma, H and Jiang, Y and Chen, J and Hu, Z and Jin, G and Shen, H},
title = {U-shaped association between telomere length and esophageal squamous cell carcinoma risk: a case-control study in Chinese population.},
journal = {Frontiers of medicine},
volume = {9},
number = {4},
pages = {478-486},
pmid = {26581417},
issn = {2095-0225},
mesh = {Asian People/genetics ; Carcinoma, Squamous Cell/*genetics ; Case-Control Studies ; Chromosomal Instability ; DNA Helicases/genetics ; Esophageal Neoplasms/*genetics ; Esophageal Squamous Cell Carcinoma ; Female ; Genetic Predisposition to Disease ; Genetic Variation ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; RNA/genetics ; Ribonucleoproteins/genetics ; Risk Factors ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis ; Telomere Shortening ; },
abstract = {Telomeres play a critical role in biological ageing by maintaining chromosomal integrity and preventing chromosome ends fusion. Epidemiological studies have suggested that inter-individual differences of telomere length could affect predisposition to multiple cancers, but evidence regarding esophageal squamous cell carcinoma (ESCC) was still uncertain. Several telomere length-related single nucleotide polymorphisms (TLSNPs) in Caucasians have been reported in genome-wide association studies. However, the effects of telomere length and TL-SNPs on ESCC development are unclear. Therefore, we conducted a case-control study (1045 ESCC cases and 1433 controls) to evaluate the associations between telomere length, TL-SNPs, and ESCC risk in Chinese population. As a result, ESCC cases showed overall shorter relative telomere length (RTL) (median: 1.34) than controls (median: 1.50, P < 0.001). More interestingly, an evident nonlinear U-shaped association was observed between RTL and ESCC risk (P < 0.001), with odds ratios (95% confidence interval) equal to 2.40 (1.84-3.14), 1.36 (1.03-1.79), 1.01 (0.76-1.35), and 1.37 (1.03-1.82) for individuals in the 1st (the shortest), 2nd, 3rd, and 5th (the longest) quintile, respectively, compared with those in the 4th quintile as reference group. No significant associations were observed between the eight reported TL-SNPs and ESCC susceptibility. These findings suggest that either short or extremely long telomeres may be risk factors for ESCC in the Chinese population.},
}
@article {pmid26581148,
year = {2015},
author = {Stanley, SE and Rao, AD and Gable, DL and McGrath-Morrow, S and Armanios, M},
title = {Radiation Sensitivity and Radiation Necrosis in the Short Telomere Syndromes.},
journal = {International journal of radiation oncology, biology, physics},
volume = {93},
number = {5},
pages = {1115-1117},
pmid = {26581148},
issn = {1879-355X},
support = {R01 CA160433/CA/NCI NIH HHS/United States ; T32 GM007814/GM/NIGMS NIH HHS/United States ; T32 GM007309/GM/NIGMS NIH HHS/United States ; R01 HL114800/HL/NHLBI NIH HHS/United States ; R01 HL119476/HL/NHLBI NIH HHS/United States ; },
mesh = {Breast Neoplasms/*radiotherapy ; Carcinoma, Ductal, Breast/*radiotherapy ; Cell Survival ; Female ; *Germ-Line Mutation ; Humans ; Middle Aged ; Necrosis/genetics ; Radiation Injuries/*genetics/pathology ; Radiation Tolerance/*genetics ; Radiotherapy, Adjuvant ; Rib Fractures/etiology ; Syndrome ; Telomere Shortening/*genetics ; Thoracic Wall/pathology/surgery ; Wound Healing/genetics ; },
}
@article {pmid26578802,
year = {2015},
author = {Poole, LA and Zhao, R and Glick, GG and Lovejoy, CA and Eischen, CM and Cortez, D},
title = {SMARCAL1 maintains telomere integrity during DNA replication.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {112},
number = {48},
pages = {14864-14869},
pmid = {26578802},
issn = {1091-6490},
support = {F31 CA189375/CA/NCI NIH HHS/United States ; R01 CA136933/CA/NCI NIH HHS/United States ; R01 GM116616/GM/NIGMS NIH HHS/United States ; R01 CA160432/CA/NCI NIH HHS/United States ; T32 GM008554/GM/NIGMS NIH HHS/United States ; CA136933/CA/NCI NIH HHS/United States ; CA160432/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Chromosomes, Human/genetics/*metabolism ; DNA Damage/physiology ; DNA Helicases/genetics/*metabolism ; DNA Replication/*physiology ; HeLa Cells ; Humans ; Mice ; Recombination, Genetic/physiology ; Telomere/genetics/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {The SMARCAL1 (SWI/SNF related, matrix-associated, actin-dependent, regulator of chromatin, subfamily A-like 1) DNA translocase is one of several related enzymes, including ZRANB3 (zinc finger, RAN-binding domain containing 3) and HLTF (helicase-like transcription factor), that are recruited to stalled replication forks to promote repair and restart replication. These enzymes can perform similar biochemical reactions such as fork reversal; however, genetic studies indicate they must have unique cellular activities. Here, we present data showing that SMARCAL1 has an important function at telomeres, which present an endogenous source of replication stress. SMARCAL1-deficient cells accumulate telomere-associated DNA damage and have greatly elevated levels of extrachromosomal telomere DNA (C-circles). Although these telomere phenotypes are often found in tumor cells using the alternative lengthening of telomeres (ALT) pathway for telomere elongation, SMARCAL1 deficiency does not yield other ALT phenotypes such as elevated telomere recombination. The activity of SMARCAL1 at telomeres can be separated from its genome-maintenance activity in bulk chromosomal replication because it does not require interaction with replication protein A. Finally, this telomere-maintenance function is not shared by ZRANB3 or HLTF. Our results provide the first identification, to our knowledge, of an endogenous source of replication stress that requires SMARCAL1 for resolution and define differences between members of this class of replication fork-repair enzymes.},
}
@article {pmid26577093,
year = {2015},
author = {Casas-Vila, N and Scheibe, M and Freiwald, A and Kappei, D and Butter, F},
title = {Identification of TTAGGG-binding proteins in Neurospora crassa, a fungus with vertebrate-like telomere repeats.},
journal = {BMC genomics},
volume = {16},
number = {},
pages = {965},
pmid = {26577093},
issn = {1471-2164},
mesh = {Animals ; Base Sequence ; Conserved Sequence ; DNA-Binding Proteins/*metabolism ; Evolution, Molecular ; Fungal Proteins/*metabolism ; Neurospora crassa/genetics/*metabolism ; *Nucleotide Motifs ; *Proteomics ; *Repetitive Sequences, Nucleic Acid ; Telomere/*genetics ; Vertebrates/genetics ; },
abstract = {BACKGROUND: To date, telomere research in fungi has mainly focused on Saccharomyces cerevisiae and Schizosaccharomyces pombe, despite the fact that both yeasts have degenerated telomeric repeats in contrast to the canonical TTAGGG motif found in vertebrates and also several other fungi.<br><br>RESULTS: Using label-free quantitative proteomics, we here investigate the telosome of Neurospora crassa, a fungus with canonical telomeric repeats. We show that at least six of the candidates detected in our screen are direct TTAGGG-repeat binding proteins. While three of the direct interactors (NCU03416 [ncTbf1], NCU01991 [ncTbf2] and NCU02182 [ncTay1]) feature the known myb/homeobox DNA interaction domain also found in the vertebrate telomeric factors, we additionally show that a zinc-finger protein (NCU07846) and two proteins without any annotated DNA-binding domain (NCU02644 and NCU05718) are also direct double-strand TTAGGG binders. We further find two single-strand binders (NCU02404 [ncGbp2] and NCU07735 [ncTcg1]).<br><br>CONCLUSION: By quantitative label-free interactomics we identify TTAGGG-binding proteins in Neurospora crassa, suggesting candidates for telomeric factors that are supported by phylogenomic comparison with yeast species. Intriguingly, homologs in yeast species with degenerated telomeric repeats are also TTAGGG-binding proteins, e.g. in S. cerevisiae Tbf1 recognizes the TTAGGG motif found in its subtelomeres. However, there is also a subset of proteins that is not conserved. While a rudimentary core TTAGGG-recognition machinery may be conserved across yeast species, our data suggests Neurospora as an emerging model organism with unique features.},
}
@article {pmid26572976,
year = {2015},
author = {Ilicheva, NV and Podgornaya, OI and Voronin, AP},
title = {Telomere Repeat-Binding Factor 2 Is Responsible for the Telomere Attachment to the Nuclear Membrane.},
journal = {Advances in protein chemistry and structural biology},
volume = {101},
number = {},
pages = {67-96},
doi = {10.1016/bs.apcsb.2015.06.009},
pmid = {26572976},
issn = {1876-1623},
mesh = {Amino Acid Sequence/genetics ; Animals ; DNA/chemistry/genetics/metabolism ; DNA-Binding Proteins/*chemistry/genetics/metabolism ; Mice ; Nuclear Envelope/genetics/metabolism ; Protein Binding ; Protein Conformation ; Shelterin Complex ; Telomere/*genetics ; Telomere-Binding Proteins/chemistry ; Telomeric Repeat Binding Protein 2/*chemistry/genetics/metabolism ; },
abstract = {Telomeres are nucleoprotein structures that specify ends of eukaryotic chromosomes. They enable complete DNA replication, protect chromosomes from end-to-end fusions, and help organize chromatin structure. These functions are mediated by special telomeric proteins. TRF2 (telomeric repeat-binding factor 2) is an essential component of shelterin, a telomere-binding protein complex. TRF2 induces formation of a special structure of telomeric DNA, counteracts activation of double-strand break response pathway and ataxia telangiectasia mutated kinase pathway at telomeres. Some line of evidence implicates TRF2 in interactions with the nuclear envelope (NE). TRF2 is tightly bound to the nuclear membrane in frog oocytes nucleus, and it was found colocalized with NE or its remnants in mouse cells. Computer analysis of TRF2 amino acid sequence has shown that TRF2 possesses motifs, which resemble rod domain characteristic of intermediate filament proteins. These observations suggest that TRF2 is a good candidate for the attachment of telomeres to the NE in somatic cells.},
}
@article {pmid26571103,
year = {2016},
author = {Bersani, FS and Lindqvist, D and Mellon, SH and Epel, ES and Yehuda, R and Flory, J and Henn-Hasse, C and Bierer, LM and Makotkine, I and Abu-Amara, D and Coy, M and Reus, VI and Lin, J and Blackburn, EH and Marmar, C and Wolkowitz, OM},
title = {Association of dimensional psychological health measures with telomere length in male war veterans.},
journal = {Journal of affective disorders},
volume = {190},
number = {},
pages = {537-542},
doi = {10.1016/j.jad.2015.10.037},
pmid = {26571103},
issn = {1573-2517},
support = {UL1TR000067/TR/NCATS NIH HHS/United States ; },
mesh = {Adult ; Cross-Sectional Studies ; Depressive Disorder, Major/complications/diagnosis/*genetics ; Humans ; Male ; Middle Aged ; Psychiatric Status Rating Scales ; Risk Factors ; Stress Disorders, Post-Traumatic/complications/diagnosis/*genetics ; *Telomere Shortening ; Veterans/*psychology ; Young Adult ; },
abstract = {BACKGROUND: Several psychiatric disorders may be characterized by peripheral telomere shortening. However, it is unclear whether telomere shortening is associated with these psychiatric disorders per se or, rather, with underlying dimensional parameters that are often, but not necessarily, associated with them. We explored the association between dimensional psychopathological measures and telomere length (TL) in granulocytes among veterans independent of psychiatric diagnosis.<br><br>METHODS: Seventy-six combat-exposed male veterans (41 psychiatrically healthy, 18 with Posttraumatic Stress Disorder [PTSD] and 17 with concomitant PTSD and Major Depressive Disorder [MDD]) had TL assayed. Assessments included Clinician-Administered PTSD Scale (CAPS), Beck Depression Inventory-II (BDI-II), Early Trauma Inventory (ETI), Symptom Checklist-90-R Global Severity Index (SCL-90-GSI), Perceived Stress Scale (PSS) and Positive and Negative Affect Schedule (PANAS). Correlations were corrected for age, BMI, antidepressants and ethnicity.<br><br>RESULTS: Across subjects, TL was negatively correlated with early trauma (p<0.001), global psychopathological severity (p=0.044) and perceived stress (p=0.019), positively correlated with positive affect (p=0.026), not significantly correlated with symptom severity of PTSD, depression or negative affect. Across these dimensions, early trauma and positive affect were associated with TL after excluding subjects with somatic illnesses.<br><br>LIMITATIONS: The study was cross-sectional with a moderate sample size and only male combat-exposed subjects.<br><br>CONCLUSIONS: These preliminary findings suggest that early trauma, severity of perceived stress and general psychopathological symptoms are more closely associated with shorter TL than is the severity of core diagnostic symptoms of PTSD or MDD, whereas positive affect is associated with longer TL. Larger-scale studies should assess TL associated with specific psychiatric dimensions, apart from only categorical psychiatric diagnoses, to develop more specific biologically-relevant endophenotypes.},
}
@article {pmid26566042,
year = {2015},
author = {Vedelek, B and Blastyák, A and Boros, IM},
title = {Cross-Species Interaction between Rapidly Evolving Telomere-Specific Drosophila Proteins.},
journal = {PloS one},
volume = {10},
number = {11},
pages = {e0142771},
pmid = {26566042},
issn = {1932-6203},
mesh = {Amino Acid Sequence ; Animals ; Cloning, Molecular ; Computational Biology ; DNA Damage ; Databases, Genetic ; Drosophila/*genetics ; Drosophila Proteins/*genetics ; Drosophila melanogaster/*genetics ; Evolution, Molecular ; Gene Expression Regulation ; Molecular Sequence Data ; Nuclear Proteins/*genetics ; Sequence Alignment ; Sequence Homology, Amino Acid ; Software ; Species Specificity ; Telomere/*ultrastructure ; },
abstract = {Telomere integrity in Drosophila melanogaster is maintained by a putative multisubunit complex called terminin that is believed to act in analogy to the mammalian shelterin complex in protecting chromosome ends from being recognized as sites of DNA damage. The five proteins supposed to form the terminin complex are HP1-ORC associated protein, HP1-HOAP interacting protein, Verrocchio, Drosophila Telomere Loss/Modigliani and Heterochromatic Protein 1. Four of these proteins evolve rapidly within the Drosophila genus. The accelerated evolution of terminin components may indicate the involvement of these proteins in the process by which new species arise, as the resulting divergence of terminin proteins might prevent hybrid formation, thus driving speciation. However, terminin is not an experimentally proven entity, and no biochemical studies have been performed to investigate its assembly and action in detail. Motivated by these facts in order to initiate biochemical studies on terminin function, we attempted to reconstitute terminin by co-expressing its subunits in bacteria and investigated the possible role of the fast-evolving parts of terminin components in complex assembly. Our results suggest formation of stable subcomplexes of terminin, but not of the whole complex in vitro. We found that the accelerated evolution is restricted to definable regions of terminin components, and that the divergence of D. melanogaster Drosophila Telomere Loss and D. yakuba Verrocchio proteins does not preclude their stable interaction.},
}
@article {pmid26565632,
year = {2015},
author = {Parolini, M and Romano, A and Khoriauli, L and Nergadze, SG and Caprioli, M and Rubolini, D and Santagostino, M and Saino, N and Giulotto, E},
title = {Early-Life Telomere Dynamics Differ between the Sexes and Predict Growth in the Barn Swallow (Hirundo rustica).},
journal = {PloS one},
volume = {10},
number = {11},
pages = {e0142530},
pmid = {26565632},
issn = {1932-6203},
mesh = {Animals ; Base Sequence ; Female ; Male ; Molecular Sequence Data ; Sex Characteristics ; Swallows/*growth &amp; development/physiology ; Telomere/*chemistry ; *Telomere Shortening ; },
abstract = {Telomeres are conserved DNA-protein structures at the termini of eukaryotic chromosomes which contribute to maintenance of genome integrity, and their shortening leads to cell senescence, with negative consequences for organismal functions. Because telomere erosion is influenced by extrinsic and endogenous factors, telomere dynamics may provide a mechanistic basis for evolutionary and physiological trade-offs. Yet, knowledge of fundamental aspects of telomere biology under natural selection regimes, including sex- and context-dependent variation in early-life, and the covariation between telomere dynamics and growth, is scant. In this study of barn swallows (Hirundo rustica) we investigated the sex-dependent telomere erosion during nestling period, and the covariation between relative telomere length and body and plumage growth. Finally, we tested whether any covariation between growth traits and relative telomere length depends on the social environment, as influenced by sibling sex ratio. Relative telomere length declined on average over the period of nestling maximal growth rate (between 7 and 16 days of age) and differently covaried with initial relative telomere length in either sex. The frequency distribution of changes in relative telomere length was bimodal, with most nestlings decreasing and some increasing relative telomere length, but none of the offspring traits predicted the a posteriori identified group to which individual nestlings belonged. Tail and wing length increased with relative telomere length, but more steeply in males than females, and this relationship held both at the within- and among-broods levels. Moreover, the increase in plumage phenotypic values was steeper when the sex ratio of an individual's siblings was female-biased. Our study provides evidence for telomere shortening during early life according to subtly different dynamics in either sex. Furthermore, it shows that the positive covariation between growth and relative telomere length depends on sex as well as social environment, in terms of sibling sex ratio.},
}
@article {pmid26560064,
year = {2015},
author = {Lian, F and Wang, J and Huang, X and Wu, Y and Cao, Y and Tan, X and Xu, X and Hong, Y and Yang, L and Gao, X},
title = {Effect of vegetable consumption on the association between peripheral leucocyte telomere length and hypertension: a case-control study.},
journal = {BMJ open},
volume = {5},
number = {11},
pages = {e009305},
pmid = {26560064},
issn = {2044-6055},
mesh = {Adult ; Aged ; Aging/physiology ; Case-Control Studies ; China ; *Diet ; *Feeding Behavior ; Female ; Humans ; Hypertension/genetics/*prevention &amp; control ; *Leukocytes ; Logistic Models ; Male ; Middle Aged ; Odds Ratio ; Real-Time Polymerase Chain Reaction ; Risk Factors ; Surveys and Questionnaires ; *Telomere ; *Telomere Shortening ; *Vegetables ; },
abstract = {OBJECTIVES: Peripheral leucocyte telomere length has been suggested to be inversely associated with hypertension risk. Both telomere length and hypertension risk can be modified by certain dietary factors, such as fruit and vegetables. This study was to examine the potential effect of these dietary factors on the association between telomere length and hypertension risk.<br><br>STUDY DESIGN: A community-based case-control study.<br><br>PARTICIPANTS: 271 hypertensive patients and 455 normotensive controls aged 40-70&#x2005;years and living in Yinzhou, Zhejiang Province, China.<br><br>OUTCOME MEASURES: Peripheral leucocyte relative telomere length (RTL) was measured using quantitative real-time PCR. Dietary intake was assessed by a brief semiquantitative food frequency questionnaire. The association between RTL and hypertension risk was analysed using logistic regression, and the modulatory effect of dietary intake on RTL-related hypertension risk was analysed using likelihood ratio tests.<br><br>RESULTS: Among controls, longer age-adjusted RTL was associated with higher vegetable intake (p=0.01). Individuals with longer age-adjusted RTL (based on median value) were 30% less likely to have hypertension (OR=0.70, 95% CI 0.52 to 0.96; p=0.03). The observed RTL-hypertension relationship appeared to be modified by vegetable intake-longer RTL was significantly associated with lower hypertension risk only in those with greater vegetable consumption (OR=0.28, 95% CI 0.14 to 0.57; p<0.001), but not in those with lower vegetable intake (P-interaction=0.008).<br><br>CONCLUSIONS: Certain dietary factors might modify telomere-related hypertension risk.},
}
@article {pmid26558766,
year = {2017},
author = {Julin, B and Shui, IM and Prescott, J and Giovannucci, EL and De Vivo, I},
title = {Plasma vitamin D biomarkers and leukocyte telomere length in men.},
journal = {European journal of nutrition},
volume = {56},
number = {2},
pages = {501-508},
pmid = {26558766},
issn = {1436-6215},
support = {R01 CA082838/CA/NCI NIH HHS/United States ; R01 CA133891/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; },
mesh = {Age Factors ; Aged ; Biomarkers/*blood ; Body Mass Index ; Cross-Sectional Studies ; Genotype ; Humans ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide/genetics ; Retinoid X Receptor alpha/genetics ; Smoking ; Telomere/*ultrastructure ; Telomere Homeostasis/genetics ; Telomere Shortening ; Vitamin D/analogs &amp; derivatives/*blood/genetics ; },
abstract = {PURPOSE: Vitamin D may reduce telomere shortening through anti-inflammatory and anti-cell proliferation mechanisms. In women, higher plasma 25-hydroxyvitamin D (25(OH)D) has been shown to be associated with longer telomere length, but the relationship has not been assessed in men.<br><br>METHODS: We conducted a cross-sectional analysis of 25(OH)D, 1,25-dihydroxyvitamin D (1,25(OH)2D) and relative leukocyte telomere length (LTL) among 2483 men [1832 men for 1,25(OH)2D] who were selected as cases and controls in three studies of telomeres and cancer nested within the Health Professionals Follow-up Study. We also genotyped 95 SNPs representing common genetic variation in vitamin D pathway genes. LTL was measured by quantitative PCR, and z-scores within each study were calculated. Associations were assessed by linear as well as logistic regression adjusting for age and other potential confounders.<br><br>RESULTS: Age (P-trend&#xa0;<&#xa0;0.0001), pack-years of smoking (P-trend&#xa0;=&#xa0;0.04) and body mass index (P-trend&#xa0;=&#xa0;0.05) were inversely associated with LTL. Neither 25(OH)D nor 1,25(OH)2D was associated with LTL (multivariable-adjusted P-trend 0.69 and 0.41, respectively, for the linear regression model). One SNP in the retinoid X receptor alpha gene was associated with long LTL (P&#xa0;=&#xa0;0.0003).<br><br>CONCLUSIONS: In this cross-sectional study of men, 25(OH)D and 1,25(OH)2D were not associated with relative LTL.},
}
@article {pmid26556853,
year = {2016},
author = {Gao, K and Li, G and Qu, Y and Wang, M and Cui, B and Ji, M and Shi, B and Hou, P},
title = {TERT promoter mutations and long telomere length predict poor survival and radiotherapy resistance in gliomas.},
journal = {Oncotarget},
volume = {7},
number = {8},
pages = {8712-8725},
pmid = {26556853},
issn = {1949-2553},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/genetics/metabolism ; Brain Neoplasms/genetics/mortality/radiotherapy ; Cohort Studies ; Female ; Follow-Up Studies ; Glioma/genetics/*mortality/radiotherapy ; Humans ; Immunoenzyme Techniques ; Male ; Middle Aged ; Mutation/*genetics ; Neoplasm Grading ; Neoplasm Recurrence, Local/etiology/mortality/radiotherapy ; Prognosis ; Promoter Regions, Genetic/*genetics ; Radiation Tolerance/*genetics ; Radiotherapy/*adverse effects ; Real-Time Polymerase Chain Reaction ; Survival Rate ; Telomerase/*genetics ; Telomere Homeostasis/genetics/*radiation effects ; Young Adult ; },
abstract = {Increasing evidences have implicated somatic gain-of-function mutations at the telomerase reverse transcriptase (TERT) promoter as one of the major mechanisms that promote transcriptional activation of TERT and subsequently maintain telomere length in human cancers including glioma. To investigate the prognostic value of these mutations and telomere length, individually and their coexistence, in gliomas, we analyzed two somatic mutations C228T and C250T in the TERT promoter, relative telomere length (RTL), IDH1 mutation and MGMT methylation in 389 glioma patients, and explored their associations with patient characteristics and clinical outcomes. Our data showed that C228T and C250T mutations were found in 17.0% (66 of 389) and 11.8% (46 of 389) of gliomas, respectively, and these two mutations were mutually exclusive in this cancer. Moreover, they were significantly associated with WHO grade. We also found that the RTL was significant longer in gliomas than in meningiomas and normal brain tissues (Median, 0.89 vs. 0.44 and 0.50; P < 0.001), and demonstrated that the RTL was strongly correlated with tumor recurrence. Importantly, TERT promoter mutations or long RTL caused a significantly poorer survival than TERT wild-type or short RTL. Coexisting TERT promoter mutations and long RTL were more commonly associated with poor patient survival than they were individually. Notably, the patients with TERT promoter mutations particularly C228T or long RTL were resistant to radiotherapy. Collectively, TERT promoter mutations and long RTL are not only prognostic factors for poor clinical outcomes, but also the predictors of radiotherapy resistance in gliomas.},
}
@article {pmid26556285,
year = {2015},
author = {Henje Blom, E and Han, LK and Connolly, CG and Ho, TC and Lin, J and LeWinn, KZ and Simmons, AN and Sacchet, MD and Mobayed, N and Luna, ME and Paulus, M and Epel, ES and Blackburn, EH and Wolkowitz, OM and Yang, TT},
title = {Peripheral telomere length and hippocampal volume in adolescents with major depressive disorder.},
journal = {Translational psychiatry},
volume = {5},
number = {11},
pages = {e676},
pmid = {26556285},
issn = {2158-3188},
support = {R01 MH083784/MH/NIMH NIH HHS/United States ; K01MH097978/MH/NIMH NIH HHS/United States ; 3R01MH085734-02S1/MH/NIMH NIH HHS/United States ; 7R01MH085734/MH/NIMH NIH HHS/United States ; R01MH085734-05S1/MH/NIMH NIH HHS/United States ; K01 MH097978/MH/NIMH NIH HHS/United States ; R01 MH085734/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; *Brain Mapping ; Depressive Disorder, Major/*metabolism/*pathology ; Female ; Hippocampus/*pathology ; Humans ; *Magnetic Resonance Imaging ; Male ; Organ Size ; Polymerase Chain Reaction ; Saliva/metabolism ; Telomere/*metabolism ; },
abstract = {Several studies have reported that adults with major depressive disorder have shorter telomere length and reduced hippocampal volumes. Moreover, studies of adult populations without major depressive disorder suggest a relationship between peripheral telomere length and hippocampal volume. However, the relationship of these findings in adolescents with major depressive disorder has yet to be explored. We examined whether adolescent major depressive disorder is associated with altered peripheral telomere length and hippocampal volume, and whether these measures relate to one another. In 54 unmedicated adolescents (13-18 years) with major depressive disorder and 63 well-matched healthy controls, telomere length was assessed from saliva using quantitative polymerase chain reaction methods, and bilateral hippocampal volumes were measured with magnetic resonance imaging. After adjusting for age and sex (and total brain volume in the hippocampal analysis), adolescents with major depressive disorder exhibited significantly shorter telomere length and significantly smaller right, but not left hippocampal volume. When corrected for age, sex, diagnostic group and total brain volume, telomere length was not significantly associated with left or right hippocampal volume, suggesting that these cellular and neural processes may be mechanistically distinct during adolescence. Our findings suggest that shortening of telomere length and reduction of hippocampal volume are already present in early-onset major depressive disorder and thus unlikely to be only a result of accumulated years of exposure to major depressive disorder.},
}
@article {pmid26554909,
year = {2015},
author = {Wei, R and DeVilbiss, FT and Liu, W},
title = {Genetic Polymorphism, Telomere Biology and Non-Small Lung Cancer Risk.},
journal = {Journal of genetics and genomics = Yi chuan xue bao},
volume = {42},
number = {10},
pages = {549-561},
doi = {10.1016/j.jgg.2015.08.005},
pmid = {26554909},
issn = {1673-8527},
mesh = {Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; Humans ; Lung Neoplasms/*genetics ; Polymorphism, Single Nucleotide/*genetics ; Telomere/*genetics ; },
abstract = {Recent genome-wide association studies (GWAS) have identified a number of chromosomal regions associated with the risk of lung cancer. Of these regions, single-nucleotide polymorphisms (SNPs), especially rs2736100 located in the telomerase reverse transcriptase (TERT) gene show unique and significant association with non-small cell lung cancer (NSCLC) in a few subpopulations including women, nonsmokers, East Asians and those with adenocarcinoma. Recent studies have also linked rs2736100 with a longer telomere length and lung cancer risk. In this review, we seek to summarize the relationship between these factors and to further link the underlying telomere biology to lung cancer etiology. We conclude that genetic alleles combined with environmental (e.g., less-smoking) and physiological factors (gender and age) that confer longer telomere length are strong risk factors for NSCLC. This linkage may be particularly relevant in lung adenocarcinoma driven by epidermal growth factor receptor (EGFR) mutations, as these mutations have also been strongly linked to female gender, less-smoking history, adenocarcinoma histology and East Asian ethnicity. By establishing this connection, a strong argument is made for further investigating of the involvement of these entities during the tumorigenesis of NSCLC.},
}
@article {pmid26551267,
year = {2016},
author = {Robles, TF and Carroll, JE and Bai, S and Reynolds, BM and Esquivel, S and Repetti, RL},
title = {Emotions and family interactions in childhood: Associations with leukocyte telomere length emotions, family interactions, and telomere length.},
journal = {Psychoneuroendocrinology},
volume = {63},
number = {},
pages = {343-350},
pmid = {26551267},
issn = {1873-3360},
support = {T32 MH015750/MH/NIMH NIH HHS/United States ; T32MH015750/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Affect ; Cellular Senescence/genetics ; Child ; Cross-Sectional Studies ; *Emotions ; Family/*psychology ; Family Conflict/psychology ; Female ; Humans ; *Interpersonal Relations ; Leukocytes/*metabolism ; Male ; Retrospective Studies ; Telomere/*metabolism ; Telomere Shortening/physiology ; },
abstract = {Conceptualizations of links between stress and cellular aging in childhood suggest that accumulating stress predicts shorter leukocyte telomere length (LTL). At the same time, several models suggest that emotional reactivity to stressors may play a key role in predicting cellular aging. Using intensive repeated measures, we tested whether exposure or emotional "reactivity" to conflict and warmth in the family were related to LTL. Children (N=39; 30 target children and 9 siblings) between 8 and 13 years of age completed daily diary questionnaires for 56 consecutive days assessing daily warmth and conflict in the marital and the parent-child dyad, and daily positive and negative mood. To assess exposure to conflict and warmth, diary scale scores were averaged over the 56 days. Mood "reactivity" was operationalized by using multilevel modeling to generate estimates of the slope of warmth or conflict scores (marital and parent-child, separately) predicting same-day mood for each individual child. After diary collection, a blood sample was collected to determine LTL. Among children aged 8-13 years, a stronger association between negative mood and marital conflict, suggesting greater negative mood reactivity to marital conflict, was related to shorter LTL (B=-1.51, p<.01). A stronger association between positive mood and marital affection, suggesting positive mood reactivity, was related to longer LTL (B=1.15, p<.05). These effects were independent of exposure to family and marital conflict and warmth, and positive and negative mood over a two-month period. To our knowledge, these findings, although cross-sectional, represent the first evidence showing that link between children's affective responses and daily family interactions may have implications for telomere length.},
}
@article {pmid26548954,
year = {2015},
author = {Shibuya, H and Hernández-Hernández, A and Morimoto, A and Negishi, L and Höög, C and Watanabe, Y},
title = {MAJIN Links Telomeric DNA to the Nuclear Membrane by Exchanging Telomere Cap.},
journal = {Cell},
volume = {163},
number = {5},
pages = {1252-1266},
doi = {10.1016/j.cell.2015.10.030},
pmid = {26548954},
issn = {1097-4172},
mesh = {Amino Acid Sequence ; Animals ; Apoptosis Regulatory Proteins/chemistry/metabolism ; Carrier Proteins/genetics/metabolism ; Cell Cycle Proteins/genetics/metabolism ; Humans ; Male ; Meiosis ; Membrane Proteins/chemistry/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Microtubule-Associated Proteins/genetics ; Molecular Sequence Data ; Nuclear Envelope/*metabolism ; Nuclear Proteins/chemistry/metabolism ; Sequence Alignment ; Telomere/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; Testis/metabolism ; },
abstract = {In meiosis, telomeres attach to the inner nuclear membrane (INM) and drive the chromosome movement required for homolog pairing and recombination. Here, we address the question of how telomeres are structurally adapted for the meiotic task. We identify a multi-subunit meiotic telomere-complex, TERB1/2-MAJIN, which takes over telomeric DNA from the shelterin complex in mouse germ cells. TERB1/2-MAJIN initially assembles on the INM sequestered by its putative transmembrane subunit MAJIN. In early meiosis, telomere attachment is achieved by the formation of a chimeric complex of TERB1/2-MAJIN and shelterin. The chimeric complex matures during prophase into DNA-bound TERB1/2-MAJIN by releasing shelterin, forming a direct link between telomeric DNA and the INM. These hierarchical processes, termed "telomere cap exchange," are regulated by CDK-dependent phosphorylation and the DNA-binding activity of MAJIN. Further, we uncover a positive feedback between telomere attachment and chromosome movement, revealing a comprehensive regulatory network underlying meiosis-specific telomere function in mammals.},
}
@article {pmid26539975,
year = {2015},
author = {De Vusser, K and Pieters, N and Janssen, B and Lerut, E and Kuypers, D and Jochmans, I and Monbaliu, D and Pirenne, J and Nawrot, T and Naesens, M},
title = {Telomere length, cardiovascular risk and arteriosclerosis in human kidneys: an observational cohort study.},
journal = {Aging},
volume = {7},
number = {10},
pages = {766-775},
pmid = {26539975},
issn = {1945-4589},
mesh = {Adult ; Age Factors ; Arteriosclerosis/*pathology ; Cohort Studies ; Female ; Humans ; Kidney/*pathology ; Kidney Diseases/*pathology ; Kidney Transplantation ; Leukocytes/pathology ; Male ; Middle Aged ; *Telomere Homeostasis ; Tissue Donors/statistics &amp; numerical data ; },
abstract = {BACKGROUND: Replicative senescence, associated with telomere shortening, plays an important role in aging and cardiovascular disease. The relation between telomere length, cardiovascular risk, and renal disease is unknown.<br><br>METHODS: Our study consisted of a cohort of 257 kidney donors for transplantation, divided into a test and a validation cohort. We used quantitative RT-PCR to measure relative telomere length (log T/S ratio) in peripheral blood leucocytes, and in kidney biopsies performed prior to implantation. The association between leucocyte and intrarenal telomere length, cardiovascular risk factors, and renal histology, was studied using multiple regression models, adjusted for calendar age, gender and other donor demographics.<br><br>RESULTS: Subjects with intrarenal arteriosclerosis had significantly shorter leucocyte telomere length compared with patients without arteriosclerosis (log T/S ratio -0.3&#xb1;0.4 vs. 0.1&#xb1;0.2 with vs. without arteriosclerosis; p=0.0008). Intrarenal arteriosclerosis was associated with shorter telomere length, independent of gender, calendar age, history of hypertension and history of cardiovascular events. For each increase of one standard deviation of the log T/S ratio, the odds for intrarenal arteriosclerosis decreased with 64% (Odds ratio 0.36; 95% CI 0.17-0.77; p=0.02). In accordance with leucocyte telomere length, shorter intrarenal telomere length associated significantly with the presence of renal arteriosclerosis (log T/S ratio -0.04&#xb1;0.06 vs. 0.08&#xb1;0.01 with vs. without arteriosclerosis, p=0.007), and not with other histological lesions.<br><br>INTERPRETATION: We demonstrate that arteriosclerosis in smaller intrarenal arteries is associated with shorter telomere length. Our study suggests a central role of replicative senescence in the progression of renovascular disease, independent of calendar age.},
}
@article {pmid26539211,
year = {2015},
author = {de Lange, T},
title = {A loopy view of telomere evolution.},
journal = {Frontiers in genetics},
volume = {6},
number = {},
pages = {321},
pmid = {26539211},
issn = {1664-8021},
support = {R01 AG016642/AG/NIA NIH HHS/United States ; },
abstract = {About a decade ago, I proposed that t-loops, the lariat structures adopted by many eukaryotic telomeres, could explain how the transition from circular to linear chromosomes was successfully negotiated by early eukaryotes. Here I reconsider this loopy hypothesis in the context of the idea that eukaryotes evolved through a period of genome invasion by Group II introns.},
}
@article {pmid26538535,
year = {2015},
author = {Haussmann, MF and Heidinger, BJ},
title = {Telomere dynamics may link stress exposure and ageing across generations.},
journal = {Biology letters},
volume = {11},
number = {11},
pages = {},
pmid = {26538535},
issn = {1744-957X},
mesh = {Aging/*physiology ; Animals ; Birds/genetics/physiology ; Environment ; *Epigenesis, Genetic ; Longevity/genetics ; Mammals/genetics/physiology ; Stress, Physiological/*physiology ; Telomere/*genetics ; Telomere Shortening/genetics/physiology ; },
abstract = {Although exposure to stressors is known to increase disease susceptibility and accelerate ageing, evidence is accumulating that these effects can span more than one generation. Stressors experienced by parents have been reported to negatively influence the longevity of their offspring and even grand offspring. The mechanisms underlying these long-term, cross-generational effects are still poorly understood, but we argue here that telomere dynamics are likely to play an important role. In this review, we begin by surveying the current connections between stress and telomere dynamics. We then lay out the evidence that exposure to stressors in the parental generation influences telomere dynamics in offspring and potentially subsequent generations. We focus on evidence in mammalian and avian studies and highlight several promising areas where our understanding is incomplete and future investigations are critically needed. Understanding the mechanisms that link stress exposure across generations requires interdisciplinary studies and is essential to both the biomedical community seeking to understand how early adversity impacts health span and evolutionary ecologists interested in how changing environmental conditions are likely to influence age-structured population dynamics.},
}
@article {pmid26525972,
year = {2016},
author = {Reig-Viader, R and Garcia-Caldés, M and Ruiz-Herrera, A},
title = {Telomere homeostasis in mammalian germ cells: a review.},
journal = {Chromosoma},
volume = {125},
number = {2},
pages = {337-351},
pmid = {26525972},
issn = {1432-0886},
mesh = {Animals ; Germ Cells/cytology/*metabolism ; Homeostasis ; Humans ; Mammals/*genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres protect against genome instability and participate in chromosomal movements during gametogenesis, especially in meiosis. Thus, maintaining telomere structure and telomeric length is essential to both cell integrity and the production of germ cells. As a result, alteration of telomere homeostasis in the germ line may result in the generation of aneuploid gametes or gametogenesis disruption, triggering fertility problems. In this work, we provide an overview on fundamental aspects of the literature regarding the organization of telomeres in mammalian germ cells, paying special attention to telomere structure and function, as well as the maintenance of telomeric length during gametogenesis. Moreover, we discuss the different roles recently described for telomerase and TERRA in maintaining telomere functionality. Finally, we review how new findings in the field of reproductive biology underscore the role of telomere homeostasis as a potential biomarker for infertility. Overall, we anticipate that the study of telomere stability and equilibrium will contribute to improve diagnoses of patients; assess the risk of infertility in the offspring; and in turn, find new treatments.},
}
@article {pmid26521726,
year = {2016},
author = {Fairlie, J and Holland, R and Pilkington, JG and Pemberton, JM and Harrington, L and Nussey, DH},
title = {Lifelong leukocyte telomere dynamics and survival in a free-living mammal.},
journal = {Aging cell},
volume = {15},
number = {1},
pages = {140-148},
pmid = {26521726},
issn = {1474-9726},
support = {BB/H021868/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/L020769/1/BB/FDA HHS/United States ; //Wellcome Trust/United Kingdom ; },
mesh = {*Aging ; Animals ; Biomarkers/blood ; Leukocytes/*cytology ; Longevity/*physiology ; Sheep ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {Telomeres play a fundamental role in the maintenance of genomic integrity at a cellular level, and average leukocyte telomere length (LTL) has been proposed as a biomarker of organismal aging. However, studies tracking LTL across the entire life course of individuals are lacking. Here, we examined lifelong patterns of variation in LTL among four birth cohorts of female Soay sheep (Ovis aries) that were longitudinally monitored and sampled from birth to death. Over the first 4 months of life, there was within-individual loss of LTL, consistent with findings in the human and primate literature, but there was little evidence of consistent LTL loss associated with age after this point. Overall, we observed only weak evidence of individual consistency in LTL across years and over the entire lifespan: Within-individual variation was considerable, and birth cohorts differed markedly in their telomere dynamics. Despite the high levels of LTL variation within the lifetimes of individuals, there remained significant associations between LTL and longevity. Detailed analysis of the longitudinal data set showed that this association was driven by improved survival of individuals with longer LTL over the first 2 years of life. There was no evidence that LTL predicted survival in later adulthood. Our data provide the first evidence from a mammal that LTL can predict mortality and lifespan under natural conditions, and also highlight the potentially dynamic nature of LTL within the lifetimes of individuals experiencing a complex and highly variable environment.},
}
@article {pmid26520623,
year = {2015},
author = {Arons, E and Zhou, H and Edelman, DC and Gomez, A and Steinberg, SM and Petersen, D and Wang, Y and Meltzer, PS and Kreitman, RJ},
title = {Impact of telomere length on survival in classic and variant hairy cell leukemia.},
journal = {Leukemia research},
volume = {39},
number = {12},
pages = {1360-1366},
pmid = {26520623},
issn = {1873-5835},
support = {Z01 BC010301-11//Intramural NIH HHS/United States ; Z99 CA999999//Intramural NIH HHS/United States ; },
mesh = {Age Factors ; Antimetabolites, Antineoplastic/therapeutic use ; Combined Modality Therapy ; DNA, Neoplasm/genetics ; Drug Resistance, Neoplasm ; Female ; Gene Rearrangement, B-Lymphocyte, Heavy Chain ; Humans ; Immunoglobulin Heavy Chains/genetics ; Immunophenotyping ; Kaplan-Meier Estimate ; Leukemia, Hairy Cell/classification/drug therapy/*genetics/mortality/surgery ; Leukocyte Count ; Male ; Middle Aged ; Prognosis ; Proportional Hazards Models ; Risk Factors ; Splenectomy ; Telomere/*ultrastructure ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Telomeres, which protect the ends of chromosomes, are shortened in several hematologic malignancies, often with adverse prognostic implications, but their effect on prognosis of classic and variant hairy cell leukemia (HCL and HCLv) has not been reported. HCL/HCLv genomic DNA from 46 patients was studied by PCR to determine the ratio of telomere to single copy gene number (T/S). T/S was unrelated to diagnosis of HCL or HCLv (p=0.27), but shorter T/S was associated with unmutated immunoglobulin rearrangements (p=0.033) and age above the median at diagnosis (p=0.017). Low T/S was associated with shorter overall survival from diagnosis (OS), particularly T/S <0.655 (p=0.0064, adjusted p=0.019). Shorter OS was also associated with presence of unmutated (p<0.0001) or IGHV4-34+ (p<0.0001) rearrangements, or increasing age (p=0.0002). Multivariable analysis with Cox modeling showed that short T/S along with either unmutated or IGHV4-34+ rearrangements remained associated with reduced OS (p=0.0071, p=0.0024, respectively) after age adjustment. While T/S is relatively long in HCL and the disease usually indolent with excellent survival, shortened telomeres in HCL/HCLv are associated with decreased survival. Shortened T/S could represent a risk factor needing further investigation/intervention to determine if non-chemotherapy treatment options, in addition to or instead of chemotherapy, might be particularly useful.},
}
@article {pmid26520377,
year = {2015},
author = {Khaw, AK and Sameni, S and Venkatesan, S and Kalthur, G and Hande, MP},
title = {Plumbagin alters telomere dynamics, induces DNA damage and cell death in human brain tumour cells.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {793},
number = {},
pages = {86-95},
doi = {10.1016/j.mrgentox.2015.06.004},
pmid = {26520377},
issn = {1879-3592},
mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis ; Brain Neoplasms/enzymology/*genetics ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Damage ; Gene Expression Regulation, Neoplastic/drug effects ; Glioblastoma/enzymology/*genetics ; Humans ; Naphthoquinones/*pharmacology ; Telomerase/*antagonists &amp; inhibitors/genetics ; Telomere/*drug effects ; Telomere Shortening ; },
abstract = {Natural plant products may possess much potential in palliative therapy and supportive strategies of current cancer treatments with lesser cytotoxicity to normal cells compared to conventional chemotherapy. In the current study, anti-cancer properties of plumbagin, a plant-derived naphthoquinone, on brain cancer cells were determined. Plumbagin treatment resulted in the induction of DNA damage, cell cycle arrest and apoptosis, followed by suppression of the colony forming ability of the brain tumour cells. These effects were substantiated by upregulation of PTEN, TNFRSF1A and downregulation of E2F1 genes, along with a drop in MDM2, cyclin B1, survivin and BCL2 protein expression. Plumbagin induced elevated levels of caspase-3/7 activity as well. For the first time, we show here that plumbagin inhibits telomerase in brain tumour cells and results in telomere shortening following chronic long-term treatment. This observation implies considerable cytotoxicity of plumbagin towards cancer cells with higher telomerase activity. Collectively, our findings suggest plumbagin as a potential chemotherapeutic phytochemical in brain tumour treatment modalities.},
}
@article {pmid26519084,
year = {2015},
author = {Bodelon, C and Heaphy, CM and Meeker, AK and Geller, B and Vacek, PM and Weaver, DL and Chicoine, RE and Shepherd, JA and Mahmoudzadeh, AP and Patel, DA and Brinton, LA and Sherman, ME and Gierach, GL},
title = {Leukocyte telomere length and its association with mammographic density and proliferative diagnosis among women undergoing diagnostic image-guided breast biopsy.},
journal = {BMC cancer},
volume = {15},
number = {},
pages = {823},
pmid = {26519084},
issn = {1471-2407},
support = {R01 CA166945/CA/NCI NIH HHS/United States ; U01CA70013/CA/NCI NIH HHS/United States ; M01 RR000109/RR/NCRR NIH HHS/United States ; //Intramural NIH HHS/United States ; R21 CA157254/CA/NCI NIH HHS/United States ; HHSN261200800001E//PHS HHS/United States ; HHSN261200800001C/RC/CCR NIH HHS/United States ; U01 CA070013/CA/NCI NIH HHS/United States ; 1R21CA157254/CA/NCI NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Breast Density ; Breast Neoplasms/*diagnosis/*genetics ; Cross-Sectional Studies ; Female ; Humans ; Image-Guided Biopsy ; Leukocytes/*metabolism ; Mammary Glands, Human/*abnormalities ; Middle Aged ; Neoplasm Staging ; Risk Factors ; Telomere/*genetics ; },
abstract = {BACKGROUND: Elevated mammographic density (MD) is a strong breast cancer risk factor but the mechanisms underlying the association are poorly understood. High MD and breast cancer risk may reflect cumulative exposures to factors that promote epithelial cell division. One marker of cellular replicative history is telomere length, but its association with MD is unknown. We investigated the relation of telomere length, a marker of cellular replicative history, with MD and biopsy diagnosis.<br><br>METHODS: One hundred and ninety-five women, ages 40-65, were clinically referred for image-guided breast biopsies at an academic facility in Vermont. Relative peripheral blood leukocyte telomere length (LTL) was measured using quantitative polymerase chain reaction. MD volume was quantified in cranio-caudal views of the breast contralateral to the primary diagnosis in digital mammograms using a breast density phantom, while MD area (cm(2)) was measured using thresholding software. Associations between log-transformed LTL and continuous MD measurements (volume and area) were evaluated using linear regression models adjusted for age and body mass index. Analyses were stratified by biopsy diagnosis: proliferative (hyperplasia, in-situ or invasive carcinoma) or non-proliferative (benign or other non-proliferative benign diagnoses).<br><br>RESULTS: Mean relative LTL in women with proliferative disease (n = 141) was 1.6 (SD = 0.9) vs. 1.2 (SD = 0.6) in those with non-proliferative diagnoses (n = 54) (P = 0.002). Mean percent MD volume did not differ by diagnosis (P = 0.69). LTL was not associated with MD in women with proliferative (P = 0.89) or non-proliferative (P = 0.48) diagnoses. However, LTL was associated with a significant increased risk of proliferative diagnosis (adjusted OR = 2.46, 95% CI: 1.47, 4.42).<br><br>CONCLUSIONS: Our analysis of LTL did not find an association with MD. However, our findings suggest that LTL may be a marker of risk for proliferative pathology among women referred for biopsy based on breast imaging.},
}
@article {pmid26517359,
year = {2015},
author = {Janson, C and Nyhan, K and Murnane, JP},
title = {Replication Stress and Telomere Dysfunction Are Present in Cultured Human Embryonic Stem Cells.},
journal = {Cytogenetic and genome research},
volume = {146},
number = {4},
pages = {251-260},
doi = {10.1159/000441245},
pmid = {26517359},
issn = {1424-859X},
mesh = {Activins/pharmacology ; Aphidicolin/pharmacology ; Cell Differentiation/drug effects ; Cell Line ; Cell Proliferation/drug effects ; *DNA Replication ; Embryonic Stem Cells/drug effects/*ultrastructure ; Humans ; In Situ Hybridization, Fluorescence ; Nucleosides/pharmacology ; *Telomere ; },
abstract = {Replication stress causes DNA damage at fragile sites in the genome. DNA damage at telomeres can initiate breakage-fusion-bridge cycles and chromosome instability, which can result in replicative senescence or tumor formation. Little is known about the extent of replication stress or telomere dysfunction in human embryonic stem cells (hESCs). hESCs are grown in culture with the expectation of being used therapeutically in humans, making it important to minimize the levels of replication stress and telomere dysfunction. Here, the hESC line UCSF4 was cultured in a defined medium with growth factor Activin A, exogenous nucleosides, or DNA polymerase inhibitor aphidicolin. We used quantitative fluorescence in situ hybridization to analyze individual telomeres for dysfunction and observed that it can be increased by aphidicolin or Activin A. In contrast, adding exogenous nucleosides relieved dysfunction, suggesting that telomere dysfunction results from replication stress. Whether these findings can be applied to other hESC lines remains to be determined. However, because the loss of telomeres can lead to chromosome instability and cancer, we conclude that hESCs grown in culture for future therapeutic purposes should be routinely checked for replication stress and telomere dysfunction.},
}
@article {pmid26515461,
year = {2016},
author = {Uziel, O and Yerushalmi, R and Zuriano, L and Naser, S and Beery, E and Nordenberg, J and Lubin, I and Adel, Y and Shepshelovich, D and Yavin, H and Ben Aharon, I and Pery, S and Rizel, S and Pasmanik-Chor, M and Frumkin, D and Lahav, M},
title = {BRCA1/2 mutations perturb telomere biology: characterization of structural and functional abnormalities in vitro and in vivo.},
journal = {Oncotarget},
volume = {7},
number = {3},
pages = {2433-2454},
pmid = {26515461},
issn = {1949-2553},
mesh = {Adult ; BRCA1 Protein/*genetics ; BRCA2 Protein/*genetics ; Base Sequence ; Blotting, Western ; Breast/metabolism/*pathology ; Case-Control Studies ; Cell Transformation, Neoplastic/genetics/*pathology ; Cells, Cultured ; DNA Damage ; DNA Repair ; Female ; Heterozygote ; Humans ; In Vitro Techniques ; Leukocytes, Mononuclear ; Molecular Sequence Data ; Mutation/*genetics ; Real-Time Polymerase Chain Reaction ; Telomerase ; Telomere/*genetics ; },
abstract = {BRCA1 mutation is associated with carcinogenesis, especially of breast tissue. Telomere maintenance is crucial for malignant transformation. Being a part of the DNA repair machinery, BRCA1 may be implicated in telomere biology. We explored the role of BRCA1 in telomere maintenance in lymphocytes of BRCA1/2 mutation carriers and in in vitro system by knocking down its expression in non-malignant breast epithelial cells.The results in both systems were similar. BRCA1/2 mutation caused perturbation of telomere homeostasis, shortening of the single stranded telomere overhang and increased the intercellular telomere length variability as well as the number of telomere free chromosomal ends and telomeric circles. These changes resulted in an increased DNA damage status. Telomerase activity, inducibility and expression remained unchanged. BRCA1 mutation resulted also in changes in the binding of shelterin proteins to telomeres. DNMT-1 levels were markedly reduced both in the carriers and in in vitro system. The methylation pattern of the sub-telomeric regions in carriers suggested hypomethylation in chromosome 10. The expression of a distinct set of genes was also changed, some of which may relate to pre-disposition to malignancy.These results show that BRCA gene products have a role in telomere length homeostasis. It is plausible that these perturbations contribute to malignant transformation in BRCA mutants.},
}
@article {pmid26513689,
year = {2015},
author = {Kepinska, M and Szyller, J and Milnerowicz, H},
title = {The influence of oxidative stress induced by iron on telomere length.},
journal = {Environmental toxicology and pharmacology},
volume = {40},
number = {3},
pages = {931-935},
doi = {10.1016/j.etap.2015.10.002},
pmid = {26513689},
issn = {1872-7077},
mesh = {Endothelial Cells/cytology/metabolism ; Gene Expression Regulation/drug effects ; Hemochromatosis/genetics ; Humans ; Iron/*adverse effects ; *Oxidative Stress ; Telomerase/metabolism ; Telomere/*drug effects ; Telomere Shortening ; Transferrin/metabolism ; },
abstract = {Oxidative stress can be induced by increased concentrations of iron in the body and consequently can cause shortening of telomeres. Telomeres, called mitotic clocks, are non-coding fragments at the end of chromosomes. During the replication of genetic material they are shortened, playing the role of ageing biomarkers in eukaryotes. In human endothelial cells, oxidative stress causes a decrease in telomerase activity. Shortening of chromosomes in telomeric parts was found in patients with primary hemochromatosis and in patients taking supplements containing iron. Increased level of transferrin saturation is associated with the presence of shorter telomeres in the chromosomes of leukocytes. The relationship between iron status and telomere length is still not fully understood.},
}
@article {pmid26508703,
year = {2016},
author = {Marques, FZ and Booth, SA and Prestes, PR and Curl, CL and Delbridge, LM and Lewandowski, P and Harrap, SB and Charchar, FJ},
title = {Telomere dynamics during aging in polygenic left ventricular hypertrophy.},
journal = {Physiological genomics},
volume = {48},
number = {1},
pages = {42-49},
pmid = {26508703},
issn = {1531-2267},
support = {G10M5155//PHS HHS/United States ; },
mesh = {Aging/*pathology ; Animals ; Cardiomegaly/complications/genetics ; DNA-Binding Proteins/genetics/metabolism ; Heart Ventricles/pathology ; Hypertrophy, Left Ventricular/complications/*genetics ; Leukocytes/metabolism ; MicroRNAs/genetics/metabolism ; Multifactorial Inheritance/*genetics ; Organ Size ; Rats, Inbred F344 ; Regression Analysis ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {Short telomeres are associated with increased risk of cardiovascular disease. Here we studied cardiomyocyte telomere length at key ages during the ontogeny of cardiac hypertrophy and failure in the hypertrophic heart rat (HHR) and compared these with the normal heart rat (NHR) control strain. Key ages corresponded with the pathophysiological sequence beginning with fewer cardiomyocytes (2 days), leading to left ventricular hypertrophy (LVH) (13 wk) and subsequently progression to heart failure (38 wk). We measured telomere length, tissue activity of telomerase, mRNA levels of telomerase reverse transcriptase (Tert) and telomerase RNA component (Terc), and expression of the telomeric regulator microRNA miR-34a. Cardiac telomere length was longer in the HHR compared with the control strain at 2 days and 38 wk, but shorter at 13 wk. Neonatal HHR had higher cardiac telomerase activity and expression of Tert and miR-34a. Telomerase activity was not different at 13 or 38 wk. Tert mRNA and Terc RNA were overexpressed at 38 wk, while miR-34a was overexpressed at 13 wk but downregulated at 38 wk. Circulating leukocytes were strongly correlated with cardiac telomere length in the HHR only. The longer neonatal telomeres in HHR are likely to reflect fewer fetal and early postnatal cardiomyocyte cell divisions and explain the reduced total cardiomyocyte complement that predisposes to later hypertrophy and failure. Although shorter telomeres were a feature of cardiac hypertrophy at 13 wk, they were not present at the progression to heart failure at 38 wk.},
}
@article {pmid26503784,
year = {2016},
author = {Chu, TW and D'Souza, Y and Autexier, C},
title = {The Insertion in Fingers Domain in Human Telomerase Can Mediate Enzyme Processivity and Telomerase Recruitment to Telomeres in a TPP1-Dependent Manner.},
journal = {Molecular and cellular biology},
volume = {36},
number = {1},
pages = {210-222},
pmid = {26503784},
issn = {1098-5549},
support = {MOP-133449//CIHR/Canada ; },
mesh = {Amino Acid Sequence ; Aminopeptidases/*metabolism ; Animals ; Cell Line ; DNA Damage/physiology ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/*metabolism ; Humans ; Molecular Sequence Data ; Sequence Alignment ; Serine Proteases/*metabolism ; Shelterin Complex/*genetics/metabolism ; Telomerase/chemistry/genetics/*metabolism ; Telomere/*enzymology/*genetics ; Telomere Shortening/physiology ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {In most human cancer cells, cellular immortalization relies on the activation and recruitment of telomerase to telomeres. The telomere-binding protein TPP1 and the TEN domain of the telomerase catalytic subunit TERT regulate telomerase recruitment. TERT contains a unique domain, called the insertion in fingers domain (IFD), located within the conserved reverse transcriptase domain. We report the role of specific hTERT IFD residues in the regulation of telomerase activity and processivity, recruitment to telomeres, and cell survival. One hTERT IFD variant, hTERT-L805A, with reduced activity and processivity showed impaired telomere association, which could be partially rescued by overexpression of TPP1-POT1. Another previously reported hTERT IFD mutant enzyme with similarly low levels of activity and processivity, hTERT-V791Y, displayed defects in telomere binding and was insensitive to TPP1-POT1 overexpression. Our results provide the first evidence that the IFD can mediate enzyme processivity and telomerase recruitment to telomeres in a TPP1-dependent manner. Moreover, unlike hTERT-V791Y, hTERT-V763S, a variant with reduced activity but increased processivity, and hTERT-L805A, could both immortalize limited-life-span cells, but cells expressing these two mutant enzymes displayed growth defects, increased apoptosis, DNA damage at telomeres, and short telomeres. Our results highlight the importance of the IFD in maintaining short telomeres and in cell survival.},
}
@article {pmid26503492,
year = {2016},
author = {Satoh, H},
title = {Telomere length and survival in IPF patients.},
journal = {Respirology (Carlton, Vic.)},
volume = {21},
number = {1},
pages = {195},
doi = {10.1111/resp.12667},
pmid = {26503492},
issn = {1440-1843},
mesh = {Female ; Humans ; Idiopathic Pulmonary Fibrosis/*mortality/*physiopathology ; Male ; *Telomere Homeostasis ; },
}
@article {pmid26503413,
year = {2016},
author = {Dai, J and Gao, Q},
title = {Telomere length and survival in IPF patients - Reply.},
journal = {Respirology (Carlton, Vic.)},
volume = {21},
number = {1},
pages = {195},
doi = {10.1111/resp.12666},
pmid = {26503413},
issn = {1440-1843},
mesh = {Female ; Humans ; Idiopathic Pulmonary Fibrosis/*mortality/*physiopathology ; Male ; *Telomere Homeostasis ; },
}
@article {pmid26497538,
year = {2017},
author = {Bethancourt, HJ and Kratz, M and Beresford, SAA and Hayes, MG and Kuzawa, CW and Duazo, PL and Borja, JB and Eisenberg, DTA},
title = {No association between blood telomere length and longitudinally assessed diet or adiposity in a young adult Filipino population.},
journal = {European journal of nutrition},
volume = {56},
number = {1},
pages = {295-308},
pmid = {26497538},
issn = {1436-6215},
support = {P30 ES010126/ES/NIEHS NIH HHS/United States ; T32 HD007543/HD/NICHD NIH HHS/United States ; P2C HD042828/HD/NICHD NIH HHS/United States ; P20 RR020649/RR/NCRR NIH HHS/United States ; R01 TW005596/TW/FIC NIH HHS/United States ; P30 DK056350/DK/NIDDK NIH HHS/United States ; R24 HD042828/HD/NICHD NIH HHS/United States ; R01 DK078150/DK/NIDDK NIH HHS/United States ; },
mesh = {Adiposity/*genetics ; Body Composition ; Body Mass Index ; Chronic Disease ; Cross-Sectional Studies ; *Diet ; Female ; Follow-Up Studies ; Humans ; Inflammation/blood/genetics ; Longitudinal Studies ; Male ; Nutrition Surveys ; Nutritional Status ; Obesity/blood/*epidemiology/genetics ; Overweight/blood/*epidemiology/genetics ; Philippines ; Rural Population ; Telomere/*ultrastructure ; Thinness/blood/*epidemiology/genetics ; Urban Population ; Waist Circumference ; Young Adult ; },
abstract = {PURPOSE: Telomeres, DNA-protein structures that cap and protect chromosomes, are thought to shorten more rapidly when exposed to chronic inflammation and oxidative stress. Diet and nutritional status may be a source of inflammation and oxidative stress. However, relationships between telomere length (TL) and diet or adiposity have primarily been studied cross-sectionally among older, overweight/obese populations and yielded inconsistent results. Little is known about the relationship between diet or body composition and TL among younger, low- to normal-weight populations. It also remains unclear how cumulative exposure to a specific diet or body composition during the years of growth and development, when telomere attrition is most rapid, may be related to TL in adulthood.<br><br>METHODS: In a sample of 1459 young adult Filipinos, we assessed the relationship between blood TL at ages 20.8-22.5 and measures of BMI z-score, waist circumference, and diet collected between the ages of 8.5 and 22.5. TL was measured using monochrome multiplex quantitative PCR, and diet was measured using multiple 24-h recalls.<br><br>RESULTS: We found no associations between blood TL and any of the measures of adiposity or between blood TL and the seven dietary factors examined: processed meats, fried/grilled meats and fish, non-fried fish, coconut oil, fruits and vegetables, bread and bread products, and sugar-sweetened beverages.<br><br>CONCLUSIONS: Considering the inconsistencies in the literature and our null results, small differences in body composition and consumption of any single pro- or anti-inflammatory dietary component may not by themselves have a meaningful impact on telomere integrity, or the impact may differ across distinct ecological circumstances.},
}
@article {pmid26493667,
year = {2015},
author = {Izikki, M and Hoang, E and Draskovic, I and Mercier, O and Lecerf, F and Lamrani, L and Liu, WY and Guignabert, C and Fadel, E and Dorfmuller, P and Humbert, M and Londoño-Vallejo, A and Eddahibi, S},
title = {Telomere Maintenance Is a Critical Determinant in the Physiopathology of Pulmonary Hypertension.},
journal = {Journal of the American College of Cardiology},
volume = {66},
number = {17},
pages = {1942-1943},
doi = {10.1016/j.jacc.2015.08.869},
pmid = {26493667},
issn = {1558-3597},
mesh = {Cell Proliferation/physiology ; Humans ; Hypertension, Pulmonary/*physiopathology ; Pulmonary Artery/*cytology ; Telomere/*physiology ; },
}
@article {pmid26492073,
year = {2015},
author = {Yu, EY and Pérez-Martín, J and Holloman, WK and Lue, NF},
title = {Mre11 and Blm-Dependent Formation of ALT-Like Telomeres in Ku-Deficient Ustilago maydis.},
journal = {PLoS genetics},
volume = {11},
number = {10},
pages = {e1005570},
pmid = {26492073},
issn = {1553-7404},
mesh = {Antigens, Nuclear/*genetics ; Cell Proliferation/genetics ; Chromosomes/genetics ; DNA Damage/genetics ; DNA Repair/genetics ; DNA-Binding Proteins/*genetics ; G2 Phase Cell Cycle Checkpoints/genetics ; Humans ; Ku Autoantigen ; Rad51 Recombinase/genetics ; RecQ Helicases/genetics ; *Recombination, Genetic ; Telomerase/genetics ; Telomere/*genetics ; Ustilago/*genetics ; },
abstract = {A subset of human cancer cells uses a specialized, aberrant recombination pathway known as ALT to maintain telomeres, which in these cells are characterized by complex aberrations including length heterogeneity, high levels of unpaired C-strand, and accumulation of extra-chromosomal telomere repeats (ECTR). These phenotypes have not been recapitulated in any standard budding or fission yeast mutant. We found that eliminating Ku70 or Ku80 in the yeast-like fungus Ustilago maydis results initially in all the characteristic telomere aberrations of ALT cancer cells, including C-circles, a highly specific marker of ALT. Subsequently the ku mutants experience permanent G2 cell cycle arrest, accompanied by loss of telomere repeats from chromosome ends and even more drastic accumulation of very short ECTRs (vsECTRs). The deletion of atr1 or chk1 rescued the lethality of the ku mutant, and "trapped" the telomere aberrations in the early ALT-like stage. Telomere abnormalities are telomerase-independent, but dramatically suppressed by deletion of mre11 or blm, suggesting major roles for these factors in the induction of the ALT pathway. In contrast, removal of other DNA damage response and repair factors such as Rad51 has disparate effects on the ALT phenotypes, suggesting that these factors process ALT intermediates or products. Notably, the antagonism of Ku and Mre11 in the induction of ALT is reminiscent of their roles in DSB resection, in which Blm is also known to play a key role. We suggest that an aberrant resection reaction may constitute an early trigger for ALT telomeres, and that the outcomes of ALT are distinct from DSB because of the unique telomere nucleoprotein structure.},
}
@article {pmid26486788,
year = {2015},
author = {Hummel, S and Ventura Ferreira, MS and Heudobler, D and Huber, E and Fahrenkamp, D and Gremse, F and Schmid, K and Müller-Newen, G and Ziegler, P and Jost, E and Blasco, MA and Brümmendorf, TH and Holler, E and Beier, F},
title = {Telomere shortening in enterocytes of patients with uncontrolled acute intestinal graft-versus-host disease.},
journal = {Blood},
volume = {126},
number = {22},
pages = {2518-2521},
doi = {10.1182/blood-2015-03-633289},
pmid = {26486788},
issn = {1528-0020},
mesh = {Acute Disease ; Allografts ; *Cell Proliferation ; Enterocytes/*metabolism/pathology ; Female ; Graft vs Host Disease/*metabolism/pathology ; *Hematopoietic Stem Cell Transplantation ; Humans ; Intestinal Diseases/*metabolism/pathology ; Male ; Retrospective Studies ; *Telomere Shortening ; },
abstract = {Acute intestinal graft-versus-host disease (aGVHD) refractory to immunosuppressive treatment is a serious complication after allogenic hematopoietic stem cell transplantation (HSCT). The underlying mechanisms of refractory aGVHD of the gut are not fully understood. Although telomere length (TL) reflects the replicative history of a cell, critically short telomeres have been associated with replicative exhaustion and tissue failure. In this study, we demonstrate that enterocytes of patients with refractory intestinal aGVHD show significantly increased proliferation, which translates into significant and critical telomere attrition following HSCT as compared with unaffected patients undergoing HSCT. Calculated telomere loss in aGVHD patients is 190 bp/wk, thereby massively exceeding physiological steady-state TL shortening rates such as in lymphocytes (∼50 bp/y). Our data support the hypothesis that increased compensatory proliferation following continued tissue damage can result in massive telomere loss in enterocytes of aGVHD patients. The present study introduces aGVHD-triggered increased cellular turnover and telomere loss with subsequent replicative exhaustion as a mechanism for refractory gut GVHD that is compatible with the long-term clinical aspect of the disease and provides a basis for stem cell protective therapies in the treatment of aGVHD.},
}
@article {pmid26485466,
year = {2015},
author = {Tran, TD and Cao, HX and Jovtchev, G and Neumann, P and Novák, P and Fojtová, M and Vu, GT and Macas, J and Fajkus, J and Schubert, I and Fuchs, J},
title = {Centromere and telomere sequence alterations reflect the rapid genome evolution within the carnivorous plant genus Genlisea.},
journal = {The Plant journal : for cell and molecular biology},
volume = {84},
number = {6},
pages = {1087-1099},
doi = {10.1111/tpj.13058},
pmid = {26485466},
issn = {1365-313X},
mesh = {Base Sequence ; *Biological Evolution ; Centromere/*genetics ; Chromosomes, Plant/*genetics ; Genetic Variation ; Genome, Plant/*genetics/physiology ; Magnoliopsida/*genetics/physiology ; Molecular Sequence Data ; Species Specificity ; Telomere/*genetics ; Time Factors ; },
abstract = {Linear chromosomes of eukaryotic organisms invariably possess centromeres and telomeres to ensure proper chromosome segregation during nuclear divisions and to protect the chromosome ends from deterioration and fusion, respectively. While centromeric sequences may differ between species, with arrays of tandemly repeated sequences and retrotransposons being the most abundant sequence types in plant centromeres, telomeric sequences are usually highly conserved among plants and other organisms. The genome size of the carnivorous genus Genlisea (Lentibulariaceae) is highly variable. Here we study evolutionary sequence plasticity of these chromosomal domains at an intrageneric level. We show that Genlisea nigrocaulis (1C = 86 Mbp; 2n = 40) and G. hispidula (1C = 1550 Mbp; 2n = 40) differ as to their DNA composition at centromeres and telomeres. G. nigrocaulis and its close relative G. pygmaea revealed mainly 161 bp tandem repeats, while G. hispidula and its close relative G. subglabra displayed a combination of four retroelements at centromeric positions. G. nigrocaulis and G. pygmaea chromosome ends are characterized by the Arabidopsis-type telomeric repeats (TTTAGGG); G. hispidula and G. subglabra instead revealed two intermingled sequence variants (TTCAGG and TTTCAGG). These differences in centromeric and, surprisingly, also in telomeric DNA sequences, uncovered between groups with on average a > 9-fold genome size difference, emphasize the fast genome evolution within this genus. Such intrageneric evolutionary alteration of telomeric repeats with cytosine in the guanine-rich strand, not yet known for plants, might impact the epigenetic telomere chromatin modification.},
}
@article {pmid26483096,
year = {2015},
author = {Yu, R and Tang, N and Leung, J and Woo, J},
title = {Telomere length is not associated with frailty in older Chinese elderly: Cross-sectional and longitudinal analysis.},
journal = {Mechanisms of ageing and development},
volume = {152},
number = {},
pages = {74-79},
doi = {10.1016/j.mad.2015.10.002},
pmid = {26483096},
issn = {1872-6216},
support = {5R01 AR049439-02/AR/NIAMS NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*metabolism ; Cross-Sectional Studies ; Female ; Follow-Up Studies ; Frail Elderly ; Hong Kong ; Humans ; Longitudinal Studies ; Male ; *Sex Characteristics ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Telomere shortening has been associated with biological age and several chronic degenerative diseases. However, less is known about telomere length and frailty, which is an indicator of biological age. This study examines the association between telomere length and frailty in a prospective study over five years of 2006 men and women aged 65 years and older living in the community. The frailty status was determined by the Fried's criteria. Telomere length in leukocytes was measured using the quantitative polymerase chain reaction. Logistic regression was used to examine the association between telomere length and incidence of frailty. Among 2006 subjects (mean age 72.4±5.1 years, 51.3% women), the mean telomere length at baseline was 9.1±2.0kb and the frailty phenotype was detected in 127 subjects (6.3%). Male gender was related to shorter telomere length, with increased years of age related to a shortened telomere length (P<0.05). In both men and women, no statistically significant difference of telomere length and the frailty phenotype was observed at baseline. After 4 years of follow-up, 116 cases of frailty were identified. There was no association between telomere length and incident frailty. In conclusion, telomere length was not associated with frailty in this study population.},
}
@article {pmid26475708,
year = {2016},
author = {de Frutos, C and López-Cardona, AP and Fonseca Balvís, N and Laguna-Barraza, R and Rizos, D and Gutierrez-Adán, A and Bermejo-Álvarez, P},
title = {Spermatozoa telomeres determine telomere length in early embryos and offspring.},
journal = {Reproduction (Cambridge, England)},
volume = {151},
number = {1},
pages = {1-7},
doi = {10.1530/REP-15-0375},
pmid = {26475708},
issn = {1741-7899},
mesh = {Aging ; Animals ; Base Sequence ; Blastocyst/ultrastructure ; Embryo, Mammalian/*ultrastructure ; Female ; Fertilization in Vitro ; Male ; Mice ; Molecular Sequence Data ; Oocytes/ultrastructure ; Parthenogenesis ; Spermatozoa/*ultrastructure ; Telomerase/metabolism ; Telomere/chemistry/*ultrastructure ; Telomere Homeostasis ; Zygote/ultrastructure ; },
abstract = {Offspring telomere length (TL) has been correlated with paternal TL, but the mechanism for this parent of origin-specific inheritance remains unclear. The objective of this study has been to determine the role of spermatozoa TL in embryonic telomere lengthening by using two mouse models showing dimorphism in their spermatozoa TL: Mus musculus vs Mus spretus and old vs young Mus musculus. Mus spretus spermatozoa displayed a shorter TL than Mus musculus. Hybrid offspring exhibited lower TL compared with Mus musculus starting at the two-cell stage, before the onset of telomerase expression. To analyze the role of spermatozoa telomeres in early telomere lengthening, we compared the TL in oocytes, zygotes, two-cell embryos and blastocysts produced by parthenogenesis or by fertilization with Mus musculus or Mus spretus spermatozoa. TL was significantly higher in spermatozoa compared with oocytes, and it increased significantly from the oocyte to the zygote stage in those embryos fertilized with Mus musculus spermatozoa, but not in those fertilized with Mus spretus spermatozoa or produced by parthenogenesis. A further increase was noted from the zygote to the two-cell stage in fertilized Mus musculus embryos, whereas hybrid embryos maintained the oocyte TL. Spermatozoa TL shortened with age in Mus musculus and the offspring from young males showed a significantly higher TL compared with that fathered by old males. These significant differences were already noticeable at the two-cell stage. These results suggest that spermatozoa telomeres act as a guide for telomerase-independent telomere lengthening resulting in differences in TL that persist after birth.},
}
@article {pmid26472030,
year = {2015},
author = {Ci, X and Li, B and Ma, X and Kong, F and Zheng, C and Björkholm, M and Jia, J and Xu, D},
title = {Bortezomib-mediated down-regulation of telomerase and disruption of telomere homeostasis contributes to apoptosis of malignant cells.},
journal = {Oncotarget},
volume = {6},
number = {35},
pages = {38079-38092},
pmid = {26472030},
issn = {1949-2553},
mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Bortezomib/*pharmacology ; Cell Line, Tumor ; DNA Damage ; Dose-Response Relationship, Drug ; Down-Regulation ; Drug Resistance, Neoplasm ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Humans ; Leukemia/*drug therapy/enzymology/genetics/pathology ; Proteasome Inhibitors/*pharmacology ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Shelterin Complex ; Stomach Neoplasms/*drug therapy/enzymology/genetics/pathology ; Telomerase/genetics/*metabolism ; Telomere Homeostasis/*drug effects ; Telomere Shortening/drug effects ; Telomere-Binding Proteins/genetics/metabolism ; Time Factors ; Transfection ; },
abstract = {Bortezomib inhibits the ubiquitin/proteasome pathway to achieve its anti-cancer effect and its well characterized activity is the NF-κB inhibition through which the anti-apoptotic bcl-2 expression is down-regulated and apoptosis is subsequently induced. However, the downstream molecular targets of bortezomib are still incompletely defined. Because telomere stabilization via activation of telomerase, induction of telomerase reverse transcriptase (hTERT) and appropriate expression of shelterin proteins is essential to cancer development and progression, we investigated the effect of bortezomib on telomere homeostasis/function in malignant cells. The bortezomib treatment of leukemic (HEL) and gastric cancer cells (BGC-823) led to significant inhibition of hTERT and telomerase expression, widespread dysregulation of shelterin protein expression, and telomere shortening, thereby triggering telomere dysfunction and DNA damage. hTERT over-expression attenuated bortezomib-induced telomere shortening, abnormal shelterin expression and telomere dysfunction. Importantly, bortezomib-mediated apoptosis of malignant cells was partially prevented by hTERT over-expression. Mechanistically, hTERT first robustly enhances bcl2 expression and maintains significantly high residual levels of bcl2 even in bortezomib-treated HEL cells. Second, hTERT protects against bortezomib-induced DNA damage. Our findings collectively reveal a profound impact of bortezomib on telomere homeostasis/function. Down-regulation of hTERT expression and telomere dysfunction induced by bortezomib both contribute to its cancer cell killing actions. It is evident from the present study that hTERT can confer resistance of malignant cells to bortezomib-based target cancer therapy, which may have important clinical implications.},
}
@article {pmid26468778,
year = {2015},
author = {Bourgeron, T and Xu, Z and Doumic, M and Teixeira, MT},
title = {The asymmetry of telomere replication contributes to replicative senescence heterogeneity.},
journal = {Scientific reports},
volume = {5},
number = {},
pages = {15326},
pmid = {26468778},
issn = {2045-2322},
support = {260906/ERC_/European Research Council/International ; },
mesh = {*Cellular Senescence ; DNA, Fungal/genetics/metabolism ; *Models, Theoretical ; Saccharomyces cerevisiae/genetics/physiology ; Saccharomyces cerevisiae Proteins/genetics ; Telomere/*metabolism ; Telomere Shortening ; },
abstract = {In eukaryotes, the absence of telomerase results in telomere shortening, eventually leading to replicative senescence, an arrested state that prevents further cell divisions. While replicative senescence is mainly controlled by telomere length, the heterogeneity of its onset is not well understood. This study proposes a mathematical model based on the molecular mechanisms of telomere replication and shortening to decipher the causes of this heterogeneity. Using simulations fitted on experimental data obtained from individual lineages of senescent Saccharomyces cerevisiae cells, we decompose the sources of senescence heterogeneity into interclonal and intraclonal components, and show that the latter is based on the asymmetry of the telomere replication mechanism. We also evidence telomere rank-switching events with distinct frequencies in short-lived versus long-lived lineages, revealing that telomere shortening dynamics display important variations. Thus, the intrinsic heterogeneity of replicative senescence and its consequences find their roots in the asymmetric structure of telomeres.},
}
@article {pmid26468615,
year = {2015},
author = {Werner, B and Beier, F and Hummel, S and Balabanov, S and Lassay, L and Orlikowsky, T and Dingli, D and Brümmendorf, TH and Traulsen, A},
title = {Reconstructing the in vivo dynamics of hematopoietic stem cells from telomere length distributions.},
journal = {eLife},
volume = {4},
number = {},
pages = {},
pmid = {26468615},
issn = {2050-084X},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; *Cell Proliferation ; Child ; Child, Preschool ; Cytological Techniques ; Granulocytes/cytology/physiology ; Healthy Volunteers ; Hematopoietic Stem Cells/*physiology ; Humans ; Infant ; Infant, Newborn ; Lymphocytes/cytology/physiology ; Middle Aged ; Models, Theoretical ; Prospective Studies ; *Telomere ; Young Adult ; },
abstract = {We investigate the in vivo patterns of stem cell divisions in the human hematopoietic system throughout life. In particular, we analyze the shape of telomere length distributions underlying stem cell behavior within individuals. Our mathematical model shows that these distributions contain a fingerprint of the progressive telomere loss and the fraction of symmetric cell proliferations. Our predictions are tested against measured telomere length distributions in humans across all ages, collected from lymphocyte and granulocyte sorted telomere length data of 356 healthy individuals, including 47 cord blood and 28 bone marrow samples. We find an increasing stem cell pool during childhood and adolescence and an approximately maintained stem cell population in adults. Furthermore, our method is able to detect individual differences from a single tissue sample, i.e. a single snapshot. Prospectively, this allows us to compare cell proliferation between individuals and identify abnormal stem cell dynamics, which affects the risk of stem cell related diseases.},
}
@article {pmid26466102,
year = {2015},
author = {Garcia-Cisneros, A and Pérez-Portela, R and Almroth, BC and Degerman, S and Palacín, C and Sköld, HN},
title = {Long telomeres are associated with clonality in wild populations of the fissiparous starfish Coscinasterias tenuispina.},
journal = {Heredity},
volume = {115},
number = {5},
pages = {480},
doi = {10.1038/hdy.2015.75},
pmid = {26466102},
issn = {1365-2540},
}
@article {pmid26465752,
year = {2015},
author = {Nanbu, T and Nguyễn, LC and Habib, AG and Hirata, N and Ukimori, S and Tanaka, D and Masuda, K and Takahashi, K and Yukawa, M and Tsuchiya, E and Ueno, M},
title = {Fission Yeast Exo1 and Rqh1-Dna2 Redundantly Contribute to Resection of Uncapped Telomeres.},
journal = {PloS one},
volume = {10},
number = {10},
pages = {e0140456},
pmid = {26465752},
issn = {1932-6203},
mesh = {Chromosomes, Fungal/genetics/metabolism ; DNA Helicases/*genetics/metabolism ; Exodeoxyribonucleases/*genetics/metabolism ; Flap Endonucleases/*genetics/metabolism ; Gene Deletion ; Microbial Viability/genetics ; Schizosaccharomyces/*genetics/metabolism ; Schizosaccharomyces pombe Proteins/*genetics/metabolism ; Shelterin Complex ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/genetics ; },
abstract = {The uncapping of telomeres induces a DNA damage response. In Schizosaccharomyces pombe, deletion of pot1+ causes telomere uncapping and rapid telomere resection, resulting in chromosome fusion. Using the nmt-pot1-aid strain, we previously reported that Pot1 shut-off causes telomere loss and chromosome fusion in S. pombe. However, the factors responsible for the resection of uncapped telomeres remain unknown. In this study, we investigated these factors and found that concomitant deletion of rqh1+ and exo1+ alleviated the loss of telomeres following Pot1 shut-off, suggesting that Rqh1 and Exo1 are redundantly involved in the resection of uncapped telomeres. We also investigated the role of Rqh1 helicase activity and found it to be essential for the resection of uncapped telomeres. Moreover, we found that Dna2 and Exo1 function redundantly in the resection of uncapped telomeres. Taken together, these results suggest that Exo1 and Rqh1-Dna2 redundantly contribute to the resection of uncapped telomeres. Therefore, our results demonstrate that nmt-pot1-aid is an important model strain to study the role of helicases and nucleases in the resection of uncapped telomeres and to improve our understanding of DNA double-strand break repair.},
}
@article {pmid26465358,
year = {2015},
author = {Pierson, CA},
title = {Will knowing my telomere length really improve my life?.},
journal = {Journal of the American Association of Nurse Practitioners},
volume = {27},
number = {10},
pages = {545},
doi = {10.1002/2327-6924.12321},
pmid = {26465358},
issn = {2327-6924},
mesh = {*Genetic Counseling ; Humans ; Nurse Practitioners ; *Quality of Life ; },
}
@article {pmid26464091,
year = {2015},
author = {Matsubara, K and Uno, Y and Srikulnath, K and Matsuda, Y and Miller, E and Olsson, M},
title = {No Interstitial Telomeres on Autosomes but Remarkable Amplification of Telomeric Repeats on the W Sex Chromosome in the Sand Lizard (Lacerta agilis).},
journal = {The Journal of heredity},
volume = {106},
number = {6},
pages = {753-757},
doi = {10.1093/jhered/esv083},
pmid = {26464091},
issn = {1465-7333},
mesh = {Animals ; Chromosome Banding ; Female ; *Genetic Fitness ; Heterochromatin ; Lizards/*genetics ; Male ; *Repetitive Sequences, Nucleic Acid ; Sex Chromosomes/*genetics ; Telomere/*genetics ; },
abstract = {Telomeres are repeat (TTAGGG) n sequences that form terminal ends of chromosomes and have several functions, such as protecting the coding DNA from erosion at mitosis. Due to chromosomal rearrangements through evolutionary history (e.g., inversions and fusions), telomeric sequences are also found between the centromere and the terminal ends (i.e., at interstitial telomeric sites, ITSs). ITS telomere sequences have been implicated in heritable disease caused by genomic instability of ITS polymorphic variants, both with respect to copy number and sequence. In the sand lizard (Lacerta agilis), we have shown that telomere length is predictive of lifetime fitness in females but not males. To assess whether this sex specific fitness effect could be traced to ITSs differences, we mapped (TTAGGG) n sequences using fluorescence in situ hybridization in fibroblast cells cultured from 4 specimens of known sex. No ITSs could be found on autosomes in either sex. However, females have heterogametic sex chromosomes in sand lizards (ZW, 2n = 38) and the female W chromosome showed degeneration and remarkable (TTAGGG) n amplification, which was absent in the Z chromosomes. This work warrants further research on sex chromosome content, in particular of the degenerate W chromosome, and links to female fitness in sand lizards.},
}
@article {pmid26462146,
year = {2015},
author = {Xiong, YX and Su, HF and Lv, P and Ma, Y and Wang, SK and Miao, H and Liu, HY and Tan, JH and Ou, TM and Gu, LQ and Huang, ZS},
title = {A newly identified berberine derivative induces cancer cell senescence by stabilizing endogenous G-quadruplexes and sparking a DNA damage response at the telomere region.},
journal = {Oncotarget},
volume = {6},
number = {34},
pages = {35625-35635},
pmid = {26462146},
issn = {1949-2553},
mesh = {Anticarcinogenic Agents/chemical synthesis/*pharmacology ; Berberine/analogs &amp; derivatives/chemical synthesis/*pharmacology ; Carcinoma/*drug therapy/pathology ; Cell Cycle/drug effects ; Cellular Senescence/drug effects ; DNA Damage/drug effects ; Female ; Fibroblasts/*drug effects/physiology ; G-Quadruplexes/*drug effects ; HL-60 Cells ; Humans ; Shelterin Complex ; Telomere/genetics ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; Uterine Cervical Neoplasms/*drug therapy/pathology ; },
abstract = {The guanine-rich sequences are able to fold into G-quadruplexes in living cells, making these structures promising anti-cancer drug targets. In the current study, we identified a small molecule, Ber8, from a series of 9-substituted berberine derivatives and found that it could induce acute cell growth arrest and senescence in cancer cells, but not in normal fibroblasts. Further analysis revealed that the cell growth arrest was directly associated with apparent cell cycle arrest, cell senescence, and profound DNA damage at the telomere region. Significantly, our studies also provided evidence that Ber8 could stabilize endogenous telomeric G-quadruplexes structures in cells. Ber8 could then induce the delocalization of TRF1 and POT1 from the telomere accompanied by a rapid telomere uncapping. These results provide compelling insights into direct binding of telomeric G-quadruplexes and might contribute to the development of more selective, effective anticancer drugs.},
}
@article {pmid26458319,
year = {2015},
author = {Li, JP and Zhu, SW and Chen, YH and Wang, XL and Gao, X},
title = {Suppression of PinX1 resulted in telomere dysfunction and enhanced radiosensitivity in osteosarcoma cell lines.},
journal = {Neoplasma},
volume = {62},
number = {6},
pages = {887-893},
doi = {10.4149/neo_2015_108},
pmid = {26458319},
issn = {0028-2685},
abstract = {Telomeres have emerged as a promising and important factor modulating cellular and organism responses to ionizing radiation (IR). Pin2/TRF1 interacting protein X1 (PinX1) is an intrinsic telomerase inhibitor and a putative tumor suppressor gene in human cancers. The aim of this study is to investigate the role PinX1 in osteosarcoma (OS) radioresistance. A telomerase-positive OS cell line Saos-2 and a telomerase-negative OS cell line U2OS were used. PinX1 shRNA lentiviral vetors were constructed and transfected to cells. PinX1 expression was determined by real-time quantitative PCR (qPCR) and Western blotting. Relative telomere length (RTL) was detected by using qPCR. Flow cytometric analysis was used to detect cell cycle and apoptosis. Radiosensitivity was determined by colony formation assay. Data showed that, PinX1 knockdown resulted in telomere shortening, G1 phase arrest, increased apoptosis and enhanced IR sensitivity both in Saos-2 and U2OS cell lines, regardless of telomerase status. Our study concluded that PinX1 could serve as a novel predictor for radiotherapy response to OS patients, and the pathway of PinX1-mediated telomere stability might represent a new target to improve the radiotherapy effect of OS.},
}
@article {pmid26457630,
year = {2015},
author = {Zhan, Y and Song, C and Karlsson, R and Tillander, A and Reynolds, CA and Pedersen, NL and Hägg, S},
title = {Telomere Length Shortening and Alzheimer Disease--A Mendelian Randomization Study.},
journal = {JAMA neurology},
volume = {72},
number = {10},
pages = {1202-1203},
doi = {10.1001/jamaneurol.2015.1513},
pmid = {26457630},
issn = {2168-6157},
mesh = {Alzheimer Disease/complications/diagnosis/*genetics ; *Genetic Testing ; Humans ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide/*genetics ; Risk ; Telomere/*genetics ; },
}
@article {pmid26457386,
year = {2016},
author = {Sellmann, L and Scholtysik, R and de Beer, D and Eisele, L and Klein-Hitpass, L and Nückel, H and Dührsen, U and Dürig, J and Röth, A and Baerlocher, GM},
title = {Shorter telomeres correlate with an increase in the number of uniparental disomies in patients with chronic lymphocytic leukemia.},
journal = {Leukemia &amp; lymphoma},
volume = {57},
number = {3},
pages = {590-595},
doi = {10.3109/10428194.2015.1076929},
pmid = {26457386},
issn = {1029-2403},
mesh = {Chromosome Aberrations ; Female ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/mortality ; Male ; Oligonucleotide Array Sequence Analysis ; Polymorphism, Single Nucleotide ; Prognosis ; Retrospective Studies ; Telomere/genetics ; *Telomere Shortening ; *Uniparental Disomy ; },
abstract = {This study investigated the correlation of the extent of chromosomal aberrations including uniparental disomies (UPDs) by SNP-chip analysis and FISH to telomere length in 46 patients with CLL. CLL harboring high risk aberrations, i.e. deletions of 11q22-23 or 17p13, had significantly shorter telomeres (higher ΔTL) compared to patients with CLL without such abnormalities. Patients with high chromosomal aberration rates had a worse overall survival compared to cases with lower aberration rates. Interestingly, however, an increase was found in the number of UPDs with shorter telomeres. These findings support the idea that telomeres in CLL cells play a role in the overall chromosome stability and could be involved in the occurrence of UPDs.},
}
@article {pmid26455356,
year = {2016},
author = {Rane, JK and Greener, S and Frame, FM and Mann, VM and Simms, MS and Collins, AT and Berney, DM and Maitland, NJ},
title = {Telomerase Activity and Telomere Length in Human Benign Prostatic Hyperplasia Stem-like Cells and Their Progeny Implies the Existence of Distinct Basal and Luminal Cell Lineages.},
journal = {European urology},
volume = {69},
number = {4},
pages = {551-554},
doi = {10.1016/j.eururo.2015.09.039},
pmid = {26455356},
issn = {1873-7560},
support = {G2012-37/PCUK_/Prostate Cancer UK/United Kingdom ; },
mesh = {Biomarkers/metabolism ; *Cell Lineage ; *Cell Proliferation ; Humans ; Male ; Phenotype ; Prostate/*enzymology/pathology/surgery ; Prostatic Hyperplasia/*enzymology/genetics/pathology/surgery ; RNA/metabolism ; Stem Cells/*enzymology/pathology ; Telomerase/genetics/*metabolism ; *Telomere Homeostasis ; Transurethral Resection of Prostate ; },
abstract = {UNLABELLED: Benign prostatic hyperplasia (BPH) treatments have changed little over many years and do not directly address the underlying cause. Because BPH is characterised by uncontrolled cell growth, the chromosomal telomeres should be eroded in the reported absence or low levels of telomerase activity, but this is not observed. We investigated the telomere biology of cell subpopulations from BPH patients undergoing transurethral resection of prostate (TURP). Measurement of TERC, TERT, and telomerase activity revealed that only the epithelial stem-like and progenitor fractions expressed high levels of telomerase activity (p<0.01) and individual enzyme components (p<0.01). Telomerase activity and TERT expression were not detected in stromal cells. Telomere length measurements reflected this activity, although the average telomere length of (telomerase-negative) luminal cells was equivalent to that of telomerase-expressing stem/progenitor cells. Immunohistochemical analysis of patient-derived BPH arrays identified distinct areas of luminal hyperproliferation, basal hyperproliferation, and basal-luminal hyperproliferation, suggesting that basal and luminal cells can proliferate independently of each other. We propose a separate lineage for the luminal and basal cell components in BPH.<br><br>PATIENT SUMMARY: We unexpectedly found an enzyme called telomerase in the cells that maintain benign prostatic hyperplasia (BPH), suggesting that telomerase inhibitors could be used to alleviate BPH symptoms.},
}
@article {pmid26452299,
year = {2016},
author = {Mitro, SD and Birnbaum, LS and Needham, BL and Zota, AR},
title = {Cross-sectional Associations between Exposure to Persistent Organic Pollutants and Leukocyte Telomere Length among U.S. Adults in NHANES, 2001-2002.},
journal = {Environmental health perspectives},
volume = {124},
number = {5},
pages = {651-658},
pmid = {26452299},
issn = {1552-9924},
support = {R00 ES019881/ES/NIEHS NIH HHS/United States ; },
mesh = {Benzofurans ; Cross-Sectional Studies ; Dioxins ; Environmental Exposure/*statistics &amp; numerical data ; Environmental Pollutants/*toxicity ; Humans ; *Leukocytes ; Nutrition Surveys ; Polychlorinated Biphenyls/toxicity ; Polychlorinated Dibenzodioxins ; Receptors, Aryl Hydrocarbon ; *Telomere ; United States ; },
abstract = {BACKGROUND: Exposure to persistent organic pollutants (POPs) such as dioxins, furans, and polychlorinated biphenyls (PCBs) may influence leukocyte telomere length (LTL), a biomarker associated with chronic disease. In vitro research suggests dioxins may bind to the aryl hydrocarbon receptor (AhR) and induce telomerase activity, which elongates LTL. However, few epidemiologic studies have investigated associations between POPs and LTL.<br><br>OBJECTIVES: We examined the association between 18 PCBs, 7 dioxins, and 9 furans and LTL among 1,330 U.S. adults from NHANES 2001-2002.<br><br>METHODS: We created three summed POP metrics based on toxic equivalency factor (TEF), a potency measure including affinity for the AhR: a) non-dioxin-like PCBs (composed of 10 non-dioxin-like PCBs; no AhR affinity and no TEF); b) non-ortho PCBs (composed of 2 non-ortho-substituted PCBs with high TEFs); and c) toxic equivalency (TEQ) (composed of 7 dioxins, 9 furans, 2 non-ortho-substituted PCBs, and 6 mono-ortho-substituted PCBs; weighted by TEF). We tested the association between each metric and LTL using linear regression, adjusting for demographics, blood cell count and distribution, and another metric with a different TEF (i.e., non-ortho PCBs and TEQ adjusted for non-dioxin-like PCBs; non-dioxin-like PCBs adjusted for non-ortho PCBs).<br><br>RESULTS: In adjusted models, each doubling of serum concentrations of non-ortho PCBs and TEQ was associated with 3.74% (95% CI: 2.10, 5.40) and 5.29% (95% CI: 1.66, 9.05) longer LTLs, respectively. Compared with the lowest quartile, the highest quartile of exposure was associated with 9.16% (95% CI: 2.96, 15.73) and 7.84% (95% CI: -0.53, 16.92) longer LTLs, respectively. Non-dioxin-like PCBs were not associated with LTL.<br><br>CONCLUSIONS: POPs with high TEFs and AhR affinity were associated with longer LTL. Because many dioxin-associated cancers are also associated with longer LTL, these results may provide insight into the mechanisms underlying PCB- and dioxin-related carcinogenesis.<br><br>CITATION: Mitro SD, Birnbaum LS, Needham BL, Zota AR. 2016. Cross-sectional associations between exposure to persistent organic pollutants and leukocyte telomere length among U.S. adults in NHANES, 2001-2002. Environ Health Perspect 124:651-658;&#x2002;http://dx.doi.org/10.1289/ehp.1510187.},
}
@article {pmid26449496,
year = {2015},
author = {Zhou, MC and Min, R and Ji, JJ and Zhang, S and Tong, AL and Xu, JP and Li, ZY and Zhang, HB and Li, YX},
title = {Analysis of association among clinical features and shorter leukocyte telomere length in mitochondrial diabetes with m.3243A&gt;G mitochondrial DNA mutation.},
journal = {BMC medical genetics},
volume = {16},
number = {},
pages = {92},
pmid = {26449496},
issn = {1471-2350},
mesh = {Adenine/metabolism ; Adolescent ; Adult ; Age of Onset ; Aged ; DNA, Mitochondrial/*genetics ; Deafness/*genetics/pathology ; Diabetes Mellitus, Type 2/*genetics/pathology ; Female ; Genetic Association Studies/*methods ; Guanine/metabolism ; Humans ; Male ; Middle Aged ; Mitochondrial Diseases/*genetics/pathology ; Pedigree ; Polymorphism, Single Nucleotide ; Telomere/*metabolism ; Young Adult ; },
abstract = {BACKGROUND: Mitochondrial diabetes is a kind of rare diabetes caused by monogenic mutation in mitochondria. The study aimed to summarize the clinical phenotype profiles in mitochondrial diabetes with m.3243 A>G mitochondrial DNA mutation and to investigate the mechanism in this kind of diabetes by analyzing the relationship among clinical phenotypes and peripheral leukocyte DNA telomere length.<br><br>METHODS: Fifteen patients with maternally inherited diabetes in five families were confirmed as carrying the m.3243 A>G mitochondrial DNA mutation. One hundred patients with type 2 diabetes and one hundred healthy control subjects were recruited to participate in the study. Sanger sequencing was used to detect the m.3243 A>G mitochondrial DNA mutation. The peak height G/A ratio in the sequence diagram was calculated. Real-time polymerase chain reaction (PCR) was used to measure telomere length.<br><br>RESULTS: The patients with mitochondrial diabetes all had definite maternally inherited history, normal BMI (19.5 &#xb1; 2.36 kg/m(2)), early onset of diabetes (35.0 &#xb1; 14.6 years) and deafness. The peak height G/A ratio correlated significantly and negatively with the age at onset of diabetes (&#x2266; 25 years, 61.6 &#xb1; 20.17%; 25-45 years, 16.59 &#xb1; 8.64%; >45 years, 6.37 &#xb1; 0.59%; p = 0.000). Telomere length was significantly shorter among patients with mitochondrial diabetes and type 2 diabetes than in the control group (1.28 &#xb1; 0.54 vs. 1.14 &#xb1; 0.43 vs. 1.63 &#xb1; 0.61; p = 0.000). However, there was no significant difference between patients with mitochondrial diabetes and those with type 2 diabetes. There was no correlation between telomere length and the peak height G/A ratio.<br><br>CONCLUSION: Deafness with definite maternal inheritance and normal BMI, associated with elevated blood lactic acid and encephalomyopathy, for the most part, suggest the diagnosis of mitochondrial diabetes . The peak height G/A ratio could reflect the spectrum of age at onset of the disease. Telomere length was shorter in patients with mitochondrial diabetes and those with type 2 diabetes, which suggests that the shorter telomere length is likely involved in the pathogenesis of diabetes but is not specific for this kind of diabetes.},
}
@article {pmid26448623,
year = {2015},
author = {Matsumoto, R and Fukuoka, H and Iguchi, G and Odake, Y and Yoshida, K and Bando, H and Suda, K and Nishizawa, H and Takahashi, M and Yamada, S and Ogawa, W and Takahashi, Y},
title = {Accelerated Telomere Shortening in Acromegaly; IGF-I Induces Telomere Shortening and Cellular Senescence.},
journal = {PloS one},
volume = {10},
number = {10},
pages = {e0140189},
pmid = {26448623},
issn = {1932-6203},
mesh = {Acromegaly/*genetics/pathology ; Adult ; Aged ; Cells, Cultured ; Cellular Senescence ; Female ; Fibroblasts/physiology ; Human Growth Hormone/physiology ; Humans ; Insulin-Like Growth Factor I/*physiology ; Male ; Middle Aged ; Signal Transduction ; *Telomere Shortening ; },
abstract = {OBJECTIVE: Patients with acromegaly exhibit reduced life expectancy and increased prevalence of age-related diseases, such as diabetes, hypertension, and cardiovascular disease. However, the underlying mechanism has not been fully elucidated. Telomere shortening is reportedly associated with reduced life expectancy and increased prevalence of these age-related diseases.<br><br>METHODS: We measured telomere length in patients with acromegaly using quantitative PCR method. The effect of GH and IGF-I on telomere length and cellular senescence was examined in human skin fibroblasts.<br><br>RESULTS: Patients with acromegaly exhibited shorter telomere length than age-, sex-, smoking-, and diabetes-matched control patients with non-functioning pituitary adenoma (0.62 &#xb1; 0.23 vs. 0.75 &#xb1; 0.35, respectively, P = 0.047). In addition, telomere length in acromegaly was negatively correlated with the disease duration (R2 = 0.210, P = 0.003). In vitro analysis revealed that not GH but IGF-I induced telomere shortening in human skin fibroblasts. Furthermore, IGF-I-treated cells showed increased senescence-associated &#x3b2;-galactosidase activity and expression of p53 and p21 protein. IGF-I-treated cells reached the Hayflick limit earlier than GH- or vehicle-treated cells, indicating that IGF-I induces cellular senescence.<br><br>CONCLUSION: Shortened telomeres in acromegaly and cellular senescence induced by IGF-I can explain, in part, the underlying mechanisms by which acromegaly exhibits an increased morbidity and mortality in association with the excess secretion of IGF-I.},
}
@article {pmid26446451,
year = {2016},
author = {Banfic, H and Crljen, V and Lukinovic-Skudar, V and Dembitz, V and Lalic, H and Bedalov, A and Visnjic, D},
title = {Inositol pyrophosphates modulate cell cycle independently of alteration in telomere length.},
journal = {Advances in biological regulation},
volume = {60},
number = {},
pages = {22-28},
doi = {10.1016/j.jbior.2015.09.003},
pmid = {26446451},
issn = {2212-4934},
mesh = {*Cell Cycle ; Cell Division ; Inositol Phosphates/*metabolism ; Saccharomyces cerevisiae/*cytology/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Signal Transduction ; Telomere/genetics/*metabolism ; },
abstract = {Synthesis of inositol pyrophosphates through activation of Kcs1 plays an important role in the signalling response required for cell cycle progression after mating pheromone arrest. Overexpression of Kcs1 doubled the level of inositol pyrophosphates when compared to wild type cells and 30 min following the release from α-factor block further increase in inositol pyrophosphates was observed, which resulted that cells overexpressing Kcs1 reached G2/M phase earlier than wild type cells. Similar effect was observed in ipk1Δ cells, which are unable to synthesize IP6-derived inositol pyrophosphates (IP7 and IP8) but will synthesize IP5-derived inositol pyrophosphates (PP-IP4 and (PP)2-IP3). Although ipk1Δ cells have shorter telomeres than wild type cells, overexpression of Kcs1 in both strains have similar effect on cell cycle progression. As it is known that PP-IP4 regulates telomere length through Tel1, inositol polyphosphates, cell cycle and telomere length were determined in tel1Δ cells. The release of the cells from α-factor block and overexpression of Kcs1 in tel1Δ cells produced similar effects on inositol pyrophosphates level and cell cycle progression when compared to wild type cells, although tel1Δ cells possesses shorter telomeres than wild type cells. It can be concluded that telomere length does not affect cell cycle progression, since cells with short telomeres (ipk1Δ and tel1Δ) progress through cell cycle in a similar manner as wild type cells and that overexpression of Kcs1 in cells with either short or normal telomeres will increase S phase progression without affecting telomere length. Furthermore, IP5-derived inositol pyrophosphates can compensate for the loss of IP6-derived inositol pyrophosphates, in modulating S phase progression of the cell cycle.},
}
@article {pmid26446377,
year = {2015},
author = {Liu, M and Maselli, J and Hales, BF and Robaire, B},
title = {The effects of chemotherapy with bleomycin, etoposide, and cis-platinum on telomeres in rat male germ cells.},
journal = {Andrology},
volume = {3},
number = {6},
pages = {1104-1112},
doi = {10.1111/andr.12102},
pmid = {26446377},
issn = {2047-2927},
mesh = {Animals ; Antineoplastic Combined Chemotherapy Protocols/*toxicity ; Bleomycin/*toxicity ; Cell Line ; Cisplatin/*toxicity ; DNA Breaks, Double-Stranded ; Etoposide/*toxicity ; Histones/metabolism ; Male ; Phosphorylation ; Rats, Inbred BN ; Spermatogonia/*drug effects/metabolism/pathology ; Telomere/*drug effects/metabolism ; Telomere Shortening/*drug effects ; Time Factors ; },
abstract = {Co-administration of bleomycin, etoposide, and cis-platinum (BEP) has increased the 5-year survival rate of testis cancer patients to over 90%; however, this treatment induces chemotoxic effects on male germ cells. Treatment of male rats with BEP, using a similar schedule to that used in man, affects reproductive organ weights and sperm count, motility, and DNA integrity, as well as pup survival rates. Telomeres, specialized structures at the termini of chromosomes, play an important role in the maintenance of genetic stability. In previous studies, we demonstrated, using a spermatogonial cell line, that cis-platinum and bleomycin damage telomeres and that cis-platinum also inhibits telomerase activity. Our objective here was to test the hypothesis that in vivo exposure to the BEP regimen used to treat testis cancer targets telomeres in the male germ line. Adult male Brown Norway rats received chronic treatment with a BEP regimen. DNA double strand breaks were increased significantly in zygotene germ cells, as assessed by γ-H2AX immunofluorescence. Interestingly, treatment with this BEP regimen increased γ-H2AX foci in the telomere region of zygotene spermatocytes, but not in other germ cell types, such as pachytene cells, round spermatids, or elongating spermatids. Mean telomere lengths were reduced in zygotene, pachytene, round spermatid, elongating spermatid and cauda epididymal spermatozoa compared with the saline control group. Thus, telomere lengths did not recover during germ cell development. These studies demonstrate that BEP treatment is associated with an effect on telomeres.},
}
@article {pmid26445446,
year = {2015},
author = {Kepten, E and Weron, A and Bronstein, I and Burnecki, K and Garini, Y},
title = {Uniform Contraction-Expansion Description of Relative Centromere and Telomere Motion.},
journal = {Biophysical journal},
volume = {109},
number = {7},
pages = {1454-1462},
pmid = {26445446},
issn = {1542-0086},
mesh = {Anisotropy ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Cell Nucleus Size/physiology ; Centromere/*metabolism ; Computer Simulation ; Diffusion ; Humans ; Microscopy, Confocal ; Microscopy, Fluorescence ; Models, Biological ; *Motion ; Stochastic Processes ; Telomere/*metabolism ; Time ; Video Recording ; Viscoelastic Substances/metabolism ; },
abstract = {Internal organization and dynamics of the eukaryotic nucleus have been at the front of biophysical research in recent years. It is believed that both dynamics and location of chromatin segments are crucial for genetic regulation. Here we study the relative motion between centromeres and telomeres at various distances and at times relevant for genetic activity. Using live-imaging fluorescent microscopy coupled to stochastic analysis of relative trajectories, we find that the interlocus motion is distance-dependent with a varying fractional memory. In addition to short-range constraining, we also observe long-range anisotropic-enhanced parallel diffusion, which contradicts the expectation for classic viscoelastic systems. This motion is linked to uniform expansion and contraction of chromatin in the nucleus, and leads us to define and measure a new (to our knowledge) uniform contraction-expansion diffusion coefficient that enriches the contemporary picture of nuclear behavior. Finally, differences between loci types suggest that different sites along the genome experience distinctive coupling to the nucleoplasm environment at all scales.},
}
@article {pmid26445269,
year = {2015},
author = {Neuner, B and Lenfers, A and Kelsch, R and Jäger, K and Brüggmann, N and van der Harst, P and Walter, M},
title = {Telomere Length Is Not Related to Established Cardiovascular Risk Factors but Does Correlate with Red and White Blood Cell Counts in a German Blood Donor Population.},
journal = {PloS one},
volume = {10},
number = {10},
pages = {e0139308},
pmid = {26445269},
issn = {1932-6203},
mesh = {Adolescent ; Adult ; Aged ; Aging/genetics ; Biomarkers/metabolism ; Blood Donors ; Cardiovascular Diseases/*genetics/*metabolism ; Cholesterol/metabolism ; Erythrocyte Count/methods ; Erythrocytes/*metabolism ; Female ; Hematocrit/methods ; Hemoglobins/metabolism ; Humans ; Leukocyte Count/methods ; Leukocytes/*metabolism ; Male ; Middle Aged ; Risk Factors ; Telomere/*genetics ; Triglycerides/metabolism ; Young Adult ; },
abstract = {Telomere length (TL) is considered a marker of biological aging and has been associated with the presence of various coronary risk factors in patients. Much less is known about the relationships between TL and classic coronary risk factors in other populations. We measured TL in peripheral blood leukocytes of 343 middle-aged blood donors (mean age 40.2 ± 12.4 years; 201 men, 142 women) using quantitative polymerase chain reaction. Median TL was 0.86 (range: 0.48-1.85) relative TL units. In linear regression analyses with natural log-transformed T to S ratio as the dependent variable, there was a significant association with age (per year: beta = -0.007, p<0.001) and sex (males vs. females: beta = 0.075, p = 0.007) with longer telomeres in men. After adjusting for these two variables, we observed no association of TL with classic coronary risk factors including cholesterol (p = 0.36), triglyceride (p = 0.09), HDL-cholesterol (p = 0.26), LDL-cholesterol (p = 0.36), smoking (p = 0.97), and personal (p = 0.46) or family history (p = 0.63) of cardiovascular disease. However, we did find a significant positive association with white (p = 0.011) and red blood cell count (p = 0.031), hemoglobin (p = 0.014) and hematocrit (p = 0.013); we also found a borderline positive association with thrombocytes (p = 0.074). Positive associations remained significant for hemoglobin (p = 0.017), hematocrit (p = 0.023), and leukocytes (p = 0.009) in a subgroup with no reported vascular disease; associations were of borderline significance for erythrocytes (p = 0.053) and thrombocytes (p = 0.088) in this subgroup. The data do not support the concept that classic coronary risk factors contribute to telomere attrition in a blood donor population. However, telomere attrition may be a marker for reduced proliferation reserve in hematopoietic progenitor cells.},
}
@article {pmid26439854,
year = {2016},
author = {Ray, A and Hong, CS and Feingold, E and Ghosh, P and Ghosh, P and Bhaumik, P and Dey, S and Ghosh, S},
title = {Maternal Telomere Length and Risk of Down Syndrome: Epidemiological Impact of Smokeless Chewing Tobacco and Oral Contraceptive on Segregation of Chromosome 21.},
journal = {Public health genomics},
volume = {19},
number = {1},
pages = {11-18},
doi = {10.1159/000439245},
pmid = {26439854},
issn = {1662-8063},
mesh = {Adult ; Case-Control Studies ; Child ; Chromosomes, Human, Pair 21/*genetics ; Contraceptives, Oral/*adverse effects ; *Down Syndrome/diagnosis/epidemiology/genetics ; Female ; Humans ; India/epidemiology ; Maternal Age ; Nondisjunction, Genetic ; Pregnancy ; *Prenatal Exposure Delayed Effects/diagnosis/epidemiology/etiology ; Risk Factors ; Statistics as Topic ; Telomere/*pathology ; Tobacco, Smokeless/*adverse effects ; },
abstract = {BACKGROUND: We have previously demonstrated a relationship between children born with Down syndrome and maternal telomere length. Similarly, exposure to tobacco and oral contraceptives has been explored in one of our earlier studies as a risk factor for Down syndrome.<br><br>OBJECTIVE: In the present study, we consider the interactions among these risk factors associated with Down syndrome in a population from Kolkata, India, using analyses stratified by maternal age.<br><br>METHODS: We estimated the telomere length of women with children with Down syndrome by restriction enzyme/Southern blot methods. Linear regression was employed to estimate telomere shortening as an indicator of the maternal age of conception. Interactions among the various factors were analyzed by logistic regression.<br><br>RESULT: We found an association between the use of smokeless chewing tobacco and shorter telomere length among women who experienced meiosis I nondisjunction at gametogenesis; the effect is seen across all maternal age groups. In contrast, oral contraceptive use alone did not exhibit a statistically significant association with maternal telomere length, but there was an interaction with the use of smokeless chewing tobacco in the older mothers who experienced meiotic II nondisjunction.<br><br>CONCLUSION: Environmental/habitual factors interact with molecular components of the oocyte, which ultimately increases the risk of chromosome 21 nondisjunction and subsequently of giving birth to a child with Down syndrome.},
}
@article {pmid26438644,
year = {2015},
author = {Czamanski-Cohen, J and Sarid, O and Cwikel, J and Douvdevani, A and Levitas, E and Lunenfeld, E and Har-Vardi, I},
title = {Cell-free DNA and telomere length among women undergoing in vitro fertilization treatment.},
journal = {Journal of assisted reproduction and genetics},
volume = {32},
number = {11},
pages = {1697-1703},
pmid = {26438644},
issn = {1573-7330},
support = {R25 CA078447/CA/NCI NIH HHS/United States ; CA078447-14/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Case-Control Studies ; DNA/*blood ; Female ; Fertilization in Vitro/methods ; Humans ; Hydrocortisone/blood ; Infertility, Female/*genetics ; Lymphocytes/physiology ; Telomere/*physiology ; Telomere Homeostasis/genetics ; Young Adult ; },
abstract = {PURPOSE: The current research is aimed at finding potential non-invasive bio-markers that will help us learn more about the mechanisms at play in failed assisted reproduction treatment. This exploratory pilot study examined the relationship between cell-free DNA (CFD) in plasma and telomere length in lymphocytes among women undergoing in vitro fertilization (IVF) and compared telomere length and CFD levels to a healthy control group.<br><br>METHODS: Blood of 20 women undergoing IVF was collected at three time points during the IVF cycle. We assessed the relationship between CFD and telomere length as well as controlling for morning cortisol levels. We also collected blood of 10 healthy controls at two time points (luteal and follicular phases of the menstrual cycle) and compared mean telomere length, CFD, and cortisol levels between the IVF patients and healthy controls.<br><br>RESULTS: The results revealed an inverse relationship between CFD levels and telomere lengths at several time points that remained significant even after controlling for cortisol levels. Women undergoing IVF had statistically significant higher levels of CFD and shorter telomeres compared to healthy controls.<br><br>CONCLUSIONS: The relationship between telomere length and CFD should be further explored in larger studies in order to uncover potential mechanisms that cause both shortened telomere length and elevated CFD in women undergoing IVF.},
}
@article {pmid26435846,
year = {2015},
author = {Lustig, AJ},
title = {Potential Risks in the Paradigm of Basic to Translational Research: A Critical Evaluation of qPCR Telomere Size Techniques.},
journal = {Journal of cancer epidemiology &amp; treatment},
volume = {1},
number = {1},
pages = {28-37},
pmid = {26435846},
issn = {2059-8556},
support = {R01 GM069943/GM/NIGMS NIH HHS/United States ; R56 GM069943/GM/NIGMS NIH HHS/United States ; },
abstract = {Real time qPCR has become the method of choice for rapid large-scale telomere length measurements. Large samples sizes are critical for clinical trials, and epidemiological studies. QPCR has become such routine procedure that it is often used with little critical analysis. With proper controls, the mean telomere size can be derived from the data and even the size can be estimated. But there is a need for more consistent and reliable controls that will provide closer to the actual mean size can be obtained with uniform consensus controls. Although originating at the level of basic telomere research, many researchers less familiar with telomeres often misunderstand the source and significance of the qPCR metric. These include researchers and clinicians who are interested in having a rapid tool to produce exciting results in disease prognostics and diagnostics than in the multiple characteristics of telomeres that form the basis of the measurement. But other characteristics of the non-bimodal and heterogeneous telomeres as well as the complexities of telomere dynamics are not easily related to qPCR mean telomere values. The qPCR metric does not reveal the heterogeneity and dynamics of telomeres. This is a critical issue since mutations in multiple genes including telomerase can cause telomere dysfunction and a loss of repeats. The smallest cellular telomere has been shown to arrest growth of the cell carrying the dysfunction telomere. A goal for the future is a simple method that takes into account the heterogeneity by measuring the highest and lowest values as part of the scheme to compare. In the absence of this technique, Southern blots need to be performed in a subset of qPCR samples for both mean telomere size and the upper and lower extremes of the distribution. Most importantly, there is a need for greater transparency in discussing the limitations of the qPCR data. Given the potentially exciting qPCR telomere size results emerging from clinical studies that relate qPCR mean telomere size estimates to disease states, the current ambiguities have become urgent issues to validate the findings and to set the right course for future clinical investigations.},
}
@article {pmid26429668,
year = {2015},
author = {Glade, MJ and Meguid, MM},
title = {A glance at … telomeres, oxidative stress, antioxidants, and biological aging.},
journal = {Nutrition (Burbank, Los Angeles County, Calif.)},
volume = {31},
number = {11-12},
pages = {1447-1451},
doi = {10.1016/j.nut.2015.05.018},
pmid = {26429668},
issn = {1873-1244},
mesh = {*Aging ; Antioxidants/*pharmacology ; *Diet ; Humans ; Oxidative Stress/*drug effects ; Telomere/*drug effects ; Telomere Shortening/*drug effects ; },
}
@article {pmid26428317,
year = {2015},
author = {Liau, JY and Lee, JC and Tsai, JH and Yang, CY and Liu, TL and Ke, ZL and Hsu, HH and Jeng, YM},
title = {Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas.},
journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},
volume = {28},
number = {12},
pages = {1545-1554},
pmid = {26428317},
issn = {1530-0285},
mesh = {Adaptor Proteins, Signal Transducing/analysis/biosynthesis ; Co-Repressor Proteins ; DNA Helicases/analysis/*biosynthesis ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Molecular Chaperones ; Nuclear Proteins/analysis/*biosynthesis ; Phenotype ; Sarcoma/*genetics/pathology ; Soft Tissue Neoplasms/*genetics/pathology ; Telomere/genetics ; Telomere Homeostasis/*physiology ; X-linked Nuclear Protein ; },
abstract = {According to cytogenetic aberrations, sarcomas can be categorized as complex or simple karyotype tumors. Alternative lengthening of telomeres is a telomere-maintenance mechanism common in sarcomas. Recently, this mechanism was found to be associated with loss of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. We previously reported that alternative lengthening of telomeres and loss of ATRX expression were common in leiomyosarcoma, angiosarcoma, pleomorphic liposarcoma, and dedifferentiated liposarcoma. In the present study, we screened an additional 245 sarcomas of other types to determine the prevalence of alternative lengthening of telomeres, loss of ATRX/DAXX expression, and their relationship. Undifferentiated pleomorphic sarcomas were frequently alternative lengthening of telomeres positive (65%) and loss of ATRX was seen in approximately half of the alternative lengthening of telomeres-positive tumors. Nineteen of 25 myxofibrosarcomas were alternative lengthening of telomeres-positive, but only one was ATRX deficient. Three of 15 radiation-associated sarcomas were alternative lengthening of telomeres positive, but none of them was ATRX deficient. Alternative lengthening of telomeres and/or loss of ATRX were uncommon in malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, and embryonal rhabdomyosarcomas. By contrast, none of the 71 gene fusion-associated sarcomas was ATRX deficient or alternative lengthening of telomeres positive. All tumors exhibited preserved DAXX expression. Combining our previous studies and this study, a total of 384 sarcomas with complex karyotypes were examined, 83 of which were ATRX deficient (22%). By telomere-specific fluorescence in situ hybridization, 45% (138/308) were alternative lengthening of telomeres positive, 55% (76/138) of which were ATRX deficient. Loss of ATRX was highly associated with alternative lengthening of telomeres (P<0.001). We conclude that alternative lengthening of telomeres is a frequent telomere-maintenance mechanism in cytogenetically complex sarcomas. Loss of ATRX is highly associated with this feature.},
}
@article {pmid26427727,
year = {2015},
author = {Beier, F and Masouleh, BK and Buesche, G and Ventura Ferreira, MS and Schneider, RK and Ziegler, P and Wilop, S and Vankann, L and Gattermann, N and Platzbecker, U and Giagounidis, A and Götze, KS and Nolte, F and Hofmann, WK and Haase, D and Kreipe, H and Panse, J and Blasco, MA and Germing, U and Brümmendorf, TH},
title = {Telomere dynamics in patients with del (5q) MDS before and under treatment with lenalidomide.},
journal = {Leukemia research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.leukres.2015.09.003},
pmid = {26427727},
issn = {1873-5835},
abstract = {Myelodysplastic syndrome (MDS) associated with an acquired, isolated deletion of chromosome 5q (del (5q) MDS), represent a clonal disorder of hematopoiesis and a clinically distinct entity of MDS. Treatment of del (5q) MDS with the drug lenalidomide has significantly improved quality of life leading to transfusion independence and complete cytogenetic response rates (CCR) in the majority of patients. Telomeres are located at the end of eukaryotic chromosomes and are linked to replicative history/potential as well as genetic (in) stability of hematopoietic stem cells. Here, we analyzed telomere length (TL) dynamics before and under lenalidomide treatment in the peripheral blood and/or bone marrow of del (5q) patients enrolled in the LEMON-5 study (NCT01081431). Hematopoietic cells from del (5q) MDS patients were characterized by significantly shortened TL compared to age-matched healthy controls. Telomere loss was more accelerated in patients with longer disease duration (>2 years) and more pronounced cytopenias. Sequential analysis under lenalidomide treatment revealed that previously shortened TL in peripheral blood cells was significantly "elongated" towards normal levels within the first six months suggesting a shift from clonal del (5q) cells towards normal hematopoiesis in lenalidomide treated MDS patients. Taken together our findings suggest that the development of the del (5q) clone is associated with accelerated telomere shortening at diagnosis. However, upon induction of CCR and reoccurrence of normal hematopoiesis, the lack of a persistent TL deficit argues against telomere-mediated genetic instability neither as a disease-promoting event of del (5q) MDS nor for lenalidomide mediated development of secondary primary malignancies of the hematopoietic system in responding patients.},
}
@article {pmid26426910,
year = {2016},
author = {Kahl, VF and Simon, D and Salvador, M and Branco, Cdos S and Dias, JF and da Silva, FR and de Souza, CT and da Silva, J},
title = {Telomere measurement in individuals occupationally exposed to pesticide mixtures in tobacco fields.},
journal = {Environmental and molecular mutagenesis},
volume = {57},
number = {1},
pages = {74-84},
doi = {10.1002/em.21984},
pmid = {26426910},
issn = {1098-2280},
mesh = {Adolescent ; Adult ; Aged ; Brazil ; Case-Control Studies ; DNA Damage ; Female ; Humans ; Life Style ; Male ; Middle Aged ; Occupational Exposure/*adverse effects ; Pesticides/*toxicity ; Public Health Surveillance ; Risk Factors ; Smoking/*adverse effects ; Telomere/*drug effects ; Telomere Homeostasis/drug effects ; Nicotiana/*adverse effects ; Young Adult ; },
abstract = {Occupational exposure to pesticides in tobacco fields causes genetic damage in farmers. The aim of this study was to analyze tobacco farmers chronically exposed to low doses of pesticides and nicotine (present in the tobacco leaves) in relation to absolute telomere length (aTL), and explore the influence of lifestyle characteristics, oxidative stress, and inorganic element levels. DNA was isolated from peripheral blood samples from agricultural workers and non-exposed individuals, and aTL was measured by quantitative real time polymerase chain reaction (qPCR) analysis. Oxidative stress (thiobarbituric acid reactive substances [TBARS], which measures oxidative damage to lipids; and toxic equivalent antioxidant capacity [TEAC], which measures total equivalent antioxidant capacity) was evaluated in serum, and inorganic element content was analyzed in whole blood through particle-induced X-ray emission technique. It was found that exposure to pesticides and tobacco smoking had significant effects on aTL. Individuals occupationally exposed to complex mixtures of pesticides in tobacco fields and individuals who smoked had decreased aTL compared with the non-exposed group. TBARS and TEAC were significantly elevated in the exposed group. There were no significant differences in inorganic elements. There was no evidence of an influence of age, gender, consumption of alcoholic beverages, or intake of fruits and vegetables on aTL within the groups. In addition, years of work in the tobacco field in the exposed group did not influence any of the variables analyzed. Although further studies were needed, these results suggested differences in telomere maintenance in tobacco farmers compared with the control group, indicating that telomere length may be a good biomarker of occupational exposure.},
}
@article {pmid26425704,
year = {2015},
author = {Nezu, T and Hosomi, N and Takahashi, T and Anno, K and Aoki, S and Shimamoto, A and Maruyama, H and Hayashi, T and Matsumoto, M and Tahara, H},
title = {Telomere G-tail Length is a Promising Biomarker Related to White Matter Lesions and Endothelial Dysfunction in Patients With Cardiovascular Risk: A Cross-sectional Study.},
journal = {EBioMedicine},
volume = {2},
number = {8},
pages = {960-967},
pmid = {26425704},
issn = {2352-3964},
mesh = {Aged ; Aged, 80 and over ; Aging/*metabolism/pathology ; Biomarkers/metabolism ; Cardiovascular Diseases/*metabolism/pathology ; Female ; Humans ; Leukocytes/*metabolism/pathology ; Male ; Risk Factors ; Telomere/*metabolism ; *Telomere Homeostasis ; White Matter/*metabolism/pathology ; },
abstract = {BACKGROUND: The telomeric 3'-overhang (G-tail) length is essential for the biological effects of telomere dysfunction in vitro, but the association of length with aging and cardiovascular risk is unclear in humans. We investigated the association between the telomere G-tail length of leukocytes and cardiovascular risk, age-related white matter changes (ARWMCs), and endothelial function.<br><br>METHODS: Patients with a history of cerebrovascular disease and comorbidity were enrolled (n&#xa0;=&#xa0;102; 69 males and 33 females, 70.1&#xa0;&#xb1;&#xa0;9.2&#xa0;years). Total telomere and telomere G-tail lengths were measured using a hybridization protection assay. Endothelial function was evaluated by ultrasound assessment of brachial flow-mediated dilation (FMD).<br><br>FINDINGS: Shortened telomere G-tail length was associated with age and Framingham risk score (P&#xa0;=&#xa0;0.018 and P&#xa0;=&#xa0;0.012). In addition, telomere G-tail length was positively correlated with FMD values (P&#xa0;=&#xa0;0.031) and negatively with the severity of ARWMCs (P&#xa0;=&#xa0;0.002). On multivariate regression analysis, telomere G-tail length was independently associated with FMD values (P&#xa0;=&#xa0;0.022) and the severity of ARWMCs (P&#xa0;=&#xa0;0.033), whereas total telomere length was not associated with these indicators.<br><br>INTERPRETATION: Telomere G-tail length is associated with age and vascular risk factors, and might be superior to total telomere length as a marker of endothelial dysfunction and ARWMC severity.},
}
@article {pmid26425685,
year = {2015},
author = {Seimiya, H},
title = {Predicting Risk at the End of the End: Telomere G-tail as a Biomarker.},
journal = {EBioMedicine},
volume = {2},
number = {8},
pages = {804-805},
pmid = {26425685},
issn = {2352-3964},
mesh = {Aging/genetics/*metabolism ; Animals ; Biomarkers/metabolism ; Dyskeratosis Congenita/genetics/*metabolism ; Humans ; Progeria/genetics/*metabolism ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; Werner Syndrome/genetics/*metabolism ; },
}
@article {pmid26425659,
year = {2015},
author = {Mender, I and Gryaznov, S and Shay, JW},
title = {A novel telomerase substrate precursor rapidly induces telomere dysfunction in telomerase positive cancer cells but not telomerase silent normal cells.},
journal = {Oncoscience},
volume = {2},
number = {8},
pages = {693-695},
pmid = {26425659},
issn = {2331-4737},
support = {C06 RR030414/RR/NCRR NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; },
abstract = {Although telomerase is an almost universal target for cancer therapy, there has been no effective telomerase targeted inhibitor that has progressed to late stage human clinical trials. Recently, we reported that a telomerase-mediated telomere-disrupting compound, 6-thio-2'-deoxyguanosine (6-thio-dG), was very effective at targeting telomerase positive cancer cells while sparing telomerase silent normal cells. 6-thio-dG, a nucleoside analogue of the already-approved drug 6-thioguanine, is incorporated into telomeres by telomerase, resulting in disruption of the telomere-protecting shelterin complex. This disruption leads to Telomere dysfunction-Induced Foci (TIFs) formation and rapid cell death for the vast majority of cancer cells. Since most chemotherapies eventually fail due to drug acquired resistance, novel drugs such as 6-thio-dG, as a single first line agent or in the maintenance setting, may represent an effective new treatment for cancer patients.},
}
@article {pmid26423240,
year = {2015},
author = {Raschenberger, J and Kollerits, B and Titze, S and Köttgen, A and Bärthlein, B and Ekici, AB and Forer, L and Schönherr, S and Weissensteiner, H and Haun, M and Wanner, C and Eckardt, KU and Kronenberg, F and , },
title = {Do telomeres have a higher plasticity than thought? Results from the German Chronic Kidney Disease (GCKD) study as a high-risk population.},
journal = {Experimental gerontology},
volume = {72},
number = {},
pages = {162-166},
doi = {10.1016/j.exger.2015.09.019},
pmid = {26423240},
issn = {1873-6815},
mesh = {Aged ; Aging/*genetics ; Biomarkers ; Cross-Sectional Studies ; Female ; Germany ; Humans ; Linear Models ; Male ; Middle Aged ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; Renal Insufficiency, Chronic/*genetics ; Risk Factors ; Telomere/*ultrastructure ; },
abstract = {Telomere length is considered as a biological marker for aging. It is expected that telomeres shorten with age and with conditions associated with oxidative stress and inflammation. Both are present in patients with chronic kidney disease (CKD) who have a very high cardiovascular risk. We investigated whether CKD duration is associated with relative telomere length (RTL) in 4802 patients from the German Chronic Kidney Disease (GCKD) study. We measured RTL in each sample in quadruplicates using a quantitative polymerase chain reaction (qPCR). We observed a U-shaped association of RTL with CKD duration: the longest RTL was found in those 339 patients who reported the shortest disease duration (<6 months) and shorter RTL in 2108 patients with duration between 6 months and less than 5 years. Most importantly, those 2331 patients who reported a CKD duration of 5 years and more had significantly longer RTL compared to those with intermediate CKD duration (6 months to less than 5 years): mean 0.954, 95%CI 0.946-0.961 versus 0.937, 95%CI 0.929-0.944, p=0.002). Due to the cross-sectional nature of the study these surprising results have to be considered with caution and as hypothesis-generating. Whether the longer RTL in patients with long-lasting disease is caused by an activation of telomerase to counteract the shortening of RTL due to oxidative stress and inflammation or whether they are caused by a survival bias needs to be investigated in longitudinal studies. Our data are in support of a higher plasticity of shortening and elongations of RTL as until recently anticipated.},
}
@article {pmid26422132,
year = {2015},
author = {Jia, P and Her, C and Chai, W},
title = {DNA excision repair at telomeres.},
journal = {DNA repair},
volume = {36},
number = {},
pages = {137-145},
pmid = {26422132},
issn = {1568-7856},
support = {R01 GM112864/GM/NIGMS NIH HHS/United States ; R01GM112864/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; DNA/metabolism ; *DNA Damage ; *DNA Repair ; Genomic Instability ; Humans ; Saccharomyces cerevisiae/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {DNA damage is caused by either endogenous cellular metabolic processes such as hydrolysis, oxidation, alkylation, and DNA base mismatches, or exogenous sources including ultraviolet (UV) light, ionizing radiation, and chemical agents. Damaged DNA that is not properly repaired can lead to genomic instability, driving tumorigenesis. To protect genomic stability, mammalian cells have evolved highly conserved DNA repair mechanisms to remove and repair DNA lesions. Telomeres are composed of long tandem TTAGGG repeats located at the ends of chromosomes. Maintenance of functional telomeres is critical for preventing genome instability. The telomeric sequence possesses unique features that predispose telomeres to a variety of DNA damage induced by environmental genotoxins. This review briefly describes the relevance of excision repair pathways in telomere maintenance, with the focus on base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). By summarizing current knowledge on excision repair of telomere damage and outlining many unanswered questions, it is our hope to stimulate further interest in a better understanding of excision repair processes at telomeres and in how these processes contribute to telomere maintenance.},
}
@article {pmid26420717,
year = {2015},
author = {Rai, R and Chang, S},
title = {Monitoring the DNA Damage Response at Dysfunctional Telomeres.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1343},
number = {},
pages = {175-180},
doi = {10.1007/978-1-4939-2963-4_14},
pmid = {26420717},
issn = {1940-6029},
mesh = {*DNA Damage ; HEK293 Cells ; Humans ; In Situ Hybridization, Fluorescence/methods ; Telomere/*metabolism ; },
abstract = {Telomeres are repetitive DNA repeats that cap the ends of all eukaryotic chromosomes. Their proper maintenance is essential for genomic stability and cellular viability. Dysfunctional telomeres could arise through natural attrition of telomeric DNA or due to the removal of shelterin components. These uncapped chromosomal ends are recognized as DSBs by the DDR pathway, leading to the accumulation of DNA damage sensors at telomeres. The association of these DDR proteins with dysfunctional telomeres forms telomere dysfunction induced DNA damage foci (TIFs). Detection of TIFs at telomeres provides an opportunity to quantify the extent of telomere dysfunction and monitor downstream DNA damage signaling pathways. Here we describe a method for the detection of TIFs using a fluorescent in situ hybridization (FISH) approach.},
}
@article {pmid26419237,
year = {2015},
author = {Menke, A and Casagrande, S and Cowie, CC},
title = {Leukocyte telomere length and diabetes status, duration, and control: the 1999-2002 National Health and Nutrition Examination Survey.},
journal = {BMC endocrine disorders},
volume = {15},
number = {},
pages = {52},
pmid = {26419237},
issn = {1472-6823},
support = {GS10F0381L//PHS HHS/United States ; },
mesh = {Adult ; Blood Glucose/analysis ; Diabetes Mellitus/*physiopathology ; Female ; Glycated Hemoglobin/analysis ; Humans ; Leukocytes/*pathology ; Male ; Middle Aged ; Nutrition Surveys ; Telomere Homeostasis/*genetics ; Time Factors ; },
abstract = {BACKGROUND: Studies investigating the association between telomere length and diabetes have been inconsistent, and there are few data available investigating the associations of telomere length with diabetes duration and control. We evaluated the relationship of leukocyte telomere length with diabetes, and the relationship of leukocyte telomere length with diabetes duration and poor glucose control among people with diabetes.<br><br>METHODS: We used data from the 1999-2002 National Health and Nutrition Examination Survey, a representative sample of the US civilian non-institutionalized population. In 3921 participants, leukocyte telomere length was measured and diabetes status was determined based on a previous diagnosis, hemoglobin A1c &#x2265; 6.5 %, or fasting glucose &#x2265; 126 mg/dL.<br><br>RESULTS: The odds ratios (95 % confidence intervals) of diabetes associated with the first, second, and third quartile of leukocyte telomere length, compared to the highest quartile, was 2.09 (1.46-2.98), 1.74 (1.30-2.31), and 1.08 (0.76-1.54), respectively (p-trend < 0.01), in unadjusted models and 0.74 (0.48-1.14), 0.91 (0.61-1.34), and 0.87 (0.59-1.29), respectively (p-trend = 0.20), in multivariable adjusted models. Among participants with diabetes, unadjusted and adjusted leukocyte telomere length was not associated with diabetes duration or glucose control based on an hemoglobin A1c < 7 or < 8 % (all p > 0.05).<br><br>CONCLUSIONS: In this study of the US general population, leukocyte telomere length was not associated with diabetes status, diabetes duration, or diabetes control.},
}
@article {pmid26415882,
year = {2015},
author = {Barutcu, AR and Lajoie, BR and McCord, RP and Tye, CE and Hong, D and Messier, TL and Browne, G and van Wijnen, AJ and Lian, JB and Stein, JL and Dekker, J and Imbalzano, AN and Stein, GS},
title = {Chromatin interaction analysis reveals changes in small chromosome and telomere clustering between epithelial and breast cancer cells.},
journal = {Genome biology},
volume = {16},
number = {},
pages = {214},
pmid = {26415882},
issn = {1474-760X},
support = {P01 CA082834/CA/NCI NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; R37 DE012528/DE/NIDCR NIH HHS/United States ; },
mesh = {Breast Neoplasms/*genetics/pathology ; *Carcinogenesis ; Chromatin/*genetics ; Epigenesis, Genetic ; Epithelial Cells/*metabolism/pathology ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; MCF-7 Cells ; Mammary Glands, Human/metabolism/pathology ; Telomere/*genetics ; },
abstract = {BACKGROUND: Higher-order chromatin structure is often perturbed in cancer and other pathological states. Although several genetic and epigenetic differences have been charted between normal and breast cancer tissues, changes in higher-order chromatin organization during tumorigenesis have not been fully explored. To probe the differences in higher-order chromatin structure between mammary epithelial and breast cancer cells, we performed Hi-C analysis on MCF-10A mammary epithelial and MCF-7 breast cancer cell lines.<br><br>RESULTS: Our studies reveal that the small, gene-rich chromosomes chr16 through chr22 in the MCF-7 breast cancer genome display decreased interaction frequency with each other compared to the inter-chromosomal interaction frequency in the MCF-10A epithelial cells. Interestingly, this finding is associated with a higher occurrence of open compartments on chr16-22 in MCF-7 cells. Pathway analysis of the MCF-7 up-regulated genes located in altered compartment regions on chr16-22 reveals pathways related to repression of WNT signaling. There are also differences in intra-chromosomal interactions between the cell lines; telomeric and sub-telomeric regions in the MCF-10A cells display more frequent interactions than are observed in the MCF-7 cells.<br><br>CONCLUSIONS: We show evidence of an intricate relationship between chromosomal organization and gene expression between epithelial and breast cancer cells. Importantly, this work provides a genome-wide view of higher-order chromatin dynamics and a resource for studying higher-order chromatin interactions in two cell lines commonly used to study the progression of breast cancer.},
}
@article {pmid26411311,
year = {2015},
author = {Antunes, DM and Kalmbach, KH and Wang, F and Dracxler, RC and Seth-Smith, ML and Kramer, Y and Buldo-Licciardi, J and Kohlrausch, FB and Keefe, DL},
title = {A single-cell assay for telomere DNA content shows increasing telomere length heterogeneity, as well as increasing mean telomere length in human spermatozoa with advancing age.},
journal = {Journal of assisted reproduction and genetics},
volume = {32},
number = {11},
pages = {1685-1690},
pmid = {26411311},
issn = {1573-7330},
support = {UL1 RR029893/RR/NCRR NIH HHS/United States ; 1UL1RR029893/RR/NCRR NIH HHS/United States ; },
mesh = {Adult ; Cross-Sectional Studies ; DNA/*analysis ; Humans ; Male ; Middle Aged ; Paternal Age ; Prospective Studies ; Single-Cell Analysis/*methods ; Spermatozoa/*physiology ; Telomere/*genetics ; Telomere Homeostasis/genetics ; },
abstract = {PURPOSE: The effect of age on telomere length heterogeneity in men has not been studied previously. Our aims were to determine the relationship between variation in sperm telomere length (STL), men's age, and semen parameters in spermatozoa from men undergoing in vitro fertilization (IVF) treatment.<br><br>METHODS: To perform this prospective cross-sectional pilot study, telomere length was estimated in 200 individual spermatozoa from men undergoing IVF treatment at the NYU Fertility Center. A novel single-cell telomere content assay (SCT-pqPCR) measured telomere length in individual spermatozoa.<br><br>RESULTS: Telomere length among individual spermatozoa within an ejaculate varies markedly and increases with age. Older men not only have longer STL but also have more variable STL compared to younger men. STL from samples with normal semen parameters was significantly longer than that from samples with abnormal parameters, but STL did not differ between spermatozoa with normal versus abnormal morphology.<br><br>CONCLUSION: The marked increase in STL heterogeneity as men age is consistent with a role for ALT during spermatogenesis. No data have yet reported the effect of age on STL heterogeneity. Based on these results, future studies should expand this modest sample size to search for molecular evidence of ALT in human testes during spermatogenesis.},
}
@article {pmid26408916,
year = {2015},
author = {Trivanović, D and Jauković, A and Popović, B and Krstić, J and Mojsilović, S and Okić-Djordjević, I and Kukolj, T and Obradović, H and Santibanez, JF and Bugarski, D},
title = {Mesenchymal stem cells of different origin: Comparative evaluation of proliferative capacity, telomere length and pluripotency marker expression.},
journal = {Life sciences},
volume = {141},
number = {},
pages = {61-73},
doi = {10.1016/j.lfs.2015.09.019},
pmid = {26408916},
issn = {1879-0631},
mesh = {Adipogenesis/genetics ; Adipose Tissue/cytology ; Biomarkers/analysis ; Blood Cells/physiology ; Cell Differentiation ; Cell Line ; Cell Proliferation ; Humans ; Ligaments/cytology ; Mesenchymal Stem Cells/chemistry/*physiology/ultrastructure ; Osteogenesis/genetics ; Pluripotent Stem Cells/chemistry/*physiology/ultrastructure ; Telomere/*ultrastructure ; Telomere Shortening ; Tooth, Deciduous/cytology ; Umbilical Cord/cytology ; },
abstract = {AIMS: In vitro expansion changes replication and differentiation capacity of mesenchymal stem cells (MSCs), increasing challenges and risks, while limiting the sufficient number of MSCs required for cytotherapy. Here, we characterized and compared proliferation, differentiation, telomere length and pluripotency marker expression in MSCs of various origins.<br><br>MAIN METHODS: Immunophenotyping, proliferation and differentiation assays were performed. Pluripotency marker (Nanog, Oct-4, SOX-2, SSEA-4) expression was determined by immunofluorescence. Quantitative PCR was performed for relative telomere length (RTL) analyses, while expression of relevant genes for pluripotency markers, differentiation state (Cbfa1, human placental alkaline phosphatase, peroxisome proliferator activated receptor, Sox9 and Collagen II a1), and telomerase reverse transcriptase (hTERT) was determined by semiquantitative RT-PCR.<br><br>KEY FINDINGS: Peripheral blood MSCs (PB-MSCs) and umbilical cord MSCs (UC-MSCs) showed the highest, while periodontal ligament MSCs (PDL-MSCs) and adipose tissue MSCs (AT-MSCs) the lowest values of both the replication potential and RTL. Although MSCs from exfoliated deciduous teeth (SHEDs), PDL-MSCs and AT-MSCs showed higher mRNA expression of pluripotency markers, all MSCs expressed pluripotency marker proteins. SHEDs and PDL-MSCs showed prominent capacity for osteogenesis, PB-MSCs and UC-MSCs showed strengthened adipogenic differentiation potential, while AT-MSCs displayed similar differentiation into both lines.<br><br>SIGNIFICANCE: The MSCs populations derived from different sources, although displaying similar phenotype, exhibited high degree of variability regarding biological properties related to their self-renewal and differentiation capacity. These data indicate that for more accurate use in cell therapy, individualities of MSCs isolated from different tissues should be identified and taken into consideration when planning their use in clinical protocols.},
}
@article {pmid26408804,
year = {2016},
author = {Piciocchi, M and Cardin, R and Cillo, U and Vitale, A and Cappon, A and Mescoli, C and Guido, M and Rugge, M and Burra, P and Floreani, A and Farinati, F},
title = {Differential timing of oxidative DNA damage and telomere shortening in hepatitis C and B virus-related liver carcinogenesis.},
journal = {Translational research : the journal of laboratory and clinical medicine},
volume = {168},
number = {},
pages = {122-133},
doi = {10.1016/j.trsl.2015.08.012},
pmid = {26408804},
issn = {1878-1810},
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Carcinogenesis ; *DNA Damage ; DNA Glycosylases/genetics/metabolism ; DNA, Mitochondrial/genetics ; Deoxyguanosine/analogs &amp; derivatives ; Gene Expression Regulation, Neoplastic/physiology ; Hepacivirus ; Hepatitis B/*complications/virology ; Hepatitis B virus ; Hepatitis C/*complications/virology ; Humans ; Liver Neoplasms/*etiology/virology ; Oxidation-Reduction ; Polymorphism, Genetic ; Telomerase/genetics/metabolism ; *Telomere Shortening ; },
abstract = {In viral hepatitis, inflammation is correlated with chronic oxidative stress, one of the biological events leading to DNA damage and hepatocellular carcinoma (HCC) development. Aim of this study was to investigate the complex molecular network linking oxidative damage to telomere length and telomerase activity and regulation in hepatitis C and B virus-related liver carcinogenesis. We investigated 142 patients: 21 with HCC (in both tumor and peritumor tissues) and 121 with chronic viral hepatitis in different stages. We evaluated 8-hydroxydeoxyguanosine (8-OHdG), marker of oxidative DNA damage, OGG1 gene polymorphism, telomere length, telomerase activity, TERT promoter methylation, and mitochondrial TERT localization. In hepatitis C-related damage, 8-OHdG levels increased since the early disease stages, whereas hepatitis B-related liver disease was characterized by a later and sharper 8-OHdG accumulation (P = 0.005). In C virus-infected patients, telomeres were shorter (P = 0.03), whereas telomerase activity was higher in tumors than that in the less advanced stages of disease in both groups (P = 0.0001, P = 0.05), with an earlier increase in hepatitis C. Similarly, TERT promoter methylation was higher in tumor and peritumor tissues in both groups (P = 0.02, P = 0.0001). Finally, TERT was localized in mitochondria in tumor and peritumor samples, with 8-OHdG levels significantly lower in mitochondrial than those in genomic DNA (P = 0.0003). These data describe a pathway in which oxidative DNA damage accumulates in correspondence with telomere shortening, telomerase activation, and TERT promoter methylation with a different time course in hepatitis B and C virus-related liver carcinogenesis. Finally, TERT localizes in mitochondria in HCC, where it lacks a canonical function.},
}
@article {pmid26407969,
year = {2015},
author = {Albizua, I and Rambo-Martin, BL and Allen, EG and He, W and Amin, AS and Sherman, SL},
title = {Association between telomere length and chromosome 21 nondisjunction in the oocyte.},
journal = {Human genetics},
volume = {134},
number = {11-12},
pages = {1263-1270},
pmid = {26407969},
issn = {1432-1203},
support = {R01 HD038979/HD/NICHD NIH HHS/United States ; R01 HD38979/HD/NICHD NIH HHS/United States ; //Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Case-Control Studies ; Chromosomes, Human, Pair 21/*genetics ; Down Syndrome/genetics ; Female ; Humans ; Infant, Newborn ; Maternal Age ; *Nondisjunction, Genetic ; Oocytes/*metabolism ; Pregnancy ; Telomere/genetics/*metabolism ; Telomere Homeostasis/*genetics ; Young Adult ; },
abstract = {Chromosome 21 nondisjunction in oocytes is the most common cause of trisomy 21, the primary chromosomal abnormality responsible for Down syndrome (DS). This specific type of error is estimated to account for over 90 % of live births with DS, with maternal age being the best known risk factor for chromosome 21 nondisjunction. The loss of telomere length and the concomitant shortening of chromosomes are considered a biological marker for aging. Thus, we tested the hypothesis that mothers who had a maternal nondisjunction error leading to a live birth with DS (n = 404) have shorter telomeres than mothers with live births without DS (n = 42). In effect, our hypothesis suggests that mothers of children with DS will appear "biologically older" as compared to the mothers of euploid children. We applied a quantitative PCR assay to measure the genome-wide relative telomere length to test this hypothesis. The results of our study support the hypothesis that young mothers of DS babies are "biologically older" than mothers of euploid babies in the same age group and supports telomere length as a biomarker of age and hence risk for chromosome nondisjunction.},
}
@article {pmid26407932,
year = {2015},
author = {Mundstock, E and Sarria, EE and Zatti, H and Mattos Louzada, F and Kich Grun, L and Herbert Jones, M and Guma, FT and Mazzola In Memoriam, J and Epifanio, M and Stein, RT and Barbé-Tuana, FM and Mattiello, R},
title = {Effect of obesity on telomere length: Systematic review and meta-analysis.},
journal = {Obesity (Silver Spring, Md.)},
volume = {23},
number = {11},
pages = {2165-2174},
doi = {10.1002/oby.21183},
pmid = {26407932},
issn = {1930-739X},
mesh = {Adiposity/genetics ; Body Weight/genetics/physiology ; Female ; Humans ; Leukocytes/metabolism/pathology ; Obesity/complications/epidemiology/*genetics ; Overweight/complications/epidemiology/genetics ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {OBJECTIVE: The main objective of this systematic review is to assess the effects of obesity on telomere length.<br><br>METHODS: The following databases were searched: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), LILACS, SPORTdiscus, and Web of Science from inception to August 2014. The search was performed using the following combinations of terms: telomere AND "overweight" OR "obesity" OR "adiposity," without language restriction.<br><br>RESULTS: Sixty-three original studies were included in this systematic review, comprising 119,439 subjects. Thirty-nine studies showed either weak or moderate correlation between obesity and telomere length; however, they showed an important heterogeneity.<br><br>CONCLUSIONS: There is a tendency toward demonstrating negative correlation between obesity and telomere length. The selected studies showed weak to moderate correlation for the main search, and there was an important heterogeneity. For this reason, the causal relationship of obesity and telomere length remains open. Additional controlled longitudinal studies are needed to investigate this issue.},
}
@article {pmid26405259,
year = {2016},
author = {Skilton, MR and Nakhla, S and Ayer, JG and Harmer, JA and Toelle, BG and Leeder, SR and Jones, G and Marks, GB and Celermajer, DS and , },
title = {Telomere length in early childhood: Early life risk factors and association with carotid intima-media thickness in later childhood.},
journal = {European journal of preventive cardiology},
volume = {23},
number = {10},
pages = {1086-1092},
doi = {10.1177/2047487315607075},
pmid = {26405259},
issn = {2047-4881},
mesh = {Adult ; Atherosclerosis/epidemiology/*etiology/genetics ; Body Mass Index ; *Carotid Intima-Media Thickness ; Child, Preschool ; DNA/*analysis ; Female ; Follow-Up Studies ; Genetic Markers ; *Genetic Predisposition to Disease ; Humans ; Incidence ; Infant ; Infant, Newborn ; Male ; New South Wales/epidemiology ; Odds Ratio ; Prognosis ; Real-Time Polymerase Chain Reaction ; Retrospective Studies ; *Risk Assessment ; Risk Factors ; *Telomere ; Time Factors ; },
abstract = {BACKGROUND: Reduced telomere length is a measure of biological aging that is predictive of cardiac events in adults, and has been mechanistically implicated in the onset and progression of atherosclerosis. We sought to describe the early life factors associated with leukocyte telomere length in early childhood, and to determine whether telomere length measured during early childhood is associated with arterial wall thickening later in childhood.<br><br>DESIGN: A longitudinal birth cohort recruited antenatally in Sydney from 1997 to 1999.<br><br>METHODS: Leukocyte telomere length was measured in 331 children at age 3.6 years (SD 1.0); of whom 268 children without diabetes had carotid intima-media thickness assessed by ultrasound at age 8 years.<br><br>RESULTS: Male sex, younger paternal age and higher maternal body mass index were associated with shorter telomere length in early childhood, which in turn was associated with greater carotid intima-media thickness at age 8 years (standardised &#x3b2;&#x2009;=&#x2009;-0.159, P&#x2009;=&#x2009;0.01). There was a graded association across quartiles of telomere length (Ptrend&#x2009;=&#x2009;0.001) with the highest odds of elevated intima-media thickness (>75th percentile) being in children with the shortest telomeres (odds ratio 4.00 (95% confidence interval 1.58 to 10.14) relative to those with the longest telomeres, P&#x2009;=&#x2009;0.003). This association remained after adjustment for early life risk factors (Ptrend&#x2009;=&#x2009;0.001).<br><br>CONCLUSIONS: Reduced telomere length in early childhood is independently associated with arterial wall thickness in later childhood, suggesting that reduced telomere length during early childhood may be a marker of vascular disease risk.},
}
@article {pmid26403813,
year = {2015},
author = {Martin-Ruiz, CM and Baird, D and Roger, L and Boukamp, P and Krunic, D and Cawthon, R and Dokter, MM and Van Der Harst, P and Bekaert, S and De Meyer, T and Roos, G and Svenson, U and Codd, V and Samani, NJ and Mcglynn, L and Shiels, PG and Pooley, KA and Dunning, AM and Cooper, R and Wong, A and Kingston, A and Von Zglinicki, T},
title = {Is Southern blotting necessary to measure telomere length reproducibly? Authors' Response to: Commentary: The reliability of telomere length measurements.},
journal = {International journal of epidemiology},
volume = {44},
number = {5},
pages = {1686-1687},
doi = {10.1093/ije/dyv169},
pmid = {26403813},
issn = {1464-3685},
support = {16565/CRUK_/Cancer Research UK/United Kingdom ; G0601333/MRC_/Medical Research Council/United Kingdom ; MC_UU_12019/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {*Blotting, Southern ; Humans ; Reproducibility of Results ; *Telomere ; },
}
@article {pmid26403812,
year = {2015},
author = {Verhulst, S and Susser, E and Factor-Litvak, PR and Simons, MJ and Benetos, A and Steenstrup, T and Kark, JD and Aviv, A},
title = {Commentary: The reliability of telomere length measurements.},
journal = {International journal of epidemiology},
volume = {44},
number = {5},
pages = {1683-1686},
pmid = {26403812},
issn = {1464-3685},
support = {R01 HD071180/HD/NICHD NIH HHS/United States ; },
mesh = {Humans ; *Reproducibility of Results ; *Telomere ; },
}
@article {pmid26403811,
year = {2015},
author = {Martin-Ruiz, CM and Baird, D and Roger, L and Boukamp, P and Krunic, D and Cawthon, R and Dokter, MM and Van Der Harst, P and Bekaert, S and De Meyer, T and Roos, G and Svenson, U and Codd, V and Samani, NJ and Mcglynn, L and Shiels, PG and Pooley, KA and Dunning, AM and Cooper, R and Wong, A and Kingston, A and Von Zglinicki, T},
title = {Reproducibility of telomere length assessment: Authors' Response to Damjan Krstajic and Ljubomir Buturovic.},
journal = {International journal of epidemiology},
volume = {44},
number = {5},
pages = {1739-1741},
doi = {10.1093/ije/dyv170},
pmid = {26403811},
issn = {1464-3685},
support = {16565/CRUK_/Cancer Research UK/United Kingdom ; G0601333/MRC_/Medical Research Council/United Kingdom ; MC_UU_12019/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; *Reproducibility of Results ; *Telomere ; },
}
@article {pmid26403810,
year = {2015},
author = {Krstajic, D and Buturovic, L},
title = {Reproducibility of telomere length assessment.},
journal = {International journal of epidemiology},
volume = {44},
number = {5},
pages = {1738-1739},
doi = {10.1093/ije/dyv167},
pmid = {26403810},
issn = {1464-3685},
mesh = {Humans ; *Reproducibility of Results ; *Telomere ; },
}
@article {pmid26403809,
year = {2015},
author = {Martin-Ruiz, CM and Baird, D and Roger, L and Boukamp, P and Krunic, D and Cawthon, R and Dokter, MM and van der Harst, P and Bekaert, S and de Meyer, T and Roos, G and Svenson, U and Codd, V and Samani, NJ and McGlynn, L and Shiels, PG and Pooley, KA and Dunning, AM and Cooper, R and Wong, A and Kingston, A and von Zglinicki, T},
title = {Reproducibility of Telomere Length Assessment--An International Collaborative Study.},
journal = {International journal of epidemiology},
volume = {44},
number = {5},
pages = {1749-1754},
doi = {10.1093/ije/dyv171},
pmid = {26403809},
issn = {1464-3685},
support = {10-0021/AICR_/Worldwide Cancer Research/United Kingdom ; 16565/CRUK_/Cancer Research UK/United Kingdom ; G0601333/MRC_/Medical Research Council/United Kingdom ; MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; },
}
@article {pmid26403416,
year = {2015},
author = {Nisticò, S and Ehrlich, J and Gliozzi, M and Maiuolo, J and Del Duca, E and Muscoli, C and Mollace, V},
title = {TELOMERE AND TELOMERASE MODULATION BY BERGAMOT POLYPHENOLIC FRACTION IN EXPERIMENTAL PHOTOAGEING IN HUMAN KERATINOCYTES.},
journal = {Journal of biological regulators and homeostatic agents},
volume = {29},
number = {3},
pages = {723-728},
pmid = {26403416},
issn = {0393-974X},
mesh = {Cell Line, Transformed ; Citrus/*chemistry ; Humans ; Keratinocytes/*metabolism/pathology ; Oxidative Stress/drug effects/radiation effects ; Polyphenols/chemistry/*pharmacology ; *Skin Aging/drug effects/radiation effects ; Telomerase/*metabolism ; Telomere/*metabolism ; Ultraviolet Rays/*adverse effects ; },
abstract = {Photoageing represents the addition of extrinsic chronic ultraviolet radiation-induced damage on intrinsic ageing and accounts for most age-associated changes in skin appearance. In this study, we evaluated the effect of 38% BPF, a highly concentrated extract of the bergamot fruit (Citrus bergamia) on UVB-induced photoageing by examining inflammatory cytokine expression, telomere length/telomerase alterations and cellular viability in human immortalized HaCaT keratinocytes. Our results suggest that 38% BPF protects HaCaT cells against UVB-induced oxidative stress and markers of photoageing in a dose-dependent manner and could be a useful supplement in skin care products. Together with antioxidant properties, BPF, a highly concentrated extract of the bergamot fruit, appears to modulate basic cellular signal transduction pathways leading to anti-proliferative, anti-aging and immune modulating responses.},
}
@article {pmid26402514,
year = {2015},
author = {Tedone, E and Arosio, B and Colombo, F and Ferri, E and Asselineau, D and Piette, F and Gussago, C and Belmin, J and Pariel, S and Benlhassan, K and Casati, M and Bornand, A and Rossi, PD and Mazzola, P and Annoni, G and Doulazmi, M and Mariani, J and Porretti, L and Bray, DH and Mari, D},
title = {Leukocyte Telomere Length in Alzheimer's Disease Patients with a Different Rate of Progression.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {46},
number = {3},
pages = {761-769},
doi = {10.3233/JAD-142808},
pmid = {26402514},
issn = {1875-8908},
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*genetics/*pathology ; Amyloid beta-Peptides/pharmacology ; Analysis of Variance ; Apolipoproteins E/genetics ; Case-Control Studies ; Cells, Cultured ; Enzyme-Linked Immunosorbent Assay ; Female ; Flow Cytometry ; Humans ; Interleukin-10/metabolism ; Leukocytes, Mononuclear/drug effects/*pathology ; Lipopolysaccharides/pharmacology ; Male ; Mental Status Schedule ; RNA, Messenger/metabolism ; Telomere/*genetics/*pathology ; },
abstract = {BACKGROUND: Age and short leukocyte telomeres have been associated with a higher risk of Alzheimer's disease (AD). Inflammation is involved in AD and it is suggested that anti-inflammatory interleukin-10 (IL-10) may partly antagonize these processes.<br><br>OBJECTIVE: The aim is to correlate telomere length (TL) in peripheral blood mononuclear cells (PBMC) from patients with AD to disease progression rate. Moreover, we evaluated whether TL was associated with IL-10 production by unstimulated or amyloid-&#x3b2; (A&#x3b2;)-stimulated PBMC.<br><br>METHODS: We enrolled 31 late-onset AD and 20 age-matched healthy elderly (HE). After a two-year follow-up period, patients were retrospectively evaluated as slow-progressing (ADS) (Mini Mental State Examination (MMSE) decline over the two years of follow-up &#x2264;3 points) or fast progressing AD (ADF) (MMSE decline &#x2265;5 points). TL was measured by flow cytometry and in vitro IL-10 production by enzyme-linked immunosorbent assay.<br><br>RESULTS: TL (mean&#xb1;SD) for HE, ADS, and ADF was 2.3&#xb1;0.1, 2.0&#xb1;0.1, and 2.5&#xb1;0.1 Kb, respectively. ADS showed a shorter TL compared to HE (p&#x200a;=&#x200a;0.034) and to ADF (p&#x200a;=&#x200a;0.005). MMSE decline correlated with TL in AD (R2&#x200a;=&#x200a;0.284; p&#x200a;=&#x200a;0.008). We found a significant difference in IL-10 production between unstimulated and A&#x3b2;-stimulated PBMC from ADS (40.7&#xb1;13.7 versus 59.0&#xb1;27.0; p&#x200a;=&#x200a;0.004) but not from ADF (39.7&#xb1;14.4 versus 42.2&#xb1;22.4). HE showed a trend toward significance (47.1&#xb1;25.4 versus 55.3&#xb1;27.9; p&#x200a;=&#x200a;0.10).<br><br>CONCLUSION: PBMC from ADF may be characterized by an impaired response induced by A&#x3b2; and by a reduced proliferative response responsible for the longer telomeres. TL might be a contributing factor in predicting the rate of AD progression.},
}
@article {pmid26400640,
year = {2016},
author = {Bertuch, AA},
title = {The molecular genetics of the telomere biology disorders.},
journal = {RNA biology},
volume = {13},
number = {8},
pages = {696-706},
pmid = {26400640},
issn = {1555-8584},
support = {R01 HL131744/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; DNA Replication ; Dyskeratosis Congenita/genetics/metabolism ; Enzyme Activation/genetics ; Exoribonucleases/genetics/metabolism ; *Genetic Association Studies ; *Genetic Predisposition to Disease ; Genomic Instability ; Humans ; Mutation ; Nucleic Acid Conformation ; Protein Binding ; Protein Transport ; Syndrome ; Telomerase/genetics/metabolism ; Telomere/*genetics/*metabolism ; *Telomere Shortening ; },
abstract = {The importance of telomere function for human health is exemplified by a collection of Mendelian disorders referred to as the telomere biology disorders (TBDs), telomeropathies, or syndromes of telomere shortening. Collectively, the TBDs cover a spectrum of conditions from multisystem disease presenting in infancy to isolated disease presentations in adulthood, most notably idiopathic pulmonary fibrosis. Eleven genes have been found mutated in the TBDs to date, each of which is linked to some aspect of telomere maintenance. This review summarizes the molecular defects that result from mutations in these genes, highlighting recent advances, including the addition of PARN to the TBD gene family and the discovery of heterozygous mutations in RTEL1 as a cause of familial pulmonary fibrosis.},
}
@article {pmid26399229,
year = {2015},
author = {Guidi, M and Ruault, M and Marbouty, M and Loïodice, I and Cournac, A and Billaudeau, C and Hocher, A and Mozziconacci, J and Koszul, R and Taddei, A},
title = {Spatial reorganization of telomeres in long-lived quiescent cells.},
journal = {Genome biology},
volume = {16},
number = {1},
pages = {206},
pmid = {26399229},
issn = {1474-760X},
support = {210508/ERC_/European Research Council/International ; 260822/ERC_/European Research Council/International ; },
mesh = {Carbon/metabolism ; Centromere ; Chromosomes, Fungal ; Reactive Oxygen Species/metabolism ; Resting Phase, Cell Cycle/*genetics ; Saccharomyces cerevisiae/genetics/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: The spatiotemporal behavior of chromatin is an important control mechanism of genomic function. Studies in Saccharomyces cerevisiae have broadly contributed to demonstrate the functional importance of nuclear organization. Although in the wild yeast survival depends on their ability to withstand adverse conditions, most of these studies were conducted on cells undergoing exponential growth. In these conditions, as in most eukaryotic cells, silent chromatin that is mainly found at the 32 telomeres accumulates at the nuclear envelope, forming three to five foci.<br><br>RESULTS: Here, combining live microscopy, DNA FISH and chromosome conformation capture (HiC) techniques, we report that chromosomes adopt distinct organizations according to the metabolic status of the cell. In particular, following carbon source exhaustion the genome of long-lived quiescent cells undergoes a major spatial re-organization driven by the grouping of telomeres into a unique focus or hypercluster localized in the center of the nucleus. This change in genome conformation is specific to quiescent cells able to sustain long-term viability. We further show that reactive oxygen species produced by mitochondrial activity during respiration commit the cell to form a hypercluster upon starvation. Importantly, deleting the gene encoding telomere associated silencing factor SIR3 abolishes telomere grouping and decreases longevity, a defect that is rescued by expressing a silencing defective SIR3 allele competent for hypercluster formation.<br><br>CONCLUSIONS: Our data show that mitochondrial activity primes cells to group their telomeres into a hypercluster upon starvation, reshaping the genome architecture into a conformation that may contribute to maintain longevity of quiescent cells.},
}
@article {pmid26398001,
year = {2016},
author = {Chae, DH and Epel, ES and Nuru-Jeter, AM and Lincoln, KD and Taylor, RJ and Lin, J and Blackburn, EH and Thomas, SB},
title = {Discrimination, mental health, and leukocyte telomere length among African American men.},
journal = {Psychoneuroendocrinology},
volume = {63},
number = {},
pages = {10-16},
pmid = {26398001},
issn = {1873-3360},
support = {K01 AG041787/AG/NIA NIH HHS/United States ; P20 MD006737/MD/NIMHD NIH HHS/United States ; K01AG041787/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Black or African American/*psychology ; Aging/*metabolism/psychology ; Anxiety/*psychology ; Cellular Senescence ; Depression/*psychology ; Humans ; Leukocytes/metabolism ; Male ; Men/*psychology ; *Mental Health ; Middle Aged ; Racism/*psychology ; Risk Factors ; Stress, Psychological/*metabolism/psychology ; Telomere/*metabolism ; Telomere Shortening ; },
abstract = {African American men in the US experience disparities across multiple health outcomes. A common mechanism underlying premature declines in health may be accelerated biological aging, as reflected by leukocyte telomere length (LTL). Racial discrimination, a qualitatively unique source of social stress reported by African American men, in tandem with poor mental health, may negatively impact LTL in this population. The current study examined cross-sectional associations between LTL, self-reported racial discrimination, and symptoms of depression and anxiety among 92 African American men 30-50 years of age. LTL was measured in kilobase pairs using quantitative polymerase chain reaction assay. Controlling for sociodemographic factors, greater anxiety symptoms were associated with shorter LTL (b=-0.029, standard error [SE]=0.014; p<0.05). There were no main effects of racial discrimination or depressive symptoms on LTL, but we found evidence for a significant interaction between the two (b=0.011, SE=0.005; p<0.05). Racial discrimination was associated with shorter LTL among those with lower levels of depressive symptoms. Findings from this study highlight the role of social stressors and individual-level psychological factors for physiologic deterioration among African American men. Consistent with research on other populations, greater anxiety may reflect elevated stress associated with shorter LTL. Racial discrimination may represent an additional source of social stress among African American men that has detrimental consequences for cellular aging among those with lower levels of depression.},
}
@article {pmid26397719,
year = {2015},
author = {Polettini, J and Behnia, F and Taylor, BD and Saade, GR and Taylor, RN and Menon, R},
title = {Telomere Fragment Induced Amnion Cell Senescence: A Contributor to Parturition?.},
journal = {PloS one},
volume = {10},
number = {9},
pages = {e0137188},
pmid = {26397719},
issn = {1932-6203},
mesh = {Adolescent ; Adult ; Amnion/*pathology ; Animals ; Cells, Cultured ; *Cellular Senescence ; Cross-Sectional Studies ; DNA Damage ; Enzyme Activation ; Epithelial Cells/physiology ; Female ; Humans ; Male ; Mice ; Obstetric Labor, Premature/*metabolism ; Parturition ; Pregnancy ; Telomere/*physiology ; Tumor Suppressor Protein p53/metabolism ; Young Adult ; p38 Mitogen-Activated Protein Kinases/metabolism ; },
abstract = {Oxidative stress (OS)-induced senescence of the amniochorion has been associated with parturition at term. We investigated whether telomere fragments shed into the amniotic fluid (AF) correlated with labor status and tested if exogenous telomere fragments (T-oligos) could induce human and murine amnion cell senescence. In a cross-sectional clinical study, AF telomere fragment concentrations quantitated by a validated real-time PCR assay were higher in women in labor at term compared to those not in labor. In vitro treatment of primary human amnion epithelial cells with 40 μM T-oligos ([TTAGGG]2) that mimic telomere fragments, activated p38MAPK, produced senescence-associated (SA) β-gal staining and increased interleukin (IL)-6 and IL-8 production compared to cells treated with complementary DNA sequences (Cont-oligos, [AATCCC]2). T-oligos injected into the uteri of pregnant CD1 mice on day 14 of gestation, led to increased p38MAPK, SA-β-gal (SA β-gal) staining in murine amniotic sacs and higher AF IL-8 levels on day 18, compared to saline treated controls. In summary, term labor AF samples had higher telomere fragments than term not in labor AF. In vitro and in situ telomere fragments increased human and murine amnion p38MAPK, senescence and inflammatory cytokines. We propose that telomere fragments released from senescent fetal cells are indicative of fetal cell aging. Based on our data, these telomere fragments cause oxidative stress associated damages to the term amniotic sac and force them to release other DAMPS, which, in turn, provide a sterile immune response that may be one of the many inflammatory signals required to initiate parturition at term.},
}
@article {pmid26392399,
year = {2016},
author = {Sui, B and Hu, C and Jin, Y},
title = {Mitochondrial metabolic failure in telomere attrition-provoked aging of bone marrow mesenchymal stem cells.},
journal = {Biogerontology},
volume = {17},
number = {2},
pages = {267-279},
doi = {10.1007/s10522-015-9609-5},
pmid = {26392399},
issn = {1573-6768},
mesh = {Animals ; Bone Marrow Cells/*cytology ; Cellular Senescence/*genetics ; Humans ; Mesenchymal Stem Cells/*cytology ; Mitochondria/*metabolism ; *Telomere ; },
abstract = {The proliferation and differentiation potential of bone marrow mesenchymal stem cells (BMMSCs) declines with age and with in vitro passages. However, the underlying mechanisms and putative approaches to maintain their function are not fully understood. Recent studies have revealed telomere attrition as the core initiator determining functional decline in aging of BMMSCs. Telomere attrition activates downstream p53 signaling and compromises mitochondrial metabolism via the peroxisome proliferator-activated receptor gamma co-activator 1α/β (PGC-1α/β), a key process possesses peculiarities in BMMSCs distinct from other stem cells and their mature derivatives. Despite of the shortened telomere, the mitochondrial failure could be overcome through metabolic regulation by caloric restriction (CR) and its mediator Sirtuin 1 (SIRT1). Researches have shown that mitochondrial metabolic reprogramming by CR and SIRT1 alleviates functional decline of BMMSCs in aging. In this review, we intend to summarize our understanding about how telomere attrition initiates and induces mitochondrial compromise in functional decline of BMMSCs in aging, and the potential therapeutic strategies based on metabolic reprogramming.},
}
@article {pmid26386121,
year = {2015},
author = {Birch, J and Anderson, RK and Correia-Melo, C and Jurk, D and Hewitt, G and Marques, FM and Green, NJ and Moisey, E and Birrell, MA and Belvisi, MG and Black, F and Taylor, JJ and Fisher, AJ and De Soyza, A and Passos, JF},
title = {DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease.},
journal = {American journal of physiology. Lung cellular and molecular physiology},
volume = {309},
number = {10},
pages = {L1124-37},
pmid = {26386121},
issn = {1522-1504},
support = {BB/H022384/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MR/K006312/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aged ; Aging ; Animals ; Case-Control Studies ; Cell Line ; *DNA Damage ; DNA Repair ; Epithelial Cells/pathology ; Female ; Humans ; Lung/*pathology ; Male ; Mice, Inbred C57BL ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/*genetics ; Respiratory Mucosa/pathology ; Smoking/adverse effects ; Telomere/*genetics ; },
abstract = {Cellular senescence has been associated with the structural and functional decline observed during physiological lung aging and in chronic obstructive pulmonary disease (COPD). Airway epithelial cells are the first line of defense in the lungs and are important to COPD pathogenesis. However, the mechanisms underlying airway epithelial cell senescence, and particularly the role of telomere dysfunction in this process, are poorly understood. We aimed to investigate telomere dysfunction in airway epithelial cells from patients with COPD, in the aging murine lung and following cigarette smoke exposure. We evaluated colocalization of γ-histone protein 2A.X and telomeres and telomere length in small airway epithelial cells from patients with COPD, during murine lung aging, and following cigarette smoke exposure in vivo and in vitro. We found that telomere-associated DNA damage foci increase in small airway epithelial cells from patients with COPD, without significant telomere shortening detected. With age, telomere-associated foci increase in small airway epithelial cells of the murine lung, which is accelerated by cigarette smoke exposure. Moreover, telomere-associated foci predict age-dependent emphysema, and late-generation Terc null mice, which harbor dysfunctional telomeres, show early-onset emphysema. We found that cigarette smoke accelerates telomere dysfunction via reactive oxygen species in vitro and may be associated with ataxia telangiectasia mutated-dependent secretion of inflammatory cytokines interleukin-6 and -8. We propose that telomeres are highly sensitive to cigarette smoke-induced damage, and telomere dysfunction may underlie decline of lung function observed during aging and in COPD.},
}
@article {pmid26385889,
year = {2015},
author = {Sun, Y and Zhang, L and Zhao, L and Wu, X and Gu, J},
title = {Association of leukocyte telomere length in peripheral blood leukocytes with endometrial cancer risk in Caucasian Americans.},
journal = {Carcinogenesis},
volume = {36},
number = {11},
pages = {1327-1332},
doi = {10.1093/carcin/bgv133},
pmid = {26385889},
issn = {1460-2180},
mesh = {Aged ; Case-Control Studies ; Endometrial Neoplasms/blood/*genetics ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Leukocytes, Mononuclear/*physiology ; Middle Aged ; Risk Factors ; Telomere/genetics ; *Telomere Homeostasis ; },
abstract = {Telomeres are the protective structure at the ends of each chromosome and play an important role in maintaining genomic integrity. Interindividual variation of telomere length in peripheral blood leukocytes has been associated with the risks of developing many human diseases including several cancers. The association between leukocyte telomere length (LTL) and endometrial cancer risk is still inconsistent. Using a case-control study of endometrial cancer patients (n = 139) and control subjects (n = 139) in a Caucasian population, we assessed the association of relative LTL with the risk of endometrial cancer. We calculated odds ratios and 95% confidence intervals using multivariate logistic regression. We also determined the joint effects of LTL with established risk factors of endometrial cancer. The normalized LTL was significantly longer in endometrial cancer cases (median, 0.93; range, 0.19-1.62) than in controls (median, 0.70; range, 0.03-2.14) (P < 0.001). When individuals were dichotomized into long and short groups based on the median LTL value in the controls, individuals with long LTL had a significantly increased risk of endometrial cancer (adjusted OR, 3.84; 95%CI, 2.16-6.85; P < 0.001) compared to those with short LTL. When individuals were categorized into three groups or four groups according to tertile or quartile LTL value in the controls, there was a significant dose-response association between LTL and the risk of endometrial cancer (P < 0.001). Joint effects between LTL and smoking status, body mass index and a history of hypertension or diabetes in elevating endometrial cancer risk were observed. Long telomere length in peripheral blood leukocytes is associated with a significantly increased risk of endometrial cancer.},
}
@article {pmid26385867,
year = {2015},
author = {Dalgård, C and Benetos, A and Verhulst, S and Labat, C and Kark, JD and Christensen, K and Kimura, M and Kyvik, KO and Aviv, A},
title = {Leukocyte telomere length dynamics in women and men: menopause vs age effects.},
journal = {International journal of epidemiology},
volume = {44},
number = {5},
pages = {1688-1695},
pmid = {26385867},
issn = {1464-3685},
support = {AG030678/AG/NIA NIH HHS/United States ; HD071180/HD/NICHD NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aging/*genetics ; Biometry ; Denmark ; Female ; Healthy Volunteers ; Humans ; Leukocytes/*metabolism ; Longitudinal Studies ; Male ; Menopause/*genetics ; Middle Aged ; Postmenopause ; Sex Characteristics ; Telomere/*genetics ; Twins/*genetics ; Young Adult ; },
abstract = {BACKGROUND: A longer leukocyte telomere length (LTL) in women than men has been attributed to a slow rate of LTL attrition in women, perhaps due to high estrogen exposure during the premenopausal period.<br><br>METHODS: To test this premise we performed a longitudinal study (an average follow-up of 12 years) in a subset of the population-based Danish National Twin Registry. Participants consisted of 405 women, aged 37.5 (range 18.0-64.3) years, and 329 men, aged 38.8 (range 18.0-58.5) years, at baseline examination.<br><br>RESULTS: Women showed a longer LTL [kb &#xb1; standard error(SE)] than men (baseline: 7.01 &#xb1; 0.03 vs 6.87 &#xb1; 0.04; follow-up: 6.79 &#xb1; 0.03 vs 6.65 &#xb1; 0.03; both P = 0.005). Women displayed deceleration of LTL attrition (bp/years &#xb1; SE), as they transitioned from the premenopausal period (20.6 &#xb1; 1.0) through the perimenopausal period (16.5 &#xb1; 1.3) to the postmenopausal period (15.1 &#xb1; 1.7). Age was not associated with LTL attrition in women after statistical control for menopausal status. Men, in contrast, displayed a trend for age-dependent increase in the rate of LTL attrition, which differed significantly from the pattern in women (P for interaction = 0.01).<br><br>CONCLUSIONS: Results indicate that the premenopausal period is expressed in a higher rate of LTL attrition than the postmenopausal period. They further suggest that the sex gap in LTL stems from earlier ages-the period of growth and development. The higher rate of LTL attrition in premenopausal women, we propose, might relate to estrogen-mediated increased turnover of erythrocytes, menstrual bleeding or both.},
}
@article {pmid26382656,
year = {2015},
author = {Seo, B and Kim, C and Hills, M and Sung, S and Kim, H and Kim, E and Lim, DS and Oh, HS and Choi, RMJ and Chun, J and Shim, J and Lee, J},
title = {Telomere maintenance through recruitment of internal genomic regions.},
journal = {Nature communications},
volume = {6},
number = {},
pages = {8189},
pmid = {26382656},
issn = {2041-1723},
mesh = {Animals ; Animals, Genetically Modified ; Blotting, Southern ; Caenorhabditis elegans ; Caenorhabditis elegans Proteins/*genetics ; DNA/*genetics ; In Situ Hybridization, Fluorescence ; Recombination, Genetic/*genetics ; Telomerase/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Cells surviving crisis are often tumorigenic and their telomeres are commonly maintained through the reactivation of telomerase. However, surviving cells occasionally activate a recombination-based mechanism called alternative lengthening of telomeres (ALT). Here we establish stably maintained survivors in telomerase-deleted Caenorhabditis elegans that escape from sterility by activating ALT. ALT survivors trans-duplicate an internal genomic region, which is already cis-duplicated to chromosome ends, across the telomeres of all chromosomes. These 'Template for ALT' (TALT) regions consist of a block of genomic DNA flanked by telomere-like sequences, and are different between two genetic background. We establish a model that an ancestral duplication of a donor TALT region to a proximal telomere region forms a genomic reservoir ready to be incorporated into telomeres on ALT activation.},
}
@article {pmid26382074,
year = {2015},
author = {Meillère, A and Brischoux, F and Ribout, C and Angelier, F},
title = {Traffic noise exposure affects telomere length in nestling house sparrows.},
journal = {Biology letters},
volume = {11},
number = {9},
pages = {20150559},
pmid = {26382074},
issn = {1744-957X},
mesh = {Animals ; Noise, Transportation/*adverse effects ; Sparrows/growth &amp; development/*physiology ; Stress, Physiological ; Telomere/*physiology ; Telomere Shortening ; },
abstract = {In a consistently urbanizing world, anthropogenic noise has become almost omnipresent, and there are increasing evidence that high noise levels can have major impacts on wildlife. While the effects of anthropogenic noise exposure on adult animals have been widely studied, surprisingly, there has been little consideration of the effects of noise pollution on developing organisms. Yet, environmental conditions experienced in early life can have dramatic lifelong consequences for fitness. Here, we experimentally manipulated the acoustic environment of free-living house sparrows (Passer domesticus) breeding in nest boxes. We focused on the impact of such disturbance on nestlings' telomere length and fledging success, as telomeres (the protective ends of chromosomes) appear to be a promising predictor of longevity. We showed that despite the absence of any obvious immediate consequences (growth and fledging success), nestlings reared under traffic noise exposure exhibited reduced telomere lengths compared with their unexposed neighbours. Although the mechanisms responsible for this effect remain to be determined, our results provide the first experimental evidence that noise alone can affect a wild vertebrate's early-life telomere length. This suggests that noise exposure may entail important costs for developing organisms.},
}
@article {pmid26381690,
year = {2016},
author = {Pawlas, N and Płachetka, A and Kozłowska, A and Mikołajczyk, A and Kasperczyk, A and Dobrakowski, M and Kasperczyk, S},
title = {Telomere length, telomerase expression, and oxidative stress in lead smelters.},
journal = {Toxicology and industrial health},
volume = {32},
number = {12},
pages = {1961-1970},
doi = {10.1177/0748233715601758},
pmid = {26381690},
issn = {1477-0393},
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Cadmium/blood/toxicity ; Case-Control Studies ; Cohort Studies ; Deoxyguanosine/analogs &amp; derivatives/blood ; Humans ; Lead/blood/*toxicity ; Lipid Peroxides/blood ; Male ; Malondialdehyde/blood ; Middle Aged ; Occupational Exposure/*adverse effects ; Oxidative Stress/*genetics ; Selenium/blood ; Spectrophotometry, Atomic ; Telomerase/genetics/*metabolism ; Telomere/*ultrastructure ; },
abstract = {The negative health effects caused by lead (Pb) exposure are widely recognized; however, the molecular mechanisms remain unknown. The aim of this study was to assess the effect of occupational Pb exposure on telomere length and to investigate the potential mechanisms leading to telomere shortening. A cohort of 334 male Pb smelters (exposed group) and 60 age-adjusted males unexposed to Pb (control group) were examined. Assessments of relative telomere length (rTL) and telomerase reverse transcriptase (TERT) gene expression were performed using quantitative real-time polymerase chain reactions. Assessments of whole blood Pb (B-Pb) and whole blood cadmium (B-Cd) concentrations and serum selenium concentration (S-Se) were performed using graphite furnace atomic absorption spectrometry. We analyzed total oxidation status (TOS), lipid hydroperoxides (LHPs), malonylodialdehyde levels in serum (MDA) and in erythrocyte hemolysates (MDA-hgb), and 8-hydroxy-deoxy-guanosine (8-OHdG). The Pb-exposed group had higher B-Pb values and shorter rTL than the control group. The arithmetic mean values calculated for B-Pb were 33 µg/dL versus 2.2 µg/dL (p < 0.0001), and the rTL values were 0.928 and 1.126 relative units (p = 0.001), respectively, for the Pb-exposed and control groups. The rTL was found to gradually shorten in response to the increasing levels of Pb exposure. The Pb-exposed group also demonstrated a higher level of oxidative stress than the control group, which was indicated by increased TOS and MDA-hgb values. rTL was negatively associated with parameters that indicated increased oxidative stress, including TOS (Spearman's rank coefficient (rS) = -0.16; p < 0.01) and MDA-hgb (rS = -0.17; p < 0.001). No correlations were found between rTL and B-Cd and S-Se or smoking and MDA and LHP levels. Univariate analysis indicated that B-Pb was associated with decreased rTL (β =-0.0041; p = 0.0063) and that the association between B-Pb and rTL remained significant, even when adjusting for age (β = -0.0041; p = 0.0065) and in multivariable-adjusted model (β = -0.0042; p = 0.0063). In conclusion, occupational Pb exposure resulted in decreased rTL and may represent a mechanism that contributes to Pb-related diseases.},
}
@article {pmid26380096,
year = {2015},
author = {Hardikar, S and Song, X and Risques, RA and Montine, TJ and Duggan, C and Blount, PL and Reid, BJ and Anderson, GL and Kratz, M and White, E and Vaughan, TL},
title = {Obesity and inflammation markers in relation to leukocyte telomere length in a cross-sectional study of persons with Barrett's esophagus.},
journal = {BMC obesity},
volume = {2},
number = {},
pages = {32},
pmid = {26380096},
issn = {2052-9538},
support = {K05 CA124911/CA/NCI NIH HHS/United States ; P01 CA091955/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R25 CA094880/CA/NCI NIH HHS/United States ; },
abstract = {BACKGROUND: Telomere shortening is associated with increasing age, male gender and lifestyle factors such as obesity and smoking. Inflammation has also been implicated in cellular senescence and may promote telomere shortening in chronic conditions such as obesity and diabetes. However, little is known about the relationship between markers of obesity and inflammation, and leukocyte telomere length (LTL).<br><br>METHODS: LTL was measured using quantitative polymerase chain reaction in peripheral leukocytes from 295 individuals diagnosed with Barrett's esophagus (BE) between 1995 and 2009. Data on lifestyle variables including obesity and smoking were collected at in-person interviews. Biomarkers of obesity (leptin, adiponectin), diabetes (glucose, insulin), inflammation (C-reactive protein, Interleukin-6, surface tumor necrosis factor receptor (sTNFR) I &amp; II) and oxidative stress (F2-isoprostanes) were measured in stored blood samples. We examined associations between these covariates and LTL in a cross-sectional analysis using linear and logistic regression models, adjusting for possible confounders.<br><br>RESULTS: LTL was significantly associated with age (r&#x2009;=&#x2009;-0.30, p&#x2009;<&#x2009;0.001), gender (r&#x2009;=&#x2009;0.14 for females, p&#x2009;=&#x2009;0.01) and inversely associated with cigarette pack-years (r&#x2009;=&#x2009;-0.11, p&#x2009;=&#x2009;0.04). Odds of having short LTL were significantly higher for participants in the highest tertile for sTNF-RI (Odds ratio adjusted for age, gender, smoking, and obesity&#x2009;=&#x2009;2.19; 95&#xa0;% CI 1.00-4.85, p-trend&#x2009;=&#x2009;0.02). LTL was not significantly associated with any other lifestyle factors, including smoking or obesity, or other inflammation-, obesity-/diabetes-related biomarkers measured.<br><br>CONCLUSIONS: Increasing age, male gender, smoking history, and sTNF-RI levels were associated with short LTL among persons with BE but no correlations were observed between LTL and other inflammatory markers or measures of obesity. Larger longitudinal studies are necessary in order to further establish the potential relationships between obesity, inflammation markers and LTL.},
}
@article {pmid26376872,
year = {2015},
author = {Meena, J and Rudolph, KL and Günes, C},
title = {Telomere Dysfunction, Chromosomal Instability and Cancer.},
journal = {Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer},
volume = {200},
number = {},
pages = {61-79},
doi = {10.1007/978-3-319-20291-4_3},
pmid = {26376872},
issn = {0080-0015},
mesh = {Animals ; Cell Proliferation ; *Chromosomal Instability ; Humans ; Neoplasms/*genetics ; Telomerase/physiology ; Telomere/*physiology ; Telomeric Repeat Binding Protein 1/physiology ; },
abstract = {Telomeres form protective caps at the ends of linear chromosomes to prevent nucleolytic degradation, end-to-end fusion, irregular recombination, and chromosomal instability. Telomeres are composed of repetitive DNA sequences (TTAGGG)n in humans, that are bound by specialized telomere binding proteins. Telomeres lose capping function in response to telomere shortening, which occurs during each division of cells that lack telomerase activity-the enzyme that can synthesize telomeres de novo. Telomeres have a dual role in cancer: telomere shortening can lead to induction of chromosomal instability and to the initiation of tumors, however, initiated tumors need to reactivate telomerase in order to stabilize chromosomes and to gain immortal growth capacity. In this review, we summarize current knowledge on the role of telomeres in the maintenance of chromosomal stability and carcinogenesis.},
}
@article {pmid26374947,
year = {2015},
author = {Verhoeven, JE and van Oppen, P and Puterman, E and Elzinga, B and Penninx, BW},
title = {The Association of Early and Recent Psychosocial Life Stress With Leukocyte Telomere Length.},
journal = {Psychosomatic medicine},
volume = {77},
number = {8},
pages = {882-891},
doi = {10.1097/PSY.0000000000000226},
pmid = {26374947},
issn = {1534-7796},
mesh = {Adolescent ; Adult ; *Adult Survivors of Child Adverse Events ; Aged ; Female ; Humans ; Leukocytes/*physiology ; *Life Change Events ; Male ; Middle Aged ; Netherlands ; *Stress, Psychological ; Telomere/*physiology ; Telomere Shortening/*physiology ; Time Factors ; Young Adult ; },
abstract = {OBJECTIVES: Chronic exposure to psychosocial stressors is related to worse somatic health. This association applies both to stressors early in life, such as childhood adversities, and more recent life stress, such as stressful life events. This study examined whether accelerated telomere shortening, as an indicator of cellular aging, might be an explanatory mechanism.<br><br>METHODS: We examined whether childhood adversities and recent stressful life events were associated with shorter telomeres in 2936 participants (mean [standard deviation] age = 41.8 [13.1] years, 66% women, 57% current depression) of the Netherlands Study of Depression and Anxiety. Telomeres are specialized nucleic acid-protein complexes at the ends of linear DNA that shorten with age; telomere length (TL) was measured with quantitative polymerase chain reaction.<br><br>RESULTS: Childhood life events (&#x3b2; = .004, p = .805) and childhood trauma (&#x3b2; = -.023, p = .205) were not related to shorter TL. However, we found negative associations between recent stressful life events and TL. Persons had shorter telomeres if they reported more stressful life events in the past year (&#x3b2; = -.039, p = .028) and 1 to 5 years ago (&#x3b2; = -.042, p = .018, adjusted for sociodemographics). The relationship between stressful life events and TL became borderline significant when further adjusted for smoking status. No associations with TL were found when stressful life events occurred more than 6 years ago (p > .10).<br><br>CONCLUSIONS: Results show that recent stressful life events are associated with shorter TL. This association is not observed for psychosocial stressors that occur earlier in life. Whether these results are indicative of physiological resiliency remains to be explored by future longitudinal research.},
}
@article {pmid26373285,
year = {2016},
author = {Singh, AK and Lakhotia, SC},
title = {The hnRNP A1 homolog Hrb87F/Hrp36 is important for telomere maintenance in Drosophila melanogaster.},
journal = {Chromosoma},
volume = {125},
number = {3},
pages = {373-388},
pmid = {26373285},
issn = {1432-0886},
mesh = {Animals ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster ; Heterogeneous-Nuclear Ribonucleoproteins/genetics/*metabolism ; Nuclear Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere Homeostasis/*physiology ; X Chromosome/genetics/*metabolism ; },
abstract = {Unlike the telomerase-dependent mammalian telomeres, HeT-A, TART, and TAHRE (HTT) retroposon arrays regulate Drosophila telomere length. Cap prevents telomeric associations (TAs) and telomeric fusions (TFs). Our results suggest important roles of Hrb87F in telomeric HTT array and cap maintenance in Drosophila. All chromosome arms, except 2L, in Df(3R)Hrb87F homozygotes (Hrb87F-null) displayed significantly elongated telomeres with amplified HTT arrays and high TAs, all of which resolved without damage. Presence of FLAG-tagged Hrb87F (FLAG-Hrb87F) on cap and subtelomeric regions following hsFLAG-Hrb87F transgene expression in Df(3R)Hrb87F homozygotes suppressed TAs without affecting telomere length. A normal X-chromosome telomere expanded within five generations in Hrb87F-null background and displayed high TAs, but not when hsFLAG-Hrb87F was co-expressed. Tel (1) /Gaiano line or HP1 loss-of-function mutant-derived expanded telomeres carry Hrb87F on cap and HTT arrays while Hrb87F-null telomeres have HP1 and HOAP on caps and expanded HTT arrays. ISWI, seen only on cap on normal telomeres, was abundant on Hrb87F-null expanded HTT arrays. Extended telomeres derived from Tel (1) (Gaiano) or HP1-null mutation background interact with those from Hrb87F-null, since while the end association frequency was negligible in Df(3R)Hrb87F/+ nuclei, it increased significantly in co-presence of Tel (1) or HP1-null-based expanded telomere/s. Together, these suggest complex interactions between members of the proteome of telomere so that absence of any key member leads to telomere expansion and/or enhanced TAs/TFs. HTT expansion in Hrb87F-null condition is not developmental but a germline event presumably because absence of Hrb87F in germline may deregulate HTT retroposition/replication leading to telomere elongation.},
}
@article {pmid26373281,
year = {2015},
author = {Ramamoorthy, M and Smith, S},
title = {Loss of ATRX Suppresses Resolution of Telomere Cohesion to Control Recombination in ALT Cancer Cells.},
journal = {Cancer cell},
volume = {28},
number = {3},
pages = {357-369},
pmid = {26373281},
issn = {1878-3686},
support = {R01 CA116352/CA/NCI NIH HHS/United States ; R01CA116352/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line ; Cell Line, Tumor ; Chromatin Assembly and Disassembly/genetics ; DNA Helicases/*genetics ; Genomic Instability/genetics ; HEK293 Cells ; HeLa Cells ; Histones/genetics ; Humans ; Nuclear Proteins/*genetics ; Poly(ADP-ribose) Polymerases/genetics ; Recombination, Genetic/*genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis/genetics ; X-linked Nuclear Protein ; },
abstract = {The chromatin-remodeler ATRX is frequently lost in cancer cells that use ALT (alternative lengthening of telomeres) for telomere maintenance, but its function in telomere recombination is unknown. Here we show that loss of ATRX suppresses the timely resolution of sister telomere cohesion that normally occurs prior to mitosis. In the absence of ATRX, the histone variant macroH2A1.1 binds to the poly(ADP-ribose) polymerase tankyrase 1, preventing it from localizing to telomeres and resolving cohesion. The resulting persistent telomere cohesion promotes recombination between sister telomeres, while it suppresses inappropriate recombination between non-sisters. Forced resolution of sister telomere cohesion induces excessive recombination between non-homologs, genomic instability, and impaired cell growth, indicating the ATRX-macroH2A1.1-tankyrase axis as a potential therapeutic target in ALT tumors.},
}
@article {pmid26373274,
year = {2015},
author = {Roake, CM and Artandi, SE},
title = {Keeping It in the Family: ATRX Loss Promotes Persistent Sister Telomere Cohesion in ALT Cancer Cells.},
journal = {Cancer cell},
volume = {28},
number = {3},
pages = {277-279},
doi = {10.1016/j.ccell.2015.08.005},
pmid = {26373274},
issn = {1878-3686},
mesh = {DNA Helicases/*genetics ; Humans ; Nuclear Proteins/*genetics ; Recombination, Genetic/*genetics ; Telomere/*genetics ; },
abstract = {In this issue of Cancer Cell, Ramamoorthy and Smith report that cancer cells that maintain their chromosome ends through alternative lengthening of telomeres (ALT) display persistent sister telomere cohesion. This delayed resolution of sister telomere cohesion depends upon the loss of ATRX and its histone-sequestering function and is associated with increased recombination between sister telomeres.},
}
@article {pmid26371764,
year = {2015},
author = {Mamdani, F and Rollins, B and Morgan, L and Myers, RM and Barchas, JD and Schatzberg, AF and Watson, SJ and Akil, H and Potkin, SG and Bunney, WE and Vawter, MP and Sequeira, PA},
title = {Variable telomere length across post-mortem human brain regions and specific reduction in the hippocampus of major depressive disorder.},
journal = {Translational psychiatry},
volume = {5},
number = {9},
pages = {e636},
pmid = {26371764},
issn = {2158-3188},
support = {R21 MH099440/MH/NIMH NIH HHS/United States ; R01 MH104261/MH/NIMH NIH HHS/United States ; R01 MH085801/MH/NIMH NIH HHS/United States ; R01 MH097082/MH/NIMH NIH HHS/United States ; R01MH097082/MH/NIMH NIH HHS/United States ; },
mesh = {Analysis of Variance ; Brain/pathology ; Cadaver ; Depressive Disorder, Major/*genetics/*pathology ; Dissection ; Female ; Genetic Techniques ; Hippocampus/*pathology ; Humans ; Male ; Middle Aged ; Polymerase Chain Reaction ; Telomere/*genetics/*pathology ; },
abstract = {Stress can be a predisposing factor to psychiatric disorders and has been associated with decreased neurogenesis and reduced hippocampal volume especially in depression. Similarly, in white blood cells chronic psychological stress has been associated with telomere shortening and with mood disorders and schizophrenia (SZ). However, in previous post-mortem brain studies from occipital cortex and cerebellum, no difference in telomere length was observed in depression. We hypothesized that in psychiatric disorders, stress-driven accelerated cellular aging can be observed in brain regions particularly sensitive to stress. Telomere length was measured by quantitative-PCR in five brain regions (dorsolateral prefrontal cortex, hippocampus (HIPP), amygdala, nucleus accumbens and substantia nigra (SN)) in major depressive disorder (MDD), bipolar disorder, SZ and normal control subjects (N = 40, 10 subjects per group). We observed significant differences in telomere length across brain regions suggesting variable levels of cell aging, with SN and HIPP having the longest telomeres and the dorsolateral prefrontal cortex the shortest. A significant decrease (P < 0.02) in telomere length was observed specifically in the HIPP of MDD subjects even after controlling for age. In the HIPP of MDD subjects, several genes involved in neuroprotection and in stress response (FKBP5, CRH) showed altered levels of mRNA. Our results suggest the presence of hippocampal stress-mediated accelerated cellular aging in depression. Further studies are needed to investigate the cellular specificity of these findings.},
}
@article {pmid26369986,
year = {2015},
author = {Wenn, K and Tomala, L and Wilop, S and Vankann, L and Hasenbank, C and Frank, O and Hochhaus, A and Giles, FJ and Lange, T and Müller, MC and Koschmieder, S and Beier, F and Ziegler, P and Brümmendorf, TH},
title = {Telomere length at diagnosis of chronic phase chronic myeloid leukemia (CML-CP) identifies a subgroup with favourable prognostic parameters and molecular response according to the ELN criteria after 12 months of treatment with nilotinib.},
journal = {Leukemia},
volume = {29},
number = {12},
pages = {2402-2404},
pmid = {26369986},
issn = {1476-5551},
mesh = {Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/*therapeutic use ; Humans ; Leukemia, Myeloid, Chronic-Phase/drug therapy/*genetics ; Middle Aged ; Prognosis ; Pyrimidines/*therapeutic use ; *Telomere ; },
}
@article {pmid26367189,
year = {2016},
author = {Sletten, S and Bourgeon, S and Bårdsen, BJ and Herzke, D and Criscuolo, F and Massemin, S and Zahn, S and Johnsen, TV and Bustnes, JO},
title = {Organohalogenated contaminants in white-tailed eagle (Haliaeetus albicilla) nestlings: An assessment of relationships to immunoglobulin levels, telomeres and oxidative stress.},
journal = {The Science of the total environment},
volume = {539},
number = {},
pages = {337-349},
doi = {10.1016/j.scitotenv.2015.08.123},
pmid = {26367189},
issn = {1879-1026},
mesh = {Animals ; Biomarkers/metabolism ; Eagles/*metabolism ; *Environmental Monitoring ; Environmental Pollutants/*metabolism ; Hydrocarbons, Chlorinated/*metabolism ; Oxidative Stress/physiology ; },
abstract = {Biomagnifying organohalogenated compounds (OHCs) may have adverse effects on the health of birds, especially marine avian top predators that accumulate high OHC loads. Contaminants may impair the humoral immunity and also influence the antioxidant enzyme activity (i.e. oxidative stress). Moreover, physical conditions and oxidative stress during development may reduce telomere lengths, one of the main mechanisms explaining cell senescence. To examine the potential effects of environmental contaminants on physiological biomarkers of health, OHCs with different 'physicochemical' properties were related to immunoglobulin Y levels (IgY; humoral immunity), superoxide dismutase enzyme (SOD) activity in blood plasma, and telomere length (measured in red blood cells) in individual 7-8weeks old nestlings (n=35) of white-tailed eagles (Haliaeetus albicilla) in the Norwegian Sub-Arctic. Different organochlorines (OCs) and perfluoroalkylated substances (PFASs) were measured in blood plasma of nestlings, demonstrating higher concentrations of the emerging contaminants (PFASs), notably perfluorooctane sulfonate (PFOS), compared to legacy OCs. There were no relationships between the contaminant loads and plasma IgY levels. Moreover, differences between years were found for telomere lengths, but this was not related to contaminants and more likely a result of different developmental conditions. However, there were significant and negative relationships between the OC loadings and the SOD activity. This suggests that some legacy OCs challenge the antioxidant capacity in nestlings of white-tailed eagles.},
}
@article {pmid26366868,
year = {2015},
author = {Panero, J and Stella, F and Schutz, N and Fantl, DB and Slavutsky, I},
title = {Differential Expression of Non-Shelterin Genes Associated with High Telomerase Levels and Telomere Shortening in Plasma Cell Disorders.},
journal = {PloS one},
volume = {10},
number = {9},
pages = {e0137972},
pmid = {26366868},
issn = {1932-6203},
mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Follow-Up Studies ; *Gene Expression Regulation, Neoplastic ; *Genes, Neoplasm ; Humans ; Male ; Middle Aged ; Monoclonal Gammopathy of Undetermined Significance/etiology/*metabolism/pathology ; Multiple Myeloma/genetics/*metabolism/pathology ; Neoplasm Proteins/*biosynthesis/genetics ; Telomere/genetics/*metabolism/pathology ; *Telomere Homeostasis ; },
abstract = {Telomerase, shelterin proteins and various interacting factors, named non-shelterin proteins, are involved in the regulation of telomere length (TL). Altered expression of any of these telomere-associated genes can lead to telomere dysfunction, causing genomic instability and disease development. In this study, we investigated the expression profile of a set of non-shelterin genes involved in essential processes such as replication (RPA1), DNA damage repair pathways (MRE11-RAD50-NBS1) and stabilization of telomerase complex (DKC1), in 35 patients with monoclonal gammopathy of undetermined significance (MGUS) and 40 cases with multiple myeloma (MM). Results were correlated with hTERT expression, TL and clinical parameters. Overall, a significant increase in DKC1, RAD50, MRE11, NBS1 and RPA1 expression along with an upregulation of hTERT in MM compared with MGUS was observed (p≤0.032). Interestingly, in both entities high mRNA levels of non-shelterin genes were associated with short TLs and increased hTERT expression. Significant differences were observed for DKC1 in MM (p ≤0.026), suggesting an important role for this gene in the maintenance of short telomeres by telomerase in myeloma plasma cells. With regard to clinical associations, we observed a significant increase in DKC1, RAD50, MRE11 and RPA1 expression in MM cases with high bone marrow infiltration (p≤0.03) and a tendency towards cases with advanced ISS stage, providing the first evidence of non-shelterin genes associated to risk factors in MM. Taken together, our findings bring new insights into the intricate mechanisms by which telomere-associated proteins collaborate in the maintenance of plasma cells immortalization and suggest a role for the upregulation of these genes in the progression of the disease.},
}
@article {pmid26365526,
year = {2015},
author = {Lin, KW and McDonald, KR and Guise, AJ and Chan, A and Cristea, IM and Zakian, VA},
title = {Proteomics of yeast telomerase identified Cdc48-Npl4-Ufd1 and Ufd4 as regulators of Est1 and telomere length.},
journal = {Nature communications},
volume = {6},
number = {},
pages = {8290},
pmid = {26365526},
issn = {2041-1723},
support = {DP1 DA026192/DA/NIDA NIH HHS/United States ; GM43265/GM/NIGMS NIH HHS/United States ; R01 GM043265/GM/NIGMS NIH HHS/United States ; R01 GM114141/GM/NIGMS NIH HHS/United States ; HD073044/HD/NICHD NIH HHS/United States ; R37 GM026938/GM/NIGMS NIH HHS/United States ; R21 HD073044/HD/NICHD NIH HHS/United States ; DA026192/DA/NIDA NIH HHS/United States ; R35 GM118279/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases/*metabolism ; Blotting, Southern ; Blotting, Western ; Cell Cycle Proteins/*metabolism ; Mass Spectrometry ; Nucleocytoplasmic Transport Proteins/*metabolism ; Proteomics ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/*metabolism ; Tandem Mass Spectrometry ; Telomerase/*metabolism ; *Telomere Homeostasis ; Ubiquitin-Protein Ligases/*metabolism ; Valosin Containing Protein ; Vesicular Transport Proteins/*metabolism ; },
abstract = {Almost 400 genes affect yeast telomere length, including Est1, which is critical for recruitment and activation of telomerase. Here we use mass spectrometry to identify novel telomerase regulators by their co-purification with the telomerase holoenzyme. In addition to all known subunits, over 100 proteins are telomerase associated, including all three subunits of the essential Cdc48-Npl4-Ufd1 complex as well as three E3 ubiquitin ligases. The Cdc48 complex is evolutionarily conserved and targets ubiquitinated proteins for degradation. Est1 levels are ∼40-fold higher in cells with reduced Cdc48, yet, paradoxically, telomeres are shorter. Furthermore, Est1 is ubiquitinated and its cell cycle-regulated abundance is lost in Cdc48-deficient cells. Deletion of the telomerase-associated E3 ligase, Ufd4, in cdc48-3 cells further increases Est1 abundance but suppresses the telomere length phenotype of the single mutant. These data argue that, in concert with Ufd4, the Cdc48 complex regulates telomerase by controlling the level and activity of Est1.},
}
@article {pmid26360549,
year = {2015},
author = {Singh, I and Nunia, V and Sharma, R and Barupal, J and Govindaraj, P and Jain, R and Gupta, GN and Goyal, PK},
title = {Mutational analysis of telomere complex genes in Indian population with acquired aplastic anemia.},
journal = {Leukemia research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.leukres.2015.08.018},
pmid = {26360549},
issn = {1873-5835},
abstract = {BACKGROUND: Acquired aplastic anemia (AAA) is rare disorders caused due to the profound or almost complete bone marrow failure. It is a life threatening hematopoietic stem cells disorder, which is characterized by pancytopenia or complete loss of blood-forming cells. The aim of the present study is to screen for the mutations in telomerase complex genes, and to establish a molecular and hematological profile of Indian sub population.<br><br>METHODOLOGY: We have conducted a case control study of total 70 participants; 50 patients, who fulfilled the blood count and bone marrow criteria of the International agranulocytosis &amp; AAA, and 20 healthy controls. These samples were selected from hematology clinics at Jaipur, India, during the period of two years (January 2012-December 2013). We screened four telomere complex genes; TERT, DKC1, NOP10 and NHP2 of mutations at single base pair in sampled blood and bone marrows. We have predicated the consequences of mutations on protein structure using 3D multilevel modeling protein structure software Phyre2, PolyPhen2 and YASARA.<br><br>RESULTS: The hematological and molecular basis of acquired aplastic anemia was investigated in 50 anemia patients and 20 healthy controls. AAA patients showed hematologic abnormalities (macrocytic anemia, thrombocytopenia, &amp; granulocytopenia) in peripheral blood and severe hypoplastic bone marrows. Screening of telomere complex genes TERT, DKC1, NOP10 and NHP2 in AAA patients and controls revealed; novel and reported mutations in TERT and DKC1, whereas, no pathogenic mutations were observed in NOP10 and NHP2 genes. In TERT gene, one non-synonymous mutation (Chr5: 1287,825 C&#x2192;T; Arg979Trp) was identified in exon 12 and two heterozygous non-synonymous mutations (Chr X: 153,994,542 T&#x2192;K; Val105Gly &amp; Chr X: 153,994,591 T&#x2192;K; Ser121Arg) were found in exon 5 of DKC1 gene. To determine and visualize the possible effect of TERT and DKC1 mutations on protein structure YASARA with FoldX functionality has been used and many structural consequences were found that might destabilize the protein. Predicated structural consequences may destabilize the TERT and DKC1 proteins ultimately causing blood disorders..<br><br>CONCLUSION: The present study indicates the mutation spectrum in the genes implicated in AAA, i.e. TERT, DKC1, NOP10 and NHP2 on small case-control group in an Indian sub population.},
}
@article {pmid26359627,
year = {2015},
author = {Rastgou Talemi, S and Kollarovic, G and Lapytsko, A and Schaber, J},
title = {Development of a robust DNA damage model including persistent telomere-associated damage with application to secondary cancer risk assessment.},
journal = {Scientific reports},
volume = {5},
number = {},
pages = {13540},
pmid = {26359627},
issn = {2045-2322},
mesh = {Algorithms ; *DNA Damage ; Humans ; *Models, Theoretical ; Neoplasms/epidemiology/*etiology/*metabolism ; Reproducibility of Results ; Risk Assessment ; Telomere/*metabolism ; },
abstract = {Mathematical modelling has been instrumental to understand kinetics of radiation-induced DNA damage repair and associated secondary cancer risk. The widely accepted two-lesion kinetic (TLK) model assumes two kinds of double strand breaks, simple and complex ones, with different repair rates. Recently, persistent DNA damage associated with telomeres was reported as a new kind of DNA damage. We therefore extended existing versions of the TLK model by new categories of DNA damage and re-evaluated those models using extensive data. We subjected different versions of the TLK model to a rigorous model discrimination approach. This enabled us to robustly select a best approximating parsimonious model that can both recapitulate and predict transient and persistent DNA damage after ionizing radiation. Models and data argue for i) nonlinear dose-damage relationships, and ii) negligible saturation of repair kinetics even for high doses. Additionally, we show that simulated radiation-induced persistent telomere-associated DNA damage foci (TAF) can be used to predict excess relative risk (ERR) of developing secondary leukemia after fractionated radiotherapy. We suggest that TAF may serve as an additional measure to predict cancer risk after radiotherapy using high dose rates. This may improve predicting risk-dose dependency of ionizing radiation especially for long-term therapies.},
}
@article {pmid26359233,
year = {2015},
author = {Robin, JD and Ludlow, AT and Batten, K and Gaillard, MC and Stadler, G and Magdinier, F and Wright, WE and Shay, JW},
title = {SORBS2 transcription is activated by telomere position effect-over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy.},
journal = {Genome research},
volume = {25},
number = {12},
pages = {1781-1790},
pmid = {26359233},
issn = {1549-5469},
support = {AG01228/AG/NIA NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; T32CA124334/CA/NCI NIH HHS/United States ; C06 RR030414/RR/NCRR NIH HHS/United States ; C06 RR30414/RR/NCRR NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing ; Biopsy ; Chromosome Deletion ; Chromosomes, Human, Pair 4 ; DNA Methylation ; Epistasis, Genetic ; Gene Expression Regulation ; Genetic Loci ; Homeodomain Proteins/*genetics/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Muscle Cells/*metabolism ; Muscle, Skeletal/metabolism/pathology ; Muscular Dystrophy, Facioscapulohumeral/*genetics/metabolism/pathology ; MyoD Protein/genetics/metabolism ; Myoblasts ; RNA-Binding Proteins ; Telomere/*genetics ; *Telomere Shortening ; *Transcriptional Activation ; },
abstract = {DNA is organized into complex three-dimensional chromatin structures, but how this spatial organization regulates gene expression remains a central question. These DNA/chromatin looping structures can range in size from 10-20 kb (enhancers/repressors) to many megabases during intra- and inter-chromosomal interactions. Recently, the influence of telomere length on chromatin organization prior to senescence has revealed the existence of long-distance chromatin loops that dictate the expression of genes located up to 10 Mb from the telomeres (Telomere Position Effect-Over Long Distances [TPE-OLD]). Here, we demonstrate the existence of a telomere loop at the 4q35 locus involving the sorbin and SH3 domain-containing protein 2 gene, SORBS2, a skeletal muscle protein using a modification of the chromosome conformation capture method. The loop reveals a cis-acting mechanism modifying SORBS2 transcription. The expression of this gene is altered by TPE-OLD in myoblasts from patients affected with the age-associated genetic disease, facioscapulohumeral muscular dystrophy (FSHD1A, MIM 158900). SORBS2 is expressed in FSHD myoblasts with short telomeres, while not detectable in FSHD myoblasts with long telomeres or in healthy myoblasts regardless of telomere length. This indicates that TPE-OLD may modify the regulation of the 4q35 locus in a pathogenic context. Upon differentiation, both FSHD and healthy myotubes express SORBS2, suggesting that SORBS2 is normally up-regulated by maturation/differentiation of skeletal muscle and is misregulated by TPE-OLD-dependent variegation in FSHD myoblasts. These findings provide additional insights for the complexity and age-related symptoms of FSHD.},
}
@article {pmid26356673,
year = {2015},
author = {Wu, X and Tanaka, H},
title = {Aberrant reduction of telomere repetitive sequences in plasma cell-free DNA for early breast cancer detection.},
journal = {Oncotarget},
volume = {6},
number = {30},
pages = {29795-29807},
pmid = {26356673},
issn = {1949-2553},
mesh = {Adult ; Age Factors ; Aged ; Breast Neoplasms/blood/diagnosis/*genetics ; Carcinoma, Ductal, Breast/blood/diagnosis/genetics ; Carcinoma, Intraductal, Noninfiltrating/blood/diagnosis/genetics ; Carcinoma, Lobular/blood/diagnosis/genetics ; DNA, Neoplasm/blood/*genetics ; Diagnosis, Differential ; Early Detection of Cancer/*methods ; Female ; Humans ; Middle Aged ; Polymerase Chain Reaction/methods ; ROC Curve ; Repetitive Sequences, Nucleic Acid/*genetics ; Reproducibility of Results ; Telomere/*genetics ; Telomere Shortening/genetics ; },
abstract = {Excessive telomere shortening is observed in breast cancer lesions when compared to adjacent non-cancerous tissues, suggesting that telomere length may represent a key biomarker for early cancer detection. Because tumor-derived, cell-free DNA (cfDNA) is often released from cancer cells and circulates in the bloodstream, we hypothesized that breast cancer development is associated with changes in the amount of telomeric cfDNA that can be detected in the plasma. To test this hypothesis, we devised a novel, highly sensitive and specific quantitative PCR (qPCR) assay, termed telomeric cfDNA qPCR, to quantify plasma telomeric cfDNA levels. Indeed, the internal reference primers of our design correctly reflected input cfDNA amount (R(2) = 0.910, P = 7.82 × 10(-52)), implying accuracy of this assay. We found that plasma telomeric cfDNA levels decreased with age in healthy individuals (n = 42, R(2) = 0.094, P = 0.048), suggesting that cfDNA is likely derived from somatic cells in which telomere length shortens with increasing age. Our results also showed a significant decrease in telomeric cfDNA level from breast cancer patients with no prior treatment (n = 47), compared to control individuals (n = 42) (P = 4.06 × 10(-8)). The sensitivity and specificity for the telomeric cfDNA qPCR assay was 91.49% and 76.19%, respectively. Furthermore, the telomeric cfDNA level distinguished even the Ductal Carcinoma In Situ (DCIS) group (n = 7) from the healthy group (n = 42) (P = 1.51 × 10(-3)). Taken together, decreasing plasma telomeric cfDNA levels could be an informative genetic biomarker for early breast cancer detection.},
}
@article {pmid26355460,
year = {2015},
author = {Hadchouel, A and Marchand-Martin, L and Franco-Montoya, ML and Peaudecerf, L and Ancel, PY and Delacourt, C and , },
title = {Salivary Telomere Length and Lung Function in Adolescents Born Very Preterm: A Prospective Multicenter Study.},
journal = {PloS one},
volume = {10},
number = {9},
pages = {e0136123},
pmid = {26355460},
issn = {1932-6203},
mesh = {Adolescent ; Adult ; Confounding Factors, Epidemiologic ; Female ; Gestational Age ; Humans ; Infant, Extremely Premature/*metabolism ; Lung/*physiology ; Male ; Prospective Studies ; Respiratory Function Tests ; Saliva/*metabolism ; *Telomere Homeostasis ; },
abstract = {Preterm birth is associated with abnormal respiratory functions throughout life. The mechanisms underlying these long-term consequences are still unclear. Shortening of telomeres was associated with many conditions, such as chronic obstructive pulmonary disease. We aimed to search for an association between telomere length and lung function in adolescents born preterm. Lung function and telomere length were measured in 236 adolescents born preterm and 38 born full-term from the longitudinal EPIPAGE cohort. Associations between telomere length and spirometric indices were tested in univariate and multivariate models accounting for confounding factors in the study population. Airflows were significantly lower in adolescents born preterm than controls; forced expiratory volume in one second was 12% lower in the extremely preterm born group than controls (p<0.001). Lower birth weight, bronchopulmonary dysplasia and postnatal sepsis were significantly associated with lower airflow values. Gender was the only factor that was significantly associated with telomere length. Telomere length correlated with forced expiratory flow 25-75 in the extremely preterm adolescent group in univariate and multivariate analyses (p = 0.01 and p = 0.02, respectively). We evidenced an association between telomere length and abnormal airflow in a population of adolescents born extremely preterm. There was no evident association with perinatal events. This suggests other involved factors, such as a continuing airway oxidative stress leading to persistent inflammation and altered lung function, ultimately increasing susceptibility to chronic obstructive pulmonary disease.},
}
@article {pmid26354530,
year = {2015},
author = {García-Calzón, S and Zalba, G and Ruiz-Canela, M and Shivappa, N and Hébert, JR and Martínez, JA and Fitó, M and Gómez-Gracia, E and Martínez-González, MA and Marti, A},
title = {Dietary inflammatory index and telomere length in subjects with a high cardiovascular disease risk from the PREDIMED-NAVARRA study: cross-sectional and longitudinal analyses over 5 y.},
journal = {The American journal of clinical nutrition},
volume = {102},
number = {4},
pages = {897-904},
pmid = {26354530},
issn = {1938-3207},
support = {R44DK103377/DK/NIDDK NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/genetics ; Body Mass Index ; Cardiovascular Diseases/diagnosis/*epidemiology/genetics ; Cholesterol, HDL/blood ; Cholesterol, LDL/blood ; Cross-Sectional Studies ; Diet, Fat-Restricted ; Diet, Mediterranean ; Dietary Carbohydrates/administration &amp; dosage ; Dietary Fats/administration &amp; dosage ; Dietary Proteins/administration &amp; dosage ; Energy Intake ; *Feeding Behavior ; Female ; Follow-Up Studies ; Genetic Markers ; Humans ; Inflammation/diagnosis/*epidemiology/genetics ; Leukocytes/metabolism ; Linear Models ; Longitudinal Studies ; Male ; Micronutrients/administration &amp; dosage ; Middle Aged ; Motor Activity ; Nuts ; Olive Oil/administration &amp; dosage ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; Risk Factors ; Surveys and Questionnaires ; Telomere/*genetics/ultrastructure ; Triglycerides/blood ; },
abstract = {BACKGROUND: Dietary factors can affect telomere length (TL), a biomarker of aging, through oxidation and inflammation-related mechanisms. A Dietary Inflammatory Index (DII) could help to understand the effect of the inflammatory potential of the diet on telomere shortening.<br><br>OBJECTIVE: This study aimed to determine the association of the DII with TL and to examine whether diet-associated inflammation could modify the telomere attrition rate after a 5-y follow-up of a Mediterranean dietary intervention.<br><br>DESIGN: This was a prospective study of 520 participants at high cardiovascular disease risk (mean &#xb1; SD age: 67.0 &#xb1; 6.0 y, 45% males) from the PREDIMED-NAVARRA (PREvenci&#xf3;n con DIeta MEDiterr&#xe1;nea-NAVARRA) trial. Leukocyte TL was measured by quantitative real-time polymerase chain reaction at baseline and after 5 y of follow-up. The DII was calculated from self-reported data by using a validated 137-item food-frequency questionnaire.<br><br>RESULTS: Longer telomeres at baseline were found in participants who had a more anti-inflammatory diet (lowest DII score) (P-trend = 0.012). Longitudinal analyses further showed that a greater anti-inflammatory potential of the diet (i.e., a decrease in the DII) could significantly slow down the rate of telomere shortening. Moreover, the multivariable-adjusted OR for short telomeres (z score &#x2264;20th percentile) was 1.80 (95% CI: 1.03, 3.17) in a comparison between the highest (proinflammatory) and the lowest (anti-inflammatory) DII tertiles. Similarly, a greater DII (greatest proinflammatory values) after a 5-y follow-up was associated with almost a 2-fold higher risk of accelerated telomere attrition compared with the highest decrease in DII (greatest anti-inflammatory values) during this period (P-trend = 0.025).<br><br>CONCLUSIONS: This study showed both cross-sectional and longitudinal associations between the inflammatory potential of the diet and telomere shortening in subjects with a high cardiovascular disease risk. Our findings are consistent with, but do not show, a beneficial effect of adherence to an anti-inflammatory diet on aging and health by slowing down telomere shortening. These results suggest that diet might play a key role as a determinant of TL through proinflammatory or anti-inflammatory mechanisms. This trial was registered at controlled-trials.com as ISRCTN35739639.},
}
@article {pmid26354422,
year = {2015},
author = {Moser, BA and Raguimova, ON and Nakamura, TM},
title = {Ccq1-Tpz1TPP1 interaction facilitates telomerase and SHREC association with telomeres in fission yeast.},
journal = {Molecular biology of the cell},
volume = {26},
number = {21},
pages = {3857-3866},
pmid = {26354422},
issn = {1939-4586},
support = {R01 GM078253/GM/NIGMS NIH HHS/United States ; GM078253/GM/NIGMS NIH HHS/United States ; },
mesh = {Carrier Proteins/*metabolism ; Cell Cycle Proteins/metabolism ; Checkpoint Kinase 2/genetics ; DNA-Binding Proteins ; Heterochromatin/metabolism ; Nucleotidases/*metabolism ; Phosphorylation ; Protein Kinases/metabolism ; Protein Structure, Tertiary ; Schizosaccharomyces/metabolism ; Schizosaccharomyces pombe Proteins/*metabolism ; Telomerase/*metabolism ; Telomere/metabolism ; Telomere Shortening/physiology ; Telomere-Binding Proteins/metabolism ; },
abstract = {Evolutionarily conserved shelterin complex is essential for telomere maintenance in the fission yeast Schizosaccharomyces pombe. Elimination of the fission yeast shelterin subunit Ccq1 causes progressive loss of telomeres due to the inability to recruit telomerase, activates the DNA damage checkpoint, and loses heterochromatin at telomere/subtelomere regions due to reduced recruitment of the heterochromatin regulator complex Snf2/histone deacetylase-containing repressor complex (SHREC). The shelterin subunit Tpz1(TPP1) directly interacts with Ccq1 through conserved C-terminal residues in Tpz1(TPP1), and tpz1 mutants that fail to interact with Ccq1 show telomere shortening, checkpoint activation, and loss of heterochromatin. While we have previously concluded that Ccq1-Tpz1(TPP1) interaction contributes to Ccq1 accumulation and telomerase recruitment based on analysis of tpz1 mutants that fail to interact with Ccq1, another study reported that loss of Ccq1-Tpz1(TPP1) interaction does not affect accumulation of Ccq1 or telomerase. Furthermore, it remained unclear whether loss of Ccq1-Tpz1(TPP1) interaction affects SHREC accumulation at telomeres. To resolve these issues, we identified and characterized a series of ccq1 mutations that disrupt Ccq1-Tpz1(TPP1) interaction. Characterization of these ccq1 mutants established that Ccq1-Tpz1(TPP1) interaction contributes to optimal binding of the Ccq1-SHREC complex, and is critical for Rad3(ATR)/Tel1(ATM)-dependent Ccq1 Thr93 phosphorylation and telomerase recruitment.},
}
@article {pmid26354067,
year = {2015},
author = {Do, SK and Yoo, SS and Choi, YY and Choi, JE and Jeon, HS and Lee, WK and Lee, SY and Lee, J and Cha, SI and Kim, CH and Park, JY},
title = {Replication of the results of genome-wide and candidate gene association studies on telomere length in a Korean population.},
journal = {The Korean journal of internal medicine},
volume = {30},
number = {5},
pages = {719-726},
pmid = {26354067},
issn = {2005-6648},
mesh = {Adult ; Aged ; Asian People/*genetics ; Case-Control Studies ; DNA-Binding Proteins/genetics ; Female ; Genome-Wide Association Study ; Genotype ; Humans ; Kruppel-Like Transcription Factors/genetics ; Male ; Middle Aged ; Phenotype ; *Polymorphism, Single Nucleotide ; Republic of Korea ; Telomerase/genetics ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; Transcription Factors ; Zinc Fingers ; },
abstract = {BACKGROUND/AIMS: A number of genome-wide and candidate gene association studies have identified polymorphisms associated with telomere length in Caucasian populations. This study was conducted to determine the impacts of 17 polymorphisms identified in Caucasians on telomere length in a Korean population.<br><br>METHODS: Ninety-four healthy individuals were enrolled in this study. Relative telomere length of chromosomes from peripheral blood samples was measured using quantitative polymerase chain reaction.<br><br>RESULTS: Two polymorphisms, rs10936599 of MYNN and rs412658 of ZNF676, were found to be associated w ith telomere length (under dominant model, p = 0.04; under recessive model, p = 0.001). Three polymorphisms, rs2853669, rs7705526, and rs2736108, at the TERT locus were also associated with telomere length (under recessive model, p = 0.01, p = 0.02, and p = 0.01, respectively). The genotypes of the five polymorphisms associated with short telomere length were considered bad genotypes; telomere length was significantly decreased with increasing number of bad genotypes (p= 1.7 &#xd7; 10(-5)).<br><br>CONCLUSIONS: We have identified polymorphisms associated with telomere length in a Korean population.},
}
@article {pmid26353719,
year = {2015},
author = {Choi, Y and De Siqueira Neto, JL and Moraes, C and Freitas, L and Song, R},
title = {Synthesis and Evaluation of DNA Based Quantum Dot Fluorescence In Situ Hybridization (FISH) Probe for Telomere Detection.},
journal = {Journal of nanoscience and nanotechnology},
volume = {15},
number = {2},
pages = {1708-1713},
doi = {10.1166/jnn.2015.9500},
pmid = {26353719},
issn = {1533-4880},
mesh = {Base Sequence ; DNA/chemistry/*genetics ; DNA Probes/genetics ; Equipment Design ; Equipment Failure Analysis ; In Situ Hybridization, Fluorescence/*methods ; Leishmania major/*genetics ; Materials Testing ; Molecular Sequence Data ; Nanoconjugates/chemistry ; *Quantum Dots ; Reproducibility of Results ; Sensitivity and Specificity ; Sequence Analysis, DNA/*methods ; Telomere/*genetics ; },
abstract = {Efficient oligonucleotide probe design and synthesis based on polymer-coated CdSe/ZnS quantum dot (QD) is demonstrated for detection of telomeres in human monocyte and Leishmania major, a protozoan pathogenic parasite. The highly photoluminescent polymer-coated QDs conjugated with various length of telomere probe sequences were prepared via carbodiimide chemistry and characterized. Specific detection of telomere was observed when DNA sequence was (CCCAAT)n (n = 5 or 3) probe sequence, rather than (GGGTTA)n (n = 3, 5, 8). The sensitivity and specificity were comparable with commercially available PNA probe for human telomere detection.},
}
@article {pmid26351750,
year = {2015},
author = {Nikolic, N and Anicic, B and Carkic, J and Simonovic, J and Toljic, B and Tanic, N and Tepavcevic, Z and Vukadinovic, M and Konstantinovic, VS and Milasin, J},
title = {High frequency of p16 and p14 promoter hypermethylation and marked telomere instability in salivary gland tumors.},
journal = {Archives of oral biology},
volume = {60},
number = {11},
pages = {1662-1666},
doi = {10.1016/j.archoralbio.2015.08.011},
pmid = {26351750},
issn = {1879-1506},
mesh = {Adenoma, Pleomorphic/*genetics/metabolism/pathology ; Adult ; Aged ; Cyclin-Dependent Kinase Inhibitor p16/genetics/metabolism ; *DNA Methylation ; Female ; Genes, Tumor Suppressor ; *Genes, p16 ; Humans ; Male ; Middle Aged ; Neoplasm Grading ; Oncogene Proteins/*genetics/metabolism ; Parotid Neoplasms/*genetics/metabolism/pathology ; Promoter Regions, Genetic ; Telomere/*genetics/metabolism ; Telomere Homeostasis ; Young Adult ; },
abstract = {OBJECTIVES: to investigate p16(INK4a) and p14(ARF) tumor suppressor gene methylation status, determine telomere length and assess the importance of these epigenetic and genetic parameters in the development of pleomorphic adenoma and carcinoma ex pleomorphic adenoma of the parotid salivary glands.<br><br>MATERIALS AND METHODS: Genomic DNA from paraffin-embedded samples of 50 pleomorphic adenomas and 10 carcinomas ex pleomorphic adenoma was subjected to methylation specific polymerase chain reaction for hypermethylation analyses and real time polymerase chain reaction for the relative telomere length calculations.<br><br>RESULTS: Promoter hypermethylation of the two genes was a very frequent event in both neoplasms - between 60% and 90% of samples were hypermethylated - but without significant difference between the groups. The mean relative telomere length in the pleomorphic adenoma group was significantly increased in comparison to the control group (P=0.00), and significantly decreased in comparison to the carcinoma group (P=0.05). Telomeres were also longer in myxoid and cellular histological subtypes of adenomas than in the classic type (P=0.044 and P=0.018, respectively). Longer telomeres were more frequent in tumors with hypermethylated p14(ARF) alleles (P=0.013).<br><br>CONCLUSION: Promoter hypermethylations seems to be an important mechanism of p16(INK4a) and p14(ARF) inactivation in parotid gland tumors. Telomeric lengthening appears to be involved in the pathogenesis of both benign and malignant tumors of the parotid glands.},
}
@article {pmid26351258,
year = {2015},
author = {Parikh, D and Fouquerel, E and Murphy, CT and Wang, H and Opresko, PL},
title = {Telomeres are partly shielded from ultraviolet-induced damage and proficient for nucleotide excision repair of photoproducts.},
journal = {Nature communications},
volume = {6},
number = {},
pages = {8214},
pmid = {26351258},
issn = {2041-1723},
support = {P30 ES025128/ES/NIEHS NIH HHS/United States ; R00 ES016758/ES/NIEHS NIH HHS/United States ; R00ES016758/ES/NIEHS NIH HHS/United States ; 5P50CA121973/CA/NCI NIH HHS/United States ; P50 CA121973/CA/NCI NIH HHS/United States ; R01 ES022944/ES/NIEHS NIH HHS/United States ; R01ES022944/ES/NIEHS NIH HHS/United States ; },
mesh = {Cell Line ; Cell Proliferation ; Cell Survival ; DNA Damage/*radiation effects ; DNA Repair/*physiology ; Fibroblasts/cytology/radiation effects ; Humans ; Telomere/*radiation effects ; Ultraviolet Rays ; },
abstract = {Ultraviolet light induces cyclobutane pyrimidine dimers (CPD) and pyrimidine(6-4)pyrimidone photoproducts, which interfere with DNA replication and transcription. Nucleotide excision repair (NER) removes these photoproducts, but whether NER functions at telomeres is unresolved. Here we use immunospot blotting to examine the efficiency of photoproduct formation and removal at telomeres purified from UVC irradiated cells at various recovery times. Telomeres exhibit approximately twofold fewer photoproducts compared with the bulk genome in cells, and telomere-binding protein TRF1 significantly reduces photoproduct formation in telomeric fragments in vitro. CPD removal from telomeres occurs 1.5-fold faster than the bulk genome, and is completed by 48 h. 6-4PP removal is rapidly completed by 6 h in both telomeres and the overall genome. A requirement for XPA protein indicates the mechanism of telomeric photoproduct removal is NER. These data provide new evidence that telomeres are partially protected from ultraviolet irradiation and that NER preserves telomere integrity.},
}
@article {pmid26348426,
year = {2015},
author = {Dantzer, B and Fletcher, QE},
title = {Telomeres shorten more slowly in slow-aging wild animals than in fast-aging ones.},
journal = {Experimental gerontology},
volume = {71},
number = {},
pages = {38-47},
doi = {10.1016/j.exger.2015.08.012},
pmid = {26348426},
issn = {1873-6815},
mesh = {Aging/*genetics/physiology ; Animals ; Animals, Wild/genetics/*physiology ; Longevity/genetics/physiology ; Species Specificity ; Telomere Shortening/*physiology ; },
abstract = {Research on the physiological causes of senescence aim to identify common physiological mechanisms that explain age-related declines in fitness across taxonomic groups. Telomeres are repetitive nucleotide sequences found on the ends of eukaryotic chromosomes. Past research indicates that telomere attrition is strongly correlated with inter-specific rates of aging, though these studies cannot distinguish whether telomere attrition is a cause or consequence of the aging process. We extend previous research on this topic by incorporating recent studies to test the hypothesis that telomeres shorten more slowly with age in slow-aging animals than in fast-aging ones. We assembled all studies that have quantified cross-sectional (i.e. between-individual) telomere rates of change (TROC) over the lifespans of wild animals. This included 22 estimates reflecting absolute TROC (TROCabs, bp/yr, primarily measured using the terminal restriction fragment length method), and 10 estimates reflecting relative TROC (TROCrel, relative telomere length/yr, measured using qPCR), from five classes (Aves, Mammalia, Bivalvia, Reptilia, and Actinopterygii). In 14 bird species, we correlated between-individual (i.e. cross-sectional) TROCabs estimates with both maximum lifespan and a phylogenetically-corrected principle component axis (pcPC1) that reflected the slow-fast axis of life-history variation. Bird species characterized by faster life-histories and shorter maximum lifespans had faster TROCabs. In nine studies, both between-individual and within-individual TROC estimates were available (n=8 for TROCabs, n=1 for TROCrel). Within-individual TROC estimates were generally greater than between-individual TROC estimates, which is indicative of selective disappearance of individuals with shorter telomeres. However, the difference between within- and between-individual TROC estimates was only significant in two out of nine studies. The relationship between within-individual TROCabs and maximum lifespan did not differ from the relationship of between-individual TROCabs and maximum lifespan. Overall, our results provide additional support for the hypothesis that TROC is correlated with inter-specific rates of aging and complement the intra-specific research that also find relationships between telomere attrition and components of fitness.},
}
@article {pmid26346823,
year = {2015},
author = {Tajbakhsh, S and Aliakbari, K and Hussey, DJ and Lower, KM and Donato, AJ and Sokoya, EM},
title = {Differential Telomere Shortening in Blood versus Arteries in an Animal Model of Type 2 Diabetes.},
journal = {Journal of diabetes research},
volume = {2015},
number = {},
pages = {153829},
pmid = {26346823},
issn = {2314-6753},
support = {K02 AG045339/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Antioxidants/metabolism ; Arteries/*pathology ; Blood Pressure ; Diabetes Mellitus, Type 2/*blood ; Disease Models, Animal ; Endothelium, Vascular/metabolism ; Hyperglycemia/pathology ; Leukocytes/cytology/metabolism ; Male ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Oxidative Stress ; Phenotype ; Rats ; Rats, Wistar ; Sirtuin 1/metabolism ; Superoxides/metabolism ; Telomere/*ultrastructure ; *Telomere Shortening ; },
abstract = {Vascular dysfunction is an early feature of diabetic vascular disease, due to increased oxidative stress and reduced nitric oxide (NO) bioavailability. This can lead to endothelial cell senescence and clinical complications such as stroke. Cells can become senescent by shortened telomeres and oxidative stress is known to accelerate telomere attrition. Sirtuin 1 (SIRT1) has been linked to vascular health by upregulating endothelial nitric oxide synthase (eNOS), suppressing oxidative stress, and attenuating telomere shortening. Accelerated leukocyte telomere attrition appears to be a feature of clinical type 2 diabetes (T2D) and therefore the telomere system may be a potential therapeutic target in preventing vascular complications of T2D. However the effect of T2D on vascular telomere length is currently unknown. We hypothesized that T2D gives rise to shortened leukocyte and vascular telomeres alongside reduced vascular SIRT1 expression and increased oxidative stress. Accelerated telomere attrition was observed in circulating leukocytes, but not arteries, in T2D compared to control rats. T2D rats had blunted arterial SIRT1 and eNOS protein expression levels which were associated with reduced antioxidant defense capacity. Our findings suggest that hyperglycemia and a deficit in vascular SIRT1 per se are not sufficient to prematurely shorten vascular telomeres.},
}
@article {pmid26345860,
year = {2015},
author = {Du, H and Yang, L and Xu, XY and Hai, L and Han, YQ and Shi, YX},
title = {Telomere-associated factor expression in replicative senescence of human embryonic lung fibroblasts.},
journal = {Genetics and molecular research : GMR},
volume = {14},
number = {3},
pages = {9269-9276},
doi = {10.4238/2015.August.10.7},
pmid = {26345860},
issn = {1676-5680},
mesh = {Cell Line ; Cellular Senescence/*genetics ; Fibroblasts/*metabolism ; *Gene Expression ; Humans ; RNA/genetics ; Shelterin Complex ; Tankyrases/genetics/metabolism ; Telomerase/genetics ; Telomere-Binding Proteins/*genetics/metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; },
abstract = {The objective of this study was to find the key regulatory molecules in the cell senescence process through observing the expression of telomere-associated factor during the normal cell replicative senescence process. Based on the established cell replicative senescence model, reverse transcription-polymerase chain reaction and western blot analyses were used to detect telomere-associated factor expression at the mRNA and protein levels, including that of human telomere binding protein 1, tankyrase 1, telomerase RNA, telomere protection protein 1 (POT1), and p53 during the process of human embryonic lung fibroblast replicative senescence. The results showed that transcription of human telomere binding protein 1 did not change with cell senescence, whereas the protein expression of human telomere binding protein 1 increased gradually and then decreased rapidly; there was no change in the mRNA and protein expression of POT1; with the replicative senescence of human embryonic lung fibroblasts, expression of POT1 decreased gradually; TRF1 showed an increasing trend with cell senescence; and p53 protein expression did not change. Together, the results from this study suggest that human telomere binding protein 1, POT1, and TRF1 played important roles in cell senescence.},
}
@article {pmid26345285,
year = {2015},
author = {Spinella, JF and Cassart, P and Garnier, N and Rousseau, P and Drullion, C and Richer, C and Ouimet, M and Saillour, V and Healy, J and Autexier, C and Sinnett, D},
title = {A novel somatic mutation in ACD induces telomere lengthening and apoptosis resistance in leukemia cells.},
journal = {BMC cancer},
volume = {15},
number = {},
pages = {621},
pmid = {26345285},
issn = {1471-2407},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Apoptosis/*genetics ; Child ; Child, Preschool ; DNA Mutational Analysis/*methods ; Exome/genetics ; Female ; Humans ; Male ; *Mutation ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics/pathology ; Shelterin Complex ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {BACKGROUND: The identification of oncogenic driver mutations has largely relied on the assumption that genes that exhibit more mutations than expected by chance are more likely to play an active role in tumorigenesis. Major cancer sequencing initiatives have therefore focused on recurrent mutations that are more likely to be drivers. However, in specific genetic contexts, low frequency mutations may also be capable of participating in oncogenic processes. Reliable strategies for identifying these rare or even patient-specific (private) mutations are needed in order to elucidate more personalized approaches to cancer diagnosis and treatment.<br><br>METHODS: Here we performed whole-exome sequencing on three cases of childhood pre-B acute lymphoblastic leukemia (cALL), representing three cytogenetically-defined subgroups (high hyperdiploid, t(12;21) translocation, and cytogenetically normal). We applied a data reduction strategy to identify both common and rare/private somatic events with high functional potential. Top-ranked candidate mutations were subsequently validated at high sequencing depth on an independent platform and in vitro expression assays were performed to evaluate the impact of identified mutations on cell growth and survival.<br><br>RESULTS: We identified 6 putatively damaging non-synonymous somatic mutations among the three cALL patients. Three of these mutations were well-characterized common cALL mutations involved in constitutive activation of the mitogen-activated protein kinase pathway (FLT3 p.D835Y, NRAS p.G13D, BRAF p.G466A). The remaining three patient-specific mutations (ACD p.G223V, DOT1L p.V114F, HCFC1 p.Y103H) were novel mutations previously undescribed in public cancer databases. Cytotoxicity assays demonstrated a protective effect of the ACD p.G223V mutation against apoptosis in leukemia cells. ACD plays a key role in protecting telomeres and recruiting telomerase. Using a telomere restriction fragment assay, we also showed that this novel mutation in ACD leads to increased telomere length in leukemia cells.<br><br>CONCLUSION: This study identified ACD as a novel gene involved in cALL and points to a functional role for ACD in enhancing leukemia cell survival. These results highlight the importance of rare/private somatic mutations in understanding cALL etiology, even within well-characterized molecular subgroups.},
}
@article {pmid26344230,
year = {2015},
author = {Ishizuka, T and Xu, Y and Komiyama, M},
title = {Clipping of Telomere from Human Chromosomes Using a Chemistry-Based Artificial Restriction DNA Cutter.},
journal = {Current protocols in nucleic acid chemistry},
volume = {61},
number = {},
pages = {6.13.1-6.13.13},
doi = {10.1002/0471142700.nc0613s61},
pmid = {26344230},
issn = {1934-9289},
mesh = {Biotechnology/methods ; Chromosomes, Human/genetics ; Humans ; Peptide Nucleic Acids/*chemistry ; Telomere/genetics ; },
abstract = {The detection of individual telomere lengths of human chromosomes can provide crucial information on genome stability, cancer, and telomere-related diseases. However, current methods to measure telomere length entail shortcomings that have limited their use. Recently, we have developed a method for detection of individual telomere lengths (DITL) that uses a chemistry-based DNA-cutting approach. The most beneficial feature of the DITL approach is to cleave the sequence adjacent to the telomere followed by resolution of the telomere length at the nucleotide level of a single chromosome. In this unit, a protocol for successful detection of individual telomere lengths from individual chromosomes is described in detail.},
}
@article {pmid26342126,
year = {2015},
author = {Wang, H and Wang, Y and Kota, KK and Kallakury, B and Mikhail, NN and Sayed, D and Mokhtar, A and Maximous, D and Yassin, EH and Gouda, I and Sobitan, A and Sun, B and Loffredo, CA and Zheng, YL},
title = {Strong association between long and heterogeneous telomere length in blood lymphocytes and bladder cancer risk in Egyptian.},
journal = {Carcinogenesis},
volume = {36},
number = {11},
pages = {1284-1290},
pmid = {26342126},
issn = {1460-2180},
support = {P30 CA051008/CA/NCI NIH HHS/United States ; P30 CA51008/CA/NCI NIH HHS/United States ; R01CA115618/CA/NCI NIH HHS/United States ; R01CA132996/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Biomarkers, Tumor/genetics ; Case-Control Studies ; Egypt ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Lymphocytes/*physiology ; Male ; Middle Aged ; Risk Factors ; Telomere/*genetics ; *Telomere Homeostasis ; Urinary Bladder Neoplasms/*genetics ; },
abstract = {Although it is widely recognized that telomere dysfunction plays an important role in cancer, the relationship between telomere function and bladder cancer risk is not well defined. In a case-control study of bladder cancer in Egypt, we examined relationships between two telomere features and bladder cancer risk. Telomere fluorescent in situ hybridization was used to measure telomere features using short-term cultured blood lymphocytes. Logistic regression was used to estimate the strength of association between telomere features and the risk of urothelial carcinoma of the bladder. High telomere length variation (TLV) across all chromosomal ends was significantly associated with an increased risk of bladder cancer [adjusted odds ratios (OR) = 2.22, 95% confidence interval (CI) = 1.48-3.35], as was long average telomere length (OR = 3.19, 95% CI = 2.07, 4.91). Further, TLV and average telomere length jointly affected bladder cancer risk: when comparing individuals with long telomere length and high TLV to those with short telomere length and low TLV, the adjusted OR was 14.68 (95% CI: 6.74-31.98). These associations were stronger among individuals who are 60 years of age or younger. In summary, long and heterogeneous telomere length in blood lymphocytes was strongly associated with an increased bladder cancer risk in Egyptian and the association was modulated by age.},
}
@article {pmid26341697,
year = {2015},
author = {Caini, S and Raimondi, S and Johansson, H and De Giorgi, V and Zanna, I and Palli, D and Gandini, S},
title = {Telomere length and the risk of cutaneous melanoma and non-melanoma skin cancer: a review of the literature and meta-analysis.},
journal = {Journal of dermatological science},
volume = {80},
number = {3},
pages = {168-174},
doi = {10.1016/j.jdermsci.2015.08.003},
pmid = {26341697},
issn = {1873-569X},
mesh = {Carcinoma, Basal Cell/*genetics ; Carcinoma, Squamous Cell/*genetics ; Humans ; Leukocytes ; Melanoma/*genetics ; Risk Factors ; Skin Neoplasms/*genetics ; Telomere/*genetics ; *Telomere Shortening ; },
abstract = {There is much evidence supporting the role of telomeres in cancer pathogenesis, however the studies that investigated the association between telomere length and skin cancer risk provided inconsistent results. To help clarify this issue, we performed a systematic review and meta-analysis of published papers on the association between peripheral leukocytes telomere length (PLTL) and the risk of cutaneous melanoma and non-melanoma skin cancer (NMSC). We calculated summary relative risks (SRR) and 95% confidence intervals (95% CI) using random effect models with maximum likelihood estimates, and explored causes of between-studies heterogeneity of risk estimates. We included 1629 cutaneous melanoma and 1439 NMSC from eight independent studies published until March 2015. The SRR of cutaneous melanoma for those in the lowest (vs. highest) category of PLTL distribution was 0.25 (95% CI 0.09-0.67). The results were less clear for NMSC, with two studies reporting no association and one study showing an increase in risk for those in the lowest (vs. highest) category of PLTL distribution. For both cutaneous melanoma and NMSC, the between-studies heterogeneity was large, mainly due to inclusion of hospital-based case-control studies. Our meta-analysis shows evidence of an association between short PLTL and reduced risk for cutaneous melanoma.},
}
@article {pmid26339993,
year = {2015},
author = {Guzzardi, MA and Iozzo, P and Salonen, M and Kajantie, E and Eriksson, JG},
title = {Rate of telomere shortening and metabolic and cardiovascular risk factors: a longitudinal study in the 1934-44 Helsinki Birth Cohort Study.},
journal = {Annals of medicine},
volume = {47},
number = {6},
pages = {499-505},
doi = {10.3109/07853890.2015.1074718},
pmid = {26339993},
issn = {1365-2060},
mesh = {Adiposity/genetics ; Age Factors ; Aged ; Cardiovascular Diseases/epidemiology/*genetics ; Cholesterol, HDL/blood/genetics ; Cohort Studies ; Female ; Finland/epidemiology ; Humans ; Leukocytes/metabolism/ultrastructure ; Longitudinal Studies ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction/methods ; Risk Factors ; Telomere/*genetics/metabolism ; Telomere Homeostasis ; Telomere Shortening ; Triglycerides/blood ; },
abstract = {INTRODUCTION: Leucocyte telomere length (LTL) is associated with age-related health outcomes, but only few longitudinal studies have assessed changes in LTL in an ageing population.<br><br>METHODS: A total of 1,082 subjects from the Helsinki Birth Cohort Study (born 1934-1944), undergoing two clinical visits &#x223c;10 years apart, were studied. Relative LTL was measured twice by quantitative real-time PCR. Simple and multiple regressions were used to study associations between cardiometabolic risk factors and LTL.<br><br>RESULTS: Telomere shortening was observed in 93.7%, and telomere elongation in 6.3% of the study participants. Telomere shortening was more rapid among males (-39.5% &#xb1; 1.1% versus -35.5% &#xb1; 1.0%, P < 0.01). In men a decrease in weight, waist circumference, BMI, and body fat percentage were all associated with telomere shortening during the follow-up (P < 0.05) independently of age and use of medication. Furthermore, higher body fat percentage and higher HDL-cholesterol level were associated with a slower rate of shortening in LTL (P < 0.05). Lower blood pressure levels were also associated with slower rate of telomere shortening in men (P < 0.05). No similar associations were observed among women.<br><br>DISCUSSION: A decrease in adiposity was associated with telomere shortening, and higher body fat percentage and HDL-cholesterol were associated with a slower rate of shortening in telomere length in men.},
}
@article {pmid26336104,
year = {2015},
author = {Reddy, V and Wu, M and Ciavattone, N and McKenty, N and Menon, M and Barrack, ER and Reddy, GP and Kim, SH},
title = {ATM Inhibition Potentiates Death of Androgen Receptor-inactivated Prostate Cancer Cells with Telomere Dysfunction.},
journal = {The Journal of biological chemistry},
volume = {290},
number = {42},
pages = {25522-25533},
pmid = {26336104},
issn = {1083-351X},
support = {P30CA022455/CA/NCI NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins/*antagonists &amp; inhibitors/metabolism ; Cell Death/*physiology ; Cell Line, Tumor ; Enzyme Activation ; Humans ; Male ; Prostatic Neoplasms/genetics/*pathology ; Receptors, Androgen/*physiology ; *Telomere ; },
abstract = {Androgen receptor (AR) plays a role in maintaining telomere stability in prostate cancer cells, as AR inactivation induces telomere dysfunction within 3 h. Since telomere dysfunction in other systems is known to activate ATM (ataxia telangiectasia mutated)-mediated DNA damage response (DDR) signaling pathways, we investigated the role of ATM-mediated DDR signaling in AR-inactivated prostate cancer cells. Indeed, the induction of telomere dysfunction in cells treated with AR-antagonists (Casodex or MDV3100) or AR-siRNA was associated with a dramatic increase in phosphorylation (activation) of ATM and its downstream effector Chk2 and the presenceof phosphorylated ATM at telomeres, indicating activation of DDR signaling at telomeres. Moreover, Casodex washout led to the reversal of telomere dysfunction, indicating repair of damaged telomeres. ATM inhibitor blocked ATM phosphorylation, induced PARP cleavage, abrogated cell cycle checkpoint activation and attenuated the formation of γH2AX foci at telomeres in AR-inactivated cells, suggesting that ATM inhibitor induces apoptosis in AR-inactivated cells by blocking the repair of damaged DNA at telomeres. Finally, colony formation assay revealed a dramatic decrease in the survival of cells co-treated with Casodex and ATM inhibitor as compared with those treated with either Casodex or ATM inhibitor alone. These observations indicate that inhibitors of DDR signaling pathways may offer a unique opportunity to enhance the potency of AR-targeted therapies for the treatment of androgen-sensitive as well as castration-resistant prostate cancer.},
}
@article {pmid26335747,
year = {2015},
author = {Aida, S and Aida, J and Hasegawa, K and Kumasaka, T and Shimazaki, H and Tamai, S and Takubo, K},
title = {Telomere Length of Human Adult Bronchial Epithelium and Bronchogenic Squamous Cell Carcinoma Measured Using Tissue Quantitative Fluorescence in situ Hybridization.},
journal = {Respiration; international review of thoracic diseases},
volume = {90},
number = {4},
pages = {321-326},
doi = {10.1159/000437357},
pmid = {26335747},
issn = {1423-0356},
mesh = {Aged ; Aged, 80 and over ; Aging/pathology ; Carcinoma, Bronchogenic/*pathology ; Carcinoma, Squamous Cell/*pathology ; Case-Control Studies ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Lung Neoplasms/*pathology ; Male ; Middle Aged ; Respiratory Mucosa/*pathology ; Smoking/pathology ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Telomeres are repetitive DNA sequences located at the ends of chromosomes. Chromosomal and genomic instability due to telomere dysfunction has been known to play an important role in the carcinogenesis of some organs.<br><br>OBJECTIVES: The aim of this study was to examine the correlation between smoking and the telomere length of human bronchial epithelial cells in individuals with and without lung cancer.<br><br>PATIENTS AND METHODS: We examined 68 non-lung cancer adult autopsy cases and 24 surgically resected cases of lung squamous cell carcinoma. Telomere lengths of the basal cells of bronchial epithelium were measured using the tissue quantitative fluorescence in situ hybridization method and were expressed in normalized telomere-to-centromere ratios (NTCRs).<br><br>RESULTS: The autopsied individuals included 27 current smokers (CuS), 33 never-smokers (NeS), and 8 ex-smokers (ExS). The NTCRs in the central bronchi of CuS, NeS, and ExS were 1.515, 1.372, and 1.204, respectively. The bronchial epithelial telomeres of CuS were significantly longer than those of non-CuS (NeS + ExS). When the analysis was conducted separately for females and males, a significant difference between CuS and NeS + ExS was recognized only for males. The NTCRs of the bronchial epithelium of lung cancer cases and lung cancer tissue are 1.514 and 1.385, respectively.<br><br>CONCLUSIONS: Our findings suggest that smoking causes telomeric elongation in the bronchial epithelium. Therefore, it appears that the mechanism of carcinogenesis in smoking-related carcinomas may differ from that of many other carcinomas in which genetic instability due to aging-related telomeric shortening is assumed to play a role.},
}
@article {pmid26330309,
year = {2016},
author = {Xin, X and Senthilkumar, PK and Schnoor, JL and Ludewig, G},
title = {Effects of PCB126 and PCB153 on telomerase activity and telomere length in undifferentiated and differentiated HL-60 cells.},
journal = {Environmental science and pollution research international},
volume = {23},
number = {3},
pages = {2173-2185},
pmid = {26330309},
issn = {1614-7499},
support = {P30 ES005605/ES/NIEHS NIH HHS/United States ; P42 ES013661/ES/NIEHS NIH HHS/United States ; },
mesh = {Cell Differentiation/*drug effects ; Enzyme Inhibitors/chemistry/*toxicity ; Gene Expression/drug effects ; HL-60 Cells ; Humans ; Polychlorinated Biphenyls/chemistry/*toxicity ; Telomerase/*antagonists &amp; inhibitors/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {PCBs are persistent organic pollutants that are carcinogenic and immunotoxic and have developmental toxicity. This suggests that they may interfere with normal cell maturation. Cancer and stem/progenitor cells have telomerase activity to maintain and protect the chromosome ends, but lose this activity during differentiation. We hypothesized that PCBs interfere with telomerase activity and the telomere complex, thereby disturbing cell differentiation and stem/progenitor cell function. HL-60 cells are cancer cells that can differentiated into granulocytes and monocytes. We exposed HL-60 cells to PCB126 (dioxin-like) and PCB153 (nondioxin-like) 6 days before and during 3 days of differentiation. The differentiated cells showed G0/G1 phase arrest and very low telomerase activity. hTERT and hTR, two telomerase-related genes, were downregulated. The telomere shelterins TRF1, TRF2, and POT1 were upregulated in granulocytes, and TRF2 was upregulated and POT1 downregulated in monocytes. Both PCBs further reduced telomerase activity in differentiated cells, but had only small effects on the differentiation and telomere-related genes. Treatment of undifferentiated HL-60 cells for 30 days with PCB126 produced a downregulation of telomerase activity and a decrease of hTERT, hTR, TRF1, and POT1 gene expression. With PCB153, the effects were less pronounced and some shelterin genes were increased after 30 days of exposure. With each PCB, no differentiation of cells was observed and cells continued to proliferate despite reduced telomerase activity, resulting in shortened telomeres after 30 days of exposure. These results indicate cell-type and PCB congener-specific effects on telomere/telomerase-related genes. Although PCBs do not seem to strongly affect differentiation, they may influence stem or progenitor cells through telomere attrition with potential long-term consequences for health.},
}
@article {pmid26327598,
year = {2015},
author = {Menendez, JA and Benboudjema, L and Vellon, L and Rubio, MA and Espinoza, I and Campisi, J and Lupu, R},
title = {Heregulin, a new interactor of the telosome/shelterin complex in human telomeres.},
journal = {Oncotarget},
volume = {6},
number = {37},
pages = {39408-39421},
pmid = {26327598},
issn = {1949-2553},
support = {R01 CA118975/CA/NCI NIH HHS/United States ; R01-CA118975/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Cell Nucleus/genetics/metabolism ; Gene Deletion ; Humans ; Immunoprecipitation ; In Situ Hybridization, Fluorescence ; MCF-7 Cells ; Microscopy, Fluorescence ; Mutation ; Neuregulin-1/genetics/*metabolism ; Protein Binding ; RNA Interference ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere Shortening/genetics ; Telomere-Binding Proteins/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Two-Hybrid System Techniques ; },
abstract = {Telomere length, shape and function depend on a complex of six core telomere-associated proteins referred to as the telosome or shelterin complex. We here demonstrate that the isoform β2 of the heregulin family of growth factors (HRGβ2) is a novel interactor of the telosome/shelterin complex in human telomeres. Analysis of protein-protein interactions using a high-throughput yeast two-hybrid (Y2H) screen identified RAP1, the only telomere protein that is conserved from yeasts to mammals, as a novel interacting partner of HRGβ2. Deletion analysis of RAP1 revealed that the linker domain, a region previously suggested to recruit negative regulators of telomere length, interacts specifically with HRGβ2. Co-immunoprecipitation and imaging experiments demonstrated that, in addition to RAP1, HRGβ2 could associate with the RAP1-associated telomeric repeat binding factor 2 (TRF2). Deletion analysis of HRGβ2 confirmed that a putative nuclear localization signal (NLS) was necessary for nuclear HRGβ2 to exert a negative regulation of telomere length whereas the N-terminus (extracellular) amino acids of HRGβ2 were sufficient to interact with RAP1/TRF2 and promote telomere shortening. Taken together, our studies identify nuclear HRGβ2 as one of the previously unknown regulators predicted to be recruited by the RAP1 linker domain to negatively regulate telomere length in human cells. Our current findings reveal that a new, but likely not the last, unexpected visitor has arrived to the "telosome/shelterin town".},
}
@article {pmid26321036,
year = {2016},
author = {Sukenik-Halevy, R and Amiel, A and Kidron, D and Liberman, M and Ganor-Paz, Y and Biron-Shental, T},
title = {Telomere homeostasis in trophoblasts and in cord blood cells from pregnancies complicated with preeclampsia.},
journal = {American journal of obstetrics and gynecology},
volume = {214},
number = {2},
pages = {283.e1-283.e7},
doi = {10.1016/j.ajog.2015.08.050},
pmid = {26321036},
issn = {1097-6868},
mesh = {Adult ; Blood Cells/*metabolism ; Case-Control Studies ; Cellular Senescence/*genetics ; Female ; Fetal Blood/cytology/*metabolism ; Gene Dosage ; Humans ; In Situ Hybridization, Fluorescence ; Placenta/metabolism ; Pre-Eclampsia/*genetics ; Pregnancy ; Prospective Studies ; RNA/*genetics ; Telomerase/*genetics ; Telomere Homeostasis/*genetics ; Telomere Shortening/*genetics ; Trophoblasts/*metabolism ; Young Adult ; },
abstract = {BACKGROUND: Telomeres are nucleoprotein structures, essential for chromosome stability and cell survival. Telomeres are progressively shortened with each cell division and by environmental factors. Telomere loss has been linked to age and stress-induced premature senescence. Dysfunctional telomeres tend to form aggregates, which consist of the end-to-end fusion of telomeres. Telomere elongation is carried out by telomerase, which is a specific reverse transcriptase capable of adding telomeric repeats to chromosome termini. The TERC gene encodes the RNA template of the telomerase. Another compensatory mechanism that is enhanced in response to telomere shortening and senescence is the telomere capture (TC). Telomere shortening and elevated aggregate formation have been observed in trophoblasts from pregnancies complicated with preeclampsia (PE).<br><br>OBJECTIVE: We opted to study mechanisms of telomere shortening in trophoblasts from pregnancies complicated with PE and to assess telomere length and homeostasis in fetal cord blood cells from PE pregnancies.<br><br>STUDY DESIGN: Placental specimens and cord blood samples from uncomplicated pregnancies and from pregnancies complicated with PE were collected. Staining with 4',6-diamidino-2-phenylindole was used to assess nuclear fragmentation: senescence-associated heterochromatin foci (SAHF). Fluorescence in situ hybridization was used to evaluate TERC gene copy number and TC. Telomere length and aggregate formation were assessed in cord blood using quantitative fluorescence in situ hybridization. Nonparametric Kruskal-Wallis and Mann-Whitney U tests were applied to test the differences between the study groups.<br><br>RESULTS: Nine samples from pregnant patients with PE without intrauterine growth restriction and 14 samples from uncomplicated pregnancies that served as controls were collected. In cord blood cells, no differences were observed in telomere length, aggregate formation, TERC copy number, TC, or SAHF between PE and controls. In PE trophoblasts the percentage of cells with SAHF was higher in PE trophoblasts compared to controls (56.8 SD = 10.5% vs 35.2 SD = 10.7%, P = .028). The percentage of cells with abnormal TERC copy number was increased in PE trophoblasts compared to controls (31 &#xb1; 3.6% vs 12.97 SD = 5%, P = .004) as well as the percentage of cells with TC (27.4 SD = 9.4% vs 16 SD = 4.67%, P = .028).<br><br>CONCLUSION: We suggest that telomere shortening in PE trophoblasts is linked to cellular increased senescence. Alterations in telomere homeostasis mechanisms are present in such cases. These findings support the role of telomeres in the pathogenesis of trophoblastic dysfunction in PE. The lack of telomere shortening, modified telomere homeostasis mechanisms, and increased senescence in cord blood from pregnancies complicated with PE suggests that these processes are probably restricted primarily to the placenta.},
}
@article {pmid26318724,
year = {2015},
author = {Menendez, JA and Rubio, MA and Campisi, J and Lupu, R},
title = {Heregulin, a new regulator of telomere length in human cells.},
journal = {Oncotarget},
volume = {6},
number = {37},
pages = {39422-39436},
pmid = {26318724},
issn = {1949-2553},
support = {R01 CA118975/CA/NCI NIH HHS/United States ; },
mesh = {Blotting, Western ; Cell Line, Tumor ; Cell Nucleus/genetics/metabolism ; *Gene Expression Regulation, Neoplastic ; Humans ; In Situ Hybridization, Fluorescence ; MCF-7 Cells ; Microscopy, Fluorescence ; Neuregulin-1/*genetics/metabolism ; Protein Binding ; RNA Interference ; Shelterin Complex ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics ; Telomere Shortening/genetics ; Telomere-Binding Proteins/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; },
abstract = {The growth factor heregulin (HRG) promotes breast cancer (BC) tumorigenesis and metastasis and differentially modulates BC cell responses to DNA-damaging agents via its dual extracellular and nuclear localization. Given the central role of telomere dysfunction to drive carcinogenesis and to alter the chemotherapeutic profile of transformed cells, we hypothesized that an unanticipated nuclear function of HRG might be to regulate telomere length. Engineered overexpression of the HRGβ2 isoform in non-aggressive, HRG-negative MCF-7 BC cells resulted in a significant shortening of telomeres (up to 1.3 kb) as measured by Southern blotting of telomere terminal restriction fragments. Conversely, antisense-mediated suppression of HRGβ2 in highly aggressive, HRG-overexpressing MDA-MB-231 and Hs578T cells increased telomere length up to 3.0 kb. HRGβ2 overexpression promoted a marked upregulation of telomere-binding protein 2 (TRF2) protein expression, whereas its knockdown profoundly decreased TRF2 expression. Double staining of endogenous HRGβ2 with telomere-specific peptide nucleic acid probe/fluorescence in situ hybridization (PNA/FISH) revealed the partial localization of HRG at the chromosome ends. Moreover, a predominantly nucleoplasmic staining pattern of endogenous HRGβ2 appeared to co-localize with TRF2 and, concomitantly with RAP1, a telomere regulator that specifically interacts with TRF2. Small interfering RNA-mediated knockdown of HRG decreased the expression of TRF2 and RAP1, decreased their presence at chromosome ends, and coincidentally resulted in the formation of longer telomeres. This study uncovers a new function for HRGβ2 in controlling telomere length, in part due to its ability to regulate and interact with the telomere-associated proteins TRF2 and RAP1.},
}
@article {pmid26318587,
year = {2015},
author = {Domínguez, D and Feijoo, P and Bernal, A and Ercilla, A and Agell, N and Genescà, A and Tusell, L},
title = {Centrosome aberrations in human mammary epithelial cells driven by cooperative interactions between p16INK4a deficiency and telomere-dependent genotoxic stress.},
journal = {Oncotarget},
volume = {6},
number = {29},
pages = {28238-28256},
pmid = {26318587},
issn = {1949-2553},
mesh = {Blotting, Western ; Cells, Cultured ; Centrioles/genetics/metabolism ; Centrosome/*metabolism ; Cyclin-Dependent Kinase Inhibitor p16/*genetics/metabolism ; *DNA Damage ; Epithelial Cells/*metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Mammary Glands, Human/cytology ; Microscopy, Fluorescence ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; Tetraploidy ; Tumor Suppressor Protein p53/genetics/metabolism ; },
abstract = {Virtually all human cancers display chromosome instability (CIN), a condition in which chromosomes are gained or lost at a high rate. CIN occurs early in cancer development where it may undermine the advance of the neoplastic disease. With the aim of establishing the mechanisms underlying CIN in cancer, we investigated possible links between telomere-dysfunction and centrosome defects, which were seen to coincide in early in breast carcinogenesis using human mammary epithelial cells (HMECs). In this study, we show that TP53 proficient vHMECs cells develop centrosome aberrations when telomere-dysfunction genotoxic stress is produced in the presence of a defective p16INK4a setting and in parallel with an activation of the DNA damage checkpoint response. These aberrations consist of the accumulation of centrosomes in polyploid vHMECs, plus centriole overduplication in both diploid and polyploid cells, thus reflecting that distinct mechanisms underlie the generation of centrosome aberrations in vHMECs. Transduction of vHMEC with hTERT, which rescued the telomere dysfunction phenotype and consequently reduced DNA damage checkpoint activation, led to a progressive reduction of centrosome aberrations with cell culture, both in diploid and in polyploid vHMECs. Radiation-induced DNA damage also raised centrosome aberrations in vHMEC-hTERT. Collectively, our results, using vHMECs define a model where p16INK4a deficiency along with short dysfunctional telomeres cooperatively engenders centrosome abnormalities before p53 function is compromised.},
}
@article {pmid26315930,
year = {2015},
author = {Narita, A and Muramatsu, H and Sekiya, Y and Okuno, Y and Sakaguchi, H and Nishio, N and Yoshida, N and Wang, X and Xu, Y and Kawashima, N and Doisaki, S and Hama, A and Takahashi, Y and Kudo, K and Moritake, H and Kobayashi, M and Kobayashi, R and Ito, E and Yabe, H and Ohga, S and Ohara, A and Kojima, S and , },
title = {Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia.},
journal = {Haematologica},
volume = {100},
number = {12},
pages = {1546-1552},
pmid = {26315930},
issn = {1592-8721},
mesh = {Adolescent ; *Anemia, Aplastic/diagnosis/metabolism/therapy ; Child ; Child, Preschool ; Female ; *Hemoglobinuria, Paroxysmal/diagnosis/metabolism/therapy ; Humans ; *Immunosuppression Therapy ; Infant ; Male ; Prognosis ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Acquired aplastic anemia is an immune-mediated disease characterized by severe defects in stem cell number resulting in hypocellular marrow and peripheral blood cytopenias. Minor paroxysmal nocturnal hemoglobinuria populations and a short telomere length were identified as predictive biomarkers of immunosuppressive therapy responsiveness in aplastic anemia. We enrolled 113 aplastic anemia patients (63 boys and 50 girls) in this study to evaluate their response to immunosuppressive therapy. The paroxysmal nocturnal hemoglobinuria populations and telomere length were detected by flow cytometry. Forty-seven patients (42%) carried a minor paroxysmal nocturnal hemoglobinuria population. The median telomere length of aplastic anemia patients was -0.99 standard deviation (SD) (range -4.01-+3.01 SD). Overall, 60 patients (53%) responded to immunosuppressive therapy after six months. Multivariate logistic regression analysis identified the absence of a paroxysmal nocturnal hemoglobinuria population and a shorter telomere length as independent unfavorable predictors of immunosuppressive therapy response at six months. The cohort was stratified into a group of poor prognosis (paroxysmal nocturnal hemoglobinuria negative and shorter telomere length; 37 patients) and good prognosis (paroxysmal nocturnal hemoglobinuria positive and/or longer telomere length; 76 patients), respectively. The response rates of the poor prognosis and good prognosis groups at six months were 19% and 70%, respectively (P<0.001). The combined absence of a minor paroxysmal nocturnal hemoglobinuria population and a short telomere length is an efficient predictor of poor immunosuppressive therapy response, which should be considered while deciding treatment options: immunosuppressive therapy or first-line hematopoietic stem cell transplantation. The trial was registered in www.umin.ac.jp with number UMIN000017972.},
}
@article {pmid26315236,
year = {2015},
author = {Næss, AB and Kirkengen, AL},
title = {Is childhood stress associated with shorter telomeres?.},
journal = {Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke},
volume = {135},
number = {15},
pages = {1356-1360},
doi = {10.4045/tidsskr.14.1194},
pmid = {26315236},
issn = {0807-7096},
mesh = {Child ; Child Abuse ; Female ; Humans ; Parenting ; Pregnancy ; Prenatal Exposure Delayed Effects ; Psychosocial Deprivation ; Socioeconomic Factors ; Stress, Psychological/*complications ; Telomere Shortening/*physiology ; },
abstract = {BACKGROUND: It has been shown that severe stress in childhood is harmful to later health. New research aims to ascertain whether – and if so, how – the telomeres, the protective caps at the end of our chromosomes, may be one of the links between this type of experience and later morbidity. Here we present an overview of studies which have examined the association between stress in childhood and length of telomeres.<br><br>METHOD: The review encompasses 26 original studies found through a literature search in PubMed. We included studies of the relationship between length of telomeres and various stress-inducing factors from conception throughout childhood and adolescence.<br><br>RESULTS: The studies were grouped into four topics. The empirical research base for mother's stress in pregnancy and parents' ability to care for their children is too small to draw any conclusions. Psychosocial stress in childhood was associated with shorter telomere length in 12 of 14 studies. Socioeconomic status in childhood was not unequivocally associated with telomere length.<br><br>INTERPRETATION: Shorter telomeres are possibly associated with psychosocial stress in childhood. This field of research is still new, and more longitudinal studies are needed with an emphasis on childhood experiences and coordination of measurement variables and results measurement in order to confirm this association.},
}
@article {pmid26314343,
year = {2015},
author = {Stier, A and Massemin, S and Zahn, S and Tissier, ML and Criscuolo, F},
title = {Starting with a handicap: effects of asynchronous hatching on growth rate, oxidative stress and telomere dynamics in free-living great tits.},
journal = {Oecologia},
volume = {179},
number = {4},
pages = {999-1010},
pmid = {26314343},
issn = {1432-1939},
mesh = {*Aging ; Animals ; Antioxidants/metabolism ; Body Size/*physiology ; Female ; Male ; Nesting Behavior/physiology ; *Oxidative Stress ; Passeriformes/blood/*growth &amp; development ; Reactive Oxygen Species/blood ; Telomere/*physiology ; Testosterone/blood ; },
abstract = {A trade-off between resource investment into growth rate and body self-maintenance is likely to occur, but the underlying molecular mediators of such a trade-off remain to be determined. In many altricial birds, hatching asynchrony creates a sibling competitive hierarchy within the brood, with first-hatched nestlings enjoying substantial advantages compared to last-hatched nestlings. We used this opportunity to test for a trade-off between growth and self-maintenance processes (oxidative stress, telomere erosion) in great tit nestlings, since resource availability and allocation are likely to differ between first-hatched and last-hatched nestlings. We found that despite their starting competitive handicap (i.e. being smaller/lighter before day 16), last-hatched nestlings exhibited growth rate and mass/size at fledging similar to first-hatched ones. However, last-hatched nestlings suffered more in terms of oxidative stress, and ended growth with shorter telomeres than first-hatched ones. Interestingly, growth rate was positively related to plasma antioxidant capacity and early life telomere length (i.e. at 7 days old), but among last-hatched nestlings, those exhibiting the faster body size growth were also those exhibiting the greatest telomere erosion. Last-hatched nestlings exhibited elevated levels of plasma testosterone (T), but only at day 7. T levels were positively associated with oxidative damage levels and plasma antioxidant capacity, the latter being only significant for first-hatched nestlings. Our results suggest that last-hatched nestlings present a specific trade-off between growth rate and self-maintenance processes, which is possibly driven by their need to compete with their older siblings and potentially mediated by elevated levels of T.},
}
@article {pmid26314088,
year = {2016},
author = {Loprinzi, PD and Loenneke, JP},
title = {Lower Extremity Muscular Strength and Leukocyte Telomere Length: Implications of Muscular Strength in Attenuating Age-Related Chronic Disease.},
journal = {Journal of physical activity &amp; health},
volume = {13},
number = {4},
pages = {454-457},
doi = {10.1123/jpah.2015-0120},
pmid = {26314088},
issn = {1543-5474},
mesh = {Aging/*physiology ; Chronic Disease ; Female ; Humans ; Leukocytes/*metabolism ; Lower Extremity/*physiology ; Male ; Middle Aged ; Muscle Strength/*physiology ; Nutrition Surveys ; Telomere/genetics/*metabolism ; Telomere Shortening/*physiology ; },
abstract = {OBJECTIVE: Leukocyte telomere length (LTL) shortening is characteristic of aging and is associated with morbidity and mortality, independent of age. Research demonstrates that lower extremity muscular strength is associated with mobility, morbidity and mortality; however, no study, to our knowledge, had examined the association between lower extremity muscular strength and LTL, which was the purpose of this brief study.<br><br>METHODS: Data from the 1999-2002 NHANES was used (N = 2410; 50-85 years). Peak isokinetic knee extensor strength (IKES) was objectively measured with LTL assessed from a blood sample.<br><br>RESULTS: After adjustments, for every 50 N increase in IKES, participants had a 9% reduced odds (P = .04) of being in the 1st (vs. 4th) LTL quartile.<br><br>DISCUSSION: Lower extremity muscular strength is associated with LTL, suggesting a possible mechanism through which lower extremity muscular strength may be associated with morbidity and mortality.},
}
@article {pmid26312502,
year = {2015},
author = {Chojnowski, A and Ong, PF and Wong, ES and Lim, JS and Mutalif, RA and Navasankari, R and Dutta, B and Yang, H and Liow, YY and Sze, SK and Boudier, T and Wright, GD and Colman, A and Burke, B and Stewart, CL and Dreesen, O},
title = {Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria.},
journal = {eLife},
volume = {4},
number = {},
pages = {},
pmid = {26312502},
issn = {2050-084X},
mesh = {DNA-Binding Proteins/*metabolism ; Humans ; Lamin Type A/*metabolism ; Membrane Proteins/*metabolism ; Microscopy ; Progeria/*pathology ; Protein Binding ; Telomere/*metabolism ; },
abstract = {Hutchinson-Gilford progeria (HGPS) is a premature ageing syndrome caused by a mutation in LMNA, resulting in a truncated form of lamin A called progerin. Progerin triggers loss of the heterochromatic marker H3K27me3, and premature senescence, which is prevented by telomerase. However, the mechanism how progerin causes disease remains unclear. Here, we describe an inducible cellular system to model HGPS and find that LAP2α (lamina-associated polypeptide-α) interacts with lamin A, while its interaction with progerin is significantly reduced. Super-resolution microscopy revealed that over 50% of telomeres localize to the lamina and that LAP2α association with telomeres is impaired in HGPS. This impaired interaction is central to HGPS since increasing LAP2α levels rescues progerin-induced proliferation defects and loss of H3K27me3, whereas lowering LAP2 levels exacerbates progerin-induced defects. These findings provide novel insights into the pathophysiology underlying HGPS, and how the nuclear lamina regulates proliferation and chromatin organization.},
}
@article {pmid26311298,
year = {2015},
author = {Shen, X and Zhan, Y},
title = {RE: The Effect on Melanoma Risk of Genes Previously Associated With Telomere Length.},
journal = {Journal of the National Cancer Institute},
volume = {107},
number = {10},
pages = {},
doi = {10.1093/jnci/djv237},
pmid = {26311298},
issn = {1460-2105},
mesh = {*Germ-Line Mutation ; Humans ; Melanoma/*genetics ; *Polymorphism, Single Nucleotide ; Skin Neoplasms/*genetics ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics ; },
}
@article {pmid26309358,
year = {2015},
author = {Choi, BJ and Yoon, JH and Kim, O and Choi, WS and Nam, SW and Lee, JY and Park, WS},
title = {Influence of the hTERT rs2736100 polymorphism on telomere length in gastric cancer.},
journal = {World journal of gastroenterology},
volume = {21},
number = {31},
pages = {9328-9336},
pmid = {26309358},
issn = {2219-2840},
mesh = {Adenocarcinoma/enzymology/*genetics/pathology ; Adult ; Aged ; Aged, 80 and over ; Case-Control Studies ; Cell Line, Tumor ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Phenotype ; *Polymorphism, Single Nucleotide ; Risk Factors ; Stomach Neoplasms/enzymology/*genetics/pathology ; Telomerase/*genetics/metabolism ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; Young Adult ; },
abstract = {AIM: To investigate the functional consequences of rs2736100 polymorphism in telomere length and examine its link to gastric cancer risk.<br><br>METHODS: Telomere length and human telomerase reverse transcriptase (hTERT) mRNA expression were measured in 35 gastric cancer tissues and 5 cell lines and correlated to rs2736100 polymorphism. The relationship between rs2736100 polymorphism and the risk of gastric cancer were examined in 243 gastric cancer patients and 246 healthy individuals.<br><br>RESULTS: The rs2736100 A allele carrier is closely associated with reduced hTERT mRNA expression and shortened telomere length in gastric cancer tissue and cell lines. When gastric cancers were stratified by histological subtype, telomere length and hTERT mRNA levels were significantly increased in those with the C/C genotype in intestinal-type gastric cancer, but not in diffuse-type gastric cancer. Interestingly, there was no significant difference in the genotype and allele frequencies of the rs2736100 polymorphism between the patients with gastric cancer and healthy controls.<br><br>CONCLUSION: The rs2736100 polymorphism of the hTERT gene is involved in the regulation of hTERT expression and telomere length, but not in the risk of gastric cancer.},
}
@article {pmid26308091,
year = {2015},
author = {Strazhesko, I and Tkacheva, O and Boytsov, S and Akasheva, D and Dudinskaya, E and Vygodin, V and Skvortsov, D and Nilsson, P},
title = {Association of Insulin Resistance, Arterial Stiffness and Telomere Length in Adults Free of Cardiovascular Diseases.},
journal = {PloS one},
volume = {10},
number = {8},
pages = {e0136676},
pmid = {26308091},
issn = {1932-6203},
mesh = {Adult ; *Aging ; Blood Flow Velocity/physiology ; Blood Pressure/physiology ; Cardiovascular Diseases/*epidemiology ; Carotid Arteries/physiopathology ; *Cellular Senescence ; Female ; Femoral Artery/physiopathology ; Humans ; Inflammation/immunology ; *Insulin Resistance ; Male ; Middle Aged ; Oxidative Stress/physiology ; *Telomere Homeostasis ; *Vascular Stiffness ; },
abstract = {BACKGROUND: Chronic inflammation and oxidative stress might be considered the key mechanisms of aging. Insulin resistance (IR) is a phenomenon related to inflammatory and oxidative stress. We tested the hypothesis that IR may be associated with cellular senescence, as measured by leukocyte telomere length (LTL), and arterial stiffness (core feature of arterial aging), as measured by carotid-femoral pulse wave velocity (c-f PWV).<br><br>METHODS: The study group included 303 subjects, mean age 51.8 &#xb1;13.3 years, free of known cardiovascular diseases and regular drug consumption. For each patient, blood pressure was measured, blood samples were available for biochemical parameters, and LTL was analyzed by real time q PCR. C-f PWV was measured with the help of SphygmoCor. SAS 9.1 was used for statistical analysis.<br><br>RESULTS: Through multiple linear regression analysis, c-f PWV is independently and positively associated with age (p = 0.0001) and the homeostasis model assessment of insulin resistance (HOMA-IR; p = 0.0001) and independently negatively associated with LTL (p = 0.0378). HOMA-IR seems to have a stronger influence than SBP on arterial stiffness. In all subjects, age, HOMA-IR, LTL, and SBP predicted 32% of the variance in c-f PWV. LTL was inversely associated with HOMA-IR (p = 0.0001) and age (p = 0.0001). In all subjects, HOMA-IR, age, sex, and SBP predicted 16% of the variance in LTL.<br><br>CONCLUSIONS: These data suggest that IR is associated with cell senescence and arterial aging and could, therefore, become the main target in preventing accelerated arterial aging, besides blood pressure control. Research in telomere biology may reveal new ways of estimating cardiovascular aging and risk.},
}
@article {pmid26305931,
year = {2015},
author = {Webb, CJ and Zakian, VA},
title = {Telomerase RNA stem terminus element affects template boundary element function, telomere sequence, and shelterin binding.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {112},
number = {36},
pages = {11312-11317},
pmid = {26305931},
issn = {1091-6490},
support = {R01 GM043265/GM/NIGMS NIH HHS/United States ; R35 GM118279/GM/NIGMS NIH HHS/United States ; R37 GM026938/GM/NIGMS NIH HHS/United States ; GM043265/GM/NIGMS NIH HHS/United States ; },
mesh = {Autophagy-Related Proteins ; Base Sequence ; Blotting, Western ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; In Situ Hybridization, Fluorescence ; Insulator Elements/*genetics ; Models, Genetic ; Mutation ; Protein Binding ; RNA/*genetics/metabolism ; Regulatory Sequences, Ribonucleic Acid/*genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Reverse Transcription ; Schizosaccharomyces/genetics/metabolism ; Schizosaccharomyces pombe Proteins/genetics/metabolism ; Sequence Homology, Nucleic Acid ; Telomerase/*genetics/metabolism ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Templates, Genetic ; Transcription Factors/genetics/metabolism ; },
abstract = {The stem terminus element (STE), which was discovered 13 y ago in human telomerase RNA, is required for telomerase activity, yet its mode of action is unknown. We report that the Schizosaccharomyces pombe telomerase RNA, TER1 (telomerase RNA 1), also contains a STE, which is essential for telomere maintenance. Cells expressing a partial loss-of-function TER1 STE allele maintained short stable telomeres by a recombination-independent mechanism. Remarkably, the mutant telomere sequence was different from that of wild-type cells. Generation of the altered sequence is explained by reverse transcription into the template boundary element, demonstrating that the STE helps maintain template boundary element function. The altered telomeres bound less Pot1 (protection of telomeres 1) and Taz1 (telomere-associated in Schizosaccharomyces pombe 1) in vivo. Thus, the S. pombe STE, although distant from the template, ensures proper telomere sequence, which in turn promotes proper assembly of the shelterin complex.},
}
@article {pmid26304838,
year = {2015},
author = {Simons, MJ},
title = {Questioning causal involvement of telomeres in aging.},
journal = {Ageing research reviews},
volume = {24},
number = {Pt B},
pages = {191-196},
doi = {10.1016/j.arr.2015.08.002},
pmid = {26304838},
issn = {1872-9649},
mesh = {Aging/*genetics ; Causality ; Epidemiologic Measurements ; Humans ; Telomere Homeostasis/*physiology ; Telomere Shortening/*physiology ; },
abstract = {Multiple studies have demonstrated that telomere length predicts mortality and that telomeres shorten with age. Although rarely acknowledged these associations do not dictate causality. I review telomerase knockout and overexpression studies and find little support that telomeres cause aging. In addition, the causality hypothesis assumes that there is a critical telomere length at which senescence is induced. This generates the prediction that variance in telomere length decreases with age. In contrast, using meta-analysis of human data, I find no such decline. Inferring the causal involvement of telomeres in aging from current knowledge is therefore speculative and could hinder scientific progress.},
}
@article {pmid26304540,
year = {2015},
author = {Udugama, M and M Chang, FT and Chan, FL and Tang, MC and Pickett, HA and R McGhie, JD and Mayne, L and Collas, P and Mann, JR and Wong, LH},
title = {Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres.},
journal = {Nucleic acids research},
volume = {43},
number = {21},
pages = {10227-10237},
pmid = {26304540},
issn = {1362-4962},
mesh = {Animals ; Cells, Cultured ; DNA Damage ; Gene Deletion ; Heterochromatin/*metabolism ; *Histone Code ; Histones/chemistry/genetics/*metabolism ; Lysine/*metabolism ; Methylation ; Mice ; Sister Chromatid Exchange ; Telomere/*metabolism ; Transcription, Genetic ; },
abstract = {In addition to being a hallmark at active genes, histone variant H3.3 is deposited by ATRX at repressive chromatin regions, including the telomeres. It is unclear how H3.3 promotes heterochromatin assembly. We show that H3.3 is targeted for K9 trimethylation to establish a heterochromatic state enriched in trimethylated H3.3K9 at telomeres. In H3f3a(-/-) and H3f3b(-/-) mouse embryonic stem cells (ESCs), H3.3 deficiency results in reduced levels of H3K9me3, H4K20me3 and ATRX at telomeres. The H3f3b(-/-) cells show increased levels of telomeric damage and sister chromatid exchange (t-SCE) activity when telomeres are compromised by treatment with a G-quadruplex (G4) DNA binding ligand or by ASF1 depletion. Overexpression of wild-type H3.3 (but not a H3.3K9 mutant) in H3f3b(-/-) cells increases H3K9 trimethylation level at telomeres and represses t-SCE activity induced by a G4 ligand. This study demonstrates the importance of H3.3K9 trimethylation in heterochromatin formation at telomeres. It provides insights into H3.3 function in maintaining integrity of mammalian constitutive heterochromatin, adding to its role in mediating transcription memory in the genome.},
}
@article {pmid26302167,
year = {2015},
author = {Raschenberger, J and Kollerits, B and Titze, S and Köttgen, A and Bärthlein, B and Ekici, AB and Forer, L and Schönherr, S and Weissensteiner, H and Haun, M and Wanner, C and Eckardt, KU and Kronenberg, F and , },
title = {Association of relative telomere length with cardiovascular disease in a large chronic kidney disease cohort: the GCKD study.},
journal = {Atherosclerosis},
volume = {242},
number = {2},
pages = {529-534},
doi = {10.1016/j.atherosclerosis.2015.08.020},
pmid = {26302167},
issn = {1879-1484},
mesh = {Aged ; Aortic Aneurysm/complications/genetics ; Cardiovascular Diseases/complications/*genetics ; Female ; Germany ; Glomerular Filtration Rate ; Humans ; Kidney Failure, Chronic/complications/*genetics ; Male ; Middle Aged ; Odds Ratio ; Polymerase Chain Reaction ; Prospective Studies ; Risk Factors ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Chronic kidney disease (CKD) affects 10-15% of the general population and affected individuals are at an increased risk for cardiovascular disease (CVD). Since telomere length is considered to be involved in biological aging, we tested whether relative telomere length (RTL) might be a marker for these two diseases.<br><br>METHODS: The German Chronic Kidney Disease (GCKD) study is an ongoing prospective cohort study including patients with CKD of moderate severity. RTL was measured by qPCR in 4955 out of 5217 GCKD patients at baseline.<br><br>RESULTS: RTL was distributed in the cohort with a mean &#xb1; SD of 0.95 &#xb1; 0.19. CVD was present in 1266 patients. Each decrease of RTL by 0.1 unit was associated with a higher probability for prevalent CVD: OR = 1.06, 95% CI 1.02-1.11, p = 0.007 (adjusted for age, sex, eGFR, BMI, ln-CRP, smoking, hypertension, diabetes, and lipids). Similar findings were observed for history of specific CVD entities, such as coronary artery disease (OR = 1.05, p = 0.025), myocardial infarction (OR = 1.08, p = 0.013) and percutaneous transluminal coronary angioplasty (OR = 1.06, p = 0.032). The strongest associations were found for interventions at the carotid arteries (OR = 1.25, p = 0.001) as well as aortic aneurysms (OR = 1.22, p = 0.001).<br><br>CONCLUSIONS: In the presence of CKD there is a significant association between shorter RTL and CVD manifestations. RTL appears to be a marker reflecting changes in homeostasis associated with CKD that may contribute to the excess CVD risk.},
}
@article {pmid26299964,
year = {2015},
author = {Xiong, S and Patrushev, N and Forouzandeh, F and Hilenski, L and Alexander, RW},
title = {PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases.},
journal = {Cell reports},
volume = {12},
number = {9},
pages = {1391-1399},
pmid = {26299964},
issn = {2211-1247},
support = {HHSN268201000043C/HL/NHLBI NIH HHS/United States ; R01 HL060728/HL/NHLBI NIH HHS/United States ; HHSN268201000043C//PHS HHS/United States ; HL60728/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Antioxidant Response Elements ; Atherosclerosis/*genetics ; Blood Vessels/*growth &amp; development/metabolism/pathology ; *DNA Damage ; Mice ; Mice, Inbred C57BL ; NF-E2-Related Factor 2/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Telomerase/genetics/metabolism ; Telomere/genetics ; *Telomere Shortening ; Thioctic Acid/metabolism ; Transcription Factors/*genetics/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; },
abstract = {Cellular senescence and organismal aging predispose age-related chronic diseases, such as neurodegenerative, metabolic, and cardiovascular disorders. These diseases emerge coincidently from elevated oxidative/electrophilic stress, inflammation, mitochondrial dysfunction, DNA damage, and telomere dysfunction and shortening. Mechanistic linkages are incompletely understood. Here, we show that ablation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) accelerates vascular aging and atherosclerosis, coinciding with telomere dysfunction and shortening and DNA damage. PGC-1α deletion reduces expression and activity of telomerase reverse transcriptase (TERT) and increases p53 levels. Ectopic expression of PGC-1α coactivates TERT transcription and reverses telomere malfunction and DNA damage. Furthermore, alpha lipoic acid (ALA), a non-dispensable mitochondrial cofactor, upregulates PGC-1α-dependent TERT and the cytoprotective Nrf-2-mediated antioxidant/electrophile-responsive element (ARE/ERE) signaling cascades, and counteracts high-fat-diet-induced, age-dependent arteriopathy. These results illustrate the pivotal importance of PGC-1α in ameliorating senescence, aging, and associated chronic diseases, and may inform novel therapeutic approaches involving electrophilic specificity.},
}
@article {pmid26299856,
year = {2015},
author = {Voropaeva, EN and Maksimov, VN and Malyutina, SK and Bobak, M and Voevoda, MI},
title = {[Effects of DNA quality on the measurement of telomere length].},
journal = {Molekuliarnaia biologiia},
volume = {49},
number = {4},
pages = {571-576},
doi = {10.7868/S0026898415040199},
pmid = {26299856},
issn = {0026-8984},
abstract = {Existing evidence on the association of telomere length with life expectancy and the risk of various age related diseases is discordant. This inconsistency in the data may be due to methodological factors, e.g., the differences in the techniques for measuring telomere length, cell harvesting, DNA isolation, and material. One of the general requirements to experiments concerned with the measurement of telomere length is the high quality of DNA samples under study. The current review considers the most common errors during the measurement of telomere length associated with the improper quality of the biological material.},
}
@article {pmid26297686,
year = {2015},
author = {Shenassa, ED and Rossen, LM},
title = {Telomere length and age-at-menopause in the US.},
journal = {Maturitas},
volume = {82},
number = {2},
pages = {215-221},
pmid = {26297686},
issn = {1873-4111},
support = {CC999999//Intramural CDC HHS/United States ; R24 HD041041/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Biomarkers ; Cross-Sectional Studies ; Ethnicity ; Female ; Humans ; Leukocytes/*physiology ; *Menopause ; Middle Aged ; Nutrition Surveys ; Telomere/*physiology ; United States ; },
abstract = {OBJECTIVES: Age-at-menopause and leukocyte telomere length (LTL) are both associated with biologic aging. Therefore, it would be reasonable to hypothesize that LTL may also serve as a marker for reproductive aging as shorter LTL may be associated with earlier age-at-menopause.<br><br>METHODS: We analyzed data from 799 post-menopausal (ages 41-85) participants in the National Health and Nutrition Examination Survey (1999-2002), a nationally representative sample of U.S. women.<br><br>RESULTS: Controlling for behavioral, socio-demographic, and health-related determinants of menopause, we found that among non-Hispanic white women, an increase of one standard deviation in LTL was associated with a 0.43 year higher reported age-at-menopause. Among Mexican-Americans, an increase of one standard deviation in LTL was associated with a 1.56 year earlier menopause. There was no significant association between LTL and age-at-menopause among non-Hispanic black women.<br><br>CONCLUSIONS: Our main finding is evidence of a strong interaction by race/ethnicity in the association between LTL and age-at-menopause. This evidence does not support the hypothesis that shorter LTL is a predictor of earlier age-at-menopause, as the magnitude and direction of the associations between LTL and age-at-menopause varied across racial/ethnic groups.},
}
@article {pmid26294668,
year = {2015},
author = {Kaizer, H and Connelly, CJ and Bettridge, K and Viggiani, C and Greider, CW},
title = {Regulation of Telomere Length Requires a Conserved N-Terminal Domain of Rif2 in Saccharomyces cerevisiae.},
journal = {Genetics},
volume = {201},
number = {2},
pages = {573-586},
pmid = {26294668},
issn = {1943-2631},
support = {R01 GM043080/GM/NIGMS NIH HHS/United States ; 5R01GM043080/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes, Fungal ; DNA Damage/genetics ; Mitochondrial Proteins/genetics ; Mutation ; Repressor Proteins/genetics ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/*genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/*genetics ; Transaminases/genetics ; },
abstract = {The regulation of telomere length equilibrium is essential for cell growth and survival since critically short telomeres signal DNA damage and cell cycle arrest. While the broad principles of length regulation are well established, the molecular mechanism of how these steps occur is not fully understood. We mutagenized the RIF2 gene in Saccharomyces cerevisiae to understand how this protein blocks excess telomere elongation. We identified an N-terminal domain in Rif2 that is essential for length regulation, which we have termed BAT domain for Blocks Addition of Telomeres. Tethering this BAT domain to Rap1 blocked telomere elongation not only in rif2Δ mutants but also in rif1Δ and rap1C-terminal deletion mutants. Mutation of a single amino acid in the BAT domain, phenylalanine at position 8 to alanine, recapitulated the rif2Δ mutant phenotype. Substitution of F8 with tryptophan mimicked the wild-type phenylalanine, suggesting the aromatic amino acid represents a protein interaction site that is essential for telomere length regulation.},
}
@article {pmid26294352,
year = {2016},
author = {de Martino, M and Taus, C and Lucca, I and Hofbauer, SL and Haitel, A and Shariat, SF and Klatte, T},
title = {Association of human telomerase reverse transcriptase gene polymorphisms, serum levels, and telomere length with renal cell carcinoma risk and pathology.},
journal = {Molecular carcinogenesis},
volume = {55},
number = {10},
pages = {1458-1466},
doi = {10.1002/mc.22388},
pmid = {26294352},
issn = {1098-2744},
mesh = {Aged ; Carcinoma, Renal Cell/*genetics/metabolism ; Case-Control Studies ; Female ; Genetic Predisposition to Disease ; Humans ; Kidney Neoplasms/*genetics ; Logistic Models ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; Telomerase/*blood/*genetics ; Telomere/genetics ; Telomere Homeostasis ; },
abstract = {Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of the human telomerase and plays a key role in telomere restitution and gene regulation. Evidence suggests that hTERT is linked with the risk and progression of several malignancies, but there are no comprehensive data in renal cell carcinoma (RCC). In this case-control study, we assessed seven polymorphic hTERT gene variants (MNS16A, rs2736100, rs2736098, rs7726159, rs2853677, rs13172201, and rs10069690), hTERT serum levels, and the telomere length of 663 individuals, including 243 with clear cell RCC and 420 age- and gender-matched healthy controls. The SL and SS genotypes of MNS16A were associated with a decreased risk for RCC on the multivariable logistic regression analysis (SL-OR 0.72, SS-OR 0.37, P < 0.001). The GG genotype of rs2736098 was associated with a decreased risk for RCC compared with AA (OR 0.18, P < 0.001). Both telomere length and hTERT serum levels increased with every G allele in rs2736098 (P = 0.008). Pretherapeutic hTERT serum levels were higher in patients with advanced tumor stages (P = 0.037) and distant metastases (P = 0.006). Rs2736100, rs7726159, rs2853677, rs13172201, and rs10069690 were not linked with RCC risk, and none of the polymorphisms was associated with RCC pathology. In conclusion, the polymorphic number of tandem repeats in hTERT (MNS16A) and rs2736098 may be linked with the risk for RCC. Rs2736098 may have an important role in telomere length restitution and serum hTERT levels may represent a novel biomarker for RCC. © 2015 Wiley Periodicals, Inc.},
}
@article {pmid26293976,
year = {2016},
author = {Pusceddu, I and Herrmann, M and Kirsch, SH and Werner, C and Hübner, U and Bodis, M and Laufs, U and Wagenpfeil, S and Geisel, J and Herrmann, W},
title = {Prospective study of telomere length and LINE-1 methylation in peripheral blood cells: the role of B vitamins supplementation.},
journal = {European journal of nutrition},
volume = {55},
number = {5},
pages = {1863-1873},
pmid = {26293976},
issn = {1436-6215},
mesh = {Aged ; Blood Cells/*drug effects ; Calcium/administration &amp; dosage/blood ; Cross-Sectional Studies ; DNA Methylation/*drug effects ; *Dietary Supplements ; Female ; Folic Acid/administration &amp; dosage/blood ; Homocysteine/blood ; Humans ; Hyperhomocysteinemia/drug therapy ; Linear Models ; Long Interspersed Nucleotide Elements/*genetics ; Male ; Middle Aged ; Prospective Studies ; S-Adenosylhomocysteine/blood ; S-Adenosylmethionine/blood ; Telomere/*ultrastructure ; Tetrahydrofolates/blood ; Vitamin B 12/administration &amp; dosage/blood ; Vitamin B 6/administration &amp; dosage/blood ; Vitamin B Complex/*administration &amp; dosage/blood ; Vitamin D/administration &amp; dosage/blood ; },
abstract = {PURPOSE: Deficiencies of folate, vitamins B12 and D are common age-related conditions. Vitamin B12 and folate are necessary for DNA methylation. Telomeres appear to be regulated by DNA methylation. Here, we study the effect of B vitamins supplementation on telomere length and global DNA methylation in a prospective study.<br><br>METHODS: In total, 60 elderly subjects were supplemented for 1&#xa0;year with either vitamin B12, B6, folate, vitamin D and calcium (group A n&#xa0;=&#xa0;31) or only vitamin D and calcium (group B n&#xa0;=&#xa0;29). LINE-1 methylation, relative telomere length (T/S), vitamin B12, folate, homocysteine (tHcy) , 5-methyltetrahydrofolate (5-methylTHF), S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), cystathionine and vitamin D were quantified before and after supplementation.<br><br>RESULTS: At baseline, tHcy was high, vitamin D was low, and T/S did not differ between groups A and B. Vitamin supplementation increased LINE-1 methylation in group A at site 317 but reduced LINE-1 methylation in group B at site 327. There was no correlation between T/S and LINE-1 methylation at baseline. Multiple backward regression analysis revealed baseline tHcy and 5-methylTHF are significant predictors of T/S. After supplementation in group B but not in group A, LINE-1 methylation correlated inversely with T/S, and LINE-1 methylation variation was an independent predictor of T/S variation. B vitamins decreased tHcy significantly in group A. Multiple backward regression analysis showed 5-methylTHF in group A and tHcy in group B were significant predictors for LINE-1 methylation. At baseline, the lower LINE-1 methylation observed in subjects with 5-methylTHF >10&#xa0;nmol/l was in agreement with a reduced methyl group transfer due to a lower SAM formation. In group B, an increase in telomere length was correlated with lower LINE-1 methylation. Subjects with hyperhomocysteinemia >12&#xa0;&#xb5;mol/L had compared to those with normal tHcy a reduced LINE-1 methylation accompanied by a higher SAM and SAH (that inhibits demethylation of SAM) as well as lower 5-methylTHF. Additionally, subjects with tHcy&#xa0;>&#xa0;12&#xa0;&#xb5;mol/L had longer telomeres when compared with subjects having tHcy&#xa0;<&#xa0;12&#xa0;&#xb5;mol/L.<br><br>CONCLUSIONS: The results suggest a possible effect of B vitamins for telomere biology in blood cells. Suboptimal B vitamins status and hyperhomocysteinemia are associated with altered DNA methylation and telomere length. These data have to be confirmed in future studies.},
}
@article {pmid26292083,
year = {2015},
author = {Xia, Y and Chen, R and Wang, C and Cai, J and Wang, L and Zhao, Z and Qian, J and Kan, H},
title = {Ambient air pollution, blood mitochondrial DNA copy number and telomere length in a panel of diabetes patients.},
journal = {Inhalation toxicology},
volume = {27},
number = {10},
pages = {481-487},
doi = {10.3109/08958378.2015.1075090},
pmid = {26292083},
issn = {1091-7691},
mesh = {Aged ; Air Pollutants/toxicity ; Air Pollution/*adverse effects ; DNA Copy Number Variations/drug effects ; DNA, Mitochondrial/*blood ; Diabetes Mellitus, Type 2/*blood ; Female ; Humans ; Male ; Middle Aged ; Particulate Matter/toxicity ; Telomere ; },
abstract = {CONTEXT: Several previous studies proposed a link between particulate matter (PM) pollution and mitochondrial DNA copy number (MtDNAcn) and telomere length (TL). However, this evidence is quite limited and inconsistent, especially on how the particle size affects the associations and on whether there exists such an association with gaseous pollutants.<br><br>OBJECTIVE: We aimed to investigate the short-term associations of size-fractionated PM and gaseous pollutants with blood MtDNAcn and TL.<br><br>METHODS: We conducted a longitudinal panel study involving 6 repeated measurements among 35 Type 2 diabetes patients in Shanghai, China from April to June 2013. We measured the real-time concentrations of size-fractionated PM (0.25-10&#x2009;&#x3bc;m) and criteria gaseous pollutants. Blood MtDNAcn and TL were tested by a quantitative real-time PCR-based assay. Linear mixed-effect models were used to explore their short-term associations using multiple lag periods, after controlling for individual characteristics, time trends and weather conditions.<br><br>RESULTS: In general, there were inverse but statistically non-significant associations between all pollutants and MtDNAcn. Coarse PM appeared to be more closely linked with MtDNAcn than smaller PM. The associations between various air pollutants and TL were generally positive but very weak. There were no clear lag patterns for these associations. The associations between air pollutants and MtDNAcn and TL were strengthened but still not significant among those who did not take statins regularly.<br><br>CONCLUSIONS: This study did not support short-term associations of PM or gaseous pollutants with blood MtDNAcn and TL in type 2 diabetes patients.},
}
@article {pmid26291128,
year = {2015},
author = {Rousseau, P and Autexier, C},
title = {Telomere biology: Rationale for diagnostics and therapeutics in cancer.},
journal = {RNA biology},
volume = {12},
number = {10},
pages = {1078-1082},
pmid = {26291128},
issn = {1555-8584},
support = {MOP-133449//Canadian Institutes of Health Research/Canada ; },
mesh = {Cell Transformation, Neoplastic/*genetics ; Humans ; Neoplasms/diagnosis/*genetics/pathology/therapy ; Telomerase/genetics ; Telomere/*genetics/pathology ; },
abstract = {The key step of carcinogenesis is the malignant transformation which is fundamentally a telomere biology dysfunction permitting cells to bypass the Hayflick limit and to divide indefinitely and uncontrollably. Thus all partners and structures involved in normal and abnormal telomere maintenance, protection and lengthening can be considered as potential anti-cancer therapeutic targets. In this Point of View we discuss, highlight and provide new perspectives from the current knowledge and understanding to position the different aspects of telomere biology and dysfunction as diagnostic, preventive and curative tools in the field of cancer.},
}
@article {pmid26288820,
year = {2015},
author = {Hou, L and Joyce, BT and Gao, T and Liu, L and Zheng, Y and Penedo, FJ and Liu, S and Zhang, W and Bergan, R and Dai, Q and Vokonas, P and Hoxha, M and Schwartz, J and Baccarelli, A},
title = {Blood Telomere Length Attrition and Cancer Development in the Normative Aging Study Cohort.},
journal = {EBioMedicine},
volume = {2},
number = {6},
pages = {591-596},
pmid = {26288820},
issn = {2352-3964},
support = {R01 ES015172/ES/NIEHS NIH HHS/United States ; P30ES00002/ES/NIEHS NIH HHS/United States ; R01ES015172/ES/NIEHS NIH HHS/United States ; P30 CA060553/CA/NCI NIH HHS/United States ; R01ES021733/ES/NIEHS NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*physiology ; Biomarkers, Tumor ; Cohort Studies ; Humans ; Leukocytes/physiology ; Longitudinal Studies ; Male ; Middle Aged ; Neoplasms/epidemiology/*physiopathology ; Prospective Studies ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; Telomere Shortening/*physiology ; },
abstract = {BACKGROUND: Accelerated telomere shortening may cause cancer via chromosomal instability, making it a potentially useful biomarker. However, publications on blood telomere length (BTL) and cancer are inconsistent. We prospectively examined BTL measures over time and cancer incidence.<br><br>METHODS: We included 792 Normative Aging Study participants with 1-4 BTL measurements from 1999 to 2012. We used linear mixed-effects models to examine BTL attrition by cancer status (relative to increasing age and decreasing years pre-diagnosis), Cox models for time-dependent associations, and logistic regression for cancer incidence stratified by years between BTL measurement and diagnosis.<br><br>FINDINGS: Age-related BTL attrition was faster in cancer cases pre-diagnosis than in cancer-free participants (pdifference&#xa0;=&#xa0;0.017); all participants had similar age-adjusted BTL 8-14&#xa0;years pre-diagnosis, followed by decelerated attrition in cancer cases resulting in longer BTL three (p&#xa0;=&#xa0;0.003) and four (p&#xa0;=&#xa0;0.012) years pre-diagnosis. Longer time-dependent BTL was associated with prostate cancer (HR&#xa0;=&#xa0;1.79, p&#xa0;=&#xa0;0.03), and longer BTL measured &#x2264;&#xa0;4&#xa0;years pre-diagnosis with any (OR&#xa0;=&#xa0;3.27, p&#xa0;<&#xa0;0.001) and prostate cancers (OR&#xa0;=&#xa0;6.87, p&#xa0;<&#xa0;0.001).<br><br>INTERPRETATION: Age-related BTL attrition was faster in cancer cases but their age-adjusted BTL attrition began decelerating as diagnosis approached. This may explain prior inconsistencies and help develop BTL as a cancer detection biomarker.},
}
@article {pmid26286192,
year = {2015},
author = {Lee, JH and Jeong, SA and Khadka, P and Hong, J and Chung, IK},
title = {Involvement of SRSF11 in cell cycle-specific recruitment of telomerase to telomeres at nuclear speckles.},
journal = {Nucleic acids research},
volume = {43},
number = {17},
pages = {8435-8451},
pmid = {26286192},
issn = {1362-4962},
mesh = {*Cell Cycle/genetics ; Cell Line, Tumor ; Cell Nucleus Structures/*enzymology/genetics ; HeLa Cells ; Humans ; Protein Interaction Domains and Motifs ; RNA/metabolism ; Serine-Arginine Splicing Factors/chemistry/*metabolism ; Telomerase/chemistry/*metabolism ; Telomere/*enzymology ; Telomere Homeostasis ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Telomerase, a unique ribonucleoprotein complex that contains the telomerase reverse transcriptase (TERT), the telomerase RNA component (TERC) and the TERC-binding protein dyskerin, is required for continued cell proliferation in stem cells and cancer cells. Here we identify SRSF11 as a novel TERC-binding protein that localizes to nuclear speckles, subnuclear structures that are enriched in pre-messenger RNA splicing factors. SRSF11 associates with active telomerase enzyme through an interaction with TERC and directs it to nuclear speckles specifically during S phase of the cell cycle. On the other hand, a subset of telomeres is shown to be constitutively present at nuclear speckles irrespective of cell cycle phase, suggesting that nuclear speckles could be the nuclear sites for telomerase recruitment to telomeres. SRSF11 also associates with telomeres through an interaction with TRF2, which facilitates translocation of telomerase to telomeres. Depletion of SRSF11 prevents telomerase from associating with nuclear speckles and disrupts telomerase recruitment to telomeres, thereby abrogating telomere elongation by telomerase. These findings suggest that SRSF11 acts as a nuclear speckle-targeting factor that is essential for telomerase association with telomeres through the interactions with TERC and TRF2, and provides a potential target for modulating telomerase activity in cancer.},
}
@article {pmid26286096,
year = {2015},
author = {Gu, J},
title = {Leukocyte Telomere Length and Cancer Risk: A Dynamic Problem.},
journal = {EBioMedicine},
volume = {2},
number = {6},
pages = {493-494},
pmid = {26286096},
issn = {2352-3964},
mesh = {Aging/*physiology ; Humans ; Male ; Neoplasms/*physiopathology ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; Telomere Shortening/*physiology ; },
}
@article {pmid26275065,
year = {2015},
author = {Akasheva, DU and Plokhova, EV and Tkacheva, ON and Strazhesko, ID and Dudinskaya, EN and Kruglikova, AS and Pykhtina, VS and Brailova, NV and Pokshubina, IA and Sharashkina, NV and Agaltsov, MV and Skvortsov, D and Boytsov, SA},
title = {Age-Related Left Ventricular Changes and Their Association with Leukocyte Telomere Length in Healthy People.},
journal = {PloS one},
volume = {10},
number = {8},
pages = {e0135883},
pmid = {26275065},
issn = {1932-6203},
mesh = {Adult ; Aged ; Aging/*metabolism/pathology ; Female ; Heart Ventricles/*metabolism/pathology ; Humans ; Leukocytes/*metabolism/pathology ; Male ; Middle Aged ; Myocardium/*metabolism/pathology ; *Telomere Homeostasis ; *Ventricular Function, Left ; },
abstract = {INTRODUCTION: With advancing age the left ventricle (LV) undergoes structural and functional changes, thereby creating the substrate for the development of diseases. One possible mechanism of the ageing heart is a cellular senescence. Leukocyte telomere length (LTL) is a marker of replicative ageing. The purpose of this study was to evaluate the structure and function of the LV in people of different ages free of cardiovascular diseases (CVD) and regular drug medication and to assess their relationship with LTL. We hypothesized that age-related changes in LV myocardium are associated with telomere length.<br><br>METHODS: The study population consisted of 150 healthy, non-obese volunteers aged 28 to 78 years without history of CVD, significant deviations by 12-lead electrocardiogram and negative exercise test (treadmill stress test). All the participants underwent standardized transthoracic echocardiography using an available system (iE33; Philips). The LTL was measured by real-time quantitative polymerase chain reaction. We determined the relative ratio of telomere repeat copy number (T) to single-copy gene copy number (S).<br><br>RESULTS: In the older people there was a higher wall thickness than in the younger (1.03 &#xb1; 0.09 vs. 0.88 &#xb1; 0.10, p<0.01), whereas LV mass index was comparable between them (85.8 &#xb1; 15.40 vs. 83.1 &#xb1; 11.8, p = 0.20). There was a decrease in LV dimensions with advancing age (p<0.001). Older subjects had impairment in LV relaxation. LTL was associated with decreased E/A, Em/Am ratio (&#x3b2; = -0.323, p = 0.0001) after adjusting for age, sex and risk factors. There is no relation between the LTL and the structure of LV.<br><br>CONCLUSIONS: Our data suggest that the ageing process leads to changes in LV structure and diastolic function and is linked with a phenotype of concentric LV remodeling. Telomere attrition is associated with age-related LV diastolic dysfunction. Telomere length appears to be a biomarker of myocardial ageing.},
}
@article {pmid26268318,
year = {2015},
author = {Pauliny, A and Devlin, RH and Johnsson, JI and Blomqvist, D},
title = {Rapid growth accelerates telomere attrition in a transgenic fish.},
journal = {BMC evolutionary biology},
volume = {15},
number = {},
pages = {159},
pmid = {26268318},
issn = {1471-2148},
mesh = {Aging ; Animal Fins/physiology ; Animal Husbandry ; Animals ; Animals, Genetically Modified ; Regeneration ; Salmon/*genetics/*growth &amp; development/metabolism ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Individuals rarely grow as fast as their physiologies permit despite the fitness advantages of being large. One reason may be that rapid growth is costly, resulting for example in somatic damage. The chromosomal ends, the telomeres, are particularly vulnerable to such damage, and telomere attrition thus influences the rate of ageing. Here, we used a transgenic salmon model with an artificially increased growth rate to test the hypothesis that rapid growth is traded off against the ability to maintain somatic health, assessed as telomere attrition.<br><br>RESULTS: We found substantial telomere attrition in transgenic fish, while maternal half-sibs growing at a lower, wild-type rate seemed better able to maintain the length of their telomeres during the same time period.<br><br>CONCLUSIONS: Our results are consistent with a trade-off between rapid growth and somatic (telomere) maintenance in growth-manipulated fish. Since telomere erosion reflects cellular ageing, our findings also support theories of ageing postulating that unrepaired somatic damage is associated with senescence.},
}
@article {pmid26265356,
year = {2016},
author = {Schaakxs, R and Wielaard, I and Verhoeven, JE and Beekman, AT and Penninx, BW and Comijs, HC},
title = {Early and recent psychosocial stress and telomere length in older adults.},
journal = {International psychogeriatrics},
volume = {28},
number = {3},
pages = {405-413},
doi = {10.1017/S1041610215001155},
pmid = {26265356},
issn = {1741-203X},
mesh = {*Adult Survivors of Child Adverse Events ; Cellular Senescence/*genetics ; Child ; Child Abuse ; Depression ; Depressive Disorder ; Female ; Humans ; Leukocytes/*physiology ; *Life Change Events ; Male ; Netherlands ; Real-Time Polymerase Chain Reaction ; Regression Analysis ; Stress, Psychological/complications/*psychology ; Telomere/*physiology ; Telomere Shortening/*physiology ; },
abstract = {BACKGROUND: Psychosocial stress has been associated with an increased risk for mental and somatic health problems across the life span. Some studies in younger adults linked this to accelerated cellular aging, indexed by shortened telomere length (TL). In older adults, the impact of psychosocial stress on TL may be different due to the lifetime exposure to competing causes of TL-shortening. This study aims to assess whether early and recent psychosocial stressors (childhood abuse, childhood adverse events, recent negative life events, and loneliness) were associated with TL in older adults.<br><br>METHODS: Data were from the Netherlands Study of Depression in Older Persons (NESDO) in which psychosocial stressors were measured in 496 persons aged 60 and older (mean age 70.6 (SD 7.4) years) during a face-to-face interview. Leukocyte TL was determined using fasting blood samples by performing quantitative polymerase chain reaction (qPCR) and was expressed in base pairs (bp).<br><br>RESULTS: Multiple regression analyses, adjusted for age, sex, and chronic diseases, showed that childhood abuse, recent negative life events and loneliness were unrelated to TL. Only having experienced any childhood adverse event was weakly but significantly negatively associated with TL.<br><br>CONCLUSIONS: Our findings did not consistently confirm our hypothesis that psychosocial stress is associated with shorter TL in older adults. Healthy survivorship or other TL-damaging factors such as somatic health problems seem to dominate a potential effect of psychosocial stress on TL in older adults.},
}
@article {pmid26264873,
year = {2015},
author = {Greetham, M and Skordalakes, E and Lydall, D and Connolly, BA},
title = {The Telomere Binding Protein Cdc13 and the Single-Stranded DNA Binding Protein RPA Protect Telomeric DNA from Resection by Exonucleases.},
journal = {Journal of molecular biology},
volume = {427},
number = {19},
pages = {3023-3030},
pmid = {26264873},
issn = {1089-8638},
support = {13314/CRUK_/Cancer Research UK/United Kingdom ; P30 CA010815/CA/NCI NIH HHS/United States ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; P30 CA10815/CA/NCI NIH HHS/United States ; R01 GM088332/GM/NIGMS NIH HHS/United States ; MR/L001284/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Bacteriophage lambda/*enzymology ; Base Sequence ; DNA, Fungal/chemistry/*metabolism ; DNA, Single-Stranded/chemistry/metabolism ; Exodeoxyribonucleases/*metabolism ; Molecular Sequence Data ; Replication Protein A/*metabolism ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomere/chemistry/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {The telomere is present at the ends of all eukaryotic chromosomes and usually consists of repetitive TG-rich DNA that terminates in a single-stranded 3' TG extension and a 5' CA-rich recessed strand. A biochemical assay that allows the in vitro observation of exonuclease-catalyzed degradation (resection) of telomeres has been developed. The approach uses an oligodeoxynucleotide that folds to a stem-loop with a TG-rich double-stranded region and a 3' single-stranded extension, typical of telomeres. Cdc13, the major component of the telomere-specific CST complex, strongly protects the recessed strand from the 5'→3' exonuclease activity of the model exonuclease from bacteriophage λ. The isolated DNA binding domain of Cdc13 is less effective at shielding telomeres. Protection is specific, not being observed in control DNA lacking the specific TG-rich telomere sequence. RPA, the eukaryotic single-stranded DNA binding protein, also inhibits telomere resection. However, this protein is non-specific, equally hindering the degradation of non-telomere controls.},
}
@article {pmid26260984,
year = {2016},
author = {Shin, C and Kim, NH and Baik, I},
title = {Sex-Specific Association between Longitudinal Changes in Adiposity, FTO rs9939609 Polymorphism, and Leukocyte Telomere Length.},
journal = {Journal of the American College of Nutrition},
volume = {35},
number = {3},
pages = {245-254},
doi = {10.1080/07315724.2015.1005197},
pmid = {26260984},
issn = {1541-1087},
mesh = {Adiposity/genetics/*physiology ; Adult ; Aged ; Aging ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/*genetics/*metabolism ; Female ; Humans ; Leukocytes/*physiology ; Longitudinal Studies ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; Sex Factors ; Telomere/*physiology ; },
abstract = {OBJECTIVE: A longitudinal study was conducted to examine sex-specific associations between changes in adiposity over a 10-year period, the FTO rs9939609 polymorphism, and leukocyte telomere length (LTL).<br><br>METHODS: A population-based cohort including 2128 middle-aged and older Korean men (n = 1087) and women (n = 1041) participated in a prospective study. Anthropometric measurements of weight, height, and waist and hip circumference were taken at baseline (from 2001 to 2003) and at the 10-year follow-up period (from 2011 to 2012). The FTO rs9939609 polymorphism was genotyped using DNA samples collected at baseline and LTL was assessed at the 10-year follow-up period. Multiple linear regression analysis was used with adjustments for age, baseline body mass index, and other potential confounders.<br><br>RESULTS: Presence of the FTO rs9939609 polymorphism risk allele was inversely associated with LTL (p < 0.01) in all participants, with a significant association seen only in women when the genders were modeled separately. Conversely, a significant inverse association between changes in waist circumference and LTL was found in men (p < 0.001) but not in women. No significant interaction between adiposity measures and the FTO polymorphism in association with LTL was identified for either sex.<br><br>CONCLUSIONS: These data suggest that biological aging in men may be accelerated by increasing waist circumference, whereas in women, aging may be affected by genetic variations in FTO regardless of adiposity changes over time.},
}
@article {pmid26259805,
year = {2015},
author = {Gupta, P and Rastede, EE and Appella, DH},
title = {Multivalent LKγ-PNA oligomers bind to a human telomere DNA G-rich sequence to form quadruplexes.},
journal = {Bioorganic &amp; medicinal chemistry letters},
volume = {25},
number = {21},
pages = {4757-4760},
pmid = {26259805},
issn = {1464-3405},
support = {Z01 DK031119-03//Intramural NIH HHS/United States ; },
mesh = {Base Sequence ; Binding Sites ; DNA/*chemistry ; *G-Quadruplexes ; Guanine/*chemistry ; Humans ; Molecular Structure ; Peptide Nucleic Acids/*chemistry ; Telomere/*chemistry ; },
abstract = {We report G-quadruplex formation between peptide nucleic acids (PNAs) composed of (L)Kγ-PNA-G monomers and a known portion of human telomeric DNA that adopts three G3 tracts via intramolecular hydrogen bonding. The resulting complex is a bimolecular PNA-DNA heteroquadruplex. In this Letter, we show that introduction of a γ-modification and addition of a peptide ligand does not disrupt the heteroquadruplex. Although the unmodified PNA1 forms a quadruplex with itself, the γ-substituted PNAs (PNA2-PNA6) do not form G-quadruplexes on their own, at even high concentrations. The selectivity of these PNAs could influence the design of new quadruplex-targeting molecules or allow the quadruplex structure to be used as a scaffold for multivalent display of protein binding ligands.},
}
@article {pmid26256637,
year = {2015},
author = {Strefford, JC and Kadalayil, L and Forster, J and Rose-Zerilli, MJ and Parker, A and Lin, TT and Heppel, N and Norris, K and Gardiner, A and Davies, Z and Gonzalez de Castro, D and Else, M and Steele, AJ and Parker, H and Stankovic, T and Pepper, C and Fegan, C and Baird, D and Collins, A and Catovsky, D and Oscier, DG},
title = {Telomere length predicts progression and overall survival in chronic lymphocytic leukemia: data from the UK LRF CLL4 trial.},
journal = {Leukemia},
volume = {29},
number = {12},
pages = {2411-2414},
pmid = {26256637},
issn = {1476-5551},
support = {11052/LLR_/Blood Cancer UK/United Kingdom ; 12036/LLR_/Blood Cancer UK/United Kingdom ; },
mesh = {Disease Progression ; Genes, p53 ; Humans ; Immunoglobulin Heavy Chains/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/mortality ; Mutation ; *Telomere ; },
}
@article {pmid26255046,
year = {2015},
author = {Müezzinler, A and Mons, U and Dieffenbach, AK and Butterbach, K and Saum, KU and Schick, M and Stammer, H and Boukamp, P and Holleczek, B and Stegmaier, C and Brenner, H},
title = {Smoking habits and leukocyte telomere length dynamics among older adults: Results from the ESTHER cohort.},
journal = {Experimental gerontology},
volume = {70},
number = {},
pages = {18-25},
doi = {10.1016/j.exger.2015.07.002},
pmid = {26255046},
issn = {1873-6815},
mesh = {Aged ; Aging/blood/*genetics ; Cross-Sectional Studies ; Female ; Follow-Up Studies ; Humans ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Smoking/blood/*genetics ; Telomere/physiology ; Telomere Homeostasis/*physiology ; Telomere Shortening/physiology ; },
abstract = {BACKGROUND &amp; AIMS: Leukocyte telomere length (LTL) shortens with age and short LTL has been associated with increased mortality and increased risk for some age-related outcomes. This study aims to analyse the associations of smoking habits with LTL and rate of LTL change per year in older adults.<br><br>METHODS: LTL was measured by quantitative PCR at baseline in 3600 older adults, who were enrolled in a population-based cohort study in Germany. For longitudinal analyses, measurements were repeated in blood samples obtained at 8-year follow-up from 1000 participants. Terminal Restriction Fragment analysis was additionally performed in a sub-sample to obtain absolute LTL in base pairs. Multivariate linear regression models were used to estimate associations of smoking habits with baseline LTL and changes in LTL over time.<br><br>RESULTS: LTL was inversely associated with age (r=-0.090, p<0.0001). Women had longer LTL than men (p<0.0001). Smoking was inversely associated with LTL. On average, current smokers had 73 base pairs (BP) shorter LTL compared to never smokers. Smoking intensity and pack-years of smoking were also inversely associated with LTL, and a positive association was observed with years since smoking cessation. Slower LTL attrition rates were observed in ever smokers over 8years of follow-up.<br><br>CONCLUSIONS: Our cross-sectional analysis supports suggestions that smoking might contribute to shortening of LTL but this relationship could not be shown longitudinally. The overall rather small effect sizes observed for smoking-related variables suggest that LTL reflects smoking-related health hazards only to a very limited extent.},
}
@article {pmid26253905,
year = {2015},
author = {Colpo, GD and Leffa, DD and Köhler, CA and Kapczinski, F and Quevedo, J and Carvalho, AF},
title = {Is bipolar disorder associated with accelerating aging? A meta-analysis of telomere length studies.},
journal = {Journal of affective disorders},
volume = {186},
number = {},
pages = {241-248},
doi = {10.1016/j.jad.2015.06.034},
pmid = {26253905},
issn = {1573-2517},
mesh = {Adult ; Aging/*genetics ; Bipolar Disorder/*genetics ; Case-Control Studies ; Comorbidity ; Female ; Humans ; Male ; Middle Aged ; Prevalence ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Bipolar disorder (BD) is associated with a reduced life expectancy compared to the general population mainly due to a high prevalence of comorbid somatic illnesses. A model of accelerated aging has been proposed as a potential explanation to these epidemiological findings. Nevertheless, studies measuring telomere length (TL) in patients with BD compared to healthy controls have provided mixed results.<br><br>OBJECTIVE: To compare TL between BD patients and healthy controls, and to search for potential modeP<rators for observed differences.<br><br>METHODS: We performed a systematic review and meta-analysis of original studies comparing TL in patients with BD vs. healthy controls published up to February 24th, 2015 in main electronic databases. Heterogeneity was explored through meta-regression and subgroup analysis.<br><br>RESULTS: Seven studies met inclusion criteria (N=1115). There was no difference in TL between participants with BD and healthy controls (Hedges's g=-0.012; 95% CI=-0.418 to 0.393, P=0.952). There was no evidence for publication bias. Heterogeneity was high (I(2)=89.65%). In meta-regression analyses, the percentage of females in healthy control samples (P=0.04) and the methodological quality of included studies (P<0.001) emerged as significant moderators, while subgroup analyses suggest that the type of assay employed to measure TL and age- and gender-matching of BD and HC participants may contribute to heterogeneity.<br><br>CONCLUSIONS: Telomere length does not differ between participants with BD vs. healthy controls; this finding does not support the view of BD as an illness associated with accelerated cellular aging. However, more studies controlling for potential confounders are necessary.},
}
@article {pmid26252159,
year = {2015},
author = {Hadj Salem, I and Dubé, J and Boulet, LP and Chakir, J},
title = {Telomere shortening correlates with accelerated replicative senescence of bronchial fibroblasts in asthma.},
journal = {Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology},
volume = {45},
number = {11},
pages = {1713-1715},
doi = {10.1111/cea.12611},
pmid = {26252159},
issn = {1365-2222},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Asthma/*genetics ; Cellular Senescence/*genetics ; Fibroblasts/*metabolism ; Humans ; *Telomere Shortening ; },
}
@article {pmid26250468,
year = {2015},
author = {Fernández-Marcelo, T and Gómez, A and Pascua, I and de Juan, C and Head, J and Hernando, F and Jarabo, JR and Calatayud, J and Torres-García, AJ and Iniesta, P},
title = {Telomere length and telomerase activity in non-small cell lung cancer prognosis: clinical usefulness of a specific telomere status.},
journal = {Journal of experimental &amp; clinical cancer research : CR},
volume = {34},
number = {1},
pages = {78},
pmid = {26250468},
issn = {1756-9966},
mesh = {Carcinoma, Non-Small-Cell Lung/*genetics ; Disease-Free Survival ; Female ; Humans ; Lung Neoplasms/*genetics ; Male ; Prognosis ; Telomerase/*genetics ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Considering previous data and the need to incorporate new biomarkers for the prognosis of solid tumours into the clinic, our aim in this work consists of evaluating the potential clinical use of telomeres and telomerase in non-small cell lung cancer (NSCLC).<br><br>METHODS: Telomere status was established by determination of telomere length using the Terminal Restriction Fragment length method, and telomerase activity by the Telomeric Repeat Amplification Protocol in 142 NSCLCs and their corresponding control samples, obtained from patients submitted to surgery. Group-oriented curves for disease-free survival were calculated according to the Kaplan-Meier method considering telomere length, T/N ratio (telomere length in tumour to control tissue) and telomerase activity.<br><br>RESULTS: Overall, tumours had significantly shorter telomeres compared with telomeres in control tissues (P&#x2009;=&#x2009;0.027). More than 80 % of NSCLCs displayed telomerase activity. Regarding prognosis studies, patients whose tumours showed a mean telomere length (MTL) <7.29 Kb or T/N ratio <0.97 showed a significantly poor clinical evolution (P&#x2009;=&#x2009;0.034 and P&#x2009;=&#x2009;0.040, respectively). As result of a Cox multivariate analysis including pathologic state and lymph node dissemination, the MTL and T/N ratio emerged as independent significant prognostic factors.<br><br>CONCLUSIONS: Telomerase activity was identified as a marker of poor prognosis. The novel finding of this study is the independent prognosis role of a specific telomere status in NSCLC patients. According to our results, telomere function may emerge as a useful molecular tool that allow to select groups of NSCLC patients with different clinical evolution, in order to establish personalized therapy protocols.},
}
@article {pmid26249011,
year = {2015},
author = {Carty, CL and Kooperberg, C and Liu, J and Herndon, M and Assimes, T and Hou, L and Kroenke, CH and LaCroix, AZ and Kimura, M and Aviv, A and Reiner, AP},
title = {Leukocyte Telomere Length and Risks of Incident Coronary Heart Disease and Mortality in a Racially Diverse Population of Postmenopausal Women.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {35},
number = {10},
pages = {2225-2231},
pmid = {26249011},
issn = {1524-4636},
support = {HHSN268201100001I/HL/NHLBI NIH HHS/United States ; R01 HL116446/HL/NHLBI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; HHSN268201100004I/HL/NHLBI NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; HHSN268201100003C/WH/WHI NIH HHS/United States ; HHSN268201300007C/HL/NHLBI NIH HHS/United States ; HHSN271201100004C/AG/NIA NIH HHS/United States ; HHSN268201100002C/WH/WHI NIH HHS/United States ; HHSN268201100002I/HL/NHLBI NIH HHS/United States ; HHSN268201100001C/WH/WHI NIH HHS/United States ; HHSN268201100004C/WH/WHI NIH HHS/United States ; },
mesh = {Black or African American/*genetics ; Aged ; Case-Control Studies ; Confidence Intervals ; Coronary Disease/*ethnology/*genetics/physiopathology ; Female ; Genetic Predisposition to Disease/*epidemiology ; Humans ; Incidence ; Leukocytes ; Middle Aged ; Postmenopause/ethnology/genetics ; Prognosis ; Proportional Hazards Models ; Risk Assessment ; Severity of Illness Index ; Survival Rate ; Telomere/*genetics ; White People/genetics ; },
abstract = {OBJECTIVE: Telomeres are regions at the ends of chromosomes that maintain chromosomal structural integrity and genomic stability. In studies of mainly older, white populations, shorter leukocyte telomere length (LTL) is associated with cardiometabolic risk factors and increased risks of mortality and coronary heart disease (CHD). On average, African Americans (AfAm) have longer LTL than whites, but the LTL-CHD relationship in AfAm is unknown. We investigated the relationship of LTL with CHD and mortality among AfAm.<br><br>APPROACH AND RESULTS: Using a case-cohort design, 1525 postmenopausal women (667 AfAm and 858 whites) from the Women's Health Initiative had LTL measured in baseline blood samples by Southern blotting. CHD or mortality hazards ratios were estimated using race-stratified and risk factor-adjusted Cox proportional hazards models. There were 367 incident CHD (226 mortality) events in whites, whereas AfAm experienced 269 incident CHD (216 mortality) events during median follow-up of 13 years. Shorter LTL was associated with older age, current smoking, and white race/ethnicity. In whites, each 1 kilobase decrease in LTL was associated with 50% increased hazard of CHD, hazard ratio=1.50 (95% confidence interval, 1.08-2.10), P=0.017. There was no association between CHD and LTL in AfAm. White women with shorter LTL had higher risks of mortality. In contrast, shorter LTL was weakly associated with decreased mortality hazard in AfAm.<br><br>CONCLUSIONS: As one of the largest prospective studies of LTL associations with incident CHD and mortality in a racially diverse sample, our study suggests differences in LTL associations with CHD and mortality between white and AfAm postmenopausal women.},
}
@article {pmid26247919,
year = {2016},
author = {Barbaro, PM and Ziegler, DS and Reddel, RR},
title = {The wide-ranging clinical implications of the short telomere syndromes.},
journal = {Internal medicine journal},
volume = {46},
number = {4},
pages = {393-403},
doi = {10.1111/imj.12868},
pmid = {26247919},
issn = {1445-5994},
mesh = {Australia ; Congresses as Topic/trends ; Dyskeratosis Congenita/*diagnosis/*genetics/therapy ; Humans ; Syndrome ; Telomere/genetics/metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {There is an increasing number of inherited disorders in which excessive telomere shortening underlies the molecular defect, with dyskeratosis congenita (DC) being the archetypal short telomere syndrome. DC is classically described as a mucocutaneous triad of oral leukoplakia, nail dystrophy and abnormal skin pigmentation. However, excessive telomere shortening can affect almost any organ system, so the clinical manifestations are protean, including developmental delay, cerebellar hypoplasia, exudative retinopathy, aplastic anaemia, acute myeloid leukaemia, idiopathic pulmonary fibrosis, idiopathic hepatic cirrhosis, head and neck cancer and dental abnormalities, and may be multi-systemic. Undiagnosed patients may be seen by essentially any medical subspecialist. Correct diagnosis is important to ensure appropriate management, and for initiating investigations to identify affected family members. Treatment is often supportive, with transplantation offering cure for pulmonary fibrosis or bone marrow failure. Higher rates of mortality and morbidity with transplantation often require regimen alterations, underscoring the need for correct diagnosis. Short telomeres result from mutations in genes essential for telomere maintenance (e.g. genes encoding subunits of the telomerase enzyme complex). Disease severity reflects not only the severity of the defect, but also the inheritance of short telomeres, giving rise to incomplete penetrance and genetic anticipation. Attendees of the inaugural Australian Short Telomere Syndrome Conference were updated on the current scientific and clinical understanding of these disorders, and discussed the best approach for management of these patients in the Australian context. This review will include recommendations from the conference and aims to increase awareness of short telomere disorders.},
}
@article {pmid26239175,
year = {2015},
author = {Honig, LS and Kang, MS and Cheng, R and Eckfeldt, JH and Thyagarajan, B and Leiendecker-Foster, C and Province, MA and Sanders, JL and Perls, T and Christensen, K and Lee, JH and Mayeux, R and Schupf, N},
title = {Heritability of telomere length in a study of long-lived families.},
journal = {Neurobiology of aging},
volume = {36},
number = {10},
pages = {2785-2790},
pmid = {26239175},
issn = {1558-1497},
support = {U01 AG023712/AG/NIA NIH HHS/United States ; M01 RR000645/RR/NCRR NIH HHS/United States ; U01 AG023744/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; U01AG023746/AG/NIA NIH HHS/United States ; P30 AG034424/AG/NIA NIH HHS/United States ; P50AG008702/AG/NIA NIH HHS/United States ; U01AG23744/AG/NIA NIH HHS/United States ; U01 AG023749/AG/NIA NIH HHS/United States ; U01AG023755/AG/NIA NIH HHS/United States ; U01 AG023755/AG/NIA NIH HHS/United States ; U01AG023712/AG/NIA NIH HHS/United States ; U01AG023749/AG/NIA NIH HHS/United States ; U01 AG023746/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/genetics ; DNA/*genetics ; Female ; Humans ; *Leukocytes ; Longevity/*genetics ; Male ; Middle Aged ; Telomere Homeostasis/*genetics ; },
abstract = {Chromosomal telomere length shortens with repeated cell divisions. Human leukocyte DNA telomere length (LTL) has been shown to shorten during aging. LTL shortening has correlated with decreased longevity, dementia, and other age-associated processes. Because LTL varies widely between individuals in a given age group, it has been hypothesized to be a marker of biological aging. However, the principal basis for the variation of human LTL has not been established, although various studies have reported heritability. Here, we use a family-based study of longevity to study heritability of LTL in 3037 individuals. We show that LTL is shorter in older individuals, and in males, and has a high heritability (overall h(2) = 0.54). In the offspring generation, who are in middle-life, we find an ordinal relationship: persons more-closely-related to elderly probands have longer LTL than persons less-closely-related, who nonetheless have longer LTL than unrelated spouses of the offspring generation. These results support a prominent genetic underpinning of LTL. Elucidation of such genetic bases may provide avenues for intervening in the aging process.},
}
@article {pmid26238505,
year = {2015},
author = {Raj, DD and Moser, J and van der Pol, SM and van Os, RP and Holtman, IR and Brouwer, N and Oeseburg, H and Schaafsma, W and Wesseling, EM and den Dunnen, W and Biber, KP and de Vries, HE and Eggen, BJ and Boddeke, HW},
title = {Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening.},
journal = {Aging cell},
volume = {14},
number = {6},
pages = {1003-1013},
pmid = {26238505},
issn = {1474-9726},
mesh = {Aging/immunology ; Animals ; Blood-Brain Barrier/*physiopathology ; Brain/cytology/*physiopathology ; Cell Proliferation/genetics ; Disease Models, Animal ; Inflammation/*immunology/pathology ; Lipopolysaccharides/pharmacology ; Macrophages/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microglia/*immunology ; Telomerase/genetics ; Telomere/genetics ; Telomere Shortening/*genetics ; },
abstract = {Microglia are a proliferative population of resident brain macrophages that under physiological conditions self-renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as 'priming'. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue using early (first-generation G1 mTerc(-/-))- and late-generation (third-generation G3 and G4 mTerc(-/-)) telomerase-deficient mice, which carry a homozygous deletion for the telomerase RNA component gene (mTerc). Late-generation mTerc(-/-) microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G3 mTerc(-/-) microglia are comparable with microglia derived from G1 mTerc(-/-) mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide (LPS), G3 mTerc(-/-) microglia mice show an enhanced pro-inflammatory response. Nevertheless, this enhanced inflammatory response was not accompanied by an increased expression of genes known to be associated with age-associated microglia priming. The increased inflammatory response in microglia correlates closely with increased peripheral inflammation, a loss of blood-brain barrier integrity, and infiltration of immune cells in the brain parenchyma in this mouse model of telomere shortening.},
}
@article {pmid26237044,
year = {2015},
author = {Mason, PJ and Bessler, M},
title = {mRNA deadenylation and telomere disease.},
journal = {The Journal of clinical investigation},
volume = {125},
number = {8},
pages = {3304},
doi = {10.1172/JCI82903},
pmid = {26237044},
issn = {1558-8238},
}
@article {pmid26232870,
year = {2015},
author = {Lin, PY},
title = {Shortened leukocyte telomere length in patients with schizophrenia is related to disease status.},
journal = {Schizophrenia research},
volume = {168},
number = {1-2},
pages = {597-598},
doi = {10.1016/j.schres.2015.07.038},
pmid = {26232870},
issn = {1573-2509},
mesh = {Humans ; Leukocytes/*metabolism ; Schizophrenia/*genetics/*physiopathology ; Telomere/*metabolism ; Telomere Shortening/*physiology ; },
}
@article {pmid26232478,
year = {2015},
author = {Kropski, JA and Loyd, JE},
title = {Telomeres revisited: RTEL1 variants in pulmonary fibrosis.},
journal = {The European respiratory journal},
volume = {46},
number = {2},
pages = {312-314},
pmid = {26232478},
issn = {1399-3003},
support = {P01 HL092870/HL/NHLBI NIH HHS/United States ; T32 HL094296/HL/NHLBI NIH HHS/United States ; HL094296/HL/NHLBI NIH HHS/United States ; HL92870/HL/NHLBI NIH HHS/United States ; },
mesh = {DNA Helicases/*genetics ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/*genetics ; Male ; *Telomere Shortening ; },
}
@article {pmid26232116,
year = {2015},
author = {Stanley, SE and Armanios, M},
title = {The short and long telomere syndromes: paired paradigms for molecular medicine.},
journal = {Current opinion in genetics &amp; development},
volume = {33},
number = {},
pages = {1-9},
pmid = {26232116},
issn = {1879-0380},
support = {R01 CA160433/CA/NCI NIH HHS/United States ; R01 HL119476/HL/NHLBI NIH HHS/United States ; T32 GM007309/GM/NIGMS NIH HHS/United States ; },
mesh = {Aging/*genetics/pathology ; Humans ; Molecular Medicine ; Mutation ; Neoplasms/*genetics/pathology ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis/genetics ; Telomere Shortening/genetics ; },
abstract = {Recent advances have defined a role for abnormally short telomeres in a broad spectrum of genetic disorders. They include rare conditions such as dyskeratosis congenita as well pulmonary fibrosis and emphysema. Now, there is new evidence that some familial cancers, such as melanoma, are caused by mutations that lengthen telomeres. Here, we examine the significance of these short and long telomere length extremes for understanding the molecular basis of age-related disease and cancer.},
}
@article {pmid26231419,
year = {2016},
author = {Carlquist, JF and Knight, S and Cawthon, RM and Le, VT and Jared Bunch, T and Horne, BD and Rollo, JS and Huntinghouse, JA and Brent Muhlestein, J and Anderson, JL},
title = {Shortened telomere length is associated with paroxysmal atrial fibrillation among cardiovascular patients enrolled in the Intermountain Heart Collaborative Study.},
journal = {Heart rhythm},
volume = {13},
number = {1},
pages = {21-27},
doi = {10.1016/j.hrthm.2015.07.032},
pmid = {26231419},
issn = {1556-3871},
mesh = {Aged ; *Atrial Fibrillation/genetics/physiopathology ; DNA Damage/genetics ; Female ; Humans ; Male ; Middle Aged ; Recurrence ; Risk Factors ; Statistics as Topic ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {BACKGROUND: Atrial fibrillation (AF) diminishes quality of life and accounts for approximately one-third of all strokes. Studies have associated mitochondrial dysfunction with both AF and telomere length (TL).<br><br>OBJECTIVE: The purpose of this study was to test the hypothesis of a relationship between AF and TL.<br><br>METHODS: Blood was collected from consenting participants in the Intermountain Heart Collaborative Study (n = 3576) and DNA extracted. TL was determined by multiplex quantitative polymerase chain reaction, normalized to a single copy gene, and reported as telomere/single gene ratio (t/s). Patient information was extracted from Intermountain Healthcare's electronic records database. Prevalent AF was determined by discharge ICD-9 code. AF subtype (paroxysmal [Px], persistent [Ps], long-standing persistent/permanent [Pm]) was determined by chart review.<br><br>RESULTS: The t/s decreased with age (P <.00001). Subjects with a history of AF (n = 379 [10.6%] had shorter telomeres (mean t/s &#xb1; SD = 0.87 &#xb1; 0.29) compared to subjects without AF (mean t/s 0.95 &#xb1; 0.32, P <.0001). The association remained after adjustment for age (P = .017) and cardiovascular risk factors (P = .016). AF subtype was determined for 277 subjects; 110 (39.7%) had Px AF, 65 (23.5%) Ps, and 102 (36.8%) Pm AF. Mean t/s did not differ between Ps, Pm, and subjects without AF (0.94 &#xb1; 0.40, 0.94 &#xb1; 0.27, and 0.95 &#xb1; 0.32, respectively). However, the mean t/s for Px (0.81 &#xb1; 0.22) was significantly shorter than for Ps (P = .026), Pm (P = .004), or subjects without AF (P <.0001).<br><br>CONCLUSION: The present study supports an association between Px AF and TL. Short TL may be a previously unrecognized risk factor for AF with potential applications in diagnosis and therapy.},
}
@article {pmid26230851,
year = {2015},
author = {Udomsinprasert, W and Poovorawan, Y and Chongsrisawat, V and Vejchapipat, P and Zhan, D and Honsawek, S},
title = {Telomere Length in Peripheral Blood Leukocytes Is Associated with Severity of Biliary Atresia.},
journal = {PloS one},
volume = {10},
number = {7},
pages = {e0134689},
pmid = {26230851},
issn = {1932-6203},
mesh = {Adolescent ; Adult ; Biliary Atresia/blood/*genetics ; Case-Control Studies ; Child ; Child, Preschool ; Female ; Humans ; Leukocytes/*ultrastructure ; Male ; Severity of Illness Index ; *Telomere ; Young Adult ; },
abstract = {OBJECTIVE: The purpose of this study was to investigate the association of telomere length in peripheral blood leukocytes with the severity of biliary atresia (BA).<br><br>METHODS: One hundred and fourteen BA patients and 114 age-matched healthy controls were enrolled. Relative telomere length (RTL) was assessed using a quantitative real-time polymerase chain reaction. Multivariate regression analysis was used to estimate RTL as an independent risk factor of BA. Receiver operating characteristic curve analysis was used to calculate the accuracy of biomarkers in the prediction of liver cirrhosis.<br><br>RESULTS: BA patients had significantly shorter telomeres than healthy controls (p < 0.0001). The RTL in BA patients with jaundice was considerably lower than that of patients without jaundice (p = 0.005). Moreover, RTL was markedly shorter in patients with cirrhosis (F4), as compared to patients with mild fibrosis (F2) and non-fibrosis (F0-F1, p < 0.0001). Logistic regression analysis indicated that short RTL was associated with a higher risk of liver cirrhosis in BA. Tertile analysis showed a dose-response effect for this association (p trend < 0.0001). Additionally, RTL in BA children revealed a negative correlation with age (r = -0.50, p < 0.001). We noted an association between reduction of RTL and liver stiffness scores, adjusted for age and gender (b = -0.01, p < 0.0001). Short RTL can be employed to distinguish cirrhosis patients from non-cirrhosis patients (AUC = 0.78). Further analysis showed a linear correlation between leukocyte RTL and liver RTL in BA patients (r = 0.83, p < 0.001).<br><br>CONCLUSION: The findings of this study provide evidence that telomere shortening is associated with an elevated risk of liver cirrhosis in BA.},
}
@article {pmid26230315,
year = {2015},
author = {Frank, AK and Tran, DC and Qu, RW and Stohr, BA and Segal, DJ and Xu, L},
title = {The Shelterin TIN2 Subunit Mediates Recruitment of Telomerase to Telomeres.},
journal = {PLoS genetics},
volume = {11},
number = {7},
pages = {e1005410},
pmid = {26230315},
issn = {1553-7404},
support = {T32 CA108459/CA/NCI NIH HHS/United States ; },
mesh = {Aminopeptidases/metabolism ; Cell Line, Tumor ; DNA Repair/genetics ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism ; Dyskeratosis Congenita/genetics ; Gene Knock-In Techniques ; HCT116 Cells ; Humans ; Mutation/genetics ; Serine Proteases/metabolism ; Shelterin Complex ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/genetics ; Telomere Shortening/*genetics ; Telomere-Binding Proteins/*genetics ; Telomeric Repeat Binding Protein 1/genetics ; Tripeptidyl-Peptidase 1 ; },
abstract = {Dyskeratosis Congenita (DC) is a heritable multi-system disorder caused by abnormally short telomeres. Clinically diagnosed by the mucocutaneous symptoms, DC patients are at high risk for bone marrow failure, pulmonary fibrosis, and multiple types of cancers. We have recapitulated the most common DC-causing mutation in the shelterin component TIN2 by introducing a TIN2-R282H mutation into cultured telomerase-positive human cells via a knock-in approach. The resulting heterozygous TIN2-R282H mutation does not perturb occupancy of other shelterin components on telomeres, result in activation of telomeric DNA damage signaling or exhibit other characteristics indicative of a telomere deprotection defect. Using a novel assay that monitors the frequency and extension rate of telomerase activity at individual telomeres, we show instead that telomerase elongates telomeres at a reduced frequency in TIN2-R282H heterozygous cells; this recruitment defect is further corroborated by examining the effect of this mutation on telomerase-telomere co-localization. These observations suggest a direct role for TIN2 in mediating telomere length through telomerase, separable from its role in telomere protection.},
}
@article {pmid26222390,
year = {2015},
author = {Bateson, M and Emmerson, M and Ergün, G and Monaghan, P and Nettle, D},
title = {Opposite Effects of Early-Life Competition and Developmental Telomere Attrition on Cognitive Biases in Juvenile European Starlings.},
journal = {PloS one},
volume = {10},
number = {7},
pages = {e0132602},
pmid = {26222390},
issn = {1932-6203},
support = {BB/J015091/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/J016446/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; NC/K000802/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; *Cognition ; *Depression ; Passeriformes/*growth &amp; development ; *Telomere Homeostasis ; },
abstract = {Moods are enduring affective states that we hypothesise should be affected by an individual's developmental experience and its current somatic state. We tested whether early-life adversity, induced by manipulating brood size, subsequently altered juvenile European starlings' (Sturnus vulgaris) decisions in a judgment bias task designed to provide a cognitive measure of mood. We predicted that starlings from larger broods, specifically those that had experienced more nest competitors larger than themselves would exhibit reduced expectation of reward, indicative of a 'pessimistic', depression-like mood. We used a go/no-go task, in which 30 starlings were trained to probe a grey card disc associated with a palatable mealworm hidden underneath and avoid a different shade of grey card disc associated with a noxious quinine-injected mealworm hidden underneath. Birds' response latencies to the trained stimuli and also to novel, ambiguous stimuli intermediate between these were subsequently tested. Birds that had experienced greater competition in the nest were faster to probe trained stimuli, and it was therefore necessary to control statistically for this difference in subsequent analyses of the birds' responses to the ambiguous stimuli. As predicted, birds with more, larger nest competitors showed relatively longer latencies to probe ambiguous stimuli, suggesting reduced expectation of reward and a 'pessimistic', depression-like mood. However, birds with greater developmental telomere attrition--a measure of cellular aging associated with increased morbidity and reduced life-expectancy that we argue could be used as a measure of somatic state--showed shorter latencies to probe ambiguous stimuli. This would usually be interpreted as evidence for a more positive or 'optimistic' affective state. Thus, increased competition in the nest and poor current somatic state appear to have opposite effects on cognitive biases. Our results lead us to question whether increased expectation of reward when presented with ambiguous stimuli always indicates a more positive affective state. We discuss the possibility that birds in poor current somatic state may adopt a 'hungry' cognitive phenotype that could drive behaviour commonly interpreted as 'optimism' in food-rewarded cognitive bias tasks.},
}
@article {pmid26221147,
year = {2015},
author = {Sadr, M and Noori Mugahi, SM and Hassanzadeh, G and Nadji, SA and Kiani, A and Abedini, A and Javadi, A and Mohammadi, F and Masjedi, MR and Bahadori, M},
title = {Telomere Shortening in Blood Leukocytes of Patients with Chronic Obstructive Pulmonary Disease.},
journal = {Tanaffos},
volume = {14},
number = {1},
pages = {10-16},
pmid = {26221147},
issn = {1735-0344},
abstract = {INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is not completely reversible by administration of inhaled bronchodilators. Many studies propose that telomere length shortening might have occurred in COPD patients. We aimed to determine the telomere length in COPD patients and compare the results of non-smoking and smoking control subjects.<br><br>MATERIALS AND METHODS: In our case-control study, 84 clinically stable COPD patients were recruited on admission to Masih Daneshvari Hospital. Eighty-five healthy controls were also selected including 45 non-smokers and 40 smokers admitted for diseases other than COPD. Spirometry was done for all subjects. Telomere length was measured by quantitative real time PCR as described by Cawthon. The telomere repeat copy number (T) to single-gene copy number (S) ratio was calculated using the comparative Ct method.<br><br>RESULTS: The mean &#xb1;SD of age was 64.33&#xb1;10.04 years in patients and 65.06 &#xb1;10.02 years in controls (P=0.693). The mean &#xb1;SD of FEV1 was 1.62&#xb1;0.75 L in patients, 2.84&#xb1;0.54 L in smoker controls and 2.83&#xb1;0.56 L in non-smoker controls; significant differences were detected in this regard between cases and controls (P<0.001). T/S ratio was significantly lower in COPD patients (0.61&#xb1;0.08) than in the control subjects (0.69&#xb1;0.09) (P<0.001). However, telomere length was shorter in the patients than in controls in each age group (P<0.001). Additionally, there were no statistically significant differences in telomere length between the smoker and non-smoker control subjects. Regarding the correlation between BMI and telomere length, there were no significant differences among the patients and control groups.<br><br>CONCLUSION: In conclusion, we found that telomere length in COPD patients was shorter than that in smoker and non-smoker controls, irrespective of age, sex, spirometric variables, BMI and history of cigarette smoking.},
}
@article {pmid26219269,
year = {2015},
author = {van Ockenburg, SL and Bos, EH and de Jonge, P and van der Harst, P and Gans, RO and Rosmalen, JG},
title = {Stressful life events and leukocyte telomere attrition in adulthood: a prospective population-based cohort study.},
journal = {Psychological medicine},
volume = {45},
number = {14},
pages = {2975-2984},
doi = {10.1017/S0033291715000914},
pmid = {26219269},
issn = {1469-8978},
mesh = {Adult ; Aged ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/*ultrastructure ; *Life Change Events ; Linear Models ; Male ; Middle Aged ; Prospective Studies ; Risk Factors ; Telomere/*pathology ; Telomere Shortening/*genetics ; },
abstract = {BACKGROUND: Telomere attrition might be one of the mechanisms through which psychosocial stress leads to somatic disease. To date it is unknown if exposure to adverse life events in adulthood is associated with telomere shortening prospectively. In the current study we investigated whether life events are associated with shortening of telomere length (TL).<br><br>METHOD: Participants were 1094 adults (mean age 53.1, range 33-79 years) from the PREVEND cohort. Data were collected at baseline (T1) and at two follow-up visits after 4 years (T2) and 6 years (T3). Life events were assessed with an adjusted version of the List of Threatening Events (LTE). TL was measured by monochrome multiplex quantitative PCR at T1, T2, and T3. A linear mixed model was used to assess the effect of recent life events on TL prospectively. Multivariable regression analyses were performed to assess whether the lifetime life events score or the score of life events experienced before the age of 12 predicted TL cross-sectionally. All final models were adjusted for age, sex, body mass index, presence of chronic diseases, frequency of sports, smoking status, and level of education.<br><br>RESULTS: Recent life events significantly predicted telomere attrition prospectively (B = -0.031, p = 0.007). We were not able to demonstrate a significant cross-sectional relationship between the lifetime LTE score and TL. Nor did we find exposure to adverse life events before the age of 12 to be associated with TL in adulthood.<br><br>CONCLUSIONS: Exposure to recent adverse life events in adulthood is associated with telomere attrition prospectively.},
}
@article {pmid26218760,
year = {2015},
author = {Edmonds, GW and Côté, HC and Hampson, SE},
title = {Childhood Conscientiousness and Leukocyte Telomere Length 40 Years Later in Adult Women--Preliminary Findings of a Prospective Association.},
journal = {PloS one},
volume = {10},
number = {7},
pages = {e0134077},
pmid = {26218760},
issn = {1932-6203},
support = {R01 AG020048/AG/NIA NIH HHS/United States ; R21 AG045015/AG/NIA NIH HHS/United States ; AG020048/AG/NIA NIH HHS/United States ; R21AG045015/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Child ; Female ; Hawaii ; *Health Behavior ; Humans ; Leukocytes/*physiology ; Longitudinal Studies ; Middle Aged ; *Personality ; Prospective Studies ; Telomere Homeostasis/*genetics ; },
abstract = {Leukocyte telomere length (LTL) shortens with age, and is a prospective marker of mortality related to cardiovascular disease. Many health behaviors and social environmental factors have been found to be associated with LTL. Several of these are also associated with conscientiousness, a dispositional personality trait. Conscientiousness is a propensity to be planful, adhere to social norms, and inhibit pre-potent responses. Like LTL, conscientiousness is prospectively related to mortality, possibly through cumulative effects on health over the life course via multiple pathways. As a result, we hypothesized that childhood levels of conscientiousness would predict LTL prospectively in adulthood. We selected a sample of 60 women in the Hawaii Personality and Health Cohort; 30 described by their teachers as high on conscientiousness in childhood and 30 described as low on the trait. Dried blood spot samples collected in adulthood 40 years later were used as sources of DNA for the LTL assay. Conscientiousness was associated with longer LTL (p = .02). Controlling for age did not account for this association. Controlling for education and physiological dysregulation partially attenuated the association, and the effect remained significant when accounting for differences in LTL across cultural groups. These results represent the first evidence that childhood personality prospectively predicts LTL 40 years later in adulthood. Our findings would be consistent with a mediation hypothesis whereby conscientiousness predicts life paths and trajectories of health that are reflected in rates of LTL erosion across the lifespan.},
}
@article {pmid26218225,
year = {2015},
author = {Hass, EP and Zappulla, DC},
title = {The Ku subunit of telomerase binds Sir4 to recruit telomerase to lengthen telomeres in S. cerevisiae.},
journal = {eLife},
volume = {4},
number = {},
pages = {},
pmid = {26218225},
issn = {2050-084X},
support = {R00 GM080400/GM/NIGMS NIH HHS/United States ; T32 GM007231/GM/NIGMS NIH HHS/United States ; GM080400/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatin Immunoprecipitation ; Protein Binding ; Protein Subunits/metabolism ; Saccharomyces cerevisiae/*enzymology ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {In Saccharomyces cerevisiae and in humans, the telomerase RNA subunit is bound by Ku, a ring-shaped protein heterodimer best known for its function in DNA repair. Ku binding to yeast telomerase RNA promotes telomere lengthening and telomerase recruitment to telomeres, but how this is achieved remains unknown. Using telomere-length analysis and chromatin immunoprecipitation, we show that Sir4 - a previously identified Ku-binding protein that is a component of telomeric silent chromatin - is required for Ku-mediated telomere lengthening and telomerase recruitment. We also find that specifically tethering Sir4 directly to Ku-binding-defective telomerase RNA restores otherwise-shortened telomeres to wild-type length. These findings suggest that Sir4 is the telomere-bound target of Ku-mediated telomerase recruitment and provide one mechanism for how the Sir4-competing Rif1 and Rif2 proteins negatively regulate telomere length in yeast.},
}
@article {pmid26218071,
year = {2015},
author = {Tachtatzis, PM and Marshall, A and Aravinthan, A and Verma, S and Penrhyn-Lowe, S and Mela, M and Scarpini, C and Davies, SE and Coleman, N and Alexander, GJ},
title = {Correction: Chronic Hepatitis B Virus Infection: The Relation between Hepatitis B Antigen Expression, Telomere Length, Senescence, Inflammation and Fibrosis.},
journal = {PloS one},
volume = {10},
number = {7},
pages = {e0134315},
pmid = {26218071},
issn = {1932-6203},
support = {13080/CRUK_/Cancer Research UK/United Kingdom ; MC_U105359875/MRC_/Medical Research Council/United Kingdom ; },
}
@article {pmid26217705,
year = {2015},
author = {Uziel, O and Lahav, M},
title = {Proteomic and microRNA data clarifying the effects of telomere shortening on cancer cells.},
journal = {Data in brief},
volume = {2},
number = {},
pages = {48-51},
pmid = {26217705},
issn = {2352-3409},
abstract = {In a previous study, we have shown that shortening of telomeres by telomerase inhibition sensitized cancer cells to cisplatinum, slower their migration, increased DNA damage and impaired DNA repair [1]. In the following study, we present a network model combining microRNA and proteomic profiling attempting to decipher the molecular mechanism underlying the effect of shortened telomeres on the obtained phenotype of cancer cells [2]. The microRNA and proteomic data were used for a network model construction, which provided us with several nodal candidates that may potentially mediate the shortened-telomeres dependent features. These protein expressions were experimentally validated, supporting their potential central role in this system [2]. In this article, we delineate the full proteomic data and a microarray analyses performed on cells with shortened telomeres compared to their cognate parental intact telomere cells. The data is attached as excel files. In principle, clarifying the mechanism behind telomere shortened phenotype may facilitate novel therapeutics development and may also obviate the time consuming process of telomere shortening achieved by telomerase inhibition.},
}
@article {pmid26217174,
year = {2015},
author = {Costa, Dde S and Rosa, DV and Barros, AG and Romano-Silva, MA and Malloy-Diniz, LF and Mattos, P and de Miranda, DM},
title = {Telomere length is highly inherited and associated with hyperactivity-impulsivity in children with attention deficit/hyperactivity disorder.},
journal = {Frontiers in molecular neuroscience},
volume = {8},
number = {},
pages = {28},
pmid = {26217174},
issn = {1662-5099},
abstract = {Telomere length (TL) is highly heritable, and a shorter telomere at birth may increase the risk of age-related problems. Additionally, a shorter TL may represent a biomarker of chronic stress and has been associated with psychiatric disorders. However, no study has explored whether there is an association between TL and the symptoms of one of the most common neurodevelopmental disorders in childhood: Attention Deficit/Hyperactive Disorder (ADHD). We evaluated 61 (range, 6-16 years) ADHD children and their parents between 2012 and 2014. TL was measured with a quantitative polymerase chain reaction method with telomere signal normalized to the signal from a single copy gene (36B4) to generate a T/S ratio. Family data was processed through a generalized estimated equations (GEE) model to determine the effect of parental TL on children TL. Inattentive and hyperactive-impulsive symptoms were also evaluated in relation to TL. For the first time, we found general heritability to be the major mechanism explaining interindividual TL variation in ADHD (father-child: 95% CI = 0.35/0.91, p < 0.001; mother-child: 95% CI = 0.38/0.74, p < 0.001). The hyperactive-impulsive dimension of ADHD was related with children's TL (r = -339, p = 0.008) and maternal TL (r = -264, p = 0.047), but not with paternal TL (p > 0.05). The ADHD inattentive dimension was not significant associated with TL in this study (p > 0.05). TL was shown to be a potential biomarker of the ADHD symptoms burden in families affected by this neurodevelopmental disorder. However, it is crucial that future studies investigating the rate of telomere attrition in relation to psychiatric problems to consider the strong determination of TL at birth by inheritance.},
}
@article {pmid26208647,
year = {2015},
author = {Idziak, D and Robaszkiewicz, E and Hasterok, R},
title = {Spatial distribution of centromeres and telomeres at interphase varies among Brachypodium species.},
journal = {Journal of experimental botany},
volume = {66},
number = {21},
pages = {6623-6634},
pmid = {26208647},
issn = {1460-2431},
mesh = {Brachypodium/*genetics ; Centromere/*genetics ; *Chromosomes, Plant ; Genome, Plant ; Meristem ; Species Specificity ; Telomere/*genetics ; },
abstract = {In this study the 3-D distribution of centromeres and telomeres was analysed in the interphase nuclei of three Brachypodium species, i.e. B. distachyon (2n=10), B. stacei (2n=20) and B. hybridum (2n=30), which is presumably a hybrid between the first two species. Using fluorescence in situ hybridization (FISH) with centromeric and telomeric DNA probes, it was observed that the majority of B. distachyon nuclei in the root tip cells displayed the Rabl configuration while both B. stacei and B. hybridum mostly lacked the centromere-telomere polarization. In addition, differentiated leaf cells of B. distachyon did not display the Rabl pattern. In order to analyse the possible connection between the occurrence of the Rabl pattern and the phase of cell cycle or DNA content, FISH was combined with digital image cytometry. The results revealed that the frequency of nuclei with the Rabl configuration in the root tip nuclei was positively correlated with an increase in DNA content, which resulted from DNA replication. Also, the analysis of the influence of the nuclear shape on the nuclear architecture indicated that an increasing elongation of the nuclei negatively affected the occurrence of the Rabl pattern. Some possible explanations of these phenomena are discussed.},
}
@article {pmid26206796,
year = {2015},
author = {Bär, C and Huber, N and Beier, F and Blasco, MA},
title = {Therapeutic effect of androgen therapy in a mouse model of aplastic anemia produced by short telomeres.},
journal = {Haematologica},
volume = {100},
number = {10},
pages = {1267-1274},
pmid = {26206796},
issn = {1592-8721},
mesh = {Androgens/administration &amp; dosage/*pharmacology ; Anemia, Aplastic/blood/drug therapy/*genetics/mortality ; Animals ; Bone Marrow Cells/drug effects/metabolism ; Disease Models, Animal ; Estradiol/administration &amp; dosage/pharmacology ; Fibroblasts/drug effects/metabolism ; Gene Expression ; Humans ; Mice ; Mice, Transgenic ; RNA, Messenger/genetics ; Telomerase/genetics/metabolism ; *Telomere Shortening ; Testosterone/administration &amp; dosage/pharmacology ; },
abstract = {Aplastic anemia is a rare but life-threatening disorder characterized by cytopenia in at least two of the three blood lineages. A frequent feature of patients with aplastic anemia is that they have shorter telomeres than those of age-matched controls. Testosterone has been used for over half a century in the treatment of aplastic anemia. However, although remissions are frequent following hormone therapy, the molecular mechanism underlying the response to treatment has remained unknown. Here we explored the possibility that the recently described regulation of telomerase activity by sex hormones may be the mechanism responsible. To this end, we used a mouse model of aplastic anemia induced by short telomeres in the bone marrow compartment. We found that testosterone therapy results in telomerase up-regulation, improved blood counts, and a significant extension of life-span of these mice. Importantly, longitudinal follow-up studies revealed longer telomeres in peripheral blood in mice subjected to hormone treatment. Our results demonstrate that testosterone-mediated telomerase activation can attenuate or reverse aplastic anemia disease progression associated with the presence of short telomeres.},
}
@article {pmid26196902,
year = {2015},
author = {Andreotti, G and Hoppin, JA and Hou, L and Koutros, S and Gadalla, SM and Savage, SA and Lubin, J and Blair, A and Hoxha, M and Baccarelli, A and Sandler, D and Alavanja, M and Beane Freeman, LE},
title = {Pesticide Use and Relative Leukocyte Telomere Length in the Agricultural Health Study.},
journal = {PloS one},
volume = {10},
number = {7},
pages = {e0133382},
pmid = {26196902},
issn = {1932-6203},
support = {//Intramural NIH HHS/United States ; },
mesh = {Acetamides/poisoning ; Adult ; Aged ; Aged, 80 and over ; Agricultural Workers' Diseases/chemically induced/diagnosis/genetics ; Health Occupations/statistics &amp; numerical data ; Humans ; Iowa ; Leukocytes/*drug effects/metabolism ; Malathion ; Male ; Middle Aged ; North Carolina ; Occupational Exposure/*analysis ; Organophosphate Poisoning/diagnosis/genetics ; Pesticides/*poisoning ; Prospective Studies ; Surveys and Questionnaires ; Telomere/*drug effects/genetics ; Telomere Homeostasis/drug effects ; Telomere Shortening/drug effects ; },
abstract = {Some studies suggest that telomere length (TL) may be influenced by environmental exposures, including pesticides. We examined associations between occupational pesticide use reported at three time points and relative telomere length (RTL) in the Agricultural Health Study (AHS), a prospective cohort study of pesticide applicators in Iowa and North Carolina. RTL was measured by qPCR using leukocyte DNA from 568 cancer-free male AHS participants aged 31-94 years with blood samples collected between 2006 and 2008. Self-reported information, including pesticide use, was collected at three time points: enrollment (1993-1997) and two follow-up questionnaires (1998-2003, 2005-2008). For each pesticide, we evaluated cumulative use (using data from all three questionnaires), and more recent use (using data from the last follow-up questionnaire). Multivariable linear regression was used to examine the associations between pesticide use (ever, lifetime days, intensity-weighted lifetime days (lifetime days*intensity score)) and RTL, adjusting for age at blood draw and use of other pesticides. Of the 57 pesticides evaluated with cumulative use, increasing lifetime days of 2,4-D (p-trend=0.001), diazinon (p-trend=0.002), and butylate (p-trend=0.01) were significantly associated with shorter RTL, while increasing lifetime days of alachlor was significantly associated with longer RTL (p-trend=0.03). Only the association with 2,4-D was significant after adjustment for multiple comparisons. Of the 40 pesticides evaluated for recent use, malathion was associated with shorter RTL (p=0.03), and alachlor with longer RTL (p=0.03). Our findings suggest that leukocyte TL may be impacted by cumulative use and recent use of certain pesticides.},
}
@article {pmid26195664,
year = {2015},
author = {Drosopoulos, WC and Kosiyatrakul, ST and Schildkraut, CL},
title = {BLM helicase facilitates telomere replication during leading strand synthesis of telomeres.},
journal = {The Journal of cell biology},
volume = {210},
number = {2},
pages = {191-208},
pmid = {26195664},
issn = {1540-8140},
support = {R01 GM045751/GM/NIGMS NIH HHS/United States ; 5R01-GM045751/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; *DNA Replication ; G-Quadruplexes ; GC Rich Sequence ; Gene Knockout Techniques ; Kinetics ; Mice, Knockout ; RecQ Helicases/genetics/metabolism/*physiology ; Replication Origin ; Telomere/*physiology ; Werner Syndrome Helicase ; },
abstract = {Based on its in vitro unwinding activity on G-quadruplex (G4) DNA, the Bloom syndrome-associated helicase BLM is proposed to participate in telomere replication by aiding fork progression through G-rich telomeric DNA. Single molecule analysis of replicated DNA (SMARD) was used to determine the contribution of BLM helicase to telomere replication. In BLM-deficient cells, replication forks initiating from origins within the telomere, which copy the G-rich strand by leading strand synthesis, moved slower through the telomere compared with the adjacent subtelomere. Fork progression through the telomere was further slowed in the presence of a G4 stabilizer. Using a G4-specific antibody, we found that deficiency of BLM, or another G4-unwinding helicase, the Werner syndrome-associated helicase WRN, resulted in increased G4 structures in cells. Importantly, deficiency of either helicase led to greater increases in G4 DNA detected in the telomere compared with G4 seen genome-wide. Collectively, our findings are consistent with BLM helicase facilitating telomere replication by resolving G4 structures formed during copying of the G-rich strand by leading strand synthesis.},
}
@article {pmid26195663,
year = {2015},
author = {Gerbi, SA},
title = {Beginning at the end: DNA replication within the telomere.},
journal = {The Journal of cell biology},
volume = {210},
number = {2},
pages = {177-179},
pmid = {26195663},
issn = {1540-8140},
mesh = {Animals ; *DNA Replication ; RecQ Helicases/*physiology ; Telomere/*physiology ; },
abstract = {Using single molecule analysis of replicated DNA (SMARD), Drosopoulos et al. (2015; J. Cell Biol. http://dx.doi.org/10.1083/jcb.201410061) report that DNA replication initiates at measurable frequency within the telomere of mouse chromosome arm 14q. They demonstrate that resolution of G4 structures on the G-rich template strand of the telomere requires some overlapping functions of BLM and WRN helicase for leading strand synthesis.},
}
@article {pmid26191279,
year = {2015},
author = {Liu, C and Li, B and Li, L and Zhang, H and Chen, Y and Cui, X and Hu, J and Jiang, J and Qi, Y and Li, F},
title = {Correlations of telomere length, P53 mutation, and chromosomal translocation in soft tissue sarcomas.},
journal = {International journal of clinical and experimental pathology},
volume = {8},
number = {5},
pages = {5666-5673},
pmid = {26191279},
issn = {1936-2625},
mesh = {Adolescent ; Adult ; Aged ; Biomarkers, Tumor/*genetics ; *Chromosomes, Human ; DNA Mutational Analysis ; Female ; Gene Fusion ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; *Mutation ; Reverse Transcriptase Polymerase Chain Reaction ; Sarcoma/*genetics/pathology ; Soft Tissue Neoplasms/*genetics/pathology ; *Telomere Homeostasis ; Telomere Shortening ; *Translocation, Genetic ; Tumor Suppressor Protein p53/*genetics ; Young Adult ; },
abstract = {Soft tissue sarcomas (STSs) are a heterogeneous group of malignant tumors that can be divided into specific reciprocal translocation associated in STSs (SRTSs) and nonspecific reciprocal translocation associated in STSs (NRTSs). Telomeres play a key role in maintaining chromosomal stability; pathological telomere elongation is found in a number of cancers. In this study, we aimed to assess telomere lengths in the two types of sarcomas. Twenty formalin-fixed paraffin-embedded (FFPE) archival tissues, namely, 10 sarcomas with characteristic translocations and 10 without characteristic translocations, were included in this study. Expression levels of special fusion gene transcripts were detected in these tumors by reverse transcription polymerase chain reaction. Telomere lengths were assessed by fluorescence in situ hybridization. Results showed that in 10 of the 10 cases of SRTSs, telomere lengths were similar to or reduced compared with the surrounding normal cells. Telomere lengths were elongated in eight of 10 cases of NRTSs, but reduced in two cases. The difference in telomere length was statistically significant in the two types of sarcomas (P=0.001). Upon combining the P53 mutation status, we found that the telomere length was short in eight cases, and only one case demonstrated p53 mutation. However, the telomere length was long in eight cases, and p53 mutation was observed in five cases. These data suggested that p53 mutation was accompanied with long telomeres, and telomeres possibly play an important role in NRTSs. Therefore, telomere-targeting therapy may lead to novel therapeutic strategies to improve treatment of NRTS patients.},
}
@article {pmid26190196,
year = {2015},
author = {Liau, JY and Tsai, JH and Yang, CY and Lee, JC and Liang, CW and Hsu, HH and Jeng, YM},
title = {Alternative lengthening of telomeres phenotype in malignant vascular tumors is highly associated with loss of ATRX expression and is frequently observed in hepatic angiosarcomas.},
journal = {Human pathology},
volume = {46},
number = {9},
pages = {1360-1366},
doi = {10.1016/j.humpath.2015.05.019},
pmid = {26190196},
issn = {1532-8392},
mesh = {Adult ; Aged ; Biomarkers, Tumor/*analysis/*genetics ; DNA Helicases/*analysis ; DNA Mutational Analysis ; Down-Regulation ; Female ; Hemangioendothelioma, Epithelioid/enzymology/genetics/pathology ; Hemangiosarcoma/*enzymology/*genetics/mortality/pathology ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Liver Neoplasms/*enzymology/*genetics/mortality/pathology ; Male ; Middle Aged ; Mutation ; Nuclear Proteins/*analysis ; Prognosis ; Promoter Regions, Genetic ; Sarcoma, Kaposi/enzymology/genetics/pathology ; Skin Neoplasms/enzymology/genetics/pathology ; Telomerase/genetics ; Telomere/*genetics ; *Telomere Homeostasis ; X-linked Nuclear Protein ; },
abstract = {Alternative lengthening of telomeres (ALT) is a mechanism using homologous recombination to maintain telomere length and sustain limitless replicability of cancer cells. Recently, ALT has been found to be associated with inactivation of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. In this study, 119 tumors (88 angiosarcomas, 11 epithelioid hemangioendotheliomas, and 20 Kaposi sarcomas) were analyzed to determine the ALT status, its relationship to loss of ATRX/DAXX expression, and the clinicopathological features. In addition, the mutation status in the telomerase reverse transcriptase gene (TERT) promoter was also studied. Loss of ATRX expression was observed in 21% (16/77) of the primary angiosarcomas and 9% (1/11) of epithelioid hemangioendotheliomas. DAXX expression was intact in all but 2 ATRX-deficient angiosarcomas. Telomere-specific fluorescence in situ hybridization assay showed 28% (17/61) of the primary angiosarcomas were ALT positive. Remarkably, ALT was highly associated with loss of ATRX expression: all but 2 ALT-positive angiosarcomas were ATRX deficient. Notably, hepatic angiosarcomas were frequently ATRX deficient (8/13) and/or ALT positive (8/12). None of the secondary angiosarcomas were ATRX/DAXX deficient or ALT positive. The only ATRX-deficient epithelioid hemangioendothelioma was positive for ALT. Forty-seven angiosarcomas were tested for TERT promoter mutation. Despite the fact that angiosarcoma occurs most commonly in sun-damaged skin, mutation was detected in only 1 radiation-associated angiosarcoma (2%). We conclude that ALT is an important telomere maintenance mechanism in primary angiosarcomas. This feature is highly associated with loss of ATRX expression and is frequently observed in hepatic angiosarcomas.},
}
@article {pmid26190020,
year = {2015},
author = {Melicher, D and Buzas, EI and Falus, A},
title = {Genetic and epigenetic trends in telomere research: a novel way in immunoepigenetics.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {72},
number = {21},
pages = {4095-4109},
pmid = {26190020},
issn = {1420-9071},
mesh = {Aging/genetics ; *Epigenesis, Genetic ; Humans ; Immunogenetics/*methods/*trends ; Lymphocytes/cytology/physiology ; Mutation ; Myeloid Cells/cytology/physiology ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; Twin Studies as Topic ; Twins/genetics ; },
abstract = {Telomeres are protective heterochromatic structures that cap the end of linear chromosomes and play a key role in preserving genomic stability. Telomere length represents a balance between processes that shorten telomeres during cell divisions with incomplete DNA replication and the ones that lengthen telomeres by the action of telomerase, an RNA-protein complex with reverse transcriptase activity which adds telomeric repeats to DNA molecule ends. Telomerase activity and telomere length have a crucial role in cellular ageing and in the pathobiology of several human diseases attracting intense research. The last few decades have witnessed remarkable advances in our understanding about telomeres, telomere-associated proteins, and the biogenesis and regulation of the telomerase holoenzyme complex, as well as about telomerase activation and the telomere-independent functions of telomerase. Emerging data have revealed that telomere length can be modified by genetic and epigenetic factors, sex hormones, reactive oxygen species and inflammatory reactions. It has become clear that, in order to find out more about the factors influencing the rate of telomere attrition in vivo, it is crucial to explore both genetic and epigenetic mechanisms. Since the telomere/telomerase assembly is under the control of multiple epigenetic influences, the unique design of twin studies could help disentangle genetic and environmental factors in the functioning of the telomere/telomerase system. It is surprising that the literature on twin studies investigating this topic is rather scarce. This review aims to provide an overview of some important immune response- and epigenetics-related aspects of the telomere/telomerase system demanding more research, while presenting the available twin data published in connection with telomere research so far. By emphasising what we know and what we still do not know in these areas, another purpose of this review is to urge more twin studies in telomere research.},
}
@article {pmid26188776,
year = {2015},
author = {Martínez, P and Blasco, MA},
title = {Replicating through telomeres: a means to an end.},
journal = {Trends in biochemical sciences},
volume = {40},
number = {9},
pages = {504-515},
doi = {10.1016/j.tibs.2015.06.003},
pmid = {26188776},
issn = {0968-0004},
mesh = {Animals ; DNA/genetics/metabolism ; DNA Replication/genetics/physiology ; G-Quadruplexes ; Humans ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Proper replication of the telomeric DNA at chromosome ends is critical for preserving genome integrity. Yet, telomeres present challenges for the replication machinery, such as their repetitive and heterochromatic nature and their potential to form non-Watson-Crick structures as well as the fact that they are transcribed. Numerous telomere-bound proteins are required to facilitate progression of the replication fork throughout telomeric DNA. In particular, shelterin plays crucial functions in telomere length regulation, protection of telomeres from nuclease degradation, control of DNA damage response at telomeres, and the recruitment of associated factors required for telomere DNA processing and replication. In this review we discuss the recently uncovered functions of mammalian telomere-specific and telomere-associated proteins that facilitate proper telomere replication.},
}
@article {pmid26188111,
year = {2015},
author = {Konvalinová, H and Dvořáková, Z and Renčiuk, D and Bednářová, K and Kejnovská, I and Trantírek, L and Vorlíčková, M and Sagi, J},
title = {Diverse effects of naturally occurring base lesions on the structure and stability of the human telomere DNA quadruplex.},
journal = {Biochimie},
volume = {118},
number = {},
pages = {15-25},
doi = {10.1016/j.biochi.2015.07.013},
pmid = {26188111},
issn = {1638-6183},
mesh = {Circular Dichroism ; DNA Damage/*genetics ; *G-Quadruplexes ; Humans ; *Models, Molecular ; *Nucleic Acid Conformation ; Telomere/*chemistry/genetics ; },
abstract = {Various base lesions continuously form in cellular nucleic acids and the unrepaired lesions are promutagenic and procarcinogenic. Though natural base lesions have been extensively studied in double-stranded DNA models, these studies are only less than a decade old for non-canonical DNA models, such as quadruplexes. Here we present a report on the effects of three frequently occurring natural lesions that can form in the TTA loops on the structure of the human telomere quadruplex d[AG3(TTAG3)3]. We compared the effect of the abasic site and 8-oxoadenine replacing adenine and 5-hydroxymethyluracil substituting for thymine. The results showed that the three lesions impacted the stability and quadruplex folding in markedly different ways. The effects depended on the type of lesion and the position in the sequence. Analogous lesions of guanine in the G-tetrads extensively destabilized the quadruplex and the effects depended more on the position than on the type of lesion. The distinct effects of the loop substitutions as well as comparison of the modifications of the loops and the quadruplex tetrads are discussed in this communication.},
}
@article {pmid26185173,
year = {2015},
author = {Dahlström, J and Zhang, X and Ghaderi, M and Hultcrantz, M and Björkholm, M and Xu, D},
title = {Dysregulation of shelterin factors coupled with telomere shortening in Philadelphia chromosome negative myeloproliferative neoplasms.},
journal = {Haematologica},
volume = {100},
number = {10},
pages = {e402-5},
pmid = {26185173},
issn = {1592-8721},
mesh = {*Gene Expression Regulation, Neoplastic ; Humans ; Myeloproliferative Disorders/*genetics ; *Philadelphia Chromosome ; Shelterin Complex ; *Telomere Shortening ; Telomere-Binding Proteins/*genetics/metabolism ; },
}
@article {pmid26178721,
year = {2015},
author = {de Rooij, SR and van Pelt, AM and Ozanne, SE and Korver, CM and van Daalen, SK and Painter, RC and Schwab, M and Viegas, MH and Roseboom, TJ},
title = {Prenatal undernutrition and leukocyte telomere length in late adulthood: the Dutch famine birth cohort study.},
journal = {The American journal of clinical nutrition},
volume = {102},
number = {3},
pages = {655-660},
doi = {10.3945/ajcn.115.112326},
pmid = {26178721},
issn = {1938-3207},
support = {FS/09/029/27902/BHF_/British Heart Foundation/United Kingdom ; MC_UU_12012/4/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aged ; Cohort Studies ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes/*metabolism ; Linear Models ; Logistic Models ; Male ; Malnutrition/*blood/etiology ; *Maternal Nutritional Physiological Phenomena ; Netherlands ; Pregnancy ; Prenatal Exposure Delayed Effects/*genetics ; Socioeconomic Factors ; Starvation/*blood/complications ; Telomere/*genetics ; },
abstract = {BACKGROUND: Energy restriction in prenatal life has detrimental effects on later life health and longevity. Studies in rats have shown that the shortening of telomeres in key tissues plays an important role in this association.<br><br>OBJECTIVE: The aim of the current study was to investigate leukocyte telomere length in relation to prenatal famine exposure.<br><br>DESIGN: The Dutch famine birth cohort consists of 2414 term singleton men and women who were born between 1943 and 1947 in Amsterdam around the time of the famine. At a mean age of 68 y, telomere length and the percentage of short telomeres was assessed in a subsample of 131 cohort members, of whom 45 were born before the famine (control), 41 were exposed to famine during early gestation, and 45 were conceived after the famine (control). Median telomere length was determined in peripheral blood leukocytes by a high-throughput quantitative fluorescent in situ hybridization-based technology.<br><br>RESULTS: Leukocyte telomere length and the percentage of short telomeres did not differ between those exposed to famine during early gestation and those unexposed during gestation. A lower socioeconomic status at birth, frequent consumption of alcohol (specifically consumption of spirits), a history of cancer, and a lower self-reported health status were significantly associated with shorter leukocyte telomere length (all P &#x2264; 0.03). Currently having a job was significantly associated with a smaller percentage of short telomeres (P = 0.04).<br><br>CONCLUSION: The results of the current study suggest that prenatal exposure to famine is not associated with the shortening of telomeres in peripheral blood leukocytes at age 68 y.},
}
@article {pmid26177192,
year = {2015},
author = {Zhang, C and Chen, X and Li, L and Zhou, Y and Wang, C and Hou, S},
title = {The Association between Telomere Length and Cancer Prognosis: Evidence from a Meta-Analysis.},
journal = {PloS one},
volume = {10},
number = {7},
pages = {e0133174},
pmid = {26177192},
issn = {1932-6203},
mesh = {Disease Progression ; Humans ; Neoplasms/*diagnosis/pathology ; Prognosis ; Publication Bias ; Survival Analysis ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Telomeres are essential for chromosomal integrity and stability. Shortened telomere length (TL) has been associated with risk of cancers and aging-related diseases. Several studies have explored associations between TL and cancer prognosis, but the results are conflicting.<br><br>METHODS: Prospective studies on the relationship between TL and cancer survival were identified by a search of PubMed up to May 25, 2015. There were no restrictions on the cancer type or DNA source. The quality of the included studies was assessed using the Newcastle-Ottawa Scale. Meta-analysis approaches were conducted to determine pooled relative risks and 95% confidence intervals.<br><br>RESULTS: Thirty-three articles containing forty-five independent studies were ultimately involved in our meta-analysis, of which twenty-seven were about overall cancer survival and eighteen were about cancer progression. Short TL was associated with increased cancer mortality risk (RR = 1.30, 95%CI: 1.06-1.59) and poor cancer progression (RR = 1.44, 95%CI: 1.10-1.88), both with high levels of heterogeneity (I2 = 83.5%, P = 0.012for overall survival and I2 = 75.4%, P = 0.008 for progression). TL was an independent predictor of overall cancer survival and progression in chronic lymphocytic leukemia. Besides, short telomeres were also associated with increased colorectal cancer mortality and decreased overall survival of esophageal cancer, but not in other cancers. Cancer progression was associated with TL in Asian and America populations and short TL predicted poor cancer survival in older populations. Compared with tumor tissue cells, TL in blood lymphocyte cells was better for prediction. In addition, the associations remained significant when restricted to studies with adjustments for age, with larger sample sizes, measuring TL using southern blotting or estimating risk effects by hazard ratios.<br><br>CONCLUSION: Short TL demonstrated a significant association with poor cancer survival, suggesting the potential prognostic significance of TL. Additional large well-designed studies are needed to confirm our findings.},
}
@article {pmid26174679,
year = {2015},
author = {Speck-Hernández, CA and Ojeda, DA and Castro-Vega, LJ and Forero, DA},
title = {Relative telomere length is associated with a functional polymorphism in the monoamine oxidase A gene in a South American sample.},
journal = {Journal of genetics},
volume = {94},
number = {2},
pages = {305-308},
pmid = {26174679},
issn = {0973-7731},
mesh = {Adolescent ; Adult ; Female ; *Genetic Association Studies ; Humans ; Male ; Minisatellite Repeats/genetics ; Monoamine Oxidase/*genetics ; *Polymorphism, Genetic/genetics ; South America ; Telomere Homeostasis/*genetics ; Young Adult ; },
}
@article {pmid26169243,
year = {2015},
author = {Ma, L and Li, Y and Wang, J},
title = {Telomeres and essential hypertension.},
journal = {Clinical biochemistry},
volume = {48},
number = {16-17},
pages = {1195-1199},
doi = {10.1016/j.clinbiochem.2015.07.013},
pmid = {26169243},
issn = {1873-2933},
mesh = {Animals ; Essential Hypertension ; Humans ; Hypertension/*metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {OBJECTIVES: This review aims to clarify the relationship between telomeres and essential hypertension.<br><br>DESIGN AND METHODS: A PubMed search and a critical review were performed relating to studies about the clinical and biological relevance of telomeres in essential hypertension.<br><br>RESULTS: Telomeres and telomerase activity play an important role in the occurrence and development of hypertension in both animal and human studies.<br><br>CONCLUSIONS: A more complete understanding of the molecular mechanisms underlying the development of hypertension could reduce the incidence of hypertension-related diseases.},
}
@article {pmid26168240,
year = {2015},
author = {Narayanan, S and Dubarry, M and Lawless, C and Banks, AP and Wilkinson, DJ and Whitehall, SK and Lydall, D},
title = {Quantitative Fitness Analysis Identifies exo1∆ and Other Suppressors or Enhancers of Telomere Defects in Schizosaccharomyces pombe.},
journal = {PloS one},
volume = {10},
number = {7},
pages = {e0132240},
pmid = {26168240},
issn = {1932-6203},
support = {13314/CRUK_/Cancer Research UK/United Kingdom ; BB/F023545/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MR/L001284/1/MRC_/Medical Research Council/United Kingdom ; C23629/A13314//Cancer Research UK/United Kingdom ; },
mesh = {Enhancer Elements, Genetic/physiology ; Gene Deletion ; Genes, Suppressor/physiology ; Genetic Fitness/*physiology ; Mutation ; Oligonucleotide Array Sequence Analysis ; Regulatory Sequences, Nucleic Acid/physiology ; Schizosaccharomyces/*genetics/physiology ; Telomere/*genetics/physiology ; },
abstract = {Synthetic genetic array (SGA) has been successfully used to identify genetic interactions in S. cerevisiae and S. pombe. In S. pombe, SGA methods use either cycloheximide (C) or heat shock (HS) to select double mutants before measuring colony size as a surrogate for fitness. Quantitative Fitness Analysis (QFA) is a different method for determining fitness of microbial strains. In QFA, liquid cultures are spotted onto solid agar and growth curves determined for each spot by photography and model fitting. Here, we compared the two S. pombe SGA methods and found that the HS method was more reproducible for us. We also developed a QFA procedure for S. pombe. We used QFA to identify genetic interactions affecting two temperature sensitive, telomere associated query mutations (taz1Δ and pot1-1). We identify exo1∆ and other gene deletions as suppressors or enhancers of S. pombe telomere defects. Our study identifies known and novel gene deletions affecting the fitness of strains with telomere defects. The interactions we identify may be relevant in human cells.},
}
@article {pmid26163216,
year = {2015},
author = {Beletsky, AV and Malyavko, AN and Sukhanova, MV and Mardanova, ES and Zvereva, ME and Mardanov, AV and Dontsova, OA and Lavrik, OI and Ravin, NV},
title = {Expression of genes involved in DNA repair and telomere maintenance in the yeast Hansenula polymorpha DL1 under heat stress.},
journal = {Doklady. Biochemistry and biophysics},
volume = {462},
number = {},
pages = {185-188},
pmid = {26163216},
issn = {1608-3091},
mesh = {DNA Repair/*genetics ; Genome, Fungal/genetics ; Genomics ; Heat-Shock Response/*genetics ; Pichia/*genetics/*physiology ; Telomere/*genetics ; Transcription, Genetic ; Transcriptome/*genetics/*physiology ; },
}
@article {pmid26160350,
year = {2015},
author = {Shen, ZJ and Hsu, PH and Su, YT and Yang, CW and Kao, L and Tseng, SF and Tsai, MD and Teng, SC},
title = {Corrigendum: PP2A and Aurora differentially modify Cdc13 to promote telomerase release from telomeres at G2/M phase.},
journal = {Nature communications},
volume = {6},
number = {},
pages = {7819},
doi = {10.1038/ncomms8819},
pmid = {26160350},
issn = {2041-1723},
}
@article {pmid26158642,
year = {2015},
author = {Gorgy, AI and Jonassaint, NL and Stanley, SE and Koteish, A and DeZern, AE and Walter, JE and Sopha, SC and Hamilton, JP and Hoover-Fong, J and Chen, AR and Anders, RA and Kamel, IR and Armanios, M},
title = {Hepatopulmonary syndrome is a frequent cause of dyspnea in the short telomere disorders.},
journal = {Chest},
volume = {148},
number = {4},
pages = {1019-1026},
pmid = {26158642},
issn = {1931-3543},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; R01 CA160433/CA/NCI NIH HHS/United States ; R01 HL119476/HL/NHLBI NIH HHS/United States ; T32 GM007309/GM/NIGMS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Dyspnea/*etiology/genetics/metabolism ; Female ; Hepatopulmonary Syndrome/complications/*genetics/metabolism ; Heterozygote ; Humans ; Male ; Middle Aged ; *Mutation ; Retrospective Studies ; Telomerase/genetics ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Telomere syndromes have their most common manifestation in idiopathic pulmonary fibrosis and emphysema. The short telomere defect in these patients may manifest systemically as bone marrow failure and liver disease. We sought to understand the causes of dyspnea in telomerase and telomere gene mutation carriers who have no parenchymal lung disease.<br><br>METHODS: Clinical and pathologic data were reviewed as part of a Johns Hopkins-based natural history study of short telomere syndromes including dyskeratosis congenita.<br><br>RESULTS: Hepatopulmonary syndrome (HPS) was diagnosed in nine of 42 cases (21%). Their age at presentation was significantly younger than that of cases initially presenting with pulmonary fibrosis and emphysema (median, 25 years vs 55 years; P < .001). Cases had evidence of intra- and extrapulmonary arteriovascular malformations that caused shunt physiology. Nodular regenerative hyperplasia was the most frequent histopathologic abnormality, and it was seen in the absence of cirrhosis. Dyspnea and portal hypertension were progressive, and the median time to death or liver transplantation was 6 years (range, 4-10 years; n = 6). In cases that underwent liver transplantation, dyspnea and hypoxia improved, but pulmonary fibrosis subsequently developed.<br><br>CONCLUSIONS: This report identifies HPS as a frequent cause of dyspnea in telomerase and telomere gene mutation carriers. While it usually precedes the development of parenchymal lung disease, HPS may also co-occur with pulmonary fibrosis and emphysema. Recognizing this genetic diagnosis is critical for management, especially in the lung and liver transplantation setting.},
}
@article {pmid26158306,
year = {2015},
author = {Arora, R and Azzalin, CM},
title = {Telomere elongation chooses TERRA ALTernatives.},
journal = {RNA biology},
volume = {12},
number = {9},
pages = {938-941},
pmid = {26158306},
issn = {1555-8584},
mesh = {Homologous Recombination ; Humans ; Models, Biological ; Protein Binding ; RNA, Long Noncoding/*genetics/metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/metabolism ; Transcription, Genetic ; },
abstract = {Alternative Lengthening of Telomeres (ALT) mechanisms allow telomerase-negative immortal cells to buffer replicative telomere shortening. ALT is naturally active in a number of human cancers and might be selected upon telomerase inactivation. ALT is thought to operate through homologous recombination (HR) occurring between telomeric repeats from independent chromosome ends. Indeed, suppression of a number of HR factors impairs ALT cell proliferation. Yet, how HR is initiated at ALT telomeres remains elusive. Mounting evidence suggests that the long noncoding telomeric RNA TERRA renders ALT telomeres recombinogenic by forming RNA:DNA hybrids with the telomeric C-rich strand. TERRA and telomeric hybrids act in concert with a number of other factors, including the RNA endoribonuclease RNaseH1 and the single stranded DNA binding protein RPA. The functional interaction network built upon these different players seems indispensable for ALT telomere maintenance, and digging into the molecular details of this previously unappreciated network might open the way to novel avenues for cancer treatments.},
}
@article {pmid26153476,
year = {2015},
author = {Loprinzi, PD},
title = {Cardiorespiratory Capacity and Leukocyte Telomere Length Among Adults in the United States.},
journal = {American journal of epidemiology},
volume = {182},
number = {3},
pages = {198-201},
doi = {10.1093/aje/kwv056},
pmid = {26153476},
issn = {1476-6256},
mesh = {Adult ; Aging/*physiology ; Confidence Intervals ; Exercise Test ; Female ; Heart Function Tests ; Humans ; Leukocytes/*cytology/*physiology ; Linear Models ; Male ; Physical Fitness/*physiology ; Telomere/classification ; Telomere Homeostasis/*physiology ; Total Lung Capacity ; United States ; },
abstract = {Short leukocyte telomere length (LTL) has become a hallmark characteristic of aging and is associated with higher morbidity and mortality. Physical activity (PA) has been implicated in attenuating age-induced diseases by, for example, preserving LTL. Results from studies of the relationship between PA and LTL have been mixed, which might be because PA was assessed over a short period of time. There have been few studies in which investigators have examined the association between LTL and cardiorespiratory fitness (CRF), an enduring trait influenced by chronic habituation of PA that takes place over months or years. The purpose of the present study was to examine the association between CRF and LTL in a national sample of US adults who were 20-49 years of age from the 1999-2002 National Health and Nutrition Examination Survey (n = 1,764). LTL was assessed using quantitative polymerase chain reaction, and CRF assessed using a treadmill-based exercise test. After adjustments, compared with subjects in the lowest CRF tertile, those in the middle tertile (β = 0.03, 95% confidence interval: 0.005, 0.06; P = 0.02) and upper tertile (β = 0.05, 95% confidence interval: 0.004, 0.09; P = 0.04) had longer LTL. These findings suggest that higher CRF is associated with longer LTL.},
}
@article {pmid26150720,
year = {2015},
author = {Pawelczyk, T and Szymanska, B and Grancow-Grabka, M and Kotlicka-Antczak, M and Pawelczyk, A},
title = {Telomere length in blood cells is related to the chronicity, severity, and recurrence rate of schizophrenia.},
journal = {Neuropsychiatric disease and treatment},
volume = {11},
number = {},
pages = {1493-1503},
pmid = {26150720},
issn = {1176-6328},
abstract = {INTRODUCTION: Telomere shortening is strongly associated with higher mortality rates and has been shown in a number of age-related diseases, such as cardiovascular disorders, diabetes mellitus, Alzheimer's disease, and psychiatric disorders. Oxidative stress is known to induce DNA breaks and genome instability. Telomeric DNA rich in guanosine is particularly sensitive to such oxidative damages. Psychosis is associated with a disequilibrium between free radical production and antioxidative defense. Although telomere attrition has been demonstrated in schizophrenia, no relationship has been reported between telomere length and severity of schizophrenia.<br><br>AIM: The aim of the present study was to identify differences in telomere length in peripheral blood cells between patients with chronic schizophrenia (C-SCZ) and early schizophrenia (E-SCZ) and to identify any relationship between telomere length and disease chronicity and severity.<br><br>METHODS: Relative average telomere lengths were determined using qPCR assay in patients with E-SCZ (n=42) and C-SCZ (n=44) hospitalized due to schizophrenia exacerbation. E-SCZ was diagnosed when less than 2 years had passed since the beginning of psychotic symptoms. The severity of symptoms was assessed using appropriate scales.<br><br>RESULTS: The severity of schizophrenia symptoms, as well as the number of psychotic episodes and hospital admissions, correlated significantly with telomere length in univariate analyses. Regression analysis revealed that a model incorporating study group (E-SCZ or C-ECZ), sex, and age, as well as the combined number of documented psychotic episodes and hospital admissions, can significantly predict the length of telomeres in patients with schizophrenia, with over 50% of variance in telomere length explained by the model (adjusted R (2)=0.512).<br><br>CONCLUSION: The results of the current study indicate that the recurrence of psychotic symptoms as well as their intensity and chronicity may be correlated with telomere attrition, which is well known to contribute to the development of premature senescence and age-related diseases.},
}
@article {pmid26149682,
year = {2015},
author = {Raschenberger, J and Kollerits, B and Ritchie, J and Lane, B and Kalra, PA and Ritz, E and Kronenberg, F},
title = {Association of relative telomere length with progression of chronic kidney disease in two cohorts: effect modification by smoking and diabetes.},
journal = {Scientific reports},
volume = {5},
number = {},
pages = {11887},
pmid = {26149682},
issn = {2045-2322},
mesh = {Aged ; Cohort Studies ; Creatinine/blood ; Demography ; Diabetes Mellitus, Type 2/*complications ; Disease Progression ; Female ; Follow-Up Studies ; Glomerular Filtration Rate ; Humans ; Male ; Middle Aged ; Proportional Hazards Models ; Prospective Studies ; Proteinuria/etiology ; Renal Insufficiency, Chronic/complications/*pathology ; Risk Factors ; *Smoking ; Telomere/*metabolism ; },
abstract = {Chronic kidney disease (CKD) is a highly progressive disease. We studied the association between relative telomere length (RTL) and CKD progression and tested whether this association is modified by smoking and diabetes mellitus. RTL was measured by qPCR in two prospective cohort studies, the MMKD-Study (n = 166) and the CRISIS-Study (n = 889) with a median follow-up of 4.5 and 2.8 years, respectively. Progression was defined as doubling of baseline serum creatinine (MMKD-Study) and/or end stage renal disease (both studies). 59 and 105 of the patients from MMKD and CRISIS experienced a progression of CKD. Mean standardized pooled RTL was 0.74 ± 0.29. In the meta-analysis shorter RTL at baseline showed a borderline association with CKD progression (HR = 1.07 [95%CI 1.00-1.15]; p = 0.06). We observed an effect modification of RTL and CKD progression by smoking and diabetes (p-values of interaction p = 0.02 and p = 0.09, respectively). Each 0.1 unit shorter RTL was significantly associated with an increased hazard for CKD progression in active-smokers by 44% (HR = 1.44 [1.16-1.81]; p = 0.001) and in patients with diabetes mellitus by 16% (HR = 1.16 [1.01-1.34]; p = 0.03). Estimates were adjusted for baseline age, sex, proteinuria and GFR. This study in two independent cohorts reinforces that RTL is a marker and potentially a pathogenetic factor for CKD progression.},
}
@article {pmid26146081,
year = {2015},
author = {Povedano, JM and Martinez, P and Flores, JM and Mulero, F and Blasco, MA},
title = {Mice with Pulmonary Fibrosis Driven by Telomere Dysfunction.},
journal = {Cell reports},
volume = {12},
number = {2},
pages = {286-299},
doi = {10.1016/j.celrep.2015.06.028},
pmid = {26146081},
issn = {2211-1247},
mesh = {Animals ; Bleomycin/toxicity ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; DNA Damage/drug effects ; DNA Repair/drug effects ; Disease Models, Animal ; Female ; Idiopathic Pulmonary Fibrosis/metabolism/*pathology ; Lung/diagnostic imaging/metabolism/*pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Radiography ; Tamoxifen/pharmacology ; Telomerase/deficiency/genetics ; Telomere/*metabolism ; Telomere Shortening ; Telomeric Repeat Binding Protein 1/deficiency/genetics/metabolism ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Idiopathic pulmonary fibrosis (IPF) is a degenerative disease of the lungs with an average survival post-diagnosis of 2-3 years. New therapeutic targets and treatments are necessary. Mutations in components of the telomere-maintenance enzyme telomerase or in proteins important for telomere protection are found in both familial and sporadic IPF cases. However, the lack of mouse models that faithfully recapitulate the human disease has hampered new advances. Here, we generate two independent mouse models that develop IPF owing to either critically short telomeres (telomerase-deficient mice) or severe telomere dysfunction in the absence of telomere shortening (mice with Trf1 deletion in type II alveolar cells). We show that both mouse models develop pulmonary fibrosis through induction of telomere damage, thus providing proof of principle of the causal role of DNA damage stemming from dysfunctional telomeres in IPF development and identifying telomeres as promising targets for new treatments.},
}
@article {pmid26143912,
year = {2015},
author = {Clynes, D and Jelinska, C and Xella, B and Ayyub, H and Scott, C and Mitson, M and Taylor, S and Higgs, DR and Gibbons, RJ},
title = {Suppression of the alternative lengthening of telomere pathway by the chromatin remodelling factor ATRX.},
journal = {Nature communications},
volume = {6},
number = {},
pages = {7538},
pmid = {26143912},
issn = {2041-1723},
support = {MC_U137961147/MRC_/Medical Research Council/United Kingdom ; MC_UU_12009/3/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Cell Line, Tumor ; Cells ; Chromatin Assembly and Disassembly/*physiology ; DNA Helicases/genetics/*metabolism ; DNA Replication ; Humans ; Nuclear Proteins/genetics/*metabolism ; Telomere/metabolism ; Telomere Homeostasis/*physiology ; X-linked Nuclear Protein ; },
abstract = {Fifteen per cent of cancers maintain telomere length independently of telomerase by the homologous recombination (HR)-associated alternative lengthening of telomeres (ALT) pathway. A unifying feature of these tumours are mutations in ATRX. Here we show that expression of ectopic ATRX triggers a suppression of the pathway and telomere shortening. Importantly ATRX-mediated ALT suppression is dependent on the histone chaperone DAXX. Re-expression of ATRX is associated with a reduction in replication fork stalling, a known trigger for HR and loss of MRN from telomeres. A G-quadruplex stabilizer partially reverses the effect of ATRX, inferring ATRX may normally facilitate replication through these sequences that, if they persist, promote ALT. We propose that defective telomere chromatinization through loss of ATRX promotes the persistence of aberrant DNA secondary structures, which in turn present a barrier to DNA replication, leading to replication fork stalling, collapse, HR and subsequent recombination-mediated telomere synthesis in ALT cancers.},
}
@article {pmid26138067,
year = {2015},
author = {Zhang, C and Doherty, JA and Burgess, S and Hung, RJ and Lindström, S and Kraft, P and Gong, J and Amos, CI and Sellers, TA and Monteiro, AN and Chenevix-Trench, G and Bickeböller, H and Risch, A and Brennan, P and Mckay, JD and Houlston, RS and Landi, MT and Timofeeva, MN and Wang, Y and Heinrich, J and Kote-Jarai, Z and Eeles, RA and Muir, K and Wiklund, F and Grönberg, H and Berndt, SI and Chanock, SJ and Schumacher, F and Haiman, CA and Henderson, BE and Amin Al Olama, A and Andrulis, IL and Hopper, JL and Chang-Claude, J and John, EM and Malone, KE and Gammon, MD and Ursin, G and Whittemore, AS and Hunter, DJ and Gruber, SB and Knight, JA and Hou, L and Le Marchand, L and Newcomb, PA and Hudson, TJ and Chan, AT and Li, L and Woods, MO and Ahsan, H and Pierce, BL and , },
title = {Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study.},
journal = {Human molecular genetics},
volume = {24},
number = {18},
pages = {5356-5366},
pmid = {26138067},
issn = {1460-2083},
support = {R01 CA059045/CA/NCI NIH HHS/United States ; MR/L003120/1/MRC_/Medical Research Council/United Kingdom ; P30 CA015704/CA/NCI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; T32AG000243/AG/NIA NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; U01 CA164930/CA/NCI NIH HHS/United States ; R01ES020506/ES/NIEHS NIH HHS/United States ; R01 ES020506/ES/NIEHS NIH HHS/United States ; P30 CA060553/CA/NCI NIH HHS/United States ; U19 CA148065/CA/NCI NIH HHS/United States ; RG/08/014/24067/BHF_/British Heart Foundation/United Kingdom ; UM1 CA167551/CA/NCI NIH HHS/United States ; R01 CA151989/CA/NCI NIH HHS/United States ; U19 CA148537/CA/NCI NIH HHS/United States ; T32 AG000243/AG/NIA NIH HHS/United States ; U01 HG007601/HG/NHGRI NIH HHS/United States ; UL1 TR000430/TR/NCATS NIH HHS/United States ; P30AG012857/AG/NIA NIH HHS/United States ; R35 CA197449/CA/NCI NIH HHS/United States ; 100114/WT_/Wellcome Trust/United Kingdom ; U19 CA148112/CA/NCI NIH HHS/United States ; P30 CA023108/CA/NCI NIH HHS/United States ; 17528/CRUK_/Cancer Research UK/United Kingdom ; U01 CA164973/CA/NCI NIH HHS/United States ; U19 CA148127/CA/NCI NIH HHS/United States ; 15007/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Adult ; Aged ; Case-Control Studies ; Female ; Genetic Association Studies ; *Genetic Predisposition to Disease ; Genetic Variation ; Humans ; Male ; *Mendelian Randomization Analysis ; Middle Aged ; Neoplasms/*epidemiology/*genetics ; Odds Ratio ; Polymorphism, Single Nucleotide ; Risk ; Telomere Homeostasis/*genetics ; },
abstract = {Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.},
}
@article {pmid26137248,
year = {2015},
author = {Lei, H and Zhou, FX and Xu, H and Peng, XH and Zhang, ZG and Wang, WB and Yu, HJ and Xie, CH and Zhou, YF},
title = {Expression of various protection of telomeres 1 variants is associated with telomere length and radiosensitivity in colon and gastric adenocarcinoma cells in vitro.},
journal = {Biomedical reports},
volume = {3},
number = {3},
pages = {420-424},
pmid = {26137248},
issn = {2049-9434},
abstract = {Protection of telomeres 1 (POT1) is a telomere-binding protein, which binds to the single-stranded DNA extensions of telomeres and regulates telomere length. Different POT1 mRNA variants were examined and compared with telomere length and radiosensitivity in colon and gastric adenocarcinoma cells. POT1 production and telomere lengths were assessed using 10 human cancer cell lines by quantitative polymerase chain reaction (qPCR). POT1 mRNA levels, which were relatively stable, were significantly correlated with telomere length in gastric cancer cells and colon cancer cells, except for HT29 (P<0.01). POT1 v5 indexes were closely associated with radiosensitivity in colon cancer cells and gastric cancer cells (P<0.05). In conclusion, POT1 may be a good marker for the examination of cell-specific telomere length and radiosensitivity.},
}
@article {pmid26135248,
year = {2016},
author = {Hartmann, K and Illing, A and Leithäuser, F and Baisantry, A and Quintanilla-Martinez, L and Rudolph, KL},
title = {Gene dosage reductions of Trf1 and/or Tin2 induce telomere DNA damage and lymphoma formation in aging mice.},
journal = {Leukemia},
volume = {30},
number = {3},
pages = {749-753},
pmid = {26135248},
issn = {1476-5551},
mesh = {Aging/*genetics/metabolism ; Animals ; Bone Marrow/metabolism/pathology ; DNA Damage ; Disease Models, Animal ; *Gene Dosage ; *Gene Expression Regulation, Neoplastic ; Heterozygote ; Humans ; Lymphoma/*genetics/metabolism/pathology ; Metaphase ; Mice ; Signal Transduction ; Survival Analysis ; Telomere/chemistry ; *Telomere Shortening ; Telomere-Binding Proteins/deficiency/*genetics ; Telomeric Repeat Binding Protein 1/deficiency/*genetics ; },
}
@article {pmid26134037,
year = {2015},
author = {Phillippe, M},
title = {Cell-Free Fetal DNA, Telomeres, and the Spontaneous Onset of Parturition.},
journal = {Reproductive sciences (Thousand Oaks, Calif.)},
volume = {22},
number = {10},
pages = {1186-1201},
doi = {10.1177/1933719115592714},
pmid = {26134037},
issn = {1933-7205},
mesh = {Animals ; *Apoptosis ; DNA/*genetics/immunology/metabolism ; Extraembryonic Membranes/immunology/*metabolism/pathology ; Female ; Humans ; Inflammation/genetics/metabolism ; Inflammation Mediators/metabolism ; Interleukin-10/metabolism ; Labor Onset/*genetics/immunology ; Parturition/*genetics/immunology ; Placenta/immunology/*metabolism/pathology ; Pregnancy ; Signal Transduction ; Telomere/*genetics/immunology/metabolism ; Toll-Like Receptor 9/metabolism ; },
abstract = {Multiple previous reports have provided compelling support for the premise that spontaneous parturition is mediated by activation of inflammation-related signaling pathways leading to increased secretion of cytokines and chemokines, the influx of neutrophils and macrophages into the pregnant uterus, increased production of uterine activation proteins (eg, connexin-43, cyclo-oxygenase-2, oxytocin receptors, etc), activation of matrix metalloproteinases, and the release of uterotonins leading to cervical ripening, membrane rupture, and myometrial contractions. The missing link has been the fetal/placental signal that triggers these proinflammatory events in the absence of microbial invasion and intrauterine infection. This article reviews the biomedical literature regarding the increase in cell-free fetal DNA (cffDNA), which is released during apoptosis in the placenta and fetal membranes at term, the ability of apoptosis modified vertebrate DNA to stimulate toll-like receptor-9 (TLR9) leading to increased release of cytokines and chemokines, and the potential "fail-safe" role for the anti-inflammatory cytokine IL-10. This article also reviews the literature supporting the key role that telomere loss plays in regard to increasing the ability of vertebrate (including placental) DNA to stimulate TLR9, and in regard to signaling the onset of apoptosis in the placenta and fetal membranes, thereby providing a biologic clock that determines the length of gestation and the timing for the onset of parturition. In summary, this literature review provides a strong rationale for future research to test the hypothesis that telomere loss and increased cffDNA levels trigger the proinflammatory events leading to the spontaneous onset of parturition in mammals: the "cffDNA/telomere hypothesis."},
}
@article {pmid26133370,
year = {2015},
author = {Raval, A and Behbehani, GK and Nguyen, le XT and Thomas, D and Kusler, B and Garbuzov, A and Ramunas, J and Holbrook, C and Park, CY and Blau, H and Nolan, GP and Artandi, SE and Mitchell, BS},
title = {Reversibility of Defective Hematopoiesis Caused by Telomere Shortening in Telomerase Knockout Mice.},
journal = {PloS one},
volume = {10},
number = {7},
pages = {e0131722},
pmid = {26133370},
issn = {1932-6203},
support = {U01 HL100397/HL/NHLBI NIH HHS/United States ; R01 CA130826/CA/NCI NIH HHS/United States ; U01 HL099997/HL/NHLBI NIH HHS/United States ; PN2 EY018228/EY/NEI NIH HHS/United States ; P01 CA034233/CA/NCI NIH HHS/United States ; U19 AI057229/AI/NIAID NIH HHS/United States ; R21 AG044815/AG/NIA NIH HHS/United States ; R35 CA197563/CA/NCI NIH HHS/United States ; HHSN272200700038C/AI/NIAID NIH HHS/United States ; R01 AR063963/AR/NIAMS NIH HHS/United States ; },
mesh = {Anemia, Aplastic/genetics/metabolism ; Animals ; Cell Proliferation/genetics ; DNA Damage ; Erythroid Precursor Cells/*metabolism ; Hematopoiesis/*genetics ; Mice ; Mice, Knockout ; Telomerase/genetics/*metabolism ; *Telomere ; Telomere Shortening/*genetics ; },
abstract = {Telomere shortening is common in bone marrow failure syndromes such as dyskeratosis congenita (DC), aplastic anemia (AA) and myelodysplastic syndromes (MDS). However, improved knowledge of the lineage-specific consequences of telomere erosion and restoration of telomere length in hematopoietic progenitors is required to advance therapeutic approaches. We have employed a reversible murine model of telomerase deficiency to compare the dependence of erythroid and myeloid lineage differentiation on telomerase activity. Fifth generation Tert-/- (G5 Tert-/-) mice with shortened telomeres have significant anemia, decreased erythroblasts and reduced hematopoietic stem cell (HSC) populations associated with neutrophilia and increased myelopoiesis. Intracellular multiparameter analysis by mass cytometry showed significantly reduced cell proliferation and increased sensitivity to activation of DNA damage checkpoints in erythroid progenitors and in erythroid-biased CD150hi HSC, but not in myeloid progenitors. Strikingly, Cre-inducible reactivation of telomerase activity restored hematopoietic stem and progenitor cell (HSPC) proliferation, normalized the DNA damage response, and improved red cell production and hemoglobin levels. These data establish a direct link between the loss of TERT activity, telomere shortening and defective erythropoiesis and suggest that novel strategies to restore telomerase function may have an important role in the treatment of the resulting anemia.},
}
@article {pmid26133009,
year = {2015},
author = {Révész, D and Milaneschi, Y and Verhoeven, JE and Lin, J and Penninx, BW},
title = {Longitudinal Associations Between Metabolic Syndrome Components and Telomere Shortening.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {100},
number = {8},
pages = {3050-3059},
doi = {10.1210/JC.2015-1995},
pmid = {26133009},
issn = {1945-7197},
mesh = {Adolescent ; Adult ; Aged ; Female ; Humans ; Longitudinal Studies ; Male ; Metabolic Syndrome/epidemiology/etiology/*genetics ; Middle Aged ; Netherlands/epidemiology ; Risk Factors ; Telomere Shortening/*physiology ; Young Adult ; },
abstract = {CONTEXT: Deterioration of metabolic syndrome (MetS) has been associated with short telomere length (TL). Large-scale longitudinal studies with repeated measures of MetS and TL are lacking.<br><br>OBJECTIVES: We examined whether baseline MetS components predict TL over time, and whether deteriorations in MetS parallel telomere attrition.<br><br>DESIGN AND SETTING: Participants were part of The Netherlands Study of Depression and Anxiety, an ongoing prospective cohort study.<br><br>PARTICIPANTS: This study included 1808 participants age 18-65 years.<br><br>MAIN OUTCOME MEASURES: Leukocyte TL (using qPCR) and MetS components (waist circumference, triglycerides, high-density lipoprotein [HDL] cholesterol, systolic blood pressure, and fasting glucose) were determined at baseline and after 6 years. Generalized estimated equation models were used to examine the associations between baseline MetS and TL over time, and linear regressions were used to associate 6-year changes in both MetS components and TL, while adjusting for sociodemographic and lifestyle factors.<br><br>RESULTS: Higher baseline waist circumference (B = -29.7; P = .006) and glucose (B = -26.4; P = .02), and lower HDL (B = 25.5; P = .03) were consistently associated with shorter TL over followup. Greater 6-year increase in waist circumference was associated with larger telomere attrition (B = -41.8; P = .01), and similar but nonsignificant associations were observed for larger increase in triglycerides and glucose levels.<br><br>CONCLUSIONS: Metabolic dysregulations are associated with shorter telomeres over two time points. In particular, increasing abdominal adiposity is accompanied by accelerated telomere attrition. Future studies should elucidate underlying mechanisms of this bidirectional relationship and investigate whether targeting obesity may reduce telomere attrition to prevent further deterioration toward cardiovascular and aging-related complications.},
}
@article {pmid26132175,
year = {2015},
author = {Cesare, AJ and Heaphy, CM and O'Sullivan, RJ},
title = {Visualization of Telomere Integrity and Function In Vitro and In Vivo Using Immunofluorescence Techniques.},
journal = {Current protocols in cytometry},
volume = {73},
number = {},
pages = {12.40.1-12.40.31},
pmid = {26132175},
issn = {1934-9300},
support = {P30 CA047904/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; Cell Adhesion ; Centrifugation ; Chromosomes ; DNA/metabolism ; Fluorescent Antibody Technique/*methods ; Humans ; In Situ Hybridization, Fluorescence ; Mitosis ; Sister Chromatid Exchange ; Telomere/*metabolism ; Tissue Banks ; },
abstract = {In cancer cells, telomere length maintenance occurs largely via the direct synthesis of TTAGGG repeats at chromosome ends by telomerase, or less frequently by the recombination-dependent alternative lengthening of telomeres (ALT) pathway. The latter is characterized by the atypical clustering of telomeres within promyelocytic leukemia (PML) nuclear bodies, which harbor proteins that are linked with DNA repair and recombination activity. For this reason, it is speculated that these associated PML bodies represent the sites of the recombination that maintains telomere length. The protocols described here can be employed for the routine investigation of the structural integrity of telomeres and the association of proteins at telomeres in normal cells, challenged cells, and archived formalin-fixed paraffin-embedded clinical tissue specimens that may have activated the ALT pathway.},
}
@article {pmid26131731,
year = {2015},
author = {Larrivée-Vanier, S and Magne, F and Patey, N and Chanoine, JP and Vuissoz, JM and Van Vliet, G and Deladoëy, J},
title = {Conserved Telomere Length in Human Ectopic Thyroids: An Argument Against Premature Differentiation Causing Arrested Migration.},
journal = {Thyroid : official journal of the American Thyroid Association},
volume = {25},
number = {9},
pages = {1050-1054},
pmid = {26131731},
issn = {1557-9077},
support = {130390-1//Canadian Institutes of Health Research/Canada ; CIHR-MOP-130390//Canadian Institutes of Health Research/Canada ; },
mesh = {Adolescent ; Cell Differentiation ; Cell Movement ; Child ; Female ; Humans ; Hypothyroidism/genetics ; Male ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/metabolism ; Telomere/*ultrastructure ; Thyroid Dysgenesis/*metabolism/pathology ; Thyroid Gland/abnormalities/*metabolism/pathology ; Thyroid Neoplasms/metabolism/pathology ; Thyrotropin/metabolism ; },
abstract = {BACKGROUND: In humans, the cause of arrested migration of the median thyroid anlage resulting in an ectopic sublingual gland is unknown. These ectopic glands have a normal follicular architecture but their thyrotropin-induced growth is insufficient, leading to congenital hypothyroidism in the vast majority of affected subjects. We hypothesized that arrested migration is due to premature differentiation [reflected by decreased telomere length (TL)], as observed in neural tube defects in mice.<br><br>METHODS: Absolute TL and telomerase reverse transcriptase (hTERT) expression was measured in four ectopic and six orthotopic thyroids. TL was measured by quantitative polymerase chain reaction of genomic DNA, whereas hTERT expression was measured by quantitative polymerase chain reaction of total RNA.<br><br>RESULTS: The mean&#xb1;standard deviation TL (in kilobases per diploid genome) was 140.45&#xb1;40.07 in ectopic and 97.50&#xb1;30.48 in orthotopic thyroids (p=0.12). Expression of hTERT was quiescent in both ectopic and orthotopic thyroids.<br><br>CONCLUSIONS: Compared with orthotopic thyroids, TL shortening is not observed in ectopic thyroid tissues and, consequently, no compensatory hTERT expression was measured. This makes premature differentiation an unlikely cause of arrested migration and it suggests, indirectly, that ectopic thyroids are not at higher risk of cancer than orthotopic thyroids.},
}
@article {pmid26119948,
year = {2015},
author = {Chambers, DC},
title = {In the end it's a replication problem: What measuring telomere length can tell us about idiopathic pulmonary fibrosis.},
journal = {Respirology (Carlton, Vic.)},
volume = {20},
number = {6},
pages = {855-856},
doi = {10.1111/resp.12580},
pmid = {26119948},
issn = {1440-1843},
mesh = {Humans ; Idiopathic Pulmonary Fibrosis/*etiology ; Telomere Homeostasis/*physiology ; },
}
@article {pmid26119943,
year = {2016},
author = {Marchesini, M and Matocci, R and Tasselli, L and Cambiaghi, V and Orleth, A and Furia, L and Marinelli, C and Lombardi, S and Sammarelli, G and Aversa, F and Minucci, S and Faretta, M and Pelicci, PG and Grignani, F},
title = {PML is required for telomere stability in non-neoplastic human cells.},
journal = {Oncogene},
volume = {35},
number = {14},
pages = {1811-1821},
pmid = {26119943},
issn = {1476-5594},
mesh = {Animals ; Carcinogenesis/genetics ; Cell Line ; Cell Proliferation/genetics ; Cellular Senescence/genetics ; Genomic Instability ; Humans ; Mice ; Nuclear Proteins/*genetics ; Oncogene Proteins, Fusion/*genetics ; Promyelocytic Leukemia Protein ; Receptors, Retinoic Acid/*genetics ; Retinoic Acid Receptor alpha ; T-Lymphocytes/pathology ; Telomerase/genetics ; Telomere/*genetics ; Transcription Factors/*genetics ; Tumor Suppressor Proteins/*genetics ; },
abstract = {Telomeres interact with numerous proteins, including components of the shelterin complex, whose alteration, similarly to proliferation-induced telomere shortening, initiates cellular senescence. In tumors, telomere length is maintained by Telomerase activity or by the Alternative Lengthening of Telomeres mechanism, whose hallmark is the telomeric localization of the promyelocytic leukemia (PML) protein. Whether PML contributes to telomeres maintenance in normal cells is unknown. We show that in normal human fibroblasts the PML protein associates with few telomeres, preferentially when they are damaged. Proliferation-induced telomere attrition or their damage due to alteration of the shelterin complex enhances the telomeric localization of PML, which is increased in human T-lymphocytes derived from patients genetically deficient in telomerase. In normal fibroblasts, PML depletion induces telomere damage, nuclear and chromosomal abnormalities, and senescence. Expression of the leukemia protein PML/RARα in hematopoietic progenitors displaces PML from telomeres and induces telomere shortening in the bone marrow of pre-leukemic mice. Our work provides a novel view of the physiologic function of PML, which participates in telomeres surveillance in normal cells. Our data further imply that a diminished PML function may contribute to cell senescence, genomic instability, and tumorigenesis.},
}
@article {pmid26116823,
year = {2015},
author = {Tummala, H and Walne, AJ},
title = {Long tails, short telomeres: Dyskeratosis congenita.},
journal = {Oncotarget},
volume = {6},
number = {16},
pages = {13856-13857},
pmid = {26116823},
issn = {1949-2553},
mesh = {Dyskeratosis Congenita/*genetics ; Exoribonucleases/*deficiency ; Female ; Humans ; Male ; *Mutation ; Telomere Homeostasis/*genetics ; },
}
@article {pmid26110638,
year = {2015},
author = {Cenci, G and Ciapponi, L and Marzullo, M and Raffa, GD and Morciano, P and Raimondo, D and Burla, R and Saggio, I and Gatti, M},
title = {The Analysis of Pendolino (peo) Mutants Reveals Differences in the Fusigenic Potential among Drosophila Telomeres.},
journal = {PLoS genetics},
volume = {11},
number = {6},
pages = {e1005260},
pmid = {26110638},
issn = {1553-7404},
mesh = {Animals ; Animals, Genetically Modified ; Brain/metabolism ; Chromosomes, Insect/genetics/metabolism ; DNA Replication ; Drosophila Proteins/*genetics/metabolism ; Drosophila melanogaster/*genetics ; Heterochromatin/metabolism ; Mutation ; Nuclear Proteins/*genetics/metabolism ; Polymorphism, Single Nucleotide ; Proliferating Cell Nuclear Antigen/metabolism ; Telomere/*genetics/metabolism ; Y Chromosome/genetics/metabolism ; },
abstract = {Drosophila telomeres are sequence-independent structures that are maintained by transposition to chromosome ends of three specialized retroelements (HeT-A, TART and TAHRE; collectively designated as HTT) rather than telomerase activity. Fly telomeres are protected by the terminin complex (HOAP-HipHop-Moi-Ver) that localizes and functions exclusively at telomeres and by non-terminin proteins that do not serve telomere-specific functions. Although all Drosophila telomeres terminate with HTT arrays and are capped by terminin, they differ in the type of subtelomeric chromatin; the Y, XR, and 4L HTT are juxtaposed to constitutive heterochromatin, while the XL, 2L, 2R, 3L and 3R HTT are linked to the TAS repetitive sequences; the 4R HTT is associated with a chromatin that has features common to both euchromatin and heterochromatin. Here we show that mutations in pendolino (peo) cause telomeric fusions (TFs). The analysis of several peo mutant combinations showed that these TFs preferentially involve the Y, XR and 4th chromosome telomeres, a TF pattern never observed in the other 10 telomere-capping mutants so far characterized. peo encodes a non-terminin protein homologous to the E2 variant ubiquitin-conjugating enzymes. The Peo protein directly interacts with the terminin components, but peo mutations do not affect telomeric localization of HOAP, Moi, Ver and HP1a, suggesting that the peo-dependent telomere fusion phenotype is not due to loss of terminin from chromosome ends. peo mutants are also defective in DNA replication and PCNA recruitment. However, our results suggest that general defects in DNA replication are unable to induce TFs in Drosophila cells. We thus hypothesize that DNA replication in Peo-depleted cells results in specific fusigenic lesions concentrated in heterochromatin-associated telomeres. Alternatively, it is possible that Peo plays a dual function being independently required for DNA replication and telomere capping.},
}
@article {pmid26110559,
year = {2015},
author = {Ding, Y and Fleming, AM and He, L and Burrows, CJ},
title = {Unfolding Kinetics of the Human Telomere i-Motif Under a 10 pN Force Imposed by the α-Hemolysin Nanopore Identify Transient Folded-State Lifetimes at Physiological pH.},
journal = {Journal of the American Chemical Society},
volume = {137},
number = {28},
pages = {9053-9060},
pmid = {26110559},
issn = {1520-5126},
support = {P30 CA042014/CA/NCI NIH HHS/United States ; R01 GM093099/GM/NIGMS NIH HHS/United States ; R01GM093099/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Biosensing Techniques ; DNA/*chemistry ; Hemolysin Proteins/*chemistry ; Humans ; Hydrogen-Ion Concentration ; Kinetics ; Models, Molecular ; *Nanopores/ultrastructure ; Nucleic Acid Conformation ; Telomere/*chemistry ; },
abstract = {Cytosine (C)-rich DNA can adopt i-motif folds under acidic conditions, with the human telomere i-motif providing a well-studied example. The dimensions of this i-motif are appropriate for capture in the nanocavity of the α-hemolysin (α-HL) protein pore under an electrophoretic force. Interrogation of the current vs time (i-t) traces when the i-motif interacts with α-HL identified characteristic signals that were pH dependent. These features were evaluated from pH 5.0 to 7.2, a region surrounding the transition pH of the i-motif (6.1). When the i-motif without polynucleotide tails was studied at pH 5.0, the folded structure entered the nanocavity of α-HL from either the top or bottom face to yield characteristic current patterns. Addition of a 5' 25-mer poly-2'-deoxyadensosine tail allowed capture of the i-motif from the unfolded terminus, and this was used to analyze the pH dependency of unfolding. At pH values below the transition point, only folded strands were observed, and when the pH was increased above the transition pH, the number of folded events decreased, while the unfolded events increased. At pH 6.8 and 7.2 4% and 2% of the strands were still folded, respectively. The lifetimes for the folded states at pH 6.8 and 7.2 were 21 and 9 ms, respectively, at 160 mV electrophoretic force. These lifetimes are sufficiently long to affect enzymes operating on DNA. Furthermore, these transient lifetimes are readily obtained using the α-HL nanopore, a feature that is not easily achievable by other methods.},
}
@article {pmid26110528,
year = {2015},
author = {Burla, R and Carcuro, M and Raffa, GD and Galati, A and Raimondo, D and Rizzo, A and La Torre, M and Micheli, E and Ciapponi, L and Cenci, G and Cundari, E and Musio, A and Biroccio, A and Cacchione, S and Gatti, M and Saggio, I},
title = {AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance.},
journal = {PLoS genetics},
volume = {11},
number = {6},
pages = {e1005167},
pmid = {26110528},
issn = {1553-7404},
mesh = {Adaptor Proteins, Signal Transducing/chemistry/genetics/*metabolism ; Animals ; Apoptosis Regulatory Proteins/chemistry/genetics/*metabolism ; Cell Cycle/genetics ; Cells, Cultured ; DNA Damage/genetics ; DNA Replication ; Drosophila Proteins/chemistry/metabolism ; Fibroblasts/physiology ; Genes, p53 ; Humans ; Mice ; Nuclear Proteins/chemistry/metabolism ; Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Telomeres are nucleoprotein complexes that protect the ends of linear chromosomes from incomplete replication, degradation and detection as DNA breaks. Mammalian telomeres are protected by shelterin, a multiprotein complex that binds the TTAGGG telomeric repeats and recruits a series of additional factors that are essential for telomere function. Although many shelterin-associated proteins have been so far identified, the inventory of shelterin-interacting factors required for telomere maintenance is still largely incomplete. Here, we characterize AKTIP/Ft1 (human AKTIP and mouse Ft1 are orthologous), a novel mammalian shelterin-bound factor identified on the basis of its homology with the Drosophila telomere protein Pendolino. AKTIP/Ft1 shares homology with the E2 variant ubiquitin-conjugating (UEV) enzymes and has been previously implicated in the control of apoptosis and in vesicle trafficking. RNAi-mediated depletion of AKTIP results in formation of telomere dysfunction foci (TIFs). Consistent with these results, AKTIP interacts with telomeric DNA and binds the shelterin components TRF1 and TRF2 both in vivo and in vitro. Analysis of AKTIP- depleted human primary fibroblasts showed that they are defective in PCNA recruiting and arrest in the S phase due to the activation of the intra S checkpoint. Accordingly, AKTIP physically interacts with PCNA and the RPA70 DNA replication factor. Ft1-depleted p53-/- MEFs did not arrest in the S phase but displayed significant increases in multiple telomeric signals (MTS) and sister telomere associations (STAs), two hallmarks of defective telomere replication. In addition, we found an epistatic relation for MST formation between Ft1 and TRF1, which has been previously shown to be required for replication fork progression through telomeric DNA. Ch-IP experiments further suggested that in AKTIP-depleted cells undergoing the S phase, TRF1 is less tightly bound to telomeric DNA than in controls. Thus, our results collectively suggest that AKTIP/Ft1 works in concert with TRF1 to facilitate telomeric DNA replication.},
}
@article {pmid26109322,
year = {2015},
author = {Soler, JJ and Ruiz Castellano, C and Martínez-de la Puente, J and Tomás, G and Ruiz-Rodríguez, M and Figuerola, J},
title = {Telomere dynamics in parasitic great spotted cuckoos and their magpie hosts.},
journal = {Journal of evolutionary biology},
volume = {28},
number = {9},
pages = {1610-1617},
doi = {10.1111/jeb.12680},
pmid = {26109322},
issn = {1420-9101},
mesh = {Animals ; Birds/*physiology ; Host-Parasite Interactions/genetics ; Passeriformes/*parasitology ; Species Specificity ; Telomere Homeostasis ; *Telomere Shortening ; Time Factors ; },
abstract = {Although little is known on the impact of environment on telomere length dynamics, it has been suggested to be affected by stress, lifestyle and/or life-history strategies of animals. We here compared telomere dynamics in erythrocytes of hatchlings and fledglings of the brood parasite great spotted cuckoos (Clamator glandarius) and of magpies (Pica pica), their main host in Europe. In magpie chicks, telomere length decreased from hatching to fledging, whereas no significant change in telomere length of great spotted cuckoo chicks was found. Moreover, we found interspecific differences in the association between laying date and telomere shortening. Interspecific differences in telomere shortening were interpreted as a consequence of differences in lifestyle and life-history characteristics of magpies and great spotted cuckoos. In comparison with magpies, cuckoos experience reduced sibling competition and higher access to resources and, consequently, lower stressful environmental conditions during the nestling phase. These characteristics also explain the associations between telomere attrition and environmental conditions (i.e. laying date) for magpies and the absence of association for great spotted cuckoos. These results therefore fit expectations on telomere dynamics derived from interspecific differences in lifestyle and life history of brood parasites and their bird hosts.},
}
@article {pmid26108857,
year = {2015},
author = {Hayashi, MT and Cesare, AJ and Rivera, T and Karlseder, J},
title = {Cell death during crisis is mediated by mitotic telomere deprotection.},
journal = {Nature},
volume = {522},
number = {7557},
pages = {492-496},
pmid = {26108857},
issn = {1476-4687},
support = {R01CA174942/CA/NCI NIH HHS/United States ; R01 CA174942/CA/NCI NIH HHS/United States ; 5T32CA009370/CA/NCI NIH HHS/United States ; R01GM087476/GM/NIGMS NIH HHS/United States ; T32 CA009370/CA/NCI NIH HHS/United States ; P30CA014195/CA/NCI NIH HHS/United States ; R01 GM087476/GM/NIGMS NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; },
mesh = {*Cell Cycle Checkpoints/genetics ; *Cell Death/drug effects/genetics ; Cell Line ; Cellular Senescence ; *Chromosome Aberrations ; Chromosomes, Human/genetics/metabolism ; DNA Damage ; Gene Fusion/genetics ; Genomic Instability ; Humans ; *Mitosis/drug effects/genetics ; Neoplasms/drug therapy/genetics/*pathology ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/deficiency/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; },
abstract = {Tumour formation is blocked by two barriers: replicative senescence and crisis. Senescence is triggered by short telomeres and is bypassed by disruption of tumour-suppressive pathways. After senescence bypass, cells undergo crisis, during which almost all of the cells in the population die. Cells that escape crisis harbour unstable genomes and other parameters of transformation. The mechanism of cell death during crisis remains unexplained. Here we show that human cells in crisis undergo spontaneous mitotic arrest, resulting in death during mitosis or in the following cell cycle. This phenotype is induced by loss of p53 function, and is suppressed by telomerase overexpression. Telomere fusions triggered mitotic arrest in p53-compromised non-crisis cells, indicating that such fusions are the underlying cause of cell death. Exacerbation of mitotic telomere deprotection by partial TRF2 (also known as TERF2) knockdown increased the ratio of cells that died during mitotic arrest and sensitized cancer cells to mitotic poisons. We propose a crisis pathway wherein chromosome fusions induce mitotic arrest, resulting in mitotic telomere deprotection and cell death, thereby eliminating precancerous cells from the population.},
}
@article {pmid26106805,
year = {2016},
author = {Raymond, AR and Becker, J and Woodiwiss, AJ and Booysen, HL and Norton, GR and Brooksbank, RL},
title = {Ethanol-Associated Cardiomyocyte Apoptosis and Left Ventricular Dilation Are Unrelated to Changes in Myocardial Telomere Length in Rats.},
journal = {Journal of cardiac failure},
volume = {22},
number = {4},
pages = {294-302},
doi = {10.1016/j.cardfail.2015.06.013},
pmid = {26106805},
issn = {1532-8414},
mesh = {Animals ; Apoptosis/*drug effects/physiology ; Ethanol/administration &amp; dosage/*toxicity ; Hypertrophy, Left Ventricular/*chemically induced/pathology ; Male ; Myocytes, Cardiac/*drug effects/pathology/physiology ; Rats ; Rats, Sprague-Dawley ; Telomere Homeostasis/*drug effects/physiology ; Ventricular Remodeling/*drug effects/physiology ; },
abstract = {AIM: The aim of this work was to determine whether ethanol-associated myocardial apoptosis and cardiac dilation are related to myocardial telomere shortening in rats.<br><br>METHODS AND RESULTS: Sprague-Dawley (SD) rats received either drinking water with (ethanol: n&#xa0;= 19) or without (control: n&#xa0;= 19) 5% (v/v) ethanol ad libitum, for 4 months. Left ventricular (LV) dimensions and function (echocardiography and isolated perfused heart preparations), cardiomyocyte apoptosis (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling), and leukocyte and myocardial telomere length (real-time polymerase chain reaction) were determined at the end of the study. Ethanol administration resulted in a marked increase in cardiomyocyte apoptosis (ethanol 0.85 &#xb1; 0.13% vs control 0.36 &#xb1; 0.06%; P&#xa0;= .0021) and LV dilation (LV end-diastolic diameter: ethanol 8.20 &#xb1; 0.14 mm vs control 7.56 &#xb1; 0.11 mm [P&#xa0;= .0014]; volume intercept at 0 mm Hg (V0) of the LV end-diastolic pressure-volume relationship: ethanol 0.40 &#xb1; 0.03 mL vs control 0.31 &#xb1; 0.02 mL [P&#xa0;= .020]). However, there were no changes in systolic chamber function as indexed by LV endocardial fractional shortening or the slope of the LV systolic pressure-volume relationship (end systolic elastance). The percentage of myocardial apoptosis was correlated with the degree of LV dilation (% apoptosis vs LV EDD: r&#xa0;= 0.39; n&#xa0;= 38; P&#xa0;= .021; vs V0: r&#xa0;= 0.44; n&#xa0;= 19; P&#xa0;= .046). No differences in leukocyte or cardiac telomere length were noted between the ethanol and control groups. Furthermore, cardiac telomere length was not associated with indexes of LV dilation (LVEDD and V0) or cardiomyocyte apoptosis.<br><br>CONCLUSIONS: Chronic ethanol-associated myocardial apoptosis and adverse remodeling occurs independently from changes in cardiac telomere length. Telomere shortening may not be a critical mechanism responsible for cardiomyocyte apoptosis and adverse cardiac remodeling.},
}
@article {pmid26105212,
year = {2016},
author = {Cabrero, M and Yu, Y and Verma, A and Yang, H and Colla, S and Jia, Y and Zheng, H and Bohannan, Z and Ganan-Gomez, I and Futreal, A and Takahashi, K and Chin, L and Kantarjian, H and Pellagatti, A and Bowman, T and Boultwood, J and Garcia-Manero, G and Wei, Y},
title = {Downregulation of Protection of Telomeres 1 expression in myelodysplastic syndromes with 7q deletion.},
journal = {British journal of haematology},
volume = {173},
number = {1},
pages = {161-165},
pmid = {26105212},
issn = {1365-2141},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; *Chromosome Deletion ; Chromosomes, Human, Pair 7/*genetics ; *Down-Regulation ; Female ; Humans ; Male ; Middle Aged ; Myelodysplastic Syndromes/*genetics/*metabolism/mortality ; Shelterin Complex ; Telomere-Binding Proteins/*biosynthesis/genetics ; },
}
@article {pmid26104581,
year = {2015},
author = {Wang, Z and Liu, JP},
title = {Characterization of potassium binding with human telomeres.},
journal = {Clinical and experimental pharmacology &amp; physiology},
volume = {42},
number = {9},
pages = {902-909},
doi = {10.1111/1440-1681.12443},
pmid = {26104581},
issn = {1440-1681},
abstract = {Human telomeres are G-rich tandem repeats that assume G-quadruplex structures at the ends of chromosomes. Stabilization of telomeric G-quadruplex represents a significant drug target for inhibiting the telomerase activity that is required in about 85% of cancers. Metal ions have been revealed as important stabilizers to DNA G-quadruplexes, but their binding process with human telomeric G-quadruplex remains unclear. In this report, we show that K[+] traverses into the G-tetrads centre of two G-tetrad layers through the half-capped top pathway constructed by the two edge-wise loop bases. The binding is mediated by the electrostatic interactions between K[+] and the nearby bases of G-tetrads. However, direct traverse of K[+] into the interior of G-quadruplex is negatively regulated by the steric hindrance of water molecules. Once K[+] enters the G-quadruplex, stabilization of the in-plane or sandwiched conformation of the telomeric G-quadruplex-K[+] complex is maintained by surrounding water molecules. These findings provide insights into the atomic interactions between K[+] and telomere G-tetrads for targeted drug design.},
}
@article {pmid26104454,
year = {2014},
author = {Kobryn, K and Chaconas, G},
title = {Hairpin Telomere Resolvases.},
journal = {Microbiology spectrum},
volume = {2},
number = {6},
pages = {},
doi = {10.1128/microbiolspec.MDNA3-0023-2014},
pmid = {26104454},
issn = {2165-0497},
support = {MOP 53086//Canadian Institutes of Health Research/Canada ; MOP 79344//Canadian Institutes of Health Research/Canada ; },
mesh = {Bacteria/*enzymology/*genetics ; Bacteriophages/*enzymology/*genetics ; Catalytic Domain ; Genetic Variation ; Recombinases/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Covalently closed hairpin ends, also known as hairpin telomeres, provide an unusual solution to the end replication problem. The hairpin telomeres are generated from replication intermediates by a process known as telomere resolution. This is a DNA breakage and reunion reaction promoted by hairpin telomere resolvases (also referred to as protelomerases) found in a limited number of phage and bacteria. The reaction promoted by these enzymes is a chemically isoenergetic two-step transesterification without a requirement for divalent metal ions or high-energy cofactors and uses an active site and mechanism similar to that for type IB topoisomerases and tyrosine recombinases. The small number of unrelated telomere resolvases characterized to date all contain a central, catalytic core domain with the active site, but in addition carry variable C- and N-terminal domains with different functions. Similarities and differences in the structure and function of the telomere resolvases are discussed. Of particular interest are the properties of the Borrelia telomere resolvases, which have been studied most extensively at the biochemical level and appear to play a role in shaping the unusual segmented genomes in these organisms and, perhaps, to play a role in recombinational events.},
}
@article {pmid26096607,
year = {2015},
author = {Adnot, S and Amsellem, V and Boyer, L and Marcos, E and Saker, M and Houssaini, A and Kebe, K and Dagouassat, M and Lipskaia, L and Boczkowski, J},
title = {Telomere Dysfunction and Cell Senescence in Chronic Lung Diseases: Therapeutic Potential.},
journal = {Pharmacology &amp; therapeutics},
volume = {153},
number = {},
pages = {125-134},
doi = {10.1016/j.pharmthera.2015.06.007},
pmid = {26096607},
issn = {1879-016X},
mesh = {Animals ; Cellular Senescence/*drug effects ; Humans ; Lung Diseases/*drug therapy/*pathology ; Molecular Targeted Therapy/*methods ; Pulmonary Disease, Chronic Obstructive/drug therapy/pathology ; Telomere/*drug effects/metabolism/*pathology ; Telomere Homeostasis/*drug effects ; },
abstract = {Cellular senescence--defined as a stable cell-cycle arrest combined with stereotyped phenotypic changes--might play a causal role in various lung diseases, including chronic obstructive pulmonary disease (COPD), which is predicted to become the third leading cause of death worldwide by 2020. COPD is characterized by slowly progressive airflow obstruction and emphysema due to destruction of the lung parenchyma and is often complicated by pulmonary hypertension (PH). No curative treatment is available. Senescent cells, which accumulate with age, are increased in lungs from patients with COPD and express a robust senescence-associated secretory phenotype (SASP), which is proinflammatory. The aim of this review is to show how senescent cells can drive the lung alterations seen in COPD, which mechanisms may be involved, and whether therapeutic interventions may slow or delay the in vitro cell-senescence process and in vivo lung alterations.},
}
@article {pmid26093291,
year = {2015},
author = {Habib, AG and Masuda, K and Yukawa, M and Tsuchiya, E and Ueno, M},
title = {Long G2 accumulates recombination intermediates and disturbs chromosome segregation at dysfunction telomere in Schizosaccharomyces pombe.},
journal = {Biochemical and biophysical research communications},
volume = {464},
number = {1},
pages = {140-146},
doi = {10.1016/j.bbrc.2015.06.098},
pmid = {26093291},
issn = {1090-2104},
mesh = {Binding Sites ; CDC2 Protein Kinase/genetics/metabolism ; Cell Cycle Proteins/genetics/metabolism ; Checkpoint Kinase 1 ; Chromosome Segregation/*drug effects ; Chromosomes, Fungal/chemistry/drug effects/metabolism ; DNA Helicases/genetics/metabolism ; G2 Phase/drug effects/*genetics ; *Gene Expression Regulation, Fungal ; *Genome, Fungal ; Genomic Instability ; Homologous Recombination/*drug effects ; Microbial Sensitivity Tests ; Microtubules/chemistry/drug effects/metabolism ; Mutation ; Nuclear Proteins/genetics/metabolism ; Protein Binding ; Protein Kinases/deficiency/genetics ; Protein-Tyrosine Kinases/genetics/metabolism ; Schizosaccharomyces/drug effects/*genetics/growth &amp; development ; Schizosaccharomyces pombe Proteins/genetics/metabolism ; Shelterin Complex ; Telomere/chemistry/drug effects/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Thiabendazole/pharmacology ; Tubulin Modulators/pharmacology ; },
abstract = {Protection of telomere (Pot1) is a single-stranded telomere binding protein which is essential for chromosome ends protection. Fission yeast Rqh1 is a member of RecQ helicases family which has essential roles in the maintenance of genomic stability and regulation of homologous recombination. Double mutant between fission yeast pot1Δ and rqh1 helicase dead (rqh1-hd) maintains telomere by homologous recombination. In pot1Δ rqh1-hd double mutant, recombination intermediates accumulate near telomere which disturb chromosome segregation and make cells sensitive to microtubule inhibitors thiabendazole (TBZ). Deletion of chk1(+) or mutation of its kinase domain shortens the G2 of pot1Δ rqh1-hd double mutant and suppresses both the accumulation of recombination intermediates and the TBZ sensitivity of that double mutant. In this study, we asked whether the long G2 is the reason for the TBZ sensitivity of pot1Δ rqh1-hd double mutant. We found that shortening the G2 of pot1Δ rqh1-hd double mutant by additional mutations of wee1 and mik1 or gain of function mutation of Cdc2 suppresses both the accumulation of recombination intermediates and the TBZ sensitivity of pot1Δ rqh1-hd double mutant. Our results suggest that long G2 of pot1Δ rqh1-hd double mutant may allow time for the accumulation of recombination intermediates which disturb chromosome segregation and make cells sensitive to TBZ.},
}
@article {pmid26092717,
year = {2015},
author = {Lapham, K and Kvale, MN and Lin, J and Connell, S and Croen, LA and Dispensa, BP and Fang, L and Hesselson, S and Hoffmann, TJ and Iribarren, C and Jorgenson, E and Kushi, LH and Ludwig, D and Matsuguchi, T and McGuire, WB and Miles, S and Quesenberry, CP and Rowell, S and Sadler, M and Sakoda, LC and Smethurst, D and Somkin, CP and Van Den Eeden, SK and Walter, L and Whitmer, RA and Kwok, PY and Risch, N and Schaefer, C and Blackburn, EH},
title = {Automated Assay of Telomere Length Measurement and Informatics for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort.},
journal = {Genetics},
volume = {200},
number = {4},
pages = {1061-1072},
pmid = {26092717},
issn = {1943-2631},
support = {R21 AA021223/AA/NIAAA NIH HHS/United States ; RC2 AG036607/AG/NIA NIH HHS/United States ; RC2AG036607/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aging/*genetics ; Automation ; Cohort Studies ; Computational Biology/*methods ; Female ; Genotype ; *Health ; Humans ; Leukocytes, Mononuclear/metabolism ; Male ; Molecular Epidemiology ; Sex Characteristics ; Telomere/*genetics ; },
abstract = {The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort includes DNA specimens extracted from saliva samples of 110,266 individuals. Because of its relationship to aging, telomere length measurement was considered an important biomarker to develop on these subjects. To assay relative telomere length (TL) on this large cohort over a short time period, we created a novel high throughput robotic system for TL analysis and informatics. Samples were run in triplicate, along with control samples, in a randomized design. As part of quality control, we determined the within-sample variability and employed thresholds for the elimination of outlying measurements. Of 106,902 samples assayed, 105,539 (98.7%) passed all quality control (QC) measures. As expected, TL in general showed a decline with age and a sex difference. While telomeres showed a negative correlation with age up to 75 years, in those older than 75 years, age positively correlated with longer telomeres, indicative of an association of longer telomeres with more years of survival in those older than 75. Furthermore, while females in general had longer telomeres than males, this difference was significant only for those older than age 50. An additional novel finding was that the variance of TL between individuals increased with age. This study establishes reliable assay and analysis methodologies for measurement of TL in large, population-based human studies. The GERA cohort represents the largest currently available such resource, linked to comprehensive electronic health and genotype data for analysis.},
}
@article {pmid26092192,
year = {2015},
author = {Heaphy, CM and Asch-Kendrick, R and Argani, P and Meeker, AK and Cimino-Mathews, A},
title = {Telomere length alterations unique to invasive lobular carcinoma.},
journal = {Human pathology},
volume = {46},
number = {8},
pages = {1197-1203},
doi = {10.1016/j.humpath.2015.05.001},
pmid = {26092192},
issn = {1532-8392},
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/*genetics ; Breast Neoplasms/*genetics ; Carcinoma, Lobular/*genetics ; Female ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Middle Aged ; Telomere/*genetics ; },
abstract = {Telomeres are nucleoprotein complexes located at the extreme ends of eukaryotic chromosomes and protect chromosomal ends from degradation and recombination. Dysfunctional telomeres contribute to genomic instability, promote tumorigenesis, and, in breast cancer, have been associated with increased cancer risk and poor prognosis. Short telomere lengths have been previously associated with triple-negative and human epidermal growth factor receptor (Her2)--positive ductal carcinomas. However, these investigations have not specifically assessed invasive lobular carcinomas (ILCs), which accounts for 5% to 15% of all invasive breast cancers. Here, we evaluate telomere lengths within 48 primary ILCs with complete characterization of estrogen receptor (ER), progesterone receptor (PR), and Her2 status, including 32 luminal/Her2- (ER+/PR+/Her2-), 8 luminal/Her2+ (ER+/PR+/Her2+), 3 Her2+ (ER-/PR-/Her2+), and 5 triple-negative (ER-/PR-/Her2-) carcinomas. A telomere-specific fluorescence in situ hybridization assay, which provides single-cell telomere length resolution, was used to evaluate telomere lengths and compare with standard clinicopathological markers. In contrast to breast ductal carcinoma, in which more than 85% of cases display abnormally short telomeres, approximately half (52%) of the ILCs displayed either normal or long telomeres. Short telomere length was associated with older patient age. Interestingly, 3 cases (6%) displayed a unique telomere pattern consisting of 1 or 2 bright telomere spots among the normal telomere signals within each individual cancer cell, a phenotype that has not been previously described. Additional studies are needed to further evaluate the significance of the unique bright telomere spot phenotype and the potential utility of telomere length as a prognostic marker in ILC.},
}
@article {pmid26088664,
year = {2015},
author = {Nelson, CA and Varcin, KJ and Coman, NK and De Vivo, I and Tager-Flusberg, H},
title = {Shortened Telomeres in Families With a Propensity to Autism.},
journal = {Journal of the American Academy of Child and Adolescent Psychiatry},
volume = {54},
number = {7},
pages = {588-594},
doi = {10.1016/j.jaac.2015.04.006},
pmid = {26088664},
issn = {1527-5418},
support = {1R01DC010290/DC/NIDCD NIH HHS/United States ; P01CA006516/CA/NCI NIH HHS/United States ; R01 CA082838/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Autism Spectrum Disorder/*genetics ; Biomarkers/analysis ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Longitudinal Studies ; Male ; Massachusetts ; Middle Aged ; Parents ; Saliva ; Siblings ; Stress, Psychological ; Telomere/*ultrastructure ; Young Adult ; },
abstract = {OBJECTIVE: Shortened telomeres have been linked to poorer health outcomes. Exposure to psychological stress is associated with accelerated telomere shortening, and a well-established body of evidence indicates that families with a child with autism spectrum disorder (ASD) experience heightened levels of psychological stress. Also, alterations in a number of biological processes implicated in telomere length dynamics (i.e., oxidative stress, DNA methylation) have been linked to ASD susceptibility. We examined whether families of children with ASD who have an infant show shortened telomeres.<br><br>METHOD: Saliva samples were collected from infants, their older sibling (proband), and parents in families with or without a child with ASD. Infants and their families were designated as high-risk for ASD (HRA; n&#xa0;= 86) or low-risk for ASD (LRA; n&#xa0;= 118) according to the older siblings' diagnostic status. We used the real-time polymerase chain reaction (PCR) telomere assay to determine relative average telomere length for each participant.<br><br>RESULTS: HRA families demonstrated significantly shorter telomere length relative to LRA families. This effect was observed at the individual family member level, with infants, probands, and mothers in HRA families showing reduced relative telomere length compared to individuals in LRA families; although not significant, fathers of high-risk infants showed a similar pattern of decreased telomere length.<br><br>CONCLUSION: Families of children with ASD who have an infant show shortened telomeres relative to families with no history of ASD. These results suggest that such "high-risk" families should be monitored for the physical and mental health consequences that are often associated with accelerated telomere shortening.},
}
@article {pmid26088657,
year = {2015},
author = {Drury, SS},
title = {Unraveling the Meaning of Telomeres for Child Psychiatry.},
journal = {Journal of the American Academy of Child and Adolescent Psychiatry},
volume = {54},
number = {7},
pages = {539-540},
pmid = {26088657},
issn = {1527-5418},
support = {R01 MH101533/MH/NIMH NIH HHS/United States ; R01MH101533/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent Psychiatry ; Child ; *Child Psychiatry ; Humans ; Psychiatry ; *Telomere ; },
}
@article {pmid26088418,
year = {2015},
author = {Deng, W and Wu, J and Wang, F and Kanoh, J and Dehe, PM and Inoue, H and Chen, J and Lei, M},
title = {Fission yeast telomere-binding protein Taz1 is a functional but not a structural counterpart of human TRF1 and TRF2.},
journal = {Cell research},
volume = {25},
number = {7},
pages = {881-884},
pmid = {26088418},
issn = {1748-7838},
mesh = {Humans ; Schizosaccharomyces/metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Telomere/metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
}
@article {pmid26088247,
year = {2015},
author = {Niederberger, C},
title = {Re: Telomere Homeostasis is Compromised in Spermatocytes from Patients with Idiopathic Infertility.},
journal = {The Journal of urology},
volume = {194},
number = {1},
pages = {171},
doi = {10.1016/j.juro.2015.04.006},
pmid = {26088247},
issn = {1527-3792},
mesh = {Humans ; Infertility, Male/*genetics ; Male ; Spermatocytes/*metabolism ; *Telomere Homeostasis ; },
}
@article {pmid26084629,
year = {2016},
author = {Babizhayev, MA and Yegorov, YE},
title = {Telomere Attrition in Human Lens Epithelial Cells Associated with Oxidative Stress Provide a New Therapeutic Target for the Treatment, Dissolving and Prevention of Cataract with N-Acetylcarnosine Lubricant Eye Drops. Kinetic, Pharmacological and Activity-Dependent Separation of Therapeutic Targeting: Transcorneal Penetration and Delivery of L-Carnosine in the Aqueous Humor and Hormone-Like Hypothalamic Antiaging Effects of the Instilled Ophthalmic Drug Through a Safe Eye Medication Technique.},
journal = {Recent patents on drug delivery &amp; formulation},
volume = {10},
number = {2},
pages = {82-129},
doi = {10.2174/1872211309666150618104657},
pmid = {26084629},
issn = {2212-4039},
mesh = {Administration, Ophthalmic ; Age Factors ; Aging/genetics/metabolism/pathology ; Animals ; Antioxidants/*administration &amp; dosage/adverse effects/chemistry/pharmacokinetics ; Carnosine/administration &amp; dosage/adverse effects/*analogs &amp; derivatives/chemistry/pharmacokinetics ; Cataract/genetics/metabolism/pathology/*prevention &amp; control ; Cornea/metabolism ; Drug Compounding ; Drug Delivery Systems ; Epithelial Cells/*drug effects/metabolism/pathology ; Humans ; Lens, Crystalline/*drug effects/metabolism/pathology ; Ocular Absorption ; Ophthalmic Solutions ; Oxidative Stress/*drug effects ; Solubility ; Telomere Homeostasis/*drug effects ; },
abstract = {BACKGROUND: Visual impairment broadly impacts the ability of affected people to maintain their function and to remain independent during their daily occupations as they grow older. Visual impairment affects survival of older patients, quality of life, can affect a person's self-ranking of health, may be associated with social and functional decline, use of community support services, depression, falls, nursing home placement, and increased mortality. It has been hypothesized that senile cataract may serve as a marker for generalised tissue aging, since structural changes occurring in the proteins of the lens during cataract formation are similar to those which occur elsewhere as part of the aging process. The published analysis revealed a strong age-dependent relationship between undergoing cataract surgery and subsequent mortality.<br><br>METHODS: Nuclear opacity, particularly severe nuclear opacity, and mixed opacities with nuclear were significant predictors of mortality independent of body mass index, comorbid conditions, smoking, age, race, and sex. The lens opacity status is considered as an independent predictor of 2-year mortality, an association that could not be explained by potential confounders. Telomeres have become important biomarkers for aging as well as for oxidative stress-related disease. The lens epithelium is especially vulnerable to oxidative stress. Oxidative damage to the cuboidal epithelial cells on the anterior surface of the lens mediated by reactive oxygen species and phospholipid hydroperoxides can precede and contribute to human lens cataract formation. The erosion and shortening of telomeres in human lens epithelial cells in the lack of telomerase activity has been recognized as a primary cause of premature lens senescence phenotype that trigger human cataractogenesis. In this study we aimed to be focused on research defining the mechanisms that underlie linkages among telomere attrition in human lens epithelial cells associated with oxidative stress, biology of the lens response to oxidative damages, aging and health, cataract versus neuroendocrine regulation and disease. The cumulative results demonstrate that carnosine, released ophthalmically from the patented 1% Nacetylcarnosine prodrug lubricant eye drops, at physiological concentration might remarkably reduce the rate of telomere shortening in the lens cells subjected to oxidative stress in the lack of efficient antioxidant lens protection. Carnosine promotes the protection of normal cells from acquiring phenotypic characteristics of cellular senescence. The data of visual functions (visual acuity, glare sensitivity) in older adult subjects and older subjects with cataract treated with 1% N-acetylcarnosine lubricant eye drops showed significant improvement as compared, by contrast with the control group which showed generally no improvement in visual functions, with no difference from baseline in visual acuity and glare sensitivity readings.<br><br>RESULTS: N-acetylcarnosine derived from the lubricant eye drops may be transported into the hypothalamic tuberomammillary nucleus (TMN) histamine neurons and gradually hydrolyzed. The resulting L-histidine may subsequently be converted into histamine, which could be responsible for the effects of carnosine on neurotransmission and hormone-like antiaging and anti-cataract physiological function.<br><br>CONCLUSION: The research utilizing the N-acetylcarnosine lubricant eye drops powerful therapeutic platform provides the findings related to the intraocular uptake exposure sources as well as a timing dosage and duration systemic absorption of said preparation from the conjunctional sac reaching the hypothalamus with activities transfer into the hypothalamic-neuroendocrine pathways affecting across the hypothalamus metabolic pathway the telomere biology and cataract disease occurrence, reversal and prevention and the average expected lifespan of an individual. Such findings can be translated into clinical practice and may provide a basis for personalized cataract disease and aging prevention and treatment approaches.},
}
@article {pmid26083930,
year = {2015},
author = {Bončina, M and Hamon, F and Islam, B and Teulade-Fichou, MP and Vesnaver, G and Haider, S and Lah, J},
title = {Dominant Driving Forces in Human Telomere Quadruplex Binding-Induced Structural Alterations.},
journal = {Biophysical journal},
volume = {108},
number = {12},
pages = {2903-2911},
pmid = {26083930},
issn = {1542-0086},
mesh = {*G-Quadruplexes ; Humans ; Molecular Dynamics Simulation ; Potassium/chemistry ; Sodium/chemistry ; Telomere/*chemistry ; },
abstract = {Recently various pathways of human telomere (ht) DNA folding into G-quadruplexes and of ligand binding to these structures have been proposed. However, the key issue as to the nature of forces driving the folding and recognition processes remains unanswered. In this study, structural changes of 22-mer ht-DNA fragment (Tel22), induced by binding of ions (K(+), Na(+)) and specific bisquinolinium ligands, were monitored by calorimetric and spectroscopic methods and by gel electrophoresis. Using the global model analysis of a wide variety of experimental data, we were able to characterize the thermodynamic forces that govern the formation of stable Tel22 G-quadruplexes, folding intermediates, and ligand-quadruplex complexes, and then predict Tel22 behavior in aqueous solutions as a function of temperature, salt concentration, and ligand concentration. On the basis of the above, we believe that our work sets the framework for better understanding the heterogeneity of ht-DNA folding and binding pathways, and its structural polymorphism.},
}
@article {pmid26083773,
year = {2015},
author = {Soares-Miranda, L and Imamura, F and Siscovick, D and Jenny, NS and Fitzpatrick, AL and Mozaffarian, D},
title = {Physical Activity, Physical Fitness, and Leukocyte Telomere Length: The Cardiovascular Health Study.},
journal = {Medicine and science in sports and exercise},
volume = {47},
number = {12},
pages = {2525-2534},
pmid = {26083773},
issn = {1530-0315},
support = {HHSN268200800007C/HL/NHLBI NIH HHS/United States ; N01HC55222/HL/NHLBI NIH HHS/United States ; N01HC85086/HL/NHLBI NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; R01AG023629/AG/NIA NIH HHS/United States ; N01HC85083/HL/NHLBI NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; N01HC85080/HL/NHLBI NIH HHS/United States ; N01HC85081/HL/NHLBI NIH HHS/United States ; MC_UP_A100_1003/MRC_/Medical Research Council/United Kingdom ; U01 HL080295/HL/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; N01HC85082/HL/NHLBI NIH HHS/United States ; MC_UU_12015/5/MRC_/Medical Research Council/United Kingdom ; U01HL080295/HL/NHLBI NIH HHS/United States ; N01HC85079/HL/NHLBI NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aging/*physiology ; Cross-Sectional Studies ; Exercise Test ; Female ; Hand Strength ; Humans ; Leukocytes/*cytology ; Male ; *Motor Activity ; *Physical Fitness ; Prospective Studies ; *Telomere Homeostasis ; Walking/physiology ; },
abstract = {INTRODUCTION: The influence of physical activity (PA) and physical fitness (PF) at older ages on changes in telomere length (TL)--repetitive DNA sequences that may mark biologic aging--is not well-established. Few prior studies (mainly cross-sectional) have been conducted in older adults, and few studies have evaluated PF.<br><br>METHODS: We investigated cross-sectional and prospective associations of PA and PF with leukocyte TL among 582 older adults (mean &#xb1; SD age, 73 &#xb1; 5 yr at baseline) in the Cardiovascular Health Study, with serial TL measures and PA and PF assessed multiple times. Cross-sectional associations were assessed using multivariable repeated-measures regression, in which cumulatively averaged PA and PF measures were related to TL. Longitudinal analyses assessed cumulatively averaged PA and PF against later changes in TL, and changes in cumulatively averaged PA and PF against changes in TL.<br><br>RESULTS: Cross-sectionally, greater walking distance and chair test performance, but not other PA and PF measures, were each associated with longer TL (P trend = 0.007 and 0.04, respectively). In longitudinal analyses, no significant associations of baseline PA and PF with change in TL were observed. In contrast, changes in leisure-time activity and chair test performance were each inversely associated with changes in TL.<br><br>CONCLUSIONS: Cross-sectional analyses suggest that greater PA and PF are associated with longer TL. Prospective analyses show that changes in PA and PF are associated with differences in changes in TL. Even later in life, changes in certain PA and PF measures are associated with changes in TL, suggesting that leisure-time activity and fitness could reduce leukocyte telomere attrition among older adults.},
}
@article {pmid26083263,
year = {2015},
author = {Park, M and Verhoeven, JE and Cuijpers, P and Reynolds, CF and Penninx, BW},
title = {Where You Live May Make You Old: The Association between Perceived Poor Neighborhood Quality and Leukocyte Telomere Length.},
journal = {PloS one},
volume = {10},
number = {6},
pages = {e0128460},
pmid = {26083263},
issn = {1932-6203},
support = {P30 AG024827/AG/NIA NIH HHS/United States ; UL1 TR000005/TR/NCATS NIH HHS/United States ; P30 MH090333/MH/NIMH NIH HHS/United States ; K01NR015101/NR/NINR NIH HHS/United States ; P30 MH90333/MH/NIMH NIH HHS/United States ; K01 NR015101/NR/NINR NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aging/*genetics ; Cellular Senescence ; Demography ; Female ; Health Status ; Humans ; Leukocytes/cytology/*metabolism ; Life Style ; Male ; Mental Health ; Middle Aged ; Residence Characteristics/classification ; Social Class ; Telomere/*physiology ; Telomere Homeostasis/physiology ; Young Adult ; },
abstract = {BACKGROUND: Strong evidence supports that living in disadvantaged neighborhoods has direct unfavorable impact on mental and physical health. However, whether it also has direct impact on cellular health is largely unknown. Thus we examined whether neighborhood quality was associated with leukocyte telomere length, an indicator of cellular aging.<br><br>METHODS: In May 2014, we extracted and analyzed baseline data from the Netherlands Study of Depression and Anxiety (NESDA), a large epidemiological study of individuals age between 18-65 years (n=2902). Telomere length was determined using quantitative polymerase chain reaction. Neighborhood quality was assessed using modified measures of perceived neighborhood disorder, fear of crime, and noise. We used multivariable linear regression models to examine association between perceived neighborhood quality and telomere length with comprehensive adjustment for individual and community characteristics related to socioeconomic and demographic status, urbanization level, mental and physical health, and lifestyle.<br><br>RESULTS: Compared to individuals who reported good neighborhood quality, the mean telomere length of those who reported moderate neighborhood quality was approximately 69 base pair shorter (&#x3b2; =-69.33, 95% CI: -119.49, -19.17, p= 0.007), and that of those who reported poor neighborhood quality were 174 base pair shorter (&#x3b2; =-173.80, 95% CI: -298.80, -49.01, p=0.006). For illustrative purposes, one could extrapolate these outcomes to 8.7 and 11.9 years in chronological age, respectively.<br><br>CONCLUSION: We have established an association between perceived neighborhood quality and cellular aging over and above a range of individual attributes. Biological aging processes may be impacted by socioeconomic milieu.},
}
@article {pmid26082495,
year = {2015},
author = {Sun, L and Tan, R and Xu, J and LaFace, J and Gao, Y and Xiao, Y and Attar, M and Neumann, C and Li, GM and Su, B and Liu, Y and Nakajima, S and Levine, AS and Lan, L},
title = {Targeted DNA damage at individual telomeres disrupts their integrity and triggers cell death.},
journal = {Nucleic acids research},
volume = {43},
number = {13},
pages = {6334-6347},
pmid = {26082495},
issn = {1362-4962},
support = {AG045545-01/AG/NIA NIH HHS/United States ; R01 EB016657/EB/NIBIB NIH HHS/United States ; P30CA047904/CA/NCI NIH HHS/United States ; R01 CA185363/CA/NCI NIH HHS/United States ; CA185363/CA/NCI NIH HHS/United States ; EB016657/EB/NIBIB NIH HHS/United States ; },
mesh = {Cell Death ; Cell Line ; Cellular Senescence ; *DNA Damage ; DNA Repair ; Green Fluorescent Proteins/genetics ; Guanine/analogs &amp; derivatives/metabolism ; Humans ; *Oxidative Stress ; Repetitive Sequences, Nucleic Acid ; Telomere/chemistry/*metabolism ; *Telomere Shortening ; Telomeric Repeat Binding Protein 1/genetics ; },
abstract = {Cellular DNA is organized into chromosomes and capped by a unique nucleoprotein structure, the telomere. Both oxidative stress and telomere shortening/dysfunction cause aging-related degenerative pathologies and increase cancer risk. However, a direct connection between oxidative damage to telomeric DNA, comprising <1% of the genome, and telomere dysfunction has not been established. By fusing the KillerRed chromophore with the telomere repeat binding factor 1, TRF1, we developed a novel approach to generate localized damage to telomere DNA and to monitor the real time damage response at the single telomere level. We found that DNA damage at long telomeres in U2OS cells is not repaired efficiently compared to DNA damage in non-telomeric regions of the same length in heterochromatin. Telomeric DNA damage shortens the average length of telomeres and leads to cell senescence in HeLa cells and cell death in HeLa, U2OS and IMR90 cells, when DNA damage at non-telomeric regions is undetectable. Telomere-specific damage induces chromosomal aberrations, including chromatid telomere loss and telomere associations, distinct from the damage induced by ionizing irradiation. Taken together, our results demonstrate that oxidative damage induces telomere dysfunction and underline the importance of maintaining telomere integrity upon oxidative damage.},
}
@article {pmid26082483,
year = {2015},
author = {Yang, Q and Zhao, F and Dai, S and Zhang, N and Zhao, W and Bai, R and Sun, Y},
title = {Sperm telomere length is positively associated with the quality of early embryonic development.},
journal = {Human reproduction (Oxford, England)},
volume = {30},
number = {8},
pages = {1876-1881},
doi = {10.1093/humrep/dev144},
pmid = {26082483},
issn = {1460-2350},
mesh = {Adult ; Age Factors ; Embryonic Development/*physiology ; Female ; Fertilization in Vitro/methods ; Humans ; Male ; Pregnancy ; Pregnancy Rate ; Sperm Count ; Spermatozoa/*metabolism ; Telomere/*genetics/metabolism ; },
abstract = {STUDY QUESTION: What is the relationship between telomere length in sperm and early embryonic development in in vitro fertilization (IVF)?<br><br>SUMMARY ANSWER: Sperm telomere length (STL) is positively associated with embryo quality in IVF.<br><br>WHAT IS KNOWN ALREADY: Previous studies have shown that STL differs among human males.<br><br>STUDY DESIGN, SIZE, DURATION: In order to determine the associations between STL, fertilization laboratory parameters and clinical pregnancy in IVF, 418 couples were recruited from August 2013 to August 2014.<br><br>MATERIALS, SETTING, METHODS: We collected semen samples and used quantitative PCR technique to detect the mean STL for each patient. These data were compared with the IVF outcomes.<br><br>The mean STL was positively correlated with the age of patient (rP = 0.100; P = 0.041) and total sperm count/ejaculate (rp = 0.28; P < 0.001). Analysis of the age-adjusted mean STL in relation to the male patient's paternal and maternal ages at the time of his conception showed significant positive relationships between STL and both paternal (r = 0.16; P = 0.003) and maternal (r = 0.19; P < 0.001) ages at the time of conception. In addition, significant correlations were found between STL and good quality embryo (regression coefficient: 1.63; P < 0.001) and transplantable embryo rates (regression coefficient: 1.57; P < 0.001), but clinical pregnancy rates were not affected (odds ratio = 1.00 [95% CI: 0.93-1.07]; P = 0.90).<br><br>This study showed that STL was positively associated with embryo quality in IVF. Additional studies are needed to confirm these observations.<br><br>STL has the potential to be used as a marker for the prediction of embryonic quality.<br><br>This work was supported by the National Natural Science Foundation of China (Grants 31271605 and 31471404), and the National Science Foundation for Young Scientists of China (Grant 31401274), and Science Foundation of First Affiliated Hospital of Zhengzhou University for Yong Scientists. The authors have declared that no competing interests exist.},
}
@article {pmid26080929,
year = {2015},
author = {Kammori, M and Sugishita, Y and Okamoto, T and Kobayashi, M and Yamazaki, K and Yamada, E and Yamada, T},
title = {Telomere shortening in breast cancer correlates with the pathological features of tumor progression.},
journal = {Oncology reports},
volume = {34},
number = {2},
pages = {627-632},
doi = {10.3892/or.2015.4063},
pmid = {26080929},
issn = {1791-2431},
mesh = {Adult ; Aged ; Breast Neoplasms/*genetics/*pathology ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Middle Aged ; Neoplasm Invasiveness ; Neoplasm Metastasis ; *Telomere Shortening ; },
abstract = {Telomeres are involved in the maintenance of genomic stability. Telomere alteration has been observed in most human cancer types, and is known to be a feature of malignancy. The aim of the present study was to evaluate whether the telomere length of breast cancer cells correlates with TNM stage and several pathological features. We investigated a total of 44 breast cancers, including 17 scirrhous, 15 papillotubular and 12 solid-tubular carcinomas. Telomere lengths were determined by tissue quantitative fluorescence in situ hybridization (Q-FISH), and compared according to the TNM stage, histological tumor size, lymph node metastases, vascular invasion and immunohistochemical status (ER, PR, HER2 status and Ki67 labeling index). In all histological types, telomeres of cancer cells were significantly shorter than those of normal epithelial cells. Mean telomere length was significantly less in patients with TNM stage III, and in those with large tumors, lymph node metastases and vascular invasion. Our results suggest that the telomere length of cancer cells is strongly correlated with the degree of cancer progression.},
}
@article {pmid26080316,
year = {2015},
author = {Wojcicki, JM and Heyman, MB and Elwan, D and Shiboski, S and Lin, J and Blackburn, E and Epel, E},
title = {Telomere length is associated with oppositional defiant behavior and maternal clinical depression in Latino preschool children.},
journal = {Translational psychiatry},
volume = {5},
number = {6},
pages = {e581},
pmid = {26080316},
issn = {2158-3188},
support = {K01 DK080825/DK/NIDDK NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; NH-NIDDK 08085//PHS HHS/United States ; },
mesh = {Adult ; Attention Deficit and Disruptive Behavior Disorders/*genetics ; Child, Preschool ; Cohort Studies ; Depression/*psychology ; Depressive Disorder/*psychology ; Female ; *Hispanic or Latino ; Humans ; Linear Models ; Longitudinal Studies ; Male ; Mothers/*psychology ; Multivariate Analysis ; Paternal Age ; Poverty ; Prospective Studies ; Stress, Psychological/*genetics ; Telomere/*genetics ; },
abstract = {Exposure to psychological stress and depression are associated with shorter white blood cell telomere length (TL) in adults, possibly via associated lifelong oxidative stressors. Exposure to maternal depression increases risk for future depression and behavior problems in children, and Latino youth are at high risk. Few studies have evaluated the role of exposure to maternal depression or child behavior in relation to TL in children. We assessed early-childhood exposures to maternal depression from birth to the age of 5 years and child behavior from ages 3-5 years in a cohort of Latino children in relation to child leukocyte TL at ages 4 and 5 years. Children who had oppositional defiant behavior at 3, 4 or 5 years had shorter TL than those without by ~450 base pairs (P < 0.01). In multivariate analyses, independent predictors for shorter TL at 4 and 5 years of age included oppositional defiant disorder at 3, 4 or 5 years (β = -359.25, 95% CI -633.84 to 84.66; P = 0.01), exposure to maternal clinical depression at 3 years of age (β = -363.99, 95% CI -651.24 to 764.74; P = 0.01), shorter maternal TL (β = 502.92, 95% CI 189.21-816.63) and younger paternal age at the child's birth (β = 24.63, 95% CI 1.14-48.12). Thus, exposure to maternal clinical depression (versus depressive symptoms) in early childhood was associated with deleterious consequences on child cellular health as indicated by shorter TL at 4 and 5 years of age. Similarly, children with oppositional defiant behavior also had shorter TL, possibly related to early exposures to maternal clinical depression. Our study is the first to link maternal clinical depression and oppositional defiant behavior with shorter TL in the preschool years in a relatively homogenous population of low-income Latino children.},
}
@article {pmid26076919,
year = {2016},
author = {Cohen-Manheim, I and Doniger, GM and Sinnreich, R and Simon, ES and Pinchas, R and Aviv, A and Kark, JD},
title = {Increased attrition of leukocyte telomere length in young adults is associated with poorer cognitive function in midlife.},
journal = {European journal of epidemiology},
volume = {31},
number = {2},
pages = {147-157},
pmid = {26076919},
issn = {1573-7284},
support = {R01 AG030678/AG/NIA NIH HHS/United States ; R01 HL116446/HL/NHLBI NIH HHS/United States ; R0I-HL116446/HL/NHLBI NIH HHS/United States ; T32 AI007140/AI/NIAID NIH HHS/United States ; R01-HD071180/HD/NICHD NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; R0I-AG030678/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Aged ; Aging/*psychology ; Biomarkers/analysis ; Cognition/*physiology ; Cognition Disorders/*genetics/metabolism ; Female ; Humans ; Leukocytes/*metabolism ; Longitudinal Studies ; Male ; Memory ; Middle Aged ; Odds Ratio ; *Population Surveillance ; Prospective Studies ; Sex Factors ; Smoking ; Telomere/*physiology ; Telomere Shortening ; Young Adult ; },
abstract = {Evidence for an association of leukocyte telomere length (LTL) with cognitive function, predominantly in older adults, is inconsistent. No report has examined the association of LTL dynamics (age-specific LTL and its attrition rate) with cognitive function. We aimed to examine the association of LTL dynamics over 13 years in young adulthood with cognitive function in midlife. 497 individuals who had LTL measured at ages 28-32 and 41-46 years were assessed at ages 48-52 for global cognitive function and its five specific component domains with a NeuroTrax computerized test battery. Multivariable regression and logistic models were applied for cognition treated as a continuous and categorical variable, respectively. We found that LTL attrition (adjusted for sex, baseline LTL and potential confounders including socioeconomic variables) was inversely associated with global cognition (standardized β = -.119, p = .004) and its component domains: information processing speed (β = -.102, p = .024), visual-spatial function (β = -.102, p = .017) and memory (β = -.093, p = .045), but less so for the attention and executive domains. The multivariable-adjusted odds ratio for low global cognition comparing the upper versus lower thirds of LTL attrition was 2.12 (95 % CI 1.11-4.08, p for trend = .023). There was no association of baseline or follow-up LTL with cognition. No effect modification was evident for sex, smoking or inflammatory markers. In conclusion, faster LTL attrition in young adulthood was associated with poorer global and domain-specific cognitive function in midlife, suggesting that more rapid LTL attrition may be predictive of cognitive aging in healthy young adults.},
}
@article {pmid26076322,
year = {2015},
author = {de Zegher, F and Díaz, M and Ibáñez, L},
title = {Association Between Long Telomere Length and Insulin Sensitization in Adolescent Girls With Hyperinsulinemic Androgen Excess.},
journal = {JAMA pediatrics},
volume = {169},
number = {8},
pages = {787-788},
doi = {10.1001/jamapediatrics.2015.0439},
pmid = {26076322},
issn = {2168-6211},
mesh = {Adolescent ; Female ; Humans ; Hyperandrogenism/*genetics ; Hyperinsulinism/*genetics ; Insulin Resistance/*physiology ; Polymerase Chain Reaction ; *Telomere ; },
}
@article {pmid26075606,
year = {2015},
author = {, },
title = {Correction: Inhibition of Telomere Recombination by Inactivation of KEOPS Subunit Cgi121 Promotes Cell Longevity.},
journal = {PLoS genetics},
volume = {11},
number = {6},
pages = {e1005313},
pmid = {26075606},
issn = {1553-7404},
}
@article {pmid26073170,
year = {2015},
author = {Dai, J and Cai, H and Li, H and Zhuang, Y and Min, H and Wen, Y and Yang, J and Gao, Q and Shi, Y and Yi, L},
title = {Association between telomere length and survival in patients with idiopathic pulmonary fibrosis.},
journal = {Respirology (Carlton, Vic.)},
volume = {20},
number = {6},
pages = {947-952},
doi = {10.1111/resp.12566},
pmid = {26073170},
issn = {1440-1843},
mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/*mortality/*physiopathology ; Male ; Middle Aged ; Risk Factors ; *Telomere Homeostasis ; },
abstract = {BACKGROUND AND OBJECTIVE: Short telomere is a crucial risk factor for idiopathic pulmonary fibrosis (IPF). However, little is known about the association between baseline telomere length and survival in IPF. We aimed to determine whether telomere length is associated with survival of IPF.<br><br>METHODS: Leukocyte telomere lengths were measured by quantitative polymerase chain reaction in IPF patients at the time of the initial enrolment assessment in Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University. The primary endpoint was the survival of the IPF patients since their initial enrolment assessment.<br><br>RESULTS: Ninety-four IPF patients were enrolled between 1 January 2012 and 30 June 2014. The mean age-adjusted telomere length of IPF patients (0.85&#x2009;&#xb1;&#x2009;0.60) was significantly shorter than age-matched controls (1.15&#x2009;&#xb1;&#x2009;0.60, P&#x2009;=&#x2009;0.001). During the follow-up period, 43 IPF patients died. The mean age-adjusted telomere length of the non-survivors (0.61&#x2009;&#xb1;&#x2009;0.53) was significantly shorter than that of the survivors (1.03&#x2009;&#xb1;&#x2009;0.59, P&#x2009;=&#x2009;0.005). The association between telomere length (hazard ratio (HR) 0.470 (95% confidence interval (CI): 0.25-0. 89); P&#x2009;=&#x2009;0&#xb7;019) and survival in patients with IPF was independent of age, sex, forced vital capacity or diffusing capacity of carbon monoxide. After excluding the six patients with telomerase gene mutations, telomere length (HR 0.46 (95% CI: 0.24-0.88); P&#x2009;=&#x2009;0&#xb7;018) remained an independent predictor of survival time in patients with IPF.<br><br>CONCLUSIONS: Short telomere length is independently associated with worse survival in IPF. Future research should focus on the molecular mechanism underlying the shortening of telomere length in IPF.},
}
@article {pmid26068215,
year = {2015},
author = {López-Panadès, E and Gavis, ER and Casacuberta, E},
title = {Specific Localization of the Drosophila Telomere Transposon Proteins and RNAs, Give Insight in Their Behavior, Control and Telomere Biology in This Organism.},
journal = {PloS one},
volume = {10},
number = {6},
pages = {e0128573},
pmid = {26068215},
issn = {1932-6203},
support = {R01 GM061107/GM/NIGMS NIH HHS/United States ; R01 GM067758/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Behavior, Animal ; Drosophila/*physiology ; Drosophila Proteins/genetics/*metabolism ; Female ; Gene Expression ; Mutation ; Protein Transport ; RNA/genetics/*metabolism ; RNA Transport ; Retroelements ; Telomere/genetics/metabolism ; },
abstract = {Drosophila telomeres constitute a remarkable exception to the telomerase mechanism. Although maintaining the same cytological and functional properties as telomerase maintain telomeres, Drosophila telomeres embed the telomere retrotransposons whose specific and highly regulated terminal transposition maintains the appropriate telomere length in this organism. Nevertheless, our current understanding of how the mechanism of the retrotransposon telomere works and which features are shared with the telomerase system is very limited. We report for the first time a detailed study of the localization of the main components that constitute the telomeres in Drosophila, HeT-A and TART RNAs and proteins. Our results in wild type and mutant strains reveal localizations of HeT-A Gag and TART Pol that give insight in the behavior of the telomere retrotransposons and their control. We find that TART Pol and HeT-A Gag only co-localize at the telomeres during the interphase of cells undergoing mitotic cycles. In addition, unexpected protein and RNA localizations with a well-defined pattern in cells such as the ovarian border cells and nurse cells, suggest possible strategies for the telomere transposons to reach the oocyte, and/or additional functions that might be important for the correct development of the organism. Finally, we have been able to visualize the telomere RNAs at different ovarian stages of development in wild type and mutant lines, demonstrating their presence in spite of being tightly regulated by the piRNA mechanism.},
}
@article {pmid26067849,
year = {2015},
author = {Entringer, S and Epel, ES and Lin, J and Blackburn, EH and Buss, C and Shahbaba, B and Gillen, DL and Venkataramanan, R and Simhan, HN and Wadhwa, PD},
title = {Maternal Folate Concentration in Early Pregnancy and Newborn Telomere Length.},
journal = {Annals of nutrition &amp; metabolism},
volume = {66},
number = {4},
pages = {202-208},
pmid = {26067849},
issn = {1421-9697},
support = {R01 HD-041663/HD/NICHD NIH HHS/United States ; P01 HD047609/HD/NICHD NIH HHS/United States ; HD-065825/HD/NICHD NIH HHS/United States ; R01 HD-052732/HD/NICHD NIH HHS/United States ; R01 HD041663/HD/NICHD NIH HHS/United States ; R01 HD052732/HD/NICHD NIH HHS/United States ; R01 HD065825/HD/NICHD NIH HHS/United States ; R01 HD-06028/HD/NICHD NIH HHS/United States ; R01 HD060628/HD/NICHD NIH HHS/United States ; P01 HD-047609/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; *Asymptomatic Diseases ; Cohort Studies ; Female ; Fetal Blood ; *Fetal Development ; Folic Acid/*blood ; Folic Acid Deficiency/*blood/physiopathology ; Humans ; Infant, Newborn ; Leukocytes, Mononuclear ; Longitudinal Studies ; Male ; *Maternal Nutritional Physiological Phenomena ; Philadelphia ; Pregnancy ; Pregnancy Complications/*blood/physiopathology ; Pregnancy Trimester, First ; Pregnancy, High-Risk/blood ; Prospective Studies ; *Telomere Shortening ; Young Adult ; },
abstract = {BACKGROUND/AIMS: Telomere biology plays a fundamental role in genomic integrity and cell physiology. The newborn setting of telomere length (TL) likely has important implications for telomere dynamics over the lifespan; however, its determinants are poorly understood. Folate is essential for DNA integrity. The maternal compartment is the only source of folate for the developing fetus. We, therefore, tested the hypothesis that variation in maternal folate during pregnancy is associated with newborn TL.<br><br>METHODS: A prospective, longitudinal study was conducted in 119 mother-newborn dyads. Eligible mothers were enrolled at 9.5 (SD &#xb1;2.1) weeks gestation and followed through birth. Concentrations of maternal serum folate were measured in the first trimester of pregnancy. Newborn telomere length was measured in cord blood mononuclear cells (CBMC).<br><br>RESULTS: After accounting for the effects of other established determinants of newborn TL, each 10 ng/ml increase in maternal total folate was associated with a 5.8% increase in median TL (p = 0.03). The median TL in newborns of mother in the lowest quartile of total folate levels was approximately 10% shorter than that of newborns of mothers in the highest folate quartile.<br><br>CONCLUSIONS: Our findings suggest that fetal TL exhibits developmental plasticity, and provide evidence that maternal nutrition may exert a 'programming' effect on this system.},
}
@article {pmid26067555,
year = {2015},
author = {Yamada, T and Higuchi, M and Nakanishi, N},
title = {Effect of the anatomical site on telomere length and pref-1 gene expression in bovine adipose tissues.},
journal = {Biochemical and biophysical research communications},
volume = {463},
number = {4},
pages = {923-927},
doi = {10.1016/j.bbrc.2015.06.036},
pmid = {26067555},
issn = {1090-2104},
mesh = {Adipose Tissue/*anatomy &amp; histology/metabolism ; Animals ; Base Sequence ; Cattle ; DNA Primers ; *Gene Expression ; Membrane Proteins/*genetics ; Real-Time Polymerase Chain Reaction ; *Telomere ; },
abstract = {Adipose tissue growth is associated with preadipocyte proliferation and differentiation. Telomere length is a biological marker for cell proliferation. Preadipocyte factor-1 (pref-1) is specifically expressed in preadipocytes and acts as a molecular gatekeeper of adipogenesis. In the present study, we investigated the fat depot-specific differences in telomere length and pref-1 gene expression in various anatomical sites (subcutaneous, intramuscular and visceral) of fattening Wagyu cattle. Visceral adipose tissue expressed higher pref-1 mRNA than did subcutaneous and intramuscular adipose tissues. The telomere length in visceral adipose tissue tended to be longer than that of subcutaneous and intramuscular adipose tissues. The telomere length of adipose tissue was not associated with adipocyte size from three anatomical sites. No significant correlation was found between the pref-1 mRNA level and the subcutaneous adipocyte size. In contrast, the pref-1 mRNA level was negatively correlated with the intramuscular and visceral adipocyte size. These results suggest that anatomical sites of adipose tissue affect the telomere length and expression pattern of the pref-1 gene in a fat depot-specific manner.},
}
@article {pmid26067306,
year = {2015},
author = {Gilchrest, BA},
title = {Telomere-Based Protective Responses to DNA Damage.},
journal = {The journal of investigative dermatology. Symposium proceedings},
volume = {17},
number = {1},
pages = {15-16},
doi = {10.1038/jidsymp.2015.11},
pmid = {26067306},
issn = {1529-1774},
mesh = {*DNA Damage ; *DNA Repair ; Humans ; Skin/*radiation effects ; Telomere/*physiology ; Ultraviolet Rays/adverse effects ; },
}
@article {pmid26063574,
year = {2015},
author = {Pan, L and Hildebrand, K and Stutz, C and Thomä, N and Baumann, P},
title = {Minishelterins separate telomere length regulation and end protection in fission yeast.},
journal = {Genes &amp; development},
volume = {29},
number = {11},
pages = {1164-1174},
pmid = {26063574},
issn = {1549-5477},
support = {//Howard Hughes Medical Institute/United States ; },
mesh = {Protein Binding ; Schizosaccharomyces/*genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Sequence Deletion ; Telomerase/metabolism ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*physiology ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {The conserved shelterin complex is critical for chromosome capping and maintaining telomere length homeostasis. In fission yeast, shelterin is comprised of five proteins. Taz1, Rap1, and Poz1 function as negative regulators of telomere elongation, whereas Pot1 and Tpz1 are critical for end capping and telomerase recruitment. How the five proteins work together to safeguard chromosome ends and promote telomere length homeostasis is a matter of great interest. Using a combination of deletions, fusions, and tethers, we define key elements of shelterin important for telomere length regulation. Surprisingly, deletion of the entire Rap1 and Poz1 proteins does not impair telomere length regulation as long as a static bridge is provided between Taz1 and Tpz1. Cells harboring minishelterin display wild-type telomere length and intact subtelomeric silencing. However, protection against end fusions in G1 is compromised in the absence of Rap1. Our data reveal a remarkable plasticity in shelterin architecture and separate functions in length regulation and end protection.},
}
@article {pmid26062516,
year = {2015},
author = {Jankowska, M and Fuchs, J and Klocke, E and Fojtová, M and Polanská, P and Fajkus, J and Schubert, V and Houben, A},
title = {Holokinetic centromeres and efficient telomere healing enable rapid karyotype evolution.},
journal = {Chromosoma},
volume = {124},
number = {4},
pages = {519-528},
pmid = {26062516},
issn = {1432-0886},
mesh = {Autoantigens ; *Centromere ; Centromere Protein A ; Chromosomal Proteins, Non-Histone ; Chromosome Breakage ; Chromosomes, Plant/*genetics ; *Evolution, Molecular ; Histones ; *Karyotype ; Magnoliopsida/*genetics/metabolism ; Plant Proteins ; *Telomere ; },
abstract = {Species with holocentric chromosomes are often characterized by a rapid karyotype evolution. In contrast to species with monocentric chromosomes where acentric fragments are lost during cell division, breakage of holocentric chromosomes creates fragments with normal centromere activity. To decipher the mechanism that allows holocentric species an accelerated karyotype evolution via chromosome breakage, we analyzed the chromosome complements of irradiated Luzula elegans plants. The resulting chromosomal fragments and rearranged chromosomes revealed holocentromere-typical CENH3 and histone H2AThr120ph signals as well as the same mitotic mobility like unfragmented chromosomes. Newly synthesized telomeres at break points become detectable 3 weeks after irradiation. The presence of active telomerase suggests a telomerase-based mechanism of chromosome healing. A successful transmission of holocentric chromosome fragments across different generations was found for most offspring of irradiated plants. Hence, a combination of holokinetic centromere activity and the fast formation of new telomeres at break points enables holocentric species a rapid karyotype evolution involving chromosome fissions and rearrangements.},
}
@article {pmid26059974,
year = {2015},
author = {Anjomani Virmouni, S and Al-Mahdawi, S and Sandi, C and Yasaei, H and Giunti, P and Slijepcevic, P and Pook, MA},
title = {Identification of telomere dysfunction in Friedreich ataxia.},
journal = {Molecular neurodegeneration},
volume = {10},
number = {},
pages = {22},
pmid = {26059974},
issn = {1750-1326},
support = {089757//Wellcome Trust/United Kingdom ; },
mesh = {Adolescent ; Adult ; Animals ; Cell Division ; Cells, Cultured ; Cerebellum/ultrastructure ; DNA Damage ; DNA Repair ; Female ; Fibroblasts/ultrastructure ; Friedreich Ataxia/*genetics/pathology ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes/ultrastructure ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Oxidative Stress ; Recombination, Genetic ; Telomerase/metabolism ; Telomere/*genetics/ultrastructure ; Telomere Homeostasis/physiology ; *Telomere Shortening/genetics ; Young Adult ; },
abstract = {BACKGROUND: Friedreich ataxia (FRDA) is a progressive inherited neurodegenerative disorder caused by mutation of the FXN gene, resulting in decreased frataxin expression, mitochondrial dysfunction and oxidative stress. A recent study has identified shorter telomeres in FRDA patient leukocytes as a possible disease biomarker.<br><br>RESULTS: Here we aimed to investigate both telomere structure and function in FRDA cells. Our results confirmed telomere shortening in FRDA patient leukocytes and identified similar telomere shortening in FRDA patient autopsy cerebellar tissues. However, FRDA fibroblasts showed significantly longer telomeres at early passage, occurring in the absence of telomerase activity, but with activation of an alternative lengthening of telomeres (ALT)-like mechanism. These cells also showed accelerated telomere shortening as population doubling increases. Furthermore, telomere dysfunction-induced foci (TIF) analysis revealed that FRDA fibroblasts have dysfunctional telomeres.<br><br>CONCLUSIONS: Our finding of dysfunctional telomeres in FRDA cells provides further insight into FRDA molecular disease mechanisms, which may have implications for future FRDA therapy.},
}
@article {pmid26058898,
year = {2015},
author = {Amelina, H and Subramaniam, S and Moiseeva, V and Armstrong, CA and Pearson, SR and Tomita, K},
title = {Telomere protein Rap1 is a charge resistant scaffolding protein in chromosomal bouquet formation.},
journal = {BMC biology},
volume = {13},
number = {},
pages = {37},
pmid = {26058898},
issn = {1741-7007},
support = {12097/CRUK_/Cancer Research UK/United Kingdom ; 281722/ERC_/European Research Council/International ; C36439/A12097//Cancer Research UK/United Kingdom ; },
mesh = {Amino Acid Sequence ; Chromosomes, Fungal/*metabolism ; Meiosis ; Molecular Sequence Data ; Phosphorylation ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Interaction Maps ; Schizosaccharomyces/chemistry/cytology/*metabolism ; Schizosaccharomyces pombe Proteins/chemistry/*metabolism ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {BACKGROUND: Chromosomes reorganize in early meiotic prophase to form the so-called telomere bouquet. In fission yeast, telomeres localize to the nuclear periphery via interaction of the telomeric protein Rap1 with the membrane protein Bqt4. During meiotic prophase, the meiotic proteins Bqt1-2 bind Rap1 and tether to the spindle pole body to form the bouquet. Although it is known that this polarized chromosomal arrangement plays a crucial role in meiotic progression, the molecular mechanisms of telomere bouquet regulation are poorly understood.<br><br>RESULTS: Here, we detected high levels of Rap1 phospho-modification throughout meiotic prophase, and identified a maximum of 35 phosphorylation sites. Concomitant phosphomimetic mutation of the modification sites suggests that Rap1 hyper-phosphorylation does not directly regulate telomere bouquet formation or dissociation. Despite the negative charge conferred by its highly phosphorylated state, Rap1 maintains interactions with its binding partners. Interestingly, mutations that change the charge of negatively charged residues within the Bqt1-2 binding site of Rap1 abolished the affinity to the Bqt1-2 complex, suggesting that the intrinsic negative charge of Rap1 is crucial for telomere bouquet formation.<br><br>CONCLUSIONS: Whereas Rap1 hyper-phosphorylation observed in meiotic prophase does not have an apparent role in bouquet formation, the intrinsic negative charge of Rap1 is important for forming interactions with its binding partners. Thus, Rap1 is able to retain bouquet formation under heavily phosphorylated status.},
}
@article {pmid26055325,
year = {2015},
author = {Eid, R and Demattei, MV and Episkopou, H and Augé-Gouillou, C and Decottignies, A and Grandin, N and Charbonneau, M},
title = {Genetic Inactivation of ATRX Leads to a Decrease in the Amount of Telomeric Cohesin and Level of Telomere Transcription in Human Glioma Cells.},
journal = {Molecular and cellular biology},
volume = {35},
number = {16},
pages = {2818-2830},
pmid = {26055325},
issn = {1098-5549},
mesh = {Cell Cycle Proteins/analysis/*metabolism ; Cell Line, Tumor ; Chromatin/metabolism ; Chromosomal Proteins, Non-Histone/analysis/*metabolism ; DNA Helicases/analysis/*genetics ; Glioma/*genetics/metabolism ; Humans ; Nuclear Proteins/analysis/*genetics ; RNA Interference ; RNA Polymerase II/metabolism ; RNA, Untranslated/metabolism ; Telomerase/metabolism ; Telomere/*genetics/metabolism/ultrastructure ; Telomere Homeostasis ; *Transcription, Genetic ; X-linked Nuclear Protein ; Cohesins ; },
abstract = {Mutations in ATRX (alpha thalassemia/mental retardation syndrome X-linked), a chromatin-remodeling protein, are associated with the telomerase-independent ALT (alternative lengthening of telomeres) pathway of telomere maintenance in several types of cancer, including human gliomas. In telomerase-positive glioma cells, we found by immunofluorescence that ATRX localized not far from the chromosome ends but not exactly at the telomere termini. Chromatin immunoprecipitation (ChIP) experiments confirmed a subtelomeric localization for ATRX, yet short hairpin RNA (shRNA)-mediated genetic inactivation of ATRX failed to trigger the ALT pathway. Cohesin has been recently shown to be part of telomeric chromatin. Here, using ChIP, we showed that genetic inactivation of ATRX provoked diminution in the amount of cohesin in subtelomeric regions of telomerase-positive glioma cells. Inactivation of ATRX also led to diminution in the amount of TERRAs, noncoding RNAs resulting from transcription of telomeric DNA, as well as to a decrease in RNA polymerase II (RNAP II) levels at the telomeres. Our data suggest that ATRX might establish functional interactions with cohesin on telomeric chromatin in order to control TERRA levels and that one or the other or both of these events might be relevant to the triggering of the ALT pathway in cancer cells that exhibit genetic inactivation of ATRX.},
}
@article {pmid26053088,
year = {2015},
author = {Mason, SM and Prescott, J and Tworoger, SS and De Vivo, I and Rich-Edwards, JW},
title = {Childhood Physical and Sexual Abuse History and Leukocyte Telomere Length among Women in Middle Adulthood.},
journal = {PloS one},
volume = {10},
number = {6},
pages = {e0124493},
pmid = {26053088},
issn = {1932-6203},
support = {R01 CA067262/CA/NCI NIH HHS/United States ; UM1 CA176726/CA/NCI NIH HHS/United States ; P2C HD041023/HD/NICHD NIH HHS/United States ; R01 HD057929/HD/NICHD NIH HHS/United States ; R01 HL081557/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Child ; Child Abuse, Sexual/*psychology ; Female ; Humans ; Leukocytes/*metabolism ; Middle Aged ; *Telomere Homeostasis ; },
abstract = {OBJECTIVE: Abuse victimization in childhood is associated with a variety of age-related cardiometabolic diseases, but the mechanisms remain unknown. Telomeres, which form the protective caps at the ends of chromosomes, have been proposed as measures of biological age, and a growing body of research suggests that telomere attrition may help to explain relationships between stress and cardiometabolic degradation. We examined the association between childhood abuse victimization and leukocyte telomere length among 1,135 participants in the Nurses' Health Study II (NHSII).<br><br>METHODS: The NHSII ascertained physical and sexual child abuse histories in 2001. Telomere length was measured in genomic DNA extracted from peripheral blood leukocytes collected between 1996 and 1999. The ratio of telomere repeat copy number to a single gene copy number (T/S) was determined by a modified version of the quantitative real-time PCR telomere assay. Telomere length was log-transformed and corrected for assay variation across batch. We regressed telomere length on childhood abuse exposure variables and covariates using linear regression.<br><br>RESULTS: We observed a reduction in telomere length associated with moderate physical abuse versus no physical abuse, but there was no evidence of a dose-response relationship for increased severity of physical abuse. No associations were noted for sexual abuse.<br><br>CONCLUSIONS: We found no evidence of an association between severity of childhood physical or sexual abuse and leukocyte telomere length in the NHSII.},
}
@article {pmid26049047,
year = {2015},
author = {Weng, X and Zhang, H and Kan, M and Ye, J and Liu, F and Wang, T and Deng, J and Tan, Y and He, L and Liu, Y},
title = {Leukocyte telomere length is associated with advanced age-related macular degeneration in the Han Chinese population.},
journal = {Experimental gerontology},
volume = {69},
number = {},
pages = {36-40},
doi = {10.1016/j.exger.2015.06.004},
pmid = {26049047},
issn = {1873-6815},
mesh = {Aged ; *Aging/pathology/physiology ; Case-Control Studies ; China/epidemiology ; Female ; Genomic Instability/physiology ; *Geographic Atrophy/blood/etiology/pathology ; Humans ; Leukocytes/*physiology ; *Macular Degeneration/blood/complications/epidemiology/pathology ; Male ; Middle Aged ; Statistics as Topic ; Telomere/*physiology ; },
abstract = {Telomeres located at the ends of chromosomes are involved in genomic stability and play a key role in various cancers and age-related diseases. Age-related macular degeneration (AMD) is a late-onset, age-associated progressive neurodegenerative disease, which includes the geographic atrophy (GA) subtype and the choroidal neovascularization (CNV) subtype. To better understand how leukocyte telomere length (LTL) is related to AMD, we conducted an association study in 197 AMD patients and 259 healthy controls using the established quantitative PCR technique. Logistic regression was performed to evaluate the association of LTL and AMD with the age-adjusted ratio of the telomere length to the copy number of a single-copy gene (T/S). Notably, we found a significant association between AMD and LTL (OR=2.24; 95% CI=1.68-3.07; P=0.0001) after adjusting for age and sex. Furthermore, the results showed a strongly significant association between the GA subtype and the LTL (OR=4.81; 95% CI=3.15-7.82; P=0.0001) after adjusting for age and sex. Our findings provide evidence of the role that LTL plays in the pathological mechanisms of AMD, mainly in the GA subgroup but not the CNV subgroup.},
}
@article {pmid26048252,
year = {2015},
author = {Laish, I and Katz, H and Stein, A and Liberman, M and Naftali, T and Kitay-Cohen, Y and Biron-Shental, T and Konikoff, FM and Amiel, A},
title = {Telomere dysfunction in peripheral blood lymphocytes from patients with primary sclerosing cholangitis and inflammatory bowel disease.},
journal = {Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver},
volume = {47},
number = {9},
pages = {790-796},
doi = {10.1016/j.dld.2015.05.002},
pmid = {26048252},
issn = {1878-3562},
mesh = {Adult ; Case-Control Studies ; Cholangitis, Sclerosing/*blood ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Inflammatory Bowel Diseases/*blood ; Israel ; Lymphocytes/*pathology ; Male ; Middle Aged ; Prospective Studies ; Telomerase/*blood ; Telomere/*genetics ; Tertiary Care Centers ; },
abstract = {BACKGROUND AND AIMS: Primary sclerosing cholangitis and inflammatory bowel disease are two associated, chronic inflammatory, pre-malignant conditions. We hypothesized that patients with these disorders may harbour telomere dysfunction as a marker of chromosomal instability. The aim of our study was to compare parameters of the telomere-telomerase system in these cohorts.<br><br>METHODS: In this prospective study, peripheral blood was withdrawn from patients with primary sclerosing cholangitis (N=20), inflammatory bowel disease (N=20) and healthy controls (N=20), and lymphocytes were isolated. Telomere length was quantified as a function of the signal intensity and telomere number. Random aneuploidy and telomere capture were determined by fluorescence in situ hybridization technique with specific probes.<br><br>RESULTS: Patients with inflammatory bowel disease had higher measures of intestinal disease activity than patients with primary sclerosing cholangitis. Despite this, shorter telomere length and telomere aggregates, especially the fusion of 2-5 telomeres, were observed at significantly higher rate in patients with primary sclerosing cholangitis relative to inflammatory bowel disease or healthy controls. Rates of aneuploidy and telomere capture were higher in the two probes in both diseases compared to controls (p<0.001).<br><br>CONCLUSION: Dysfunction of telomeres was demonstrated in primary sclerosing cholangitis patients more than inflammatory bowel disease and healthy controls patients, which attests to genetic instability and immunosenescence.<br><br>TRIAL REGISTRATION NUMBER: NCT02247622.},
}
@article {pmid26047604,
year = {2015},
author = {Mzahma, R and Kharrat, M and Fetiriche, F and Bouasker, and Ben Moussa, M and Ben Safta, Z and Dziri, C and Zaouche, A and Chaabouni-Bouhamed, H},
title = {The relationship between telomere length and clinicopathologic characteristics in colorectal cancers among Tunisian patients.},
journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine},
volume = {36},
number = {11},
pages = {8703-8713},
pmid = {26047604},
issn = {1423-0380},
mesh = {Adult ; Aged ; Aged, 80 and over ; Chromosomal Instability/*genetics ; Colorectal Neoplasms/classification/*genetics/*pathology ; Female ; Humans ; Male ; Middle Aged ; Prognosis ; Telomerase/genetics ; Telomere/genetics ; Telomere Homeostasis/*genetics ; Tunisia ; },
abstract = {Alterations in telomere dynamics have emerged as having a causative role in carcinogenesis. Both the telomere attrition contribute to tumor initiation via increasing chromosomal instability and that the telomere elongation induces cell immortalization and leads to tumor progression. The objectives of this study are to investigate the dynamics of telomere length in colorectal cancer (CRC) and the clinicopathological parameters implicated. We measured the relative telomere length (RTL) in cancerous tissues and in corresponding peripheral blood leukocytes (PBL) using quantitative PCR (Q-PCR) from 94 patients with CRC. Telomere length correlated significantly in cancer tissues and corresponding PBL (r = 0.705). Overall, cancer tissue had shorter telomeres than PBL (p = 0.033). In both cancer tissue and PBL, the RTL was significantly correlated with age groups (p = 0.008 and p = 0.012, respectively). The RTL in cancer tissue was significantly longer in rectal tumors (p = 0.04) and in the late stage of tumors (p = 0.01). In PBL, the RTL was significantly correlated with the macroscopic aspect of tumors (p = 0.02). In addition, the telomere-length ratio of cancer to corresponding PBL increased significantly with late-stage groups. Shortening of the telomere was detected in 44.7%, elongation in 36.2%, and telomeres were unchanged in 19.1% of 94 tumors. Telomere shortening occurred more frequently in the early stage of tumors (p = 0.01). This study suggests that the telomere length in PBL is affected by the macroscopic aspect of tumors and that telomere length in cancer tissues is a marker for progression of CRC and depends on tumor-origin site.},
}
@article {pmid26045446,
year = {2015},
author = {Ikeda, A and Muneoka, T and Murakami, S and Hirota, A and Yabuki, Y and Karashima, T and Nakazono, K and Tsuruno, M and Pichler, H and Shirahige, K and Kodama, Y and Shimamoto, T and Mizuta, K and Funato, K},
title = {Sphingolipids regulate telomere clustering by affecting the transcription of genes involved in telomere homeostasis.},
journal = {Journal of cell science},
volume = {128},
number = {14},
pages = {2454-2467},
doi = {10.1242/jcs.164160},
pmid = {26045446},
issn = {1477-9137},
mesh = {Chromosomes, Fungal/genetics/metabolism ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Sphingolipids/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere Homeostasis/*physiology ; Transcription Factors/genetics/*metabolism ; },
abstract = {In eukaryotic organisms, including mammals, nematodes and yeasts, the ends of chromosomes, telomeres are clustered at the nuclear periphery. Telomere clustering is assumed to be functionally important because proper organization of chromosomes is necessary for proper genome function and stability. However, the mechanisms and physiological roles of telomere clustering remain poorly understood. In this study, we demonstrate a role for sphingolipids in telomere clustering in the budding yeast Saccharomyces cerevisiae. Because abnormal sphingolipid metabolism causes downregulation of expression levels of genes involved in telomere organization, sphingolipids appear to control telomere clustering at the transcriptional level. In addition, the data presented here provide evidence that telomere clustering is required to protect chromosome ends from DNA-damage checkpoint signaling. As sphingolipids are found in all eukaryotes, we speculate that sphingolipid-based regulation of telomere clustering and the protective role of telomere clusters in maintaining genome stability might be conserved in eukaryotes.},
}
@article {pmid26043380,
year = {2015},
author = {Hammerl, JA and Roschanski, N and Lurz, R and Johne, R and Lanka, E and Hertwig, S},
title = {The Molecular Switch of Telomere Phages: High Binding Specificity of the PY54 Cro Lytic Repressor to a Single Operator Site.},
journal = {Viruses},
volume = {7},
number = {6},
pages = {2771-2793},
pmid = {26043380},
issn = {1999-4915},
mesh = {Coliphages/genetics/*physiology ; DNA, Viral/*metabolism ; Electrophoretic Mobility Shift Assay ; *Gene Expression Regulation, Viral ; *Operator Regions, Genetic ; Promoter Regions, Genetic ; Protein Binding ; Repressor Proteins/isolation &amp; purification/*metabolism ; Viral Regulatory and Accessory Proteins/isolation &amp; purification/metabolism ; *Virus Latency ; *Virus Replication ; },
abstract = {Temperate bacteriophages possess a molecular switch, which regulates the lytic and lysogenic growth. The genomes of the temperate telomere phages N15, PY54 and ɸKO2 harbor a primary immunity region (immB) comprising genes for the prophage repressor, the lytic repressor and a putative antiterminator. The roles of these products are thought to be similar to those of the lambda proteins CI, Cro and Q, respectively. Moreover, the gene order and the location of several operator sites in the prototype telomere phage N15 and in ɸKO2 are also reminiscent of lambda-like phages. By contrast, in silico analyses revealed the presence of only one operator (O\(_{\rm{R}
}
\)3) in PY54. The purified PY54 Cro protein was used for EMSA studies demonstrating that it exclusively binds to a 16-bp palindromic site (O\(_{\rm{R}
}
\)3) upstream of the prophage repressor gene. The O\(_{\rm{R}
}
\)3 operator sequences of PY54 and ɸKO2/N15 only differ by their peripheral base pairs, which are responsible for Cro specificity. PY54 cI and cro transcription is regulated by highly active promoters initiating the synthesis of a homogenious species of leaderless mRNA. The location of the PY54 Cro binding site and of the identified promoters suggests that the lytic repressor suppresses cI transcription but not its own synthesis. The results indicate an unexpected diversity of the growth regulation mechanisms in lambda-related phages.},
}
@article {pmid26041456,
year = {2015},
author = {Audry, J and Maestroni, L and Delagoutte, E and Gauthier, T and Nakamura, TM and Gachet, Y and Saintomé, C and Géli, V and Coulon, S},
title = {RPA prevents G-rich structure formation at lagging-strand telomeres to allow maintenance of chromosome ends.},
journal = {The EMBO journal},
volume = {34},
number = {14},
pages = {1942-1958},
pmid = {26041456},
issn = {1460-2075},
support = {R01 GM078253/GM/NIGMS NIH HHS/United States ; GM078253/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes, Fungal/*metabolism ; DNA Helicases/genetics/metabolism ; DNA Polymerase I/metabolism ; DNA Polymerase II/metabolism ; DNA Replication ; DNA, Single-Stranded ; DNA-Binding Proteins/genetics/metabolism ; G-Quadruplexes ; Mutation ; Replication Protein A/genetics/*metabolism ; Schizosaccharomyces/*genetics ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Shelterin Complex ; Telomere/chemistry/*metabolism ; Telomere Shortening ; Telomere-Binding Proteins/metabolism ; },
abstract = {Replication protein A (RPA) is a highly conserved heterotrimeric single-stranded DNA-binding protein involved in DNA replication, recombination, and repair. In fission yeast, the Rpa1-D223Y mutation provokes telomere shortening. Here, we show that this mutation impairs lagging-strand telomere replication and leads to the accumulation of secondary structures and recruitment of the homologous recombination factor Rad52. The presence of these secondary DNA structures correlates with reduced association of shelterin subunits Pot1 and Ccq1 at telomeres. Strikingly, heterologous expression of the budding yeast Pif1 known to efficiently unwind G-quadruplex rescues all the telomeric defects of the D223Y cells. Furthermore, in vitro data show that the identical D to Y mutation in human RPA specifically affects its ability to bind G-quadruplex. We propose that RPA prevents the formation of G-quadruplex structures at lagging-strand telomeres to promote shelterin association and facilitate telomerase action at telomeres.},
}
@article {pmid26039272,
year = {2015},
author = {Needham, BL and Rehkopf, D and Adler, N and Gregorich, S and Lin, J and Blackburn, EH and Epel, ES},
title = {Leukocyte telomere length and mortality in the National Health and Nutrition Examination Survey, 1999-2002.},
journal = {Epidemiology (Cambridge, Mass.)},
volume = {26},
number = {4},
pages = {528-535},
pmid = {26039272},
issn = {1531-5487},
support = {K01 AG047280/AG/NIA NIH HHS/United States ; R01 AG033592/AG/NIA NIH HHS/United States ; R01AG033592-01A1/AG/NIA NIH HHS/United States ; },
mesh = {Black or African American ; Aged ; Aged, 80 and over ; Cardiovascular Diseases/*mortality ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Mexican Americans ; Middle Aged ; Mortality/*ethnology ; Neoplasms/*mortality ; Nutrition Surveys ; Proportional Hazards Models ; Risk Factors ; Telomere/*metabolism ; United States/epidemiology ; White People ; },
abstract = {BACKGROUND: This study examined the association between leukocyte telomere length--a marker of cell aging--and mortality in a nationally representative sample of US adults ages 50-84 years. We also examined moderating effects of age, sex, race/ethnicity, and education.<br><br>METHODS: Data were from the National Health and Nutrition Examination Survey, 1999-2002 (n = 3,091). Cox proportional hazards regression was used to estimate the risk of all-cause and cause- specific mortality adjusting for sociodemographic characteristics, smoking, body mass index, and chronic conditions.<br><br>RESULTS: Eight hundred and seventy deaths occurred over an average of 9.5 years of follow-up. In the full sample, a decrease of 1 kilobase pair in telomere length at baseline was marginally associated with a 10% increased hazard of all-cause mortality (hazard ratio [HR]: 1.1, 95% confidence interval [CI]: 0.9, 1.4) and a 30% increased hazard of death due to diseases other than cardiovascular disease or cancer (HR: 1.3, 95% CI: 0.9, 1.9). Among African-American but not white or Mexican-American respondents, a decrease of 1 kilobase pair in telomere length at baseline was associated with a two-fold increased hazard of cardiovascular mortality (HR: 2.0, 95% CI: 1.3, 3.1). There was no association between telomere length and cancer mortality.<br><br>CONCLUSIONS: The association between leukocyte telomere length and mortality differs by race/ethnicity and cause of death.},
}
@article {pmid26034119,
year = {2015},
author = {Dudinskaya, EN and Tkacheva, ON and Shestakova, MV and Brailova, NV and Strazhesko, ID and Akasheva, DU and Isaykina, OY and Sharashkina, NV and Kashtanova, DA and Boytsov, SA},
title = {Short telomere length is associated with arterial aging in patients with type 2 diabetes mellitus.},
journal = {Endocrine connections},
volume = {4},
number = {3},
pages = {136-143},
pmid = {26034119},
issn = {2049-3614},
abstract = {It is known that glucose disturbances contribute to micro- and macrovascular complications and vascular aging. Telomere length is considered to be a cellular aging biomarker. It is important to determine the telomere length role in vascular structural and functional changes in patients with diabetes mellitus. We conducted a cross-sectional observational study in a high-risk population from Moscow, Russia. The study included 50 patients with diabetes and without clinical cardiovascular disease and 49 control group participants. Glucose metabolism assessment tests, measuring intima-media complex thickness and determining the presence of atherosclerotic plaques, pulse wave velocity measurement, and telomere length measurement were administered to all participants. Vascular changes were more dramatic in patients with diabetes than in the control group, and the telomeres were shorter in patients with diabetes. Significant differences were found in the vascular wall condition among diabetes patients, and there were no substantial differences in the arterial structure between patients with 'long' telomeres; however, there were statistically significant differences in the vascular wall condition between patients with 'short' telomeres. Vascular ageing signs were more prominent in patients with diabetes. However, despite diabetes, vascular changes in patients with long telomeres were very modest and were similar to the vascular walls in healthy individuals. Thus, long lymphocyte telomeres may have a protective effect on the vascular wall and may prevent vascular wall deterioration caused by glucose metabolism disorders.},
}
@article {pmid26033121,
year = {2015},
author = {Garcia, CK},
title = {Running short on time: lung transplant evaluation for telomere-related pulmonary fibrosis.},
journal = {Chest},
volume = {147},
number = {6},
pages = {1450-1452},
pmid = {26033121},
issn = {1931-3543},
support = {R01 HL093096/HL/NHLBI NIH HHS/United States ; },
mesh = {Bone Marrow/*pathology ; Female ; Humans ; Liver/*pathology ; Lung Diseases, Interstitial/*pathology ; Male ; Telomere/*enzymology/*pathology ; },
}
@article {pmid26028466,
year = {2015},
author = {Nasir, NF and Kannan, TP and Sulaiman, SA and Shamsuddin, S and Azlina, A and Stangaciu, S},
title = {The relationship between telomere length and beekeeping among Malaysians.},
journal = {Age (Dordrecht, Netherlands)},
volume = {37},
number = {3},
pages = {9797},
pmid = {26028466},
issn = {1574-4647},
mesh = {Adult ; Animals ; *Beekeeping ; Bees ; Blood Pressure/physiology ; Blotting, Southern ; Humans ; Longevity ; Malaysia ; Male ; Telomere Homeostasis/*physiology ; },
abstract = {The belief that beekeepers live longer than anyone else is present since ages. However, no research has been done to explore the longevity of life in beekeepers. Here, we investigated the telomere length in 30 male beekeepers and 30 male non-beekeepers and associated them with the longevity of life using Southern analysis of terminal restriction fragments (TRFs) generated by Hinf I/Rsa I digestion of human genomic DNA using TeloTAGGG Telomere Length Assay. Interestingly, we found that the telomere length of male beekeepers was significantly longer than those of male non-beekeepers with a p value of less than 0.05, suggesting that beekeepers may have longer life compared to non-beekeepers. We further found that the consumption of bee products for a long period and frequent consumption of bee products per day are associated with telomere length. An increase of year in consuming bee products is associated with a mean increase in telomere length of 0.258 kbp. In addition, an increase in frequency of eating bee products per day was also associated with a mean increase of 2.66 kbp in telomere length. These results suggested that bee products might play some roles in telomere length maintenance.},
}
@article {pmid26026117,
year = {2015},
author = {Kim, HS and Lee, HS and Nam, KH and Choi, J and Kim, WH},
title = {Telomere length abnormalities and telomerase RNA component expression in gastroenteropancreatic neuroendocrine tumors.},
journal = {Anticancer research},
volume = {35},
number = {6},
pages = {3501-3510},
pmid = {26026117},
issn = {1791-7530},
mesh = {Adaptor Proteins, Signal Transducing/biosynthesis ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Co-Repressor Proteins ; DNA Helicases/biosynthesis ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; In Situ Hybridization, Fluorescence ; Intestinal Neoplasms/*genetics/pathology ; Male ; Middle Aged ; Molecular Chaperones ; Neuroendocrine Tumors/*genetics/pathology ; Nuclear Proteins/biosynthesis ; Pancreatic Neoplasms/*genetics/pathology ; *Prognosis ; RNA/*biosynthesis/genetics ; Stomach Neoplasms/*genetics/pathology ; Telomerase/*biosynthesis/genetics ; Telomere Shortening/*genetics ; X-linked Nuclear Protein ; },
abstract = {Telomere lengths in normal human cells are tightly regulated within a narrow range. Telomere length abnormalities are prevalent genetic alterations in malignant transformation. We studied telomere length abnormalities, telomerase RNA component (TERC) expression, alpha-thalassemia X-linked mental retardation (ATRX) expression, and death domain-associated protein (DAXX) expression in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We used tissue microarrays to perform telomere fluorescent in situ hybridization (FISH) and TERC in situ hybridization in 327 formalin-fixed paraffin-embedded tissues of GEP-NETs. Telomere length abnormalities were detected in 35% of 253 informative cases by using telomere FISH. Ten cases had altered lengthening of telomeres (ALT), an ALT-positive phenotype (4%), and 79 cases had telomere shortening (31%). The ALT-positive phenotype was significantly associated with tumors of pancreatic origin (7/10) and loss of ATRX or DAXX protein (8/10). Telomere shortening was significantly associated with low TERC expression. In the survival analysis, loss of ATRX or DAXX protein was associated with a decreased overall survival. Multivariate regression analysis showed that lymph node metastasis and high TERC expression were independent prognostic factors of reduced overall survival (OS) for patients with GEP-NETs. Our results showed that telomere lengthening (the ALT-positive phenotype) and telomere shortening accompanied by low TERC levels are two types of clinically significant telomere abnormalities in GEP-NETs.},
}
@article {pmid26025910,
year = {2015},
author = {Du, J and Zhu, X and Xie, C and Dai, N and Gu, Y and Zhu, M and Wang, C and Gao, Y and Pan, F and Ren, C and Ji, Y and Dai, J and Ma, H and Jiang, Y and Chen, J and Yi, H and Zhao, Y and Hu, Z and Shen, H and Jin, G},
title = {Telomere length, genetic variants and gastric cancer risk in a Chinese population.},
journal = {Carcinogenesis},
volume = {36},
number = {9},
pages = {963-970},
doi = {10.1093/carcin/bgv075},
pmid = {26025910},
issn = {1460-2180},
mesh = {Case-Control Studies ; China ; Female ; *Genetic Predisposition to Disease ; Genetic Variation/genetics ; Genome-Wide Association Study ; Humans ; Male ; Middle Aged ; Risk ; Stomach Neoplasms/*epidemiology/*genetics ; Telomerase/genetics ; Telomere/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Telomeres maintain chromosomal stability and integrity and are crucial in carcinogenesis. Telomere length is implicated in multiple cancer risk, but the results are conflicting. Genome-wide association studies have identified several genetic loci associated with telomere length in Caucasians. However, the roles of telomere length and related variants on gastric cancer development are largely unknown. We conducted a case-control study including 1136 gastric cancer cases and 1012 controls to evaluate the associations between telomere length, eight telomere length-related variants identified in Caucasians and gastric cancer risk in Chinese population. We observed an obvious U-shaped association between telomere length and gastric cancer risk (P < 0.001), with odds ratios (95% confidence intervals) being 3.81 (2.82-5.13), 1.65 (1.21-2.26), 1.28 (0.93-1.77) and 1.78 (1.30-2.44) for individuals in the first (the shortest), second, third and fifth (the longest) quintile as compared with those in the fourth quintile as reference group. The weighted genetic score (WGS) of eight variants was significantly associated with telomere length (P < 0.001), and in particular, the G allele of rs2736100 in TERT at 5p15.33 exhibited a significant association with long telomeres (P = 0.047). However, we did not observe significant associations between these genetic variants and gastric cancer risk for both single-variant and WGS analyses. These findings suggest that either short or extreme long telomeres may be risk factor for gastric cancer. Genetic variants identified in Caucasians may also contribute to the variation of telomere length in Chinese but seems not to gastric cancer susceptibility.},
}
@article {pmid26025689,
year = {2016},
author = {Al-Issa, K and Tolle, LB and Purysko, AS and Hanouneh, IA},
title = {Short telomere syndrome and fibrosis.},
journal = {QJM : monthly journal of the Association of Physicians},
volume = {109},
number = {2},
pages = {125-126},
doi = {10.1093/qjmed/hcv115},
pmid = {26025689},
issn = {1460-2393},
mesh = {Adult ; Diagnosis, Differential ; Humans ; Hypertension, Portal/diagnosis/physiopathology ; Liver/pathology ; *Liver Cirrhosis/diagnosis/physiopathology ; Lung/pathology ; Male ; *Pulmonary Fibrosis/diagnosis/physiopathology ; Spirometry/methods ; Syndrome ; Telomere Shortening/*physiology ; Tomography, X-Ray Computed/methods ; },
}
@article {pmid26024529,
year = {2015},
author = {Tachtatzis, PM and Marshall, A and Arvinthan, A and Verma, S and Penrhyn-Lowe, S and Mela, M and Scarpini, C and Davies, SE and Coleman, N and Alexander, GJ},
title = {Chronic Hepatitis B Virus Infection: The Relation between Hepatitis B Antigen Expression, Telomere Length, Senescence, Inflammation and Fibrosis.},
journal = {PloS one},
volume = {10},
number = {5},
pages = {e0127511},
pmid = {26024529},
issn = {1932-6203},
support = {13080/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Antigens, Viral/*biosynthesis/genetics ; Cell Cycle Checkpoints ; *Cellular Senescence ; Female ; Hep G2 Cells ; Hepatitis B virus/genetics/*metabolism ; Hepatitis B, Chronic/genetics/*metabolism/pathology ; Hepatocytes/*metabolism/pathology/virology ; Humans ; Inflammation/genetics/metabolism/pathology/virology ; Liver Cirrhosis/genetics/*metabolism/pathology/virology ; Male ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Chronic Hepatitis B virus (HBV) infection can lead to the development of chronic hepatitis, cirrhosis and hepatocellular carcinoma. We hypothesized that HBV might accelerate hepatocyte ageing and investigated the effect of HBV on hepatocyte cell cycle state and biological age. We also investigated the relation between inflammation, fibrosis and cell cycle phase.<br><br>METHODS: Liver samples from patients with chronic HBV (n = 91), normal liver (n = 55) and regenerating liver (n = 15) were studied. Immunohistochemistry for cell cycle phase markers and HBV antigens was used to determine host cell cycle phase. Hepatocyte-specific telomere length was evaluated by quantitative fluorescent in-situ hybridization (Q-FISH) in conjunction with hepatocyte nuclear area and HBV antigen expression. The effects of induced cell cycle arrest and induced cellular senescence on HBV production were assessed in vitro.<br><br>RESULTS: 13.7% hepatocytes in chronic HBV had entered cell cycle, but expression of markers for S, G2 and M phase was low compared with regenerating liver. Hepatocyte p21 expression was increased (10.9%) in chronic HBV and correlated with liver fibrosis. Mean telomere length was reduced in chronic HBV compared to normal. However, within HBV-affected livers, hepatocytes expressing HBV antigens had longer telomeres. Telomere length declined and hepatocyte nuclear size increased as HBV core antigen (HBcAg) expression shifted from the nucleus to cytoplasm. Nuclear co-expression of HBcAg and p21 was not observed. Cell cycle arrest induced in vitro was associated with increased HBV production, in contrast to in vitro induction of cellular senescence, which had no effect.<br><br>CONCLUSION: Chronic HBV infection was associated with hepatocyte G1 cell cycle arrest and accelerated hepatocyte ageing, implying that HBV induced cellular senescence. However, HBV replication was confined to biologically younger hepatocytes. Changes in the cellular location of HBcAg may be related to the onset of cellular senescence.},
}
@article {pmid26022559,
year = {2014},
author = {Gurung, RL and Lim, SN and Low, GK and Hande, MP},
title = {MST-312 Alters Telomere Dynamics, Gene Expression Profiles and Growth in Human Breast Cancer Cells.},
journal = {Journal of nutrigenetics and nutrigenomics},
volume = {7},
number = {4-6},
pages = {283-298},
doi = {10.1159/000381346},
pmid = {26022559},
issn = {1661-6758},
mesh = {Antineoplastic Agents/administration &amp; dosage/pharmacology ; Benzamides/administration &amp; dosage/*pharmacology ; Breast Neoplasms/*drug therapy/genetics/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Damage ; Down-Regulation/drug effects ; Drug Synergism ; Enzyme Inhibitors/administration &amp; dosage/pharmacology ; Female ; Humans ; MCF-7 Cells ; Nutrigenomics ; Phenanthrenes/administration &amp; dosage/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/administration &amp; dosage/pharmacology ; Recombinational DNA Repair/drug effects/genetics ; Telomerase/antagonists &amp; inhibitors ; Telomere/*drug effects/genetics ; Telomere Shortening/drug effects ; Transcriptome/drug effects ; },
abstract = {BACKGROUND: Targeting telomerase is a potential cancer management strategy given that it allows unlimited cellular replication in the majority of cancers. Dysfunctional telomeres are recognized as double-strand breaks. However, the status of DNA repair response pathways following telomerase inhibition is not well understood in human breast cancer cells. Here, we evaluated the effects of MST-312, a chemically modified derivative from tea catechin, epigallocatechin gallate, on telomere dynamics and DNA damage gene expression in breast cancer cells.<br><br>METHODOLOGY: Breast cancer cells MCF-7 and MDA-MB-231 were treated with MST-312, and telomere-telomerase homeostasis, induced DNA damage and gene expression profiling were analyzed.<br><br>RESULTS: MST-312 decreased telomerase activity and induced telomere dysfunction and growth arrest in breast cancer cells with more profound effects in MDA-MB-231 than in MCF-7 cells. Consistent with these data, the telomere-protective protein TRF2 was downregulated in MDA-MB-231 cells. MST-312 induced DNA damage at telomeres accompanied by reduced expression of DNA damage-related genes ATM and RAD50. Co-treatment with MST-312 and the poly(ADP-ribose) polymerase 1 (PARP-1) inhibitor PJ-34 further enhanced growth reduction as compared to single treatment with MST-312 or PJ-34.<br><br>CONCLUSIONS: Our work demonstrates potential importance for the establishment of antitelomerase cancer therapy using MST-312 along with PARP-1 inhibition in breast cancer therapy.},
}
@article {pmid26022452,
year = {2015},
author = {Lee, JC and Jeng, YM and Liau, JY and Tsai, JH and Hsu, HH and Yang, CY},
title = {Alternative lengthening of telomeres and loss of ATRX are frequent events in pleomorphic and dedifferentiated liposarcomas.},
journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},
volume = {28},
number = {8},
pages = {1064-1073},
pmid = {26022452},
issn = {1530-0285},
mesh = {Adaptor Proteins, Signal Transducing/analysis ; Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/*analysis/genetics ; *Cell Dedifferentiation ; Co-Repressor Proteins ; DNA Helicases/*analysis ; Disease Progression ; Disease-Free Survival ; Down-Regulation ; Female ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Kaplan-Meier Estimate ; Liposarcoma/*enzymology/genetics/mortality/pathology/therapy ; Male ; Middle Aged ; Molecular Chaperones ; Nuclear Proteins/*analysis ; Proportional Hazards Models ; Risk Factors ; *Telomere Homeostasis ; Time Factors ; Treatment Outcome ; X-linked Nuclear Protein ; },
abstract = {Telomerase activation and alternative lengthening of telomeres are two major mechanisms of telomere length maintenance. Soft tissue sarcomas appear to use the alternative lengthening of telomeres more frequently. Loss of α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated protein 6 (DAXX) expression has been implicated in the pathogenesis of alternative telomere lengthening in pancreatic endocrine neoplasm and glioma. The mechanism leading to the alternative lengthening of telomeres in liposarcoma remains unknown. Whereas alternative telomere lengthening was determined to be an indicator of poor prognosis in liposarcomas as a whole, its prognostic power has not been verified in any subtype of liposarcoma. In this study, we characterized the status of alternative telomere lengthening and expression of ATRX and DAXX in 111 liposarcomas (28 well-differentiated, 52 dedifferentiated, 20 myxoid or round cell, and 11 pleomorphic liposarcomas) by telomere fluorescence in situ hybridization and immunohistochemistry, respectively. Alternative lengthening of telomere was observed in 0% (0/16) of well-differentiated, 30% (14/46) of dedifferentiated, 5% (1/19) of myxoid or round cell, and 80% (8/10) of pleomorphic liposarcomas. Eighteen (16%) and one (1%) tumors were negative for ATRX and DAXX immunostaining, respectively. Remarkably, all cases with loss of either ATRX or DAXX expression had alternative lengthening of telomeres, and 83% (19/23) of tumors that had alternative lengthening of telomeres showed loss of either protein. The correlation between loss of either ATRX or DAXX and alternative telomere lengthening was 100% in dedifferentiated liposarcoma. The presence of alternative telomere lengthening in dedifferentiated liposarcoma suggested poor overall survival (hazard ratio=1.954, P=0.077) and was the most significant indicator of short progression-free survival (hazard ratio=3.119, P=0.003). In conclusion, we found that ATRX loss was the most likely mechanism of alternative telomere lengthening in liposarcoma and alternative telomere lengthening was a prognostic factor of poor outcome in dedifferentiated liposarcoma.},
}
@article {pmid26021168,
year = {2015},
author = {Runov, AL and Vonsky, MS and Mikhelson, VM},
title = {[DNA methylation level and telomere length as a basis for the biological aging clock model construction].},
journal = {Tsitologiia},
volume = {57},
number = {3},
pages = {192-196},
pmid = {26021168},
issn = {0041-3771},
mesh = {Aging/*genetics ; Cellular Senescence/genetics ; DNA/genetics/metabolism ; *DNA Methylation ; Epigenesis, Genetic ; Eukaryotic Cells/cytology/metabolism ; Humans ; Longevity/*genetics ; *Models, Biological ; Nucleic Acid Denaturation ; Real-Time Polymerase Chain Reaction ; Telomere/*chemistry ; Telomere Homeostasis/*genetics ; },
abstract = {Aging is a process that depends on a variety of both external and internal factors. The biological age of a person determines body deterioration and the risk of age-related diseases. Currently, as indicators of biological age are considered different characteristics including average length of telomeres in cells and the level DNA methylation. We propose to combine the two approaches to create a model to assess the biological age of the person. Application of qPCR to determina the length of telomeres and MS-HRM for analysis of DNA methylation will help us to determine the parameters of interest quickly when using a minimum set of equipment.},
}
@article {pmid26016050,
year = {2015},
author = {Trăilă, D and Mlădinescu, OF and Oancea, C and Tudorache, V},
title = {Short telomeres in pulmonary fibrosis: from genetics to clinical significance.},
journal = {Pneumologia (Bucharest, Romania)},
volume = {64},
number = {1},
pages = {8, 11-3},
pmid = {26016050},
issn = {2067-2993},
mesh = {Genetic Markers/genetics ; Humans ; *Mutation ; Phenotype ; Predictive Value of Tests ; Pulmonary Fibrosis/diagnosis/*genetics ; RNA/genetics ; Risk Factors ; Sensitivity and Specificity ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {Pulmonary fibrosis has been linked molecularly and pathophysiologically by abnormal telomere maintenance. Short telomere lengths are commonly found in both the familial and sporadic forms, telomerase mutations being the most common identifiable genetic cause of the disease. Telomeres are repeated nucleotide sequences that cap the ends of chromosomes and protect them from damage. Telomeres are eroded with cell division and shorten with age. Telomere integrity is mediated by the telomerase complex, a specialized polymerase that adds sequences to the ends of chromosomes. Mutations in the genes encoding telomerase (TERT and TERC) cause pulmonary fibrosis through low telomerase activity, accelerated telomere shortening and exhaustion of lung stem cells. Mutations in TERTor TERC account for only 19% of familial pulmonary fibrosis cases, and it is likely that additional environmental, genetic and epigenetic factors contribute to telomere erosion and to disease phenotype. Identification of short telomeres has potential clinical implications in pulmonary fibrosis: it may be a marker for an increased predisposition toward the development of the disease, it might affect risk stratification as it has been associated with lower survival rates and post-transplant complications that reflect the syndromic nature of this molecular defect.},
}
@article {pmid26014050,
year = {2015},
author = {Walsh, KM and Wiencke, JK and Lachance, DH and Wiemels, JL and Molinaro, AM and Eckel-Passow, JE and Jenkins, RB and Wrensch, MR},
title = {Telomere maintenance and the etiology of adult glioma.},
journal = {Neuro-oncology},
volume = {17},
number = {11},
pages = {1445-1452},
pmid = {26014050},
issn = {1523-5866},
support = {R01CA126831/CA/NCI NIH HHS/United States ; RC1NS068222Z/NS/NINDS NIH HHS/United States ; P50 CA097257/CA/NCI NIH HHS/United States ; R25CA112355/CA/NCI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; P50CA097257/CA/NCI NIH HHS/United States ; P50CA108961/CA/NCI NIH HHS/United States ; R01CA52689/CA/NCI NIH HHS/United States ; R01 CA052689/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Brain Neoplasms/*genetics ; Glioma/*genetics ; Humans ; Telomere/*genetics ; },
abstract = {A growing body of epidemiologic and tumor genomic research has identified an important role for telomere maintenance in glioma susceptibility, initiation, and prognosis. Telomere length has long been investigated in relation to cancer, but whether longer or shorter telomere length might be associated with glioma risk has remained elusive. Recent data address this question and are reviewed here. Common inherited variants near the telomerase-component genes TERC and TERT are associated both with longer telomere length and increased risk of glioma. Exome sequencing of glioma patients from families with multiple affected members has identified rare inherited mutations in POT1 (protection of telomeres protein 1) as high-penetrance glioma risk factors. These heritable POT1 mutations are also associated with increased telomere length in leukocytes. Tumor sequencing studies further indicate that acquired somatic mutations of TERT and ATRX are among the most frequent alterations found in adult gliomas. These mutations facilitate telomere lengthening, thus bypassing a critical mechanism of apoptosis. Although future research is needed, mounting evidence suggests that glioma is, at least in part, a disease of telomere dysregulation. Specifically, several inherited and acquired variants underlying gliomagenesis affect telomere pathways and are also associated with increased telomere length.},
}
@article {pmid26013103,
year = {2015},
author = {Li, H and Hedmer, M and Wojdacz, T and Hossain, MB and Lindh, CH and Tinnerberg, H and Albin, M and Broberg, K},
title = {Oxidative stress, telomere shortening, and DNA methylation in relation to low-to-moderate occupational exposure to welding fumes.},
journal = {Environmental and molecular mutagenesis},
volume = {56},
number = {8},
pages = {684-693},
pmid = {26013103},
issn = {1098-2280},
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Adult ; Biomarkers/analysis ; Case-Control Studies ; DNA Methylation/*drug effects ; Deoxyguanosine/analogs &amp; derivatives/urine ; Homeodomain Proteins/genetics ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Middle Aged ; Occupational Exposure/*adverse effects/analysis ; Oxidative Stress/*drug effects ; Telomere Shortening/*drug effects ; Tumor Suppressor Proteins/genetics ; *Welding ; Young Adult ; },
abstract = {Evidence suggests that exposure to welding fumes is a risk factor for lung cancer. We examined relationships between low-to-moderate occupational exposure to particles from welding fumes and cancer-related biomarkers for oxidative stress, changes in telomere length, and alterations in DNA methylation. We enrolled 101 welders and 127 controls (all currently nonsmoking men) from southern Sweden. We performed personal sampling of respirable dust and measured 8-oxodG concentrations in urine using a simplified liquid chromatography tandem mass spectrometry method. Telomere length in peripheral blood was measured by quantitative polymerase chain reaction. Methylation status of 10 tumor suppressor genes was determined by methylation-sensitive high-resolution melting analysis. All analyses were adjusted for age, body mass index, previous smoking, passive smoking, current residence, and wood burning stove/boiler at home. Welders were exposed to respirable dust at 1.2 mg/m(3) (standard deviation, 3.3 mg/m(3); range, 0.1-19.3), whereas control exposures did not exceed 0.1 mg/m(3) (P < 0.001). Welders and controls did not differ in 8-oxodG levels (β = 1.2, P = 0.17) or relative telomere length (β = -0.053, P = 0.083) in adjusted models. Welders showed higher probability of adenomatous polyposis coli (APC) methylation in the unadjusted model (odds ratio = 14, P = 0.014), but this was not significant in the fully adjusted model (P = 0.052). Every working year as a welder was associated with 0.0066 units shorter telomeres (95% confidence interval -0.013 to -0.00053, P = 0.033). Although there were no clear associations between concentrations of respirable dust and the biomarkers, there were modest signs of associations between oxidative stress, telomere alterations, DNA methylation, and occupational exposure to low-to-moderate levels of particles.},
}
@article {pmid26008147,
year = {2015},
author = {Dos Santos, P and Panero, J and Palau Nagore, V and Stanganelli, C and Bezares, RF and Slavutsky, I},
title = {Telomere shortening associated with increased genomic complexity in chronic lymphocytic leukemia.},
journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine},
volume = {36},
number = {11},
pages = {8317-8324},
pmid = {26008147},
issn = {1423-0380},
mesh = {Adult ; Aged ; Aged, 80 and over ; Chromosome Aberrations ; Chromosomes, Human, Pair 11/genetics ; Chromosomes, Human, Pair 17/genetics ; Female ; *Genome, Human ; Genomic Instability ; Genomics ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/pathology ; Male ; Middle Aged ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Telomeric dysfunction has been proposed as an emerging prognostic factor in chronic lymphocytic leukemia (CLL). We have explored the relationship between telomere length (TL) and chromosome alterations studied by fluorescence in situ hybridization (FISH) and conventional cytogenetics in 107 newly diagnosed CLL patients; 61 normal controls were also evaluated. Results were correlated with clinical parameters and outcome. Absolute TL measurement was carried out on DNA samples by real-time quantitative PCR. A significant telomere shortening in patients compared to controls was observed (p = 0.0001). The analysis taking into account FISH risk groups showed shorter TLs in cases with del11q/17p compared to patients with 13q14 deletion as a single alteration (p = 0.0037), no alterations (NA) (p = 0.028), and cases with abnormal karyotypes (p = 0.014). In addition, a significant TL reduction in cases with two or more anomalies with respect to those with NA (p = 0.033) and with one alteration (p = 0.045), and no differences compared to cases with deletions 11q/17p were observed. Patients with only one anomaly did not show statistical differences with respect to controls; meanwhile, a significant TL reduction in cases with two or more aberrations was observed (p = 0.025). The shortest telomeres were associated to 11q/17p deletion with significant differences compared to the remaining groups (p ≤ 0.045). Significantly shorter treatment free survival in patients with two or more alterations compared to those with NA plus one abnormality was observed (p = 0.0006). Our findings support the association between short TL and chromosome alterations in CLL and indicate the importance of telomere dysfunction in driving genomic instability in this pathology.},
}
@article {pmid26007659,
year = {2015},
author = {Lucyshyn, D and Huang, SH and Kobryn, K},
title = {Spring loading a pre-cleavage intermediate for hairpin telomere formation.},
journal = {Nucleic acids research},
volume = {43},
number = {12},
pages = {6062-6074},
pmid = {26007659},
issn = {1362-4962},
support = {MOP 79344//Canadian Institutes of Health Research/Canada ; },
mesh = {Bacterial Proteins/chemistry/genetics/*metabolism ; Catalytic Domain/genetics ; Cold Temperature ; DNA/chemistry/metabolism ; DNA Cleavage ; DNA Replication ; Endodeoxyribonucleases/chemistry/genetics/*metabolism ; Models, Genetic ; Mutation ; Nucleic Acid Conformation ; Recombinases/chemistry/genetics/*metabolism ; Telomere/*chemistry/*metabolism ; },
abstract = {The Borrelia telomere resolvase, ResT, forms the unusual hairpin telomeres of the linear Borrelia replicons in a process referred to as telomere resolution. Telomere resolution is a DNA cleavage and rejoining reaction that proceeds from a replicated telomere intermediate in a reaction with mechanistic similarities to that catalyzed by type IB topoisomerases. Previous reports have implicated the hairpin-binding module, at the end of the N-terminal domain of ResT, in distorting the DNA between the scissile phosphates so as to promote DNA cleavage and hairpin formation by the catalytic domain. We report that unwinding the DNA between the scissile phosphates, prior to DNA cleavage, is a key cold-sensitive step in telomere resolution. Through the analysis of ResT mutants, rescued by substrate modifications that mimic DNA unwinding between the cleavage sites, we show that formation and/or stabilization of an underwound pre-cleavage intermediate depends upon cooperation of the hairpin-binding module and catalytic domain. The phenotype of the mutants argues that the pre-cleavage intermediate promotes strand ejection to favor the forward reaction and that subsequent hairpin capture is a reversible reaction step. These reaction features are proposed to promote hairpin formation over strand resealing while allowing reversal back to substrate of aborted reactions.},
}
@article {pmid26004986,
year = {2016},
author = {Ferrari, F and Facchinetti, F and Saade, G and Menon, R},
title = {Placental telomere shortening in stillbirth: a sign of premature senescence?.},
journal = {The journal of maternal-fetal &amp; neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians},
volume = {29},
number = {8},
pages = {1283-1288},
doi = {10.3109/14767058.2015.1046045},
pmid = {26004986},
issn = {1476-4954},
mesh = {Adult ; Aging/pathology ; Female ; Gestational Age ; Humans ; Placenta/*pathology ; Placental Insufficiency/pathology ; Pregnancy ; Premature Birth ; Real-Time Polymerase Chain Reaction ; Stillbirth/*genetics ; *Telomere Shortening ; Young Adult ; },
abstract = {OBJECTIVE: The objective of this study is to investigate placental telomere shortening in unexplained stillbirths (SBs) as an indication of premature senescence.<br><br>METHODS: Placentas were collected from 42 unexplained SB (>22 weeks), 43 term and 15 preterm live births, at the Policlinico Hospital of Modena (Italy). DNA extracted from placentae was studied for telomere length by real time PCR. Standard curves were generated for telomere lengths from single copy gene amplifications using a reference DNA. The telomere length for each sample was derived based on the ratio of telomere length between the sample and single copy gene standard (T/S ratio). The mean ratio of placental telomere in term live births was 5.181 &#xb1; 3.841.<br><br>RESULTS: A twofold decrease in telomere length was seen in SBs (over all 2.455 &#xb1; 1.239; p < 0.001). For early SBs (above 34 weeks), the T/S was 2.8884 &#xb1; 1.224 and for late SBs, the T/S was 2.207 &#xb1; 1.201, both lower than term live births (both p < 0.01). T/S remained lower both in small for gestational age-SB (2.639 &#xb1; 1.619) and appropriate for gestational age-SB (2.653 &#xb1; 1.335) with no difference between these subgroups (p = ns). T/S was lower in SB compared with spontaneous preterm births (PTBs) (6.382 &#xb1; 5.525; p < 0.01), whereas SBs telomere length were similar to those of preterm premature rupture of membranes (pPROM) (3.296 &#xb1; 3.599; p = ns).<br><br>CONCLUSIONS: Substantial reduction in telomere length in SBs is indicative of placental senescence. These data provide mechanistic insights that premature aging may lead to placental dysfunction as an initiator of fetal demise in unexplained SBs.},
}
@article {pmid26004856,
year = {2015},
author = {Marcomini, I and Gasser, SM},
title = {Nuclear organization in DNA end processing: Telomeres vs double-strand breaks.},
journal = {DNA repair},
volume = {32},
number = {},
pages = {134-140},
doi = {10.1016/j.dnarep.2015.04.024},
pmid = {26004856},
issn = {1568-7856},
mesh = {Animals ; Cell Nucleus/metabolism ; DNA/*chemistry/metabolism ; *DNA Breaks, Double-Stranded ; *DNA Repair ; DNA-Binding Proteins/genetics/metabolism ; Endodeoxyribonucleases/genetics/metabolism ; Endonucleases/genetics/metabolism ; Eukaryotic Cells/cytology/metabolism ; Exodeoxyribonucleases/genetics/metabolism ; Gene Expression Regulation ; Humans ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomerase/*genetics/metabolism ; Telomere/*chemistry/metabolism ; },
abstract = {Many proteins ligands are shared between double-strand breaks and natural chromosomal ends or telomeres. The structural similarity of the 3' overhang, and the efficiency of cellular DNA end degradation machineries, highlight the need for mechanisms that resect selectively to promote or restrict recombination events. Here we examine the means used by eukaryotic cells to suppress resection at telomeres, target telomerase to short telomeres, and process broken ends for appropriate repair. Not only molecular ligands, but the spatial sequestration of telomeres and damage likely ensure that these two very similar structures have very distinct outcomes with respect to the DNA damage response and repair.},
}
@article {pmid26001753,
year = {2015},
author = {Borghini, A and Giardini, G and Tonacci, A and Mastorci, F and Mercuri, A and Mrakic-Sposta, S and Moretti, S and Andreassi, MG and Pratali, L},
title = {Chronic and acute effects of endurance training on telomere length.},
journal = {Mutagenesis},
volume = {30},
number = {5},
pages = {711-716},
doi = {10.1093/mutage/gev038},
pmid = {26001753},
issn = {1464-3804},
mesh = {Adult ; Aging/physiology ; Athletes ; Humans ; Male ; Middle Aged ; *Physical Endurance ; Real-Time Polymerase Chain Reaction ; Running/*physiology ; Telomere Shortening/*physiology ; },
abstract = {Telomere shortening is considered a cellular marker of health status and biological ageing. Exercise may influence the health and lifespan of an individual by affecting telomere length (TL). However, it is unclear whether different endurance exercise levels may have beneficial or detrimental effects on biological aging. The aims of the study were to assess both chronic and acute effects of endurance training on TL after an exceptional and extreme trail race. TL was assessed in 20 endurance athletes (17 males; age = 45.4 ± 9.2 years) and 42 age- and gender-matched sedentary controls (32 males; age = 45.9 ± 9.5 years) with quantitative real-time PCR at baseline conditions. Of the 20 runners enrolled in the 'Tor des Géants ®' ultra-distance trail race, 15 athletes (12 males; age = 47.2 ± 8.5 years) were re-evaluated at the intermediate point and 14 athletes (11 males; age = 47.1 ± 8.8 years) completed the competition and were analysed at the final point. Comparison between the two groups (endurance athletes vs. sedentary controls) revealed a significant difference in TL (1.28 ± 0.4 vs. 1.02 ± 0.3, P = 0.005). TL was better preserved in elder endurance runners compared with the same age control group (1.3 ± 0.27 vs. 0.91 ± 0.21, P = 0.003). TL was significantly reduced at the intermediate (0.88 ± 0.36 vs. 1.11 ± 0.34, P = 0.002) and final point compared with baseline measurements (0.86 ± 0.4 vs. 1.11 ± 0.34, P = 0.0006) for athletes engaged in the ultra-marathon race. Our data suggest that chronic endurance training may provide protective effects on TL attenuating biological aging. Conversely, acute exposure to an ultra-distance endurance trail race implies telomere shortening probably caused by oxidative DNA damage.},
}
@article {pmid26001292,
year = {2015},
author = {Napier, CE and Huschtscha, LI and Harvey, A and Bower, K and Noble, JR and Hendrickson, EA and Reddel, RR},
title = {ATRX represses alternative lengthening of telomeres.},
journal = {Oncotarget},
volume = {6},
number = {18},
pages = {16543-16558},
pmid = {26001292},
issn = {1949-2553},
support = {CA154461/CA/NCI NIH HHS/United States ; GM088351/GM/NIGMS NIH HHS/United States ; R01 CA154461/CA/NCI NIH HHS/United States ; R01 GM088351/GM/NIGMS NIH HHS/United States ; R01 CA190492/CA/NCI NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing/biosynthesis/*genetics ; Cell Line, Transformed ; Co-Repressor Proteins ; DNA Helicases/biosynthesis/*genetics ; Humans ; Male ; Molecular Chaperones ; Neoplasms/genetics ; Nuclear Proteins/biosynthesis/*genetics ; RNA Interference ; RNA, Small Interfering ; Simian virus 40/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; X-linked Nuclear Protein ; },
abstract = {The unlimited proliferation of cancer cells requires a mechanism to prevent telomere shortening. Alternative Lengthening of Telomeres (ALT) is an homologous recombination-mediated mechanism of telomere elongation used in tumors, including osteosarcomas, soft tissue sarcoma subtypes, and glial brain tumors. Mutations in the ATRX/DAXX chromatin remodeling complex have been reported in tumors and cell lines that use the ALT mechanism, suggesting that ATRX may be an ALT repressor. We show here that knockout or knockdown of ATRX in mortal cells or immortal telomerase-positive cells is insufficient to activate ALT. Notably, however, in SV40-transformed mortal fibroblasts ATRX loss results in either a significant increase in the proportion of cell lines activating ALT (instead of telomerase) or in a significant decrease in the time prior to ALT activation. These data indicate that loss of ATRX function cooperates with one or more as-yet unidentified genetic or epigenetic alterations to activate ALT. Moreover, transient ATRX expression in ALT-positive/ATRX-negative cells represses ALT activity. These data provide the first direct, functional evidence that ATRX represses ALT.},
}
@article {pmid25999344,
year = {2015},
author = {Galati, A and Micheli, E and Alicata, C and Ingegnere, T and Cicconi, A and Pusch, MC and Giraud-Panis, MJ and Gilson, E and Cacchione, S},
title = {TRF1 and TRF2 binding to telomeres is modulated by nucleosomal organization.},
journal = {Nucleic acids research},
volume = {43},
number = {12},
pages = {5824-5837},
pmid = {25999344},
issn = {1362-4962},
mesh = {Binding Sites ; DNA/metabolism ; Histones/metabolism ; Nucleosomes/chemistry/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Repetitive Sequences, Nucleic Acid ; Telomere/chemistry/*metabolism ; Telomeric Repeat Binding Protein 1/chemistry/*metabolism ; Telomeric Repeat Binding Protein 2/chemistry/*metabolism ; },
abstract = {The ends of eukaryotic chromosomes need to be protected from the activation of a DNA damage response that leads the cell to replicative senescence or apoptosis. In mammals, protection is accomplished by a six-factor complex named shelterin, which organizes the terminal TTAGGG repeats in a still ill-defined structure, the telomere. The stable interaction of shelterin with telomeres mainly depends on the binding of two of its components, TRF1 and TRF2, to double-stranded telomeric repeats. Tethering of TRF proteins to telomeres occurs in a chromatin environment characterized by a very compact nucleosomal organization. In this work we show that binding of TRF1 and TRF2 to telomeric sequences is modulated by the histone octamer. By means of in vitro models, we found that TRF2 binding is strongly hampered by the presence of telomeric nucleosomes, whereas TRF1 binds efficiently to telomeric DNA in a nucleosomal context and is able to remodel telomeric nucleosomal arrays. Our results indicate that the different behavior of TRF proteins partly depends on the interaction with histone tails of their divergent N-terminal domains. We propose that the interplay between the histone octamer and TRF proteins plays a role in the steps leading to telomere deprotection.},
}
@article {pmid25999341,
year = {2015},
author = {Sui, J and Lin, YF and Xu, K and Lee, KJ and Wang, D and Chen, BP},
title = {DNA-PKcs phosphorylates hnRNP-A1 to facilitate the RPA-to-POT1 switch and telomere capping after replication.},
journal = {Nucleic acids research},
volume = {43},
number = {12},
pages = {5971-5983},
pmid = {25999341},
issn = {1362-4962},
support = {R01 CA166677/CA/NCI NIH HHS/United States ; CA166677/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; DNA Repair ; *DNA Replication ; DNA, Single-Stranded/metabolism ; DNA-Activated Protein Kinase/*metabolism ; Heterogeneous Nuclear Ribonucleoprotein A1 ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/*metabolism ; Humans ; Nuclear Proteins/*metabolism ; Phosphorylation ; Replication Protein A/*metabolism ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {The heterogeneous nuclear ribonucleoprotein A1 (hnRNP-A1) has been implicated in telomere protection and telomerase activation. Recent evidence has further demonstrated that hnRNP-A1 plays a crucial role in maintaining newly replicated telomeric 3' overhangs and facilitating the switch from replication protein A (RPA) to protection of telomeres 1 (POT1). The role of hnRNP-A1 in telomere protection also involves DNA-dependent protein kinase catalytic subunit (DNA-PKcs), although the detailed regulation mechanism has not been clear. Here we report that hnRNP-A1 is phosphorylated by DNA-PKcs during the G2 and M phases and that DNA-PK-dependent hnRNP-A1 phosphorylation promotes the RPA-to-POT1 switch on telomeric single-stranded 3' overhangs. Consequently, in cells lacking hnRNP-A1 or DNA-PKcs-dependent hnRNP-A1 phosphorylation, impairment of the RPA-to-POT1 switch results in DNA damage response at telomeres during mitosis as well as induction of fragile telomeres. Taken together, our results indicate that DNA-PKcs-dependent hnRNP-A1 phosphorylation is critical for capping of the newly replicated telomeres and prevention of telomeric aberrations.},
}
@article {pmid25999120,
year = {2015},
author = {Lindqvist, D and Epel, ES and Mellon, SH and Penninx, BW and Révész, D and Verhoeven, JE and Reus, VI and Lin, J and Mahan, L and Hough, CM and Rosser, R and Bersani, FS and Blackburn, EH and Wolkowitz, OM},
title = {Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging.},
journal = {Neuroscience and biobehavioral reviews},
volume = {55},
number = {},
pages = {333-364},
pmid = {25999120},
issn = {1873-7528},
support = {R01 AG030424/AG/NIA NIH HHS/United States ; R01 MH083784/MH/NIMH NIH HHS/United States ; 01AG030424-01A1/AG/NIA NIH HHS/United States ; R01MH083784/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Cellular Senescence/*genetics ; Child ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Mental Disorders/*genetics ; Middle Aged ; Telomere/*metabolism ; Young Adult ; },
abstract = {Many psychiatric illnesses are associated with early mortality and with an increased risk of developing physical diseases that are more typically seen in the elderly. Moreover, certain psychiatric illnesses may be associated with accelerated cellular aging, evidenced by shortened leukocyte telomere length (LTL), which could underlie this association. Shortened LTL reflects a cell's mitotic history and cumulative exposure to inflammation and oxidation as well as the availability of telomerase, a telomere-lengthening enzyme. Critically short telomeres can cause cells to undergo senescence, apoptosis or genomic instability, and shorter LTL correlates with poorer health and predicts mortality. Emerging data suggest that LTL may be reduced in certain psychiatric illnesses, perhaps in proportion to exposure to the psychiatric illnesses, although conflicting data exist. Telomerase has been less well characterized in psychiatric illnesses, but a role in depression and in antidepressant and neurotrophic effects has been suggested by preclinical and clinical studies. In this article, studies on LTL and telomerase activity in psychiatric illnesses are critically reviewed, potential mediators are discussed, and future directions are suggested. A deeper understanding of cellular aging in psychiatric illnesses could lead to re-conceptualizing them as systemic illnesses with manifestations inside and outside the brain and could identify new treatment targets.},
}
@article {pmid25998404,
year = {2015},
author = {},
title = {Telomere Dysfunction-Induced DNA Damage Drives Myelodysplastic Syndrome.},
journal = {Cancer discovery},
volume = {5},
number = {7},
pages = {OF25},
doi = {10.1158/2159-8290.CD-RW2015-092},
pmid = {25998404},
issn = {2159-8290},
mesh = {DNA Damage ; Humans ; Myelodysplastic Syndromes/genetics/*pathology ; RNA Splicing ; *Telomere Shortening ; },
abstract = {Telomere erosion-induced DNA damage alters myeloid progenitor differentiation and induces MDS.},
}
@article {pmid25998012,
year = {2016},
author = {Toutain, J and Prochazkova-Carlotti, M and Horovitz, J and Saura, R and Merlio, JP and Chevret, E},
title = {Evaluation of Quantitative Fluorescence in situ Hybridization for Relative Measurement of Telomere Length in Placental Mesenchymal Core Cells.},
journal = {Gynecologic and obstetric investigation},
volume = {81},
number = {1},
pages = {54-60},
doi = {10.1159/000381896},
pmid = {25998012},
issn = {1423-002X},
mesh = {Adult ; Chorionic Villi Sampling ; Female ; Humans ; In Situ Hybridization, Fluorescence/*standards ; Placenta/*cytology ; Pregnancy ; Telomere/*chemistry ; },
abstract = {BACKGROUND: Reduced telomere length in placental mesenchymal core cells has been reported during pregnancies complicated by intrauterine growth restriction. To estimate telomere length, a precise, accurate and reproducible technique must be used.<br><br>OBJECTIVE: We evaluated the characteristics of a quantitative fluorescence in situ hybridization (Q-FISH) technique for measuring relative telomere length in placental mesenchymal core cells.<br><br>METHODS: From late chorionic villus samplings, telomere length in placental mesenchymal core cells was estimated by a Q-FISH technique using peptide nucleic acid telomere probes. The main characteristics of the Q-FISH technique, such as precision and reproducibility, were evaluated.<br><br>RESULTS: The telomere length of the cultured placental mesenchymal cells did not follow a normal distribution. When the Q-FISH technique was performed on interphase nuclei of uncultured mesenchymal core cells, normal telomere length distribution was observed. The precision of the technique when applied to cultured placental mesenchymal core cells was estimated to be <6%, and its reproducibility ranged from to 92.9 to 104.7%.<br><br>CONCLUSION: Our results showed that cell culture of placental villi produced a non-normal telomere length distribution, probably related to telomere DNA replication during the cell cycle. Despite the influence of cell culture, the Q-FISH technique reported herein showed good precision and reproducibility.},
}
@article {pmid25997822,
year = {2015},
author = {Virgilio, A and Esposito, V and Mayol, L and Giancola, C and Petraccone, L and Galeone, A},
title = {The oxidative damage to the human telomere: effects of 5-hydroxymethyl-2'-deoxyuridine on telomeric G-quadruplex structures.},
journal = {Organic &amp; biomolecular chemistry},
volume = {13},
number = {27},
pages = {7421-7429},
doi = {10.1039/c5ob00748h},
pmid = {25997822},
issn = {1477-0539},
mesh = {Calorimetry, Differential Scanning ; Circular Dichroism ; Electrophoresis, Polyacrylamide Gel ; *G-Quadruplexes ; Humans ; Nucleic Acid Denaturation ; Oxidation-Reduction ; Telomere/*chemistry ; Temperature ; Thymidine/*analogs &amp; derivatives/chemistry ; },
abstract = {As part of the genome, human telomeric regions can be damaged by the chemically reactive molecules responsible for oxidative DNA damage. Considering that G-quadruplex structures have been proven to occur in human telomere regions, several studies have been devoted to investigating the effect of oxidation products on the properties of these structures. However only investigations concerning the presence in G-quadruplexes of the main oxidation products of deoxyguanosine and deoxyadenosine have appeared in the literature. Here, we investigated the effects of 5-hydroxymethyl-2'-deoxyuridine (5-hmdU), one of the main oxidation products of T, on the physical-chemical properties of the G-quadruplex structures formed by two human telomeric sequences. Collected calorimetric, circular dichroism and electrophoretic data suggest that, in contrast to most of the results on other damage, the replacement of a T with a 5-hmdU results in only negligible effects on structural stability. Reported results and other data from literature suggest a possible protecting effect of the loop residues on the other parts of the G-quadruplexes.},
}
@article {pmid25996625,
year = {2015},
author = {Verde, Z and Reinoso-Barbero, L and Chicharro, L and Garatachea, N and Resano, P and Sánchez-Hernández, I and Rodríguez González-Moro, JM and Bandrés, F and Santiago, C and Gómez-Gallego, F},
title = {Effects of cigarette smoking and nicotine metabolite ratio on leukocyte telomere length.},
journal = {Environmental research},
volume = {140},
number = {},
pages = {488-494},
doi = {10.1016/j.envres.2015.05.008},
pmid = {25996625},
issn = {1096-0953},
mesh = {Biomarkers/urine ; Cytochrome P-450 CYP2A6/genetics ; Humans ; Leukocytes/*ultrastructure ; Nicotine/*metabolism ; *Smoking ; *Telomere ; *Nicotiana ; },
abstract = {Studies of the effects of smoking on leukocyte telomere length (LTL) using cigarettes smoked per day or pack years smoked (PYS) present limitations. Reported high levels of smoking may not increase toxin exposure levels proportionally. Nicotine metabolism ratio (NMR) predicts total cigarette puff volume and overall exposure based on total N-nitrosamines, is highly reproducible and independent of time since the last cigarette. We hypothesized that smokers with higher NMRs will exhibit increased total puff volume, reflecting efforts to extract more nicotine from their cigarettes and increasing toxin exposure. In addition, higher levels of smoking could cause a gross damage in LTL. The urinary cotinine, 3-OH cotinine and nicotine levels of 147 smokers were analyzed using a LC/MS system Triple-Q6410. LTL and CYP2A6 genotype was determined by PCR in blood samples. We found a significant association between NMR and CYP2A6 genotype. Reduction in LTL was seen in relation to accumulated tobacco consumption and years smoking when we adjusted for age and gender. However, there were no significant differences between NMR values and LTL. In our study the higher exposure was associated with lower number of PYS. Smokers with reduced cigarette consumption may exhibit compensatory smoking behavior that results in no reduced tobacco toxin exposure. Our results suggest that lifetime accumulated smoking exposure could cause a gross damage in LTL rather than NMR or PYS. Nevertheless, a combination of smoking topography (NMR) and consumption (PYS) measures may provide useful information about smoking effects on health outcomes.},
}
@article {pmid25992652,
year = {2015},
author = {Gu, BW and Apicella, M and Mills, J and Fan, JM and Reeves, DA and French, D and Podsakoff, GM and Bessler, M and Mason, PJ},
title = {Impaired Telomere Maintenance and Decreased Canonical WNT Signaling but Normal Ribosome Biogenesis in Induced Pluripotent Stem Cells from X-Linked Dyskeratosis Congenita Patients.},
journal = {PloS one},
volume = {10},
number = {5},
pages = {e0127414},
pmid = {25992652},
issn = {1932-6203},
support = {P30 DK090969/DK/NIDDK NIH HHS/United States ; R01 CA106995/CA/NCI NIH HHS/United States ; 2R01CA106995/CA/NCI NIH HHS/United States ; R01 CA105312/CA/NCI NIH HHS/United States ; 2R01 CA105312/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle Proteins/*genetics ; Cells, Cultured ; Dyskeratosis Congenita/genetics/metabolism/*pathology ; Female ; Gene Expression Regulation ; Humans ; Induced Pluripotent Stem Cells/metabolism/*pathology ; Male ; Mice ; Mutation ; Nuclear Proteins/*genetics ; Ribosomes/*metabolism ; Telomerase/metabolism ; Telomere/*pathology ; Wnt Signaling Pathway ; },
abstract = {Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by the presence of short telomeres at presentation. Mutations in ten different genes, whose products are involved in the telomere maintenance pathway, have been shown to cause DC. The X-linked form is the most common form of the disease and is caused by mutations in the gene DKC1, encoding the protein dyskerin. Dyskerin is required for the assembly and stability of telomerase and is also involved in ribosomal RNA (rRNA) processing where it converts specific uridines to pseudouridine. DC is thought to result from failure to maintain tissues, like blood, that are renewed by stem cell activity, but research into pathogenic mechanisms has been hampered by the difficulty of obtaining stem cells from patients. We reasoned that induced pluripotent stem (iPS) cells from X-linked DC patients may provide information about the mechanisms involved. Here we describe the production of iPS cells from DC patients with DKC1 mutations Q31E, A353V and ΔL37. In addition we constructed "corrected" lines with a copy of the wild type dyskerin cDNA expressed from the AAVS1 safe harbor locus. We show that in iPS cells with DKC1 mutations telomere maintenance is compromised with short telomere lengths and decreased telomerase activity. The degree to which telomere lengths are affected by expression of telomerase during reprograming, or with ectopic expression of wild type dyskerin, is variable. The recurrent mutation A353V shows the most severe effect on telomere maintenance. A353V cells but not Q31E or ΔL37 cells, are refractory to correction by expression of wild type DKC1 cDNA. Because dyskerin is involved in both telomere maintenance and ribosome biogenesis it has been postulated that defective ribosome biogenesis and translation may contribute to the disease phenotype. Evidence from mouse and zebra fish models has supported the involvement of ribosome biogenesis but primary cells from human patients have so far not shown defects in pseudouridylation or ribosomal RNA processing. None of the mutant iPS cells presented here show decreased pseudouridine levels in rRNA or defective rRNA processing suggesting telomere maintenance defects account for most of the phenotype of X-linked DC. Finally gene expression analysis of the iPS cells shows that WNT signaling is significantly decreased in all mutant cells, raising the possibility that defective WNT signaling may contribute to disease pathogenesis.},
}
@article {pmid25990879,
year = {2015},
author = {Garcia-Cisneros, A and Pérez-Portela, R and Almroth, BC and Degerman, S and Palacín, C and Sköld, HN},
title = {Long telomeres are associated with clonality in wild populations of the fissiparous starfish Coscinasterias tenuispina.},
journal = {Heredity},
volume = {115},
number = {5},
pages = {437-443},
pmid = {25990879},
issn = {1365-2540},
mesh = {Animals ; Atlantic Ocean ; Body Size ; *Genetic Variation ; *Genetics, Population ; Genotype ; Mediterranean Sea ; Microsatellite Repeats ; Regeneration ; Reproduction, Asexual ; Sequence Analysis, DNA ; Starfish/*genetics ; Telomere/*genetics ; },
abstract = {Telomeres usually shorten during an organism's lifespan and have thus been used as an aging and health marker. When telomeres become sufficiently short, senescence is induced. The most common method of restoring telomere length is via telomerase reverse transcriptase activity, highly expressed during embryogenesis. However, although asexual reproduction from adult tissues has an important role in the life cycles of certain species, its effect on the aging and fitness of wild populations, as well as its implications for the long-term survival of populations with limited genetic variation, is largely unknown. Here we compare relative telomere length of 58 individuals from four populations of the asexually reproducing starfish Coscinasterias tenuispina. Additionally, 12 individuals were used to compare telomere lengths in regenerating and non-regenerating arms, in two different tissues (tube feet and pyloric cecum). The level of clonality was assessed by genotyping the populations based on 12 specific microsatellite loci and relative telomere length was measured via quantitative PCR. The results revealed significantly longer telomeres in Mediterranean populations than Atlantic ones as demonstrated by the Kruskal-Wallis test (K=24.17, significant value: P-value<0.001), with the former also characterized by higher levels of clonality derived from asexual reproduction. Telomeres were furthermore significantly longer in regenerating arms than in non-regenerating arms within individuals (pyloric cecum tissue: Mann-Whitney test, V=299, P-value<10(-6); and tube feet tissue Student's t=2.28, P-value=0.029). Our study suggests that one of the mechanisms responsible for the long-term somatic maintenance and persistence of clonal populations is telomere elongation.},
}
@article {pmid25990736,
year = {2015},
author = {Sarkar, J and Wan, B and Yin, J and Vallabhaneni, H and Horvath, K and Kulikowicz, T and Bohr, VA and Zhang, Y and Lei, M and Liu, Y},
title = {SLX4 contributes to telomere preservation and regulated processing of telomeric joint molecule intermediates.},
journal = {Nucleic acids research},
volume = {43},
number = {12},
pages = {5912-5923},
pmid = {25990736},
issn = {1362-4962},
mesh = {Cell Cycle ; DNA/metabolism ; Endodeoxyribonucleases ; Endonucleases/metabolism ; HeLa Cells ; Homologous Recombination ; Humans ; RecQ Helicases/metabolism ; Recombinases/*metabolism ; Sister Chromatid Exchange ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {SLX4 assembles a toolkit of endonucleases SLX1, MUS81 and XPF, which is recruited to telomeres via direct interaction of SLX4 with TRF2. Telomeres present an inherent obstacle for DNA replication and repair due to their high propensity to form branched DNA intermediates. Here we provide novel insight into the mechanism and regulation of the SLX4 complex in telomere preservation. SLX4 associates with telomeres throughout the cell cycle, peaking in late S phase and under genotoxic stress. Disruption of SLX4's interaction with TRF2 or SLX1 and SLX1's nuclease activity independently causes telomere fragility, suggesting a requirement of the SLX4 complex for nucleolytic resolution of branched intermediates during telomere replication. Indeed, the SLX1-SLX4 complex processes a variety of telomeric joint molecules in vitro. The nucleolytic activity of SLX1-SLX4 is negatively regulated by telomeric DNA-binding proteins TRF1 and TRF2 and is suppressed by the RecQ helicase BLM in vitro. In vivo, in the presence of functional BLM, telomeric circle formation and telomere sister chromatid exchange, both arising out of nucleolytic processing of telomeric homologous recombination intermediates, are suppressed. We propose that the SLX4-toolkit is a telomere accessory complex that, in conjunction with other telomere maintenance proteins, ensures unhindered, but regulated telomere maintenance.},
}
@article {pmid25990087,
year = {2015},
author = {Joshu, CE and Peskoe, SB and Heaphy, CM and Kenfield, SA and Van Blarigan, EL and Mucci, LA and Giovannucci, EL and Stampfer, MJ and Yoon, G and Lee, TK and Hicks, JL and De Marzo, AM and Meeker, AK and Platz, EA},
title = {Prediagnostic Obesity and Physical Inactivity Are Associated with Shorter Telomere Length in Prostate Stromal Cells.},
journal = {Cancer prevention research (Philadelphia, Pa.)},
volume = {8},
number = {8},
pages = {737-742},
pmid = {25990087},
issn = {1940-6215},
support = {CA133891/CA/NCI NIH HHS/United States ; P50 CA058236/CA/NCI NIH HHS/United States ; R01 CA072036/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; CA141298/CA/NCI NIH HHS/United States ; CA55075/CA/NCI NIH HHS/United States ; R01 CA133891/CA/NCI NIH HHS/United States ; HL35464/HL/NHLBI NIH HHS/United States ; P50 CA58236/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; R01 HL035464/HL/NHLBI NIH HHS/United States ; R01 CA141298/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Follow-Up Studies ; Humans ; *Life Style ; Male ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; Obesity/*physiopathology ; Prognosis ; Prostatic Neoplasms/*genetics/*pathology ; Risk Factors ; Stromal Cells/metabolism/*pathology ; Telomere Homeostasis/genetics ; Telomere Shortening/*genetics ; Tissue Array Analysis ; },
abstract = {Obesity and inactivity have been associated with advanced-stage prostate cancer, and poor prostate cancer outcomes, though the underlying mechanism(s) is unknown. To determine whether telomere shortening, which has been associated with lethal prostate cancer, may be a potential underlying mechanism, we prospectively evaluated the association between measures of adiposity, physical activity, and telomere length in 596 participants in the Health Professionals Follow-up Study, who were surgically treated for prostate cancer. Using tissue microarrays, we measured telomere length in cancer and benign cells using a telomere-specific FISH assay. Adiposity and activity were assessed via questionnaire within 2 years of diagnosis. Adjusting for age, pathologic stage, and grade, the median and SD of the per cell telomere signals were determined for each man for stromal cells and cancer cells by adiposity and activity categories. Overweight/obese men (54%) were similar to normal weight men on most factors, but had higher Gleason sum and lower activity levels. Overweight/obese men had 7.4% shorter telomeres in stromal cells than normal weight men (P = 0.06). The least active men had shorter telomeres in stromal cells than more active men (Ptrend = 0.002). Men who were overweight/obese and the least active had the shortest telomeres in stromal cells (20.7% shorter; P = 0.0005) compared with normal weight men who were the most active. Cancer cell telomere length and telomere length variability did not differ by measures of adiposity or activity. Telomere shortening in prostate cells may be one mechanism through which lifestyle influences prostate cancer risk and outcomes.},
}
@article {pmid25987675,
year = {2016},
author = {Verde, Z and Reinoso-Barbero, L and Chicharro, L and Resano, P and Sánchez-Hernández, I and Rodríguez González-Moro, JM and Bandrés, F and Gómez-Gallego, F and Santiago, C},
title = {The Effect of Polymorphisms in DNA Repair Genes and Carcinogen Metabolizers on Leukocyte Telomere Length: A Cohort of Healthy Spanish Smokers.},
journal = {Nicotine &amp; tobacco research : official journal of the Society for Research on Nicotine and Tobacco},
volume = {18},
number = {4},
pages = {447-452},
doi = {10.1093/ntr/ntv106},
pmid = {25987675},
issn = {1469-994X},
mesh = {Adult ; Aged ; Alleles ; Carcinogens/*metabolism ; Cohort Studies ; DNA Repair/*genetics ; DNA-Binding Proteins/*genetics ; Humans ; Leukocytes/*physiology ; Middle Aged ; Polymorphism, Genetic/*genetics ; Smoking/epidemiology/*genetics ; Spain/epidemiology ; Telomere/*genetics ; White People/*genetics ; X-ray Repair Cross Complementing Protein 1 ; },
abstract = {INTRODUCTION: Smoking implies exposure to carcinogenic agents that causes DNA damage, which could be suspected to enhance telomere attrition. To protect and deal with DNA damage, cells possess mechanisms that repair and neutralize harmful substances. Polymorphisms altering DNA repair capacity or carcinogen metabolism may lead to synergistic effects with tobacco carcinogen-induced shorter telomere length independently of cancer interaction. The aim of this study was to explore the association between leukocyte telomere length (LTL) and several genetic polymorphisms in DNA repair genes and carcinogen metabolizers in a cohort of healthy smokers.<br><br>METHODS: We evaluated the effect of six genetic polymorphisms in cytochrome P1A1 (Ile462Val), XRCC1 (Arg399Gln), APEX1 (Asp148Glu), XRCC3 (Thr241Met), and XPD (Asp312Asn; Lys751Gln) on LTL in a cohort of 145 healthy smokers in addition to smoking habits.<br><br>RESULTS: Logistic regression analysis showed an association between XRCC1 399Gln allele and shorter telomere length (OR = 5.03, 95% CI = 1.08% to 23.36%). There were not association between the rest of polymorphisms analyzed and LTL.<br><br>CONCLUSIONS: Continuous exposure to tobacco could overwhelm the DNA repair machinery, making the effect of the polymorphisms that reduce repair capacity more pronounced. Analyzing the function of smoking-induced DNA-repair genes and LTL is an important goal in order to identify therapeutic targets to treat smoking-induced diseases.},
}
@article {pmid25987236,
year = {2015},
author = {Cerne, JZ and Pohar-Perme, M and Cerkovnik, P and Gersak, K and Novakovic, S},
title = {Functional variants in CYP1B1, KRAS and MTHFR genes are associated with shorter telomere length in postmenopausal women.},
journal = {Mechanisms of ageing and development},
volume = {149},
number = {},
pages = {1-7},
doi = {10.1016/j.mad.2015.05.003},
pmid = {25987236},
issn = {1872-6216},
mesh = {Aged ; Alleles ; Case-Control Studies ; Cytochrome P-450 CYP1B1/*genetics ; Estrogens/metabolism/therapeutic use ; Female ; Folic Acid/chemistry ; *Genes, ras ; Genetic Variation ; Genotype ; Hormone Replacement Therapy ; Humans ; Methylenetetrahydrofolate Reductase (NADPH2)/*genetics ; Middle Aged ; Multivariate Analysis ; Polymorphism, Genetic ; *Postmenopause ; Real-Time Polymerase Chain Reaction ; Telomere/*ultrastructure ; },
abstract = {Estrogens and antioxidants indirectly alleviate telomere attrition. However, available clinical data on the association between hormone exposure and telomere length are inconclusive. In the present study, we examined the effects of exogenous estrogen use and of some genetic factors implicated in estrogen metabolism and oxidative stress response on mean leukocyte telomere length. We studied 259 postmenopausal women. Genotyping was conducted for CYP1B1 (rs1056836), COMT (rs4680), GSTP1 (rs1695), MnSOD (rs4880), KRAS (rs61764370), and MTHFR (rs1801133 and rs1801131) polymorphisms. Mean leukocyte telomere length was measured using a quantitative real-time PCR assay. In multivariate analysis we found no association between oral contraceptives or hormone replacement therapy (HRT) and mean leukocyte telomere length. The presence of variant alleles in CYP1B1, KRAS and MTHFR genes was statistically significantly associated with shorter mean leukocyte telomere length. Further, the data provided evidence for the effect modification of the association between HRT and mean leukocyte telomere length by the CYP1B1, KRAS and MTHFR genotypes. Our findings suggest that functionally relevant genetic variants within estrogen and folate metabolic pathways may influence telomere length. We propose these genetic factors should be taken into consideration when interpreting associations between hormone exposure and telomere length.},
}
@article {pmid25986438,
year = {2015},
author = {Barrett, JH and Iles, MM and Dunning, AM and Pooley, KA},
title = {Telomere length and common disease: study design and analytical challenges.},
journal = {Human genetics},
volume = {134},
number = {7},
pages = {679-689},
pmid = {25986438},
issn = {1432-1203},
support = {C588/A19167/CRUK_/Cancer Research UK/United Kingdom ; C588/A10589/CRUK_/Cancer Research UK/United Kingdom ; MR/L01629X/1/MRC_/Medical Research Council/United Kingdom ; 16565/CRUK_/Cancer Research UK/United Kingdom ; C8197/A16565/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Cardiovascular Diseases/genetics/*metabolism ; Humans ; Neoplasms/genetics/*metabolism ; Obesity/genetics/*metabolism ; Risk Factors ; Smoking/genetics/*metabolism ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; },
abstract = {Telomeres, the repetitive sequences that protect the ends of chromosomes, help to maintain genomic integrity and are of key importance to human health. The aim here is to give an overview of the evidence for the importance of telomere length (TL) to the risk of common disease, considering the strengths and weaknesses of different epidemiological study designs. Methods for measuring TL are described, all of which are subject to considerable measurement error. TL declines with age and varies in relation to factors such as smoking and obesity. It is also highly heritable (estimated heritability of ~40 to 50%), and genome-wide studies have identified a number of associated genetic variants. Epidemiological studies have shown shorter TL to be associated with risk of a number of common diseases, including cardiovascular disease and some cancers. The relationship with cancer appears complex, in that longer telomeres are associated with higher risk of some cancers. Prospective studies of the relationship between TL and disease, where TL is measured before diagnosis, have numerous advantages over retrospective studies, since they avoid the problems of reverse causality and differences in sample handling, but they are still subject to potential confounding. Studies of the genetic predictors of TL in relation to disease risk avoid these drawbacks, although they are not without limitations. Telomere biology is of major importance to the risk of common disease, but the complexities of the relationship are only now beginning to be understood.},
}
@article {pmid25983743,
year = {2015},
author = {Steinberg-Neifach, O and Lue, NF},
title = {Telomere DNA recognition in Saccharomycotina yeast: potential lessons for the co-evolution of ssDNA and dsDNA-binding proteins and their target sites.},
journal = {Frontiers in genetics},
volume = {6},
number = {},
pages = {162},
pmid = {25983743},
issn = {1664-8021},
support = {R01 GM107287/GM/NIGMS NIH HHS/United States ; },
abstract = {In principle, alterations in the telomere repeat sequence would be expected to disrupt the protective nucleoprotein complexes that confer stability to chromosome ends, and hence relatively rare events in evolution. Indeed, numerous organisms in diverse phyla share a canonical 6 bp telomere repeat unit (5'-TTAGGG-3'/5'-CCCTAA-3'), suggesting common descent from an ancestor that carries this particular repeat. All the more remarkable, then, are the extraordinarily divergent telomere sequences that populate the Saccharomycotina subphylum of budding yeast. These sequences are distinguished from the canonical telomere repeat in being long, occasionally degenerate, and frequently non-G/C-rich. Despite the divergent telomere repeat sequences, studies to date indicate that the same families of single-strand and double-strand telomere binding proteins (i.e., the Cdc13 and Rap1 families) are responsible for telomere protection in Saccharomycotina yeast. The recognition mechanisms of the protein family members therefore offer an informative paradigm for understanding the co-evolution of DNA-binding proteins and the cognate target sequences. Existing data suggest three potential, inter-related solutions to the DNA recognition problem: (i) duplication of the recognition protein and functional modification; (ii) combinatorial recognition of target site; and (iii) flexibility of the recognition surfaces of the DNA-binding proteins to adopt alternative conformations. Evidence in support of these solutions and the relevance of these solutions to other DNA-protein regulatory systems are discussed.},
}
@article {pmid25983570,
year = {2015},
author = {Laine, MK and Eriksson, JG and Kujala, UM and Raj, R and Kaprio, J and Bäckmand, HM and Peltonen, M and Sarna, S},
title = {Effect of intensive exercise in early adult life on telomere length in later life in men.},
journal = {Journal of sports science &amp; medicine},
volume = {14},
number = {2},
pages = {239-245},
pmid = {25983570},
issn = {1303-2968},
abstract = {A career as an elite-class male athlete seems to improve metabolic heath in later life and is also associated with longer life expectancy. Telomere length is a biomarker of biological cellular ageing and could thus predict morbidity and mortality. The main aim of this study was to assess the association between vigorous elite-class physical activity during young adulthood on later life leukocyte telomere length (LTL). The study participants consist of former male Finnish elite athletes (n = 392) and their age-matched controls (n = 207). Relative telomere length was determined from peripheral blood leukocytes by quantitative real-time polymerase chain reaction. Volume of leisure-time physical activity (LTPA) was self-reported and expressed in metabolic equivalent hours. No significant difference in mean age-adjusted LTL in late life (p = 0.845) was observed when comparing former male elite athletes and their age-matched controls. Current volume of LTPA had no marked influence on mean age-adjusted LTL (p for trend 0.788). LTL was inversely associated with age (p = 0.004).Our study findings suggest that a former elite athlete career is not associated with LTL later in life. Key pointsA career as an elite-class athlete is associated with improved metabolic health in late life and is associated with longer life expectancy.A career as an elite-class athlete during young adulthood was not associated with leukocyte telomere length in later life.Current volume of leisure-time physical activity did not influence telomere length in later life.},
}
@article {pmid25983303,
year = {2015},
author = {Kłoda, K and Drozd, A and Borowiecka, E and Domański, L},
title = {[Telomere length and transrenal DNA isolated from transplanted kidney recipients' urine].},
journal = {Postepy higieny i medycyny doswiadczalnej (Online)},
volume = {69},
number = {},
pages = {649-653},
doi = {10.5604/17322693.1153083},
pmid = {25983303},
issn = {1732-2693},
mesh = {DNA/*urine ; Graft Rejection/diagnosis/*epidemiology/metabolism ; Humans ; Kidney/*metabolism ; *Kidney Transplantation ; Prevalence ; *Telomere Shortening ; },
abstract = {Transplantation is the preferred method of end stage renal insufficiency treatment due to better quality of life and extended life of transplanted patients. Currently a non-invasive test, which evaluates the risk of acute or chronic rejection or deterioration of the transplanted organ's function, is being sought. An increase of the transrenal DNA concentration in the urine of urinary tract infection patients and in renal graft recipients during an episode of acute rejection was observed. There were also reports on shortening of telomeres in transplanted organ chromosomes, as the result of accelerated aging of cells, and its connection with the onset of chronic allograft nephropathy and the degree of its completion, and thus the deterioration of kidney function. The aim of this paper is to describe the urine genetic analysis through determining the length of the telomeres and the content of transrenal DNA to monitor kidney function and to evaluate the prevalence of acute and chronic rejection in patients after kidney transplantation. The genetic analysis of the biological material collected from patients relies on the determination of transrenal DNA content and length of DNA telomeres isolated from the urine of kidney recipients. The presented methods assume that the genetic profile of the transplanted organ recipient as well as kidney donor can be determined, so the source of the genetic material in the urine of the patient can be identified. A measurable effect of these methods' use would be to complement the evaluation of the prevalence of acute and chronic rejection and transplanted kidney function with a modern, non-invasive method, which is the analysis of telomere length from sediment of urine and the content of transrenal DNA in the urine.},
}
@article {pmid25982091,
year = {2015},
author = {Yang, Q and Zhang, N and Zhao, F and Zhao, W and Dai, S and Liu, J and Bukhari, I and Xin, H and Niu, W and Sun, Y},
title = {Processing of semen by density gradient centrifugation selects spermatozoa with longer telomeres for assisted reproduction techniques.},
journal = {Reproductive biomedicine online},
volume = {31},
number = {1},
pages = {44-50},
doi = {10.1016/j.rbmo.2015.02.016},
pmid = {25982091},
issn = {1472-6491},
mesh = {Cell Separation/methods ; *Centrifugation, Density Gradient ; Humans ; Male ; *Reproductive Techniques, Assisted ; *Semen Analysis ; Specimen Handling/methods ; Spermatozoa/*physiology ; Telomere/*genetics ; },
abstract = {The ends of eukaryotic chromosomes contain specialized chromatin structures called telomeres, the length of which plays a key role in early human embryonic development. Although the effect of sperm preparation techniques on major sperm characteristics, such as concentration, motility and morphology have been previously documented, the possible status of telomere length and its relation with sperm preparation techniques is not well-known for humans. The aim of this study was to investigate the role of density gradient centrifugation in the selection of spermatozoa with longer telomeres for use in assisted reproduction techniques in 105 samples before and after sperm processing. After density gradient centrifugation, the average telomere length of the sperm was significantly longer (6.51 ± 2.54 versus 5.16 ± 2.29, P < 0.01), the average motile sperm rate was significantly higher (77.9 ± 11.8 versus 44.6 ± 11.2, P < 0.01), but average DNA fragmentation rate was significantly lower (11.1 ± 5.9 versus 25.9 ± 12.9, P < 0.01) compared with raw semen. Additionally, telomere length was positively correlated with semen sperm count (rs = 0.58; P < 0.01). In conclusion, density gradient centrifugation is a useful technique for selection of sperm with longer telomeres.},
}
@article {pmid25981164,
year = {2015},
author = {Pawlas, N and Płachetka, A and Kozłowska, A and Broberg, K and Kasperczyk, S},
title = {Telomere length in children environmentally exposed to low-to-moderate levels of lead.},
journal = {Toxicology and applied pharmacology},
volume = {287},
number = {2},
pages = {111-118},
doi = {10.1016/j.taap.2015.05.005},
pmid = {25981164},
issn = {1096-0333},
mesh = {Child ; Cross-Sectional Studies ; Environmental Exposure/*adverse effects/*analysis ; Female ; Humans ; Lead/*adverse effects/*blood ; Male ; Risk Factors ; Socioeconomic Factors ; Telomere/*drug effects ; },
abstract = {Shorter relative telomere length in peripheral blood is a risk marker for some types of cancers and cardiovascular diseases. Several environmental hazards appear to shorten telomeres, and this shortening may predispose individuals to disease. The aim of the present cross-sectional study was to assess the effect of environmental exposure to lead on relative telomere length (rTL) in children. A cohort of 99 8-year-old children was enrolled from 2007-2010. Blood lead concentrations (B-Pb) were measured by graphite furnace atomic absorption spectrometry, and blood rTL was measured by quantitative PCR. The geometric mean of B-Pb was 3.28 μg/dl (range: 0.90-14.2), and the geometric mean of rTL was 1.08 (range: 0.49-2.09). B-Pb was significantly inversely associated with rTL in the children (rS = -0.25, p = 0.013; in further analyses both log-transformed-univariate regression analysis β = -0.13, p = 0.026, and R(2)adj 4%; and β = -0.12, p = 0.056 when adjusting for mothers' smoking during pregnancy, Apgar score, mother's and father's ages at delivery, sex and mother's education, R(2)adj 12%, p = 0.011). The effect of lead remained significant in children without prenatal tobacco exposure (N = 87, rS = -0.24, p = 0.024; in further analyses, β = -0.13, p = 0.029, and R(2)adj 4%). rTL was not affected by sex, the concentrations of other elements in the blood (i.e., cadmium and selenium concentrations), or oxidative injury parameters (total antioxidant status, 8-hydroxydeoxyguanosine and thiobarbituric acid-reactive substances). Lead exposure in childhood appears to be associated with shorter telomeres, which might contribute to diseases, such as cardiovascular disease. The inverse association between blood lead level and the telomeres in children emphasizes the importance of further reducing lead levels in the environment.},
}
@article {pmid25980416,
year = {2015},
author = {Tan, Z and Tang, J and Kan, ZY and Hao, YH},
title = {Telomere G-Quadruplex as a Potential Target to Accelerate Telomere Shortening by Expanding the Incomplete End-Replication of Telomere DNA.},
journal = {Current topics in medicinal chemistry},
volume = {15},
number = {19},
pages = {1940-1946},
doi = {10.2174/1568026615666150515145552},
pmid = {25980416},
issn = {1873-4294},
mesh = {DNA/*biosynthesis/chemistry ; *DNA Replication ; *G-Quadruplexes ; Humans ; Neoplasms/genetics/metabolism/pathology ; Telomere/*chemistry/genetics/*metabolism ; *Telomere Shortening ; },
abstract = {Chromosomes in human cells are protected by telomeres. Telomere shortens during each round of cell division because of the DNA end-replication problem. Cancer cells maintain telomere length homeostasis by either telomerase or/and the alternative lengthening of telomere (ALT) mechanism to sustain their division potential. Telomeric DNA tends to form G-quadruplex preferentially at the extreme 3' end. This unique feature prevents the 3' end from being used as a substrate of telomerase and as a primer in the ALT. Therefore, stabilizing telomere G-quadruplex is expected to inhibit both pathways and limit the proliferation of cancer cells. Based on a mathematical modeling and experimental results, this mini-review proposes a hypothesis that the formation of G-quadruplex in telomere may constitute a significant contribution to the incomplete end-replication of telomere DNA by preventing the priming of DNA synthesis near the 3' end during telomere replication. According to this, stabilization of telomere G-quadruplex by chemical ligand may promise to accelerate telomere shortening in proliferating cells.},
}
@article {pmid25975826,
year = {2015},
author = {Polho, GB and De-Paula, VJ and Cardillo, G and dos Santos, B and Kerr, DS},
title = {Leukocyte telomere length in patients with schizophrenia: A meta-analysis.},
journal = {Schizophrenia research},
volume = {165},
number = {2-3},
pages = {195-200},
doi = {10.1016/j.schres.2015.04.025},
pmid = {25975826},
issn = {1573-2509},
mesh = {Humans ; Leukocytes/*pathology ; PubMed/statistics &amp; numerical data ; Schizophrenia/*genetics/*pathology ; Telomere Shortening/*physiology ; },
abstract = {Schizophrenia has been suggested as a syndrome of accelerated aging. Telomere length (TL) decrease is considered one biological marker associated with age and can be accelerated by pathological characteristics present in schizophrenia. Several studies evaluated TL in schizophrenia, but the results are still controversial. The aim of this study was to conduct a meta-analysis of the existing results of TL in leukocytes of individuals with schizophrenia compared to healthy controls. A search was performed in PubMed, using the keywords 'telomere schizophrenia' and 'telomere psychosis'. We included data from original articles that measured TL in leukocytes of human patients with schizophrenia and healthy control subjects. 45 articles were found, but only 7 met our criteria. Telomere length of controls was not statistically different from that of patients with schizophrenia (p=0.07). Crossvalidation with the leave-one-out method resulted in a significant model (p=0.03) in which TL of individuals with schizophrenia is smaller than control (SMD=0.38; 95% CI=[0.05, 0.72]). We also propose a biological pathway through which schizophrenia could promote telomere erosion and how antipsychotics might compensate this loss. There are few studies made on this subject with diverse methodology and heterogeneous sample. Some articles did not consider other possible influences on TL. Overall our results suggest that TL is decreased in schizophrenia. Although this is consistent with the idea of accelerated aging, schizophrenia is a complex disease and there are several factors that influence TL that should be controlled in future studies.},
}
@article {pmid25975004,
year = {2015},
author = {Qiu, C and Enquobahrie, DA and Gelaye, B and Hevner, K and Williams, MA},
title = {The association between leukocyte telomere length and mitochondrial DNA copy number in pregnant women: a pilot study.},
journal = {Clinical laboratory},
volume = {61},
number = {3-4},
pages = {363-369},
doi = {10.7754/clin.lab.2014.140313},
pmid = {25975004},
issn = {1433-6510},
support = {HD R01-32562/HD/NICHD NIH HHS/United States ; HD R01-34888/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Biomarkers ; Cellular Senescence ; Cross-Sectional Studies ; DNA, Mitochondrial/*genetics ; Female ; *Gene Dosage ; Humans ; Leukocytes/*ultrastructure ; Mitochondria/metabolism ; Multivariate Analysis ; Oxidative Stress ; Pilot Projects ; Pregnancy ; Regression Analysis ; Telomere/*ultrastructure ; Young Adult ; },
abstract = {BACKGROUND: Both short telomere length and mitochondrial dysfunction have been associated with pregnancy complications, such as preeclampsia and intrauterine growth restriction. However, the relationship between these two biomarkers of oxidative stress, during pregnancy, is unknown. This study investigated the association of leukocyte telomere length with mitochondrial DNA (mtDNA) copy number, an indicator of mitochondrial density and possible mitochondrial dysfunction, using maternal blood samples collected from women with pregnancies uncomplicated by gestational diabetes or hypertensive disorders.<br><br>METHODS: Leukocyte telomere length and mtDNA copy number were determined in 75 pregnant women using quantitative real-time quantitative PCR. Bivariate and multivariable linear regression procedures were used to evaluate associations of these two biomarkers.<br><br>RESULTS: Leukocyte mtDNA copy number (natural-logarithm) was positively associated with telomere length (Pearson correlation coefficient = 0.30, p-value = 0.009). After adjusting for maternal age and plasma vitamin B12, natural-log mtDNA copy number increased by 0.80 (f = 0.80; 95% CI 0.25 - 1.34, p-value = 0.005) for every 1 unit increase of telomere length. Approximately 11% of the variation in natural-long mtDNA copy number was explained by the model (adjusted R2 = 0.11).<br><br>CONCLUSIONS: This cross sectional data suggests an association of mtDNA copy number with telomere length, two emergent biological markers of potential importance in perinatal health research. The consequences of oxidative stress, cellular senescence (as reflected by relatively shorter telomere length) and mitochondrial dysfunction, on the course and outcomes of pregnancy remain to be elucidated in larger prospective studies that include these biological markers.},
}
@article {pmid25973743,
year = {2015},
author = {Snetselaar, R and van Moorsel, CHM and Kazemier, KM and van der Vis, JJ and Zanen, P and van Oosterhout, MFM and Grutters, JC},
title = {Telomere length in interstitial lung diseases.},
journal = {Chest},
volume = {148},
number = {4},
pages = {1011-1018},
doi = {10.1378/chest.14-3078},
pmid = {25973743},
issn = {1931-3543},
mesh = {Adult ; Aged ; Female ; Humans ; Lung Diseases, Interstitial/*genetics ; Male ; Middle Aged ; *Mutation ; Polymerase Chain Reaction ; RNA/*genetics ; Retrospective Studies ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {BACKGROUND: Interstitial lung disease (ILD) is a heterogeneous group of rare diseases that primarily affect the pulmonary interstitium. Studies have implicated a role for telomere length (TL) maintenance in ILD, particularly in idiopathic interstitial pneumonia (IIP). Here, we measure TL in a wide spectrum of sporadic and familial cohorts of ILD and compare TL between patient cohorts and control subjects.<br><br>METHODS: A multiplex quantitative polymerase chain reaction method was used to measure TL in 173 healthy subjects and 359 patients with various ILDs, including familial interstitial pneumonia (FIP). The FIP cohort was divided into patients carrying TERT mutations, patients carrying SFTPA2 or SFTPC mutations, and patients without a proven mutation (FIP-no mutation).<br><br>RESULTS: TL in all cases of ILD was significantly shorter compared with those of control subjects (P range: .038 to < .0001). Furthermore, TL in patients with idiopathic pulmonary fibrosis (IPF) was significantly shorter than in patients with other IIPs (P = .002) and in patients with sarcoidosis (P < .0001). Within the FIP cohort, patients in the FIP-telomerase reverse transcriptase (TERT) group had the shortest telomeres (P < .0001), and those in the FIP-no mutation group had TL comparable to that of patients with IPF (P = .049). Remarkably, TL of patients with FIP-surfactant protein (SFTP) was significantly longer than in patients with IPF, but similar to that observed in patients with other sporadic IIPs.<br><br>CONCLUSIONS: The results show telomere shortening across all ILD diagnoses. The difference in TL between the FIP-TERT and FIP-SFTP groups indicates the distinction between acquired and innate telomere shortening. Short TL in the IPF and FIP-no mutation groups is indicative of an innate telomere-biology defect, while a stress-induced, acquired telomere shortening might be the underlying process for the other ILD diagnoses.},
}
@article {pmid25972055,
year = {2015},
author = {Savolainen, K and Eriksson, JG and Kajantie, E and Pesonen, AK and Räikkönen, K},
title = {Associations between the five-factor model of personality and leukocyte telomere length in elderly men and women: The Helsinki Birth Cohort Study (HBCS).},
journal = {Journal of psychosomatic research},
volume = {79},
number = {3},
pages = {233-238},
doi = {10.1016/j.jpsychores.2015.04.011},
pmid = {25972055},
issn = {1879-1360},
mesh = {Aged ; Anxiety Disorders ; Cellular Senescence/*genetics ; Cohort Studies ; Extraversion, Psychological ; Female ; Finland/epidemiology ; Humans ; *Leukocytes ; Male ; Middle Aged ; Neuroticism ; *Personality/genetics ; Personality Disorders/genetics ; Personality Inventory ; *Telomere Homeostasis ; },
abstract = {OBJECTIVE: Personality traits have been associated with cardiometabolic diseases and mental disorders as well as with longevity. However, the underlying mechanisms are not fully understood. Accelerated cellular aging may play a role in this process. We studied whether personality traits in late adulthood, as defined in the five-factor model (FFM), were associated with a biomarker of cellular vitality, leukocyte telomere length (LTL).<br><br>METHODS: At a mean age of 63.4 (SD=2.8) years, 1671 (742 men, 929 women) participants from the Helsinki Birth Cohort Study filled in the Neuroticism, Extraversion and Openness Personality Inventory (NEO-PI). LTL was measured at a mean age of 61.5 (SD=2.9) years by using a real-time quantitative PCR method.<br><br>RESULTS: None of the FFM personality dimensions were significantly associated with the LTL in the analyses of both sexes combined. We however found interaction between sex and agreeableness (B=0.020, 95% CI=.008, 0.032, p=.001) and in the sex-specific analyses, men who scored higher on agreeableness (B=-0.086, 95% CI=-0.155, -0.016, p=.016) and women who scored lower on agreeableness (B=0.074, 95% CI=0.014, 0.134, p=.016) had shorter LTL.<br><br>CONCLUSIONS: FFM dimensions of personality were not associated with LTL in a sample of elderly individuals. The counterintuitive and sporadic sex specific finding on agreeableness requires replication. Overall our findings suggest that LTL, a biomarker of cellular aging, may not offer insight into the associations between personality, longevity and health.},
}
@article {pmid25971865,
year = {2015},
author = {Tanday, S},
title = {Pattern of change in telomere length: possible predictor of cancer.},
journal = {The Lancet. Oncology},
volume = {16},
number = {6},
pages = {e267},
doi = {10.1016/S1470-2045(15)70231-7},
pmid = {25971865},
issn = {1474-5488},
mesh = {Humans ; Neoplasms/diagnosis/*genetics/pathology ; Risk Factors ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
}
@article {pmid25970659,
year = {2015},
author = {Loprinzi, PD and Loenneke, JP and Blackburn, EH},
title = {Movement-Based Behaviors and Leukocyte Telomere Length among US Adults.},
journal = {Medicine and science in sports and exercise},
volume = {47},
number = {11},
pages = {2347-2352},
pmid = {25970659},
issn = {1530-0315},
support = {R01 AG033592/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*physiology ; Humans ; Leukocytes/*physiology ; Middle Aged ; Motor Activity/*physiology ; Nutrition Surveys ; *Telomere Shortening ; Young Adult ; },
abstract = {INTRODUCTION: Short leukocyte telomere length (LTL) has become a hallmark characteristic of aging. Some, but not all, evidence suggests that physical activity (PA) may play an important role in attenuating age-related diseases and may provide a protective effect for telomeres. The purpose of this study was to examine the association between PA and LTL in a national sample of US adults from the National Health and Nutrition Examination Survey.<br><br>METHODS: National Health and Nutrition Examination Survey data from 1999 to 2002 (n = 6503; 20-84 yr) were used. Four self-report questions related to movement-based behaviors (MBB) were assessed. The four MBB included whether individuals participated in moderate-intensity PA, vigorous-intensity PA, walking/cycling for transportation, and muscle-strengthening activities. An MBB index variable was created by summing the number of MBB an individual engaged in (range, 0-4).<br><br>RESULTS: A clear dose-response relation was observed between MBB and LTL; across the LTL tertiles, respectively, the mean numbers of MBB were 1.18, 1.44, and 1.54 (Ptrend < 0.001). After adjustments (including age) and compared with those engaging in 0 MBB, those engaging in 1, 2, 3, and 4 MBB, respectively, had a 3% (P = 0.84), 24% (P = 0.02), 29% (P = 0.04), and 52% (P = 0.004) reduced odds of being in the lowest (vs highest) tertile of LTL; MBB was not associated with being in the middle (vs highest) tertile of LTL.<br><br>CONCLUSIONS: Greater engagement in MBB was associated with reduced odds of being in the lowest LTL tertile.},
}
@article {pmid25965571,
year = {2015},
author = {Colla, S and Ong, DS and Ogoti, Y and Marchesini, M and Mistry, NA and Clise-Dwyer, K and Ang, SA and Storti, P and Viale, A and Giuliani, N and Ruisaard, K and Ganan Gomez, I and Bristow, CA and Estecio, M and Weksberg, DC and Ho, YW and Hu, B and Genovese, G and Pettazzoni, P and Multani, AS and Jiang, S and Hua, S and Ryan, MC and Carugo, A and Nezi, L and Wei, Y and Yang, H and D'Anca, M and Zhang, L and Gaddis, S and Gong, T and Horner, JW and Heffernan, TP and Jones, P and Cooper, LJ and Liang, H and Kantarjian, H and Wang, YA and Chin, L and Bueso-Ramos, C and Garcia-Manero, G and DePinho, RA},
title = {Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome.},
journal = {Cancer cell},
volume = {27},
number = {5},
pages = {644-657},
pmid = {25965571},
issn = {1878-3686},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; CA143883/CA/NCI NIH HHS/United States ; P30 CA16672/CA/NCI NIH HHS/United States ; R01 CA084628/CA/NCI NIH HHS/United States ; U24 CA143883/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Differentiation/*genetics ; Haploinsufficiency ; Hematopoiesis/*genetics ; Humans ; Mice ; Myelodysplastic Syndromes/*genetics/pathology ; Nuclear Proteins/genetics ; RNA Splicing ; Ribonucleoproteins/genetics ; Serine-Arginine Splicing Factors ; *Telomere ; },
abstract = {Myelodysplastic syndrome (MDS) risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly induces MDS is unknown. Here, we provide the genetic evidence that telomere dysfunction-induced DNA damage drives classical MDS phenotypes and alters common myeloid progenitor (CMP) differentiation by repressing the expression of mRNA splicing/processing genes, including SRSF2. RNA-seq analyses of telomere dysfunctional CMP identified aberrantly spliced transcripts linked to pathways relevant to MDS pathogenesis such as genome stability, DNA repair, chromatin remodeling, and histone modification, which are also enriched in mouse CMP haploinsufficient for SRSF2 and in CD34(+) CMML patient cells harboring SRSF2 mutation. Together, our studies establish an intimate link across telomere biology, aberrant RNA splicing, and myeloid progenitor differentiation.},
}
@article {pmid25962353,
year = {2015},
author = {Zhao, X and Ueda, Y and Kajigaya, S and Alaks, G and Desierto, MJ and Townsley, DM and Dumitriu, B and Chen, J and Lacy, RC and Young, NS},
title = {Cloning and molecular characterization of telomerase reverse transcriptase (TERT) and telomere length analysis of Peromyscus leucopus.},
journal = {Gene},
volume = {568},
number = {1},
pages = {8-18},
pmid = {25962353},
issn = {1879-0038},
support = {Z99 HL999999//Intramural NIH HHS/United States ; },
mesh = {Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Base Sequence ; Cloning, Molecular ; Female ; Gene Expression ; Male ; Molecular Sequence Data ; Organ Specificity ; Peromyscus/*genetics ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; Telomerase/chemistry/*genetics/metabolism ; Telomere/*genetics ; Telomere Homeostasis ; Testis/enzymology ; },
abstract = {Telomerase reverse transcriptase (TERT) is the catalytic subunit of telomerase complex that regulates telomerase activity to maintain telomere length for all animals with linear chromosomes. As the Mus musculus (MM) laboratory mouse has very long telomeres compared to humans, a potential alternative animal model for telomere research is the Peromyscus leucopus (PL) mouse that has telomere lengths close to the human range and has the wild counterparts for comparison. We report the full TERT coding sequence (pTERT) from PL mice to use in the telomere research. Comparative analysis with eight other mammalian TERTs revealed a pTERT protein considerably homologous to other TERTs and preserved all TERT specific-sequence signatures, yet with some distinctive features. pTERT displayed the highest nucleotide and amino acid sequence homology with hamster TERT. Unlike human but similar to MM mice, pTERT expression was detected in various adult somatic tissues of PL mice, with the highest expression in testes. Four different captive stocks of PL mice and wild-captured PL mice each displayed group-specific average telomere lengths, with the longest and shortest telomeres in inbred and outbred stock mice, respectively. pTERT showed considerable numbers of synonymous and nonsynonymous mutations. A pTERT proximal promoter region cloned was homologous among PL and MM mice and rat, but with species-specific features. From PL mice, we further cloned and characterized ribosomal protein, large, P0 (pRPLP0) to use as an internal control for various assays. Peromyscus mice have been extensively used for various studies, including human diseases, for which pTERT and pRPLP0 would be useful tools.},
}
@article {pmid25962144,
year = {2015},
author = {Schumpert, C and Nelson, J and Kim, E and Dudycha, JL and Patel, RC},
title = {Telomerase activity and telomere length in Daphnia.},
journal = {PloS one},
volume = {10},
number = {5},
pages = {e0127196},
pmid = {25962144},
issn = {1932-6203},
support = {R01 AG037969/AG/NIA NIH HHS/United States ; 1R01AG037969-01/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*genetics ; Amino Acid Sequence ; Animals ; Arthropod Proteins/*genetics ; Cell Division ; Cellular Senescence/genetics ; Daphnia/*genetics ; Female ; Gene Expression Regulation ; Longevity/genetics ; Male ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; Sequence Alignment ; Telomerase/*genetics ; Telomere/*chemistry ; *Telomere Shortening ; },
abstract = {Telomeres, comprised of short repetitive sequences, are essential for genome stability and have been studied in relation to cellular senescence and aging. Telomerase, the enzyme that adds telomeric repeats to chromosome ends, is essential for maintaining the overall telomere length. A lack of telomerase activity in mammalian somatic cells results in progressive shortening of telomeres with each cellular replication event. Mammals exhibit high rates of cell proliferation during embryonic and juvenile stages but very little somatic cell proliferation occurs during adult and senescent stages. The telomere hypothesis of cellular aging states that telomeres serve as an internal mitotic clock and telomere length erosion leads to cellular senescence and eventual cell death. In this report, we have examined telomerase activity, processivity, and telomere length in Daphnia, an organism that grows continuously throughout its life. Similar to insects, Daphnia telomeric repeat sequence was determined to be TTAGG and telomerase products with five-nucleotide periodicity were generated in the telomerase activity assay. We investigated telomerase function and telomere lengths in two closely related ecotypes of Daphnia with divergent lifespans, short-lived D. pulex and long-lived D. pulicaria. Our results indicate that there is no age-dependent decline in telomere length, telomerase activity, or processivity in short-lived D. pulex. On the contrary, a significant age dependent decline in telomere length, telomerase activity and processivity is observed during life span in long-lived D. pulicaria. While providing the first report on characterization of Daphnia telomeres and telomerase activity, our results also indicate that mechanisms other than telomere shortening may be responsible for the strikingly short life span of D. pulex.},
}
@article {pmid25961132,
year = {2015},
author = {Wood, AM and Laster, K and Rice, EL and Kosak, ST},
title = {A beginning of the end: new insights into the functional organization of telomeres.},
journal = {Nucleus (Austin, Tex.)},
volume = {6},
number = {3},
pages = {172-178},
pmid = {25961132},
issn = {1949-1042},
support = {DP2 OD008717/OD/NIH HHS/United States ; R25 GM079300/GM/NIGMS NIH HHS/United States ; DP2 OD008717-0/OD/NIH HHS/United States ; },
mesh = {Cell Division ; DNA/*chemistry/metabolism ; Gene Expression Regulation ; Genomic Instability ; Heterochromatin/chemistry/metabolism ; Humans ; Lamin Type A/genetics/metabolism ; Nucleic Acid Conformation ; Progeria/*genetics/metabolism/pathology ; Shelterin Complex ; Signal Transduction ; Telomerase/genetics/metabolism ; Telomere/*chemistry/metabolism ; *Telomere Shortening ; Telomere-Binding Proteins/genetics/metabolism ; Telomeric Repeat Binding Protein 2/*genetics/metabolism ; },
abstract = {Ever since the first demonstration of their repetitive sequence and unique replication pathway, telomeres have beguiled researchers with how they function in protecting chromosome ends. Of course much has been learned over the years, and we now appreciate that telomeres are comprised of the multimeric protein/DNA shelterin complex and that the formation of t-loops provides protection from DNA damage machinery. Deriving their name from D-loops, t-loops are generated by the insertion of the 3' overhang into telomeric repeats facilitated by the binding of TRF2. Recent studies have uncovered novel forms of chromosome end-structure that may implicate telomere organization in cellular processes beyond its essential role in telomere protection and homeostasis. In particular, we have recently described that t-loops form in a TRF2-dependent manner at interstitial telomere repeat sequences, which we termed interstitial telomere loops (ITLs). These structures are also dependent on association of lamin A/C, a canonical component of the nucleoskeleton that is mutated in myriad human diseases, including human segmental progeroid syndromes. Since ITLs are associated with telomere stability and require functional lamin A/C, our study suggests a mechanistic link between cellular aging (replicative senescence induced by telomere shortening) and organismal aging (modeled by Hutchinson Gilford Progeria Syndrome). Here we speculate on other potential ramifications of ITL formation, from gene expression to genome stability to chromosome structure.},
}
@article {pmid25960381,
year = {2015},
author = {Hunt, SC and Kimura, M and Hopkins, PN and Carr, JJ and Heiss, G and Province, MA and Aviv, A},
title = {Leukocyte telomere length and coronary artery calcium.},
journal = {The American journal of cardiology},
volume = {116},
number = {2},
pages = {214-218},
pmid = {25960381},
issn = {1879-1913},
support = {U01 HL067897/HL/NHLBI NIH HHS/United States ; HL67895/HL/NHLBI NIH HHS/United States ; HL67901/HL/NHLBI NIH HHS/United States ; U01 HL067893/HL/NHLBI NIH HHS/United States ; R01 AG020132/AG/NIA NIH HHS/United States ; U01 HL056567/HL/NHLBI NIH HHS/United States ; U01 HL067896/HL/NHLBI NIH HHS/United States ; HL67900/HL/NHLBI NIH HHS/United States ; HL67896/HL/NHLBI NIH HHS/United States ; AG020132/AG/NIA NIH HHS/United States ; U01 HL067901/HL/NHLBI NIH HHS/United States ; HL67894/HL/NHLBI NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; U01 HL067900/HL/NHLBI NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; U01 HL067898/HL/NHLBI NIH HHS/United States ; HL67902/HL/NHLBI NIH HHS/United States ; U01 HL067894/HL/NHLBI NIH HHS/United States ; HL67897/HL/NHLBI NIH HHS/United States ; HL67899/HL/NHLBI NIH HHS/United States ; HL67898/HL/NHLBI NIH HHS/United States ; U01 HL067895/HL/NHLBI NIH HHS/United States ; U01 HL067899/HL/NHLBI NIH HHS/United States ; HL67893/HL/NHLBI NIH HHS/United States ; R01 HL117078/HL/NHLBI NIH HHS/United States ; U01 HL067902/HL/NHLBI NIH HHS/United States ; },
mesh = {Blotting, Southern ; Calcinosis/*genetics/metabolism ; Calcium/*analysis ; Coronary Artery Disease/*genetics/metabolism ; Coronary Vessels/*metabolism ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Retrospective Studies ; *Telomere ; },
abstract = {Patients with histories of myocardial infarction display shortened leukocyte telomere length (LTL), but conflicting findings have been reported on the relation between LTL and subclinical coronary artery atherosclerosis, as expressed by coronary artery calcium (CAC). The aim of this study was to examine the relation between LTL, measured by Southern blots, and CAC in 3,169 participants in the National Heart, Lung, and Blood Institute Family Heart Study. Participants consisted of 2,556 whites, 613 blacks, 1,790 women, and 1,379 men. The odds of having CAC ≥100 for the shortest LTL tertile versus the longest LTL tertile were 1.95 (95% confidence interval [CI] 1.28 to 3.16) in white men and 1.76 (95% CI 1.18 to 2.45) in white women, after adjusting for multiple covariates of CAC. The corresponding odds ratios for blacks were 1.53 (95% CI 0.67 to 3.50) and 0.87 (95% CI 0.37 to 2.00). Significance levels of tests for trend across LTL tertiles were p = 0.002 in white men, p = 0.006 in white women, p = 0.32 in black men, and p = 0.74 in black women. The associations, or lack of associations, were independent of C-reactive protein levels and other risk factors for CAC. As previously shown in other studies, whites displayed shorter LTLs than blacks (p <0.0001). In conclusion, the higher the coronary artery atherosclerotic burden in whites, the shorter the LTL. This LTL-atherosclerosis connection is not found in blacks. The mechanisms for the racial difference in LTL, CAC, and their interrelations do not seem to be related to inflammation and merit further research.},
}
@article {pmid25958390,
year = {2015},
author = {Stolarek, M and Gruszka, D and Braszewska-Zalewska, A and Maluszynski, M},
title = {Functional analysis of the new barley gene HvKu80 indicates that it plays a key role in double-strand DNA break repair and telomere length regulation.},
journal = {Mutagenesis},
volume = {30},
number = {6},
pages = {785-797},
doi = {10.1093/mutage/gev033},
pmid = {25958390},
issn = {1464-3804},
mesh = {Alleles ; Amino Acid Sequence ; *DNA Breaks, Double-Stranded ; DNA Helicases/chemistry/*genetics/metabolism ; DNA Mutational Analysis ; *DNA Repair ; Gene Expression Regulation, Plant ; Gene Order ; *Genes, Plant ; Genetic Fitness ; Homozygote ; Hordeum/*genetics/growth &amp; development/metabolism ; Molecular Sequence Data ; Mutation ; Open Reading Frames ; Sequence Alignment ; Telomere Homeostasis/*genetics ; },
abstract = {Genotoxic stress causes a reduced stability of the plant genome and has a detrimental effect on plant growth and productivity. Double-strand breaks (DSBs) are the most harmful of all DNA lesions because they cause the loss of genetic information on both strands of the DNA helix. In the presented study the coding and genomic sequences of the HvKu80 gene were determined. A mutational analysis of two fragments of HvKu80 using TILLING (Targeting Induced Local Lesions IN Genomes) allowed 12 mutations to be detected, which resulted in identification of 11 alleles. Multidirectional analyses demonstrated that the HvKu80 gene is involved in the elimination of DSBs in Hordeum vulgare. The barley mutants carrying the identified ku80.c and ku80.j alleles accumulated bleomycin-induced DSBs to a much greater extent than the parent cultivar 'Sebastian'. The altered reaction of the mutants to DSB-inducing agent and the kinetics of DNA repair in these genotypes are associated with a lower expression level of the mutated gene. The study also demonstrated the significant role of the HvKu80 gene in the regulation of telomere length in barley.},
}
@article {pmid25956165,
year = {2015},
author = {Mundstock, E and Zatti, H and Louzada, FM and Oliveira, SG and Guma, FT and Paris, MM and Rueda, AB and Machado, DG and Stein, RT and Jones, MH and Sarria, EE and Barbé-Tuana, FM and Mattiello, R},
title = {Effects of physical activity in telomere length: Systematic review and meta-analysis.},
journal = {Ageing research reviews},
volume = {22},
number = {},
pages = {72-80},
doi = {10.1016/j.arr.2015.02.004},
pmid = {25956165},
issn = {1872-9649},
mesh = {Humans ; Motor Activity/*physiology ; Statistics as Topic ; *Telomere ; Telomere Homeostasis/*physiology ; },
abstract = {The aim of this systematic review is to assess the effects of exercise on telomeres length. We searched the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Scopus, LILACS, SPORTDiscus and Web of Science from inception to August 2014. All articles that assessed the effects of exercise in telomere length were included in this review. The search strategy used the following combinations of terms: telomere AND "motor activity" OR exercise OR "physical activity". Two reviewers, working independently, screened all titles and abstracts to identify studies that could meet inclusion criteria. Whenever possible, and if appropriate, we performed a random-effect meta-analysis of study outcomes. Thirty-seven original studies were included in this systematic review, including 41,230 participants. Twenty articles did not find statistically significant association, whereas 15 described a positive association. Two papers found an inverted "U" correlation. There is a tendency toward demonstrating an effect of exercise on telomere length. Few prospective studies were found, many studies did not reach statistical significance and there was an important methodological diversity. For this reason, a possible significant association between physical activity and telomere length remains an open question.},
}
@article {pmid25954657,
year = {2015},
author = {de Beer, D and Völzmann, J and Kalka, C and Baerlocher, GM},
title = {Longitudinal Telomere Erosion in Lymphocyte Subsets of Patients with Atherosclerotic Peripheral Arterial Disease (PAD).},
journal = {Journal of clinical and diagnostic research : JCDR},
volume = {9},
number = {3},
pages = {OM01-3},
pmid = {25954657},
issn = {2249-782X},
abstract = {Telomere attrition has been linked to accelerate vascular ageing and seems to predispose for vascular disease. Our aim was to study the telomere length dynamics over time and in subsets of leukocytes from 15 patients with peripheral arterial disease (PAD). The mean telomere length in subsets of leukocytes of patients with PAD was in the normal range of age-related telomere length values from healthy individuals. However, we found significant higher telomere attrition for T-cells from patients with PAD over a time period of six months when compared to the controls. The higher telomere loss in T-cells of patients with PAD most likely reflects a higher cell turnover of this leukocyte subset, which is involved in the process of chronic inflammatory disease underlying vascular disease. Further studies are needed to confirm these data and to assess how far this T-cell telomere attrition will correlate to the extent of the disease.},
}
@article {pmid25954614,
year = {2015},
author = {Krishna, BH and Keerthi, GS and Kumar, CK and Reddy, NM},
title = {Association of leukocyte telomere length with oxidative stress in yoga practitioners.},
journal = {Journal of clinical and diagnostic research : JCDR},
volume = {9},
number = {3},
pages = {CC01-3},
pmid = {25954614},
issn = {2249-782X},
abstract = {OBJECTIVE: Yoga is a mind-body modulation technique that has been shown to have beneficial effects on various diseases related to various systems in the body. However, the molecular basis of mechanism of action is not clear. Hence, this study was designed to study the leukocyte telomere biology and its relation with homocysteine and oxidative stress in yoga practitioners.<br><br>MATERIALS AND METHODS: This is a prospective case-control study involving Yoga practitioners aged 30-40 y with minimum of two years yoga practice (Yoga group) and age, gender and body mass index matched sedentary healthy general population with no medical problems (Control group). Leukocyte telomere length (LTL) was measured by using quantitative PCR (qPCR), fasting plasma homocysteine was measured by a rapid high-performance liquid chromatography assay and the oxidative stress was assessed with total antioxidant status (TAOS), malondialdehyde (MDA) measured by calorimetry.<br><br>RESULTS: The LTL was shorter in control group than in yoga group (p<0.001). The TAOS was more in yoga group when compared to control group (p=0.008), MDA and homocysteine was high in control group when compared to Yoga group (p<0.001). Further, the LTL was positively correlated with TAOS (r=0.841, p<0.001) and negatively correlated with MDA (r=-0.931, p<0.001) and Homocysteine (r=-0.756, p<0.001).<br><br>CONCLUSION: The LTL is well-preserved in people who practice Yoga regularly with lower systemic oxidative stress compared to those who have a relatively sedentary lifestyle despite lack of any medical disorders. The habitual yoga practice seems to inhibit replicative cellular senescence.},
}
@article {pmid25952298,
year = {2015},
author = {Martins, CS and Santana-Lemos, BA and Saggioro, FP and Neder, L and Machado, HR and Moreira, AC and Calado, RT and de Castro, M},
title = {Telomere length and telomerase expression in pituitary tumors.},
journal = {Journal of endocrinological investigation},
volume = {38},
number = {11},
pages = {1243-1246},
pmid = {25952298},
issn = {1720-8386},
mesh = {Adult ; Gene Expression/*physiology ; Humans ; Middle Aged ; Pituitary Neoplasms/enzymology/*metabolism ; RNA/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {PURPOSE: Telomere dysfunction and telomerase activation underlie cancer transformation. This study aims to investigate the contribution of telomere biology to pituitary tumor behavior.<br><br>SUBJECTS AND METHODS: Samples from 50 patients with pituitary tumors (11 ACTH-secreting, 18 GH-secreting, and 21 non-secreting tumors) and 7 subjects without pituitary lesions were collected. The expressions of telomerase essential components TERT and TERC and tumor telomere content were measured by quantitative PCR techniques.<br><br>RESULTS: Telomerase (TERT) expression was detected in 36% of tumors. No correlation was observed between TERT and TERC expression level and tumor size in any tumor type. There was no association between gene expression and clinical findings. Telomere content (T/S ratio) was similar between pituitary adenomas (0.39 &#xb1; 0.16) and normal pituitaries (0.47 &#xb1; 0.12; p = 0.24) and also was between the different adenoma types: ACTH-secreting (0.43 &#xb1; 0.08), GH-secreting (0.31 &#xb1; 0.12), and non-secreting (0.42 &#xb1; 0.20; p = 0.10) tumors.<br><br>CONCLUSIONS: The telomere content and expression of telomerase components are comparable between normal pituitary glands and tumor tissues, suggesting that telomere biology does not play an important role in pituitary tumor development.},
}
@article {pmid25952108,
year = {2015},
author = {Holohan, B and De Meyer, T and Batten, K and Mangino, M and Hunt, SC and Bekaert, S and De Buyzere, ML and Rietzschel, ER and Spector, TD and Wright, WE and Shay, JW},
title = {Decreasing initial telomere length in humans intergenerationally understates age-associated telomere shortening.},
journal = {Aging cell},
volume = {14},
number = {4},
pages = {669-677},
pmid = {25952108},
issn = {1474-9726},
support = {U01 HL56565/HL/NHLBI NIH HHS/United States ; U01 HL56564/HL/NHLBI NIH HHS/United States ; U01 HL56566/HL/NHLBI NIH HHS/United States ; 5P30 CA142543/CA/NCI NIH HHS/United States ; U01 HL56569/HL/NHLBI NIH HHS/United States ; R13 CA113094/CA/NCI NIH HHS/United States ; U01 HL56568/HL/NHLBI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; U01 HL56567/HL/NHLBI NIH HHS/United States ; U01 HL56563/HL/NHLBI NIH HHS/United States ; //Wellcome Trust/United Kingdom ; C06 RR30414/RR/NCRR NIH HHS/United States ; },
mesh = {Aging/*genetics ; Cross-Sectional Studies ; Datasets as Topic ; Female ; Gene Expression ; Humans ; *Inheritance Patterns ; Longitudinal Studies ; Male ; Paternal Age ; Telomerase/*genetics ; Telomere/chemistry/*genetics ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Telomere length shortens with aging, and short telomeres have been linked to a wide variety of pathologies. Previous studies suggested a discrepancy in age-associated telomere shortening rate estimated by cross-sectional studies versus the rate measured in longitudinal studies, indicating a potential bias in cross-sectional estimates. Intergenerational changes in initial telomere length, such as that predicted by the previously described effect of a father's age at birth of his offspring (FAB), could explain the discrepancy in shortening rate measurements. We evaluated whether changes occur in initial telomere length over multiple generations in three large datasets and identified paternal birth year (PBY) as a variable that reconciles the difference between longitudinal and cross-sectional measurements. We also clarify the association between FAB and offspring telomere length, demonstrating that this effect is substantially larger than reported in the past. These results indicate the presence of a downward secular trend in telomere length at birth over generational time with potential public health implications.},
}
@article {pmid25948570,
year = {2015},
author = {Kim, SY and Velando, A},
title = {Antioxidants safeguard telomeres in bold chicks.},
journal = {Biology letters},
volume = {11},
number = {5},
pages = {20150211},
pmid = {25948570},
issn = {1744-957X},
mesh = {Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; Ascorbic Acid/administration &amp; dosage/*pharmacology ; Charadriiformes/growth &amp; development/*physiology ; *Diet ; Dietary Supplements ; Immobility Response, Tonic/*drug effects ; Oxidative Stress/drug effects ; Random Allocation ; Spain ; Telomere Shortening/*drug effects ; Vitamin E/administration &amp; dosage/*pharmacology ; },
abstract = {Telomeres are sensitive to damage induced by oxidative stress, and thus it is expected that dietary antioxidants may support the maintenance of telomere length in animals, particularly those with a fast rate of life (e.g. fast metabolism, activity and growth). We tested experimentally the effect of antioxidant supplements on telomere length during early development in wild gull chicks with natural individual variations in behaviour pattern and growth rate. Proactive chicks had shorter telomeres than reactive chicks, but the penalty for the bold behaviour pattern was reduced by antioxidant supplementation. Chicks growing faster had longer telomeres during early growth, suggesting that inherited quality supports a fast life history.},
}
@article {pmid25944259,
year = {2015},
author = {Loprinzi, PD},
title = {Leisure-Time Screen-Based Sedentary Behavior and Leukocyte Telomere Length: Implications for a New Leisure-Time Screen-Based Sedentary Behavior Mechanism.},
journal = {Mayo Clinic proceedings},
volume = {90},
number = {6},
pages = {786-790},
doi = {10.1016/j.mayocp.2015.02.018},
pmid = {25944259},
issn = {1942-5546},
mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; *Health Behavior ; Humans ; *Leukocytes ; Male ; Middle Aged ; Nutrition Surveys ; *Sedentary Behavior ; Surveys and Questionnaires ; Television ; *Telomere Homeostasis ; United States ; Video Games ; Young Adult ; },
abstract = {The field of sedentary behavior epidemiology is emerging. Short leukocyte telomere length (LTL) is a hallmark characteristic of aging, but LTL is also associated with morbidity and mortality independent of age. To my knowledge, only one study has examined the association between sedentary behavior and LTL. The purpose of this study was to examine the association between screen-based sedentary behavior and LTL. Data from the 1999-2002 National Health and Nutrition Examination Survey were used (N=6405; age, 20-84 years). Leisure-time screen-based sedentary behavior (television, video games, computer use) was assessed via questionnaire, and LTL was extracted from DNA in whole blood with the LTL assay performed using quantitative polymerase chain reaction. After adjustments (including age and physical activity), for every 1-hour increase in leisure-time screen-based sedentary behavior, participants had a 7% increased odds (odds ratio, 1.07; 95% CI, 1.00-1.13; P=.04) of having LTL in the lowest tertile (vs highest); leisure-time screen-based sedentary behavior was not associated with values in the middle (vs highest) tertile (odds ratio, 1.01; 95% CI, 0.95-1.07; P=.62). The results of this study revealed that greater leisure-time screen-based sedentary behavior is associated with shorter LTL.},
}
@article {pmid25940403,
year = {2015},
author = {Glousker, G and Touzot, F and Revy, P and Tzfati, Y and Savage, SA},
title = {Unraveling the pathogenesis of Hoyeraal-Hreidarsson syndrome, a complex telomere biology disorder.},
journal = {British journal of haematology},
volume = {170},
number = {4},
pages = {457-471},
pmid = {25940403},
issn = {1365-2141},
support = {249816/ERC_/European Research Council/International ; ZIA CP010144-15/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Dyskeratosis Congenita/*genetics/*metabolism/pathology ; Fetal Growth Retardation/*genetics/*metabolism/pathology ; Humans ; Intellectual Disability/*genetics/*metabolism/pathology ; Microcephaly/*genetics/*metabolism/pathology ; *Mutation ; Telomere/*genetics/*metabolism/pathology ; Telomere Homeostasis/*genetics ; },
abstract = {Hoyeraal-Hreidarsson (HH) syndrome is a multisystem genetic disorder characterized by very short telomeres and considered a clinically severe variant of dyskeratosis congenita. The main cause of mortality, usually in early childhood, is bone marrow failure. Mutations in several telomere biology genes have been reported to cause HH in about 60% of the HH patients, but the genetic defects in the rest of the patients are still unknown. Understanding the aetiology of HH and its diverse manifestations is challenging because of the complexity of telomere biology and the multiple telomeric and non-telomeric functions played by telomere-associated proteins in processes such as telomere replication, telomere protection, DNA damage response and ribosome and spliceosome assembly. Here we review the known clinical complications, molecular defects and germline mutations associated with HH, and elucidate possible mechanistic explanations and remaining questions in our understanding of the disease.},
}
@article {pmid25938489,
year = {2015},
author = {Gao, J and Munch, SB},
title = {Does Reproductive Investment Decrease Telomere Length in Menidia menidia?.},
journal = {PloS one},
volume = {10},
number = {5},
pages = {e0125674},
pmid = {25938489},
issn = {1932-6203},
mesh = {Animals ; Brain/metabolism ; Female ; Fertility ; Gonads/anatomy &amp; histology ; Male ; Muscles/metabolism ; Organ Size ; Ovum/metabolism ; Regression Analysis ; Reproduction/*physiology ; Smegmamorpha/*physiology ; *Telomere Homeostasis ; },
abstract = {Given finite resources, intense investment in one life history trait is expected to reduce investment in others. Although telomere length appears to be strongly tied to age in many taxa, telomere maintenance requires energy. We therefore hypothesize that telomere maintenance may trade off against other life history characters. We used natural variation in laboratory populations of Atlantic silversides (Menidia menidia) to study the relationship between growth, fecundity, life expectancy, and relative telomere length. In keeping with several other studies on fishes, we found no clear dependence of telomere length on age. However, we did find that more fecund fish tended to have both reduced life expectancy and shorter telomeres. This result is consistent with the hypothesis that there is a trade-off between telomere maintenance and reproductive output.},
}
@article {pmid25937286,
year = {2015},
author = {González-García, MP and Pavelescu, I and Canela, A and Sevillano, X and Leehy, KA and Nelson, ADL and Ibañes, M and Shippen, DE and Blasco, MA and Caño-Delgado, AI},
title = {Single-cell telomere-length quantification couples telomere length to meristem activity and stem cell development in Arabidopsis.},
journal = {Cell reports},
volume = {11},
number = {6},
pages = {977-989},
pmid = {25937286},
issn = {2211-1247},
support = {232854/ERC_/European Research Council/International ; R01 GM065383/GM/NIGMS NIH HHS/United States ; R01-GM065383/GM/NIGMS NIH HHS/United States ; },
mesh = {Arabidopsis/*cytology/*metabolism ; Arabidopsis Proteins/metabolism ; Cell Compartmentation ; Cell Differentiation ; Cell Division ; In Situ Hybridization, Fluorescence ; Meristem/*cytology/metabolism ; Mutation/genetics ; Single-Cell Analysis/*methods ; Stem Cell Niche ; Stem Cells/*cytology/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are specialized nucleoprotein caps that protect chromosome ends assuring cell division. Single-cell telomere quantification in animals established a critical role for telomerase in stem cells, yet, in plants, telomere-length quantification has been reported only at the organ level. Here, a quantitative analysis of telomere length of single cells in Arabidopsis root apex uncovered a heterogeneous telomere-length distribution of different cell lineages showing the longest telomeres at the stem cells. The defects in meristem and stem cell renewal observed in tert mutants demonstrate that telomere lengthening by TERT sets a replicative limit in the root meristem. Conversely, the long telomeres of the columella cells and the premature stem cell differentiation plt1,2 mutants suggest that differentiation can prevent telomere erosion. Overall, our results indicate that telomere dynamics are coupled to meristem activity and continuous growth, disclosing a critical association between telomere length, stem cell function, and the extended lifespan of plants.},
}
@article {pmid25932992,
year = {2015},
author = {Simon, NM and Walton, ZE and Bui, E and Prescott, J and Hoge, E and Keshaviah, A and Schwarz, N and Dryman, T and Ojserkis, RA and Kovachy, B and Mischoulon, D and Worthington, J and De Vivo, I and Fava, M and Wong, KK},
title = {Telomere length and telomerase in a well-characterized sample of individuals with major depressive disorder compared to controls.},
journal = {Psychoneuroendocrinology},
volume = {58},
number = {},
pages = {9-22},
pmid = {25932992},
issn = {1873-3360},
support = {R01 MH077700/MH/NIMH NIH HHS/United States ; 5 R01MH077700-05/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Depressive Disorder, Major/*genetics/metabolism ; Female ; Humans ; Male ; Middle Aged ; Telomerase/*blood ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; Young Adult ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) is a marker of cellular turnover and oxidative stress. Studies suggest major depressive disorder (MDD) is associated with oxidative stress, but examinations of MDD and LTL have yielded mixed results, likely because of differences in measurement methods and unmeasured confounding. This study examined LTL and telomerase activity in 166 individuals with MDD compared to 166 age- and gender-matched matched controls free of any psychiatric disorder, using well-validated assays and clinical assessment methods, and controlling for a range of potential confounders.<br><br>METHODS: Subjects aged 18 to 70 were evaluated by trained raters and provided blood for LTL and telomerase activity measurement. LTL was assayed using Southern blot and replicated with qPCR, and telomerase activity was assayed with a repeat amplification protocol using a commercial kit.<br><br>RESULTS: There was no significant difference in telomere length for individuals with MDD [mean (SD)=9.1 (3.0)kbp] compared to controls [mean(SD)=8.9(2.5)kbp] measured by Southern blot (p=0.65) or by confirmatory qPCR (p=0.91) assays. Controlling for potential confounders did not alter the results. Telomerase activity did not differ by MDD diagnosis overall (p=0.40), but the effect of MDD was significantly modified by gender (t(299)=2.67, p=0.0079) even after controlling for potential confounders, with telomerase activity significantly greater only in males with MDD versus controls.<br><br>CONCLUSION: Our well-characterized, well-powered examination of concurrently assessed telomere length and telomerase activity in individuals with clinically significant, chronic MDD and matched controls failed to provide strong evidence of an association of MDD with shorter LTL, while telomerase activity was higher in men with MDD [corrected].},
}
@article {pmid25930147,
year = {2015},
author = {Geronimus, AT and Pearson, JA and Linnenbringer, E and Schulz, AJ and Reyes, AG and Epel, ES and Lin, J and Blackburn, EH},
title = {Race-Ethnicity, Poverty, Urban Stressors, and Telomere Length in a Detroit Community-based Sample.},
journal = {Journal of health and social behavior},
volume = {56},
number = {2},
pages = {199-224},
pmid = {25930147},
issn = {2150-6000},
support = {T32 AG000221/AG/NIA NIH HHS/United States ; P30 AG012846/AG/NIA NIH HHS/United States ; R24 HD041028/HD/NICHD NIH HHS/United States ; R01 AG032632/AG/NIA NIH HHS/United States ; P2C HD041028/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; *Black or African American ; Female ; Humans ; Male ; *Mexican Americans ; Michigan ; Middle Aged ; *Poverty ; Residence Characteristics ; *Telomere ; *Urban Population ; *White People ; },
abstract = {Residents of distressed urban areas suffer early aging-related disease and excess mortality. Using a community-based participatory research approach in a collaboration between social researchers and cellular biologists, we collected a unique data set of 239 black, white, or Mexican adults from a stratified, multistage probability sample of three Detroit neighborhoods. We drew venous blood and measured telomere length (TL), an indicator of stress-mediated biological aging, linking respondents' TL to their community survey responses. We regressed TL on socioeconomic, psychosocial, neighborhood, and behavioral stressors, hypothesizing and finding an interaction between poverty and racial-ethnic group. Poor whites had shorter TL than nonpoor whites; poor and nonpoor blacks had equivalent TL; and poor Mexicans had longer TL than nonpoor Mexicans. Findings suggest unobserved heterogeneity bias is an important threat to the validity of estimates of TL differences by race-ethnicity. They point to health impacts of social identity as contingent, the products of structurally rooted biopsychosocial processes.},
}
@article {pmid25926849,
year = {2015},
author = {Cusanelli, E and Chartrand, P},
title = {Telomeric repeat-containing RNA TERRA: a noncoding RNA connecting telomere biology to genome integrity.},
journal = {Frontiers in genetics},
volume = {6},
number = {},
pages = {143},
pmid = {25926849},
issn = {1664-8021},
abstract = {Telomeres are dynamic nucleoprotein structures that protect the ends of chromosomes from degradation and activation of DNA damage response. For this reason, telomeres are essential to genome integrity. Chromosome ends are enriched in heterochromatic marks and proper organization of telomeric chromatin is important to telomere stability. Despite their heterochromatic state, telomeres are transcribed giving rise to long noncoding RNAs (lncRNA) called TERRA (telomeric repeat-containing RNA). TERRA molecules play critical roles in telomere biology, including regulation of telomerase activity and heterochromatin formation at chromosome ends. Emerging evidence indicate that TERRA transcripts form DNA-RNA hybrids at chromosome ends which can promote homologous recombination among telomeres, delaying cellular senescence and sustaining genome instability. Intriguingly, TERRA RNA-telomeric DNA hybrids are involved in telomere length homeostasis of telomerase-negative cancer cells. Furthermore, TERRA transcripts play a role in the DNA damage response (DDR) triggered by dysfunctional telomeres. We discuss here recent developments on TERRA's role in telomere biology and genome integrity, and its implication in cancer.},
}
@article {pmid25923330,
year = {2015},
author = {Nersisyan, L and Arakelyan, A},
title = {Computel: computation of mean telomere length from whole-genome next-generation sequencing data.},
journal = {PloS one},
volume = {10},
number = {4},
pages = {e0125201},
pmid = {25923330},
issn = {1932-6203},
mesh = {Base Sequence ; Cell Division ; Cellular Senescence/*genetics ; Computational Biology ; Genome, Human ; *High-Throughput Nucleotide Sequencing ; Humans ; Software ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Telomeres are the ends of eukaryotic chromosomes, consisting of consecutive short repeats that protect chromosome ends from degradation. Telomeres shorten with each cell division, leading to replicative cell senescence. Deregulation of telomere length homeostasis is associated with the development of various age-related diseases and cancers. A number of experimental techniques exist for telomere length measurement; however, until recently, the absence of tools for extracting telomere lengths from high-throughput sequencing data has significantly obscured the association of telomere length with molecular processes in normal and diseased conditions. We have developed Computel, a program in R for computing mean telomere length from whole-genome next-generation sequencing data. Computel is open source, and is freely available at https://github.com/lilit-nersisyan/computel. It utilizes a short-read alignment-based approach and integrates various popular tools for sequencing data analysis. We validated it with synthetic and experimental data, and compared its performance with the previously available software. The results have shown that Computel outperforms existing software in accuracy, independence of results from sequencing conditions, stability against inherent sequencing errors, and better ability to distinguish pure telomeric sequences from interstitial telomeric repeats. By providing a highly reliable methodology for determining telomere lengths from whole-genome sequencing data, Computel should help to elucidate the role of telomeres in cellular health and disease.},
}
@article {pmid25922071,
year = {2015},
author = {Teasley, DC and Parajuli, S and Nguyen, M and Moore, HR and Alspach, E and Lock, YJ and Honaker, Y and Saharia, A and Piwnica-Worms, H and Stewart, SA},
title = {Flap Endonuclease 1 Limits Telomere Fragility on the Leading Strand.},
journal = {The Journal of biological chemistry},
volume = {290},
number = {24},
pages = {15133-15145},
pmid = {25922071},
issn = {1083-351X},
support = {T32 CA113275/CA/NCI NIH HHS/United States ; R01 GM095924/GM/NIGMS NIH HHS/United States ; GM007067/GM/NIGMS NIH HHS/United States ; GM95924/GM/NIGMS NIH HHS/United States ; T32 GM007067/GM/NIGMS NIH HHS/United States ; },
mesh = {Blotting, Western ; DNA Damage ; DNA Replication ; Flap Endonucleases/genetics/*metabolism ; HEK293 Cells ; Humans ; In Situ Hybridization, Fluorescence ; Reverse Transcriptase Polymerase Chain Reaction ; *Telomere ; Transcription, Genetic ; },
abstract = {The existence of redundant replication and repair systems that ensure genome stability underscores the importance of faithful DNA replication. Nowhere is this complexity more evident than in challenging DNA templates, including highly repetitive or transcribed sequences. Here, we demonstrate that flap endonuclease 1 (FEN1), a canonical lagging strand DNA replication protein, is required for normal, complete leading strand replication at telomeres. We find that the loss of FEN1 nuclease activity, but not DNA repair activities, results in leading strand-specific telomere fragility. Furthermore, we show that FEN1 depletion-induced telomere fragility is increased by RNA polymerase II inhibition and is rescued by ectopic RNase H1 expression. These data suggest that FEN1 limits leading strand-specific telomere fragility by processing RNA:DNA hybrid/flap intermediates that arise from co-directional collisions occurring between the replisome and RNA polymerase. Our data reveal the first molecular mechanism for leading strand-specific telomere fragility and the first known role for FEN1 in leading strand DNA replication. Because FEN1 mutations have been identified in human cancers, our findings raise the possibility that unresolved RNA:DNA hybrid structures contribute to the genomic instability associated with cancer.},
}
@article {pmid25917938,
year = {2016},
author = {Tu, L and Huda, N and Grimes, BR and Slee, RB and Bates, AM and Cheng, L and Gilley, D},
title = {Widespread telomere instability in prostatic lesions.},
journal = {Molecular carcinogenesis},
volume = {55},
number = {5},
pages = {842-852},
doi = {10.1002/mc.22326},
pmid = {25917938},
issn = {1098-2744},
mesh = {Aged ; Aged, 80 and over ; Cell Line, Tumor ; *Chromosomal Instability ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Neoplasm Grading ; Prostatic Hyperplasia/*genetics ; Prostatic Intraepithelial Neoplasia/*genetics/metabolism/pathology ; Prostatic Neoplasms/*genetics/metabolism/pathology ; Telomere/*metabolism ; },
abstract = {A critical function of the telomere is to disguise chromosome ends from cellular recognition as double strand breaks, thereby preventing aberrant chromosome fusion events. Such chromosome end-to-end fusions are known to initiate genomic instability via breakage-fusion-bridge cycles. Telomere dysfunction and other forms of genomic assault likely result in misregulation of genes involved in growth control, cell death, and senescence pathways, lowering the threshold to malignancy and likely drive disease progression. Shortened telomeres and anaphase bridges have been reported in a wide variety of early precursor and malignant cancer lesions including those of the prostate. These findings are being extended using methods for the analysis of telomere fusions (decisive genetic markers for telomere dysfunction) specifically within human tissue DNA. Here we report that benign prostatic hyperplasia (BPH), high-grade prostatic intraepithelial neoplasia (PIN), and prostate cancer (PCa) prostate lesions all contain similarly high frequencies of telomere fusions and anaphase bridges. Tumor-adjacent, histologically normal prostate tissue generally did not contain telomere fusions or anaphase bridges as compared to matched PCa tissues. However, we found relatively high levels of telomerase activity in this histologically normal tumor-adjacent tissue that was reduced but closely correlated with telomerase levels in corresponding PCa samples. Thus, we present evidence of high levels of telomere dysfunction in BPH, an established early precursor (PIN) and prostate cancer lesions but not generally in tumor adjacent normal tissue. Our results suggest that telomere dysfunction may be a common gateway event leading to genomic instability in prostate tumorigenesis. .},
}
@article {pmid25908860,
year = {2015},
author = {Osterwald, S and Deeg, KI and Chung, I and Parisotto, D and Wörz, S and Rohr, K and Erfle, H and Rippe, K},
title = {PML induces compaction, TRF2 depletion and DNA damage signaling at telomeres and promotes their alternative lengthening.},
journal = {Journal of cell science},
volume = {128},
number = {10},
pages = {1887-1900},
doi = {10.1242/jcs.148296},
pmid = {25908860},
issn = {1477-9137},
mesh = {Cell Line, Tumor ; *DNA Damage ; DNA Repair ; Humans ; Leukemia, Promyelocytic, Acute/*genetics/metabolism ; Nuclear Proteins/*genetics/metabolism ; Promyelocytic Leukemia Protein ; Signal Transduction ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/*genetics/metabolism ; Transcription Factors/*genetics/metabolism ; Tumor Suppressor Proteins/*genetics/metabolism ; },
abstract = {The alternative lengthening of telomeres (ALT) mechanism allows cancer cells to escape senescence and apoptosis in the absence of active telomerase. A characteristic feature of this pathway is the assembly of ALT-associated promyelocytic leukemia (PML) nuclear bodies (APBs) at telomeres. Here, we dissected the role of APBs in a human ALT cell line by performing an RNA interference screen using an automated 3D fluorescence microscopy platform and advanced 3D image analysis. We identified 29 proteins that affected APB formation, which included proteins involved in telomere and chromatin organization, protein sumoylation and DNA repair. By integrating and extending these findings, we found that APB formation induced clustering of telomere repeats, telomere compaction and concomitant depletion of the shelterin protein TRF2 (also known as TERF2). These APB-dependent changes correlated with the induction of a DNA damage response at telomeres in APBs as evident by a strong enrichment of the phosphorylated form of the ataxia telangiectasia mutated (ATM) kinase. Accordingly, we propose that APBs promote telomere maintenance by inducing a DNA damage response in ALT-positive tumor cells through changing the telomeric chromatin state to trigger ATM phosphorylation.},
}
@article {pmid25908850,
year = {2015},
author = {Dubruille, R and Loppin, B},
title = {Protection of Drosophila chromosome ends through minimal telomere capping.},
journal = {Journal of cell science},
volume = {128},
number = {10},
pages = {1969-1981},
pmid = {25908850},
issn = {1477-9137},
support = {R01 GM084947/GM/NIGMS NIH HHS/United States ; R01-GM084947/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Animals, Genetically Modified ; Drosophila Proteins/*genetics/metabolism ; Drosophila melanogaster ; Male ; Spermatogenesis/*genetics ; Telomere/*genetics/metabolism ; },
abstract = {In Drosophila, telomere-capping proteins have the remarkable capacity to recognize chromosome ends in a sequence-independent manner. This epigenetic protection is essential to prevent catastrophic ligations of chromosome extremities. Interestingly, capping proteins occupy a large telomere chromatin domain of several kilobases; however, the functional relevance of this to end protection is unknown. Here, we investigate the role of the large capping domain by manipulating HOAP (encoded by caravaggio) capping-protein expression in the male germ cells, where telomere protection can be challenged without compromising viability. We show that the exhaustion of HOAP results in a dramatic reduction of other capping proteins at telomeres, including K81 [encoded by ms(3)K81], which is essential for male fertility. Strikingly however, we demonstrate that, although capping complexes are barely detected in HOAP-depleted male germ cells, telomere protection and male fertility are not dramatically affected. Our study thus demonstrates that efficient protection of Drosophila telomeres can be achieved with surprisingly low amounts of capping complexes. We propose that these complexes prevent fusions by acting at the very extremity of chromosomes, reminiscent of the protection conferred by extremely short telomeric arrays in yeast or mammalian systems.},
}
@article {pmid25907089,
year = {2015},
author = {Andreassi, MG and Piccaluga, E and Gargani, L and Sabatino, L and Borghini, A and Faita, F and Bruno, RM and Padovani, R and Guagliumi, G and Picano, E},
title = {Subclinical carotid atherosclerosis and early vascular aging from long-term low-dose ionizing radiation exposure: a genetic, telomere, and vascular ultrasound study in cardiac catheterization laboratory staff.},
journal = {JACC. Cardiovascular interventions},
volume = {8},
number = {4},
pages = {616-627},
doi = {10.1016/j.jcin.2014.12.233},
pmid = {25907089},
issn = {1876-7605},
mesh = {Adult ; Aging/genetics ; *Cardiac Catheterization ; Carotid Artery Diseases/diagnostic imaging/epidemiology/*etiology ; *Carotid Intima-Media Thickness ; Case-Control Studies ; Female ; Humans ; Laboratories, Hospital ; Male ; Medical Staff, Hospital ; Middle Aged ; Multivariate Analysis ; Occupational Exposure/*adverse effects ; Occupational Health ; Radiation Dosage ; Radiation Exposure/*adverse effects ; Regression Analysis ; Telomere/radiation effects ; Time Factors ; Ultrasonography, Interventional/methods ; },
abstract = {OBJECTIVES: This study sought to assess the association between long-term radiation exposure in the catheterization laboratory (cath lab) and early signs of subclinical atherosclerosis.<br><br>BACKGROUND: There is growing evidence of an excess risk of cardiovascular disease at low-dose levels of ionizing radiation exposure.<br><br>METHODS: Left and right carotid intima-media thickness (CIMT) was measured in 223 cath lab personnel (141 male; age, 45 &#xb1; 8 years) and 222 unexposed subjects (113 male; age, 44&#xb1;10 years). Leukocyte telomere length (LTL) was evaluated by quantitative reverse transcriptase polymerase chain reaction. The DNA repair gene XRCC3 Thr241Met polymorphism was also analyzed to explore the possible interaction with radiation exposure. The occupational radiological risk score (ORRS) was computed for each subject on the basis of the length of employment, individual caseload, and proximity to the radiation source. A complete lifetime effective dose (mSv) was recorded for 57 workers.<br><br>RESULTS: Left, right, and averaged CIMTs were significantly increased in high-exposure workers compared with both control subjects and low-exposure workers (all p values<0.04). On the left side, but not on the right, there was a significant correlation between CIMT and ORRS (p=0.001) as well as lifetime dose (p=0.006). LTL was significantly reduced in exposed workers compared with control subjects (p=0.008). There was a significant correlation between LTL and both ORRS (p=0.002) and lifetime dose (p=0.03). The XRCC3 Met241 allele presented a significant interaction with high exposure for right side (pinteraction=0.002), left side (pinteraction<0.0001), and averaged (pinteraction<0.0001) CIMTs.<br><br>CONCLUSIONS: Long-term radiation exposure in a cath lab may be associated with increased subclinical CIMT and telomere length shortening, suggesting evidence of accelerated vascular aging and early atherosclerosis.},
}
@article {pmid25906514,
year = {2014},
author = {Agarwal, MB},
title = {Telomeres and diseases.},
journal = {The Journal of the Association of Physicians of India},
volume = {62},
number = {10},
pages = {9-11},
pmid = {25906514},
issn = {0004-5772},
mesh = {Dyskeratosis Congenita/*genetics/metabolism ; Humans ; Idiopathic Pulmonary Fibrosis/*genetics/metabolism ; Liver Cirrhosis/*genetics/metabolism ; Telomerase/*genetics/metabolism ; Telomere Homeostasis/*genetics/physiology ; },
}
@article {pmid25906395,
year = {2015},
author = {Phillips, JA and Chan, A and Paeschke, K and Zakian, VA},
title = {The pif1 helicase, a negative regulator of telomerase, acts preferentially at long telomeres.},
journal = {PLoS genetics},
volume = {11},
number = {4},
pages = {e1005186},
pmid = {25906395},
issn = {1553-7404},
support = {R01 GM043265/GM/NIGMS NIH HHS/United States ; GM043265/GM/NIGMS NIH HHS/United States ; R37 GM026938/GM/NIGMS NIH HHS/United States ; R01 GM026938/GM/NIGMS NIH HHS/United States ; GM026938/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Breaks, Double-Stranded ; DNA Helicases/*genetics ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/*genetics ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Homeostasis/genetics ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {Telomerase, the enzyme that maintains telomeres, preferentially lengthens short telomeres. The S. cerevisiae Pif1 DNA helicase inhibits both telomerase-mediated telomere lengthening and de novo telomere addition at double strand breaks (DSB). Here, we report that the association of the telomerase subunits Est2 and Est1 at a DSB was increased in the absence of Pif1, as it is at telomeres, suggesting that Pif1 suppresses de novo telomere addition by removing telomerase from the break. To determine how the absence of Pif1 results in telomere lengthening, we used the single telomere extension assay (STEX), which monitors lengthening of individual telomeres in a single cell cycle. In the absence of Pif1, telomerase added significantly more telomeric DNA, an average of 72 nucleotides per telomere compared to the 45 nucleotides in wild type cells, and the fraction of telomeres lengthened increased almost four-fold. Using an inducible short telomere assay, Est2 and Est1 no longer bound preferentially to a short telomere in pif1 mutant cells while binding of Yku80, a telomere structural protein, was unaffected by the status of the PIF1 locus. Two experiments demonstrate that Pif1 binding is affected by telomere length: Pif1 (but not Yku80) -associated telomeres were 70 bps longer than bulk telomeres, and in the inducible short telomere assay, Pif1 bound better to wild type length telomeres than to short telomeres. Thus, preferential lengthening of short yeast telomeres is achieved in part by targeting the negative regulator Pif1 to long telomeres.},
}
@article {pmid25904853,
year = {2015},
author = {Blaze, J and Asok, A and Roth, TL},
title = {The long-term impact of adverse caregiving environments on epigenetic modifications and telomeres.},
journal = {Frontiers in behavioral neuroscience},
volume = {9},
number = {},
pages = {79},
pmid = {25904853},
issn = {1662-5153},
support = {P20 GM103653/GM/NIGMS NIH HHS/United States ; },
abstract = {Early childhood is a sensitive period in which infant-caregiver experiences have profound effects on brain development and behavior. Clinical studies have demonstrated that infants who experience stress and adversity in the context of caregiving are at an increased risk for the development of psychiatric disorders. Animal models have helped to elucidate some molecular substrates of these risk factors, but a complete picture of the biological basis remains unknown. Studies continue to indicate that environmentally-driven epigenetic modifications may be an important mediator between adverse caregiving environments and psychopathology. Epigenetic modifications such as DNA methylation, which normally represses gene transcription, and microRNA processing, which interferes with both transcription and translation, show long-term changes throughout the brain and body following adverse caregiving. Recent evidence has also shown that telomeres (TTAGGG nucleotide repeats that cap the ends of DNA) exhibit long-term changes in the brain and in the periphery following exposure to adverse caregiving environments. Interestingly, telomeric enzymes and subtelomeric regions are subject to epigenetic modifications-a factor which may play an important role in regulating telomere length and contribute to future mental health. This review will focus on clinical and animal studies that highlight the long-term epigenetic and telomeric changes produced by adverse caregiving in early-life.},
}
@article {pmid25904662,
year = {2015},
author = {Becker, PJ and Reichert, S and Zahn, S and Hegelbach, J and Massemin, S and Keller, LF and Postma, E and Criscuolo, F},
title = {Mother-offspring and nest-mate resemblance but no heritability in early-life telomere length in white-throated dippers.},
journal = {Proceedings. Biological sciences},
volume = {282},
number = {1807},
pages = {20142924},
pmid = {25904662},
issn = {1471-2954},
mesh = {Animals ; Female ; *Inheritance Patterns ; Male ; Passeriformes/*genetics/physiology ; Regression Analysis ; Sex Factors ; Telomere/*genetics ; },
abstract = {Telomeres are protective DNA-protein complexes located at the ends of eukaryotic chromosomes, whose length has been shown to predict life-history parameters in various species. Although this suggests that telomere length is subject to natural selection, its evolutionary dynamics crucially depends on its heritability. Using pedigree data for a population of white-throated dippers (Cinclus cinclus), we test whether and how variation in early-life relative telomere length (RTL, measured as the number of telomeric repeats relative to a control gene using qPCR) is transmitted across generations. We disentangle the relative effects of genes and environment and test for sex-specific patterns of inheritance. There was strong and significant resemblance among offspring sharing the same nest and offspring of the same cohort. Furthermore, although offspring resemble their mother, and there is some indication for an effect of inbreeding, additive genetic variance and heritability are close to zero. We find no evidence for a role of either maternal imprinting or Z-linked inheritance in generating these patterns, suggesting they are due to non-genetic maternal and common environment effects instead. We conclude that in this wild bird population, environmental factors are the main drivers of variation in early-life RTL, which will severely bias estimates of heritability when not modelled explicitly.},
}
@article {pmid25897084,
year = {2015},
author = {Li, P and Shao, Y and Jin, H and Yu, HG},
title = {Ndj1, a telomere-associated protein, regulates centrosome separation in budding yeast meiosis.},
journal = {The Journal of cell biology},
volume = {209},
number = {2},
pages = {247-259},
pmid = {25897084},
issn = {1540-8140},
mesh = {Blotting, Western ; Cell Cycle Proteins/*metabolism ; Cells, Cultured ; Centrosome/*physiology ; Chromatography, Affinity ; *Chromosome Segregation ; Flow Cytometry ; Meiosis/*physiology ; Microscopy, Fluorescence ; Saccharomyces cerevisiae Proteins/*metabolism ; Saccharomycetales/*physiology ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Spindle Apparatus/*physiology ; Telomere/physiology ; },
abstract = {Yeast centrosomes (called spindle pole bodies [SPBs]) remain cohesive for hours during meiotic G2 when recombination takes place. In contrast, SPBs separate within minutes after duplication in vegetative cells. We report here that Ndj1, a previously known meiosis-specific telomere-associated protein, is required for protecting SPB cohesion. Ndj1 localizes to the SPB but dissociates from it ∼16 min before SPB separation. Without Ndj1, meiotic SPBs lost cohesion prematurely, whereas overproduction of Ndj1 delayed SPB separation. When produced ectopically in vegetative cells, Ndj1 caused SPB separation defects and cell lethality. Localization of Ndj1 to the SPB depended on the SUN domain protein Mps3, and removal of the N terminus of Mps3 allowed SPB separation and suppressed the lethality of NDJ1-expressing vegetative cells. Finally, we show that Ndj1 forms oligomeric complexes with Mps3, and that the Polo-like kinase Cdc5 regulates Ndj1 protein stability and SPB separation. These findings reveal the underlying mechanism that coordinates yeast centrosome dynamics with meiotic telomere movement and cell cycle progression.},
}
@article {pmid25896211,
year = {2015},
author = {Boccardi, V and Pelini, L and Ercolani, S and Ruggiero, C and Mecocci, P},
title = {From cellular senescence to Alzheimer's disease: The role of telomere shortening.},
journal = {Ageing research reviews},
volume = {22},
number = {},
pages = {1-8},
doi = {10.1016/j.arr.2015.04.003},
pmid = {25896211},
issn = {1872-9649},
mesh = {Aging/*physiology ; Alzheimer Disease/*metabolism ; Animals ; Cellular Senescence/*physiology ; Humans ; Oxidative Stress ; Risk Factors ; Telomere Shortening/*physiology ; },
abstract = {The old age population is increasing worldwide as well as age related diseases, including neurodegenerative disorders, such as Alzheimer's disease (AD), which negatively impacts on the health care systems. Aging represents per se a risk factor for AD. Thus, the study and identification of pathways within the biology of aging represent an important end point for the development of novel and effective disease-modifying drugs to treat, delay, or prevent AD. Cellular senescence and telomere shortening represent suitable and promising targets. Several studies show that cellular senescence is tightly interconnected to aging and AD, while the role of telomere dynamic and stability in AD pathogenesis is still unclear. This review will focus on the linking mechanisms between cellular senescence, telomere shortening, and AD.},
}
@article {pmid25895768,
year = {2015},
author = {Griebling, TL},
title = {Re: Telomere length as a risk factor for hereditary prostate cancer.},
journal = {The Journal of urology},
volume = {193},
number = {5},
pages = {1542},
doi = {10.1016/j.juro.2015.02.047},
pmid = {25895768},
issn = {1527-3792},
mesh = {*Genetic Predisposition to Disease ; Humans ; Male ; Prostatic Neoplasms/*genetics ; *Telomere Shortening ; },
}
@article {pmid25894013,
year = {2015},
author = {Stefanidis, I and Voliotis, G and Papanikolaou, V and Chronopoulou, I and Eleftheriadis, T and Kowald, A and Zintzaras, E and Tsezou, A},
title = {Telomere Length in Peripheral Blood Mononuclear Cells of Patients on Chronic Hemodialysis Is Related With Telomerase Activity and Treatment Duration.},
journal = {Artificial organs},
volume = {39},
number = {9},
pages = {756-764},
doi = {10.1111/aor.12453},
pmid = {25894013},
issn = {1525-1594},
mesh = {Aged ; Cross-Sectional Studies ; Female ; Humans ; Kidney Failure, Chronic/*therapy ; Leukocytes, Mononuclear/cytology/enzymology/*metabolism ; Male ; Middle Aged ; Oxidative Stress ; *Renal Dialysis ; Telomerase/*metabolism ; Telomere/chemistry/*metabolism ; *Telomere Shortening ; Time Factors ; },
abstract = {Telomere shortening to a critical limit is associated with replicative senescence. This process is prevented by the enzyme telomerase. Oxidative stress and chronic inflammation are factors accelerating telomere loss. Chronic hemodialysis, typically accompanied by oxidative stress and inflammation, may be also associated with replicative senescence. To test this hypothesis, we determined telomere length and telomerase activity in peripheral blood mononuclear cells (PBMCs) in a cross-sectional study. Hemodialysis patients at the University Hospital Larissa and healthy controls were studied. Telomere length was determined by the TeloTAGGG Telomere Length Assay and telomerase activity by Telomerase PCR-ELISA (Roche Diagnostics GmbH, Mannheim, Germany). We enrolled 43 hemodialysis patients (17 females; age 65.0 ± 12.7 years) and 23 controls (six females; age 62.1 ± 15.7 years). Between the two groups, there was no difference in telomere length (6.95 ± 3.25 vs. 7.31 ± 1.96 kb; P = 0.244) or in telomerase activity (1.82 ± 2.91 vs. 2.71 ± 3.0; P = 0.085). Telomere length correlated inversely with vintage of hemodialysis (r = -0.332, P = 0.030). In hemodialysis patients, positive telomerase activity correlated with telomere length (r = 0.443, P = 0.030). Only age, and neither telomere length nor telomerase activity, was an independent survival predictor (hazard ratio 1.116, 95% confidence interval 1.009-1.234, P = 0.033). In this study, telomere length and telomerase activity in PBMCs are not altered in hemodialysis patients compared with healthy controls. Long duration of hemodialysis treatment is associated with telomere shortening and positive telomerase activity with an increased telomere length in PBMCs of hemodialysis patients. The underlying mechanism and clinical implications of our findings require further investigation.},
}
@article {pmid25893825,
year = {2015},
author = {Heaphy, CM and Gaonkar, G and Peskoe, SB and Joshu, CE and De Marzo, AM and Lucia, MS and Goodman, PJ and Lippman, SM and Thompson, IM and Platz, EA and Meeker, AK},
title = {Prostate stromal cell telomere shortening is associated with risk of prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial.},
journal = {The Prostate},
volume = {75},
number = {11},
pages = {1160-1166},
pmid = {25893825},
issn = {1097-0045},
support = {U10 CA037429/CA/NCI NIH HHS/United States ; P50 CA058236/CA/NCI NIH HHS/United States ; P01 CA108964/CA/NCI NIH HHS/United States ; U10 CA37429/CA/NCI NIH HHS/United States ; UG1 CA189974/CA/NCI NIH HHS/United States ; P50 CA58236/CA/NCI NIH HHS/United States ; UM1 CA182883/CA/NCI NIH HHS/United States ; },
mesh = {5-alpha Reductase Inhibitors/administration &amp; dosage ; Biopsy ; Chromosomal Instability ; Disease Progression ; Finasteride/*administration &amp; dosage ; Humans ; Male ; Middle Aged ; Prostate/*pathology ; *Prostatic Neoplasms/drug therapy/genetics/pathology/physiopathology ; Risk Factors ; Stromal Cells/*pathology ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {BACKGROUND: Telomeres are repetitive nucleoproteins that help maintain chromosomal stability by inhibiting exonucleolytic degradation, prohibiting inappropriate homologous recombination, and preventing chromosomal fusions by suppressing double-strand break signals. We recently observed that men treated for clinically localized prostate cancer with shorter telomeres in their cancer-associated stromal cells, in combination with greater variation in cancer cell telomere lengths, were significantly more likely to progress to distant metastases, and die from their disease. Here, we hypothesized that shorter stromal cell telomere length would be associated with prostate cancer risk at time of biopsy.<br><br>METHODS: Telomere-specific fluorescence in situ hybridization (FISH) analysis was performed in normal-appearing stromal, basal epithelial, and luminal epithelial cells in biopsies from men randomized to the placebo arm of the Prostate Cancer Prevention Trial. Prostate cancer cases (N&#x2009;=&#x2009;32) were either detected on a biopsy performed for cause or at the end of the study per trial protocol, and controls (N&#x2009;=&#x2009;50), defined as negative for cancer on an end-of-study biopsy performed per trial protocol (e.g., irrespective of indication), were sampled. Logistic regression was used to estimate the association between mean telomere length of the particular cell populations, cell-to-cell telomere length variability, and risk of prostate cancer.<br><br>RESULTS: Men with short stromal cell telomere lengths (below median) had 2.66 (95% CI 1.04-3.06; P&#x2009;=&#x2009;0.04) times the odds of prostate cancer compared with men who had longer lengths (at or above median). Conversely, we did not observe statistically significant associations for short telomere lengths in normal-appearing basal (OR&#x2009;=&#x2009;2.15, 95% CI 0.86-5.39; P=&#x2009;0&#x2009;.10) or luminal (OR&#x2009;=&#x2009;1.15, 95% CI 0.47-2.80; P&#x2009;=&#x2009;0.77) cells.<br><br>CONCLUSIONS: These findings suggest that telomere shortening in normal stromal cells is associated with prostate cancer risk. It is essential to extend and validate these findings, while also identifying the cellular milieu that comprises the subset of cells with short telomeres within the prostate tumor microenvironment.},
}
@article {pmid25893599,
year = {2015},
author = {Tummala, H and Walne, A and Collopy, L and Cardoso, S and de la Fuente, J and Lawson, S and Powell, J and Cooper, N and Foster, A and Mohammed, S and Plagnol, V and Vulliamy, T and Dokal, I},
title = {Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita.},
journal = {The Journal of clinical investigation},
volume = {125},
number = {5},
pages = {2151-2160},
pmid = {25893599},
issn = {1558-8238},
support = {MR/K000292/1//Medical Research Council/United Kingdom ; },
mesh = {Alleles ; Cells, Cultured ; Child ; Child, Preschool ; Consanguinity ; DNA Damage ; Down-Regulation ; Dyskeratosis Congenita/*genetics ; Exome/genetics ; Exoribonucleases/*deficiency/genetics/physiology ; Female ; Frameshift Mutation ; Humans ; Male ; Models, Molecular ; *Mutation ; Mutation, Missense ; Pakistan/ethnology ; Pedigree ; Phenotype ; Protein Conformation ; Protein Isoforms/genetics ; Protein Structure, Tertiary ; RNA, Small Interfering/pharmacology ; Sequence Deletion ; Telomere Homeostasis/*genetics ; },
abstract = {Dyskeratosis congenita (DC) and related syndromes are inherited, life-threatening bone marrow (BM) failure disorders, and approximately 40% of cases are currently uncharacterized at the genetic level. Here, using whole exome sequencing (WES), we have identified biallelic mutations in the gene encoding poly(A)-specific ribonuclease (PARN) in 3 families with individuals exhibiting severe DC. PARN is an extensively characterized exonuclease with deadenylation activity that controls mRNA stability in part and therefore regulates expression of a large number of genes. The DC-associated mutations identified affect key domains within the protein, and evaluation of patient cells revealed reduced deadenylation activity. This deadenylation deficiency caused an early DNA damage response in terms of nuclear p53 regulation, cell-cycle arrest, and reduced cell viability upon UV treatment. Individuals with biallelic PARN mutations and PARN-depleted cells exhibited reduced RNA levels for several key genes that are associated with telomere biology, specifically TERC, DKC1, RTEL1, and TERF1. Moreover, PARN-deficient cells also possessed critically short telomeres. Collectively, these results identify a role for PARN in telomere maintenance and demonstrate that it is a disease-causing gene in a subset of patients with severe DC.},
}
@article {pmid25893598,
year = {2015},
author = {Mason, PJ and Bessler, M},
title = {mRNA deadenylation and telomere disease.},
journal = {The Journal of clinical investigation},
volume = {125},
number = {5},
pages = {1796-1798},
pmid = {25893598},
issn = {1558-8238},
support = {R01 CA105312/CA/NCI NIH HHS/United States ; R01 CA106995/CA/NCI NIH HHS/United States ; },
mesh = {Dyskeratosis Congenita/*genetics ; Exoribonucleases/*deficiency ; Female ; Humans ; Male ; *Mutation ; Telomere Homeostasis/*genetics ; },
abstract = {Dyskeratosis congenita (DC) is an inherited BM failure disorder that is associated with mutations in genes involved with telomere function and maintenance; however, the genetic cause of many instances of DC remains uncharacterized. In this issue of the JCI, Tummala and colleagues identify mutations in the gene encoding the poly(A)-specific ribonuclease (PARN) in individuals with a severe form of DC in three different families. PARN deficiency resulted in decreased expression of genes required for telomere maintenance and an aberrant DNA damage response, including increased levels of p53. Together, the results of this study support PARN as a DC-associated gene and suggest a potential link between p53 and telomere shortening.},
}
@article {pmid25892231,
year = {2015},
author = {Lee, CY and Horn, HF and Stewart, CL and Burke, B and Bolcun-Filas, E and Schimenti, JC and Dresser, ME and Pezza, RJ},
title = {Mechanism and regulation of rapid telomere prophase movements in mouse meiotic chromosomes.},
journal = {Cell reports},
volume = {11},
number = {4},
pages = {551-563},
pmid = {25892231},
issn = {2211-1247},
support = {P20 GM103636/GM/NIGMS NIH HHS/United States ; P20GM103636/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle Proteins/metabolism ; Cytoskeletal Proteins ; Male ; Mice ; Mice, Inbred C57BL ; Microtubule-Associated Proteins/metabolism ; Microtubules/metabolism ; Nuclear Envelope/metabolism/ultrastructure ; Nuclear Proteins/metabolism ; *Prophase ; Seminiferous Tubules/metabolism/*ultrastructure ; Telomere/*genetics/ultrastructure ; },
abstract = {Telomere-led rapid prophase movements (RPMs) in meiotic prophase have been observed in diverse eukaryote species. A shared feature of RPMs is that the force that drives the chromosomal movements is transmitted from the cytoskeleton, through the nuclear envelope, to the telomeres. Studies in mice suggested that dynein movement along microtubules is transmitted to telomeres through SUN1/KASH5 nuclear envelope bridges to generate RPMs. We monitored RPMs in mouse seminiferous tubules using 4D fluorescence imaging and quantitative motion analysis to characterize patterns of movement in the RPM process. We find that RPMs reflect a combination of nuclear rotation and individual chromosome movements. The telomeres move along microtubule tracks that are apparently continuous with the cytoskeletal network and exhibit characteristic arrangements at different stages of prophase. Quantitative measurements confirmed that SUN1/KASH5, microtubules, and dynein, but not actin, were necessary for RPMs and that defects in meiotic recombination and synapsis resulted in altered RPMs.},
}
@article {pmid25892207,
year = {2015},
author = {Khan, AM and Babcock, AA and Saeed, H and Myhre, CL and Kassem, M and Finsen, B},
title = {Telomere dysfunction reduces microglial numbers without fully inducing an aging phenotype.},
journal = {Neurobiology of aging},
volume = {36},
number = {6},
pages = {2164-2175},
doi = {10.1016/j.neurobiolaging.2015.03.008},
pmid = {25892207},
issn = {1558-1497},
mesh = {Aging/*genetics/*pathology ; Animals ; Antigens, CD ; Antigens, Differentiation, Myelomonocytic ; Apoptosis/genetics ; Cellular Senescence/*genetics/*physiology ; Dentate Gyrus/cytology/pathology ; Ferritins ; Leukocyte Common Antigens ; Mice, Inbred C57BL ; Mice, Knockout ; Microglia/*pathology ; Neurodegenerative Diseases ; *Phenotype ; RNA/*genetics ; Spatial Learning ; Telomerase/*deficiency/*genetics ; Telomere/*pathology/physiology ; },
abstract = {The susceptibility of the aging brain to neurodegenerative disease may in part be attributed to cellular aging of the microglial cells that survey it. We investigated the effect of cellular aging induced by telomere shortening on microglia by the use of mice lacking the telomerase RNA component (TERC) and design-based stereology. TERC knockout (KO) mice had a significantly reduced number of CD11b(+) microglia in the dentate gyrus. Because of an even greater reduction in dentate gyrus volume, microglial density was, however, increased. Microglia in TERC KO mice maintained a homogenous distribution and normal expression of CD45 and CD68 and the aging marker, ferritin, but were morphologically distinct from microglia in both adult and old wild-type mice. TERC KO mice also showed increased cellular apoptosis and impaired spatial learning. Our results suggest that individual microglia are relatively resistant to telomerase deficiency during steady state conditions, despite an overall reduction in microglial numbers. Furthermore, telomerase deficiency and aging may provide disparate cues leading to distinct changes in microglial morphology and phenotype.},
}
@article {pmid25890781,
year = {2015},
author = {Tempaku, PF and Mazzotti, DR and Tufik, S},
title = {Telomere length as a marker of sleep loss and sleep disturbances: a potential link between sleep and cellular senescence.},
journal = {Sleep medicine},
volume = {16},
number = {5},
pages = {559-563},
doi = {10.1016/j.sleep.2015.02.519},
pmid = {25890781},
issn = {1878-5506},
mesh = {Aging/physiology ; Biomarkers ; Cellular Senescence/*physiology ; Humans ; Sleep/physiology ; Sleep Deprivation/diagnosis/*physiopathology ; Sleep Wake Disorders/diagnosis/*physiopathology ; Telomere/physiology ; *Telomere Shortening ; },
abstract = {The identification of biological markers that allow the early diagnosis, or even the prevention of age-related diseases, is an important goal that is being actively pursued in the research community. Sleep is one of the physiological processes that is most affected by aging, and there is a strong relationship between age-related sleep alterations and diseases. Changes in cellular senescence and the linked changes in telomere length might be potential markers of age-related sleep changes. In this review, we present some of the most recent evidence showing that telomere length has been associated with sleep loss and sleep disturbances in cross-sectional and case-control studies. We also present insights into the cellular senescence mechanisms relating to changes in telomere length, and we suggest that this field lacks basic and clinical research studies, especially long-term longitudinal studies, which may bring opportunities to sleep researchers to investigate this relationship in more depth.},
}
@article {pmid25886908,
year = {2015},
author = {Rizzo, A and Iachettini, S and Zizza, P and Cingolani, C and Porru, M and Artuso, S and Stevens, M and Hummersone, M and Biroccio, A and Salvati, E and Leonetti, C},
title = {Erratum: identification of novel RHPS4-derivative ligands with improved toxicological profiles and telomere-targeting activities.},
journal = {Journal of experimental &amp; clinical cancer research : CR},
volume = {34},
number = {1},
pages = {9},
pmid = {25886908},
issn = {1756-9966},
}
@article {pmid25885433,
year = {2015},
author = {Liu, JC and Leung, JM and Ngan, DA and Nashta, NF and Guillemi, S and Harris, M and Lima, VD and Um, SJ and Li, Y and Tam, S and Shaipanich, T and Raju, R and Hague, C and Leipsic, JA and Bourbeau, J and Tan, WC and Harrigan, PR and Sin, DD and Montaner, J and Man, SF},
title = {Absolute leukocyte telomere length in HIV-infected and uninfected individuals: evidence of accelerated cell senescence in HIV-associated chronic obstructive pulmonary disease.},
journal = {PloS one},
volume = {10},
number = {4},
pages = {e0124426},
pmid = {25885433},
issn = {1932-6203},
support = {DCB 120265//Canadian Institutes of Health Research/Canada ; },
mesh = {Adult ; Cellular Senescence/*genetics ; Cohort Studies ; Female ; HIV Infections/blood/complications/*genetics ; Humans ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/*complications/pathology ; *Telomere ; },
abstract = {Combination antiretroviral therapy (cART) has extended the longevity of human immunodeficiency virus (HIV)-infected individuals. However, this has resulted in greater awareness of age-associated diseases such as chronic obstructive pulmonary disease (COPD). Accelerated cellular senescence may be responsible, but its magnitude as measured by leukocyte telomere length is unknown and its relationship to HIV-associated COPD has not yet been established. We measured absolute telomere length (aTL) in peripheral leukocytes from 231 HIV-infected adults. Comparisons were made to 691 HIV-uninfected individuals from a population-based sample. Subject quartiles of aTL were assessed for relationships with measures of HIV disease severity, airflow obstruction, and emphysema severity on computed tomographic (CT) imaging. Multivariable regression models identified factors associated with shortened aTL. Compared to HIV-uninfected subjects, the mean aTL in HIV-infected patients was markedly shorter by 27 kbp/genome (p<0.001); however, the slopes of aTL vs. age were not different (p=0.469). Patients with longer known durations of HIV infection (p=0.019) and lower nadir CD4 cell counts (p=0.023) had shorter aTL. Shorter aTL were also associated with older age (p=0.026), smoking (p=0.005), reduced forced expiratory volume in one second (p=0.030), and worse CT emphysema severity score (p=0.049). HIV-infected subjects demonstrate advanced cellular aging, yet in a cART-treated cohort, the relationship between aTL and age appears no different from that of HIV-uninfected subjects.},
}
@article {pmid25884882,
year = {2015},
author = {Domański, L and Kłoda, K and Kwiatkowska, E and Borowiecka, E and Safranow, K and Drozd, A and Ciechanowicz, A and Ciechanowski, K},
title = {Effect of delayed graft function, acute rejection and chronic allograft dysfunction on kidney allograft telomere length in patients after transplantation: a prospective cohort study.},
journal = {BMC nephrology},
volume = {16},
number = {},
pages = {23},
pmid = {25884882},
issn = {1471-2369},
mesh = {Acute Disease ; Adult ; Allografts/metabolism/pathology ; Cadaver ; Cellular Senescence/*genetics ; Chronic Disease ; Cohort Studies ; Delayed Graft Function/*genetics/metabolism/pathology ; Female ; Graft Rejection/*genetics/metabolism/pathology ; Humans ; Kidney/*metabolism/pathology ; Kidney Failure, Chronic/*therapy ; *Kidney Transplantation ; Male ; Middle Aged ; Primary Graft Dysfunction/*genetics/metabolism/pathology ; Prospective Studies ; Renal Dialysis ; Telomere/*metabolism ; Telomere Shortening/*genetics ; Time Factors ; },
abstract = {BACKGROUND: The outcome of kidney allograft transplantation is associated with numerous donor-dependent and recipient-dependent immunological and non-immunological factors. Studies on genetic factors affecting the non-immunological aspects, like ageing of the kidney allograft and patient outcome are still lacking. The aim of this study was the analysis of relative telomere length (RTL; T/S ratio) in the biopsy specimens of the transplanted kidney allograft and its correlation with the delayed graft function (DGF), acute rejection (AR) and chronic allograft dysfunction (CAD).<br><br>METHODS: The study enrolled 119 Caucasian kidney allograft recipients (64 M/55 F, mean age 47.32&#x2009;&#xb1;&#x2009;14.03; transplantation performed between 2001 and 2012). Organs were harvested from cadaveric donors (59.8 M/40.2 F, mean age 45.99&#x2009;&#xb1;&#x2009;14.62).<br><br>RESULTS: There were significant differences in RTL assessed in kidney allograft biopsy specimens collected 3-6 months after transplantation between patients with DGF and without DGF (181.8&#x2009;&#xb1;&#x2009;82.0 vs. 284.6&#x2009;&#xb1;&#x2009;149.6; p&#x2009;<&#x2009;0.05) and in RTL of kidney allograft biopsy specimens collected 18-60 months after transplantation between patients with AR and without AR (188.1&#x2009;&#xb1;&#x2009;162.1 vs. 263.3&#x2009;&#xb1;&#x2009;134.7; p&#x2009;=&#x2009;0.047). There were significant differences in RTL assessed in kidney allograft biopsy specimens collected 12-24 months after transplantation between patients with CAD and without CAD (168.0&#x2009;&#xb1;&#x2009;120.0 vs. 282.1&#x2009;&#xb1;&#x2009;158.4; p&#x2009;=&#x2009;0.038).<br><br>CONCLUSIONS: Duration of dialysis before transplantation and PRA influence the kidney allograft ageing. Telomere length assessed in biopsy specimens collected in the peri-transplant period predicts the long-term kidney allograft function. Complications of kidney transplantation, like DGF, AR and CAD are linked with the telomere length and thus, graft ageing.},
}
@article {pmid25883134,
year = {2015},
author = {Yang, CC and Tseng, SM and Chen, CW},
title = {Telomere-associated proteins add deoxynucleotides to terminal proteins during replication of the telomeres of linear chromosomes and plasmids in Streptomyces.},
journal = {Nucleic acids research},
volume = {43},
number = {13},
pages = {6373-6383},
pmid = {25883134},
issn = {1362-4962},
mesh = {Chromosomes, Fungal ; DNA Polymerase I/metabolism ; *DNA Replication ; DNA, Fungal/metabolism ; Deoxyribonucleotides/*metabolism ; Fungal Proteins/*metabolism ; Manganese/pharmacology ; Plasmids/genetics ; Streptomyces/*genetics/metabolism ; Telomere/chemistry/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Typical telomeres of linear chromosomes and plasmids of soil bacteria Streptomyces consist of tightly packed palindromic sequences with a terminal protein ('TP') covalently attached to the 5' end of the DNA. Replication of these linear replicons is initiated internally and proceeds bidirectionally toward the telomeres, which leaves single-strand overhangs at the 3' ends. These overhangs are filled by DNA synthesis using the TPs as the primers ('end patching'). The gene encoding for typical TP, tpg, forms an operon with tap, encoding an essential telomere-associated protein, which binds TP and the secondary structures formed by the 3' overhangs. Previously one of the two translesion synthesis DNA polymerases, DinB1 or DinB2, was proposed to catalyze the protein-primed synthesis. However, using an in vitro end-patching system, we discovered that Tpg and Tap alone could carry out the protein-primed synthesis to a length of 13 nt. Similarly, an 'atypical' terminal protein, Tpc, and its cognate telomere-associated protein, Tac, of SCP1 plasmid, were sufficient to achieve protein-primed synthesis in the absence of additional polymerase. These results indicate that these two telomere-associated proteins possess polymerase activities alone or in complex with the cognate TPs.},
}
@article {pmid25882681,
year = {2015},
author = {Trochet, D and Mergui, X and Ivkovic, I and Porreca, RM and Gerbault-Seureau, M and Sidibe, A and Richard, F and Londono-Vallejo, A and Perret, M and Aujard, F and Riou, JF},
title = {Telomere regulation during ageing and tumorigenesis of the grey mouse lemur.},
journal = {Biochimie},
volume = {113},
number = {},
pages = {100-110},
doi = {10.1016/j.biochi.2015.04.002},
pmid = {25882681},
issn = {1638-6183},
mesh = {Animals ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics/*metabolism/pathology ; *Cellular Senescence ; Cheirogaleidae ; Humans ; Mice ; Neoplasm Proteins/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism/pathology ; *Telomere Homeostasis ; },
abstract = {Telomere erosion leading to replicative senescence has been well documented in human and anthropoid primates, and provides a clue against tumorigenesis. In contrast, other mammals, such as laboratory mice, with short lifespan and low body weight mass have different telomere biology without replicative senescence. We analyzed telomere biology in the grey mouse lemur, a small prosimian model with a relative long lifespan currently used in ageing research. We report an average telomere length by telomere restriction fragment (TRF) among the longest reported so far for a primate species (25-30 kb), but without detectable overall telomere shortening with ageing on blood samples. However, we demonstrate using universal STELA (Single Telomere Length Amplification) the existence of short telomeres, the increase of which, while correlating with ageing might be related to another mechanism than replicative senescence. We also found a low stringency of telomerase restriction in tissues and an ease to immortalize fibroblasts in vitro upon spontaneous telomerase activation. Finally, we describe the first grey mouse lemur cancer cell line showing a dramatic telomere shortening and high telomerase activity associated with polyploidy. Our overall results suggest that telomere biology in grey mouse lemur is an exception among primates, with at best a physiologically limited replicative telomere ageing and closest to that observed in small rodents.},
}
@article {pmid25874893,
year = {2015},
author = {Fujita, T and Yuno, M and Okuzaki, D and Ohki, R and Fujii, H},
title = {Identification of non-coding RNAs associated with telomeres using a combination of enChIP and RNA sequencing.},
journal = {PloS one},
volume = {10},
number = {4},
pages = {e0123387},
pmid = {25874893},
issn = {1932-6203},
mesh = {Animals ; Base Sequence ; Cell Line ; Cell Line, Tumor ; *Chromatin Immunoprecipitation ; Genetic Engineering ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; Molecular Sequence Data ; RNA/genetics ; RNA, Untranslated/*genetics ; *Sequence Analysis, RNA ; Telomerase/genetics ; Telomere/*ultrastructure ; },
abstract = {Accumulating evidence suggests that RNAs interacting with genomic regions play important roles in the regulation of genome functions, including X chromosome inactivation and gene expression. However, to our knowledge, no non-biased methods of identifying RNAs that interact with a specific genomic region have been reported. Here, we used enChIP-RNA-Seq, a combination of engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) and RNA sequencing (RNA-Seq), to perform a non-biased search for RNAs interacting with telomeres. In enChIP-RNA-Seq, the target genomic regions are captured using an engineered DNA-binding molecule such as a transcription activator-like protein. Subsequently, RNAs that interact with the target genomic regions are purified and sequenced. The RNAs detected by enChIP-RNA-Seq contained known telomere-binding RNAs, including the telomerase RNA component (Terc), the RNA component of mitochondrial RNA processing endoribonuclease (Rmrp), and Cajal body-specific RNAs. In addition, a number of novel telomere-binding non-coding RNAs were also identified. Binding of two candidate non-coding RNAs to telomeres was confirmed by immunofluorescence microscopy and RNA fluorescence in situ hybridization (RNA-FISH) analyses. The novel telomere-binding non-coding RNAs identified here may play important roles in telomere functions. To our knowledge, this study is the first non-biased identification of RNAs associated with specific genomic regions. The results presented here suggest that enChIP-RNA-Seq analyses are useful for the identification of RNAs interacting with specific genomic regions, and may help to contribute to current understanding of the regulation of genome functions.},
}
@article {pmid25873347,
year = {2015},
author = {Valls-Bautista, C and Piñol-Felis, C and Reñé-Espinet, JM and Buenestado-García, J and Viñas-Salas, J},
title = {In colon cancer, normal colon tissue and blood cells have altered telomere lengths.},
journal = {Journal of surgical oncology},
volume = {111},
number = {7},
pages = {899-904},
doi = {10.1002/jso.23894},
pmid = {25873347},
issn = {1096-9098},
mesh = {Aged ; Aged, 80 and over ; Biomarkers, Tumor/*genetics ; Blood Cells/metabolism/*pathology ; Case-Control Studies ; Colon/*metabolism ; Colorectal Neoplasms/blood/genetics/*pathology ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: Telomere length (TL) shortened occurs in colorectal carcinogenetic process. Our objective is to determine if it is only a local fact or there are alterations in normal colon cells and in other body cells.<br><br>METHODS: TL of tumoral and normal mucosa and leukocytes of 40 patients operated of colorectal cancer (CRC) and 40 control patients with normal colonoscopy were measured by Southern-blot. Groups were matched by the same localization as tumors, sex, and age.<br><br>RESULTS: In CRC patients, TRFL (Telomere Repeat Factor Length) leukocytes mean was 8.84&#x2009;kpb, normal colonic mucosa 7.97&#x2009;kpb, and tumoral mucosa 7.33&#x2009;kpb (P&#x2009;<&#x2009;0.001). In the 40 normal control patients, mean TRFL of colonic mucosa was 7.76&#x2009;kpb, while in blood cells was 7.01&#x2009;kpb (P&#x2009;<&#x2009;0.001). We observed an inverse correlation between leukocytes TRFL and age (r(2) &#x2009;=&#x2009;0.17, P&#x2009;=&#x2009;0.008). Mucosa TRFL correlates significantly with patient's age (r(2) &#x2009;=&#x2009;0.138, P&#x2009;=&#x2009;0.018). TRFL of controls colonic mucosa correlates with TRFL of their blood cells (r(2) &#x2009;=&#x2009;0.354, P&#x2009;<&#x2009;0.001).<br><br>CONCLUSIONS: Normal colonic mucosa and leukocytes in CCR patients presents telomere altered in respect to normal patients. Telomere length in normal leukocytes could be an initial marker for colorectal cancer.},
}
@article {pmid25872911,
year = {2015},
author = {Lee, JY and Jun, NR and Yoon, D and Shin, C and Baik, I},
title = {Association between dietary patterns in the remote past and telomere length.},
journal = {European journal of clinical nutrition},
volume = {69},
number = {9},
pages = {1048-1052},
pmid = {25872911},
issn = {1476-5640},
mesh = {Adult ; Aged ; Aging/*physiology ; Asian People ; Cohort Studies ; Diet/*statistics &amp; numerical data ; Diet Surveys/methods/*statistics &amp; numerical data ; Feeding Behavior/*physiology ; Female ; Follow-Up Studies ; Humans ; Linear Models ; Male ; Middle Aged ; Prospective Studies ; Republic of Korea ; Telomere Homeostasis/*physiology ; },
abstract = {BACKGROUND/OBJECTIVES: There are limited data on the association between dietary information and leukocyte telomere length (LTL), which is considered an indicator of biological aging. In this study, we aimed at determining the association between dietary patterns or consumption of specific foods and LTL in Korean adults.<br><br>SUBJECT/METHODS: A total of 1958 middle-aged and older Korean adults from a population-based cohort were included in the study. Dietary data were collected from a semi-quantitative food frequency questionnaire at baseline (June 2001 to January 2003). LTL was assessed using real-time PCR during the 10-year follow-up period (February 2011 to November 2012).<br><br>RESULTS: We identified two major factors and generated factor scores using factor analysis. The first factor labeled 'prudent dietary pattern' was characterized by high intake of whole grains, seafood, legumes, vegetables and seaweed, whereas the second factor labeled 'Western dietary pattern' was characterized by high intake of refined grain, red meat or processed meat and sweetened carbonated beverages. In a multiple linear regression model adjusted for age, sex, body mass index and other potential confounding variables, the prudent dietary pattern was positively associated with LTL. In the analysis of particular food items, higher consumption of legumes, nuts, seaweed, fruits and dairy products and lower consumption of red meat or processed meat and sweetened carbonated beverages were associated with longer LTL.<br><br>CONCLUSIONS: Our findings suggest that diet in the remote past, that is, 10 years earlier, may affect the degree of biological aging in middle-aged and older adults.},
}
@article {pmid25869605,
year = {2015},
author = {Zhu, H and Bhagatwala, J and Pollock, NK and Parikh, S and Gutin, B and Stallmann-Jorgensen, I and Thomas, J and Harshfield, GA and Dong, Y},
title = {High sodium intake is associated with short leukocyte telomere length in overweight and obese adolescents.},
journal = {International journal of obesity (2005)},
volume = {39},
number = {8},
pages = {1249-1253},
pmid = {25869605},
issn = {1476-5497},
support = {R01 HL064157/HL/NHLBI NIH HHS/United States ; HL064157/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Body Mass Index ; Cellular Senescence/drug effects ; Diet/*adverse effects ; Female ; Georgia/epidemiology ; Humans ; Leukocytes/pathology ; Male ; Pediatric Obesity/*complications/epidemiology/physiopathology ; Sodium, Dietary/*adverse effects ; Telomere/pathology ; *Telomere Shortening/drug effects ; },
abstract = {BACKGROUND/OBJECTIVES: Telomere shortening has an important role in cellular aging. However, the impact of high sodium intake, an important risk factor of age-related diseases, on telomere shortening remains unknown. Therefore, we examined the relationship between high dietary sodium intake and leukocyte telomere length (LTL), particularly in the context of obesity, as obesity increases salt sensitivity.<br><br>SUBJECTS/METHODS: LTL was determined by a quantitative polymerase chain reaction method in 766 adolescents aged 14-18 years (50% females, 49% African Americans). Dietary sodium intake was assessed by seven independent 24-h dietary recalls. We divided the sample into low sodium (mean 2388&#xb1;522&#x2009;mg per day) or high sodium groups (mean 4142&#xb1;882&#x2009;mg per day) based on the median value (3280.9&#x2009;mg per day).<br><br>RESULTS: In the entire cohort, there was no significant association between sodium intake and LTL (r=-0.05, P=0.24). However, there was a significant interaction between sodium intake and obesity status (P=0.049). Further multiple linear regression analyses revealed that higher dietary sodium intake was associated with shorter LTL in the overweight/obese group (body mass index &#x2a7e;85th percentile, &#x3b2;=-0.37, P=0.04), but not in the normal-weight group (&#x3b2;=0.01, P=0.93) after adjusting for multiple confounding factors. In the overweight/obese group, LTL was significantly shorter in the high sodium intake subjects vs low sodium intake subjects (1.24&#xb1;0.22 vs. 1.32&#xb1;0.20, P=0.02), but not the normal-weight group (1.29&#xb1;0.24 vs 1.30&#xb1;0.24, P=0.69).<br><br>CONCLUSIONS: Higher dietary sodium intake is associated with shorter telomere length in overweight and obese adolescents.},
}
@article {pmid25868397,
year = {2015},
author = {Nielsen, BR and Linneberg, A and Bendix, L and Harboe, M and Christensen, K and Schwarz, P},
title = {Association between leukocyte telomere length and bone mineral density in women 25-93 years of age.},
journal = {Experimental gerontology},
volume = {66},
number = {},
pages = {25-31},
doi = {10.1016/j.exger.2015.04.004},
pmid = {25868397},
issn = {1873-6815},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Body Mass Index ; Bone Density/*genetics ; Female ; Femur Neck ; Hip ; Humans ; Leukocytes/*physiology ; Lumbar Vertebrae ; Middle Aged ; Osteoporosis/*genetics ; Regression Analysis ; Surveys and Questionnaires ; Telomere/*genetics ; },
abstract = {Leukocyte telomere length (LTL) and bone mineral density (BMD) are associated with health and mortality. Because osteoporosis is an age-related condition and LTL is considered to be a biomarker of aging, we hypothesized that shorter LTL could predict lower BMD. The aim of our study was to assess whether there is an association of LTL with BMD and to determine whether this possible association is independent of age. The BMDs of the lumbar spine (LS), femoral neck (FN) and total hip (TH) were evaluated in 460 women using DXA. LTL was analyzed using quantitative polymerase chain reaction. The women completed a health and lifestyle questionnaire. The associations were estimated by regression models that considered age, body mass index (BMI), menopause, physical activity, alcohol consumption and smoking habits. We found a statistically significant unadjusted association between LTL and age (estimate and 95% confidence interval (CI): -0.003 (-0.005; -0.002)); and between BMI adjusted age and logarithmic transformed BMD. Estimates and 95% CI were as follows: LS: -0.13 (-0.26; -0.01); right TH: -0.44 (-0.53; -0.34); left TH: -0.38 (-0.48; -0.28); right FN: -0.57 (-0.67; -0.46) and left FN: -0.51 (-0.62; -0.40). There were no statistically significant associations between BMD and LTL (both logarithmically transformed) with or without age adjustments. The age-adjusted estimates and CI were as follows: LS: -0.10 (-0.71; 0.52); right TH: -0.13 (-0.66; 0.41); left TH: -0.13 (-0.67; 0.42); right FN: -0.03 (-0.58; 0.52) and left FN: 0.09 (-0.47; 0.66). In conclusion, we found no statistically significant associations between BMD and LTL, although the estimates of the crude associations were all positive, indicating hypothesis consistency; that shorter LTL predict lower BMD values. This positive association was no longer apparent after adjusting for age. As expected, age was statistically significantly associated with both telomere length and BMI adjusted BMD.},
}
@article {pmid25865872,
year = {2015},
author = {Hjelmborg, JB and Dalgård, C and Mangino, M and Spector, TD and Halekoh, U and Möller, S and Kimura, M and Horvath, K and Kark, JD and Christensen, K and Kyvik, KO and Aviv, A},
title = {Paternal age and telomere length in twins: the germ stem cell selection paradigm.},
journal = {Aging cell},
volume = {14},
number = {4},
pages = {701-703},
pmid = {25865872},
issn = {1474-9726},
support = {R01 AG030678/AG/NIA NIH HHS/United States ; AG030678/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*genetics ; Epigenesis, Genetic ; Female ; Gene Expression ; Germ Cells/cytology/*metabolism ; Humans ; Inheritance Patterns ; Leukocytes/cytology/metabolism ; Male ; *Paternal Age ; Stem Cells/cytology/metabolism ; Telomerase/genetics ; Telomere/chemistry/*genetics ; Telomere Homeostasis ; Telomere Shortening ; Twins, Dizygotic/*genetics ; Twins, Monozygotic/*genetics ; },
abstract = {Telomere length, a highly heritable trait, is longer in offspring of older fathers. This perplexing feature has been attributed to the longer telomeres in sperm of older men and it might be an 'epigenetic' mechanism through which paternal age plays a role in telomere length regulation in humans. Based on two independent (discovery and replication) twin studies, comprising 889 twin pairs, we show an increase in the resemblance of leukocyte telomere length between dizygotic twins of older fathers, which is not seen in monozygotic twins. This phenomenon might result from a paternal age-dependent germ stem cell selection process, whereby the selected stem cells have longer telomeres, are more homogenous with respect to telomere length, and share resistance to aging.},
}
@article {pmid25865647,
year = {2015},
author = {Ashbridge, B and Zehir, A and Lubin, M and Barker, JN and Moore, MA},
title = {Evaluation of Initial Telomere Length and Changes after Transplantation in Adult Double-Unit Cord Blood Transplant Recipients.},
journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation},
volume = {21},
number = {7},
pages = {1334-1336},
pmid = {25865647},
issn = {1523-6536},
support = {P01 CA023766/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA23766/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Cord Blood Stem Cell Transplantation/*methods ; Female ; Graft Survival ; Hematologic Neoplasms/immunology/pathology/*therapy ; Humans ; Leukocytes, Mononuclear/chemistry/metabolism ; Male ; Middle Aged ; Myeloablative Agonists/*therapeutic use ; Retrospective Studies ; Telomere/*chemistry ; *Telomere Homeostasis ; Transplant Recipients ; *Transplantation Conditioning ; Treatment Outcome ; Unrelated Donors ; },
abstract = {Cord blood (CB) leukocytes have inherent telomere length (TL) variation, and CB hematopoietic stem cells (HSC) can maintain high telomerase levels preventing telomere attrition in vitro. We evaluated TL changes in 13 adult double-unit CB transplant (CBT) recipients. In the 26 units, we observed a marked variation in CB TL at thaw (median, 9.99 kilobases [kb]; range, 6.85 to 13.5). All 13 patients engrafted. Of 11 engrafting with 1 unit, there was no correlation between unit dominance and TL (mean dominant unit TL, 8.84 kb ± 1.76; mean nonengrafting unit TL, 10.3 kb ± 1.81; P = .77). Serial measurements of TL up to 1 year after CBT demonstrated an overall mean 3.04 kb ± .16 TL decrease with only 1 patient exhibiting telomere maintenance. In summary, initial TL does not predict CB unit dominance. Moreover, our analysis suggests neonatal hematopoiesis makes a transition to an HSC characterized by changes in average TL and potentially low telomerase asymmetric cell division in adult CBT recipients. Further investigation of alterations in telomere length and its clinical implications after transplantation of this observation are indicated.},
}
@article {pmid25862531,
year = {2015},
author = {Rode, L and Nordestgaard, BG and Bojesen, SE},
title = {Peripheral blood leukocyte telomere length and mortality among 64,637 individuals from the general population.},
journal = {Journal of the National Cancer Institute},
volume = {107},
number = {6},
pages = {djv074},
doi = {10.1093/jnci/djv074},
pmid = {25862531},
issn = {1460-2105},
mesh = {Adult ; Aged ; Denmark/epidemiology ; Female ; Humans ; *Leukocytes ; Male ; Mendelian Randomization Analysis ; Middle Aged ; Mortality/trends ; Neoplasms/*genetics/*mortality ; Odds Ratio ; Polymerase Chain Reaction ; Proportional Hazards Models ; Prospective Studies ; Risk Factors ; *Telomere ; *Telomere Shortening ; },
abstract = {BACKGROUND: Short telomeres in peripheral blood leukocytes are associated with older age and age-related diseases. We tested the hypotheses that short telomeres are associated with both increased cancer mortality and all-cause mortality.<br><br>METHODS: Individuals (n = 64637) were recruited from 1991 onwards from two Danish prospective cohort studies: the Copenhagen City Heart Study and the Copenhagen General Population Study. All had telomere length measured by quantitative polymerase chain reaction and the genotypes rs1317082 (TERC), rs7726159 (TERT), and rs2487999 (OBFC1) determined. The sum of telomere-shortening alleles from these three genotypes was calculated. We conducted Cox regression analyses and instrumental variable analyses using the allele sum as an instrument. All statistical tests were two-sided.<br><br>RESULTS: Among 7607 individuals who died during follow-up (0-22 years, median = 7 years), 2420 had cancer and 2633 had cardiovascular disease as causes of death. Decreasing telomere length deciles were associated with increasing all-cause mortality (P(trend) = 2*10(-15)). The multivariable-adjusted hazard ratio of all-cause mortality was 1.40 (95% confidence interval [CI] = 1.25 to 1.57) for individuals in the shortest vs the longest decile. Results were similar for cancer mortality and cardiovascular mortality. Telomere length decreased 69 base pairs (95% CI = 61 to 76) per allele for the allele sum, and the per-allele hazard ratio for cancer mortality was 0.95 (95% CI = 0.91 to 0.99). Allele sum was not associated with cardiovascular, other, or all-cause mortality.<br><br>CONCLUSION: Short telomeres in peripheral blood leukocytes were associated with high mortality in association analyses. In contrast, genetically determined short telomeres were associated with low cancer mortality but not with all-cause mortality.},
}
@article {pmid25848748,
year = {2015},
author = {Stuart, BD and Choi, J and Zaidi, S and Xing, C and Holohan, B and Chen, R and Choi, M and Dharwadkar, P and Torres, F and Girod, CE and Weissler, J and Fitzgerald, J and Kershaw, C and Klesney-Tait, J and Mageto, Y and Shay, JW and Ji, W and Bilguvar, K and Mane, S and Lifton, RP and Garcia, CK},
title = {Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.},
journal = {Nature genetics},
volume = {47},
number = {5},
pages = {512-517},
pmid = {25848748},
issn = {1546-1718},
support = {UL1 TR001105/TR/NCATS NIH HHS/United States ; P30 ES005605/ES/NIEHS NIH HHS/United States ; R01 HL093096/HL/NHLBI NIH HHS/United States ; K12HD068369/HD/NICHD NIH HHS/United States ; UL1TR001105/TR/NCATS NIH HHS/United States ; T32 GM007205/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; P30 DK054759/DK/NIDDK NIH HHS/United States ; K12 HD068369/HD/NICHD NIH HHS/United States ; U54HG006504/HG/NHGRI NIH HHS/United States ; U54 HG006504/HG/NHGRI NIH HHS/United States ; R01HL093096/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Amino Acid Sequence ; Case-Control Studies ; Cells, Cultured ; DNA Helicases/*genetics ; DNA Mutational Analysis ; Exome/*genetics ; Exoribonucleases/*genetics ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Idiopathic Pulmonary Fibrosis/*genetics/pathology ; Leukocytes/physiology ; Lod Score ; Male ; Middle Aged ; Molecular Sequence Data ; Pedigree ; Telomere/*genetics ; *Telomere Shortening ; },
abstract = {Idiopathic pulmonary fibrosis (IPF) is an age-related disease featuring progressive lung scarring. To elucidate the molecular basis of IPF, we performed exome sequencing of familial kindreds with pulmonary fibrosis. Gene burden analysis comparing 78 European cases and 2,816 controls implicated PARN, an exoribonuclease with no previous connection to telomere biology or disease, with five new heterozygous damaging mutations in unrelated cases and none in controls (P = 1.3 × 10(-8)); mutations were shared by all affected relatives (odds in favor of linkage = 4,096:1). RTEL1, an established locus for dyskeratosis congenita, harbored significantly more new damaging and missense variants at conserved residues in cases than in controls (P = 1.6 × 10(-6)). PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic inheritance of short telomeres in family members. Together, these genes explain ~7% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction.},
}
@article {pmid25846142,
year = {2015},
author = {Sabater, L and Nicolau-Travers, ML and De Rache, A and Prado, E and Dejeu, J and Bombarde, O and Lacroix, J and Calsou, P and Defrancq, E and Mergny, JL and Gomez, D and Pratviel, G},
title = {The nickel(II) complex of guanidinium phenyl porphyrin, a specific G-quadruplex ligand, targets telomeres and leads to POT1 mislocalization in culture cells.},
journal = {Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry},
volume = {20},
number = {4},
pages = {729-738},
pmid = {25846142},
issn = {1432-1327},
mesh = {Binding Sites/drug effects ; Cell Proliferation/drug effects ; Circular Dichroism ; Cobalt/chemistry ; Dose-Response Relationship, Drug ; Fluorescence Resonance Energy Transfer ; G-Quadruplexes/*drug effects ; Guanidine/*chemistry ; Humans ; Ligands ; Metalloporphyrins/chemical synthesis/chemistry/*pharmacology ; Molecular Structure ; Nickel/*chemistry ; Porphyrins/*chemistry ; Protein Transport/drug effects ; Shelterin Complex ; Structure-Activity Relationship ; Surface Plasmon Resonance ; Telomere/*drug effects ; Telomere-Binding Proteins/*metabolism ; Tumor Cells, Cultured ; },
abstract = {With the aim of finding selective and biologically active G-quadruplex ligands, modified porphyrin with bulky cationic substituents, meso-5,10,15,20-tetrakis(4-guanidinophenyl)porphyrin tetrahydrochloride, referred to as guanidinium phenyl porphyrin, was prepared. The corresponding nickel(II) and cobalt(III) metallated porphyrins were also synthesized. Interaction with quadruplexes was examined by means of fluorescence resonance energy transfer melting and surface plasmon resonance-based assays: the three compounds proved to bind to G-quadruplex DNA in a similar and highly selective way. Guanidinium phenyl porphyrin and its nickel(II) metallated derivative exhibit moderate cytotoxicity toward cells in culture. Strikingly, the nickel porphyrin derivative was able to displace hPOT1 shelterin protein from telomeres in human cells. Nickel(II) guanidinium phenyl porphyrin, a cationic bulky porphyrin is a powerful specific G-quadruplex DNA ligand. It enters the cells and induces shelterin modification.},
}
@article {pmid25845980,
year = {2015},
author = {Tyrka, AR and Carpenter, LL and Kao, HT and Porton, B and Philip, NS and Ridout, SJ and Ridout, KK and Price, LH},
title = {Association of telomere length and mitochondrial DNA copy number in a community sample of healthy adults.},
journal = {Experimental gerontology},
volume = {66},
number = {},
pages = {17-20},
pmid = {25845980},
issn = {1873-6815},
support = {R25 MH101076/MH/NIMH NIH HHS/United States ; IK2 CX000724/CX/CSRD VA/United States ; R01 MH068767/MH/NIMH NIH HHS/United States ; R01 MH068767-08S1/MH/NIMH NIH HHS/United States ; R21 MH091508/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Adult Survivors of Child Adverse Events ; Aging/genetics ; Body Mass Index ; Cellular Senescence/genetics ; *DNA Copy Number Variations ; DNA, Mitochondrial/*genetics ; Depression ; Female ; Healthy Volunteers ; Humans ; Male ; Middle Aged ; Mitochondria/genetics ; Residence Characteristics ; Smoking ; Telomere/*genetics ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {Cellular aging plays a role in longevity and senescence, and has been implicated in medical and psychiatric conditions, including heart disease, cancer, major depression and posttraumatic stress disorder. Telomere shortening and mitochondrial dysfunction are thought to be central to the cellular aging process. The present study examined the association between mitochondrial DNA (mtDNA) copy number and telomere length in a sample of medically healthy adults. Participants (total n=392) were divided into 4 groups based on the presence or absence of early life adversity and lifetime psychopathology: No Adversity/No Disorder, n=136; Adversity/No Disorder, n=91; No Adversity/Disorder, n=46; Adversity/Disorder, n=119. Telomere length and mtDNA copy number were measured using quantitative polymerase chain reaction. There was a positive correlation between mtDNA and telomere length in the entire sample (r=0.120, p<0.001) and in each of the four groups of participants (No Adversity/No Disorder, r=0.291, p=0.001; Adversity/No Disorder r=0.279, p=0.007; No Adversity/Disorder r=0.449, p=0.002; Adversity/Disorder, r=0.558, p<0.001). These correlations remained significant when controlling for age, smoking, and body mass index and establish an association between mtDNA and telomere length in a large group of women and men both with and without early adversity and psychopathology, suggesting co-regulation of telomeres and mitochondrial function. The mechanisms underlying this association may be important in the pathophysiology of age-related medical conditions, such as heart disease and cancer, as well as for stress-associated psychiatric disorders.},
}
@article {pmid25841297,
year = {2015},
author = {Vaez-Azizi, LM and Ruby, E and Dracxler, R and Rothman, K and Perrin, M and Walsh-Messinger, J and Antonius, D and Goetz, RR and Goetz, DM and Keefe, DL and Malaspina, D},
title = {Telomere length variability is related to symptoms and cognition in schizophrenia.},
journal = {Schizophrenia research},
volume = {164},
number = {1-3},
pages = {268-269},
doi = {10.1016/j.schres.2015.03.011},
pmid = {25841297},
issn = {1573-2509},
mesh = {Adult ; Cognition Disorders/*etiology/*genetics ; Female ; Humans ; Male ; Middle Aged ; Schizophrenia/*complications/genetics ; Telomere/*genetics ; },
}
@article {pmid25840848,
year = {2015},
author = {Sun, B and Wang, Y and Kota, K and Shi, Y and Motlak, S and Makambi, K and Loffredo, CA and Shields, PG and Yang, Q and Harris, CC and Zheng, YL},
title = {Telomere length variation: A potential new telomere biomarker for lung cancer risk.},
journal = {Lung cancer (Amsterdam, Netherlands)},
volume = {88},
number = {3},
pages = {297-303},
pmid = {25840848},
issn = {1872-8332},
support = {R01 CA132996/CA/NCI NIH HHS/United States ; R01CA132996/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; Case-Control Studies ; Chromosomes, Human ; Female ; Humans ; Lung Neoplasms/*genetics ; Lymphocytes/metabolism ; Male ; Middle Aged ; Odds Ratio ; Risk Factors ; Telomere/*genetics ; Telomere Homeostasis ; Telomere Shortening ; },
abstract = {OBJECTIVES: In this report the associations between telomere length variation (TLV), mean telomere length in blood lymphocytes and lung cancer risk were examined.<br><br>MATERIALS AND METHODS: The study design is case-control. Cases (N=191) were patients newly diagnosed with histologically confirmed non-small cell lung cancer. Controls (N=207) were healthy individuals recruited from the same counties as cases and matched to cases on age and gender. Telomere fluorescent in situ hybridization was used to measure telomere features using short-term cultured blood lymphocytes. Logistic regression was used to estimate the strength of association between telomere features and lung cancer risk.<br><br>RESULTS: Telomere length variation across all chromosomal ends was significantly associated with lung cancer risk; adjusted odds ratios 4.67 [95% confidence interval (CI): 1.46-14.9] and 0.46 (95% CI: 0.25-0.84) for younger (age&#x2264;60) and older (age>60) individuals, respectively. TLV and mean telomere length jointly affected lung cancer risk: when comparing individuals with short telomere length and high TLV to those with long telomere length and low TLV, adjusted odd ratios were 8.21 (95% CI: 1.71-39.5) and 0.33 (95% CI: 0.15-0.72) for younger and older individuals, respectively.<br><br>CONCLUSIONS: TLV in blood lymphocytes is significantly associated with lung cancer risk and the associations were modulated by age. TLV in combination with mean telomere length might be useful in identifying high risk population for lung cancer computerized tomography screening.},
}
@article {pmid25840590,
year = {2015},
author = {Alder, JK and Barkauskas, CE and Limjunyawong, N and Stanley, SE and Kembou, F and Tuder, RM and Hogan, BL and Mitzner, W and Armanios, M},
title = {Telomere dysfunction causes alveolar stem cell failure.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {112},
number = {16},
pages = {5099-5104},
pmid = {25840590},
issn = {1091-6490},
support = {K08 HL122521/HL/NHLBI NIH HHS/United States ; T32 GM007309/GM/NIGMS NIH HHS/United States ; P01 HL010342/HL/NHLBI NIH HHS/United States ; K99 HL113105/HL/NHLBI NIH HHS/United States ; P01 HL10342/HL/NHLBI NIH HHS/United States ; R01 HL119476/HL/NHLBI NIH HHS/United States ; R00 HL113105/HL/NHLBI NIH HHS/United States ; },
mesh = {Aging/pathology ; Animals ; Cell Differentiation ; Cell Proliferation ; Epithelial Cells/metabolism ; Gene Deletion ; Immunity ; Inflammation/pathology ; Intercellular Signaling Peptides and Proteins ; Mesoderm/pathology ; Mice ; Paracrine Communication ; Peptides/metabolism ; Pulmonary Alveoli/metabolism/*pathology ; Pulmonary Surfactant-Associated Protein C ; Signal Transduction/immunology ; Spheroids, Cellular/pathology ; Stem Cells/*pathology ; Stromal Cells/pathology ; Telomere/*pathology ; *Telomere Shortening ; Telomeric Repeat Binding Protein 2/metabolism ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Telomere syndromes have their most common manifestation in lung disease that is recognized as idiopathic pulmonary fibrosis and emphysema. In both conditions, there is loss of alveolar integrity, but the underlying mechanisms are not known. We tested the capacity of alveolar epithelial and stromal cells from mice with short telomeres to support alveolar organoid colony formation and found that type 2 alveolar epithelial cells (AEC2s), the stem cell-containing population, were limiting. When telomere dysfunction was induced in adult AEC2s by conditional deletion of the shelterin component telomeric repeat-binding factor 2, cells survived but remained dormant and showed all the hallmarks of cellular senescence. Telomere dysfunction in AEC2s triggered an immune response, and this was associated with AEC2-derived up-regulation of cytokine signaling pathways that are known to provoke inflammation in the lung. Mice uniformly died after challenge with bleomycin, underscoring an essential role for telomere function in AEC2s for alveolar repair. Our data show that alveoloar progenitor senescence is sufficient to recapitulate the regenerative defects, inflammatory responses, and susceptibility to injury that are characteristic of telomere-mediated lung disease. They suggest alveolar stem cell failure is a driver of telomere-mediated lung disease and that efforts to reverse it may be clinically beneficial.},
}
@article {pmid25840550,
year = {2015},
author = {Haver, VG and Hartman, MH and Mateo Leach, I and Lipsic, E and Lexis, CP and van Veldhuisen, DJ and van Gilst, WH and van der Horst, IC and van der Harst, P},
title = {Leukocyte telomere length and left ventricular function after acute ST-elevation myocardial infarction: data from the glycometabolic intervention as adjunct to primary coronary intervention in ST elevation myocardial infarction (GIPS-III) trial.},
journal = {Clinical research in cardiology : official journal of the German Cardiac Society},
volume = {104},
number = {10},
pages = {812-821},
pmid = {25840550},
issn = {1861-0692},
mesh = {Acute Disease ; Causality ; Combined Modality Therapy ; Comorbidity ; Double-Blind Method ; Female ; Genetic Predisposition to Disease/epidemiology/genetics ; Humans ; Hypoglycemic Agents/therapeutic use ; Incidence ; Leukocytes ; Longitudinal Studies ; Male ; Metformin/therapeutic use ; Middle Aged ; Myocardial Infarction/*epidemiology/*genetics/therapy ; Netherlands/epidemiology ; Percutaneous Coronary Intervention/statistics &amp; numerical data ; Placebo Effect ; Risk Assessment ; Telomere Shortening/*genetics ; Treatment Outcome ; Ventricular Dysfunction, Left/*epidemiology/*genetics/therapy ; },
abstract = {BACKGROUND: Telomere length has been associated with coronary artery disease and heart failure. We studied whether leukocyte telomere length is associated with left ventricular ejection fraction (LVEF) after ST-elevation myocardial infarction (STEMI).<br><br>METHODS AND RESULTS: Leukocyte telomere length (LTL) was determined using the monochrome multiplex quantitative PCR method in 353 patients participating in the glycometabolic intervention as adjunct to primary percutaneous coronary intervention in STEMI III trial. LVEF was assessed by magnetic resonance imaging. The mean age of patients was 58.9&#xa0;&#xb1;&#xa0;11.6&#xa0;years, 75&#xa0;% were male. In age- and gender-adjusted models, LTL at baseline was significantly associated with age (beta&#xa0;&#xb1;&#xa0;standard error; -0.33&#xa0;&#xb1;&#xa0;0.01; P&#xa0;<&#xa0;0.01), gender (0.15&#xa0;&#xb1;&#xa0;0.03; P&#xa0;<&#xa0;0.01), TIMI flow pre-PCI (0.05&#xa0;&#xb1;&#xa0;0.03; P&#xa0;<&#xa0;0.01), TIMI flow post-PCI (0.03&#xa0;&#xb1;&#xa0;0.04; P&#xa0;<&#xa0;0.01), myocardial blush grade (-0.05&#xa0;&#xb1;&#xa0;0.07; P&#xa0;<&#xa0;0.01), serum glucose levels (-0.11&#xa0;&#xb1;&#xa0;0.01; P&#xa0;=&#xa0;0.03), and total leukocyte count (-0.11&#xa0;&#xb1;&#xa0;0.01; P&#xa0;=&#xa0;0.04). At 4&#xa0;months after STEMI, LVEF was well preserved (54.1&#xa0;&#xb1;&#xa0;8.4&#xa0;%) and was not associated with baseline LTL (P&#xa0;=&#xa0;0.95). Baseline LTL was associated with n-terminal pro-brain natriuretic peptide (NT-proBNP) at 4&#xa0;months (-0.14&#xa0;&#xb1;&#xa0;0.01; P&#xa0;=&#xa0;0.02), albeit not independent for age and gender.<br><br>CONCLUSION: Our study does not support a role for LTL as a causal factor related to left ventricular ejection fraction after STEMI.},
}
@article {pmid25832516,
year = {2015},
author = {Ridout, SJ and Ridout, KK and Kao, HT and Carpenter, LL and Philip, NS and Tyrka, AR and Price, LH},
title = {Telomeres, early-life stress and mental illness.},
journal = {Advances in psychosomatic medicine},
volume = {34},
number = {},
pages = {92-108},
pmid = {25832516},
issn = {0065-3268},
support = {IK2 CX000724/CX/CSRD VA/United States ; R01 MH068767/MH/NIMH NIH HHS/United States ; },
mesh = {Biomarkers/*metabolism ; Child ; *Child Abuse ; Humans ; Mental Disorders/*metabolism ; Stress, Psychological/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are structures of tandem TTAGGG repeats that are found at the ends of chromosomes and preserve genomic DNA by serving as a disposable buffer to protect DNA termini during chromosome replication. In this process, the telomere itself shortens with each cell division and can consequently be thought of as a cellular 'clock', reflecting the age of a cell and the time until senescence. Telomere shortening and changes in the levels of telomerase, the enzyme that maintains telomeres, occur in the context of certain somatic diseases and in response to selected physical stressors. Emerging evidence indicates that telomeres shorten with exposure to psychosocial stress (including early-life stress) and perhaps in association with some psychiatric disorders. These discoveries suggest that telomere shortening might be a useful biomarker for the overall stress response of an organism to various pathogenic conditions. In this regard, telomeres and their response to both somatic and psychiatric illness could serve as a unifying stress-response biomarker that crosses the brain/body distinction that is often made in medicine. Prospective studies will help to clarify whether this biomarker has broad utility in psychiatry and medicine for the evaluation of responses to psychosocial stressors. The possibility that telomere shortening can be slowed or reversed by psychiatric and psychosocial interventions could represent an opportunity for developing novel preventative and therapeutic approaches.},
}
@article {pmid25834722,
year = {2014},
author = {Nussey, DH and Baird, D and Barrett, E and Boner, W and Fairlie, J and Gemmell, N and Hartmann, N and Horn, T and Haussmann, M and Olsson, M and Turbill, C and Verhulst, S and Zahn, S and Monaghan, P},
title = {Measuring telomere length and telomere dynamics in evolutionary biology and ecology.},
journal = {Methods in ecology and evolution},
volume = {5},
number = {4},
pages = {299-310},
pmid = {25834722},
issn = {2041-210X},
support = {BB/H021868/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
abstract = {Telomeres play a fundamental role in the protection of chromosomal DNA and in the regulation of cellular senescence. Recent work in human epidemiology and evolutionary ecology suggests adult telomere length (TL) may reflect past physiological stress and predict subsequent morbidity and mortality, independent of chronological age.Several different methods have been developed to measure TL, each offering its own technical challenges. The aim of this review is to provide an overview of the advantages and drawbacks of each method for researchers, with a particular focus on issues that are likely to face ecologists and evolutionary biologists collecting samples in the field or in organisms that may never have been studied in this context before.We discuss the key issues to consider and wherever possible try to provide current consensus view regarding best practice with regard to sample collection and storage, DNA extraction and storage, and the five main methods currently available to measure TL.Decisions regarding which tissues to sample, how to store them, how to extract DNA, and which TL measurement method to use cannot be prescribed, and are dependent on the biological question addressed and the constraints imposed by the study system. What is essential for future studies of telomere dynamics in evolution and ecology is that researchers publish full details of their methods and the quality control thresholds they employ.},
}
@article {pmid25828846,
year = {2015},
author = {Peška, V and Fajkus, P and Fojtová, M and Dvořáčková, M and Hapala, J and Dvořáček, V and Polanská, P and Leitch, AR and Sýkorová, E and Fajkus, J},
title = {Characterisation of an unusual telomere motif (TTTTTTAGGG)n in the plant Cestrum elegans (Solanaceae), a species with a large genome.},
journal = {The Plant journal : for cell and molecular biology},
volume = {82},
number = {4},
pages = {644-654},
doi = {10.1111/tpj.12839},
pmid = {25828846},
issn = {1365-313X},
mesh = {Cestrum/*genetics ; Chromosomes, Plant/*genetics ; Telomere/*chemistry/*genetics ; },
abstract = {The characterization of unusual telomere sequence sheds light on patterns of telomere evolution, maintenance and function. Plant species from the closely related genera Cestrum, Vestia and Sessea (family Solanaceae) lack known plant telomeric sequences. Here we characterize the telomere of Cestrum elegans, work that was a challenge because of its large genome size and few chromosomes (1C 9.76 pg; n = 8). We developed an approach that combines BAL31 digestion, which digests DNA from the ends and chromosome breaks, with next-generation sequencing (NGS), to generate data analysed in RepeatExplorer, designed for de novo repeats identification and quantification. We identify an unique repeat motif (TTTTTTAGGG)n in C. elegans, occurring in ca. 30 400 copies per haploid genome, averaging ca. 1900 copies per telomere, and synthesized by telomerase. We demonstrate that the motif is synthesized by telomerase. The occurrence of an unusual eukaryote (TTTTTTAGGG)n telomeric motif in C. elegans represents a switch in motif from the 'typical' angiosperm telomere (TTTAGGG)n . That switch may have happened with the divergence of Cestrum, Sessea and Vestia. The shift in motif when it arose would have had profound effects on telomere activity. Thus our finding provides a unique handle to study how telomerase and telomeres responded to genetic change, studies that will shed more light on telomere function.},
}
@article {pmid25828247,
year = {2015},
author = {Najarro, K and Nguyen, H and Chen, G and Xu, M and Alcorta, S and Yao, X and Zukley, L and Metter, EJ and Truong, T and Lin, Y and Li, H and Oelke, M and Xu, X and Ling, SM and Longo, DL and Schneck, J and Leng, S and Ferrucci, L and Weng, NP},
title = {Telomere Length as an Indicator of the Robustness of B- and T-Cell Response to Influenza in Older Adults.},
journal = {The Journal of infectious diseases},
volume = {212},
number = {8},
pages = {1261-1269},
pmid = {25828247},
issn = {1537-6613},
support = {R01 AI108907/AI/NIAID NIH HHS/United States ; ZIA AG000112-08/ImNIH/Intramural NIH HHS/United States ; ZIA AG000112-09/ImNIH/Intramural NIH HHS/United States ; ZIA AG000756-19/ImNIH/Intramural NIH HHS/United States ; ZIA AG000756-18/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Age Factors ; Aged ; Aged, 80 and over ; Aging ; Antigen-Presenting Cells/immunology ; B-Lymphocytes/*immunology ; CD8-Positive T-Lymphocytes/*immunology ; Female ; HLA-A2 Antigen/*immunology ; Humans ; Influenza Vaccines/*immunology ; Influenza, Human/*immunology ; Male ; Telomere Shortening/*immunology ; },
abstract = {BACKGROUND: Telomeres provide a key mechanism for protecting the integrity of chromosomes and their attrition after cell division and during aging are evident in lymphocytes. However, the significance of telomere shortening in age-associated decline of immune function is unknown.<br><br>METHODS: We selected 22 HLA-A2-positive healthy older adults who have relatively short or long telomere lengths to compare their antibody response against the influenza vaccine, and their CD8(+) T-cell response against an influenza antigen.<br><br>RESULTS: B cells from individuals with a robust antibody response to the influenza vaccine had significantly longer telomeres than those with a poor antibody response. Monocyte-derived antigen-presenting cells of both short and long telomere groups induced similar expansions of influenza M1-specific CD8(+) T cells. Vaccination did not increase M1-specific CD8(+) T cells in blood, but M1-specific CD8(+) T cells from the long telomere group exhibited significantly greater expansion in vitro than those from the short telomere group. Finally, M1-specific CD8(+) T cells that underwent more expansions had significantly longer telomeres than cells with fewer divisions.<br><br>CONCLUSIONS: Telomere length is positively associated with a robust lymphocyte response, and telomere attrition may contribute to the age-associated decline of adaptive immunity.},
}
@article {pmid25827887,
year = {2015},
author = {Banerjee, PP and Jagadeesh, S},
title = {Non-radioactive assay methods for the assessment of telomerase activity and telomere length.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1288},
number = {},
pages = {305-316},
doi = {10.1007/978-1-4939-2474-5_17},
pmid = {25827887},
issn = {1940-6029},
mesh = {Biological Assay/*methods ; Enzyme Activation ; Humans ; Luminescent Measurements/methods ; Nucleic Acid Hybridization/methods ; Repetitive Sequences, Nucleic Acid ; Telomerase/*metabolism ; Telomere/*genetics/*metabolism ; *Telomere Homeostasis ; },
abstract = {The Telomeric repeat amplification protocol (TRAP) is a highly sensitive PCR-based assay and prove to be an important tool for understanding the role of telomerase in cancer and various tissues that harbors telomerase positive stem cells. This assay measures telomerase activity where the amount of target is dependent upon the activity of the enzyme. This protocol consists of two steps: first, telomeric repeats are added to the substrate by telomerase present in the cell and second, the extended products are amplified by Taq-DNA polymerase. The amplified TRAP products are separated on 10 % native PAGE and detected by SYBR Green I dye.},
}
@article {pmid25823445,
year = {2015},
author = {Ellahi, A and Thurtle, DM and Rine, J},
title = {The Chromatin and Transcriptional Landscape of Native Saccharomyces cerevisiae Telomeres and Subtelomeric Domains.},
journal = {Genetics},
volume = {200},
number = {2},
pages = {505-521},
pmid = {25823445},
issn = {1943-2631},
support = {R37 GM031105/GM/NIGMS NIH HHS/United States ; S10-RR029668/RR/NCRR NIH HHS/United States ; R01 GM031105/GM/NIGMS NIH HHS/United States ; GM-31105/GM/NIGMS NIH HHS/United States ; T32 GM 007127/GM/NIGMS NIH HHS/United States ; S10 RR029668/RR/NCRR NIH HHS/United States ; S10 RR027303/RR/NCRR NIH HHS/United States ; T32 GM007127/GM/NIGMS NIH HHS/United States ; S10-RR027303/RR/NCRR NIH HHS/United States ; },
mesh = {Acetylation ; Catalysis ; Chromatin/*genetics/metabolism ; Diploidy ; *Gene Expression Regulation, Fungal ; Gene Silencing ; Haploidy ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Telomere/*genetics/metabolism ; *Transcription, Genetic ; },
abstract = {Saccharomyces cerevisiae telomeres have been a paradigm for studying telomere position effects on gene expression. Telomere position effect was first described in yeast by its effect on the expression of reporter genes inserted adjacent to truncated telomeres. The reporter genes showed variable silencing that depended on the Sir2/3/4 complex. Later studies examining subtelomeric reporter genes inserted at natural telomeres hinted that telomere position effects were less pervasive than previously thought. Additionally, more recent data using the sensitive technology of chromatin immunoprecipitation and massively parallel sequencing (ChIP-Seq) revealed a discrete and noncontinuous pattern of coenrichment for all three Sir proteins at a few telomeres, calling the generality of these conclusions into question. Here we combined the ChIP-Seq of the Sir proteins with RNA sequencing (RNA-Seq) of messenger RNAs (mRNAs) in wild-type and in SIR2, SIR3, and SIR4 deletion mutants to characterize the chromatin and transcriptional landscape of all native S. cerevisiae telomeres at the highest achievable resolution. Most S. cerevisiae chromosomes had subtelomeric genes that were expressed, with only ∼6% of subtelomeric genes silenced in a SIR-dependent manner. In addition, we uncovered 29 genes with previously unknown cell-type-specific patterns of expression. These detailed data provided a comprehensive assessment of the chromatin and transcriptional landscape of the subtelomeric domains of a eukaryotic genome.},
}
@article {pmid25822194,
year = {2015},
author = {Peng, J and He, MH and Duan, YM and Liu, YT and Zhou, JQ},
title = {Inhibition of telomere recombination by inactivation of KEOPS subunit Cgi121 promotes cell longevity.},
journal = {PLoS genetics},
volume = {11},
number = {3},
pages = {e1005071},
pmid = {25822194},
issn = {1553-7404},
mesh = {DNA Breaks, Double-Stranded ; DNA Repair/genetics ; Genomic Instability ; Longevity/*genetics ; *Recombination, Genetic ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/*genetics ; Telomerase/genetics ; Telomere/genetics ; },
abstract = {DNA double strand break (DSB) is one of the major damages that cause genome instability and cellular aging. The homologous recombination (HR)-mediated repair of DSBs plays an essential role in assurance of genome stability and cell longevity. Telomeres resemble DSBs and are competent for HR. Here we show that in budding yeast Saccharomyces cerevisiae telomere recombination elicits genome instability and accelerates cellular aging. Inactivation of KEOPS subunit Cgi121 specifically inhibits telomere recombination, and significantly extends cell longevity in both telomerase-positive and pre-senescing telomerase-negative cells. Deletion of CGI121 in the short-lived yku80(tel) mutant restores lifespan to cgi121Δ level, supporting the function of Cgi121 in telomeric single-stranded DNA generation and thus in promotion of telomere recombination. Strikingly, inhibition of telomere recombination is able to further slow down the aging process in long-lived fob1Δ cells, in which rDNA recombination is restrained. Our study indicates that HR activity at telomeres interferes with telomerase to pose a negative impact on cellular longevity.},
}
@article {pmid25820263,
year = {2015},
author = {Meena, JK and Cerutti, A and Beichler, C and Morita, Y and Bruhn, C and Kumar, M and Kraus, JM and Speicher, MR and Wang, ZQ and Kestler, HA and d'Adda di Fagagna, F and Günes, C and Rudolph, KL},
title = {Telomerase abrogates aneuploidy-induced telomere replication stress, senescence and cell depletion.},
journal = {The EMBO journal},
volume = {34},
number = {10},
pages = {1371-1384},
pmid = {25820263},
issn = {1460-2075},
support = {322726/ERC_/European Research Council/International ; GGP12059/TI_/Telethon/Italy ; P 23284/FWF_/Austrian Science Fund FWF/Austria ; },
mesh = {*Aneuploidy ; Animals ; Cellular Senescence/genetics/physiology ; DNA Replication/genetics/physiology ; Hematopoietic Stem Cells/metabolism ; Humans ; Mice ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {The causal role of aneuploidy in cancer initiation remains under debate since mutations of euploidy-controlling genes reduce cell fitness but aneuploidy strongly associates with human cancers. Telomerase activation allows immortal growth by stabilizing telomere length, but its role in aneuploidy survival has not been characterized. Here, we analyze the response of primary human cells and murine hematopoietic stem cells (HSCs) to aneuploidy induction and the role of telomeres and the telomerase in this process. The study shows that aneuploidy induces replication stress at telomeres leading to telomeric DNA damage and p53 activation. This results in p53/Rb-dependent, premature senescence of human fibroblast, and in the depletion of hematopoietic cells in telomerase-deficient mice. Endogenous telomerase expression in HSCs and enforced expression of telomerase in human fibroblasts are sufficient to abrogate aneuploidy-induced replication stress at telomeres and the consequent induction of premature senescence and hematopoietic cell depletion. Together, these results identify telomerase as an aneuploidy survival factor in mammalian cells based on its capacity to alleviate telomere replication stress in response to aneuploidy induction.},
}
@article {pmid25819580,
year = {2015},
author = {Nagai, K and Matsushita, T and Matsuzaki, T and Takayama, K and Matsumoto, T and Kuroda, R and Kurosaka, M},
title = {Depletion of SIRT6 causes cellular senescence, DNA damage, and telomere dysfunction in human chondrocytes.},
journal = {Osteoarthritis and cartilage},
volume = {23},
number = {8},
pages = {1412-1420},
doi = {10.1016/j.joca.2015.03.024},
pmid = {25819580},
issn = {1522-9653},
mesh = {Cell Proliferation ; Cells, Cultured ; *Cellular Senescence ; Chondrocytes/metabolism/*pathology ; *DNA Damage ; Histones/metabolism ; Humans ; Matrix Metalloproteinase 1/genetics/metabolism ; Matrix Metalloproteinase 13/genetics/metabolism ; Osteoarthritis, Knee/pathology ; RNA Interference ; RNA, Messenger/metabolism ; Real-Time Polymerase Chain Reaction ; Sirtuins/*deficiency/genetics ; *Telomere ; Up-Regulation ; beta-Galactosidase/metabolism ; },
abstract = {OBJECTIVE: SIRT6, a member of the sirtuin family of nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylases, has been implicated as a key factor in aging-related diseases. However, the role of SIRT6 in chondrocytes has not been fully explored. The purpose of this study was to examine the role of SIRT6 in human chondrocytes by inhibiting SIRT6 in vitro.<br><br>DESIGN: First, the localization of SIRT6 and proliferation cell nuclear antigen (PCNA) in human cartilages was examined by immunohistochemistry. Next, SIRT6 was depleted by RNA interference (RNAi), and the effect of SIRT6 depletion on changes in gene expression, protein levels, proliferation, and senescence in human chondrocytes was assessed. Furthermore, to detect DNA damage and telomere dysfunction, &#x3b3;H2AX foci and telomere dysfunction-induced foci (TIFs) were examined using immunofluorescence microscopy. The protein levels of two mediators for DNA damage induced-senescence, p16 and p21, were examined by western blotting.<br><br>RESULTS: Immunohistochemical analysis showed SIRT6 was preferentially expressed in the superficial zone chondrocytes and PCNA-positive cluster-forming chondrocytes in the osteoarthritic cartilage tissue samples. Real-time PCR analysis showed that matrix metalloproteinase 1 (MMP-1) and MMP-13 mRNA were significantly increased by SIRT6 inhibition. Moreover, SIRT6 inhibition significantly reduced proliferation and increased senescence associated &#x3b2;-galactosidase (SA-&#x3b2;-Gal)-positive chondrocytes; it also led to increased p16 levels. Immunofluorescence microscopy showed that &#x3b3;H2AX foci and TIFs were increased by SIRT6 inhibition.<br><br>CONCLUSION: Depletion of SIRT6 in human chondrocytes caused increased DNA damage and telomere dysfunction, and subsequent premature senescence. These findings suggest that SIRT6 plays an important role in the regulation of senescence of human chondrocytes.},
}
@article {pmid25809917,
year = {2015},
author = {Hosen, I and Rachakonda, PS and Heidenreich, B and de Verdier, PJ and Ryk, C and Steineck, G and Hemminki, K and Kumar, R},
title = {Mutations in TERT promoter and FGFR3 and telomere length in bladder cancer.},
journal = {International journal of cancer},
volume = {137},
number = {7},
pages = {1621-1629},
doi = {10.1002/ijc.29526},
pmid = {25809917},
issn = {1097-0215},
mesh = {Aged ; Female ; Humans ; Male ; *Mutation ; Promoter Regions, Genetic ; Receptor, Fibroblast Growth Factor, Type 3/*genetics ; Telomerase/*genetics ; Telomere/*genetics ; Urinary Bladder Neoplasms/*genetics/pathology ; },
abstract = {Mutations in the promoter of the telomerase reverse transcriptase (TERT) and fibroblast growth factor receptor 3 (FGFR3) genes constitute the most recurrent somatic alterations in urothelial carcinoma of bladder. In this study, we screened DNA from 327 urothelial bladder carcinomas from well-documented patients, with different stages and grades and known TERT promoter mutational status, for FGFR3 alterations and measured relative telomere length (RTL). Although, the frequency of the TERT promoter mutations was higher than those in FGFR3; however, the alterations at the two loci occurred together more frequently than per chance [Odds ratio (OR) = 4.93, 95% CI = 2.72-8.92, p < 0.0001]. While tumors with TERT promoter and FGFR3 mutations had shorter RTL than those without mutations (p < 0.0001), the TERT promoter mutations in conjunction with the common allele of the rs2853669 polymorphism defined sub-group of patients with an observed decreased overall survival (OR = 2.15, 95% CI = 1.00-4.61) and increased recurrence in patients with TaG1+TaG2 disease categories (OR = 3.68, 95%CI = 1.12-12.05). The finding of shorter telomeres in tumors with TERT promoter and/or FGFR3 mutations than without mutations implies mechanistic relevance of telomere biology in cancer progression. The observed association with recurrence and survival shows that the TERT promoter mutations can potentially be used as markers to refine selection of patients for different treatments. The overwhelming frequency of the TERT promoter mutations also represents a case for development of an eventual therapeutic target.},
}
@article {pmid25808442,
year = {2015},
author = {Nagelkerke, A and van Kuijk, SJ and Martens, JW and Sweep, FC and Hoogerbrugge, N and Bussink, J and Span, PN},
title = {Poor prognosis of constitutive γ-H2AX expressing triple-negative breast cancers is associated with telomere length.},
journal = {Biomarkers in medicine},
volume = {9},
number = {4},
pages = {383-390},
doi = {10.2217/bmm.15.2},
pmid = {25808442},
issn = {1752-0371},
mesh = {BRCA1 Protein/genetics ; Cell Line, Tumor ; *Gene Expression Regulation, Neoplastic ; Histones/*metabolism ; Humans ; Mutation ; Prognosis ; Telomere/*genetics ; Triple Negative Breast Neoplasms/diagnosis/genetics/metabolism/*pathology ; },
abstract = {AIM: Here, we set out to establish whether endogenous γ-H2AX is a biomarker in triple-negative breast cancer.<br><br>METHODS: We explored the association of &#x3b3;-H2AX with mutation status and sensitivity to 139 different anticancer drugs in up to 41 breast cancer cell lines. Further, we correlated &#x3b3;-H2AX expression in breast cancer tumor tissues with telomere length.<br><br>RESULTS: &#x3b3;-H2AX positive breast cancer cells exhibit more mutations, and - when p53 mutated - have shorter telomeres. In breast cancer patients &#x3b3;-H2AX is also related to shorter telomeres, which was in turn associated with poorer prognosis of triple-negative breast cancer patients.<br><br>CONCLUSION: Thus, endogenous &#x3b3;-H2AX is associated with short telomeres, which might offer a specific target for therapy for triple-negative breast cancer patients.},
}
@article {pmid25803084,
year = {2015},
author = {Pusceddu, I and Farrell, CJ and Di Pierro, AM and Jani, E and Herrmann, W and Herrmann, M},
title = {The role of telomeres and vitamin D in cellular aging and age-related diseases.},
journal = {Clinical chemistry and laboratory medicine},
volume = {53},
number = {11},
pages = {1661-1678},
doi = {10.1515/cclm-2014-1184},
pmid = {25803084},
issn = {1437-4331},
mesh = {*Aging/genetics/metabolism/pathology ; Animals ; Cardiovascular Diseases/genetics/*metabolism ; *Cellular Senescence ; Diabetes Mellitus, Type 2/genetics/*metabolism ; Dyskeratosis Congenita/genetics/*metabolism ; Humans ; Neurodegenerative Diseases/genetics/*metabolism ; Telomere/genetics/*metabolism ; Vitamin D/*metabolism ; },
abstract = {Aging is a complex biological process characterized by a progressive decline of organ functions leading to an increased risk of age-associated diseases and death. Decades of intensive research have identified a range of molecular and biochemical pathways contributing to aging. However, many aspects regarding the regulation and interplay of these pathways are insufficiently understood. Telomere dysfunction and genomic instability appear to be of critical importance for aging at a cellular level. For example, age-related diseases and premature aging syndromes are frequently associated with telomere shortening. Telomeres are repetitive nucleotide sequences that together with the associated sheltrin complex protect the ends of chromosomes and maintain genomic stability. Recent studies suggest that micronutrients, such as vitamin D, folate and vitamin B12, are involved in telomere biology and cellular aging. In particular, vitamin D is important for a range of vital cellular processes including cellular differentiation, proliferation and apoptosis. As a result of the multiple functions of vitamin D it has been speculated that vitamin D might play a role in telomere biology and genomic stability. Here we review existing knowledge about the link between telomere biology and cellular aging with a focus on the role of vitamin D. We searched the literature up to November 2014 for human studies, animal models and in vitro experiments that addressed this topic.},
}
@article {pmid25799990,
year = {2015},
author = {Boersma, V and Moatti, N and Segura-Bayona, S and Peuscher, MH and van der Torre, J and Wevers, BA and Orthwein, A and Durocher, D and Jacobs, JJL},
title = {MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5' end resection.},
journal = {Nature},
volume = {521},
number = {7553},
pages = {537-540},
pmid = {25799990},
issn = {1476-4687},
support = {311565/ERC_/European Research Council/International ; MOP89754//Canadian Institutes of Health Research/Canada ; },
mesh = {Ataxia Telangiectasia Mutated Proteins/metabolism ; Carrier Proteins/metabolism ; Cell Line, Tumor ; *DNA Breaks, Double-Stranded/radiation effects ; *DNA End-Joining Repair/genetics ; DNA Repair Enzymes/metabolism ; DNA Replication ; DNA-Binding Proteins/metabolism ; Exodeoxyribonucleases/metabolism ; Genomic Instability ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Mad2 Proteins/*metabolism ; Nuclear Proteins/metabolism ; *Recombinational DNA Repair/genetics ; Repressor Proteins ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/metabolism ; Tumor Suppressor p53-Binding Protein 1 ; Ubiquitin-Protein Ligases/metabolism ; },
abstract = {Appropriate repair of DNA lesions and the inhibition of DNA repair activities at telomeres are crucial to prevent genomic instability. By fuelling the generation of genetic alterations and by compromising cell viability, genomic instability is a driving force in cancer and ageing. Here we identify MAD2L2 (also known as MAD2B or REV7) through functional genetic screening as a novel factor controlling DNA repair activities at mammalian telomeres. We show that MAD2L2 accumulates at uncapped telomeres and promotes non-homologous end-joining (NHEJ)-mediated fusion of deprotected chromosome ends and genomic instability. MAD2L2 depletion causes elongated 3' telomeric overhangs, indicating that MAD2L2 inhibits 5' end resection. End resection blocks NHEJ while committing to homology-directed repair, and is under the control of 53BP1, RIF1 and PTIP. Consistent with MAD2L2 promoting NHEJ-mediated telomere fusion by inhibiting 5' end resection, knockdown of the nucleases CTIP or EXO1 partially restores telomere-driven genomic instability in MAD2L2-depleted cells. Control of DNA repair by MAD2L2 is not limited to telomeres. MAD2L2 also accumulates and inhibits end resection at irradiation-induced DNA double-strand breaks and promotes end-joining of DNA double-strand breaks in several settings, including during immunoglobulin class switch recombination. These activities of MAD2L2 depend on ATM kinase activity, RNF8, RNF168, 53BP1 and RIF1, but not on PTIP, REV1 and REV3, the latter two acting with MAD2L2 in translesion synthesis. Together, our data establish MAD2L2 as a crucial contributor to the control of DNA repair activity by 53BP1 that promotes NHEJ by inhibiting 5' end resection downstream of RIF1.},
}
@article {pmid25799396,
year = {2015},
author = {Aulinas, A and Ramírez, MJ and Barahona, MJ and Valassi, E and Resmini, E and Mato, E and Santos, A and Crespo, I and Bell, O and Surrallés, J and Webb, SM},
title = {Dyslipidemia and chronic inflammation markers are correlated with telomere length shortening in Cushing's syndrome.},
journal = {PloS one},
volume = {10},
number = {3},
pages = {e0120185},
pmid = {25799396},
issn = {1932-6203},
mesh = {Adiponectin/blood ; Adult ; Biomarkers/blood ; C-Reactive Protein/metabolism ; Case-Control Studies ; Cushing Syndrome/blood/*genetics ; Dyslipidemias/blood/*genetics ; Female ; Humans ; Inflammation/blood/genetics ; Interleukin-6/blood ; Lipids/blood ; Male ; Middle Aged ; *Telomere Shortening ; },
abstract = {INTRODUCTION: Cushing's syndrome (CS) increases cardiovascular risk (CVR) and adipocytokine imbalance, associated with an increased inflammatory state. Telomere length (TL) shortening is a novel CVR marker, associated with inflammation biomarkers. We hypothesized that inflammatory state and higher CVR in CS might be related to TL shortening, as observed in premature aging.<br><br>AIM: To evaluate relationships between TL, CVR and inflammation markers in CS.<br><br>METHODS: In a cross-sectional study, 77 patients with CS (14 males, 59 pituitary-, 17 adrenal- and 1 ectopic-origin; 21 active disease) and 77 age-, gender-, smoking-matched controls were included. Total white blood cell TL was measured by TRF-Southern technique. Clinical data and blood samples were collected (lipids, adrenal function, glucose). Adiponectin, interleukin-6 (IL6) and C-reactive protein (CRP) were available in a subgroup of patients (n=32). Correlations between TL and clinical features were examined and multiple linear regression analysis was performed to investigate potential predictors of TL.<br><br>RESULTS: Dyslipidemic CS had shorter TL than non-dyslipidemic subjects (7328&#xb1;1274 vs 7957&#xb1;1137 bp, p<0.05). After adjustment for age and body mass index, cured and active CS dyslipidemic patients had shorter TL than non-dyslipidemic CS (cured: 7187&#xb1;1309 vs 7868&#xb1;1104; active: 7203&#xb1;1262 vs 8615&#xb1;1056, respectively, p<0.05). Total cholesterol and triglycerides negatively correlated with TL (r-0.279 and -0.259, respectively, p<0.05), as well as CRP and IL6 (r-0.412 and -0.441, respectively, p<0.05). No difference in TL according the presence of other individual CVR factors (hypertension, diabetes mellitus, obesity) were observed in CS or in the control group. Additional TL shortening was observed in dyslipidemic obese patients who were also hypertensive, compared to those with two or less CVR factors (6956&#xb1;1280 vs 7860&#xb1;1180, respectively, p<0.001). Age and dyslipidemia were independent negative predictors of TL.<br><br>CONCLUSION: TL is shortened in dyslipidemic CS patients, further worse if hypertension and/or obesity coexist and is negatively correlated with increased inflammation markers. Increased lipids and a "low" grade inflammation may contribute to TL shortening and consequently to premature ageing and increased morbidity in CS.},
}
@article {pmid25798839,
year = {2016},
author = {Aschacher, T and Wolf, B and Enzmann, F and Kienzl, P and Messner, B and Sampl, S and Svoboda, M and Mechtcheriakova, D and Holzmann, K and Bergmann, M},
title = {LINE-1 induces hTERT and ensures telomere maintenance in tumour cell lines.},
journal = {Oncogene},
volume = {35},
number = {1},
pages = {94-104},
pmid = {25798839},
issn = {1476-5594},
mesh = {Animals ; Cell Line, Tumor ; Dogs ; Endonucleases/genetics/metabolism ; HCT116 Cells ; Humans ; *Long Interspersed Nucleotide Elements ; Madin Darby Canine Kidney Cells ; Melanoma, Experimental ; RNA-Directed DNA Polymerase/genetics/metabolism ; Ribonucleoproteins/*genetics/metabolism ; Telomerase/biosynthesis/*genetics/*metabolism ; Telomere/*genetics/*metabolism ; Up-Regulation ; },
abstract = {A hallmark of cancer cells is an activated telomere maintenance mechanism, which allows prolonged survival of the malignant cells. In more than 80% of tumours, telomeres are elongated by the enzyme telomerase, which adds de novo telomere repeats to the ends of chromosomes. Cancer cells are also characterized by expression of active LINE-1 elements (L1s, long interspersed nuclear elements-1). L1 elements are abundant retrotransposons in the eukaryotic genome that are primarily known for facilitating aberrant recombination. Using L1-knockdown (KD), we show for the first time that L1 is critical for telomere maintenance in telomerase-positive tumour cells. The reduced length of telomeres in the L1-KD-treated cells correlated with an increased rate of telomere dysfunction foci, a reduced expression of shelterin proteins and an increased rate of anaphase bridges. The decreased telomere length was associated with a decreased telomerase activity and decreased telomerase mRNA level; the latter was increased upon L1 overexpression. L1-KD also led to a decrease in mRNA and protein expression of cMyc and KLF-4, two main transcription factors of telomerase and altered mRNA levels of other stem-cell-associated proteins such as CD44 and hMyb, as well as a corresponding reduced growth of spheroids. The KD of KLF-4 or cMyc decreased the level of L1-ORF1 mRNA, suggesting a specific reciprocal regulation with L1. Thus, our findings contribute to the understanding of L1 as a pathogenicity factor in cancer cells. As L1 is only expressed in pathophysiological conditions, L1 now appears to be target in the rational treatment of telomerase-positive cancer.},
}
@article {pmid25797251,
year = {2015},
author = {Heidenreich, B and Rachakonda, PS and Hosen, I and Volz, F and Hemminki, K and Weyerbrock, A and Kumar, R},
title = {TERT promoter mutations and telomere length in adult malignant gliomas and recurrences.},
journal = {Oncotarget},
volume = {6},
number = {12},
pages = {10617-10633},
pmid = {25797251},
issn = {1949-2553},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Brain Neoplasms/enzymology/*genetics/pathology ; Child ; Disease-Free Survival ; Female ; Glioma/enzymology/*genetics/pathology ; Humans ; Male ; Middle Aged ; *Mutation ; Neoplasm Recurrence, Local/enzymology/genetics/pathology ; Prognosis ; Promoter Regions, Genetic ; Telomerase/*genetics ; Telomere/genetics ; Young Adult ; },
abstract = {In this report on 303 gliomas we show the highest frequency of TERT promoter mutations in gliobastomas (80%) followed by oligodendrogliomas (70%) and astrocytomas (39%). We observed positive association between TERT promoter and IDH mutations in oligodendroglial tumors (OR = 26.3; 95% CI 2.5-250.2) and inverse association in primary glioblastomas (OR = 0.13; 95% CI 0.03-0.58). Tumors with TERT promoter mutations compared to those without showed increased TERT transcription; we also showed difference in the transcription levels due to the two main mutations. Tumors with TERT promoter mutations had shorter telomeres than those without. The patients with only TERT promoter mutations showed worst survival (median survival 14.6 months) and patients with both IDH and TERT promoter mutations showed best survival (246.5 months). In patients with astrocytoma, the TERT promoter mutations only associated with poor survival (P < 0.0001); IDH mutations and 1p/19q deletions associated with increased survival (P = 0.0004). TERT promoter mutations in low grade gliomas associated with reduced progression free survival (HR 10.2; 95% CI 1.9 - 55.9). While our data affirm the role of TERT promoter mutations in glial tumors, effects on transcription and telomere length emphasise the importance of telomere biology in disease genesis and outcome.},
}
@article {pmid25793372,
year = {2015},
author = {, },
title = {Correction: Recruitment of Rpd3 to the telomere depends on the protein arginine methyltransferase Hmt1.},
journal = {PloS one},
volume = {10},
number = {3},
pages = {e0120968},
pmid = {25793372},
issn = {1932-6203},
}
@article {pmid25792135,
year = {2015},
author = {Kłoda, K and Domanski, L and Kwiatkowska, E and Borowiecka, E and Safranow, K and Drozd, A and Ciechanowicz, A and Maciejewska-Karłowska, A and Sawczuk, M and Pawlik, A and Ciechanowski, K},
title = {hTERT, BICD1 and chromosome 18 polymorphisms associated with telomere length affect kidney allograft function after transplantation.},
journal = {Kidney &amp; blood pressure research},
volume = {40},
number = {2},
pages = {111-120},
doi = {10.1159/000368487},
pmid = {25792135},
issn = {1423-0143},
mesh = {Adaptor Proteins, Signal Transducing/*genetics ; Adult ; Chromosomes, Human, Pair 18/*genetics ; Creatinine/blood ; Cytoskeletal Proteins/*genetics ; DNA/genetics ; Female ; Graft Rejection/genetics ; Humans ; *Kidney Transplantation ; Male ; Middle Aged ; Poland ; Polymorphism, Genetic/*genetics ; Telomerase/*genetics ; Telomere/*genetics ; Treatment Failure ; Treatment Outcome ; },
abstract = {BACKGROUND/AIMS: It has been confirmed that telomere length (TL) correlates with chronological donor age and that telomere shortening is accelerated in allografts. The aim of this study was to analyse the associations between graft rs2735940 hTERT and rs2630578 BICD1 gene polymorphisms and rs7235755/rs2162440 chromosome 18 polymorphisms, relative TL and kidney function after transplantation.<br><br>METHODS: The study enrolled 119 Polish Caucasian kidney allograft recipients (64M/55F, mean age 47.3&#xb1;14.0 years). The relative TL was assessed in biopsy specimens. To identify genotypes of the studied polymorphisms, real-time PCR was performed.<br><br>RESULTS: The graft rs2735940 hTERT gene polymorphism TT genotype was associated with a significantly lower risk of delayed graft function (DGF) (TT vs. TC+CC; OR=0, p=0.009) and significantly shorter TL in the '0' biopsy (TT vs. CC: 207&#xb1;153 vs. 400&#xb1;161, p=0.036). The graft rs2630578 BICD1 gene polymorphism CC genotype was associated with lower creatinine concentrations in the first month (CC vs. GC: 1.11&#xb1;0.06 vs. 2.0&#xb1;1.25 mg/dL, p=0.03). The AA genotype of the graft rs7235755 chromosome 18 polymorphism was associated with longer relative TL in specimens collected 12 to 60 months after transplantation (AA vs. GG+GA p=0.04; AA vs. GG: 489&#xb1;152 vs. 246&#xb1;145, p=0.035) and the presence of A allele was associated with higher creatinine concentrations one month after transplantation (GA+AA vs. GG p=0.026; GA vs. GG: 2.18&#xb1;1.59 vs. 1.76&#xb1;0.88 mg/dL, p=0.02). It was found that shorter TL in the first six months was associated with higher creatinine concentrations 12 and 18 months after transplantation (Rs=-0.32; p=0.07 and Rs=-0.54; p=0.006, respectively).<br><br>CONCLUSIONS: Graft rs2735940 hTERT and rs2630578 BICD1 gene polymorphisms and rs7235755/rs2162440 chromosome 18 polymorphisms, apart from the association with TL, affect early kidney function after transplantation. Relative TL correlated negatively with creatinine concentrations, allowing the use of TL as a predictor of long-term kidney function.},
}
@article {pmid25789788,
year = {2015},
author = {Petti, E and Jordi, F and Buemi, V and Dinami, R and Benetti, R and Blasco, MA and Schoeftner, S},
title = {Altered telomere homeostasis and resistance to skin carcinogenesis in Suv39h1 transgenic mice.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {14},
number = {9},
pages = {1438-1446},
pmid = {25789788},
issn = {1551-4005},
mesh = {9,10-Dimethyl-1,2-benzanthracene ; Animals ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics/*metabolism/pathology ; Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/metabolism ; Epidermis/*enzymology/pathology ; Female ; Histones/metabolism ; Humans ; Male ; Methylation ; Methyltransferases/genetics/*metabolism ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Mice, Transgenic ; Mutation ; Repressor Proteins/genetics/*metabolism ; Skin Neoplasms/chemically induced/enzymology/genetics/pathology/*prevention &amp; control ; Telomere/*metabolism ; *Telomere Homeostasis ; Telomere Shortening ; ras Proteins/genetics/metabolism ; },
abstract = {The Suv39h1 and Suv39h2 H3K9 histone methyltransferases (HMTs) have a conserved role in the formation of constitutive heterochromatin and gene silencing. Using a transgenic mouse model system we demonstrate that elevated expression of Suv39h1 increases global H3K9me3 levels in vivo. More specifically, Suv39h1 overexpression enhances the imposition of H3K9me3 levels at constitutive heterochromatin at telomeric and major satellite repeats in primary mouse embryonic fibroblasts. Chromatin compaction is paralleled by telomere shortening, indicating that telomere length is controlled by H3K9me3 density at telomeres. We further show that increased Suv39h1 levels result in an impaired clonogenic potential of transgenic epidermal stem cells and Ras/E1A transduced transgenic primary mouse embryonic fibroblasts. Importantly, Suv39h1 overexpression in mice confers resistance to a DMBA/TPA induced skin carcinogenesis protocol that is characterized by the accumulation of activating H-ras mutations. Our results provide genetic evidence that Suv39h1 controls telomere homeostasis and mediates resistance to oncogenic stress in vivo. This identifies Suv39h1 as an interesting target to improve oncogene induced senescence in premalignant lesions.},
}
@article {pmid25786194,
year = {2015},
author = {Gruszecka, A and Kopczyński, P and Cudziło, D and Lipińska, N and Romaniuk, A and Barczak, W and Rozwadowska, N and Totoń, E and Rubiś, B},
title = {Telomere shortening in Down syndrome patients--when does it start?.},
journal = {DNA and cell biology},
volume = {34},
number = {6},
pages = {412-417},
pmid = {25786194},
issn = {1557-7430},
mesh = {Adolescent ; Case-Control Studies ; Child ; Child, Preschool ; Down Syndrome/*genetics ; Female ; Humans ; Male ; Telomere/*genetics ; *Telomere Shortening ; Young Adult ; },
abstract = {Down syndrome (DS) is one of the most common aneuploidy. In general population, its prevalence is 1:600-1:800 live births. It is caused by a trisomy of chromosome 21. DS is phenotypically manifested by premature aging, upward slant to the eyes, epicanthus, flattened face, and poor muscle tone. In addition to physical changes, this syndrome is characterized by early onset of diseases specific to old age, such as Alzheimer's disease, vision and hearing problems, and precocious menopause. Since DS symptoms include premature aging, the shortening of telomeres might be one of the markers of cellular aging. Consequently, the aim of the study was to determine the length of the telomeres in leukocytes from the blood of juvenile patients with DS (n=68) compared to an age-matched control group (n=56) and also to determine the diagnostic or predictive value for this parameter. We show that, for the first time, in juveniles, the average relative telomere length in studied subjects is significantly longer than in the control group (50.46 vs. 40.56, respectively arbitrary units [AU]; p=0.0026). The results provide interesting basis for further research to determine the causes and consequences of telomere maintaining and the dynamics of this process in patients with DS.},
}
@article {pmid25785045,
year = {2015},
author = {Pei, S and Zhao, F and Liu, J and Fu, Q and Shang, P},
title = {Association between regulator of telomere elongation helicase 1 polymorphism and susceptibility to glioma.},
journal = {International journal of clinical and experimental medicine},
volume = {8},
number = {1},
pages = {690-697},
pmid = {25785045},
issn = {1940-5901},
abstract = {BACKGROUND: Glioma is the most devastating type of malignant brain tumors in adults. Genetic factors play important roles in the pathogenesis of glioma. In recent years, some studies found that there were significant association between regulator of telomere elongation helicase 1 rs6010620 polymorphism and glioma susceptibility, however, the results were controversial. The aim of this study was to obtain a more exact estimation of the association between regulator of telomere elongation helicase 1 rs6010620 polymorphism and glioma through a meta-analysis.<br><br>METHODS: The meta-analysis included 19 published case-control studies involving 8541 cases and 14226 controls. The included papers were searched from PubMed and Embase database. Odds ratio (OR) with 95% confidence interval (95% CI) were used to evaluate the association of regulator of telomere elongation helicase 1 rs6010620 polymorphism with glioma.<br><br>RESULTS: A significant association between regulator of telomere elongation helicase 1 rs6010620 polymorphism and glioma susceptibility was observed for GG vs. AA+AG (OR=1.28, 95% CI=1.14-1.43) and G vs. A (OR=1.07, 95% CI=1.03-1.10). Further subgroup analysis based on ethnicity showed similar results in Asians and Caucasians. In the subgroup analysis of source of control, a significant association between the G allele and glioma susceptibility were found in population-based group and hospital-based group.<br><br>CONCLUSIONS: The meta-analysis suggested that regulator of telomere elongation helicase 1 rs6010620 polymorphism was a risk factor for glioma. And this study also suggested that rs6010620 GG genotype and G allele may be indicators for the risk of glioma.},
}
@article {pmid25780774,
year = {2015},
author = {Wang, DT and He, J and Wu, M and Li, SM and Gao, Q and Zeng, QP},
title = {Artemisinin mimics calorie restriction to trigger mitochondrial biogenesis and compromise telomere shortening in mice.},
journal = {PeerJ},
volume = {3},
number = {},
pages = {e822},
pmid = {25780774},
issn = {2167-8359},
abstract = {Calorie restriction is known to extend lifespan among organisms by a debating mechanism underlying nitric oxide-driven mitochondrial biogenesis. We report here that nitric oxide generators including artemisinin, sodium nitroprusside, and L-arginine mimics calorie restriction and resembles hydrogen peroxide to initiate the nitric oxide signaling cascades and elicit the global antioxidative responses in mice. The large quantities of antioxidant enzymes are correlated with the low levels of reactive oxygen species, which allow the down-regulation of tumor suppressors and accessory DNA repair partners, eventually leading to the compromise of telomere shortening. Accompanying with the up-regulation of signal transducers and respiratory chain signatures, mitochondrial biogenesis occurs with the elevation of adenosine triphosphate levels upon exposure of mouse skeletal muscles to the mimetics of calorie restriction. In conclusion, calorie restriction-triggered nitric oxide provides antioxidative protection and alleviates telomere attrition via mitochondrial biogenesis, thereby maintaining chromosomal stability and integrity, which are the hallmarks of longevity.},
}
@article {pmid25778919,
year = {2015},
author = {Reyes, C and Serrurier, C and Gauthier, T and Gachet, Y and Tournier, S},
title = {Aurora B prevents chromosome arm separation defects by promoting telomere dispersion and disjunction.},
journal = {The Journal of cell biology},
volume = {208},
number = {6},
pages = {713-727},
pmid = {25778919},
issn = {1540-8140},
mesh = {Adenosine Triphosphatases/metabolism ; Aurora Kinases/*physiology ; Cell Cycle Proteins/metabolism ; Chromatin/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes, Fungal/*physiology ; DNA-Binding Proteins/metabolism ; Mitosis ; Multiprotein Complexes/metabolism ; Nondisjunction, Genetic ; Nuclear Proteins/metabolism ; Phosphoproteins/metabolism ; Phosphorylation ; Protein Processing, Post-Translational ; Schizosaccharomyces/cytology/*enzymology/genetics ; Schizosaccharomyces pombe Proteins/metabolism/*physiology ; Shelterin Complex ; Spindle Apparatus/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {The segregation of centromeres and telomeres at mitosis is coordinated at multiple levels to prevent the formation of aneuploid cells, a phenotype frequently observed in cancer. Mitotic instability arises from chromosome segregation defects, giving rise to chromatin bridges at anaphase. Most of these defects are corrected before anaphase onset by a mechanism involving Aurora B kinase, a key regulator of mitosis in a wide range of organisms. Here, we describe a new role for Aurora B in telomere dispersion and disjunction during fission yeast mitosis. Telomere dispersion initiates in metaphase, whereas disjunction takes place in anaphase. Dispersion is promoted by the dissociation of Swi6/HP1 and cohesin Rad21 from telomeres, whereas disjunction occurs at anaphase after the phosphorylation of condensin subunit Cnd2. Strikingly, we demonstrate that deletion of Ccq1, a telomeric shelterin component, rescued cell death after Aurora inhibition by promoting the loading of condensin on chromosome arms. Our findings reveal an essential role for telomeres in chromosome arm segregation.},
}
@article {pmid25775131,
year = {2015},
author = {Pariona-Llanos, R and Pavani, RS and Reis, M and Noël, V and Silber, AM and Armelin, HA and Cano, MI and Elias, MC},
title = {Glyceraldehyde 3-phosphate dehydrogenase-telomere association correlates with redox status in Trypanosoma cruzi.},
journal = {PloS one},
volume = {10},
number = {3},
pages = {e0120896},
pmid = {25775131},
issn = {1932-6203},
mesh = {Active Transport, Cell Nucleus ; Glyceraldehyde-3-Phosphate Dehydrogenases/*metabolism ; Models, Theoretical ; NAD/metabolism ; *Oxidation-Reduction ; Protein Binding ; Protein Transport ; Telomere/genetics/*metabolism ; Trypanosoma cruzi/genetics/growth &amp; development/*metabolism ; },
abstract = {Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a classical metabolic enzyme involved in energy production and plays a role in additional nuclear functions, including transcriptional control, recognition of misincorporated nucleotides in DNA and maintenance of telomere structure. Here, we show that the recombinant protein T. cruzi GAPDH (rTcGAPDH) binds single-stranded telomeric DNA. We demonstrate that the binding of GAPDH to telomeric DNA correlates with the balance between oxidized and reduced forms of nicotinamide adenine dinucleotides (NAD+/NADH). We observed that GAPDH-telomere association and NAD+/NADH balance changed throughout the T. cruzi life cycle. For example, in replicative epimastigote forms of T. cruzi, which show similar intracellular concentrations of NAD+ and NADH, GAPDH binds to telomeric DNA in vivo and this binding activity is inhibited by exogenous NAD+. In contrast, in the T. cruzi non-proliferative trypomastigote forms, which show higher NAD+ concentration, GAPDH was absent from telomeres. In addition, NAD+ abolishes physical interaction between recombinant GAPDH and synthetic telomere oligonucleotide in a cell free system, mimicking exogenous NAD+ that reduces GAPDH-telomere interaction in vivo. We propose that the balance in the NAD+/NADH ratio during T. cruzi life cycle homeostatically regulates GAPDH telomere association, suggesting that in trypanosomes redox status locally modulates GAPDH association with telomeric DNA.},
}
@article {pmid25774833,
year = {2015},
author = {Klutstein, M and Fennell, A and Fernández-Álvarez, A and Cooper, JP},
title = {The telomere bouquet regulates meiotic centromere assembly.},
journal = {Nature cell biology},
volume = {17},
number = {4},
pages = {458-469},
pmid = {25774833},
issn = {1476-4679},
support = {/WT_/Wellcome Trust/United Kingdom ; Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; ZIA BC011519/ImNIH/Intramural NIH HHS/United States ; /CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Centromere/*metabolism ; Chromosomal Proteins, Non-Histone/biosynthesis/genetics ; Heterochromatin/metabolism ; Histones/metabolism ; Kinetochores/metabolism ; Meiosis/*genetics ; Schizosaccharomyces/*genetics ; Schizosaccharomyces pombe Proteins/biosynthesis/genetics ; Spindle Apparatus/*genetics ; Telomere/*metabolism ; Telomere-Binding Proteins/biosynthesis/genetics ; },
abstract = {The role of the conserved meiotic telomere bouquet has been enigmatic for over a century. We showed previously that disruption of the fission yeast bouquet impairs spindle formation in approximately half of meiotic cells. Surprisingly, bouquet-deficient meiocytes with functional spindles harbour chromosomes that fail to achieve spindle attachment. Kinetochore proteins and the centromeric histone H3 variant Cnp1 fail to localize to those centromeres that exhibit spindle attachment defects in the bouquet's absence. The HP1 orthologue Swi6 also fails to bind these centromeres, suggesting that compromised pericentromeric heterochromatin underlies the kinetochore defects. We find that centromeres are prone to disassembly during meiosis, but this is reversed by localization of centromeres to the telomere-proximal microenvironment, which is conducive to heterochromatin formation and centromere reassembly. Accordingly, artificially tethering a centromere to a telomere rescues the tethered centromere but not other centromeres. These results reveal an unanticipated level of control of centromeres by telomeres.},
}
@article {pmid25774608,
year = {2015},
author = {Aviv, A and Kark, JD and Susser, E},
title = {Telomeres, atherosclerosis, and human longevity: a causal hypothesis.},
journal = {Epidemiology (Cambridge, Mass.)},
volume = {26},
number = {3},
pages = {295-299},
pmid = {25774608},
issn = {1531-5487},
support = {R01 AG030678/AG/NIA NIH HHS/United States ; R01 AG020132/AG/NIA NIH HHS/United States ; R01HD071180/HD/NICHD NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; R01AG030678/AG/NIA NIH HHS/United States ; },
mesh = {Aging/physiology ; Atherosclerosis/*etiology ; Humans ; Leukocytes/physiology ; *Longevity/physiology ; Models, Biological ; *Telomere Homeostasis/physiology ; },
}
@article {pmid25773002,
year = {2015},
author = {Wolkowitz, OM and Mellon, SH and Lindqvist, D and Epel, ES and Blackburn, EH and Lin, J and Reus, VI and Burke, H and Rosser, R and Mahan, L and Mackin, S and Yang, T and Weiner, M and Mueller, S},
title = {PBMC telomerase activity, but not leukocyte telomere length, correlates with hippocampal volume in major depression.},
journal = {Psychiatry research},
volume = {232},
number = {1},
pages = {58-64},
pmid = {25773002},
issn = {1872-7123},
support = {R01 MH083784/MH/NIMH NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; UL1RR024131/RR/NCRR NIH HHS/United States ; 1R01 MH083784/MH/NIMH NIH HHS/United States ; R01 MH098062/MH/NIMH NIH HHS/United States ; R01 MH085734/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Cellular Senescence/physiology ; Depressive Disorder, Major/enzymology/*pathology ; Female ; Hippocampus/*pathology ; Humans ; Leukocytes/metabolism ; Leukocytes, Mononuclear/*enzymology ; Male ; Middle Aged ; Organ Size/physiology ; Telomerase/*metabolism ; *Telomere ; },
abstract = {Accelerated cell aging, indexed in peripheral leukocytes by telomere shortness and in peripheral blood mononuclear cells (PBMCs) by telomerase activity, has been reported in several studies of major depressive disorder (MDD). However, the relevance of these peripheral measures for brain indices that are presumably more directly related to MDD pathophysiology is unknown. In this study, we explored the relationship between PBMC telomerase activity and leukocyte telomere length and magnetic resonance imaging-estimated hippocampal volume in un-medicated depressed individuals and healthy controls. We predicted that, to the extent peripheral and central telomerase activity are directly related, PBMC telomerase activity would be positively correlated with hippocampal volume, perhaps due to hippocampal telomerase-associated neurogenesis, neuroprotection or neurotrophic facilitation, and that this effect would be clearer in individuals with increased PBMC telomerase activity, as previously reported in un-medicated MDD. We did not have specific hypotheses regarding the relationship between leukocyte telomere length and hippocampal volume, due to conflicting reports in the published literature. We found, in 25 un-medicated MDD subjects, that PBMC telomerase activity was significantly positively correlated with hippocampal volume; this relationship was not observed in 18 healthy controls. Leukocyte telomere length was not significantly related to hippocampal volume in either group (19 unmedicated MDD subjects and 17 healthy controls). Although the nature of the relationship between peripheral telomerase activity and telomere length and the hippocampus is unclear, these preliminary data are consistent with the possibility that PBMC telomerase activity indexes, and may provide a novel window into, hippocampal neuroprotection and/or neurogenesis in MDD.},
}
@article {pmid25771980,
year = {2015},
author = {Gonzalez-Vasconcellos, I and Alonso-Rodríguez, S and López-Baltar, I and Fernández, JL},
title = {Telomere Chromatin Condensation Assay (TCCA): a novel approach to study structural telomere integrity.},
journal = {Mutation research},
volume = {771},
number = {},
pages = {51-55},
doi = {10.1016/j.mrfmmm.2014.12.004},
pmid = {25771980},
issn = {1873-135X},
mesh = {Animals ; Antimetabolites, Antineoplastic/pharmacology ; Azacitidine/pharmacology ; Cell Line, Transformed ; Cell Line, Tumor ; Chromatin/*chemistry/genetics/pathology ; *Chromatin Assembly and Disassembly ; DNA/*chemistry/genetics/metabolism ; Deoxyribonucleases/*chemistry ; Humans ; Mice ; Mice, Inbred BALB C ; Polymerase Chain Reaction/*methods ; Telomere/*chemistry/genetics/metabolism ; },
abstract = {Telomeres, the DNA-protein complexes located at the end of linear eukaryotic chromosomes are essential for genome stability. Improper higher-order chromatin organization at the chromosome ends can give rise to telomeric recombination and genomic instability. We report the development of an assay to quantify differences in the condensation of telomeric chromatin, thereby offering new opportunities to study telomere biology and stability. We have combined a DNA nuclease digestion with a quantitative PCR (qPCR) assay of telomeric DNA, which we term the Telomere Chromatin Condensation Assay (TCCA). By quantifying the relative quantities of telomeric DNA that are progressively digested with the exonuclease Bal 31 the method can discriminate between different levels of telomeric chromatin condensation. The structural chromatin packaging at telomeres shielded against exonuclease digestion delivered an estimate, which we term Chromatin Protection Factor (CPF) that ranged from 1.7 to 2.3 fold greater than that present in unpacked DNA. The CPF was significantly decreased when cell cultures were incubated with the DNA hypomethylating agent 5-azacytidine, demonstrating the ability of the TCCA assay to discriminate between packaging levels of telomeric DNA.},
}
@article {pmid25771869,
year = {2014},
author = {M'kacher, R and Maalouf, EE and Ricoul, M and Heidingsfelder, L and Laplagne, E and Cuceu, C and Hempel, WM and Colicchio, B and Dieterlen, A and Sabatier, L},
title = {New tool for biological dosimetry: reevaluation and automation of the gold standard method following telomere and centromere staining.},
journal = {Mutation research},
volume = {770},
number = {},
pages = {45-53},
doi = {10.1016/j.mrfmmm.2014.09.007},
pmid = {25771869},
issn = {1873-135X},
mesh = {Adult ; Blood Cells/metabolism/radiation effects ; *Centromere/radiation effects ; Chromosome Aberrations/radiation effects ; Dose-Response Relationship, Radiation ; Electronic Data Processing ; Female ; Humans ; Male ; Middle Aged ; Radiation, Ionizing ; Radiometry/instrumentation/*methods/standards ; Staining and Labeling/*methods ; *Telomere/radiation effects ; Young Adult ; },
abstract = {PURPOSE: The dicentric chromosome (dicentric) assay is the international gold-standard method for biological dosimetry and classification of genotoxic agents. The introduction of telomere and centromere (TC) staining offers the potential to render dicentric scoring more efficient and robust. In this study, we improved the detection of dicentrics and all unstable chromosomal aberrations (CA) leading to a significant reevaluation of the dose-effect curve and developed an automated approach following TC staining.<br><br>MATERIAL AND METHODS: Blood samples from 16 healthy donors were exposed to (137)Cs at 8 doses from 0.1 to 6Gy. CA were manually and automatically scored following uniform (Giemsa) or TC staining. The detection of centromeric regions and telomeric sequences using PNA probes allowed the detection of all unstable CA: dicentrics, centric and acentric rings, and all acentric fragments (with 2, 4 or no telomeres) leading to the precise quantification of estimated double strand breaks (DSB).<br><br>RESULTS: Manual scoring following TC staining revealed a significantly higher frequency of dicentrics (p<10(-3)) (up to 30%) and estimated DSB (p<10(-4)) compared to uniform staining due to improved detection of dicentrics with centromeres juxtaposed with other centromeres or telomeres. This improvement permitted the development of the software, TCScore, that detected 95% of manually scored dicentrics compared to 50% for the best currently available software (DCScore&#x2122;).<br><br>CONCLUSION: The use of TC staining has permitted a reevaluation of the dose-response curve and the highly efficient automation of the scoring process, marking a new step in the management and follow-up of populations exposed to genotoxic agents including ionizing radiation.},
}
@article {pmid25771075,
year = {2015},
author = {Boscolo-Rizzo, P and Rampazzo, E and Perissinotto, E and Piano, MA and Giunco, S and Baboci, L and Spinato, G and Spinato, R and Tirelli, G and Da Mosto, MC and Del Mistro, A and De Rossi, A},
title = {Telomere shortening in mucosa surrounding the tumor: biosensor of field cancerization and prognostic marker of mucosal failure in head and neck squamous cell carcinoma.},
journal = {Oral oncology},
volume = {51},
number = {5},
pages = {500-507},
doi = {10.1016/j.oraloncology.2015.02.100},
pmid = {25771075},
issn = {1879-0593},
mesh = {Biomarkers, Tumor/*metabolism ; *Biosensing Techniques ; Carcinoma, Squamous Cell/*metabolism/pathology ; Head and Neck Neoplasms/*metabolism/pathology ; Humans ; Mucous Membrane/*metabolism ; Prognosis ; Telomerase/metabolism ; *Telomere ; },
abstract = {OBJECTIVES: The aim of the present study was to investigate the pattern of telomere length and telomerase expression in cancer tissues and the surrounding mucosa (SM), as markers of field cancerization and clinical outcome in patients successfully treated for with head and neck squamous cell carcinoma (HNSCC).<br><br>MATERIALS AND METHODS: This investigation was a prospective cohort study. Telomere length and levels of telomerase reverse transcriptase (TERT) transcripts were quantified by real-time PCR in cancer tissues and SM from 139 and 90 patients with HNSCC, respectively.<br><br>RESULTS: No correlation was found between age and telomere length in SM. Patients with short telomeres in SM had a higher risk of mucosal failure (adjusted HR=4.29). Patients with high TERT levels in cancer tissues had a higher risk of regional failure (HR=2.88), distant failure (HR=7.27), worse disease-specific survival (HR for related death=2.62) but not mucosal failure. High-risk patients having both short telomeres in SM and high levels of TERT in cancer showed a significantly lower overall survival (HR=2.46).<br><br>CONCLUSIONS: Overall these findings suggest that telomere shortening in SM is a marker of field cancerization and may precede reactivation of TERT. Short telomeres in SM are strongly prognostic of mucosal failure, whereas TERT levels in cancer tissues increase with the aggressiveness of the disease and are prognostic of tumor spread.},
}
@article {pmid25770094,
year = {2015},
author = {Hjelmborg, JB and Dalgård, C and Möller, S and Steenstrup, T and Kimura, M and Christensen, K and Kyvik, KO and Aviv, A},
title = {The heritability of leucocyte telomere length dynamics.},
journal = {Journal of medical genetics},
volume = {52},
number = {5},
pages = {297-302},
pmid = {25770094},
issn = {1468-6244},
support = {R01 AG030678/AG/NIA NIH HHS/United States ; AG030678/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Biometry ; Female ; Follow-Up Studies ; Humans ; *Leukocytes ; Male ; Middle Aged ; Registries ; Telomere/*genetics/*metabolism ; *Telomere Homeostasis ; Twins/genetics ; Young Adult ; },
abstract = {BACKGROUND: Leucocyte telomere length (LTL) is a complex trait associated with ageing and longevity. LTL dynamics are defined by LTL and its age-dependent attrition. Strong, but indirect evidence suggests that LTL at birth and its attrition during childhood largely explains interindividual LTL variation among adults. A number of studies have estimated the heritability of LTL, but none has assessed the heritability of age-dependent LTL attrition.<br><br>METHODS: We examined the heritability of LTL dynamics based on a longitudinal evaluation (an average follow-up of 12 years) in 355 monozygotic and 297 dizygotic same-sex twins (aged 19-64 years at baseline).<br><br>RESULTS: Heritability of LTL at baseline was estimated at 64% (95% CI 39% to 83%) with 22% (95% CI 6% to 49%) of shared environmental effects. Heritability of age-dependent LTL attrition rate was estimated at 28% (95% CI 16% to 44%). Individually unique environmental factors, estimated at 72% (95% CI 56% to 84%) affected LTL attrition rate with no indication of shared environmental effects.<br><br>CONCLUSIONS: This is the first study that estimated heritability of LTL and also its age-dependent attrition. As LTL attrition is much slower in adults than in children and given that having a long or a short LTL is largely determined before adulthood, our findings suggest that heritability and early life environment are the main determinants of LTL throughout the human life course. Thus, insights into factors that influence LTL at birth and its dynamics during childhood are crucial for understanding the role of telomere genetics in human ageing and longevity.},
}
@article {pmid25769384,
year = {2015},
author = {Pal, D and Sharma, U and Khajuria, R and Singh, SK and Kakkar, N and Prasad, R},
title = {Augmented telomerase activity, reduced telomere length and the presence of alternative lengthening of telomere in renal cell carcinoma: plausible predictive and diagnostic markers.},
journal = {Gene},
volume = {562},
number = {2},
pages = {145-151},
doi = {10.1016/j.gene.2015.02.079},
pmid = {25769384},
issn = {1879-0038},
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/genetics/*metabolism ; Carcinoma, Renal Cell/*enzymology/genetics/pathology ; Female ; Humans ; Kidney Neoplasms/*enzymology/genetics/pathology ; Male ; Middle Aged ; Prognosis ; Telomerase/*metabolism ; *Telomere Homeostasis ; },
abstract = {In this study, we analyzed 100 cases of renal cell carcinoma (RCC) for telomerase activity, telomere length and alternative lengthening of telomeres (ALT) using the TRAP assay, TeloTTAGGG assay kit and immunohistochemical analysis of ALT associated promyelocytic leukemia (PML) bodies respectively. A significantly higher (P=0.000) telomerase activity was observed in 81 cases of RCC which was correlated with clinicopathological features of tumor for instance, stage (P=0.008) and grades (P=0.000) but not with the subtypes of RCC (P = 0.355). Notwithstanding, no correlation was found between telomerase activity and subtypes of RCC. Strikingly, the telomere length was found to be significantly shorter in RCC (P=0.000) to that of corresponding normal renal tissues and it is well correlated with grades (P=0.016) but not with stages (P=0.202) and subtypes (P=0.669) of RCC. In this study, telomere length was also negatively correlated with the age of patients (r(2)=0.528; P=0.000) which supports the notion that it could be used as a marker for biological aging. ALT associated PML bodies containing PML protein was found in telomerase negative cases of RCC. It suggests the presence of an ALT pathway mechanism to maintain the telomere length in telomerase negative RCC tissues which was associated with high stages of RCC, suggesting a prevalent mechanism for telomere maintenance in high stages. In conclusion, the telomerase activity and telomere length can be used as a diagnostic as well as a predictive marker in RCC. The prevalence of ALT mechanism in high stages of RCC is warranted for the development of anti-ALT inhibitors along with telomerase inhibitor against RCC as a therapeutic approach.},
}
@article {pmid25768204,
year = {2015},
author = {An, N and Fleming, AM and White, HS and Burrows, CJ},
title = {Nanopore detection of 8-oxoguanine in the human telomere repeat sequence.},
journal = {ACS nano},
volume = {9},
number = {4},
pages = {4296-4307},
pmid = {25768204},
issn = {1936-086X},
support = {R01 GM093099/GM/NIGMS NIH HHS/United States ; },
mesh = {Crown Ethers/chemistry ; G-Quadruplexes ; Guanine/*analogs &amp; derivatives/analysis/chemistry ; Hemolysin Proteins/chemistry ; Humans ; Kinetics ; Nanomedicine ; *Nanopores ; Nanotechnology/*methods ; *Repetitive Sequences, Nucleic Acid ; Singlet Oxygen/pharmacology ; Telomere/chemistry/*genetics ; },
abstract = {The human telomere repeat sequence 5'-TTAGGG-3' is a hot spot for oxidation at guanine, yielding 8-oxo-7,8-dihydroguanine (OG), a biomarker of oxidative stress. Telomere shortening resulting from oxidation will ultimately induce cellular senescence. In this study, α-hemolysin (α-HL) nanopore technology was applied to detect and quantify OG in the human telomeric DNA sequence. This repeat sequence adopts a basket G-quadruplex in the NaCl electrolyte used for analysis that enters the α-HL channel, slowly unfolds, and translocates. The basket fold containing OG disrupts the structure, leading to >10× increase in the unfolding kinetics without yielding a detectable current pattern. Therefore, detection of OG with α-HL required labeling of OG with aminomethyl-[18-crown-6] using a mild oxidant. The labeled OG yielded a pulse-like signal in the current vs time trace when the DNA strand was electrophoretically passed through α-HL in NaCl electrolyte. However, the rate of translocation was too slow using NaCl salts, leading us to further refine the method. A mixture of NH4Cl and LiCl electrolytes induced the propeller fold that unravels quickly outside the α-HL channel. This electrolyte allowed observation of the labeled OG, while providing a faster recording of the currents. Lastly, OG distributions were probed with this method in a 120-mer stretch of the human telomere sequence exposed to the cellular oxidant (1)O2. Single-molecule profiles determined the OG distributions to be random in this context. Application of the method in nanomedicine can potentially address many questions surrounding oxidative stress and telomere attrition observed in various disease phenotypes including prostate cancer and diabetes.},
}
@article {pmid25767920,
year = {2015},
author = {Stanley, SE and Noth, I and Armanios, M},
title = {What the genetics "RTEL"ing us about telomeres and pulmonary fibrosis.},
journal = {American journal of respiratory and critical care medicine},
volume = {191},
number = {6},
pages = {608-610},
pmid = {25767920},
issn = {1535-4970},
support = {T32 GM007309/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Helicases/*genetics ; Female ; Humans ; Lung Diseases, Interstitial/*genetics ; Male ; },
}
@article {pmid25766694,
year = {2015},
author = {Badie, S and Carlos, AR and Folio, C and Okamoto, K and Bouwman, P and Jonkers, J and Tarsounas, M},
title = {BRCA1 and CtIP promote alternative non-homologous end-joining at uncapped telomeres.},
journal = {The EMBO journal},
volume = {34},
number = {6},
pages = {828},
doi = {10.15252/embj.201570610},
pmid = {25766694},
issn = {1460-2075},
}
@article {pmid25758014,
year = {2015},
author = {Badás, EP and Martínez, J and Rivero de Aguilar Cachafeiro, J and Miranda, F and Figuerola, J and Merino, S},
title = {Ageing and reproduction: antioxidant supplementation alleviates telomere loss in wild birds.},
journal = {Journal of evolutionary biology},
volume = {28},
number = {4},
pages = {896-905},
doi = {10.1111/jeb.12615},
pmid = {25758014},
issn = {1420-9101},
mesh = {Aging/drug effects/*genetics ; Animals ; Antimalarials/pharmacology ; Antioxidants/*pharmacology ; Body Weight/drug effects ; Male ; Parasite Load ; Passeriformes/parasitology/*physiology ; Reproduction/*physiology ; Spain ; Telomere/*drug effects ; },
abstract = {Reproduction is inherently costly. Environmental stressors, such as infection and limited food resources, can compromise investment at each breeding attempt. For example, recent data on captive birds showed that increased reproductive effort accelerates ageing. However, the effects of nutritional status and infection on ageing remain unknown. Telomeres function as protective caps at the ends of eukaryotic chromosomes, and changes in telomere length is a commonly used proxy for ageing. To partially address the mechanisms of ageing following reproduction, we supplemented, medicated or administered a combined treatment to wild blue tits (Cyanistes caeruleus) breeding in central Spain during 2012. The nutritional supplement consisted of two different antioxidants, whereas the medication was an antimalarial treatment against blood parasites. We evaluated the effect of these manipulations on reproductive success and parasite loads in the first breeding season, and on changes in telomere length between two consecutive breeding seasons. Supplemented birds showed no reduction in blood parasite infections in 2012, although they exhibited higher body mass and fledging success. The antimalarial drugs reduced infections by several parasite species, but this had no effect on fitness parameters. In the following season, telomeres from supplemented birds had shortened less. Altogether, we found that supplementation with antioxidants provided fitness benefits in the short term and reduced telomere loss a year following treatment. Our results provide indirect empirical support for accelerated telomere loss as a cost of reproduction.},
}
@article {pmid25757675,
year = {2015},
author = {Eisenberg, DT and Kuzawa, CW and Hayes, MG},
title = {Improving qPCR telomere length assays: Controlling for well position effects increases statistical power.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {27},
number = {4},
pages = {570-575},
pmid = {25757675},
issn = {1520-6300},
support = {DK078150/DK/NIDDK NIH HHS/United States ; P30 ES010126/ES/NIEHS NIH HHS/United States ; P2C HD042828/HD/NICHD NIH HHS/United States ; ES10126/ES/NIEHS NIH HHS/United States ; P20 RR020649/RR/NCRR NIH HHS/United States ; R01 TW005596/TW/FIC NIH HHS/United States ; TW05596/TW/FIC NIH HHS/United States ; RR20649/RR/NCRR NIH HHS/United States ; P30 DK056350/DK/NIDDK NIH HHS/United States ; DK056350/DK/NIDDK NIH HHS/United States ; R24 HD042828/HD/NICHD NIH HHS/United States ; R01 DK078150/DK/NIDDK NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Factors ; Child ; Child, Preschool ; Cohort Studies ; Humans ; Infant ; Infant, Newborn ; Models, Genetic ; Models, Statistical ; Philippines ; Polymerase Chain Reaction/*methods ; Telomere/*physiology ; *Telomere Homeostasis ; Young Adult ; },
abstract = {OBJECTIVES: Telomere length (TL) is commonly measured using quantitative PCR (qPCR). Although, easier than the southern blot of terminal restriction fragments (TRF) TL measurement method, one drawback of qPCR is that it introduces greater measurement error and thus reduces the statistical power of analyses. To address a potential source of measurement error, we consider the effect of well position on qPCR TL measurements.<br><br>METHODS: qPCR TL data from 3,638 people run on a Bio-Rad iCycler iQ are reanalyzed here. To evaluate measurement validity, correspondence with TRF, age, and between mother and offspring are examined.<br><br>RESULTS: First, we present evidence for systematic variation in qPCR TL measurements in relation to thermocycler well position. Controlling for these well-position effects consistently improves measurement validity and yields estimated improvements in statistical power equivalent to increasing sample sizes by 16%. We additionally evaluated the linearity of the relationships between telomere and single copy gene control amplicons and between qPCR and TRF measures. We find that, unlike some previous reports, our data exhibit linear relationships. We introduce the standard error in percent, a superior method for quantifying measurement error as compared to the commonly used coefficient of variation. Using this measure, we find that excluding samples with high measurement error does not improve measurement validity in our study.<br><br>CONCLUSIONS: Future studies using block-based thermocyclers should consider well position effects. Since additional information can be gleaned from well position corrections, rerunning analyses of previous results with well position correction could serve as an independent test of the validity of these results.},
}
@article {pmid25757415,
year = {2015},
author = {Minton, K},
title = {Genome instability: Targeted telomere insertion.},
journal = {Nature reviews. Molecular cell biology},
volume = {16},
number = {4},
pages = {203},
pmid = {25757415},
issn = {1471-0080},
mesh = {*Genomic Instability ; Humans ; Neoplasms/*genetics ; Receptors, N-Methyl-D-Aspartate/*metabolism ; Telomere/*metabolism ; },
}
@article {pmid25756235,
year = {2015},
author = {Bijnens, E and Zeegers, MP and Gielen, M and Kicinski, M and Hageman, GJ and Pachen, D and Derom, C and Vlietinck, R and Nawrot, TS},
title = {Lower placental telomere length may be attributed to maternal residential traffic exposure; a twin study.},
journal = {Environment international},
volume = {79},
number = {},
pages = {1-7},
doi = {10.1016/j.envint.2015.02.008},
pmid = {25756235},
issn = {1873-6750},
mesh = {Adult ; Air Pollution/*adverse effects/statistics &amp; numerical data ; Belgium ; Environmental Exposure/*adverse effects ; Female ; Free Radicals/toxicity ; Humans ; Infant, Newborn ; Male ; Maternal Exposure/*adverse effects ; Placenta/*physiology ; Pregnancy ; Prospective Studies ; Telomere Shortening/*physiology ; Vehicle Emissions/*toxicity ; Young Adult ; },
abstract = {BACKGROUND: High variation in telomere length between individuals is already present before birth and is as wide among newborns as in adults. Environmental exposures likely have an impact on this observation, but remain largely unidentified. We hypothesize that placental telomere length in twins is associated with residential traffic exposure, an important environmental source of free radicals that might accelerate aging. Next, we intend to unravel the nature-nurture contribution to placental telomere length by estimating the heritability of placental telomere length.<br><br>METHODS: We measured the telomere length in placental tissues of 211 twins in the East Flanders Prospective Twin Survey. Maternal traffic exposure was determined using a geographic information system. Additionally, we estimated the relative importance of genetic and environmental sources of variance.<br><br>RESULTS: In this twin study, a variation in telomere length in the placental tissue was mainly determined by the common environment. Maternal residential proximity to a major road was associated with placental telomere length: a doubling in the distance to the nearest major road was associated with a 5.32% (95% CI: 1.90 to 8.86%; p=0.003) longer placental telomere length at birth. In addition, an interquartile increase (22%) in maternal residential surrounding greenness (5 km buffer) was associated with an increase of 3.62% (95% CI: 0.20 to 7.15%; p=0.04) in placental telomere length.<br><br>CONCLUSIONS: In conclusion, we showed that maternal residential proximity to traffic and lower residential surrounding greenness is associated with shorter placental telomere length at birth. This may explain a significant proportion of air pollution-related adverse health outcomes starting from early life, since shortened telomeres accelerate the progression of many diseases.},
}
@article {pmid25753893,
year = {2015},
author = {Luo, Z and Feng, X and Wang, H and Xu, W and Zhao, Y and Ma, W and Jiang, S and Liu, D and Huang, J and Songyang, Z},
title = {Mir-23a induces telomere dysfunction and cellular senescence by inhibiting TRF2 expression.},
journal = {Aging cell},
volume = {14},
number = {3},
pages = {391-399},
pmid = {25753893},
issn = {1474-9726},
support = {P30 CA125123/CA/NCI NIH HHS/United States ; R01 GM095599/GM/NIGMS NIH HHS/United States ; GM095599/GM/NIGMS NIH HHS/United States ; P30CA125123/CA/NCI NIH HHS/United States ; },
mesh = {Cell Proliferation/*physiology ; Cellular Senescence/*genetics ; DNA Damage/genetics ; Fibroblasts/metabolism ; Humans ; MicroRNAs/*genetics ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {Telomeric repeat binding factor 2 (TRF2) is essential for telomere maintenance and has been implicated in DNA damage response and aging. Telomere dysfunction induced by TRF2 inhibition can accelerate cellular senescence in human fibroblasts. While previous work has demonstrated that a variety of factors can regulate TRF2 expression transcriptionally and post-translationally, whether microRNAs (miRNAs) also participate in post-transcriptionally modulating TRF2 levels remains largely unknown. To better understand the regulatory pathways that control TRF2, we carried out a large-scale luciferase reporter screen using a miRNA expression library and identified four miRNAs that could target human TRF2 and significantly reduce the level of endogenous TRF2 proteins. In particular, our data revealed that miR-23a could directly target the 3' untranslated region (3'UTR) of TRF2. Overexpression of miR-23a not only reduced telomere-bound TRF2 and increased telomere dysfunction-induced foci (TIFs), but also accelerated senescence of human fibroblast cells, which could be rescued by ectopically expressed TRF2. Our findings demonstrate that TRF2 is a specific target of miR-23a, and uncover a previously unknown role for miR-23a in telomere regulation and cellular senescence.},
}
@article {pmid25752831,
year = {2015},
author = {Dan, J and Yang, J and Liu, Y and Xiao, A and Liu, L},
title = {Roles for Histone Acetylation in Regulation of Telomere Elongation and Two-cell State in Mouse ES Cells.},
journal = {Journal of cellular physiology},
volume = {230},
number = {10},
pages = {2337-2344},
pmid = {25752831},
issn = {1097-4652},
support = {R01 GM114205/GM/NIGMS NIH HHS/United States ; },
mesh = {Acetylation ; Animals ; DNA Methylation/physiology ; Embryonic Stem Cells/*cytology/metabolism ; Epigenesis, Genetic/genetics ; Histone Acetyltransferases/*metabolism ; Histones/*metabolism ; Mice ; RNA/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {Mammalian telomeres and subtelomeres are marked by heterochromatic epigenetic modifications, including repressive DNA methylation and histone methylation (e.g., H3K9me3 and H4K20me3). Loss of these epigenetic marks results in increased rates of telomere recombination and elongation. Other than these repressive epigenetic marks, telomeric and subtelomeric H3 and H4 are underacetylated. Yet, whether histone acetylation also regulates telomere length has not been directly addressed. We thought to test the effects of histone acetylation levels on telomere length using histone deacetylase (HDAC) inhibitor (sodium butyrate, NaB) that mediates histone hyperacetylation and histone acetyltransferase (HAT) inhibitor (C646) that mediates histone hypoacetylation. We show that histone hyperacetylation dramatically elongates telomeres in wild-type ES cells, and only slightly elongates telomeres in Terc(-/-) ES cells, suggesting that Terc is involved in histone acetylation-induced telomere elongation. In contrast, histone hypoacetylation shortens telomeres in both wild-type and Terc(-/-) ES cells. Additionally, histone hyperacetylation activates 2-cell (2C) specific genes including Zscan4, which is involved in telomere recombination and elongation, whereas histone hypoacetylation represses Zscan4 and 2C genes. These data suggest that histone acetylation levels affect the heterochromatic state at telomeres and subtelomeres, and regulate gene expression at subtelomeres, linking histone acetylation to telomere length maintenance.},
}
@article {pmid25752316,
year = {2015},
author = {Dvořáčková, M and Fojtová, M and Fajkus, J},
title = {Chromatin dynamics of plant telomeres and ribosomal genes.},
journal = {The Plant journal : for cell and molecular biology},
volume = {83},
number = {1},
pages = {18-37},
doi = {10.1111/tpj.12822},
pmid = {25752316},
issn = {1365-313X},
mesh = {Chromatin/*chemistry/metabolism ; DNA Replication ; DNA, Plant/chemistry/metabolism ; DNA, Ribosomal/chemistry/*metabolism ; Epigenesis, Genetic ; Genomic Instability ; Histones/genetics/metabolism ; Plants/*genetics ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres and genes encoding 45S ribosomal RNA (rDNA) are frequently located adjacent to each other on eukaryotic chromosomes. Although their primary roles are different, they show striking similarities with respect to their features and additional functions. Both genome domains have remarkably dynamic chromatin structures. Both are hypersensitive to dysfunctional histone chaperones, responding at the genomic and epigenomic levels. Both generate non-coding transcripts that, in addition to their epigenetic roles, may induce gross chromosomal rearrangements. Both give rise to chromosomal fragile sites, as their replication is intrinsically problematic. However, at the same time, both are essential for maintenance of genomic stability and integrity. Here we discuss the structural and functional inter-connectivity of telomeres and rDNA, with a focus on recent results obtained in plants.},
}
@article {pmid25752197,
year = {2015},
author = {Simpson, K and Jones, RE and Grimstead, JW and Hills, R and Pepper, C and Baird, DM},
title = {Telomere fusion threshold identifies a poor prognostic subset of breast cancer patients.},
journal = {Molecular oncology},
volume = {9},
number = {6},
pages = {1186-1193},
pmid = {25752197},
issn = {1878-0261},
support = {C17199/A13490//Cancer Research UK/United Kingdom ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; Breast Neoplasms/genetics/*metabolism/*mortality/pathology ; Disease-Free Survival ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Survival Rate ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; },
abstract = {Telomere dysfunction and fusion can drive genomic instability and clonal evolution in human tumours, including breast cancer. Telomere length is a critical determinant of telomere function and has been evaluated as a prognostic marker in several tumour types, but it has yet to be used in the clinical setting. Here we show that high-resolution telomere length analysis, together with a specific telomere fusion threshold, is highly prognostic for overall survival in a cohort of patients diagnosed with invasive ductal carcinoma of the breast (n = 120). The telomere fusion threshold defined a small subset of patients with an extremely poor clinical outcome, with a median survival of less than 12 months (HR = 21.4 (7.9-57.6), P < 0.0001). Furthermore, this telomere length threshold was independent of ER, PGR, HER2 status, NPI, or grade and was the dominant variable in multivariate analysis. We conclude that the fusogenic telomere length threshold provides a powerful, independent prognostic marker with clinical utility in breast cancer. Larger prospective studies are now required to determine the optimal way to incorporate high-resolution telomere length analysis into multivariate prognostic algorithms for patients diagnosed with breast cancer.},
}
@article {pmid25751002,
year = {2015},
author = {Mar, FA and Debnath, J and Stohr, BA},
title = {Autophagy-independent senescence and genome instability driven by targeted telomere dysfunction.},
journal = {Autophagy},
volume = {11},
number = {3},
pages = {527-537},
pmid = {25751002},
issn = {1554-8635},
support = {K08 CA134552/CA/NCI NIH HHS/United States ; R01 CA188404/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; *Autophagy ; Autophagy-Related Protein 5 ; Autophagy-Related Protein 7 ; Cell Proliferation ; *Cellular Senescence ; Chromosomes/ultrastructure ; DNA Repair ; Enzyme-Linked Immunosorbent Assay ; Fibroblasts/metabolism ; *Genomic Instability ; Genomics ; Humans ; In Situ Hybridization, Fluorescence ; Interleukin-6/metabolism ; Interleukin-8/metabolism ; Mice ; Mice, Knockout ; Microscopy, Fluorescence ; Microtubule-Associated Proteins/genetics ; Phenotype ; Shelterin Complex ; Telomere/*ultrastructure ; Telomere-Binding Proteins ; },
abstract = {Telomere dysfunction plays a complex role in tumorigenesis. While dysfunctional telomeres can block the proliferation of incipient cancer clones by inducing replicative senescence, fusion of dysfunctional telomeres can drive genome instability and oncogenic genomic rearrangements. Therefore, it is important to define the regulatory pathways that guide these opposing effects. Recent work has shown that the autophagy pathway regulates both senescence and genome instability in various contexts. Here, we apply models of acute telomere dysfunction to determine whether autophagy modulates the resulting genome instability and senescence responses. While telomere dysfunction rapidly induces autophagic flux in human fibroblast cell lines, inhibition of the autophagy pathway does not have a significant impact upon the transition to senescence, in contrast to what has previously been reported for oncogene-induced senescence. Our results suggest that this difference may be explained by disparities in the development of the senescence-associated secretory phenotype. We also show that chromosome fusions induced by telomere dysfunction are comparable in autophagy-proficient and autophagy-deficient cells. Altogether, our results highlight the complexity of the senescence-autophagy interface and indicate that autophagy induction is unlikely to play a significant role in telomere dysfunction-driven senescence and chromosome fusions.},
}
@article {pmid25750063,
year = {2015},
author = {Gu, Y and Honig, LS and Schupf, N and Lee, JH and Luchsinger, JA and Stern, Y and Scarmeas, N},
title = {Mediterranean diet and leukocyte telomere length in a multi-ethnic elderly population.},
journal = {Age (Dordrecht, Netherlands)},
volume = {37},
number = {2},
pages = {24},
pmid = {25750063},
issn = {1574-4647},
support = {K99AG042483/AG/NIA NIH HHS/United States ; K99 AG042483/AG/NIA NIH HHS/United States ; P01AG07232/AG/NIA NIH HHS/United States ; P60 MD000206/MD/NIMHD NIH HHS/United States ; P60MD000206/MD/NIMHD NIH HHS/United States ; P01 AG007232/AG/NIA NIH HHS/United States ; R01AG028506/AG/NIA NIH HHS/United States ; R01AG037212/AG/NIA NIH HHS/United States ; R01 AG037212/AG/NIA NIH HHS/United States ; R01 AG028506/AG/NIA NIH HHS/United States ; },
mesh = {Black or African American ; Aged ; Aged, 80 and over ; Cross-Sectional Studies ; *Diet, Mediterranean ; Ethnicity ; Female ; Health Behavior ; Hispanic or Latino ; Humans ; Life Style ; Male ; Patient Compliance ; Telomere Homeostasis/*physiology ; White People ; },
abstract = {Leukocyte telomere length (LTL) is considered as the marker of biological aging and may be related to environmental factors. The current study aimed to examine the relation between Mediterranean-type diet and LTL. We used a cross-sectional study of 1743 multi-ethnic community residents of New York aged 65 years or older. Mediterranean-type diet (MeDi) was calculated from dietary information collected using a food frequency questionnaire. LTL was measured from leukocyte DNA using a real-time PCR method to measure T/S ratio, the ratio of telomere (T) to single-copy gene (S) sequence. Regression analysis showed that the MeDi score was not associated with LTL in the overall study population (β = 12.5; p = 0.32) after adjusting for age, sex, education, ethnicity, caloric intake, smoking, and physical and leisure activities. However, we found a significant association between MeDi and LTL among non-Hispanic whites (β = 48.3; p = 0.05), and the results held after excluding dementia subjects (β = 49.6; p = 0.05). We further found that, in the whole population, vegetable and cereal consumption above the sex-specific population median was associated with longer LTL (β = 89.1, p = 0.04) and shorter LTL (β = -93.5; p = 0.03), respectively. Among non-Hispanic whites, intake of meat or dairy below sex-specific population medians was associated with longer LTL (β = 154.7, p = 0.05; β = 240.5, p < 0.001, respectively). We found that higher adherence to a MeDi was associated with longer LTL among whites but not among African Americans and Hispanics. Additionally, a diet high in vegetables but low in cereal, meat, and dairy might be associated with longer LTL among healthy elderly.},
}
@article {pmid25749099,
year = {2016},
author = {Tyrka, AR and Parade, SH and Price, LH and Kao, HT and Porton, B and Philip, NS and Welch, ES and Carpenter, LL},
title = {Alterations of Mitochondrial DNA Copy Number and Telomere Length With Early Adversity and Psychopathology.},
journal = {Biological psychiatry},
volume = {79},
number = {2},
pages = {78-86},
pmid = {25749099},
issn = {1873-2402},
support = {IK2 CX000724/CX/CSRD VA/United States ; R01 MH068767/MH/NIMH NIH HHS/United States ; R21 MH091508/MH/NIMH NIH HHS/United States ; R01 MH068767-08S1/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aging/genetics ; Anxiety Disorders/*epidemiology ; Biomarkers/metabolism ; Cellular Senescence/genetics ; Child Abuse ; DNA Copy Number Variations/*genetics ; DNA, Mitochondrial/*genetics ; Depressive Disorder, Major/*epidemiology ; Female ; Humans ; Male ; Middle Aged ; Parental Death ; Psychiatric Status Rating Scales ; Stress, Psychological/*genetics ; Substance-Related Disorders/*epidemiology ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {BACKGROUND: Telomere shortening and alterations of mitochondrial biogenesis are involved in cellular aging. Childhood adversity is associated with telomere shortening, and several investigations have shown short telomeres in psychiatric disorders. Recent studies have examined whether mitochondria might be involved in neuropsychiatric conditions; findings are limited and no prior work has examined this in relation to stress exposure.<br><br>METHODS: Two-hundred ninety healthy adults provided information on childhood parental loss and maltreatment and completed diagnostic interviews. Participants were categorized into four groups based upon the presence or absence of childhood adversity and the presence or absence of lifetime psychopathology (depressive, anxiety, and substance use disorders). Telomere length and mitochondrial DNA (mtDNA) copy number were measured from leukocyte DNA by quantitative polymerase chain reaction.<br><br>RESULTS: Childhood adversity and lifetime psychopathology were each associated with shorter telomeres (p < .01) and higher mtDNA copy numbers (p < .001). Significantly higher mtDNA copy numbers and shorter telomeres were seen in individuals with major depression, depressive disorders, and anxiety disorders, as well as those with parental loss and childhood maltreatment. A history of substance disorders was also associated with significantly higher mtDNA copy numbers.<br><br>CONCLUSIONS: This study provides the first evidence of an alteration of mitochondrial biogenesis with early life stress and with anxiety and substance use disorders. We replicate prior work on telomere length and psychopathology and show that this effect is not secondary to medication use or comorbid medical illness. Finally, we show that early life stress and psychopathology are each associated with these markers of cellular aging.},
}
@article {pmid25748629,
year = {2015},
author = {Bull, C and Christensen, H and Fenech, M},
title = {Cortisol is not associated with telomere shortening or chromosomal instability in human lymphocytes cultured under low and high folate conditions.},
journal = {PloS one},
volume = {10},
number = {3},
pages = {e0119367},
pmid = {25748629},
issn = {1932-6203},
mesh = {Cells, Cultured ; Chromosomal Instability/*drug effects ; *DNA Damage ; Female ; Folic Acid/*pharmacology ; Humans ; Hydrocortisone/*pharmacology ; Male ; Telomere Homeostasis/*drug effects ; },
abstract = {Chronic psychological stress and nutritional deficiencies are factors that impact negatively on human health and disease risk. Chronic stress has been associated with accelerated leukocyte telomere shortening in numerous cohorts, however, a mechanistic link has proven elusive. This study tested the hypotheses that chronic exposure to the stress hormone, cortisol, causes telomere shortening and chromosome instability (CIN) in vitro, and that these effects would be further exacerbated by folate (vitamin B9) deficiency. Primary human lymphocytes were maintained in vitro for 12 days in medium containing either 25 nM folic acid (FA(low)) or 100 nM FA (FA(high)), together with either 0, 400, 1000 or 3500 nM cortisol. The interactive effects of cortisol and FA were examined by comparing telomere length (TL), biomarkers of DNA damage, and cytostasis. At day 12 TL was 5-17% longer in lymphocytes cultured in FA(low) conditions (mean ± SD;10.2% ± 1.6), compared with those in FA(high) medium (9.1% ± 1, p = 0.02). Refuting the hypothesis, TL was consistently greater in the presence of cortisol. The effect of FA deficiency on the frequency of DNA damage was significant for nucleoplasmic bridges, circular nuclei, micronuclei and nuclear buds, (p < 0.0001-0.001). The effect of cortisol, however, was negligible, only reaching statistical significance for the frequency of fused nuclei (p = 0.04). Cortisol was significantly associated with reduced cell division and growth and had an apparent protective effect on cell viability in the FA(low) conditions. Conclusions: Both chronic cortisol exposure, and folate deficiency, resulted in telomere elongation, however, the effect of cortisol was marginal relative to that of folate. Cortisol was not associated with increased chromosomal instability, but caused a significant reduction in cell division and growth. Together these results indicate that cortisol is not directly genotoxic and that the telomere shortening associated with increased psychological stress in vivo may not be explained by a direct effect of cortisol.},
}
@article {pmid25745990,
year = {2015},
author = {Zhuang, XD and Liao, LZ and Guo, Y and Li, Y and Liao, XX and Hu, X and Du, ZM},
title = {Rationale and design of RETAIN study: Rosuvastatin Effect on Telomere-telomerase system in Acute coronary syndrome patients undergoing percutaneous coronary Intervention.},
journal = {International journal of cardiology},
volume = {184},
number = {},
pages = {388-390},
doi = {10.1016/j.ijcard.2015.02.032},
pmid = {25745990},
issn = {1874-1754},
mesh = {Acute Coronary Syndrome/diagnosis/*drug therapy/genetics ; Adult ; Female ; Follow-Up Studies ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology/*therapeutic use ; Male ; Middle Aged ; Percutaneous Coronary Intervention ; Prospective Studies ; Rosuvastatin Calcium/pharmacology/*therapeutic use ; Telomerase/*physiology ; Telomere Homeostasis/drug effects/*physiology ; Treatment Outcome ; Young Adult ; },
}
@article {pmid25744032,
year = {2015},
author = {Strohmaier, J and van Dongen, J and Willemsen, G and Nyholt, DR and Zhu, G and Codd, V and Novakovic, B and Hansell, N and Wright, MJ and Rietschel, L and Streit, F and Henders, AK and Montgomery, GW and Samani, NJ and Gillespie, NA and Hickie, IB and Craig, JM and Saffery, R and Boomsma, DI and Rietschel, M and Martin, NG},
title = {Low Birth Weight in MZ Twins Discordant for Birth Weight is Associated with Shorter Telomere Length and lower IQ, but not Anxiety/Depression in Later Life.},
journal = {Twin research and human genetics : the official journal of the International Society for Twin Studies},
volume = {18},
number = {2},
pages = {198-209},
doi = {10.1017/thg.2015.3},
pmid = {25744032},
issn = {1832-4274},
support = {MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adolescent ; Anxiety/genetics ; Child ; Child, Preschool ; Depression/genetics ; Female ; Humans ; Infant ; Infant, Low Birth Weight ; Infant, Newborn ; Intelligence/*genetics ; Longitudinal Studies ; Male ; *Telomere Homeostasis ; Twins, Dizygotic/genetics ; Twins, Monozygotic/*genetics ; },
abstract = {Shorter telomere length (TL) has found to be associated with lower birth weight and with lower cognitive ability and psychiatric disorders. However, the direction of causation of these associations and the extent to which they are genetically or environmentally mediated are unclear. Within-pair comparisons of monozygotic (MZ) and dizygotic (DZ) twins can throw light on these questions. We investigated correlations of within pair differences in telomere length, IQ, and anxiety/depression in an initial sample from Brisbane (242 MZ pairs, 245 DZ same sex (DZSS) pairs) and in replication samples from Amsterdam (514 MZ pairs, 233 DZSS pairs) and Melbourne (19 pairs selected for extreme high or low birth weight difference). Intra-pair differences of birth weight and telomere length were significantly correlated in MZ twins, but not in DZSS twins. Greater intra-pair differences of telomere length were observed in the 10% of MZ twins with the greatest difference in birth weight compared to the bottom 90% in both samples and also in the Melbourne sample. Intra-pair differences of telomere length and IQ, but not of TL and anxiety/depression, were correlated in MZ twins, and to a smaller extent in DZSS twins. Our findings suggest that the same prenatal effects that reduce birth weight also influence telomere length in MZ twins. The association between telomere length and IQ is partly driven by the same prenatal effects that decrease birth weight.},
}
@article {pmid25736869,
year = {2015},
author = {Pieters, N and Janssen, BG and Valeri, L and Cox, B and Cuypers, A and Dewitte, H and Plusquin, M and Smeets, K and Nawrot, TS},
title = {Molecular responses in the telomere-mitochondrial axis of ageing in the elderly: a candidate gene approach.},
journal = {Mechanisms of ageing and development},
volume = {145},
number = {},
pages = {51-57},
doi = {10.1016/j.mad.2015.02.003},
pmid = {25736869},
issn = {1872-6216},
mesh = {Aged ; *Aging/genetics/metabolism ; DNA, Mitochondrial/*genetics ; Female ; *Gene Expression Regulation ; Humans ; Leukocytes/*metabolism ; Male ; *Telomere/genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {Experimental evidence shows that telomere shortening induces mitochondrial damage but so far studies in humans are scarce. Here, we investigated the association between leukocyte telomere length (LTL) and mitochondrial DNA (mtDNA) content in elderly and explored possible intermediate mechanisms by determining the gene expression profile of candidate genes in the telomere-mitochondrial axis of ageing. Among 166 non-smoking elderly, LTL, leukocyte mtDNA content and expression of candidate genes: sirtuin1 (SIRT1), tumor protein p53 (TP53), peroxisome proliferator-activated receptor γ-coactivator1α (PGC-1α), peroxisome proliferator-activated receptor γ-coactivator1β (PGC-1β), nuclear respiratory factor 1 (NRF1) and nuclear factor, erythroid 2 like 2 (NRF2), using a quantitave real time polymerase chain assay (qPCR). Statistical mediation analysis was used to study intermediate mechanisms of the telomere-mitochondrial axis of ageing. LTL correlated with leukocyte mtDNA content in our studied elderly (r = 0.23, p = 0.0047). SIRT1 gene expression correlated positively with LTL (r = 0.26, p = 0.0094) and leukocyte mtDNA content (r = 0.43, p < 0.0001). The other studied candidates showed significant correlations in the telomere-mitochondrial interactome but not independent from SIRT1. SIRT1 gene expression was estimated to mediate 40% of the positive association between LTL and leukocyte mtDNA content. The key finding of our study was that SIRT1 expression plays a pivotal role in the telomere-mitochondrial interactome.},
}
@article {pmid25730846,
year = {2015},
author = {Zahran, S and Snodgrass, JG and Maranon, DG and Upadhyay, C and Granger, DA and Bailey, SM},
title = {Stress and telomere shortening among central Indian conservation refugees.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {112},
number = {9},
pages = {E928-36},
pmid = {25730846},
issn = {1091-6490},
mesh = {Adult ; Female ; Humans ; Hydrocortisone/metabolism ; Indians, North American/*genetics ; Longevity/*genetics ; Male ; *Stress, Psychological/genetics/metabolism/pathology ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Research links psychosocial stress to premature telomere shortening and accelerated human aging; however, this association has only been demonstrated in so-called "WEIRD" societies (Western, educated, industrialized, rich, and democratic), where stress is typically lower and life expectancies longer. By contrast, we examine stress and telomere shortening in a non-Western setting among a highly stressed population with overall lower life expectancies: poor indigenous people--the Sahariya--who were displaced (between 1998 and 2002) from their ancestral homes in a central Indian wildlife sanctuary. In this setting, we examined adult populations in two representative villages, one relocated to accommodate the introduction of Asiatic lions into the sanctuary (n = 24 individuals), and the other newly isolated in the sanctuary buffer zone after their previous neighbors were moved (n = 22). Our research strategy combined physical stress measures via the salivary analytes cortisol and α-amylase with self-assessments of psychosomatic stress, ethnographic observations, and telomere length assessment [telomere-fluorescence in situ hybridization (TEL-FISH) coupled with 3D imaging of buccal cell nuclei], providing high-resolution data amenable to multilevel statistical analysis. Consistent with expectations, we found significant associations between each of our stress measures--the two salivary analytes and the psychosomatic symptom survey--and telomere length, after adjusting for relevant behavioral, health, and demographic traits. As the first study (to our knowledge) to link stress to telomere length in a non-WEIRD population, our research strengthens the case for stress-induced telomere shortening as a pancultural biomarker of compromised health and aging.},
}
@article {pmid25730259,
year = {2015},
author = {Pal, D and Sharma, U and Singh, SK and Kakkar, N and Prasad, R},
title = {Over-expression of telomere binding factors (TRF1 &amp; TRF2) in renal cell carcinoma and their inhibition by using SiRNA induce apoptosis, reduce cell proliferation and migration invitro.},
journal = {PloS one},
volume = {10},
number = {3},
pages = {e0115651},
pmid = {25730259},
issn = {1932-6203},
mesh = {Adult ; Aged ; Apoptosis ; Carcinoma, Renal Cell/metabolism/*pathology ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Female ; G1 Phase Cell Cycle Checkpoints ; Humans ; Immunohistochemistry ; Kidney/metabolism ; Kidney Neoplasms/metabolism/*pathology ; Male ; Middle Aged ; RNA, Small Interfering/*metabolism ; S Phase Cell Cycle Checkpoints ; Telomeric Repeat Binding Protein 1/antagonists &amp; inhibitors/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/antagonists &amp; inhibitors/genetics/*metabolism ; Up-Regulation ; },
abstract = {Telomere binding factors viz. TRF1 and TRF2 are a part of sheltrin complex that are present exclusively at the ends of chromosomes. These factors play an important role in maintaining chromosomal integrity at the ends. However, their status and role are not clear in renal cell carcinoma (RCC). Therefore, the present study was conducted to evaluate TRF1 and TRF2 expressions in RCC tissues. Further, the role of these factors involved in tumorigenesis was elucidated by gene silencing using siRNA in RCC cell line (A498). The present study documented a significant over-expression of TRF1 (P = 0.005) and TRF2 (P = 0.0048) mRNAs by real time PCR in RCC tissues as compared with adjacent normal kidney tissues. Immunohistochemistry studies also revealed higher expression of TRF1 and TRF2 proteins in RCC. Moreover, TRF1 or TRF2 gene silencing using siRNA showed marked reduction in proliferation of RCC cells (P = 0.000). Further, significantly induced cell cycle arrest (P = 0.000) and apoptosis of RCC cells (P = 0.000) was documented upon TRF1 or TRF2 gene silencing. Henceforth, the results deduce that TRF1 or TRF2 inhibitions play an important role in the induction of apoptosis in A498 cells, which may serve as a potential therapeutic target in RCC.},
}
@article {pmid25726322,
year = {2015},
author = {Rattiste, K and Klandorf, H and Urvik, J and Sepp, T and Asghar, M and Hasselquist, D and Cooey, C and Hõrak, P},
title = {Skin pentosidine and telomere length do not covary with age in a long-lived seabird.},
journal = {Biogerontology},
volume = {16},
number = {4},
pages = {435-441},
doi = {10.1007/s10522-015-9564-1},
pmid = {25726322},
issn = {1573-6768},
mesh = {Age Factors ; Animals ; Arginine/*analogs &amp; derivatives/metabolism ; *Cellular Senescence ; Charadriiformes/blood/genetics/*metabolism ; Genetic Fitness ; Lysine/*analogs &amp; derivatives/metabolism ; Male ; Reproduction ; Skin/*metabolism ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; },
abstract = {The questions about why and how senescence occurs in the wild are among the most pertinent ones in evolutionary ecology. Telomere length is a commonly used marker for aging, while other biomarkers of aging have received considerably less attention. Here we studied how another potent indicator of aging-skin pentosidine concentration-relates to age and blood telomere length in a long-lived seabird with well-documented reproductive senescence. We found no associations between telomere length, skin pentosidine and chronological age in male common gulls (Larus canus), aging from 2 to 30 years. However, the variance in telomere length was 4.6 times higher among the birds older than 13 years, which hints at relaxed selection on telomere length among the birds that have passed their prime age of reproduction. These results suggest that physiological and chronological ages may be largely uncoupled in our study system. Furthermore, our findings do not support a hypothesis about the presence of a common physiological factor (e.g., such as oxidative stress) that would cause covariation between two independent markers of aging.},
}
@article {pmid25723462,
year = {2015},
author = {Egusquiaguirre, SP and Pedraz, JL and Hernandez, RM and Igartua, M},
title = {Emerging therapeutic approaches based on nanotechnology for the treatment of diseases associated with telomere dysfunction.},
journal = {Mini reviews in medicinal chemistry},
volume = {15},
number = {6},
pages = {490-502},
doi = {10.2174/1389557515666150226114522},
pmid = {25723462},
issn = {1875-5607},
mesh = {Aging, Premature/genetics/therapy ; Disease/*genetics ; Humans ; Nanomedicine/*methods ; Telomere/*genetics ; },
abstract = {Telomeric diseases are a group of rare progeroid genetic syndromes, presenting premature aging phenotypes, characterized for defects on telomere maintenance. In humans, telomeres are heterochromatic structures consisting of long TTAGGG repeats located at the chromosomal ends, which shorten progressively after each DNA replication because of the 'end replication problem'. Critically short telomeres activate a DNA damage response that leads to the arrest of the cell cycle and resulting in cellular senescence or apoptosis. Furthermore, excessively short telomeres are prone to create telomeric fusions, causing genomic instability and malignant transformation. In order to counteract this process, there are two enzymatic complexes, the telomerase complex, with the capacity to elongate telomeres; and the shelterin complex, which protects them from being recognized as DNA breaks. Over the last few decades, several studies have confirmed that critically short telomeres and defects in telomere-associated enzymatic complexes are involved in the development of a group of rare human genetic diseases, with the accumulation of excessive telomere attrition as the underlying cause of these pathologies. Despite the severity of these disorders, there is no curative treatment for any of them. In light of this, this review summarizes the most important defective telomere diseases, their current management, and it presents possible therapeutic strategies based on nanotechnology which may open up new possibilities for their treatment.},
}
@article {pmid25723167,
year = {2015},
author = {Xie, Z and Jay, KA and Smith, DL and Zhang, Y and Liu, Z and Zheng, J and Tian, R and Li, H and Blackburn, EH},
title = {Early telomerase inactivation accelerates aging independently of telomere length.},
journal = {Cell},
volume = {160},
number = {5},
pages = {928-939},
pmid = {25723167},
issn = {1097-4172},
support = {R01 GM070808/GM/NIGMS NIH HHS/United States ; T32 GM008284/GM/NIGMS NIH HHS/United States ; GM26259/GM/NIGMS NIH HHS/United States ; P50 GM081879/GM/NIGMS NIH HHS/United States ; AG043080/AG/NIA NIH HHS/United States ; GM070808/GM/NIGMS NIH HHS/United States ; R01 GM026259/GM/NIGMS NIH HHS/United States ; R01 AG043080/AG/NIA NIH HHS/United States ; R37 GM026259/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle ; Chromosomes, Fungal/metabolism ; DNA Replication ; Mitochondria/metabolism ; Ribonucleoside Diphosphate Reductase/metabolism ; Saccharomyces cerevisiae/*cytology/enzymology/*metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Telomerase/*metabolism ; Telomere/metabolism ; },
abstract = {Telomerase is required for long-term telomere maintenance and protection. Using single budding yeast mother cell analyses we found that, even early after telomerase inactivation (ETI), yeast mother cells show transient DNA damage response (DDR) episodes, stochastically altered cell-cycle dynamics, and accelerated mother cell aging. The acceleration of ETI mother cell aging was not explained by increased reactive oxygen species (ROS), Sir protein perturbation, or deprotected telomeres. ETI phenotypes occurred well before the population senescence caused late after telomerase inactivation (LTI). They were morphologically distinct from LTI senescence, were genetically uncoupled from telomere length, and were rescued by elevating dNTP pools. Our combined genetic and single-cell analyses show that, well before critical telomere shortening, telomerase is continuously required to respond to transient DNA replication stress in mother cells and that a lack of telomerase accelerates otherwise normal aging.},
}
@article {pmid25723166,
year = {2015},
author = {Marzec, P and Armenise, C and Pérot, G and Roumelioti, FM and Basyuk, E and Gagos, S and Chibon, F and Déjardin, J},
title = {Nuclear-receptor-mediated telomere insertion leads to genome instability in ALT cancers.},
journal = {Cell},
volume = {160},
number = {5},
pages = {913-927},
doi = {10.1016/j.cell.2015.01.044},
pmid = {25723166},
issn = {1097-4172},
mesh = {Chromosomes, Human/metabolism ; DNA Breaks, Double-Stranded ; *Genomic Instability ; Humans ; Neoplasms/*genetics ; Receptors, N-Methyl-D-Aspartate/*metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; Translocation, Genetic ; },
abstract = {The breakage-fusion-bridge cycle is a classical mechanism of telomere-driven genome instability in which dysfunctional telomeres are fused to other chromosomal extremities, creating dicentric chromosomes that eventually break at mitosis. Here, we uncover a distinct pathway of telomere-driven genome instability, specifically occurring in cells that maintain telomeres with the alternative lengthening of telomeres mechanism. We show that, in these cells, telomeric DNA is added to multiple discrete sites throughout the genome, corresponding to regions regulated by NR2C/F transcription factors. These proteins drive local telomere DNA addition by recruiting telomeric chromatin. This mechanism, which we name targeted telomere insertion (TTI), generates potential common fragile sites that destabilize the genome. We propose that TTI driven by NR2C/F proteins contributes to the formation of complex karyotypes in ALT tumors.},
}
@article {pmid25723159,
year = {2015},
author = {Aeby, E and Lingner, J},
title = {ALT telomeres get together with nuclear receptors.},
journal = {Cell},
volume = {160},
number = {5},
pages = {811-813},
doi = {10.1016/j.cell.2015.02.006},
pmid = {25723159},
issn = {1097-4172},
mesh = {*Genomic Instability ; Humans ; Neoplasms/*genetics ; Receptors, N-Methyl-D-Aspartate/*metabolism ; Telomere/*metabolism ; },
abstract = {Nuclear receptors bind chromosome ends in "alternative lengthening of telomeres" (ALT) cancer cells that maintain their ends by homologous recombination instead of telomerase. Marzec et al. now demonstrate that, in ALT cells, nuclear receptors not only trigger distal chromatin associations to mediate telomere-telomere recombination events, but also drive chromosome-internal targeted telomere insertions (TTI).},
}
@article {pmid25722236,
year = {2015},
author = {Crunkhorn, S},
title = {Anticancer agents: An alternative route to targeting telomere elongation.},
journal = {Nature reviews. Drug discovery},
volume = {14},
number = {3},
pages = {164-165},
pmid = {25722236},
issn = {1474-1784},
mesh = {Antineoplastic Agents/*pharmacology ; Humans ; Pyrazines/*pharmacology ; Sulfones/*pharmacology ; Telomere/*drug effects/*metabolism ; *Telomere Homeostasis ; },
}
@article {pmid25720088,
year = {2015},
author = {Ichikawa, Y and Nishimura, Y and Kurumizaka, H and Shimizu, M},
title = {Nucleosome organization and chromatin dynamics in telomeres.},
journal = {Biomolecular concepts},
volume = {6},
number = {1},
pages = {67-75},
doi = {10.1515/bmc-2014-0035},
pmid = {25720088},
issn = {1868-503X},
mesh = {Chromatin/*metabolism ; DNA/chemistry ; Histones/*metabolism ; Humans ; Nucleosomes/*chemistry/*metabolism ; Protein Isoforms/metabolism ; Protein Processing, Post-Translational ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; Yeasts ; },
abstract = {Telomeres are DNA-protein complexes located at the ends of linear eukaryotic chromosomes, and are essential for chromosome stability and maintenance. In most organisms, telomeres consist of tandemly repeated sequences of guanine-clusters. In higher eukaryotes, most of the telomeric repeat regions are tightly packaged into nucleosomes, even though telomeric repeats act as nucleosome-disfavoring sequences. Although telomeres were considered to be condensed heterochromatin structures, recent studies revealed that the chromatin structures in telomeres are actually dynamic. The dynamic properties of telomeric chromatin are considered to be important for the structural changes between the euchromatic and heterochromatic states during the cell cycle and in cellular differentiation. We propose that the nucleosome-disfavoring property of telomeric repeats is a crucial determinant for the lability of telomeric nucleosomes, and provides a platform for chromatin dynamics in telomeres. Furthermore, we discuss the influences of telomeric components on the nucleosome organization and chromatin dynamics in telomeres.},
}
@article {pmid25716168,
year = {2015},
author = {Yang, H and Li, J and Tang, R and Liu, Y and Shao, Y and Huang, Q and Shi, J},
title = {Telomere reverse transcriptase (TERT) rs2735940 increases cancer risk.},
journal = {Medical science monitor : international medical journal of experimental and clinical research},
volume = {21},
number = {},
pages = {612-616},
pmid = {25716168},
issn = {1643-3750},
mesh = {Genetic Association Studies ; *Genetic Predisposition to Disease ; Humans ; Neoplasms/*enzymology/*genetics ; Polymorphism, Single Nucleotide/*genetics ; Risk Factors ; Telomerase/*genetics ; },
abstract = {BACKGROUND: Telomerase reverse transcriptase (TERT) rs2735940 polymorphism was found to be associated with increased cancer risk. However, recent studies reported controversial results. The aim of our study was to detect its relationship with cancer risk.<br><br>MATERIAL AND METHODS: EMBASE and PubMed databases were searched for all publications until October 2014. ORs and 95% CIs were applied to investigate the association in the random-effects model.<br><br>RESULTS: Thirteen case-control studies with 19385 cases and 17558 controls were included in this study. We found a significant association between cancer risk and TERT rs2735940 polymorphism (OR=1.06, 95% CI 1.02-1.11, P=0.005). In the subgroup analysis by ethnicity, a marginal association was found in Caucasians (OR=1.05, 95% CI 1.00-1.10, P=0.05), but not in Asians (OR=1.01, 95% CI 0.82-1.24, P=0.93). In the subgroup analysis by cancer site, this polymorphism was significantly associated with lung cancer risk (OR=1.08, 95% CI 1.02-1.13, P=0.004).<br><br>CONCLUSIONS: TERT rs2735940 polymorphism was significantly associated with cancer risk, especially lung cancer.},
}
@article {pmid25716089,
year = {2015},
author = {Lewin, N and Treidel, LA and Holekamp, KE and Place, NJ and Haussmann, MF},
title = {Socioecological variables predict telomere length in wild spotted hyenas.},
journal = {Biology letters},
volume = {11},
number = {2},
pages = {20140991},
pmid = {25716089},
issn = {1744-957X},
support = {R01 GM105042/GM/NIGMS NIH HHS/United States ; 1R01GM105042/GM/NIGMS NIH HHS/United States ; },
mesh = {Aging/genetics ; Animals ; Behavior, Animal ; Female ; Hyaenidae/genetics/*physiology ; Kenya ; Male ; Predatory Behavior ; *Social Behavior ; *Social Dominance ; Telomere/*genetics ; },
abstract = {Telomeres are regarded as important biomarkers of ageing and serve as useful tools in revealing how stress acts at the cellular level. However, the effects of social and ecological factors on telomere length remain poorly understood, particularly in free-ranging mammals. Here, we investigated the influences of within-group dominance rank and group membership on telomere length in wild adult spotted hyenas (Crocuta crocuta). We found large effects of both factors; high-ranking hyenas exhibited significantly greater mean telomere length than did subordinate animals, and group membership significantly predicted mean telomere length within high-ranking females. We further inquired whether prey availability mediates the observed effect of group membership on telomere length, but this hypothesis was not supported. Interestingly, adult telomere length was not predicted by age. Our work shows for the first time, to the best of our knowledge, the effects of social rank on telomere length in a wild mammal and enhances our understanding of how social and ecological variables may contribute to organismal senescence.},
}
@article {pmid25716087,
year = {2015},
author = {Noguera, JC and Metcalfe, NB and Boner, W and Monaghan, P},
title = {Sex-dependent effects of nutrition on telomere dynamics in zebra finches (Taeniopygia guttata).},
journal = {Biology letters},
volume = {11},
number = {2},
pages = {20140938},
pmid = {25716087},
issn = {1744-957X},
support = {268926/ERC_/European Research Council/International ; },
mesh = {Aging/genetics ; Animals ; Antioxidants/administration &amp; dosage ; Diet ; Female ; Male ; Micronutrients/*administration &amp; dosage/deficiency ; Nutritional Status/genetics/*physiology ; Oxidative Stress/genetics/physiology ; *Sex Characteristics ; Sexual Maturation/physiology ; Songbirds/genetics/*growth &amp; development/metabolism ; Telomere/physiology ; },
abstract = {At a cellular level, oxidative stress is known to increase telomere attrition, and hence cellular senescence and risk of disease. It has been proposed that dietary micronutrients play an important role in telomere protection due to their antioxidant properties. We experimentally manipulated dietary micronutrients during early life in zebra finches (Taeniopygia guttata). We found no effects of micronutrient intake on telomere loss during chick growth. However, females given a diet high in micronutrients during sexual maturation showed reduced telomere loss; there was no such effect in males. These results suggest that micronutrients may influence rates of cellular senescence, but differences in micronutrient requirement and allocation strategies, probably linked to the development of sexual coloration, may underlie sex differences in response.},
}
@article {pmid25711790,
year = {2015},
author = {Steurer, J},
title = {[Telomere length and Mediterranean diet - a clear association].},
journal = {Praxis},
volume = {104},
number = {5},
pages = {255},
doi = {10.1024/1661-8157/a001940},
pmid = {25711790},
issn = {1661-8157},
mesh = {Aging/*physiology ; *Diet, Mediterranean ; Female ; Humans ; Telomere/*ultrastructure ; },
}
@article {pmid25711129,
year = {2015},
author = {Factor-Litvak, P and Susser, E},
title = {The importance of early life studies of telomere attrition.},
journal = {Paediatric and perinatal epidemiology},
volume = {29},
number = {2},
pages = {144-145},
pmid = {25711129},
issn = {1365-3016},
support = {P30 ES009089/ES/NIEHS NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; },
mesh = {Female ; *Genome-Wide Association Study ; Humans ; Leukocytes/*physiology ; Male ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics ; },
}
@article {pmid25709105,
year = {2015},
author = {Schutte, NS and Malouff, JM},
title = {The association between depression and leukocyte telomere length: a meta-analysis.},
journal = {Depression and anxiety},
volume = {32},
number = {4},
pages = {229-238},
doi = {10.1002/da.22351},
pmid = {25709105},
issn = {1520-6394},
mesh = {Depression/*genetics ; Depressive Disorder/*genetics ; Humans ; Leukocytes/*ultrastructure ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Telomeres protect the ends of chromosomes, and shorter leukocyte telomeres are associated with poor health. Depression may be associated with the shortening of leukocyte telomeres. The present study set out to consolidate the varying effect sizes found so far in studies of depression and telomere length and to identify moderators of the relationship between depression and telomere length.<br><br>METHODS: A meta-analytic investigation of the relationship between depression and leukocyte telomere length used information from 21,040 participants.<br><br>RESULTS: A significant effect size, r = -.12, P < .001, indicated that depression was associated with shorter telomere length. Several variables significantly moderated effect size. Concurrent associations (k = 25) between depression and telomere length were significantly stronger than longitudinal associations (k = 5). Studies that used the Southern blot (k = 3) and fluorescent in situ hybridization (FISH; k = 2) assays to measure telomere length showed larger effect sizes than studies that used quantitative polymerase chain reaction (qPCR; k = 25). Finally, study reports that indicated that the telomere assays were conducted blind to depression level of participants (k = 11) had significantly lower effect sizes than those of other studies (k = 19).<br><br>CONCLUSIONS: The significant relationship between depression and shorter telomere length is consistent with a theoretical model positing that distress, such as experienced in depression, results in physiological changes leading to shortened telomeres.},
}
@article {pmid25704912,
year = {2015},
author = {Mirjolet, C and Boidot, R and Saliques, S and Ghiringhelli, F and Maingon, P and Créhange, G},
title = {The role of telomeres in predicting individual radiosensitivity of patients with cancer in the era of personalized radiotherapy.},
journal = {Cancer treatment reviews},
volume = {41},
number = {4},
pages = {354-360},
doi = {10.1016/j.ctrv.2015.02.005},
pmid = {25704912},
issn = {1532-1967},
mesh = {Animals ; Humans ; Neoplasms/*genetics/metabolism/*radiotherapy ; Precision Medicine/*methods ; Predictive Value of Tests ; Radiation Tolerance/genetics ; Telomere/*genetics/metabolism ; },
abstract = {Radiotherapy plays a key role in cancer treatments, but tumor cell death differs from one tumor to another. The response of patients to radiotherapy varies considerably and adverse side effects are difficult to prevent. The mechanisms involved in the heterogeneity of this response are not well understood. In order to enhance the efficacy and safety of radiotherapy, it is important to identify subpopulations most at risk of developing a late adverse response to radiotherapy. Telomeres are composed of multiple repeats of a unique sequence of nucleotides forming a TTAGGG pattern. They protect chromosomes from end-to-end fusion and maintain genomic stability. Telomeres have been shown to be extremely sensitive to radiotherapy especially because of their atypical DNA damage repair response, which includes partial inhibition of the non-homologous end joining repair pathway. Ionizing Radiation (IR)-induced damage to telomere DNA could lead to chromosome instability and the initiation or progression of tumor processes. Telomeres could thus be a reliable marker of IR exposure and as such become a new parameter for predicting radiosensitivity. Furthermore, short telomeres are more sensitive to radiotherapy, which could partially explain differences in tumor cell death and in inter-individual sensitivity to radiotherapy. Telomere length could be used to identify subpopulations of patients who could benefit from higher or lower doses per fraction. Finally, pharmacological interference with tumor-cell telomere biology to reduce telomere length and/or telomere stability could also enhance the effectiveness and safety of radiotherapy. Telomeres could play a key role in radiotherapy in the era of personalized medicine.},
}
@article {pmid25702101,
year = {2015},
author = {Chen, Y and Wu, Y and Huang, X and Qu, P and Li, G and Jin, T and Xing, J and He, S},
title = {Leukocyte telomere length: a novel biomarker to predict the prognosis of glioma patients.},
journal = {Journal of cancer research and clinical oncology},
volume = {141},
number = {10},
pages = {1739-1747},
pmid = {25702101},
issn = {1432-1335},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/*genetics ; Child ; Cytokines/metabolism ; Disease-Free Survival ; Female ; Glioma/*genetics/metabolism/*pathology ; Humans ; Leukocytes, Mononuclear/*metabolism/*pathology ; Male ; Middle Aged ; Prognosis ; Telomere/*genetics ; Young Adult ; },
abstract = {PURPOSE: Epidemiological studies have demonstrated that leukocyte telomere length is associated with the developing risk of various malignancies, including glioma. However, its prognostic value in glioma patients has never been investigated.<br><br>METHODS: Relative telomere length (RTL) of peripheral blood leukocytes from 301 glioma patients were examined using a real-time PCR-based method. Kaplan-Meier curves and Cox proportional hazards regression model were used to assess the association of RTL with clinical outcomes of patients. To explore the potential mechanism, the immune phenotype of peripheral blood mononuclear cells (PBMCs) and concentrations of several cytokines from another 20 glioma patients were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. The relationship between RTL and immunological characteristics of PBMCs were further analyzed.<br><br>RESULTS: Patients with short RTL showed both poorer overall survival (OS) and progression-free survival (PFS) than those with long RTL. Multivariate Cox regression analysis demonstrated that RTL was an independent prognostic factor for both OS and PFS in glioma patients. Moreover, the effects of RTL on the prognosis of patients exhibited a dose-dependent manner. Stratified analysis showed that the prognostic value of RTL was not affected by host characteristics except for age. In addition, flow cytometry and ELISA analyses indicated that there was no significant association between RTL and frequency of different immune cell subsets or plasma cytokine concentrations.<br><br>CONCLUSIONS: Our study for the first time demonstrates that leukocyte RTL is an independent prognostic marker for glioma patients. The potential mechanism needs further investigation.},
}
@article {pmid25701469,
year = {2015},
author = {Fojtová, M and Sýkorová, E and Najdekrová, L and Polanská, P and Zachová, D and Vagnerová, R and Angelis, KJ and Fajkus, J},
title = {Telomere dynamics in the lower plant Physcomitrella patens.},
journal = {Plant molecular biology},
volume = {87},
number = {6},
pages = {591-601},
pmid = {25701469},
issn = {1573-5028},
mesh = {Amino Acid Sequence ; Arabidopsis/genetics ; Base Sequence ; Bryopsida/*genetics/metabolism ; Chromosomes, Plant/*genetics ; DNA Breaks, Double-Stranded ; *DNA Repair ; DNA, Plant/genetics ; Homologous Recombination ; Molecular Sequence Data ; Mutation ; Phenotype ; Phylogeny ; Plant Proteins/genetics/metabolism ; Sequence Alignment ; Sequence Analysis, DNA ; Telomerase/*genetics/metabolism ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {A comparative approach in biology is needed to assess the universality of rules governing this discipline. In plant telomere research, most of the key principles were established based on studies in only single model plant, Arabidopsis thaliana. These principles include the absence of telomere shortening during plant development and the corresponding activity of telomerase in dividing (meristem) plant cells. Here we examine these principles in Physcomitrella patens as a representative of lower plants. To follow telomerase expression, we first characterize the gene coding for the telomerase reverse transcriptase subunit PpTERT in P. patens, for which only incomplete prediction has been available so far. In protonema cultures of P. patens, growing by filament apical cell division, the proportion of apical (dividing) cells was quantified and telomere length, telomerase expression and activity were determined. Our results show telomere stability and demonstrate proportionality of telomerase activity and expression with the number of apical cells. In addition, we analyze telomere maintenance in mre11, rad50, nbs1, ku70 and lig4 mutants of P. patens and compare the impact of these mutations in double-strand-break (DSB) repair pathways with earlier observations in corresponding A. thaliana mutants. Telomere phenotypes are absent and DSB repair kinetics is not affected in P. patens mutants for DSB factors involved in non-homologous end joining (NHEJ). This is compliant with the overall dominance of homologous recombination over NHEJ pathways in the moss, contrary to the inverse situation in flowering plants.},
}
@article {pmid25698140,
year = {2015},
author = {Näslund, J and Pauliny, A and Blomqvist, D and Johnsson, JI},
title = {Telomere dynamics in wild brown trout: effects of compensatory growth and early growth investment.},
journal = {Oecologia},
volume = {177},
number = {4},
pages = {1221-1230},
pmid = {25698140},
issn = {1432-1939},
mesh = {*Adaptation, Physiological ; Animals ; Body Size/*physiology ; DNA/*physiology ; Fasting/*physiology ; Food Deprivation/physiology ; Investments ; Seasons ; *Telomere/metabolism ; *Telomere Shortening ; Trout/genetics/growth &amp; development/*physiology ; Weight Gain ; },
abstract = {After a period of food deprivation, animals often respond with a period of faster than normal growth. Such responses have been suggested to result in decreased chromosomal maintenance, which in turn may affect the future fitness of an individual. Here, we present a field experiment in which a food deprivation period of 24 days was enforced on fish from a natural population of juvenile brown trout (Salmo trutta) at the start of the high-growth season in spring. The growth of the food-deprived fish and a non-deprived control group was then monitored in the wild during 1 year. Fin tissue samples were taken at the start of the experiment and 1 year after food deprivation to monitor the telomere dynamics, using reduced telomere length as an indicator of maintenance cost. The food-deprived fish showed partial compensatory growth in both mass and length relative to the control group. However, we found no treatment effects on telomere dynamics, suggesting that growth-compensating brown trout juveniles are able to maintain their telomeres during their second year in the stream. However, body size at the start of the experiment, reflecting growth rate during their first year of life, was negatively correlated with change in telomere length over the following year. This result raises the possibility that rapid growth early in life induces delayed costs in cellular maintenance.},
}
@article {pmid25697340,
year = {2015},
author = {Beilstein, MA and Renfrew, KB and Song, X and Shakirov, EV and Zanis, MJ and Shippen, DE},
title = {Evolution of the Telomere-Associated Protein POT1a in Arabidopsis thaliana Is Characterized by Positive Selection to Reinforce Protein-Protein Interaction.},
journal = {Molecular biology and evolution},
volume = {32},
number = {5},
pages = {1329-1341},
pmid = {25697340},
issn = {1537-1719},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; F32GM09363/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Arabidopsis Proteins/*genetics ; *Evolution, Molecular ; Nuclear Proteins/*genetics ; Phylogeny ; Protein Interaction Maps/genetics ; Selection, Genetic/*genetics ; Telomere-Binding Proteins/genetics ; },
abstract = {Gene duplication is a major driving force in genome evolution. Here, we explore the nature and origin of the POT1 gene duplication in Arabidopsis thaliana. Protection of Telomeres (POT1) is a conserved multifunctional protein that modulates telomerase activity and its engagement with telomeres. Arabidopsis thaliana encodes two divergent POT1 paralogs termed AtPOT1a and AtPOT1b. AtPOT1a positively regulates telomerase activity, whereas AtPOT1b is proposed to negatively regulate telomerase and promote chromosome end protection. Phylogenetic analysis uncovered two independent POT1 duplication events in the plant kingdom, including one at the base of Brassicaceae. Tests for positive selection implemented in PAML revealed that the Brassicaceae POT1a lineage experienced positive selection postduplication and identified three amino acid residues with signatures of positive selection. A sensitive and quantitative genetic complementation assay was developed to assess POT1a function in A. thaliana. The assay showed that AtPOT1a is functionally distinct from single-copy POT1 genes in other plants. Moreover, for two of the sites with a strong signature of positive selection, substitutions that swap the amino acids in AtPOT1a for residues found in AtPOT1b dramatically compromised AtPOT1a function in vivo. In vitro-binding studies demonstrated that all three sites under positive selection specifically enhance the AtPOT1a interaction with CTC1, a core component of the highly conserved CST (CTC1/STN1/TEN1) telomere protein complex. Our results reveal a molecular mechanism for the role of these positively selected sites in AtPOT1a. The data also provide an important empirical example to refine theories of duplicate gene retention, as the outcome of positive selection here appears to be reinforcement of an ancestral function, rather than neofunctionalization. We propose that this outcome may not be unusual when the duplicated protein is a component of a multisubunit complex whose function is in part specified by other members.},
}
@article {pmid25694275,
year = {2015},
author = {Pagano, B and Amato, J and Iaccarino, N and Cingolani, C and Zizza, P and Biroccio, A and Novellino, E and Randazzo, A},
title = {Looking for efficient G-quadruplex ligands: evidence for selective stabilizing properties and telomere damage by drug-like molecules.},
journal = {ChemMedChem},
volume = {10},
number = {4},
pages = {640-649},
doi = {10.1002/cmdc.201402552},
pmid = {25694275},
issn = {1860-7187},
mesh = {Antineoplastic Agents/chemistry/pharmacology ; Base Sequence ; Cell Line ; DNA/chemistry ; *Drug Design ; G-Quadruplexes/*drug effects ; Humans ; Ligands ; Molecular Docking Simulation ; Nucleic Acid Denaturation/drug effects ; Telomere/chemistry/*drug effects ; },
abstract = {There is currently significant interest in the development of G-quadruplex-interactive compounds, given the relationship between the ability to stabilize these non-canonical DNA structures and anticancer activity. In this study, a set of biophysical assays was applied to evaluate the binding of six drug-like ligands to DNA G-quadruplexes with different folding topologies. Interestingly, two of the investigated ligands showed selective G-quadruplex-stabilizing properties and biological activity. These compounds may represent useful leads for the development of more potent and selective ligands.},
}
@article {pmid25691684,
year = {2015},
author = {Hunt, SC and Kark, JD and Aviv, A},
title = {Association between shortened leukocyte telomere length and cardio-metabolic outcomes.},
journal = {Circulation. Cardiovascular genetics},
volume = {8},
number = {1},
pages = {4-7},
doi = {10.1161/CIRCGENETICS.114.000964},
pmid = {25691684},
issn = {1942-3268},
support = {HHSN2682013000//PHS HHS/United States ; R01HD071180/HD/NICHD NIH HHS/United States ; R01HL116446/HL/NHLBI NIH HHS/United States ; },
mesh = {Aging/*metabolism ; Diabetes Mellitus, Type 2/*metabolism ; Humans ; Leukocytes/*metabolism ; Myocardial Infarction/*metabolism ; Stroke/*metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
}
@article {pmid25689229,
year = {2015},
author = {Gong, H and Zhu, W and Zhang, J and Li, X and Meng, Q and Zhou, G and Wang, M and Wang, H and Miao, L and Qin, Q and Zhang, H},
title = {TTAGG-repeat telomeres and characterization of telomerase in the beet armyworm, Spodoptera exigua (Lepidoptera: Noctuidae).},
journal = {Insect molecular biology},
volume = {24},
number = {3},
pages = {358-367},
doi = {10.1111/imb.12163},
pmid = {25689229},
issn = {1365-2583},
mesh = {Amino Acid Motifs ; Animals ; Humans ; Spodoptera/*genetics ; Tandem Repeat Sequences ; Telomerase/chemistry/*genetics ; Telomere/*genetics ; },
abstract = {Telomeres are maintained usually by telomerase, a specialized reverse transcriptase that adds this sequence to chromosome ends. In this study, telomerase activity was detected in the in different somatic tissues, such as midgut and fat bodies, by the telomeric repeat amplification protocol (TRAP) in Spodoptera exigua. The structure of the telomeres of S. exigua was evaluated by sequence analysis of the TRAP products, revealing that the telomerase synthesized a (TTAGG)n repeat. The presence of a telomerase reverse transcriptase (TERT) subunit coding gene has been cloned, sequenced and expressed in vitro successively. Notably, the S. exigua telomerase (SpexTERT) gene structure lacks the N-terminal GQ motif. Telomerase contains a large RNA subunit, TER, and a protein catalytic subunit, TERT. Here we report an in vitro system that was reconstructed by all components of the telomerase complex, a purified recombinant SpexTERT without a N-terminal GQ motif and a mutant human telomerase RNA (TER), showed telomerase activity. Together, these results suggest the GQ motif is not essential for telomerase catalysis.},
}
@article {pmid25688260,
year = {2015},
author = {Shimamoto, A and Yokote, K and Tahara, H},
title = {Werner Syndrome-specific induced pluripotent stem cells: recovery of telomere function by reprogramming.},
journal = {Frontiers in genetics},
volume = {6},
number = {},
pages = {10},
pmid = {25688260},
issn = {1664-8021},
abstract = {Werner syndrome (WS) is a rare human autosomal recessive premature aging disorder characterized by early onset of aging-associated diseases, chromosomal instability, and cancer predisposition. The function of the DNA helicase encoded by WRN, the gene responsible for WS, has been studied extensively. WRN helicase is involved in the maintenance of chromosome integrity through DNA replication, repair, and recombination by interacting with a variety of proteins associated with DNA repair and telomere maintenance. The accelerated aging associated with WS is reportedly caused by telomere dysfunction, and the underlying mechanism of the disease is yet to be elucidated. Although it was reported that the life expectancy for patients with WS has improved over the last two decades, definitive therapy for these patients has not seen much development. Severe symptoms of the disease, such as leg ulcers, cause a significant decline in the quality of life in patients with WS. Therefore, the establishment of new therapeutic strategies for the disease is of utmost importance. Induced pluripotent stem cells (iPSCs) can be established by the introduction of several pluripotency genes, including Oct3/4, Sox2, Klf4, and c-myc into differentiated cells. iPSCs have the potential to differentiate into a variety of cell types that constitute the human body, and possess infinite proliferative capacity. Recent studies have reported the generation of iPSCs from the cells of patients with WS, and they have concluded that reprogramming represses premature senescence phenotypes in these cells. In this review, we summarize the findings of WS patient-specific iPSCs (WS iPSCs) and focus on the roles of telomere and telomerase in the maintenance of these cells. Finally, we discuss the potential use of WS iPSCs for clinical applications.},
}
@article {pmid25688135,
year = {2015},
author = {Fennell, A and Fernández-Álvarez, A and Tomita, K and Cooper, JP},
title = {Telomeres and centromeres have interchangeable roles in promoting meiotic spindle formation.},
journal = {The Journal of cell biology},
volume = {208},
number = {4},
pages = {415-428},
pmid = {25688135},
issn = {1540-8140},
support = {12097/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Cell Cycle Proteins/biosynthesis/genetics ; Centromere/*genetics ; Centrosome/*metabolism ; Chromatin/genetics ; Chromosomes, Fungal/genetics ; Dyneins/genetics ; Endoribonucleases/genetics ; Green Fluorescent Proteins/biosynthesis/genetics ; *Meiosis ; Nuclear Envelope/metabolism ; Nuclear Proteins/genetics ; Schizosaccharomyces/cytology/*genetics ; Schizosaccharomyces pombe Proteins/biosynthesis/genetics/metabolism ; Spindle Apparatus/*genetics ; Telomere/*genetics ; Telomere-Binding Proteins/biosynthesis/genetics ; },
abstract = {Telomeres and centromeres have traditionally been considered to perform distinct roles. During meiotic prophase, in a conserved chromosomal configuration called the bouquet, telomeres gather to the nuclear membrane (NM), often near centrosomes. We found previously that upon disruption of the fission yeast bouquet, centrosomes failed to insert into the NM at meiosis I and nucleate bipolar spindles. Hence, the trans-NM association of telomeres with centrosomes during prophase is crucial for efficient spindle formation. Nonetheless, in approximately half of bouquet-deficient meiocytes, spindles form properly. Here, we show that bouquet-deficient cells can successfully undergo meiosis using centromere-centrosome contact instead of telomere-centrosome contact to generate spindle formation. Accordingly, forced association between centromeres and centrosomes fully rescued the spindle defects incurred by bouquet disruption. Telomeres and centromeres both stimulate focal accumulation of the SUN domain protein Sad1 beneath the centrosome, suggesting a molecular underpinning for their shared spindle-generating ability. Our observations demonstrate an unanticipated level of interchangeability between the two most prominent chromosomal landmarks.},
}
@article {pmid25687075,
year = {2015},
author = {Zhang, JY and An, WB and Zhang, L and Chang, LX and Qi, BQ and Liu, TF and Liu, F and Yang, WY and Guo, Y and Zhu, XF},
title = {[Genotype analysis and telomere length measure in patients with dyskeratosis congenita].},
journal = {Zhongguo shi yan xue ye xue za zhi},
volume = {23},
number = {1},
pages = {212-216},
doi = {10.7534/j.issn.1009-2137.2015.01.040},
pmid = {25687075},
issn = {1009-2137},
mesh = {Base Sequence ; Bone Marrow ; China ; *Dyskeratosis Congenita ; Exons ; Genotype ; Humans ; In Situ Hybridization, Fluorescence ; Polymerase Chain Reaction ; Sequence Analysis, DNA ; *Telomere ; Telomere-Binding Proteins ; },
abstract = {OBJECTIVE: To analysze genotype and measure telomere length in two Chinese patients with dyskeratosis congenita(DC).<br><br>METHODS: The peripleral blood DNA was extracted in two patients characterized by mucocutaneous abnormalities (abnormal nails, lacy reticulated skin pigmentation, and oral leukoplakia), bone marrow failure, DC genes were amplified by polymerase chain reaction (PCR), including DKC1, TERT, TERC, TINF2, NOP10, NHP2, then DNA sequencing was performed for abnormal exons. Lymphocyte telomere length was measured by flow cytometry-fluorescence in situ hybridization(Flow-FISH).<br><br>RESULTS: Abnormal peaks were found in exon 6 of TINF2 gene of the two patients and a 811C&#x2192;T transition in TINF2 gene in one patient. DNA sequencing showed a 848C&#x2192;A transition in TINF2 gene in another patient. Relative telomere length was remarkable less than that of normal children with same age.<br><br>CONCLUSIONS: Physician should think about DC if the young patients with mucocutaneous abnormalities and marrow failure. Early detection of related genes and measurernant of tolomere length may contribute to avoid misdiagnosis. TINF2 c.811C&#x2192;T (Q271X) and TINF2 c.848C&#x2192;A (P283H) exist in the two patients, it is reported in China for the first time.},
}
@article {pmid25684230,
year = {2015},
author = {Boccardi, V and Razdan, N and Kaplunov, J and Mundra, JJ and Kimura, M and Aviv, A and Herbig, U},
title = {Stn1 is critical for telomere maintenance and long-term viability of somatic human cells.},
journal = {Aging cell},
volume = {14},
number = {3},
pages = {372-381},
pmid = {25684230},
issn = {1474-9726},
support = {AG030678/AG/NIA NIH HHS/United States ; R01 CA136533/CA/NCI NIH HHS/United States ; R01 AG030678/AG/NIA NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; R01 CA184572/CA/NCI NIH HHS/United States ; R01CA136533/CA/NCI NIH HHS/United States ; R01CA184572/CA/NCI NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics ; Cell Line ; Cellular Senescence/genetics ; DNA Replication/*genetics ; Humans ; Oxidative Stress/genetics ; Telomerase/*genetics ; Telomere/genetics/*metabolism ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {Disruption of telomere maintenance pathways leads to accelerated entry into cellular senescence, a stable proliferative arrest that promotes aging-associated disorders in some mammals. The budding yeast CST complex, comprising Cdc13, Stn1, and Ctc1, is critical for telomere replication, length regulation, and end protection. Although mammalian homologues of CST have been identified recently, their role and function for telomere maintenance in normal somatic human cells are still incompletely understood. Here, we characterize the function of human Stn1 in cultured human fibroblasts and demonstrate its critical role in telomere replication, length regulation, and function. In the absence of high telomerase activity, shRNA-mediated knockdown of hStn1 resulted in aberrant and fragile telomeric structures, stochastic telomere attrition, increased telomere erosion rates, telomere dysfunction, and consequently accelerated entry into cellular senescence. Oxidative stress augmented the defects caused by Stn1 knockdown leading to almost immediate cessation of cell proliferation. In contrast, overexpression of hTERT suppressed some of the defects caused by hStn1 knockdown suggesting that telomerase can partially compensate for hStn1 loss. Our findings reveal a critical role for human Stn1 in telomere length maintenance and function, supporting the model that efficient replication of telomeric repeats is critical for long-term viability of normal somatic mammalian cells.},
}
@article {pmid25682873,
year = {2015},
author = {Zhang, X and Li, B and de Jonge, N and Björkholm, M and Xu, D},
title = {The DNA methylation inhibitor induces telomere dysfunction and apoptosis of leukemia cells that is attenuated by telomerase over-expression.},
journal = {Oncotarget},
volume = {6},
number = {7},
pages = {4888-4900},
pmid = {25682873},
issn = {1949-2553},
mesh = {Adult ; Aged ; Apoptosis/drug effects/genetics ; Azacitidine/*pharmacology ; Cell Line, Tumor ; DNA Damage ; DNA Methylation/*drug effects ; Female ; Humans ; Leukemia, Myeloid, Acute/*drug therapy/*genetics/metabolism/pathology ; Male ; Middle Aged ; Telomerase/*biosynthesis/genetics ; Telomere/*drug effects/*genetics/metabolism ; Young Adult ; },
abstract = {DNA methyltransferase inhibitors (DNMTIs) such as 5-azacytidine (5-AZA) have been used for treatment of acute myeloid leukemia (AML) and other malignancies. Although inhibiting global/gene-specific DNA methylation is widely accepted as a key mechanism behind DNMTI anti-tumor activity, other mechanisms are likely involved in DNMTI's action. Because telomerase reverse transcriptase (TERT) plays key roles in cancer through telomere elongation and telomere lengthening-independent activities, and TERT has been shown to confer chemo- or radio-resistance to cancer cells, we determine whether DNMTIs affect telomere function and whether TERT/telomerase interferes with their anti-cancer efficacy. We showed that 5-AZA induced DNA damage and telomere dysfunction in AML cell lines by demonstrating the presence of 53-BP1 foci and the co-localization of 53-BP1 foci with telomere signals, respectively. Telomere dysfunction was coupled with diminished TERT expression, shorter telomere and apoptosis in 5-AZA-treated cells. However, 5-AZA treatment did not lead to changes in the methylation status of subtelomere regions. Down-regulation of TERT expression similarly occurred in primary leukemic cells derived from AML patients exposed to 5-AZA. TERT over-expression significantly attenuated 5-AZA-mediated DNA damage, telomere dysfunction and apoptosis of AML cells. Collectively, 5-AZA mediates the down-regulation of TERT expression, and induces telomere dysfunction, which consequently exerts an anti-tumor activity.},
}
@article {pmid25681203,
year = {2015},
author = {Drury, SS and Esteves, K and Hatch, V and Woodbury, M and Borne, S and Adamski, A and Theall, KP},
title = {Setting the trajectory: racial disparities in newborn telomere length.},
journal = {The Journal of pediatrics},
volume = {166},
number = {5},
pages = {1181-1186},
pmid = {25681203},
issn = {1097-6833},
support = {R01 MH101533/MH/NIMH NIH HHS/United States ; K12 HD043451/HD/NICHD NIH HHS/United States ; 3R01MH101533-02S3/MH/NIMH NIH HHS/United States ; 1 R01 MH101533-01/MH/NIMH NIH HHS/United States ; K12HD043451/HD/NICHD NIH HHS/United States ; 2K12HD043451-06/HD/NICHD NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Black or African American ; Black People ; Dried Blood Spot Testing/*methods ; Ethnicity ; Female ; *Health Status Disparities ; Humans ; Infant, Newborn ; Male ; Neonatal Screening/*methods ; New Orleans ; Pregnancy ; Real-Time Polymerase Chain Reaction ; Sequence Analysis, DNA ; Sex Factors ; Telomere/*ultrastructure ; White People ; },
abstract = {OBJECTIVE: To explore racial differences in newborn telomere length (TL) and the effect moderation of the sex of the infant while establishing the methodology for the use of newborn blood spots for TL analyses.<br><br>STUDY DESIGN: Pregnant mothers were recruited from the Greater New Orleans area. TL was determined via monochrome multiplex quantitative real-time polymerase chain reaction on DNA extracted from infant blood spots. Demographic data and other covariates were obtained via maternal report before the infant's birth. Birth outcome data were obtained from medical records and maternal report.<br><br>RESULTS: Black infants weighed significantly less than white infants at birth and had significantly longer TL than white infants (P=.0134), with the strongest effect observed in black female infants. No significant differences in gestational age were present.<br><br>CONCLUSIONS: Significant racial differences in TL were present at birth in this sample, even after we controlled for a range of birth outcomes and demographic factors. Because longer initial TL is predictive of more rapid TL attrition across the life course, these findings provide evidence that, even at birth, biological vulnerability to early life stress may differ by race and sex.},
}
@article {pmid25678850,
year = {2015},
author = {Wang, C and Zhao, L and Lu, S},
title = {Role of TERRA in the regulation of telomere length.},
journal = {International journal of biological sciences},
volume = {11},
number = {3},
pages = {316-323},
pmid = {25678850},
issn = {1449-2288},
mesh = {Humans ; *Models, Genetic ; RNA, Long Noncoding/metabolism/*physiology ; Saccharomyces cerevisiae/genetics ; Telomere/metabolism ; *Telomere Homeostasis ; },
abstract = {Telomere dysfunction is closely associated with human diseases such as cancer and ageing. Inappropriate changes in telomere length and/or structure result in telomere dysfunction. Telomeres have been considered to be transcriptionally silent, but it was recently demonstrated that mammalian telomeres are transcribed into telomeric repeat-containing RNA (TERRA). TERRA, a long non-coding RNA, participates in the regulation of telomere length, telomerase activity and heterochromatinization. The correct regulation of telomere length may be crucial to telomeric homeostasis and functions. Here, we summarize recent advances in our understanding of the crucial role of TERRA in the maintenance of telomere length, with focus on the variety of mechanisms by which TERRA is involved in the regulation of telomere length. This review aims to enable further understanding of how TERRA-targeted drugs can target telomere-related diseases.},
}
@article {pmid25677239,
year = {2015},
author = {Qi Nan, W and Ling, Z and Bing, C},
title = {The influence of the telomere-telomerase system on diabetes mellitus and its vascular complications.},
journal = {Expert opinion on therapeutic targets},
volume = {19},
number = {6},
pages = {849-864},
doi = {10.1517/14728222.2015.1016500},
pmid = {25677239},
issn = {1744-7631},
mesh = {Animals ; DNA Damage/genetics ; Diabetes Mellitus/physiopathology/*therapy ; Diabetic Angiopathies/physiopathology/therapy ; Disease Progression ; Genetic Therapy/methods ; Humans ; Molecular Targeted Therapy ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/physiology ; },
abstract = {The telomere-telomerase system plays an important role in the pathogenesis and disease progression of diabetes mellitus as well as in its vascular complications. Recent studies suggest that telomere shortening and abnormal telomerase activity occur in patients with diabetes mellitus, and targeting the telomere-telomerase system has become a prospective treatment for diabetes mellitus and its vascular complications. This review highlights the significance of the telomere-telomerase system and supports its role as a possible therapeutic target for patients with diabetes mellitus and its vascular complications Areas covered: This review covers the advances in understanding the telomere-telomerase system over the last 30 years and its significance in diabetes mellitus. In addition, it provides knowledge regarding the significance of the telomere-telomerase system in diabetes mellitus and its vascular complications as well as its role and mechanisms in oxidative stress, cell therapy and antioxidant activity Expert opinion: The telomere-telomerase system may be a potential therapeutic target that can protect against DNA damage and apoptosis in patients with diabetes mellitus and its vascular complications. DNA damage and apoptosis are associated with oxidative stress and are involved in the dysfunction of pancreatic β cells, insulin resistance, and its vascular complications. Abnormalities in the telomere-telomerase system may be associated with diabetes mellitus and its vascular complications. Therapies targeting telomere-telomerase system, telomerase reverse transcriptase transfection and alterative telomere lengthening must be identified before gene therapy can commence.},
}
@article {pmid25675824,
year = {2014},
author = {Yamazaki, H and Ishikawa, F},
title = {[Telomere maintenance by DNA damage sensor kinases, ATM and ATR].},
journal = {Seikagaku. The Journal of Japanese Biochemical Society},
volume = {86},
number = {6},
pages = {812-816},
pmid = {25675824},
issn = {0037-1017},
mesh = {Ataxia Telangiectasia Mutated Proteins/*physiology ; DNA Damage/*genetics/*physiology ; DNA, Fungal/metabolism ; Genes, Switch ; Humans ; Protein Binding ; Schizosaccharomyces/*genetics ; Schizosaccharomyces pombe Proteins/genetics/metabolism/physiology ; Shelterin Complex ; Telomerase/metabolism ; Telomere/enzymology/*genetics ; Telomere Homeostasis/*genetics/*physiology ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
}
@article {pmid25668263,
year = {2015},
author = {Gadalla, SM and Wang, T and Haagenson, M and Spellman, SR and Lee, SJ and Williams, KM and Wong, JY and De Vivo, I and Savage, SA},
title = {Association between donor leukocyte telomere length and survival after unrelated allogeneic hematopoietic cell transplantation for severe aplastic anemia.},
journal = {JAMA},
volume = {313},
number = {6},
pages = {594-602},
pmid = {25668263},
issn = {1538-3598},
support = {U24 CA076518/CA/NCI NIH HHS/United States ; 2R01 CA082838/CA/NCI NIH HHS/United States ; R01 CA082838/CA/NCI NIH HHS/United States ; HHSH234200637015C//PHS HHS/United States ; U24-CA76518/CA/NCI NIH HHS/United States ; Z99 CA999999//Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Anemia, Aplastic/mortality/*therapy ; Child ; Child, Preschool ; Female ; *Hematopoietic Stem Cell Transplantation ; Humans ; Infant ; Kaplan-Meier Estimate ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Telomere/*ultrastructure ; *Tissue Donors ; Transplantation, Homologous ; Young Adult ; },
abstract = {IMPORTANCE: Telomeres protect chromosome ends and are markers of cellular aging and replicative capacity.<br><br>OBJECTIVE: To evaluate the association between recipient and donor pretransplant leukocyte telomere length with outcomes after unrelated donor allogeneic hematopoietic cell transplantation (HCT) for patients with severe aplastic anemia.<br><br>The study included 330 patients (235 acquired, 85 Fanconi anemia, and 10 Diamond-Blackfan anemia) and their unrelated donors who had pre-HCT blood samples and clinical and outcome data available at the Center for International Blood and Marrow Transplant Research. Patients underwent HCT between 1989 and 2007 in 84 centers and were followed-up to March 2013.<br><br>EXPOSURES: Recipient and donor pre-HCT leukocyte telomere length classified into long (third tertile) and short (first and second tertiles combined) based on donor telomere length distribution.<br><br>MAIN OUTCOMES AND MEASURES: Overall survival, neutrophil recovery, and acute and chronic graft-vs-host disease, as ascertained by transplant centers through regular patient follow-up.<br><br>RESULTS: Longer donor leukocyte telomere length was associated with higher survival probability (5-year overall survival, 56%; number at risk, 57; cumulative deaths, 50) than shorter donor leukocyte telomere length (5-year overall survival, 40%; number at risk, 71; cumulative deaths, 128; P&#x2009;=&#x2009;.009). The association remained statistically significant after adjusting for donor age, disease subtype, Karnofsky performance score, graft type, HLA matching, prior aplastic anemia therapy, race/ethnicity, and calendar year of transplant (hazard ratio [HR], 0.61; 95% CI, 0.44-0.86). Similar results were noted in analyses stratified on severe aplastic anemia subtype, recipient age, HLA matching, calendar year of transplant, and conditioning regimen. There was no association between donor telomere length and neutrophil engraftment at 28 days (cumulative incidence, 86% vs 85%; HR, 0.94; 95% CI, 0.73-1.22), acute graft-vs-host disease grades III-IV at 100 days (cumulative incidence, 22% vs 28%; HR, 0.77; 95% CI, 0.48-1.23), or chronic graft-vs-host disease at 1-year (cumulative incidence, 28% vs 30%; HR, 0.81; 95% CI, 0.53-1.24) for long vs short, respectively. Pretransplant leukocyte telomere length in the recipients was not associated with posttransplant survival (HR, 0.91; 95% CI, 0.64-1.30).<br><br>CONCLUSIONS AND RELEVANCE: Longer donor leukocyte telomere length was associated with increased 5-year survival in patients who received HCT for severe aplastic anemia. Patient leukocyte telomere length was not associated with survival. The results of this observational study suggest that donor leukocyte telomere length may have a role in long-term posttransplant survival.},
}
@article {pmid25668259,
year = {2015},
author = {Saad, A and Mineishi, S and Innis-Shelton, R},
title = {Telomere length in hematopoietic stem cell transplantation for severe aplastic anemia: is it ready for "prime time"?.},
journal = {JAMA},
volume = {313},
number = {6},
pages = {571-572},
doi = {10.1001/jama.2015.8},
pmid = {25668259},
issn = {1538-3598},
mesh = {Anemia, Aplastic/*therapy ; Female ; *Hematopoietic Stem Cell Transplantation ; Humans ; Leukocytes/*ultrastructure ; Male ; Telomere/*ultrastructure ; *Tissue Donors ; },
}
@article {pmid25662607,
year = {2015},
author = {Steinberg-Neifach, O and Wellington, K and Vazquez, L and Lue, NF},
title = {Combinatorial recognition of a complex telomere repeat sequence by the Candida parapsilosis Cdc13AB heterodimer.},
journal = {Nucleic acids research},
volume = {43},
number = {4},
pages = {2164-2176},
pmid = {25662607},
issn = {1362-4962},
mesh = {Candida/*genetics ; DNA, Fungal/chemistry/metabolism ; Fungal Proteins/chemistry/*metabolism ; Protein Multimerization ; Protein Structure, Tertiary ; Repetitive Sequences, Nucleic Acid ; Telomere/chemistry/*metabolism ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {The telomere repeat units of Candida species are substantially longer and more complex than those in other organisms, raising interesting questions concerning the recognition mechanisms of telomere-binding proteins. Herein we characterized the properties of Candida parapsilosis Cdc13A and Cdc13B, two paralogs that are responsible for binding and protecting the telomere G-strand tails. We found that Cdc13A and Cdc13B can each form complexes with itself and a heterodimeric complex with each other. However, only the heterodimer exhibits high-affinity and sequence-specific binding to the telomere G-tail. EMSA and crosslinking analysis revealed a combinatorial mechanism of DNA recognition, which entails the A and B subunit making contacts to the 3' and 5' region of the repeat unit. While both the DBD and OB4 domain of Cdc13A can bind to the equivalent domain in Cdc13B, only the OB4 complex behaves as a stable heterodimer. The unstable Cdc13AB(DBD) complex binds G-strand with greatly reduced affinity but the same sequence specificity. Thus the OB4 domains evidently contribute to binding by promoting dimerization of the DBDs. Our investigation reveals a rare example of combinatorial recognition of single-stranded DNA and offers insights into the co-evolution of telomere DNA and cognate binding proteins.},
}
@article {pmid25662602,
year = {2015},
author = {Komosa, M and Root, H and Meyn, MS},
title = {Visualization and quantitative analysis of extrachromosomal telomere-repeat DNA in individual human cells by Halo-FISH.},
journal = {Nucleic acids research},
volume = {43},
number = {4},
pages = {2152-2163},
pmid = {25662602},
issn = {1362-4962},
mesh = {Cell Cycle ; Cell Line ; Cell Nucleus/genetics ; DNA/*analysis/chemistry ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; Telomere Homeostasis ; },
abstract = {Current methods for characterizing extrachromosomal nuclear DNA in mammalian cells do not permit single-cell analysis, are often semi-quantitative and frequently biased toward the detection of circular species. To overcome these limitations, we developed Halo-FISH to visualize and quantitatively analyze extrachromosomal DNA in single cells. We demonstrate Halo-FISH by using it to analyze extrachromosomal telomere-repeat (ECTR) in human cells that use the Alternative Lengthening of Telomeres (ALT) pathway(s) to maintain telomere lengths. We find that GM847 and VA13 ALT cells average ∼80 detectable G/C-strand ECTR DNA molecules/nucleus, while U2OS ALT cells average ∼18 molecules/nucleus. In comparison, human primary and telomerase-positive cells contain <5 ECTR DNA molecules/nucleus. ECTR DNA in ALT cells exhibit striking cell-to-cell variations in number (<20 to >300), range widely in length (<1 to >200 kb) and are composed of primarily G- or C-strand telomere-repeat DNA. Halo-FISH enables, for the first time, the simultaneous analysis of ECTR DNA and chromosomal telomeres in a single cell. We find that ECTR DNA comprises ∼15% of telomere-repeat DNA in GM847 and VA13 cells, but <4% in U2OS cells. In addition to its use in ALT cell analysis, Halo-FISH can facilitate the study of a wide variety of extrachromosomal DNA in mammalian cells.},
}
@article {pmid25660060,
year = {2015},
author = {Zole, E and Elferts, D and Kimsis, J and Krumina, A and Narels, K and Pole, I and Ranka, R and Pliss, L},
title = {Comparison of telomere length between population-specific mitochondrial haplogroups among different age groups in a Latvian population.},
journal = {Mechanisms of ageing and development},
volume = {145},
number = {},
pages = {13-17},
doi = {10.1016/j.mad.2015.01.002},
pmid = {25660060},
issn = {1872-6216},
mesh = {Adult ; Aged ; Aged, 80 and over ; DNA, Mitochondrial/*genetics ; Female ; *Haplotypes ; Humans ; Latvia ; Longevity/*genetics ; Male ; Middle Aged ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Population studies have demonstrated that telomere length (TL) displays great diversity among different populations. Previously described controversial findings associated longevity with specific mitochondrial DNA haplogroups (hgs) (e.g., J and U). These observations may be influenced by population diversity, geographic location, and/or specific historic background. The aims of this study were to identify a specific hg which correlates with aging in a Latvian populating and to evaluate the possible association of TL variability with specific mitochondrial hgs. The results show no significant correlation between TL, mitochondrial DNA hgs and longevity. A slight increase in frequency was observed among centenarians of hg H; however, these findings were not statistically significant. TL did not show any statically significant difference, only hg W had slightly longer telomeres among others. An insignificant increase in TL was observed in the 55-89 age group of hg W but in the <90 age group for hg J which also had the longest TL in the 20-45 age group. In conclusion this study indicates that specific mitochondrial DNA hgs do not have a significant, if any, influence on the variation of TL in Latvians.},
}
@article {pmid25658358,
year = {2015},
author = {Matsuda, Y and Ishiwata, T and Izumiyama-Shimomura, N and Hamayasu, H and Fujiwara, M and Tomita, K and Hiraishi, N and Nakamura, K and Ishikawa, N and Aida, J and Takubo, K and Arai, T},
title = {Gradual telomere shortening and increasing chromosomal instability among PanIN grades and normal ductal epithelia with and without cancer in the pancreas.},
journal = {PloS one},
volume = {10},
number = {2},
pages = {e0117575},
pmid = {25658358},
issn = {1932-6203},
mesh = {Carcinoma in Situ/genetics/metabolism/*pathology ; Chromosomal Instability/*genetics ; Epithelium/metabolism/*pathology ; Humans ; Pancreas/metabolism/*pathology ; Pancreatic Neoplasms/genetics/metabolism/*pathology ; Telomere/genetics/*pathology ; *Telomere Shortening ; },
abstract = {A large body of evidence supports a key role for telomere dysfunction in carcinogenesis due to the induction of chromosomal instability. To study telomere shortening in precancerous pancreatic lesions, we measured telomere lengths using quantitative fluorescence in situ hybridization in the normal pancreatic duct epithelium, pancreatic intraepithelial neoplasias (PanINs), and cancers. The materials employed included surgically resected pancreatic specimens without cancer (n = 33) and with invasive ductal carcinoma (n = 36), as well as control autopsy cases (n = 150). In comparison with normal ducts, telomere length was decreased in PanIN-1, -2 and -3 and cancer. Furthermore, telomeres were shorter in cancer than in PanIN-1 and -2. Telomere length in cancer was not associated with histological type, lesion location, or cancer stage. PanINs with or without cancer showed similar telomere lengths. The incidences of atypical mitosis and anaphase bridges, which are morphological characteristics of chromosomal instability, were negatively correlated with telomere length. The telomeres in normal duct epithelium became shorter with aging, and those in PanINs or cancers were shorter than in age-matched controls, suggesting that telomere shortening occurs even when histological changes are absent. Our data strongly suggest that telomere shortening occurs in the early stages of pancreatic carcinogenesis and progresses with precancerous development. Telomere shortening and chromosomal instability in the duct epithelium might be associated with carcinogenesis of the pancreas. Determination of telomere length in pancreatic ductal lesions may be valuable for accurate detection and risk assessment of pancreatic cancer.},
}
@article {pmid25653721,
year = {2015},
author = {Padhi, S and Saha, A and Kar, M and Ghosh, C and Adhya, A and Baisakh, M and Mohapatra, N and Venkatesan, S and Hande, MP and Banerjee, B},
title = {Clinico-Pathological Correlation of β-Catenin and Telomere Dysfunction in Head and Neck Squamous Cell Carcinoma Patients.},
journal = {Journal of Cancer},
volume = {6},
number = {2},
pages = {192-202},
pmid = {25653721},
issn = {1837-9664},
abstract = {BACKGROUND: Tumorigenesis is a complex process of accumulated alteration in function of multiple genes and pathways. Wnt signalling pathway is involved in various differentiation events during embryonic development and is conserved in various species.<br><br>OBJECTIVE: A multicentre collaborative initiative is undertaken to study the occurrence, prognosis and molecular mechanism of HNSCC (Head and Neck Squamous Cell Carcinoma) which is highly prevalent in eastern parts of India. From a large cohort of HNSCC tissue repository, 67 cases were selected for multi-parametric investigation.<br><br>RESULTS: 67 cases showed stable &#x3b2;-catenin expression. We have seen correlation, if any, of the transcription factor - &#x3b2;-catenin, telomere maintenance and shelterin complex proteins - TRF2, Rap1 and hTert with respect to tumor differentiation and telomere dysfunction. Immunohistochemistry of &#x3b2;-catenin protein showed stable and high expression in tumor when compared to stroma. MDSCC (Moderately Differentiated Squamous cell carcinoma) cases expressed nuclear expression of &#x3b2;-catenin in invasive fronts and showed increased genomic instability. Higher frequency of Anaphase bridges was observed ranging from <3% in normal cut margin to 13% in WDSCC (Well differentiated squamous cell carcinoma) and 18% in MDSCC (Moderately differentiated Squamous cell carcinoma). There was significant decrease in telomere length in MDSCC (<4) when compared to the normal cut margin samples (<7). Quantitative Real Time-PCR confirmed a significant correlationship between stable &#x3b2;-catenin expression and poor clinical and pathological outcome.<br><br>CONCLUSION: The Stabilisation and accumulation of &#x3b2;-catenin was significant and correlated well with de-differentiation process as well as prognosis and therapy outcome of the patients in the cohort. Expression status of molecular markers such as &#x3b2;-catenin, hTert, TRF2 and RAP1 correlate significantly with the process of tumorigenesis and prognosis and may play a role in therapeutic management of Head and neck patients.},
}
@article {pmid25653166,
year = {2015},
author = {de Sena-Tomás, C and Yu, EY and Calzada, A and Holloman, WK and Lue, NF and Pérez-Martín, J},
title = {Fungal Ku prevents permanent cell cycle arrest by suppressing DNA damage signaling at telomeres.},
journal = {Nucleic acids research},
volume = {43},
number = {4},
pages = {2138-2151},
pmid = {25653166},
issn = {1362-4962},
support = {GM042482/GM/NIGMS NIH HHS/United States ; GM079859/GM/NIGMS NIH HHS/United States ; },
mesh = {Antigens, Nuclear/genetics/*physiology ; DNA Damage ; *DNA Repair ; DNA-Binding Proteins/analysis/genetics/metabolism/*physiology ; Down-Regulation ; Fungal Proteins/*physiology ; G2 Phase Cell Cycle Checkpoints/*genetics ; Ku Autoantigen ; Signal Transduction ; Telomere/chemistry/*metabolism ; Telomere Homeostasis ; Ustilago/genetics ; },
abstract = {The Ku heterodimer serves in the initial step in repairing DNA double-strand breaks by the non-homologous end-joining pathway. Besides this key function, Ku also plays a role in other cellular processes including telomere maintenance. Inactivation of Ku can lead to DNA repair defects and telomere aberrations. In model organisms where Ku has been studied, inactivation can lead to DNA repair defects and telomere aberrations. In general Ku deficient mutants are viable, but a notable exception to this is human where Ku has been found to be essential. Here we report that similar to the situation in human Ku is required for cell proliferation in the fungus Ustilago maydis. Using conditional strains for Ku expression, we found that cells arrest permanently in G2 phase when Ku expression is turned off. Arrest results from cell cycle checkpoint activation due to persistent signaling via the DNA damage response (DDR). Our results point to the telomeres as the most likely source of the DNA damage signal. Inactivation of the DDR makes the Ku complex dispensable for proliferation in this organism. Our findings suggest that in U. maydis, unprotected telomeres arising from Ku depletion are the source of the signal that activates the DDR leading to cell cycle arrest.},
}
@article {pmid25646618,
year = {2015},
author = {Zhang, WG and Wang, Y and Hou, K and Jia, LP and Ma, J and Zhao, DL and Zhu, SY and Bai, XJ and Cai, GY and Wang, YP and Sun, XF and Chen, XM},
title = {A correlation study of telomere length in peripheral blood leukocytes and kidney function with age.},
journal = {Molecular medicine reports},
volume = {11},
number = {6},
pages = {4359-4364},
doi = {10.3892/mmr.2015.3292},
pmid = {25646618},
issn = {1791-3004},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Cystatin C/blood ; Female ; Healthy Volunteers ; Humans ; Kidney/*physiopathology ; Kidney Function Tests ; Leukocytes/*metabolism ; Male ; Middle Aged ; Telomere/*metabolism ; },
abstract = {The current study aimed to investigate the association between telomere length in peripheral blood leukocytes and kidney function in various age groups of a healthy population. A total of 139 healthy individuals were divided into five groups according to their age: 35‑44, 45‑54, 55‑64, 65‑74 and >75 years old. Peripheral blood leukocytes were obtained and the telomere restriction fragment (TRF) length was assayed using a digoxigenin‑labeled hybridization probe in Southern blot assays. Laboratory assays of kidney function were also performed. A correlation was observed between TRF length and age (r=‑0.314, P<0.001), with the telomere length of the individuals >75 years group being significantly shorter than the telomere length of the 35‑44, 45‑54 and 55‑64 years age groups (P<0.05). By contrast, the TRF length for males versus females did not differ for any of the age groups, while a correlation was observed between TRF length and serum levels of cystatin C (r=‑0.195, P<0.05). There was also a correlation between TRF length and glomerular filtration rate (r=‑0.184, P<0.05). The current study demonstrated that in this cohort, leukocyte telomere length reduced with age and was correlated with serum levels of cystatin C and glomerular filtration rate. Therefore, TRF length is associated with kidney function and may serve as a marker of aging.},
}
@article {pmid25644606,
year = {2015},
author = {Lopez, V and Barinova, N and Onishi, M and Pobiega, S and Pringle, JR and Dubrana, K and Marcand, S},
title = {Cytokinesis breaks dicentric chromosomes preferentially at pericentromeric regions and telomere fusions.},
journal = {Genes &amp; development},
volume = {29},
number = {3},
pages = {322-336},
pmid = {25644606},
issn = {1549-5477},
mesh = {Cell Nucleus Division ; Centromere/*genetics ; *Chromosome Breakage ; Chromosomes, Fungal/*genetics ; *Cytokinesis ; Mitosis ; Saccharomyces cerevisiae/*genetics ; Telomere/*metabolism ; },
abstract = {Dicentric chromosomes are unstable products of erroneous DNA repair events that can lead to further genome rearrangements and extended gene copy number variations. During mitosis, they form anaphase bridges, resulting in chromosome breakage by an unknown mechanism. In budding yeast, dicentrics generated by telomere fusion break at the fusion, a process that restores the parental karyotype and protects cells from rare accidental telomere fusion. Here, we observed that dicentrics lacking telomere fusion preferentially break within a 25- to 30-kb-long region next to the centromeres. In all cases, dicentric breakage requires anaphase exit, ruling out stretching by the elongated mitotic spindle as the cause of breakage. Instead, breakage requires cytokinesis. In the presence of dicentrics, the cytokinetic septa pinch the nucleus, suggesting that dicentrics are severed after actomyosin ring contraction. At this time, centromeres and spindle pole bodies relocate to the bud neck, explaining how cytokinesis can sever dicentrics near centromeres.},
}
@article {pmid25641522,
year = {2015},
author = {Stathopoulou, MG and Petrelis, AM and Buxton, JL and Froguel, P and Blakemore, AI and Visvikis-Siest, S},
title = {Genetic determinants of leucocyte telomere length in children: a neglected and challenging field.},
journal = {Paediatric and perinatal epidemiology},
volume = {29},
number = {2},
pages = {146-150},
doi = {10.1111/ppe.12173},
pmid = {25641522},
issn = {1365-3016},
support = {08/0003775/DUK_/Diabetes UK/United Kingdom ; MR/K014536/1/MRC_/Medical Research Council/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; },
mesh = {Adolescent ; Age Distribution ; Age Factors ; Body Mass Index ; Child ; Environmental Exposure ; Female ; *Genome-Wide Association Study ; Humans ; Leukocytes/*physiology ; Male ; Maternal Age ; Real-Time Polymerase Chain Reaction ; Sex Distribution ; Telomere/*genetics/physiology ; Telomere-Binding Proteins/*genetics/physiology ; },
abstract = {BACKGROUND: Telomere length is associated with a large range of human diseases. Genome-wide association studies (GWAS) have identified genetic variants that are associated with leucocyte telomere length (LTL). However, these studies are limited to adult populations. Nevertheless, childhood is a crucial period for the determination of LTL, and the assessment of age-specific genetic determinants, although neglected, could be of great importance. Our aim was to provide insights and preliminary results on genetic determinants of LTL in children.<br><br>METHODS: Healthy children (n = 322, age range = 6.75-17 years) with available GWAS data (Illumina Human CNV370-Duo array) were included. The LTL was measured using multiplex quantitative real-time polymerase chain reaction. Linear regression models adjusted for age, gender, parental age at child's birth, and body mass index were used to test the associations of LTL with polymorphisms identified in adult GWAS and to perform a discovery-only GWAS.<br><br>RESULTS: The previously GWAS-identified variants in adults were not associated with LTL in our paediatric sample. This lack of association was not due to possible interactions with age or gene &#xd7; gene interactions. Furthermore, a discovery-only GWAS approach demonstrated six novel variants that reached the level of suggestive association (P &#x2264; 5 &#xd7; 10(-5)) and explain a high percentage of children's LTL.<br><br>CONCLUSIONS: The study of genetic determinants of LTL in children may identify novel variants not previously identified in adults. Studies in large-scale children populations are needed for the confirmation of these results, possibly through a childhood consortium that could better handle the methodological challenges of LTL genetic epidemiology field.},
}
@article {pmid25639660,
year = {2015},
author = {Haver, VG and Mateo Leach, I and Kjekshus, J and Fox, JC and Wedel, H and Wikstrand, J and de Boer, RA and van Gilst, WH and McMurray, JJ and van Veldhuisen, DJ and van der Harst, P},
title = {Telomere length and outcomes in ischaemic heart failure: data from the COntrolled ROsuvastatin multiNAtional Trial in Heart Failure (CORONA).},
journal = {European journal of heart failure},
volume = {17},
number = {3},
pages = {313-319},
doi = {10.1002/ejhf.237},
pmid = {25639660},
issn = {1879-0844},
mesh = {Aged ; Aged, 80 and over ; Aging/physiology ; Biomarkers ; Double-Blind Method ; Female ; Heart Failure/*diagnosis/mortality ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use ; Leukocytes/physiology ; Male ; Myocardial Ischemia/drug therapy/*genetics ; Retrospective Studies ; Rosuvastatin Calcium/*therapeutic use ; *Telomere ; },
abstract = {AIMS: Leucocyte telomere length is considered a marker of biological ageing and has been suggested to be shorter in patients with CAD and heart failure compared with healthy controls. The aim of this study was to determine whether telomere length is associated with clinical outcomes in patients with ischaemic heart failure and whether this association is superior to chronological age as defined by date of birth.<br><br>METHODS AND RESULTS: We measured leucocyte telomere length in 3275 patients with chronic ischaemic systolic heart failure participating in the COntrolled ROsuvastatin multiNAtional Trial in Heart Failure (CORONA) study. The primary composite endpoint was cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, which occurred in 575 patients during follow-up. We observed a significant association of leucocyte telomere lengths with the primary endpoint (hazard ratio 1.10; 95% confidence interval 1.01-1.20; P=0.03). However, this observation was not superior to age as defined by date of birth. The neutral effect of rosuvastatin treatment on clinical outcomes was not modified by baseline telomere length.<br><br>CONCLUSION: Biological age as defined by leucocyte telomere length was associated with clinical outcomes in patients with ischaemic heart failure, but this association did not add prognostic information above age as defined by date of birth.},
}
@article {pmid25631672,
year = {2015},
author = {Crocco, P and Barale, R and Rose, G and Rizzato, C and Santoro, A and De Rango, F and Carrai, M and Fogar, P and Monti, D and Biondi, F and Bucci, L and Ostan, R and Tallaro, F and Montesanto, A and Zambon, CF and Franceschi, C and Canzian, F and Passarino, G and Campa, D},
title = {Population-specific association of genes for telomere-associated proteins with longevity in an Italian population.},
journal = {Biogerontology},
volume = {16},
number = {3},
pages = {353-364},
doi = {10.1007/s10522-015-9551-6},
pmid = {25631672},
issn = {1573-6768},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/genetics/physiology ; Female ; Genetic Variation/genetics/physiology ; Humans ; Italy ; Longevity/*genetics/physiology ; Male ; Middle Aged ; Polymorphism, Genetic/genetics/physiology ; Population Groups/ethnology/*genetics ; Shelterin Complex ; Tankyrases/*genetics/physiology ; Telomere/genetics/physiology ; Telomere Homeostasis/genetics ; Telomere-Binding Proteins/*genetics/physiology ; },
abstract = {Leukocyte telomere length (LTL) has been observed to be hereditable and correlated with longevity. However, contrasting results have been reported in different populations on the value of LTL heritability and on how biology of telomeres influences longevity. We investigated whether the variability of genes correlated to telomere maintenance is associated with telomere length and affects longevity in a population from Southern Italy (20-106 years). For this purpose we analyzed thirty-one polymorphisms in eight telomerase-associated genes of which twelve in the genes coding for the core enzyme (TERT and TERC) and the remaining in genes coding for components of the telomerase complex (TERF1, TERF2, TERF2IP, TNKS, TNKS2 and TEP1). We did not observe (after correcting for multiple testing) statistically significant associations between SNPs and LTL, possibly suggesting a low genetic influence of the variability of these genes on LTL in the elderly. On the other hand, we found that the variability of genes encoding for TERF1 and TNKS2, not directly involved in LTL, but important for keeping the integrity of the structure, shows a significant association with longevity. This suggests that the maintenance of these chromosomal structures may be critically important for preventing, or delaying, senescence and aging. Such a correlation was not observed in a population from northern Italy that we used as an independent replication set. This discrepancy is in line with previous reports regarding both the population specificity of results on telomere biology and the differences of aging in northern and southern Italy.},
}
@article {pmid25631622,
year = {2015},
author = {Chaichompoo, P and Pattanapanyasat, K and Winichagoon, P and Fucharoen, S and Svasti, S},
title = {Accelerated telomere shortening in β-thalassemia/HbE patients.},
journal = {Blood cells, molecules &amp; diseases},
volume = {55},
number = {2},
pages = {173-179},
doi = {10.1016/j.bcmd.2015.01.003},
pmid = {25631622},
issn = {1096-0961},
mesh = {Adolescent ; Adult ; Aged ; Aging ; Erythrocyte Indices ; Female ; Genotype ; Hemoglobin E/*genetics ; Humans ; Male ; Middle Aged ; Oxidative Stress ; Reticulocytosis ; Severity of Illness Index ; Telomerase/metabolism ; *Telomere Shortening ; Young Adult ; alpha-Globins/genetics ; beta-Globins/genetics ; beta-Thalassemia/diagnosis/*genetics/metabolism ; },
abstract = {β-Thalassemia/HbE disease is caused by a defective β-globin synthesis that leads to accumulation of excess unbound α-globins, and consequently oxidative stress, ineffective erythropoiesis and chronic anemia. Cell replication and oxidative stress are factors contributing to erosion of telomeres responsible for maintaining genomic stability and cell replication capability. In this study, the rate of telomere shortening in β-thalassemia/HbE patients was compared to the rate of telomere shortening in normal individuals. Telomere length was determined from peripheral blood mononuclear cells of 43 β-thalassemia/HbE patients and 22 normal controls using Flow-FISH analysis. The telomere length was shown to be age-dependent in normal group (rs = 0.715, P = 0.002), whereas severity-dependent telomere shortening was observed in the patients. The telomere length of patients who had severe clinical symptoms (10.07 ± 2.15%) was shorter than that of patients who showed mild symptoms (15.59 ± 2.27%), moderate symptoms (14.50 ± 1.41%) and those in the normal group (14.75 ± 3.11%, P < 0.05). Additionally, reticulocyte count and oxidative stress were correlated with telomere length. This indicates that increased oxidative stress and markedly enhanced erythropoiesis in β-thalassemia/HbE patients leads to accelerated telomere erosion in clinically severe patients.},
}
@article {pmid25628358,
year = {2015},
author = {Schertzer, M and Jouravleva, K and Perderiset, M and Dingli, F and Loew, D and Le Guen, T and Bardoni, B and de Villartay, JP and Revy, P and Londoño-Vallejo, A},
title = {Human regulator of telomere elongation helicase 1 (RTEL1) is required for the nuclear and cytoplasmic trafficking of pre-U2 RNA.},
journal = {Nucleic acids research},
volume = {43},
number = {3},
pages = {1834-1847},
pmid = {25628358},
issn = {1362-4962},
mesh = {Base Sequence ; Biological Transport ; Blotting, Northern ; Cell Nucleus/*metabolism ; Chromatography, Liquid ; Cytoplasm/*metabolism ; DNA Helicases/genetics/*physiology ; DNA Primers ; HEK293 Cells ; HeLa Cells ; Humans ; Polymerase Chain Reaction ; RNA Precursors/*metabolism ; RNA, Small Interfering ; RNA, Small Nuclear/*metabolism ; Tandem Mass Spectrometry ; },
abstract = {Hoyeraal-Hreidarsson syndrome (HHS) is a severe form of Dyskeratosis congenita characterized by developmental defects, bone marrow failure and immunodeficiency and has been associated with telomere dysfunction. Recently, mutations in Regulator of Telomere ELongation helicase 1 (RTEL1), a helicase first identified in Mus musculus as being responsible for the maintenance of long telomeres, have been identified in several HHS patients. Here we show that RTEL1 is required for the export and the correct cytoplasmic trafficking of the small nuclear (sn) RNA pre-U2, a component of the major spliceosome complex. RTEL1-HHS cells show abnormal subcellular partitioning of pre-U2, defects in the recycling of ribonucleotide proteins (RNP) in the cytoplasm and splicing defects. While most of these phenotypes can be suppressed by re-expressing the wild-type protein in RTEL1-HHS cells, expression of RTEL1 mutated variants in immortalized cells provokes cytoplasmic mislocalizations of pre-U2 and other RNP components, as well as splicing defects, thus phenocopying RTEL1-HHS cellular defects. Strikingly, expression of a cytoplasmic form of RTEL1 is sufficient to correct RNP mislocalizations both in RTEL1-HHS cells and in cells expressing nuclear mutated forms of RTEL1. This work unravels completely unanticipated roles for RTEL1 in RNP trafficking and strongly suggests that defects in RNP biogenesis pathways contribute to the pathology of HHS.},
}
@article {pmid25628010,
year = {2015},
author = {Kwon, AM and Baik, I and Thomas, RJ and Shin, C},
title = {The association between leukocyte telomere lengths and sleep instability based on cardiopulmonary coupling analysis.},
journal = {Sleep &amp; breathing = Schlaf &amp; Atmung},
volume = {19},
number = {3},
pages = {963-968},
pmid = {25628010},
issn = {1522-1709},
mesh = {Aged ; Cohort Studies ; Delta Rhythm/physiology ; *Electrocardiography ; *Electroencephalography ; Fourier Analysis ; Homeostasis/physiology ; Humans ; Leukocytes/*metabolism ; Linear Models ; Male ; Middle Aged ; *Polysomnography ; Prospective Studies ; Republic of Korea ; Signal Processing, Computer-Assisted ; Sleep Apnea, Obstructive/*genetics/*physiopathology ; Sleep Deprivation/*genetics/*physiopathology ; Statistics as Topic ; Telomere Shortening/*physiology ; },
abstract = {PURPOSE: The purpose of the study is to examine the objective association between sleep stability and leukocyte telomere lengths (LTL) using cardiopulmonary coupling (CPC) analysis, which is an electrocardiogram (ECG)-based technique to quantify physiologic sleep stability.<br><br>METHODS: Three hundred eighty-one healthy subjects were recruited from a community-based cohort study from the Korean Genome and Epidemiology Study (KoGES), and the associations between LTL and total quantities of different frequency coupling bands were examined using generalized linear model (GLM) with adjustment of significant covariates.<br><br>RESULTS: LTL showed a significant association with elevated narrow-band low frequency coupling (e-LFCNB, a CPC marker of periodic breathing or sleep fragmentation due to pathological respiratory chemoreflex activation) by interacting with obstructive sleep apnea (OSA) severity (p value of <0.0001). Especially, sleep stability significantly reduced with shortened LTL in OSA patients (Apnea-Hypopnea Index (AHI) &#x2265;15) based on increased e-LFCNB which had a negative correlation with high-frequency coupling band (HFC), a marker of stable sleep.<br><br>CONCLUSION: The present study suggested that shorter LTL might contribute to reduced sleep stability by interacting with OSA severity due to the stress of chronic sleep fragmentation or invariant sympathetic activity by respiratory chemoreflex activation.},
}
@article {pmid25625311,
year = {2016},
author = {Sunpaweravong, S and Sunpaweravong, P and Sathitruangsak, C and Mai, S},
title = {Three-dimensional telomere architecture of esophageal squamous cell carcinoma: comparison of tumor and normal epithelial cells.},
journal = {Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus},
volume = {29},
number = {4},
pages = {307-313},
doi = {10.1111/dote.12317},
pmid = {25625311},
issn = {1442-2050},
mesh = {Adult ; Age Factors ; Aged, 80 and over ; Biopsy/methods ; *Carcinoma, Squamous Cell/genetics/pathology ; Cellular Senescence ; Epithelial Cells/*pathology ; *Esophageal Neoplasms/genetics/pathology ; Esophageal Squamous Cell Carcinoma ; Esophagus/*pathology ; Female ; Humans ; Imaging, Three-Dimensional/methods ; In Situ Hybridization, Fluorescence/methods ; Male ; Statistics as Topic ; Telomere Homeostasis/*genetics ; Telomere Shortening ; },
abstract = {Telomeres are repetitive nucleotide sequences (TTAGGG)n located at the ends of chromosomes that function to preserve chromosomal integrity and prevent terminal end-to-end fusions. Telomere loss or dysfunction results in breakage-bridge-fusion cycles, aneuploidy, gene amplification and chromosomal rearrangements, which can lead to genomic instability and promote carcinogenesis. Evaluating the hypothesis that changes in telomeres contribute to the development of esophageal squamous cell carcinoma (ESCC) and to determine whether there are differences between young and old patients, we compared the three-dimensional (3D) nuclear telomere architecture in ESCC tumor cells with that of normal epithelial cells obtained from the same patient. Patients were equally divided by age into two groups, one comprising those less than 45 years of age and the other consisting of those over 80 years of age. Tumor and normal epithelial cells located at least 10 cm from the border of the tumor were biopsied in ESCC patients. Hematoxylin and eosin staining was performed for each sample to confirm and identify the cancer and normal epithelial cells. This study was based on quantitative 3D fluorescence in situ hybridization (Q-FISH), 3D imaging and 3D analysis of paraffin-embedded slides. The 3D telomere architecture data were computer analyzed using 100 nuclei per slide. The following were the main parameters compared: the number of signals (number of telomeres), signal intensity (telomere length), number of telomere aggregates, and nuclear volume. Tumor and normal epithelial samples from 16 patients were compared. The normal epithelial cells had more telomere signals and higher intensities than the tumor cells, with P-values of P < 0.0001 and P = 0.0078, respectively. There were no statistically significant differences in the numbers of telomere aggregates or the nuclear volumes between the tumor and normal epithelial cells. Secondary analyses examined the effects of age on 3D telomere architecture and found no statistically significant differences in any parameter tested between the young and old patients in either the tumor or epithelial cells. The 3D nuclear telomeric signature was able to detect differences in telomere architecture between the ESCC and normal epithelial tissues. However, there were no differences observed between the young and old patients.},
}
@article {pmid25624920,
year = {2015},
author = {Liu, Y and Ling, Y and Qi, Q and Zhu, M and Wan, M and Zhang, Y and Zhang, C},
title = {Trastuzumab increases the sensitivity of HER2-amplified human gastric cancer cells to oxaliplatin and cisplatin by affecting the expression of telomere-associated proteins.},
journal = {Oncology letters},
volume = {9},
number = {2},
pages = {999-1005},
pmid = {25624920},
issn = {1792-1074},
abstract = {HER2 amplification occurs in ~20% of gastric cancer (GC) cases; however, in gastric and gastroesophageal junction cancer with HER2 gene amplification, trastuzumab in combination with cisplatin (DDP)-based chemotherapy has been reported to improve the oncological outcome. The aim of the present study was to evaluate the combined antitumor efficacy of trastuzumab and various platinum agents in GC cells and to elucidate mechanisms that may be involved in the interaction between trastuzumab and the platinum agents. The in vitro chemosensitivity of the GC cells to platinum agents was evaluated using the CellTiter 96[®] AQueous One Solution Cell Proliferation Assay kit. Treatment with 1.0μg/ml trastuzumab for 48 h significantly increased the sensitivity of NCI-N87 cells with HER2 amplification to oxaliplatin (Oxa) and DDP. This chemosensitivity was most prominent in the NCI-N87 cells, in which the half maximal inhibitory concentration of Oxa and DDP was decreased to ~3.29 and 6.91 times, respectively. The apoptotic effect of the platinum agents was evaluated by double-staining the GC cells with Annexin V-fluorescein isothiocyanate and propodium iodide. Consistent with the chemosensitivity analysis, apoptotic analysis indicated that trastuzumab significantly increased Oxa- and DDP-induced apoptosis in the NCI-N87 cells. Furthermore, the mRNA expression levels of various telomere-associated genes was determined by performing quantitative reverse transcription-polymerase chain reactions in a number of GC cell lines, and revealed that trastuzumab (alone and in combination with DDP) may downregulate the mRNA expression levels of the TPP1, TRF1, TRF2, TRF2IP and POT1 genes. However, western blot analysis demonstrated that trastuzumab (alone and in combination with DDP) may significantly downregulate the protein expression levels of telomeric repeat binding factor 2, protection of telomere 1 and TPP1 (formerly known as TINT1, PTOP and PIP). The results of the present study indicate a potential role of low-dose trastuzumab administration for increasing Oxa and DDP sensitivity in HER2-amplified GC cells, possibly via the downregulation of telomere-associated gene expression.},
}
@article {pmid25624462,
year = {2015},
author = {Mangino, M and Christiansen, L and Stone, R and Hunt, SC and Horvath, K and Eisenberg, DT and Kimura, M and Petersen, I and Kark, JD and Herbig, U and Reiner, AP and Benetos, A and Codd, V and Nyholt, DR and Sinnreich, R and Christensen, K and Nassar, H and Hwang, SJ and Levy, D and Bataille, V and Fitzpatrick, AL and Chen, W and Berenson, GS and Samani, NJ and Martin, NG and Tishkoff, S and Schork, NJ and Kyvik, KO and Dalgård, C and Spector, TD and Aviv, A},
title = {DCAF4, a novel gene associated with leucocyte telomere length.},
journal = {Journal of medical genetics},
volume = {52},
number = {3},
pages = {157-162},
pmid = {25624462},
issn = {1468-6244},
support = {U10 HL054472/HL/NHLBI NIH HHS/United States ; U01 HL054472/HL/NHLBI NIH HHS/United States ; N01-HC-25195/HC/NHLBI NIH HHS/United States ; U01 HL054471/HL/NHLBI NIH HHS/United States ; U01 HL054496/HL/NHLBI NIH HHS/United States ; //British Heart Foundation/United Kingdom ; R01 AG030678/AG/NIA NIH HHS/United States ; U10 HL054509/HL/NHLBI NIH HHS/United States ; R01 HL116446/HL/NHLBI NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; R01 AG020132/AG/NIA NIH HHS/United States ; HL105756/HL/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; U01 HL054509/HL/NHLBI NIH HHS/United States ; R01 HL087652/HL/NHLBI NIH HHS/United States ; HL055673/HL/NHLBI NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; HL54515/HL/NHLBI NIH HHS/United States ; R01 AG016592/AG/NIA NIH HHS/United States ; R01 ES021724/ES/NIEHS NIH HHS/United States ; HL087652/HL/NHLBI NIH HHS/United States ; N01HC55222/HL/NHLBI NIH HHS/United States ; N01HC85086/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; R01AG21593/AG/NIA NIH HHS/United States ; //Intramural NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; HL54496/HL/NHLBI NIH HHS/United States ; R01AG20132/AG/NIA NIH HHS/United States ; R01 HL080295/HL/NHLBI NIH HHS/United States ; HL54473/HL/NHLBI NIH HHS/United States ; HHSN268200800007C//PHS HHS/United States ; N01HC85082/HL/NHLBI NIH HHS/United States ; 2R01AG016592/AG/NIA NIH HHS/United States ; R01 GM113657/GM/NIGMS NIH HHS/United States ; N01HC85083/HL/NHLBI NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; //Wellcome Trust/United Kingdom ; U10 HL054473/HL/NHLBI NIH HHS/United States ; HHSN268201200036C//PHS HHS/United States ; 5R01ES021724/ES/NIEHS NIH HHS/United States ; HL080295/HL/NHLBI NIH HHS/United States ; U10 HL054495/HL/NHLBI NIH HHS/United States ; U10 HL054496/HL/NHLBI NIH HHS/United States ; U10 HL054471/HL/NHLBI NIH HHS/United States ; HL54495/HL/NHLBI NIH HHS/United States ; N01HC85079/HL/NHLBI NIH HHS/United States ; R24 HD042828/HD/NICHD NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; R01AG030678/AG/NIA NIH HHS/United States ; N01HC85080/HL/NHLBI NIH HHS/United States ; AG023629/AG/NIA NIH HHS/United States ; U01 HL054495/HL/NHLBI NIH HHS/United States ; R56 AG023629/AG/NIA NIH HHS/United States ; HL54471/HL/NHLBI NIH HHS/United States ; HL54509/HL/NHLBI NIH HHS/United States ; R01 HL055673/HL/NHLBI NIH HHS/United States ; U01 HL054473/HL/NHLBI NIH HHS/United States ; N01HC85081/HL/NHLBI NIH HHS/United States ; HL54472/HL/NHLBI NIH HHS/United States ; },
mesh = {Alleles ; Carrier Proteins/biosynthesis/blood/*genetics ; Gene Expression Regulation ; Genome-Wide Association Study ; Humans ; Leukocytes/*cytology ; Melanoma/blood/*genetics/pathology ; Risk Factors ; Telomere/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR).<br><br>RESULTS: Genome-wide association (GWA) meta-analysis and de novo genotyping of 20&#x2005;022 individuals revealed a novel association (p=6.4&#xd7;10(-10)) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1&#xd7;10(-3) and 2&#xd7;10(-3), respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97&#xd7;10(-169) to 3.42&#xd7;10(-24).<br><br>CONCLUSIONS: We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.},
}
@article {pmid25622010,
year = {2015},
author = {Savolainen, K and Eriksson, JG and Kajantie, E and Lahti, J and Räikkönen, K},
title = {Telomere length and hypothalamic-pituitary-adrenal axis response to stress in elderly adults.},
journal = {Psychoneuroendocrinology},
volume = {53},
number = {},
pages = {179-184},
doi = {10.1016/j.psyneuen.2014.12.020},
pmid = {25622010},
issn = {1873-3360},
support = {//British Heart Foundation/United Kingdom ; },
mesh = {Adrenocorticotropic Hormone/*blood ; Aged ; Area Under Curve ; Cohort Studies ; Female ; Humans ; Hydrocortisone/blood/*metabolism ; Hypothalamo-Hypophyseal System/*metabolism ; Leukocytes/metabolism ; Linear Models ; Male ; Middle Aged ; Nonlinear Dynamics ; Pituitary-Adrenal System/*metabolism ; Saliva/chemistry ; Stress, Psychological/*metabolism ; Telomere/*metabolism ; },
abstract = {OBJECTIVE: Telomere shortening, a biomarker of cellular aging, has been associated with aging-related diseases. While psychological stress has been implicated in the process of telomere shortening, associations with activity of physiological stress systems have remained elusive. We studied whether leukocyte telomere length (LTL) is associated with hypothalamic-pituitary-adrenal (HPA) axis responses to psychosocial stress in elderly adults.<br><br>METHODS: LTL, measured by qPCR method was available in 1964 women and men from the Helsinki Birth Cohort Study at a mean age of 61.5 (SD=2.9) years. At a mean age of 63.5 (SD=2.7) years a subsample of them took part in the Trier Social Stress Test (TSST) during which salivary cortisol (n=283) and plasma cortisol and ACTH concentrations (n=215) were measured.<br><br>RESULTS: Mixed model regression analyses showed no linear or non-linear associations between LTL and HPA axis activity during TSST (p-values for LTL main effects >298; p-values for LTL&#xd7;time interactions >096). Only one non-linear association between LTL and plasma ACTH area under the curve increment was significant after adjustments for covariates and confounders. This association did not survive correction for multiple testing.<br><br>CONCLUSIONS: Our findings suggest that LTL is not consistently associated with HPA axis activity during a standardized psychosocial stress test in elderly adults.},
}
@article {pmid25621325,
year = {2015},
author = {Asghar, M and Bensch, S and Tarka, M and Hansson, B and Hasselquist, D},
title = {Maternal and genetic factors determine early life telomere length.},
journal = {Proceedings. Biological sciences},
volume = {282},
number = {1799},
pages = {20142263},
pmid = {25621325},
issn = {1471-2954},
mesh = {Animals ; Longevity/*genetics ; Maternal Age ; Pedigree ; Regression Analysis ; Reproductive History ; Songbirds/*genetics/physiology ; *Telomere Homeostasis ; Telomere Shortening ; },
abstract = {In a broad range of species--including humans--it has been demonstrated that telomere length declines throughout life and that it may be involved in cell and organismal senescence. This potential link to ageing and thus to fitness has triggered recent interest in understanding how variation in telomere length is inherited and maintained. However, previous studies suffer from two main drawbacks that limit the possibility of understanding the relative importance of genetic, parental and environmental influences on telomere length variation. These studies have been based on (i) telomere lengths measured at different time points in different individuals, despite the fact that telomere length changes over life, and (ii) parent-offspring regression techniques, which do not enable differentiation between genetic and parental components of inheritance. To overcome these drawbacks, in our study of a songbird, the great reed warbler, we have analysed telomere length measured early in life in both parents and offspring and applied statistical models (so-called 'animal models') that are based on long-term pedigree data. Our results showed a significant heritability of telomere length on the maternal but not on the paternal side, and that the mother's age was positively correlated with their offspring's telomere length. Furthermore, the pedigree-based analyses revealed a significant heritability and an equally large maternal effect. Our study demonstrates strong maternal influence on telomere length and future studies now need to elucidate possible underlying factors, including which types of maternal effects are involved.},
}
@article {pmid25621169,
year = {2014},
author = {de Castro, A and Minty, F and Hattinger, E and Wolf, R and Parkinson, EK},
title = {The secreted protein S100A7 (psoriasin) is induced by telomere dysfunction in human keratinocytes independently of a DNA damage response and cell cycle regulators.},
journal = {Longevity &amp; healthspan},
volume = {3},
number = {},
pages = {8},
pmid = {25621169},
issn = {2046-2395},
abstract = {BACKGROUND: Replicative senescence is preceded by loss of repeat sequences of DNA from the telomeres that eventually leads to telomere dysfunction, the accumulation of irreparable DNA double strand breaks and a DNA damage response (DDR). However, we have previously reported that whilst telomere dysfunction in human keratinocytes is associated with a permanent cell cycle arrest, the DDR was very weak and transcriptional profiling also revealed several molecules normally associated with keratinocytes terminal differentiation, including S100A7 (psoriasin).<br><br>RESULTS: We show here that S100A7 and the closely related S100A15 (koebnerisin) are not induced by repairable or irreparable DSBs, ruling out the hypotheses that these genes are induced either by the low DDR observed or by non-specific cell cycle arrest. We next tested whether S100A7 was induced by the cell cycle effectors ARF (p14(ARF)), CDKN2A (p16(INK4A)) and TP53 (p53) and found that, although all induced a similar level of acute and permanent cell cycle arrest to telomere dysfunction, none induced S100A7 (except p53 over-expression at high levels), showing that cell cycle arrest is not sufficient for its induction. The closely related transcript S100A15 was also upregulated by telomere dysfunction, to a similar extent by p16(INK4A) and p53 and to a lesser extent by p14(ARF).<br><br>CONCLUSIONS: Our results show that mere cell cycle arrest, the upregulation of senescence-associated cell cycle effectors and DNA damage are not sufficient for the induction of the S100 transcripts; they further suggest that whilst the induction of S100A15 expression is linked to both telomere-dependent and -independent senescence, S100A7 expression is specifically associated with telomere-dependent senescence in normal keratinocytes. As both S100A7 and S100A15 are secreted proteins, they may find utility in the early detection of human keratinocyte telomere dysfunction and senescence.},
}
@article {pmid25620558,
year = {2015},
author = {Sarek, G and Vannier, JB and Panier, S and Petrini, JHJ and Boulton, SJ},
title = {TRF2 recruits RTEL1 to telomeres in S phase to promote t-loop unwinding.},
journal = {Molecular cell},
volume = {57},
number = {4},
pages = {622-635},
pmid = {25620558},
issn = {1097-4164},
support = {R37 GM059413/GM/NIGMS NIH HHS/United States ; 11581/CRUK_/Cancer Research UK/United Kingdom ; R13 CA162528/CA/NCI NIH HHS/United States ; 268639/ERC_/European Research Council/International ; 637798/ERC_/European Research Council/International ; P30 CA008748/CA/NCI NIH HHS/United States ; GM56888/GM/NIGMS NIH HHS/United States ; R01 GM056888/GM/NIGMS NIH HHS/United States ; 104558/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Cells, Cultured ; DNA Helicases/chemistry/metabolism/*physiology ; Humans ; Metaphase ; Mice ; *Models, Genetic ; Protein Structure, Tertiary ; Protein Transport ; *S Phase ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/metabolism/*physiology ; },
abstract = {The helicase RTEL1 promotes t-loop unwinding and suppresses telomere fragility to maintain the integrity of vertebrate telomeres. An interaction between RTEL1 and PCNA is important to prevent telomere fragility, but how RTEL1 engages with the telomere to promote t-loop unwinding is unclear. Here, we establish that the shelterin protein TRF2 recruits RTEL1 to telomeres in S phase, which is required to prevent catastrophic t-loop processing by structure-specific nucleases. We show that the TRF2-RTEL1 interaction is mediated by a metal-coordinating C4C4 motif in RTEL1, which is compromised by the Hoyeraal-Hreidarsson syndrome (HHS) mutation, RTEL1(R1264H). Conversely, we define a TRF2(I124D) substitution mutation within the TRFH domain of TRF2, which eliminates RTEL1 binding and phenocopies the RTEL1(R1264H) mutation, giving rise to aberrant t-loop excision, telomere length heterogeneity, and loss of the telomere as a circle. These results implicate TRF2 in the recruitment of RTEL1 to facilitate t-loop disassembly at telomeres in S phase.},
}
@article {pmid25618850,
year = {2015},
author = {Salvati, E and Rizzo, A and Iachettini, S and Zizza, P and Cingolani, C and D'Angelo, C and Porru, M and Mondello, C and Aiello, A and Farsetti, A and Gilson, E and Leonetti, C and Biroccio, A},
title = {A basal level of DNA damage and telomere deprotection increases the sensitivity of cancer cells to G-quadruplex interactive compounds.},
journal = {Nucleic acids research},
volume = {43},
number = {3},
pages = {1759-1769},
pmid = {25618850},
issn = {1362-4962},
mesh = {Blotting, Western ; Chromatin Immunoprecipitation ; *DNA Damage ; G-Quadruplexes/*drug effects ; Humans ; In Situ Hybridization, Fluorescence ; Neoplasms/*genetics ; *Telomere ; Tumor Cells, Cultured ; },
abstract = {Here, with the aim of obtaining insight into the intriguing selectivity of G-quadruplex (G4) ligands toward cancer compared to normal cells, a genetically controlled system of progressive transformation in human BJ fibroblasts was analyzed. Among the different comparative evaluations, we found a progressive increase of DNA damage response (DDR) markers throughout the genome from normal toward immortalized and transformed cells. More interestingly, sensitivity to G4 ligands strongly correlated with the presence of a basal level of DNA damage, including at the telomeres, where the chromosome ends were exposed to the DDR without concurrent induction of DNA repair activity, as revealed by the lack of 53BP1 recruitment and telomere aberrations. The link between telomere uncapping and the response to G4 stabilization was directly assessed by showing that a partial TRF2 depletion, causing a basal level of telomere localized DDR, rendered telomerized fibroblasts prone to G4-induced telomere damage and anti-proliferative defects. Taken together these data strongly indicate that the presence of a basal level of telomere-associated DDR is a determinant of susceptibility to G4 stabilization.},
}
@article {pmid25617465,
year = {2015},
author = {Watson, H and Bolton, M and Monaghan, P},
title = {Variation in early-life telomere dynamics in a long-lived bird: links to environmental conditions and survival.},
journal = {The Journal of experimental biology},
volume = {218},
number = {Pt 5},
pages = {668-674},
pmid = {25617465},
issn = {1477-9145},
support = {BB/F016700/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Birds/blood/growth &amp; development/*physiology ; *Environment ; Erythrocytes/ultrastructure ; Longevity ; Stress, Physiological/*genetics ; Telomere/*physiology ; Telomere Shortening ; },
abstract = {Conditions experienced during early life can have profound consequences for both short- and long-term fitness. Variation in the natal environment has been shown to influence survival and reproductive performance of entire cohorts in wild vertebrate populations. Telomere dynamics potentially provide a link between the early environment and long-term fitness outcomes, yet we know little about how the environment can influence telomere dynamics in early life. We found that environmental conditions during growth have an important influence on early-life telomere length (TL) and attrition in nestlings of a long-lived bird, the European storm petrel Hydrobates pelagicus. Nestlings reared under unfavourable environmental conditions experienced significantly greater telomere loss during postnatal development compared with nestlings reared under more favourable natal conditions, which displayed a negligible change in TL. There was, however, no significant difference in pre-fledging TL between cohorts. The results suggest that early-life telomere dynamics could contribute to the marked differences in life-history traits that can arise among cohorts reared under different environmental conditions. Early-life TL was also found to be a significant predictor of survival during the nestling phase, providing further evidence for a link between variation in TL and individual fitness. To what extent the relationship between early-life TL and mortality during the nestling phase is a consequence of genetic, parental and environmental factors is currently unknown, but it is an interesting area for future research. Accelerated telomere attrition under unfavourable conditions, as observed in this study, might play a role in mediating the effects of the early-life environment on later-life performance.},
}
@article {pmid25614443,
year = {2015},
author = {Ramunas, J and Yakubov, E and Brady, JJ and Corbel, SY and Holbrook, C and Brandt, M and Stein, J and Santiago, JG and Cooke, JP and Blau, HM},
title = {Transient delivery of modified mRNA encoding TERT rapidly extends telomeres in human cells.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {29},
number = {5},
pages = {1930-1939},
pmid = {25614443},
issn = {1530-6860},
support = {U01 HL100397/HL/NHLBI NIH HHS/United States ; U01 HL099997/HL/NHLBI NIH HHS/United States ; R21 AG044815/AG/NIA NIH HHS/United States ; U01HL100397/HL/NHLBI NIH HHS/United States ; R01AR063963/AR/NIAMS NIH HHS/United States ; R01 HL095716/HL/NHLBI NIH HHS/United States ; U01HL099997/HL/NHLBI NIH HHS/United States ; AG044815-01/AG/NIA NIH HHS/United States ; R01 AR063963/AR/NIAMS NIH HHS/United States ; },
mesh = {Blotting, Western ; Cell Division ; Cell Proliferation ; Cells, Cultured ; Cellular Senescence/*physiology ; Fetus/cytology/metabolism ; Fibroblasts/cytology/*metabolism ; Flow Cytometry ; Humans ; Immunoenzyme Techniques ; In Situ Hybridization, Fluorescence ; Lung/cytology/*metabolism ; Myoblasts/cytology/*metabolism ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/genetics/*metabolism ; Telomere/*genetics ; },
abstract = {Telomere extension has been proposed as a means to improve cell culture and tissue engineering and to treat disease. However, telomere extension by nonviral, nonintegrating methods remains inefficient. Here we report that delivery of modified mRNA encoding TERT to human fibroblasts and myoblasts increases telomerase activity transiently (24-48 h) and rapidly extends telomeres, after which telomeres resume shortening. Three successive transfections over a 4 d period extended telomeres up to 0.9 kb in a cell type-specific manner in fibroblasts and myoblasts and conferred an additional 28 ± 1.5 and 3.4 ± 0.4 population doublings (PDs), respectively. Proliferative capacity increased in a dose-dependent manner. The second and third transfections had less effect on proliferative capacity than the first, revealing a refractory period. However, the refractory period was transient as a later fourth transfection increased fibroblast proliferative capacity by an additional 15.2 ± 1.1 PDs, similar to the first transfection. Overall, these treatments led to an increase in absolute cell number of more than 10(12)-fold. Notably, unlike immortalized cells, all treated cell populations eventually stopped increasing in number and expressed senescence markers to the same extent as untreated cells. This rapid method of extending telomeres and increasing cell proliferative capacity without risk of insertional mutagenesis should have broad utility in disease modeling, drug screening, and regenerative medicine.},
}
@article {pmid25614145,
year = {2015},
author = {Liang, J and Jiang, C and Peng, H and Shi, Q and Guo, X and Yuan, Y and Huang, L},
title = {Analysis of the age of Panax ginseng based on telomere length and telomerase activity.},
journal = {Scientific reports},
volume = {5},
number = {},
pages = {7985},
pmid = {25614145},
issn = {2045-2322},
mesh = {Chromosomes, Plant/genetics/*metabolism ; Panax/genetics/*metabolism ; Plant Proteins/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {Ginseng, which is the root of Panax ginseng (Araliaceae), has been used in Oriental medicine as a stimulant and dietary supplement for more than 7,000 years. Older ginseng plants are substantially more medically potent, but ginseng age can be simulated using unscrupulous cultivation practices. Telomeres progressively shorten with each cell division until they reach a critical length, at which point cells enter replicative senescence. However, in some cells, telomerase maintains telomere length. In this study, to determine whether telomere length reflects ginseng age and which tissue is best for such an analysis, we examined telomerase activity in the main roots, leaves, stems, secondary roots and seeds of ginseng plants of known age. Telomere length in the main root (approximately 1 cm below the rhizome) was found to be the best indicator of age. Telomeric terminal restriction fragment (TRF) lengths, which are indicators of telomere length, were determined for the main roots of plants of different ages through Southern hybridization analysis. Telomere length was shown to be positively correlated with plant age, and a simple mathematical model was formulated to describe the relationship between telomere length and age for P. ginseng.},
}
@article {pmid25614111,
year = {2015},
author = {Guo, C and Kawamoto, Y and Asamitsu, S and Sawatani, Y and Hashiya, K and Bando, T and Sugiyama, H},
title = {Rational design of specific binding hairpin Py-Im polyamides targeting human telomere sequences.},
journal = {Bioorganic &amp; medicinal chemistry},
volume = {23},
number = {4},
pages = {855-860},
doi = {10.1016/j.bmc.2014.12.025},
pmid = {25614111},
issn = {1464-3391},
mesh = {Base Sequence ; DNA/chemistry/*metabolism ; Humans ; Imidazoles/chemistry/pharmacology ; Nucleic Acid Conformation ; Nylons/*chemistry/*pharmacology ; Pyrroles/chemistry/pharmacology ; Surface Plasmon Resonance ; Telomere/chemistry/*metabolism ; },
abstract = {N-Methylpyrrole (Py)-N-methylimidazole (Im) polyamides are organic molecules that can recognize predetermined DNA sequences in a sequence-specific manner. Human telomeres contain regions of (TTAGGG)n repetitive nucleotide sequences at each end of chromosomes, and these regions protect the chromosome from deterioration or from fusion with neighboring chromosomes. The telomeres are disposable buffers at the ends of chromosomes that are truncated during cell division. Tandem hairpin Py-Im polyamide TH59, which recognizes human telomere sequences, was reported by Laemmli's group in 2001. Here, we synthesized three types of Py-Im polyamides 1-3 based on TH59 for specific recognition of human telomere repeat sequences. Thermal melting temperature (Tm) measurements and surface plasmon resonance analysis were used to evaluate the abilities of the three types of Py-Im polyamides to discriminate between three kinds of DNA sequences. Significantly, the results showed that polyamides 1 and 2 have better affinities to TTAAGG than to TTAGGG. In contrast, polyamide 3 displayed good specificity to human telomere sequence, TTAGGG, as expected on the basis of Py-Im binding rules.},
}
@article {pmid25613889,
year = {2015},
author = {Asghar, M and Hasselquist, D and Hansson, B and Zehtindjiev, P and Westerdahl, H and Bensch, S},
title = {Chronic infection. Hidden costs of infection: chronic malaria accelerates telomere degradation and senescence in wild birds.},
journal = {Science (New York, N.Y.)},
volume = {347},
number = {6220},
pages = {436-438},
doi = {10.1126/science.1261121},
pmid = {25613889},
issn = {1095-9203},
mesh = {Aging/*genetics ; Animals ; Breeding ; *Genetic Fitness ; Malaria/genetics/physiopathology/*veterinary ; Malaria, Avian/*genetics/*physiopathology ; Plasmodium ; Songbirds/genetics/*parasitology/physiology ; Telomere Homeostasis/*genetics ; },
abstract = {Recovery from infection is not always complete, and mild chronic infection may persist. Although the direct costs of such infections are apparently small, the potential for any long-term effects on Darwinian fitness is poorly understood. In a wild population of great reed warblers, we found that low-level chronic malaria infection reduced life span as well as the lifetime number and quality of offspring. These delayed fitness effects of malaria appear to be mediated by telomere degradation, a result supported by controlled infection experiments on birds in captivity. The results of this study imply that chronic infection may be causing a series of small adverse effects that accumulate and eventually impair phenotypic quality and Darwinian fitness.},
}
@article {pmid25612739,
year = {2014},
author = {Rizvi, S and Raza, ST and Mahdi, F},
title = {Telomere length variations in aging and age-related diseases.},
journal = {Current aging science},
volume = {7},
number = {3},
pages = {161-167},
doi = {10.2174/1874609808666150122153151},
pmid = {25612739},
issn = {1874-6128},
mesh = {Age Factors ; Aging/genetics/*metabolism ; Alzheimer Disease/epidemiology/genetics/metabolism ; Animals ; Cardiovascular Diseases/epidemiology/genetics/metabolism ; Diabetes Mellitus/epidemiology/genetics/metabolism ; Genetic Predisposition to Disease ; Humans ; Neoplasms/epidemiology/genetics/metabolism ; Risk Factors ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Telomeres are gene sequences present at chromosomal ends and are responsible for maintaining genome integrity. Telomere length is maximum at birth and decreases progressively with advancing age and thus is considered as a biomarker of chronological aging. This age associated decrease in the length of telomere is linked to various ageing associated diseases like diabetes, hypertension, Alzheimer's disease, cancer etc. and their associated complications. Telomere length is a result of combined effect of oxidative stress, inflammation and repeated cell replication on it, and thus forming an association between telomere length and chronological aging and related diseases. Thus, decrease in telomere length was found to be important in determining both, the variations in longevity and age-related diseases in an individual. Ongoing and progressive research in the field of telomere length dynamics has proved that aging and age-related diseases apart from having a synergistic effect on telomere length were also found to effect telomere length independently also. Here a short description about telomere length variations and its association with human aging and age-related diseases is reviewed.},
}
@article {pmid25611794,
year = {2015},
author = {Armstrong, RE and Riskowski, RA and Strouse, GF},
title = {Nanometal surface energy transfer optical ruler for measuring a human telomere structure.},
journal = {Photochemistry and photobiology},
volume = {91},
number = {3},
pages = {732-738},
doi = {10.1111/php.12423},
pmid = {25611794},
issn = {1751-1097},
mesh = {*Energy Transfer ; Gold/*chemistry ; Humans ; Nanoparticles/*chemistry ; Nucleic Acid Conformation ; Optics and Photonics ; Telomere/*chemistry ; },
abstract = {Nanometal surface energy transfer (NSET) techniques on gold nanoparticles (AuNPs) have become an essential tool in molecular biophysics to identify structural details at long-range donor-acceptor distances. The NSET mechanism is well described, but it has been suggested that the use of large AuNPs in NSET may manipulate natural biomolecular function. If, in fact, such nonspecific interactions with the AuNP surface can be quantified or contained, then NSET may offer more potential in tracking biomolecular folding than the most comprehensive methods in conformer determination (X-ray crystallography, NMR, EPR). Here, we describe an NSET ruler capable of tracking Hybrid-2 telomere quadruplex folding and we demonstrate that nucleic acid appendage to AuNPs up to 10 nm in diameter does not manipulate biomolecular function. The quadruplex folding of Hybrid-2 sequences was tracked by monitoring the emission of a DY680 dye on selected basepairs in the telomere sequence when appended to the surface of AuNPs (5-10 nm). Emission-derived distances extracted from NSET theory correlate well to reported NMR structures of the hybrid quadruplex. Moreover, NSET theory calculates identical donor-acceptor distal points between DY680 and all sizes of AuNPs, indicating that the AuNP tether is not dominant or disruptive towards nucleic acid folding.},
}
@article {pmid25610541,
year = {2014},
author = {Mandrioli, M and Zanasi, F and Manicardi, GC},
title = {Karyotype rearrangements and telomere analysis in Myzuspersicae (Hemiptera, Aphididae) strains collected on Lavandula sp. plants.},
journal = {Comparative cytogenetics},
volume = {8},
number = {4},
pages = {259-274},
pmid = {25610541},
issn = {1993-0771},
abstract = {Karyotype analysis of nine strains of the peach-potato aphid Myzuspersicae (Sulzer, 1776), collected on Lavandula sp. plants, evidenced showed that five of them had a standard 2n = 12 karyotype, one possessed a fragmentation of the X chromosome occurring at the telomere opposite to the NOR-bearing one and three strains had a chromosome number 2n = 11 due to a non-reciprocal translocation of an autosome A3 onto an A1 chromosome. Interestingly, the terminal portion of the autosome A1 involved in the translocation was the same in all the three strains, as evidenced by FISH with the histone cluster as a probe. The study of telomeres in the Myzuspersicae strain with the X fission evidenced that telomerase synthesised de novo telomeres at the breakpoints resulting in the stabilization of the chromosomal fragments. Lastly, despite the presence of a conserved telomerase, aphid genome is devoid of genes coding for shelterin, a complex of proteins involved in telomere functioning frequently reported as conserved in eukaryotes. The absence of this complex, also confirmed in the genome of other arthropods, suggests that the shift in the sequence of the telomeric repeats has been accompanied by other changes in the telomere components in arthropods in respect to other metazoans.},
}
@article {pmid25599669,
year = {2015},
author = {Martin, CL and Ledbetter, DH},
title = {Molecular cytogenetic analysis of telomere rearrangements.},
journal = {Current protocols in human genetics},
volume = {84},
number = {},
pages = {8.11.1-8.11.15},
pmid = {25599669},
issn = {1934-8258},
support = {R01 MH074090/MH/NIMH NIH HHS/United States ; },
mesh = {Chromosomes, Human/*chemistry/metabolism/ultrastructure ; Comparative Genomic Hybridization/*methods ; DNA Probes/chemical synthesis ; Fluorescent Dyes/chemistry ; Gene Dosage ; *Gene Rearrangement ; Genomic Instability ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Telomere/*chemistry/metabolism/ultrastructure ; Translocation, Genetic ; },
abstract = {Genomic imbalances involving the telomeric regions of human chromosomes, which contain the highest gene concentration in the genome, are proposed to have severe phenotypic consequences. For this reason, it is important to identify telomere rearrangements and assess their contribution to human pathology. This unit describes the structure and function of human telomeres and outlines several methodologies that can be employed to study these unique regions of human chromosomes. It is a revision of the original version of the unit published in 2000, now including an introductory section describing advances in the discipline that have taken place since the original publication.},
}
@article {pmid25598199,
year = {2015},
author = {Tellechea, M and Gianotti, TF and Alvariñas, J and González, CD and Sookoian, S and Pirola, CJ},
title = {Telomere length in the two extremes of abnormal fetal growth and the programming effect of maternal arterial hypertension.},
journal = {Scientific reports},
volume = {5},
number = {},
pages = {7869},
pmid = {25598199},
issn = {2045-2322},
mesh = {Adult ; Birth Weight/genetics/radiation effects ; Female ; Fetal Development/*genetics/physiology ; Genetic Association Studies ; Humans ; Hypertension/*genetics/physiopathology ; Infant, Newborn ; Leukocytes/pathology ; Pregnancy ; Telomere/genetics ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {We tested the hypothesis that leukocyte telomere length (LTL) is associated with birth weight in both extremes of abnormal fetal growth: small (SGA) and large for gestational age newborns (LGA). Clinical and laboratory variables of the mothers and the neonates were explored; 45 newborns with appropriate weight for gestational age (AGA), 12 SGA and 12 LGA were included. Whether the differences might be explained by variation in OBFC1 (rs9419958) and CTC1 (rs3027234) genes associated with LTL was determined. A significant association between birth weight and LTL was observed; LTL was significantly shorter in LGA newborns (1.01 ± 0.12) compared with SGA (1.73 ± 0.19) p < 0.005, mean ± SE. Maternal (Spearman R = -0.6, p = 0.03) and neonatal LTL (R = -0.25, p = 0.03) were significantly and inversely correlated with maternal history of arterial hypertension in previous gestations. Neonatal LTL was not significantly associated with either rs9419950 or rs3027234, suggesting that the association between neonatal LTL and birth weight is not influenced by genetic variation in genes that modify the interindividual LTL. In conclusion, telomere biology seems to be modulated by abnormal fetal growth; modifications in telomere length might be programmed by an adverse environment in utero.},
}
@article {pmid25596130,
year = {2015},
author = {Lakowa, N and Trieu, N and Flehmig, G and Lohmann, T and Schön, MR and Dietrich, A and Zeplin, PH and Langer, S and Stumvoll, M and Blüher, M and Klöting, N},
title = {Telomere length differences between subcutaneous and visceral adipose tissue in humans.},
journal = {Biochemical and biophysical research communications},
volume = {457},
number = {3},
pages = {426-432},
doi = {10.1016/j.bbrc.2014.12.122},
pmid = {25596130},
issn = {1090-2104},
mesh = {Adipocytes, White/metabolism/pathology ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/genetics/metabolism/pathology ; Body Mass Index ; Cell Size ; Cross-Sectional Studies ; Diabetes Mellitus, Type 2/genetics/metabolism/pathology ; Female ; Glycated Hemoglobin/metabolism ; Humans ; Intra-Abdominal Fat/*metabolism/*pathology ; Male ; Middle Aged ; Obesity/*genetics/metabolism/pathology ; Subcutaneous Fat/*metabolism/*pathology ; Telomere Homeostasis/*genetics ; Telomere Shortening/*genetics ; Thinness/genetics/metabolism/pathology ; Young Adult ; },
abstract = {Adipocyte hypertrophy and hyperplasia have been shown to be associated with shorter telomere length, which may reflect aging, altered cell proliferation and adipose tissue (AT) dysfunction. In individuals with obesity, differences in fat distribution and AT cellular composition may contribute to obesity related metabolic diseases. Here, we tested the hypotheses that telomere lengths (TL) are different between: (1) abdominal subcutaneous and omental fat depots, (2) superficial and deep abdominal subcutaneous AT (SAT), and (3) adipocytes and cells of the stromal vascular fraction (SVF). We further asked whether AT TL is related to age, anthropometric and metabolic traits. TL was analyzed by quantitative PCR in total human genomic DNA isolated from paired subcutaneous and visceral AT of 47 lean and 50 obese individuals. In subgroups, we analyzed TL in isolated small and large adipocytes and SVF cells. We find significantly shorter TL in subcutaneous compared to visceral AT (P < 0.001) which is consistent in men and subgroups of lean and obese, and individuals with or without type 2 diabetes (T2D). Shorter TL in SAT is entirely due to shorter TL in the SVF compared to visceral AT (P < 0.01). SAT TL is most strongly correlated with age (r = -0.205, P < 0.05) and independently of age with HbA1c (r = -0.5, P < 0.05). We found significant TL differences between superficial SAT of lean and obese as well as between individuals with our without T2D, but not between the two layers of SAT. Our data indicate that fat depot differences in TL mainly reflect shorter TL of SVF cells. In addition, we found an age and BMI-independent relationship between shorter TL and HbA1c suggesting that chronic hyperglycemia may impair the regenerative capacity of AT more strongly than obesity alone.},
}
@article {pmid25596111,
year = {2015},
author = {M'kacher, R and El Maalouf, E and Terzoudi, G and Ricoul, M and Heidingsfelder, L and Karachristou, I and Laplagne, E and Hempel, WM and Colicchio, B and Dieterlen, A and Pantelias, G and Sabatier, L},
title = {Detection and automated scoring of dicentric chromosomes in nonstimulated lymphocyte prematurely condensed chromosomes after telomere and centromere staining.},
journal = {International journal of radiation oncology, biology, physics},
volume = {91},
number = {3},
pages = {640-649},
doi = {10.1016/j.ijrobp.2014.10.048},
pmid = {25596111},
issn = {1879-355X},
mesh = {Centromere/*genetics ; *Chromosome Aberrations ; Cobalt Radioisotopes ; DNA Repair ; Dose-Response Relationship, Radiation ; Humans ; Lymphocytes/*radiation effects ; Metaphase ; Radiation Dosage ; *Staining and Labeling ; *Telomere ; Time Factors ; },
abstract = {PURPOSE: To combine telomere and centromere (TC) staining of premature chromosome condensation (PCC) fusions to identify dicentrics, centric rings, and acentric chromosomes, making possible the realization of a dose-response curve and automation of the process.<br><br>METHODS AND MATERIALS: Blood samples from healthy donors were exposed to (60)Co irradiation at varying doses up to 8 Gy, followed by a repair period of 8 hours. Premature chromosome condensation fusions were carried out, and TC staining using peptide nucleic acid probes was performed. Chromosomal aberration (CA) scoring was carried out manually and automatically using PCC-TCScore software, developed in our laboratory.<br><br>RESULTS: We successfully optimized the hybridization conditions and image capture parameters, to increase the sensitivity and effectiveness of CA scoring. Dicentrics, centric rings, and acentric chromosomes were rapidly and accurately detected, leading to a linear-quadratic dose-response curve by manual scoring at up to 8 Gy. Using PCC-TCScore software for automatic scoring, we were able to detect 95% of dicentrics and centric rings.<br><br>CONCLUSION: The introduction of TC staining to the PCC fusion technique has made possible the rapid scoring of unstable CAs, including dicentrics, with a level of accuracy and ease not previously possible. This new approach can be used for biological dosimetry in radiation emergency medicine, where the rapid and accurate detection of dicentrics is a high priority using automated scoring. Because there is no culture time, this new approach can also be used for the follow-up of patients treated by genotoxic therapy, creating the possibility to perform the estimation of induced chromosomal aberrations immediately after the blood draw.},
}
@article {pmid25595889,
year = {2015},
author = {Pezzolo, A and Pistorio, A and Gambini, C and Haupt, R and Ferraro, M and Erminio, G and De Bernardi, B and Garaventa, A and Pistoia, V},
title = {Intratumoral diversity of telomere length in individual neuroblastoma tumors.},
journal = {Oncotarget},
volume = {6},
number = {10},
pages = {7493-7503},
pmid = {25595889},
issn = {1949-2553},
mesh = {Cell Line, Tumor ; Disease-Free Survival ; Female ; Humans ; Male ; Neuroblastoma/*genetics/mortality ; Retrospective Studies ; Survival Analysis ; Telomerase/*genetics ; Telomere/*metabolism ; },
abstract = {The purpose of the work was to investigate telomere length (TL) and mechanisms involved in TL maintenance in individual neuroblastoma (NB) tumors. Primary NB tumors from 102 patients, ninety Italian and twelve Spanish, diagnosed from 2000 to 2008 were studied. TL was investigated by quantitative fluorescence in situ hybridization (IQ-FISH) that allows to analyze individual cells in paraffin-embedded tissues. Fluorescence intensity of chromosome 2 centromere was used as internal control to normalize TL values to ploidy. Human telomerase reverse transcriptase (hTERT) expression was detected by immunofluorescence in 99/102 NB specimens.The main findings are the following: 1) two intratumoral subpopulations of cancer cells displaying telomeres of different length were identified in 32/102 tumors belonging to all stages. 2) hTERT expression was detected in 99/102 tumors, of which 31 displayed high expression and 68 low expression. Alternative lengthening of telomeres (ALT)-mechanism was present in 60/102 tumors, 20 of which showed high hTERT expression. Neither ALT-mechanism nor hTERT expression correlated with heterogeneous TL. 3) High hTERT expression and ALT positivity were associated with significantly reduced Overall Survival. 4) High hTERT expression predicted relapse irrespective of patient age. Intratumoral diversity in TL represents a novel feature in NB.In conclusion, diversity of TL in individual NB tumors was strongly associated with disease progression and death, suggesting that these findings are of translational relevance. The combination of high hTERT expression and ALT positivity may represent a novel biomarker of poor prognosis that deserves further investigation.},
}
@article {pmid25593453,
year = {2015},
author = {Carulli, L},
title = {Telomere shortening as genetic risk factor of liver cirrhosis.},
journal = {World journal of gastroenterology},
volume = {21},
number = {2},
pages = {379-383},
pmid = {25593453},
issn = {2219-2840},
mesh = {Animals ; Diseases in Twins/ethnology/*genetics ; Genetic Markers ; Genetic Predisposition to Disease ; Humans ; Liver Cirrhosis/ethnology/*genetics ; Phenotype ; Polymorphism, Single Nucleotide ; Prognosis ; Risk Assessment ; Risk Factors ; *Telomere Shortening ; Twins/genetics ; },
abstract = {Cirrhosis is the main complication of chronic liver disease, leads to progressive liver function impairment and is the main risk factor for the development of liver cancer. Liver failure at endstage cirrhosis is associated with increased mortality with liver transplantation as the only possible treatment at this stage. The pathogenesis of liver cirrhosis is not completely elucidated. Although the common factors leading to liver injury, such as viral hepatitis, alcohol consume or fatty liver disease can be identified in the majority of patients a small percentage of patients have no apparent risk factors. Moreover given the same risk factors, some patients progress to cirrhosis whereas others have a benign course, the reason remains unclear. In order to develop new diagnostic and therapeutic tools, it is s essential to understand the pathogenesis of cirrhosis. The identification of genetic risk factors associated with cirrhosis is one of the possible approach to achieve these goal. In the past years several studies have supported the role of telomere shortening and cirrhosis. In the recent year several studies on the relation between several single nucleotide polymorphism (SNPs) and cirrhosis have been published; it has been proposed also a cirrhosis risk score based on seven SNPs. Also epidemiological studies on identical twins and in different ethnic groups have been supporting the importance of the role of genetic risk factors. Finally in the very recent years it has been suggested that telomere shortening may represent a genetic risk factor for the development of cirrhosis.},
}
@article {pmid25593184,
year = {2015},
author = {Flynn, RL and Cox, KE and Jeitany, M and Wakimoto, H and Bryll, AR and Ganem, NJ and Bersani, F and Pineda, JR and Suvà, ML and Benes, CH and Haber, DA and Boussin, FD and Zou, L},
title = {Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors.},
journal = {Science (New York, N.Y.)},
volume = {347},
number = {6219},
pages = {273-277},
pmid = {25593184},
issn = {1095-9203},
support = {102696/WT_/Wellcome Trust/United Kingdom ; GM076388/GM/NIGMS NIH HHS/United States ; R01 CA129933/CA/NCI NIH HHS/United States ; K99/R00 CA166729/CA/NCI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; K99 CA166729/CA/NCI NIH HHS/United States ; R01 GM076388/GM/NIGMS NIH HHS/United States ; T32 GM008541/GM/NIGMS NIH HHS/United States ; R00 CA166729/CA/NCI NIH HHS/United States ; 102696HABER/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis ; Ataxia Telangiectasia Mutated Proteins/antagonists &amp; inhibitors/metabolism ; Cell Cycle ; Cell Line, Tumor ; DNA Helicases/genetics/metabolism ; Gene Knockdown Techniques ; Glioma/drug therapy/genetics ; HeLa Cells ; Homologous Recombination ; Humans ; Nuclear Proteins/genetics/metabolism ; Osteosarcoma/drug therapy/genetics ; Promyelocytic Leukemia Protein ; Pyrazines/*pharmacology ; RNA, Untranslated/genetics/metabolism ; Replication Protein A/metabolism ; Sulfones/*pharmacology ; Telomerase/metabolism ; Telomere/*drug effects/genetics/*metabolism ; *Telomere Homeostasis ; Telomeric Repeat Binding Protein 2/metabolism ; Transcription Factors/metabolism ; Tumor Suppressor Proteins/metabolism ; X-linked Nuclear Protein ; },
abstract = {Cancer cells rely on telomerase or the alternative lengthening of telomeres (ALT) pathway to overcome replicative mortality. ALT is mediated by recombination and is prevalent in a subset of human cancers, yet whether it can be exploited therapeutically remains unknown. Loss of the chromatin-remodeling protein ATRX associates with ALT in cancers. Here, we show that ATRX loss compromises cell-cycle regulation of the telomeric noncoding RNA TERRA and leads to persistent association of replication protein A (RPA) with telomeres after DNA replication, creating a recombinogenic nucleoprotein structure. Inhibition of the protein kinase ATR, a critical regulator of recombination recruited by RPA, disrupts ALT and triggers chromosome fragmentation and apoptosis in ALT cells. The cell death induced by ATR inhibitors is highly selective for cancer cells that rely on ALT, suggesting that such inhibitors may be useful for treatment of ALT-positive cancers.},
}
@article {pmid25592011,
year = {2015},
author = {Milne, E and O'Callaghan, N and Ramankutty, P and de Klerk, NH and Greenop, KR and Armstrong, BK and Miller, M and Fenech, M},
title = {Plasma micronutrient levels and telomere length in children.},
journal = {Nutrition (Burbank, Los Angeles County, Calif.)},
volume = {31},
number = {2},
pages = {331-336},
doi = {10.1016/j.nut.2014.08.005},
pmid = {25592011},
issn = {1873-1244},
mesh = {Calcium/blood ; Child ; Child, Preschool ; Cotinine/blood ; Cross-Sectional Studies ; DNA Damage ; Environmental Exposure/*analysis ; Female ; Folic Acid/blood ; Follow-Up Studies ; Gene Frequency ; Genotype ; Genotyping Techniques ; Healthy Volunteers ; Humans ; Hydrocortisone/blood ; Magnesium/blood ; Male ; Micronutrients/*blood ; Oxidative Stress ; Pesticides/blood ; Polymorphism, Genetic ; Prospective Studies ; Replication Protein C/genetics ; Selenium/blood ; Socioeconomic Factors ; Surveys and Questionnaires ; Telomere/*genetics ; *Telomere Homeostasis ; X-Rays/adverse effects ; Zinc/blood ; },
abstract = {OBJECTIVE: Telomeres are long hexamer (TTAGGG) repeats at the ends of chromosomes, and contribute to maintenance of chromosomal stability. Telomere shortening has been linked to cancers and other chronic diseases in adults, although evidence for causal associations is limited. The aim of this study was to determine whether nutritional factors are associated with telomere length (TL) in children.<br><br>METHODS: We conducted a cross-sectional study of nutritional factors and TL in 437 children between 2009 and 2011. Healthy children ages 3, 6, and 9 y provided blood samples, and their parents completed a food frequency questionnaire and a telephone interview about relevant environmental exposures. TL and blood micronutrient levels were measured, and genotyping at 10 loci was undertaken. Associations between the micronutrients and other variables were assessed using linear regression.<br><br>RESULTS: No significant main or interactive effects of age or sex were seen. After adjustment for age, sex, parental education, and month of blood collection, TL was inversely associated with plasma zinc, and shorter in children with the homozygous mutant genotype of the RFC G80A (rs1051266) polymorphism.<br><br>CONCLUSIONS: To the best of our knowledge, this is the first investigation of the association between telomere length and micronutrients in healthy children. The reason for the inverse relationship of TL with zinc is unknown but could be the result of an increase in telomere sequence deletions caused by labile zinc induction of oxidative stress. These findings should be corroborated in other studies before nutritional recommendations might be considered.},
}
@article {pmid25589350,
year = {2015},
author = {Pandita, RK and Chow, TT and Udayakumar, D and Bain, AL and Cubeddu, L and Hunt, CR and Shi, W and Horikoshi, N and Zhao, Y and Wright, WE and Khanna, KK and Shay, JW and Pandita, TK},
title = {Single-strand DNA-binding protein SSB1 facilitates TERT recruitment to telomeres and maintains telomere G-overhangs.},
journal = {Cancer research},
volume = {75},
number = {5},
pages = {858-869},
pmid = {25589350},
issn = {1538-7445},
support = {R01 GM109768/GM/NIGMS NIH HHS/United States ; GM109768/GM/NIGMS NIH HHS/United States ; CA154320/CA/NCI NIH HHS/United States ; CA129537/CA/NCI NIH HHS/United States ; R01 CA154320/CA/NCI NIH HHS/United States ; R01 CA129537/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; DNA Damage ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/*metabolism ; HCT116 Cells ; HEK293 Cells ; Humans ; Mice ; Mice, Knockout ; Mitochondrial Proteins/metabolism ; Protein Binding ; S Phase/physiology ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; },
abstract = {Proliferating mammalian stem and cancer cells express telomerase [telomerase reverse transcriptase (TERT)] in an effort to extend chromosomal G-overhangs and maintain telomere ends. Telomerase-expressing cells also have higher levels of the single-stranded DNA-binding protein SSB1, which has a critical role in DNA double-strand break (DSB) repair. Here, we report that SSB1 binds specifically to G-strand telomeric DNA in vitro and associates with telomeres in vivo. SSB1 interacts with the TERT catalytic subunit and regulates its interaction with telomeres. Deletion of SSB1 reduces TERT interaction with telomeres and leads to G-overhang loss. Although SSB1 is recruited to DSB sites, we found no corresponding change in TERT levels at these sites, implying that SSB1-TERT interaction relies upon a specific chromatin structure or context. Our findings offer an explanation for how telomerase is recruited to telomeres to facilitate G-strand DNA extension, a critical step in maintaining telomere ends and cell viability in all cancer cells. Cancer Res; 75(5); 858-69. ©2015 AACR.},
}
@article {pmid25582120,
year = {2015},
author = {Badie, S and Carlos, AR and Folio, C and Okamoto, K and Bouwman, P and Jonkers, J and Tarsounas, M},
title = {BRCA1 and CtIP promote alternative non-homologous end-joining at uncapped telomeres.},
journal = {The EMBO journal},
volume = {34},
number = {3},
pages = {410-424},
pmid = {25582120},
issn = {1460-2075},
support = {17201/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Animals ; Antigens, Nuclear/genetics/metabolism ; Ataxia Telangiectasia Mutated Proteins/genetics/metabolism ; BRCA1 Protein/genetics/*metabolism ; Carrier Proteins/genetics/*metabolism ; Cell Cycle Proteins/genetics/*metabolism ; DNA Damage ; DNA End-Joining Repair/*physiology ; DNA Ligase ATP ; DNA Ligases/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; HEK293 Cells ; Humans ; Ku Autoantigen ; Mice ; Mice, Knockout ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases/genetics/metabolism ; Poly-ADP-Ribose Binding Proteins ; Telomere/genetics/*metabolism ; Xenopus Proteins ; },
abstract = {Loss of telomere protection occurs during physiological cell senescence and ageing, due to attrition of telomeric repeats and insufficient retention of the telomere-binding factor TRF2. Subsequently formed telomere fusions trigger rampant genomic instability leading to cell death or tumorigenesis. Mechanistically, telomere fusions require either the classical non-homologous end-joining (C-NHEJ) pathway dependent on Ku70/80 and LIG4, or the alternative non-homologous end-joining (A-NHEJ), which relies on PARP1 and LIG3. Here, we show that the tumour suppressor BRCA1, together with its interacting partner CtIP, both acting in end resection, also promotes end-joining of uncapped telomeres. BRCA1 and CtIP do not function in the ATM-dependent telomere damage signalling, nor in telomere overhang removal, which are critical for telomere fusions by C-NHEJ. Instead, BRCA1 and CtIP act in the same pathway as LIG3 to promote joining of de-protected telomeres by A-NHEJ. Our work therefore ascribes novel roles for BRCA1 and CtIP in end-processing and fusion reactions at uncapped telomeres, underlining the complexity of DNA repair pathways that act at chromosome ends lacking protective structures. Moreover, A-NHEJ provides a mechanism of previously unanticipated significance in telomere dysfunction-induced genome instability.},
}
@article {pmid25576484,
year = {2015},
author = {Li, B},
title = {DNA double-strand breaks and telomeres play important roles in trypanosoma brucei antigenic variation.},
journal = {Eukaryotic cell},
volume = {14},
number = {3},
pages = {196-205},
pmid = {25576484},
issn = {1535-9786},
support = {R01 AI066095/AI/NIAID NIH HHS/United States ; },
mesh = {Antigens, Protozoan/*genetics ; *DNA Breaks, Double-Stranded ; Telomere/*genetics ; Trypanosoma brucei brucei/*genetics/immunology ; },
abstract = {Human-infecting microbial pathogens all face a serious problem of elimination by the host immune response. Antigenic variation is an effective immune evasion mechanism where the pathogen regularly switches its major surface antigen. In many cases, the major surface antigen is encoded by genes from the same gene family, and its expression is strictly monoallelic. Among pathogens that undergo antigenic variation, Trypanosoma brucei (a kinetoplastid), which causes human African trypanosomiasis, Plasmodium falciparum (an apicomplexan), which causes malaria, Pneumocystis jirovecii (a fungus), which causes pneumonia, and Borrelia burgdorferi (a bacterium), which causes Lyme disease, also express their major surface antigens from loci next to the telomere. Except for Plasmodium, DNA recombination-mediated gene conversion is a major pathway for surface antigen switching in these pathogens. In the last decade, more sophisticated molecular and genetic tools have been developed in T. brucei, and our knowledge of functions of DNA recombination in antigenic variation has been greatly advanced. VSG is the major surface antigen in T. brucei. In subtelomeric VSG expression sites (ESs), VSG genes invariably are flanked by a long stretch of upstream 70-bp repeats. Recent studies have shown that DNA double-strand breaks (DSBs), particularly those in 70-bp repeats in the active ES, are a natural potent trigger for antigenic variation in T. brucei. In addition, telomere proteins can influence VSG switching by reducing the DSB amount at subtelomeric regions. These findings will be summarized and their implications will be discussed in this review.},
}
@article {pmid25573617,
year = {2015},
author = {Haldar, P and Ramesh, V and Kant, S},
title = {Effect of sedentary activity on telomere length may not be so straightforward.},
journal = {British journal of sports medicine},
volume = {49},
number = {24},
pages = {1604},
doi = {10.1136/bjsports-2014-094473},
pmid = {25573617},
issn = {1473-0480},
mesh = {Exercise/*physiology ; Female ; Humans ; Male ; *Sedentary Behavior ; Telomere Homeostasis/*physiology ; },
}
@article {pmid25572391,
year = {2015},
author = {Vallabhaneni, H and Zhou, F and Maul, RW and Sarkar, J and Yin, J and Lei, M and Harrington, L and Gearhart, PJ and Liu, Y},
title = {Defective repair of uracil causes telomere defects in mouse hematopoietic cells.},
journal = {The Journal of biological chemistry},
volume = {290},
number = {9},
pages = {5502-5511},
pmid = {25572391},
issn = {1083-351X},
support = {//Intramural NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Bone Marrow Cells/*metabolism ; Cells, Cultured ; DNA Damage ; *DNA Repair ; DNA-Binding Proteins/genetics/metabolism ; In Situ Hybridization, Fluorescence ; Mice, Knockout ; Protein Binding ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere Homeostasis/genetics ; Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Thymine/metabolism ; Uracil/*metabolism ; Uracil-DNA Glycosidase/deficiency/genetics ; },
abstract = {Uracil in the genome can result from misincorporation of dUTP instead of dTTP during DNA synthesis, and is primarily removed by uracil DNA glycosylase (UNG) during base excision repair. Telomeres contain long arrays of TTAGGG repeats and may be susceptible to uracil misincorporation. Using model telomeric DNA substrates, we showed that the position and number of uracil substitutions of thymine in telomeric DNA decreased recognition by the telomere single-strand binding protein, POT1. In primary mouse hematopoietic cells, uracil was detectable at telomeres, and UNG deficiency further increased uracil loads and led to abnormal telomere lengthening. In UNG-deficient cells, the frequencies of sister chromatid exchange and fragility in telomeres also significantly increased in the absence of telomerase. Thus, accumulation of uracil and/or UNG deficiency interferes with telomere maintenance, thereby underscoring the necessity of UNG-initiated base excision repair for the preservation of telomere integrity.},
}
@article {pmid25568305,
year = {2015},
author = {Ozturk, S},
title = {Telomerase activity and telomere length in male germ cells.},
journal = {Biology of reproduction},
volume = {92},
number = {2},
pages = {53},
doi = {10.1095/biolreprod.114.124008},
pmid = {25568305},
issn = {1529-7268},
mesh = {Animals ; Germ Cells/*metabolism ; Humans ; Male ; Spermatogenesis/*physiology ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are located at the outermost ends of all eukaryotic chromosomes and provide for the maintenance of genomic stability and integrity during the life span of organisms. The length of telomeres shortens due to each round of DNA replication, genotoxic insults, and/or reactive oxygen species. To counteract this shortening, certain types of cells, including stem cells, male/female germline cells, granulosa cells, early embryos, and most cancerous cells, express an enzyme known as telomerase, which has the potential of restoring the shortened telomeres. Presence of telomerase activity in the male germ cells ensures maintenance of telomere length at maximum levels during spermatogenesis despite telomere attrition due to DNA replication or other genotoxic factors. In this review, telomerase activity and telomere length in mammalian male germ cells during spermatogenesis are evaluated in detail based on the studies in this field. Also, the relationship between telomerase activity/telomere length and development of male infertility is comprehensively discussed.},
}
@article {pmid25566806,
year = {2015},
author = {Ghosh, S and Jana, J and Kar, RK and Chatterjee, S and Dasgupta, D},
title = {Plant alkaloid chelerythrine induced aggregation of human telomere sequence--a unique mode of association between a small molecule and a quadruplex.},
journal = {Biochemistry},
volume = {54},
number = {4},
pages = {974-986},
doi = {10.1021/bi501117x},
pmid = {25566806},
issn = {1520-4995},
mesh = {Alkaloids/metabolism ; Base Sequence/*physiology ; Benzophenanthridines/*chemistry/*metabolism ; Crystallography, X-Ray ; G-Quadruplexes ; HeLa Cells ; Humans ; Protein Aggregates/*physiology ; Protein Binding/physiology ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Telomere/*chemistry/*metabolism ; },
abstract = {Small molecules that interact with G-quadruplex structures formed by the human telomeric region and stabilize them have the potential to evolve as anticancer therapeutic agents. Herein we report the interaction of a putative anticancer agent from a plant source, chelerythrine, with the human telomeric DNA sequence. It has telomerase inhibitory potential as demonstrated from telomerase repeat amplification assay in cancer cell line extract. We have attributed this to the quadruplex binding potential of the molecule and characterized the molecular details of the interaction by means of optical spectroscopy such as absorbance and circular dichroism and calorimetric techniques such as isothermal titration calorimetry and differential scanning calorimetry. The results show that chelerythrine binds with micromolar dissociation constant and 2:1 binding stoichiometry to the human telomeric DNA sequence. Chelerythrine association stabilizes the G-quadruplex. Nuclear magnetic resonance spectroscopy ((1)H and (31)P) shows that chelerythrine binds to both G-quartet and phosphate backbone of the quadruplex leading to quadruplex aggregation. Molecular dynamics simulation studies support the above inferences and provide further insight into the mechanism of ligand binding. The specificity toward quartet binding for chelerythrine is higher compared to that of groove binding. MM-PBSA calculation mines out the energy penalty for quartet binding to be -4.7 kcal/mol, whereas that of the groove binding is -1.7 kcal/mol. We propose that the first chelerythrine molecule binds to the quartet followed by a second molecule which binds to the groove. This second molecule might bring about aggregation of the quadruplex structure which is evident from the results of nuclear magnetic resonance.},
}
@article {pmid25563818,
year = {2016},
author = {Tahara, T and Shibata, T and Kawamura, T and Ishizuka, T and Okubo, M and Nagasaka, M and Nakagawa, Y and Arisawa, T and Ohmiya, N and Hirata, I},
title = {Telomere length in non-neoplastic gastric mucosa and its relationship to H. pylori infection, degree of gastritis, and NSAID use.},
journal = {Clinical and experimental medicine},
volume = {16},
number = {1},
pages = {65-71},
pmid = {25563818},
issn = {1591-9528},
mesh = {Anti-Inflammatory Agents, Non-Steroidal/*administration &amp; dosage/pharmacology ; Antigens, CD ; Cadherins/*genetics ; DNA Methylation/drug effects ; Female ; Gastric Mucosa/*drug effects ; Gastritis/*drug therapy/genetics/*microbiology ; Helicobacter Infections/*drug therapy/genetics ; Humans ; Male ; Middle Aged ; Pepsinogens/blood ; Promoter Regions, Genetic/drug effects ; Telomere/drug effects/*genetics ; Telomere Shortening/drug effects ; },
abstract = {Telomere shortening occurs with human aging in many organs and tissues and is accelerated by rapid cell turnover and oxidative injury. We measured average telomere length using quantitative real-time PCR in non-neoplastic gastric mucosa and assessed its relationship to H. pylori-related gastritis, DNA methylation, ulcer disease, and nonsteroidal anti-inflammatory drug (NSAID) usage. Gastric biopsies were obtained from 151 cancer-free subjects including 49 chronic NSAID users and 102 nonusers. Relative telomere length in genomic DNA was measured by real-time PCR. H. pylori infection status, histological severity of gastritis, and serum pepsinogens (PGs) were also investigated. E-cadherin (CDH1) methylation status was determined by methylation-specific PCR (MSP). Average relative telomere length of H. pylori-infected subjects was significantly shortened when compared to H. pylori-negative subjects (p = 0.002) and was closely associated with all histological parameter of gastritis (all p values <0.01) and CDH1 methylation (p = 0.0002). In H. pylori-negative subjects, NSAID users presented significantly shorter telomere length than nonusers (p = 0.028). Shorter telomere length was observed in duodenal and gastric ulcer patients compared with non-ulcer subjects among NSAID users. Telomere shortening is closely associated with severity of H. pylori-induced gastritis and CDH1 methylation status. Also, telomere shortening is accelerated by NSAID usage especially in H. pylori-negative subjects.},
}
@article {pmid25562437,
year = {2015},
author = {Julin, B and Shui, I and Heaphy, CM and Joshu, CE and Meeker, AK and Giovannucci, E and De Vivo, I and Platz, EA},
title = {Circulating leukocyte telomere length and risk of overall and aggressive prostate cancer.},
journal = {British journal of cancer},
volume = {112},
number = {4},
pages = {769-776},
pmid = {25562437},
issn = {1532-1827},
support = {R01 CA082838/CA/NCI NIH HHS/United States ; R01 CA133891/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Case-Control Studies ; Genetic Predisposition to Disease ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Neoplasm Invasiveness ; Polymorphism, Single Nucleotide ; Prostatic Neoplasms/*genetics/mortality/pathology ; Risk Factors ; *Telomere ; Telomere Homeostasis/genetics ; },
abstract = {BACKGROUND: Recent large-scale prospective studies suggest that long telomeres are associated with an increase cancer risk, counter to conventional wisdom.<br><br>METHODS: To further clarify the association between leukocyte telomere length (LTL) and prostate cancer, and assess genetic variability in relation to both LTL and prostate cancer, we performed a nested case-control study (922 cases and 935 controls). The participants provided blood in 1993-1995 and were followed through August 2004 (prostate cancer incidence) or until 28 February 2013 (lethal or fatal prostate cancer). Relative LTL was measured by quantitative PCR and was calculated as the ratio of telomere repeat copy number to a single gene (36B4) copy number (T/S). Genotyping was performed using the TaqMan OpenArray SNP Genotyping Platform. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of all prostate cancer and subtypes defined by Gleason grade, stage and lethality (metastasis or death).<br><br>RESULTS: We observed a positive association between each s.d. increase in LTL and all (multivariable-adjusted OR 1.11, 95% CI: 1.01-1.22), low-grade (OR 1.13, 95% CI:1.01-1.27), and localised (OR 1.12, 95% CI:1.01-1.24) prostate cancer. Associations for other subtypes were similar, but did not reach statistical significance. In subgroup analyses, associations for high grade and advanced stage (OR=2.04, 95% CI 1.00-4.17; Pinteraction=0.06) or lethal disease (OR=2.37, 95% CI 1.19-4.72; Pinteraction=0.01) were stronger in men with a family history of the disease compared with those without. The minor allele of SNP, rs7726159, which has previously been shown to be positively associated with LTL, showed an inverse association with all prostate cancer risk after correction for multiple testing (P=0.0005).<br><br>CONCLUSION: In this prospective study, longer LTL was modestly associated with higher risk of prostate cancer. A stronger association for more aggressive cancer in men with a family history of the disease needs to be confirmed in larger studies.},
}
@article {pmid25561286,
year = {2015},
author = {Shang, Y and Yu, D and Hao, L},
title = {Liposome-Adenoviral hTERT-siRNA Knockdown in Fibroblasts from Keloids Reduce Telomere Length and Fibroblast Growth.},
journal = {Cell biochemistry and biophysics},
volume = {72},
number = {2},
pages = {405-410},
doi = {10.1007/s12013-014-0476-5},
pmid = {25561286},
issn = {1559-0283},
mesh = {Apoptosis ; Cells, Cultured ; Fibroblasts/*metabolism/physiology ; Humans ; Keloid/genetics/*metabolism ; Telomerase/deficiency/*genetics ; *Telomere Homeostasis ; },
abstract = {Keloids, which possess invasive tumor-like behavior, have been clinically challenging to clinicians especially surgeons. Excessive extracellular matrix secreted from fibroblasts is the main histo-pathological feature of keloids. In this study, we transfected hTERT-siRNA into scar fibroblasts by liposome-adenoviral transduction in order to disrupt telomere length homeostasis and influence the cell cycle of fibroblasts. Our results showed that liposome hTERT-siRNA was able to knock down hTERT gene expression in scar fibroblasts. Moreover, the telomerase activity in hTERT-siRNA group was significantly reduced compared with the control groups. And the telomeric length of hTERT-siRNA group was significantly shortened as well. Further, flow cytometry studies and MTT assay demonstrated that apoptosis rate of fibroblasts in liposome hTERT-siRNA group significantly increased. These results indicated that the liposome-mediated hTERT gene transduction could inhibit the growth of fibroblasts in scar tissues suggesting a promising strategy of keloids treatment in the future.},
}
@article {pmid25549560,
year = {2014},
author = {Dangi-Garimella, S},
title = {Early cellular aging: salt and the telomeres.},
journal = {The American journal of managed care},
volume = {20},
number = {10 Spec No},
pages = {E9},
pmid = {25549560},
issn = {1936-2692},
mesh = {Body Mass Index ; *Cellular Senescence ; Humans ; Longevity ; Obesity/genetics/prevention &amp; control ; Sodium, Dietary/*adverse effects ; *Telomere ; },
}
@article {pmid25546508,
year = {2015},
author = {Rane, G and Koh, WP and Kanchi, MM and Wang, R and Yuan, JM and Wang, X},
title = {Association Between Leukocyte Telomere Length and Plasma Homocysteine in a Singapore Chinese Population.},
journal = {Rejuvenation research},
volume = {18},
number = {3},
pages = {203-210},
pmid = {25546508},
issn = {1557-8577},
support = {UM1 CA182876/CA/NCI NIH HHS/United States ; R01 CA144034/CA/NCI NIH HHS/United States ; UM1CA182876/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Cardiovascular Diseases/blood/*epidemiology/genetics ; Cohort Studies ; Female ; Follow-Up Studies ; Homocysteine/*blood ; Humans ; Incidence ; Leukocytes/*metabolism ; Male ; Middle Aged ; Prognosis ; Risk Factors ; Singapore/epidemiology ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {RATIONALE: Leukocyte telomere length (LTL) and plasma homocysteine (HCY) have been independently associated with cardiovascular disease (CVD) morbidity and mortality. However, few studies have investigated the association between LTL and HCY levels.<br><br>OBJECTIVE: This study investigated the association of LTL with CVD risk factors, including HCY, in an overt CVD-free Singapore Chinese population comprised of middle aged and elderly, the age group at risk of developing CVD.<br><br>APPROACH: The association of plasma HCY and other CVD biomarkers with LTL were assessed in 100 samples drawn from the Singapore Chinese Health Study (SCHS). SCHS, a population-based cohort, recruited Chinese individuals, aged 45-74 years, between 1993 and 1998. Questionnaire data were collected via face-to-face interviews. Known CVD biomarkers were measured from the blood collected at the time of recruitment, and LTL was measured using the conventional Southern blot method.<br><br>RESULTS: After adjustment for age, gender, smoking status, education, and dialect, LTL was found to be inversely associated with plasma HCY levels (p for trend=0.014). Serum urate showed a weak association (p for trend=0.056). Other CVD risk factors and nutrients, namely total cholesterol, low-density lipoprotein (LDL), triglycerides and creatinine, high-density lipoprotein (HDL), folate, and vitamin B6 showed the expected trend with LTL, but did not reach statistical significance.<br><br>CONCLUSION: LTL displayed an inverse association with plasma HCY. This LTL-HCY inverse association in subjects lacking obvious cardiovascular events suggests that telomere length may be an intermediary in the biological mechanism by which elevated HCY leads to CVD.},
}
@article {pmid25541866,
year = {2015},
author = {Kota, LN and Bharath, S and Purushottam, M and Moily, NS and Sivakumar, PT and Varghese, M and Pal, PK and Jain, S},
title = {Reduced telomere length in neurodegenerative disorders may suggest shared biology.},
journal = {The Journal of neuropsychiatry and clinical neurosciences},
volume = {27},
number = {2},
pages = {e92-6},
doi = {10.1176/appi.neuropsych.13100240},
pmid = {25541866},
issn = {1545-7222},
mesh = {Adolescent ; Aged ; Child ; Dementia/complications/genetics ; Female ; Humans ; Male ; Middle Aged ; Neurodegenerative Diseases/classification/complications/*genetics ; Telomere ; *Telomere Shortening ; },
abstract = {Early cell death is a feature of neurodegenerative disorders. Telomere shortening is related to premature cellular senescence and could be a marker for cellular pathology in neurological diseases. Relative telomere length in dementia (N=70), Huntington's disease (N=35), ataxia telangiectasia (N=9), and age-group matched control samples (N=105) was measured as relative telomere copy/single copy gene ratios. Individuals with Huntington's disease had the lowest relative telomere copy/single copy gene ratio (0.21), followed by ataxia telangiectasia (0.31) and dementia (0.48). The younger control group had the highest relative telomere copy/single copy gene ratio (1.07). The reduced telomere length could be indicative of shared biological pathways across these disorders contributing to cellular senescence.},
}
@article {pmid25539923,
year = {2015},
author = {Renčiuk, D and Kejnovská, I and Školáková, P and Bednářová, K and Motlová, J and Vorlíčková, M},
title = {Arrangements of human telomere DNA quadruplex in physiologically relevant K+ solutions.},
journal = {Nucleic acids research},
volume = {43},
number = {3},
pages = {1985},
doi = {10.1093/nar/gku1274},
pmid = {25539923},
issn = {1362-4962},
}
@article {pmid25539318,
year = {2015},
author = {Nava, MB and Catanuto, G and Pennati, AE and Rocco, N and Spano, A and Villa, R and Daidone, M},
title = {Lack of activation of telomere maintenance mechanisms in human adipose stromal cells derived from fatty portion of lipoaspirates.},
journal = {Plastic and reconstructive surgery},
volume = {135},
number = {1},
pages = {114e-123e},
doi = {10.1097/PRS.0000000000001008},
pmid = {25539318},
issn = {1529-4242},
mesh = {Adipocytes/cytology/*physiology ; Adipose Tissue/*cytology ; Adult ; Aged ; Cell Differentiation ; Cell Transformation, Neoplastic ; Cells, Cultured ; Female ; Humans ; Lipectomy ; Middle Aged ; Stromal Cells/cytology ; Telomere/*physiology ; },
abstract = {BACKGROUND: Significant improvement in the understanding of mesenchymal stem cell biology paved the way to their clinical use. Human lipoaspirates derived from mesenchymal stem cells (adipose-derived stem cells) continue to draw the attention of researchers in the field of basic and applied research due to their regenerative, reparative, angiogenic, antiapoptotic, and immunosuppressive properties, all of which collectively point out their therapeutic potential. There is still, however, a need for further investigation to improve the knowledge of stem cell biology, to broaden their field of use, and to enhance their therapeutic effectiveness.<br><br>METHODS: The authors characterized human adipose-derived stem cells at different in vitro culture time points in terms of immunophenotype, multilineage differentiation, long-term survival with self-renewal capacity, and presence of telomere maintenance mechanisms (telomerase activity and alternative lengthening of telomere) for excluding their eventual susceptibility to malignant transformation.<br><br>RESULTS: Adipose-derived stem cells were isolated from the abdomen and peritrochanteric region of 31 female donors, propagated, and monitored in vitro for several passages. The outgrown cells shared the biological properties of mesenchymal stem cells, with adherence to plastic, expression of the typical surface markers, and induction of adipogenic, osteogenic, and chondrogenic differentiation. Telomerase activity and alternative lengthening of telomere mechanisms at different passages of cultures were not evidenced.<br><br>CONCLUSION: The results support the concept that in vitro expanded adipose-derived stem cells obtained from fat tissue are not susceptible to developing one of the hallmarks of malignant transformation and can be considered amenable for cell therapy approaches.},
}
@article {pmid25536555,
year = {2014},
author = {Bazyka, DA and Ilyenko, IM and Loganovsky, KN and Benotmane, MA and Chumak, SA},
title = {TERF1 and TERF2 downregulate telomere length in cognitive deficit at the late period after low-dose exposure.},
journal = {Problemy radiatsiinoi medytsyny ta radiobiolohii},
volume = {19},
number = {},
pages = {170-185},
pmid = {25536555},
issn = {2304-8336},
abstract = {Purpose - to explore the role of radiation dose on gene regulation of telomere length and its influence on the patho-genesis of cerebrovascular neurocognitive deficit at the remote period of low-dose irradiation as a result of the Chornobyl accident. Materials and methods. We performed a study of TERF1, TERF2 and TERT genes expression (GE) by RT-PCR, and relative telomere length (RTL) by flow-FISH in 258 clean-up workers of Chornobyl accident divided by radiation dose groups (range 22-2800 mSv) and 78 controls with vascular cognitive deficit. Detailed psychometric interviews were performed to obtain quantitative data on the stage of cognitive deficit. Results. Statistically significant telomere shortening was demonstrated in groups of clean-up workers with radiation doses in 100-250 mSv and 250-500 mSv range (subsequently M ± SD: 15.85 ± 0.27; p< 0.02; 15.89 ± 0,33; p< 0.02; control: 17.21 ± 0,23). A decrease in RTL was in parallel to radiation dose increase and overexpression of negative telomere length regulators: TERF2 genes and, to a lesser extent TERF1; the opposite tendency was demonstrated for TERT GE. In exposed over 500 mSv a significant TERT overexpression was combined with decreased TERF1 and TERF2 GE, and absence of significant RTL changes in comparison with clean-up workers exposed to lower doses indicating a certain independency between gene expression and telomere length changes and possible threshold effects at this dose range. Analysis of the group of exposed in comparison with non-exposed demonstrated a significant decrease (p = 0.03) both of the mean MMSE and RTL parameters suggesting influence of previous exposure. Conclusion. This study shows parallel changes in decline of cognitive function and telomere length and differences in TERF2, TERT and TERF1 gene regulation at the late period after low dose and over 500 mSv exposure.},
}
@article {pmid25535858,
year = {2015},
author = {Prather, AA and Gurfein, B and Moran, P and Daubenmier, J and Acree, M and Bacchetti, P and Sinclair, E and Lin, J and Blackburn, E and Hecht, FM and Epel, ES},
title = {Tired telomeres: Poor global sleep quality, perceived stress, and telomere length in immune cell subsets in obese men and women.},
journal = {Brain, behavior, and immunity},
volume = {47},
number = {},
pages = {155-162},
pmid = {25535858},
issn = {1090-2139},
support = {K08HL112961/HL/NHLBI NIH HHS/United States ; P01 AT005013/AT/NCCIH NIH HHS/United States ; K24 AT007827/AT/NCCIH NIH HHS/United States ; P01AT005013/AT/NCCIH NIH HHS/United States ; P30 AI027763/AI/NIAID NIH HHS/United States ; K08 HL112961/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Obesity/genetics/*metabolism/physiopathology ; Sleep/*physiology ; Stress, Psychological/genetics/*metabolism/physiopathology ; Telomere/*metabolism ; Telomere Shortening ; },
abstract = {Poor sleep quality and short sleep duration are associated with increased incidence and progression of a number of chronic health conditions observed at greater frequency among the obese and those experiencing high levels of stress. Accelerated cellular aging, as indexed by telomere attrition in immune cells, is a plausible pathway linking sleep and disease risk. Prior studies linking sleep and telomere length are mixed. One factor may be reliance on leukocytes, which are composed of varied immune cell types, as the sole measure of telomere length. To better clarify these associations, we investigated the relationships of global sleep quality, measured by the Pittsburgh Sleep Quality Index (PSQI), and diary-reported sleep duration with telomere length in different immune cell subsets, including granulocytes, peripheral blood mononuclear cells (PBMCs), CD8+ and CD4+ T lymphocytes, and B lymphocytes in a sample of 87 obese men and women (BMI mean=35.4, SD=3.6; 81.6% women; 62.8% Caucasian). Multiple linear regression analyses were performed adjusting for age, gender, race, education, BMI, sleep apnea risk, and perceived stress. Poorer PSQI global sleep quality was associated with statistically significantly shorter telomere length in lymphocytes but not granulocytes and in particular CD8+ T cells (b=-56.8 base pairs per one point increase in PSQI, SE=20.4, p=0.007) and CD4+ T cells (b=-37.2, SE=15.9, p=0.022). Among separate aspects of global sleep quality, low perceived sleep quality and decrements in daytime function were most related to shorter telomeres. In addition, perceived stress moderated the sleep-CD8+ telomere association. Poorer global sleep quality predicted shorter telomere length in CD8+ T cells among those with high perceived stress but not in low stress participants. These findings provide preliminary evidence that poorer global sleep quality is related to telomere length in several immune cell types, which may serve as a pathway linking sleep and disease risk in obese individuals.},
}
@article {pmid25535668,
year = {2015},
author = {Jodczyk, S and Pearson, JF and Aitchison, A and Miller, AL and Hampton, MB and Kennedy, MA},
title = {Telomere length measurement on the Roche LightCycler 480 Platform.},
journal = {Genetic testing and molecular biomarkers},
volume = {19},
number = {2},
pages = {63-68},
doi = {10.1089/gtmb.2014.0208},
pmid = {25535668},
issn = {1945-0257},
mesh = {Blotting, Southern ; DNA Primers ; Electrophoresis, Agar Gel ; Humans ; Nucleic Acid Denaturation ; Polymorphism, Restriction Fragment Length ; Real-Time Polymerase Chain Reaction/*instrumentation/methods ; Reference Standards ; Reproducibility of Results ; Telomere/*ultrastructure ; Temperature ; },
abstract = {BACKGROUND: The average length of telomeres as measured in genomic DNA from human peripheral blood leukocytes is proving to be a potential biomarker of great interest, particularly with respect to studies of aging, specific diseases, and the effects of various stresses on overall health.<br><br>AIMS: The aim of this study was to establish an effective real-time quantitative polymerase chain reaction (qPCR) method for telomere length measurement on the Roche LightCycler&#xae; 480 (LC480) real-time PCR platform.<br><br>METHODS: Measurement of relative average telomere length was achieved by comparing products amplified from telomere-specific primers and single copy reference gene primers in a ratio (T/S).<br><br>RESULTS: Extensive testing led us to conclude that a modification of the original two-plate T/S assay was more compatible with this platform than the recently developed single-plate assay, and that choice of hot-start Taq polymerase and intercalating dye were critical factors.<br><br>CONCLUSIONS: This modified assay generates reliable measurements as judged by correlation with data derived by the telomeric restriction fragment Southern blot-based method.},
}
@article {pmid25531224,
year = {2015},
author = {Wrighton, KH},
title = {Telomeres: Chaperonin' telomerase.},
journal = {Nature reviews. Molecular cell biology},
volume = {16},
number = {1},
pages = {4},
pmid = {25531224},
issn = {1471-0080},
mesh = {Chaperonin Containing TCP-1/*metabolism ; Humans ; Telomerase/*metabolism ; Telomere/*metabolism ; },
}
@article {pmid25528024,
year = {2015},
author = {Benitez-Buelga, C and Sanchez-Barroso, L and Gallardo, M and Apellániz-Ruiz, M and Inglada-Pérez, L and Yanowski, K and Carrillo, J and Garcia-Estevez, L and Calvo, I and Perona, R and Urioste, M and Osorio, A and Blasco, MA and Rodriguez-Antona, C and Benitez, J},
title = {Impact of chemotherapy on telomere length in sporadic and familial breast cancer patients.},
journal = {Breast cancer research and treatment},
volume = {149},
number = {2},
pages = {385-394},
pmid = {25528024},
issn = {1573-7217},
support = {232854/ERC_/European Research Council/International ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Breast Neoplasms/drug therapy/*genetics ; Case-Control Studies ; Cross-Sectional Studies ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Humans ; Longitudinal Studies ; Middle Aged ; Mutation ; Risk Factors ; Telomere/*genetics/metabolism ; Telomere Shortening ; Young Adult ; },
abstract = {Recently, we observed that telomeres of BRCA1/2 mutation carriers were shorter than those of controls or sporadic breast cancer patients, suggesting that mutations in these genes might be responsible for this event. Given the contradictory results reported in the literature, we tested whether other parameters, such as chemotherapy, could be modifying telomere length (TL). We performed a cross-sectional study measuring leukocyte TL of 266 sporadic breasts cancer patients treated with first-line chemotherapy, with a median follow-up of 240 days. Additionally, we performed both cross-sectional and longitudinal studies in a series of 236 familial breast cancer patients that included affected and non-affected BRCA1/2 mutation carriers. We have measured in leukocytes from peripheral blood: the TL, percentage of short telomeres (<3 kb), telomerase activity levels and the annual telomere shortening speed. In sporadic cases we found that chemotherapy exerts a transient telomere shortening effect (around 2 years) that varies depending on the drug combination. In familial cases, only patients receiving treatment were associated with telomere shortening but they recovered normal TL after a period of 2 years. Chemotherapy affects TL and should be considered in the studies that correlate TL with disease susceptibility.},
}
@article {pmid25520162,
year = {2015},
author = {Corbett, N and Alda, M},
title = {On telomeres long and short.},
journal = {Journal of psychiatry &amp; neuroscience : JPN},
volume = {40},
number = {1},
pages = {3-4},
pmid = {25520162},
issn = {1488-2434},
mesh = {Aging/metabolism ; Humans ; Mental Disorders/*metabolism ; Telomere/*metabolism ; Telomere Shortening ; },
}
@article {pmid25518961,
year = {2015},
author = {Chen, L and Zhu, X and Zou, Y and Xing, J and Gilson, E and Lu, Y and Ye, J},
title = {The topoisomerase II catalytic inhibitor ICRF-193 preferentially targets telomeres that are capped by TRF2.},
journal = {American journal of physiology. Cell physiology},
volume = {308},
number = {5},
pages = {C372-7},
doi = {10.1152/ajpcell.00321.2014},
pmid = {25518961},
issn = {1522-1563},
mesh = {Cell Line, Tumor ; DNA Damage/drug effects/physiology ; Diketopiperazines ; *Drug Delivery Systems/methods ; HEK293 Cells ; Humans ; Piperazines/*administration &amp; dosage ; Telomere/*drug effects/metabolism/pathology ; Telomeric Repeat Binding Protein 2/*antagonists &amp; inhibitors/metabolism ; Topoisomerase II Inhibitors/*administration &amp; dosage ; },
abstract = {The increased level of chromosome instability in cancer cells is not only a driving force for oncogenesis but also can be the Achille's heel of the disease since many chemotherapies kill cells by inducing a nontolerable rate of DNA damage. A wealth of published evidence showed that telomere stability can be more affected than the bulk of the genome by several conventional antineoplastic drugs. In the present study, HT1080 cell lines compromised for either telomere repeats binding factor 2 (TRF2) or POT1 were treated with ICRF-193 (3 μM, 24 h) or bleomycin (1 μM, 24 h). DNA damage was assayed by combining telomeric DNA staining of a (CCCTAA)n PNA probe with immunofluorescence of 53BP1 to score the rate of telomere colocalization with 53BP1 foci. We found that ICRF-193, but not bleomycin, leads to DNA damage preferentially at telomeres, which can be rescued by TRF2 inhibition. POT1 inhibition exacerbates telomere dysfunction induced by ICRF-193. Thus, ICRF-193 induces damage at telomeres properly capped by TRF2 but not by POT1. These findings are expected to broaden our view on the mechanism by which conventional therapeutic molecules act to eliminate cancer cells and how to use TRF2 and POT1 levels as surrogate markers for anti-topoisomerase II sensitivity.},
}
@article {pmid25516442,
year = {2015},
author = {Machiela, MJ and Hsiung, CA and Shu, XO and Seow, WJ and Wang, Z and Matsuo, K and Hong, YC and Seow, A and Wu, C and Hosgood, HD and Chen, K and Wang, JC and Wen, W and Cawthon, R and Chatterjee, N and Hu, W and Caporaso, NE and Park, JY and Chen, CJ and Kim, YH and Kim, YT and Landi, MT and Shen, H and Lawrence, C and Burdett, L and Yeager, M and Chang, IS and Mitsudomi, T and Kim, HN and Chang, GC and Bassig, BA and Tucker, M and Wei, F and Yin, Z and An, SJ and Qian, B and Lee, VH and Lu, D and Liu, J and Jeon, HS and Hsiao, CF and Sung, JS and Kim, JH and Gao, YT and Tsai, YH and Jung, YJ and Guo, H and Hu, Z and Hutchinson, A and Wang, WC and Klein, RJ and Chung, CC and Oh, IJ and Chen, KY and Berndt, SI and Wu, W and Chang, J and Zhang, XC and Huang, MS and Zheng, H and Wang, J and Zhao, X and Li, Y and Choi, JE and Su, WC and Park, KH and Sung, SW and Chen, YM and Liu, L and Kang, CH and Hu, L and Chen, CH and Pao, W and Kim, YC and Yang, TY and Xu, J and Guan, P and Tan, W and Su, J and Wang, CL and Li, H and Sihoe, AD and Zhao, Z and Chen, Y and Choi, YY and Hung, JY and Kim, JS and Yoon, HI and Cai, Q and Lin, CC and Park, IK and Xu, P and Dong, J and Kim, C and He, Q and Perng, RP and Kohno, T and Kweon, SS and Chen, CY and Vermeulen, RC and Wu, J and Lim, WY and Chen, KC and Chow, WH and Ji, BT and Chan, JK and Chu, M and Li, YJ and Yokota, J and Li, J and Chen, H and Xiang, YB and Yu, CJ and Kunitoh, H and Wu, G and Jin, L and Lo, YL and Shiraishi, K and Chen, YH and Lin, HC and Wu, T and Wong, MP and Wu, YL and Yang, PC and Zhou, B and Shin, MH and Fraumeni, JF and Zheng, W and Lin, D and Chanock, SJ and Rothman, N and Lan, Q},
title = {Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: a report from the female lung cancer consortium in Asia.},
journal = {International journal of cancer},
volume = {137},
number = {2},
pages = {311-319},
pmid = {25516442},
issn = {1097-0215},
support = {NCI R01-CA121210/CA/NCI NIH HHS/United States ; R37 CA070867/CA/NCI NIH HHS/United States ; //Intramural NIH HHS/United States ; R01 CA121210/CA/NCI NIH HHS/United States ; UM1 CA182910/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Asian People/genetics ; China ; Female ; Genetic Predisposition to Disease/ethnology/*genetics ; Genome-Wide Association Study/statistics &amp; numerical data ; Hong Kong ; Humans ; Japan ; Lung Neoplasms/ethnology/*genetics ; Middle Aged ; Odds Ratio ; *Polymorphism, Single Nucleotide ; Prospective Studies ; Republic of Korea ; Risk Factors ; Singapore ; Smoking ; Taiwan ; Telomere/*genetics ; Telomere Homeostasis/genetics ; },
abstract = {Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14)) even after removing rs2736100 (p value = 4.81 × 10(-3)), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.},
}
@article {pmid25516420,
year = {2015},
author = {Mender, I and Gryaznov, S and Dikmen, ZG and Wright, WE and Shay, JW},
title = {Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2'-deoxyguanosine.},
journal = {Cancer discovery},
volume = {5},
number = {1},
pages = {82-95},
pmid = {25516420},
issn = {2159-8290},
support = {5P30 CA142543/CA/NCI NIH HHS/United States ; P50CA70907/CA/NCI NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; C06 RR030414/RR/NCRR NIH HHS/United States ; C06 RR30414/RR/NCRR NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Line, Tumor ; Cell Survival/drug effects ; Cell Transformation, Neoplastic/drug effects ; DNA Damage/drug effects ; Deoxyguanosine/*analogs &amp; derivatives/metabolism/pharmacology ; Epithelial Cells/drug effects/metabolism ; Female ; Fibroblasts/drug effects/metabolism ; Heterografts ; Humans ; Kidney/drug effects/metabolism/pathology ; Liver/drug effects/metabolism/pathology ; Mice ; Substrate Specificity ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/drug effects/genetics ; Telomere Shortening/drug effects/genetics ; Thioguanine/pharmacology ; Thionucleosides/metabolism/*pharmacology ; Tumor Burden/drug effects/genetics ; Xenograft Model Antitumor Assays ; },
abstract = {UNLABELLED: The relationships between telomerase and telomeres represent attractive targets for new anticancer agents. Here, we report that the nucleoside analogue 6-thio-2'-deoxyguanosine (6-thio-dG) is recognized by telomerase and is incorporated into de novo-synthesized telomeres. This results in modified telomeres, leading to telomere dysfunction, but only in cells expressing telomerase. 6-Thio-dG, but not 6-thioguanine, induced telomere dysfunction in telomerase-positive human cancer cells and hTERT-expressing human fibroblasts, but not in telomerase-negative cells. Treatment with 6-thio-dG resulted in rapid cell death for the vast majority of the cancer cell lines tested, whereas normal human fibroblasts and human colonic epithelial cells were largely unaffected. In A549 lung cancer cell-based mouse xenograft studies, 6-thio-dG caused a decrease in the tumor growth rate superior to that observed with 6-thioguanine treatment. In addition, 6-thio-dG increased telomere dysfunction in tumor cells in vivo. These results indicate that 6-thio-dG may provide a new telomere-addressed telomerase-dependent anticancer approach.<br><br>SIGNIFICANCE: Telomerase is an almost universal oncology target, yet there are few telomerase-directed therapies in human clinical trials. In the present study, we demonstrate a small-molecule telomerase substrate approach that induces telomerase-mediated targeted "telomere uncapping," but only in telomerase-positive cancer cells, with minimal effects in normal telomerase-negative cells.},
}
@article {pmid25515040,
year = {2015},
author = {Qu, F and Li, R and He, X and Li, Q and Xie, S and Gong, L and Ji, G and Lu, J and Bao, G},
title = {Short telomere length in peripheral blood leukocyte predicts poor prognosis and indicates an immunosuppressive phenotype in gastric cancer patients.},
journal = {Molecular oncology},
volume = {9},
number = {3},
pages = {727-739},
pmid = {25515040},
issn = {1878-0261},
mesh = {Cytokines/blood ; Disease-Free Survival ; Female ; Humans ; Immunophenotyping ; *Immunosuppression Therapy ; Kaplan-Meier Estimate ; Leukocytes, Mononuclear/*metabolism ; Male ; Middle Aged ; Multivariate Analysis ; Neoplasm Recurrence, Local/pathology ; Neoplasm Staging ; Phenotype ; Prognosis ; Proportional Hazards Models ; Stomach Neoplasms/blood/*metabolism/pathology ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {Compelling evidences indicate that relative telomere length (RTL) in peripheral blood leukocytes (PBLs) can predict the clinical outcome of several cancers. However, to date, the prognostic value of leukocyte RTL in gastric cancer (GC) patients has not been explored. In this study, relative telomere length (RTL) in peripheral blood leukocytes (PBLs) was measured using a real-time PCR-based method in a total of 693 GC patients receiving surgical resection. The prognostic value of leukocyte RTL was first explored in the training set (112 patients) using Kaplan-Meier and Cox proportional hazards regression analyses. Then an independent cohort of 581 patients was used as a validation set. To explore potential mechanism, we detected the immunophenotypes of peripheral blood mononuclear cells and plasma concentrations of several cytokines in GC patients. Patients with short RTL showed significantly worse overall survival (OS) and relapse-free survival (RFS) than those with long RTL in all patient sets. Furthermore, leukocyte RTL and TNM stage exhibited a notable joint effect in prognosis prediction. Integration of TNM stage and leukocyte RTL significantly improved the prognosis prediction efficacy for GC. In addition, we found that patients with short RTL had a higher CD4(+) T cell percentage in PBMCs, CD19(+)IL-10(+) Breg percentage in B cells and plasma IL-10 concentration, indicating an enhanced immunosuppressive status with short leukocyte RTL. In conclusion, our study for the first time demonstrates that leukocyte RTL is an independent prognostic marker complementing TNM stage and associated with an immunosuppressive phenotype in the peripheral blood lymphocytes in GC patients.},
}
@article {pmid25506937,
year = {2014},
author = {Denil, SL and Rietzschel, ER and De Buyzere, ML and Van Daele, CM and Segers, P and De Bacquer, D and Van Criekinge, W and Bekaert, S and Gillebert, TC and De Meyer, T and , },
title = {On cross-sectional associations of leukocyte telomere length with cardiac systolic, diastolic and vascular function: the Asklepios study.},
journal = {PloS one},
volume = {9},
number = {12},
pages = {e115071},
pmid = {25506937},
issn = {1932-6203},
mesh = {Adult ; Blood Pressure/physiology ; Cross-Sectional Studies ; Female ; Heart/*physiology ; Heart Rate/physiology ; Humans ; Leukocytes/*physiology ; Male ; Middle Aged ; Myocardial Contraction/*physiology ; Telomere/*metabolism ; Vascular Stiffness/*physiology ; },
abstract = {BACKGROUND: Systemic telomere length has been associated with measures of diastolic function, vascular stiffness and left ventricular mass mainly in smaller, patient-specific settings and not in a general population. In this study we describe the applicability of these findings in a large, representative population.<br><br>METHODS AND RESULTS: Peripheral blood leukocyte telomere length (PBL TL) was measured using telomere restriction fragment analysis in the young to middle-aged (>2500 volunteers, &#x223c;35 to 55 years old) Asklepios study population, free from overt cardiovascular disease. Subjects underwent extensive echocardiographic, hemodynamic and biochemical phenotyping. After adjusting for relevant confounders (age, sex, systolic blood pressure, heart rate, body mass index and use of antihypertensive drugs) we found no associations between PBL TL and left ventricular mass index (P&#x200a;=&#x200a;0.943), ejection fraction (P&#x200a;=&#x200a;0.933), peak systolic septal annular motion (P&#x200a;=&#x200a;0.238), pulse wave velocity (P&#x200a;=&#x200a;0.971) or pulse pressure (P&#x200a;=&#x200a;0.999). In contrast, our data showed positive associations between PBL TL and parameters of LV filling: the transmitral flow early (E) to late (A) velocity ratio (E/A-ratio; P<0.001), the ratio of early (e') to late (a') mitral annular velocities (e'/a'-ratio; P&#x200a;=&#x200a;0.012) and isovolumic relaxation time (P&#x200a;=&#x200a;0.015). Interestingly, these associations were stronger in women than in men and were driven by associations between PBL TL and the late diastolic components (A and a').<br><br>CONCLUSIONS: In a generally healthy, young to middle-aged population, PBL TL is not related to LV mass or systolic function, but might be associated with an altered LV filling pattern, especially in women.},
}
@article {pmid25504027,
year = {2015},
author = {Zota, AR and Needham, BL and Blackburn, EH and Lin, J and Park, SK and Rehkopf, DH and Epel, ES},
title = {Associations of cadmium and lead exposure with leukocyte telomere length: findings from National Health and Nutrition Examination Survey, 1999-2002.},
journal = {American journal of epidemiology},
volume = {181},
number = {2},
pages = {127-136},
pmid = {25504027},
issn = {1476-6256},
support = {R00ES019881/ES/NIEHS NIH HHS/United States ; R01AG033592-01A1/AG/NIA NIH HHS/United States ; R00 ES019881/ES/NIEHS NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; K01 ES016587/ES/NIEHS NIH HHS/United States ; K01ES016587/ES/NIEHS NIH HHS/United States ; R01 AG033592/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Cadmium/*adverse effects/blood/urine ; Cellular Senescence/drug effects ; Dose-Response Relationship, Drug ; Environmental Exposure/*adverse effects/analysis ; Environmental Pollutants/*adverse effects/blood ; Female ; Health Behavior ; Humans ; Lead/*adverse effects/blood ; Leukocytes/drug effects ; Male ; Middle Aged ; Nutrition Surveys ; Socioeconomic Factors ; Telomere/*drug effects ; },
abstract = {Cadmium and lead are ubiquitous environmental contaminants that might increase risks of cardiovascular disease and other aging-related diseases, but their relationships with leukocyte telomere length (LTL), a marker of cellular aging, are poorly understood. In experimental studies, they have been shown to induce telomere shortening, but no epidemiologic study to date has examined their associations with LTL in the general population. We examined associations of blood lead and cadmium (n = 6,796) and urine cadmium (n = 2,093) levels with LTL among a nationally representative sample of US adults from the National Health and Nutrition Examination Survey (1999-2002). The study population geometric mean concentrations were 1.67 µg/dL (95% confidence interval (CI): 1.63, 1.70) for blood lead, 0.44 µg/L (95% CI: 0.42, 0.47) for blood cadmium, and 0.28 µg/L (95% CI: 0.27, 0.30) for urine cadmium. After adjustment for potential confounders, the highest (versus lowest) quartiles of blood and urine cadmium were associated with -5.54% (95% CI: -8.70, -2.37) and -4.50% (95% CI: -8.79, -0.20) shorter LTLs, respectively, with evidence of dose-response relationship (P for trend < 0.05). There was no association between blood lead concentration and LTL. These findings provide further evidence of physiological impacts of cadmium at environmental levels and might provide insight into biological pathways underlying cadmium toxicity and chronic disease risks.},
}
@article {pmid25501936,
year = {2015},
author = {Ke, S and Zhou, F and Yang, H and Wei, Y and Gong, J and Mei, Z and Wu, L and Yu, H and Zhou, Y},
title = {Downregulation of high mobility group box 1 modulates telomere homeostasis and increases the radiosensitivity of human breast cancer cells.},
journal = {International journal of oncology},
volume = {46},
number = {3},
pages = {1051-1058},
doi = {10.3892/ijo.2014.2793},
pmid = {25501936},
issn = {1791-2423},
mesh = {Aminopeptidases/genetics/metabolism ; Apoptosis/genetics ; Breast Neoplasms/genetics/metabolism/*radiotherapy ; Cell Cycle/genetics ; Cell Proliferation/genetics ; DNA Damage/genetics/radiation effects ; DNA Repair/genetics ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics/metabolism ; Down-Regulation ; Female ; Gene Knockdown Techniques ; HMGB1 Protein/*genetics/metabolism ; Humans ; MCF-7 Cells/radiation effects ; Radiation Tolerance/genetics ; Radiation, Ionizing ; Serine Proteases/genetics/metabolism ; Shelterin Complex ; Telomerase/genetics/metabolism ; Telomere Homeostasis/*physiology ; Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; },
abstract = {The functions of the high mobility group box 1 (HMGB1) in tumor cells include replenishing telomeric DNA and maintaining cell immortality. There is a negative correlation between human telomerase reverse transcriptase (hTERT) and radiosensitivity in tumor cells. Our aim was to elucidate the relationship among HMGB1, telomere homeostasis and radiosensitivity in MCF-7 cells. In this study, we established stably transfected control (MCF-7-NC) and HMGB1 knockdown (MCF-7-shHMGB1) cell lines. The expression of HMGB1 mRNA and the relative telomere length were examined by real-time PCR. Radiosensitivity was detected by clonogenic assay. The protein expressions were determined by western blot analysis. The telomerase activity was detected by PCR-ELISA. Proliferation ability was examined by CCK-8 assay. Cell cycle and apoptosis were examined by flow cytometry. DNA damage foci were detected by immunofluorescence. ShRNA-mediated downregulation of HMGB1 expression increased the radiosensitivity of MCF-7 cells, and reduced the accumulation of hTERT and cyclin D1. Moreover, knockdown of HMGB1 in MCF-7 cells inhibited telomerase activity and cell proliferation, while increasing the extent of apoptosis. Downregulation of HMGB1 modulated telomere homeostasis by changing the level of telomere-binding proteins, such as TPP1 (PTOP), TRF1 and TRF2. This downregulation also inhibited the ATM and ATR signaling pathways. The current data demonstrate that knockdown of HMGB1 breaks telomere homeostasis, enhances radiosensitivity, and suppresses the repair of DNA damage in human breast cancer cells. These results suggested that HMGB1 might be a potential radiotherapy target in human breast cancer.},
}
@article {pmid25501556,
year = {2014},
author = {Degerman, S and Domellöf, M and Landfors, M and Linder, J and Lundin, M and Haraldsson, S and Elgh, E and Roos, G and Forsgren, L},
title = {Long leukocyte telomere length at diagnosis is a risk factor for dementia progression in idiopathic parkinsonism.},
journal = {PloS one},
volume = {9},
number = {12},
pages = {e113387},
pmid = {25501556},
issn = {1932-6203},
mesh = {Adult ; Aged ; Aged, 80 and over ; Dementia/*diagnosis ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Multiple System Atrophy/genetics/pathology ; Parkinson Disease/*genetics/*psychology ; Prognosis ; Supranuclear Palsy, Progressive/genetics/pathology ; Telomere/*metabolism ; },
abstract = {Telomere length (TL) is regarded as a marker of cellular aging due to the gradual shortening by each cell division, but is influenced by a number of factors including oxidative stress and inflammation. Parkinson's disease and atypical forms of parkinsonism occur mainly in the elderly, with oxidative stress and inflammation in afflicted cells. In this study the relationship between blood TL and prognosis of 168 patients with idiopathic parkinsonism (136 Parkinson's disease [PD], 17 Progressive Supranuclear Palsy [PSP], and 15 Multiple System Atrophy [MSA]) and 30 controls was investigated. TL and motor and cognitive performance were assessed at baseline (diagnosis) and repeatedly up to three to five years follow up. No difference in TL between controls and patients was shown at baseline, nor any significant difference in TL stability or attrition during follow up. Interestingly, a significant relationship between TL at diagnosis and cognitive phenotype at follow up in PD and PSP patients was found, with longer mean TL at diagnosis in patients that developed dementia within three years.},
}
@article {pmid25499762,
year = {2015},
author = {Balakumaran, A and Mishra, PJ and Pawelczyk, E and Yoshizawa, S and Sworder, BJ and Cherman, N and Kuznetsov, SA and Bianco, P and Giri, N and Savage, SA and Merlino, G and Dumitriu, B and Dunbar, CE and Young, NS and Alter, BP and Robey, PG},
title = {Bone marrow skeletal stem/progenitor cell defects in dyskeratosis congenita and telomere biology disorders.},
journal = {Blood},
volume = {125},
number = {5},
pages = {793-802},
pmid = {25499762},
issn = {1528-0020},
support = {GGP09227/TI_/Telethon/Italy ; //Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Animals ; Base Sequence ; Bone Marrow Cells/*metabolism/pathology ; Cell Differentiation ; Cell Proliferation ; Cellular Senescence ; Child ; Child, Preschool ; Colony-Forming Units Assay ; DNA Helicases/genetics/metabolism ; Dyskeratosis Congenita/*genetics/pathology ; Female ; Hematopoiesis/genetics ; Humans ; Male ; Mesenchymal Stem Cells/*metabolism/pathology ; Mice ; Middle Aged ; Molecular Sequence Data ; Mutation ; RNA/antagonists &amp; inhibitors/*genetics/metabolism ; RNA, Small Interfering/genetics/metabolism ; Telomerase/antagonists &amp; inhibitors/*genetics/metabolism ; Telomere/chemistry/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Dyskeratosis congenita (DC) is an inherited multisystem disorder, characterized by oral leukoplakia, nail dystrophy, and abnormal skin pigmentation, as well as high rates of bone marrow (BM) failure, solid tumors, and other medical problems such as osteopenia. DC and telomere biology disorders (collectively referred to as TBD here) are caused by germline mutations in telomere biology genes leading to very short telomeres and limited proliferative potential of hematopoietic stem cells. We found that skeletal stem cells (SSCs) within the BM stromal cell population (BMSCs, also known as BM-derived mesenchymal stem cells), may contribute to the hematologic phenotype. TBD-BMSCs exhibited reduced clonogenicity, spontaneous differentiation into adipocytes and fibrotic cells, and increased senescence in vitro. Upon in vivo transplantation into mice, TBD-BMSCs failed to form bone or support hematopoiesis, unlike normal BMSCs. TERC reduction (a TBD-associated gene) in normal BMSCs by small interfering TERC-RNA (siTERC-RNA) recapitulated the TBD-BMSC phenotype by reducing proliferation and secondary colony-forming efficiency, and by accelerating senescence in vitro. Microarray profiles of control and siTERC-BMSCs showed decreased hematopoietic factors at the messenger RNA level and decreased secretion of factors at the protein level. These findings are consistent with defects in SSCs/BMSCs contributing to BM failure in TBD.},
}
@article {pmid25499309,
year = {2015},
author = {Biron-Shental, T and Sukenik-Halevy, R and Naboani, H and Liberman, M and Kats, R and Amiel, A},
title = {Telomeres are shorter in placentas from pregnancies with uncontrolled diabetes.},
journal = {Placenta},
volume = {36},
number = {2},
pages = {199-203},
doi = {10.1016/j.placenta.2014.11.011},
pmid = {25499309},
issn = {1532-3102},
mesh = {Adult ; Blood Glucose/*metabolism ; Case-Control Studies ; Cellular Senescence/physiology ; Diabetes, Gestational/*blood/genetics/pathology ; Female ; Glycated Hemoglobin/*metabolism ; Humans ; Infant, Newborn ; Placenta/*metabolism/pathology/physiopathology ; Pregnancy ; Telomere/*physiology ; *Telomere Shortening ; Trophoblasts/pathology/physiology ; },
abstract = {INTRODUCTION: The intrauterine environment, including the placenta, is influenced by a variety of factors, among which is diabetes during pregnancy. These factors can affect lifetime morbidity. Senescence is a state of cellular metabolic arrest, known to be correlated with age-related diseases and is usually accompanied by short telomeres. This study evaluated telomere characteristics in placentas and in cord blood from term pregnancies complicated by uncontrolled diabetes mellitus.<br><br>METHODS: Placental biopsies and cord blood were collected from 16 pregnancies with poorly controlled diabetes and from 16 healthy controls. Senescence-associated heterochromatin foci (SAHF) and senescence-associated &#x3b2;-galactosidase (SA&#x3b2;-Gal) staining were evaluated. Apoptosis was evaluated using tunel staining. Telomere length and aggregate formation were assessed in placentas and in cord blood using Q-FISH.<br><br>RESULTS: Increased SAHF (19.28% &#xb1; 7.93 vs. 7.78% &#xb1; 5.31, P < 0.001) and SA&#x3b2;-Gal (7.1% &#xb1; 1.32 vs. 0.8% &#xb1; 0.41, P < 0.001), but not apoptosis were present in placentas from diabetic pregnancies compared to controls. Higher percentage of trophoblasts with short telomeres (24.42% &#xb1; 12.6 vs. 4.92% &#xb1; 6.4, P = 0.013) and noticeably more aggregate formation (2.75% &#xb1; 1.14 vs. 0.62% &#xb1; 0.87, P < 0.001) were observed in diabetic placentas compared to controls. These differences were not observed in cord blood samples.<br><br>DISCUSSION: Poorly controlled diabetes is related to increased senescence and shorter telomeres in placentas. Those findings may partially explain increased long-term, related morbidity.},
}
@article {pmid25497088,
year = {2014},
author = {Deng, Z and Kim, ET and Vladimirova, O and Dheekollu, J and Wang, Z and Newhart, A and Liu, D and Myers, JL and Hensley, SE and Moffat, J and Janicki, SM and Fraser, NW and Knipe, DM and Weitzman, MD and Lieberman, PM},
title = {HSV-1 remodels host telomeres to facilitate viral replication.},
journal = {Cell reports},
volume = {9},
number = {6},
pages = {2263-2278},
pmid = {25497088},
issn = {2211-1247},
support = {AI063106/AI/NIAID NIH HHS/United States ; R01 AI063106/AI/NIAID NIH HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; R01 NS082240/NS/NINDS NIH HHS/United States ; R01NS082240/NS/NINDS NIH HHS/United States ; R01CA140652/CA/NCI NIH HHS/United States ; P30 CA10815/CA/NCI NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line ; Chromosome Aberrations ; DNA Damage ; DNA-Binding Proteins/genetics/metabolism ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics/metabolism ; Herpesvirus 1, Human/metabolism/*physiology ; Humans ; Immediate-Early Proteins/genetics/metabolism ; Proteolysis ; RNA, Untranslated/genetics/metabolism ; Repetitive Sequences, Nucleic Acid ; Serine Proteases/genetics/metabolism ; Shelterin Complex/metabolism ; Telomere/chemistry/genetics/*virology ; Telomere-Binding Proteins/metabolism ; Ubiquitin-Protein Ligases/genetics/metabolism ; Viral Proteins/genetics/metabolism ; *Virus Replication ; },
abstract = {Telomeres protect the ends of cellular chromosomes. We show here that infection with herpes simplex virus 1 (HSV-1) results in chromosomal structural aberrations at telomeres and the accumulation of telomere dysfunction-induced DNA damage foci (TIFs). At the molecular level, HSV-1 induces transcription of telomere repeat-containing RNA (TERRA), followed by the proteolytic degradation of the telomere protein TPP1 and loss of the telomere repeat DNA signal. The HSV-1-encoded E3 ubiquitin ligase ICP0 is required for TERRA transcription and facilitates TPP1 degradation. Small hairpin RNA (shRNA) depletion of TPP1 increases viral replication, indicating that TPP1 inhibits viral replication. Viral replication protein ICP8 forms foci that coincide with telomeric proteins, and ICP8-null virus failed to degrade telomere DNA signal. These findings suggest that HSV-1 reorganizes telomeres to form ICP8-associated prereplication foci and to promote viral genomic replication.},
}
@article {pmid25492305,
year = {2015},
author = {Mursalimov, S and Sidorchuk, Y and Baiborodin, S and Deineko, E},
title = {Distribution of telomeres in the tobacco meiotic nuclei during cytomixis.},
journal = {Cell biology international},
volume = {39},
number = {4},
pages = {491-495},
doi = {10.1002/cbin.10406},
pmid = {25492305},
issn = {1095-8355},
mesh = {Cell Nucleus/metabolism ; Chromatin/metabolism ; In Situ Hybridization, Fluorescence ; *Meiosis ; Telomere/*metabolism ; Nicotiana/*metabolism ; },
abstract = {Cytomixis is the migration of nuclei from one cell to another in higher plants, most frequently observable during microsporogenesis, which has a potential evolutionary significance. Currently, a major challenge is to label the chromatin migrating between cells to clarify its further fate. We have for the first time succeeded in visualizing the telomeric chromatin regions in the nuclei migrating between cells using fluorescent in situ hybridization. It has been shown that the telomeric signals in tobacco microsporocytes are randomly distributed in migrating nuclei without any deviations from their normal meiotic dynamics. According to our data, the chromatin migrating during cytomixis always contains telomeres and the telomeric signals are retained in the micronuclei formed after cytomixis.},
}
@article {pmid25491286,
year = {2015},
author = {Sánchez-Guillén, RA and Capilla, L and Reig-Viader, R and Martínez-Plana, M and Pardo-Camacho, C and Andrés-Nieto, M and Ventura, J and Ruiz-Herrera, A},
title = {On the origin of Robertsonian fusions in nature: evidence of telomere shortening in wild house mice.},
journal = {Journal of evolutionary biology},
volume = {28},
number = {1},
pages = {241-249},
doi = {10.1111/jeb.12568},
pmid = {25491286},
issn = {1420-9101},
mesh = {Animals ; Biological Evolution ; Chromosomes ; Diploidy ; In Situ Hybridization, Fluorescence ; Male ; Mice/*genetics ; Mice, Inbred C57BL ; *Telomere Shortening ; },
abstract = {The role of telomere shortening to explain the occurrence of Robertsonian (Rb) fusions, as well as the importance of the average telomere length vs. the proportion of short telomeres, especially in nature populations, is largely unexplored. In this study, we have analysed telomere shortening in nine wild house mice from the Barcelona Rb system with diploid numbers ranging from 29 to 40 chromosomes. We also included two standard (2n=40) laboratory mice for comparison. Our data showed that the average telomere length (considering all chromosomal arms) is influenced by both the diploid number and the origin of the mice (wild vs. laboratory). In detail, we detected that wild mice from the Rb Barcelona system (fused and standard) present shorter telomeres than standard laboratory mice. However, only wild mice with Rb fusions showed a high proportion of short telomeres (only in p-arms), thus revealing the importance of telomere shortening in the origin of the Rb fusions in the Barcelona system. Overall, our study confirms that the number of critically short telomeres, and not a simple reduction in the average telomere length, is more likely to lead to the origin of Rb fusions in the Barcelona system and ultimately in nature.},
}
@article {pmid25488978,
year = {2015},
author = {Fulcher, N and Teubenbacher, A and Kerdaffrec, E and Farlow, A and Nordborg, M and Riha, K},
title = {Genetic architecture of natural variation of telomere length in Arabidopsis thaliana.},
journal = {Genetics},
volume = {199},
number = {2},
pages = {625-635},
pmid = {25488978},
issn = {1943-2631},
support = {268962/ERC_/European Research Council/International ; },
mesh = {Arabidopsis/*genetics ; Chromosome Mapping ; Evolution, Molecular ; *Genetic Variation ; Genetics, Population ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; *Selection, Genetic ; *Telomere ; },
abstract = {Telomeres represent the repetitive sequences that cap chromosome ends and are essential for their protection. Telomere length is known to be highly heritable and is derived from a homeostatic balance between telomeric lengthening and shortening activities. Specific loci that form the genetic framework underlying telomere length homeostasis, however, are not well understood. To investigate the extent of natural variation of telomere length in Arabidopsis thaliana, we examined 229 worldwide accessions by terminal restriction fragment analysis. The results showed a wide range of telomere lengths that are specific to individual accessions. To identify loci that are responsible for this variation, we adopted a quantitative trait loci (QTL) mapping approach with multiple recombinant inbred line (RIL) populations. A doubled haploid RIL population was first produced using centromere-mediated genome elimination between accessions with long (Pro-0) and intermediate (Col-0) telomere lengths. Composite interval mapping analysis of this population along with two established RIL populations (Ler-2/Cvi-0 and Est-1/Col-0) revealed a number of shared and unique QTL. QTL detected in the Ler-2/Cvi-0 population were examined using near isogenic lines that confirmed causative regions on chromosomes 1 and 2. In conclusion, this work describes the extent of natural variation of telomere length in A. thaliana, identifies a network of QTL that influence telomere length homeostasis, examines telomere length dynamics in plants with hybrid backgrounds, and shows the effects of two identified regions on telomere length regulation.},
}
@article {pmid25486025,
year = {2015},
author = {Pascua, I and Fernández-Marcelo, T and Sánchez-Pernaute, A and de Juan, C and Head, J and Torres-García, AJ and Iniesta, P},
title = {Prognostic value of telomere function in gastric cancers with and without microsatellite instability.},
journal = {European journal of gastroenterology &amp; hepatology},
volume = {27},
number = {2},
pages = {162-169},
doi = {10.1097/MEG.0000000000000250},
pmid = {25486025},
issn = {1473-5687},
mesh = {Adenocarcinoma/diagnosis/*genetics/pathology/secondary ; Aged ; Biomarkers, Tumor/metabolism ; Female ; Humans ; Kaplan-Meier Estimate ; Lymphatic Metastasis ; Male ; *Microsatellite Instability ; Neoplasm Staging ; Prognosis ; Stomach Neoplasms/diagnosis/*genetics/pathology ; Telomere/*physiology ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {OBJECTIVE: To identify molecular markers that may be useful in the selection of gastric cancer patients with different prognoses, we investigated telomere function in gastric cancers with and without microsatellite instability (MSI).<br><br>MATERIALS AND METHODS: We analyzed 83 gastric cancers and its paired-normal tissues to investigate MSI and telomere function. MSI was established using five polymorphic human repeat DNA markers. Telomere function was evaluated by determining telomerase activity, telomere length, and telomere-repeat factors 1 and 2 (TRF1 and TRF2) expression.<br><br>RESULTS: Patients with high microsatellite instability (MSI-H) gastric cancers showed a significantly better prognosis than those affected by microsatellite stable or low microsatellite instability (MSS/MSI-L) tumors (P = 0.03). The lowest expression levels of TRF1 and TRF2 were associated with MSI-H gastric cancers (P = 0.008 and 0.006, respectively). Moreover, a clear trend toward a worse prognosis was found in the group of patients who had tumors with the shortest telomeres (P = 0.01). Cox multivariate analysis showed that MSI emerged as a protective prognostic factor; MSS/MSI-L tumors conferred a significantly poor prognosis in patients (relative risk = 4.862-fold greater than the MSI-H group) (P = 0.033). Telomere length of gastric tumors less than 2.86 kbp was a factor that led to a poor prognosis (relative risk = 4.420, with respect to tumors showing telomere length &#x2265; 2.86 kbp) (P = 0.002).<br><br>CONCLUSION: We propose telomere status as a potential molecular marker with usefulness in the establishment of the prognosis of gastric cancers both for the mutator phenotype and for the suppressor pathway.},
}
@article {pmid25485673,
year = {2014},
author = {Beach, SR and Lei, MK and Brody, GH and Yu, T and Philibert, RA},
title = {Nonsupportive parenting affects telomere length in young adulthood among African Americans: mediation through substance use.},
journal = {Journal of family psychology : JFP : journal of the Division of Family Psychology of the American Psychological Association (Division 43)},
volume = {28},
number = {6},
pages = {967-972},
pmid = {25485673},
issn = {1939-1293},
support = {P30 DA027827/DA/NIDA NIH HHS/United States ; R01 HD030588/HD/NICHD NIH HHS/United States ; P30DA027827/DA/NIDA NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Black or African American/*genetics/*psychology ; Alcoholism/complications/genetics/psychology ; Female ; Humans ; Male ; Parenting/*psychology ; Smoking/adverse effects/psychology ; *Social Support ; Substance-Related Disorders/*complications/genetics/*psychology ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {Telomere length (TL) is an indicator of age-related changes at the cellular level associated with heightened mortality risk. The effect of nonsupportive parenting (NSP) during late adolescence and young adulthood on TL 5 years later was examined in a sample of N = 183 young adult African Americans to determine if effects of NSP on TL were mediated by substance use. Results indicated that the effect of caregiver reported NSP on diminished TL was mediated by escalation of drinking and smoking in young adulthood, even after controlling effects of socioeconomic status risk, gender, BMI, young adult stress, and intervention status. Results suggest that prevention of NSP may influence later physical health consequences by influencing substance use trajectory.},
}
@article {pmid25484304,
year = {2015},
author = {Fairlie, J and Harrington, L},
title = {Enforced telomere elongation increases the sensitivity of human tumour cells to ionizing radiation.},
journal = {DNA repair},
volume = {25},
number = {},
pages = {54-59},
pmid = {25484304},
issn = {1568-7856},
support = {84637//Wellcome Trust/United Kingdom ; },
mesh = {Cell Survival/genetics/radiation effects ; DNA Damage ; Gamma Rays ; Humans ; Neoplasms/*genetics ; Telomere/*metabolism ; Telomere Homeostasis ; Tumor Cells, Cultured ; },
abstract = {More than 85% of all human cancers possess the ability to maintain chromosome ends, or telomeres, by virtue of telomerase activity. Loss of functional telomeres is incompatible with survival, and telomerase inhibition has been established in several model systems to be a tractable target for cancer therapy. As human tumour cells typically maintain short equilibrium telomere lengths, we wondered if enforced telomere elongation would positively or negatively impact cell survival. We found that telomere elongation beyond a certain length significantly decreased cell clonogenic survival after gamma irradiation. Susceptibility to irradiation was dosage-dependent and increased at telomere lengths exceeding 17kbp despite the fact that all chromosome ends retained telomeric DNA. These data suggest that an optimal telomere length may promote human cancer cell survival in the presence of genotoxic stress.},
}
@article {pmid25483196,
year = {2014},
author = {Saint-Léger, A and Koelblen, M and Civitelli, L and Bah, A and Djerbi, N and Giraud-Panis, MJ and Londoño-Vallejo, A and Ascenzioni, F and Gilson, E},
title = {The basic N-terminal domain of TRF2 limits recombination endonuclease action at human telomeres.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {13},
number = {15},
pages = {2469-2474},
pmid = {25483196},
issn = {1551-4005},
mesh = {DNA-Binding Proteins/metabolism ; Endonucleases/metabolism ; HEK293 Cells ; Holliday Junction Resolvases/metabolism ; Humans ; Plasmids ; Recombinases/metabolism ; *Recombination, Genetic ; Telomere/*metabolism ; Telomere Homeostasis ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; Transfection ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {The stability of mammalian telomeres depends upon TRF2, which prevents inappropriate repair and checkpoint activation. By using a plasmid integration assay in yeasts carrying humanized telomeres, we demonstrated that TRF2 possesses the intrinsic property to both stimulate initial homologous recombination events and to prevent their resolution via its basic N-terminal domain. In human cells, we further showed that this TRF2 domain prevents telomere shortening mediated by the resolvase-associated protein SLX4 as well as GEN1 and MUS81, 2 different types of endonucleases with resolvase activities. We propose that various types of resolvase activities are kept in check by the basic N-terminal domain of TRF2 in order to favor an accurate repair of the stalled forks that occur during telomere replication.},
}
@article {pmid25477378,
year = {2015},
author = {Chen, Y and Deng, Z and Jiang, S and Hu, Q and Liu, H and Songyang, Z and Ma, W and Chen, S and Zhao, Y},
title = {Human cells lacking coilin and Cajal bodies are proficient in telomerase assembly, trafficking and telomere maintenance.},
journal = {Nucleic acids research},
volume = {43},
number = {1},
pages = {385-395},
pmid = {25477378},
issn = {1362-4962},
mesh = {Coiled Bodies/*physiology ; Humans ; Molecular Chaperones ; Mutagenesis ; Nuclear Proteins/genetics/*physiology ; S Phase/genetics ; Shelterin Complex ; Telomerase/*metabolism ; Telomere/enzymology ; *Telomere Homeostasis ; Telomere-Binding Proteins/metabolism ; },
abstract = {The RNA component of human telomerase (hTR) localizes to Cajal bodies, and it has been proposed that Cajal bodies play a role in the assembly of telomerase holoenzyme and telomerase trafficking. Here, the role of Cajal bodies was examined in Human cells deficient of coilin (i.e. coilin-knockout (KO) cells), in which no Cajal bodies are detected. In coilin-KO cells, a normal level of telomerase activity is detected and interactions between core factors of holoenzyme are preserved, indicating that telomerase assembly occurs in the absence of Cajal bodies. Moreover, dispersed hTR aggregates and forms foci specifically during S and G2 phase in coilin-KO cells. Colocalization of these hTR foci with telomeres implies proper telomerase trafficking, independent of Cajal bodies. Therefore, telomerase adds similar numbers of TTAGGG repeats to telomeres in coilin-KO and controls cells. Overexpression of TPP1-OB-fold blocks cell cycle-dependent formation of hTR foci and inhibits telomere extension. These findings suggest that telomerase assembly, trafficking and extension occur with normal efficiency in Cajal bodies deficient human cells. Thus, Cajal bodies, as such, are not essential in these processes, although it remains possible that non-coilin components of Cajal bodies and/or telomere binding proteins (e.g. TPP1) do play roles in telomerase biogenesis and telomere homeostasis.},
}
@article {pmid25475541,
year = {2014},
author = {Denham, J and Marques, FZ and Charchar, FJ},
title = {Leukocyte telomere length variation due to DNA extraction method.},
journal = {BMC research notes},
volume = {7},
number = {},
pages = {877},
pmid = {25475541},
issn = {1756-0500},
mesh = {Adolescent ; Adult ; DNA/chemistry/*isolation &amp; purification/ultrastructure ; Humans ; Leukocytes/*ultrastructure ; Male ; *Telomere ; Young Adult ; },
abstract = {BACKGROUND: Telomere length is indicative of biological age. Shorter telomeres have been associated with several disease and health states. There are inconsistencies throughout the literature amongst relative telomere length measured by quantitative PCR (qPCR) and different extraction methods or kits used. We quantified whole-blood leukocyte telomere length using the telomere to single copy gene (T/S) ratio by qPCR in 20 young (18-25 yrs) men after extracting DNA using three common extraction methods: Lahiri and Nurnberger (high salt) method, PureLink Genomic DNA Mini kit (Life Technologies) and QiaAmp DNA Mini kit (Qiagen). Telomere length differences of DNA extracted from the three extraction methods was assessed by one-way analysis of variance (ANOVA).<br><br>RESULTS: DNA purity differed between extraction methods used (P=0.01). Telomere length was impacted by the DNA extraction method used (P=0.01). Telomeres extracted using the Lahiri and Nurnberger method (mean T/S ratio: 2.43, range: 1.57-3.02) and PureLink Genomic DNA Mini Kit (mean T/S ratio: 2.57, range: 2.24-2.80) did not differ (P=0.13). Likewise, QiaAmp and Purelink-extracted telomeres were not statistically different (P=0.14). The Lahiri-extracted telomeres, however, were significantly shorter than those extracted using the QiaAmp DNA Mini Kit (mean T/S ratio: 2.71, range: 2.32-3.02; P=0.003). DNA purity was associated with telomere length.<br><br>CONCLUSION: There are discrepancies between the length of leukocyte telomeres extracted from the same individuals according to the DNA extraction method used. DNA purity could be responsible for the discrepancy in telomere length but this will require validation studies. We recommend using the same DNA extraction kit when quantifying leukocyte telomere length by qPCR or when comparing different cohorts to avoid erroneous associations between telomere length and traits of interest.},
}
@article {pmid25473012,
year = {2015},
author = {Bateson, M and Brilot, BO and Gillespie, R and Monaghan, P and Nettle, D},
title = {Developmental telomere attrition predicts impulsive decision-making in adult starlings.},
journal = {Proceedings. Biological sciences},
volume = {282},
number = {1799},
pages = {20142140},
pmid = {25473012},
issn = {1471-2954},
support = {BB/J015091/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/J016446/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Biomarkers ; Decision Making ; Starlings/*genetics/growth &amp; development/physiology ; *Stress, Physiological ; *Telomere Homeostasis ; },
abstract = {Animals in a poor biological state face reduced life expectancy, and as a consequence should make decisions that prioritize immediate survival and reproduction over long-term benefits. We tested the prediction that if, as has been suggested, developmental telomere attrition is a biomarker of state and future life expectancy, then individuals who have undergone greater developmental telomere attrition should display greater choice impulsivity as adults. We measured impulsive decision-making in a cohort of European starlings (Sturnus vulgaris) in which we had previously manipulated developmental telomere attrition by cross-fostering sibling chicks into broods of different sizes. We show that as predicted by state-dependent optimality models, individuals who had sustained greater developmental telomere attrition and who had shorter current telomeres made more impulsive foraging decisions as adults, valuing smaller, sooner food rewards more highly than birds with less attrition and longer telomeres. Our findings shed light on the biological embedding of early adversity and support a functional explanation for its consequences that could be applicable to other species, including humans.},
}
@article {pmid25472675,
year = {2014},
author = {Kibriya, MG and Jasmine, F and Roy, S and Ahsan, H and Pierce, B},
title = {Measurement of telomere length: a new assay using QuantiGene chemistry on a Luminex platform.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {23},
number = {12},
pages = {2667-2672},
pmid = {25472675},
issn = {1538-7755},
support = {UL1 TR000430/TR/NCATS NIH HHS/United States ; R01ES020506/ES/NIEHS NIH HHS/United States ; R01 ES020506/ES/NIEHS NIH HHS/United States ; R01 CA107431/CA/NCI NIH HHS/United States ; R01CA107431/CA/NCI NIH HHS/United States ; },
mesh = {Biological Assay ; Blotting, Southern/*methods ; DNA/*genetics ; Humans ; Telomere/*chemistry ; Telomere Shortening/*physiology ; },
abstract = {BACKGROUND: Telomeres are tandem repeats of sequences present at the end of the chromosomes that maintain chromosomal integrity. After repeated cell division, telomeres shorten to a critical level, triggering replicative senescence or apoptosis, which is a key determinant of cellular aging. Short telomeres also contribute to genome instability and are a hallmark of many cancers. There are several methods for estimating telomere length (TL) from extracted DNA samples. Southern blot is accurate but requires a large quantity of DNA and is expensive. qPCR is cost-effective and requires a small quantity of DNA and is therefore widely used for large-scale epidemiologic studies; however, it typically requires triplicates. We describe a novel multiplexed probe-based non-PCR method for TL measurement.<br><br>METHODS: A small amount of DNA (&#x223c;50 ng) is hybridized to telomere repeat sequence-specific probes (T) and a reference single gene probes (R). T and R signals are detected from a single reaction well containing the same input DNA. Branching DNA technology is used to amplify the signal, which is detected by Luminex technology.<br><br>RESULTS: The intra- and interassay CV (&#x223c;3% and &#x223c;5%, respectively) shows the precision of the new assay and the measurements from single well correlated well with traditional single-plex qPCR run in triplicate (r = 0.7 to 0.8). The assay was also validated in an independent set of samples using Southern blot (r = 0.74).<br><br>CONCLUSION: We describe a novel assay for TL assessment using the Luminex platform.<br><br>IMPACT: This may offer an alternative cost-efficient way to study TL in extracted DNA samples. See all the articles in this CEBP Focus section, "Biomarkers, Biospecimens, and New Technologies in Molecular Epidemiology."},
}
@article {pmid25471051,
year = {2015},
author = {Borodovsky, A and Meeker, AK and Kirkness, EF and Zhao, Q and Eberhart, CG and Gallia, GL and Riggins, GJ},
title = {A model of a patient-derived IDH1 mutant anaplastic astrocytoma with alternative lengthening of telomeres.},
journal = {Journal of neuro-oncology},
volume = {121},
number = {3},
pages = {479-487},
pmid = {25471051},
issn = {1573-7373},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; R01 CA190223/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Animals ; Astrocytoma/*genetics/*pathology ; DNA Helicases/genetics ; Disease Models, Animal ; Genes, p16 ; Heterografts ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Isocitrate Dehydrogenase/*genetics ; Male ; Mice ; *Mutation ; Neoplasm Transplantation/methods ; Nuclear Proteins/genetics ; Phenotype ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*pathology ; Tumor Suppressor Protein p53/genetics ; X-linked Nuclear Protein ; },
abstract = {Mutations in isocitrate dehydrogenase 1 (IDH1) have been found in the vast majority of low grade and progressive infiltrating gliomas and are characterized by the production of 2-hydroxyglutarate from α-ketoglutarate. Recent investigations of malignant gliomas have identified additional genetic and chromosomal abnormalities which cluster with IDH1 mutations into two distinct subgroups. The astrocytic subgroup was found to have frequent mutations in ATRX, TP53 and displays alternative lengthening of telomeres. The second subgroup with oligodendrocytic morphology has frequent mutations in CIC or FUBP1, and is linked to co-deletion of the 1p/19q arms. These mutations reflect the development of two distinct molecular pathways representing the majority of IDH1 mutant gliomas. Unfortunately, due to the scarcity of endogenously derived IDH1 mutant models, there is a lack of accurate models to study mechanism and develop new therapy. Here we report the generation of an endogenous IDH1 anaplastic astrocytoma in vivo model with concurrent mutations in TP53, CDKN2A and ATRX. The model has a similar phenotype and histopathology as the original patient tumor, expresses the IDH1 (R132H) mutant protein and exhibits an alternative lengthening of telomeres phenotype. The JHH-273 model is characteristic of anaplastic astrocytoma and represents a valuable tool for investigating the pathogenesis of this distinct molecular subset of gliomas and for preclinical testing of compounds targeting IDH1 mutations or alternative lengthening of telomeres.},
}
@article {pmid25469684,
year = {2015},
author = {von Känel, R and Malan, NT and Hamer, M and Malan, L},
title = {Comparison of telomere length in black and white teachers from South Africa: the sympathetic activity and ambulatory blood pressure in Africans study.},
journal = {Psychosomatic medicine},
volume = {77},
number = {1},
pages = {26-32},
doi = {10.1097/PSY.0000000000000123},
pmid = {25469684},
issn = {1534-7796},
support = {//Medical Research Council/United Kingdom ; },
mesh = {Adult ; Aged ; Alcoholism ; *Black People ; C-Reactive Protein ; Depression ; Dyslipidemias ; *Faculty ; Female ; Glycated Hemoglobin ; HIV Infections ; Humans ; Hyperglycemia ; Hypertension ; Leukocytes/*metabolism ; Male ; Middle Aged ; Motor Activity ; Obesity ; Smoking ; South Africa ; Stress, Psychological ; Telomere/*metabolism ; Telomere Homeostasis ; *White People ; Young Adult ; },
abstract = {OBJECTIVE: Telomere length is a marker of biological aging that has been linked to cardiovascular disease risk. The black South African population is witnessing a tremendous increase in the prevalence of cardiovascular disease, part of which might be explained through urbanization. We compared telomere length between black South Africans and white South Africans and examined which biological and psychosocial variables played a role in ethnic difference in telomere length.<br><br>METHODS: We measured leukocyte telomere length in 161 black South African teachers and 180 white South African teachers aged 23 to 66 years without a history of atherothrombotic vascular disease. Age, sex, years having lived in the area, human immunodeficiency virus (HIV) infection, hypertension, body mass index, dyslipidemia, hemoglobin A1c, C-reactive protein, smoking, physical activity, alcohol abuse, depressive symptoms, psychological distress, and work stress were considered as covariates.<br><br>RESULTS: Black participants had shorter (median, interquartile range) relative telomere length (0.79, 0.70-0.95) than did white participants (1.06, 0.87-1.21; p < .001), and this difference changed very little after adjusting for covariates. In fully adjusted models, age (p < .001), male sex (p = .011), and HIV positive status (p = .023) were associated with shorter telomere length. Ethnicity did not significantly interact with any covariates in determining telomere length, including psychosocial characteristics.<br><br>CONCLUSIONS: Black South Africans showed markedly shorter telomeres than did white South African counterparts. Age, male sex, and HIV status were associated with shorter telomere length. No interactions between ethnicity and biomedical or psychosocial factors were found. Ethnic difference in telomere length might primarily be explained by genetic factors.},
}
@article {pmid25469445,
year = {2015},
author = {Gilchrist, GC and Kurjanowicz, P and Mereilles, FV and King, WA and LaMarre, J},
title = {Telomere length and telomerase activity in bovine pre-implantation embryos in vitro.},
journal = {Reproduction in domestic animals = Zuchthygiene},
volume = {50},
number = {1},
pages = {58-67},
doi = {10.1111/rda.12449},
pmid = {25469445},
issn = {1439-0531},
mesh = {Animals ; Blastocyst/enzymology/*ultrastructure ; Cattle/*embryology ; Female ; Fertilization in Vitro/veterinary ; Male ; Morula/enzymology/ultrastructure ; Oocytes/enzymology/*ultrastructure ; RNA/analysis/genetics ; RNA, Messenger/analysis ; Telomerase/analysis/genetics/*metabolism ; Telomere/genetics/*ultrastructure ; },
abstract = {Telomeres are specialized structures that cap the ends of chromosomes and help to maintain genomic integrity and stability. Telomeres undergo dynamic changes during embryo development, which also represents an important stage for telomere elongation through telomerase enzyme activity. The objectives of this study were to examine changes in telomere length and telomerase activity from the early oocyte, through to the blastocysts stage of development, and the expression of factors with the potential to directly regulate telomeres. In vitro-produced bovine embryos were lysed and analysed for either relative telomere length, or telomerase activity using quantitative real-time PCR protocols. Our results reveal that relative telomere length is the shortest in the presumptive zygote stage of development and gradually increases to the blastocyst stage. We also demonstrate that differences between the mean telomere lengths throughout these stages are statistically significant (p < 0.05). Telomerase activity in the stages examined appears relatively constant until the blastocyst, where the highest level of activity is detected, leading to a significant difference in telomerase activity across embryonic stages (p < 0.005). Bovine telomerase RNA component (bTERC) expression levels were highest in the blastocyst, TERF1 transcripts showed little change in expression, and TERF2 expression decreased in the blastocysts (p < 0.05). Our results suggest that a complex integration of telomere-related RNA and proteins influences the regulatory mechanisms involved in 'reprogramming' of telomeres during early embryonic stages.},
}
@article {pmid25467755,
year = {2014},
author = {Nilsson, PM},
title = {Mediterranean diet and telomere length.},
journal = {BMJ (Clinical research ed.)},
volume = {349},
number = {},
pages = {g6843},
doi = {10.1136/bmj.g6843},
pmid = {25467755},
issn = {1756-1833},
mesh = {Aging/*physiology ; *Diet, Mediterranean ; Female ; Humans ; Telomere/*ultrastructure ; },
}
@article {pmid25467041,
year = {2015},
author = {Pedroso, DC and Miranda-Furtado, CL and Kogure, GS and Meola, J and Okuka, M and Silva, C and Calado, RT and Ferriani, RA and Keefe, DL and dos Reis, RM},
title = {Inflammatory biomarkers and telomere length in women with polycystic ovary syndrome.},
journal = {Fertility and sterility},
volume = {103},
number = {2},
pages = {542-7.e2},
doi = {10.1016/j.fertnstert.2014.10.035},
pmid = {25467041},
issn = {1556-5653},
mesh = {Adolescent ; Adult ; Biomarkers/blood ; Case-Control Studies ; Female ; Humans ; Inflammation Mediators/*blood ; Middle Aged ; Polycystic Ovary Syndrome/*blood/*diagnosis ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; Young Adult ; },
abstract = {OBJECTIVE: To analyze whether leukocyte telomere length (LTL) is impaired in women with polycystic ovary syndrome (PCOS).<br><br>DESIGN: Case-control study.<br><br>SETTING: Hospital.<br><br>PATIENT(S): A total of 274 women, including 150 patients with PCOS and 124 controls.<br><br>INTERVENTION(S): None.<br><br>MAIN OUTCOME MEASURE(S): Body mass index (BMI), waist circumference, systemic arterial pressure, lipid profile, E(2), LH, T, androstenedione, PRL, TSH, sex hormone-binding globulin, C-reactive protein (CRP), homocysteine, free androgen index, and the homeostatic model of insulin sensitivity (HOMA-IR) index were analyzed. The LTL evaluation was measured by quantitative polymerase chain reaction.<br><br>RESULT(S): The PCOS group had higher values for weight, BMI, waist circumference, systolic arterial pressure, triglycerides, LH, T, insulin, CRP, free androgen index, and HOMA-IR compared with the control group. Sex hormone-binding globulin and E(2) levels were lower in the PCOS group than in the control group. The LTL did not differ between groups. Age, BMI, and HOMA-IR had no significant effect on LTL. The inflammatory biomarkers CRP and homocysteine were negatively correlated with LTL in patients with PCOS.<br><br>CONCLUSION(S): Our results showed no differences in LTL between patients with PCOS and controls, but CRP and homocysteine biomarkers negatively correlated with LTL in the PCOS group.},
}
@article {pmid25467028,
year = {2014},
author = {Crous-Bou, M and Fung, TT and Prescott, J and Julin, B and Du, M and Sun, Q and Rexrode, KM and Hu, FB and De Vivo, I},
title = {Mediterranean diet and telomere length in Nurses' Health Study: population based cohort study.},
journal = {BMJ (Clinical research ed.)},
volume = {349},
number = {},
pages = {g6674},
pmid = {25467028},
issn = {1756-1833},
support = {HL34594/HL/NHLBI NIH HHS/United States ; CA139586/CA/NCI NIH HHS/United States ; CA065725/CA/NCI NIH HHS/United States ; 1R01 CA134958/CA/NCI NIH HHS/United States ; R00HL098459/HL/NHLBI NIH HHS/United States ; R01 CA163451/CA/NCI NIH HHS/United States ; R25 CA94880/CA/NCI NIH HHS/United States ; CA163451/CA/NCI NIH HHS/United States ; HL60712/HL/NHLBI NIH HHS/United States ; R25 CA094880/CA/NCI NIH HHS/United States ; HL088521/HL/NHLBI NIH HHS/United States ; R01 CA49449/CA/NCI NIH HHS/United States ; 2R01 CA082838/CA/NCI NIH HHS/United States ; CA133914/CA/NCI NIH HHS/United States ; R01 AR059073/AR/NIAMS NIH HHS/United States ; CA132175/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; CA132190/CA/NCI NIH HHS/United States ; CA140790/CA/NCI NIH HHS/United States ; U54 CA155626/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging/genetics/*physiology ; Biomarkers ; Case-Control Studies ; Cross-Sectional Studies ; Diet Records ; *Diet, Mediterranean ; Female ; Humans ; Leukocyte Count ; Leukocytes/physiology ; Middle Aged ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; Telomere/*ultrastructure ; United States ; },
abstract = {OBJECTIVE: To examine whether adherence to the Mediterranean diet was associated with longer telomere length, a biomarker of aging.<br><br>DESIGN: Population based cohort study.<br><br>SETTING: Nurses' Health Study, an ongoing prospective cohort study of 121,700 nurses enrolled in 1976; in 1989-90 a subset of 32,825 women provided blood samples.<br><br>PARTICIPANTS: 4676 disease-free women from nested case-control studies within the Nurses' Health Study with telomere length measured who also completed food frequency questionnaires.<br><br>MAIN OUTCOME MEASURE: Association between relative telomere lengths in peripheral blood leukocytes measured by quantitative real time polymerase chain reaction and Alternate Mediterranean Diet score calculated from self reported dietary data.<br><br>RESULTS: Greater adherence to the Mediterranean diet was associated with longer telomeres after adjustment for potential confounders. Least squares mean telomere length z scores were -0.038 (SE 0.035) for the lowest Mediterranean diet score groups and 0.072 (0.030) for the highest group (P for trend = 0.004).<br><br>CONCLUSION: In this large study, greater adherence to the Mediterranean diet was associated with longer telomeres. These results further support the benefits of adherence to the Mediterranean diet for promoting health and longevity.},
}
@article {pmid25464850,
year = {2014},
author = {Sung, LY and Chang, WF and Zhang, Q and Liu, CC and Liou, JY and Chang, CC and Ou-Yang, H and Guo, R and Fu, H and Cheng, WTK and Ding, ST and Chen, CM and Okuka, M and Keefe, DL and Chen, YE and Liu, L and Xu, J},
title = {Telomere elongation and naive pluripotent stem cells achieved from telomerase haplo-insufficient cells by somatic cell nuclear transfer.},
journal = {Cell reports},
volume = {9},
number = {5},
pages = {1603-1609},
pmid = {25464850},
issn = {2211-1247},
support = {R03 HD053066/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Cell Differentiation ; Cells, Cultured ; Female ; Haploinsufficiency ; Induced Pluripotent Stem Cells/*enzymology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Nuclear Transfer Techniques ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis ; },
abstract = {Haplo-insufficiency of telomerase genes in humans leads to telomere syndromes such as dyskeratosis congenital and idiopathic pulmonary fibrosis. Generation of pluripotent stem cells from telomerase haplo-insufficient donor cells would provide unique opportunities toward the realization of patient-specific stem cell therapies. Recently, pluripotent human embryonic stem cells (ntESCs) have been efficiently achieved by somatic cell nuclear transfer (SCNT). We tested the hypothesis that SCNT could effectively elongate shortening telomeres of telomerase haplo-insufficient cells in the ntESCs with relevant mouse models. Indeed, telomeres of telomerase haplo-insufficient (Terc(+/-)) mouse cells are elongated in ntESCs. Moreover, ntESCs derived from Terc(+/-) cells exhibit naive pluripotency as evidenced by generation of Terc(+/-) ntESC clone pups by tetraploid embryo complementation, the most stringent test of naive pluripotency. These data suggest that SCNT could offer a powerful tool to reprogram telomeres and to discover the factors for robust restoration of telomeres and pluripotency of telomerase haplo-insufficient somatic cells.},
}
@article {pmid25464224,
year = {2015},
author = {Perseguini, NM and Verlengia, R and Milan, JC and Minatel, V and Rehder-Santos, P and Takahashi, AC and Santana-Lemos, BA and Calado, RT and Ferreira Filho, P and Porta, A and Catai, AM},
title = {Cardiac autonomic modulation, C-reactive protein or telomere length: which of these variables has greater importance to aging?.},
journal = {International journal of cardiology},
volume = {178},
number = {},
pages = {79-81},
doi = {10.1016/j.ijcard.2014.10.123},
pmid = {25464224},
issn = {1874-1754},
mesh = {Adult ; Aged ; Aging/*blood/*physiology ; Biomarkers/blood ; C-Reactive Protein/*metabolism ; Female ; Heart Rate/*physiology ; Humans ; Male ; Middle Aged ; Telomere/physiology ; Telomere Homeostasis/*physiology ; Young Adult ; },
}
@article {pmid25460668,
year = {2015},
author = {Gao, J and Roy, S and Tong, L and Argos, M and Jasmine, F and Rahaman, R and Rakibuz-Zaman, M and Parvez, F and Ahmed, A and Hore, SK and Sarwar, G and Slavkovich, V and Yunus, M and Rahman, M and Baron, JA and Graziano, JH and Ahsan, H and Pierce, BL},
title = {Arsenic exposure, telomere length, and expression of telomere-related genes among Bangladeshi individuals.},
journal = {Environmental research},
volume = {136},
number = {},
pages = {462-469},
pmid = {25460668},
issn = {1096-0953},
support = {UL1 TR000430/TR/NCATS NIH HHS/United States ; R01ES020506/ES/NIEHS NIH HHS/United States ; P42 ES010349/ES/NIEHS NIH HHS/United States ; R01 ES020506/ES/NIEHS NIH HHS/United States ; R01 CA107431/CA/NCI NIH HHS/United States ; R01CA107431/CA/NCI NIH HHS/United States ; P42ES010349/ES/NIEHS NIH HHS/United States ; R01 CA102484/CA/NCI NIH HHS/United States ; R01CA1024/CA/NCI NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; Arsenic/*toxicity ; Bangladesh ; *Environmental Exposure ; Female ; Humans ; Male ; Middle Aged ; *Telomere ; },
abstract = {BACKGROUND: Inorganic arsenic is a carcinogen whose mode of action may involve telomere dysfunction. Recent epidemiological studies suggest that chronic arsenic exposure is associated with longer telomeres and altered expression of telomere-related genes in peripheral blood. In this study, we evaluated the association of urinary arsenic concentration with expression of telomere-related genes and telomere length in Bangladeshi individuals with a wide range of arsenic exposure through naturally contaminated drinking water.<br><br>METHODS: We used linear regression models to estimate associations between urinary arsenic and array-based expression measures for 69 telomere related genes using mononuclear cell RNA samples from 1799 individuals. Association between arsenic exposure and a qPCR-based telomere length measure was assessed among 167 individuals.<br><br>RESULTS: Urinary arsenic was positively associated with expression of WRN, and negatively associated with TERF2, DKC1, TERF2IP and OBFC1 (all P<0.00035, Bonferroni-corrected threshold). We detected interaction between urinary arsenic and arsenic metabolism efficiency in relation to expression of WRN (P for interaction =0.00008). In addition, we observed that very high arsenic exposure was associated with longer telomeres compared to very low exposure (P=0.02).<br><br>DISCUSSION: Our findings suggest that arsenic's carcinogenic mode of action may involve alteration of telomere maintenance and/or telomere damage. This study extends our knowledge regarding the effect of arsenic on telomere length and expression of telomere-related genes.},
}
@article {pmid25457634,
year = {2014},
author = {Llorca-Cardeñosa, MJ and Peña-Chilet, M and Mayor, M and Gomez-Fernandez, C and Casado, B and Martin-Gonzalez, M and Carretero, G and Lluch, A and Martinez-Cadenas, C and Ibarrola-Villava, M and Ribas, G},
title = {Long telomere length and a TERT-CLPTM1 locus polymorphism association with melanoma risk.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {50},
number = {18},
pages = {3168-3177},
doi = {10.1016/j.ejca.2014.09.017},
pmid = {25457634},
issn = {1879-0852},
mesh = {Adult ; Case-Control Studies ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Humans ; Male ; Melanoma/*genetics ; Membrane Proteins/*genetics ; Middle Aged ; Polymorphism, Single Nucleotide/*genetics ; Risk Factors ; Skin Neoplasms/*genetics ; Telomerase/*genetics ; Telomere/*genetics ; Telomeric Repeat Binding Protein 1/genetics ; Melanoma, Cutaneous Malignant ; },
abstract = {Telomere length has been associated with the development of cancer. Studies have shown that shorter telomere length may be related to a decreased risk of cutaneous melanoma. Furthermore, deregulation of the telomere-maintaining gene complexes, has been related to this oncogenic process. Some variants in these genes seem to be correlated with a change in telomerase expression. We examined the effect of 10 single nucleotide polymorphisms (SNPs) in the TERT gene (encoding telomerase), one SNP in the related TERT-CLPTM1L locus and one SNP in the TRF1 gene with telomere length, and its influence on melanoma risk in 970 Spanish cases and 733 Spanish controls. Genotypes were determined using KASP technology, and telomere length was measured by quantitative polymerase chain reaction (PCR) on DNA extracted from peripheral blood leucocytes. Our results demonstrate that shorter telomere length is associated with a decreased risk of melanoma in our population (global p-value, 2.69×10(-11)), which may be caused by a diminution of proliferative potential of nevi (melanoma precursor cells). We also obtained significant results when we tested the association between rs401681 variant (TERT-CLPTM1L locus) with melanoma risk (Odds ratio, OR; 95% confidence interval, CI=1.24 (1.08-1.43); p-value, 3×10(-3)). This is the largest telomere-related study undertaken in a Spanish population to date. Furthermore, this study represents a comprehensive analysis of some of the most relevant telomere pathway genes in relation to cutaneous melanoma susceptibility.},
}
@article {pmid25454987,
year = {2014},
author = {Roberts, RO and Boardman, LA and Cha, RH and Pankratz, VS and Johnson, RA and Druliner, BR and Christianson, TJ and Roberts, LR and Petersen, RC},
title = {Short and long telomeres increase risk of amnestic mild cognitive impairment.},
journal = {Mechanisms of ageing and development},
volume = {141-142},
number = {},
pages = {64-69},
pmid = {25454987},
issn = {1872-6216},
support = {R01 AG034676/AG/NIA NIH HHS/United States ; UL1 TR000135/TR/NCATS NIH HHS/United States ; K01 AG028573/AG/NIA NIH HHS/United States ; P30 DK084567/DK/NIDDK NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*metabolism/pathology ; Alzheimer Disease/metabolism/pathology ; Amnesia/*metabolism/pathology ; Cognitive Dysfunction/*metabolism/pathology ; Female ; Humans ; Male ; Risk Factors ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {Peripheral blood telomere length has been associated with age-related conditions including Alzheimer's disease (AD). This suggests that telomere length may identify subjects at increased risk of AD. Thus, we investigated the associations of peripheral blood telomere length with amnestic mild cognitive impairment (aMCI), a putative precursor of AD, among Mayo Clinic Study of Aging participants who were prospectively followed for incident aMCI. We matched 137 incident aMCI cases (mean age 81.1 years, [range 70.9-90.8]; 49.6% men) by age and sex to 137 cognitively normal controls. We measured telomere length (T/S ratio) at baseline using quantitative PCR. Compared to the middle T/S quintile (Q3), the risk of aMCI was elevated for subjects with the shortest (Q1: HR, 2.85, 95% Confidence interval [CI] 0.98, 8.25; p=0.05) and the longest telomere lengths (Q5: HR, 5.58, 95%CI, 2.21, 14.11; p=0.0003). In this elderly cohort, short and long telomeres were associated with increased risk of aMCI. Our findings suggest that both long and short telomere lengths may play a role in the pathogenesis of aMCI, and may be markers of increased risk of aMCI.},
}
@article {pmid25453752,
year = {2014},
author = {Kabir, S and Hockemeyer, D and de Lange, T},
title = {TALEN gene knockouts reveal no requirement for the conserved human shelterin protein Rap1 in telomere protection and length regulation.},
journal = {Cell reports},
volume = {9},
number = {4},
pages = {1273-1280},
pmid = {25453752},
issn = {2211-1247},
support = {R01 AG016642/AG/NIA NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; 5R01AG16642/AG/NIA NIH HHS/United States ; 5R37GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Proliferation ; Chromatin/metabolism ; *Conserved Sequence ; Endonucleases/*metabolism ; Gene Expression Regulation ; *Gene Knockout Techniques ; Humans ; Mice ; Shelterin Complex ; Telomere/*metabolism ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/deficiency/*genetics/metabolism ; Trans-Activators/*metabolism ; Transcription, Genetic ; },
abstract = {The conserved protein Rap1 functions at telomeres in fungi, protozoa, and vertebrates. Like yeast Rap1, human Rap1 has been implicated in telomere length regulation and repression of nonhomologous end-joining (NHEJ) at telomeres. However, mouse telomeres lacking Rap1 do not succumb to NHEJ. To determine the functions of human Rap1, we generated several transcription activator-like effector nuclease (TALEN)-mediated human cell lines lacking Rap1. Loss of Rap1 did not affect the other components of shelterin, the modification of telomeric histones, the subnuclear position of telomeres, or the 3' telomeric overhang. Telomeres lacking Rap1 did not show a DNA damage response, NHEJ, or consistent changes in their length, indicating that Rap1 does not have an important function in protection or length regulation of human telomeres. As human Rap1, like its mouse and unicellular orthologs, affects gene expression, we propose that the conservation of Rap1 reflects its role in transcriptional regulation rather than a function at telomeres.},
}
@article {pmid25451739,
year = {2015},
author = {Uziel, O and Yosef, N and Sharan, R and Ruppin, E and Kupiec, M and Kushnir, M and Beery, E and Cohen-Diker, T and Nordenberg, J and Lahav, M},
title = {The effects of telomere shortening on cancer cells: a network model of proteomic and microRNA analysis.},
journal = {Genomics},
volume = {105},
number = {1},
pages = {5-16},
doi = {10.1016/j.ygeno.2014.10.013},
pmid = {25451739},
issn = {1089-8646},
mesh = {Gene Expression Regulation, Neoplastic/drug effects ; Gene Regulatory Networks ; Humans ; MicroRNAs/*genetics ; Neoplasms/*genetics/*metabolism ; Oligonucleotides/pharmacology ; Proteome/*analysis ; Proteomics ; *Telomere Shortening ; Tumor Cells, Cultured ; },
abstract = {Previously, we have shown that shortening of telomeres by telomerase inhibition sensitized cancer cells to cisplatinum, slowed their migration, increased DNA damage and impaired DNA repair. The mechanism behind these effects is not fully characterized. Its clarification could facilitate novel therapeutics development and may obviate the time consuming process of telomere shortening achieved by telomerase inhibition. Here we aimed to decipher the microRNA and proteomic profiling of cancer cells with shortened telomeres and identify the key mediators in telomere shortening-induced damage to those cells. Of 870 identified proteins, 98 were differentially expressed in shortened-telomere cells. 47 microRNAs were differentially expressed in these cells; some are implicated in growth arrest or act as oncogene repressors. The obtained data was used for a network construction, which provided us with nodal candidates that may mediate the shortened-telomere dependent features. These proteins' expression was experimentally validated, supporting their potential central role in this system.},
}
@article {pmid25451394,
year = {2015},
author = {Lima, IM and Barros, A and Rosa, DV and Albuquerque, M and Malloy-Diniz, L and Neves, FS and Romano-Silva, MA and de Miranda, DM},
title = {Analysis of telomere attrition in bipolar disorder.},
journal = {Journal of affective disorders},
volume = {172},
number = {},
pages = {43-47},
doi = {10.1016/j.jad.2014.09.043},
pmid = {25451394},
issn = {1573-2517},
mesh = {Adult ; *Aging ; Bipolar Disorder/*genetics ; Case-Control Studies ; Comorbidity ; Female ; Humans ; Leukocytes ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Risk Factors ; *Telomere ; *Telomere Shortening ; },
abstract = {BACKGROUND: Telomeres can be considered a marker of biological aging. Studies have suggested that telomere shortening may be associated with aging related diseases and also psychiatric disorders.<br><br>OBJECTIVES: Investigate whether bipolar disorder (BD) and its clinical specificities are associated with telomere shortening.<br><br>METHODS: Eighty-five BD patients and 95 healthy controls were paired for age, sex and educational level. Volunteers were submitted to a psychiatric interview and clinical evaluation. Patients and controls were compared as a whole sample and within specific telomere range (short and long telomeres). Intrapatients group comparison involved type of BD and comorbidities. A Real Time Quantitative PCR was performed in order to verify leukocytes telomere length.<br><br>RESULTS: Bipolar disorder patients presented shorter telomeres when compared to controls (p<0.001). However, there was no significant difference in telomere length between different BD subtypes. When two groups of patients (long and short telomeres) were compared, only panic disorder showed an association with telomere categories (&#x3c7;(2)=6.91; p=0.009; OR=4.27).<br><br>LIMITATIONS: It was not possible to collect information about time since diagnosis, which limited conclusions regarding BD chronicity and telomere length. Furthermore, medication interference upon telomere length was not controlled.<br><br>CONCLUSIONS: Results suggest that BD is associated with reduced telomere length. Also, panic comorbidity may represent an additive risk factor. Understanding aspects that contribute to determination of telomere size in bipolar patients allows us to understand what the impact on telomeres size is, which is a health vulnerability marker.},
}
@article {pmid25446500,
year = {2015},
author = {Compté, N and Bailly, B and De Breucker, S and Goriely, S and Pepersack, T},
title = {Study of the association of total and differential white blood cell counts with geriatric conditions, cardio-vascular diseases, seric IL-6 levels and telomere length.},
journal = {Experimental gerontology},
volume = {61},
number = {},
pages = {105-112},
doi = {10.1016/j.exger.2014.11.016},
pmid = {25446500},
issn = {1873-6815},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*immunology ; Cardiovascular Diseases/*etiology ; Female ; Humans ; Interleukin-6/*blood ; *Leukocyte Count ; Male ; Middle Aged ; Monocytes/immunology ; Neutrophils/immunology ; *Telomere ; },
abstract = {BACKGROUND/OBJECTIVES: Geriatric patients are highly susceptible to infections. While reduced lymphocyte count has been associated with age, other studies found no change in WBC counts with age. Increased circulating white blood cell (WBC) count has been associated with cardiovascular (CV) diseases and frailty but there are discrepancies. Frailty, geriatric conditions, cardiovascular diseases and WBC count have also been associated with low grade inflammation. Association between geriatric conditions and WBC has been scarcely studied. The aim of the study is to assess the association between WBC and geriatric conditions, CV diseases, and seric IL-6 levels.<br><br>We recruited 100 subjects in the general population and hospitalized for chronic medical conditions (age, 23-96years). We collected information on clinical status (medical history, comorbidities, treatments and geriatric syndromes), biological parameters (hematological tests, cytomegalovirus serology) and cytokine production (basal IL-6). Using stepwise backward multivariate analyses, we defined which set of clinical and biological variables could be predictive of increased total and differential WBC counts.<br><br>RESULTS: We found that low-grade inflammation is independently associated with total WBC, monocyte and neutrophil counts, but not geriatric conditions. CV diseases were the only significant associated factor for high monocyte count.<br><br>CONCLUSION: In this study, we observed that differential and total WBC counts do not seem to be associated with geriatric conditions but with CV diseases, low-grade inflammation and telomere length.},
}
@article {pmid25440562,
year = {2014},
author = {Kota, LN and Bharath, S and Purushottam, M and Paul, P and Sivakumar, PT and Varghese, M and Jain, S},
title = {Reduced telomere length in subjects with dementia and diabetes mellitus type 2 is independent of apolipoprotein E4 genotype.},
journal = {Asian journal of psychiatry},
volume = {12},
number = {},
pages = {58-62},
doi = {10.1016/j.ajp.2014.06.012},
pmid = {25440562},
issn = {1876-2026},
mesh = {Aged ; Alleles ; Apolipoprotein E4/*genetics ; Dementia/*genetics ; Diabetes Mellitus, Type 2/*genetics ; Female ; Gene Frequency ; Genetic Association Studies ; Genotype ; Humans ; Male ; Middle Aged ; Polymorphism, Genetic ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Apolipoprotein E4 gene is associated with increased risk of dementia with comorbid diabetes mellitus. Both dementia and diabetes mellitus type 2 are independently associated with telomere shortening. We assessed relative telomere length and apolipoprotein E genotype in subjects with dementia (n=70) and cognitively normal control groups (n=55) with and without comorbid diabetes mellitus type 2. Relative telomere length was highest in the control group (Q2=0.91) followed by dementia (Q2=0.48) and dementia with comorbid diabetes mellitus type 2 (Q2=0.39). Apolipoprotein E4 allele frequency was highest in dementia with comorbid diabetes mellitus type 2 (0.26). Apolipoprotein E4 allele was not significantly associated with telomere attrition in both dementia and cognitively normal group irrespective of comorbid diabetes mellitus type 2 (P>0.05). The findings suggest that relative telomere length is unrelated to apolipoprotein E4 genotype in dementia and cognitive normal subjects with or without comorbid diabetes mellitus type 2.},
}
@article {pmid25430998,
year = {2015},
author = {Tacconi, EM and Tarsounas, M},
title = {How homologous recombination maintains telomere integrity.},
journal = {Chromosoma},
volume = {124},
number = {2},
pages = {119-130},
pmid = {25430998},
issn = {1432-0886},
support = {17201/CRUK_/Cancer Research UK/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; DNA/genetics ; DNA Damage ; DNA Repair ; DNA Replication ; Genomic Instability ; Homologous Recombination/*genetics ; Humans ; Mammals/genetics ; Neoplasms/genetics ; Shelterin Complex ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Telomeres protect the ends of linear chromosomes against loss of genetic information and inappropriate processing as damaged DNA and are therefore crucial to the maintenance of chromosome integrity. In addition to providing a pathway for genome-wide DNA repair, homologous recombination (HR) plays a key role in telomere replication and capping. Consistent with this, the genomic instability characteristic of HR-deficient cells and tumours is driven in part by telomere dysfunction. Here, we discuss the mechanisms by which HR modulates the response to intrinsic cellular challenges that arise during telomere replication, as well as its impact on the assembly of telomere protective structures. How normal and tumour cells differ in their ability to maintain telomeres is deeply relevant to the search for treatments that would selectively eliminate cells whose capacity for HR-mediated repair has been compromised.},
}
@article {pmid25430532,
year = {2015},
author = {Kota, LN and Purushottam, M and Moily, NS and Jain, S},
title = {Shortened telomere in unremitted schizophrenia.},
journal = {Psychiatry and clinical neurosciences},
volume = {69},
number = {5},
pages = {292-297},
doi = {10.1111/pcn.12260},
pmid = {25430532},
issn = {1440-1819},
mesh = {Adult ; Case-Control Studies ; Female ; Humans ; Male ; Remission Induction ; Schizophrenia/*genetics ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {AIM: Telomere attrition has been noted in many neuropsychiatric and neurodegenerative syndromes, and may indicate a shared molecular pathology across conditions. We evaluated telomere length in subjects with remitted and unremitted schizophrenia and in control subjects.<br><br>METHODS: We measured telomere length as relative telomere/single-copy gene ratios in subjects with schizophrenia (n&#x2009;=&#x2009;71) using quantitative real-time polymerase chain reaction. This was compared with relative telomere/single-copy gene ratios in age-matched controls without neuropsychiatric illness (n&#x2009;=&#x2009;73).<br><br>RESULTS: The relative telomere/single-copy gene ratios were significantly lower in subjects with unremitted schizophrenia when compared with control subjects (r&#x2009;=&#x2009;-0.281, P&#x2009;=&#x2009;0.003), as well as the individuals with remitted schizophrenia.<br><br>CONCLUSION: The lower relative telomere length in unremitted schizophrenia subjects may thus indicate shared biological pathways with other neurodegenerative disorders that are also characterized by increased cellular senescence.},
}
@article {pmid25428887,
year = {2015},
author = {Hemminki, K and Rachakonda, S and Musak, L and Vymetalkova, V and Halasova, E and Försti, A and Vodickova, L and Buchancova, J and Vodicka, P and Kumar, R},
title = {Telomere length in circulating lymphocytes: Association with chromosomal aberrations.},
journal = {Genes, chromosomes &amp; cancer},
volume = {54},
number = {3},
pages = {194-196},
doi = {10.1002/gcc.22225},
pmid = {25428887},
issn = {1098-2264},
mesh = {Adult ; *Chromosome Aberrations ; Female ; Humans ; Lymphocytes/ultrastructure ; Telomere Homeostasis/*genetics ; },
}
@article {pmid25428739,
year = {2014},
author = {Dlouha, D and Maluskova, J and Kralova Lesna, I and Lanska, V and Hubacek, JA},
title = {Comparison of the relative telomere length measured in leukocytes and eleven different human tissues.},
journal = {Physiological research},
volume = {63},
number = {Suppl 3},
pages = {S343-50},
doi = {10.33549/physiolres.932856},
pmid = {25428739},
issn = {1802-9973},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/pathology/*physiology ; Brain/pathology/*physiology ; Child ; Child, Preschool ; DNA Damage/physiology ; Female ; Fetus/pathology/physiology ; Humans ; Infant ; Infant, Newborn ; Leukocytes, Mononuclear/pathology/*physiology ; Male ; Middle Aged ; Telomere/pathology/*physiology ; Telomere Shortening/*physiology ; Young Adult ; },
abstract = {The relative length of telomeres measured in peripheral blood leukocytes is a commonly used system marker for biological aging and can also be used as a biomarker of cardiovascular aging. However, to what extent the telomere length in peripheral leukocytes reflects telomere length in different organ tissues is still unclear. Therefore, we have measured relative telomere length (rTL) in twelve different human tissues (peripheral blood leukocytes, liver, kidney, heart, spleen, brain, skin, triceps, tongue mucosa, intercostal skeletal muscle, subcutaneous fat, and abdominal fat) from twelve cadavers (age range of 29 week of gestation to 88 years old). The highest rTL variability was observed in peripheral leukocytes, and the lowest variability was found in brain. We found a significant linear correlation between leukocyte rTL and both intercostal muscle (R=0.68, P<0.02) and liver rTL (R=0.60, P<0.05) only. High rTL variability was observed between different organs from one individual. Furthermore, we have shown that even slight DNA degradation (modeled by sonication of genomic DNA) leads to false rTL shortening. We conclude that the rTL in peripheral leukocytes is not strongly correlated with the rTL in different organs.},
}
@article {pmid25428355,
year = {2014},
author = {Babinský, M and Fiala, R and Kejnovská, I and Bednářová, K and Marek, R and Sagi, J and Sklenář, V and Vorlíčková, M},
title = {Loss of loop adenines alters human telomere d[AG3(TTAG3)3] quadruplex folding.},
journal = {Nucleic acids research},
volume = {42},
number = {22},
pages = {14031-14041},
pmid = {25428355},
issn = {1362-4962},
mesh = {Adenine/*chemistry ; *DNA Damage ; *G-Quadruplexes ; Guanine/chemistry ; Humans ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Potassium/chemistry ; Telomere/*chemistry ; },
abstract = {Abasic (AP) lesions are the most frequent type of damages occurring in cellular DNA. Here we describe the conformational effects of AP sites substituted for 2'-deoxyadenosine in the first (ap7), second (ap13) or third (ap19) loop of the quadruplex formed in K(+) by the human telomere DNA 5'-d[AG3(TTAG3)3]. CD spectra and electrophoresis reveal that the presence of AP sites does not hinder the formation of intramolecular quadruplexes. NMR spectra show that the structural heterogeneity is substantially reduced in ap7 and ap19 as compared to that in the wild-type. These two (ap7 and ap19) sequences are shown to adopt the hybrid-1 and hybrid-2 quadruplex topology, respectively, with AP site located in a propeller-like loop. All three studied sequences transform easily into parallel quadruplex in dehydrating ethanol solution. Thus, the AP site in any loop region facilitates the formation of the propeller loop. Substitution of all adenines by AP sites stabilizes the parallel quadruplex even in the absence of ethanol. Whereas guanines are the major determinants of quadruplex stability, the presence or absence of loop adenines substantially influences quadruplex folding. The naturally occurring adenine-lacking sites in the human telomere DNA can change the quadruplex topology in vivo with potentially vital biological consequences.},
}
@article {pmid25425294,
year = {2015},
author = {Gan, Y and Lu, J and Yeung, BZ and Cottage, CT and Wientjes, MG and Au, JL},
title = {Pharmacodynamics of telomerase inhibition and telomere shortening by noncytotoxic suramin.},
journal = {The AAPS journal},
volume = {17},
number = {1},
pages = {268-276},
pmid = {25425294},
issn = {1550-7416},
support = {R01 CA077091/CA/NCI NIH HHS/United States ; R01CA77091/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Antineoplastic Agents/administration &amp; dosage/*pharmacology ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Humans ; Inhibitory Concentration 50 ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasms/drug therapy/pathology ; Suramin/administration &amp; dosage/*pharmacology ; Telomerase/*antagonists &amp; inhibitors ; Telomere/drug effects/metabolism ; Telomere Shortening/*drug effects ; },
abstract = {We reported that suramin is an effective chemosensitizer at noncytotoxic concentrations (<50 μM); this effect was observed in multiple types of human xenograft tumors in vitro and in vivo. Clinical evaluation of noncytotoxic suramin is ongoing. Because (a) suramin inhibits reverse transcriptase, (b) telomerase is a reverse transcriptase, and (c) inhibition of telomerase enhances tumor chemosensitivity, we studied the pharmacodynamics of noncytotoxic suramin on telomerase activity and telomere length in cultured cells and tumors grown in animals. In three human cancer cells that depend on telomerase for telomere maintenance (pharynx FaDu, prostate PC3, breast MCF7), suramin inhibited telomerase activity in cell extracts and intact cells at concentrations that exhibited no cytotoxicity (IC50 of telomerase was between 1 and 3 μM vs. >60 μM for cytotoxicity), and continuous treatment at 10-25 μM for 6 weeks resulted in gradual telomere shortening (maximum of 30%) and cell senescence (measured by β-galactosidase activity and elevation of mRNA levels of two senescence markers p16 and p21). In contrast, noncytotoxic suramin did not shorten the telomere in telomerase-independent human osteosarcoma Saos-2 cells. In mice bearing FaDu tumors, treatment with noncytotoxic suramin for 6 weeks resulted in telomere erosion in >95% of the tumor cells with an average telomere shortening of >40%. These results indicate noncytotoxic suramin inhibits telomerase, shortens telomere and induces cell senescence, and suggest telomerase inhibition as a potential mechanism of its chemosensitization.},
}
@article {pmid25424527,
year = {2015},
author = {Guan, JZ and Guan, WP and Maeda, T and Guoqing, X and GuangZhi, W and Makino, N},
title = {Patients with multiple sclerosis show increased oxidative stress markers and somatic telomere length shortening.},
journal = {Molecular and cellular biochemistry},
volume = {400},
number = {1-2},
pages = {183-187},
pmid = {25424527},
issn = {1573-4919},
mesh = {Adult ; Dinoprost/analogs &amp; derivatives/urine ; Female ; Humans ; Leukocytes, Mononuclear/pathology ; Lipid Peroxidation/genetics ; Male ; Middle Aged ; Multiple Sclerosis/*blood/genetics/*urine ; *Oxidative Stress ; Telomere Shortening/*genetics ; },
abstract = {Lipid peroxidation due to oxidative stress (OS) may play an important role in the pathogenesis of chronic systemic inflammatory diseases such as multiple sclerosis (MS). Telomeres, repeated sequences that cap chromosome ends, undergo shortening with each cycle of cell division, resulting in cellular senescence. Research regarding telomere shortening has provided novel insight into the pathogenesis of various diseases. We hypothesized that OS damage leads to inflammatory reactions, which subsequently shortens the telomere length in MS. We enrolled 59 patients with MS, and age- and gender-matched 60 healthy controls. We divided MS subjects into three groups matched for age and gender according to the severity of disability: relatively benign course (BMS), secondary progressive MS, and primary progressive MS (PPMS). We analyzed the telomere length in peripheral blood mononuclear cells and the 8-iso-PGF2α concentration in urine, a reliable and stable marker of lipid peroxidation in vivo. The data showed significant higher levels of urinary 8-iso-PGF2α in MS subjects than in the controls. The lag-time, which represents the direct measurement of the resistance of low-density lipoprotein to oxidation, was shorter in the PPMS subjects than in the groups. Compared to that observed in the controls, the mean telomere length was significantly shorter in the PPMS group, whereas no significant telomere shortening was found between the controls and other subjects. Our data suggest that a decreased telomere length and enhanced lipid peroxidation reflects the severest stage of MS.},
}
@article {pmid25418689,
year = {2015},
author = {Sanders, AE and Divaris, K and Naorungroj, S and Heiss, G and Risques, RA},
title = {Telomere length attrition and chronic periodontitis: an ARIC Study nested case-control study.},
journal = {Journal of clinical periodontology},
volume = {42},
number = {1},
pages = {12-20},
pmid = {25418689},
issn = {1600-051X},
support = {HHSN268201100012C/HL/NHLBI NIH HHS/United States ; HHSN268201100009I/HL/NHLBI NIH HHS/United States ; R01 DE011551/DE/NIDCR NIH HHS/United States ; HHSN268201100010C/HL/NHLBI NIH HHS/United States ; HHSN268201100008C/HL/NHLBI NIH HHS/United States ; HHSN268201100005G/HL/NHLBI NIH HHS/United States ; HHSN268201100008I/HL/NHLBI NIH HHS/United States ; HHSN268201100005C//PHS HHS/United States ; HHSN268201100007C/HL/NHLBI NIH HHS/United States ; HHSN268201100009C//PHS HHS/United States ; HHSN268201100011I/HL/NHLBI NIH HHS/United States ; HHSN268201100011C/HL/NHLBI NIH HHS/United States ; HHSN268201100010C//PHS HHS/United States ; HHSN268201100006C/HL/NHLBI NIH HHS/United States ; HHSN268201100008C//PHS HHS/United States ; HHSN268201100012C//PHS HHS/United States ; R01-DE11551/DE/NIDCR NIH HHS/United States ; R03 DE022555/DE/NIDCR NIH HHS/United States ; HHSN268201100005I/HL/NHLBI NIH HHS/United States ; HHSN268201100007C//PHS HHS/United States ; HHSN268201100009C/HL/NHLBI NIH HHS/United States ; HHSN268201100011C//PHS HHS/United States ; HHSN268201100005C/HL/NHLBI NIH HHS/United States ; HHSN268201100007I/HL/NHLBI NIH HHS/United States ; HHSN268201100006C//PHS HHS/United States ; R03-DE022555/DE/NIDCR NIH HHS/United States ; },
mesh = {Black or African American ; Aged ; Case-Control Studies ; Chronic Periodontitis/pathology/*physiopathology ; Cohort Studies ; DNA/analysis ; Diabetes Complications ; Educational Status ; Female ; Follow-Up Studies ; Humans ; Hypertension/complications ; Income ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Obesity/complications ; Prospective Studies ; Protein Serine-Threonine Kinases/analysis ; Ribosomal Proteins/analysis ; Sex Factors ; Smoking ; Telomere Shortening/*physiology ; Tooth Loss/complications ; White People ; },
abstract = {AIM: This nested case-control study sought to determine whether an accelerated rate of leukocyte telomere length (LTL) shortening over 6 years was associated with chronic periodontitis.<br><br>MATERIALS AND METHODS: We sampled cases (n&#xa0;=&#xa0;178) with severe chronic periodontitis and controls (n&#xa0;=&#xa0;178) with no/mild chronic periodontitis from the Atherosclerosis Risk in Communities study. Controls were frequency-matched to cases by study site, age, sex and race. Age ranged from 53 to 73&#xa0;years. Severe chronic periodontitis was defined using the CDC-AAP case classification. LTL was measured from DNA collected at two time points, 6&#xa0;years apart, with quantitative polymerase chain reaction relative to a single-copy control gene. Multiple linear regression evaluated associations between LTL measured at baseline, follow-up and change scores with severe chronic periodontitis, adjusting for potential confounders.<br><br>RESULTS: Cases had shorter LTL than controls at baseline (p&#xa0;=&#xa0;0.03) and follow-up (p&#xa0;=&#xa0;0.04) after adjusting for confounding. Overall there was a net reduction in LTL over time (p&#xa0;=&#xa0;0.02). The rate of LTL did not differ between cases and controls (p&#xa0;=&#xa0;0.80).<br><br>CONCLUSIONS: Leukocyte telomere length shortening occurred at the same rate among adults with and without severe chronic periodontitis. This suggests that LTL shortening may have occurred earlier in the life course.},
}
@article {pmid25416818,
year = {2015},
author = {Tang, M and Li, Y and Zhang, Y and Chen, Y and Huang, W and Wang, D and Zaug, AJ and Liu, D and Zhao, Y and Cech, TR and Ma, W and Songyang, Z},
title = {Disease mutant analysis identifies a new function of DAXX in telomerase regulation and telomere maintenance.},
journal = {Journal of cell science},
volume = {128},
number = {2},
pages = {331-341},
pmid = {25416818},
issn = {1477-9137},
support = {GM081627/GM/NIGMS NIH HHS/United States ; P30CA125123/CA/NCI NIH HHS/United States ; P01 GM081627/GM/NIGMS NIH HHS/United States ; NCI CA133249/CA/NCI NIH HHS/United States ; P30 CA125123/CA/NCI NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; R01 GM095599/GM/NIGMS NIH HHS/United States ; R01 CA133249/CA/NCI NIH HHS/United States ; GM095599/GM/NIGMS NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing/antagonists &amp; inhibitors/*genetics/metabolism ; Co-Repressor Proteins ; Coiled Bodies/genetics/metabolism ; DNA Helicases/genetics ; Humans ; In Situ Hybridization, Fluorescence ; Molecular Chaperones ; Mutation ; Nuclear Proteins/antagonists &amp; inhibitors/*genetics/metabolism ; RNA Interference ; Telomerase/*genetics/metabolism ; Telomere/genetics/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Most human cancers depend on the telomerase to maintain telomeres; however, about 10% of cancers are telomerase negative and utilize the alternative lengthening of telomeres (ALT) mechanism. Mutations in the DAXX gene have been found frequently in both telomerase-positive and ALT cells, and how DAXX mutations contribute to cancers remains unclear. We report here that endogenous DAXX can localize to Cajal bodies, associate with the telomerase and regulate telomerase targeting to telomeres. Furthermore, disease mutations that are located in different regions of DAXX differentially impact on its ability to interact with its binding partners and its targeting to Cajal bodies and telomeres. In addition, DAXX knockdown by RNA interference led to reduced telomerase targeting to telomeres and telomere shortening. These findings collectively support a DAXX-centric pathway for telomere maintenance, where DAXX interaction with the telomerase regulates telomerase assembly in Cajal bodies and telomerase targeting to telomeres.},
}
@article {pmid25416716,
year = {2015},
author = {Lin, J and Blalock, JA and Chen, M and Ye, Y and Gu, J and Cohen, L and Cinciripini, PM and Wu, X},
title = {Depressive symptoms and short telomere length are associated with increased mortality in bladder cancer patients.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {24},
number = {2},
pages = {336-343},
pmid = {25416716},
issn = {1538-7755},
support = {P50 CA091846/CA/NCI NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; U01 CA127615/CA/NCI NIH HHS/United States ; U01 CA 127615/CA/NCI NIH HHS/United States ; P50 CA 91846/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Biomarkers/blood ; Cause of Death ; Depressive Disorder/*diagnosis ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; *Telomere Shortening ; Urinary Bladder Neoplasms/*mortality ; },
abstract = {BACKGROUND: Depression is associated with an increased risk of mortality in patients with cancer; it has been hypothesized that depression-associated alterations in cell aging mechanisms, in particular, the telomere/telomerase maintenance system, may underlie this increased risk. We evaluated the association of depressive symptoms and telomere length to mortality and recurrence/progression in 464 patients with bladder cancer.<br><br>METHODS: We used the Center for Epidemiologic Studies Depression Scale (CES-D) and Structured Clinical Interview for DSM-IV Disorder (SCID) to assess current depressive symptoms and lifetime major depressive disorder (MDD), respectively, and telomere length was assessed from peripheral blood lymphocytes. Multivariate Cox regression was used to assess the association of depression and telomere length to outcomes and the joint effect of both. Kaplan-Meier plots and log-rank tests were used to compare survival time of subgroups by depression variables and telomere length.<br><br>RESULTS: Patients with depressive symptoms (CES-D &#x2265; 16) had a 1.83-fold [95% confidence interval (CI), 1.08-3.08; P = 0.024] increased risk of mortality compared with patients without depressive symptoms (CES-D < 16) and shorter disease-free survival time (P = 0.004). Patients with both depressive symptoms and lifetime history of MDD were at 4.88-fold (95% CI, 1.40-16.99; P = 0.013) increased risk compared with patients with neither condition. Compared to patients without depressive symptoms and long telomere length, patients with depressive symptoms and short telomeres exhibited a 4-fold increased risk of mortality (HR, 3.96; 95% CI, 1.86-8.41; P = 0.0003) and significantly shorter disease-free survival time (P < 0.001).<br><br>CONCLUSION: Short telomere length and depressive symptoms are associated with bladder cancer mortality individually and jointly.<br><br>IMPACT: Further investigation of interventions that impact depression and telomere length may be warranted in patients with cancer.},
}
@article {pmid25415503,
year = {2014},
author = {Zlotorynski, E},
title = {Chromosome biology: Short telomeres can't reach.},
journal = {Nature reviews. Molecular cell biology},
volume = {15},
number = {12},
pages = {766-767},
pmid = {25415503},
issn = {1471-0080},
mesh = {*Gene Expression Regulation ; Humans ; Telomere/*genetics/*metabolism ; Telomere Shortening/*genetics ; },
}
@article {pmid25414434,
year = {2014},
author = {Nakamura-Ishizu, A and Suda, T},
title = {Not merely quiescent: telomeres in quiescent HSCs.},
journal = {Blood},
volume = {124},
number = {22},
pages = {3179-3180},
doi = {10.1182/blood-2014-10-603258},
pmid = {25414434},
issn = {1528-0020},
mesh = {Animals ; Apoptosis/*physiology ; Cellular Senescence/*physiology ; *Hematopoiesis ; Hematopoietic Stem Cells/*physiology ; Telomere Shortening/*physiology ; },
abstract = {In this issue of Blood, Wang et al elegantly show that telomere shortening results in DNA damage that induces apoptosis and senescence in quiescent hematopoietic stem cells (HSCs).},
}
@article {pmid25413841,
year = {2015},
author = {Raymond, AR and Norton, GR and Woodiwiss, AJ and Brooksbank, RL},
title = {Impact of gender and menopausal status on relationships between biological aging, as indexed by telomere length, and aortic stiffness.},
journal = {American journal of hypertension},
volume = {28},
number = {5},
pages = {623-630},
doi = {10.1093/ajh/hpu212},
pmid = {25413841},
issn = {1941-7225},
mesh = {Adult ; *Aging ; Blood Flow Velocity/physiology ; Blood Pressure/*physiology ; DNA/analysis ; Female ; Humans ; Hypertension/*genetics/physiopathology ; Male ; *Menopause ; Pulse Wave Analysis ; Real-Time Polymerase Chain Reaction ; Sex Factors ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Vascular Stiffness/*physiology ; },
abstract = {BACKGROUND: Telomere length predicts cardiovascular disease (CVD) possibly through an impact of telomere attrition on aortic stiffness. Whether reduced biological aging and a lack of telomere length-aortic stiffness relationships in women contribute to the lower prevalence of CVD in women, prior to menopause, is uncertain.<br><br>METHODS: We evaluated the relationship between telomere length and carotid-femoral (aortic) pulse wave velocity (PWV) in 580 randomly recruited participants of Black African descent (age = 44 &#xb1; 19 years; women: n = 361; premenopausal: n = 195). PWV was determined using carotid and femoral applanation tonometry (SphygmoCor). Relative leukocyte telomere length (T/S) was measured using quantitative real-time polymerase chain reaction assays.<br><br>RESULTS: Men and women had similar T/S. T/S was inversely correlated with age (r = -0.14, P < 0.001) and this association was similar in all (r = -0.14, P < 0.01) and premenopausal (r = -0.17, P < 0.05) women as in men (r = -0.14, P < 0.05). An inverse relationship between T/S and PWV was noted both before (r = -0.20, P < 0.0001) and after (partial r = -0.14, P < 0.001) adjustments for confounders. No interaction between T/S and either sex or menopausal status was independently associated with PWV, and T/S was independently correlated with PWV in all (partial r = -0.14, P < 0.01) and premenopausal (partial r = -0.18, P < 0.05) women and in men (partial r = -0.15, P < 0.05).<br><br>CONCLUSIONS: Gender and premenopausal status do not affect age-related decreases in T/S and associations between T/S and PWV. In participants of African descent in whom telomere length did not differ by gender, the impact of gender prior to menopause on CVD is unlikely to be attributed to differences in the effect of biological aging on aortic stiffness.},
}
@article {pmid25413191,
year = {2014},
author = {Brault, ME and Ohayon, SM and Kwan, R and Bergman, H and Eisenberg, MJ and Boivin, JF and Morin, JF and Langlois, Y and Autexier, C and Afilalo, J},
title = {Telomere length and the clinical phenotype of frailty in older adults undergoing cardiac surgery.},
journal = {Journal of the American Geriatrics Society},
volume = {62},
number = {11},
pages = {2205-2207},
doi = {10.1111/jgs.13076},
pmid = {25413191},
issn = {1532-5415},
support = {IAO-82035//Canadian Institutes of Health Research/Canada ; MOP-86672//Canadian Institutes of Health Research/Canada ; },
mesh = {Aged ; Aged, 80 and over ; Cohort Studies ; Feasibility Studies ; *Frail Elderly ; Genetic Markers/*genetics ; Genetic Predisposition to Disease/*genetics ; Health Status Indicators ; Heart Diseases/mortality/*surgery ; Hospital Mortality ; Humans ; Length of Stay/statistics &amp; numerical data ; Male ; *Phenotype ; Postoperative Complications/*genetics/mortality ; Predictive Value of Tests ; Telomere Homeostasis ; Telomere Shortening/*genetics ; },
}
@article {pmid25412235,
year = {2015},
author = {Augustine, TA and Baig, M and Sood, A and Budagov, T and Atzmon, G and Mariadason, JM and Aparo, S and Maitra, R and Goel, S},
title = {Telomere length is a novel predictive biomarker of sensitivity to anti-EGFR therapy in metastatic colorectal cancer.},
journal = {British journal of cancer},
volume = {112},
number = {2},
pages = {313-318},
pmid = {25412235},
issn = {1532-1827},
support = {K12 CA132783/CA/NCI NIH HHS/United States ; P30 CA013330/CA/NCI NIH HHS/United States ; 1K12CA132783-01A1/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal/pharmacology/therapeutic use ; Antibodies, Monoclonal, Humanized/pharmacology/therapeutic use ; Antineoplastic Agents/*pharmacology/therapeutic use ; Biomarkers, Tumor/*genetics ; Cell Line, Tumor ; Cetuximab ; Colorectal Neoplasms/*drug therapy/genetics/mortality/pathology ; Disease-Free Survival ; Drug Resistance, Neoplasm ; ErbB Receptors/*antagonists &amp; inhibitors ; Female ; Humans ; Liver Neoplasms/*drug therapy/genetics/mortality/secondary ; Male ; Middle Aged ; Molecular Targeted Therapy ; Panitumumab ; Telomere ; *Telomere Shortening ; },
abstract = {BACKGROUND: Telomeres are TTAGGG tandem repeats capping chromosomal ends and partially controlled by the telomerase enzyme. The EGFR pathway putatively regulates telomerase function, prompting an investigation of telomere length (TL) and its association with anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC).<br><br>METHODS: Colorectal cancer cell lines were treated with multiple drugs and sensitivity determined. Clinical information was gathered from 75 patients who had received anti-EGFR drugs. Telomere length was measured using a validated qRT-PCR technique.<br><br>RESULTS: In CRC cell lines, TL independently predicted cetuximab sensitivity. Cells with shorter TL had growth inhibition of 18.6&#xb1;3.41% as compared with 41.39&#xb1;8.58% in longer TL (P=0.02). These in vitro findings were validated clinically, in a robust multivariate model. Among patients with KRas WT tumours, those with longer TL had a superior median progression-free survival (PFS) of 24.9 weeks than those with shorter TL; median 11.1 weeks, HR 0.31; P=0.048.<br><br>CONCLUSION: Telomere length could be a potential unique biomarker predictive of clinical benefit (PFS) of mCRC patients treated with anti-EGFR therapy. This is the novel demonstration of a complex hitherto undescribed interaction, placing anti-EGFR therapy, EGFR pathway, and the telomerase complex within a clinical context.},
}
@article {pmid25411450,
year = {2015},
author = {Nettle, D and Monaghan, P and Gillespie, R and Brilot, B and Bedford, T and Bateson, M},
title = {An experimental demonstration that early-life competitive disadvantage accelerates telomere loss.},
journal = {Proceedings. Biological sciences},
volume = {282},
number = {1798},
pages = {20141610},
pmid = {25411450},
issn = {1471-2954},
support = {BB/J015091/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/J016446/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {*Aging ; Animals ; *Competitive Behavior ; England ; Female ; Male ; *Oxidative Stress ; Starlings/genetics/growth &amp; development/*physiology ; *Telomere Shortening ; },
abstract = {Adverse experiences in early life can exert powerful delayed effects on adult survival and health. Telomere attrition is a potentially important mechanism in such effects. One source of early-life adversity is the stress caused by competitive disadvantage. Although previous avian experiments suggest that competitive disadvantage may accelerate telomere attrition, they do not clearly isolate the effects of competitive disadvantage from other sources of variation. Here, we present data from an experiment in European starlings (Sturnus vulgaris) that used cross-fostering to expose siblings to divergent early experience. Birds were assigned either to competitive advantage (being larger than their brood competitors) or competitive disadvantage (being smaller than their brood competitors) between days 3 and 12 post-hatching. Disadvantage did not affect weight gain, but it increased telomere attrition, leading to shorter telomere length in disadvantaged birds by day 12. There were no effects of disadvantage on oxidative damage as measured by plasma lipid peroxidation. We thus found strong evidence that early-life competitive disadvantage can accelerate telomere loss. This could lead to faster age-related deterioration and poorer health in later life.},
}
@article {pmid25409313,
year = {2014},
author = {Gutierrez-Rodrigues, F and Santana-Lemos, BA and Scheucher, PS and Alves-Paiva, RM and Calado, RT},
title = {Direct comparison of flow-FISH and qPCR as diagnostic tests for telomere length measurement in humans.},
journal = {PloS one},
volume = {9},
number = {11},
pages = {e113747},
pmid = {25409313},
issn = {1932-6203},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Anemia, Aplastic/metabolism/pathology ; Child ; Child, Preschool ; Dyskeratosis Congenita/metabolism/pathology ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/metabolism/pathology ; In Situ Hybridization, Fluorescence/*methods ; Infant ; Infant, Newborn ; Leukocytes/cytology/metabolism ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction/*methods ; Sensitivity and Specificity ; Telomere/*metabolism ; Telomere Shortening/*physiology ; Young Adult ; },
abstract = {Telomere length measurement is an essential test for the diagnosis of telomeropathies, which are caused by excessive telomere erosion. Commonly used methods are terminal restriction fragment (TRF) analysis by Southern blot, fluorescence in situ hybridization coupled with flow cytometry (flow-FISH), and quantitative PCR (qPCR). Although these methods have been used in the clinic, they have not been comprehensively compared. Here, we directly compared the performance of flow-FISH and qPCR to measure leukocytes' telomere length of healthy individuals and patients evaluated for telomeropathies, using TRF as standard. TRF and flow-FISH showed good agreement and correlation in the analysis of healthy subjects (R(2) = 0.60; p<0.0001) and patients (R(2) = 0.51; p<0.0001). In contrast, the comparison between TRF and qPCR yielded modest correlation for the analysis of samples of healthy individuals (R(2) = 0.35; p<0.0001) and low correlation for patients (R(2) = 0.20; p = 0.001); Bland-Altman analysis showed poor agreement between the two methods for both patients and controls. Quantitative PCR and flow-FISH modestly correlated in the analysis of healthy individuals (R(2) = 0.33; p<0.0001) and did not correlate in the comparison of patients' samples (R(2) = 0.1, p = 0.08). Intra-assay coefficient of variation (CV) was similar for flow-FISH (10.8 ± 7.1%) and qPCR (9.5 ± 7.4%; p = 0.35), but the inter-assay CV was lower for flow-FISH (9.6 ± 7.6% vs. 16 ± 19.5%; p = 0.02). Bland-Altman analysis indicated that flow-FISH was more precise and reproducible than qPCR. Flow-FISH and qPCR were sensitive (both 100%) and specific (93% and 89%, respectively) to distinguish very short telomeres. However, qPCR sensitivity (40%) and specificity (63%) to detect telomeres below the tenth percentile were lower compared to flow-FISH (80% sensitivity and 85% specificity). In the clinical setting, flow-FISH was more accurate, reproducible, sensitive, and specific in the measurement of human leukocyte's telomere length in comparison to qPCR. In conclusion, flow-FISH appears to be a more appropriate method for diagnostic purposes.},
}
@article {pmid25407781,
year = {2014},
author = {Wolna, AH and Fleming, AM and Burrows, CJ},
title = {Single-molecule analysis of thymine dimer-containing G-quadruplexes formed from the human telomere sequence.},
journal = {Biochemistry},
volume = {53},
number = {48},
pages = {7484-7493},
pmid = {25407781},
issn = {1520-4995},
support = {R01 GM093099/GM/NIGMS NIH HHS/United States ; },
mesh = {Bacterial Toxins ; Base Sequence ; Circular Dichroism ; DNA Damage ; Electrophoretic Mobility Shift Assay ; *G-Quadruplexes/radiation effects ; Hemolysin Proteins ; Humans ; Models, Molecular ; Nanopores ; Nucleic Acid Conformation/radiation effects ; Pyrimidine Dimers/*chemistry ; Telomere/*chemistry/*genetics/radiation effects ; Ultraviolet Rays ; },
abstract = {The human telomere plays crucial roles in maintaining genome stability. In the presence of suitable cations, the repetitive 5'-TTAGGG-3' human telomere sequence can fold into G-quadruplexes that adopt the hybrid, basket, or propeller fold. The telomere sequence is hypersensitive to UV-induced thymine dimer (T=T) formation, yet it does not cause telomere shortening. In this work, the potential structural disruption and thermodynamic stability of the T=T-containing natural telomere sequences were studied to understand why this damage is tolerated in telomeres. First, established methods, such as thermal melting measurements, electrophoretic mobility shift assays, and circular dichroism spectroscopy, were utilized to determine the effects of the damage on these structures. Second, a single-molecule ion channel recording technique using α-hemolysin (α-HL) was employed to examine further the structural differences between the damaged sequences. It was observed that the damage caused slightly lower thermal stabilities and subtle changes in the circular dichroism spectra for hybrid and basket folds. The α-HL experiments determined that T=Ts disrupt double-chain reversal loop formation but are tolerated in edgewise and diagonal loops. The largest change was observed for the T=T-containing natural telomere sequence when the propeller fold (all double-chain reversal loops) was studied. On the basis of the α-HL experiments, it was determined that a triplexlike structure exists under conditions that favor a propeller structure. The biological significance of these observations is discussed.},
}
@article {pmid25406353,
year = {2015},
author = {Dumitriu, B and Feng, X and Townsley, DM and Ueda, Y and Yoshizato, T and Calado, RT and Yang, Y and Wakabayashi, Y and Kajigaya, S and Ogawa, S and Zhu, J and Young, NS},
title = {Telomere attrition and candidate gene mutations preceding monosomy 7 in aplastic anemia.},
journal = {Blood},
volume = {125},
number = {4},
pages = {706-709},
pmid = {25406353},
issn = {1528-0020},
support = {//Intramural NIH HHS/United States ; },
mesh = {Anemia, Aplastic/*genetics/metabolism/pathology ; Chromosome Deletion ; Chromosomes, Human, Pair 7/genetics/metabolism ; Female ; *Hematopoietic Stem Cells ; Humans ; Leukemia, Myeloid, Acute/genetics/metabolism/pathology ; Male ; Myelodysplastic Syndromes/genetics/metabolism/pathology ; *Telomere Homeostasis ; },
abstract = {The pathophysiology of severe aplastic anemia (SAA) is immune-mediated destruction of hematopoietic stem and progenitor cells (HSPCs). Most patients respond to immunosuppressive therapies, but a minority transform to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), frequently associated with monosomy 7 (-7). Thirteen SAA patients were analyzed for acquired mutations in myeloid cells at the time of evolution to -7, and all had a dominant HSPC clone bearing specific acquired mutations. However, mutations in genes associated with MDS/AML were present in only 4 cases. Patients who evolved to MDS and AML showed marked progressive telomere attrition before the emergence of -7. Single telomere length analysis confirmed accumulation of short telomere fragments of individual chromosomes. Our results indicate that accelerated telomere attrition in the setting of a decreased HSPC pool is characteristic of early myeloid oncogenesis, specifically chromosome 7 loss, in MDS/AML after SAA, and provides a possible mechanism for development of aneuploidy.},
}
@article {pmid25406242,
year = {2015},
author = {García-Calzón, S and Martínez-González, MA and Razquin, C and Corella, D and Salas-Salvadó, J and Martínez, JA and Zalba, G and Marti, A},
title = {Pro12Ala polymorphism of the PPARγ2 gene interacts with a mediterranean diet to prevent telomere shortening in the PREDIMED-NAVARRA randomized trial.},
journal = {Circulation. Cardiovascular genetics},
volume = {8},
number = {1},
pages = {91-99},
doi = {10.1161/CIRCGENETICS.114.000635},
pmid = {25406242},
issn = {1942-3268},
mesh = {Aged ; Aged, 80 and over ; *Cardiovascular Diseases/genetics/mortality ; *Diet, Mediterranean ; Female ; Follow-Up Studies ; Humans ; Longevity/*genetics ; Male ; Middle Aged ; PPAR gamma/*genetics ; *Polymorphism, Genetic ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: The gene variant Pro/Ala (rs1801282) in the PPARγ2 has been associated with lower cardiovascular risk and greater benefit from lifestyle interventions. This polymorphism also seems to be associated with longer lifespan, but no information on telomere length (TL) is available. Our aim was to study the association between the Ala allele and changes in TL in high cardiovascular risk subjects and the potential interaction with a Mediterranean dietary pattern.<br><br>METHODS AND RESULTS: A total of 521 subjects (55-80 years) participating in the Prevenci&#xf3;n con Dieta Mediterr&#xe1;nea randomized trial were genotyped. Changes in TL, measured by quantitative real-time polymerase chain reaction (PCR), were assessed over 5 years of a nutritional intervention, which promoted adherence to the Mediterranean diet (MeDiet). Interestingly, Ala carriers showed lower telomere shortening after 5 years compared with the Pro/Pro genotype (P=0.031). This association was modulated by MeDiet because those Ala carriers who reported better conformity to the MeDiet exhibited increased TL (P<0.001). Moreover, a reduction in carbohydrate intake (&#x2264;9.5 g/d) resulted in increased TL among Ala carriers. Notably, an apparent gene-diet interaction was found through the observed changes in the MUFA+PUFA/carbohydrates ratio: as this ratio increased, TL lengthening was detected to a greater extent in the Ala carriers compared with the Pro/Pro subjects (P for interaction <0.001).<br><br>CONCLUSIONS: The Pro12Ala polymorphism is associated with TL homeostasis after 5 years follow-up in subjects at high cardiovascular risk. In addition, a higher adherence to the MeDiet pattern strengthens the prevention of telomere shortening among Ala carriers.<br><br>CLINICAL TRIAL REGISTRATION: www.controlled-trials.com; Unique Identifier: ISRCTN35739639.},
}
@article {pmid25406241,
year = {2015},
author = {D'Mello, MJ and Ross, SA and Briel, M and Anand, SS and Gerstein, H and Paré, G},
title = {Association between shortened leukocyte telomere length and cardiometabolic outcomes: systematic review and meta-analysis.},
journal = {Circulation. Cardiovascular genetics},
volume = {8},
number = {1},
pages = {82-90},
doi = {10.1161/CIRCGENETICS.113.000485},
pmid = {25406241},
issn = {1942-3268},
mesh = {Aging/*metabolism/pathology ; Cellular Senescence ; Diabetes Mellitus, Type 2/*metabolism/pathology ; Humans ; Leukocytes/*metabolism/pathology ; Myocardial Infarction/*metabolism/pathology ; Stroke/*metabolism/pathology ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Telomeres are repetitive, gene-poor regions that cap the ends of DNA and help maintain chromosomal integrity. Their shortening is caused by inflammation and oxidative stress within the cellular environment and ultimately leads to cellular senescence. Shortened leukocyte telomere length is hypothesized to be a novel biomarker for age and age-related diseases, yet reports on its association with cardiometabolic outcomes in the literature are conflicting.<br><br>METHODS AND RESULTS: MEDLINE (1966 to present) and EMBASE (1980 to present) were last searched on September 9, 2013. Reference lists of retrieved citations were hand searched for relevant studies. No restrictions were placed on sample size, language, or publication type or date. Fifteen cohort and 12 case-control studies reporting the association between leukocyte telomere length and stroke, myocardial infarction, and type 2 diabetes mellitus were independently selected for inclusion by 2 reviewers. Data extraction and risk of bias assessment were completed independently by 2 reviewers using predefined criteria. Studies were pooled using the generic inverse variance method and both fixed and random effects models. A 1-SD decrease in leukocyte telomere length was significantly associated with stroke (odds ratio, 1.21; 95% confidence interval, 1.06-1.37; I(2)=61%), myocardial infarction (odds ratio, 1.24; 95% confidence interval, 1.04-1.47; I(2)=68%), and type 2 diabetes mellitus (odds ratio, 1.37; 95% confidence interval, 1.10-1.72; I(2)=91%). Stratification by measurement technique, study design, study size, and ethnicity explained heterogeneity in certain cardiometabolic outcomes.<br><br>CONCLUSIONS: Shortened leukocyte telomere length demonstrates a significant association with stroke, myocardial infarction, and type 2 diabetes mellitus. Larger, well-designed studies are needed to confirm these findings and explore sources of heterogeneity.},
}
@article {pmid25404302,
year = {2014},
author = {Xiang, Y and Miller, DE and Ross, EJ and Sánchez Alvarado, A and Hawley, RS},
title = {Synaptonemal complex extension from clustered telomeres mediates full-length chromosome pairing in Schmidtea mediterranea.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {111},
number = {48},
pages = {E5159-68},
pmid = {25404302},
issn = {1091-6490},
support = {R37 GM057260/GM/NIGMS NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Chromosome Pairing/*genetics ; DNA Breaks, Double-Stranded ; Endodeoxyribonucleases/genetics/metabolism ; Helminth Proteins/genetics/metabolism ; In Situ Hybridization, Fluorescence ; Male ; Meiotic Prophase I/genetics ; Molecular Sequence Data ; Nuclear Proteins/genetics/metabolism ; Pachytene Stage/genetics ; Planarians/*genetics/metabolism ; RNA Interference ; Rad51 Recombinase/genetics/metabolism ; Sequence Homology, Amino Acid ; Spermatocytes/metabolism ; Synaptonemal Complex/*genetics/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {In the 1920s, József Gelei proposed that chromosome pairing in flatworms resulted from the formation of a telomere bouquet followed by the extension of synapsis from telomeres at the base of the bouquet, thus facilitating homolog pairing in a processive manner. A modern interpretation of Gelei's model postulates that the synaptonemal complex (SC) is nucleated close to the telomeres and then extends progressively along the full length of chromosome arms. We used the easily visible meiotic chromosomes, a well-characterized genome, and RNAi in the sexual biotype of the planarian Schmidtea mediterranea to test that hypothesis. By identifying and characterizing S. mediterranea homologs of genes encoding synaptonemal complex protein 1 (SYCP1), the topoisomerase-like protein SPO11, and RAD51, a key player in homologous recombination, we confirmed that SC formation begins near the telomeres and progresses along chromosome arms during zygotene. Although distal regions pair at the time of bouquet formation, pairing of a unique interstitial locus is not observed until the formation of full-length SC at pachytene. Moreover, neither full extension of the SC nor homologous pairing is dependent on the formation of double-strand breaks. These findings validate Gelei's speculation that full-length pairing of homologous chromosomes is mediated by the extension of the SC formed near the telomeres. S. mediterranea thus becomes the first organism described (to our knowledge) that forms a canonical telomere bouquet but does not require double-strand breaks for synapsis between homologous chromosomes. However, the initiation of SC formation at the base of the telomere bouquet, which then is followed by full-length homologous pairing in planarian spermatocytes, is not observed in other species and may not be conserved.},
}
@article {pmid25403178,
year = {2014},
author = {Robin, JD and Ludlow, AT and Batten, K and Magdinier, F and Stadler, G and Wagner, KR and Shay, JW and Wright, WE},
title = {Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances.},
journal = {Genes &amp; development},
volume = {28},
number = {22},
pages = {2464-2476},
pmid = {25403178},
issn = {1549-5477},
support = {AG01228/AG/NIA NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; P50CA70907/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; C06 RR030414/RR/NCRR NIH HHS/United States ; C06 RR30414/RR/NCRR NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; },
mesh = {Cells, Cultured ; Chromatin/metabolism ; Gene Expression Profiling ; *Gene Expression Regulation ; Humans ; Myoblasts/cytology ; Telomere/*genetics/*metabolism ; Telomere Shortening/*genetics ; },
abstract = {While global chromatin conformation studies are emerging, very little is known about the chromatin conformation of human telomeres. Most studies have focused on the role of telomeres as a tumor suppressor mechanism. Here we describe how telomere length regulates gene expression long before telomeres become short enough to produce a DNA damage response (senescence). We directly mapped the interactions adjacent to specific telomere ends using a Hi-C (chromosome capture followed by high-throughput sequencing) technique modified to enrich for specific genomic regions. We demonstrate that chromosome looping brings the telomere close to genes up to 10 Mb away from the telomere when telomeres are long and that the same loci become separated when telomeres are short. Furthermore, expression array analysis reveals that many loci, including noncoding RNAs, may be regulated by telomere length. We report three genes (ISG15 [interferon-stimulated gene 15 kd], DSP [Desmoplakin], and C1S [complement component 1s subcomplement]) located at three different subtelomeric ends (1p, 6p, and 12p) whose expressions are altered with telomere length. Additionally, we confirmed by in situ analysis (3D-FISH [three-dimensional fluorescence in situ hybridization]) that chromosomal looping occurs between the loci of those genes and their respective telomere ends. We term this process TPE-OLD for "telomere position effect over long distances." Our results suggest a potential novel mechanism for how telomere shortening could contribute to aging and disease initiation/progression in human cells long before the induction of a critical DNA damage response.},
}
@article {pmid25403176,
year = {2014},
author = {Misteli, T},
title = {The long reach of telomeres.},
journal = {Genes &amp; development},
volume = {28},
number = {22},
pages = {2445-2446},
pmid = {25403176},
issn = {1549-5477},
mesh = {*Gene Expression Regulation ; Humans ; Telomere/*genetics/*metabolism ; Telomere Shortening/*genetics ; },
abstract = {The primary purpose of telomeres is to protect chromosome ends from erosion during cell division cycles. New observations suggest an additional function for telomeres, namely in gene silencing via formation of long-range chromatin interactions.},
}
@article {pmid25399515,
year = {2014},
author = {Li, Z and Tang, J and Li, H and Chen, S and He, Y and Liao, Y and Wei, Z and Wan, G and Xiang, X and Xia, K and Chen, X},
title = {Shorter telomere length in peripheral blood leukocytes is associated with childhood autism.},
journal = {Scientific reports},
volume = {4},
number = {},
pages = {7073},
pmid = {25399515},
issn = {2045-2322},
mesh = {Autistic Disorder/blood/*genetics/pathology ; Child ; Child, Preschool ; Female ; Humans ; Leukocytes/*pathology/ultrastructure ; Male ; Telomere/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Telomeres are protective chromosomal structures that play a key role in preserving genomic stability. Epidemiologic studies have shown that the abnormal telomere length in leukocytes is associated with some mental disorders and age-related diseases. However, the association between leukocyte telomere length and autism has not been investigated. Here we investigated the possible association between relative telomere length (RTL) in peripheral blood leukocytes and childhood autism by using an established real-time polymerase chain reaction method. We observed significantly shorter RTL in patients with childhood autism than in controls (p = 0.006). Individuals with shorter RTL had a significantly increased presence of childhood autism compared with those who had long RTL. In patients, we found that family training interventions have a significant effect on telomere length (P = 0.012), but no correlations between RTL and clinical features (paternal age, maternal age, age of onset, illness of duration, CARS score and ABC score) were observed in this study. These results provided the first evidence that shorter leukocytes telomere length is significantly associated with childhood autism. The molecular mechanism underlying telomere length may be implicated in the development of autism.},
}
@article {pmid25398909,
year = {2015},
author = {Lorenzi, LE and Bah, A and Wischnewski, H and Shchepachev, V and Soneson, C and Santagostino, M and Azzalin, CM},
title = {Fission yeast Cactin restricts telomere transcription and elongation by controlling Rap1 levels.},
journal = {The EMBO journal},
volume = {34},
number = {1},
pages = {115-129},
pmid = {25398909},
issn = {1460-2075},
mesh = {Chromosome Aberrations ; Chromosomes, Fungal/genetics/*metabolism ; Gene Deletion ; Nuclear Proteins/genetics/*metabolism ; Protein Stability ; RNA Splicing/physiology ; RNA, Fungal/genetics/metabolism ; RNA, Messenger/genetics/metabolism ; Retroelements/physiology ; Schizosaccharomyces/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/metabolism ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Transcription, Genetic/*physiology ; },
abstract = {The telomeric transcriptome comprises multiple long non-coding RNAs generated by transcription of linear chromosome ends. In a screening performed in Schizosaccharomyces pombe, we identified factors modulating the cellular levels of the telomeric transcriptome. Among these factors, Cay1 is the fission yeast member of the conserved family of Cactins, uncharacterized proteins crucial for cell growth and survival. In cay1∆ mutants, the cellular levels of the telomeric factor Rap1 are drastically diminished due to defects in rap1+ pre-mRNA splicing and Rap1 protein stability. cay1∆ cells accumulate histone H3 acetylated at lysine 9 at telomeres, which become transcriptionally desilenced, are over-elongated by telomerase and cause chromosomal aberrations in the cold. Overexpressing Rap1 in cay1+ deleted cells significantly reverts all telomeric defects. Additionally, cay1∆ mutants accumulate unprocessed Tf2 retrotransposon RNA through Rap1-independent mechanisms. Thus, Cay1 plays crucial roles in cells by ultimately harmonizing expression of transcripts originating from seemingly unrelated genomic loci.},
}
@article {pmid25393420,
year = {2015},
author = {George, G and Rosas, IO and Cui, Y and McKane, C and Hunninghake, GM and Camp, PC and Raby, BA and Goldberg, HJ and El-Chemaly, S},
title = {Short telomeres, telomeropathy, and subclinical extrapulmonary organ damage in patients with interstitial lung disease.},
journal = {Chest},
volume = {147},
number = {6},
pages = {1549-1557},
pmid = {25393420},
issn = {1931-3543},
support = {U01HL105371/HL/NHLBI NIH HHS/United States ; U01 HL105371/HL/NHLBI NIH HHS/United States ; P01HL114501/HL/NHLBI NIH HHS/United States ; R01 HL111024/HL/NHLBI NIH HHS/United States ; R21 HL119902/HL/NHLBI NIH HHS/United States ; P01 HL114501/HL/NHLBI NIH HHS/United States ; R21 HL119902-01/HL/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Biopsy ; Blood Cell Count ; Bone Marrow/*pathology ; Cohort Studies ; Female ; Humans ; Liver/*pathology ; Liver Function Tests ; Lung Diseases, Interstitial/blood/*pathology ; Lung Transplantation ; Male ; Middle Aged ; Mutation/genetics ; Patient Selection ; Prospective Studies ; Retrospective Studies ; Telomerase/genetics ; Telomere/*enzymology/genetics/*pathology ; },
abstract = {BACKGROUND: Human telomere disease consists of a wide spectrum of disorders, including pulmonary, hepatic, and bone marrow abnormalities. The extent of bone marrow and liver abnormalities in patients with interstitial lung disease (ILD) and short telomeres is unknown.<br><br>METHODS: The lung transplant clinic established a prospective protocol to identify short telomeres in patients with ILD not related to connective tissue disease or sarcoidosis. Patients with short telomeres underwent bone marrow biopsies, liver biopsies, or both as part of the evaluation for transplant candidacy.<br><br>RESULTS: One hundred twenty-seven patients met ILD categorization for inclusion. Thirty were suspected to have short telomeres, and 15 had the diagnosis confirmed. Eight of 13 (53%) patients had bone marrow abnormalities. Four patients had hypocellular marrow associated with macrocytosis and relatively normal blood counts, which resulted in changes to planned immunosuppression at the time of transplant. Four patients with more severe hematologic abnormalities were not listed because of myelodysplastic syndrome (two); monoclonal gammopathy of unclear significance (one); and hypocellular marrow, decreased megakaryocyte lineage associated with thrombocytopenia (one). Seven patients underwent liver biopsies, and six had abnormal liver pathology. These abnormalities did not affect listing for lung transplant, and liver biopsies are no longer routinely obtained.<br><br>CONCLUSIONS: Subclinical bone marrow and liver abnormalities can be seen in patients with ILD and short telomeres, in some cases in the absence of clinically significant abnormalities in peripheral blood counts and liver function tests. A larger study examining the implication of these findings on the outcome of patients with ILD and short telomeres is needed.},
}
@article {pmid25393133,
year = {2016},
author = {Schutte, NS and Malouff, JM},
title = {The Relationship Between Perceived Stress and Telomere Length: A Meta-analysis.},
journal = {Stress and health : journal of the International Society for the Investigation of Stress},
volume = {32},
number = {4},
pages = {313-319},
doi = {10.1002/smi.2607},
pmid = {25393133},
issn = {1532-2998},
mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Stress, Psychological/*genetics ; Telomere/*genetics ; },
abstract = {Telomeres protect the ends of chromosomes, and short telomere length is associated with poor health and mortality. This study reports a meta-analytic investigation of the relationship between perceived stress and telomere length, including results from eight studies with a total of 1143 participants. A meta-analytic effect size of r = -0.25, p < 0.001, indicated that higher levels of perceived stress were associated with shorter telomere length. Examination of the studies for moderators of effect size identified some significant moderators, such as a difference in effect sizes between samples comprised of only women and mixed-sex samples. These results are only suggestive as they are based on a small set of studies, and funnel plot analyses indicated a publication bias. A significant relationship between more perceived stress and shorter telomere length is consistent with theoretical frameworks positing that stress induces physiological changes that result in shortened telomeres. Copyright © 2014 John Wiley &amp; Sons, Ltd.},
}
@article {pmid25392421,
year = {2015},
author = {Huang, Z and Ma, L and Wang, Y and Pan, Z and Ren, J and Liu, Z and Xue, Y},
title = {MiCroKiTS 4.0: a database of midbody, centrosome, kinetochore, telomere and spindle.},
journal = {Nucleic acids research},
volume = {43},
number = {Database issue},
pages = {D328-34},
pmid = {25392421},
issn = {1362-4962},
mesh = {Animals ; *Cell Division ; Centrosome/*chemistry ; *Databases, Protein ; Humans ; Internet ; Kinetochores/*chemistry ; Mice ; Proteins/analysis ; Spindle Apparatus/*chemistry ; Telomere/*chemistry ; },
abstract = {We reported an updated database of MiCroKiTS 4.0 (http://microkit.biocuckoo.org) for proteins temporally and spatially localized in distinct subcellular positions including midbody, centrosome, kinetochore, telomere and mitotic spindle during cell division/mitosis. The database was updated from our previously developed database of MiCroKit 3.0, which contained 1489 proteins mostly forming super-complexes at midbody, centrosome and kinetochore from seven eukaryotes. Since the telomere and spindle apparatus are critical for cell division, the proteins localized at the two positions were also integrated. From the scientific literature, we curated 1872 experimentally identified proteins which at least locate in one of the five positions from eight species. Then the ortholog detection was performed to identify potential MiCroKiTS proteins from 144 eukaryotic organisms, which contains 66, 45 and 33 species of animals, fungi and plants, respectively. In total, 87,983 unique proteins with corresponding localization information were integrated into the database. The primary references of experimentally identified localizations were provided and the fluorescence microscope figures for the localizations of human proteins were shown. The orthologous relations between predicted and experimental localizations were also present. Taken together, we anticipate the database can serve as a useful resource for further analyzing the molecular mechanisms during cell division.},
}
@article {pmid25390655,
year = {2014},
author = {Willeit, P and Raschenberger, J and Heydon, EE and Tsimikas, S and Haun, M and Mayr, A and Weger, S and Witztum, JL and Butterworth, AS and Willeit, J and Kronenberg, F and Kiechl, S},
title = {Leucocyte telomere length and risk of type 2 diabetes mellitus: new prospective cohort study and literature-based meta-analysis.},
journal = {PloS one},
volume = {9},
number = {11},
pages = {e112483},
pmid = {25390655},
issn = {1932-6203},
support = {MR/L003120/1/MRC_/Medical Research Council/United Kingdom ; RG/08/014/24067/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Adult ; Age Factors ; Aged ; Alcohol Drinking/physiopathology ; Body Mass Index ; C-Reactive Protein/metabolism ; Cholesterol, HDL/blood ; Diabetes Mellitus, Type 2/*genetics/metabolism/pathology ; Female ; Humans ; Leukocytes/*metabolism/pathology ; Male ; Middle Aged ; Motor Activity ; Proportional Hazards Models ; Prospective Studies ; Risk Factors ; Sex Factors ; Social Class ; Telomere/*chemistry/metabolism ; *Telomere Shortening ; Waist-Hip Ratio ; },
abstract = {BACKGROUND: Short telomeres have been linked to various age-related diseases. We aimed to assess the association of telomere length with incident type 2 diabetes mellitus (T2DM) in prospective cohort studies.<br><br>METHODS: Leucocyte relative telomere length (RTL) was measured using quantitative polymerase chain reaction in 684 participants of the prospective population-based Bruneck Study (1995 baseline), with repeat RTL measurements performed in 2005 (n = 558) and 2010 (n = 479). Hazard ratios for T2DM were calculated across quartiles of baseline RTL using Cox regression models adjusted for age, sex, body-mass index, smoking, socio-economic status, physical activity, alcohol consumption, high-density lipoprotein cholesterol, log high-sensitivity C-reactive protein, and waist-hip ratio. Separate analyses corrected hazard ratios for within-person variability using multivariate regression calibration of repeated measurements. To contextualise findings, we systematically sought PubMed, Web of Science and EMBASE for relevant articles and pooled results using random-effects meta-analysis.<br><br>RESULTS: Over 15 years of follow-up, 44 out of 606 participants free of diabetes at baseline developed incident T2DM. The adjusted hazard ratio for T2DM comparing the bottom vs. the top quartile of baseline RTL (i.e. shortest vs. longest) was 2.00 (95% confidence interval: 0.90 to 4.49; P = 0.091), and 2.31 comparing the bottom quartile vs. the remainder (1.21 to 4.41; P = 0.011). The corresponding hazard ratios corrected for within-person RTL variability were 3.22 (1.27 to 8.14; P = 0.014) and 2.86 (1.45 to 5.65; P = 0.003). In a random-effects meta-analysis of three prospective cohort studies involving 6,991 participants and 2,011 incident T2DM events, the pooled relative risk was 1.31 (1.07 to 1.60; P = 0.010; I2 = 69%).<br><br>CONCLUSIONS/INTERPRETATION: Low RTL is independently associated with the risk of incident T2DM. To avoid regression dilution biases in observed associations of RTL with disease risk, future studies should implement methods correcting for within-person variability in RTL. The causal role of short telomeres in T2DM development remains to be determined.},
}
@article {pmid25389173,
year = {2014},
author = {Baranasic, D and Oppermann, T and Cheaib, M and Cullum, J and Schmidt, H and Simon, M},
title = {Genomic characterization of variable surface antigens reveals a telomere position effect as a prerequisite for RNA interference-mediated silencing in Paramecium tetraurelia.},
journal = {mBio},
volume = {5},
number = {6},
pages = {e01328},
pmid = {25389173},
issn = {2150-7511},
mesh = {Adaptation, Biological ; Adaptation, Physiological ; Antigenic Variation/*genetics ; Antigens, Surface/*genetics ; Evolution, Molecular ; Gene Duplication ; *Gene Expression ; Gene Expression Profiling ; *Gene Silencing ; Molecular Sequence Data ; Multigene Family ; Paramecium tetraurelia/*genetics/immunology ; *RNA Interference ; RNA-Dependent RNA Polymerase/genetics/metabolism ; Sequence Analysis, DNA ; *Telomere ; },
abstract = {UNLABELLED: Antigenic or phenotypic variation is a widespread phenomenon of expression of variable surface protein coats on eukaryotic microbes. To clarify the mechanism behind mutually exclusive gene expression, we characterized the genetic properties of the surface antigen multigene family in the ciliate Paramecium tetraurelia and the epigenetic factors controlling expression and silencing. Genome analysis indicated that the multigene family consists of intrachromosomal and subtelomeric genes; both classes apparently derive from different gene duplication events: whole-genome and intrachromosomal duplication. Expression analysis provides evidence for telomere position effects, because only subtelomeric genes follow mutually exclusive transcription. Microarray analysis of cultures deficient in Rdr3, an RNA-dependent RNA polymerase, in comparison to serotype-pure wild-type cultures, shows cotranscription of a subset of subtelomeric genes, indicating that the telomere position effect is due to a selective occurrence of Rdr3-mediated silencing in subtelomeric regions. We present a model of surface antigen evolution by intrachromosomal gene duplication involving the maintenance of positive selection of structurally relevant regions. Further analysis of chromosome heterogeneity shows that alternative telomere addition regions clearly affect transcription of closely related genes. Consequently, chromosome fragmentation appears to be of crucial importance for surface antigen expression and evolution. Our data suggest that RNAi-mediated control of this genetic network by trans-acting RNAs allows rapid epigenetic adaptation by phenotypic variation in combination with long-term genetic adaptation by Darwinian evolution of antigen genes.<br><br>IMPORTANCE: Alternating surface protein structures have been described for almost all eukaryotic microbes, and a broad variety of functions have been described, such as virulence factors, adhesion molecules, and molecular camouflage. Mechanisms controlling gene expression of variable surface proteins therefore represent a powerful tool for rapid phenotypic variation across kingdoms in pathogenic as well as free-living eukaryotic microbes. However, the epigenetic mechanisms controlling synchronous expression and silencing of individual genes are hardly understood. Using the ciliate Paramecium tetraurelia as a (epi)genetic model, we showed that a subtelomeric gene position effect is associated with the selective occurrence of RNAi-mediated silencing of silent surface protein genes, suggesting small interfering RNA (siRNA)-mediated epigenetic cross talks between silent and active surface antigen genes. Our integrated genomic and molecular approach discloses the correlation between gene position effects and siRNA-mediated trans-silencing, thus providing two new parameters for regulation of mutually exclusive gene expression and the genomic organization of variant gene families.},
}
@article {pmid25387524,
year = {2014},
author = {Shen, ZJ and Hsu, PH and Su, YT and Yang, CW and Kao, L and Tseng, SF and Tsai, MD and Teng, SC},
title = {PP2A and Aurora differentially modify Cdc13 to promote telomerase release from telomeres at G2/M phase.},
journal = {Nature communications},
volume = {5},
number = {},
pages = {5312},
doi = {10.1038/ncomms6312},
pmid = {25387524},
issn = {2041-1723},
mesh = {Aurora Kinases/metabolism/*physiology ; Cell Division/*physiology ; G2 Phase/*physiology ; Protein Phosphatase 2/metabolism/*physiology ; Saccharomyces cerevisiae Proteins/metabolism/*physiology ; Telomerase/metabolism/*physiology ; Telomere/metabolism/*physiology ; Telomere-Binding Proteins/metabolism/*physiology ; },
abstract = {In yeast, the initiation of telomere replication at the late S phase involves in combined actions of kinases on Cdc13, the telomere binding protein. Cdc13 recruits telomerase to telomeres through its interaction with Est1, a component of telomerase. However, how cells terminate the function of telomerase at G2/M is still elusive. Here we show that the protein phosphatase 2A (PP2A) subunit Pph22 and the yeast Aurora kinase homologue Ipl1 coordinately inhibit telomerase at G2/M by dephosphorylating and phosphorylating the telomerase recruitment domain of Cdc13, respectively. While Pph22 removes Tel1/Mec1-mediated Cdc13 phosphorylation to reduce Cdc13-Est1 interaction, Ipl1-dependent Cdc13 phosphorylation elicits dissociation of Est1-TLC1, the template RNA component of telomerase. Failure of these regulations prevents telomerase from departing telomeres, causing perturbed telomere lengthening and prolonged M phase. Together our results demonstrate that differential and additive actions of PP2A and Aurora on Cdc13 limit telomerase action by removing active telomerase from telomeres at G2/M phase.},
}
@article {pmid25381796,
year = {2014},
author = {Roberts, JD and Dewland, TA and Longoria, J and Fitzpatrick, AL and Ziv, E and Hu, D and Lin, J and Glidden, DV and Psaty, BM and Burchard, EG and Blackburn, EH and Olgin, JE and Heckbert, SR and Marcus, GM},
title = {Telomere length and the risk of atrial fibrillation: insights into the role of biological versus chronological aging.},
journal = {Circulation. Arrhythmia and electrophysiology},
volume = {7},
number = {6},
pages = {1026-1032},
pmid = {25381796},
issn = {1941-3084},
support = {U01 HL080295/HL/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; R01 HL080698/HL/NHLBI NIH HHS/United States ; N01HC55222/HL/NHLBI NIH HHS/United States ; N01HC85086/HL/NHLBI NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; R01 HL102214/HL/NHLBI NIH HHS/United States ; R01 HL080295/HL/NHLBI NIH HHS/United States ; R01 AA022222/AA/NIAAA NIH HHS/United States ; HL102214/HL/NHLBI NIH HHS/United States ; HHSN268200800007C//PHS HHS/United States ; N01HC85082/HL/NHLBI NIH HHS/United States ; N01HC85083/HL/NHLBI NIH HHS/United States ; HHSN268201200036C//PHS HHS/United States ; HL080295/HL/NHLBI NIH HHS/United States ; N01HC85079/HL/NHLBI NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; N01HC85080/HL/NHLBI NIH HHS/United States ; AG023629/AG/NIA NIH HHS/United States ; R56 AG023629/AG/NIA NIH HHS/United States ; R01 HL80698-01/HL/NHLBI NIH HHS/United States ; N01HC85081/HL/NHLBI NIH HHS/United States ; N01 HC55222/HC/NHLBI NIH HHS/United States ; },
mesh = {Age Factors ; Aged ; Aging/*genetics ; Atrial Fibrillation/diagnosis/epidemiology/*genetics/surgery ; California/epidemiology ; Cardiac Surgical Procedures ; *Cellular Senescence ; Cross-Sectional Studies ; Female ; Genetic Predisposition to Disease ; Humans ; Incidence ; Leukocytes/*chemistry ; Male ; Phenotype ; *Polymorphism, Single Nucleotide ; Prospective Studies ; Risk Assessment ; Risk Factors ; Telomerase/*genetics/metabolism ; Telomere/*genetics ; Time Factors ; },
abstract = {BACKGROUND: Advanced age is the most important risk factor for atrial fibrillation (AF); however, the mechanism remains unknown. Telomeres, regions of DNA that shorten with cell division, are considered reliable markers of biological aging. We sought to examine the association between leukocyte telomere length (LTL) and incident AF in a large population-based cohort using direct LTL measurements and genetic data. To further explore our findings, we compared atrial cell telomere length and LTL in cardiac surgery patients.<br><br>METHODS AND RESULTS: Mean LTL and the TERT rs2736100 single nucleotide polymorphism were assessed as predictors of incident AF in the Cardiovascular Health Study (CHS). Among the surgical patients, within subject comparison of atrial cell telomere length versus LTL was assessed. Among 1639 CHS participants, we observed no relationship between mean LTL and incident AF before and after adjustment for potential confounders (adjusted hazard ratio, 1.09; 95% confidence interval: 0.92-1.29; P=0.299); chronologic age remained strongly associated with AF in the same model. No association was observed between the TERT rs2736100 single nucleotide polymorphism and incident AF (adjusted hazard ratio: 0.95; 95% confidence interval: 0.88-1.04; P=0.265). In 35 cardiac surgery patients (26 with AF), atrial cell telomere length was longer than LTL (1.19 &#xb1; 0.20 versus 1.02 &#xb1; 0.25 [T/S ratio], P<0.001), a finding that remained consistent within the AF subgroup.<br><br>CONCLUSIONS: Our study revealed no evidence of an association between LTL and incident AF and no evidence of relative atrial cell telomere shortening in AF. Chronological aging independent of biological markers of aging is the primary risk factor for AF.},
}
@article {pmid25381775,
year = {2014},
author = {Zong, S and Wang, Z and Chen, H and Cui, Y},
title = {Assessing telomere length using surface enhanced Raman scattering.},
journal = {Scientific reports},
volume = {4},
number = {},
pages = {6977},
pmid = {25381775},
issn = {2045-2322},
mesh = {HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Spectrum Analysis, Raman/*methods ; Telomere/genetics/*metabolism ; },
abstract = {Telomere length can provide valuable insight into telomeres and telomerase related diseases, including cancer. Here, we present a brand-new optical telomere length measurement protocol using surface enhanced Raman scattering (SERS). In this protocol, two single strand DNA are used as SERS probes. They are labeled with two different Raman molecules and can specifically hybridize with telomeres and centromere, respectively. First, genome DNA is extracted from cells. Then the telomere and centromere SERS probes are added into the genome DNA. After hybridization with genome DNA, excess SERS probes are removed by magnetic capturing nanoparticles. Finally, the genome DNA with SERS probes attached is dropped onto a SERS substrate and subjected to SERS measurement. Longer telomeres result in more attached telomere probes, thus a stronger SERS signal. Consequently, SERS signal can be used as an indicator of telomere length. Centromere is used as the inner control. By calibrating the SERS intensity of telomere probe with that of the centromere probe, SERS based telomere measurement is realized. This protocol does not require polymerase chain reaction (PCR) or electrophoresis procedures, which greatly simplifies the detection process. We anticipate that this easy-operation and cost-effective protocol is a fine alternative for the assessment of telomere length.},
}
@article {pmid25380821,
year = {2015},
author = {Viera, A and Alsheimer, M and Gómez, R and Berenguer, I and Ortega, S and Symonds, CE and Santamaría, D and Benavente, R and Suja, JA},
title = {CDK2 regulates nuclear envelope protein dynamics and telomere attachment in mouse meiotic prophase.},
journal = {Journal of cell science},
volume = {128},
number = {1},
pages = {88-99},
doi = {10.1242/jcs.154922},
pmid = {25380821},
issn = {1477-9137},
mesh = {Animals ; Cell Cycle Proteins/genetics ; Cyclin-Dependent Kinase 2/genetics/*metabolism ; Cytoskeletal Proteins ; Laminin/genetics/metabolism ; Male ; Meiotic Prophase I/*physiology ; Mice ; Mice, Knockout ; Microtubule-Associated Proteins/genetics/metabolism ; Nuclear Envelope/genetics/*metabolism ; Nuclear Proteins/genetics ; Phosphorylation/physiology ; Spermatocytes/cytology/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {In most organisms, telomeres attach to the nuclear envelope at the onset of meiosis to promote the crucial processes of pairing, recombination and synapsis during prophase I. This attachment of meiotic telomeres is mediated by the specific distribution of several nuclear envelope components that interact with the attachment plates of the synaptonemal complex. We have determined by immunofluorescence and electron microscopy that the ablation of the kinase CDK2 alters the nuclear envelope in mouse spermatocytes, and that the proteins SUN1, KASH5 (also known as CCDC155) and lamin C2 show an abnormal cap-like distribution facing the centrosome. Strikingly, some telomeres are not attached to the nuclear envelope but remain at the nuclear interior where they are associated with SUN1 and with nuclear-envelope-detached vesicles. We also demonstrate that mouse testis CDK2 phosphorylates SUN1 in vitro. We propose that during mammalian prophase I the kinase CDK2 is a key factor governing the structure of the nuclear envelope and the telomere-led chromosome movements essential for homolog pairing.},
}
@article {pmid25379018,
year = {2014},
author = {Tanaka, H and Beam, MJ and Caruana, K},
title = {The presence of telomere fusion in sporadic colon cancer independently of disease stage, TP53/KRAS mutation status, mean telomere length, and telomerase activity.},
journal = {Neoplasia (New York, N.Y.)},
volume = {16},
number = {10},
pages = {814-823},
pmid = {25379018},
issn = {1476-5586},
support = {P30 CA082709/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Colonic Neoplasms/*genetics/*pathology ; Female ; Humans ; Lymph Nodes/pathology ; Lymphatic Metastasis/genetics ; Male ; Middle Aged ; Mutation ; Proto-Oncogene Proteins/*genetics ; Proto-Oncogene Proteins p21(ras) ; Telomerase/genetics/*metabolism ; Telomere/genetics/*pathology ; Telomere Shortening ; Tumor Suppressor Protein p53/*genetics ; ras Proteins/*genetics ; },
abstract = {Defects in telomere maintenance can result in telomere fusions that likely play a causative role in carcinogenesis by promoting genomic instability. However, this proposition remains to be fully understood in human colon carcinogenesis. In the present study, the temporal sequence of telomere dysfunction dynamics was delineated by analyzing telomere fusion, telomere length, telomerase activity, hotspot mutations in KRAS or BRAF, and TP53 of tissue samples obtained from 18 colon cancer patients. Our results revealed that both the deficiency of p53 and the shortening of mean telomere length were not necessary for producing telomere fusions in colon tissue. In five cases, telomere fusion was observed even in tissue adjacent to cancerous lesions, suggesting that genomic instability is initiated in pathologically non-cancerous lesions. The extent of mean telomere attrition increased with lymph node invasiveness of tumors, implying that mean telomere shortening correlates with colon cancer progression. Telomerase activity was relatively higher in most cancer tissues containing mutation(s) in KRAS or BRAF and/or TP53 compared to those without these hotspot mutations, suggesting that telomerase could become fully active at the late stage of colon cancer development. Interestingly, the majority of telomere fusion junctions in colon cancer appeared to be a chromatid-type containing chromosome 7q or 12q. In sum, this meticulous correlative study not only highlights the concept that telomere fusion is present in the early stages of cancer regardless of TP53/KRAS mutation status, mean telomere length, and telomerase activity, but also provides additional insights targeting key telomere fusion junctions which may have significant implications for colon cancer diagnoses.},
}
@article {pmid25375789,
year = {2014},
author = {Churikov, D and Charifi, F and Simon, MN and Géli, V},
title = {Rad59-facilitated acquisition of Y' elements by short telomeres delays the onset of senescence.},
journal = {PLoS genetics},
volume = {10},
number = {11},
pages = {e1004736},
pmid = {25375789},
issn = {1553-7404},
mesh = {Aging/*genetics ; DNA-Binding Proteins/*genetics/metabolism ; Rad51 Recombinase/genetics/metabolism ; Rad52 DNA Repair and Recombination Protein/*genetics/metabolism ; *Recombination, Genetic ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Telomerase/genetics ; Telomere/*genetics ; Telomere Shortening/genetics ; },
abstract = {Telomerase-negative yeasts survive via one of the two Rad52-dependent recombination pathways, which have distinct genetic requirements. Although the telomere pattern of type I and type II survivors is well characterized, the mechanistic details of short telomere rearrangement into highly evolved pattern observed in survivors are still missing. Here, we analyze immediate events taking place at the abruptly shortened VII-L and native telomeres. We show that short telomeres engage in pairing with internal Rap1-bound TG1-3-like tracts present between subtelomeric X and Y' elements, which is followed by BIR-mediated non-reciprocal translocation of Y' element and terminal TG1-3 repeats from the donor end onto the shortened telomere. We found that choice of the Y' donor was not random, since both engineered telomere VII-L and native VI-R acquired Y' elements from partially overlapping sets of specific chromosome ends. Although short telomere repair was associated with transient delay in cell divisions, Y' translocation on native telomeres did not require Mec1-dependent checkpoint. Furthermore, the homeologous pairing between the terminal TG1-3 repeats at VII-L and internal repeats on other chromosome ends was largely independent of Rad51, but instead it was facilitated by Rad59 that stimulates Rad52 strand annealing activity. Therefore, Y' translocation events taking place during presenescence are genetically separable from Rad51-dependent Y' amplification process that occurs later during type I survivor formation. We show that Rad59-facilitated Y' translocations on X-only telomeres delay the onset of senescence while preparing ground for type I survivor formation.},
}
@article {pmid25368992,
year = {2014},
author = {Solomon, A and Tennakoon, S and Leeansyah, E and Arribas, J and Hill, A and Van Delft, Y and Moecklinghoff, C and Lewin, SR},
title = {No difference in the rate of change in telomere length or telomerase activity in HIV-infected patients after three years of darunavir/ritonavir with and without nucleoside analogues in the MONET trial.},
journal = {PloS one},
volume = {9},
number = {11},
pages = {e109718},
pmid = {25368992},
issn = {1932-6203},
support = {R56 AI095073/AI/NIAID NIH HHS/United States ; U19 AI096109/AI/NIAID NIH HHS/United States ; 1R56AI095073-01A1/AI/NIAID NIH HHS/United States ; },
mesh = {Adult ; Anti-HIV Agents/pharmacology/*therapeutic use ; Darunavir ; Drug Therapy, Combination ; Female ; HIV Infections/*drug therapy/pathology/virology ; HIV-1/genetics ; Humans ; Leukocytes, Mononuclear/metabolism ; Male ; Middle Aged ; Nucleosides/*chemistry/pharmacology/therapeutic use ; RNA, Viral/analysis ; Ritonavir/pharmacology/*therapeutic use ; Sulfonamides/pharmacology/*therapeutic use ; Telomerase/*metabolism ; Telomere/*drug effects/*metabolism ; },
abstract = {OBJECTIVE: To determine whether nucleos(t)ide reverse transcriptase inhibitors (NRTI) contribute to an accelerated loss in telomere length (TL) in HIV-infected patients on antiretroviral therapy (ART).<br><br>DESIGN: Substudy of randomised controlled trial.<br><br>METHODS: Patients with HIV RNA <50 copies/mL on combination ART (n = 256) were randomised to darunavir/ritonavir (DRV/r) 800/100 mg once daily, either as monotherapy (n = 127) or with 2 NRTIs (n = 129) for up to 144 weeks. TL and telomerase activity was quantified on stored peripheral blood mononuclear cells (PBMC; n = 124) using quantitative real time PCR.<br><br>RESULTS: Patients in the sub-study had a mean age of 44 years and had received NRTI for a mean of 6.4 years (range 1-20 years). As expected, older patients have significantly shorter TL (p = 0.006), while women had significantly longer TL (p = 0.026). There was no significant association between TL and either the duration of prior NRTI treatment (p = 0.894) or the use of a PI versus NNRTI (p = 0.107). There was no significant difference between patients who continued or ceased NRTI in the mean change/year of TL or telomerase (p = 0.580 and 0.280 respectively).<br><br>CONCLUSION: Continuation versus cessation of NRTI treatment was not associated with an accelerated loss in TL or telomerase activity.},
}
@article {pmid25367403,
year = {2015},
author = {Carlson, LE and Beattie, TL and Giese-Davis, J and Faris, P and Tamagawa, R and Fick, LJ and Degelman, ES and Speca, M},
title = {Mindfulness-based cancer recovery and supportive-expressive therapy maintain telomere length relative to controls in distressed breast cancer survivors.},
journal = {Cancer},
volume = {121},
number = {3},
pages = {476-484},
doi = {10.1002/cncr.29063},
pmid = {25367403},
issn = {1097-0142},
mesh = {Breast Neoplasms/*metabolism/psychology/*therapy ; Female ; Humans ; Hydrocortisone/metabolism ; Longitudinal Studies ; Meditation ; Middle Aged ; Mindfulness ; Psychotherapy/*methods ; Survivors/psychology ; Telomere/*metabolism ; Yoga ; },
abstract = {BACKGROUND: Group psychosocial interventions including mindfulness-based cancer recovery (MBCR) and supportive-expressive group therapy (SET) can help breast cancer survivors decrease distress and influence cortisol levels. Although telomere length (TL) has been associated with breast cancer prognosis, the impact of these two interventions on TL has not been studied to date.<br><br>METHODS: The objective of the current study was to compare the effects of MBCR and SET with a minimal intervention control condition (a 1-day stress management seminar) on TL in distressed breast cancer survivors in a randomized controlled trial. MBCR focused on training in mindfulness meditation and gentle Hatha yoga whereas SET focused on emotional expression and group support. The primary outcome measure was relative TL, the telomere/single-copy gene ratio, assessed before and after each intervention. Secondary outcomes were self-reported mood and stress symptoms.<br><br>RESULTS: Eighty-eight distressed breast cancer survivors with a diagnosis of stage I to III cancer (using the American Joint Committee on Cancer (AJCC) TNM staging system) who had completed treatment at least 3 months prior participated. Using analyses of covariance on a per-protocol sample, there were no differences noted between the MBCR and SET groups with regard to the telomere/single-copy gene ratio, but a trend effect was observed between the combined intervention group and controls (F [1,84], 3.82; P = .054; &#x3b7;(2) &#x2009;=&#x2009;.043); TL in the intervention group was maintained whereas it was found to decrease for control participants. There were no associations noted between changes in TL and changes in mood or stress scores over time.<br><br>CONCLUSIONS: Psychosocial interventions providing stress reduction and emotional support resulted in trends toward TL maintenance in distressed breast cancer survivors, compared with decreases in usual care.},
}
@article {pmid25366419,
year = {2015},
author = {Kuszel, L and Trzeciak, T and Richter, M and Czarny-Ratajczak, M},
title = {Osteoarthritis and telomere shortening.},
journal = {Journal of applied genetics},
volume = {56},
number = {2},
pages = {169-176},
pmid = {25366419},
issn = {2190-3883},
mesh = {Aging ; Animals ; Cartilage, Articular/pathology ; Chondrocytes/pathology ; Disease Models, Animal ; *Epigenesis, Genetic ; Humans ; Osteoarthritis/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Osteoarthritis is the most common disease of joints caused by degradation of articular cartilage and subchondral bone. It is classified as primary form with unknown cause and as secondary form with known etiology. Genetic and epigenetic factors interact with environmental factors and contribute to the development of primary osteoarthritis. Thus far, many polymorphisms associated with osteoarthritis have been identified and recent studies also indicate the involvement of epigenetic factors (e.g., telomere shortening) in the initiation of this disorder. Accelerated shortening of telomeres was detected in osteoarthritis and other age-related diseases. Studies revealed that telomere length is severely reduced in blood leukocytes and chondrocytes of patients with osteoarthritis, and this may contribute to the initiation and development of osteoarthritis, whose major cause is still unknown.},
}
@article {pmid25365256,
year = {2014},
author = {Pan, W and Cheng, G and Xing, H and Shi, J and Lu, C and Wei, J and Li, L and Zhou, C and Yuan, Q and Zhou, L and Yang, M},
title = {Leukocyte telomere length-related rs621559 and rs398652 genetic variants influence risk of HBV-related hepatocellular carcinoma.},
journal = {PloS one},
volume = {9},
number = {11},
pages = {e110863},
pmid = {25365256},
issn = {1932-6203},
mesh = {Adult ; Aged ; *Alleles ; Carcinoma, Hepatocellular/*etiology ; Case-Control Studies ; Female ; Gene Frequency ; Genetic Variation ; Genome-Wide Association Study ; Genotype ; Hepatitis B/*complications/*genetics ; *Hepatitis B virus ; Humans ; *Leukocytes ; Liver Neoplasms/*etiology ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Risk ; Risk Factors ; Telomere/*genetics ; },
abstract = {Recent genome-wide association studies (GWAS) have identified eleven leukocyte telomere length (LTL)-related single nucleotide polymorphisms (SNPs). Since LTL has been associated with risk of many malignancies, LTL-related SNPs may contribute to cancer susceptibility. To test this hypothesis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we genotyped these eleven LTL-related SNPs in a case-control set including 1186 HBV-related HCC cases, 508 chronic HBV carriers and 1308 healthy controls at the discovery stage. The associations of HCC risk with these SNPs were further confirmed in an independent case-control set. We found that 1p34.2 rs621559 and 14q21 rs398652 were significantly associated with HBV-related HCC risk (both P<0.005 after Bonferroni corrections). There was no significant difference of either rs621559 or rs398652 genotypes between chronic HBV carriers and healthy controls, demonstrating that the association was not due to predisposition to HBV infection. In the pooled analyses (1806 HBV-related HCC cases and 1954 controls), we observed a decreased HCC risk, 0.72-times, associated with the 1p34.2 rs621559 AA genotype compared to the GG genotype (P = 1.6×10(-6)). Additionally, there was an increased HCC risk, 1.27-fold, associated with the rs398652 GG genotype (P = 3.3×10(-6)). A statistical joint effect between the rs621559 GG and rs398652 GG genotypes may exist in elevating risk of HBV-related HCC. We show, for the first time, that rs398652 and rs621559 might be marker genetic variants for risk of HBV-related HCC in the Chinese population.},
}
@article {pmid25363232,
year = {2014},
author = {Franceschin, M and Nocioni, D and Biroccio, A and Micheli, E and Cacchione, S and Cingolani, C and Venditti, A and Zizza, P and Bianco, A and Altieri, A},
title = {Design and synthesis of a new dimeric xanthone derivative: enhancement of G-quadruplex selectivity and telomere damage.},
journal = {Organic &amp; biomolecular chemistry},
volume = {12},
number = {47},
pages = {9572-9582},
doi = {10.1039/c4ob01658k},
pmid = {25363232},
issn = {1477-0539},
mesh = {Antineoplastic Agents/chemical synthesis/*chemistry/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dimerization ; G-Quadruplexes/*drug effects ; Humans ; Molecular Docking Simulation ; Neoplasms/drug therapy/genetics/pathology ; Telomere/*drug effects ; Xanthones/chemical synthesis/*chemistry/*pharmacology ; },
abstract = {Following the results we previously reported on a series of xanthene and xanthone derivatives as G-quadruplex stabilizing ligands, in order to obtain a more selective compound with respect to the previous generation of derivatives, we decided to modify the structure of the core ligand, specifically its aromatic extension. In particular, here we report the design, synthesis and activity data of a new compound obtained by dimerization of the xanthene core (HELIXA4C). The reported results show that extension of the aromatic core and the increase of the number of polar side chains led to a great enhancement of G-quadruplex selectivity and telomere damage capability, as derived using ESI-MS evaluation, in vitro cancer screening and specific immunofluorescence assays.},
}
@article {pmid25359981,
year = {2014},
author = {Bertuch, AA},
title = {A new mutant at the end: TPP1, telomeres, and BMF.},
journal = {Blood},
volume = {124},
number = {18},
pages = {2757-2758},
doi = {10.1182/blood-2014-09-599688},
pmid = {25359981},
issn = {1528-0020},
mesh = {Bone Marrow/*pathology ; Bone Marrow Diseases/*genetics ; Female ; Germ-Line Mutation/*genetics ; Humans ; Inheritance Patterns/*genetics ; Male ; Serine Proteases/*genetics ; Shelterin Complex/*genetics ; Telomere/*metabolism ; Telomere-Binding Proteins/*genetics ; },
}
@article {pmid25359189,
year = {2014},
author = {Porro, A and Feuerhahn, S and Delafontaine, J and Riethman, H and Rougemont, J and Lingner, J},
title = {Functional characterization of the TERRA transcriptome at damaged telomeres.},
journal = {Nature communications},
volume = {5},
number = {},
pages = {5379},
pmid = {25359189},
issn = {2041-1723},
support = {P30 CA010815/CA/NCI NIH HHS/United States ; R21 CA177395/CA/NCI NIH HHS/United States ; R21 HG007205/HG/NHGRI NIH HHS/United States ; HG007205/HG/NHGRI NIH HHS/United States ; },
mesh = {DNA Damage ; Gene Expression Profiling ; HeLa Cells ; Histone Acetyltransferases/metabolism ; Humans ; Lysine Acetyltransferase 5 ; Methyltransferases/metabolism ; Protein Structure, Tertiary ; RNA, Long Noncoding/*metabolism ; Repressor Proteins/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; *Transcriptome ; Up-Regulation ; },
abstract = {Telomere deprotection occurs during tumorigenesis and aging upon telomere shortening or loss of the telomeric shelterin component TRF2. Deprotected telomeres undergo changes in chromatin structure and elicit a DNA damage response (DDR) that leads to cellular senescence. The telomeric long noncoding RNA TERRA has been implicated in modulating the structure and processing of deprotected telomeres. Here, we characterize the human TERRA transcriptome at normal and TRF2-depleted telomeres and demonstrate that TERRA upregulation is occurring upon depletion of TRF2 at all transcribed telomeres. TRF2 represses TERRA transcription through its homodimerization domain, which was previously shown to induce chromatin compaction and to prevent the early steps of DDR activation. We show that TERRA associates with SUV39H1 H3K9 histone methyltransferase, which promotes accumulation of H3K9me3 at damaged telomeres and end-to-end fusions. Altogether our data elucidate the TERRA landscape and defines critical roles for this RNA in the telomeric DNA damage response.},
}
@article {pmid25355508,
year = {2014},
author = {Pope-Varsalona, H and Liu, FJ and Guzik, L and Opresko, PL},
title = {Polymerase η suppresses telomere defects induced by DNA damaging agents.},
journal = {Nucleic acids research},
volume = {42},
number = {21},
pages = {13096-13109},
pmid = {25355508},
issn = {1362-4962},
support = {R01 ES022944/ES/NIEHS NIH HHS/United States ; R01ES022944/ES/NIEHS NIH HHS/United States ; 5P50CA121973/CA/NCI NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins/analysis ; Cell Line ; Cell Line, Transformed ; Cells, Cultured ; Chromium/toxicity ; Chromosome Aberrations ; *DNA Damage ; *DNA Repair ; DNA Replication/drug effects ; DNA-Directed DNA Polymerase/analysis/genetics/*physiology ; Humans ; Mutagens/toxicity ; Signal Transduction ; Telomere/drug effects/*enzymology/metabolism/radiation effects ; Ultraviolet Rays ; },
abstract = {Telomeres at chromosome ends are normally masked from proteins that signal and repair DNA double strand breaks (DSBs). Bulky DNA lesions can cause DSBs if they block DNA replication, unless they are bypassed by translesion (TLS) DNA polymerases. Here, we investigated roles for TLS polymerase η, (polη) in preserving telomeres following acute physical UVC exposure and chronic chemical Cr(VI) exposure, which both induce blocking lesions. We report that polη protects against cytotoxicity and replication stress caused by Cr(VI), similar to results with ultraviolet C light (UVC). Both exposures induce ataxia telangiectasia and Rad3-related (ATR) kinase and polη accumulation into nuclear foci and localization to individual telomeres, consistent with replication fork stalling at DNA lesions. Polη-deficient cells exhibited greater numbers of telomeres that co-localized with DSB response proteins after exposures. Furthermore, the genotoxic exposures induced telomere aberrations associated with failures in telomere replication that were suppressed by polη. We propose that polη's ability to bypass bulky DNA lesions at telomeres is critical for proper telomere replication following genotoxic exposures.},
}
@article {pmid25352948,
year = {2014},
author = {Lee, JH and Anver, M and Kost-Alimova, M and Protopopov, A and DePinho, RA and Rane, SG},
title = {Telomere dysfunction suppresses multiple endocrine neoplasia in mice.},
journal = {Genes &amp; cancer},
volume = {5},
number = {9-10},
pages = {306-319},
pmid = {25352948},
issn = {1947-6019},
support = {HHSN261200800001C/RC/CCR NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; },
abstract = {Multiple endocrine neoplasia (MEN) syndrome is typified by the occurrence of tumors in two or more hormonal tissues. Whereas the genetics of MEN syndrome is relatively well understood, the tumorigenic mechanisms for these cancers remain relatively obscure. The Cdk4 (R24C) mouse model develops highly penetrant pituitary tumors and endocrine pancreas adenomas, and, as such, this model is appropriate to gain insight into mechanisms underlying MEN. Using this model, here we provide evidence supporting an important role for telomerase in the pathogenesis of MEN. We observed increased aneuploidy in Cdk4 (R/R) fibroblasts along with significantly elevated telomerase activity and telomere length in Cdk4 (R/R) islets and embryonic fibroblasts. To better understand the role of telomerase, we generated Cdk4 (R24C) mice with inactivation of the mTERC locus, which codes for the essential RNA component of the enzyme telomerase (mTERC (-/-) Cdk4 (R/R) mice). Embryonic fibroblasts and islets derived from mTERC (-/-) Cdk4 (R/R) mice exhibit reduced telomere length and proliferative capacity. Further, mTERC (-/-) Cdk4 (R/R) fibroblasts display reduced transformation potential. Importantly, mTERC (-/-) Cdk4 (R/R) mice display significantly reduced spontaneous tumorigenesis. Strikingly, we observed dramatic suppression of pituitary tumors and endocrine pancreas adenomas in mTERC (-/-) Cdk4 (R/R) mice. Telomere dysfunction suppressed tumor initiation and increased latency of tumor development while not affecting the progression of established tumors. In summary, these results are suggestive of an important role for telomerase in tumor development in the Cdk4 (R24C) mouse model, specifically in the genesis of tumors in the pituitary and the endocrine pancreas.},
}
@article {pmid25351806,
year = {2015},
author = {Blackburn, NB and Charlesworth, JC and Marthick, JR and Tegg, EM and Marsden, KA and Srikanth, V and Blangero, J and Lowenthal, RM and Foote, SJ and Dickinson, JL},
title = {A retrospective examination of mean relative telomere length in the Tasmanian Familial Hematological Malignancies Study.},
journal = {Oncology reports},
volume = {33},
number = {1},
pages = {25-32},
pmid = {25351806},
issn = {1791-2431},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Female ; Hematologic Neoplasms/*genetics ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Risk Factors ; Tasmania ; *Telomere Shortening ; Young Adult ; },
abstract = {Telomere length has a biological link to cancer, with excessive telomere shortening leading to genetic instability and resultant malignant transformation. Telomere length is heritable and genetic variants determining telomere length have been identified. Telomere biology has been implicated in the development of hematological malignancies (HMs), therefore, closer examination of telomere length in HMs may provide further insight into genetic etiology of disease development and support for telomere length as a prognostic factor in HMs. We retrospectively examined mean relative telomere length in the Tasmanian Familial Hematological Malignancies Study using a quantitative PCR method on genomic DNA from peripheral blood samples. Fifty-five familial HM cases, 191 unaffected relatives of familial HM cases and 75 non-familial HM cases were compared with 758 population controls. Variance components modeling was employed to identify factors influencing variation in telomere length. Overall, HM cases had shorter mean relative telomere length (p=2.9×10-6) and this was observed across both familial and non-familial HM cases (p=2.2x10-4 and 2.2x10-5, respectively) as well as additional subgroupings of HM cases according to broad subtypes. Mean relative telomere length was also significantly heritable (62.6%; p=4.7x10-5) in the HM families in the present study. We present new evidence of significantly shorter mean relative telomere length in both familial and non-familial HM cases from the same population adding further support to the potential use of telomere length as a prognostic factor in HMs. Whether telomere shortening is the cause of or the result of HMs is yet to be determined, but as telomere length was found to be highly heritable in our HM families this suggests that genetics driving the variation in telomere length is related to HM disease risk.},
}
@article {pmid25346280,
year = {2015},
author = {Dai, J and Cai, H and Zhuang, Y and Wu, Y and Min, H and Li, J and Shi, Y and Gao, Q and Yi, L},
title = {Telomerase gene mutations and telomere length shortening in patients with idiopathic pulmonary fibrosis in a Chinese population.},
journal = {Respirology (Carlton, Vic.)},
volume = {20},
number = {1},
pages = {122-128},
doi = {10.1111/resp.12422},
pmid = {25346280},
issn = {1440-1843},
mesh = {Adult ; China ; Female ; Humans ; *Idiopathic Pulmonary Fibrosis/epidemiology/genetics ; Male ; Middle Aged ; Mutation ; RNA/*genetics ; Telomerase/*genetics ; Telomere/genetics ; *Telomere Shortening ; },
abstract = {BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is an age-related disease and the most common manifestation of telomere-mediated disorders.<br><br>METHODS: We collected detailed medical histories and DNA samples from 100 IPF patients seen at Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University. All patients had sporadic IPF, with no family history reported. We screened all patients for telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) variants, and measured their telomere lengths in lymphocytes.<br><br>RESULTS: Six novel telomerase gene mutations were identified in six IPF patients enrolled in the studies. They were two heterozygous mutations in TERC (257 G>A and 108 C>T) and four in TERT (R622H, T644M, V777L and F1032I). IPF patients with TERT/TERC mutations had significant thrombocytopaenia (160.167&#x2009;&#xb1;&#x2009;28.089&#x2009;&#xd7;&#x2009;10(9)) compared with the non-mutation groups (191.018&#x2009;&#xb1;&#x2009;71.187&#x2009;&#xd7;&#x2009;10(9), P&#x2009;=&#x2009;0.047). All IPF patients with TERT/TERC mutations had shortened telomeres (0.656&#x2009;&#xb1;&#x2009;0.125) compared with the patients lacking TERT/TERC mutations (1.080&#x2009;&#xb1;&#x2009;0.6819, P&#x2009;=&#x2009;0.0184). IPF patients lacking TERT or TERC mutations (1.080&#x2009;&#xb1;&#x2009;0.6819) had significantly shorter telomeres compared with age-matched healthy controls (1.244&#x2009;&#xb1;&#x2009;0.5890, P&#x2009;=&#x2009;0.0355).<br><br>CONCLUSIONS: Six novel mutations in the telomerase genes were identified for the first time in individuals diagnosed with sporadic IPF in a Chinese Han population. Shorter telomeres and mild thrombocytopaenia could be clues to association with telomerase gene mutation and sporadic IPF.},
}
@article {pmid25345632,
year = {2014},
author = {Koliada, AK and Vaĭserman, AM and Krasnenkov, DS and Karaban', IN},
title = {[The study of telomere length in patients with Parkinson's disease].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {114},
number = {8},
pages = {58-61},
pmid = {25345632},
issn = {1997-7298},
mesh = {Aged ; Biomarkers ; DNA Breaks ; Female ; Humans ; Leukocytes ; Male ; Middle Aged ; Mouth Mucosa ; Oxidative Stress/genetics ; Parkinson Disease/*pathology ; Telomere/genetics ; *Telomere Homeostasis ; },
abstract = {OBJECTIVE: Telomeres which are formed by double-strand breaks and DNA under replication, cause cell cycle arrest resulting in cellular senescence and apoptosis. The erosion of telomeres is an important mechanism for regulating the aging process by limiting cell proliferation. Over the last decade, many investigations in the field of telomeric biology showed that telomeric DNA and telomeric proteins are involved in the pathogenesis of some human diseases. The aim of the study was to compare telomere length in patients with Parkinson's disease (PD).<br><br>MATERIAL AND METHODS: Telomere length was measured in buccal epithelial cells and leukocytes in PD patients and controls.<br><br>RESULTS AND CONCLUSION: The length of telomeres in cells of buccal epithelium was shorter in patients with PD than in the control group. In blood cells, telomere length did not differ. It is suggested that shortening of telomeres in buccal epithelial cells may be due to oxidative stress and, hence, it can be used as a marker for the early stages of disease.},
}
@article {pmid25344918,
year = {2014},
author = {Yoon, JH and Seo, HS and Choi, WS and Kim, O and Nam, SW and Lee, JY and Park, WS},
title = {Gastrokine 1 induces senescence and apoptosis through regulating telomere length in gastric cancer.},
journal = {Oncotarget},
volume = {5},
number = {22},
pages = {11695-11708},
pmid = {25344918},
issn = {1949-2553},
mesh = {*Apoptosis ; Cell Line, Tumor ; Cellular Senescence ; Chromatin Immunoprecipitation ; Humans ; Peptide Hormones/*metabolism ; Promoter Regions, Genetic ; Protein Binding ; Proto-Oncogene Proteins c-myc/antagonists &amp; inhibitors/metabolism ; RNA, Messenger/metabolism ; Stomach Neoplasms/*metabolism ; Telomerase/metabolism ; Telomere/metabolism/*ultrastructure ; Telomeric Repeat Binding Protein 1/metabolism ; },
abstract = {The present study aims to investigate whether gastrokine 1 (GKN1) induces senescence and apoptosis in gastric cancer cells by regulating telomere length and telomerase activity. Telomere length, telomerase activity, and hTERT expression decreased significantly in AGSGKN1 and MKN1GKN1 cells. Both stable cell lines showed increased expression of TRF1 and reduced expression of the hTERT and c-myc proteins. In addition, TRF1 induced a considerable decrease in cell growth, telomerase activity, and expression of hTERT mRNA and protein. GKN1 completely counteracted the effects of c-myc on cell growth, telomere length, and telomerase activity. Interestingly, GKN1 directly bound to c-myc and down-regulated its expression as well as inhibited its binding to the TRF1 protein and a hTERT promoter. Furthermore, GKN1 triggered senescence, followed by apoptosis via up-regulating the p53, p21, p27, and p16 proteins and down-regulating Skp2. Telomere length in 35 gastric cancers was shortened significantly compared with the corresponding gastric mucosae, whereas GKN1 expression was inversely correlated with telomere length and c-myc and hTERT mRNA expression. Taken together, these results suggest that GKN1 may shorten telomeres by acting as a potential c-myc inhibitor that eventually leads to senescence and apoptosis in gastric cancer cells.},
}
@article {pmid25343365,
year = {2014},
author = {Vasunilashorn, S and Cohen, AA},
title = {Stress responsive biochemical anabolic/catabolic ratio and telomere length in older adults.},
journal = {Biodemography and social biology},
volume = {60},
number = {2},
pages = {174-184},
pmid = {25343365},
issn = {1948-5573},
support = {R24 HD047879/HD/NICHD NIH HHS/United States ; R01 AG016790/AG/NIA NIH HHS/United States ; T32 AG023480/AG/NIA NIH HHS/United States ; R01 AG16661/AG/NIA NIH HHS/United States ; R01 AG016661/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; *Anabolic Agents ; Cellular Senescence/*physiology ; Female ; Humans ; Male ; Metabolism/*physiology ; Odds Ratio ; *Stress, Physiological ; Stress, Psychological/*genetics ; Taiwan ; Telomere/*physiology ; },
abstract = {It has been hypothesized that chronic psychological stress is associated with shorter telomere length; however, the mechanisms that link stress and telomere length are not well understood. To examine the interplay between biochemical factors related to stress arousal and cellular aging, we investigate the association between anabolic/catabolic (A/C) imbalance and leukocyte telomere length (LTL) in the Social Environment and Biomarkers of Aging Study (SEBAS), conducted in Taiwan (N = 925). SEBAS participants aged 54 and older (mean age 68.3) with values for two anabolic hormones (serum dehydroepiandrosterone sulfate [DHEAS] and insulin growth factor [IGF]-1), four catabolic hormones (cortisol, epinephrine, norepinephrine, and interleukin-6 [IL-6]), and LTL were examined. We found that high IL-6 was associated with short LTL (≤ 0.88 T/S ratio; odds ratio [OR] 1.41, 95% confidence interval [CI] = 1.04-1.92). Neither DHEAS/cortisol nor IGF-1/cortisol ratio was associated with telomere length; however, a high A/C imbalance summary score was associated with greater odds of having a short LTL relative to long LTL (OR 1.19, 95% CI = 1.05-1.35). These results indicate that our A/C imbalance score, defined by several anabolic and catabolic biochemical factors, may be one mechanism through which psychological stress is associated with short LTL and possibly cellular senescence.},
}
@article {pmid25343364,
year = {2014},
author = {Needham, BL and Diez Roux, AV and Bird, CE and Bradley, R and Fitzpatrick, AL and Jacobs, DR and Ouyang, P and Seeman, TE and Thurston, RC and Vaidya, D and Wang, S},
title = {A test of biological and behavioral explanations for gender differences in telomere length: the multi-ethnic study of atherosclerosis.},
journal = {Biodemography and social biology},
volume = {60},
number = {2},
pages = {156-173},
pmid = {25343364},
issn = {1948-5573},
support = {R01 HL101161/HL/NHLBI NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; UL1 RR024156/RR/NCRR NIH HHS/United States ; R01 HL076831/HL/NHLBI NIH HHS/United States ; R01 HL074406/HL/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; UL1 RR025014/RR/NCRR NIH HHS/United States ; UL1-RR-02501401/RR/NCRR NIH HHS/United States ; R01-HL-074406/HL/NHLBI NIH HHS/United States ; UL1 RR025005/RR/NCRR NIH HHS/United States ; R01-HL-101161/HL/NHLBI NIH HHS/United States ; R01-HL-074338/HL/NHLBI NIH HHS/United States ; UL1 TR000423/TR/NCATS NIH HHS/United States ; R01 HL074338/HL/NHLBI NIH HHS/United States ; R01-HL-076831/HL/NHLBI NIH HHS/United States ; },
mesh = {Atherosclerosis/*ethnology/genetics ; *Biomarkers ; Female ; Gender Identity ; Humans ; Longevity/genetics ; Longitudinal Studies ; Male ; Sex Characteristics ; Sex Factors ; Telomere/*genetics/physiology ; Telomere Shortening/*genetics/physiology ; },
abstract = {The purpose of this study was to examine biological and behavioral explanations for gender differences in leukocyte telomere length (LTL), a biomarker of cell aging that has been hypothesized to contribute to women's greater longevity. Data are from a subsample (n = 851) of the Multi-Ethnic Study of Atherosclerosis, a population-based study of women and men aged 45 to 84. Mediation models were used to examine study hypotheses. We found that women had longer LTL than men, but the gender difference was smaller at older ages. Gender differences in smoking and processed meat consumption partially mediated gender differences in telomere length, whereas gender differences in estradiol, total testosterone, oxidative stress, and body mass index did not. Neither behavioral nor biological factors explained why the gender difference in LTL was smaller at older ages. Longitudinal studies are needed to assess gender differences in the rate of change in LTL over time; to identify the biological, behavioral, and psychosocial factors that contribute to these differences throughout the life course; and to determine whether gender differences in LTL explain the gender gap in longevity.},
}
@article {pmid25337925,
year = {2015},
author = {Entringer, S and Epel, ES and Lin, J and Blackburn, EH and Buss, C and Simhan, HN and Wadhwa, PD},
title = {Maternal estriol concentrations in early gestation predict infant telomere length.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {100},
number = {1},
pages = {267-273},
pmid = {25337925},
issn = {1945-7197},
support = {P01 HD047609/HD/NICHD NIH HHS/United States ; R01 HD-060628/HD/NICHD NIH HHS/United States ; R01 HD065825/HD/NICHD NIH HHS/United States ; R01 HD-065825/HD/NICHD NIH HHS/United States ; R01 HD060628/HD/NICHD NIH HHS/United States ; P01 HD-047609/HD/NICHD NIH HHS/United States ; },
mesh = {Child, Preschool ; Estriol/*blood ; Female ; Humans ; Infant ; Infant, Newborn ; Mouth Mucosa ; Pregnancy ; Pregnancy Trimester, First/*blood ; *Telomere ; },
abstract = {CONTEXT: Telomere biology plays a fundamental role in genomic integrity, cellular regeneration, physiology, aging, disease risk, and mortality. The initial setting of telomere length (TL) in early life has important implications for telomere maintenance and related disorders throughout the life span. However, little is known about the predictors of this initial setting.<br><br>OBJECTIVE: Given the established role of estrogen on adult TL and the role of estriol (E3) in the context of fetal development, the goal of this study was to test the hypothesis that higher maternal E3 concentration during early pregnancy is associated with longer infant telomere length.<br><br>Study participants comprised a cohort of N = 100 infants followed prospectively from intrauterine life and birth through early childhood from a population-based, representative sample of pregnant mothers recruited in early pregnancy at university-based obstetric clinics in Southern California. Maternal unconjugated E3 concentrations were assessed in plasma in early gestation (around wk 15). Infant TL was assessed in buccal cells at approximately 15 months of age.<br><br>RESULTS: After accounting for the effects of potential confounding maternal and infant variables, there was a significant, independent effect of maternal E3 concentration on infant TL (unstandardized &#x3b2; = 0.297; P = .001; 95% Cl, 0.121-0.473). Specifically, a one-multiple-of-the-median (MoM) increase in maternal E3 concentration during early pregnancy was associated with a 14.42% increase in infant TL.<br><br>CONCLUSIONS: This study supports the concept of developmental plasticity of the telomere biology system and highlights specifically the role of a potentially modifiable intrauterine factor for additional mechanistic and clinical investigation.},
}
@article {pmid25331286,
year = {2014},
author = {Nilsson, PM},
title = {Genetics: telomere length and the metabolic syndrome-a causal link?.},
journal = {Nature reviews. Endocrinology},
volume = {10},
number = {12},
pages = {706-707},
pmid = {25331286},
issn = {1759-5037},
mesh = {Adult ; Aged ; Humans ; Metabolic Syndrome/*genetics ; Middle Aged ; Telomere Shortening/*genetics ; Young Adult ; },
}
@article {pmid25330849,
year = {2014},
author = {Arora, R and Lee, Y and Wischnewski, H and Brun, CM and Schwarz, T and Azzalin, CM},
title = {RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells.},
journal = {Nature communications},
volume = {5},
number = {},
pages = {5220},
pmid = {25330849},
issn = {2041-1723},
mesh = {Cell Line, Tumor ; DNA/chemistry ; DNA, Single-Stranded ; Endonucleases/metabolism ; *Gene Expression Regulation, Neoplastic ; HEK293 Cells ; HeLa Cells ; Homeostasis ; Homologous Recombination ; Humans ; Imaging, Three-Dimensional ; In Situ Hybridization, Fluorescence ; Nucleic Acids/chemistry ; RNA, Small Interfering/metabolism ; Recombination, Genetic ; Replication Protein A/metabolism ; Ribonuclease H/*metabolism ; Telomerase/metabolism ; Telomere/*ultrastructure ; Telomere Shortening ; },
abstract = {A fraction of cancer cells maintain telomeres through the telomerase-independent, 'Alternative Lengthening of Telomeres' (ALT) pathway. ALT relies on homologous recombination (HR) between telomeric sequences; yet, what makes ALT telomeres recombinogenic remains unclear. Here we show that the RNA endonuclease RNaseH1 regulates the levels of RNA-DNA hybrids between telomeric DNA and the long noncoding RNA TERRA, and is a key mediator of telomere maintenance in ALT cells. RNaseH1 associated to telomeres specifically in ALT cells and its depletion led to telomeric hybrid accumulation, exposure of single-stranded telomeric DNA, activation of replication protein A at telomeres and abrupt telomere excision. Conversely, overexpression of RNaseH1 weakened the recombinogenic nature of ALT telomeres and led to telomere shortening. Altering cellular RNaseH1 levels did not perturb telomere homoeostasis in telomerase-positive cells. RNaseH1 maintains regulated levels of telomeric RNA-DNA hybrids at ALT telomeres to trigger HR without compromising telomere integrity too severely.},
}
@article {pmid25329891,
year = {2014},
author = {Sridhar, A and Kedziora, S and Donaldson, AD},
title = {At short telomeres Tel1 directs early replication and phosphorylates Rif1.},
journal = {PLoS genetics},
volume = {10},
number = {10},
pages = {e1004691},
pmid = {25329891},
issn = {1553-7404},
support = {13356/CRUK_/Cancer Research UK/United Kingdom ; A13356/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Amino Acid Sequence ; *DNA Replication ; DNA Replication Timing ; Intracellular Signaling Peptides and Proteins/genetics/*metabolism ; Molecular Sequence Data ; Mutation ; Phosphorylation ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Repressor Proteins/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Serine/metabolism ; Telomere/metabolism ; Telomere Shortening ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {The replication time of Saccharomyces cerevisiae telomeres responds to TG1-3 repeat length, with telomeres of normal length replicating late during S phase and short telomeres replicating early. Here we show that Tel1 kinase, which is recruited to short telomeres, specifies their early replication, because we find a tel1Δ mutant has short telomeres that nonetheless replicate late. Consistent with a role for Tel1 in driving early telomere replication, initiation at a replication origin close to an induced short telomere was reduced in tel1Δ cells, in an S phase blocked by hydroxyurea. The telomeric chromatin component Rif1 mediates late replication of normal telomeres and is a potential substrate of Tel1 phosphorylation, so we tested whether Tel1 directs early replication of short telomeres by inactivating Rif1. A strain lacking both Rif1 and Tel1 behaves like a rif1Δ mutant by replicating its telomeres early, implying that Tel1 can counteract the delaying effect of Rif1 to control telomere replication time. Proteomic analyses reveals that in yku70Δ cells that have short telomeres, Rif1 is phosphorylated at Tel1 consensus sequences (S/TQ sites), with phosphorylation of Serine-1308 being completely dependent on Tel1. Replication timing analysis of a strain mutated at these phosphorylation sites, however, suggested that Tel1-mediated phosphorylation of Rif1 is not the sole mechanism of replication timing control at telomeres. Overall, our results reveal two new functions of Tel1 at shortened telomeres: phosphorylation of Rif1, and specification of early replication by counteracting the Rif1-mediated delay in initiation at nearby replication origins.},
}
@article {pmid25329304,
year = {2014},
author = {Vasianovich, Y and Harrington, LA and Makovets, S},
title = {Break-induced replication requires DNA damage-induced phosphorylation of Pif1 and leads to telomere lengthening.},
journal = {PLoS genetics},
volume = {10},
number = {10},
pages = {e1004679},
pmid = {25329304},
issn = {1553-7404},
support = {//Wellcome Trust/United Kingdom ; G0900500/MRC_/Medical Research Council/United Kingdom ; 84637/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Cell Cycle Proteins/genetics/metabolism ; Checkpoint Kinase 2/genetics/metabolism ; DNA Breaks, Single-Stranded ; *DNA Damage ; DNA Helicases/genetics/*metabolism ; DNA Ligase ATP ; DNA Ligases/genetics/metabolism ; DNA Replication ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Mutation ; Phosphorylation ; Protein Serine-Threonine Kinases/genetics/metabolism ; Replication Protein C/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Signal Transduction ; Telomerase/genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {Broken replication forks result in DNA breaks that are normally repaired via homologous recombination or break induced replication (BIR). Mild insufficiency in the replicative ligase Cdc9 in budding yeast Saccharomyces cerevisiae resulted in a population of cells with persistent DNA damage, most likely due to broken replication forks, constitutive activation of the DNA damage checkpoint and longer telomeres. This telomere lengthening required functional telomerase, the core DNA damage signaling cascade Mec1-Rad9-Rad53, and the components of the BIR repair pathway - Rad51, Rad52, Pol32, and Pif1. The Mec1-Rad53 induced phosphorylation of Pif1, previously found necessary for inhibition of telomerase at double strand breaks, was also important for the role of Pif1 in BIR and telomere elongation in cdc9-1 cells. Two other mutants with impaired DNA replication, cdc44-5 and rrm3Δ, were similar to cdc9-1: their long telomere phenotype was dependent on the Pif1 phosphorylation locus. We propose a model whereby the passage of BIR forks through telomeres promotes telomerase activity and leads to telomere lengthening.},
}
@article {pmid25326284,
year = {2015},
author = {Glei, DA and Goldman, N and Weinstein, M and Risques, RA},
title = {Shorter Ends, Faster End? Leukocyte Telomere Length and Mortality Among Older Taiwanese.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {70},
number = {12},
pages = {1490-1498},
pmid = {25326284},
issn = {1758-535X},
support = {R01AG16790/AG/NIA NIH HHS/United States ; R01 AG16790/AG/NIA NIH HHS/United States ; R01AG16661/AG/NIA NIH HHS/United States ; R01 AG016790/AG/NIA NIH HHS/United States ; R01 AG16661/AG/NIA NIH HHS/United States ; R24HD047879/HD/NICHD NIH HHS/United States ; },
mesh = {Aged ; Aging/*genetics ; Female ; Humans ; Leukocytes/*physiology ; Male ; *Mortality ; Taiwan ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Recent studies have found mixed results regarding the association between leukocyte telomere length (LTL)--thought to be a marker of cellular aging--and all-cause mortality. Some studies have reported a significant inverse relationship, but others have not, perhaps in part owing to insufficient power. We examine the relationship using data from a nationally representative sample of older Taiwanese (54+ in 2000), which is larger (n = 942) than most previous studies, and which includes comprehensive information on potential confounders including white blood cell distribution and inflammatory markers. Results from a Cox hazards model demonstrate a small, but significant, association between LTL and mortality that is independent of age, sex, and lifestyle factors. White blood cell distribution, especially the proportion of neutrophils, is an important predictor of LTL; however, the association between LTL and mortality changes little controlling for white blood cell distribution. In contrast, the association between LTL and mortality weakens considerably (by 48%) after adjustment for inflammatory markers and homocysteine. Our results suggest that the relationship between short telomeres and mortality is tied to inflammation and homocysteine. Longitudinal studies are needed to explore bidirectional influences resulting from the fact that inflammation leads to shorter leukocyte telomeres, which in turn results in senescence, which exacerbates inflammation.},
}
@article {pmid25325479,
year = {2015},
author = {Salihu, HM and King, L and Patel, P and Paothong, A and Pradhan, A and Louis, J and Naik, E and Marty, PJ and Whiteman, V},
title = {Association between maternal symptoms of sleep disordered breathing and fetal telomere length.},
journal = {Sleep},
volume = {38},
number = {4},
pages = {559-566},
pmid = {25325479},
issn = {1550-9109},
mesh = {Adolescent ; Adult ; Berlin ; Cellular Senescence/*genetics ; DNA/genetics/isolation &amp; purification/metabolism ; Female ; Fetal Blood/cytology/metabolism ; Fetus/cytology/*metabolism ; Humans ; Leukocytes/cytology/metabolism ; Polymerase Chain Reaction ; Pregnancy ; Pregnancy Complications/*physiopathology ; Prenatal Exposure Delayed Effects/*genetics/pathology ; Sleep Apnea Syndromes/*physiopathology ; Sleep Stages/physiology ; Snoring/physiopathology ; Surveys and Questionnaires ; Tandem Repeat Sequences/genetics ; Telomere/*genetics/physiology ; Young Adult ; },
abstract = {STUDY OBJECTIVES: Our investigation aims to assess the impact of symptoms of maternal sleep-disordered breathing, specifically sleep apnea risk and daytime sleepiness, on fetal leukocyte telomere length.<br><br>PARTICIPANTS AND SETTING: Pregnant women were recruited upon hospital delivery admission.<br><br>INTERVENTIONS: Sleep exposure outcomes were measured using the Berlin Questionnaire to quantify sleep apnea and the Epworth Sleepiness Scale to measure daytime sleepiness. Participants were classified as "High Risk" or "Low Risk" for sleep apnea based on responses to the Berlin, while "Normal" or "Abnormal" daytime sleepiness was determined based on responses to the Epworth.<br><br>DESIGN: Neonatal umbilical cord blood samples (N = 67) were collected and genomic DNA was isolated from cord blood leukocytes using Quantitative PCR. A ratio of relative telomere length was derived by telomere repeat copy number and single copy gene copy number (T/S ratio) and used to compare telomere lengths. Bootstrap and ANOVA statistical procedures were employed.<br><br>MEASUREMENTS AND RESULTS: On the Berlin, 68.7% of participants were classified as Low Risk while 31.3% were classified as High Risk for sleep apnea. According to the Epworth scale, 80.6% were determined to have Normal daytime sleepiness, and 19.4% were found to have Abnormal daytime sleepiness. The T/S ratio among pregnant women at High Risk for sleep apnea was significantly shorter than for those at Low Risk (P value < 0.05), and the T/S ratio among habitual snorers was significantly shorter than among non-habitual snorers (P value < 0.05). Although those with Normal Sleepiness had a longer T/S ratio than those with Abnormal Sleepiness, the difference was not statistically significant.<br><br>CONCLUSION: Our results provide the first evidence demonstrating shortened telomere length among fetuses exposed to maternal symptoms of sleep disordered breathing during pregnancy, and suggest sleep disordered breathing as a possible mechanism of accelerated chromosomal aging.},
}
@article {pmid25324139,
year = {2014},
author = {Lajud, SA and Nagda, DA and Yamashita, T and Zheng, J and Tanaka, N and Abuzeid, WM and Civantos, A and Bezpalko, O and O'Malley, BW and Li, D},
title = {Dual disruption of DNA repair and telomere maintenance for the treatment of head and neck cancer.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {20},
number = {24},
pages = {6465-6478},
doi = {10.1158/1078-0432.CCR-14-0176},
pmid = {25324139},
issn = {1557-3265},
mesh = {Acid Anhydride Hydrolases ; Animals ; BRCA1 Protein/genetics ; Carcinoma, Squamous Cell/genetics ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Breaks, Single-Stranded/drug effects ; *DNA Repair ; DNA Repair Enzymes/metabolism ; DNA-Binding Proteins/metabolism ; Disease Models, Animal ; Female ; Genomic Instability ; Head and Neck Neoplasms/*genetics/*metabolism/pathology/therapy ; Humans ; MRE11 Homologue Protein ; Mice ; Models, Biological ; Multiprotein Complexes/metabolism ; Nuclear Proteins/metabolism ; Organic Chemicals/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/metabolism ; Squamous Cell Carcinoma of Head and Neck ; Telomere/*genetics/*metabolism ; Telomere Shortening ; Tumor Burden/drug effects/genetics ; Xenograft Model Antitumor Assays ; },
abstract = {PURPOSE: Poly(ADP-ribose) polymerases (PARP) and the Mre11, Rad50, and Nbs1 (MRN) complex are key regulators of DNA repair, and have been recently shown to independently regulate telomere length. Sensitivity of cancers to PARPi is largely dependent on the BRCAness of the cells. Unfortunately, the vast majority of cancers are BRCA-proficient. In this study, therefore, we investigated whether a targeted molecular "hit" on the MRN complex, which is upstream of BRCA, can effectively sensitize BRCA-proficient head and neck squamous cell carcinoma (HNSCC) to PARP inhibitor (PARPi).<br><br>EXPERIMENTAL DESIGN: Human HNSCC cell lines and a mouse model with HNSCC xenografts were used in this study. In vitro and in vivo studies were conducted to evaluate the effects and underlying mechanisms of dual molecular disruption of PARP and the MRN complex, using a pharmacologic inhibitor and a dominant-negative Nbs1 expression vector, respectively.<br><br>RESULTS: Our findings demonstrate that downregulation of the MRN complex disrupts homologous recombination, and, when combined with PARPi, leads to accumulation of lethal DNA double-strand breaks. Moreover, we show that PARPi and MRN complex disruption induces significantly shortening telomere length. Together, our results demonstrate that dual disruption of these pathways causes significant cell death in BRCA-proficient tumor cells both in vitro and in vivo.<br><br>CONCLUSION: Our study, for the first time, elucidates a novel mechanism for MRN complex and PARP inhibition beyond DNA repair, demonstrating the feasibility of a dual disruption approach that extends the utility of PARPi to the treatment of BRCA-proficient cancers.},
}
@article {pmid25322305,
year = {2014},
author = {Leung, CW and Laraia, BA and Needham, BL and Rehkopf, DH and Adler, NE and Lin, J and Blackburn, EH and Epel, ES},
title = {Soda and cell aging: associations between sugar-sweetened beverage consumption and leukocyte telomere length in healthy adults from the National Health and Nutrition Examination Surveys.},
journal = {American journal of public health},
volume = {104},
number = {12},
pages = {2425-2431},
pmid = {25322305},
issn = {1541-0048},
support = {R01 AG033592/AG/NIA NIH HHS/United States ; R01AG033592-01A1/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; *Beverages ; Blotting, Southern ; Cellular Senescence/*drug effects ; Cross-Sectional Studies ; Demography ; Dietary Sucrose/*administration &amp; dosage ; Female ; Humans ; Leukocytes/*drug effects ; Male ; Middle Aged ; Nutrition Surveys ; Polymerase Chain Reaction ; Telomere Shortening/*drug effects ; United States ; },
abstract = {OBJECTIVES: We tested whether leukocyte telomere length maintenance, which underlies healthy cellular aging, provides a link between sugar-sweetened beverage (SSB) consumption and the risk of cardiometabolic disease.<br><br>METHODS: We examined cross-sectional associations between the consumption of SSBs, diet soda, and fruit juice and telomere length in a nationally representative sample of healthy adults. The study population included 5309 US adults, aged 20 to 65 years, with no history of diabetes or cardiovascular disease, from the 1999 to 2002 National Health and Nutrition Examination Surveys. Leukocyte telomere length was assayed from DNA specimens. Diet was assessed using 24-hour dietary recalls. Associations were examined using multivariate linear regression for the outcome of log-transformed telomere length.<br><br>RESULTS: After adjustment for sociodemographic and health-related characteristics, sugar-sweetened soda consumption was associated with shorter telomeres (b&#x2009;=&#x2009;-0.010; 95% confidence interval [CI]&#x2009;=&#x2009;-0.020, -0.001; P&#x2009;=&#x2009;.04). Consumption of 100% fruit juice was marginally associated with longer telomeres (b&#x2009;=&#x2009;0.016; 95% CI&#x2009;=&#x2009;-0.000, 0.033; P&#x2009;=&#x2009;.05). No significant associations were observed between consumption of diet sodas or noncarbonated SSBs and telomere length.<br><br>CONCLUSIONS: Regular consumption of sugar-sweetened sodas might influence metabolic disease development through accelerated cell aging.},
}
@article {pmid25321176,
year = {2015},
author = {Blanco, JR and Jarrin, I and Martinez, A and Siles, E and Larrayoz, IM and Cañuelo, A and Gutierrez, F and Gonzalez-Garcia, J and Vidal, F and Moreno, S and , },
title = {Shorter telomere length predicts poorer immunological recovery in virologically suppressed HIV-1-infected patients treated with combined antiretroviral therapy.},
journal = {Journal of acquired immune deficiency syndromes (1999)},
volume = {68},
number = {1},
pages = {21-29},
doi = {10.1097/QAI.0000000000000398},
pmid = {25321176},
issn = {1944-7884},
mesh = {Anti-HIV Agents/administration &amp; dosage/*therapeutic use ; Base Sequence ; DNA Primers ; Drug Therapy, Combination ; HIV Infections/*drug therapy/genetics/immunology ; HIV-1 ; Polymerase Chain Reaction ; *Telomere ; },
abstract = {BACKGROUND: Successful combined antiretroviral therapy (cART) does not always result in complete CD4 T-cell recovery despite the effective control of HIV replication. Because telomere dysregulation can lead to an abnormal cell proliferation, we hypothesized that the lack of CD4 recovery may be related to telomere defects; We thus evaluated the association between telomere length (TL) and CD4 T-cell recovery 48 weeks after cART initiation in virologically suppressed patients, and its possible relationship to oxidative stress (OS) and nitrosative stress (NOx) markers.<br><br>METHODS: We studied HIV-infected patients on stable cART who achieved a viral load <50 copies per milliliter after 48 weeks of their first cART. Leukocyte TL was measured and categorized into tertiles. We calculated mean increases in CD4 T-cell at 48 weeks from cART initiation and used multivariate linear regression models to estimate differences in mean increases according to tertiles of TL.<br><br>RESULTS: One hundred thirty-two patients, 86% male, 81% <50 years at cART initiation were studied. Mean increases in CD4 were greater in patients with long TL than in those with medium and short TLs (P = 0.007). After adjustment for sex, age, CD4 T-cell counts, viral load, and hepatitis C infection at cART initiation, differences in mean CD4 T-cell count increases according to TL remained statistically significant (P = 0.02). Additional adjustment for NOx and OS did not change the results.<br><br>CONCLUSION: A lower immunological response despite a successful virological response is associated with a shorter TL. The effect is not related to NOx or OS.},
}
@article {pmid25320237,
year = {2014},
author = {Gazzaniga, FS and Blackburn, EH},
title = {An antiapoptotic role for telomerase RNA in human immune cells independent of telomere integrity or telomerase enzymatic activity.},
journal = {Blood},
volume = {124},
number = {25},
pages = {3675-3684},
pmid = {25320237},
issn = {1528-0020},
support = {AG030424/AG/NIA NIH HHS/United States ; R56 AG030424/AG/NIA NIH HHS/United States ; CA096840/CA/NCI NIH HHS/United States ; R01 AG030424/AG/NIA NIH HHS/United States ; R01 CA096840/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Anti-Inflammatory Agents/pharmacology ; Apoptosis/drug effects/*genetics ; Apoptosis Regulatory Proteins/genetics/metabolism ; Bcl-2-Like Protein 11 ; Blotting, Western ; CD4-Positive T-Lymphocytes/drug effects/*metabolism ; Cells, Cultured ; Dexamethasone/pharmacology ; Gene Expression ; Humans ; Membrane Proteins/genetics/metabolism ; Mutation ; Proto-Oncogene Proteins/genetics/metabolism ; RNA/*genetics/metabolism ; RNA Interference ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*genetics/metabolism ; Telomere/*genetics/metabolism ; Young Adult ; },
abstract = {Telomerase is a ribonucleoprotein complex that adds telomeric DNA to the ends of linear chromosomes. It contains two core canonical components: the essential RNA component, hTR, which provides the template for DNA synthesis, and the reverse transcriptase protein component, hTERT. Low telomerase activity in circulating peripheral blood mononuclear cells has been associated with a variety of diseases. It is unknown, however, whether telomerase, in addition to its long-term requirement for telomere maintenance, is also necessary for short-term immune cell proliferation and survival. We report that overexpression of enzymatically inactive hTR mutants protected against dexamethasone-induced apoptosis in stimulated CD4 T cells. Furthermore, hTR knockdown reproducibly induced apoptosis in the absence of any detectable telomere shortening or DNA damage response. In contrast, hTERT knockdown did not induce apoptosis. Strikingly, overexpression of hTERT protein caused apoptosis that was rescued by overexpression of enzymatically inactive hTR mutants. Hence, we propose that hTR can function as a noncoding RNA that protects from apoptosis independent of its function in telomerase enzymatic activity and long-term telomere maintenance in normal human immune cells. These results imply that genetic or environmental factors that alter hTR levels can directly affect immune cell function to influence health and disease.},
}
@article {pmid25317735,
year = {2015},
author = {Lin, Y and Damjanovic, A and Metter, EJ and Nguyen, H and Truong, T and Najarro, K and Morris, C and Longo, DL and Zhan, M and Ferrucci, L and Hodes, RJ and Weng, NP},
title = {Age-associated telomere attrition of lymphocytes in vivo is co-ordinated with changes in telomerase activity, composition of lymphocyte subsets and health conditions.},
journal = {Clinical science (London, England : 1979)},
volume = {128},
number = {6},
pages = {367-377},
pmid = {25317735},
issn = {1470-8736},
support = {ZIA AG000112-09//Intramural NIH HHS/United States ; ZIA AG000756-19//Intramural NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*genetics/immunology/metabolism ; B-Lymphocytes/enzymology/physiology ; Follow-Up Studies ; Humans ; Leukocytes, Mononuclear/metabolism ; Lymphocyte Activation/genetics/immunology ; Lymphocyte Subsets/*enzymology/immunology ; Middle Aged ; Monocytes/physiology ; T-Lymphocytes/enzymology/physiology ; Telomerase/*blood ; Telomere Homeostasis/*immunology/physiology ; Young Adult ; },
abstract = {Telomeres are essential in maintaining chromosome integrity and in controlling cellular replication. Attrition of telomere length in peripheral blood mononuclear cells (PBMCs) with age is well documented from cross-sectional studies. But the actual in vivo changes in telomere lengths and its relationship with the contributing factors within the individuals with age have not been fully addressed. In the present paper, we report a longitudinal analysis of telomere length in the PBMCs, lymphocytes and monocytes of 216 human subjects aged from 20-90 years assessed at 0-, 5- and 12-year follow-up. For the 5- and 12-year follow-up, telomere length in the PBMCs decreased in 34% and 46%, exhibited no detectable change in 56% and 47% and increased in 10% and 7% of the subjects respectively. The rate of telomere change was distinct for T-cells, B-cells and monocytes for any given subject. Telomerase activity declined with age in the resting T-cells and B-cells and the activated T-cells. Finally, a significant portion of telomere attrition in T-cells with age was explained by a decline in the telomerase activity, decreased naïve cells and the change in physiological conditions such as elevated blood glucose and interleukin (IL)-6 levels. These findings show that changes in the telomere length of the PBMCs with age in vivo occur at different rates in different individuals and cell types and reveal that changes in the telomere length in the T-cells with age is influenced by the telomerase activity, naïve T-cell percentage and changes in health conditions.},
}
@article {pmid25315281,
year = {2014},
author = {Mangerel, J and Price, A and Castelo-Branco, P and Brzezinski, J and Buczkowicz, P and Rakopoulos, P and Merino, D and Baskin, B and Wasserman, J and Mistry, M and Barszczyk, M and Picard, D and Mack, S and Remke, M and Starkman, H and Elizabeth, C and Zhang, C and Alon, N and Lees, J and Andrulis, IL and Wunder, JS and Jabado, N and Johnston, DL and Rutka, JT and Dirks, PB and Bouffet, E and Taylor, MD and Huang, A and Malkin, D and Hawkins, C and Tabori, U},
title = {Alternative lengthening of telomeres is enriched in, and impacts survival of TP53 mutant pediatric malignant brain tumors.},
journal = {Acta neuropathologica},
volume = {128},
number = {6},
pages = {853-862},
doi = {10.1007/s00401-014-1348-1},
pmid = {25315281},
issn = {1432-0533},
support = {MOP86558//Canadian Institutes of Health Research/Canada ; },
mesh = {Adolescent ; Brain Neoplasms/*genetics/physiopathology ; Carcinoma/*genetics/physiopathology ; Choroid Plexus Neoplasms/*genetics/physiopathology ; Cohort Studies ; DNA Helicases/genetics ; Glioma/*genetics/physiopathology ; Humans ; Kaplan-Meier Estimate ; Mutation ; Neoplasm Grading ; Neuroectodermal Tumors, Primitive/*genetics/physiopathology ; Nuclear Proteins/genetics ; Phenotype ; Prognosis ; *Telomere/metabolism ; Tumor Suppressor Protein p53/*genetics ; X-linked Nuclear Protein ; },
abstract = {Although telomeres are maintained in most cancers by telomerase activation, a subset of tumors utilize alternative lengthening of telomeres (ALT) to sustain self-renewal capacity. In order to study the prevalence and significance of ALT in childhood brain tumors we screened 517 pediatric brain tumors using the novel C-circle assay. We examined the association of ALT with alterations in genes found to segregate with specific histological phenotypes and with clinical outcome. ALT was detected almost exclusively in malignant tumors (p = 0.001). ALT was highly enriched in primitive neuroectodermal tumors (12 %), choroid plexus carcinomas (23 %) and high-grade gliomas (22 %). Furthermore, in contrast to adult gliomas, pediatric low grade gliomas which progressed to high-grade tumors did not exhibit the ALT phenotype. Somatic but not germline TP53 mutations were highly associated with ALT (p = 1.01 × 10(-8)). Of the other alterations examined, only ATRX point mutations and reduced expression were associated with the ALT phenotype (p = 0.0005). Interestingly, ALT attenuated the poor outcome conferred by TP53 mutations in specific pediatric brain tumors. Due to very poor prognosis, one year overall survival was quantified in malignant gliomas, while in children with choroid plexus carcinoma, five year overall survival was investigated. For children with TP53 mutant malignant gliomas, one year overall survival was 63 ± 12 and 23 ± 10 % for ALT positive and negative tumors, respectively (p = 0.03), while for children with TP53 mutant choroid plexus carcinomas, 5 years overall survival was 67 ± 19 and 27 ± 13 % for ALT positive and negative tumors, respectively (p = 0.07). These observations suggest that the presence of ALT is limited to a specific group of childhood brain cancers which harbor somatic TP53 mutations and may influence the outcome of these patients. Analysis of ALT may contribute to risk stratification and targeted therapies to improve outcome for these children.},
}
@article {pmid25314332,
year = {2015},
author = {Riddell, NE and Griffiths, SJ and Rivino, L and King, DC and Teo, GH and Henson, SM and Cantisan, S and Solana, R and Kemeny, DM and MacAry, PA and Larbi, A and Akbar, AN},
title = {Multifunctional cytomegalovirus (CMV)-specific CD8(+) T cells are not restricted by telomere-related senescence in young or old adults.},
journal = {Immunology},
volume = {144},
number = {4},
pages = {549-560},
pmid = {25314332},
issn = {1365-2567},
support = {//Biotechnology and Biological Sciences Research Council/United Kingdom ; //Medical Research Council/United Kingdom ; },
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Aging/ethnology/genetics/*immunology ; Asian People/genetics ; Biomarkers/metabolism ; CD8-Positive T-Lymphocytes/*immunology/metabolism/virology ; Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; *Cellular Senescence ; Cytokines/immunology/metabolism ; Cytomegalovirus/*immunology/pathogenicity ; Cytomegalovirus Infections/genetics/*immunology/metabolism/virology ; Flow Cytometry ; Humans ; Immunophenotyping/methods ; Leukocyte Common Antigens/immunology/metabolism ; London ; *Lymphocyte Activation ; Phenotype ; Singapore ; Telomere/genetics/*immunology ; *Telomere Shortening ; Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology/metabolism ; White People/genetics ; Young Adult ; },
abstract = {Antigen-specific multifunctional T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α simultaneously after activation are important for the control of many infections. It is unclear if these CD8(+) T cells are at an early or late stage of differentiation and whether telomere erosion restricts their replicative capacity. We developed a multi-parameter flow cytometric method for investigating the relationship between differentiation (CD45RA and CD27 surface phenotype), function (cytokine production) and replicative capacity (telomere length) in individual cytomegalovirus (CMV) antigen-specific CD8(+) T cells. This involves surface and intracellular cell staining coupled to fluorescence in situ hybridization to detect telomeres (flow-FISH). The end-stage/senescent CD8(+) CD45RA(+) CD27(-) T-cell subset increases significantly during ageing and this is exaggerated in CMV immune-responsive subjects. However, these end-stage cells do not have the shortest telomeres, implicating additional non-telomere-related mechanisms in inducing their senescence. The telomere lengths in total and CMV (NLV)-specific CD8(+) T cells in all four subsets defined by CD45RA and CD27 expression were significantly shorter in old compared with young individuals in both a Caucasian and an Asian cohort. Following stimulation by anti-CD3 or NLV peptide, similar proportions of triple-cytokine-producing cells are found in CD8(+) T cells at all stages of differentiation in both age groups. Furthermore, these multi-functional cells had intermediate telomere lengths compared with cells producing only one or two cytokines after activation. Therefore, global and CMV (NLV)-specific CD8(+) T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α are at an intermediate stage of differentiation and are not restricted by excessive telomere erosion.},
}
@article {pmid25311116,
year = {2015},
author = {Panero, J and O'Callaghan, NJ and Fenech, M and Slavutsky, I},
title = {Absolute qPCR for measuring telomere length in bone marrow samples of plasma cell disorders.},
journal = {Molecular biotechnology},
volume = {57},
number = {2},
pages = {155-159},
pmid = {25311116},
issn = {1559-0305},
mesh = {Bone Marrow Cells/*pathology ; Disease Progression ; Hematologic Neoplasms/diagnosis/*genetics/pathology ; Humans ; Plasma Cells ; *Polymerase Chain Reaction ; Telomere/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Telomere length (TL) is currently used as an emerging biomarker in understanding the development/progression of hematological malignancies. The absolute quantitative PCR (qPCR) methodology has allowed the study of TL from a variety of mammalian tissues, but it has not been tested for bone marrow (BM) samples. In this study, we have examined the relationship between TL data generated by absolute qPCR versus those obtained by terminal restriction fragments (TRF) in 102 BM samples from patients with plasma cell disorders. A significant linear correlation between both methodologies was observed (p < 0.0001; r (2) = 0.70). Results were also analyzed in relation to clinical characteristics and significant associations between telomere shortening and parameters of adverse prognosis were observed. Furthermore, another set of 47 BM samples from patients with low quantity of DNA for TRF assay were suitably analyzed by qPCR, indicating the usefulness of the absolute qPCR methodology for the inclusion of patients with scarce material to the study. Taken together, these findings are of interest considering the importance of telomere dysfunction in the pathogenesis of cancer and give a new alternative to measure TL in hematologic disorders with substantial time and cost savings.},
}
@article {pmid25308469,
year = {2014},
author = {Pepper, C and Baird, D and Fegan, C},
title = {Telomere analysis to predict chronic lymphocytic leukemia outcome: a STELA test to change clinical practice?.},
journal = {Expert review of hematology},
volume = {7},
number = {6},
pages = {701-703},
doi = {10.1586/17474086.2014.969705},
pmid = {25308469},
issn = {1747-4094},
mesh = {Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*diagnosis/genetics/pathology ; Prognosis ; Telomere/genetics/*pathology ; *Telomere Homeostasis ; },
abstract = {Defining the prognosis of individual chronic lymphocytic leukemia patients remains a significant clinical challenge. Consequently, there is a need to identify tests that can provide reliable personalized risk assessments. Here we discuss the problems associated with the currently used prognostic markers and emphasize the potential for using high-resolution telomere length analysis (STELA) for the accurate prediction of clinical outcome. Given the development of targeted, less toxic therapeutics in chronic lymphocytic leukemia, it is crucial to accurately identify those patients who might benefit from early treatment and equally those who may not require treatment at all. In this context, there is also a clear need for dependable predictive markers of response to drugs so that optimal treatment decisions can be made for individual patients.},
}
@article {pmid25304614,
year = {2015},
author = {Alter, BP and Giri, N and Savage, SA and Rosenberg, PS},
title = {Telomere length in inherited bone marrow failure syndromes.},
journal = {Haematologica},
volume = {100},
number = {1},
pages = {49-54},
pmid = {25304614},
issn = {1592-8721},
support = {HHSN261201100018C/CA/NCI NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Anemia, Aplastic ; Anemia, Diamond-Blackfan/*genetics/pathology ; Bone Marrow Diseases ; Bone Marrow Failure Disorders ; Case-Control Studies ; Child ; Child, Preschool ; Dyskeratosis Congenita/*genetics/pathology ; Fanconi Anemia/*genetics/pathology ; Female ; Follow-Up Studies ; Hemoglobinuria, Paroxysmal/*genetics/pathology ; Humans ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Young Adult ; },
abstract = {Telomeres are long DNA repeats and a protein complex at chromosome ends that are essential for genome integrity. Telomeres are very short in patients with dyskeratosis congenita due to germline mutations in telomere biology genes. We compared telomere length in patients with Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome with telomere length in dyskeratosis congenita. Telomere length was measured in six leukocyte subsets by automated multicolor flow fluorescence in situ hybridization, and age-adjusted using Z-scores (-2.326 = 1(st) percentile) were created. We examined individual data, and used canonical variate analysis for group comparisons and outlier detection. Most dyskeratosis congenita telomere lengths were below the 1(st) percentile, while only 2 Fanconi anemia and one each Diamond-Blackfan anemia and Shwachman-Diamond syndrome were that low. However, Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome clustered in the bottom half of the normal range. Canonical variate analysis separated dyskeratosis congenita widely from the other three syndromes by the first canonical variable (89.7% of the variance); the second variable (10.0%) separated Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and Fanconi anemia from each other. Overall, unlike in dyskeratosis congenita, telomere lengths in patients with non-dyskeratosis congenita inherited bone marrow failure syndromes were usually in the normal range, albeit shorter than in unaffected individuals. Clinicaltrials.gov identifier: 00027274.},
}
@article {pmid25303953,
year = {2014},
author = {Cranert, S and Heyse, S and Linger, BR and Lescasse, R and Price, C},
title = {Tetrahymena Pot2 is a developmentally regulated paralog of Pot1 that localizes to chromosome breakage sites but not to telomeres.},
journal = {Eukaryotic cell},
volume = {13},
number = {12},
pages = {1519-1529},
pmid = {25303953},
issn = {1535-9786},
support = {R01 GM088728/GM/NIGMS NIH HHS/United States ; T32 CA117846/CA/NCI NIH HHS/United States ; T32 ES007250/ES/NIEHS NIH HHS/United States ; },
mesh = {Chromosome Breakpoints ; DNA-Binding Proteins/*metabolism ; Gene Expression ; Protein Binding ; Protein Transport ; Protozoan Proteins/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; Tetrahymena thermophila/*metabolism ; },
abstract = {Tetrahymena telomeres are protected by a protein complex composed of Pot1, Tpt1, Pat1, and Pat2. Pot1 binds the 3' overhang and serves multiple roles in telomere maintenance. Here we describe Pot2, a paralog of Pot1 which has evolved a novel function during Tetrahymena sexual reproduction. Pot2 is unnecessary for telomere maintenance during vegetative growth, as the telomere structure is unaffected by POT2 macronuclear gene disruption. Pot2 is expressed only in mated cells, where it accumulates in developing macronuclei around the time of two chromosome processing events: internal eliminated sequence (IES) excision and chromosome breakage. Chromatin immunoprecipitation (ChIP) demonstrated Pot2 localization to regions of chromosome breakage but not to telomeres or IESs. Pot2 association with chromosome breakage sites (CBSs) occurs slightly before chromosome breakage. Pot2 did not bind CBSs or telomeric DNA in vitro, suggesting that it is recruited to CBSs by another factor. The telomere proteins Pot1, Pat1, and Tpt1 and the IES binding factor Pdd1 fail to colocalize with Pot2. Thus, Pot2 is the first protein found to associate specifically with CBSs. The selective association of Pot2 versus Pdd1 with CBSs or IESs indicates a mechanistic difference between the chromosome processing events at these two sites. Moreover, ChIP revealed that histone marks characteristic of IES processing, H3K9me3 and H3K27me3, are absent from CBSs. Thus, the mechanisms of chromosome breakage and IES excision must be fundamentally different. Our results lead to a model where Pot2 directs chromosome breakage by recruiting telomerase and/or the endonuclease responsible for DNA cleavage to CBSs.},
}
@article {pmid25303777,
year = {2014},
author = {McDonald, KR and Sabouri, N and Webb, CJ and Zakian, VA},
title = {The Pif1 family helicase Pfh1 facilitates telomere replication and has an RPA-dependent role during telomere lengthening.},
journal = {DNA repair},
volume = {24},
number = {},
pages = {80-86},
pmid = {25303777},
issn = {1568-7856},
support = {R01 GM026938/GM/NIGMS NIH HHS/United States ; R01 GM043265/GM/NIGMS NIH HHS/United States ; T32 GM007388/GM/NIGMS NIH HHS/United States ; GM43265/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Helicases/genetics/*metabolism ; Gene Expression Regulation, Fungal ; Mutation ; Replication Protein A/metabolism ; Schizosaccharomyces/genetics ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Telomere/*physiology ; },
abstract = {Pif1 family helicases are evolutionary conserved 5'-3' DNA helicases. Pfh1, the sole Schizosaccharomyces pombe Pif1 family DNA helicase, is essential for maintenance of both nuclear and mitochondrial DNAs. Here we show that its nuclear functions include roles in telomere replication and telomerase action. Pfh1 promoted semi-conservative replication through telomeric DNA, as replication forks moved more slowly through telomeres when Pfh1 levels were reduced. Unlike other organisms, S. pombe cells overexpressing Pfh1 displayed markedly longer telomeres. Because this lengthening occurred in the absence of homologous recombination but not in a replication protein A mutant (rad11-D223Y) that has defects in telomerase function, it is probably telomerase-mediated. The effects of Pfh1 on telomere replication and telomere length are likely direct as Pfh1 exhibited high telomere binding in cells expressing endogenous levels of Pfh1. These findings argue that Pfh1 is a positive regulator of telomere length and telomere replication.},
}
@article {pmid25299252,
year = {2014},
author = {Derboven, E and Ekker, H and Kusenda, B and Bulankova, P and Riha, K},
title = {Role of STN1 and DNA polymerase α in telomere stability and genome-wide replication in Arabidopsis.},
journal = {PLoS genetics},
volume = {10},
number = {10},
pages = {e1004682},
pmid = {25299252},
issn = {1553-7404},
mesh = {Arabidopsis/*genetics/metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Cell Cycle Proteins/genetics/metabolism ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; DNA Polymerase I/genetics/metabolism ; DNA Replication ; Exodeoxyribonucleases/metabolism ; Genome, Plant ; Heterochromatin/genetics/metabolism ; Mutation ; Telomerase/genetics/metabolism ; *Telomere/metabolism ; },
abstract = {The CST (Cdc13/CTC1-STN1-TEN1) complex was proposed to have evolved kingdom specific roles in telomere capping and replication. To shed light on its evolutionary conserved function, we examined the effect of STN1 dysfunction on telomere structure in plants. STN1 inactivation in Arabidopsis leads to a progressive loss of telomeric DNA and the onset of telomeric defects depends on the initial telomere size. While EXO1 aggravates defects associated with STN1 dysfunction, it does not contribute to the formation of long G-overhangs. Instead, these G-overhangs arise, at least partially, from telomerase-mediated telomere extension indicating a deficiency in C-strand fill-in synthesis. Analysis of hypomorphic DNA polymerase α mutants revealed that the impaired function of a general replication factor mimics the telomeric defects associated with CST dysfunction. Furthermore, we show that STN1-deficiency hinders re-replication of heterochromatic regions to a similar extent as polymerase α mutations. This comparative analysis of stn1 and pol α mutants suggests that STN1 plays a genome-wide role in DNA replication and that chromosome-end deprotection in stn1 mutants may represent a manifestation of aberrant replication through telomeres.},
}
@article {pmid25299235,
year = {2015},
author = {Kim, ES and Ye, Y and Vaporciyan, AA and Xing, J and Huang, M and Gu, J and Roth, JA and Lippman, SM and Wu, X},
title = {Telomere length and recurrence risk after curative resection in patients with early-stage non-small-cell lung cancer: a prospective cohort study.},
journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer},
volume = {10},
number = {2},
pages = {302-308},
pmid = {25299235},
issn = {1556-1380},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; R01 CA176568/CA/NCI NIH HHS/United States ; RP130502//PHS HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Carcinoma, Non-Small-Cell Lung/genetics/*metabolism/pathology/*surgery ; Cohort Studies ; Female ; Humans ; Lung Neoplasms/genetics/*metabolism/pathology/*surgery ; Male ; Middle Aged ; Neoplasm Staging ; Prospective Studies ; Risk Factors ; Telomere/genetics/*metabolism ; },
abstract = {BACKGROUND: We hypothesized that telomere length in peripheral blood would have significant predictive value for risk of recurrence after curative resection in non-small-cell lung cancer (NSCLC).<br><br>METHODS: This prospective study included 473 patients with histologically confirmed early stage NSCLC who underwent curative therapy at MD Anderson Cancer Center between 1995 and 2008. Relative telomere length (RTL) of peripheral leukocytes was measured by real-time polymerase chain reaction. The risk of recurrence was estimated as hazard ratios (HRs) and 95% confidence intervals (CIs) using a multivariable Cox proportional hazard regression model.<br><br>RESULTS: Median duration of follow-up was 61 months, and 151 patients (32%) had developed recurrence at time of analysis. Patients who developed recurrence had significantly longer mean RTL compared with those without recurrence (1.13 versus 1.07, p = 0.046). A subgroup analysis indicates that women had longer RTL compared with men (1.12 versus 1.06, p = 0.025), and the patients with adenocarcinoma demonstrated longer RTL compared with those with other histologic types (1.11 versus 1.05, p = 0.042). To determine whether longer RTL in women and adenocarcinoma subgroup would predict risk of recurrence, multivariate Cox analysis adjusting for age, sex, stage, pack year and treatment regimens was performed. Longer telomeres were significantly associated with higher risk of developing recurrence in women (hazard ratio [HR], 2.25; 95% confidence interval [CI], 1.02-4.96, p = 0.044) and adenocarcinoma subgroups (HR, 2.19; 95% CI, 1.05-4.55, p = 0.036). The increased risk of recurrence due to long RTL was more apparent in women with adenocarcinoma (HR, 2.67; 95% CI, 1.19-6.03, p = 0.018).<br><br>CONCLUSIONS: This is the first prospective study to suggest that long RTL is associated with recurrence in early stage NSCLC after curative resection. Women and adenocarcinoma seem to be special subgroups in which telomere biology may play an important role.},
}
@article {pmid25295271,
year = {2014},
author = {Woo, SR and Ham, Y and Kang, W and Yang, H and Kim, S and Jin, J and Joo, KM and Nam, DH},
title = {KML001, a telomere-targeting drug, sensitizes glioblastoma cells to temozolomide chemotherapy and radiotherapy through DNA damage and apoptosis.},
journal = {BioMed research international},
volume = {2014},
number = {},
pages = {747415},
pmid = {25295271},
issn = {2314-6141},
mesh = {Animals ; Apoptosis/drug effects ; Arsenites/*administration &amp; dosage ; DNA Damage/drug effects ; Dacarbazine/administration &amp; dosage/*analogs &amp; derivatives ; Drug Synergism ; Glioblastoma/*drug therapy/genetics/radiotherapy ; Humans ; Mice ; Neoplasm Recurrence, Local/*drug therapy/pathology/radiotherapy ; Radiation-Sensitizing Agents/administration &amp; dosage ; Sodium Compounds/*administration &amp; dosage ; Telomere/*drug effects/genetics ; Temozolomide ; Xenograft Model Antitumor Assays ; },
abstract = {Standard treatment for glioblastoma comprises surgical resection, chemotherapy with temozolomide, and radiotherapy. Nevertheless, majority of glioblastoma patients have recurrence from resistance to the cytotoxic conventional therapies. We examined combinational effects of KML001, an arsenic compound targeting telomeres of chromosomes with temozolomide or irradiation, in glioblastoma cell lines and xenograft models, to overcome the therapeutic limitation of chemoradiation therapy for glioblastoma. Although KML001 alone showed little effects on in vitro survival of glioblastoma cells, cell death by in vitro temozolomide treatment or irradiation was synergistically potentiated by combination with KML001. Since phosphorylated γ-H2AX, cleaved casepase-3, and cleaved PARP were dramatically increased by KML001, the synergistic effects would be mediated by increased DNA damage and subsequent tumor cell apoptosis. Combinatorial effects of KML001 were observed not only in chemo- and radiosensitive glioblastoma cell line, U87MG, but also in the resistant cell line, U251MG. In the U87MG glioblastoma xenograft models, KML001 did not have systemic toxicity but showed synergistic therapeutic effects in combination with temozolomide or irradiation to reduce tumor volumes significantly. These data indicated that KML001 could be a candidate sensitizer to potentiate therapeutic effects of conventional cytotoxic treatment for glioblastoma.},
}
@article {pmid25288403,
year = {2014},
author = {Rizzo, A and Iachettini, S and Zizza, P and Cingolani, C and Porru, M and Artuso, S and Stevens, M and Hummersone, M and Biroccio, A and Salvati, E and Leonetti, C},
title = {Identification of novel RHPS4-derivative ligands with improved toxicological profiles and telomere-targeting activities.},
journal = {Journal of experimental &amp; clinical cancer research : CR},
volume = {33},
number = {1},
pages = {81},
pmid = {25288403},
issn = {1756-9966},
mesh = {Acridines/chemistry/*pharmacology/toxicity ; Antineoplastic Agents/*pharmacology/toxicity ; Cell Proliferation/drug effects ; Colorectal Neoplasms/*drug therapy/genetics/metabolism/pathology ; *DNA Damage ; Dose-Response Relationship, Drug ; *Drug Design ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels/antagonists &amp; inhibitors/metabolism ; HT29 Cells ; Humans ; Ligands ; Membrane Potentials ; Molecular Structure ; Receptors, Adrenergic, beta-2/drug effects/metabolism ; Structure-Activity Relationship ; Telomere/*drug effects/genetics/metabolism ; },
abstract = {The pentacyclic acridinium salt RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino [4,3,2-kl] acridinium methosulfate, compound 1) is one of the most interesting DNA G-quadruplex binding molecules due to its high efficacy in tumor cell growth inhibition both in in vitro models and in vivo against human tumor xenografts in combination with conventional chemotherapeutics. Despite compound 1 having desirable chemical and pharmaceutical properties, its potential as a therapeutic agent is compromised by off-target effects on cardiovascular physiology. In this paper we report a new series of structurally-related compounds which were developed in an attempt to minimize its off-target profile, but maintaining the same favorable chemical and pharmacological features of the lead compound. By performing a comparative analysis it was possible to identify which derivatives had the following properties: (i) to show a reduced capacity in respect to compound 1 to inhibit the hERG tail current tested in a patch clamp assay and/or to interact with the human recombinant β2 receptor; (ii) to maintain both a good G4-binding affinity and cancer cell selectivity; and (iii) to trigger DNA damage with specific telomere uncapping. These studies allowed us to identify a novel G4-stabilizing molecule, compound 8, being characterized by reduced off-target effects and potent telomere on-target properties compared to the prototypic compound 1. Moreover, compound 8 shares with compound 1 the same molecular mode of action and an anti-tumour activity specifically restricted to replicating cells, as evident with its particularly efficient activity in combination therapy with a topoisomerase I inhibitor. In conclusion, we have identified a new pentacyclic derivative 8 having suitable properties to be the focus of further investigations as a clinical candidate for cancer therapy.},
}
@article {pmid25285314,
year = {2013},
author = {Morrish, TA and Bekbolysnov, D and Velliquette, D and Morgan, M and Ross, B and Wang, Y and Chaney, B and McQuigg, J and Fager, N and Maine, IP},
title = {Multiple Mechanisms Contribute To Telomere Maintenance.},
journal = {Journal of cancer biology &amp; research},
volume = {1},
number = {3},
pages = {},
pmid = {25285314},
issn = {2373-9436},
support = {R00 CA154889/CA/NCI NIH HHS/United States ; },
abstract = {The unlimited growth potential of tumors depends on telomere maintenance and typically depends on telomerase, an RNA-dependent DNA polymerase, which reverse transcribes the telomerase RNA template, synthesizing telomere repeats at the ends of chromosomes. Studies in various model organisms genetically deleted for telomerase indicate that several recombination-based mechanisms also contribute to telomere maintenance. Understanding the molecular basis of these mechanisms is critical since some human tumors form without telomerase, yet the sequence is maintained at the telomeres. Recombination-based mechanisms also likely contribute at some frequency to telomere maintenance in tumors expressing telomerase. Preventing telomere maintenance is predicted to impact tumor growth, yet inhibiting telomerase may select for the recombination-based mechanisms. Telomere recombination mechanisms likely involve altered or unregulated pathways of DNA repair. The use of some DNA damaging agents may encourage the use of these unregulated pathways of DNA repair to be utilized and may allow some tumors to generate resistance to these agents depending on which repair pathways are altered in the tumors. This review will discuss the various telomere recombination mechanisms and will provide rationale regarding the possibility that L1 retrotransposition may contribute to telomere maintenance in tumors lacking telomerase.},
}
@article {pmid25277538,
year = {2014},
author = {Mandrioli, M and Bandinelli, S and Manicardi, GC},
title = {Occurrence of Rabl-like telomere clustering in the holocentric chromosomes of the peach potato aphid Myzus persicae (Hemiptera; Aphididae).},
journal = {Cytogenetic and genome research},
volume = {144},
number = {1},
pages = {68-75},
doi = {10.1159/000366049},
pmid = {25277538},
issn = {1424-859X},
mesh = {Animals ; Aphids/*genetics/metabolism ; Chromosome Mapping ; Chromosomes, Insect/*genetics ; Female ; Heterochromatin/genetics/metabolism ; In Situ Hybridization, Fluorescence ; Insect Proteins/genetics/metabolism ; Karyotype ; Telomere/*genetics/metabolism ; },
abstract = {Several studies demonstrated that chromosome anchoring to nuclear structures is involved in the organization of the interphase nucleus. The Rabl configuration, a well-studied chromosome organization in the interphase nucleus, has been deeply studied in organisms with monocentric chromosomes but just slightly touched in species with holocentric chromosomes. In the present paper, by means of the isolation and chromosomal mapping of the C0t DNA fraction and chromatin immunoprecipitation with anti-LEM-2 antibodies, we evidenced the presence of few foci where telomeres and subtelomeric regions cluster in the aphid interphase nuclei, suggesting the occurrence of a Rabl-like chromosome configuration. The same experimental approaches also evidenced that most of the repetitive DNA of the 2 X chromosomes is located at the periphery of the nucleus, whereas the ribosomal genes, located at 1 telomere of each X chromosome, are present towards the inner portion of the nucleus, favoring their transcriptional activity.},
}
@article {pmid25277145,
year = {2014},
author = {Enokido, M and Suzuki, A and Sadahiro, R and Matsumoto, Y and Kuwahata, F and Takahashi, N and Goto, K and Otani, K},
title = {Parental care influences leukocyte telomere length with gender specificity in parents and offsprings.},
journal = {BMC psychiatry},
volume = {14},
number = {},
pages = {277},
pmid = {25277145},
issn = {1471-244X},
mesh = {Asian People ; Child ; *Child Rearing ; Female ; Healthy Volunteers ; Humans ; Leukocytes/*ultrastructure ; Male ; Parent-Child Relations ; Parents ; Sex Characteristics ; *Sex Factors ; Telomere/*physiology ; Young Adult ; },
abstract = {BACKGROUND: There have been several reports suggesting that adverse childhood experiences such as physical maltreatment and long institutionalization influence telomere length. However, there has been no study examining the relationship of telomere length with variations in parental rearing. In the present study, we examined the relationship of leukocyte telomere length with parental rearing in healthy subjects.<br><br>METHODS: The subjects were 581 unrelated healthy Japanese subjects. Perceived parental rearing was assessed by the Parental Bonding Instrument consisting of the care and protection factors. Leukocyte relative telomere length was determined by a quantitative real-time PCR method for a ratio of telomere/single copy gene.<br><br>RESULTS: In the multiple regression analyses, shorter telomere length in males was related to lower scores of paternal care (&#x3b2;&#x2009;=&#x2009;0.139, p&#x2009;<&#x2009;0.05), while that in females was related to lower scores of maternal care (&#x3b2;&#x2009;=&#x2009;0.195, p&#x2009;<&#x2009;0.01).<br><br>CONCLUSION: The present study suggests that there is linear relationship between parental care and telomere length which covers both lower and higher ends of parental care, and that the effects of parental care on telomere length are gender-specific in parents and offsprings.},
}
@article {pmid25274733,
year = {2014},
author = {Amiard, S and Olivier, M and Allain, E and Choi, K and Smith-Unna, R and Henderson, IR and White, CI and Gallego, ME},
title = {Telomere stability and development of ctc1 mutants are rescued by inhibition of EJ recombination pathways in a telomerase-dependent manner.},
journal = {Nucleic acids research},
volume = {42},
number = {19},
pages = {11979-11991},
pmid = {25274733},
issn = {1362-4962},
mesh = {Arabidopsis/genetics/growth &amp; development ; Arabidopsis Proteins/*genetics/*physiology ; *DNA End-Joining Repair ; DNA Helicases/genetics ; DNA Repair ; Mutation ; *Recombination, Genetic ; Repetitive Sequences, Nucleic Acid ; Telomerase/genetics/*physiology ; Telomere/chemistry ; *Telomere Homeostasis ; Telomere Shortening ; Telomere-Binding Proteins/*genetics ; },
abstract = {The telomeres of linear eukaryotic chromosomes are protected by caps consisting of evolutionarily conserved nucleoprotein complexes. Telomere dysfunction leads to recombination of chromosome ends and this can result in fusions which initiate chromosomal breakage-fusion-bridge cycles, causing genomic instability and potentially cell death or cancer. We hypothesize that in the absence of the recombination pathways implicated in these fusions, deprotected chromosome ends will instead be eroded by nucleases, also leading to the loss of genes and cell death. In this work, we set out to specifically test this hypothesis in the plant, Arabidopsis. Telomere protection in Arabidopsis implicates KU and CST and their absence leads to chromosome fusions, severe genomic instability and dramatic developmental defects. We have analysed the involvement of end-joining recombination pathways in telomere fusions and the consequences of this on genomic instability and growth. Strikingly, the absence of the multiple end-joining pathways eliminates chromosome fusion and restores normal growth and development to cst ku80 mutant plants. It is thus the chromosomal fusions, per se, which are the underlying cause of the severe developmental defects. This rescue is mediated by telomerase-dependent telomere extension, revealing a competition between telomerase and end-joining recombination proteins for access to deprotected telomeres.},
}
@article {pmid25274533,
year = {2015},
author = {M'kacher, R and Girinsky, T and Colicchio, B and Ricoul, M and Dieterlen, A and Jeandidier, E and Heidingsfelder, L and Cuceu, C and Shim, G and Frenzel, M and Lenain, A and Morat, L and Bourhis, J and Hempel, WM and Koscielny, S and Paul, JF and Carde, P and Sabatier, L},
title = {Telomere shortening: a new prognostic factor for cardiovascular disease post-radiation exposure.},
journal = {Radiation protection dosimetry},
volume = {164},
number = {1-2},
pages = {134-137},
doi = {10.1093/rpd/ncu296},
pmid = {25274533},
issn = {1742-3406},
mesh = {Adolescent ; Adult ; Aged ; Biological Assay/methods/statistics &amp; numerical data ; Causality ; Child ; Cohort Studies ; Comorbidity ; Coronary Artery Disease/*genetics/*mortality ; Female ; Hodgkin Disease/mortality/*radiotherapy ; Humans ; Incidence ; Male ; Middle Aged ; Prognosis ; Radiometry/methods/*statistics &amp; numerical data ; Radiotherapy Dosage ; Radiotherapy, Conformal/*statistics &amp; numerical data ; Reproducibility of Results ; Risk Assessment/methods ; Sensitivity and Specificity ; Survival Rate ; Telomere Shortening/genetics/*physiology ; Young Adult ; },
abstract = {Telomere length has been proposed as a marker of mitotic cell age and as a general index of human organism aging. Telomere shortening in peripheral blood lymphocytes has been linked to cardiovascular-related morbidity and mortality. The authors investigated the potential correlation of conventional risk factors, radiation dose and telomere shortening with the development of coronary artery disease (CAD) following radiation therapy in a large cohort of Hodgkin lymphoma (HL) patients. Multivariate analysis demonstrated that hypertension and telomere length were the only independent risk factors. This is the first study in a large cohort of patients that demonstrates significant telomere shortening in patients treated by radiation therapy who developed cardiovascular disease. Telomere length appears to be an independent prognostic factor that could help determine patients at high risk of developing CAD after exposure in order to implement early detection and prevention.},
}
@article {pmid25271372,
year = {2014},
author = {Schmidt, JC and Dalby, AB and Cech, TR},
title = {Identification of human TERT elements necessary for telomerase recruitment to telomeres.},
journal = {eLife},
volume = {3},
number = {},
pages = {},
pmid = {25271372},
issn = {2050-084X},
support = {R01 GM099705/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Base Sequence ; Chromosomes, Human/*chemistry/metabolism ; Gene Expression Regulation ; HEK293 Cells ; HeLa Cells ; Humans ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Subunits/*chemistry/genetics/metabolism ; Protein Transport ; Recombinant Proteins/chemistry/genetics/metabolism ; Sequence Alignment ; Shelterin Complex ; Telomerase/*chemistry/genetics/metabolism ; Telomere/*chemistry/metabolism ; Telomere-Binding Proteins/*chemistry/genetics/metabolism ; },
abstract = {Human chromosomes terminate in telomeres, repetitive DNA sequences bound by the shelterin complex. Shelterin protects chromosome ends, prevents recognition by the DNA damage machinery, and recruits telomerase. A patch of amino acids, termed the TEL-patch, on the OB-fold domain of the shelterin component TPP1 is essential to recruit telomerase to telomeres. In contrast, the site on telomerase that interacts with the TPP1 OB-fold is not well defined. In this study, we identify separation-of-function mutations in the TEN-domain of human telomerase reverse transcriptase (hTERT) that disrupt the interaction of telomerase with TPP1 in vivo and in vitro but have very little effect on the catalytic activity of telomerase. Suppression of a TEN-domain mutation with a compensatory charge-swap mutation in the TEL-patch indicates that their association is direct. Our findings define the interaction interface required for telomerase recruitment to telomeres, an important step towards developing modulators of this interaction as therapeutics for human disease.},
}
@article {pmid25268841,
year = {2014},
author = {Beirne, C and Delahay, R and Hares, M and Young, A},
title = {Age-related declines and disease-associated variation in immune cell telomere length in a wild mammal.},
journal = {PloS one},
volume = {9},
number = {9},
pages = {e108964},
pmid = {25268841},
issn = {1932-6203},
support = {BB/H022716/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {*Aging ; Animals ; Cattle ; Female ; Leukocytes/*metabolism ; Longevity ; Male ; Mustelidae/*genetics ; Telomere/*metabolism ; Telomere Shortening ; Tuberculosis, Bovine/*pathology ; },
abstract = {Immunosenescence, the deterioration of immune system capability with age, may play a key role in mediating age-related declines in whole-organism performance, but the mechanisms that underpin immunosenescence are poorly understood. Biomedical research on humans and laboratory models has documented age and disease related declines in the telomere lengths of leukocytes ('immune cells'), stimulating interest their having a potentially general role in the emergence of immunosenescent phenotypes. However, it is unknown whether such observations generalise to the immune cell populations of wild vertebrates living under ecologically realistic conditions. Here we examine longitudinal changes in the mean telomere lengths of immune cells in wild European badgers (Meles meles). Our findings provide the first evidence of within-individual age-related declines in immune cell telomere lengths in a wild vertebrate. That the rate of age-related decline in telomere length appears to be steeper within individuals than at the overall population level raises the possibility that individuals with short immune cell telomeres and/or higher rates of immune cell telomere attrition may be selectively lost from this population. We also report evidence suggestive of associations between immune cell telomere length and bovine tuberculosis infection status, with individuals detected at the most advanced stage of infection tending to have shorter immune cell telomeres than disease positive individuals. While male European badgers are larger and show higher rates of annual mortality than females, we found no evidence of a sex difference in either mean telomere length or the average rate of within-individual telomere attrition with age. Our findings lend support to the view that age-related declines in the telomere lengths of immune cells may provide one potentially general mechanism underpinning age-related declines in immunocompetence in natural populations.},
}
@article {pmid25266121,
year = {2015},
author = {Gotlib, IH and LeMoult, J and Colich, NL and Foland-Ross, LC and Hallmayer, J and Joormann, J and Lin, J and Wolkowitz, OM},
title = {Telomere length and cortisol reactivity in children of depressed mothers.},
journal = {Molecular psychiatry},
volume = {20},
number = {5},
pages = {615-620},
pmid = {25266121},
issn = {1476-5578},
support = {R01 MH074849/MH/NIMH NIH HHS/United States ; MH74849/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Child ; Depressive Disorder, Major/*metabolism/*pathology ; Female ; Humans ; Hydrocortisone/*metabolism ; Linear Models ; Mother-Child Relations/*psychology ; Mothers/psychology ; Saliva/metabolism ; Statistics as Topic ; Surveys and Questionnaires ; Telomere/*genetics/pathology ; Time Factors ; },
abstract = {A growing body of research demonstrates that individuals diagnosed with major depressive disorder (MDD) are characterized by shortened telomere length, which has been posited to underlie the association between depression and increased instances of medical illness. The temporal nature of the relation between MDD and shortened telomere length, however, is not clear. Importantly, both MDD and telomere length have been associated independently with high levels of stress, implicating dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and anomalous levels of cortisol secretion in this relation. Despite these associations, no study has assessed telomere length or its relation with HPA-axis activity in individuals at risk for depression, before the onset of disorder. In the present study, we assessed cortisol levels in response to a laboratory stressor and telomere length in 97 healthy young daughters of mothers either with recurrent episodes of depression (i.e., daughters at familial risk for depression) or with no history of psychopathology. We found that daughters of depressed mothers had shorter telomeres than did daughters of never-depressed mothers and, further, that shorter telomeres were associated with greater cortisol reactivity to stress. This study is the first to demonstrate that children at familial risk of developing MDD are characterized by accelerated biological aging, operationalized as shortened telomere length, before they had experienced an onset of depression; this may predispose them to develop not only MDD but also other age-related medical illnesses. It is critical, therefore, that we attempt to identify and distinguish genetic and environmental mechanisms that contribute to telomere shortening.},
}
@article {pmid25264618,
year = {2014},
author = {Rybanska-Spaeder, I and Ghosh, R and Franco, S},
title = {53BP1 mediates the fusion of mammalian telomeres rendered dysfunctional by DNA-PKcs loss or inhibition.},
journal = {PloS one},
volume = {9},
number = {9},
pages = {e108731},
pmid = {25264618},
issn = {1932-6203},
mesh = {Adaptor Proteins, Signal Transducing ; Animals ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Cell Cycle Proteins ; Chromones/pharmacology ; Chromosomal Proteins, Non-Histone/*metabolism ; DNA Ligases/metabolism ; DNA Replication/drug effects ; DNA-Activated Protein Kinase/*antagonists &amp; inhibitors/*deficiency/metabolism ; DNA-Binding Proteins/*metabolism ; Embryo, Mammalian/cytology ; Epistasis, Genetic/drug effects ; Fibroblasts/drug effects/enzymology/metabolism ; G1 Phase ; Histones/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Mammals/*metabolism ; Mice ; Morpholines/pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; Protein Kinase Inhibitors/pharmacology ; S Phase/drug effects ; Telomere/*metabolism ; Tumor Suppressor p53-Binding Protein 1 ; },
abstract = {Telomere dysfunction promotes genomic instability and carcinogenesis via inappropriate end-to-end chromosomal rearrangements, or telomere fusions. Previous work indicates that the DNA Damage Response (DDR) factor 53BP1 promotes the fusion of telomeres rendered dysfunctional by loss of TRF2, but is dispensable for the fusion of telomeres lacking Pot1 or critically shortened (in telomerase-deficient mice). Here, we examine a role for 53BP1 at telomeres rendered dysfunctional by loss or catalytic inhibition of DNA-PKcs. Using mouse embryonic fibroblasts lacking 53BP1 and/or DNA-PKcs, we show that 53BP1 deficiency suppresses G1-generated telomere fusions that normally accumulate in DNA-PKcs-deficient fibroblasts with passage. Likewise, we find that 53BP1 promotes telomere fusions during the replicative phases of the cell cycle in cells treated with the specific DNA-PKcs inhibitor NU7026. However, telomere fusions are not fully abrogated in DNA-PKcs-inhibited 53BP1-deficient cells, but occur with a frequency approximately 10-fold lower than in control 53BP1-proficient cells. Treatment with PARP inhibitors or PARP1 depletion abrogates residual fusions, while Ligase IV depletion has no measurable effect, suggesting that PARP1-dependent alternative end-joining operates at low efficiency at 53BP1-deficient, DNA-PKcs-inhibited telomeres. Finally, we have also examined the requirement for DDR factors ATM, MDC1 or H2AX in this context. We find that ATM loss or inhibition has no measurable effect on the frequency of NU7026-induced fusions in wild-type MEFs. Moreover, analysis of MEFs lacking both ATM and 53BP1 indicates that ATM is also dispensable for telomere fusions via PARP-dependent end-joining. In contrast, loss of either MDC1 or H2AX abrogates telomere fusions in response to DNA-PKcs inhibition, suggesting that these factors operate upstream of both 53BP1-dependent and -independent telomere rejoining. Together, these experiments define a novel requirement for 53BP1 in the fusions of DNA-PKcs-deficient telomeres throughout the cell cycle and uncover a Ligase IV-independent, PARP1-dependent pathway that fuses telomeres at reduced efficiency in the absence of 53BP1.},
}
@article {pmid25263563,
year = {2014},
author = {Klermund, J and Bender, K and Luke, B},
title = {High nutrient levels and TORC1 activity reduce cell viability following prolonged telomere dysfunction and cell cycle arrest.},
journal = {Cell reports},
volume = {9},
number = {1},
pages = {324-335},
doi = {10.1016/j.celrep.2014.08.053},
pmid = {25263563},
issn = {2211-1247},
mesh = {Cell Cycle Checkpoints/genetics/*physiology ; Cell Survival/physiology ; *DNA Damage ; DNA Repair ; Mechanistic Target of Rapamycin Complex 1 ; Multiprotein Complexes/*genetics/*metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/*genetics/*metabolism ; Telomere/genetics/*metabolism ; Yeasts ; },
abstract = {Cells challenged with DNA damage activate checkpoints to arrest the cell cycle and allow time for repair. Successful repair coupled to subsequent checkpoint inactivation is referred to as recovery. When DNA damage cannot be repaired, a choice between permanent arrest and cycling in the presence of damage (checkpoint adaptation) must be made. While permanent arrest jeopardizes future lineages, continued proliferation is associated with the risk of genome instability. We demonstrate that nutritional signaling through target of rapamycin complex 1 (TORC1) influences the outcome of this decision. Rapamycin-mediated TORC1 inhibition prevents checkpoint adaptation via both Cdc5 inactivation and autophagy induction. Preventing adaptation results in increased cell viability and hence proliferative potential. In accordance, the ability of rapamycin to increase longevity is dependent upon the DNA damage checkpoint. The crosstalk between TORC1 and the DNA damage checkpoint may have important implications in terms of therapeutic alternatives for diseases associated with genome instability.},
}
@article {pmid25259924,
year = {2014},
author = {Cho, NW and Dilley, RL and Lampson, MA and Greenberg, RA},
title = {Interchromosomal homology searches drive directional ALT telomere movement and synapsis.},
journal = {Cell},
volume = {159},
number = {1},
pages = {108-121},
pmid = {25259924},
issn = {1097-4172},
support = {CA138835/CA/NCI NIH HHS/United States ; R01 GM083988/GM/NIGMS NIH HHS/United States ; R01 CA174904/CA/NCI NIH HHS/United States ; T32 GM007170/GM/NIGMS NIH HHS/United States ; R01 GM101149/GM/NIGMS NIH HHS/United States ; CA17494/CA/NCI NIH HHS/United States ; R01 CA138835/CA/NCI NIH HHS/United States ; GM101149/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Chromatin/metabolism ; *Chromosome Pairing ; DNA Breaks, Double-Stranded ; Homologous Recombination ; Humans ; Nuclear Proteins/metabolism ; *Recombination, Genetic ; Site-Specific DNA-Methyltransferase (Adenine-Specific)/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; Trans-Activators/metabolism ; },
abstract = {Telomere length maintenance is a requisite feature of cellular immortalization and a hallmark of human cancer. While most human cancers express telomerase activity, ∼10%-15% employ a recombination-dependent telomere maintenance pathway known as alternative lengthening of telomeres (ALT) that is characterized by multitelomere clusters and associated promyelocytic leukemia protein bodies. Here, we show that a DNA double-strand break (DSB) response at ALT telomeres triggers long-range movement and clustering between chromosome termini, resulting in homology-directed telomere synthesis. Damaged telomeres initiate increased random surveillance of nuclear space before displaying rapid directional movement and association with recipient telomeres over micron-range distances. This phenomenon required Rad51 and the Hop2-Mnd1 heterodimer, which are essential for homologous chromosome synapsis during meiosis. These findings implicate a specialized homology searching mechanism in ALT-dependent telomere maintenance and provide a molecular basis underlying the preference for recombination between nonsister telomeres during ALT.},
}
@article {pmid25259914,
year = {2014},
author = {Arnoult, N and Karlseder, J},
title = {ALT telomeres borrow from meiosis to get moving.},
journal = {Cell},
volume = {159},
number = {1},
pages = {11-12},
pmid = {25259914},
issn = {1097-4172},
support = {R01 CA174942/CA/NCI NIH HHS/United States ; R01 GM087476/GM/NIGMS NIH HHS/United States ; GM087476/GM/NIGMS NIH HHS/United States ; CA174942/CA/NCI NIH HHS/United States ; },
mesh = {*Chromosome Pairing ; Humans ; *Recombination, Genetic ; Telomere/*metabolism ; },
abstract = {Telomere clustering is required for the homologous recombination events that maintain chromosome ends in cells relying on alternative lengthening of telomeres (ALT). New data demonstrate that damage signaling at telomeres, a likely step in activating maintenance mechanisms, induces directional movement and synapsis driven by the machinery responsible for recombination in meiosis.},
}
@article {pmid25257970,
year = {2015},
author = {Ishii, T and Gemma, A and Kida, K},
title = {Senescence is involved in the pathogenesis of chronic obstructive pulmonary disease through effects on telomeres and the anti-aging molecule fibroblast growth factor 23.},
journal = {Geriatrics &amp; gerontology international},
volume = {15},
number = {7},
pages = {827-833},
doi = {10.1111/ggi.12354},
pmid = {25257970},
issn = {1447-0594},
mesh = {Aged ; Aging/blood/*genetics ; Animals ; DNA/*genetics ; Female ; Fibroblast Growth Factor-23 ; Fibroblast Growth Factors/blood/*genetics ; Genotype ; Humans ; Male ; Mice ; Middle Aged ; Multidetector Computed Tomography ; Polymerase Chain Reaction ; *Polymorphism, Single Nucleotide ; Pulmonary Disease, Chronic Obstructive/blood/diagnostic imaging/*genetics ; *Telomere ; },
abstract = {AIM: Fibroblast growth factor 23 knockout mice develop premature aging and emphysema, indicating that dysregulation of the normal aging process is involved in the pathobiology of chronic obstructive pulmonary disease. Thus, we explored the association among a coding single-nucleotide polymorphism of fibroblast growth factor 23, its protein concentration in serum and telomere length in patients with chronic obstructive pulmonary disease.<br><br>METHODS: The study involved 361 smokers; among whom, 244 were patients with chronic obstructive pulmonary disease. We genotyped a coding single-nucleotide polymorphism of fibroblast growth factor&#x2009;23, rs7955866, and measured the telomere length of the peripheral blood cells. We also determined emphysema severity and airflow obstruction using computed tomography and pulmonary function tests, respectively. Furthermore, we analyzed the association between the disease phenotypes and fibroblast growth factor&#x2009;23 genotypes or telomere length of peripheral blood leukocytes, as well as the association between the serum level of the studied protein and its genotypes.<br><br>RESULTS: The mice with A&#x2009;alleles on rs7955866 showed severe upper lung emphysema (P&#x2009;=&#x2009;0.008). The serum concentration of the tested protein was lower in the mice with A&#x2009;allele than in the G&#x2009;homozygotes (P&#x2009;=&#x2009;0.004). Telomere shortening was associated with airflow obstruction (P&#x2009;=&#x2009;0.009), but not with upper lung emphysema.<br><br>CONCLUSIONS: A variation of fibroblast growth factor&#x2009;23 with a reduced serum concentration appeared to promote emphysema formation. Telomere shortening in peripheral blood leukocytes was not associated with emphysema, but with airflow obstruction in chronic obstructive pulmonary disease through an independent mechanism.},
}
@article {pmid25257515,
year = {2015},
author = {Azzalin, CM and Lingner, J},
title = {Telomere functions grounding on TERRA firma.},
journal = {Trends in cell biology},
volume = {25},
number = {1},
pages = {29-36},
doi = {10.1016/j.tcb.2014.08.007},
pmid = {25257515},
issn = {1879-3088},
mesh = {Animals ; Cell Cycle/physiology ; DNA Replication/physiology ; Humans ; RNA, Long Noncoding/*physiology ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; Transcription, Genetic/physiology ; },
abstract = {Long noncoding telomeric repeat-containing RNAs - TERRAs - are transcribed in a regulated manner from telomeres throughout eukaryotes. TERRA molecules consist of chromosome end-specific subtelomeric sequences and telomeric repeats at their 3' ends. Recent work suggests that TERRA sustains several important functions at chromosome ends. TERRA can regulate telomere length through modulation of exonuclease 1 and telomerase, it may promote recruitment of chromatin modifiers to damaged telomeres and thereby enable DNA end-processing, and it may promote telomere protein composition changes during cell cycle progression. Furthermore, telomere transcription regulates chromosome-end mobility within the nucleus. We review how TERRA, by regulated expression and by providing a molecular scaffold for various protein enzymes, can support a large variety of vital functions.},
}
@article {pmid25256607,
year = {2015},
author = {Chen, X and Velez, JC and Barbosa, C and Pepper, M and Andrade, A and Stoner, L and De Vivo, I and Gelaye, B and Williams, MA},
title = {Smoking and perceived stress in relation to short salivary telomere length among caregivers of children with disabilities.},
journal = {Stress (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {20-28},
pmid = {25256607},
issn = {1607-8888},
support = {8UL1TR000170-05/TR/NCATS NIH HHS/United States ; T37 MD001449/MD/NIMHD NIH HHS/United States ; 2R01 CA082838/CA/NCI NIH HHS/United States ; R01 CA082838/CA/NCI NIH HHS/United States ; UL1 TR000170/TR/NCATS NIH HHS/United States ; T37-MD001449/MD/NIMHD NIH HHS/United States ; },
mesh = {Adaptation, Psychological ; Adult ; Aged ; Caregivers/*psychology ; Chi-Square Distribution ; Child ; Chile ; Cross-Sectional Studies ; Disabled Children/*rehabilitation ; Female ; *Health Knowledge, Attitudes, Practice ; Humans ; Linear Models ; Logistic Models ; Male ; Middle Aged ; Odds Ratio ; *Perception ; Polymerase Chain Reaction ; Risk Factors ; Saliva/*chemistry ; Smoking/adverse effects/genetics/*psychology ; Stress, Psychological/diagnosis/*etiology/genetics ; Surveys and Questionnaires ; *Telomere Shortening ; Young Adult ; },
abstract = {Telomere length (TL), the length of repeated DNA sequence that forms protective caps at the end of chromosomes, has emerged as a novel biomarker of cell aging and oxidative stress. There is increasing research exploring the associations of smoking and perceived stress with TL, and the results are inconsistent. This study aimed to examine whether smoking and perceived stress were associated with shortened salivary TL among primary caregivers of children with disabilities. Using a quantitative polymerase chain reaction method, salivary TL was assessed among 89 caregivers aged 19-69 years (87% were women) who took care of disabled children in the Patagonia Region, Chile. Interviewer-administered questionnaires were used to collect information on sociodemographic and lifestyle factors. The 14-item Perceived Stress Scale was used to assess perceived stress. Mean relative TL was 0.92 (standard error = 0.03). Smokers had age-adjusted mean TL that was 0.07 units lower (β = -0.07, standard error = 0.03; p = 0.012) than non-smokers. Smokers were 2.17 times more likely to have shorter TL (< 0.73, the lowest quartile of TL) than non-smokers (odds ratio = 3.17; 95% confidence interval = 1.05-9.52) with adjustment for age and perceived stress. Caregivers with higher perceived stress were 2.13 times more likely to have shorter TL (odds ratio = 3.13; 95% confidence interval = 1.03-9.55) than caregivers with lower perceived stress after adjustment for age and smoking. This study provides the first evidence of strong associations between smoking and perceived stress and shortened salivary TL among caregivers of children with disabilities. Larger studies with detailed information on smoking status are warranted to confirm our findings.},
}
@article {pmid25254351,
year = {2014},
author = {Hardy, J and Churikov, D and Géli, V and Simon, MN},
title = {Sgs1 and Sae2 promote telomere replication by limiting accumulation of ssDNA.},
journal = {Nature communications},
volume = {5},
number = {},
pages = {5004},
doi = {10.1038/ncomms6004},
pmid = {25254351},
issn = {2041-1723},
mesh = {DNA, Fungal/genetics/metabolism ; DNA, Single-Stranded/genetics/*metabolism ; Endonucleases/genetics/*metabolism ; RecQ Helicases/genetics/*metabolism ; Saccharomyces cerevisiae/*enzymology/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {In budding yeast, DNA ends are processed by the consecutive action of MRX/Sae2 and two redundant pathways dependent on Sgs1/Dna2 and Exo1, and this processing is counteracted by Ku heterodimer. Here we show that DNA end resection by Sae2 and Sgs1 is dispensable for normal telomere maintenance by telomerase. Instead, these proteins facilitate telomere replication and limit the accumulation of single-strand DNA (ssDNA) at replication fork pause sites. Loss of Sae2 and Sgs1 drives selection for compensatory mutations, notably in Ku, which are responsible for abrupt telomere shortening in cells lacking Sae2 and Sgs1. In telomerase-negative cells, Sae2 and Sgs1 play non-overlapping roles in generating ssDNA at eroded telomeres and are required for the formation of type II survivors. Thus, although their primary function in telomerase-positive cells is to sustain DNA replication over the sites that are prone to fork pausing, Sae2 and Sgs1 contribute to telomere resection in telomerase-deficient cells.},
}
@article {pmid25247188,
year = {2014},
author = {Di Domenico, EG and Romano, E and Del Porto, P and Ascenzioni, F},
title = {Multifunctional role of ATM/Tel1 kinase in genome stability: from the DNA damage response to telomere maintenance.},
journal = {BioMed research international},
volume = {2014},
number = {},
pages = {787404},
pmid = {25247188},
issn = {2314-6141},
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins/*genetics ; Cell Survival/*genetics ; DNA/*genetics ; DNA Damage/*genetics ; Genomic Instability/*genetics ; Humans ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {The mammalian protein kinase ataxia telangiectasia mutated (ATM) is a key regulator of the DNA double-strand-break response and belongs to the evolutionary conserved phosphatidylinositol-3-kinase-related protein kinases. ATM deficiency causes ataxia telangiectasia (AT), a genetic disorder that is characterized by premature aging, cerebellar neuropathy, immunodeficiency, and predisposition to cancer. AT cells show defects in the DNA damage-response pathway, cell-cycle control, and telomere maintenance and length regulation. Likewise, in Saccharomyces cerevisiae, haploid strains defective in the TEL1 gene, the ATM ortholog, show chromosomal aberrations and short telomeres. In this review, we outline the complex role of ATM/Tel1 in maintaining genomic stability through its control of numerous aspects of cellular survival. In particular, we describe how ATM/Tel1 participates in the signal transduction pathways elicited by DNA damage and in telomere homeostasis and its importance as a barrier to cancer development.},
}
@article {pmid25245948,
year = {2014},
author = {Wang, J and Tadeo, X and Hou, H and Andrews, S and Moresco, JJ and Yates, JR and Nagy, PL and Jia, S},
title = {Tls1 regulates splicing of shelterin components to control telomeric heterochromatin assembly and telomere length.},
journal = {Nucleic acids research},
volume = {42},
number = {18},
pages = {11419-11432},
pmid = {25245948},
issn = {1362-4962},
support = {P41 GM103533/GM/NIGMS NIH HHS/United States ; R01 MH067880/MH/NIMH NIH HHS/United States ; R01-GM085145/GM/NIGMS NIH HHS/United States ; HHSN268201000035C/HL/NHLBI NIH HHS/United States ; R01 GM085145/GM/NIGMS NIH HHS/United States ; R01-NS064253/NS/NINDS NIH HHS/United States ; P41 RR011823/RR/NCRR NIH HHS/United States ; },
mesh = {Heterochromatin/*metabolism ; Nuclear Proteins/genetics/*metabolism/physiology ; *RNA Splicing ; RNA Splicing Factors ; Schizosaccharomyces/genetics/metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism/physiology ; Spliceosomes/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {Heterochromatin preferentially forms at repetitive DNA elements through RNAi-mediated targeting of histone-modifying enzymes. It was proposed that splicing factors interact with the RNAi machinery or regulate the splicing of repeat transcripts to directly participate in heterochromatin assembly. Here, by screening the fission yeast deletion library, we comprehensively identified factors required for telomeric heterochromatin assembly, including a novel gene tls1+. Purification of Tls1 and mass spectrometry analysis of its interacting proteins show that Tls1 associates with the spliceosome subunit Brr2. RNA sequencing analysis shows that the splicing of a subset of mRNAs are affected in tls1Δ cells, including mRNAs of shelterin components rap1+ and poz1+. Importantly, replacing rap1+ and poz1+ with their cDNAs significantly alleviated heterochromatin defects of tls1Δ cells, suggesting that the missplicing of shelterin components is the cause of such defects, and that splicing factors regulate telomeric heterochromatin through the proper splicing of heterochromatin factors. In addition to its role in telomeric heterochromatin assembly, Tls1-mediated splicing of shelterin mRNAs also regulates telomere length. Given that its human homologue C9ORF78 also associates with the spliceosome and is overexpressed in multiple cancer cell lines, our results suggest that C9ORF78 overexpression might alter the proper splicing of genes during cancer progression.},
}
@article {pmid25245454,
year = {2014},
author = {Hussein, SS and Kreskowski, K and Ziegler, M and Klein, E and Hamid, AB and Kosyakova, N and Volleth, M and Liehr, T and Fan, X and Piaszinski, K},
title = {Mitotic stability of small supernumerary marker chromosomes depends on their shape and telomeres - a long term in vitro study.},
journal = {Gene},
volume = {552},
number = {2},
pages = {246-248},
doi = {10.1016/j.gene.2014.09.041},
pmid = {25245454},
issn = {1879-0038},
mesh = {Cell Line ; *Chromosome Aberrations ; *Chromosomes, Human ; Humans ; In Situ Hybridization, Fluorescence ; *Mitosis ; Mosaicism ; Telomere ; },
abstract = {Mosaicism is present in more than 50% of the cases with small supernumerary marker chromosomes (sSMCs) and karyotype 47,XX,+mar/46,XX or 47,XY,+mar/46,XY. Recently we provided first evidence that the mitotic stability of sSMC is dependent on their structure, i.e. their shape. Thus, here we performed a long term in vitro study on 12 selected cell lines from the Else Kröner-Fresenius-sSMC-cellbank (http://ssmc-tl.com/ekf-cellbank.html) to test mitotic sSMC stability systematically. The obtained results showed that inverted duplicated shaped and also the so-called complex sSMCs (group 1) are by far more stable, than centric-minute- or ring-shaped sSMCs (groups 2). Generally speaking, the percentage of cells with group-1-sSMCs remained stable over 90 days of cell culture, while that of group-2-sSMCs in parts dramatically decreased. In one group-2-cell line the sSMC was even lost completely after 30 days of in vitro culture, in others the sSMC was depleted in up to 40% of the cells. Still the highest rate of sSMC loss was recorded during EBV-transformation. Overall, the major difference between groups 1 and 2 was the number of telomeres per sSMC. In group 1 the sSMCs had "original" telomeres at both of their ends; in group 2 the sSMCs had either no, possibly secondary acquired and/or only one original telomere. This absence of protective telomeric sequences in group 2 seems to make sSMC more susceptible for loss during cell division. Still, also a growth advantage of cells without sSMC cannot be neglected entirely.},
}
@article {pmid25244922,
year = {2015},
author = {Robles-Espinoza, CD and Velasco-Herrera, Mdel C and Hayward, NK and Adams, DJ},
title = {Telomere-regulating genes and the telomere interactome in familial cancers.},
journal = {Molecular cancer research : MCR},
volume = {13},
number = {2},
pages = {211-222},
pmid = {25244922},
issn = {1557-3125},
support = {A12401/CRUK_/Cancer Research UK/United Kingdom ; A13031/CRUK_/Cancer Research UK/United Kingdom ; A14356/CRUK_/Cancer Research UK/United Kingdom ; 13031/CRUK_/Cancer Research UK/United Kingdom ; WT098051/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Cell Cycle Proteins/*genetics/metabolism ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Humans ; Neoplasms/*genetics/pathology ; Telomere/*metabolism/pathology ; Telomere Shortening ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomeres are repetitive sequence structures at the ends of linear chromosomes that consist of double-stranded DNA repeats followed by a short single-stranded DNA protrusion. Telomeres need to be replicated in each cell cycle and protected from DNA-processing enzymes, tasks that cells execute using specialized protein complexes such as telomerase (that includes TERT), which aids in telomere maintenance and replication, and the shelterin complex, which protects chromosome ends. These complexes are also able to interact with a variety of other proteins, referred to as the telomere interactome, to fulfill their biological functions and control signaling cascades originating from telomeres. Given their essential role in genomic maintenance and cell-cycle control, germline mutations in telomere-regulating proteins and their interacting partners have been found to underlie a variety of diseases and cancer-predisposition syndromes. These syndromes can be characterized by progressively shortening telomeres, in which carriers can present with organ failure due to stem cell senescence among other characteristics, or can also present with long or unprotected telomeres, providing an alternative route for cancer formation. This review summarizes the critical roles that telomere-regulating proteins play in cell-cycle control and cell fate and explores the current knowledge on different cancer-predisposing conditions that have been linked to germline defects in these proteins and their interacting partners.},
}
@article {pmid25244563,
year = {2014},
author = {von Känel, R and Malan, NT and Hamer, M and van der Westhuizen, FH and Malan, L},
title = {Leukocyte telomere length and hemostatic factors in a South African cohort: the SABPA Study.},
journal = {Journal of thrombosis and haemostasis : JTH},
volume = {12},
number = {12},
pages = {1975-1985},
doi = {10.1111/jth.12733},
pmid = {25244563},
issn = {1538-7836},
support = {//Medical Research Council/United Kingdom ; },
mesh = {Adult ; Algorithms ; Black People ; Cardiovascular Diseases/*blood ; Cohort Studies ; Female ; Fibrin Fibrinogen Degradation Products/chemistry ; Fibrinogen/chemistry ; Fibrinolysis ; Hemostasis ; Humans ; Incidence ; Leukocytes/cytology/*metabolism ; Male ; Middle Aged ; Plasminogen Activator Inhibitor 1/chemistry ; Software ; South Africa ; Telomere/*ultrastructure ; von Willebrand Factor/chemistry ; },
abstract = {BACKGROUND: Incident atherothrombotic disease is predicted by leukocyte telomere length, a marker of biological age, and hemostatic factor levels, indicating a hypercoagulable state. We hypothesized that shorter telomeres are associated with elevated circulating levels of hemostatic factors.<br><br>METHODS: We examined 171 South African (black) and 182 Caucasian (white) schoolteachers (mean age &#xb1; standard deviation, 48.5 &#xb1; 9.0 years; 50.4% women). Levels of fibrinogen, von Willebrand factor antigen (VWF:Ag), D-dimer and plasminogen activator inhibitor-1 antigen (PAI-1:Ag) were measured in plasma, and values were log-transformed before analysis. Relative average telomere length (content of telomere PCR product/content of human &#x3b2;-globin PCR product ratio, i.e. telomere/single-copy gene ratio) was assessed with multiplex quantitative real-time PCRs. Multivariate analyses included demographics, metabolic factors, health behavior, and medication.<br><br>RESULTS: Africans had shorter mean telomere length (0.82, 95% confidence interval [CI] 0.79-0.86 vs. 1.07, 95% CI 1.04-1.10) and higher fibrinogen (B = 0.085, 95% CI 0.061-0.109) and PAI-1:Ag (B = 0.255, 95% CI 0.206-0.303) levels, but lower VWF:Ag levels (B = - 0.059, 95% CI - 0.089 to - 0.028), than Caucasians. Shorter telomeres were associated with higher fibrinogen (B = - 0.045, 95% CI - 0.088 to - 0.001), VWF:Ag (B = - 0.137, 95% CI - 0.193 to - 0.081) and D-dimer (B = - 0.201, 95% CI - 0.377 to - 0.025) levels, conditional on ethnicity. An interaction emerged between ethnicity and telomere length for VWF:Ag level; that is, shorter telomeres were associated with higher VWF:Ag levels in Caucasians (B = - 0.170, 95% CI - 0.232 to - 0.108) but not in Africans.<br><br>CONCLUSIONS: Shorter telomeres were associated with increased levels of several hemostatic factors after adjustment for confounding variables, whereby ethnicity partially moderated this effect. A relationship between accelerated biological aging and hypercoagulability might contribute to the risk of premature atherothrombotic events.},
}
@article {pmid25239152,
year = {2015},
author = {Martin-Ruiz, CM and Baird, D and Roger, L and Boukamp, P and Krunic, D and Cawthon, R and Dokter, MM and van der Harst, P and Bekaert, S and de Meyer, T and Roos, G and Svenson, U and Codd, V and Samani, NJ and McGlynn, L and Shiels, PG and Pooley, KA and Dunning, AM and Cooper, R and Wong, A and Kingston, A and von Zglinicki, T},
title = {Reproducibility of telomere length assessment: an international collaborative study.},
journal = {International journal of epidemiology},
volume = {44},
number = {5},
pages = {1673-1683},
pmid = {25239152},
issn = {1464-3685},
support = {G0601333/MRC_/Medical Research Council/United Kingdom ; MC_UU_12019/1/MRC_/Medical Research Council/United Kingdom ; 16565/CRUK_/Cancer Research UK/United Kingdom ; 10-0021/AICR_/Worldwide Cancer Research/United Kingdom ; BB/F010966/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; G0500997/MRC_/Medical Research Council/United Kingdom ; BB/I020748/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Aging/*genetics ; Biomarkers ; Blotting, Southern ; DNA/*genetics ; Humans ; International Cooperation ; Real-Time Polymerase Chain Reaction ; Reproducibility of Results ; Telomere/*genetics ; },
abstract = {BACKGROUND: Telomere length is a putative biomarker of ageing, morbidity and mortality. Its application is hampered by lack of widely applicable reference ranges and uncertainty regarding the present limits of measurement reproducibility within and between laboratories.<br><br>METHODS: We instigated an international collaborative study of telomere length assessment: 10 different laboratories, employing 3 different techniques [Southern blotting, single telomere length analysis (STELA) and real-time quantitative PCR (qPCR)] performed two rounds of fully blinded measurements on 10 human DNA samples per round to enable unbiased assessment of intra- and inter-batch variation between laboratories and techniques.<br><br>RESULTS: Absolute results from different laboratories differed widely and could thus not be compared directly, but rankings of relative telomere lengths were highly correlated (correlation coefficients of 0.63-0.99). Intra-technique correlations were similar for Southern blotting and qPCR and were stronger than inter-technique ones. However, inter-laboratory coefficients of variation (CVs) averaged about 10% for Southern blotting and STELA and more than 20% for qPCR. This difference was compensated for by a higher dynamic range for the qPCR method as shown by equal variance after z-scoring. Technical variation per laboratory, measured as median of intra- and inter-batch CVs, ranged from 1.4% to 9.5%, with differences between laboratories only marginally significant (P = 0.06). Gel-based and PCR-based techniques were not different in accuracy.<br><br>CONCLUSIONS: Intra- and inter-laboratory technical variation severely limits the usefulness of data pooling and excludes sharing of reference ranges between laboratories. We propose to establish a common set of physical telomere length standards to improve comparability of telomere length estimates between laboratories.},
}
@article {pmid25234236,
year = {2014},
author = {Russo, A and Modica, F and Guarrera, S and Fiorito, G and Pardini, B and Viberti, C and Allione, A and Critelli, R and Bosio, A and Casetta, G and Cucchiarale, G and Destefanis, P and Gontero, P and Rolle, L and Zitella, A and Fontana, D and Frea, B and Vineis, P and Sacerdote, C and Matullo, G},
title = {Shorter leukocyte telomere length is independently associated with poor survival in patients with bladder cancer.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {23},
number = {11},
pages = {2439-2446},
doi = {10.1158/1055-9965.EPI-14-0228},
pmid = {25234236},
issn = {1538-7755},
mesh = {Aged ; Case-Control Studies ; Female ; Humans ; Male ; Prognosis ; Telomere/*genetics/pathology ; Telomere Shortening/*genetics ; Urinary Bladder Neoplasms/genetics/mortality ; },
abstract = {BACKGROUND: Shorter telomere length (TL) has been reported to be associated with increased risk of early death in elder individuals. Telomere shortening has been also related to chromosomal instability, which may possibly contribute to the development of several types of digestive or urogenital system cancers and smoking-related tumors. Therefore, we investigated the impact of TL on bladder cancer survival.<br><br>METHODS: TL was measured in leukocyte DNA from whole peripheral blood using quantitative real-time PCR in 463 patients with bladder cancer from a total 726 cases who were followed for up to 18 years.<br><br>RESULTS: Patients with muscle-invasive tumor/any grade had shorter telomere than patients with non-muscle-invasive tumor/high-grade and with non-muscle-invasive tumor/non-high-grade (TL reference 0.7 &#xb1; 0.2; vs. respectively, 0.8 &#xb1; 0.2, P = 3.4 &#xd7; 10(-2) and 0.8 &#xb1; 0.2, P = 3.6 &#xd7; 10(-2)). Moreover, patients in the lowest quartiles of TL were associated with decreased survival after diagnosis (log-rank test, P = 3.9 &#xd7; 10(-4)). A Cox regression adjusted by age, cancer aggressiveness, Bacillus Calmette-Gu&#xe9;rin, radical cystectomy, radiotherapy, and chemotherapy showed an independent effect of TL on bladder cancer survival (HR, 3.9; 95% confidence interval, 1.7-9.1; P = 1.2 &#xd7; 10(-3)).<br><br>CONCLUSIONS: Our results suggest that leukocyte TL is only partly related to tumor aggressiveness and that shorter telomeres act as independent prognostic predictor of survival in patients with bladder cancer. TL information may allow to better select therapeutic approaches in patients with the same stage and grade.<br><br>IMPACT: Blood leukocyte TL levels could provide an additional noninvasive prognostic marker to better predict survival and personalize therapies in patients with bladder cancer.},
}
@article {pmid25233904,
year = {2014},
author = {Kocak, H and Ballew, BJ and Bisht, K and Eggebeen, R and Hicks, BD and Suman, S and O'Neil, A and Giri, N and , and , and Maillard, I and Alter, BP and Keegan, CE and Nandakumar, J and Savage, SA},
title = {Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1.},
journal = {Genes &amp; development},
volume = {28},
number = {19},
pages = {2090-2102},
pmid = {25233904},
issn = {1549-5477},
support = {2612006550018C//PHS HHS/United States ; R01 HD058606/HD/NICHD NIH HHS/United States ; R00-CA-167644-03/CA/NCI NIH HHS/United States ; R00 CA167644/CA/NCI NIH HHS/United States ; R01-HD-058606/HD/NICHD NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; P30 AG013283/AG/NIA NIH HHS/United States ; P30-AG-013283/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Child ; Child, Preschool ; Dyskeratosis Congenita/*genetics/pathology ; Female ; Fetal Growth Retardation/*genetics/pathology ; Germ-Line Mutation/*genetics ; HeLa Cells ; Humans ; Infant ; Intellectual Disability/*genetics/pathology ; Male ; Microcephaly/*genetics/pathology ; Models, Molecular ; Mutation, Missense/genetics ; Pedigree ; Protein Structure, Tertiary ; Sequence Deletion/genetics ; Serine Proteases/chemistry/*genetics ; Shelterin Complex ; Telomerase/metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Germline mutations in telomere biology genes cause dyskeratosis congenita (DC), an inherited bone marrow failure and cancer predisposition syndrome. DC is a clinically heterogeneous disorder diagnosed by the triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia; Hoyeraal-Hreidarsson syndrome (HH), a clinically severe variant of DC, also includes cerebellar hypoplasia, immunodeficiency, and intrauterine growth retardation. Approximately 70% of DC cases are associated with a germline mutation in one of nine genes, the products of which are all involved in telomere biology. Using exome sequencing, we identified mutations in Adrenocortical Dysplasia Homolog (ACD) (encoding TPP1), a component of the telomeric shelterin complex, in one family affected by HH. The proband inherited a deletion from his father and a missense mutation from his mother, resulting in extremely short telomeres and a severe clinical phenotype. Characterization of the mutations revealed that the single-amino-acid deletion affecting the TEL patch surface of the TPP1 protein significantly compromises both telomerase recruitment and processivity, while the missense mutation in the TIN2-binding region of TPP1 is not as clearly deleterious to TPP1 function. Our results emphasize the critical roles of the TEL patch in proper stem cell function and demonstrate that TPP1 is the second shelterin component (in addition to TIN2) to be implicated in DC.},
}
@article {pmid25233189,
year = {2014},
author = {Missios, P and Zhou, Y and Guachalla, LM and von Figura, G and Wegner, A and Chakkarappan, SR and Binz, T and Gompf, A and Hartleben, G and Burkhalter, MD and Wulff, V and Günes, C and Sattler, RW and Song, Z and Illig, T and Klaus, S and Böhm, BO and Wenz, T and Hiller, K and Rudolph, KL},
title = {Glucose substitution prolongs maintenance of energy homeostasis and lifespan of telomere dysfunctional mice.},
journal = {Nature communications},
volume = {5},
number = {},
pages = {4924},
pmid = {25233189},
issn = {2041-1723},
mesh = {Aging ; Animals ; Blood Glucose/metabolism ; Calorimetry ; Crosses, Genetic ; DNA Damage ; Diet ; Energy Metabolism ; Fibroblasts/metabolism ; Gas Chromatography-Mass Spectrometry ; Glucose/*chemistry ; Glycolysis ; Heterozygote ; Homeostasis ; Insulin-Like Growth Factor I/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Oxygen/chemistry ; Sirolimus/chemistry ; TOR Serine-Threonine Kinases/metabolism ; Telomere/*ultrastructure ; Thymus Gland/metabolism ; },
abstract = {DNA damage and telomere dysfunction shorten organismal lifespan. Here we show that oral glucose administration at advanced age increases health and lifespan of telomere dysfunctional mice. The study reveals that energy consumption increases in telomere dysfunctional cells resulting in enhanced glucose metabolism both in glycolysis and in the tricarboxylic acid cycle at organismal level. In ageing telomere dysfunctional mice, normal diet provides insufficient amounts of glucose thus leading to impaired energy homeostasis, catabolism, suppression of IGF-1/mTOR signalling, suppression of mitochondrial biogenesis and tissue atrophy. A glucose-enriched diet reverts these defects by activating glycolysis, mitochondrial biogenesis and oxidative glucose metabolism. The beneficial effects of glucose substitution on mitochondrial function and glucose metabolism are blocked by mTOR inhibition but mimicked by IGF-1 application. Together, these results provide the first experimental evidence that telomere dysfunction enhances the requirement of glucose substitution for the maintenance of energy homeostasis and IGF-1/mTOR-dependent mitochondrial biogenesis in ageing tissues.},
}
@article {pmid25232467,
year = {2014},
author = {Kouroupis, D and Churchman, SM and McGonagle, D and Jones, EA},
title = {The assessment of CD146-based cell sorting and telomere length analysis for establishing the identity of mesenchymal stem cells in human umbilical cord.},
journal = {F1000Research},
volume = {3},
number = {},
pages = {126},
pmid = {25232467},
issn = {2046-1402},
support = {//Wellcome Trust/United Kingdom ; },
abstract = {Adult stem cells are characterised by longer telomeres compared to mature cells from the same tissue. In this study, candidate CD146 (+) umbilical cord (UC) mesenchymal stem cells (MSCs) were purified by cell sorting from UC tissue digests and their telomere lengths were measured in comparison to donor-matched CD146-negative fraction. UC tissue fragments were enzymatically treated with collagenase and the cells were used for cell sorting, colony-forming fibroblast (CFU-F) assay or for long-term MSC cultivation. Telomere lengths were measured by qPCR in both culture-expanded MSCs and candidate native UC MSCs. Immunohistochemistry was undertaken to study the topography of CD146 (+) cells. Culture-expanded UC MSCs had a stable expression of CD73, CD90 and CD105, whereas CD146 declined in later passages which correlated with the shortening of telomeres in the same cultures. In five out of seven donors, telomeres in candidate native UC MSCs (CD45 (-)CD235α (-)CD31 (-)CD146 (+)) were longer compared to donor-matched CD146 (-) population (CD45 (-)CD235α (-)CD31 (-)CD146 (-)). The frequency of CD45 (-)CD235α (-)CD31 (-)CD146 (+) cells measured by flow cytometry was ~1000-fold above that of CFU-Fs (means 10.4% and 0.01%, respectively). CD146 (+) cells were also abundant in situ having a broad topography including high levels of positivity in muscle areas in addition to vessels. Although qPCR-based telomere length analysis in sorted populations could be limited in its sensitivity, very high frequency of CD146 (+) cells in UC tissue suggests that CD146 expression alone is unlikely to be sufficient to identify and purify native MSCs from the UC tissue.},
}
@article {pmid25232057,
year = {2014},
author = {Wang, J and Lu, X and Sakk, V and Klein, CA and Rudolph, KL},
title = {Senescence and apoptosis block hematopoietic activation of quiescent hematopoietic stem cells with short telomeres.},
journal = {Blood},
volume = {124},
number = {22},
pages = {3237-3240},
pmid = {25232057},
issn = {1528-0020},
support = {322602/ERC_/European Research Council/International ; },
mesh = {Animals ; Apoptosis/*physiology ; Cell Cycle/genetics ; Cell Survival/genetics ; Cells, Cultured ; Cellular Senescence/*physiology ; Down-Regulation ; *Hematopoiesis/genetics ; Hematopoietic Stem Cells/*physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Telomere Shortening/*physiology ; },
abstract = {Telomere shortening limits the proliferative capacity of human cells, and age-dependent shortening of telomeres occurs in somatic tissues including hematopoietic stem cells (HSCs). It is currently unknown whether genomic and molecular damage that occurs in HSCs induced by telomere shortening is transmitted to the progenitor cells. Here we show that telomere shortening results in DNA damage accumulation and gene expression changes in quiescent HSCs of aged mice. Upon activation, a subset of HSCs with elevated levels of DNA damage and p16 expression are blocked from cell cycle entry, and apoptosis is induced in HSCs entering the cell cycle. Activation of both checkpoints associates with normalization of DNA damage and gene expression profiles at early progenitor stages. These findings indicate that quiescent HSCs have an elevated tolerance to accumulate genomic alterations in response to telomere shortening, but the transmission of these aberrations to the progenitor cell level is prevented by senescence and apoptosis.},
}
@article {pmid25231748,
year = {2014},
author = {Iles, MM and Bishop, DT and Taylor, JC and Hayward, NK and Brossard, M and Cust, AE and Dunning, AM and Lee, JE and Moses, EK and Akslen, LA and , and Andresen, PA and Avril, MF and Azizi, E and Scarrà, GB and Brown, KM and Dębniak, T and Elder, DE and Friedman, E and Ghiorzo, P and Gillanders, EM and Goldstein, AM and Gruis, NA and Hansson, J and Harland, M and Helsing, P and Hočevar, M and Höiom, V and , and Ingvar, C and Kanetsky, PA and Landi, MT and Lang, J and Lathrop, GM and Lubiński, J and Mackie, RM and Martin, NG and Molven, A and Montgomery, GW and Novaković, S and Olsson, H and Puig, S and Puig-Butille, JA and , and Radford-Smith, GL and Randerson-Moor, J and , and van der Stoep, N and van Doorn, R and Whiteman, DC and MacGregor, S and Pooley, KA and Ward, SV and Mann, GJ and Amos, CI and Pharoah, PD and Demenais, F and Law, MH and Newton Bishop, JA and Barrett, JH and , },
title = {The effect on melanoma risk of genes previously associated with telomere length.},
journal = {Journal of the National Cancer Institute},
volume = {106},
number = {10},
pages = {},
pmid = {25231748},
issn = {1460-2105},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; R01 CA083115/CA/NCI NIH HHS/United States ; C8216/A6129/CRUK_/Cancer Research UK/United Kingdom ; 19167/CRUK_/Cancer Research UK/United Kingdom ; 076113/WT_/Wellcome Trust/United Kingdom ; 294576/ERC_/European Research Council/International ; P30 CA023108/CA/NCI NIH HHS/United States ; CA83115/CA/NCI NIH HHS/United States ; C588/A10589/CRUK_/Cancer Research UK/United Kingdom ; 16565/CRUK_/Cancer Research UK/United Kingdom ; 16561/CRUK_/Cancer Research UK/United Kingdom ; /ImNIH/Intramural NIH HHS/United States ; MR/L01629X/1/MRC_/Medical Research Council/United Kingdom ; C588/A4994/CRUK_/Cancer Research UK/United Kingdom ; 10589/CRUK_/Cancer Research UK/United Kingdom ; 10124/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Australia ; Confounding Factors, Epidemiologic ; DNA Helicases/genetics ; Europe ; *Germ-Line Mutation ; Humans ; Israel ; Melanoma/*genetics ; *Polymorphism, Single Nucleotide ; Predictive Value of Tests ; RNA/genetics ; Research Design ; Ribonucleoproteins/genetics ; Skin Neoplasms/*genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics ; United States ; Zinc Fingers/genetics ; },
abstract = {Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10(-9), two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.},
}
@article {pmid25229770,
year = {2015},
author = {Liau, JY and Tsai, JH and Jeng, YM and Lee, JC and Hsu, HH and Yang, CY},
title = {Leiomyosarcoma with alternative lengthening of telomeres is associated with aggressive histologic features, loss of ATRX expression, and poor clinical outcome.},
journal = {The American journal of surgical pathology},
volume = {39},
number = {2},
pages = {236-244},
doi = {10.1097/PAS.0000000000000324},
pmid = {25229770},
issn = {1532-0979},
mesh = {Adult ; Aged ; Aged, 80 and over ; DNA Helicases/*biosynthesis/genetics ; DNA Mutational Analysis ; Female ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Kaplan-Meier Estimate ; Leiomyosarcoma/genetics/mortality/*pathology ; Male ; Middle Aged ; Nuclear Proteins/*biosynthesis/genetics ; Retrospective Studies ; Telomerase/genetics ; Telomere/genetics/*pathology ; Telomere Homeostasis/*physiology ; X-linked Nuclear Protein ; },
abstract = {Leiomyosarcoma is an aggressive soft tissue sarcoma with poor patient survival. Recently, it was shown that 53% to 62% of leiomyosarcomas use the alternative lengthening of telomeres (ALT) as their telomere maintenance mechanism. The molecular basis of this mechanism has not been elucidated. Studies of pancreatic neuroendocrine tumor have suggested that the inactivation of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein is associated with the ALT phenotype. In this study, we sought to determine the clinicopathologic features of leiomyosarcoma with the ALT phenotype and the possible relationship between this phenotype and ATRX/DAXX expression. Telomerase reverse transcriptase gene (TERT) promoter mutation analysis was also performed. Ninety-two leiomyosarcomas derived from the uterus, retroperitoneum/intra-abdomen, and various other sites were analyzed. Telomere-specific fluorescence in situ hybridization revealed that 59% (51/86) of leiomyosarcomas had the ALT phenotype. Loss of ATRX expression was observed in 33% of the tumors (30/92), and all but 2 ATRX-deficient tumors were ALT positive. Both the ALT phenotype and loss of ATRX expression were associated with epithelioid/pleomorphic cell morphology, tumor necrosis, and poor differentiation. None of the 92 cases lost DAXX expression. No TERT promoter mutation was detected (n=39). For survival analysis, poor differentiation, high FNCLCC grade, tumor size, and ALT phenotype were correlated with poor overall survival in univariate analysis. Tumor size and ALT phenotype remained independent prognostic factors in multivariate analysis. We concluded that the ALT phenotype in the leiomyosarcoma is associated with aggressive histologic features, loss of ATRX expression, and poor clinical outcome.},
}
@article {pmid25228584,
year = {2014},
author = {Doksani, Y and de Lange, T},
title = {The role of double-strand break repair pathways at functional and dysfunctional telomeres.},
journal = {Cold Spring Harbor perspectives in biology},
volume = {6},
number = {12},
pages = {a016576},
pmid = {25228584},
issn = {1943-0264},
support = {R01 AG016642/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *DNA Breaks, Double-Stranded ; DNA End-Joining Repair/physiology ; DNA Repair/*physiology ; *Evolution, Molecular ; Homologous Recombination/*physiology ; Humans ; *Models, Genetic ; Shelterin Complex ; Telomere/*physiology ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomeres have evolved to protect the ends of linear chromosomes from the myriad of threats posed by the cellular DNA damage signaling and repair pathways. Mammalian telomeres have to block nonhomologous end joining (NHEJ), thus preventing chromosome fusions; they need to control homologous recombination (HR), which could change telomere lengths; they have to avoid activating the ATM (ataxia telangiectasia mutated) and ATR (ATM- and RAD3-related) kinase pathways, which could induce cell cycle arrest; and they have to protect chromosome ends from hyperresection. Recent studies of telomeres have provided insights into the mechanisms of NHEJ and HR, how these double-strand break (DSB) repair pathways can be thwarted, and how telomeres have co-opted DNA repair factors to help in the protection of chromosome ends. These aspects of telomere biology are reviewed here with particular emphasis on recombination, the main focus of this collection.},
}
@article {pmid25228433,
year = {2014},
author = {Sudyka, J and Arct, A and Drobniak, S and Dubiec, A and Gustafsson, L and Cichoń, M},
title = {Experimentally increased reproductive effort alters telomere length in the blue tit (Cyanistes caeruleus).},
journal = {Journal of evolutionary biology},
volume = {27},
number = {10},
pages = {2258-2264},
doi = {10.1111/jeb.12479},
pmid = {25228433},
issn = {1420-9101},
mesh = {Aging ; Animals ; *Clutch Size ; Female ; Linear Models ; Longevity ; Male ; Passeriformes/embryology/genetics/*physiology ; Reproduction/*physiology ; Stress, Physiological ; Telomere/*genetics ; },
abstract = {Telomeres have recently been suggested to play important role in ageing and are considered to be a reliable ageing biomarkers. The life history theory predicts that costs of reproduction should be expressed in terms of accelerated senescence, and some empirical studies do confirm such presumption. Thus, a link between reproductive effort and telomere dynamics should be anticipated. Recent studies have indeed demonstrated that reproduction may trigger telomere loss, but actual impact of reproductive effort has not received adequate attention in experimental studies. Here, we experimentally manipulated reproductive effort by increasing the brood size in the wild blue tit (Cyanistes caeruleus). We show that parents attending enlarged broods experienced larger yearly telomere decay in comparison to control birds attending unaltered broods. In addition, we demonstrate that the change in telomere length differs between sexes, but this effect was independent from our treatment. To our knowledge, this is the first experimental study in the wild revealing that telomere dynamics may be linked to reproductive effort. Thus, telomere shortening may constitute one of the potential proximate mechanisms mediating the costs of reproduction.},
}
@article {pmid25225404,
year = {2014},
author = {An, N and Fleming, AM and Middleton, EG and Burrows, CJ},
title = {Single-molecule investigation of G-quadruplex folds of the human telomere sequence in a protein nanocavity.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {111},
number = {40},
pages = {14325-14331},
pmid = {25225404},
issn = {1091-6490},
support = {R01 GM093099/GM/NIGMS NIH HHS/United States ; GM093099/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; DNA/*chemistry/genetics/metabolism ; *G-Quadruplexes ; Hemolysin Proteins/chemistry/metabolism ; Humans ; Kinetics ; Models, Molecular ; Nanostructures/*chemistry ; Nanotechnology ; Nucleic Acid Conformation ; Oligonucleotides/chemistry/genetics/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Proteins/*chemistry/metabolism ; Tandem Repeat Sequences/genetics ; Telomere/*chemistry/genetics/metabolism ; },
abstract = {Human telomeric DNA consists of tandem repeats of the sequence 5'-TTAGGG-3' that can fold into various G-quadruplexes, including the hybrid, basket, and propeller folds. In this report, we demonstrate use of the α-hemolysin ion channel to analyze these subtle topological changes at a nanometer scale by providing structure-dependent electrical signatures through DNA-protein interactions. Whereas the dimensions of hybrid and basket folds allowed them to enter the protein vestibule, the propeller fold exceeds the size of the latch region, producing only brief collisions. After attaching a 25-mer poly-2'-deoxyadenosine extension to these structures, unraveling kinetics also were evaluated. Both the locations where the unfolding processes occur and the molecular shapes of the G-quadruplexes play important roles in determining their unfolding profiles. These results provide insights into the application of α-hemolysin as a molecular sieve to differentiate nanostructures as well as the potential technical hurdles DNA secondary structures may present to nanopore technology.},
}
@article {pmid25225329,
year = {2014},
author = {Upton, HE and Hong, K and Collins, K},
title = {Direct single-stranded DNA binding by Teb1 mediates the recruitment of Tetrahymena thermophila telomerase to telomeres.},
journal = {Molecular and cellular biology},
volume = {34},
number = {22},
pages = {4200-4212},
pmid = {25225329},
issn = {1098-5549},
support = {P41 GM103311/GM/NIGMS NIH HHS/United States ; R01 GM054198/GM/NIGMS NIH HHS/United States ; P41-GM103311/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle ; DNA, Single-Stranded/*metabolism ; DNA-Binding Proteins/analysis/*metabolism ; Models, Molecular ; Protein Binding ; Protozoan Proteins/analysis/*metabolism ; Telomerase/analysis/*metabolism ; Telomere/*metabolism ; Tetrahymena thermophila/cytology/*metabolism ; },
abstract = {The eukaryotic reverse transcriptase telomerase copies its internal RNA template to synthesize telomeric DNA repeats at chromosome ends in balance with sequence loss during cell proliferation. Previous work has established several factors involved in telomerase recruitment to telomeres in yeast and mammalian cells; however, it remains unclear what determines the association of telomerase with telomeres in other organisms. Here we investigate the cell cycle dependence of telomere binding by each of the seven Tetrahymena thermophila telomerase holoenzyme proteins TERT, p65, Teb1, p50, p75, p45, and p19. We observed coordinate cell cycle-regulated recruitment and release of all of the subunits, including the telomeric-repeat DNA-binding subunit Teb1. Using domain truncation and mutagenesis approaches, we investigated which subunits govern the interaction of telomerase holoenzyme with telomeres. Our results show that Teb1 is critical for telomere interaction of other holoenzyme subunits and demonstrate that high-affinity Teb1 DNA-binding activity is necessary and sufficient for cell cycle-regulated telomere association. Overall, these and additional findings indicate that in the ciliate Tetrahymena, telomerase recruitment to telomeres requires direct binding to single-stranded DNA, unlike the indirect DNA recognition through telomere-bound proteins essential in yeast and mammalian cells.},
}
@article {pmid25223896,
year = {2014},
author = {Lu, F and Liu, Y and Jiang, L and Yamaguchi, S and Zhang, Y},
title = {Role of Tet proteins in enhancer activity and telomere elongation.},
journal = {Genes &amp; development},
volume = {28},
number = {19},
pages = {2103-2119},
pmid = {25223896},
issn = {1549-5477},
support = {U01 DK089565/DK/NIDDK NIH HHS/United States ; U01DK089565/DK/NIDDK NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Animals ; DNA Methylation ; DNA-Binding Proteins/*genetics/*metabolism ; Dioxygenases ; Embryonic Stem Cells ; Enhancer Elements, Genetic/*physiology ; Gene Expression Profiling ; Gene Expression Regulation ; Gene Knockout Techniques ; Mice ; Promoter Regions, Genetic/physiology ; Proto-Oncogene Proteins/genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {DNA methylation at the C-5 position of cytosine (5mC) is one of the best-studied epigenetic modifications and plays important roles in diverse biological processes. Iterative oxidation of 5mC by the ten-eleven translocation (Tet) family of proteins generates 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). 5fC and 5caC are selectively recognized and excised by thymine DNA glycosylase (TDG), leading to DNA demethylation. Functional characterization of Tet proteins has been complicated by the redundancy between the three family members. Using CRISPR/Cas9 technology, we generated mouse embryonic stem cells (ESCs) deficient for all three Tet proteins (Tet triple knockout [TKO]). Whole-genome bisulfite sequencing (WGBS) analysis revealed that Tet-mediated DNA demethylation mainly occurs at distally located enhancers and fine-tunes the transcription of genes associated with these regions. Functional characterization of Tet TKO ESCs revealed a role for Tet proteins in regulating the two-cell embryo (2C)-like state under ESC culture conditions. In addition, Tet TKO ESCs exhibited increased telomere-sister chromatid exchange and elongated telomeres. Collectively, our study reveals a role for Tet proteins in not only DNA demethylation at enhancers but also regulating the 2C-like state and telomere homeostasis.},
}
@article {pmid25221511,
year = {2014},
author = {Marzetti, E and Lorenzi, M and Antocicco, M and Bonassi, S and Celi, M and Mastropaolo, S and Settanni, S and Valdiglesias, V and Landi, F and Bernabei, R and Onder, G},
title = {Shorter telomeres in peripheral blood mononuclear cells from older persons with sarcopenia: results from an exploratory study.},
journal = {Frontiers in aging neuroscience},
volume = {6},
number = {},
pages = {233},
pmid = {25221511},
issn = {1663-4365},
abstract = {BACKGROUND: Telomere shortening in peripheral blood mononuclear cells (PBMCs) has been associated with biological age and several chronic degenerative diseases. However, the relationship between telomere length and sarcopenia, a hallmark of the aging process, is unknown. The aim of the present study was therefore to determine whether PBMC telomeres obtained from sarcopenic older persons were shorter relative to non-sarcopenic peers. We further explored if PBMC telomere length was associated with frailty, a major clinical correlate of sarcopenia.<br><br>METHODS: Analyses were conducted in 142 persons aged &#x2265;65&#x2009;years referred to a geriatric outpatient clinic (University Hospital). The presence of sarcopenia was established according to the European Working Group on Sarcopenia in Older People criteria, with bioelectrical impedance analysis used for muscle mass estimation. The frailty status was determined by both the Fried's criteria (physical frailty, PF) and a modified Rockwood's frailty index (FI). Telomere length was measured in PBMCs by quantitative real-time polymerase chain reaction according to the telomere/single-copy gene ratio (T/S) method.<br><br>RESULTS: Among 142 outpatients (mean age 75.0&#x2009;&#xb1;&#x2009;6.5&#x2009;years, 59.2% women), sarcopenia was diagnosed in 23 individuals (19.3%). The PF phenotype was detected in 74 participants (52.1%). The average FI score was 0.46&#x2009;&#xb1;&#x2009;0.17. PBMC telomeres were shorter in sarcopenic subjects (T/S&#x2009;=&#x2009;0.21; 95% CI: 0.18-0.24) relative to non-sarcopenic individuals (T/S&#x2009;=&#x2009;0.26; 95% CI: 0.24-0.28; p&#x2009;=&#x2009;0.01), independent of age, gender, smoking habit, or comorbidity. No significant associations were determined between telomere length and either PF or the FI.<br><br>CONCLUSION: PBMC telomere length, expressed as T/S values, is shorter in older outpatients with sarcopenia. The cross-sectional assessment of PBMC telomere length is not sufficient at capturing the complex, multidimensional syndrome of frailty.},
}
@article {pmid25220466,
year = {2014},
author = {Wu, H and Becker, D and Krebber, H},
title = {Telomerase RNA TLC1 shuttling to the cytoplasm requires mRNA export factors and is important for telomere maintenance.},
journal = {Cell reports},
volume = {8},
number = {6},
pages = {1630-1638},
doi = {10.1016/j.celrep.2014.08.021},
pmid = {25220466},
issn = {2211-1247},
mesh = {Active Transport, Cell Nucleus ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; DEAD-box RNA Helicases/genetics/metabolism ; Karyopherins/metabolism ; Mutagenesis ; Nuclear Proteins/genetics/metabolism ; Nucleocytoplasmic Transport Proteins/genetics/metabolism ; Protein Binding ; RNA/*metabolism ; RNA-Binding Proteins/genetics/metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; ran GTP-Binding Protein/metabolism ; Exportin 1 Protein ; },
abstract = {Telomerases protect the ends of linear chromosomes from shortening. They are composed of an RNA (TLC1 in S. cerevisiae) and several proteins. TLC1 undergoes several maturation steps before it is exported into the cytoplasm to recruit the Est proteins for complete assembly. The mature telomerase is subsequently reimported into the nucleus, where it fulfills its function on telomeres. Here, we show that TLC1 export into the cytoplasm requires not only the Ran GTPase-dependent karyopherin Crm1/Xpo1 but also the mRNA export machinery. mRNA export factor mutants accumulate mature and export-competent TLC1 RNAs in their nuclei. Moreover, TLC1 physically interacts with the mRNA transport factors Mex67 and Dbp5/Rat8. Most importantly, we show that the nuclear export of TLC1 is an essential step for the formation of the functional RNA containing enzyme, because blocking TLC1 export in the mex67-5 xpo1-1 double mutant prevents its cytoplasmic maturation and leads to telomere shortening.},
}
@article {pmid25217290,
year = {2014},
author = {Terai, M and Izumiyama-Shimomura, N and Aida, J and Ishikawa, N and Kuroiwa, M and Arai, T and Toyoda, M and Nakamura, K and Takubo, K},
title = {Arm-specific telomere dynamics of each individual chromosome in induced pluripotent stem cells revealed by quantitative fluorescence in situ hybridization.},
journal = {Tissue &amp; cell},
volume = {46},
number = {6},
pages = {470-476},
doi = {10.1016/j.tice.2014.08.005},
pmid = {25217290},
issn = {1532-3072},
mesh = {Cells, Cultured ; *Chromosome Aberrations ; Chromosomes/genetics/*ultrastructure ; Diploidy ; Humans ; In Situ Hybridization, Fluorescence ; Induced Pluripotent Stem Cells/*ultrastructure ; Telomerase/metabolism ; Telomere/genetics/*ultrastructure ; },
abstract = {We have reported that telomere fluorescence units (TFUs) of established induced pluripotent stem cells (iPSCs) derived from human amnion (hAM933) and fetal lung fibroblasts (MRC-5) were significantly longer than those of the parental cells, and that the telomere extension rates varied quite significantly among clones without chromosomal instability, although the telomeres of other iPSCs derived from MRC-5 became shorter as the number of passages increased along with chromosomal abnormalities from an early stage. In the present study we attempted to clarify telomere dynamics in each individual chromosomal arm of parental cells and their derived clonal human iPSCs at different numbers of passages using quantitative fluorescence in situ hybridization (Q-FISH). Although no specific arm of any particular chromosome appeared to be consistently shorter or longer than most of the other chromosomes in any of the cell strains, telomere elongation in each chromosome of an iPSC appeared to be random and stochastic. However, in terms of the whole genome of any specific cell, the telomeres showed overall elongation associated with iPSC generation. We have thus demonstrated the specific telomere dynamics of each individual chromosomal arm in iPSCs derived from parental cells, and in the parental cells themselves, using Q-FISH.},
}
@article {pmid25215179,
year = {2014},
author = {Fesahat, F and Sheikhha, MH and Rasti, A and Nodoshan, FS and Zare-Zardini, H and Navabazam, AR},
title = {An Investigation on Mitochondrial DNA Deletions and Telomere Shortening during Multiple Passages of Adult Stem Cells.},
journal = {Avicenna journal of medical biotechnology},
volume = {6},
number = {3},
pages = {156-162},
pmid = {25215179},
issn = {2008-2835},
abstract = {BACKGROUND: Limited resources for adult stem cells necessitate their in vitro culture prior to clinical use. Investigating mitochondrial DNA (mtDNA) and telomere shortening has proved to be important indications of stem cell validity. This study was designed to investigate these indicators in multiple passages of three adult stem cell lines which were produced in our stem cell laboratory.<br><br>METHODS: In this study, Dental Pulp Stem Cells (DPSCs), Periapical Follicle Stem Cells (PAFSCs) and Human Foreskin Fibroblast (HFF) cell lines were expanded for 20 passages. After 1, 5, 10, 15 and 20 passages, expanded cells were harvested and DNA was extracted for further studies. Common mtDNA mutation was detected by multiplex PCR and telomere shortening was tested by Southern blot analysis.<br><br>RESULTS: The common deletion was not detected in any of the stem cells or cell lines after several passages. In addition, Southern blot analysis indicated that the mean difference of telomere length between first and last passage was 0.25 kb in DPSC, 0.1 kb in PAFSC and 0.32 kb in HFF which indicates that the mean telomere length in various passages of the samples showed insignificant changes.<br><br>CONCLUSION: Absence of mtDNA mutations in adult stem cell lines indicates good mitochondrial function even after 20 passages. In addition, absence of telomere shortening indicates stem cells validity after multiple passages. It is hoped this information could pave the way for using in vitro expansion of adult stem cells for future clinical applications.},
}
@article {pmid25212092,
year = {2016},
author = {Yoshikawa, H and Maranon, DG and Battaglia, CLR and Ehrhart, EJ and Charles, JB and Bailey, SM and LaRue, SM},
title = {Predicting clinical outcome in feline oral squamous cell carcinoma: tumour initiating cells, telomeres and telomerase.},
journal = {Veterinary and comparative oncology},
volume = {14},
number = {4},
pages = {371-383},
doi = {10.1111/vco.12117},
pmid = {25212092},
issn = {1476-5829},
mesh = {Animals ; Biomarkers, Tumor ; Carcinoma, Squamous Cell/pathology/*veterinary ; Cat Diseases/*pathology/therapy ; Cats ; Female ; Male ; Mouth Neoplasms/pathology/*veterinary ; Neoplastic Stem Cells/*pathology ; Predictive Value of Tests ; Telomerase/*metabolism ; Telomere ; },
abstract = {Feline oral squamous cell carcinoma (SCC) has very poor prognosis. Here, a retrospective pilot study was conducted on 20 feline oral SCC patients who underwent stereotactic radiation therapy (SRT), to evaluate: (1) the value of putative tumour initiating cell (TIC) markers of human head and neck SCC (CD44, Bmi-1); (2) telomere length (TL) specifically in putative TICs; and (3) tumour relative telomerase activity (TA). Significant inverse correlations were found between treatment outcomes and Bmi-1 expression, supporting the predictive value of Bmi-1 as a negative prognostic indicator. While TL exhibited a wide range of variability, particularly in very short fractions, many tumours possessed high levels of TA, which correlated with high levels of Bmi-1, Ki67 and EGFR. Taken together, our results imply that Bmi-1 and telomerase may represent novel therapeutic targets in feline oral SCC, as their inhibition - in combination with SRT - would be expected to have beneficial treatment outcome.},
}
@article {pmid25205116,
year = {2014},
author = {Guo, Y and Kartawinata, M and Li, J and Pickett, HA and Teo, J and Kilo, T and Barbaro, PM and Keating, B and Chen, Y and Tian, L and Al-Odaib, A and Reddel, RR and Christodoulou, J and Xu, X and Hakonarson, H and Bryan, TM},
title = {Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1.},
journal = {Blood},
volume = {124},
number = {18},
pages = {2767-2774},
pmid = {25205116},
issn = {1528-0020},
mesh = {Adult ; Alleles ; Anemia/genetics ; Bone Marrow/*pathology ; Bone Marrow Diseases/*genetics ; Child ; Exome/genetics ; Female ; Genome, Human/genetics ; Germ-Line Mutation/*genetics ; Humans ; Inheritance Patterns/*genetics ; Male ; Middle Aged ; Molecular Sequence Data ; Mutant Proteins/metabolism ; Neoplasms/genetics ; Pedigree ; Phenotype ; RNA, Messenger/genetics/metabolism ; Serine Proteases/*genetics ; Shelterin Complex ; Telomerase/*genetics/metabolism ; Telomere/*metabolism ; Telomere Homeostasis/genetics ; Telomere-Binding Proteins ; },
abstract = {Telomerase is a ribonucleoprotein enzyme that is necessary for overcoming telomere shortening in human germ and stem cells. Mutations in telomerase or other telomere-maintenance proteins can lead to diseases characterized by depletion of hematopoietic stem cells and bone marrow failure (BMF). Telomerase localization to telomeres requires an interaction with a region on the surface of the telomere-binding protein TPP1 known as the TEL patch. Here, we identify a family with aplastic anemia and other related hematopoietic disorders in which a 1-amino-acid deletion in the TEL patch of TPP1 (ΔK170) segregates with disease. All family members carrying this mutation, but not those with wild-type TPP1, have short telomeres. When introduced into 293T cells, TPP1 with the ΔK170 mutation is able to localize to telomeres but fails to recruit telomerase to telomeres, supporting a causal relationship between this TPP1 mutation and bone marrow disorders. ACD/TPP1 is thus a newly identified telomere-related gene in which mutations cause aplastic anemia and related BMF disorders.},
}
@article {pmid25199652,
year = {2014},
author = {Lyon, DE and Starkweather, AR and Montpetit, A and Menzies, V and Jallo, N},
title = {A biobehavioral perspective on telomere length and the exposome.},
journal = {Biological research for nursing},
volume = {16},
number = {4},
pages = {448-455},
pmid = {25199652},
issn = {1552-4175},
support = {P30 NR011403/NR/NINR NIH HHS/United States ; R01 NR012667/NR/NINR NIH HHS/United States ; },
mesh = {Behavior ; Biomarkers/metabolism ; *Environmental Exposure ; Epigenesis, Genetic ; Humans ; *Telomere ; },
abstract = {A major objective of biobehavioral research is defining the mechanisms that underlie linkages among behavior, biology, health, and disease. The genomic revolution has demonstrated the importance of studying the role of the environment in (epi)genetic mechanisms. The idea that interactions between environment and genetics influence health outcomes is a central concept of the exposome, a measure of environmental exposures throughout a lifetime. Research suggests that telomere length (TL) and biologic factors involved in telomere stability may provide an understanding of the effects of gene-environment interaction on disease risk. Telomeres, thus, have become important biomarkers for aging as well as for stress-related disease. However, incorporating telomeres into biobehavioral research requires consideration of several aspects of the exposome. Internal and external modifiable and nonmodifiable exposures have the potential to influence TL. Future research utilizing the concept of the exposome will provide meaningful findings related to exposure sources as well as dosage and duration across the life span that influence telomere biology and disease occurrence. Such findings can be translated into clinical practice and may provide a basis for personalized disease prevention and treatment approaches.},
}
@article {pmid25197827,
year = {2014},
author = {Srinivasa, S and Fitch, KV and Petrow, E and Burdo, TH and Williams, KC and Lo, J and Cȏté, HCF and Grinspoon, SK},
title = {Soluble CD163 is associated with shortened telomere length in HIV-infected patients.},
journal = {Journal of acquired immune deficiency syndromes (1999)},
volume = {67},
number = {4},
pages = {414-418},
pmid = {25197827},
issn = {1944-7884},
support = {P30 DK040561/DK/NIDDK NIH HHS/United States ; R01 HL095123/HL/NHLBI NIH HHS/United States ; R01 HL095123-04/HL/NHLBI NIH HHS/United States ; R01 NS040237/NS/NINDS NIH HHS/United States ; NS37654/NS/NINDS NIH HHS/United States ; 1 UL1 RR025758-01/RR/NCRR NIH HHS/United States ; NS40237/NS/NINDS NIH HHS/United States ; M01 RR001066/RR/NCRR NIH HHS/United States ; UL1 RR025758/RR/NCRR NIH HHS/United States ; M01-RR-01066/RR/NCRR NIH HHS/United States ; R01 NS037654/NS/NINDS NIH HHS/United States ; P30DK040561/DK/NIDDK NIH HHS/United States ; K23 HL092792/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Antigens, CD/*blood ; Antigens, Differentiation, Myelomonocytic/*blood ; Case-Control Studies ; HIV Infections/immunology/*physiopathology ; Humans ; Immunity, Cellular/physiology ; Male ; Middle Aged ; Receptors, Cell Surface/*blood ; *Telomere Shortening ; Young Adult ; },
abstract = {Telomere length (TL) and immune activation markers were measured in a cohort of HIV-infected (n = 102) and age-matched non-HIV-infected (n = 41) men. TL was significantly shorter in HIV-infected compared with non-HIV-infected subjects (P = 0.04). Univariate analysis revealed a strong inverse relationship of TL to sCD163, and thus, monocyte/macrophage activation, among the HIV group (ρ = -0.30, P = 0.003). In multivariate modeling among the whole group, HIV-positive serostatus (P = 0.06) and sCD163 (P = 0.05) remained predictors of TL controlling for age and smoking status. Our data demonstrate that increased immune activation relates to shorter TL in HIV.},
}
@article {pmid25195039,
year = {2014},
author = {Labib, HA and Elshorbagy, S and Elantonuy, NG},
title = {Significance of telomere capture in myelodysplastic syndromes.},
journal = {Medical oncology (Northwood, London, England)},
volume = {31},
number = {10},
pages = {216},
pmid = {25195039},
issn = {1559-131X},
mesh = {Adult ; Aged ; Chromosome Aberrations ; Chromosomes, Human, Pair 7/genetics ; Disease Progression ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Myelodysplastic Syndromes/*genetics ; Telomere/*physiology ; Young Adult ; },
abstract = {Addition of telomeres to the ends of broken chromosomes has been observed in many malignant cells through the capture of the ends of other chromosomes as a result of nonreciprocal translocations. In this study, we aimed to evaluate the percentage of nuclei with telomere capture (TC%) as a prognostic marker in myelodysplastic syndromes (MDS) patients. This study included 45 newly diagnosed MDS patients, 36 cases with denovo MDS and 9 cases with therapy-related MDS, and another 35 apparently healthy volunteers as a control group. Telomere capture percentage was investigated with fluorescent in situ hybridization technique using a probe for 15qter. We found that median TC% rate was significantly increased in those with bad cytogenetic abnormalities, patients with blast cells>10% in BM, and patients categorized as high risk according to WHO and IPSS classification; also, there was a significant negative correlation with progression-free survival. Telomere capture serves as a useful marker for the assessment of MDS patient's risk, and also it had a clinical importance for the early detection of disease progression.},
}
@article {pmid25194619,
year = {2014},
author = {Das, UN},
title = {Telomere length and polyunsaturated fatty acids.},
journal = {Nutrition (Burbank, Los Angeles County, Calif.)},
volume = {30},
number = {10},
pages = {1218-1221},
doi = {10.1016/j.nut.2014.04.001},
pmid = {25194619},
issn = {1873-1244},
mesh = {Fatty Acids, Unsaturated/*metabolism ; Humans ; *Telomere ; *Telomere Shortening ; },
}
@article {pmid25194444,
year = {2014},
author = {Izgi, A and Gunal, A and Yalcin, S and Gunduz, U},
title = {Telomere 1 (POT1) gene expression and its association with telomerase activity in colorectal tumor samples with different pathological features.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {68},
number = {7},
pages = {841-846},
doi = {10.1016/j.biopha.2014.08.014},
pmid = {25194444},
issn = {1950-6007},
mesh = {Adult ; Colorectal Neoplasms/*genetics/*pathology ; DNA/genetics ; Female ; Gene Expression/*genetics ; Humans ; Lymphatic Metastasis/genetics/pathology ; Male ; Neoplasm Staging ; Shelterin Complex ; Telomerase/genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {The ends of chromosoms, telomeres are bound with a number of proteins which protect and stabilize telomeres against degredation, end to end fusion and aberrant recombinations. Telomeric DNA is bound of two groups of proteins, which are double-stranded telomeric DNA bindings proteins, and single stranded telomeric binding proteins. Among telomere binding proteins, protections of telomere 1 protein is a single stranded telomere binding proteins and suggested to be a significant player for telomere elongation and has an association with an enzyme called as telomerase which is an intrinsic reverse transcriptase. Telomerase synthesizes hexameric telomeric repeats onto the chromosomes thereby compansating telomere loss in immortal cells, such as tumor cells, whereas telomeres are shorthened with each division in normal cells. PCR-based TRAP (telomeric repeat amplification protocol) assay is a very sensitive assay for the detection of enzymatic activity of telomerase even if a few numbers of cancerous cells are available. The association between telomerase activity and hPOT1 expression in colorectal cancer is still unclear. Protein extraction was performed from specimens of matched normal and colorectal cancer specimens. Protein concentrations were determined by Bradford assay. Optimized protein concentrations were used for TRAP Assay. TRAP products were seperated by vertical gel electrophoresis on 12.5% polyacrylamide gels and visualized by silver staining. Gene expression of hPOT1 was determined by qPCR analysis. The results demonstrated that all tumor tissues were telomerase positive whereas all corresponding normal tissue was telomerase negative. Among clinicopathological findings, telomerase activity was found to be associated with stage, histology, localization, distant metastasis and lymph node metastasis of tumor in the current study. Although all of the clinicopathological findings differed in the expression of hPOT1 compared to normal tissues, they did not differ from each other significantly, except side of tumor and lymph node metastasis. Telomerase activity and hPOT1 gene expression may serve as a promising tumor marker for colorectal cancer and there is a close association between the enzymatic activty of telomerase and the expression of human protection of telomere 1 gene.},
}
@article {pmid25190315,
year = {2014},
author = {Tian, X and Hou, W and Bai, S and Fan, J and Tong, H and Bai, Y},
title = {XAV939 promotes apoptosis in a neuroblastoma cell line via telomere shortening.},
journal = {Oncology reports},
volume = {32},
number = {5},
pages = {1999-2006},
doi = {10.3892/or.2014.3460},
pmid = {25190315},
issn = {1791-2431},
mesh = {Apoptosis ; Cell Line, Tumor ; Cell Movement ; Enzyme Inhibitors/*pharmacology ; Heterocyclic Compounds, 3-Ring/*pharmacology ; Humans ; Neuroblastoma/drug therapy/*genetics/pathology ; RNA, Small Interfering/pharmacology ; Tankyrases/antagonists &amp; inhibitors ; Telomere Shortening/*drug effects ; },
abstract = {Telomeres, telomerase and tankyrase (TNKS) have an extremely important and special association with human cell aging and cancer. Telomerase activity is abnormally high in cancer cells and is accompanied by the overexpression of tankyrase 1 (TNKS1). TNKS1 is a positive regulator of telomerase activation and telomere extension in the human body, indicating that TNKS1 may be a possible therapeutic target for cancer. XAV939 is a small-molecule inhibitor of TNKS1. The objective of the present study was to investigate the apoptotic effect of XAV939 on the neuroblastoma (NB) SH-SY5Y cell line, as well as the change in telomere length and telomerase activity and elucidate the mechanism from this perspective. In the present study, we initially treated SH-SY5Y cells with XAV939 and RNA interference (RNAi)-TNKS1, and subsequently chose the optimal sequence for RNAi-TNKS1. We then measured the telomere length using quantitative real-time polymerase chain reaction (qPCR) assay, detected the telomerase activity using the ELISA kit, observed apoptotic morphology by transmission electron microscopy, and detected the percentages of apoptotic cells using flow cytometry and Hoechst 33342 staining. We also determined the invasive ability by a cell invasion assay. The results showed that short hairpin RNA-2 (shRNA-2) was the optimal sequence for RNAi-TNKS1. Treatment with both XAV939 and RNAi-TNKS1 shortened the telomere length, promoted apoptosis and reduced the invasive ability of the SH-SY5Y cells, yet had no effect on telomerase activity. XAV939 promoted apoptosis and reduced the invasiveness of SH-SY5Y cells dependent on telomere shortening, and further research should be conducted to clarify the exact mechanisms. This research may contribute to the cure of malignant NB using multi-targeted therapy with small-molecule agents.},
}
@article {pmid25188715,
year = {2014},
author = {Révész, D and Milaneschi, Y and Verhoeven, JE and Penninx, BW},
title = {Telomere length as a marker of cellular aging is associated with prevalence and progression of metabolic syndrome.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {99},
number = {12},
pages = {4607-4615},
doi = {10.1210/jc.2014-1851},
pmid = {25188715},
issn = {1945-7197},
mesh = {Adolescent ; Adult ; Aged ; Biomarkers ; *Cellular Senescence ; Cholesterol, HDL/blood ; Cohort Studies ; Cross-Sectional Studies ; Female ; Follow-Up Studies ; Humans ; Longitudinal Studies ; Male ; Metabolic Syndrome/*epidemiology/*pathology ; Middle Aged ; Netherlands/epidemiology ; Prevalence ; Prospective Studies ; *Telomere Shortening ; Triglycerides/blood ; Waist Circumference ; Young Adult ; },
abstract = {CONTEXT: Metabolic syndrome (MetS) clusters risk factors for age-related conditions including cardiovascular disease and diabetes. Shorter telomere length (TL), a cellular marker for biological age, may predict an individual's deteriorating metabolic condition.<br><br>OBJECTIVE: We examined whether shorter baseline TL is associated with a worse metabolic profile and with less favorable trajectories of MetS components over a 6-year follow-up.<br><br>DESIGN AND SETTING: PARTICIPANTS were part of The Netherlands Study of Depression and Anxiety, an ongoing prospective cohort study with 6-year follow-up.<br><br>PARTICIPANTS: This study included 2848 participants age 18-65 years.<br><br>MAIN OUTCOME MEASURES: Baseline TL from leukocytes was determined using qPCR and MetS components (waist circumference, triglycerides, high-density lipoprotein [HDL] cholesterol, systolic blood pressure, and fasting glucose) were determined at baseline, and after 2 and 6 years. Cross-sectional and longitudinal analyses were adjusted for relevant sociodemographic, lifestyle, and health factors.<br><br>RESULTS: Shorter baseline TL was cross-sectionally associated with HDL (&#x3b2; = -0.016, SE = 0.008, P = .05), waist circumference (&#x3b2; = 0.647, SE = 0.238, P = .007), triglycerides (&#x3b2; = 0.038, SE = 0.009, P < .001), and fasting glucose (&#x3b2; = 0.011, SE = 0.003, P < .001), as well as with the total number of MetS components (&#x3b2; = 0.075, SE = 0.023, P = .001) and the presence of MetS (OR = 1.19; 95% CI, 1.07-1.33; P = .002). Although baseline differences progressively reduced over time, shorter baseline TL was still significantly associated with unfavorable scores of most MetS components at the 2- or 6-year follow-up.<br><br>CONCLUSIONS: Cellular aging, as assessed by TL, is associated with a higher metabolic risk profile, which remains unfavorable even after a period of 6 years. These findings suggest that cellular aging might play a role in the onset of various aging-related somatic diseases via its effect on metabolic alterations.},
}
@article {pmid25185586,
year = {2014},
author = {Sjögren, P and Fisher, R and Kallings, L and Svenson, U and Roos, G and Hellénius, ML},
title = {Stand up for health--avoiding sedentary behaviour might lengthen your telomeres: secondary outcomes from a physical activity RCT in older people.},
journal = {British journal of sports medicine},
volume = {48},
number = {19},
pages = {1407-1409},
doi = {10.1136/bjsports-2013-093342},
pmid = {25185586},
issn = {1473-0480},
mesh = {Aged ; Blood Cells/ultrastructure ; Exercise/*physiology ; Female ; Humans ; Male ; Overweight/physiopathology ; Pilot Projects ; Prospective Studies ; *Sedentary Behavior ; Telomere Homeostasis/*physiology ; },
abstract = {BACKGROUND: Telomere length has been associated with a healthy lifestyle and longevity. However, the effect of increased physical activity on telomere length is still unknown. Therefore, the aim was to study the relationship between changes in physical activity level and sedentary behaviour and changes in telomere length.<br><br>METHODS: Telomere length was measured in blood cells 6&#x2005;months apart in 49, 68-year-old, sedentary, overweight individuals taking part in a randomised controlled physical activity intervention trial. The intervention group received individualised physical activity on prescription. Physical activity was measured with a 7-day diary, questionnaires and a pedometer. Sitting time was measured with the short version of The International Physical Activity Questionnaire.<br><br>RESULTS: Time spent exercising as well as steps per day increased significantly in the intervention group. Reported sitting time decreased in both groups. No significant associations between changes in steps per day and changes in telomere length were noted. In the intervention group, there was a negative correlation between changes in time spent exercising and changes in telomere length (rho=-0.39, p=0.07). On the other hand, in the intervention group, telomere lengthening was significantly associated with reduced sitting time (rho=-0.68, p=0.02).<br><br>CONCLUSIONS: Reduced sitting time was associated with telomere lengthening in blood cells in sedentary, overweight 68-year-old individuals participating in a 6-month physical activity intervention trial.},
}
@article {pmid25184673,
year = {2014},
author = {Karlseder, J},
title = {Modern genome editing meets telomeres: the many functions of TPP1.},
journal = {Genes &amp; development},
volume = {28},
number = {17},
pages = {1857-1858},
pmid = {25184673},
issn = {1549-5477},
support = {R01 GM087476/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; Shelterin Complex ; Telomerase/*metabolism ; Telomere/*enzymology ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins ; },
abstract = {The telomeric complex has been analyzed in detail for its role in regulating telomere protection and telomere length. Now, modern genome-editing techniques in human embryonic stem cells reveal TPP1 as the essential recruitment factor for telomerase, with additional functions in telomerase activation and definition of telomere length homeostasis.},
}
@article {pmid25182538,
year = {2014},
author = {Woo, J and Yu, R and Tang, N and Leung, J},
title = {Telomere length is associated with decline in grip strength in older persons aged 65 years and over.},
journal = {Age (Dordrecht, Netherlands)},
volume = {36},
number = {5},
pages = {9711},
pmid = {25182538},
issn = {1574-4647},
mesh = {Aged ; Body Mass Index ; Cytokines/metabolism ; DNA/*genetics ; Female ; Follow-Up Studies ; Hand Strength/*physiology ; Humans ; Male ; Muscle, Skeletal/metabolism/*physiopathology ; Polymerase Chain Reaction ; Prospective Studies ; Sarcopenia/*genetics/metabolism/physiopathology ; Telomere/genetics/*metabolism ; Time Factors ; Walking/*physiology ; },
abstract = {Telomere length (TL) attrition is associated with chronic diseases characterized by chronic inflammatory states. Inflammatory cytokines may play a role in sarcopenia. This study examines the association between TL and the diagnosis of sarcopenia based on appendicular skeletal mass index (ASMI), grip strength, walking speed, and chair stand in a prospective study over 5 years of 976 men and 1,030 women aged 65 years and over living in the community. TL in leukocytes was measured using the quantitative PCR method. TL was divided into quartiles, and analysis of covariance (ANCOVA) was adopted to examine its association with components of sarcopenia, adjusting for age, education, body mass index, smoking, physical activity, and probable dementia. In both men and women, the percentage decline in grip strength over the 5-year period of follow-up was slower in those in the highest quartile of TL than those in the lower quartiles (multivariate-adjusted p < 0.05). No association between TL and the diagnosis of sarcopenia, ASMI, walking speed, or chair stand was observed. In conclusion, longer TL was associated with slower decline in grip strength in Chinese older persons.},
}
@article {pmid25182072,
year = {2014},
author = {López de Silanes, I and Graña, O and De Bonis, ML and Dominguez, O and Pisano, DG and Blasco, MA},
title = {Identification of TERRA locus unveils a telomere protection role through association to nearly all chromosomes.},
journal = {Nature communications},
volume = {5},
number = {},
pages = {4723},
pmid = {25182072},
issn = {2041-1723},
support = {232854/ERC_/European Research Council/International ; },
mesh = {Animals ; Cell Cycle/genetics ; Chromosomes, Mammalian/*chemistry/metabolism ; Embryo, Mammalian ; Fibroblasts/cytology/metabolism ; Gene Expression ; Genes, Reporter ; Genetic Loci ; *Genome ; High-Throughput Nucleotide Sequencing ; In Situ Hybridization, Fluorescence ; Luciferases/genetics/metabolism ; Mice ; Primary Cell Culture ; Protein Binding ; RNA, Messenger/*chemistry/metabolism ; RNA-Binding Proteins/genetics/*metabolism ; Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry/metabolism ; Transcription Factors/genetics/*metabolism ; },
abstract = {Telomeric RNAs (TERRAs) are UUAGGG repeat-containing RNAs that are transcribed from the subtelomere towards the telomere. The precise genomic origin of TERRA has remained elusive. Using a whole-genome RNA-sequencing approach, we identify novel mouse transcripts arising mainly from the subtelomere of chromosome 18, and to a lesser extend chromosome 9, that resemble TERRA in several key aspects. Those transcripts contain UUAGGG-repeats and are heterogeneous in size, fluctuate in abundance in a TERRA-like manner during the cell cycle, are bound by TERRA RNA-binding proteins and are regulated in a manner similar to TERRA in response to stress and the induction of pluripotency. These transcripts are also found to associate with nearly all chromosome ends and downregulation of the transcripts that originate from chromosome 18 causes a reduction in TERRA abundance. Interestingly, downregulation of either chromosome 18 transcripts or TERRA results in increased number of telomere dysfunction-induced foci, suggesting a protective role at telomeres.},
}
@article {pmid25178165,
year = {2015},
author = {Needham, BL and Mezuk, B and Bareis, N and Lin, J and Blackburn, EH and Epel, ES},
title = {Depression, anxiety and telomere length in young adults: evidence from the National Health and Nutrition Examination Survey.},
journal = {Molecular psychiatry},
volume = {20},
number = {4},
pages = {520-528},
pmid = {25178165},
issn = {1476-5578},
support = {R01AG033592-01A1/AG/NIA NIH HHS/United States ; P60 MD002249/MD/NIMHD NIH HHS/United States ; K01 MH093642/MH/NIMH NIH HHS/United States ; 2P60-MD002249/MD/NIMHD NIH HHS/United States ; R01 AG033592/AG/NIA NIH HHS/United States ; K01-MH093642-A1/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Anxiety Disorders/epidemiology/*pathology ; Depressive Disorder, Major/epidemiology/*pathology ; Female ; Humans ; Male ; Nutrition Surveys ; Regression Analysis ; Retrospective Studies ; *Telomere ; *Telomere Shortening ; United States/epidemiology ; },
abstract = {Telomere length has been hypothesized to be a marker of cumulative exposure to stress, and stress is an established cause of depression and anxiety disorders. The aim of this study was to examine the relationship between depression, anxiety and telomere length, and to assess whether this relationship is moderated by race/ethnicity, gender and/or antidepressant use. Data were from the 1999-2002 National Health and Nutrition Examination Survey. Telomere length was assessed using the quantitative PCR method of telomere length relative to standard reference DNA. Past-year major depression (MD), generalized anxiety disorder (GAD) and panic disorder (PD), as well as depressed affect and anxious affect, were assessed using the Composite International Diagnostic Inventory (N=1290). Multiple linear regression was used to assess the relationship between depression and anxiety disorders and telomere length. Among women, those with GAD or PD had shorter telomeres than those with no anxious affect (β: -0.07, P<0.01), but there was no relationship among men (β: 0.08, P>0.05). Among respondents currently taking an antidepressant, those with MD had shorter telomeres than those without (β: -0.26, P<0.05), but there was no association between MD and telomere length among those not using antidepressants (β: -0.00, P>0.05). Neither depressive nor anxiety disorders were directly associated with telomere length in young adults. There was suggestive evidence that pharmacologically treated MD is associated with shorter telomere length, likely reflecting the more severe nature of MD that has come to clinical attention.},
}
@article {pmid25177787,
year = {2014},
author = {Drapkina, OM and Shepel', RN},
title = {[Telomeres and chronic heart failure].},
journal = {Kardiologiia},
volume = {54},
number = {4},
pages = {60-67},
doi = {10.18565/cardio.2014.4.60-67},
pmid = {25177787},
issn = {0022-9040},
mesh = {Aging/*physiology ; Cardiovascular Agents/*therapeutic use ; Chronic Disease ; Disease Management ; *Heart Failure/diagnosis/drug therapy/etiology/physiopathology ; Humans ; Telomere/*physiology ; *Ventricular Function, Left/drug effects/genetics ; },
abstract = {With age, a person's cardio-vascular system changes gradually formed at different functional levels, which are the basis for the development of chronic heart failure. While aging itself does not lead to chronic heart failure, it is likely that age-related changes in the human body can accelerate the time onset of signs and symptoms of the disease. Different groups of patients start time and rate of progression of heart failure is extremely constant. Recently, particular attention is paid to the study of diastolic heart failure because of the high prevalence and some of the difficulties in diagnosis and treatment.},
}
@article {pmid25175359,
year = {2015},
author = {Jeitany, M and Pineda, JR and Liu, Q and Porreca, RM and Hoffschir, F and Desmaze, C and Silvestre, DC and Mailliet, P and Junier, MP and Londoño-Vallejo, A and Ségal-Bendirdjian, E and Chneiweiss, H and Boussin, FD},
title = {A preclinical mouse model of glioma with an alternative mechanism of telomere maintenance (ALT).},
journal = {International journal of cancer},
volume = {136},
number = {7},
pages = {1546-1558},
pmid = {25175359},
issn = {1097-0215},
mesh = {Adult ; Animals ; Cell Line, Tumor ; DNA Methylation ; Disease Models, Animal ; G-Quadruplexes ; Gene Expression Regulation ; Glioma/*genetics/metabolism ; Heterografts ; Humans ; Interleukin Receptor Common gamma Subunit/genetics ; Ligands ; Male ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Mice, Transgenic ; Phenotype ; Sister Chromatid Exchange ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; Telomere Homeostasis ; },
abstract = {Glioblastoma multiforme is the most aggressive primary tumor of the central nervous system. Glioma stem cells (GSCs), a small population of tumor cells with stem-like properties, are supposedly responsible for glioblastoma multiforme relapse after current therapies. In approximately thirty percent of glioblastoma multiforme tumors, telomeres are not maintained by telomerase but through an alternative mechanism, termed alternative lengthening of telomere (ALT), suggesting potential interest in developing specific therapeutic strategies. However, no preclinical model of ALT glioma was available until the isolation of TG20 cells from a human ALT glioma. Herein, we show that TG20 cells exhibit a high level of telomeric recombination but a stable karyotype, indicating that their telomeres retain their protective function against chromosomal instability. TG20 cells possess all of the characteristic features of GSCs: the expression of neural stem cell markers, the generation of intracerebral tumors in NOD-SCID-IL2Rγ (NSG) mice as well as in nude mice, and the ability to sustain serial intracerebral transplantations without expressing telomerase, demonstrating the stability of the ALT phenotype in vivo. Furthermore, we also demonstrate that 360B, a G-quadruplex ligand of the pyridine derivative series that impairs telomere replication and mitotic progression in cancer cells, prevents the development of TG20 tumors. Together, our results show that intracerebral grafts of TG20 cells in immunodeficient mice constitute an efficient preclinical model of ALT glioblastoma multiforme and that G-quadruplex ligands are a potential therapy for this specific type of tumor.},
}
@article {pmid25173430,
year = {2014},
author = {Chen, SH and Epel, ES and Mellon, SH and Lin, J and Reus, VI and Rosser, R and Kupferman, E and Burke, H and Mahan, L and Blackburn, EH and Wolkowitz, OM},
title = {Adverse childhood experiences and leukocyte telomere maintenance in depressed and healthy adults.},
journal = {Journal of affective disorders},
volume = {169},
number = {},
pages = {86-90},
pmid = {25173430},
issn = {1573-2517},
support = {R01 MH083784/MH/NIMH NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; UL1RR024131/RR/NCRR NIH HHS/United States ; 1R01MH083784/MH/NIMH NIH HHS/United States ; UL1 TR000004/TR/NCATS NIH HHS/United States ; },
mesh = {Adult ; Case-Control Studies ; Child ; Depressive Disorder, Major/genetics/*pathology ; Female ; Humans ; Leukocytes/metabolism ; Leukocytes, Mononuclear/pathology ; Life Change Events ; Male ; Mental Disorders/genetics ; Retrospective Studies ; Telomerase/metabolism ; Telomere ; *Telomere Homeostasis ; Telomere Shortening ; },
abstract = {BACKGROUND: Adverse childhood experiences (ACEs) are associated with poor physical and mental health outcomes in adulthood. Adverse childhood experiences are also associated with shortened leukocyte telomere length (LTL) in adults, suggesting accelerated cell aging. No studies have yet assessed the relationship of ACEs to LTL in individuals with major depressive disorder (MDD), despite the high incidence of antecedent ACEs in individuals with MDD. Further, no studies in any population have assessed the relationship of ACEs to the activity of telomerase, the major enzyme responsible for maintaining LTL, or the relationship between telomerase and LTL in individuals with ACEs.<br><br>METHODS: Twenty healthy, unmedicated adults with MDD and 20 healthy age-, sex- and ethnicity-matched controls had ACEs assessed and had blood drawn for LTL and peripheral blood mononuclear cell (PBMC) resting telomerase activity.<br><br>RESULTS: In healthy controls, greater ACE exposure was associated with shorter LTL (p<.05) but was unassociated with telomerase activity. In MDD, however, the opposite pattern was seen: greater ACE exposure was unrelated to LTL but was associated with increased telomerase activity (p<.05) and with a higher telomerase:LTL ratio (p=.022).<br><br>LIMITATIONS: Study limitations include the small sample size, a single timepoint assessment of telomerase activity, and the use of retrospective self-report to assess ACEs.<br><br>CONCLUSIONS: These results replicate prior findings of shortened LTL in healthy adults with histories of multiple ACEs. However, in MDD, this relationship was substantially altered, raising the possibility that activation of telomerase in ACE-exposed individuals with MDD could represent a compensatory response to endangered telomeres.},
}
@article {pmid25173189,
year = {2015},
author = {Salihu, HM and Pradhan, A and King, L and Paothong, A and Nwoga, C and Marty, PJ and Whiteman, V},
title = {Impact of intrauterine tobacco exposure on fetal telomere length.},
journal = {American journal of obstetrics and gynecology},
volume = {212},
number = {2},
pages = {205.e1-8},
doi = {10.1016/j.ajog.2014.08.026},
pmid = {25173189},
issn = {1097-6868},
mesh = {Adult ; Case-Control Studies ; Cotinine/analysis ; DNA/*analysis ; Female ; *Fetal Blood ; *Fetus ; Humans ; *Maternal Exposure ; Pregnancy ; Saliva/chemistry ; Smoking/*genetics ; Telomere/*genetics ; Telomere Shortening ; Tobacco Smoke Pollution ; Young Adult ; },
abstract = {OBJECTIVE: We sought to investigate whether maternal smoking during pregnancy affects telomere length of the fetus.<br><br>STUDY DESIGN: Pregnant women were recruited on hospital admission at delivery. A self-report questionnaire and salivary cotinine test were used to confirm tobacco exposure. Neonatal umbilical cord blood samples were collected, and genomic DNA was isolated from cord blood leukocytes and was analyzed for fetal telomere length based on quantitative polymerase chain reaction. A ratio of relative telomere length was determined by telomere repeat copy number and single copy gene copy number (T/S ratio) and used to compare the telomere length of active, passive, and nonsmokers. Bootstrap and analysis of variance statistical methods were used to evaluate the relationship between prenatal smoking status and fetal telomere length.<br><br>RESULTS: Of the 86 women who were included in this study, approximately 69.8% of the participants were covered by Medicaid, and 55.8% of the participants were black or Hispanic. The overall mean T/S ratio was 0.8608 &#xb1; 1.0442. We noted an inverse relationship between smoking and fetal telomere length in a dose-response pattern (T/S ratio of nonsmokers that was more than passive smokers that was more than active smokers). Telomere length was significantly different for each pairwise comparison, and the greatest difference was between active and nonsmokers.<br><br>CONCLUSION: Our results provide the first evidence to demonstrate a positive association between shortened fetal telomere length and smoking during pregnancy. Our findings suggest the possibility of early intrauterine programming for accelerated aging that is the result of tobacco exposure.},
}
@article {pmid25172657,
year = {2014},
author = {Yun, JH and Lee, WK and Kim, H and Kim, E and Cheong, C and Cho, MH and Lee, W},
title = {Solution structure of telomere binding domain of AtTRB2 derived from Arabidopsis thaliana.},
journal = {Biochemical and biophysical research communications},
volume = {452},
number = {3},
pages = {436-442},
doi = {10.1016/j.bbrc.2014.08.095},
pmid = {25172657},
issn = {1090-2104},
mesh = {Amino Acid Sequence ; Arabidopsis/*chemistry ; Arabidopsis Proteins/*chemistry/genetics/metabolism ; Arginine/chemistry/metabolism ; Binding Sites ; Conserved Sequence ; DNA/*chemistry/metabolism ; Electrophoretic Mobility Shift Assay ; Escherichia coli/genetics/metabolism ; Gene Expression ; Humans ; Models, Molecular ; Molecular Sequence Data ; Protein Binding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Recombinant Proteins/chemistry/genetics/metabolism ; Sequence Alignment ; Telomere/*chemistry ; Telomere-Binding Proteins/*chemistry/genetics/metabolism ; Tryptophan/chemistry/metabolism ; Valine/chemistry/metabolism ; },
abstract = {Telomere homeostasis is regulated by telomere-associated proteins, and the Myb domain is well conserved for telomere binding. AtTRB2 is a member of the SMH (Single-Myb-Histone)-like family in Arabidopsis thaliana, having an N-terminal Myb domain, which is responsible for DNA binding. The Myb domain of AtTRB2 contains three α-helices and loops for DNA binding, which is unusual given that other plant telomere-binding proteins have an additional fourth helix that is essential for DNA binding. To understand the structural role for telomeric DNA binding of AtTRB2, we determined the solution structure of the Myb domain of AtTRB2 (AtTRB21-64) using nuclear magnetic resonance (NMR) spectroscopy. In addition, the inter-molecular interaction between AtTRB21-64 and telomeric DNA has been characterized by the electrophoretic mobility shift assay (EMSA) and NMR titration analyses for both plant (TTTAGGG)n and human (TTAGGG)n telomere sequences. Data revealed that Trp28, Arg29, and Val47 residues located in Helix 2 and Helix 3 are crucial for DNA binding, which are well conserved among other plant telomere binding proteins. We concluded that although AtTRB2 is devoid of the additional fourth helix in the Myb-extension domain, it is able to bind to plant telomeric repeat sequences as well as human telomeric repeat sequences.},
}
@article {pmid25171524,
year = {2014},
author = {Cesare, AJ},
title = {Mitosis, double strand break repair, and telomeres: a view from the end: how telomeres and the DNA damage response cooperate during mitosis to maintain genome stability.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {36},
number = {11},
pages = {1054-1061},
pmid = {25171524},
issn = {1521-1878},
mesh = {Chromatin/genetics ; *DNA Breaks, Double-Stranded ; DNA Repair/*genetics ; DNA-Binding Proteins/metabolism ; G1 Phase Cell Cycle Checkpoints/genetics ; Genomic Instability/*genetics ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Mitosis/*genetics ; Phosphorylation ; Telomere/*genetics ; Tumor Suppressor p53-Binding Protein 1 ; Ubiquitin-Protein Ligases ; Ubiquitination ; },
abstract = {Double strand break (DSB) repair is suppressed during mitosis because RNF8 and downstream DNA damage response (DDR) factors, including 53BP1, do not localize to mitotic chromatin. Discovery of the mitotic kinase-dependent mechanism that inhibits DSB repair during cell division was recently reported. It was shown that restoring mitotic DSB repair was detrimental, resulting in repair dependent genome instability and covalent telomere fusions. The telomere DDR that occurs naturally during cellular aging and in cancer is known to be refractory to G2/M checkpoint activation. Such DDR-positive telomeres, and those that occur as part of the telomere-dependent prolonged mitotic arrest checkpoint, normally pass through mitosis without covalent ligation, but result in cell growth arrest in G1 phase. The discovery that suppressing DSB repair during mitosis may function primarily to protect DDR-positive telomeres from fusing during cell division reinforces the unique cooperation between telomeres and the DDR to mediate tumor suppression.},
}
@article {pmid25159293,
year = {2014},
author = {Kotsopoulos, J and Prescott, J and De Vivo, I and Fan, I and Mclaughlin, J and Rosen, B and Risch, H and Sun, P and Narod, SA},
title = {Telomere length and mortality following a diagnosis of ovarian cancer.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {23},
number = {11},
pages = {2603-2606},
pmid = {25159293},
issn = {1538-7755},
support = {/CAPMC/CIHR/Canada ; R01 CA063678/CA/NCI NIH HHS/United States ; R01 CA082838/CA/NCI NIH HHS/United States ; U01 CA167763/CA/NCI NIH HHS/United States ; R01 CA063682/CA/NCI NIH HHS/United States ; R01CA063678/CA/NCI NIH HHS/United States ; R01CA063682/CA/NCI NIH HHS/United States ; },
mesh = {Female ; Humans ; Middle Aged ; Ovarian Neoplasms/*diagnosis/genetics/mortality ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {BACKGROUND: Telomeres are essential for the maintenance of chromosomal integrity. Telomere shortening leads to genomic instability, which is hypothesized to play a role in cancer development and prognosis. No studies to date have evaluated the prognostic significance of telomere length for ovarian cancer.<br><br>METHODS: We examined whether relative telomere length in peripheral blood leukocytes was associated with survival following a diagnosis of ovarian cancer. We analyzed data from a large population-based study of incident ovarian cancer conducted in Ontario between 1995 and 2004. Telomere length was measured using the quantitative PCR-based relative telomere length assay and vital status was determined by computerized record linkage and by chart review (n = 1,042). Proportional hazard models were used to estimate ovarian cancer-specific survival HRs and 95% confidence intervals (CI) associated with quartiles of telomere length z score.<br><br>RESULTS: We found no significant relationship between telomere length and ovarian cancer-specific mortality (P log-rank test = 0.55). Compared with women in the lowest quartile of telomere length z score, the HR for women in the highest three quartiles of telomere length z score combined was 0.88 (95% CI, 0.77-1.10). The corresponding estimates for serous and nonserous tumors were 0.68 (95% CI, 0.66-1.13) and 1.13 (95% CI, 0.71-1.79), respectively.<br><br>CONCLUSIONS: Our data provide preliminary evidence that telomere length likely does not predict outcome after a diagnosis of ovarian cancer.<br><br>IMPACT: This represents the first study to suggest no prognostic role of telomere length for ovarian cancer.},
}
@article {pmid25153662,
year = {2014},
author = {Yu, Q and Yang, J and Liu, B and Li, W and Hu, G and Qiu, H and Huang, L and Xiong, H and Yuan, X},
title = {Combined effects of leukocyte telomere length, p53 polymorphism and human papillomavirus infection on esophageal squamous cell carcinoma in a Han Chinese population.},
journal = {Cancer epidemiology},
volume = {38},
number = {5},
pages = {569-575},
doi = {10.1016/j.canep.2014.07.010},
pmid = {25153662},
issn = {1877-783X},
mesh = {Adult ; Aged ; Aged, 80 and over ; Asian People/genetics ; Carcinoma, Squamous Cell/genetics/*pathology/virology ; Case-Control Studies ; China/epidemiology ; Esophageal Neoplasms/genetics/*pathology/virology ; Esophageal Squamous Cell Carcinoma ; Female ; Genetic Predisposition to Disease ; Genotype ; Human papillomavirus 16/isolation &amp; purification ; Humans ; Leukocytes/metabolism ; Male ; Middle Aged ; Papillomavirus Infections/*epidemiology ; Polymorphism, Genetic ; Risk ; Risk Factors ; Telomere Shortening/*genetics ; Tumor Suppressor Protein p53/*genetics ; },
abstract = {Telomere shortening has been suggested to be a genetic predictor for various cancers. However, evidences about this point with respect to esophageal squamous cell carcinoma (ESCC) in Han Chinese populations remain limited. Our previous study demonstrated that p53 Arg72Pro polymorphism was associated with the risk of human papillomavirus (HPV)-related ESCC. Telomeres and p53 play important roles in maintaining genomic stability and regulating the cell cycle. HPV impacts both telomere length stabilization and p53 degradation. Given the roles of the three factors, we evaluated leukocyte telomere length, p53 variants and HPV-16 serology to examine the potential associations between them and ESCC risk in a case-control study with 308 patients and 309 cancer-free controls matched by age and sex. Compared with long telomere length, short telomere length was significantly associated with an increased risk of ESCC (adjusted OR 2.01; 95% CI 1.41-2.80). Moreover, this association was enhanced when combined with HPV-16 seropositivity and p53 Arg/Arg or Arg/Pro genotypes. Notably, individuals with short telomere length, Arg/Pro or Arg/Arg genotypes and HPV-16 seropositivity had a 12.08-fold (95% CI 5.49-26.56) increased risk of ESCC compared to those with none of the three investigated risk factors. Taken together, these results indicate that short telomere length in peripheral blood leukocytes is a biomarker for ESCC risk, and has statistically additive effects with p53 variants and HPV seropositivity with regard to the risk of ESCC in a Han Chinese population.},
}
@article {pmid25153587,
year = {2015},
author = {Babizhayev, MA and Vishnyakova, KS and Yegorov, YE},
title = {Hormone-brain-aging relationships, broadly reactive with imidazole-containing dipeptides: targeting of telomere attrition as an aging biomarker and dynamic telomerase activity flirting.},
journal = {Journal of basic and clinical physiology and pharmacology},
volume = {26},
number = {2},
pages = {115-140},
doi = {10.1515/jbcpp-2014-0045},
pmid = {25153587},
issn = {2191-0286},
mesh = {Aged ; Aging/*drug effects/physiology ; Animals ; Biomarkers/metabolism ; Brain/metabolism ; Dipeptides/chemistry/*pharmacology ; Humans ; Imidazoles/chemistry/*pharmacology ; Molecular Targeted Therapy ; Oxidative Stress/physiology ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere Shortening/drug effects/physiology ; },
abstract = {It has been documented that telomere-associated cellular senescence may contribute to certain age-related disorders, and telomere length (TL) may be an informative biomarker of healthy aging. Hormone-brain-aging behavior-modulated telomere dynamics and changes in telomerase activity are consistent elements of cellular alterations associated with changes in proliferative state, and these processes are consequently considered as the new therapeutic drug targets for physiological control with advanced drug delivery and nutritional formulations. We raise and support a therapeutic concept of using nonhydrolyzed forms of naturally occurring neuron-specific imidazole dipeptide-based compounds carnosine and carcinine, making it clinically possible that slowing down the rate of telomere shortening could slow down the human aging process in specific tissues where proliferative senescence is known to occur, with the demonstrated evidence of telomere shortening that appeared to be a hallmark of oxidative stress and disease. Carnosine released from skeletal muscle during exercise may be transported into the hypothalamic tuberomammillary nucleus (TMN) histamine neurons and hydrolyzed. The resulting L-histidine may subsequently be converted into histamine, which could be responsible for the effects of carnosine on neurotransmission and hormone-like antiaging physiological function. The preliminary longitudinal studies of elderly individuals suggest that longer telomeres are associated with better survival, and an advanced oral nutritional support with nonhydrolyzed carnosine (or carcinine and patented compositions thereof) is a useful therapeutic tool for a critical TL maintenance that may fundamentally be applied in the treatment of age-related sight-threatening eye disorders, prolonged life expectancy, increased survival and chronological age of an organism in health control, smoking behavior, and disease. "Our pleasures were simple-they included survival." -Dwight D. Eisenhower, 34th President of the United States, 1953-1961.},
}
@article {pmid25153197,
year = {2014},
author = {Zhang, ZX and Wang, Y and Tao, ZZ and Chen, SM and Xiao, BK and Zhou, T},
title = {Subtelomeric demethylation deregulated hTERT expression, telomerase activity, and telomere length in four nasopharyngeal carcinoma cell lines.},
journal = {Cancer biotherapy &amp; radiopharmaceuticals},
volume = {29},
number = {7},
pages = {289-294},
doi = {10.1089/cbr.2013.1581},
pmid = {25153197},
issn = {1557-8852},
mesh = {Carcinoma ; Cell Line, Tumor ; CpG Islands/genetics ; DNA Methylation/*genetics ; DNA-Binding Proteins/genetics ; Down-Regulation/genetics ; Humans ; Nasopharyngeal Carcinoma ; Nasopharyngeal Neoplasms/*genetics ; Promoter Regions, Genetic/genetics ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {Global DNA hypomethylation, in particular that of the gene promoter sequence in gene hypermethylation, is a well-known characteristic of human cancer. Subtelomeres are enriched CpG islands; methylation is believed to be a potential epigenetic regulator. However, regulation on the telomere length remains largely unknown. To demonstrate this correlation, four nasopharyngeal carcinoma cell lines (CNE, CNE1, CNE2, 5-8F) were treated for 72 hours with 0, 1, or 2.5 μM of the demethylating agent 5-aza-2'-deoxycytidine (5-aza-dC). Subtelomeric (D4Z4) level methylation was evaluated with a bisulfite assay, the human telomerase catalytic subunit (hTERT) expression was assayed by reverse transcription-polymerase chain reaction, the telomerase activity was detected using a telomeric repeat amplification protocol assay, and the telomere length was measured by Southern blot terminal restriction fragment analysis. There was significant demethylation following 5-aza-dC treatment, and a strongly repressed hTERT expression decreased the telomerase activity and remarkably shortened telomeres. Thus, partial subtelomeric methylation does not repress hTERT expression; conversely, demethylation may downregulate hTERT expression and shorten telomeres.},
}
@article {pmid25150861,
year = {2014},
author = {Conomos, D and Reddel, RR and Pickett, HA},
title = {NuRD-ZNF827 recruitment to telomeres creates a molecular scaffold for homologous recombination.},
journal = {Nature structural &amp; molecular biology},
volume = {21},
number = {9},
pages = {760-770},
pmid = {25150861},
issn = {1545-9985},
mesh = {Apoptosis ; Cell Cycle ; Cell Line ; Chromatin Assembly and Disassembly ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Gene Knockdown Techniques ; *Homologous Recombination ; Humans ; Mi-2 Nucleosome Remodeling and Deacetylase Complex/*metabolism ; Telomere/*metabolism ; },
abstract = {Alternative lengthening of telomeres (ALT) is a homologous recombination (HR)-dependent mechanism for de novo synthesis of telomeric DNA in mammalian cells. Nuclear receptors are bound to the telomeres of cells that use ALT. Here we demonstrate that nuclear receptors recruit ZNF827, a zinc-finger protein of unknown function, which recruits the nucleosome remodeling and histone deacetylation (NuRD) complex via binding to an N-terminal RRK motif within ZNF827. This results in decreased shelterin binding, hypoacetylation of telomeric chromatin, enhanced telomere-telomere interactions and recruitment of HR proteins, and it is critically important for cell viability and proliferation. We propose that NuRD-ZNF827 recruitment to human telomeres causes remodeling of telomeric chromatin and creates an environment that promotes telomere-telomere recombination and integrates and controls multiple mechanistic elements of ALT activity.},
}
@article {pmid25150772,
year = {2014},
author = {Carulli, L and Annicchiarico, E},
title = {WITHDRAWN: Telomeres and atherosclerosis.},
journal = {Nutrition, metabolism, and cardiovascular diseases : NMCD},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.numecd.2014.07.004},
pmid = {25150772},
issn = {1590-3729},
abstract = {This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.},
}
@article {pmid25150678,
year = {2014},
author = {Saum, KU and Dieffenbach, AK and Müezzinler, A and Müller, H and Holleczek, B and Stegmaier, C and Butterbach, K and Schick, M and Canzian, F and Stammer, H and Boukamp, P and Hauer, K and Brenner, H},
title = {Frailty and telomere length: cross-sectional analysis in 3537 older adults from the ESTHER cohort.},
journal = {Experimental gerontology},
volume = {58},
number = {},
pages = {250-255},
doi = {10.1016/j.exger.2014.08.009},
pmid = {25150678},
issn = {1873-6815},
mesh = {Age Distribution ; Age Factors ; Aged ; Aging/*genetics/metabolism ; Cross-Sectional Studies ; Female ; *Frail Elderly ; Gene Dosage ; Genetic Markers ; Geriatric Assessment/methods ; Germany ; Humans ; Male ; Middle Aged ; Polymerase Chain Reaction ; Predictive Value of Tests ; Sex Distribution ; Sex Factors ; Telomere/*genetics/metabolism ; *Telomere Shortening ; },
abstract = {Both telomere length and frailty were observed to be associated with aging. Whether and to what extent telomere length is related to frailty is essentially unknown. In this cross-sectional analysis of baseline data of 3537 community-dwelling adults aged 50 to 75 years of a large German cohort study, we assessed the hypothesis that shorter telomere length might be a biological marker for frailty. Using whole blood DNA we examined mean telomere repeat copy to single gene copy number (T/S ratio) using quantitative PCR. Construction of a frailty index (FI) was based on a deficit accumulation approach, which quantifies frailty as ratio of the deficits present divided by the total number of deficits considered. Mean FI was determined according to age by tertiles of T/S ratio. Furthermore, we used correlation analyses stratified for gender and age groups to examine the association of the T/S ratio with frailty. Mean FI value was similar across tertiles of the T/S ratio (0.24±0.14, 0.24±0.14 and 0.23±0.14, respectively (p=0.09)), and FI and the T/S ratio were uncorrelated in gender- and age-specific analyses. In conclusion, T/S ratio and frailty were unrelated in this large sample of older adults. T/S ratio may therefore not be a meaningful biological marker for frailty.},
}
@article {pmid25142166,
year = {2014},
author = {Maeda, T and Guan, JZ and Koyanagi, M and Makino, N},
title = {Altered expression of genes associated with telomere maintenance and cell function of human vascular endothelial cell at elevated temperature.},
journal = {Molecular and cellular biochemistry},
volume = {397},
number = {1-2},
pages = {305-312},
pmid = {25142166},
issn = {1573-4919},
mesh = {Cell Survival/physiology ; Cellular Senescence/physiology ; Cyclin-Dependent Kinase Inhibitor p21/biosynthesis ; Gene Expression Regulation/*physiology ; Heat-Shock Response/*physiology ; *Hot Temperature ; Human Umbilical Vein Endothelial Cells/cytology/*metabolism ; Humans ; Nitric Oxide Synthase Type III/biosynthesis ; RNA/biosynthesis ; Telomerase/biosynthesis ; Telomere/*metabolism ; Tumor Suppressor Protein p53/biosynthesis ; },
abstract = {The pathophysiological alterations of vascular endothelial cells induced by heat were studied. Human umbilical venous endothelial cells were cultured for 1 day at three different temperatures (37, 39, and 42 °C). The telomere lengths, the expressions of proteins associated with telomere length maintenance, apoptosis, heat shock, and vascular function were analyzed. The cell growth was not suppressed at 39 °C but suppressed at 42 °C. The mean telomere length did not change, whereas the telomere length distribution altered at 42 °C. Long telomere decreased and middle-sized telomere increased in the telomere length distribution at 42 °C. The telomerase activity did not show any heat-associated alterations. However, of the components of telomerase, telomerase reverse transcriptase was up-regulated along temperature elevation. In contrast, the expression level of RNA component TERC did not altered. Among the analyzed apoptosis-associated proteins, p21 was down-regulated and phosphorylated p53 was up-regulated. Heat shock proteins and NO synthase were up-regulated at 42 °C. These results suggested that induced growth suppression or cell senescence was induced by strong heat stress rather than mild one predominantly in cells bearing long telomeres with p53 activation, and simultaneously activated some telomere-associated factors, heat shock proteins, and NO synthesis probably for heat-resistant cell survival.},
}
@article {pmid25139287,
year = {2014},
author = {Wang, L and Xiao, H and Zhang, X and Wang, C and Huang, H},
title = {The role of telomeres and telomerase in hematologic malignancies and hematopoietic stem cell transplantation.},
journal = {Journal of hematology &amp; oncology},
volume = {7},
number = {},
pages = {61},
pmid = {25139287},
issn = {1756-8722},
mesh = {Animals ; Hematologic Neoplasms/*enzymology/genetics/*pathology/therapy ; *Hematopoietic Stem Cell Transplantation ; Humans ; Telomerase/*metabolism ; Telomere/*pathology ; Treatment Outcome ; },
abstract = {Telomeres are specific nucleoprotein structures at the ends of eukaryotic chromosomes. Telomeres and telomere-associated proteins maintain genome stability by protecting the ends of chromosomes from fusion and degradation. In normal somatic cells, the length of the telomeres gradually becomes shortened with cell division. In tumor cells, the shortening of telomeres length is accelerated under the increased proliferation pressure. However, it will be maintained at an extremely short length as the result of activation of telomerase. Significantly shortened telomeres, activation of telomerase, and altered expression of telomere-associated proteins are common features of various hematologic malignancies and are related with progression or chemotherapy resistance in these diseases. In patients who have received hematopoietic stem cell transplantation (HSCT), the telomere length and the telomerase activity of the engrafted donor cells have a significant influence on HSCT outcomes. Transplantation-related factors should be taken into consideration because of their impacts on telomere homeostasis. As activation of telomerase is widespread in tumor cells, it has been employed as a target point in the treatment of neoplastic hematologic disorders. In this review, the characteristics and roles of telomeres and telomerase both in hematologic malignancies and in HSCT will be summarized. The current status of telomerase-targeted therapies utilized in the treatment of hematologic malignancies will also be reviewed.},
}
@article {pmid25138576,
year = {2015},
author = {Wang, X and Jin, D and Wang, Z and Guo, H and Zhang, L and Wang, L and Li, J and Paterson, AH},
title = {Telomere-centric genome repatterning determines recurring chromosome number reductions during the evolution of eukaryotes.},
journal = {The New phytologist},
volume = {205},
number = {1},
pages = {378-389},
doi = {10.1111/nph.12985},
pmid = {25138576},
issn = {1469-8137},
mesh = {Arabidopsis/genetics ; *Biological Evolution ; Chromosomes, Plant/*genetics ; Computer Simulation ; Eukaryota/*genetics ; *Genome, Plant ; Karyotyping ; Models, Genetic ; Musa/genetics ; Oryza/genetics ; Poaceae/genetics ; Telomere/*genetics ; },
abstract = {Whole-genome duplication (WGD) is central to the evolution of many eukaryotic genomes, in particular rendering angiosperm (flowering plant) genomes much less stable than those of animals. Following repeated duplication/triplication(s), angiosperm chromosome numbers have usually been restored to a narrow range, as one element in a 'diploidization' process that re-establishes diploid heredity. In several angiosperms affected by WGD, we show that chromosome number reduction (CNR) is best explained by intra- and/or inter-chromosomal crossovers to form new chromosomes that utilize the existing telomeres of 'invaded' and centromeres of 'invading' chromosomes, the alternative centromeres and telomeres being lost. Comparison with the banana (Musa acuminata) genome supports a 'fusion model' for the evolution of rice (Oryza sativa) chromosomes 2 and 3, implying that the grass common ancestor had seven chromosomes rather than the five implied by a 'fission model.' The 'invading' and 'invaded' chromosomes are frequently homoeologs, originating from duplication of a common ancestral chromosome and with greater-than-average DNA-level correspondence to one another. Telomere-centric CNR following recursive WGD in plants is also important in mammals and yeast, and may be a general mechanism of restoring small linear chromosome numbers in higher eukaryotes.},
}
@article {pmid25131600,
year = {2015},
author = {García-Calzón, S and Moleres, A and Martínez-González, MA and Martínez, JA and Zalba, G and Marti, A and , },
title = {Dietary total antioxidant capacity is associated with leukocyte telomere length in a children and adolescent population.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {34},
number = {4},
pages = {694-699},
doi = {10.1016/j.clnu.2014.07.015},
pmid = {25131600},
issn = {1532-1983},
mesh = {Adolescent ; Antioxidants/*administration &amp; dosage ; Bread ; Child ; Cross-Sectional Studies ; Diet ; Dietary Carbohydrates/administration &amp; dosage ; Dietary Fats/administration &amp; dosage ; Dietary Proteins/administration &amp; dosage ; Edible Grain ; Energy Intake ; *Feeding Behavior ; Female ; Genomics ; Humans ; Leukocytes/chemistry/*drug effects ; Male ; Nutrition Assessment ; Spain ; Surveys and Questionnaires ; Telomere/drug effects/metabolism ; Telomere Homeostasis/*drug effects ; Telomere Shortening ; },
abstract = {BACKGROUND &amp; AIMS: Oxidative stress and inflammation seem to be potential underlying mechanisms for telomere attrition. A lack of specific antioxidants is believed to increase free radical damage and a greater risk for telomere shortening. Our aim was to evaluate the relationship between diet and leukocyte telomere length in a cross-sectional study of children and adolescents. We hypothesized that dietary total antioxidant capacity would be positively associated with telomere length.<br><br>METHODS: Telomere length was measured by quantitative real-time polymerase chain reaction in 287 participants (55% males, 6-18 years), who were randomly selected from the GENOI study.<br><br>RESULTS: A positive correlation between dietary total antioxidant capacity and telomere length (r = 0.157, p = 0.007) was found after adjustment for age and energy intake. However, higher white bread consumption was associated with shorter telomeres (&#x3b2; = -0.204, p = 0.002) in fully-adjusted models. Interestingly, those individuals who had simultaneously higher dietary total antioxidant capacity and lower white bread consumption significantly presented the longest telomeres. Moreover, the multivariable-adjusted odds ratio for very short telomeres was 0.30 for dietary total antioxidant capacity (p = 0.023) and 1.37 for white bread (p = 0.025).<br><br>CONCLUSION: It was concluded that longer telomeres were associated with higher dietary total antioxidant capacity and lower white bread consumption in Spanish children and adolescents. These findings might open a new line of investigation about the potential role of an antioxidant diet in maintaining telomere length.},
}
@article {pmid25129579,
year = {2015},
author = {Boks, MP and van Mierlo, HC and Rutten, BP and Radstake, TR and De Witte, L and Geuze, E and Horvath, S and Schalkwyk, LC and Vinkers, CH and Broen, JC and Vermetten, E},
title = {Longitudinal changes of telomere length and epigenetic age related to traumatic stress and post-traumatic stress disorder.},
journal = {Psychoneuroendocrinology},
volume = {51},
number = {},
pages = {506-512},
doi = {10.1016/j.psyneuen.2014.07.011},
pmid = {25129579},
issn = {1873-3360},
mesh = {Adolescent ; Adult ; Afghan Campaign 2001- ; Cellular Senescence/*genetics ; Combat Disorders/*genetics/psychology ; *Epigenesis, Genetic ; Humans ; Male ; Military Personnel/*psychology ; Risk Factors ; Stress Disorders, Post-Traumatic/*genetics/psychology ; *Telomere ; Young Adult ; },
abstract = {Several studies have reported an association between traumatic stress and telomere length suggesting that traumatic stress has an impact on ageing at the cellular level. A newly derived tool provides an additional means to investigate cellular ageing by estimating epigenetic age based on DNA methylation profiles. We therefore hypothesise that in a longitudinal study of traumatic stress both indicators of cellular ageing will show increased ageing. We expect that particularly in individuals that developed symptoms of post-traumatic stress disorder (PTSD) increases in these ageing parameters would stand out. From an existing longitudinal cohort study, ninety-six male soldiers were selected based on trauma exposure and the presence of symptoms of PTSD. All military personnel were deployed in a combat zone in Afghanistan and assessed before and 6 months after deployment. The Self-Rating Inventory for PTSD was used to measure the presence of PTSD symptoms, while exposure to combat trauma during deployment was measured with a 19-item deployment experiences checklist. These groups did not differ for age, gender, alcohol consumption, cigarette smoking, military rank, length, weight, or medication use. In DNA from whole blood telomere length was measured and DNA methylation levels were assessed using the Illumina 450K DNA methylation arrays. Epigenetic ageing was estimated using the DNAm age estimator procedure. The association of trauma with telomere length was in the expected direction but not significant (B=-10.2, p=0.52). However, contrary to our expectations, development of PTSD symptoms was associated with the reverse process, telomere lengthening (B=1.91, p=0.018). In concordance, trauma significantly accelerated epigenetic ageing (B=1.97, p=0.032) and similar to the findings in telomeres, development of PTSD symptoms was inversely associated with epigenetic ageing (B=-0.10, p=0.044). Blood cell count, medication and premorbid early life trauma exposure did not confound the results. Overall, in this longitudinal study of military personnel deployed to Afghanistan we show an acceleration of ageing by trauma. However, development of PTSD symptoms was associated with telomere lengthening and reversed epigenetic ageing. These findings warrant further study of a perhaps dysfunctional compensatory cellular ageing reversal in PTSD.},
}
@article {pmid25129574,
year = {2014},
author = {Balistreri, CR and Pisano, C and Martorana, A and Triolo, OF and Lio, D and Candore, G and Ruvolo, G},
title = {Are the leukocyte telomere length attrition and telomerase activity alteration potential predictor biomarkers for sporadic TAA in aged individuals?.},
journal = {Age (Dordrecht, Netherlands)},
volume = {36},
number = {5},
pages = {9700},
pmid = {25129574},
issn = {1574-4647},
mesh = {Aging/*genetics/metabolism/pathology ; Aortic Aneurysm, Thoracic/*genetics/metabolism/pathology ; Biomarkers/metabolism ; DNA/*genetics ; DNA Replication ; Enzyme-Linked Immunosorbent Assay ; Female ; *Genetic Predisposition to Disease ; Genotype ; Humans ; Immunohistochemistry ; In Situ Nick-End Labeling ; Leukocytes/*metabolism ; Male ; Middle Aged ; Polymerase Chain Reaction ; Risk Factors ; Telomere/*metabolism ; Telomere Shortening/*genetics ; },
abstract = {A large variability in occurrence, complications, and age/gender manifestations characterizes individual susceptibility of sporadic thoracic aortic aneurysms (TAA), even in subjects with the same risk factor profiles. The reasons are poorly understood. On the other hand, TAA pathophysiology mechanisms remain unclear than those involved in abdominal aorta aneurysms. However, recent evidence is suggesting a crucial role of biological ageing in inter-individual risk variation of cardiovascular diseases, including sporadic TAA. Biological age rather than chronological age is a better predictor of vascular risk. Relevant assumptions support this concept. In confirming this evidence and our preliminary data, the mean of blood leukocyte telomere length, through use of terminal restriction fragment assay and in blood samples from sporadic TAA patients and controls, was examined. Telomerase activity was also analyzed in two groups. In addition, we verified the weight of genetic inflammatory variants and the major TAA risk factors in telomere/telomerase impairment. Aorta histopathological abnormalities and systemic inflammatory mediators were ultimately correlated with telomere/telomerase impairment. Data obtained demonstrated shorter telomeres and a reduced telomerase activity in TAA patients significantly associated with a genetic inflammatory risk profile, age, gender, smoking, hypertension, a histopathological phenotype, and higher levels of systemic inflammatory mediators than controls. In conclusion, telomere and telomerase activity's detection might be used as predictor biomarkers of sporadic TAA. Their impairment also suggests a strong role of vascular ageing in sporadic TAA, evocated by both environmental and genetic inflammatory factors.},
}
@article {pmid25127300,
year = {2014},
author = {Guerra, S},
title = {New asthma biomarkers: shorter telomeres, longer disease?.},
journal = {American journal of respiratory and critical care medicine},
volume = {190},
number = {4},
pages = {356-358},
doi = {10.1164/rccm.201407-1248ED},
pmid = {25127300},
issn = {1535-4970},
mesh = {Aging/*blood/*genetics ; Asthma/*blood/*genetics ; Female ; Humans ; Leukocytes/*physiology ; Male ; Telomere Homeostasis/*physiology ; },
}
@article {pmid25127141,
year = {2014},
author = {Jones, RE and Oh, S and Grimstead, JW and Zimbric, J and Roger, L and Heppel, NH and Ashelford, KE and Liddiard, K and Hendrickson, EA and Baird, DM},
title = {Escape from telomere-driven crisis is DNA ligase III dependent.},
journal = {Cell reports},
volume = {8},
number = {4},
pages = {1063-1076},
doi = {10.1016/j.celrep.2014.07.007},
pmid = {25127141},
issn = {2211-1247},
support = {C17199/A13490/CRUK_/Cancer Research UK/United Kingdom ; 10-0021/AICR_/Worldwide Cancer Research/United Kingdom ; R01 GM088351/GM/NIGMS NIH HHS/United States ; GM088351/GM/NIGMS NIH HHS/United States ; R01 CA154461/CA/NCI NIH HHS/United States ; CA15446/CA/NCI NIH HHS/United States ; },
mesh = {Apoptosis ; Catalytic Domain ; DNA End-Joining Repair ; DNA Ligase ATP ; DNA Ligases/*physiology ; HCT116 Cells ; Humans ; Poly-ADP-Ribose Binding Proteins ; Recombination, Genetic ; *Telomere Homeostasis ; Xenopus Proteins ; },
abstract = {Short dysfunctional telomeres are capable of fusion, generating dicentric chromosomes and initiating breakage-fusion-bridge cycles. Cells that escape the ensuing cellular crisis exhibit large-scale genomic rearrangements that drive clonal evolution and malignant progression. We demonstrate that there is an absolute requirement for fully functional DNA ligase III (LIG3), but not ligase IV (LIG4), to facilitate the escape from a telomere-driven crisis. LIG3- and LIG4-dependent alternative (A) and classical (C) nonhomologous end-joining (NHEJ) pathways were capable of mediating the fusion of short dysfunctional telomeres, both displaying characteristic patterns of microhomology and deletion. Cells that failed to escape crisis exhibited increased proportions of C-NHEJ-mediated interchromosomal fusions, whereas those that escaped displayed increased proportions of intrachromosomal fusions. We propose that the balance between inter- and intrachromosomal telomere fusions dictates the ability of human cells to escape crisis and is influenced by the relative activities of A- and C-NHEJ at short dysfunctional telomeres.},
}
@article {pmid25122631,
year = {2014},
author = {Cooley, C and Davé, A and Garg, M and Bianchi, A},
title = {Tel1ATM dictates the replication timing of short yeast telomeres.},
journal = {EMBO reports},
volume = {15},
number = {10},
pages = {1093-1101},
pmid = {25122631},
issn = {1469-3178},
support = {12720/CRUK_/Cancer Research UK/United Kingdom ; G0701428/MRC_/Medical Research Council/United Kingdom ; C28567/A12720/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {DNA Breaks, Double-Stranded ; DNA Replication/*genetics ; Intracellular Signaling Peptides and Proteins/*genetics/metabolism ; Protein Serine-Threonine Kinases/*genetics/metabolism ; Replication Origin/genetics ; Repressor Proteins/genetics ; S Phase/genetics ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Telomerase/genetics ; Telomere/*genetics ; Telomere Shortening/*genetics ; Telomere-Binding Proteins/genetics ; },
abstract = {Telomerase action is temporally linked to DNA replication. Although yeast telomeres are normally late replicating, telomere shortening leads to early firing of subtelomeric DNA replication origins. We show that double-strand breaks flanked by short telomeric arrays cause origin firing early in S phase at late-replicating loci and that this effect on origin firing time is dependent on the Tel1(ATM) checkpoint kinase. The effect of Tel1(ATM) on telomere replication timing extends to endogenous telomeres and is stronger than that elicited by Rif1 loss. These results establish that Tel1(ATM) specifies not only the extent but also the timing of telomerase recruitment.},
}
@article {pmid25121374,
year = {2014},
author = {Sekhri, K},
title = {Telomeres and telomerase: understanding basic structure and potential new therapeutic strategies targeting it in the treatment of cancer.},
journal = {Journal of postgraduate medicine},
volume = {60},
number = {3},
pages = {303-308},
doi = {10.4103/0022-3859.138797},
pmid = {25121374},
issn = {0972-2823},
mesh = {Antineoplastic Agents/*pharmacology ; Enzyme Inhibitors/pharmacology/therapeutic use ; Genetic Therapy ; Humans ; Immunotherapy ; Neoplasms/pathology/*therapy ; RNA, Messenger/genetics/metabolism ; Telomerase/*antagonists &amp; inhibitors/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {The impact of cancer on humanity is huge and a great deal of research is going on worldwide to find novel therapeutic targets. Telomerase is one such exciting target. Increased telomerase activity provides cancer cells with unlimited proliferative potential and is one of the hallmarks of cancer. This article provides a basic understanding of telomere and telomerase in cancer and summarizes various potential therapeutic approaches used for strategic targeting of telomerase enzyme. Medline, Medscape, EMBASE, Cochrane database, Scopus and clinicaltrials.gov were searched using terms like "telomeres", "telomerase" and "targeted cancer therapy". Journal articles published from 2005 to 2013 describing telomerase-based cancer therapy were screened.},
}
@article {pmid25120649,
year = {2014},
author = {Yuan, P and Wang, Z and Lv, W and Pan, H and Yang, Y and Yuan, X and Hu, J},
title = {Telomerase Cajal body protein 1 depletion inhibits telomerase trafficking to telomeres and induces G1 cell cycle arrest in A549 cells.},
journal = {Oncology letters},
volume = {8},
number = {3},
pages = {1009-1016},
pmid = {25120649},
issn = {1792-1074},
abstract = {Telomerase Cajal body protein 1 (TCAB1) is a telomerase holoenzyme, which is markedly enriched in Cajal bodies (CBs) and facilitates the recruitment of telomerase to CBs in the S phase of the cell cycle. This recruitment is dependent on TCAB1 binding to a telomerase RNA component. The majority of cancer cells are able to grow indefinitely due to telomerase and its mechanism of trafficking to telomeres. In the present study, a certain level of TCAB1 expression in A549 human lung cells was identified and TCAB1 knockdown exhibited a potent antiproliferative effect on these cells, which was coupled with a decrease in the cell density and activity of the cellular enzymes. In addition, TCAB1-depletion was demonstrated to inhibit telomerase trafficking to telomeres in the A549 cells, leading to subsequent G1 cell cycle arrest without inducing apoptotic cell death. Overall, these observations indicated that TCAB1 may be essential for A549 cell proliferation and cell cycle regulation, and may be a potential candidate for the development of a therapeutic target for lung adenocarcinomas.},
}
@article {pmid25119516,
year = {2014},
author = {Cui, X and Wang, J and Cai, Z and Wang, J and Liu, K and Cui, S and Zhang, J and Luo, Y and Wang, X and Li, W and Jing, J},
title = {Complete sequence analysis of mitochondrial DNA and telomere length in aplastic anemia.},
journal = {International journal of molecular medicine},
volume = {34},
number = {5},
pages = {1309-1314},
doi = {10.3892/ijmm.2014.1898},
pmid = {25119516},
issn = {1791-244X},
mesh = {Adolescent ; Adult ; Aged ; Anemia, Aplastic/diagnosis/*genetics ; Bone Marrow/metabolism ; Case-Control Studies ; Child ; DNA, Mitochondrial/*genetics ; Female ; Hemoglobins/metabolism ; Humans ; Leukocyte Count ; Male ; Middle Aged ; Mutation ; Polymorphism, Genetic ; Real-Time Polymerase Chain Reaction ; Sequence Analysis, DNA ; Specimen Handling ; Telomere/chemistry/*genetics ; Young Adult ; },
abstract = {The present study was primarily undertaken to examine the hypothesis that mitochondrial DNA (mtDNA) mutations and telomere length may be associated with aplastic anemia (AA). Our study included a single institution analysis of 40 patients presenting with AA first diagnosed at the Affiliated Hospital of Shandong, University of Traditional Chinese Medicine between 2010 and 2013. Bone marrow and oral epithelial samples were collected from patients with AA (n=40) for mtDNA mutation and telomere length determinations. Bone marrow specimens were collected from 40 healthy volunteers as controls for the examination of telomere length. The mitochondrial genome was amplified by polymerase chain reaction (PCR), and the products were used for sequencing and analysis. We detected 146 heteroplasmic mutations in 18 genes from 40 patients with AA, including 39 silent mutations and 28 frameshift mutations. We used the gamma globin gene (HBG) as the control gene in real-time PCR to survey the relative telomere length measurements of the patients with AA and the healthy volunteers. Telomere length was expressed as the relative T/S value. We observed a negative correlation between the mtDNA non-silent mutation and the white blood cell (WBC) count, hemoglobin and platelet count. Of note, there was a positive correlation between the relative T/S value and WBC count, hemoglobin and platelet count, and a negative correlation between the non-silent mutation and the relative T/S value. We conclude that the functional impairment of the mitochondrial respiratory chain induced by mutation and telomere length shortening may play an important role in the process of hematopoietic failure in patients with AA. Additionally, mtDNA mutations and telomere length shortening influenced each other.},
}
@article {pmid25115693,
year = {2014},
author = {Pham, HH and Murphy, CT and Sureshkumar, G and Ly, DH and Opresko, PL and Armitage, BA},
title = {Cooperative hybridization of γPNA miniprobes to a repeating sequence motif and application to telomere analysis.},
journal = {Organic &amp; biomolecular chemistry},
volume = {12},
number = {37},
pages = {7345-7354},
pmid = {25115693},
issn = {1477-0539},
support = {R43 GM108187/GM/NIGMS NIH HHS/United States ; R43GM108187/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; DNA/*chemistry ; Humans ; *In Situ Hybridization, Fluorescence ; Jurkat Cells ; Molecular Structure ; Peptide Nucleic Acids/chemical synthesis/*chemistry ; Spectrometry, Fluorescence ; Telomere/*chemistry ; },
abstract = {GammaPNA oligomers having one or two repeats of the sequence AATCCC were designed to hybridize to DNA having one or more repeats of the complementary TTAGGG sequence found in the human telomere. UV melting curves and surface plasmon resonance experiments demonstrate high affinity and cooperativity for hybridization of these miniprobes to DNA having multiple complementary repeats. Fluorescence spectroscopy for Cy3-labeled miniprobes demonstrate increases in fluorescence intensity for assembling multiple short probes on a DNA target compared with fewer longer probes. The fluorescent γPNA miniprobes were then used to stain telomeres in metaphase chromosomes derived from U2OS cells possessing heterogeneous long telomeres and Jurkat cells harboring homogenous short telomeres. The miniprobes yielded comparable fluorescence intensity to a commercially available PNA 18mer probe in U2OS cells, but significantly brighter fluorescence was observed for telomeres in Jurkat cells. These results suggest that γPNA miniprobes can be effective telomere-staining reagents with applications toward analysis of critically short telomeres, which have been implicated in a range of human diseases.},
}
@article {pmid25111028,
year = {2014},
author = {Garland, SN and Palmer, C and Donelson, M and Gehrman, P and Johnson, FB and Mao, JJ},
title = {A nested case-controlled comparison of telomere length and psychological functioning in breast cancer survivors with and without insomnia symptoms.},
journal = {Rejuvenation research},
volume = {17},
number = {5},
pages = {453-457},
pmid = {25111028},
issn = {1557-8577},
support = {R01 CA158243/CA/NCI NIH HHS/United States ; K23 AT004112/AT/NCCIH NIH HHS/United States ; /CAPMC/CIHR/Canada ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Anxiety/complications ; Breast Neoplasms/*complications/*psychology ; Case-Control Studies ; Demography ; Depression/complications ; Fatigue/complications ; Female ; Humans ; Middle Aged ; Sleep Initiation and Maintenance Disorders/*complications/*psychology ; Survivors/*psychology ; *Telomere Homeostasis ; },
abstract = {The ability to achieve sufficient restorative sleep is important in the maintenance of physical and mental health; however, disturbed sleep and insomnia symptoms are a common experience among women with breast cancer. In non-cancer populations, insufficient sleep quantity and quality has been associated with shortened telomere length (TL), a measure of accumulated cellular damage and human aging. This feasibility study compared TL in women previously diagnosed with breast cancer with clinically significant insomnia symptoms (n=70) to an age- and body mass index (BMI)-matched comparison group (n=70) of breast cancer survivors. Women with significant insomnia symptoms had higher levels of unemployment compared to women without insomnia. TL was positively skewed and shorter in the insomnia group (Median=6.000, S=1.000, standard error [SE]=0.287) than the control group (Median=6.195, S=-0.269, SE=0.287); however, this was not significant (p=0.29). Women with insomnia also reported significantly higher levels of depression (p<0.001), anxiety (p<0.001), and fatigue (p<0.001). This study provides the first measure of effect size and variability of TL in women with breast cancer and highlights the need for larger sample sizes to investigate the impact of insomnia and co-morbid symptom distress on cellular aging.},
}
@article {pmid25110842,
year = {2015},
author = {Uchino, BN and Cawthon, RM and Smith, TW and Kent, RG and Bowen, K and Light, KC},
title = {A cross-sectional analysis of the association between perceived network social control and telomere length.},
journal = {Health psychology : official journal of the Division of Health Psychology, American Psychological Association},
volume = {34},
number = {5},
pages = {531-538},
doi = {10.1037/hea0000148},
pmid = {25110842},
issn = {1930-7810},
support = {C06-RR11234/RR/NCRR NIH HHS/United States ; R21AG029239/AG/NIA NIH HHS/United States ; UL1-RR025764/RR/NCRR NIH HHS/United States ; },
mesh = {Aged ; Cross-Sectional Studies ; Female ; Health Behavior ; Humans ; Leukocytes, Mononuclear ; Male ; Middle Aged ; *Perception ; *Social Control, Informal ; *Social Support ; *Telomere ; },
abstract = {OBJECTIVE: Social control in the health domain refers to attempts by social network members to get an individual to modify their health behaviors. According to the dual effects model of social control, having one's health behavior controlled by others should be related to healthier behavioral change, but might arouse psychological distress as one may resent being controlled. Despite potential healthy behavior change, the stress of social control may thus be detrimental as interpersonal stress has been related to negative health outcomes. In the present study, the association between perceived social control and telomere length was tested to examine its association to biological outcomes.<br><br>METHOD: In this cross-sectional study, a relatively healthy community sample of 140 middle age and older adults completed measures of perceived social control, perceived stress, and health behaviors. Peripheral blood mononuclear cells were used to determine telomere length.<br><br>RESULTS: Main results showed that higher levels of perceived direct social network control were associated with shorter telomere length. These links were not influenced by statistical controls for medication use, self-rated health, trait hostility, and optimism. Perceived social control was also related to greater perceived stress but not health behaviors overall. However, neither perceived stress nor health behaviors mediated the link between social control and telomere length.<br><br>CONCLUSIONS: Although the study design precludes strong inferences, these results suggest that perceived social control may be associated with cellular aging. These data also highlight the utility of integrating biological outcomes into social control models. (PsycINFO Database Record},
}
@article {pmid25109806,
year = {2014},
author = {Chen, WD and Wen, MS and Shie, SS and Lo, YL and Wo, HT and Wang, CC and Hsieh, IC and Lee, TH and Wang, CY},
title = {The circadian rhythm controls telomeres and telomerase activity.},
journal = {Biochemical and biophysical research communications},
volume = {451},
number = {3},
pages = {408-414},
doi = {10.1016/j.bbrc.2014.07.138},
pmid = {25109806},
issn = {1090-2104},
mesh = {ARNTL Transcription Factors/physiology ; Aging/physiology ; Animals ; CLOCK Proteins/deficiency/physiology ; Circadian Clocks ; Circadian Rhythm/*physiology ; Emergency Medical Services ; Humans ; Mice ; Physicians ; RNA, Messenger ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; Work Schedule Tolerance/*physiology ; Workforce ; },
abstract = {Circadian clocks are fundamental machinery in organisms ranging from archaea to humans. Disruption of the circadian system is associated with premature aging in mice, but the molecular basis underlying this phenomenon is still unclear. In this study, we found that telomerase activity exhibits endogenous circadian rhythmicity in humans and mice. Human and mouse TERT mRNA expression oscillates with circadian rhythms and are under the control of CLOCK-BMAL1 heterodimers. CLOCK deficiency in mice causes loss of rhythmic telomerase activities, TERT mRNA oscillation, and shortened telomere length. Physicians with regular work schedules have circadian oscillation of telomerase activity while emergency physicians working in shifts lose the circadian rhythms of telomerase activity. These findings identify the circadian rhythm as a mechanism underlying telomere and telomerase activity control that serve as interconnections between circadian systems and aging.},
}
@article {pmid25108466,
year = {2014},
author = {Keefe, DL},
title = {In every end there is a beginning--telomeres in male reproduction.},
journal = {Fertility and sterility},
volume = {102},
number = {3},
pages = {690-691},
doi = {10.1016/j.fertnstert.2014.07.1236},
pmid = {25108466},
issn = {1556-5653},
mesh = {Humans ; Infertility, Male/*genetics ; Male ; Spermatocytes/*metabolism ; *Telomere Homeostasis ; },
}
@article {pmid25104460,
year = {2014},
author = {Zhang, W and Hui, R and Yang, S},
title = {Telomeres, cardiovascular aging, and potential intervention for cellular senescence.},
journal = {Science China. Life sciences},
volume = {57},
number = {8},
pages = {858-862},
doi = {10.1007/s11427-014-4700-8},
pmid = {25104460},
issn = {1869-1889},
mesh = {Atherosclerosis/genetics/pathology/therapy ; Cardiovascular System/*cytology ; Cellular Senescence/*genetics ; Humans ; *Telomere ; Telomere Shortening ; },
abstract = {A consistent association has been observed between leukocyte telomere length (LTL) and atherosclerosis, but the mechanisms underlying these associations are still not well understood. Premature biology aging was evident in atherosclerotic plaques, characterized by reduced cell proliferation, irreversible growth arrest and apoptosis, and telomere attrition. As atherosclerosis is a state of chronic low-grade inflammation and increased oxidative stress, shortened LTL in patients with atherosclerosis might stem from the two sources, one is an accelerated rate in hematopoietic stem cells (HSCs) replication to replace leukocytes consumed in the inflammatory process, and another is the increase in the loss of telomere repeats per replication. Thus, diminished HSC reserves at birth and age-dependent telomere attrition afterward are mirrored in shortened LTL during the adulthood. In addition, the inter-individual variation of LTL in the general population can be partly explained by genetic factors regulating telomere maintenance and the rate of HSCs replication. Atherosclerosis is an aging-related disease, and practically all humans develop atherosclerosis if they live long enough. Here we overview the potential roles of LTL dynamics in the imbalance between injurious oxidative stress/inflammation and endothelial repair during the pathogenesis of age-related atherosclerosis, and discuss the possibility that preventing accelerated cellular senescence is a potential target in prevention of atherosclerosis.},
}
@article {pmid25103821,
year = {2014},
author = {Campa, D and Mergarten, B and De Vivo, I and Boutron-Ruault, MC and Racine, A and Severi, G and Nieters, A and Katzke, VA and Trichopoulou, A and Yiannakouris, N and Trichopoulos, D and Boeing, H and Quirós, JR and Duell, EJ and Molina-Montes, E and Huerta, JM and Ardanaz, E and Dorronsoro, M and Khaw, KT and Wareham, N and Travis, RC and Palli, D and Pala, V and Tumino, R and Naccarati, A and Panico, S and Vineis, P and Riboli, E and Siddiq, A and Bueno-de-Mesquita, HB and Peeters, PH and Nilsson, PM and Sund, M and Ye, W and Lund, E and Jareid, M and Weiderpass, E and Duarte-Salles, T and Kong, SY and Stepien, M and Canzian, F and Kaaks, R},
title = {Leukocyte telomere length in relation to pancreatic cancer risk: a prospective study.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {23},
number = {11},
pages = {2447-2454},
doi = {10.1158/1055-9965.EPI-14-0247},
pmid = {25103821},
issn = {1538-7755},
support = {/WT_/Wellcome Trust/United Kingdom ; /BHF_/British Heart Foundation/United Kingdom ; /DH_/Department of Health/United Kingdom ; G0401527/MRC_/Medical Research Council/United Kingdom ; G1000143/MRC_/Medical Research Council/United Kingdom ; 16491/CRUK_/Cancer Research UK/United Kingdom ; 14136/CRUK_/Cancer Research UK/United Kingdom ; 001/WHO_/World Health Organization/International ; },
mesh = {Adult ; Aged ; Cohort Studies ; Female ; Humans ; Leukocytes ; Male ; Middle Aged ; Pancreatic Neoplasms/*genetics ; Prospective Studies ; Risk Factors ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {BACKGROUND: Several studies have examined leukocyte telomere length (LTL) as a possible predictor for cancer at various organ sites. The hypothesis originally motivating many of these studies was that shorter telomeres would be associated with an increase in cancer risk; the results of epidemiologic studies have been inconsistent, however, and suggested positive, negative, or null associations. Two studies have addressed the association of LTL in relation to pancreatic cancer risk and the results are contrasting.<br><br>METHODS: We measured LTL in a prospective study of 331 pancreatic cancer cases and 331 controls in the context of the European Prospective Investigation into Cancer and Nutrition (EPIC).<br><br>RESULTS: We observed that the mean LTL was higher in cases (0.59 &#xb1; 0.20) than in controls (0.57 &#xb1; 0.17), although this difference was not statistically significant (P = 0.07), and a basic logistic regression model showed no association of LTL with pancreas cancer risk. When adjusting for levels of HbA1c and C-peptide, however, there was a weakly positive association between longer LTL and pancreatic cancer risk [OR, 1.13; 95% confidence interval (CI), 1.01-1.27]. Additional analyses by cubic spline regression suggested a possible nonlinear relationship between LTL and pancreatic cancer risk (P = 0.022), with a statistically nonsignificant increase in risk at very low LTL, as well as a significant increase at high LTL.<br><br>CONCLUSION: Taken together, the results from our study do not support LTL as a uniform and strong predictor of pancreatic cancer.<br><br>IMPACT: The results of this article can provide insights into telomere dynamics and highlight the complex relationship between LTL and pancreatic cancer risk.},
}
@article {pmid25097306,
year = {2014},
author = {Mucciardi, G and Gali', A and Barresi, V and Mucciardi, M and Aguennouz, M and Inferrera, A and Magno, C},
title = {Telomere instability in papillary bladder urothelial carcinomas: Comparison with grading and risk of recurrence.},
journal = {Indian journal of urology : IJU : journal of the Urological Society of India},
volume = {30},
number = {3},
pages = {245-251},
pmid = {25097306},
issn = {0970-1591},
abstract = {INTRODUCTION: Shortening of telomere is associated with cellular senescence and cancer. This study aims to investigate the relationship between tumor grade and recurrence in relation to telomere length (TL), telomerase activity (TA) and telomere-binding proteins expression (TBPs) in patients with non-muscle invasive bladder cancer (NMIBC).<br><br>MATERIALS AND METHODS: Tumor/healthy tissues were collected from 58 patients (35 with and 23 without NMIBC). Cystoscopy was performed at 3, 6 and 12 months to determine recurrence. Tumor grades and recurrence were correlated with TL, TA and TBPs using the Kruskal-Wallis non-parametric test. Results were considered significant at P < 0.05.<br><br>RESULTS: Histological evaluation indicated 15 patients (42.9%) with high-grade (HG) and 20 patients (57.1%) with low-grade (LG) NMIBC. TL, TA and TBPs were found to be significantly different in tumors as compared with controls. A significant (P < 0.05) difference in the expression of TBPs was observed in the disease-free mucosa of cancer patients as compared with HG and LG tumors. In the follow-up, a total of 11 tumor recurrences were observed; among these eight recurrences were observed in patients with HG tumors and three in patients with LG tumors. TL, &#x200a;Human telomerase reverse transcriptase (hTERT) (that represents TA) and poly (ADP-ribose) polymerase 1 (PARP-1) in tumor samples and telomeric repeat binding factors TRF1, TRF2 and tankyrase (TANK) in normal mucosa obtained from the tumor group were respectively found to exhibit a positive and negative association with the risk of recurrence.<br><br>CONCLUSIONS: Our study demonstrates that TL, TA and TBPs are altered in tumors and non-cancerous mucosa in patients with papillary urothelial NMIBC. Further studies are warranted to identify their suitability as a potential biomarker.},
}
@article {pmid25096951,
year = {2014},
author = {Gielen, M and Hageman, G and Pachen, D and Derom, C and Vlietinck, R and Zeegers, MP},
title = {Placental telomere length decreases with gestational age and is influenced by parity: a study of third trimester live-born twins.},
journal = {Placenta},
volume = {35},
number = {10},
pages = {791-796},
doi = {10.1016/j.placenta.2014.05.010},
pmid = {25096951},
issn = {1532-3102},
mesh = {Female ; *Gestational Age ; Humans ; Male ; Parity/*physiology ; Placenta/*metabolism ; Pregnancy ; Pregnancy Trimester, Third ; Prospective Studies ; Telomere/*metabolism ; Telomere Shortening/*physiology ; Twins ; },
abstract = {BACKGROUND: In contrast to the postnatal period, little is known about telomere length (TL) during prenatal life. The decrease in placental TL remains unknown, although intra uterine growth retardation and preeclampsia are associated with shorter placental TL. The aim of this study is to assess the decrease of placental TL during the third trimester of gestation and to explore the role of potential "growth influencing factors".<br><br>METHODS: The study sample consisted of 329 live-born twins from the East Flanders Prospective Twin Survey. TL was determined using a multiplex quantitative PCR method. Gestational age, sex, birth order, placental characteristics, parity, maternal and paternal age, diabetes, hypertension, smoking, alcohol use, and socio economic status (SES) were considered "growth influencing factors". Bivariable multilevel regression analysis with "growth influencing factors" was performed.<br><br>RESULTS: Placental TL ranged from 4.3&#xa0;kbp to 84.4&#xa0;kbp with a median of 10.8&#xa0;kbp. Ln(TL) decreased in a linear fashion with an estimated TL decreasing from 13.98&#xa0;kbp at 28 weeks to 10.56&#xa0;kbp at 42 weeks. The regression coefficient of gestational age became smaller if considered together with SES (b&#xa0;=&#xa0;-0.017; p&#xa0;=&#xa0;0.08) or diabetes (b&#xa0;=&#xa0;-0.018; p&#xa0;=&#xa0;0.07) and bigger if considered together with parity (b&#xa0;=&#xa0;-0.022; p&#xa0;=&#xa0;0.02), indicating that part of the association between gestational age and telomere length is explained by these three confounding factors.<br><br>CONCLUSION: Placental TL decreases during the third trimester of gestation of live-born twins with approximately 25% indicating that telomere shortening may play a role in aging of the placenta.},
}
@article {pmid25092726,
year = {2014},
author = {},
title = {Glioma a downside of long telomeres.},
journal = {Cancer discovery},
volume = {4},
number = {8},
pages = {861},
doi = {10.1158/2159-8290.CD-NB2014-097},
pmid = {25092726},
issn = {2159-8290},
mesh = {Glioma/*genetics/pathology ; Humans ; Risk Factors ; Telomere/*genetics ; },
}
@article {pmid25090243,
year = {2014},
author = {King, KS and Kozlitina, J and Rosenberg, RN and Peshock, RM and McColl, RW and Garcia, CK},
title = {Effect of leukocyte telomere length on total and regional brain volumes in a large population-based cohort.},
journal = {JAMA neurology},
volume = {71},
number = {10},
pages = {1247-1254},
pmid = {25090243},
issn = {2168-6157},
support = {UL1 TR001105/TR/NCATS NIH HHS/United States ; R01 HL093096/HL/NHLBI NIH HHS/United States ; P30 AG012300/AG/NIA NIH HHS/United States ; P3012300-19//PHS HHS/United States ; KL2 TR000453/TR/NCATS NIH HHS/United States ; KL2 TR001103/TR/NCATS NIH HHS/United States ; UL1TR000451/TR/NCATS NIH HHS/United States ; KL2TR000453/TR/NCATS NIH HHS/United States ; UL1 TR000451/TR/NCATS NIH HHS/United States ; R01HL093096/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics/pathology ; Amygdala/pathology ; Brain/*pathology ; Cerebral Cortex/pathology ; Cohort Studies ; Diencephalon/pathology ; Female ; Frontal Lobe/pathology ; Gray Matter/pathology ; Gyrus Cinguli/pathology ; Hippocampus/pathology ; Humans ; Image Processing, Computer-Assisted ; Leukocytes/*ultrastructure ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Organ Size ; Parietal Lobe/pathology ; Telomere/*genetics ; Temporal Lobe/pathology ; Thalamus/pathology ; White Matter/pathology ; Young Adult ; },
abstract = {IMPORTANCE: Telomere length has been associated with dementia and psychological stress, but its relationship with human brain size is unknown.<br><br>OBJECTIVE: To determine if peripheral blood telomere length is associated with brain volume.<br><br>Peripheral blood leukocyte telomere length and brain volumes were measured for 1960 individuals in the Dallas Heart Study, a population-based, probability sample of Dallas County, Texas, residents, with a median (25th-75th percentile) age of 50 (42-58) years. Global and 48 regional brain volumes were assessed from the automated analysis of magnetic resonance imaging.<br><br>MAIN OUTCOMES AND MEASURES: Telomere length and global and regional brain volumes.<br><br>RESULTS: Leukocyte telomere length was associated with total cerebral volume (&#x3b2; [SE], 0.06 [0.01], P&#x2009;<.001) including white and cortical gray matter volume (&#x3b2; [SE], 0.04 [0.01], P&#x2009;=&#x2009;.002; &#x3b2; [SE], 0.07 [0.02], P&#x2009;<.001, respectively), independent of age, sex, ethnicity, and total intracranial volume. While age was associated with the size of most subsegmental regions of the cerebral cortex, telomere length was associated with certain subsegmental regions. Compared with age, telomere length (TL) explained a sizeable proportion of the variance in volume of the hippocampus, amygdala, and inferior temporal region (hippocampus: &#x3b2;TL [SE], 0.08 [0.02], R2, 0.91% vs &#x3b2;age [SE], -0.16 [0.02], R2, 3.80%; amygdala: &#x3b2;TL [SE], 0.08 [0.02], R2, 0.78% vs &#x3b2;age [SE],-0.19 [0.02], R2,4.63%; inferior temporal: &#x3b2;TL [SE], 0.07 [0.02], R2, 0.92% vs &#x3b2;age [SE], -0.14 [0.02], R2, 3.98%) (P&#x2009;<.001 for all). The association of telomere length and the size of the inferior and superior parietal, hippocampus, and fusiform regions was stronger in individuals older than 50 years than younger individuals (inferior parietal: &#x3b2;>50 [SE], 0.13 [0.03], P&#x2009;<.001 vs &#x3b2;&#x2264;50 [SE], 0.02 [0.02], P&#x2009;=&#x2009;.51, P for interaction = .001; superior parietal: &#x3b2;>50 [SE], 0.11 [0.03], P&#x2009;<.001 vs &#x3b2;&#x2264;50 [SE], 0.01 [0.02], P&#x2009;=&#x2009;.71, P for interaction = .004; hippocampus: &#x3b2;>50 [SE], 0.10 [0.03], P&#x2009;=&#x2009;.004 vs &#x3b2;&#x2264;50 [SE], 0.05 [0.02], P&#x2009;=&#x2009;.07, P for interaction = .04; fusiform: &#x3b2;>50 [SE], 0.09 [0.03], P&#x2009;=&#x2009;.002, &#x3b2;&#x2264;50 [SE], 0.03 [0.02], P&#x2009;=&#x2009;.31, P for interaction = .03). The volume of the hippocampus, amygdala, superior and inferior temporal, precuneus, lateral orbitofrontal, posterior cingulate, thalamus and ventral diencephalon were independently associated with telomere length after adjustment for all covariates (age, gender, ethnicity, total intracranial volume, body mass index, blood pressure, diabetes, smoking status, and APOE genotype).<br><br>CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first population-based study to date to evaluate telomere length as an independent predictor of global and regional brain size. Future studies are needed to determine how telomere length and anatomic structural changes are related to cognitive function, dementia, and psychological disease.},
}
@article {pmid25084169,
year = {2014},
author = {Acharya, S and Kaul, Z and Gocha, AS and Martinez, AR and Harris, J and Parvin, JD and Groden, J},
title = {Association of BLM and BRCA1 during Telomere Maintenance in ALT Cells.},
journal = {PloS one},
volume = {9},
number = {8},
pages = {e103819},
pmid = {25084169},
issn = {1932-6203},
support = {UL1 TR000090/TR/NCATS NIH HHS/United States ; 8KL2TR000112-05/TR/NCATS NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; UL1 TR001070/TR/NCATS NIH HHS/United States ; 8UL1TR000090-05/TR/NCATS NIH HHS/United States ; KL2 TR000112/TR/NCATS NIH HHS/United States ; TL1 TR000091/TR/NCATS NIH HHS/United States ; 8TL1TR000091-05/TR/NCATS NIH HHS/United States ; R01 CA117898/CA/NCI NIH HHS/United States ; },
mesh = {BRCA1 Protein/genetics/*metabolism ; Blotting, Western ; Cell Cycle/genetics/physiology ; Cell Line, Tumor ; DNA Repair/genetics/physiology ; Fluorescent Antibody Technique ; HeLa Cells ; Humans ; Immunoprecipitation ; RNA, Small Interfering ; RecQ Helicases/genetics/*metabolism ; Telomere Homeostasis/genetics/*physiology ; },
abstract = {Fifteen percent of tumors utilize recombination-based alternative lengthening of telomeres (ALT) to maintain telomeres. The mechanisms underlying ALT are unclear but involve several proteins involved in homologous recombination including the BLM helicase, mutated in Bloom's syndrome, and the BRCA1 tumor suppressor. Cells deficient in either BLM or BRCA1 have phenotypes consistent with telomere dysfunction. Although BLM associates with numerous DNA damage repair proteins including BRCA1 during DNA repair, the functional consequences of BLM-BRCA1 association in telomere maintenance are not completely understood. Our earlier work showed the involvement of BRCA1 in different mechanisms of ALT, and telomere shortening upon loss of BLM in ALT cells. In order to delineate their roles in telomere maintenance, we studied their association in telomere metabolism in cells using ALT. This work shows that BLM and BRCA1 co-localize with RAD50 at telomeres during S- and G2-phases of the cell cycle in immortalized human cells using ALT but not in cells using telomerase to maintain telomeres. Co-immunoprecipitation of BRCA1 and BLM is enhanced in ALT cells at G2. Furthermore, BRCA1 and BLM interact with RAD50 predominantly in S- and G2-phases, respectively. Biochemical assays demonstrate that full-length BRCA1 increases the unwinding rate of BLM three-fold in assays using a DNA substrate that models a forked structure composed of telomeric repeats. Our results suggest that BRCA1 participates in ALT through its interactions with RAD50 and BLM.},
}
@article {pmid25077175,
year = {2014},
author = {Malaspina, D and Dracxler, R and Walsh-Messinger, J and Harlap, S and Goetz, RR and Keefe, D and Perrin, MC},
title = {Telomere length, family history, and paternal age in schizophrenia.},
journal = {Molecular genetics &amp; genomic medicine},
volume = {2},
number = {4},
pages = {326-331},
pmid = {25077175},
issn = {2324-9269},
support = {K24 MH001699/MH/NIMH NIH HHS/United States ; RC1 MH088843/MH/NIMH NIH HHS/United States ; },
abstract = {Leukocyte telomere length (LTL) is longer in association with advanced paternal age, but this association has not been examined along with family history (FH) in schizophrenia. LTL was measured by PCR and compared across cases and controls as part of a study to examine the characteristics of paternal age related schizophrenia. The 53 schizophrenia cases had similar mean LTL as 20 controls, although cases were significantly older than controls and overwhelmingly smoked cigarettes. Multivariate analyses showed that a FH of schizophrenia was associated with longer LTL in both male and female cases. Later paternal age was also related to longer LTL in male cases, but with shorter LTL in female cases. Male cases with older fathers and a FH had the longest LTL. The genetic architecture associated with a familial risk for schizophrenia may include pathways that lengthen LTL. Paternal aging conferred an additional increase in LTL lengthening in male cases, but reduced LTL in female cases. The gender difference in LTL for paternal aging is consistent with the severe illness features reported for female cases with older fathers and could implicate epigenetic alterations in the paternal X chromosomal region with advanced paternal age in association with the risk for schizophrenia.},
}
@article {pmid25074648,
year = {2014},
author = {Garland, SN and Johnson, B and Palmer, C and Speck, RM and Donelson, M and Xie, SX and DeMichele, A and Mao, JJ},
title = {Physical activity and telomere length in early stage breast cancer survivors.},
journal = {Breast cancer research : BCR},
volume = {16},
number = {4},
pages = {413},
pmid = {25074648},
issn = {1465-542X},
support = {K23 AT004112/AT/NCCIH NIH HHS/United States ; R01 CA158243/CA/NCI NIH HHS/United States ; /CAPMC/CIHR/Canada ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Breast Neoplasms/drug therapy/*etiology/*pathology ; Cross-Sectional Studies ; Female ; Humans ; Middle Aged ; *Motor Activity ; Neoplasm Staging ; Patient Outcome Assessment ; Risk Factors ; *Survivors ; *Telomere ; },
abstract = {INTRODUCTION: Telomere length (TL) is a biomarker of accumulated cellular damage and human aging. Evidence in healthy populations suggests that TL is impacted by a host of psychosocial and lifestyle factors, including physical activity. This is the first study to evaluate the relationship between self-reported physical activity and telomere length in early stage breast cancer survivors.<br><br>METHODS: A cross-sectional sample of 392 postmenopausal women with stage I-III breast cancer at an outpatient oncology clinic of a large university hospital completed questionnaires and provided a blood sample. TL was determined using terminal restriction fragment length analysis of genomic DNA isolated from peripheral blood mononuclear cells. Physical activity was dichotomized into two groups (none versus moderate to vigorous) using the International Physical Activity Questionnaire. Multivariate linear and logistic regression analyses were performed to identify factors associated with mean TL and physical activity.<br><br>RESULTS: Among participants, 66 (17%) did not participate in any physical activity. In multivariate model adjusted for age, compared to those who participated in moderate to vigorous physical activity, women who participated in no physical activity had significantly shorter TL (adjusted coefficient &#x3b2;=-0.22; 95% confidence interval (CI), -0.41 to -0.03; P=.03). Non-white race, lower education and depressive symptoms were associated with lack of self-reported physical activity (P<0.05 for all) but not TL.<br><br>CONCLUSION: Lack of physical activity is associated with shortened TL, warranting prospective investigation of the potential role of physical activity on cellular aging in breast cancer survivors.},
}
@article {pmid25073436,
year = {2015},
author = {Laster, BH and Isaacson, C and Perets, E and Msamra, M and Priel, E and Kalef-Ezra, J and Kost, J},
title = {Keeping those telomeres short! an innovative intratumoral long-term drug delivery system.},
journal = {Journal of cancer research and clinical oncology},
volume = {141},
number = {1},
pages = {23-34},
pmid = {25073436},
issn = {1432-1335},
mesh = {Angiogenesis Inhibitors/*administration &amp; dosage/pharmacology ; Animals ; Cell Proliferation/*drug effects ; DNA, Neoplasm/genetics ; *Drug Delivery Systems ; Female ; Hodgkin Disease/genetics/pathology/*prevention &amp; control ; Humans ; Lactic Acid/chemistry ; Mammary Neoplasms, Animal/genetics/pathology/*prevention &amp; control ; Mice ; Mice, Inbred BALB C ; Palladium/chemistry ; Polyglycolic Acid/chemistry ; Polylactic Acid-Polyglycolic Acid Copolymer ; Porphyrins/*administration &amp; dosage/pharmacology ; Telomerase/metabolism ; Telomere/*genetics ; Tumor Cells, Cultured ; },
abstract = {BACKGROUND: Telomerase activation and an alternative lengthening of telomeres (ALT) mechanism are two telomere-lengthening cancer cell survival mechanisms elicited by both chemo- and/or radiotherapy. Telomere lengthening interferes with cell lethality and results in the immortalization of cancer cells. To counteract these mechanisms, we developed a drug delivery system (DDS) consisting of a polymeric implant that is inserted directly into tumors. The DDS releases, continuously and gradually, a cationic porphyrin (PdTMPyP4) for >30 days after a single application, and inhibits telomerase activation.<br><br>METHODS: The PdTMPyP4 porphyrin is incorporated into a poly(co-glycolic lactic)acid (PLGA) polymer, solidified and cut into small rods. PdTMPyP4 release from the rods was measured spectrophotometrically over time. Uptake of Pd in the DNA of in L428 Hodgkins lymphoma cells was measured by ICP-MS, and telomerase activation by the TRAP assay. The rods were placed into the growth medium of cells whose growth rate was measured for 11 and 19 days. The cylinders were also inserted directly into KHJJ murine mammary tumors borne on the thighs of BALB/c mice and the tumor growth rate measured.<br><br>RESULTS: In vitro, >10(9)Pd atoms were measured in the DNA of each L428 cell and telomerase activity was reduced by ~15% within 24 h. A one-time application of the rod in the cell medium induced a factor of >5 greater lethality compared to a blank rod or untreated controls. In vivo, a one-time insertion of the rod into tumors resulted in the retardation of the growth rate by factors of 3-5 compared to untreated controls. Systemic uptake after intratumoral insertion of the rod was negligible.<br><br>CONCLUSION: The results suggest that the direct intratumoral insertion of a PdTMPyP4-containing polymeric rod would be of benefit as an adjuvant treatment for patients undergoing chemo- or radiotherapy. By preventing the lengthening of telomeres and therefore the unrestricted growth of cancer cells, our DDS will provide a significant therapeutic advantage to these treatments without affecting normal tissues.},
}
@article {pmid25071797,
year = {2014},
author = {Murphy, SP and Gumber, HK and Mao, Y and Bass, HW},
title = {A dynamic meiotic SUN belt includes the zygotene-stage telomere bouquet and is disrupted in chromosome segregation mutants of maize (Zea mays L.).},
journal = {Frontiers in plant science},
volume = {5},
number = {},
pages = {314},
pmid = {25071797},
issn = {1664-462X},
abstract = {The nuclear envelope (NE) plays an essential role in meiotic telomere behavior and links the cytoplasm and nucleoplasm during homologous chromosome pairing and recombination in many eukaryotic species. Resident NE proteins including SUN (Sad-1/UNC-84) and KASH (Klarsicht/ANC-1/Syne-homology) domain proteins are known to interact forming the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex that connects chromatin to the cytoskeleton. To investigate the possible cross-kingdom conservation of SUN protein functions in plant meiosis, we immunolocalized maize SUN2 using 3D microscopy of pollen mother cells from maize (Zea mays L.), a large-genome plant model with a canonical NE zygotene-stage telomere bouquet. We detected SUN2 at the nuclear periphery and found that it exhibited a distinct belt-like structure that transitioned to a half-belt during the zygotene stage and back to a full belt during and beyond the pachytene stage. The zygotene-stage half-belt SUN structure was shown by 3D immuno-FISH to include the NE-associated telomere cluster that defines the bouquet stage and coincides with homologous chromosome synapsis. Microtubule and filamentous actin staining patterns did not show any obvious belt or a retracted-like structure other than a general enrichment of tubulin staining distributed widely around the nucleus and throughout the cytoplasm. Genetic disruption of the meiotic SUN belt staining patterns with three different meiosis-specific mutants, desynaptic (dy1), asynaptic1 (as1), and divergent spindle1 (dv1) provides additional evidence for the role of the nuclear envelope in meiotic chromosome behavior. Taking into account all of the observations from this study, we propose that the maize SUN belt is directly or indirectly involved in meiotic telomere dynamics, chromosome synapsis, and possibly integration of signals and forces across the meiotic prophase nuclear envelope.},
}
@article {pmid25070535,
year = {2015},
author = {Puterman, E and Lin, J and Krauss, J and Blackburn, EH and Epel, ES},
title = {Determinants of telomere attrition over 1 year in healthy older women: stress and health behaviors matter.},
journal = {Molecular psychiatry},
volume = {20},
number = {4},
pages = {529-535},
pmid = {25070535},
issn = {1476-5578},
support = {R00 HL109247/HL/NHLBI NIH HHS/United States ; R00 HL 109247/HL/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Female ; Follow-Up Studies ; *Health Behavior ; Humans ; Life Change Events ; Middle Aged ; Multivariate Analysis ; Predictive Value of Tests ; Stress, Psychological/*pathology ; Telomere/*pathology ; *Telomere Shortening ; },
abstract = {Telomere length, a reliable predictor of disease pathogenesis, can be affected by genetics, chronic stress and health behaviors. Cross-sectionally, highly stressed postmenopausal women have shorter telomeres, but only if they are inactive. However, no studies have prospectively examined telomere length change over a short period, and if rate of attrition is affected by naturalistic factors such as stress and engagement in healthy behaviors, including diet, exercise, and sleep. Here we followed healthy women over 1 year to test if major stressors that occurred over the year predicted telomere shortening, and whether engaging in healthy behaviors during this period mitigates this effect. In 239 postmenopausal, non-smoking, disease-free women, accumulation of major life stressors across a 1-year period predicted telomere attrition over the same period-for every major life stressor that occurred during the year, there was a significantly greater decline in telomere length over the year of 35 bp (P<0.05). Yet, these effects were moderated by health behaviors (interaction B=0.19, P=0.04). Women who maintained relatively higher levels of health behaviors (1 s.d. above the mean) appeared to be protected when exposed to stress. This finding has implications for understanding malleability of telomere length, as well as expectations for possible intervention effects. This is the first study to identify predictors of telomere length change over the short period of a year.},
}
@article {pmid25066524,
year = {2015},
author = {Campa, D and Martino, A and Varkonyi, J and Lesueur, F and Jamroziak, K and Landi, S and Jurczyszyn, A and Marques, H and Andersen, V and Jurado, M and Brenner, H and Petrini, M and Vogel, U and García-Sanz, R and Buda, G and Gemignani, F and Ríos, R and Vangsted, AJ and Dumontet, C and Martínez-López, J and Moreno, MJ and Stępień, A and Wątek, M and Moreno, V and Dieffenbach, AK and Rossi, AM and Butterbach, K and Jacobsen, SE and Goldschmidt, H and Sainz, J and Hillengass, J and Orciuolo, E and Dudziński, M and Weinhold, N and Reis, RM and Canzian, F},
title = {Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length.},
journal = {International journal of cancer},
volume = {136},
number = {5},
pages = {E351-8},
doi = {10.1002/ijc.29101},
pmid = {25066524},
issn = {1097-0215},
mesh = {Aged ; Case-Control Studies ; Cohort Studies ; Computational Biology ; Female ; Follow-Up Studies ; Genetic Predisposition to Disease ; Germany/epidemiology ; Humans ; Leukocytes ; Male ; Middle Aged ; Multiple Myeloma/epidemiology/*genetics ; Polymorphism, Genetic/*genetics ; Prognosis ; Risk Factors ; Telomerase/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Compelling biological and epidemiological evidences point to a key role of genetic variants of the TERT and TERC genes in cancer development. We analyzed the genetic variability of these two gene regions using samples of 2,267 multiple myeloma (MM) cases and 2,796 healthy controls. We found that a TERT variant, rs2242652, is associated with reduced MM susceptibility (OR = 0.81; 95% CI: 0.72-0.92; p = 0.001). In addition we measured the leukocyte telomere length (LTL) in a subgroup of 140 cases who were chemotherapy-free at the time of blood donation and 468 controls, and found that MM patients had longer telomeres compared to controls (OR = 1.19; 95% CI: 0.63-2.24; p(trend) = 0.01 comparing the quartile with the longest LTL versus the shortest LTL). Our data suggest the hypothesis of decreased disease risk by genetic variants that reduce the efficiency of the telomerase complex. This reduced efficiency leads to shorter telomere ends, which in turn may also be a marker of decreased MM risk.},
}
@article {pmid25064619,
year = {2014},
author = {Broer, L and Raschenberger, J and Deelen, J and Mangino, M and Codd, V and Pietiläinen, KH and Albrecht, E and Amin, N and Beekman, M and de Craen, AJ and Gieger, C and Haun, M and Henneman, P and Herder, C and Hovatta, I and Laser, A and Kedenko, L and Koenig, W and Kollerits, B and Moilanen, E and Oostra, BA and Paulweber, B and Quaye, L and Rissanen, A and Roden, M and Surakka, I and Valdes, AM and Vuolteenaho, K and Thorand, B and van Dijk, KW and Kaprio, J and Spector, TD and Slagboom, PE and Samani, NJ and Kronenberg, F and van Duijn, CM and Ladwig, KH},
title = {Association of adiponectin and leptin with relative telomere length in seven independent cohorts including 11,448 participants.},
journal = {European journal of epidemiology},
volume = {29},
number = {9},
pages = {629-638},
pmid = {25064619},
issn = {1573-7284},
mesh = {Adiponectin/blood/*genetics ; Adult ; Biomarkers/blood ; Body Mass Index ; C-Reactive Protein/*metabolism ; Cohort Studies ; Cross-Sectional Studies ; Female ; Humans ; Inflammation ; Leptin/blood/*genetics ; Male ; Middle Aged ; Oxidative Stress ; Telomere/*genetics ; },
abstract = {Oxidative stress and inflammation are major contributors to accelerated age-related relative telomere length (RTL) shortening. Both conditions are strongly linked to leptin and adiponectin, the most prominent adipocyte-derived protein hormones. As high leptin levels and low levels of adiponectin have been implicated in inflammation, one expects adiponectin to be positively associated with RTL while leptin should be negatively associated. Within the ENGAGE consortium, we investigated the association of RTL with adiponectin and leptin in seven independent cohorts with a total of 11,448 participants. We performed partial correlation analysis on Z-transformed RTL and LN-transformed leptin/adiponectin, adjusting for age and sex. In extended models we adjusted for body mass index (BMI) and C-reactive protein (CRP). Adiponectin showed a borderline significant association with RTL. This appeared to be determined by a single study and when the outlier study was removed, this association disappeared. The association between RTL and leptin was highly significant (r = -0.05; p = 1.81 × 10(-7)). Additional adjustment for BMI or CRP did not change the results. Sex-stratified analysis revealed no difference between men and women. Our study suggests that high leptin levels are associated with short RTL.},
}
@article {pmid25060906,
year = {2014},
author = {Guan, JZ and Guan, WP and Maeda, T and Makino, N},
title = {Changes in telomere length distribution in low-dose X-ray-irradiated human umbilical vein endothelial cells.},
journal = {Molecular and cellular biochemistry},
volume = {396},
number = {1-2},
pages = {129-135},
pmid = {25060906},
issn = {1573-4919},
mesh = {Apoptosis/genetics/radiation effects ; Cell Survival/genetics/radiation effects ; Dose-Response Relationship, Radiation ; Human Umbilical Vein Endothelial Cells/*radiation effects ; Humans ; Telomerase/metabolism ; Telomere/*radiation effects ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; X-Rays ; },
abstract = {Ionizing radiation (IR) is known to be a cause of telomere dysfunction in tumor cells; however, very few studies have investigated X-ray-related changes in telomere length and the telomerase activity in normal human cells, such as umbilical vein endothelial cells (HUVECs). The loss of a few hundred base pairs from a shortened telomere has been shown to be important with respect to cellular senescence, although it may not be detected according to traditional mean telomere length [assessed as the terminal restriction fragment (TRF)] analyses. In the present study, a continuous time window from irradiation was selected to examine changes in the telomere length, including the mean TRF length, percentage of the telomere length, telomerase activity, apoptotic rate, and survival rate in HUVECs from the first day to the fourth day after the administration of a 0.5-Gy dose of irradiation. The mean TRF length in the irradiated HUVECs showed shorter telomere length in first 3 days, but they were not statistically significant. On the other hand, according to the percentage analysis of the telomere length, a decreasing tendency was noted in the longer telomere lengths (9.4-4.4 kb), with a significant increase in the shortest telomeres (4.4-2.3 kb) among the irradiated cells versus the controls from the first day to the third after irradiation; no significant differences were noted on the fourth day. These results suggest that the shortest telomeres are sensitive to the late stage of radiation damage. The proliferation of irradiated cells was suppressed after IR in contrast to the non-irradiated cells. The apoptotic rate was elevated initially both in IR- and non-IR-cells, but that of IR-cells was maintained at an elevated level thereafter in contrast to that of non-IR-cells decreasing promptly. Therefore, a 0.5-Gy dose of IR induces persistent apoptosis leading to an apparent growth arrest of the normal HUVECs.},
}
@article {pmid25059482,
year = {2014},
author = {Samassekou, O and Bastien, N and Lichtensztejn, D and Yan, J and Mai, S and Drouin, R},
title = {Different TP53 mutations are associated with specific chromosomal rearrangements, telomere length changes, and remodeling of the nuclear architecture of telomeres.},
journal = {Genes, chromosomes &amp; cancer},
volume = {53},
number = {11},
pages = {934-950},
doi = {10.1002/gcc.22205},
pmid = {25059482},
issn = {1098-2264},
mesh = {Cell Line, Tumor ; Cell Nucleus/*metabolism/ultrastructure ; Cell Proliferation ; *Chromosomal Instability ; Colonic Neoplasms ; Humans ; Mutation ; Shelterin Complex ; Telomere/*ultrastructure ; Telomere-Binding Proteins/genetics/metabolism ; Transcriptome ; Tumor Suppressor Protein p53/*genetics ; },
abstract = {TP53 mutations are the most common mutations in human cancers, and TP53-R175H and TP53-R273H are the most frequent. The impact of these mutations on genomic instability after tumor initiation is still uncovered. To gain insight into this, we studied the effects of three specific TP53 mutants (TP53-V143A, TP53-R175H, and TP53-R273H) on genomic instability using four isogenic lines of LoVo cells. Multicolor fluorescence in situ hybridization (FISH), three-dimensional (3D) quantitative FISH (Q-FISH) on interphase and Q-FISH on metaphases were used to investigate genomic instability. We found that LoVo cells expressing mutant TP53-R175H displayed the highest level of chromosomal instability among the LoVo cell lines. Furthermore, we observed that mutant TP53-R175H and TP53-V143A showed more alterations in their 3D nuclear architecture of telomeres than the mutant TP53-R273H and the wild type. Moreover, we noted an association between some chromosomal abnormalities and telomere elongation in the mutant TP53-R175H. Taken together, our results indicate that the mutation TP53-R175H is more likely to cause higher levels of genomic instability than the other TP53 mutations. We proposed that the type of TP53 mutations and the genetic background of a cancer cell are major determinants of the TP53-dependent genomic instability.},
}
@article {pmid25057900,
year = {2014},
author = {Anderson, MZ and Gerstein, AC and Wigen, L and Baller, JA and Berman, J},
title = {Silencing is noisy: population and cell level noise in telomere-adjacent genes is dependent on telomere position and sir2.},
journal = {PLoS genetics},
volume = {10},
number = {7},
pages = {e1004436},
pmid = {25057900},
issn = {1553-7404},
support = {R01 AI075096/AI/NIAID NIH HHS/United States ; R01AI0624273/AI/NIAID NIH HHS/United States ; R01AI075096/AI/NIAID NIH HHS/United States ; },
mesh = {Cell Communication/genetics ; Chromatin/genetics ; DNA-Binding Proteins/*biosynthesis/genetics ; Gene Expression Regulation, Fungal/genetics ; Histone Deacetylases/genetics/metabolism ; Protein Processing, Post-Translational/genetics ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/genetics ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/*genetics/metabolism ; Sirtuin 2/*genetics/metabolism ; Telomere/*genetics ; *Transcription, Genetic ; },
abstract = {Cell-to-cell gene expression noise is thought to be an important mechanism for generating phenotypic diversity. Furthermore, telomeric regions are major sites for gene amplification, which is thought to drive genetic diversity. Here we found that individual subtelomeric TLO genes exhibit increased variation in transcript and protein levels at both the cell-to-cell level as well as at the population-level. The cell-to-cell variation, termed Telomere-Adjacent Gene Expression Noise (TAGEN) was largely intrinsic noise and was dependent upon genome position: noise was reduced when a TLO gene was expressed at an ectopic internal locus and noise was elevated when a non-telomeric gene was expressed at a telomere-adjacent locus. This position-dependent TAGEN also was dependent on Sir2p, an NAD+-dependent histone deacetylase. Finally, we found that telomere silencing and TAGEN are tightly linked and regulated in cis: selection for either silencing or activation of a TLO-adjacent URA3 gene resulted in reduced noise at the neighboring TLO but not at other TLO genes. This provides experimental support to computational predictions that the ability to shift between silent and active chromatin states has a major effect on cell-to-cell noise. Furthermore, it demonstrates that these shifts affect the degree of expression variation at each telomere individually.},
}
@article {pmid25056954,
year = {2014},
author = {Frescas, D and de Lange, T},
title = {Binding of TPP1 protein to TIN2 protein is required for POT1a,b protein-mediated telomere protection.},
journal = {The Journal of biological chemistry},
volume = {289},
number = {35},
pages = {24180-24187},
pmid = {25056954},
issn = {1083-351X},
support = {R01 AG016642/AG/NIA NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; 5R37GM49046/GM/NIGMS NIH HHS/United States ; 5R01AG16642/AG/NIA NIH HHS/United States ; },
mesh = {Alleles ; Amino Acid Sequence ; Animals ; Cell Line, Transformed ; DNA-Binding Proteins/*physiology ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Serine Proteases/chemistry/*metabolism ; Shelterin Complex ; *Telomerase/metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {The single-stranded DNA binding proteins in mouse shelterin, POT1a and POT1b, accumulate at telomeres as heterodimers with TPP1, which binds TIN2 and thus links the TPP1/POT1 dimers with TRF1 and TRF2/Rap1. When TPP1 is tethered to TIN2/TRF1/TRF2, POT1a is thought to block replication protein A binding to the single-stranded telomeric DNA and prevent ataxia telangiectasia and Rad3-related kinase activation. Similarly, TPP1/POT1b tethered to TIN2 can control the formation of the correct single-stranded telomeric overhang. Consistent with this view, the telomeric phenotypes following deletion of POT1a,b or TPP1 are phenocopied in TIN2-deficient cells. However, the loading of TRF1 and TRF2/Rap1 is additionally compromised in TIN2 KO cells, leading to added phenotypes. Therefore, it could not be excluded that, in addition to TIN2, other components of shelterin contribute to the recruitment of TPP1/POT1a,b as suggested by previous reports. To test whether TIN2 is the sole link between TPP1/POT1a,b and telomeres, we defined the TPP1 interaction domain of TIN2 and generated a TIN2 allele that was unable to interact with TPP1 but retained its interaction with TRF1 and TRF2. We demonstrated that cells expressing TIN2ΔTPP1 instead of wild-type TIN2 phenocopy the POT1a,b knockout setting without showing additional phenotypes. Therefore, these results are consistent with TIN2 being the only mechanism by which TPP1/POT1 heterodimers bind to shelterin and function in telomere protection.},
}
@article {pmid25056338,
year = {2014},
author = {Benetos, A and Dalgård, C and Labat, C and Kark, JD and Verhulst, S and Christensen, K and Kimura, M and Horvath, K and Kyvik, KO and Aviv, A},
title = {Sex difference in leukocyte telomere length is ablated in opposite-sex co-twins.},
journal = {International journal of epidemiology},
volume = {43},
number = {6},
pages = {1799-1805},
pmid = {25056338},
issn = {1464-3685},
support = {AG030678/AG/NIA NIH HHS/United States ; HD071180/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Aging/*genetics ; Blotting, Southern ; Female ; Humans ; Leukocytes/metabolism ; Male ; Middle Aged ; Sex Factors ; Telomere/*metabolism ; Twins, Dizygotic/*genetics ; Twins, Monozygotic/*genetics ; },
abstract = {BACKGROUND: In eutherian mammals and in humans, the female fetus may be masculinized while sharing the intra-uterine environment with a male fetus. Telomere length (TL), as expressed in leukocytes, is heritable and is longer in women than in men. The main determinant of leukocyte TL (LTL) is LTL at birth. However, LTL is modified by age-dependent attrition.<br><br>METHODS: We studied LTL dynamics (LTL and its attrition) in adult same-sex (monozygotic, n&#x2009;=&#x2009;268; dizygotic, n&#x2009;=&#x2009;308) twins and opposite-sex (n&#x2009;=&#x2009;144) twins. LTL was measured by Southern blots of the terminal restriction fragments.<br><br>RESULTS: We observed that in same-sex (both monozygotic and dizygotic) twins, as reported in singletons, LTL was longer in females than in males [estimate&#x2009;&#xb1;&#x2009;standard error (SE):163&#x2009;&#xb1;&#x2009;63&#x2009;bp, P&#x2009;<&#x2009;0.01]. However, in opposite-sex twins, female LTL was indistinguishable from that of males (-31&#x2009;&#xb1;&#x2009;52&#x2009;bp, P&#x2009;=&#x2009;0.6), whereas male LTL was not affected. Findings were similar when the comparison was restricted to opposite-sex and same-sex dizygotic twins (females relative to males: same-sex: 188&#x2009;&#xb1;&#x2009;90&#x2009;bp, P&#x2009;<&#x2009;0.05; other-sex: -32&#x2009;&#xb1;&#x2009;64&#x2009;bp, P&#x2009;=&#x2009;0.6).<br><br>CONCLUSIONS: These findings are compatible with masculinization of the female fetus in opposite-sex twins. They suggest that the sex difference in LTL, seen in the general population, is largely determined in utero, perhaps by the intrauterine hormonal environment. Further studies in newborn twins are warranted to test this thesis.},
}
@article {pmid25052602,
year = {2014},
author = {Zhang, J and Fu, R and Wang, Y and Li, L and Liu, H and Ding, K and Liu, C and Zhang, T and Ding, S and Ruan, E and Qu, W and Wang, H and Wang, X and Wang, G and Wu, Y and Song, J and Liu, H and Xing, L and Guan, J and Shao, Z},
title = {[Telomere length of peripheral lymphocytes in patients with immuno-related pancytopenia].},
journal = {Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi},
volume = {35},
number = {7},
pages = {605-608},
doi = {10.3760/cma.j.issn.0253-2727.2014.07.008},
pmid = {25052602},
issn = {0253-2727},
mesh = {Adolescent ; Adult ; B-Lymphocyte Subsets/immunology ; Child ; Female ; Humans ; Lymphocytes/*ultrastructure ; Male ; Middle Aged ; Pancytopenia/*immunology/pathology ; T-Lymphocyte Subsets/immunology ; Telomere/*ultrastructure ; Young Adult ; },
abstract = {OBJECTIVE: To investigate the changes of relative telomere length (RTL) of peripheral blood (PB) CD3[+], CD3[+]CD4[+], CD3[+]CD8[+]T lymphocytes, CD19[+]B lymphocytes and bone marrow (BM) CD34[+] cells and its association with disease severity in untreated patients with immuno-related pancytopenia (IRP).<br><br>METHODS: The PB CD3&#x207a; , CD3&#x207a; CD4&#x207a; , CD3&#x207a; CD8&#x207a; T lymphocytes, CD19&#x207a; B lymphocytes, and BM CD34&#x207a; cells were purified by magnetic activated cell sorting (MACS), and RTL were measured with flow-fluorescence in situ hybridization (FLOW-FISH).<br><br>RESULTS: The RTL of CD3&#x207a;, CD3&#x207a;CD4&#x207a; , and CD3&#x207a;CD8&#x207a;T lymphocytes in untreated IRP patients were (27.754 &#xb1; 16.323)%, (7.526 &#xb1; 3.745)% and (25.854 &#xb1; 14.789)%, respectivly, which were significantly shorter than those in healthy-controls (54.555 &#xb1; 19.782)%, (12.096 &#xb1; 2.805)%, and (38.367 &#xb1; 4.626)% (P<0.05). The RTL of CD19&#x207a; lymphocytes in untreated IRP patients was (22.136 &#xb1; 16.142)%, which was significantly shorter than that in healthy controls (42.846 &#xb1; 16.353)% (P<0.01). There was no significant difference of BM CD34&#x207a; cells RTL between the untreated IRP patients (22.528 &#xb1; 21.601)% and the healthy controls (23.936 &#xb1; 19.822)% (P>0.05). There were significantly positive correlations between the RTL of B lymphocytes and the count of white blood cell (r=0.706, P=0.015). There were negative correlations between RTL of B lymphocytes and the clinical symptoms (r=-0.613, P=0.045) and positive correlations with therapeutic effect (r=0.775, P=0.005).<br><br>CONCLUSION: The shorter RTL of CD3&#x207a;, CD3&#x207a;CD4&#x207a;, CD3&#x207a;CD8&#x207a;, CD19&#x207a; lymphocytes, and the normal RTL of BM CD34&#x207a; cells in untreated IRP patients were identified, which might imply that IRP is a type of acquired autoimmune diseases.},
}
@article {pmid25052413,
year = {2015},
author = {Reichert, S and Rojas, ER and Zahn, S and Robin, JP and Criscuolo, F and Massemin, S},
title = {Maternal telomere length inheritance in the king penguin.},
journal = {Heredity},
volume = {114},
number = {1},
pages = {10-16},
pmid = {25052413},
issn = {1365-2540},
mesh = {Animals ; Female ; *Inheritance Patterns ; Longevity/*genetics ; Male ; Spheniscidae/*genetics ; Telomere/*genetics ; },
abstract = {Telomeres are emerging as a biomarker for ageing and survival, and are likely important in shaping life-history trade-offs. In particular, telomere length with which one starts in life has been linked to lifelong survival, suggesting that early telomere dynamics are somehow related to life-history trajectories. This result highlights the importance of determining the extent to which telomere length is inherited, as a crucial factor determining early life telomere length. Given the scarcity of species for which telomere length inheritance has been studied, it is pressing to assess the generality of telomere length inheritance patterns. Further, information on how this pattern changes over the course of growth in individuals living under natural conditions should provide some insight on the extent to which environmental constraints also shape telomere dynamics. To fill this gap partly, we followed telomere inheritance in a population of king penguins (Aptenodytes patagonicus). We tested for paternal and maternal influence on chick initial telomere length (10 days old after hatching), and how these relationships changed with chick age (at 70, 200 and 300 days old). Based on a correlative approach, offspring telomere length was positively associated with maternal telomere length early in life (at 10 days old). However, this relationship was not significant at older ages. These data suggest that telomere length in birds is maternally inherited. Nonetheless, the influence of environmental conditions during growth remained an important factor shaping telomere length, as the maternal link disappeared with chicks' age.},
}
@article {pmid25049225,
year = {2014},
author = {Ivanauskiene, K and Delbarre, E and McGhie, JD and Küntziger, T and Wong, LH and Collas, P},
title = {The PML-associated protein DEK regulates the balance of H3.3 loading on chromatin and is important for telomere integrity.},
journal = {Genome research},
volume = {24},
number = {10},
pages = {1584-1594},
pmid = {25049225},
issn = {1549-5469},
mesh = {Animals ; Cell Line ; Chromatin/*metabolism ; Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/*metabolism ; DNA-Binding Proteins/*metabolism ; Embryonic Stem Cells/metabolism ; Histones/*metabolism ; Humans ; Mice ; Oncogene Proteins/*metabolism ; Poly-ADP-Ribose Binding Proteins ; Telomere/*metabolism ; },
abstract = {Histone variant H3.3 is deposited in chromatin at active sites, telomeres, and pericentric heterochromatin by distinct chaperones, but the mechanisms of regulation and coordination of chaperone-mediated H3.3 loading remain largely unknown. We show here that the chromatin-associated oncoprotein DEK regulates differential HIRA- and DAAX/ATRX-dependent distribution of H3.3 on chromosomes in somatic cells and embryonic stem cells. Live cell imaging studies show that nonnucleosomal H3.3 normally destined to PML nuclear bodies is re-routed to chromatin after depletion of DEK. This results in HIRA-dependent widespread chromatin deposition of H3.3 and H3.3 incorporation in the foci of heterochromatin in a process requiring the DAXX/ATRX complex. In embryonic stem cells, loss of DEK leads to displacement of PML bodies and ATRX from telomeres, redistribution of H3.3 from telomeres to chromosome arms and pericentric heterochromatin, induction of a fragile telomere phenotype, and telomere dysfunction. Our results indicate that DEK is required for proper loading of ATRX and H3.3 on telomeres and for telomeric chromatin architecture. We propose that DEK acts as a "gatekeeper" of chromatin, controlling chromatin integrity by restricting broad access to H3.3 by dedicated chaperones. Our results also suggest that telomere stability relies on mechanisms ensuring proper histone supply and routing.},
}
@article {pmid27123041,
year = {2013},
author = {Fadri-Moskwik, M and Zhou, Q and Chai, W},
title = {Beyond Telomerase: Telomere Instability as a Novel Target for Cancer Therapy.},
journal = {Journal of molecular and genetic medicine : an international journal of biomedical research},
volume = {7},
number = {4},
pages = {},
pmid = {27123041},
issn = {1747-0862},
support = {R15 GM099008/GM/NIGMS NIH HHS/United States ; },
abstract = {Telomeres are areas of heterochromatin composed of TTAGGG repeats located at the ends of linear chromosomes. They play a critical role in keeping genome stable and preventing premature aging diseases and the development of cancer. Characterizing mechanisms of telomere maintenance and understanding how their deregulation contributes to human diseases are therefore important for developing novel therapies. A key mechanism driving telomere maintenance and replicative immortality in cancer cells is telomere elongation by telomerase, and many emerging potential telomere-based therapies have focused on targeting telomerase components. By contrast, recent studies on telomere maintenance mechanism suggest that disrupting telomere stability by interfering with alternative mechanisms of telomere synthesis or protection may also yield new strategies for the treatment of cancer. This review will focus on emerging regulators of telomere synthesis or maintenance, such as G4 telomeric DNA, the CST complex, the t-loop, and shelterins, and discuss their potential as targets for anti-cancer chemotherapeutic intervention in the future.},
}
@article {pmid25436550,
year = {2012},
author = {Mandrioli, M and Monti, V and Manicardi, GC},
title = {Starting at the end: telomeres and telomerase in arthropods.},
journal = {Biomolecular concepts},
volume = {3},
number = {5},
pages = {465-470},
doi = {10.1515/bmc-2012-0008},
pmid = {25436550},
issn = {1868-5021},
abstract = {Abstract Telomere composition and structure have been studied in several arthropods allowing us to better understand the evolution of such an important portion of the eukaryotic chromosomes. Genes coding for telomerase reverse transcriptase (TERT) have been sequenced and studied in few arthropod species only, where they resulted highly transcribed also in somatic tissues suggesting a different TERT regulation in respect to vertebrates. Contrary to the strict conservation of telomeres, subtelomeric regions were more polymorphic and heterogeneous in composition and frequently contained retrotransposable elements that strongly influenced subtelomere evolution.},
}
@article {pmid25436544,
year = {2012},
author = {Chang, M},
title = {Long telomeres: too much of a good thing.},
journal = {Biomolecular concepts},
volume = {3},
number = {4},
pages = {387-393},
doi = {10.1515/bmc-2012-0009},
pmid = {25436544},
issn = {1868-5021},
abstract = {Abstract Telomeres, the physical ends of linear eukaryotic chromosomes, protect chromosome ends from end fusions and degradation. Telomere length is tightly regulated to ensure that telomeres are neither too short nor too long. Short telomeres are preferentially elongated by the enzyme telomerase. In the absence of telomerase, telomeres progressively shorten with each round of cell division. Critically shortened telomeres lose their ability to protect chromosome ends, inducing cell cycle arrest and senescence. While the consequences and cellular response to short telomeres are frequently explored, long telomeres also pose problems and cells have evolved mechanisms to shorten over-elongated telomeres. These aspects of long telomeres are discussed in this short conceptual overview.},
}
@article {pmid25047690,
year = {2014},
author = {Janssen, BG and Byun, HM and Cox, B and Gyselaers, W and Izzi, B and Baccarelli, AA and Nawrot, TS},
title = {Variation of DNA methylation in candidate age-related targets on the mitochondrial-telomere axis in cord blood and placenta.},
journal = {Placenta},
volume = {35},
number = {9},
pages = {665-672},
pmid = {25047690},
issn = {1532-3102},
support = {R01 ES021357/ES/NIEHS NIH HHS/United States ; R01 ES021733/ES/NIEHS NIH HHS/United States ; R01ES021357/ES/NIEHS NIH HHS/United States ; R01ES021733/ES/NIEHS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aging/*metabolism ; Cohort Studies ; *DNA Methylation ; Female ; Fetal Blood/*chemistry ; *Genome, Mitochondrial ; Humans ; Placenta/*metabolism ; Pregnancy ; Promoter Regions, Genetic ; Telomere/metabolism ; Young Adult ; },
abstract = {BACKGROUND: Epigenetics is tissue-specific and potentially even cell-specific, but little information is available from human reproductive studies about the concordance of DNA methylation patterns in cord blood and placenta, as well as within-placenta variations. We evaluated methylation levels at promoter regions of candidate genes in biological ageing pathways (SIRT1, TP53, PPARG, PPARGC1A, and TFAM), a subtelomeric region (D4Z4) and the mitochondrial genome (MT-RNR1, D-loop).<br><br>METHODS: Ninety individuals were randomly chosen from the ENVIRONAGE birth cohort to evaluate methylation concordance between cord blood and placenta using highly quantitative bisulfite-PCR pyrosequencing. In a subset of nineteen individuals, a more extensive sampling scheme was performed to examine within-placenta variation.<br><br>RESULTS: The DNA methylation levels of the subtelomeric region and mitochondrial genome showed concordance between cord blood and placenta with correlation coefficients ranging from r&#xa0;=&#xa0;0.31 to 0.43, p&#xa0;&#x2264;&#xa0;0.005, and also between the maternal and foetal sides of placental tissue (r&#xa0;=&#xa0;0.53 to 0.72, p&#xa0;&#x2264;&#xa0;0.05). For the majority of targets, an agreement in methylation levels between four foetal biopsies was found (with intra-class correlation coefficients ranging from 0.16 to 0.72), indicating small within-placenta variation.<br><br>CONCLUSIONS: The methylation levels of the subtelomeric region (D4Z4) and mitochondrial genome (MT-RNR1, D-loop) showed concordance between cord blood and placenta, suggesting a common epigenetic signature of these targets between tissues. Concordance was lacking between the other genes that were studied. In placental tissue, methylation patterns of most targets on the mitochondrial-telomere axis were not strongly influenced by sample location.},
}
@article {pmid25045845,
year = {2014},
author = {Tian, XP and Qian, D and He, LR and Huang, H and Mai, SJ and Li, CP and Huang, XX and Cai, MY and Liao, YJ and Kung, HF and Zeng, YX and Xie, D},
title = {The telomere/telomerase binding factor PinX1 regulates paclitaxel sensitivity depending on spindle assembly checkpoint in human cervical squamous cell carcinomas.},
journal = {Cancer letters},
volume = {353},
number = {1},
pages = {104-114},
doi = {10.1016/j.canlet.2014.07.012},
pmid = {25045845},
issn = {1872-7980},
mesh = {Animals ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Apoptosis/drug effects ; Carcinoma, Squamous Cell/*drug therapy/genetics/metabolism/mortality/pathology ; Cell Cycle Proteins ; Cisplatin/administration &amp; dosage ; Drug Resistance, Neoplasm ; Female ; HeLa Cells ; Humans ; Kinetochores/drug effects/metabolism ; M Phase Cell Cycle Checkpoints/*drug effects ; Mice ; Mice, Nude ; Middle Aged ; Paclitaxel/administration &amp; dosage ; RNA Interference ; Spindle Apparatus/*drug effects/metabolism ; Survival Analysis ; Telomerase/metabolism ; Telomere/*drug effects/metabolism ; Time Factors ; Transfection ; Treatment Outcome ; Tubulin Modulators/administration &amp; dosage ; Tumor Suppressor Proteins/genetics/*metabolism ; Uterine Cervical Neoplasms/*drug therapy/genetics/metabolism/mortality/pathology ; Xenograft Model Antitumor Assays ; },
abstract = {Paclitaxel is a main ingredient in the combination chemotherapy treatment of advanced human cervical squamous cell carcinomas. We investigated the roles and underlying molecular mechanisms of PinX1 in cervical squamous cell carcinomas (CSCC) cells response to paclitaxel and its clinical significances. The expression dynamics of PinX1 was first examined by immunohistochemistry in 122 advanced CSCC patients treated with cisplatin/paclitaxel chemotherapy. The expression of PinX1 was significantly associated with the effects of cisplatin/paclitaxel chemotherapy in advanced CSCCs (P<0.05). High expression of PinX1 correlated with CSCC's response to cisplatin/paclitaxel chemotherapy, and was an independent predictor of shortened survival (P<0.05). A series of in vivo and in vitro assays were performed to elucidate the function of PinX1 on CSCC cells chemosensitivity to paclitaxel and underlying mechanisms. In CSCC cells, the levels of PinX1 were only associated with the cytotoxicity and sensitivity of paclitaxel, in which knockdown of PinX1 dramatically enhanced paclitaxel cytotoxicity, whereas the reestablishment of PinX1 levels substantially reduced the paclitaxel-induced killing effect. In addition, we identified that the ability of PinX1 to stabilize the tension between sister kinetochores and maintain the spindle assembly checkpoint was the main reason CSCC cells undergo apoptosis when treated with paclitaxel, and further studies demonstrated that shortened distance between sisters kinetochores by nocodazole confers upon PinX1-replenished cells a sensitivity to the death inducing paclitaxel effects. Furthermore, our study of CSCC cells xenografts in nude mice confirmed the role of PinX1 in paclitaxel sensitivity in vivo. Our data reveal that PinX1 could be used as a novel predictor for CSCC patient response to paclitaxel, and the role of PinX1-mediated paclitaxel sensitivity might represent a new direction for the development of a new generation of microtubule drugs.},
}
@article {pmid25044979,
year = {2014},
author = {Saito, K and Sakai, C and Kawasaki, T and Sakai, N},
title = {Telomere distribution pattern and synapsis initiation during spermatogenesis in zebrafish.},
journal = {Developmental dynamics : an official publication of the American Association of Anatomists},
volume = {243},
number = {11},
pages = {1448-1456},
doi = {10.1002/dvdy.24166},
pmid = {25044979},
issn = {1097-0177},
mesh = {Animals ; Chromosome Pairing/*physiology ; DNA Primers/genetics ; Gene Expression Regulation, Developmental/*physiology ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Male ; Prophase/physiology ; Spermatogenesis/*physiology ; Telomere/*physiology ; Tubulin/metabolism ; Zebrafish/*physiology ; Zebrafish Proteins/metabolism ; },
abstract = {BACKGROUND: Telomeres are located at ends of eukaryotic chromosomes and can affect proper chromosomal positioning. During spermatogenesis, the appropriate dynamics and behavior of chromosomes is crucial to generate haploid cells through meiosis. Here, we describe telomere distribution patterns during spermatogenesis in zebrafish, especially during meiotic prophase I, using fluorescence in situ hybridization. This was combined with synaptonemal complex protein 3 immunostaining, which allows the staging of spermatocytes.<br><br>RESULTS: During spermatogonial proliferation and the preleptotene stage, telomeres were dispersed throughout the nucleus. During the leptotene stage, telomeres temporarily moved to one pole of the nucleus at which &#x3b3;-tubulin was located, forming the telomere bouquet. The cluster lasted until the onset of zygotene where it coincided with terminal synapsis initiation. They then spread around the periphery of the nucleus during the zygotene to pachytene stages. During postmeiotic stages, telomeres in spermatids and sperm were again dispersed throughout the nuclei. Application of this procedure in meiotic mutants confirmed that meiotic telomere clustering is independent of axial element formation of the synaptonemal complex.<br><br>CONCLUSIONS: These data clearly showed the clustering and distributions of telomeres throughout spermatogenesis in zebrafish. This procedure could be used to screen for mutants that have primary defects in telomere clustering.},
}
@article {pmid25044768,
year = {2015},
author = {Ma, D and Yu, Y and Yu, X and Zhang, M and Yang, Y},
title = {The changes of leukocyte telomere length and telomerase activity after sitagliptin intervention in newly diagnosed type 2 diabetes.},
journal = {Diabetes/metabolism research and reviews},
volume = {31},
number = {3},
pages = {256-261},
doi = {10.1002/dmrr.2578},
pmid = {25044768},
issn = {1520-7560},
mesh = {Adult ; Diabetes Mellitus, Type 2/drug therapy/enzymology/*genetics/pathology ; Enzyme-Linked Immunosorbent Assay ; Female ; Follow-Up Studies ; Humans ; Hypoglycemic Agents/*therapeutic use ; Insulin Resistance/genetics ; Leukocytes/drug effects/*metabolism/pathology ; Male ; Middle Aged ; Polymerase Chain Reaction ; Prognosis ; Sitagliptin Phosphate/*therapeutic use ; Telomerase/genetics/*metabolism ; Telomere Homeostasis ; },
abstract = {BACKGROUND: In recent years, increasing evidence suggests a potential importance of telomere biology in type 2 diabetes. The aim of this study was to determine whether sitagliptin, a medicine generally used in diabetes, can influence the telomere and telomerase in newly diagnosed type 2 diabetic patients.<br><br>METHODS: Type 2 diabetic patients (T2D, n&#x2009;=&#x2009;38) and non-diabetic subjects (control, n&#x2009;=&#x2009;31) were randomly selected from the outpatient of Tongji Hospital, Tongji Medical College, Huazhong university of Science and Technology. Leukocyte telomere length ratio was measured using a quantitative polymerase chain reaction and was analysed. Telomerase activity was measured by polymerase chain reaction enzyme-linked immunosorbent assay method. Peripheral insulin resistance (homeostasis model assessment) was calculated from fasting plasma glucose and fasting plasma insulin.<br><br>RESULTS: Telomere length of the type 2 diabetic patients (1.58&#x2009;&#xb1;&#x2009;0.57) was significantly shorter than those of control subjects (3.98&#x2009;&#xb1;&#x2009;0.90) and was significantly elongated after intervention by sitagliptin. There was no significant difference between the T2D and control group in telomerase activity, and the treatment of sitagliptin in T2D group showed no significant effect on the telomerase activity.<br><br>CONCLUSIONS: In type 2 diabetes patients, leukocyte telomere length is significantly reduced, whereas the telomerase activity seems less influenced. Sitagliptin might protect &#x3b2;-cells in the pancreas by elongating the telomere length.},
}
@article {pmid25040775,
year = {2015},
author = {Baragetti, A and Palmen, J and Garlaschelli, K and Grigore, L and Pellegatta, F and Tragni, E and Catapano, AL and Humphries, SE and Norata, GD and Talmud, PJ},
title = {Telomere shortening over 6 years is associated with increased subclinical carotid vascular damage and worse cardiovascular prognosis in the general population.},
journal = {Journal of internal medicine},
volume = {277},
number = {4},
pages = {478-487},
doi = {10.1111/joim.12282},
pmid = {25040775},
issn = {1365-2796},
support = {GGP13002/TI_/Telethon/Italy ; RG/08/008/25291/BHF_/British Heart Foundation/United Kingdom ; PG08/008/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Carotid Artery Diseases/*pathology ; Disease Progression ; Female ; Humans ; Male ; Polymerase Chain Reaction ; Prognosis ; ROC Curve ; Telomere/chemistry/*pathology ; },
abstract = {INTRODUCTION: Leucocyte telomere length (LTL) is an important determinant of telomere function and cellular replicative capacity. The aim of the present study was to examine prospectively the associations between telomere shortening (TS) and both the progression of atherosclerosis and the incidence of cardiovascular events (CVEs).<br><br>MATERIALS AND METHODS: Leucocyte telomere length was measured by quantitative polymerase chain reaction to determine the ratio of telomere length to single-copy gene (T/S) in 768 subjects (462 female and 306 male) enrolled in a large general population survey [the Progressione della Lesione Intimale Carotidea (PLIC study)]. Common carotid artery intima-media thickness was determined at baseline and after 6&#xa0;years of follow-up, and the associations between TS and the progression of atherosclerosis and incidence of CVEs were evaluated.<br><br>RESULTS: Mean LTL was 1.25&#xa0;&#xb1;&#xa0;0.92&#xa0;T/S (median 1.14) at baseline and 0.70&#xa0;&#xb1;&#xa0;0.37&#xa0;T/S (median 0.70) after 6&#xa0;years of follow-up. Median 6-year LTL change was -0.46&#xa0;T/S [interquartile range (IQR) -0.57 to 1.06], equating to -0.078 T/S [IQR(-0.092 to 0.176)] per year. Of note, telomere lengthening occurred in 30.4% of subjects. After adjustment for classical cardiovascular disease (CVD) risk factors (age, gender, smoking, physical activity, alcohol consumption, systolic blood pressure, glucose levels, lipid profile and therapies), TS was associated with incident subclinical carotid vascular damage [hazard ratio (HR) 5.19, 95% confidence interval (CI) 1.20-22.4, P&#xa0;=&#xa0;0.028]. Finally, subjects in whom LTL shortened over time showed an increased risk of incident CVE, compared to those in whom LTL lengthened (HR 1.69, CI 1.02-2.78, P&#xa0;=&#xa0;0.041).<br><br>CONCLUSION: These data indicate that TS is associated with increased risk of subclinical carotid vascular damage and increased incidence of CVEs beyond CVD risk factors in the general population, whereas LTL lengthening is protective.},
}
@article {pmid25040628,
year = {2014},
author = {Suram, A and Herbig, U},
title = {The replicometer is broken: telomeres activate cellular senescence in response to genotoxic stresses.},
journal = {Aging cell},
volume = {13},
number = {5},
pages = {780-786},
pmid = {25040628},
issn = {1474-9726},
support = {R01 CA136533/CA/NCI NIH HHS/United States ; R01 CA184572/CA/NCI NIH HHS/United States ; R01CA184572/CA/NCI NIH HHS/United States ; R01CA136533/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cellular Senescence/*physiology ; DNA Damage/*physiology ; Humans ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres, the ends of our linear chromosomes, can function as 'replicometers', capable of counting cell division cycles as they progressively erode with every round of DNA replication. Once they are critically short, telomeres become dysfunctional and consequently activate a proliferative arrest called replicative senescence. For many years, telomeres were thought to be autonomous structures, largely isolated from cell intrinsic and extrinsic signals, whose function is to prevent limitless cellular proliferation, a characteristic of most cancer cells. It is becoming increasingly evident, however, that telomeres not only count cell divisions, but also function as sensors of genotoxic stresses to stop cell cycle progression prematurely and long before cells would have entered replicative senescence. This stable growth arrest, triggered by dysfunctional telomeres that are not necessarily critically short, likely evolved as a tumor-suppressing mechanism as it prevents proliferation of cells that are at risk for acquiring potentially hazardous and transforming mutations both in vitro and in vivo. Here, we review studies supporting the concept that telomeres are important cellular structures whose function not only is to count cell divisions, but also to act as molecular switches that can rapidly stop cell cycle progression permanently in response to a variety of stresses, including oncogenic signals.},
}
@article {pmid25039510,
year = {2014},
author = {Chen, C and Upton, C and Braidy, N and Khalil, J and Fang, ZM and Xu, YH and Chan, DK},
title = {Association between leukocyte telomere length and vascular dementia and cancer mortality in an elderly population.},
journal = {Journal of the American Geriatrics Society},
volume = {62},
number = {7},
pages = {1384-1386},
doi = {10.1111/jgs.12910},
pmid = {25039510},
issn = {1532-5415},
mesh = {Aged ; Dementia, Vascular/*blood/complications ; Humans ; *Leukocytes/ultrastructure ; Neoplasms/*blood/complications/*mortality ; Telomere/*ultrastructure ; },
}
@article {pmid25038516,
year = {2014},
author = {Al-Ajmi, N and Saretzki, G and Miles, C and Spyridopoulos, I},
title = {Dietary restriction ameliorates haematopoietic ageing independent of telomerase, whilst lack of telomerase and short telomeres exacerbates the ageing phenotype.},
journal = {Experimental gerontology},
volume = {58},
number = {},
pages = {113-119},
doi = {10.1016/j.exger.2014.07.010},
pmid = {25038516},
issn = {1873-6815},
mesh = {Age Factors ; Aging/genetics/*metabolism ; Animals ; *Caloric Restriction ; Cell Differentiation ; Cell Lineage ; Cell Proliferation ; *Cellular Senescence ; Genotype ; Hematopoietic Stem Cells/*enzymology ; Male ; Mice, Knockout ; Phenotype ; RNA/genetics ; Telomerase/*deficiency/genetics ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {Ageing is associated with an overall decline in the functional capacity of tissues and stem cells, including haematopoietic stem and progenitor cells (HSPCs), as well as telomere dysfunction. Dietary restriction (DR) is a recognised anti-ageing intervention that extends lifespan and improves health in several organisms. To investigate the role of telomeres and telomerase in haematopoietic ageing, we compared the HSPC profile and clonogenic capacity of bone marrow cells from wild type with telomerase-deficient mice and the effect of DR on these parameters. Compared with young mice, aged wild type mice demonstrated a significant accumulation of HSPCs (1.3% vs 0.2%, P=0.002) and elevated numbers of granulocyte/macrophage colony forming units (CFU-GM, 26.4 vs 17.3, P=0.0037) consistent with myeloid "skewing" of haematopoiesis. DR was able to restrict the increase in HSPC number as well as the myeloid "skewing" in aged wild type mice. In order to analyse the influence of short telomeres on the ageing phenotype we examined mice lacking the RNA template for telomerase, TERC(-/-). Telomere shortening resulted in a similar bone marrow phenotype to that seen in aged mice, with significantly increased HSPC numbers and an increased formation of all myeloid colony types but at a younger age than wild type mice. However, an additional increase in erythroid colonies (BFU-E) was also evident. Mice lacking telomerase reverse transcriptase without shortened telomeres, TERT(-/-), also presented with augmented haematopoietic ageing which was ameliorated by DR, demonstrating that the effect of DR was not dependent on the presence of telomerase in HSPCs. We conclude that whilst shortened telomeres mimic some aspects of haematopoietic ageing, both shortened telomeres and the lack of telomerase produce specific phenotypes, some of which can be prevented by dietary restriction.},
}
@article {pmid25036716,
year = {2014},
author = {Hirata, A and Nokihara, K and Kawamoto, Y and Bando, T and Sasaki, A and Ide, S and Maeshima, K and Kasama, T and Sugiyama, H},
title = {Structural evaluation of tandem hairpin pyrrole-imidazole polyamides recognizing human telomeres.},
journal = {Journal of the American Chemical Society},
volume = {136},
number = {32},
pages = {11546-11554},
doi = {10.1021/ja506058e},
pmid = {25036716},
issn = {1520-5126},
mesh = {DNA/chemistry ; Fluorescent Dyes/chemistry ; HeLa Cells ; Humans ; Imidazoles/*chemistry ; Nylons/*chemistry ; Protein Binding ; Pyrroles/*chemistry ; Rhodamines/chemistry ; Spectrometry, Mass, Electrospray Ionization ; Surface Plasmon Resonance ; Tandem Mass Spectrometry ; Telomere/chemistry/*ultrastructure ; Temperature ; Thermodynamics ; Xanthenes/chemistry ; },
abstract = {A polyamide containing N-methylpyrrole (Py) and N-methylimidazole (Im), designated PIPA, binds with high affinity and specificity to specific nucleotide sequences in the minor groove of double-helical DNA. Based on a recent report of the synthesis of PIPA for telomere visualization, the present paper focused on the size of the connecting part (hinge region) of two PIPA segments of the tandem hairpin PIPA, Dab(Im-Im-Py)-Py-Py-Py-Im-[Hinge]-Dab(Im-Im-Py)-Py-Py-Py-Im-βAla-NH(CH2)3N(CH3)-(CH2)3NH-[Dye]. The present paper also describes the characterization of binding by measuring the thermal melting temperature and surface plasmon resonance and by specific staining of telomeres (TTAGGG)n in human cells. Microheterogeneity was also investigated by high-resolution mass spectrometry. We found that the optimal compound as the hinge segment for telomere staining was [-NH(C2H4O)2(C2H4)CO-] with tetramethylrhodamine as the fluorescent dye.},
}
@article {pmid25034635,
year = {2015},
author = {Tada, S and Ohkuchi, H and Matsushita-Morita, M and Furukawa, I and Hattori, R and Suzuki, S and Kashiwagi, Y and Kusumoto, K},
title = {Telomere-mediated chromosomal truncation in Aspergillus oryzae.},
journal = {Journal of bioscience and bioengineering},
volume = {119},
number = {1},
pages = {43-46},
doi = {10.1016/j.jbiosc.2014.06.011},
pmid = {25034635},
issn = {1347-4421},
mesh = {Aflatoxins/biosynthesis ; Aspergillus oryzae/*genetics ; Chromosomes, Artificial/*genetics ; Chromosomes, Fungal/*genetics ; *Gene Deletion ; Multigene Family/genetics ; Telomere/*genetics/*metabolism ; },
abstract = {We truncated the short arm of chromosome 3 to delete the aflatoxin biosynthesis gene homolog cluster using telomeric repeats in Aspergillus oryzae. The predicted deletion was confirmed by Southern blot analyses. This telomere-mediated chromosomal truncation method enables the development of an artificial chromosome in A. oryzae.},
}
@article {pmid25032857,
year = {2014},
author = {Gao, B and Li, K and Wei, YY and Zhang, J and Li, J and Zhang, L and Gao, JP and Li, YY and Huang, LG and Lin, P and Wei, YQ},
title = {Zinc finger protein 637 protects cells against oxidative stress-induced premature senescence by mTERT-mediated telomerase activity and telomere maintenance.},
journal = {Cell death &amp; disease},
volume = {5},
number = {7},
pages = {e1334},
pmid = {25032857},
issn = {2041-4889},
mesh = {3T3 Cells ; Animals ; *Cellular Senescence ; DNA-Binding Proteins/genetics/*metabolism ; Hydrogen Peroxide/pharmacology ; Male ; Mice ; Mice, Inbred BALB C ; *Oxidative Stress/drug effects ; Promoter Regions, Genetic ; Protein Binding ; Telomerase/genetics/*metabolism ; Telomere/drug effects/genetics/*metabolism ; Transcriptional Activation ; },
abstract = {Oxidative stress is believed to be an important inducer of cellular senescence and aging. Zinc finger protein 637 (Zfp637), which belongs to the Krüppel-like protein family, has been hypothesized to play a role in oxidative stress. Nevertheless, the precise function of Zfp637 has seldom been reported, and it remains unclear whether Zfp637 is involved in oxidative stress-induced premature senescence. In this study, we show that the endogenous expression levels of Zfp637 and mouse telomerase reverse transcriptase (mTERT) are downregulated during oxidative stress-induced premature senescence and in senescent tissues from naturally aged mice. The overexpression of Zfp637 markedly increases mTERT expression and telomerase activity, maintains telomere length, and inhibits both H2O2 and D-galactose-induced senescence accompanied by a reduction in the production of reactive oxygen species (ROS). In contrast, the knockdown of Zfp637 significantly aggravates cellular senescence by downregulating mTERT and telomerase activity, accelerating telomere shortening, and increasing ROS accumulation. In addition, the protective effect of Zfp637 against premature senescence is abrogated in the absence of mTERT. We further confirm that Zfp637 binds to and transactivates the mTERT promoter (-535/-502) specifically. As a result, the mTERT-mediated telomerase activity and telomere maintenance are responsible for the protective effect of Zfp637 against oxidative stress-induced senescence. We therefore propose that Zfp637 prevents oxidative stress-induced premature senescence in an mTERT-dependent manner, and these results provide a new foundation for the investigation of cellular senescence and aging.},
}
@article {pmid25028345,
year = {2015},
author = {Schaakxs, R and Verhoeven, JE and Oude Voshaar, RC and Comijs, HC and Penninx, BWJH},
title = {Leukocyte telomere length and late-life depression.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {23},
number = {4},
pages = {423-432},
doi = {10.1016/j.jagp.2014.06.003},
pmid = {25028345},
issn = {1545-7214},
mesh = {Age of Onset ; Aged ; Aged, 80 and over ; Case-Control Studies ; Comorbidity ; Cross-Sectional Studies ; Depressive Disorder/*epidemiology/genetics/pathology ; Female ; Humans ; Late Onset Disorders/*epidemiology/genetics/pathology ; Leukocytes/*physiology ; Male ; Middle Aged ; Netherlands/epidemiology ; Telomere Shortening/*genetics ; },
abstract = {OBJECTIVE: Depressive disorders have been associated with increased risk for aging-related diseases, possibly as a consequence of accelerated cellular aging. Cellular aging, indexed by telomere length (TL) shortening, has been linked to depression in adults younger than 60 years; however, it remains unclear whether this is the case in late-life depression (age >60 years). The objective of this study was to assess differences in TL between persons with current late-life depression and never-depressed comparisons and to examine the association between characteristics of late-life depression and TL.<br><br>METHODS: In this cross-sectional study using the Netherlands Study of Depression in Older Persons, 355 persons with current late-life depression and 128 never-depressed comparisons, aged 60-93 years (mean age [SD]: 70.5 [7.4] years, 65% women), were recruited through primary care and mental healthcare. Late-life depression was established using a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-based structured psychiatric interview. Leukocyte TL, expressed in base pairs (bp), was determined in fasting blood samples by performing quantitative polymerase chain reaction.<br><br>RESULTS: Mean TL did not differ between depressed persons (bp [SD]: 5,035 [431]) and never-depressed (bp [SD]: 5,057 [729]) comparisons. Further, TL was not associated with severity, duration, and age at onset of depression; comorbid anxiety disorders; anxiety symptoms; apathy severity; antidepressant use; benzodiazepine use; cognitive functioning; and childhood trauma.<br><br>CONCLUSION: Late-life depression was not associated with increased cellular aging. This absent association, which contradicts observations in younger adults, may be due to the potential larger heterogenic nature of late-life depression and lifetime cumulative exposure to other TL-damaging factors, possibly overruling effects of late-life depression.},
}
@article {pmid25023551,
year = {2014},
author = {Jacobs, EG and Epel, ES and Lin, J and Blackburn, EH and Rasgon, NL},
title = {Relationship between leukocyte telomere length, telomerase activity, and hippocampal volume in early aging.},
journal = {JAMA neurology},
volume = {71},
number = {7},
pages = {921-923},
pmid = {25023551},
issn = {2168-6157},
support = {M01 RR000070/RR/NCRR NIH HHS/United States ; R01 AG022008/AG/NIA NIH HHS/United States ; R01 AG22008/AG/NIA NIH HHS/United States ; M01 RR-00070/RR/NCRR NIH HHS/United States ; },
mesh = {Age of Onset ; Aged ; Aging/pathology/*physiology ; Biomarkers/metabolism ; Cognition Disorders/genetics/*metabolism/pathology ; Female ; Hippocampus/*enzymology/pathology ; Humans ; Leukocytes/enzymology/metabolism/*physiology ; Longitudinal Studies ; Magnetic Resonance Imaging ; Middle Aged ; Telomerase/*metabolism ; Telomere/*physiology ; },
}
@article {pmid25015931,
year = {2014},
author = {Reste, J and Zvigule, G and Zvagule, T and Kurjane, N and Eglite, M and Gabruseva, N and Berzina, D and Plonis, J and Miklasevics, E},
title = {Telomere length in Chernobyl accident recovery workers in the late period after the disaster.},
journal = {Journal of radiation research},
volume = {55},
number = {6},
pages = {1089-1100},
pmid = {25015931},
issn = {1349-9157},
mesh = {Adult ; Aged ; Case-Control Studies ; *Chernobyl Nuclear Accident ; Cross-Sectional Studies ; Humans ; Leukocytes/radiation effects ; Male ; Middle Aged ; *Occupational Exposure ; Telomere/genetics/radiation effects ; Telomere Homeostasis/genetics/*radiation effects ; Telomere Shortening/genetics/radiation effects ; Time Factors ; },
abstract = {The outcome of the Chernobyl nuclear power plant (CNPP) accident was that a huge number of people were exposed to ionizing radiation. Previous studies of CNPP clean-up workers from Latvia revealed a high occurrence of age-associated degenerative diseases and cancer in young adults, as well as a high mortality as a result of cardiovascular disorders at age 45-54 years. DNA tandem repeats that cap chromosome ends, known as telomeres, are sensitive to oxidative damage and exposure to ionizing radiation. Telomeres are important in aging processes and carcinogenesis. The aim of this study was to investigate the long-term effect of protracted ionizing radiation exposure on telomere length in CNPP clean-up workers. Relative telomere length (RTL) was measured in peripheral blood leukocytes of 595 CNPP clean-up workers and 236 gender- and age-matched controls using real-time quantitative polymerase chain reaction (q-PCR). Close attention was paid to participation year and tasks performed during the worker's stay in Chernobyl, health status, and RTL differences between subgroups. Telomere shortening was not found in CNPP clean-up workers; on the contrary, their RTL was slightly greater than in controls (P = 0.001). Longer telomeres were found in people who worked during 1986, in those undertaking 'dirty' tasks (digging and deactivation), and in people with cancer. Shorter telomeres appeared frequently in those with cataract, osteoporosis, atherosclerosis, or coronary heart disease. We conclude that the longer telomeres revealed in people more heavily exposed to ionizing radiation probably indicate activation of telomerase as a chromosome healing mechanism following damage, and reflect defects in telomerase regulation that could potentiate carcinogenesis.},
}
@article {pmid25012820,
year = {2014},
author = {Khadka, P and Lee, JH and Baek, SH and Oh, SY and Chung, IK},
title = {DNA-PKcs-interacting protein KIP binding to TRF2 is required for the maintenance of functional telomeres.},
journal = {The Biochemical journal},
volume = {463},
number = {1},
pages = {19-30},
doi = {10.1042/BJ20131395},
pmid = {25012820},
issn = {1470-8728},
mesh = {Calcium-Binding Proteins/genetics/*metabolism ; Cell Cycle Checkpoints/genetics ; Cell Line, Tumor ; Cellular Senescence ; *DNA Damage ; Humans ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; },
abstract = {Human telomeres associate with shelterin, a six-protein complex that protects chromosome ends from being recognized as sites of DNA damage. The shelterin subunit TRF2 (telomeric repeat-binding factor 2) protects telomeres by facilitating their organization into the protective capping structure. We have reported previously that the DNA-PKcs (DNA-dependent protein kinase catalytic subunit)-interacting protein KIP associates with telomerase through an interaction with hTERT (human telomerase reverse transcriptase). In the present study, we identify KIP as a novel interacting partner of TRF2. KIP is able to interact with both TRF2 and DNA-PKcs at telomeres. Because KIP is required for the association between TRF2 and DNA-PKcs, the interplay of these three proteins may provide a mechanism for the recruitment of DNA-PKcs to telomeres. We also show that KIP binding to TRF2 enhances the telomere-binding activity of TRF2, suggesting that KIP acts as a positive regulator of TRF2 function. Furthermore, depletion of KIP induces DNA-damage response foci at telomeres, thereby leading to induction of growth arrest, cellular senescence and altered cell cycle distribution. Collectively, our findings suggest that KIP, in addition to its association with catalytically active telomerase, plays important roles in the maintenance of functional telomeres and the regulation of telomere-associated DNA-damage response. Thus KIP represents a new pathway for modulating telomerase and telomere function in cancer.},
}
@article {pmid25012274,
year = {2014},
author = {González-Guardia, L and Yubero-Serrano, EM and Rangel-Zuñiga, O and Marin, C and Camargo, A and Pérez-Martínez, P and Delgado-Lista, J and Gómez-Delgado, F and Garcia-Rios, A and Tinahones, FJ and Roche, HM and Pérez-Jiménez, F and López-Miranda, J},
title = {Influence of endothelial dysfunction on telomere length in subjects with metabolic syndrome: LIPGENE study.},
journal = {Age (Dordrecht, Netherlands)},
volume = {36},
number = {4},
pages = {9681},
pmid = {25012274},
issn = {1574-4647},
mesh = {Aging/*physiology ; Cardiovascular Diseases/epidemiology/metabolism/*physiopathology ; Cross-Sectional Studies ; DNA/*genetics ; Endothelium, Vascular/metabolism/*physiopathology ; Europe/epidemiology ; Female ; Follow-Up Studies ; Humans ; Incidence ; Male ; Metabolic Syndrome/complications/genetics/*metabolism ; Middle Aged ; Oxidative Stress ; Polymerase Chain Reaction ; Telomere/*genetics/metabolism ; Vasodilation/*physiology ; },
abstract = {Previous evidences support that increased oxidative stress (OxS) may play an important role in metabolic syndrome (MetS) and both are closely linked to vascular dysfunction. This study determined whether there is a relationship between endothelial function and relative telomere length (RTL) in MetS subjects. In this cross-sectional study from the LIPGENE cohort, a total of 88 subjects (36 men and 52 women) were divided into four groups by quartiles of telomere length. We measured ischemic reactive hyperemia (IRH), total nitrite (NO) and protein carbonyl (PC) plasma levels, F2-isoprostanes urinary levels, and superoxide dismutase (SOD) and glutathione peroxidase (GPx) plasma activities. IRH and NO plasma levels were higher in subjects with longer RTL (quartiles 3 and 4), while PC plasma levels, F2-isoprostanes urinary levels, and GPx and SOD plasma activities were lower in quartile 4 subjects (longest RTL). Additionally, MetS subjects with longer RTL had greater homeostatic model assessment-β level and lower triglycerides plasma levels. Our results suggest that endothelial dysfunction, associated with high levels of OxS, could be entailed in an increment of telomere attrition. Thus, further support of the molecular and cellular mechanisms involved in vascular dysfunction may contribute to the development of strategies to decelerate vascular aging or prevent cardiovascular disease.},
}
@article {pmid25010904,
year = {2014},
author = {Biron-Shental, T and Sukenik-Halevy, R and Sharon, Y and Laish, I and Fejgin, MD and Amiel, A},
title = {Telomere shortening in intra uterine growth restriction placentas.},
journal = {Early human development},
volume = {90},
number = {9},
pages = {465-469},
doi = {10.1016/j.earlhumdev.2014.06.003},
pmid = {25010904},
issn = {1872-6232},
mesh = {Case-Control Studies ; Female ; Fetal Growth Retardation/*genetics/pathology ; Homeostasis ; Humans ; In Situ Hybridization, Fluorescence ; Reverse Transcriptase Polymerase Chain Reaction ; *Telomere Shortening ; },
abstract = {INTRODUCTION: Placentas from pregnancies complicated with IUGR (intrauterine growth restriction) express altered telomere homeostasis. In the current study, we examined mechanisms of telomere shortening in these placentas.<br><br>METHODS: Placental biopsies from 15 IUGR and 15 healthy control pregnancies were examined. The percentage of trophoblasts with fragmented nuclei: senescence-associated heterochromatin foci (SAHF), was calculated using DAPI staining. The amount of human telomerase reverse transcriptase (hTERT) mRNA was evaluated using RtPCR levels of telomere capture using FISH in those samples were estimated.<br><br>RESULTS: The percentage of trophoblasts with SAHF was higher in IUGR compared to control samples, (25&#xb1;13.4% vs. 1.6&#xb1;1.6%, P<0.0001), hTERT mRNA was decreased (0.5&#xb1;0.2 vs. 0.9&#xb1;0.1, P<0.0001) and telomere capture was increased (13.2&#xb1;9.7% vs.1.3&#xb1;2.5%, P<0.001).<br><br>CONCLUSIONS: We suggest that IUGR placentas express increased signs of senescence as part of the impaired telomere homeostasis. One factor that mediates telomere shortening in these placentas is decreased hTERT mRNA, leading to decreased protein expression and therefore, reduced telomere elongation. Telomere capture, which is a healing process, is increased in IUGR trophoblasts as a compensatory mechanism.},
}
@article {pmid25008368,
year = {2014},
author = {Hoshide, S},
title = {Role of telomere length in interindividual variation in cardiovascular protection in hypertensive patients.},
journal = {Circulation journal : official journal of the Japanese Circulation Society},
volume = {78},
number = {8},
pages = {1828-1829},
doi = {10.1253/circj.cj-14-0673},
pmid = {25008368},
issn = {1347-4820},
mesh = {Animals ; *DNA Methylation ; Female ; Humans ; Hyperhomocysteinemia/*enzymology ; Hypertension/*enzymology ; Leukocytes/*enzymology ; Male ; Telomerase/*biosynthesis ; Telomere/*enzymology ; *Telomere Homeostasis ; },
}
@article {pmid25006006,
year = {2014},
author = {Haycock, PC and Heydon, EE and Kaptoge, S and Butterworth, AS and Thompson, A and Willeit, P},
title = {Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis.},
journal = {BMJ (Clinical research ed.)},
volume = {349},
number = {},
pages = {g4227},
pmid = {25006006},
issn = {1756-1833},
support = {G0800270/MRC_/Medical Research Council/United Kingdom ; RG/08/014/24067/BHF_/British Heart Foundation/United Kingdom ; MR/L003120/1/MRC_/Medical Research Council/United Kingdom ; RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Cardiovascular Diseases/*etiology ; Humans ; Leukocytes/*physiology ; Models, Statistical ; Odds Ratio ; Regression Analysis ; Risk Factors ; *Telomere Shortening ; },
abstract = {OBJECTIVE: To assess the association between leucocyte telomere length and risk of cardiovascular disease.<br><br>DESIGN: Systematic review and meta-analysis.<br><br>DATA SOURCES: Studies published up to March 2014 identified through searches of Medline, Web of Science, and Embase.<br><br>ELIGIBILITY CRITERIA: Prospective and retrospective studies that reported on associations between leucocyte telomere length and coronary heart disease (defined as non-fatal myocardial infarction, coronary heart disease death, or coronary revascularisation) or cerebrovascular disease (defined as non-fatal stroke or death from cerebrovascular disease) and were broadly representative of general populations--that is, they did not select cohort or control participants on the basis of pre-existing cardiovascular disease or diabetes.<br><br>RESULTS: Twenty four studies involving 43,725 participants and 8400 patients with cardiovascular disease (5566 with coronary heart disease and 2834 with cerebrovascular disease) were found to be eligible. In a comparison of the shortest versus longest third of leucocyte telomere length, the pooled relative risk for coronary heart disease was 1.54 (95% confidence interval 1.30 to 1.83) in all studies, 1.40 (1.15 to 1.70) in prospective studies, and 1.80 (1.32 to 2.44) in retrospective studies. Heterogeneity between studies was moderate (I(2) = 64%, 41% to 77%, Phet<0.001) and was not significantly explained by mean age of participants (P = 0.23), the proportion of male participants (P = 0.45), or distinction between retrospective versus prospective studies (P = 0.32). Findings for coronary heart disease were similar in meta-analyses restricted to studies that adjusted for conventional vascular risk factors (relative risk 1.42, 95% confidence interval 1.17 to 1.73); studies with &#x2265; 200 cases (1.44, 1.20 to 1.74); studies with a high quality score (1.53, 1.22 to 1.92); and in analyses that corrected for publication bias (1.34, 1.12 to 1.60). The pooled relative risk for cerebrovascular disease was 1.42 (1.11 to 1.81), with no significant heterogeneity between studies (I(2) = 41%, 0% to 72%, Phet = 0.08). Shorter telomeres were not significantly associated with cerebrovascular disease risk in prospective studies (1.14, 0.85 to 1.54) or in studies with a high quality score (1.21, 0.83 to 1.76).<br><br>CONCLUSION: Available observational data show an inverse association between leucocyte telomere length and risk of coronary heart disease independent of conventional vascular risk factors. The association with cerebrovascular disease is less certain.},
}
@article {pmid25005709,
year = {2014},
author = {Spyridopoulos, I and von Zglinicki, T},
title = {Telomere length predicts cardiovascular disease.},
journal = {BMJ (Clinical research ed.)},
volume = {349},
number = {},
pages = {g4373},
doi = {10.1136/bmj.g4373},
pmid = {25005709},
issn = {1756-1833},
support = {//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Cardiovascular Diseases/*etiology ; Humans ; Leukocytes/*physiology ; *Telomere Shortening ; },
}
@article {pmid24996852,
year = {2014},
author = {Wang, Y and Zhou, WD and Yang, Y and Ma, L and Zhao, Y and Bai, Z and Ge, RL},
title = {Telomeres are elongated in rats exposed to moderate altitude.},
journal = {Journal of physiological anthropology},
volume = {33},
number = {1},
pages = {19},
pmid = {24996852},
issn = {1880-6805},
mesh = {*Altitude ; Animals ; Hypoxia/*blood ; Hypoxia-Inducible Factor 1, alpha Subunit/blood ; Leukocytes/chemistry/physiology ; Male ; Malondialdehyde/blood ; Rats ; Rats, Wistar ; Superoxide Dismutase/blood ; Telomerase/blood ; Telomere/*chemistry ; },
abstract = {BACKGROUND: Leukocyte telomere length has been shown to be associated with life span. Hypoxia-associated changes of telomere length have been detected in cell cultures, but no in vivo studies have reported the changes of telomere length under different hypoxic conditions. This study aimed to evaluate the effects of altitude on telomere length in rat leukocytes.<br><br>METHODS: One hundred and ten male Wistar rats were randomized into 3 groups and maintained at sea-level (altitude of 10 m) (SL group, n=10), moderate altitude (2,260 m) (MA group, n=50), or simulated high altitude (5,000 m (SHA group, n=50). The last two groups were further divided into 5 subgroups and exposed to hypoxia for 1, 3, 7, 15, or 30 days (n=10). The leukocyte telomere length, hemoglobin concentration, red blood cell count, hematocrit, and plasma levels of telomerase reverse transcriptase (TERT), hypoxia-inducible factor 1&#x3b1; (HIF-1&#x3b1;), malondialdehyde (MDA) and superoxide dismutase (SOD) were measured.<br><br>RESULTS: Leukocyte telomere length was significantly longer in the MA group than in the SL or SHA groups, and the TERT expression changed in a similar manner as the leukocyte telomere length. However, HIF-1&#x3b1; level was significantly higher in both MA and SHA groups than the SL group. SOD level was decreased and MDA level was elevated in SHA group.<br><br>CONCLUSIONS: The telomere length of blood leukocytes is elongated at a moderate altitude, but not at a high altitude. A mild hypoxic state may increase telomere length.},
}
@article {pmid24996497,
year = {2014},
author = {Reig-Viader, R and Capilla, L and Vila-Cejudo, M and Garcia, F and Anguita, B and Garcia-Caldés, M and Ruiz-Herrera, A},
title = {Telomere homeostasis is compromised in spermatocytes from patients with idiopathic infertility.},
journal = {Fertility and sterility},
volume = {102},
number = {3},
pages = {728-738.e1},
doi = {10.1016/j.fertnstert.2014.06.005},
pmid = {24996497},
issn = {1556-5653},
mesh = {Case-Control Studies ; Cell Nucleus/genetics/metabolism ; DNA-Binding Proteins/metabolism ; HeLa Cells ; Humans ; Infertility, Male/*genetics ; Male ; Recombination, Genetic ; Spermatocytes/*metabolism ; Telomerase/metabolism ; Telomere/metabolism ; *Telomere Homeostasis ; Transcription Factors/metabolism ; },
abstract = {OBJECTIVE: To study whether the telomere structure of germ cells from idiopathic infertile men is altered and if this impairment is influenced by meiotic recombination and telomere length.<br><br>DESIGN: We performed a detailed analysis of both telomeric repeat-containing RNA (TERRA) and telomerase distribution in testis cell spreads by combining immunofluorescence and RNA fluorescent in situ hybridization. In addition we analyzed meiotic recombination between homologous chromosomes by immunofluorescence and telomere length by quantitative fluorescent in situ hybridization.<br><br>SETTING: University.<br><br>PATIENT(S): Men consulting for fertility problems.<br><br>INTERVENTION(S): Unilateral testicular biopsies.<br><br>MAIN OUTCOME MEASURE(S): We observed that TERRA levels and its nuclear distribution were compromised in infertile patients. In addition, the presence of the protein component of telomerase at telomeres decreased in the affected patients. However, neither telomerase-TERRA association nor telomere length was altered in spermatocytes I of infertile samples compared with control individuals. In addition, we observed that meiotic recombination was reduced in infertile individuals.<br><br>RESULT(S): Telomere homeostasis is impaired in infertile patients, and this was translated into a decrease in TERRA levels together with an alteration of the TERRA-protein component of telomerase telomeric association in primary spermatocytes.<br><br>CONCLUSION(S): This study demonstrates for the first time that telomere structure and homeostasis in germ cells is compromised in infertile individuals. In the light of our results we propose that the analysis of telomeric structure (i.e., TERRA levels and telomere association with TERRA and telomerase) would provide new tools for our understanding of the origin of human infertility.},
}
@article {pmid24996455,
year = {2014},
author = {Karabatsiakis, A and Kolassa, IT and Kolassa, S and Rudolph, KL and Dietrich, DE},
title = {Telomere shortening in leukocyte subpopulations in depression.},
journal = {BMC psychiatry},
volume = {14},
number = {},
pages = {192},
pmid = {24996455},
issn = {1471-244X},
mesh = {Adult ; CD8-Positive T-Lymphocytes ; Depressive Disorder/*genetics ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes ; Leukocytes, Mononuclear ; Risk ; Telomere/*genetics ; *Telomere Shortening ; },
abstract = {BACKGROUND: Telomere shortening is a normal age-related process. However, premature shortening of telomeres in leukocytes--as has been reported in depression--may increase the risk for age-related diseases. While previous studies investigated telomere length in peripheral blood mononuclear cells (PBMCs) as a whole, this study investigated specific changes in the clonal composition of white blood cells of the adaptive immune system (CD4+ helper and CD8+ cytotoxic T lymphocytes, and CD20+ B lymphocytes).<br><br>METHODS: Forty-four females with a history of unipolar depression were investigated and compared to fifty age-matched female controls. Telomere lengths were compared between three groups: 1) individuals with a history of depression but currently no clinically relevant depressive symptoms, 2) individuals with a history of depression with relevant symptoms of depression, and 3) healthy age-matched controls. Telomere length was assessed using quantitative fluorescence in situ hybridization (qFISH).<br><br>RESULTS: Both groups with a history of unipolar depression (with and without current depressive symptoms) showed significantly shorter telomeres in all three lymphocyte subpopulations. The effect was stronger in CD8+ and CD20+ cells than in CD4+ cells. Individuals with a history of depression and with (without) current symptoms exhibited a CD8+ telomere length shortening corresponding to an age differential of 27.9 (25.3) years.<br><br>CONCLUSIONS: A history of depression is associated with shortened telomeres in the main effector populations of the adaptive immune system. Shorter telomeres seem to persist in individuals with lifetime depression independently of the severity of depressive symptoms. CD8+ cytotoxic T cells and CD20+ B cells seem to be particularly affected in depression. The total number of depressive episodes did not influence telomere length in the investigated adaptive immune cell populations.},
}
@article {pmid24995160,
year = {2014},
author = {Baichoo, E and Boardman, LA},
title = {Toward a molecular classification of colorectal cancer: the role of telomere length.},
journal = {Frontiers in oncology},
volume = {4},
number = {},
pages = {158},
pmid = {24995160},
issn = {2234-943X},
abstract = {Telomere biology is central to the maintenance of genomic stability and telomeric dysfunction is thought to be an early stage in carcinogenesis. Reports of telomere lengths and their ascribed colorectal cancer (CRC) risks have been discordant, with both very short and very long telomeres implicated. Nevertheless, telomeres appear to play a very central role in cancer initiation. Telomere length changes also appear to impact disease burden, progression, and overall survival. This review covers contemporary views on telomere biology and CRC risk, with a brief overview of analytical methods employed in telomere measurement. We conclude with arguments in favor of including telomere assessment in the molecular profiling of CRCs.},
}
@article {pmid24993704,
year = {2014},
author = {Calado, RT},
title = {The recognition of the role of telomeres in cell biology dates back to the 1930s. Introduction.},
journal = {Progress in molecular biology and translational science},
volume = {125},
number = {},
pages = {xi-xii},
doi = {10.1016/B978-0-12-397898-1.10000-3},
pmid = {24993704},
issn = {1878-0814},
mesh = {Animals ; Cell Biology/*history ; History, 20th Century ; History, 21st Century ; Humans ; Signal Transduction ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
}
@article {pmid24993703,
year = {2014},
author = {Calado, RT},
title = {Telomeres in lung diseases.},
journal = {Progress in molecular biology and translational science},
volume = {125},
number = {},
pages = {173-183},
doi = {10.1016/B978-0-12-397898-1.00008-6},
pmid = {24993703},
issn = {1878-0814},
mesh = {Animals ; Humans ; Lung Diseases/*genetics/*pathology ; Telomerase/metabolism ; Telomere/*physiology ; },
abstract = {Idiopathic pulmonary fibrosis is a progressive and fatal interstitial lung disease leading to respiratory failure. Mutations in telomerase complex genes (TERT or TERC) and short telomeres are genetic risk factors for the development of familial or sporadic idiopathic pulmonary fibrosis. Up to 15% of familial cases and approximately 5% of sporadic cases carry a heterozygous mutation in one of the genes, and patients' cells retain approximately 50% of telomerase activity. Pulmonary fibrosis also is a manifestation of dyskeratosis congenita, an inherited bone marrow failure syndrome caused by telomere dysfunction. Short telomeres even in the absence of telomerase mutations are a feature of most patients with idiopathic pulmonary fibrosis. Telomerase mutations also have been linked to pulmonary fibrosis and emphysema syndrome. Although short telomeres have been clearly linked to idiopathic pulmonary fibrosis, the mechanisms of disease are still unclear.},
}
@article {pmid24993702,
year = {2014},
author = {Sunami, Y and von Figura, G and Kleger, A and Strnad, P and Hüser, N and Hartmann, D},
title = {The role of telomeres in liver disease.},
journal = {Progress in molecular biology and translational science},
volume = {125},
number = {},
pages = {159-172},
doi = {10.1016/B978-0-12-397898-1.00007-4},
pmid = {24993702},
issn = {1878-0814},
mesh = {Animals ; Humans ; Liver Diseases/*genetics/*pathology ; Telomerase/metabolism ; Telomere/*physiology ; },
abstract = {Telomeres stabilize open chromosome ends and protect them against chromosomal end-to-end fusions, breakage, instability, and nonreciprocal translocations. Telomere dysfunction is known to lead to an impaired regenerative capacity of hepatocytes and an increased cirrhosis formation in the context of acute and chronic liver injury. In addition, telomere dysfunction and telomerase mutations have been associated with the induction of chromosomal instability and consequently with cirrhosis development and hepatocarcinogenesis. The identification of molecular mechanisms related to telomere dysfunction and telomerase activation might lead to new therapeutic strategies. In this chapter, we are reviewing the current knowledge about the importance of telomere dysfunction in liver diseases.},
}
@article {pmid24993701,
year = {2014},
author = {Paiva, RM and Calado, RT},
title = {Telomere dysfunction and hematologic disorders.},
journal = {Progress in molecular biology and translational science},
volume = {125},
number = {},
pages = {133-157},
doi = {10.1016/B978-0-12-397898-1.00006-2},
pmid = {24993701},
issn = {1878-0814},
mesh = {Animals ; Hematologic Diseases/*genetics/*pathology ; Humans ; Telomerase/metabolism ; Telomere/genetics/metabolism/*pathology ; },
abstract = {Aplastic anemia is a disease in which the hematopoietic stem cell fails to adequately produce peripheral blood cells, causing pancytopenia. In some cases of acquired aplastic anemia and in inherited type of aplastic anemia, dyskeratosis congenita, telomere biology gene mutations and telomere shortening are etiologic. Telomere erosion hampers the ability of hematopoietic stem and progenitor cells to adequately replicate, clinically resulting in bone marrow failure. Additionally, telomerase mutations and short telomeres are genetic risk factors for the development of some hematologic cancers, including myelodysplastic syndrome, acute myeloid leukemia, and chronic lymphocytic leukemia.},
}
@article {pmid24993700,
year = {2014},
author = {Bodelon, C and Savage, SA and Gadalla, SM},
title = {Telomeres in molecular epidemiology studies.},
journal = {Progress in molecular biology and translational science},
volume = {125},
number = {},
pages = {113-131},
pmid = {24993700},
issn = {1878-0814},
support = {ZIA CP010190-04//Intramural NIH HHS/United States ; ZIA CP010190-13//Intramural NIH HHS/United States ; ZIA CP010190-07//Intramural NIH HHS/United States ; ZIA CP010190-12//Intramural NIH HHS/United States ; ZIA CP010190-8//Intramural NIH HHS/United States ; ZIA CP010190-06//Intramural NIH HHS/United States ; Z99 CA999999//Intramural NIH HHS/United States ; Z01 CP010190-02//Intramural NIH HHS/United States ; ZIA CP010190-09//Intramural NIH HHS/United States ; ZIA CP010190-05//Intramural NIH HHS/United States ; ZIA CP010190-11//Intramural NIH HHS/United States ; Z01 CP010190-03//Intramural NIH HHS/United States ; ZIA CP010190-10//Intramural NIH HHS/United States ; },
mesh = {Animals ; Genetic Diseases, Inborn/*epidemiology/*genetics ; Humans ; Telomerase/metabolism ; Telomere/*physiology ; },
abstract = {Telomeres are long nucleotide repeats and protein complexes at the ends of chromosomes that are essential for maintaining chromosomal stability. They shorten with each cell division, and therefore, telomere length is a marker for cellular aging and senescence. Epidemiological research of telomeres investigates the role that these genetic structures have in disease risk and mortality in human populations. This chapter provides an overview of the current telomere epidemiology research and discusses approaches taken in these investigations. We also highlight important methodological considerations that may affect data interpretation.},
}
@article {pmid24993699,
year = {2014},
author = {Aubert, G},
title = {Telomere dynamics and aging.},
journal = {Progress in molecular biology and translational science},
volume = {125},
number = {},
pages = {89-111},
doi = {10.1016/B978-0-12-397898-1.00004-9},
pmid = {24993699},
issn = {1878-0814},
support = {R01GM094146/GM/NIGMS NIH HHS/United States ; RMF-92093//Canadian Institutes of Health Research/Canada ; },
mesh = {Animals ; Cellular Senescence/*genetics ; Humans ; Telomerase/metabolism ; Telomere/*physiology ; },
abstract = {Telomeres consist of repetitive DNA-protein complexes that cap the ends of vertebrate linear chromosomes. Their capping function and dynamics both with regard to structure and length are carefully orchestrated by many regulatory mechanisms and factors, with likely more yet to be described. Telomere shortening has been shown to be a major measurable molecular characteristic of aging of cells in vitro and in vivo and is thought to have evolved as a tumor protection mechanism in long-lived species. Regulators and modifiers of telomere dynamics and dynamics with age together with the consequences of telomere shortening and telomere dysfunction in the context of aging and aging-related disorders are discussed in this chapter.},
}
@article {pmid24993698,
year = {2014},
author = {Batista, LF},
title = {Telomere biology in stem cells and reprogramming.},
journal = {Progress in molecular biology and translational science},
volume = {125},
number = {},
pages = {67-88},
doi = {10.1016/B978-0-12-397898-1.00003-7},
pmid = {24993698},
issn = {1878-0814},
support = {R00 HL114732/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Animals ; *Cellular Reprogramming ; Humans ; Stem Cells/cytology/*metabolism ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomerase expression in humans is restricted to different populations of stem and progenitor cells, being silenced in most somatic tissues. Efficient telomere homeostasis is essential for embryonic and adult stem cell function and therefore essential for tissue homeostasis throughout organismal life. Accordingly, the mutations in telomerase culminate in reduced stem cell function both in vivo and in vitro and have been associated with tissue dysfunction in human patients. Despite the importance of telomerase for stem cell biology, the mechanisms behind telomerase regulation during development are still poorly understood, mostly due to difficulties in acquiring and maintaining pluripotent stem cell populations in culture. In this chapter, we will analyze recent developments in this field, including the importance of efficient telomere homeostasis in different stem cell types and the role of telomerase in different techniques used for cellular reprogramming.},
}
@article {pmid24993697,
year = {2014},
author = {Savage, SA},
title = {Human telomeres and telomere biology disorders.},
journal = {Progress in molecular biology and translational science},
volume = {125},
number = {},
pages = {41-66},
doi = {10.1016/B978-0-12-397898-1.00002-5},
pmid = {24993697},
issn = {1878-0814},
support = {//Intramural NIH HHS/United States ; },
mesh = {Animals ; Genetic Diseases, Inborn/*genetics ; Humans ; Telomerase/metabolism ; Telomere/*physiology ; },
abstract = {Telomeres consist of long nucleotide repeats and a protein complex at chromosome ends essential for chromosome stability. Telomeres shorten with each cell division and thus are markers of cellular age. Dyskeratosis congenita (DC) is a cancer-prone inherited bone marrow failure syndrome caused by germ-line mutations in key telomere biology genes that result in extremely short telomeres. The triad of nail dysplasia, abnormal skin pigmentation, and oral leukoplakia is diagnostic of DC but highly variable. Patients with DC may also have but numerous other medical problems, including pulmonary fibrosis, liver abnormalities, avascular necrosis of the hips, and stenosis of the esophagus, lacrimal ducts, and/or urethra. All modes of inheritance have been reported in DC and de novo mutations are common. Broad phenotypic heterogeneity occurs within DC. Clinically severe variants of DC are Hoyeraal-Hreidarsson syndrome and Revesz syndrome. Coats plus syndrome joined the spectrum of DC with the discovery that it is caused by mutations in a telomere-capping gene. Less clinically severe variants, such as subsets of apparently isolated aplastic anemia or pulmonary fibrosis, have also been recognized. These patients may not have the DC-associated mucocutaneous triad or complicated medical features, but they do have the same underlying genetic etiology. This has led to the use of the descriptive term telomere biology disorder (TBD). This chapter will review the connection between telomere biology and human disease through the examples of DC and its related TBDs.},
}
@article {pmid24993696,
year = {2014},
author = {Giardini, MA and Segatto, M and da Silva, MS and Nunes, VS and Cano, MI},
title = {Telomere and telomerase biology.},
journal = {Progress in molecular biology and translational science},
volume = {125},
number = {},
pages = {1-40},
doi = {10.1016/B978-0-12-397898-1.00001-3},
pmid = {24993696},
issn = {1878-0814},
mesh = {Animals ; Cellular Senescence/*genetics ; *Genomic Instability ; Humans ; Telomerase/metabolism ; Telomere/*physiology ; },
abstract = {Telomeres are the physical ends of eukaryotic linear chromosomes. Telomeres form special structures that cap chromosome ends to prevent degradation by nucleolytic attack and to distinguish chromosome termini from DNA double-strand breaks. With few exceptions, telomeres are composed primarily of repetitive DNA associated with proteins that interact specifically with double- or single-stranded telomeric DNA or with each other, forming highly ordered and dynamic complexes involved in telomere maintenance and length regulation. In proliferative cells and unicellular organisms, telomeric DNA is replicated by the actions of telomerase, a specialized reverse transcriptase. In the absence of telomerase, some cells employ a recombination-based DNA replication pathway known as alternative lengthening of telomeres. However, mammalian somatic cells that naturally lack telomerase activity show telomere shortening with increasing age leading to cell cycle arrest and senescence. In another way, mutations or deletions of telomerase components can lead to inherited genetic disorders, and the depletion of telomeric proteins can elicit the action of distinct kinases-dependent DNA damage response, culminating in chromosomal abnormalities that are incompatible with life. In addition to the intricate network formed by the interrelationships among telomeric proteins, long noncoding RNAs that arise from subtelomeric regions, named telomeric repeat-containing RNA, are also implicated in telomerase regulation and telomere maintenance. The goal for the next years is to increase our knowledge about the mechanisms that regulate telomere homeostasis and the means by which their absence or defect can elicit telomere dysfunction, which generally results in gross genomic instability and genetic diseases.},
}
@article {pmid24993398,
year = {2014},
author = {Aini, W and Miyagawa-Hayashino, A and Ozeki, M and Adeeb, S and Hirata, M and Tamaki, K and Uemoto, S and Haga, H},
title = {Accelerated telomere reduction and hepatocyte senescence in tolerated human liver allografts.},
journal = {Transplant immunology},
volume = {31},
number = {2},
pages = {55-59},
doi = {10.1016/j.trim.2014.06.008},
pmid = {24993398},
issn = {1878-5492},
mesh = {Adolescent ; Adult ; Aging ; Allografts/immunology/physiology ; Cell Cycle/physiology ; Cell Nucleus Size/physiology ; Child ; Child, Preschool ; Cyclin-Dependent Kinase Inhibitor p21/biosynthesis ; Female ; Graft Survival/immunology ; Hepatocytes/*cytology ; Humans ; Infant ; Liver/immunology/physiology ; Liver Transplantation ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; Telomere Shortening/*physiology ; Transplantation Tolerance/*immunology ; Young Adult ; },
abstract = {BACKGROUND: In living donor liver transplantation, the biological organ age of the donated allograft is unknown in young patients who receive grafts from older donors. Few studies have focused on the effects of aging on allografts in the state of tolerance. The purpose of this study was to assess the biological organ age of liver grafts.<br><br>METHODS: In 20 tolerated allografts over a 10-year post-transplant follow-up period, the relative telomere lengths were measured by multiplex quantitative polymerase chain reaction, and hepatocyte nuclear size and cell cycle phase markers were determined by immunohistochemistry. The results were compared with the same measurements that had been obtained prior to transplantation in the recipients' pre-implantation donor livers. Tolerance was defined strictly as a condition in which the allograft functioned normally and showed normal histology without any histological signs of rejection, fibrosis or inflammation in the absence of immunosuppression.<br><br>RESULTS: First, telomere length correlated with chronological donor age (n=41). Accelerated telomere reduction was seen in tolerated grafts compared with the predicted telomere length of each allograft calculated from the regression line of donor livers. Tolerated grafts were associated with higher hepatocyte p21 expression and greater nuclear area than in the donor livers prior to transplantation.<br><br>CONCLUSIONS: These findings suggest that allografts age more rapidly than in the normal population, and that grafts may reach the limit of proliferative capacity even in the state of tolerance.},
}
@article {pmid24990087,
year = {2014},
author = {Lin, TT and Norris, K and Heppel, NH and Pratt, G and Allan, JM and Allsup, DJ and Bailey, J and Cawkwell, L and Hills, R and Grimstead, JW and Jones, RE and Britt-Compton, B and Fegan, C and Baird, DM and Pepper, C},
title = {Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease.},
journal = {British journal of haematology},
volume = {167},
number = {2},
pages = {214-223},
doi = {10.1111/bjh.13023},
pmid = {24990087},
issn = {1365-2141},
support = {C17199/A13490//Cancer Research UK/United Kingdom ; },
mesh = {Cohort Studies ; DNA, Neoplasm/genetics ; Humans ; Immunoglobulin Variable Region/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis/*genetics/pathology ; Mutation ; Neoplasm Staging ; Prognosis ; Survival Analysis ; Telomere/*physiology ; Telomere Homeostasis/physiology ; Telomere Shortening/*physiology ; },
abstract = {Defining the prognosis of individual cancer sufferers remains a significant clinical challenge. Here we assessed the ability of high-resolution single telomere length analysis (STELA), combined with an experimentally derived definition of telomere dysfunction, to predict the clinical outcome of patients with chronic lymphocytic leukaemia (CLL). We defined the upper telomere length threshold at which telomere fusions occur and then used the mean of the telomere 'fusogenic' range as a prognostic tool. Patients with telomeres within the fusogenic range had a significantly shorter overall survival (P < 0·0001; Hazard ratio [HR] = 13·2, 95% confidence interval [CI] = 11·6-106·4) and this was preserved in early-stage disease patients (P < 0·0001, HR=19·3, 95% CI = 17·8-802·5). Indeed, our assay allowed the accurate stratification of Binet stage A patients into those with indolent disease (91% survival at 10 years) and those with poor prognosis (13% survival at 10 years). Furthermore, patients with telomeres above the fusogenic mean showed superior prognosis regardless of their IGHV mutation status or cytogenetic risk group. In keeping with this finding, telomere dysfunction was the dominant variable in multivariate analysis. Taken together, this study provides compelling evidence for the use of high-resolution telomere length analysis coupled with a definition of telomere dysfunction in the prognostic assessment of CLL.},
}
@article {pmid24986515,
year = {2014},
author = {Ning, XH and Zhang, N and Li, T and Wu, PJ and Wang, X and Li, XY and Peng, SH and Wang, JY and Chen, JC and Gong, K},
title = {Telomere shortening is associated with genetic anticipation in Chinese Von Hippel-Lindau disease families.},
journal = {Cancer research},
volume = {74},
number = {14},
pages = {3802-3809},
doi = {10.1158/0008-5472.CAN-14-0024},
pmid = {24986515},
issn = {1538-7445},
mesh = {Adolescent ; Adult ; Age of Onset ; Aged ; Aged, 80 and over ; *Anticipation, Genetic ; Asian People/*genetics ; Case-Control Studies ; Child ; China ; Female ; Genetic Predisposition to Disease ; Genotype ; Germ-Line Mutation ; Humans ; Male ; Middle Aged ; Pedigree ; Phenotype ; *Telomere Shortening ; Young Adult ; von Hippel-Lindau Disease/diagnosis/*genetics/mortality ; },
abstract = {Von Hippel-Lindau (VHL) disease is a rare autosomal dominant cancer syndrome. A phenomenon known as genetic anticipation has been documented in some hereditary cancer syndromes, where it was proved to relate to telomere shortening. Because studies of this phenomenon in VHL disease have been relatively scarce, we investigated anticipation in 18 Chinese VHL disease families. We recruited 34 parent-child patient pairs (57 patients) from 18 families with VHL disease. Onset age was defined as the age when any symptom or sign of VHL disease first appeared. Anticipation of onset age was analyzed by paired t test and the other two special tests (HV and RY2). Relative telomere length of peripheral leukocytes was measured in 29 patients and 325 healthy controls. Onset age was younger in child than in parent in 31 of the 34 parent-child pairs. Patients in the first generation had older onset age with longer age-adjusted relative telomere length, and those in the next generation had younger onset age with shorter age-adjusted relative telomere length (P < 0.001) in the 10 parent-child pairs from eight families with VHL disease. In addition, relative telomere length was shorter in the 29 patients with VHL disease than in the normal controls (P = 0.003). The anticipation may relate to the shortening of telomere length in patients with VHL in successive generations. These findings indicate that anticipation is present in families with VHL disease and may be helpful for genetic counseling for families with VHL disease families and for further understanding the pathogenesis of VHL disease.},
}
@article {pmid24986269,
year = {2014},
author = {Vaquero-Sedas, MI and Vega-Palas, MA},
title = {Determination of Arabidopsis thaliana telomere length by PCR.},
journal = {Scientific reports},
volume = {4},
number = {},
pages = {5540},
pmid = {24986269},
issn = {2045-2322},
mesh = {Arabidopsis/*genetics ; Base Sequence ; Chromosomes, Plant/*genetics ; Molecular Sequence Data ; Polymerase Chain Reaction/*methods ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {In humans, telomere length studies have acquired great relevance because the length of telomeres has been related to natural processes like disease, aging and cancer. However, very little is known about the influence of telomere length on the biology of wild type plants. The length of plant telomeres has been usually studied by Terminal Restriction Fragment (TRF) analyses. This technique requires high amounts of tissue, including multiple cell types, which might be the reason why very little is known about the influence of telomere length on plant natural processes. In contrast, many of the human telomere length studies have focused on homogenous cell populations. Most of these studies have been performed by PCR, using telomeric degenerated primers, which allow the determination of telomere length from small amounts of human cells. Here, we have adapted the human PCR procedure to analyze the length of Arabidopsis thaliana telomeres. This PCR approach will facilitate the analysis of telomere length from low amounts of tissue. We have used it to determine that CG and non CG DNA methylation positively regulates Arabidopsis telomere length.},
}
@article {pmid24984965,
year = {2014},
author = {Borisov, VI and Korolkova, OY and Kozhevnikov, VS},
title = {Application of flow-FISH for dynamic measurement of telomere length in cell division.},
journal = {Current protocols in cytometry},
volume = {69},
number = {},
pages = {8.14.1-8.14.10},
doi = {10.1002/0471142956.cy0814s69},
pmid = {24984965},
issn = {1934-9300},
mesh = {Animals ; Cell Division/*physiology ; DNA Probes/*chemistry/genetics ; Fluorescent Dyes/*chemistry ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Telomere/genetics/*metabolism ; },
abstract = {This method makes it possible to measure the fluorescence of a DNA probe in cells with known division number and targeted surface antigen. In fact, this method is a combination or consistent application of three other methods: cell tracking by vital dye, surface immunophenotyping, and flow-FISH. The idea in developing this method was to study telomere length changes in cells with known surface antigen after every new cell division. First, the in vitro cell culturing and staining with CFSE vital dye are performed. Then, cells are stained with surface MAbs labeled with biotin, followed by incubation with streptavidin-labeled fluorochrome. After that, cells are fixed with BS(3) reagent followed by the flow-FISH procedure with PNA-probe complementary to telomere DNA repeats. Finally, in one tube, it is possible to determine telomere length in surface antigen-labeled cells that have made the exact same number of divisions after incubation.},
}
@article {pmid24983884,
year = {2014},
author = {Asok, A and Bernard, K and Rosen, JB and Dozier, M and Roth, TL},
title = {Infant-caregiver experiences alter telomere length in the brain.},
journal = {PloS one},
volume = {9},
number = {7},
pages = {e101437},
pmid = {24983884},
issn = {1932-6203},
support = {P20 GM103653/GM/NIGMS NIH HHS/United States ; R01 HD075066/HD/NICHD NIH HHS/United States ; 1P20GM103653/GM/NIGMS NIH HHS/United States ; },
mesh = {Amygdala/*growth &amp; development ; Animals ; Female ; Male ; Rats ; Rats, Long-Evans ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {Following adverse childhood experiences, high quality maternal care can protect against accelerated telomere shortening in peripheral cells. It is less clear, however, how telomere length in the brain is influenced by early caregiving experiences. Using rats, we investigated if quality of care (i.e., aversive or nurturing care outside of the homecage) during the first seven days of postnatal (PN) life affected telomere length in the adult brain (PN90) of male and female rats. At PN90, we found that nurturing care outside of the homecage was associated with longer telomeres in the medial prefrontal cortex relative to nurturing care inside the homecage (i.e., normal maternal care) and aversive care outside of the homecage. Further, pups exposed to aversive care outside of the homecage demonstrated longer telomeres in the amygdala relative to pups exposed to nurturing care inside the homecage. These effects were specific to females. No differences in telomere length between caregiving conditions were observed in the ventral hippocampus. Thus, positive and negative early-life experiences result in long-term, sex-specific changes of telomeres in the brain.},
}
@article {pmid24983628,
year = {2014},
author = {Zhang, Y and Calado, R and Rao, M and Hong, JA and Meeker, AK and Dumitriu, B and Atay, S and McCormick, PJ and Garfield, SH and Wangsa, D and Padilla-Nash, HM and Burkett, S and Zhang, M and Kunst, TF and Peterson, NR and Xi, S and Inchauste, S and Altorki, NK and Casson, AG and Beer, DG and Harris, CC and Ried, T and Young, NS and Schrump, DS},
title = {Telomerase variant A279T induces telomere dysfunction and inhibits non-canonical telomerase activity in esophageal carcinomas.},
journal = {PloS one},
volume = {9},
number = {7},
pages = {e101010},
pmid = {24983628},
issn = {1932-6203},
support = {//Intramural NIH HHS/United States ; },
mesh = {Amino Acid Substitution ; Animals ; Cell Line, Tumor ; Esophageal Neoplasms/*enzymology/genetics/pathology ; Female ; *Gene Expression Regulation, Enzymologic ; *Gene Expression Regulation, Neoplastic ; Humans ; Male ; Mice ; Mice, Nude ; *Mutation, Missense ; Neoplasm Proteins/*biosynthesis/genetics ; RNA/biosynthesis/genetics ; RNA, Neoplasm/biosynthesis/genetics ; Telomerase/*biosynthesis/genetics ; Telomere/enzymology/genetics ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Although implicated in the pathogenesis of several chronic inflammatory disorders and hematologic malignancies, telomerase mutations have not been thoroughly characterized in human cancers. The present study was performed to examine the frequency and potential clinical relevance of telomerase mutations in esophageal carcinomas.<br><br>METHODS: Sequencing techniques were used to evaluate mutational status of telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) in neoplastic and adjacent normal mucosa from 143 esophageal cancer (EsC) patients. MTS, flow cytometry, time lapse microscopy, and murine xenograft techniques were used to assess proliferation, apoptosis, chemotaxis, and tumorigenicity of EsC cells expressing either wtTERT or TERT variants. Immunoprecipitation, immunoblot, immunofluorescence, promoter-reporter and qRT-PCR techniques were used to evaluate interactions of TERT and several TERT variants with BRG-1 and &#x3b2;-catenin, and to assess expression of cytoskeletal proteins, and cell signaling. Fluorescence in-situ hybridization and spectral karyotyping techniques were used to examine telomere length and chromosomal stability.<br><br>RESULTS: Sequencing analysis revealed one deletion involving TERC (TERC del 341-360), and two non-synonymous TERT variants [A279T (2 homozygous, 9 heterozygous); A1062T (4 heterozygous)]. The minor allele frequency of the A279T variant was five-fold higher in EsC patients compared to healthy blood donors (p<0.01). Relative to wtTERT, A279T decreased telomere length, destabilized TERT-BRG-1-&#x3b2;-catenin complex, markedly depleted &#x3b2;-catenin, and down-regulated canonical Wnt signaling in cancer cells; these phenomena coincided with decreased proliferation, depletion of additional cytoskeletal proteins, impaired chemotaxis, increased chemosensitivity, and significantly decreased tumorigenicity of EsC cells. A279T expression significantly increased chromosomal aberrations in mouse embryonic fibroblasts (MEFs) following Zeocin&#x2122; exposure, as well as Li Fraumeni fibroblasts in the absence of pharmacologically-induced DNA damage.<br><br>CONCLUSIONS: A279T induces telomere dysfunction and inhibits non-canonical telomerase activity in esophageal cancer cells. These findings warrant further analysis of A279T expression in esophageal cancers and premalignant esophageal lesions.},
}
@article {pmid24981509,
year = {2014},
author = {Li, JR and Yu, TY and Chien, IC and Lu, CY and Lin, JJ and Li, HW},
title = {Pif1 regulates telomere length by preferentially removing telomerase from long telomere ends.},
journal = {Nucleic acids research},
volume = {42},
number = {13},
pages = {8527-8536},
pmid = {24981509},
issn = {1362-4962},
mesh = {DNA/metabolism ; DNA Helicases/*metabolism ; DNA, Single-Stranded/metabolism ; Saccharomyces cerevisiae/enzymology/genetics ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Telomerase, a ribonucleoprotein complex, is responsible for maintaining the telomere length at chromosome ends. Using its RNA component as a template, telomerase uses its reverse transcriptase activity to extend the 3'-end single-stranded, repetitive telomeric DNA sequence. Pif1, a 5'-to-3' helicase, has been suggested to regulate telomerase activity. We used single-molecule experiments to directly show that Pif1 helicase regulates telomerase activity by removing telomerase from telomere ends, allowing the cycling of the telomerase for additional extension processes. This telomerase removal efficiency increases at longer ssDNA gaps and at higher Pif1 concentrations. The enhanced telomerase removal efficiency by Pif1 at the longer single-stranded telomeric DNA suggests a way of how Pif1 regulates telomerase activity and maintains telomere length.},
}
@article {pmid24977726,
year = {2014},
author = {Montpetit, AJ and Alhareeri, AA and Montpetit, M and Starkweather, AR and Elmore, LW and Filler, K and Mohanraj, L and Burton, CW and Menzies, VS and Lyon, DE and Jackson-Cook, CK},
title = {Telomere length: a review of methods for measurement.},
journal = {Nursing research},
volume = {63},
number = {4},
pages = {289-299},
pmid = {24977726},
issn = {1538-9847},
support = {P30 NR011403/NR/NINR NIH HHS/United States ; R00 NR012016/NR/NINR NIH HHS/United States ; R01 AG037986/AG/NIA NIH HHS/United States ; R01NR012667/NR/NINR NIH HHS/United States ; R01AG037986/AG/NIA NIH HHS/United States ; K99/R00NR012016/NR/NINR NIH HHS/United States ; R01 NR012667/NR/NINR NIH HHS/United States ; },
mesh = {Biomarkers/*analysis ; Chromosome Mapping/*methods ; Fluorescent Dyes ; *Genetic Techniques ; Humans ; In Situ Hybridization, Fluorescence ; Polymerase Chain Reaction ; Polymorphism, Restriction Fragment Length ; Telomere/*classification ; Weights and Measures ; },
abstract = {BACKGROUND: The exciting discovery that telomere shortening is associated with many health conditions and that telomere lengths can be altered in response to social and environmental exposures has underscored the need for methods to accurately and consistently quantify telomere length.<br><br>OBJECTIVES: The purpose of this article is to provide a comprehensive summary that compares and contrasts the current technologies used to assess telomere length.<br><br>DISCUSSION: Multiple methods have been developed for the study of telomeres. These techniques include quantification of telomere length by terminal restriction fragmentation-which was one of the earliest tools used for length assessment-making it the gold standard in telomere biology. Quantitative polymerase chain reaction provides the advantage of being able to use smaller amounts of DNA, thereby making it amenable to epidemiology studies involving large numbers of people. An alternative method uses fluorescent probes to quantify not only mean telomere lengths but also chromosome-specific telomere lengths; however, the downside of this approach is that it can only be used on mitotically active cells. Additional methods that permit assessment of the length of a subset of chromosome-specific telomeres or the subset of telomeres that demonstrate shortening are also reviewed.<br><br>CONCLUSION: Given the increased utility for telomere assessments as a biomarker in physiological, psychological, and biobehavioral research, it is important that investigators become familiar with the methodological nuances of the various procedures used for measuring telomere length. This will ensure that they are empowered to select an optimal assessment approach to meet the needs of their study designs. Gaining a better understanding of the benefits and drawbacks of various measurement techniques is important not only in individual studies, but also to further establish the science of telomere associations with biobehavioral phenomena.},
}
@article {pmid24977331,
year = {2014},
author = {Jergović, M and Tomičević, M and Vidović, A and Bendelja, K and Savić, A and Vojvoda, V and Rac, D and Lovrić-Čavar, D and Rabatić, S and Jovanovic, T and Sabioncello, A},
title = {Telomere shortening and immune activity in war veterans with posttraumatic stress disorder.},
journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry},
volume = {54},
number = {},
pages = {275-283},
doi = {10.1016/j.pnpbp.2014.06.010},
pmid = {24977331},
issn = {1878-4216},
mesh = {Aged, 80 and over ; Aging/*genetics/*immunology ; B7-H1 Antigen/metabolism ; Cell Proliferation/physiology ; Croatia ; Cytokines/metabolism ; Female ; Humans ; Male ; Middle Aged ; Programmed Cell Death 1 Receptor/metabolism ; Regression Analysis ; Stress Disorders, Post-Traumatic/*genetics/*immunology ; T-Lymphocytes/physiology ; Telomerase/metabolism ; *Telomere Shortening ; *Veterans ; Warfare ; },
abstract = {BACKGROUND: There is increasing evidence that chronic stress accelerates telomere erosion in leukocytes/peripheral blood mononuclear cells (PBMCs). However, functional changes associated with telomere shortening are poorly understood. We hypothesized that war veterans with PTSD would have shorter telomeres in PBMCs and that these cells might exhibit changes in measures of immune reactivity such as proliferation, cytokine production and expression of regulators of immune responses.<br><br>METHODS: We measured relative telomere length and basal telomerase activity in PBMCs of 62 individuals (PTSD patients (N=30); age-matched healthy controls (N=17), elderly volunteers (N=15)). In parallel, we have assessed proliferation of activated T cells, interferon (IFN)-&#x3b3;, interleukin (IL)-2, IL-4, tumor necrosis factor (TNF)-&#x3b1; and IL-6 cytokine production and expression of programmed death 1 (PD-1) receptor and its ligand PD-L1 on activated T cells.<br><br>RESULTS: Middle-aged war veterans with current PTSD had shorter PBMC telomere length than their age-matched healthy controls while the elderly had the shortest telomeres. There was no difference in telomerase activity between PTSD patients and healthy controls while telomerase activity was significantly lower in the elderly. While the elderly group exhibited robust changes in immune activity such as increased production of proinflammatory cytokines (TNF-&#x3b1;, IL-6) and reduced proliferation of all T cells, the PTSD group showed reduced proliferative response of CD8(+) T cells to high concentrations of mitogen and reduced spontaneous production of IL-2 and IFN-&#x3b3;.<br><br>CONCLUSIONS: This study adds to the accumulating evidence that psychological trauma and chronic stress are associated with accelerated telomere attrition. However, changes in immune function associated with stress-related telomere shortening are not well understood. Although much less pronounced in PTSD patients than in elderly persons, reduced proliferative responses of T cells accompanied by shorter telomeres might be a sign of early immunosenescence. Together with reduced production of Th1 cytokines, observed immune changes may contribute to health risks associated with PTSD.},
}
@article {pmid24975612,
year = {2014},
author = {Feijoo, P and Dominguez, D and Tusell, L and Genesca, A},
title = {Telomere-dependent genomic integrity: evolution of the fusion-bridge-breakage cycle concept.},
journal = {Current pharmaceutical design},
volume = {20},
number = {41},
pages = {6375-6385},
doi = {10.2174/1381612820666140630085416},
pmid = {24975612},
issn = {1873-4286},
mesh = {Animals ; *Chromosome Aberrations ; *Genomic Instability ; Humans ; Neoplasms/*genetics ; Telomere/*genetics ; },
abstract = {Most cancer genomes show abnormalities in chromosome structure and number, two types of aberrations that could share a common mechanistic origin through proliferation-dependent loss of telomere function. Impairment of checkpoints that limit cell proliferation when telomeres are critically short might allow unrestrained cell division. The resulting uncapped chromosomes can fuse to each other, forming unstable configurations that can bridge during mitosis. Chromatin bridges can break to generate new broken ends that will then fuse with other broken ends. Successive events of break and fusion will continuously generate unbalanced chromosomal rearrangements, leading to gene-copy gains and losses. However, chromosome bridges do not always break. Evidence has recently been obtained to suggest that telomere-dependent chromosome bridges remaining unbroken can hinder cytokinesis and yield tetraploid cells. This might constitute an unstable intermediate in tumorigenesis, as progressive losses of individual chromosomes due to geometrical defects during cell division result in subtetraploid karyotypes. Additionally, the presence of short dysfunctional telomeres in cells can also cause these cells to become sensitive to mutagens, and particularly to radiation exposure. Human individuals exhibit differences in their sensitivity to radiation, which can be relevant for choice of therapy. Telomere function may well be involved in cellular and organism responses to ionizing radiation. Since eroded telomeres are sensed and act as double-strand breaks, they can interact with radiation-induced breaks, sharply increasing the possibility of misjoining. Altogether, this scenario provides certain clues to understanding the important role of telomeres in maintaining genomic integrity.},
}
@article {pmid24975611,
year = {2014},
author = {Draskovic, I and Londono-Vallejo, A},
title = {Telomere recombination and the ALT pathway: a therapeutic perspective for cancer.},
journal = {Current pharmaceutical design},
volume = {20},
number = {41},
pages = {6466-6471},
doi = {10.2174/1381612820666140630085857},
pmid = {24975611},
issn = {1873-4286},
mesh = {Animals ; Antineoplastic Agents/*therapeutic use ; Humans ; Neoplasms/*drug therapy/*metabolism ; Recombination, Genetic/*drug effects ; Telomere/*metabolism ; },
abstract = {Telomeres are essential for cell proliferation and tumor cell immortalization requires the presence of a telomere maintenance mechanism. Thus, interfering with this mechanism constitutes a potential means to impede cell proliferation and tumor progression. Many cancer cells rely on telomerase activity to ensure indefinite proliferation capacity and developing therapeutic approaches that target telomerase has attracted much attention in the last couple of decades. Nevertheless, a non-negligible proportion of tumors utilize telomerase- independent, alternative mechanisms to lengthen telomeres (ALT). Here we briefly discuss both our current understanding of ALT mechanisms and the potential to develop a therapeutic approach targeting ALT.},
}
@article {pmid24975607,
year = {2014},
author = {Santambrogio, F and Gandellini, P and Cimino-Reale, G and Zaffaroni, N and Folini, M},
title = {MicroRNA-dependent regulation of telomere maintenance mechanisms: a field as much unexplored as potentially promising.},
journal = {Current pharmaceutical design},
volume = {20},
number = {41},
pages = {6404-6421},
doi = {10.2174/1381612820666140630095918},
pmid = {24975607},
issn = {1873-4286},
mesh = {Animals ; Humans ; MicroRNAs/*genetics ; Neoplasms/*genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {The activation of telomere maintenance mechanisms, which rely on telomerase reactivation or on a recombination-based process known as alternative lengthening of telomeres, guarantees a limitless proliferative potential to human tumor cells. To date, the molecular underpinnings that drive the activation of telomere maintenance mechanisms during tumorigenesis are poorly understood, but there are indications that complex signaling networks might be involved. Since telomerase activity has been mainly detected in tumors of epithelial origin and the alternative lengthening of telomere mechanisms is more frequently expressed in mesenchymal and neuroepithelial cancers, it could be hypothesized that cell-type specific mechanisms can favor their activation during tumor development. In this context, microRNAs - small non coding RNAs that regulate gene expression at post-transcriptional level - have emerged as key players in the development and progression of human cancers, being involved in the control of all the typical features of cancer cells, including the limitless replicative potential. In the present review, we will summarize the recent findings concerning the identification and biological validation of microRNAs which may play a role in the regulation of telomere biology as well as of the mechanisms that govern telomere maintenance.},
}
@article {pmid24975606,
year = {2014},
author = {Uziel, O and Lahav, M},
title = {Conventional anticancer therapeutics and telomere maintenance mechanisms.},
journal = {Current pharmaceutical design},
volume = {20},
number = {41},
pages = {6452-6465},
doi = {10.2174/1381612820666140630100130},
pmid = {24975606},
issn = {1873-4286},
mesh = {Animals ; Antineoplastic Agents/*therapeutic use ; Humans ; Neoplasms/*drug therapy/*metabolism ; Telomere/*metabolism ; },
abstract = {The telomere-telomerase system has a unique role in the biology of cancer. Telomere maintenance, mostly affected by the up regulation of telomerase activity, is a prerequisite for perpetuation of malignant cells. This fundamental biologic feature defines telomere maintenance as an attractive therapeutic target for most types of cancer. This review summarizes some critical aspects of telomere biology with special emphasis on the connection to anticancer therapy. In particular, the effects on the telomere - telomerase system of conventional anticancer treatments, including various cytotoxic drugs, targeted biological agents and radiotherapy, and their possible combination with telomerase-directed therapy are discussed. Several potential problems, including side effects and complications inherent to perturbations of telomere biology in normal cells, are also highlighted. In spite of significant progress in this field, there are still several issues that have to be addressed and ultimately resolved in order to obtain a better characterization of the pros and cons of telomerase-directed therapies and, consequently, their clinical relevance.},
}
@article {pmid24975605,
year = {2014},
author = {Crees, Z and Girard, J and Rios, Z and Botting, GM and Harrington, K and Shearrow, C and Wojdyla, L and Stone, AL and Uppada, SB and Devito, JT and Puri, N},
title = {Oligonucleotides and G-quadruplex stabilizers: targeting telomeres and telomerase in cancer therapy.},
journal = {Current pharmaceutical design},
volume = {20},
number = {41},
pages = {6422-6437},
doi = {10.2174/1381612820666140630100702},
pmid = {24975605},
issn = {1873-4286},
mesh = {Animals ; Antineoplastic Agents/*therapeutic use ; G-Quadruplexes/*drug effects ; Humans ; Neoplasms/*drug therapy/*metabolism ; Oligonucleotides/*chemistry ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/chemistry/*metabolism ; },
abstract = {Cancer is a leading cause of death worldwide and an estimated 1 in 4 deaths in the United States is due to cancer. Despite recent advances in cancer treatment, adverse effects related to cancer therapy remain a limiting factor for many patients. The ideal cancer treatment would selectively target cancerous cells while sparing normal, healthy cells to offer maximal therapeutic benefit while minimizing toxicity. Telomeres are structurally unique DNA sequences at the end of human chromosomes, which play an integral role in the cellular mortality of normal cells. As telomeres shorten with successive cellular divisions, cells develop chromosomal instability and undergo either apoptosis or senescence. In many cancers, this apoptosis or senescence is avoided as normal telomere length is maintained by a ribonucleoprotein reverse transcriptase called telomerase. Telomerase is expressed in more than 85% of all cancers and confers cancerous cells with a replicative immortality, which is a hallmark of malignant tumors. In contrast, telomerase activity is not detectable in the majority of normal somatic cell populations. Therefore, the targeting of telomerase and telomere maintenance mechanisms represent a potentially promising therapeutic approach for various types of cancer. This review evaluates the roles of GRN163L, T-oligo and small molecule G-quadruplex stabilizers as potential anticancer therapies by targeting telomerase and other telomere maintenance mechanisms.},
}
@article {pmid24975603,
year = {2014},
author = {Reddel, RR},
title = {Telomere maintenance mechanisms in cancer: clinical implications.},
journal = {Current pharmaceutical design},
volume = {20},
number = {41},
pages = {6361-6374},
pmid = {24975603},
issn = {1873-4286},
mesh = {Animals ; Antineoplastic Agents/*therapeutic use ; Humans ; Neoplasms/*drug therapy/*metabolism ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/*metabolism ; },
abstract = {The presence of immortal cell populations with an up-regulated telomere maintenance mechanism (TMM) is an almost universal characteristic of cancers, whereas normal somatic cells are unable to prevent proliferation-associated telomere shortening and have a limited proliferative potential. TMMs and related aspects of telomere structure and function therefore appear to be ideal targets for the development of anticancer therapeutics. Such treatments would be targeted to a specific cancer-related molecular abnormality, and also be broad-spectrum in that they would be expected to be potentially applicable to most cancers. However, the telomere biology of normal and malignant human cells is a relatively young research field with large numbers of unanswered questions, so the optimal design of TMM-targeted therapeutic approaches remains unclear. This review outlines the opportunities and challenges presented by telomeres and TMMs for clinical management of cancer.},
}
@article {pmid24975602,
year = {2014},
author = {Folini, M},
title = {Targeting telomere maintenance mechanisms in cancer therapy.},
journal = {Current pharmaceutical design},
volume = {20},
number = {41},
pages = {6359-6360},
doi = {10.2174/1381612820666140630101745},
pmid = {24975602},
issn = {1873-4286},
mesh = {Animals ; Antineoplastic Agents/*therapeutic use ; Humans ; Neoplasms/*drug therapy/*metabolism ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/*metabolism ; },
}
@article {pmid24975295,
year = {2014},
author = {Tedone, E and Arosio, B and Gussago, C and Casati, M and Ferri, E and Ogliari, G and Ronchetti, F and Porta, A and Massariello, F and Nicolini, P and Mari, D},
title = {Leukocyte telomere length and prevalence of age-related diseases in semisupercentenarians, centenarians and centenarians' offspring.},
journal = {Experimental gerontology},
volume = {58},
number = {},
pages = {90-95},
doi = {10.1016/j.exger.2014.06.018},
pmid = {24975295},
issn = {1873-6815},
mesh = {Age Factors ; Aged, 80 and over ; Aging/blood/*genetics ; Cardiovascular Diseases/blood/epidemiology/genetics ; Depression/blood/epidemiology/genetics ; Female ; Genetic Markers ; Geriatric Assessment ; Humans ; Italy/epidemiology ; Leukocytes/*metabolism ; Life Expectancy ; Longevity/genetics ; Male ; Pedigree ; Prevalence ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; Telomere Shortening ; },
abstract = {Centenarians and their offspring are increasingly considered a useful model to study and characterize the mechanisms underlying healthy aging and longevity. The aim of this project is to compare the prevalence of age-related diseases and telomere length (TL), a marker of biological age and mortality, across five groups of subjects: semisupercentenarians (SSCENT) (105-109years old), centenarians (CENT) (100-104years old), centenarians' offspring (CO), age- and gender-matched offspring of parents who both died at an age in line with life expectancy (CT) and age- and gender-matched offspring of both non-long-lived parents (NLO). Information was collected on lifestyle, past and current diseases, medical history and medication use. SSCENT displayed a lower prevalence of acute myocardial infarction (p=0.027), angina (p=0.016) and depression (p=0.021) relative to CENT. CO appeared to be healthier compared to CT who, in turn, displayed a lower prevalence of both arrhythmia (p=0.034) and hypertension (p=0.046) than NLO, characterized by the lowest parental longevity. Interestingly, CO and SSCENT exhibited the longest (p<0.001) and the shortest (p<0.001) telomeres respectively while CENT showed no difference in TL compared to the younger CT and NLO. Our results strengthen the hypothesis that the longevity of parents may influence the health status of their offspring. Moreover, our data also suggest that both CENT and their offspring may be characterized by a better TL maintenance which, in turn, may contribute to their longevity and healthy aging. The observation that SSCENT showed considerable shorter telomeres compared to CENT may suggest a progressive impairment of TL maintenance mechanisms over the transition from centenarian to semisupercentenarian age.},
}
@article {pmid24974313,
year = {2015},
author = {Zeljezic, D and Bjelis, M and Mladinic, M},
title = {Evaluation of the mechanism of nucleoplasmic bridge formation due to premature telomere shortening in agricultural workers exposed to mixed pesticides: indication for further studies.},
journal = {Chemosphere},
volume = {120},
number = {},
pages = {45-51},
doi = {10.1016/j.chemosphere.2014.05.085},
pmid = {24974313},
issn = {1879-1298},
mesh = {Age Factors ; Alcohol Drinking ; DNA Damage/*genetics ; Farmers/*statistics &amp; numerical data ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Lymphocytes/drug effects ; Male ; Occupational Exposure/*analysis ; Pesticides/analysis/*toxicity ; Sex Factors ; Smoking ; Telomere/*metabolism ; Telomere Shortening/*drug effects/genetics ; },
abstract = {Agricultural workers are often exposed to high levels of pesticides over prolonged periods of time. We attempted to determine whether exposure to multiple pesticides shortens relative telomere length (RTL) and causes nucleoplasmic bridge (NPB) formation via the mechanism of telomere-end fusion in the lymphocytes of agricultural workers. For measuring RTL, we used quantitative fluorescent in situ hybridization, while NPB frequency was measured as part of the cytome assay. Multivariate analysis of variances taking into account confounding factors (age, gender, years of exposure, smoking, and alcohol intake) did not show a decrease, but rather an increase of RTL in agricultural workers compared to control individuals. In the exposed population, NPB frequency was significantly higher compared to controls (6 times, p<0.05). Multiple regression between NPB, RTL, and confounding factors was not significant. Using Spearman correlation, we did not find proof for our initial hypothesis. Our hypothesis that telomere shortening is a mechanism of NPB origin was not proven, indicating that telomere-end fusion is not a mechanism of NPB formation under our experimental conditions for agricultural workers.},
}
@article {pmid24973280,
year = {2014},
author = {Stanley, SE and Armanios, M},
title = {Short telomeres: a repeat offender in IPF.},
journal = {The Lancet. Respiratory medicine},
volume = {2},
number = {7},
pages = {513-514},
doi = {10.1016/S2213-2600(14)70140-7},
pmid = {24973280},
issn = {2213-2619},
mesh = {DNA/*analysis ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/*genetics/*mortality ; Male ; *Telomere Shortening ; },
}
@article {pmid24970385,
year = {2014},
author = {Grandjenette, C and Schnekenburger, M and Karius, T and Ghelfi, J and Gaigneaux, A and Henry, E and Dicato, M and Diederich, M},
title = {5-aza-2'-deoxycytidine-mediated c-myc Down-regulation triggers telomere-dependent senescence by regulating human telomerase reverse transcriptase in chronic myeloid leukemia.},
journal = {Neoplasia (New York, N.Y.)},
volume = {16},
number = {6},
pages = {511-528},
pmid = {24970385},
issn = {1476-5586},
mesh = {Antimetabolites, Antineoplastic/*pharmacology ; Azacitidine/*analogs &amp; derivatives/pharmacology ; Cell Cycle Proteins/genetics/metabolism ; Cell Line, Tumor ; Cellular Senescence/*genetics ; DNA Damage/drug effects ; Decitabine ; Down-Regulation ; Epigenesis, Genetic ; Gene Expression Regulation, Leukemic/*drug effects ; Humans ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*genetics/metabolism ; Promoter Regions, Genetic ; Protein Binding ; Proto-Oncogene Proteins c-myc/*genetics/metabolism ; Telomerase/*genetics ; Telomere Shortening ; Transcription, Genetic ; },
abstract = {Increased proliferation rates as well as resistance to apoptosis are considered major obstacles for the treatment of patients with chronic myelogenous leukemia (CML), thus highlighting the need for novel therapeutic approaches. Since senescence has been recognized as a physiological barrier against tumorigenesis, senescence-based therapy could represent a new strategy against CML. DNA demethylating agent 5-aza-2'-deoxycytidine (DAC) was reported to induce cellular senescence but underlying mechanisms remain to be elucidated. Here, we report that exposure to DAC triggers senescence in chronic leukemia cell lines as evidenced by increased senescence-associated β-galactosidase activity and lysosomal mass, accompanied by an up-regulation of cell cycle-related genes. We provide evidence that DAC is able to decrease telomere length, to reduce telomerase activity and to decrease human telomerase reverse transcriptase (hTERT) expression through decreased binding of c-myc to the hTERT promoter. Altogether, our results reveal the role of c-myc in telomere-dependent DAC-induced senescence and therefore provide new clues for improving chronic human leukemia treatments.},
}
@article {pmid24969495,
year = {2014},
author = {Naranjo, T},
title = {Dynamics of rye telomeres in a wheat background during early meiosis.},
journal = {Cytogenetic and genome research},
volume = {143},
number = {1-3},
pages = {60-68},
doi = {10.1159/000363524},
pmid = {24969495},
issn = {1424-859X},
mesh = {Chromosome Pairing/genetics ; Chromosomes, Plant/*genetics ; Meiosis/*genetics ; Secale/*genetics ; Telomere/*genetics ; Triticum/*genetics ; },
abstract = {Migration of the telomere of the short arm of rye chromosome 5R (5RS) during bouquet organization is dependent on the conformation that this chromosome adopts in its intact, submetacentric, or truncated, metacentric, form. In order to establish whether the telomere migration dependence on chromosome conformation is a common feature of all rye chromosomes, the behavior of the telomeres of 2 other rye chromosomes, 1R and 6R, with apparent differences in the arm ratio, has been studied at the bouquet stage and compared with that of 5R. The presence of subtelomeric heterochromatic chromomeres in both arms of 1R and 6R, which were visualized by FISH, revealed the position of the adjacent telomeres in the bouquet. While the end of the long arms of both chromosomes was, with some exceptions, always included in the telomere cluster, the end of the short arms failed to migrate to the telomere pole. Disturbed telomere migration was more often observed in the short arm of the submetacentric chromosome 6R than in the short arm of the almost metacentric chromosome 1R. Thus, the chromosomal conformation effect on telomere mobility is a common feature of all rye chromosomes. Incomplete telomere clustering is followed by failure of synapsis and chiasma formation in chromosomes 5R and 6R. Chromosome arm 1RS, which carries the NOR, completes synapsis earlier than 5RS or 6RS, facilitated by the nucleolar fusion that occurs during early zygotene.},
}
@article {pmid24967945,
year = {2014},
author = {Szebeni, A and Szebeni, K and DiPeri, T and Chandley, MJ and Crawford, JD and Stockmeier, CA and Ordway, GA},
title = {Shortened telomere length in white matter oligodendrocytes in major depression: potential role of oxidative stress.},
journal = {The international journal of neuropsychopharmacology},
volume = {17},
number = {10},
pages = {1579-1589},
doi = {10.1017/S1461145714000698},
pmid = {24967945},
issn = {1469-5111},
support = {GM103328/GM/NIGMS NIH HHS/United States ; MH46692/MH/NIMH NIH HHS/United States ; },
mesh = {2',3'-Cyclic Nucleotide 3'-Phosphodiesterase/metabolism ; Adult ; Aged ; Aged, 80 and over ; Catalase/genetics/metabolism ; Depressive Disorder, Major/*genetics/*pathology ; Female ; Gene Expression Regulation/genetics ; Glial Fibrillary Acidic Protein/metabolism ; Glutathione Peroxidase/genetics/metabolism ; Humans ; Laser Capture Microdissection ; Male ; Middle Aged ; Multivariate Analysis ; Oligodendroglia/*metabolism ; *Oxidative Stress ; RNA, Messenger ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; White Matter/*pathology ; Young Adult ; },
abstract = {Telomere shortening is observed in peripheral mononuclear cells from patients with major depressive disorder (MDD). Whether this finding and its biological causes impact the health of the brain in MDD is unknown. Brain cells have differing vulnerabilities to biological mechanisms known to play a role in accelerating telomere shortening. Here, two glia cell populations (oligodendrocytes and astrocytes) known to have different vulnerabilities to a key mediator of telomere shortening, oxidative stress, were studied. The two cell populations were separately collected by laser capture micro-dissection of two white matter regions shown previously to demonstrate pathology in MDD patients. Cells were collected from brain donors with MDD at the time of death and age-matched psychiatrically normal control donors (N = 12 donor pairs). Relative telomere lengths in white matter oligodendrocytes, but not astrocytes, from both brain regions were significantly shorter for MDD donors as compared to matched control donors. Gene expression levels of telomerase reverse transcriptase were significantly lower in white matter oligodendrocytes from MDD as compared to control donors. Likewise, the gene expression of oxidative defence enzymes superoxide dismutases (SOD1 and SOD2), catalase (CAT) and glutathione peroxidase (GPX1) were significantly lower in oligodendrocytes from MDD as compared to control donors. No such gene expression changes were observed in astrocytes from MDD donors. These findings suggest that attenuated oxidative stress defence and deficient telomerase contribute to telomere shortening in oligodendrocytes in MDD, and suggest an aetiological link between telomere shortening and white matter abnormalities previously described in MDD.},
}
@article {pmid24960204,
year = {2014},
author = {Jurk, D and Wilson, C and Passos, JF and Oakley, F and Correia-Melo, C and Greaves, L and Saretzki, G and Fox, C and Lawless, C and Anderson, R and Hewitt, G and Pender, SL and Fullard, N and Nelson, G and Mann, J and van de Sluis, B and Mann, DA and von Zglinicki, T},
title = {Chronic inflammation induces telomere dysfunction and accelerates ageing in mice.},
journal = {Nature communications},
volume = {2},
number = {},
pages = {4172},
pmid = {24960204},
issn = {2041-1723},
support = {MR/K001949/1/MRC_/Medical Research Council/United Kingdom ; BB/I020748/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MK/K001949/1/MRC_/Medical Research Council/United Kingdom ; BB/C008200/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; WT084961MA/WT_/Wellcome Trust/United Kingdom ; NC/K000748/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; BB/F010966/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; G0700890/MRC_/Medical Research Council/United Kingdom ; G0700718/MRC_/Medical Research Council/United Kingdom ; BB/H022384/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MR/L016354/1/MRC_/Medical Research Council/United Kingdom ; G0900535/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aging, Premature/*genetics/immunology ; Animals ; Cellular Senescence/genetics/immunology ; Chronic Disease ; Cyclooxygenase 2/metabolism ; DNA Damage/genetics/immunology ; Feedback, Physiological ; Fibroblasts/immunology/*metabolism ; Inflammation/*genetics/immunology ; Liver Regeneration/*genetics/immunology ; Mice ; Mice, Knockout ; NF-kappa B/genetics/immunology ; NF-kappa B p50 Subunit/*genetics/immunology ; Reactive Oxygen Species/metabolism ; Regeneration/genetics/immunology ; Telomere Homeostasis/*genetics/immunology ; },
abstract = {Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-κB induces premature ageing in mice. We also show that these mice have reduced regeneration in liver and gut. nfkb1(-/-) fibroblasts exhibit aggravated cell senescence because of an enhanced autocrine and paracrine feedback through NF-κB, COX-2 and ROS, which stabilizes DNA damage. Preferential accumulation of telomere-dysfunctional senescent cells in nfkb1(-/-) tissues is blocked by anti-inflammatory or antioxidant treatment of mice, and this rescues tissue regenerative potential. Frequencies of senescent cells in liver and intestinal crypts quantitatively predict mean and maximum lifespan in both short- and long-lived mice cohorts. These data indicate that systemic chronic inflammation can accelerate ageing via ROS-mediated exacerbation of telomere dysfunction and cell senescence in the absence of any other genetic or environmental factor.},
}
@article {pmid24957071,
year = {2014},
author = {Muller, M and Rabelink, TJ},
title = {Telomere shortening: a diagnostic tool and therapeutic target for cardiovascular disease?.},
journal = {European heart journal},
volume = {35},
number = {46},
pages = {3245-3247},
doi = {10.1093/eurheartj/ehu252},
pmid = {24957071},
issn = {1522-9645},
support = {MC_UU_12019/1/MRC_/Medical Research Council/United Kingdom ; MC_UU_12019/2/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Cardiovascular Diseases/*etiology ; Female ; Humans ; Male ; Telomere Shortening/*physiology ; },
}
@article {pmid24957070,
year = {2014},
author = {Masi, S and D'Aiuto, F and Martin-Ruiz, C and Kahn, T and Wong, A and Ghosh, AK and Whincup, P and Kuh, D and Hughes, A and von Zglinicki, T and Hardy, R and Deanfield, JE and , },
title = {Rate of telomere shortening and cardiovascular damage: a longitudinal study in the 1946 British Birth Cohort.},
journal = {European heart journal},
volume = {35},
number = {46},
pages = {3296-3303},
pmid = {24957070},
issn = {1522-9645},
support = {G0601333/MRC_/Medical Research Council/United Kingdom ; MC_UU_12019/1/MRC_/Medical Research Council/United Kingdom ; /BHF_/British Heart Foundation/United Kingdom ; /DH_/Department of Health/United Kingdom ; MC_UU_12019/2/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; },
mesh = {Cardiovascular Diseases/*etiology ; Carotid Artery Diseases/etiology ; Carotid Intima-Media Thickness ; Cellular Senescence/physiology ; Disease Progression ; Female ; Humans ; Leukocytes/physiology ; Longitudinal Studies ; Male ; Middle Aged ; Phenotype ; Risk Factors ; Telomere Shortening/*physiology ; },
abstract = {AIM: Cross-sectional studies reported associations between short leucocyte telomere length (LTL) and measures of vascular and cardiac damage. However, the contribution of LTL dynamics to the age-related process of cardiovascular (CV) remodelling remains unknown. In this study, we explored whether the rate of LTL shortening can predict CV phenotypes over 10-year follow-up and the influence of established CV risk factors on this relationship.<br><br>METHODS AND RESULTS: All the participants from the MRC National Survey of Health and Development (NSHD) with measures of LTL and traditional CV risk factors at 53 and 60-64 years and common carotid intima-media thickness (cIMT), cardiac mass and left ventricular function at 60-64 years were included. LTL was measured by real-time polymerase chain reaction and available at both time points in 1033 individuals. While LTL at 53 years was not linked with any CV phenotype at 60-64 years, a negative association was found between LTL and cIMT at 60-64 years (&#x3b2; = -0.017, P = 0.015). However, the strongest association was found between rate of telomere shortening between 53 and 60-64 years and values of cIMT at 60-64 years (&#x3b2; = -0.020, P = 0.006). This association was not affected by adjustment for traditional CV risk factors. Cardiac measurements were not associated with cross-sectional or longitudinal measures of LTL.<br><br>CONCLUSION: These findings suggest that the rate of progression of cellular ageing in late midlife (reflected by the rate of LTL attrition) relates to vascular damage, independently from contribution of CV risk factor exposure.},
}
@article {pmid24956257,
year = {2014},
author = {Belsky, DW and Shalev, I and Sears, MR and Hancox, RJ and Lee Harrington, H and Houts, R and Moffitt, TE and Sugden, K and Williams, B and Poulton, R and Caspi, A},
title = {Is chronic asthma associated with shorter leukocyte telomere length at midlife?.},
journal = {American journal of respiratory and critical care medicine},
volume = {190},
number = {4},
pages = {384-391},
pmid = {24956257},
issn = {1535-4970},
support = {R01 AG048895/AG/NIA NIH HHS/United States ; MR/K00381X/MRC_/Medical Research Council/United Kingdom ; P30 AG028716/AG/NIA NIH HHS/United States ; R01 AG032282/AG/NIA NIH HHS/United States ; L60 MD007327/MD/NIMHD NIH HHS/United States ; AG032282/AG/NIA NIH HHS/United States ; P30 AG028716-08/AG/NIA NIH HHS/United States ; T32 AG000029/AG/NIA NIH HHS/United States ; MR/K00381X/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aging/*blood/*genetics ; Asthma/*blood/*genetics ; Biomarkers/blood ; C-Reactive Protein/metabolism ; Child ; Child, Preschool ; Chronic Disease ; Cohort Studies ; Female ; Humans ; Leukocyte Count/methods ; Leukocytes/*physiology ; Longitudinal Studies ; Male ; New Zealand ; Telomere Homeostasis/*physiology ; Young Adult ; },
abstract = {RATIONALE: Asthma is prospectively associated with age-related chronic diseases and mortality, suggesting the hypothesis that asthma may relate to a general, multisystem phenotype of accelerated aging.<br><br>OBJECTIVES: To test whether chronic asthma is associated with a proposed biomarker of accelerated aging, leukocyte telomere length.<br><br>METHODS: Asthma was ascertained prospectively in the Dunedin Multidisciplinary Health and Development Study cohort (n = 1,037) at nine in-person assessments spanning ages 9-38 years. Leukocyte telomere length was measured at ages 26 and 38 years. Asthma was classified as life-course-persistent, childhood-onset not meeting criteria for persistence, and adolescent/adult-onset. We tested associations between asthma and leukocyte telomere length using regression models. We tested for confounding of asthma-leukocyte telomere length associations using covariate adjustment. We tested serum C-reactive protein and white blood cell counts as potential mediators of asthma-leukocyte telomere length associations.<br><br>MEASUREMENTS AND MAIN RESULTS: Study members with life-course-persistent asthma had shorter leukocyte telomere length as compared with sex- and age-matched peers with no reported asthma. In contrast, leukocyte telomere length in study members with childhood-onset and adolescent/adult-onset asthma was not different from leukocyte telomere length in peers with no reported asthma. Adjustment for life histories of obesity and smoking did not change results. Study members with life-course-persistent asthma had elevated blood eosinophil counts. Blood eosinophil count mediated 29% of the life-course-persistent asthma-leukocyte telomere length association.<br><br>CONCLUSIONS: Life-course-persistent asthma is related to a proposed biomarker of accelerated aging, possibly via systemic eosinophilic inflammation. Life histories of asthma can inform studies of aging.},
}
@article {pmid24948432,
year = {2014},
author = {Stuart, BD and Lee, JS and Kozlitina, J and Noth, I and Devine, MS and Glazer, CS and Torres, F and Kaza, V and Girod, CE and Jones, KD and Elicker, BM and Ma, SF and Vij, R and Collard, HR and Wolters, PJ and Garcia, CK},
title = {Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis: an observational cohort study with independent validation.},
journal = {The Lancet. Respiratory medicine},
volume = {2},
number = {7},
pages = {557-565},
pmid = {24948432},
issn = {2213-2619},
support = {UL1 TR000430/TR/NCATS NIH HHS/United States ; KL2 TR000143/TR/NCATS NIH HHS/United States ; UL1 TR001105/TR/NCATS NIH HHS/United States ; R01 HL093096/HL/NHLBI NIH HHS/United States ; K12 HD-068369/HD/NICHD NIH HHS/United States ; K12 HD068369/HD/NICHD NIH HHS/United States ; RC1 HL099619/HL/NHLBI NIH HHS/United States ; P01 HL108794/HL/NHLBI NIH HHS/United States ; UL1TR001105/TR/NCATS NIH HHS/United States ; },
mesh = {Adult ; Aged ; Biomarkers ; Chicago/epidemiology ; Cohort Studies ; DNA/*analysis ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/*genetics/*mortality ; Leukocytes ; Male ; Middle Aged ; Risk Assessment ; San Francisco/epidemiology ; Survival Rate ; *Telomere Shortening ; Texas/epidemiology ; },
abstract = {BACKGROUND: Short telomere lengths are found in a subset of patients with idiopathic pulmonary fibrosis, but their clinical significance is unknown. Our aim was to investigate whether patients with various blood leucocyte telomere lengths had different overall survival.<br><br>METHODS: In this observational cohort study, we enrolled patients with interstitial lung disease from Dallas, TX (primary cohort), and from Chicago, IL, and San Francisco, CA (replication cohorts). We obtained genomic DNA samples from unrelated healthy controls in Dallas, TX, and spouses of patients were also enrolled as an independent control group. Telomere lengths were measured in genomic DNA samples isolated from peripheral blood obtained at the time of the initial enrolment assessment. The primary endpoint was transplant-free survival (ie, time to death or lung transplantation) in the Dallas cohort. Findings were validated in the two independent idiopathic pulmonary fibrosis cohorts (Chicago and San Francisco).<br><br>FINDINGS: 370 patients were enrolled into the Dallas cohort between June 17, 2003, and Aug 25, 2011. The 149 patients with idiopathic pulmonary fibrosis had shorter telomere lengths than did the 195 healthy controls (mean age-adjusted log-transformed ratio of telomere to single copy gene was -0.16 [SD 0.23] vs 0.00 [0.18]; p<0.0001); however, telomere lengths of the Dallas patients with idiopathic pulmonary fibrosis (1.33 [SD 0.25]) were similar to the 221 patients with other interstitial lung disease diagnoses (1.46 [0.24]) after adjusting for age, sex, and ethnicity (p=0.47). Telomere length was independently associated with transplant-free survival time for patients with idiopathic pulmonary fibrosis (HR 0.22 [95% CI 0.08-0.63]; p=0.0048), but not for patients with interstitial lung disease diagnoses other than idiopathic pulmonary fibrosis (HR 0.73 [0.16-3.41]; p=0.69). The association between telomere length and survival in patients with idiopathic pulmonary fibrosis was independent of age, sex, forced vital capacity, or diffusing capacity of carbon monoxide, and was replicated in the two independent idiopathic pulmonary fibrosis replication cohorts (Chicago cohort, HR 0.11 [0.03-0.39], p=0.00066; San Francisco cohort, HR 0.25 [0.07-0.87], p=0.029).<br><br>INTERPRETATION: Shorter leucocyte telomere lengths are associated with worse survival in idiopathic pulmonary fibrosis. Additional studies will be needed to establish clinically relevant thresholds for telomere length and how this biomarker might affect risk stratification of patients with idiopathic pulmonary fibrosis.<br><br>FUNDING: US National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, Harroun Family Foundation, and Nina Ireland Lung Disease Program.},
}
@article {pmid24947481,
year = {2014},
author = {Xu, Y and Suzuki, Y and Ishizuka, T and Xiao, CD and Liu, X and Hayashi, T and Komiyama, M},
title = {Finding a human telomere DNA-RNA hybrid G-quadruplex formed by human telomeric 6-mer RNA and 16-mer DNA using click chemistry: a protective structure for telomere end.},
journal = {Bioorganic &amp; medicinal chemistry},
volume = {22},
number = {16},
pages = {4419-4421},
doi = {10.1016/j.bmc.2014.05.053},
pmid = {24947481},
issn = {1464-3391},
mesh = {*Click Chemistry ; DNA/*chemistry ; *G-Quadruplexes ; Humans ; Nucleic Acid Conformation ; RNA/*chemistry ; Telomere/*chemistry ; },
abstract = {Telomeric repeat-containing RNA is a non-coding RNA molecule newly found in mammalian cells. The telomere RNA has been found to localize to the telomere DNA, but how the newly discovered RNA molecule interacts with telomere DNA is less known. In this study, using the click chemistry we successfully found that a 6-mer human telomere RNA and 16-mer human telomere DNA sequence can form a DNA-RNA hybrid type G-quadruplex structure. Detection of the click-reaction products directly probes DNA-RNA G-quadruplex structures in a complicated solution, whereas traditional methods such as NMR and crystallography may not be suitable. Importantly, we found that formation of DNA-RNA G-quadruplex induced an exonuclease resistance for telomere DNA, indicating that such structures might be important for protecting telomeric DNA from enzyme digestion to avoid telomere DNA shortening. These results provide the direct evidence for formation of DNA-RNA hybrid G-quadruplex structure by human telomere DNA and RNA sequence, suggesting DNA-RNA hybrid G-quadruplex structure associated between telomere DNA and RNA may respond to chromosome end protection and/or present a valuable target for drug design.},
}
@article {pmid24945723,
year = {2014},
author = {Bassig, BA and Zhang, L and Cawthon, RM and Smith, MT and Yin, S and Li, G and Hu, W and Shen, M and Rappaport, S and Barone-Adesi, F and Rothman, N and Vermeulen, R and Lan, Q},
title = {Alterations in leukocyte telomere length in workers occupationally exposed to benzene.},
journal = {Environmental and molecular mutagenesis},
volume = {55},
number = {8},
pages = {673-678},
pmid = {24945723},
issn = {1098-2280},
support = {P42 ES004705/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Benzene/*toxicity ; Case-Control Studies ; China ; Female ; Humans ; Leukocytes/*drug effects ; Male ; Occupational Exposure/*adverse effects ; Polymerase Chain Reaction/methods ; Telomere/*drug effects ; },
abstract = {Exposure to benzene, a known leukemogen and probable lymphomagen, has been demonstrated to result in oxidative stress, which has previously been associated with altered telomere length (TL). TL specifically has been associated with several health outcomes in epidemiologic studies, including cancer risk, and has been demonstrated to be altered following exposure to a variety of chemical agents. To evaluate the association between benzene exposure and TL, we measured TL by monochrome multiplex quantitative PCR in 43 workers exposed to high levels of benzene and 43 age and sex-matched unexposed workers in Shanghai, China. Benzene exposure levels were monitored using organic vapor passive dosimetry badges before phlebotomy. The median benzene exposure level in exposed workers was 31 ppm. The mean TL in controls, workers exposed to levels of benzene below the median (≤31 ppm), and above the median (>31 ppm) was 1.26 ± 0.17, 1.25 ± 0.16, and 1.37 ± 0.23, respectively. Mean TL was significantly elevated in workers exposed to >31 ppm of benzene compared with controls (P = 0.03). Our findings provide evidence that high levels of occupational benzene exposure are associated with TL. Environ.},
}
@article {pmid24936455,
year = {2014},
author = {De Bonis, ML and Ortega, S and Blasco, MA},
title = {SIRT1 is necessary for proficient telomere elongation and genomic stability of induced pluripotent stem cells.},
journal = {Stem cell reports},
volume = {2},
number = {5},
pages = {690-706},
pmid = {24936455},
issn = {2213-6711},
support = {232854/ERC_/European Research Council/International ; },
mesh = {Animals ; Cell Differentiation ; Cell Line ; Cell Proliferation ; Cellular Reprogramming ; Chromatin Assembly and Disassembly ; Epithelial-Mesenchymal Transition ; *Genomic Instability ; HEK293 Cells ; Homeodomain Proteins/genetics/metabolism ; Humans ; Immunohistochemistry ; Induced Pluripotent Stem Cells/cytology/*metabolism/transplantation ; Linear Models ; Metaphase ; Mice ; Mice, Nude ; Proto-Oncogene Proteins c-myc/genetics/metabolism ; Sirtuin 1/genetics/*metabolism ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {The NAD-dependent deacetylase SIRT1 is involved in chromatin silencing and genome stability. Elevated SIRT1 levels in embryonic stem cells also suggest a role for SIRT1 in pluripotency. Murine SIRT1 attenuates telomere attrition in vivo and is recruited at telomeres in induced pluripotent stem cells (iPSCs). Because telomere elongation is an iPSC hallmark, we set out to study the role of SIRT1 in pluripotency in the setting of murine embryonic fibroblasts reprogramming into iPSCs. We find that SIRT1 is required for efficient postreprogramming telomere elongation, and that this effect is mediated by a c-MYC-dependent regulation of the mTert gene. We further demonstrate that SIRT1-deficient iPSCs accumulate chromosomal aberrations and show a derepression of telomeric heterochromatin. Finally, SIRT1-deficient iPSCs form larger teratomas that are poorly differentiated, highlighting a role for SIRT1 in exit from pluripotency. In summary, this work demonstrates a role for SIRT1 in the maintenance of pluripotency and modulation of differentiation.},
}
@article {pmid24936002,
year = {2014},
author = {Drury, SS and Mabile, E and Brett, ZH and Esteves, K and Jones, E and Shirtcliff, EA and Theall, KP},
title = {The association of telomere length with family violence and disruption.},
journal = {Pediatrics},
volume = {134},
number = {1},
pages = {e128-37},
pmid = {24936002},
issn = {1098-4275},
support = {R01 ES020447/ES/NIEHS NIH HHS/United States ; K12 HD043451/HD/NICHD NIH HHS/United States ; K12HD043451/HD/NICHD NIH HHS/United States ; 2K12HD043451-06/HD/NICHD NIH HHS/United States ; R01 MH101533/MH/NIMH NIH HHS/United States ; 1R01ES020447-01/ES/NIEHS NIH HHS/United States ; R21 MH094688-01/MH/NIMH NIH HHS/United States ; R21 MH094688/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Child ; Child, Preschool ; *Domestic Violence ; *Family Conflict ; Female ; Humans ; Male ; Sex Factors ; *Telomere ; },
abstract = {BACKGROUND: To enhance the understanding of biological mechanisms connecting early adversity and negative health, we examine the association between family interpersonal violence and disruption and telomere length in youth. These specific exposures were selected because of their established links with negative health consequences across the life-course.<br><br>METHODS: Children, age 5 to 15, were recruited from the greater New Orleans area, and exposure to family disruption and violence was assessed through caregiver report. Telomere length, from buccal cell DNA (buccal telomere length [bTL]), was determined by using monochrome multiplex quantitative real-time polymerase chain reaction. The association between bTL and adversity exposure was tested (n = 80).<br><br>RESULTS: Cumulative exposure to interpersonal violence and family disruption was correlated with bTL. Controlling for other sociodemographic factors, bTL was significantly shorter in children with higher exposure to family violence and disruption. Witnessing family violence exerted a particularly potent impact. A significant gender interaction was found (&#x3b2; = -0.0086, SE = 0.0031, z test= -2.79, P = .0053) and analysis revealed the effect only in girls.<br><br>CONCLUSIONS: bTL is a molecular biomarker of adversity and allostatic load that is detectable in childhood. The present results extend previous studies by demonstrating that telomeres are sensitive to adversity within the overarching family domain. These findings suggest that the family ecology may be an important target for interventions to reduce the biological impact of adversity in the lives of children.},
}
@article {pmid24927411,
year = {2014},
author = {Wang, N and Rizvydeen, S and Vahedi, M and Vargas Gonzalez, DM and Allred, AL and Perry, DW and Mirabito, PM and Kirk, KE},
title = {Novel telomere-anchored PCR approach for studying sexual stage telomeres in Aspergillus nidulans.},
journal = {PloS one},
volume = {9},
number = {6},
pages = {e99491},
pmid = {24927411},
issn = {1932-6203},
mesh = {Aspergillus nidulans/genetics/*physiology ; Chromosomes, Fungal/genetics ; Fungal Proteins/genetics ; Gene Knockdown Techniques ; Meiosis ; Polymerase Chain Reaction/*methods ; Telomerase/*genetics ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Telomere length varies between germline and somatic cells of the same organism, leading to the hypothesis that telomeres are lengthened during meiosis. However, little is known about the meiotic telomere length in many organisms. In the filamentous fungus Aspergillus nidulans, the telomere lengths in hyphae and asexual spores are invariant. No study using existing techniques has determined the telomere length of the sexual ascospores due to the relatively low abundance of pure meiotic cells in A. nidulans and the small quantity of DNA present. To address this, we developed a simple and sensitive PCR strategy to measure the telomere length of A. nidulans meiotic cells. This novel technique, termed "telomere-anchored PCR," measures the length of the telomere on chromosome II-L using a small fraction of the DNA required for the traditional terminal restriction fragment (TRF) Southern analysis. Using this approach, we determined that the A. nidulans ascospore telomere length is virtually identical to telomeres of other cell types from this organism, approximately 110 bp, indicating that a surprisingly strict telomere length regulation exists in the major cell types of A. nidulans. When the hyphal telomeres were measured in a telomerase reverse transcriptase (TERT) knockout strain, small decreases in length were readily detected. Thus, this technique can detect telomeres in relatively rare cell types and is particularly sensitive in measuring exceptionally short telomeres. This rapid and inexpensive telomere-anchored PCR method potentially can be utilized in other filamentous fungi and types of organisms.},
}
@article {pmid24925640,
year = {2015},
author = {Tahara, T and Shibata, T and Okubo, M and Kawamura, T and Sumi, K and Ishizuka, T and Nakamura, M and Nagasaka, M and Nakagawa, Y and Ohmiya, N and Arisawa, T and Hirata, I},
title = {Telomere length in non-neoplastic colonic mucosa in ulcerative colitis (UC) and its relationship to the severe clinical phenotypes.},
journal = {Clinical and experimental medicine},
volume = {15},
number = {3},
pages = {327-332},
pmid = {24925640},
issn = {1591-9528},
mesh = {Adult ; Biopsy ; Colitis, Ulcerative/*pathology ; Colon/*pathology ; Colonoscopy ; Female ; Humans ; Intestinal Mucosa/*pathology ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Telomere/*genetics ; },
abstract = {Telomere shortening occurs with human aging in many organs and tissues and is accelerated by rapid cell turnover and oxidative injury. To clarify the clinical importance of telomere shortening in colonic mucosa in ulcerative colitis (UC), we measured average telomere length using quantitative real-time PCR in non-neoplastic colonic mucosa in UC patients and assessed its relationship to various clinical subtypes. Relative telomere length in genomic DNA was measured in colonic biopsies obtained from rectal inflammatory mucosa from 86 UC patients as well as paired non-inflammatory proximal colonic mucosae from 10 patients. Data were correlated with various clinical phenotypes. In paired samples, average relative telomere length of rectal inflammatory mucosa was shortened compared to normal appearing proximal colon in eight out of ten cases (p = 0.01). Telomere length shortening was significantly associated with more severe Mayo endoscopic subscore (p < 0.0001) and cases needing surgery due to toxic megacolon or cancer occurrence (p = 0.043). When the severe clinical phenotype was defined as having at least one of following phenotypes, more than two times of hospitalization, highest Mayo endoscopic subscore, steroid dependent, refractory, or needing operation, average relative telomere length was significantly shortened in the same phenotypes than the others (p = 0.003). Telomere shortening is associated with more severe clinical phenotypes of UC, reflecting severe inflammatory state in the colonic mucosa.},
}
@article {pmid24925530,
year = {2014},
author = {Garg, M and Gurung, RL and Mansoubi, S and Ahmed, JO and Davé, A and Watts, FZ and Bianchi, A},
title = {Tpz1TPP1 SUMOylation reveals evolutionary conservation of SUMO-dependent Stn1 telomere association.},
journal = {EMBO reports},
volume = {15},
number = {8},
pages = {871-877},
pmid = {24925530},
issn = {1469-3178},
support = {11978/CRUK_/Cancer Research UK/United Kingdom ; 12720/CRUK_/Cancer Research UK/United Kingdom ; G0701428/MRC_/Medical Research Council/United Kingdom ; C28567/A12720/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Amino Acid Sequence ; Carrier Proteins/chemistry/*metabolism ; DNA-Binding Proteins ; Evolution, Molecular ; Molecular Sequence Data ; Protein Binding ; SUMO-1 Protein/metabolism ; Schizosaccharomyces/cytology/*metabolism ; Schizosaccharomyces pombe Proteins/chemistry/*metabolism ; *Shelterin Complex ; *Sumoylation ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Elongation of the telomeric overhang by telomerase is counteracted by synthesis of the complementary strand by the CST complex, CTC1(Cdc13)/Stn1/Ten1. Interaction of budding yeast Stn1 with overhang-binding Cdc13 is increased by Cdc13 SUMOylation. Human and fission yeast CST instead interact with overhang-binding TPP1/POT1. We show that the fission yeast TPP1 ortholog, Tpz1, is SUMOylated. Tpz1 SUMOylation restricts telomere elongation and promotes Stn1/Ten1 telomere association, and a SUMO-Tpz1 fusion protein has increased affinity for Stn1. Our data suggest that SUMO inhibits telomerase through stimulation of Stn1/Ten1 action by Tpz1, highlighting the evolutionary conservation of the regulation of CST function by SUMOylation.},
}
@article {pmid24920220,
year = {2014},
author = {García-Beccaria, M and Martínez, P and Flores, JM and Blasco, MA},
title = {In vivo role of checkpoint kinase 2 in signaling telomere dysfunction.},
journal = {Aging cell},
volume = {13},
number = {5},
pages = {810-816},
pmid = {24920220},
issn = {1474-9726},
support = {232854/ERC_/European Research Council/International ; },
mesh = {Aging/*physiology ; Animals ; Cell Proliferation ; Checkpoint Kinase 2/*metabolism ; DNA Damage ; Mice ; Mice, Knockout ; Models, Animal ; Signal Transduction ; Telomere/*metabolism ; },
abstract = {Checkpoint kinase 2 (CHK2) is a downstream effector of the DNA damage response (DDR). Dysfunctional telomeres, either owing to critical shortening or disruption of the shelterin complex, activate a DDR, which eventually results in cell cycle arrest, senescence and/or apoptosis. Successive generations of telomerase-deficient (Terc) mice show accelerated aging and shorter lifespan due to tissue atrophy and impaired organ regeneration associated to progressive telomere shortening. In contrast, mice deficient for the shelterin component TRF1 in stratified epithelia show a rapid and massive induction of DDR, leading to perinatal lethality and severe skin defects. In both mouse models, p53 deficiency can rescue survival. Here, we set to address the role of CHK2 in signaling telomere dysfunction in both mouse models. To this end, we generated mice doubly deficient for Chk2 and either Terc (Chk2(-/-) Terc(-/-)) or Trf1 (Trf1(Δ/Δ) K5Cre Chk2(-/-)). We show that Chk2 deletion improves Terc-associated phenotypes, including lifespan and age-associated pathologies. Similarly, Chk2 deficiency partially rescues perinatal mortality and attenuates degenerative pathologies of Trf1(Δ/Δ) K5Cre mice. In both cases, we show that the effects are mediated by a significant attenuation of p53/p21 signaling pathway. Our results represent the first demonstration of a role for CHK2 in the in vivo signaling of dysfunctional telomeres.},
}
@article {pmid24919187,
year = {2014},
author = {Buxton, JL and Das, S and Rodriguez, A and Kaakinen, M and Couto Alves, A and Sebert, S and Millwood, IY and Laitinen, J and O'Reilly, PF and Jarvelin, MR and Blakemore, AI},
title = {Multiple measures of adiposity are associated with mean leukocyte telomere length in the northern Finland birth cohort 1966.},
journal = {PloS one},
volume = {9},
number = {6},
pages = {e99133},
pmid = {24919187},
issn = {1932-6203},
support = {R01 MH063706/MH/NIMH NIH HHS/United States ; R01 HL087679/HL/NHLBI NIH HHS/United States ; GR069224/WT_/Wellcome Trust/United Kingdom ; WT088431MA/WT_/Wellcome Trust/United Kingdom ; HEALTH-F4-2007-201413//PHS HHS/United States ; G0500539/MRC_/Medical Research Council/United Kingdom ; MR/K014536/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; G0600705/MRC_/Medical Research Council/United Kingdom ; 5R01MH63706/MH/NIMH NIH HHS/United States ; 1RL1MH083268-01/MH/NIMH NIH HHS/United States ; 5R01HL087679-02/HL/NHLBI NIH HHS/United States ; RL1 MH083268/MH/NIMH NIH HHS/United States ; },
mesh = {Adiposity/*genetics ; Adolescent ; Body Mass Index ; Child ; Child, Preschool ; Cohort Studies ; Finland ; Humans ; Infant ; Leukocytes/*ultrastructure ; Middle Aged ; *Telomere ; },
abstract = {Studies of leukocyte telomere length (LTL) and adiposity have produced conflicting results, and the relationship between body mass index (BMI) and telomere length throughout life remains unclear. We therefore tested association of adult LTL measured in 5,598 participants with: i) childhood growth measures (BMI and age at adiposity rebound (AR)); ii) change in BMI from childhood to adulthood and iii) adult BMI, waist-to-hip ratio (WHR), body adiposity index (BAI). Childhood BMI at AR was positively associated with LTL at 31 years in women (P = 0.041). Adult BMI and WHR in both men (P = 0.025 and P = 0.049, respectively) and women (P = 0.029 and P = 0.008, respectively), and BAI in women (P = 0.021) were inversely associated with LTL at 31 years. An increase in standardised BMI between early childhood and adulthood was associated with shorter adult LTL in women (P = 0.008). We show that LTL is inversely associated with multiple measures of adiposity in both men and women. Additionally, BMI increase in women from childhood to adulthood is associated with shorter telomeres at age 31, potentially indicating accelerated biological ageing.},
}
@article {pmid24918337,
year = {2014},
author = {Hopfner, KP},
title = {Single-molecule choreography between telomere proteins and G quadruplexes.},
journal = {Structure (London, England : 1993)},
volume = {22},
number = {6},
pages = {801-802},
doi = {10.1016/j.str.2014.05.011},
pmid = {24918337},
issn = {1878-4186},
mesh = {Humans ; Telomerase/*metabolism ; Telomere/*chemistry/*metabolism ; },
abstract = {Telomeric DNA binds proteins to protect chromosome ends, but it also adopts G quadruplex (GQ) structures. Two new studies by Hwang and colleagues (in this issue of Structure) and Ray and colleagues (published elsewhere) use single molecule imaging to reveal how GQs affect the binding of different telomere associated proteins. The data suggest that GQs play important roles in regulating accessibility of telomeres.},
}
@article {pmid24917814,
year = {2014},
author = {Chen, H and Liu, X and Zhu, W and Chen, H and Hu, X and Jiang, Z and Xu, Y and Wang, L and Zhou, Y and Chen, P and Zhang, N and Hu, D and Zhang, L and Wang, Y and Xu, Q and Wu, R and Yu, H and Wang, J},
title = {SIRT1 ameliorates age-related senescence of mesenchymal stem cells via modulating telomere shelterin.},
journal = {Frontiers in aging neuroscience},
volume = {6},
number = {},
pages = {103},
pmid = {24917814},
issn = {1663-4365},
abstract = {Mesenchymal stem cells (MSCs) senescence is an age-related process that impairs the capacity for tissue repair and compromises the clinical use of autologous MSCs for tissue regeneration. Here, we describe the effects of SIRT1, a NAD(+)-dependent deacetylase, on age-related MSCs senescence. Knockdown of SIRT1 in young MSCs induced cellular senescence and inhibited cell proliferation whereas overexpression of SIRT1 in aged MSCs reversed the senescence phenotype and stimulated cell proliferation. These results suggest that SIRT1 plays a key role in modulating age-induced MSCs senescence. Aging-related proteins, P16 and P21 may be downstream effectors of the SIRT1-mediated anti-aging effects. SIRT1 protected MSCs from age-related DNA damage, induced telomerase reverse transcriptase (TERT) expression and enhanced telomerase activity but did not affect telomere length. SIRT1 positively regulated the expression of tripeptidyl peptidase 1 (TPP1), a component of the shelterin pathway that protects chromosome ends from DNA damage. Together, the results demonstrate that SIRT1 quenches age-related MSCs senescence by mechanisms that include enhanced TPP1 expression, increased telomerase activity and reduced DNA damage.},
}
@article {pmid24914478,
year = {2014},
author = {Malyavko, AN and Parfenova, YY and Zvereva, MI and Dontsova, OA},
title = {Telomere length regulation in budding yeasts.},
journal = {FEBS letters},
volume = {588},
number = {15},
pages = {2530-2536},
doi = {10.1016/j.febslet.2014.05.049},
pmid = {24914478},
issn = {1873-3468},
mesh = {Chromosomes, Fungal/genetics ; Saccharomyces cerevisiae/*genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {Telomeres are the nucleoprotein caps of chromosomes. Their length must be tightly regulated in order to maintain the stability of the genome. This is achieved by the intricate network of interactions between different proteins and protein-RNA complexes. Different organisms use various mechanisms for telomere length homeostasis. However, details of these mechanisms are not yet completely understood. In this review we have summarized our latest achievements in the understanding of telomere length regulation in budding yeasts.},
}
@article {pmid24914236,
year = {2014},
author = {Sau, S and Conrad, MN and Lee, CY and Kaback, DB and Dresser, ME and Jayaram, M},
title = {A selfish DNA element engages a meiosis-specific motor and telomeres for germ-line propagation.},
journal = {The Journal of cell biology},
volume = {205},
number = {5},
pages = {643-661},
pmid = {24914236},
issn = {1540-8140},
mesh = {Cell Cycle Proteins/genetics ; Chromosome Segregation ; Chromosomes, Fungal/genetics ; Cytoskeletal Proteins/genetics ; DNA, Fungal/*genetics ; *Gene Expression Regulation, Fungal ; Genes, Reporter ; Green Fluorescent Proteins/metabolism ; Kinetochores ; *Meiosis ; Membrane Proteins/genetics ; Mitosis ; Nuclear Proteins/genetics ; Plasmids/metabolism ; Prophase ; Repetitive Sequences, Nucleic Acid/*genetics ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/genetics ; Shelterin Complex ; Spindle Apparatus/genetics ; Telomere/*ultrastructure ; Telomere-Binding Proteins/genetics ; Transcription Factors/genetics ; },
abstract = {The chromosome-like mitotic stability of the yeast 2 micron plasmid is conferred by the plasmid proteins Rep1-Rep2 and the cis-acting locus STB, likely by promoting plasmid-chromosome association and segregation by hitchhiking. Our analysis reveals that stable plasmid segregation during meiosis requires the bouquet proteins Ndj1 and Csm4. Plasmid relocalization from the nuclear interior in mitotic cells to the periphery at or proximal to telomeres rises from early meiosis to pachytene. Analogous to chromosomes, the plasmid undergoes Csm4- and Ndj1-dependent rapid prophase movements with speeds comparable to those of telomeres. Lack of Ndj1 partially disrupts plasmid-telomere association without affecting plasmid colocalization with the telomere-binding protein Rap1. The plasmid appears to engage a meiosis-specific motor that orchestrates telomere-led chromosome movements for its telomere-associated segregation during meiosis I. This hitherto uncharacterized mode of germ-line transmission by a selfish genetic element signifies a mechanistic variation within the shared theme of chromosome-coupled plasmid segregation during mitosis and meiosis.},
}
@article {pmid24913665,
year = {2014},
author = {Ye, J and Renault, VM and Jamet, K and Gilson, E},
title = {Transcriptional outcome of telomere signalling.},
journal = {Nature reviews. Genetics},
volume = {15},
number = {7},
pages = {491-503},
pmid = {24913665},
issn = {1471-0064},
mesh = {Apoptosis ; Cellular Senescence ; DNA Damage ; *DNA Repair ; Gene Expression Regulation ; Humans ; RNA, Long Noncoding/genetics/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Shelterin Complex ; Signal Transduction/*genetics ; Telomerase/genetics/metabolism ; Telomere/*chemistry/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Transcription Factors/genetics/metabolism ; *Transcription, Genetic ; },
abstract = {Telomeres protect chromosome ends from degradation and inappropriate DNA damage response activation through their association with specific factors. Interestingly, these telomeric factors are able to localize outside telomeric regions, where they can regulate the transcription of genes involved in metabolism, immunity and differentiation. These findings delineate a signalling pathway by which telomeric changes control the ability of their associated factors to regulate transcription. This mechanism is expected to enable a greater diversity of cellular responses that are adapted to specific cell types and telomeric changes, and may therefore represent a pivotal aspect of development, ageing and telomere-mediated diseases.},
}
@article {pmid24913239,
year = {2014},
author = {Formichi, C and Cantara, S and Ciuoli, C and Neri, O and Chiofalo, F and Selmi, F and Tirone, A and Colasanto, G and Di Cosmo, L and Vuolo, G and Pacini, F},
title = {Weight loss associated with bariatric surgery does not restore short telomere length of severe obese patients after 1 year.},
journal = {Obesity surgery},
volume = {24},
number = {12},
pages = {2089-2093},
pmid = {24913239},
issn = {1708-0428},
mesh = {Adult ; Bariatric Surgery ; Case-Control Studies ; Female ; Humans ; Male ; Metabolic Syndrome/genetics ; Middle Aged ; Obesity, Morbid/genetics/*surgery ; Telomere/*physiology ; Telomere Shortening/*physiology ; *Weight Loss ; },
abstract = {BACKGROUND: Telomere shortening is physiologically associated with ageing but it may be influenced by oxidative stress and chronic inflammation, linked to obesity. Thus, obesity might represent an additional cause of telomere attrition. We aim to study relative telomere length (RTL) in obese subjects with and without metabolic syndrome and to assess the effect of weight loss induced by bariatric surgery.<br><br>METHODS: We evaluated RTL in 107 obese subjects (62 with metabolic syndrome and 45 without metabolic syndrome), compared to 130 age-matched non-obese subjects. We also measured RTL in a subgroup of 93 obese patients prior to and 3, 6, 9 and 12 months after surgery.<br><br>RESULTS: RTL of obese subjects was significantly shorter (p<0.0001) than non-obese subjects but without differences between patients with and without metabolic syndrome (p=0.19). RTL was significantly shorter than baseline at 3, 6, 9 and 12 months after bariatric surgery.<br><br>CONCLUSIONS: These results confirm that obese subjects have shorter telomeres compared to non-obese subjects, but RTL is not influenced by the presence of metabolic syndrome. RTL shows an additional attrition during the immediate post-operative period, probably due to a catabolic state.},
}
@article {pmid24910283,
year = {2014},
author = {Babizhayev, MA and Kasus-Jacobi, A and Vishnyakova, KS and Yegorov, YE},
title = {Novel neuroendocrine and metabolic mechanism provides the patented platform for important rejuvenation therapies: targeted therapy of telomere attrition and lifestyle changes of telomerase activity with the timing of neuron-specific imidazole-containing dipeptide-dominant pharmaconutrition provision.},
journal = {Recent patents on endocrine, metabolic &amp; immune drug discovery},
volume = {8},
number = {3},
pages = {153-179},
doi = {10.2174/1872214808666140608145810},
pmid = {24910283},
issn = {2212-3334},
mesh = {Aging/drug effects ; Carnosine/analogs &amp; derivatives/pharmacology/therapeutic use ; Dipeptides/*pharmacology/therapeutic use ; Humans ; Imidazoles/*pharmacology/therapeutic use ; *Life Style ; Molecular Targeted Therapy/*methods ; *Patents as Topic ; *Rejuvenation ; Telomere Homeostasis/*drug effects ; Telomere Shortening/*drug effects ; },
abstract = {Telomere length is emerging as a biomarker for aging and survival is paternally inherited and associated with parental lifespan. Telomere-associated cellular senescence may contribute to certain age-related disorders, including an increase in cancer incidence, wrinkling and diminished skin elasticity, atherosclerosis, osteoporosis, weight loss, age-related cataract, glaucoma and others. Shorter telomere length in leukocytes was associated cross-sectionally with cardiovascular disorders and its risk factors, including pulse pressure and vascular aging, obesity, vascular dementia, diabetes, coronary artery disease, myocardial infarction (although not in all studies), cellular turnover and exposure to oxidative and inflammatory damage in chronic obstructive pulmonary disease. Effective regulation of abnormal therapeutic targets of an age-related disease requires the alteration of either the topological structure or dynamic characteristics of telomeres which are DNA-protein structures at the ends of eukaryotic chromosomes, the DNA of which comprise noncoding repeats of guanine-rich sequences. Telomeric DNA plays a fundamental role in protecting the cell from recombination and degradation, including those as the metabolic super-achievers in the body, organ systems in a given target network of a disease and aging. In order to manage and control the complex direct and indirect target hubs, in this paper, a review of the recent patents is made analyzing techniques, new approaches developed during the last years in adaptive pharmacology directed at slowing and preventing the loss of telomere length that may slow aging using pharmaceutical and nutritional module-based designs, such as with regard to the timing of administration of imidazole-containing dipeptides. We discuss our recent identification of the role of neuron-specific imidazole- containing dipeptide based compounds (L-carnosine, N-acetylcarnosine, carcinine) that regulate and therapeutically control telomere shortening, telomerase activity and cellular senescence. We support a therapeutic concept of using nonhydrolyzed forms of naturally occurring imidazole-dipeptide based compounds carnosine and carcinine, making it clinically possible that slowing down the rate of telomere shortening could slow down the human aging process in specific tissues where proliferative senescence is known to occur with the demonstrated evidence of telomere shortening appeared to be a hallmark of oxidative stress and disease. The preliminary longitudinal studies of elderly individuals suggest that longer telomeres are associated with better survival and an advanced oral pharmaconutrition provision with non-hydrolyzed carnosine (or carcinine and patented compositions thereof) is a useful therapeutic tool of a critical telomere length maintenance (allowing indirectly to manipulate with telomerase activity) that may fundamentally be applied in the therapeutic treatment of agerelated sight-threatening eye disorders, Diabetes mellitus, sarcopenia (that is the gradual loss of muscle mass) that can affect elderly people and subjects under the effect of exhausting exercises and physical load, prolong life expectancy, increase survival and chronological age of an organism in health control, smoking behavior, metabolic syndrome increasing the risk of developing cardio-vascular diseases, age-related neurodegenerative diseases, including Alzheimer's disease and cognitive impairment.},
}
@article {pmid24908248,
year = {2014},
author = {Walsh, KM and Codd, V and Smirnov, IV and Rice, T and Decker, PA and Hansen, HM and Kollmeyer, T and Kosel, ML and Molinaro, AM and McCoy, LS and Bracci, PM and Cabriga, BS and Pekmezci, M and Zheng, S and Wiemels, JL and Pico, AR and Tihan, T and Berger, MS and Chang, SM and Prados, MD and Lachance, DH and O'Neill, BP and Sicotte, H and Eckel-Passow, JE and , and van der Harst, P and Wiencke, JK and Samani, NJ and Jenkins, RB and Wrensch, MR},
title = {Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk.},
journal = {Nature genetics},
volume = {46},
number = {7},
pages = {731-735},
pmid = {24908248},
issn = {1546-1718},
support = {R01 CA139020/CA/NCI NIH HHS/United States ; R01CA126831/CA/NCI NIH HHS/United States ; U58DP003862-01/DP/NCCDPHP CDC HHS/United States ; HHSN261201000140C/CA/NCI NIH HHS/United States ; P50 CA108961/CA/NCI NIH HHS/United States ; HHSN261201000035C/CA/NCI NIH HHS/United States ; RC1NS068222Z/NS/NINDS NIH HHS/United States ; R25 CA112355/CA/NCI NIH HHS/United States ; R01 CA126831/CA/NCI NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; P50 CA097257/CA/NCI NIH HHS/United States ; UL1RR024131/RR/NCRR NIH HHS/United States ; P30CA15083/CA/NCI NIH HHS/United States ; UL1 TR000004/TR/NCATS NIH HHS/United States ; R01 CA052689/CA/NCI NIH HHS/United States ; /BHF_/British Heart Foundation/United Kingdom ; RC1 NS068222/NS/NINDS NIH HHS/United States ; R25CA112355/CA/NCI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; HHSN261201000035I/CA/NCI NIH HHS/United States ; P50CA097257/CA/NCI NIH HHS/United States ; HHSN261201000034C/CA/NCI NIH HHS/United States ; P50CA108961/CA/NCI NIH HHS/United States ; R01CA139020/CA/NCI NIH HHS/United States ; R01CA52689/CA/NCI NIH HHS/United States ; U58 DP003862/DP/NCCDPHP CDC HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; },
mesh = {Adult ; Case-Control Studies ; Genome-Wide Association Study ; Genotype ; Glioma/*genetics/pathology ; Humans ; Leukocytes/metabolism/pathology ; Neoplasm Grading ; Polymorphism, Single Nucleotide/*genetics ; Prognosis ; RNA/*genetics ; Risk Factors ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {Glioma, the most common central nervous system cancer in adults, has poor prognosis. Here we identify a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10(-9)) in a meta-analysis of genome-wide association studies (GWAS) of high-grade glioma and replication data (1,644 cases and 7,736 controls). This region has previously been associated with mean leukocyte telomere length (LTL). We therefore examined the relationship between LTL and both this new risk locus and other previously established risk loci for glioma using data from a recent GWAS of LTL (n = 37,684 individuals). Alleles associated with glioma risk near TERC and TERT were strongly associated with longer LTL (P = 5.5 × 10(-20) and 4.4 × 10(-19), respectively). In contrast, risk-associated alleles near RTEL1 were inconsistently associated with LTL, suggesting the presence of distinct causal alleles. No other risk loci for glioma were associated with LTL. The identification of risk alleles for glioma near TERC and TERT that also associate with telomere length implicates telomerase in gliomagenesis.},
}
@article {pmid24906415,
year = {2014},
author = {Hawkins, C and Friedman, KL},
title = {Normal telomere length maintenance in Saccharomyces cerevisiae requires nuclear import of the ever shorter telomeres 1 (Est1) protein via the importin alpha pathway.},
journal = {Eukaryotic cell},
volume = {13},
number = {8},
pages = {1036-1050},
pmid = {24906415},
issn = {1535-9786},
support = {R01 GM080393/GM/NIGMS NIH HHS/United States ; R25 GM062459/GM/NIGMS NIH HHS/United States ; T32 GM008554/GM/NIGMS NIH HHS/United States ; R01-GM080393-01A1/GM/NIGMS NIH HHS/United States ; 1F31CA154124-01A1/CA/NCI NIH HHS/United States ; F31 CA154124/CA/NCI NIH HHS/United States ; },
mesh = {Active Transport, Cell Nucleus ; Amino Acid Sequence ; Cell Nucleus/*metabolism ; Molecular Sequence Data ; Nuclear Localization Signals ; Nucleocytoplasmic Transport Proteins/metabolism ; RNA-Binding Proteins/metabolism ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; Telomerase/chemistry/*metabolism ; *Telomere Homeostasis ; beta Karyopherins/metabolism ; },
abstract = {The Est1 (ever shorter telomeres 1) protein is an essential component of yeast telomerase, a ribonucleoprotein complex that restores the repetitive sequences at chromosome ends (telomeres) that would otherwise be lost during DNA replication. Previous work has shown that the telomerase RNA component (TLC1) transits through the cytoplasm during telomerase biogenesis, but mechanisms of protein import have not been addressed. Here we identify three nuclear localization sequences (NLSs) in Est1p. Mutation of the most N-terminal NLS in the context of full-length Est1p reduces Est1p nuclear localization and causes telomere shortening-phenotypes that are rescued by fusion with the NLS from the simian virus 40 (SV40) large-T antigen. In contrast to that of the TLC1 RNA, Est1p nuclear import is facilitated by Srp1p, the yeast homolog of importin α. The reduction in telomere length observed at the semipermissive temperature in a srp1 mutant strain is rescued by increased Est1p expression, consistent with a defect in Est1p nuclear import. These studies suggest that at least two nuclear import pathways are required to achieve normal telomere length homeostasis in yeast.},
}
@article {pmid24906368,
year = {2014},
author = {Rode, L and Bojesen, SE and Weischer, M and Nordestgaard, BG},
title = {High tobacco consumption is causally associated with increased all-cause mortality in a general population sample of 55,568 individuals, but not with short telomeres: a Mendelian randomization study.},
journal = {International journal of epidemiology},
volume = {43},
number = {5},
pages = {1473-1483},
doi = {10.1093/ije/dyu119},
pmid = {24906368},
issn = {1464-3685},
mesh = {Denmark/epidemiology ; Female ; Follow-Up Studies ; Genotype ; Humans ; Incidence ; Male ; *Mendelian Randomization Analysis ; *Mortality ; Multivariate Analysis ; Polymorphism, Genetic ; Risk Factors ; Smoking/*genetics/mortality ; Telomere/*genetics ; Tobacco Use Disorder/*genetics/mortality ; },
abstract = {BACKGROUND: High cumulative tobacco consumption is associated with short telomeres and with increased all-cause mortality. We tested the hypothesis that high tobacco consumption is causally associated with short telomeres and with increased all-cause mortality.<br><br>METHODS: We studied 55,568 individuals including 32,823 ever smokers from the Danish general population, of whom 3430 died during 10 years of follow-up. All had telomere length measured, detailed information on smoking history, and CHRNA3 rs1051730 genotype, which is associated with tobacco consumption, determined. In a Mendelian randomization study, we conducted observational, genetic, and mediation analyses.<br><br>RESULTS: First, tobacco consumption was 21.1 pack-years in non-carriers, 22.8 in heterozygotes and 24.8 in homozygotes (P-trend<0.001). Second, the observational multivariable adjusted hazard ratio for all-cause mortality was 1.12 [95% confidence interval (CI): 1.09, 1.15] per doubling in tobacco consumption. In Mendelian randomization analysis, the hazard ratio was 1.08 (1.02, 1.14) per minor CHRNA3 allele in ever smokers. Third, in observational analysis telomeres shortened with -13 base pairs (-18, -8) per doubling in tobacco consumption. In Mendelian randomization analysis, the estimate was +3 base pairs (-10, +15) per minor CHRNA3 allele. Finally, individuals with the shortest vs longest telomeres had a multivariable adjusted hazard ratio of 1.30 (1.13, 1.50) for all-cause mortality; however, in mediation analysis short telomeres explained only +0.4% (-3.5%, +4.3%) of the association between high tobacco consumption and increased all-cause mortality.<br><br>CONCLUSIONS: High tobacco consumption is causally associated with increased all-cause mortality. High cumulative tobacco consumption is associated with short telomeres observationally, but there is no clear genetic association.},
}
@article {pmid24906327,
year = {2014},
author = {Moser, BA and Chang, YT and Nakamura, TM},
title = {Telomere regulation during the cell cycle in fission yeast.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1170},
number = {},
pages = {411-424},
pmid = {24906327},
issn = {1940-6029},
support = {R01 GM078253/GM/NIGMS NIH HHS/United States ; GM078253/GM/NIGMS NIH HHS/United States ; },
mesh = {Bromodeoxyuridine/analysis ; Cell Culture Techniques/methods ; Cell Cycle ; Chromatin Immunoprecipitation/methods ; DNA, Fungal/analysis ; Immunoblotting/methods ; Polymerase Chain Reaction/methods ; Schizosaccharomyces/*cytology/metabolism ; Telomere/*metabolism ; },
abstract = {The fission yeast Schizosaccharomyces pombe has emerged as a useful model organism to study telomere maintenance mechanisms. In this chapter, we provide detailed protocols for quantitative ChIP and BrdU incorporation analyses to investigate how fission yeast telomeres are regulated during the cell cycle by utilizing cdc25-22 synchronized cell cultures.},
}
@article {pmid24904205,
year = {2014},
author = {Ding, H and Yan, F and Zhou, LL and Ji, XH and Gu, XN and Tang, ZW and Chen, RH},
title = {Association between previously identified loci affecting telomere length and coronary heart disease (CHD) in Han Chinese population.},
journal = {Clinical interventions in aging},
volume = {9},
number = {},
pages = {857-861},
pmid = {24904205},
issn = {1178-1998},
mesh = {Age of Onset ; Alleles ; Asian People/*genetics ; Case-Control Studies ; China/epidemiology ; Coronary Disease/etiology/*genetics ; Female ; Genetic Loci/*genetics ; Genome-Wide Association Study ; Genotype ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/genetics ; Ribonucleoproteins/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {PURPOSE: To replicate previously confirmed telomere-length loci in a Chinese Han population with coronary heart disease (CHD), and investigate these loci and the possibility of and age at onset of CHD.<br><br>PATIENTS AND METHODS: 1514 CHD patients and 2470 normal controls were recruited. Medical data including age, sex, body mass index, lipid profiles, history of hypertension, type 2 diabetes mellitus, and dyslipidemia were collected from all the participants. Seven previously identified single-nucleotide polymorphisms (SNPs) related to leucocyte telomere length were genotyped, including rs10936599 in TERC, rs2736100 in TERT, rs7675998 in NAF1, rs9420907 in OBFC1, rs8105767 in ZNF208, rs755017 in RTEL1, and rs11125529 in ACYP2.<br><br>RESULTS: No significant difference in genotype frequencies from the Hardy-Weinberg equilibrium test was noted for all tested SNPs both in the CHD patients and the normal controls. No polymorphism was observed for rs9420907, and AA genotype was noted in both the CHD patients and the controls. Neither the genotype nor the allele frequencies of rs2736100, rs8105767, rs11125529, and rs2967374 were significantly different between the CHD patients and the normal controls. For rs10936599 and rs755017, statistical difference was found for the allele frequency but not genotype. Distributions of genotype and allele were significantly different between the two groups for rs7675998. The odds ratio for carriers of CHD was 2.127 (95% confidence interval: 1.909-2.370) for the A allele of rs7675998. By one-way analysis of variance test, rs7675998 was associated with the onset age of CHD. CHD patients with the AA genotype of rs7675998 had significantly lower onset age (P<0.05).<br><br>CONCLUSION: In a Chinese Han population, NAF1 gene encoding proteins with known function in telomere biology may influence both the possibility of and the age at onset of CHD, as previously reported in European studies.},
}
@article {pmid24903994,
year = {2014},
author = {Lu, YY and Yang, X and Chen, WQ and Ju, ZY and Shou, ZF and Jin, J and Zhang, XH and Chen, JH and Jiang, H},
title = {Proteins induced by telomere dysfunction are associated with human IgA nephropathy.},
journal = {Journal of Zhejiang University. Science. B},
volume = {15},
number = {6},
pages = {566-574},
pmid = {24903994},
issn = {1862-1783},
mesh = {Adult ; Aging/*metabolism ; Antimicrobial Cationic Peptides ; Biomarkers/metabolism ; Cathelicidins/*metabolism ; Chitinases/*metabolism ; Female ; Glomerulonephritis, IGA/*metabolism ; Humans ; Male ; Peptide Elongation Factor 1/*metabolism ; Stathmin/*metabolism ; Telomere/physiology ; Telomere Homeostasis/physiology ; Telomere Shortening/*physiology ; },
abstract = {Aging is one of the contributing risk factors for kidney diseases. Accumulating evidence prompts the view that telomere length in kidney tissue cells is an indicator for organismal aging. Previously identified aging markers (cathelin-related antimicrobial peptide (CRAMP), stathmin, elongation factor-1α (EF-1α), and chitinase) were associated not only with telomere driven aging in mice but also with human aging and chronic diseases. This study focuses on the relationship between these biomarkers and IgA nephropathy (IgAN) progression in the Chinese population. For 260 individuals, the four markers are determined in blind datasets using direct enzyme-linked immunosorbent assay (ELISA) and immunofluorescence staining. The expression levels of CRAMP and chitinase increased in blood plasma, urine, and kidney tissues during human IgAN progression. And for the other nephropathy, such as systemic lupus erythematosus (SLE), diabetic nephropathy (DN), and focal segmental glomerulosclerosis (FSGS), there is no protein upregulation with telomere shortening. Moreover, a combination of CRAMP and chitinase can distinguish patients with IgAN from healthy individuals with 88.2%/92.5% (plasma) and 74.3%/84.2% (urine) sensitivity/specificity. These data provide the experimental evidence that telomere shortening and related inflammatory proteins are associated with human IgAN, and it could be a new direction for the disease progression study.},
}
@article {pmid24902894,
year = {2014},
author = {Chen, S and Lin, J and Matsuguchi, T and Blackburn, E and Yeh, F and Best, LG and Devereux, RB and Lee, ET and Howard, BV and Roman, MJ and Zhao, J},
title = {Short leukocyte telomere length predicts incidence and progression of carotid atherosclerosis in American Indians: the Strong Heart Family Study.},
journal = {Aging},
volume = {6},
number = {5},
pages = {414-427},
pmid = {24902894},
issn = {1945-4589},
support = {R01DK091369/DK/NIDDK NIH HHS/United States ; U01 HL041642/HL/NHLBI NIH HHS/United States ; U01 HL041654/HL/NHLBI NIH HHS/United States ; K01 AG034259/AG/NIA NIH HHS/United States ; D43 TW009107/TW/FIC NIH HHS/United States ; U01 HL041652/HL/NHLBI NIH HHS/United States ; U01HL41642/HL/NHLBI NIH HHS/United States ; U01HL65521/HL/NHLBI NIH HHS/United States ; R21HL092363/HL/NHLBI NIH HHS/United States ; K01AG034259/AG/NIA NIH HHS/United States ; U01 HL065521/HL/NHLBI NIH HHS/United States ; U01HL41654/HL/NHLBI NIH HHS/United States ; U01 HL065520/HL/NHLBI NIH HHS/United States ; D43TW009107/TW/FIC NIH HHS/United States ; R01 DK091369/DK/NIDDK NIH HHS/United States ; U01HL41652/HL/NHLBI NIH HHS/United States ; R21 HL092363/HL/NHLBI NIH HHS/United States ; U01HL65520/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Carotid Artery Diseases/*epidemiology/*pathology ; Disease Progression ; Female ; Humans ; Incidence ; Indians, North American ; Leukocytes/*pathology ; Male ; Middle Aged ; Proportional Hazards Models ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; Telomere/*pathology ; Young Adult ; },
abstract = {Short leukocyte telomere length (LTL) has been associated with atherosclerosis in cross-sectional studies, but the prospective relationship between telomere shortening and risk of developing carotid atherosclerosis has not been well-established. This study examines whether LTL at baseline predicts incidence and progression of carotid atherosclerosis in American Indians in the Strong Heart Study. The analysis included 2,819 participants who were free of overt cardiovascular disease at baseline (2001-2003) and were followed through the end of 2006-2009 (average 5.5-yr follow-up). Discrete atherosclerotic plaque was defined as focal protrusion with an arterial wall thickness ≥50% the surrounding wall. Carotid progression was defined as having a higher plaque score at the end of study follow-up compared to baseline. Associations of LTL with incidence and progression of carotid plaque were examined using Cox proportional hazard regression, adjusting for standard coronary risk factors. Compared to participants in the highest LTL tertile, those in the lowest tertile had significantly elevated risk for both incident plaque (HR, 1.49; 95% CI, 1.09-2.03) and plaque progression (HR, 1.61; 95% CI, 1.26-2.07). Our results provide initial evidence for a potential prognostic utility of LTL in risk prediction for atherosclerosis.},
}
@article {pmid24899707,
year = {2014},
author = {Lee, Y and Brown, EJ and Chang, S and McKinnon, PJ},
title = {Pot1a prevents telomere dysfunction and ATM-dependent neuronal loss.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {34},
number = {23},
pages = {7836-7844},
pmid = {24899707},
issn = {1529-2401},
support = {R56 NS037956/NS/NINDS NIH HHS/United States ; R01 AG027376/AG/NIA NIH HHS/United States ; R01 NS037956/NS/NINDS NIH HHS/United States ; NS-37956/NS/NINDS NIH HHS/United States ; P30 CA21765/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; AG-027376/AG/NIA NIH HHS/United States ; P01 CA096832/CA/NCI NIH HHS/United States ; CA-129037/CA/NCI NIH HHS/United States ; CA-96832/CA/NCI NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Animals, Newborn ; Ataxia Telangiectasia Mutated Proteins/genetics/metabolism ; Brain/cytology ; Cell Cycle/genetics ; Cell Cycle Proteins/genetics/metabolism ; Cells, Cultured ; DNA Damage/*physiology ; DNA-Binding Proteins/genetics/*physiology ; Embryo, Mammalian ; Female ; Gene Expression Regulation/genetics ; Male ; Mice ; Mice, Transgenic ; Nestin/genetics ; Neurons/*physiology ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins ; beta-Galactosidase/metabolism ; },
abstract = {Genome stability is essential for neural development and the prevention of neurological disease. Here we determined how DNA damage signaling from dysfunctional telomeres affects neurogenesis. We found that telomere uncapping by Pot1a inactivation resulted in an Atm-dependent loss of cerebellar interneurons and granule neuron precursors in the mouse nervous system. The activation of Atm by Pot1a loss occurred in an Atr-dependent manner, revealing an Atr to Atm signaling axis in the nervous system after telomere dysfunction. In contrast to telomere lesions, Brca2 inactivation in neural progenitors also led to ablation of cerebellar interneurons, but this did not require Atm. These data reveal that neural cell loss after DNA damage selectively engages Atm signaling, highlighting how specific DNA lesions can dictate neuropathology arising in human neurodegenerative syndromes.},
}
@article {pmid24896148,
year = {2015},
author = {Concetti, F and Carpi, FM and Nabissi, M and Picciolini, M and Santoni, G and Napolioni, V},
title = {The functional polymorphism rs73598374:G&gt;A (p.Asp8Asn) of the ADA gene is associated with telomerase activity and leukocyte telomere length.},
journal = {European journal of human genetics : EJHG},
volume = {23},
number = {2},
pages = {267-270},
pmid = {24896148},
issn = {1476-5438},
mesh = {Adenosine Deaminase/*genetics/metabolism ; Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Leukocytes/metabolism ; Male ; *Polymorphism, Single Nucleotide ; Telomerase/*metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Recent evidence demonstrated a relevant role of adenosine deaminase (ADA) in replicative senescence of T cells through its capacity to modulate telomerase activity (TA). Herein, we tested the impact of the functional polymorphism ADA rs73598374:G>A (c.22G>A, p.Asp8Asn) on telomere biology, by measuring TA and leukocyte telomere length (LTL) in healthy subjects selected according to rs73598374 genotype. rs73598374-A carriers showed lower TA (P=0.019) and shorter LTL (P=0.003), respectively, compared to G/G carriers. rs73598374-A carriers showed a stronger cross-sectional age reduction of LTL (r=-0.314, P=0.005) compared to G/G carriers (r=-0.243, P=0.022). The reduced ADA activity associated to rs73598374-A variant predisposes those carriers to display higher levels of adenosine compared to G/G carriers. Consequently, it may lead to an accelerated process of replicative senescence, causing a stronger reduction of TA and in turn shorter LTL. In conclusion, the crucial role played by replicative senescence of the immune system in several human diseases and in the aging process underscores the relevance of the present findings and also spurs interest into the possible involvement of rs73598374 in shaping the susceptibility to several age-related diseases.},
}
@article {pmid24894799,
year = {2014},
author = {Babizhayev, MA and Vishnyakova, KS and Yegorov, YE},
title = {Oxidative damage impact on aging and age-related diseases: drug targeting of telomere attrition and dynamic telomerase activity flirting with imidazole-containing dipeptides.},
journal = {Recent patents on drug delivery &amp; formulation},
volume = {8},
number = {3},
pages = {163-192},
doi = {10.2174/1872211308666140602125505},
pmid = {24894799},
issn = {2212-4039},
mesh = {Aging/drug effects/*metabolism/pathology ; Animals ; Carnosine/administration &amp; dosage ; Dipeptides/*administration &amp; dosage ; Drug Delivery Systems/*methods ; Enzyme Activation/drug effects/physiology ; Enzyme Inhibitors/administration &amp; dosage ; Humans ; Imidazoles/*administration &amp; dosage ; Oxidative Stress/drug effects/*physiology ; Telomerase/antagonists &amp; inhibitors/*metabolism ; Telomere/drug effects/*metabolism ; Telomere Homeostasis/drug effects/physiology ; },
abstract = {It has been documented that telomere-associated cellular senescence may contribute to certain age-related disorders, including an increase in cancer incidence, wrinkling and diminished skin elasticity, atherosclerosis, osteoporosis, weight loss, age-related cataract, glaucoma and others. Shorter telomere length in leukocytes was associated crosssectionally with cardiovascular disorders and their risk factors, including pulse pressure and vascular aging, obesity, vascular dementia, diabetes, coronary artery disease, myocardial infarction (although not in all studies), cellular turnover and exposure to oxidative and inflammatory damage in chronic obstructive pulmonary disease. It has been proposed that telomere length may not be a strong biomarker of survival in older individuals, but it may be an informative biomarker of healthy aging. The data reveal that telomere dynamics and changes in telomerase activity are consistent elements of cellular alterations associated with changes in proliferative state and in this article these processes are consequently considered as the new therapeutic drug targets for physiological control with advanced drug delivery and nutritional formulations. In particular, the presence of highly specific correlations and early causal relationships between telomere loss in the absence of telomerase activity and replicative senescence or crisis, and from the other side, telomerase reactivation and cell immortality, point to new and important treatment strategies or the therapeutic manipulation during treatment of age related disorders and cancer. Once better controls and therapeutic treatments for aging and age-related disorders are achieved, cellular rejuvenation by manipulating telomeres and enzyme telomerase activity may reduce some of the physiological declines that accompany aging. In this work, we raise and support a therapeutic concept of using non-hydrolyzed forms of naturally occurring imidazoledipeptide based compounds carnosine and carcinine, making it clinically possible that slowing down the rate of telomere shortening could slow down the human aging process in specific tissues where proliferative senescence is known to occur with the demonstrated evidence of telomere shortening appeared to be a hallmark of oxidative stress and disease. The preliminary longitudinal studies of elderly individuals suggest that longer telomeres are associated with better survival and an advanced oral nutritional support with non-hydrolyzed carnosine (or carcinine and patented compositions thereof) and patented N-acetylcarnosine lubricant eye drops are useful therapeutic tools of a critical telomere length maintenance that may fundamentally be applied in the treatment of age-related sight-threatening eye disorders, prolong life expectancy, increase survival and chronological age of an organism in health control, smoking behavior and disease.},
}
@article {pmid24892036,
year = {2014},
author = {Wang, T and Mei, SC and Fu, R and Wang, HQ and Shao, ZH},
title = {Expression of Shelterin component POT1 is associated with decreased telomere length and immunity condition in humans with severe aplastic anemia.},
journal = {Journal of immunology research},
volume = {2014},
number = {},
pages = {439530},
pmid = {24892036},
issn = {2314-7156},
mesh = {Adolescent ; Adult ; Aged ; Anemia, Aplastic/*genetics/immunology/pathology ; Apoptosis/drug effects ; Ataxia Telangiectasia Mutated Proteins/genetics/immunology ; Bone Marrow Cells/drug effects/*immunology/pathology ; Case-Control Studies ; Child ; Child, Preschool ; Female ; Gene Expression ; Humans ; Interferon-gamma/pharmacology ; Leukocytes, Mononuclear/drug effects/*immunology/pathology ; Male ; Middle Aged ; Primary Cell Culture ; Severity of Illness Index ; Shelterin Complex ; Telomere/*genetics/pathology ; Telomere Homeostasis ; Telomere-Binding Proteins/genetics/*immunology ; Telomeric Repeat Binding Protein 1/genetics/immunology ; Telomeric Repeat Binding Protein 2/genetics/immunology ; Tumor Necrosis Factor-alpha/pharmacology ; },
abstract = {Abnormal telomere attrition has been found to be closely related to patients with SAA in recent years. To identify the incidence of telomere attrition in SAA patients and investigate the relationship of telomere length with clinical parameters, SAA patients (n=27) and healthy controls (n=15) were enrolled in this study. Telomere length of PWBCs was significantly shorter in SAA patients than in controls. Analysis of gene expression of Shelterin complex revealed markedly low levels of POT1 expression in SAA groups relative to controls. No differences in the gene expression of the other Shelterin components-TRF1, TRF2, TIN2, TPP1, and RAP1-were identified. Addition of IFN-γ to culture media induced a similar fall in POT1 expression in bone marrow cells to that observed in cells cultured in the presence of SAA serum, suggesting IFN-γ is the agent responsible for this effect of SAA serum. Furthermore, ATR, phosphorylated ATR, and phosphorylated ATM/ATR substrate were all found similarly increased in bone marrow cells exposed to SAA serum, TNF-α, or IFN-γ. In summary, SAA patients have short telomeres and decreased POT1 expression. TNF-α and IFN-γ are found at high concentrations in SAA patients and may be the effectors that trigger apoptosis through POT1 and ATR.},
}
@article {pmid24889645,
year = {2014},
author = {Drury, S and Theall, K},
title = {Carefully thinking about telomeres.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {111},
number = {24},
pages = {E2441},
pmid = {24889645},
issn = {1091-6490},
mesh = {Humans ; Male ; *Social Environment ; Telomere Homeostasis/*genetics ; *Vulnerable Populations ; },
}
@article {pmid24886862,
year = {2014},
author = {Quinlan, J and Tu, MT and Langlois, EV and Kapoor, M and Ziegler, D and Fahmi, H and Zunzunegui, MV},
title = {Protocol for a systematic review of the association between chronic stress during the life course and telomere length.},
journal = {Systematic reviews},
volume = {3},
number = {},
pages = {40},
pmid = {24886862},
issn = {2046-4053},
support = {CHUM 50679//Cancer Research UK/United Kingdom ; //Canadian Institutes of Health Research/Canada ; },
mesh = {Adult ; Humans ; Stress, Psychological/*complications/physiopathology ; Systematic Reviews as Topic ; *Telomere Shortening/physiology ; },
abstract = {BACKGROUND: The effects of stress on ill health have become evident in recent years. Under acute stress situations, a cascade of physiological events helps the body mount an appropriate adaptive response. However, under chronic stress situations, this physiological response may lead to wear and tear on the body that accelerates the decline in physiological functioning and increases the risk of chronic conditions. Recent evidence for social stress experienced during childhood suggests serious consequences many years later, even later life. Telomere length, a marker of cell aging, may provide a link between chronic social stress and age-associated physical and mental decline and risk of chronic conditions. This study examines whether chronic social stress is associated with telomere length throughout the life course.<br><br>METHODS/DESIGN: We will perform a systematic review of the literature on the relationship between chronic social stress, for example, due to violence, extreme poverty, or caregiving of people with disabling conditions (exposure), and telomere length (outcome) by searching electronic databases in MEDLINE (PubMed interface), EMBASE (OVID interface), Cochrane Central (OVID interface) and gray literature from their start date onwards. We will limit the search to studies performed on human populations. Two reviewers will conduct standardized screening, eligibility assessment, data abstraction, and scientific quality assessment. All study designs investigating the association between chronic social stress and telomere length in healthy or diseased adults and children will be eligible for inclusion in the review. We will extract individual demographic and socioeconomic characteristics, research setting, method of measuring telomere length, reported outcome, and determinants of interest. Studies will also be stratified by 1) age into 3 groups: childhood (0 to 18&#xa0;years), adulthood (19 to 64&#xa0;years) and late life (65+); 2) cell type; 3) study design; and 4) telomere length assessment method. Where feasible, study results will be combined through meta-analyses to obtain a pooled measure of associations. Results will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement.<br><br>DISCUSSION: This systematic review will provide knowledge on the existing evidence for chronic social stress and its association with telomere lengths throughout the life course.},
}
@article {pmid24885367,
year = {2014},
author = {Daniel, K and Tränkner, D and Wojtasz, L and Shibuya, H and Watanabe, Y and Alsheimer, M and Tóth, A},
title = {Mouse CCDC79 (TERB1) is a meiosis-specific telomere associated protein.},
journal = {BMC cell biology},
volume = {15},
number = {},
pages = {17},
pmid = {24885367},
issn = {1471-2121},
mesh = {Amino Acid Sequence ; Animals ; Carrier Proteins/*analysis/genetics/metabolism ; Cell Cycle Proteins/*analysis/genetics/metabolism ; Female ; Gene Expression Regulation ; Germ Cells/cytology/metabolism ; Male ; *Meiosis ; Mice ; Mice, Inbred C57BL ; Microtubule-Associated Proteins/analysis/genetics/metabolism ; Molecular Sequence Data ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Telomeres have crucial meiosis-specific roles in the orderly reduction of chromosome numbers and in ensuring the integrity of the genome during meiosis. One such role is the attachment of telomeres to trans-nuclear envelope protein complexes that connect telomeres to motor proteins in the cytoplasm. These trans-nuclear envelope connections between telomeres and cytoplasmic motor proteins permit the active movement of telomeres and chromosomes during the first meiotic prophase. Movements of chromosomes/telomeres facilitate the meiotic recombination process, and allow high fidelity pairing of homologous chromosomes. Pairing of homologous chromosomes is a prerequisite for their correct segregation during the first meiotic division. Although inner-nuclear envelope proteins, such as SUN1 and potentially SUN2, are known to bind and recruit meiotic telomeres, these proteins are not meiosis-specific, therefore cannot solely account for telomere-nuclear envelope attachment and/or for other meiosis-specific characteristics of telomeres in mammals.<br><br>RESULTS: We identify CCDC79, alternatively named TERB1, as a meiosis-specific protein that localizes to telomeres from leptotene to diplotene stages of the first meiotic prophase. CCDC79 and SUN1 associate with telomeres almost concurrently at the onset of prophase, indicating a possible role for CCDC79 in telomere-nuclear envelope interactions and/or telomere movements. Consistent with this scenario, CCDC79 is missing from most telomeres that fail to connect to SUN1 protein in spermatocytes lacking the meiosis-specific cohesin SMC1B. SMC1B-deficient spermatocytes display both reduced efficiency in telomere-nuclear envelope attachment and reduced stability of telomeres specifically during meiotic prophase. Importantly, CCDC79 associates with telomeres in SUN1-deficient spermatocytes, which strongly indicates that localization of CCDC79 to telomeres does not require telomere-nuclear envelope attachment.<br><br>CONCLUSION: CCDC79 is a meiosis-specific telomere associated protein. Based on our findings we propose that CCDC79 plays a role in meiosis-specific telomere functions. In particular, we favour the possibility that CCDC79 is involved in telomere-nuclear envelope attachment and/or the stabilization of meiotic telomeres. These conclusions are consistent with the findings of an independently initiated study that analysed CCDC79/TERB1 functions.},
}
@article {pmid24885363,
year = {2014},
author = {Ahn, EY and Yoo, JE and Rhee, H and Kim, MS and Choi, J and Ko, JE and Lee, JS and Park, YN},
title = {Increased expression of stathmin and elongation factor 1α in precancerous nodules with telomere dysfunction in hepatitis B viral cirrhotic patients.},
journal = {Journal of translational medicine},
volume = {12},
number = {},
pages = {154},
pmid = {24885363},
issn = {1479-5876},
mesh = {Adult ; Female ; Hepatitis B/complications/*metabolism ; Humans ; Liver Cirrhosis/etiology/genetics/*metabolism ; Liver Neoplasms/etiology/genetics/*metabolism ; Male ; Middle Aged ; Peptide Elongation Factor 1/*metabolism ; Precancerous Conditions/genetics/*metabolism ; Stathmin/*metabolism ; *Telomere ; },
abstract = {BACKGROUND: Telomere dysfunction is important in carcinogenesis, and recently, stathmin and elongation factor 1α (EF1α) were reported to be up-regulated in telomere dysfunctional mice.<br><br>METHODS: In the present study, the expression levels of stathmin and EF1&#x3b1; in relation to telomere length, telomere dysfunction-induced foci (TIF), &#x3b3;-H2AX, and p21WAF1/CIP1 expression were assessed in specimens of hepatitis B virus (HBV)-related multistep hepatocarcinogenesis, including 13 liver cirrhosis specimens, 14 low-grade dysplastic nodules (DN), 17 high-grade DNs, and 14 hepatocellular carcinomas (HCC). Five normal liver specimens were used as controls. TIF were analyzed by telomere fluorescent in situ hybridization (FISH) combined with immunostaining, while the protein expressions of stathmin, EF1&#x3b1;, &#x3b3;-H2AX, and p21WAF1/CIP1 were detected by immunohistochemistry.<br><br>RESULT: The expressions of stathmin and EF1&#x3b1; gradually increased as multistep hepatocarcinogenesis progressed, showing the highest levels in HCC. Stathmin mRNA levels were higher in high-grade DNs than normal liver and liver cirrhosis, whereas EF1&#x3b1; mRNA expression did not show such a difference. The protein expressions of stathmin and EF1&#x3b1; were found in DNs of precancerous lesions, whereas they were absent or present at very low levels in normal liver and liver cirrhosis. Stathmin histoscores were higher in high-grade DNs and low-grade DNs than in normal liver (all, P<0.05). EF1&#x3b1; histoscores were higher in high-grade DNs than in normal liver and liver cirrhosis (all, P<0.05). Stathmin mRNA levels and histoscores, as well as EF1&#x3b1; histoscores (but not mRNA levels), were positively correlated with telomere shortening and &#x3b3;-H2AX labeling index (all, P<0.05). EF1&#x3b1; histoscores were also positively correlated with TIF (P<0.001). Significantly greater inactivation of p21WAF1/CIP1 was observed in low-grade DNs, high-grade DNs, and HCC, compared to liver cirrhosis (all, P<0.05). p21WAF1/CIP1 labeling index was inversely correlated with TIF, stathmin mRNA level, and EF1&#x3b1; histoscore (all, P<0.05).<br><br>CONCLUSION: Stathmin and EF1&#x3b1; are suggested to be closely related to telomere dysfunction, DNA damage, and inactivation of p21WAF1/CIP1 in HBV-related multistep hepatocarcinogenesis. Accordingly, assessment of stathmin and EF1&#x3b1; levels as a reflection of telomere dysfunction may be helpful in evaluating the biological characteristics of precancerous hepatic nodules in hepatitis B viral cirrhotic patients.},
}
@article {pmid24882684,
year = {2014},
author = {Špaková, T and Pristaš, P and Javorský, P},
title = {Telomere repeats and macronuclear DNA organization in the soil ciliate Kahliella matisi (Ciliophora, Hypotricha).},
journal = {European journal of protistology},
volume = {50},
number = {3},
pages = {231-235},
doi = {10.1016/j.ejop.2014.03.002},
pmid = {24882684},
issn = {1618-0429},
mesh = {Ciliophora/*genetics ; DNA, Protozoan/*genetics ; Gene Order ; Macronucleus/*genetics ; Microsatellite Repeats/genetics ; Molecular Sequence Data ; Soil/*parasitology ; Telomere/*genetics ; },
abstract = {To better understand the structure of macronuclear chromosomes in ciliates, the organization of macronuclear DNA was investigated in the hypotrich Kahliella matisi. Total DNA of K. matisi separated by agarose gel electrophoresis showed continuous smear ranging in size from ∼500bp to ∼15kb. This fragmentation was found to be due to the presence of gene-sized macronuclear chromosomes. The sequence analysis of four randomly cloned macronuclear chromosomes showed that K. matisi telomeres consist of 5'-dC4A4-3' repeats and carry one or two open reading frames. The transcription unit was found to be flanked with non-coding AT rich 5' leader and 3' trailer. No consensus transcription-regulatory sequences were identified in 5' leader and only one of analyzed gene-sized chromosomes showed the presence of conserved poly(A) addition signal sequence in 3' trailer. All ORFs showed highest relatedness to Oxytricha trifallax macronuclear chromosomes with conserved exon/intron structure. Sequence comparisons indicate that macronuclear chromosome organization is at least partially conserved in ciliates.},
}
@article {pmid24882549,
year = {2014},
author = {Zhang, DH and Wen, XM and Zhang, L and Cui, W},
title = {DNA methylation of human telomerase reverse transcriptase associated with leukocyte telomere length shortening in hyperhomocysteinemia-type hypertension in humans and in a rat model.},
journal = {Circulation journal : official journal of the Japanese Circulation Society},
volume = {78},
number = {8},
pages = {1915-1923},
doi = {10.1253/circj.cj-14-0233},
pmid = {24882549},
issn = {1347-4820},
mesh = {Age Factors ; Aged ; Animals ; Cross-Sectional Studies ; *DNA Methylation ; Disease Models, Animal ; Female ; Gene Expression Regulation, Enzymologic ; Humans ; Hyperhomocysteinemia/*enzymology ; Hypertension/*enzymology ; Leukocytes/*enzymology ; Male ; Middle Aged ; RNA, Messenger/biosynthesis ; Rats ; Rats, Sprague-Dawley ; Sex Factors ; Telomerase/*biosynthesis ; Telomere/*enzymology ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Elevated homocysteine (Hcy) levels might play a role in the development of essential hypertension (EH). Telomere dynamics provide valuable insight into the pathogenesis of age-related diseases. The contribution of Hcy to leukocyte telomere length (LTL) shortening in EH and the underlying mechanism was examined.<br><br>METHODS AND RESULTS: LTL (ratio of the copy number of telomere [T] repeats to that of a single [S] gene, T/S ratio) was inversely associated with age in patients with EH (n=258) and healthy controls (n=137), but significantly decreased with the Hcy level only in patients with hypertension after adjustment for age and sex. Age, hypertension and levels of Hcy and low-density lipoprotein combined contributed to LTL shortening; an increased serum folate level could reverse the Hcy effect seen on multivariate regression analysis. In addition, qPCR and methylation-speci&#xfb01;c PCR assay revealed that LTL shortening and mRNA expression and the methylation ratio of human telomerase reverse transcriptase (hTERT) were lower in patients with EH than in controls, and gradually decreased with increasing Hcy level, but not with blood pressure, in EH patients (Ptrend<0.0001, 0.004 and 0.012, respectively). Furthermore, Hyperhomocysteinemia, but not hypertension, promoted telomerase reverse transcriptase DNA hypomethylation and reduced mRNA levels, which contributed to shortened LTL in the hypertension rat model.<br><br>CONCLUSIONS: Elevated Hcy but not hypertension was related to hTERT DNA hypomethylation and reduced mRNA level, thus contributing to the shortening of LTL hypertension.},
}
@article {pmid24881030,
year = {2014},
author = {Zhang, WG and Zhu, SY and Zhao, DL and Jiang, SM and Li, J and Li, ZX and Fu, B and Zhang, M and Li, DG and Bai, XJ and Cai, GY and Sun, XF and Chen, XM},
title = {The correlation between peripheral leukocyte telomere length and indicators of cardiovascular aging.},
journal = {Heart, lung &amp; circulation},
volume = {23},
number = {9},
pages = {883-890},
doi = {10.1016/j.hlc.2013.12.016},
pmid = {24881030},
issn = {1444-2892},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*genetics/physiology ; Asian People/*genetics ; Blood Pressure ; China ; Cholesterol/blood ; Echocardiography ; Electrocardiography ; Female ; Humans ; Leukocytes/*cytology ; Lipoproteins, HDL/blood ; Lipoproteins, LDL/blood ; Male ; Middle Aged ; Mitral Valve/physiopathology ; Stroke Volume ; *Telomere Shortening ; Triglycerides/blood ; },
abstract = {OBJECTIVES: To investigate the relationship between telomere length in peripheral blood white cells and cardiovascular function in a healthy, aging Han Chinese population.<br><br>METHODS: In 2012, peripheral blood leukocytes were obtained from 139 healthy individuals in Beijing, China, and telomere restriction fragment (TRF) length was assayed using a digoxigenin-labeled hybridization probe in Southern blot assays. Indicators of cardiovascular function were also evaluated, including electrocardiograms (ECG), (RR, P, PR, QRS, ST and T intervals); blood pressure (BP), (SBP, DBP, PP, PPI); cardiovascular ultrasound (left ventricular ejection fraction, LVEF); mitral early and late diastolic peak flow velocity (MVE and MVA); and lipid indices (TC, TG, HDL, LDL, LCI). The relationships of these cardiovascular indictors to telomere length were evaluated.<br><br>RESULTS: No correlations were found between telomere length and ECG, BP or lipid indices even after adjustment for age. Correlations were found between TFR length and some cardiovascular ultrasound indictors (D, MVEA, MVEDT, MVES, MVEL, MVEI, IMT), but these were not seen after adjusting for age.<br><br>CONCLUSIONS: We did not find that leukocyte TFR length was associated with cardiovascular ultrasound indictors, ECG, BP, or lipid indices in this population of healthy Han Chinese individuals. Telomere length may serve as a genetic factor in biological aging.},
}
@article {pmid24879463,
year = {2014},
author = {Williams, JM and Ouenzar, F and Lemon, LD and Chartrand, P and Bertuch, AA},
title = {The principal role of Ku in telomere length maintenance is promotion of Est1 association with telomeres.},
journal = {Genetics},
volume = {197},
number = {4},
pages = {1123-1136},
pmid = {24879463},
issn = {1943-2631},
support = {MOP-89768/CAPMC/CIHR/Canada ; T32GM008307/GM/NIGMS NIH HHS/United States ; R01 GM077509/GM/NIGMS NIH HHS/United States ; GM077509/GM/NIGMS NIH HHS/United States ; T32 GM008307/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA, Fungal/genetics ; DNA-Binding Proteins/genetics/*metabolism ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Promoter Regions, Genetic ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Telomere length is tightly regulated in cells that express telomerase. The Saccharomyces cerevisiae Ku heterodimer, a DNA end-binding complex, positively regulates telomere length in a telomerase-dependent manner. Ku associates with the telomerase RNA subunit TLC1, and this association is required for TLC1 nuclear retention. Ku-TLC1 interaction also impacts the cell-cycle-regulated association of the telomerase catalytic subunit Est2 to telomeres. The promotion of TLC1 nuclear localization and Est2 recruitment have been proposed to be the principal role of Ku in telomere length maintenance, but neither model has been directly tested. Here we study the impact of forced recruitment of Est2 to telomeres on telomere length in the absence of Ku's ability to bind TLC1 or DNA ends. We show that tethering Est2 to telomeres does not promote efficient telomere elongation in the absence of Ku-TLC1 interaction or DNA end binding. Moreover, restoration of TLC1 nuclear localization, even when combined with Est2 recruitment, does not bypass the role of Ku. In contrast, forced recruitment of Est1, which has roles in telomerase recruitment and activation, to telomeres promotes efficient and progressive telomere elongation in the absence of Ku-TLC1 interaction, Ku DNA end binding, or Ku altogether. Ku associates with Est1 and Est2 in a TLC1-dependent manner and enhances Est1 recruitment to telomeres independently of Est2. Together, our results unexpectedly demonstrate that the principal role of Ku in telomere length maintenance is to promote the association of Est1 with telomeres, which may in turn allow for efficient recruitment and activation of the telomerase holoenzyme.},
}
@article {pmid24876749,
year = {2014},
author = {Carulli, L and Anzivino, C},
title = {Telomere and telomerase in chronic liver disease and hepatocarcinoma.},
journal = {World journal of gastroenterology},
volume = {20},
number = {20},
pages = {6287-6292},
pmid = {24876749},
issn = {2219-2840},
mesh = {Carcinoma, Hepatocellular/enzymology/*genetics ; Cellular Senescence ; Disease Progression ; End Stage Liver Disease/enzymology/*genetics ; Humans ; Liver Cirrhosis/enzymology/*genetics ; Liver Neoplasms/enzymology/*genetics ; Mutation ; Polymorphism, Genetic ; Regeneration ; Risk Factors ; Telomerase/genetics/*metabolism ; Telomere/*ultrastructure ; },
abstract = {The pathogenesis of liver cirrhosis is not completely elucidated. Although in the majority of patients, the risk factors may be identified in B and C viral hepatitis, alcohol intake, drugs or fatty liver disease, there is a small percentage of patients with no apparent risk factors. In addition, the evolution of chronic liver disease is highly heterogeneous from one patient to another. Among patient with identical risk factors, some rapidly progress to cirrhosis and hepatocellular carcinoma (HCC) whereas others have a benign course. Therefore, a genetic predisposition may contribute to the development of cirrhosis and HCC. Evidence supporting the role of genetic factors as a risk for cirrhosis has been accumulating during the past years. In addition to the results from epidemiological studies, polymorphisms studies and data on twins, the concept of telomere shortening as a genetic risk factor for chronic liver disease and HCC has been proposed. Here we review the literature on telomerase mutations, telomere shortening and liver disease including hepatocellular carcinoma.},
}
@article {pmid24876105,
year = {2014},
author = {Dinami, R and Ercolani, C and Petti, E and Piazza, S and Ciani, Y and Sestito, R and Sacconi, A and Biagioni, F and le Sage, C and Agami, R and Benetti, R and Mottolese, M and Schneider, C and Blandino, G and Schoeftner, S},
title = {miR-155 drives telomere fragility in human breast cancer by targeting TRF1.},
journal = {Cancer research},
volume = {74},
number = {15},
pages = {4145-4156},
doi = {10.1158/0008-5472.CAN-13-2038},
pmid = {24876105},
issn = {1538-7445},
mesh = {3' Untranslated Regions ; Animals ; Base Sequence ; Breast Neoplasms/*genetics/metabolism ; Cell Culture Techniques ; Female ; HCT116 Cells ; HeLa Cells ; Humans ; MCF-7 Cells ; MicroRNAs/*genetics/metabolism ; Molecular Sequence Data ; Sequence Homology, Nucleic Acid ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 1/*genetics/metabolism ; Transfection ; },
abstract = {Telomeres consist of DNA tandem repeats that recruit the multiprotein complex shelterin to build a chromatin structure that protects chromosome ends. Although cancer formation is linked to alterations in telomere homeostasis, there is little understanding of how shelterin function is limited in cancer cells. Using a small-scale screening approach, we identified miR-155 as a key regulator in breast cancer cell expression of the shelterin component TERF1 (TRF1). miR-155 targeted a conserved sequence motif in the 3'UTR of TRF1, resulting in its translational repression. miR-155 was upregulated commonly in breast cancer specimens, as associated with reduced TRF1 protein expression, metastasis-free survival, and relapse-free survival in estrogen receptor-positive cases. Modulating miR-155 expression in cells altered TRF1 levels and TRF1 abundance at telomeres. Compromising TRF1 expression by elevating miR-155 increased telomere fragility and altered the structure of metaphase chromosomes. In contrast, reducing miR-155 levels improved telomere function and genomic stability. These results implied that miR-155 upregulation antagonizes telomere integrity in breast cancer cells, increasing genomic instability linked to poor clinical outcome in estrogen receptor-positive disease. Our work argued that miRNA-dependent regulation of shelterin function has a clinically significant impact on telomere function, suggesting the existence of "telo-miRNAs" that have an impact on cancer and aging.},
}
@article {pmid24875221,
year = {2014},
author = {Zhang, L and Hu, XZ and Li, X and Li, H and Smerin, S and Russell, D and Ursano, RJ},
title = {Telomere length - a cellular aging marker for depression and Post-traumatic Stress Disorder.},
journal = {Medical hypotheses},
volume = {83},
number = {2},
pages = {182-185},
doi = {10.1016/j.mehy.2014.04.033},
pmid = {24875221},
issn = {1532-2777},
mesh = {Cellular Senescence/*genetics ; Depression/*diagnosis ; Genetic Markers/*genetics ; Humans ; Leukocytes/chemistry ; *Models, Biological ; Stress Disorders, Post-Traumatic/*diagnosis ; Telomere/*genetics ; },
abstract = {Telomeres play a central role in cell fate and aging by adjusting the cellular response to both biological and psychological stress. Human telomeres are regions of tandem TTAGGG repeats at chromosomal ends that protect chromosomes from degradation, fusion, and recombination. They are made up of approximately 1000-2500 copies of the repeated DNA sequence. Over time, at each cell division, the telomere ends become shorter. Thus, telomere length (TL) has been considered a cellular marker for age-related diseases. In addition to biochemical stressors such as oxidation and inflammation, psychosocial traumatic stress has also been linked to shorter telomeres. TL is significantly inversely correlated with long-term depression, even after controlling for age. Average TL in depressed subjects, who were above the median of lifetime depression, was 281 base pairs shorter than that in controls, corresponding to approximately 7years of accelerated cell aging. Several recent studies have also demonstrated an inverse relationship between leukocyte telomere length (LTL) and the risk of PTSD. TL was inversely correlated with the duration of caregiving and PTSD. Here, we focus on the discussion of findings in studies of the relationships between stress-related disorders (e.g., depression and PTSD) and telomeres. We also present direct evidence that TL is associated with traumatic stress, depression, and PTSD, and hypothesize that traumatic stress affects not only mental disorders but also cellular aging. The nature of this relationship between stress and TL warrants further evaluation in psychiatry.},
}
@article {pmid24874905,
year = {2014},
author = {Villalobos, LA and Uryga, A and Romacho, T and Leivas, A and Sánchez-Ferrer, CF and Erusalimsky, JD and Peiró, C},
title = {Visfatin/Nampt induces telomere damage and senescence in human endothelial cells.},
journal = {International journal of cardiology},
volume = {175},
number = {3},
pages = {573-575},
doi = {10.1016/j.ijcard.2014.05.028},
pmid = {24874905},
issn = {1874-1754},
mesh = {Cells, Cultured ; *Cellular Senescence/drug effects/physiology ; Cytokines/*toxicity ; Dose-Response Relationship, Drug ; Endothelial Cells/drug effects/metabolism/*pathology ; Humans ; Nicotinamide Phosphoribosyltransferase/*toxicity ; Oxidative Stress/drug effects/physiology ; Telomere/drug effects/metabolism/*pathology ; },
}
@article {pmid24870409,
year = {2014},
author = {Shibuya, H and Watanabe, Y},
title = {The meiosis-specific modification of mammalian telomeres.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {13},
number = {13},
pages = {2024-2028},
pmid = {24870409},
issn = {1551-4005},
mesh = {Animals ; Carrier Proteins/metabolism ; Cell Cycle Proteins/metabolism ; Chromosomes, Mammalian/*metabolism ; Cytoskeletal Proteins ; Mammals ; Meiosis/*physiology ; Meiotic Prophase I/physiology ; Microtubule-Associated Proteins/metabolism ; Nuclear Proteins/metabolism ; Telomere/*metabolism ; },
abstract = {During meiosis, rapid chromosome movements within the nucleus enable homologous chromosomes to acquire physical juxtaposition. In most organisms, chromosome ends, telomeres, tethered to the transmembrane LINC-complex mediate this movement by transmitting cytoskeletal forces to the chromosomes. While the majority of molecular studies have been performed using lower eukaryotes as model systems, recent studies have identified mammalian meiotic telomere regulators, including the LINC-complex SUN1/KASH5 and the meiosis-specific telomere binding protein TERB1. This review highlights the molecular regulations of mammalian meiotic telomeres in comparison with other model systems and discusses some future perspectives.},
}
@article {pmid24868316,
year = {2014},
author = {Liu, Z and Zhang, J and Yan, J and Wang, Y and Li, Y},
title = {Leucocyte telomere shortening in relation to newly diagnosed type 2 diabetic patients with depression.},
journal = {Oxidative medicine and cellular longevity},
volume = {2014},
number = {},
pages = {673959},
pmid = {24868316},
issn = {1942-0994},
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Age Factors ; Aged ; Blood Glucose/analysis ; Deoxyguanosine/analogs &amp; derivatives/analysis ; Depression/*complications/metabolism/pathology ; Diabetes Mellitus, Type 2/complications/*diagnosis/pathology ; Female ; Glycated Hemoglobin/analysis ; Humans ; Insulin Resistance ; Leukocytes/*cytology/metabolism ; Male ; Middle Aged ; Oxidative Stress ; Telomere/*metabolism ; Telomere Shortening ; },
abstract = {The goal of this study is to investigate the association between oxidative stress and telomere length shortening in the comorbid depression and diabetes. Therefore, 71 patients with newly diagnosed type 2 diabetes (T2D) and 52 subjects with normal glycemic level (control, Ctrl) were enrolled. Depressive status was identified with the Depression Subscale of Hospital Anxiety and Depression Scale (HADS-D). Leukocyte telomere length ratio (T/S ratio) was determined with quantitative PCR. Oxidative stress status was evaluated with 8-hydroxy-desoxyguanosine (8-OHdG) assay kit. Some other biochemical blood testing was also performed. The data showed that T2D patients had higher proportion of depression evaluated by the HADS-D (x(2) = 4.196, P = 0.041). T/S ratio was significantly negatively correlated with 8-OHdG, HADS-D, age, HbA1c, FPG, and HOMA-IR. In addition, HADS-D was significantly positively correlated with HbA1c, FPG, HOMA-IR, and 8-OHdG. Both HADS-D and 8-OHdG were the major independent predictors for T/S ratio. This study indicates that oxidative stress contributes to both telomere length shortening and depression development in newly diagnosed type 2 diabetic patients, while in depression status, some other mechanisms besides oxidative stress may also affect the telomere length.},
}
@article {pmid24861044,
year = {2014},
author = {Chen, S and Yeh, F and Lin, J and Matsuguchi, T and Blackburn, E and Lee, ET and Howard, BV and Zhao, J},
title = {Short leukocyte telomere length is associated with obesity in American Indians: the Strong Heart Family study.},
journal = {Aging},
volume = {6},
number = {5},
pages = {380-389},
pmid = {24861044},
issn = {1945-4589},
support = {R01DK091369/DK/NIDDK NIH HHS/United States ; U01 HL041642/HL/NHLBI NIH HHS/United States ; U01 HL041654/HL/NHLBI NIH HHS/United States ; K01 AG034259/AG/NIA NIH HHS/United States ; D43 TW009107/TW/FIC NIH HHS/United States ; U01 HL041652/HL/NHLBI NIH HHS/United States ; U01HL41642/HL/NHLBI NIH HHS/United States ; U01HL65521/HL/NHLBI NIH HHS/United States ; R21HL092363/HL/NHLBI NIH HHS/United States ; K01AG034259/AG/NIA NIH HHS/United States ; U01 HL065521/HL/NHLBI NIH HHS/United States ; U01HL41654/HL/NHLBI NIH HHS/United States ; U01 HL065520/HL/NHLBI NIH HHS/United States ; D43TW009107/TW/FIC NIH HHS/United States ; R01 DK091369/DK/NIDDK NIH HHS/United States ; U01HL41652/HL/NHLBI NIH HHS/United States ; R21 HL092363/HL/NHLBI NIH HHS/United States ; U01HL65520/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/genetics ; Anthropometry ; Female ; High-Throughput Screening Assays ; Humans ; Indians, North American/genetics ; Leukocytes/*pathology ; Male ; Middle Aged ; Obesity/*genetics ; Telomere/*pathology ; Young Adult ; },
abstract = {Shorter leukocyte telomere length (LTL) has been associated with a wide range of age-related disorders including cardiovascular disease (CVD) and diabetes. Obesity is an important risk factor for CVD and diabetes. The association of LTL with obesity is not well understood. This study for the first time examines the association of LTL with obesity indices including body mass index, waist circumference, percent body fat, waist-to-hip ratio, and waist-to-height ratio in 3,256 American Indians (14-93 years old, 60% women) participating in the Strong Heart Family Study. Association of LTL with each adiposity index was examined using multivariate generalized linear mixed model, adjusting for chronological age, sex, study center, education, lifestyle (smoking, alcohol consumption, and total energy intake), high-sensitivity C-reactive protein, hypertension and diabetes. Results show that obese participants had significantly shorter LTL than non-obese individuals (age-adjusted P=0.0002). Multivariate analyses demonstrate that LTL was significantly and inversely associated with all of the studied obesity parameters. Our results may shed light on the potential role of biological aging in pathogenesis of obesity and its comorbidities.},
}
@article {pmid24859373,
year = {2014},
author = {Needham, BL and Carroll, JE and Diez Roux, AV and Fitzpatrick, AL and Moore, K and Seeman, TE},
title = {Neighborhood characteristics and leukocyte telomere length: the Multi-Ethnic Study of Atherosclerosis.},
journal = {Health &amp; place},
volume = {28},
number = {},
pages = {167-172},
pmid = {24859373},
issn = {1873-2054},
support = {R01HL076831/HL/NHLBI NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; R01HL101161/HL/NHLBI NIH HHS/United States ; P30 AG017265/AG/NIA NIH HHS/United States ; R01HL071759/HL/NHLBI NIH HHS/United States ; N01 HC-95165/HC/NHLBI NIH HHS/United States ; P30-AG028748/AG/NIA NIH HHS/United States ; R01 HL101161/HL/NHLBI NIH HHS/United States ; R01 HL071759/HL/NHLBI NIH HHS/United States ; N01-HC-95159/HC/NHLBI NIH HHS/United States ; R01 HL076831/HL/NHLBI NIH HHS/United States ; N01-HC-95169/HC/NHLBI NIH HHS/United States ; P30 AG028748/AG/NIA NIH HHS/United States ; N01HC95165/HL/NHLBI NIH HHS/United States ; },
mesh = {Black or African American ; Aged ; Aged, 80 and over ; Aging ; Atherosclerosis/*blood ; Biomarkers ; Female ; Hispanic or Latino ; Humans ; Leukocytes ; Longitudinal Studies ; Los Angeles ; Male ; Middle Aged ; New York City ; *Residence Characteristics ; Risk Factors ; *Social Environment ; Stress, Psychological ; Telomere/*physiology ; },
abstract = {Telomeres are the protective caps at the ends of eukaryotic chromosomes. Telomeres get shorter each time a cell divides, and critically shortened telomeres trigger cellular senescence. Thus, telomere length is hypothesized to be a biological marker of aging. The purpose of this study was to examine the association between neighborhood characteristics and leukocyte telomere length. Using data from a subsample (n=978) of the Multi-Ethnic Study of Atherosclerosis, a population-based study of women and men aged 45-84, we found that neighborhood social environment (but not neighborhood socioeconomic disadvantage) was associated with telomere length. Respondents who lived in neighborhoods characterized by lower aesthetic quality, safety, and social cohesion had shorter telomeres than those who lived in neighborhoods with a more salutary social environment, even after adjusting for individual-level socioeconomic status and biomedical and lifestyle factors related to telomere length. Telomere length may be one biological mechanism by which neighborhood characteristics influence an individual׳s risk of disease and death.},
}
@article {pmid24858709,
year = {2014},
author = {Baylis, D and Ntani, G and Edwards, MH and Syddall, HE and Bartlett, DB and Dennison, EM and Martin-Ruiz, C and von Zglinicki, T and Kuh, D and Lord, JM and Aihie Sayer, A and Cooper, C},
title = {Inflammation, telomere length, and grip strength: a 10-year longitudinal study.},
journal = {Calcified tissue international},
volume = {95},
number = {1},
pages = {54-63},
pmid = {24858709},
issn = {1432-0827},
support = {MC_UP_A620_1015/MRC_/Medical Research Council/United Kingdom ; MC_UU_12019/4/MRC_/Medical Research Council/United Kingdom ; DRF-2011-04-011/DH_/Department of Health/United Kingdom ; MC_U147585819/MRC_/Medical Research Council/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MC_UU_12011/2/MRC_/Medical Research Council/United Kingdom ; MC_UU_12011/1/MRC_/Medical Research Council/United Kingdom ; MC_UP_A620_1014/MRC_/Medical Research Council/United Kingdom ; MC_UU_12019/1/MRC_/Medical Research Council/United Kingdom ; /ARC_/Arthritis Research UK/United Kingdom ; MR/K00414X/1/MRC_/Medical Research Council/United Kingdom ; MC_U147585824/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aged ; Aging/genetics/*pathology ; Female ; Hand Strength/*physiology ; Humans ; Inflammation/*complications ; Longitudinal Studies ; Male ; Real-Time Polymerase Chain Reaction ; Telomere/*pathology ; },
abstract = {Telomere attrition has been associated with age-related diseases, although causality is unclear and controversial; low-grade systemic inflammation (inflammaging) has also been implicated in age-related pathogenesis. Unpicking the relationship between aging, telomere length (TL), and inflammaging is hence essential to the understanding of aging and management of age-related diseases. This longitudinal study explored whether telomere attrition is a cause or consequence of aging and whether inflammaging explains some of the associations between TL and one marker of aging, grip strength. We studied 253 Hertfordshire Ageing Study participants at baseline and 10-year follow-up (mean age at baseline 67.1 years). Participants completed a health questionnaire and had blood samples collected for immune-endocrine and telomere analysis at both time points. Physical aging was characterized at follow-up using grip strength. Faster telomere attrition was associated with lower grip strength at follow-up (β = 0.98, p = 0.035). This association was completely attenuated when adjusted for inflammaging burden (p = 0.86) over the same period. Similarly, greater inflammaging burden was associated with lower grip strength at follow-up (e.g., interleukin [IL]-1β: β = -2.18, p = 0.001). However, these associations were maintained when adjusted for telomere attrition (IL-1β, p = 0.006). We present evidence that inflammaging may be driving telomere attrition and in part explains the associations that have previously been reported between TL and grip strength. Thus, biomarkers of physical aging, such as inflammaging, may require greater exploration. Further work is now indicated.},
}
@article {pmid24857325,
year = {2014},
author = {Raymond, AR and Norton, GR and Harden, LM and Woodiwiss, AJ and Brooksbank, RL},
title = {Chronic inflammation reduces cardiac relative telomere length without altering left ventricular chamber function.},
journal = {International journal of cardiology},
volume = {175},
number = {2},
pages = {367-369},
doi = {10.1016/j.ijcard.2014.04.253},
pmid = {24857325},
issn = {1874-1754},
mesh = {Animals ; Inflammation/microbiology/pathology ; Myocardium/*pathology ; Organ Culture Techniques ; Rats ; Rats, Sprague-Dawley ; Staphylococcus aureus ; Telomere/*pathology/*physiology ; Telomere Homeostasis/*physiology ; Ventricular Function, Left/*physiology ; },
}
@article {pmid24853549,
year = {2014},
author = {Seow, WJ and Cawthon, RM and Purdue, MP and Hu, W and Gao, YT and Huang, WY and Weinstein, SJ and Ji, BT and Virtamo, J and Hosgood, HD and Bassig, BA and Shu, XO and Cai, Q and Xiang, YB and Min, S and Chow, WH and Berndt, SI and Kim, C and Lim, U and Albanes, D and Caporaso, NE and Chanock, S and Zheng, W and Rothman, N and Lan, Q},
title = {Telomere length in white blood cell DNA and lung cancer: a pooled analysis of three prospective cohorts.},
journal = {Cancer research},
volume = {74},
number = {15},
pages = {4090-4098},
pmid = {24853549},
issn = {1538-7445},
support = {HHSN261201000006C/CP/NCI NIH HHS/United States ; N01 CN045035/CN/NCI NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; N01RC37004/RC/CCR NIH HHS/United States ; N01 CN045165/CN/NCI NIH HHS/United States ; UM1 CA182910/CA/NCI NIH HHS/United States ; N01-RC-45035/RC/CCR NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; },
mesh = {Case-Control Studies ; Cohort Studies ; DNA/*blood/genetics ; DNA, Neoplasm/blood/genetics ; Female ; Humans ; Leukocytes/metabolism/*ultrastructure ; Lung Neoplasms/*blood/*genetics ; Male ; Middle Aged ; Prospective Studies ; Risk Factors ; Telomere/*genetics ; },
abstract = {We investigated the relationship between telomere length and lung cancer in a pooled analysis from three prospective cohort studies: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, conducted among men and women in the United States, and previously published data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Trial conducted among male smokers in Finland, and the Shanghai Women's Health Study (SWHS), which is comprised primarily of never-smokers. The pooled population included 847 cases and 847 controls matched by study, age, and sex. Leukocyte telomere length was measured by a monochrome multiplex qPCR assay. We used conditional logistic regression models to calculate ORs and their 95% confidence intervals (CI) for the association between telomere length and lung cancer risk, adjusted for age and pack-years of smoking. Longer telomere length was associated with increased lung cancer risk in the pooled analysis [OR (95% CI) by quartile: 1.00; 1.24 (0.90-1.71); 1.27 (0.91-1.78); and 1.86 (1.33-2.62); P trend = 0.000022]. Findings were consistent across the three cohorts and strongest for subjects with very long telomere length, i.e., lung cancer risks for telomere length [OR (95% CI)] in the upper half of the fourth quartile were 2.41 (1.28-4.52), 2.16 (1.11-4.23), and 3.02(1.39-6.58) for the PLCO trial, the ATBC trial, and the SWHS, respectively. In addition, the association persisted among cases diagnosed more than 6 years after blood collection and was particularly evident for female adenocarcinoma cases. Telomere length in white blood cell DNA may be a biomarker of future increased risk of lung cancer in diverse populations.},
}
@article {pmid24846723,
year = {2014},
author = {Nelson, AD and Forsythe, ES and Gan, X and Tsiantis, M and Beilstein, MA},
title = {Extending the model of Arabidopsis telomere length and composition across Brassicaceae.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {22},
number = {2},
pages = {153-166},
pmid = {24846723},
issn = {1573-6849},
support = {BB/H006974/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Arabidopsis/classification/*genetics ; Arabidopsis Proteins/genetics/metabolism ; DNA, Plant/genetics ; DNA-Binding Proteins/genetics/metabolism ; *Genes, Plant ; Histones/genetics/metabolism ; Phylogeny ; Sequence Alignment ; Sequence Analysis, DNA ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Telomeres are repetitive TG-rich DNA elements essential for maintaining the stability of genomes and replicative capacity of cells in almost all eukaryotes. Most of what is known about telomeres in plants comes from the angiosperm Arabidopsis thaliana, which has become an important comparative model for telomere biology. Arabidopsis tolerates numerous insults to its genome, many of which are catastrophic or lethal in other eukaryotic systems such as yeast and vertebrates. Despite the importance of Arabidopsis in establishing a model for the structure and regulation of plant telomeres, only a handful of studies have used this information to assay components of telomeres from across land plants, or even among the closest relatives of Arabidopsis in the plant family Brassicaceae. Here, we determined how well Arabidopsis represents Brassicaceae by comparing multiple aspects of telomere biology in species that represent major clades in the family tree. Specifically, we determined the telomeric repeat sequence, measured bulk telomere length, and analyzed variation in telomere length on syntenic chromosome arms. In addition, we used a phylogenetic approach to infer the evolutionary history of putative telomere-binding proteins, CTC1, STN1, TEN1 (CST), telomere repeat-binding factor like (TRFL), and single Myb histone (SMH). Our analyses revealed conservation of the telomeric DNA repeat sequence, but considerable variation in telomere length among the sampled species, even in comparisons of syntenic chromosome arms. We also found that the single-stranded and double-stranded telomeric DNA-binding complexes CST and TRFL, respectively, differ in their pattern of gene duplication and loss. The TRFL and SMH gene families have undergone numerous duplication events, and these duplicate copies are often retained in the genome. In contrast, CST components occur as single-copy genes in all sampled genomes, even in species that experienced recent whole genome duplication events. Taken together, our results place the Arabidopsis model in the context of other species in Brassicaceae, making the family the best characterized plant group in regard to telomere architecture.},
}
@article {pmid24844311,
year = {2014},
author = {Chen, YD and Lu, C and Wei, J and Han, S and Wang, H and Jiang, T and Qiu, XG and Yang, M},
title = {1p34.2 rs621559 and 14q21 rs398652 leukocyte telomere length-related genetic variants contribute to glioma susceptibility.},
journal = {Journal of neuro-oncology},
volume = {119},
number = {1},
pages = {71-78},
pmid = {24844311},
issn = {1573-7373},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Brain Neoplasms/*genetics/metabolism/pathology ; Case-Control Studies ; Child ; Child, Preschool ; *Chromosomes, Human, Pair 1 ; *Chromosomes, Human, Pair 14 ; Female ; Genetic Association Studies ; *Genetic Predisposition to Disease ; Genotype ; Glioma/*genetics/metabolism/pathology ; Haplotypes ; Humans ; Leukocytes/metabolism ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Telomere ; Telomere Homeostasis/*genetics ; Young Adult ; },
abstract = {Recent genome-wide association studies have identified several leukocyte telomere length (LTL)-related single nucleotide polymorphisms (SNPs). Our previous data demonstrated that two SNPs (rs398652 on 14q21 and rs621559 on 1p34.2) were associated with LTL and risk of esophageal squamous cell carcinoma in Chinese. However, the role of these genetic variants on glioma risk is still unknown. Therefore, we examined if these genetic variants have impact on the genetic susceptibility of glioma in Chinese. On the basis of analyzing 404 glioma patients and frequency-matched 820 controls, we found that subjects having the 1p34.2 rs621559 AG or GG genotype had an OR of 1.82 (95 % CI = 1.07-3.09, P = 0.026) or 2.12 (95 % CI = 1.26-3.56, P = 0.005) for developing glioma, respectively, compared with subjects having the rs621559 AA genotype. Similarly, the 14q21 rs398652 AG or GG genotype was associated with increased glioma risk (OR = 1.39, 95 % CI = 1.07-1.80, P = 0.012; OR = 1.52, 95 % CI = 1.04-2.20, P = 0.029) compared to AA genotype. In all, our results highlight the possible role of telomere in carcinogenesis.},
}
@article {pmid24842907,
year = {2014},
author = {Zhdanova, NS and Draskovic, I and Minina, JM and Karamysheva, TV and Novo, CL and Liu, WY and Porreca, RM and Gibaud, A and Zvereva, ME and Skvortsov, DA and Rubtsov, NB and Londoño-Vallejo, A},
title = {Recombinogenic telomeres in diploid Sorex granarius (Soricidae, Eulipotyphla) fibroblast cells.},
journal = {Molecular and cellular biology},
volume = {34},
number = {15},
pages = {2786-2799},
pmid = {24842907},
issn = {1098-5549},
mesh = {Animals ; Cells, Cultured ; Chromosomes, Mammalian/genetics/metabolism ; DNA, Ribosomal/genetics ; Diploidy ; Fibroblasts/*metabolism ; Recombination, Genetic/*genetics ; Shrews/*genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {The telomere structure in the Iberian shrew Sorex granarius is characterized by unique, striking features, with short arms of acrocentric chromosomes carrying extremely long telomeres (up to 300 kb) with interspersed ribosomal DNA (rDNA) repeat blocks. In this work, we investigated the telomere physiology of S. granarius fibroblast cells and found that telomere repeats are transcribed on both strands and that there is no telomere-dependent senescence mechanism. Although telomerase activity is detectable throughout cell culture and appears to act on both short and long telomeres, we also discovered that signatures of a recombinogenic activity are omnipresent, including telomere-sister chromatid exchanges, formation of alternative lengthening of telomeres (ALT)-associated PML-like bodies, production of telomere circles, and a high frequency of telomeres carrying marks of a DNA damage response. Our results suggest that recombination participates in the maintenance of the very long telomeres in normal S. granarius fibroblasts. We discuss the possible interplay between the interspersed telomere and rDNA repeats in the stabilization of the very long telomeres in this organism.},
}
@article {pmid24840723,
year = {2014},
author = {Zhang, DH and Chen, JY and Hong, CQ and Yi, DQ and Wang, F and Cui, W},
title = {High-risk human papillomavirus infection associated with telomere elongation in patients with esophageal squamous cell carcinoma with poor prognosis.},
journal = {Cancer},
volume = {120},
number = {17},
pages = {2673-2683},
doi = {10.1002/cncr.28797},
pmid = {24840723},
issn = {1097-0142},
mesh = {Carcinoma, Squamous Cell/genetics/mortality/pathology/*virology ; DNA Methylation ; Esophageal Neoplasms/genetics/mortality/pathology/*virology ; Esophageal Squamous Cell Carcinoma ; Female ; Gene Dosage ; Host-Pathogen Interactions ; Human papillomavirus 16/*physiology ; Human papillomavirus 18/*physiology ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Papillomavirus Infections/genetics/pathology/*virology ; Prognosis ; Proportional Hazards Models ; Risk Factors ; Telomerase/genetics ; Telomere/genetics/metabolism/virology ; *Telomere Homeostasis ; Telomeric Repeat Binding Protein 2/genetics ; },
abstract = {BACKGROUND: Telomere maintenance is crucial in carcinogenesis and tumor progression. The results of a previous study from the authors indicated that infection with high-risk human papillomavirus (HR-HPV) types 16, 18, and 58 was a risk factor for esophageal squamous cell carcinoma (ESCC) in the Shantou region of China. In the current study, the authors explored the association between HR-HPV infection, telomere length (TL), and DNA methylation and their significance in the prognosis of patients with ESCC.<br><br>METHODS: TL and DNA methylation were analyzed by real-time polymerase chain reaction and methylation-specific polymerase chain reaction in 70 cases of ESCC tumor (T) and paired nontumor (NT) tissues and 50 cases of normal esophagus (NE). The prognostic value of TL and DNA methylation in ESCC was analyzed.<br><br>RESULTS: TL gradually decreased from NE to NT to T tissue. TL in tumor tissue (T-TL) was found to be longer in tissue that was positive for HR-HPV compared with negative tissue and was found to be positively associated with viral load (Spearman correlation, 0.410; P&#x2009;=&#x2009;.037) and integration (represented by the ratio of HR-HPV E2 to E6/E7 genes; P&#x2009;=&#x2009;.01). The DNA methylation ratio of human telomerase reverse transcriptase was more prevalent with long (&#x2265; 0.7) compared with short (< 0.7) T-TL and was positively correlated with T-TL (Spearman correlation, 0.318; P&#x2009;=&#x2009;.007) and HR-HPV integration (P&#x2009;=&#x2009;.036). Furthermore, Cox proportional hazards modeling revealed a high ratio of T-TL to NT-TL (&#x2265; 0.80) as a factor of poor prognosis, independent of other clinicopathologic variables.<br><br>CONCLUSIONS: HR-HPV infection and integration related to telomere elongation and DNA methylation of human telomerase reverse transcriptase may be a potential biomarker of prognosis in patients with ESCC.},
}
@article {pmid24835988,
year = {2014},
author = {Holstein, EM and Clark, KR and Lydall, D},
title = {Interplay between nonsense-mediated mRNA decay and DNA damage response pathways reveals that Stn1 and Ten1 are the key CST telomere-cap components.},
journal = {Cell reports},
volume = {7},
number = {4},
pages = {1259-1269},
pmid = {24835988},
issn = {2211-1247},
support = {13314/CRUK_/Cancer Research UK/United Kingdom ; BBF016980/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/F006039/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MR/L001284/1/MRC_/Medical Research Council/United Kingdom ; WT093088MA/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Cell Cycle Proteins/genetics/*metabolism ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; *DNA Damage ; DNA, Single-Stranded/genetics/metabolism ; *Nonsense Mediated mRNA Decay ; Protein Binding ; Protein Structure, Secondary ; RNA, Messenger/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Yeasts ; },
abstract = {A large and diverse set of proteins, including CST complex, nonsense mediated decay (NMD), and DNA damage response (DDR) proteins, play important roles at the telomere in mammals and yeast. Here, we report that NMD, like the DDR, affects single-stranded DNA (ssDNA) production at uncapped telomeres. Remarkably, we find that the requirement for Cdc13, one of the components of CST, can be efficiently bypassed when aspects of DDR and NMD pathways are inactivated. However, identical genetic interventions do not bypass the need for Stn1 and Ten1, the partners of Cdc13. We show that disabling NMD alters the stoichiometry of CST components at telomeres and permits Stn1 to bind telomeres in the absence of Cdc13. Our data support a model that Stn1 and Ten1 can function in a Cdc13-independent manner and have implications for the function of CST components across eukaryotes.},
}
@article {pmid24829382,
year = {2014},
author = {Lisaingo, K and Uringa, EJ and Lansdorp, PM},
title = {Resolution of telomere associations by TRF1 cleavage in mouse embryonic stem cells.},
journal = {Molecular biology of the cell},
volume = {25},
number = {13},
pages = {1958-1968},
pmid = {24829382},
issn = {1939-4586},
mesh = {Animals ; Bacterial Proteins/metabolism ; Cell Cycle ; Cell Survival ; Embryonic Stem Cells/metabolism/*ultrastructure ; Endopeptidases/biosynthesis ; Luminescent Proteins/metabolism ; Mice, 129 Strain ; Mitosis ; Proteolysis ; Recombinant Fusion Proteins/metabolism ; Telomere/*metabolism/ultrastructure ; Telomeric Repeat Binding Protein 1/*metabolism ; },
abstract = {Telomere associations have been observed during key cellular processes such as mitosis, meiosis, and carcinogenesis and must be resolved before cell division to prevent genome instability. Here we establish that telomeric repeat-binding factor 1 (TRF1), a core component of the telomere protein complex, is a mediator of telomere associations in mammalian cells. Using live-cell imaging, we show that expression of TRF1 or yellow fluorescent protein (YFP)-TRF1 fusion protein above endogenous levels prevents proper telomere resolution during mitosis. TRF1 overexpression results in telomere anaphase bridges and aggregates containing TRF1 protein and telomeric DNA. Site-specific protein cleavage of YFP-TRF1 by tobacco etch virus protease resolves telomere aggregates, indicating that telomere associations are mediated by TRF1. This study provides novel insight into the formation and resolution of telomere associations.},
}
@article {pmid24828261,
year = {2014},
author = {Buxton, JL and Suderman, M and Pappas, JJ and Borghol, N and McArdle, W and Blakemore, AI and Hertzman, C and Power, C and Szyf, M and Pembrey, M},
title = {Human leukocyte telomere length is associated with DNA methylation levels in multiple subtelomeric and imprinted loci.},
journal = {Scientific reports},
volume = {4},
number = {},
pages = {4954},
pmid = {24828261},
issn = {2045-2322},
support = {068545/Z/02/WT_/Wellcome Trust/United Kingdom ; WT088431MA/WT_/Wellcome Trust/United Kingdom ; 072937/Z/03/Z/WT_/Wellcome Trust/United Kingdom ; G0000934/MRC_/Medical Research Council/United Kingdom ; MR/K014536/1/MRC_/Medical Research Council/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MOP-42411/CAPMC/CIHR/Canada ; },
mesh = {Adolescent ; Adult ; Binding Sites ; Child ; Child, Preschool ; Cluster Analysis ; CpG Islands ; *DNA Methylation ; DNA-Binding Proteins/metabolism ; *Genomic Imprinting ; Humans ; Infant ; Infant, Newborn ; Leukocytes/*metabolism ; Male ; Middle Aged ; Promoter Regions, Genetic ; Protein Binding ; Repressor Proteins ; Signal Transduction ; Telomere/*genetics/*metabolism ; *Telomere Homeostasis ; Transcription Factors/metabolism ; Transcription Initiation Site ; Young Adult ; },
abstract = {In humans, leukocyte telomere length (LTL) is positively correlated with lifespan, and shorter LTL is associated with increased risk of age-related disease. In this study we tested for association between telomere length and methylated cytosine levels. Measurements of mean telomere length and DNA methylation at >450,000 CpG sites were obtained for both blood (N = 24) and EBV-transformed cell-line (N = 36) DNA samples from men aged 44-45 years. We identified 65 gene promoters enriched for CpG sites at which methylation levels are associated with leukocyte telomere length, and 36 gene promoters enriched for CpG sites at which methylation levels are associated with telomere length in DNA from EBV-transformed cell-lines. We observed significant enrichment of positively associated methylated CpG sites in subtelomeric loci (within 4 Mb of the telomere) (P < 0.01), and also at loci in imprinted regions (P < 0.001). Our results pave the way for further investigations to help elucidate the relationships between telomere length, DNA methylation and gene expression in health and disease.},
}
@article {pmid24816913,
year = {2014},
author = {Jodczyk, S and Fergusson, DM and Horwood, LJ and Pearson, JF and Kennedy, MA},
title = {No association between mean telomere length and life stress observed in a 30 year birth cohort.},
journal = {PloS one},
volume = {9},
number = {5},
pages = {e97102},
pmid = {24816913},
issn = {1932-6203},
mesh = {Adult ; Age Factors ; Cohort Studies ; DNA Primers/genetics ; Humans ; Longitudinal Studies ; New Zealand ; Polymerase Chain Reaction ; Regression Analysis ; Stress, Psychological/*physiopathology ; Telomere Homeostasis/genetics/*physiology ; },
abstract = {Telomeres are specialised structures that cap the ends of chromosomes. They shorten with each cell division and have been proposed as a marker of cellular aging. Previous studies suggest that early life stressors increase the rate of telomere shortening with potential impact on disease states and mortality later in life. This study examined the associations between telomere length and exposure to a number of stressors that arise during development from the antenatal/perinatal period through to young adulthood. Participants were from the Christchurch Health and Development Study (CHDS), a New Zealand longitudinal birth cohort which has followed participants from birth until age 30. Telomere length was obtained on DNA from peripheral blood samples collected from consenting participants (n = 677) at age 28-30, using a quantitative PCR assay. These data were assessed for associations with 26 measures of life course adversity or stress which occurred prior to 25 years of age. No associations were found between telomere length measured at age 28-30 years and life course adversity or stress for specific measures and for the summary risk scores for each developmental domain. The correlations were very small ranging from -0.06 to 0.06 with a median of 0.01, and none were statistically significant. Our results in this well-studied birth cohort do not support prior reports of such associations, and underscore the need for more extensive replication of proposed links between stress and telomere biology in larger cohorts with appropriate phenotypic data.},
}
@article {pmid24816243,
year = {2014},
author = {Sakaguchi, H and Nishio, N and Hama, A and Kawashima, N and Wang, X and Narita, A and Doisaki, S and Xu, Y and Muramatsu, H and Yoshida, N and Takahashi, Y and Kudo, K and Moritake, H and Nakamura, K and Kobayashi, R and Ito, E and Yabe, H and Ohga, S and Ohara, A and Kojima, S and , },
title = {Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia.},
journal = {Haematologica},
volume = {99},
number = {8},
pages = {1312-1316},
pmid = {24816243},
issn = {1592-8721},
mesh = {Adolescent ; Anemia, Aplastic/*diagnosis/*drug therapy/immunology ; Child ; Child, Preschool ; Female ; Humans ; Immunosuppressive Agents/pharmacology/*therapeutic use ; Infant ; Lymphocytes/*drug effects/immunology/pathology ; Male ; Predictive Value of Tests ; Telomere/*drug effects/immunology/pathology ; Telomere Homeostasis/*drug effects/physiology ; Treatment Outcome ; },
abstract = {Predicting the response to immunosuppressive therapy could provide useful information to help the clinician define treatment strategies for patients with aplastic anemia. In our current study, we evaluated the relationship between telomere length of lymphocytes at diagnosis and the response to immunosuppressive therapy in 64 children with aplastic anemia, using flow fluorescence in situ hybridization. Median age of patients was ten years (range 1.5-16.2 years). Severity of the disease was classified as very severe in 23, severe in 21, and moderate in 20 patients. All patients were enrolled in multicenter studies using antithymocyte globulin and cyclosporine. The response rate to immunosuppressive therapy at six months was 52% (33 of 64). The probability of 5-year failure-free survival and overall survival were 56% (95% confidence interval (CI): 41-69%) and 97% (95%CI: 87-99%), respectively. Median telomere length in responders was -0.4 standard deviation (SD) (-2.7 to +3.0 SD) and -1.5 SD (-4.0 to +1.6 (SD)) in non-responders (P<0.001). Multivariate analysis showed that telomere length shorter than -1.0 SD (hazard ratio (HR): 22.0; 95%CI: 4.19-115; P<0.001), platelet count at diagnosis less than 25×10(9)/L (HR: 13.9; 95%CI: 2.00-96.1; P=0.008), and interval from diagnosis to immunosuppressive therapy longer than 25 days (HR: 4.81; 95%CI: 1.15-20.1; P=0.031) were the significant variables for poor response to immunosuppressive therapy. Conversely to what has been found in adult patients, measurement of the telomere length of lymphocytes at diagnosis is a promising assay in predicting the response to immunosuppressive therapy in children with aplastic anemia.},
}
@article {pmid24813883,
year = {2014},
author = {Bartocci, C and Diedrich, JK and Ouzounov, I and Li, J and Piunti, A and Pasini, D and Yates, JR and Lazzerini Denchi, E},
title = {Isolation of chromatin from dysfunctional telomeres reveals an important role for Ring1b in NHEJ-mediated chromosome fusions.},
journal = {Cell reports},
volume = {7},
number = {4},
pages = {1320-1332},
pmid = {24813883},
issn = {2211-1247},
support = {P41 GM103533/GM/NIGMS NIH HHS/United States ; P41 RR011823/RR/NCRR NIH HHS/United States ; R01 AG038677/AG/NIA NIH HHS/United States ; AG038677/AG/NIA NIH HHS/United States ; },
mesh = {Chromatin/*genetics/isolation &amp; purification/metabolism ; DNA Damage ; *DNA End-Joining Repair ; Humans ; Polycomb Repressive Complex 1/*genetics/metabolism ; Telomere/chemistry/*genetics/metabolism ; },
abstract = {When telomeres become critically short, DNA damage response factors are recruited at chromosome ends, initiating a cellular response to DNA damage. We performed proteomic isolation of chromatin fragments (PICh) in order to define changes in chromatin composition that occur upon onset of acute telomere dysfunction triggered by depletion of the telomere-associated factor TRF2. This unbiased purification of telomere-associated proteins in functional or dysfunctional conditions revealed the dynamic changes in chromatin composition that take place at telomeres upon DNA damage induction. On the basis of our results, we describe a critical role for the polycomb group protein Ring1b in nonhomologous end-joining (NHEJ)-mediated end-to-end chromosome fusions. We show that cells with reduced levels of Ring1b have a reduced ability to repair uncapped telomeric chromatin. Our data represent an unbiased isolation of chromatin undergoing DNA damage and are a valuable resource to map the changes in chromatin composition in response to DNA damage activation.},
}
@article {pmid24807106,
year = {2014},
author = {Motevalli, A and Yasaei, H and Virmouni, SA and Slijepcevic, P and Roberts, T},
title = {The effect of chemotherapeutic agents on telomere length maintenance in breast cancer cell lines.},
journal = {Breast cancer research and treatment},
volume = {145},
number = {3},
pages = {581-591},
pmid = {24807106},
issn = {1573-7217},
mesh = {Antineoplastic Agents/pharmacology ; Azacitidine/*analogs &amp; derivatives/pharmacology ; Breast Neoplasms/*drug therapy ; Cell Line, Tumor ; DNA/genetics ; DNA Methylation/genetics ; Decitabine ; Epigenesis, Genetic ; Female ; Histones/metabolism ; Humans ; Hydroxamic Acids/*pharmacology ; MCF-7 Cells ; Methyltransferases/antagonists &amp; inhibitors ; Promoter Regions, Genetic/genetics ; Shelterin Complex ; Telomere/drug effects/physiology ; Telomere Homeostasis/*drug effects ; Telomere-Binding Proteins/*biosynthesis/genetics ; },
abstract = {Mammalian telomeric DNA consists of tandem repeats of the sequence TTAGGG associated with a specialized set of proteins, known collectively as Shelterin. These telosomal proteins protect the ends of chromosomes against end-to-end fusion and degradation. Short telomeres in breast cancer cells confer telomere dysfunction and this can be related to Shelterin proteins and their level of expression in breast cancer cell lines. This study investigates whether expression of Shelterin and Shelterin-associated proteins are altered, and influence the protection and maintenance of telomeres, in breast cancer cells. 5-aza-2'-deoxycytidine (5-aza-CdR) and trichostatin A (TSA) were used in an attempt to reactivate the expression of silenced genes. Our studies have shown that Shelterin and Shelterin-associated genes were down-regulated in breast cancer cell lines; this may be due to epigenetic modification of DNA as the promoter region of POT1 was found to be partially methylated. Shelterin genes expression was up-regulated upon treatment of 21NT breast cancer cells with 5-aza-CdR and TSA. The telomere length of treated 21NT cells was measured by q-PCR showed an increase in telomere length at different time points. Our studies have shown that down-regulation of Shelterin genes is partially due to methylation in some epithelial breast cancer cell lines. Removal of epigenetic silencing results in up-regulation of Shelterin and Shelterin-associated genes which can then lead to telomere length elongation and stability.},
}
@article {pmid24805953,
year = {2014},
author = {Laganović, M and Bendix, L and Rubelj, I and Kirhmajer, MV and Slade, N and Lela, IV and Premužić, V and Nilsson, PM and Jelaković, B},
title = {Reduced telomere length is not associated with early signs of vascular aging in young men born after intrauterine growth restriction: a paradox?.},
journal = {Journal of hypertension},
volume = {32},
number = {8},
pages = {1613-19; discussion 1619-20},
doi = {10.1097/HJH.0000000000000217},
pmid = {24805953},
issn = {1473-5598},
mesh = {Adult ; Blood Pressure/*physiology ; Cardiovascular Diseases/etiology ; Carotid Intima-Media Thickness ; *Cellular Senescence ; Cross-Sectional Studies ; Fetal Growth Retardation/*physiopathology ; Humans ; Infant, Small for Gestational Age ; Linear Models ; Male ; *Telomere ; Young Adult ; },
abstract = {OBJECTIVE: The mechanisms that increase cardiovascular risk in individuals born small for gestational age (SGA) are not well understood. Telomere shortening has been suggested to be a predictor of disease onset. Our aim was to determine whether impaired intrauterine growth is associated with early signs of vascular aging and whether telomere length could be a biomarker of this pathway.<br><br>METHODS: One hundred and fourteen healthy young men born SGA or after normal pregnancy [appropriate for gestational age (AGA)] were enrolled. Patient data were gathered from questionnaires and clinical exams, including blood pressure (BP) measurement routine laboratory analyses, and carotid intima-media thickness (cIMT). Leukocyte telomere length (LTL) was assessed by quantitative PCR. Birth data were obtained from medical records.<br><br>RESULTS: The SGA group had significantly higher pulse pressure and cIMT, and a trend to increased SBP and heart rate in comparison to the AGA group. Interestingly, SGA men exhibited a 42% longer LTL than the AGA group. LTL was inversely associated with age, BMI, BP and birth parameters. In multiple regression analysis, BMI was the key determinant of SBP and cIMT.<br><br>CONCLUSION: Young men born SGA show early signs of vascular aging. Unexpectedly, in our cohort, the SGA group had longer telomeres than the normal controls. Although longer telomeres are predictive of better health in the future, our findings could indicate a faster telomere attrition rate and probable early onset of cardiovascular risk in SGA participants. Follow-up of this cohort will clarify hypothesis and validate telomere dynamics as indicators of future health risks.},
}
@article {pmid24803574,
year = {2014},
author = {Wendland, J and Walther, A},
title = {Chromosome number reduction in Eremothecium coryli by two telomere-to-telomere fusions.},
journal = {Genome biology and evolution},
volume = {6},
number = {5},
pages = {1186-1198},
pmid = {24803574},
issn = {1759-6653},
mesh = {Biological Evolution ; Centromere/genetics ; *Chromosomes, Fungal ; DNA Transposable Elements ; Eremothecium/*genetics ; *Genome, Fungal ; Molecular Sequence Data ; *Telomere ; },
abstract = {The genus Eremothecium belongs to the Saccharomyces complex of pre-whole-genome duplication (WGD) yeasts and contains both dimorphic and filamentous species. We established the 9.1-Mb draft genome of Eremothecium coryli, which encodes 4,682 genes, 186 tRNA genes, and harbors several Ty3 transposons as well as more than 60 remnants of transposition events (LTRs). The initial de novo assembly resulted in 19 scaffolds, which were assembled based on synteny to other Eremothecium genomes into six chromosomes. Interestingly, we identified eight E. coryli loci that bear centromeres in the closely related species E. cymbalariae. Two of these E. coryli loci, CEN1 and CEN8, however, lack conserved DNA elements and did not convey centromere function in a plasmid stability assay. Correspondingly, using a comparative genomics approach we identified two telomere-to-telomere fusion events in E. coryli as the cause of chromosome number reduction from eight to six chromosomes. Finally, with the genome sequences of E. coryli, E. cymbalariae, and Ashbya gossypii a reconstruction of three complete chromosomes of an Eremothecium ancestor revealed that E. coryli is more syntenic to this ancestor than the other Eremothecium species.},
}
@article {pmid24798729,
year = {2014},
author = {Hofmann, JN and Hutchinson, AA and Cawthon, R and Liu, CS and Lynch, SM and Lan, Q and Rothman, N and Stolzenberg-Solomon, R and Purdue, MP},
title = {Telomere length varies by DNA extraction method: implications for epidemiologic research-letter.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {23},
number = {6},
pages = {1129-1130},
pmid = {24798729},
issn = {1538-7755},
support = {Z99 CA999999//Intramural NIH HHS/United States ; },
mesh = {DNA/*isolation &amp; purification ; Female ; Humans ; Leukocytes/*chemistry ; Male ; Telomere/*chemistry ; },
}
@article {pmid24798728,
year = {2014},
author = {Boardman, LA and Skinner, HG and Litzelman, K},
title = {Telomere length varies by DNA extraction method: implications for epidemiologic research--response.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {23},
number = {6},
pages = {1131},
pmid = {24798728},
issn = {1538-7755},
support = {R01 CA132718/CA/NCI NIH HHS/United States ; },
mesh = {DNA/*isolation &amp; purification ; Female ; Humans ; Leukocytes/*chemistry ; Male ; Telomere/*chemistry ; },
}
@article {pmid24796612,
year = {2014},
author = {Turner, KJ and Vasu, V and Greenall, J and Griffin, DK},
title = {Telomere length analysis and preterm infant health: the importance of assay design in the search for novel biomarkers.},
journal = {Biomarkers in medicine},
volume = {8},
number = {4},
pages = {485-498},
doi = {10.2217/bmm.14.13},
pmid = {24796612},
issn = {1752-0371},
support = {//Medical Research Council/United Kingdom ; },
mesh = {Biomarkers/metabolism ; Fetal Membranes, Premature Rupture ; Humans ; In Situ Hybridization, Fluorescence ; Infant, Newborn ; Infant, Premature ; Real-Time Polymerase Chain Reaction ; Telomere/*metabolism ; },
abstract = {Preterm infants develop an 'aged' phenotype in comparison with term-born infants, one component of which is adverse metabolic health and, therefore, long-term health follow-up is warranted to identify morbidity. In light of this, the identification and use of biomarkers to aid with prognosis would be a welcome development. Telomeres are repeat sequences at the ends of each chromosome arm known to shorten as a consequence of cellular aging, and in relation to several disease conditions. The hypothesis that expreterm infants manifest alterations in telomere attrition rate is, therefore, one of interest. Analysis of telomere length maybe a plausible technique to predict prognosis in relation to preterm birth, and early life environmental and nutritional exposures. In this article, we review the literature on telomere length analysis in the preterm infant population and examine the tools available to measure telomere length.},
}
@article {pmid24795349,
year = {2014},
author = {Saxena, R and Bjonnes, A and Prescott, J and Dib, P and Natt, P and Lane, J and Lerner, M and Cooper, JA and Ye, Y and Li, KW and Maubaret, CG and Codd, V and Brackett, D and Mirabello, L and Kraft, P and Dinney, CP and Stowell, D and Peyton, M and Ralhan, S and Wander, GS and Mehra, NK and Salpea, KD and Gu, J and Wu, X and Mangino, M and Hunter, DJ and De Vivo, I and Humphries, SE and Samani, NJ and Spector, TD and Savage, SA and Sanghera, DK},
title = {Genome-wide association study identifies variants in casein kinase II (CSNK2A2) to be associated with leukocyte telomere length in a Punjabi Sikh diabetic cohort.},
journal = {Circulation. Cardiovascular genetics},
volume = {7},
number = {3},
pages = {287-295},
pmid = {24795349},
issn = {1942-3268},
support = {RG/08/008/25291/BHF_/British Heart Foundation/United Kingdom ; PG08/008/BHF_/British Heart Foundation/United Kingdom ; R01 DK082766/DK/NIDDK NIH HHS/United States ; R01DK082766/DK/NIDDK NIH HHS/United States ; K01 TW006087/TW/FIC NIH HHS/United States ; },
mesh = {Adult ; Aged ; Asian People/genetics ; Casein Kinase II/*genetics/metabolism ; Cohort Studies ; Diabetes Mellitus, Type 2/*enzymology/genetics/metabolism ; Female ; Genetic Predisposition to Disease ; Genetic Variation ; Genome-Wide Association Study ; Humans ; India ; Leukocytes/enzymology/*metabolism ; Male ; Middle Aged ; Phosphorylation ; Polymorphism, Single Nucleotide ; Religion ; Telomere/*metabolism ; Young Adult ; },
abstract = {BACKGROUND: Telomere length is a heritable trait, and short telomere length has been associated with multiple chronic diseases. We investigated the relationship of relative leukocyte telomere length with cardiometabolic risk and performed the first genome-wide association study and meta-analysis to identify variants influencing relative telomere length in a population of Sikhs from South Asia.<br><br>METHODS AND RESULTS: Our results revealed a significant independent association of shorter relative telomere length with type 2 diabetes mellitus and heart disease. Our discovery genome-wide association study (n=1616) was followed by stage 1 replication of 25 top signals (P<10(-6)) in an additional Sikhs (n=2397). On combined discovery and stage 1 meta-analysis (n= 4013), we identified a novel relative telomere length locus at chromosome 16q21 represented by an intronic variant (rs74019828) in the CSNK2A2 gene (&#x3b2;=-0.38; P=4.5&#xd7;10(-8)). We further tested 3 top variants by genotyping in UK cardiovascular disease (UKCVD) (whites n=2952) for stage 2. Next, we performed in silico replication of 139 top signals (P<10(-5)) in UK Twin, Nurses Heart Study, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and MD Anderson Cancer Controls (n=10&#x2009;033) and joint meta-analysis (n=16&#x2009;998). The observed signal in CSNK2A2 was confined to South Asians and could not be replicated in whites because of significant difference in allele frequencies (P<0.001). CSNK2A2 phosphorylates telomeric repeat binding factor 1 and plays an important role for regulation of telomere length homoeostasis.<br><br>CONCLUSIONS: By identification of a novel signal in telomere pathway genes, our study provides new molecular insight into the underlying mechanism that may regulate telomere length and its association with human aging and cardiometabolic pathophysiology.},
}
@article {pmid24793435,
year = {2015},
author = {Paul, L and Jacques, PF and Aviv, A and Vasan, RS and D'Agostino, RB and Levy, D and Selhub, J},
title = {High plasma folate is negatively associated with leukocyte telomere length in Framingham Offspring cohort.},
journal = {European journal of nutrition},
volume = {54},
number = {2},
pages = {235-241},
pmid = {24793435},
issn = {1436-6215},
support = {N01 HC025195/HC/NHLBI NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; ZIA HL006001-07//Intramural NIH HHS/United States ; N01-HC-25195/HC/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Cohort Studies ; Dietary Supplements/*adverse effects ; Female ; Folic Acid/*adverse effects/blood ; Food, Fortified/*adverse effects ; Homocysteine/blood ; Humans ; Leukocytes/*immunology/metabolism ; Male ; Massachusetts ; Middle Aged ; *Telomere Shortening ; *Up-Regulation ; },
abstract = {PURPOSE: Shortening of telomeres, the protective structures at the ends of eukaryotic chromosomes, is associated with age-related pathologies. Telomere length is influenced by DNA integrity and DNA and histone methylation. Folate plays a role in providing precursors for nucleotides and methyl groups for methylation reactions and has the potential to influence telomere length.<br><br>METHOD: We determined the association between leukocyte telomere length and long-term plasma folate status (mean of 4 years) in Framingham Offspring Study (n = 1,044, females = 52.1 %, mean age 59 years) using data from samples collected before and after folic acid fortification. Leukocyte telomere length was determined by Southern analysis and fasting plasma folate concentration using microbiological assay.<br><br>RESULTS: There was no significant positive association between long-term plasma folate and leukocyte telomere length among the Framingham Offspring Study participants perhaps due to their adequate folate status. While the leukocyte telomere length in the second quintile of plasma folate was longer than that in the first quintile, the difference was not statistically significant. The leukocyte telomere length of the individuals in the fifth quintile of plasma folate was shorter than that of those in the second quintile by 180 bp (P < 0.01). There was a linear decrease in leukocyte telomere length with higher plasma folate concentrations in the upper four quintiles of plasma folate (P for trend = 0.001). Multivitamin use was associated with shorter telomeres in this cohort (P = 0.015).<br><br>CONCLUSIONS: High plasma folate status possibly resulting from high folic acid intake may interfere with the role of folate in maintaining telomere integrity.},
}
@article {pmid24793325,
year = {2014},
author = {Svensson, J and Karlsson, MK and Ljunggren, &#xd6; and Tivesten, &#xc5; and Mellström, D and Movérare-Skrtic, S},
title = {Leukocyte telomere length is not associated with mortality in older men.},
journal = {Experimental gerontology},
volume = {57},
number = {},
pages = {6-12},
doi = {10.1016/j.exger.2014.04.013},
pmid = {24793325},
issn = {1873-6815},
mesh = {Aged ; Aged, 80 and over ; Humans ; Leukocytes ; Male ; *Mortality ; Sweden/epidemiology ; *Telomere ; *Telomere Homeostasis ; },
abstract = {Leukocyte telomere length (LTL) is related to the aging of somatic cells. We hypothesized that LTL is inversely associated with mortality in elderly men. LTL was measured in 2744 elderly men (mean age 75.5, range 69-81years) included in the prospective population-based MrOS-Sweden study. Mortality data were obtained from national health registers with no loss of follow-up. During the follow-up (mean 6.0years), 556 (20%) of the participants died. Using Cox proportional hazards regression, tertile of LTL did not associate with all-cause mortality [tertile 1 (shortest) or 2 (middle) vs. tertile 3 (longest); hazard ratio (HR)=1.05, 95% confidence interval (CI) 0.85-1.28 and HR=0.97, 95% CI 0.79-1.19, respectively]. Furthermore, LTL did not associate with cancer (197 events) or cardiovascular disease (CVD, 206 events) mortality (tertile 1 vs. tertile 3; HR=0.94, 95% CI 0.67-1.34 and HR=0.94, 95% CI 0.68-1.30, respectively). The lack of association between LTL and mortality remained also after adjustment for multiple covariates. Our results demonstrate that LTL is not associated with all-cause mortality or mortality due to cancer or CVD in elderly men. Further studies are needed to determine whether LTL can predict the risk of mortality in elderly women.},
}
@article {pmid24792868,
year = {2014},
author = {Simpson, JL and Wells, D},
title = {Telomere length and aneuploidy: clinical and biological insights into human preimplantation embryos.},
journal = {Reproductive biomedicine online},
volume = {28},
number = {5},
pages = {531-532},
doi = {10.1016/j.rbmo.2014.03.009},
pmid = {24792868},
issn = {1472-6491},
mesh = {*Aneuploidy ; Biopsy ; Blastocyst/*metabolism/pathology ; Embryonic Development/genetics ; Humans ; Preimplantation Diagnosis ; Reproductive Techniques, Assisted ; Telomere/*physiology ; Telomere Shortening/physiology ; },
}
@article {pmid24792489,
year = {2014},
author = {Farooqi, AS and Dagg, RA and Choi, LM and Shay, JW and Reynolds, CP and Lau, LM},
title = {Alternative lengthening of telomeres in neuroblastoma cell lines is associated with a lack of MYCN genomic amplification and with p53 pathway aberrations.},
journal = {Journal of neuro-oncology},
volume = {119},
number = {1},
pages = {17-26},
pmid = {24792489},
issn = {1573-7373},
support = {C06 RR030414/RR/NCRR NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; R01 CA082830/CA/NCI NIH HHS/United States ; CA82830/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Gene Amplification ; Humans ; N-Myc Proto-Oncogene Protein ; Nuclear Proteins/*genetics/metabolism ; Oncogene Proteins/*genetics/metabolism ; Signal Transduction/*genetics ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; Tumor Suppressor Protein p53/*genetics/metabolism ; },
abstract = {Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere length maintenance mechanism that enables the unlimited proliferation of a subset of cancer cells. Some neuroblastoma (NB) tumors appear to maintain telomere length by activating ALT. Of 40 NB cell lines, we identified four potential ALT cell lines (CHLA-90, SK-N-FI, LA-N-6, and COG-N-291) that were telomerase-negative and had long telomeres (a feature of ALT cells). All four cell lines lacked MYCN amplification and were p53 non-functional upon irradiation. Two of these cell lines (CHLA-90 and SK-N-FI) were positive for C-circles (telomeric DNA circles) and ALT-associated promyelocytic leukemia nuclear bodies, both of which are phenotypic characteristics of ALT. Mutation of ATRX (associated with ALT in tumors) was only found in CHLA-90. Thus, the ALT phenotype in NB may not be limited to tumors with ATRX mutations but is associated with a lack of MYCN amplification and alterations in the p53 pathway.},
}
@article {pmid24789893,
year = {2014},
author = {Boonekamp, JJ and Mulder, GA and Salomons, HM and Dijkstra, C and Verhulst, S},
title = {Nestling telomere shortening, but not telomere length, reflects developmental stress and predicts survival in wild birds.},
journal = {Proceedings. Biological sciences},
volume = {281},
number = {1785},
pages = {20133287},
pmid = {24789893},
issn = {1471-2954},
mesh = {Animals ; Crows/genetics/*physiology ; Electrophoresis, Gel, Pulsed-Field ; Erythrocytes/chemistry ; *Longevity ; Stress, Physiological/*genetics ; Telomere/chemistry ; *Telomere Shortening ; },
abstract = {Developmental stressors often have long-term fitness consequences, but linking offspring traits to fitness prospects has remained a challenge. Telomere length predicts mortality in adult birds, and may provide a link between developmental conditions and fitness prospects. Here, we examine the effects of manipulated brood size on growth, telomere dynamics and post-fledging survival in free-living jackdaws. Nestlings in enlarged broods achieved lower mass and lost 21% more telomere repeats relative to nestlings in reduced broods, showing that developmental stress accelerates telomere shortening. Adult telomere length was positively correlated with their telomere length as nestling (r = 0.83). Thus, an advantage of long telomeres in nestlings is carried through to adulthood. Nestling telomere shortening predicted post-fledging survival and recruitment independent of manipulation and fledgling mass. This effect was strong, with a threefold difference in recruitment probability over the telomere shortening range. By contrast, absolute telomere length was neither affected by brood size manipulation nor related to survival. We conclude that telomere loss, but not absolute telomere length, links developmental conditions to subsequent survival and suggest that telomere shortening may provide a key to unravelling the physiological causes of developmental effects on fitness.},
}
@article {pmid24783234,
year = {2014},
author = {Babizhayev, MA and Yegorov, YE},
title = {Biomarkers of oxidative stress and cataract. Novel drug delivery therapeutic strategies targeting telomere reduction and the expression of telomerase activity in the lens epithelial cells with N-acetylcarnosine lubricant eye drops: anti-cataract which helps to prevent and treat cataracts in the eyes of dogs and other animals.},
journal = {Current drug delivery},
volume = {11},
number = {1},
pages = {24-61},
doi = {10.2174/15672018113106660062},
pmid = {24783234},
issn = {1875-5704},
mesh = {Administration, Ophthalmic ; Animals ; Antioxidants/*administration &amp; dosage/chemistry ; Biomarkers/metabolism ; Carnosine/administration &amp; dosage/*analogs &amp; derivatives/chemistry ; Cataract/*drug therapy/enzymology/genetics/pathology ; Cell Membrane/drug effects/enzymology/pathology ; Cellular Senescence/drug effects ; Ceruloplasmin/metabolism ; Chemistry, Pharmaceutical ; Dogs ; Drug Carriers ; Epithelial Cells/*drug effects/enzymology/pathology ; Lens, Crystalline/*drug effects/enzymology/pathology ; Ophthalmic Solutions ; Oxidative Stress/*drug effects ; Prodrugs/*administration &amp; dosage/chemistry ; Technology, Pharmaceutical/methods ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/*metabolism ; },
abstract = {Cataracts in small animals are shown to be at least partially caused by oxidative damage to lens epithelial cells (LECs) and the internal lens; biomarkers of oxidative stress in the lens are considered as general biomarkers for life expectancy in the canine and other animals. Telomeres lengths and expressed telomerase activity in canine LECs may serve as important monitors of oxidative damage in normal LECs with documented higher levels of telomerase activity in cataractous LECs during cells' lifespan. Loss of functional telomere length below a critical threshold in LECs of canines during the effect of UV and chronic oxidative stress or metabolic failure, can activate programs leading to LEC senescence or death. Telomerase is induced in LECs of canines at critical stages of cataractogenesis initiation and exposure to oxidative stress through the involvement of catalytically active prooxidant transition metal (iron) ions. This work documents that transition metal ions (such as, ferrous ions- catalytic oxidants) might induce premature senescence in LECs of canines, telomere shortening with increased telomerase activity as adaptive response to UV light, oxidative and metabolic stresses. The therapeutic treatment with 1% N-acetylcarnosine (NAC) prodrug delivery is beneficial for prevention and dissolution of ripe cataracts in canines. This biological activity is based on the findings of ferroxidase activity pertinent to the dipeptide carnosine released ophthalmically from NAC prodrug of L-carnosine, stabilizing properties of carnosine on biological membranes based on the ability of the imidazole-containing dipeptides to interact with lipid peroxidation products and reactive oxygen species (ROS), to prevent membrane damage and delute the associated with membrane fragements protein aggregates. The advent of therapeutic treatment of cataracts in canines with N-acetylcarnosine lubricant eye drops through targeting the prevention of loss of functional telomere length below a critical threshold and "flirting" with an indirect effect with telomerase expression in LECs of canines during the effects of UV, chronic oxidative stress increases the successful rate of cataract management challenges in home veterinary care.},
}
@article {pmid24781401,
year = {2014},
author = {Srettabunjong, S and Satitsri, S and Thongnoppakhun, W and Tirawanchai, N},
title = {The study on telomere length for age estimation in a Thai population.},
journal = {The American journal of forensic medicine and pathology},
volume = {35},
number = {2},
pages = {148-153},
doi = {10.1097/PAF.0000000000000095},
pmid = {24781401},
issn = {1533-404X},
mesh = {Adolescent ; Adult ; Aging/*genetics ; Asian People/genetics ; Cadaver ; Child ; Child, Preschool ; Cross-Sectional Studies ; Female ; Forensic Genetics/*methods ; Genetic Markers ; Humans ; Infant ; Infant, Newborn ; Linear Models ; Male ; Middle Aged ; *Sex Determination Analysis ; Telomere/*genetics/physiology ; Thailand ; Young Adult ; },
abstract = {Age is one of the key parameters in establishing a physical characteristic profile of an individual. For biological evidence left in crime scenes such as blood, saliva, hair, etc, the evidence owner's age can be determined only by DNA extracted from these materials. Previous researches have found that there are certain DNA regions with specialized characteristic and function called telomere being able to predict age. The present study was to determine the correlation between telomere length and age as well as the effect of sex on the correlation and to create linear regression equation for age estimation in Thai population for forensic purposes. Blood samples obtained from unrelated healthy Thai fresh cadavers without anatomical organ abnormalities were used in this study. All cadaver subjects underwent the postmortem examination in jurisdiction of the Department of Forensic Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, and Institute of Forensic Medicine, Police General Hospital. Fifty blood samples from both sexes of all ages divided into 6 groups for equal age distribution (0-11, 12-23, 24-35, 36-47, 48-59, and 60 years old and older) were collected for a total of 100 samples. The extracted genomic DNA samples were then subjected to telomere length estimation by terminal restriction fragment (TRF) assay. The results showed that the mean TRF length was inversely correlated with age (r = -0.625), and sex did not have a statistically significant influence on the association between age and mean TRF length (P > 0.05). The obtained linear regression equation was y = 113.538 ± 9.604 - 0.012 × (R = 0.391; P < 0.001). However, the correlation was too low to be used for age estimation with high certainty and a possible reason for this in part would be the postmortem DNA degradation at some level, even using fresh cadaver blood, and other biological factors such as ethnicity and DNA sources. Roughly, those individuals who had a mean TRF length longer than 6.3 kilobase (kb), between 5.5 and 6.3 kb, and shorter than 5.5 kb aged younger than 28 years, 30 to 44 years, and older than 46 years, respectively (P < 0.01). As a preliminary study, this study highlighted that telomere length could act as a useful biomarker of aging in human population and might be used for rough age estimation in a Thai population. However, further studies with a larger sample size and/or in living human bloods as well as other cell types are recommended to support the results of this study.},
}
@article {pmid24780581,
year = {2014},
author = {Rajavel, M and Mullins, MR and Taylor, DJ},
title = {Multiple facets of TPP1 in telomere maintenance.},
journal = {Biochimica et biophysica acta},
volume = {1844},
number = {9},
pages = {1550-1559},
pmid = {24780581},
issn = {0006-3002},
support = {DP2 CA186571/CA/NCI NIH HHS/United States ; R21 CA169611/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Ciliophora/genetics/metabolism ; DNA, Single-Stranded/genetics/metabolism ; Gene Expression Regulation ; Humans ; Protein Binding ; Sequence Homology, Amino Acid ; Shelterin Complex ; Telomerase/*genetics/metabolism ; *Telomere ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {Telomeres are nucleoprotein complexes that cap the ends of all linear chromosomes and function to prevent aberrant repair and end-to-end chromosome fusions. In somatic cells, telomere shortening is a natural part of the aging process as it occurs with each round of cell division. In germ and stem cells, however, the enzyme telomerase synthesizes telomere DNA to counter-balance telomere shortening and help maintain cellular proliferation. Of the primary telomere end-binding proteins, TPP1 has recently emerged as a primary contributor in protecting telomere DNA and in recruiting telomerase to the telomere ends. In this review, we summarize the current knowledge regarding the role of TPP1 in telomere maintenance.},
}
@article {pmid24779348,
year = {2014},
author = {Le, HT and Dean, WL and Buscaglia, R and Chaires, JB and Trent, JO},
title = {An investigation of G-quadruplex structural polymorphism in the human telomere using a combined approach of hydrodynamic bead modeling and molecular dynamics simulation.},
journal = {The journal of physical chemistry. B},
volume = {118},
number = {20},
pages = {5390-5405},
pmid = {24779348},
issn = {1520-5207},
support = {GM077422/GM/NIGMS NIH HHS/United States ; P20 RR018733/RR/NCRR NIH HHS/United States ; R01 CA035635/CA/NCI NIH HHS/United States ; P41 RR001081/RR/NCRR NIH HHS/United States ; R01 GM077422/GM/NIGMS NIH HHS/United States ; P30 GM106396/GM/NIGMS NIH HHS/United States ; CA35635/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; Cluster Analysis ; Crystallography, X-Ray ; *G-Quadruplexes ; Humans ; *Hydrodynamics ; *Molecular Dynamics Simulation ; Nucleic Acid Conformation ; *Polymorphism, Genetic ; Principal Component Analysis ; Telomere/*genetics ; Thermodynamics ; Ultracentrifugation ; },
abstract = {Guanine-rich oligonucleotides can adopt noncanonical tertiary structures known as G-quadruplexes, which can exist in different forms depending on experimental conditions. High-resolution structural methods, such as X-ray crystallography and NMR spectroscopy, have been of limited usefulness in resolving the inherent structural polymorphism associated with G-quadruplex formation. The lack of, or the ambiguous nature of, currently available high-resolution structural data, in turn, has severely hindered investigations into the nature of these structures and their interactions with small-molecule inhibitors. We have used molecular dynamics in conjunction with hydrodynamic bead modeling to study the structures of the human telomeric G-quadruplex-forming sequences at the atomic level. We demonstrated that molecular dynamics can reproduce experimental hydrodynamic measurements and thus can be a powerful tool in the structural study of existing G-quadruplex sequences or in the prediction of new G-quadruplex structures.},
}
@article {pmid24771230,
year = {2014},
author = {Hosnijeh, FS and Matullo, G and Russo, A and Guarrera, S and Modica, F and Nieters, A and Overvad, K and Guldberg, P and Tjønneland, A and Canzian, F and Boeing, H and Aleksandrova, K and Trichopoulou, A and Lagiou, P and Trichopoulos, D and Tagliabue, G and Tumino, R and Panico, S and Palli, D and Olsen, KS and Weiderpass, E and Dorronsoro, M and Ardanaz, E and Chirlaque, MD and Sánchez, MJ and Quirós, JR and Venceslá, A and Melin, B and Johansson, AS and Nilsson, P and Borgquist, S and Peeters, PH and Onland-Moret, NC and Bueno-de-Mesquita, HB and Travis, RC and Khaw, KT and Wareham, N and Brennan, P and Ferrari, P and Gunter, MJ and Vineis, P and Vermeulen, R},
title = {Prediagnostic telomere length and risk of B-cell lymphoma-Results from the EPIC cohort study.},
journal = {International journal of cancer},
volume = {135},
number = {12},
pages = {2910-2917},
doi = {10.1002/ijc.28934},
pmid = {24771230},
issn = {1097-0215},
support = {MC_UU_12015/1/MRC_/Medical Research Council/United Kingdom ; G0401527/MRC_/Medical Research Council/United Kingdom ; G1000143/MRC_/Medical Research Council/United Kingdom ; 16491/CRUK_/Cancer Research UK/United Kingdom ; 14136/CRUK_/Cancer Research UK/United Kingdom ; MC_U106179471/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Case-Control Studies ; DNA/analysis ; Europe ; Female ; Follow-Up Studies ; Hodgkin Disease/epidemiology/genetics ; Humans ; Incidence ; Leukocytes/cytology ; Lymphoma, B-Cell/*epidemiology/*genetics ; Male ; Middle Aged ; Multivariate Analysis ; Odds Ratio ; Prospective Studies ; Risk Factors ; Telomere/*ultrastructure ; },
abstract = {Recent epidemiological investigations have reported on the association between telomere length (TL) and a number of malignancies, including B-cell lymphoma (BCL). The reported results for BCLs are however inconsistent. We carried out a nested case-control study to determine whether TL is associated with future risk of BCL. Using quantitative polymerase chain reaction, the relative TL (i.e. the ratio of telomere repeat copy number to single gene copy number) was measured in mononuclear cell DNA of prediagnostic peripheral blood samples of 464 lymphoma cases and 464 matched controls (median time between blood collection and diagnosis, 4.6 years). Conditional logistic regression was used to analyze the association between TL and the risk of developing lymphoma and histologic subtypes. TL was significantly longer in cases compared to controls (p = 0.01). Multivariable models showed a significantly increased risk of BCL [odds ratio (OR) = 1.66, 1.80 and 3.20 for quartiles 2-4, respectively, p-trend = 0.001], diffuse large B-cell lymphoma (DLBCL) (OR = 1.20, 2.48 and 2.36 for quartiles 2-4, respectively, p-trend = 0.03) and follicular lymphoma (FL) (OR = 1.39, 1.90 and 2.69 for quartiles 2-4, respectively, p-trend = 0.02) with increasing TL. This study suggests an association between longer leucocyte TL and increased risk of BCL which was most pronounced for DLBCL and FL.},
}
@article {pmid24769426,
year = {2014},
author = {Tamayo, M and Pértega, S and Mosquera, A and Rodríguez, M and Blanco, FJ and Fernández-Sueiro, JL and Gosálvez, J and Fernández, JL},
title = {Individual telomere length decay in patients with spondyloarthritis.},
journal = {Mutation research},
volume = {765},
number = {},
pages = {1-5},
doi = {10.1016/j.mrfmmm.2014.04.006},
pmid = {24769426},
issn = {1873-135X},
mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Follow-Up Studies ; Humans ; Leukocytes/*metabolism/pathology ; Male ; Middle Aged ; Polymerase Chain Reaction/methods ; Psoriasis/genetics/metabolism/pathology ; Spondylitis, Ankylosing/genetics/*metabolism/pathology ; Telomere/genetics/*metabolism/pathology ; *Telomere Homeostasis ; },
abstract = {Telomere length was sequentially determined in peripheral blood leukocytes (PBL) from patients with ankylosing spondylitis (AS; n = 44) and psoriatic arthritis (PsA; n = 42) followed through 2.93 ± 0.99 years, using a quantitative PCR (qPCR) assay. The initial telomere size from PsA patients was higher than those with cutaneous psoriasis only (n = 53), possibly due to the inflammatory condition. The qPCR assay was sensitive enough to evidence a significant telomere length shortening in PBL from practically all subjects and PsA patients showed a higher rate of loss of telomere sequence than patients with AS during the follow-up time.},
}
@article {pmid24768472,
year = {2015},
author = {Sadahiro, R and Suzuki, A and Enokido, M and Matsumoto, Y and Shibuya, N and Kamata, M and Goto, K and Otani, K},
title = {Relationship between leukocyte telomere length and personality traits in healthy subjects.},
journal = {European psychiatry : the journal of the Association of European Psychiatrists},
volume = {30},
number = {2},
pages = {291-295},
doi = {10.1016/j.eurpsy.2014.03.003},
pmid = {24768472},
issn = {1778-3585},
mesh = {Adult ; Anxiety Disorders ; Asian People/*statistics &amp; numerical data ; Character ; Cooperative Behavior ; Extraversion, Psychological ; Female ; Healthy Volunteers ; Humans ; Japan ; *Leukocytes ; Male ; Mortality ; Neuroticism ; *Personality/genetics ; Personality Inventory ; Reward ; Self Efficacy ; *Telomere ; Temperament ; },
abstract = {BACKGROUND: It has been shown that certain personality traits are related to mortality and disease morbidity, but the biological mechanism linking them remains unclear. Telomeres are tandem repeat DNA sequences located at the ends of chromosomes, and shorter telomere length is a predictor of mortality and late-life disease morbidity. Thus, it is possible that personality traits influence telomere length. In the present study, we examined the relationship of leukocyte telomere length with personality traits in healthy subjects.<br><br>SUBJECTS AND METHODS: The subjects were 209 unrelated healthy Japanese who were recruited from medical students at 4th-5th grade. Assessment of personality traits was performed by the Revised NEO Personality Inventory (NEO-PI-R) and the Temperament and Character Inventory (TCI). Leukocyte relative telomere length was determined by a quantitative real-time PCR method for a ratio of telomere/single copy gene.<br><br>RESULTS: In the stepwise multiple regression analysis, shorter telomere length was related to lower scores of neuroticism (P<0.01) and conscientiousness (P<0.05) of the NEO-PI-R, and lower scores of harm avoidance (P<0.05) and reward dependence (P<0.05) of the TCI.<br><br>CONCLUSIONS: The present study suggests that leukocyte telomere length is associated with some personality traits, and this association may be implicated in the relationship between personality traits and mortality.},
}
@article {pmid24763308,
year = {2014},
author = {Saferali, A and Lee, J and Sin, DD and Rouhani, FN and Brantly, ML and Sandford, AJ},
title = {Longer telomere length in COPD patients with α1-antitrypsin deficiency independent of lung function.},
journal = {PloS one},
volume = {9},
number = {4},
pages = {e95600},
pmid = {24763308},
issn = {1932-6203},
mesh = {Adult ; Case-Control Studies ; Female ; Forced Expiratory Volume ; Humans ; Lung/pathology/physiopathology ; Male ; Middle Aged ; Organ Specificity ; Pulmonary Disease, Chronic Obstructive/*genetics/physiopathology ; Telomere/*genetics ; Telomere Homeostasis ; alpha 1-Antitrypsin Deficiency/*genetics/physiopathology ; },
abstract = {Oxidative stress is involved in the pathogenesis of airway obstruction in α1-antitrypsin deficient patients. This may result in a shortening of telomere length, resulting in cellular senescence. To test whether telomere length differs in α1-antitrypsin deficient patients compared with controls, we measured telomere length in DNA from peripheral blood cells of 217 α1-antitrypsin deficient patients and 217 control COPD patients. We also tested for differences in telomere length between DNA from blood and DNA from lung tissue in a subset of 51 controls. We found that telomere length in the blood was significantly longer in α1-antitrypsin deficient COPD patients compared with control COPD patients (p = 1×10(-29)). Telomere length was not related to lung function in α1-antitrypsin deficient patients (p = 0.3122) or in COPD controls (p = 0.1430). Although mean telomere length was significantly shorter in the blood when compared with the lungs (p = 0.0078), telomere length was correlated between the two tissue types (p = 0.0122). Our results indicate that telomere length is better preserved in α1-antitrypsin deficient COPD patients than in non-deficient patients. In addition, measurement of telomere length in the blood may be a suitable surrogate for measurement in the lung.},
}
@article {pmid24762112,
year = {2014},
author = {Rode, L and Nordestgaard, BG and Weischer, M and Bojesen, SE},
title = {Increased body mass index, elevated C-reactive protein, and short telomere length.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {99},
number = {9},
pages = {E1671-5},
doi = {10.1210/jc.2014-1161},
pmid = {24762112},
issn = {1945-7197},
mesh = {Adult ; Aged ; Aged, 80 and over ; *Body Mass Index ; C-Reactive Protein/*metabolism ; Female ; Humans ; Inflammation/genetics/immunology/*metabolism ; Male ; Middle Aged ; Multivariate Analysis ; Obesity/genetics/immunology/*metabolism ; Polymorphism, Genetic ; Telomere/genetics/immunology/*metabolism ; Young Adult ; },
abstract = {CONTEXT: Obesity is associated with short telomere length. The cause of this association is unknown.<br><br>OBJECTIVE: We hypothesized that genetically increased body mass index (BMI) is associated with telomere length shortening and that low-grade inflammation might contribute through elevated C-reactive protein.<br><br>SETTING AND DESIGN: We studied 45,069 individuals from the Copenhagen General Population Study with measurements of leukocyte telomere length, BMI, and C-reactive protein in a Mendelian randomization study. Using the three obesity-associated polymorphisms FTO rs9939609, MC4R rs17782313, and TMEM18 rs6548238, and the CRP promoter polymorphism rs3091244 in instrumental variable analyses, we estimated the associations between genetically increased BMI and telomere length and between genetically increased C-reactive protein and telomere length.<br><br>RESULTS: In multivariable-adjusted observational analyses, telomere length decreased with seven base pairs (95% confidence interval, -9--5) per unit increase in BMI, and further adjustment for C-reactive protein attenuated this association to -5 base pairs (-8--3). In accordance, instrumental variable analysis showed a non-significant telomere length shortening of six base pairs (-37-25) per unit increase in genetically determined BMI. Furthermore, in observational analyses, telomere length decreased with nine base pairs (-16--2) for a doubling in C-reactive protein, supported by the instrumental variable analyses showing a corresponding genetically determined decrease of 66 base pairs (-124--7).<br><br>CONCLUSIONS: High BMI is associated with short telomere length observationally. This might possibly be mediated through elevated C-reactive protein, given that genetically elevated C-reactive protein levels are associated with short telomere length.},
}
@article {pmid24758186,
year = {2014},
author = {Wang, N and Xu, D and Sofiadis, A and Höög, A and Vukojević, V and Bäckdahl, M and Zedenius, J and Larsson, C},
title = {Telomerase-dependent and independent telomere maintenance and its clinical implications in medullary thyroid carcinoma.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {99},
number = {8},
pages = {E1571-9},
pmid = {24758186},
issn = {1945-7197},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Neuroendocrine ; DNA Mutational Analysis ; Female ; HEK293 Cells ; HeLa Cells ; Humans ; Male ; Middle Aged ; Prognosis ; Proto-Oncogene Proteins c-ret/genetics ; Survival Analysis ; Telomerase/*genetics ; Telomere/metabolism ; Telomere Homeostasis/*genetics ; Thyroid Neoplasms/*genetics/*mortality/pathology ; Young Adult ; },
abstract = {CONTEXT: Telomere maintenance via telomerase activation and the alternative lengthening of telomeres (ALT) mechanism was assessed in medullary thyroid carcinoma.<br><br>SETTING AND DESIGN: In total, 42 medullary thyroid carcinomas (MTC) were studied including 24 rearranged during transfection (RET)- mutated cases. Relative telomerase reverse transcriptase (TERT) expression, splice forms, and telomere length were determined by PCR-based methods, and telomerase activity by ELISA. The ALT mechanism was detected by Southern blot analysis and immunofluorescence.<br><br>RESULTS: TERT expression and telomerase activity were detected in 21/42 tumors (50%), and was independent of the common somatic M918T RET mutation. Mean telomere length was shorter in MTCs compared with thyroids. Telomerase activation was associated with large tumor size (P = .027), advanced clinical stage (P = .0001), and short survival (P = .0001). Full-length TERT and the &#x3b1;(-) and &#x3b2;(-)-deletion forms were revealed, and the full-length form was associated with short survival (P = .04). A subset of cases without telomerase activation showed involvement of the ALT mechanism, which was associated with a low MIB-1 proliferation index (P = .024).<br><br>CONCLUSIONS: Stabilization of telomeres by telomerase activation occurs in half of the MTCs and by the ALT mechanism in a subset of cases. Telomerase activation may be used as an additional prognostic marker in medullary thyroid carcinoma.},
}
@article {pmid24755952,
year = {2015},
author = {De Meyer, T and Eisenberg, DT},
title = {Possible technical and biological explanations for the 'parental telomere length inheritance discrepancy' enigma.},
journal = {European journal of human genetics : EJHG},
volume = {23},
number = {1},
pages = {3-4},
pmid = {24755952},
issn = {1476-5438},
support = {R24 HD042828/HD/NICHD NIH HHS/United States ; },
mesh = {Female ; Humans ; Male ; *Paternal Age ; *Pedigree ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
}
@article {pmid24754043,
year = {2014},
author = {Kupiec, M},
title = {Biology of telomeres: lessons from budding yeast.},
journal = {FEMS microbiology reviews},
volume = {38},
number = {2},
pages = {144-171},
doi = {10.1111/1574-6976.12054},
pmid = {24754043},
issn = {1574-6976},
mesh = {Animals ; DNA Replication ; Mammals ; Saccharomyces cerevisiae/cytology/enzymology/genetics/*physiology ; Telomere/genetics/metabolism/*physiology ; Telomere Homeostasis/physiology ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Telomeres are nucleoprotein structures that cap the ends of the linear eukaryotic chromosomes and thereby protect their stability and integrity. Telomeres play central roles in maintaining the genome's integrity, distinguishing between the natural chromosomal ends and unwanted double-stranded breaks. In addition, telomeres are replicated by a special reverse transcriptase called telomerase, in a complex mechanism that is coordinated with the genome's replication. Telomeres also play an important role in tethering the chromosomes to the nuclear envelope, thus helping in positioning the chromosomes within the nucleus. The special chromatin configuration of telomeres affects the expression of nearby genes; nonetheless, telomeres are transcribed, creating noncoding RNA molecules that hybridize to the chromosomal ends and seem to play regulatory roles. The yeast Saccharomyces cerevisiae, with its sophisticated genetics and molecular biology, has provided many fundamental concepts in telomere biology, which were later found to be conserved in all organisms. Here, we present an overview of all the aspects of telomere biology investigated in yeast, which continues to provide new insights into this complex and important subject, which has significant medical implications, especially in the fields of aging and cancer.},
}
@article {pmid24753044,
year = {2014},
author = {Liu, F and Wang, WT and Wei, YG and Li, B},
title = {Prognostic impact of telomere maintenance gene polymorphisms in hepatocellular carcinoma patients: some issues need to be clarified.},
journal = {Hepatology (Baltimore, Md.)},
volume = {60},
number = {6},
pages = {2131-2132},
doi = {10.1002/hep.27184},
pmid = {24753044},
issn = {1527-3350},
mesh = {Carcinoma, Hepatocellular/*genetics ; Female ; Hepatitis B, Chronic/*complications ; Humans ; Liver Neoplasms/*genetics ; Male ; *Polymorphism, Single Nucleotide ; *Telomere ; },
}
@article {pmid24752326,
year = {2014},
author = {Chilton, WL and Marques, FZ and West, J and Kannourakis, G and Berzins, SP and O'Brien, BJ and Charchar, FJ},
title = {Acute exercise leads to regulation of telomere-associated genes and microRNA expression in immune cells.},
journal = {PloS one},
volume = {9},
number = {4},
pages = {e92088},
pmid = {24752326},
issn = {1932-6203},
support = {//Medical Research Council/United Kingdom ; },
mesh = {Adult ; Exercise/*physiology ; Exercise Test ; *Gene Expression Regulation ; Genome, Human/genetics ; Humans ; Immune System/*cytology ; Leukocytes/*metabolism ; Male ; MicroRNAs/*genetics/metabolism ; Polymerase Chain Reaction ; RNA, Messenger/genetics/metabolism ; Reproducibility of Results ; T-Lymphocytes/cytology/metabolism ; Telomere/*genetics ; },
abstract = {Telomeres are specialized nucleoprotein structures that protect chromosomal ends from degradation. These structures progressively shorten during cellular division and can signal replicative senescence below a critical length. Telomere length is predominantly maintained by the enzyme telomerase. Significant decreases in telomere length and telomerase activity are associated with a host of chronic diseases; conversely their maintenance underpins the optimal function of the adaptive immune system. Habitual physical activity is associated with longer leukocyte telomere length; however, the precise mechanisms are unclear. Potential hypotheses include regulation of telomeric gene transcription and/or microRNAs (miRNAs). We investigated the acute exercise-induced response of telomeric genes and miRNAs in twenty-two healthy males (mean age = 24.1±1.55 years). Participants undertook 30 minutes of treadmill running at 80% of peak oxygen uptake. Blood samples were taken before exercise, immediately post-exercise and 60 minutes post-exercise. Total RNA from white blood cells was submitted to miRNA arrays and telomere extension mRNA array. Results were individually validated in white blood cells and sorted T cell lymphocyte subsets using quantitative real-time PCR (qPCR). Telomerase reverse transcriptase (TERT) mRNA (P = 0.001) and sirtuin-6 (SIRT6) (P<0.05) mRNA expression were upregulated in white blood cells after exercise. Fifty-six miRNAs were also differentially regulated post-exercise (FDR <0.05). In silico analysis identified four miRNAs (miR-186, miR-181, miR-15a and miR-96) that potentially targeted telomeric gene mRNA. The four miRNAs exhibited significant upregulation 60 minutes post-exercise (P<0.001). Telomeric repeat binding factor 2, interacting protein (TERF2IP) was identified as a potential binding target for miR-186 and miR-96 and demonstrated concomitant downregulation (P<0.01) at the corresponding time point. Intense cardiorespiratory exercise was sufficient to differentially regulate key telomeric genes and miRNAs in white blood cells. These results may provide a mechanistic insight into telomere homeostasis and improved immune function and physical health.},
}
@article {pmid24750833,
year = {2014},
author = {Wang, XG and Wang, X and Liu, S and Zhou, YJ and Wang, DF},
title = {[Telomere length and telomerase mutations in peripheral blood leukocytes of children with chronic aplastic anemia].},
journal = {Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics},
volume = {16},
number = {4},
pages = {375-379},
pmid = {24750833},
issn = {1008-8830},
mesh = {Adolescent ; Anemia, Aplastic/drug therapy/*genetics ; Child ; Child, Preschool ; Chronic Disease ; Humans ; Immunosuppressive Agents/therapeutic use ; Infant ; Leukocytes/*metabolism ; Male ; *Mutation ; Telomerase/*genetics ; *Telomere ; },
abstract = {OBJECTIVE: To investigate the change in telomere length and TERC and TERT mutations in peripheral blood leukocytes of children with chronic aplastic anemia (CAA).<br><br>METHODS: Sixty-nine children with CAA were divided into untreated group (n=24) who did not receive immunosuppressive therapy (IST), response group (n=36) who showed response to IST, and non-response group (n=9) who showed no response to IST; another 35 healthy children matched for age and sex were selected as the control group. The telomere-to-single copy gene (T/S) ratio in peripheral blood leukocytes was measured by real-time PCR in all groups. PCR was performed to detect TERC and TERT mutations in all children with CAA.<br><br>RESULTS: The untreated and non-response groups had significantly lower T/S ratios than the control and response groups (P<0.01), whereas there was no significant difference in T/S ratio between the response and control groups (P>0.05). TERC and TERT mutations were not found in all children with CAA.<br><br>CONCLUSIONS: The change in telomere length in children with CAA may be related to the development and progression of disease. Telomere length measurement may be used as a prognostic indicator in children with CAA.},
}
@article {pmid24748617,
year = {2014},
author = {Bandy, NJ and Salman-Dilgimen, A and Chaconas, G},
title = {Construction and characterization of a Borrelia burgdorferi strain with conditional expression of the essential telomere resolvase, ResT.},
journal = {Journal of bacteriology},
volume = {196},
number = {13},
pages = {2396-2404},
pmid = {24748617},
issn = {1098-5530},
support = {MOP 53086//Canadian Institutes of Health Research/Canada ; },
mesh = {Bacterial Proteins/genetics/*metabolism ; Borrelia burgdorferi/genetics/*metabolism ; DNA, Bacterial ; Endodeoxyribonucleases/genetics/*metabolism ; Gene Expression Regulation, Bacterial/*physiology ; Mutation ; },
abstract = {Borrelia species are unique in the bacterial world in possessing segmented genomes which sometimes contain over 20 genetic elements. Most elements are linear and contain covalently closed hairpin ends requiring a specialized process, telomere resolution, for their generation. Hairpin telomere resolution is mediated by the telomere resolvase, ResT. Although the process has been studied extensively in vitro, the essential nature of the resT gene has precluded biological studies to further probe the role of ResT. In this work, we have generated a B. burgdorferi strain that carries an isopropyl-β-d-thiogalactopyranoside (IPTG)-inducible resT gene controlled by a tightly regulated promoter. ResT is expressed in this strain at ~14,000 monomers per cell, similar to the ~15,000 monomers observed for the parental strain. We demonstrate ResT depletion with a half-life of 16 h upon IPTG washout. ResT depletion resulted in arrested growth 48 h after washout. Interestingly, not all spirochetes died after ResT washout, and at least 15% remained quiescent and could be resuscitated even at 2 weeks postwashout. Significant levels of DNA synthesis were not observed upon growth arrest, suggesting that ResT might interact directly or indirectly with factors controlling the initiation or elongation of DNA synthesis. Analysis of the linear plasmids lp17 and lp28-2 showed that the linear forms of these plasmids began to disappear and be replaced by higher-molecular-weight forms by 24 h post-IPTG washout. Treatment of DNA from the ResT-depleted strain with ResT in vitro revealed the presence of replicated telomeres expected in replication intermediates.},
}
@article {pmid24747221,
year = {2014},
author = {Jang, JH and Bruse, S and Huneidi, S and Schrader, RM and Monick, MM and Lin, Y and Carter, AB and Klingelhutz, AJ and Nyunoya, T},
title = {Acrolein-exposed normal human lung fibroblasts in vitro: cellular senescence, enhanced telomere erosion, and degradation of Werner's syndrome protein.},
journal = {Environmental health perspectives},
volume = {122},
number = {9},
pages = {955-962},
pmid = {24747221},
issn = {1552-9924},
support = {R01 HL096625/HL/NHLBI NIH HHS/United States ; R21 HL109589/HL/NHLBI NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; R01 ES015981/ES/NIEHS NIH HHS/United States ; R01 HL079901/HL/NHLBI NIH HHS/United States ; K08 HL089135/HL/NHLBI NIH HHS/United States ; K08 KHL089135A//PHS HHS/United States ; R03 AG037768-01/AG/NIA NIH HHS/United States ; R03 AG037768/AG/NIA NIH HHS/United States ; },
mesh = {Acrolein/*toxicity ; Cells, Cultured ; Cellular Senescence/*drug effects ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; DNA Repair/drug effects ; Down-Regulation ; Environmental Pollutants/*toxicity ; Exodeoxyribonucleases/*metabolism ; Fibroblasts/*drug effects ; Humans ; Lung/cytology/metabolism ; RecQ Helicases/*metabolism ; Telomere/*drug effects/metabolism ; Tumor Suppressor Protein p53/metabolism ; Werner Syndrome Helicase ; beta-Galactosidase/metabolism ; },
abstract = {BACKGROUND: Acrolein is a ubiquitous environmental hazard to human health. Acrolein has been reported to activate the DNA damage response and induce apoptosis. However, little is known about the effects of acrolein on cellular senescence.<br><br>OBJECTIVES: We examined whether acrolein induces cellular senescence in cultured normal human lung fibroblasts (NHLF).<br><br>METHODS: We cultured NHLF in the presence or absence of acrolein and determined the effects of acrolein on cell proliferative capacity, senescence-associated &#x3b2;-galactosidase activity, the known senescence-inducing pathways (e.g., p53, p21), and telomere length.<br><br>RESULTS: We found that acrolein induced cellular senescence by increasing both p53 and p21. The knockdown of p53 mediated by small interfering RNA (siRNA) attenuated acrolein-induced cellular senescence. Acrolein decreased Werner's syndrome protein (WRN), a member of the RecQ helicase family involved in DNA repair and telomere maintenance. Acrolein-induced down-regulation of WRN protein was rescued by p53 knockdown or proteasome inhibition. Finally, we found that acrolein accelerated p53-mediated telomere shortening.<br><br>CONCLUSIONS: These results suggest that acrolein induces p53-mediated cellular senescence accompanied by enhanced telomere attrition and WRN protein down-regulation.},
}
@article {pmid24743394,
year = {2014},
author = {Aulinas, A and Ramírez, MJ and Barahona, MJ and Valassi, E and Resmini, E and Mato, E and Santos, A and Crespo, I and Bell, O and Surrallés, J and Webb, SM},
title = {Telomere length analysis in Cushing's syndrome.},
journal = {European journal of endocrinology},
volume = {171},
number = {1},
pages = {21-29},
doi = {10.1530/EJE-14-0098},
pmid = {24743394},
issn = {1479-683X},
mesh = {Adult ; Cushing Syndrome/*genetics ; Female ; Humans ; Leukocyte Count ; Longitudinal Studies ; Male ; Middle Aged ; Telomere/*genetics ; },
abstract = {INTRODUCTION: Hypercortisolism in Cushing's syndrome (CS) is associated with increased morbidity and mortality. Hypercortisolism also occurs in chronic depressive disorders and stress, where telomere length (TL) is shorter than in controls. We hypothesized that shortening of telomere might occur in CS and contribute to premature aging and morbidity.<br><br>AIM: To investigate TL in CS patients compared with controls.<br><br>METHODS: Seventy-seven CS patients (14 males, 59 pituitary, 17 adrenal, and one ectopic; 21 with active disease) were compared with 77 gender-, age-, and smoking-matched controls. Fifteen CS were evaluated longitudinally, during active disease and after remission of hypercortisolism. Leukocyte TL was measured by telomere restriction fragment-Southern technique. Clinical markers were included in a multiple linear regression analysis to investigate potential predictors of TL.<br><br>RESULTS: Mean TL in CS patients and controls was similar (7667 vs 7483&#x200a;bp, NS). After adjustment for age, in the longitudinal evaluation, TL was shorter in active disease than after remission (7273 vs 7870, P<0.05). Age and dyslipidemia were negative predictors (P<0.05), and total leukocyte count was a positive predictor for TL (P<0.05). As expected, a negative correlation was found between TL and age (CS, R=-0.400 and controls, R=-0.292; P<0.05). No correlation was found between circulating cortisol, duration of exposure to hypercortisolism or biochemical cure and TL.<br><br>CONCLUSION: Even though in the cross-sectional comparison of CS and controls no difference in TL was found, in the longitudinal evaluation, patients with active CS had shorter TL than after biochemical cure of hypercortisolism. These preliminary results suggest that hypercortisolism might negatively impact telomere maintenance. Larger studies are needed to confirm these findings.},
}
@article {pmid24735877,
year = {2014},
author = {Dan, J and Liu, Y and Liu, N and Chiourea, M and Okuka, M and Wu, T and Ye, X and Mou, C and Wang, L and Wang, L and Yin, Y and Yuan, J and Zuo, B and Wang, F and Li, Z and Pan, X and Yin, Z and Chen, L and Keefe, DL and Gagos, S and Xiao, A and Liu, L},
title = {Rif1 maintains telomere length homeostasis of ESCs by mediating heterochromatin silencing.},
journal = {Developmental cell},
volume = {29},
number = {1},
pages = {7-19},
pmid = {24735877},
issn = {1878-1551},
support = {P01 GM099130/GM/NIGMS NIH HHS/United States ; R00 CA131560/CA/NCI NIH HHS/United States ; 5R00CA131560/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Embryonic Stem Cells/*metabolism/physiology ; Gene Deletion ; Gene Expression Regulation, Developmental ; *Gene Silencing ; Heterochromatin/genetics/*metabolism ; Histones/metabolism ; Methylation ; Mice ; Protein Binding ; Protein Processing, Post-Translational ; RNA, Messenger/genetics/metabolism ; Recombination, Genetic ; Telomere/genetics/metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/genetics/*metabolism ; Transcription Factors/genetics/*metabolism ; },
abstract = {Telomere length homeostasis is essential for genomic stability and unlimited self-renewal of embryonic stem cells (ESCs). We show that telomere-associated protein Rif1 is required to maintain telomere length homeostasis by negatively regulating Zscan4 expression, a critical factor for telomere elongation by recombination. Depletion of Rif1 results in terminal hyperrecombination, telomere length heterogeneity, and chromosomal fusions. Reduction of Zscan4 by shRNA significantly rescues telomere recombination defects of Rif1-depleted ESCs and associated embryonic lethality. Further, Rif1 negatively modulates Zscan4 expression by maintaining H3K9me3 levels at subtelomeric regions. Mechanistically, Rif1 interacts and stabilizes H3K9 methylation complex. Thus, Rif1 regulates telomere length homeostasis of ESCs by mediating heterochromatic silencing.},
}
@article {pmid24735425,
year = {2014},
author = {Tamura, Y and Izumiyama-Shimomura, N and Kimbara, Y and Nakamura, K and Ishikawa, N and Aida, J and Chiba, Y and Mori, S and Arai, T and Aizawa, T and Araki, A and Takubo, K and Ito, H},
title = {β-cell telomere attrition in diabetes: inverse correlation between HbA1c and telomere length.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {99},
number = {8},
pages = {2771-2777},
doi = {10.1210/jc.2014-1222},
pmid = {24735425},
issn = {1945-7197},
mesh = {Aged ; Aged, 80 and over ; Aging/blood/genetics ; Case-Control Studies ; Diabetes Mellitus, Type 2/*blood/*genetics ; Female ; Glycated Hemoglobin/*metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Insulin-Secreting Cells/*metabolism/pathology ; Male ; Telomere/metabolism ; *Telomere Shortening ; },
abstract = {CONTEXT: Although accelerated β-cell telomere shortening may be associated with diabetes that shows a dramatically increased incidence with aging, β-cell telomere length in diabetes has never been explored.<br><br>OBJECTIVE: The objective of the present study was to examine telomere length in the &#x3b2;-cells of patients with diabetes.<br><br>DESIGN AND PATIENTS: We determined telomere length in &#x3b2;- and &#x3b1;-cells of pancreases obtained at autopsy from 47 patients with type 2 diabetes and 51 controls, all older than 60 years.<br><br>MAIN OUTCOME MEASURE: The normalized telomere to centromere ratio (NTCR), an index of telomere length, was determined for &#x3b2;- (NTCR&#x3b2;) and &#x3b1;- (NTCR&#x3b1;) cells by quantitative fluorescence in situ hybridization.<br><br>RESULTS: The NTCR&#x3b2; was reduced by 27% &#xb1; 25% and NTCR&#x3b1; by 15% &#xb1; 27% in the patients with diabetes relative to the controls (P < .01 for both). Importantly, the degree of shortening was significantly (P < .01) greater in &#x3b2;-cells than in &#x3b1;-cells. The histogram of NTCR distribution was significantly skewed to the left in the patients with diabetes relative to the controls for both &#x3b2;- and &#x3b1;-cells, indicating preferential depletion of longer-telomere islet cells. Glycated hemoglobin was negatively correlated with &#x3b2;-cell telomere length, and the telomeres were significantly shorter in patients who had used hypoglycemic agents than in those who had not.<br><br>CONCLUSION: The telomeres of &#x3b2;-cells are shortened in patients with type 2 diabetes. There may be a vicious cycle involving &#x3b2;-cell telomere attrition and sustained hyperglycemia.},
}
@article {pmid24732358,
year = {2014},
author = {Ko, E and Jung, G},
title = {Positive association of long telomeres with the invasive capacity of hepatocellular carcinoma cells.},
journal = {Biochemical and biophysical research communications},
volume = {447},
number = {2},
pages = {358-363},
doi = {10.1016/j.bbrc.2014.04.022},
pmid = {24732358},
issn = {1090-2104},
mesh = {Carcinoma, Hepatocellular/genetics/*pathology ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Humans ; Liver Neoplasms/genetics/*pathology ; Neoplasm Invasiveness ; Telomere/*physiology ; *Telomere Homeostasis ; },
abstract = {Invasion, the representative feature of malignant tumors, leads to an increase in mortality. The malignant liver tumor - hepatocellular carcinoma (HCC) - has an enhanced invasive capacity that results in increased patient mortality. Moreover, this enhanced invasive capacity is due to the up-regulation of invasion promoters such as zinc finger protein SNAI1 (Snail) and matrix metalloproteinases (MMPs), and the down-regulation of invasion suppressor molecules such as E-cadherin. Telomerase reverse transcriptase (TERT), which encodes the catalytic subunit of telomerase, is highly expressed in a variety of invasive cancers, including HCC. Telomerase activation induces telomere elongation, thereby leading to cell immortalization during malignant tumor progression. However, the relationship between telomere length and invasion is yet to be experimentally corroborated. In this paper, we revealed that invasive HCC cells passing through the Matrigel display significantly longer telomeres than non-invasive HCC cells. Moreover, we established a method that can distinguish and sort cells containing long telomeres and short telomeres. Using this system, we observed that the HCC cells containing long telomeres had a high-level expression of invasion-promoting genes and a low-level expression of invasion-suppressing E-cadherin. Furthermore, HCC cells containing long telomeres exhibited a higher invasive capacity than HCC cells containing short telomeres. Taken together, our findings suggest that long telomeres are positively associated with the invasive capacity of HCC cells and may be a potent target for malignant liver cancer treatment.},
}
@article {pmid24730869,
year = {2014},
author = {Kollár, R and Bod'ová, K and Nosek, J and Tomáška, L},
title = {Mathematical model of alternative mechanism of telomere length maintenance.},
journal = {Physical review. E, Statistical, nonlinear, and soft matter physics},
volume = {89},
number = {3},
pages = {032701},
doi = {10.1103/PhysRevE.89.032701},
pmid = {24730869},
issn = {1550-2376},
mesh = {Computer Simulation ; DNA, Mitochondrial/*chemistry/*ultrastructure ; Kinetics ; *Models, Chemical ; *Models, Molecular ; Nucleic Acid Conformation ; Telomere/*chemistry/*ultrastructure ; *Telomere Homeostasis ; },
abstract = {Biopolymer length regulation is a complex process that involves a large number of biological, chemical, and physical subprocesses acting simultaneously across multiple spatial and temporal scales. An illustrative example important for genomic stability is the length regulation of telomeres-nucleoprotein structures at the ends of linear chromosomes consisting of tandemly repeated DNA sequences and a specialized set of proteins. Maintenance of telomeres is often facilitated by the enzyme telomerase but, particularly in telomerase-free systems, the maintenance of chromosomal termini depends on alternative lengthening of telomeres (ALT) mechanisms mediated by recombination. Various linear and circular DNA structures were identified to participate in ALT, however, dynamics of the whole process is still poorly understood. We propose a chemical kinetics model of ALT with kinetic rates systematically derived from the biophysics of DNA diffusion and looping. The reaction system is reduced to a coagulation-fragmentation system by quasi-steady-state approximation. The detailed treatment of kinetic rates yields explicit formulas for expected size distributions of telomeres that demonstrate the key role played by the J factor, a quantitative measure of bending of polymers. The results are in agreement with experimental data and point out interesting phenomena: an appearance of very long telomeric circles if the total telomere density exceeds a critical value (excess mass) and a nonlinear response of the telomere size distributions to the amount of telomeric DNA in the system. The results can be of general importance for understanding dynamics of telomeres in telomerase-independent systems as this mode of telomere maintenance is similar to the situation in tumor cells lacking telomerase activity. Furthermore, due to its universality, the model may also serve as a prototype of an interaction between linear and circular DNA structures in various settings.},
}
@article {pmid24728996,
year = {2014},
author = {Rubinstein, L and Ungar, L and Harari, Y and Babin, V and Ben-Aroya, S and Merenyi, G and Marjavaara, L and Chabes, A and Kupiec, M},
title = {Telomere length kinetics assay (TELKA) sorts the telomere length maintenance (tlm) mutants into functional groups.},
journal = {Nucleic acids research},
volume = {42},
number = {10},
pages = {6314-6325},
pmid = {24728996},
issn = {1362-4962},
mesh = {Blotting, Southern ; DNA End-Joining Repair ; DNA-Binding Proteins/genetics/metabolism ; *Mutation ; Peptide Synthases/genetics/metabolism ; Ribonucleotide Reductases/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Genome-wide systematic screens in yeast have uncovered a large gene network (the telomere length maintenance network or TLM), encompassing more than 400 genes, which acts coordinatively to maintain telomere length. Identifying the genes was an important first stage; the next challenge is to decipher their mechanism of action and to organize then into functional groups or pathways. Here we present a new telomere-length measuring program, TelQuant, and a novel assay, telomere length kinetics assay, and use them to organize tlm mutants into functional classes. Our results show that a mutant defective for the relatively unknown MET7 gene has the same telomeric kinetics as mutants defective for the ribonucleotide reductase subunit Rnr1, in charge of the limiting step in dNTP synthesis, or for the Ku heterodimer, a well-established telomere complex. We confirm the epistatic relationship between the mutants and show that physical interactions exist between Rnr1 and Met7. We also show that Met7 and the Ku heterodimer affect dNTP formation, and play a role in non-homologous end joining. Thus, our telomere kinetics assay uncovers new functional groups, as well as complex genetic interactions between tlm mutants.},
}
@article {pmid24727734,
year = {2014},
author = {Kawano, Y and Ishikawa, N and Aida, J and Sanada, Y and Izumiyama-Shimomura, N and Nakamura, K and Poon, SS and Matsumoto, K and Mizuta, K and Uchida, E and Tajiri, T and Kawarasaki, H and Takubo, K},
title = {Q-FISH measurement of hepatocyte telomere lengths in donor liver and graft after pediatric living-donor liver transplantation: donor age affects telomere length sustainability.},
journal = {PloS one},
volume = {9},
number = {4},
pages = {e93749},
pmid = {24727734},
issn = {1932-6203},
mesh = {Adult ; Age Factors ; Child ; Female ; Hepatocytes/metabolism ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Infant ; Liver Transplantation/*adverse effects ; *Living Donors ; Male ; Telomere/*genetics ; },
abstract = {Along with the increasing need for living-donor liver transplantation (LDLT), the issue of organ shortage has become a serious problem. Therefore, the use of organs from elderly donors has been increasing. While the short-term results of LDLT have greatly improved, problems affecting the long-term outcome of transplant patients remain unsolved. Furthermore, since contradictory data have been reported with regard to the relationship between donor age and LT/LDLT outcome, the question of whether the use of elderly donors influences the long-term outcome of a graft after LT/LDLT remains unsettled. To address whether hepatocyte telomere length reflects the outcome of LDLT, we analyzed the telomere lengths of hepatocytes in informative biopsy samples from 12 paired donors and recipients (grafts) of pediatric LDLT more than 5 years after adult-to-child LDLT because of primary biliary atresia, using quantitative fluorescence in situ hybridization (Q-FISH). The telomere lengths in the paired samples showed a robust relationship between the donor and grafted hepatocytes (r = 0.765, p = 0.0038), demonstrating the feasibility of our Q-FISH method for cell-specific evaluation. While 8 pairs showed no significant difference between the telomere lengths for the donor and the recipient, the other 4 pairs showed significantly shorter telomeres in the recipient than in the donor. Multiple regression analysis revealed that the donors in the latter group were older than those in the former (p = 0.001). Despite the small number of subjects, this pilot study indicates that donor age is a crucial factor affecting telomere length sustainability in hepatocytes after pediatric LDLT, and that the telomeres in grafted livers may be elongated somewhat longer when the grafts are immunologically well controlled.},
}
@article {pmid24727158,
year = {2014},
author = {Qian, Y and Yang, L and Cao, S},
title = {Telomeres and telomerase in T cells of tumor immunity.},
journal = {Cellular immunology},
volume = {289},
number = {1-2},
pages = {63-69},
doi = {10.1016/j.cellimm.2014.03.009},
pmid = {24727158},
issn = {1090-2163},
mesh = {Cell Proliferation ; Cell Survival ; Humans ; Immunotherapy, Adoptive ; Lymphocyte Activation/immunology ; Neoplasms/*immunology ; T-Lymphocytes/*enzymology/*immunology ; Telomerase/*immunology ; Telomere/*immunology ; },
abstract = {Telomeres are specific nucleoprotein structures at the end of a eukaryotic chromosomes characterized by repeats of the sequence TTAGGG and regulated by the enzyme telomerase which prevents their degradation, loss, rearrangement and end-to-end fusion. During activation, T lymphocytes actively divide, albeit through only a finite number of cell divisions due to shortening of telomeres. However, studies have demonstrated that human telomerase reverse transcriptase (hTERT), thought to be the major component regulating telomerase activity, can enhance the proliferation of T cells when overexpressed. There are many treatments for cancers, most of which are targeting the telomere and telomerase of tumor cells. However, the hTERT-transduced T cells improve their potential for proliferation, making them an appropriate cell resource for tumor adoptive immunotherapy, a procedure whereby T cells are isolated from patients, expanded ex vivo and eventually delivered back into the patients, provides a new approach for tumor therapy through improved overall survival rates in cancer patients. In this review, we will focus on the telomerase activity in T cells, the regulation of telomerase activity, and hTERT-transduced T cells used in adoptive immunotherapy for cancer.},
}
@article {pmid24725274,
year = {2014},
author = {Martínez, P and Ferrara-Romeo, I and Flores, JM and Blasco, MA},
title = {Essential role for the TRF2 telomere protein in adult skin homeostasis.},
journal = {Aging cell},
volume = {13},
number = {4},
pages = {656-668},
pmid = {24725274},
issn = {1474-9726},
support = {232854/ERC_/European Research Council/International ; },
mesh = {Aging/*metabolism ; Animals ; Apoptosis ; Chromosomal Proteins, Non-Histone/deficiency/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; DNA Damage ; DNA-Binding Proteins/deficiency/metabolism ; Embryo Loss/metabolism/pathology ; Embryonic Development ; Epidermis/metabolism/pathology ; Epithelium/metabolism/pathology ; Gene Deletion ; *Homeostasis ; Integrases/metabolism ; Keratin-5/metabolism ; Keratinocytes/metabolism/pathology ; Mice ; Skin/embryology/*metabolism/pathology ; Stem Cells/metabolism/pathology ; Telomere/*metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 2/*metabolism ; Tumor Suppressor Protein p53/deficiency/metabolism ; Tumor Suppressor p53-Binding Protein 1 ; },
abstract = {TRF2 is a component of shelterin, the protein complex that protects the ends of mammalian chromosomes. TRF2 is essential for telomere capping owing to its roles in suppressing an ATM-dependent DNA damage response (DDR) at chromosome ends and inhibiting end-to-end chromosome fusions. Mice deficient for TRF2 are early embryonic lethal. However, the role of TRF2 in later stages of development and in the adult organism remains largely unaddressed, with the exception of liver, where TRF2 was found to be dispensable for maintaining tissue function. Here, we study the impact of TRF2 conditional deletion in stratified epithelia by generating the TRF2(∆/∆) -K5-Cre mouse model, which targets TRF2 deletion to the skin from embryonic day E11.5. In marked contrast to TRF2 deletion in the liver, TRF2(∆/∆) -K5-Cre mice show lethality in utero reaching 100% lethality perinataly. At the molecular and cellular level, TRF2 deletion provokes induction of an acute DDR at telomeres, leading to activation of p53 signaling pathways and to programed cell death since the time of Cre expression at E11.5. Unexpectedly, neither inhibition of the NHEJ pathway by abrogation of 53BP1 nor inhibition of DDR by p53 deficiency rescued these severe phenotypes. Instead, TRF2 deletion provokes an extensive epidermal cell death accompanied by severe inflammation already at E16.5 embryos, which are independent of p53. These results are in contrast with conditional deletion of TRF1 and TPP1 in the skin, where p53 deficiency rescued the associated skin phenotypes, highlighting the comparatively more essential role of TRF2 in skin homeostasis.},
}
@article {pmid24725010,
year = {2014},
author = {Li, Y and Liu, C and Feng, X and Xu, Y and Liu, BF},
title = {Ultrafast microfluidic mixer for tracking the early folding kinetics of human telomere G-quadruplex.},
journal = {Analytical chemistry},
volume = {86},
number = {9},
pages = {4333-4339},
doi = {10.1021/ac500112d},
pmid = {24725010},
issn = {1520-6882},
mesh = {*G-Quadruplexes ; Humans ; Kinetics ; Microfluidics/*instrumentation ; *Nucleic Acid Conformation ; *Telomere ; },
abstract = {The folding of G-quadruplex is hypothesized to undergo a complex process, from the formation of a hairpin structure to a triplex intermediate and to the final G-quadruplex. Currently, no experimental evidence has been found for the hairpin formation, because it folds in the time regime of 10-100 μs, entailing the development of microfluidic mixers with a mixing time of less than 10 μs. In this paper, we reported an ultrarapid micromixer with a mixing time of 5.5 μs, which represents the fastest turbulent micromixer to our best knowledge. Evaluations of the micromixer were conducted to confirm its mixing efficiency for small molecules and macromolecules. This new micromixer enabled us to interrogate the hairpin formation in the early folding process of human telomere G-quadruplex. The experimental kinetic evidence for the formation of hairpin was obtained for the first time.},
}
@article {pmid24721976,
year = {2014},
author = {Zheng, YL and Zhang, F and Sun, B and Du, J and Sun, C and Yuan, J and Wang, Y and Tao, L and Kota, K and Liu, X and Schlegel, R and Yang, Q},
title = {Telomerase enzymatic component hTERT shortens long telomeres in human cells.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {13},
number = {11},
pages = {1765-1776},
pmid = {24721976},
issn = {1551-4005},
support = {R01 CA132996/CA/NCI NIH HHS/United States ; R01 CA129440/CA/NCI NIH HHS/United States ; R33 CA177466/CA/NCI NIH HHS/United States ; P30 CA051008/CA/NCI NIH HHS/United States ; R21 CA180524/CA/NCI NIH HHS/United States ; },
mesh = {Blotting, Western ; Cytogenetic Analysis ; DNA, Circular/genetics ; Electrophoresis, Gel, Two-Dimensional ; Fibroblasts ; Fluorescent Antibody Technique ; Humans ; Immunoprecipitation ; In Situ Hybridization, Fluorescence ; Shelterin Complex ; Telomerase/genetics/*metabolism ; Telomere Shortening/*physiology ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Telomere lengths are tightly regulated within a narrow range in normal human cells. Previous studies have extensively focused on how short telomeres are extended and have demonstrated that telomerase plays a central role in elongating short telomeres. However, much about the molecular mechanisms of regulating excessively long telomeres is unknown. In this report, we demonstrated that the telomerase enzymatic component, hTERT, plays a dual role in the regulation of telomere length. It shortens excessively long telomeres and elongates short telomeres simultaneously in one cell, maintaining the optimal telomere length at each chromosomal end for efficient protection. This novel hTERT-mediated telomere-shortening mechanism not only exists in cancer cells, but also in primary human cells. The hTERT-mediated telomere shortening requires hTERT's enzymatic activity, but the telomerase RNA component, hTR, is not involved in that process. We found that expression of hTERT increases telomeric circular DNA formation, suggesting that telomere homologous recombination is involved in the telomere-shortening process. We further demonstrated that shelterin protein TPP1 interacts with hTERT and recruits hTERT onto the telomeres, suggesting that TPP1 might be involved in regulation of telomere shortening. This study reveals a novel function of hTERT in telomere length regulation and adds a new element to the current molecular model of telomere length maintenance.},
}
@article {pmid24719895,
year = {2014},
author = {Kalmbach, K and Robinson, LG and Wang, F and Liu, L and Keefe, D},
title = {Telomere length reprogramming in embryos and stem cells.},
journal = {BioMed research international},
volume = {2014},
number = {},
pages = {925121},
pmid = {24719895},
issn = {2314-6141},
support = {UL1 RR029893/RR/NCRR NIH HHS/United States ; 1UL1RR029893/RR/NCRR NIH HHS/United States ; },
mesh = {Animals ; Embryo, Mammalian/cytology/*metabolism ; Female ; Humans ; Male ; Ovum/cytology/*metabolism ; Stem Cells/cytology/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {Telomeres protect and cap linear chromosome ends, yet these genomic buffers erode over an organism's lifespan. Short telomeres have been associated with many age-related conditions in humans, and genetic mutations resulting in short telomeres in humans manifest as syndromes of precocious aging. In women, telomere length limits a fertilized egg's capacity to develop into a healthy embryo. Thus, telomere length must be reset with each subsequent generation. Although telomerase is purportedly responsible for restoring telomere DNA, recent studies have elucidated the role of alternative telomeres lengthening mechanisms in the reprogramming of early embryos and stem cells, which we review here.},
}
@article {pmid24719256,
year = {2014},
author = {Reig-Viader, R and Vila-Cejudo, M and Vitelli, V and Buscà, R and Sabaté, M and Giulotto, E and Caldés, MG and Ruiz-Herrera, A},
title = {Telomeric repeat-containing RNA (TERRA) and telomerase are components of telomeres during mammalian gametogenesis.},
journal = {Biology of reproduction},
volume = {90},
number = {5},
pages = {103},
doi = {10.1095/biolreprod.113.116954},
pmid = {24719256},
issn = {1529-7268},
mesh = {Animals ; Female ; Flow Cytometry ; Gametogenesis/*genetics ; Gene Expression Regulation, Developmental/*physiology ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Meiosis/*physiology ; Mice, Inbred C57BL ; Microscopy, Fluorescence ; RNA/chemistry/genetics ; RNA, Untranslated/genetics/*metabolism ; Real-Time Polymerase Chain Reaction ; Telomerase/genetics/*metabolism ; Telomere/enzymology/genetics/*metabolism ; },
abstract = {Telomeres are ribonucleoprotein structures at the end of chromosomes composed of telomeric DNA, specific-binding proteins, and noncoding RNA (TERRA). Despite their importance in preventing chromosome instability, little is known about the cross talk between these three elements during the formation of the germ line. Here, we provide evidence that both TERRA and the telomerase enzymatic subunit (TERT) are components of telomeres in mammalian germ cells. We found that TERRA colocalizes with telomeres during mammalian meiosis and that its expression progressively increases during spermatogenesis until the beginning of spermiogenesis. While both TERRA levels and distribution would be regulated in a gender-specific manner, telomere-TERT colocalization appears to be regulated based on species-specific characteristics of the telomeric structure. Moreover, we found that TERT localization at telomeres is maintained throughout spermatogenesis as a structural component without affecting telomere elongation. Our results represent the first evidence of colocalization between telomerase and telomeres during mammalian gametogenesis.},
}
@article {pmid24718655,
year = {2014},
author = {Luo, YM and Xia, NX and Yang, L and Li, Z and Yang, H and Yu, HJ and Liu, Y and Lei, H and Zhou, FX and Xie, CH and Zhou, YF},
title = {CTC1 increases the radioresistance of human melanoma cells by inhibiting telomere shortening and apoptosis.},
journal = {International journal of molecular medicine},
volume = {33},
number = {6},
pages = {1484-1490},
pmid = {24718655},
issn = {1791-244X},
mesh = {Apoptosis/genetics/*physiology ; Cell Line, Tumor ; DNA Breaks, Double-Stranded ; Humans ; Melanoma/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere Shortening/genetics/*physiology ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Melanoma has traditionally been viewed as a radioresistant cancer. However, recent studies suggest that under certain clinical circumstances, radiotherapy may play a significant role in the treatment of melanoma. Previous studies have demonstrated that telomere length is a hallmark of radiosensitivity. The newly discovered mammalian CTC1‑STN1-TEN1 (CST) complex has been demonstrated to be an important telomere maintenance factor. In this study, by establishing a radiosensitive/radioresistant human melanoma cell model, MDA-MB-435/MDA-MB‑435R, we aimed to investigate the association of CTC1 expression with radiosensitivity in human melanoma cell lines, and to elucidate the possible underlying mechanisms. We found that CTC1 mRNA and protein levels were markedly increased in the MDA-MB‑435R cells compared with the MDA-MB‑435 cells. Moreover, the downregulation of CTC1 enhanced radiosensitivity, induced DNA damage and promoted telomere shortening and apoptosis in both cell lines. Taken together, our findings suggest that CTC1 increases the radioresistance of human melanoma cells by inhibiting telomere shortening and apoptosis. Thus, CTC1 may be an attractive target gene for the treatment of human melanoma.},
}
@article {pmid24714070,
year = {2014},
author = {Fojtová, M and Fajkus, J},
title = {Epigenetic regulation of telomere maintenance.},
journal = {Cytogenetic and genome research},
volume = {143},
number = {1-3},
pages = {125-135},
doi = {10.1159/000360775},
pmid = {24714070},
issn = {1424-859X},
mesh = {Animals ; Chromatin/genetics ; Chromosomes, Plant/*genetics ; Epigenesis, Genetic/*genetics ; Humans ; Telomere/*genetics ; },
abstract = {As chromatin structures, telomeres undergo epigenetic regulation of their maintenance and function. In plants, these processes are likely of a higher complexity than in animals or yeasts, as exemplified by methylation of cytosines in plant telomeric DNA or reversible developmental regulation of plant telomerase. We highlight the dual role of telomeres from the epigenetic point of view: (i) as chromatin structures that are the subject of epigenetic regulation (e.g. DNA and histone modifications), and (ii) as chromosome domains acting themselves as epigenetic regulatory elements (e.g. in the telomere position effect). Possibly, some molecular tools (e.g. telomeric transcripts) are common to both these aspects of telomere epigenetics. We further discuss the justification for the classical textbook view of telomeres as heterochromatic structures.},
}
@article {pmid24713631,
year = {2014},
author = {Zlotorynski, E},
title = {DNA damage response: Mitosis: don't 'repair' the telomere!.},
journal = {Nature reviews. Molecular cell biology},
volume = {15},
number = {5},
pages = {300},
pmid = {24713631},
issn = {1471-0080},
mesh = {Animals ; *DNA Breaks, Double-Stranded ; DNA End-Joining Repair/*physiology ; Humans ; Mitosis/*physiology ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; },
}
@article {pmid24711987,
year = {2014},
author = {Mu, Y and Ren, LF and Xun, ZL and Zhang, DD and Song, H and Lu, H and Li, FL and Liu, D},
title = {Sex- and season-dependent differences in telomere length and telomerase activity in the leaves of ash and willow.},
journal = {SpringerPlus},
volume = {3},
number = {},
pages = {163},
pmid = {24711987},
issn = {2193-1801},
abstract = {Telomeres and telomerase have important biological functions and can protect chromosome ends. In this study, sex- and season-dependent changes in telomere length and telomerase activity in ash and willow were analyzed. A statistical analysis showed that the telomere lengths of male and female trees differed significantly (P < 0.05). In ash, the telomere lengths of female trees were shorter than those of male trees. In willow, the telomere lengths of female trees were longer than those of male trees. During the annual developmental cycle, the telomere lengths of male and female ash and willow increased from April to May (P < 0.05), remained stable from May to August (P > 0.05), and decreased significantly in September and October (P < 0.05). Additionally, telomerase activities could be detected in both male and female ash and willow trees from April to October. Our results show that the telomere lengths changed according to season and sex in ash and willow. Telomere length did not have a direct positive correlation with telomerase activity.},
}
@article {pmid24711392,
year = {2014},
author = {Miyagawa, K and Low, RS and Santosa, V and Tsuji, H and Moser, BA and Fujisawa, S and Harland, JL and Raguimova, ON and Go, A and Ueno, M and Matsuyama, A and Yoshida, M and Nakamura, TM and Tanaka, K},
title = {SUMOylation regulates telomere length by targeting the shelterin subunit Tpz1(Tpp1) to modulate shelterin-Stn1 interaction in fission yeast.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {111},
number = {16},
pages = {5950-5955},
pmid = {24711392},
issn = {1091-6490},
support = {R01 GM078253/GM/NIGMS NIH HHS/United States ; GM078253/GM/NIGMS NIH HHS/United States ; },
mesh = {Carrier Proteins/*metabolism ; DNA-Binding Proteins ; G2 Phase ; Ligases ; Lysine/metabolism ; Models, Biological ; Protein Binding ; Protein Subunits/*metabolism ; S Phase ; Schizosaccharomyces/cytology/*metabolism ; Schizosaccharomyces pombe Proteins/*metabolism ; *Sumoylation ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; Telomere Shortening ; Telomere-Binding Proteins/*metabolism ; Ubiquitin-Protein Ligases/metabolism ; },
abstract = {Telomeres protect DNA ends of linear eukaryotic chromosomes from degradation and fusion, and ensure complete replication of the terminal DNA through recruitment of telomerase. The regulation of telomerase is a critical area of telomere research and includes cis regulation by the shelterin complex in mammals and fission yeast. We have identified a key component of this regulatory pathway as the SUMOylation [the covalent attachment of a small ubiquitin-like modifier (SUMO) to target proteins] of a shelterin subunit in fission yeast. SUMOylation is known to be involved in the negative regulation of telomere extension by telomerase; however, how SUMOylation limits the action of telomerase was unknown until now. We show that SUMOylation of the shelterin subunit TPP1 homolog in Schizosaccharomyces pombe (Tpz1) on lysine 242 is important for telomere length homeostasis. Furthermore, we establish that Tpz1 SUMOylation prevents telomerase accumulation at telomeres by promoting recruitment of Stn1-Ten1 to telomeres. Our findings provide major mechanistic insights into how the SUMOylation pathway collaborates with shelterin and Stn1-Ten1 complexes to regulate telomere length.},
}
@article {pmid24711381,
year = {2014},
author = {Mitchell, C and Hobcraft, J and McLanahan, SS and Siegel, SR and Berg, A and Brooks-Gunn, J and Garfinkel, I and Notterman, D},
title = {Social disadvantage, genetic sensitivity, and children's telomere length.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {111},
number = {16},
pages = {5944-5949},
pmid = {24711381},
issn = {1091-6490},
support = {R01HD39135/HD/NICHD NIH HHS/United States ; R01 HD039135/HD/NICHD NIH HHS/United States ; TL1 TR00012503/TR/NCATS NIH HHS/United States ; R01 HD036916/HD/NICHD NIH HHS/United States ; UL1 TR000127/TR/NCATS NIH HHS/United States ; R24 HD047879/HD/NICHD NIH HHS/United States ; R01HD36916/HD/NICHD NIH HHS/United States ; R01HD40421/HD/NICHD NIH HHS/United States ; R01 HD076592/HD/NICHD NIH HHS/United States ; R01 HD040421/HD/NICHD NIH HHS/United States ; R24 HD058486/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Child ; Dopamine/metabolism ; Gene-Environment Interaction ; Humans ; Male ; Regression Analysis ; Serotonin/metabolism ; Signal Transduction ; *Social Environment ; Telomere Homeostasis/*genetics ; *Vulnerable Populations ; },
abstract = {Disadvantaged social environments are associated with adverse health outcomes. This has been attributed, in part, to chronic stress. Telomere length (TL) has been used as a biomarker of chronic stress: TL is shorter in adults in a variety of contexts, including disadvantaged social standing and depression. We use data from 40, 9-y-old boys participating in the Fragile Families and Child Wellbeing Study to extend this observation to African American children. We report that exposure to disadvantaged environments is associated with reduced TL by age 9 y. We document significant associations between low income, low maternal education, unstable family structure, and harsh parenting and TL. These effects were moderated by genetic variants in serotonergic and dopaminergic pathways. Consistent with the differential susceptibility hypothesis, subjects with the highest genetic sensitivity scores had the shortest TL when exposed to disadvantaged social environments and the longest TL when exposed to advantaged environments.},
}
@article {pmid24710073,
year = {2014},
author = {Li, P and Liu, T and Liu, J and Zhang, Q and Lou, F and Kong, F and Cheng, G and Björkholm, M and Zheng, C and Xu, D},
title = {Promoter polymorphism in the serotonin transporter (5-HTT) gene is significantly associated with leukocyte telomere length in Han Chinese.},
journal = {PloS one},
volume = {9},
number = {4},
pages = {e94442},
pmid = {24710073},
issn = {1932-6203},
mesh = {Adult ; Aged ; Aged, 80 and over ; Asian People/*ethnology/genetics/psychology ; Base Sequence ; Cohort Studies ; Ethnicity/*genetics/psychology ; Female ; Genotype ; Healthy Volunteers ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; *Polymorphism, Genetic ; Promoter Regions, Genetic/*genetics ; Serotonin Plasma Membrane Transport Proteins/*genetics ; Stress, Psychological/genetics ; Telomere/*genetics ; Young Adult ; },
abstract = {The serotonin transporter gene (5-HTT)-linked polymorphic region (5-HTTLPR) plays an important role in modulating mood and behavior by regulating 5-HTT expression and thereby controlling the concentration of serotonin (5-HT) in brain synapses: The homozygous shorter allele (S/S) in 5-HTTLPR results in lower 5-HTT expression coupled with stronger psycho-pathological reactions to stressful experiences compared to the homozygous long (L/L) and heterozygous (S/L) alleles. Psychological insults and mood disorders have been shown to cause accelerated telomere shortening, a marker of biological aging, however, it is currently unclear whether the allelic variants of 5-HTTLPR affect telomere length (TL) in the healthy population without mood disorders. In the present study, we determined the relationship between TL and the 5-HTTLPR variants in healthy Han Chinese. The 5-HTTLPR genotyping and leukocyte TL analysis of 280 young female Han Chinese freshmen showed a significantly shorter TL in 149 of them carrying the 5-HTTLPR S/S version compared to those (131) with the L/S or L/S plus L/L genotypes (mean ± SD, 0.533±0.241 for S/S vs 0.607±0.312 for L/S, P = 0.034; or vs 0.604±0.313 for L/S plus L/L, P = 0.038). Similar results were achieved in the other cohort including 220 adult healthy individuals of different age, gender and profession (0.691±0.168 for S/S vs 0.729±0.211 for L/S, P = 0.046, or vs 0.725±0.213 for L/S plus L/L, P = 0.039). Taken together, shorter leukocyte TL is significantly associated with the 5-HTTLPR S/S allelic variant, which may be implicated in psychological stress-related health problems.},
}
@article {pmid24709898,
year = {2014},
author = {Gocha, AR and Acharya, S and Groden, J},
title = {WRN loss induces switching of telomerase-independent mechanisms of telomere elongation.},
journal = {PloS one},
volume = {9},
number = {4},
pages = {e93991},
pmid = {24709898},
issn = {1932-6203},
support = {UL1 TR000090/TR/NCATS NIH HHS/United States ; 8KL2TR000112-05/TR/NCATS NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; CA-117898/CA/NCI NIH HHS/United States ; UL1 TR001070/TR/NCATS NIH HHS/United States ; 8UL1TR000090-05/TR/NCATS NIH HHS/United States ; KL2 TR000112/TR/NCATS NIH HHS/United States ; TL1 TR000091/TR/NCATS NIH HHS/United States ; 8TL1TR000091-05/TR/NCATS NIH HHS/United States ; R01 CA117898/CA/NCI NIH HHS/United States ; },
mesh = {BRCA1 Protein/genetics/metabolism ; Cell Line ; Exodeoxyribonucleases/genetics/*metabolism ; Humans ; RNA, Small Interfering ; RecQ Helicases/genetics/*metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomere Homeostasis/*physiology ; Werner Syndrome Helicase ; },
abstract = {Telomere maintenance can occur in the presence of telomerase or in its absence, termed alternative lengthening of telomeres (ALT). ALT adds telomere repeats using recombination-based processes and DNA repair proteins that function in homologous recombination. Our previous work reported that the RecQ-like BLM helicase is required for ALT and that it unwinds telomeric substrates in vitro. WRN is also a RecQ-like helicase that shares many biochemical functions with BLM. WRN interacts with BLM, unwinds telomeric substrates, and co-localizes to ALT-associated PML bodies (APBs), suggesting that it may also be required for ALT processes. Using long-term siRNA knockdown of WRN in three ALT cell lines, we show that some, but not all, cell lines require WRN for telomere maintenance. VA-13 cells require WRN to prevent telomere loss and for the formation of APBs; Saos-2 cells do not. A third ALT cell line, U-2 OS, requires WRN for APB formation, however WRN loss results in p53-mediated apoptosis. In the absence of WRN and p53, U-2 OS cells undergo telomere loss for an intermediate number of population doublings (50-70), at which point they maintain telomere length even with the continued loss of WRN. WRN and the tumor suppressor BRCA1 co-localize to APBs in VA-13 and U-2 OS, but not in Saos-2 cells. WRN loss in U-2 OS is associated with a loss of BRCA1 from APBs. While the loss of WRN significantly increases telomere sister chromatid exchanges (T-SCE) in these three ALT cell lines, loss of both BRCA1 and WRN does not significantly alter T-SCE. This work demonstrates that ALT cell lines use different telomerase-independent maintenance mechanisms that variably require the WRN helicase and that some cells can switch from one mechanism to another that permits telomere elongation in the absence of WRN. Our data suggest that BRCA1 localization may define these mechanisms.},
}
@article {pmid24706380,
year = {2014},
author = {Hoxha, M and Fabris, S and Agnelli, L and Bollati, V and Cutrona, G and Matis, S and Recchia, AG and Gentile, M and Cortelezzi, A and Morabito, F and Bertazzi, PA and Ferrarini, M and Neri, A},
title = {Relevance of telomere/telomerase system impairment in early stage chronic lymphocytic leukemia.},
journal = {Genes, chromosomes &amp; cancer},
volume = {53},
number = {7},
pages = {612-621},
doi = {10.1002/gcc.22171},
pmid = {24706380},
issn = {1098-2264},
mesh = {Adult ; Aged ; Aged, 80 and over ; B-Lymphocytes/metabolism ; Case-Control Studies ; DNA Methylation ; Gene Expression Profiling ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/metabolism ; Middle Aged ; Retrospective Studies ; Telomerase/genetics/*metabolism ; Telomere/*genetics ; *Telomere Shortening ; },
abstract = {Several studies have proposed telomere length and telomerase activity as prognostic factors in chronic lymphocytic leukemia (CLL), whereas information addressing the role of telomere-associated genes is limited. We measured relative telomere length (RTL) and TERT expression levels in purified peripheral CD19(+) B-cells from seven healthy donors and 77 untreated CLLs in early stage disease (Binet A). Data were correlated with the major biological and cytogenetic markers, global DNA methylation (Alu and LINE-1), and clinical outcome. The expression profiles of telomere-associated genes were also investigated. RTL was decreased in CLLs as compared with controls (P < 0.001); within CLL, a progressive and significant RTL shortening was observed in patients from 13q- through +12, 11q-, and 17p- alterations; short telomeres were significantly associated with unmutated IGHV configuration and global DNA hypomethylation. Decreased RTL was associated with a shorter time to first treatment. A significant upregulation of POT1, TRF1, RAP1, MRE11A, RAD50, and RPA1 transcript levels was observed in CLLs compared with controls. Our study suggests that impairment of telomere/telomerase system represents an early event in CLL pathogenesis. Moreover, the correlation between telomere shortening and global DNA hypomethylation supports the involvement of DNA hypomethylation to increase chromosome instability. © 2014 Wiley Periodicals, Inc.},
}
@article {pmid24705445,
year = {2014},
author = {Aydinonat, D and Penn, DJ and Smith, S and Moodley, Y and Hoelzl, F and Knauer, F and Schwarzenberger, F},
title = {Social isolation shortens telomeres in African Grey parrots (Psittacus erithacus erithacus).},
journal = {PloS one},
volume = {9},
number = {4},
pages = {e93839},
pmid = {24705445},
issn = {1932-6203},
mesh = {Age Factors ; Animals ; Biomarkers/analysis ; DNA Primers/genetics ; Erythrocytes/chemistry ; Parrots/*genetics/physiology ; Social Isolation/*psychology ; Stress, Psychological/genetics/*physiopathology ; Telomere Shortening/genetics/*physiology ; },
abstract = {Telomeres, the caps of eukaryotic chromosomes, control chromosome stability and cellular senescence, but aging and exposure to chronic stress are suspected to cause attrition of telomere length. We investigated the effect of social isolation on telomere length in the highly social and intelligent African Grey parrot (Psittacus erithacus erithacus). Our study population consisted of single-housed (n = 26) and pair-housed (n = 19) captive individuals between 0.75 to 45 years of age. Relative telomere length of erythrocyte DNA was measured by quantitative real-time PCR. We found that telomere length declined with age (p<0.001), and socially isolated parrots had significantly shorter telomeres compared to pair-housed birds (p<0.001) - even among birds of similar ages. Our findings provide the first evidence that social isolation affects telomere length, which supports the hypothesis that telomeres provide a biomarker indicating exposure to chronic stress.},
}
@article {pmid24701373,
year = {2014},
author = {Cherfils-Vicini, J and Zizza, P and Gilson, E and Biroccio, A},
title = {A novel pathway links telomeres to NK-cell activity: Implications for immunotherapy.},
journal = {Oncoimmunology},
volume = {3},
number = {1},
pages = {e27358},
pmid = {24701373},
issn = {2162-4011},
abstract = {Here, we describe a model in which telomeric repeat-binding factor 2 (TERF2) can control tumorigenesis not only via cancer cell-intrinsic mechanisms but also via non-cancer cell autonomous pathways. Indeed, we have recently shown that TERF2 regulates tissue homeostasis as it promotes the elimination of aged, damaged, and neoplastic cells by the immune system, opening the way to new therapeutic options against cancer.},
}
@article {pmid24699249,
year = {2014},
author = {Putnam, CD and Pallis, K and Hayes, TK and Kolodner, RD},
title = {DNA repair pathway selection caused by defects in TEL1, SAE2, and de novo telomere addition generates specific chromosomal rearrangement signatures.},
journal = {PLoS genetics},
volume = {10},
number = {4},
pages = {e1004277},
pmid = {24699249},
issn = {1553-7404},
support = {R01 GM026017/GM/NIGMS NIH HHS/United States ; R37 GM026017/GM/NIGMS NIH HHS/United States ; GM26017/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes, Fungal/*genetics ; DNA Damage/genetics ; DNA Repair/*genetics ; Endonucleases/*genetics ; Gene Rearrangement/*genetics ; Genome, Fungal/genetics ; Intracellular Signaling Peptides and Proteins/*genetics ; Mutation/genetics ; Protein Serine-Threonine Kinases/*genetics ; Recombination, Genetic/genetics ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/*genetics ; Telomere/*genetics ; },
abstract = {Whole genome sequencing of cancer genomes has revealed a diversity of recurrent gross chromosomal rearrangements (GCRs) that are likely signatures of specific defects in DNA damage response pathways. However, inferring the underlying defects has been difficult due to insufficient information relating defects in DNA metabolism to GCR signatures. By analyzing over 95 mutant strains of Saccharomyces cerevisiae, we found that the frequency of GCRs that deleted an internal CAN1/URA3 cassette on chrV L while retaining a chrV L telomeric hph marker was significantly higher in tel1Δ, sae2Δ, rad53Δ sml1Δ, and mrc1Δ tof1Δ mutants. The hph-retaining GCRs isolated from tel1Δ mutants contained either an interstitial deletion dependent on non-homologous end-joining or an inverted duplication that appeared to be initiated from a double strand break (DSB) on chrV L followed by hairpin formation, copying of chrV L from the DSB toward the centromere, and homologous recombination to capture the hph-containing end of chrV L. In contrast, hph-containing GCRs from other mutants were primarily interstitial deletions (mrc1Δ tof1Δ) or inverted duplications (sae2Δ and rad53Δ sml1Δ). Mutants with impaired de novo telomere addition had increased frequencies of hph-containing GCRs, whereas mutants with increased de novo telomere addition had decreased frequencies of hph-containing GCRs. Both types of hph-retaining GCRs occurred in wild-type strains, suggesting that the increased frequencies of hph retention were due to the relative efficiencies of competing DNA repair pathways. Interestingly, the inverted duplications observed here resemble common GCRs in metastatic pancreatic cancer.},
}
@article {pmid24698125,
year = {2014},
author = {Eitan, E and Hutchison, ER and Mattson, MP},
title = {Telomere shortening in neurological disorders: an abundance of unanswered questions.},
journal = {Trends in neurosciences},
volume = {37},
number = {5},
pages = {256-263},
pmid = {24698125},
issn = {1878-108X},
support = {ZIA AG000313-13//Intramural NIH HHS/United States ; ZIA AG000314-13//Intramural NIH HHS/United States ; ZIA AG000331-05//Intramural NIH HHS/United States ; },
mesh = {Animals ; Humans ; Nervous System Diseases/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Telomeres, ribonucleoprotein complexes that cap eukaryotic chromosomes, typically shorten in leukocytes with aging. Aging is a primary risk factor for neurodegenerative disease (ND), and a common assumption has arisen that leukocyte telomere length (LTL) can serve as a predictor of neurological disease. However, the evidence for shorter LTL in Alzheimer's and Parkinson's patients is inconsistent. The diverse causes of telomere shortening may explain variability in LTL between studies and individuals. Additional research is needed to determine whether neuronal and glial telomeres shorten during aging and in neurodegenerative disorders, if and how LTL is related to brain cell telomere shortening, and whether telomere shortening plays a causal role in or exacerbates neurological disorders.},
}
@article {pmid24693429,
year = {2014},
author = {Bendix, L and Thinggaard, M and Kimura, M and Aviv, A and Christensen, K and Osler, M and Avlund, K},
title = {Association of leukocyte telomere length with fatigue in nondisabled older adults.},
journal = {Journal of aging research},
volume = {2014},
number = {},
pages = {403253},
pmid = {24693429},
issn = {2090-2204},
support = {P01 AG008761/AG/NIA NIH HHS/United States ; R01 AG030678/AG/NIA NIH HHS/United States ; },
abstract = {Introduction. Fatigue is often present in older adults with no identified underlying cause. The accruing burden of oxidative stress and inflammation might be underlying factors of fatigue. We therefore hypothesized that leukocyte telomere length (LTL) is relatively short in older adults who experience fatigue. Materials and Methods. We assessed 439 older nondisabled Danish twins. LTL was measured using Southern blots of terminal restriction fragments. Fatigue was measured by the Mob-T Scale based on questions on whether the respondents felt fatigued after performing six mobility items. Results. LTL was significantly associated with fatigue (P = 0.023), showing an increase of 0.038 kb/fatigue score unit. Aging-related diseases and mental health did not explain the association, while lifestyle factors slightly attenuated the estimates. Conclusion. Our results support an association between LTL and fatigue. Further studies are required to confirm this finding and the link of LTL with oxidative stress/inflammation over the life course.},
}
@article {pmid24686071,
year = {2014},
author = {Rewak, M and Buka, S and Prescott, J and De Vivo, I and Loucks, EB and Kawachi, I and Non, AL and Kubzansky, LD},
title = {Race-related health disparities and biological aging: does rate of telomere shortening differ across blacks and whites?.},
journal = {Biological psychology},
volume = {99},
number = {},
pages = {92-99},
pmid = {24686071},
issn = {1873-6246},
support = {P50 CA98029/CA/NCI NIH HHS/United States ; R01 AG023397/AG/NIA NIH HHS/United States ; P50 CA084719/CA/NCI NIH HHS/United States ; AG023397/AG/NIA NIH HHS/United States ; CA084719/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aging/*genetics ; Analysis of Variance ; Black People/*genetics ; Cohort Studies ; Female ; Healthcare Disparities ; Humans ; Infant ; Leukocytes/physiology ; Male ; Middle Aged ; Regression Analysis ; Sex Factors ; Telomere Shortening/*genetics ; White People/*genetics ; },
abstract = {Recent work suggests that leukocyte telomere length (LTL), a marker of cellular aging, is sensitive to effects of social stress and may also provide early indication of premature aging. Using data from a birth cohort with LTL information at birth and in middle adulthood we examined a potential source of race-based health disparity by testing the hypothesis that Blacks would demonstrate a faster rate of telomere shortening than Whites. Linear regression analyses were conducted and adjusted for pack years, BMI, education and social factors, diet, exercise, marital status, and age. At birth black individuals had LTLs that were longer, on average, than their White counterparts (b=3.85, p<0.01). However, rate of shortening was greater for Blacks, who showed a larger difference in length between birth and adulthood (b=5.10, p=0.01) as compared with Whites, resulting in smaller racial differences in absolute adult LTL.},
}
@article {pmid24686009,
year = {2014},
author = {Morgan, RG and Ives, SJ and Walker, AE and Cawthon, RM and Andtbacka, RH and Noyes, D and Lesniewski, LA and Richardson, RS and Donato, AJ},
title = {Role of arterial telomere dysfunction in hypertension: relative contributions of telomere shortening and telomere uncapping.},
journal = {Journal of hypertension},
volume = {32},
number = {6},
pages = {1293-1299},
pmid = {24686009},
issn = {1473-5598},
support = {K01 AG029337/AG/NIA NIH HHS/United States ; R21 AG043952/AG/NIA NIH HHS/United States ; K01 AG046326/AG/NIA NIH HHS/United States ; K01 AG033196/AG/NIA NIH HHS/United States ; K02 AG045339/AG/NIA NIH HHS/United States ; AG029337/AG/NIA NIH HHS/United States ; R01 AG040297/AG/NIA NIH HHS/United States ; AG033196/AG/NIA NIH HHS/United States ; R21 AG033755/AG/NIA NIH HHS/United States ; T32 HL007576/HL/NHLBI NIH HHS/United States ; F32 HL009183/HL/NHLBI NIH HHS/United States ; AG033755/AG/NIA NIH HHS/United States ; HL09183/HL/NHLBI NIH HHS/United States ; AG040297/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Arteries/*pathology ; Biopsy ; *Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p21/genetics ; Female ; *Gene Expression Regulation ; Humans ; Hypertension/*genetics/pathology ; Male ; Middle Aged ; Phosphorylation ; Regression Analysis ; Telomere/pathology ; *Telomere Shortening ; Tumor Suppressor Protein p53/genetics ; },
abstract = {OBJECTIVE: Telomere shortening in arteries could lead to telomere uncapping and cellular senescence, which in turn could promote the development of hypertension.<br><br>METHODS AND RESULTS: To assess the novel role of arterial telomere dysfunction in hypertension, we compared mean telomere length (qPCR), telomere uncapping (serine 139 phosphorylated histone &#x3b3;-H2A.X (&#x3b3;-H2) localized to telomeres: ChIP), and tumor suppressor protein p53 (P53)/cyclin-dependent kinase inhibitor 1A (P21)-induced senescence (P53 bound to P21 gene promoter: ChIP) in arteries from 55 age-matched hypertensive and nonhypertensive individuals. Arterial mean telomere length was not different in hypertensive patients compared with nonhypertensive individuals (P&#x200a;=&#x200a;0.29). Arterial telomere uncapping and P53/P21-induced senescence were two-fold greater in hypertensive patients compared with nonhypertensive individuals (P&#x200a;=&#x200a;0.04 and P&#x200a;=&#x200a;0.02, respectively). Arterial mean telomere length was not associated with telomere uncapping or P53/P21-induced senescence (r&#x200a;=&#x200a;-0.02, P&#x200a;=&#x200a;0.44 and r&#x200a;=&#x200a;0.01, P&#x200a;=&#x200a;0.50, respectively), but telomere uncapping was a highly influential covariate for the hypertension group difference in P53/P21-induced senescence (r&#x200a;=&#x200a;0.62, P&#x200a;<&#x200a;0.001, &#x3b7;(p)(2)&#x200a;=&#x200a;0.35). Finally, telomere uncapping was a significant predictor of hypertension status (P&#x200a;=&#x200a;0.03), whereas mean telomere length was not (P&#x200a;=&#x200a;0.68).<br><br>CONCLUSION: Collectively, these findings demonstrate that arterial telomere uncapping and P53/P21-induced senescence are linked to hypertension independently of mean telomere length, and telomere uncapping influences hypertension status more than mean telomere length.},
}
@article {pmid24675987,
year = {2014},
author = {Dracxler, RC and Oh, C and Kalmbach, K and Wang, F and Liu, L and Kallas, EG and Giret, MT and Seth-Smith, ML and Antunes, D and Keefe, DL and Abrao, MS},
title = {Peripheral blood telomere content is greater in patients with endometriosis than in controls.},
journal = {Reproductive sciences (Thousand Oaks, Calif.)},
volume = {21},
number = {12},
pages = {1465-1471},
doi = {10.1177/1933719114527353},
pmid = {24675987},
issn = {1933-7205},
mesh = {Adult ; Case-Control Studies ; Endometriosis/blood/diagnosis/*genetics ; Female ; Genetic Markers ; Humans ; Lymphocytes/*metabolism ; Polymerase Chain Reaction ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {UNLABELLED: The etiology of endometriosis remains poorly understood but circulating stem cells may contribute. Telomeres shorten with cell divisions and age. Stem cells attempt to compensate for telomere attrition through the action of telomerase. Since circulating stem cells may contribute to endometriosis, we compared telomere content in lymphocytes of patients with and without endometriosis.<br><br>METHODS: Observational study comparing peripheral lymphocytes telomere content, measured by quantitative polymerase chain reaction, in patients with (n = 86) and without endometriosis (n = 21).<br><br>FINDINGS: Patients with endometriosis had longer telomeres than that of matched, endometriosis-free controls (telomere to single copy gene ratio [T/S ratio] of 1.62 vs 1.34, respectively, P = .00002). Patients with endometriosis were 8.1-fold more likely to have long telomeres. (odds ratio = 8.1, 95% confidence interval: 1.28-51.57, P = .0264).<br><br>INTERPRETATION: Longer telomeres could be consistent with a stem cell origin of endometriosis.},
}
@article {pmid24666613,
year = {2014},
author = {Zietzer, A and Hillmeister, P},
title = {Leucocyte telomere length as marker for cardiovascular ageing.},
journal = {Acta physiologica (Oxford, England)},
volume = {211},
number = {2},
pages = {251-256},
doi = {10.1111/apha.12284},
pmid = {24666613},
issn = {1748-1716},
mesh = {Aging/*genetics ; Cardiovascular Diseases/*genetics ; Cardiovascular System/physiopathology ; Humans ; Immune System/*physiopathology ; Leukocytes/*physiology ; Oxidative Stress/genetics ; Telomere/*genetics ; },
}
@article {pmid24666270,
year = {2014},
author = {Drašar, ER and Jiang, J and Gardner, K and Howard, J and Vulliamy, T and Vasavda, N and Thein, SL},
title = {Leucocyte telomere length in patients with sickle cell disease.},
journal = {British journal of haematology},
volume = {165},
number = {5},
pages = {725-727},
doi = {10.1111/bjh.12776},
pmid = {24666270},
issn = {1365-2141},
support = {G0000111/MRC_/Medical Research Council/United Kingdom ; G0001249/MRC_/Medical Research Council/United Kingdom ; ID 56477/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/genetics ; Anemia, Sickle Cell/*genetics ; Case-Control Studies ; Child ; Female ; Humans ; Leukocytes/*pathology ; Male ; Middle Aged ; Telomere Homeostasis/*physiology ; Young Adult ; },
}
@article {pmid24665044,
year = {2015},
author = {Chatterjee, D and Bhattacharjee, P and Sau, TJ and Das, JK and Sarma, N and Bandyopadhyay, AK and Roy, SS and Giri, AK},
title = {Arsenic exposure through drinking water leads to senescence and alteration of telomere length in humans: A case-control study in West Bengal, India.},
journal = {Molecular carcinogenesis},
volume = {54},
number = {9},
pages = {800-809},
doi = {10.1002/mc.22150},
pmid = {24665044},
issn = {1098-2744},
mesh = {Adult ; Aging/*drug effects ; Arsenic/*toxicity ; Carcinogenesis/chemically induced/metabolism/pathology ; Case-Control Studies ; Drinking Water/*adverse effects/analysis ; Female ; Humans ; India/epidemiology ; Male ; Middle Aged ; Signal Transduction/drug effects ; Skin/drug effects/metabolism/pathology ; Skin Diseases/chemically induced/epidemiology/metabolism/pathology ; Telomerase/metabolism ; Telomere/*drug effects/pathology ; Tumor Suppressor Protein p53/metabolism ; Water Pollutants, Chemical/*toxicity ; },
abstract = {Arsenic (As) induces pre-malignant and malignant dermatological lesions, non-dermatological health effects and cancers in humans. Senescence involves telomere length changes and acquisition of senescence-associated secretory phenotype (SASP), which promotes carcinogenesis. Though in vitro studies have shown that As induces senescence, population based studies are lacking. We investigated the arsenic-induced senescence, telomere length alteration and its contribution towards development of As-induced skin cancer. The study participants included 60 each of As-exposed individuals with skin lesion (WSL), without skin lesions (WOSL) and 60 unexposed controls. Exposure assessment of drinking water and urine was done. SA β-gal activity, ELISA, and quantification of senescence proteins, alternative lengthening of telomere (ALT) associated proteins and telomerase activity were performed. Relative telomere length (RTL) was determined by qPCR. A significantly higher number of senescent cells, over-expression of p53 and p21 were observed in the As-exposed individuals when compared to unexposed. SASP markers, MMP-1/MMP-3 were significantly higher in the WSL but not IL-6/IL-8. A significant increase of RTL was observed in the WSL group, which was telomerase-independent but exhibited an over-expression of ALT associated proteins TRF-1 and TRF-2 with higher increase in TRF-2. An increased risk for developing As-induced skin lesions was found for individuals having RTL greater than 0.827 (odds ratio, 13.75; 95% CI: 5.66-33.41; P < 0.0001). Arsenic induces senescence in vivo, but the SASP markers are not strictly over-expressed in the As-induced skin lesion group, whereas telomerase-independent elongation of telomere length might be useful for predicting the risk of development of As-induced skin lesions.},
}
@article {pmid24662969,
year = {2014},
author = {Stimpson, KM and Sullivan, LL and Kuo, ME and Sullivan, BA},
title = {Nucleolar organization, ribosomal DNA array stability, and acrocentric chromosome integrity are linked to telomere function.},
journal = {PloS one},
volume = {9},
number = {3},
pages = {e92432},
pmid = {24662969},
issn = {1932-6203},
support = {F31 AG034749/AG/NIA NIH HHS/United States ; R01 GM098500/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line ; *Chromosomal Instability ; DNA Damage/genetics ; DNA Repair/genetics ; DNA, Ribosomal/*genetics ; Gene Expression Regulation/genetics ; Humans ; Nucleolus Organizer Region/*genetics ; Pol1 Transcription Initiation Complex Proteins/metabolism ; Telomere/*genetics ; Telomeric Repeat Binding Protein 2/genetics ; },
abstract = {The short arms of the ten acrocentric human chromosomes share several repetitive DNAs, including ribosomal RNA genes (rDNA). The rDNA arrays correspond to nucleolar organizing regions that coalesce each cell cycle to form the nucleolus. Telomere disruption by expressing a mutant version of telomere binding protein TRF2 (dnTRF2) causes non-random acrocentric fusions, as well as large-scale nucleolar defects. The mechanisms responsible for acrocentric chromosome sensitivity to dysfunctional telomeres are unclear. In this study, we show that TRF2 normally associates with the nucleolus and rDNA. However, when telomeres are crippled by dnTRF2 or RNAi knockdown of TRF2, gross nucleolar and chromosomal changes occur. We used the controllable dnTRF2 system to precisely dissect the timing and progression of nucleolar and chromosomal instability induced by telomere dysfunction, demonstrating that nucleolar changes precede the DNA damage and morphological changes that occur at acrocentric short arms. The rDNA repeat arrays on the short arms decondense, and are coated by RNA polymerase I transcription binding factor UBF, physically linking acrocentrics to one another as they become fusogenic. These results highlight the importance of telomere function in nucleolar stability and structural integrity of acrocentric chromosomes, particularly the rDNA arrays. Telomeric stress is widely accepted to cause DNA damage at chromosome ends, but our findings suggest that it also disrupts chromosome structure beyond the telomere region, specifically within the rDNA arrays located on acrocentric chromosomes. These results have relevance for Robertsonian translocation formation in humans and mechanisms by which acrocentric-acrocentric fusions are promoted by DNA damage and repair.},
}
@article {pmid24661353,
year = {2015},
author = {Bunout, D and Barrera, G and de la Maza, MP and Leiva, L and Hirsch, S},
title = {Effect of weight maintenance or gain in a 10 years period over telomere length, sirtuin 1 and 6 expression and carotid intima media thickness.},
journal = {Journal of human nutrition and dietetics : the official journal of the British Dietetic Association},
volume = {28},
number = {2},
pages = {155-164},
doi = {10.1111/jhn.12231},
pmid = {24661353},
issn = {1365-277X},
mesh = {Adult ; Aging/physiology ; Body Composition ; Body Mass Index ; Body Weight ; *Carotid Intima-Media Thickness ; DNA/blood ; Diet Records ; Female ; *Gene Expression ; Humans ; Male ; Middle Aged ; RNA/blood ; Sirtuin 1/*genetics ; Sirtuins/*genetics ; Telomere Homeostasis/*physiology ; Waist Circumference ; Weight Gain/*physiology ; Weight Loss ; },
abstract = {BACKGROUND: Lack of weight gain throughout adult life could mimic the beneficial effects of energy restriction in humans. The present study aimed to assess the effects of weight stability or gain, over a period of 10 years, on telomere length, sirtuin 1 and 6 expression, and carotid intima media thickness.<br><br>METHODS: We studied 148 healthy adults (age range 20-59&#xa0;years; 101 females) who had an objective record of their weight 10&#xa0;years before. They were classified as weight losers, weight maintainers, weight gainers and extreme weight gainers. A fasting blood sample was obtained for routine laboratory and isolation of peripheral blood mononuclear cells, to extract DNA and RNA, and to measure telomere length and sirtuin 1 and 6 expression, respectively. Carotid intima media thickness was measured by ultrasound. Body composition was measured by Dual-energy X-ray absorptiometry.<br><br>RESULTS: In the 10-year period, 24 participants lost weight (17 females), 65 maintained weight (41 females), 25 gained weight (15 females) and 34 were extreme weight gainers (28 females). Female weight gainers had a higher body mass index, waist circumference, total body fat and homeostatic model assessment insulin resistance. Male weight gainers had a higher hip circumference and total body fat. No differences in telomere length, sirtuin 1 expression and carotid intima media thickness were observed between weight gainers and maintainers.<br><br>CONCLUSIONS: No effect of weight maintenance or gain was observed on metabolic and vascular markers of ageing.},
}
@article {pmid24659482,
year = {2014},
author = {Zhang, WG and Zhu, SY and Bai, XJ and Zhao, DL and Jian, SM and Li, J and Li, ZX and Fu, B and Cai, GY and Sun, XF and Chen, XM},
title = {Select aging biomarkers based on telomere length and chronological age to build a biological age equation.},
journal = {Age (Dordrecht, Netherlands)},
volume = {36},
number = {3},
pages = {9639},
pmid = {24659482},
issn = {1574-4647},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*genetics/metabolism ; Biomarkers/*metabolism ; Female ; Follow-Up Studies ; Healthy Volunteers ; Humans ; Male ; Middle Aged ; Oxidative Stress/*genetics ; Retrospective Studies ; Telomere/*genetics/metabolism ; },
abstract = {The purpose of this study is to build a biological age (BA) equation combining telomere length with chronological age (CA) and associated aging biomarkers. In total, 139 healthy volunteers were recruited from a Chinese Han cohort in Beijing. A genetic index, renal function indices, cardiovascular function indices, brain function indices, and oxidative stress and inflammation indices (C-reactive protein [CRP]) were measured and analyzed. A BA equation was proposed based on selected parameters, with terminal telomere restriction fragment (TRF) and CA as the two principal components. The selected aging markers included mitral annulus peak E anterior wall (MVEA), intima-media thickness (IMT), cystatin C (CYSC), D-dimer (DD), and digital symbol test (DST). The BA equation was: BA = −2.281TRF + 26.321CYSC + 0.025DD − 104.419MVEA + 34.863IMT − 0.265DST + 0.305CA + 26.346. To conclude, telomere length and CA as double benchmarks may be a new method to build a BA.},
}
@article {pmid24658836,
year = {2014},
author = {He, L and Zheng, Y and Wan, Y and Song, J},
title = {A shorter telomere is the key factor in preventing cultured human mesenchymal stem cells from senescence escape.},
journal = {Histochemistry and cell biology},
volume = {142},
number = {3},
pages = {257-267},
pmid = {24658836},
issn = {1432-119X},
mesh = {Animals ; Apoptosis ; Cell Proliferation ; Cell Transformation, Neoplastic/pathology ; Cells, Cultured ; *Cellular Senescence ; Humans ; Mesenchymal Stem Cells/*cytology/*metabolism ; Rats ; Rats, Sprague-Dawley ; Species Specificity ; Telomere/*metabolism ; },
abstract = {Mesenchymal stem cells (MSCs) from various animals undergo spontaneous transformation in vitro,establishing some malignant characteristics. However,this phenomenon seems seldom appearing in human (h)MSCs. To address the question whether the hMSCs really do not undergo the spontaneous transformation and why,the present study compared MSCs from two species under the same conditions, the commercialized primary hMSCs whose in vitro life span is very uniform, and the rat (r)MSCs whose spontaneous transformation in vitro is well defined.It was demonstrated that in rMSCs, there were small numbers of re-proliferating cells appearing after a substantial senescent period. These “senescence-escaped”rMSCs were highly proliferative and did not show any sign of growth arrest during the following subcultures upto observed passage 32. Whereas after entering senescence, hMSCs no longer re-proliferated and finally died from apoptosis. Compared with rMSCs, the hMSCs possessed a much shorter telomere, and lacked both telomerase reverse transcriptase expression and telomerase activity. When proliferating from pre-senescent to senescent stages,the hMSCs had a greater loss of relative telomere length(51 % in hMSC vs. 15 % in rMSC), but both cells displayed a similar average telomere shortening per population doubling (0.50 ± 0.06 kb in rMSC vs. 0.49 ± 0.06 kbin hMSC; p > 0.05), indicating that the greater relative shortening of the hMSC telomeres was due to their original shorter length, rather than lack of telomere maintenance mechanisms. In conclusion, the hMSCs do not spontaneously initiate transformation, because they cannot escape senescence. This is particularly due to their much shorter telomere.},
}
@article {pmid24655849,
year = {2014},
author = {Dogeas, E and Karagkounis, G and Heaphy, CM and Hirose, K and Pawlik, TM and Wolfgang, CL and Meeker, A and Hruban, RH and Cameron, JL and Choti, MA},
title = {Alternative lengthening of telomeres predicts site of origin in neuroendocrine tumor liver metastases.},
journal = {Journal of the American College of Surgeons},
volume = {218},
number = {4},
pages = {628-635},
pmid = {24655849},
issn = {1879-1190},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Female ; Gastrointestinal Neoplasms/genetics/*pathology ; Genetic Markers ; Hepatectomy ; Humans ; In Situ Hybridization, Fluorescence ; Liver Neoplasms/genetics/mortality/*secondary/surgery ; Male ; Middle Aged ; Neuroendocrine Tumors/genetics/mortality/*secondary/surgery ; Pancreatic Neoplasms/genetics/*pathology ; Predictive Value of Tests ; Prognosis ; Sensitivity and Specificity ; Single-Blind Method ; Survival Analysis ; Telomere/*pathology ; *Telomere Homeostasis ; Tissue Array Analysis ; Young Adult ; },
abstract = {BACKGROUND: The determination of the primary tumor origin in patients with neuroendocrine tumor liver metastases (NELM) can pose a considerable management challenge. Recent studies have shown that the alternative lengthening of telomeres (ALT) is prevalent in some human tumors, including pancreatic neuroendocrine tumors (PanNET), and can be useful in predicting tumor biology. In this study, we aimed to evaluate the use of ALT as a biomarker in patients with NELM, in particular to predict the site of origin of metastases.<br><br>METHODS: Tissue microarrays (TMAs) were constructed using tumor tissue from NELM patients undergoing liver resection between 1998 and 2010. These included 43 PanNET and 47 gastrointestinal carcinoid tumors. The TMAs were tested for ALT using telomere-specific fluorescent in situ hybridization. The association between ALT positivity and clinicopathologic features and long-term outcomes was investigated.<br><br>RESULTS: Alternative lengthening of telomeres was positive (ALT+) in 26 (29%) of the 90 tumors included in the TMAs. Pancreatic neuroendocrine tumors were ALT+ in 56% of patients, compared with only 4% ALT+ among gastrointestinal carcinoid tumors (p < 0.001). The specificity of ALT for detecting pancreatic origin was 96% and the positive predictive value was 92%, and sensitivity was 56% and the negative predictive value was 70%. Additionally, ALT was associated with the pattern of metastatic disease: ALT+ NELM were more likely to have oligometastases (p = 0.001) and less likely to be bilateral in distribution (p = 0.05) than were ALT tumors. In addition, ALT+ was associated with improved prognosis in the PanNET patient population.<br><br>CONCLUSIONS: Alternative lengthening of telomeres was found to be a useful biomarker in patients with NELM. This marker can be helpful in guiding therapy by identifying the site of origin in patients in whom the primary site is unknown.},
}
@article {pmid24652939,
year = {2014},
author = {Orthwein, A and Fradet-Turcotte, A and Noordermeer, SM and Canny, MD and Brun, CM and Strecker, J and Escribano-Diaz, C and Durocher, D},
title = {Mitosis inhibits DNA double-strand break repair to guard against telomere fusions.},
journal = {Science (New York, N.Y.)},
volume = {344},
number = {6180},
pages = {189-193},
doi = {10.1126/science.1248024},
pmid = {24652939},
issn = {1095-9203},
support = {MOP89754//Canadian Institutes of Health Research/Canada ; },
mesh = {Adaptor Proteins, Signal Transducing ; Animals ; Aurora Kinase B/metabolism ; Cell Cycle Proteins ; Cell Line, Tumor ; *DNA Breaks, Double-Stranded ; DNA End-Joining Repair/*physiology ; DNA-Binding Proteins/genetics/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Mice ; Mitosis/*physiology ; Nuclear Proteins/genetics/metabolism ; RNA, Small Interfering/genetics ; Telomere/genetics/*physiology ; Telomere Homeostasis/genetics/*physiology ; Trans-Activators/genetics/metabolism ; Tumor Suppressor p53-Binding Protein 1 ; Ubiquitin-Protein Ligases/genetics/metabolism ; },
abstract = {Mitotic cells inactivate DNA double-strand break (DSB) repair, but the rationale behind this suppression remains unknown. Here, we unravel how mitosis blocks DSB repair and determine the consequences of repair reactivation. Mitotic kinases phosphorylate the E3 ubiquitin ligase RNF8 and the nonhomologous end joining factor 53BP1 to inhibit their recruitment to DSB-flanking chromatin. Restoration of RNF8 and 53BP1 accumulation at mitotic DSB sites activates DNA repair but is, paradoxically, deleterious. Aberrantly controlled mitotic DSB repair leads to Aurora B kinase-dependent sister telomere fusions that produce dicentric chromosomes and aneuploidy, especially in the presence of exogenous genotoxic stress. We conclude that the capacity of mitotic DSB repair to destabilize the genome explains the necessity for its suppression during mitosis, principally due to the fusogenic potential of mitotic telomeres.},
}
@article {pmid24652728,
year = {2014},
author = {Masi, S and Gkranias, N and Li, K and Salpea, KD and Parkar, M and Orlandi, M and Suvan, JE and Eng, HL and Taddei, S and Patel, K and Darbar, U and Donos, N and Deanfield, JE and Hurel, S and Humphries, SE and D'Aiuto, F},
title = {Association between short leukocyte telomere length, endotoxemia, and severe periodontitis in people with diabetes: a cross-sectional survey.},
journal = {Diabetes care},
volume = {37},
number = {4},
pages = {1140-1147},
doi = {10.2337/dc13-2106},
pmid = {24652728},
issn = {1935-5548},
support = {MC_PC_13041/MRC_/Medical Research Council/United Kingdom ; MR/K006584/1/MRC_/Medical Research Council/United Kingdom ; RG/08/008/25291/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Adult ; Aged ; Cross-Sectional Studies ; Diabetes Mellitus, Type 1/*complications/immunology ; Diabetes Mellitus, Type 2/*complications ; Endotoxemia/*complications ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Periodontitis/*complications ; Real-Time Polymerase Chain Reaction ; *Telomere Shortening ; },
abstract = {OBJECTIVE Shortened leukocyte telomere length (LTL) and diagnosis of periodontitis are associated with an increased risk of complications and mortality in diabetes. This study investigated the association between LTL, endotoxemia, and severity of periodontitis in a large cohort of people with diabetes. RESEARCH DESIGN AND METHODS Six hundred thirty individuals (371 with type 2 and 259 with type 1 diabetes) were recruited from the University College Hospital in London, U.K. During a baseline visit, blood was collected for standard biochemical tests and DNA extraction, while a dental examination was performed to determine diagnosis and extent of periodontitis. LTL was measured by real-time PCR, and endotoxemia was assessed by the limulus amoebocyte lysate method. RESULTS Two hundred fifty-five individuals were diagnosed with gingivitis, 327 with periodontitis (114 with moderate and 213 with severe disease), and 48 with edentulous. Diagnosis of periodontitis was associated with shorter LTL (P = 0.04). A negative association between LTL and endotoxemia was found in the severe periodontitis and type 2 diabetes groups (P = 0.01 for both). Shorter LTL was associated with increased extent of periodontitis (P = 0.01) and increased insulin resistance (homeostatic model assessment). Multiple adjustments for biochemical, anthropometric, and medication-use variables did not affect the results. CONCLUSIONS LTL is associated with endotoxemia and diagnosis of periodontitis in people with diabetes. LTL shortening might represent a novel biological pathway accounting for previous epidemiological data that documented higher prevalence of diabetes and its complications in people with periodontitis and vice versa.},
}
@article {pmid24648221,
year = {2014},
author = {Herborn, KA and Heidinger, BJ and Boner, W and Noguera, JC and Adam, A and Daunt, F and Monaghan, P},
title = {Stress exposure in early post-natal life reduces telomere length: an experimental demonstration in a long-lived seabird.},
journal = {Proceedings. Biological sciences},
volume = {281},
number = {1782},
pages = {20133151},
pmid = {24648221},
issn = {1471-2954},
mesh = {Aging/*genetics ; Animals ; Birds/*genetics ; Corticosterone/pharmacology ; Erythrocytes ; Longevity ; Stress, Physiological/*genetics ; *Telomere Shortening ; },
abstract = {Exposure to stressors early in life is associated with faster ageing and reduced longevity. One important mechanism that could underlie these late life effects is increased telomere loss. Telomere length in early post-natal life is an important predictor of subsequent lifespan, but the factors underpinning its variability are poorly understood. Recent human studies have linked stress exposure to increased telomere loss. These studies have of necessity been non-experimental and are consequently subjected to several confounding factors; also, being based on leucocyte populations, where cell composition is variable and some telomere restoration can occur, the extent to which these effects extend beyond the immune system has been questioned. In this study, we experimentally manipulated stress exposure early in post-natal life in nestling European shags (Phalacrocorax aristotelis) in the wild and examined the effect on telomere length in erythrocytes. Our results show that greater stress exposure during early post-natal life increases telomere loss at this life-history stage, and that such an effect is not confined to immune cells. The delayed effects of increased telomere attrition in early life could therefore give rise to a 'time bomb' that reduces longevity in the absence of any obvious phenotypic consequences early in life.},
}
@article {pmid24645211,
year = {2014},
author = {},
title = {New evidence: bariatric surgery also reverses the effects of aging. Telomeres, genetic biomarkers of aging, are found to be longer after the surgery.},
journal = {DukeMedicine healthnews},
volume = {20},
number = {2},
pages = {6},
pmid = {24645211},
issn = {2153-8387},
mesh = {Aging/*physiology ; Bariatric Surgery/*statistics &amp; numerical data ; C-Reactive Protein/analysis ; Diabetes Mellitus, Type 2/prevention &amp; control ; Heart Diseases/prevention &amp; control ; Humans ; Life Expectancy/*trends ; Neoplasms/prevention &amp; control ; Obesity, Morbid/*surgery ; Respiratory Tract Diseases/prevention &amp; control ; Risk Reduction Behavior ; Treatment Outcome ; },
}
@article {pmid24643066,
year = {2014},
author = {Cukusic Kalajzic, A and Vidacek, NS and Huzak, M and Ivankovic, M and Rubelj, I},
title = {Telomere Q-PNA-FISH--reliable results from stochastic signals.},
journal = {PloS one},
volume = {9},
number = {3},
pages = {e92559},
pmid = {24643066},
issn = {1932-6203},
mesh = {Cell Line ; Fibroblasts/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Metaphase ; Reproducibility of Results ; Stochastic Processes ; Telomere/*genetics ; Telomere Homeostasis ; },
abstract = {Structural and functional analysis of telomeres is very important for understanding basic biological functions such as genome stability, cell growth control, senescence and aging. Recently, serious concerns have been raised regarding the reliability of current telomere measurement methods such as Southern blot and quantitative polymerase chain reaction. Since telomere length is associated with age related pathologies, including cardiovascular disease and cancer, both at the individual and population level, accurate interpretation of measured results is a necessity. The telomere Q-PNA-FISH technique has been widely used in these studies as well as in commercial analysis for the general population. A hallmark of telomere Q-PNA-FISH is the wide variation among telomere signals which has a major impact on obtained results. In the present study we introduce a specific mathematical and statistical analysis of sister telomere signals during cell culture senescence which enabled us to identify high regularity in their variations. This phenomenon explains the reproducibility of results observed in numerous telomere studies when the Q-PNA-FISH technique is used. In addition, we discuss the molecular mechanisms which probably underlie the observed telomere behavior.},
}
@article {pmid24642354,
year = {2014},
author = {Pooley, KA and McGuffog, L and Barrowdale, D and Frost, D and Ellis, SD and Fineberg, E and Platte, R and Izatt, L and Adlard, J and Bardwell, J and Brewer, C and Cole, T and Cook, J and Davidson, R and Donaldson, A and Dorkins, H and Douglas, F and Eason, J and Houghton, C and Kennedy, MJ and McCann, E and Miedzybrodzka, Z and Murray, A and Porteous, ME and Rogers, MT and Side, LE and Tischkowitz, M and Walker, L and Hodgson, S and Eccles, DM and Morrison, PJ and Evans, DG and Eeles, RA and Antoniou, AC and Easton, DF and Dunning, AM and , },
title = {Lymphocyte telomere length is long in BRCA1 and BRCA2 mutation carriers regardless of cancer-affected status.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {23},
number = {6},
pages = {1018-1024},
pmid = {24642354},
issn = {1538-7755},
support = {16563/CRUK_/Cancer Research UK/United Kingdom ; 1U19CA148537-01/CA/NCI NIH HHS/United States ; C8197/A10865/CAPMC/CIHR/Canada ; 1U19CA148965-01/CA/NCI NIH HHS/United States ; 11174/CRUK_/Cancer Research UK/United Kingdom ; 17528/CRUK_/Cancer Research UK/United Kingdom ; C1287/A9540/CAPMC/CIHR/Canada ; U19 CA148537/CA/NCI NIH HHS/United States ; 16565/CRUK_/Cancer Research UK/United Kingdom ; A10123/CRUK_/Cancer Research UK/United Kingdom ; 11022/CRUK_/Cancer Research UK/United Kingdom ; C8197/A10123/CAPMC/CIHR/Canada ; 15007/CRUK_/Cancer Research UK/United Kingdom ; 17523/CRUK_/Cancer Research UK/United Kingdom ; 10118/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Breast Neoplasms/*genetics ; Female ; Genes, BRCA1/*physiology ; Genes, BRCA2/*physiology ; Humans ; Lymphocytes ; Male ; Mutation ; Telomere/*genetics ; },
abstract = {BACKGROUND: Telomere length has been linked to risk of common diseases, including cancer, and has previously been proposed as a biomarker for cancer risk. Germline BRCA1 and BRCA2 mutations predispose to breast, ovarian, and other cancer types.<br><br>METHODS: We investigated telomere length in BRCA mutation carriers and their non-carrier relatives and further examined whether telomere length is a modifier of cancer risk in mutation carriers. We measured mean telomere length in DNA extracted from whole blood using high-throughput quantitative PCR. Participants were from the EMBRACE study in United Kingdom and Eire (n = 4,822) and comprised BRCA1 (n = 1,628) and BRCA2 (n = 1,506) mutation carriers and their non-carrier relatives (n = 1,688).<br><br>RESULTS: We find no significant evidence that mean telomere length is associated with breast or ovarian cancer risk in BRCA mutation carriers. However, we find mutation carriers to have longer mean telomere length than their non-carrier relatives (all carriers vs. non-carriers, Ptrend = 0.0018), particularly in families with BRCA2 mutations (BRCA2 mutation carriers vs. all non-carriers, Ptrend = 0.0016).<br><br>CONCLUSIONS: Our findings lend little support to the hypothesis that short mean telomere length predisposes to cancer. Conversely, our main and unexpected finding is that BRCA mutation carriers (regardless of cancer status) have longer telomeres than their non-mutation carrier, non-cancer-affected relatives. The longer telomere length in BRCA2 mutation carriers is consistent with its role in DNA damage response. Overall, it seems that increased telomere length may be a consequence of these mutations, but is not itself directly related to the increased cancer risk in carriers.<br><br>IMPACT: The finding that mutation carriers have longer mean telomere lengths than their non-carrier relatives is unexpected but biologically plausible and could open up new lines of research into the functions of the BRCA proteins. To our knowledge, this is the largest study of telomere length in BRCA mutation carriers and their relatives. The null cancer-risk association supports recent large prospective studies of breast and ovarian cancer and indicates that mean telomere length would not be a useful biomarker in these cancers. Cancer Epidemiol Biomarkers Prev; 23(6); 1018-24. &#xa9;2014 AACR.},
}
@article {pmid24636503,
year = {2014},
author = {Ikeda, A and Schwartz, J and Peters, JL and Baccarelli, AA and Hoxha, M and Dioni, L and Spiro, A and Sparrow, D and Vokonas, P and Kubzansky, LD},
title = {Pessimistic orientation in relation to telomere length in older men: the VA normative aging study.},
journal = {Psychoneuroendocrinology},
volume = {42},
number = {},
pages = {68-76},
pmid = {24636503},
issn = {1873-3360},
support = {R01 AG018436/AG/NIA NIH HHS/United States ; R01 ES015172/ES/NIEHS NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*physiology/psychology ; Humans ; Leukocytes/*physiology ; Male ; Middle Aged ; *Personality ; Telomere/*physiology ; },
abstract = {BACKGROUND: Recent research suggests pessimistic orientation is associated with shorter leukocyte telomere length (LTL). However, this is the first study to look not only at effects of pessimistic orientation on average LTL at multiple time points, but also at effects on the rate of change in LTL over time.<br><br>METHODS: Participants were older men from the VA Normative Aging Study (n=490). The life orientation test (LOT) was used to measure optimistic and pessimistic orientations at study baseline, and relative LTL by telomere to single copy gene ratio (T:S ratio) was obtained repeatedly over the course of the study (1999-2008). A total of 1010 observations were included in the analysis. Linear mixed effect models with a random subject intercept were used to estimate associations.<br><br>RESULTS: Higher pessimistic orientation scores were associated with shorter average LTL (percent difference by 1-SD increase in pessimistic orientation (95% CI): -3.08 (-5.62, -0.46)), and the finding was maintained after adjusting for the higher likelihood that healthier individuals return for follow-up visits (-3.44 (-5.95, -0.86)). However, pessimistic orientation scores were not associated with rate of change in LTL over time. No associations were found between overall optimism and optimistic orientation subscale scores and LTL.<br><br>CONCLUSION: Higher pessimistic orientation scores were associated with shorter LTL in older men. While there was no evidence that pessimistic orientation was associated with rate of change in LTL over time, higher levels of pessimistic orientation were associated with shorter LTL at baseline and this association persisted over time.},
}
@article {pmid24634940,
year = {2013},
author = {Biron-Shental, T and Amiel, A and Anchidin, R and Sharony, R and Hadary, R and Kitay-Cohen, Y},
title = {Telomere length and telomerase reverse transcriptase mRNA expression in patients with hepatitis C.},
journal = {Hepato-gastroenterology},
volume = {60},
number = {127},
pages = {1713-1716},
pmid = {24634940},
issn = {0172-6390},
mesh = {Adult ; Antiviral Agents/therapeutic use ; Case-Control Studies ; Cells, Cultured ; Disease Progression ; Hepatitis C, Chronic/blood/drug therapy/*enzymology/genetics ; Humans ; In Situ Hybridization, Fluorescence ; Lymphocytes/enzymology ; Middle Aged ; RNA, Messenger/*analysis ; Remission Induction ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/blood/*genetics ; *Telomere Shortening ; Treatment Outcome ; },
abstract = {BACKGROUND/AIMS: Shortened telomeres reflect genetic instability that might lead to increased aneuploidy and malignant transformations. Chronic hepatitis C (HCV) viral infection is considered a pre-neoplastic condition that might progress to hepatocellular carcinoma. We evaluated telomere length and elongation, in patients with different stages of HCV to study the correlation between telomere length and the progression of HCV.<br><br>METHODOLOGY: We analyzed peripheral lymphocytes from 10 patients with chronic active HCV, 10 patients with HCV infection in a remission stage, and 10 healthy, age-matched patients, as controls. The expression of hTERT mRNA, which is correlated with elongation of telomeres was measured using RT-PCR and telomere length was analyzed using Q-FISH and a novel computerized technique.<br><br>RESULTS: hTERT mRNA was significantly decreased in patients with active HCV and slightly decreased in patients who were in remission, compared to healthy individuals. Telomere length was shorter in patients with chronic active HCV and in patients in remission, compared to the healthy controls.<br><br>CONCLUSIONS: There is a correlation between telomerase reverse transcriptase mRNA expression and telomere length in patients with different stages of HCV infection that might be related to the risk of malignant transformation.},
}
@article {pmid24633909,
year = {2014},
author = {Tackney, J and Cawthon, RM and Coxworth, JE and Hawkes, K},
title = {Blood cell telomere lengths and shortening rates of chimpanzee and human females.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {26},
number = {4},
pages = {452-460},
pmid = {24633909},
issn = {1520-6300},
support = {P51 OD011133/OD/NIH HHS/United States ; P51 RR000165/RR/NCRR NIH HHS/United States ; P51 RR013986/RR/NCRR NIH HHS/United States ; P51RR013986/RR/NCRR NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Animals ; Child ; Cohort Studies ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/*cytology ; Middle Aged ; Multiplex Polymerase Chain Reaction ; Pan troglodytes/*genetics ; Telomere/*genetics ; *Telomere Shortening ; Young Adult ; },
abstract = {OBJECTIVES: Slower rates of aging distinguish humans from our nearest living cousins. Chimpanzees rarely survive their forties while large fractions of women are postmenopausal even in high-mortality hunter-gatherer populations. Cellular and molecular mechanisms for these somatic aging differences remain to be identified, though telomeres might play a role. To find out, we compared telomere lengths across age-matched samples of female chimpanzees and women.<br><br>METHODS: We used a monochrome multiplex quantitative polymerase chain reaction to assay canonical telomere repeats in blood cells from captive female chimpanzees (65 individuals; age: 6.2-56.7 years) and compared them to the same measure in human females (43 individuals; age: 7.4-57.3 years).<br><br>RESULTS: Our samples showed little difference in attrition rates between the species (~0.022 T/S per year for chimpanzees and ~0.012 T/S per year for humans with overlapping 95% confidence intervals), but telomeres were twice as long in chimpanzees as in humans (T/S ratios = 2.70 and 1.26, respectively).<br><br>CONCLUSIONS: Based on the longevity differences, we initially hypothesized that telomere shortening rates would be faster in chimpanzees than in humans. Instead, it is shorter telomere length that appears to be the derived state in humans. This comparison indicates that better characterization of physiological aging in our closest living relatives will be indispensable for understanding the evolution of distinctive human longevity.},
}
@article {pmid24631651,
year = {2014},
author = {He, Q and Zeng, P and Tan, JH and Ou, TM and Gu, LQ and Huang, ZS and Li, D},
title = {G-quadruplex-mediated regulation of telomere binding protein POT1 gene expression.},
journal = {Biochimica et biophysica acta},
volume = {1840},
number = {7},
pages = {2222-2233},
doi = {10.1016/j.bbagen.2014.03.001},
pmid = {24631651},
issn = {0006-3002},
mesh = {Binding Sites ; DNA, Single-Stranded/genetics ; G-Quadruplexes/*drug effects ; Gene Expression Regulation ; Humans ; Porphyrins/pharmacology ; Protein Binding ; Shelterin Complex ; Telomerase/genetics/metabolism ; Telomere/*genetics ; Telomere-Binding Proteins/*biosynthesis/chemistry/*genetics ; },
abstract = {BACKGROUND: Telomere is protected by its G-quadruplex, T-loop structure, telomerase, and binding protein complex. Protein POT1 (protection of telomeres 1) is one subunit of telomere binding protein complex Shelterin. POT1 acts as a regulator of telomerase-dependent telomere length, and it can help telomere to form D-loop structure to stabilize telomere. POT1 protects telomere ends from ATR-dependent DNA damage response as well.<br><br>METHODS: Extensive methods were used, including CD, EMSA, ITC, PCR stop assay, luciferase reporter assay, quantitative real-time PCR, Western blot, chromatin immunoprecipitation (Ch-IP), cloning, expression and purification of proteins.<br><br>RESULTS: We found a new G-rich 30-base-pair long sequence (P-pot1 G18) located from -165 to -136 base pairs upstream of the translation starting site of protein POT1. This sequence in the promoter region of pot1 gene formed G-quadruplex resulting in down-regulation of pot1 gene transcription. This G-rich sequence is close to a binding site "TCCC" for transcription factor hnRNP K (heterogeneous nuclear ribonucleoprotein K), and its conversion to G-quadruplex prevented the access of hnRNP K to this binding site. The binding of hnRNP K could up-regulate pot1 gene transcription. TMPyP4 (meso-tetra(N-methyl-4-pyridyl)porphine) has been widely used as G-quadruplex binding ligand, which stabilized the G-quadruplex in vitro and in cellulo, resulting in down-regulation of pot1 gene transcription.<br><br>CONCLUSIONS: This G-quadruplex might become a potentially new drug target for antitumor agents.<br><br>GENERAL SIGNIFICANCE: Our results first demonstrated that G-quadruplex formation can affect the binding of transcription factor to its nearby binding site, and thus making additional influence to gene transcription.},
}
@article {pmid24630967,
year = {2014},
author = {Wenger, SL and Hansroth, J and Shackelford, AL},
title = {Decreased telomere length in metaphase and interphase cells from newborns with trisomy 21.},
journal = {Gene},
volume = {542},
number = {1},
pages = {87},
doi = {10.1016/j.gene.2014.03.019},
pmid = {24630967},
issn = {1879-0038},
support = {P20GM103434/GM/NIGMS NIH HHS/United States ; P20RR016477/RR/NCRR NIH HHS/United States ; },
mesh = {Down Syndrome/*genetics ; Humans ; Infant, Newborn ; Interphase/*genetics ; Metaphase/*genetics ; Telomere/genetics ; Telomere Homeostasis/genetics ; Telomere Shortening/*genetics ; },
}
@article {pmid24627998,
year = {2014},
author = {Wong, JY and De Vivo, I and Lin, X and Christiani, DC},
title = {Cumulative PM(2.5) exposure and telomere length in workers exposed to welding fumes.},
journal = {Journal of toxicology and environmental health. Part A},
volume = {77},
number = {8},
pages = {441-455},
pmid = {24627998},
issn = {1528-7394},
support = {P30 ES000002/ES/NIEHS NIH HHS/United States ; R01 ES009860/ES/NIEHS NIH HHS/United States ; P50ES00002/ES/NIEHS NIH HHS/United States ; R01ES009860/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; Air/analysis ; Biomarkers/blood ; Cohort Studies ; Hematopoietic Stem Cells/*drug effects ; Humans ; Inhalation Exposure/*adverse effects ; Labor Unions ; Leukocytes/drug effects ; Longitudinal Studies ; Male ; Massachusetts ; Mutagens/analysis/*toxicity ; Occupational Exposure/*adverse effects ; Oxidative Stress/drug effects ; Particulate Matter/analysis/blood/*toxicity ; Prospective Studies ; Telomere Homeostasis/*drug effects ; Telomere Shortening/drug effects ; *Welding ; Workforce ; },
abstract = {Telomeres are genomic structures that reflect both mitotic history and biochemical trauma to the genome. Metals inherent in fine particulate matter (PM(2.5)) were shown to be genotoxic via oxidative damage. However, few studies investigated the induction time of cumulative PM(2.5) exposure on telomere length in a longitudinal setting. Therefore, the purpose of this study was to assess the association between occupational PM(2.5) exposure in various time windows and telomere length. The study population consisted of 48 boilermakers and the follow-up period was 8 yr. The main exposures were cumulative occupational PM(2.5) in the month, year, and career prior to each blood draw, assessed via work history questionnaires and area air measures. Repeated telomere length measurements from leukocytes were assessed via real-time qualitative polymerase chain reaction (qPCR). Analysis was performed using linear mixed models controlling for confounders and white blood cell differentials. Cumulative PM(2.5) exposure was treated continuously and categorized into quartiles, in separate analyses. At any follow-up time, for each milligram per cubic meter per hour increase in cumulative PM(2.5) exposure in the prior month, there was a statistically significant decrease in relative telomere length of -0.04 units. When categorizing the exposure into quartiles, there was a significant negative association between telomere length and highest quartile of cumulative PM(2.5) exposure in the prior month (-0.16). These findings suggest that genomic trauma to leukocyte telomeres was more consistent with recent occupational PM(2.5) exposure, as opposed to cumulative exposure extending into the distant past.},
}
@article {pmid24627273,
year = {2014},
author = {Duggan, C and Risques, R and Alfano, C and Prunkard, D and Imayama, I and Holte, S and Baumgartner, K and Baumgartner, R and Bernstein, L and Ballard-Barbash, R and Rabinovitch, P and McTiernan, A},
title = {Change in peripheral blood leukocyte telomere length and mortality in breast cancer survivors.},
journal = {Journal of the National Cancer Institute},
volume = {106},
number = {4},
pages = {dju035},
pmid = {24627273},
issn = {1460-2105},
support = {N01-PC-67010/PC/NCI NIH HHS/United States ; M01-RR-00037/RR/NCRR NIH HHS/United States ; N01-CN-75036-20/CN/NCI NIH HHS/United States ; R25-CA94880/CA/NCI NIH HHS/United States ; U54-CA116847/CA/NCI NIH HHS/United States ; U54CA116848/CA/NCI NIH HHS/United States ; N01-CN-05228/CN/NCI NIH HHS/United States ; M01-RR-0997/RR/NCRR NIH HHS/United States ; N01-HD-3-3175/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Aged ; Breast Neoplasms/blood/genetics/*mortality/*pathology ; Female ; Follow-Up Studies ; Humans ; *Leukocytes ; Middle Aged ; Predictive Value of Tests ; Prognosis ; Proportional Hazards Models ; Prospective Studies ; Risk Assessment ; Risk Factors ; Survivors/statistics &amp; numerical data ; Telomere/*pathology ; *Telomere Shortening ; },
abstract = {BACKGROUND: Progressive telomere shortening with cell division is a hallmark of aging. Short telomeres are associated with increased cancer risk, but there are conflicting reports about telomere length and mortality in breast cancer survivors.<br><br>METHODS: We measured peripheral blood leukocyte telomere length at two time points in women enrolled in a multiethnic, prospective cohort of stage I to stage IIIA breast cancer survivors diagnosed between 1995 and 1999 with a median follow-up of 11.2 years. We evaluated associations between telomere length measured at mean 6 (baseline; LTL0; n = 611) and 30 months (LTL30; n = 478) after diagnosis and the change between those time points (n = 478), with breast cancer-specific and all-cause mortality using Cox proportional hazards models adjusted for possible confounders. Statistical tests were two-sided.<br><br>RESULTS: There were 135 deaths, of which 74 were due to breast cancer. Neither baseline nor 30-month telomere length was associated with either all-cause or breast cancer-specific mortality (LTL0: hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.67 to 1.02; HR = 0.88; 95% CI = 0.67 to 1.15; LTL30: HR = 0.78, 95% CI = 0.59 to 1.05; HR = 0.86; 95% = CI = 0.58 to 1.26, respectively). However, participants whose telomeres shortened between baseline and 30 months were at a statistically significantly increased risk of breast cancer-specific (HR = 3.03; 95% CI = 1.11 to 8.18) and all-cause mortality (HR = 2.38; 95% CI = 1.28 to 4.39) compared with participants whose telomeres lengthened. When follow-up was censored at 5-years after diagnosis, LTL0 (HR = 0.66; 95% CI = 0.45 to 0.96), LTL30 (HR = 0.51; 95% CI = 0.29 to 0.92), and change in telomere length (HR = 3.45; 95% CI = 1.11 to 10.75) were statistically significantly associated with all-cause mortality.<br><br>CONCLUSIONS: Telomere shortening was associated with increased risk of breast cancer-specific and all-cause mortality, suggesting that change in blood telomere length over time could be a biomarker of prognosis. Research on determinants of telomere length and change is needed.},
}
@article {pmid24626990,
year = {2014},
author = {Brennan, TA and Egan, KP and Lindborg, CM and Chen, Q and Sweetwyne, MT and Hankenson, KD and Xie, SX and Johnson, FB and Pignolo, RJ},
title = {Mouse models of telomere dysfunction phenocopy skeletal changes found in human age-related osteoporosis.},
journal = {Disease models &amp; mechanisms},
volume = {7},
number = {5},
pages = {583-592},
pmid = {24626990},
issn = {1754-8411},
support = {P30 AR050950/AR/NIAMS NIH HHS/United States ; R01 AG028873/AG/NIA NIH HHS/United States ; R01AG028873/AG/NIA NIH HHS/United States ; P30-AR050950/AR/NIAMS NIH HHS/United States ; },
mesh = {Adiposity ; Animals ; Bone Marrow/pathology ; Bone Resorption/pathology ; Bone and Bones/*pathology ; Cell Count ; Disease Models, Animal ; Humans ; Kinetics ; Mice ; Mutation/genetics ; Osteoblasts/metabolism/pathology ; Osteoclasts/pathology ; Osteogenesis ; Osteoporosis/*pathology ; Phenotype ; RecQ Helicases/deficiency/metabolism ; Telomerase/deficiency/metabolism ; Telomere/*pathology ; Werner Syndrome Helicase ; },
abstract = {A major medical challenge in the elderly is osteoporosis and the high risk of fracture. Telomere dysfunction is a cause of cellular senescence and telomere shortening, which occurs with age in cells from most human tissues, including bone. Telomere defects contribute to the pathogenesis of two progeroid disorders characterized by premature osteoporosis, Werner syndrome and dyskeratosis congenital. It is hypothesized that telomere shortening contributes to bone aging. We evaluated the skeletal phenotypes of mice with disrupted telomere maintenance mechanisms as models for human bone aging, including mutants in Werner helicase (Wrn(-/-)), telomerase (Terc(-/-)) and Wrn(-/-)Terc(-/-) double mutants. Compared with young wild-type (WT) mice, micro-computerized tomography analysis revealed that young Terc(-/-) and Wrn(-/-)Terc(-/-) mice have decreased trabecular bone volume, trabecular number and trabecular thickness, as well as increased trabecular spacing. In cortical bone, young Terc(-/-) and Wrn(-/-)Terc(-/-) mice have increased cortical thinning, and increased porosity relative to age-matched WT mice. These trabecular and cortical changes were accelerated with age in Terc(-/-) and Wrn(-/-)Terc(-/-) mice compared with older WT mice. Histological quantification of osteoblasts in aged mice showed a similar number of osteoblasts in all genotypes; however, significant decreases in osteoid, mineralization surface, mineral apposition rate and bone formation rate in older Terc(-/-) and Wrn(-/-)Terc(-/-) bone suggest that osteoblast dysfunction is a prominent feature of precocious aging in these mice. Except in the Wrn(-/-) single mutant, osteoclast number did not increase in any genotype. Significant alterations in mechanical parameters (structure model index, degree of anistrophy and moment of inertia) of the Terc(-/-) and Wrn(-/-)Terc(-/-) femurs compared with WT mice were also observed. Young Wrn(-/-)Terc(-/-) mice had a statistically significant increase in bone-marrow fat content compared with young WT mice, which remained elevated in aged double mutants. Taken together, our results suggest that Terc(-/-) and Wrn(-/-)Terc(-/-) mutants recapitulate the human bone aging phenotype and are useful models for studying age-related osteoporosis.},
}
@article {pmid24626180,
year = {2014},
author = {d'Alcontres, MS and Palacios, JA and Mejias, D and Blasco, MA},
title = {TopoIIα prevents telomere fragility and formation of ultra thin DNA bridges during mitosis through TRF1-dependent binding to telomeres.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {13},
number = {9},
pages = {1463-1481},
pmid = {24626180},
issn = {1551-4005},
support = {232854/ERC_/European Research Council/International ; },
mesh = {Antigens, Neoplasm/*metabolism ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; *Chromosome Fragile Sites ; DNA/*metabolism ; DNA Topoisomerases, Type II/*metabolism ; DNA-Binding Proteins/*metabolism ; Humans ; M Phase Cell Cycle Checkpoints ; Microtubule-Associated Proteins/metabolism ; Mitosis/*physiology ; Nuclear Proteins/metabolism ; Protein Serine-Threonine Kinases/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; },
abstract = {Telomeres are repetitive nucleoprotein structures at the ends of chromosomes. Like most genomic regions consisting of repetitive DNA, telomeres are fragile sites prone to replication fork stalling and generation of chromosomal instability. In particular, abrogation of the TRF1 telomere binding protein leads to stalled replication forks and aberrant telomere structures known as "multitelomeric signals". Here, we report that TRF1 deficiency also leads to the formation of "ultra-fine bridges" (UFB) during mitosis, and to an increased time to complete mitosis mediated by the spindle assembly checkpoint proteins (SAC). We find that topoisomerase IIα (TopoIIα), an enzyme essential for resolution of DNA replication intermediates, binds telomeres in a TRF1-mediated manner. Indeed, similar to TRF1 abrogation, TopoIIα downregulation leads to telomere fragility and UFB, suggesting that these phenotypes are due to decreased TopoIIα at telomeres. We find that SAC proteins bind telomeres in vivo, and that this is disrupted upon TRF1 deletion. These findings suggest that TRF1 links TopoIIα and SAC proteins in a pathway that ensures correct telomere replication and mitotic segregation, unveiling how TRF1 protects from telomere fragility and mitotic defects.},
}
@article {pmid24625632,
year = {2014},
author = {Weischer, M and Bojesen, SE and Nordestgaard, BG},
title = {Telomere shortening unrelated to smoking, body weight, physical activity, and alcohol intake: 4,576 general population individuals with repeat measurements 10 years apart.},
journal = {PLoS genetics},
volume = {10},
number = {3},
pages = {e1004191},
pmid = {24625632},
issn = {1553-7404},
mesh = {Adult ; Alcohol Drinking/*genetics ; Body Mass Index ; Body Weight/*genetics ; Female ; Genetics, Population ; Humans ; Leukocytes/cytology ; Male ; Middle Aged ; Motor Activity/*genetics ; Risk Factors ; Smoking/*genetics ; Telomere/genetics ; Telomere Shortening/*genetics ; },
abstract = {Cross-sectional studies have associated short telomere length with smoking, body weight, physical activity, and possibly alcohol intake; however, whether these associations are due to confounding is unknown. We tested these hypotheses in 4,576 individuals from the general population cross-sectionally, and with repeat measurement of relative telomere length 10 years apart. We also tested whether change in telomere length is associated with mortality and morbidity in the general population. Relative telomere length was measured with quantitative polymerase chain reaction. Cross-sectionally at the first examination, short telomere length was associated with increased age (P for trend across quartiles = 3 × 10(-77)), current smoking (P = 8 × 10(-3)), increased body mass index (P = 7 × 10(-14)), physical inactivity (P = 4 × 10(-17)), but not with increased alcohol intake (P = 0.10). At the second examination 10 years later, 56% of participants had lost and 44% gained telomere length with a mean loss of 193 basepairs. Change in leukocyte telomere length during 10 years was associated inversely with baseline telomere length (P<1 × 10(-300)) and age at baseline (P = 1 × 10(-27)), but not with baseline or 10-year inter-observational tobacco consumption, body weight, physical activity, or alcohol intake. Prospectively during a further 10 years follow-up after the second examination, quartiles of telomere length change did not associate with risk of all-cause mortality, cancer, chronic obstructive pulmonary disease, diabetes mellitus, ischemic cerebrovascular disease, or ischemic heart disease. In conclusion, smoking, increased body weight, and physical inactivity were associated with short telomere length cross-sectionally, but not with telomere length change during 10 years observation, and alcohol intake was associated with neither. Also, change in telomere length did not associate prospectively with mortality or morbidity in the general population.},
}
@article {pmid24623817,
year = {2014},
author = {Popuri, V and Hsu, J and Khadka, P and Horvath, K and Liu, Y and Croteau, DL and Bohr, VA},
title = {Human RECQL1 participates in telomere maintenance.},
journal = {Nucleic acids research},
volume = {42},
number = {9},
pages = {5671-5688},
pmid = {24623817},
issn = {1362-4962},
support = {AG000726-20/AG/NIA NIH HHS/United States ; //Intramural NIH HHS/United States ; },
mesh = {Animals ; DNA Replication ; Electrophoretic Mobility Shift Assay ; Exodeoxyribonucleases/metabolism ; HeLa Cells ; Humans ; Protein Binding ; Protein Transport ; RecQ Helicases/metabolism/*physiology ; Telomerase/metabolism ; *Telomere Homeostasis ; Telomeric Repeat Binding Protein 2/metabolism ; Werner Syndrome Helicase ; },
abstract = {A variety of human tumors employ alternative and recombination-mediated lengthening for telomere maintenance (ALT). Human RecQ helicases, such as BLM and WRN, can efficiently unwind alternate/secondary structures during telomere replication and/or recombination. Here, we report a novel role for RECQL1, the most abundant human RecQ helicase but functionally least studied, in telomere maintenance. RECQL1 associates with telomeres in ALT cells and actively resolves telomeric D-loops and Holliday junction substrates. RECQL1 physically and functionally interacts with telomere repeat-binding factor 2 that in turn regulates its helicase activity on telomeric substrates. The telomeric single-stranded binding protein, protection of telomeres 1 efficiently stimulates RECQL1 on telomeric substrates containing thymine glycol, a replicative blocking lesion. Loss of RECQL1 results in dysfunctional telomeres, telomere loss and telomere shortening, elevation of telomere sister-chromatid exchanges and increased aphidicolin-induced telomere fragility, indicating a role for RECQL1 in telomere maintenance. Further, our results indicate that RECQL1 may participate in the same pathway as WRN, probably in telomere replication.},
}
@article {pmid24622247,
year = {2014},
author = {Moreno-Palomo, J and Creus, A and Marcos, R and Hernández, A},
title = {Genomic instability in newborn with short telomeres.},
journal = {PloS one},
volume = {9},
number = {3},
pages = {e91753},
pmid = {24622247},
issn = {1932-6203},
mesh = {Fetal Blood/drug effects/metabolism ; Genomic Instability/drug effects/*genetics ; Humans ; Infant, Newborn ; Micronucleus Tests ; Mitomycin/toxicity ; Mutagens/toxicity ; Risk Factors ; Telomere/drug effects/*genetics ; Telomere Shortening/drug effects ; },
abstract = {UNLABELLED: Telomere length is considered to be a risk factor in adults due to its proved association with cancer incidence and mortality. Since newborn present a wide interindividual variation in mean telomere length, it is relevant to demonstrate if these differences in length can act also as an early risk indicator. To answer this question, we have measured the mean telomere length of 74 samples of cord blood from newborns and studied its association with the basal genetic damage, measured as the frequency of binucleated cells carrying micronuclei. In addition, we have challenged the cells of a subgroup of individuals (N = 35) against mitomycin-C (MMC) to establish their sensitivity to induced genomic instability. Results indicate that newborn with shorter telomeres present significantly higher levels of genetic damage when compared to those with longer telomeres. In addition, the cellular response to MMC was also significantly higher among those samples from subjects with shorter telomeres. Independently of the causal mechanisms involved, our results show for the first time that telomere length at delivery influence both the basal and induced genetic damage of the individual.<br><br>IMPACT: Individuals born with shorter telomeres may be at increased risk, especially for those biological processes triggered by genomic instability as is the case of cancer and other age-related diseases.},
}
@article {pmid24618342,
year = {2014},
author = {Sanchez-Espiridion, B and Chen, M and Chang, JY and Lu, C and Chang, DW and Roth, JA and Wu, X and Gu, J},
title = {Telomere length in peripheral blood leukocytes and lung cancer risk: a large case-control study in Caucasians.},
journal = {Cancer research},
volume = {74},
number = {9},
pages = {2476-2486},
pmid = {24618342},
issn = {1538-7445},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; R01 CA131335/CA/NCI NIH HHS/United States ; P50CA070907/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma/*genetics/pathology ; Aged ; Carcinoma, Squamous Cell/*genetics/pathology ; Case-Control Studies ; Female ; Humans ; Leukocytes, Mononuclear/*metabolism ; Lung Neoplasms/*genetics/pathology ; Male ; Middle Aged ; Risk Factors ; Telomere/*genetics ; Telomere Homeostasis ; White People ; },
abstract = {Telomere dysfunction is a crucial event in malignant transformation and tumorigenesis. Telomere length in peripheral blood leukocytes has been associated with lung cancer risk, but the relationship has remained controversial. In this study, we investigated whether the association might be confounded by study of different histological subtypes of lung cancer. We measured relative telomere lengths in patients in a large case-control study of lung cancer and performed stratified analyses according to the two major histologic subtypes [adenocarcinoma and squamous cell carcinoma (SCC)]. Notably, patients with adenocarcinoma had longer telomeres than controls, whereas patients with SCC had shorter telomeres compared with controls. Long telomeres were associated with increased risk of adenocarcinoma, with the highest risk associated with female sex, younger age (<60 years), and lighter smoking (<30 pack-years). In contrast, long telomeres were protective against SCC, particularly in male patients. Our results extend the concept that telomere length affects risk of lung cancer in a manner that differs with histologic subtype.},
}
@article {pmid24616570,
year = {2014},
author = {Bertorelle, R and Rampazzo, E and Pucciarelli, S and Nitti, D and De Rossi, A},
title = {Telomeres, telomerase and colorectal cancer.},
journal = {World journal of gastroenterology},
volume = {20},
number = {8},
pages = {1940-1950},
pmid = {24616570},
issn = {2219-2840},
mesh = {Biomarkers, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic/genetics ; Cellular Senescence ; Chromosomal Instability ; Chromosomes/ultrastructure ; Colorectal Neoplasms/*genetics/*pathology ; DNA/chemistry ; Disease Progression ; Epigenesis, Genetic ; Humans ; Prognosis ; Telomerase/*genetics/metabolism ; Telomere/*pathology/ultrastructure ; Treatment Outcome ; },
abstract = {Colorectal cancer (CRC) is the third most common cancer worldwide and, despite improved treatments, is still an important cause of cancer-related deaths. CRC encompasses a complex of diseases arising from a multi-step process of genetic and epigenetic events. Besides heterogeneity in the molecular and biological features of CRC, chromosomal instability is a hallmark of cancer and cancer cells may also circumvent replicative senescence and acquire the ability to sustain unlimited proliferation. Telomere/telomerase interplay is an important mechanism involved in both genomic stability and cellular replicative potential, and its dysfunction plays a key role in the oncogenetic process. The erosion of telomeres, mainly because of cell proliferation, may be accelerated by specific alterations in the genes involved in CRC, such as APC and MSH2. Although there is general agreement that the shortening of telomeres plays a role in the early steps of CRC carcinogenesis by promoting chromosomal instability, the prognostic role of telomere length in CRC is still under debate. The activation of telomerase reverse transcriptase (TERT), the catalytic component of the telomerase complex, allows cancer cells to grow indefinitely by maintaining the length of the telomeres, thus favouring tumour formation/progression. Several studies indicate that TERT increases with disease progression, and most studies suggest that telomerase is a useful prognostic factor. Plasma TERT mRNA may also be a promising marker for the minimally invasive monitoring of disease progression and response to therapy.},
}
@article {pmid24616496,
year = {2014},
author = {Zalli, A and Carvalho, LA and Lin, J and Hamer, M and Erusalimsky, JD and Blackburn, EH and Steptoe, A},
title = {Shorter telomeres with high telomerase activity are associated with raised allostatic load and impoverished psychosocial resources.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {111},
number = {12},
pages = {4519-4524},
pmid = {24616496},
issn = {1091-6490},
support = {G0601647//Medical Research Council/United Kingdom ; RG/10/005/28296//British Heart Foundation/United Kingdom ; },
mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; Stress, Psychological/*genetics ; Telomerase/*metabolism ; *Telomere ; },
abstract = {Recent work has linked psychological stress with premature cellular aging as indexed by reduced leukocyte telomere length. The combination of shorter telomeres with high telomerase activity (TA) may be indicative of active cell stress. We hypothesized that older individuals characterized by shorter telomeres with high TA in unstimulated leukocytes would show signs of high allostatic load and low levels of protective psychosocial resources. We studied 333 healthy men and women aged 54-76 y who underwent laboratory testing in which we measured cardiovascular, neuroendocrine, and inflammatory responses to standardized mental stress tasks. The tasks elicited prompt increases in blood pressure (BP), heart rate, cortisol, and mediators of inflammation and reductions in heart rate variability, returning toward baseline levels following stress. However, men having shorter telomeres with high TA showed blunted poststress recovery in systolic BP, heart rate variability, and monocyte chemoattractant protein-1, together with reduced responsivity in diastolic BP, heart rate, and cortisol, in comparison to men with longer telomeres or men with shorter telomeres and low TA. Shorter telomeres with high TA were also associated with reduced social support, lower optimism, higher hostility, and greater early life adversity. These effects were independent of age, socioeconomic status, and body mass index. We did not observe differences among older women. Our findings suggest that active cell stress is associated with impaired physiological stress responses and impoverished psychosocial resources, reflecting an integration of cellular, systemic, and psychological stress processes potentially relevant to health in older men.},
}
@article {pmid24616077,
year = {2014},
author = {Wong, JY and De Vivo, I and Lin, X and Grashow, R and Cavallari, J and Christiani, DC},
title = {The association between global DNA methylation and telomere length in a longitudinal study of boilermakers.},
journal = {Genetic epidemiology},
volume = {38},
number = {3},
pages = {254-264},
pmid = {24616077},
issn = {1098-2272},
support = {R01ES009860/ES/NIEHS NIH HHS/United States ; R01 ES009860/ES/NIEHS NIH HHS/United States ; U60OH009762//ACL HHS/United States ; OH009762/OH/NIOSH CDC HHS/United States ; P30 ES000002/ES/NIEHS NIH HHS/United States ; P50ES00002/ES/NIEHS NIH HHS/United States ; U60 OH009762/OH/NIOSH CDC HHS/United States ; },
mesh = {Adult ; Alu Elements/genetics ; *DNA Methylation/drug effects ; Epigenesis, Genetic/drug effects ; Humans ; Leukocytes/drug effects/metabolism ; Long Interspersed Nucleotide Elements/genetics ; Longitudinal Studies ; Male ; Massachusetts ; Metals, Heavy/adverse effects/analysis/chemistry/pharmacology ; Models, Genetic ; Nails/chemistry ; *Occupations ; Particulate Matter/adverse effects/chemistry/pharmacology ; Real-Time Polymerase Chain Reaction ; Sequence Analysis, DNA ; Telomere/drug effects/*genetics/*metabolism ; Time Factors ; },
abstract = {The objectives of this study were to determine if global DNA methylation, as reflected in LINE-1 and Alu elements, is associated with telomere length and whether it modifies the rate of telomeric change. A repeated-measures longitudinal study was performed with a panel of 87 boilermaker subjects. The follow-up period was 29 months. LINE-1 and Alu methylation was determined using pyrosequencing. Leukocyte relative telomere length was assessed via real-time qPCR. Linear-mixed models were used to estimate the association between DNA methylation and telomere length. A structural equation model (SEM) was used to explore the hypothesized relationship between DNA methylation, proxies of particulate matter exposure, and telomere length at baseline. There appeared to be a positive association between both LINE-1 and Alu methylation levels, and telomere length. For every incremental increase in LINE-1 methylation, there was a statistically significant 1.0 × 10(-1) (95% CI: 4.6 × 10(-2), 1.5 × 10(-1), P < 0.01) unit increase in relative telomere length, controlling for age at baseline, current and past smoking status, work history, BMI (log kg/m(2)) and leukocyte differentials. Furthermore, for every incremental increase in Alu methylation, there was a statistically significant 6.2 × 10(-2) (95% CI: 1.0 × 10(-2), 1.1 × 10(-1), P = 0.02) unit increase in relative telomere length. The interaction between LINE-1 methylation and follow-up time was statistically significant with an estimate -9.8 × 10(-3) (95% CI: -1.8 × 10(-2), -1.9 × 10(-3), P = 0.02); suggesting that the rate of telomeric change was modified by the degree of LINE-1 methylation. No statistically significant association was found between the cumulative PM exposure construct, with global DNA methylation and telomere length at baseline.},
}
@article {pmid24615938,
year = {2014},
author = {Rehkopf, DH and Dow, WH and Rosero-Bixby, L and Lin, J and Epel, ES and Blackburn, EH},
title = {Seasonal variation of peripheral blood leukocyte telomere length in Costa Rica: A population-based observational study.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {26},
number = {3},
pages = {367-375},
pmid = {24615938},
issn = {1520-6300},
support = {072406/WT_/Wellcome Trust/United Kingdom ; R01 AG031716/AG/NIA NIH HHS/United States ; P30 AG012839/AG/NIA NIH HHS/United States ; //Wellcome Trust/United Kingdom ; P30AG012839/AG/NIA NIH HHS/United States ; R01AG031716/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; *Aging ; Biomarkers/metabolism ; Costa Rica ; *Genetic Variation ; Humans ; Leukocytes/cytology/*metabolism ; Longitudinal Studies ; Middle Aged ; Multivariate Analysis ; Regression Analysis ; Seasons ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {OBJECTIVES: Peripheral blood leukocyte telomere length (LTL) is increasingly being used as a biomarker of aging, but its natural variation in human populations is not well understood. Several other biomarkers show seasonal variation, as do several determinants of LTL. We examined whether there was monthly variation in LTL in Costa Rica, a country with strong seasonal differences in precipitation and infection.<br><br>METHODS: We examined a longitudinal population-based cohort of 581 Costa Rican adults age 60 and above, from which blood samples were drawn between October 2006 and July 2008. LTL was assayed from these samples using the quantitative PCR method. Multivariate regression models were used to examine correlations between month of blood draw and LTL.<br><br>RESULTS: Telomere length from peripheral blood leukocytes varied by as much as 200 base pairs depending on month of blood draw, and this difference is not likely to be due to random variation. A moderate proportion of this association is statistically accounted for by month and region specific average rainfall. We found shorter telomere length associated with greater rainfall.<br><br>CONCLUSIONS: There are two possible explanations of our findings. First, there could be relatively rapid month-to-month changes in LTL. This conclusion would have implications for understanding the natural population dynamics of telomere length. Second, there could be seasonal differences in constituent cell populations. This conclusion would suggest that future studies of LTL use methods to account for the potential impact of constituent cell type.},
}
@article {pmid24609383,
year = {2014},
author = {Ding, Z and Mangino, M and Aviv, A and Spector, T and Durbin, R and , },
title = {Estimating telomere length from whole genome sequence data.},
journal = {Nucleic acids research},
volume = {42},
number = {9},
pages = {e75},
pmid = {24609383},
issn = {1362-4962},
support = {G0600717/MRC_/Medical Research Council/United Kingdom ; R01HD071180/HD/NICHD NIH HHS/United States ; WT091310/WT_/Wellcome Trust/United Kingdom ; WT098051/WT_/Wellcome Trust/United Kingdom ; 100140/WT_/Wellcome Trust/United Kingdom ; R01AG030678/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Base Sequence ; Cross-Sectional Studies ; Exome ; Genome, Human ; Humans ; Leukocytes/physiology ; Middle Aged ; Models, Genetic ; Repetitive Sequences, Nucleic Acid ; *Sequence Analysis, DNA ; Software ; Telomere/*genetics ; Telomere Homeostasis ; },
abstract = {Telomeres play a key role in replicative ageing and undergo age-dependent attrition in vivo. Here, we report a novel method, TelSeq, to measure average telomere length from whole genome or exome shotgun sequence data. In 260 leukocyte samples, we show that TelSeq results correlate with Southern blot measurements of the mean length of terminal restriction fragments (mTRFs) and display age-dependent attrition comparably well as mTRFs.},
}
@article {pmid24608194,
year = {2014},
author = {Chen, Y and Qu, F and He, X and Bao, G and Liu, X and Wan, S and Xing, J},
title = {Short leukocyte telomere length predicts poor prognosis and indicates altered immune functions in colorectal cancer patients.},
journal = {Annals of oncology : official journal of the European Society for Medical Oncology},
volume = {25},
number = {4},
pages = {869-876},
doi = {10.1093/annonc/mdu016},
pmid = {24608194},
issn = {1569-8041},
mesh = {Aged ; Colorectal Neoplasms/drug therapy/*genetics/immunology/pathology/surgery ; Disease-Free Survival ; Female ; Humans ; Immunophenotyping ; Leukocytes/immunology/pathology ; Male ; Middle Aged ; Neoplasm Recurrence, Local/drug therapy/*genetics/immunology/pathology/surgery ; *Prognosis ; Risk Factors ; Telomere/genetics ; Telomere Shortening/*genetics/immunology ; },
abstract = {BACKGROUND: Numerous studies indicate that the leukocyte telomere length is associated with the risk of cancers, including colorectal cancer (CRC). However, the prognostic value of leukocyte telomere length in CRC patients has not been investigated.<br><br>PATIENTS AND METHODS: Relative telomere length (RTL) of peripheral blood leukocytes (PBLs) from 571 CRC patients receiving surgical resection was measured using a polymerase chain reaction-based method. The Cox proportional hazards ratio model and the Kaplan-Meier curve were used to estimate the association between RTL and the clinical outcome of CRC patients in the training set (90 patients) and the testing set (86 patients). Finally, an independent cohort of 395 patients was used as an external validation set. The immunophenotype of PBLs and the plasma concentration of several immune-related cytokines were determined by flow cytometry and enzyme-linked immunosorbent assay, respectively.<br><br>RESULTS: Patients with shorter RTL had significantly poorer overall survival and relapse-free survival than those with longer RTL in the training, testing and validation sets. Furthermore, leukocyte RTL and Tumor-Node-Metastasis (TNM) stage exhibited a significant joint effect in the prognosis prediction of combined CRC patients, indicating that patients with both short RTL and advanced stages had the worst prognosis, when compared with other subgroups. In addition, patients with short RTL showed the higher percentage of CD4(+) T cell and the lower percentage of B cell in peripheral blood mononuclear cells, as well as the lower concentration of plasma transforming growth factor-&#x3b2;1, suggesting a possibility that the immune functions changed with RTL alteration.<br><br>CONCLUSIONS: Our study for the first time demonstrates that leukocyte RTL is an independent prognostic marker complementing TNM stage and associated with the immune functions in CRC patients.},
}
@article {pmid24603533,
year = {2014},
author = {Braig, M and Pällmann, N and Preukschas, M and Steinemann, D and Hofmann, W and Gompf, A and Streichert, T and Braunschweig, T and Copland, M and Rudolph, KL and Bokemeyer, C and Koschmieder, S and Schuppert, A and Balabanov, S and Brümmendorf, TH},
title = {A 'telomere-associated secretory phenotype' cooperates with BCR-ABL to drive malignant proliferation of leukemic cells.},
journal = {Leukemia},
volume = {28},
number = {10},
pages = {2028-2039},
pmid = {24603533},
issn = {1476-5551},
support = {SCD/04/CSO_/Chief Scientist Office/United Kingdom ; },
mesh = {Animals ; Apoptosis ; Bone Marrow Cells/cytology ; Cell Cycle ; Cell Line, Tumor ; *Cell Proliferation ; Cellular Senescence ; Chemokines/metabolism ; Cytokines/metabolism ; Disease Progression ; Fusion Proteins, bcr-abl/*metabolism ; *Gene Expression Regulation, Leukemic ; Humans ; Inflammation/metabolism ; Leukemia/metabolism/*pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Phenotype ; Telomere/*ultrastructure ; },
abstract = {Telomere biology is frequently associated with disease evolution in human cancer and dysfunctional telomeres have been demonstrated to contribute to genetic instability. In BCR-ABL(+) chronic myeloid leukemia (CML), accelerated telomere shortening has been shown to correlate with leukemia progression, risk score and response to treatment. Here, we demonstrate that proliferation of murine CML-like bone marrow cells strongly depends on telomere maintenance. CML-like cells of telomerase knockout mice with critically short telomeres (CML-iG4) are growth retarded and proliferation is terminally stalled by a robust senescent cell cycle arrest. In sharp contrast, CML-like cells with pre-shortened, but not critically short telomere lengths (CML-G2) grew most rapidly and were found to express a specific 'telomere-associated secretory phenotype', comprising secretion of chemokines, interleukins and other growth factors, thereby potentiating oncogene-driven growth. Moreover, conditioned supernatant of CML-G2 cells markedly enhanced proliferation of CML-WT and pre-senescent CML-iG4 cells. Strikingly, a similar inflammatory mRNA expression pattern was found with disease progression from chronic phase to accelerated phase in CML patients. These findings demonstrate that telomere-induced senescence needs to be bypassed by leukemic cells in order to progress to blast crisis and provide a novel mechanism by which telomere shortening may contribute to disease evolution in CML.},
}
@article {pmid24601774,
year = {2014},
author = {Tsuta, H and Shinzato, C and Satoh, N and Hidaka, M},
title = {Telomere shortening in the colonial coral Acropora digitifera during development.},
journal = {Zoological science},
volume = {31},
number = {3},
pages = {129-134},
doi = {10.2108/zsj.31.129},
pmid = {24601774},
issn = {0289-0003},
mesh = {Animals ; Anthozoa/*genetics ; DNA ; Larva/genetics ; Male ; Spermatozoa ; Telomere/*physiology ; *Telomere Shortening ; },
abstract = {To test whether telomere length can be used in estimating the age of colonial corals, we used terminal restriction fragment (TRF) length analysis to compare the telomere lengths of the coral Acropora digitifera at three developmental stages: sperm, planula larvae, and polyps of adult colonies. We also compared the mean TRF lengths between branches at the center and periphery of tabular colonies of A. digitifera. A significant difference was observed in the mean TRF lengths in sperm, planulae, and polyps. The mean TRF length was longest in sperm and shortest in polyps from adult colonies. These results suggest that telomere length decreases during coral development and may be useful for estimating coral age. However, the mean TRF length of branches at the center of a table-form colony tended to be longer than that of peripheral branches, although this difference was not statistically significant. This suggests that both the chronological age of polyps and cell proliferation rate influence telomere length in polyps, and that estimating coral age based on telomere length is not a simple endeavor.},
}
@article {pmid24599483,
year = {2015},
author = {Brody, GH and Yu, T and Beach, SR and Philibert, RA},
title = {Prevention effects ameliorate the prospective association between nonsupportive parenting and diminished telomere length.},
journal = {Prevention science : the official journal of the Society for Prevention Research},
volume = {16},
number = {2},
pages = {171-180},
pmid = {24599483},
issn = {1573-6695},
support = {P30 DA027827/DA/NIDA NIH HHS/United States ; R01 DA019230/DA/NIDA NIH HHS/United States ; R01 HD030588/HD/NICHD NIH HHS/United States ; P30DA027827/DA/NIDA NIH HHS/United States ; },
mesh = {Adolescent ; Conflict, Psychological ; Emotions ; Female ; Humans ; Male ; Parent-Child Relations ; *Parenting ; *Telomere Shortening ; },
abstract = {Telomere length (TL) is an indicator of general systemic aging, with diminished TL associated with several chronic diseases of aging and with heightened mortality risk. Research has begun to focus on the ways in which stress contributes to telomere attrition. The purposes of this study were (a) to establish whether exposure to nonsupportive parenting, defined as high levels of conflict and rancor with low levels of warmth and emotional support, at age 17 would forecast TL 5 years later; and (b) to determine whether participation in an efficacious family-centered prevention program could ameliorate any associations that emerged. Rural African American adolescents participated in the Adults in the Making (AIM) program or a control condition. Primary caregivers provided data on nonsupportive parenting during a pretest when adolescents were age 17. Adolescents provided data on anger at the pretest and at a posttest administered 7 months later. When the youths were age 22, TL was assayed from a blood draw. The results indicated that heightened nonsupportive parenting forecast diminished TL among young adults in the control condition but not among those who participated in AIM; socioeconomic status risk, life stress, and the use of alcohol and cigarettes at age 17, and blood pressure and body mass index at age 22, were controlled. Subsequent exploratory analyses suggested that AIM-induced reductions in adolescents' anger served as a mediator connecting group assignment to TL. The results suggest that the cellular-level sequelae of nonsupportive parenting and stress are not immutable.},
}
@article {pmid24598784,
year = {2014},
author = {Boardman, LA and Litzelman, K and Seo, S and Johnson, RA and Vanderboom, RJ and Kimmel, GW and Cunningham, JM and Gangnon, RE and Engelman, CD and Riegert-Johnson, DL and Potter, J and Haile, R and Buchanan, D and Jenkins, MA and Rider, DN and Thibodeau, SN and Petersen, GM and Skinner, HG},
title = {The association of telomere length with colorectal cancer differs by the age of cancer onset.},
journal = {Clinical and translational gastroenterology},
volume = {5},
number = {3},
pages = {e52},
pmid = {24598784},
issn = {2155-384X},
support = {U01 CA074799/CA/NCI NIH HHS/United States ; U24 CA074783/CA/NCI NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; UM1 CA167551/CA/NCI NIH HHS/United States ; P30 DK084567/DK/NIDDK NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; U24 CA074799/CA/NCI NIH HHS/United States ; U24 CA074800/CA/NCI NIH HHS/United States ; U01 CA074800/CA/NCI NIH HHS/United States ; U24 CA097735/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; U01 CA097735/CA/NCI NIH HHS/United States ; T35 HL007690/HL/NHLBI NIH HHS/United States ; },
abstract = {OBJECTIVES: Telomeres are nucleoprotein structures that cap the end of chromosomes and shorten with sequential cell divisions in normal aging. Short telomeres are also implicated in the incidence of many cancers, but the evidence is not conclusive for colorectal cancer (CRC). Therefore, the aim of this study was to assess the association of CRC and telomere length.<br><br>METHODS: In this case-control study, we measured relative telomere length from peripheral blood leukocytes (PBLs) DNA with quantitative PCR in 598 CRC patients and 2,212 healthy controls.<br><br>RESULTS: Multivariate analysis indicated that telomere length was associated with risk for CRC, and this association varied in an age-related manner; younger individuals (&#x2264;50 years of age) with longer telomeres (80-99 percentiles) had a 2-6 times higher risk of CRC, while older individuals (>50 years of age) with shortened telomeres (1-10 percentiles) had 2-12 times the risk for CRC. The risk for CRC varies with extremes in telomere length in an age-associated manner.<br><br>CONCLUSIONS: Younger individuals with longer telomeres or older individuals with shorter telomeres are at higher risk for CRC. These findings indicate that the association of PBL telomere length varies according to the age of cancer onset and that CRC is likely associated with at minimum two different mechanisms of telomere dynamics.},
}
@article {pmid24595021,
year = {2014},
author = {Giesbrecht, CJ and Thornton, AE and Hall-Patch, C and Maan, EJ and Côté, HC and Money, DM and Murray, M and Pick, N},
title = {Select neurocognitive impairment in HIV-infected women: associations with HIV viral load, hepatitis C virus, and depression, but not leukocyte telomere length.},
journal = {PloS one},
volume = {9},
number = {3},
pages = {e89556},
pmid = {24595021},
issn = {1932-6203},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Adult ; Cognition Disorders/*complications/virology ; Demography ; Depression/*complications/virology ; Female ; HIV Infections/*complications/virology ; HIV Seropositivity/complications/virology ; Hepacivirus/*physiology ; Humans ; Leukocytes/metabolism/*pathology ; Middle Aged ; Reference Standards ; Telomere/*metabolism ; *Viral Load ; },
abstract = {BACKGROUND: Through implementation of combination antiretroviral therapy (cART) remarkable gains have been achieved in the management of HIV infection; nonetheless, the neurocognitive consequences of infection remain a pivotal concern in the cART era. Research has often employed norm-referenced neuropsychological scores, derived from healthy populations (excluding many seronegative individuals at high risk for HIV infection), to characterize impairments in predominately male HIV-infected populations.<br><br>METHODS: Using matched-group methodology, we assessed 81 HIV-seropositive (HIV+) women with established neuropsychological measures validated for detection of HIV-related impairments, as well as additional detailed tests of executive function and decision-making from the Cambridge Neuropsychological Test Automated Battery (CANTAB).<br><br>RESULTS: On validated tests, the HIV+ women exhibited impairments that were limited to significantly slower information processing speed when compared with 45 HIV-seronegative (HIV-) women with very similar demographic backgrounds and illness comorbidities. Additionally, select executive impairments in shifting attention (i.e., reversal learning) and in decision-making quality were revealed in HIV+ participants. Modifiers of neurocognition in HIV-infected women included detectable HIV plasma viral load, active hepatitis C virus co-infection, and self-reported depression symptoms. In contrast, leukocyte telomere length (LTL), a marker of cellular aging, did not significantly differ between HIV+ and HIV- women, nor was LTL associated with overall neurocognition in the HIV+ group.<br><br>CONCLUSIONS: The findings suggest that well-managed HIV infection may entail a more circumscribed neurocognitive deficit pattern than that reported in many norm-referenced studies, and that common comorbidities make a secondary contribution to HIV-related neurocognitive impairments.},
}
@article {pmid24594632,
year = {2014},
author = {Fu, XH and Duan, YM and Liu, YT and Cai, C and Meng, FL and Zhou, JQ},
title = {Telomere recombination preferentially occurs at short telomeres in telomerase-null type II survivors.},
journal = {PloS one},
volume = {9},
number = {3},
pages = {e90644},
pmid = {24594632},
issn = {1932-6203},
mesh = {Aging/*physiology ; Base Sequence ; Blotting, Southern ; DNA-Binding Proteins/genetics ; Gene Knockout Techniques ; Molecular Sequence Data ; Polymerase Chain Reaction ; Recombination, Genetic/*physiology ; Saccharomyces cerevisiae/genetics/*physiology ; Saccharomyces cerevisiae Proteins/genetics ; Sequence Analysis, DNA ; Telomerase/*deficiency ; Telomere/*genetics ; },
abstract = {In telomerase negative yeast cells, Rad52-dependent recombination is activated to maintain telomeres. This recombination-mediated telomere elongation usually involves two independent pathways, type I and type II, and leads to generation of type I and type II survivors. It remains elusive whether the recombination-mediated telomere elongation prefers to take place on shorter or longer telomeres. In this study, we exploited the de novo telomere addition system to examine the telomere recombination event in telomerase negative cells. We show that recombination preferentially occurs on shorter rather than longer telomeres in both pre-survivors and established type II survivors. In type II survivors, the short VII-L telomeres could invade either terminal TG1-3 sequence or short tracts of TG1-3 sequence in subtelomeric Y'-X and Y'-Y' junction to initiate recombination. Unexpectedly, short VII-L telomere recombination still takes place in type II survivors lacking either Rad50 or Rad59, which are required for type II survivor generation in senescing telomerase-null cells. Our results support the notion that Rad50 and Rad59 are not essential for the maintenance of type II survivors once established.},
}
@article {pmid24587065,
year = {2014},
author = {García-Calzón, S and Moleres, A and Marcos, A and Campoy, C and Moreno, LA and Azcona-Sanjulián, MC and Martínez-González, MA and Martínez, JA and Zalba, G and Marti, A and , },
title = {Telomere length as a biomarker for adiposity changes after a multidisciplinary intervention in overweight/obese adolescents: the EVASYON study.},
journal = {PloS one},
volume = {9},
number = {2},
pages = {e89828},
pmid = {24587065},
issn = {1932-6203},
mesh = {Adiposity/*genetics/physiology ; Adolescent ; Anthropometry ; Biomarkers/*chemistry ; DNA Primers/genetics ; Diet, Reducing/methods ; Female ; Humans ; Linear Models ; Male ; Obesity/*genetics/therapy ; Overweight/*genetics/therapy ; Real-Time Polymerase Chain Reaction ; Telomere/*genetics ; *Weight Reduction Programs ; },
abstract = {CONTEXT: Telomeres are biomarkers of biological aging. Shorter telomeres have been associated with increased adiposity in adults. However, this relationship remains unclear in children and adolescents.<br><br>OBJECTIVE: To evaluate the association between telomere length (TL) and adiposity markers in overweight/obese adolescents after an intensive program. We hypothesize that greater TL at baseline would predict a better response to a weight loss treatment.<br><br>The EVASYON is a multidisciplinary treatment program for adolescents with overweight and obesity that is aimed at applying the intervention to all possibly involved areas of the individual, such as dietary habits, physical activity and cognitive and psychological profiles. Seventy-four participants (36 males, 38 females, 12-16 yr) were enrolled in the intervention program: 2 months of an energy-restricted diet and a follow-up period (6 months).<br><br>MAIN OUTCOME: TL was measured by quantitative real-time polymerase chain reaction at baseline and after 2 months; meanwhile, anthropometric variables were also assessed after 6 months of follow-up.<br><br>RESULTS: TL lengthened in participants during the intensive period (+1.9&#xb1;1.0, p<0.001) being greater in overweight/obese adolescents with the shortest telomeres at baseline (r&#x200a;=&#x200a;-0.962, p<0.001). Multivariable linear regression analysis showed that higher baseline TL significantly predicted a higher decrease in body weight (B&#x200a;=&#x200a;-1.53, p&#x200a;=&#x200a;0.005; B&#x200a;=&#x200a;-2.25, p&#x200a;=&#x200a;0.047) and in standard deviation score for body mass index (BMI-SDS) (B&#x200a;=&#x200a;-0.22, p&#x200a;=&#x200a;0.010; B&#x200a;=&#x200a;-0.47, p&#x200a;=&#x200a;0.005) after the intensive and extensive period treatment respectively, in boys.<br><br>CONCLUSION: Our study shows that a weight loss intervention is accompanied by a significant increase in TL in overweight/obese adolescents. Moreover, we suggest that initial longer TL could be a potential predictor for a better weight loss response.},
}
@article {pmid24586195,
year = {2014},
author = {Martinerie, L and Manterola, M and Chung, SS and Panigrahi, SK and Weisbach, M and Vasileva, A and Geng, Y and Sicinski, P and Wolgemuth, DJ},
title = {Mammalian E-type cyclins control chromosome pairing, telomere stability and CDK2 localization in male meiosis.},
journal = {PLoS genetics},
volume = {10},
number = {2},
pages = {e1004165},
pmid = {24586195},
issn = {1553-7404},
support = {R01 CA108950/CA/NCI NIH HHS/United States ; R01 HD034915/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Chromosome Pairing/genetics ; Cyclin E/biosynthesis/*genetics ; Cyclin-Dependent Kinase 2/*genetics/metabolism ; Cyclins/*biosynthesis/genetics ; DNA Breaks, Double-Stranded ; Gene Expression Regulation, Developmental ; Humans ; Male ; Meiosis ; Mice ; Oncogene Proteins/biosynthesis/*genetics ; Spermatocytes/metabolism ; Spermatogenesis/genetics ; Telomere/genetics ; Testis/metabolism ; },
abstract = {Loss of function of cyclin E1 or E2, important regulators of the mitotic cell cycle, yields viable mice, but E2-deficient males display reduced fertility. To elucidate the role of E-type cyclins during spermatogenesis, we characterized their expression patterns and produced additional deletions of Ccne1 and Ccne2 alleles in the germline, revealing unexpected meiotic functions. While Ccne2 mRNA and protein are abundantly expressed in spermatocytes, Ccne1 mRNA is present but its protein is detected only at low levels. However, abundant levels of cyclin E1 protein are detected in spermatocytes deficient in cyclin E2 protein. Additional depletion of E-type cyclins in the germline resulted in increasingly enhanced spermatogenic abnormalities and corresponding decreased fertility and loss of germ cells by apoptosis. Profound meiotic defects were observed in spermatocytes, including abnormal pairing and synapsis of homologous chromosomes, heterologous chromosome associations, unrepaired double-strand DNA breaks, disruptions in telomeric structure and defects in cyclin-dependent-kinase 2 localization. These results highlight a new role for E-type cyclins as important regulators of male meiosis.},
}
@article {pmid24581987,
year = {2014},
author = {Mania, A and Mantzouratou, A and Delhanty, JD and Baio, G and Serhal, P and Sengupta, SB},
title = {Telomere length in human blastocysts.},
journal = {Reproductive biomedicine online},
volume = {28},
number = {5},
pages = {624-637},
doi = {10.1016/j.rbmo.2013.12.010},
pmid = {24581987},
issn = {1472-6491},
support = {//Department of Health/United Kingdom ; },
mesh = {Adult ; Aneuploidy ; Blastocyst/*metabolism ; Cells, Cultured ; Chromosome Aberrations/embryology/statistics &amp; numerical data ; Embryo Culture Techniques ; Embryonic Development/genetics ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Lymphocytes/cytology/metabolism ; Male ; Retrospective Studies ; Telomere/*physiology ; },
abstract = {This is a retrospective study aiming to assess telomere length in human embryos 4 days post fertilization and to determine whether it is correlated to chromosomal ploidy, embryo developmental rate and patient age. Embryos were donated from patients undergoing treatment in the assisted conception unit. Seven couples took part, generating 35 embryos consisting of 1130 cells. Quantitative fluorescent in-situ hybridization (FISH) measured the telomere length of every cell using a pan-telomeric probe. Conventional FISH on six chromosomes was used to assess aneuploidy in the same cells. Maternal and paternal age, referral reason, embryo developmental rate and type of chromosomal error were taken into account. Chromosomally abnormal cells were associated with shorter telomeres than normal cells for embryos that were developmentally slow. Cells produced by women of advanced maternal age and those with a history of repeated miscarriage tended to have substantially shorter telomeres. There was no significant difference in telomere length with respect to the rate of embryo development 5 days post fertilization. Telomeres play an important role in cell division and shorter telomeres may affect embryonic ploidy. Reduced telomere length was associated with aneuploid cells and embryos from women of advanced maternal age.},
}
@article {pmid24580894,
year = {2014},
author = {Martínez-Guitarte, JL and de la Fuente, M and Morcillo, G},
title = {Telomeric transcriptome from Chironomus riparius (Diptera), a species with noncanonical telomeres.},
journal = {Insect molecular biology},
volume = {23},
number = {3},
pages = {367-380},
doi = {10.1111/imb.12087},
pmid = {24580894},
issn = {1365-2583},
mesh = {Animals ; Chironomidae/*genetics ; Heat-Shock Response ; Larva ; RNA ; RNA Polymerase II/antagonists &amp; inhibitors ; RNA Polymerase III/antagonists &amp; inhibitors ; RNA, Untranslated ; Telomere/*genetics ; *Transcriptome ; },
abstract = {Although there are alternative telomere structures, most telomeres contain DNA arrays of short repeats (6-26 bp) maintained by telomerase. Like other diptera, Chironomus riparius has noncanonical telomeres and three subfamilies, TsA, TsB and TsC, of longer sequences (176 bp) are found at their chromosomal ends. Reverse transcription PCR was used to show that different RNAs are transcribed from these sequences. Only one strand from TsA sequences seems to render a noncoding RNA (named CriTER-A); transcripts from both TsB strands were found (CriTER-B and αCriTER-B) but no TsC transcripts were detected. Interestingly, these sequences showed a differential transcriptional response upon heat shock, and they were also differentially affected by inhibitors of RNA polymerase II and RNA polymerase III. A computer search for transcription factor binding sites revealed putative regulatory cis-elements within the transcribed sequence, reinforcing the experimental evidence which suggests that the telomeric repeat might function as a promoter. This work describes the telomeric transcriptome of an insect with non-telomerase telomeres, confirming the evolutionary conservation of telomere transcription. Our data reveal differences in the regulation of telomeric transcripts between control and stressful environmental conditions, supporting the idea that telomeric RNAs could have a relevant role in cellular metabolism in insect cells.},
}
@article {pmid24580844,
year = {2014},
author = {Trusina, A},
title = {Stress induced telomere shortening: longer life with less mutations?.},
journal = {BMC systems biology},
volume = {8},
number = {},
pages = {27},
pmid = {24580844},
issn = {1752-0509},
mesh = {*DNA Damage ; Longevity/*genetics ; *Models, Genetic ; *Mutation Rate ; Telomere Shortening/*genetics ; },
abstract = {BACKGROUND: Mutations accumulate as a result of DNA damage and imperfect DNA repair machinery. In higher eukaryotes the accumulation and spread of mutations is limited in two primary ways: through p53-mediated programmed cell death and cellular senescence mediated by telomeres. Telomeres shorten at every cell division and cell stops dividing once the shortest telomere reaches a critical length. It has been shown that the rate of telomere attrition is accelerated when cells are exposed to DNA damaging agents. However the implications of this mechanism are not fully understood.<br><br>RESULTS: With the help of in silico model we investigate the effect of genotoxic stress on telomere attrition and apoptosis in a population of non-identical replicating cells. When comparing the populations of cells with constant vs. stress-induced rate of telomere shortening we find that stress induced telomere shortening (SITS) increases longevity while reducing mutation rate. Interestingly, however, the effect takes place only when genotoxic stresses (e.g. reactive oxygen species due to metabolic activity) are distributed non-equally among cells.<br><br>CONCLUSIONS: Our results for the first time show how non-equal distribution of metabolic load (and associated genotoxic stresses) combined with stress induced telomere shortening can delay aging and minimize mutations.},
}
@article {pmid24572116,
year = {2014},
author = {Decottignies, A},
title = {[The telomere position effect: silence in the back row!].},
journal = {Medecine sciences : M/S},
volume = {30},
number = {2},
pages = {173-178},
doi = {10.1051/medsci/20143002015},
pmid = {24572116},
issn = {0767-0974},
mesh = {Animals ; Drosophila melanogaster/genetics ; Gene Silencing ; Heterochromatin/*physiology ; Humans ; Mutation ; Saccharomyces cerevisiae/genetics ; Telomere/physiology/*ultrastructure ; },
abstract = {Heterochromatin displays repressive histone marks that down-regulate transcription. In the absence of specialized barriers, these repressive marks spread onto nearby nucleosomes and induce transcriptional silencing of these regions. Accordingly, in various species, transgenes that are experimentally inserted directly next to telomeric repeats are silenced. Transcriptional repression induced by the spreading of telomeric heterochromatin is known as the "telomere position effect". Although it is attenuated by the presence of natural subtelomeric barriers acting against the spreading of telomeric heterochromatin, telomere-induced silencing is also observed at the level of endogenous loci where it was initially proposed to provide a mean to regulate gene expression during senescence. This, however, remains to be formally demonstrated. Here, I review the current evidences for a telomere position effect, from yeast to human.},
}
@article {pmid24571982,
year = {2014},
author = {Liu, M and Hales, BF and Robaire, B},
title = {Effects of four chemotherapeutic agents, bleomycin, etoposide, cisplatin, and cyclophosphamide, on DNA damage and telomeres in a mouse spermatogonial cell line.},
journal = {Biology of reproduction},
volume = {90},
number = {4},
pages = {72},
doi = {10.1095/biolreprod.114.117754},
pmid = {24571982},
issn = {1529-7268},
support = {MOP-119275//Canadian Institutes of Health Research/Canada ; },
mesh = {Animals ; Antibiotics, Antineoplastic/toxicity ; Antigens, Surface/drug effects ; Antineoplastic Agents/toxicity ; Antineoplastic Agents, Alkylating/toxicity ; Antineoplastic Agents, Phytogenic/toxicity ; Bleomycin/*toxicity ; Cell Line ; Cisplatin/*toxicity ; Cyclophosphamide/*toxicity ; DNA Breaks, Double-Stranded/drug effects ; *DNA Damage ; Etoposide/*toxicity ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Spermatogonia/cytology/*drug effects ; Telomere/drug effects ; },
abstract = {Treatment with chemotherapeutics agents may induce persistent DNA damage in male germ cells with the possibility of long-term consequences on fertility and progeny outcome. Telomeres, specialized structures at the physical ends of chromosomes, play an important role in the maintenance of genetic stability and in the response of somatic cells to anticancer drugs. Our objective was to test the hypothesis that exposure to bleomycin, etoposide, or cisplatin (the drugs used to treat testicular cancer) or cyclophosphamide (an anticancer agent and immunosuppressant) targets telomeres in the male germ line. C18-4 spermatogonial cells were exposed to bleomycin, etoposide, cisplatin, or 4-hydroperoxycyclophosphamide (4OOH-CPA, a preactivated analog of cyclophosphamide). All four anticancer drugs induced a significant increase in DNA damage in C18-4 cells, as assessed by gamma-H2AX immunofluorescence. Interestingly, the gamma-H2AX signal was localized to telomeres after treatment with bleomycin, cisplatin, and 4OOH-CPA, but not etoposide. Mean telomere lengths, the intensity of the telomere fluorescence in situ hybridization signal, telomerase activity, and the expression of the telomerase enzyme mRNA components, Tert and Terc, were reduced by exposure to cisplatin and 4OOH-CPA, but not by bleomycin or etoposide. Thus, although all four anticancer drugs induced DNA damage in this spermatogonial cell line, telomeres were not specifically affected by etoposide and only the two alkylating agents, cisplatin and 4OOH-CPA, induced telomere dysfunction. This telomere dysfunction may contribute to infertility and developmental defects in the offspring.},
}
@article {pmid24569170,
year = {2014},
author = {Lin, J and Kaur, P and Countryman, P and Opresko, PL and Wang, H},
title = {Unraveling secrets of telomeres: one molecule at a time.},
journal = {DNA repair},
volume = {20},
number = {},
pages = {142-153},
pmid = {24569170},
issn = {1568-7856},
support = {R00 ES016758/ES/NIEHS NIH HHS/United States ; 4R00ES016758/ES/NIEHS NIH HHS/United States ; ES0515052/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; Fluorescence Resonance Energy Transfer/*methods ; Humans ; Microscopy, Atomic Force/*methods ; Microscopy, Fluorescence/methods ; *Optical Tweezers ; Telomere/*chemistry/metabolism ; Telomere-Binding Proteins/*chemistry/metabolism ; },
abstract = {Telomeres play important roles in maintaining the stability of linear chromosomes. Telomere maintenance involves dynamic actions of multiple proteins interacting with long repetitive sequences and complex dynamic DNA structures, such as G-quadruplexes, T-loops and t-circles. Given the heterogeneity and complexity of telomeres, single-molecule approaches are essential to fully understand the structure-function relationships that govern telomere maintenance. In this review, we present a brief overview of the principles of single-molecule imaging and manipulation techniques. We then highlight results obtained from applying these single-molecule techniques for studying structure, dynamics and functions of G-quadruplexes, telomerase, and shelterin proteins.},
}
@article {pmid24563826,
year = {2013},
author = {Advani, VM and Belew, AT and Dinman, JD},
title = {Yeast telomere maintenance is globally controlled by programmed ribosomal frameshifting and the nonsense-mediated mRNA decay pathway.},
journal = {Translation (Austin, Tex.)},
volume = {1},
number = {1},
pages = {e24418},
pmid = {24563826},
issn = {2169-074X},
support = {R01 GM058859/GM/NIGMS NIH HHS/United States ; R21 GM068123/GM/NIGMS NIH HHS/United States ; },
abstract = {We have previously shown that ~10% of all eukaryotic mRNAs contain potential programmed -1 ribosomal frameshifting (-1 PRF) signals and that some function as mRNA destabilizing elements through the Nonsense-Mediated mRNA Decay (NMD) pathway by directing translating ribosomes to premature termination codons. Here, the connection between -1 PRF, NMD and telomere end maintenance are explored. Functional -1 PRF signals were identified in the mRNAs encoding two components of yeast telomerase, EST1 and EST2, and in mRNAs encoding proteins involved in recruiting telomerase to chromosome ends, STN1 and CDC13. All of these elements responded to mutants and drugs previously known to stimulate or inhibit -1 PRF, further supporting the hypothesis that they promote -1 PRF through the canonical mechanism. All affected the steady-state abundance of a reporter mRNA and the wide range of -1 PRF efficiencies promoted by these elements enabled the determination of an inverse logarithmic relationship between -1 PRF efficiency and mRNA accumulation. Steady-state abundances of the endogenous EST1, EST2, STN1 and CDC13 mRNAs were similarly inversely proportional to changes in -1 PRF efficiency promoted by mutants and drugs, supporting the hypothesis that expression of these genes is post-transcriptionally controlled by -1 PRF under native conditions. Overexpression of EST2 by ablation of -1 PRF signals or inhibition of NMD promoted formation of shorter telomeres and accumulation of large budded cells at the G2/M boundary. A model is presented describing how limitation and maintenance of correct stoichiometries of telomerase components by -1 PRF is used to maintain yeast telomere length.},
}
@article {pmid24563217,
year = {2014},
author = {Huang, Y and Liang, P and Liu, D and Huang, J and Songyang, Z},
title = {Telomere regulation in pluripotent stem cells.},
journal = {Protein &amp; cell},
volume = {5},
number = {3},
pages = {194-202},
pmid = {24563217},
issn = {1674-8018},
mesh = {Animals ; Humans ; Models, Biological ; Pluripotent Stem Cells/*metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Pluripotent stem cells (PSCs) have the potential to produce any types of cells from all three basic germ layers and the capacity to self-renew and proliferate indefinitely in vitro. The two main types of PSCs, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), share common features such as colony morphology, high expression of Oct4 and Nanog, and strong alkaline phosphatase activity. In recent years, increasing evidences suggest that telomere length represents another important internal factor in maintaining stem cell pluripotency. Telomere length homeostasis and its structural integrity help to protect chromosome ends from recombination, end fusion, and DNA damage responses, ensuring the divisional ability of mammalian cells. PSCs generally exhibit high telomerase activity to maintain their extremely long and stable telomeres, and emerging data indicate the alternative lengthening of telomeres (ALT) pathway may play an important role in telomere functions too. Such characteristics are likely key to their abilities to differentiate into diverse cell types in vivo. In this review, we will focus on the function and regulation of telomeres in ESCs and iPSCs, thereby shedding light on the importance of telomere length to pluripotency and the mechanisms that regulate telomeres in PSCs.},
}
@article {pmid24562933,
year = {2014},
author = {Sugishita, Y and Kammori, M and Yamada, O and Yamazaki, K and Ito, K and Fukumori, T and Yoshikawa, K and Yamada, T},
title = {Biological differential diagnosis of follicular thyroid tumor and Hürthle cell tumor on the basis of telomere length and hTERT expression.},
journal = {Annals of surgical oncology},
volume = {21},
number = {7},
pages = {2318-2325},
doi = {10.1245/s10434-014-3552-6},
pmid = {24562933},
issn = {1534-4681},
mesh = {Adenocarcinoma, Follicular/*diagnosis/genetics/metabolism ; Adenoma/*diagnosis/genetics/metabolism ; Adenoma, Oxyphilic/*diagnosis/genetics/metabolism ; Diagnosis, Differential ; Female ; Follow-Up Studies ; *Gene Expression Regulation, Neoplastic ; Humans ; Immunoenzyme Techniques ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis ; Telomerase/*metabolism ; Telomere Homeostasis/*genetics ; Thyroid Neoplasms/*diagnosis/genetics/metabolism ; },
abstract = {BACKGROUND: The most difficult thyroid tumors to diagnose by histology are follicular carcinomas (FTCs) and Hürthle cell carcinomas (HCCs). Telomere alteration and human telomerase reverse transcriptase (hTERT) expression have been observed in most human cancers and are known to be a feature of malignancy. The purpose of this study was to clarify whether hTERT protein expression and telomere alteration could be applicable biological markers for distinguishing FTC from HCC.<br><br>METHODS: We investigated a total of 78 thyroid tumor cases, including 14 FTCs, 47 follicular adenomas (FTAs), 5 HCCs, and 12 H&#xfc;rthle cell adenomas (HCAs). hTERT protein expression was examined by immunohistochemistry, and telomere length was determined by tissue quantitative fluorescence in situ hybridization.<br><br>RESULTS: Positivity for hTERT protein expression was observed in 86 % of FTCs and 49 % of FTAs. Telomeres in FTCs were significantly shorter than those in FTAs. All HCCs and HCAs (100 %) expressed hTERT protein. Telomeres in HCCs were significantly shorter than those in HCAs.<br><br>CONCLUSIONS: Our results suggest that hTERT protein expression and telomere shortening would be applicable as biological markers to distinguish FTC from FTA. Previous studies have suggested that follicular tumor and H&#xfc;rthle cell tumor should be classified biologically as distinct tumors. All H&#xfc;rthle cell tumors expressed hTERT protein and HCCs had markedly shortened telomeres, suggesting that follicular tumor and H&#xfc;rthle cell tumor might be biologically distinct entities.},
}
@article {pmid24561847,
year = {2014},
author = {Mengual Gómez, DL and Armando, RG and Farina, HG and Gómez, DE},
title = {[Telomerase and telomere: their structure and dynamics in health and disease].},
journal = {Medicina},
volume = {74},
number = {1},
pages = {69-76},
pmid = {24561847},
issn = {0025-7680},
mesh = {Animals ; Cell Division/physiology ; Cellular Senescence/genetics ; Humans ; Neoplasms/enzymology/*genetics ; Telomerase/*genetics/metabolism ; Telomere/*physiology ; Telomeric Repeat Binding Protein 1/physiology ; Telomeric Repeat Binding Protein 2/physiology ; },
abstract = {Telomerase is the enzyme responsible for the maintenance of telomere length by adding guanine-rich repetitive sequences. Its activity can be seen in gametes, stem cells and tumor cells. In human somatic cells the proliferative potential is limited, reaching senescence after 50-70 cell divisions, because the DNA polymerase is not able to copy the DNA at the ends of chromosomes. By contrast, in most tumor cells the replicative potential is unlimited due to the maintenance of the telomeric length given by telomerase. Telomeres have additional proteins that regulate the binding of telomerase, likewise telomerase associates, with a protein complex that regulates its activity. This work focuses on the structure and function of the telomere/telomerase complex and how changes in its behavior lead to the development of different diseases, mainly cancer. Development of inhibitors of the telomere/telomerase complex could be a target with promising possibilities.},
}
@article {pmid24558398,
year = {2014},
author = {Wakai, M and Abe, S and Kazuki, Y and Oshimura, M and Ishikawa, F},
title = {A human artificial chromosome recapitulates the metabolism of native telomeres in mammalian cells.},
journal = {PloS one},
volume = {9},
number = {2},
pages = {e88530},
pmid = {24558398},
issn = {1932-6203},
mesh = {Animals ; Antibodies/chemistry ; Base Sequence ; Cell Cycle ; Cell Line ; Chromatin/chemistry ; Chromosomes, Artificial, Human/*genetics ; Chromosomes, Human ; DNA Primers/genetics ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; Molecular Sequence Data ; NIH 3T3 Cells ; Poly A/chemistry ; RNA/genetics ; RNA Polymerase II/chemistry ; RNA, Small Interfering/metabolism ; Repetitive Sequences, Nucleic Acid ; Sequence Analysis, DNA/*methods ; Telomere/*ultrastructure ; Transcription, Genetic ; },
abstract = {Telomeric and subtelomeric regions of human chromosomes largely consist of highly repetitive and redundant DNA sequences, resulting in a paucity of unique DNA sequences specific to individual telomeres. Accordingly, it is difficult to analyze telomere metabolism on a single-telomere basis. To circumvent this problem, we have exploited a human artificial chromosome (HAC#21) derived from human chromosome 21 (hChr21). HAC#21 was generated through truncation of the long arm of native hChr21 by the targeted telomere seeding technique. The newly established telomere of HAC#21 lacks canonical subtelomere structures but possesses unique sequences derived from the target vector backbone and the internal region of hChr21 used for telomere targeting, which enabled us to molecularly characterize the single HAC telomere. We established HeLa and NIH-3T3 sub-lines containing a single copy of HAC#21, where it was robustly maintained. The seeded telomere is associated with telomeric proteins over a length similar to that reported in native telomeres, and is faithfully replicated in mid-S phase in HeLa cells. We found that the seeded telomere on HAC#21 is transcribed from the newly juxtaposed site. The transcript, HAC-telRNA, shares several features with TERRA (telomeric repeat-containing RNA): it is a short-lived RNA polymerase II transcript, rarely contains a poly(A) tail, and associates with chromatin. Interestingly, HAC-telRNA undergoes splicing. These results suggest that transcription into TERRA is locally influenced by the subtelomeric context. Taken together, we have established human and mouse cell lines that will be useful for analyzing the behavior of a uniquely identifiable, functional telomere.},
}
@article {pmid24557807,
year = {2014},
author = {Palmieri, D and Cafueri, G and Mongelli, F and Pezzolo, A and Pistoia, V and Palombo, D},
title = {Telomere shortening and increased oxidative stress are restricted to venous tissue in patients with varicose veins: A merely local disease?.},
journal = {Vascular medicine (London, England)},
volume = {19},
number = {2},
pages = {125-130},
doi = {10.1177/1358863X14525002},
pmid = {24557807},
issn = {1477-0377},
abstract = {Shortened telomere length (TL) and oxidative stress have been described in several vascular disorders at both the tissue and circulating level. However, to our knowledge, there are no reports about TL associated with varicose vein (VV) disease. This paper aimed to evaluate, at the tissue and circulating level, TL and oxidative stress in VV disease, compared to the corresponding counterparts from abdominal aortic aneurysm (AAA) patients and control healthy subjects. TL was measured using quantitative fluorescence in situ hybridization (Q-FISH). Oxidative stress was evaluated by measuring the malondialdehyde (MDA) concentration by thiobarbituric acid reactive substance/s (TBARS) assay. At the vascular tissue level, VV patients had shortened TL and a high MDA concentration, similarly to AAA patients. Conversely, blood lymphocytes and epidermal cells from VV patients had a TL similar to healthy controls and significantly longer than the same cells from AAA patients. Moreover, the MDA concentration in plasma from VV patients was significantly lower than from the AAA group. Linear regression analysis showed a statistically significant inverse correlation between the blood lymphocyte TL and plasma MDA level. Our results suggest that, unlike AAA, telomere attrition in VV tissue is not a systemic phenomenon but it may be attributable to tissue microenvironment conditions and possibly to high local oxidative stress.},
}
@article {pmid24551184,
year = {2014},
author = {Boltz, KA and Jasti, M and Townley, JM and Shippen, DE},
title = {Analysis of poly(ADP-Ribose) polymerases in Arabidopsis telomere biology.},
journal = {PloS one},
volume = {9},
number = {2},
pages = {e88872},
pmid = {24551184},
issn = {1932-6203},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; T32 CA009156/CA/NCI NIH HHS/United States ; GM065383/GM/NIGMS NIH HHS/United States ; },
mesh = {Arabidopsis/*genetics/metabolism ; Benzamides/pharmacology ; Bleomycin/pharmacology ; Enzyme Inhibitors/pharmacology ; Gene Deletion ; *Gene Expression Regulation, Plant ; Isoenzymes/genetics/metabolism ; Mutation ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/*genetics/metabolism ; RNA, Messenger/genetics/metabolism ; Telomerase/*genetics/metabolism ; Telomere/*chemistry ; Telomere Homeostasis/genetics ; },
abstract = {Maintaining the length of the telomere tract at chromosome ends is a complex process vital to normal cell division. Telomere length is controlled through the action of telomerase as well as a cadre of telomere-associated proteins that facilitate replication of the chromosome end and protect it from eliciting a DNA damage response. In vertebrates, multiple poly(ADP-ribose) polymerases (PARPs) have been implicated in the regulation of telomere length, telomerase activity and chromosome end protection. Here we investigate the role of PARPs in plant telomere biology. We analyzed Arabidopsis thaliana mutants null for PARP1 and PARP2 as well as plants treated with the PARP competitive inhibitor 3-AB. Plants deficient in PARP were hypersensitive to genotoxic stress, and expression of PARP1 and PARP2 mRNA was elevated in response to MMS or zeocin treatment or by the loss of telomerase. Additionally, PARP1 mRNA was induced in parp2 mutants, and conversely, PARP2 mRNA was induced in parp1 mutants. PARP3 mRNA, by contrast, was elevated in both parp1 and parp2 mutants, but not in seedlings treated with 3-AB or zeocin. PARP mutants and 3-AB treated plants displayed robust telomerase activity, no significant changes in telomere length, and no end-to-end chromosome fusions. Although there remains a possibility that PARPs play a role in Arabidopsis telomere biology, these findings argue that the contribution is a minor one.},
}
@article {pmid24550456,
year = {2014},
author = {Yu, TY and Kao, YW and Lin, JJ},
title = {Telomeric transcripts stimulate telomere recombination to suppress senescence in cells lacking telomerase.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {111},
number = {9},
pages = {3377-3382},
pmid = {24550456},
issn = {1091-6490},
mesh = {Cellular Senescence/genetics/*physiology ; Chromatin Immunoprecipitation ; Multiprotein Complexes/*genetics ; Mutation/genetics ; RNA, Long Noncoding/*genetics/metabolism ; Real-Time Polymerase Chain Reaction ; Recombination, Genetic/*genetics ; Saccharomyces cerevisiae ; Telomerase/*deficiency ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {In human somatic cells or yeast cells lacking telomerase, telomeres are shortened upon each cell division. This gradual shortening of telomeres eventually leads to senescence. However, a small population of telomerase-deficient cells can survive by bypassing senescence through the activation of alternative recombination pathways to maintain their telomeres. Although genes involved in telomere recombination have been identified, mechanisms that trigger telomere recombination are less known. The THO (suppressor of the transcriptional defects of Hpr1 mutants by overexpression) complex is involved in transcription elongation and mRNA export. Here we demonstrate that mutations in THO complex components can stimulate early senescence and type II telomere recombination in cells lacking telomerase. The accumulation of telomere-associated noncoding telomere repeat-containing RNA (TERRA) is required for the observed telomere effects in THO complex mutants; reduced transcriptional efficiency, or overexpression of RNase H or C(1-3)A RNA can severely impair the type II telomere recombination. The results highlight a unique function for telomere-associated TERRA, in the formation of type II survivors. Moreover, because TERRA is a long noncoding RNA, these results reveal a function for long noncoding RNA in regulating recombination.},
}
@article {pmid24533124,
year = {2014},
author = {Gao, H and Moss, DL and Parke, C and Tatum, D and Lustig, AJ},
title = {The Ctf18RFC clamp loader is essential for telomere stability in telomerase-negative and mre11 mutant alleles.},
journal = {PloS one},
volume = {9},
number = {2},
pages = {e88633},
pmid = {24533124},
issn = {1932-6203},
mesh = {Alleles ; Cell Cycle Proteins/metabolism ; Checkpoint Kinase 2/metabolism ; Chromatids/chemistry ; DNA Repair ; Endodeoxyribonucleases/*genetics/metabolism ; Exodeoxyribonucleases/*genetics/metabolism ; Hydroxyurea/chemistry ; Kinetics ; Methyl Methanesulfonate/chemistry ; *Mutation ; Phenotype ; Replication Protein C/*metabolism ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/*metabolism ; Telomerase/*metabolism ; Telomere/*ultrastructure ; Temperature ; },
abstract = {The function of the replication clamp loaders in the semi-conservative telomere replication and their relationship to telomerase- and recombination mechanisms of telomere addition remains ambiguous. We have investigated the variant clamp loader Ctf18 RFC (Replication Factor C). To understand the role of Ctf18 at the telomere, we first investigated genetic interactions after loss of Ctf18 and TLC1 (the yeast telomerase RNA). We find that the tlc1Δ ctf18Δ double mutant confers a rapid >1000-fold decrease in viability. The rate of loss was similar to the kinetics of cell death in rad52Δ tlc1Δ cells. However, the Ctf18 pathway is distinct from Rad52, required for the repair of DSBs, as demonstrated by the synthetic lethality of rad52▵ tlc1Δ ctf18Δ triple mutants. These data suggest that each mutant elicits non-redundant defects acting on the same substrate. Second, interactions of the yeast hyper-recombinational mutant, mre11A470T, with ctf18▵ confer a synergistic cold sensitivity. The phenotype of these double mutants ultimately results in telomere loss and the generation of recombinational survivors. We observed a similar synergism between single mutants that led to hypersensitivity to the DNA alkylating agent, methane methyl sulphonate (MMS), the replication fork inhibitor hydroxyurea (HU), and to a failure to separate telomeres of sister chromatids. Hence, ctf18Δ and mre11A470T act in different pathways on telomere substrates for multiple phenotypes. The mre11A470T cells also displayed a DNA damage response (DDR) at 15°C but not at 30°C while ctf18Δ mutants conferred a constitutive DDR activity. Both the 15°C DDR pattern and growth rate were reversible at 30°C and displayed telomerase activity in vivo. We hypothesize that Ctf18 confers protection against stalling and/or breaks at the replication fork in cells that either lack, or are compromised for, telomerase activity. This Ctf18-based function is likely to contribute another level to telomere size homeostasis.},
}
@article {pmid24531712,
year = {2015},
author = {Bojovic, B and Booth, RE and Jin, Y and Zhou, X and Crowe, DL},
title = {Alternative lengthening of telomeres in cancer stem cells in vivo.},
journal = {Oncogene},
volume = {34},
number = {5},
pages = {611-620},
pmid = {24531712},
issn = {1476-5594},
support = {R03 DE014283/DE/NIDCR NIH HHS/United States ; DE14283/DE/NIDCR NIH HHS/United States ; },
mesh = {Animals ; Apoptosis/genetics ; Cell Line ; Chromosomes/genetics ; DNA Damage/genetics ; Humans ; Mice ; Neoplasms/*genetics/pathology ; Neoplastic Stem Cells/*pathology ; RNA/*genetics ; Recombination, Genetic ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere Shortening/genetics ; },
abstract = {Chromosome ends are protected by telomeres that prevent DNA damage response and degradation. Telomerase expression extends telomeres and inhibits DNA damage response. Telomeres are also maintained by the recombination-based alternative lengthening pathway. Telomerase is believed to be the sole mechanism for telomere maintenance in the epidermis. We show that basal cells in the epidermis maintain telomeres both by telomerase and alternative lengthening of telomere (ALT) mechanisms in vivo. ALT was detected in epidermal stem cells in Terc(-/-) mice, and normal human epidermal keratinocytes are also ALT-positive. The ALT pathway is suppressed in primary, but not metastatic, epidermal squamous cell carcinomas (SCC) in Terc(+/+) mice. The ALT pathway is expressed in stem cells and basal cells in epidermal SCC in Terc(-/-) mice, and in some telomerase-positive human SCC lines. Telomeres shorten markedly in stem cells and basal cells in epidermal SCC in vivo. Telomere shortening is associated with telomeric DNA damage response and apoptosis in stem cells and basal cells. Stem cells were transformed in both primary and metastatic epidermal SCC. Genetic ablation of this small cell population resulted in significant tumor regression in vivo. We concluded that alternative lengthening of telomeres is important in epidermal homeostasis and tumorigenesis in vivo.},
}
@article {pmid24530884,
year = {2014},
author = {Savolainen, K and Eriksson, JG and Kananen, L and Kajantie, E and Pesonen, AK and Heinonen, K and Räikkönen, K},
title = {Associations between early life stress, self-reported traumatic experiences across the lifespan and leukocyte telomere length in elderly adults.},
journal = {Biological psychology},
volume = {97},
number = {},
pages = {35-42},
doi = {10.1016/j.biopsycho.2014.02.002},
pmid = {24530884},
issn = {1873-6246},
mesh = {Aged ; Anxiety, Separation/psychology ; Biomarkers ; Cellular Senescence ; Child, Preschool ; Cohort Studies ; DNA/genetics ; Female ; Finland ; Humans ; Male ; Mental Disorders/psychology ; Middle Aged ; Parents ; Polymerase Chain Reaction ; Stress, Psychological/*genetics ; Telomere/*ultrastructure ; Telomere Shortening/*physiology ; Warfare ; Wounds and Injuries/*psychology ; },
abstract = {Early life stress (ELS) poses a risk for mental disorders and aging-related diseases. Accelerated biological aging, reflected in shorter leukocyte telomere length (LTL), may underlie these risks. We examined whether objectively recorded ELS and retrospectively self-reported traumatic experiences across the lifespan are associated with LTL in later adulthood. Of 1486 participants, 215 had been exposed to ELS, namely to temporary separation from both parents in childhood. Participants self-reported emotionally or physically traumatic experiences across the lifespan at a mean age of 63.2 years. LTL was measured using a quantitative PCR method at a mean age of 61.5 years. Separation or self-reported traumatic experiences were not associated with LTL. However, separated participants who self-reported traumatic experiences had shorter LTL. Our results suggest that while ELS or self-reported traumatic experiences are not per se associated with LTL measured decades later, ELS may in combination with self-reported traumatic events be associated with accelerated biological aging.},
}
@article {pmid24530766,
year = {2014},
author = {Cui, G and Sun, J and Zhang, L and Li, R and Wang, Y and Cianflone, K and Ding, H and Wang, DW},
title = {Lack of causal relationship between leukocyte telomere length and coronary heart disease.},
journal = {Atherosclerosis},
volume = {233},
number = {2},
pages = {375-380},
doi = {10.1016/j.atherosclerosis.2014.01.008},
pmid = {24530766},
issn = {1879-1484},
mesh = {Atherosclerosis/blood/genetics ; Case-Control Studies ; Causality ; Cellular Senescence ; China ; Coronary Angiography ; Coronary Disease/blood/diagnostic imaging/*etiology/genetics ; Ethnicity ; Female ; Humans ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Observer Variation ; *Polymorphism, Single Nucleotide ; RNA/*blood ; Sequence Analysis, DNA ; Single-Blind Method ; Telomerase/*blood ; Telomere/*ultrastructure ; *Telomere Homeostasis ; },
abstract = {OBJECTIVE: To investigate the association between genetic variation in telomerase RNA component (TERC) and leukocyte telomere length (LTL) with risk of coronary heart disease (CHD).<br><br>METHODS AND RESULTS: An analysis of LTL was conducted, focusing on two SNPs in 2 community-based cohort populations comprising 3500 Chinese Han individuals. In addition, LTL ratio was determined in a case-control setting involving 4351 participants: 2211 healthy individuals and 2140 CHD patients. The association between LTL and the presence and extent of cardiovascular and cerebrovascular lesions were tested. Results confirmed the association of rs12696304 and rs16847897 with LTL in the Chinese Han population (P=1.63&#xd7;10(-6) and P=1.44&#xd7;10(-7), respectively). However, these SNPs confer a moderate risk for CHD but did not achieve significant threshold after multiple corrections. Decreased LTL ratio was associated with CHD (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.02-1.34; P<0.01). In addition, the LTL ratio in CHD patients was related to numbers of vascular disease lesions.<br><br>CONCLUSIONS: Our results do not support a causal role of LTL for the development of CHD. However, LTL may be related to complex conditions associated with cardiovascular and cerebrovascular disease manifestations.},
}
@article {pmid24529708,
year = {2014},
author = {Porro, A and Feuerhahn, S and Lingner, J},
title = {TERRA-reinforced association of LSD1 with MRE11 promotes processing of uncapped telomeres.},
journal = {Cell reports},
volume = {6},
number = {4},
pages = {765-776},
doi = {10.1016/j.celrep.2014.01.022},
pmid = {24529708},
issn = {2211-1247},
mesh = {DNA-Binding Proteins/genetics/*metabolism ; HeLa Cells ; Histone Demethylases/genetics/*metabolism ; Humans ; MRE11 Homologue Protein ; Protein Binding ; RNA, Long Noncoding/genetics/*metabolism ; Telomere/*metabolism ; *Telomere Shortening ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Up-Regulation ; },
abstract = {Telomeres protect chromosome ends from being recognized as sites of DNA damage. Upon telomere shortening or telomere uncapping induced by loss of telomeric repeat-binding factor 2 (TRF2), telomeres elicit a DNA-damage response leading to cellular senescence. Here, we show that following TRF2 depletion, the levels of the long noncoding RNA TERRA increase and LSD1, which binds TERRA, is recruited to telomeres. At uncapped telomeres, LSD1 associates with MRE11, one of the nucleases implicated in the processing of 3' telomeric G overhangs, and we show that LSD1 is required for efficient removal of these structures. The LSD1-MRE11 interaction is reinforced in vivo following TERRA upregulation in TRF2-deficient cells and in vitro by TERRA-mimicking RNA oligonucleotides. Furthermore, LSD1 enhances the nuclease activity of MRE11 in vitro. Our data indicate that recruitment of LSD1 to deprotected telomeres requires MRE11 and is promoted by TERRA. LSD1 stimulates MRE11 catalytic activity and nucleolytic processing of uncapped telomeres.},
}
@article {pmid24525824,
year = {2014},
author = {Balk, B and Dees, M and Bender, K and Luke, B},
title = {The differential processing of telomeres in response to increased telomeric transcription and RNA-DNA hybrid accumulation.},
journal = {RNA biology},
volume = {11},
number = {2},
pages = {95-100},
pmid = {24525824},
issn = {1555-8584},
mesh = {Bacteria/genetics ; Cellular Senescence/genetics ; Chromosomes ; DNA/*metabolism ; Exodeoxyribonucleases/metabolism ; Humans ; Models, Molecular ; RNA/*metabolism ; Rad52 DNA Repair and Recombination Protein/metabolism ; Repetitive Sequences, Nucleic Acid/physiology ; Telomere/*metabolism ; *Telomere Shortening ; *Transcription, Genetic ; Yeasts/genetics ; },
abstract = {Telomeres are protective nucleoprotein structures at the ends of eukaryotic chromosomes. Despite the heterochromatic state of telomeres they are transcribed, generating non-coding telomeric repeat-containing RNA (TERRA). Strongly induced TERRA transcription has been shown to cause telomere shortening and accelerated senescence in the absence of both telomerase and homology-directed repair (HDR). Moreover, it has recently been demonstrated that TERRA forms RNA-DNA hybrids at chromosome ends. The accumulation of RNA-DNA hybrids at telomeres also leads to rapid senescence and telomere loss in the absence of telomerase and HDR. Conversely, in the presence of HDR, telomeric RNA-DNA hybrid accumulation and increased telomere transcription promote telomere recombination, and hence, delayed senescence. Here, we demonstrate that despite these similar phenotypic outcomes, telomeres that are highly transcribed are not processed in the same manner as those that accumulate RNA-DNA hybrids.},
}
@article {pmid24525820,
year = {2014},
author = {Oeckl, P and Scheffold, A and Lechel, A and Rudolph, KL and Ferger, B},
title = {Substantial telomere shortening in the substantia nigra of telomerase-deficient mice does not increase susceptibility to MPTP-induced dopamine depletion.},
journal = {Neuroreport},
volume = {25},
number = {5},
pages = {335-339},
doi = {10.1097/WNR.0000000000000099},
pmid = {24525820},
issn = {1473-558X},
mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/*pharmacology ; 3,4-Dihydroxyphenylacetic Acid/metabolism ; Animals ; Corpus Striatum/drug effects/metabolism ; Dopamine/analogs &amp; derivatives/*metabolism ; Dopamine Agents/*pharmacology ; Homovanillic Acid/metabolism ; Male ; Metallothionein 3 ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Motor Activity/drug effects/physiology ; Neurons/drug effects/metabolism ; Parkinsonian Disorders/metabolism ; Substantia Nigra/*drug effects/metabolism ; Telomerase/*deficiency/genetics ; *Telomere Shortening ; Tyrosine 3-Monooxygenase/metabolism ; },
abstract = {The most important risk factor for developing Parkinson's disease (PD) is age. Aging is ascribed to different mechanisms, including telomere shortening. Telomeres consist of repetitive DNA sequences and stabilize chromosome integrity. Currently, however, the data reported on telomere shortening in PD patients are inconsistent. We investigated the effect of telomere shortening in the MPTP mouse model of PD using late-generation telomerase-deficient mice (G3 Terc mice). G3 Terc mice showed a reduction in telomere length in nigral tyrosine hydroxylase-positive neurons by 40%, as indicated by quantitative fluorescence in-situ hybridization. There was no difference in the total motor activity and striatal tissue concentrations of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid), HVA (4-hydroxy-3-methoxyphenylacetic acid), and 3-MT (3-methoxytyramine) concentrations or dopamine turnover in G3 Terc mice in comparison with controls without MPTP treatment. Low-dose MPTP treatment (four injections, 2 h intervals, 2 × 5 and 2 × 7.5 mg/kg) led to a significant decrease in striatal dopamine concentrations that did not differ in G3 Terc mice compared with control mice (19.15 ± 0.44 to 12.81 ± 1.26 ng/mg in control mice in comparison with 19.51 ± 0.59 to 13.56 ± 1.10 ng/mg in G3 Terc mice). In conclusion, telomere shortening does not increase susceptibility to MPTP-induced dopamine depletion in mice. These data indicate that other age-related mechanisms in the brain may play a more important role in enhancing MPTP-induced dopamine depletion.},
}
@article {pmid24523222,
year = {2014},
author = {Cusanelli, E and Chartrand, P},
title = {Telomeric noncoding RNA: telomeric repeat-containing RNA in telomere biology.},
journal = {Wiley interdisciplinary reviews. RNA},
volume = {5},
number = {3},
pages = {407-419},
doi = {10.1002/wrna.1220},
pmid = {24523222},
issn = {1757-7012},
support = {MOP-89768//Canadian Institutes of Health Research/Canada ; },
mesh = {Animals ; Face/abnormalities ; Gene Expression Regulation ; Heterochromatin/genetics/metabolism ; Humans ; Immunologic Deficiency Syndromes/genetics/metabolism ; Neoplasms/genetics/metabolism ; Primary Immunodeficiency Diseases ; RNA, Untranslated/analysis/*genetics/metabolism ; Telomere/chemistry/*genetics/metabolism ; },
abstract = {Telomeres are nucleoprotein structures that cap the ends of eukaryotic chromosomes, protecting them from degradation and activation of DNA damage response. For this reason, functional telomeres are vital to genome stability. For years, telomeres were assumed to be transcriptionally silent, because of their heterochromatic state. It was only recently shown that, in several organisms, telomeres are transcribed, giving rise to a long noncoding RNA (lncRNA) called telomeric repeat-containing RNA (TERRA). Several lines of evidence now indicate that TERRA molecules play crucial roles in telomere homeostasis and telomere functions. Recent studies have shown that the expression and regulation of TERRA are dynamically controlled by each chromosome end. TERRA has been involved in the regulation of telomere length, telomerase activity, and heterochromatin formation at telomeres. The correct regulation of the telomeric transcripts may be essential to genome stability, and altered TERRA levels associate with tumorigenesis and cellular senescence. Thus, the study of the molecular mechanisms of TERRA biogenesis and function may advance the understanding of telomere-related diseases, including cancer and aging.},
}
@article {pmid24523019,
year = {2014},
author = {Zhao, W and Bian, Y and Zhu, W and Zou, P and Tang, G},
title = {Regulator of telomere elongation helicase 1 (RTEL1) rs6010620 polymorphism contribute to increased risk of glioma.},
journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine},
volume = {35},
number = {6},
pages = {5259-5266},
pmid = {24523019},
issn = {1423-0380},
mesh = {DNA Helicases/*genetics ; *Genetic Predisposition to Disease ; Glioma/etiology/*genetics ; Humans ; *Polymorphism, Genetic ; Risk ; },
abstract = {Regulator of telomere elongation helicase 1 (RTEL1) is critical for genome stability and tumor avoidance. Many studies have reported the associations of RTEL1 rs6010620 with glioma risk, but individually published results were inconclusive. This meta-analysis was performed to quantitatively summarize the evidence for such a relationship. The PubMed, Embase, and Web of Science were systematically searched to identify relevant studies. The odds ratio (OR) and 95 % confidence interval (95 % CI) were computed to estimate the strength of the association using a fixed or random effects model. Ten studies were eligible for meta-analysis including data on glioma with 6,490 cases and 9,288 controls. Overall, there was a significant association between RTEL1 rs6010620 polymorphism and glioma risk in all four genetic models (GG vs. AA: OR=1.87, 95 % CI=1.60-2.18, P heterogeneity=0.552; GA vs. AA: OR=1.30, 95 % CI=1.16-1.46, P heterogeneity=0.495; dominant model-GG+GA vs. AA: OR=1.46, 95 % CI=1.31-1.63, P heterogeneity=0.528; recessive model-GG vs. GA+AA: OR=1.36, 95 % CI=1.27-1.46, P heterogeneity=0.093). Subgroup analyses by ethnicity showed that RTEL1 rs6010620 polymorphism resulted in a higher risk of glioma among both Asians and Caucasians. In the stratified analysis by ethnicity and source of controls, significantly increased risk was observed for Asians and Europeans in all genetic models, population-based studies in all genetic models, and hospital-based studies in three genetic models (heterozygote comparison, homozygote comparison, and dominant model). Our meta-analysis suggested that RTEL1 rs6010620 polymorphism is likely to be associated with increased glioma risk, which lends further biological plausibility to these findings.},
}
@article {pmid24522463,
year = {2014},
author = {O'Callaghan, NJ and Bull, C and Fenech, M},
title = {Elevated plasma magnesium and calcium may be associated with shorter telomeres in older South Australian women.},
journal = {The journal of nutrition, health &amp; aging},
volume = {18},
number = {2},
pages = {131-136},
pmid = {24522463},
issn = {1760-4788},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Australia ; Body Mass Index ; Calcium, Dietary/administration &amp; dosage/*blood ; Female ; Humans ; Lymphocytes/drug effects/metabolism ; Magnesium/administration &amp; dosage/*blood ; Male ; Micronutrients/administration &amp; dosage ; Multivariate Analysis ; Sequence Analysis, DNA ; Telomere/*metabolism ; *Telomere Shortening ; Young Adult ; },
abstract = {Telomeres are structures that cap the ends of chromosomes. The integrity of the telomere structure and its DNA hexamer (TTAGGG)n repeat sequence is critical for protecting the ends of chromosomes from degradation and in maintaining overall chromosomal stability. Currently, there are limited data on the influence that nutrition has on telomere length. Recent studies have suggested that micronutrients may influence telomere length. Here we examined the relationship between telomere length in lymphocytes and plasma calcium, magnesium, selenium and zinc status in a healthy cohort of younger and older adults. We report a negative association between telomere length and both plasma calcium and magnesium levels, (r=-0.47, P=0.03 and r=-0.61, P=0.001 respectively), in older females; Intriguingly Ca/Mg ratio was positively associated with telomere length (r=0.55, P=0.007). These relationships were not observed in the younger adults, nor in the older males. In conclusion, our study provides preliminary evidence suggesting that levels of plasma magnesium and calcium may impact on telomere length in lymphocytes in older women.},
}
@article {pmid24522077,
year = {2014},
author = {Atala, A},
title = {Re: telomere length influences cancer cell differentiation in vivo.},
journal = {The Journal of urology},
volume = {191},
number = {3},
pages = {867-868},
doi = {10.1016/j.juro.2013.11.038},
pmid = {24522077},
issn = {1527-3792},
mesh = {Animals ; Female ; Humans ; Male ; Prostate/*pathology ; Prostatic Neoplasms/*metabolism/*pathology ; Telomerase/*metabolism ; Telomere/*metabolism ; },
}
@article {pmid24516170,
year = {2014},
author = {Ray, S and Bandaria, JN and Qureshi, MH and Yildiz, A and Balci, H},
title = {G-quadruplex formation in telomeres enhances POT1/TPP1 protection against RPA binding.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {111},
number = {8},
pages = {2990-2995},
pmid = {24516170},
issn = {1091-6490},
mesh = {Escherichia coli ; Fluorescence Resonance Energy Transfer ; *G-Quadruplexes ; Humans ; Microscopy, Fluorescence ; *Models, Molecular ; *Protein Conformation ; Replication Protein A/*metabolism ; Serine Proteases/chemistry/*metabolism ; Shelterin Complex ; Telomere/*chemistry/metabolism ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {Human telomeres terminate with a single-stranded 3' G overhang, which can be recognized as a DNA damage site by replication protein A (RPA). The protection of telomeres (POT1)/POT1-interacting protein 1 (TPP1) heterodimer binds specifically to single-stranded telomeric DNA (ssTEL) and protects G overhangs against RPA binding. The G overhang spontaneously folds into various G-quadruplex (GQ) conformations. It remains unclear whether GQ formation affects the ability of POT1/TPP1 to compete against RPA to access ssTEL. Using single-molecule Förster resonance energy transfer, we showed that POT1 stably loads to a minimal DNA sequence adjacent to a folded GQ. At 150 mM K(+), POT1 loading unfolds the antiparallel GQ, as the parallel conformation remains folded. POT1/TPP1 loading blocks RPA's access to both folded and unfolded telomeres by two orders of magnitude. This protection is not observed at 150 mM Na(+), in which ssTEL forms only a less-stable antiparallel GQ. These results suggest that GQ formation of telomeric overhangs may contribute to suppression of DNA damage signals.},
}
@article {pmid24513288,
year = {2014},
author = {Qiang, W and Wu, Q and Zhou, F and Xie, C and Wu, C and Zhou, Y},
title = {Suppression of telomere-binding protein TPP1 resulted in telomere dysfunction and enhanced radiation sensitivity in telomerase-negative osteosarcoma cell line.},
journal = {Biochemical and biophysical research communications},
volume = {445},
number = {2},
pages = {363-368},
doi = {10.1016/j.bbrc.2014.02.001},
pmid = {24513288},
issn = {1090-2104},
mesh = {Apoptosis ; Cell Line, Tumor ; Cell Survival/radiation effects ; Down-Regulation ; Gene Deletion ; Humans ; Osteosarcoma/*genetics/pathology/radiotherapy ; RNA Interference ; *Radiation Tolerance ; Shelterin Complex ; Telomerase/*genetics ; Telomere/*genetics/pathology/radiation effects ; Telomere-Binding Proteins/*genetics ; },
abstract = {Mammalian telomeres are protected by the shelterin complex that contains the six core proteins POT1, TPP1, TIN2, TRF1, TRF2 and RAP1. TPP1, formerly known as TINT1, PTOP, and PIP1, is a key factor that regulates telomerase recruitment and activity. In addition to this, TPP1 is required to mediate the shelterin assembly and stabilize telomere. Previous work has found that TPP1 expression was elevated in radioresistant cells and that overexpression of TPP1 led to radioresistance and telomere lengthening in telomerase-positive cells. However, the exact effects and mechanism of TPP1 on radiosensitivity are yet to be precisely defined in the ALT cells. Here we report on the phenotypes of the conditional deletion of TPP1 from the human osteosarcoma U2OS cells using ALT pathway to extend the telomeres.TPP1 deletion resulted in telomere shortening, increased apoptosis and radiation sensitivity enhancement. Together, our findings show that TPP1 plays a vital role in telomere maintenance and protection and establish an intimate relationship between TPP1, telomere and cellular response to ionizing radiation, but likely has the specific mechanism yet to be defined.},
}
@article {pmid24510582,
year = {2014},
author = {Kong, Q and Ji, G and Xie, B and Li, J and Mao, J and Wang, J and Liu, S and Liu, L and Liu, Z},
title = {Telomere elongation facilitated by trichostatin a in cloned embryos and pigs by somatic cell nuclear transfer.},
journal = {Stem cell reviews and reports},
volume = {10},
number = {3},
pages = {399-407},
pmid = {24510582},
issn = {2629-3277},
mesh = {Animals ; Blastocyst/drug effects/enzymology ; Cloning, Organism ; Enzyme Induction/drug effects ; Histone Deacetylase Inhibitors/*pharmacology ; Hydroxamic Acids/*pharmacology ; Nuclear Transfer Techniques ; Sus scrofa ; Telomerase/metabolism ; Telomere/genetics ; Telomere Homeostasis/*drug effects ; },
abstract = {Telomere attrition and genomic instability are associated with organism aging. Concerns still exist regarding telomere length resetting in cloned embryos and ntES cells, and possibilities of premature aging of cloned animals achieved by somatic cell nuclear transfer (SCNT). Trichostatin A (TSA), a histone deacetylase inhibitor, effectively improves the developmental competence of cloned embryos and animals, and recently contributes to successful generation of human ntES cells by SCNT. To test the function of TSA on resetting telomere length, we analyzed telomeres in cloned blastocysts and pigs following treatment of SCNT embryos with TSA. Here, we show that telomeres of cloned pigs generated by standard SCNT methods are not effectively restored, compared with those of donor cells, however TSA significantly increases telomere lengths in cloned pigs. Telomeres elongate in cloned porcine embryos during early cleavage from one-cell to four-cell stages. Notably, TSA facilitates telomere lengthening of cloned embryos mainly at morula-blastocyst stages. Knockdown of pTert by shRNA in donor cells reduces telomerase activity in cloned blastocysts but does not abrogate telomere elongation in the TSA-treated embryos (p > 0.05). However, genes associated with recombination or telomerase-independent mechanism of alternative lengthening of telomeres (ALT) Rad50 and BLM show increased expression in TSA-treated embryos. These data suggest that TSA may promote telomere elongation of cloned porcine embryos by ALT. Together, TSA can elongate telomeres in cloned embryos and piglets, and this could be one of the mechanisms underlying improved development of cloned embryos and animals treated with TSA.},
}
@article {pmid24508600,
year = {2014},
author = {David Wilson, W and Paul, A},
title = {Kinetics and structures on the molecular path to the quadruplex form of the human telomere.},
journal = {Journal of molecular biology},
volume = {426},
number = {8},
pages = {1625-1628},
doi = {10.1016/j.jmb.2014.02.001},
pmid = {24508600},
issn = {1089-8638},
mesh = {DNA/*chemistry ; *G-Quadruplexes ; Humans ; },
}
@article {pmid24508371,
year = {2014},
author = {Wang, WL and Yeh, YT and Chen, LJ and Chiu, JJ},
title = {Regulation of fibrillar collagen-mediated smooth muscle cell proliferation in response to chemical stimuli by telomere reverse transcriptase through c-Myc.},
journal = {Biomaterials},
volume = {35},
number = {12},
pages = {3829-3839},
doi = {10.1016/j.biomaterials.2014.01.049},
pmid = {24508371},
issn = {1878-5905},
mesh = {Base Sequence ; *Cell Proliferation ; Cells, Cultured ; Collagen/*physiology ; DNA Primers ; Humans ; Proto-Oncogene Proteins c-myc/*metabolism ; RNA-Directed DNA Polymerase/*metabolism ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Shelterin Complex ; Telomere/*enzymology ; Telomere-Binding Proteins ; },
abstract = {Human telomerase reverse transcriptase (hTERT) and oncogene c-Myc have been shown to regulate cell proliferation. Our previous studies demonstrated that fibrillar collagen mediates vascular smooth muscle cell (SMC) cycle progression and proliferation in response to platelet-derived growth factor (PDGF)-BB and interleukin (IL)-1β. However, whether hTERT and c-Myc are involved in these fibrillar collagen-mediated SMC responses remain unclear. The present study elucidated the regulatory role of hTERT and c-Myc in PDGF-BB/IL-1β-induced cell cycle progression in SMCs on fibrillar collagen and its underlying mechanisms. Our results showed that PDGF-BB and IL-1β exert synergistic effects to induce hTERT expression, but not its activity, in human arterial SMCs on fibrillar collagen. This PDGF-BB/IL-1β-induced up-regulation of hTERT contributes to cell cycle progression in SMCs through the up-regulation of cyclin-dependent kinase-6 and down-regulations of p27(KIP1) and p21(CIP1). In addition, PDGF-BB/IL-1β induces up-regulation of c-Myc in SMCs on fibrillar collagen; this response is mediated by the increased binding of hTERT, which can form complexes with TPP1 and hnRNPK, to the guanine-rich region of the c-Myc promoter and consequently contributes to cell cycle progression in SMCs on fibrillar collagen. Moreover, the PDGF-BB/IL-1β-induced hTERT and c-Myc expressions are regulated by phosphatidylinositol 3-kinase/Akt in SMCs on fibrillar collagen. Our findings provide insights into the mechanisms by which hTERT and c-Myc regulates SMC cell cycle progression and proliferation on fibrillar collagen in response to chemical stimuli.},
}
@article {pmid24500201,
year = {2014},
author = {Episkopou, H and Draskovic, I and Van Beneden, A and Tilman, G and Mattiussi, M and Gobin, M and Arnoult, N and Londoño-Vallejo, A and Decottignies, A},
title = {Alternative Lengthening of Telomeres is characterized by reduced compaction of telomeric chromatin.},
journal = {Nucleic acids research},
volume = {42},
number = {7},
pages = {4391-4405},
pmid = {24500201},
issn = {1362-4962},
mesh = {Cell Line ; Chromatin/*chemistry ; DNA/chemistry ; Fibroblasts/metabolism ; Gene Expression Regulation ; Humans ; Nuclear Proteins/metabolism ; Repetitive Sequences, Nucleic Acid ; Telomerase/metabolism ; Telomere/*chemistry ; *Telomere Homeostasis ; Transcription, Genetic ; },
abstract = {Proper telomeric chromatin configuration is thought to be essential for telomere homeostasis and stability. Previous studies in mouse suggested that loss of heterochromatin marks at telomeres might favor onset of Alternative Lengthening of Telomeres (ALT) pathway, by promoting homologous recombination. However, analysis of chromatin status at human ALT telomeres has never been reported. Here, using isogenic human cell lines and cellular hybrids, which rely either on telomerase or ALT to maintain telomeres, we show that chromatin compaction is reduced at ALT telomeres and this is associated with a global decrease in telomeric H3K9me3. This, subsequently, leads to upregulation of telomere transcription. Accordingly, restoration of a more condensed telomeric chromatin through telomerase-dependent elongation of short ALT telomeres reduces telomere transcription. We further show that loss of ATRX chromatin remodeler function, a frequent characteristic of ALT cells, is not sufficient to decrease chromatin condensation at telomeres nor to increase the expression of telomeric RNA species. These results offer new insight on telomeric chromatin properties in ALT cells and support the hypothesis that telomeric chromatin decondensation is important for ALT pathway.},
}
@article {pmid24498432,
year = {2014},
author = {Qin, Q and Sun, J and Yin, J and Liu, L and Chen, J and Zhang, Y and Li, T and Shi, Y and Wei, S and Nie, S},
title = {Telomere length in peripheral blood leukocytes is associated with risk of colorectal cancer in Chinese population.},
journal = {PloS one},
volume = {9},
number = {2},
pages = {e88135},
pmid = {24498432},
issn = {1932-6203},
mesh = {Adult ; Asian People/*genetics ; Case-Control Studies ; Colon/metabolism ; Colorectal Neoplasms/*genetics/pathology ; Female ; Humans ; Leukocytes, Mononuclear/*metabolism ; Male ; Middle Aged ; Polymerase Chain Reaction ; Prognosis ; Rectum/metabolism ; Risk Factors ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: Human telomeres, tandem repeats of TTAGGG nucleotides at the ends of chromosomes, are essential for maintaining genomic integrity and stability. Results of previous epidemiologic studies about the association of telomere length with risk of colorectal cancer (CRC) have been conflicting.<br><br>METHODS: A case-control study was conducted in a Han population in Wuhan, central China. The relative telomere length (RTL) was measured in peripheral blood leukocytes (PBLs) using quantitative real-time polymerase chain reaction (PCR) in 628 CRC cases and 1,256 age and sex frequency matched cancer-free controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression models to evaluate the association between RTL and CRC risk.<br><br>RESULTS: Using median RTL in the controls as the cutoff, individuals with shorter RTL were associated with a significantly increased risk of CRC (adjusted OR&#x200a;=&#x200a;1.27, 95%CI: 1.05-1.55). When participants were further categorized into 3 and 4 groups according to the tertile and quartile RTL values of controls, significant relationships were still observed between shorter RTL and increased CRC risk (OR per tertile&#x200a;=&#x200a;1.13, 95%CI: 1.00-1.28, P(trend)&#x200a;=&#x200a;0.045; OR per quartile&#x200a;=&#x200a;1.12, 95%CI: 1.03-1.23, P(trend)&#x200a;=&#x200a;0.012). In stratified analyses, significant association between shorter RTL and increased CRC risk was found in females, individuals younger than 60 years old, never smokers and never drinkers.<br><br>CONCLUSIONS: This study suggested that short telomere length in PBLs was significantly associated with an increased risk of CRC in Chinese Han population. Further validation in large prospective studies and investigation of the biologic mechanisms are warranted.},
}
@article {pmid24498269,
year = {2014},
author = {Seguí, N and Guinó, E and Pineda, M and Navarro, M and Bellido, F and Lázaro, C and Blanco, I and Moreno, V and Capellá, G and Valle, L},
title = {Longer telomeres are associated with cancer risk in MMR-proficient hereditary non-polyposis colorectal cancer.},
journal = {PloS one},
volume = {9},
number = {2},
pages = {e86063},
pmid = {24498269},
issn = {1932-6203},
mesh = {Adult ; Colorectal Neoplasms, Hereditary Nonpolyposis/blood/*genetics ; DNA Mismatch Repair/*genetics ; Family Health ; Female ; Heterozygote ; Humans ; Male ; Middle Aged ; *Mutation ; Polymerase Chain Reaction/methods ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Telomere/*genetics ; Telomere Homeostasis ; Telomere Shortening ; },
abstract = {Aberrant telomere length measured in blood has been associated with increased risk of several cancer types. In the field of hereditary non-polyposis colorectal cancer (CRC), and more particularly in Lynch syndrome, caused by germline mutations in the mismatch repair (MMR) genes, we recently found that cancer-affected MMR gene mutation carriers had shorter telomeres and more pronounced shortening of telomere length with age than controls and unaffected MMR gene mutation carriers. Here we evaluate blood telomere length in MMR-proficient hereditary non-polyposis CRC, i.e. familial CRC type X (fCRC-X). A total of 57 cancer-affected and 57 cancer-free individuals from 34 Amsterdam-positive fCRC-X families were analyzed and compared to the data previously published on 144 cancer-affected and 100 cancer-free MMR gene mutation carriers, and 234 controls. Relative telomere length was measured using a monochrome multiplex quantitative PCR method, following strict measures to avoid sources of bias and adjusting by age. Despite the retrospective nature of our study, the results show that longer telomeres associate with cancer risk in fCRC-X, thus identifying different patterns of telomere length according to the status of the MMR system.},
}
@article {pmid24495131,
year = {2014},
author = {Haghighi, MM and Aghagolzadeh, P and Zadeh, SM and Molaei, M and Zali, MR and Radpour, R},
title = {Telomere shortening: a biological marker of sporadic colorectal cancer with normal expression of p53 and mismatch repair proteins.},
journal = {Genetic testing and molecular biomarkers},
volume = {18},
number = {4},
pages = {236-244},
doi = {10.1089/gtmb.2013.0436},
pmid = {24495131},
issn = {1945-0257},
mesh = {Adult ; Aged ; Aged, 80 and over ; *Base Pair Mismatch ; *Biomarkers, Tumor ; Cohort Studies ; Colorectal Neoplasms/*genetics/pathology ; *DNA Repair ; *Genes, p53 ; Humans ; Middle Aged ; Sensitivity and Specificity ; *Telomere Shortening ; },
abstract = {Uncontrolled growth of cells, a main criterion of cancer, is merged with pathologic telomere length alteration. Thereby, measurement of telomere length could provide important information on cell proliferation and senescence in cancer tissues. Telomere shortening and its potential correlation with clinicopathological predictive markers in sporadic colorectal cancer (CRC) with normal expression of mismatch repair (MMR) proteins (including Mlh1, Msh2, Pms2, and Msh6) and normal p53 expression was completely explored. Relative telomere length (RTL) was quantitatively measured in a cohort of 164 samples (68 patients with sporadic CRC and 96 healthy unrelated controls). Our results demonstrated a significant shortening of RTL in the tumor-derived tissue of patients compared with the control group (p<0.001). Interestingly, significant telomere shortening was observed in tumors from an ascending and sigmoid colon in comparison with tumors located in a descending colon. Additionally, the telomere length was significantly shorter in those with lymph node metastasis (p<0.05). The results suggest that pathological telomere shortening, leading to genome instability and lymphatic transformation, could serve as a potential sensitive detection and also as a classification marker for facilitating diagnosis and management of CRC.},
}
@article {pmid24493020,
year = {2014},
author = {Stindl, R},
title = {The telomeric sync model of speciation: species-wide telomere erosion triggers cycles of transposon-mediated genomic rearrangements, which underlie the saltatory appearance of nonadaptive characters.},
journal = {Die Naturwissenschaften},
volume = {101},
number = {3},
pages = {163-186},
pmid = {24493020},
issn = {1432-1904},
mesh = {Animals ; DNA Transposable Elements/*genetics ; Evolution, Molecular ; Fossils ; Gene Rearrangement/*genetics ; Genetic Speciation ; Humans ; Models, Biological ; Telomere/*genetics ; },
abstract = {Charles Darwin knew that the fossil record is not overwhelmingly supportive of genetic and phenotypic gradualism; therefore, he developed the core of his theory on the basis of breeding experiments. Here, I present evidence for the existence of a cell biological mechanism that strongly points to the almost forgotten European concept of saltatory evolution of nonadaptive characters, which is in perfect agreement with the gaps in the fossil record. The standard model of chromosomal evolution has always been handicapped by a paradox, namely, how speciation can occur by spontaneous chromosomal rearrangements that are known to decrease the fertility of heterozygotes in a population. However, the hallmark of almost all closely related species is a differing chromosome complement and therefore chromosomal rearrangements seem to be crucial for speciation. Telomeres, the caps of eukaryotic chromosomes, erode in somatic tissues during life, but have been thought to remain stable in the germline of a species. Recently, a large human study spanning three healthy generations clearly found a cumulative telomere effect, which is indicative of transgenerational telomere erosion in the human species. The telomeric sync model of speciation presented here is based on telomere erosion between generations, which leads to identical fusions of chromosomes and triggers a transposon-mediated genomic repatterning in the germline of many individuals of a species. The phenotypic outcome of the telomere-triggered transposon activity is the saltatory appearance of nonadaptive characters simultaneously in many individuals. Transgenerational telomere erosion is therefore the material basis of aging at the species level.},
}
@article {pmid24492422,
year = {2014},
author = {Oetting, WS and Guan, W and Schladt, DP and Wildebush, WA and Becker, J and Thyagarajan, B and Jacobson, PA and Matas, AJ and Israni, AK},
title = {Telomere length of recipients and living kidney donors and chronic graft dysfunction in kidney transplants.},
journal = {Transplantation},
volume = {97},
number = {3},
pages = {325-329},
pmid = {24492422},
issn = {1534-6080},
support = {U01 AI058013/AI/NIAID NIH HHS/United States ; U19 AI070119/AI/NIAID NIH HHS/United States ; 5U19-AI070119/AI/NIAID NIH HHS/United States ; 5U01-AI058013/AI/NIAID NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Aged ; Biomarkers/metabolism ; DNA/analysis ; Delayed Graft Function/genetics ; Female ; Genotype ; Graft Rejection/*genetics ; Graft Survival/genetics ; Humans ; Kidney/physiopathology ; Kidney Transplantation/*methods ; Leukocytes/cytology ; Living Donors ; Male ; Middle Aged ; Multivariate Analysis ; Polymerase Chain Reaction ; Prospective Studies ; Renal Insufficiency/physiopathology/*therapy ; Risk ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: A biological marker that would allow clinicians to determine the length of time an allograft will remain functional after transplantation would greatly aid the ability to stratify donors by risk and to use biologically "young" allografts in young recipients, maximizing the use of this rare resource. Telomere length (TL) has been proposed to be such a marker to determine the biological age of a tissue.<br><br>METHODS: We genotyped DNA from 1805 recipients and 1038 living kidney donors for TL to determine the association of TL with acute rejection (AR), chronic graft dysfunction (CGD), and graft failure of kidney allografts. DNA was isolated from peripheral blood white blood cells and TL was measured in DNA using the multiplexed monochrome quantitative polymerase chain reaction assay.<br><br>RESULTS: As has been previously shown, we found a significant association between log-transformed TL and donor age (P=3.8&#xd7;10) and recipient age (P=5.6&#xd7;10). Univariate and multivariate analysis did not show any significant associations between log-transformed TL in donor or recipient DNA with AR, CGD, or graft failure, although we did observe an association between donor chronological age and CGD (P=0.018).<br><br>CONCLUSION: Although older allografts have been shown to be at greater risk for AR and CGD, this does not appear to be associated with shorter TL. Different markers will need to be identified to determine how biological age impacts transplant outcome, such as age-related fibrosis or tubular atrophy and tubular loss.},
}
@article {pmid24490687,
year = {2014},
author = {Yamamoto, M and Bando, T and Kawamoto, Y and Taylor, RD and Hashiya, K and Sugiyama, H},
title = {Specific alkylation of human telomere repeat sequences by a tandem-hairpin motif of pyrrole-imidazole polyamides with indole-seco-CBI.},
journal = {Bioconjugate chemistry},
volume = {25},
number = {3},
pages = {552-559},
doi = {10.1021/bc400567m},
pmid = {24490687},
issn = {1520-4812},
mesh = {Alkylating Agents/chemical synthesis/chemistry/*pharmacology ; Alkylation ; Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Electrophoresis, Polyacrylamide Gel ; Humans ; Imidazoles/chemistry/*pharmacology ; Indoles/chemistry/*pharmacology ; Molecular Conformation ; Pyrroles/chemistry/*pharmacology ; Structure-Activity Relationship ; Telomere/*drug effects ; Terminal Repeat Sequences/*drug effects ; Tumor Cells, Cultured ; },
abstract = {We designed and synthesized a tandem-hairpin motif of pyrrole (P)-imidazole (I) polyamide 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI) conjugates (1) that targets the human telomere repeat sequence 5'-d(CCCTAA)n-3'. As a control, conjugate 2 (hairpin PI polyamide with seco-CBI), which also targets the human telomere repeat sequence, was synthesized. High-resolution denaturing polyacrylamide gel electrophoresis (PAGE) using 5' Texas Red-labeled 219-bp DNA fragments revealed the outstandingly high sequence selectivity of 1, with no mismatch alkylation. Furthermore, an evaluation performed in human cancer cell lines demonstrated that conjugate 1 has low cytotoxicity compared with conjugate 2. In addition, a cell-staining analysis indicated that conjugate 1 induced apoptosis moderately by DNA damage. This study demonstrated that conjugate 1 can be used as an effective alkylator for telomere repeat sequences or as an apoptotic inducer.},
}
@article {pmid24489760,
year = {2014},
author = {Killick, E and Tymrakiewicz, M and Cieza-Borrella, C and Smith, P and Thompson, DJ and Pooley, KA and Easton, DF and Bancroft, E and Page, E and Leongamornlert, D and , and Kote-Jarai, Z and Eeles, RA},
title = {Telomere length shows no association with BRCA1 and BRCA2 mutation status.},
journal = {PloS one},
volume = {9},
number = {1},
pages = {e86659},
pmid = {24489760},
issn = {1932-6203},
support = {16563/CRUK_/Cancer Research UK/United Kingdom ; 13232/CRUK_/Cancer Research UK/United Kingdom ; P30 CA016520/CA/NCI NIH HHS/United States ; 10118/CRUK_/Cancer Research UK/United Kingdom ; 11022/CRUK_/Cancer Research UK/United Kingdom ; 15007/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Adult ; Aged ; BRCA1 Protein/*genetics ; BRCA2 Protein/*genetics ; Breast Neoplasms/diagnosis/*genetics ; Female ; Heterozygote ; Humans ; Male ; Middle Aged ; *Mutation ; Prognosis ; Proportional Hazards Models ; Prostatic Neoplasms/diagnosis/*genetics ; Risk ; Telomere/chemistry/*genetics ; Telomere Homeostasis ; },
abstract = {This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy at time of enrollment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years), half of whom had been diagnosed with breast cancer prior to enrollment. TL was quantified by qPCR from DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2 mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don't support the previous finding of association between hereditary breast cancer and shorter TL.},
}
@article {pmid24486644,
year = {2014},
author = {Chen, X and Kamranvar, SA and Masucci, MG},
title = {Tumor viruses and replicative immortality--avoiding the telomere hurdle.},
journal = {Seminars in cancer biology},
volume = {26},
number = {},
pages = {43-51},
doi = {10.1016/j.semcancer.2014.01.006},
pmid = {24486644},
issn = {1096-3650},
mesh = {Animals ; Cell Transformation, Viral ; Cellular Senescence/genetics ; Genomic Instability ; Humans ; Neoplasms/genetics/metabolism/virology ; Oncogenic Viruses/*physiology ; Telomere/*genetics/*metabolism ; Tumor Virus Infections/genetics/metabolism/virology ; *Virus Replication ; },
abstract = {Tumor viruses promote cell proliferation in order to gain access to an environment suitable for persistence and replication. The expression of viral products that promote growth transformation is often accompanied by the induction of multiple signs of telomere dysfunction, including telomere shortening, damage of telomeric DNA and chromosome instability. Long-term survival and progression to full malignancy require the bypassing of senescence programs that are triggered by the damaged telomeres. Here we review different strategies by which tumor viruses interfere with telomere homeostasis during cell transformation. This frequently involves the activation of telomerase, which assures both the integrity and functionality of telomeres. In addition, recent evidence suggests that oncogenic viruses may activate a recombination-based mechanism for telomere elongation known as Alternative Lengthening of Telomeres (ALT). This error-prone strategy promotes genomic instability and could play an important role in viral oncogenesis.},
}
@article {pmid24486376,
year = {2014},
author = {Shim, G and Ricoul, M and Hempel, WM and Azzam, EI and Sabatier, L},
title = {Crosstalk between telomere maintenance and radiation effects: A key player in the process of radiation-induced carcinogenesis.},
journal = {Mutation research. Reviews in mutation research},
volume = {},
number = {},
pages = {},
pmid = {24486376},
issn = {1388-2139},
support = {P01 CA049062/CA/NCI NIH HHS/United States ; },
abstract = {It is well established that ionizing radiation induces chromosomal damage, both following direct radiation exposure and via non-targeted (bystander) effects, activating DNA damage repair pathways, of which the proteins are closely linked to telomeric proteins and telomere maintenance. Long-term propagation of this radiation-induced chromosomal damage during cell proliferation results in chromosomal instability. Many studies have shown the link between radiation exposure and radiation-induced changes in oxidative stress and DNA damage repair in both targeted and non-targeted cells. However, the effect of these factors on telomeres, long established as guardians of the genome, still remains to be clarified. In this review, we will focus on what is known about how telomeres are affected by exposure to low- and high-LET ionizing radiation and during proliferation, and will discuss how telomeres may be a key player in the process of radiation-induced carcinogenesis.},
}
@article {pmid24481629,
year = {2014},
author = {Yin, Y and Liu, N and Ye, X and Guo, R and Hao, J and Wang, F and Liu, L},
title = {Telomere elongation in parthenogenetic stem cells.},
journal = {Protein &amp; cell},
volume = {5},
number = {1},
pages = {8-11},
pmid = {24481629},
issn = {1674-8018},
mesh = {Animals ; Embryonic Stem Cells/*diagnostic imaging/metabolism ; Humans ; Mice, Inbred C57BL ; *Parthenogenesis ; Telomere/*diagnostic imaging/metabolism ; Transcriptome ; Ultrasonography ; },
}
@article {pmid24480597,
year = {2014},
author = {Reichert, S and Bize, P and Arrivé, M and Zahn, S and Massemin, S and Criscuolo, F},
title = {Experimental increase in telomere length leads to faster feather regeneration.},
journal = {Experimental gerontology},
volume = {52},
number = {},
pages = {36-38},
doi = {10.1016/j.exger.2014.01.019},
pmid = {24480597},
issn = {1873-6815},
mesh = {Animals ; Birds ; Feathers/*physiology ; Male ; Regeneration/*physiology ; Telomerase/physiology ; *Telomere ; },
abstract = {Telomeres - the protective ends of linear chromosomes - reveal themselves not only as a good proxy in terms of longevity, but more recently also as a marker of healthy ageing in laboratory rodents. Telomere erosion is prevented by the activation of telomerase, an enzyme suspected to be also vital for tissue regeneration and which experimental activation improves health state in mice. One emerging hypothesis is that telomerase activity accounts for the frequently reported positive links between telomere lengths and individual quality in a wide range of organisms. Still, we lack an experimental approach testing the exact impact of inter-individual differences in telomere length on individual trait variability. In a first step study, we tested the impact of the TA-65, a plant-derived product stimulating the expression and the activity of telomerase, on telomere lengths and flight feather renewal capacity of captive zebra finches (Taenopygia guttata). Telomere length was longer in TA-65 treated finches while their feather grew faster than in controls. Our data support the idea that long telomeres could reflect high telomerase activity, and in so doing be a good predictor of greater telomerase-dependent tissue regeneration, which may ultimately explain variation in organism quality and longevity.},
}
@article {pmid24478790,
year = {2013},
author = {Lee, JH and Cheng, R and Honig, LS and Feitosa, M and Kammerer, CM and Kang, MS and Schupf, N and Lin, SJ and Sanders, JL and Bae, H and Druley, T and Perls, T and Christensen, K and Province, M and Mayeux, R},
title = {Genome wide association and linkage analyses identified three loci-4q25, 17q23.2, and 10q11.21-associated with variation in leukocyte telomere length: the Long Life Family Study.},
journal = {Frontiers in genetics},
volume = {4},
number = {},
pages = {310},
pmid = {24478790},
issn = {1664-8021},
support = {U01 AG023712/AG/NIA NIH HHS/United States ; U01 AG023744/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; P30 AG034424/AG/NIA NIH HHS/United States ; U01 AG023749/AG/NIA NIH HHS/United States ; U01 AG023755/AG/NIA NIH HHS/United States ; U01 AG023746/AG/NIA NIH HHS/United States ; R01 MH084995/MH/NIMH NIH HHS/United States ; },
abstract = {Leukocyte telomere length is believed to measure cellular aging in humans, and short leukocyte telomere length is associated with increased risks of late onset diseases, including cardiovascular disease, dementia, etc. Many studies have shown that leukocyte telomere length is a heritable trait, and several candidate genes have been identified, including TERT, TERC, OBFC1, and CTC1. Unlike most studies that have focused on genetic causes of chronic diseases such as heart disease and diabetes in relation to leukocyte telomere length, the present study examined the genome to identify variants that may contribute to variation in leukocyte telomere length among families with exceptional longevity. From the genome wide association analysis in 4,289 LLFS participants, we identified a novel intergenic SNP rs7680468 located near PAPSS1 and DKK2 on 4q25 (p = 4.7E-8). From our linkage analysis, we identified two additional novel loci with HLOD scores exceeding three, including 4.77 for 17q23.2, and 4.36 for 10q11.21. These two loci harbor a number of novel candidate genes with SNPs, and our gene-wise association analysis identified multiple genes, including DCAF7, POLG2, CEP95, and SMURF2 at 17q23.2; and RASGEF1A, HNRNPF, ANF487, CSTF2T, and PRKG1 at 10q11.21. Among these genes, multiple SNPs were associated with leukocyte telomere length, but the strongest association was observed with one contiguous haplotype in CEP95 and SMURF2. We also show that three previously reported genes-TERC, MYNN, and OBFC1-were significantly associated with leukocyte telomere length at p empirical < 0.05.},
}
@article {pmid24477622,
year = {2014},
author = {Dorris, K and Sobo, M and Onar-Thomas, A and Panditharatna, E and Stevenson, CB and Gardner, SL and Dewire, MD and Pierson, CR and Olshefski, R and Rempel, SA and Goldman, S and Miles, L and Fouladi, M and Drissi, R},
title = {Prognostic significance of telomere maintenance mechanisms in pediatric high-grade gliomas.},
journal = {Journal of neuro-oncology},
volume = {117},
number = {1},
pages = {67-76},
pmid = {24477622},
issn = {1573-7373},
support = {P30 CA016087/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; UL1 TR001425/TR/NCATS NIH HHS/United States ; T32 ES010957/ES/NIEHS NIH HHS/United States ; UL1 RR026314/RR/NCRR NIH HHS/United States ; UL1RR026314/RR/NCRR NIH HHS/United States ; },
mesh = {Adolescent ; Astrocytoma/diagnosis/metabolism/pathology/surgery ; Brain Neoplasms/diagnosis/*metabolism/pathology/surgery ; Brain Stem Neoplasms/diagnosis/*metabolism/pathology/surgery ; Child ; Child, Preschool ; Disease-Free Survival ; Female ; Glioma/diagnosis/*metabolism/pathology/surgery ; Humans ; Infant ; Kaplan-Meier Estimate ; Male ; Neoplasm Grading ; Prognosis ; RNA/metabolism ; RNA, Messenger/metabolism ; Retrospective Studies ; Telomerase/metabolism ; Telomere/enzymology/*metabolism ; Young Adult ; },
abstract = {Children with high-grade glioma, including diffuse intrinsic pontine glioma (DIPG), have a poor prognosis despite multimodal therapy. Identifying novel therapeutic targets is critical to improve their outcome. We evaluated prognostic roles of telomere maintenance mechanisms in children with HGG, including DIPG. A multi-institutional retrospective study was conducted involving 50 flash-frozen HGG (35 non-brainstem; 15 DIPG) tumors from 45 children (30 non-brainstem; 15 DIPG). Telomerase activity, expression of hTERT mRNA (encoding telomerase catalytic component) and TERC (telomerase RNA template) and alternative lengthening of telomeres (ALT) mechanism were assayed. Cox Proportional Hazard regression analyses assessed association of clinical and pathological variables, TERC and hTERT levels, telomerase activity, and ALT use with progression-free or overall survival (OS). High TERC and hTERT expression was detected in 13/28 non-brainstem HGG samples as compared to non-neoplastic controls. High TERC and hTERT expression was identified in 13/15 and 11/15 DIPG samples, respectively, compared to controls. Evidence of ALT was noted in 3/11 DIPG and 10/19 non-brainstem HGG specimens. ALT and telomerase use were identified in 4/19 non-brainstem HGG and 2/11 DIPG specimens. In multivariable analyses, increased TERC and hTERT levels were associated with worse OS in patients with non-brainstem HGG, after controlling for tumor grade or resection extent. Children with HGG and DIPG, have increased hTERT and TERC expression. In children with non-brainstem HGG, increased TERC and hTERT expression levels are associated with a worse OS, making telomerase a promising potential therapeutic target in pediatric HGG.},
}
@article {pmid24475279,
year = {2014},
author = {Wong, JY and De Vivo, I and Lin, X and Fang, SC and Christiani, DC},
title = {The relationship between inflammatory biomarkers and telomere length in an occupational prospective cohort study.},
journal = {PloS one},
volume = {9},
number = {1},
pages = {e87348},
pmid = {24475279},
issn = {1932-6203},
support = {P30 ES000002/ES/NIEHS NIH HHS/United States ; R01 ES009860/ES/NIEHS NIH HHS/United States ; P50ES00002/ES/NIEHS NIH HHS/United States ; R01ES009860/ES/NIEHS NIH HHS/United States ; },
mesh = {Biomarkers/*blood ; C-Reactive Protein/metabolism ; Chronic Disease ; Cohort Studies ; Humans ; Inflammation/genetics/*physiopathology ; Interleukin-10/blood ; Interleukin-1beta/blood ; Interleukin-2/blood ; Interleukin-6/blood ; Interleukin-8/blood ; Longitudinal Studies ; Occupational Diseases/genetics/*physiopathology ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; Regression Analysis ; Telomere Homeostasis/*physiology ; Tumor Necrosis Factor-alpha/blood ; Vascular Endothelial Growth Factor A/blood ; },
abstract = {BACKGROUND: Chronic inflammation from recurring trauma is an underlying pathophysiological basis of numerous diseases. Furthermore, it may result in cell death, scarring, fibrosis, and loss of tissue function. In states of inflammation, subsequent increases in oxidative stress and cellular division may lead to the accelerated erosion of telomeres, crucial genomic structures which protect chromosomes from decay. However, the association between plasma inflammatory marker concentrations and telomere length has been inconsistent in previous studies.<br><br>OBJECTIVE: The purpose of this study was to determine the longitudinal association between telomere length and plasma inflammatory biomarker concentrations including: CRP, SAA, sICAM-1, sVCAM-1, VEGF, TNF-&#x3b1;, IL-1&#x3b2;, IL-2, IL-6, IL-8, and IL-10.<br><br>METHODS: The longitudinal study population consisted of 87 subjects. The follow-up period was approximately 2 years. Plasma inflammatory biomarker concentrations were assessed using highly sensitive electrochemiluminescent assays. Leukocyte relative telomere length was assessed using Real-Time qPCR. Linear mixed effects regression models were used to analyze the association between repeated-measurements of relative telomere length as the outcome and each inflammatory biomarker concentration as continuous exposures separately. The analyses controlled for major potential confounders and white blood cell differentials.<br><br>RESULTS: At any follow-up time, each incremental ng/mL increase in plasma CRP concentration was associated with a decrease in telomere length of -2.6&#xd7;10&#x207b;&#xb2; (95%CI: -4.3&#xd7;10&#x207b;&#xb2;, -8.2&#xd7;10&#x207b;&#xb3;, p&#x200a;=&#x200a;0.004) units. Similarly, the estimate for the negative linear association between SAA and telomere length was -2.6&#xd7;10&#x207b;&#xb2; (95%CI:-4.5&#xd7;10&#x207b;&#xb2;, -6.1&#xd7;10&#x207b;&#xb3;, p&#x200a;=&#x200a;0.011). No statistically significant associations were observed between telomere length and plasma concentrations of pro-inflammatory interleukins, TNF-&#x3b1;, and VEGF.<br><br>CONCLUSIONS: Findings from this study suggest that increased systemic inflammation, consistent with vascular injury, is associated with decreased leukocyte telomere length.},
}
@article {pmid24474557,
year = {2014},
author = {Petrova, NV and Velichko, AK and Kantidze, OL and Razin, SV},
title = {Heat shock-induced dissociation of TRF2 from telomeres does not initiate a telomere-dependent DNA damage response.},
journal = {Cell biology international},
volume = {38},
number = {5},
pages = {675-681},
doi = {10.1002/cbin.10252},
pmid = {24474557},
issn = {1095-8355},
mesh = {Cell Line ; DNA Damage/*physiology ; Fibroblasts/metabolism ; Hot Temperature/*adverse effects ; Humans ; MCF-7 Cells ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {Telomeric repeat binding factor 2 (TRF2) is a well-studied shelterin complex subunit that plays a major role in the protection of chomosome ends and the prevention of the telomere-associated DNA damage response. We show that heat shock induces the dissociation of TRF2 from telomeres in human primary and cancer cell cultures. TRF2 is not simply degraded in response to heat shock, but redistributed thoughout the nucleoplasm. This TRF2 depletion/redistribution does not initiate the DNA damage response at chomosome termini.},
}
@article {pmid24472817,
year = {2014},
author = {Wang, W and Chen, H and Li, R and Ouyang, N and Chen, J and Huang, L and Mai, M and Zhang, N and Zhang, Q and Yang, D},
title = {Telomerase activity is more significant for predicting the outcome of IVF treatment than telomere length in granulosa cells.},
journal = {Reproduction (Cambridge, England)},
volume = {147},
number = {5},
pages = {649-657},
doi = {10.1530/REP-13-0223},
pmid = {24472817},
issn = {1741-7899},
mesh = {Adult ; Biomarkers/blood ; Embryonic Development/physiology ; Estradiol/blood ; Female ; *Fertilization in Vitro ; Follicle Stimulating Hormone/blood ; Granulosa Cells/cytology/*physiology/ultrastructure ; Humans ; Oocytes/cytology/physiology/ultrastructure ; Predictive Value of Tests ; Pregnancy ; *Pregnancy Outcome ; Telomerase/*physiology ; Telomere/*ultrastructure ; Telomere Homeostasis/*physiology ; },
abstract = {Our previous study has demonstrated that luteinized granulosa cells (GCs) have the potential to proliferate and that the telomerase activity (TA) of luteinized GCs may predict the clinical outcomes of IVF treatment. However, in the field of telomere research, there have always been different opinions regarding the significance of TA and telomere length (TL). Thus, in the present study, we compared the effects of these two parameters on IVF treatment outcomes in the same individuals. TL did not differ significantly between the pregnant group and the non-pregnant group. The TA, number of retrieved oocytes and rate of blastocyst transfer were significantly higher in the pregnant group than in the non-pregnant group (0.8825 OD×mm, 12.75±2.20 and 34.48%, respectively, in the pregnant group vs 0.513 OD×mm, 11.60±0.93 and 14.89%, respectively, in the non-pregnant group (P<0.05)), while basal FSH level was lower in the pregnant group than in the non-pregnant group. The subjects did not differ with regard to ovarian stimulation or other clinical characteristics. A TA increase of 1 OD×mm increased the chance of becoming pregnant 4.769-fold (odds ratio: 5.769, 95% CI: 1.434-23.212, P<0.014). The areas under the receiver operating characteristic curves were 0.576 for TL and 0.674 for TA (P=0.271 and P<0. 012 respectively). The corresponding cut-off points were 4.470 for TL and 0.650 OD×mm for TA. These results demonstrate that TA is a better predictor of pregnancy outcomes following IVF treatment than TL. No other clinical parameters, including age, baseline FSH level or peak oestradiol level, distinguished between the pregnant group and the non-pregnant group as effectively as TA.},
}
@article {pmid24472138,
year = {2014},
author = {Correia-Melo, C and Hewitt, G and Passos, JF},
title = {Telomeres, oxidative stress and inflammatory factors: partners in cellular senescence?.},
journal = {Longevity &amp; healthspan},
volume = {3},
number = {1},
pages = {1},
pmid = {24472138},
issn = {2046-2395},
support = {BB/H022384/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
abstract = {Senescence, the state of irreversible cell-cycle arrest, plays paradoxical albeit important roles in vivo: it protects organisms against cancer but also contributes to age-related loss of tissue function. The DNA damage response (DDR) has a central role in cellular senescence. Not only does it contribute to the irreversible loss of replicative capacity but also to the production and secretion of reactive oxygen species (ROS), and bioactive peptides collectively known as the senescence-associated secretory phenotype (SASP). Both ROS and the SASP have been shown to impact on senescence in an autocrine as well as paracrine fashion; however, the underlying mechanisms are not well understood. In this review we describe our current understanding of cellular senescence, examine in detail the intricate pathways linking the DDR, ROS and SASP, and evaluate their impact on the stability of the senescent phenotype.},
}
@article {pmid24470704,
year = {2014},
author = {Lee, KA and Gay, C and Humphreys, J and Portillo, CJ and Pullinger, CR and Aouizerat, BE},
title = {Telomere length is associated with sleep duration but not sleep quality in adults with human immunodeficiency virus.},
journal = {Sleep},
volume = {37},
number = {1},
pages = {157-166},
pmid = {24470704},
issn = {1550-9109},
support = {P30 AI027763/AI/NIAID NIH HHS/United States ; 1UL RR024131/RR/NCRR NIH HHS/United States ; 5 R01 MH074358/MH/NIMH NIH HHS/United States ; },
mesh = {Actigraphy ; Adult ; Aged ; Aging/metabolism ; Anxiety Disorders/metabolism ; Body Mass Index ; Cellular Senescence ; Chronic Disease ; Cross-Sectional Studies ; Depression/metabolism ; Female ; HIV Infections/*metabolism/*physiopathology ; Hormones/metabolism ; Humans ; Leukocytes/metabolism ; Male ; Middle Aged ; Racial Groups ; San Francisco ; Self Report ; Sex Characteristics ; Sleep/*physiology ; Telomere/*metabolism ; Time Factors ; Wakefulness ; Young Adult ; },
abstract = {Telomere length provides an estimate of cellular aging and is influenced by oxidative stress and health behaviors such as diet and exercise. This article describes relationships between telomere length and sleep parameters that included total sleep time (TST), wake after sleep onset (WASO), and self-reported sleep quality in a sample of adults with chronic illness.<br><br>DESIGN AND PARTICIPANTS: Cross-sectional study of 283 adults (74% male, 42% Caucasian) infected with human immunodeficiency virus (HIV) while living in the San Francisco Bay area, CA, USA. Ages ranged from 22-77 y.<br><br>MEASUREMENTS AND RESULTS: TST and WASO were estimated with wrist actigraphy across 72 h; self-reported sleep quality was assessed with the Pittsburgh Sleep Quality Index. Relative telomere length (RTL) in leukocytes was estimated by quantitative polymerase chain reaction assays. Shorter RTL was associated with older age, and RTL was shorter in males than females. RTL was unrelated to HIV disease characteristics. RTL was not associated with WASO or self-reported sleep quality. Participants with at least 7 h sleep had longer RTL than those with less than 7 h, even after controlling for the effects of age, sex, race, education, body mass index, metabolic hormones (i.e., leptin, ghrelin, adiponectin, and resistin), depression and anxiety, and sleep quality.<br><br>CONCLUSION: Results suggest that sleep duration is associated with preserving telomere length in a population of human immunodeficiency virus-infected adults. Getting at least 7 hours of sleep at night may either protect telomeres from damage or restore them on a nightly basis.},
}
@article {pmid24470696,
year = {2014},
author = {Cribbet, MR and Carlisle, M and Cawthon, RM and Uchino, BN and Williams, PG and Smith, TW and Gunn, HE and Light, KC},
title = {Cellular aging and restorative processes: subjective sleep quality and duration moderate the association between age and telomere length in a sample of middle-aged and older adults.},
journal = {Sleep},
volume = {37},
number = {1},
pages = {65-70},
pmid = {24470696},
issn = {1550-9109},
support = {C06-RR11234/RR/NCRR NIH HHS/United States ; R21 AG029239/AG/NIA NIH HHS/United States ; UL1-RR025764/RR/NCRR NIH HHS/United States ; },
mesh = {Aged ; Aging/blood/genetics/*physiology ; Cellular Senescence/*physiology ; Female ; Humans ; Leukocytes, Mononuclear/cytology/pathology ; Male ; Middle Aged ; Self Report ; Sleep/*physiology ; Sleep Initiation and Maintenance Disorders/blood/genetics/*physiopathology ; Surveys and Questionnaires ; Telomere/*metabolism ; },
abstract = {STUDY OBJECTIVES: To examine whether subjective sleep quality and sleep duration moderate the association between age and telomere length (TL).<br><br>DESIGN: Participants completed a demographic and sleep quality questionnaire, followed by a blood draw.<br><br>SETTING: Social Neuroscience Laboratory.<br><br>PARTICIPANTS: One hundred fifty-four middle-aged to older adults (age 45-77 y) participated. Participants were excluded if they were on immunosuppressive treatment and/or had a disease with a clear immunologic (e.g., cancer) component.<br><br>INTERVENTIONS: N/A.<br><br>MEASUREMENTS AND RESULTS: Subjective sleep quality and sleep duration were assessed using the Pittsburgh Sleep Quality Index (PSQI) and TL was determined using peripheral blood mononuclear cells (PBMCs). There was a significant first-order negative association between age and TL. Age was also negatively associated with the self-reported sleep quality item and sleep duration component of the PSQI. A significant age &#xd7; self-reported sleep quality interaction revealed that age was more strongly related to TL among poor sleepers, and that good sleep quality attenuated the association between age and TL. Moreover, adequate subjective sleep duration among older adults (i.e. greater than 7 h per night) was associated with TL comparable to that in middle-aged adults, whereas sleep duration was unrelated to TL for the middle-aged adults in our study.<br><br>CONCLUSIONS: The current study provides evidence for an association between sleep quality, sleep duration, and cellular aging. Among older adults, better subjective sleep quality was associated with the extent of cellular aging, suggesting that sleep duration and sleep quality may be added to a growing list of modifiable behaviors associated with the adverse effects of aging.},
}
@article {pmid24470590,
year = {2014},
author = {Chevret, E and Andrique, L and Prochazkova-Carlotti, M and Ferrer, J and Cappellen, D and Laharanne, E and Idrissi, Y and Boettiger, A and Sahraoui, W and Ruiz, F and Pham-Ledard, A and Vergier, B and Belloc, F and Dubus, P and Beylot-Barry, M and Merlio, JP},
title = {Telomerase functions beyond telomere maintenance in primary cutaneous T-cell lymphoma.},
journal = {Blood},
volume = {123},
number = {12},
pages = {1850-1859},
doi = {10.1182/blood-2013-05-500686},
pmid = {24470590},
issn = {1528-0020},
mesh = {Animals ; Case-Control Studies ; Cell Death ; Cell Line, Tumor ; Cell Proliferation ; Female ; Heterografts ; Humans ; Lymphoma, Large-Cell, Anaplastic/enzymology/genetics ; Lymphoma, T-Cell, Cutaneous/*enzymology/genetics/pathology ; Male ; Mice ; Mice, SCID ; Mycosis Fungoides/enzymology/genetics ; Neoplasm Transplantation ; RNA, Messenger/genetics/metabolism ; RNA, Neoplasm/genetics/metabolism ; Sezary Syndrome/enzymology/genetics ; Skin Neoplasms/*enzymology/genetics/pathology ; Telomerase/antagonists &amp; inhibitors/genetics/*physiology ; Telomere Homeostasis/genetics/*physiology ; },
abstract = {Telomere erosion may be counteracted by telomerase. Here we explored telomere length (TL) and telomerase activity (TA) in primary cutaneous T-cell lymphoma (CTCL) by using quantitative polymerase chain reaction and interphase quantitative fluorescence in situ hybridization assays. Samples from patients with Sézary syndrome (SS), transformed mycosis fungoides (T-MF), and cutaneous anaplastic large cell lymphoma were studied in parallel with corresponding cell lines to evaluate the relevance of TL and TA as target candidates for diagnostic and therapeutic purposes. Compared with controls, short telomeres were observed in aggressive CTCL subtypes such as SS and T-MF and were restricted to neoplastic cells in SS. While no genomic alteration of the hTERT (human telomerase catalytic subunit) locus was observed in patients' tumor cells, TA was detected. To understand the role of telomerase in CTCL, we manipulated its expression in CTCL cell lines. Telomerase inhibition rapidly impeded in vitro cell proliferation and led to cell death, while telomerase overexpression stimulated in vitro proliferation and clonogenicity properties and favored tumor development in immunodeficient mice. Our data indicate that, besides maintenance of TL, telomerase exerts additional functions in CTCL. Therefore, targeting these functions might represent an attractive therapeutic strategy, especially in aggressive CTCL.},
}
@article {pmid24469890,
year = {2014},
author = {Rana, KS and Arif, M and Hill, EJ and Aldred, S and Nagel, DA and Nevill, A and Randeva, HS and Bailey, CJ and Bellary, S and Brown, JE},
title = {Plasma irisin levels predict telomere length in healthy adults.},
journal = {Age (Dordrecht, Netherlands)},
volume = {36},
number = {2},
pages = {995-1001},
pmid = {24469890},
issn = {1574-4647},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; DNA/*genetics ; Energy Metabolism/*genetics ; Female ; Fibronectins/*blood/genetics ; Healthy Volunteers ; Humans ; Male ; Middle Aged ; Prognosis ; Real-Time Polymerase Chain Reaction ; Telomere/*genetics ; Telomere Homeostasis/*physiology ; Young Adult ; },
abstract = {The ageing process is strongly influenced by nutrient balance, such that modest calorie restriction (CR) extends lifespan in mammals. Irisin, a newly described hormone released from skeletal muscles after exercise, may induce CR-like effects by increasing adipose tissue energy expenditure. Using telomere length as a marker of ageing, this study investigates associations between body composition, plasma irisin levels and peripheral blood mononuclear cell telomere length in healthy, non-obese individuals. Segmental body composition (by bioimpedance), telomere length and plasma irisin levels were assessed in 81 healthy individuals (age 43 ± 15.8 years, BMI 24.3 ± 2.9 kg/m(2)). Data showed significant correlations between log-transformed relative telomere length and the following: age (p < 0.001), height (p = 0.045), total body fat percentage (p = 0.031), abdominal fat percentage (p = 0.038), visceral fat level (p < 0.001), plasma leptin (p = 0.029) and plasma irisin (p = 0.011), respectively. Multiple regression analysis using backward elimination revealed that relative telomere length can be predicted by age (b = -0.00735, p = 0.001) and plasma irisin levels (b = 0.04527, p = 0.021). These data support the view that irisin may have a role in the modulation of both energy balance and the ageing process.},
}
@article {pmid24469404,
year = {2014},
author = {Frescas, D and de Lange, T},
title = {TRF2-tethered TIN2 can mediate telomere protection by TPP1/POT1.},
journal = {Molecular and cellular biology},
volume = {34},
number = {7},
pages = {1349-1362},
pmid = {24469404},
issn = {1098-5549},
support = {R01 AG016642/AG/NIA NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; 5R37GM49046/GM/NIGMS NIH HHS/United States ; 5R01AG16642/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; DNA-Binding Proteins/*metabolism ; Mice ; Mutagenesis, Site-Directed ; Protein Binding ; Protein Interaction Domains and Motifs ; Recombinant Fusion Proteins/chemistry/genetics/metabolism ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere Homeostasis/genetics/physiology ; Telomere-Binding Proteins/deficiency/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/chemistry/genetics/metabolism ; Telomeric Repeat Binding Protein 2/chemistry/genetics/*metabolism ; },
abstract = {The shelterin protein TIN2 is required for the telomeric accumulation of TPP1/POT1 heterodimers and for the protection of telomeres by the POT1 proteins (POT1a and POT1b in the mouse). TIN2 also binds to TRF1 and TRF2, improving the telomeric localization of TRF2 and its function. Here, we ask whether TIN2 needs to interact with both TRF1 and TRF2 to mediate the telomere protection afforded by TRF2 and POT1a/b. Using a TIN2 allele deficient in TRF1 binding (TIN2-L247E), we demonstrate that TRF1 is required for optimal recruitment of TIN2 to telomeres and document phenotypes associated with the TIN2-L247E allele that are explained by insufficient TIN2 loading onto telomeres. To bypass the requirement for TRF1-dependent recruitment, we fused TIN2-L247E to the TRF2-interacting (RCT) domain of Rap1. The RCT-TIN2-L247E fusion showed improved telomeric localization and was fully functional in terms of chromosome end protection by TRF2, TPP1/POT1a, and TPP1/POT1b. These data indicate that when sufficient TIN2 is loaded onto telomeres, its interaction with TRF1 is not required to mediate the function of TRF2 and the TPP1/POT1 heterodimers. We therefore conclude that shelterin can protect chromosome ends as a TRF2-tethered TIN2/TPP1/POT1 complex that lacks a physical connection to TRF1.},
}
@article {pmid24469396,
year = {2014},
author = {Nakano, A and Masuda, K and Hiromoto, T and Takahashi, K and Matsumoto, Y and Habib, AG and Darwish, AG and Yukawa, M and Tsuchiya, E and Ueno, M},
title = {Rad51-dependent aberrant chromosome structures at telomeres and ribosomal DNA activate the spindle assembly checkpoint.},
journal = {Molecular and cellular biology},
volume = {34},
number = {8},
pages = {1389-1397},
pmid = {24469396},
issn = {1098-5549},
mesh = {Animals ; Cell Cycle Proteins/genetics ; Chromosome Segregation/genetics ; Chromosomes, Fungal/genetics ; DNA Repair/genetics ; DNA, Ribosomal/*genetics ; Genes, cdc/*genetics ; Kinetochores/metabolism ; M Phase Cell Cycle Checkpoints/genetics ; Mitosis/genetics/physiology ; Mutation/genetics ; Rad51 Recombinase/*genetics ; Schizosaccharomyces/*genetics ; Schizosaccharomyces pombe Proteins/*genetics/metabolism ; Spindle Apparatus/*genetics ; Telomere/*genetics ; },
abstract = {The spindle assembly checkpoint (SAC) monitors defects in kinetochore-microtubule attachment or lack of tension at kinetochores and arrests cells at prometaphase. In fission yeast, the double mutant between pot1Δ and the helicase-dead point mutant of the RecQ helicase Rqh1 gene (rqh1-hd) accumulates Rad51-dependent recombination intermediates at telomeres and enters mitosis with those intermediates. Here, we found that SAC-dependent prometaphase arrest occurred more frequently in pot1Δ rqh1-hd double mutants than in rqh1-hd single mutants. SAC-dependent prometaphase arrest also occurred more frequently in rqh1-hd single mutants after cells were released from DNA replication block compared to the rqh1-hd single mutant in the absence of exogenous insult to the DNA. In both cases, Mad2 foci persisted longer than usual at kinetochores, suggesting a defect in kinetochore-microtubule attachment. In pot1Δ rqh1-hd double mutants and rqh1-hd single mutants released from DNA replication block, SAC-dependent prometaphase arrest was suppressed by the removal of the recombination or replication intermediates. Our results indicate that the accumulation of recombination or replication intermediates induces SAC-dependent prometaphase arrest, possibly by affecting kinetochore-microtubule attachment.},
}
@article {pmid24468621,
year = {2014},
author = {Angrisani, A and Vicidomini, R and Turano, M and Furia, M},
title = {Human dyskerin: beyond telomeres.},
journal = {Biological chemistry},
volume = {395},
number = {6},
pages = {593-610},
doi = {10.1515/hsz-2013-0287},
pmid = {24468621},
issn = {1437-4315},
mesh = {Cell Cycle Proteins/genetics/*metabolism ; Dyskeratosis Congenita/genetics/*metabolism ; Humans ; Nuclear Proteins/genetics/*metabolism ; Ribonucleoproteins, Small Nucleolar/*metabolism ; Telomere ; },
abstract = {Human dyskerin is an evolutively conserved protein that participates in diverse nuclear complexes: the H/ACA snoRNPs, that control ribosome biogenesis, RNA pseudouridylation, and stability of H/ACA snoRNAs; the scaRNPs, that control pseudouridylation of snRNAs; and the telomerase active holoenzyme, which safeguards telomere integrity. The biological importance of dyskerin is further outlined by the fact that its deficiency causes the X-linked dyskeratosis congenita disease, while its over-expression characterizes several types of cancers and has been proposed as prognostic marker. The role of dyskerin in telomere maintenance has widely been discussed, while its functions as H/ACA sno/scaRNP component has been so far mostly overlooked and represent the main goal of this review. Here we summarize how increasing evidence indicates that the snoRNA/microRNA pathways can be interlaced, and that dyskerin-dependent RNA pseudouridylation represents a flexible mechanism able to modulate RNA function in different ways, including modulation of splicing, change of mRNA coding properties, and selective regulation of IRES-dependent translation. We also propose a speculative model that suggests that the dynamics of pre-assembly and nuclear import of H/ACA RNPs are crucial regulatory steps that can be finely controlled in the cytoplasm in response to developmental, differentiative and stress stimuli.},
}
@article {pmid24466378,
year = {2013},
author = {Klewes, L and Vallente, R and Dupas, E and Brand, C and Grün, D and Guffei, A and Sathitruangsak, C and Awe, JA and Kuzyk, A and Lichtensztejn, D and Tammur, P and Ilus, T and Tamm, A and Punab, M and Rubinger, M and Olujohungbe, A and Mai, S},
title = {Three-dimensional Nuclear Telomere Organization in Multiple Myeloma.},
journal = {Translational oncology},
volume = {6},
number = {6},
pages = {749-756},
pmid = {24466378},
issn = {1936-5233},
abstract = {Multiple myeloma (MM) is preceded by monoclonal gammopathy of undetermined significance (MGUS). Up to date, it is difficult to predict an individual's time to disease progression and the treatment response. To examine whether the nuclear telomeric architecture will unravel some of these questions, we carried out. Three-dimensional (3D) telomere analysis on samples from patients diagnosed with MGUS and MM, as well as from patients who went into relapse. Telomere signal intensity, number of telomere aggregates, nuclear volume, and the overall nuclear telomere distribution (a/c ratio) were analyzed. The telomeric profiles allowed for the differentiation of the disease stages. The telomeric profiles of myeloma cells obtained from blood and bone marrow aspirates were identical. Based on this study, we discuss the use of 3D telomere profiling as a potential future tool for risk stratification and personalized treatment decisions.},
}
@article {pmid24465970,
year = {2014},
author = {Amiard, S and Da Ines, O and Gallego, ME and White, CI},
title = {Responses to telomere erosion in plants.},
journal = {PloS one},
volume = {9},
number = {1},
pages = {e86220},
pmid = {24465970},
issn = {1932-6203},
mesh = {Arabidopsis/*genetics/*metabolism ; Arabidopsis Proteins/*genetics/metabolism ; Chromosomes, Plant/genetics/metabolism ; DNA Damage/*genetics ; Genomic Instability/genetics ; Telomerase/genetics/metabolism ; Telomere/*genetics/*metabolism ; Transcriptome/genetics ; },
abstract = {In striking contrast to animals, plants are able to develop and reproduce in the presence of significant levels of genome damage. This is seen clearly in both the viability of plants carrying knockouts for key recombination and DNA repair genes, which are lethal in vertebrates, and in the impact of telomere dysfunction. Telomerase knockout mice show accelerated ageing and severe developmental phenotypes, with effects on both highly proliferative and on more quiescent tissues, while cell death in Arabidopsis tert mutants is mostly restricted to actively dividing meristematic cells. Through phenotypic and whole-transcriptome RNAseq studies, we present here an analysis of the response of Arabidopsis plants to the continued presence of telomere damage. Comparison of second-generation and seventh-generation tert mutant plants has permitted separation of the effects of the absence of the telomerase enzyme and the ensuing chromosome damage. In addition to identifying a large number of genes affected by telomere damage, many of which are of unknown function, the striking conclusion of this study is the clear difference observed at both cellular and transcriptome levels between the ways in which mammals and plants respond to chronic telomeric damage.},
}
@article {pmid24465936,
year = {2014},
author = {Xu, J and Ye, J and Wu, Y and Zhang, H and Luo, Q and Han, C and Ye, X and Wang, H and He, J and Huang, H and Liu, Y and Dong, M},
title = {Reduced fetal telomere length in gestational diabetes.},
journal = {PloS one},
volume = {9},
number = {1},
pages = {e86161},
pmid = {24465936},
issn = {1932-6203},
mesh = {Adult ; Diabetes, Gestational/*metabolism ; Female ; Fetus/*metabolism ; Humans ; Hypertension, Pregnancy-Induced/metabolism ; Leukocytes/metabolism ; Male ; Pre-Eclampsia/metabolism ; Pregnancy ; *Telomere Shortening ; },
abstract = {Gestational diabetes mellitus (GDM) is an important complication of pregnancy that poses significant threats to women and their offspring. Telomere length shortens as cellular damage increases and is associated with metabolic diseases. Telomere length in fetal leucocytes was determined in 82 infants of women with GDM (N = 82) and 65 normal pregnant women (N = 65). Women with preeclampsia (N = 45) and gestational hypertension (N = 23) were also studied. In the GDM group, telomere length was significantly shorter than normal pregnancy (P = 0.028), but there were no significant differences in fetal telomere length between preeclampsia and normal pregnancy (P = 0.841) and between gestational hypertension and normal pregnancy (P = 0.561). Regression analysis revealed that fetal telomere length was significantly associated with intrauterine exposure to GDM (P = 0.027 after adjustment for maternal age, gestational age at delivery, birth weight and fetal gender). Shortened telomere length may increase the risk of metabolic diseases in adulthood of GDM offspring.},
}
@article {pmid24465473,
year = {2014},
author = {Liu, Y and Cao, L and Li, Z and Zhou, D and Liu, W and Shen, Q and Wu, Y and Zhang, D and Hu, X and Wang, T and Ye, J and Weng, X and Zhang, H and Zhang, D and Zhang, Z and Liu, F and He, L and Shi, Y},
title = {A genome-wide association study identifies a locus on TERT for mean telomere length in Han Chinese.},
journal = {PloS one},
volume = {9},
number = {1},
pages = {e85043},
pmid = {24465473},
issn = {1932-6203},
mesh = {Age Factors ; Alleles ; *Asian People ; Chromosomes, Human, Pair 5/chemistry ; *Genetic Loci ; Genome-Wide Association Study ; Humans ; Keratins/genetics ; Leukocytes/cytology/metabolism ; Telomerase/*genetics ; *Telomere ; *Telomere Homeostasis ; White People ; },
abstract = {Leukocyte telomere length (LTL) is a predictor of aging and a number of age-related diseases. We performed genome-wide association studies of mean LTL in 2632 individuals,with a two-stage replication in 3917 individuals from Chinese populations. To further validate our findings, we get the results of 696 samples from a cohort of European ancestry. We identified two loci associated with LTL that map in telomerase reverse transcriptase (TERT; rs2736100, P = 1.93×10(-5)) on chromosome 5p15.33 and near keratin 80 (KRT80; rs17653722, P = 6.96×10(-6)) on 12q13.13. In Chinese population each C allele of rs2736100 and T allele of rs17653722 was associated with a longer mean telomere length of 0.026 and 0.059 T/S, respectively, equivalent to about 3 and 7 years of average age-related telomere attrition. Our findings provide new insights into telomere regulatory mechanism and even pathogenesis of age-related diseases.},
}
@article {pmid24462487,
year = {2014},
author = {Buss, J and Havel, PJ and Epel, E and Lin, J and Blackburn, E and Daubenmier, J},
title = {Associations of ghrelin with eating behaviors, stress, metabolic factors, and telomere length among overweight and obese women: preliminary evidence of attenuated ghrelin effects in obesity?.},
journal = {Appetite},
volume = {76},
number = {},
pages = {84-94},
pmid = {24462487},
issn = {1095-8304},
support = {U24 DK092993/DK/NIDDK NIH HHS/United States ; DK-095980/DK/NIDDK NIH HHS/United States ; HL-091333/HL/NHLBI NIH HHS/United States ; U24DK092993/DK/NIDDK NIH HHS/United States ; HL-107256/HL/NHLBI NIH HHS/United States ; K01 AT004199/AT/NCCIH NIH HHS/United States ; K01AT004199/AT/NCCIH NIH HHS/United States ; TL1 TR000144/TR/NCATS NIH HHS/United States ; R01 HL107256/HL/NHLBI NIH HHS/United States ; R01 HL091333/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Cross-Sectional Studies ; Diet Records ; Energy Intake ; Feeding Behavior/*physiology ; Female ; Ghrelin/*blood ; Humans ; Insulin Resistance ; Middle Aged ; Obesity/*blood ; Overweight/*blood ; Randomized Controlled Trials as Topic ; *Stress, Psychological ; Telomere/*metabolism ; },
abstract = {Ghrelin regulates homeostatic food intake, hedonic eating, and is a mediator in the stress response. In addition, ghrelin has metabolic, cardiovascular, and anti-aging effects. This cross-sectional study examined associations between total plasma ghrelin, caloric intake based on 3day diet diaries, hedonic eating attitudes, stress-related and metabolic factors, and leukocyte telomere length in overweight (n=25) and obese women (n=22). We hypothesized associations between total plasma ghrelin and eating behaviors, stress, metabolic, cardiovascular, and cell aging factors among overweight women, but not among obese women due to lower circulating ghrelin levels and/or central resistance to ghrelin. Confirming previous studies demonstrating lowered plasma ghrelin in obesity, ghrelin levels were lower in the obese compared with overweight women. Among the overweight, ghrelin was positively correlated with caloric intake, giving in to cravings for highly palatable foods, and a flatter diurnal cortisol slope across 3days. These relationships were non-significant among the obese group. Among overweight women, ghrelin was negatively correlated with insulin resistance, systolic blood pressure, and heart rate, and positively correlated with telomere length. Among the obese subjects, plasma ghrelin concentrations were negatively correlated with insulin resistance, but were not significantly correlated with blood pressure, heart rate or telomere length. Total plasma ghrelin and its associations with food intake, hedonic eating, and stress are decreased in obesity, providing evidence consistent with the theory that central resistance to ghrelin develops in obesity and ghrelin's function in appetite regulation may have evolved to prevent starvation in food scarcity rather than cope with modern food excess. Furthermore, ghrelin is associated with metabolic and cardiovascular health, and may have anti-aging effects, but these effects may be attenuated in obesity.},
}
@article {pmid24457340,
year = {2014},
author = {Zanet, DL and Thorne, A and Singer, J and Maan, EJ and Sattha, B and Le Campion, A and Soudeyns, H and Pick, N and Murray, M and Money, DM and Côté, HC and , },
title = {Association between short leukocyte telomere length and HIV infection in a cohort study: No evidence of a relationship with antiretroviral therapy.},
journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America},
volume = {58},
number = {9},
pages = {1322-1332},
doi = {10.1093/cid/ciu051},
pmid = {24457340},
issn = {1537-6591},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Adult ; Aged ; Anti-HIV Agents/*therapeutic use ; Biomarkers ; Cellular Senescence ; Cohort Studies ; Female ; HIV Infections/complications/drug therapy/*genetics ; Humans ; *Leukocytes ; Male ; Middle Aged ; Multivariate Analysis ; Regression Analysis ; Telomere/*chemistry ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Individuals infected with human immunodeficiency virus (HIV) appear to age faster than the general population, possibly related to HIV infection, antiretroviral therapy, and/or social/environmental factors. We evaluated leukocyte telomere length (LTL), a marker of cellular aging, in HIV-infected and uninfected adults.<br><br>METHODS: Clinical data and blood were collected from Children and women: AntiRetrovirals and the Mechanism of Aging (CARMA) cohort study participants. Variables found to be important in univariate analysis were multivariate model candidates.<br><br>RESULTS: Of the 229 HIV-infected and 166 HIV-uninfected participants, 76% were women, and 71% were current/previous smokers. In a multivariate model of all participants, older age (P < .001), HIV infection (P = .04), active hepatitis C virus (HCV) infection (P = .02), and smoking (P < .003) were associated with shorter LTL. An interaction was detected, whereby smoking was associated with shorter LTL in HIV-uninfected subjects only. Among those, age and smoking (P &#x2264; .01) were related to shorter LTL. In 2 models of HIV-infected individuals, age (P &#x2264; .002) and either active HCV infection (P = .05) or peak HIV RNA &#x2265;100 000 copies/mL (P = .04) were associated with shorter LTL, whereas other HIV disease or treatment parameters were unrelated.<br><br>CONCLUSIONS: Our results suggest that acquisition of HIV and viral load are primarily responsible for the association between HIV-positive status and shorter LTL. The lack of association between LTL and time since HIV diagnosis, antiretroviral treatment, or degree of immune suppression would implicate HIV infection-related factors rather than disease progression or treatment. Smoking effects on LTL appear masked by HIV, and HCV infection may accelerate LTL shortening, particularly in coinfected individuals. The effect of early therapeutic intervention on LTL in HIV and HCV infections should be evaluated.},
}
@article {pmid24455708,
year = {2013},
author = {Ludlow, AT and Ludlow, LW and Roth, SM},
title = {Do telomeres adapt to physiological stress? Exploring the effect of exercise on telomere length and telomere-related proteins.},
journal = {BioMed research international},
volume = {2013},
number = {},
pages = {601368},
pmid = {24455708},
issn = {2314-6141},
support = {CA12433404/CA/NCI NIH HHS/United States ; },
mesh = {Aging/genetics/pathology ; Alzheimer Disease/*genetics/therapy ; Cardiovascular Diseases/*genetics/therapy ; Exercise ; Humans ; Stress, Physiological ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Aging is associated with a tissue degeneration phenotype marked by a loss of tissue regenerative capacity. Regenerative capacity is dictated by environmental and genetic factors that govern the balance between damage and repair. The age-associated changes in the ability of tissues to replace lost or damaged cells is partly the cause of many age-related diseases such as Alzheimer's disease, cardiovascular disease, type II diabetes, and sarcopenia. A well-established marker of the aging process is the length of the protective cap at the ends of chromosomes, called telomeres. Telomeres shorten with each cell division and with increasing chronological age and short telomeres have been associated with a range of age-related diseases. Several studies have shown that chronic exposure to exercise (i.e., exercise training) is associated with telomere length maintenance; however, recent evidence points out several controversial issues concerning tissue-specific telomere length responses. The goals of the review are to familiarize the reader with the current telomere dogma, review the literature exploring the interactions of exercise with telomere phenotypes, discuss the mechanistic research relating telomere dynamics to exercise stimuli, and finally propose future directions for work related to telomeres and physiological stress.},
}
@article {pmid24453794,
year = {2013},
author = {Gutmajster, E and Witecka, J and Wyskida, M and Koscinska-Marczewska, J and Szwed, M and Owczarz, M and Mossakowska, M and Milewicz, A and Puzianowska-Kuznicka, M and Zejda, J and Wiecek, A and Chudek, J and Sieron, AL},
title = {Telomere length in elderly Caucasians weakly correlates with blood cell counts.},
journal = {TheScientificWorldJournal},
volume = {2013},
number = {},
pages = {153608},
pmid = {24453794},
issn = {1537-744X},
mesh = {Aged ; Aging/*blood ; DNA/genetics ; Female ; Hematopoiesis ; Humans ; *Leukocyte Count ; Leukocytes/*cytology ; Leukocytes, Mononuclear/cytology ; Male ; Poland ; Regression Analysis ; Surveys and Questionnaires ; Telomere/*ultrastructure ; White People ; },
abstract = {BACKGROUND: Age-related decrease in bone marrow erythropoietic capacity is often accompanied by the telomere length shortening in peripheral white blood cells. However, limited and conflicting data hamper the conclusive opinion regarding this relationship. Therefore, the aim of this study was to assess an association between telomere length and peripheral blood cell count parameters in the Polish elderly population.<br><br>MATERIAL AND METHODS: The substudy included 1573 of 4981 subjects aged 65 years or over, participants of the population-based PolSenior study. High-molecular-weight DNA was isolated from blood mononuclear cells. Telomere length (TL) was measured by QRT-PCR as abundance of telomere template versus a single gene copy encoding acidic ribosomal phosphoprotein P0.<br><br>RESULTS: Only white blood count (WBC) was significantly different in TL tertile subgroups in all subjects (P = 0.02) and in men (P = 0.01), but not in women. Merely in men significant but weak positive correlations were found between TL and WBC (r = 0.11, P < 0.05) and RBC (r = 0.08, P < 0.05). The multiple regression analysis models confirmed a weak, independent contribution of TL to both RBC and WBC.<br><br>CONCLUSIONS: In the elderly, telomere shortening limits hematopoiesis capacity to a very limited extent.},
}
@article {pmid24450811,
year = {2014},
author = {Carbonari, M and Tedesco, T and Fiorilli, M},
title = {Correlation between terminal restriction fragments and flow-FISH measures in samples over wide range telomere lengths.},
journal = {Cell proliferation},
volume = {47},
number = {1},
pages = {20-27},
pmid = {24450811},
issn = {1365-2184},
mesh = {B-Lymphocytes/*cytology ; Burkitt Lymphoma ; Cell Line, Tumor ; Chromosomes/genetics ; DNA Fragmentation ; DNA Probes/genetics ; Flow Cytometry ; Formamides ; Humans ; In Situ Hybridization, Fluorescence/*methods ; *Polymorphism, Restriction Fragment Length ; Telomere/*genetics ; },
abstract = {OBJECTIVES: Terminal restriction fragment (TRF) analysis of human telomeres was used to calibrate flow-fluorescence in situ hybridization (FF) measures of telomere lengths to expand the range of measures and increase power of resolution of our previously published protocol. TRF data used as the gold standard should be obtained by electrophoresis with suitable resolution applied to appropriately isolated genomic DNA. When we considered TRF attained by correct methods, we found our method to be insufficiently accurate, thus we have reviewed our previously published FF protocol to obtain the best coefficient of determination (r(2)) between our experimental results and valid TRF lengths.<br><br>MATERIALS AND METHODS: Using human telomere-specific PNA probe, Cy5-OO-(CCCTAA)3 , we measured telomere lengths of continuous cell line and of peripheral blood lymphocytes by FF. We modified hybridization, stringency, negative control handling, stoichiometric DNA staining and telomere fluorescence assessment of the protocol.<br><br>RESULTS: We realized a procedure with increased power of resolution, improved TRF versus FF r(2) values that allowed simultaneous analysis of DNA and telomere duplication. Notwithstanding multiple steps in formamide sampling, recovery was satisfactory.<br><br>DISCUSSION: The reviewed FF protocol appeared at least as suitable as the TRF method. Measures obtained by TRF can be affected by chromosome end variability, DNA fragmentation, incomplete digestion and unsuitable electrophoresis. In contrast, the FF technique analyses telomeric sequences confined to preserved nuclei thus overcome most previous limitations. As yet, however, the FF telomere measure cannot be performed together with immunophenotyping and/or generation study by the dye dilution method.},
}
@article {pmid24449270,
year = {2014},
author = {Frescas, D and de Lange, T},
title = {A TIN2 dyskeratosis congenita mutation causes telomerase-independent telomere shortening in mice.},
journal = {Genes &amp; development},
volume = {28},
number = {2},
pages = {153-166},
pmid = {24449270},
issn = {1549-5477},
support = {R01 AG016642/AG/NIA NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; 5R37GM49046/GM/NIGMS NIH HHS/United States ; 5R01AG16642/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Cell Line, Tumor ; Disease Models, Animal ; Dyskeratosis Congenita/genetics ; Fertility/genetics ; Gene Knock-In Techniques ; HeLa Cells ; Humans ; Mice ; Mutation ; Pancytopenia/genetics ; Signal Transduction ; Telomerase/metabolism ; Telomere/pathology ; Telomere Shortening/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {The progressive bone marrow failure syndrome dyskeratosis congenita (DC) is often caused by mutations in telomerase or the factors involved in telomerase biogenesis and trafficking. However, a subset of DC patients is heterozygous for mutations in the shelterin component TIN2. To determine how the TIN2-DC mutations affect telomere function, we generated mice with the equivalent of the TIN2 K280E DC allele (TIN2(DC)) by gene targeting. Whereas homozygous TIN2(DC/DC) mice were not viable, first-generation TIN2(+/DC) mice were healthy and fertile. In the second and third generations, the TIN2(+/DC) mice developed mild pancytopenia, consistent with hematopoietic dysfunction in DC, as well as diminished fecundity. Bone marrow telomeres of TIN2(+/DC) mice shortened over the generations, and immortalized TIN2(+/DC) mouse embryonic fibroblasts (MEFs) showed telomere shortening with proliferation. Unexpectedly, telomere shortening was accelerated in TIN2(+/DC) mTR(-/-) mice and MEFs compared with TIN2(+/+) mTR(-/-) controls, establishing that the TIN2(DC) telomere maintenance defect was not solely due to diminished telomerase action. The TIN2(DC) allele induced mild ATR kinase signaling at telomeres and a fragile telomere phenotype, suggestive of telomere replication problems. These data suggest that this TIN2-DC mutation could induce telomeric dysfunction phenotypes in telomerase-negative somatic cells and tissues that further exacerbate the telomere maintenance problems in telomerase-positive stem cell compartments.},
}
@article {pmid24442241,
year = {2014},
author = {Martín, GM and King, DA and Green, EM and Garcia-Nieto, PE and Alexander, R and Collins, SR and Krogan, NJ and Gozani, OP and Morrison, AJ},
title = {Set5 and Set1 cooperate to repress gene expression at telomeres and retrotransposons.},
journal = {Epigenetics},
volume = {9},
number = {4},
pages = {513-522},
pmid = {24442241},
issn = {1559-2308},
support = {R00 GM085212/GM/NIGMS NIH HHS/United States ; R01 CA172560/CA/NCI NIH HHS/United States ; T32 CA009302/CA/NCI NIH HHS/United States ; R00GM085212/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatin/metabolism ; Gene Expression ; Histone-Lysine N-Methyltransferase/genetics/*metabolism ; *Retroelements ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {A complex interplay between multiple chromatin modifiers is critical for cells to regulate chromatin structure and accessibility during essential DNA-templated processes such as transcription. However, the coordinated activities of these chromatin modifiers in the regulation of gene expression are not fully understood. We previously determined that the budding yeast histone H4 methyltransferase Set5 functions together with Set1, the H3K4 methyltransferase, in specific cellular contexts. Here, we sought to understand the relationship between these evolutionarily conserved enzymes in the regulation of gene expression. We generated a comprehensive genetic interaction map of the functionally uncharacterized Set5 methyltransferase and expanded the existing genetic interactome of the global chromatin modifier Set1, revealing functional overlap of the two enzymes in chromatin-related networks, such as transcription. Furthermore, gene expression profiling via RNA-Seq revealed an unexpected synergistic role of Set1 and Set5 in repressing transcription of Ty transposable elements and genes located in subtelomeric regions. This study uncovers novel pathways in which the methyltransferase Set5 participates and, more importantly, reveals a partnership between Set1 and Set5 in transcriptional repression near repetitive DNA elements in budding yeast. Together, our results define a new functional relationship between histone H3 and H4 methyltransferases, whose combined activity may be implicated in preserving genomic integrity.},
}
@article {pmid24439343,
year = {2014},
author = {Chae, DH and Nuru-Jeter, AM and Adler, NE and Brody, GH and Lin, J and Blackburn, EH and Epel, ES},
title = {Discrimination, racial bias, and telomere length in African-American men.},
journal = {American journal of preventive medicine},
volume = {46},
number = {2},
pages = {103-111},
pmid = {24439343},
issn = {1873-2607},
support = {K01 AG041787/AG/NIA NIH HHS/United States ; K01AG041787/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Black or African American/ethnology/genetics/*psychology ; Aging/genetics/*physiology/psychology ; Cross-Sectional Studies ; Humans ; Leukocytes/physiology ; Male ; Middle Aged ; *Racism ; *Telomere Homeostasis/genetics ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) is an indicator of general systemic aging, with shorter LTL being associated with several chronic diseases of aging and earlier mortality. Identifying factors related to LTL among African Americans may yield insights into mechanisms underlying racial disparities in health.<br><br>PURPOSE: To test whether the combination of more frequent reports of racial discrimination and holding a greater implicit anti-black racial bias is associated with shorter LTL among African-American men.<br><br>METHODS: Cross-sectional study of a community sample of 92 African-American men aged between 30 and 50 years. Participants were recruited from February to May 2010. Ordinary least squares regressions were used to examine LTL in kilobase pairs in relation to racial discrimination and implicit racial bias. Data analysis was completed in July 2013.<br><br>RESULTS: After controlling for chronologic age and socioeconomic and health-related characteristics, the interaction between racial discrimination and implicit racial bias was significantly associated with LTL (b=-0.10, SE=0.04, p=0.02). Those demonstrating a stronger implicit anti-black bias and reporting higher levels of racial discrimination had the shortest LTL. Household income-to-poverty threshold ratio was also associated with LTL (b=0.05, SE=0.02, p<0.01).<br><br>CONCLUSIONS: Results suggest that multiple levels of racism, including interpersonal experiences of racial discrimination and the internalization of negative racial bias, operate jointly to accelerate biological aging among African-American men. Societal efforts to address racial discrimination in concert with efforts to promote positive in-group racial attitudes may protect against premature biological aging in this population.},
}
@article {pmid24429681,
year = {2014},
author = {Schultner, J and Moe, B and Chastel, O and Bech, C and Kitaysky, AS},
title = {Migration and stress during reproduction govern telomere dynamics in a seabird.},
journal = {Biology letters},
volume = {10},
number = {1},
pages = {20130889},
pmid = {24429681},
issn = {1744-957X},
mesh = {*Animal Migration ; Animals ; Birds/genetics/*physiology ; *Reproduction ; *Stress, Physiological ; *Telomere ; },
abstract = {Changes in telomere length are believed to reflect changes in physiological state and life expectancy in animals. However, much remains unknown about the determinants of telomere dynamics in wild populations, and specifically the influence of conditions during highly mobile life-history stages, for example migration. We tested whether telomere dynamics were associated with migratory behaviour and/or with stress during reproduction in free-living seabirds. We induced short-term stress during reproduction in chick-rearing, black-legged kittiwakes (Rissa tridactyla), tracked winter migration with geolocators and measured telomere length before and after winter migration. We found that time spent at wintering grounds correlated with reduced telomere loss, while stress during reproduction accelerated telomere shortening. Our results suggest that different life-history stages interact to influence telomere length, and that migratory patterns may be important determinants of variation in an individual's telomere dynamics.},
}
@article {pmid24428184,
year = {2014},
author = {Sen, A and Marsche, G and Freudenberger, P and Schallert, M and Toeglhofer, AM and Nagl, C and Schmidt, R and Launer, LJ and Schmidt, H},
title = {Association between higher plasma lutein, zeaxanthin, and vitamin C concentrations and longer telomere length: results of the Austrian Stroke Prevention Study.},
journal = {Journal of the American Geriatrics Society},
volume = {62},
number = {2},
pages = {222-229},
pmid = {24428184},
issn = {1532-5415},
support = {P 20545/FWF_/Austrian Science Fund FWF/Austria ; /ImNIH/Intramural NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*physiology ; Antioxidants/metabolism/pharmacokinetics ; Ascorbic Acid/*blood/therapeutic use ; Austria/epidemiology ; Chromatography, High Pressure Liquid ; Cross-Sectional Studies ; DNA/analysis ; Female ; Follow-Up Studies ; Humans ; Incidence ; Leukocytes/*metabolism ; Lutein/*blood/therapeutic use ; Male ; Middle Aged ; Oxidative Stress ; Real-Time Polymerase Chain Reaction ; Retrospective Studies ; Spectrophotometry ; Stroke/blood/epidemiology/*prevention &amp; control ; Telomere Homeostasis/*physiology ; Xanthophylls/*blood/therapeutic use ; Zeaxanthins ; },
abstract = {OBJECTIVES: To examine the association between plasma concentrations of antioxidative micronutrients and leukocyte telomere length (LTL) in elderly adults.<br><br>DESIGN: Cross-sectional cohort study.<br><br>SETTING: Austrian Stroke Prevention Study, a population-based cohort study on brain aging.<br><br>PARTICIPANTS: Individuals with a mean age of 66 &#xb1; 7 (n = 786; 58% female).<br><br>MEASUREMENTS: Concentrations of vitamin C, lutein, zeaxanthin, &#x3b2;-cryptoxanthin, canthaxanthin, lycopene, &#x3b1;- and &#x3b3;-tocopherol, &#x3b1;- and &#x3b2;-carotene, and retinol in plasma, advanced oxidation protein products as a measure of oxidative stress in serum, and LTL were measured. Vitamins and carotenoids were measured using high-performance liquid chromatography, advanced oxidation protein products using spectrophotometry, and telomere length using quantitative real-time polymerase chain reaction.<br><br>RESULTS: Multiple linear regression analyses with adjustment for age and sex demonstrated that higher lutein, zeaxanthin, and vitamin C concentrations were strongly associated with longer telomere length. The associations were independent of body mass index, maximum oxygen uptake, and vascular risk factors and were not mediated by advanced oxidation protein products content.<br><br>CONCLUSION: This study provides first evidence that higher lutein, zeaxanthin, and vitamin C concentrations in plasma are associated with longer LTL in normal elderly persons and suggest a protective role of these vitamins in telomere maintenance.},
}
@article {pmid24425829,
year = {2014},
author = {Deelen, J and Beekman, M and Codd, V and Trompet, S and Broer, L and Hägg, S and Fischer, K and Thijssen, PE and Suchiman, HE and Postmus, I and Uitterlinden, AG and Hofman, A and de Craen, AJ and Metspalu, A and Pedersen, NL and van Duijn, CM and Jukema, JW and Houwing-Duistermaat, JJ and Samani, NJ and Slagboom, PE},
title = {Leukocyte telomere length associates with prospective mortality independent of immune-related parameters and known genetic markers.},
journal = {International journal of epidemiology},
volume = {43},
number = {3},
pages = {878-886},
pmid = {24425829},
issn = {1464-3685},
support = {AG04563/AG/NIA NIH HHS/United States ; //British Heart Foundation/United Kingdom ; AG10175/AG/NIA NIH HHS/United States ; AG028555/AG/NIA NIH HHS/United States ; AG08861/AG/NIA NIH HHS/United States ; AG08724/AG/NIA NIH HHS/United States ; DK U01-066134/DK/NIDDK NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*immunology ; Biomarkers ; *Family ; Female ; Health Status ; Humans ; Immunoproteins/analysis ; Inflammation Mediators/blood ; Leukocytes/*immunology ; Longevity/*immunology ; Male ; Middle Aged ; Prospective Studies ; Telomere/*immunology ; },
abstract = {BACKGROUND: Human leukocyte telomere length (LTL) decreases with age and shorter LTL has previously been associated with increased prospective mortality. However, it is not clear whether LTL merely marks the health status of an individual by its association with parameters of immune function, for example, or whether telomere shortening also contributes causally to lifespan variation in humans.<br><br>METHODS: We measured LTL in 870 nonagenarian siblings (mean age 93 years), 1580 of their offspring and 725 spouses thereof (mean age 59 years) from the Leiden Longevity Study (LLS).<br><br>RESULTS: We found that shorter LTL is associated with increased prospective mortality in middle (30-80 years; hazard ratio (HR)=0.75, P=0.001) and highly advanced age (&#x2265;90 years; HR=0.92, P=0.028), and show that this association cannot be explained by the association of LTL with the immune-related markers insulin-like growth factor 1 to insulin-like growth factor binding protein 3 molar ratio, C-reactive protein, interleukin 6, cytomegalovirus serostatus or white blood cell counts. We found no difference in LTL between the middle-aged LLS offspring and their spouses (&#x3b2;=0.006, P=0.932). Neither did we observe an association of LTL-associated genetic variants with mortality in a prospective meta-analysis of multiple cohorts (n=8165).<br><br>CONCLUSIONS: We confirm LTL to be a marker of prospective mortality in middle and highly advanced age and additionally show that this association could not be explained by the association of LTL with various immune-related markers. Furthermore, the approaches performed here do not further support the hypothesis that LTL variation contributes to the genetic propensity for longevity.},
}
@article {pmid24419143,
year = {2014},
author = {Postepska-Igielska, A and Grummt, I},
title = {NoRC silences rRNA genes, telomeres, and centromeres.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {13},
number = {4},
pages = {493-494},
doi = {10.4161/cc.27783},
pmid = {24419143},
issn = {1551-4005},
mesh = {Centromere/*metabolism ; *Chromatin Assembly and Disassembly ; *Genes, rRNA ; Heterochromatin/*genetics ; Humans ; *Mitosis ; Telomere/*metabolism ; },
}
@article {pmid24419039,
year = {2014},
author = {Shalev, I and Moffitt, TE and Braithwaite, AW and Danese, A and Fleming, NI and Goldman-Mellor, S and Harrington, HL and Houts, RM and Israel, S and Poulton, R and Robertson, SP and Sugden, K and Williams, B and Caspi, A},
title = {Internalizing disorders and leukocyte telomere erosion: a prospective study of depression, generalized anxiety disorder and post-traumatic stress disorder.},
journal = {Molecular psychiatry},
volume = {19},
number = {11},
pages = {1163-1170},
pmid = {24419039},
issn = {1476-5578},
support = {R24 HD065563/HD/NICHD NIH HHS/United States ; R01 AG048895/AG/NIA NIH HHS/United States ; MR/K00381X/MRC_/Medical Research Council/United Kingdom ; MR/K00381X/1/MRC_/Medical Research Council/United Kingdom ; R01 AG032282/AG/NIA NIH HHS/United States ; P2C HD065563/HD/NICHD NIH HHS/United States ; AG032282/AG/NIA NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aging/genetics/physiology ; Anxiety Disorders/genetics/*physiopathology ; Child ; Depressive Disorder/genetics/*physiopathology ; Female ; Humans ; Leukocytes/*physiology ; Longitudinal Studies ; Male ; Prospective Studies ; Sex Characteristics ; Stress Disorders, Post-Traumatic/genetics/*physiopathology ; Telomere/*metabolism ; Young Adult ; },
abstract = {There is evidence that persistent psychiatric disorders lead to age-related disease and premature mortality. Telomere length has emerged as a promising biomarker in studies that test the hypothesis that internalizing psychiatric disorders are associated with accumulating cellular damage. We tested the association between the persistence of internalizing disorders (depression, generalized anxiety disorder and post-traumatic stress disorder) and leukocyte telomere length (LTL) in the prospective longitudinal Dunedin Study (n=1037). Analyses showed that the persistence of internalizing disorders across repeated assessments from ages 11 to 38 years predicted shorter LTL at age 38 years in a dose-response manner, specifically in men (β=-0.137, 95% confidence interval (CI): -0.232, -0.042, P=0.005). This association was not accounted for by alternative explanatory factors, including childhood maltreatment, tobacco smoking, substance dependence, psychiatric medication use, poor physical health or low socioeconomic status. Additional analyses using DNA from blood collected at two time points (ages 26 and 38 years) showed that LTL erosion was accelerated among men who were diagnosed with internalizing disorder in the interim (β=-0.111, 95% CI: -0.184, -0.037, P=0.003). No significant associations were found among women in any analysis, highlighting potential sex differences in internalizing-related telomere biology. These findings point to a potential mechanism linking internalizing disorders to accelerated biological aging in the first half of the life course, particularly in men. Because internalizing disorders are treatable, the findings suggest the hypothesis that treating psychiatric disorders in the first half of the life course may reduce the population burden of age-related disease and extend health expectancy.},
}
@article {pmid24418792,
year = {2014},
author = {Ludlow, AT and Spangenburg, EE and Chin, ER and Cheng, WH and Roth, SM},
title = {Telomeres shorten in response to oxidative stress in mouse skeletal muscle fibers.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {69},
number = {7},
pages = {821-830},
pmid = {24418792},
issn = {1758-535X},
support = {CA12433404/CA/NCI NIH HHS/United States ; T32 AG000268/AG/NIA NIH HHS/United States ; },
mesh = {Aging/genetics/*metabolism ; Animals ; Cells, Cultured ; DNA Damage ; Hydrogen Peroxide/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Muscle Fibers, Skeletal/drug effects/*metabolism ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Species Specificity ; Telomerase/metabolism ; *Telomere Shortening/drug effects/genetics ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Aging phenotypes are dictated by myriad cellular changes including telomere shortening. In most tissues, telomere shortening is accelerated during replication if unrepaired oxidative damage to telomere sequences is present. However, the effect of reactive oxygen species exposure on skeletal muscle telomeres is unknown. We sought to determine if oxidative stress shortens telomeres in isolated adult rodent skeletal muscle fibers. Flexor digitorum brevis muscles were dissected from male mice (C57BL/6, long telomere and CAST/Ei, wild-derived, short telomere) and dissociated into single fibers. Fibers were cultured at an oxygen tension of 2%-5% for 5 days in control, hydrogen peroxide (oxidant), or a combination of N-acetylcysteine (antioxidant) and oxidant containing media. Telomere length, telomerase enzyme activity, and protein content of TRF1 and TRF2 were subsequently measured. In both strains, oxidative stress resulted in significant telomere shortening in isolated skeletal muscle fibers, likely by different mechanisms. Telomerase activity was not altered by oxidative stress treatment but was significantly different between strains, with greater telomerase activity in long-telomere-bearing C57BL/6 mice. These results provide important insights into mechanisms by which oxidative stress could shorten skeletal muscle telomeres.},
}
@article {pmid24415760,
year = {2014},
author = {Yoo, JE and Park, YN and Oh, BK},
title = {PinX1, a telomere repeat-binding factor 1 (TRF1)-interacting protein, maintains telomere integrity by modulating TRF1 homeostasis, the process in which human telomerase reverse Transcriptase (hTERT) plays dual roles.},
journal = {The Journal of biological chemistry},
volume = {289},
number = {10},
pages = {6886-6898},
pmid = {24415760},
issn = {1083-351X},
mesh = {Cell Cycle Proteins ; HeLa Cells ; Humans ; Protein Stability ; Telomerase/genetics/*physiology ; Telomere/genetics/*physiology ; Telomere Homeostasis/genetics/*physiology ; Telomeric Repeat Binding Protein 1/chemistry/*metabolism ; Tumor Suppressor Proteins/genetics/*physiology ; },
abstract = {TRF1, a telomere-binding protein, is important for telomere protection and homeostasis. PinX1 interacts with TRF1, but the physiological consequences of their interaction in telomere protection are not yet understood. Here we investigated PinX1 function on TRF1 stability in HeLa cells. PinX1 overexpression stabilized TRF1, but PinX1 depletion by siRNA led to TRF1 degradation, TRF1 ubiquitination, and less TRF1 telomere association. The depletion also induced DNA damage responses at telomeres and chromosome instability. These telomere dysfunctional phenotypes were in fact due to TRF1 deficiency. We also report that hTERT, a catalytic component of telomerase, plays dual roles in the TRF1 steady state pathway. PinX1-mediated TRF1 stability was not observed in hTERT-negative immortal cells, but was pronounced when hTERT was ectopically expressed in the cells, suggesting that hTERT may be needed in the PinX1-mediated TRF1 stability pathway. Interestingly, the knockdown of both PinX1 and hTERT in HeLa cells stabilized TRF1, suppressed DNA damage response activation, and restored chromosome stability. In summary, our findings suggested that PinX1 may maintain telomere integrity by regulating TRF1 stability and that hTERT may act as both a positive and a negative regulator of TRF1 homeostasis in a PinX1-dependent manner.},
}
@article {pmid24413667,
year = {2014},
author = {Yamamoto, A},
title = {Gathering up meiotic telomeres: a novel function of the microtubule-organizing center.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {71},
number = {11},
pages = {2119-2134},
pmid = {24413667},
issn = {1420-9071},
mesh = {Gene Expression Regulation ; Humans ; *Meiosis ; Membrane Proteins/chemistry/genetics/metabolism ; Microtubule-Organizing Center/chemistry/*physiology ; Microtubules/chemistry/*genetics/metabolism ; Molecular Motor Proteins/chemistry/genetics/metabolism ; Nuclear Envelope/chemistry/genetics/metabolism ; Nuclear Matrix/chemistry/genetics/metabolism ; Nuclear Proteins/chemistry/genetics/metabolism ; Protein Structure, Tertiary ; Schizosaccharomyces/chemistry/*genetics/metabolism ; Telomere/chemistry/genetics/metabolism ; },
abstract = {During meiosis, telomeres cluster and promote homologous chromosome pairing. Telomere clustering depends on conserved SUN and KASH domain nuclear membrane proteins, which form a complex called the linker of nucleoskeleton and cytoskeleton (LINC) and connect telomeres with the cytoskeleton. It has been thought that LINC-mediated cytoskeletal forces induce telomere clustering. However, how cytoskeletal forces induce telomere clustering is not fully understood. Recent study of fission yeast has shown that the LINC complex forms the microtubule-organizing center (MTOC) at the telomere, which has been designated as the "telocentrosome", and that microtubule motors gather telomeres via telocentrosome-nucleated microtubules. This MTOC-dependent telomere clustering might be conserved in other eukaryotes. Furthermore, the MTOC-dependent clustering mechanism appears to function in various other biological events. This review presents an overview of the current understanding of the mechanism of meiotic telomere clustering and discusses the universality of the MTOC-dependent clustering mechanism.},
}
@article {pmid24413564,
year = {2014},
author = {Wang, J and Chen, Y and Ren, J and Zhao, C and Qu, X},
title = {G-Quadruplex binding enantiomers show chiral selective interactions with human telomere.},
journal = {Nucleic acids research},
volume = {42},
number = {6},
pages = {3792-3802},
pmid = {24413564},
issn = {1362-4962},
mesh = {Apoptosis ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cellular Senescence ; Coordination Complexes/chemistry/*pharmacology ; DNA/chemistry/metabolism ; DNA Damage ; G-Quadruplexes/*drug effects ; Humans ; Isomerism ; MCF-7 Cells ; Telomere/*drug effects/metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Chiral recognition of DNA molecules is important because DNA chiral transition and its different conformations are involved in a series of important life events. Among them, polymorphic human telomere DNA has attracted great interests in recent years because of its important roles in chromosome structural integrity. In this report, we examine the short-term effect of chiral metallo-supramolecular complex enantiomers treatment on tumor cells, and find that a zinc-finger-like alpha helical chiral metallo-supramolecular complex, [Ni2L3](4+)-P enantiomer (NiP), can selectively provoke the rapid telomere uncapping, trigger DNA damage responses at telomere and degradation of G-overhang and the delocalization of telomeric protein from telomeres. Further studies indicate that NiP can induce an acute cellular apoptosis and senescence in cancer cells rather than normal cells. These results are further evidenced by the upregulation of p21 and p16 proteins. Moreover, NiP can cause translocation of hTERT from nuclear to cytoplasm through Tyr 707 phosphorylation. While its enantiomer, [Ni2L3](4+)-M (NiM), has no such mentioned effects, these results clearly demonstrate the compound's chiral selectivity in cancer cells. Our work will shed light on design of chiral anticancer drugs targeting G-quadruplex DNA, and developing telomere and telomerase modulation agents.},
}
@article {pmid24413433,
year = {2014},
author = {Shibuya, H and Ishiguro, K and Watanabe, Y},
title = {The TRF1-binding protein TERB1 promotes chromosome movement and telomere rigidity in meiosis.},
journal = {Nature cell biology},
volume = {16},
number = {2},
pages = {145-156},
pmid = {24413433},
issn = {1476-4679},
mesh = {Amino Acid Sequence ; Animals ; Carrier Proteins/chemistry/genetics/*physiology ; Cell Cycle Proteins/chemistry/genetics/*physiology ; *Chromosomes ; Female ; Fertility/genetics ; Male ; *Meiosis ; Mice ; Molecular Sequence Data ; Protein Binding ; Sequence Homology, Amino Acid ; *Telomere ; Telomeric Repeat Binding Protein 1/*metabolism ; },
abstract = {During meiotic prophase, telomere-mediated chromosomal movement along the nuclear envelope is crucial for homologue pairing and synapsis. However, how telomeres are modified to mediate chromosome movement is largely elusive. Here we show that mammalian meiotic telomeres are fundamentally modified by a meiosis-specific Myb-domain protein, TERB1, that localizes at telomeres in mouse germ cells. TERB1 forms a heterocomplex with the canonical telomeric protein TRF1 and binds telomere repeat DNA. Disruption of Terb1 in mice abolishes meiotic chromosomal movement and impairs homologous pairing and synapsis, causing infertility in both sexes. TERB1 promotes telomere association with the nuclear envelope and deposition of the SUN-KASH complex, which recruits cytoplasmic motor complexes. TERB1 also binds and recruits cohesin to telomeres to develop structural rigidity, strikingly reminiscent of centromeres. Our study suggests that TERB1 acts as a central hub for the assembly of a conserved meiotic telomere complex required for chromosome movements.},
}
@article {pmid24413054,
year = {2014},
author = {O'Sullivan, RJ and Arnoult, N and Lackner, DH and Oganesian, L and Haggblom, C and Corpet, A and Almouzni, G and Karlseder, J},
title = {Rapid induction of alternative lengthening of telomeres by depletion of the histone chaperone ASF1.},
journal = {Nature structural &amp; molecular biology},
volume = {21},
number = {2},
pages = {167-174},
pmid = {24413054},
issn = {1545-9985},
support = {R01CA174942/CA/NCI NIH HHS/United States ; R01 CA174942/CA/NCI NIH HHS/United States ; R01GM087476/GM/NIGMS NIH HHS/United States ; P30CA014195/CA/NCI NIH HHS/United States ; R01 GM087476/GM/NIGMS NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics/metabolism/*physiology ; Cell Line, Tumor ; DNA Replication ; Gene Expression Regulation ; Humans ; Kinetics ; Molecular Chaperones/genetics/metabolism/*physiology ; Telomerase/genetics/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {The mechanism of activation of the alternative lengthening of telomeres (ALT) pathway of mammalian chromosome-end maintenance has been unclear. We have now discovered that co-depletion of the histone chaperones ASF1a and ASF1b in human cells induced all hallmarks of ALT in both primary and cancer cells. These included the formation of ALT-associated PML (promyelocytic leukemia) bodies (APBs), the presence of extrachromosomal telomeric DNA species, an elevated frequency of telomeric sister chromatid exchanges (t-SCE) events and intertelomeric exchange of an integrated tag. The induction of ALT characteristics in this setting led to the simultaneous suppression of telomerase. We determined that ALT induction is positively regulated by the proteins RAD17 and BLM and negatively regulated by EXO1 and DNA2. The induction of ALT phenotypes as a consequence of ASF1 depletion strongly supports the hypothesis that ALT is a consequence of histone management dysfunction.},
}
@article {pmid24411948,
year = {2014},
author = {Ikeda, H and Aida, J and Hatamochi, A and Hamasaki, Y and Izumiyama-Shimomura, N and Nakamura, K and Ishikawa, N and Poon, SS and Fujiwara, M and Tomita, K and Hiraishi, N and Kuroiwa, M and Matsuura, M and Sanada, Y and Kawano, Y and Arai, T and Takubo, K},
title = {Quantitative fluorescence in situ hybridization measurement of telomere length in skin with/without sun exposure or actinic keratosis.},
journal = {Human pathology},
volume = {45},
number = {3},
pages = {473-480},
doi = {10.1016/j.humpath.2013.10.009},
pmid = {24411948},
issn = {1532-8392},
mesh = {Aged ; Female ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Keratosis, Actinic/genetics/*metabolism/pathology ; Male ; Middle Aged ; Skin/*metabolism/pathology ; Skin Aging/*genetics/pathology ; Telomere/*metabolism/pathology ; Telomere Shortening/*genetics ; },
abstract = {Chromosomal and genomic instability due to telomere dysfunction is known to play an important role in carcinogenesis. To study telomere shortening in the epidermis surrounding actinic keratosis, we measured telomere lengths of basal, parabasal, and suprabasal cells in epidermis with actinic keratosis (actinic keratosis group, n = 18) and without actinic keratosis (sun-protected, n = 15, and sun-exposed, n = 13 groups) and in actinic keratosis itself as well as in dermal fibroblasts in the 3 groups, using quantitative fluorescence in situ hybridization. Among the 3 cell types, telomeres of basal cells were not always the longest, suggesting that tissue stem cells are not necessarily located among basal cells. Telomeres of basal cells in the sun-exposed group were shorter than those in the sun-protected group. Telomeres in the background of actinic keratosis and in actinic keratosis itself and those of fibroblasts in actinic keratosis were significantly shorter than those in the controls. Our findings demonstrate that sun exposure induces telomere shortening and that actinic keratosis arises from epidermis with shorter telomeres despite the absence of any histologic atypia.},
}
@article {pmid24406867,
year = {2014},
author = {Paviolo, NS and Castrogiovanni, DC and Bolzán, AD},
title = {The radiomimetic compound streptonigrin induces persistent telomere dysfunction in mammalian cells.},
journal = {Mutation research},
volume = {760},
number = {},
pages = {16-23},
doi = {10.1016/j.mrfmmm.2013.11.009},
pmid = {24406867},
issn = {0027-5107},
mesh = {Adipose Tissue/drug effects/*pathology ; Animals ; Antibiotics, Antineoplastic/*toxicity ; Cells, Cultured ; Chromosome Aberrations/*drug effects ; Fibroblasts/drug effects/*pathology ; In Situ Hybridization, Fluorescence ; Rats ; Rats, Sprague-Dawley ; Streptonigrin/*toxicity ; Telomere/drug effects/*pathology ; },
abstract = {We analyzed the chromosomal aberrations involving telomeres in the progeny of mammalian cells exposed to the radiomimetic compound streptonigrin (SN) in order to determine if this antineoplastic drug induces long-term telomere instability. To this end, rat cells (ADIPO-P2 cell line, derived from adipose cells from Sprague-Dawley rat) were treated with a single concentration of SN (100ng/ml), and chromosomal aberrations were analyzed 18h and 10 and 15 days after treatment by using PNA-FISH with a pan-telomeric probe [Cy3-(CCCTAA)3] to detect (TTAGGG)n repeats. Cytogenetic analysis revealed a higher frequency of telomere dysfunction-related aberrations (additional telomeric FISH signals, extra-chromosomal telomeric FISH signals, and telomere FISH signal loss and duplications) in SN-exposed cultures vs. untreated cultures at every time points analyzed. The yield of SN-induced aberrations remained very similar at 18h, 10 days as well as 15 days after treatment. Thus, our data demonstrate that SN induces persistent telomere dysfunction in mammalian cells. Moreover, we found that the level of telomerase activity in SN-treated cells was significantly lower (up to 77%) than that of untreated control cells at each time points analyzed. This fact suggests that telomerase could be involved in SN-induced telomere dysfunction.},
}
@article {pmid24406510,
year = {2014},
author = {Zhang, Y and Wang, LJ and Zhang, CY},
title = {Highly sensitive detection of telomerase using a telomere-triggered isothermal exponential amplification-based DNAzyme biosensor.},
journal = {Chemical communications (Cambridge, England)},
volume = {50},
number = {15},
pages = {1909-1911},
doi = {10.1039/c3cc48518h},
pmid = {24406510},
issn = {1364-548X},
mesh = {Biosensing Techniques/*methods ; DNA, Catalytic/*metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Nucleic Acid Amplification Techniques/*methods ; Telomerase/*metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {A telomere-triggered isothermal exponential amplification-based DNAzyme biosensor is developed for highly sensitive detection of telomerase in cancer cells even at the single-cell level. This biosensor can be further applied for the screening of telomerase inhibitors for anticancer drug development.},
}
@article {pmid24405569,
year = {2014},
author = {Friis-Ottessen, M and Bendix, L and Kølvraa, S and Norheim-Andersen, S and De Angelis, PM and Clausen, OP},
title = {Telomere shortening correlates to dysplasia but not to DNA aneuploidy in longstanding ulcerative colitis.},
journal = {BMC gastroenterology},
volume = {14},
number = {},
pages = {8},
pmid = {24405569},
issn = {1471-230X},
mesh = {Adenocarcinoma/chemistry/*genetics ; *Aneuploidy ; Cell Transformation, Neoplastic/*genetics/pathology ; Chromosomal Instability ; Colitis, Ulcerative/*genetics/pathology ; Colonic Neoplasms/chemistry/*genetics ; DNA/*analysis ; Diploidy ; Disease Progression ; Female ; Humans ; Intestinal Mucosa/chemistry ; Male ; *Telomere Shortening ; },
abstract = {BACKGROUND: Ulcerative colitis (UC) is a chronic, inflammatory bowel disease which may lead to dysplasia and adenocarcinoma in patients when long-lasting. Short telomeres have been reported in mucosal cells of UC patients. Telomeres are repetitive base sequences capping the ends of linear chromosomes, and protect them from erosion and subsequent wrongful recombination and end-to-end joining during cell division. Short telomeres are associated with the development of chromosomal instability and aneuploidy, the latter being risk factors for development of dysplasia and cancer. Specifically, the abrupt shortening of one or more telomeres to a critical length, rather than bulk shortening of telomeres, seems to be associated with chromosomal instability.<br><br>METHODS: We investigated possible associations between dysplasia, aneuploidy and telomere status in a total of eight lesions from each of ten progressors and four nonprogressors suffering from longstanding UC. We have analyzed mean telomere length by qPCR, as well as the amount of ultra-short telomeres by the Universal STELA method.<br><br>RESULTS: An increased amount of ultra-short telomeres, as well as general shortening of mean telomere length are significantly associated with dysplasia in longstanding UC. Furthermore, levels of ultra-short telomeres are also significantly increased in progressors (colons harbouring cancer/dysplasia and/or aneuploidy) compared to nonprogressors (without cancer/dysplasia/aneuploidy), whereas general shortening of telomeres did not show such associations.<br><br>CONCLUSIONS: Our data suggest that ultra-short telomeres may be more tightly linked to colorectal carcinogenesis through development of dysplasia in UC than general telomere shortening. Telomere status was not seen to associate with DNA aneuploidy.},
}
@article {pmid24399050,
year = {2014},
author = {Sharma, VR and Sheardy, RD},
title = {The human telomere sequence, (TTAGGG)4, in the absence and presence of cosolutes: a spectroscopic investigation.},
journal = {Molecules (Basel, Switzerland)},
volume = {19},
number = {1},
pages = {595-608},
pmid = {24399050},
issn = {1420-3049},
mesh = {Base Sequence ; Circular Dichroism ; G-Quadruplexes/drug effects ; Humans ; Nucleic Acid Conformation/*drug effects ; Osmotic Pressure ; Phosphates/*pharmacology ; Polyethylene Glycols/chemistry ; Potassium Compounds/*pharmacology ; Telomere/*chemistry/*drug effects/genetics ; Thermodynamics ; },
abstract = {Historically, biophysical studies of nucleic acids have been carried out under near ideal conditions, i.e., low buffer concentration (e.g., 10 mM phosphate), pH 7, low ionic strength (e.g., 100 mM) and, for optical studies, low concentrations of DNA (e.g., 1×10[-6] M). Although valuable structural and thermodynamic data have come out of these studies, the conditions, for the most, part, are inadequate to simulate realistic cellular conditions. The increasing interest in studying biomolecules under more cellular-like conditions prompted us to investigate the effect of osmotic stress on the structural and thermodynamic properties of DNA oligomers containing the human telomere sequence (TTAGGG). Here, we report the characterization of (TTAGGG)4 in potassium phosphate buffer with increasing percent PEG (polyethylene glycol) or acetonitrile. In general, the presence of these cosolutes induces a conformational change from a unimolecular hybrid structure to a multimolecular parallel stranded structure. Hence, the structural change is accompanied with a change in the molecularity of quadruplex formation.},
}
@article {pmid24397874,
year = {2014},
author = {Schrumpfová, PP and Vychodilová, I and Dvořáčková, M and Majerská, J and Dokládal, L and Schořová, S and Fajkus, J},
title = {Telomere repeat binding proteins are functional components of Arabidopsis telomeres and interact with telomerase.},
journal = {The Plant journal : for cell and molecular biology},
volume = {77},
number = {5},
pages = {770-781},
pmid = {24397874},
issn = {1365-313X},
mesh = {Arabidopsis/*enzymology/genetics ; Arabidopsis Proteins/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Although telomere-binding proteins constitute an essential part of telomeres, in vivo data indicating the existence of a structure similar to mammalian shelterin complex in plants are limited. Partial characterization of a number of candidate proteins has not identified true components of plant shelterin or elucidated their functional mechanisms. Telomere repeat binding (TRB) proteins from Arabidopsis thaliana bind plant telomeric repeats through a Myb domain of the telobox type in vitro, and have been shown to interact with POT1b (Protection of telomeres 1). Here we demonstrate co-localization of TRB1 protein with telomeres in situ using fluorescence microscopy, as well as in vivo interaction using chromatin immunoprecipitation. Classification of the TRB1 protein as a component of plant telomeres is further confirmed by the observation of shortening of telomeres in knockout mutants of the trb1 gene. Moreover, TRB proteins physically interact with plant telomerase catalytic subunits. These findings integrate TRB proteins into the telomeric interactome of A. thaliana.},
}
@article {pmid24394156,
year = {2014},
author = {Gruber, H and Schaible, R and Ridgway, ID and Chow, TT and Held, C and Philipp, EE},
title = {Telomere-independent ageing in the longest-lived non-colonial animal, Arctica islandica.},
journal = {Experimental gerontology},
volume = {51},
number = {},
pages = {38-45},
doi = {10.1016/j.exger.2013.12.014},
pmid = {24394156},
issn = {1873-6815},
mesh = {Aging/genetics/*physiology ; Animals ; Base Sequence ; Bivalvia/enzymology/genetics/*physiology ; Conserved Sequence ; DNA/analysis ; Genome/genetics ; Longevity/genetics/*physiology ; Telomerase/metabolism ; Telomere/enzymology/genetics/*physiology ; Telomere Homeostasis/genetics/*physiology ; },
abstract = {The shortening of telomeres as a causative factor in ageing is a widely discussed hypothesis in ageing research. The study of telomere length and its regenerating enzyme telomerase in the longest-lived non-colonial animal on earth, Arctica islandica, should inform whether the maintenance of telomere length plays a role in reaching the extreme maximum lifespan (MLSP) of >500years in this species. Since longitudinal measurements on living animals cannot be achieved, a cross-sectional analysis of a short-lived (MLSP 40years from the Baltic Sea) and a long-lived population (MLSP 226years Northeast of Iceland) and in different tissues of young and old animals from the Irish Sea was performed. A high heterogeneity of telomere length was observed in investigated A. islandica over a wide age range (10-36years for the Baltic Sea, 11-194years for Irish Sea, 6-226years for Iceland). Constant telomerase activity and telomere lengths were detected at any age and in different tissues; neither correlated with age or population habitat. Stable telomere maintenance might contribute to the long lifespan of A. islandica. Telomere dynamics are no explanation for the distinct MLSPs of the examined populations and thus the cause of it remains to be investigated.},
}
@article {pmid24393774,
year = {2014},
author = {Fallet, E and Jolivet, P and Soudet, J and Lisby, M and Gilson, E and Teixeira, MT},
title = {Length-dependent processing of telomeres in the absence of telomerase.},
journal = {Nucleic acids research},
volume = {42},
number = {6},
pages = {3648-3665},
pmid = {24393774},
issn = {1362-4962},
support = {260906/ERC_/European Research Council/International ; },
mesh = {DNA Helicases/analysis ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/metabolism ; Endonucleases/metabolism ; G2 Phase/genetics ; RecQ Helicases/metabolism ; *Recombinational DNA Repair ; S Phase/genetics ; Saccharomyces cerevisiae/enzymology/genetics ; Saccharomyces cerevisiae Proteins/analysis/metabolism ; Telomerase/genetics ; Telomere/chemistry ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {In the absence of telomerase, telomeres progressively shorten with every round of DNA replication, leading to replicative senescence. In telomerase-deficient Saccharomyces cerevisiae, the shortest telomere triggers the onset of senescence by activating the DNA damage checkpoint and recruiting homologous recombination (HR) factors. Yet, the molecular structures that trigger this checkpoint and the mechanisms of repair have remained elusive. By tracking individual telomeres, we show that telomeres are subjected to different pathways depending on their length. We first demonstrate a progressive accumulation of subtelomeric single-stranded DNA (ssDNA) through 5'-3' resection as telomeres shorten. Thus, exposure of subtelomeric ssDNA could be the signal for cell cycle arrest in senescence. Strikingly, early after loss of telomerase, HR counteracts subtelomeric ssDNA accumulation rather than elongates telomeres. We then asked whether replication repair pathways contribute to this mechanism. We uncovered that Rad5, a DNA helicase/Ubiquitin ligase of the error-free branch of the DNA damage tolerance (DDT) pathway, associates with native telomeres and cooperates with HR in senescent cells. We propose that DDT acts in a length-independent manner, whereas an HR-based repair using the sister chromatid as a template buffers precocious 5'-3' resection at the shortest telomeres.},
}
@article {pmid24393457,
year = {2014},
author = {Surace, C and Berardinelli, F and Masotti, A and Roberti, MC and Da Sacco, L and D'Elia, G and Sirleto, P and Digilio, MC and Cusmai, R and Grotta, S and Petrocchi, S and Hachem, ME and Pisaneschi, E and Ciocca, L and Russo, S and Lepri, FR and Sgura, A and Angioni, A},
title = {Telomere shortening and telomere position effect in mild ring 17 syndrome.},
journal = {Epigenetics &amp; chromatin},
volume = {7},
number = {1},
pages = {1},
pmid = {24393457},
issn = {1756-8935},
abstract = {BACKGROUND: Ring chromosome 17 syndrome is a rare disease that arises from the breakage and reunion of the short and long arms of chromosome 17. Usually this abnormality results in deletion of genetic material, which explains the clinical features of the syndrome. Moreover, similar phenotypic features have been observed in cases with complete or partial loss of the telomeric repeats and conservation of the euchromatic regions. We studied two different cases of ring 17 syndrome, firstly, to clarify, by analyzing gene expression analysis using real-time qPCR, the role of the telomere absence in relationship with the clinical symptoms, and secondly, to look for a new model of the mechanism of ring chromosome transmission in a rare case of familial mosaicism, through cytomolecular and quantitative fluorescence in-situ hybridization (Q-FISH) investigations.<br><br>RESULTS: The results for the first case showed that the expression levels of genes selected, which were located close to the p and q ends of chromosome 17, were significantly downregulated in comparison with controls. Moreover, for the second case, we demonstrated that the telomeres were conserved, but were significantly shorter than those of age-matched controls; data from segregation analysis showed that the ring chromosome was transmitted only to the affected subjects of the family.<br><br>CONCLUSIONS: Subtelomeric gene regulation is responsible for the phenotypic aspects of ring 17 syndrome; telomere shortening influences the phenotypic spectrum of this disease and strongly contributes to the familial transmission of the mosaic ring. Together, these results provide new insights into the genotype-phenotype relationships in mild ring 17 syndrome.},
}
@article {pmid24386235,
year = {2013},
author = {Nettle, D and Monaghan, P and Boner, W and Gillespie, R and Bateson, M},
title = {Bottom of the heap: having heavier competitors accelerates early-life telomere loss in the European starling, Sturnus vulgaris.},
journal = {PloS one},
volume = {8},
number = {12},
pages = {e83617},
pmid = {24386235},
issn = {1932-6203},
support = {BB/J015091/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/J016446/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; *Environment ; Female ; Male ; *Starlings/growth &amp; development ; Stress, Physiological ; Telomere/metabolism ; Telomere Shortening ; },
abstract = {Early-life adversity is associated with poorer health and survival in adulthood in humans and other animals. One pathway by which early-life environmental stressors could affect the adult phenotype is via effects on telomere dynamics. Several studies have shown that early-life adversity is associated with relatively short telomeres, but these are often cross-sectional and usually correlational in design. Here, we present a novel experimental system for studying the relationship between early-life adversity and telomere dynamics using a wild bird, the European starling (Sturnus vulgaris). We used cross-fostering to experimentally assign sibling chicks to either small or large broods for twelve days of the growth period. We measured telomere length in red blood cells using quantitative PCR near the beginning of the experimental manipulation (4 days old), at the end of the experimental manipulation (15 days old), and once the birds were independent (55 days old). Being in a larger brood slowed growth and retarded wing development and the timing of fledging. We found no evidence that overall brood size affected telomere dynamics. However, the greater the number of competitors above the focal bird in the within-brood size hierarchy, the greater was the telomere loss during the period of the experimental manipulation. The number of competitors below the focal in the hierarchy had no effect. The effect of heavier competitors was still evident when we controlled for the weight of the focal bird at the end of the manipulation, suggesting it was not due to retarded growth per se. Moreover, the impact of early competition on telomeres was still evident at independence, suggesting persistence beyond early life. Our study provides experimental support for the hypothesis that social stress, in this case induced by the presence of a greater number of dominant competitors, accelerates the rate of telomere loss.},
}
@article {pmid24379680,
year = {2013},
author = {Mulnix, RE and Pitman, RT and Retzer, A and Bertram, C and Arasi, K and Crees, Z and Girard, J and Uppada, SB and Stone, AL and Puri, N},
title = {hnRNP C1/C2 and Pur-beta proteins mediate induction of senescence by oligonucleotides homologous to the telomere overhang.},
journal = {OncoTargets and therapy},
volume = {7},
number = {},
pages = {23-32},
pmid = {24379680},
issn = {1178-6930},
abstract = {BACKGROUND: Experimental disruption of the telomere overhang induces a potent DNA damage response and is the target of newly emerging cancer therapeutics. Introduction of T-oligo, an eleven-base oligonucleotide homologous to the 3'-telomeric overhang, mimics telomere disruption and induces DNA damage responses through activation of p53, p73, p95/Nbs1, E2F1, pRb, and other DNA damage response proteins. ATM (ataxia telangiectasia mutated) was once thought to be the primary driver of T-oligo-induced DNA damage responses; however, recent experiments have highlighted other key proteins that may also play a significant role.<br><br>METHODS: To identify proteins associated with T-oligo, MM-AN cells were treated with biotinylated T-oligo or complementary oligonucleotide, cell lysates were run on SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis), and the protein bands observed after treatment of cells with T-oligo or complementary oligonucleotide were analyzed using mass spectrometry. To study the effect of T-oligo on expression of hnRNP C1/C2 (heterogeneous nuclear ribonucleoprotein C1 and C2) and purine-rich element binding proteins (Pur proteins), cells were treated with T-oligo, and immunoblotting experiments were performed. To determine their role in senescence, cells were treated with shRNA (short hairpin ribonucleic acid) against these proteins, and senescence was studied using the senescence associated beta-galactosidase assay.<br><br>RESULTS: Using mass spectrometry, RNA-binding hnRNP C1/C2 and DNA-binding Pur proteins were found to associate with T-oligo. hnRNP C1/C2 exhibited increased expression (3.6-12.0-fold) in non-small-cell lung cancer (NSCLC) and in melanoma cells (4.5-5.2-fold), and Pur proteins exhibited increased expression of 2.2-fold in NSCLC and 2.0-fold in melanoma cells after T-oligo treatment. Experimental knockdown of hnRNP C1/C2 and Pur-beta completely abrogated T-oligo induced senescence in both MU melanoma and H358 NSCLC cells. Additionally, knockdown of Pur-beta prevented T-oligo-induced phosphorylation of p53, hypophosphorylation of pRb, and upregulation of E2F1, p21, and p53.<br><br>CONCLUSION: These novel findings highlight proteins essential to T-oligo's anticancer effects that may be of interest in telomere biology and cancer therapeutics.},
}
@article {pmid24379272,
year = {2013},
author = {Wysoczańska, B},
title = {[Maintaining telomere length].},
journal = {Postepy higieny i medycyny doswiadczalnej (Online)},
volume = {67},
number = {},
pages = {1319-1330},
doi = {10.5604/17322693.1081034},
pmid = {24379272},
issn = {1732-2693},
mesh = {Animals ; Cell Cycle/genetics ; *Chromosomal Instability ; DNA Damage ; Hematologic Neoplasms/genetics ; Humans ; Mutation ; Neurodegenerative Diseases/genetics ; Shelterin Complex ; Telomerase/metabolism ; Telomere Homeostasis/*physiology ; Telomere-Binding Proteins/*genetics/*metabolism ; },
abstract = {Telomeres protect the ends of chromosomes maintaining genome stability. The activity of telomerase enzyme, or alternatively the process of recombination, regulates the length of telomeres. In the absence of these mechanisms, excessive shortening of telomeres reach its critical level. Excessively shortened telomeres do not protect chromosome ends, the cell division cycle is stopped while the inactivity of replication process generates cellular senescence and cell death. On the other hand, critically shortened telomeres may promote chromosomal instability. These changes can lead to the development of carcinogenesis. In this process enzymatic activity of telomerase is reactivated. To maintain the protection of the chromosome ends, telomeres bind the stabilizing protein complex (shelterin). The presence of these protective proteins prevents undesirable DNA damage and initiates the repair system pathways. Molecular technologies enable the evaluation of telomere lengths, the analysis of telomerase expression and activity, and detection of mutations, polymorphic and epigenetic changes in telomere--shelterin--telomerase complex related genes. The purpose of research is to describe new mechanisms that affect the biology of telomere lengths, and to determine the impact on bone marrow failures, development of haematological malignancies, neurodegenerative diseases and others disorders associated with chromosomal instability. The model of modern therapies based on telomere biology explains the significance of the maintenance of telomere lengths in the process of cellular senescence and carcinogenesis.},
}
@article {pmid24378524,
year = {2014},
author = {Invernizzi, P and Bernuzzi, F and Lleo, A and Pozzoli, V and Bignotto, M and Zermiani, P and Crosignani, A and Battezzati, PM and Zuin, M and Podda, M and Raggi, C},
title = {Telomere dysfunction in peripheral blood mononuclear cells from patients with primary biliary cirrhosis.},
journal = {Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver},
volume = {46},
number = {4},
pages = {363-368},
doi = {10.1016/j.dld.2013.11.008},
pmid = {24378524},
issn = {1878-3562},
mesh = {Adult ; Aged ; Case-Control Studies ; Cellular Senescence/genetics ; Female ; Hepatitis C, Chronic/enzymology/genetics ; Humans ; Leukocytes, Mononuclear/enzymology/*metabolism ; Liver Cirrhosis/enzymology/genetics ; Liver Cirrhosis, Biliary/enzymology/*genetics ; Middle Aged ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*genetics ; *Telomere Shortening ; },
abstract = {BACKGROUND: Chromosomal instability in peripheral blood mononuclear cells has a role in the onset of primary biliary cirrhosis. We hypothesized that patients with primary biliary cirrhosis may harbour telomere dysfunction, with consequent chromosomal instability and cellular senescence.<br><br>AIM: To evaluate the clinical significance of telomerase activity and telomere length in peripheral blood mononuclear cells from patients with primary biliary cirrhosis.<br><br>STUDY DESIGN: In this population-based case control study, 48 women with primary biliary cirrhosis (25 with cirrhosis), 12 with chronic hepatitis C matched by age and severity of disease, and 55 age-matched healthy women were identified. Mononuclear cells from the peripheral blood of patients and controls were isolated. Telomere length and telomerase activity were measured.<br><br>RESULTS: Telomere length and telomerase activity did not differ between cases (5.9 &#xb1; 1.5 kb) and controls (6.2 &#xb1; 1.4 kb, pc=0.164). Telomere shortening and advanced-stage disease strongly correlated with telomerase activity. Patients with advanced disease retained significantly less telomerase activity than those with early-stage disease (0.6 &#xb1; 0.9 OD vs. 1.5 &#xb1; 3.7 OD, p=0.03). Telomere loss correlated with age, suggesting premature cellular ageing in patients with primary biliary cirrhosis.<br><br>CONCLUSION: Our data strongly support the telomere hypothesis of human cirrhosis, indicating that telomere shortening and telomerase activity represent a molecular mechanism in the evolution of human cirrhosis in a selected population of patients.},
}
@article {pmid24374808,
year = {2014},
author = {Zhao, Z and Pan, X and Liu, L and Liu, N},
title = {Telomere length maintenance, shortening, and lengthening.},
journal = {Journal of cellular physiology},
volume = {229},
number = {10},
pages = {1323-1329},
doi = {10.1002/jcp.24537},
pmid = {24374808},
issn = {1097-4652},
mesh = {Animals ; Cell Differentiation ; Cell Lineage ; Cellular Reprogramming ; Cellular Senescence ; Embryonic Stem Cells/*metabolism ; Gene Expression Regulation, Developmental ; Humans ; Pluripotent Stem Cells/*metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Telomeres maintain chromosome stability and cell replicative capacity. Telomere shortening occurs concomitant with aging. Short telomeres are associated with some diseases, such as dyskeratosis congenita, idiopathic pulmonary fibrosis, and aplastic anemia. Telomeres are longer in pluripotent stem cells than in somatic cells and lengthen significantly during preimplantation development. Furthermore, telomere elongation during somatic cell reprogramming is of great importance in the acquisition of authentic pluripotency. This review focuses primarily on regulatory mechanisms of telomere length maintenance in pluripotent cells, telomere length extension in early embryo development, and also telomere rejuvenation in somatic cell reprogramming. Telomere related diseases are also discussed in this review.},
}
@article {pmid24367594,
year = {2013},
author = {Long, X and Stone, MD},
title = {Kinetic partitioning modulates human telomere DNA G-quadruplex structural polymorphism.},
journal = {PloS one},
volume = {8},
number = {12},
pages = {e83420},
pmid = {24367594},
issn = {1932-6203},
support = {R01 GM095850/GM/NIGMS NIH HHS/United States ; GM095850/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; DNA/*chemistry/genetics ; *G-Quadruplexes ; Humans ; Kinetics ; Osmolar Concentration ; *Telomere ; Temperature ; },
abstract = {Telomeres are specialized chromatin structures found at the end of chromosomes and are crucial to the maintenance of eukaryotic genome stability. Human telomere DNA is comprised of the repeating sequence (T2AG3)n, which is predominantly double-stranded but terminates with a 3' single-stranded tail. The guanine-rich tail can fold into secondary structures known as a G-quadruplexes (GQs) that may exist as a polymorphic mixture of anti-parallel, parallel, and several hybrid topological isomers. Using single-molecule Förster resonance energy transfer (smFRET), we have reconstructed distributions of telomere DNA GQ conformations generated by an in situ refolding protocol commonly employed in single-molecule studies of GQ structure, or using a slow cooling DNA annealing protocol typically used in the preparation of GQ samples for ensemble biophysical analyses. We find the choice of GQ folding protocol has a marked impact on the observed distributions of DNA conformations under otherwise identical buffer conditions. A detailed analysis of the kinetics of GQ folding over timescales ranging from minutes to hours revealed the distribution of GQ structures generated by in situ refolding gradually equilibrates to resemble the distribution generated by the slow cooling DNA annealing protocol. Interestingly, conditions of low ionic strength, which promote transient GQ unfolding, permit the fraction of folded DNA molecules to partition into a distribution that more closely approximates the thermodynamic folding equilibrium. Our results are consistent with a model in which kinetic partitioning occurs during in situ folding at room temperature in the presence of K(+) ions, producing a long-lived non-equilibrium distribution of GQ structures in which the parallel conformation predominates on the timescale of minutes. These results suggest that telomere DNA GQ folding kinetics, and not just thermodynamic stability, likely contributes to the physiological ensemble GQ structures.},
}
@article {pmid24366909,
year = {2014},
author = {Wang, S and Chen, Y and Qu, F and He, S and Huang, X and Jiang, H and Jin, T and Wan, S and Xing, J},
title = {Association between leukocyte telomere length and glioma risk: a case-control study.},
journal = {Neuro-oncology},
volume = {16},
number = {4},
pages = {505-512},
pmid = {24366909},
issn = {1523-5866},
mesh = {Adult ; Brain Neoplasms/*genetics/*pathology ; Case-Control Studies ; Female ; Follow-Up Studies ; Glioma ; Humans ; Leukocytes/metabolism/*pathology ; Male ; Neoplasm Grading ; Odds Ratio ; Prognosis ; Real-Time Polymerase Chain Reaction ; Risk Factors ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: Compelling epidemiological evidence indicates that alterations of telomere length are associated with risks of many malignancies in a tumor-specific manner, such as lung cancer, breast cancer, and non-Hodgkin's lymphoma. However, the association between leukocyte telomere length and glioma risk has not been investigated.<br><br>METHODS: Relative telomere length (RTL) of peripheral blood leukocytes from 467 glioma patients and 467 healthy controls, matched by age and sex, was measured using the real-time PCR-based method in a case-control study. An unconditional multivariate logistic regression model was applied to estimate the association between RTL and glioma risk.<br><br>RESULTS: Glioma patients showed notably longer RTL than controls (median, 0.555 vs 0.444; P > .04). RTL was negatively correlated with age in both cases (&#x3c1; = -0.430; P < .001) and controls (&#x3c1; = -0.388; P < .001). After adjusting for age, sex, smoking status and family history of cancer, multivariate logistic regression analysis showed that there was a U-shaped association between RTL and glioma risk (P for nonlinearity <.001). Compared with individuals in the second tertile of RTL, the odds ratios (95% CI) for participants in the first and third tertiles were 2.16 (range, 1.52-3.09) and 3.51 (range, 2.45-5.00), respectively. Stratified analysis showed that the association between RTL and glioma risk was not modulated by major host characteristics.<br><br>CONCLUSIONS: Our study demonstrates for the first time that either shorter or longer RTL in peripheral blood leukocytes is associated with increased glioma risk, which warrants further investigation in the future.},
}
@article {pmid24366880,
year = {2014},
author = {Göhring, J and Fulcher, N and Jacak, J and Riha, K},
title = {TeloTool: a new tool for telomere length measurement from terminal restriction fragment analysis with improved probe intensity correction.},
journal = {Nucleic acids research},
volume = {42},
number = {3},
pages = {e21},
pmid = {24366880},
issn = {1362-4962},
support = {Y 418/FWF_/Austrian Science Fund FWF/Austria ; },
mesh = {Blotting, Southern ; DNA Restriction Enzymes ; Nucleic Acid Probes ; *Software ; Telomere/*chemistry ; *Telomere Homeostasis ; },
abstract = {Telomeres comprise the protective caps of natural chromosome ends and function in the suppression of DNA damage signaling and cellular senescence. Therefore, techniques used to determine telomere length are important in a number of studies, ranging from those investigating telomeric structure to effects on human disease. Terminal restriction fragment (TRF) analysis has for a long time shown to be one of the most accurate methods for quantification of absolute telomere length and range from a number of species. As this technique centers on standard Southern blotting, telomeric DNA is observed on resulting autoradiograms as a heterogeneous smear. Methods to accurately determine telomere length from telomeric smears have proven problematic, and no reliable technique has been suggested to obtain mean telomere length values. Here, we present TeloTool, a new program allowing thorough statistical analysis of TRF data. Using this new method, a number of methodical biases are removed from previously stated techniques, including assumptions based on probe intensity corrections. This program provides a standardized mean for quick and reliable extraction of quantitative data from TRF autoradiograms; its wide application will allow accurate comparison between datasets generated in different laboratories.},
}
@article {pmid24366690,
year = {2014},
author = {Shay, JW},
title = {Are short telomeres hallmarks of cancer recurrence?.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {20},
number = {4},
pages = {779-781},
pmid = {24366690},
issn = {1557-3265},
support = {5P30CA 142543/CA/NCI NIH HHS/United States ; R13 CA113094/CA/NCI NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; C06 RR030414/RR/NCRR NIH HHS/United States ; C06 RR30414/RR/NCRR NIH HHS/United States ; },
mesh = {Female ; Hodgkin Disease/*genetics ; Humans ; Male ; Neoplasms, Second Primary/*genetics ; Telomere/*metabolism ; Thyroid Neoplasms/*genetics ; },
abstract = {Exposure to radiation and some chemotherapeutic agents is associated with an increased risk of developing second cancers. Short telomeres are almost universally associated with malignant cancer progression. An unanswered question is whether inherited short telomeres or therapy-related telomere shortening is a biomarker of the development of second malignant neoplasms.},
}
@article {pmid24365661,
year = {2014},
author = {Gardner, M and Bann, D and Wiley, L and Cooper, R and Hardy, R and Nitsch, D and Martin-Ruiz, C and Shiels, P and Sayer, AA and Barbieri, M and Bekaert, S and Bischoff, C and Brooks-Wilson, A and Chen, W and Cooper, C and Christensen, K and De Meyer, T and Deary, I and Der, G and Diez Roux, A and Fitzpatrick, A and Hajat, A and Halaschek-Wiener, J and Harris, S and Hunt, SC and Jagger, C and Jeon, HS and Kaplan, R and Kimura, M and Lansdorp, P and Li, C and Maeda, T and Mangino, M and Nawrot, TS and Nilsson, P and Nordfjall, K and Paolisso, G and Ren, F and Riabowol, K and Robertson, T and Roos, G and Staessen, JA and Spector, T and Tang, N and Unryn, B and van der Harst, P and Woo, J and Xing, C and Yadegarfar, ME and Park, JY and Young, N and Kuh, D and von Zglinicki, T and Ben-Shlomo, Y and , },
title = {Gender and telomere length: systematic review and meta-analysis.},
journal = {Experimental gerontology},
volume = {51},
number = {},
pages = {15-27},
pmid = {24365661},
issn = {1873-6815},
support = {N01-HC-95162/HC/NHLBI NIH HHS/United States ; HL80698/HL/NHLBI NIH HHS/United States ; UL1-RR-024156/RR/NCRR NIH HHS/United States ; UL1 RR024156/RR/NCRR NIH HHS/United States ; N01HC85086/HL/NHLBI NIH HHS/United States ; MC_UP_A620_1014/MRC_/Medical Research Council/United Kingdom ; N01HC95159/HL/NHLBI NIH HHS/United States ; R01 HL080295/HL/NHLBI NIH HHS/United States ; N01HC85082/HL/NHLBI NIH HHS/United States ; N01HC85083/HL/NHLBI NIH HHS/United States ; HL080295/HL/NHLBI NIH HHS/United States ; N01HC85080/HL/NHLBI NIH HHS/United States ; G0601333/MRC_/Medical Research Council/United Kingdom ; MC_UP_A620_1015/MRC_/Medical Research Council/United Kingdom ; UL1 RR025005/RR/NCRR NIH HHS/United States ; UL1-RR-025005/RR/NCRR NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; N01-HC-95163/HC/NHLBI NIH HHS/United States ; N01-HC-95168/HC/NHLBI NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; N01-HC-95159/HC/NHLBI NIH HHS/United States ; ETM/55/CSO_/Chief Scientist Office/United Kingdom ; MC_UU_12011/2/MRC_/Medical Research Council/United Kingdom ; G0700704/MRC_/Medical Research Council/United Kingdom ; MC_PC_13040/MRC_/Medical Research Council/United Kingdom ; MC_UU_12017/7/MRC_/Medical Research Council/United Kingdom ; MC_UU_12011/1/MRC_/Medical Research Council/United Kingdom ; N01-HC-95165/HC/NHLBI NIH HHS/United States ; R01 HL080698/HL/NHLBI NIH HHS/United States ; N01HC55222/HL/NHLBI NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; MC_UP_A540_1021/MRC_/Medical Research Council/United Kingdom ; N01-HC-95169/HC/NHLBI NIH HHS/United States ; MR/K007017/1/MRC_/Medical Research Council/United Kingdom ; N01-HC-95164/HC/NHLBI NIH HHS/United States ; G0500997/MRC_/Medical Research Council/United Kingdom ; MR/K023209/1/MRC_/Medical Research Council/United Kingdom ; N01-HC-95160/HC/NHLBI NIH HHS/United States ; N01-HC-95161/HC/NHLBI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; N01HC85079/HL/NHLBI NIH HHS/United States ; N01-HC-95166/HC/NHLBI NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; AG023629/AG/NIA NIH HHS/United States ; R56 AG023629/AG/NIA NIH HHS/United States ; CZB/4/505/CSO_/Chief Scientist Office/United Kingdom ; SPHSU2/CSO_/Chief Scientist Office/United Kingdom ; MC_U147585824/MRC_/Medical Research Council/United Kingdom ; BB/F019394/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MC_UU_12017/5/MRC_/Medical Research Council/United Kingdom ; N01-HC-95167/HC/NHLBI NIH HHS/United States ; N01HC85081/HL/NHLBI NIH HHS/United States ; MR/K026992/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*physiology ; Female ; Humans ; Male ; Middle Aged ; *Sex Factors ; Telomere/*physiology ; },
abstract = {BACKGROUND: It is widely believed that females have longer telomeres than males, although results from studies have been contradictory.<br><br>METHODS: We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression.<br><br>RESULTS: Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p=1.00) or cell type (p=0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error.<br><br>CONCLUSIONS: Telomere length is longer in females than males, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required.},
}
@article {pmid24364913,
year = {2013},
author = {Gopalakrishnan, S and Cheung, NK and Yip, BW and Au, DW},
title = {Medaka fish exhibits longevity gender gap, a natural drop in estrogen and telomere shortening during aging: a unique model for studying sex-dependent longevity.},
journal = {Frontiers in zoology},
volume = {10},
number = {1},
pages = {78},
pmid = {24364913},
issn = {1742-9994},
abstract = {INTRODUCTION: Females having a longer telomere and lifespan than males have been documented in many animals. Such linkage however has never been reported in fish. Progressive shortening of telomere length is an important aging mechanism. Mounting in vitro evidence has shown that telomere shortening beyond a critical length triggered replicative senescence or cell death. Estrogen has been postulated as a key factor contributing to maintenance of telomere and sex-dependent longevity in animals. This postulation remains unproven due to the lack of a suitable animal system for testing. Here, we introduce a teleost model, the Japanese medaka Oryzias latipes, which shows promise for research into the molecular mechanism(s) controlling sex difference in aging.<br><br>RESULTS: Using the medaka, we demonstrate for the first time in teleost that (i) sex differences (female&#x2009;>&#x2009;male) in telomere length and longevity also exist in fish, and (ii) a natural, 'menopause'-like decline of plasma estrogen was evident in females during aging. Estrogen levels significantly correlated with telomerase activity as well as telomere length in female organs (not in males), suggesting estrogen could modulate telomere length via telomerase activation in a sex -specific manner. A hypothetical in vivo 'critical' terminal restriction fragment (TRF, representing telomere) length of approximately 4&#xa0;kb was deduced in medaka liver for prediction of organismal mortality, which is highly comparable with that for human cells. An age conversion model was also established to enable age translation between medaka (in months) and human (in years). These novel tools are useful for future research on comparative biology of aging using medaka.<br><br>CONCLUSION: The striking similarity in estrogen profile between aging female O. latipes and women enables studying the influence of "postmenopausal" decline of estrogen on telomere and longevity without the need of invasive ovariectomy. Medaka fish is advantageous for studying the direct effect of increased estrogen on telomere length and longevity without the breast cancer complications reported in rodents. The findings strongly support the notion that O. latipes is a unique non-mammalian model for validation of estrogenic influence on telomere and longevity in vertebrates. This laboratory model fish is of potential significance for deciphering the ostensibly conserved mechanism(s) of sex-associated longevity in vertebrates.},
}
@article {pmid24360984,
year = {2014},
author = {Savolainen, K and Eriksson, JG and Kajantie, E and Lahti, M and Räikkönen, K},
title = {The history of sleep apnea is associated with shorter leukocyte telomere length: the Helsinki Birth Cohort Study.},
journal = {Sleep medicine},
volume = {15},
number = {2},
pages = {209-212},
doi = {10.1016/j.sleep.2013.11.779},
pmid = {24360984},
issn = {1878-5506},
mesh = {Aging/physiology ; Female ; Humans ; Leukocytes ; Male ; Middle Aged ; Risk Factors ; Sleep Apnea Syndromes/*complications ; Snoring/complications ; *Telomere Shortening/physiology ; },
abstract = {OBJECTIVES: Sleep apnea poses an elevated risk for chronic age-related diseases. Leukocyte telomere length (LTL), a biomarker and factor associated with accelerated cellular aging processes, may serve as a novel mechanism underlying these disease risks. We investigated if a history of clinician-diagnosed sleep apnea or primary snoring was associated with LTL in later adulthood.<br><br>METHODS: Data on sleep apnea, primary snoring and LTL, were available for 1948 participants from the Helsinki Birth Cohort Study. Patients with sleep apnea (n=44) and primary snoring (n=29) severe enough to be recorded as an inpatient diagnosis for hospitalization were identified by their case records through the Finnish Hospital Discharge Register. The LTL was measured by using the realtime quantitative polymerase chain reaction (PCR) method at a mean age of 61.5 years (standard deviation [SD], 2.9).<br><br>RESULTS: A history of sleep apnea was associated with shorter LTL (P=.010). Adjustment for a number of covariates did not alter the association.<br><br>CONCLUSIONS: Accelerated cellular aging reflected in shorter LTL in patients with a history of sleep apnea may partly explain their higher risk for age-related diseases. Future studies elucidating the impacts of long-term or successful treatment history of sleep apnea on the maintenance of LTL are warranted.},
}
@article {pmid24357701,
year = {2014},
author = {Elks, CE and Scott, RA},
title = {The long and short of telomere length and diabetes.},
journal = {Diabetes},
volume = {63},
number = {1},
pages = {65-67},
doi = {10.2337/db13-1469},
pmid = {24357701},
issn = {1939-327X},
support = {MC_U106179471/MRC_/Medical Research Council/United Kingdom ; MC_UU_12015/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Diabetes Mellitus, Type 2/*genetics ; Female ; Humans ; Indians, North American/*genetics ; *Leukocytes ; Male ; Telomere Shortening/*genetics ; },
}
@article {pmid24356145,
year = {2013},
author = {Le Guen, T and Jullien, L and Schertzer, M and Lefebvre, A and Kermasson, L and de Villartay, JP and Londoño-Vallejo, A and Revy, P},
title = {[RTEL1 (regulator of telomere elongation helicase 1), a DNA helicase essential for genome stability].},
journal = {Medecine sciences : M/S},
volume = {29},
number = {12},
pages = {1138-1144},
doi = {10.1051/medsci/20132912018},
pmid = {24356145},
issn = {0767-0974},
mesh = {Animals ; DNA Helicases/genetics/*physiology ; DNA Repair ; Dyskeratosis Congenita/genetics ; Fetal Growth Retardation/genetics ; Genetic Phenomena/genetics/physiology ; Genomic Instability/genetics/*physiology ; Humans ; Intellectual Disability/genetics ; Mice ; Microcephaly/genetics ; Mutation ; Telomere/physiology ; },
abstract = {RTEL1 (regulator of telomere length helicase 1) is a DNA helicase that has been identified more than 10 years ago. Many works since, mainly in the nematode Caenorhabditis elegans and the mouse, have highlighted its role in chromosomal stability, maintenance of telomere length, and DNA repair. Recently, four laboratories have characterized RTEL1 mutations in patients with dyskeratosis congenita (DC) and Hoyeraal-Hreidarsson (HH) syndrome, a rare and severe variant of DC. We here summarize the current knowledge on RTEL1 and discuss the possible other functions that RTEL1 could play.},
}
@article {pmid24356130,
year = {2013},
author = {Jaber, S and Simeonova, I and Toledo, F},
title = {[Moderation in all things: p53 deregulation, cancer and telomere syndromes].},
journal = {Medecine sciences : M/S},
volume = {29},
number = {12},
pages = {1071-1073},
doi = {10.1051/medsci/20132912003},
pmid = {24356130},
issn = {0767-0974},
mesh = {Animals ; Humans ; Mice ; Mutation ; Neoplasms/*genetics ; Telomere/*genetics ; Tumor Suppressor Protein p53/genetics/*physiology ; },
}
@article {pmid24353204,
year = {2014},
author = {Monaghan, P},
title = {Organismal stress, telomeres and life histories.},
journal = {The Journal of experimental biology},
volume = {217},
number = {Pt 1},
pages = {57-66},
doi = {10.1242/jeb.090043},
pmid = {24353204},
issn = {1477-9145},
mesh = {Adaptation, Physiological/genetics/*physiology ; Aging/physiology ; Animals ; Biological Evolution ; Chickens ; Environment ; Finches ; Genetic Fitness/*genetics/physiology ; Glucocorticoids/blood ; Longevity/*physiology ; Stress, Physiological/*physiology ; Telomere/*genetics ; Telomere Homeostasis/genetics/physiology ; },
abstract = {Most organisms, including ourselves, are exposed to environmental stressors at various points during life, and responses to such stressors have been optimised by evolution to give the best fitness outcomes. It is expected that environmental change will substantially increase long-term stress exposure in many animal groups in the coming decades. A major challenge for biologists is to understand and predict how this will influence individuals, populations and ecosystems, and over what time scale such effects will occur. This requires a multi-disciplinary approach, combining studies of mechanisms with studies of fitness consequences for individuals and their descendants. In this review, I discuss the positive and negative fitness consequences of responses to stressful environments, particularly during early life, and with an emphasis on studies in birds. As many of the mechanisms underlying stress responses are highly conserved across the vertebrate groups, the findings from these studies have general applicability when interpreted in a life history context. One important route that has recently been identified whereby chronic stress exposure can affect health and longevity over long time frames is via effects on telomere dynamics. Much of this work has so far been done on humans, and is correlational in nature, but studies on other taxa, and experimental work, are increasing. I summarise the relevant aspects of vertebrate telomere biology and critically appraise our current knowledge with a view to pointing out important future research directions for our understanding of how stress exposure influences life histories.},
}
@article {pmid24350925,
year = {2014},
author = {Tzanetakou, IP and Nzietchueng, R and Perrea, DN and Benetos, A},
title = {Telomeres and their role in aging and longevity.},
journal = {Current vascular pharmacology},
volume = {12},
number = {5},
pages = {726-734},
doi = {10.2174/1570161111666131219112946},
pmid = {24350925},
issn = {1875-6212},
mesh = {Aging/*physiology ; Animals ; Cellular Senescence/physiology ; Humans ; Longevity/*physiology ; Oxidative Stress/physiology ; Telomere/*physiology ; },
abstract = {Telomeres are DNA-protein structures that form protective caps at the end of eukaryotic chromosomes. They constitute the safeguards of chromosome degradation and are responsible for maintaining genomic integrity. The multifactorial nature of telomere length (TL) regulation increases the perplexity of studies in the field. TL is characterized by a high variability among individuals (birth and later life) and among species but it is unknown whether this is associated with their lifespan potential. TL is also highly heritable, longer in women than in men; it is highly variable between tissues and organs and inversely related to chronological age. Accelerated telomere loss has been associated with many chronic diseases of aging. Premature aging or cellular senescence, seen in early life, through increased oxidative stress and DNA damage to telomeric ends may be initiators of processes related to these diseases. During the recent decade, research around telomere biology has rapidly expanded due to its dynamic involvement in aging and longevity. However, longevity is not necessarily an indication of disability-free aging. There is substantial scientific disagreement and controversial results, regarding even the basic nature of aging and the path to longevity. We review the current evidence linking telomere biology to aging processes and mechanisms leading to longevity.},
}
@article {pmid24349443,
year = {2013},
author = {Maubaret, CG and Salpea, KD and Romanoski, CE and Folkersen, L and Cooper, JA and Stephanou, C and Li, KW and Palmen, J and Hamsten, A and Neil, A and Stephens, JW and Lusis, AJ and Eriksson, P and Talmud, PJ and Humphries, SE and , and , },
title = {Association of TERC and OBFC1 haplotypes with mean leukocyte telomere length and risk for coronary heart disease.},
journal = {PloS one},
volume = {8},
number = {12},
pages = {e83122},
pmid = {24349443},
issn = {1932-6203},
support = {RG/08/008/25291/BHF_/British Heart Foundation/United Kingdom ; FS/06/053/BHF_/British Heart Foundation/United Kingdom ; RG2008/08/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Aged ; Coronary Disease/*genetics/metabolism/pathology ; Diabetes Mellitus, Type 2/genetics/metabolism/pathology ; Female ; Haplotypes ; Humans ; *Leukocytes ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; RNA/*genetics/metabolism ; Risk Factors ; Telomerase/*genetics/metabolism ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {OBJECTIVE: To replicate the associations of leukocyte telomere length (LTL) with variants at four loci and to investigate their associations with coronary heart disease (CHD) and type II diabetes (T2D), in order to examine possible causal effects of telomere maintenance machinery on disease aetiology.<br><br>METHODS: Four SNPs at three loci BICD1 (rs2630578 G&#x3b3;C), 18q12.2 (rs2162440 G&#x3b3;T), and OBFC1 (rs10786775 C&#x3b3;G, rs11591710 A&#x3b3;C) were genotyped in four studies comprised of 2353 subjects out of which 1148 had CHD and 566 T2D. Three SNPs (rs12696304 C&#x3b3;G, rs10936601G>T and rs16847897 G&#x3b3;C) at the TERC locus were genotyped in these four studies, in addition to an offspring study of 765 healthy students. For all samples, LTL had been measured using a real-time PCR-based method.<br><br>RESULTS: Only one SNP was associated with a significant effect on LTL, with the minor allele G of OBFC1 rs10786775 SNP being associated with longer LTL (&#x3b2;=0.029, P=0.04). No SNPs were significantly associated with CHD or T2D. For OBFC1 the haplotype carrying both rare alleles (rs10786775G and rs11591710C, haplotype frequency 0.089) was associated with lower CHD prevalence (OR: 0.77; 95% CI: 0.61-0.97; P= 0.03). The TERC haplotype GTC (rs12696304G, rs10936601T and rs16847897C, haplotype frequency 0.210) was associated with lower risk for both CHD (OR: 0.86; 95% CI: 0.75-0.99; P=0.04) and T2D (OR: 0.74; 95% CI: 0.61-0.91; P= 0.004), with no effect on LTL. Only the last association remained after adjusting for multiple testing.<br><br>CONCLUSION: Of reported associations, only that between the OBFC1 rs10786775 SNP and LTL was confirmed, although our study has a limited power to detect modest effects. A 2-SNP OBFC1 haplotype was associated with higher risk of CHD, and a 3-SNP TERC haplotype was associated with both higher risk of CHD and T2D. Further work is required to confirm these results and explore the mechanisms of these effects.},
}
@article {pmid24349076,
year = {2013},
author = {Reichert, S and Criscuolo, F and Verinaud, E and Zahn, S and Massemin, S},
title = {Telomere length correlations among somatic tissues in adult zebra finches.},
journal = {PloS one},
volume = {8},
number = {12},
pages = {e81496},
pmid = {24349076},
issn = {1932-6203},
mesh = {Animals ; Finches/*anatomy &amp; histology/*genetics ; Telomere/*physiology ; },
abstract = {Telomeres are repetitive non coding DNA sequences located at the end of eukaryotic chromosomes, which maintain the integrity of the genome by hiding the chromosome ends from being recognised as double stranded breaks. Telomeres are emerging as biomarkers for ageing and survival, and are susceptible to reflect different individual life history trajectories. In particular, the telomere length with which one starts in life has been shown to be linked with individual life-long survival, suggesting that telomere dynamics can be a proxy for individual fitness and thereby be implicated in evolutionary trade-offs. As a consequence, an increasing number of studies were conducted on telomeres in the fields of ecology and evolutionary biology, in which telomere length was almost exclusively measured from blood samples. However, not only do the number of repeats of the telomeric sequences vary among species, but also within species with great inter-individual telomere lengths variability with age, tissues, and chromosomes. This raises the issue of the exact biological meaning of telomere measurement in blood cells and stimulated the study of the correlation of telomere lengths among tissues over age. By measuring telomere length in adult zebra finches (Taeniopygia guttata) in different somatic tissues displaying variable cell turnovers (bone marrow, brain, spleen, pectoral muscle, heart, liver and in red blood cells), we checked that the measure of telomere length in red blood cells is related to telomere lengths in the other tissues. Here we show significant relationships between the telomere lengths of red blood cells and several somatic tissues at adulthood. As red blood cells are easily accessible and suitable for the longitudinal monitoring of the individual rate of telomere loss, our study confirms that telomere length measured in red blood cells could serve as a surrogate for telomere length in the whole avian organism.},
}
@article {pmid24344315,
year = {2014},
author = {Rao, T and Lubin, JW and Armstrong, GS and Tucey, TM and Lundblad, V and Wuttke, DS},
title = {Structure of Est3 reveals a bimodal surface with differential roles in telomere replication.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {111},
number = {1},
pages = {214-218},
pmid = {24344315},
issn = {1091-6490},
support = {R37AG11728/AG/NIA NIH HHS/United States ; R37 AG011728/AG/NIA NIH HHS/United States ; R01GM059414/GM/NIGMS NIH HHS/United States ; T32 GM008759/GM/NIGMS NIH HHS/United States ; T32 GM007240/GM/NIGMS NIH HHS/United States ; R01 GM059414/GM/NIGMS NIH HHS/United States ; T32 GM142607/GM/NIGMS NIH HHS/United States ; T32GM08759/GM/NIGMS NIH HHS/United States ; T32GM007240/GM/NIGMS NIH HHS/United States ; P30 CA046934/CA/NCI NIH HHS/United States ; },
mesh = {Algorithms ; Catalytic Domain ; Cell Proliferation ; Cloning, Molecular ; Cluster Analysis ; *DNA Replication ; Genetic Complementation Test ; Humans ; Magnetic Resonance Spectroscopy ; Mutagenesis ; Mutation, Missense ; Protein Folding ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/*chemistry/*genetics ; Serine Proteases/chemistry ; Shelterin Complex ; Telomerase/*chemistry/*genetics ; Telomere/*metabolism ; Telomere-Binding Proteins ; },
abstract = {Telomerase is essential for continuous cellular proliferation. Substantial insights have come from studies of budding yeast telomerase, which consists of a catalytic core in association with two regulatory proteins, ever shorter telomeres 1 and 3 (Est1 and Est3). We report here a high-resolution structure of the Est3 telomerase subunit determined using a recently developed strategy that combines minimal NMR experimental data with Rosetta de novo structure prediction algorithms. Est3 adopts an overall protein fold which is structurally similar to that adopted by the shelterin component TPP1. However, the characteristics of the surface of the experimentally determined Est3 structure are substantially different from those predicted by prior homology-based models of Est3. Structure-guided mutagenesis of the complete surface of the Est3 protein reveals two adjacent patches on a noncanonical face of the protein that differentially mediate telomere function. Mapping these two patches on the Est3 structure defines a set of shared features between Est3 and HsTPP1, suggesting an analogous multifunctional surface on TPP1.},
}
@article {pmid24342530,
year = {2014},
author = {O'Callaghan, N and Parletta, N and Milte, CM and Benassi-Evans, B and Fenech, M and Howe, PR},
title = {Telomere shortening in elderly individuals with mild cognitive impairment may be attenuated with ω-3 fatty acid supplementation: a randomized controlled pilot study.},
journal = {Nutrition (Burbank, Los Angeles County, Calif.)},
volume = {30},
number = {4},
pages = {489-491},
doi = {10.1016/j.nut.2013.09.013},
pmid = {24342530},
issn = {1873-1244},
mesh = {Aged ; Aging/drug effects ; Cognitive Dysfunction/*complications ; *Dietary Supplements ; Docosahexaenoic Acids/blood/*pharmacology ; Eicosapentaenoic Acid/*pharmacology ; Erythrocytes/metabolism ; Humans ; Pilot Projects ; Telomere Shortening/*drug effects ; alpha-Linolenic Acid/*pharmacology ; },
abstract = {OBJECTIVES: Excessive shortening of the telomeric ends of chromosomes is a marker of accelerated aging. Oxidative stress and nutritional deficiency may influence this process. The aim of this study was to investigate the effect of ω-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation on telomeric shortening in elderly individuals with mild cognitive impairment (MCI).<br><br>METHODS: Thirty-three adults ages > 65 y with MCI were randomized to receive a supplement rich in the long-chain &#x3c9;-3 PUFAs eicosapentaenoic acid (EPA; 1.67 g EPA + 0.16 g docosahexaenoic acid DHA/d; n = 12) or DHA (1.55 g DHA + 0.40 g EPA/d; n = 12), versus &#x3c9;-6 PUFA linoleic acid (LA; 2.2 g/d; n = 9) for 6 mo.<br><br>RESULTS: The intervention did not show an increase in telomere length with treatment and there was a trend toward telomere shortening during the intervention period. Linear mixed modeling produced a robust model although statistically underpowered. Telomere shortening was greatest in the LA group (d = 0.21) than in the DHA (d = 0.12) and EPA groups (d = 0.06). Increased erythrocyte DHA levels were associated with reduced telomere shortening (r = -0.67; P = 0.02) in the DHA group.<br><br>CONCLUSION: Telomeric shortening may be attenuated by &#x3c9;-3 PUFA supplementation, requiring further investigation in larger samples.},
}
@article {pmid24339742,
year = {2013},
author = {Sakellariou, D and Chiourea, M and Raftopoulou, C and Gagos, S},
title = {Alternative lengthening of telomeres: recurrent cytogenetic aberrations and chromosome stability under extreme telomere dysfunction.},
journal = {Neoplasia (New York, N.Y.)},
volume = {15},
number = {11},
pages = {1301-1313},
pmid = {24339742},
issn = {1476-5586},
mesh = {Cell Line, Tumor ; *Chromosomal Instability ; *Chromosome Aberrations ; Chromosomes, Human/genetics/*metabolism ; Humans ; Karyotyping ; Telomere/*genetics/*metabolism ; Telomere Homeostasis/*genetics ; Translocation, Genetic/genetics ; },
abstract = {Human tumors using the alternative lengthening of telomeres (ALT) exert high rates of telomere dysfunction. Numerical chromosomal aberrations are very frequent, and structural rearrangements are widely scattered among the genome. This challenging context allows the study of telomere dysfunction-driven chromosomal instability in neoplasia (CIN) in a massive scale. We used molecular cytogenetics to achieve detailed karyotyping in 10 human ALT neoplastic cell lines. We identified 518 clonal recombinant chromosomes affected by 649 structural rearrangements. While all human chromosomes were involved in random or clonal, terminal, or pericentromeric rearrangements and were capable to undergo telomere healing at broken ends, a differential recombinatorial propensity of specific genomic regions was noted. We show that ALT cells undergo epigenetic modifications rendering polycentric chromosomes functionally monocentric, and because of increased terminal recombinogenicity, they generate clonal recombinant chromosomes with interstitial telomeric repeats. Losses of chromosomes 13, X, and 22, gains of 2, 3, 5, and 20, and translocation/deletion events involving several common chromosomal fragile sites (CFSs) were recurrent. Long-term reconstitution of telomerase activity in ALT cells reduced significantly the rates of random ongoing telomeric and pericentromeric CIN. However, the contribution of CFS in overall CIN remained unaffected, suggesting that in ALT cells whole-genome replication stress is not suppressed by telomerase activation. Our results provide novel insights into ALT-driven CIN, unveiling in parallel specific genomic sites that may harbor genes critical for ALT cancerous cell growth.},
}
@article {pmid24338368,
year = {2014},
author = {Zeng, S and Liu, L and Sun, Y and Xie, P and Hu, L and Yuan, D and Chen, D and Ouyang, Q and Lin, G and Lu, G},
title = {Telomerase-mediated telomere elongation from human blastocysts to embryonic stem cells.},
journal = {Journal of cell science},
volume = {127},
number = {Pt 4},
pages = {752-762},
doi = {10.1242/jcs.131433},
pmid = {24338368},
issn = {1477-9137},
mesh = {Animals ; Biomarkers/metabolism ; Blastocyst/*enzymology ; Cell Differentiation ; Cell Proliferation ; Cell Transformation, Neoplastic/metabolism ; Cells, Cultured ; Chromatin/metabolism ; Embryonic Stem Cells/*enzymology ; Genomic Instability ; Histones/metabolism ; Humans ; Methylation ; Mice ; Neoplasm Transplantation ; Protein Processing, Post-Translational ; Telomerase/*physiology ; Telomere/*metabolism ; *Telomere Homeostasis ; Teratoma/enzymology/pathology ; Wnt Signaling Pathway ; },
abstract = {High telomerase activity is a characteristic of human embryonic stem cells (hESCs), however, the regulation and maintenance of correct telomere length in hESCs is unclear. In this study we investigated telomere elongation in hESCs in vitro and found that telomeres lengthened from their derivation in blastocysts through early expansion, but stabilized at later passages. We report that the core unit of telomerase, hTERT, was highly expressed in hESCs in blastocysts and throughout long-term culture; furthermore, this was regulated in a Wnt-β-catenin-signaling-dependent manner. Our observations that the alternative lengthening of telomeres (ALT) pathway was suppressed in hESCs and that hTERT knockdown partially inhibited telomere elongation, demonstrated that high telomerase activity was required for telomere elongation. We observed that chromatin modification through trimethylation of H3K9 and H4K20 at telomeric regions decreased during early culture. This was concurrent with telomere elongation, suggesting that epigenetic regulation of telomeric chromatin may influence telomerase function. By measuring telomere length in 96 hESC lines, we were able to establish that telomere length remained relatively stable at 12.02 ± 1.01 kb during later passages (15-95). In contrast, telomere length varied in hESCs with genomic instability and hESC-derived teratomas. In summary, we propose that correct, stable telomere length may serve as a potential biomarker for genetically stable hESCs.},
}
@article {pmid24337410,
year = {2014},
author = {Mainous, AG and Wright, RU and Hulihan, MM and Twal, WO and McLaren, CE and Diaz, VA and McLaren, GD and Argraves, WS and Grant, AM},
title = {Elevated transferrin saturation, health-related quality of life and telomere length.},
journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine},
volume = {27},
number = {1},
pages = {135-141},
pmid = {24337410},
issn = {1572-8773},
support = {P20 RR016434/RR/NCRR NIH HHS/United States ; F06 TW002117/TW/FIC NIH HHS/United States ; P30 CA062203/CA/NCI NIH HHS/United States ; P20RR16461/RR/NCRR NIH HHS/United States ; P20 RR016461/RR/NCRR NIH HHS/United States ; AVU3//Intramural CDC HHS/United States ; },
mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; *Quality of Life ; Real-Time Polymerase Chain Reaction ; Telomere/genetics/*metabolism ; Transferrin/*analysis/metabolism ; },
abstract = {We sought to examine the relationship between elevated transferrin saturation (TS) and measures of health status (telomere length and patient-reported health-related quality of life) to assess whether elevated TS is associated with negative patient outcomes beyond increased risk for morbidity and mortality, using a cross-sectional analysis of the Hemochromatosis and Iron Overload Screening Study supplemented with assays for leukocyte telomere length in adults ≥25 years old (n = 669). Among individuals with elevated TS (≥45 % for women and ≥50 % for men), who also had a usual source of care, only 5.2 % reported ever being told by a doctor that they had an elevated iron condition. In a fully adjusted general linear regression model controlling for demographic characteristics as well as health conditions associated with iron overload, elevated TS versus non-elevated TS was associated with worse general health status (60.4 vs. 63.8, P < 0.05), mental health status (76.5 vs. 82.2, P < 0.0001) and shorter telomere length (241.4 vs. 261.3, P < 0.05). Increased surveillance of elevated TS may be in order as elevated TS is associated with decreased health status and very few patients with elevated TS are aware of their condition.},
}
@article {pmid24336466,
year = {2013},
author = {Dan, J and Li, M and Yang, J and Li, J and Okuka, M and Ye, X and Liu, L},
title = {Roles for Tbx3 in regulation of two-cell state and telomere elongation in mouse ES cells.},
journal = {Scientific reports},
volume = {3},
number = {},
pages = {3492},
pmid = {24336466},
issn = {2045-2322},
mesh = {Animals ; Cells, Cultured ; DNA Methylation ; Embryonic Stem Cells/*cytology/*metabolism ; Epigenesis, Genetic ; Gene Expression Regulation ; Mice ; Models, Biological ; Promoter Regions, Genetic ; T-Box Domain Proteins/genetics/*metabolism ; Telomerase/genetics/metabolism ; *Telomere Homeostasis ; Transcription Factors/genetics ; Up-Regulation ; },
abstract = {Mouse embryonic stem (ES) cell cultures exhibit heterogeneity and recently are discovered to sporadically enter the 2-cell (2C)-embryo state, critical for ES potency. Zscan4 could mark the sporadic 2C-state of ES cells. However, factors that regulate the Zscan4(+)/2C state remain to be elucidated. We show that Tbx3 plays a novel role in regulation of Zscan4(+)/2C state. Tbx3 activates 2-cell genes including Zscan4 and Tcstv1/3, but not vise versa. Ectopic expression of Tbx3 results in telomere elongation, consistent with a role for Zscan4 in telomere lengthening. Mechanistically, Tbx3 decreases Dnmt3b and increases Tet2 protein levels, and reduces binding of Dnmt3b to subtelomeres, resulting in reduced DNA methylation and derepression of genes at subtelomeres, e.g. Zscan4. These data suggest that Tbx3 can activate Zscan4(+)/2C state by negative regulation of DNA methylation at repeated sequences, linking to telomere maintenance and self-renewal of ES cells.},
}
@article {pmid24335912,
year = {2014},
author = {Starkweather, AR and Alhaeeri, AA and Montpetit, A and Brumelle, J and Filler, K and Montpetit, M and Mohanraj, L and Lyon, DE and Jackson-Cook, CK},
title = {An integrative review of factors associated with telomere length and implications for biobehavioral research.},
journal = {Nursing research},
volume = {63},
number = {1},
pages = {36-50},
pmid = {24335912},
issn = {1538-9847},
support = {P30 NR011403/NR/NINR NIH HHS/United States ; R00 NR012016/NR/NINR NIH HHS/United States ; R01 AG037986/AG/NIA NIH HHS/United States ; NINR P30NR011403//PHS HHS/United States ; R01AG037986/AG/NIA NIH HHS/United States ; K99/R00NR012016/NR/NINR NIH HHS/United States ; R01 NR012667/NR/NINR NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aging/*genetics/*physiology ; Behavior/*physiology ; Child ; Child, Preschool ; Female ; Humans ; Male ; Mental Disorders/*genetics ; Middle Aged ; Stress, Psychological/*genetics ; *Telomere Homeostasis ; *Telomere Shortening ; Young Adult ; },
abstract = {BACKGROUND: Although telomere shortening occurs as a natural part of aging, there is now a robust body of research that suggests that there is a relationship between psychosocial, environmental, and behavioral factors and changes in telomere length. These factors need to be considered when integrating telomere measurement in biobehavioral research studies.<br><br>OBJECTIVES: This article provides a brief summary of the known facts about telomere biology and an integrative review of current human research studies that assessed relationships between psychosocial, environmental, or behavioral factors and telomere length.<br><br>METHODS: An integrative review was conducted to examine human research studies that focused on psychosocial, environmental, and behavioral factors affecting telomere length and telomerase activity using the electronic databases PubMed/Medline and CINAHL from 2003 to the present. In addition to the known individual factors that are associated with telomere length, the results of the integrative review suggest that perceived stress, childhood adversities, major depressive disorder, educational attainment, physical activity, and sleep duration should also be measured.<br><br>DISCUSSION: Multiple factors have been shown to affect telomere length. To advance understanding of the role of telomere length in health and disease risk, it will be important to further elucidate the mechanisms that contribute to telomere shortening.},
}
@article {pmid24334955,
year = {2014},
author = {Ogrocká, A and Polanská, P and Majerová, E and Janeba, Z and Fajkus, J and Fojtová, M},
title = {Compromised telomere maintenance in hypomethylated Arabidopsis thaliana plants.},
journal = {Nucleic acids research},
volume = {42},
number = {5},
pages = {2919-2931},
pmid = {24334955},
issn = {1362-4962},
mesh = {Arabidopsis/enzymology/*genetics/metabolism ; Cytosine/metabolism ; *DNA Methylation ; Plants/genetics/metabolism ; Repetitive Sequences, Nucleic Acid ; Telomerase/metabolism ; Telomere/chemistry/*metabolism ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Telomeres, nucleoprotein structures at the ends of linear eukaryotic chromosomes, are important for the maintenance of genomic stability. Telomeres were considered as typical heterochromatic regions, but in light of recent results, this view should be reconsidered. Asymmetrically located cytosines in plant telomeric DNA repeats may be substrates for a DNA methyltransferase enzyme and indeed, it was shown that these repeats are methylated. Here, we analyse the methylation of telomeric cytosines and the length of telomeres in Arabidopsis thaliana methylation mutants (met 1-3 and ddm 1-8), and in their wild-type siblings that were germinated in the presence of hypomethylation drugs. Our results show that cytosine methylation in telomeric repeats depends on the activity of MET1 and DDM1 enzymes. Significantly shortened telomeres occur in later generations of methylation mutants as well as in plants germinated in the presence of hypomethylation drugs, and this phenotype is stably transmitted to the next plant generation. A possible role of compromised in vivo telomerase action in the observed telomere shortening is hypothesized based on telomere analysis of hypomethylated telomerase knockout plants. Results are discussed in connection with previous data in this field obtained using different model systems.},
}
@article {pmid24331919,
year = {2013},
author = {Queisser, A and Heeg, S and Thaler, M and von Werder, A and Opitz, OG},
title = {Inhibition of telomerase induces alternative lengthening of telomeres during human esophageal carcinogenesis.},
journal = {Cancer genetics},
volume = {206},
number = {11},
pages = {374-386},
doi = {10.1016/j.cancergen.2013.10.001},
pmid = {24331919},
issn = {2210-7762},
mesh = {Carcinogenesis/genetics/metabolism ; Cell Cycle/physiology ; Cell Transformation, Neoplastic/*genetics/metabolism ; Enzyme Activation ; Epithelial Cells/cytology/enzymology ; Esophageal Neoplasms/*enzymology/*genetics/metabolism ; Esophagus/cytology ; HEK293 Cells ; Humans ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; Transfection ; },
abstract = {Immortalization is an important step toward the malignant transformation of human cells and is critically dependent upon telomere maintenance. Two mechanisms are known to maintain human telomeres. The process of telomere maintenance is either mediated through activation of the enzyme telomerase or through an alternative mechanism of telomere lengthening called alternative lengthening of telomeres (ALT). Whereas 85% of all human tumors show reactivation of telomerase, the remaining 15% are able to maintain telomeres via ALT. Telomerase inhibitors are already investigated in clinical trials, although the regulation as well as potential coexistence and redundancy of both telomere maintenance mechanisms during distinct steps of carcinogenesis are poorly understood. Herein, we demonstrate that telomerase activity and ALT alternate in a cell cycle dependent fashion in human esophageal epithelial cells, and can coexist in a genetically defined model of oral-esophageal squamous carcinogenesis. Moreover, we show that immortalized premalignant cells as well as cancer cells are able to switch from telomerase activation to ALT upon inhibition of telomerase. This indicates that cancer cells treated with telomerase inhibitors can use alternative and adaptive ways to maintain their telomeres and thereby escape telomere-based therapeutic strategies.},
}
@article {pmid24330541,
year = {2013},
author = {Iachettini, S and Stevens, MF and Frigerio, M and Hummersone, MG and Hutchinson, I and Garner, TP and Searle, MS and Wilson, DW and Munde, M and Nanjunda, R and D'Angelo, C and Zizza, P and Rizzo, A and Cingolani, C and De Cicco, F and Porru, M and D'Incalci, M and Leonetti, C and Biroccio, A and Salvati, E},
title = {On and off-target effects of telomere uncapping G-quadruplex selective ligands based on pentacyclic acridinium salts.},
journal = {Journal of experimental &amp; clinical cancer research : CR},
volume = {32},
number = {1},
pages = {68},
pmid = {24330541},
issn = {1756-9966},
mesh = {Acridines/chemical synthesis/*chemistry/*pharmacology ; Animals ; Cell Proliferation/drug effects ; Cells, Cultured ; *G-Quadruplexes ; Guinea Pigs ; Humans ; Ligands ; Telomerase/antagonists &amp; inhibitors ; Telomere/*metabolism ; },
abstract = {Quadruplexes DNA are present in telomeric DNA as well as in several cancer-related gene promoters and hence affect gene expression and subsequent biological processes. The conformations of G4 provide selective recognition sites for small molecules and thus these structures have become important drug-design targets for cancer treatment. The DNA G-quadruplex binding pentacyclic acridinium salt RHPS4 (1) has many pharmacological attributes of an ideal telomere-targeting agent but has undesirable off-target liabilities. Notably a cardiovascular effect was evident in a guinea pig model, manifested by a marked and sustained increase in QTcB interval. In accordance with this, significant interaction with the human recombinant ß2 adrenergic receptor, and M1, M2 and M3 muscarinic receptors was observed, together with a high inhibition of the hERG tail current tested in a patch clamp assay. Two related pentacyclic structures, the acetylamines (2) and (3), both show a modest interaction with ß2 adrenergic receptor, and do not significatively inhibit the hERG tail current while demonstrating potent telomere on-target properties comparing closely with 1. Of the two isomers, the 2-acetyl-aminopentacycle (2) more closely mimics the overall biological profile of 1 and this information will be used to guide further synthetic efforts to identify novel variants of this chemotype, to maximize on-target and minimize off-target activities. Consequently, the improvement of toxicological profile of these compounds could therefore lead to the obtainment of suitable molecules for clinical development offering new pharmacological strategies in cancer treatment.},
}
@article {pmid24329474,
year = {2013},
author = {Duc, KD and Holcman, D},
title = {Computing the length of the shortest telomere in the nucleus.},
journal = {Physical review letters},
volume = {111},
number = {22},
pages = {228104},
doi = {10.1103/PhysRevLett.111.228104},
pmid = {24329474},
issn = {1079-7114},
mesh = {Cell Nucleus/*diagnostic imaging/enzymology ; Markov Chains ; *Models, Genetic ; Telomerase/metabolism ; Telomere/metabolism/*ultrastructure ; Ultrasonography ; },
abstract = {The telomere length can either be shortened or elongated by an enzyme called telomerase after each cell division. Interestingly, the shortest telomere is involved in controlling the ability of a cell to divide. Yet, its dynamics remains elusive. We present here a stochastic approach where we model this dynamics using a Markov jump process. We solve the forward Fokker-Planck equation to obtain the steady state distribution and the statistical moments of telomere lengths. We focus specifically on the shortest one and we estimate its length difference with the second shortest telomere. After extracting key parameters such as elongation and shortening dynamics from experimental data, we compute the length of telomeres in yeast and obtain as a possible prediction the minimum concentration of telomerase required to ensure a proper cell division.},
}
@article {pmid24311771,
year = {2014},
author = {Albrecht, E and Sillanpää, E and Karrasch, S and Alves, AC and Codd, V and Hovatta, I and Buxton, JL and Nelson, CP and Broer, L and Hägg, S and Mangino, M and Willemsen, G and Surakka, I and Ferreira, MA and Amin, N and Oostra, BA and Bäckmand, HM and Peltonen, M and Sarna, S and Rantanen, T and Sipilä, S and Korhonen, T and Madden, PA and Gieger, C and Jörres, RA and Heinrich, J and Behr, J and Huber, RM and Peters, A and Strauch, K and Wichmann, HE and Waldenberger, M and Blakemore, AI and de Geus, EJ and Nyholt, DR and Henders, AK and Piirilä, PL and Rissanen, A and Magnusson, PK and Viñuela, A and Pietiläinen, KH and Martin, NG and Pedersen, NL and Boomsma, DI and Spector, TD and van Duijn, CM and Kaprio, J and Samani, NJ and Jarvelin, MR and Schulz, H},
title = {Telomere length in circulating leukocytes is associated with lung function and disease.},
journal = {The European respiratory journal},
volume = {43},
number = {4},
pages = {983-992},
doi = {10.1183/09031936.00046213},
pmid = {24311771},
issn = {1399-3003},
support = {MR/K014536/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aged ; Asthma/*blood/genetics ; Case-Control Studies ; Cohort Studies ; Europe ; Female ; Forced Expiratory Volume ; Humans ; Leukocytes/*cytology ; Lung Diseases/*blood/genetics ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/*blood/genetics ; Regression Analysis ; Smoking ; Spirometry ; Telomere/*ultrastructure ; Vital Capacity ; },
abstract = {Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (β= -0.0452, p=0.024) as well as COPD (β= -0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07×10(-7)), FVC (p=2.07×10(-5)), and FEV1/FVC (p=5.27×10(-3)). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.},
}
@article {pmid24308314,
year = {2013},
author = {Lin, SW and Abnet, CC and Freedman, ND and Murphy, G and Risques, R and Prunkard, D and Rabinovitch, P and Pan, QJ and Roth, MJ and Wang, GQ and Wei, WQ and Lu, N and Taylor, PR and Qiao, YL and Dawsey, SM},
title = {Measuring telomere length for the early detection of precursor lesions of esophageal squamous cell carcinoma.},
journal = {BMC cancer},
volume = {13},
number = {},
pages = {578},
pmid = {24308314},
issn = {1471-2407},
support = {N01-SC-91019/SC/NCI NIH HHS/United States ; //Intramural NIH HHS/United States ; },
mesh = {Area Under Curve ; Biomarkers, Tumor/*genetics ; Carcinoma, Squamous Cell/*diagnosis/genetics ; Case-Control Studies ; *Early Detection of Cancer ; Esophageal Neoplasms/*diagnosis/genetics ; Esophageal Squamous Cell Carcinoma ; Female ; Humans ; Male ; Middle Aged ; ROC Curve ; Telomere/*genetics ; Telomere Homeostasis ; },
abstract = {BACKGROUND: Esophageal cancer is the sixth leading cause of cancer death worldwide; current early detection screening tests are inadequate. Esophageal balloon cytology successfully retrieves exfoliated and scraped superficial esophageal epithelial cells, but cytologic reading of these cells has poor sensitivity and specificity for detecting esophageal squamous dysplasia (ESD), the precursor lesion of esophageal squamous cell carcinoma (ESCC). Measuring telomere length, a marker for chromosomal instability, may improve the utility of balloon cytology for detecting ESD and early ESCC.<br><br>METHODS: We examined balloon cytology specimens from 89 asymptomatic cases of ESD (37 low-grade and 52 high-grade) and 92 age- and sex-matched normal controls from an esophageal cancer early detection screening study. All subjects also underwent endoscopy and biopsy, and ESD was diagnosed histopathologically. DNA was extracted from the balloon cytology cells, and telomere length was measured by quantitative PCR. A receiver operating characteristic (ROC) curve was plotted for telomere length as a diagnostic marker for high-grade dysplasia.<br><br>RESULTS: Telomere lengths were comparable among the low- and high-grade dysplasia cases and controls, with means of 0.96, 0.96, and 0.92, respectively. The area under the ROC curve was 0.55 for telomere length as a diagnostic marker for high-grade dysplasia. Further adjustment for subject characteristics, including sex, age, smoking, drinking, hypertension, and body mass index did not improve the use of telomere length as a marker for ESD.<br><br>CONCLUSIONS: Telomere length of esophageal balloon cytology cells was not associated with ESCC precursor lesions. Therefore, telomere length shows little promise as an early detection marker for ESCC in esophageal balloon samples.},
}
@article {pmid24302747,
year = {2014},
author = {Li, Q and Du, J and Feng, R and Xu, Y and Wang, H and Sang, Q and Xing, Q and Zhao, X and Jin, L and He, L and Wang, L},
title = {A possible new mechanism in the pathophysiology of polycystic ovary syndrome (PCOS): the discovery that leukocyte telomere length is strongly associated with PCOS.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {99},
number = {2},
pages = {E234-40},
doi = {10.1210/jc.2013-3685},
pmid = {24302747},
issn = {1945-7197},
mesh = {Adult ; Aging/genetics/*metabolism ; Female ; Humans ; Leukocytes/*metabolism ; Polycystic Ovary Syndrome/*etiology/genetics/metabolism ; Telomere/*metabolism ; Telomere Shortening/*physiology ; },
abstract = {CONTEXT: Telomeres are specialized chromatin structures located at the ends of eukaryotic chromosomes, and telomere length plays a clear role in various diseases. However, it is not known whether telomere length is related to polycystic ovary syndrome (PCOS).<br><br>OBJECTIVE: We hypothesized that leukocyte telomere length (LTL) plays an important role in the pathophysiology of PCOS.<br><br>DESIGN: We used an established and validated quantitative PCR technique to measure the mean LTL in a large sample of PCOS patients and controls. We used logistic regression and multiple linear regression to analyze the association of PCOS and several related clinical parameters with the age-adjusted ratio of the telomere repeat length to the copy number of a single-copy gene (T/S).<br><br>RESULTS: Individuals with PCOS (n = 698) exhibited significantly shorter LTLs than the controls (n = 611) after adjusting for age (0.764 &#xb1; 0.016 vs 0.876 &#xb1; 0.023; P = .001; odds ratio = 1.403; 95% confidence interval, 1.150-1.712). The mean telomere length in the leukocytes of PCOS patients was comparable to that of control individuals who were on average 6.16 years older. Individuals having shorter telomere lengths (middle and lowest tertile) had significantly higher disease risk than those having the longest telomere length (highest tertile) (odds ratio = 1.614; 95% confidence interval, 1.262-2.066; P = .0001) after adjusting for age. In addition, a significant correlation between the LTL and the level of dehydroepiandrosterone sulfate was observed in controls (r = -0.185; P = .01).<br><br>CONCLUSION: We provide the first report that LTL is strongly associated with PCOS. This study suggests a new role for LTL in the pathophysiology of PCOS and might have important implications for our understanding of the etiology of the disease.},
}
@article {pmid24297748,
year = {2013},
author = {Ferreira, HC and Towbin, BD and Jegou, T and Gasser, SM},
title = {The shelterin protein POT-1 anchors Caenorhabditis elegans telomeres through SUN-1 at the nuclear periphery.},
journal = {The Journal of cell biology},
volume = {203},
number = {5},
pages = {727-735},
pmid = {24297748},
issn = {1540-8140},
mesh = {Animals ; Caenorhabditis elegans/embryology/genetics/*metabolism ; Caenorhabditis elegans Proteins/analysis/metabolism/*physiology ; Cell Nucleus/metabolism/ultrastructure ; Chromosome Positioning ; DNA-Binding Proteins/analysis/metabolism/*physiology ; Embryo, Nonmammalian/metabolism/ultrastructure ; Embryonic Development/genetics ; Receptors, Cytoplasmic and Nuclear/analysis/metabolism/*physiology ; Sumoylation ; Telomere/*metabolism ; Telomere-Binding Proteins/analysis/metabolism/physiology ; Ubiquitin-Protein Ligases/metabolism/physiology ; },
abstract = {Telomeres are specialized protein-DNA structures that protect chromosome ends. In budding yeast, telomeres form clusters at the nuclear periphery. By imaging telomeres in embryos of the metazoan Caenorhabditis elegans, we found that telomeres clustered only in strains that had activated an alternative telomere maintenance pathway (ALT). Moreover, as in yeast, the unclustered telomeres in wild-type embryos were located near the nuclear envelope (NE). This bias for perinuclear localization increased during embryogenesis and persisted in differentiated cells. Telomere position in early embryos required the NE protein SUN-1, the single-strand binding protein POT-1, and the small ubiquitin-like modifier (SUMO) ligase GEI-17. However, in postmitotic larval cells, none of these factors individually were required for telomere anchoring, which suggests that additional mechanisms anchor in late development. Importantly, targeted POT-1 was sufficient to anchor chromatin to the NE in a SUN-1-dependent manner, arguing that its effect at telomeres is direct. This high-resolution description of telomere position within C. elegans extends our understanding of telomere organization in eukaryotes.},
}
@article {pmid24297442,
year = {2014},
author = {Premkumar, VL and Cranert, S and Linger, BR and Morin, GB and Minium, S and Price, C},
title = {The 3' overhangs at Tetrahymena thermophila telomeres are packaged by four proteins, Pot1a, Tpt1, Pat1, and Pat2.},
journal = {Eukaryotic cell},
volume = {13},
number = {2},
pages = {240-245},
pmid = {24297442},
issn = {1535-9786},
support = {R01 GM088728/GM/NIGMS NIH HHS/United States ; T32 CA117846/CA/NCI NIH HHS/United States ; T32 ES007250/ES/NIEHS NIH HHS/United States ; GM088728/GM/NIGMS NIH HHS/United States ; },
mesh = {*3' Flanking Region ; DNA, Protozoan/metabolism ; Protein Binding ; Protozoan Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Tetrahymena thermophila/*genetics/metabolism ; },
abstract = {Although studies with the ciliate Tetrahymena thermophila have played a central role in advancing our understanding of telomere biology and telomerase mechanisms and composition, the full complement of Tetrahymena telomere proteins has not yet been identified. Previously, we demonstrated that in Tetrahymena, the telomeric 3' overhang is protected by a three-protein complex composed of Pot1a, Tpt1, and Pat1. Here we show that Tpt1 and Pat1 associate with a fourth protein, Pat2 (Pot1 associated Tetrahymena 2). Mass spectrometry of proteins copurifying with Pat1 or Tpt1 identified peptides from Pat2, Pot1a, Tpt1, and Pat1. The lack of other proteins copurifying with Pat1 or Tpt1 implies that the overhang is protected by a four-protein Pot1a-Tpt1-Pat1-Pat2 complex. We verified that Pat2 localizes to telomeres, but we were unable to detect direct binding to telomeric DNA. Cells depleted of Pat2 continue to divide, but the telomeres exhibit gradual shortening. The lack of growth arrest indicates that, in contrast to Pot1a and Tpt1, Pat2 is not required for the sequestration of the telomere from the DNA repair machinery. Instead, Pat2 is needed to regulate telomere length, most likely by acting in conjunction with Pat1 to allow telomerase access to the telomere.},
}
@article {pmid24296509,
year = {2014},
author = {El-Mahdy, AF and Shibata, T and Kabashima, T and Kai, M},
title = {Dendrimer-like polymeric DNAs as chemiluminescence probes for amplified detection of telomere DNA on a solid-phase membrane.},
journal = {Chemical communications (Cambridge, England)},
volume = {50},
number = {7},
pages = {859-861},
doi = {10.1039/c3cc47454b},
pmid = {24296509},
issn = {1364-548X},
mesh = {DNA/*analysis/chemistry ; Dendrimers ; Luminescence ; Membranes, Artificial ; Nucleic Acid Hybridization ; Nylons ; Polymers/chemistry ; Telomere/genetics ; },
abstract = {For the first time, an amplified chemiluminescence (CL) detection of the telomere DNA spotted on a nylon membrane is described here, based on the direct hybridization with the CL probe of dendrimer-like polymeric DNAs possessing a large number of guanine moieties. This probe was synthesized by sense and antisense hybridization between Y-shaped DNAs and then could hybridize with the target DNA.},
}
@article {pmid24290493,
year = {2014},
author = {Perez-Rivera, JA and Pabon-Osuna, P and Cieza-Borrella, C and Duran-Bobin, O and Martin-Herrero, F and Gonzalez-Porras, JR and Gonzalez-Sarmiento, R},
title = {Effect of telomere length on prognosis in men with acute coronary syndrome.},
journal = {The American journal of cardiology},
volume = {113},
number = {3},
pages = {418-421},
doi = {10.1016/j.amjcard.2013.10.009},
pmid = {24290493},
issn = {1879-1913},
mesh = {Acute Coronary Syndrome/diagnosis/*genetics/metabolism ; Aged ; Aged, 80 and over ; Aging/*genetics ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Polymerase Chain Reaction ; *Polymorphism, Genetic ; Prognosis ; Retrospective Studies ; Telomerase/genetics/metabolism ; Telomere/*ultrastructure ; },
abstract = {Telomere length is related to cellular aging and cardiovascular disease. Nevertheless, the specific role of cellular aging in this process is still unclear. The aim of this report was to analyze the prognostic value of telomere length in men admitted for acute coronary syndrome. Telomere length was measured by quantitative polymerase chain reaction in peripheral blood leukocytes of 203 men classified into 2 groups: those aged 50 to 75 years and those >75 years. Clinical follow-up had been done for >600 days, and a prognostic combined event was defined. In men aged 50 to 75 years, we found a statistically significant worse prognosis in patients with short telomeres (log-rank: 5.22, p <0.05) but not in men >75 years (log-rank: 0.01, p = 0.91). Cox analysis confirmed short telomeres in men aged 50 to 75 years as an independent prognostic risk factor. In conclusion, telomere length is a good predictor of cardiovascular prognosis in men admitted for acute coronary syndrome, but this relation depends on the chronological age of the population studied.},
}
@article {pmid24285042,
year = {2014},
author = {Hurwitz, LM and Heaphy, CM and Joshu, CE and Isaacs, WB and Konishi, Y and De Marzo, AM and Isaacs, SD and Wiley, KE and Platz, EA and Meeker, AK},
title = {Telomere length as a risk factor for hereditary prostate cancer.},
journal = {The Prostate},
volume = {74},
number = {4},
pages = {359-364},
pmid = {24285042},
issn = {1097-0045},
support = {U01 CA089600/CA/NCI NIH HHS/United States ; U01 CA89600/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; *Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Prospective Studies ; Prostatic Neoplasms/*genetics ; Risk Factors ; Smoking/genetics ; Telomere ; *Telomere Shortening ; },
abstract = {BACKGROUND: Telomeres are repetitive nucleotide sequences that stabilize the ends of chromosomes. Critically short telomeres are thought to contribute to cancer development by increasing chromosomal instability. We hypothesized that shorter leukocyte telomere length, a surrogate for inherited prostate cell telomere length, would be associated with increased risk of prostate cancer in hereditary prostate cancer (HPC) families.<br><br>METHODS: One hundred twelve affected and 63 unaffected men from 28 families were drawn from the Johns Hopkins HPC family database. Relative mean telomere length was measured in isolated peripheral leukocyte DNA by quantitative PCR. Conditional logistic regression was used to estimate the association between quartile of age-adjusted telomere length and prostate cancer.<br><br>RESULTS: Men in the shortest quartile of telomere length did not have increased odds of prostate cancer compared to men in the other three quartiles (OR&#x2009;=&#x2009;0.84, 95% CI: 0.32-2.20, P&#x2009;=&#x2009;0.73). However, when the analysis was restricted to affected men with blood drawn before or within a year of diagnosis (N&#x2009;=&#x2009;39) and all unaffected men, shorter telomere length was moderately associated with increased odds of prostate cancer (OR&#x2009;=&#x2009;3.55, 95% CI: 0.82-15.43, P&#x2009;=&#x2009;0.09).<br><br>CONCLUSIONS: Though we found no association overall, shorter leukocyte telomere length may be associated with increased odds of prostate cancer when measured in pre-diagnostic samples. Further prospective research is warranted exploring the utility of telomere length as a prostate cancer biomarker.},
}
@article {pmid24278245,
year = {2013},
author = {Ala-Mursula, L and Buxton, JL and Ek, E and Koiranen, M and Taanila, A and Blakemore, AI and Järvelin, MR},
title = {Long-term unemployment is associated with short telomeres in 31-year-old men: an observational study in the northern Finland birth cohort 1966.},
journal = {PloS one},
volume = {8},
number = {11},
pages = {e80094},
pmid = {24278245},
issn = {1932-6203},
support = {/WT_/Wellcome Trust/United Kingdom ; G0600705/MRC_/Medical Research Council/United Kingdom ; MR/K014536/1/MRC_/Medical Research Council/United Kingdom ; WT088431MA/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Cohort Studies ; Finland ; Humans ; Male ; Middle Aged ; Socioeconomic Factors ; *Telomere ; *Unemployment ; },
abstract = {OBJECTIVE: Life stress resulting from early-life experiences and domestic stress is linked with shorter leukocyte telomere length (LTL), but evidence on employment-related stress is scarce. We explored whether unemployment in early adulthood is associated with shorter LTL, a potential biomarker of premature aging.<br><br>METHODS: We used data from 5620 men and women belonging to the Northern Finland Birth Cohort 1966. Individually registered unemployment days in 1995-97 were compared with data on biological, behavioral and socioeconomic health predictors and existing medical conditions obtained by surveys and clinical examinations at follow-up in 1997-98. Mean LTL at follow-up was measured by multiplex quantitative real-time PCR. We calculated odds ratios and their 95% confidence intervals (CI) of belonging to the sex-stratified shortest decile of standardized relative mean LTL according to the categories of: 0, <260, <500 and over 500 unemployment days, representing 0, <1, <2 and over 2 calendar years.<br><br>RESULTS: Among men, unemployment exceeding 500 days during three years was associated with having shorter LTL at follow-up, compared to being continuously employed. The corresponding odds ratio was 2.61 (95% CI 1.16 to 5.85) in the fully adjusted model. Such an association was not found among women in this study.<br><br>CONCLUSIONS: Long-term unemployment in early adulthood is associated with shorter LTL among men.},
}
@article {pmid24278232,
year = {2013},
author = {Boardman, LA and Johnson, RA and Viker, KB and Hafner, KA and Jenkins, RB and Riegert-Johnson, DL and Smyrk, TC and Litzelman, K and Seo, S and Gangnon, RE and Engelman, CD and Rider, DN and Vanderboom, RJ and Thibodeau, SN and Petersen, GM and Skinner, HG},
title = {Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: a molecular subclass of rectal cancer.},
journal = {PloS one},
volume = {8},
number = {11},
pages = {e80015},
pmid = {24278232},
issn = {1932-6203},
support = {P30 CA014520/CA/NCI NIH HHS/United States ; P30 DK084567/DK/NIDDK NIH HHS/United States ; P50 CA102701/CA/NCI NIH HHS/United States ; R01 CA132718/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; *Chromosomal Instability ; Comparative Genomic Hybridization ; DNA Primers ; Enzyme Activation ; Genes, p53 ; Humans ; Microsatellite Repeats/*genetics ; Middle Aged ; Point Mutation ; Real-Time Polymerase Chain Reaction ; Rectal Neoplasms/enzymology/*genetics ; Telomerase/metabolism ; *Telomere ; },
abstract = {INTRODUCTION: Colorectal cancer (CRC) tumor DNA is characterized by chromosomal damage termed chromosomal instability (CIN) and excessively shortened telomeres. Up to 80% of CRC is microsatellite stable (MSS) and is historically considered to be chromosomally unstable (CIN+). However, tumor phenotyping depicts some MSS CRC with little or no genetic changes, thus being chromosomally stable (CIN-). MSS CIN- tumors have not been assessed for telomere attrition.<br><br>EXPERIMENTAL DESIGN: MSS rectal cancers from patients &#x2264;50 years old with Stage II (B2 or higher) or Stage III disease were assessed for CIN, telomere length and telomere maintenance mechanism (telomerase activation [TA]; alternative lengthening of telomeres [ALT]). Relative telomere length was measured by qPCR in somatic epithelial and cancer DNA. TA was measured with the TRAPeze assay, and tumors were evaluated for the presence of C-circles indicative of ALT. p53 mutation status was assessed in all available samples. DNA copy number changes were evaluated with Spectral Genomics aCGH.<br><br>RESULTS: Tumors were classified as chromosomally stable (CIN-) and chromosomally instable (CIN+) by degree of DNA copy number changes. CIN- tumors (35%; n=6) had fewer copy number changes (<17% of their clones with DNA copy number changes) than CIN+ tumors (65%; n=13) which had high levels of copy number changes in 20% to 49% of clones. Telomere lengths were longer in CIN- compared to CIN+ tumors (p=0.0066) and in those in which telomerase was not activated (p=0.004). Tumors exhibiting activation of telomerase had shorter tumor telomeres (p=0.0040); and tended to be CIN+ (p=0.0949).<br><br>CONCLUSIONS: MSS rectal cancer appears to represent a heterogeneous group of tumors that may be categorized both on the basis of CIN status and telomere maintenance mechanism. MSS CIN- rectal cancers appear to have longer telomeres than those of MSS CIN+ rectal cancers and to utilize ALT rather than activation of telomerase.},
}
@article {pmid24278229,
year = {2013},
author = {Zhao, J and Miao, K and Wang, H and Ding, H and Wang, DW},
title = {Association between telomere length and type 2 diabetes mellitus: a meta-analysis.},
journal = {PloS one},
volume = {8},
number = {11},
pages = {e79993},
pmid = {24278229},
issn = {1932-6203},
mesh = {Case-Control Studies ; Cohort Studies ; Diabetes Mellitus, Type 2/*genetics ; Humans ; *Telomere ; },
abstract = {BACKGROUND: Several epidemiological studies have examined the association between shortened telomere length and type 2 diabetes mellitus (T2DM), while the results remained conflicting. We conducted a meta-analysis to derive a more precise estimation of the relationship between them.<br><br>METHODS: We systematically reviewed the databases of PubMed, EMBASE, and Web of Science for all studies on the association between telomere length and T2DM. We conducted this study assessed by STATA 11.0. Data were summarized using random-effects or fixed-effects meta-analysis. The heterogeneity and publication bias among studies were examined by using &#x3c7;(2)-based Q statistic test and Egger's test, respectively.<br><br>RESULTS: Nine cohorts consisting of 5759 cases and 6518 controls were selected into the meta-analysis. The results indicated that shortened telomere length was significantly associated with T2DM risk (OR: 1.291; 95% CI: 1.112, 1.498; P<0.001) with heterogeneity (I(2)&#x200a;=&#x200a;71.6%). When three cohorts responsible for the heterogeneity were excluded, the pooled OR for the remaining cohorts indicated a significant association between shortened telomere length and T2DM (OR: 1.117; 95% CI: 1.002, 1.246; P&#x200a;=&#x200a;0.045) without heterogeneity.<br><br>CONCLUSION: We found a statistically significant association between shortened telomere length and T2DM.},
}
@article {pmid24278041,
year = {2013},
author = {Yin, B and Jiang, X},
title = {Telomere shortening in cultured human dermal fibroblasts is associated with acute photodamage induced by UVA irradiation.},
journal = {Postepy dermatologii i alergologii},
volume = {30},
number = {1},
pages = {13-18},
pmid = {24278041},
issn = {1642-395X},
abstract = {INTRODUCTION: Photoaging is the superposition of chronic ultraviolet (UV)-induced damage on intrinsic aging. Telomere length is a molecular marker of cell aging, and genomic instability due to telomere shortening has been linked to several aging-related diseases.<br><br>AIM: To explore the effects of different doses of ultraviolet A (UVA) on the length of telomeres in human skin fibroblasts and partly reveal the mechanism of skin photoaging initiated by UVA irradiation.<br><br>MATERIAL AND METHODS: Primary cultured human skin fibroblasts were irradiated with different doses of UVA light. Cell viability, cell cycle phase, &#x3b2;-galactosidase, and the length of telomeres were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, cytochemical staining, and real-time polymerase chain reactions, respectively.<br><br>RESULTS: After UVA irradiation, inhibited proliferation, S phase accumulation and increased expression of senescence-associated &#x3b2;-galactosidase were observed in cultured fibroblasts. Moreover, the length of telomeres in UVA-treated cells was shortened in a dose-dependent manner as compared to controls (p < 0.05).<br><br>CONCLUSIONS: These results suggest that telomere length in human dermal fibroblasts can be shortened by a single high dosage of UVA radiation, and that acute photodamage might contribute to early photoaging in human skin via rapid telomere shortening. This study potentially provides the basis for better understanding of the molecular mechanism of photoaging.},
}
@article {pmid24277454,
year = {2014},
author = {Gramatges, MM and Liu, Q and Yasui, Y and Okcu, MF and Neglia, JP and Strong, LC and Armstrong, GT and Robison, LL and Bhatia, S},
title = {Telomere content and risk of second malignant neoplasm in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {20},
number = {4},
pages = {904-911},
pmid = {24277454},
issn = {1557-3265},
support = {U24 CA55727/CA/NCI NIH HHS/United States ; K12 CA090433/CA/NCI NIH HHS/United States ; 5K12CA090433-10/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; K23 CA158148/CA/NCI NIH HHS/United States ; L40 CA153043/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Case-Control Studies ; Child ; Female ; Hodgkin Disease/epidemiology/*genetics ; Humans ; Male ; Multivariate Analysis ; Neoplasms, Second Primary/epidemiology/*genetics ; Retrospective Studies ; Sex Distribution ; Survivors ; Telomere/genetics/*metabolism ; Thyroid Neoplasms/epidemiology/*genetics ; Young Adult ; },
abstract = {PURPOSE: Shorter constitutional telomere length has been associated with increased cancer incidence. Furthermore, telomere shortening is observed in response to intensive chemotherapy and/or ionizing radiation exposure. We aimed to determine whether less telomere content was associated with treatment-related second malignant neoplasms (SMN) in childhood cancer survivors.<br><br>EXPERIMENTAL DESIGN: Using a nested case-control design, 147 cancer survivors with breast cancer, thyroid cancer, or sarcoma developing after treatment for childhood cancer (cases) were matched (1:1) with childhood cancer survivors without a SMN (controls). Cases and controls were matched by primary cancer diagnosis, years since diagnosis, age at the time of sample collection, years of follow-up from childhood cancer diagnosis, exposure to specific chemotherapy agents, and to specific radiation fields. We performed conditional logistic regression using telomere content as a continuous variable to estimate ORs with corresponding 95% confidence intervals (CI) for development of SMN. ORs were also estimated for specific SMN types, i.e., breast cancer, thyroid cancer, and sarcoma.<br><br>RESULTS: There was an inverse relationship between telomere content and SMN, with an adjusted OR of 0.3 per unit change in telomere length to single-copy gene ratio (95% CI, 0.09-1.02; P = 0.05). Patients with thyroid cancer SMN were less likely to have more telomere content (OR, 0.04; 95% CI, 0.00-0.55; P = 0.01), but statistically significant associations could not be demonstrated for breast cancer or sarcoma.<br><br>CONCLUSIONS: A relation between less telomere content and treatment-related thyroid cancer was observed, suggesting that shorter telomeres may contribute to certain SMNs in childhood cancer survivors.},
}
@article {pmid24274429,
year = {2014},
author = {Bauch, C and Becker, PH and Verhulst, S},
title = {Within the genome, long telomeres are more informative than short telomeres with respect to fitness components in a long-lived seabird.},
journal = {Molecular ecology},
volume = {23},
number = {2},
pages = {300-310},
doi = {10.1111/mec.12602},
pmid = {24274429},
issn = {1365-294X},
mesh = {Aging/genetics ; Animals ; Biomarkers ; Cellular Senescence ; Charadriiformes/*genetics ; Erythrocytes ; Female ; *Genetic Fitness ; Longevity/genetics ; Male ; Telomere/*genetics ; *Telomere Shortening ; },
abstract = {Telomeres, DNA-protein structures at chromosome ends, shorten with age, and telomere length has been linked to age-related diseases and survival. In vitro studies revealed that the shortest telomeres trigger cell senescence, but whether the shortest telomeres are also the best biomarker of ageing is not known. We measured telomeres in erythrocytes of wild common terns Sterna hirundo using terminal restriction fragment analysis. This yields a distribution of telomere lengths for each sample, and we investigated how different telomere subpopulations (percentiles) varied in their relation to age and fitness proxies. Longer telomeres within a genome lost more base pairs with age and were better predictors of survival than shorter telomeres. Likewise, fitness proxies such as arrival date at the breeding grounds and reproductive success were best predicted by telomere length at the higher percentiles. Our finding that longer telomeres within a genome predict fitness components better than the shorter telomeres indicates that they are a more informative ageing biomarker. This finding contrasts with the fact that cell senescence is triggered by the shortest telomeres. We suggest that this paradox arises, because longer telomeres lose more base pairs per unit time and thus better reflect the various forms of stress that accelerate telomere shortening, and that telomeres primarily function as biomarker because their shortening reflects cumulative effects of various stressors rather than reflecting telomere-induced cell senescence.},
}
@article {pmid24271387,
year = {2014},
author = {Lin, J and Countryman, P and Buncher, N and Kaur, P and E, L and Zhang, Y and Gibson, G and You, C and Watkins, SC and Piehler, J and Opresko, PL and Kad, NM and Wang, H},
title = {TRF1 and TRF2 use different mechanisms to find telomeric DNA but share a novel mechanism to search for protein partners at telomeres.},
journal = {Nucleic acids research},
volume = {42},
number = {4},
pages = {2493-2504},
pmid = {24271387},
issn = {1362-4962},
support = {R00 ES016758/ES/NIEHS NIH HHS/United States ; ES0515052/ES/NIEHS NIH HHS/United States ; R01 ES015052/ES/NIEHS NIH HHS/United States ; U54 GM103529/GM/NIGMS NIH HHS/United States ; 4R00ES016758/ES/NIEHS NIH HHS/United States ; BB/I003460/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {DNA/chemistry/*metabolism ; Diffusion ; Protein Binding ; Protein Structure, Tertiary ; Repetitive Sequences, Nucleic Acid ; Telomere/chemistry/*metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; Telomeric Repeat Binding Protein 2/chemistry/*metabolism ; },
abstract = {Human telomeres are maintained by the shelterin protein complex in which TRF1 and TRF2 bind directly to duplex telomeric DNA. How these proteins find telomeric sequences among a genome of billions of base pairs and how they find protein partners to form the shelterin complex remains uncertain. Using single-molecule fluorescence imaging of quantum dot-labeled TRF1 and TRF2, we study how these proteins locate TTAGGG repeats on DNA tightropes. By virtue of its basic domain TRF2 performs an extensive 1D search on nontelomeric DNA, whereas TRF1's 1D search is limited. Unlike the stable and static associations observed for other proteins at specific binding sites, TRF proteins possess reduced binding stability marked by transient binding (∼ 9-17 s) and slow 1D diffusion on specific telomeric regions. These slow diffusion constants yield activation energy barriers to sliding ∼ 2.8-3.6 κ(B)T greater than those for nontelomeric DNA. We propose that the TRF proteins use 1D sliding to find protein partners and assemble the shelterin complex, which in turn stabilizes the interaction with specific telomeric DNA. This 'tag-team proofreading' represents a more general mechanism to ensure a specific set of proteins interact with each other on long repetitive specific DNA sequences without requiring external energy sources.},
}
@article {pmid24268696,
year = {2014},
author = {Le, R and Kou, Z and Jiang, Y and Li, M and Huang, B and Liu, W and Li, H and Kou, X and He, W and Rudolph, KL and Ju, Z and Gao, S},
title = {Enhanced telomere rejuvenation in pluripotent cells reprogrammed via nuclear transfer relative to induced pluripotent stem cells.},
journal = {Cell stem cell},
volume = {14},
number = {1},
pages = {27-39},
doi = {10.1016/j.stem.2013.11.005},
pmid = {24268696},
issn = {1875-9777},
mesh = {Adenosine Triphosphate/metabolism ; Animals ; *Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; *Cellular Reprogramming ; Embryonic Stem Cells/*cytology/metabolism ; In Situ Hybridization, Fluorescence ; Induced Pluripotent Stem Cells/*cytology/metabolism ; Mice ; Mice, Knockout ; Mitochondria/metabolism/pathology ; Neural Plate/metabolism/pathology ; *Nuclear Transfer Techniques ; RNA/*physiology ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*physiology ; Telomere/*genetics ; },
abstract = {Although somatic cell nuclear transfer (SCNT) and induction of pluripotency (to form iPSCs) are both recognized reprogramming methods, there has been relatively little comparative analysis of the resulting pluripotent cells. Here, we examine the capacity of these two reprogramming approaches to rejuvenate telomeres using late-generation telomerase-deficient (Terc(-/-)) mice that exhibit telomere dysfunction and premature aging. We found that embryonic stem cells established from Terc(-/-) SCNT embryos (Terc(-/-) ntESCs) have greater differentiation potential and self-renewal capacity than Terc(-/-) iPSCs. Remarkably, SCNT results in extensive telomere lengthening in cloned embryos and improved telomere capping function in the established Terc(-/-) ntESCs. In addition, mitochondrial function is severely impaired in Terc(-/-) iPSCs and their differentiated derivatives but significantly improved in Terc(-/-) ntESCs. Thus, our results suggest that SCNT-mediated reprogramming mitigates telomere dysfunction and mitochondrial defects to a greater extent than iPSC-based reprogramming. Understanding the basis of this differential could help optimize reprogramming strategies.},
}
@article {pmid24261933,
year = {2013},
author = {Yamada-Fukunaga, T and Yamada, M and Hamatani, T and Chikazawa, N and Ogawa, S and Akutsu, H and Miura, T and Miyado, K and Tarín, JJ and Kuji, N and Umezawa, A and Yoshimura, Y},
title = {Age-associated telomere shortening in mouse oocytes.},
journal = {Reproductive biology and endocrinology : RB&amp;E},
volume = {11},
number = {},
pages = {108},
pmid = {24261933},
issn = {1477-7827},
mesh = {Age Factors ; Animals ; Cellular Microenvironment ; Female ; In Situ Hybridization, Fluorescence ; Maternal Age ; Mice ; Oocytes/growth &amp; development/*physiology ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Telomerase/genetics/metabolism ; *Telomere Shortening ; Time Factors ; },
abstract = {BACKGROUND: Oocytes may undergo two types of aging. The first is induced by exposure to an aged ovarian microenvironment before being ovulated, known as 'reproductive or maternal aging', and the second by either a prolonged stay in the oviduct before fertilization or in vitro aging prior to insemination, known as 'postovulatory aging'. However, the molecular mechanisms underlying these aging processes remain to be elucidated. As telomere shortening in cultured somatic cells triggers replicative senescence, telomere shortening in oocytes during reproductive and postovulatory aging may predict developmental competence. This study aimed to ascertain the mechanisms underlying altered telomere biology in mouse oocytes during reproductive and postovulatory aging.<br><br>METHODS: We studied Tert expression patterns, telomerase activity, cytosolic reactive oxygen species (ROS) production, and telomere length in fresh oocytes from young versus reproductively-aged female mice retrieved from oviducts at 14 h post-human chorionic gonadotropin (hCG), in vivo or in vitro postovulatory-aged mouse oocytes at 23 h post-hCG. Oocytes were collected from super-ovulated C57BL/6 J mice of 6-8 weeks or 42-48 weeks of age. mRNA and protein expressions of the Tert gene were quantified using real-time quantitative reverse transcriptase polymerase chain reaction (Q-PCR) and immunochemistry. Telomerase activity was measured by a telomeric repeat amplification protocol assay, while telomere length was measured by Q-PCR and quantitative fluorescence in situ hybridization analyses.<br><br>RESULTS: The abundance of Tert expression in oocytes significantly decreased during reproductive and postovulatory aging. Immunofluorescent staining clearly demonstrated an altered pattern and intensity of TERT protein expression in oocytes during reproductive aging. Furthermore, relative telomerase activity (RTA) in oocytes from reproductively-aged females was significantly lower than that in oocytes from young females. In contrast, RTA in postovulatory-aged oocytes was similar to that in fresh oocytes. Oocytes from reproductively-aged females and postovulatory-aged oocytes showed higher ROS levels than oocytes from young females. Relative telomere length (RTL) was remarkably shorter in oocytes from reproductively-aged females compared to oocytes from young females. However, postovulatory aging had no significant effect on RTL of oocytes.<br><br>CONCLUSIONS: Long-term adverse effects of low telomerase activity and increased ROS exposure are likely associated with telomere shortening in oocytes from reproductively-aged female mice.},
}
@article {pmid24260532,
year = {2013},
author = {Yang, L and Wang, W and Hu, L and Yang, X and Zhong, J and Li, Z and Yang, H and Lei, H and Yu, H and Liao, Z and Zhou, F and Xie, C and Zhou, Y},
title = {Telomere-binding protein TPP1 modulates telomere homeostasis and confers radioresistance to human colorectal cancer cells.},
journal = {PloS one},
volume = {8},
number = {11},
pages = {e81034},
pmid = {24260532},
issn = {1932-6203},
mesh = {Apoptosis/radiation effects ; Ataxia Telangiectasia Mutated Proteins/genetics/metabolism ; Cell Line, Tumor ; Checkpoint Kinase 1 ; DNA Damage ; DNA Repair/*genetics ; DNA, Neoplasm/*metabolism ; G2 Phase Cell Cycle Checkpoints/radiation effects ; *Gene Expression Regulation, Neoplastic ; Humans ; Radiation Tolerance/*genetics ; Shelterin Complex ; Signal Transduction ; Telomere/chemistry/*metabolism/radiation effects ; Telomere Homeostasis/genetics ; Telomere-Binding Proteins ; X-Rays ; },
abstract = {BACKGROUND: Radiotherapy is one of the major therapeutic strategies in cancer treatment. The telomere-binding protein TPP1 is an important component of the shelterin complex at mammalian telomeres. Our previous reports showed that TPP1 expression was elevated in radioresistant cells, but the exact effects and mechanisms of TPP1 on radiosensitivity is unclear.<br><br>PRINCIPAL FINDINGS: In this study, we found that elevated TPP1 expression significantly correlated with radioresistance and longer telomere length in human colorectal cancer cell lines. Moreover, TPP1 overexpression showed lengthened telomere length and a significant decrease of radiosensitivity to X-rays. TPP1 mediated radioresistance was correlated with a decreased apoptosis rate after IR exposure. Furthermore, TPP1 overexpression showed prolonged G2/M arrest mediated by ATM/ATR-Chk1 signal pathway after IR exposure. Moreover, TPP1 overexpression accelerated the repair kinetics of total DNA damage and telomere dysfunction induced by ionizing radiation.<br><br>CONCLUSIONS: We demonstrated that elevated expressions of TPP1 in human colorectal cancer cells could protect telomere from DNA damage and confer radioresistance. These results suggested that TPP1 may be a potential target in the radiotherapy of colorectal cancer.},
}
@article {pmid24254728,
year = {2014},
author = {Ojeda, D and López-Costa, JJ and Sede, M and López, EM and Berria, MI and Quarleri, J},
title = {Increased in vitro glial fibrillary acidic protein expression, telomerase activity, and telomere length after productive human immunodeficiency virus-1 infection in murine astrocytes.},
journal = {Journal of neuroscience research},
volume = {92},
number = {2},
pages = {267-274},
doi = {10.1002/jnr.23294},
pmid = {24254728},
issn = {1097-4547},
mesh = {AIDS Dementia Complex ; Animals ; Astrocytes/*metabolism/pathology/*virology ; Cells, Cultured ; Disease Models, Animal ; Glial Fibrillary Acidic Protein/*biosynthesis ; HIV-1 ; Mice ; Mice, Inbred BALB C ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*metabolism ; Telomere/metabolism/*pathology ; },
abstract = {Although HIV-associated neurocognitive disorders (HAND) result from injury and loss of neurons, productive infection routinely takes place in cells of macrophage lineage. In such a complex context, astrocytosis induced by local chemokines/cytokines is one of the hallmarks of HIV neuropathology. Whether this sustained astrocyte activation is able to alter telomere-aging process is unknown. We hypothesized that interaction of HIV with astrocytes may impact astrocyte telomerase activity (TA) and telomere length in a scenario of astrocytic activation measured by expression of glial fibrillary acidic protein (GFAP). To test this hypothesis, cultured murine astrocytes were challenged with pseudotyped HIV/vesicular stomatitis virus (HIV/VSV) to circumvent the absence of viral receptors; and GFAP, telomerase activity, and telomere length were quantified. As an early and transient event after HIV infection, both TA activity and telomere length were significantly augmented (P < 0.001). Later, a strong negative correlation (-0.8616, P < 0.0001) between virus production and telomerase activity was demonstrated. Once HIV production had reached a peak (7 dpi), the TA decreased, showing levels similar to those of noninfected cells. In contrast, the astrocyte became activated, exhibiting significantly increased levels of GFAP expression directly related to the level of HIV/VSV replication (P < 0.0001). Our results suggest that HIV-infected astrocytes exhibit early disturbance in their cellular functions, such as telomerase activity and telomere length, that may attenuate cell proliferation and enhance the astrocyte dysregulation, contributing to HIV neuropathogenesis. Understanding the mechanisms involved in HIV-mediated persistence by altering the telomere-related aging processes could aid in the development of therapeutic modalities for neurological complications of HIV infection.},
}
@article {pmid24253316,
year = {2014},
author = {Bull, CF and Mayrhofer, G and O'Callaghan, NJ and Au, AY and Pickett, HA and Low, GK and Zeegers, D and Hande, MP and Fenech, MF},
title = {Folate deficiency induces dysfunctional long and short telomeres; both states are associated with hypomethylation and DNA damage in human WIL2-NS cells.},
journal = {Cancer prevention research (Philadelphia, Pa.)},
volume = {7},
number = {1},
pages = {128-138},
doi = {10.1158/1940-6207.CAPR-13-0264},
pmid = {24253316},
issn = {1940-6215},
mesh = {Azacitidine/analogs &amp; derivatives/chemistry ; Biomarkers/metabolism ; Chromosomal Instability ; Cytokinesis ; *DNA Damage ; *DNA Methylation ; Decitabine ; *Diet ; Folic Acid/*chemistry ; Folic Acid Deficiency/*genetics ; Humans ; Telomerase/metabolism ; Telomere/*ultrastructure ; Uracil/chemistry ; },
abstract = {The essential role of dietary micronutrients for genome stability is well documented, yet the effect of folate deficiency or excess on telomeres is not known. Accordingly, human WIL2-NS cells were maintained in medium containing 30, 300, or 3,000 nmol/L folic acid (FA) for 42 days to test the hypothesis that chronic folate deficiency would cause telomere shortening and dysfunction. After 14 days, telomere length (TL) in FA-deficient (30 nmol/L) cultures was 26% longer than that of 3,000 nmol/L FA cultures; however, this was followed by rapid telomere attrition over the subsequent 28 days (P trend, P < 0.0001); both long and short telomere status was positively correlated with biomarkers of chromosome instability (P ≤ 0.003) and mitotic dysfunction (P = 0.01), measured by the cytokinesis-block micronucleus cytome (CBMN-cyt) assay. The early increase in TL was associated with FA-deficiency-induced global DNA hypomethylation (P = 0.05), with an effect size similar to that induced by the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine. Quantitative PCR analysis indicated a negative association between FA concentration and uracil incorporation into telomeric DNA (r = -0.47, P = 0.1), suggesting a possible plausible mechanism for uracil as a cause of folate deficiency-induced telomere dysfunction or deletion. Peptide nucleic acid-FISH (PNA-FISH) analysis showed that FA deficiency resulted in 60% of micronuclei containing acentric terminal fragments, an observation consistent with the 3-fold increase in terminal deletions (P = 0.0001). Together, these results demonstrate the impact of folate deficiency on biomarkers of telomere maintenance and integrity, and provide evidence that dysfunctional long telomeres may be as important as critically short telomeres as a cause of chromosomal instability.},
}
@article {pmid24246679,
year = {2013},
author = {Cheng, G and Kong, F and Luan, Y and Sun, C and Wang, J and Zhang, L and Jiang, B and Qi, T and Zhao, J and Zheng, C and Xu, D},
title = {Differential shortening rate of telomere length in the development of human fetus.},
journal = {Biochemical and biophysical research communications},
volume = {442},
number = {1-2},
pages = {112-115},
doi = {10.1016/j.bbrc.2013.11.022},
pmid = {24246679},
issn = {1090-2104},
mesh = {Fetal Development/*genetics ; Fetus/enzymology/physiology ; Gestational Age ; Humans ; Telomerase/metabolism ; Telomere/*genetics ; *Telomere Shortening ; },
abstract = {Telomeres play an important role in the maintenance of genomic stability/integrity and are synthesized by the RNA-dependent polymerase telomerase. Progressive telomere shortening contributes to both in vitro and in vivo aging, and telomere length dynamics and telomerase expression profile in human tissues during extrauterine life have been well characterized. However, little is known about these changes in the early stage of gestation. In the present study, we determined telomere length and the expression of telomerase core units (telomerase reverse transcriptase, hTERT, and telomerase RNA component, hTERC) in human fetus tissues from 6 to 11 weeks of gestational age. A sharp decline in telomere length occurred between 6 and 7 weeks of gestational age, and a relatively stable or slightly shortened telomere length was thereafter maintained until birth. The inverse correlation between TERT or TERC expression and gestational age was steadily observed in these fetus tissues. Taken together, there is a rapid reduction followed by a slow erosion of telomere length in human fetus from gestational age 6-11 weeks, while hTERT and hTERC expression decreases steadily during this period. The present findings not only contribute to better understandings of telomere/telomerase biology in human embryonic development, but also are implicated in telomere/telomerase-related diseases or problems.},
}
@article {pmid24244743,
year = {2013},
author = {Silva-Sousa, R and Casacuberta, E},
title = {The JIL-1 kinase affects telomere expression in the different telomere domains of Drosophila.},
journal = {PloS one},
volume = {8},
number = {11},
pages = {e81543},
pmid = {24244743},
issn = {1932-6203},
mesh = {Animals ; Drosophila/*genetics/*metabolism ; Drosophila Proteins/genetics/*metabolism ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Telomere/chemistry/*metabolism ; },
abstract = {In Drosophila, the non-LTR retrotransposons HeT-A, TART and TAHRE build a head-to-tail array of repetitions that constitute the telomere domain by targeted transposition at the end of the chromosome whenever needed. As a consequence, Drosophila telomeres have the peculiarity to harbor the genes in charge of telomere elongation. Understanding telomere expression is important in Drosophila since telomere homeostasis depends in part on the expression of this genomic compartment. We have recently shown that the essential kinase JIL-1 is the first positive regulator of the telomere retrotransposons. JIL-1 mediates chromatin changes at the promoter of the HeT-A retrotransposon that are necessary to obtain wild type levels of expression of these telomere transposons. With the present study, we show how JIL-1 is also needed for the expression of a reporter gene embedded in the telomere domain. Our analysis, using different reporter lines from the telomere and subtelomere domains of different chromosomes, indicates that JIL-1 likely acts protecting the telomere domain from the spreading of repressive chromatin from the adjacent subtelomere domain. Moreover, the analysis of the 4R telomere suggests a slightly different chromatin structure at this telomere. In summary, our results strongly suggest that the action of JIL-1 depends on which telomere domain, which chromosome and which promoter is embedded in the telomere chromatin.},
}
@article {pmid24244195,
year = {2013},
author = {Chang, YT and Moser, BA and Nakamura, TM},
title = {Fission yeast shelterin regulates DNA polymerases and Rad3(ATR) kinase to limit telomere extension.},
journal = {PLoS genetics},
volume = {9},
number = {11},
pages = {e1003936},
pmid = {24244195},
issn = {1553-7404},
support = {R01 GM078253/GM/NIGMS NIH HHS/United States ; GM078253/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle/genetics ; Checkpoint Kinase 2/genetics/*metabolism ; DNA-Directed DNA Polymerase/*genetics/metabolism ; Mutation ; Phosphorylation ; Schizosaccharomyces ; Schizosaccharomyces pombe Proteins/*genetics/*metabolism ; Shelterin Complex ; Telomerase/genetics/metabolism ; Telomere/genetics ; Telomere Homeostasis/genetics ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {Studies in fission yeast have previously identified evolutionarily conserved shelterin and Stn1-Ten1 complexes, and established Rad3(ATR)/Tel1(ATM)-dependent phosphorylation of the shelterin subunit Ccq1 at Thr93 as the critical post-translational modification for telomerase recruitment to telomeres. Furthermore, shelterin subunits Poz1, Rap1 and Taz1 have been identified as negative regulators of Thr93 phosphorylation and telomerase recruitment. However, it remained unclear how telomere maintenance is dynamically regulated during the cell cycle. Thus, we investigated how loss of Poz1, Rap1 and Taz1 affects cell cycle regulation of Ccq1 Thr93 phosphorylation and telomere association of telomerase (Trt1(TERT)), DNA polymerases, Replication Protein A (RPA) complex, Rad3(ATR)-Rad26(ATRIP) checkpoint kinase complex, Tel1(ATM) kinase, shelterin subunits (Tpz1, Ccq1 and Poz1) and Stn1. We further investigated how telomere shortening, caused by trt1Δ or catalytically dead Trt1-D743A, affects cell cycle-regulated telomere association of telomerase and DNA polymerases. These analyses established that fission yeast shelterin maintains telomere length homeostasis by coordinating the differential arrival of leading (Polε) and lagging (Polα) strand DNA polymerases at telomeres to modulate Rad3(ATR) association, Ccq1 Thr93 phosphorylation and telomerase recruitment.},
}
@article {pmid24243983,
year = {2013},
author = {Zhang, X and Lin, S and Funk, WE and Hou, L},
title = {Environmental and occupational exposure to chemicals and telomere length in human studies.},
journal = {Postgraduate medical journal},
volume = {89},
number = {1058},
pages = {722-728},
doi = {10.1136/postgradmedj-2012-101350rep},
pmid = {24243983},
issn = {1469-0756},
support = {R21 ES020010/ES/NIEHS NIH HHS/United States ; R21 ES020984-01/ES/NIEHS NIH HHS/United States ; },
abstract = {Telomeres are complexes of tandem repeats of DNA (5'-TTAGGG-3') and protein that cap eukaryotic chromosomes and play a critical role in chromosome stability. Telomeres shorten with aging and this process can be accelerated by increased oxidative stress and episodes of inflammation. Evidence is rapidly growing that telomere length (TL) may be affected by environmental chemicals that have frequently been associated with chronic diseases. In this article, we review the published data on TL in relation to environmental and occupational exposure to several chemicals based on our own and others' studies. The environmental and occupational exposures associated with shorter TL include traffic-related air pollution (ie, particulate matter (PM), black carbon (BC), and benzene and toluene), polycyclic aromatic hydrocarbons (PAHs), N-nitrosamines, pesticides, lead, exposure in car mechanical workshops, and hazardous waste exposure. Arsenic, persistent organic pollutants (POPs) and short-term exposure to PM are associated with longer TL. We discuss the possible reasons for the differences in results, including time- and dose-related issues, study design, and possible mechanisms involved in telomere regulation. We also discuss the future directions and challenges for TL-related environmental and occupational health research, such as investigation of TL in subpopulations of blood leukocytes, and the study of genetic and epigenetic factors that may regulate telomere integrity using longitudinal designs.},
}
@article {pmid24237966,
year = {2013},
author = {Morgan, CC and Mc Cartney, AM and Donoghue, MT and Loughran, NB and Spillane, C and Teeling, EC and O'Connell, MJ},
title = {Molecular adaptation of telomere associated genes in mammals.},
journal = {BMC evolutionary biology},
volume = {13},
number = {},
pages = {251},
pmid = {24237966},
issn = {1471-2148},
mesh = {Adaptation, Physiological ; Aging/genetics ; Animals ; Body Size ; Chiroptera/*genetics ; Humans ; Longevity/genetics ; Mammals/genetics/physiology ; Mole Rats/*genetics ; Phylogeny ; Selection, Genetic ; Telomere/*genetics ; },
abstract = {BACKGROUND: Placental mammals display a huge range of life history traits, including size, longevity, metabolic rate and germ line generation time. Although a number of general trends have been proposed between these traits, there are exceptions that warrant further investigation. Species such as naked mole rat, human and certain bat species all exhibit extreme longevity with respect to body size. It has long been established that telomeres and telomere maintenance have a clear role in ageing but it has not yet been established whether there is evidence for adaptation in telomere maintenance proteins that could account for increased longevity in these species.<br><br>RESULTS: Here we carry out a molecular investigation of selective pressure variation, specifically focusing on telomere associated genes across placental mammals. In general we observe a large number of instances of positive selection acting on telomere genes. Although these signatures of selection overall are not significantly correlated with either longevity or body size we do identify positive selection in the microbat species Myotis lucifugus in functionally important regions of the telomere maintenance genes DKC1 and TERT, and in naked mole rat in the DNA repair gene BRCA1.<br><br>CONCLUSION: These results demonstrate the multifarious selective pressures acting across the mammal phylogeny driving lineage-specific adaptations of telomere associated genes. Our results show that regardless of the longevity of a species, these proteins have evolved under positive selection thereby removing increased longevity as the single selective force driving this rapid rate of evolution. However, evidence of molecular adaptations specific to naked mole rat and Myotis lucifugus highlight functionally significant regions in genes that may alter the way in which telomeres are regulated and maintained in these longer-lived species.},
}
@article {pmid24236830,
year = {2014},
author = {Tutelman, PR and Aubert, G and Milner, RA and Dalal, BI and Schultz, KR and Deyell, RJ},
title = {Paroxysmal nocturnal haemoglobinuria phenotype cells and leucocyte subset telomere length in childhood acquired aplastic anaemia.},
journal = {British journal of haematology},
volume = {164},
number = {5},
pages = {717-721},
doi = {10.1111/bjh.12656},
pmid = {24236830},
issn = {1365-2141},
support = {R01GM094146/GM/NIGMS NIH HHS/United States ; RMF-92093//Canadian Institutes of Health Research/Canada ; },
mesh = {Adolescent ; Anemia, Aplastic/*complications/drug therapy/genetics/immunology ; Child ; Child, Preschool ; Female ; Hemoglobinuria, Paroxysmal/*complications/genetics/immunology ; Humans ; Immunophenotyping ; Immunosuppressive Agents/therapeutic use ; Infant ; Leukocytes/*ultrastructure ; Male ; Prognosis ; Retrospective Studies ; Telomere/*ultrastructure ; Telomere Homeostasis ; Treatment Outcome ; },
abstract = {The significance of paroxysmal nocturnal haemoglobinuria (PNH(pos)) cells and leucocyte subset telomere lengths in paediatric aplastic anaemia (AA) is unknown. Among 22 children receiving immunosuppressive therapy (IST) for AA, 73% (16/22) were PNH(pos) , of whom 94% achieved at least a partial response (PR) to IST; 11/16 (69%) achieved complete response (CR). Only 2/6 (33%) PNH(neg) patients achieved PR. PNH(pos) patients were less likely to fail IST compared to PNH(neg) patients (odds ratio 0·033; 95% confidence interval 0·002-0·468; P = 0·012). Children with AA had short granulocyte (P = 7·8 × 10(-9)), natural killer cell (P = 6·0 × 10(-4)), naïve T lymphocyte (P = 0·002) and B lymphocyte (P = 0·005) telomeres compared to age-matched normative data.},
}
@article {pmid24231584,
year = {2014},
author = {Wikgren, M and Karlsson, T and Söderlund, H and Nordin, A and Roos, G and Nilsson, LG and Adolfsson, R and Norrback, KF},
title = {Shorter telomere length is linked to brain atrophy and white matter hyperintensities.},
journal = {Age and ageing},
volume = {43},
number = {2},
pages = {212-217},
doi = {10.1093/ageing/aft172},
pmid = {24231584},
issn = {1468-2834},
mesh = {Age Factors ; Aged ; Aging/genetics/pathology ; Atrophy ; Biomarkers/blood ; Brain/*pathology ; Female ; Humans ; Leukocytes/*chemistry ; Leukoencephalopathies/blood/*genetics/*pathology ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Telomere/*chemistry ; *Telomere Shortening ; },
abstract = {BACKGROUND: leukocyte telomere length (TL) is considered a marker of biological aging. Several studies have investigated the link between leukocyte TL and aging-associated functional attributes of the brain, but no prior study has investigated whether TL can be linked to brain atrophy and white matter hyperintensities (WMHs); two prominent structural manifestations of brain aging.<br><br>METHODS: we investigated whether leukocyte TL was related to brain atrophy and WMHs in a sample of 102 non-demented individuals aged 64-75 years.<br><br>RESULTS: shorter TL was related to greater degree of subcortical atrophy (&#x3b2; = -0.217, P = 0.034), but not to cortical atrophy. Furthermore, TL was 371 bp shorter (P = 0.041) in participants exhibiting subcortical WMHs, and 552 bp shorter (P = 0.009) in older participants exhibiting periventricular WMHs.<br><br>CONCLUSION: this study provides the first evidence of leukocyte TL being associated with cerebral subcortical atrophy and WMHs, lending further support to the concept of TL as a marker of biological aging, and in particular that of the aging brain.},
}
@article {pmid24231251,
year = {2013},
author = {Walcott, F and Rajaraman, P and Gadalla, SM and Inskip, PD and Purdue, MP and Albanes, D and Orr, E and De Vivo, I and Savage, SA},
title = {Telomere length and risk of glioma.},
journal = {Cancer epidemiology},
volume = {37},
number = {6},
pages = {935-938},
pmid = {24231251},
issn = {1877-783X},
support = {N01 CN25514/CA/NCI NIH HHS/United States ; N01 CN25524/CA/NCI NIH HHS/United States ; N01 CN25513/CA/NCI NIH HHS/United States ; N01 CN25518/CA/NCI NIH HHS/United States ; N01 CN25516/CA/NCI NIH HHS/United States ; N01 CN25511/CA/NCI NIH HHS/United States ; N01 CN25476/CA/NCI NIH HHS/United States ; N01 CN25404/CA/NCI NIH HHS/United States ; N01 CN75022/CA/NCI NIH HHS/United States ; N01 CN25512/CA/NCI NIH HHS/United States ; N01 CN25522/CA/NCI NIH HHS/United States ; ZIA CP010133-18//Intramural NIH HHS/United States ; N01 CN25515/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Case-Control Studies ; DNA/*genetics ; Female ; Follow-Up Studies ; Glioma/*etiology ; Humans ; Male ; Middle Aged ; Polymerase Chain Reaction ; Prognosis ; Prospective Studies ; Risk Factors ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: Telomere length in blood or buccal cell DNA has been associated with risk of various cancers. Glioma can be a highly malignant brain tumor and has few known risk factors. Genetic variants in or near RTEL1 and TERT, key components of telomere biology, are associated with glioma risk. Therefore, we evaluated the association between relative telomere length (RTL) and glioma in a prospective study.<br><br>MATERIALS AND METHODS: We performed a nested case-control study within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. RTL was determined by quantitative PCR on blood or buccal cell DNA obtained at least 2 years prior to diagnosis from 101 individuals with glioma cases. Healthy controls (n=198) were matched to cases (2:1) on age, gender, smoking status, calendar year, and DNA source. Conditional logistic regression was used to investigate the association between RTL and glioma.<br><br>RESULTS: As expected, RTL declined with increasing age in both cases and controls. There was no statistically significant association between RTL and glioma overall. An analysis stratified by gender suggested that short RTL (1st tertile) in males was associated with glioma (odds ratio, [OR]=2.29, 95% confidence interval [CI] 1.02-5.11); this association was not observed for females (OR=0.41, 95% CI 0.14-1.17).<br><br>CONCLUSIONS: This prospective study did not identify significant associations between RTL and glioma risk, but there may be gender-specific differences. Larger, prospective studies are needed to evaluate these findings.},
}
@article {pmid24229212,
year = {2013},
author = {Holbek, S and Bendtsen, KM and Juul, J},
title = {Moderate stem-cell telomere shortening rate postpones cancer onset in a stochastic model.},
journal = {Physical review. E, Statistical, nonlinear, and soft matter physics},
volume = {88},
number = {4},
pages = {042706},
doi = {10.1103/PhysRevE.88.042706},
pmid = {24229212},
issn = {1550-2376},
mesh = {Aging/genetics/pathology ; Cell Cycle/genetics ; *Models, Biological ; Neoplasms/*genetics/*pathology ; Stem Cells/*metabolism ; Stochastic Processes ; Telomere/genetics ; *Telomere Shortening ; },
abstract = {Mammalian cells are restricted from proliferating indefinitely. Telomeres at the end of each chromosome are shortened at cell division and when they reach a critical length, the cell will enter permanent cell cycle arrest-a state known as senescence. This mechanism is thought to be tumor suppressing, as it helps prevent precancerous cells from dividing uncontrollably. Stem cells express the enzyme telomerase, which elongates the telomeres, thereby postponing senescence. However, unlike germ cells and most types of cancer cells, stem cells only express telomerase at levels insufficient to fully maintain the length of their telomeres, leading to a slow decline in proliferation potential. It is not yet fully understood how this decline influences the risk of cancer and the longevity of the organism. We here develop a stochastic model to explore the role of telomere dynamics in relation to both senescence and cancer. The model describes the accumulation of cancerous mutations in a multicellular organism and creates a coherent theoretical framework for interpreting the results of several recent experiments on telomerase regulation. We demonstrate that the longest average cancer-free lifespan before cancer onset is obtained when stem cells start with relatively long telomeres that are shortened at a steady rate at cell division. Furthermore, the risk of cancer early in life can be reduced by having a short initial telomere length. Finally, our model suggests that evolution will favor a shorter than optimal average cancer-free lifespan in order to postpone cancer onset until late in life.},
}
@article {pmid24228928,
year = {2013},
author = {Mitteldorf, JJ},
title = {Telomere biology: cancer firewall or aging clock?.},
journal = {Biochemistry. Biokhimiia},
volume = {78},
number = {9},
pages = {1054-1060},
doi = {10.1134/S0006297913090125},
pmid = {24228928},
issn = {1608-3040},
mesh = {Aging/genetics/*physiology ; Animals ; Biological Clocks/*physiology ; Humans ; Neoplasms/genetics/*metabolism ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {It has been a decade since the first surprising discovery that longer telomeres in humans are statistically associated with longer life expectancies. Since then, it has been firmly established that telomere shortening imposes an individual fitness cost in a number of mammalian species, including humans. But telomere shortening is easily avoided by application of telomerase, an enzyme which is coded into nearly every eukaryotic genome, but whose expression is suppressed most of the time. This raises the question how the sequestration of telomerase might have evolved. The predominant assumption is that in higher organisms, shortening telomeres provide a firewall against tumor growth. A more straightforward interpretation is that telomere attrition provides an aging clock, reliably programming lifespans. The latter hypothesis is routinely rejected by most biologists because the benefit of programmed lifespan applies only to the community, and in fact the individual pays a substantial fitness cost. There is a long-standing skepticism that the concept of fitness can be applied on a communal level, and of group selection in general. But the cancer hypothesis is problematic as well. Animal studies indicate that there is a net fitness cost in sequestration of telomerase, even when cancer risk is lowered. The hypothesis of protection against cancer has never been tested in animals that actually limit telomerase expression, but only in mice, whose lifespans are not telomerase-limited. And human medical evidence suggests a net aggravation of cancer risk from the sequestration of telomerase, because cells with short telomeres are at high risk of neoplastic transformation, and they also secrete cytokines that exacerbate inflammation globally. The aging clock hypothesis fits well with what is known about ancestral origins of telomerase sequestration, and the prejudices concerning group selection are without merit. If telomeres are an aging clock, then telomerase makes an attractive target for medical technologies that seek to expand the human life- and health-spans.},
}
@article {pmid24225324,
year = {2014},
author = {Lee, M and Hills, M and Conomos, D and Stutz, MD and Dagg, RA and Lau, LM and Reddel, RR and Pickett, HA},
title = {Telomere extension by telomerase and ALT generates variant repeats by mechanistically distinct processes.},
journal = {Nucleic acids research},
volume = {42},
number = {3},
pages = {1733-1746},
pmid = {24225324},
issn = {1362-4962},
mesh = {Cell Line ; Genetic Variation ; Humans ; Repetitive Sequences, Nucleic Acid ; Sequence Analysis, DNA ; Telomerase/metabolism ; Telomere/*chemistry ; *Telomere Homeostasis ; },
abstract = {Telomeres are terminal repetitive DNA sequences on chromosomes, and are considered to comprise almost exclusively hexameric TTAGGG repeats. We have evaluated telomere sequence content in human cells using whole-genome sequencing followed by telomere read extraction in a panel of mortal cell strains and immortal cell lines. We identified a wide range of telomere variant repeats in human cells, and found evidence that variant repeats are generated by mechanistically distinct processes during telomerase- and ALT-mediated telomere lengthening. Telomerase-mediated telomere extension resulted in biased repeat synthesis of variant repeats that differed from the canonical sequence at positions 1 and 3, but not at positions 2, 4, 5 or 6. This indicates that telomerase is most likely an error-prone reverse transcriptase that misincorporates nucleotides at specific positions on the telomerase RNA template. In contrast, cell lines that use the ALT pathway contained a large range of variant repeats that varied greatly between lines. This is consistent with variant repeats spreading from proximal telomeric regions throughout telomeres in a stochastic manner by recombination-mediated templating of DNA synthesis. The presence of unexpectedly large numbers of variant repeats in cells utilizing either telomere maintenance mechanism suggests a conserved role for variant sequences at human telomeres.},
}
@article {pmid24215409,
year = {2013},
author = {Dehbi, AZ and Radstake, TR and Broen, JC},
title = {Accelerated telomere shortening in rheumatic diseases: cause or consequence?.},
journal = {Expert review of clinical immunology},
volume = {9},
number = {12},
pages = {1193-1204},
doi = {10.1586/1744666X.2013.850031},
pmid = {24215409},
issn = {1744-8409},
mesh = {Aging, Premature/*genetics/*immunology ; Animals ; Humans ; Immune System ; Rheumatic Diseases/*genetics/*immunology ; T-Lymphocytes/*immunology ; *Telomere Shortening/immunology ; },
abstract = {Accelerated aging of the immune system (immune aging), represented by telomere shortening, has been implicated in a variety of rheumatic diseases. Studies addressing telomere shortening in rheumatic diseases so far yielded controversial results. The current review aims to provide an overview on the role of immune aging in a plethora of immune-mediated conditions including systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis. The main question this review aims to answer is whether rheumatic diseases cause accelerated aging or that accelerated aging drives rheumatic diseases.},
}
@article {pmid24213145,
year = {2014},
author = {Gray, KE and Schiff, MA and Fitzpatrick, AL and Kimura, M and Aviv, A and Starr, JR},
title = {Leukocyte telomere length and age at menopause.},
journal = {Epidemiology (Cambridge, Mass.)},
volume = {25},
number = {1},
pages = {139-146},
pmid = {24213145},
issn = {1531-5487},
support = {N01 HC085086/HC/NHLBI NIH HHS/United States ; T32 HD052462/HD/NICHD NIH HHS/United States ; AG -027058/AG/NIA NIH HHS/United States ; N01 HC085081/HC/NHLBI NIH HHS/United States ; N01 HC075150/HC/NHLBI NIH HHS/United States ; R56 AG020098/AG/NIA NIH HHS/United States ; N01 HC085085/HC/NHLBI NIH HHS/United States ; AG -15928/AG/NIA NIH HHS/United States ; N01 HC085082/HC/NHLBI NIH HHS/United States ; N01 HC085080/HC/NHLBI NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; N01-HC-55222/HC/NHLBI NIH HHS/United States ; N01-HC-75150/HC/NHLBI NIH HHS/United States ; R01 HL080295/HL/NHLBI NIH HHS/United States ; N01-HC-85079/HC/NHLBI NIH HHS/United States ; HL080295/HL/NHLBI NIH HHS/United States ; R01 AG015928/AG/NIA NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; N01 HC015103/HC/NHLBI NIH HHS/United States ; N01 HC085083/HC/NHLBI NIH HHS/United States ; R01 HL080698/HL/NHLBI NIH HHS/United States ; N01HC55222/HL/NHLBI NIH HHS/United States ; N01-HC-85086/HC/NHLBI NIH HHS/United States ; N01HC85086/HL/NHLBI NIH HHS/United States ; AG -023629/AG/NIA NIH HHS/United States ; 1 R01 HL80698-01/HL/NHLBI NIH HHS/United States ; N01 HC085084/HC/NHLBI NIH HHS/United States ; R01 AG020098/AG/NIA NIH HHS/United States ; N01HC75150/HL/NHLBI NIH HHS/United States ; N01-HC-85239/HC/NHLBI NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; N01HC85079/HL/NHLBI NIH HHS/United States ; N01 HC085079/HC/NHLBI NIH HHS/United States ; R01 AG027058/AG/NIA NIH HHS/United States ; N01 HC045133/HC/NHLBI NIH HHS/United States ; N01 HC035129/HC/NHLBI NIH HHS/United States ; R56 AG023629/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Age of Onset ; Aged ; Aging/*physiology ; Alcohol Drinking ; Body Mass Index ; Educational Status ; Female ; Humans ; Leukocytes/metabolism ; Linear Models ; Menopause/*physiology ; Middle Aged ; Motor Activity ; Smoking ; Telomere/*metabolism ; White People ; },
abstract = {BACKGROUND: Telomere length is a marker of cellular aging that varies with the individual, is inherited, and is highly correlated across somatic cell types within persons. Interindividual variability of telomere length may partly explain differences in reproductive aging rates. We examined whether leukocyte telomere length was associated with menopausal age.<br><br>METHODS: We evaluated the relationship between leukocyte telomere length and age at natural menopause in 486 white women &#x2265;65 years of age. We fit linear regression models adjusted for age, income, education, body mass index, physical activity, smoking, and alcohol intake. We repeated the analysis in women with surgical menopause. We also performed sensitivity analyses excluding women (1) with unilateral oophorectomy, (2) who were nulliparous, or (3) reporting menopausal age <40 years, among other exclusions.<br><br>RESULTS: For every 1-kb increase in leukocyte telomere length, average age at natural menopause increased by 10.2 months (95% confidence interval = 1.3 to 19.0). There was no association among 179 women reporting surgical menopause. In all but one sensitivity analysis, the association between leukocyte telomere length and age at menopause became stronger. However, when excluding women with menopausal age <40 years, the association decreased to 7.5 months (-0.4 to 15.5).<br><br>CONCLUSIONS: Women with the longest leukocyte telomere length underwent menopause 3 years later than those with the shortest leukocyte telomere length. If an artifact, an association would likely also have been observed in women with surgical menopause. If these results are replicated, leukocyte telomere length may prove to be a useful predictor of age at menopause.},
}
@article {pmid24210919,
year = {2013},
author = {Lee, NN and Chalamcharla, VR and Reyes-Turcu, F and Mehta, S and Zofall, M and Balachandran, V and Dhakshnamoorthy, J and Taneja, N and Yamanaka, S and Zhou, M and Grewal, SI},
title = {Mtr4-like protein coordinates nuclear RNA processing for heterochromatin assembly and for telomere maintenance.},
journal = {Cell},
volume = {155},
number = {5},
pages = {1061-1074},
pmid = {24210919},
issn = {1097-4172},
support = {ZIA BC010523-10//Intramural NIH HHS/United States ; ZIA BC010523-07//Intramural NIH HHS/United States ; ZIA BC010523-09//Intramural NIH HHS/United States ; Z01 BC010523-04//Intramural NIH HHS/United States ; Z01 BC010523-05//Intramural NIH HHS/United States ; ZIA BC010523-11//Intramural NIH HHS/United States ; },
mesh = {Animals ; Caenorhabditis elegans/metabolism ; Carrier Proteins/metabolism ; Chromatin Assembly and Disassembly ; DEAD-box RNA Helicases/*metabolism ; Heterochromatin/metabolism ; Introns ; *RNA Processing, Post-Transcriptional ; Schizosaccharomyces/*genetics/*metabolism ; Schizosaccharomyces pombe Proteins/*metabolism ; Telomere/*metabolism ; },
abstract = {The regulation of protein-coding and noncoding RNAs is linked to nuclear processes, including chromatin modifications and gene silencing. However, the mechanisms that distinguish RNAs and mediate their functions are poorly understood. We describe a nuclear RNA-processing network in fission yeast with a core module comprising the Mtr4-like protein, Mtl1, and the zinc-finger protein, Red1. The Mtl1-Red1 core promotes degradation of mRNAs and noncoding RNAs and associates with different proteins to assemble heterochromatin via distinct mechanisms. Mtl1 also forms Red1-independent interactions with evolutionarily conserved proteins named Nrl1 and Ctr1, which associate with splicing factors. Whereas Nrl1 targets transcripts with cryptic introns to form heterochromatin at developmental genes and retrotransposons, Ctr1 functions in processing intron-containing telomerase RNA. Together with our discovery of widespread cryptic introns, including in noncoding RNAs, these findings reveal unique cellular strategies for recognizing regulatory RNAs and coordinating their functions in response to developmental and environmental cues.},
}
@article {pmid24202335,
year = {2013},
author = {Samassekou, O},
title = {Dynamic length changes of telomeres and their nuclear organization in chronic myeloid leukemia.},
journal = {Cancers},
volume = {5},
number = {3},
pages = {1086-1102},
pmid = {24202335},
issn = {2072-6694},
abstract = {Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the t(9;22) translocation. As in most cancers, short telomeres are one of the features of CML cells, and telomere shortening accentuates as the disease progresses from the chronic phase to the blastic phase. Although most individual telomeres are short, some of them are lengthened, and long individual telomeres occur non-randomly and might be associated with clonal selection. Telomerase is the main mechanism used to maintain telomere lengths, and its activity increases when CML evolves toward advanced stages. ALT might be another mechanism employed by CML cells to sustain the homeostasis of their telomere lengths and this mechanism seems predominant at the early stage of leukemogenesis. Also, telomerase and ALT might jointly act to maintain telomere lengths at the chronic phase, and as CML progresses, telomerase becomes the major mechanism. Finally, CML cells display an altered nuclear organization of their telomeres which is characterized by the presence of high number of telomeric aggregates, a feature of genomic instability, and differential positioning of telomeres. CML represents a good model to study mechanisms responsible for dynamic changes of individual telomere lengths and the remodeling of telomeric nuclear organization throughout cancer progression.},
}
@article {pmid24202323,
year = {2013},
author = {Vajen, B and Thomay, K and Schlegelberger, B},
title = {Induction of Chromosomal Instability via Telomere Dysfunction and Epigenetic Alterations in Myeloid Neoplasia.},
journal = {Cancers},
volume = {5},
number = {3},
pages = {857-874},
pmid = {24202323},
issn = {2072-6694},
abstract = {Chromosomal instability (CIN) is a characteristic feature of cancer. In this review, we concentrate on mechanisms leading to CIN in myeloid neoplasia, i.e., myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The pathogenesis of myeloid neoplasia is complex and involves genetic and epigenetic alterations. Chromosome aberrations define specific subgroups and guide clinical decisions. Genomic instability may play an essential role in leukemogenesis by promoting the accumulation of genetic lesions responsible for clonal evolution. Indeed, disease progression is often driven by clonal evolution into complex karyotypes. Earlier studies have shown an association between telomere shortening and advanced MDS and underlined the important role of dysfunctional telomeres in the development of genetic instability and cancer. Several studies link chromosome rearrangements and aberrant DNA and histone methylation. Genes implicated in epigenetic control, like DNMT3A, ASXL1, EZH2 and TET2, have been discovered to be mutated in MDS. Moreover, gene-specific hypermethylation correlates highly significantly with the risk score according to the International Prognostic Scoring System. In AML, methylation profiling also revealed clustering dependent on the genetic status. Clearly, genetic instability and clonal evolution are driving forces for leukemic transformation. Understanding the mechanisms inducing CIN will be important for prevention and for novel approaches towards therapeutic interventions.},
}
@article {pmid24201379,
year = {2013},
author = {Fujita, T and Asano, Y and Ohtsuka, J and Takada, Y and Saito, K and Ohki, R and Fujii, H},
title = {Identification of telomere-associated molecules by engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP).},
journal = {Scientific reports},
volume = {3},
number = {},
pages = {3171},
pmid = {24201379},
issn = {2045-2322},
mesh = {Base Sequence ; Binding Sites ; Cell Line ; Chromatin Immunoprecipitation/*methods ; DNA-Binding Proteins/*metabolism ; Humans ; Nucleotide Motifs ; Protein Binding ; Protein Transport ; RNA/genetics/metabolism ; Telomerase/genetics ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Biochemical analysis of molecular interactions in specific genomic regions requires their isolation while retaining molecular interactions in vivo. Here, we report isolation of telomeres by engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) using a transcription activator-like (TAL) protein recognizing telomere repeats. Telomeres recognized by the tagged TAL protein were immunoprecipitated with an antibody against the tag and subjected to identification of telomere-binding molecules. enChIP-mass spectrometry (enChIP-MS) targeting telomeres identified known and novel telomere-binding proteins. The data have been deposited to the ProteomeXchange with identifier PXD000461. In addition, we showed that RNA associated with telomeres could be isolated by enChIP. Identified telomere-binding molecules may play important roles in telomere biology. enChIP using TAL proteins would be a useful tool for biochemical analysis of specific genomic regions of interest.},
}
@article {pmid24199571,
year = {2013},
author = {Zhang, XP and Liu, J and Xu, CY and Wei, Q and Li, J and Wang, L and Wang, JW and Wang, YP},
title = {[Effect of Angelica sinensis polysaccharide on expression of telomere, telomerase and P53 in mice aging hematopoietic stem cells].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {38},
number = {14},
pages = {2354-2358},
pmid = {24199571},
issn = {1001-5302},
mesh = {Angelica sinensis/*chemistry ; Animals ; Cell Cycle/drug effects/physiology ; Cellular Senescence/drug effects/physiology ; Female ; Hematopoietic Stem Cells/cytology/*drug effects/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Plant Extracts/chemistry/pharmacology ; Plants, Medicinal/chemistry ; Polysaccharides/isolation &amp; purification/*pharmacology ; Telomerase/*biosynthesis/metabolism ; Telomere/*drug effects/metabolism ; Tumor Suppressor Protein p53/*biosynthesis/metabolism ; },
abstract = {OBJECTIVE: To observe the effect of Angelica sinensis polysaccharides (ASP) on the length of telomere, the activity of telomerase and the expression of P53 protein in mice hematopoietic stem cells (HSCs), and explore ASP's potential mechanism for regulating HSC aging.<br><br>METHOD: C57BL/6J mice were randomly divided into the normal group, the aging group and the intervention group. The aging group was radiated with X ray to establish the mice aging HSC model. The intervention group was orally administered with ASP during X-ray irradiation, while the normal group was orally administered with NS. Their HSCs were isolated by immunomagnetic beads. Cell cycles analysis and senescence-associated beta-galactosidase (SA-beta-Gal) staining were used to detect changes in aging HSCs. The expression of P53 was determined by western blot analysis. The length of telomere and the vitality of telomerase were analyzed by southern blot and TRAP-PCR, respectively.<br><br>RESULT: Compared with the normal group, X-ray irradiation could significantly increase the cell ratio of in HSC G1 stage, rate of SA-beta-Gal positive cells and expression of P53 protein, and reduce the length of telomere and the vitality of telomerase. Compared with the aging group, ASP could significantly inhibit the cell ratio of in HSC G1 stage and the increase in the number of SA-beta-Gal positive cells, down-regulate the expression of P53 protein, and increase the length of telomere and the vitality of telomerase in HSCs.<br><br>CONCLUSION: ASP could antagonize X-ray-induced aging of HSCs, which may be related to the increase in the length of telomere and the activity of telomerase, as well as the down-regulation of the expression of P53 protein.},
}
@article {pmid24196442,
year = {2014},
author = {Singh, U and Maturi, V and Jones, RE and Paulsson, Y and Baird, DM and Westermark, B},
title = {CGGBP1 phosphorylation constitutes a telomere-protection signal.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {13},
number = {1},
pages = {96-105},
pmid = {24196442},
issn = {1551-4005},
support = {C17199/A13490//Cancer Research UK/United Kingdom ; },
mesh = {Cell Cycle Proteins/genetics ; DNA Damage/*genetics ; DNA-Binding Proteins/*genetics ; Gene Expression Regulation ; Humans ; Phosphorylation ; Serine/*genetics ; Shelterin Complex ; Signal Transduction/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; },
abstract = {The shelterin proteins are required for telomere integrity. Shelterin dysfunction can lead to initiation of unwarranted DNA damage and repair pathways at chromosomal termini. Interestingly, many shelterin accessory proteins are involved in DNA damage signaling and repair. We demonstrate here that in normal human fibroblasts, telomeric ends are protected by phosphorylation of CGG triplet repeat-binding protein 1 (CGGBP1) at serine 164 (S164). We show that serine 164 is a major phosphorylation site on CGGBP1 with important functions. We provide evidence that one of the kinases that can phosphorylate S164 CGGBP1 is ATR. Overexpression of S164A phospho-deficient CGGBP1 exerted a dominant-negative effect, causing telomeric dysfunction, accelerated telomere shortening, enhanced fusion of telomeres, and crisis. However, overexpression of wild-type or phospho-mimicking S164E CGGBP1 did not cause these effects. This telomere damage was associated with reduced binding of the shelterin protein POT1 to telomeric DNA. Our results suggest that CGGBP1 phosphorylation at S164 is a novel telomere protection signal, which can affect telomere-protective function of the shelterin complex.},
}
@article {pmid24192547,
year = {2014},
author = {Thomay, K and Schienke, A and Vajen, B and Modlich, U and Schambach, A and Hofmann, W and Schlegelberger, B and Göhring, G},
title = {Chromosomal instability and telomere shortening in long-term culture of hematopoietic stem cells: insights from a cell culture model of RPS14 haploinsufficiency.},
journal = {Cytogenetic and genome research},
volume = {142},
number = {1},
pages = {14-20},
doi = {10.1159/000356096},
pmid = {24192547},
issn = {1424-859X},
mesh = {Antigens, CD34/analysis ; *Artifacts ; *Cell Culture Techniques ; Cells, Cultured ; Chromosomal Instability/*genetics ; Chromosome Deletion ; Chromosomes, Human, Pair 5/*genetics/ultrastructure ; Colony-Forming Units Assay ; DNA Repair ; Fetal Blood/cytology ; Genes, Reporter ; Hematopoietic Stem Cells/cytology/*ultrastructure ; Humans ; In Situ Hybridization, Fluorescence ; K562 Cells ; Karyotyping ; Myelodysplastic Syndromes/genetics/pathology ; Polymerase Chain Reaction ; RNA Interference ; RNA, Small Interfering/genetics ; Ribosomal Proteins/biosynthesis/deficiency/*genetics/physiology ; Telomerase/metabolism ; Telomere Shortening/*genetics ; Transduction, Genetic ; },
abstract = {The fate of cultivated primary hematopoietic stem cells (HSCs) with respect to genetic instability and telomere attrition has not yet been described in great detail. Thus, knowledge of the genetic constitution of HSCs is important when interpreting results of HSCs in culture. While establishing a cell culture model for myelodysplastic syndrome with a deletion in 5q by performing RPS14 knockdown, we found surprising data that may be of importance for any CD34+ cell culture experiments. We performed cytogenetic analyses and telomere length measurement on transduced CD34+ cells and untransduced control cells to observe the effects of long-term culturing. Initially, CD34+ cells had a normal median telomere length of about 12 kb and showed no signs of chromosomal instability. During follow-up, the median telomere length seemed to decrease and, simultaneously, increased chromosomal instability could be observed - in modified and control cells. One culture showed a clonal monosomy 7 - independent of prior RPS14 knockdown. During further culturing, it seemed that the telomeres re-elongated, and chromosomes stabilized, while TERT expression was not elevated. In summary, irrespective of our results of RPS14 knockdown in the long-term culture of CD34+ cells, it becomes clear that cell culture artefacts inducing telomere shortening and chromosomal instability have to be taken into account and regular cytogenetic analyses should always be performed.},
}
@article {pmid24189343,
year = {2014},
author = {Zhang, L and Hu, XZ and Benedek, DM and Fullerton, CS and Forsten, RD and Naifeh, JA and Li, X and Li, H and Benevides, KN and Smerin, S and Le, T and Choi, K and Ursano, RJ},
title = {The interaction between stressful life events and leukocyte telomere length is associated with PTSD.},
journal = {Molecular psychiatry},
volume = {19},
number = {8},
pages = {855-856},
pmid = {24189343},
issn = {1476-5578},
mesh = {Adolescent ; Adult ; Age Factors ; Case-Control Studies ; Humans ; Leukocytes/*metabolism ; *Life Change Events ; Middle Aged ; Stress Disorders, Post-Traumatic/*genetics/pathology ; Stress, Psychological/*genetics/pathology ; Telomere Shortening/*genetics ; Young Adult ; },
}
@article {pmid24173716,
year = {2014},
author = {Kim, MK and Smith, S},
title = {Persistent telomere cohesion triggers a prolonged anaphase.},
journal = {Molecular biology of the cell},
volume = {25},
number = {1},
pages = {30-40},
pmid = {24173716},
issn = {1939-4586},
support = {R01 CA116352/CA/NCI NIH HHS/United States ; R01CA116352/CA/NCI NIH HHS/United States ; },
mesh = {*Anaphase ; Cell Adhesion Molecules/genetics/metabolism ; Cellular Senescence ; Fibroblasts/enzymology/physiology ; Gene Expression ; Gene Knockdown Techniques ; HeLa Cells ; Heterocyclic Compounds, 3-Ring/pharmacology ; Humans ; In Situ Hybridization, Fluorescence ; Nuclear Proteins/genetics/metabolism ; RNA, Small Interfering/genetics ; Tankyrases/antagonists &amp; inhibitors/genetics/metabolism ; Telomere/physiology ; *Telomere Homeostasis ; },
abstract = {Telomeres use distinct mechanisms (not used by arms or centromeres) to mediate cohesion between sister chromatids. However, the motivation for a specialized mechanism at telomeres is not well understood. Here we show, using fluorescence in situ hybridization and live-cell imaging, that persistent sister chromatid cohesion at telomeres triggers a prolonged anaphase in normal human cells and cancer cells. Excess cohesion at telomeres can be induced by inhibition of tankyrase 1, a poly(ADP-ribose) polymerase that is required for resolution of telomere cohesion, or by overexpression of proteins required to establish telomere cohesion, the shelterin subunit TIN2 and the cohesin subunit SA1. Regardless of the method of induction, excess cohesion at telomeres in mitosis prevents a robust and efficient anaphase. SA1- or TIN2-induced excess cohesion and anaphase delay can be rescued by overexpression of tankyrase 1. Moreover, we show that primary fibroblasts, which accumulate excess telomere cohesion at mitosis naturally during replicative aging, undergo a similar delay in anaphase progression that can also be rescued by overexpression of tankyrase 1. Our study demonstrates that there are opposing forces that regulate telomere cohesion. The observation that cells respond to unresolved telomere cohesion by delaying (but not completely disrupting) anaphase progression suggests a mechanism for tolerating excess cohesion and maintaining telomere integrity. This attempt to deal with telomere damage may be ultimately futile for aging fibroblasts but useful for cancer cells.},
}
@article {pmid24168161,
year = {2014},
author = {Berardinelli, F and Sgura, A and Di Masi, A and Leone, S and Cirrone, GA and Romano, F and Tanzarella, C and Antoccia, A},
title = {Radiation-induced telomere length variations in normal and in Nijmegen Breakage Syndrome cells.},
journal = {International journal of radiation biology},
volume = {90},
number = {1},
pages = {45-52},
doi = {10.3109/09553002.2014.859400},
pmid = {24168161},
issn = {1362-3095},
mesh = {Acid Anhydride Hydrolases ; Cells, Cultured ; DNA Damage ; DNA Repair/*genetics/radiation effects ; DNA Repair Enzymes/*genetics ; DNA-Binding Proteins/*genetics ; Humans ; Lymphocytes/*radiation effects ; MRE11 Homologue Protein ; Nijmegen Breakage Syndrome/*pathology/*physiopathology ; Telomere Homeostasis/*radiation effects ; },
abstract = {PURPOSE: The meiotic recombination protein 11 (MRE11), radiation sensitive 50 (RAD50) and nibrin (NBN) are members of the MRE11/RAD50/NBN (MRN) complex which plays a fundamental role in the double-strand break damage response, including DNA damage sensing, signalling and repair after exposure to ionizing radiations. In addition the MRN complex is involved in the mechanisms regulating telomere length maintenance. Based on our previous results indicating that, in contrast to X-rays, high linear energy transfer (LET) radiations were able to elongate telomeres, we investigated the behavior of cells mutated in components of the MRN complex after exposure either to 62 MeV carbon-ions (50 keV/μm, at cell surface) or X-rays.<br><br>MATERIALS AND METHODS: Epstein Barr Virus (EBV)-transformed lymphoblastoid cell lines (LCL) established from normal, heterozygous for the NBN gene, homozygous for either mutant/deleted NBN, RAD50 or ataxia telangiectasia mutated (ATM) genes were irradiated with 4 Gy, with telomere length being evaluated 24 h later or in time course-experiments up to 15 days later. The induction of telomeric sister chromatid exchanges (T-SCE) was measured as a hallmark of homologous directed recombinational repair.<br><br>RESULTS: NBN and RAD50 mutated cells failed to elongate telomeres that instead occurred in the remaining cell lines as a response only to high-LET irradiation. Also, a kinetic study with 0.5-4 Gy up to 15 days from irradiation confirmed that NBN gene was indispensable for telomere elongation. Furthermore, such an elongation, was accompanied by an increased frequency of sister chromatid exchanges at telomeres (T-SCE). In contrast, the induction of genomic sister chromatid exchanges (G-SCE) occurred for carbon-ions irrespective of NBN gene status.<br><br>CONCLUSIONS: We speculate that the MRN is necessary to process a subclass of high-LET radiation-induced complex DNA damage through a recombinational-repair mediated mechanism which in turn is responsible for telomere elongation.},
}
@article {pmid24166593,
year = {2013},
author = {Ferlin, A and Rampazzo, E and Rocca, MS and Keppel, S and Frigo, AC and De Rossi, A and Foresta, C},
title = {In young men sperm telomere length is related to sperm number and parental age.},
journal = {Human reproduction (Oxford, England)},
volume = {28},
number = {12},
pages = {3370-3376},
doi = {10.1093/humrep/det392},
pmid = {24166593},
issn = {1460-2350},
mesh = {Adolescent ; Female ; Humans ; Leukocytes/ultrastructure ; Male ; Maternal Age ; Oligospermia/*genetics ; *Parents ; Sperm Count ; Spermatozoa/physiology/*ultrastructure ; Telomere ; Young Adult ; },
abstract = {STUDY QUESTION: What are the relationships between telomere lengths in leukocytes and sperm, sperm count and parents' age at conception in a group of apparently healthy subjects of the same age?<br><br>SUMMARY ANSWER: Sperm telomere length (STL) is related to sperm count, it is lower in oligozoospermic than in normozoospermic men and it is directly related to parents' age at conception.<br><br>WHAT IS KNOWN ALREADY: Leukocyte telomere length (LTL) decreases with age but STL increases and offspring of older fathers tend to have longer leukocyte telomeres. Only one study analyzed STL in relation to male fertility, and reported shorter telomeres in infertile versus fertile men. No data have been reported on STL in relation to parents' age at conception.<br><br>STUDY DESIGN, SIZE, DURATION: Prospective study conducted from January to December 2012 of 18-19-year-old high school students.<br><br>The volunteers were 81 apparently healthy subjects, including 61 with normozoospermia and 20 with idiopathic oligozoospermia. Leukocyte and sperm telomere length were measured by real-time PCR. Data were analyzed for determining the relationships between LTL, STL, sperm count and parents' age at conception.<br><br>Sperm and leukocyte telomere length were strongly correlated, but STL was significantly longer. A significant positive correlation between STL and total sperm number was found. STL was significantly lower in oligozoospermic than in normozoospermic men. Finally, we found a significant positive relationship between maternal age and both leukocyte and sperm telomere length and a significant positive relation between paternal age and STL in the offspring. The relative contributions of mothers' and fathers' ages to their offspring's telomere length could not be determined because of the high correlation between paternal and maternal ages.<br><br>Although consistent with previous findings, this is the first study on telomere length in oligo- and normozoospermic men and included a relatively low number of subjects. Our study was also restricted to young (18-19 year old) men, so future studies should determine whether our findings can be generalized to men at ages typically encountered at fertility centers. Future studies should also try to determine the possible effect of abstinence time and frequency of ejaculation with STL.<br><br>Our study sheds new light on the association between STL and sperm count and on the inheritance of telomere length (in leukocytes and sperm) in relation to the parents' age at conception. Additional studies are needed to confirm these observations, to clarify if the association between shorter STL and damaged spermatogenesis represents a pathophysiological link, and to determine the effect on offspring telomere length of assisted reproduction techniques performed on couples of advanced age or where the man is oligozoospermic.<br><br>This work was supported by the Italian Ministry of University and Research (grant no. 2009AMPA9C to C.F.) and Padova University (grant 2010 to A.D.R.). The authors have no competing interests to declare.},
}
@article {pmid24165286,
year = {2014},
author = {Müezzinler, A and Zaineddin, AK and Brenner, H},
title = {Body mass index and leukocyte telomere length in adults: a systematic review and meta-analysis.},
journal = {Obesity reviews : an official journal of the International Association for the Study of Obesity},
volume = {15},
number = {3},
pages = {192-201},
doi = {10.1111/obr.12126},
pmid = {24165286},
issn = {1467-789X},
mesh = {Adult ; *Body Mass Index ; Female ; Humans ; Leukocytes/*physiology/*ultrastructure ; Male ; Telomere/*ultrastructure ; },
abstract = {The objective of this study was to provide a systematic review and meta-analysis of studies on the relationship between body mass index (BMI) and leukocyte telomere length (LTL). Relevant studies were identified by a systematic search of MEDLINE, Embase and Web of Knowledge databases. Pooled correlation and regression coefficients were calculated using meta-analysis methods for both cross-sectional and longitudinal studies. Studies without suitable data for meta-analysis were summarized separately. Overall, 29 studies were included, of which 16 were eligible for meta-analysis, including two longitudinal studies. The majority of studies reported an inverse relationship between BMI and telomere length. For cross-sectional studies, the pooled estimates for correlation and regression coefficients were -0.057 (95% confidence interval [CI]: -0.102 to -0.012) and -0.008 kBP kg m[-2] (95% CI: -0.016 to 0.000), respectively. The two longitudinal studies were small (70 and 311 subjects), covered different age ranges and yielded inconsistent results. No evidence of any gender difference was observed. Despite some variation between studies and very limited data from longitudinal studies, the results of this meta-analysis suggest a biologically plausible inverse association between BMI and LTL in adults. However, the associations require clarification, in particular by large longitudinal studies with careful control for possible confounding factors in overall, age- and sex-specific analyses.},
}
@article {pmid24164896,
year = {2014},
author = {Liu, CC and Gopalakrishnan, V and Poon, LF and Yan, T and Li, S},
title = {Cdk1 regulates the temporal recruitment of telomerase and Cdc13-Stn1-Ten1 complex for telomere replication.},
journal = {Molecular and cellular biology},
volume = {34},
number = {1},
pages = {57-70},
pmid = {24164896},
issn = {1098-5549},
mesh = {Amino Acid Sequence ; Blotting, Western ; CDC2 Protein Kinase/genetics/*metabolism ; Cell Cycle ; Cell Cycle Proteins/genetics/*metabolism ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; DNA Damage ; DNA Replication ; Molecular Sequence Data ; Multiprotein Complexes ; Mutation ; Phosphorylation ; Protein Binding ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Serine/genetics/metabolism ; Telomerase/genetics/*metabolism ; Telomere/*genetics/metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/genetics/*metabolism ; Threonine/genetics/metabolism ; Time Factors ; Two-Hybrid System Techniques ; },
abstract = {In budding yeast (Saccharomyces cerevisiae), the cell cycle-dependent telomere elongation by telomerase is controlled by the cyclin-dependent kinase 1 (Cdk1). The telomere length homeostasis is balanced between telomerase-unextendable and telomerase-extendable states that both require Cdc13. The recruitment of telomerase complex by Cdc13 promotes telomere elongation, while the formation of Cdc13-Stn1-Ten1 (CST) complex at the telomere blocks telomere elongation by telomerase. However, the cellular signaling that regulates the timing of the telomerase-extendable and telomerase-unextendable states is largely unknown. Phosphorylation of Cdc13 by Cdk1 promotes the interaction between Cdc13 and Est1 and hence telomere elongation. Here, we show that Cdk1 also phosphorylates Stn1 at threonine 223 and serine 250 both in vitro and in vivo, and these phosphorylation events are essential for the stability of the CST complexes at the telomeres. By controlling the timing of Cdc13 and Stn1 phosphorylations during cell cycle progression, Cdk1 regulates the temporal recruitment of telomerase complexes and CST complexes to the telomeres to facilitate telomere maintenance.},
}
@article {pmid24161135,
year = {2013},
author = {Basu, N and Skinner, HG and Litzelman, K and Vanderboom, R and Baichoo, E and Boardman, LA},
title = {Telomeres and telomere dynamics: relevance to cancers of the GI tract.},
journal = {Expert review of gastroenterology &amp; hepatology},
volume = {7},
number = {8},
pages = {733-748},
pmid = {24161135},
issn = {1747-4132},
support = {R01 CA132718/CA/NCI NIH HHS/United States ; R0-1 CA132718/CA/NCI NIH HHS/United States ; R0-1 CA 170357/CA/NCI NIH HHS/United States ; R01 CA170357/CA/NCI NIH HHS/United States ; P30 DK084567/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Antineoplastic Agents/therapeutic use ; Biomarkers, Tumor/genetics ; Cell Transformation, Neoplastic/genetics/metabolism ; Enzyme Inhibitors/therapeutic use ; Gastrointestinal Neoplasms/drug therapy/genetics/*metabolism ; Genetic Predisposition to Disease ; Humans ; Molecular Targeted Therapy ; Phenotype ; Risk Factors ; Telomerase/antagonists &amp; inhibitors/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Aberrations in telomere length and telomere maintenance contribute to cancer development. In this article, we review the basic principles of telomere length in normal and tumor tissue and the presence of the two main telomere maintenance pathways as they pertain to gastrointestinal tract cancer. Peripheral blood telomeres are shorter in patients with many types of gastrointestinal tract cancers. Telomere length in tumor DNA also appears to shorten early in cancer development. Tumor telomere shortening is often accompanied by telomerase activation to protect genetically damaged DNA from normal cell senescence or apoptosis, allowing immortalized but damaged DNA to persist. Alternative lengthening of telomeres is another mechanism used by cancer to maintain telomere length in cancer cells. Telomerase and alternative lengthening of telomeres activators and inhibitors may become important chemopreventive or chemotherapeutic agents as our understanding of telomere biology, specific telomere-related phenotypes and its relationship to carcinogenesis increases.},
}
@article {pmid24156433,
year = {2013},
author = {Guo, TJ and Sun, WL and Zhang, W and Ma, XC and Liu, CY and He, JJ and Xu, J},
title = {[Application of flow cytometry-fluorescence in situ hybridization in the measurement of relative telomere length of bone marrow CD34(+) cells in patients with myelodysplastic syndrome].},
journal = {Zhongguo shi yan xue ye xue za zhi},
volume = {21},
number = {5},
pages = {1195-1199},
doi = {10.7534/j.issn.1009-2137.2013.05.022},
pmid = {24156433},
issn = {1009-2137},
mesh = {Aged ; Aged, 80 and over ; Antigens, CD34/immunology ; Bone Marrow Cells/cytology/immunology ; DNA ; Female ; Flow Cytometry/*methods ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Male ; Middle Aged ; Myelodysplastic Syndromes/*genetics ; Telomere/*genetics ; },
abstract = {This study was aimed to investigate the feasibility of flow cytometry-fluorescence in situ hybridization (Flow-FISH) in measuring the telomere length of bone marrow cell subgroups in patients with myelodysplastic syndrome (MDS). Seven newly diagnosed patients with low-risk MDS and seven nutritional anemia patients who were matched with age and sex, were enrolled in this study. Heparinized bone marrow were sampled. Taking Molt-4 cell line as internal control cells, leukocytes isolated from whole bone marrow were labeled with CD34-Alexa Fluork ® 647, then denatured by high temperature and hybridized with FITC-conjugated telomere probe. The DNA was counterstained and the relative telomere length (RTL) of nucleated cells and CD34(+) cells in bone marrow were measured by four-color flow cytometry. The results showed that CD34(+) cells could be gated for the measurement of RTL in both groups, undergoing the denaturation and hybridization. Primary analysis indicated that the RTL of bone marrow CD34(+) cells in MDS patients was significantly shorter than that of bone marrow nucleated cells (P = 0.001), and the RTL of both CD34(+) cells and nucleated cells in bone marrow of MDS patients were significantly shorter than that of control group (P = 0.020, 0.002). It is concluded that the application of Flow-FISH in the measurement of RTL of certain cell subgroup is feasible by labeling the cell with thermostable fluorescence-conjugated antibody, and this technique is worthy to be investigated further.},
}
@article {pmid24153156,
year = {2013},
author = {Das, A and Grotsky, DA and Neumann, MA and Kreienkamp, R and Gonzalez-Suarez, I and Redwood, AB and Kennedy, BK and Stewart, CL and Gonzalo, S},
title = {Lamin A Δexon9 mutation leads to telomere and chromatin defects but not genomic instability.},
journal = {Nucleus (Austin, Tex.)},
volume = {4},
number = {5},
pages = {410-419},
pmid = {24153156},
issn = {1949-1042},
support = {R01 GM094513/GM/NIGMS NIH HHS/United States ; R01GM094513-01/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; BRCA1 Protein/metabolism ; Cell Line ; Chromatin/chemistry/*genetics/pathology ; Chromosomal Proteins, Non-Histone/metabolism ; DNA Repair/genetics ; DNA-Binding Proteins/metabolism ; Exons/*genetics ; Fibroblasts/cytology/metabolism ; Genomic Instability/*genetics ; Heterochromatin/chemistry/genetics/metabolism ; Humans ; Lamin Type A/*genetics ; Mice ; Rad51 Recombinase/metabolism ; Sequence Deletion/*genetics ; Telomere/*genetics/pathology ; Telomere Shortening/genetics ; Tumor Suppressor p53-Binding Protein 1 ; },
abstract = {Over 300 mutations in the LMNA gene, encoding A-type lamins, are associated with 15 human degenerative disorders and premature aging syndromes. Although genomic instability seems to contribute to the pathophysiology of some laminopathies, there is limited information about what mutations cause genomic instability and by which molecular mechanisms. Mouse embryonic fibroblasts depleted of A-type lamins or expressing mutants lacking exons 8-11 (Lmna(Δ8-11/Δ8-11)) exhibit alterations in telomere biology and DNA repair caused by cathepsin L-mediated degradation of 53BP1 and reduced expression of BRCA1 and RAD51. Thus, a region encompassing exons 8-11 seems essential for genome integrity. Given that deletion of lamin A exon 9 in the mouse (Lmna(Δ9/Δ9)) results in a progeria phenotype, we tested if this domain is important for genome integrity. Lmna(Δ9/Δ9) MEFs exhibit telomere shortening and heterochromatin alterations but do not activate cathepsin L-mediated degradation of 53BP1 and maintain expression of BRCA1 and RAD51. Accordingly, Lmna(Δ9/Δ9) MEFs do not present genomic instability, and expression of mutant lamin A Δexon9 in lamin-depleted cells restores DNA repair factors levels and partially rescues nuclear abnormalities. These data reveal that the domain encoded by exon 9 is important to maintain telomere homeostasis and heterochromatin structure but does not play a role in DNA repair, thus pointing to other exons in the lamin A tail as responsible for the genomic instability phenotype in Lmna(Δ8-11/Δ8-11) mice. Our study also suggests that the levels of DNA repair factors 53BP1, BRCA1 and RAD51 could potentially serve as biomarkers to identify laminopathies that present with genomic instability.},
}
@article {pmid24149546,
year = {2014},
author = {De Meyer, T and Vandepitte, K and Denil, S and De Buyzere, ML and Rietzschel, ER and Bekaert, S},
title = {A non-genetic, epigenetic-like mechanism of telomere length inheritance?.},
journal = {European journal of human genetics : EJHG},
volume = {22},
number = {1},
pages = {10-11},
pmid = {24149546},
issn = {1476-5438},
mesh = {Female ; Humans ; Male ; *Paternal Age ; *Pedigree ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
}
@article {pmid24149432,
year = {2014},
author = {Bendix, L and Thinggaard, M and Fenger, M and Kolvraa, S and Avlund, K and Linneberg, A and Osler, M},
title = {Longitudinal changes in leukocyte telomere length and mortality in humans.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {69},
number = {2},
pages = {231-239},
doi = {10.1093/gerona/glt153},
pmid = {24149432},
issn = {1758-535X},
mesh = {Adult ; Age Factors ; Aged ; Alcohol Drinking ; Female ; Health Status ; Humans ; Leukocytes/*pathology ; Life Style ; Longevity/*physiology ; Longitudinal Studies ; Male ; Middle Aged ; Risk Factors ; Smoking ; Socioeconomic Factors ; Telomere Shortening/*physiology ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) ostensibly shortens with age and has been moderately associated with mortality. In humans, these findings have come almost solely from cross-sectional studies. Only recently has LTL shortening within individuals been analyzed in longitudinal studies. Such studies are relevant to establish LTL dynamics as biomarkers of mortality as well as to disentangle the causality of telomeres on aging.<br><br>METHODS: We present a large longitudinal study on LTL and human mortality, where the 10-year change of LTL is analyzed in 1,356 individuals aged 30-70 years.<br><br>RESULTS: We find age, smoking status, and alcohol consumption to be associated with LTL attrition and confirm a strong association with baseline LTL. The latter association might be an epiphenomenon of regression to the mean. We do not find an association of mortality with either absolute LTL or LTL attrition. Further, we show that DNA quality has an impact on TS ratios.<br><br>CONCLUSIONS: This study establishes that certain lifestyle factors influence LTL dynamics. However, it questions the applicability of LTL dynamics as a predictor of mortality. We suggest cautiousness when assessing actual LTL attrition due to the need for high-quality DNA and the phenomena of regression to the mean.},
}
@article {pmid24141777,
year = {2014},
author = {Liu, T and Wang, N and Cao, J and Sofiadis, A and Dinets, A and Zedenius, J and Larsson, C and Xu, D},
title = {The age- and shorter telomere-dependent TERT promoter mutation in follicular thyroid cell-derived carcinomas.},
journal = {Oncogene},
volume = {33},
number = {42},
pages = {4978-4984},
doi = {10.1038/onc.2013.446},
pmid = {24141777},
issn = {1476-5594},
mesh = {Adenocarcinoma, Follicular/*genetics/mortality ; Adult ; Aged ; Aged, 80 and over ; Base Sequence ; Cell Line, Tumor ; DNA Mutational Analysis ; Gene Frequency ; Genetic Association Studies ; Humans ; Kaplan-Meier Estimate ; Middle Aged ; Mutation, Missense ; Point Mutation ; Proto-Oncogene Proteins B-raf/genetics ; Telomerase/*genetics ; Telomere/*genetics ; Thyroid Neoplasms/*genetics/mortality ; Young Adult ; },
abstract = {Telomerase activation through induction of its catalytic component telomerase reverse transcriptase (TERT) expression is essential for malignant transformation. TERT promoter mutations namely C228T and C250T that stimulate TERT transcription and telomerase activation have recently been identified in many human malignancies. We thus determined these mutations and their biological and clinical implications in thyroid carcinomas in the present study. The TERT promoter was sequenced in 10 thyroid cancer cell lines and 144 tumors from 20 patients with anaplastic thyroid carcinoma (ATC), 51 with papillary thyroid carcinoma (PTC), 36 with follicular thyroid carcinoma (FTC), and 37 with medullary thyroid carcinoma (MTC). We identified C228T or C250T mutation in 6/8 of ATC cell lines, as well as in tumor tissue from 10/20, 13/51, 8/36 and 0/37 patients with ATC, PTC, FTC and MTC, respectively. In PTC patients, these mutations were exclusively present in the group with age >45 years (P<0.0001), and highly correlated shorter telomeres (P<0.0001) and distant metastasis (P=0.028). The previous radioactivity exposure did not induce the mutation. The presence of C228T or C250T was an independent predictor associated with shorter disease-related survival (DRS) in the entire cohort (P<0.0001), as well as among patients >45 years (P=0.021). ATC patients carrying the mutation survived shorter than those without mutations, although not statistically significant (P=0.129). The TERT promoter mutation was associated with overall survival (P=0.038) and DRS (P=0.058) of FTC patients. Taken together, age- and shorter telomere-dependent TERT promoter mutations occur frequently in follicular cell-derived thyroid carcinoma (ATC, PTC and FTC) but not in parafollicular cell-originated MTC, and may serve as a marker for aggressive disease and poor outcome.},
}
@article {pmid24141383,
year = {2013},
author = {Uziel, O and Laish, I and Bulcheniko, M and Harif, Y and Kochavi-Shalem, N and Aharoni, M and Braunstein, R and Lahav, M and Ben-Ari, Z},
title = {Telomere shortening in liver transplant recipients is not influenced by underlying disease or metabolic derangements.},
journal = {Annals of transplantation},
volume = {18},
number = {},
pages = {567-575},
doi = {10.12659/AOT.889272},
pmid = {24141383},
issn = {2329-0358},
mesh = {Adult ; Aged ; Aging ; Female ; Humans ; *Liver Transplantation ; Male ; Middle Aged ; *Telomere ; *Telomere Shortening ; },
abstract = {BACKGROUND: Telomeres are non-coding regions of DNA that cap the ends of chromosomes. Their length is considered a marker of human replicative senescence and premature aging. Given the high association of liver transplantation with the metabolic syndrome, we hypothesized that liver transplant recipients may exhibit premature and accelerated aging.<br><br>MATERIAL AND METHODS: Telomere length in peripheral blood lymphocytes was measured by polymerase chain reaction in 62 consecutive liver-transplant recipients and 59 healthy control subjects aged 20-76 years. Clinical and laboratory parameters were collected from the medical files.<br><br>RESULTS: The liver transplant recipients were significantly older than the control subjects (p=0.012), with significantly higher rates of obesity (BMI >30 kg/m(2)), dyslipidemia, hypertension, diabetes, and fatty liver. Mean telomere length was significantly shorter in the transplant group (0.59&#xb1;0.6 vs. 1.91&#xb1;1.78 in the controls, p<0.0001). Within the transplant group, there was no significant association between mean telomere length and underlying liver disease or presence of the metabolic syndrome or its constituents. On multivariate analysis, telomere length was negatively associated with patient age (p=0.0001), male sex (p=0.04), acute rejection (p=0.005), and fatty liver (p=0.009), and was positively associated with time from transplantation (p=0.006).<br><br>CONCLUSIONS: Liver transplantation is associated with shortened telomere length in peripheral blood lymphocytes, suggesting accelerated senescence.},
}
@article {pmid24137170,
year = {2013},
author = {Amiard, S and Gallego, ME and White, CI},
title = {Signaling of double strand breaks and deprotected telomeres in Arabidopsis.},
journal = {Frontiers in plant science},
volume = {4},
number = {},
pages = {405},
pmid = {24137170},
issn = {1664-462X},
abstract = {Failure to repair DNA double strand breaks (DSB) can lead to chromosomal rearrangements and eventually to cancer or cell death. Radiation and environmental pollutants induce DSB and this is of particular relevance to plants due to their sessile life style. DSB also occur naturally in cells during DNA replication and programmed induction of DSB initiates the meiotic recombination essential for gametogenesis in most eukaryotes. The linear nature of most eukaryotic chromosomes means that each chromosome has two "broken" ends. Chromosome ends, or telomeres, are protected by nucleoprotein caps which avoid their recognition as DSB by the cellular DNA repair machinery. Deprotected telomeres are recognized as DSB and become substrates for recombination leading to chromosome fusions, the "bridge-breakage-fusion" cycle, genome rearrangements and cell death. The importance of repair of DSB and the severity of the consequences of their misrepair have led to the presence of multiple, robust mechanisms for their detection and repair. After a brief overview of DSB repair pathways to set the context, we present here an update of current understanding of the detection and signaling of DSB in the plant, Arabidopsis thaliana.},
}
@article {pmid24130507,
year = {2013},
author = {Valerio-Santiago, M and de Los Santos-Velázquez, AI and Monje-Casas, F},
title = {Inhibition of the mitotic exit network in response to damaged telomeres.},
journal = {PLoS genetics},
volume = {9},
number = {10},
pages = {e1003859},
pmid = {24130507},
issn = {1553-7404},
mesh = {Cell Cycle/genetics ; Cell Cycle Checkpoints/genetics ; Cell Cycle Proteins/genetics ; Checkpoint Kinase 2/genetics ; Cytoskeletal Proteins/genetics ; DNA Damage/*genetics ; G2 Phase Cell Cycle Checkpoints/genetics ; *Mitosis ; Phosphorylation/*genetics ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/genetics ; Spindle Apparatus/genetics ; Telomere/*genetics ; },
abstract = {When chromosomal DNA is damaged, progression through the cell cycle is halted to provide the cells with time to repair the genetic material before it is distributed between the mother and daughter cells. In Saccharomyces cerevisiae, this cell cycle arrest occurs at the G2/M transition. However, it is also necessary to restrain exit from mitosis by maintaining Bfa1-Bub2, the inhibitor of the Mitotic Exit Network (MEN), in an active state. While the role of Bfa1 and Bub2 in the inhibition of mitotic exit when the spindle is not properly aligned and the spindle position checkpoint is activated has been extensively studied, the mechanism by which these proteins prevent MEN function after DNA damage is still unclear. Here, we propose that the inhibition of the MEN is specifically required when telomeres are damaged but it is not necessary to face all types of chromosomal DNA damage, which is in agreement with previous data in mammals suggesting the existence of a putative telomere-specific DNA damage response that inhibits mitotic exit. Furthermore, we demonstrate that the mechanism of MEN inhibition when telomeres are damaged relies on the Rad53-dependent inhibition of Bfa1 phosphorylation by the Polo-like kinase Cdc5, establishing a new key role of this kinase in regulating cell cycle progression.},
}
@article {pmid24129736,
year = {2013},
author = {Wang, YP and Yang, YZ and Ma, L and Zhao, YX and Ge, RL},
title = {[Effect of different altitudes on telomere length of rat peripheral blood leukocyte].},
journal = {Sheng li xue bao : [Acta physiologica Sinica]},
volume = {65},
number = {5},
pages = {540-546},
pmid = {24129736},
issn = {0371-0874},
mesh = {*Altitude ; Animals ; Hemoglobins/metabolism ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit/blood ; Leukocytes/*physiology ; Male ; Malondialdehyde/blood ; Oxidative Stress ; Rats ; Superoxide Dismutase/metabolism ; Telomerase/blood ; Telomere/*physiology ; },
abstract = {The present study was aimed to investigate the effect of different altitudes on telomere length of rat peripheral blood leukocyte and possible mechanism. Sixty male rats were randomly divided into three groups, lower altitude control group (10 m), moderate altitude group (2 260 m) and very high altitude group (simulated 5 000 m). The moderate altitude group and very high altitude group rats were transported to Xining and hypobaric chamber in Qinghai University, respectively. The peripheral blood specimens were extracted 30 d after the transportation. By means of real-time PCR, automatic blood cell analyzer, ELISA, TBA and WST-1 methods, the telomere lengths of blood leukocyte, the hemoglobin (Hb) contents, the plasma levels of telomerase reverse transcriptase (TERT) and hypoxia-inducible factor 1α (HIF-1α), the plasma content of malondialdehyde (MDA) and superoxide dismutase (SOD) activity were measured, respectively. The results showed that the telomere lengths of peripheral blood leukocyte in moderate altitude group were longer than those in control group and very high altitude group. The changes of TERT were compatible with the telomere length of peripheral blood leukocyte under different altitudes. The levels of HIF-1α in moderate altitude group and very high altitude group were higher than that of control group. The very high altitude group showed decreased SOD activities and increased level of MDA, compared with the other two groups. These results suggest that the telomere lengths of rat peripheral blood leukocyte in moderate altitude are elongated, and that the telomere-elongating effect is lost under very high altitude. The changes of HIF-1α, TERT and oxidative stress damage are the main mechanisms of telomere length changes. Moderate altitude living might be beneficial to increasing the life span in mammals.},
}
@article {pmid24127938,
year = {2013},
author = {Bojesen, SE},
title = {Telomeres and human health.},
journal = {Journal of internal medicine},
volume = {274},
number = {5},
pages = {399-413},
doi = {10.1111/joim.12083},
pmid = {24127938},
issn = {1365-2796},
mesh = {Age Factors ; Biomarkers/metabolism ; Heart Diseases/etiology ; Humans ; Mortality ; Risk Factors ; Telomere/*physiology ; Telomere Homeostasis/physiology ; },
abstract = {Telomeres are the tips of chromosomes and consist of proteins and hexanucleotide tandem repeats of DNA. The DNA repeats are shortened at each mitotic division of normal cells, and the telomere length chronicles how many divisions the cell has undergone. Thus, telomere length is a marker of fundamental biological pathways. It has been possible to measure telomere length for more than 20 years, and it has been established that telomere length is associated with age, sex and lifestyle factors. Here, the current knowledge of telomere length as a biomarker of disease susceptibility and mortality will be reviewed. In addition, technical difficulties and the reasons why measurement of telomeres has still not been introduced into routine clinical practice will be discussed. Findings from recent studies conducted in many thousands of individuals indicate that telomere length is not-or at best only marginally-independently associated with risk of common disorders such as cardiovascular, pulmonary and neoplastic diseases. However, in sufficiently powered studies, short telomeres are repeatedly and independently found to be associated with increased risk of early death in the general population or in subsets of individuals. This indicates that measurement of telomeres could be a valuable prognostic biomarker in many clinical settings. However, whether short telomeres are a causal factor for or simply a marker of increased risk of early death must be determined. Finally, how Mendelian randomization studies could clarify this issue, and which clinical studies might be carried out to refine this very promising biomarker for routine clinical use will be considered.},
}
@article {pmid24127576,
year = {2013},
author = {Madlener, S and Ströbel, T and Vose, S and Saydam, O and Price, BD and Demple, B and Saydam, N},
title = {Essential role for mammalian apurinic/apyrimidinic (AP) endonuclease Ape1/Ref-1 in telomere maintenance.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {110},
number = {44},
pages = {17844-17849},
pmid = {24127576},
issn = {1091-6490},
support = {R01 CA177884/CA/NCI NIH HHS/United States ; R01 GM040000/GM/NIGMS NIH HHS/United States ; T32 ES016645/ES/NIEHS NIH HHS/United States ; GM040000/GM/NIGMS NIH HHS/United States ; },
mesh = {Blotting, Western ; Cell Line, Tumor ; Chromatin Immunoprecipitation ; DNA Primers/genetics ; DNA Repair/*physiology ; DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics/*metabolism ; Fluorescent Antibody Technique ; Humans ; Immunoprecipitation ; In Situ Hybridization, Fluorescence ; Telomerase/metabolism ; Telomere Homeostasis/*genetics/physiology ; },
abstract = {The major mammalian apurinic/apyrimidinic endonuclease Ape1 is a multifunctional protein operating in protection of cells from oxidative stress via its DNA repair, redox, and transcription regulatory activities. The importance of Ape1 has been marked by previous work demonstrating its requirement for viability in mammalian cells. However, beyond a requirement for Ape1-dependent DNA repair activity, deeper molecular mechanisms of the fundamental role of Ape1 in cell survival have not been defined. Here, we report that Ape1 is an essential factor stabilizing telomeric DNA, and its deficiency is associated with telomere dysfunction and segregation defects in immortalized cells maintaining telomeres by either the alternative lengthening of telomeres pathway (U2OS) or telomerase expression (BJ-hTERT), or in normal human fibroblasts (IMR90). Through the expression of Ape1 derivatives with site-specific changes, we found that the DNA repair and N-terminal acetylation domains are required for the Ape1 function at telomeres. Ape1 associates with telomere proteins in U2OS cells, and Ape1 depletion causes dissociation of TRF2 protein from telomeres. Consistent with this effect, we also observed that Ape1 depletion caused telomere shortening in both BJ-hTERT and in HeLa cells. Thus, our study describes a unique and unpredicted role for Ape1 in telomere protection, providing a direct link between base excision DNA repair activities and telomere metabolism.},
}
@article {pmid24125430,
year = {2013},
author = {Zhang, D and Wen, X and Wu, W and Xu, E and Zhang, Y and Cui, W},
title = {Homocysteine-related hTERT DNA demethylation contributes to shortened leukocyte telomere length in atherosclerosis.},
journal = {Atherosclerosis},
volume = {231},
number = {1},
pages = {173-179},
doi = {10.1016/j.atherosclerosis.2013.08.029},
pmid = {24125430},
issn = {1879-1484},
mesh = {Animals ; Atherosclerosis/genetics/metabolism ; Epigenesis, Genetic ; Homocysteine/metabolism ; Humans ; Hyperhomocysteinemia/blood ; Leukocytes/metabolism ; Mice ; Telomerase/*metabolism ; Telomere/metabolism ; *Telomere Shortening ; },
abstract = {AIMS: Leukocyte telomere length (LTL) is shortened in patients with clinical atherosclerosis (AS). Here we aimed to explore the contribution of elevated homocysteine (Hcy) level to LTL shortening in AS patients and the underlying mechanism.<br><br>METHODS: Circulating leukocytes were collected from 197 patients with AS and 165 sex- and age-matched healthy subjects for LTL determination. mRNA expression or DNA methylation of human telomerase reverse transcriptase (hTERT) was determined by real-time PCR and methylation-specific PCR assay, respectively. We established a hyperhomocysteinemia (HHcy) mice model to confirm human results.<br><br>RESULTS: Hcy was negatively correlated with LTL shortening in AS patients (r = -0.179, p = 0.015) and controls (r = -0.146, p = 0.031). Serum folate and high-sensitivity C-reactive protein levels significantly interacted with Hcy in LTL shortening. Hcy was related to hTERT mRNA downregulation and promoter demethylation, which combined was associated with LTL shortening in AS patients. Hcy-induced LTL shortening did not differ by sites of AS lesions or infarction. Similar to clinical observations, our HHcy mice model suggested that Hcy induced DNA demethylation and downregulation of mouse TERT and further contributed to LTL shortening.<br><br>CONCLUSIONS: Elevated Hcy level induced DNA demethylation of hTERT and was closely related with hTERT downregulation, which led to LTL shortening in AS. These findings provide novel insights into an epigenetic mechanism for Hcy-related AS.},
}
@article {pmid24124228,
year = {2013},
author = {Shay, JW},
title = {Are short telomeres predictive of advanced cancer?.},
journal = {Cancer discovery},
volume = {3},
number = {10},
pages = {1096-1098},
pmid = {24124228},
issn = {2159-8290},
support = {P50CA70907/CA/NCI NIH HHS/United States ; R13 CA113094/CA/NCI NIH HHS/United States ; 5P30 CA 142543-03/CA/NCI NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; C06 RR030414/RR/NCRR NIH HHS/United States ; C06 RR30414/RR/NCRR NIH HHS/United States ; },
mesh = {Animals ; Biomarkers, Tumor ; Disease Progression ; Humans ; Male ; Neoplasm Metastasis/*genetics ; Precision Medicine ; Prostatic Neoplasms/*diagnosis/*genetics ; Rats ; Telomere/*genetics/*metabolism ; },
abstract = {The combination of variable telomere length in cancer cells and shorter telomere length in cancer-associated stromal cells strongly correlates with progression to prostate cancer metastasis and cancer death. The implication is that telomere length measurements have potential not only as prognostic indicators of prostate cancer outcomes but also as risk stratification enrichment biomarkers for individualized therapeutic interventions.},
}
@article {pmid24122006,
year = {2013},
author = {Bonetti, D and Martina, M and Falcettoni, M and Longhese, MP},
title = {Telomere-end processing: mechanisms and regulation.},
journal = {Chromosoma},
volume = {},
number = {},
pages = {},
pmid = {24122006},
issn = {1432-0886},
abstract = {Telomeres are specialized nucleoprotein complexes that provide protection to the ends of eukaryotic chromosomes. Telomeric DNA consists of tandemly repeated G-rich sequences that terminate with a 3' single-stranded overhang, which is important for telomere extension by the telomerase enzyme. This structure, as well as most of the proteins that specifically bind double and single-stranded telomeric DNA, are conserved from yeast to humans, suggesting that the mechanisms underlying telomere identity are based on common principles. The telomeric 3' overhang is generated by different events depending on whether the newly synthesized strand is the product of leading- or lagging-strand synthesis. Here, we review the mechanisms that regulate these processes at Saccharomyces cerevisiae and mammalian telomeres.},
}
@article {pmid24121960,
year = {2014},
author = {Mathur, S and Glogowska, A and McAvoy, E and Righolt, C and Rutherford, J and Willing, C and Banik, U and Ruthirakuhan, M and Mai, S and Garcia, A},
title = {Three-dimensional quantitative imaging of telomeres in buccal cells identifies mild, moderate, and severe Alzheimer's disease patients.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {39},
number = {1},
pages = {35-48},
doi = {10.3233/JAD-130866},
pmid = {24121960},
issn = {1875-8908},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Aged ; Alzheimer Disease/classification/*genetics/*pathology ; Female ; Genomic Instability/*genetics ; Humans ; Imaging, Three-Dimensional ; In Situ Hybridization, Fluorescence ; Interphase/genetics ; Male ; Mouth Mucosa/*pathology ; Reference Values ; Telomere/*ultrastructure ; },
abstract = {Using three-dimensional (3D) telomeric analysis of buccal cells of 82 Alzheimer's disease (AD) patients and cognitively normal age and gender-matched controls, we have for the first time examined changes in the 3D nuclear telomeric architecture of buccal cells among levels of AD severity based on five 3D parameters: i) telomere length, ii) telomere number, iii) telomere aggregation, iv) nuclear volume, and v) a/c ratio, a measure of spatial telomere distribution. Our data indicate that matched controls have significantly different 3D telomere profiles compared to mild, moderate, and severe AD patients (p < 0.0001). Distinct profiles were also evident for each AD severity group. An increase in telomere number and aggregation concomitant with a decrease in telomere length from normal to severe AD defines the individual stages of the disease (p < 0.0001).},
}
@article {pmid24120135,
year = {2013},
author = {Doksani, Y and Wu, JY and de Lange, T and Zhuang, X},
title = {Super-resolution fluorescence imaging of telomeres reveals TRF2-dependent T-loop formation.},
journal = {Cell},
volume = {155},
number = {2},
pages = {345-356},
pmid = {24120135},
issn = {1097-4172},
support = {/HHMI/Howard Hughes Medical Institute/United States ; AG016642/AG/NIA NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; GM068518/GM/NIGMS NIH HHS/United States ; GM049046/GM/NIGMS NIH HHS/United States ; R01 GM049046/GM/NIGMS NIH HHS/United States ; GM096450/GM/NIGMS NIH HHS/United States ; R01 GM096450/GM/NIGMS NIH HHS/United States ; R01 GM068518/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; DNA-Binding Proteins/metabolism ; Fibroblasts/metabolism ; Mice ; Microscopy, Fluorescence ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {We have applied a super-resolution fluorescence imaging method, stochastic optical reconstruction microscopy (STORM), to visualize the structure of functional telomeres and telomeres rendered dysfunctional through removal of shelterin proteins. The STORM images showed that functional telomeres frequently exhibit a t-loop configuration. Conditional deletion of individual components of shelterin showed that TRF2 was required for the formation and/or maintenance of t-loops, whereas deletion of TRF1, Rap1, or the POT1 proteins (POT1a and POT1b) had no effect on the frequency of t-loop occurrence. Within the shelterin complex, TRF2 uniquely serves to protect telomeres from two pathways that are initiated on free DNA ends: classical nonhomologous end-joining (NHEJ) and ATM-dependent DNA damage signaling. The TRF2-dependent remodeling of telomeres into t-loop structures, which sequester the ends of chromosomes, can explain why NHEJ and the ATM signaling pathway are repressed when TRF2 is present.},
}
@article {pmid24118582,
year = {2014},
author = {Huzen, J and Wong, LS and van Veldhuisen, DJ and Samani, NJ and Zwinderman, AH and Codd, V and Cawthon, RM and Benus, GF and van der Horst, IC and Navis, G and Bakker, SJ and Gansevoort, RT and de Jong, PE and Hillege, HL and van Gilst, WH and de Boer, RA and van der Harst, P},
title = {Telomere length loss due to smoking and metabolic traits.},
journal = {Journal of internal medicine},
volume = {275},
number = {2},
pages = {155-163},
doi = {10.1111/joim.12149},
pmid = {24118582},
issn = {1365-2796},
mesh = {Adult ; Body Mass Index ; Cellular Senescence/*genetics ; Female ; Humans ; Leukocytes ; Male ; Metabolic Syndrome/genetics ; Middle Aged ; Smoking/*adverse effects/genetics/mortality ; Telomere/genetics ; *Telomere Shortening/genetics ; },
abstract = {OBJECTIVES: Human age-dependent telomere attrition and telomere shortening are associated with several age-associated diseases and poorer overall survival. The aim of this study was to determine longitudinal leucocyte telomere length dynamics and identify factors associated with temporal changes in telomere length.<br><br>DESIGN AND METHODS: Leucocyte telomere length was measured by quantitative polymerase chain reaction in 8074 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, an ongoing community-based prospective cohort study initiated in 1997. Follow-up data were available at two time-points up to 2007. Leucocyte telomere length was measured, on between one and three separate occasions, in a total of 16 783 DNA samples. Multilevel growth models were created to identify the factors that influence leucocyte telomere dynamics.<br><br>RESULTS: We observed an average attrition rate of 0.47 &#xb1; 0.16 relative telomere length units (RTLUs) per year in the study population aged 48 (range 39-60) years at baseline. Annual telomere attrition rate increased with age (P < 0.001) and was faster on average in men than in women (P for interaction 0.043). The major independent factors determining telomere attrition rate were active smoking (approximately tripled the loss of RTLU per year, P < 0.0001) and multiple traits of the metabolic syndrome (waist-hip ratio, P = 0.007; blood glucose level, P = 0.045, and HDL cholesterol level, P < 0.001).<br><br>CONCLUSIONS: Smoking and variables linked to the metabolic syndrome are modifiable lifestyle factors that accelerate telomere attrition in humans. The higher rate of cellular ageing may mediate the link between smoking and the metabolic syndrome to an increased risk of several age-associated diseases.},
}
@article {pmid24115768,
year = {2013},
author = {Chen, LY and Majerská, J and Lingner, J},
title = {Molecular basis of telomere syndrome caused by CTC1 mutations.},
journal = {Genes &amp; development},
volume = {27},
number = {19},
pages = {2099-2108},
pmid = {24115768},
issn = {1549-5477},
support = {232812/ERC_/European Research Council/International ; },
mesh = {Ataxia/genetics ; Brain Neoplasms/genetics ; Calcinosis/genetics ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Central Nervous System Cysts/genetics ; Dyskeratosis Congenita/genetics ; Gene Expression Regulation ; Genes, myc/genetics ; Genetic Diseases, Inborn/*genetics ; HEK293 Cells ; Humans ; Leukoencephalopathies/genetics ; Muscle Spasticity/genetics ; *Mutation ; Retinal Diseases/genetics ; Seizures/genetics ; Syndrome ; Telomere/*genetics/*metabolism ; Telomere Homeostasis/genetics ; Telomere-Binding Proteins/*genetics/*metabolism ; Tubulin/genetics ; },
abstract = {Mutations in CTC1 lead to the telomere syndromes Coats Plus and dyskeratosis congenita (DC), but the molecular mechanisms involved remain unknown. CTC1 forms with STN1 and TEN1 a trimeric complex termed CST, which binds ssDNA, promotes telomere DNA synthesis, and inhibits telomerase-mediated telomere elongation. Here we identify CTC1 disease mutations that disrupt CST complex formation, the physical interaction with DNA polymerase α-primase (polα-primase), telomeric ssDNA binding in vitro, accumulation in the nucleus, and/or telomere association in vivo. While having diverse molecular defects, CTC1 mutations commonly lead to the accumulation of internal single-stranded gaps of telomeric DNA, suggesting telomere DNA replication defects as a primary cause of the disease. Strikingly, mutations in CTC1 may also unleash telomerase repression and telomere length control. Hence, the telomere defect initiated by CTC1 mutations is distinct from the telomerase insufficiencies seen in classical forms of telomere syndromes, which cause short telomeres due to reduced maintenance of distal telomeric ends by telomerase. Our analysis provides molecular evidence that CST collaborates with DNA polα-primase to promote faithful telomere DNA replication.},
}
@article {pmid24115439,
year = {2013},
author = {Vannier, JB and Sandhu, S and Petalcorin, MI and Wu, X and Nabi, Z and Ding, H and Boulton, SJ},
title = {RTEL1 is a replisome-associated helicase that promotes telomere and genome-wide replication.},
journal = {Science (New York, N.Y.)},
volume = {342},
number = {6155},
pages = {239-242},
doi = {10.1126/science.1241779},
pmid = {24115439},
issn = {1095-9203},
support = {11581/CRUK_/Cancer Research UK/United Kingdom ; /CAPMC/CIHR/Canada ; },
mesh = {Animals ; Cell Line ; Cell Transformation, Neoplastic/genetics/*metabolism ; DNA Helicases/genetics/*metabolism ; *DNA Replication ; Genome/*genetics ; Mice ; Mice, Mutant Strains ; Proliferating Cell Nuclear Antigen/*metabolism ; Telomere/*genetics ; Tumor Suppressor Protein p53/genetics ; },
abstract = {Regulator of telomere length 1 (RTEL1) is an essential DNA helicase that disassembles telomere loops (T loops) and suppresses telomere fragility to maintain the integrity of chromosome ends. We established that RTEL1 also associates with the replisome through binding to proliferating cell nuclear antigen (PCNA). Mouse cells disrupted for the RTEL1-PCNA interaction (PIP mutant) exhibited accelerated senescence, replication fork instability, reduced replication fork extension rates, and increased origin usage. Although T-loop disassembly at telomeres was unaffected in the mutant cells, telomere replication was compromised, leading to fragile sites at telomeres. RTEL1-PIP mutant mice were viable, but loss of the RTEL1-PCNA interaction accelerated the onset of tumorigenesis in p53-deficient mice. We propose that RTEL1 plays a critical role in both telomere and genome-wide replication, which is crucial for genetic stability and tumor avoidance.},
}
@article {pmid24114494,
year = {2014},
author = {Fenech, MF},
title = {Nutriomes and personalised nutrition for DNA damage prevention, telomere integrity maintenance and cancer growth control.},
journal = {Cancer treatment and research},
volume = {159},
number = {},
pages = {427-441},
doi = {10.1007/978-3-642-38007-5_24},
pmid = {24114494},
issn = {0927-3042},
mesh = {Chromosomes, Human ; DNA Damage/*drug effects ; Diet/*standards ; Humans ; Micronutrients/*therapeutic use ; Neoplasms/genetics/*prevention &amp; control ; *Nutrigenomics ; Nutritional Physiological Phenomena ; *Precision Medicine ; Telomere/*drug effects ; },
abstract = {DNA damage at the base sequence and chromosome level is a fundamental cause of developmental and degenerative diseases. Multiple micronutrients and their interactions with the inherited and/or acquired genome determine DNA damage and genomic instability rates. The challenge is to identify for each individual the combination of micronutrients and their doses (i.e. the nutriome) that optimises genome stability, including telomere integrity and functionality and DNA repair. Using nutrient array systems with high-content analysis diagnostics of DNA damage, cell death and cell growth, it is possible to define, on an individual basis, the optimal nutriome for DNA damage prevention and cancer growth control. This knowledge can also be used to improve culture systems for cells used in therapeutics such as stem cells to ensure that they are not genetically aberrant when returned to the body. Furthermore, this information could be used to design dietary patterns that deliver the micronutrient combinations and concentrations required for preventing DNA damage by micronutrient deficiency or excess. Using this approach, new knowledge could be obtained to identify the dietary restrictions and/or supplementations required to control specific cancers, which is particularly important given that reliable validated advice is not yet available for those diagnosed with cancer.},
}
@article {pmid24105340,
year = {2013},
author = {Bau, DT and Lippman, SM and Xu, E and Gong, Y and Lee, JJ and Wu, X and Gu, J},
title = {Short telomere lengths in peripheral blood leukocytes are associated with an increased risk of oral premalignant lesion and oral squamous cell carcinoma.},
journal = {Cancer},
volume = {119},
number = {24},
pages = {4277-4283},
pmid = {24105340},
issn = {1097-0142},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; P50 CA097007/CA/NCI NIH HHS/United States ; },
mesh = {Alcohol Drinking/adverse effects ; Carcinoma, Squamous Cell/blood/*genetics/metabolism/pathology ; Female ; Head and Neck Neoplasms/blood/*genetics/metabolism/pathology ; Humans ; Leukocytes/metabolism/pathology/*ultrastructure ; Male ; Middle Aged ; Mouth Diseases/genetics/pathology ; Mouth Neoplasms/blood/*genetics/metabolism/pathology ; Precancerous Conditions/blood/*genetics/metabolism/pathology ; Risk ; Risk Factors ; Smoking/adverse effects ; Squamous Cell Carcinoma of Head and Neck ; Telomere/*genetics/metabolism ; Telomere Shortening ; },
abstract = {BACKGROUND: Oral premalignant lesions (OPLs) are precursors of oral squamous cell carcinoma (OSCC). Short telomeres in peripheral blood leukocytes (PBLs) are associated with increased risks of several cancers. However, it is unclear whether short leukocyte telomere length (LTL) predisposes individuals to OPL and OSCC.<br><br>METHODS: LTL was measured in PBLs from 266 patients who had a diagnosis of either OPL (N = 174) or OSCC (N = 92) and from 394 age-matched and sex-matched controls. The association between LTL and the risk of OPL or OSCC, as well as the interaction of telomere length, cigarette smoking, and alcohol drinking on the risk of OPL or OSCC, were analyzed.<br><br>RESULTS: The age-adjusted relative LTL was shortest in the OSCC group (1.64 &#xb1; 0.29), intermediate in the OPL group (1.75 &#xb1; 0.43), and longest in the control group (1.82 &#xb1; 0.36; Ptrend < .001). When the analysis was dichotomized at the median value in controls, adjusting for age, sex, smoking status, and alcohol drinking status, the odds ratio for the risk of OPL and OSCC associated with short LTL was 2.03 (95% confidence interval, 1.29-3.21) and 3.47 (95% CI, 1.84-6.53), respectively, with significant dose-response effects for both associations. Among 174 patients with OPL, 23 progressed to OSCC, and the mean LTL was shorter in progressors than in nonprogressors (mean &#xb1; standard deviation: 1.66 &#xb1; 0.35 vs 1.77 &#xb1; 0.44, respectively), although the difference did not reach statistical significance (P = .258), probably because of the small number of progressors. An interaction analysis identified short LTL, smoking, and drinking alcohol as independent risk factors for OPL and OSCC.<br><br>CONCLUSIONS: Short LTL was associated with increased risks of developing OPL and OSCC. The current results also indicated that short LTL likely predisposes patients to the malignant progression of OPL.},
}
@article {pmid24103875,
year = {2013},
author = {Song, JY and Kuang, LP and Wang, Y and Li, YH and Wu, JL and Zhang, H and Li, L and Wang, YC and Jiang, ZJ and Xiao, Y},
title = {[The relationship of telomere and telomerase activity with outcome of aplastic anemia after immunosuppressive therapy].},
journal = {Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi},
volume = {34},
number = {9},
pages = {771-776},
doi = {10.3760/cma.j.issn.0253-2727.2013.09.008},
pmid = {24103875},
issn = {0253-2727},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Anemia, Aplastic/*enzymology/*therapy ; Case-Control Studies ; Child ; Female ; Humans ; *Immunosuppression Therapy ; Leukocytes, Mononuclear/metabolism ; Male ; Middle Aged ; Telomerase/*metabolism ; Telomere/*metabolism ; Treatment Outcome ; Young Adult ; },
abstract = {OBJECTIVE: To observe the changes of telomere length and telomerase activity in patients with aplastic anemia (AA), and relationship with immunosuppressive therapy (IST) efficacy, to explore the pathogenesis of AA and the role of telomere length in evaluating immunosuppressive therapy efficacy.<br><br>METHODS: 71 cases of AA patients between September 2010 and March 2013 were enrolled into this study. 3 ml peripheral blood specimens from this cohort of patients were collected to test the telomere length in peripheral blood mononuclear cell (PBMNC) with flow-FISH and detect telomerase activity with TRAP-PCR-ELISA method.<br><br>RESULTS: Telomere length and age showed negative correlation (b=-0.387, P=0.001) in normal control, NSAA and SAA + VSAA groups, telomere length became shorter with the growth of age, and normal control group telomere length decreased along with the age growth slightly greater than the other two groups (NSAA, SAA+VSAA). Besides the effect of age on telomere length, no significant difference was observed between NSAA and SAA+VSAA groups (P=0.573), and NSAA, SAA+VSAA (30.957 &#xb1; 4.502,29.510 &#xb1; 5.911)groups were significantly shorter than normal control group (51.086&#xb1;10.844) (P<0.01). Telomere length in NR group (25.357&#xb1;4.848)was significantly lower than normal control group (51.086 &#xb1; 10.844) (P=0.005), telomere length in CR(32.808 &#xb1; 4.685)/PR groups (30.334&#xb1;4.464) compared with normal control group had no significant difference (P=0.517, P=0.254). Telomere length below 29.21% obviously decreased outcomes of IST. Telomerase activity had significant difference (&#x3c7;&#xb2;=20.385, P<0.01). The telomerase activity had no significant difference in terms of age and gender in three groups, multiple comparison found that telomerase activities in SAA + VSAA (0.324&#xb1;0.178) (P<0.01), and NSAA (0.234&#xb1;0.175) groups (P=0.002) were significantly higher than normal control group (0.107&#xb1;0.083).<br><br>CONCLUSION: Telomere length of PBMNC in AA patients was significantly shortened than normal control group with telomerase activity increased, and telomere shorted more apparently in NR group, these patients should adjust the treatment as early as possible. Telomeres could predict the curative effect of IST.},
}
@article {pmid24100424,
year = {2014},
author = {el Bouazzaoui, F and Henneman, P and Thijssen, P and Visser, A and Koning, F and Lips, MA and Janssen, I and Pijl, H and Willems van Dijk, K and van Harmelen, V},
title = {Adipocyte telomere length associates negatively with adipocyte size, whereas adipose tissue telomere length associates negatively with the extent of fibrosis in severely obese women.},
journal = {International journal of obesity (2005)},
volume = {38},
number = {5},
pages = {746-749},
pmid = {24100424},
issn = {1476-5497},
mesh = {Adipocytes/ultrastructure ; Adult ; Female ; Fibrosis/genetics/*pathology ; Humans ; Hypertrophy ; Intra-Abdominal Fat/*pathology ; Middle Aged ; Obesity, Morbid/genetics/*pathology ; Real-Time Polymerase Chain Reaction ; Telomere/ultrastructure ; },
abstract = {Telomere length can be considered as a biological marker for cell proliferation and aging. Obesity is associated with adipocyte hypertrophy and proliferation as well as with shorter telomeres in adipose tissue. As adipose tissue is a mixture of different cell types and the cellular composition of adipose tissue changes with obesity, it is unclear what determines telomere length of whole adipose tissue. We aimed to investigate telomere length in whole adipose tissue and isolated adipocytes in relation to adiposity, adipocyte hypertrophy and adipose tissue inflammation and fibrosis. Telomere length was measured by real-time PCR in visceral adipose tissue, and isolated adipocytes of 21 obese women with a waist ranging from 110 to 147 cm and age from 31 to 61 years. Telomere length in adipocytes was shorter than in whole adipose tissue. Telomere length of adipocytes but not whole adipose tissue correlated negatively with waist and adipocyte size, which was still significant after correction for age. Telomere length of whole adipose tissue associated negatively with fibrosis as determined by collagen content. Thus, in extremely obese individuals, adipocyte telomere length is a marker of adiposity, whereas whole adipose tissue telomere length reflects the extent of fibrosis and may indicate adipose tissue dysfunction.},
}
@article {pmid24098638,
year = {2013},
author = {Ji, G and Ruan, W and Liu, K and Wang, F and Sakellariou, D and Chen, J and Yang, Y and Okuka, M and Han, J and Liu, Z and Lai, L and Gagos, S and Xiao, L and Deng, H and Li, N and Liu, L},
title = {Telomere reprogramming and maintenance in porcine iPS cells.},
journal = {PloS one},
volume = {8},
number = {9},
pages = {e74202},
pmid = {24098638},
issn = {1932-6203},
mesh = {Analysis of Variance ; Animals ; Cell Differentiation/physiology ; DNA Primers/genetics ; Electrophoresis, Gel, Two-Dimensional ; Gene Expression Regulation/physiology ; Histological Techniques ; In Situ Hybridization, Fluorescence ; Induced Pluripotent Stem Cells/*physiology ; Microscopy, Fluorescence ; Real-Time Polymerase Chain Reaction ; Swine ; Telomerase/metabolism ; Telomere/*genetics/*physiology/ultrastructure ; Telomere Homeostasis/physiology ; },
abstract = {Telomere reprogramming and silencing of exogenous genes have been demonstrated in mouse and human induced pluripotent stem cells (iPS cells). Pigs have the potential to provide xenotransplant for humans, and to model and test human diseases. We investigated the telomere length and maintenance in porcine iPS cells generated and cultured under various conditions. Telomere lengths vary among different porcine iPS cell lines, some with telomere elongation and maintenance, and others telomere shortening. Porcine iPS cells with sufficient telomere length maintenance show the ability to differentiate in vivo by teratoma formation test. IPS cells with short or dysfunctional telomeres exhibit reduced ability to form teratomas. Moreover, insufficient telomerase and incomplete telomere reprogramming and/or maintenance link to sustained activation of exogenous genes in porcine iPS cells. In contrast, porcine iPS cells with reduced expression of exogenous genes or partial exogene silencing exhibit insufficient activation of endogenous pluripotent genes and telomerase genes, accompanied by telomere shortening with increasing passages. Moreover, telomere doublets, telomere sister chromatid exchanges and t-circles that presumably are involved in telomere lengthening by recombination also are found in porcine iPS cells. These data suggest that both telomerase-dependent and telomerase-independent mechanisms are involved in telomere reprogramming during induction and passages of porcine iPS cells, but these are insufficient, resulting in increased telomere damage and shortening, and chromosomal instability. Active exogenes might compensate for insufficient activation of endogenous genes and incomplete telomere reprogramming and maintenance of porcine iPS cells. Further understanding of telomere reprogramming and maintenance may help improve the quality of porcine iPS cells.},
}
@article {pmid24097228,
year = {2013},
author = {Salk, JJ and Bansal, A and Lai, LA and Crispin, DA and Ussakli, CH and Horwitz, MS and Bronner, MP and Brentnall, TA and Loeb, LA and Rabinovitch, PS and Risques, RA},
title = {Clonal expansions and short telomeres are associated with neoplasia in early-onset, but not late-onset, ulcerative colitis.},
journal = {Inflammatory bowel diseases},
volume = {19},
number = {12},
pages = {2593-2602},
pmid = {24097228},
issn = {1536-4844},
support = {R01 CA068124/CA/NCI NIH HHS/United States ; K07 CA137136/CA/NCI NIH HHS/United States ; P30 AG13280/AG/NIA NIH HHS/United States ; P01 AG001751/AG/NIA NIH HHS/United States ; R01 CA160674/CA/NCI NIH HHS/United States ; T32 GM007266/GM/NIGMS NIH HHS/United States ; UL1 TR000423/TR/NCATS NIH HHS/United States ; P30 AG013280/AG/NIA NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age of Onset ; Aged ; Aged, 80 and over ; Biomarkers/analysis ; Case-Control Studies ; Child ; Clone Cells/*pathology ; Colitis, Ulcerative/*complications/genetics/pathology ; Colonic Neoplasms/*etiology/pathology ; Disease Progression ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Mutation/genetics ; Poly G/genetics ; Polymerase Chain Reaction ; Precancerous Conditions/*etiology/pathology ; Prognosis ; Telomere/*genetics ; Young Adult ; },
abstract = {BACKGROUND: Patients with ulcerative colitis (UC) are at risk of developing colorectal cancer. We have previously reported that cancer progression is associated with the presence of clonal expansions and shorter telomeres in nondysplastic mucosa. We sought to validate these findings in an independent case-control study.<br><br>METHODS: This study included 33 patients with UC: 14 progressors (patients with high-grade dysplasia or cancer) and 19 nonprogressors. For each patient, a mean of 5 nondysplastic biopsies from proximal, mid, and distal colon were assessed for clonal expansions, as determined by clonal length altering mutations in polyguanine tracts, and telomere length, as measured by quantitative PCR. Both parameters were compared with individual clinicopathological characteristics.<br><br>RESULTS: Clonal expansions and shorter telomeres were more frequent in nondysplastic biopsies from UC progressors than nonprogressors, but only for patients with early-onset of UC (diagnosis at younger than 50 years of age). Late-onset progressor patients had very few or no clonal expansions and longer telomeres. A few nonprogressors exhibited clonal expansions, which were associated with older age and shorter telomeres. In progressors, clonal expansions were associated with proximity to dysplasia. The mean percentage of clonally expanded mutations distinguished early-onset progressors from nonprogressors with 100% sensitivity and 80% specificity.<br><br>CONCLUSIONS: Early-onset progressors develop cancer in a field of clonally expanded epithelium with shorter telomeres. The detection of these clones in a few random nondysplastic colon biopsies is a promising cancer biomarker in early-onset UC. Curiously, patients with late-onset UC seem to develop cancer without the involvement of such fields.},
}
@article {pmid24095731,
year = {2013},
author = {Ribes-Zamora, A and Indiviglio, SM and Mihalek, I and Williams, CL and Bertuch, AA},
title = {TRF2 interaction with Ku heterotetramerization interface gives insight into c-NHEJ prevention at human telomeres.},
journal = {Cell reports},
volume = {5},
number = {1},
pages = {194-206},
pmid = {24095731},
issn = {2211-1247},
support = {HD007495/HD/NICHD NIH HHS/United States ; K12 GM084897/GM/NIGMS NIH HHS/United States ; T32 HD007495/HD/NICHD NIH HHS/United States ; U54 HD007495/HD/NICHD NIH HHS/United States ; P30 CA125123/CA/NCI NIH HHS/United States ; DK56338/DK/NIDDK NIH HHS/United States ; R01 GM077509/GM/NIGMS NIH HHS/United States ; R01GM077509/GM/NIGMS NIH HHS/United States ; F31 AG034764/AG/NIA NIH HHS/United States ; P30 HD007495/HD/NICHD NIH HHS/United States ; F31AG034764/AG/NIA NIH HHS/United States ; CA125123/CA/NCI NIH HHS/United States ; P30 DK056338/DK/NIDDK NIH HHS/United States ; K12GM084897/GM/NIGMS NIH HHS/United States ; },
mesh = {Antigens, Nuclear/chemistry/genetics/*metabolism ; *DNA End-Joining Repair ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Humans ; Ku Autoantigen ; Models, Molecular ; Protein Multimerization ; Recombination, Genetic ; Telomere/chemistry/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; },
abstract = {Telomeres are protected from nonhomologous end-joining (NHEJ) to avoid deleterious chromosome fusions, yet they associate with the Ku heterodimer that is principal in the classical NHEJ (c-NHEJ) pathway. T-loops have been proposed to inhibit Ku's association with telomeric ends, thus inhibiting c-NHEJ; however, deficiencies in the t-loop model suggest additional mechanisms are in effect. We demonstrate that TRF2 interacts with Ku at telomeres and via residues in Ku70 helix 5 (α5), which are vital for NHEJ. We show that Ku's interaction with a TRF2 mutant that induces telomeric fusions is significantly impaired. Additionally, we demonstrate that Ku70 α5 is required for Ku self-association in live cells, which can bridge DNA ends. Together, these findings lead us to propose a model in which telomeres are directly protected from c-NHEJ via TRF2 impeding Ku's ability to synapse telomere ends.},
}
@article {pmid24095110,
year = {2013},
author = {Poloni, A and Serrani, F and Berardinelli, E and Maurizi, G and Mariani, M and Costantini, B and Trappolini, S and Mancini, S and Olivieri, A and Leoni, P},
title = {Telomere length, c-myc and mad-1 expression could represent prognosis markers of myelodysplastic syndrome.},
journal = {Leukemia research},
volume = {37},
number = {11},
pages = {1538-1544},
doi = {10.1016/j.leukres.2013.07.022},
pmid = {24095110},
issn = {1873-5835},
mesh = {Aged ; Biomarkers, Tumor/*genetics ; Blotting, Western ; Case-Control Studies ; Cell Cycle ; Cell Cycle Proteins/*genetics ; Female ; Follow-Up Studies ; Humans ; Male ; Myelodysplastic Syndromes/classification/*genetics/pathology ; Nuclear Proteins/*genetics ; Prognosis ; Proto-Oncogene Proteins c-myc/*genetics ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Telomere dysfunction might generate genomic instability leading to the progression of myelodysplastic syndromes (MDS) into acute myeloid leukemia (AML). We investigated telomere length (TL), telomerase activity (TA) and hTERT, c-myc, mad1, and p53 expression in the bone marrow of patients with MDS (n=109), AML (n=47) and in controls (n=24). TL was lower in MDS patients than in controls (p<0.001) and higher in L-MDS (low, intermediate-1 IPSS, p<0.01) respect H-MDS (high, intermediate-2 IPSS, p<0.01) patients. Mad-1 expression was higher in MDS patients than in controls (p<0.01), c-myc expression was highest in AML and in H-MDS patients. Our results show that the telomere dynamics might be useful for stratifying patients according to a risk scoring system.},
}
@article {pmid24091643,
year = {2014},
author = {Simons, MJ and Stulp, G and Nakagawa, S},
title = {A statistical approach to distinguish telomere elongation from error in longitudinal datasets.},
journal = {Biogerontology},
volume = {15},
number = {1},
pages = {99-103},
doi = {10.1007/s10522-013-9471-2},
pmid = {24091643},
issn = {1573-6768},
mesh = {Aging/*physiology ; Bias ; *Data Interpretation, Statistical ; Databases, Factual/*statistics &amp; numerical data ; Humans ; Telomere/*ultrastructure ; Telomere Homeostasis/*physiology ; },
abstract = {Telomere length and the rate of telomere attrition vary between individuals and have been interpreted as the rate at which individuals have aged. The biology of telomeres dictates shortening with age, although telomere elongation with age has repeatedly been observed within a minority of individuals in several populations. These findings have been attributed to error, rather than actual telomere elongation, restricting our understanding of its possible biological significance. Here we present a method to distinguish between error and telomere elongation in longitudinal datasets, which is easy to apply and has few assumptions. Using simulations, we show that the method has considerable statistical power (>80 %) to detect even a small proportion (6.7 %) of TL increases in the population, within a relatively small sample (N = 200), while maintaining the standard level of Type I error rate (α ≤ 0.05).},
}
@article {pmid24091626,
year = {2013},
author = {Harari, Y and Romano, GH and Ungar, L and Kupiec, M},
title = {Nature vs nurture: interplay between the genetic control of telomere length and environmental factors.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {12},
number = {22},
pages = {3465-3470},
pmid = {24091626},
issn = {1551-4005},
mesh = {DNA-Binding Proteins/*metabolism ; Humans ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/*genetics/*metabolism ; Sirolimus/*pharmacology ; *Stress, Physiological ; Telomere/*genetics/*metabolism ; Telomere Homeostasis/*genetics ; *Telomere Shortening ; Telomere-Binding Proteins/*genetics ; Transcription Factors/*genetics/*metabolism ; },
abstract = {Telomeres are nucleoprotein structures that cap the ends of the linear eukaryotic chromosomes, thus protecting their stability and integrity. They play important roles in DNA replication and repair and are central to our understanding of aging and cancer development. In rapidly dividing cells, telomere length is maintained by the activity of telomerase. About 400 TLM (telomere length maintenance) genes have been identified in yeast, as participants of an intricate homeostasis network that keeps telomere length constant. Two papers have recently shown that despite this extremely complex control, telomere length can be manipulated by external stimuli. These results have profound implications for our understanding of cellular homeostatic systems in general and of telomere length maintenance in particular. In addition, they point to the possibility of developing aging and cancer therapies based on telomere length manipulation.},
}
@article {pmid24091330,
year = {2013},
author = {Wang, Y and Sharpless, N and Chang, S},
title = {p16(INK4a) protects against dysfunctional telomere-induced ATR-dependent DNA damage responses.},
journal = {The Journal of clinical investigation},
volume = {123},
number = {10},
pages = {4489-4501},
pmid = {24091330},
issn = {1558-8238},
support = {R01 AG024379/AG/NIA NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; },
mesh = {Aging ; Animals ; Apoptosis ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Bone Marrow Transplantation ; Cell Proliferation ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p16/*physiology ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; *DNA Damage ; DNA Repair ; DNA-Binding Proteins/genetics/metabolism ; Female ; Hematopoiesis ; Hematopoietic Stem Cells/physiology ; Intestine, Small/pathology ; Male ; Mice ; Mice, SCID ; Mice, Transgenic ; Protein Stability ; Sequence Deletion ; Spleen/pathology ; Telomere/*physiology ; Telomere Homeostasis ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Dysfunctional telomeres limit cellular proliferative capacity by activating the p53-p21- and p16(INK4a)-Rb-dependent DNA damage responses (DDRs). The p16(INK4a) tumor suppressor accumulates in aging tissues, is a biomarker for cellular senescence, and limits stem cell function in vivo. While the activation of a p53-dependent DDR by dysfunctional telomeres has been well documented in human cells and mouse models, the role for p16(INK4a) in response to telomere dysfunction remains unclear. Here, we generated protection of telomeres 1b p16-/- mice (Pot1bΔ/Δ;p16-/-) to address the function of p16(INK4a) in the setting of telomere dysfunction in vivo. We found that deletion of p16(INK4a) accelerated organ impairment and observed functional defects in highly proliferative organs, including the hematopoietic system, small intestine, and testes. Pot1bΔ/Δ;p16-/- hematopoietic cells exhibited increased telomere loss, increased chromosomal fusions, and telomere replication defects. p16(INK4a) deletion enhanced the activation of the ATR-dependent DDR in Pot1bΔ/Δ hematopoietic cells, leading to p53 stabilization, increased p21-dependent cell cycle arrest, and elevated p53-dependent apoptosis. In contrast to p16(INK4a), deletion of p21 did not activate ATR, rescued proliferative defects in Pot1bΔ/Δ hematopoietic cells, and significantly increased organismal lifespan. Our results provide experimental evidence that p16(INK4a) exerts protective functions in proliferative cells bearing dysfunctional telomeres.},
}
@article {pmid24090770,
year = {2013},
author = {Pal, J and Gold, JS and Munshi, NC and Shammas, MA},
title = {Biology of telomeres: importance in etiology of esophageal cancer and as therapeutic target.},
journal = {Translational research : the journal of laboratory and clinical medicine},
volume = {162},
number = {6},
pages = {364-370},
pmid = {24090770},
issn = {1878-1810},
support = {P01 CA155258/CA/NCI NIH HHS/United States ; I01 BX001584/BX/BLRD VA/United States ; R01 CA125711/CA/NCI NIH HHS/United States ; R01CA125711/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma/etiology/therapy ; Esophageal Neoplasms/*etiology/therapy ; Genomic Instability ; Homologous Recombination ; Humans ; Risk Factors ; Telomerase/genetics/physiology ; Telomere/genetics/*physiology ; Telomere Shortening ; Translational Research, Biomedical ; },
abstract = {The purpose of this review is to highlight the importance of telomeres, the mechanisms implicated in their maintenance, and their role in the etiology as well as the treatment of human esophageal cancer. We will also discuss the role of telomeres in the maintenance and preservation of genomic integrity, the consequences of telomere dysfunction, and the various factors that may affect telomere health in esophageal tissue predisposing it to oncogenesis. There has been growing evidence that telomeres, which can be affected by various intrinsic and extrinsic factors, contribute to genomic instability, oncogenesis, as well as proliferation of cancer cells. Telomeres are the protective DNA-protein complexes at chromosome ends. Telomeric DNA undergoes progressive shortening with age leading to cellular senescence and/or apoptosis. If senescence/apoptosis is prevented as a consequence of specific genomic changes, continued proliferation leads to very short (ie, dysfunctional) telomeres that can potentially cause genomic instability, thus, increasing the risk for activation of telomere maintenance mechanisms and oncogenesis. Like many other cancers, esophageal cancer cells have short telomeres and elevated telomerase, the enzyme that maintains telomeres in most cancer cells. Homologous recombination, which is implicated in the alternate pathway of telomere elongation, is also elevated in Barrett's-associated esophageal adenocarcinoma. Evidence from our laboratory indicates that both telomerase and homologous recombination contribute to telomere maintenance, DNA repair, and the ongoing survival of esophageal cancer cells. This indicates that telomere maintenance mechanisms may potentially be targeted to make esophageal cancer cells static. The rate at which telomeres in healthy cells shorten is determined by a number of intrinsic and extrinsic factors, including those associated with lifestyle. Avoidance of factors that may directly or indirectly injure esophageal tissue including its telomeric and other genomic DNA can not only reduce the risk of development of esophageal cancer but may also have positive impact on overall health and lifespan.},
}
@article {pmid24088028,
year = {2013},
author = {Wilson, T and Costa, PJ and Félix, V and Williamson, MP and Thomas, JA},
title = {Structural studies on dinuclear ruthenium(II) complexes that bind diastereoselectively to an antiparallel folded human telomere sequence.},
journal = {Journal of medicinal chemistry},
volume = {56},
number = {21},
pages = {8674-8683},
pmid = {24088028},
issn = {1520-4804},
mesh = {DNA/chemistry/genetics/metabolism ; Humans ; Models, Molecular ; Molecular Structure ; Organometallic Compounds/chemical synthesis/*chemistry/*metabolism ; Ruthenium/*chemistry/metabolism ; Stereoisomerism ; Telomere/chemistry/genetics/*metabolism ; },
abstract = {We report DNA binding studies of the dinuclear ruthenium ligand [{Ru(phen)2}
2tpphz](4+) in enantiomerically pure forms. As expected from previous studies of related complexes, both isomers bind with similar affinity to B-DNA and have enhanced luminescence. However, when tested against the G-quadruplex from human telomeres (which we show to form an antiparallel basket structure with a diagonal loop across one end), the ΛΛ isomer binds approximately 40 times more tightly than the ΔΔ, with a stronger luminescence. NMR studies show that the complex binds at both ends of the quadruplex. Modeling studies, based on experimentally derived restraints obtained for the closely related [{Ru(bipy)2}
2tpphz](4+), show that the ΛΛ isomer fits neatly under the diagonal loop, whereas the ΔΔ isomer is unable to bind here and binds at the lateral loop end. Molecular dynamics simulations show that the ΔΔ isomer is prevented from binding under the diagonal loop by the rigidity of the loop. We thus present a novel enantioselective binding substrate for antiparallel basket G-quadruplexes, with features that make it a useful tool for quadruplex studies.},
}
@article {pmid24086293,
year = {2013},
author = {Salpea, KD and Maubaret, CG and Kathagen, A and Ken-Dror, G and Gilroy, DW and Humphries, SE},
title = {The effect of pro-inflammatory conditioning and/or high glucose on telomere shortening of aging fibroblasts.},
journal = {PloS one},
volume = {8},
number = {9},
pages = {e73756},
pmid = {24086293},
issn = {1932-6203},
support = {087520/WT_/Wellcome Trust/United Kingdom ; RG/08/008/25291/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Base Sequence ; Cell Death ; Cells, Cultured ; *Cellular Senescence ; DNA Primers ; DNA, Mitochondrial/genetics ; Fibroblasts/metabolism ; Gene Expression Profiling ; Glucose/*administration &amp; dosage ; Humans ; Inflammation/*genetics/metabolism ; Reactive Oxygen Species/metabolism ; *Telomere ; },
abstract = {UNLABELLED: Cardiovascular disease and diabetes have been linked to shorter telomeres, but it is not yet clear which risk factors contribute to shorter telomeres in patients. Our aim was to examine whether pro-inflammatory conditioning, in combination or not with high glucose, result in a higher rate of telomere shortening during in vitro cellular ageing. Human fibroblasts from four donors were cultured for 90 days in: 1) medium lacking ascorbic acid only, 2) 10 mM buthionine sulphoximine (BSO) (pro-oxidant), 3) 25 mM D-glucose, 4) 1 ng/ml IL1B and 5) 25 mM D-glucose+1 ng/ml IL1B. Telomere length was measured with qPCR and intracellular reactive oxygen species (ROS) content and cell death with flow cytometry. Cultures treated with high glucose and BSO displayed a significantly lower growth rate, and cultures treated with IL1B showed a trend towards a higher growth rate, compared to the control [Glucose:0.14 PD/day, p<0.001, BSO: 0.11 PD/day, p = 0.006 and IL1B: 0.19 PD/day, p = 0.093 vs.<br><br>CONTROL: 0.16 PD/day]. Telomere shortening with time was significantly accelerated in cultures treated with IL1B compared to the control [IL1B:-0.8%/day (95%CI:-1.1, -0.5) vs.<br><br>CONTROL: -0.6%/day (95%CI:-0.8, -0.3), p&#x200a;=&#x200a;0.012]. The hastening of telomere shortening by IL1B was only in part attenuated after adjustment for the number of cell divisions [IL1B:-4.1%/PD (95%CI:-5.7, -2.4) vs.<br><br>CONTROL: -2.5%/PD (95%CI:-4.4, -0.7), p&#x200a;=&#x200a;0.067]. The intracellular ROS content displayed 69% increase (p&#x200a;=&#x200a;0.033) in BSO compared to the control. In aging fibroblasts, pro-inflammatory conditioning aggravates the shortening of telomeres, an effect which was only in part driven by increased cell turnover. High glucose alone did not result in greater production of ROS or telomere shortening.},
}
@article {pmid24084588,
year = {2013},
author = {Pfeiffer, V and Crittin, J and Grolimund, L and Lingner, J},
title = {The THO complex component Thp2 counteracts telomeric R-loops and telomere shortening.},
journal = {The EMBO journal},
volume = {32},
number = {21},
pages = {2861-2871},
pmid = {24084588},
issn = {1460-2075},
mesh = {DNA, Fungal/genetics ; DNA-Binding Proteins/*metabolism ; Nuclear Proteins/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomere/chemistry/*physiology ; Telomere Shortening/genetics ; Transcription Factors/metabolism ; },
abstract = {Telomere maintenance by the conventional DNA replication machinery and telomerase is assisted by specialized DNA helicases, nucleases and telomere binding proteins. Here, we identify the THO components at telomeres and define critical roles of this complex in telomere stability. Deletion of the THO-subunit THP2 leads to telomere shortening. We discover that telomeres contain RNA:DNA hybrid structures or R-loops which involve the long-noncoding RNA TERRA and which accumulate in thp2-Δ cells. Telomere length is not restored by R-loop removal upon RNase H overexpression, but by deletion of Exonuclease 1 (Exo1). Replication stress further enhances the short telomere phenotype of THP2 mutants. Similar events occur upon induced transcription of TERRA and genetic analysis links Thp2 to TERRA function. Altogether, our data indicate that THO, through the interplay with TERRA, regulates chromosome end processing activities and prevents interference with semiconservative DNA replication of telomeric DNA.},
}
@article {pmid24083880,
year = {2013},
author = {Kawamoto, Y and Bando, T and Kamada, F and Li, Y and Hashiya, K and Maeshima, K and Sugiyama, H},
title = {Development of a new method for synthesis of tandem hairpin pyrrole-imidazole polyamide probes targeting human telomeres.},
journal = {Journal of the American Chemical Society},
volume = {135},
number = {44},
pages = {16468-16477},
doi = {10.1021/ja406737n},
pmid = {24083880},
issn = {1520-5126},
mesh = {Animals ; Cell Line ; Fluorescent Dyes/chemical synthesis/*chemistry ; HeLa Cells ; Humans ; Imidazoles/chemistry ; Mice ; Molecular Structure ; Nylons/chemistry ; Pyrroles/chemistry ; Spectrometry, Fluorescence/*methods ; Spectrophotometry, Ultraviolet/*methods ; Staining and Labeling ; Telomere/*chemistry ; },
abstract = {Pyrrole–imidazole (PI) polyamides bind to the minor groove of DNA in a sequence-specific manner without causing denaturation of DNA. To visualize telomeres specifically, tandem hairpin PI polyamides conjugated with a fluorescent dye have been synthesized, but the study of telomeres using these PI polyamides has not been reported because of difficulties synthesizing these tandem hairpin PI polyamides. To synthesize tandem hairpin PI polyamides more easily, we have developed new PI polyamide fragments and have used them as units in Fmoc solid-phase peptide synthesis. Using this new method, we synthesized four fluorescent polyamide probes for the human telomeric repeat TTAGGG, and we examined the binding affinities and specificities of the tandem hairpin PI polyamides, the UV–vis absorption and fluorescence spectra of the fluorescent polyamide probes, and telomere staining in mouse MC12 and human HeLa cells. The polyamides synthesized using the new method successfully targeted to human and mouse telomeres under mild conditions and allow easier labeling of telomeres in the cells while maintaining the telomere structure. Using the fluorescent polyamides, we demonstrated that the telomere length at a single telomere level is related to the abundance of TRF1 protein, a shelterin complex component in the telomere.},
}
@article {pmid24080483,
year = {2014},
author = {Nakamura, K and Ishikawa, N and Izumiyama, N and Aida, J and Kuroiwa, M and Hiraishi, N and Fujiwara, M and Nakao, A and Kawakami, T and Poon, SS and Matsuura, M and Sawabe, M and Arai, T and Takubo, K},
title = {Telomere lengths at birth in trisomies 18 and 21 measured by Q-FISH.},
journal = {Gene},
volume = {533},
number = {1},
pages = {199-207},
doi = {10.1016/j.gene.2013.09.086},
pmid = {24080483},
issn = {1879-0038},
mesh = {Calibration ; *Chromosomes, Human, Pair 18 ; Diploidy ; Down Syndrome/*genetics ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Infant, Newborn ; Karyotyping ; *Telomere ; *Trisomy ; },
abstract = {Trisomies 18 and 21 are genetic disorders in which cells possess an extra copy of each of the relevant chromosomes. Individuals with these disorders who survive birth generally have a shortened life expectancy. As telomeres are known to play an important role in the maintenance of genomic integrity by protecting the chromosomal ends, we conducted a study to determine whether there are differences in telomere length at birth between individuals with trisomy and diploidy, and between trisomic chromosomes and normal chromosomes. We examined samples of peripheral blood lymphocytes (PBLs) from 31 live neonates (diploidy: 10, trisomy 18: 10, trisomy 21: 11) and estimated the telomere length of each chromosome arm using Q-FISH. We observed that the telomeres of trisomic chromosomes were neither shorter nor longer than the mean telomere length of chromosomes as a whole among subjects with trisomies 18 and 21 (intra-cell comparison), and we were unable to conclude that there were differences in telomere length between 18 trisomy and diploid subjects, or between 21 trisomy and diploid subjects (inter-individual comparison). Although it has been reported that telomeres are shorter in older individuals with trisomy 21 and show accelerated telomere shortening with age, our data suggest that patients with trisomies 18 and 21 may have comparably sized telomeres. Therefore, it would be advisable for them to avoid lifestyle habits and characteristics such as obesity, cigarette smoking, chronic stress, and alcohol intake, which lead to marked telomere shortening.},
}
@article {pmid24078448,
year = {2014},
author = {Jin, K and Xiang, Y and Tang, J and Wu, G and Li, J and Xiao, H and Li, C and Chen, Y and Zhao, J},
title = {miR-34 is associated with poor prognosis of patients with gallbladder cancer through regulating telomere length in tumor stem cells.},
journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine},
volume = {35},
number = {2},
pages = {1503-1510},
pmid = {24078448},
issn = {1423-0380},
mesh = {Adenocarcinoma/*genetics/pathology ; Adult ; Aged ; Animals ; Cell Line, Tumor ; Female ; Gallbladder Neoplasms/*genetics/pathology ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Mice ; MicroRNAs/biosynthesis/*genetics ; Middle Aged ; Neoplastic Stem Cells ; Prognosis ; Telomere Homeostasis/*genetics ; Xenograft Model Antitumor Assays ; },
abstract = {miR-34a has been identified as a tumor suppressor in several tumors, but its involvement in gallbladder cancer (GBC) has not been reported. In this study, the miR-34a level and telomere length were measured in 77 gallbladder adenocarcinomas and 36 peritumoral tissues by real-time PCR. Forced miR-34a expression was established by an adenovirus carrying a miR-34a expression cassette. The colony-forming ability of isolated CD44+CD133+ GBC tumor stem-like cells was measured by matrigel colony assay. The xenograft tumor models were established by inoculating nude mice with CD44+CD133+cells. Results showed that significantly lower miR-34a expression and longer telomere length were observed in gallbladder adenocarcinoma tissues, which correlated with poor prognosis of GBC patients. Forced overexpression of miR-34a inhibited the colony-forming ability of CD44+CD133+ GBC tumor stem-like cells in vitro and xenograft tumor growth in vivo. Injection of Ad-miR-34a downregulated PNUTS expression and reduced telomere length in xenograft GBC tumor cells. In conclusion, miR-34a is a tumor suppressor in gallbladder cancer. Both low miR-34a expression and long telomere length are markers for poor prognosis of patients with gallbladder adenocarcinoma. Our study also suggests that the miR-34a gene could be a target for targeting therapy of GBC.},
}
@article {pmid24074956,
year = {2013},
author = {Cusanelli, E and Romero, CA and Chartrand, P},
title = {Telomeric noncoding RNA TERRA is induced by telomere shortening to nucleate telomerase molecules at short telomeres.},
journal = {Molecular cell},
volume = {51},
number = {6},
pages = {780-791},
doi = {10.1016/j.molcel.2013.08.029},
pmid = {24074956},
issn = {1097-4164},
support = {89768-2//Canadian Institutes of Health Research/Canada ; MOP-89768/CAPMC/CIHR/Canada ; },
mesh = {DNA Replication/genetics ; In Situ Hybridization, Fluorescence ; RNA, Untranslated/*genetics/metabolism/ultrastructure ; S Phase/genetics ; Saccharomyces cerevisiae/*genetics ; Telomerase/*genetics/metabolism ; Telomere/genetics/ultrastructure ; Telomere Shortening/*genetics ; },
abstract = {Elongation of a short telomere depends on the action of multiple telomerase molecules, which are visible as telomerase RNA foci or clusters associated with telomeres in yeast and mammalian cells. How several telomerase molecules act on a single short telomere is unknown. Herein, we report that the telomeric noncoding RNA TERRA is involved in the nucleation of telomerase molecules into clusters prior to their recruitment at a short telomere. We find that telomere shortening induces TERRA expression, leading to the accumulation of TERRA molecules into a nuclear focus. Simultaneous time-lapse imaging of telomerase RNA and TERRA reveals spontaneous events of telomerase nucleation on TERRA foci in early S phase, generating TERRA-telomerase clusters. This cluster is subsequently recruited to the short telomere from which TERRA transcripts originate during S phase. We propose that telomere shortening induces noncoding RNA expression to coordinate the recruitment and activity of telomerase molecules at short telomeres.},
}
@article {pmid24070997,
year = {2013},
author = {Mason, PJ and Perdigones, N},
title = {Telomere biology and translational research.},
journal = {Translational research : the journal of laboratory and clinical medicine},
volume = {162},
number = {6},
pages = {333-342},
pmid = {24070997},
issn = {1878-1810},
support = {R01 CA106995/CA/NCI NIH HHS/United States ; },
mesh = {Aging ; Animals ; Humans ; Neoplasms/enzymology/etiology ; Stress, Physiological ; Telomerase/genetics/physiology ; *Telomere/genetics/physiology ; Telomere Shortening ; Translational Research, Biomedical ; },
}
@article {pmid24066279,
year = {2013},
author = {Vitelli, V and Falvo, P and Khoriauli, L and Smirnova, A and Gamba, R and Santagostino, M and Nergadze, SG and Giulotto, E},
title = {More on the Lack of Correlation between Terra Expression and Telomere Length.},
journal = {Frontiers in oncology},
volume = {3},
number = {},
pages = {245},
pmid = {24066279},
issn = {2234-943X},
}
@article {pmid24065372,
year = {2014},
author = {Carrillo, J and González, A and Manguán-García, C and Pintado-Berninches, L and Perona, R},
title = {p53 pathway activation by telomere attrition in X-DC primary fibroblasts occurs in the absence of ribosome biogenesis failure and as a consequence of DNA damage.},
journal = {Clinical &amp; translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico},
volume = {16},
number = {6},
pages = {529-538},
pmid = {24065372},
issn = {1699-3055},
mesh = {Biomarkers/metabolism ; Blotting, Western ; Cell Cycle ; Cell Cycle Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Cell Proliferation ; Cells, Cultured ; Cellular Senescence/physiology ; DNA Damage/*genetics ; Dyskeratosis Congenita/*genetics/metabolism/pathology ; Fibroblasts/cytology/*metabolism ; Gene Expression Profiling ; Humans ; Nuclear Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Oligonucleotide Array Sequence Analysis ; RNA, Messenger/genetics ; RNA, Small Interfering ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Ribosomes/*physiology ; Telomere/*genetics ; Tumor Suppressor Protein p53/*genetics/metabolism ; },
abstract = {BACKGROUND: Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome with high clinical heterogeneity. Various mutations have been reported in DC patients, affecting genes that code for components of H/ACA ribonucleoproteins, proteins of the telomerase complex and components of the shelterin complex.<br><br>OBJECTIVES: We aim to clarify the role of ribosome biogenesis failure in senescence induction in X-DC since some studies in animal models have reported a decrease in ribosome biogenesis as a major role in the disease.<br><br>METHODS: Dyskerin was depleted in normal human fibroblasts by expressing two DKC1 shRNAs. Common changes in gene expression profile between these dyskerin-depleted cells and X-DC fibroblasts were analyzed.<br><br>RESULTS: Dyskerin depletion induced early activation of the p53 pathway probably secondary to ribosome biogenesis failure. However, the p53 pathway in the fibroblasts from X-DC patients was activated only after an equivalent number of passes to AD-DC fibroblasts, in which telomere attrition in each division rendered shorter telomeres than control fibroblasts. Indeed, no induction of DNA damage was observed in dyskerin-depleted fibroblasts in contrast to X-DC or AD-DC fibroblasts suggesting that DNA damage induced by telomere attrition is responsible for p53 activation in X-DC and AD-DC fibroblasts. Moreover, p53 depletion in senescent DC fibroblasts rescued their proliferative capacity and reverted the morphological changes produced after prolonged culture.<br><br>CONCLUSIONS: Our data indicate that ribosome biogenesis do not seem to play an important role in dyskeratosis congenita, conversely increasing DNA damage and activation of p53 pathway triggered by telomere shortening is the main activator of cell senescence.},
}
@article {pmid24064949,
year = {2013},
author = {Silva, BA and Stambaugh, JR and Berns, MW},
title = {Targeting telomere-containing chromosome ends with a near-infrared femtosecond laser to study the activation of the DNA damage response and DNA damage repair pathways.},
journal = {Journal of biomedical optics},
volume = {18},
number = {9},
pages = {095003},
pmid = {24064949},
issn = {1560-2281},
support = {GM055246/GM/NIGMS NIH HHS/United States ; P41 EB015890/EB/NIBIB NIH HHS/United States ; RR01192/RR/NCRR NIH HHS/United States ; P41 RR001192/RR/NCRR NIH HHS/United States ; R25 GM055246/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; DNA Damage/*physiology/radiation effects ; DNA Repair/*physiology ; DNA Repair Enzymes/metabolism/radiation effects ; In Situ Nick-End Labeling ; *Infrared Rays ; Lasers ; Male ; Microscopy ; Potoroidae ; Telomere/*radiation effects ; },
abstract = {Telomeres are at the ends of chromosomes. Previous evidence suggests that laser-induced deoxyribose nucleic acid (DNA) breaks at chromosome ends during anaphase results in delayed cytokinesis. A possible explanation for this delay is that the DNA damage response (DDR) mechanism has been activated. We describe a live imaging method to study the effects of DDR activation following focal point near-infrared femtosecond laser microirradiation either at a single chromosome end or at a chromosome arm in mitotic anaphase cells. Laser microirradiation is used in combination with dual fluorescent labeling to monitor the co-localization of double-strand break marker γH2AX along with the DDR factors in PtK2 (Potorous tridactylus) cells. Laser-induced DNA breaks in chromosome ends as well as in chromosome arms results in recruitment of the following: poly(ADP-ribose) polymerase 1, checkpoint sensors (p-Chk1, p-Chk2), DNA repair protein Ku70/Ku80, and proliferating cell nuclear antigen. However, phosphorylated p53 at serine 15 is detected only at chromosome ends and not at chromosome arms. Full activation of DDR on damaged chromosome ends may explain previously published results that showed the delay of cytokinesis.},
}
@article {pmid24064542,
year = {2013},
author = {David, R},
title = {Telomeres: Plan B for staying long.},
journal = {Nature reviews. Molecular cell biology},
volume = {14},
number = {11},
pages = {690},
pmid = {24064542},
issn = {1471-0080},
mesh = {Aging/*genetics ; DNA, Fungal/*chemistry ; *Nucleic Acid Hybridization ; RNA, Fungal/*chemistry ; *Telomere ; },
}
@article {pmid24063536,
year = {2013},
author = {Murillo-Ortiz, B and Albarrán-Tamayo, F and López-Briones, S and Martínez-Garza, S and Benítez-Bribiesca, L and Arenas-Aranda, D},
title = {Increased telomere length and proliferative potential in peripheral blood mononuclear cells of adults of different ages stimulated with concanavalin A.},
journal = {BMC geriatrics},
volume = {13},
number = {},
pages = {99},
pmid = {24063536},
issn = {1471-2318},
mesh = {Adult ; Aged ; Aging/*drug effects/physiology ; Cell Proliferation/*drug effects ; Cells, Cultured ; Concanavalin A/*pharmacology ; Humans ; Leukocytes, Mononuclear/*drug effects/physiology ; Male ; Middle Aged ; Telomere Homeostasis/*drug effects/physiology ; Young Adult ; },
abstract = {BACKGROUND: Recently, a direct correlation with telomere length, proliferative potential and telomerase activity has been found in the process of aging in peripheral blood cells. The objective of the study was to evaluate telomere length and proliferative potential in peripheral blood mononuclear cells (PBMCs) after stimulation with Concanavalin A (ConA) of young adults compared with older adults.<br><br>METHODS: Blood samples were obtained from 20 healthy young males (20-25 years old) (group Y) and 20 males (60-65 years old) (group O). We compared PBMC proliferation before and after stimulation with ConA. DNA was isolated from cells separated before and after culture with ConA for telomeric measurement by real-time polymerase chain reaction.<br><br>RESULTS: In vitro stimulation of PBMCs from young subjects induced an increase of telomere length as well as a higher replicative capacity of cell proliferation. Samples from older adults showed higher loss of telomeric DNA (p = 0.03) and higher levels of senescent (&#x2264;6.2 kb) telomeric DNA (p = 0.02) and displayed a marked decrease of proliferation capacity. Viability cell counts and CFSE tracking in 72-h-old cell cultures indicated that group O PBMCs (CD8+ and CD4+ T cells) underwent fewer mitotic cycles and had shorter telomeres than group Y (p = 0.04).<br><br>CONCLUSIONS: Our findings confirm that telomere length in older-age adults is shorter than in younger subjects. After stimulation with ConA, cells are not restored to the previous telomere length and undergo replicative senescence. This is in sharp contrast to the response observed in young adults after ConA stimulation where cells increase in telomere length and replicative capacity. The mechanisms involved in this phenomenon are not yet clear and merit further investigation.},
}
@article {pmid24062009,
year = {2013},
author = {Raymond, AR and Hodson, B and Woodiwiss, AJ and Norton, GR and Brooksbank, RL},
title = {Telomere length and adrenergic-induced left ventricular dilatation and systolic chamber dysfunction in rats.},
journal = {European journal of applied physiology},
volume = {113},
number = {11},
pages = {2803-2811},
pmid = {24062009},
issn = {1439-6327},
mesh = {Adrenergic beta-Agonists/*toxicity ; Animals ; Cardiomyopathy, Dilated/chemically induced/*metabolism/physiopathology ; Heart Ventricles/metabolism/pathology/physiopathology ; Isoproterenol/*toxicity ; Male ; Rats ; Rats, Sprague-Dawley ; Systole ; Telomere/genetics/*metabolism ; *Telomere Shortening ; Ventricular Dysfunction, Left/chemically induced/*metabolism/physiopathology ; },
abstract = {PURPOSE: The mechanisms responsible for telomere shortening in heart failure are uncertain. We evaluated whether left ventricular (LV) dilatation and systolic chamber dysfunction produced by chronic β-adrenergic receptor (β-AR) activation is associated with leukocyte or cardiac telomere shortening.<br><br>METHODS: Following 6 months of daily injections of the &#x3b2;-AR agonist, isoproterenol (0.02 mg/kg/day) or the saline vehicle to rats, the extent of LV dilatation and LV systolic chamber dysfunction were determined using echocardiography and isolated perfused heart procedures, and relative telomere length of leukocyte (LTL) and cardiac (CTL) deoxyribonucleic acid were determined using a quantitative real-time polymerase chain reaction assay.<br><br>RESULTS: &#x3b2;-AR activation resulted in LV dilatation as indexed by increased LV diastolic diameters (9.2 &#xb1; 0.6 vs. 8.4 &#xb1; 0.9 mm, P = 0.01) and increased diastolic volume intercepts at zero pressure of the LV diastolic pressure-volume relationship (isolated, perfused heart preparation) (0.40 &#xb1; 0.06 vs. 0.37 &#xb1; 0.08 ml, P = 0.03). Moreover, &#x3b2;-AR activation resulted in LV systolic chamber dysfunction as indexed by reductions in LV endocardial fractional shortening (0.40 &#xb1; 0.05 vs. 0.45 &#xb1; 0.06, P = 0.01) and the slope of the LV systolic pressure-volume relation (609 &#xb1; 176 vs. 901 &#xb1; 230, P = 0.01). Although LTL decreased with age in rats receiving either the &#x3b2;-AR agonist or the saline vehicle (P < 0.05), neither CTL (-0.10 &#xb1; 0.14 vs. -0.15 &#xb1; 0.12, P = 0.3) nor LTL (-0.11 &#xb1; 0.19 vs. -0.15 &#xb1; 0.18, P = 0.5) were modified by &#x3b2;-AR activation.<br><br>CONCLUSION: In conclusion, chronic &#x3b2;-AR activation sufficient to produce LV dilatation and systolic chamber dysfunction is not associated with alterations in leukocyte or cardiac telomere length. Telomere shortening in chronic heart failure is unlikely to be attributed to chronic &#x3b2;-AR activation.},
}
@article {pmid24057216,
year = {2014},
author = {Lewis, KA and Pfaff, DA and Earley, JN and Altschuler, SE and Wuttke, DS},
title = {The tenacious recognition of yeast telomere sequence by Cdc13 is fully exerted by a single OB-fold domain.},
journal = {Nucleic acids research},
volume = {42},
number = {1},
pages = {475-484},
pmid = {24057216},
issn = {1362-4962},
support = {GM065103/GM/NIGMS NIH HHS/United States ; GM093528/GM/NIGMS NIH HHS/United States ; T32 GM008732/GM/NIGMS NIH HHS/United States ; GM059414/GM/NIGMS NIH HHS/United States ; P30 CA046934/CA/NCI NIH HHS/United States ; R01 GM059414/GM/NIGMS NIH HHS/United States ; GM008732/GM/NIGMS NIH HHS/United States ; T32 GM065103/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA, Single-Stranded/*metabolism ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {Cdc13, the telomere end-binding protein from Saccharomyces cerevisiae, is a multidomain protein that specifically binds telomeric single-stranded DNA (ssDNA) with exquisitely high affinity to coordinate telomere maintenance. Recent structural and genetic data have led to the proposal that Cdc13 is the paralog of RPA70 within a telomere-specific RPA complex. Our understanding of Cdc13 structure and biochemistry has been largely restricted to studies of individual domains, precluding analysis of how each domain influences the activity of the others. To better facilitate a comparison to RPA70, we evaluated the ssDNA binding of full-length S. cerevisiae Cdc13 to its minimal substrate, Tel11. We found that, unlike RPA70 and the other known telomere end-binding proteins, the core Cdc13 ssDNA-binding activity is wholly contained within a single tight-binding oligosaccharide/oligonucleotide/oligopeptide binding (OB)-fold. Because two OB-folds are implicated in dimerization, we also evaluated the relationship between dimerization and ssDNA-binding activity and found that the two activities are independent. We also find that Cdc13 binding exhibits positive cooperativity that is independent of dimerization. This study reveals that, while Cdc13 and RPA70 share similar domain topologies, the corresponding domains have evolved different and specialized functions.},
}
@article {pmid24057213,
year = {2014},
author = {Huang, Y and Hidalgo-Bravo, A and Zhang, E and Cotton, VE and Mendez-Bermudez, A and Wig, G and Medina-Calzada, Z and Neumann, R and Jeffreys, AJ and Winney, B and Wilson, JF and Clark, DA and Dyer, MJ and Royle, NJ},
title = {Human telomeres that carry an integrated copy of human herpesvirus 6 are often short and unstable, facilitating release of the viral genome from the chromosome.},
journal = {Nucleic acids research},
volume = {42},
number = {1},
pages = {315-327},
pmid = {24057213},
issn = {1362-4962},
support = {CZB/4/710/CSO_/Chief Scientist Office/United Kingdom ; G0901657/MRC_/Medical Research Council/United Kingdom ; G9806740/MRC_/Medical Research Council/United Kingdom ; 097828MF/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Base Sequence ; Cell Line ; Chromosomes ; Genes, Viral ; *Genome, Viral ; Herpesvirus 6, Human/*genetics ; Humans ; Molecular Sequence Data ; RNA Splicing ; Repetitive Sequences, Nucleic Acid ; Telomere/chemistry/*metabolism ; *Telomere Shortening ; *Virus Integration ; },
abstract = {Linear chromosomes are stabilized by telomeres, but the presence of short dysfunctional telomeres triggers cellular senescence in human somatic tissues, thus contributing to ageing. Approximately 1% of the population inherits a chromosomally integrated copy of human herpesvirus 6 (CI-HHV-6), but the consequences of integration for the virus and for the telomere with the insertion are unknown. Here we show that the telomere on the distal end of the integrated virus is frequently the shortest measured in somatic cells but not the germline. The telomere carrying the CI-HHV-6 is also prone to truncations that result in the formation of a short telomere at a novel location within the viral genome. We detected extra-chromosomal circular HHV-6 molecules, some surprisingly comprising the entire viral genome with a single fully reconstituted direct repeat region (DR) with both terminal cleavage and packaging elements (PAC1 and PAC2). Truncated CI-HHV-6 and extra-chromosomal circular molecules are likely reciprocal products that arise through excision of a telomere-loop (t-loop) formed within the CI-HHV-6 genome. In summary, we show that the CI-HHV-6 genome disrupts stability of the associated telomere and this facilitates the release of viral sequences as circular molecules, some of which have the potential to become fully functioning viruses.},
}
@article {pmid24053950,
year = {2013},
author = {Cao, L and Liu, Y and Shen, Q and Zhao, X and Wang, T and He, L},
title = {Association analysis of four single nucleotide polymorphisms with leukocyte telomere length in two Chinese populations.},
journal = {Journal of genetics and genomics = Yi chuan xue bao},
volume = {40},
number = {9},
pages = {489-491},
doi = {10.1016/j.jgg.2013.08.001},
pmid = {24053950},
issn = {1673-8527},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Alleles ; Asian People/genetics ; Cohort Studies ; Female ; Genome-Wide Association Study ; Genotype ; Humans ; Leukocytes/*physiology ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/*genetics ; Telomere/genetics/*physiology ; Telomere Homeostasis ; Young Adult ; },
}
@article {pmid24053596,
year = {2014},
author = {Sekaran, V and Soares, J and Jarstfer, MB},
title = {Telomere maintenance as a target for drug discovery.},
journal = {Journal of medicinal chemistry},
volume = {57},
number = {3},
pages = {521-538},
doi = {10.1021/jm400528t},
pmid = {24053596},
issn = {1520-4804},
mesh = {Animals ; Antineoplastic Agents/chemistry/*pharmacology/therapeutic use ; Drug Delivery Systems ; G-Quadruplexes/drug effects ; Gene Transfer Techniques ; Humans ; Immunotherapy ; Molecular Targeted Therapy ; Neoplasms/enzymology/immunology/*therapy ; Telomerase/antagonists &amp; inhibitors/genetics/*metabolism ; Telomere/*metabolism ; Transcription, Genetic ; },
abstract = {The observation that the enzyme telomerase is up-regulated in 80-90% of cancer cells isolated from primary human tumors but is absent in neighboring cells of healthy tissue has resulted in significant efforts to validate telomerase as an anticancer drug target and to develop effective approaches toward its inhibition. In addition to inhibitors that target the enzymatic function of telomerase, efforts toward immunotherapy using peptides derived from its catalytic subunit hTERT and hTERT-promoter driven gene therapy have made significant advances. The increased level of telomerase in cancer cells also provides a potential platform for cancer diagnostics. Telomerase inhibition leads to disruption of a cell's ability to maintain the very ends of the chromosomes, which are called telomeres. Thus, the telomere itself has also attracted attention as an anticancer drug target. In this Perspective, interdisciplinary efforts to realize the therapeutic potential of targeting telomere maintenance with a focus on telomerase are discussed.},
}
@article {pmid24052939,
year = {2013},
author = {Kannan, N and Huda, N and Tu, L and Droumeva, R and Aubert, G and Chavez, E and Brinkman, RR and Lansdorp, P and Emerman, J and Abe, S and Eaves, C and Gilley, D},
title = {The luminal progenitor compartment of the normal human mammary gland constitutes a unique site of telomere dysfunction.},
journal = {Stem cell reports},
volume = {1},
number = {1},
pages = {28-37},
pmid = {24052939},
issn = {2213-6711},
support = {P30 CA082709/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Adult Stem Cells/*cytology/metabolism ; Aged ; Cells, Cultured ; DNA Damage ; Female ; Humans ; Mammary Glands, Human/*cytology/metabolism ; Middle Aged ; Telomerase/genetics/metabolism ; Telomere/*genetics ; *Telomere Shortening ; },
abstract = {Telomeres are essential for genomic integrity, but little is known about their regulation in the normal human mammary gland. We now demonstrate that a phenotypically defined cell population enriched in luminal progenitors (LPs) is characterized by unusually short telomeres independently of donor age. Furthermore, we find that multiple DNA damage response proteins colocalize with telomeres in >95% of LPs but in <5% of basal cells. Paradoxically, 25% of LPs are still capable of exhibiting robust clonogenic activity in vitro. This may be partially explained by the elevated telomerase activity that was also seen only in LPs. Interestingly, this potential telomere salvage mechanism declines with age. Our findings thus reveal marked differences in the telomere biology of different subsets of primitive normal human mammary cells. The chronically dysfunctional telomeres unique to LPs have potentially important implications for normal mammary tissue homeostasis as well as the development of certain breast cancers.},
}
@article {pmid24051140,
year = {2013},
author = {Ornish, D and Lin, J and Chan, JM and Epel, E and Kemp, C and Weidner, G and Marlin, R and Frenda, SJ and Magbanua, MJM and Daubenmier, J and Estay, I and Hills, NK and Chainani-Wu, N and Carroll, PR and Blackburn, EH},
title = {Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study.},
journal = {The Lancet. Oncology},
volume = {14},
number = {11},
pages = {1112-1120},
doi = {10.1016/S1470-2045(13)70366-8},
pmid = {24051140},
issn = {1474-5488},
support = {R01 R01CA101042/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Case-Control Studies ; DNA/analysis/genetics ; *Diet ; *Exercise ; Follow-Up Studies ; Humans ; *Life Style ; Male ; Middle Aged ; Pilot Projects ; Polymerase Chain Reaction ; Prognosis ; Prostatic Neoplasms/enzymology/genetics/*therapy ; Telomerase/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: Telomere shortness in human beings is a prognostic marker of ageing, disease, and premature morbidity. We previously found an association between 3 months of comprehensive lifestyle changes and increased telomerase activity in human immune-system cells. We followed up participants to investigate long-term effects.<br><br>METHODS: This follow-up study compared ten men and 25 external controls who had biopsy-proven low-risk prostate cancer and had chosen to undergo active surveillance. Eligible participants were enrolled between 2003 and 2007 from previous studies and selected according to the same criteria. Men in the intervention group followed a programme of comprehensive lifestyle changes (diet, activity, stress management, and social support), and the men in the control group underwent active surveillance alone. We took blood samples at 5 years and compared relative telomere length and telomerase enzymatic activity per viable cell with those at baseline, and assessed their relation to the degree of lifestyle changes.<br><br>FINDINGS: Relative telomere length increased from baseline by a median of 0&#xb7;06 telomere to single-copy gene ratio (T/S)units (IQR-0&#xb7;05 to 0&#xb7;11) in the lifestyle intervention group, but decreased in the control group (-0&#xb7;03 T/S units, -0&#xb7;05 to 0&#xb7;03, difference p=0&#xb7;03). When data from the two groups were combined, adherence to lifestyle changes was significantly associated with relative telomere length after adjustment for age and the length of follow-up (for each percentage point increase in lifestyle adherence score, T/S units increased by 0&#xb7;07, 95% CI 0&#xb7;02-0&#xb7;12, p=0&#xb7;005). At 5 years, telomerase activity had decreased from baseline by 0&#xb7;25 (-2&#xb7;25 to 2&#xb7;23) units in the lifestyle intervention group, and by 1&#xb7;08 (-3&#xb7;25 to 1&#xb7;86) units in the control group (p=0&#xb7;64), and was not associated with adherence to lifestyle changes (relative risk 0&#xb7;93, 95% CI 0&#xb7;72-1&#xb7;20, p=0&#xb7;57).<br><br>INTERPRETATION: Our comprehensive lifestyle intervention was associated with increases in relative telomere length after 5 years of follow-up, compared with controls, in this small pilot study. Larger randomised controlled trials are warranted to confirm this finding.<br><br>FUNDING: US Department of Defense, NIH/NCI, Furlotti Family Foundation, Bahna Foundation, DeJoria Foundation, Walton Family Foundation, Resnick Foundation, Greenbaum Foundation, Natwin Foundation, Safeway Foundation, Prostate Cancer Foundation.},
}
@article {pmid24049070,
year = {2013},
author = {Mir, T and Huang, SH and Kobryn, K},
title = {The telomere resolvase of the Lyme disease spirochete, Borrelia burgdorferi, promotes DNA single-strand annealing and strand exchange.},
journal = {Nucleic acids research},
volume = {41},
number = {22},
pages = {10438-10448},
pmid = {24049070},
issn = {1362-4962},
support = {MOP79344//Canadian Institutes of Health Research/Canada ; },
mesh = {Bacterial Proteins/chemistry/*metabolism ; Borrelia burgdorferi/*enzymology ; DNA, Single-Stranded/chemistry/*metabolism ; Endodeoxyribonucleases/chemistry/*metabolism ; Protein Structure, Tertiary ; Recombinases/chemistry/*metabolism ; Telomere/enzymology ; },
abstract = {Spirochetes of the genus Borrelia include the tick-transmitted causative agents of Lyme disease and relapsing fever. They possess unusual genomes composed mainly of linear replicons terminated by closed DNA hairpin telomeres. Hairpin telomeres present an uninterrupted DNA chain to the replication machinery overcoming the 'end-replication problem' for the linear replicons. Hairpin telomeres are formed from inverted repeat replicated telomere junctions by the telomere resolvase, ResT. ResT uses a reaction mechanism similar to that of the type IB topoisomerases and tyrosine recombinases. We report here that ResT also possesses single-strand annealing activity and a limited ability to promote DNA strand exchange reactions on partial duplex substrates. This combination of activities suggests ResT is a nexus between the seemingly distinct processes of telomere resolution and homologous recombination. Implications for hairpin telomere replication and linear plasmid recombination, including antigenic variation, are discussed.},
}
@article {pmid24041868,
year = {2014},
author = {Puri, N and Pitman, RT and Mulnix, RE and Erickson, T and Iness, AN and Vitali, C and Zhao, Y and Salgia, R},
title = {Non-small cell lung cancer is susceptible to induction of DNA damage responses and inhibition of angiogenesis by telomere overhang oligonucleotides.},
journal = {Cancer letters},
volume = {343},
number = {1},
pages = {14-23},
pmid = {24041868},
issn = {1872-7980},
support = {R01 HL091916/HL/NHLBI NIH HHS/United States ; R01 HL112791/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Bronchi/pathology ; Carcinoma, Non-Small-Cell Lung/*genetics ; Cell Line, Tumor ; Cell Proliferation ; Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Cyclin-Dependent Kinase Inhibitor p27/metabolism ; *DNA Damage ; Epithelial Cells/cytology ; Gene Expression Regulation, Neoplastic ; *Genetic Predisposition to Disease ; Humans ; Inhibitor of Growth Protein 1 ; Intracellular Signaling Peptides and Proteins/metabolism ; Male ; Mice ; Mice, Nude ; Neoplasm Transplantation ; *Neovascularization, Pathologic ; Nuclear Proteins/metabolism ; Oligonucleotides/genetics ; Signal Transduction ; Telomere/*ultrastructure ; Tumor Suppressor Proteins/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; },
abstract = {Exposure of the telomere overhang acts as a DNA damage signal, and exogenous administration of an 11-base oligonucleotide homologous to the 3'-telomere overhang sequence (T-oligo) mimics the effects of overhang exposure by inducing senescence and cell death in non-small cell lung cancer (NSCLC) cells, but not in normal bronchial epithelial cells. T-oligo-induced decrease in cellular proliferation in NSCLC is likely directed through both p53 and its homolog, p73, with subsequent induction of senescence and expression of senescence-associated proteins, p21, p33(ING), and p27(Kip1) both in vivo and in vitro. Additionally, T-oligo decreases tumor size and inhibits angiogenesis through decreased VEGF signaling and increased TSP-1 expression.},
}
@article {pmid24039592,
year = {2013},
author = {Romano, GH and Harari, Y and Yehuda, T and Podhorzer, A and Rubinstein, L and Shamir, R and Gottlieb, A and Silberberg, Y and Pe'er, D and Ruppin, E and Sharan, R and Kupiec, M},
title = {Environmental stresses disrupt telomere length homeostasis.},
journal = {PLoS genetics},
volume = {9},
number = {9},
pages = {e1003721},
pmid = {24039592},
issn = {1553-7404},
mesh = {Acetic Acid/pharmacology ; Alcohols/pharmacology ; Chromosomes, Fungal/drug effects/metabolism ; Gene-Environment Interaction ; Homeostasis/drug effects/genetics ; Humans ; Oxidative Stress/genetics/physiology ; Saccharomyces cerevisiae/genetics/physiology ; Saccharomyces cerevisiae Proteins/*genetics ; Shelterin Complex ; *Stress, Physiological ; Telomere/drug effects/*genetics ; Telomere Homeostasis/drug effects/*genetics ; Telomere-Binding Proteins/*genetics/metabolism ; Transcription Factors/*genetics ; },
abstract = {Telomeres protect the chromosome ends from degradation and play crucial roles in cellular aging and disease. Recent studies have additionally found a correlation between psychological stress, telomere length, and health outcome in humans. However, studies have not yet explored the causal relationship between stress and telomere length, or the molecular mechanisms underlying that relationship. Using yeast as a model organism, we show that stresses may have very different outcomes: alcohol and acetic acid elongate telomeres, whereas caffeine and high temperatures shorten telomeres. Additional treatments, such as oxidative stress, show no effect. By combining genome-wide expression measurements with a systematic genetic screen, we identify the Rap1/Rif1 pathway as the central mediator of the telomeric response to environmental signals. These results demonstrate that telomere length can be manipulated, and that a carefully regulated homeostasis may become markedly deregulated in opposing directions in response to different environmental cues.},
}
@article {pmid24037480,
year = {2014},
author = {Kejnovská, I and Vorlíčková, M and Brázdová, M and Sagi, J},
title = {Stability of human telomere quadruplexes at high DNA concentrations.},
journal = {Biopolymers},
volume = {101},
number = {4},
pages = {428-438},
doi = {10.1002/bip.22400},
pmid = {24037480},
issn = {1097-0282},
mesh = {Circular Dichroism ; DNA/*chemistry ; Densitometry ; Electrophoresis, Polyacrylamide Gel ; Entropy ; *G-Quadruplexes ; Humans ; Microscopy, Atomic Force ; Spectrophotometry, Ultraviolet ; Telomere/*chemistry ; },
abstract = {For mimicking macromolecular crowding of DNA quadruplexes, various crowding agents have been used, typically PEG, with quadruplexes of micromolar strand concentrations. Thermal and thermodynamic stabilities of these quadruplexes increased with the concentration of the agents, the rise depended on the crowder used. A different phenomenon was observed, and is presented in this article, when the crowder was the quadruplex itself. With DNA strand concentrations ranging from 3 µM to 9 mM, the thermostability did not change up to ∼2 mM, above which it increased, indicating that the unfolding quadruplex units were not monomolecular above ∼2 mM. The results are explained by self-association of the G-quadruplexes above this concentration. The ΔG(°) 37 values, evaluated only below 2 mM, did not become more negative, as with the non-DNA crowders, instead, slightly increased. Folding topology changed from antiparallel to hybrid above 2 mM, and then to parallel quadruplexes at high, 6-9 mM strand concentrations. In this range, the concentration of the DNA phosphate anions approached the concentration of the K(+) counterions used. Volume exclusion is assumed to promote the topological changes of quadruplexes toward the parallel, and the decreased screening of anions could affect their stability.},
}
@article {pmid24036693,
year = {2013},
author = {Martinez-Delgado, B and Gallardo, M and Tanic, M and Yanowsky, K and Inglada-Perez, L and Barroso, A and Rodriguez-Pinilla, M and Cañamero, M and Blasco, MA and Benitez, J},
title = {Short telomeres are frequent in hereditary breast tumors and are associated with high tumor grade.},
journal = {Breast cancer research and treatment},
volume = {141},
number = {2},
pages = {231-242},
doi = {10.1007/s10549-013-2696-6},
pmid = {24036693},
issn = {1573-7217},
mesh = {Adult ; Aged ; Biomarkers, Tumor/genetics/metabolism ; Breast Neoplasms/*genetics/*pathology ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Humans ; Immunohistochemistry ; Middle Aged ; Mutation ; Neoplasm Grading ; *Telomere Shortening ; },
abstract = {Telomere shortening is a common event involved in malignant transformation. Critically short telomeres may trigger chromosomal aberrations and produce genomic instability leading to cancer development. Therefore, telomere shortening is a frequent molecular alteration in early stages of many epithelial tumors and in breast cancer correlates with stage and prognosis. A better understanding of the involvement of short telomeres in tumors may have a significant impact on patient management and the design of more specific treatments. To understand the role of telomere length (TL) in breast cancer etiology we measured the length of individual telomere signals in single cells by using quantitative telomere in situ hybridization in paraffin-embedded tissue from hereditary and sporadic breast cancers. A total of 104 tumor tissue samples from 75 familial breast tumors (BRCA1, n = 14; BRCA2, n = 13; non-BRCA1/2, n = 48) and 29 sporadic tumors were analyzed. Assessment of telomere signal intensity allowed estimation of the mean TL and related variables, such as percentage of critically short telomeres and percentage of cells with short telomeres. These data were correlated with the immunohistochemical expression of molecular breast cancer markers. Hereditary BRCA1, BRCA2, and non-BRCA1/2 tumors were characterized by shorter TL comparing to sporadic tumors. Considering all tumors, tumor grade was a strong risk factor determining the proportion of short telomeres or short telomere cells. Moreover, some histopathological features appeared to be differentially associated to hereditary or sporadic subgroups. Short telomeres correlated with ER-negative tumors in sporadic cases but not in familial cases, whereas a high level of apoptosis was associated with shorter telomeres in hereditary BRCA1 and BRCA2 tumors. In addition, TL helped to define a subset of non-BRCA1/2 tumors with short telomeres associated with increased expression of antiapoptotic proteins. These findings highlight the potential interest of TL measurements as markers of aggressiveness in breast cancer.},
}
@article {pmid24036517,
year = {2013},
author = {Zhu, Y and Voruganti, VS and Lin, J and Matsuguchi, T and Blackburn, E and Best, LG and Lee, ET and MacCluer, JW and Cole, SA and Zhao, J},
title = {QTL mapping of leukocyte telomere length in American Indians: the Strong Heart Family Study.},
journal = {Aging},
volume = {5},
number = {9},
pages = {704-716},
pmid = {24036517},
issn = {1945-4589},
support = {R01DK091369/DK/NIDDK NIH HHS/United States ; U01 HL041642/HL/NHLBI NIH HHS/United States ; U01 HL041654/HL/NHLBI NIH HHS/United States ; K01 AG034259/AG/NIA NIH HHS/United States ; C06RR013556/RR/NCRR NIH HHS/United States ; U01 HL041652/HL/NHLBI NIH HHS/United States ; C06 RR013556/RR/NCRR NIH HHS/United States ; U01HL41642/HL/NHLBI NIH HHS/United States ; U01HL65521/HL/NHLBI NIH HHS/United States ; R21HL092363/HL/NHLBI NIH HHS/United States ; K01AG034259/AG/NIA NIH HHS/United States ; U01 HL065521/HL/NHLBI NIH HHS/United States ; U01HL41654/HL/NHLBI NIH HHS/United States ; R01 HL109301/HL/NHLBI NIH HHS/United States ; U01 HL065520/HL/NHLBI NIH HHS/United States ; R01 DK091369/DK/NIDDK NIH HHS/United States ; U01HL41652/HL/NHLBI NIH HHS/United States ; R21 HL092363/HL/NHLBI NIH HHS/United States ; U01HL65520/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/genetics ; Cardiovascular Diseases/genetics ; Chromosome Mapping ; Female ; Genome-Wide Association Study ; Humans ; Indians, North American/*genetics ; Leukocytes/metabolism ; Male ; Middle Aged ; Prospective Studies ; *Quantitative Trait Loci ; Risk Factors ; Telomere Homeostasis/*genetics ; United States ; Young Adult ; },
abstract = {Telomeres play a central role in cellular senescence and are associated with a variety of age-related disorders such as dementia, Alzheimer's disease and atherosclerosis. Telomere length varies greatly among individuals of the same age, and is heritable. Here we performed a genome-wide linkage scan to identify quantitative trait loci (QTL) influencing leukocyte telomere length (LTL) measured by quantitative PCR in 3,665 American Indians (aged 14-93 years) from 94 large, multi-generational families. All participants were recruited by the Strong Heart Family Study (SHFS), a prospective study to identify genetic factors for cardiovascular disease and its risk factors in American Indians residing in Oklahoma, Arizona and Dakota. LTL heritability was estimated to be between 51% and 62%, suggesting a strong genetic predisposition to interindividual variation of LTL in this population. Significant QTLs were localized to chromosome 13 (Logarithm of odds score (LOD)=3.9) at 13q12.11, to 18q22.2 (LOD=3.2) and to 3p14.1 (LOD=3.0) for Oklahoma. This is the first study to identify susceptibility loci influencing leukocyte telomere variation in American Indians, a minority group suffering from a disproportionately high rate of type 2 diabetes and other age-related disorders.},
}
@article {pmid24028717,
year = {2013},
author = {Wang, T and Fu, R and Wang, HQ and Qu, W and Ruan, EB and Wang, GJ and Liu, H and Wu, YH and Wang, XM and Song, J and Xing, LM and Guan, J and Li, LJ and Liu, H and Liu, CY and Wang, YH and Jiang, HJ and Ding, K and Dong, XF and Wang, HL and Zhang, T and Shao, ZH},
title = {[Telomere length and gene expression of shelterin in CD3(+) T cell of severe aplastic anemia patients].},
journal = {Zhonghua yi xue za zhi},
volume = {93},
number = {20},
pages = {1533-1536},
pmid = {24028717},
issn = {0376-2491},
mesh = {Adolescent ; Adult ; Aged ; Anemia, Aplastic/genetics/*metabolism ; CD3 Complex/metabolism ; Case-Control Studies ; Child ; Female ; Gene Expression ; Humans ; Male ; Middle Aged ; Shelterin Complex ; T-Lymphocytes/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Young Adult ; },
abstract = {OBJECTIVE: To explore the changes in telomere length and gene expression of complex shelterin (composed of 6 core components: TRF1, TRF2, POT1, TIN2, TPP1 and RAP1) in severe aplastic anemia (SAA).<br><br>METHODS: Bone marrow samples were obtained from 20 SAA patients and 10 normal controls. CD3(+)T cells were sorted by immunomagnetic separation. Telomere length was tested by Southern blot and the gene expressions of TRF1, TRF2, POT1, TIN2, TPP1 and RAP1 were detected by reverse transcription-PCR(RT-PCR).<br><br>RESULTS: Telomeres of CD3(+)T cells were found significantly shorter in SAA untreated ((4.4 &#xb1; 1.1) kb, n = 9) and recovering groups((5.8 &#xb1; 1.0) kb, n = 11) than control group ((9.2 &#xb1; 3.3) kb, P < 0.05). Telomere length of CD3(+)T cells shortened with TH/S decreasing (r = 0.564, P = 0.029). The mRNA expression of POT1 decreased in untreated SAA patients (0.16(0.02-0.29)) and over-expressed in recovering patients (1.17(0.82-1.86), P < 0.05). The mRNA expression of RAP1 was significantly higher in untreated patients (4.14 (1.93-6.92)) than that in recovering group (0.87 (0.30-1.73)) and controls (0.62 (0.45-4.07) , both P < 0.05).<br><br>CONCLUSION: Changes in telomere length and shelterin gene expression occur in CD3(+)T cells of SAA patients and may be correlated with disease severity.},
}
@article {pmid24025336,
year = {2013},
author = {Kasbek, C and Wang, F and Price, CM},
title = {Human TEN1 maintains telomere integrity and functions in genome-wide replication restart.},
journal = {The Journal of biological chemistry},
volume = {288},
number = {42},
pages = {30139-30150},
pmid = {24025336},
issn = {1083-351X},
support = {F32CA177120/CA/NCI NIH HHS/United States ; T32 CA117846/CA/NCI NIH HHS/United States ; GM041803/GM/NIGMS NIH HHS/United States ; R01 GM041803/GM/NIGMS NIH HHS/United States ; F32 CA177120/CA/NCI NIH HHS/United States ; T32CA117846/CA/NCI NIH HHS/United States ; },
mesh = {Cell Cycle/*physiology ; DNA Replication/*physiology ; Genome, Human/*physiology ; HeLa Cells ; Humans ; Telomerase/genetics/metabolism ; Telomere Homeostasis/*physiology ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {TEN1 is a component of the mammalian CTC1-STN1-TEN1 complex. CTC1 and/or STN1 functions in telomere duplex replication, C-strand fill-in, and genome-wide restart of replication following fork stalling. Here we examine the role of human TEN1 and ask whether it also functions as a specialized replication factor. TEN1 depletion causes an increase in multitelomere fluorescent in situ hybridization (FISH) signals similar to that observed after CTC1 or STN1 depletion. However, TEN1 depletion also results in increased telomere loss. This loss is not accompanied by increased telomere deprotection, recombination, or T-circle release. Thus, it appears that both the multiple telomere signals and telomere loss stem from problems in telomere duplex replication. TEN1 depletion can also affect telomere length, but whether telomeres lengthen or shorten is cell line-dependent. Like CTC1 and STN1, TEN1 is needed for G-overhang processing. Depletion of TEN1 does not effect overhang elongation in mid-S phase, but it delays overhang shortening in late S/G2. These results indicate a role for TEN1 in C-strand fill-in but do not support a direct role in telomerase regulation. Finally, TEN1 depletion causes a decrease in genome-wide replication restart following fork stalling similar to that observed after STN1 depletion. However, anaphase bridge formation is more severe than with CTC1 or STN1 depletion. Our findings indicate that TEN1 likely functions in conjunction with CTC1 and STN1 at the telomere and elsewhere in the genome. They also raise the possibility that TEN1 has additional roles and indicate that TEN1/CTC1-STN1-TEN1 helps solve a wide range of challenges to the replication machinery.},
}
@article {pmid24023967,
year = {2013},
author = {Young, RC and Kitaysky, AS and Haussmann, MF and Descamps, S and Orben, RA and Elliott, KH and Gaston, AJ},
title = {Age, sex, and telomere dynamics in a long-lived seabird with male-biased parental care.},
journal = {PloS one},
volume = {8},
number = {9},
pages = {e74931},
pmid = {24023967},
issn = {1932-6203},
mesh = {*Aging/genetics/physiology ; Animals ; Behavior, Animal ; Breeding ; Charadriiformes/*genetics/*physiology ; Female ; Longevity/*genetics/*physiology ; Male ; *Sex Characteristics ; Telomere/*genetics ; },
abstract = {The examination of telomere dynamics is a recent technique in ecology for assessing physiological state and age-related traits from individuals of unknown age. Telomeres shorten with age in most species and are expected to reflect physiological state, reproductive investment, and chronological age. Loss of telomere length is used as an indicator of biological aging, as this detrimental deterioration is associated with lowered survival. Lifespan dimorphism and more rapid senescence in the larger, shorter-lived sex are predicted in species with sexual size dimorphism, however, little is known about the effects of behavioral dimorphism on senescence and life history traits in species with sexual monomorphism. Here we compare telomere dynamics of thick-billed murres (Urialomvia), a species with male-biased parental care, in two ways: 1) cross-sectionally in birds of known-age (0-28 years) from one colony and 2) longitudinally in birds from four colonies. Telomere dynamics are compared using three measures: the telomere restriction fragment (TRF), a lower window of TRF (TOE), and qPCR. All showed age-related shortening of telomeres, but the TRF measure also indicated that adult female murres have shorter telomere length than adult males, consistent with sex-specific patterns of ageing. Adult males had longer telomeres than adult females on all colonies examined, but chick telomere length did not differ by sex. Additionally, inter-annual telomere changes may be related to environmental conditions; birds from a potentially low quality colony lost telomeres, while those at more hospitable colonies maintained telomere length. We conclude that sex-specific patterns of telomere loss exist in the sexually monomorphic thick-billed murre but are likely to occur between fledging and recruitment. Longer telomeres in males may be related to their homogamous sex chromosomes (ZZ) or to selection for longer life in the care-giving sex. Environmental conditions appeared to be the primary drivers of annual changes in adult birds.},
}
@article {pmid24022427,
year = {2013},
author = {Heaphy, CM and Schreck, KC and Raabe, E and Mao, XG and An, P and Chu, Q and Poh, W and Jiao, Y and Rodriguez, FJ and Odia, Y and Meeker, AK and Eberhart, CG},
title = {A glioblastoma neurosphere line with alternative lengthening of telomeres.},
journal = {Acta neuropathologica},
volume = {126},
number = {4},
pages = {607-608},
pmid = {24022427},
issn = {1432-0533},
support = {R01 CA172380/CA/NCI NIH HHS/United States ; R01 NS055089/NS/NINDS NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing/genetics/physiology ; Aged ; Brain Neoplasms/genetics/*pathology ; Cell Line, Tumor ; Co-Repressor Proteins ; DNA/genetics ; DNA Helicases/genetics/physiology ; Flow Cytometry ; Glioblastoma/genetics/*pathology ; Humans ; Male ; Molecular Chaperones ; Mutation ; Nuclear Proteins/genetics/physiology ; Telomerase/genetics ; Telomere/genetics/*pathology/ultrastructure ; Telomere Shortening/genetics ; X-linked Nuclear Protein ; },
}
@article {pmid24022299,
year = {2014},
author = {Eisenberg, DT},
title = {Inconsistent inheritance of telomere length (TL): is offspring TL more strongly correlated with maternal or paternal TL?.},
journal = {European journal of human genetics : EJHG},
volume = {22},
number = {1},
pages = {8-9},
pmid = {24022299},
issn = {1476-5438},
support = {R24 HD042828/HD/NICHD NIH HHS/United States ; },
mesh = {Female ; Humans ; Male ; *Paternal Age ; *Pedigree ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
}
@article {pmid24021055,
year = {2013},
author = {Rizzo, LB and Do Prado, CH and Grassi-Oliveira, R and Wieck, A and Correa, BL and Teixeira, AL and Bauer, ME},
title = {Immunosenescence is associated with human cytomegalovirus and shortened telomeres in type I bipolar disorder.},
journal = {Bipolar disorders},
volume = {15},
number = {8},
pages = {832-838},
doi = {10.1111/bdi.12121},
pmid = {24021055},
issn = {1399-5618},
mesh = {Adult ; Aging/*genetics ; Analysis of Variance ; Antigens, CD/metabolism ; Antimanic Agents/pharmacology/therapeutic use ; Bipolar Disorder/drug therapy/*genetics/pathology/*virology ; Case-Control Studies ; Cytomegalovirus/genetics/*immunology ; Female ; Flow Cytometry ; Humans ; Immunoglobulins/pharmacology ; Lithium Chloride/pharmacology/therapeutic use ; Lymphocytes/metabolism/virology ; Middle Aged ; Statistics, Nonparametric ; Telomere/drug effects/*genetics/pathology ; },
abstract = {OBJECTIVE: Bipolar disorder (BD) has been associated with persistent low-grade inflammation and premature cell senescence, as shown by reduced telomere length (TL). The human cytomegalovirus (CMV) has increasingly been implicated in accelerated immunosenescence in aging studies. Here, we compared CMV serology and its relationships with cell senescence markers, including TL and lymphocyte subsets, in patients with type I BD and healthy controls.<br><br>METHODS: Twenty-two euthymic female patients with BD type I and 17 age-matched healthy controls were selected for the study. A sample of blood was collected and mononuclear cells and DNA were isolated and TL measured. CMV immunoglobulin M (IgM) and IgG titers were measured using chemiluminescent assays. Lymphocyte subsets [T, natural killer (NK) and NKT] were phenotyped by flow cytometry.<br><br>RESULTS: Individuals with BD had shorter TLs but higher CMV IgG levels than controls (both p < 0.01). CMV IgG level was inversely correlated with TL. None of the subjects showed IgM reactivity for CMV, excluding acute viral infection. CMV IgG level was associated with expansion of senescent CD8+CD28- T cells and NK cells, which are involved in viral control.<br><br>CONCLUSIONS: These data support the hypothesis of accelerated aging in BD, as shown by shortened telomeres, higher seropositivity for CMV, and expansion of senescent T cells.},
}
@article {pmid24020493,
year = {2013},
author = {El Idrissi, M and Hervieu, V and Merle, P and Mortreux, F and Wattel, E},
title = {Cause-specific telomere factors deregulation in hepatocellular carcinoma.},
journal = {Journal of experimental &amp; clinical cancer research : CR},
volume = {32},
number = {1},
pages = {64},
pmid = {24020493},
issn = {1756-9966},
mesh = {Adult ; Aged ; Carcinoma, Hepatocellular/*genetics/metabolism/pathology/virology ; Female ; Hepacivirus/isolation &amp; purification ; Hepatitis B/pathology ; Hepatitis B virus/isolation &amp; purification ; Hepatitis C/pathology ; Humans ; Immunohistochemistry ; Liver Neoplasms/*genetics/metabolism/pathology/virology ; Male ; Middle Aged ; RNA/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism/pathology ; },
abstract = {BACKGROUND: Among the numerous genetic defects associated with hepatocarcinogenesis, telomere abnormalities appear to play a role both in tumor promotion and maintenance. Telomeres, the chromosome extremities, are protected by specific proteins, the shelterin complex and by additional factors. Besides telomerase dysregulation, expression changes of these telomere factors have been observed in cancers.<br><br>METHODS: Here, we tested the hypothesis that such dysregulation might occur in hepatocellular carcinoma (HCC) with specific patterns depending on the cause of HCC. We compared telomere length, telomerase activity (TA), hTERT and telomere genes expression using PCR and Western-blot analyses between non-cirrhotic liver, peritumoral cirrhotic tissue (40 samples) and cancerous tissue (40 samples) derived from 40 patients with HBV-, HCV-, or alcohol-related HCC.<br><br>RESULTS: Alterations in TA, hTERT expression and telomere length between non-cirrhotic, cirrhotic, and tumor samples were not significantly influenced by the cause of HCC. In contrast, the expression pattern of hTR, shelterin, and non-shelterin telomere protective factors clearly distinguished the 3 causes of cirrhosis and HCC. For patients with HBV diseased liver, when compared with non-cirrhotic liver, the cirrhotic tissue underexpressed all shelterin and all but HMRE11A and RAD50 non-shelterin telomere factors. For HCV the expression level of POT1, RAP1, Ku80, and RAD50 was higher in cirrhotic than in non-cirrhotic liver samples without evidence for significant transcriptional change for the remaining genes. For alcohol-related liver diseases, the expression level of POT1, RAP1, TIN2, hMRE11A, hMRE11B, Ku70, Ku80, RAD50, TANK1, and PINX1 was higher in cirrhotic than in non-cirrhotic liver samples. For the 3 causes of HCC, there was no significant change in shelterin and non-shelterin gene expression between cirrhosis and HCC samples.<br><br>CONCLUSIONS: These results validate our hypotheses and demonstrate that cirrhosis and HCC add-up numerous telomere dysfunctions including numerous cause-specific changes that appear to occur early during the course of the disease.},
}
@article {pmid24019396,
year = {2013},
author = {Cunningham, JM and Johnson, RA and Litzelman, K and Skinner, HG and Seo, S and Engelman, CD and Vanderboom, RJ and Kimmel, GW and Gangnon, RE and Riegert-Johnson, DL and Baron, JA and Potter, JD and Haile, R and Buchanan, DD and Jenkins, MA and Rider, DN and Thibodeau, SN and Petersen, GM and Boardman, LA},
title = {Telomere length varies by DNA extraction method: implications for epidemiologic research.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {22},
number = {11},
pages = {2047-2054},
pmid = {24019396},
issn = {1538-7755},
support = {R01 CA132718/CA/NCI NIH HHS/United States ; U24 CA074783/CA/NCI NIH HHS/United States ; P30 CA014520/CA/NCI NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; P50 CA102701/CA/NCI NIH HHS/United States ; R0-1 CA132718/CA/NCI NIH HHS/United States ; UM1 CA167551/CA/NCI NIH HHS/United States ; P30 DK084567/DK/NIDDK NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; U24 CA074799/CA/NCI NIH HHS/United States ; U01 CA074800/CA/NCI NIH HHS/United States ; U01 CA074799/CA/NCI NIH HHS/United States ; CA-96-011/CA/NCI NIH HHS/United States ; U24 CA097735/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; P30DK084567/DK/NIDDK NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; U01 CA097735/CA/NCI NIH HHS/United States ; T35 HL007690/HL/NHLBI NIH HHS/United States ; U01 CA074806/CA/NCI NIH HHS/United States ; U24 CA074800/CA/NCI NIH HHS/United States ; },
mesh = {Case-Control Studies ; Colorectal Neoplasms/blood/genetics ; DNA/blood/genetics/*isolation &amp; purification ; DNA, Neoplasm/blood/genetics/isolation &amp; purification ; Epidemiologic Studies ; Female ; Humans ; Leukocytes/*chemistry/ultrastructure ; Male ; Middle Aged ; Telomere/*chemistry/genetics ; },
abstract = {BACKGROUND: Both shorter and longer telomeres in peripheral blood leukocyte (PBL) DNA have been associated with cancer risk. However, associations remain inconsistent across studies of the same cancer type. This study compares DNA preparation methods to determine telomere length from patients with colorectal cancer.<br><br>METHODS: We examined PBL relative telomere length (RTL) measured by quantitative PCR (qPCR) in 1,033 patients with colorectal cancer and 2,952 healthy controls. DNA was extracted with phenol/chloroform, PureGene, or QIAamp.<br><br>RESULTS: We observed differences in RTL depending on DNA extraction method (P < 0.001). Phenol/chloroform-extracted DNA had a mean RTL (T/S ratio) of 0.78 (range 0.01-6.54) compared with PureGene-extracted DNA (mean RTL of 0.75; range 0.00-12.33). DNA extracted by QIAamp yielded a mean RTL of 0.38 (range 0.02-3.69). We subsequently compared RTL measured by qPCR from an independent set of 20 colorectal cancer cases and 24 normal controls in PBL DNA extracted by each of the three extraction methods. The range of RTL measured by qPCR from QIAamp-extracted DNA (0.17-0.58) was less than from either PureGene or phenol/chloroform (ranges, 0.04-2.67 and 0.32-2.81, respectively).<br><br>CONCLUSIONS: RTL measured by qPCR from QIAamp-extracted DNA was less than from either PureGene or phenol/chloroform (P < 0.001).<br><br>IMPACT: Differences in DNA extraction method may contribute to the discrepancies between studies seeking to find an association between the risk of cancer or other diseases and RTL.},
}
@article {pmid24013362,
year = {2013},
author = {Zhou, X and Zhang, X and Xie, Y and Tanaka, K and Wang, B and Zhang, H},
title = {DNA-PKcs inhibition sensitizes cancer cells to carbon-ion irradiation via telomere capping disruption.},
journal = {PloS one},
volume = {8},
number = {8},
pages = {e72641},
pmid = {24013362},
issn = {1932-6203},
mesh = {*DNA Damage ; *DNA End-Joining Repair/drug effects/radiation effects ; DNA-Activated Protein Kinase/antagonists &amp; inhibitors/genetics/*metabolism ; HeLa Cells ; Humans ; Nuclear Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Protein Kinase Inhibitors/*pharmacology ; *Radiation, Ionizing ; Telomere/genetics/*metabolism ; Time Factors ; Tumor Suppressor Protein p53/genetics/metabolism ; },
abstract = {Heavy-ion irradiation induces a higher frequency of DNA double strand breaks (DSBs) which must be properly repaired. Critical shortening of telomeres can trigger DNA damage responses such as DSBs. Telomeres are very sensitive to oxidative stress such as ionizing radiation. The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is the central component in the non-homologous end joining (NHEJ) repair complex and participates in telomere maintenance. Therefore, it is expected to enhance the cell killing effect of heavy-ion irradiation via DNA-PKcs inhibition. To test this hypothesis, cellular radiosensitivity was measured by the clonal genetic assay. DNA damage repair was relatively quantified by long PCR. Apoptosis was quantified by flow-cytometric analysis of annexin V/PI double staining, and senescence was analyzed by galactosidase activity. Telomere length was semi-quantified by real-time PCR. P53 and p21 expression was determined by western blotting. Our data demonstrated that MCF-7 and HeLa cells with DNA-PKcs inhibition were more susceptible to carbon-ion irradiation than Those without DNA-PKcs inhibition. Even though NHEJ was inhibited by the DNA-PKcs specific inhibitor, NU7026, most DNA damage induced by carbon-ion irradiation was repaired within 24 hours after irradiation in both cell lines. However, potential lethal damage repair (PLDR) could not restore cellular inactivation in DNA-PKcs inhibited cells. MCF-7 cells showed extensive senescence and accelerated telomere length reduction, while HeLa cells underwent significant apoptosis after irradiation with NU7026 incubation. In addition, both cell lines with shorter telomere were more susceptible to carbon-ion radiation. Our current data suggested that DNA-PKcs inhibition could enhance cellular sensitivity to carbon-ion radiation via disturbing its functional role in telomere end protection. The combination of DNA-PKcs inhibition and carbon-ion irradiation may be an efficient method of heavy-ion therapy.},
}
@article {pmid24013207,
year = {2013},
author = {Balk, B and Maicher, A and Dees, M and Klermund, J and Luke-Glaser, S and Bender, K and Luke, B},
title = {Telomeric RNA-DNA hybrids affect telomere-length dynamics and senescence.},
journal = {Nature structural &amp; molecular biology},
volume = {20},
number = {10},
pages = {1199-1205},
pmid = {24013207},
issn = {1545-9985},
mesh = {Aging/*genetics ; DNA, Fungal/*chemistry ; *Nucleic Acid Hybridization ; RNA, Fungal/*chemistry ; Recombination, Genetic ; Ribonuclease H/metabolism ; Saccharomyces cerevisiae/enzymology ; *Telomere ; },
abstract = {Although telomeres are heterochromatic, they are transcribed into noncoding telomeric repeat-containing RNA (TERRA). Here we show that RNA-DNA hybrids form at telomeres and are removed by RNase H enzymes in the budding yeast, Saccharomyces cerevisiae. In recombination-competent telomerase mutants, telomeric RNA-DNA hybrids promote recombination-mediated elongation events that delay the onset of cellular senescence. Reduction of TERRA and telomeric RNA-DNA-hybrid levels diminishes rates of recombination-mediated telomere elongation in cis. Overexpression of RNase H decreases telomere recombination rates and accelerates senescence in recombination-competent but not recombination-deficient cells. In contrast, in the absence of both telomerase and homologous recombination, accumulation of telomeric RNA-DNA hybrids leads to telomere loss and accelerated rates of cellular senescence. Therefore, the regulation of TERRA transcription and telomeric RNA-DNA-hybrid formation are important determinants of both telomere-length dynamics and proliferative potential after the inactivation of telomerase.},
}
@article {pmid24012755,
year = {2013},
author = {Wan, B and Yin, J and Horvath, K and Sarkar, J and Chen, Y and Wu, J and Wan, K and Lu, J and Gu, P and Yu, EY and Lue, NF and Chang, S and Liu, Y and Lei, M},
title = {SLX4 assembles a telomere maintenance toolkit by bridging multiple endonucleases with telomeres.},
journal = {Cell reports},
volume = {4},
number = {5},
pages = {861-869},
pmid = {24012755},
issn = {2211-1247},
support = {/HHMI/Howard Hughes Medical Institute/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; ZIA AG000754-01/ImNIH/Intramural NIH HHS/United States ; },
mesh = {*DNA Repair ; Endonucleases/genetics/*metabolism ; Humans ; Recombinases/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {SLX4 interacts with several endonucleases to resolve structural barriers in DNA metabolism. SLX4 also interacts with telomeric protein TRF2 in human cells. The molecular mechanism of these interactions at telomeres remains unknown. Here, we report the crystal structure of the TRF2-binding motif of SLX4 (SLX4TBM) in complex with the TRFH domain of TRF2 (TRF2TRFH) and map the interactions of SLX4 with endonucleases SLX1, XPF, and MUS81. TRF2 recognizes a unique HxLxP motif on SLX4 via the peptide-binding site in its TRFH domain. Telomeric localization of SLX4 and associated nucleases depend on the SLX4-endonuclease and SLX4-TRF2 interactions and the protein levels of SLX4 and TRF2. SLX4 assembles an endonuclease toolkit that negatively regulates telomere length via SLX1-catalyzed nucleolytic resolution of telomere DNA structures. We propose that the SLX4-TRF2 complex serves as a double-layer scaffold bridging multiple endonucleases with telomeres for recombination-based telomere maintenance.},
}
@article {pmid24010387,
year = {2014},
author = {Schürks, M and Buring, J and Dushkes, R and Gaziano, JM and Zee, RY and Kurth, T},
title = {Telomere length and Parkinson's disease in men: a nested case-control study.},
journal = {European journal of neurology},
volume = {21},
number = {1},
pages = {93-99},
pmid = {24010387},
issn = {1468-1331},
support = {CA-40360/CA/NCI NIH HHS/United States ; CA-34944/CA/NCI NIH HHS/United States ; HL-34595/HL/NHLBI NIH HHS/United States ; HL-26490/HL/NHLBI NIH HHS/United States ; R01 HL034595/HL/NHLBI NIH HHS/United States ; R01 CA034944-03/CA/NCI NIH HHS/United States ; R01 HL026490/HL/NHLBI NIH HHS/United States ; R01 CA040360/CA/NCI NIH HHS/United States ; R01 HL026490-03/HL/NHLBI NIH HHS/United States ; R01 CA097193/CA/NCI NIH HHS/United States ; R01 CA034944/CA/NCI NIH HHS/United States ; R01 HL034595-07/HL/NHLBI NIH HHS/United States ; CA-097193/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Case-Control Studies ; Humans ; Male ; Parkinson Disease/*genetics ; Polymerase Chain Reaction ; Telomere/*genetics ; },
abstract = {BACKGROUND AND PURPOSE: Telomere shortening has been implicated in neurodegenerative disorders. However, available data on the association between telomere length and Parkinson's disease (PD) are inconclusive.<br><br>METHODS: A nested case-control design was used amongst men participating in the prospective Physicians' Health Study. A large proportion of participants provided blood samples in 1997 and they were followed through 2010. Men with self-reported PD were age-matched to controls in a 1:2 ratio. Quantitative PCR was used to determine the telomere repeat copy number to single gene copy number ratio (TSR) in genomic DNA extracted from peripheral blood leukocytes. TSR was used as a measure for relative telomere length (RTL) in our analyses. Conditional logistic regression was used to determine the risk of PD associated with RTL.<br><br>RESULTS: Data on RTL were available from 408 cases and 809 controls. Median TSR was shorter in controls than in cases (47.7 vs. 50.2; P = 0.02). The age-adjusted odds ratio (OR) for PD was 0.66 [95% confidence interval (CI) 0.46-0.95; Ptrend over quartiles 0.02] comparing the lowest to the highest quartile. The pattern of association was unchanged when comparing RTL below versus above the median (age-adjusted OR 0.75; 95% CI 0.59-0.96). Associations were similar after additional adjustment for many covariates.<br><br>CONCLUSION: Contrary to what was expected, in this large nested case-control study amongst men shorter telomeres were associated with reduced PD risk. Future research on the nature of this counterintuitive association is warranted.},
}
@article {pmid24009516,
year = {2013},
author = {Ballew, BJ and Joseph, V and De, S and Sarek, G and Vannier, JB and Stracker, T and Schrader, KA and Small, TN and O'Reilly, R and Manschreck, C and Harlan Fleischut, MM and Zhang, L and Sullivan, J and Stratton, K and Yeager, M and Jacobs, K and Giri, N and Alter, BP and Boland, J and Burdett, L and Offit, K and Boulton, SJ and Savage, SA and Petrini, JH},
title = {A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome.},
journal = {PLoS genetics},
volume = {9},
number = {8},
pages = {e1003695},
pmid = {24009516},
issn = {1553-7404},
support = {R37 GM059413/GM/NIGMS NIH HHS/United States ; 11581/CRUK_/Cancer Research UK/United Kingdom ; R13 CA162528/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; GM56888/GM/NIGMS NIH HHS/United States ; N02-CP-91026/CP/NCI NIH HHS/United States ; R01 GM056888/GM/NIGMS NIH HHS/United States ; N02-CP-11019/CP/NCI NIH HHS/United States ; N02CP11019/CP/NCI NIH HHS/United States ; },
mesh = {Adult ; DNA Helicases/*genetics ; Dyskeratosis Congenita/etiology/*genetics/*pathology ; Female ; Fetal Growth Retardation/etiology/*genetics/*pathology ; Genes, Recessive ; Germ-Line Mutation ; Homozygote ; Humans ; Immunologic Deficiency Syndromes/genetics/*pathology ; Intellectual Disability/etiology/*genetics/*pathology ; Jews ; Microcephaly/etiology/*genetics/*pathology ; Molecular Sequence Data ; Mutation ; Phenotype ; Telomerase/genetics ; Telomere/genetics ; },
abstract = {Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1.},
}
@article {pmid24009150,
year = {2013},
author = {Qiu, H},
title = {Early telomere shortening and genomic instability in tubo-ovarian preneoplastic lesions--letter.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {19},
number = {18},
pages = {5254},
doi = {10.1158/1078-0432.CCR-13-1412},
pmid = {24009150},
issn = {1557-3265},
mesh = {Fallopian Tube Neoplasms/*genetics/*pathology ; Female ; *Genomic Instability ; Humans ; Ovarian Neoplasms/*genetics/*pathology ; *Precancerous Conditions ; *Telomere Shortening ; },
}
@article {pmid24009148,
year = {2013},
author = {Chene, G and Tchirkov, A and Penault-Llorca, F},
title = {Early telomere shortening and genomic instability in tubo-ovarian preneoplastic lesions--response.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {19},
number = {18},
pages = {5255},
doi = {10.1158/1078-0432.CCR-13-1915},
pmid = {24009148},
issn = {1557-3265},
mesh = {Fallopian Tube Neoplasms/*genetics/*pathology ; Female ; *Genomic Instability ; Humans ; Ovarian Neoplasms/*genetics/*pathology ; *Precancerous Conditions ; *Telomere Shortening ; },
}
@article {pmid24002149,
year = {2013},
author = {Emanuele, E and Altabas, V and Altabas, K and Berardesca, E},
title = {Topical application of preparations containing DNA repair enzymes prevents ultraviolet-induced telomere shortening and c-FOS proto-oncogene hyperexpression in human skin: an experimental pilot study.},
journal = {Journal of drugs in dermatology : JDD},
volume = {12},
number = {9},
pages = {1017-1021},
pmid = {24002149},
issn = {1545-9616},
mesh = {Adult ; DNA/isolation &amp; purification/radiation effects ; DNA Repair Enzymes/administration &amp; dosage/*pharmacology ; Data Interpretation, Statistical ; Deoxyribodipyrimidine Photo-Lyase/pharmacology ; Endonucleases/pharmacology ; Female ; Gene Expression/*drug effects/radiation effects ; Genes, fos/drug effects/*genetics/radiation effects ; Humans ; Liposomes ; Male ; Pilot Projects ; Proto-Oncogene Mas ; Skin/drug effects/*metabolism/radiation effects ; Sunlight ; Sunscreening Agents/pharmacology ; Telomere Shortening/*drug effects/*radiation effects ; Ultraviolet Rays/*adverse effects ; },
abstract = {The exposure to ultraviolet radiation (UVR) is one of the most important risk factors for skin aging and increases the risk of malignant transformation. Telomere shortening and an altered expression of the proto-oncogene c-FOS are among the key molecular mechanisms associated with photoaging and tumorigenesis. Photolyase from A. nidulans and endonuclease from M. luteus are xenogenic DNA repair enzymes which can reverse the molecular events associated with skin aging and carcinogenosis caused by UVR exposure. Therefore, the purpose of this study was to investigate whether the topical application of preparations containing DNA repair enzymes may prevent UVR-induced acute telomere shortening and FOS gene hyperexpression in human skin biopsies. Twelve volunteers (Fitzpatrick skin types I and II) were enrolled for this experimental study, and six circular areas (10 mm diameter) were marked out on the nonexposed lower back of each participant. One site was left untreated (site 1: negative control), whereas the remaining five sites (designated sites 2-6) were exposed to solar-simulated UVR at 3 times the MED on four consecutive days. Site 2 received UVR only (site 2: positive control), whereas the following products were applied to sites 3-6, respectively: vehicle (moisturizer base cream; applied both 30 minutes before and immediately after each irradiation; site 3); a traditional sunscreen (SS, SPF 50) 30 minutes before irradiation and a vehicle immediately after irradiation (site 4); a SS 30 minutes before irradiation and an endonuclease preparation immediately after irradiation (site 5); a SS plus photolyase 30 minutes before irradiation and an endonuclease preparation immediately after irradiation (site 6). Skin biopsies were taken 24 h after the last irradiation. The degree of telomere shortening and c-FOS gene expression were measured in all specimens. Strikingly, the combined use of a SS plus photolyase 30 minutes before irradiation and an endonuclease preparation immediately after irradiation completely abrogated telomere shortening and c-FOS gene hyperexpression induced by the experimental irradiations. We conclude that the topical application of preparations containing both photolyase from A. nidulans and endonuclease from M. luteus may be clinically useful to prevent skin aging and carcinogenesis by abrogating UVR-induced telomere shortening and c-FOS gene hyperexpression.},
}
@article {pmid23999095,
year = {2013},
author = {Lim, KW and Ng, VC and Martín-Pintado, N and Heddi, B and Phan, AT},
title = {Structure of the human telomere in Na+ solution: an antiparallel (2+2) G-quadruplex scaffold reveals additional diversity.},
journal = {Nucleic acids research},
volume = {41},
number = {22},
pages = {10556-10562},
pmid = {23999095},
issn = {1362-4962},
mesh = {DNA/chemistry ; *G-Quadruplexes ; Humans ; Models, Molecular ; Repetitive Sequences, Nucleic Acid ; Sodium/chemistry ; Telomere/*chemistry ; },
abstract = {Single-stranded DNA overhangs at the ends of human telomeric repeats are capable of adopting four-stranded G-quadruplex structures, which could serve as potential anticancer targets. Out of the five reported intramolecular human telomeric G-quadruplex structures, four were formed in the presence of K(+) ions and only one in the presence of Na(+) ions, leading often to a perception that this structural polymorphism occurs exclusively in the presence of K(+) but not Na(+). Here we present the structure of a new antiparallel (2+2) G-quadruplex formed by a derivative of a 27-nt human telomeric sequence in Na(+) solution, which comprises a novel core arrangement distinct from the known topologies. This structure complements the previously elucidated basket-type human telomeric G-quadruplex to serve as reference structures in Na(+)-containing environment. These structures, together with the coexistence of other conformations in Na(+) solution as observed by nuclear magnetic resonance spectroscopy, establish the polymorphic nature of human telomeric repeats beyond the influence of K(+) ions.},
}
@article {pmid23994477,
year = {2013},
author = {Wilson, JS and Tejera, AM and Castor, D and Toth, R and Blasco, MA and Rouse, J},
title = {Localization-dependent and -independent roles of SLX4 in regulating telomeres.},
journal = {Cell reports},
volume = {4},
number = {5},
pages = {853-860},
pmid = {23994477},
issn = {2211-1247},
support = {/WT_/Wellcome Trust/United Kingdom ; 232854/ERC_/European Research Council/International ; MC_U127070192/MRC_/Medical Research Council/United Kingdom ; MC_UU_12016/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Cell Line, Tumor ; *DNA Repair ; Humans ; Recombinases/*genetics/*metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {SLX4, a scaffold for structure-specific DNA repair nucleases, is important for several types of DNA repair. Many repair proteins bind to sites of DNA damage, resulting in subnuclear "foci," but SLX4 forms foci in human cells even without DNA damage. Using several approaches, we show that most, but not all, SLX4 foci localize to telomeres in a range of human cell lines irrespective of the mechanisms used to maintain telomere length. The SLX1 Holliday-junction-processing enzyme is recruited to telomeres by SLX4, and SLX4, in turn, is recruited by a motif that binds to the shelterin subunit TRF2 directly. We also show that TRF2-dependent recruitment of SLX4 prevents telomere damage. Furthermore, SLX4 prevents telomere lengthening and fragility in a manner that appears to be independent of telomere association. These findings reveal that SLX4 plays multiple roles in regulating telomere homeostasis.},
}
@article {pmid23993228,
year = {2013},
author = {Batista, LF and Artandi, SE},
title = {Understanding telomere diseases through analysis of patient-derived iPS cells.},
journal = {Current opinion in genetics &amp; development},
volume = {23},
number = {5},
pages = {526-533},
pmid = {23993228},
issn = {1879-0380},
support = {AG036695/AG/NIA NIH HHS/United States ; P01 AG036695/AG/NIA NIH HHS/United States ; K99 HL114732/HL/NHLBI NIH HHS/United States ; K99HL114732/HL/NHLBI NIH HHS/United States ; R01 CA125453/CA/NCI NIH HHS/United States ; R01 AG033747/AG/NIA NIH HHS/United States ; CA125453/CA/NCI NIH HHS/United States ; CA111691/CA/NCI NIH HHS/United States ; R01 CA111691/CA/NCI NIH HHS/United States ; AG033747/AG/NIA NIH HHS/United States ; },
mesh = {Anemia, Aplastic/etiology/genetics/pathology ; Cell Division/*genetics ; Dyskeratosis Congenita/etiology/genetics/pathology ; Humans ; Induced Pluripotent Stem Cells/*cytology/metabolism ; Liver Cirrhosis/etiology/genetics/pathology ; Mutation ; Neoplasms/etiology/genetics/pathology ; Pulmonary Fibrosis/etiology/genetics/pathology ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {A unique characteristic of tissue stem cells is the ability to self-renew, a process that enables the life-long maintenance of many organs. Stem cell self-renewal is dependent in part on the synthesis of telomere repeats by the enzyme telomerase. Defects in telomerase and in genes in the telomere maintenance pathway result in diverse disease states, including dyskeratosis congenita, pulmonary fibrosis, aplastic anemia, liver cirrhosis and cancer. Many of these disease states share a tissue failure phenotype, such as loss of bone marrow cells or failure of pulmonary epithelium, suggesting that stem cell dysfunction is a common pathophysiological mechanism underlying these telomere diseases. Studies of telomere diseases in undifferentiated iPS cells have provided a quantitative relationship between the magnitude of biochemical defects in the telomerase pathway and disease severity in patients, thereby establishing a clear correlation between genotype and phenotype in telomere disease states. Modeling telomere diseases in iPS cells has also revealed diverse underlying disease mechanisms, including reduced telomerase catalytic activity, diminished assembly of the telomerase holoenzyme and impaired trafficking of the enzyme within the nucleus. These studies highlight the need for therapies tailored to the underlying biochemical defect in each class of patients.},
}
@article {pmid23990928,
year = {2013},
author = {Burke, LS and Hyland, PL and Pfeiffer, RM and Prescott, J and Wheeler, W and Mirabello, L and Savage, SA and Burdette, L and Yeager, M and Chanock, S and De Vivo, I and Tucker, MA and Goldstein, AM and Yang, XR},
title = {Telomere length and the risk of cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations.},
journal = {PloS one},
volume = {8},
number = {8},
pages = {e71121},
pmid = {23990928},
issn = {1932-6203},
mesh = {Adult ; Cyclin-Dependent Kinase Inhibitor p16/*genetics ; Female ; *Genetic Predisposition to Disease ; Genotype ; Germ-Line Mutation ; Humans ; Male ; Melanoma/*genetics/metabolism ; Middle Aged ; *Mutation ; Phenotype ; Pigmentation ; Polymorphism, Single Nucleotide ; Skin Neoplasms/*genetics/metabolism ; Sunlight ; Telomere/ultrastructure ; Melanoma, Cutaneous Malignant ; },
abstract = {INTRODUCTION: Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations.<br><br>MATERIALS AND METHODS: We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT.<br><br>RESULTS: We found that longer telomeres were associated with an increased risk of CMM (adjusted OR&#x200a;=&#x200a;2.81, 95% CI&#x200a;=&#x200a;1.02-7.72, P&#x200a;=&#x200a;0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P&#x200a;=&#x200a;0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P&#x200a;=&#x200a;0.002) after Bonferroni correction.<br><br>DISCUSSION: Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk.},
}
@article {pmid23990212,
year = {2013},
author = {Verhulst, S and Aviv, A and Benetos, A and Berenson, GS and Kark, JD},
title = {Do leukocyte telomere length dynamics depend on baseline telomere length? An analysis that corrects for 'regression to the mean'.},
journal = {European journal of epidemiology},
volume = {28},
number = {11},
pages = {859-866},
pmid = {23990212},
issn = {1573-7284},
support = {R01 AG016592/AG/NIA NIH HHS/United States ; R01-HD071180/HD/NICHD NIH HHS/United States ; AG16592/AG/NIA NIH HHS/United States ; AG030678/AG/NIA NIH HHS/United States ; },
mesh = {Age Factors ; Aging/*genetics ; Female ; Humans ; Leukocytes/*physiology ; Longitudinal Studies ; Male ; Population Surveillance ; Regression Analysis ; Sex Factors ; Telomere/*genetics/physiology ; },
abstract = {Leukocyte telomere length (LTL) shortens with age. Longitudinal studies have reported accelerated LTL attrition when baseline LTL is longer. However, the dependency of LTL attrition on baseline LTL might stem from a statistical artifact known as regression to the mean (RTM). To our knowledge no published study of LTL dynamics (LTL and its attrition rate) has corrected for this phenomenon. We illustrate the RTM effect using replicate LTL measurements, and show, using simulated data, how the RTM effect increases with a rise in stochastic measurement variation (representing LTL measurement error), resulting in spurious increasingly elevated dependencies of attrition on baseline values. In addition, we re-analyzed longitudinal LTL data collected from four study populations to test the hypothesis that LTL attrition depends on baseline LTL. We observed that the rate of LTL attrition was proportional to baseline LTL, but correction for the RTM effect reduced the slope of the relationship by 57% when measurement error was low (coefficient of variation ~2%). A modest but statistically significant effect remained however, indicating that high baseline LTL is associated with higher LTL attrition even when correcting for the RTM effect. Baseline LTL explained 1.3% of the variation in LTL attrition, but this effect, which differed significantly between the study samples, appeared to be primarily attributable to the association in men (3.7%).},
}
@article {pmid23988653,
year = {2013},
author = {Rehkopf, DH and Dow, WH and Rosero-Bixby, L and Lin, J and Epel, ES and Blackburn, EH},
title = {Longer leukocyte telomere length in Costa Rica's Nicoya Peninsula: a population-based study.},
journal = {Experimental gerontology},
volume = {48},
number = {11},
pages = {1266-1273},
pmid = {23988653},
issn = {1873-6815},
support = {072406/WT_/Wellcome Trust/United Kingdom ; R01 AG031716/AG/NIA NIH HHS/United States ; P30 AG012839/AG/NIA NIH HHS/United States ; P30AG012839/AG/NIA NIH HHS/United States ; R01AG031716/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*genetics ; Costa Rica ; Female ; Genetics, Population ; Humans ; Leukocytes/metabolism ; Longevity/*genetics ; Male ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Studies in humans suggest that leukocyte telomere length may act as a marker of biological aging. We investigated whether individuals in the Nicoya region of Costa Rica, known for exceptional longevity, had longer telomere length than those in other parts of the country. After controlling for age, age squared, rurality, rainy season and gender, the mean leukocyte telomere length in Nicoya was substantially longer (81 base pairs, p<0.05) than in other areas of Costa Rica, providing evidence of a biological pathway to which this notable longevity may be related. This relationship remains unchanged (79 base pairs, p<0.05) after statistically controlling for nineteen potential biological, dietary and social and demographic mediators. Thus the difference in the mean leukocyte telomere length that characterizes this unique region does not appear to be explainable by traditional behavioral and biological risk factors. More detailed examination of mean leukocyte telomere length by age shows that the regional telomere length difference declines at older ages.},
}
@article {pmid23988378,
year = {2013},
author = {Ocalewicz, K},
title = {Telomeres in fishes.},
journal = {Cytogenetic and genome research},
volume = {141},
number = {2-3},
pages = {114-125},
doi = {10.1159/000354278},
pmid = {23988378},
issn = {1424-859X},
mesh = {Animals ; Base Sequence ; Chromosomes/*genetics ; DNA Damage ; Fishes/*genetics ; Humans ; Telomere/*genetics ; },
abstract = {In fishes, as in other vertebrate species, the DNA component of the telomeres consists of the tandemly repeated TTAGGG motif. The length of the telomeric arrays in fishes ranges from 2 to 25 kb and shortens with age in some of the species. To date, chromosomal distribution of the telomeric DNA sequences has been examined in approximately 80 fish species of which about 42% show additional telomeric hybridization signals far from the chromosomal termini. Based on the chromosomal location, such internally located telomeric repeats may be classified into 4 categories: (1) telomeric DNA sequences located at the pericentromeric regions, (2) interstitial telomeric sites observed between centromeres and the bona fide telomeres, (3) telomeric DNA sequences that scatter along the nucleolus organizer regions, and (4) telomeric DNA repeats interspersed with the entire chromosomes. Most of the pericentromeric and interstitial telomeric sequences in fish are possible relicts of chromosome fusion events. The origin of the telomeric sequences co- localizing with the major rDNA sequences or scattered along the whole chromosomes is not clear. Internally located telomeric repeats are considered as 'hot spots' for recombination and thus may potentially increase the rates of chromosome breaks and rearrangements leading to the various chromosomal polymorphisms in fishes. FISH with telomeric probe applied to metaphase spreads of androgenetic specimens that hatched from eggs exposed to ionizing radiation before insemination enabled the detection of small radiation-induced fragments of maternal chromosomes. Remnants of the irradiated chromosomes were found to be ring chromosomes with the interstitial telomeric signals, telomerless rings, fragments with fused sister chromatids, and linear fragments with telomeres detected at both of their ends. The increasing availability of techniques enabling the study of fish telomeres and telomerase and the easy access to numerous fish species strongly confirm that these animals are promising models in research concerning the role of telomeres and telomerase in vertebrate aging, repair of ionizing radiation-induced DNA double strand breaks, and chromosomal rearrangements.},
}
@article {pmid23979016,
year = {2013},
author = {Min, JN and Tian, Y and Xiao, Y and Wu, L and Li, L and Chang, S},
title = {The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability.},
journal = {Cell research},
volume = {23},
number = {12},
pages = {1396-1413},
pmid = {23979016},
issn = {1748-7838},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; P01 CA097175/CA/NCI NIH HHS/United States ; CA097175/CA/NCI NIH HHS/United States ; R01 CA127945/CA/NCI NIH HHS/United States ; CA127945/CA/NCI NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; },
mesh = {Alleles ; Animals ; Cells, Cultured ; Cellular Senescence ; Chromatin/*metabolism ; Chromatin Assembly and Disassembly ; DNA Breaks, Double-Stranded ; DNA Helicases/deficiency/genetics/*metabolism ; DNA Repair ; DNA Replication/drug effects ; Fibroblasts/cytology/metabolism ; *Genomic Instability ; Hydroxyurea/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mutation ; Nucleic Acid Synthesis Inhibitors/pharmacology ; Telomere/*metabolism ; Tumor Suppressor Protein p53/deficiency/genetics/metabolism ; },
abstract = {The INO80 (inositol requiring mutant 80) chromatin remodeling complex plays important roles in transcriptional regulation and DNA replication and repair, and consists of several functional protein subunits, including the critical Ino80 ATPase catalytic subunit. While the function of INO80 has been studied in yeast and mammalian cell lines, we do not know how mIno80 contributes to the maintenance of genome stability to prevent cancer development in mice. Here, we use a conditional knockout approach to explore the cellular and organismal functions of mIno80. Deletion of mIno80 results in profound cellular proliferative defects and activation of p21-dependent cellular senescence. While mIno80 is required for efficient repair of DNA double strand breaks, its depletion did not impact upon the formation of γ-H2AX and 53BP1 DNA damage foci, or the activation of the ATM-CHK2-dependent DNA damage response. mIno80 deletion inhibited the generation of single-strand DNA, resulting in defects in homology-directed DNA repair (HDR) at telomeres. Fragile telomeres were prominent in mIno80(Δ/Δ) MEFs, suggesting that chromatin remodeling is required for efficient telomere replication. mIno80(-/-) mouse embryos die early during embryogenesis, while conditional deletion of mIno80 in adult mice results in weight loss and premature death. In a p53(-/-) tumor-prone background, mIno80 haploinsufficiency favored the development of sarcomas. Our studies suggest that the mIno80 chromatin remodeling complex plays important roles in telomere replication, HDR-mediated repair of dysfunctional telomeres, and maintenance of genome stability.},
}
@article {pmid23977114,
year = {2013},
author = {Yang, S and Counter, CM},
title = {Cell cycle regulated phosphorylation of the telomere-associated protein TIN2.},
journal = {PloS one},
volume = {8},
number = {8},
pages = {e71697},
pmid = {23977114},
issn = {1932-6203},
support = {R01 CA094184/CA/NCI NIH HHS/United States ; CA094184/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Antibodies, Phospho-Specific/metabolism ; *Cell Cycle/drug effects ; HeLa Cells ; Humans ; Mass Spectrometry ; Mitosis/drug effects ; Molecular Sequence Data ; Nocodazole/pharmacology ; Phosphorylation/drug effects ; Phosphoserine/metabolism ; Pteridines/pharmacology ; Ribosomal Protein S6 Kinases, 90-kDa/antagonists &amp; inhibitors/metabolism ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {The protein TIN2 is a member of telomere-binding protein complex that serves to cap and protect mammalian chromosome ends. As a number of proteins in this complex are phosphorylated in a cell cycle-dependent manner, we investigated whether TIN2 is modified by phosphorylation as well. We performed phospho-proteomic analysis of human TIN2, and identified two phosphorylated residues, serines 295 and 330. We demonstrated that both these sites were phosphorylated during mitosis in human cells, as detected by Phos-tag reagent and phosphorylation-specific antibodies. Phosphorylation of serines 295 and 330 appeared to be mediated, at least in part, by the mitotic kinase RSK2. Specifically, phosphorylation of TIN2 at both these residues was increased upon expression of RSK2 and reduced by an inhibitor of the RSK family of kinases. Moreover, RSK2 phosphorylated TIN2 in vitro. The identification of these specifically timed post-translational events during the cell cycle suggests a potential mitotic regulation of TIN2 by phosphorylation.},
}
@article {pmid23971624,
year = {2013},
author = {O'Bryan, JM and Woda, M and Co, M and Mathew, A and Rothman, AL},
title = {Telomere length dynamics in human memory T cells specific for viruses causing acute or latent infections.},
journal = {Immunity &amp; ageing : I &amp; A},
volume = {10},
number = {1},
pages = {37},
pmid = {23971624},
issn = {1742-4933},
support = {T32 AI007349/AI/NIAID NIH HHS/United States ; },
abstract = {BACKGROUND: Declining telomere length (TL) is associated with T cell senescence. While TL in naïve and memory T cells declines with increasing age, there is limited data on TL dynamics in virus-specific memory CD4+ T cells in healthy adults. We combined BrdU-labeling of virus-stimulated T cells followed with flow cytometry-fluorescent in situ hybridization for TL determination. We analyzed TL in T cells specific for several virus infections: non-recurring acute (vaccinia virus, VACV), recurring-acute (influenza A virus, IAV), and reactivating viruses (varicella-zoster virus, VZV, and cytomegalovirus, CMV) in 10 healthy subjects. Additionally, five subjects provided multiple blood samples separated by up to 10 years.<br><br>RESULTS: VACV- and CMV-specific T cells had longer average TL than IAV-specific CD4+ T cells. Although most virus-specific cells were CD45RA-, we observed a minor population of BrdU+ CD45RA+ T cells characterized by long telomeres. Longitudinal analysis demonstrated a slow decline in average TL in virus-specific T cells. However, in one subject, VZV reactivation led to an increase in average TL in VZV-specific memory T cells, suggesting a conversion of longer TL cells from the na&#xef;ve T cell repertoire.<br><br>CONCLUSIONS: TLs in memory CD4+ T cells in otherwise healthy adults are heterogeneous and follow distinct virus-specific kinetics. These findings suggests that the distribution of TL and the creation and maintenance of long TL memory T cells could be important for the persistence of long-lived T cell memory.},
}
@article {pmid23969227,
year = {2013},
author = {Biniossek, ML and Lechel, A and Rudolph, KL and Martens, UM and Zimmermann, S},
title = {Quantitative proteomic profiling of tumor cell response to telomere dysfunction using isotope-coded protein labeling (ICPL) reveals interaction network of candidate senescence markers.},
journal = {Journal of proteomics},
volume = {91},
number = {},
pages = {515-535},
doi = {10.1016/j.jprot.2013.08.007},
pmid = {23969227},
issn = {1876-7737},
mesh = {Animals ; Biomarkers, Tumor/metabolism ; Cell Line, Tumor ; *Cellular Senescence ; Colonic Neoplasms/*enzymology ; Cytoskeleton/metabolism ; Fibroblasts/metabolism ; Genes, Dominant ; Humans ; Mice ; Mice, Knockout ; Mitochondria/metabolism ; Mutation ; *Proteomics ; Ribosomes/metabolism ; Signal Transduction ; Telomerase/metabolism ; Telomere/*ultrastructure ; },
abstract = {UNLABELLED: Telomerase inhibition causes progressive telomere shortening and cellular senescence, which constitutes a universal barrier to tumor growth and therefore an attractive target for tumor therapy. To expand our previous studies, we investigated the global effects of telomere dysfunction on the proteome of tumor cells in order to find novel senescence biomarkers. Telomerase-deficient HCT-116 cell clones were analyzed by a quantitative proteomic approach using isotope-coded protein labeling (ICPL) and nanoflow-HPLC-MS/MS. Stringent reduction of the extensive proteomic data from this tumor cell model revealed a list of 59 markers including proteins identified in our former studies and a number of novel proteins involved in tumorigenesis and metastasis such as SFN, S100A4, ANXA2, and LGALS1. A loss of the chromatin protein HMGB2 was demonstrated not only in various telomerase-inhibited clones of different tumor cell lines, but also in normal human fibroblasts undergoing replicative senescence and in aging telomerase knockout mice. Impressively, a coherent and dense network of protein-protein interactions for the bulk of the markers and their implementation in signaling pathways involving key regulators for tumorigenesis were revealed. These results have an impact on the understanding of telomere- and senescence-related signal transduction in tumor cells in consideration of the general lack of senescence markers.<br><br>BIOLOGICAL SIGNIFICANCE: Induction of cellular senescence constitutes a potent concept for tumor therapy which interferes with immortalization and additional hallmarks of cancer. The application of a powerful quantitative proteomic approach using isotope-coded protein labeling to an approved model for senescence represented by telomerase inhibited tumor cells led to the identification of novel candidate biomarkers for telomere dysfunction and replicative senescence. Thereby, the identified markers not only fit in the context of the investigated processes with a relevance for additional hallmarks of cancer but are also involved in a strong interaction network and integrated in canonical pathways centered around key cancer-relevant proteins. These potential markers alone or in combination will significantly extend the view on telomere-associated signal transduction in tumor cells and contribute to the field of cellular senescence and aging in consideration of the general lack of biomarkers in this regard.},
}
@article {pmid23965999,
year = {2013},
author = {Lue, NF and Chan, J},
title = {Duplication and functional specialization of the telomere-capping protein Cdc13 in Candida species.},
journal = {The Journal of biological chemistry},
volume = {288},
number = {40},
pages = {29115-29123},
pmid = {23965999},
issn = {1083-351X},
support = {R01 GM062631/GM/NIGMS NIH HHS/United States ; GM062631/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Candida/genetics/*metabolism ; DNA, Fungal/metabolism ; Evolution, Molecular ; Fungal Proteins/chemistry/*genetics/*metabolism ; *Gene Duplication ; Glycerol/metabolism ; Models, Biological ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Telomere/*metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/chemistry/*genetics/*metabolism ; },
abstract = {The budding yeast G-tail binding complex CST (Cdc13-Stn1-Ten1) is crucial for both telomere protection and replication. Previous studies revealed a family of Cdc13 orthologues (Cdc13A) in Candida species that are unusually small but are nevertheless responsible for G-tail binding and the regulation of telomere lengths and structures. Here we report the identification and characterization of a second family of Cdc13-like proteins in the Candida clade, named Cdc13B. Phylogenetic analysis and sequence alignment indicate that Cdc13B probably arose through gene duplication prior to Candida speciation. Like Cdc13A, Cdc13B appears to be essential. Deleting one copy each of the CDC13A and CDC13B genes caused a synergistic effect on aberrant telomere elongation and t-circle accumulation, suggesting that the two paralogues mediate overlapping and nonredundant functions in telomere regulation. Interestingly, Cdc13B utilizes its C-terminal OB-fold domain (OB4) to mediate self-association and binding to Cdc13A. Moreover, the stability of the heterodimer is evidently greater than that of either homodimer. Both the Cdc13 A/A homodimer and A/B heterodimer, but not the B/B homodimer, recognized the telomere G-tail repeat with high affinity and sequence specificity. Our results reveal novel evolutionary elaborations of the G-tail-binding protein in Saccharomycotina yeast, suggesting a drastic remodeling of CDC13 that entails gene duplication, fusion, and functional specialization. The repeated and independent duplication of G-tail-binding proteins such as Cdc13 and Pot1 hints at the evolutionary advantage of having multiple G-tail-binding proteins.},
}
@article {pmid23963699,
year = {2013},
author = {Diolaiti, ME and Cimini, BA and Kageyama, R and Charles, FA and Stohr, BA},
title = {In situ visualization of telomere elongation patterns in human cells.},
journal = {Nucleic acids research},
volume = {41},
number = {18},
pages = {e176},
pmid = {23963699},
issn = {1362-4962},
support = {K08 CA134552/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line ; Cell Line, Tumor ; Cell Nucleus/genetics ; DNA/chemistry ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Mutation ; RNA-Directed DNA Polymerase/genetics/metabolism ; Real-Time Polymerase Chain Reaction ; Repetitive Sequences, Nucleic Acid ; Telomere/chemistry ; *Telomere Homeostasis ; },
abstract = {The telomerase enzyme plays a critical role in human aging and cancer biology by maintaining telomere length and extending the proliferative lifespan of most stem cells and cancer cells. Despite the importance of this enzyme, our understanding of the mechanisms that regulate its activity and establish telomere length homeostasis in mammalian cells is incomplete, in part because the perfect repetitive nature of telomeric sequence hampers in situ detection of telomere elongation patterns. Here, we describe a novel assay using a mutant telomerase that adds a well-tolerated variant telomeric repeat sequence to telomere ends. By specifically detecting the addition of these variant repeats, we can directly visualize telomere elongation events in human cells. We validate this approach by in situ mapping of telomere elongation patterns within individual nuclei and across a population of cells.},
}
@article {pmid23963457,
year = {2013},
author = {Budd, ME and Campbell, JL},
title = {Dna2 is involved in CA strand resection and nascent lagging strand completion at native yeast telomeres.},
journal = {The Journal of biological chemistry},
volume = {288},
number = {41},
pages = {29414-29429},
pmid = {23963457},
issn = {1083-351X},
support = {R01 GM078666/GM/NIGMS NIH HHS/United States ; GM078666/GM/NIGMS NIH HHS/United States ; },
mesh = {Acetyltransferases/genetics/metabolism ; DNA Breaks, Double-Stranded ; DNA Helicases/*genetics/metabolism ; DNA Repair ; DNA, Fungal/*genetics/metabolism ; DNA, Single-Stranded/genetics/metabolism ; Electrophoresis, Agar Gel ; Endodeoxyribonucleases/genetics/metabolism ; Exodeoxyribonucleases/genetics/metabolism ; Flow Cytometry ; Membrane Proteins/genetics/metabolism ; Mutation ; Protein Binding ; S Phase/genetics ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Post-replicational telomere end processing involves both extension by telomerase and resection to produce 3'-GT-overhangs that extend beyond the complementary 5'-CA-rich strand. Resection must be carefully controlled to maintain telomere length. At short de novo telomeres generated artificially by HO endonuclease in the G2 phase, we show that dna2-defective strains are impaired in both telomere elongation and sequential 5'-CA resection. At native telomeres in dna2 mutants, GT-overhangs do clearly elongate during late S phase but are shorter than in wild type, suggesting a role for Dna2 in 5'-CA resection but also indicating significant redundancy with other nucleases. Surprisingly, elimination of Mre11 nuclease or Exo1, which are complementary to Dna2 in resection of internal double strand breaks, does not lead to further shortening of GT-overhangs in dna2 mutants. A second step in end processing involves filling in of the CA-strand to maintain appropriate telomere length. We show that Dna2 is required for normal telomeric CA-strand fill-in. Yeast dna2 mutants, like mutants in DNA ligase 1 (cdc9), accumulate low molecular weight, nascent lagging strand DNA replication intermediates at telomeres. Based on this and other results, we propose that FEN1 is not sufficient and that either Dna2 or Exo1 is required to supplement FEN1 in maturing lagging strands at telomeres. Telomeres may be among the subset of genomic locations where Dna2 helicase/nuclease is essential for the two-nuclease pathway of primer processing on lagging strands.},
}
@article {pmid23959892,
year = {2013},
author = {Deng, Z and Glousker, G and Molczan, A and Fox, AJ and Lamm, N and Dheekollu, J and Weizman, OE and Schertzer, M and Wang, Z and Vladimirova, O and Schug, J and Aker, M and Londoño-Vallejo, A and Kaestner, KH and Lieberman, PM and Tzfati, Y},
title = {Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal-Hreidarsson syndrome.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {110},
number = {36},
pages = {E3408-16},
pmid = {23959892},
issn = {1091-6490},
support = {P30 CA010815/CA/NCI NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; P30 CA10815/CA/NCI NIH HHS/United States ; R01CA140652/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Blotting, Western ; Cell Proliferation ; Cells, Cultured ; DNA Helicases/*genetics/metabolism ; Dyskeratosis Congenita/*genetics/metabolism/pathology ; Family Health ; Female ; Fetal Growth Retardation/*genetics/metabolism/pathology ; Gene Expression ; Genomic Instability/genetics ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Intellectual Disability/*genetics/metabolism/pathology ; Male ; Mice ; Microcephaly/*genetics/metabolism/pathology ; *Mutation ; Pedigree ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*genetics ; Telomere Shortening/genetics ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; },
abstract = {Telomeres repress the DNA damage response at the natural chromosome ends to prevent cell-cycle arrest and maintain genome stability. Telomeres are elongated by telomerase in a tightly regulated manner to ensure a sufficient number of cell divisions throughout life, yet prevent unlimited cell division and cancer development. Hoyeraal-Hreidarsson syndrome (HHS) is characterized by accelerated telomere shortening and a broad range of pathologies, including bone marrow failure, immunodeficiency, and developmental defects. HHS-causing mutations have previously been found in telomerase and the shelterin component telomeric repeat binding factor 1 (TRF1)-interacting nuclear factor 2 (TIN2). We identified by whole-genome exome sequencing compound heterozygous mutations in four siblings affected with HHS, in the gene encoding the regulator of telomere elongation helicase 1 (RTEL1). Rtel1 was identified in mouse by its genetic association with telomere length. However, its mechanism of action and whether it regulates telomere length in human remained unknown. Lymphoblastoid cell lines obtained from a patient and from the healthy parents carrying heterozygous RTEL1 mutations displayed telomere shortening, fragility and fusion, and growth defects in culture. Ectopic expression of WT RTEL1 suppressed the telomere shortening and growth defect, confirming the causal role of the RTEL1 mutations in HHS and demonstrating the essential function of human RTEL1 in telomere protection and elongation. Finally, we show that human RTEL1 interacts with the shelterin protein TRF1, providing a potential recruitment mechanism of RTEL1 to telomeres.},
}
@article {pmid23956466,
year = {2013},
author = {Calado, RT and Dumitriu, B},
title = {Telomere dynamics in mice and humans.},
journal = {Seminars in hematology},
volume = {50},
number = {2},
pages = {165-174},
pmid = {23956466},
issn = {1532-8686},
support = {Z99 HL999999//Intramural NIH HHS/United States ; },
mesh = {Aging ; Animals ; Humans ; Mice ; Mutation ; Neoplasms/genetics/metabolism ; Phenotype ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are ribonucleoprotein structures capping the end of every linear chromosome. In all vertebrates, they are composed of TTAGGG repeats coated with specific protecting proteins. Telomeres shorten with each mitotic cell division, but telomerase, a reverse transcriptase, elongate telomeres in very specific cells, such as embryonic and adult stem cells. Although telomere sequence is identical in mice and humans and telomeres serve the same role of protecting chromosomes and genetic information from damage and erosion in both species, abnormalities in telomere maintenance and in telomerase function do not coincide in phenotype in humans and mice. The telomeres of most laboratory mice are 5 to 10 times longer than in humans, but their lifespan is 30 times shorter. Complete absence of telomerase has little expression in phenotype over several generations in mice, whereas heterozygosity for telomerase mutations in humans is sufficient to result in organ regeneration defect and cancer development. Patients with telomerase deficiency and very short telomeres may develop aplastic anemia, pulmonary fibrosis, or cirrhosis, whereas telomerase-null murine models display only modest hematopoietic deficiency and develop emphysema when exposed to cigarette smoke. In summary, telomerase deficiency in both humans and mice accelerate telomere shortening, but its consequences in the different organs and in the organism diverge, mainly due to telomere length differences.},
}
@article {pmid23955078,
year = {2014},
author = {Leufke, C and Leykauf, J and Krunic, D and Jauch, A and Holtgreve-Grez, H and Böhm-Steuer, B and Bröcker, EB and Mauch, C and Utikal, J and Hartschuh, W and Purdie, KJ and Boukamp, P},
title = {The telomere profile distinguishes two classes of genetically distinct cutaneous squamous cell carcinomas.},
journal = {Oncogene},
volume = {33},
number = {27},
pages = {3506-3518},
doi = {10.1038/onc.2013.323},
pmid = {23955078},
issn = {1476-5594},
support = {13044/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Squamous Cell/*classification/enzymology/*genetics/pathology ; Cell Line, Tumor ; Child ; Cyclin D1/metabolism ; Disease Progression ; Genomic Instability/radiation effects ; Humans ; Male ; Melanoma/enzymology/genetics/pathology ; Middle Aged ; Skin Neoplasms/*classification/enzymology/*genetics/pathology ; Telomerase/metabolism ; Telomere/*genetics/radiation effects ; Tumor Suppressor Protein p53/metabolism ; Ultraviolet Rays ; Young Adult ; },
abstract = {The incidence of skin cancer is increasing worldwide and cutaneous squamous cell carcinomas (SCCs) are associated with considerable morbidity and mortality, particularly in immunosuppressed individuals ('carcinomatous catastrophy'). Yet, molecular mechanisms are still insufficiently understood. Besides ultraviolet (UV)-indicative mutations, chromosomal aberrations are prominent. As telomeres are essential in preserving chromosome integrity, and telomere erosion as well as aberrant spatial telomere distribution contribute to genomic instability, we first established telomere length profiles across the whole tissue and identified normal skin (10/30) harboring discrete epidermal sites (stem cell territories) of evenly short telomeres. Precancerous actinic keratoses (AKs) (17) and SCCs (27) expressed two telomere phenotypes: (i) tissue-wide evenly short to intermediate and (ii) longer and tissue-wide heterogeneous telomere lengths, suggesting two modes of initiation, with one likely to originate in the epidermal stem cells. Although tumor histotype, location, patient gender or age failed to distinguish the two SCC telomere phenotypes, as did telomerase activity, we found a trend for a higher degree of aberrant p53 and cyclin D1 expression with long/heterogeneous telomeres. In addition, we established an association for the short/homogeneous telomeres with a simpler and the heterogeneous telomeres with a more complex karyotype correlating also with distinct chromosomal changes. SCCs (13) from renal transplant recipients displayed the same telomere dichotomy, suggesting that both telomere subtypes contribute to 'carcinomatous catastrophy' under immunosuppression by selecting for a common set (3, 9p and 17q) and subtype-specific aberrations (e.g., 6p gain, 13q loss). As a second mechanism of telomere-dependent genomic instability, we investigated changes in telomere distribution with its most severe form of telomeric aggregates (TAs). We identified a telomere length-independent but progression-dependent increase in cells with small telomere associations in AKs (17/17) and additional TAs in SCCs (24/32), basal cell carcinomas (30/31) and malignant melanomas (15/15), and provide evidence for a reactive oxygen species-dependent mechanism in this UV-induced telomere organization-dependent genomic instability.},
}
@article {pmid23954395,
year = {2013},
author = {Kiecolt-Glaser, JK and Jaremka, LM and Derry, HM and Glaser, R},
title = {Telomere length: a marker of disease susceptibility?.},
journal = {Brain, behavior, and immunity},
volume = {34},
number = {},
pages = {29-30},
pmid = {23954395},
issn = {1090-2139},
support = {AG038621/AG/NIA NIH HHS/United States ; CA16058/CA/NCI NIH HHS/United States ; R01 CA131029/CA/NCI NIH HHS/United States ; UL1RR025755/RR/NCRR NIH HHS/United States ; R21 CA158868/CA/NCI NIH HHS/United States ; CA131029/CA/NCI NIH HHS/United States ; CA158868/CA/NCI NIH HHS/United States ; R01 AG038621/AG/NIA NIH HHS/United States ; UL1 RR025755/RR/NCRR NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; CA172296/CA/NCI NIH HHS/United States ; K05 CA172296/CA/NCI NIH HHS/United States ; },
mesh = {Common Cold/*genetics ; Female ; Humans ; Male ; Respiratory Tract Infections/*genetics ; *Telomere Shortening ; },
}
@article {pmid23949319,
year = {2014},
author = {Zhao, J and Zhu, Y and Lin, J and Matsuguchi, T and Blackburn, E and Zhang, Y and Cole, SA and Best, LG and Lee, ET and Howard, BV},
title = {Short leukocyte telomere length predicts risk of diabetes in american indians: the strong heart family study.},
journal = {Diabetes},
volume = {63},
number = {1},
pages = {354-362},
pmid = {23949319},
issn = {1939-327X},
support = {R01DK091369/DK/NIDDK NIH HHS/United States ; U01 HL041642/HL/NHLBI NIH HHS/United States ; U01 HL041654/HL/NHLBI NIH HHS/United States ; K01 AG034259/AG/NIA NIH HHS/United States ; U01 HL041652/HL/NHLBI NIH HHS/United States ; U01HL41642/HL/NHLBI NIH HHS/United States ; U01HL65521/HL/NHLBI NIH HHS/United States ; R21HL092363/HL/NHLBI NIH HHS/United States ; K01AG034259/AG/NIA NIH HHS/United States ; U01 HL065521/HL/NHLBI NIH HHS/United States ; U01HL41654/HL/NHLBI NIH HHS/United States ; R01 HL109301/HL/NHLBI NIH HHS/United States ; U01 HL065520/HL/NHLBI NIH HHS/United States ; R01 DK091369/DK/NIDDK NIH HHS/United States ; U01HL41652/HL/NHLBI NIH HHS/United States ; R21 HL092363/HL/NHLBI NIH HHS/United States ; U01HL65520/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Cellular Senescence/genetics ; Diabetes Mellitus, Type 2/epidemiology/*genetics ; Female ; Humans ; Incidence ; Indians, North American/*genetics ; *Leukocytes ; Male ; Middle Aged ; Risk ; Telomere Shortening/*genetics ; },
abstract = {Telomeres play a central role in cellular aging, and shorter telomere length has been associated with age-related disorders including diabetes. However, a causal link between telomere shortening and diabetes risk has not been established. In a well-characterized longitudinal cohort of American Indians participating in the Strong Heart Family Study, we examined whether leukocyte telomere length (LTL) at baseline predicts incident diabetes independent of known diabetes risk factors. Among 2,328 participants free of diabetes at baseline, 292 subjects developed diabetes during an average 5.5 years of follow-up. Compared with subjects in the highest quartile (longest) of LTL, those in the lowest quartile (shortest) had an almost twofold increased risk of incident diabetes (hazard ratio [HR] 1.83 [95% CI 1.26-2.66]), whereas the risk for those in the second (HR 0.87 [95% CI 0.59-1.29]) and the third (HR 0.95 [95% CI 0.65-1.38]) quartiles was statistically nonsignificant. These findings suggest a nonlinear association between LTL and incident diabetes and indicate that LTL could serve as a predictive marker for diabetes development in American Indians, who suffer from disproportionately high rates of diabetes.},
}
@article {pmid23946336,
year = {2014},
author = {Elbers, CC and Garcia, ME and Kimura, M and Cummings, SR and Nalls, MA and Newman, AB and Park, V and Sanders, JL and Tranah, GJ and Tishkoff, SA and Harris, TB and Aviv, A},
title = {Comparison between southern blots and qPCR analysis of leukocyte telomere length in the health ABC study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {69},
number = {5},
pages = {527-531},
pmid = {23946336},
issn = {1758-535X},
support = {N01 AG062101/AG/NIA NIH HHS/United States ; P30 AG024827/AG/NIA NIH HHS/United States ; R01AG030678/AG/NIA NIH HHS/United States ; R01HD071180/HD/NICHD NIH HHS/United States ; },
mesh = {Black or African American ; Aged ; Aging ; *Blotting, Southern ; Body Composition ; Female ; Humans ; Leukocytes/*physiology ; Male ; *Real-Time Polymerase Chain Reaction ; Telomere/*physiology ; White People ; },
abstract = {Only a few studies, primarily limited to small samples, have examined the relationship between leukocyte telomere length (LTL) data generated by Southern blots, expressed in kilobases, versus quantitative PCR data, expressed in the telomere product/a single gene product (T/S). In the present study, we compared LTL data generated by the two methods in 681 elderly participants (50% African Americans, 50% of European origin, 49.2% women, mean age 73.7±2.9 years) in the Health Aging and Body Composition Study. The correlation between the data generated by the two methods was modest (R (2) = .27). Both methods captured the age effect on LTL and the longer LTL in women than in men. However, only the Southern blot method showed a significantly longer LTL in African Americans than in European decent individuals, which might be attributed to the larger measurement error of the quantitative PCR-based method than the Southern blots.},
}
@article {pmid23946118,
year = {2013},
author = {Alder, JK and Parry, EM and Yegnasubramanian, S and Wagner, CL and Lieblich, LM and Auerbach, R and Auerbach, AD and Wheelan, SJ and Armanios, M},
title = {Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene.},
journal = {Human mutation},
volume = {34},
number = {11},
pages = {1481-1485},
pmid = {23946118},
issn = {1098-1004},
support = {R01 CA160433/CA/NCI NIH HHS/United States ; K99 HL113105/HL/NHLBI NIH HHS/United States ; R01CA160433/CA/NCI NIH HHS/United States ; K99HL113105/HL/NHLBI NIH HHS/United States ; P30CA006973/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Cell Cycle Proteins/chemistry/*genetics ; Dyskeratosis Congenita/diagnosis/*genetics ; Female ; *Heterozygote ; Humans ; Male ; Middle Aged ; Molecular Sequence Data ; *Mutation ; Nuclear Proteins/chemistry/*genetics ; *Phenotype ; Sequence Alignment ; Telomere/*genetics ; },
abstract = {Dyskeratosis congenita (DC) is a telomere-mediated syndrome defined by mucocutaneous features. The X-linked mode of inheritance accounts for half the cases, and is thought to predominantly manifest in childhood as bone marrow failure. We identified two male probands who presented in the fifth decade with idiopathic pulmonary fibrosis and cancer. Their pedigrees displayed consecutively affected generations. Five of six females (83%) manifested mucocutaneous features of DC, and two had wound-healing complications. No mutations in autosomal dominant telomere genes were present, but exome sequencing revealed novel variants in the X-chromosome DKC1 gene that predicted missense mutations in conserved residues, p.Thr49Ser and p.Pro409Arg. Variants segregated with the telomere phenotype, and affected females were heterozygotes, showing skewed X-inactivation. Telomerase RNA levels were compromised in cells from DKC1 mutation carriers, consistent with their pathogenic role. These findings indicate that females with heterozygous DKC1 mutations may be at increased risk for developing penetrant telomere phenotypes that, at times, may be associated with clinical morbidity.},
}
@article {pmid23945210,
year = {2013},
author = {Mizutani, Y and Tomita, N and Niizuma, Y and Yoda, K},
title = {Environmental perturbations influence telomere dynamics in long-lived birds in their natural habitat.},
journal = {Biology letters},
volume = {9},
number = {5},
pages = {20130511},
pmid = {23945210},
issn = {1744-957X},
mesh = {Animals ; Charadriiformes/*genetics/physiology ; *Ecosystem ; Female ; Japan ; Longevity/genetics ; Male ; *Telomere ; },
abstract = {Telomeres are regarded as markers of biological or cellular ageing because they shorten with the degree of stress exposure. Accordingly, telomere lengths should show different rates of change when animals are faced with different intensities of environmental challenges. However, a relationship between telomere length and the environment has not yet been tested within a natural setting. Here, we report longitudinal telomere dynamics in free-living, black-tailed gulls (Larus crassirostris) through the recapture of birds of a known age over 2-5 consecutive years. The rate of change in telomere lengths differed with respect to year but not sex or age. The years when gulls showed stable telomere lengths or increases in telomere lengths (from 2009 to 2010) and decreases in telomere lengths (from 2010 to 2011) were characterized by El Niño and the Great Japan Earthquake, respectively. Both events are suspected to have had long-lasting effects on food availability and/or weather conditions. Thus, our findings that telomere dynamics in long-lived birds are influenced by dramatic changes in environmental conditions highlight the importance of environmental fluctuations in affecting stress and lifespan.},
}
@article {pmid23938394,
year = {2013},
author = {Saeed, H and Iqtedar, M},
title = {Stem cell function and maintenance - ends that matter: role of telomeres and telomerase.},
journal = {Journal of biosciences},
volume = {38},
number = {3},
pages = {641-649},
pmid = {23938394},
issn = {0973-7138},
mesh = {Aging/*genetics/pathology ; Animals ; Humans ; Neoplastic Stem Cells/pathology ; Stem Cells/pathology/*physiology ; Telomerase/*genetics/metabolism ; Telomere/*genetics ; },
abstract = {Stem cell research holds a promise to treat and prevent age-related degenerative changes in humans. Literature is replete with studies showing that stem cell function declines with aging, especially in highly proliferative tissues/ organs. Among others, telomerase and telomere damage is one of the intrinsic physical instigators that drive agerelated degenerative changes. In this review we provide brief overview of telomerase-deficient aging affects in diverse stem cells populations. Furthermore, potential disease phenotypes associated with telomerase dysregulation in a specific stem cell population is also discussed in this review. Additionally, the role of telomerase in stem cell driven cancer is also briefly touched upon.},
}
@article {pmid23937625,
year = {2013},
author = {Aulinas, A and Ramírez, MJ and Barahona, MJ and Mato, E and Bell, O and Surrallés, J and Webb, SM},
title = {Telomeres and endocrine dysfunction of the adrenal and GH/IGF-1 axes.},
journal = {Clinical endocrinology},
volume = {79},
number = {6},
pages = {751-759},
doi = {10.1111/cen.12310},
pmid = {23937625},
issn = {1365-2265},
mesh = {Aging/physiology ; Human Growth Hormone/*physiology ; Humans ; Hypothalamo-Hypophyseal System/physiopathology ; Insulin-Like Growth Factor I/*physiology ; Models, Biological ; Oxidative Stress ; Pituitary-Adrenal System/*physiopathology ; Stress, Psychological ; Telomere/*physiology ; Telomere Homeostasis/physiology ; },
abstract = {Telomeres, located at the end of linear chromosomes, are essential to maintain genomic stability. Telomere biology has recently emerged as an important player in the fields of ageing and disease. To maintain telomere length (TL) and reduce its degradation after mitosis, the telomerase enzyme complex is produced. Genetic, epigenetic, hormonal and environmental factors can regulate telomerase function. These include stress hormones such as cortisol and growth factors. The hypothalamic-pituitary-adrenal (HPA) axis has been evaluated in psychiatric diseases where hypercortisolism and oxidative stress are often present. Some researches have linked TL shortening to increases in stress-related cortisol, but others have not. The effects of cortisol on the telomere system are complex and may depend on the intensity and duration of exposure. On the other hand, low levels of IGF-1 are associated with inflammation and ageing-related diseases (ischaemic heart disease, congestive heart failure). Both IGF-1 and TL diminish with age and are positively and strongly correlated with each other. It is not clear whether this positive correlation reflects a single association or a cause-effect relationship. Further research will ideally investigate longitudinal changes in telomeres and both these hormonal axes. To our knowledge, TL dysfunction has not been described in either endogenous hypercortisolism (Cushing's syndrome) or acromegaly where excessive amounts of GH and consequently IGF-1 are produced. This review focuses on the possible relationships between telomere dysfunction and the hypothalamic-pituitary-adrenal (HPA) axis and GH-IGF-1 system.},
}
@article {pmid23936074,
year = {2013},
author = {Castillo, AG and Pidoux, AL and Catania, S and Durand-Dubief, M and Choi, ES and Hamilton, G and Ekwall, K and Allshire, RC},
title = {Telomeric repeats facilitate CENP-A(Cnp1) incorporation via telomere binding proteins.},
journal = {PloS one},
volume = {8},
number = {7},
pages = {e69673},
pmid = {23936074},
issn = {1932-6203},
support = {//Wellcome Trust/United Kingdom ; 065061//Wellcome Trust/United Kingdom ; 095021//Wellcome Trust/United Kingdom ; 092076/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Blotting, Western ; Centromere/genetics/metabolism ; Chromatin/genetics/metabolism ; Chromosomal Proteins, Non-Histone/*genetics/metabolism ; Chromosomes, Fungal/genetics/metabolism ; DNA, Ribosomal/genetics/metabolism ; Gene Expression Profiling ; Gene Expression Regulation, Fungal ; Heterochromatin/genetics/metabolism ; Histones/metabolism ; Lysine/metabolism ; Methylation ; Repetitive Sequences, Nucleic Acid/*genetics ; Schizosaccharomyces/genetics/metabolism ; Schizosaccharomyces pombe Proteins/*genetics/metabolism ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {The histone H3 variant, CENP-A, is normally assembled upon canonical centromeric sequences, but there is no apparent obligate coupling of sequence and assembly, suggesting that centromere location can be epigenetically determined. To explore the tolerances and constraints on CENP-A deposition we investigated whether certain locations are favoured when additional CENP-A(Cnp1) is present in fission yeast cells. Our analyses show that additional CENP-A(Cnp1) accumulates within and close to heterochromatic centromeric outer repeats, and over regions adjacent to rDNA and telomeres. The use of minichromosome derivatives with unique DNA sequences internal to chromosome ends shows that telomeres are sufficient to direct CENP-A(Cnp1) deposition. However, chromosome ends are not required as CENP-A(Cnp1) deposition also occurs at telomere repeats inserted at an internal locus and correlates with the presence of H3K9 methylation near these repeats. The Ccq1 protein, which is known to bind telomere repeats and recruit telomerase, was found to be required to induce H3K9 methylation and thus promote the incorporation of CENP-A(Cnp1) near telomere repeats. These analyses demonstrate that at non-centromeric chromosomal locations the presence of heterochromatin influences the sites at which CENP-A is incorporated into chromatin and, thus, potentially the location of centromeres.},
}
@article {pmid23936000,
year = {2013},
author = {Denham, J and Nelson, CP and O'Brien, BJ and Nankervis, SA and Denniff, M and Harvey, JT and Marques, FZ and Codd, V and Zukowska-Szczechowska, E and Samani, NJ and Tomaszewski, M and Charchar, FJ},
title = {Longer leukocyte telomeres are associated with ultra-endurance exercise independent of cardiovascular risk factors.},
journal = {PloS one},
volume = {8},
number = {7},
pages = {e69377},
pmid = {23936000},
issn = {1932-6203},
support = {PG/12/9/29376//British Heart Foundation/United Kingdom ; },
mesh = {Adult ; Aging/genetics ; Blood Pressure/physiology ; Body Mass Index ; C-Reactive Protein/metabolism ; Cardiovascular Diseases/blood/genetics/physiopathology ; Cholesterol/blood ; Cholesterol, HDL/blood ; E-Selectin/blood ; *Exercise ; Humans ; Intercellular Adhesion Molecule-1/blood ; Interleukin-6/blood ; Leptin/blood ; Leukocytes/*metabolism ; Linear Models ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Risk Factors ; *Running ; Telomere/*genetics ; Triglycerides/blood ; },
abstract = {Telomere length is recognized as a marker of biological age, and shorter mean leukocyte telomere length is associated with increased risk of cardiovascular disease. It is unclear whether repeated exposure to ultra-endurance aerobic exercise is beneficial or detrimental in the long-term and whether it attenuates biological aging. We quantified 67 ultra-marathon runners' and 56 apparently healthy males' leukocyte telomere length (T/S ratio) using real-time quantitative PCR. The ultra-marathon runners had 11% longer telomeres (T/S ratio) than controls (ultra-marathon runners: T/S ratio = 3.5±0.68, controls: T/S ratio = 3.1±0.41; β = 0.40, SE = 0.10, P = 1.4×10(-4)) in age-adjusted analysis. The difference remained statistically significant after adjustment for cardiovascular risk factors (P = 2.2×10(-4)). The magnitude of this association translates into 16.2±0.26 years difference in biological age and approximately 324-648bp difference in leukocyte telomere length between ultra-marathon runners and healthy controls. Neither traditional cardiovascular risk factors nor markers of inflammation/adhesion molecules explained the difference in leukocyte telomere length between ultra-marathon runners and controls. Taken together these data suggest that regular engagement in ultra-endurance aerobic exercise attenuates cellular aging.},
}
@article {pmid23929129,
year = {2013},
author = {Terai, M and Izumiyama-Shimomura, N and Aida, J and Ishikawa, N and Sawabe, M and Arai, T and Fujiwara, M and Ishii, A and Nakamura, K and Takubo, K},
title = {Association of telomere shortening in myocardium with heart weight gain and cause of death.},
journal = {Scientific reports},
volume = {3},
number = {},
pages = {2401},
pmid = {23929129},
issn = {2045-2322},
mesh = {Adult ; Age Distribution ; Aged ; Aged, 80 and over ; Aging/*genetics ; Cause of Death ; Female ; Heart/*physiopathology ; Heart Diseases/*mortality/*physiopathology ; Humans ; Incidence ; Japan/epidemiology ; Male ; Middle Aged ; Organ Size/genetics ; Risk Factors ; Survival Rate ; Telomere Shortening/*genetics ; },
abstract = {We attempted to clarify myocardial telomere dynamics using samples from 530 autopsied patients using Southern blot analysis. Overall regression analysis demonstrated yearly telomere reduction rate of 20 base pairs in the myocardium. There was a significant correlation between myocardial telomere and aging. Moreover, regression analyses of telomere and heart weight yielded a telomere reduction rate of 3 base pairs per gram, and a small but significant correlation between telomere reduction and heart weight was demonstrated. Hearts of autopsied patients who had died of heart disease were significantly heavier than those of patients who had died of cancer or other diseases, and heart disease was significantly more correlated with myocardial telomere shortening than cancer or other diseases. Here we show that telomeres in myocardial tissue become shortened with aging and heart disease, and that heart disease was associated with a gain of heart weight and telomere shortening in the myocardium.},
}
@article {pmid23928994,
year = {2013},
author = {Zhang, Y and Sturgis, EM and Dahlstrom, KR and Wen, J and Liu, H and Wei, Q and Li, G and Liu, Z},
title = {Telomere length in peripheral blood lymphocytes contributes to the development of HPV-associated oropharyngeal carcinoma.},
journal = {Cancer research},
volume = {73},
number = {19},
pages = {5996-6003},
pmid = {23928994},
issn = {1538-7445},
support = {R01 CA131274/CA/NCI NIH HHS/United States ; K12 CA088084/CA/NCI NIH HHS/United States ; R01 ES011740/ES/NIEHS NIH HHS/United States ; ES 011740/ES/NIEHS NIH HHS/United States ; K07 CA133099/CA/NCI NIH HHS/United States ; K-12 CA88084/CA/NCI NIH HHS/United States ; CA133099/CA/NCI NIH HHS/United States ; CA135679/CA/NCI NIH HHS/United States ; CA131274/CA/NCI NIH HHS/United States ; R03 CA135679/CA/NCI NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; R25 CA057730/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Carcinoma, Squamous Cell/*etiology/pathology ; Case-Control Studies ; Female ; Follow-Up Studies ; Human papillomavirus 16/genetics ; Humans ; Lymphocytes/*pathology/virology ; Male ; Middle Aged ; Mouth Neoplasms/*etiology/pathology ; Oropharyngeal Neoplasms/*etiology/pathology ; Papillomavirus Infections/complications/genetics/virology ; Prognosis ; Telomere Homeostasis/*genetics ; },
abstract = {Sexual transmission of human papillomavirus (HPV), particularly HPV16, has been associated with an increasing incidence of oropharyngeal squamous cell carcinoma (OPC). Telomere shortening results in chromosomal instability, subsequently leading to cancer development. Given that HPV16 can affect telomerase activity and telomere length, we conjectured that telomere length in peripheral blood lymphocytes (PBL) might affect the risk of HPV16-associated OPC and tumor HPV16 status in patients. Telomere length in PBLs and HPV16 serologic status were measured in peripheral blood samples in 188 patients with OPC, 137 patients with oral cavity cancer (OCC) and 335 controls of non-Hispanic Whites. Tumor HPV status was determined in 349 OPC cases. ORs and 95% confidence intervals were calculated in univariate and multivariable logistic regression models. Overall, as compared with the long telomere length, short telomere length was significantly associated with a moderately increased risk of OPC but not with increased risk of OCC. When we stratified the data by HPV16 serologic status, using long telomere length and HPV16 seronegativity as the reference group, we found that the risk associated with HPV16 seropositivity was higher among patients with OPC with short telomere length. Notably, such risk was particularly pronounced in never smokers, never drinkers, and those more than 50 years of age. Furthermore, short telomere length was also associated significantly with tumor HPV-positive OPC. Together, our findings suggest that telomere length in PBLs may be associated with higher risk of HPV16-associated OPC and tumor HPV16 status, particularly in certain patient subgroups. Larger studies are needed to validate these findings.},
}
@article {pmid23928219,
year = {2013},
author = {Terai, M and Izumiyama-Shimomura, N and Aida, J and Ishikawa, N and Kuroiwa, M and Poon, SS and Arai, T and Toyoda, M and Akutsu, H and Umezawa, A and Nakamura, K and Takubo, K},
title = {Investigation of telomere length dynamics in induced pluripotent stem cells using quantitative fluorescence in situ hybridization.},
journal = {Tissue &amp; cell},
volume = {45},
number = {6},
pages = {407-413},
doi = {10.1016/j.tice.2013.07.003},
pmid = {23928219},
issn = {1532-3072},
mesh = {Chromosomes, Human, Pair 12/genetics ; Chromosomes, Human, X/genetics ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Induced Pluripotent Stem Cells/*cytology ; Karyotyping ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Trisomy/genetics ; },
abstract = {Here we attempted to clarify telomere metabolism in parental cells and their derived clonal human induced pluripotent stem cells (iPSCs) at different passages using quantitative fluorescence in situ hybridization (Q-FISH). Our methodology involved estimation of the individual telomere lengths of chromosomal arms in individual cells within each clone in relation to telomere fluorescence units (TFUs) determined by Q-FISH. TFUs were very variable within the same metaphase spread and within the same cell. TFUs of the established iPSCs derived from human amnion (hAM933 iPSCs), expressed as mean values of the median TFUs of 20 karyotypes, were significantly longer than those of the parental cells, although the telomere extension rates varied quite significantly among the clones. Twenty metaphase spreads from hAM933 iPSCs demonstrated no chromosomal instability. The iPSCs established from fetal lung fibroblasts (MRC-5) did not exhibit telomere shortening and chromosomal instability as the number of passages increased. However, the telomeres of other iPSCs derived from MRC-5 became shorter as the number of passages increased, and one (5%) of 20 metaphase spreads showed chromosomal abnormalities including X trisomy at an early stage and all 20 showed abnormalities including X and 12 trisomies at the late stage.},
}
@article {pmid23928157,
year = {2014},
author = {Ozturk, S and Sozen, B and Demir, N},
title = {Telomere length and telomerase activity during oocyte maturation and early embryo development in mammalian species.},
journal = {Molecular human reproduction},
volume = {20},
number = {1},
pages = {15-30},
doi = {10.1093/molehr/gat055},
pmid = {23928157},
issn = {1460-2407},
mesh = {Aging ; Animals ; Cattle ; *Embryonic Development ; Female ; Granulosa Cells/*cytology ; Humans ; Mice ; Oocytes/cytology/*growth &amp; development ; Oxidative Stress ; Telomerase/*metabolism ; Telomere/genetics/metabolism ; Telomere Homeostasis/*genetics ; Telomere Shortening/genetics ; Telomere-Binding Proteins ; },
abstract = {Telomeres are located at the ends of all eukaryotic chromosomes and protect them from deleterious events such as inappropriate DNA repair, illegitimate recombination or improper segregation of the chromosomes during mitotic or meiotic divisions. However, telomeres gradually shorten primarily due to successive rounds of genomic DNA replication and also as the result of the adverse effects of oxidative stress, genotoxic agents, diseases related to ageing and environmental factors on the nuclear materials of dividing or non-dividing cells. Germline cells, proliferative granulosa cells, early embryos, stem cells, highly proliferative somatic cells and many cancer cells contain the enzyme telomerase so that they are capable of elongating the shortened telomeres. Although numerous studies have revealed the length of telomeres and telomerase activity in oocytes, granulosa cells and early embryos, only a few studies have analyzed and compared the work performed on distinct mammalian species. In this comprehensive review article, we compare and discuss telomere length and telomerase activity in oocytes, granulosa cells and early embryos in different mammalian species including mice, bovines and humans.},
}
@article {pmid23927510,
year = {2013},
author = {Theall, KP and McKasson, S and Mabile, E and Dunaway, LF and Drury, SS},
title = {Early hits and long-term consequences: tracking the lasting impact of prenatal smoke exposure on telomere length in children.},
journal = {American journal of public health},
volume = {103 Suppl 1},
number = {Suppl 1},
pages = {S133-5},
pmid = {23927510},
issn = {1541-0048},
support = {R01 ES020447/ES/NIEHS NIH HHS/United States ; R21 MH094688/MH/NIMH NIH HHS/United States ; 1R01ES020447-01/ES/NIEHS NIH HHS/United States ; R21 MH094688-01/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Black or African American ; Child ; Child, Preschool ; Female ; Humans ; Male ; *Maternal Exposure ; New Orleans ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Real-Time Polymerase Chain Reaction ; Retrospective Studies ; Surveys and Questionnaires ; Telomere/*ultrastructure ; *Tobacco Smoke Pollution ; },
abstract = {We examined the association between telomere length and prenatal tobacco exposure (PTE) in 104 children aged 4 to 14 years. Salivary telomere length (STL) was determined from salivary DNA using quantitative polymerase chain reaction. Of the children, 18% had maternal reported PTE. Mean STL was significantly lower among children with PTE (6.4 vs 7.5, P < .05). Findings extend the literature demonstrating the negative long-term effects of PTE to include a cellular marker of aging linked to multiple negative health outcomes.},
}
@article {pmid23922731,
year = {2013},
author = {Gardner, MP and Martin-Ruiz, C and Cooper, R and Hardy, R and Sayer, AA and Cooper, C and Deary, IJ and Gallacher, J and Harris, SE and Shiels, PG and Starr, JM and Kuh, D and von Zglinicki, T and Ben-Shlomo, Y and , },
title = {Telomere length and physical performance at older ages: an individual participant meta-analysis.},
journal = {PloS one},
volume = {8},
number = {7},
pages = {e69526},
pmid = {23922731},
issn = {1932-6203},
support = {MC_U123092724/MRC_/Medical Research Council/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MC_UU_12011/1/MRC_/Medical Research Council/United Kingdom ; MC_UP_A620_1014/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; MC_U147585824/MRC_/Medical Research Council/United Kingdom ; G0601333/MRC_/Medical Research Council/United Kingdom ; MC_UP_A620_1015/MRC_/Medical Research Council/United Kingdom ; MC_U123092720/MRC_/Medical Research Council/United Kingdom ; MC_U147585819/MRC_/Medical Research Council/United Kingdom ; ETM/55/CSO_/Chief Scientist Office/United Kingdom ; MC_UU_12011/2/MRC_/Medical Research Council/United Kingdom ; G0700704/MRC_/Medical Research Council/United Kingdom ; CZB/4/505/CSO_/Chief Scientist Office/United Kingdom ; MR/K026992/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Hand Strength/physiology ; Humans ; Male ; Middle Aged ; Physical Fitness/*physiology ; Posture/physiology ; Telomere Homeostasis/*physiology ; Walking/physiology ; },
abstract = {BACKGROUND: Telomeres are involved in cellular ageing and shorten with increasing age. If telomere length is a valuable biomarker of ageing, then telomere shortening should be associated with worse physical performance, an ageing trait, but evidence for such an association is lacking. The purpose of this study was to examine whether change in telomere length is associated with physical performance.<br><br>METHODS: Using data from four UK adult cohorts (ages 53-80 years at baseline), we undertook cross-sectional and longitudinal analyses. We analysed each study separately and then used meta-analytic methods to pool the results. Physical performance was measured using walking and chair rise speed, standing balance time and grip strength. Telomere length was measured by quantitative real-time polymerase chain reaction (PCR) in whole blood at baseline and follow-up (time 1, time 2).<br><br>RESULTS: Total sample sizes in meta-analyses ranged from 1,217 to 3,707. There was little evidence that telomere length was associated with walking speed, balance or grip strength, though weak associations were seen with chair rise speed and grip strength at baseline (p = 0.02 and 0.01 respectively). Faster chair rise speed at follow-up, was associated with a smaller decline in telomere length between time 1 and time 2 (standardised coefficient per SD increase 0.061, 95% CI 0.006, 0.115, p = 0.03) but this was consistent with chance (p =0.08) after further adjustment.<br><br>CONCLUSIONS: Whereas shortening of leukocyte telomeres might be an important measure of cellular ageing, there is little evidence that it is a strong biomarker for physical performance.},
}
@article {pmid23919820,
year = {2013},
author = {Zole, E and Pliss, L and Ranka, R and Krumina, A and Baumanis, V},
title = {Dynamics of telomere length in different age groups in a Latvian population.},
journal = {Current aging science},
volume = {6},
number = {3},
pages = {244-250},
doi = {10.2174/18746098113069990038},
pmid = {23919820},
issn = {1874-6128},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Aging/blood/*genetics ; Case-Control Studies ; Cellular Senescence ; Female ; Humans ; Latvia ; Leukocytes, Mononuclear/metabolism ; Male ; Middle Aged ; Telomere/*metabolism ; *Telomere Homeostasis ; *Telomere Shortening ; Time Factors ; Young Adult ; },
abstract = {The shortening of telomeres with ageing is a well-documented observation; however, the reported number of nucleotides in telomeres varies between different laboratories and studies. Such variability is likely caused by ethnic differences between the populations studied. Until now, there were no studies that investigated the variability of telomere length in a senescent Latvian population of the most common mitochondrial haplogroups, defined as H (45%), U (25%), Y chromosomal N1c (40%) and R1a1 (40%). Telomere length was determined in 121 individuals in different age groups, including a control group containing individuals of 20-40 years old and groups of individuals between 60-70 years old, 71-80 years old, 81-90 years old, and above 90 years old. Telomere length was determined using the Southern blot telomeric restriction fragment assay (TRF). Decreased telomere length with ageing was confirmed, but a comparison of centenarians and individuals between 60-90 years of age did not demonstrate a significant difference in telomere length. However, significant variability in telomere length was observed in the control group, indicating probable rapid telomere shortening in some individuals that could lead up to development of health status decline appearing with ageing. Telomere length measured in mononuclear blood cells (MNC) was compared with the telomere length measured in whole peripheral white blood cells (WBC) using TRF. Telomere length in MNC was longer than in WBC for the control group with individuals 20 to 40 years old; in contrast, for the group of individuals aged 65 to 85 years old, measured telomere length was shorter in MNC when compared to WBC.},
}
@article {pmid23918447,
year = {2013},
author = {Roger, L and Jones, RE and Heppel, NH and Williams, GT and Sampson, JR and Baird, DM},
title = {Extensive telomere erosion in the initiation of colorectal adenomas and its association with chromosomal instability.},
journal = {Journal of the National Cancer Institute},
volume = {105},
number = {16},
pages = {1202-1211},
doi = {10.1093/jnci/djt191},
pmid = {23918447},
issn = {1460-2105},
support = {10-0021/AICR_/Worldwide Cancer Research/United Kingdom ; C17199/A13490/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Adenomatous Polyposis Coli/*genetics ; Aneuploidy ; *Cell Transformation, Neoplastic ; *Chromosomal Instability ; Colorectal Neoplasms/*genetics ; Comparative Genomic Hybridization ; DNA, Neoplasm/analysis/isolation &amp; purification ; Disease Progression ; Humans ; *Telomere Shortening ; Wnt Signaling Pathway/genetics ; },
abstract = {BACKGROUND: Telomere shortening, dysfunction, and fusion may facilitate the acquisition of large-scale genomic rearrangements, driving clonal evolution and tumor progression. The relative contribution that telomere dysfunction and/or APC mutation play in the chromosome instability that occurs during colorectal tumorigenesis is not clear.<br><br>METHODS: We used high-resolution telomere length and fusion analysis to analyze 85 adenomatous colorectal polyps obtained from 10 patients with familial adenomatous polyposis and a panel of 50 colorectal carcinomas with patient-matched normal colonic mucosa. Telomerase activity was determined using the telomeric repeat amplification protocol. Array-CGH was used to detect large-scale genomic rearrangements. Pearson correlation and Student t test were used, and all statistical tests were two-sided.<br><br>RESULTS: Despite the presence of telomerase activity, we observed apparent telomere shortening in colorectal polyps that correlated with large-scale genomic rearrangements (P < .0001) but was independent of polyp size and indistinguishable from that observed in colorectal carcinomas (P = .82). We also observed apparent lengthening of telomeres in both polyps and carcinomas. The extensive differences in mean telomere length of up to 4.6kb between patient-matched normal mucosa and polyps were too large to be accounted for by replicative telomere erosion alone. Telomere fusion events were detected in both polyps and carcinomas; the mutational spectrum accompanying fusion was consistent with alternative nonhomologous end joining.<br><br>CONCLUSIONS: Telomere length distributions observed in colorectal polyps reflect the telomere length composition of the normal originating cells from which clonal growth was initiated. Originating cells containing both short telomeres and APC mutations may give rise to polyps that exhibit short telomeres and are prone to telomere dysfunction, driving genomic instability and progression to malignancy. J Natl Cancer Inst;2013;105:1202-1211.},
}
@article {pmid23918446,
year = {2013},
author = {Shay, JW},
title = {Determining if telomeres matter in colon cancer initiation or progression.},
journal = {Journal of the National Cancer Institute},
volume = {105},
number = {16},
pages = {1166-1168},
pmid = {23918446},
issn = {1460-2105},
support = {5P30 CA 142543-03/CA/NCI NIH HHS/United States ; C06 RR30414/RR/NCRR NIH HHS/United States ; P50CA70907/CA/NCI NIH HHS/United States ; },
mesh = {Adenomatous Polyposis Coli/*genetics ; *Cell Transformation, Neoplastic ; *Chromosomal Instability ; Colorectal Neoplasms/*genetics ; Humans ; *Telomere Shortening ; },
}
@article {pmid23917070,
year = {2014},
author = {Georgin-Lavialle, S and Moura, DS and Bruneau, J and Chauvet-Gélinier, JC and Damaj, G and Soucie, E and Barete, S and Gacon, AL and Grandpeix-Guyodo, C and Suarez, F and Launay, JM and Durieu, I and Esparcieux, A and Guichard, I and Sparsa, A and Nicolini, F and Gennes, Cd and Trojak, B and Haffen, E and Vandel, P and Lortholary, O and Dubreuil, P and Bonin, B and Sultan, S and Teyssier, JR and Hermine, O},
title = {Leukocyte telomere length in mastocytosis: correlations with depression and perceived stress.},
journal = {Brain, behavior, and immunity},
volume = {35},
number = {},
pages = {51-57},
doi = {10.1016/j.bbi.2013.07.009},
pmid = {23917070},
issn = {1090-2139},
mesh = {Adult ; Aged ; Depression/*genetics ; Female ; Humans ; Leukocytes, Mononuclear/metabolism ; Male ; Mastocytosis/*genetics/*psychology ; Middle Aged ; Stress, Psychological/*genetics ; *Telomere Shortening ; Young Adult ; },
abstract = {BACKGROUND: Mastocytosisis a rare disease associated with chronic symptoms related to mast cell mediator release. Patients with mastocytosis display high level of negative emotionality such as depression and stress sensibility. Brain mast cells are mainly localized in the diencephalon, which is linked to emotion regulatory systems. Negative emotionality has been shown to be associated with telomere shortening. Taken together these observations led us to hypothesize that mast cells activity could be involved in both negative emotionality and telomere shortening in mastocytosis.<br><br>OBJECTIVE: To demonstrate a possible relationship between negative emotionality in mastocytosis and leukocytes telomere length.<br><br>METHODS: Leukocyte telomere length and telomerase activity were measured among mastocytosis patients and were correlated with perceived stress and depression assessed by the Beck Depression Inventory revised and the Perceived Stress Scale.<br><br>RESULTS: Mild-severe depression scores were frequent (78.9%) as well as high perceived stress (42.11%). Telomere length was correlated to perceived stress (r=0.77; p=0.0001) but not to depression in our population. Patients displaying Wild-type KIT significantly presented higher perceived stress levels. Patients with the D816VC KIT mutation who had high perceived stress scores displayed significantly shorter telomere but not if they had high depression scores.<br><br>CONCLUSION: These findings suggest that high perceived stress in mastocytosis could accelerate the rate of leukocytes telomere shortening. Since mastocytosis is, by definition, a mast cell mediated disease; these cells could be involved in this phenomenon. Mechanistic causal relationships between these parameters need to be investigated.},
}
@article {pmid23909872,
year = {2013},
author = {Gabelica, V and Maeda, R and Fujimoto, T and Yaku, H and Murashima, T and Sugimoto, N and Miyoshi, D},
title = {Multiple and cooperative binding of fluorescence light-up probe thioflavin T with human telomere DNA G-quadruplex.},
journal = {Biochemistry},
volume = {52},
number = {33},
pages = {5620-5628},
doi = {10.1021/bi4006072},
pmid = {23909872},
issn = {1520-4995},
mesh = {Algorithms ; Benzothiazoles ; Binding Sites ; Circular Dichroism ; DNA/chemistry/metabolism ; Fluorescent Dyes/*chemistry/metabolism ; *G-Quadruplexes ; Humans ; Kinetics ; Models, Molecular ; Molecular Structure ; Spectrometry, Mass, Electrospray Ionization ; Telomere/*genetics ; Thiazoles/*chemistry/metabolism ; },
abstract = {Thioflavin T (ThT), a typical probe for protein fibrils, also binds human telomeric G-quadruplexes with a fluorescent light-up signal change and high specificity against DNA duplexes. Cell penetration and low cytotoxicity of fibril probes having been widely established, modifying ThT and other fibril probes is an attractive means of generating new G-quadruplex ligands. Thus, elucidating the binding mechanism is important for the design of new drugs and fluorescent probes based on ThT. Here, we investigated the binding mechanism of ThT with several variants of the human telomeric sequence in the presence of monovalent cations. Fluorescence titrations and electrospray ionization mass spectrometry (ESI-MS) analyses demonstrated that each G-quadruplex unit cooperatively binds to several ThT molecules. ThT brightly fluoresces when a single ligand is bound to the G-quadruplex and is quenched as ligand binding stoichiometry increases. Both the light-up signal and the dissociation constants are exquisitely sensitive to the base sequence and to the G-quadruplex structure. These results are crucial for the sensible design and interpretation of G-quadruplex detection assays using fluorescent ligands in general and ThT in particular.},
}
@article {pmid23907815,
year = {2014},
author = {Jung, SW and Park, NH and Shin, JW and Park, BR and Kim, CJ and Lee, JE and Shin, ES and Kim, JA and Chung, YH},
title = {Prognostic impact of telomere maintenance gene polymorphisms on hepatocellular carcinoma patients with chronic hepatitis B.},
journal = {Hepatology (Baltimore, Md.)},
volume = {59},
number = {5},
pages = {1912-1920},
doi = {10.1002/hep.26655},
pmid = {23907815},
issn = {1527-3350},
mesh = {Adult ; Aged ; Carcinoma, Hepatocellular/*genetics/mortality ; Carrier Proteins/genetics ; Female ; Genotype ; Hepatitis B, Chronic/*complications ; Humans ; Liver Neoplasms/*genetics/mortality ; Logistic Models ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; Prognosis ; Proportional Hazards Models ; RNA-Binding Proteins ; Shelterin Complex ; *Telomere ; Telomere-Binding Proteins/genetics ; },
abstract = {UNLABELLED: Our goal was to determine whether single-nucleotide polymorphisms (SNPs) of telomere maintenance genes influence the development and clinical outcomes of patients with hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). We evaluated 20 SNPs of five telomere maintenance genes in 702 patients with HCC and 351 hepatitis B virus surface antigen-positive controls without HCC. Significant SNPs were then validated in an independent cohort of 857 HCC patients and 429 controls. We assessed the association of each SNP with the development of HCC and overall survival through a multivariate Cox proportional analysis. A significantly increased risk of HCC development was identified for the telomerase-associated protein 1 (TEP1) rs1713449 SNP in both the discovery and replication phases (combined odds ratio = 1.42, P = 9.378 × 10(-5)). In addition, the TEP1 rs1713449, TEP1 rs872072, protection of telomeres 1 homolog rs7784168, telomerase reverse transcriptase rs13167280, and telomeric repeat binding factor 1 rs2306494 SNPs had a significant effect on the overall survival, and a similar survival effect was validated in the replication cohort. Moreover, there was a significant dose-dependent association between the number of putatively high-risk genotypes of the five aforementioned SNPs and overall survival. The median survival time was significantly prolonged for patients with HCC with two or fewer putatively high-risk genotypes versus those with three or more high-risk genotypes (85 versus 44 months, log-rank P = 4.483 × 10(-5)), and this was demonstrated in the replication cohort (52 versus 37 months, log-rank P = 0.026).<br><br>CONCLUSION: These observations suggest that the SNPs of telomere maintenance genes play a potential role in the development of HCC and the survival of HCC patients with chronic HBV infections.},
}
@article {pmid23900074,
year = {2013},
author = {Pooley, KA and Bojesen, SE and Weischer, M and Nielsen, SF and Thompson, D and Amin Al Olama, A and Michailidou, K and Tyrer, JP and Benlloch, S and Brown, J and Audley, T and Luben, R and Khaw, KT and Neal, DE and Hamdy, FC and Donovan, JL and Kote-Jarai, Z and Baynes, C and Shah, M and Bolla, MK and Wang, Q and Dennis, J and Dicks, E and Yang, R and Rudolph, A and Schildkraut, J and Chang-Claude, J and Burwinkel, B and Chenevix-Trench, G and Pharoah, PD and Berchuck, A and Eeles, RA and Easton, DF and Dunning, AM and Nordestgaard, BG},
title = {A genome-wide association scan (GWAS) for mean telomere length within the COGS project: identified loci show little association with hormone-related cancer risk.},
journal = {Human molecular genetics},
volume = {22},
number = {24},
pages = {5056-5064},
pmid = {23900074},
issn = {1460-2083},
support = {CA128978/CA/NCI NIH HHS/United States ; G0900871/MRC_/Medical Research Council/United Kingdom ; /CAPMC/CIHR/Canada ; C5047/A10692/CRUK_/Cancer Research UK/United Kingdom ; C5047/A8384/CRUK_/Cancer Research UK/United Kingdom ; C1287/A 10710/CRUK_/Cancer Research UK/United Kingdom ; G0401527/MRC_/Medical Research Council/United Kingdom ; 16565/CRUK_/Cancer Research UK/United Kingdom ; 11022/CRUK_/Cancer Research UK/United Kingdom ; C1287/A9540/CRUK_/Cancer Research UK/United Kingdom ; 16563/CRUK_/Cancer Research UK/United Kingdom ; 10124/CRUK_/Cancer Research UK/United Kingdom ; C12292/A11174/CRUK_/Cancer Research UK/United Kingdom ; C8197/A10123/CRUK_/Cancer Research UK/United Kingdom ; C5047/A15007/CRUK_/Cancer Research UK/United Kingdom ; G1000143/MRC_/Medical Research Council/United Kingdom ; 16561/CRUK_/Cancer Research UK/United Kingdom ; 10118/CRUK_/Cancer Research UK/United Kingdom ; 14136/CRUK_/Cancer Research UK/United Kingdom ; C1287/A10118/CRUK_/Cancer Research UK/United Kingdom ; 15007/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Case-Control Studies ; Chromosome Mapping ; Female ; *Genetic Loci ; Genetic Predisposition to Disease ; *Genome-Wide Association Study ; Humans ; Male ; Neoplasms/*genetics/metabolism ; Polymorphism, Single Nucleotide ; Risk ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Mean telomere length (TL) in blood cells is heritable and has been reported to be associated with risks of several diseases, including cancer. We conducted a meta-analysis of three GWAS for TL (total n=2240) and selected 1629 variants for replication via the "iCOGS" custom genotyping array. All ∼200 000 iCOGS variants were analysed with TL, and those displaying associations in healthy controls (n = 15 065) were further tested in breast cancer cases (n = 11 024). We found a novel TL association (Ptrend < 4 × 10(-10)) at 3p14.4 close to PXK and evidence (Ptrend < 7 × 10(-7)) for TL loci at 6p22.1 (ZNF311) and 20q11.2 (BCL2L1). We additionally confirmed (Ptrend < 5 × 10(-14)) the previously reported loci at 3q26.2 (TERC), 5p15.3 (TERT) and 10q24.3 (OBFC1) and found supportive evidence (Ptrend < 5 × 10(-4)) for the published loci at 2p16.2 (ACYP2), 4q32.2 (NAF1) and 20q13.3 (RTEL1). SNPs tagging these loci explain TL differences of up to 731 bp (corresponding to 18% of total TL in healthy individuals), however, they display little direct evidence for association with breast, ovarian or prostate cancer risks.},
}
@article {pmid23896060,
year = {2013},
author = {Yan, S and Han, B and Li, H and Wu, Y and Zhou, D and Zhao, Y},
title = {Telomerase gene screening and telomere overhang detection in Chinese patients with myelodysplastic syndrome.},
journal = {Leukemia research},
volume = {37},
number = {10},
pages = {1359-1362},
doi = {10.1016/j.leukres.2013.06.011},
pmid = {23896060},
issn = {1873-5835},
mesh = {Adolescent ; Adult ; Aged ; Asian People/*genetics ; China ; Female ; Humans ; Male ; Middle Aged ; Myelodysplastic Syndromes/*diagnosis/*genetics ; Prognosis ; Telomerase/*genetics/metabolism ; Telomere/*genetics/metabolism ; Young Adult ; },
abstract = {BACKGROUND: Telomerase disfunction leads to short telometric overhangs, potentially resulting in chromosome instability.<br><br>AIMS: To better understand the role of overhang length in the progression of myelodysplastic syndrome (MDS).<br><br>METHODS: Bone marrow samples of 62 Chinese MDS patients were screened for TERT and TERC gene variants. Overhangs length was investigated.<br><br>RESULTS: No mutation was identified. MDS patients had shorter overhangs compared to controls. Abnormal karyotype ones had shorter overhang compared to normal. Telomeric overhang length decreased as IPSS/WPSS value increased.<br><br>CONCLUSIONS: Overhang changes in accordance with IPSS/WPSS in MDS. Short overhang may be an independent factor for poor prognosis in MDS.},
}
@article {pmid23893488,
year = {2013},
author = {Wesolowska, N and Amariei, FL and Rong, YS},
title = {Clustering and protein dynamics of Drosophila melanogaster telomeres.},
journal = {Genetics},
volume = {195},
number = {2},
pages = {381-391},
pmid = {23893488},
issn = {1943-2631},
mesh = {Animals ; Blastoderm/*growth &amp; development/ultrastructure ; Cell Nucleus/genetics/ultrastructure ; Chromatin/genetics/metabolism ; Chromosomal Proteins, Non-Histone/*genetics/metabolism ; Chromosomes/*genetics/metabolism/ultrastructure ; Drosophila Proteins/*genetics/metabolism ; Drosophila melanogaster ; Giant Cells/metabolism/ultrastructure ; In Situ Hybridization, Fluorescence ; Interphase/genetics ; Telomere/*genetics/ultrastructure ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Telomeres are obligatory chromosomal landmarks that demarcate the ends of linear chromosomes to distinguish them from broken ends and can also serve to organize the genome. In both budding and fission yeast, they cluster at the periphery of the nucleus, potentially to establish a compartment of silent chromatin. To gain insight into telomere organization in higher organisms, we investigated their distribution in interphase nuclei of Drosophila melanogaster. We focused on the syncytial blastoderm, an excellent developmental stage for live imaging due to the synchronous division of the nuclei at this time. We followed the EGFP-labeled telomeric protein HOAP in vivo and found that the 16 telomeres yield four to six foci per nucleus, indicative of clustering. Furthermore, we confirmed clustering in other somatic tissues. Importantly, we observed that HOAP signal intensity in the clusters increases in interphase, potentially due to loading of HOAP to newly replicated telomeres. To determine the rules governing clustering, we used in vivo imaging and fluorescence in situ hybridization to test several predictions. First, we inspected mutant embryos that develop as haploids and found that clustering is not mediated by associations between homologs. Second, we probed specifically for a telomere of novel sequence and found strong evidence against DNA sequence identity and homology as critical factors. Third, we ruled out predominance of intrachromosomal interactions by marking both ends of a chromosome. Based on these results, we propose that clustering is independent of sequence and is likely maintained by an as yet undetermined factor.},
}
@article {pmid23883575,
year = {2013},
author = {Caprioli, M and Romano, M and Romano, A and Rubolini, D and Motta, R and Folini, M and Saino, N},
title = {Nestling telomere length does not predict longevity, but covaries with adult body size in wild barn swallows.},
journal = {Biology letters},
volume = {9},
number = {5},
pages = {20130340},
pmid = {23883575},
issn = {1744-957X},
mesh = {Animals ; Body Size/*genetics ; Female ; Longevity/*genetics ; Male ; Swallows/*genetics/physiology ; *Telomere ; },
abstract = {Telomere length and dynamics are increasingly scrutinized as ultimate determinants of performance, including age-dependent mortality and fecundity. Few studies have investigated longevity in relation to telomere length (TL) in the wild and none has analysed longevity in relation to TL soon after hatching, despite the fact that telomere shortening may mostly occur early in life. We show that TL in nestling barn swallows (Hirundo rustica) in the wild does not predict longevity. However, TL positively covaries with body size, suggesting that individuals with large TL can afford to grow larger without paying the cost of reduced TL, and/or that benign rearing conditions ensure both large body size and low rates of telomere shortening. Overall, our study hints at a role of TL in developmental processes, but also indicates a need for further analyses to assess the expectation that TL in young individuals predicts longevity in the wild.},
}
@article {pmid23880207,
year = {2013},
author = {Raschenberger, J and Kollerits, B and Hammerer-Lercher, A and Rantner, B and Stadler, M and Haun, M and Klein-Weigel, P and Fraedrich, G and Kronenberg, F},
title = {The association of relative telomere length with symptomatic peripheral arterial disease: results from the CAVASIC study.},
journal = {Atherosclerosis},
volume = {229},
number = {2},
pages = {469-474},
doi = {10.1016/j.atherosclerosis.2013.05.027},
pmid = {23880207},
issn = {1879-1484},
mesh = {Adult ; Aged ; Aging/genetics ; Atherosclerosis/epidemiology/genetics ; Case-Control Studies ; Cohort Studies ; Genetic Markers ; Humans ; Intermittent Claudication/*epidemiology/*genetics ; Logistic Models ; Male ; Middle Aged ; Peripheral Arterial Disease/*epidemiology/*genetics ; Polymerase Chain Reaction/methods ; Prevalence ; Risk Factors ; Telomere/*genetics ; White People/genetics/statistics &amp; numerical data ; },
abstract = {BACKGROUND AND OBJECTIVES: Short telomere length has been described to be associated with biological aging including atherosclerosis phenotypes. However, information in patients with symptomatic peripheral arterial disease (PAD) is sparse. We therefore aimed to investigate whether inter-individual differences in relative telomere length (RTL) are associated with symptomatic PAD.<br><br>DESIGN: We measured RTL by a quantitative PCR method in the CAVASIC Study, a cohort of 241 male Caucasian patients diagnosed with intermittent claudication and 249 age- and diabetes-matched controls.<br><br>RESULTS: We observed significantly shorter mean RTL in patients than in controls (1.24 &#xb1; 0.19 vs. 1.32 &#xb1; 0.23, p < 0.001). Each shortening of RTL by one standard deviation significantly increased the odds for PAD by 44%: age-adjusted OR = 1.44 (95%CI 1.19-1.75, p < 0.001). This association remained significant after additional adjustment for log-C-reactive protein, glomerular filtration rate, HDL cholesterol, current smoking and log N-terminal pro-B-type natriuretic peptide (NT-proBNP). Excluding patients with prevalent cardiovascular disease revealed very similar results. When we compared the model fit of the various adjustment models including cardiac risk factors and/or NT-proBNP the addition of RTL significantly improved discrimination between patients and controls.<br><br>CONCLUSION: This study in a male cohort of patients with intermittent claudication and age- and diabetes-matched controls indicates a significant association of shorter relative telomere length with PAD. Our results reinforce RTL as a marker for PAD that reflects the influence of genetic and environmental risk factors. Moreover, the association remains significant after excluding patients and controls free from prevalent cardiovascular disease.},
}
@article {pmid23880188,
year = {2013},
author = {Kark, JD and Nassar, H and Shaham, D and Sinnreich, R and Goldberger, N and Aboudi, V and Bogot, NR and Kimura, M and Aviv, A},
title = {Leukocyte telomere length and coronary artery calcification in Palestinians.},
journal = {Atherosclerosis},
volume = {229},
number = {2},
pages = {363-368},
doi = {10.1016/j.atherosclerosis.2013.05.030},
pmid = {23880188},
issn = {1879-1484},
support = {AG020132/AG/NIA NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; AG030678/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Arabs/*genetics/statistics &amp; numerical data ; Coronary Artery Disease/diagnostic imaging/*ethnology/*genetics ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/physiology ; Male ; Middle Aged ; Multivariate Analysis ; Odds Ratio ; Prevalence ; Registries/statistics &amp; numerical data ; Risk Factors ; Telomere/*genetics ; Tomography, X-Ray Computed ; Vascular Calcification/diagnostic imaging/*ethnology/*genetics ; },
abstract = {OBJECTIVE: Shorter leukocyte telomere length (LTL) is associated with higher incidence of coronary heart disease (CHD) and increased mortality. We examined the association of LTL with coronary artery calcification (CAC), which reflects the cumulative burden of coronary atherosclerosis, in an urban Arab sample of Palestinians, a population at high risk of CHD.<br><br>METHODS: Using a cross-sectional design, a random sample of East Jerusalem residents, comprising 250 men aged 45-77 and women aged 55-76 and free of CHD or past stroke, was drawn from the Israel national population register. LTL was measured by Southern blots. CAC was determined by 16-slice multidetector helical CT scanning using Agatston scoring. We applied multivariable logistic modeling to examine the association between sex-specific tertiles of LTL and CAC (comparing scores >100 vs. <100, and the upper third vs. the lower 2 thirds), controlling for age, sex, education and coronary risk factors.<br><br>RESULTS: CAC, evident in 65% of men and 52% of women, was strongly associated with age (sex-adjusted Spearman's rho 0.495). The multivariable-adjusted odds ratios for CAC >100 (found in 30% of men and 29% of women) were 2.92 (95% CI 1.28-6.68) and 2.29 (0.99-5.30) for the lower and mid-tertiles of LTL vs. the upper tertile, respectively (Ptrend = 0.008). Findings were similar for CAC scores in the upper tertile (Ptrend = 0.006), and persisted after the exclusion of patients with diabetes or receiving statins.<br><br>CONCLUSIONS: Shorter LTL was associated with a greater prevalence of asymptomatic coronary atherosclerosis in an urban Arab population-based sample. Mechanisms underlying this association should be sought.},
}
@article {pmid23877500,
year = {2013},
author = {Burgess, DJ},
title = {Genome stability: Specialist responses at telomeres.},
journal = {Nature reviews. Genetics},
volume = {14},
number = {9},
pages = {597},
pmid = {23877500},
issn = {1471-0064},
mesh = {Cell Division/*physiology ; Cellular Senescence/*physiology ; DNA Damage/*genetics ; *DNA Replication ; G2 Phase/*physiology ; *Genome, Human ; Humans ; Telomere/*physiology ; },
}
@article {pmid23875458,
year = {2013},
author = {Koroleva, AG and Evtushenko, EV and Timoshkin, OA and Vershinin, AV and Kiril'chik, SV},
title = {[Telomere length and phylogenetic relationship of Baikal and Siberian planarians (Turbellaria, Tricladida)].},
journal = {Tsitologiia},
volume = {55},
number = {4},
pages = {247-252},
pmid = {23875458},
issn = {0041-3771},
mesh = {Actins/classification/*genetics ; Animals ; Body Size/genetics ; DNA, Helminth/classification/*genetics ; *Phylogeny ; Planarians/classification/*genetics ; RNA, Ribosomal, 18S/classification/*genetics ; Regeneration/genetics ; Siberia ; Species Specificity ; *Telomere ; },
abstract = {Dynamics of the telomeric DNA (tDNA) and the phylogeny of the Baikal and Siberian planarians have been studied based on the analysis of the 18S rDNA and beta-actin gene fragments. A relationship between tDNA and the planarians size has been demonstrated. Giant planarians with a minor exception have longer tDNA than little planarians. Phylogenetic affinity between the species that have the stretched tracks of tDNA, big size and similar habitats may indicate possible role of tDNA in the development of the indefinite regenerative capacity of planarians.},
}
@article {pmid23875450,
year = {2013},
author = {Cipressa, F and Cenci, G},
title = {DNA damage response, checkpoint activation and dysfunctional telomeres: face to face between mammalian cells and Drosophila.},
journal = {Tsitologiia},
volume = {55},
number = {4},
pages = {211-217},
pmid = {23875450},
issn = {0041-3771},
mesh = {Animals ; Cell Cycle Checkpoints/*genetics ; Cell Cycle Proteins/*genetics/metabolism ; DNA Damage ; Drosophila/*genetics/metabolism ; Drosophila Proteins/genetics/metabolism ; Gene Expression Regulation ; Humans ; Retinoblastoma Protein/genetics/metabolism ; *Retroelements ; Signal Transduction ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/genetics/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; },
abstract = {Eukaryotic cells evolved telomeres, specialized nucleoproteic complexes, to protect and replicate chromosome ends. In most organisms, telomeres consist of short, repetitive G-rich sequences added to chromosome ends by a reverse transcriptase with an internal RNA template, called telomerase. Specific DNA-binding protein complexes associate with telomeric sequences allowing cells to distinguish chromosome ends from sites of DNA damage. When telomeres become dysfunctional, either through excessive shortening or due to defects in the proteins that form their structure, they trigger p53/pRb pathways that limits proliferative lifespan and eventually leads to chromosome instability. Drosophila lacks telomerase, telomeres are assembled in a sequence-independent fashion and their length is maintained by transposition of three specialized retroelements. Nevertheless, fly telomeres are maintained by a number of proteins involved in telomere metabolism as in other eukaryotic systems and that are required to prevent checkpoint activation and end-to-end fusion. Uncapped Drosophila telomeres induce a DNA damage response just as dysfunctional human telomeres. Most interestingly, uncapped Drosophila telomeres also activate the spindle assembly checkpoint (SAC) by recruiting the SAC kinase BubR1. Here we review parallelisms and variations between mammalian and Drosophila cells in the crosstalks between telomeres and cell cycle regulation.},
}
@article {pmid23874233,
year = {2013},
author = {Vallabhaneni, H and O'Callaghan, N and Sidorova, J and Liu, Y},
title = {Defective repair of oxidative base lesions by the DNA glycosylase Nth1 associates with multiple telomere defects.},
journal = {PLoS genetics},
volume = {9},
number = {7},
pages = {e1003639},
pmid = {23874233},
issn = {1553-7404},
support = {//Intramural NIH HHS/United States ; },
mesh = {Animals ; Bone Marrow Cells/metabolism/pathology ; Chromosomes/genetics/metabolism/ultrastructure ; *DNA Damage ; Deoxyribonuclease (Pyrimidine Dimer)/*genetics ; *Genomic Instability ; Mice ; Mice, Knockout ; Oxidative Stress ; Oxygen/metabolism ; Recombination, Genetic ; Repetitive Sequences, Nucleic Acid/genetics ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism/pathology ; },
abstract = {Telomeres are chromosome end structures and are essential for maintenance of genome stability. Highly repetitive telomere sequences appear to be susceptible to oxidative stress-induced damage. Oxidation may therefore have a severe impact on telomere integrity and function. A wide spectrum of oxidative pyrimidine-derivatives has been reported, including thymine glycol (Tg), that are primarily removed by a DNA glycosylase, Endonuclease III-like protein 1 (Nth1). Here, we investigate the effect of Nth1 deficiency on telomere integrity in mice. Nth1 null (Nth1(-/-)) mouse tissues and primary MEFs harbor higher levels of Endonuclease III-sensitive DNA lesions at telomeric repeats, in comparison to a non-telomeric locus. Furthermore, oxidative DNA damage induced by acute exposure to an oxidant is repaired slowly at telomeres in Nth1(-/-) MEFs. Although telomere length is not affected in the hematopoietic tissues of Nth1(-/-) adult mice, telomeres suffer from attrition and increased recombination and DNA damage foci formation in Nth1(-/-) bone marrow cells that are stimulated ex vivo in the presence of 20% oxygen. Nth1 deficiency also enhances telomere fragility in mice. Lastly, in a telomerase null background, Nth1(-/-) bone marrow cells undergo severe telomere loss at some chromosome ends and cell apoptosis upon replicative stress. These results suggest that Nth1 plays an important role in telomere maintenance and base repair against oxidative stress-induced base modifications. The fact that telomerase deficiency can exacerbate telomere shortening in Nth1 deficient mouse cells supports that base excision repair cooperates with telomerase to maintain telomere integrity.},
}
@article {pmid23873360,
year = {2013},
author = {Ma, D and Zhu, W and Hu, S and Yu, X and Yang, Y},
title = {Association between oxidative stress and telomere length in Type 1 and Type 2 diabetic patients.},
journal = {Journal of endocrinological investigation},
volume = {36},
number = {11},
pages = {1032-1037},
pmid = {23873360},
issn = {1720-8386},
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Adult ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Diabetes Mellitus, Type 1/*genetics/pathology ; Diabetes Mellitus, Type 2/*genetics/pathology ; Female ; Humans ; Insulin Resistance/genetics ; Leukocytes/ultrastructure ; Male ; Middle Aged ; Oxidative Stress/*physiology ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Increasing evidence showed that telomere length was shorter in age-related diseases, but the mechanism of this phenomenon is still unclear.<br><br>AIM: To determine whether telomere shortening occurs in Type 1 diabetes (T1D) and Type 2 diabetes (T2D), and explore the effect of antioxidant status on the telomere length.<br><br>SUBJECTS AND METHODS: T2D patients (no.=62), T1D patients (no.=34), and non-diabetic subjects used as control (CTL) (no.=40) were included in this study. Leukocyte telomere length ratio (T/S ratio) was measured using a quantitative PCR and analyzed. Antioxidant status was estimated by human 8-hydroxy-desoxyguanosine quantization. Other biomarkers, such as fasting plasma glucose, fasting insulin, glycated hemoglobin (HbA1c) and lipid profile were also measured.<br><br>RESULTS: Compared with CTL group [T/S ratio (mean &#xb1; SD), 2.39 &#xb1; 0.55], leukocyte telomere length was significantly shorter in T2D group (1.67 &#xb1; 0.50) and T1D group (1.77 &#xb1; 0.50). 8-OHdG that indicated oxidative stress was significantly higher in T2D (2.99 &#xb1; 0.85 ng/ml) and T1D (2.03 &#xb1; 0.92 ng/ml) group than in CTL group (0.90 &#xb1; 0.46 ng/ml). T/S ratio was significantly negatively correlated with age, waist circumference, waist-to-hip ratio, diastolic blood pressure, fasting plasma glucose, HbA1c, homeostasis model assessment of insulin resistance and 8- OHdG in the whole population. 8-OHdG was independent risk factor for telomere shortening in both T1D (p=0.018) and T2D group (p=0.022).<br><br>CONCLUSIONS: In our study, shorter telomere length and increased oxidative stress were observed in both T1D and T2D. Older people with central obesity, hyperglycemia, insulin resistance and severe antioxidant status tended to have shorter telomere length. In addition, 8- OHdG was an independent predictor for telomere length for both T1D and T2D patients.},
}
@article {pmid23872258,
year = {2013},
author = {Harbo, M and Delaisse, JM and Kjaersgaard-Andersen, P and Soerensen, FB and Koelvraa, S and Bendix, L},
title = {The relationship between ultra-short telomeres, aging of articular cartilage and the development of human hip osteoarthritis.},
journal = {Mechanisms of ageing and development},
volume = {134},
number = {9},
pages = {367-372},
doi = {10.1016/j.mad.2013.07.002},
pmid = {23872258},
issn = {1872-6216},
mesh = {Aged ; Aged, 80 and over ; *Aging ; Arthroplasty, Replacement, Hip ; Cartilage, Articular/*pathology ; Cellular Senescence ; Chondrocytes/cytology/metabolism ; Female ; Femur Head/*pathology ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Osteoarthritis, Hip/*genetics/*pathology ; Polymerase Chain Reaction ; Stem Cells/cytology ; Stress, Mechanical ; Telomere/*ultrastructure ; Telomere Shortening ; },
abstract = {INTRODUCTION: Ultra-short telomeres caused by stress-induced telomere shortening are suggested to induce chondrocyte senescence in human osteoarthritic knees. Here we have further investigated the role of ultra-short telomeres in the development of osteoarthritis (OA) and in aging of articular cartilage in human hips.<br><br>MATERIALS AND METHODS: Cartilage was obtained from four different distances of the central weight-bearing area in human femoral heads (14 OA and 9 non-OA). Samples were split into three: one for quantification of ultra-short single telomeres by Universal STELA and mean telomere length measurement by Q-PCR; one for histological grading of OA, and one for immunohistochemical staining.<br><br>RESULTS: Load of ultra-short telomeres increased closer to the central weight-bearing area and correlated with cartilage degradation in both OA and non-OA samples. Mean telomere length decreased with decreasing distance to the central weight-bearing area, however, unexpectedly increased in the most central zone. This increase was associated with immunohistochemical findings of cells expressing markers characteristic of progenitor-like cells.<br><br>CONCLUSION: These findings suggest a role of short telomeres in the development of OA and in aging of articular cartilage. Furthermore, progenitor-like cells with long telomeres may be recruited to the most damaged areas of the cartilage.},
}
@article {pmid23870621,
year = {2013},
author = {Nieratschker, V and Lahtinen, J and Meier, S and Strohmaier, J and Frank, J and Heinrich, A and Breuer, R and Witt, SH and Nöthen, MM and Rietschel, M and Hovatta, I},
title = {Longer telomere length in patients with schizophrenia.},
journal = {Schizophrenia research},
volume = {149},
number = {1-3},
pages = {116-120},
doi = {10.1016/j.schres.2013.06.043},
pmid = {23870621},
issn = {1573-2509},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Community Health Planning ; Female ; *Genetic Predisposition to Disease ; Germany ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Schizophrenia/*genetics ; Telomere/*genetics ; Young Adult ; },
abstract = {Previous studies have reported an association between shorter leukocyte telomere length and schizophrenia (SCZ). The aim of the present study was to replicate this finding in a large sample of SCZ patients (n=539) and population-based controls (n=519). In addition, the possible influence of SCZ severity on telomere length - as measured by age of onset, mode of onset, and course of the disorder - was investigated. Telomere length was negatively associated with age in both patients and controls. This is a consistently reported phenomenon, related to the problem of DNA end-replication. However, in contrast to previous findings, SCZ patients displayed longer telomeres compared to controls (p=0.015). No association was found with any SCZ-severity subphenotype. Interestingly, recent studies have reported associations between longer leukocyte telomere length and both smaller hippocampal volume, and poorer episodic memory performance. Both phenotypes are common in patients with SCZ. Further studies are warranted to investigate whether the present association between SCZ and increased telomere length was driven by such associations, or rather by association with the clinical disease per se or other associated phenotypes, endophenotypes or lifestyle factors.},
}
@article {pmid23869908,
year = {2013},
author = {Gu, P and Chang, S},
title = {Functional characterization of human CTC1 mutations reveals novel mechanisms responsible for the pathogenesis of the telomere disease Coats plus.},
journal = {Aging cell},
volume = {12},
number = {6},
pages = {1100-1109},
pmid = {23869908},
issn = {1474-9726},
support = {R21 AG043747/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Ataxia/*genetics ; Brain Neoplasms/*genetics ; Calcinosis/*genetics ; Central Nervous System Cysts/*genetics ; DNA Polymerase I/metabolism ; Heterozygote ; Humans ; Leukoencephalopathies/*genetics ; Mice ; Muscle Spasticity/*genetics ; Mutant Proteins/metabolism ; Mutation/*genetics ; Protein Binding ; Retinal Diseases/*genetics ; Seizures/*genetics ; Telomere/*metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {Coats plus is a rare recessive disorder characterized by intracranial calcifications, hematological abnormalities, and retinal vascular defects. This disease results from mutations in CTC1, a member of the CTC1-STN1-TEN1 (CST) complex critical for telomere replication. Telomeres are specialized DNA/protein structures essential for the maintenance of genome stability. Several patients with Coats plus display critically shortened telomeres, suggesting that telomere dysfunction plays an important role in disease pathogenesis. These patients inherit CTC1 mutations in a compound heterozygous manner, with one allele encoding a frameshift mutant and the other a missense mutant. How these mutations impact upon telomere function is unknown. We report here the first biochemical characterization of human CTC1 mutations. We found that all CTC1 frameshift mutations generated truncated or unstable protein products, none of which were able to form a complex with STN1-TEN1 on telomeres, resulting in progressive telomere shortening and formation of fused chromosomes. Missense mutations are able to form the CST complex at telomeres, but their expression levels are often repressed by the frameshift mutants. Our results also demonstrate for the first time that CTC1 mutations promote telomere dysfunction by decreasing the stability of STN1 to reduce its ability to interact with DNA Polα, thus highlighting a previously unknown mechanism to induce telomere dysfunction.},
}
@article {pmid23868923,
year = {2013},
author = {Gu, J and Wu, X},
title = {Re: short telomere length, cancer survival, and cancer risk in 47 102 individuals.},
journal = {Journal of the National Cancer Institute},
volume = {105},
number = {15},
pages = {1157},
doi = {10.1093/jnci/djt154},
pmid = {23868923},
issn = {1460-2105},
mesh = {Female ; Humans ; Leukocytes/*pathology ; Male ; Neoplasms/*epidemiology/*genetics ; Telomere/*pathology ; },
}
@article {pmid23865325,
year = {2013},
author = {Huang, L and Wu, Z and Mo, H},
title = {[Experimental study of effect of low power laser on telomere length of cells].},
journal = {Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi},
volume = {30},
number = {3},
pages = {592-596},
pmid = {23865325},
issn = {1001-5515},
mesh = {Cell Line ; Cellular Senescence/*radiation effects ; Fetus ; Fibroblasts/*cytology ; Humans ; *Lasers ; Lung/cytology ; Telomere Homeostasis/*radiation effects ; },
abstract = {To investigate the effect of low power helium neon laser (He-Ne laser) on the telomere length of human fetal lung diploid fibroblast (2BS) cell, we used the laser (gamma = 632. 8 nm, P = 2 mW) to treat the young 2BS cells. Cell growth and proliferation was observed through MTT method after treating with low power laser. The relative telomere length of 2BS cells was detected by fluorescence real-time quantitative PCR (q-PCR). The results showed that the cells of the treated groups grew better than the untreated groups. The telomere DNA length of the old 2BS cells, treated by low power He-Ne laser when they were young, was longer than that of untreated group. The results of the present study indicated that the low power He-Ne laser might decrease shortening rate of telomere and delay the aging of cells. Therefore, this study provides the experimental basis for us to further investigate the effect of low power laser on cell aging at the gene level.},
}
@article {pmid23864530,
year = {2013},
author = {Lu, Y and Wei, B and Zhang, T and Chen, Z and Ye, J},
title = {How will telomeric complex be further contributed to our longevity? - the potential novel biomarkers of telomere complex counteracting both aging and cancer.},
journal = {Protein &amp; cell},
volume = {4},
number = {8},
pages = {573-581},
pmid = {23864530},
issn = {1674-8018},
mesh = {*Aging ; Biomarkers/metabolism ; Humans ; *Longevity ; Neoplasms/metabolism/pathology ; Telomerase/metabolism ; Telomere/*metabolism/ultrastructure ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {With the smooth move towards the coming expected clinical reports of anticancer pharmaceutical molecules targeting telomeres and telomerase, and also with the exciting success in the extension of lifespan by regulating telomerase activity without increased onset of oncogenesis in laboratory mouse models (Garcia-Cao et al., 2006; Jaskelioff et al., 2011), we are convinced that targeting telomeres based on telomerase will be a potential approach to conquer both aging and cancer and the idea of longevity seems to be no more mysterious. More interestingly, emerging evidences from clinical research reveal that other telomeric factors, like specific telomeric binding proteins and nonspecific telomere associated proteins also show crucial importance in aging and oncogenesis. This stems from their roles in the stability of telomere structure and in the inhibition of DNA damage response at telomeres. Uncapping these proteins from chromosome ends leads to dramatic telomere loss and telomere dysfunction which is more abrupt than those induced by telomerase inactivation. Abnormal expression of these factors results in developmental failure, aging and even oncogenesis evidenced by several experimental models and clinical cases, indicating telomere specific proteins and its associated proteins have complimentary roles to telomerase in telomere protection and controlling cellular fate. Thus, these telomeric factors might be potential clinical biomarkers for early detection or even therapeutic targets of aging and cancer. Future studies to elucidate how these proteins function in telomere protection might benefit patients suffering aging or cancer who are not sensitive to telomerase mediation.},
}
@article {pmid23864360,
year = {2013},
author = {Roberts, AR and Huang, E and Jones, L and Daxinger, L and Chong, S and Whitelaw, E},
title = {Non-telomeric epigenetic and genetic changes are associated with the inheritance of shorter telomeres in mice.},
journal = {Chromosoma},
volume = {122},
number = {6},
pages = {541-554},
pmid = {23864360},
issn = {1432-0886},
mesh = {Animals ; DNA Copy Number Variations ; DNA Methylation ; Dyskeratosis Congenita/genetics ; *Epigenesis, Genetic ; Female ; Gene Expression Regulation ; Gene Silencing ; Genetic Loci ; Green Fluorescent Proteins/genetics/metabolism ; Inbreeding ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microarray Analysis ; Pedigree ; RNA/genetics ; Telomerase/genetics ; Telomere/*genetics ; Transgenes ; },
abstract = {Studies using human and mouse cells have revealed some changes to non-telomeric chromatin and gene expression in response to abnormally short telomeres. To investigate this further, we studied the effect of inheriting shorter telomeres on transcription and genetic stability at non-telomeric sites in the mouse. Using multiple generations of Terc knockout mice, we show that inheriting shorter telomeres from one parent increases the likelihood of transcriptional silencing at a non-telomeric green fluorescent protein (GFP) transgene inherited from the other parent. In these cases, silencing must occur at or after zygote formation. In grand-offspring from a G3 Terc (-/-) parent, transgene expression was further reduced and associated with increased DNA methylation and, surprisingly, reduced copy number at the transgene array. In these cases, the transgene had been passed through the germline of a Terc-compromised parent, providing an opportunity for meiotic events. Furthermore, genome-wide microarray analysis of copy number variations revealed greater genetic instability in G3 Terc (-/-) mice than detected in wild-type mice of the same genetic background. Our results have implications for the molecular mechanisms underlying premature-ageing syndromes, such as dyskeratosis congenita. In autosomal-dominant dyskeratosis congenita, progressive telomere shortening is seen as it passes down the generations, and this is associated with anticipation, i.e. the disease becomes more severe earlier. The underlying mechanism is not known, but has been considered to be simply associated with decreases in telomere length. Epigenetic and/or genetic changes at non-telomeric regions could, in theory, be involved.},
}
@article {pmid23863881,
year = {2014},
author = {Sellers, SE and Dumitriu, B and Morgan, MJ and Hughes, WM and Wu, CO and Raghavarchari, N and Yang, Y and Uchida, N and Tisdale, JF and An, DS and Chen, IS and Hematti, P and Donahue, RE and Larochelle, A and Young, NS and Calado, RT and Dunbar, CE},
title = {No impact of lentiviral transduction on hematopoietic stem/progenitor cell telomere length or gene expression in the rhesus macaque model.},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
volume = {22},
number = {1},
pages = {52-58},
pmid = {23863881},
issn = {1525-0024},
support = {T32 AI007413/AI/NIAID NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; },
mesh = {Animals ; Antigens, CD34/metabolism ; *Gene Expression ; Genetic Vectors/*genetics ; Green Fluorescent Proteins/genetics/metabolism ; *Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/*metabolism ; Lentivirus/*genetics ; Leukocytes, Mononuclear/metabolism ; Macaca mulatta ; *Telomere ; Transcriptome ; *Transduction, Genetic ; Transgenes ; },
abstract = {The occurrence of clonal perturbations and leukemia in patients transplanted with gamma-retroviral (RV) vector-transduced autologous hematopoietic stem and progenitor cells (HSPCs) has stimulated extensive investigation, demonstrating that proviral insertions may perturb adjacent proto-oncogene expression. Although enhancer-deleted lentiviruses are less likely to result in insertional oncogenesis, there is evidence that they may perturb transcript splicing, and one patient with a benign clonal expansion of lentivirally transduced HPSC has been reported. The rhesus macaque model provides an opportunity for informative long-term analysis to ask whether transduction impacts on long-term HSPC properties. We used two techniques to examine whether lentivirally transduced HSPCs from eight rhesus macaques transplanted 1-13.5 years previously are perturbed at a population level, comparing telomere length as a measure of replicative history and gene expression profile of vector positive versus vector negative cells. There were no differences in telomere lengths between sorted GFP+ and GFP- blood cells, suggesting that lentiviral (LV) transduction did not globally disrupt replicative patterns. Bone marrow GFP+ and GF- CD34+ cells showed no differences in gene expression using unsupervised and principal component analysis. These studies did not uncover any global long-term perturbation of proliferation, differentiation, or other important functional parameters of transduced HSPCs in the rhesus macaque model.},
}
@article {pmid23862686,
year = {2013},
author = {Han, X and Liu, D and Zhang, Y and Li, Y and Lu, W and Chen, J and Songyang, Z},
title = {Akt regulates TPP1 homodimerization and telomere protection.},
journal = {Aging cell},
volume = {12},
number = {6},
pages = {1091-1099},
pmid = {23862686},
issn = {1474-9726},
support = {CA133249/CA/NCI NIH HHS/United States ; P30CA125123/CA/NCI NIH HHS/United States ; P30 HD024064/HD/NICHD NIH HHS/United States ; P30 CA125123/CA/NCI NIH HHS/United States ; R01 GM095599/GM/NIGMS NIH HHS/United States ; GM095599/GM/NIGMS NIH HHS/United States ; R01 CA133249/CA/NCI NIH HHS/United States ; 5P30HD024064/HD/NICHD NIH HHS/United States ; },
mesh = {Humans ; Isoenzymes/metabolism ; *Protein Multimerization ; Protein Structure, Secondary ; Proto-Oncogene Proteins c-akt/*metabolism ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomeres are specialized structures at the ends of eukaryotic chromosomes that are important for maintaining genome stability and integrity. Telomere dysfunction has been linked to aging and cancer development. In mammalian cells, extensive studies have been carried out to illustrate how core telomeric proteins assemble on telomeres to recruit the telomerase and additional factors for telomere maintenance and protection. In comparison, how changes in growth signaling pathways impact telomeres and telomere-binding proteins remains largely unexplored. The phosphatidylinositol 3-kinase (PI3-K)/Akt (also known as PKB) pathway, one of the best characterized growth signaling cascades, regulates a variety of cellular function including cell proliferation, survival, metabolism, and DNA repair, and dysregulation of PI3-K/Akt signaling has been linked to aging and diseases such as cancer and diabetes. In this study, we provide evidence that the Akt signaling pathway plays an important role in telomere protection. Akt inhibition either by chemical inhibitors or small interfering RNAs induced telomere dysfunction. Furthermore, we found that TPP1 could homodimerize through its OB-fold, a process that was dependent on the Akt kinase. Telomere damage and reduced TPP1 dimerization as a result of Akt inhibition was also accompanied by diminished recruitment of TPP1 and POT1 to the telomeres. Our findings highlight a previously unknown link between Akt signaling and telomere protection.},
}
@article {pmid23861874,
year = {2013},
author = {Jiang, X and Dong, M and Cheng, J and Huang, S and He, Y and Ma, K and Tang, B and Guo, Y},
title = {Decreased leukocyte telomere length (LTL) is associated with stroke but unlikely to be causative.},
journal = {PloS one},
volume = {8},
number = {7},
pages = {e68254},
pmid = {23861874},
issn = {1932-6203},
mesh = {Adult ; Biomarkers ; Cardiovascular Diseases ; Female ; Humans ; Leukocytes/*metabolism ; Life Style ; Male ; Middle Aged ; Risk Factors ; Siblings ; Stroke/*genetics ; *Telomere Shortening ; },
abstract = {AIMS: Interindividual variability in telomere length is highly heritable. Leukocyte telomere length (LTL) shortening has been shown to be associated with the process of atherosclerosis. But whether the inheritance of LTL is related to stroke is still unclear. The aim of this study was to test if telomere shortening was associated with stroke and whether this association was mainly due to inheritance or acquired cardiovascular risk factors.<br><br>METHODS: Our study was focused on stroke in patients and their siblings. 450 subjects were recruited into this study: 150 patients with ischemic stroke as case group, 150 siblings of patients free of stroke (sibling group) and 150 healthy people as normal control. LTL was measured by real-time Polymerase Chain Reactions. The association between LTL and the cardiovascular risk factors was also determined.<br><br>RESULTS: A significant decrease of LTL was found in case group when comparing with sibling (0.92&#xb1;0.77 vs 1.68&#xb1;1.24, p<0.001) and normal groups (0.92&#xb1;0.77 vs 1.95&#xb1;1.07, p<0.001), but no significant difference was found between sibling group and healthy control (p&#x200a;=&#x200a;0.330). Shorter telomere length was independently associated with hypertension (p&#x200a;=&#x200a;0.029, OR&#x200a;=&#x200a;2.189, 95%CI:1.084-4.421), recent social pressure (p&#x200a;=&#x200a;0.001, OR&#x200a;=&#x200a;3.121, 95%CI:1.597-6.101), age (p&#x200a;=&#x200a;0.004, OR&#x200a;=&#x200a;1.055, 95%CI:1.017-1.093), HDL (p&#x200a;=&#x200a;0.022, OR&#x200a;=&#x200a;0.227, 95%CI:0.064-0.810) and diabetes (p&#x200a;=&#x200a;0.018, OR&#x200a;=&#x200a;3.174, 95%CI:1.221-8.252). Additionally, shortened length of telomere (p&#x200a;=&#x200a;0.017, OR&#x200a;=&#x200a;3.996, 95%CI:1.283-12.774) was an independent risk biomarker for stroke among case and sibling groups.<br><br>CONCLUSION: The present study has demonstrated that decreased LTL might be associated with ischemic stroke but unlikely to be causative.},
}
@article {pmid23851344,
year = {2013},
author = {Chen, LY and Lingner, J},
title = {CST for the grand finale of telomere replication.},
journal = {Nucleus (Austin, Tex.)},
volume = {4},
number = {4},
pages = {277-282},
pmid = {23851344},
issn = {1949-1042},
support = {232812/ERC_/European Research Council/International ; },
mesh = {Humans ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomeric DNA at eukaryotic chromosome ends terminates with single stranded 3' G-rich overhangs. The overhang is generated by the interplay of several dynamic processes including semiconservative DNA replication, 3' end elongation by telomerase, C-strand fill-in synthesis and nucleolytic processing. The mammalian CST (CTC1-STN1-TEN1) complex is directly involved at several stages of telomere end formation. Elucidation of its structural organization and identification of interaction partners support the notion that mammalian CST is, as its yeast counterpart, a RPA-like complex. CST binding at mammalian telomere 3' overhangs increases upon their elongation by telomerase. Formation of a trimeric CST complex at telomeric 3'overhangs leads to telomerase inhibition and at the same time mediates a physical interaction with DNA polymerase-α. Thus CST seems to play critical roles in coordinating telomerase elongation and fill-in synthesis to complete telomere replication.},
}
@article {pmid23850488,
year = {2013},
author = {Cesare, AJ and Hayashi, MT and Crabbe, L and Karlseder, J},
title = {The telomere deprotection response is functionally distinct from the genomic DNA damage response.},
journal = {Molecular cell},
volume = {51},
number = {2},
pages = {141-155},
pmid = {23850488},
issn = {1097-4164},
support = {5T32CA009370/CA/NCI NIH HHS/United States ; T32 CA009370/CA/NCI NIH HHS/United States ; GM087476/GM/NIGMS NIH HHS/United States ; R01 GM087476/GM/NIGMS NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; },
mesh = {Blotting, Western ; Cell Cycle Checkpoints ; Cell Division/*physiology ; Cell Proliferation ; Cellular Senescence/*physiology ; DNA Damage/*genetics ; *DNA Replication ; Flow Cytometry ; Fluorescent Antibody Technique ; G2 Phase/*physiology ; *Genome, Human ; Humans ; Immunoprecipitation ; Mitosis/physiology ; Telomere/*physiology ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Transcriptional Activation ; Tumor Suppressor Protein p53/genetics/metabolism ; },
abstract = {Loss of chromosome end protection through telomere erosion is a hallmark of aging and senescence. Here we developed an experimental system that mimics physiological telomere deprotection in human cells and discovered that the telomere deprotection response is functionally distinct from the genomic DNA damage response. We found that, unlike genomic breaks, deprotected telomeres that are recognized as DNA damage but remain in the fusion-resistant intermediate state activate differential ataxia telangiectasia mutated (ATM) signaling where CHK2 is not phosphorylated. Also unlike genomic breaks, we found that deprotected telomeres do not contribute to the G2/M checkpoint and are instead passed through cell division to induce p53-dependent G1 arrest in the daughter cells. Telomere deprotection is therefore an epigenetic signal passed between cell generations to ensure that replication-associated telomere-dependent growth arrest occurs in stable diploid G1 phase cells before genome instability can occur.},
}
@article {pmid23847780,
year = {2013},
author = {Jacobs, JJ},
title = {Senescence: back to telomeres.},
journal = {Nature reviews. Molecular cell biology},
volume = {14},
number = {4},
pages = {196},
pmid = {23847780},
issn = {1471-0080},
mesh = {Cellular Senescence/*genetics ; DNA Damage ; Humans ; Neoplasms/genetics/pathology ; Oncogenes ; Telomere/*genetics ; Telomere Shortening ; },
}
@article {pmid23845919,
year = {2013},
author = {Cohen, S and Janicki-Deverts, D and Turner, RB and Marsland, AL and Casselbrant, ML and Li-Korotky, HS and Epel, ES and Doyle, WJ},
title = {Childhood socioeconomic status, telomere length, and susceptibility to upper respiratory infection.},
journal = {Brain, behavior, and immunity},
volume = {34},
number = {},
pages = {31-38},
pmid = {23845919},
issn = {1090-2139},
support = {UL1 RR024153/RR/NCRR NIH HHS/United States ; R01 AI066367/AI/NIAID NIH HHS/United States ; UL1TR000005/TR/NCATS NIH HHS/United States ; AT005799/AT/NCCIH NIH HHS/United States ; RC1 AT005799/AT/NCCIH NIH HHS/United States ; UL1 TR000005/TR/NCATS NIH HHS/United States ; AT006694/AT/NCCIH NIH HHS/United States ; R01 AT006694/AT/NCCIH NIH HHS/United States ; AI066367/AI/NIAID NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; CD28 Antigens/immunology ; CD8 Antigens/immunology ; Common Cold/*genetics ; Disease Susceptibility ; Female ; Humans ; Male ; Middle Aged ; Respiratory Tract Infections/*genetics ; Rhinovirus/pathogenicity ; Socioeconomic Factors ; T-Lymphocytes/immunology/ultrastructure ; *Telomere ; Telomere Homeostasis ; Young Adult ; },
abstract = {Low socioeconomic status (SES) during childhood and adolescence has been found to predict greater susceptibility to common cold viruses in adults. Here, we test whether low childhood SES is associated with shorter leukocyte telomere length in adulthood, and whether telomere length mediates the association between childhood SES and susceptibility to acute upper respiratory disease in adulthood. At baseline, 196 healthy volunteers reported whether they currently owned their home and, for each year of their childhood, whether their parents owned the family home. Volunteers also had blood drawn for assessment of specific antibody to the challenge virus, and for CD8+ CD28- T-lymphocyte telomere length (in a subset, n=135). They were subsequently quarantined in a hotel, exposed to a virus (rhinovirus [RV] 39) that causes a common cold and followed for infection and illness (clinical cold) over five post-exposure days. Lower childhood SES as measured by fewer years of parental home ownership was associated with shorter adult CD8+ CD28- telomere length and with an increased probability of developing infection and clinical illness when exposed to a common cold virus in adulthood. These associations were independent of adult SES, age, sex, race, body mass, neuroticism, and childhood family characteristics. Associations with infections and colds were also independent of pre-challenge viral-specific antibody and season. Further analyses do not support mediating roles for smoking, alcohol consumption or physical activity but suggest that CD8+ CD28- cell telomere length may act as a partial mediator of the associations between childhood SES and infection and childhood SES and colds.},
}
@article {pmid23843935,
year = {2013},
author = {Ladwig, KH and Brockhaus, AC and Baumert, J and Lukaschek, K and Emeny, RT and Kruse, J and Codd, V and Häfner, S and Albrecht, E and Illig, T and Samani, NJ and Wichmann, HE and Gieger, C and Peters, A},
title = {Posttraumatic stress disorder and not depression is associated with shorter leukocyte telomere length: findings from 3,000 participants in the population-based KORA F4 study.},
journal = {PloS one},
volume = {8},
number = {7},
pages = {e64762},
pmid = {23843935},
issn = {1932-6203},
mesh = {Adult ; Aged ; Depression/epidemiology/*genetics ; Female ; Genetic Association Studies ; Germany ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Population Surveillance ; Risk Factors ; Stress Disorders, Post-Traumatic/epidemiology/*genetics ; *Telomere Shortening ; },
abstract = {BACKGROUND: A link between severe mental stress and shorter telomere length (TL) has been suggested. We analysed the impact of Posttraumatic Stress Disorder (PTSD) on TL in the general population and postulated a dose-dependent TL association in subjects suffering from partial PTSD compared to full PTSD.<br><br>METHODS: Data are derived from the population-based KORA F4 study (2006-2008), located in southern Germany including 3,000 individuals (1,449 men and 1,551 women) with valid and complete TL data. Leukocyte TL was measured using a quantitative PCR-based technique. PTSD was assessed in a structured interview and by applying the Posttraumatic Diagnostic Scale (PDS) and the Impact of Event Scale (IES). A total of 262 (8.7%) subjects qualified for having partial PTSD and 51 (1.7%) for full PTSD. To assess the association of PTSD with the average TL, linear regression analyses with adjustments for potential confounding factors were performed.<br><br>RESULTS: The multiple model revealed a significant association between partial PTSD and TL (beta = -0.051, p = 0.009) as well as between full PTSD and shorter TL (beta = -0.103, p = 0.014) indicating shorter TL on average for partial and full PTSD. An additional adjustment for depression and depressed mood/exhaustion gave comparable beta estimations.<br><br>CONCLUSIONS: Participants with partial and full PTSD had significantly shorter leukocyte TL than participants without PTSD. The dose-dependent variation in TL of subjects with partial and full PTSD exceeded the chronological age effect, and was equivalent to an estimated 5 years in partial and 10 years in full PTSD of premature aging.},
}
@article {pmid23840724,
year = {2013},
author = {Pottier, G and Viau, M and Ricoul, M and Shim, G and Bellamy, M and Cuceu, C and Hempel, WM and Sabatier, L},
title = {Lead Exposure Induces Telomere Instability in Human Cells.},
journal = {PloS one},
volume = {8},
number = {6},
pages = {e67501},
pmid = {23840724},
issn = {1932-6203},
mesh = {Cells, Cultured ; Chromosomal Instability/*drug effects ; Environmental Exposure/adverse effects ; Humans ; Lead/*adverse effects ; Lead Poisoning/complications ; Lymphocytes/drug effects/*pathology ; Telomere/*genetics ; Telomere Homeostasis/*drug effects ; Urinary Bladder Neoplasms/chemically induced/genetics/*pathology ; },
abstract = {Lead (Pb) is an important environmental contaminant due to its widespread use over many centuries. While it affects primarily every organ system of the body, the most pernicious effects of Pb are on the central nervous system leading to cognitive and behavioral modification. Despite decades of research, the mechanisms responsible for Pb toxicity remain poorly understood. Recent work has suggested that Pb exposure may have consequences on chromosomal integrity as it was shown that Pb exposure leads to the generation of γH2Ax foci, a well-established biomarker for DNA double stranded break (DSB formation). As the chromosomal localization of γH2Ax foci plays an important role in determining the molecular mechanism responsible for their formation, we examined the localization of Pb-induced foci with respect to telomeres. Indeed, short or dysfunctional telomeres (uncapped or damaged telomeres) may be recognized as DSB by the DNA repair machinery, leading to "telomere-Induced Foci" (TIFs). In the current study, we show that while Pb exposure did not increase intra-chromosomal foci, it significantly induced TIFs, leading in some cases, to chromosomal abnormalities including telomere loss. The evidence suggests that these chromosomal abnormalities are likely due to perturbation of telomere replication, in particular on the lagging DNA strand. We propose a mechanism by which Pb exposure leads to the loss of telomere maintenance. As numerous studies have demonstrated a role for telomere maintenance in brain development and tissue homeostasis, our results suggest a possible mechanism for lead-induced neurotoxicity.},
}
@article {pmid23834823,
year = {2014},
author = {van Ockenburg, SL and de Jonge, P and van der Harst, P and Ormel, J and Rosmalen, JG},
title = {Does neuroticism make you old? Prospective associations between neuroticism and leukocyte telomere length.},
journal = {Psychological medicine},
volume = {44},
number = {4},
pages = {723-729},
doi = {10.1017/S0033291713001657},
pmid = {23834823},
issn = {1469-8978},
mesh = {Adult ; Aged ; Anxiety Disorders/*complications ; Cellular Senescence/*physiology ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Models, Psychological ; Multiplex Polymerase Chain Reaction ; Neuroticism ; Prospective Studies ; Telomere/*metabolism ; Telomere Shortening/physiology ; },
abstract = {BACKGROUND: Telomere attrition, causing accelerated aging, might be one of the mechanisms through which neuroticism leads to somatic disease and increased all-cause mortality. In the current study we investigated whether neuroticism is prospectively associated with shorter telomere length (TL), a biological marker of aging.<br><br>METHOD: Participants were 3432 adults (mean age 52.9 years, range 32-79). Data were collected at baseline (T1) and at two follow-up visits after 4 years (T2) and 6 years (T3). Neuroticism was assessed using the 12-item neuroticism scale of the Revised Eysenck Personality Questionnaire (EPQ-R) at T2 and T3. TL was measured by a monochrome multiplex quantitative polymerase chain reaction (PCR) assay at T1, T2 and T3. A linear mixed model was used to assess whether neuroticism could predict TL prospectively after adjusting for age, sex, body mass index (BMI), frequency of sports, smoking status, presence of chronic diseases and level of education.<br><br>RESULTS: Neuroticism was a significant negative predictor of TL at follow-up (B = -0.004, p = 0.044) after adjusting for sex, age, baseline TL and various biological and lifestyle factors.<br><br>CONCLUSIONS: High neuroticism is significantly and prospectively associated with telomere attrition independent of lifestyle and other risk factors.},
}
@article {pmid23831727,
year = {2013},
author = {Mourkioti, F and Kustan, J and Kraft, P and Day, JW and Zhao, MM and Kost-Alimova, M and Protopopov, A and DePinho, RA and Bernstein, D and Meeker, AK and Blau, HM},
title = {Role of telomere dysfunction in cardiac failure in Duchenne muscular dystrophy.},
journal = {Nature cell biology},
volume = {15},
number = {8},
pages = {895-904},
pmid = {23831727},
issn = {1476-4679},
support = {R37 AG009521/AG/NIA NIH HHS/United States ; NS069375/NS/NINDS NIH HHS/United States ; P30 NS069375/NS/NINDS NIH HHS/United States ; AG020961/AG/NIA NIH HHS/United States ; R21 AG044815/AG/NIA NIH HHS/United States ; R01 AG020961/AG/NIA NIH HHS/United States ; R01 HL096113/HL/NHLBI NIH HHS/United States ; HL100397/HL/NHLBI NIH HHS/United States ; HL096113/HL/NHLBI NIH HHS/United States ; HL061535/HL/NHLBI NIH HHS/United States ; R01CA84628/CA/NCI NIH HHS/United States ; U01 HL100397/HL/NHLBI NIH HHS/United States ; P50 CA058236/CA/NCI NIH HHS/United States ; AG009521/AG/NIA NIH HHS/United States ; R01 HL061535/HL/NHLBI NIH HHS/United States ; P50CA058236/CA/NCI NIH HHS/United States ; R01 AG009521/AG/NIA NIH HHS/United States ; R01 CA084628/CA/NCI NIH HHS/United States ; P30 AR057220/AR/NIAMS NIH HHS/United States ; },
mesh = {Animals ; Cell Size ; Disease Models, Animal ; Dystrophin/genetics ; Heart Failure/*etiology ; Humans ; Mice ; Mice, Inbred mdx ; Muscular Dystrophy, Duchenne/*complications/*genetics ; Myocytes, Cardiac/pathology ; Telomere/*pathology ; },
abstract = {Duchenne muscular dystrophy (DMD), the most common inherited muscular dystrophy of childhood, leads to death due to cardiorespiratory failure. Paradoxically, mdx mice with the same genetic deficiency of dystrophin exhibit minimal cardiac dysfunction, impeding the development of therapies. We postulated that the difference between mdx and DMD might result from differences in telomere lengths in mice and humans. We show here that, like DMD patients, mice that lack dystrophin and have shortened telomeres (mdx/mTR(KO)) develop severe functional cardiac deficits including ventricular dilation, contractile and conductance dysfunction, and accelerated mortality. These cardiac defects are accompanied by telomere erosion, mitochondrial fragmentation and increased oxidative stress. Treatment with antioxidants significantly retards the onset of cardiac dysfunction and death of mdx/mTR(KO) mice. In corroboration, all four of the DMD patients analysed had 45% shorter telomeres in their cardiomyocytes relative to age- and sex-matched controls. We propose that the demands of contraction in the absence of dystrophin coupled with increased oxidative stress conspire to accelerate telomere erosion culminating in cardiac failure and death. These findings provide strong support for a link between telomere length and dystrophin deficiency in the etiology of dilated cardiomyopathy in DMD and suggest preventive interventions.},
}
@article {pmid23822164,
year = {2013},
author = {Silva-Sousa, R and Varela, MD and Casacuberta, E},
title = {The Putzig partners DREF, TRF2 and KEN are involved in the regulation of the Drosophila telomere retrotransposons, HeT-A and TART.},
journal = {Mobile DNA},
volume = {4},
number = {1},
pages = {18},
pmid = {23822164},
issn = {1759-8753},
abstract = {BACKGROUND: Telomere maintenance in Drosophila relies on the targeted transposition of three very special non-LTR retrotransposons, HeT-A, TART, and TAHRE (HTT). The sequences of the retrotransposon array build up the telomere chromatin in this organism. We have recently reported the role of the chromosomal protein Putzig/Z4 in maintaining a proper chromatin structure at the telomere domain of Drosophila. Because the Putzig protein has been found in different cellular complexes related with cell proliferation, development, and immunity, we decided to investigate whether the previously described Putzig partners, DREF/TRF2 and KEN, could also be involved in the telomere function in this organism.<br><br>RESULTS: We have found that mutant alleles for Dref/Trf2 and Ken show alterations in HeT-A and TART expression, suggesting a possible role of these protein complexes in the regulation of the telomere retrotransposons. In agreement, both HeT-A and TART contain the specific DNA binding sequences for the DREF and the KEN protein proteins.<br><br>CONCLUSIONS: We have identified three new negative regulators involved in the control of the expression of the telomeric retrotransposons, Dref, Trf2, and Ken. Our results offer some clues on which other chromatin-related proteins might be involved in telomere regulation and retrotransposon control.},
}
@article {pmid23819464,
year = {2014},
author = {Wark, L and Danescu, A and Natarajan, S and Zhu, X and Cheng, SY and Hombach-Klonisch, S and Mai, S and Klonisch, T},
title = {Three-dimensional telomere dynamics in follicular thyroid cancer.},
journal = {Thyroid : official journal of the American Thyroid Association},
volume = {24},
number = {2},
pages = {296-304},
pmid = {23819464},
issn = {1557-9077},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Adenocarcinoma, Follicular/*genetics/pathology ; Animals ; Cell Proliferation ; Female ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Telomere/*chemistry ; Thyroid Gland/cytology/pathology ; Thyroid Hormone Receptors beta/*genetics ; },
abstract = {BACKGROUND: Over the last decade, annual incidence rates for thyroid cancer have been among the highest of all cancers in the Western world. However, the genomic mechanisms impacting thyroid carcinogenesis remain elusive.<br><br>METHODS: We employed an established mouse model of follicular thyroid cancer (FTC) with a homozygous proline to valine mutation (Thrb(PV/PV)) in the thyroid receptor &#x3b2;1 (TR&#x3b2;1) and applied quantitative three-dimensional (3D) telomere analysis to determine 3D telomeric profiles in Thrb(PV)(/PV), Thrb(PV/)(+), and Thrb(+/+) mouse thyrocytes before and after histological presentation of FTC.<br><br>RESULTS: Using quantitative fluorescent in situ hybridization (Q-FISH) and TeloView&#x2122; image analysis, we found altered telomeric signatures specifically in mutant mouse thyrocytes. As early as 1 month of age, Thrb(PV/PV) mouse thyrocytes showed more telomeres than normal and heterozygous age-matched counterparts. Importantly, at the very early age of 1 month, 3D telomeric profiles of Thrb(PV/PV) thyrocyte nuclei reveal genetic heterogeneity with several nuclei populations exhibiting different telomere numbers, suggestive of various degrees of aneuploidy within the same animal. This was detected exclusively in Thrb(PV/PV) mice well before the presentation of histological signs of thyroid carcinoma.<br><br>CONCLUSIONS: We identified quantitative 3D telomere analysis as a novel tool for early detection and monitoring of thyrocyte chromosomal (in)stability. This technique has the potential to identify human patients at risk for developing thyroid carcinoma.},
}
@article {pmid23813958,
year = {2013},
author = {Feng, X and Luo, Z and Jiang, S and Li, F and Han, X and Hu, Y and Wang, D and Zhao, Y and Ma, W and Liu, D and Huang, J and Songyang, Z},
title = {The telomere-associated homeobox-containing protein TAH1/HMBOX1 participates in telomere maintenance in ALT cells.},
journal = {Journal of cell science},
volume = {126},
number = {Pt 17},
pages = {3982-3989},
pmid = {23813958},
issn = {1477-9137},
support = {CA133249/CA/NCI NIH HHS/United States ; P30CA125123/CA/NCI NIH HHS/United States ; P30 HD024064/HD/NICHD NIH HHS/United States ; P30 CA125123/CA/NCI NIH HHS/United States ; R01 GM095599/GM/NIGMS NIH HHS/United States ; GM095599/GM/NIGMS NIH HHS/United States ; R01 CA133249/CA/NCI NIH HHS/United States ; 5P30HD024064/HD/NICHD NIH HHS/United States ; },
mesh = {Cell Line ; Cell Proliferation ; DNA/metabolism ; DNA Damage/genetics ; DNA Repair/*genetics ; HEK293 Cells ; Homeodomain Proteins/genetics/*metabolism ; Humans ; Leukemia, Promyelocytic, Acute/genetics/*metabolism ; Neoplasm Proteins/genetics/metabolism ; Neoplasms ; RNA Interference ; RNA, Small Interfering ; Telomerase/biosynthesis/genetics/metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {The majority of cancer cells rely on elevated telomerase expression and activity for rapid growth and proliferation. Telomerase-negative cancer cells, by contrast, often employ the alternative lengthening of telomeres (ALT) pathway to maintain telomeres. ALT cells are characterized by long and dynamic telomeres and the presence of ALT-associated promyelocytic leukemia (PML) bodies (APBs). Previous work has shown the importance of APBs to the ALT pathway, but their formation and precise role remain unclear. Here, we demonstrate that a homeobox-containing protein known as HMBOX1 can directly bind telomeric double-stranded DNA and associate with PML nuclear bodies. Hence, we renamed this protein TAH1 for telomere-associated homeobox-containing protein 1. TAH1 knockdown significantly reduced the number of APBs and led to an increase in DNA damage response signals at telomeres. Importantly, TAH1 inhibition also notably reduced the presence of telomere C-circles, indicating altered ALT activity. Our findings point to TAH1 as a novel link between pathways that regulate DNA damage responses, PML nuclear bodies, and telomere homeostasis in ALT cells, and provide insight into how ALT cells may achieve sustained growth and proliferation independent of the telomerase.},
}
@article {pmid23809762,
year = {2013},
author = {Duong, MT and Sahin, E},
title = {RAP1: protector of telomeres, defender against obesity.},
journal = {Cell reports},
volume = {3},
number = {6},
pages = {1757-1758},
doi = {10.1016/j.celrep.2013.06.011},
pmid = {23809762},
issn = {2211-1247},
mesh = {Animals ; Body Weight/*genetics ; Female ; Humans ; Male ; Obesity/*genetics ; Telomere/*metabolism ; Telomere-Binding Proteins/*genetics ; rap1 GTP-Binding Proteins/*metabolism ; },
abstract = {Telomere dysfunction has previously been linked to metabolic disorders. In this issue of Cell Reports, Martínez et al. (2013) and Yeung et al. (2013) now extend this link, demonstrating that deletion of the telomere binding protein RAP1 leads to obesity and insulin resistance.},
}
@article {pmid23808382,
year = {2013},
author = {Pines, A},
title = {Telomere length and telomerase activity in the context of menopause.},
journal = {Climacteric : the journal of the International Menopause Society},
volume = {16},
number = {6},
pages = {629-631},
doi = {10.3109/13697137.2013.812603},
pmid = {23808382},
issn = {1473-0804},
mesh = {Cellular Senescence ; Estrogen Replacement Therapy ; Female ; Humans ; Life Style ; Menopause/metabolism/*physiology ; Telomerase/*metabolism ; *Telomere Homeostasis/drug effects ; },
abstract = {Telomere length is a marker of cell aging, since shorter telomeres and a higher rate of telomere shortening with time are associated with poorer health status and survival. Various factors may determine telomere length and the function of the telomere maintenance system, including the hereditary load and several modifiable variables such as diet and lifestyle. Telomere length and telomerase activity were investigated extensively in a variety of diseases, such as malignancies (i.e. breast and colon cancer), cardiovascular disease and its related metabolic risk factors, cognitive, mental and psychiatric conditions, and many others. Some evidence points at an association between longer endogenous estrogen exposure (length of reproductive years of life) and greater telomere length and lower telomerase activity. However, there is probably no correlation in regard to menopause per se or the use of hormone therapy. Changing the nutrition and implementing healthy lifestyles may improve the telomere/telomerase parameters in postmenopausal women, but better understanding of this system is still needed.},
}
@article {pmid23804761,
year = {2013},
author = {Buscaglia, R and Miller, MC and Dean, WL and Gray, RD and Lane, AN and Trent, JO and Chaires, JB},
title = {Polyethylene glycol binding alters human telomere G-quadruplex structure by conformational selection.},
journal = {Nucleic acids research},
volume = {41},
number = {16},
pages = {7934-7946},
pmid = {23804761},
issn = {1362-4962},
support = {5P20RR018733/RR/NCRR NIH HHS/United States ; GM077422/GM/NIGMS NIH HHS/United States ; R01 CA035635/CA/NCI NIH HHS/United States ; R21 CA191663/CA/NCI NIH HHS/United States ; R01 GM077422/GM/NIGMS NIH HHS/United States ; P30 GM106396/GM/NIGMS NIH HHS/United States ; CA35635/CA/NCI NIH HHS/United States ; },
mesh = {Acetonitriles/chemistry ; *G-Quadruplexes ; Humans ; Molecular Dynamics Simulation ; Osmotic Pressure ; Polyethylene Glycols/*chemistry ; Potassium/chemistry ; Telomere/*chemistry ; Water/chemistry ; },
abstract = {Polyethylene glycols (PEGs) are widely used to perturb the conformations of nucleic acids, including G-quadruplexes. The mechanism by which PEG alters G-quadruplex conformation is poorly understood. We describe here studies designed to determine how PEG and other co-solutes affect the conformation of the human telomeric quadruplex. Osmotic stress studies using acetonitrile and ethylene glycol show that conversion of the 'hybrid' conformation to an all-parallel 'propeller' conformation is accompanied by the release of about 17 water molecules per quadruplex and is energetically unfavorable in pure aqueous solutions. Sedimentation velocity experiments show that the propeller form is hydrodynamically larger than hybrid forms, ruling out a crowding mechanism for the conversion by PEG. PEGs do not alter water activity sufficiently to perturb quadruplex hydration by osmotic stress. PEG titration experiments are most consistent with a conformational selection mechanism in which PEG binds more strongly to the propeller conformation, and binding is coupled to the conformational transition between forms. Molecular dynamics simulations show that PEG binding to the propeller form is sterically feasible and energetically favorable. We conclude that PEG does not act by crowding and is a poor mimic of the intranuclear environment, keeping open the question of the physiologically relevant quadruplex conformation.},
}
@article {pmid23803152,
year = {2013},
author = {Mompart, F and Robelin, D and Delcros, C and Yerle-Bouissou, M},
title = {3D organization of telomeres in porcine neutrophils and analysis of LPS-activation effect.},
journal = {BMC cell biology},
volume = {14},
number = {},
pages = {30},
pmid = {23803152},
issn = {1471-2121},
mesh = {Animals ; Cell Nucleus/*pathology ; Chromosomes/ultrastructure ; Chromosomes, Artificial, Bacterial/ultrastructure ; DNA Probes ; Imaging, Three-Dimensional/*methods ; In Situ Hybridization, Fluorescence/*methods ; Lipopolysaccharides/*pharmacology ; Microscopy, Confocal/methods ; Models, Animal ; Neutrophils/*pathology ; Swine ; Telomere/*drug effects/*ultrastructure ; },
abstract = {BACKGROUND: While the essential role of 3D nuclear architecture on nuclear functions has been demonstrated for various cell types, information available for neutrophils, essential components of the immune system, remains limited. In this study, we analysed the spatial arrangements of telomeres which play a central role in cell fate. Our studies were carried out in swine, which is an excellent model organism for both biomedical research and agronomic applications. We isolated bacterial artificial chromosome (BAC)-containing subtelomeric p and q sequences specific to each porcine chromosome. This allowed us to study the behaviour of p and q telomeres of homologous chromosomes for seven pairs chosen for their difference in length and morphology. This was performed using 3D-FISH on structurally preserved neutrophils, and confocal microscopy. Resting and lipopolysaccharide (LPS)-activated states were investigated to ascertain whether a response to a pathogen aggression modifies this organization.<br><br>RESULTS: The positions of the p and q telomeres relative to the nuclear outer border were determined in the two states. All p telomeres changed their position significantly during the activation process, although the effect was less pronounced for the q telomeres. The patterns of telomeric associations between homologs and their frequencies were analysed for 7 pairs of chromosomes. This analysis revealed that the distribution of pp, qq and pq associations differs significantly among the 7 chromosomes. This distribution does not fit with the theoretical distribution for each chromosome, suggesting that preferential associations occur between subtelomeres.<br><br>CONCLUSIONS: The percentage of nuclei harbouring at least one telomeric association between homologs varies significantly among the chromosomes, the smallest metacentric chromosome SSC12, which is also the richest in gene-density, harbouring the highest value. The distribution of types of telomeric associations is highly dependent on the chromosomes and is not affected by the activation process. The frequencies of telomeric associations are also highly dependent on the type of association and the type of chromosome. Overall, the LPS-activation process induces only minor changes in these patterns of associations. When telomeric associations occur, the associations of p and q arms from the same chromosome are the most frequent, suggesting that "chromosome bending" occurs in neutrophils as previously observed in gametes.},
}
@article {pmid23802008,
year = {2013},
author = {Rosen, EM},
title = {BRCA1 in the DNA damage response and at telomeres.},
journal = {Frontiers in genetics},
volume = {4},
number = {},
pages = {85},
pmid = {23802008},
issn = {1664-8021},
abstract = {Mutations of the breast and ovarian cancer susceptibility gene 1 (BRCA1) account for about 40-45% of hereditary breast cancer cases. Moreover, a significant fraction of sporadic (non-hereditary) breast and ovarian cancers exhibit reduced or absent expression of the BRCA1 protein, suggesting an additional role for BRCA1 in sporadic cancers. BRCA1 follows the classic pattern of a highly penetrant Knudsen-type tumor suppressor gene in which one allele is inactivated through a germ-line mutation and the other is mutated or deleted within the tumor. BRCA1 is a multi-functional protein but it is not fully understood which function(s) is (are) most important for tumor suppression, nor is it clear why BRCA1-mutations confer a high risk for breast and ovarian cancers and not a broad spectrum of tumor types. Here, we will review BRCA1 functions in the DNA damage response (DDR), which are likely to contribute to tumor suppression. In the process, we will highlight some of the controversies and unresolved issues in the field. We will also describe a recently identified and under-investigated role for BRCA1 in the regulation of telomeres and the implications of this role in the DDR and cancer suppression.},
}
@article {pmid23800953,
year = {2013},
author = {Pitman, RT and Wojdyla, L and Puri, N},
title = {Mechanism of DNA damage responses induced by exposure to an oligonucleotide homologous to the telomere overhang in melanoma.},
journal = {Oncotarget},
volume = {4},
number = {5},
pages = {761-771},
pmid = {23800953},
issn = {1949-2553},
support = {R03 AR050110/AR/NIAMS NIH HHS/United States ; 7R03AR050110/AR/NIAMS NIH HHS/United States ; },
mesh = {Apoptosis/genetics ; Cell Differentiation/drug effects/genetics ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cellular Senescence/genetics ; DNA Damage/drug effects/genetics ; DNA Repair/*genetics ; Gene Expression/genetics ; Heterocyclic Compounds, 3-Ring/pharmacology ; Humans ; Melanoma/genetics/*metabolism ; Oligonucleotides/genetics/metabolism/*pharmacology ; Phosphorylation/genetics ; RNA Interference ; RNA, Small Interfering ; Skin Neoplasms/genetics/*metabolism ; Tankyrases/antagonists &amp; inhibitors/*metabolism ; Telomere/genetics ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; Tumor Suppressor Protein p53/biosynthesis/genetics/*metabolism ; Up-Regulation ; },
abstract = {T-oligo, an 11-base oligonucleotide homologous to the 3'-telomeric overhang, is a novel, potent therapeutic modality in melanoma and multiple other tumor types. T-oligo is proposed to function in a manner similar to experimental disruption of the telomere overhang and induces DNA damage responses including apoptosis, differentiation and senescence. However, important components involved in T-oligo induced responses are not defined, particularly the role of p53, TRF1 and TRF2 in mediating the T-oligo induced responses. In MU, PM-WK, and MM-MC melanoma cells, exposure to T-oligo upregulates p53 expression and phosphorylation, resulting in cellular differentiation and activation of a caspase-mediated apoptotic cascade. However, siRNA-mediated knockdown of p53 completely blocks T-oligo induced differentiation and significantly decreases apoptosis, suggesting that p53 is an important mediator of T-oligo induced responses. In addition, we characterized the roles of telomere binding proteins, TRF1, TRF2, and tankyrase-1, in T-oligo induced damage responses. We demonstrate that tankyrase-1 activity is required for initiation of T-oligo induced damage responses including p53 phosphorylation and reduction of cellular proliferation. These results highlight TRF1, TRF2, tankyrase-1 and p53 as important elements in T-oligo mediated responses and suggest new avenues for research into T-oligo's mechanism of action.},
}
@article {pmid23797874,
year = {2013},
author = {Postepska-Igielska, A and Krunic, D and Schmitt, N and Greulich-Bode, KM and Boukamp, P and Grummt, I},
title = {The chromatin remodelling complex NoRC safeguards genome stability by heterochromatin formation at telomeres and centromeres.},
journal = {EMBO reports},
volume = {14},
number = {8},
pages = {704-710},
pmid = {23797874},
issn = {1469-3178},
mesh = {Autoantigens/genetics/metabolism ; Cell Nucleus/genetics/metabolism ; Centromere/*metabolism ; Centromere Protein A ; *Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/antagonists &amp; inhibitors/genetics/metabolism ; Chromosome Segregation ; Gene Expression Regulation ; *Genes, rRNA ; Genomic Instability ; HeLa Cells ; Heterochromatin/*genetics/metabolism ; Histones/genetics/metabolism ; Humans ; *Mitosis ; RNA, Small Interfering/genetics ; Telomere/*metabolism ; },
abstract = {Constitutive heterochromatin is crucial for the integrity of chromosomes and genomic stability. Here, we show that the chromatin remodelling complex NoRC, known to silence a fraction of rRNA genes, also establishes a repressive heterochromatic structure at centromeres and telomeres, preserving the structural integrity of these repetitive loci. Knockdown of NoRC leads to relaxation of centromeric and telomeric heterochromatin, abnormalities in mitotic spindle assembly, impaired chromosome segregation and enhanced chromosomal instability. The results demonstrate that NoRC safeguards genomic stability by coordinating enzymatic activities that establish features of repressive chromatin at centromeric and telomeric regions, and this heterochromatic structure is required for sustaining genomic integrity.},
}
@article {pmid23795467,
year = {2013},
author = {Raffa, GD and Cenci, G and Ciapponi, L and Gatti, M},
title = {Organization and maintenance of Drosophila telomeres: the roles of terminin and non-terminin proteins.},
journal = {Tsitologiia},
volume = {55},
number = {3},
pages = {204-208},
pmid = {23795467},
issn = {0041-3771},
mesh = {Animals ; Chromatin/genetics/ultrastructure ; DNA Damage ; DNA Transposable Elements/genetics ; DNA-Binding Proteins ; Drosophila melanogaster/cytology/*genetics/ultrastructure ; Nuclear Proteins/*genetics ; Polytene Chromosomes/*genetics/ultrastructure ; Telomerase/genetics/metabolism ; Telomere/*genetics ; },
abstract = {Drosophila telomeres are elongated by occasional transposition of specialized retroelements rather than telomerase activity, and are assembled independently of the sequence of the DNA termini. Drosophila telomeres are capped by terminin, a complex formed by the HOAP, Moi, Ver and HipHop proteins that localize exclusively at telomeres and protect them from fusion events. Other proteins required to prevent end-to-end fusion include HP 1 Eff/UbcD 1, ATM, the components of the Mrel 1-Rad50-Nbs (MRN) complex, and the Woc transcription factor. The terminin proteins are encoded by fast-evolving genes and are not evolutionarily conserved outside the Drosophila species. In contrast, the non-terminin telomere capping proteins are not fast-evolving, do not localize only at telomeres and are conserved from yeasts to mammals. We propose that following telomerase loss, Drosophila rapidly evolved terminin to bind chromosome ends in a sequence-independent manner, and that non-terminin proteins did not evolve as rapidly as terminin because of the functional constraints imposed by their involvement in diverse cellular processes. This hypothesis suggests that the Drosophila non-terminin proteins might correspond to ancestral telomere-associated proteins with homologues in other organisms including humans.},
}
@article {pmid23788667,
year = {2013},
author = {Strandberg, TE and Saijonmaa, O and Fyhrquist, F},
title = {Re: "Association of leukocyte telomere length with breast cancer risk: nested case-control findings from the Shanghai Women's Health Study".},
journal = {American journal of epidemiology},
volume = {178},
number = {4},
pages = {662-663},
doi = {10.1093/aje/kwt130},
pmid = {23788667},
issn = {1476-6256},
mesh = {Breast Neoplasms/*epidemiology ; Female ; Humans ; Leukocytes/*ultrastructure ; Telomere/*ultrastructure ; },
}
@article {pmid23785520,
year = {2013},
author = {Kim, JH and Kim, HK and Ko, JH and Bang, H and Lee, DC},
title = {The relationship between leukocyte mitochondrial DNA copy number and telomere length in community-dwelling elderly women.},
journal = {PloS one},
volume = {8},
number = {6},
pages = {e67227},
pmid = {23785520},
issn = {1932-6203},
mesh = {Aged ; Aging/*genetics ; DNA, Mitochondrial/*genetics/metabolism ; Female ; *Gene Dosage ; Humans ; Leukocytes/*metabolism ; Risk Factors ; Telomere/*genetics/metabolism ; },
abstract = {PURPOSE: Both telomere length and mitochondrial function are accepted as reflective indices of aging. Recent studies have shown that telomere dysfunction may influence impaired mitochondrial biogenesis and function. However, there has been no study regarding the possible association between telomere and mitochondrial function in humans. Therefore, the purpose of the study was to identify any relationships between mitochondrial and telomere function.<br><br>METHODS: The present study included 129 community-dwelling, elderly women. The leukocyte mitochondrial DNA copy number and telomere length were measured using a quantitative real-time polymerase chain reaction method. Anthropometric measurement, biochemical blood testing, a depression screening questionnaire using a 15-question geriatric depression scale (GDS-15), and a cognitive function test using the Korean version of the mini mental state examination (K-MMSE) were performed.<br><br>RESULTS: Leukocyte mtDNA copy number was positively associated with telomere length (r=0.39, p=<0.0001) and K-MMSE score (r=0.06, p=0.02). Additionally, leukocyte mtDNA copy number was negatively correlated with GDS-15 score (r=-0.17, p=0.04). Age (r=-0.15, p=0.09), waist circumference (r=-0.16, p=0.07), and serum ferritin level (r=-0.13, p=0.07) tended to be inversely correlated with leukocyte mtDNA copy number. With a stepwise multiple regression analysis, telomere length was found to be an independent factor associated with leukocyte mtDNA copy number after adjustment for confounding variables including age, body mass index, waist circumference, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, hs-CRP, serum ferritin, HOMA-IR, K-MMSE, GDS-15, hypertension, diabetes, dyslipidemia, currently smoking, alcohol drinking, and regular exercise.<br><br>CONCLUSIONS: This study showed that leukocyte mtDNA copy number was positively correlated with leukocyte telomere length in community-dwelling elderly women. Our findings suggest that telomere function may influence mitochondrial function in humans.},
}
@article {pmid23783570,
year = {2013},
author = {Laterreur, N and Eschbach, SH and Lafontaine, DA and Wellinger, RJ},
title = {A new telomerase RNA element that is critical for telomere elongation.},
journal = {Nucleic acids research},
volume = {41},
number = {16},
pages = {7713-7724},
pmid = {23783570},
issn = {1362-4962},
support = {MOP97874//Canadian Institutes of Health Research/Canada ; },
mesh = {Base Sequence ; Molecular Sequence Data ; Mutation ; Nucleic Acid Conformation ; RNA/*chemistry ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Telomerase/*chemistry/metabolism ; *Telomere Homeostasis ; },
abstract = {The stability of chromosome ends, the telomeres, is dependent on the ribonucleoprotein telomerase. In vitro, telomerase requires at least one RNA molecule and a reverse transcriptase-like protein. However, for telomere homeostasis in vivo, additional proteins are required. Telomerase RNAs of different species vary in size and sequence and only few features common to all telomerases are known. Here we show that stem-loop IVc of the Saccharomyces cerevisiae telomerase RNA contains a structural element that is required for telomerase function in vivo. Indeed, the distal portion of stem-loop IVc stimulates telomerase activity in vitro in a way that is independent of Est1 binding on more proximal portions of this stem-loop. Functional analyses of the RNA in vivo reveal that this distal element we call telomerase-stimulating structure (TeSS) must contain a bulged area in single stranded form and also show that Est1-dependent functions such as telomerase import or recruitment are not affected by TeSS. This study thus uncovers a new structural telomerase RNA element implicated in catalytic activity. Given previous evidence for TeSS elements in ciliate and mammalian RNAs, we speculate that this substructure is a conserved feature that is required for optimal telomerase holoenzyme function.},
}
@article {pmid23782086,
year = {2013},
author = {Ballew, BJ and Savage, SA},
title = {Updates on the biology and management of dyskeratosis congenita and related telomere biology disorders.},
journal = {Expert review of hematology},
volume = {6},
number = {3},
pages = {327-337},
doi = {10.1586/ehm.13.23},
pmid = {23782086},
issn = {1747-4094},
mesh = {Bone Marrow/physiopathology ; Cell Cycle Proteins/genetics/metabolism ; Dyskeratosis Congenita/diagnosis/*metabolism/pathology ; Genetic Heterogeneity ; Germ-Line Mutation ; Humans ; Nuclear Proteins/genetics/metabolism ; Psychotic Disorders/etiology ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Dyskeratosis congenita (DC) is a cancer-prone inherited bone marrow failure syndrome caused by aberrant telomere biology. The mucocutaneous triad of nail dysplasia, abnormal skin pigmentation and oral leukoplakia is diagnostic, but is not always present; DC can also be diagnosed by the presence of very short leukocyte telomeres. Patients with DC are at high risk of bone marrow failure, pulmonary fibrosis, liver disease, cancer and other medical problems. Germline mutations in one of nine genes associated with telomere maintenance are present in approximately 60% of patients. DC is one among the group of clinically and biologically related telomere biology disorders, including Hoyeraal-Hreidarsson syndrome, Revesz syndrome, Coats plus (also known as cranioretinal microangiopathy with calcifications and cysts) and subsets of aplastic anemia, pulmonary fibrosis, nonalcoholic and noninfectious liver disease and leukemia. The authors review the pathobiology that connects DC and the related telomere biology disorders, methods of diagnosis and management modalities.},
}
@article {pmid23781235,
year = {2013},
author = {Lehmann, G and Muradian, KK and Fraifeld, VE},
title = {Telomere length and body temperature-independent determinants of mammalian longevity?.},
journal = {Frontiers in genetics},
volume = {4},
number = {},
pages = {111},
pmid = {23781235},
issn = {1664-8021},
}
@article {pmid23779129,
year = {2013},
author = {Heaphy, CM and Yoon, GS and Peskoe, SB and Joshu, CE and Lee, TK and Giovannucci, E and Mucci, LA and Kenfield, SA and Stampfer, MJ and Hicks, JL and De Marzo, AM and Platz, EA and Meeker, AK},
title = {Prostate cancer cell telomere length variability and stromal cell telomere length as prognostic markers for metastasis and death.},
journal = {Cancer discovery},
volume = {3},
number = {10},
pages = {1130-1141},
pmid = {23779129},
issn = {2159-8290},
support = {P50 CA058236/CA/NCI NIH HHS/United States ; R01 CA072036/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; CA141298/CA/NCI NIH HHS/United States ; CA55075/CA/NCI NIH HHS/United States ; U19 CA055075/CA/NCI NIH HHS/United States ; R01 CA133891/CA/NCI NIH HHS/United States ; HL35464/HL/NHLBI NIH HHS/United States ; P50 CA58236/CA/NCI NIH HHS/United States ; R01 HL035464/HL/NHLBI NIH HHS/United States ; CA13389/CA/NCI NIH HHS/United States ; R01 CA141298/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; *Chromosomal Instability ; Cohort Studies ; Disease-Free Survival ; Genetic Variation ; Humans ; Male ; Middle Aged ; Neoplasm Metastasis/*genetics/physiopathology ; Prognosis ; Prospective Studies ; Prostatic Neoplasms/*genetics/mortality/pathology ; Risk Factors ; Stromal Cells/metabolism/*ultrastructure ; Telomere/*genetics/metabolism/*ultrastructure ; },
abstract = {UNLABELLED: Current prognostic indicators are imperfect predictors of outcome in men with clinically localized prostate cancer. Thus, tissue-based markers are urgently needed to improve treatment and surveillance decision-making. Given that shortened telomeres enhance chromosomal instability and such instability is a hallmark of metastatic lesions, we hypothesized that alterations in telomere length in the primary cancer would predict risk of progression to metastasis and prostate cancer death. To test this hypothesis, we conducted a prospective cohort study of 596 surgically treated men who participated in the ongoing Health Professionals Follow-up Study. Men who had the combination of more variable telomere length among prostate cancer cells (cell-to-cell) and shorter telomere length in prostate cancer-associated stromal (CAS) cells were substantially more likely to progress to metastasis or die of their prostate cancer. These findings point to the translational potential of this telomere biomarker for prognostication and risk stratification for individualized therapeutic and surveillance strategies.<br><br>SIGNIFICANCE: In this prospective study, the combination of more variable telomere length among cancer cells and shorter telomere length in CAS cells was strongly associated with progression to metastasis and prostate cancer death, pointing to the translational potential for prognostication and risk stratifi cation for individualized therapeutic and surveillance strategies.},
}
@article {pmid23776040,
year = {2013},
author = {Zhang, Y and Shin, SJ and Liu, D and Ivanova, E and Foerster, F and Ying, H and Zheng, H and Xiao, Y and Chen, Z and Protopopov, A and Depinho, RA and Paik, JH},
title = {ZNF365 promotes stability of fragile sites and telomeres.},
journal = {Cancer discovery},
volume = {3},
number = {7},
pages = {798-811},
pmid = {23776040},
issn = {2159-8290},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; R37 CA084628/CA/NCI NIH HHS/United States ; AG-NS-0646-10/AG/NIA NIH HHS/United States ; R01 CA084628/CA/NCI NIH HHS/United States ; R01CA84628/CA/NCI NIH HHS/United States ; UL1 TR000457/TR/NCATS NIH HHS/United States ; U01 CA141508/CA/NCI NIH HHS/United States ; U01CA141508/CA/NCI NIH HHS/United States ; },
mesh = {Cellular Senescence/genetics ; Chromosome Aberrations ; Chromosome Fragile Sites/genetics ; DNA Damage/genetics ; DNA-Binding Proteins/*genetics/metabolism ; Genomic Instability ; Humans ; Neoplasms/*genetics/pathology ; Telomere/*genetics/pathology ; Transcription Factors/*genetics/metabolism ; Tumor Suppressor Protein p53/*genetics/metabolism ; },
abstract = {Critically short telomeres activate cellular senescence or apoptosis, as mediated by the tumor suppressor p53, but in the absence of this checkpoint response, telomere dysfunction engenders chromosomal aberrations and cancer. Here, analysis of p53-regulated genes activated in the setting of telomere dysfunction identified Zfp365 (ZNF365 in humans) as a direct p53 target that promotes genome stability. Germline polymorphisms in the ZNF365 locus are associated with increased cancer risk, including those associated with telomere dysfunction. On the mechanistic level, ZNF365 suppresses expression of a subset of common fragile sites, including telomeres. In the absence of ZNF365, defective telomeres engage in aberrant recombination of telomere ends, leading to increased telomere sister chromatid exchange and formation of anaphase DNA bridges, including ultra-fine DNA bridges, and ultimately increased cytokinesis failure and aneuploidy. Thus, the p53-ZNF365 axis contributes to genomic stability in the setting of telomere dysfunction.},
}
@article {pmid23775864,
year = {2013},
author = {Zhang, X and Lin, S and Funk, WE and Hou, L},
title = {Environmental and occupational exposure to chemicals and telomere length in human studies.},
journal = {Occupational and environmental medicine},
volume = {70},
number = {10},
pages = {743-749},
doi = {10.1136/oemed-2012-101350},
pmid = {23775864},
issn = {1470-7926},
support = {R21 ES020010/ES/NIEHS NIH HHS/United States ; R21 ES020984-01/ES/NIEHS NIH HHS/United States ; },
mesh = {Air Pollutants/*adverse effects ; Environmental Exposure/*adverse effects ; Hazardous Waste/adverse effects ; Humans ; Lead/adverse effects ; Occupational Exposure/*adverse effects ; Organic Chemicals/*adverse effects ; Pesticides/adverse effects ; Polycyclic Aromatic Hydrocarbons/adverse effects ; Telomere/*drug effects ; Telomere Shortening/*drug effects ; },
abstract = {Telomeres are complexes of tandem repeats of DNA (5'-TTAGGG-3') and protein that cap eukaryotic chromosomes and play a critical role in chromosome stability. Telomeres shorten with aging and this process can be accelerated by increased oxidative stress and episodes of inflammation. Evidence is rapidly growing that telomere length (TL) may be affected by environmental chemicals that have frequently been associated with chronic diseases. In this article, we review the published data on TL in relation to environmental and occupational exposure to several chemicals based on our own and others' studies. The environmental and occupational exposures associated with shorter TL include traffic-related air pollution (ie, particulate matter (PM), black carbon (BC), and benzene and toluene), polycyclic aromatic hydrocarbons (PAHs), N-nitrosamines, pesticides, lead, exposure in car mechanical workshops, and hazardous waste exposure. Arsenic, persistent organic pollutants (POPs) and short-term exposure to PM are associated with longer TL. We discuss the possible reasons for the differences in results, including time- and dose-related issues, study design, and possible mechanisms involved in telomere regulation. We also discuss the future directions and challenges for TL-related environmental and occupational health research, such as investigation of TL in subpopulations of blood leukocytes, and the study of genetic and epigenetic factors that may regulate telomere integrity using longitudinal designs.},
}
@article {pmid23774483,
year = {2013},
author = {Hou, L and Andreotti, G and Baccarelli, AA and Savage, S and Hoppin, JA and Sandler, DP and Barker, J and Zhu, ZZ and Hoxha, M and Dioni, L and Zhang, X and Koutros, S and Freeman, LE and Alavanja, MC},
title = {Lifetime pesticide use and telomere shortening among male pesticide applicators in the Agricultural Health Study.},
journal = {Environmental health perspectives},
volume = {121},
number = {8},
pages = {919-924},
pmid = {23774483},
issn = {1552-9924},
support = {Z01 ES049030/ImNIH/Intramural NIH HHS/United States ; Z01CP0119/CP/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; *Agriculture ; DDT/toxicity ; Humans ; Iowa ; Male ; Middle Aged ; Mouth Mucosa/chemistry/*drug effects ; North Carolina ; *Occupational Exposure ; Pesticides/*toxicity ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; Telomere Shortening/*drug effects ; },
abstract = {BACKGROUND: Telomere length (TL) in surrogate tissues may be influenced by environmental exposures.<br><br>OBJECTIVE: We aimed to determine whether lifetime pesticides use is associated with buccal cell TL.<br><br>METHODS: We examined buccal cell TL in relation to lifetime use of 48 pesticides for 1,234 cancer-free white male pesticide applicators in the Agricultural Health Study (AHS), a prospective cohort study of 57,310 licensed pesticide applicators. Participants provided detailed information on lifetime use of 50 pesticides at enrollment (1993-1997). Buccal cells were collected from 1999 to 2006. Relative telomere length (RTL) was measured using quantitative real-time polymerase chain reaction. We used linear regression modeling to evaluate the associations between specific pesticides and the logarithm of RTL, adjusting for age at buccal cell collection, state of residence, applicator license type, chewing tobacco use, and total lifetime days of all pesticide use.<br><br>RESULTS: The mean RTL for participants decreased significantly in association with increased lifetime days of pesticide use for alachlor (p = 0.002), 2,4-dichlorophenoxyacetic acid (2,4-D; p = 0.004), metolachlor (p = 0.01), trifluralin (p = 0.05), permethrin (for animal application) (p = 0.02), and toxaphene (p = 0.04). A similar pattern of RTL shortening was observed with the metric lifetime intensity-weighted days of pesticide use. For dichlorodiphenyltrichloroethane (DDT), we observed significant RTL shortening for lifetime intensity-weighted days (p = 0.04), but not for lifetime days of DDT use (p = 0.08). No significant RTL lengthening was observed for any pesticide.<br><br>CONCLUSION: Seven pesticides previously associated with cancer risk in the epidemiologic literature were inversely associated with RTL in buccal cell DNA among cancer-free pesticide applicators. Replication of these findings is needed because we cannot rule out chance or fully rule out bias.},
}
@article {pmid23772418,
year = {2013},
author = {Gardano, L and Pucci, F and Christian, L and Le Bihan, T and Harrington, L},
title = {Telomeres, a busy platform for cell signaling.},
journal = {Frontiers in oncology},
volume = {3},
number = {},
pages = {146},
pmid = {23772418},
issn = {2234-943X},
support = {/WT_/Wellcome Trust/United Kingdom ; G0800081/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Telomeres are the terminal structures at the ends of linear chromosomes that represent a solution to the end replication problem. Specific binding of the six-protein subunit complex shelterin to telomeric, repetitive TTAGGG DNA sequences contributes to the stable architecture and maintenance of telomeres. Proteins involved in the DNA damage response are also localized at telomeres, and play a role in the surveillance and maintenance of telomere integrity. The enzyme responsible for telomere extension is telomerase, a ribonucleoprotein with reverse transcriptase activity. In the absence of telomerase, telomeres shorten to a length threshold that triggers the DNA damage response and replicative senescence. Here, we will summarize the latest findings concerning vertebrate telomere structure and epigenetics, and we present data regarding the impact of short telomeres upon cell signaling. In particular, in murine embryonic stem cells lacking telomerase, we found that distribution of cytosolic/nuclear β-catenin, a key component of the Wnt signaling pathway, changes when telomeres become critically short. We discuss implications and future perspectives of the effect of epigenetic modifications and/or conformational changes of telomeres on cell metabolism and signaling networks. Such an analysis may unveil potential therapeutic targets for pathologies like cancer, where the integrity of telomeres is altered.},
}
@article {pmid23770245,
year = {2013},
author = {Simeonova, I and Jaber, S and Draskovic, I and Bardot, B and Fang, M and Bouarich-Bourimi, R and Lejour, V and Charbonnier, L and Soudais, C and Bourdon, JC and Huerre, M and Londono-Vallejo, A and Toledo, F},
title = {Mutant mice lacking the p53 C-terminal domain model telomere syndromes.},
journal = {Cell reports},
volume = {3},
number = {6},
pages = {2046-2058},
doi = {10.1016/j.celrep.2013.05.028},
pmid = {23770245},
issn = {2211-1247},
mesh = {Animals ; Disease Models, Animal ; Gene Expression ; Humans ; Male ; Mice ; Mice, Mutant Strains ; Mutation ; Protein Structure, Tertiary ; Syndrome ; Telomere/*genetics/metabolism/pathology ; Telomere-Binding Proteins/*genetics/metabolism ; Tumor Suppressor Protein p53/*genetics/metabolism ; },
abstract = {Mutations in p53, although frequent in human cancers, have not been implicated in telomere-related syndromes. Here, we show that homozygous mutant mice expressing p53Δ31, a p53 lacking the C-terminal domain, exhibit increased p53 activity and suffer from aplastic anemia and pulmonary fibrosis, hallmarks of syndromes caused by short telomeres. Indeed, p53Δ31/Δ31 mice had short telomeres and other phenotypic traits associated with the telomere disease dyskeratosis congenita and its severe variant the Hoyeraal-Hreidarsson syndrome. Heterozygous p53+/Δ31 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms. Importantly, several genes involved in telomere metabolism were downregulated in p53Δ31/Δ31 cells, including Dyskerin, Rtel1, and Tinf2, which are mutated in dyskeratosis congenita, and Terf1, which is implicated in aplastic anemia. Together, these data reveal that a truncating mutation can activate p53 and that p53 plays a major role in the regulation of telomere metabolism.},
}
@article {pmid23765250,
year = {2013},
author = {Abedalthagafi, M and Phillips, JJ and Kim, GE and Mueller, S and Haas-Kogen, DA and Marshall, RE and Croul, SE and Santi, MR and Cheng, J and Zhou, S and Sullivan, LM and Martinez-Lage, M and Judkins, AR and Perry, A},
title = {The alternative lengthening of telomere phenotype is significantly associated with loss of ATRX expression in high-grade pediatric and adult astrocytomas: a multi-institutional study of 214 astrocytomas.},
journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},
volume = {26},
number = {11},
pages = {1425-1432},
pmid = {23765250},
issn = {1530-0285},
support = {P50 CA097257/CA/NCI NIH HHS/United States ; R01 NS081117/NS/NINDS NIH HHS/United States ; CA097257/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Astrocytoma/*chemistry/mortality/pathology/surgery ; Biomarkers, Tumor/*analysis/*genetics ; Brain Neoplasms/*chemistry/*genetics/mortality/pathology/surgery ; Child ; DNA Helicases/*analysis ; Female ; Gene Amplification ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Isocitrate Dehydrogenase/analysis/genetics ; Kaplan-Meier Estimate ; Male ; Mutation ; Neoplasm Grading ; North America ; Nuclear Proteins/*analysis ; Proportional Hazards Models ; Receptor, Platelet-Derived Growth Factor alpha/genetics ; Risk Factors ; Telomere/*genetics ; *Telomere Homeostasis ; Time Factors ; Treatment Outcome ; X-linked Nuclear Protein ; },
abstract = {Loss-of-function of alpha thalassemia/mental retardation syndrome X-linked (ATRX) protein leads to a phenotype called alternative lengthening of telomeres (ALT) in some tumors. High-grade astrocytomas comprise a heterogeneous group of central nervous system tumors. We examined a large cohort of adult (91) and pediatric (n=88) high-grade astrocytomas as well as lower grade forms (n=35) for immunohistochemical loss of ATRX protein expression and the presence of ALT using telomere-specific fluorescence in situ hybridization, with further correlation to other known genetic alterations. We found that in pediatric high-grade astrocytomas, 29.6% of tumors were positive for ALT and 24.5% were immunonegative for the ATRX protein, these two alterations being highly associated with one another (P<0.0001). In adult high-grade astrocytomas, 26.4% of tumors were similarly positive for ALT, including 80% of ATRX protein immunonegative cases (P<0.0001). Similar frequencies were found in 11 adult low-grade astrocytomas, whereas all 24 pilocytic astrocytomas were negative for ALT. We did not find any significant correlations between isocitrate dehydrogenase status and either ALT positivity or ATRX protein expression in our adult high-grade astrocytomas. In both cohorts, however, the ALT positive high-grade astrocytomas showed more frequent amplification of the platelet-derived growth factor receptor alpha gene (PDGFRA; 45% and 50%, respectively) than the ALT negative counterparts (18% and 26%; P=0.03 for each). In summary, our data show that the ALT and ATRX protein alterations are common in both pediatric and adult high-grade astrocytomas, often with associated PDGFRA gene amplification.},
}
@article {pmid23764353,
year = {2013},
author = {Jørgensen, PB and Fedder, J and Koelvraa, S and Graakjaer, J},
title = {Age-dependence of relative telomere length profiles during spermatogenesis in man.},
journal = {Maturitas},
volume = {75},
number = {4},
pages = {380-385},
doi = {10.1016/j.maturitas.2013.05.001},
pmid = {23764353},
issn = {1873-4111},
mesh = {Adult ; Age Factors ; Aging/*genetics ; Humans ; Male ; Middle Aged ; Spermatogenesis/*genetics ; Telomerase/*metabolism ; *Telomere ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Telomeres, the protective structures at the outmost ends of chromosomes, shorten in all somatic cells with each cell-division and by cumulative oxidative damage. To counteract that these shortened telomeres are passed on to offspring, the telomeres are elongated by the enzyme, telomerase, during human spermatogenesis. A few groups have tried to elucidate this process by measuring telomerase activity in the various cell-types during spermatogenesis, but until now, no one has ever measured telomere length (TL) during these different stages in humans. Some groups have measured TL in spermatozoa and surprisingly found that telomeres of older men are longer, than those from younger men. To elucidate this phenomenon we investigated if the distribution of TL over the various precursor germ cells in old males differed from young males, perhaps indicating a more ubiquitous telomere elongation in testes from older men. We therefore obtained testicular biopsies from 6 older and 6 younger men undergoing vasectomy. The cells were suspended as single cells and smeared onto slides, followed by characterization of cell stages by phase contrast microscopy. Mean TL in individual cells was subsequently measured by telomere QFISH. Our data revealed no difference in the TL profile during spermatogenesis between younger and older men. All men had a similar profile which strongly resembled the telomerase expression profile found by others. This indicates that the longer telomeres in older men are not caused by a wider window of telomere elongation, stretching over more cell-types of spermatogenesis.},
}
@article {pmid23759580,
year = {2013},
author = {Chai, W and Zheng, L and Shen, B},
title = {DNA2, a new player in telomere maintenance and tumor suppression.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {12},
number = {13},
pages = {1985-1986},
pmid = {23759580},
issn = {1551-4005},
support = {R01 CA085344/CA/NCI NIH HHS/United States ; R21 AG041375/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA Helicases/*physiology ; DNA Replication ; Humans ; *Telomere Homeostasis ; Tumor Suppressor Proteins/*physiology ; },
}
@article {pmid23748031,
year = {2013},
author = {Nilsson, PM and Tufvesson, H and Leosdottir, M and Melander, O},
title = {Telomeres and cardiovascular disease risk: an update 2013.},
journal = {Translational research : the journal of laboratory and clinical medicine},
volume = {162},
number = {6},
pages = {371-380},
doi = {10.1016/j.trsl.2013.05.004},
pmid = {23748031},
issn = {1878-1810},
mesh = {Cardiovascular Diseases/*etiology ; Humans ; Hypertrophy, Left Ventricular/etiology ; Leukocytes/physiology ; Risk Factors ; Telomere/genetics/*physiology ; Telomere Shortening ; Translational Research, Biomedical ; },
abstract = {Leukocyte telomere length (LTL) has been regarded as a potential marker of biologic aging because it usually shortens in a predictable way with age. Recently, a growing interest in cardiovascular aging has led to a number of new epidemiologic studies investigating LTL in various disease conditions. Some methodological problems exist because there are different methods available to determine LTL, and standardization is much needed. For example, in the majority of studies, patients with early-onset coronary heart disease have been shown to have shorter LTL. In addition, patients with diabetes mellitus complications tend to have shorter LTL than control subjects. On the other hand, increased left ventricular hypertrophy or mass is associated with longer LTL, and studies investigating hypertension have reported both shorter and longer LTL than found in normotensive control subjects. There is, therefore, a need for longitudinal studies to elucidate these complicated relationships further, to provide estimations of telomere attrition rates, and to overcome analytical problems when only cross-sectional studies are used. The understanding of cardiovascular aging and telomere biology may open up new avenues for interventions, such as stem cell therapy or agents that could retard this aging process over and beyond conventional risk factor control.},
}
@article {pmid23746845,
year = {2013},
author = {Shi, T and Bunker, RD and Mattarocci, S and Ribeyre, C and Faty, M and Gut, H and Scrima, A and Rass, U and Rubin, SM and Shore, D and Thomä, NH},
title = {Rif1 and Rif2 shape telomere function and architecture through multivalent Rap1 interactions.},
journal = {Cell},
volume = {153},
number = {6},
pages = {1340-1353},
doi = {10.1016/j.cell.2013.05.007},
pmid = {23746845},
issn = {1097-4172},
mesh = {Amino Acid Sequence ; Binding Sites ; Chromosomes, Fungal/*metabolism ; Crystallography, X-Ray ; Models, Molecular ; Molecular Sequence Data ; Protein Interaction Maps ; Repressor Proteins/*metabolism ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Sequence Alignment ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; Transcription Factors/*metabolism ; },
abstract = {Yeast telomeres comprise irregular TG1-3 DNA repeats bound by the general transcription factor Rap1. Rif1 and Rif2, along with Rap1, form the telosome, a protective cap that inhibits telomerase, counteracts SIR-mediated transcriptional silencing, and prevents inadvertent recognition of telomeres as DNA double-strand breaks. We provide a molecular, biochemical, and functional dissection of the protein backbone at the core of the yeast telosome. The X-ray structures of Rif1 and Rif2 bound to the Rap1 C-terminal domain and that of the Rif1 C terminus are presented. Both Rif1 and Rif2 have separable and independent Rap1-binding epitopes, allowing Rap1 binding over large distances (42-110 Å). We identify tetramerization (Rif1) and polymerization (Rif2) modules that, in conjunction with the long-range binding, give rise to a higher-order architecture that interlinks Rap1 units. This molecular Velcro relies on Rif1 and Rif2 to recruit and stabilize Rap1 on telomeric arrays and is required for telomere homeostasis in vivo.},
}
@article {pmid23740629,
year = {2013},
author = {Guan, JZ and Guan, WP and Maeda, T and Makino, N},
title = {Analysis of telomere length and subtelomeric methylation of circulating leukocytes in women with Alzheimer's disease.},
journal = {Aging clinical and experimental research},
volume = {25},
number = {1},
pages = {17-23},
doi = {10.1007/s40520-013-0006-0},
pmid = {23740629},
issn = {1720-8319},
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*metabolism/pathology ; Case-Control Studies ; *DNA Methylation ; Female ; Humans ; Leukocytes/metabolism/pathology ; *Telomere Homeostasis ; },
abstract = {BACKGROUNDS AND AIMS: Telomere attrition proceeds with the aging process, and is also associated with aging disease conditions, such as Alzheimer's disease (AD). The aging process also affects subtelomeric methylation status. In the present study, the telomere length and the subtelomeric methylation status in female AD patients were analyzed to see how AD affects telomere structure.<br><br>METHODS: Terminal restriction fragment length of 23 AD patients' peripheral leukocytes was analyzed with methylation sensitive- and insensitive-isoschizomer by Southern blot.<br><br>RESULTS: AD patients were found to have normal mean telomere lengths (controls; 6.4 &#xb1; 0.9 kb, AD; 6.1 &#xb1; 0.8 kb, p = 0.131), a proportionally decreased number of the longest telomeres (>9.4 kb) (controls; 30.3 &#xb1; 7.9%, AD; 24.4 &#xb1; 8.3%, p = 0.013), increased medium-sized telomeres (controls; 51.7 &#xb1; 3.3%, AD 55.5 &#xb1; 6.4%, p = 0.015) and unchanged numbers of the shortest telomeres (<4.4 kb) (controls; 18.0 &#xb1; 7.8, AD; 20.2 &#xb1; 8.9%, p = 0.371) in their peripheral leukocytes. The subtelomeres of telomeres in the shortest range (<4.4 kb) were more methylated in AD subjects than in controls (controls; 0.21 &#xb1; 0.23, AD; 0.41 &#xb1; 0.26, p = 0.016).<br><br>CONCLUSIONS: These results may indicate that AD contributes to the loss of cells bearing the shortest telomeres, with hypomethylation of subtelomeres occurring in addition to telomere attrition, resulting in an apparent normal mean telomere length in AD patients. The relatively high subtelomeric methylation status of the shortest telomeres in peripheral blood leukocytes may be a characteristic of AD. This report demonstrates that the epigenetic status of the telomeric region is affected by disease conditions.},
}
@article {pmid23740586,
year = {2013},
author = {Maeda, T and Guan, JZ and Koyanagi, M and Makino, N},
title = {Alterations in the telomere length distribution and the subtelomeric methylation status in human vascular endothelial cells under elevated temperature in culture condition.},
journal = {Aging clinical and experimental research},
volume = {25},
number = {3},
pages = {231-238},
doi = {10.1007/s40520-013-0045-6},
pmid = {23740586},
issn = {1720-8319},
mesh = {Cells, Cultured ; Cellular Senescence ; DNA Methylation/*physiology ; Endothelium, Vascular/metabolism/*pathology ; Heat-Shock Proteins/metabolism ; *Hot Temperature ; Humans ; Phenotype ; RNA/metabolism ; Telomerase/metabolism ; Telomere/*pathology/physiology ; Telomere Homeostasis/*physiology ; Telomeric Repeat Binding Protein 2/metabolism ; *Temperature ; },
abstract = {Temperature-associated alteration in the telomere lengths of vascular endothelial cells has not been well investigated. Telomere length of human umbilical vein endothelial cells (HUVECs) cultured at a high temperature (42 °C) was analyzed. Here described are heat-associated phenotypical alterations of human vascular endothelial cell under prolonged heat stress in terms of telomere length, telomerase activity, and the expression of telomere associated proteins and heat shock proteins. The genomic DNA extracted from HUVECs cultured for 3 days under 42 °C was digested with methylation-sensitive and -insensitive isoschizomers and was subjected to genomic Southern blot probed with a telomere DNA fragment. Their telomere lengths and telomere length distributions were analyzed. Telomerase activity and the expressions of telomere-associated RNA, telomere-associated proteins (TERC, TERT, TRF1, and TRF2), and heat shock proteins (Hsp60, Hsp70, and Hsp90) were also analyzed. At 42 °C, cell growth was suppressed and the cell senescence rate was transiently elevated. A proportional decrease in the number of long telomeres was observed transiently at 42 °C. A trend of subtelomeric hypomethylation and lowered telomerase activity were observed at 42 °C after 3-day culture. The altered phenotypes on day 1 seemed reactive responses for cell protection to heat, and those on day 3 seemed exhausted reactions after 3-day culture. Maintained expression was observed in Hsps, TRF2, and TERC. These altered phenotypes might contribute to cell-survival under prolonged heat stress.},
}
@article {pmid23739898,
year = {2013},
author = {Xi, H and Li, C and Ren, F and Zhang, H and Zhang, L},
title = {Telomere, aging and age-related diseases.},
journal = {Aging clinical and experimental research},
volume = {25},
number = {2},
pages = {139-146},
doi = {10.1007/s40520-013-0021-1},
pmid = {23739898},
issn = {1720-8319},
mesh = {Aging/*physiology ; Cardiovascular Diseases/etiology ; Diabetes Mellitus/etiology ; Humans ; Neoplasms/etiology ; *Telomere Homeostasis ; },
abstract = {Aging is an inevitable biological process that affects most living organisms. The process of aging is regulated at the level of the organism, as well as at the level of tissues and cells. Despite the enormous consequences associated with the aging process, relatively little systematic effort has been expended on the scientific understanding of this important life process. Many theories have been proposed to explain the aging process, the centerpiece of which is molecular damage. Located at the ends of eukaryotic chromosomes and synthesized by telomerase, telomeres maintain the stabilization of chromosomes. Thus, the loss of telomeres may lead to DNA damage. The relationship between cellular senescence and telomere shortening is well established. Furthermore, telomere attrition occurs with age, and is proposed to be a fundamental factor in the aging process. Here, we review the contemporary literatures to explore the current views on the correlation of telomere loss and telomerase action with aging and age-related diseases.},
}
@article {pmid23733785,
year = {2013},
author = {Xu, Z and Duc, KD and Holcman, D and Teixeira, MT},
title = {The length of the shortest telomere as the major determinant of the onset of replicative senescence.},
journal = {Genetics},
volume = {194},
number = {4},
pages = {847-857},
pmid = {23733785},
issn = {1943-2631},
support = {260906/ERC_/European Research Council/International ; },
mesh = {Meiosis ; Mitosis ; *Models, Genetic ; Saccharomyces cerevisiae/genetics/*metabolism/physiology ; Saccharomyces cerevisiae Proteins/metabolism ; Stochastic Processes ; Telomere/metabolism ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {The absence of telomerase in many eukaryotes leads to the gradual shortening of telomeres, causing replicative senescence. In humans, this proliferation barrier constitutes a tumor suppressor mechanism and may be involved in cellular aging. Yet the heterogeneity of the senescence phenotype has hindered the understanding of its onset. Here we investigated the regulation of telomere length and its control of senescence heterogeneity. Because the length of the shortest telomeres can potentially regulate cell fate, we focus on their dynamics in Saccharomyces cerevisiae. We developed a stochastic model of telomere dynamics built on the protein-counting model, where an increasing number of protein-bound telomeric repeats shift telomeres into a nonextendable state by telomerase. Using numerical simulations, we found that the length of the shortest telomere is well separated from the length of the others, suggesting a prominent role in triggering senescence. We evaluated this possibility using classical genetic analyses of tetrads, combined with a quantitative and sensitive assay for senescence. In contrast to mitosis of telomerase-negative cells, which produces two cells with identical senescence onset, meiosis is able to segregate a determinant of senescence onset among the telomerase-negative spores. The frequency of such segregation is in accordance with this determinant being the length of the shortest telomere. Taken together, our results substantiate the length of the shortest telomere as being the key genetic marker determining senescence onset in S. cerevisiae.},
}
@article {pmid23732473,
year = {2013},
author = {Webb, CJ and Wu, Y and Zakian, VA},
title = {DNA repair at telomeres: keeping the ends intact.},
journal = {Cold Spring Harbor perspectives in biology},
volume = {5},
number = {6},
pages = {},
pmid = {23732473},
issn = {1943-0264},
support = {R01 GM026938/GM/NIGMS NIH HHS/United States ; R01 GM043265/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Helicases/*metabolism ; DNA Repair/genetics/*physiology ; DNA Replication/*physiology ; Humans ; *Models, Biological ; Retroelements/genetics ; Telomere/genetics/*physiology ; Telomere Homeostasis/*physiology ; Telomere-Binding Proteins/*metabolism ; Yeasts ; },
abstract = {The molecular era of telomere biology began with the discovery that telomeres usually consist of G-rich simple repeats and end with 3' single-stranded tails. Enormous progress has been made in identifying the mechanisms that maintain and replenish telomeric DNA and the proteins that protect them from degradation, fusions, and checkpoint activation. Although telomeres in different organisms (or even in the same organism under different conditions) are maintained by different mechanisms, the disparate processes have the common goals of repairing defects caused by semiconservative replication through G-rich DNA, countering the shortening caused by incomplete replication, and postreplication regeneration of G tails. In addition, standard DNA repair mechanisms must be suppressed or modified at telomeres to prevent their being recognized and processed as DNA double-strand breaks. Here, we discuss the players and processes that maintain and regenerate telomere structure.},
}
@article {pmid23732052,
year = {2013},
author = {Gramatges, MM and Bertuch, AA},
title = {Short telomeres: from dyskeratosis congenita to sporadic aplastic anemia and malignancy.},
journal = {Translational research : the journal of laboratory and clinical medicine},
volume = {162},
number = {6},
pages = {353-363},
pmid = {23732052},
issn = {1878-1810},
support = {K12 CA090433/CA/NCI NIH HHS/United States ; K23 CA158148/CA/NCI NIH HHS/United States ; 1K23CA158148-01A1/CA/NCI NIH HHS/United States ; },
mesh = {Aging/genetics/physiology ; Anemia, Aplastic/*etiology ; Dyskeratosis Congenita/*etiology ; Humans ; Mutation ; Neoplasms/*etiology ; Risk Factors ; Shelterin Complex ; Telomerase/genetics/physiology ; *Telomere Shortening/genetics/physiology ; Telomere-Binding Proteins ; Translational Research, Biomedical ; },
abstract = {Telomeres are DNA-protein structures that form a protective cap on chromosome ends. As such, they prevent the natural ends of linear chromosomes from being subjected to DNA repair activities that would result in telomere fusion, degradation, or recombination. Both the DNA and protein components of the telomere are required for this essential function, because insufficient telomeric DNA length, loss of the terminal telomeric DNA structure, or deficiency of key telomere-associated factors may elicit a DNA damage response and result in cellular senescence or apoptosis. In the setting of failed checkpoint mechanisms, such DNA-protein defects can also lead to genomic instability through telomere fusions or recombination. Thus, as shown in both model systems and in humans, defects in telomere biology are implicated in cellular and organismal aging as well as in tumorigenesis. Bone marrow failure and malignancy are 2 life-threatening disease manifestations in the inherited telomere biology disorder dyskeratosis congenita. We provide an overview of basic telomere structure and maintenance. We outline the telomere biology defects observed in dyskeratosis congenita, focusing on recent discoveries in this field. Last, we review the evidence of how telomere biology may impact sporadic aplastic anemia and the risk for various cancers.},
}
@article {pmid23729739,
year = {2013},
author = {Bisht, KK and Daniloski, Z and Smith, S},
title = {SA1 binds directly to DNA through its unique AT-hook to promote sister chromatid cohesion at telomeres.},
journal = {Journal of cell science},
volume = {126},
number = {Pt 15},
pages = {3493-3503},
pmid = {23729739},
issn = {1477-9137},
support = {R01 CA116352/CA/NCI NIH HHS/United States ; R01CA116352/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Amino Acid Transport System A/genetics/*metabolism ; Cell Division/physiology ; Chromatids/genetics/*metabolism ; DNA/genetics/*metabolism ; G2 Phase/physiology ; HeLa Cells ; Humans ; Molecular Sequence Data ; Nuclear Proteins/genetics/*metabolism ; Tankyrases/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {Sister chromatid cohesion relies on cohesin, a complex comprising a tri-partite ring and a peripheral subunit Scc3, which is found as two related isoforms SA1 and SA2 in vertebrates. There is a division of labor between the vertebrate cohesin complexes; SA1-cohesin is required at telomeres and SA2-cohesin at centromeres. Depletion of SA1 has dramatic consequences for telomere function and genome integrity, but the mechanism by which SA1-cohesin mediates cohesion at telomeres is not well understood. Here we dissect the individual contribution of SA1 and the ring subunits to telomere cohesion and show that telomeres rely heavily on SA1 and to a lesser extent on the ring for cohesion. Using chromatin immunoprecipitation we show that SA1 is highly enriched at telomeres, is decreased at mitosis when cohesion is resolved, and is increased when cohesion persists. Overexpression of SA1 alone was sufficient to induce cohesion at telomeres, independent of the cohesin ring and dependent on its unique (not found in SA2) N-terminal domain, which we show binds to telomeric DNA through an AT-hook motif. We suggest that a specialized cohesion mechanism may be required to accommodate the high level of DNA replication-associated repair at telomeres.},
}
@article {pmid23729589,
year = {2013},
author = {Novo, CL and Polese, C and Matheus, N and Decottignies, A and Londono-Vallejo, A and Castronovo, V and Mottet, D},
title = {A new role for histone deacetylase 5 in the maintenance of long telomeres.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {27},
number = {9},
pages = {3632-3642},
doi = {10.1096/fj.12-224204},
pmid = {23729589},
issn = {1530-6860},
mesh = {Apoptosis/genetics/*physiology ; Blotting, Western ; Electrophoresis, Gel, Two-Dimensional ; Fluorescent Antibody Technique ; Histone Deacetylases/genetics/*metabolism ; Human Umbilical Vein Endothelial Cells/enzymology/*metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Recombination, Genetic/genetics ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres are major regulators of genome stability and cell proliferation. A detailed understanding of the mechanisms involved in their maintenance is of foremost importance. Of those, telomere chromatin remodeling is probably the least studied; thus, we intended to explore the role of a specific histone deacetylase on telomere maintenance. We uncovered a new role for histone deacetylase 5 (HDAC5) in telomere biology. We report that HDAC5 is recruited to the long telomeres of osteosarcoma- and fibrosarcoma-derived cell lines, where it ensures proper maintenance of these repetitive regions. Indeed, depletion of HDAC5 by RNAi resulted in the shortening of longer telomeres and homogenization of telomere length in cells that use either telomerase or an alternative mechanism of telomere maintenance. Furthermore, we present evidence for the activation of telomere recombination on depletion of HDAC5 in fibrosarcoma telomerase-positive cancer cells. Of potential importance, we also found that depletion of HDAC5 sensitizes cancer cells with long telomeres to chemotherapeutic drugs. Cells with shorter telomeres were used to control the specificity of HDAC5 role in the maintenance of long telomeres. HDAC5 is essential for the length maintenance of long telomeres and its depletion is required for sensitization of cancer cells with long telomeres to chemotherapy.},
}
@article {pmid23728273,
year = {2013},
author = {Axelrad, MD and Budagov, T and Atzmon, G},
title = {Telomere length and telomerase activity; a Yin and Yang of cell senescence.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {75},
pages = {e50246},
pmid = {23728273},
issn = {1940-087X},
mesh = {Cellular Senescence/genetics/*physiology ; DNA/chemistry/genetics/isolation &amp; purification ; Humans ; Leukocytes/cytology/enzymology/ultrastructure ; Nucleic Acid Amplification Techniques/*methods ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Telomerase/*metabolism ; Telomere/*chemistry/genetics/metabolism ; Terminal Repeat Sequences ; },
abstract = {Telomeres are repeating DNA sequences at the tip ends of the chromosomes that are diverse in length and in humans can reach a length of 15,000 base pairs. The telomere serves as a bioprotective mechanism of chromosome attrition at each cell division. At a certain length, telomeres become too short to allow replication, a process that may lead to chromosome instability or cell death. Telomere length is regulated by two opposing mechanisms: attrition and elongation. Attrition occurs as each cell divides. In contrast, elongation is partially modulated by the enzyme telomerase, which adds repeating sequences to the ends of the chromosomes. In this way, telomerase could possibly reverse an aging mechanism and rejuvenates cell viability. These are crucial elements in maintaining cell life and are used to assess cellular aging. In this manuscript we will describe an accurate, short, sophisticated and cheap method to assess telomere length in multiple tissues and species. This method takes advantage of two key elements, the tandem repeat of the telomere sequence and the sensitivity of the qRT-PCR to detect differential copy numbers of tested samples. In addition, we will describe a simple assay to assess telomerase activity as a complementary backbone test for telomere length.},
}
@article {pmid23727245,
year = {2013},
author = {Puterman, E and Epel, ES and Lin, J and Blackburn, EH and Gross, JJ and Whooley, MA and Cohen, BE},
title = {Multisystem resiliency moderates the major depression-telomere length association: findings from the Heart and Soul Study.},
journal = {Brain, behavior, and immunity},
volume = {33},
number = {},
pages = {65-73},
pmid = {23727245},
issn = {1090-2139},
support = {R01 HL079235/HL/NHLBI NIH HHS/United States ; K23 HL 094765-01/HL/NHLBI NIH HHS/United States ; K23 HL094765/HL/NHLBI NIH HHS/United States ; K99HL109247/HL/NHLBI NIH HHS/United States ; R00 HL109247/HL/NHLBI NIH HHS/United States ; K99 HL109247/HL/NHLBI NIH HHS/United States ; },
mesh = {Age Factors ; Aged ; Aged, 80 and over ; Cardiovascular Diseases/*genetics/immunology/*psychology ; Cellular Senescence/genetics/immunology ; Cohort Studies ; Cross-Sectional Studies ; Depressive Disorder, Major/*genetics/immunology/*psychology ; Female ; Humans ; Male ; Middle Aged ; Motor Activity/genetics/immunology ; Prospective Studies ; Psychology ; *Resilience, Psychological ; Sex Factors ; Sleep/immunology/physiology ; Telomere Homeostasis/*genetics/immunology ; },
abstract = {Major depressive disorder (MDD) has been associated with reduced leukocyte telomere length (LTL). It is not known, however, whether psychosocial and behavioral protective factors moderate this association. In the current study, we examine whether multisystem resiliency--defined by healthy emotion regulation, strong social connections, and health behaviors (sleep and exercise)--predicts LTL and mitigates previously demonstrated associations between depression diagnosis and LTL. LTL was measured, using a quantitative PCR assay, in 954 patients with stable cardiovascular disease in the Heart and Soul Study. In a fully adjusted model, high multisystem resiliency predicted longer LTL (b=80.00, SE=27.17, p=.003), whereas each individual factor did not. Multisystem resiliency significantly moderated the MDD-LTL association (p=.02). Specifically, MDD was significantly related to LTL at 1 SD below the mean of multisystem resiliency (b=-142.86, SE=56.46, p=.01), but not at 1 SD above the mean (b=49.07, SE=74.51, p=.51). This study suggests that MDD associations with biological outcomes should be examined within a psychosocial-behavioral context, because this context shapes the nature of the direct relationship. Further research should explore the cognitive, neural, and other physiological pathways through which multisystem resiliency may confer biological benefit.},
}
@article {pmid23726221,
year = {2013},
author = {Yu, EY and Kojic, M and Holloman, WK and Lue, NF},
title = {Brh2 and Rad51 promote telomere maintenance in Ustilago maydis, a new model system of DNA repair proteins at telomeres.},
journal = {DNA repair},
volume = {12},
number = {7},
pages = {472-479},
pmid = {23726221},
issn = {1568-7856},
support = {R01 GM042482/GM/NIGMS NIH HHS/United States ; R01 GM062631/GM/NIGMS NIH HHS/United States ; GM042482/GM/NIGMS NIH HHS/United States ; },
mesh = {Fungal Proteins/genetics/*metabolism ; Mutation ; Nuclear Proteins/genetics/*metabolism ; Rad51 Recombinase/genetics/*metabolism ; Recombinational DNA Repair/genetics ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; Ustilago/genetics/*metabolism ; },
abstract = {Recent studies implicate a number of DNA repair proteins in mammalian telomere maintenance. However, because several key repair proteins in mammals are missing from the well-studied budding and fission yeast, their roles at telomeres cannot be modeled in standard fungi. In this report, we explored the dimorphic fungus Ustilago maydis as an alternative model for telomere research. This fungus, which belongs to the phylum Basidiomycota, has a telomere repeat unit that is identical to the mammalian repeat, as well as a constellation of DNA repair proteins that more closely mimic the mammalian collection. We showed that the two core components of homology-directed repair (HDR) in U. maydis, namely Brh2 and Rad51, both promote telomere maintenance in telomerase positive cells, just like in mammals. In addition, we found that Brh2 is localized to telomeres in vivo, suggesting that it acts directly at chromosome ends. We surveyed a series of mutants with DNA repair defects, and found many of them to have short telomeres. Our results indicate that factors involved in DNA repair are probably also needed for optimal telomere maintenance in U. maydis, and that this fungus is a useful alternative model system for telomere research.},
}
@article {pmid23720342,
year = {2013},
author = {Quimby, JM and Maranon, DG and Battaglia, CL and McLeland, SM and Brock, WT and Bailey, SM},
title = {Feline chronic kidney disease is associated with shortened telomeres and increased cellular senescence.},
journal = {American journal of physiology. Renal physiology},
volume = {305},
number = {3},
pages = {F295-303},
doi = {10.1152/ajprenal.00527.2012},
pmid = {23720342},
issn = {1522-1466},
mesh = {Aging/physiology ; Animals ; Cats ; Cellular Senescence/*physiology ; Image Processing, Computer-Assisted ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Kidney/pathology ; Kidney Failure, Chronic/*pathology ; Liver/pathology ; Paraffin Embedding ; Skin/pathology ; Telomerase/metabolism ; Telomere/*pathology ; beta-Galactosidase/metabolism ; },
abstract = {Telomeres are protective structures at the ends of chromosomes that have important implications for aging. To address the question of whether telomeres contribute to feline chronic kidney disease (CKD), we evaluated kidney, liver, and skin samples from 12 cats with naturally occurring CKD, 12 young normal cats, and 6 old normal cats. Telomere length was assessed using standard telomere fluorescent in situ hybridization (TEL-FISH) combined with immunohistochemistry (TELI-FISH) to identify proximal (PTEC) and distal tubular epithelial cells (DTEC), whereas senescence-associated β-galactosidase (SABG) staining was used to evaluate senescence. Results revealed statistically significant decreases in the average telomere fluorescence intensity (TFI) of PTEC in CKD cats compared with young and geriatric normal cats, and in the DTEC of CKD cats compared with young normal cats. When histograms of individual TFI were compared, statistically significant decreases in the PTEC and DTEC of CKD cats were observed compared with young and geriatric normal cats. Concomitantly, a statistically significant increase in SABG staining was seen in CKD kidney samples compared with young normal cats. CKD cats tended to have increased SABG staining in the kidney compared with normal geriatric cats, but this did not reach statistical significance. No significant telomere shortening in liver or skin from any group was observed. Real-time quantitative telomeric repeat amplification protocol assessment of renal telomerase activity revealed comparable low levels of telomerase activity in all groups. Our results suggest that shortened telomeres and increased senescence in the kidneys of CKD cats may represent novel targets for interventional therapy.},
}
@article {pmid23718190,
year = {2013},
author = {Sputova, K and Garbe, JC and Pelissier, FA and Chang, E and Stampfer, MR and LaBarge, MA},
title = {Aging phenotypes in cultured normal human mammary epithelial cells are correlated with decreased telomerase activity independent of telomere length.},
journal = {Genome integrity},
volume = {4},
number = {1},
pages = {4},
pmid = {23718190},
issn = {2041-9414},
support = {R00 AG033176/AG/NIA NIH HHS/United States ; R01 AG040081/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Shortening of telomeres, which are essential for maintenance of genomic integrity, is a mechanism commonly associated with the aging process. Here we ascertained whether changes in telomere lengths or telomerase activity correlated with age in normal human mammary epithelial cells (HMEC), or with phenotypes of aging in breast. Accordingly, flow cytometry fluorescence in situ hybridization (flowFISH) was used to determine relative telomere lengths (RTL), and telomerase activity was measured by the telomeric repeat amplification protocol (TRAP), in a collection of 41 primary HMEC strains established from women aged 16 to 91 years.<br><br>RESULTS: RTL measurements of HMEC strains that were heterogeneous with respect to lineage composition revealed no significant associations between telomere length with age, maximum observed population doublings, or with lineage composition of the strains. However, within strains, luminal epithelial and cKit-expressing epithelial progenitor cells that were flow cytometry-enriched from individual HMEC strains exhibited significantly shorter telomeres relative to isogenic myoepithelial cells (P&#x2009;<&#x2009;0.01). In unsorted strains, detectable telomerase activity did not correlate with RTL. Telomerase activity declined with age; the average age of strains that exhibited TRAP activity was 29.7&#x2009;&#xb1;&#x2009;3.9y, whereas the average age of strains with no detectable TRAP activity was 49.0&#x2009;&#xb1;&#x2009;4.9y (P&#x2009;<&#x2009;0.01). Non-detectable TRAP activity also was correlated with phenotypes of aging previously described in HMEC strains; increased proportions of CD227-expressing luminal epithelial cells (P&#x2009;<&#x2009;0.05) and cKit-expressing progenitor cells (P&#x2009;<&#x2009;0.05).<br><br>CONCLUSIONS: Telomere shortening did not correlate with the chronological ages of HMEC strains, whereas decreased telomerase activity correlated with age and with lineage distribution phenotypes characteristic of aging.},
}
@article {pmid23717814,
year = {2013},
author = {Smirnova, A and Gamba, R and Khoriauli, L and Vitelli, V and Nergadze, SG and Giulotto, E},
title = {TERRA Expression Levels Do Not Correlate with Telomere Length and Radiation Sensitivity in Human Cancer Cell Lines.},
journal = {Frontiers in oncology},
volume = {3},
number = {},
pages = {115},
pmid = {23717814},
issn = {2234-943X},
abstract = {Mammalian telomeres are transcribed into long non-coding telomeric repeat-containing RNA (TERRA) molecules that seem to play a role in the maintenance of telomere stability. In human cells, CpG-island promoters drive TERRA transcription and are regulated by methylation. It was suggested that the amount of TERRA may be related to telomere length. To test this hypothesis we measured telomere length and TERRA levels in single clones isolated from five human cell lines: HeLa (cervical carcinoma), BRC-230 (breast cancer), AKG and GK2 (gastric cancers), and GM847 (SV40 immortalized skin fibroblasts). However, these two parameters did not correlate with each other. Moreover, cell survival to γ-rays did not show a significant variation among the clones, suggesting that, in this cellular system, the intra-population variability in telomere length and TERRA levels does not influence sensitivity to ionizing radiation. This conclusion was supported by the observation that in a cell line in which telomeres were greatly elongated by the ectopic expression of telomerase, TERRA expression levels and radiation sensitivity were similar to the parental HeLa cell line.},
}
@article {pmid23716593,
year = {2013},
author = {Hirashima, K and Migita, T and Sato, S and Muramatsu, Y and Ishikawa, Y and Seimiya, H},
title = {Telomere length influences cancer cell differentiation in vivo.},
journal = {Molecular and cellular biology},
volume = {33},
number = {15},
pages = {2988-2995},
pmid = {23716593},
issn = {1098-5549},
mesh = {Animals ; Cell Differentiation ; Cell Line, Tumor ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Prostate/metabolism/*pathology ; Prostatic Neoplasms/enzymology/genetics/*metabolism/*pathology ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; Up-Regulation ; },
abstract = {Limitless reproductive potential is one of the hallmarks of cancer cells. This ability is due to the maintenance of telomeres, erosion of which causes cellular senescence or death. While most cancer cells activate telomerase, a telomere-elongating enzyme, it remains elusive as to why cancer cells often maintain shorter telomeres than the cells in the surrounding normal tissues. Here, we show that forced telomere elongation in cancer cells promotes their differentiation in vivo. We elongated the telomeres of human prostate cancer cells that possess short telomeres by enhancing their telomerase activity. The resulting cells had long telomeres and retained the ability to form tumors in nude mice. Strikingly, these tumors exhibited many duct-like structures and reduced N-cadherin expression, reminiscent of well-differentiated adenocarcinoma. These changes were caused by telomere elongation and not by enhanced telomerase activity. Gene expression profiling revealed that tumor formation was accompanied by the expression of innate immune system-related genes, which have been implicated in maintaining tumor cells in an undifferentiated state and poor-prognosis cancers. In tumors derived from the telomere-elongated cells, upregulation of such gene sets is not observed. Our observations suggest a functional contribution of short telomeres to tumor malignancy by regulation of cancer cell differentiation.},
}
@article {pmid23714432,
year = {2013},
author = {Wang, X},
title = {Telomere and telomerase: implications for future prospects.},
journal = {The FEBS journal},
volume = {280},
number = {14},
pages = {3179},
doi = {10.1111/febs.12357},
pmid = {23714432},
issn = {1742-4658},
mesh = {Humans ; Neoplasms/enzymology/genetics ; Telomerase/*physiology ; Telomere/*genetics ; },
abstract = {The 2009 Nobel Prize in Physiology or Medicine was awarded to Drs Blackburn, Szostak and Greider for their discovery of how chromosomes are protected by telomeres and the enzyme telomerase. This minireview series consisting of three independent reviews discusses different aspects of this research, an area fuelling clinical applications in various human diseases including ageing and cancer.},
}
@article {pmid23711776,
year = {2014},
author = {García-Calzón, S and Gea, A and Razquin, C and Corella, D and Lamuela-Raventós, RM and Martínez, JA and Martínez-González, MA and Zalba, G and Marti, A},
title = {Longitudinal association of telomere length and obesity indices in an intervention study with a Mediterranean diet: the PREDIMED-NAVARRA trial.},
journal = {International journal of obesity (2005)},
volume = {38},
number = {2},
pages = {177-182},
pmid = {23711776},
issn = {1476-5497},
mesh = {Adiposity/*genetics ; Aged ; Aged, 80 and over ; Aging/genetics/*metabolism ; Biomarkers/metabolism ; Body Mass Index ; Diet, Fat-Restricted ; *Diet, Mediterranean ; Female ; Humans ; Male ; Middle Aged ; Obesity/epidemiology/*genetics/metabolism ; Phenotype ; Predictive Value of Tests ; Real-Time Polymerase Chain Reaction ; Risk Factors ; Telomere/*genetics ; Telomere Homeostasis/genetics ; *Telomere Shortening/genetics ; Weight Gain/genetics ; },
abstract = {BACKGROUND: Telomeres are nucleoprotein structures that protect the ends of eukaryote chromosomes. Shorter telomere length (TL) is associated with some age-related human disorders, but its relationship with obesity or adiposity parameters remains unclear.<br><br>OBJECTIVE: The aim of this study was to assess the relationship between TL and changes in adiposity indices after a 5-year nutritional intervention.<br><br>DESIGN AND SUBJECTS: TL was measured by quantitative real-time PCR in 521 subjects (55-80 years, 55% women). Participants were randomly selected from the PREDIMED-NAVARRA centre after they completed a 5-year intervention programme. Anthropometric parameters were directly measured by trained personnel at baseline and on a yearly basis thereafter. TL at baseline and changes in TL after a 5-year intervention were assessed.<br><br>RESULTS: Higher baseline TL significantly predicted a greater decrease in body weight (B=-1.09&#x2009;kg, 95% confidence interval (CI): -2.01 to -0.16), body mass index (BMI) (B=-0.47&#x2009;kg&#x2009;m(-2), 95% CI: -0.83 to -0.11), waist circumference (B=-1.15&#x2009;cm, 95% CI: -2.28 to -0.01) and waist to height ratio (B=-0.008, 95% CI: -0.010 to -0.001) in multiple-adjusted models. In addition, changes in TL during the 5-year intervention were inversely associated with changes in the four anthropometric variables. The reduction in adiposity indices during the intervention, associated with increasing TL, was even higher among subjects with the longest telomeres at baseline. Logistic regression analysis showed that the risk of remaining obese after 5 years was lower in those participants who initially had the longest telomeres and increased their TL after intervention (odds ratio=0.27, 95% CI: 0.03-2.03).<br><br>CONCLUSIONS: Our research suggests that TL is inversely associated with changes in obesity parameters. The assessment of TL can provide further insights for biological pathways leading to adiposity. We show for the first time an improvement of obesity indices when an increase in TL is observed after a 5-year Mediterranean diet intervention.},
}
@article {pmid23708666,
year = {2013},
author = {Kamranvar, SA and Chen, X and Masucci, MG},
title = {Telomere dysfunction and activation of alternative lengthening of telomeres in B-lymphocytes infected by Epstein-Barr virus.},
journal = {Oncogene},
volume = {32},
number = {49},
pages = {5522-5530},
pmid = {23708666},
issn = {1476-5594},
mesh = {B-Lymphocytes/*metabolism/*virology ; DNA Helicases/metabolism ; Enzyme Activation ; Epstein-Barr Virus Infections/*genetics ; *Herpesvirus 4, Human ; Humans ; Nuclear Proteins/metabolism ; Shelterin Complex ; Sister Chromatid Exchange ; Telomerase/metabolism ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; X-linked Nuclear Protein ; },
abstract = {Malignant cells achieve replicative immortality by two alternative mechanisms, a common one dependent on de novo synthesis of telomeric DNA by telomerase, and a rare one based on telomere recombination known as alternative lengthening of telomeres (ALT). Epstein-Barr virus (EBV) transforms human B-lymphocytes into lymphoblastoid cell lines with unlimited growth potential in vitro and in vivo. Here we show that newly EBV-infected cells exhibit multiple signs of telomere dysfunction, including the occurrence of extra-chromosomal telomeres, telomere fusion and telomere length heterogeneity, and undergo progressive increase in telomere length without a parallel increase in telomerase activity. This phenotype is accompanied by the accumulation of telomere-associated promyelocytic leukemia nuclear bodies and telomeric-sister chromatid exchange, suggesting that EBV infection promotes the activation of ALT. Newly infected cells also display a significant reduction of telomere-associated TRF2 and express low levels of TRF1, TRF2, POT1 and ATRX, pointing to telomere de-protection as an important correlate of ALT activation. Collectively, these findings highlight the involvement of recombination-dependent mechanisms for maintenance of telomere homeostasis in EBV-induced B-cell immortalization.},
}
@article {pmid23703697,
year = {2013},
author = {Sabatino, L and Botto, N and Borghini, A and Turchi, S and Andreassi, MG},
title = {Development of a new multiplex quantitative real-time PCR assay for the detection of the mtDNA(4977) deletion in coronary artery disease patients: a link with telomere shortening.},
journal = {Environmental and molecular mutagenesis},
volume = {54},
number = {5},
pages = {299-307},
doi = {10.1002/em.21783},
pmid = {23703697},
issn = {1098-2280},
mesh = {Aged ; Base Sequence ; Coronary Artery Disease/*diagnosis/*genetics ; DNA, Mitochondrial/*genetics ; Female ; Genetic Testing/*methods ; Humans ; Male ; Molecular Sequence Data ; *Multiplex Polymerase Chain Reaction ; *Real-Time Polymerase Chain Reaction ; Risk Factors ; Sequence Deletion/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Mitochondrial DNA (mtDNA) and telomere shortening have been proposed as important contributors to vascular disease and atherogenesis. The role of mitochondrial and telomere alterations has been examined frequently, but usually separately. Recently, an integrated model in which DNA damage and metabolic pathways intersect in age-associated cardiovascular disease has been proposed. In this study we developed a fast and reliable real-time PCR-based procedure to investigate relative quantification of the 4,977 bp mitochondrial DNA deletion (also indicated as "mtDNA(4977) deletion"), employing TaqMan probes with a multiplex approach. As a validation of the assay, a nested PCR coamplification was performed. Telomere shortening was evaluated by a real-time monochrome multiplex PCR technique employing a SybrGreen-based analysis. The study of mtDNA(4977) deletion and telomere shortening was carried out in atrial biopsies from 11 patients undergoing coronary artery (n = 5) and valve surgery (n = 6). The relative quantifications showed that the amount of mtDNA(4977) deletion was greater in tissue of patients with coronary artery disease (CAD) (P = 0.01) and that telomere length (expressed as telomere length relative to a single copy reference gene) was significantly shorter in tissue of CAD patients, compared to patients without CAD (P = 0.03). Moreover, most conventional risk factors were significantly more frequent in CAD patients, smoking and dyslipidemia having the strongest association with the degree of mtDNA(4977) deletion and a significant correlation with telomere attrition (P = 0.02 and P = 0.006, respectively). In conclusion, the present study suggests that mtDNA(4977) deletion and telomere shortening may represent additional and synergic major risk factors for the pathogenesis of CAD and its complications.},
}
@article {pmid23702294,
year = {2013},
author = {Garton, M and Laughton, C},
title = {A comprehensive model for the recognition of human telomeres by TRF1.},
journal = {Journal of molecular biology},
volume = {425},
number = {16},
pages = {2910-2921},
pmid = {23702294},
issn = {1089-8638},
support = {BB/F011407/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Humans ; Models, Molecular ; Molecular Dynamics Simulation ; Nucleic Acid Conformation ; Protein Binding ; Protein Conformation ; Telomere/*chemistry/*metabolism ; Telomeric Repeat Binding Protein 1/*chemistry/*metabolism ; },
abstract = {Eukaryotic chromosomes are capped by telomeres, nucleoprotein complexes that prevent chromosome end-to-end fusions and control cell ageing. Two proteins in this complex, telomere repeat binding factors (TRF1 and TRF2), specifically recognise the double-stranded TTAGGG tandem repeat sequence. TRF1 is a homodimer with roles governing DNA architecture and negatively regulating telomere length. We explore the conformational space of this protein-DNA complex using molecular dynamics and, for the first time, generate a complete model of TRF1-DNA recognition that has not been possible on the basis of crystallographic and NMR data alone. The results reconcile previous conflicting experimental models for the sequence selectivity of the recognition process, by confirming many of the findings while identifying important new interactions and behaviour. This improved characterisation also reveals extensive indirect readout, which suggests that recognition will be affected by changes to DNA helical parameters such as bending.},
}
@article {pmid23700431,
year = {2013},
author = {Hoffecker, BM and Raffield, LM and Kamen, DL and Nowling, TK},
title = {Systemic lupus erythematosus and vitamin D deficiency are associated with shorter telomere length among African Americans: a case-control study.},
journal = {PloS one},
volume = {8},
number = {5},
pages = {e63725},
pmid = {23700431},
issn = {1932-6203},
support = {K23 AR052364/AR/NIAMS NIH HHS/United States ; R03 AR053376/AR/NIAMS NIH HHS/United States ; UL1 RR029882/RR/NCRR NIH HHS/United States ; P60 AR062755/AR/NIAMS NIH HHS/United States ; AR053376/AR/NIAMS NIH HHS/United States ; I01 BX000115/BX/BLRD VA/United States ; },
mesh = {Adult ; Black or African American/genetics ; Case-Control Studies ; Female ; Humans ; Lupus Erythematosus, Systemic/blood/*genetics ; Middle Aged ; Telomere/*genetics ; Telomere Homeostasis ; Vitamin D/blood ; Vitamin D Deficiency/blood/*genetics ; },
abstract = {Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that disproportionately affects African American females. The causes of SLE are unknown but postulated to be a combination of genetic predisposition and environmental triggers. Vitamin D deficiency is one of the possible environmental triggers. In this study we evaluated relationships between vitamin D status, cellular aging (telomere length) and anti-telomere antibodies among African American Gullah women with SLE. The study population included African American female SLE patients and unaffected controls from the Sea Island region of South Carolina. Serum 25-hydroxyvitamin D levels were measured using a nonchromatographic radioimmunoassay. Telomere length was measured in genomic DNA of peripheral blood mononuclear cells (PBMCs) by monochrome multiplex quantitative PCR. Anti-telomere antibody levels were measured by enzyme-linked immunosorbent assay (ELISA). Patients with SLE had significantly shorter telomeres and higher anti-telomere antibody titers compared to age- and gender-matched unaffected controls. There was a positive correlation between anti-telomere antibody levels and disease activity among patients and a significant correlation of shorter telomeres with lower 25-hydroxyvitamin D levels in both patients and controls. In follow-up examination of a subset of the patients, the patients who remained vitamin D deficient tended to have shorter telomeres than those patients whose 25-hydroxyvitamin D levels were repleted. Increasing 25-hydroxyvitamin D levels in African American patients with SLE may be beneficial in maintaining telomere length and preventing cellular aging. Moreover, anti-telomere antibody levels may be a promising biomarker of SLE status and disease activity.},
}
@article {pmid23699225,
year = {2013},
author = {Garavís, M and González, C and Villasante, A},
title = {On the origin of the eukaryotic chromosome: the role of noncanonical DNA structures in telomere evolution.},
journal = {Genome biology and evolution},
volume = {5},
number = {6},
pages = {1142-1150},
pmid = {23699225},
issn = {1759-6653},
mesh = {Animals ; Centromere/genetics ; Chromosomes/*genetics ; *Evolution, Molecular ; *G-Quadruplexes ; Humans ; Retroelements ; Telomerase/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {The transition of an ancestral circular genome to multiple linear chromosomes was crucial for eukaryogenesis because it allowed rapid adaptive evolution through aneuploidy. Here, we propose that the ends of nascent linear chromosomes should have had a dual function in chromosome end protection (capping) and chromosome segregation to give rise to the "proto-telomeres." Later on, proper centromeres evolved at subtelomeric regions. We also propose that both noncanonical structures based on guanine-guanine interactions and the end-protection proteins recruited by the emergent telomeric heterochromatin have been required for telomere maintenance through evolution. We further suggest that the origin of Drosophila telomeres may be reminiscent of how the first telomeres arose.},
}
@article {pmid23697684,
year = {2013},
author = {Ghosh, S and Kar, A and Chowdhury, S and Dasgupta, D},
title = {Ellipticine binds to a human telomere sequence: an additional mode of action as a putative anticancer agent?.},
journal = {Biochemistry},
volume = {52},
number = {24},
pages = {4127-4137},
doi = {10.1021/bi400080t},
pmid = {23697684},
issn = {1520-4995},
mesh = {Antineoplastic Agents/*pharmacology ; Breast Neoplasms/drug therapy ; Calorimetry, Differential Scanning ; Cell Line, Tumor ; Circular Dichroism ; DNA/chemistry ; Ellipticines/*pharmacology ; Female ; G-Quadruplexes ; Humans ; Intercalating Agents/pharmacology ; Nucleic Acid Conformation ; Protein Binding ; Spectrometry, Fluorescence ; Telomere/*drug effects/*ultrastructure ; },
abstract = {Polyguanine sequences fold into G-quadruplex structures in the presence of monovalent cations. It is accepted that the telomeric DNA region consists of G-quadruplex structure. There are reports that potential G-quadruplex forming motifs are also present in the promoter region of some proto-oncogenes such as c-myc, c-kit, KRAS, etc. Small molecules with the potential to stabilize the telomeric DNA quadruplex have emerged as potential anticancer agents. We have studied the interaction of ellipticine, a putative anticancer agent from a plant source, with a human telomeric DNA sequence (H24). Spectroscopic and calorimetric studies indicate that the association of ellipticine with H24 is an entropically driven phenomenon with a 2:3 (H24:ellipticine) stoichiometry. Though ellipticine binding does not induce any major structural perturbation in H24, the association leads to formation of a complex with enhanced thermal stability. An assay with the telomerase repeat amplification protocol shows that ellipticine inhibits telomerase activity in MDAMB-231 breast cancer cell line extracts. This is the first report of the quadruplex binding ability of ellipticine. Using the results, we propose that along with DNA intercalation and/or topoisomerase II inhibition, interaction with the telomeric DNA region and the resultant inhibition of telomerase activity might be an additional mode of action for its anticancer property.},
}
@article {pmid23695236,
year = {2013},
author = {Martinsson, L and Wei, Y and Xu, D and Melas, PA and Mathé, AA and Schalling, M and Lavebratt, C and Backlund, L},
title = {Long-term lithium treatment in bipolar disorder is associated with longer leukocyte telomeres.},
journal = {Translational psychiatry},
volume = {3},
number = {5},
pages = {e261},
pmid = {23695236},
issn = {2158-3188},
mesh = {Adult ; Aged ; Aged, 80 and over ; Bipolar Disorder/*drug therapy ; Case-Control Studies ; Female ; Humans ; Leukocytes/metabolism ; Lithium Compounds/*therapeutic use ; Male ; Middle Aged ; Psychiatric Status Rating Scales ; Real-Time Polymerase Chain Reaction ; Retrospective Studies ; Telomere/drug effects ; Telomere Homeostasis/*drug effects ; Young Adult ; },
abstract = {Telomere shortening is a hallmark of aging and has been associated with oxidative stress, inflammation and chronic somatic, as well as psychiatric disorders, including schizophrenia and depression. Additionally, antidepressants have been found to protect against telomere shortening. However, pharmacological telomere studies are lacking in bipolar disorder (BD). Therefore, the objective of this study was to explore telomere length (TL) in patients with BD in the context of lithium treatment. We determined TL by quantitative real-time PCR using peripheral blood leukocytes. Participants were outpatients diagnosed with BD type 1 or 2 (n=256) and healthy controls (n=139). Retrospective case-control and case-case study designs were applied. Lithium response (LiR) was scored using the Alda-Scale. Lithium-treated BD patients overall, as well as those on lithium monotherapy, had 35% longer telomeres compared with controls (P<0.0005, partial η(2)=0.13). TL correlated positively with lithium treatment duration of >30 months (P=0.031, R(2)=0.13) and was negatively associated with increasing number of depressive episodes (P<0.007). BD patients responding well to lithium treatment had longer telomeres than those not responding well. This is the first study to report a positive effect of long-term lithium treatment on TL. Importantly, longer TL was also associated with a better LiR in BD patients. These data suggest that lithium exerts a protective effect against telomere shortening especially when therapeutically efficacious. We hypothesize that induction of telomerase activity may be involved in LiR in BD.},
}
@article {pmid23691191,
year = {2013},
author = {La Torre, D and Conti, A and Aguennouz, MH and De Pasquale, MG and Romeo, S and Angileri, FF and Cardali, S and Tomasello, C and Alafaci, C and Germanò, A},
title = {Telomere length modulation in human astroglial brain tumors.},
journal = {PloS one},
volume = {8},
number = {5},
pages = {e64296},
pmid = {23691191},
issn = {1932-6203},
mesh = {Adult ; Aged ; Astrocytoma/enzymology/*genetics/pathology ; Brain Neoplasms/enzymology/*genetics/pathology ; Disease Progression ; Female ; Gene Expression Regulation, Neoplastic ; Glioblastoma/enzymology/*genetics/pathology ; Humans ; Male ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; Poly(ADP-ribose) Polymerases/genetics ; Tankyrases/genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomeric Repeat Binding Protein 1/genetics ; Telomeric Repeat Binding Protein 2/genetics ; },
abstract = {BACKGROUND: Telomeres alteration during carcinogenesis and tumor progression has been described in several cancer types. Telomeres length is stabilized by telomerase (h-TERT) and controlled by several proteins that protect telomere integrity, such as the Telomere Repeat-binding Factor (TRF) 1 and 2 and the tankyrase-poli-ADP-ribose polymerase (TANKs-PARP) complex.<br><br>OBJECTIVE: To investigate telomere dysfunction in astroglial brain tumors we analyzed telomeres length, telomerase activity and the expression of a panel of genes controlling the length and structure of telomeres in tissue samples obtained in vivo from astroglial brain tumors with different grade of malignancy.<br><br>MATERIALS AND METHODS: Eight Low Grade Astrocytomas (LGA), 11 Anaplastic Astrocytomas (AA) and 11 Glioblastoma Multiforme (GBM) samples were analyzed. Three samples of normal brain tissue (NBT) were used as controls. Telomeres length was assessed through Southern Blotting. Telomerase activity was evaluated by a telomere repeat amplification protocol (TRAP) assay. The expression levels of TRF1, TRF2, h-TERT and TANKs-PARP complex were determined through Immunoblotting and RT-PCR.<br><br>RESULTS: LGA were featured by an up-regulation of TRF1 and 2 and by shorter telomeres. Conversely, AA and GBM were featured by a down-regulation of TRF1 and 2 and an up-regulation of both telomerase and TANKs-PARP complex.<br><br>CONCLUSIONS: In human astroglial brain tumours, up-regulation of TRF1 and TRF2 occurs in the early stages of carcinogenesis determining telomeres shortening and genomic instability. In a later stage, up-regulation of PARP-TANKs and telomerase activation may occur together with an ADP-ribosylation of TRF1, causing a reduced ability to bind telomeric DNA, telomeres elongation and tumor malignant progression.},
}
@article {pmid23687339,
year = {2013},
author = {Gonzalez-Vasconcellos, I and Anastasov, N and Sanli-Bonazzi, B and Klymenko, O and Atkinson, MJ and Rosemann, M},
title = {Rb1 haploinsufficiency promotes telomere attrition and radiation-induced genomic instability.},
journal = {Cancer research},
volume = {73},
number = {14},
pages = {4247-4255},
doi = {10.1158/0008-5472.CAN-12-3117},
pmid = {23687339},
issn = {1538-7445},
mesh = {Animals ; Bone Neoplasms/genetics ; Cell Cycle Checkpoints/drug effects/genetics ; Cells, Cultured ; *Genes, Retinoblastoma ; Genetic Predisposition to Disease ; Genomic Instability/*radiation effects ; Haploinsufficiency ; Mice ; Osteosarcoma/genetics ; Radiation ; Retinoblastoma Protein/*genetics ; Telomere/genetics/*metabolism ; },
abstract = {Germline mutations of the retinoblastoma gene (RB1) predispose to both sporadic and radiation-induced osteosarcoma, tumors characterized by high levels of genomic instability, and activation of alternative lengthening of telomeres. Mice with haploinsufficiency of the Rb1 gene in the osteoblastic lineage reiterate the radiation susceptibility to osteosarcoma seen in patients with germline RB1 mutations. We show that the susceptibility is accompanied by an increase in genomic instability, resulting from Rb1-dependent telomere erosion. Radiation exposure did not accelerate the rate of telomere loss but amplified the genomic instability resulting from the dysfunctional telomeres. These findings suggest that telomere maintenance is a noncanonical caretaker function of the retinoblastoma protein, such that its deficiency in cancer may potentiate DNA damage-induced carcinogenesis by promoting formation of chromosomal aberrations, rather than simply by affecting cell-cycle control.},
}
@article {pmid23686115,
year = {2013},
author = {Fujishiro, K and Diez-Roux, AV and Landsbergis, PA and Jenny, NS and Seeman, T},
title = {Current employment status, occupational category, occupational hazard exposure and job stress in relation to telomere length: the Multiethnic Study of Atherosclerosis (MESA).},
journal = {Occupational and environmental medicine},
volume = {70},
number = {8},
pages = {552-560},
pmid = {23686115},
issn = {1470-7926},
support = {N01-HC-95162/HC/NHLBI NIH HHS/United States ; UL1-RR-024156/RR/NCRR NIH HHS/United States ; UL1 RR024156/RR/NCRR NIH HHS/United States ; N01-HC-95159/HC/NHLBI NIH HHS/United States ; N01HC95162/HL/NHLBI NIH HHS/United States ; N01HC95168/HL/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; N01HC95167/HL/NHLBI NIH HHS/United States ; N01-HC-95161/HC/NHLBI NIH HHS/United States ; N01-HC-95167/HC/NHLBI NIH HHS/United States ; N01HC95160/HL/NHLBI NIH HHS/United States ; R01 HL101161/HL/NHLBI NIH HHS/United States ; UL1 RR025005/RR/NCRR NIH HHS/United States ; UL1-RR-025005/RR/NCRR NIH HHS/United States ; N01HC95163/HL/NHLBI NIH HHS/United States ; R01-HL-101161/HL/NHLBI NIH HHS/United States ; N01-HC-95163/HC/NHLBI NIH HHS/United States ; N01-HC-95168/HC/NHLBI NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; N01-HC-95165/HC/NHLBI NIH HHS/United States ; N01HC95164/HL/NHLBI NIH HHS/United States ; N01-HC-95169/HC/NHLBI NIH HHS/United States ; N01-HC-95164/HC/NHLBI NIH HHS/United States ; N01HC95165/HL/NHLBI NIH HHS/United States ; N01HC95161/HL/NHLBI NIH HHS/United States ; N01-HC-95160/HC/NHLBI NIH HHS/United States ; N01HC95166/HL/NHLBI NIH HHS/United States ; N01-HC-95166/HC/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Aging, Premature ; Atherosclerosis ; Biomarkers ; Cellular Senescence ; *Employment ; Female ; *Hazardous Substances/adverse effects ; Health Resources ; Humans ; Interpersonal Relations ; Leukocytes/ultrastructure ; Linear Models ; Male ; Middle Aged ; Motor Activity ; *Occupational Diseases/etiology ; *Occupational Exposure/adverse effects ; *Occupations ; Physical Exertion ; Polymerase Chain Reaction ; Self Efficacy ; *Stress, Psychological ; Surveys and Questionnaires ; Telomere/ultrastructure ; *Telomere Shortening ; Workload ; },
abstract = {OBJECTIVE: Telomere length has been proposed as a biomarker of cell senescence, which is associated with a wide array of adverse health outcomes. While work is a major determinant of health, few studies have investigated the association of telomere length with various dimensions of occupation. Accelerated cellular aging could be a common pathway linking occupational exposure to several health outcomes.<br><br>METHODS: Leukocyte telomere length was assessed using quantitative PCR in a community-based sample of 981 individuals (age: 45-84 years). Questionnaires were used to collect information on current employment status, current or main occupation before retirement and job strain. The Occupational Resource Network (O*NET) database was linked to the questionnaire data to create five exposure measures: physical activity on the job, physical hazard exposure, interpersonal stressors, job control and job demands. Linear regression was used to estimate associations of occupational characteristics with telomere lengths after adjustment for age, sex, race, socioeconomic position and several behavioural risk factors.<br><br>RESULTS: There were no mean differences in telomere lengths across current employment status, occupational category, job strain categories or levels of most O*NET exposure measures. There was also no evidence that being in lower status occupational categories or being exposed to higher levels of adverse physical or psychosocial exposures accelerated the association between age and telomere shortening.<br><br>CONCLUSIONS: Cellular aging as reflected by shorter telomeres does not appear to be an important pathway linking occupation to various health outcomes.},
}
@article {pmid23685360,
year = {2013},
author = {Tarsounas, M},
title = {It's getting HOT at telomeres.},
journal = {The EMBO journal},
volume = {32},
number = {12},
pages = {1655-1657},
pmid = {23685360},
issn = {1460-2075},
support = {17201/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Homeodomain Proteins/*metabolism ; Humans ; Multiprotein Complexes/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {EMBO J 32 12: 1681–1701 doi:; DOI: 10.1038/emboj.2013.105; published online May 17 2013 How telomerase and telomeres are brought together to alleviate telomere shortening and preserve genome integrity in the cell remains incompletely understood. A study in The EMBO Journal now identifies HOT1 as a direct telomere repeat binding protein that contributes to telomerase-mediated telomere elongation, likely by bridging telomere and telomerase interactions.},
}
@article {pmid23685356,
year = {2013},
author = {Kappei, D and Butter, F and Benda, C and Scheibe, M and Draškovič, I and Stevense, M and Novo, CL and Basquin, C and Araki, M and Araki, K and Krastev, DB and Kittler, R and Jessberger, R and Londoño-Vallejo, JA and Mann, M and Buchholz, F},
title = {HOT1 is a mammalian direct telomere repeat-binding protein contributing to telomerase recruitment.},
journal = {The EMBO journal},
volume = {32},
number = {12},
pages = {1681-1701},
pmid = {23685356},
issn = {1460-2075},
mesh = {Chromatin/genetics/metabolism ; HeLa Cells ; Homeodomain Proteins/genetics/*metabolism ; Humans ; Multiprotein Complexes/genetics/*metabolism ; Repetitive Sequences, Nucleic Acid/physiology ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Telomeres are repetitive DNA structures that, together with the shelterin and the CST complex, protect the ends of chromosomes. Telomere shortening is mitigated in stem and cancer cells through the de novo addition of telomeric repeats by telomerase. Telomere elongation requires the delivery of the telomerase complex to telomeres through a not yet fully understood mechanism. Factors promoting telomerase-telomere interaction are expected to directly bind telomeres and physically interact with the telomerase complex. In search for such a factor we carried out a SILAC-based DNA-protein interaction screen and identified HMBOX1, hereafter referred to as homeobox telomere-binding protein 1 (HOT1). HOT1 directly and specifically binds double-stranded telomere repeats, with the in vivo association correlating with binding to actively processed telomeres. Depletion and overexpression experiments classify HOT1 as a positive regulator of telomere length. Furthermore, immunoprecipitation and cell fractionation analyses show that HOT1 associates with the active telomerase complex and promotes chromatin association of telomerase. Collectively, these findings suggest that HOT1 supports telomerase-dependent telomere elongation.},
}
@article {pmid23685049,
year = {2013},
author = {Kim, H and Yoo, JE and Cho, JY and Oh, BK and Yoon, YS and Han, HS and Lee, HS and Jang, JJ and Jeong, SH and Kim, JW and Park, YN},
title = {Telomere length, TERT and shelterin complex proteins in hepatocellular carcinomas expressing "stemness"-related markers.},
journal = {Journal of hepatology},
volume = {59},
number = {4},
pages = {746-752},
doi = {10.1016/j.jhep.2013.05.011},
pmid = {23685049},
issn = {1600-0641},
mesh = {Adult ; Aged ; Antigens, Neoplasm/metabolism ; Apoptosis ; Biomarkers, Tumor/*metabolism ; Carcinoma, Hepatocellular/*genetics/*metabolism/pathology ; Cell Adhesion Molecules/metabolism ; Cell Proliferation ; Chromosomal Instability ; Epithelial Cell Adhesion Molecule ; Female ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Keratin-19/metabolism ; Liver Neoplasms/*genetics/*metabolism/pathology ; Male ; Middle Aged ; Neoplastic Stem Cells/metabolism/pathology ; Prognosis ; Shelterin Complex ; Telomerase/*metabolism ; Telomere Homeostasis/genetics/*physiology ; Telomere-Binding Proteins/*metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {BACKGROUND &amp; AIMS: Hepatocellular carcinomas (HCCs) expressing "stemness"-related markers have been associated with aggressive biological behavior and poor prognosis. We examined the relationship between "stemness"-related protein expression and telomere length, hTERT and shelterin complex protein expression and chromosomal instability.<br><br>METHODS: Quantitative fluorescent in situ hybridization for telomere length, immunohistochemistry for K19, EpCAM, CD133, c-kit, HepPar1, hTERT, TRF1, TRF2, POT1, RAP1 and TPP1, and TUNEL assay were performed in 137 HCCs, and array comparative genomic hybridization was performed with 24 HCCs.<br><br>RESULTS: Telomeres were significantly longer in HCCs expressing "stemness"-related proteins (K19: p < 0.001, EpCAM: p = 0.002, CD133: p = 0.002). On analyzing different tumor cells within EpCAM-expressing HCCs, EpCAM-positive tumor cells showed longer telomeres (1.329 &#xb1; 0.246) compared to EpCAM-negative tumor cells (0.996 &#xb1; 0.381) within the same HCCs (p = 0.031). Telomeres were significantly longer in HCCs expressing hTERT (p = 0.048) and RAP1 proteins (p = 0.031). K19-expressing HCCs expressed hTERT (p = 0.002), TRF2 (p = 0.001) and TPP1 (p = 0.013) more frequently compared to K19-negative HCCs. EpCAM-positivity was associated with more frequent hTERT (p = 0.028), TPP1 (p = 0.017), TRF2 (p = 0.027) and POT1 (p = 0.004) expression. Copy number alterations were more frequent in K19 and EpCAM-expressing HCCs compared to HCCs without these markers (K19: p = 0.038, EpCAM: p = 0.009). HCCs with longer telomeres were associated with a shorter overall (p = 0.019) and disease-free survivals (p = 0.049), and decreased disease-free survivals were seen in TRF2-positive HCCs (p = 0.018).<br><br>CONCLUSIONS: HCCs expressing "stemness"-related proteins are characterized by increased telomere length, increased expression of hTERT and shelterin complex proteins, and increased chromosomal instability compared to conventional HCCs. Longer telomeres and TRF2 expression in HCCs are associated with poor patient outcomes.},
}
@article {pmid23682802,
year = {2013},
author = {An, N and Fleming, AM and Burrows, CJ},
title = {Interactions of the human telomere sequence with the nanocavity of the α-hemolysin ion channel reveal structure-dependent electrical signatures for hybrid folds.},
journal = {Journal of the American Chemical Society},
volume = {135},
number = {23},
pages = {8562-8570},
pmid = {23682802},
issn = {1520-5126},
support = {R01 GM093099/GM/NIGMS NIH HHS/United States ; GM093099/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA/*chemistry ; *G-Quadruplexes ; Hemolysin Proteins/*chemistry ; Humans ; Ion Channels/*chemistry ; Models, Molecular ; Nanostructures/*chemistry ; Nucleic Acid Conformation ; Potassium Chloride/chemistry ; Tandem Repeat Sequences ; Telomere/*chemistry ; },
abstract = {Human telomeric DNA consists of tandem repeats of the sequence 5'-TTAGGG-3', including a 3' terminal single-stranded overhang of 100-200 nucleotides that can fold into quadruplex structures in the presence of suitable metal ions. In the presence of an applied voltage, the α-hemolysin (α-HL) protein ion channel can produce unique current patterns that are found to be characteristic for various interactions between G-quadruplexes and the protein nanocavity. In this study, the human telomere in a complete sequence context, 5'-TAGGG(TTAGGG)3TT-3', was evaluated with respect to its multiple folding topologies. Notably, the coexistence of two interchangeable conformations of the K(+)-induced folds, hybrid-1 and hybrid-2, were readily resolved at a single-molecule level along with triplex folding intermediates, whose characterization has been challenging in experiments that measure the bulk solution. These results enabled us to profile the thermal denaturation process of these structures to elucidate the relative distributions of hybrid-1, hybrid-2, and folding intermediates such as triplexes. For example, at 37 °C, pH 7.9, in 50 mM aqueous KCl, the ratio of hybrid-1:hybrid-2:triplex is approximately 11:5:1 in dilute solution. The results obtained lay the foundation for utilizing the α-HL ion channel as a simple tool for monitoring how small molecules and physical context shift the equilibrium between the many G-quadruplex folds of the human telomere sequence.},
}
@article {pmid23677619,
year = {2013},
author = {Di Domenico, EG and Mattarocci, S and Cimino-Reale, G and Parisi, P and Cifani, N and D'Ambrosio, E and Zakian, VA and Ascenzioni, F},
title = {Tel1 and Rad51 are involved in the maintenance of telomeres with capping deficiency.},
journal = {Nucleic acids research},
volume = {41},
number = {13},
pages = {6490-6500},
pmid = {23677619},
issn = {1362-4962},
support = {R01 GM043265/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA-Binding Proteins/genetics ; Gene Deletion ; Intracellular Signaling Peptides and Proteins/genetics/*physiology ; Protein Serine-Threonine Kinases/genetics/*physiology ; Rad51 Recombinase/metabolism/*physiology ; Recombination, Genetic ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism/*physiology ; Telomerase/antagonists &amp; inhibitors ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Vertebrate-like T2AG3 telomeres in tlc1-h yeast consist of short double-stranded regions and long single-stranded overhang (G-tails) and, although based on Tbf1-capping activity, they are capping deficient. Consistent with this idea, we observe Y' amplification because of homologous recombination, even in the presence of an active telomerase. In these cells, Y' amplification occurs by different pathways: in Tel1(+) tlc1h cells, it is Rad51-dependent, whereas in the absence of Tel1, it depends on Rad50. Generation of telomeric G-tail, which is cell cycle regulated, depends on the MRX (Mre11-Rad50-Xrs2) complex in tlc1h cells or is MRX-independent in tlc1h tel1Δ mutants. Unexpectedly, we observe telomere elongation in tlc1h lacking Rad51 that seems to act as a telomerase competitor for binding to telomeric G-tails. Overall, our results show that Tel1 and Rad51 have multiple roles in the maintenance of vertebrate-like telomeres in yeast, supporting the idea that they may participate to evolutionary conserved telomere protection mechanism/s acting at uncapped telomeres.},
}
@article {pmid23675571,
year = {2013},
author = {Raffa, GD and Cenci, G and Ciapponi, L and Gatti, M},
title = {Organization and Evolution of Drosophila Terminin: Similarities and Differences between Drosophila and Human Telomeres.},
journal = {Frontiers in oncology},
volume = {3},
number = {},
pages = {112},
pmid = {23675571},
issn = {2234-943X},
abstract = {Drosophila lacks telomerase and fly telomeres are elongated by occasional transposition of three specialized retroelements. Drosophila telomeres do not terminate with GC-rich repeats and are assembled independently of the sequence of chromosome ends. Recent work has shown that Drosophila telomeres are capped by the terminin complex, which includes the fast-evolving proteins HOAP, HipHop, Moi, and Ver. These proteins, which are not conserved outside Drosophilidae and closely related Diptera, localize and function exclusively at telomeres, protecting them from fusion events. Other proteins required to prevent end-to-end fusion in flies include HP1, Eff/UbcD1, ATM, the components of the Mre11-Rad50-Nbs (MRN) complex, and the Woc transcription factor. These proteins do not share the terminin properties; they are evolutionarily conserved non-fast-evolving proteins that do not accumulate only at telomeres and do not serve telomere-specific functions. We propose that following telomerase loss, Drosophila rapidly evolved terminin to bind chromosome ends in a sequence-independent manner. This hypothesis suggests that terminin is the functional analog of the shelterin complex that protects human telomeres. The non-terminin proteins are instead likely to correspond to ancestral telomere-associated proteins that did not evolve as rapidly as terminin because of the functional constraints imposed by their involvement in diverse cellular processes. Thus, it appears that the main difference between Drosophila and human telomeres is in the protective complexes that specifically associate with the DNA termini. We believe that Drosophila telomeres offer excellent opportunities for investigations on human telomere biology. The identification of additional Drosophila genes encoding non-terminin proteins involved in telomere protection might lead to the discovery of novel components of human telomeres.},
}
@article {pmid23674344,
year = {2013},
author = {Lynch, SM and Major, JM and Cawthon, R and Weinstein, SJ and Virtamo, J and Lan, Q and Rothman, N and Albanes, D and Stolzenberg-Solomon, RZ},
title = {A prospective analysis of telomere length and pancreatic cancer in the alpha-tocopherol beta-carotene cancer (ATBC) prevention study.},
journal = {International journal of cancer},
volume = {133},
number = {11},
pages = {2672-2680},
pmid = {23674344},
issn = {1097-0215},
support = {Z01 CP010195-02//Intramural NIH HHS/United States ; },
mesh = {Aged ; Case-Control Studies ; Humans ; Logistic Models ; Male ; Middle Aged ; Pancreatic Neoplasms/epidemiology/etiology/genetics/*pathology ; Prospective Studies ; Risk Factors ; Smoking/adverse effects ; Telomere Homeostasis/drug effects/*genetics ; alpha-Tocopherol/*administration &amp; dosage ; beta Carotene/*administration &amp; dosage ; },
abstract = {Smoking and diabetes, consistent risk factors for pancreatic cancer, are also factors that influence telomere length maintenance. To test whether telomere length is associated with pancreatic cancer risk, we conducted a nested case-control study in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50-69 years at baseline. Between 1992 and 2004, 193 incident cases of pancreatic adenocarcinoma occurred (mean follow-up from blood draw: 6.3 years) among participants with whole blood samples available for telomere length assays. For these cases and 660 controls, we calculated odds ratios (OR) and 95% confidence intervals using unconditional logistic regression, adjusting for age, number of years smoked regularly, and history of diabetes mellitus. Telomere length was categorized into quartiles (shortest to longest) and analyzed as both a categorical and a continuous normal variable (reported per 0.2 unit increase in telomere length). All statistical tests were two-sided. Longer telomere length was significantly associated with increased pancreatic cancer risk (continuous OR = 1.26 95% CI = 1.09-1.46; highest quartile compared to lowest, OR = 1.57, 95% CI = 1.01-2.43, p-trend = 0.007). This association remained for subjects diagnosed within the first five years of blood draw (continuous OR = 1.46, 95% CI = 1.19-1.79 highest quartile OR = 2.92, 95% CI = 1.47-5.77, p-trend = 0.002), but not those diagnosed greater than five years after blood draw (continuous OR = 1.03, 95% CI = 0.85-1.22; highest quartile OR = 1.04, 95% CI = 0.60-1.79). This is the first prospective study to suggest an association between longer blood leukocyte telomere length and increased pancreatic cancer risk.},
}
@article {pmid23671336,
year = {2013},
author = {Steenstrup, T and Hjelmborg, JV and Kark, JD and Christensen, K and Aviv, A},
title = {The telomere lengthening conundrum--artifact or biology?.},
journal = {Nucleic acids research},
volume = {41},
number = {13},
pages = {e131},
pmid = {23671336},
issn = {1362-4962},
support = {P01 AG008761/AG/NIA NIH HHS/United States ; R01AG030678A/AG/NIA NIH HHS/United States ; AG030678/AG/NIA NIH HHS/United States ; },
mesh = {*Artifacts ; *Blotting, Southern ; Humans ; Leukocytes/metabolism ; *Polymerase Chain Reaction ; *Telomere Homeostasis ; },
abstract = {Recent longitudinal studies of age-dependent leukocyte telomere length (LTL) attrition have reported that variable proportions of individuals experience LTL lengthening. Often, LTL lengthening has been taken at face value, and authors have speculated about the biological causation of this finding. Based on empirical data and theoretical considerations, we show that regardless of the method used to measure telomere length (Southern blot or quantitative polymerase chain reaction-based methods), measurement error of telomere length and duration of follow-up explain almost entirely the absence of age-dependent LTL attrition in longitudinal studies. We find that LTL lengthening is far less frequent in studies with long follow-up periods and those that used a high-precision Southern blot method (as compared with quantitative polymerase chain reaction determination, which is associated with larger laboratory error). We conclude that the LTL lengthening observed in longitudinal studies is predominantly, if not entirely, an artifact of measurement error, which is exacerbated by short follow-up periods. We offer specific suggestions for design of longitudinal studies of LTL attrition to diminish this artifact.},
}
@article {pmid23667679,
year = {2013},
author = {Aida, J and Yokoyama, A and Shimomura, N and Nakamura, K and Ishikawa, N and Terai, M and Poon, S and Matsuura, M and Fujiwara, M and Sawabe, M and Arai, T and Takubo, K},
title = {Telomere shortening in the esophagus of Japanese alcoholics: relationships with chromoendoscopic findings, ALDH2 and ADH1B genotypes and smoking history.},
journal = {PloS one},
volume = {8},
number = {5},
pages = {e63860},
pmid = {23667679},
issn = {1932-6203},
mesh = {Adult ; Aged ; Aged, 80 and over ; *Alcoholics ; Aldehyde Dehydrogenase/*genetics ; Aldehyde Dehydrogenase 1 Family ; Aldehyde Dehydrogenase, Mitochondrial ; Asian People/*genetics ; Centromere/metabolism ; Chi-Square Distribution ; Epithelium/metabolism/pathology ; Esophagoscopy ; Esophagus/metabolism/*pathology ; Genotype ; Humans ; Iodine ; Male ; Middle Aged ; Smoking/*genetics ; Staining and Labeling ; Telomere Shortening/*genetics ; },
abstract = {Chromoendoscopy with Lugol iodine staining provides important information on the development of squamous cell carcinoma (SCC). In particular, distinct iodine-unstained lesions (DIULs) larger than 10 mm show a high prevalence in high-grade intraepithelial neoplasia. It has also been reported that inactive ALDH2*1/*2 and less-active ADH1B*1/*1, and smoking, are risk factors for esophageal SCC. We previously examined telomere shortening in the esophageal epithelium of alcoholics, and suggested a high prevalence of chromosomal instability in such individuals. In the present study, we attempted to analyze telomere lengths in 52 DIULs with reference to both their size and multiplicity, ALDH2 and ADH1B genotypes, and smoking history. Patients with DIULs <10 mm (n = 42) had significantly longer telomeres than those with DIULs ≥10 mm (n = 10, p = 0.008). No significant differences in telomere length were recognized between the ALDH2 and ADH1B genotypes (ALDH2 active/inactive = 35/17, ADH1B active/inactive = 32/20; p = 0.563, 0.784, respectively) or among four groups of patients divided according to smoking history (never-, ex-, light, and heavy smokers = 3, 6, 21, and 22 patients, respectively; p = 0.956). Patients without multiple DIULs (n = 17) had significantly longer telomeres than patients with multiple DIULs (n = 35, p = 0.040). It is suggested that alcoholism reduces telomere length in the esophagus, irrespective of genotype or smoking habit. Telomere shortening may not generate cancer directly, but may create conditions under which SCC can develop more easily, depending on subsequent exposure to carcinogens.},
}
@article {pmid23666675,
year = {2013},
author = {Morgan, RG and Ives, SJ and Lesniewski, LA and Cawthon, RM and Andtbacka, RH and Noyes, RD and Richardson, RS and Donato, AJ},
title = {Age-related telomere uncapping is associated with cellular senescence and inflammation independent of telomere shortening in human arteries.},
journal = {American journal of physiology. Heart and circulatory physiology},
volume = {305},
number = {2},
pages = {H251-8},
pmid = {23666675},
issn = {1522-1539},
support = {AG-033196/AG/NIA NIH HHS/United States ; R21 AG043952/AG/NIA NIH HHS/United States ; AG-040297/AG/NIA NIH HHS/United States ; HL-09183/HL/NHLBI NIH HHS/United States ; AG-033755/AG/NIA NIH HHS/United States ; AG-029337/AG/NIA NIH HHS/United States ; R01 AG040297/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Aged ; Aging/*genetics/immunology/metabolism/pathology ; Analysis of Variance ; Arteries/immunology/metabolism/pathology ; Arteritis/*genetics/immunology/metabolism/pathology ; Binding Sites ; *Cellular Senescence ; Chemokine CCL2/genetics ; Chi-Square Distribution ; Chromatin Immunoprecipitation ; Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism ; Female ; Histones/metabolism ; Humans ; Interleukin-8/genetics ; Male ; Middle Aged ; Muscle, Skeletal/*blood supply ; Phosphorylation ; Polymerase Chain Reaction ; Prescription Drugs/therapeutic use ; Promoter Regions, Genetic ; RNA, Messenger/metabolism ; Risk Factors ; Telomere/*metabolism ; *Telomere Shortening ; Telomeric Repeat Binding Protein 2/metabolism ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Arterial telomere dysfunction may contribute to chronic arterial inflammation by inducing cellular senescence and subsequent senescence-associated inflammation. Although telomere shortening has been associated with arterial aging in humans, age-related telomere uncapping has not been described in non-cultured human tissues and may have substantial prognostic value. In skeletal muscle feed arteries from 104 younger, middle-aged, and older adults, we assessed the potential role of age-related telomere uncapping in arterial inflammation. Telomere uncapping, measured by p-histone γ-H2A.X (ser139) localized to telomeres (chromatin immunoprecipitation; ChIP), and telomeric repeat binding factor 2 bound to telomeres (ChIP) was greater in arteries from older adults compared with those from younger adults. There was greater tumor suppressor protein p53 (P53)/cyclin-dependent kinase inhibitor 1A (P21)-induced senescence, measured by P53 bound to P21 gene promoter (ChIP), and greater expression of P21, interleukin 8, and monocyte chemotactic protein 1 mRNA (RT-PCR) in arteries from older adults compared with younger adults. Telomere uncapping was a highly influential covariate for the age-group difference in P53/P21-induced senescence. Despite progressive age-related telomere shortening in human arteries, mean telomere length was not associated with telomere uncapping or P53/P21-induced senescence. Collectively, these findings demonstrate that advancing age is associated with greater telomere uncapping in arteries, which is linked to P53/P21-induced senescence independent of telomere shortening.},
}
@article {pmid23661059,
year = {2013},
author = {Wang, F and Pan, X and Kalmbach, K and Seth-Smith, ML and Ye, X and Antumes, DM and Yin, Y and Liu, L and Keefe, DL and Weissman, SM},
title = {Robust measurement of telomere length in single cells.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {110},
number = {21},
pages = {E1906-12},
pmid = {23661059},
issn = {1091-6490},
support = {UL1 RR029893/RR/NCRR NIH HHS/United States ; P01 GM099130/GM/NIGMS NIH HHS/United States ; NIH1UL1RR029893/RR/NCRR NIH HHS/United States ; 1P01GM099130-01/GM/NIGMS NIH HHS/United States ; 1R21HD066457-01/HD/NICHD NIH HHS/United States ; R21 HD066457/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Blastocyst/cytology/*metabolism ; HeLa Cells ; Humans ; Mice ; Polar Bodies/cytology/*metabolism ; Polymerase Chain Reaction/methods ; Telomere/genetics/*metabolism ; },
abstract = {Measurement of telomere length currently requires a large population of cells, which masks telomere length heterogeneity in single cells, or requires FISH in metaphase arrested cells, posing technical challenges. A practical method for measuring telomere length in single cells has been lacking. We established a simple and robust approach for single-cell telomere length measurement (SCT-pqPCR). We first optimized a multiplex preamplification specific for telomeres and reference genes from individual cells, such that the amplicon provides a consistent ratio (T/R) of telomeres (T) to the reference genes (R) by quantitative PCR (qPCR). The average T/R ratio of multiple single cells corresponded closely to that of a given cell population measured by regular qPCR, and correlated with those of telomere restriction fragments (TRF) and quantitative FISH measurements. Furthermore, SCT-pqPCR detected the telomere length for quiescent cells that are inaccessible by quantitative FISH. The reliability of SCT-pqPCR also was confirmed using sister cells from two cell embryos. Telomere length heterogeneity was identified by SCT-pqPCR among cells of various human and mouse cell types. We found that the T/R values of human fibroblasts at later passages and from old donors were lower and more heterogeneous than those of early passages and from young donors, that cancer cell lines show heterogeneous telomere lengths, that human oocytes and polar bodies have nearly identical telomere lengths, and that the telomere lengths progressively increase from the zygote, two-cell to four-cell embryo. This method will facilitate understanding of telomere heterogeneity and its role in tumorigenesis, aging, and associated diseases.},
}
@article {pmid23660800,
year = {2013},
author = {Liu, JJ and Prescott, J and Giovannucci, E and Hankinson, SE and Rosner, B and Han, J and De Vivo, I},
title = {Plasma vitamin D biomarkers and leukocyte telomere length.},
journal = {American journal of epidemiology},
volume = {177},
number = {12},
pages = {1411-1417},
pmid = {23660800},
issn = {1476-6256},
support = {P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; P01 CA87969/CA/NCI NIH HHS/United States ; R01 CA49449/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Biomarkers ; Body Mass Index ; Calcium/administration &amp; dosage ; Cross-Sectional Studies ; Female ; Genotype ; Health Behavior ; Humans ; *Leukocytes ; Middle Aged ; Polymorphism, Single Nucleotide ; Receptors, Calcitriol/genetics ; Telomere/*drug effects ; Vitamin D/administration &amp; dosage/analogs &amp; derivatives/*blood ; Vitamin D-Binding Protein/genetics ; },
abstract = {Vitamin D may reduce telomere shortening through anti-inflammatory and anti-cell proliferation mechanisms. In the present study, we examined the association between vitamin D and relative leukocyte telomere length by using both plasma 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) biomarkers. Vitamin D biomarker levels and leukocyte telomere length were measured using plasma samples collected in 1989-1990 from participants of the Nurses' Health Study, a study of nurses from 11 US states. In total, 1,424 participants had their 25(OH)D levels assessed and 837 had their 1,25(OH)2D levels assessed. Genotyping was performed on 480 participants on 12 single nucleotide polymorphisms in vitamin D-related genes. Linear and logistic regression models were used. Higher 25(OH)D levels were significantly associated with longer telomere length (P for trend = 0.05), and the odds ratio increased from 1.07 (P = 0.65) when comparing the second lowest quartile of 25(OH)D with the lowest to 1.59 (P = 0.01) when comparing the highest quartile with the lowest. Vitamin D-related single nucleotide polymorphisms and 1,25(OH)2D levels were not significantly associated with telomere length. Total calcium intake significantly modified the association between 25(OH)D and telomere length (P for interaction = 0.05). Higher plasma 25(OH)D levels may be associated with longer telomeres, and this association may be modified by calcium intake.},
}
@article {pmid23660516,
year = {2013},
author = {Brault, ME and Lauzon, C and Autexier, C},
title = {Dyskeratosis congenita mutations in dyskerin SUMOylation consensus sites lead to impaired telomerase RNA accumulation and telomere defects.},
journal = {Human molecular genetics},
volume = {22},
number = {17},
pages = {3498-3507},
doi = {10.1093/hmg/ddt204},
pmid = {23660516},
issn = {1460-2083},
support = {MOP-86672//Canadian Institutes of Health Research/Canada ; },
mesh = {Amino Acid Sequence ; Cell Cycle Proteins/*genetics ; Dyskeratosis Congenita/*genetics/metabolism ; Gene Knockdown Techniques ; HEK293 Cells ; Humans ; Molecular Sequence Data ; Mutation ; Nuclear Proteins/*genetics ; Phylogeny ; Protein Stability ; RNA/genetics/*metabolism ; Sequence Alignment ; Small Ubiquitin-Related Modifier Proteins/metabolism ; Sumoylation ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Mutations in the dyskerin gene (DKC1) cause X-linked dyskeratosis congenita (DC), a rare and fatal premature aging syndrome characterized by defective telomere maintenance. Dyskerin is a highly conserved nucleolar protein, and a component of the human telomerase complex that is essential for human telomerase RNA (hTR) stability. However, its regulation remains poorly understood. Here, we report that dyskerin can be modified by small ubiquitin-like modifiers (SUMOs). We find that human DC-causing mutations in highly conserved dyskerin SUMOylation consensus sites lead to impaired hTR accumulation, telomerase activity and telomere maintenance. Finally, we show that modification of dyskerin by SUMOylation is required for its stability. Our findings provide the first evidence that dyskerin stability is regulated by SUMOylation and that mutations altering dyskerin SUMOylation can lead to defects in telomere maintenance that are characteristics of DC.},
}
@article {pmid23656775,
year = {2013},
author = {Mondello, C and Chiodi, I},
title = {Cellular immortalization and neoplastic transformation: Simultaneous, sequential or independent? Telomeres, telomerase or karyotypic variations?.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {12},
number = {11},
pages = {1804-1805},
pmid = {23656775},
issn = {1551-4005},
mesh = {Animals ; Cell Transformation, Neoplastic/*genetics/*pathology ; Female ; Humans ; *Karyotyping ; Neoplasms/*genetics/*pathology ; },
}
@article {pmid23648233,
year = {2013},
author = {Arbuckle, JH and Pantry, SN and Medveczky, MM and Prichett, J and Loomis, KS and Ablashi, D and Medveczky, PG},
title = {Mapping the telomere integrated genome of human herpesvirus 6A and 6B.},
journal = {Virology},
volume = {442},
number = {1},
pages = {3-11},
pmid = {23648233},
issn = {1096-0341},
support = {R01 CA111196/CA/NCI NIH HHS/United States ; 5R01CA111196/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line ; *Chromosome Mapping ; Chromosomes, Human/virology ; DNA Replication ; DNA, Viral/genetics ; Female ; *Genome, Viral ; HEK293 Cells/drug effects/virology ; Herpesvirus 6, Human/*genetics ; Humans ; Hydroxamic Acids/pharmacology ; Male ; Roseolovirus Infections/virology ; Telomere/*virology ; *Virus Integration ; Virus Latency ; },
abstract = {Human herpesvirus 6B (HHV-6B) is the causative agent of roseola infantum. HHV-6A and 6B can reactivate in immunosuppressed individuals and are linked with severe inflammatory response, organ rejection and central nervous system diseases. About 0.85% of the US and UK population carries an integrated HHV-6 genome in all nucleated cells through germline transmission. We have previously reported that the HHV-6A genome integrated in telomeres of patients suffering from neurological dysfunction and also in telomeres of tissue culture cells. We now report that HHV-6B also integrates in telomeres during latency. Detailed mapping of the integrated viral genomes demonstrates that a single HHV-6 genome integrates and telomere repeats join the left end of the integrated viral genome. When HEK-293 cells carrying integrated HHV-6A were exposed to the histone deacetylase inhibitor Trichostatin A, circularization and/or formation of concatamers were detected and this assay could be used to distinguish between lytic replication and latency.},
}
@article {pmid23647631,
year = {2013},
author = {Kong, CM and Lee, XW and Wang, X},
title = {Telomere shortening in human diseases.},
journal = {The FEBS journal},
volume = {280},
number = {14},
pages = {3180-3193},
doi = {10.1111/febs.12326},
pmid = {23647631},
issn = {1742-4658},
mesh = {Anemia, Aplastic/genetics ; Animals ; DNA Repair-Deficiency Disorders/genetics ; Dyskeratosis Congenita/genetics ; Humans ; Idiopathic Pulmonary Fibrosis/genetics ; Metabolic Diseases/genetics ; Neoplasms/genetics ; *Telomere Shortening ; },
abstract = {The discovery of telomeres dates back to the early 20th century. In humans, telomeres are heterochromatic structures with tandem DNA repeats of 5'-TTAGGG-3' at the chromosomal ends. Telomere length varies greatly among species and ranges from 10 to 15 kb in humans. With each cell division, telomeres shorten progressively because of the 'end-replication problem'. Short or dysfunctional telomeres are often recognized as DNA DSBs, triggering cell-cycle arrest and result in cellular senescence or apoptotic cell death. Therefore, telomere shortening serves as an important tumor-suppressive mechanism by limiting cellular proliferative capacity by regulating senescence checkpoint activation. Although telomeres serve as a mitotic clock to cells, they also confer capping on chromosomes, with help from telomere-associated proteins. Over the past decades, many studies of telomere biology have demonstrated that telomeres and telomere-associated proteins are implicated in human genetic diseases. In addition, it has become more apparent that accelerated telomere erosion is associated with a myriad of metabolic and inflammatory diseases. Moreover, critically short or unprotected telomeres are likely to form telomeric fusions, leading to genomic instability, the cornerstone for carcinogenesis. In light of these, this minireview summarizes studies on telomeres and telomere-associated proteins in human diseases. Elucidating the roles of telomeres involved in the mechanisms underlying pathogenesis of these diseases may open up new possibilities for novel molecular targets as well as provide important diagnostic and therapeutic implications.},
}
@article {pmid23646142,
year = {2013},
author = {Boccardi, V and Esposito, A and Rizzo, MR and Marfella, R and Barbieri, M and Paolisso, G},
title = {Mediterranean diet, telomere maintenance and health status among elderly.},
journal = {PloS one},
volume = {8},
number = {4},
pages = {e62781},
pmid = {23646142},
issn = {1932-6203},
mesh = {Age Factors ; Aged ; Aged, 80 and over ; *Diet, Mediterranean ; Female ; *Health Status ; Humans ; Inflammation/genetics ; Male ; Risk Factors ; Telomere/*metabolism ; *Telomere Homeostasis ; White People ; },
abstract = {Leukocyte telomere length (LTL) and rate of telomere shortening are known biomarkers of aging while, numerous studies showed that Mediterranean diet (MD) may boost longevity. We studied association between telomere length, telomerase activity and different adherence to MD and its effects on healthy status. The study was conducted in 217 elderly subjects stratified according Mediterranean diet score (MDS) in low adherence (MDS≤3), medium adherence (MDS 4-5) and high adherence (MDS≥6) groups. LTL was measured by quantitative polymerase chain reaction and telomerase activity by a PCR-ELISA protocol. High adherence group showed longer LTL (p = 0.003) and higher telomerase activity (p = 0.013) compared to others. Linear regression analysis including age, gender, smoking habit and MDS showed that MDS was independently associated with LTL (p = 0.024) and telomerase activity levels (p = 0.006). Telomerase activity was independently associated with LTL (p = 0.007) and negatively modulated by inflammation and oxidative stress. Indeed, telomerase levels were associated with healthy status independently of multiple covariates (p = 0.048). These results support a novel role of MD in promoting health-span suggesting that telomere maintenance, rather than LTL variability is the major determinant of healthy status among elderly.},
}
@article {pmid23644600,
year = {2013},
author = {Stadler, G and Rahimov, F and King, OD and Chen, JC and Robin, JD and Wagner, KR and Shay, JW and Emerson, CP and Wright, WE},
title = {Telomere position effect regulates DUX4 in human facioscapulohumeral muscular dystrophy.},
journal = {Nature structural &amp; molecular biology},
volume = {20},
number = {6},
pages = {671-678},
pmid = {23644600},
issn = {1545-9985},
support = {J 2737/FWF_/Austrian Science Fund FWF/Austria ; AG01228/AG/NIA NIH HHS/United States ; P50 CA70907/CA/NCI NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; 5U54HD060848/HD/NICHD NIH HHS/United States ; U54 HD060848/HD/NICHD NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; },
mesh = {Cells, Cultured ; *Gene Expression Regulation ; Homeodomain Proteins/*genetics/*metabolism ; Humans ; Muscular Dystrophy, Facioscapulohumeral/*genetics/pathology ; Myoblasts/physiology ; Telomere/*metabolism ; Up-Regulation ; },
abstract = {Telomeres may regulate human disease by at least two independent mechanisms. First, replicative senescence occurs once short telomeres generate DNA-damage signals that produce a barrier to tumor progression. Second, telomere position effects (TPE) could change gene expression at intermediate telomere lengths in cultured human cells. Here we report that telomere length may contribute to the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a late-onset disease genetically residing only 25-60 kilobases from the end of chromosome 4q. We used a floxable telomerase to generate isogenic clones with different telomere lengths from affected patients and their unaffected siblings. DUX4, the primary candidate for FSHD pathogenesis, is upregulated over ten-fold in FSHD myoblasts and myotubes with short telomeres, and its expression is inversely proportional to telomere length. FSHD may be the first known human disease in which TPE contributes to age-related phenotype.},
}
@article {pmid23640743,
year = {2013},
author = {Mason, C and Risques, RA and Xiao, L and Duggan, CR and Imayama, I and Campbell, KL and Kong, A and Foster-Schubert, KE and Wang, CY and Alfano, CM and Blackburn, GL and Rabinovitch, PS and McTiernan, A},
title = {Independent and combined effects of dietary weight loss and exercise on leukocyte telomere length in postmenopausal women.},
journal = {Obesity (Silver Spring, Md.)},
volume = {21},
number = {12},
pages = {E549-54},
pmid = {23640743},
issn = {1930-739X},
support = {R25 CA057699/CA/NCI NIH HHS/United States ; R25 CA94880/CA/NCI NIH HHS/United States ; R25 CA094880/CA/NCI NIH HHS/United States ; U54-CA116847/CA/NCI NIH HHS/United States ; KL2 RR025015/RR/NCRR NIH HHS/United States ; R01 CA102504/CA/NCI NIH HHS/United States ; U54 CA116847/CA/NCI NIH HHS/United States ; R01 CA105204/CA/NCI NIH HHS/United States ; 5KL2RR025015-03/RR/NCRR NIH HHS/United States ; /CAPMC/CIHR/Canada ; 2R25CA057699-16/CA/NCI NIH HHS/United States ; R21 CA155823/CA/NCI NIH HHS/United States ; },
mesh = {Adipose Tissue ; Aged ; Body Mass Index ; *Diet, Reducing ; Exercise/*physiology ; Female ; Humans ; Leukocytes/*metabolism ; Middle Aged ; Obesity/blood/therapy ; Overweight/blood/therapy ; Postmenopause/*blood ; Telomere/*metabolism ; Weight Loss/*physiology ; },
abstract = {OBJECTIVE: Investigate the effects of 12 months of dietary weight loss and/or aerobic exercise on leukocyte telomere length in postmenopausal women.<br><br>DESIGN AND METHODS: Four hundred and thirty nine overweight or obese women (50-75 years) were randomized to: (i) dietary weight loss (N = 118); (ii) aerobic exercise (N = 117), (iii) diet + exercise (N = 117), or (iv) control (N = 87). The diet intervention was a group-based program with a 10% weight loss goal. The exercise intervention was 45 min day(-1) , 5 days week(-1) of moderate-to-vigorous aerobic activity. Fasting blood samples were taken at baseline and 12 months. DNA was extracted from isolated leukocytes and telomere length was measured by quantitative-polymerase chain reaction (qPCR). Mean changes were compared between groups (intent-to-treat) using generalized estimating equations.<br><br>RESULTS: Baseline telomere length was inversely associated with age (r = -0.12 P < 0.01) and positively associated with maximal oxygen uptake (r = 0.11, P = 0.03), but not with BMI or %body fat. Change in telomere length was inversely correlated with baseline telomere length (r = -0.47, P < 0.0001). No significant difference in leukocyte telomere length was detected in any intervention group compared to controls, nor was the magnitude of weight loss associated with telomere length at 12 months.<br><br>CONCLUSIONS: Twelve months of dietary weight loss and exercise did not change telomere length in postmenopausal women.},
}
@article {pmid23639252,
year = {2013},
author = {Shalev, I and Entringer, S and Wadhwa, PD and Wolkowitz, OM and Puterman, E and Lin, J and Epel, ES},
title = {Stress and telomere biology: a lifespan perspective.},
journal = {Psychoneuroendocrinology},
volume = {38},
number = {9},
pages = {1835-1842},
pmid = {23639252},
issn = {1873-3360},
support = {K99 HL109247/HL/NHLBI NIH HHS/United States ; HD061298/HD/NICHD NIH HHS/United States ; R01 HD065825/HD/NICHD NIH HHS/United States ; R01 HD060628/HD/NICHD NIH HHS/United States ; P01 HD047609/HD/NICHD NIH HHS/United States ; HD-065825/HD/NICHD NIH HHS/United States ; R01 MH083784/MH/NIMH NIH HHS/United States ; R00 HL109247/HL/NHLBI NIH HHS/United States ; HD-060628/HD/NICHD NIH HHS/United States ; R01 HD061298/HD/NICHD NIH HHS/United States ; R01 AG030424/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Age of Onset ; Aging/*genetics ; Cellular Senescence/genetics ; Child ; Chronic Disease/epidemiology ; Comorbidity ; Embryonic Development/genetics ; Female ; Habits ; Humans ; Infant, Newborn ; *Life Style ; Male ; Mental Disorders/epidemiology/genetics ; Pregnancy ; Prenatal Exposure Delayed Effects ; Risk-Taking ; Stress Disorders, Traumatic/epidemiology/genetics ; Stress, Psychological/epidemiology/*genetics ; Telomere Homeostasis/*physiology ; Telomere Shortening/*physiology ; },
abstract = {In the past decade, the growing field of telomere science has opened exciting new avenues for understanding the cellular and molecular substrates of stress and stress-related aging processes over the lifespan. Shorter telomere length is associated with advancing chronological age and also increased disease morbidity and mortality. Emerging studies suggest that stress accelerates the erosion of telomeres from very early in life and possibly even influences the initial (newborn) setting of telomere length. In this review, we highlight recent empirical evidence linking stress and mental illnesses at various times across the lifespan with telomere erosion. We first present findings in the developmental programming of telomere biology linking prenatal stress to newborn and adult telomere length. We then present findings linking exposure to childhood trauma and to certain mental disorders with telomere shortening. Last, we review studies that characterize the relationship between related health-risk behaviors with telomere shortening over the lifespan, and how this process may further buffer the negative effects of stress on telomeres. A better understanding of the mechanisms that govern and regulate telomere biology throughout the lifespan may inform our understanding of etiology and the long-term consequences of stress and mental illnesses on aging processes in diverse populations and settings.},
}
@article {pmid23638436,
year = {2013},
author = {Teixeira, MT},
title = {Saccharomyces cerevisiae as a Model to Study Replicative Senescence Triggered by Telomere Shortening.},
journal = {Frontiers in oncology},
volume = {3},
number = {},
pages = {101},
pmid = {23638436},
issn = {2234-943X},
support = {260906/ERC_/European Research Council/International ; },
abstract = {In many somatic human tissues, telomeres shorten progressively because of the DNA-end replication problem. Consequently, cells cease to proliferate and are maintained in a metabolically viable state called replicative senescence. These cells are characterized by an activation of DNA damage checkpoints stemming from eroded telomeres, which are bypassed in many cancer cells. Hence, replicative senescence has been considered one of the most potent tumor suppressor pathways. However, the mechanism through which short telomeres trigger this cellular response is far from being understood. When telomerase is removed experimentally in Saccharomyces cerevisiae, telomere shortening also results in a gradual arrest of population growth, suggesting that replicative senescence also occurs in this unicellular eukaryote. In this review, we present the key steps that have contributed to the understanding of the mechanisms underlying the establishment of replicative senescence in budding yeast. As in mammals, signals stemming from short telomeres activate the DNA damage checkpoints, suggesting that the early cellular response to the shortest telomere(s) is conserved in evolution. Yet closer analysis reveals a complex picture in which the apparent single checkpoint response may result from a variety of telomeric alterations expressed in the absence of telomerase. Accordingly, the DNA replication of eroding telomeres appears as a critical challenge for senescing budding yeast cells and the easy manipulation of S. cerevisiae is providing insights into the way short telomeres are integrated into their chromatin and nuclear environments. Finally, the loss of telomerase in budding yeast triggers a more general metabolic alteration that remains largely unexplored. Thus, telomerase-deficient S. cerevisiae cells may have more common points than anticipated with somatic cells, in which telomerase depletion is naturally programed, thus potentially inspiring investigations in mammalian cells.},
}
@article {pmid23637804,
year = {2013},
author = {Seguí, N and Pineda, M and Guinó, E and Borràs, E and Navarro, M and Bellido, F and Moreno, V and Lázaro, C and Blanco, I and Capellá, G and Valle, L},
title = {Telomere length and genetic anticipation in Lynch syndrome.},
journal = {PloS one},
volume = {8},
number = {4},
pages = {e61286},
pmid = {23637804},
issn = {1932-6203},
mesh = {Age of Onset ; Aged ; Aged, 80 and over ; Anticipation, Genetic/*genetics ; Child ; Colorectal Neoplasms, Hereditary Nonpolyposis/*genetics ; Female ; Humans ; Male ; Middle Aged ; Pedigree ; Telomere/*genetics ; Telomere Shortening ; },
abstract = {Telomere length variation has been associated with increased risk of several types of tumors, and telomere shortening, with genetic anticipation in a number of genetic diseases including hereditary cancer syndromes. No conclusive studies have been performed for Lynch syndrome, a hereditary colorectal cancer syndrome caused by germline mutations in the DNA mismatch repair genes. Here we evaluate telomere length in Lynch syndrome, both as a cancer risk factor and as a mechanism associated with anticipation in the age of cancer onset observed in successive generations of Lynch syndrome families. Leukocyte telomere length was measured in 244 mismatch repair gene mutation carriers from 96 Lynch syndrome families and in 234 controls using a monochrome multiplex quantitative PCR method. Cancer-affected mutation carriers showed significantly shorter telomeres than cancer-free mutation carriers. In addition, cancer-affected carriers showed the most pronounced shortening of telomere length with age, compared with unaffected carriers. The anticipation in the age of cancer onset observed in successive generations was not associated with telomere shortening, although, interestingly, all mother-son pairs showed telomere shortening. In conclusion, cancer-affected mismatch repair gene mutation carriers have distinct telomere-length pattern and dynamics. However, anticipation in the age of onset is not explained by telomere shortening. Pending further study, our findings suggest that telomere attrition might explain the previously reported dependence of cancer risk on the parent-of-origin of mismatch repair gene mutations.},
}
@article {pmid23636667,
year = {2013},
author = {Scheinberg, P},
title = {Prognostic value of telomere attrition in patients with aplastic anemia.},
journal = {International journal of hematology},
volume = {97},
number = {5},
pages = {553-557},
pmid = {23636667},
issn = {1865-3774},
mesh = {Anemia, Aplastic/*genetics/*metabolism/therapy ; Hematopoietic Stem Cell Transplantation ; Humans ; Immunosuppression Therapy ; Immunosuppressive Agents/therapeutic use ; Prognosis ; Recurrence ; Telomerase/*genetics/*metabolism ; Telomere/*metabolism ; Treatment Outcome ; },
abstract = {The decision to pursue hematopoietic stem cell transplantation or immunosuppression as first therapy in severe aplastic anemia is currently based on age and availability of a histocompatible donor. The ability to predict hematologic response, relapse and clonal evolution could improve treatment allocation. In the past 15 years, telomeres have been implicated in clinical diseases such as aplastic anemia, pulmonary fibrosis, cirrhosis and cancer development. The clinical relevance of varying telomere lengths (TL) and/or mutations in genes of the telomerase complex (TERC, TERT) is evolving in aplastic anemia. A large retrospective analysis suggests that baseline TL associate with late events of hematologic relapse and clonal evolution in aplastic anemia patients treated initially with anti-thymocyte globulin-based therapy. Further laboratory experiments propose possible mechanistic insight into genomic instability of bone marrow cells derived from patients with critically short telomeres and/or mutation in telomerase genes. The possibility of modulating telomere attrition rate with sex hormones could positively affect clonal evolution rates in humans. This review will summarize studies in marrow failure that explore the association between telomeres and aplastic anemia outcomes.},
}
@article {pmid23634944,
year = {2013},
author = {Sarkar, S and Faller, DV},
title = {Telomere-homologous G-rich oligonucleotides sensitize human ovarian cancer cells to TRAIL-induced growth inhibition and apoptosis.},
journal = {Nucleic acid therapeutics},
volume = {23},
number = {3},
pages = {167-174},
pmid = {23634944},
issn = {2159-3345},
support = {CA133654/CA/NCI NIH HHS/United States ; },
mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; CASP8 and FADD-Like Apoptosis Regulating Protein/genetics/metabolism ; Caspase 3/genetics/metabolism ; Caspase 7/genetics/metabolism ; Caspase 8/genetics/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Synergism ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; MAP Kinase Kinase 4/genetics/metabolism ; Oligonucleotides/genetics/*pharmacology ; Ovarian Neoplasms/drug therapy/genetics/metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics/metabolism ; Recombinant Proteins/pharmacology ; Signal Transduction/*drug effects ; TNF-Related Apoptosis-Inducing Ligand/*pharmacology ; Telomere/*drug effects/genetics ; },
abstract = {G-rich T-oligos (GT-oligos; oligonucleotides with homology to telomeres) elicit a DNA damage response in cells and induce cytotoxic effects in certain tumor cell lines. We have previously shown that GT-oligo inhibits growth, arrests cell cycle, and induces apoptosis in ovarian, pancreatic, and prostate cancer cells. However, not all ovarian cancer cell lines are susceptible to GT-oligo exposure. GT-oligo was found to induce transcript expression of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors DR-4 and DR-5, which are generally silenced in ovarian cancer cells, rendering them insensitive to TRAIL. Exposure of TRAIL- and GT-oligo-resistant cell lines to GT-oligo rendered them sensitive to the cytotoxic effects of TRAIL, producing more than additive inhibition of growth. An intracellular inhibitor of the extrinsic apoptotic pathway, FLICE-like Inhibitory Protein-Short (FLIPs), was down-regulated and Jun kinase (JNK) was activated by exposure to GT-oligo. JNK inhibition partially reversed the growth inhibition caused by the combination of GT-oligo and TRAIL indicating partial involvement of the Jun kinase pathway in the resulting cytotoxic effect. Both capase-8 and caspases 3/7 were activated by exposure to GT-oligo plus TRAIL, consistent with activation of the extrinsic apoptotic pathway. These results demonstrate a novel way of sensitizing resistant ovarian cancer cells to TRAIL-mediated cytotoxicity.},
}
@article {pmid23630056,
year = {2013},
author = {Danescu, A and Herrero Gonzalez, S and Di Cristofano, A and Mai, S and Hombach-Klonisch, S},
title = {Three-dimensional nuclear telomere architecture changes during endometrial carcinoma development.},
journal = {Genes, chromosomes &amp; cancer},
volume = {52},
number = {8},
pages = {716-732},
pmid = {23630056},
issn = {1098-2264},
support = {R01 CA097097/CA/NCI NIH HHS/United States ; CA097097/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Nucleus/genetics/pathology ; Cell Transformation, Neoplastic/*genetics/pathology ; Endometrial Neoplasms/*genetics/pathology ; Female ; Humans ; Immunohistochemistry ; Mice ; PTEN Phosphohydrolase/genetics ; Telomere/*genetics/pathology/*ultrastructure ; },
abstract = {Endometrioid or type-I endometrial carcinoma (EC) develops from hyperproliferative glandular pathologies. Inactivation of the tumor suppressor gene PTEN is frequently associated with type-I EC. Using a previously characterized Pten heterozygous (Pten+/-) mouse model, this study investigates the three-dimensional (3D) telomere profiles during progression from hyperplastic lesions to EC to test the hypothesis that altered 3D telomere profiles can be detected prior to Pten loss in early hyperproliferative lesions. We used immunohistochemistry and 3D-telomere fluorescent in-situ hybridization to investigate Pten expression, telomere length and signal distribution, average number and spatial distribution of telomeres and formation of telomere aggregates in uterine glandular epithelial cells from wildtype and Pten+/- mice. Pten showed nuclear and cytoplasmic localization in WT, predominantly cytoplasmic staining in simple hyperplasia (SH) and was markedly reduced in atypical hyperplasia (AH). Telomere length in glandular epithelial cells does not shorten with age. The average number of telomeres per nucleus was not different in WT and Pten+/- mice indicating the lack of substantial numeric chromosome aberrations during EC development. We observed telomere aggregates in lesions of AH and EC. SH lesions in Pten+/- mice differed from normal glandular epithelium by an increased relative number of shorter telomeres and by a telomere signal distribution indicative of a heterogeneous cell population. Our study revealed that alterations in the nuclear 3D telomere architecture are present in early proliferative lesions of mouse uterine tissues indicative of EC development. The changes in telomere length distribution and nuclear signal distribution precede the loss of Pten.},
}
@article {pmid23629941,
year = {2013},
author = {Pellatt, AJ and Wolff, RK and Torres-Mejia, G and John, EM and Herrick, JS and Lundgreen, A and Baumgartner, KB and Giuliano, AR and Hines, LM and Fejerman, L and Cawthon, R and Slattery, ML},
title = {Telomere length, telomere-related genes, and breast cancer risk: the breast cancer health disparities study.},
journal = {Genes, chromosomes &amp; cancer},
volume = {52},
number = {7},
pages = {595-609},
pmid = {23629941},
issn = {1098-2264},
support = {K01 CA160607/CA/NCI NIH HHS/United States ; CA77305/CA/NCI NIH HHS/United States ; CA078682/CA/NCI NIH HHS/United States ; R01 CA078552/CA/NCI NIH HHS/United States ; HHSN261201000036C/CA/NCI NIH HHS/United States ; R01 CA078762/CA/NCI NIH HHS/United States ; R01 CA140002/CA/NCI NIH HHS/United States ; R01 CA063446/CA/NCI NIH HHS/United States ; CA078552/CA/NCI NIH HHS/United States ; CA078802/CA/NCI NIH HHS/United States ; R01 CA078802/CA/NCI NIH HHS/United States ; R01 CA078682/CA/NCI NIH HHS/United States ; CA14002/CA/NCI NIH HHS/United States ; CA078762/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Breast Neoplasms/*genetics/pathology ; Female ; *Genetic Association Studies ; Genomic Instability ; Humans ; Middle Aged ; Polymorphism, Single Nucleotide ; Receptors, Estrogen/genetics ; Receptors, Progesterone/genetics ; Risk Factors ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Telomeres are involved in maintaining genomic stability. Previous studies have linked both telomere length (TL) and telomere-related genes with cancer. We evaluated associations between telomere-related genes, TL, and breast cancer risk in an admixed population of US non-Hispanic white (1,481 cases, 1,586 controls) and U.S. Hispanic and Mexican women (2,111 cases, 2,597 controls) from the Breast Cancer Health Disparities Study. TL was assessed in 1,500 women based on their genetic ancestry. TL-related genes assessed were MEN1, MRE11A, RECQL5, TEP1, TERC, TERF2, TERT, TNKS, and TNKS2. Longer TL was associated with increased breast cancer risk [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.38, 2.55], with the highest risk (OR 3.11, 95% CI 1.74, 5.67 p interaction 0.02) among women with high Indigenous American ancestry. Several TL-related single nucleotide polymorphisms had modest association with breast cancer risk overall, including TEP1 rs93886 (OR 0.82, 95% CI 0.70,0.95); TERF2 rs3785074 (OR 1.13, 95% CI 1.03,1.24); TERT rs4246742 (OR 0.85, 95% CI 0.77,0.93); TERT rs10069690 (OR 1.13, 95% CI 1.03,1.24); TERT rs2242652 (OR 1.51, 95% CI 1.11,2.04); and TNKS rs6990300 (OR 0.89, 95% CI 0.81,0.97). Several differences in association were detected by hormone receptor status of tumors. Most notable were associations with TERT rs2736118 (ORadj 6.18, 95% CI 2.90, 13.19) with estrogen receptor negative/progesterone receptor positive (ER-/PR+) tumors and TERT rs2735940 (ORadj 0.73, 95% CI 0.59, 0.91) with ER-/PR- tumors. These data provide support for an association between TL and TL-related genes and risk of breast cancer. The association may be modified by hormone receptor status and genetic ancestry.},
}
@article {pmid23629439,
year = {2013},
author = {Banerjee, B and Hande, MP},
title = {Age-independent telomere shortening and ion-channel defects in SCD.},
journal = {Nature reviews. Cardiology},
volume = {10},
number = {6},
pages = {362},
pmid = {23629439},
issn = {1759-5010},
mesh = {Cardiovascular Diseases/*etiology ; *Cellular Senescence ; Humans ; Male ; Telomere/*pathology ; *Telomere Shortening ; },
}
@article {pmid23621889,
year = {2013},
author = {Lee, JW},
title = {Telomere shortening by mutations in the RTEL1 helicase cause severe form of dyskeratosis congenita, Hoyerall-Hreidarsson syndrome.},
journal = {Clinical genetics},
volume = {84},
number = {3},
pages = {210},
doi = {10.1111/cge.12175},
pmid = {23621889},
issn = {1399-0004},
mesh = {DNA Helicases/*genetics ; Dyskeratosis Congenita/*genetics ; Female ; Fetal Growth Retardation/*genetics ; *Germ-Line Mutation ; Humans ; Intellectual Disability/*genetics ; Male ; Microcephaly/*genetics ; *Mutation ; *Mutation, Missense ; },
}
@article {pmid23621240,
year = {2013},
author = {Hu, L and Wu, QQ and Wang, WB and Jiang, HG and Yang, L and Liu, Y and Yu, HJ and Xie, CH and Zhou, YF and Zhou, FX},
title = {Suppression of Ku80 correlates with radiosensitivity and telomere shortening in the U2OS telomerase-negative osteosarcoma cell line.},
journal = {Asian Pacific journal of cancer prevention : APJCP},
volume = {14},
number = {2},
pages = {795-799},
doi = {10.7314/apjcp.2013.14.2.795},
pmid = {23621240},
issn = {2476-762X},
mesh = {Antigens, Nuclear/*biosynthesis/genetics ; Cell Line, Tumor ; DNA Repair ; DNA-Binding Proteins/*biosynthesis/genetics ; Down-Regulation ; Humans ; Ku Autoantigen ; Osteosarcoma/*genetics/*radiotherapy ; RNA Interference ; RNA, Small Interfering ; Radiation Tolerance/*genetics ; Telomerase/deficiency/genetics ; Telomere/metabolism ; Telomere Homeostasis/genetics ; Telomere Shortening/*genetics ; Telomeric Repeat Binding Protein 2/biosynthesis/genetics ; },
abstract = {Ku70/80 heterodimer is a central element in the nonhomologous end joining (NHEJ) DNA repair pathway, Ku80 playing a key role in regulating the multiple functions of Ku proteins. It has been found that the Ku80 protein located at telomeres is a major contributor to radiosensitivity in some telomerase positive human cancer cells. However, in ALT human osteosarcoma cells, the precise function in radiosensitivity and telomere maintenance is still unknown. The aim of this study was to investigate the effects of Ku80 depletion in the U2OS ALT cell line cell line. Suppression of Ku80 expression was performed using a vector-based shRNA and stable Ku80 knockdown in cells was verified by Western blotting. U2OS cells treated with shRNA-Ku80 showed lower radiobiological parameters (D0, Dq and SF2) in clonogenic assays. Furthermore, shRNA-Ku80 vector transfected cells displayed shortening of the telomere length and showed less expression of TRF2 protein. These results demonstrated that down-regulation of Ku80 can sensitize ALT cells U2OS to radiation, and this radiosensitization is related to telomere length shortening.},
}
@article {pmid23620229,
year = {2014},
author = {Hirt, BV and Wattis, JA and Preston, SP},
title = {Modelling the regulation of telomere length: the effects of telomerase and G-quadruplex stabilising drugs.},
journal = {Journal of mathematical biology},
volume = {68},
number = {6},
pages = {1521-1552},
pmid = {23620229},
issn = {1432-1416},
mesh = {Acridines/*pharmacology ; Computer Simulation ; G-Quadruplexes/*drug effects ; HeLa Cells ; Humans ; *Models, Biological ; Telomerase/antagonists &amp; inhibitors/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are guanine-rich sequences at the end of chromosomes which shorten during each replication event and trigger cell cycle arrest and/or controlled death (apoptosis) when reaching a threshold length. The enzyme telomerase replenishes the ends of telomeres and thus prolongs the life span of cells, but also causes cellular immortalisation in human cancer. G-quadruplex (G4) stabilising drugs are a potential anticancer treatment which work by changing the molecular structure of telomeres to inhibit the activity of telomerase. We investigate the dynamics of telomere length in different conformational states, namely t-loops, G-quadruplex structures and those being elongated by telomerase. By formulating deterministic differential equation models we study the effects of various levels of both telomerase and concentrations of a G4-stabilising drug on the distribution of telomere lengths, and analyse how these effects evolve over large numbers of cell generations. As well as calculating numerical solutions, we use quasicontinuum methods to approximate the behaviour of the system over time, and predict the shape of the telomere length distribution. We find those telomerase and G4-concentrations where telomere length maintenance is successfully regulated. Excessively high levels of telomerase lead to continuous telomere lengthening, whereas large concentrations of the drug lead to progressive telomere erosion. Furthermore, our models predict a positively skewed distribution of telomere lengths, that is, telomeres accumulate over lengths shorter than the mean telomere length at equilibrium. Our model results for telomere length distributions of telomerase-positive cells in drug-free assays are in good agreement with the limited amount of experimental data available.},
}
@article {pmid23620080,
year = {2013},
author = {Mansouri, L and Grabowski, P and Degerman, S and Svenson, U and Gunnarsson, R and Cahill, N and Smedby, KE and Geisler, C and Juliusson, G and Roos, G and Rosenquist, R},
title = {Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients.},
journal = {American journal of hematology},
volume = {88},
number = {8},
pages = {647-651},
doi = {10.1002/ajh.23466},
pmid = {23620080},
issn = {1096-8652},
mesh = {Aged ; Biomarkers, Tumor/*genetics/metabolism ; Disease-Free Survival ; Female ; Follow-Up Studies ; Humans ; *Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis/genetics/mortality/therapy ; Male ; Middle Aged ; *Mutation ; Phosphoproteins/*genetics/metabolism ; Predictive Value of Tests ; RNA Splicing Factors ; Receptor, Notch1/*genetics/metabolism ; Retrospective Studies ; Ribonucleoprotein, U2 Small Nuclear/*genetics/metabolism ; Survival Rate ; Telomere/*genetics/metabolism ; Tumor Suppressor Protein p53/*genetics/metabolism ; },
abstract = {Most previous studies on telomere length (TL) in chronic lymphocytic leukemia (CLL) are based on referral cohorts including a high proportion of aggressive cases. Here, the impact of TL was analyzed in a population-based cohort of newly diagnosed CLL (n = 265) and in relation to other prognostic markers. Short telomeres were particularly associated with high-risk genetic markers, such as NOTCH1, SF3B1, or TP53 aberrations, and predicted a short time to treatment (TTT) and overall survival (OS) (both P < 0.0001). TL was an independent prognostic factor and subdivided patients with otherwise good-prognostic features (e.g., mutated IGHV genes, favorable cytogenetics) into subgroups with different outcome. Furthermore, in follow-up samples (n = 119) taken 5-8 years after diagnosis, TL correlated well with TL at diagnosis and remained unaffected by treatment. Altogether, these novel data indicate that short TL already at diagnosis is associated with poor outcome in CLL and that TL can be measured at later stages of the disease.},
}
@article {pmid23618685,
year = {2013},
author = {Gansner, JM and Rosas, IO},
title = {Telomeres in lung disease.},
journal = {Translational research : the journal of laboratory and clinical medicine},
volume = {162},
number = {6},
pages = {343-352},
doi = {10.1016/j.trsl.2013.04.001},
pmid = {23618685},
issn = {1878-1810},
mesh = {Humans ; Idiopathic Pulmonary Fibrosis/etiology ; Lung Diseases/*etiology ; Lung Neoplasms/etiology ; Mutation ; Pulmonary Disease, Chronic Obstructive/etiology ; Telomerase/genetics/physiology ; Telomere/genetics/*physiology ; Translational Research, Biomedical ; },
abstract = {Telomeres are DNA-protein structures that cap the ends of chromosomes; telomerase is the enzyme that ensures their integrity. Telomere biology has recently been implicated in the pathogenesis of a variety of lung diseases, including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease/emphysema, and lung cancer. This review highlights recent discoveries pertaining to the role of telomere biology in lung disease.},
}
@article {pmid23616949,
year = {2013},
author = {Le, PN and Maranon, DG and Altina, NH and Battaglia, CL and Bailey, SM},
title = {TERRA, hnRNP A1, and DNA-PKcs Interactions at Human Telomeres.},
journal = {Frontiers in oncology},
volume = {3},
number = {},
pages = {91},
pmid = {23616949},
issn = {2234-943X},
abstract = {Maintenance of telomeres, repetitive elements at eukaryotic chromosomal termini, and the end-capping structure and function they provide, are imperative for preserving genome integrity and stability. The discovery that telomeres are transcribed into telomere repeat containing RNA (TERRA) has revolutionized our view of this repetitive, rather unappreciated region of the genome. We have previously shown that the non-homologous end-joining, shelterin associated DNA dependent protein kinase catalytic subunit (DNA-PKcs) participates in mammalian telomeric end-capping, exclusively at telomeres created by leading-strand synthesis. Here, we explore potential roles of DNA-PKcs and its phosphorylation target heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) in the localization of TERRA at human telomeres. Evaluation of co-localized foci utilizing RNA-FISH and three-dimensional (3D) reconstruction strategies provided evidence that both inhibition of DNA-PKcs kinase activity and siRNA depletion of hnRNP A1 result in accumulation of TERRA at individual telomeres; depletion of hnRNP A1 also resulted in increased frequencies of fragile telomeres. These observations are consistent with previous demonstrations that decreased levels of the nonsense RNA-mediated decay factors SMG1 and UPF1 increase TERRA at telomeres and interfere with replication of leading-strand telomeres. We propose that hTR mediated stimulation of DNA-PKcs and subsequent phosphorylation of hnRNP A1 influences the cell cycle dependent distribution of TERRA at telomeres by contributing to the removal of TERRA from telomeres, an action important for progression of S-phase, and thereby facilitating efficient telomere replication and end-capping.},
}
@article {pmid23616516,
year = {2013},
author = {Song, Y and You, NC and Song, Y and Kang, MK and Hou, L and Wallace, R and Eaton, CB and Tinker, LF and Liu, S},
title = {Intake of small-to-medium-chain saturated fatty acids is associated with peripheral leukocyte telomere length in postmenopausal women.},
journal = {The Journal of nutrition},
volume = {143},
number = {6},
pages = {907-914},
pmid = {23616516},
issn = {1541-6100},
support = {N01WH22110/WH/WHI NIH HHS/United States ; N01WH42129-32/WH/WHI NIH HHS/United States ; N01WH32100-2/WH/WHI NIH HHS/United States ; N01WH32108-9/WH/WHI NIH HHS/United States ; N01WH42107-26/WH/WHI NIH HHS/United States ; N01WH32122/WH/WHI NIH HHS/United States ; N01WH32105-6/WH/WHI NIH HHS/United States ; R21 DK084452/DK/NIDDK NIH HHS/United States ; N01WH32111-13/WH/WHI NIH HHS/United States ; N01WH32118-9/WH/WHI NIH HHS/United States ; N01WH32115/WH/WHI NIH HHS/United States ; N01WH44221/WH/WHI NIH HHS/United States ; N01WH24152/WH/WHI NIH HHS/United States ; },
mesh = {Aged ; Aging ; Alcohol Drinking ; Animals ; Butter ; Case-Control Studies ; Cheese ; Dietary Fats/*administration &amp; dosage ; Energy Intake ; Ethnicity ; Fatty Acids/*administration &amp; dosage ; Female ; Humans ; Leukocytes/*ultrastructure ; Middle Aged ; Milk ; *Postmenopause ; Prospective Studies ; Surveys and Questionnaires ; Telomere/*ultrastructure ; Women's Health ; },
abstract = {Dietary factors, including dietary fat, may affect the biological aging process, as reflected by the shortening of telomere length (TL), by affecting levels of oxidative stress and inflammatory responses. We examined the direct relations of total and types of dietary fats and fat-rich foods to peripheral leukocyte TL. In 4029 apparently healthy postmenopausal women who participated in the Women's Health Initiative, intakes of total fat, individual fatty acids, and fat-rich foods were assessed by a questionnaire. TL was measured by quantitative polymerase chain reaction. Intake of short-to-medium-chain saturated fatty acids (SMSFAs; aliphatic tails of ≤ 12 carbons) was inversely associated with TL. Compared with participants in other quartiles of SMSFA intake, women who were in the highest quartile (median: 1.29% of energy) had shorter TLs [mean: 4.00 kb (95% CI: 3.89, 4.11 kb)], whereas women in the lowest quartile of intake (median: 0.29% of energy) had longer TLs [mean: 4.13 kb (95% CI: 4.03, 4.24 kb); P-trend = 0.046]. Except for lauric acid, all other individual SMSFAs were inversely associated with TL (P < 0.05). In isoenergetic substitution models, the substitution of 1% of energy from SMSFAs with any other energy source was associated with 119 bp longer TLs (95% CI: 21, 216 bp). Intakes of nonskim milk, butter, and whole-milk cheese (major sources of SMSFAs) were all inversely associated with TL. No significant associations were found with long-chain saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids. In conclusion, we found that higher intakes of SMSFAs and SMSFA-rich foods were associated with shorter peripheral leukocyte TL among postmenopausal women. These findings suggest the potential roles of SMSFAs in the rate of biological aging.},
}
@article {pmid23616058,
year = {2013},
author = {Corriveau, M and Mullins, MR and Baus, D and Harris, ME and Taylor, DJ},
title = {Coordinated interactions of multiple POT1-TPP1 proteins with telomere DNA.},
journal = {The Journal of biological chemistry},
volume = {288},
number = {23},
pages = {16361-16370},
pmid = {23616058},
issn = {1083-351X},
support = {R01 GM056740/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes, Human/*chemistry/genetics/metabolism ; Circular Dichroism ; DNA, Single-Stranded/*chemistry/genetics/metabolism ; Humans ; Protein Binding ; Protein Structure, Quaternary ; Protein Structure, Secondary ; Shelterin Complex ; Telomere/*chemistry/metabolism ; Telomere-Binding Proteins/*chemistry/genetics/metabolism ; },
abstract = {Telomeres are macromolecular nucleoprotein complexes that protect the ends of eukaryotic chromosomes from degradation, end-to-end fusion events, and from engaging the DNA damage response. However, the assembly of this essential DNA-protein complex is poorly understood. Telomere DNA consists of the repeated double-stranded sequence 5'-TTAGGG-3' in vertebrates, followed by a single-stranded DNA overhang with the same sequence. Both double- and single-stranded regions are coated with high specificity by telomere end-binding proteins, including POT1 and TPP1, that bind as a heterodimer to single-stranded telomeric DNA. Multiple POT1-TPP1 proteins must fully coat the single-stranded telomere DNA to form a functional telomere. To better understand the mechanism of multiple binding, we mutated or deleted the two guanosine nucleotides residing between adjacent POT1-TPP1 recognition sites in single-stranded telomere DNA that are not required for multiple POT1-TPP1 binding events. Circular dichroism demonstrated that spectra from the native telomere sequence are characteristic of a G-quadruplex secondary structure, whereas the altered telomere sequences were devoid of these signatures. The altered telomere strands, however, facilitated more cooperative loading of multiple POT1-TPP1 proteins compared with the wild-type telomere sequence. Finally, we show that a 48-nucleotide DNA with a telomere sequence is more susceptible to nuclease digestion when coated with POT1-TPP1 proteins than when it is left uncoated. Together, these data suggest that POT1-TPP1 binds telomeric DNA in a coordinated manner to facilitate assembly of the nucleoprotein complexes into a state that is more accessible to enzymatic activity.},
}
@article {pmid23608779,
year = {2013},
author = {Thilagavathi, J and Mishra, SS and Kumar, M and Vemprala, K and Deka, D and Dhadwal, V and Dada, R},
title = {Analysis of telomere length in couples experiencing idiopathic recurrent pregnancy loss.},
journal = {Journal of assisted reproduction and genetics},
volume = {30},
number = {6},
pages = {793-798},
pmid = {23608779},
issn = {1573-7330},
mesh = {Abortion, Habitual/etiology/*genetics/pathology ; Adult ; Female ; Humans ; Leukocytes/*cytology ; Male ; Oxidative Stress/genetics ; Pregnancy ; Spermatozoa/pathology ; Telomere/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {PURPOSE: Telomere length plays a significant role in various disorders; however, its role in idiopathic recurrent pregnancy loss (iRPL) is not known. The objective of this study was to assess telomere length in peripheral blood leukocytes in couples experiencing unexplained recurrent pregnancy loss (iRPL).<br><br>METHODS: The study included 25 couples experiencing iRPL and 20 controls. The mean relative telomere length was measured by quantitative Real Time PCR (Q-PCR) based assay, which measures the average ratio of telomere repeat copy number to a single copy gene (36B4) copy number (T/S ratio) in each sample.<br><br>RESULTS: The relative leukocyte mean telomere length (T/S) in both men and women from iRPL group was significantly lower (p&#x2009;<&#x2009;0.05) when compared to controls. A significant (P&#x2009;<&#x2009;0.05) negative correlation was found between age and leukocyte telomere length (T/S ratio). Among the sperm parameters seminal volume was found to be negatively (r&#x2009;=&#x2009;-0.4679) associated with the telomere T/S ratio. The DNA fragmentation index of sperm showed positive correlation (r&#x2009;=&#x2009;0.4744) with telomere length. In this preliminary study, we found that shorter telomere length in both men and women may be associated with early pregnancy loss.<br><br>CONCLUSION: In conclusion, shorter telomere length in both male and female partners appears to play a role in the idiopathic recurrent pregnancy loss. Loss of telomeric DNA due to oxidative stress needs further analysis. Analysis of telomere length in germ cells are needed to further substantiate the findings of this study.},
}
@article {pmid23604115,
year = {2014},
author = {Lu, R and Pal, J and Buon, L and Nanjappa, P and Shi, J and Fulciniti, M and Tai, YT and Guo, L and Yu, M and Gryaznov, S and Munshi, NC and Shammas, MA},
title = {Targeting homologous recombination and telomerase in Barrett's adenocarcinoma: impact on telomere maintenance, genomic instability and tumor growth.},
journal = {Oncogene},
volume = {33},
number = {12},
pages = {1495-1505},
pmid = {23604115},
issn = {1476-5594},
support = {P01-78378//PHS HHS/United States ; P01 CA155258/CA/NCI NIH HHS/United States ; R01-1375555//PHS HHS/United States ; P50-100007//PHS HHS/United States ; R01 CA125711/CA/NCI NIH HHS/United States ; R01CA125711/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma/complications/drug therapy/*genetics/pathology ; Animals ; Antineoplastic Combined Chemotherapy Protocols ; Barrett Esophagus/*complications/enzymology/genetics/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Enzyme Inhibitors/pharmacology/therapeutic use ; Esophageal Neoplasms/complications/drug therapy/*genetics/*pathology ; Gene Knockout Techniques ; Genomic Instability/*drug effects ; Homologous Recombination/*drug effects ; Humans ; Male ; Mice ; Oligonucleotides/metabolism ; Pyrimidines/pharmacology/therapeutic use ; Rad51 Recombinase/deficiency/genetics ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/*drug effects/genetics ; },
abstract = {Homologous recombination (HR), a mechanism to accurately repair DNA in normal cells, is deregulated in cancer. Elevated/deregulated HR is implicated in genomic instability and telomere maintenance, which are critical lifelines of cancer cells. We have previously shown that HR activity is elevated and significantly contributes to genomic instability in Barrett's esophageal adenocarcinoma (BAC). The purpose of this study was to evaluate therapeutic potential of HR inhibition, alone and in combination with telomerase inhibition, in BAC. We demonstrate that telomerase inhibition in BAC cells increases HR activity, RAD51 expression, and association of RAD51 to telomeres. Suppression of HR leads to shorter telomeres as well as markedly reduced genomic instability in BAC cells over time. Combination of HR suppression (whether transgenic or chemical) with telomerase inhibition, causes a significant increase in telomere attrition and apoptotic death in all BAC cell lines tested, relative to either treatment alone. A subset of treated cells also stain positive for β-galactosidase, indicating senescence. The combined treatment is also associated with decline in S-phase and a strong G2/M arrest, indicating massive telomere attrition. In a subcutaneous tumor model, the combined treatment resulted in the smallest tumors, which were even smaller (P=0.001) than those that resulted from either treatment alone. Even the tumors removed from these mice had significantly reduced telomeres and evidence of apoptosis. We therefore conclude that although telomeres are elongated by telomerase, elevated RAD51/HR assist in their maintenance/stabilization in BAC cells. Telomerase inhibitor prevents telomere elongation but induces RAD51/HR, which contributes to telomere maintenance/stabilization and prevention of apoptosis, reducing the efficacy of treatment. Combining HR inhibition with telomerase renders telomeres more vulnerable to degradation and significantly increases/expedites their attrition, leading to apoptosis. We therefore demonstrate that a therapy targeting HR and telomerase has the potential to prevent both tumor growth and genomic evolution in BAC.},
}
@article {pmid23604076,
year = {2013},
author = {Morciano, P and Zhang, Y and Cenci, G and Rong, YS},
title = {A hypomorphic mutation reveals a stringent requirement for the ATM checkpoint protein in telomere protection during early cell division in Drosophila.},
journal = {G3 (Bethesda, Md.)},
volume = {3},
number = {6},
pages = {1043-1048},
pmid = {23604076},
issn = {2160-1836},
support = {//Intramural NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins/*genetics ; Base Sequence ; Cell Division/*genetics ; Codon, Nonsense/genetics ; DNA/metabolism ; DNA Damage/genetics ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/*cytology/embryology/*genetics ; Embryo, Nonmammalian/cytology ; Female ; Mitosis/genetics ; Molecular Sequence Data ; Mutation/*genetics ; Phosphorylation ; Protein Serine-Threonine Kinases ; Protein Transport ; Telomere/*genetics ; },
abstract = {Using Drosophila as a model system, we identified a stringent requirement for the conserved function of Ataxia Telangiectasia Mutated (ATM) in telomere protection during early embryonic development. Animals homozygous for a hypomorphic mutation in atm develop normally with minimal telomere dysfunction. However, mutant females produce inviable embryos that succumb to mitotic failure caused by covalent fusions of telomeric DNA. Interestingly, although the atm mutation encodes a premature stop codon, it must not have eliminated the production of the mutant protein, and the mutant protein retains kinase activity upon DNA damage. Moreover, although the embryonic phenotype of this mutation resembles that of hypomorphic mutations in the MRN complex, the function of MRN appears normal in the atm embryos. In contrast, there is a prominent reduction of the level of HipHop, an essential member of the Drosophila capping complex. How ATM functions in telomere protection remains poorly understood. The amenability of Drosophila embryos to molecular and biochemical investigations ensures that this newly identified mutation will facilitate future studies of ATM in telomere maintenance.},
}
@article {pmid23604072,
year = {2013},
author = {Lin, W and Sampathi, S and Dai, H and Liu, C and Zhou, M and Hu, J and Huang, Q and Campbell, J and Shin-Ya, K and Zheng, L and Chai, W and Shen, B},
title = {Mammalian DNA2 helicase/nuclease cleaves G-quadruplex DNA and is required for telomere integrity.},
journal = {The EMBO journal},
volume = {32},
number = {10},
pages = {1425-1439},
pmid = {23604072},
issn = {1460-2075},
support = {R21 AG041375/AG/NIA NIH HHS/United States ; R01 CA085344/CA/NCI NIH HHS/United States ; R15GM099008/GM/NIGMS NIH HHS/United States ; R21AG041375/AG/NIA NIH HHS/United States ; R15 GM099008/GM/NIGMS NIH HHS/United States ; R01CA085344/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma/genetics ; Adenocarcinoma of Lung ; Aneuploidy ; Animals ; Chromosome Segregation ; DNA Damage ; DNA Helicases/genetics/*metabolism ; Endodeoxyribonucleases/genetics/*metabolism ; Fetal Death ; *G-Quadruplexes ; Homozygote ; Lung Neoplasms/genetics ; Mice ; Mice, Knockout ; Mice, Transgenic ; Multifunctional Enzymes/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; },
abstract = {Efficient and faithful replication of telomeric DNA is critical for maintaining genome integrity. The G-quadruplex (G4) structure arising in the repetitive TTAGGG sequence is thought to stall replication forks, impairing efficient telomere replication and leading to telomere instabilities. However, pathways modulating telomeric G4 are poorly understood, and it is unclear whether defects in these pathways contribute to genome instabilities in vivo. Here, we report that mammalian DNA2 helicase/nuclease recognizes and cleaves telomeric G4 in vitro. Consistent with DNA2's role in removing G4, DNA2 deficiency in mouse cells leads to telomere replication defects, elevating the levels of fragile telomeres (FTs) and sister telomere associations (STAs). Such telomere defects are enhanced by stabilizers of G4. Moreover, DNA2 deficiency induces telomere DNA damage and chromosome segregation errors, resulting in tetraploidy and aneuploidy. Consequently, DNA2-deficient mice develop aneuploidy-associated cancers containing dysfunctional telomeres. Collectively, our genetic, cytological, and biochemical results suggest that mammalian DNA2 reduces replication stress at telomeres, thereby preserving genome stability and suppressing cancer development, and that this may involve, at least in part, nucleolytic processing of telomeric G4.},
}
@article {pmid23602876,
year = {2013},
author = {Hoge, EA and Chen, MM and Orr, E and Metcalf, CA and Fischer, LE and Pollack, MH and De Vivo, I and Simon, NM},
title = {Loving-Kindness Meditation practice associated with longer telomeres in women.},
journal = {Brain, behavior, and immunity},
volume = {32},
number = {},
pages = {159-163},
doi = {10.1016/j.bbi.2013.04.005},
pmid = {23602876},
issn = {1090-2139},
support = {8UL1TR000170-05/TR/NCATS NIH HHS/United States ; },
mesh = {Adult ; Body Mass Index ; DNA/genetics/ultrastructure ; Data Interpretation, Statistical ; Female ; Humans ; Leukocytes/ultrastructure ; *Love ; Male ; Meditation/*psychology ; Middle Aged ; Polymerase Chain Reaction ; Telomere/*physiology/*ultrastructure ; },
abstract = {Relatively short telomere length may serve as a marker of accelerated aging, and shorter telomeres have been linked to chronic stress. Specific lifestyle behaviors that can mitigate the effects of stress might be associated with longer telomere lengths. Previous research suggests a link between behaviors that focus on the well-being of others, such as volunteering and caregiving, and overall health and longevity. We examined relative telomere length in a group of individuals experienced in Loving-Kindness Meditation (LKM), a practice derived from the Buddhist tradition which utilizes a focus on unselfish kindness and warmth towards all people, and control participants who had done no meditation. Blood was collected by venipuncture, and Genomic DNA was extracted from peripheral blood leukocytes. Quantitative real time PCR was used to measure relative telomere length (RTL) (Cawthon, 2002) in fifteen LKM practitioners and 22 control participants. There were no significant differences in age, gender, race, education, or exposure to trauma, but the control group had a higher mean body mass index (BMI) and lower rates of past depression. The LKM practitioners had longer RTL than controls at the trend level (p=.083); among women, the LKM practitioners had significantly longer RTL than controls, (p=.007), which remained significant even after controlling for BMI and past depression. Although limited by small sample size, these results offer the intriguing possibility that LKM practice, especially in women, might alter RTL, a biomarker associated with longevity.},
}
@article {pmid23601089,
year = {2013},
author = {Benetos, A and Kark, JD and Susser, E and Kimura, M and Sinnreich, R and Chen, W and Steenstrup, T and Christensen, K and Herbig, U and von Bornemann Hjelmborg, J and Srinivasan, SR and Berenson, GS and Labat, C and Aviv, A},
title = {Tracking and fixed ranking of leukocyte telomere length across the adult life course.},
journal = {Aging cell},
volume = {12},
number = {4},
pages = {615-621},
pmid = {23601089},
issn = {1474-9726},
support = {AG030678/AG/NIA NIH HHS/United States ; R01 AG030678/AG/NIA NIH HHS/United States ; AG16592/AG/NIA NIH HHS/United States ; R21 AG030778/AG/NIA NIH HHS/United States ; R01 AG016592/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Aging/*genetics ; Body Mass Index ; Cellular Senescence ; Confidence Intervals ; Female ; Follow-Up Studies ; Humans ; Leukocytes/*cytology ; Longitudinal Studies ; Male ; Middle Aged ; Sex Factors ; Smoking/adverse effects/genetics ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; Telomere Shortening ; Young Adult ; },
abstract = {Short leukocyte telomere length (LTL) is associated with atherosclerosis in adults and diminished survival in the elderly. LTL dynamics are defined by LTL at birth, which is highly variable, and its age-dependent attrition thereafter, which is rapid during the first 20 years of life. We examined whether age-dependent LTL attrition during adulthood can substantially affect individuals' LTL ranking (e.g., longer or shorter LTL) in relation to their peers. We measured LTL in samples donated 12 years apart on average by 1156 participants in four longitudinal studies. We observed correlations of 0.91-0.96 between baseline and follow-up LTLs. Ranking individuals by deciles revealed that 94.1% (95% confidence interval of 92.6-95.4%) showed no rank change or a 1 decile change over time. We conclude that in adults, LTL is virtually anchored to a given rank with the passage of time. Accordingly, the links of LTL with atherosclerosis and longevity appear to be established early in life. It is unlikely that lifestyle and its modification during adulthood exert a major impact on LTL ranking.},
}
@article {pmid23596571,
year = {2013},
author = {Jacobs, JJ},
title = {Loss of telomere protection: consequences and opportunities.},
journal = {Frontiers in oncology},
volume = {3},
number = {},
pages = {88},
pmid = {23596571},
issn = {2234-943X},
support = {311565/ERC_/European Research Council/International ; },
abstract = {Telomeres are repetitive sequences at the natural ends of linear eukaryotic chromosomes that protect these from recognition as chromosome breaks. Their ability to do so critically depends on the binding of sufficient quantities of functional shelterin, a six-unit protein complex with specific and crucial roles in telomere maintenance and function. Insufficient telomere length, leading to insufficient concentration of shelterin at chromosome ends, or otherwise crippled shelterin function, causes telomere deprotection. While contributing to aging-related pathologies, loss of telomere protection can act as a barrier to tumorigenesis, as dysfunctional telomeres activate DNA-damage-like checkpoint responses that halt cell proliferation or trigger cell death. In addition, dysfunctional telomeres affect cancer development and progression by being a source of genomic instability. Reviewed here are the different approaches that are being undertaken to investigate the mammalian cellular response to telomere dysfunction and its consequences for cancer. Furthermore, it is discussed how current and future knowledge about the mechanisms underlying telomere damage responses might be applied for diagnostic purposes or therapeutic intervention.},
}
@article {pmid23592995,
year = {2013},
author = {Miller, J and Dakic, A and Chen, R and Palechor-Ceron, N and Dai, Y and Kallakury, B and Schlegel, R and Liu, X},
title = {HPV16 E7 protein and hTERT proteins defective for telomere maintenance cooperate to immortalize human keratinocytes.},
journal = {PLoS pathogens},
volume = {9},
number = {4},
pages = {e1003284},
pmid = {23592995},
issn = {1553-7374},
support = {P30 CA051008/CA/NCI NIH HHS/United States ; R01 CA106400/CA/NCI NIH HHS/United States ; 5P30CA051008/CA/NCI NIH HHS/United States ; R01CA106440/CA/NCI NIH HHS/United States ; },
mesh = {*Cell Transformation, Viral ; Human papillomavirus 16/genetics/*metabolism ; Humans ; Keratinocytes/cytology/*physiology ; Oncogene Proteins, Viral/genetics/*metabolism ; Papillomavirus E7 Proteins/genetics/*metabolism ; Polycomb Repressive Complex 1/genetics/*metabolism ; Promoter Regions, Genetic ; RNA, Messenger/genetics/metabolism ; Repressor Proteins/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/genetics/physiology ; },
abstract = {Previous studies have shown that wild-type human telomerase reverse transcriptase (hTERT) protein can functionally replace the human papillomavirus type 16 (HPV-16) E6 protein, which cooperates with the viral E7 protein in the immortalization of primary keratinocytes. In the current study, we made the surprising finding that catalytically inactive hTERT (hTERT-D868A), elongation-defective hTERT (hTERT-HA), and telomere recruitment-defective hTERT (hTERT N+T) also cooperate with E7 in mediating bypass of the senescence blockade and effecting cell immortalization. This suggests that hTERT has activities independent of its telomere maintenance functions that mediate transit across this restriction point. Since hTERT has been shown to have a role in gene activation, we performed microarray studies and discovered that E6, hTERT and mutant hTERT proteins altered the expression of highly overlapping sets of cellular genes. Most important, the E6 and hTERT proteins induced mRNA and protein levels of Bmi1, the core subunit of the Polycomb Group (PcG) complex 1. We show further that Bmi1 substitutes for E6 or hTERT in cell immortalization. Finally, tissue array studies demonstrated that expression of Bmi1 increased with the severity of cervical dysplasia, suggesting a potential role in the progression of cervical cancer. Together, these data demonstrate that hTERT has extra-telomeric activities that facilitate cell immortalization and that its induction of Bmi1 is one potential mechanism for mediating this activity.},
}
@article {pmid23591994,
year = {2013},
author = {Le Guen, T and Jullien, L and Touzot, F and Schertzer, M and Gaillard, L and Perderiset, M and Carpentier, W and Nitschke, P and Picard, C and Couillault, G and Soulier, J and Fischer, A and Callebaut, I and Jabado, N and Londono-Vallejo, A and de Villartay, JP and Revy, P},
title = {Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability.},
journal = {Human molecular genetics},
volume = {22},
number = {16},
pages = {3239-3249},
doi = {10.1093/hmg/ddt178},
pmid = {23591994},
issn = {1460-2083},
mesh = {Cells, Cultured ; Child, Preschool ; DNA Damage ; DNA Helicases/chemistry/deficiency/*genetics/metabolism ; DNA Replication ; Dyskeratosis Congenita/*genetics/metabolism ; Exome ; Female ; Fetal Growth Retardation/*genetics/metabolism ; Genetic Linkage ; *Genomic Instability ; Humans ; Infant ; Intellectual Disability/*genetics/metabolism ; Male ; Microcephaly/*genetics/metabolism ; Mutation ; Sequence Alignment ; Sequence Analysis, RNA ; Telomerase/genetics/metabolism ; Telomere/*metabolism/ultrastructure ; Telomere Homeostasis/*genetics ; *Telomere Shortening ; },
abstract = {Hoyeraal-Hreidarsson syndrome (HHS), a severe variant of dyskeratosis congenita (DC), is characterized by early onset bone marrow failure, immunodeficiency and developmental defects. Several factors involved in telomere length maintenance and/or protection are defective in HHS/DC, underlining the relationship between telomere dysfunction and these diseases. By combining whole-genome linkage analysis and exome sequencing, we identified compound heterozygous RTEL1 (regulator of telomere elongation helicase 1) mutations in three patients with HHS from two unrelated families. RTEL1 is a DNA helicase that participates in DNA replication, DNA repair and telomere integrity. We show that, in addition to short telomeres, RTEL1-deficient cells from patients exhibit hallmarks of genome instability, including spontaneous DNA damage, anaphase bridges and telomeric aberrations. Collectively, these results identify RTEL1 as a novel HHS-causing gene and highlight its role as a genomic caretaker in humans.},
}
@article {pmid23591355,
year = {2013},
author = {Gao, LY and Li, GD and Tong, TJ},
title = {[Comparison of Southern blotting and Real-time PCR in measuring telomere shortening].},
journal = {Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences},
volume = {45},
number = {2},
pages = {297-302},
pmid = {23591355},
issn = {1671-167X},
mesh = {*Blotting, Southern ; Cellular Senescence/genetics ; DNA/isolation &amp; purification ; Fibroblasts/cytology ; Humans ; *Real-Time Polymerase Chain Reaction ; Telomere/*genetics ; *Telomere Shortening ; },
abstract = {OBJECTIVE: To analyze and compare the performances of two telomere measurement methods (digoxigenin-labeled Southern blot and Real-time PCR) in cellular senescence research.<br><br>METHODS: Genomic DNA extracted from normal human fibroblasts (2BS) of different population doublings (PDs) was used as test samples. The Southern blot and Real-time PCR methods for telomere measurements were optimized. The specificity and sensitivity of digoxigenin detection system were analyzed by dot blot. The two methods were respectively used to measure parallel samples to analyze and compare their resolution and accuracy.<br><br>RESULTS: Digoxigenin-labeled Southern blot system could detect less than 1 &#x3bc;g of human genomic DNA, but the optimal sample size was around 4-5 &#x3bc;g when measuring telomeres. The resolution of the Southern blot method was around 150 bp while the Real-time PCR method 300-400 bp. The former could distinguish the difference of 2 PDs for 2BS cells while the latter could not distinguish the difference of less than 5 PDs. The measurement error of the repeated measurements for the Real-time PCR method was more than 10% which was bigger than that of the Southern blot method (2.5%, P<0.001).<br><br>CONCLUSION: Digoxigenin-labeled Southern blot system is fully applicable to telomere measurement. The performance of the Southern blot method is better than that of the Real-time PCR method while the latter is convenient and high-throughput. In the study of cellular senescence, the appropriate method should be selected according to specific experiment.},
}
@article {pmid23590194,
year = {2013},
author = {Lu, J and Vallabhaneni, H and Yin, J and Liu, Y},
title = {Deletion of the major peroxiredoxin Tsa1 alters telomere length homeostasis.},
journal = {Aging cell},
volume = {12},
number = {4},
pages = {635-644},
pmid = {23590194},
issn = {1474-9726},
support = {ZIA AG000749-01//Intramural NIH HHS/United States ; },
mesh = {DNA, Fungal/genetics/metabolism ; Enzyme Activation ; *Gene Deletion ; *Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Fungal ; Oxidation-Reduction ; Peroxidases/*genetics ; Reactive Oxygen Species/metabolism ; Repressor Proteins/genetics/metabolism ; Saccharomyces cerevisiae/*enzymology/genetics ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Shelterin Complex ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/genetics/metabolism ; Transcription Factors/genetics/metabolism ; },
abstract = {Reactive oxygen species (ROS) are proposed to play a major role in telomere length alterations during aging. The mechanisms by which ROS disrupt telomeres remain unclear. In Saccharomyces cerevisiae, telomere DNA consists of TG(1-3) repeats, which are maintained primarily by telomerase. Telomere length maintenance can be modulated by the expression level of telomerase subunits and telomerase activity. Additionally, telomerase-mediated telomere repeat addition is negatively modulated by the levels of telomere-bound Rap1-Rif1-Rif2 protein complex. Using a yeast strain defective in the major peroxiredoxin Tsa1 that is involved in ROS neutralization, we have investigated the effect of defective ROS detoxification on telomere DNA, telomerase, telomere-binding proteins, and telomere length. Surprisingly, the tsa1 mutant does not show significant increase in steady-state levels of oxidative DNA lesions at telomeres. The tsa1 mutant displays abnormal telomere lengthening, and reduction in oxidative exposure alleviates this phenotype. The telomere lengthening in the tsa1 cells was abolished by disruption of Est2, subtelomeric DNA, Rap1 C-terminus, or Rif2, but not by Rif1 deletion. Although telomerase expression and activity are not altered, telomere-bound Est2 is increased, while telomere-bound Rap1 is reduced in the tsa1 mutant. We propose that defective ROS scavenging can interfere with pathways that are critical in controlling telomere length homeostasis.},
}
@article {pmid23589176,
year = {2013},
author = {Chene, G and Tchirkov, A and Pierre-Eymard, E and Dauplat, J and Raoelfils, I and Cayre, A and Watkin, E and Vago, P and Penault-Llorca, F},
title = {Early telomere shortening and genomic instability in tubo-ovarian preneoplastic lesions.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {19},
number = {11},
pages = {2873-2882},
doi = {10.1158/1078-0432.CCR-12-3947},
pmid = {23589176},
issn = {1557-3265},
mesh = {Comparative Genomic Hybridization ; Fallopian Tube Neoplasms/*genetics/metabolism/*pathology ; Female ; *Genomic Instability ; Histones/metabolism ; Humans ; Ovarian Neoplasms/*genetics/metabolism/*pathology ; *Precancerous Conditions ; Retrospective Studies ; Telomere/metabolism ; *Telomere Shortening ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {PURPOSE: Genetic instability plays an important role in ovarian carcinogenesis. We investigated the level of telomere shortening and genomic instability in early and preinvasive stages of ovarian cancer, serous tubal intraepithelial carcinoma (STIC), and tubo-ovarian dysplasia (TOD).<br><br>EXPERIMENTAL DESIGN: Fifty-one TOD from prophylactic salpingo-oophorectomies with BRCA1 or 2 mutation, 12 STICs, 53 tubo-ovarian high-grade serous carcinoma, and 36 noncancerous controls were laser capture microdissected from formalin-fixed, paraffin-embedded sections, analyzed by comparative genomic hybridization (array CGH) and for telomere length (using quantitative real-time PCR based on the Cawthon's method). TOD and STICs were defined by morphologic scores and immunohistochemical expressions of p53, Ki67, and &#x3b3;H2AX.<br><br>RESULTS: TOD showed marked telomere shortening compared with noncancerous controls (P < 10(-7)). STICs had even shorter telomeres than TOD (P = 0.0008). Ovarian carcinoma had shorter telomeres than controls but longer than STICs and dysplasia. In TOD, telomeres were significantly shorter in those with BRCA1 mutation than in those with BRCA2 mutation (P = 0.005). In addition, &#x3b3;H2AX expression in TOD and STIC groups with short telomeres was significantly increased (P < 10(-7)). In dysplastic epithelium, we found subtle genomic alterations, in contrast to more important genomic imbalances in STICs. The total number of genetic alterations was the highest in ovarian cancers.<br><br>CONCLUSIONS: These findings suggest that genetic instability occurs in early stages of ovarian tumorigenesis. STICs and noninvasive dysplasia are likely an important step in early serous ovarian neoplasia.},
}
@article {pmid23585473,
year = {2013},
author = {Winkler, T and Hong, SG and Decker, JE and Morgan, MJ and Wu, C and Hughes, WM and Yang, Y and Wangsa, D and Padilla-Nash, HM and Ried, T and Young, NS and Dunbar, CE and Calado, RT},
title = {Defective telomere elongation and hematopoiesis from telomerase-mutant aplastic anemia iPSCs.},
journal = {The Journal of clinical investigation},
volume = {123},
number = {5},
pages = {1952-1963},
pmid = {23585473},
issn = {1558-8238},
support = {//Intramural NIH HHS/United States ; },
mesh = {Anemia, Aplastic/*metabolism ; Animals ; Cell Differentiation ; DNA Mutational Analysis ; Environment ; Fibroblasts/cytology ; Hematopoiesis/*physiology ; Hematopoietic Stem Cells/cytology ; Humans ; Immunohistochemistry ; Induced Pluripotent Stem Cells/*cytology ; Leukocytes/cytology ; Mice ; Mutation ; Phenotype ; Telomerase/*metabolism ; Telomere/*ultrastructure ; Transgenes ; },
abstract = {Critically short telomeres activate p53-mediated apoptosis, resulting in organ failure and leading to malignant transformation. Mutations in genes responsible for telomere maintenance are linked to a number of human diseases. We derived induced pluripotent stem cells (iPSCs) from 4 patients with aplastic anemia or hypocellular bone marrow carrying heterozygous mutations in the telomerase reverse transcriptase (TERT) or the telomerase RNA component (TERC) telomerase genes. Both mutant and control iPSCs upregulated TERT and TERC expression compared with parental fibroblasts, but mutant iPSCs elongated telomeres at a lower rate compared with healthy iPSCs, and the deficit correlated with the mutations' impact on telomerase activity. There was no evidence for alternative lengthening of telomere (ALT) pathway activation. Elongation varied among iPSC clones derived from the same patient and among clones from siblings harboring identical mutations. Clonal heterogeneity was linked to genetic and environmental factors, but was not influenced by residual expression of reprogramming transgenes. Hypoxia increased telomere extension in both mutant and normal iPSCs. Additionally, telomerase-mutant iPSCs showed defective hematopoietic differentiation in vitro, mirroring the clinical phenotype observed in patients and demonstrating that human telomere diseases can be modeled utilizing iPSCs. Our data support the necessity of studying multiple clones when using iPSCs to model disease.},
}
@article {pmid23583821,
year = {2013},
author = {Sýkorová, E and Fojtová, M and Peška, V},
title = {A polymerase chain reaction-based approach for evaluation of telomere-associated sequences and interstitial telomeric sequences.},
journal = {Analytical biochemistry},
volume = {439},
number = {1},
pages = {8-10},
doi = {10.1016/j.ab.2013.03.034},
pmid = {23583821},
issn = {1096-0309},
mesh = {Arabidopsis/genetics ; Base Sequence ; DNA, Plant/genetics ; Polymerase Chain Reaction/*methods ; Telomere/*genetics ; },
abstract = {Telomere minisatellites could be present in both terminal and internal chromosomal regions. We monitored the progress of BAL-31 nuclease digestion on Arabidopsis thaliana genomic DNA prepared by standard isolation techniques to verify its cleavage at terminal and internal genomic regions. A subtelomeric position of candidate sequences was validated using conventional polymerase chain reaction (PCR), combining the C-strand-specific telomeric primer with a subtelomeric reverse primer, and confirmed by quantitative PCR (qPCR) using sequence-specific primer pairs on DNA samples after BAL-31 digestion. qPCR amplification showed a gradual decrease in subtelomeric sequence signals, in contrast to interstitial telomeric sequences from pericentromere and control sequences.},
}
@article {pmid23576549,
year = {2013},
author = {Hozé, N and Ruault, M and Amoruso, C and Taddei, A and Holcman, D},
title = {Spatial telomere organization and clustering in yeast Saccharomyces cerevisiae nucleus is generated by a random dynamics of aggregation-dissociation.},
journal = {Molecular biology of the cell},
volume = {24},
number = {11},
pages = {1791-800, S1-10},
pmid = {23576549},
issn = {1939-4586},
mesh = {Cell Nucleus/*genetics/metabolism/ultrastructure ; *Gene Expression Regulation, Fungal ; Microscopy, Fluorescence ; Ploidies ; Saccharomyces cerevisiae/*genetics/metabolism/ultrastructure ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/*genetics/metabolism ; Stochastic Processes ; Telomere/*genetics/metabolism/ultrastructure ; Time-Lapse Imaging ; },
abstract = {Spatial and temporal behavior of chromosomes and their regulatory proteins is a key control mechanism in genomic function. This is exemplified by the clustering of the 32 budding yeast telomeres that form foci in which silencing factors concentrate. To uncover the determinants of telomere distribution, we compare live-cell imaging with a stochastic model of telomere dynamics that we developed. We show that random encounters alone are inadequate to produce the clustering observed in vivo. In contrast, telomere dynamics observed in vivo in both haploid and diploid cells follows a process of dissociation-aggregation. We determine the time that two telomeres spend in the same cluster for the telomere distribution observed in cells expressing different levels of the silencing factor Sir3 protein, limiting for telomere clustering. We conclude that telomere clusters, their dynamics, and their nuclear distribution result from random motion, aggregation, and dissociation of telomeric regions, specifically determined by the amount of Sir3.},
}
@article {pmid23572544,
year = {2013},
author = {Lee, YW and Kim, WT},
title = {Telomerase-dependent 3' G-strand overhang maintenance facilitates GTBP1-mediated telomere protection from misplaced homologous recombination.},
journal = {The Plant cell},
volume = {25},
number = {4},
pages = {1329-1342},
pmid = {23572544},
issn = {1532-298X},
mesh = {Base Sequence ; DNA, Plant/chemistry/genetics/*metabolism ; Down-Regulation ; Gene Expression Regulation, Plant ; *Homologous Recombination ; In Situ Hybridization, Fluorescence ; Plant Proteins/genetics/metabolism ; Protein Binding ; RNA Interference ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/genetics/*metabolism ; Nicotiana/genetics/metabolism ; },
abstract = {At the 3'-end of telomeres, single-stranded G-overhang telomeric repeats form a stable T-loop. Many studies have focused on the mechanisms that generate and regulate the length of telomere 3' G-strand overhangs, but the roles of G-strand overhang length control in proper T-loop formation and end protection remain unclear. Here, we examined functional relationships between the single-stranded telomere binding protein GTBP1 and G-strand overhang lengths maintained by telomerase in tobacco (Nicotiana tabacum). In tobacco plants, telomerase reverse transcriptase subunit (TERT) repression severely worsened the GTBP1 knockdown phenotypes, which were formally characterized as an outcome of telomere destabilization. TERT downregulation shortened the telomere 3' G-overhangs and increased telomere recombinational aberrations in GTBP1-suppressed plants. Correlatively, GTBP1-mediated inhibition of single-strand invasion into the double-strand telomeric sequences was impaired due to shorter single-stranded telomeres. Moreover, TERT/GTBP1 double knockdown amplified misplaced homologous recombination of G-strand overhangs into intertelomeric regions. Thus, proper G-overhang length maintenance is required to protect telomeres against intertelomeric recombination, which is achieved by the balanced functions of GTBP1 and telomerase activity.},
}
@article {pmid23572541,
year = {2013},
author = {Leehy, KA and Lee, JR and Song, X and Renfrew, KB and Shippen, DE},
title = {MERISTEM DISORGANIZATION1 encodes TEN1, an essential telomere protein that modulates telomerase processivity in Arabidopsis.},
journal = {The Plant cell},
volume = {25},
number = {4},
pages = {1343-1354},
pmid = {23572541},
issn = {1532-298X},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; R01-GM065383/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Arabidopsis/cytology/genetics/*metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Cell Nucleus/metabolism ; Cells, Cultured ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; Gene Expression Regulation, Plant ; Immunoblotting ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Mutation ; Plants, Genetically Modified ; Protein Binding ; Reverse Transcriptase Polymerase Chain Reaction ; Sequence Homology, Amino Acid ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Two-Hybrid System Techniques ; },
abstract = {Telomeres protect chromosome ends from being recognized as DNA damage, and they facilitate the complete replication of linear chromosomes. CST [for CTC1(Cdc13)/STN1/TEN1] is a trimeric chromosome end binding complex implicated in both aspects of telomere function. Here, we characterize TEN1 in the flowering plant Arabidopsis thaliana. We report that TEN1 (for telomeric pathways in association with Stn1, which stands for suppressor of cdc thirteen) is encoded by a previously characterized gene, MERISTEM DISORGANIZATION1 (MDO1). A point mutation in MDO1, mdo1-1/ten1-3 (G77E), triggers stem cell differentiation and death as well as a constitutive DNA damage response. We provide biochemical and genetic evidence that ten1-3 is likely to be a null mutation. As with ctc1 and stn1 null mutants, telomere tracts in ten1-3 are shorter and more heterogeneous than the wild type. Mutants also exhibit frequent telomere fusions, increased single-strand telomeric DNA, and telomeric circles. However, unlike stn1 or ctc1 mutants, telomerase enzyme activity is elevated in ten1-3 mutants due to an increase in repeat addition processivity. In addition, TEN1 is detected at a significantly smaller fraction of telomeres than CTC1. These data indicate that TEN1 is critical for telomere stability and also plays an unexpected role in modulating telomerase enzyme activity.},
}
@article {pmid23571757,
year = {2013},
author = {Zhang, P and Herbig, U and Coffman, F and Lambert, MW},
title = {Non-erythroid alpha spectrin prevents telomere dysfunction after DNA interstrand cross-link damage.},
journal = {Nucleic acids research},
volume = {41},
number = {10},
pages = {5321-5340},
pmid = {23571757},
issn = {1362-4962},
support = {R01 CA136533/CA/NCI NIH HHS/United States ; R01 HL054860/HL/NHLBI NIH HHS/United States ; },
mesh = {Cell Line ; Chromosome Aberrations ; Cross-Linking Reagents/toxicity ; *DNA Damage ; *DNA Repair ; DNA-Binding Proteins/analysis ; Fanconi Anemia Complementation Group D2 Protein/analysis ; Humans ; S Phase/genetics ; Spectrin/antagonists &amp; inhibitors/metabolism/*physiology ; Telomere/chemistry/metabolism/*physiology ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Telomere integrity is critical for telomere function and genomic stability. We previously demonstrated that non-erythroid α-spectrin (αIISp) is present in mammalian cell nuclei where it is important in repair of DNA interstrand cross-links (ICLs) and chromosome stability. We now demonstrate that αIISp is also important for telomere maintenance after ICL damage. It localizes to telomeres in S phase after ICL damage where it has enhanced association with TRF1 and TRF2 and is required for recruitment of the ICL repair protein, XPF, to damage-induced foci at telomeres. In telomerase-positive normal cells depleted of αIISp by siRNA or in Fanconi anemia, complementation group A (FA-A) cells, where αIISp levels are 35-40% of normal, ICL damage results in failure of XPF to localize to telomeres, markedly increased telomere dysfunction-induced foci, followed by catastrophic loss of telomeres. Restoration of αIISp levels to normal in FA-A cells corrects these deficiencies. Our studies demonstrate that αIISp is critical for repair of DNA ICLs at telomeres, likely by facilitating the recruitment of repair proteins similar, but not identical, to its proposed role in repair of DNA ICLs in genomic DNA and that this function in turn is critical for telomere maintenance after DNA ICL damage.},
}
@article {pmid23570868,
year = {2013},
author = {Chiodi, I and Belgiovine, C and Zongaro, S and Ricotti, R and Horard, B and Lossani, A and Focher, F and Gilson, E and Giulotto, E and Mondello, C},
title = {Super-telomeres in transformed human fibroblasts.},
journal = {Biochimica et biophysica acta},
volume = {1833},
number = {8},
pages = {1885-1893},
doi = {10.1016/j.bbamcr.2013.03.030},
pmid = {23570868},
issn = {0006-3002},
mesh = {Cell Line, Transformed ; Cell Transformation, Neoplastic/*genetics/metabolism ; DNA Methylation ; Fibroblasts/metabolism/*physiology ; Humans ; Microfilament Proteins ; Nuclear Proteins/genetics/metabolism ; RNA/genetics ; RNA-Binding Proteins ; Telomerase/genetics ; Telomere/*genetics/*metabolism ; Telomere Homeostasis/*genetics ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; },
abstract = {Telomere length maintenance is critical for organisms' long-term survival and cancer cell proliferation. Telomeres are kept within species-specific length ranges by the interplay between telomerase activity and telomeric chromatin organization. In this paper, we exploited telomerase immortalized human fibroblasts (cen3tel) that gradually underwent neoplastic transformation during culture propagation to study telomere composition and length regulation during the transformation process. Just after telomerase catalytic subunit (hTERT) expression, cen3tel telomeres shortened despite the presence of telomerase activity. At a later stage and concomitantly with transformation, cells started elongating telomeres, which reached a mean length greater than 100kb in about 900 population doublings. Super-telomeres were stable and compatible with cell growth and tumorigenesis. Telomere extension was associated with increasing levels of telomerase activity that were linked to the deregulation of endogenous telomerase RNA (hTERC) and exogenous telomerase reverse transcriptase (hTERT) expression. Notably, the increase in hTERC levels paralleled the increase in telomerase activity, suggesting that this subunit plays a role in regulating enzyme activity. Telomeres ranging in length between 10 and more than 100kb were maintained in an extendible state although TRF1 and TRF2 binding increased with telomere length. Super-telomeres neither influenced subtelomeric region global methylation nor the expression of the subtelomeric gene FRG1, attesting the lack of a clear-cut relationship between telomere length, subtelomeric DNA methylation and expression in human cells. The cellular levels of the telomeric proteins hTERT, TRF1, TRF2 and Hsp90 rose with transformation and were independent of telomere length, pointing to a role of these proteins in tumorigenesis.},
}
@article {pmid23567265,
year = {2013},
author = {Lee, JY and Bang, HW and Ko, JH and Kim, JH and Lee, DC},
title = {Leukocyte telomere length is independently associated with gait speed in elderly women.},
journal = {Maturitas},
volume = {75},
number = {2},
pages = {165-169},
doi = {10.1016/j.maturitas.2013.03.008},
pmid = {23567265},
issn = {1873-4111},
mesh = {Aged ; Aging/*genetics ; Cross-Sectional Studies ; Fasting ; Female ; Gait/*genetics ; Humans ; Insulin/blood/*genetics ; Insulin Resistance/*genetics ; Leukocytes/*metabolism ; Neuropsychological Tests ; Regression Analysis ; Republic of Korea ; *Telomere ; Telomere Homeostasis ; Telomere Shortening ; Triglycerides/blood/*genetics ; Walking ; },
abstract = {OBJECTIVES: Declining gait speed is common in the elderly population and is associated with age-related conditions. Because telomere length is a reflection of aging and known to affect degenerative changes in organ systems, gait speed may be associated with telomere length. We therefore investigated the relationship between gait speed and leukocyte telomere length in elderly Korean women.<br><br>STUDY DESIGN: Cross-sectional study.<br><br>MAIN OUTCOME MEASURES: A total of 117 Korean elderly women participated. Metabolic variables were assessed along with gait speed calculated as walking distance (6m) divided by time. Leukocyte telomere length was measured by real-time quantitative polymerase chain reaction.<br><br>RESULTS: Gait speed correlated with telomere length (r=0.38, p<0.01), fasting insulin (r=-0.19, p=0.04), homeostasis model assessment of insulin resistance index (HOMA-IR; r=-0.22, p=0.02), triglyceride (r=-0.20, p=0.03), and Korean Mini-Mental State Examination (K-MMSE; r=0.20, p=0.03) after adjusting for age. On step-wise multiple regression analysis, telomere length (&#x3b2;=0.35, p<0.01), K-MMSE (&#x3b2;=0.16, p=0.02), age (&#x3b2;=-0.23, p=0.01), and HOMA-IR (&#x3b2;=-0.19, p=0.03) were identified as independent variables associated with gait speed.<br><br>CONCLUSIONS: This study suggested that telomere length may have a role in maintaining overall health status as well as preserving gait speed in the elderly population. Further studies are required to better understand the significance of our findings.},
}
@article {pmid23565277,
year = {2013},
author = {Lin, S and Huo, X and Zhang, Q and Fan, X and Du, L and Xu, X and Qiu, S and Zhang, Y and Wang, Y and Gu, J},
title = {Short placental telomere was associated with cadmium pollution in an electronic waste recycling town in China.},
journal = {PloS one},
volume = {8},
number = {4},
pages = {e60815},
pmid = {23565277},
issn = {1932-6203},
mesh = {Cadmium/*toxicity ; China ; Electronic Waste/*adverse effects ; Female ; Humans ; Infant, Newborn ; Male ; Placenta/drug effects/*metabolism ; Pregnancy ; Real-Time Polymerase Chain Reaction ; Spectrophotometry, Atomic ; Surveys and Questionnaires ; Telomere/*drug effects/*genetics ; },
abstract = {In Guiyu, an electronic waste recycling site near Shantou, Guangdong province, China, primitive ways of e-waste processing have caused severe cadmium and lead pollution to the local residents. However, the possible effects of cadmium or lead pollution to genomic integrity of the local residents have not been investigated. We examined the possible relationship between cadmium and lead concentrations in placenta and placental telomere length in Guiyu and compared the data with that of a non-polluted town. Graphite furnace atomic absorption spectrometry and real-time PCR were used to determine placental cadmium and lead concentrations, and placental telomere length. We found that placental cadmium concentration was negatively correlated with placental telomere length (r = -0.138, p = 0.013). We also found that placental cadmium concentration of 0.0294 µg/g might be a critical point at which attrition of placental telomere commenced. No significant correlation between placental lead concentration and placental telomere length was detected (r = 0.027, p = 0.639). Our data suggest that exposure to cadmium pollution during pregnancy may be a risk factor for shortened placental telomere length that is known to be related to cancer development and aging. Furthermore, grave consequence on the offspring from pregnancies in e-waste polluted area is indicated.},
}
@article {pmid23564254,
year = {2013},
author = {Jaške, K and Mokroš, P and Mozgová, I and Fojtová, M and Fajkus, J},
title = {A telomerase-independent component of telomere loss in chromatin assembly factor 1 mutants of Arabidopsis thaliana.},
journal = {Chromosoma},
volume = {122},
number = {4},
pages = {285-293},
pmid = {23564254},
issn = {1432-0886},
mesh = {Arabidopsis/*enzymology/*genetics/metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Chromatin Assembly Factor-1/genetics/metabolism ; Chromosomes, Plant/genetics/metabolism ; *Mutation ; RNA Splicing Factors ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Dysfunction of chromatin assembly factor 1 in FASCIATA mutants (fas) of Arabidopsis thaliana results in progressive loss of telomeric DNA. Although replicative telomere shortening is typically associated with incomplete resynthesis of their ends by telomerase, no change in telomerase activity could be detected in vitro in extracts from fas mutants. Besides a possible telomerase malfunction, the telomere shortening in fas mutants could presumably be due to problems with conventional replication of telomeres. To distinguish between the possible contribution of suboptimal function of telomerase in fas mutants under in vivo conditions and problems in conventional telomere replication, we crossed fas and tert (telomerase reverse transcriptase) knockout mutants and analyzed telomere shortening in segregated fas mutants, tert mutants, and double fas tert mutants in parallel. We demonstrate that fas tert knockouts show greater replicative telomere shortening than that observed even in the complete absence of telomerase (tert mutants). While the effect of tert and fas mutations on telomere lengths in double mutants is additive, manifestations of telomere dysfunction in double fas tert mutants (frequency of anaphase bridges, onset of chromosome end fusions, and common involvement of 45S rDNA in chromosome fusion sites) are similar to those in tert mutants. We conclude that in addition to possible impairment of telomerase action, a further mechanism contributes to telomere shortening in fas mutants.},
}
@article {pmid23563309,
year = {2013},
author = {Watson, LA and Solomon, LA and Li, JR and Jiang, Y and Edwards, M and Shin-ya, K and Beier, F and Bérubé, NG},
title = {Atrx deficiency induces telomere dysfunction, endocrine defects, and reduced life span.},
journal = {The Journal of clinical investigation},
volume = {123},
number = {5},
pages = {2049-2063},
pmid = {23563309},
issn = {1558-8238},
support = {MOP102539//Canadian Institutes of Health Research/Canada ; MOP93697//Canadian Institutes of Health Research/Canada ; },
mesh = {Aging ; Animals ; Bone and Bones/metabolism ; Brain/*metabolism ; Cognition Disorders/genetics ; DNA Damage ; DNA Helicases/deficiency/*genetics/*physiology ; Female ; Fibroblasts/cytology ; G-Quadruplexes ; Genotype ; Heterochromatin/metabolism ; Insulin-Like Growth Factor I/metabolism ; Ligands ; Longevity ; Male ; Mice ; Mice, Transgenic ; Microscopy, Fluorescence/methods ; Nuclear Proteins/deficiency/*genetics/*physiology ; Oxazoles/pharmacology ; Phenotype ; Stem Cells/cytology ; Telomere/*ultrastructure ; Thyroxine/metabolism ; X-linked Nuclear Protein ; },
abstract = {Human ATRX mutations are associated with cognitive deficits, developmental abnormalities, and cancer. We show that the Atrx-null embryonic mouse brain accumulates replicative damage at telomeres and pericentromeric heterochromatin, which is exacerbated by loss of p53 and linked to ATM activation. ATRX-deficient neuroprogenitors exhibited higher incidence of telomere fusions and increased sensitivity to replication stress-inducing drugs. Treatment of Atrx-null neuroprogenitors with the G-quadruplex (G4) ligand telomestatin increased DNA damage, indicating that ATRX likely aids in the replication of telomeric G4-DNA structures. Unexpectedly, mutant mice displayed reduced growth, shortened life span, lordokyphosis, cataracts, heart enlargement, and hypoglycemia, as well as reduction of mineral bone density, trabecular bone content, and subcutaneous fat. We show that a subset of these defects can be attributed to loss of ATRX in the embryonic anterior pituitary that resulted in low circulating levels of thyroxine and IGF-1. Our findings suggest that loss of ATRX increases DNA damage locally in the forebrain and anterior pituitary and causes tissue attrition and other systemic defects similar to those seen in aging.},
}
@article {pmid23562763,
year = {2013},
author = {Ghosh, S and Pradhan, SK and Kar, A and Chowdhury, S and Dasgupta, D},
title = {Molecular basis of recognition of quadruplexes human telomere and c-myc promoter by the putative anticancer agent sanguinarine.},
journal = {Biochimica et biophysica acta},
volume = {1830},
number = {8},
pages = {4189-4201},
doi = {10.1016/j.bbagen.2013.03.027},
pmid = {23562763},
issn = {0006-3002},
mesh = {Antineoplastic Agents/*pharmacology ; Benzophenanthridines/*pharmacology ; Calorimetry, Differential Scanning ; Circular Dichroism ; Fluorescence Polarization ; *G-Quadruplexes ; *Genes, myc ; Humans ; Isoquinolines/*pharmacology ; *Promoter Regions, Genetic ; *Telomere ; },
abstract = {BACKGROUND: Interaction of putative anticancer agent sanguinarine with two quadruplex forming sequences, human telomeric DNA (H24) and NHE III1 upstream of the P1 promoter of c-myc (Pu27), has been studied to understand the structural basis of the recognition.<br><br>METHODS: Absorption, fluorescence and circular dichroism spectroscopy have been employed to characterize the association. Energetics of the interaction was studied by isothermal titration and differential scanning calorimetry. TRAP assay was done to assess the inhibitory potential of sanguinarine.<br><br>RESULTS: Absorption and fluorescence studies show that sanguinarine has high binding affinity of ~10(5)M(-1) for both sequences. Binding stoichiometry is 2:1 for H24 and 3:1 for Pu27. Results suggest stacking interaction between planar sanguinarine moiety and G-quartets. Circular dichroism spectra show that sanguinarine does not cause structural perturbation in the all-parallel Pu27 but causes a structural transition from mixed hybrid to basket form at higher sanguinarine concentration in case of H24. The interaction is characterized by total enthalpy-entropy compensation and high heat capacity values. Differential scanning calorimetry studies suggest that sanguinarine binding increases the melting temperature and also the total enthalpy of transition of both quadruplexes. TRAP results show that sanguinarine effectively blocks telomerase activity in a concentration dependent manner in cell extracts from MDAMB-231 breast cancer cell lines.<br><br>CONCLUSION: These results suggest that there is a difference in the structural modes of association of sanguinarine to the quadruplexes.<br><br>GENERAL SIGNIFICANCE: It helps to understand the role of quadruplex structures as a target of small molecule inhibitors of telomerase.},
}
@article {pmid23561444,
year = {2013},
author = {Pucci, F and Gardano, L and Harrington, L},
title = {Short telomeres in ESCs lead to unstable differentiation.},
journal = {Cell stem cell},
volume = {12},
number = {4},
pages = {479-486},
pmid = {23561444},
issn = {1875-9777},
support = {092076//Wellcome Trust/United Kingdom ; G0800081/MRC_/Medical Research Council/United Kingdom ; 084637/WT_/Wellcome Trust/United Kingdom ; 086580/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; *Cell Differentiation ; CpG Islands/genetics ; DNA (Cytosine-5-)-Methyltransferases/metabolism ; Embryonic Stem Cells/*cytology/enzymology/*metabolism ; Histones/metabolism ; Homeodomain Proteins/metabolism ; Lysine/metabolism ; Mice ; Nanog Homeobox Protein ; Pluripotent Stem Cells/cytology/metabolism ; Telomere/*metabolism ; DNA Methyltransferase 3B ; },
abstract = {Functional telomeres are critical for stem cell proliferation; however, whether they are equally important for the stability of stem cell differentiation is not known. We found that mouse embryonic stem cells (ESCs) with critically short telomeres (Tert(-/-) ESCs) initiated normal differentiation after leukemia inhibitory factor (LIF) withdrawal but, unlike control ESCs, failed to maintain stable differentiation when LIF was reintroduced to the growth medium. Tert(-/-) ESCs expressed higher levels of Nanog and, overall, had decreased genomic CpG methylation levels, which included the promoters of Oct4 and Nanog. This unstable differentiation phenotype could be rescued by telomere elongation via reintroduction of Tert, via suppression of Nanog by small hairpin RNA (shRNA) knockdown, or via enforced expression of the de novo DNA methyltransferase 3b. These results demonstrate an unexpected role of functional telomeres in the genome-wide epigenetic regulation of cell differentiation and suggest a potentially important role of telomere instability in cell fate during development or disease.},
}
@article {pmid23561436,
year = {2013},
author = {Allsopp, R},
title = {Short telomeres flirt with stem cell commitment.},
journal = {Cell stem cell},
volume = {12},
number = {4},
pages = {383-384},
doi = {10.1016/j.stem.2013.03.011},
pmid = {23561436},
issn = {1875-9777},
abstract = {High expression of telomerase in embryonic stem cells (ESCs) is important for their maintenance, but whether telomere length affects lineage commitment is unknown. In this issue of Cell stem cell, Pucci et al. (2013) reveal that ESCs with short telomeres exhibit unstable differentiation by inducing altered DNA methylation.},
}
@article {pmid23557232,
year = {2013},
author = {Ishikawa, F},
title = {Portrait of replication stress viewed from telomeres.},
journal = {Cancer science},
volume = {104},
number = {7},
pages = {790-794},
pmid = {23557232},
issn = {1349-7006},
mesh = {Animals ; DNA Replication/*genetics ; DNA, Neoplasm/biosynthesis/genetics ; *Genomic Instability ; Humans ; *Mutation ; Neoplasms/*genetics/pathology ; Telomere/*genetics ; },
abstract = {Genetic instability is the driving force of the malignant progression of cancer cells. Recently, replication stress has attracted much attention as a source of genetic instability that gives rise to an accumulation of mutations during the lifespan of individuals. However, the molecular details of the process are not fully understood. Here, recent progress in understanding how genetic alterations accumulate at telomeres will be reviewed. In particular, two aspects of telomere replication will be discussed in this context, covering conventional semi-conservative replication, and DNA synthesis by telomerase plus the C-strand fill-in reactions. Although these processes are seemingly telomere-specific, I will emphasize the possibility that the molecular understanding of the telomere events may shed light on genetic instability at other genetic loci in general.},
}
@article {pmid23555636,
year = {2013},
author = {Lan, Q and Cawthon, R and Gao, Y and Hu, W and Hosgood, HD and Barone-Adesi, F and Ji, BT and Bassig, B and Chow, WH and Shu, X and Cai, Q and Xiang, Y and Berndt, S and Kim, C and Chanock, S and Zheng, W and Rothman, N},
title = {Longer telomere length in peripheral white blood cells is associated with risk of lung cancer and the rs2736100 (CLPTM1L-TERT) polymorphism in a prospective cohort study among women in China.},
journal = {PloS one},
volume = {8},
number = {3},
pages = {e59230},
pmid = {23555636},
issn = {1932-6203},
support = {//Intramural NIH HHS/United States ; },
mesh = {Adenocarcinoma/diagnosis/*genetics/pathology ; Adenocarcinoma of Lung ; Adult ; Aged ; Case-Control Studies ; China ; Female ; Genetic Loci ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Leukocytes, Mononuclear/*metabolism ; Lung Neoplasms/diagnosis/*genetics/pathology ; Membrane Proteins/*genetics ; Middle Aged ; Neoplasm Proteins/*genetics ; Odds Ratio ; *Polymorphism, Single Nucleotide ; Prospective Studies ; Risk ; Telomerase/*genetics ; Telomere/*chemistry ; Telomere Homeostasis ; },
abstract = {A recent genome-wide association study of lung cancer among never-smoking females in Asia demonstrated that the rs2736100 polymorphism in the TERT-CLPTM1L locus on chromosome 5p15.33 was strongly and significantly associated with risk of adenocarcinoma of the lung. The telomerase gene TERT is a reverse transcriptase that is critical for telomere replication and stabilization by controlling telomere length. We previously found that longer telomere length measured in peripheral white blood cell DNA was associated with increased risk of lung cancer in a prospective cohort study of smoking males in Finland. To follow up on this finding, we carried out a nested case-control study of 215 female lung cancer cases and 215 female controls, 94% of whom were never-smokers, in the prospective Shanghai Women's Health Study cohort. There was a dose-response relationship between tertiles of telomere length and risk of lung cancer (odds ratio (OR), 95% confidence interval [CI]: 1.0, 1.4 [0.8-2.5], and 2.2 [1.2-4.0], respectively; P trend = 0.003). Further, the association was unchanged by the length of time from blood collection to case diagnosis. In addition, the rs2736100 G allele, which we previously have shown to be associated with risk of lung cancer in this cohort, was significantly associated with longer telomere length in these same study subjects (P trend = 0.030). Our findings suggest that individuals with longer telomere length in peripheral white blood cells may have an increased risk of lung cancer, but require replication in additional prospective cohorts and populations.},
}
@article {pmid23555296,
year = {2013},
author = {Muraki, K and Han, L and Miller, D and Murnane, JP},
title = {The role of ATM in the deficiency in nonhomologous end-joining near telomeres in a human cancer cell line.},
journal = {PLoS genetics},
volume = {9},
number = {3},
pages = {e1003386},
pmid = {23555296},
issn = {1553-7404},
support = {R01 CA120205/CA/NCI NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins ; *Cell Cycle Proteins/genetics/metabolism ; Cell Line, Tumor ; Chromosomal Instability/genetics ; Chromosome Aberrations ; DNA Breaks, Double-Stranded ; DNA End-Joining Repair/*genetics ; DNA Repair/genetics ; *DNA-Binding Proteins/genetics/metabolism ; Humans ; *Neoplasms/genetics/metabolism ; *Protein Serine-Threonine Kinases/genetics/metabolism ; Sequence Deletion/genetics ; Telomere/*genetics ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; *Tumor Suppressor Proteins/genetics/metabolism ; },
abstract = {Telomeres distinguish chromosome ends from double-strand breaks (DSBs) and prevent chromosome fusion. However, telomeres can also interfere with DNA repair, as shown by a deficiency in nonhomologous end joining (NHEJ) and an increase in large deletions at telomeric DSBs. The sensitivity of telomeric regions to DSBs is important in the cellular response to ionizing radiation and oncogene-induced replication stress, either by preventing cell division in normal cells, or by promoting chromosome instability in cancer cells. We have previously proposed that the telomeric protein TRF2 causes the sensitivity of telomeric regions to DSBs, either through its inhibition of ATM, or by promoting the processing of DSBs as though they are telomeres, which is independent of ATM. Our current study addresses the mechanism responsible for the deficiency in repair of DSBs near telomeres by combining assays for large deletions, NHEJ, small deletions, and gross chromosome rearrangements (GCRs) to compare the types of events resulting from DSBs at interstitial and telomeric DSBs. Our results confirm the sensitivity of telomeric regions to DSBs by demonstrating that the frequency of GCRs is greatly increased at DSBs near telomeres and that the role of ATM in DSB repair is very different at interstitial and telomeric DSBs. Unlike at interstitial DSBs, a deficiency in ATM decreases NHEJ and small deletions at telomeric DSBs, while it increases large deletions. These results strongly suggest that ATM is functional near telomeres and is involved in end protection at telomeric DSBs, but is not required for the extensive resection at telomeric DSBs. The results support our model in which the deficiency in DSB repair near telomeres is a result of ATM-independent processing of DSBs as though they are telomeres, leading to extensive resection, telomere loss, and GCRs involving alternative NHEJ.},
}
@article {pmid23548418,
year = {2013},
author = {Palma, M and Parker, A and Hojjat-Farsangi, M and Forster, J and Kokhaei, P and Hansson, L and Osterborg, A and Mellstedt, H},
title = {Telomere length and expression of human telomerase reverse transcriptase splice variants in chronic lymphocytic leukemia.},
journal = {Experimental hematology},
volume = {41},
number = {7},
pages = {615-626},
doi = {10.1016/j.exphem.2013.03.008},
pmid = {23548418},
issn = {1873-2399},
mesh = {Aged ; Alternative Splicing ; Disease Progression ; Female ; Gene Expression Regulation, Leukemic ; Genes, Immunoglobulin ; Humans ; Immunoglobulin Heavy Chains/genetics ; Immunoglobulin Variable Region/genetics ; Isoenzymes/genetics/physiology ; Leukemia, Lymphocytic, Chronic, B-Cell/enzymology/*genetics ; Male ; Neoplasm Proteins/*genetics/physiology ; RNA, Messenger/biosynthesis/genetics ; RNA, Neoplasm/biosynthesis/genetics ; Real-Time Polymerase Chain Reaction ; Telomerase/*genetics/physiology ; Telomere/*ultrastructure ; },
abstract = {Telomerase activity and telomere length (TL) are prognostic markers in chronic lymphocytic leukemia (CLL). The rate-limiting component of telomerase is human telomerase reverse transcriptase (hTERT), for which multiple transcripts exist. Two splicing sites, α and β, have been described that generate deleted transcripts. Only the full-length (FL; α[+]β[+]) transcript translates into a functional protein. The aim of this work was to characterize hTERT splice variants in CLL in relation to disease activity, clinical stage, immunoglobulin heavy chain variable (IGHV) genes mutational status, and TL. Real-time polymerase chain reaction assays were validated for quantification of the hTERT transcripts with either α deletion (del-α; α[-]β[+])), β deletion (del-β; α[+]β[-]) or both α and β deletions (del-αβ; α[-]β[-]). The splice variant expression pattern was studied in 97 patients with CLL, 6 healthy control subjects, and one CD34 cell sample. TL was assessed with real-time polymerase chain reaction in 71 of 97 samples. Thirty-two percent of the cases did not express any of the splice variants. Average FL expression was 5.5-fold higher in IGHV-unmutated (n = 35) compared with mutated (n = 59) patients (p < 0.0001). FL levels correlated directly with the percentage of IGHV homology (r = 0.34; p = 0.0007) and inversely with TL (r = -0.44; p = 0.0001). Overall, FL expression correlated significantly with that of the other splice variants. All transcripts were more frequently expressed in progressive compared with nonprogressive patients (p < 0.0001 for FL and del-α; p = 0.01 for del-β; and p = 0.006 for del-αβ). This study provides a detailed insight into the hTERT transcript pattern in CLL, highlighting the necessity of subgrouping patients according to IGHV mutation status when analyzing hTERT expression.},
}
@article {pmid23547895,
year = {2013},
author = {Samassekou, O and Malina, A and Hébert, J and Yan, J},
title = {Presence of alternative lengthening of telomeres associated circular extrachromosome telomere repeats in primary leukemia cells of chronic myeloid leukemia.},
journal = {Journal of hematology &amp; oncology},
volume = {6},
number = {},
pages = {26},
pmid = {23547895},
issn = {1756-8722},
mesh = {*Chromosome Aberrations ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*genetics ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Repetitive Sequences, Nucleic Acid/*genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Tumor Cells, Cultured ; },
abstract = {BACKGROUND: The predominant mechanism by which human tumors maintain telomere length is via telomerase. In ~10% of tumor samples, however, telomere length is conserved, despite no detectable telomerase activity, in part through activation of the alternative lengthening of telomeres (ALT) pathway.<br><br>METHODS: We studied the circular extra-chromosomal telomeric repeat (ECTR), an ALT hallmark, and telomerase activity in 24 chronic myeloid leukemia (CML) patients in chronic phase (CP).<br><br>RESULTS: We identified the presence of ECTR in primary leukemia cells from some of these samples, which indicates the possible involvement of an ALT mechanism. Moreover, we found that some samples exhibited both circular ECTR and telomerase activities, suggesting that both mechanisms can contribute to the onset of CML.<br><br>CONCLUSION: We propose that ALT or the combined activities of ALT and telomerase might be required for the early stages of leukemogenesis. These findings shed new light into the oncogenic pathways responsible for the maintenance of telomere length in leukemia, which will ultimately determine the effectiveness of anti-telomerase-based treatment protocols.},
}
@article {pmid23543032,
year = {2013},
author = {Pfeiffer, V and Lingner, J},
title = {Replication of telomeres and the regulation of telomerase.},
journal = {Cold Spring Harbor perspectives in biology},
volume = {5},
number = {5},
pages = {a010405},
pmid = {23543032},
issn = {1943-0264},
support = {232812/ERC_/European Research Council/International ; },
mesh = {Animals ; DNA Replication/*physiology ; Mammals/genetics ; Models, Genetic ; Saccharomyces cerevisiae/genetics ; Schizosaccharomyces/genetics ; Telomerase/*metabolism ; Telomere/chemistry/*physiology ; *Telomere Homeostasis ; },
abstract = {Telomeres are the physical ends of eukaryotic chromosomes. They protect chromosome ends from DNA degradation, recombination, and DNA end fusions, and they are important for nuclear architecture. Telomeres provide a mechanism for their replication by semiconservative DNA replication and length maintenance by telomerase. Through telomerase repression and induced telomere shortening, telomeres provide the means to regulate cellular life span. In this review, we introduce the current knowledge on telomere composition and structure. We then discuss in depth the current understanding of how telomere components mediate their function during semiconservative DNA replication and how telomerase is regulated at the end of the chromosome. We focus our discussion on the telomeres from mammals and the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe.},
}
@article {pmid23542632,
year = {2013},
author = {Ruella, M and Salmoiraghi, S and Risso, A and Carobbio, A and Buttiglieri, S and Spatola, T and Sivera, P and Ricca, I and Barbui, T and Tarella, C and Rambaldi, A},
title = {Telomere shortening in Ph-negative chronic myeloproliferative neoplasms: a biological marker of polycythemia vera and myelofibrosis, regardless of hydroxycarbamide therapy.},
journal = {Experimental hematology},
volume = {41},
number = {7},
pages = {627-634},
doi = {10.1016/j.exphem.2013.03.007},
pmid = {23542632},
issn = {1873-2399},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Biomarkers ; Child ; Child, Preschool ; Clone Cells/pathology ; Female ; Humans ; Hydroxyurea/*therapeutic use ; In Situ Hybridization, Fluorescence ; Infant ; Infant, Newborn ; Janus Kinase 2/genetics ; Male ; Middle Aged ; Mutation, Missense ; Myeloproliferative Disorders/drug therapy/*genetics/pathology ; Point Mutation ; Polycythemia/drug therapy/genetics/pathology ; Polycythemia Vera/drug therapy/genetics/pathology ; Primary Myelofibrosis/drug therapy/genetics/pathology ; Telomere/*ultrastructure ; Young Adult ; },
abstract = {The purpose of this study was to investigate telomere length (TL) in Ph-negative chronic myeloproliferative neoplasms (Ph-neg-CMNs), and the possible association of TL with disease progression and hydroxycarbamide (HU) treatment. TL was analyzed in peripheral blood samples from 239 patients with Ph-neg-CMNs, including polycythemia vera (PV), essential thrombocythemia and myelofibrosis (MF), and compared with age-matched healthy control subjects (CTR), along with some cases of secondary erythrocytosis (SE). More than half of the patients with CMN received at least 1 year of cytoreduction, mainly HU, before TL analysis. JAK2 mutation analysis was performed as well. TL was significantly shortened in patients with CMN compared with CTR (p < 0.0001). PV and MF showed the most pronounced decrease (p < 0.0001), whereas both essential thrombocythemia and SE showed no significant difference in TL compared with CTR. A short TL correlated with JAK2-V617F allele burden greater than 50% (p = 0.0025), age (p = 0.0132) and diagnosis of PV (p = 0.0122). No correlation was found with disease duration, history of thrombosis, cytoreductive treatment, antiaggregation agents, adverse cytogenetics, phlebotomies, or time to evolution to MF. In summary, TL is distinctly shortened in PV and MF, and it inversely correlates with JAK2V617F allele burden. In addition, HU is unlikely to contribute to telomere erosion. Lastly, PV and SE significantly differ in TL. Therefore, TL could be an additional diagnostic marker to identify and monitor Ph-neg-CMN patients.},
}
@article {pmid23541441,
year = {2013},
author = {Hartwig, FP and Collares, T},
title = {Telomere dysfunction and tumor suppression responses in dyskeratosis congenita: balancing cancer and tissue renewal impairment.},
journal = {Ageing research reviews},
volume = {12},
number = {2},
pages = {642-652},
doi = {10.1016/j.arr.2013.03.003},
pmid = {23541441},
issn = {1872-9649},
mesh = {Age of Onset ; Aged ; Aging, Premature/etiology/genetics ; Bone Marrow Diseases/etiology/genetics ; Cellular Senescence/genetics ; *Dyskeratosis Congenita/complications/genetics/physiopathology ; Genes, Tumor Suppressor ; Genetic Predisposition to Disease ; Humans ; Models, Theoretical ; Mutation ; Neoplasms/etiology/genetics ; Risk Factors ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Translational Research, Biomedical/methods ; },
abstract = {Dyskeratosis congenita (DC) encompasses a large spectrum of diseases and clinical manifestations generally related to premature aging, including bone marrow failure and cancer predisposition. The major risk factor for DC is to carry germline telomere-related mutations - in telomerase or telomere shelterin genes - which results in premature telomere dysfunction, thus increasing the risk of premature aging impairments. Despite the advances that have been accomplished in DC research, the molecular aspects underlying the phenotypic variability of the disease remain poorly understood. Here different aspects of telomere biology, concerning adult stem cells senescence, tumor suppression and cancer are considered in the context of DC, resulting in two translational models: late onset of DC symptoms in telomere-related mutations carriers is a potential indicator of increased cancer risk and differences in tumor suppression capacities among the genetic subgroups are (at least partial) causes of different clinical manifestations of the disease. The limitations of both models are presented, and further experiments for their validation, as well as clinical implications, are discussed.},
}
@article {pmid23540366,
year = {2013},
author = {Theall, KP and Brett, ZH and Shirtcliff, EA and Dunn, EC and Drury, SS},
title = {Neighborhood disorder and telomeres: connecting children's exposure to community level stress and cellular response.},
journal = {Social science &amp; medicine (1982)},
volume = {85},
number = {},
pages = {50-58},
pmid = {23540366},
issn = {1873-5347},
support = {1R01ES020447-01/ES/NIEHS NIH HHS/United States ; R01 ES020447/ES/NIEHS NIH HHS/United States ; K01 SH000002/SH/NCHS CDC HHS/United States ; K01 MH077687/MH/NIMH NIH HHS/United States ; K01-MH077687/MH/NIMH NIH HHS/United States ; 1K01SH000002/SH/NCHS CDC HHS/United States ; R01 MH091363/MH/NIMH NIH HHS/United States ; 1R01MH091363/MH/NIMH NIH HHS/United States ; R21 MH094688-01/MH/NIMH NIH HHS/United States ; R21 MH094688/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Child ; Child Development/*physiology ; Child, Preschool ; Female ; Humans ; Male ; New Orleans ; Residence Characteristics/*statistics &amp; numerical data ; Risk Factors ; Saliva/*cytology ; Social Environment ; Stress, Psychological/*physiopathology ; Telomere/*ultrastructure ; Urban Population/*statistics &amp; numerical data ; },
abstract = {Our objective was to explore the utility of salivary telomere length (sTL) as an early indicator of neighborhood-level social environmental risk during child development. We therefore tested the hypothesis that sTL would be associated with markers of social stress exposure in children. Children age 4-14 from 87 neighborhoods were recruited through five urban schools in New Orleans, Louisiana, U.S. Data were collected at the level of the child, family/household, and neighborhood. DNA was obtained from saliva using commercially available kits and sTL was determined for 104 children using quantitative PCR. Analysis was performed on 99 children who had complete data including sTL, social environmental stress, and additional covariates. The mean sTL value was 7.4 T/S (telomere signal/single-copy signal) ratio units (±2.4, range = 2.5-18.0), and 4.7% of the variance in sTL was attributed to differences across neighborhoods. Children living in neighborhoods characterized by high disorder had an sTL value 3.2 units lower than children not living in high disordered environments (p < 0.05) and their odds of having low relative sTL (defined as <1 standard deviation below standardized Z-score mean) values was 3.43 times that of children not living in high disorder environments (adjusted OR = 3.43, 95% CI = 1.22, 9.62). Our findings are consistent with previous studies in adults demonstrating a strong link between psychosocial stress and sTL obtained from peripheral blood, consistent with previous studies in youth demonstrating an association between early life stress and sTL obtained from buccal cell DNA and offer increased support for the hypothesis that sTL represents a non-invasive biological indicator of psychosocial stress exposure (i.e., neighborhood disorder) able to reflect differences in stress exposure levels even in young children.},
}
@article {pmid23540359,
year = {2013},
author = {Needham, BL and Adler, N and Gregorich, S and Rehkopf, D and Lin, J and Blackburn, EH and Epel, ES},
title = {Socioeconomic status, health behavior, and leukocyte telomere length in the National Health and Nutrition Examination Survey, 1999-2002.},
journal = {Social science &amp; medicine (1982)},
volume = {85},
number = {},
pages = {1-8},
pmid = {23540359},
issn = {1873-5347},
support = {R01 AG033592/AG/NIA NIH HHS/United States ; R01AG033592-01A1/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Black or African American/psychology/statistics &amp; numerical data ; Aged ; Aged, 80 and over ; Alcohol Drinking/ethnology ; Biomarkers ; Body Mass Index ; Cellular Senescence ; Cross-Sectional Studies ; Female ; Health Behavior/*ethnology ; Humans ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Nutrition Surveys ; Sedentary Behavior/ethnology ; Smoking/ethnology ; *Social Class ; Telomere/*ultrastructure ; United States ; White People/psychology/statistics &amp; numerical data ; Young Adult ; },
abstract = {The purpose of this study was to examine the association between socioeconomic status (SES) and leukocyte telomere length (LTL) - a marker of cell aging that has been linked to stressful life circumstances - in a nationally representative, socioeconomically and ethnically diverse sample of US adults aged 20-84. Using data from the National Health and Nutrition Examination Survey (NHANES), 1999-2002, we found that respondents who completed less than a high school education had significantly shorter telomeres than those who graduated from college. Income was not associated with LTL. African-Americans had significantly longer telomeres than whites, but there were no significant racial/ethnic differences in the association between education and telomere length. Finally, we found that the association between education and LTL was partially mediated by smoking and body mass index but not by drinking or sedentary behavior.},
}
@article {pmid23536479,
year = {2013},
author = {Buscaglia, R and Gray, RD and Chaires, JB},
title = {Thermodynamic characterization of human telomere quadruplex unfolding.},
journal = {Biopolymers},
volume = {99},
number = {12},
pages = {1006-1018},
pmid = {23536479},
issn = {1097-0282},
support = {5P20RR018733/RR/NCRR NIH HHS/United States ; GM077422/GM/NIGMS NIH HHS/United States ; P20 RR018733/RR/NCRR NIH HHS/United States ; R01 CA035635/CA/NCI NIH HHS/United States ; R01 GM077422/GM/NIGMS NIH HHS/United States ; P30 GM106396/GM/NIGMS NIH HHS/United States ; CA35635/CA/NCI NIH HHS/United States ; },
mesh = {Circular Dichroism ; DNA/chemistry ; DNA, Single-Stranded ; *G-Quadruplexes ; Humans ; Nucleic Acid Conformation ; *Telomere ; Thermodynamics ; },
abstract = {The 3'-terminal extensions of eukaryotic chromosomes are unique examples of functional single-stranded DNA. Human telomeres are constructed of the repeated DNA sequence 5'-d(TTAGGG). Four-repeats of human telomeric DNA have been characterized by high-resolution techniques to be capable of forming at least five distinct monomeric conformations. The predominant solution topology is influenced by solution conditions and the presence of 3'- or 5'-flanking residues. This study describes the unfolding mechanisms for human telomeric quadruplexes formed by eight sequence variants that form three unique antiparallel topologies in K(+) solution. Thermal unfolding monitored by circular dichroism is analyzed by singular value decomposition to enumerate the number of significant spectral species required to model the unfolding process. Thermal denaturation of all quadruplexes studied is found to be best modeled by a four-state sequential mechanism with two populated intermediates. The thermal unfolding was also investigated in 50% (v/v) acetonitrile in which a parallel topology is favored. Under these dehydrating conditions, quadruplex thermal denaturation is best modeled by a three-state sequential unfolding mechanism with one populated intermediate. Dehydrated parallel quadruplexes demonstrate increased thermal stability. The spectral properties of the unfolding intermediate suggest that it is most likely a triple-helical structure.},
}
@article {pmid23535734,
year = {2013},
author = {Codd, V and Nelson, CP and Albrecht, E and Mangino, M and Deelen, J and Buxton, JL and Hottenga, JJ and Fischer, K and Esko, T and Surakka, I and Broer, L and Nyholt, DR and Mateo Leach, I and Salo, P and Hägg, S and Matthews, MK and Palmen, J and Norata, GD and O'Reilly, PF and Saleheen, D and Amin, N and Balmforth, AJ and Beekman, M and de Boer, RA and Böhringer, S and Braund, PS and Burton, PR and de Craen, AJ and Denniff, M and Dong, Y and Douroudis, K and Dubinina, E and Eriksson, JG and Garlaschelli, K and Guo, D and Hartikainen, AL and Henders, AK and Houwing-Duistermaat, JJ and Kananen, L and Karssen, LC and Kettunen, J and Klopp, N and Lagou, V and van Leeuwen, EM and Madden, PA and Mägi, R and Magnusson, PK and Männistö, S and McCarthy, MI and Medland, SE and Mihailov, E and Montgomery, GW and Oostra, BA and Palotie, A and Peters, A and Pollard, H and Pouta, A and Prokopenko, I and Ripatti, S and Salomaa, V and Suchiman, HE and Valdes, AM and Verweij, N and Viñuela, A and Wang, X and Wichmann, HE and Widen, E and Willemsen, G and Wright, MJ and Xia, K and Xiao, X and van Veldhuisen, DJ and Catapano, AL and Tobin, MD and Hall, AS and Blakemore, AI and van Gilst, WH and Zhu, H and , and Erdmann, J and Reilly, MP and Kathiresan, S and Schunkert, H and Talmud, PJ and Pedersen, NL and Perola, M and Ouwehand, W and Kaprio, J and Martin, NG and van Duijn, CM and Hovatta, I and Gieger, C and Metspalu, A and Boomsma, DI and Jarvelin, MR and Slagboom, PE and Thompson, JR and Spector, TD and van der Harst, P and Samani, NJ},
title = {Identification of seven loci affecting mean telomere length and their association with disease.},
journal = {Nature genetics},
volume = {45},
number = {4},
pages = {422-7, 427e1-2},
pmid = {23535734},
issn = {1546-1718},
support = {090532/WT_/Wellcome Trust/United Kingdom ; G0902313/MRC_/Medical Research Council/United Kingdom ; MR/K014536/1/MRC_/Medical Research Council/United Kingdom ; R56 DA012854/DA/NIDA NIH HHS/United States ; },
mesh = {Biomarkers, Tumor/*genetics ; Case-Control Studies ; Disease/*genetics ; Female ; Genetic Loci/*genetics ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Leukocytes/*metabolism ; Male ; Meta-Analysis as Topic ; Risk Factors ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.},
}
@article {pmid23535731,
year = {2013},
author = {Bojesen, SE and Pooley, KA and Johnatty, SE and Beesley, J and Michailidou, K and Tyrer, JP and Edwards, SL and Pickett, HA and Shen, HC and Smart, CE and Hillman, KM and Mai, PL and Lawrenson, K and Stutz, MD and Lu, Y and Karevan, R and Woods, N and Johnston, RL and French, JD and Chen, X and Weischer, M and Nielsen, SF and Maranian, MJ and Ghoussaini, M and Ahmed, S and Baynes, C and Bolla, MK and Wang, Q and Dennis, J and McGuffog, L and Barrowdale, D and Lee, A and Healey, S and Lush, M and Tessier, DC and Vincent, D and Bacot, F and , and , and , and , and , and , and , and , and Vergote, I and Lambrechts, S and Despierre, E and Risch, HA and González-Neira, A and Rossing, MA and Pita, G and Doherty, JA and Alvarez, N and Larson, MC and Fridley, BL and Schoof, N and Chang-Claude, J and Cicek, MS and Peto, J and Kalli, KR and Broeks, A and Armasu, SM and Schmidt, MK and Braaf, LM and Winterhoff, B and Nevanlinna, H and Konecny, GE and Lambrechts, D and Rogmann, L and Guénel, P and Teoman, A and Milne, RL and Garcia, JJ and Cox, A and Shridhar, V and Burwinkel, B and Marme, F and Hein, R and Sawyer, EJ and Haiman, CA and Wang-Gohrke, S and Andrulis, IL and Moysich, KB and Hopper, JL and Odunsi, K and Lindblom, A and Giles, GG and Brenner, H and Simard, J and Lurie, G and Fasching, PA and Carney, ME and Radice, P and Wilkens, LR and Swerdlow, A and Goodman, MT and Brauch, H and Garcia-Closas, M and Hillemanns, P and Winqvist, R and Dürst, M and Devilee, P and Runnebaum, I and Jakubowska, A and Lubinski, J and Mannermaa, A and Butzow, R and Bogdanova, NV and Dörk, T and Pelttari, LM and Zheng, W and Leminen, A and Anton-Culver, H and Bunker, CH and Kristensen, V and Ness, RB and Muir, K and Edwards, R and Meindl, A and Heitz, F and Matsuo, K and du Bois, A and Wu, AH and Harter, P and Teo, SH and Schwaab, I and Shu, XO and Blot, W and Hosono, S and Kang, D and Nakanishi, T and Hartman, M and Yatabe, Y and Hamann, U and Karlan, BY and Sangrajrang, S and Kjaer, SK and Gaborieau, V and Jensen, A and Eccles, D and Høgdall, E and Shen, CY and Brown, J and Woo, YL and Shah, M and Azmi, MA and Luben, R and Omar, SZ and Czene, K and Vierkant, RA and Nordestgaard, BG and Flyger, H and Vachon, C and Olson, JE and Wang, X and Levine, DA and Rudolph, A and Weber, RP and Flesch-Janys, D and Iversen, E and Nickels, S and Schildkraut, JM and Silva, Idos S and Cramer, DW and Gibson, L and Terry, KL and Fletcher, O and Vitonis, AF and van der Schoot, CE and Poole, EM and Hogervorst, FB and Tworoger, SS and Liu, J and Bandera, EV and Li, J and Olson, SH and Humphreys, K and Orlow, I and Blomqvist, C and Rodriguez-Rodriguez, L and Aittomäki, K and Salvesen, HB and Muranen, TA and Wik, E and Brouwers, B and Krakstad, C and Wauters, E and Halle, MK and Wildiers, H and Kiemeney, LA and Mulot, C and Aben, KK and Laurent-Puig, P and Altena, AM and Truong, T and Massuger, LF and Benitez, J and Pejovic, T and Perez, JI and Hoatlin, M and Zamora, MP and Cook, LS and Balasubramanian, SP and Kelemen, LE and Schneeweiss, A and Le, ND and Sohn, C and Brooks-Wilson, A and Tomlinson, I and Kerin, MJ and Miller, N and Cybulski, C and Henderson, BE and Menkiszak, J and Schumacher, F and Wentzensen, N and Le Marchand, L and Yang, HP and Mulligan, AM and Glendon, G and Engelholm, SA and Knight, JA and Høgdall, CK and Apicella, C and Gore, M and Tsimiklis, H and Song, H and Southey, MC and Jager, A and den Ouweland, AM and Brown, R and Martens, JW and Flanagan, JM and Kriege, M and Paul, J and Margolin, S and Siddiqui, N and Severi, G and Whittemore, AS and Baglietto, L and McGuire, V and Stegmaier, C and Sieh, W and Müller, H and Arndt, V and Labrèche, F and Gao, YT and Goldberg, MS and Yang, G and Dumont, M and McLaughlin, JR and Hartmann, A and Ekici, AB and Beckmann, MW and Phelan, CM and Lux, MP and Permuth-Wey, J and Peissel, B and Sellers, TA and Ficarazzi, F and Barile, M and Ziogas, A and Ashworth, A and Gentry-Maharaj, A and Jones, M and Ramus, SJ and Orr, N and Menon, U and Pearce, CL and Brüning, T and Pike, MC and Ko, YD and Lissowska, J and Figueroa, J and Kupryjanczyk, J and Chanock, SJ and Dansonka-Mieszkowska, A and Jukkola-Vuorinen, A and Rzepecka, IK and Pylkäs, K and Bidzinski, M and Kauppila, S and Hollestelle, A and Seynaeve, C and Tollenaar, RA and Durda, K and Jaworska, K and Hartikainen, JM and Kosma, VM and Kataja, V and Antonenkova, NN and Long, J and Shrubsole, M and Deming-Halverson, S and Lophatananon, A and Siriwanarangsan, P and Stewart-Brown, S and Ditsch, N and Lichtner, P and Schmutzler, RK and Ito, H and Iwata, H and Tajima, K and Tseng, CC and Stram, DO and van den Berg, D and Yip, CH and Ikram, MK and Teh, YC and Cai, H and Lu, W and Signorello, LB and Cai, Q and Noh, DY and Yoo, KY and Miao, H and Iau, PT and Teo, YY and McKay, J and Shapiro, C and Ademuyiwa, F and Fountzilas, G and Hsiung, CN and Yu, JC and Hou, MF and Healey, CS and Luccarini, C and Peock, S and Stoppa-Lyonnet, D and Peterlongo, P and Rebbeck, TR and Piedmonte, M and Singer, CF and Friedman, E and Thomassen, M and Offit, K and Hansen, TV and Neuhausen, SL and Szabo, CI and Blanco, I and Garber, J and Narod, SA and Weitzel, JN and Montagna, M and Olah, E and Godwin, AK and Yannoukakos, D and Goldgar, DE and Caldes, T and Imyanitov, EN and Tihomirova, L and Arun, BK and Campbell, I and Mensenkamp, AR and van Asperen, CJ and van Roozendaal, KE and Meijers-Heijboer, H and Collée, JM and Oosterwijk, JC and Hooning, MJ and Rookus, MA and van der Luijt, RB and Os, TA and Evans, DG and Frost, D and Fineberg, E and Barwell, J and Walker, L and Kennedy, MJ and Platte, R and Davidson, R and Ellis, SD and Cole, T and Bressac-de Paillerets, B and Buecher, B and Damiola, F and Faivre, L and Frenay, M and Sinilnikova, OM and Caron, O and Giraud, S and Mazoyer, S and Bonadona, V and Caux-Moncoutier, V and Toloczko-Grabarek, A and Gronwald, J and Byrski, T and Spurdle, AB and Bonanni, B and Zaffaroni, D and Giannini, G and Bernard, L and Dolcetti, R and Manoukian, S and Arnold, N and Engel, C and Deissler, H and Rhiem, K and Niederacher, D and Plendl, H and Sutter, C and Wappenschmidt, B and Borg, A and Melin, B and Rantala, J and Soller, M and Nathanson, KL and Domchek, SM and Rodriguez, GC and Salani, R and Kaulich, DG and Tea, MK and Paluch, SS and Laitman, Y and Skytte, AB and Kruse, TA and Jensen, UB and Robson, M and Gerdes, AM and Ejlertsen, B and Foretova, L and Savage, SA and Lester, J and Soucy, P and Kuchenbaecker, KB and Olswold, C and Cunningham, JM and Slager, S and Pankratz, VS and Dicks, E and Lakhani, SR and Couch, FJ and Hall, P and Monteiro, AN and Gayther, SA and Pharoah, PD and Reddel, RR and Goode, EL and Greene, MH and Easton, DF and Berchuck, A and Antoniou, AC and Chenevix-Trench, G and Dunning, AM},
title = {Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.},
journal = {Nature genetics},
volume = {45},
number = {4},
pages = {371-84, 384e1-2},
pmid = {23535731},
issn = {1546-1718},
support = {CA128978/CA/NCI NIH HHS/United States ; P30 CA072720/CA/NCI NIH HHS/United States ; R37 CA070867/CA/NCI NIH HHS/United States ; C12292/A11174/CRUK_/Cancer Research UK/United Kingdom ; 076113/WT_/Wellcome Trust/United Kingdom ; 11174/CRUK_/Cancer Research UK/United Kingdom ; P30 CA076292/CA/NCI NIH HHS/United States ; R01 CA083918/CA/NCI NIH HHS/United States ; C1287/A12014/CRUK_/Cancer Research UK/United Kingdom ; P30 CA016520/CA/NCI NIH HHS/United States ; R01 CA149429/CA/NCI NIH HHS/United States ; 11022/CRUK_/Cancer Research UK/United Kingdom ; C1287/A9540/CRUK_/Cancer Research UK/United Kingdom ; 13086/CRUK_/Cancer Research UK/United Kingdom ; 10124/CRUK_/Cancer Research UK/United Kingdom ; CA116201/CA/NCI NIH HHS/United States ; RC4 CA153828/CA/NCI NIH HHS/United States ; R01 CA087538/CA/NCI NIH HHS/United States ; C1287/A10710/CRUK_/Cancer Research UK/United Kingdom ; R01 CA092447/CA/NCI NIH HHS/United States ; /CAPMC/CIHR/Canada ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA128978/CA/NCI NIH HHS/United States ; BREAST CANCER NOW RESEARCH CENTRE/BCN_/Breast Cancer Now/United Kingdom ; P50 CA116201/CA/NCI NIH HHS/United States ; 16565/CRUK_/Cancer Research UK/United Kingdom ; 090532/WT_/Wellcome Trust/United Kingdom ; R01 CA122443/CA/NCI NIH HHS/United States ; 16561/CRUK_/Cancer Research UK/United Kingdom ; 10118/CRUK_/Cancer Research UK/United Kingdom ; U19 CA148112/CA/NCI NIH HHS/United States ; C1287/A10118/CRUK_/Cancer Research UK/United Kingdom ; P30 CA071789/CA/NCI NIH HHS/United States ; R01 CA112523/CA/NCI NIH HHS/United States ; P50 CA136393/CA/NCI NIH HHS/United States ; 15960/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Alternative Splicing ; Biomarkers, Tumor/*genetics ; Breast Neoplasms/*etiology/pathology ; Case-Control Studies ; Chromatin/genetics ; DNA Methylation ; Female ; Gene Expression Profiling ; Genetic Loci/*genetics ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; Humans ; Luciferases/metabolism ; Oligonucleotide Array Sequence Analysis ; Ovarian Neoplasms/*etiology/pathology ; Polymorphism, Single Nucleotide/*genetics ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Risk Factors ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.},
}
@article {pmid23534972,
year = {2013},
author = {Kyoh, S and Venkatesan, N and Poon, AH and Nishioka, M and Lin, TY and Baglole, CJ and Eidelman, DH and Hamid, Q},
title = {Are leukocytes in asthmatic patients aging faster? A study of telomere length and disease severity.},
journal = {The Journal of allergy and clinical immunology},
volume = {132},
number = {2},
pages = {480-2.e2},
doi = {10.1016/j.jaci.2013.02.010},
pmid = {23534972},
issn = {1097-6825},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Adult ; Aging/genetics ; *Asthma/genetics/physiopathology ; Biopsy ; Bronchi/metabolism ; Cellular Senescence/*genetics/physiology ; Female ; Humans ; Leukocytes/enzymology/*physiology ; Male ; Middle Aged ; *Severity of Illness Index ; Telomerase/genetics/metabolism ; Telomere/*genetics/pathology ; Telomere Shortening/genetics ; },
}
@article {pmid23532044,
year = {2013},
author = {Donà, M and Balestrazzi, A and Mondoni, A and Rossi, G and Ventura, L and Buttafava, A and Macovei, A and Sabatini, ME and Valassi, A and Carbonera, D},
title = {DNA profiling, telomere analysis and antioxidant properties as tools for monitoring ex situ seed longevity.},
journal = {Annals of botany},
volume = {111},
number = {5},
pages = {987-998},
pmid = {23532044},
issn = {1095-8290},
mesh = {Altitude ; Antioxidants/*metabolism ; DNA Fingerprinting/*methods ; DNA Primers/metabolism ; Electron Spin Resonance Spectroscopy ; Free Radical Scavengers/metabolism ; Gene Expression Profiling ; Gene Expression Regulation, Plant ; Genes, Plant/genetics ; Germination/genetics ; Phenols/metabolism ; Phylogeny ; Plant Extracts/metabolism ; Random Amplified Polymorphic DNA Technique ; Reactive Oxygen Species/metabolism ; Seeds/*genetics/*growth &amp; development ; Silene/*genetics/*growth &amp; development ; Telomere/*metabolism ; Telomere Homeostasis/genetics ; },
abstract = {BACKGROUND AND AIMS: The germination test currently represents the most used method to assess seed viability in germplasm banks, despite the difficulties caused by the occurrence of seed dormancy. Furthermore, seed longevity can vary considerably across species and populations from different environments, and studies related to the eco-physiological processes underlying such variations are still limited in their depth. The aim of the present work was the identification of reliable molecular markers that might help in monitoring seed deterioration.<br><br>METHODS: Dry seeds were subjected to artificial ageing and collected at different time points for molecular/biochemical analyses. DNA damage was measured using the RAPD (random amplified polymorphic DNA) approach while the seed antioxidant profile was obtained using both the DPPH (1,1-diphenyl, 2-picrylhydrazyl) assay and the Folin-Ciocalteu reagent method. Electron paramagnetic resonance (EPR) provided profiles of free radicals. Quantitative real-time polymerase chain reaction (QRT-PCR) was used to assess the expression profiles of the antioxidant genes MT2 (type 2 metallothionein) and SOD (superoxide dismutase). A modified QRT-PCR protocol was used to determine telomere length.<br><br>KEY RESULTS: The RAPD profiles highlighted different capacities of the two Silene species to overcome DNA damage induced by artificial ageing. The antioxidant profiles of dry and rehydrated seeds revealed that the high-altitude taxon Silene acaulis was characterized by a lower antioxidant specific activity. Significant upregulation of the MT2 and SOD genes was observed only in the rehydrated seeds of the low-altitude species. Rehydration resulted in telomere lengthening in both Silene species.<br><br>CONCLUSIONS: Different seed viability markers have been selected for plant species showing inherent variation of seed longevity. RAPD analysis, quantification of redox activity of non-enzymatic antioxidant compounds and gene expression profiling provide deeper insights to study seed viability during storage. Telomere lengthening is a promising tool to discriminate between short- and long-lived species.},
}
@article {pmid23529001,
year = {2013},
author = {Marchesi, V},
title = {Risk factors: Short telomeres: association with cancer survival and risk.},
journal = {Nature reviews. Clinical oncology},
volume = {10},
number = {5},
pages = {247},
pmid = {23529001},
issn = {1759-4782},
}
@article {pmid23528991,
year = {2013},
author = {Yang, Z and Ye, J and Li, C and Zhou, D and Shen, Q and Wu, J and Cao, L and Wang, T and Cui, D and He, S and Qi, G and He, L and Liu, Y},
title = {Drug addiction is associated with leukocyte telomere length.},
journal = {Scientific reports},
volume = {3},
number = {},
pages = {1542},
pmid = {23528991},
issn = {2045-2322},
mesh = {Adult ; Analgesics, Opioid/administration &amp; dosage ; Cohort Studies ; Diazepam/administration &amp; dosage ; Female ; Heroin/administration &amp; dosage ; Humans ; Hypnotics and Sedatives/administration &amp; dosage ; Leukocytes/*metabolism ; Linear Models ; Male ; Multivariate Analysis ; *Substance-Related Disorders ; Telomere/*genetics ; Telomere Shortening/drug effects/*genetics ; },
abstract = {Telomeres are protective chromosomal structures that play a key role in preserving genomic stability. Telomere length is known to be associated with ageing and age-related diseases. To study the impairment of telomeres induced by drug abuse, we conducted an association study in the Chinese Han population. Multivariate linear regression analyses were performed to evaluate the correlation of leukocyte telomere length (LTL) with addiction control status adjusted for age and gender. The results showed that drug abusers exhibited significantly shorter LTLs than controls (P = 1.32e-06). The time before relapse also presented an inverse correlation with LTL (P = 0.02). Drug abusers who had used heroin and diazepam displayed a shorter LTL than those taking other drugs (P = 0.018 and P = 0.009, respectively). Drug abusers who had ingested drugs via snuff exhibited longer LTLs than those using other methods (P = 0.02). These observations may offer a partial explanation for the effects of drug addiction on health.},
}
@article {pmid23527617,
year = {2013},
author = {Ding, D and Zhou, J and Wang, M and Cong, YS},
title = {Implications of telomere-independent activities of telomerase reverse transcriptase in human cancer.},
journal = {The FEBS journal},
volume = {280},
number = {14},
pages = {3205-3211},
doi = {10.1111/febs.12258},
pmid = {23527617},
issn = {1742-4658},
mesh = {Animals ; Cellular Senescence ; Enzyme Activation ; Humans ; Neoplasms/*enzymology/pathology ; Telomerase/*physiology ; Telomere/genetics ; Telomere Homeostasis ; },
abstract = {Telomerase plays a pivotal role in the pathology of cancer by maintaining genome integrity, controlling cell proliferation, and regulating tissue homeostasis. Experimental data from genetically modified mice and human premature aging diseases clearly indicate that intact telomere function is crucial for cell proliferation and survival, whereas dysfunctional telomeres can lead to either cancer or aging pathologies, depending on the integrity of the cellular stress response pathways. The canonical function of telomerase reverse transcriptase is the synthesis of telomeric DNA repeats and the maintenance of telomere length. However, accumulating evidence indicates that telomerase reverse transcriptase may also exert some fundamental biological functions independently of its enzymatic activity in telomere maintenance. More recent studies have demonstrated that telomerase reverse transcriptase can act as a transcriptional modulator in the nucleus and exhibits RNA-dependent RNA polymerase activity in the mitochondria. Telomerase activation may have both telomere-dependent and telomere-independent implications for tumor progression. Many excellent reviews have described critical roles of telomere and telomerase in human cancer; this minireview will focus on the role of telomerase in cancer progression, with a special emphasis on the nontelomeric function of telomerase.},
}
@article {pmid23527512,
year = {2013},
author = {Asok, A and Bernard, K and Roth, TL and Rosen, JB and Dozier, M},
title = {Parental responsiveness moderates the association between early-life stress and reduced telomere length.},
journal = {Development and psychopathology},
volume = {25},
number = {3},
pages = {577-585},
pmid = {23527512},
issn = {1469-2198},
support = {P20 GM103653/GM/NIGMS NIH HHS/United States ; R01 MH052135/MH/NIMH NIH HHS/United States ; R01 MH074374/MH/NIMH NIH HHS/United States ; R01 MH084135/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Child ; Child, Preschool ; Female ; Humans ; *Life Change Events ; Longitudinal Studies ; Male ; Parenting/*psychology ; Parents/*psychology ; Stress, Psychological/*genetics/psychology ; *Telomere Shortening ; },
abstract = {Early-life stress, such as maltreatment, institutionalization, and exposure to violence, is associated with accelerated telomere shortening. Telomere shortening may thus represent a biomarker of early adversity. Previous studies have suggested that responsive parenting may protect children from the negative biological and behavioral consequences of early adversity. This study examined the role of parental responsiveness in buffering children from telomere shortening following experiences of early-life stress. We found that high-risk children had significantly shorter telomeres than low-risk children, controlling for household income, birth weight, gender, and minority status. Further, parental responsiveness moderated the association between risk and telomere length, with more responsive parenting associated with longer telomeres only among high-risk children. These findings suggest that responsive parenting may have protective benefits on telomere shortening for young children exposed to early-life stress. Therefore, this study has important implications for early parenting interventions.},
}
@article {pmid23526226,
year = {2013},
author = {Liu, T and Ullenbruch, M and Young Choi, Y and Yu, H and Ding, L and Xaubet, A and Pereda, J and Feghali-Bostwick, CA and Bitterman, PB and Henke, CA and Pardo, A and Selman, M and Phan, SH},
title = {Telomerase and telomere length in pulmonary fibrosis.},
journal = {American journal of respiratory cell and molecular biology},
volume = {49},
number = {2},
pages = {260-268},
pmid = {23526226},
issn = {1535-4989},
support = {R37 HL028737/HL/NHLBI NIH HHS/United States ; HL077297/HL/NHLBI NIH HHS/United States ; R01 HL074882/HL/NHLBI NIH HHS/United States ; AR05084/AR/NIAMS NIH HHS/United States ; HL052285/HL/NHLBI NIH HHS/United States ; R01 HL052285/HL/NHLBI NIH HHS/United States ; R01 HL077297/HL/NHLBI NIH HHS/United States ; P01 HL091775/HL/NHLBI NIH HHS/United States ; R01 HL028737/HL/NHLBI NIH HHS/United States ; HL028737/HL/NHLBI NIH HHS/United States ; HL091775/HL/NHLBI NIH HHS/United States ; HL074882/HL/NHLBI NIH HHS/United States ; R01 HL089249/HL/NHLBI NIH HHS/United States ; R01 HL112880/HL/NHLBI NIH HHS/United States ; },
mesh = {Acetylation/drug effects ; Alveolitis, Extrinsic Allergic/chemically induced/genetics/metabolism/pathology ; Animals ; Antibiotics, Antineoplastic/adverse effects/pharmacology ; Bleomycin/adverse effects/pharmacology ; Cells, Cultured ; Chronic Disease ; Female ; Fibroblasts/*metabolism/pathology ; Gene Expression Regulation, Enzymologic/drug effects/genetics ; Histones/genetics/metabolism ; Humans ; Idiopathic Pulmonary Fibrosis/chemically induced/genetics/*metabolism/pathology ; Lung/*metabolism/pathology ; Male ; Mice ; Mice, Knockout ; Promoter Regions, Genetic ; Telomerase/*biosynthesis/genetics ; Telomere/genetics/*metabolism/pathology ; Up-Regulation/drug effects/genetics ; },
abstract = {In addition to its expression in stem cells and many cancers, telomerase activity is transiently induced in murine bleomycin (BLM)-induced pulmonary fibrosis with increased levels of telomerase transcriptase (TERT) expression, which is essential for fibrosis. To extend these observations to human chronic fibrotic lung disease, we investigated the expression of telomerase activity in lung fibroblasts from patients with interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF). The results showed that telomerase activity was induced in more than 66% of IPF lung fibroblast samples, in comparison with less than 29% from control samples, some of which were obtained from lung cancer resections. Less than 4% of the human IPF lung fibroblast samples exhibited shortened telomeres, whereas less than 6% of peripheral blood leukocyte samples from patients with IPF or hypersensitivity pneumonitis demonstrated shortened telomeres. Moreover, shortened telomeres in late-generation telomerase RNA component knockout mice did not exert a significant effect on BLM-induced pulmonary fibrosis. In contrast, TERT knockout mice exhibited deficient fibrosis that was independent of telomere length. Finally, TERT expression was up-regulated by a histone deacetylase inhibitor, while the induction of TERT in lung fibroblasts was associated with the binding of acetylated histone H3K9 to the TERT promoter region. These findings indicate that significant telomerase induction was evident in fibroblasts from fibrotic murine lungs and a majority of IPF lung samples, whereas telomere shortening was not a common finding in the human blood and lung fibroblast samples. Notably, the animal studies indicated that the pathogenesis of pulmonary fibrosis was independent of telomere length.},
}
@article {pmid23523330,
year = {2013},
author = {Anic, GM and Sondak, VK and Messina, JL and Fenske, NA and Zager, JS and Cherpelis, BS and Lee, JH and Fulp, WJ and Epling-Burnette, PK and Park, JY and Rollison, DE},
title = {Telomere length and risk of melanoma, squamous cell carcinoma, and basal cell carcinoma.},
journal = {Cancer epidemiology},
volume = {37},
number = {4},
pages = {434-439},
pmid = {23523330},
issn = {1877-783X},
support = {P30 CA076292/CA/NCI NIH HHS/United States ; R25 CA147832/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Basal Cell/epidemiology/*pathology ; Carcinoma, Squamous Cell/epidemiology/*pathology ; Case-Control Studies ; Female ; Florida/epidemiology ; Humans ; Male ; Melanoma/epidemiology/*pathology ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Risk ; Skin Neoplasms/epidemiology/*pathology ; Telomere/*chemistry ; Young Adult ; },
abstract = {BACKGROUND: Telomeres help maintain chromosomal structure and may influence tumorigenesis. We examined the association between telomere length and skin cancer in a clinic-based case-control study of 198 melanoma cases, 136 squamous cell carcinoma (SCC) cases, 185 basal cell carcinoma (BCC) cases, and 372 healthy controls.<br><br>METHODS: Cases were histologically confirmed patients treated at the Moffitt Cancer Center and University of South Florida Dermatology Clinic in Tampa, FL. Controls self-reported no history of cancer and underwent a skin cancer screening exam at study enrollment to rule out the presence of skin cancer. Quantitative real time PCR was used to measure telomere length in peripheral blood samples.<br><br>RESULTS: Melanoma patients had longer telomeres than controls (odds ratio (OR)=3.75; 95% confidence interval (CI): 2.02-6.94 for highest versus lowest tertile) (P for trend=<0.0001). In contrast, longer telomere length was significantly inversely associated with SCC (OR=0.01; 95% CI: 0.00-0.05 for highest versus lowest tertile) (P for trend=<0.0001) and BCC (OR=0.10; 95% CI: 0.06-0.19 for highest versus lowest tertile) (P for trend=<0.0001).<br><br>CONCLUSION: Telomere length may be involved in the development of skin cancer, although the effect on cancer risk differs for melanoma and non-melanoma carcinomas. Our findings suggest that long telomere length is positively associated with melanoma while inversely associated with SCC and BCC.},
}
@article {pmid23521792,
year = {2013},
author = {Takahama, K and Takada, A and Tada, S and Shimizu, M and Sayama, K and Kurokawa, R and Oyoshi, T},
title = {Regulation of telomere length by G-quadruplex telomere DNA- and TERRA-binding protein TLS/FUS.},
journal = {Chemistry &amp; biology},
volume = {20},
number = {3},
pages = {341-350},
doi = {10.1016/j.chembiol.2013.02.013},
pmid = {23521792},
issn = {1879-1301},
mesh = {Amino Acid Sequence ; DNA/chemistry/*metabolism ; *G-Quadruplexes ; HeLa Cells ; Histones/metabolism ; Humans ; Methylation ; Molecular Sequence Data ; Protein Structure, Tertiary ; RNA/*genetics/*metabolism ; RNA-Binding Protein FUS/chemistry/*metabolism ; *Repetitive Sequences, Nucleic Acid ; Telomere/*genetics ; Telomere Shortening ; },
abstract = {Mammalian telomeres comprise noncoding TTAGGG repeats in double-stranded regions with a single-stranded TTAGGG repeat 3' overhang and are bound by a multiprotein complex with a telomeric repeat-containing RNA (TERRA) containing a UUAGGG repeat as a G-quadruplex noncoding RNA. TLS/FUS is a human telomere-binding protein that was first identified as an oncogenic fusion protein in human myxoid and round-cell liposarcoma. Here, we show that the Arg-Gly-Gly domain in the C-terminal region of TLS forms a ternary complex with human telomere G-quadruplex DNA and TERRA in vitro. Furthermore, TLS binds to G-quadruplex telomere DNA in double-stranded regions and to G-quadruplex TERRA, which regulates histone modifications of telomeres and telomere length in vivo. Our findings suggest that the G-quadruplex functions as a scaffold for the telomere-binding protein, TLS, to regulate telomere length by histone modifications.},
}
@article {pmid23521760,
year = {2013},
author = {Yasaei, H and Gozaly-Chianea, Y and Slijepcevic, P},
title = {Analysis of telomere length and function in radiosensitive mouse and human cells in response to DNA-PKcs inhibition.},
journal = {Genome integrity},
volume = {4},
number = {1},
pages = {2},
pmid = {23521760},
issn = {2041-9414},
abstract = {BACKGROUND: Telomeres, the physical ends of chromosomes, play an important role in preserving genomic integrity. This protection is supported by telomere binding proteins collectively known as the shelterin complex. The shelterin complex protects chromosome ends by suppressing DNA damage response and acting as a regulator of telomere length maintenance by telomerase, an enzyme that elongates telomeres. Telomere dysfunction manifests in different forms including chromosomal end-to-end fusion, telomere shortening and p53-dependent apoptosis and/or senescence. An important shelterin-associated protein with critical role in telomere protection in human and mouse cells is the catalytic subunit of DNA-protein kinase (DNA-PKcs). DNA-PKcs deficiency in mouse cells results in elevated levels of spontaneous telomeric fusion, a marker of telomere dysfunction, but does not cause telomere length shortening. Similarly, inhibition of DNA-PKcs with chemical inhibitor, IC86621, prevents chromosomal end protection through mechanism reminiscent of dominant-negative reduction in DNA-PKcs activity.<br><br>RESULTS: We demonstrate here that the IC86621 mediated inhibition of DNA-PKcs in two mouse lymphoma cell lines results not only in elevated frequencies of chromosome end-to-end fusions, but also accelerated telomere shortening in the presence of telomerase. Furthermore, we observed increased levels of spontaneous telomeric fusions in Artemis defective human primary fibroblasts in which DNA-PKcs was inhibited, but no significant changes in telomere length.<br><br>CONCLUSION: These results confirm that DNA-PKcs plays an active role in chromosome end protection in mouse and human cells. Furthermore, it appears that DNA-PKcs is also involved in telomere length regulation, independently of telomerase activity, in mouse lymphoma cells but not in human cells.},
}
@article {pmid23521613,
year = {2013},
author = {Schürks, M and Prescott, J and Dushkes, R and De Vivo, I and Rexrode, KM},
title = {Telomere length and ischaemic stroke in women: a nested case-control study.},
journal = {European journal of neurology},
volume = {20},
number = {7},
pages = {1068-1074},
pmid = {23521613},
issn = {1468-1331},
support = {HL-34594/HL/NHLBI NIH HHS/United States ; R01 HL034594/HL/NHLBI NIH HHS/United States ; R01 HL088521/HL/NHLBI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; U01 CA049449/CA/NCI NIH HHS/United States ; CA-49449/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; HL-088521/HL/NHLBI NIH HHS/United States ; CA-87969/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Brain Ischemia/complications/*genetics ; Case-Control Studies ; Female ; Humans ; Middle Aged ; Stroke/complications/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND AND PURPOSE: Telomere shortening has been implicated in cardiovascular disease (CVD). However, prospective data on the association between relative telomere length (RTL) and ischaemic stroke are scarce and inconclusive.<br><br>METHODS: We used a nested case-control design among women participating in the prospective Nurses' Health Study. Participants provided blood samples in 1990 and were followed till 2006. Women with confirmed incident ischaemic stroke were matched to controls by age, smoking, postmenopausal status and postmenopausal hormone use. Quantitative polymerase chain reaction was used to determine RTL in genomic DNA extracted from peripheral blood leukocytes. Conditional logistic regression was used to determine the risk of ischaemic stroke associated with RTL, using RTL quartiles and as dichotomous according to the median.<br><br>RESULTS: Data on RTL were available from 504 case-control pairs. Results did not suggest an association between RTL and ischaemic stroke. The odds ratio (OR) for ischaemic stroke was 0.82 [95% confidence interval (CI) 0.52-1.32] comparing lowest with the highest RTL quartile and 0.90 (95% CI 0.65-1.24) comparing RTL below the median with RTL above the median. Associations were unchanged after additional adjustment for cardiovascular risk factors. Further analyses suggested an association between RTL and fatal ischaemic stroke (54 case-control pairs; lowest versus highest quartile OR&#x2005;=&#x2005;1.99, 95%CI 0.26-14.9); however, results were statistically insignificant.<br><br>CONCLUSION: In this large nested case-control study among women RTL was not associated with ischaemic stroke. In light of the varying study results in the literature on the association between telomere length and stroke, additional research is warranted.},
}
@article {pmid23519615,
year = {2013},
author = {Novo, C and Arnoult, N and Bordes, WY and Castro-Vega, L and Gibaud, A and Dutrillaux, B and Bacchetti, S and Londoño-Vallejo, A},
title = {The heterochromatic chromosome caps in great apes impact telomere metabolism.},
journal = {Nucleic acids research},
volume = {41},
number = {9},
pages = {4792-4801},
pmid = {23519615},
issn = {1362-4962},
mesh = {Animals ; Cell Line ; Gorilla gorilla/*genetics ; Heterochromatin/*chemistry ; Hominidae ; Mitosis/genetics ; Pan troglodytes/*genetics ; RNA/metabolism ; Repetitive Sequences, Nucleic Acid ; Telomere/chemistry/*metabolism ; Transcription, Genetic ; },
abstract = {In contrast with the limited sequence divergence accumulated after separation of higher primate lineages, marked cytogenetic variation has been associated with the genome evolution in these species. Studying the impact of such structural variations on defined molecular processes can provide valuable insights on how genome structural organization contributes to organismal evolution. Here, we show that telomeres on chromosome arms carrying subtelomeric heterochromatic caps in the chimpanzee, which are completely absent in humans, replicate later than telomeres on chromosome arms without caps. In gorilla, on the other hand, a proportion of the subtelomeric heterochromatic caps present in most chromosome arms are associated with large blocks of telomere-like sequences that follow a replication program different from that of bona fide telomeres. Strikingly, telomere-containing RNA accumulates extrachromosomally in gorilla mitotic cells, suggesting that at least some aspects of telomere-containing RNA biogenesis have diverged in gorilla, perhaps in concert with the evolution of heterochromatic caps in this species.},
}
@article {pmid23519357,
year = {2013},
author = {Turner, S and Hartshorne, GM},
title = {Telomere lengths in human pronuclei, oocytes and spermatozoa.},
journal = {Molecular human reproduction},
volume = {19},
number = {8},
pages = {510-518},
doi = {10.1093/molehr/gat021},
pmid = {23519357},
issn = {1460-2407},
mesh = {Adult ; DNA Fragmentation ; Female ; Fertility Agents, Female ; Fertility Agents, Male ; Humans ; Male ; Middle Aged ; Oocytes/*cytology ; Spermatozoa/*cytology ; Telomere/*genetics/*physiology ; *Telomere Homeostasis ; Young Adult ; },
abstract = {Telomeres are chromosome ends that control functions related to cell division. Short telomeres are proposed to underlie infertility, female reproductive ageing and abnormal embryogenesis, but there is little direct evidence on telomere length in gametes and embryos. The aim of this study was to measure telomere lengths in individual human oocytes, spermatozoa, male and female pronuclei, in order to compare parental contributions to telomere lengths in the human zygote. Quantitative fluorescence in situ hybridization was used to measure average telomere length in pronuclei of oocytes fertilized for research using a known fertile sperm sample. Pronuclei derived from male and female gametes were distinguished by 5-methylcytosine staining. Results were compared with those for unfertilized mature and immature oocytes and individual spermatozoa decondensed in vitro. Fifty unselected men and one sperm donor provided semen samples and 32 women donated oocytes surplus to IVF treatment. Telomeres in mature oocytes and female pronuclei were significantly longer than those in individual spermatozoa and male pronuclei (P < 0.0001). Telomeres were longer in immature oocytes than in mature oocytes (P < 0.04). Sperm telomere length increased with male age (P < 0.05). Neither sperm nor oocyte telomere lengths were significantly associated with clinical parameters or outcome of treatment. In conclusion, telomere length measurements directly comparing human pronuclei under identical conditions show that male-derived telomeres are shorter on average than female-derived telomeres at fertilization. We propose that from this starting point, telomere lengths are probably modified by recombination events in the oocyte until telomerase increases at the blastocyst stage. Our findings do not support the use of gamete telomere lengths as a fertility diagnostic tool.},
}
@article {pmid23519133,
year = {2013},
author = {Ma, SL and Lau, ES and Suen, EW and Lam, LC and Leung, PC and Woo, J and Tang, NL},
title = {Telomere length and cognitive function in southern Chinese community-dwelling male elders.},
journal = {Age and ageing},
volume = {42},
number = {4},
pages = {450-455},
doi = {10.1093/ageing/aft036},
pmid = {23519133},
issn = {1468-2834},
mesh = {Age Factors ; Aged ; Aged, 80 and over ; Aging/*genetics/*psychology ; *Cognition ; Hong Kong ; Humans ; *Independent Living ; Linear Models ; Male ; Mental Recall ; Psychiatric Status Rating Scales ; Real-Time Polymerase Chain Reaction ; Sex Factors ; Telomere/*metabolism ; *Telomere Shortening ; Verbal Behavior ; },
abstract = {BACKGROUND: telomere attrition has been associated with an increased risk of different age-related diseases and is widely accepted as a marker of cellular ageing. On the other hand, it is well known that cognitive function declines with age. The telomere length may therefore act as a marker for the pathway associated with cognitive function.<br><br>METHODS: we examined telomere length and cognitive functions in a community-dwelling Chinese male population aged 65 years and above living in Hong Kong. The telomere length was measured by quantitative real-time PCR in 976 men. Cognitive function was assessed by Chinese (Cantonese) version of Mini-Mental State Exam and Community Screening Interview for Dementia.<br><br>RESULTS: our result showed there was a significant association between telomere length, delayed recall (P = 0.007) and category verbal fluency (P = 0.048). These associations remained significant after adjustment for age and education. Further analysis using a cut-off score for MMSE, three-item recall and word list generation tests suggested that the telomere length was positively correlated with performance in these areas (P = 0.015).<br><br>CONCLUSION: the findings support the association of telomere length and cognitive function and suggested that the telomere length may serve as a biological marker for cognitive decline.},
}
@article {pmid23514618,
year = {2013},
author = {Micco, M and Collie, GW and Dale, AG and Ohnmacht, SA and Pazitna, I and Gunaratnam, M and Reszka, AP and Neidle, S},
title = {Structure-based design and evaluation of naphthalene diimide G-quadruplex ligands as telomere targeting agents in pancreatic cancer cells.},
journal = {Journal of medicinal chemistry},
volume = {56},
number = {7},
pages = {2959-2974},
doi = {10.1021/jm301899y},
pmid = {23514618},
issn = {1520-4804},
support = {C129/A4489//Cancer Research UK/United Kingdom ; },
mesh = {Antineoplastic Agents/pharmacology/*therapeutic use ; Cell Line, Tumor ; *Drug Design ; Drug Evaluation, Preclinical ; Drug Screening Assays, Antitumor ; *G-Quadruplexes ; Humans ; Imides/pharmacology/*therapeutic use ; Ligands ; Models, Molecular ; Naphthalenes/pharmacology/*therapeutic use ; Pancreatic Neoplasms/*drug therapy/genetics/pathology ; Telomere/*drug effects ; },
abstract = {Tetra-substituted naphthalene diimide (ND) derivatives with positively charged termini are potent stabilizers of human telomeric and gene promoter DNA quadruplexes and inhibit the growth of human cancer cells in vitro and in vivo. The present study reports the enhancement of the pharmacological properties of earlier ND compounds using structure-based design. Crystal structures of three complexes with human telomeric intramolecular quadruplexes demonstrate that two of the four strongly basic N-methyl-piperazine groups can be replaced by less basic morpholine groups with no loss of intermolecular interactions in the grooves of the quadruplex. The new compounds retain high affinity to human telomeric quadruplex DNA but are 10-fold more potent against the MIA PaCa-2 pancreatic cancer cell line, with IC50 values of ~10 nM. The lead compound induces cellular senescence but does not inhibit telomerase activity at the nanomolar dosage levels required for inhibition of cellular proliferation. Gene array qPCR analysis of MIA PaCa-2 cells treated with the lead compound revealed significant dose-dependent modulation of a distinct subset of genes, including strong induction of DNA damage responsive genes CDKN1A, DDIT3, GADD45A/G, and PPM1D, and repression of genes involved in telomere maintenance, including hPOT1 and PARP1.},
}
@article {pmid23513237,
year = {2013},
author = {Phillips, AC and Robertson, T and Carroll, D and Der, G and Shiels, PG and McGlynn, L and Benzeval, M},
title = {Do symptoms of depression predict telomere length? Evidence from the west of Scotland twenty-07 study.},
journal = {Psychosomatic medicine},
volume = {75},
number = {3},
pages = {288-296},
doi = {10.1097/PSY.0b013e318289e6b5},
pmid = {23513237},
issn = {1534-7796},
support = {MC_UU_12017/7/MRC_/Medical Research Council/United Kingdom ; MC_UP_A540_1021/MRC_/Medical Research Council/United Kingdom ; MC_U130059823/MRC_/Medical Research Council/United Kingdom ; MR/K00414X/1/MRC_/Medical Research Council/United Kingdom ; SPHSU2/CSO_/Chief Scientist Office/United Kingdom ; },
mesh = {Adult ; Aged ; Aging/psychology ; Cohort Studies ; Depression/*psychology ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Psychiatric Status Rating Scales/statistics &amp; numerical data ; Risk Factors ; Scotland ; *Telomere ; *Telomere Shortening ; },
abstract = {OBJECTIVE: Psychological factors such as the stress of caregiving are emerging as predictors of telomere length, an index of biological aging. However, although lifetime major depressive disorder is associated with shorter telomeres, less is known about depressive symptoms. Depression and depressive symptoms are associated with a range of morbidities and mortality, but the extent to which they predict biological aging is unclear. The present study examined participants in the West of Scotland Twenty-07 Study across three age cohorts and four waves of data collection from 1992/1993 to 2007/2008.<br><br>METHODS: Participants were 37, 57, and 76 years old at final data collection. Depressive symptoms were measured using the Hospital Anxiety and Depression Scale at each time point. Telomere length was assessed from 1063 blood samples collected at the final wave in 2007/2008 for respondents who also had depression data.<br><br>RESULTS: Average depression symptoms (&#x3b2;= -.12, p = .047) and their change over time (&#x3b2; = -.12, p = .031) were negatively associated with telomere length, but only in the youngest cohort. Depressive symptoms were not cross sectionally associated with telomere length in 2007 to 2008 (&#x3b2;= -.03, p = .45). In the youngest cohort only, depressive symptoms assessed in 1995 to 1997 and 2000 to 2004 were associated with shorter telomere length (&#x3b2; = .14 [p = .046] and &#x3b2; = .18 [p = .012], respectively), but not 1992 to 1993 or 2007 to 2008; associations in the middle- and older-aged cohorts were nonsignificant.<br><br>CONCLUSIONS: Depressive symptoms are longitudinally associated with shorter telomere length, but only in younger adults.},
}
@article {pmid23513041,
year = {2013},
author = {Hofmann, JN and Lan, Q and Cawthon, R and Hosgood, HD and Shuch, B and Moore, LE and Rothman, N and Chow, WH and Purdue, MP},
title = {A prospective study of leukocyte telomere length and risk of renal cell carcinoma.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {22},
number = {5},
pages = {997-1000},
pmid = {23513041},
issn = {1538-7755},
support = {ZIA CP010152-13/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adult ; Aged ; Carcinoma, Renal Cell/blood/*genetics/*ultrastructure ; Case-Control Studies ; Female ; Humans ; Kidney Neoplasms/blood/*genetics/*ultrastructure ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Prospective Studies ; Risk Factors ; Telomere/pathology/*ultrastructure ; },
abstract = {BACKGROUND: It has been hypothesized that genomic instability related to telomere dysfunction may contribute to carcinogenesis. There is some evidence from case-control studies suggesting that short leukocyte telomere length may be associated with an increased risk of renal cell carcinoma (RCC); however, this association has not been investigated prospectively.<br><br>METHODS: We conducted a nested case-control study (209 cases, 410 controls) of RCC risk in relation to prediagnostic leukocyte telomere length in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. ORs and 95% confidence intervals (CI) were estimated using conditional logistic regression.<br><br>RESULTS: Leukocyte telomere length was not significantly associated with future risk of RCC (highest quartile vs. lowest: OR, 0.8; 95% CI, 0.5-1.5; Ptrend = 0.6). Analyses stratified by sex, age, and time from blood collection to RCC diagnosis were similarly null.<br><br>CONCLUSIONS: The results of this study, to our knowledge the first prospective investigation of its kind, do not support an association between prediagnostic leukocyte telomere length and risk of RCC.<br><br>IMPACT: In contrast to some earlier reports, our findings add to the evidence that leukocyte telomere length is not a biomarker of risk related to the etiology of RCC.},
}
@article {pmid23512844,
year = {2013},
author = {Mainous, AG and Wright, RU and Hulihan, MM and Twal, WO and McLaren, CE and Diaz, VA and McLaren, GD and Argraves, WS and Grant, AM},
title = {Telomere length and elevated iron: the influence of phenotype and HFE genotype.},
journal = {American journal of hematology},
volume = {88},
number = {6},
pages = {492-496},
pmid = {23512844},
issn = {1096-8652},
support = {1U01DD000754/DD/NCBDD CDC HHS/United States ; P20 RR016434/RR/NCRR NIH HHS/United States ; P20 RR016461/RR/NCRR NIH HHS/United States ; P30 CA062203/CA/NCI NIH HHS/United States ; U01 DD000754/DD/NCBDD CDC HHS/United States ; P20 RR16461/RR/NCRR NIH HHS/United States ; },
mesh = {Adult ; Female ; Genotype ; Hemochromatosis/blood/*genetics ; Hemochromatosis Protein ; Histocompatibility Antigens Class I/*genetics/metabolism ; Humans ; Iron/blood/*metabolism ; Iron Overload/genetics/metabolism ; Male ; Membrane Proteins/*genetics/metabolism ; Mutation ; Phenotype ; Telomere/chemistry/metabolism/*ultrastructure ; },
abstract = {Elevated body iron stores are associated with morbidity and mortality due to oxidative stress. Hereditary hemochromatosis, a common condition caused by HFE gene mutations, can lead to excess iron storage and disease but clinical penetrance of HFE gene mutations is low and many people with elevated iron stores lack HFE mutations. We analyzed data from the Hemochromatosis and Iron Overload Screening Study to assess the relationship among HFE genotype (individuals with either homozygous or compound heterozygous status for C282Y and/or H63D HFE mutations were defined as genotype positive, or G+), elevated iron phenotype (individuals exceeding gender-specific transferrin saturation and serum ferritin threshold levels were considered phenotype positive, or P+), and leukocyte telomere length, a marker of biological aging and cumulative oxidative stress. In unadjusted analyses in comparison to individuals who were G-P-, G+P- were not significantly different (OR 0.74; 95% CI 0.26-2.04), while the G+P+ (OR 2.03; 95% CI 1.15-3.56), and G-P+ (OR 2.24; 95% CI 1.5-3.29) had increased risk of short telomeres (<=25th percentile) rather than long telomeres (>=75th percentile). In analyses adjusting for age, gender, and race/ethnicity, the effect of individuals with elevated iron phenotypes having short telomeres persisted with G+P+ individuals (OR 1.94; 95% CI 1.02-3.72), and G-P+ individuals (OR 2.17; 95% CI 1.39-3.39) being significantly different from the G-P- group. In conclusion, elevated iron phenotype, but not HFE genotype, was associated with shortened telomeres. Further studies will be needed to determine whether telomere length provides a marker for morbidities specifically associated with iron overload.},
}
@article {pmid23511462,
year = {2013},
author = {Daniali, L and Benetos, A and Susser, E and Kark, JD and Labat, C and Kimura, M and Desai, K and Granick, M and Aviv, A},
title = {Telomeres shorten at equivalent rates in somatic tissues of adults.},
journal = {Nature communications},
volume = {4},
number = {},
pages = {1597},
pmid = {23511462},
issn = {2041-1723},
support = {AG030678/AG/NIA NIH HHS/United States ; R01 AG030678/AG/NIA NIH HHS/United States ; R01 MH059114/MH/NIMH NIH HHS/United States ; AG16592/AG/NIA NIH HHS/United States ; HD071180/HD/NICHD NIH HHS/United States ; R01 AG016592/AG/NIA NIH HHS/United States ; MH059114/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aging/*genetics ; Female ; Humans ; Male ; Middle Aged ; *Telomere ; },
abstract = {Telomere shortening in somatic tissues largely reflects stem cell replication. Previous human studies of telomere attrition were predominantly conducted on leukocytes. However, findings in leukocytes cannot be generalized to other tissues. Here we measure telomere length in leukocytes, skeletal muscle, skin and subcutaneous fat of 87 adults (aged 19-77 years). Telomeres are longest in muscle and shortest in leukocytes, yet are strongly correlated between tissues. Notably, the rates of telomere shortening are similar in the four tissues. We infer from these findings that differences in telomere length between proliferative (blood and skin) and minimally proliferative tissues (muscle and fat) are established during early life, and that in adulthood, stem cells of the four tissues replicate at a similar rate.},
}
@article {pmid23510865,
year = {2014},
author = {Izumiyama-Shimomura, N and Nakamura, K and Aida, J and Ishikawa, N and Kuroiwa, M and Hiraishi, N and Fujiwara, M and Ishikawa, Y and Inoshita, N and Yonese, J and Matsuura, M and Poon, SS and Arai, T and Takubo, K},
title = {Short telomeres and chromosome instability prior to histologic malignant progression and cytogenetic aneuploidy in papillary urothelial neoplasms.},
journal = {Urologic oncology},
volume = {32},
number = {2},
pages = {135-145},
doi = {10.1016/j.urolonc.2012.12.005},
pmid = {23510865},
issn = {1873-2496},
mesh = {Aged ; Aged, 80 and over ; Anaphase/genetics ; *Aneuploidy ; Carcinoma, Papillary/*genetics/pathology ; Carcinoma, Transitional Cell/*genetics/pathology ; Cell Transformation, Neoplastic/genetics ; *Chromosomal Instability ; Cytogenetic Analysis ; Disease Progression ; Humans ; In Situ Hybridization, Fluorescence ; Karyotype ; Middle Aged ; Spectral Karyotyping ; Telomere ; *Telomere Shortening ; Urologic Neoplasms/*genetics/pathology ; },
abstract = {PURPOSE: Evaluation of the relationships existing among 3 histologic types of urothelial tumors, chromosomal instability, and telomere length.<br><br>PATIENTS AND METHODS: We examined 37 consecutive cases of papillary urothelial neoplasm, from which 26 (70.3%) were suitable for karyotype analysis, comprising 7 papillary urothelial neoplasms of low malignant potential (PUNLMPs), 10 low-grade papillary urothelial carcinomas (PUCs), and 9 high-grade PUCs. We performed karyotype and anaphase bridge analyses, and measured telomere lengths by quantitative fluorescence in situ hybridization.<br><br>RESULTS: PUNLMPs were always diploid and had anaphase bridges. Low-grade PUCs showed diploidy (n = 2), hypoploidy (n = 4) and polyploidy (n = 4), and high-grade PUCs showed diploidy (n = 1) and polyploidy (n = 8); both had anaphase bridges. The incidence of anaphase bridges did not differ significantly between PUNLMPs and high-grade PUCs (P = 0.105). The telomere lengths of PUNLMP, low-grade PUC, and high-grade PUC, expressed as mean telomere fluorescence units (TFU) &#xb1; SD, were 7906 &#xb1; 3197, 4893 &#xb1; 1567, and 3299 &#xb1; 1406, respectively. The differences among the 3 groups were significant. However, 42.9% of the PUNLMPs had shorter telomeres than the mean value for low-grade PUCs, and 30.0% of the low-grade PUCs had shorter telomeres than those for high-grade PUCs. There was an inverse correlation between telomere length and the incidence of anaphase bridges.<br><br>CONCLUSIONS: PUNLMP appears to progress to low-grade PUC and high-grade PUC in association with telomere shortening and chromosomal instability. Our data suggest that critically shortened telomeres cause chromosomal instability during progression of papillary urothelial neoplasms.},
}
@article {pmid23509004,
year = {2013},
author = {Giraud-Panis, MJ and Pisano, S and Benarroch-Popivker, D and Pei, B and Le Du, MH and Gilson, E},
title = {One identity or more for telomeres?.},
journal = {Frontiers in oncology},
volume = {3},
number = {},
pages = {48},
pmid = {23509004},
issn = {2234-943X},
abstract = {A major issue in telomere research is to understand how the integrity of chromosome ends is controlled. The fact that different types of nucleoprotein complexes have been described at the telomeres of different organisms raises the question of whether they have in common a structural identity that explains their role in chromosome protection. We will review here how telomeric nucleoprotein complexes are structured, comparing different organisms and trying to link these structures to telomere biology. It emerges that telomeres are formed by a complex and specific network of interactions between DNA, RNA, and proteins. The fact that these interactions and associated activities are reinforcing each other might help to guarantee the robustness of telomeric functions across the cell cycle and in the event of cellular perturbations. We will also discuss the recent notion that telomeres have evolved specific systems to overcome the DNA topological stress generated during their replication and transcription. This will lead to revisit the way we envisage the functioning of telomeric complexes since the regulation of topology is central to DNA stability, replication, recombination, and transcription as well as to chromosome higher-order organization.},
}
@article {pmid23507978,
year = {2013},
author = {Bauer, K and Tao, S and Rudolph, KL},
title = {Telomere stability--Wnt it or lose it.},
journal = {EMBO reports},
volume = {14},
number = {4},
pages = {297-298},
pmid = {23507978},
issn = {1469-3178},
mesh = {Animals ; Female ; *Gene Expression Regulation ; Humans ; Male ; *Telomere Homeostasis ; Telomeric Repeat Binding Protein 2/*metabolism ; *Wnt Signaling Pathway ; },
}
@article {pmid23504035,
year = {2013},
author = {Ribeyre, C and Shore, D},
title = {Regulation of telomere addition at DNA double-strand breaks.},
journal = {Chromosoma},
volume = {122},
number = {3},
pages = {159-173},
pmid = {23504035},
issn = {1432-0886},
mesh = {Animals ; *DNA Breaks, Double-Stranded ; DNA Damage ; *Gene Expression Regulation ; Humans ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres constitute the ends of linear eukaryotic chromosomes. Due to the conventional mode of DNA replication, telomeric DNA erodes at each cell division. To counteract this, a specialized reverse transcriptase, telomerase, can elongate chromosome ends to maintain them at a constant average length. Because of their similarity to DNA double-strand breaks (DSBs), telomeres might be expected to induce a DNA damage response, which would lead to repair reactions and the generation of translocations or fusions. Many proteins present at telomeres prevent this by protecting (capping) the chromosome termini. Conversely, a DSB occurring in other regions of the genome, due, for instance, to a stalled replication fork or genotoxic agents, must be repaired by homologous recombination or end-joining to ensure genome stability. Interestingly, telomerase is able to generate a telomere de novo at an accidental DSB, with potentially lethal consequences in haploid cells and, at a minimum, loss of heterozygosity (LOH) in diploid cells. Recent data suggest that telomerase is systematically recruited to DSBs but is prevented from acting in the absence of a minimal stretch of flanking telomere-repeat sequences. In this review, we will focus on the mechanisms that regulate telomere addition to DSBs.},
}
@article {pmid23502782,
year = {2013},
author = {Ramsay, AJ and Quesada, V and Foronda, M and Conde, L and Martínez-Trillos, A and Villamor, N and Rodríguez, D and Kwarciak, A and Garabaya, C and Gallardo, M and López-Guerra, M and López-Guillermo, A and Puente, XS and Blasco, MA and Campo, E and López-Otín, C},
title = {POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia.},
journal = {Nature genetics},
volume = {45},
number = {5},
pages = {526-530},
pmid = {23502782},
issn = {1546-1718},
mesh = {Amino Acid Sequence ; Chromosome Aberrations ; Exome/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics ; Molecular Sequence Data ; Mutation/*genetics ; Oligonucleotides/metabolism ; Oligosaccharides/metabolism ; Protein Binding ; Protein Conformation ; Sequence Homology, Amino Acid ; Shelterin Complex ; Telomere/*genetics ; Telomere-Binding Proteins/chemistry/*genetics/metabolism ; Tumor Cells, Cultured ; },
abstract = {Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults. We have analyzed exome sequencing data from 127 individuals with CLL and Sanger sequencing data from 214 additional affected individuals, identifying recurrent somatic mutations in POT1 (encoding protection of telomeres 1) in 3.5% of the cases, with the frequency reaching 9% when only individuals without IGHV@ mutations were considered. POT1 encodes a component of the shelterin complex and is the first member of this telomeric structure found to be mutated in human cancer. Somatic mutation of POT1 primarily occurs in gene regions encoding the two oligonucleotide-/oligosaccharide-binding (OB) folds and affects key residues required to bind telomeric DNA. POT1-mutated CLL cells have numerous telomeric and chromosomal abnormalities that suggest that POT1 mutations favor the acquisition of the malignant features of CLL cells. The identification of POT1 as a new frequently mutated gene in CLL may facilitate novel approaches for the clinical management of this disease.},
}
@article {pmid23484702,
year = {2013},
author = {Ye, F and He, YM and Li, GX and Wang, LN and Jia, N and Ma, RX and Ma, YP},
title = {[mRNA expression of telomere protection protein TIN2 and POT1 in bone marrow of patients with myelodysplastic syndrome].},
journal = {Zhongguo shi yan xue ye xue za zhi},
volume = {21},
number = {1},
pages = {110-115},
doi = {10.7534/j.issn.1009-2137.2013.01.023},
pmid = {23484702},
issn = {1009-2137},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Bone Marrow/*metabolism/pathology ; Case-Control Studies ; Cell Adhesion Molecules/genetics/*metabolism ; Female ; Humans ; Male ; Middle Aged ; Myelodysplastic Syndromes/genetics/*metabolism/pathology ; RNA, Messenger/genetics ; Shelterin Complex ; Telomere/metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Young Adult ; },
abstract = {This study was purposed to explore the relationship between the mRNA expression of telomere protection protein TIN2 and POT1 and the pathogenesis of myelodysplastic syndrome (MDS). The expression of TIN2 and POT1 genes at the mRNA levels were detected by real-time fluorescence quantitative PCR in 51 patients with MDS and 10 normal controls. The results showed that the mRNA expressions of TIN2 in RA/RARS/RCMD/MDS-U, RAEB-1 and RAEB-2 groups according to the World Health Organization criteria were significantly higher than that in the controls (P < 0.05); the mRNA expressions of POT1 in RA/RARS/RCMD/MDS-U, RAEB-1 and RAEB-2 groups were significantly lower than that in the controls (P < 0.05). The mRNA expressions of TIN2 in high-risk group, inter risk-2 group and inter risk-1 group according to the international prognostic scoring system criteria were significantly higher than that in controls (P < 0.05). There was no significant difference between low risk group and the control group. The mRNA expressions of POT1 in high risk group, inter-risk-2 group and inter-risk-1 group were significantly lower than the controls (P < 0.05). There was no significant difference between low risk group and the control group. The mRNA expression of TIN2 in normal chromosome group was significantly lower than that in abnormal chromosome group (P < 0.05). There was no significant difference between normal chromosome group and the control group. The mRNA expression of POT1 in normal chromosome group was significantly higher than that in abnormal chromosome group (P < 0.05). There was no significant difference between normal chromosome group and the control group. It is concluded that the abnormal mRNA expression of TIN2 and POT1 may be involved in the regulation of telomere dynamics of MDS patients, the regulatory mechanism may be related to the telomere length and the pathogenesis of MDS.},
}
@article {pmid23482750,
year = {2013},
author = {Jung, AR and Yoo, JE and Shim, YH and Choi, YN and Jeung, HC and Chung, HC and Rha, SY and Oh, BK},
title = {Increased alternative lengthening of telomere phenotypes of telomerase-negative immortal cells upon trichostatin--a treatment.},
journal = {Anticancer research},
volume = {33},
number = {3},
pages = {821-829},
pmid = {23482750},
issn = {1791-7530},
mesh = {Acetylation ; Cell Survival/drug effects ; Cells, Cultured ; Histone Deacetylase Inhibitors/*pharmacology ; Histones/metabolism ; Humans ; Hydroxamic Acids/*pharmacology ; Phenotype ; Sister Chromatid Exchange ; Telomerase/genetics/*physiology ; *Telomere Homeostasis ; },
abstract = {Human immortal cells maintain their telomeres either by telomerase or by alternative lengthening of telomeres (ALT) that is based on homologous telomeric recombination. Previous studies showed that the ALT mechanism is activated in non-ALT cells when heterochromatic features are reduced. In this study, we examined the ALT phenotypes of ALT cells after treatment with trichostatin-A (TSA), which is an inhibitor of histone deacetylases and causes global chromatin decondensation. The ALT cells remained telomerase-negative after TSA treatment. ALT-associated promyelocytic leukemia (PML) nuclear bodies and telomere sister chromatid exchanges, typical ALT phenotypes, markedly increased in the TSA-treated cells, while the telomere length remained unchanged. In addition, telomerase expression in the ALT cells suppressed TSA-mediated ALT phenotype enhancement. Our results show that certain ALT phenotypes become more pronounced when chromatin is decondensed, and also suggest that the ALT mechanism may compete with telomerase for telomere maintenance in cells that lack heterochromatin.},
}
@article {pmid23478302,
year = {2013},
author = {Sandhu, R and Sanford, S and Basu, S and Park, M and Pandya, UM and Li, B and Chakrabarti, K},
title = {A trans-spliced telomerase RNA dictates telomere synthesis in Trypanosoma brucei.},
journal = {Cell research},
volume = {23},
number = {4},
pages = {537-551},
pmid = {23478302},
issn = {1748-7838},
support = {R01 AI066095/AI/NIAID NIH HHS/United States ; },
mesh = {Base Sequence ; Genetic Complementation Test ; Molecular Sequence Data ; Mutation ; Phylogeny ; Protein Folding ; Protein Structure, Secondary ; Protozoan Proteins/chemistry/classification/*genetics/metabolism ; RNA/chemistry/classification/*genetics/metabolism ; RNA Splicing ; *RNA, Protozoan ; Telomerase/chemistry/classification/*genetics/metabolism ; Telomere/*genetics/metabolism ; Trypanosoma brucei brucei/enzymology/*genetics ; },
abstract = {Telomerase is a ribonucleoprotein enzyme typically required for sustained cell proliferation. Although both telomerase activity and the telomerase catalytic protein component, TbTERT, have been identified in the eukaryotic pathogen Trypanosoma brucei, the RNA molecule that dictates telomere synthesis remains unknown. Here, we identify the RNA component of Trypanosoma brucei telomerase, TbTR, and provide phylogenetic and in vivo evidence for TbTR's native folding and activity. We show that TbTR is processed through trans-splicing, and is a capped transcript that interacts and copurifies with TbTERT in vivo. Deletion of TbTR caused progressive shortening of telomeres at a rate of 3-5 bp/population doubling (PD), which can be rescued by ectopic expression of a wild-type allele of TbTR in an apparent dose-dependent manner. Remarkably, introduction of mutations in the TbTR template domain resulted in corresponding mutant telomere sequences, demonstrating that telomere synthesis in T. brucei is dependent on TbTR. We also propose a secondary structure model for TbTR based on phylogenetic analysis and chemical probing experiments, thus defining TbTR domains that may have important functional implications in telomere synthesis. Identification and characterization of TbTR not only provide important insights into T. brucei telomere functions, which have been shown to play important roles in T. brucei pathogenesis, but also offer T. brucei as an attractive model system for studying telomerase biology in pathogenic protozoa and for comparative analysis of telomerase function with higher eukaryotes.},
}
@article {pmid23478256,
year = {2013},
author = {Fyhrquist, F and Saijonmaa, O and Strandberg, T},
title = {The roles of senescence and telomere shortening in cardiovascular disease.},
journal = {Nature reviews. Cardiology},
volume = {10},
number = {5},
pages = {274-283},
pmid = {23478256},
issn = {1759-5010},
mesh = {Cardiovascular Diseases/*etiology/genetics/pathology/therapy ; *Cellular Senescence ; Genetic Predisposition to Disease ; Humans ; Male ; Phenotype ; Telomere/metabolism/*pathology ; *Telomere Shortening ; },
abstract = {Cellular senescence, defined as arrest during the cell cycle (G0), is involved in the complex process of the biological ageing of tissues, organs, and organisms. Senescence is driven by many factors including oxidative stress, the DNA damage and repair response, inflammation, mitogenic signals, and telomere shortening. Telomeres are shortened by each cell division until a critical length is reached and dysfunction ensues. DNA-repair pathways are then recruited and cells enter senescence, losing their capacity to proliferate. In addition to cell division, factors causing telomere shortening include DNA damage, inflammation, and oxidative stress. Both cardiovascular risk factors and common cardiovascular diseases, such as atherosclerosis, heart failure, and hypertension, are associated with short leucocyte telomeres, but causality remains undetermined. Telomere length does not satisfy strict criteria for being a biomarker of ageing, but adds predictive power to that of chronological age, and can be considered a marker of cardiovascular ageing. The 'senescence-associated secretory phenotype' of senescent cells exerts a wide range of autocrine and paracrine activities aimed at tissue repair, but which also fuel degenerative and proliferative alterations that contribute to cardiovascular disease. In this Review, the relationship between telomere shortening, senescence, and cardiovascular disease is discussed.},
}
@article {pmid23472184,
year = {2013},
author = {Malan-Müller, S and Hemmings, SM and Spies, G and Kidd, M and Fennema-Notestine, C and Seedat, S},
title = {Shorter telomere length - A potential susceptibility factor for HIV-associated neurocognitive impairments in South African women [corrected].},
journal = {PloS one},
volume = {8},
number = {3},
pages = {e58351},
pmid = {23472184},
issn = {1932-6203},
support = {P30 AI036214/AI/NIAID NIH HHS/United States ; P30 MH062512/MH/NIMH NIH HHS/United States ; 10316485//PHS HHS/United States ; },
mesh = {Adolescent ; Adult ; Analysis of Variance ; *Child Abuse ; Female ; HIV Infections/blood/*genetics ; Humans ; Learning ; Leukocytes, Mononuclear/metabolism ; Middle Aged ; Neuropsychological Tests ; South Africa ; Stress Disorders, Traumatic ; *Stress, Psychological/blood ; Telomere/*ultrastructure ; Young Adult ; },
abstract = {The neuropathogenesis of the human immunodeficiency virus (HIV) may manifest as various neurocognitive impairments (NCI). HIV-positive individuals also have significantly shorter telomere length (TL) in peripheral blood mononuclear cells (PBMCs) and CD8+ T cells compared to HIV-negative individuals. Additionally, reduced TL has been found to be associated with chronic psychological stress. This study focused on the effects of HIV-infection and chronic stress associated with childhood trauma on telomere length, and investigated whether leukocyte TL (LTL), in particular, represents a risk factor for NCI. Eighty-three HIV-positive and 45 HIV-negative women were assessed for childhood trauma and were subjected to detailed neurocognitive testing. Blood from each participant was used to extract Deoxyribonucleic acid (DNA). Relative LTL were determined by performing real time quantitative PCR reactions as described by Cawthon et al. (2002). As expected, relative LTL in the HIV-positive individuals was significantly shorter than that of HIV-negative individuals (F = 51.56, p = <0.01). Notably, a significant positive correlation was evident between relative LTL and learning performance in the HIV-positive group. In addition, a significant negative correlation was observed between relative LTL and verbal fluency, but this association was only evident in HIV-positive individuals who had experienced trauma. Our results suggest that reduced LTL is associated with worse learning performance in HIV-positive individuals, indicating that TL could act as a susceptibility factor in increasing neurocognitive decline in HIV-infected individuals.},
}
@article {pmid23471838,
year = {2013},
author = {Eisenberg, DT and Kuzawa, CW},
title = {Commentary: The evolutionary biology of the paternal age effect on telomere length.},
journal = {International journal of epidemiology},
volume = {42},
number = {2},
pages = {462-465},
doi = {10.1093/ije/dyt027},
pmid = {23471838},
issn = {1464-3685},
mesh = {Aging/*genetics ; Female ; Humans ; Leukocytes/*physiology ; *Paternal Age ; Telomere/*genetics ; },
}
@article {pmid23471416,
year = {2013},
author = {Galati, A and Micheli, E and Cacchione, S},
title = {Chromatin structure in telomere dynamics.},
journal = {Frontiers in oncology},
volume = {3},
number = {},
pages = {46},
pmid = {23471416},
issn = {2234-943X},
abstract = {The establishment of a specific nucleoprotein structure, the telomere, is required to ensure the protection of chromosome ends from being recognized as DNA damage sites. Telomere shortening below a critical length triggers a DNA damage response that leads to replicative senescence. In normal human somatic cells, characterized by telomere shortening with each cell division, telomere uncapping is a regulated process associated with cell turnover. Nevertheless, telomere dysfunction has also been associated with genomic instability, cell transformation, and cancer. Despite the essential role telomeres play in chromosome protection and in tumorigenesis, our knowledge of the chromatin structure involved in telomere maintenance is still limited. Here we review the recent findings on chromatin modifications associated with the dynamic changes of telomeres from protected to deprotected state and their role in telomere functions.},
}
@article {pmid23468462,
year = {2013},
author = {Weischer, M and Nordestgaard, BG and Cawthon, RM and Freiberg, JJ and Tybjærg-Hansen, A and Bojesen, SE},
title = {Short telomere length, cancer survival, and cancer risk in 47102 individuals.},
journal = {Journal of the National Cancer Institute},
volume = {105},
number = {7},
pages = {459-468},
doi = {10.1093/jnci/djt016},
pmid = {23468462},
issn = {1460-2105},
mesh = {Age Factors ; Aged ; Denmark/epidemiology ; Female ; Follow-Up Studies ; Humans ; Incidence ; Leukocytes/*pathology ; Linear Models ; Male ; Middle Aged ; Multivariate Analysis ; Neoplasms/*epidemiology/*genetics/mortality/pathology ; Odds Ratio ; Prospective Studies ; Risk Assessment ; Risk Factors ; Survival Analysis ; Survival Rate ; Telomere/*pathology ; Telomere Shortening ; },
abstract = {BACKGROUND: Recent meta-analyses have suggested that short telomere length was associated with increased risk of cancer. We therefore tested the hypotheses that short telomere length was associated with increased risk of cancer and with increased risk of early death after cancer.<br><br>METHODS: We measured leukocyte telomere length in a prospective study of 47 102 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Participants were followed for up to 20 years for cancer diagnosis and death. Follow-up was 100% complete. All statistical tests were two-sided.<br><br>RESULTS: Telomere length decreased linearly with increasing age (P <.001). During follow-up, we observed 3142 first cancers and, among these individuals, 1730 deaths. Decreasing quartiles of telomere length were associated with decreasing survival after cancer (log-rank P <.001). Multivariable-adjusted hazard ratios of early death were 1.31 (95% confidence interval [CI] = 1.14 to 1.52) in individuals in the quartile and 1.43 (95% CI = 1.13 to 1.80) in individuals in the decile with the shortest telomeres vs the longest. Unadjusted hazard ratios of cancer risk were 1.74 (95% CI = 1.58 to 1.93) and 2.00 (95% CI = 1.70 to 2.35) in individuals in the quartile and decile with the shortest vs longest telomeres; however, multivariable adjustment changed these hazard ratios to 0.98 (95% CI = 0.88 to 1.08) and 0.95 (95% CI = 0.80 to 1.11), mainly because of age adjustment.<br><br>CONCLUSIONS: Short telomere length is associated with reduced survival after cancer but not with cancer risk. The latter contrasts with findings from recent meta-analyses.},
}
@article {pmid23468461,
year = {2013},
author = {Savage, SA and Gadalla, SM and Chanock, SJ},
title = {The long and short of telomeres and cancer association studies.},
journal = {Journal of the National Cancer Institute},
volume = {105},
number = {7},
pages = {448-449},
pmid = {23468461},
issn = {1460-2105},
mesh = {Female ; Humans ; Leukocytes/*pathology ; Male ; Neoplasms/*epidemiology/*genetics ; Telomere/*pathology ; },
}
@article {pmid23467725,
year = {2013},
author = {Sugishita, Y and Kammori, M and Yamada, O and Poon, SS and Kobayashi, M and Onoda, N and Yamazaki, K and Fukumori, T and Yoshikawa, K and Onose, H and Ishii, S and Yamada, E and Yamada, T},
title = {Amplification of the human epidermal growth factor receptor 2 gene in differentiated thyroid cancer correlates with telomere shortening.},
journal = {International journal of oncology},
volume = {42},
number = {5},
pages = {1589-1596},
doi = {10.3892/ijo.2013.1848},
pmid = {23467725},
issn = {1791-2423},
mesh = {Adult ; Aged ; Antibodies, Monoclonal, Humanized/administration &amp; dosage ; Cell Differentiation/genetics ; Female ; Gene Amplification/genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Proto-Oncogene Mas ; Receptor, ErbB-2/*genetics/metabolism ; Telomere Shortening/*genetics ; Thyroid Neoplasms/*drug therapy/*genetics/pathology ; Trastuzumab ; },
abstract = {The human epidermal growth factor receptor 2 (HER2) proto-oncogene plays an important role in the development and progression of breast and gastric cancer. Monitoring of the HER2 status and treatment with trastuzumab was performed initially in breast cancer, and subsequently in gastric cancer. However, the HER2 status of thyroid cancer remains unexplored. Telomere alteration and telomerase activity have been observed in most human cancers and are known to be a feature of malignancy. The aims of this study were to clarify the HER2 status of thyroid cancer and to examine any correlations to various characteristics of malignancy. We investigated 69 cases of differentiated thyroid cancers with reference to: i) telomere length as measured using tissue quantitative fluorescence in situ hybridization (Q-FISH), ii) expression of human telomerase reverse transcriptase (hTERT) as determined by immunohistochemistry (IHC), and iii) overexpression of the HER2 protein as determined by IHC and amplification of the HER2 gene as determined by fluorescence in situ hybridization (FISH). The telomeres of thyroid cancers, especially follicular carcinomas, were significantly shorter compared to those of adjacent normal tissues. Positivity for hTERT expression and HER2 amplification were observed in approximately 70 and 22% of thyroid cancers, respectively. Our data demonstrated that telomeres in HER2-positive cancers were significantly shorter compared to those in HER2-negative cancers. These results suggest that highly malignant differentiated thyroid cancer can be detected by monitoring HER2 status and telomere shortening, and that trastuzumab therapy may be effective for refractory thyroid cancer.},
}
@article {pmid23463217,
year = {2013},
author = {Jacobs, JJ},
title = {Senescence: back to telomeres.},
journal = {Nature reviews. Molecular cell biology},
volume = {14},
number = {4},
pages = {196},
pmid = {23463217},
issn = {1471-0080},
}
@article {pmid23460576,
year = {2012},
author = {Nelson, AD and Shippen, DE},
title = {Surprises from the chromosome front: lessons from Arabidopsis on telomeres and telomerase.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {77},
number = {},
pages = {7-15},
pmid = {23460576},
issn = {1943-4456},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; },
mesh = {Arabidopsis/*metabolism ; Arabidopsis Proteins/metabolism ; Chromosomes, Plant/genetics/*metabolism ; Multiprotein Complexes/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres serve two vital functions: They act as a buffer against the end-replication problem, and they prevent chromosome ends from being recognized as double-strand DNA (dsDNA) breaks. These functions are orchestrated by the telomerase reverse transcriptase and a variety of telomere protein complexes. Here, we discuss our recent studies with Arabidopsis thaliana that uncovered a new and highly conserved telomere complex called CST (Cdc13/CTC1, STN1, TEN1). Formerly believed to be yeast specific, CST has now been identified as a key component of both plant and vertebrate telomeres, which is essential for genome integrity and stem cell viability. We also describe the unexpected discovery of alternative telomerase ribonucleoprotein complexes in Arabidopsis. Fueled by duplication and diversification of the telomerase RNA subunit and telomerase accessory proteins, these telomerase complexes act in concert to maintain genome stability. In addition to the canonical telomerase enzyme, one of two alternative telomerase ribonucleoprotein (RNP) complexes functions as a novel negative regulator of enzyme activity in response to genotoxic stress. These contributions highlight the immense potential of Arabidopsis in probing the depths of the chromosome end.},
}
@article {pmid23459151,
year = {2013},
author = {Gu, P and Deng, W and Lei, M and Chang, S},
title = {Single strand DNA binding proteins 1 and 2 protect newly replicated telomeres.},
journal = {Cell research},
volume = {23},
number = {5},
pages = {705-719},
pmid = {23459151},
issn = {1748-7838},
support = {R01 CA129037/CA/NCI NIH HHS/United States ; },
mesh = {Alleles ; Animals ; Cell Line ; Chromatids/metabolism ; DNA Damage/radiation effects ; DNA Repair ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Genomic Instability ; Humans ; Mice ; Mice, Knockout ; Mitochondrial Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Protein Binding ; RNA Interference ; RNA, Small Interfering/metabolism ; Radiation, Ionizing ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 2/antagonists &amp; inhibitors/genetics/metabolism ; },
abstract = {Human single-strand (ss) DNA binding proteins 1 and 2 (hSSB1 and 2) are components of the hSSB1/2-INTS3-C9orf80 heterotrimeric protein complex shown to participate in DNA damage response and maintenance of genome stability. However, their roles at telomeres remain unknown. Here, we generated murine SSB1 conditional knockout mice and cells and found that mSSB1 plays a critical role in telomere end protection. Both mSSB1 and mSSB2 localize to a subset of telomeres and are required to repair TRF2-deficient telomeres. Deletion of mSSB1 resulted in increased chromatid-type fusions involving both leading- and lagging-strand telomeric DNA, suggesting that it is required for the protection of G-overhangs. mSSB1's interaction with INTS3 is required for its localization to damaged DNA. mSSB1 interacts with Pot1a, but not Pot1b, and its association with telomeric ssDNA requires Pot1a. mSSB1(Δ/Δ) mice die at birth with developmental abnormalities, while mice with the hypomorphic mSSB1(F/F) allele are born alive and display increased sensitivity to ionizing radiation (IR). Our results suggest that mSSB1 is required to maintain genome stability, and document a previously unrecognized role for mSSB1/2 in the protection of newly replicated leading- and lagging-strand telomeres.},
}
@article {pmid23457740,
year = {2013},
author = {Eissenberg, JC},
title = {Telomeres, cancer &amp; aging: live long &amp; prosper?.},
journal = {Missouri medicine},
volume = {110},
number = {1},
pages = {11-16},
pmid = {23457740},
issn = {0026-6620},
mesh = {Aging/*physiology ; Cellular Senescence/physiology ; Chromosomes, Human/metabolism ; DNA/metabolism ; Humans ; Neoplasms/*physiopathology ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {Like our clothes, our chromosomes fray at the edges with age. Some believe that if we could discover a molecular tailor to patch our age-abraded chromosome ends, we could become modern Methuselahs. Notably, cancer cells achieve immortality by protecting their chromosome ends. Drugs that selectively fray the ends of cancer cell chromosomes would be potent and general anti-cancer therapies. Here, I summarize data on the role of chromosome ends in cellular and organismal aging.},
}
@article {pmid23454763,
year = {2013},
author = {Armanios, M},
title = {Telomeres and age-related disease: how telomere biology informs clinical paradigms.},
journal = {The Journal of clinical investigation},
volume = {123},
number = {3},
pages = {996-1002},
pmid = {23454763},
issn = {1558-8238},
support = {R01 CA160433/CA/NCI NIH HHS/United States ; R21 HL104345/HL/NHLBI NIH HHS/United States ; },
mesh = {Aging/genetics/metabolism/*pathology ; Animals ; Heterozygote ; Humans ; Idiopathic Pulmonary Fibrosis/genetics/pathology ; Neoplasms/genetics/pathology ; Stem Cells/physiology ; Telomere/genetics/*metabolism/physiology ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Telomere length shortens with age and predicts the onset of replicative senescence. Recently, short telomeres have been linked to the etiology of degenerative diseases such as idiopathic pulmonary fibrosis, bone marrow failure, and cryptogenic liver cirrhosis. These disorders have recognizable clinical manifestations, and the telomere defect explains their genetics and informs the approach to their treatment. Here, I review how telomere biology has become intimately connected to clinical paradigms both for understanding pathophysiology and for individualizing therapy decisions. I also critically examine nuances of interpreting telomere length measurement in clinical studies.},
}
@article {pmid23451268,
year = {2013},
author = {Zanet, DL and Saberi, S and Oliveira, L and Sattha, B and Gadawski, I and Côté, HC},
title = {Blood and dried blood spot telomere length measurement by qPCR: assay considerations.},
journal = {PloS one},
volume = {8},
number = {2},
pages = {e57787},
pmid = {23451268},
issn = {1932-6203},
support = {YSH-80511//Canadian Institutes of Health Research/Canada ; },
mesh = {Anticoagulants/pharmacology ; DNA/chemistry/genetics ; Dried Blood Spot Testing/*methods ; Freezing ; Humans ; Leukocytes, Mononuclear/chemistry/drug effects/ultrastructure ; Polymerase Chain Reaction/*methods ; Reproducibility of Results ; Telomere/*chemistry/*genetics ; Telomere Homeostasis/drug effects/genetics ; },
abstract = {Measurement of telomere length is crucial for the study of telomere maintenance and its role in molecular pathophysiology of diseases and in aging. Several methods are used to measure telomere length, the choice of which usually depends on the type and size of sample to be assayed, as well as cost and throughput considerations. The goal of this study was to investigate the factors that may influence the reliability of qPCR-based relative telomere length measurements in whole blood. Day to day intra-individual variability, types of blood anticoagulant, sample storage conditions, processing and site of blood draw were investigated. Two qPCR-based methods to measure telomere length (monoplex vs. multiplex) were also investigated and showed a strong correlation between them. Freezing and thawing of the blood and storage of the blood at 4°C for up to 4 days did not affect telomere length values. Telomere lengths in dried blood spots were significantly higher than both whole blood and peripheral mononuclear blood cells, and were highly correlated with both. We found that telomere length measurements were significantly higher in dried blood spots collected directly from fingertip prick compared to dried blood spots prepared with anticoagulated whole blood collected from the finger, and non-blotted whole blood taken from both finger and arm venipuncture. This suggests that DNA from cells blotted on paper is not equivalent to that collected from venipuncture whole blood, and caution should be taken when comparing between blood sample types.},
}
@article {pmid23447707,
year = {2013},
author = {D'Souza, Y and Chu, TW and Autexier, C},
title = {A translocation-defective telomerase with low levels of activity and processivity stabilizes short telomeres and confers immortalization.},
journal = {Molecular biology of the cell},
volume = {24},
number = {9},
pages = {1469-1479},
pmid = {23447707},
issn = {1939-4586},
support = {MOP86672//Canadian Institutes of Health Research/Canada ; },
mesh = {Amino Acid Sequence ; Animals ; Apoptosis ; Cell-Free System ; DNA/biosynthesis ; HEK293 Cells ; Humans ; Molecular Sequence Data ; Mutation, Missense ; Protein Structure, Tertiary ; Protein Transport ; Rabbits ; Telomerase/chemistry/genetics/*metabolism ; Telomere/metabolism ; *Telomere Homeostasis ; Translocation, Genetic ; },
abstract = {Short, repetitive, G-rich telomeric sequences are synthesized by telomerase, a ribonucleoprotein consisting of telomerase reverse transcriptase (TERT) and an integrally associated RNA. Human TERT (hTERT) can repetitively reverse transcribe its RNA template, acting processively to add multiple telomeric repeats onto the same substrate. We investigated whether certain threshold levels of telomerase activity and processivity are required to maintain telomere function and immortalize human cells with limited lifespan. We assessed hTERT variants with mutations in motifs implicated in processivity and interaction with DNA, namely the insertion in fingers domain (V791Y), and the E primer grip motif (W930F). hTERT-W930F and hTERT-V791Y reconstitute reduced levels of DNA synthesis and processivity compared with wild-type telomerase. Of interest, hTERT-W930F is more defective in translocation than hTERT-V791Y. Nonetheless, hTERT-W930F, but not hTERT-V791Y, immortalizes limited-lifespan human cells. Both hTERT-W930F- and hTERT-V791Y-expressing cells harbor short telomeres, measured as signal free ends (SFEs), yet SFEs persist only in hTERT-V791Y cells, which undergo apoptosis, likely as a consequence of a defect in recruitment of hTERT-V791Y to telomeres. Our study is the first to demonstrate that low levels of DNA synthesis--on the order of 20% of wild-type telomerase levels--and extension of as few as three telomeric repeats are sufficient to maintain functional telomeres and immortalize limited-lifespan human cells.},
}
@article {pmid23447340,
year = {2013},
author = {},
title = {Young adults with shorter telomeres have lower resistance to colds.},
journal = {BMJ (Clinical research ed.)},
volume = {346},
number = {},
pages = {f1220},
doi = {10.1136/bmj.f1220},
pmid = {23447340},
issn = {1756-1833},
mesh = {Adult ; Common Cold/blood/epidemiology/*genetics/*immunology ; Human Experimentation ; Humans ; Incidence ; Rhinovirus/*pathogenicity ; T-Lymphocytes/metabolism ; Telomere/*genetics/immunology ; Telomere Shortening/*genetics/immunology ; United States/epidemiology ; Young Adult ; },
}
@article {pmid23446900,
year = {2013},
author = {Liu, JJ and Prescott, J and Giovannucci, E and Hankinson, SE and Rosner, B and De Vivo, I},
title = {One-carbon metabolism factors and leukocyte telomere length.},
journal = {The American journal of clinical nutrition},
volume = {97},
number = {4},
pages = {794-799},
pmid = {23446900},
issn = {1938-3207},
support = {P01 CA87969/CA/NCI NIH HHS/United States ; R01 CA49449/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Biomarkers/blood ; Carbon/*metabolism ; Choline/administration &amp; dosage ; Cross-Sectional Studies ; DNA/metabolism ; DNA Methylation ; *Diet ; Ethanol/administration &amp; dosage ; Folic Acid/administration &amp; dosage/blood ; Genotype ; Humans ; Leukocytes/*ultrastructure ; *Metabolic Networks and Pathways/genetics ; Methionine/administration &amp; dosage ; Middle Aged ; Multivariate Analysis ; *Nutritional Status ; Polymorphism, Single Nucleotide ; Surveys and Questionnaires ; Telomere/*ultrastructure ; Vitamin B 12/administration &amp; dosage/blood ; Vitamin B 6/administration &amp; dosage/blood ; Vitamin B Complex/administration &amp; dosage/*blood ; },
abstract = {BACKGROUND: Dietary and genetic factors involved in the one-carbon metabolism pathway may affect telomere length through DNA methylation and synthesis, but this has not been comprehensively investigated in epidemiologic studies.<br><br>OBJECTIVE: We cross-sectionally examined associations between dietary and genetic factors in the one-carbon metabolism pathway and relative peripheral blood leukocyte telomere length.<br><br>DESIGN: A total of 1715 participants from the Nurses' Health Study (NHS) had measurements of relative telomere length and plasma concentrations of folate, vitamin B-6, vitamin B-12, cysteine, and homocysteine. Food-frequency questionnaire (FFQ) measurements were also used for the assessment of folate, choline, methionine, riboflavin, vitamin B-6, vitamin B-12, and alcohol intakes. Genotyping was performed on 475 participants with telomere measurements on 29 mostly nonsynonymous single-nucleotide polymorphisms (SNPs) involved in one-carbon metabolism. Unconditional logistic and linear regression models were used.<br><br>RESULTS: There were no significant dose-response relations between any plasma- or FFQ-measured dietary factors and relative telomere length in multivariate analyses. For folate, vitamin B-6, and vitamin B-12, results from the use of FFQ data were consistent with plasma-biomarker findings. We showed no significant associations that involved SNPs and relative telomere length after we accounted for the false discovery rate.<br><br>CONCLUSION: Our analyses involving plasma and questionnaire measurements of one-carbon metabolism factors show that some key dietary and genetic factors in this metabolic network are not associated with relative peripheral blood leukocyte telomere length.},
}
@article {pmid23444102,
year = {2013},
author = {Qu, S and Wen, W and Shu, XO and Chow, WH and Xiang, YB and Wu, J and Ji, BT and Rothman, N and Yang, G and Cai, Q and Gao, YT and Zheng, W},
title = {Association of leukocyte telomere length with breast cancer risk: nested case-control findings from the Shanghai Women's Health Study.},
journal = {American journal of epidemiology},
volume = {177},
number = {7},
pages = {617-624},
pmid = {23444102},
issn = {1476-6256},
support = {P30 CA068485/CA/NCI NIH HHS/United States ; R37 CA070867/CA/NCI NIH HHS/United States ; R37 CA 070867/CA/NCI NIH HHS/United States ; P30 CA68485/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Aged ; Biomarkers ; Body Mass Index ; Breast Neoplasms/blood/*epidemiology/genetics ; Case-Control Studies ; China/epidemiology ; Estrogen Replacement Therapy ; Exercise ; Female ; Genetic Predisposition to Disease ; Humans ; Leukocytes/*ultrastructure ; Logistic Models ; Menopause ; Middle Aged ; Multiplex Polymerase Chain Reaction ; Risk Factors ; Socioeconomic Factors ; Telomere/*ultrastructure ; },
abstract = {Telomeres are specialized chromatin structures essential for the maintenance of chromosomal integrity and stability. Telomere shortening has been linked to multiple aging-related diseases, including cancer. Evidence associating telomere length with breast cancer risk-most of which has been from retrospective case-control studies-is conflicting. We conducted a nested case-control study based on the Shanghai Women's Health Study (1997-2009) in which we evaluated the association of telomere length and breast cancer risk using peripheral blood samples collected before cancer diagnosis (601 cases and 695 controls). We used monochrome multiplex quantitative polymerase chain reaction to measure relative telomere length. Multiple logistic regressions were used to derive adjusted odds ratios with 95% confidence intervals as the measure of association. Telomere length was inversely correlated with age (r = -0.22). Women with moderately long telomeres (those in the fourth quintile) had the lowest breast cancer risk. Risk increased in a dose-response manner with decreasing quintile of telomere length; odds ratios were 1.39 (95% confidence interval (CI): 0.95, 2.04), 1.79 (95% CI: 1.17, 2.75), and 2.39 (95% CI: 1.45, 3.92), respectively, for the third, second, and first quintiles compared with the fourth quintile. A slightly elevated risk of breast cancer (odds ratio = 1.35, 95% CI: 0.90, 2.04), although one that was not statistically significant, was found in the top quintile (longest telomeres). Our results support the hypothesis that telomere shortening is associated with increased risk of breast cancer and suggest a possible elevated risk associated with long telomeres.},
}
@article {pmid23438298,
year = {2013},
author = {Fleming, AM and Burrows, CJ},
title = {G-quadruplex folds of the human telomere sequence alter the site reactivity and reaction pathway of guanine oxidation compared to duplex DNA.},
journal = {Chemical research in toxicology},
volume = {26},
number = {4},
pages = {593-607},
pmid = {23438298},
issn = {1520-5010},
support = {R01 CA090689/CA/NCI NIH HHS/United States ; CA090689/CA/NCI NIH HHS/United States ; },
mesh = {DNA/chemistry/*metabolism ; *G-Quadruplexes ; Guanine/*metabolism ; Humans ; Oxidants/pharmacology ; Oxidation-Reduction ; Telomere/chemistry/*metabolism ; },
abstract = {Telomere shortening occurs during oxidative and inflammatory stress with guanine (G) as the major site of damage. In this work, a comprehensive profile of the sites of oxidation and structures of products observed from G-quadruplex and duplex structures of the human telomere sequence was studied in the G-quadruplex folds (hybrid (K(+)), basket (Na(+)), and propeller (K(+) + 50% CH3CN)) resulting from the sequence 5'-(TAGGGT)4T-3' and in an appropriate duplex containing one telomere repeat. Oxidations with four oxidant systems consisting of riboflavin photosensitization, carbonate radical generation, singlet oxygen, and the copper Fenton-like reaction were analyzed under conditions of low product conversion to determine relative reactivity. The one-electron oxidants damaged the 5'-G in G-quadruplexes leading to spiroiminodihydantoin (Sp) and 2,2,4-triamino-2H-oxazol-5-one (Z) as major products as well as 8-oxo-7,8-dihydroguanine (OG) and 5-guanidinohydantoin (Gh) in low relative yields, while oxidation in the duplex context produced damage at the 5'- and middle-Gs of GGG sequences and resulted in Gh being the major product. Addition of the reductant N-acetylcysteine (NAC) to the reaction did not alter the riboflavin-mediated damage sites but decreased Z by 2-fold and increased OG by 5-fold, while not altering the hydantoin ratio. However, NAC completely quenched the CO3(•-) reactions. Singlet oxygen oxidations of the G-quadruplex showed reactivity at all Gs on the exterior faces of G-quartets and furnished the product Sp, while no oxidation was observed in the duplex context under these conditions, and addition of NAC had no effect. Because a long telomere sequence would have higher-order structures of G-quadruplexes, studies were also conducted with 5'-(TAGGGT)8-T-3', and it provided oxidation profiles similar to those of the single G-quadruplex. Lastly, Cu(II)/H2O2-mediated oxidations were found to be indiscriminate in the damage patterns, and 5-carboxamido-5-formamido-2-iminohydantoin (2Ih) was found to be a major duplex product, while nearly equal yields of 2Ih and Sp were observed in G-quadruplex contexts. These findings indicate that the nature of the secondary structure of folded DNA greatly alters both the reactivity of G toward oxidative stress as well as the product outcome and suggest that recognition of damage in telomeric sequences by repair enzymes may be profoundly different from that of B-form duplex DNA.},
}
@article {pmid23435563,
year = {2013},
author = {Chung, I and Zhao, X},
title = {A STUbL wards off telomere fusions.},
journal = {The EMBO journal},
volume = {32},
number = {6},
pages = {775-777},
pmid = {23435563},
issn = {1460-2075},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; R01 GM080670/GM/NIGMS NIH HHS/United States ; },
mesh = {*DNA End-Joining Repair ; DNA Helicases/*physiology ; Saccharomyces cerevisiae Proteins/*physiology ; Telomere/*metabolism ; },
abstract = {EMBO J (2013) 32: 805–815 doi:; DOI: 10.1038/emboj.2013.24; published online February 15 2013 Protection of chromosomal ends from erroneous recognition as double-strand breaks (DSBs) is critical for maintaining genome integrity. Unprotected ends can activate DNA repair pathways leading to catastrophic fusions or rearrangements of chromosomes. A study in The EMBO Journal identifies Uls1 as a new player in this end-protection process, utilizing SUMO and ubiquitin modifications to prevent chromosomal fusions by clearing a polysumoylated form of Rap1.},
}
@article {pmid23430034,
year = {2013},
author = {Steenstrup, T and Hjelmborg, JV and Mortensen, LH and Kimura, M and Christensen, K and Aviv, A},
title = {Leukocyte telomere dynamics in the elderly.},
journal = {European journal of epidemiology},
volume = {28},
number = {2},
pages = {181-187},
pmid = {23430034},
issn = {1573-7284},
support = {R01 AG030678/AG/NIA NIH HHS/United States ; AG030678/AG/NIA NIH HHS/United States ; },
mesh = {Age Factors ; Aged ; Aged, 80 and over ; Aging/*genetics ; Blotting, Southern ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/*physiology ; Longitudinal Studies ; Male ; Polymorphism, Restriction Fragment Length ; Telomere/*genetics/physiology ; },
abstract = {Limited data suggest that leukocytes of the elderly display ultra-short telomeres. It was reported that in some elderly persons leukocyte telomere length (LTL) shows age-dependent elongation. Using cross-sectional and longitudinal models, we characterized LTL dynamics in participants of the Longitudinal Study of Aging Danish Twins. We measured LTL by Southern blots of the terminal restriction fragment length (TRFL) in 476 individuals (73-94 years) in a cross-sectional evaluation and in a subset of this cohort comprising 80 individuals (73-81 years at baseline) who were followed-up for approximately 10 years. Based on the mean TRFL, we found that a) the average rate of LTL attrition was respectively, 27 bp/year (P < 0.001) and 31 bp/year (P < 0.001) for the cross-sectional and longitudinal evaluations, and b) mean TRFL was 180 bp (95 % CI 43, 320) longer in females than males (P < 0.010). For the TRFL distribution, which captures telomeres of all lengths in the DNA sample, we observed significant shifts with age toward shorter telomeres. Based on the measurement error of the TRFLs, we computed that in the longitudinal evaluation 10.6 % of individuals would manifest LTL elongation over 10 years, assuming a 340 bp attrition during this period. This was not significantly different from the empirical observation of 7.5 % of individuals showing LTL elongation. We conclude that accumulation of ultra-short telomeres in leukocytes of the elderly reflects a shift toward shorter telomeres in the entire telomere distribution. Measurement error is the probable explanation for LTL elongation in longitudinal studies.},
}
@article {pmid23429341,
year = {2013},
author = {Diala, I and Wagner, N and Magdinier, F and Shkreli, M and Sirakov, M and Bauwens, S and Schluth-Bolard, C and Simonet, T and Renault, VM and Ye, J and Djerbi, A and Pineau, P and Choi, J and Artandi, S and Dejean, A and Plateroti, M and Gilson, E},
title = {Telomere protection and TRF2 expression are enhanced by the canonical Wnt signalling pathway.},
journal = {EMBO reports},
volume = {14},
number = {4},
pages = {356-363},
pmid = {23429341},
issn = {1469-3178},
support = {P01 AG036695/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; Female ; Gene Expression ; *Gene Expression Regulation ; HCT116 Cells ; Humans ; Male ; Mice ; Mice, Knockout ; Oligonucleotide Array Sequence Analysis ; Protein Binding ; RNA, Messenger/genetics/metabolism ; *Telomere Homeostasis ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; Transcriptome ; *Wnt Signaling Pathway ; beta Catenin/metabolism ; },
abstract = {The DNA-binding protein TRF2 is essential for telomere protection and chromosome stability in mammals. We show here that TRF2 expression is activated by the Wnt/β-catenin signalling pathway in human cancer and normal cells as well as in mouse intestinal tissues. Furthermore, β-catenin binds to TRF2 gene regulatory regions that are functional in a luciferase transactivating assay. Reduced β-catenin expression in cancer cells triggers a marked increase in telomere dysfunction, which can be reversed by TRF2 overexpression. We conclude that the Wnt/β-catenin signalling pathway maintains a level of TRF2 critical for telomere protection. This is expected to have an important role during development, adult stem cell function and oncogenesis.},
}
@article {pmid23429284,
year = {2013},
author = {Conomos, D and Pickett, HA and Reddel, RR},
title = {Alternative lengthening of telomeres: remodeling the telomere architecture.},
journal = {Frontiers in oncology},
volume = {3},
number = {},
pages = {27},
pmid = {23429284},
issn = {2234-943X},
abstract = {To escape from the normal limits on proliferative potential, cancer cells must employ a means to counteract the gradual telomere attrition that accompanies semi-conservative DNA replication. While the majority of human cancers do this by up-regulating telomerase enzyme activity, most of the remainder use a homologous recombination-mediated mechanism of telomere elongation known as alternative lengthening of telomeres (ALT). Many molecular details of the ALT pathway are unknown, and even less is known regarding the mechanisms by which this pathway is activated. Here, we review current findings about telomere structure in ALT cells, including DNA sequence, shelterin content, and heterochromatic state. We speculate that remodeling of the telomere architecture may contribute to the emergence and maintenance of the ALT phenotype.},
}
@article {pmid23426163,
year = {2013},
author = {Aalbers, AM and Calado, RT and Young, NS and Zwaan, CM and Wu, C and Kajigaya, S and Coenen, EA and Baruchel, A and Geleijns, K and de Haas, V and Kaspers, GJ and Kuijpers, TW and Reinhardt, D and Trka, J and Zimmermann, M and Pieters, R and van der Velden, VH and van den Heuvel-Eibrink, MM},
title = {Telomere length and telomerase complex mutations in pediatric acute myeloid leukemia.},
journal = {Leukemia},
volume = {27},
number = {8},
pages = {1786-1789},
pmid = {23426163},
issn = {1476-5551},
support = {Z99 HL999999/ImNIH/Intramural NIH HHS/United States ; ZIA HL006089-04/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Child ; Child, Preschool ; Humans ; Leukemia, Myeloid, Acute/*genetics/metabolism ; *Mutation ; RNA/genetics ; Telomerase/*genetics/metabolism ; Telomere/*genetics/metabolism ; },
}
@article {pmid23424613,
year = {2013},
author = {Du, M and Prescott, J and Cornelis, MC and Hankinson, SE and Giovannucci, E and Kraft, P and De Vivo, I},
title = {Genetic predisposition to higher body mass index or type 2 diabetes and leukocyte telomere length in the Nurses' Health Study.},
journal = {PloS one},
volume = {8},
number = {2},
pages = {e52240},
pmid = {23424613},
issn = {1932-6203},
support = {R25 CA094880/CA/NCI NIH HHS/United States ; Z01 CP010200/ImNIH/Intramural NIH HHS/United States ; HHSN268200782096C/HG/NHGRI NIH HHS/United States ; R01 DA013423/DA/NIDA NIH HHS/United States ; U01 HG004735/HG/NHGRI NIH HHS/United States ; U01 CA136792/CA/NCI NIH HHS/United States ; U01 HG004726/HG/NHGRI NIH HHS/United States ; U01HG004446/HG/NHGRI NIH HHS/United States ; CA54281/CA/NCI NIH HHS/United States ; P01CA87969/CA/NCI NIH HHS/United States ; P01CA089392/CA/NCI NIH HHS/United States ; U01HG004726/HG/NHGRI NIH HHS/United States ; U01HG004438/HG/NHGRI NIH HHS/United States ; CA139586/CA/NCI NIH HHS/United States ; CA065725/CA/NCI NIH HHS/United States ; R03 CA139586/CA/NCI NIH HHS/United States ; U01 HG004728/HG/NHGRI NIH HHS/United States ; U01 HG004438/HG/NHGRI NIH HHS/United States ; U10AA008401/AA/NIAAA NIH HHS/United States ; U01 HG004446/HG/NHGRI NIH HHS/United States ; R25CA94880/CA/NCI NIH HHS/United States ; AHG006033//PHS HHS/United States ; U01HG004738/HG/NHGRI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA134958/CA/NCI NIH HHS/United States ; R03 CA133914/CA/NCI NIH HHS/United States ; U01HG004415/HG/NHGRI NIH HHS/United States ; U01 DE018993/DE/NIDCR NIH HHS/United States ; U01HG004735/HG/NHGRI NIH HHS/United States ; R01CA49449/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; R01HL088521/HL/NHLBI NIH HHS/United States ; P01 DK070756/DK/NIDDK NIH HHS/United States ; R01HL034594/HL/NHLBI NIH HHS/United States ; P01 CA089392/CA/NCI NIH HHS/United States ; /CAPMC/CIHR/Canada ; U01 HG004424/HG/NHGRI NIH HHS/United States ; U01HG004728/HG/NHGRI NIH HHS/United States ; U01HG004399/HG/NHGRI NIH HHS/United States ; 5P01DK070756/DK/NIDDK NIH HHS/United States ; U01 HG004402/HG/NHGRI NIH HHS/United States ; CA55075/CA/NCI NIH HHS/United States ; R03 CA132175/CA/NCI NIH HHS/United States ; R01 CA065725/CA/NCI NIH HHS/United States ; U01 HG004415/HG/NHGRI NIH HHS/United States ; U01HG004402/HG/NHGRI NIH HHS/United States ; U01HG004422/HG/NHGRI NIH HHS/United States ; CA63464/CA/NCI NIH HHS/United States ; R01 CA082838/CA/NCI NIH HHS/United States ; CA133914/CA/NCI NIH HHS/United States ; T32ES01664/ES/NIEHS NIH HHS/United States ; U01 HG004729/HG/NHGRI NIH HHS/United States ; U01 HG004422/HG/NHGRI NIH HHS/United States ; U01HG04424/HG/NHGRI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; R01 HL034594/HL/NHLBI NIH HHS/United States ; U01DE018993/DE/NIDCR NIH HHS/United States ; U01HG004423/HG/NHGRI NIH HHS/United States ; HL35464/HL/NHLBI NIH HHS/United States ; R01 CA054281/CA/NCI NIH HHS/United States ; CA132175/CA/NCI NIH HHS/United States ; U01DE018903/DE/NIDCR NIH HHS/United States ; U01 CA063464/CA/NCI NIH HHS/United States ; CA132190/CA/NCI NIH HHS/United States ; U01HG004436/HG/NHGRI NIH HHS/United States ; U01HG004729/HG/NHGRI NIH HHS/United States ; 01DA013423/DA/NIDA NIH HHS/United States ; R03 CA132190/CA/NCI NIH HHS/United States ; U01 DE018903/DE/NIDCR NIH HHS/United States ; U01 HG004436/HG/NHGRI NIH HHS/United States ; T32 CA009001/CA/NCI NIH HHS/United States ; CA140790/CA/NCI NIH HHS/United States ; K07 CA140790/CA/NCI NIH HHS/United States ; R01 HL035464/HL/NHLBI NIH HHS/United States ; R01CA134958-01A1/CA/NCI NIH HHS/United States ; U01 HG004738/HG/NHGRI NIH HHS/United States ; R01 HL088521/HL/NHLBI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; U10 AA008401/AA/NIAAA NIH HHS/United States ; U01 HG004423/HG/NHGRI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; U01 HG004399/HG/NHGRI NIH HHS/United States ; T32CA09001/CA/NCI NIH HHS/United States ; CA136792/CA/NCI NIH HHS/United States ; R01 ES001664/ES/NIEHS NIH HHS/United States ; Z01CP010200/CP/NCI NIH HHS/United States ; R01CA082838/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; *Body Mass Index ; Diabetes Mellitus, Type 2/blood/*genetics ; Female ; Genetic Loci/genetics ; *Genetic Predisposition to Disease ; *Genome-Wide Association Study ; Humans ; Leukocytes/*metabolism ; Middle Aged ; Nurses/*statistics &amp; numerical data ; Telomere/*genetics ; Telomere Shortening/genetics ; },
abstract = {BACKGROUND: Although cross-sectional studies have linked higher body mass index (BMI) and type 2 diabetes (T2D) to shortened telomeres, whether these metabolic conditions play a causal role in telomere biology is unknown. We therefore examined whether genetic predisposition to higher BMI or T2D was associated with shortened leukocyte telomere length (LTL).<br><br>METHODOLOGY: We conducted an analysis of 3,968 women of European ancestry aged 43-70 years from the Nurses' Health Study, who were selected as cases or controls in genome-wide association studies and studies of telomeres and disease. Pre-diagnostic relative telomere length in peripheral blood leukocytes, collected in 1989-1990, was measured by quantitative PCR. We combined information from multiple risk variants by calculating genetic risk scores based on 32 polymorphisms near 32 loci for BMI, and 36 polymorphisms near 35 loci for T2D.<br><br>FINDINGS: After adjustment for age and case-control status, there was no association between the BMI genetic risk score and LTL (&#x3b2; per standard deviation increase: -0.01; SE: 0.02; P&#x200a;=&#x200a;0.52). Similarly, the T2D genetic score was not associated with LTL (&#x3b2; per standard deviation increase: -0.006; SE: 0.02; P&#x200a;=&#x200a;0.69).<br><br>CONCLUSIONS: In this population of middle-aged and older women of European ancestry, those genetically predisposed to higher BMI or T2D did not possess shortened telomeres. Although we cannot exclude weak or modest effects, our findings do not support a causal relation of strong magnitude between these metabolic conditions and telomere dynamics.},
}
@article {pmid23423415,
year = {2013},
author = {Cohen, S and Janicki-Deverts, D and Turner, RB and Casselbrant, ML and Li-Korotky, HS and Epel, ES and Doyle, WJ},
title = {Association between telomere length and experimentally induced upper respiratory viral infection in healthy adults.},
journal = {JAMA},
volume = {309},
number = {7},
pages = {699-705},
pmid = {23423415},
issn = {1538-3598},
support = {UL1 RR024153/RR/NCRR NIH HHS/United States ; UL1TR000005/TR/NCATS NIH HHS/United States ; UL1RR024153/RR/NCRR NIH HHS/United States ; RC1 AT005799/AT/NCCIH NIH HHS/United States ; UL1 TR000005/TR/NCATS NIH HHS/United States ; AT006694/AT/NCCIH NIH HHS/United States ; R01 AI066367/AI/NIAID NIH HHS/United States ; U01 AI100799/AI/NIAID NIH HHS/United States ; R01 AT006694/AT/NCCIH NIH HHS/United States ; AI066367/AI/NIAID NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Factors ; CD28 Antigens ; CD8 Antigens ; Common Cold/*genetics ; Disease Susceptibility ; Female ; Humans ; Male ; Middle Aged ; Odds Ratio ; Respiratory Tract Infections/*genetics/virology ; Rhinovirus ; Risk ; T-Lymphocytes ; *Telomere Shortening ; Young Adult ; },
abstract = {IMPORTANCE: Although leukocyte telomere length is associated with mortality and many chronic diseases thought to be manifestations of age-related functional decline, it is not known whether it relates to acute disease in younger healthy populations.<br><br>OBJECTIVE: To determine whether shorter telomeres in leukocytes, especially CD8CD28- T cells, are associated with decreased resistance to upper respiratory infection and clinical illness in young to midlife adults.<br><br>Between 2008 and 2011, telomere length was assessed in peripheral blood mononuclear cells (PBMCs) and T-cell subsets (CD4, CD8CD28+, CD8CD28-) from 152 healthy 18- to 55-year-old residents of Pittsburgh, Pennsylvania. Participants were subsequently quarantined (single rooms), administered nasal drops containing a common cold virus (rhinovirus 39), and monitored for 5 days for development of infection and clinical illness.<br><br>MAIN OUTCOME MEASURES: Infection (virus shedding or 4-fold increase in virus-specific antibody titer) and clinical illness (verified infection plus objective signs of illness).<br><br>RESULTS: Rates of infections and clinical illness were 69% (n = 105) and 22% (n = 33), respectively. Shorter telomeres were associated with greater odds of infection, independent of prechallenge virus-specific antibody, demographics, contraceptive use, season, and body mass index (PBMC: odds ratio [OR] per 1-SD decrease in telomere length, 1.71 [95% CI, 1.08-2.72]; n = 128 [shortest tertile 77% infected; middle, 66%; longest, 57%]; CD4: OR, 1.76 [95% CI, 1.15-2.70]; n = 146 [shortest tertile 80% infected; middle, 71%; longest, 54%]; CD8CD28+: OR, 1.93 [95% CI, 1.21-3.09], n = 132 [shortest tertile 84% infected; middle, 64%; longest, 58%]; CD8CD28-: OR, 2.02 [95% CI, 1.29-3.16]; n = 144 [shortest tertile 77% infected; middle, 75%; longest, 50%]). CD8CD28- was the only cell population in which shorter telomeres were associated with greater risk of clinical illness (OR, 1.69 [95% CI, 1.01-2.84]; n = 144 [shortest tertile, 26%; middle, 22%; longest, 13%]). The association between CD8CD28- telomere length and infection increased with age (CD8CD28- telomere length &#xd7; age interaction, b = 0.09 [95% CI, 0.02-0.16], P = .01, n = 144).<br><br>CONCLUSION AND RELEVANCE: In this preliminary study among a cohort of healthy 18- to 55-year-olds, shorter CD8CD28- T-cell telomere length was associated with increased risk for experimentally induced acute upper respiratory infection and clinical illness.},
}
@article {pmid23417015,
year = {2013},
author = {Lescasse, R and Pobiega, S and Callebaut, I and Marcand, S},
title = {End-joining inhibition at telomeres requires the translocase and polySUMO-dependent ubiquitin ligase Uls1.},
journal = {The EMBO journal},
volume = {32},
number = {6},
pages = {805-815},
pmid = {23417015},
issn = {1460-2075},
mesh = {*DNA End-Joining Repair ; DNA Helicases/metabolism/*physiology ; Down-Regulation ; Organisms, Genetically Modified ; Peptidyl Transferases/metabolism/physiology ; Protein Binding ; Protein Multimerization/physiology ; SUMO-1 Protein/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/metabolism/*physiology ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/metabolism/physiology ; Small Ubiquitin-Related Modifier Proteins/metabolism/physiology ; Sumoylation/physiology ; Telomere/*metabolism ; Ubiquitin-Protein Ligases/metabolism/physiology ; rap1 GTP-Binding Proteins/metabolism ; },
abstract = {In eukaryotes, permanent inhibition of the non-homologous end joining (NHEJ) repair pathway at telomeres ensures that chromosome ends do not fuse. In budding yeast, binding of Rap1 to telomere repeats establishes NHEJ inhibition. Here, we show that the Uls1 protein is required for the maintenance of NHEJ inhibition at telomeres. Uls1 protein is a non-essential Swi2/Snf2-related translocase and a Small Ubiquitin-related Modifier (SUMO)-Targeted Ubiquitin Ligase (STUbL) with unknown targets. Loss of Uls1 results in telomere-telomere fusions. Uls1 requirement is alleviated by the absence of poly-SUMO chains and by rap1 alleles lacking SUMOylation sites. Furthermore, Uls1 limits the accumulation of Rap1 poly-SUMO conjugates. We propose that one of Uls1 functions is to clear non-functional poly-SUMOylated Rap1 molecules from telomeres to ensure the continuous efficiency of NHEJ inhibition. Since Uls1 is the only known STUbL with a translocase activity, it can be the general molecular sweeper for the clearance of poly-SUMOylated proteins on DNA in eukaryotes.},
}
@article {pmid23408544,
year = {2013},
author = {Cui, Y and Gao, YT and Cai, Q and Qu, S and Cai, H and Li, HL and Wu, J and Ji, BT and Yang, G and Chow, WH and Shu, XO and Zheng, W},
title = {Associations of leukocyte telomere length with body anthropometric indices and weight change in Chinese women.},
journal = {Obesity (Silver Spring, Md.)},
volume = {21},
number = {12},
pages = {2582-2588},
pmid = {23408544},
issn = {1930-739X},
support = {P30 CA068485/CA/NCI NIH HHS/United States ; R37 CA070867/CA/NCI NIH HHS/United States ; R37 CA 070867/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; *Anthropometry ; *Asian People ; China/epidemiology ; Female ; Humans ; Leukocytes/*chemistry ; Middle Aged ; Neoplasms/genetics ; Obesity/genetics ; Obesity, Abdominal/epidemiology ; Overweight/epidemiology ; Prospective Studies ; Risk Factors ; Socioeconomic Factors ; Telomere/*chemistry ; Waist-Hip Ratio ; Weight Gain ; },
abstract = {OBJECTIVE: This study evaluated associations of telomere length with various anthropometric indices of general and abdominal obesity, as well as weight change.<br><br>DESIGN AND METHODS: The study included 2,912 Chinese women aged 40-70 years. Monochrome multiplex quantitative polymerase chain reaction was applied to measure relative telomere length.<br><br>RESULTS: Telomere length was inversely associated with body mass index (BMI), waist circumference, waist-to-height ratio, weight, and hip circumference (Ptrend = 0.005, 0.004, 0.004, 0.010, and 0.026, respectively), but not waist-to-hip ratio (Ptrend = 0.116) or height (Ptrend = 0.675). Weight change since age 50 was further evaluated among women over age 55. Women who maintained their weight within &#xb1;5% since age 50, particularly within a normal range (BMI = 18.5-24.9 kg/m(2)), or reduced their weight from overweight (BMI = 25-29.9 kg/m(2)) or obesity (BMI &#x2265;30 kg/m(2)) to normal range, had a longer mean of current telomere length than women who gained weight since age 50 (Ptrend = 0.025), particularly those who stayed in obesity or gained weight from normal range or overweight to obesity (P = 0.023).<br><br>CONCLUSION: Our findings show that telomere shortening is associated with obesity and that maintaining body weight within a normal range helps maintain telomere length.},
}
@article {pmid23408253,
year = {2013},
author = {Xie, H and Wu, X and Wang, S and Chang, D and Pollock, RE and Lev, D and Gu, J},
title = {Long telomeres in peripheral blood leukocytes are associated with an increased risk of soft tissue sarcoma.},
journal = {Cancer},
volume = {119},
number = {10},
pages = {1885-1891},
pmid = {23408253},
issn = {1097-0142},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; R01 CA131335/CA/NCI NIH HHS/United States ; CA131335/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Case-Control Studies ; *Chromosomal Instability ; Female ; Humans ; Incidence ; Leiomyosarcoma/epidemiology/genetics ; *Leukocytes ; Liposarcoma/epidemiology/genetics ; Male ; Middle Aged ; Odds Ratio ; Osteosarcoma/epidemiology/genetics ; Real-Time Polymerase Chain Reaction ; Sarcoma/*epidemiology/*genetics ; *Telomere ; United States/epidemiology ; },
abstract = {BACKGROUND: Human telomeres consisting of long, tandem repeats of the nucleotide sequence TTAGGG at the chromosome ends are essential for maintaining chromosomal stability. Previous epidemiologic studies have indicated that shorter telomere length in peripheral blood leukocytes (PBLs) is associated with the development of many cancers. However, the relation between PBL telomere length and the risk of soft tissue sarcoma (STS) has not been investigated.<br><br>METHODS: The relative telomere length (RTL) was determined in PBLs using real-time polymerase chain reaction in this case-control study. The study participants included 137 patients with histologically confirmed STS (cases) who had received no prior chemotherapy or radiotherapy and 137 healthy controls who were frequency-matched to cases on age, sex, and ethnicity.<br><br>RESULTS: Patients in the case group had significantly longer RTL than controls (1.46 &#xb1; 0.42 for cases vs 1.15 &#xb1; 0.39 for controls; P < .001). By using median RTL in the controls as a cutoff level, individuals who had long telomere length were associated with a significantly increased risk of STS compared with those who had short telomere length (adjusted odds ratio, 4.71; 95% confidence interval, 2.63-8.44). When participants were categorized further into 3 or 4 groups according to the tertile or quartile RTL values of healthy controls, a significant dose-response relation was observed between longer RTL and increased risks of STS.<br><br>CONCLUSIONS: The current results provided the first epidemiologic evidence that longer telomere length in PBLs is associated significantly with an increased risk of STS, potentially suggesting an important role for telomere maintenance in STS development.},
}
@article {pmid23401031,
year = {2013},
author = {Berardinelli, F and Antoccia, A and Buonsante, R and Gerardi, S and Cherubini, R and De Nadal, V and Tanzarella, C and Sgura, A},
title = {The role of telomere length modulation in delayed chromosome instability induced by ionizing radiation in human primary fibroblasts.},
journal = {Environmental and molecular mutagenesis},
volume = {54},
number = {3},
pages = {172-179},
doi = {10.1002/em.21761},
pmid = {23401031},
issn = {1098-2280},
mesh = {Anaphase/radiation effects ; Cell Line ; Chromosomal Instability/*radiation effects ; Dose-Response Relationship, Radiation ; Fibroblasts/cytology/*radiation effects/ultrastructure ; Humans ; In Situ Hybridization, Fluorescence ; Protons ; Telomere/*radiation effects/ultrastructure ; Telomere Homeostasis/*radiation effects ; Telomere Shortening/*radiation effects ; X-Rays ; },
abstract = {Telomere integrity is important for chromosome stability. The main objective of our study was to investigate the relationship between telomere length modulation and mitotic chromosome segregation induced by ionizing radiation in human primary fibroblasts. We used X-rays and low-energy protons because of their ability to induce different telomeric responses. Samples irradiated with 4 Gy were fixed at different times up to 6 days from exposure and telomere length, anaphase abnormalities, and chromosome aberrations were analyzed. We observed that X-rays induced telomere shortening in cells harvested at 96 hrs, whereas protons induced a significant increase in telomere length at short as well as at long harvesting times (24 and 96 hrs). Consistent with this, the analysis of anaphase bridges at 96 hrs showed a fourfold increase in X-ray- compared with proton-irradiated samples, suggesting a correlation between telomere length/dysfunction and chromosome missegregation. In line with these findings, the frequency of dicentrics and rings decreased with time for protons whereas it remained stable after X-rays irradiation. Telomeric FISH staining on anaphases revealed a higher percentage of bridges with telomere signals in X-ray-treated samples than that observed after proton irradiation, thus suggesting that the aberrations observed after X-ray irradiation originated from telomere attrition and consequent chromosome end-to-end fusion. This study shows that, beside an expected "early" chromosome instability induced shortly after irradiation, a delayed one occurs as a result of alterations in telomere metabolism and that this mechanism may play an important role in genomic stability.},
}
@article {pmid23401002,
year = {2013},
author = {Yoshida, M and Katsuyama, S and Tateho, K and Nakamura, H and Miyoshi, J and Ohba, T and Matsuhara, H and Miki, F and Okazaki, K and Haraguchi, T and Niwa, O and Hiraoka, Y and Yamamoto, A},
title = {Microtubule-organizing center formation at telomeres induces meiotic telomere clustering.},
journal = {The Journal of cell biology},
volume = {200},
number = {4},
pages = {385-395},
pmid = {23401002},
issn = {1540-8140},
mesh = {Cytoplasmic Dyneins/genetics/*physiology ; Gene Deletion ; Meiosis/*genetics ; Microtubule-Organizing Center/*metabolism/ultrastructure ; Microtubules/metabolism/physiology/ultrastructure ; Models, Biological ; Schizosaccharomyces/genetics/*metabolism/ultrastructure ; Schizosaccharomyces pombe Proteins/metabolism/physiology ; Telomere/*metabolism/ultrastructure ; Telomere-Binding Proteins/metabolism/physiology ; },
abstract = {During meiosis, telomeres cluster and promote homologous chromosome pairing. Telomere clustering requires the interaction of telomeres with the nuclear membrane proteins SUN (Sad1/UNC-84) and KASH (Klarsicht/ANC-1/Syne homology). The mechanism by which telomeres gather remains elusive. In this paper, we show that telomere clustering in fission yeast depends on microtubules and the microtubule motors, cytoplasmic dynein, and kinesins. Furthermore, the γ-tubulin complex (γ-TuC) is recruited to SUN- and KASH-localized telomeres to form a novel microtubule-organizing center that we termed the "telocentrosome." Telocentrosome formation depends on the γ-TuC regulator Mto1 and on the KASH protein Kms1, and depletion of either Mto1 or Kms1 caused severe telomere clustering defects. In addition, the dynein light chain (DLC) contributes to telocentrosome formation, and simultaneous depletion of DLC and dynein also caused severe clustering defects. Thus, the telocentrosome is essential for telomere clustering. We propose that telomere-localized SUN and KASH induce telocentrosome formation and that subsequent microtubule motor-dependent aggregation of telocentrosomes via the telocentrosome-nucleated microtubules causes telomere clustering.},
}
@article {pmid23400670,
year = {2013},
author = {Haque, S and Rakieh, C and Marriage, F and Ho, P and Gorodkin, R and Teh, LS and Snowden, N and Day, PJ and Bruce, IN},
title = {Shortened telomere length in patients with systemic lupus erythematosus.},
journal = {Arthritis and rheumatism},
volume = {65},
number = {5},
pages = {1319-1323},
doi = {10.1002/art.37895},
pmid = {23400670},
issn = {1529-0131},
support = {17574//Arthritis Research UK/United Kingdom ; //Department of Health/United Kingdom ; },
mesh = {Adult ; Antibodies, Antinuclear/analysis ; Atherosclerosis/diagnosis/epidemiology/*genetics ; Comorbidity ; Female ; Glucocorticoids/therapeutic use ; Humans ; Lupus Erythematosus, Systemic/epidemiology/*genetics ; Middle Aged ; Obesity/epidemiology/*genetics ; Risk Factors ; Smoking/epidemiology/*genetics ; Telomere/*genetics ; *Telomere Shortening ; United Kingdom/epidemiology ; },
abstract = {OBJECTIVE: Patients with systemic lupus erythematosus (SLE) have a higher rate of premature death compared to the general population, suggesting a phenotype of premature senescence in SLE. Telomere length can be used to assess overall biologic aging. This study was undertaken to address the hypothesis that patients with SLE have reduced telomere length.<br><br>METHODS: Telomere length was measured cross-sectionally in whole blood from SLE patients and age-matched healthy female controls, using real-time quantitative polymerase chain reaction. SLE-related and cardiovascular risk factors were assessed.<br><br>RESULTS: We compared telomere length in 63 SLE patients and 63 matched controls with a median age of 50.8 years (interquartile range [IQR] 37-59 years) and 49.9 years (IQR 32-60 years), respectively. The median relative telomere length in SLE patients was 0.97 (IQR 0.47-1.57), compared to 1.53 (IQR 0.82-2.29) in controls (P = 0.0008). We then extended our cohort to measure telomere length in 164 SLE patients. Shorter telomere length was associated with Ro antibodies (&#x3b2; &#xb1; SE -0.36 &#xb1; 0.16; P = 0.023), and longer telomere length was associated with steroid therapy (0.29 &#xb1; 0.14; P = 0.046). We also noted an association of longer telomere length with increasing body mass index (&#x3b2; &#xb1; SE 0.07 &#xb1; 0.01; P < 0.0001) and tobacco smoking (0.64 &#xb1; 0.26; P = 0.016), as well as with the presence of carotid plaque (0.203 &#xb1; 0.177; P = 0.032).<br><br>CONCLUSION: Telomere length is shortened in SLE patients compared to controls and does not appear to be a reflection of disease activity or immune cell turnover. Subsets of patients such as those positive for Ro antibodies may be particularly susceptible to premature biologic aging. The predictive value of telomere length as a biomarker of future risk of damage/mortality in SLE requires longitudinal evaluation.},
}
@article {pmid23398661,
year = {2013},
author = {Foote, CG and Vleck, D and Vleck, CM},
title = {Extent and variability of interstitial telomeric sequences and their effects on estimates of telomere length.},
journal = {Molecular ecology resources},
volume = {13},
number = {3},
pages = {417-428},
doi = {10.1111/1755-0998.12079},
pmid = {23398661},
issn = {1755-0998},
mesh = {Animals ; Blotting, Southern ; Erythrocytes/chemistry ; Genetic Variation/*genetics ; Nucleic Acid Denaturation/genetics ; Passeriformes/*genetics ; Polymerase Chain Reaction/methods ; Restriction Mapping/methods ; Species Specificity ; Telomere/*genetics/physiology ; Telomere Shortening/*genetics ; },
abstract = {Telomeres often shorten with time, although this varies between tissues, individuals and species, and their length and/or rate of change may reflect fitness and rate of senescence. Measurement of telomeres is increasingly important to ecologists, yet the relative merits of different methods for estimating telomere length are not clear. In particular the extent to which interstitial telomere sequences (ITSs), telomere repeats located away from chromosomes ends, confound estimates of telomere length is unknown. Here we present a method to estimate the extent of ITS within a species and variation among individuals. We estimated the extent of ITS by comparing the amount of label hybridized to in-gel telomere restriction fragments (TRF) before and after the TRFs were denatured. This protocol produced robust and repeatable estimates of the extent of ITS in birds. In five species, the amount of ITS was substantial, ranging from 15% to 40% of total telomeric sequence DNA. In addition, the amount of ITS can vary significantly among individuals within a species. Including ITSs in telomere length calculations always underestimated telomere length because most ITSs are shorter than most telomeres. The magnitude of that error varies with telomere length and is larger for longer telomeres. Estimating telomere length using methods that incorporate ITSs, such as Southern blot TRF and quantitative PCR analyses reduces an investigator's power to detect difference in telomere dynamics between individuals or over time within an individual.},
}
@article {pmid23395982,
year = {2013},
author = {Fulnecková, J and Sevcíková, T and Fajkus, J and Lukesová, A and Lukes, M and Vlcek, C and Lang, BF and Kim, E and Eliás, M and Sykorová, E},
title = {A broad phylogenetic survey unveils the diversity and evolution of telomeres in eukaryotes.},
journal = {Genome biology and evolution},
volume = {5},
number = {3},
pages = {468-483},
pmid = {23395982},
issn = {1759-6653},
mesh = {Base Sequence ; DNA, Algal/genetics ; Eukaryota/*classification/*genetics/metabolism ; *Evolution, Molecular ; *Genetic Variation ; Genome ; Humans ; Molecular Sequence Data ; *Phylogeny ; Tandem Repeat Sequences ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres, ubiquitous and essential structures of eukaryotic chromosomes, are known to come in a variety of forms, but knowledge about their actual diversity and evolution across the whole phylogenetic breadth of the eukaryotic life remains fragmentary. To fill this gap, we employed a complex experimental approach to probe telomeric minisatellites in various phylogenetically diverse groups of algae. Our most remarkable results include the following findings: 1) algae of the streptophyte class Klebsormidiophyceae possess the Chlamydomonas-type telomeric repeat (TTTTAGGG) or, in at least one species, a novel TTTTAGG repeat, indicating an evolutionary transition from the Arabidopsis-type repeat (TTTAGGG) ancestral for Chloroplastida; 2) the Arabidopsis-type repeat is also present in telomeres of Xanthophyceae, in contrast to the presence of the human-type repeat (TTAGGG) in other ochrophytes studied, and of the photosynthetic alveolate Chromera velia, consistent with its phylogenetic position close to apicomplexans and dinoflagellates; 3) glaucophytes and haptophytes exhibit the human-type repeat in their telomeres; and 4) ulvophytes and rhodophytes have unusual telomere structures recalcitrant to standard analysis. To obtain additional details on the distribution of different telomere types in eukaryotes, we performed in silico analyses of genomic data from major eukaryotic lineages, utilizing also genome assemblies from our on-going genome projects for representatives of three hitherto unsampled lineages (jakobids, malawimonads, and goniomonads). These analyses confirm the human-type repeat as the most common and possibly ancestral in eukaryotes, but alternative motifs replaced it along the phylogeny of diverse eukaryotic lineages, some of them several times independently.},
}
@article {pmid23390606,
year = {2013},
author = {Shtessel, L and Lowden, MR and Cheng, C and Simon, M and Wang, K and Ahmed, S},
title = {Caenorhabditis elegans POT-1 and POT-2 repress telomere maintenance pathways.},
journal = {G3 (Bethesda, Md.)},
volume = {3},
number = {2},
pages = {305-313},
pmid = {23390606},
issn = {2160-1836},
support = {GM066228/GM/NIGMS NIH HHS/United States ; R56 GM066228/GM/NIGMS NIH HHS/United States ; P40 OD010440/OD/NIH HHS/United States ; R01 GM066228/GM/NIGMS NIH HHS/United States ; T32 GM007092/GM/NIGMS NIH HHS/United States ; },
mesh = {Aging ; Animals ; Caenorhabditis elegans/genetics/*metabolism ; Caenorhabditis elegans Proteins/genetics/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Luminescent Proteins/genetics/metabolism ; Mutation ; Recombinant Fusion Proteins/biosynthesis/genetics ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Red Fluorescent Protein ; },
abstract = {Telomeres are composed of simple tandem DNA repeats that protect the ends of linear chromosomes from replicative erosion or inappropriate DNA damage response mechanisms. The mammalian Protection Of Telomeres (POT1) protein interacts with single-stranded telomeric DNA and can exert positive and negative effects on telomere length. Of four distinct POT1 homologs in the roundworm Caenorhabditis elegans, deficiency for POT-1 or POT-2 resulted in progressive telomere elongation that occurred because both proteins negatively regulate telomerase. We created a POT-1::mCherry fusion protein that forms discrete foci at C. elegans telomeres, independent of POT-2, allowing for live analysis of telomere dynamics. Transgenic pot-1::mCherry repressed telomerase in pot-1 mutants. Animals deficient for pot-1, but not pot-2, displayed mildly enhanced telomere erosion rates in the absence of the telomerase reverse transcriptase, trt-1. However, trt-1; pot-1 double mutants exhibited delayed senescence in comparison to trt-1 animals, and senescence was further delayed in trt-1; pot-2; pot-1 triple mutants, some of which survived robustly in the absence of telomerase. Our results indicate that POT-1 and POT-2 play independent roles in suppressing a telomerase-independent telomere maintenance pathway but may function together to repress telomerase.},
}
@article {pmid23390378,
year = {2013},
author = {Hu, Y and Tang, HB and Liu, NN and Tong, XJ and Dang, W and Duan, YM and Fu, XH and Zhang, Y and Peng, J and Meng, FL and Zhou, JQ},
title = {Telomerase-null survivor screening identifies novel telomere recombination regulators.},
journal = {PLoS genetics},
volume = {9},
number = {1},
pages = {e1003208},
pmid = {23390378},
issn = {1553-7404},
mesh = {Chromosomes/genetics ; *DNA Helicases/genetics/metabolism ; Fungal Proteins/genetics/metabolism ; Genomic Instability ; *Homologous Recombination ; RNA/genetics/metabolism ; *Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; Signal Transduction ; Telomerase/*genetics/metabolism ; Telomere/genetics ; Telomere Homeostasis/genetics ; Ubiquitination ; },
abstract = {Telomeres are protein-DNA structures found at the ends of linear chromosomes and are crucial for genome integrity. Telomeric DNA length is primarily maintained by the enzyme telomerase. Cells lacking telomerase will undergo senescence when telomeres become critically short. In Saccharomyces cerevisiae, a very small percentage of cells lacking telomerase can remain viable by lengthening telomeres via two distinct homologous recombination pathways. These "survivor" cells are classified as either Type I or Type II, with each class of survivor possessing distinct telomeric DNA structures and genetic requirements. To elucidate the regulatory pathways contributing to survivor generation, we knocked out the telomerase RNA gene TLC1 in 280 telomere-length-maintenance (TLM) gene mutants and examined telomere structures in post-senescent survivors. We uncovered new functional roles for 10 genes that affect the emerging ratio of Type I versus Type II survivors and 22 genes that are required for Type II survivor generation. We further verified that Pif1 helicase was required for Type I recombination and that the INO80 chromatin remodeling complex greatly affected the emerging frequency of Type I survivors. Finally, we found the Rad6-mediated ubiquitination pathway and the KEOPS complex were required for Type II recombination. Our data provide an independent line of evidence supporting the idea that these genes play important roles in telomere dynamics.},
}
@article {pmid23389666,
year = {2013},
author = {Turbill, C and Ruf, T and Smith, S and Bieber, C},
title = {Seasonal variation in telomere length of a hibernating rodent.},
journal = {Biology letters},
volume = {9},
number = {2},
pages = {20121095},
pmid = {23389666},
issn = {1744-957X},
mesh = {Aging/genetics/physiology ; Animals ; Body Weight ; Female ; Hibernation/*genetics ; Male ; Myoxidae/*genetics/physiology ; Organ Size ; Regression Analysis ; Reproduction ; *Seasons ; Telomere/*genetics ; Telomere Homeostasis ; Testis/physiology ; Time Factors ; },
abstract = {Small hibernating rodents have greater maximum lifespans and hence appear to age more slowly than similar-sized non-hibernators. We tested for a direct effect of hibernation on somatic maintenance and ageing by measuring seasonal changes in relative telomere length (RTL) in the edible dormouse Glis glis. Average RTL in our population did not change significantly over the hibernation season, and a regression model explaining individual variation in post-hibernation RTL suggested a significant negative effect of the reduction in body mass over the inactive hibernation period (an index of time spent euthermic), supporting the idea that torpor slows ageing. Over the active season, RTL on average decreased in sub-adults but increased in adults, supporting previous findings of greater telomere shortening at younger ages. Telomere length increase might also have been associated with reproduction, which occurred only in adults. Our study reveals how seasonal changes in physiological state influence the progress of life-history traits, such as somatic maintenance and ageing, in a small hibernating rodent.},
}
@article {pmid23388105,
year = {2013},
author = {Da Silveira, Rde C and Da Silva, MS and Nunes, VS and Perez, AM and Cano, MI},
title = {The natural absence of RPA1N domain did not impair Leishmania amazonensis RPA-1 participation in DNA damage response and telomere protection.},
journal = {Parasitology},
volume = {140},
number = {4},
pages = {547-559},
doi = {10.1017/S0031182012002028},
pmid = {23388105},
issn = {1469-8161},
mesh = {Cell Cycle Checkpoints/drug effects ; *DNA Breaks, Double-Stranded ; In Situ Nick-End Labeling ; Leishmania/drug effects/*genetics/*metabolism ; Nucleic Acid Synthesis Inhibitors/pharmacology ; Phleomycins/pharmacology ; Protozoan Proteins/*metabolism ; Telomere/*metabolism ; },
abstract = {We have previously shown that the subunit 1 of Leishmania amazonensis RPA (LaRPA-1) alone binds the G-rich telomeric strand and is structurally different from other RPA-1. It is analogous to telomere end-binding proteins described in model eukaryotes whose homologues were not identified in the protozoan´s genome. Here we show that LaRPA-1 is involved with damage response and telomere protection although it lacks the RPA1N domain involved with the binding with multiple checkpoint proteins. We induced DNA double-strand breaks (DSBs) in Leishmania using phleomycin. Damage was confirmed by TUNEL-positive nuclei and triggered a G1/S cell cycle arrest that was accompanied by nuclear accumulation of LaRPA-1 and RAD51 in the S phase of hydroxyurea-synchronized parasites. DSBs also increased the levels of RAD51 in non-synchronized parasites and of LaRPA-1 and RAD51 in the S phase of synchronized cells. More LaRPA-1 appeared immunoprecipitating telomeres in vivo and associated in a complex containing RAD51, although this interaction needs more investigation. RAD51 apparently co-localized with few telomeric clusters but it did not immunoprecipitate telomeric DNA. These findings suggest that LaRPA-1 and RAD51 work together in response to DNA DSBs and at telomeres, upon damage, LaRPA-1 works probably to prevent loss of single-stranded DNA and to assume a capping function.},
}
@article {pmid23387887,
year = {2012},
author = {Mikhelson, VM and Gamaley, IA},
title = {Telomere shortening is a sole mechanism of aging in mammals.},
journal = {Current aging science},
volume = {5},
number = {3},
pages = {203-208},
doi = {10.2174/1874609811205030006},
pmid = {23387887},
issn = {1874-6128},
mesh = {Age Factors ; Aging/*genetics/metabolism ; Animals ; Cellular Senescence ; DNA Damage ; Humans ; Models, Biological ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {We adduce proof that telomere shortening is the sole mechanism of aging. All apparent contradictions, particularly the absence of an inverse correlation between residual telomere length and donor age, are explained within the bounds of telomere theory. We explain in what way telomere shortening might be the cause of aging and lifespan restriction. We also show the inability of the oxidative theory to explain a number of indisputable (and easily explained by telomere theory) facts, such as malignant growth of tumor cells and why children begin aging not from the level reached by the cells of their parents at the moment of conception but from nothing. We postulate that if oxidative damage was entirely absent, telomeres would, nevertheless, shorten with each mitotic cycle because this is the mechanism of DNA replication. Aging would occur all the same, and it is the very thing we can observe under the effect of any antioxidants. If telomeres do not shorten, as is the case in transformed cells in which telomerase is working, aging will do stop and transformed cells will show no senescence. We also observe this in spite of the damaging effect of reactive oxygen species, which is even more intensive in transformed cells than in normal cells.},
}
@article {pmid23383372,
year = {2013},
author = {Vaquero-Sedas, MI and Vega-Palas, MA},
title = {Differential association of Arabidopsis telomeres and centromeres with histone H3 variants.},
journal = {Scientific reports},
volume = {3},
number = {},
pages = {1202},
pmid = {23383372},
issn = {2045-2322},
mesh = {Arabidopsis/*genetics/metabolism ; Base Sequence ; Centromere/*metabolism ; Chromatin/metabolism ; Genetic Variation ; Histones/genetics/*metabolism ; *Repetitive Sequences, Nucleic Acid ; Telomere/*metabolism ; Transcription, Genetic ; },
abstract = {Two different groups, using ChIP-seq data, have recently published the genome-wide distribution of histones H3.1 and H3.3 in Arabidopsis thaliana. In one report, Stroud and colleagues determined that, whereas H3.1 was enriched in repetitive pericentromeric and silent chromatin, H3.3 was enriched in transcriptionally active regions. This work was performed using seedlings, which contained dividing and non-dividing cells. In a second report, Wollmann and colleagues found similar results analyzing dividing or non-dividing tissue. None of these reports addressed the analysis of telomeres or centromeres. Our group has recently described an experimental approach that allows the study of the epigenetic status of some Arabidopsis repetitive sequences by analyzing ChIP-seq data. By using this approach and the data generated by Stroud, Wollmann and colleagues, we found that telomeres are enriched in H3.3 with regard to the centromeric 178 bp repeats, whereas the centromeric repeats are enriched in H3.1 with regard to telomeres.},
}
@article {pmid23383336,
year = {2013},
author = {Svenson, U and Grönlund, E and Söderström, I and Sitaram, RT and Ljungberg, B and Roos, G},
title = {Telomere length in relation to immunological parameters in patients with renal cell carcinoma.},
journal = {PloS one},
volume = {8},
number = {2},
pages = {e55543},
pmid = {23383336},
issn = {1932-6203},
mesh = {Biomarkers, Tumor/*genetics/immunology ; Carcinoma, Renal Cell/*genetics/immunology ; Cytokines/blood ; Flow Cytometry ; Humans ; Immunophenotyping ; Interleukin-10/blood ; Interleukin-7/blood ; Interleukin-8/blood ; Kidney Neoplasms/*genetics/immunology ; T-Lymphocytes, Regulatory/metabolism ; Telomere/*genetics ; },
abstract = {Over the last decade, telomere length (TL) has gained attention as a potential biomarker in cancer disease. We previously reported that long blood TL was associated with a poorer outcome in patients with breast cancer and renal cell carcinoma. Based on these findings, we hypothesized that certain immunological components may have an impact on TL dynamics in cancer patients. One aim of the present study was to investigate a possible association between serum cytokines and TL of peripheral blood cells, tumors and corresponding kidney cortex, in patients with clear cell renal cell carcinoma. For this purpose, a multiplex cytokine assay was used. Correlation analysis revealed significant positive correlations between tumor TL and peripheral levels of three cytokines (IL-7, IL-8 and IL-10). In a parallel patient group with various kidney tumors, TL was investigated in whole blood and in immune cell subsets in relation to peripheral levels of regulatory T cells (Tregs). A significant positive association was found between whole blood TL and Treg levels. However, the strongest correlation was found between Tregs and TL of the T lymphocyte fraction. Thus, patients with higher Treg levels displayed longer T cell telomeres, which might reflect a suppressed immune system with fewer cell divisions and hence less telomere shortening. These results are in line with our earlier observation that long blood TL is an unfavorable prognostic factor for cancer-specific survival. In summary, we here show that immunological components are associated with TL in patients with renal cell carcinoma, providing further insight into the field of telomere biology in cancer.},
}
@article {pmid23382649,
year = {2013},
author = {Shi, K and Huang, WM and Aihara, H},
title = {An enzyme-catalyzed multistep DNA refolding mechanism in hairpin telomere formation.},
journal = {PLoS biology},
volume = {11},
number = {1},
pages = {e1001472},
pmid = {23382649},
issn = {1545-7885},
support = {P41 RR015301/RR/NCRR NIH HHS/United States ; R01 GM095558/GM/NIGMS NIH HHS/United States ; RR15301/RR/NCRR NIH HHS/United States ; },
mesh = {*Agrobacterium tumefaciens/enzymology/genetics/metabolism ; Bacterial Proteins/chemistry ; Chromosomes, Bacterial/metabolism ; Crystallography, X-Ray ; DNA Replication ; DNA Replication Timing ; DNA, Bacterial/*chemistry/genetics/metabolism ; DNA-Binding Proteins/chemistry ; Gene Rearrangement ; *Nucleic Acid Conformation ; Telomere/*metabolism/*ultrastructure ; },
abstract = {Hairpin telomeres of bacterial linear chromosomes are generated by a DNA cutting-rejoining enzyme protelomerase. Protelomerase resolves a concatenated dimer of chromosomes as the last step of chromosome replication, converting a palindromic DNA sequence at the junctions between chromosomes into covalently closed hairpins. The mechanism by which protelomerase transforms a duplex DNA substrate into the hairpin telomeres remains largely unknown. We report here a series of crystal structures of the protelomerase TelA bound to DNA that represent distinct stages along the reaction pathway. The structures suggest that TelA converts a linear duplex substrate into hairpin turns via a transient strand-refolding intermediate that involves DNA-base flipping and wobble base-pairs. The extremely compact di-nucleotide hairpin structure of the product is fully stabilized by TelA prior to strand ligation, which drives the reaction to completion. The enzyme-catalyzed, multistep strand refolding is a novel mechanism in DNA rearrangement reactions.},
}
@article {pmid23382366,
year = {2013},
author = {Aviv, A and Susser, E},
title = {Leukocyte telomere length and the father's age enigma: implications for population health and for life course.},
journal = {International journal of epidemiology},
volume = {42},
number = {2},
pages = {457-462},
pmid = {23382366},
issn = {1464-3685},
support = {AG023028/AG/NIA NIH HHS/United States ; AG030678/AG/NIA NIH HHS/United States ; R01 AG030678/AG/NIA NIH HHS/United States ; HD071180/HD/NICHD NIH HHS/United States ; R01 AG020132/AG/NIA NIH HHS/United States ; AG020132/AG/NIA NIH HHS/United States ; R01 MH059114/MH/NIMH NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; P01 AG023028/AG/NIA NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; MH059114/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging/*genetics ; Fathers ; Female ; Humans ; Leukocytes/*physiology ; *Paternal Age ; Telomere/*genetics ; },
abstract = {What are the implications for population health of the demographic trend toward increasing paternal age at conception (PAC) in modern societies? We propose that the effects of older PAC are likely to be broad and harmful in some domains of health but beneficial in others. Harmful effects of older PAC have received the most attention. Thus, for example, older PAC is associated with an increased risk of offspring having rare conditions such as achondroplasia and Marfan syndrome, as well as with neurodevelopmental disorders such as autism. However, newly emerging evidence in the telomere field suggests potentially beneficial effects, since older PAC is associated with a longer leukocyte telomere length (LTL) in offspring, and a longer LTL is associated with a reduced risk of atherosclerosis and with increased survival in the elderly. Thus, older PAC may cumulatively increase resistance to atherosclerosis and lengthen lifespan in successive generations of modern humans. In this paper we: (i) introduce these novel findings; (ii) discuss potential explanations for the effect of older PAC on offspring LTL; (iii) draw implications for population health and for life course; (iv) put forth an evolutionary perspective as a context for the multigenerational effects of PAC; and (v) call for broad and intensive research to understand the mechanisms underlying the effects of PAC. We draw together work across a range of disciplines to offer an integrated perspective of this issue.},
}
@article {pmid23382361,
year = {2013},
author = {Skamra, C and Romero-Diaz, J and Sandhu, A and Huang, Q and Lee, J and Pearce, W and McPherson, DD and Sutton-Tyrrell, K and Pope, R and Ramsey-Goldman, R},
title = {Telomere length in patients with systemic lupus erythematosus and its associations with carotid plaque.},
journal = {Rheumatology (Oxford, England)},
volume = {52},
number = {6},
pages = {1101-1108},
pmid = {23382361},
issn = {1462-0332},
support = {UL1 TR000150/TR/NCATS NIH HHS/United States ; K24AR002138/AR/NIAMS NIH HHS/United States ; K24 AR002138/AR/NIAMS NIH HHS/United States ; P60 AR030692/AR/NIAMS NIH HHS/United States ; P60AR30692/AR/NIAMS NIH HHS/United States ; T32AR07611/AR/NIAMS NIH HHS/United States ; T32 AR007611/AR/NIAMS NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Aged ; Carotid Stenosis/*complications/diagnostic imaging/genetics ; Female ; Humans ; Lupus Erythematosus, Systemic/*complications/diagnostic imaging/genetics ; Male ; Middle Aged ; Pilot Projects ; Plaque, Atherosclerotic/*complications/diagnostic imaging/genetics ; Risk Factors ; Severity of Illness Index ; *Telomere ; Ultrasonography ; },
abstract = {OBJECTIVE: To evaluate telomere length (TL) between patients with SLE and healthy controls and to test if TL is associated with carotid plaque.<br><br>METHODS: A pilot study of 154 patients with SLE and 152 controls was performed from the SOLVABLE (Study of Lupus Vascular and Bone Long-Term Endpoints) cohort. Demographic and cardiovascular disease (CVD) factors were collected at baseline. The presence or absence of plaque was evaluated by B-mode US. Genomic DNA was isolated from whole peripheral blood. TL was quantified using real-time quantitative PCR.<br><br>RESULTS: SLE women had a short TL compared with healthy controls (4.57 vs 5.44 kb, P = 0.03). SLE women showed shorter TL than controls across all age groups: <35 years (4.38 vs 6.37 kb), 35-44 years (4.52 vs 5.30 kb), 45-54 years (4.77 vs 5.68 kb) and &#x2265;55 years (4.60 vs 4.71 kb). Among patients with SLE and carotid plaque there was a trend towards shorter TL at a younger age and it was significantly lower in the 35- to 44-year age group when compared with controls (P = 0.025). Multiple logistic regression analysis indicated a risk of carotid plaque with older age [odds ratio (OR) 1.09; 95% CI 1.06, 1.12] but not with TL (OR 1.05; 95% CI 0.97, 1.13).<br><br>CONCLUSION: SLE women had significantly shorter TL than controls. SLE women trended towards shorter TL at a younger age. When carotid plaque was identified, the younger SLE women had shorter TL. Only older age but not shorter TL was independently associated with carotid plaque. Additional studies are needed to confirm if TL is a novel biomarker for cardiovascular disease in SLE.},
}
@article {pmid23380569,
year = {2013},
author = {Samsonraj, RM and Raghunath, M and Hui, JH and Ling, L and Nurcombe, V and Cool, SM},
title = {Telomere length analysis of human mesenchymal stem cells by quantitative PCR.},
journal = {Gene},
volume = {519},
number = {2},
pages = {348-355},
doi = {10.1016/j.gene.2013.01.039},
pmid = {23380569},
issn = {1879-0038},
mesh = {Blotting, Southern ; Cell Proliferation ; Cell Survival ; Chromosomes, Human/genetics ; DNA/genetics/*isolation &amp; purification ; Gene Dosage ; Gene Expression ; Humans ; In Situ Hybridization, Fluorescence ; Mesenchymal Stem Cells/cytology/*metabolism ; Real-Time Polymerase Chain Reaction/*methods ; Telomerase/analysis/metabolism ; Telomere/*metabolism ; Telomere Shortening ; },
abstract = {Human mesenchymal stem cells (hMSCs) have attracted much attention for tissue repair and wound healing because of their self-renewal capacity and multipotentiality. In order to mediate an effective therapy, substantial numbers of cells are required, which necessitates extensive sub-culturing and expansion of hMSCs. Throughout ex vivo expansion, the cells undergo telomere shortening, and critically short telomeres can trigger loss of cell viability. Telomeres are nucleoprotein structures that cap the ends of chromosomes, and serve to protect the DNA from the degradation which occurs due to the end-replication problem in all eukaryotes. As hMSCs have only a finite ability for self-renewal like most somatic cells, assaying for telomere length in hMSCs provides critical information on the replicative capacity of the cells, an important criterion in the selection of hMSCs for therapy. Telomere length is generally quantified by Southern blotting and fluorescence in situ hybridization, and more recently by PCR-based methods. Here we describe the quantification of hMSC telomere length by real-time PCR; our results demonstrate the effect of telomere shortening on the proliferation and clonogenicity of hMSCs. Thus, this assay constitutes a useful tool for the determination of relative telomere length in hMSCs.},
}
@article {pmid23379729,
year = {2013},
author = {Williamson, SR and Zhang, S and Lopez-Beltran, A and Montironi, R and Wang, M and Cheng, L},
title = {Telomere shortening distinguishes inverted urothelial neoplasms.},
journal = {Histopathology},
volume = {62},
number = {4},
pages = {595-601},
doi = {10.1111/his.12030},
pmid = {23379729},
issn = {1365-2559},
mesh = {Carcinoma, Transitional Cell/*diagnosis/genetics ; Cell Nucleus/genetics/pathology ; Cystitis/genetics/pathology ; Humans ; In Situ Hybridization, Fluorescence ; Interphase ; Papilloma, Inverted/*diagnosis/genetics ; Telomere/*pathology ; Telomere Shortening/*genetics ; Urinary Bladder Neoplasms/*diagnosis/genetics ; Urothelium/pathology ; },
abstract = {AIMS: To investigate relative telomere length in inverted urothelial neoplasms, including inverted papilloma and urothelial carcinoma with an inverted growth pattern. Telomere shortening has been implicated as an early event in the development of epithelial malignancies in a number of organ systems.<br><br>METHODS AND RESULTS: Formalin-fixed, paraffin-embedded tissue sections from 77 cases were studied, including 26 cases of inverted papilloma, 26 urothelial carcinomas with inverted growth, and 25 cases of cystitis glandularis. Quantitative fluorescence in-situ hybridization (FISH) was performed on interphase nuclei, utilizing a telomere-specific peptide nucleic acid probe to assess telomeric signal intensity. Relative telomere lengths for urothelial carcinoma with inverted growth, cystitis glandularis and inverted papilloma were 29%, 84%, and 91%, respectively. A statistically significant reduction in relative telomere length was present between urothelial carcinoma with inverted growth and inverted papilloma (P&#xa0;<&#xa0;0.001); no significant difference was detected between normal urothelium, cystitis glandularis, and inverted papilloma.<br><br>CONCLUSIONS: Significant telomere shortening in urothelial carcinoma with inverted growth as compared with inverted papilloma distinguishes the two lesions, and supports the notion that inverted papilloma is a benign neoplasm with a distinct pathogenetic mechanism of development. Telomeric FISH analysis may be a useful biomarker in distinguishing inverted papilloma from urothelial carcinoma with inverted growth.},
}
@article {pmid23378069,
year = {2013},
author = {Piening, BD and Huang, D and Paulovich, AG},
title = {Novel connections between DNA replication, telomere homeostasis, and the DNA damage response revealed by a genome-wide screen for TEL1/ATM interactions in Saccharomyces cerevisiae.},
journal = {Genetics},
volume = {193},
number = {4},
pages = {1117-1133},
pmid = {23378069},
issn = {1943-2631},
support = {R01 CA129604/CA/NCI NIH HHS/United States ; },
mesh = {*DNA Damage ; *DNA Repair ; DNA Replication ; Gene Deletion ; *Genome, Fungal ; Intracellular Signaling Peptides and Proteins/*genetics/metabolism ; Nucleotides/metabolism ; Phenotype ; Protein Binding ; Protein Serine-Threonine Kinases/*genetics/metabolism ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {Tel1 is the budding yeast ortholog of the mammalian tumor suppressor and DNA damage response (DDR) kinase ATM. However, tel1-Δ cells, unlike ATM-deficient cells, do not exhibit sensitivity to DNA-damaging agents, but do display shortened (but stably maintained) telomere lengths. Neither the extent to which Tel1p functions in the DDR nor the mechanism by which Tel1 contributes to telomere metabolism is well understood. To address the first question, we present the results from a comprehensive genome-wide screen for genetic interactions with tel1-Δ that cause sensitivity to methyl methanesulfonate (MMS) and/or ionizing radiation, along with follow-up characterizations of the 13 interactions yielded by this screen. Surprisingly, many of the tel1-Δ interactions that confer DNA damage sensitivity also exacerbate the short telomere phenotype, suggesting a connection between these two phenomena. Restoration of normal telomere length in the tel1-Δ xxx-Δ mutants results in only minor suppression of the DNA damage sensitivity, demonstrating that the sensitivity of these mutants must also involve mechanisms independent of telomere length. In support of a model for increased replication stress in the tel1-Δ xxx-Δ mutants, we show that depletion of dNTP pools through pretreatment with hydroxyurea renders tel1-Δ cells (but not wild type) MMS-sensitive, demonstrating that, under certain conditions, Tel1p does indeed play a critical role in the DDR.},
}
@article {pmid23377770,
year = {2013},
author = {Cheng, EH and Chen, SU and Lee, TH and Pai, YP and Huang, LS and Huang, CC and Lee, MS},
title = {Evaluation of telomere length in cumulus cells as a potential biomarker of oocyte and embryo quality.},
journal = {Human reproduction (Oxford, England)},
volume = {28},
number = {4},
pages = {929-936},
doi = {10.1093/humrep/det004},
pmid = {23377770},
issn = {1460-2350},
mesh = {Adult ; Biomarkers/metabolism ; Cohort Studies ; Cumulus Cells/*cytology ; Embryo Culture Techniques ; Embryo, Mammalian/*cytology ; Female ; Fertilization in Vitro ; Humans ; Oocyte Retrieval ; Oocytes/*cytology ; Telomere/*metabolism ; },
abstract = {STUDY QUESTION: Is the relative telomere length in cumulus cells associated with embryo quality and the subject's age?<br><br>SUMMARY ANSWER: The relative telomere length in cumulus cells at the time of oocyte collection may be a new potential biomarker for selecting highly competent oocytes and good quality embryos.<br><br>WHAT IS KNOWN ALREADY: Telomeres play central roles in aging and in determining cell fate. In mammalian ovarian follicles, maturing oocytes are nurtured and supported by surrounding somatic cells, the mural granulosa and cumulus cells.<br><br>STUDY DESIGN, SIZE, DURATION: A total of 350 oocyte-cumulus complex samples were collected from 80 IVF cycles prospectively recruited for this study at the Lee Women's Hospital, Taichung, Taiwan.<br><br>Cumulus cells were manually separated from the oocyte-cumulus complex under a microscope. DNA was extracted from cumulus cells and assessed for telomere length by real-time quantitative PCR. We analyzed telomere length relative to a single copy marker gene (36B4) to evaluate the effect of the real reproductive age of cumulus cells on oocyte and embryo development.<br><br>The relative telomere length was longer in cumulus cells from mature oocytes compared with cumulus cells from immature oocytes, and in cumulus cells from good-quality embryos compared with cumulus cells from poor-quality embryos. The cut-off value of the T/S ratio between good and poor-quality embryos on embryonic Day 3 was 4.235.<br><br>Only a limited number of cumulus cells were measured for each oocyte and the corresponding embryo.<br><br>The relative telomere length in cumulus cells at the time of oocyte collection is predictive of highly competent oocytes and good-quality embryos but may not be sufficiently discriminating to be clinically useful.<br><br>National Science Council, Taiwan (NSC 97-2314-B-040-018). The authors have no conflicts of interest to declare.},
}
@article {pmid23375186,
year = {2013},
author = {Ye, S and Shaffer, JA and Kang, MS and Harlapur, M and Muntner, P and Epel, E and Guernsey, D and Schwartz, JE and Davidson, KW and Kirkland, S and Honig, LS and Shimbo, D},
title = {Relation between leukocyte telomere length and incident coronary heart disease events (from the 1995 Canadian Nova Scotia Health Survey).},
journal = {The American journal of cardiology},
volume = {111},
number = {7},
pages = {962-967},
pmid = {23375186},
issn = {1879-1913},
support = {HL-084034/HL/NHLBI NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; T32HL007854-16/HL/NHLBI NIH HHS/United States ; P50AG008702/AG/NIA NIH HHS/United States ; P01 HL088117/HL/NHLBI NIH HHS/United States ; K24 HL084034/HL/NHLBI NIH HHS/United States ; R01 HL091099/HL/NHLBI NIH HHS/United States ; HL-091099/HL/NHLBI NIH HHS/United States ; T32 HL007854/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Biomarkers/blood ; Confidence Intervals ; Coronary Disease/*epidemiology ; Female ; Humans ; Incidence ; *Leukocytes ; Linear Models ; Male ; Middle Aged ; Nova Scotia/epidemiology ; Proportional Hazards Models ; Risk Factors ; Telomere/*ultrastructure ; },
abstract = {Leukocyte telomere length has been proposed as a biomarker of cellular aging and atherosclerosis. The aim of this study was to determine whether leukocyte telomere length is independently associated with incident coronary heart disease (CHD) in the general population. Telomere length was measured using a polymerase chain reaction method for participants enrolled in the 1995 Nova Scotia Health Survey (NSHS95; n = 1,917). The primary end point was the first occurrence of a fatal or nonfatal CHD event. During a mean follow-up period of 8.7 years, 164 fatal or nonfatal CHD events occurred. Compared with participants in the longest tertile of telomere length, those in the middle and shortest tertiles had increased incidence of CHD events (6.2, 11.2, and 12.2 per 1,000 person-years, respectively). After adjustment for demographics, traditional risk factors, and inflammatory markers including high-sensitivity C-reactive protein, interleukin-6, and soluble intercellular adhesion molecule-1, those in the middle tertile had significantly elevated risk for incident CHD (hazard ratio 1.63, 95% confidence interval 1.07 to 2.51, p = 0.02) compared with the longest tertile, whereas the risk for those in the shortest tertile was nonsignificantly elevated (hazard ratio 1.25, 95% confidence interval 0.82 to 1.90, p = 0.30). In conclusion, these findings do not support a linear association between leukocyte telomere length and incident CHD risk in the general population.},
}
@article {pmid23374336,
year = {2013},
author = {Günes, C and Rudolph, KL},
title = {The role of telomeres in stem cells and cancer.},
journal = {Cell},
volume = {152},
number = {3},
pages = {390-393},
doi = {10.1016/j.cell.2013.01.010},
pmid = {23374336},
issn = {1097-4172},
mesh = {Animals ; DNA Repair ; DNA Replication ; Humans ; Neoplasms/*genetics ; Stem Cells/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomere shortening impairs proliferation of transformed cells but also leads to cancer initiation by inducing chromosomal instability. Here, we discuss recent developments in our understanding of the role of telomeres in replication stress and how telomerase expression in somatic stem cells may affect genome integrity control and carcinogenesis.},
}
@article {pmid23370895,
year = {2013},
author = {Carroll, JE and Diez Roux, AV and Fitzpatrick, AL and Seeman, T},
title = {Low social support is associated with shorter leukocyte telomere length in late life: multi-ethnic study of atherosclerosis.},
journal = {Psychosomatic medicine},
volume = {75},
number = {2},
pages = {171-177},
pmid = {23370895},
issn = {1534-7796},
support = {R01 HL101161/HL/NHLBI NIH HHS/United States ; N01 HC095167/HC/NHLBI NIH HHS/United States ; T32-MH19925/MH/NIMH NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; N01 HC095161/HC/NHLBI NIH HHS/United States ; N01 HC095164/HC/NHLBI NIH HHS/United States ; N01-HC 95159/HC/NHLBI NIH HHS/United States ; T32 MH019925/MH/NIMH NIH HHS/United States ; N01 HC095169/HC/NHLBI NIH HHS/United States ; N01 HC095168/HC/NHLBI NIH HHS/United States ; N01 HC095163/HC/NHLBI NIH HHS/United States ; N01 HC095162/HC/NHLBI NIH HHS/United States ; N01 HC095159/HC/NHLBI NIH HHS/United States ; N01 HC095166/HC/NHLBI NIH HHS/United States ; N01 HC095160/HC/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; N01-HC 95169/HC/NHLBI NIH HHS/United States ; N01 HC095165/HC/NHLBI NIH HHS/United States ; P30 AG017265/AG/NIA NIH HHS/United States ; },
mesh = {Black or African American/statistics &amp; numerical data ; Age Factors ; Aged ; Aged, 80 and over ; Aging/*physiology/psychology ; Atherosclerosis/ethnology ; Cellular Senescence/*physiology ; Cross-Sectional Studies ; Female ; Hispanic or Latino/statistics &amp; numerical data ; Humans ; *Leukocytes ; Linear Models ; Loneliness/psychology ; Longitudinal Studies ; Male ; Middle Aged ; Polymerase Chain Reaction ; Risk Factors ; Social Isolation/psychology ; *Social Support ; Telomere Shortening/*physiology ; United States/epidemiology ; White People/statistics &amp; numerical data ; },
abstract = {OBJECTIVE: The primary goal was to test the hypothesis that limited social support (SS) is related to shorter leukocyte telomere length (LTL), particularly in an older adult population.<br><br>METHODS: Cross-sectional analyses were performed on 948 participants aged 45 to 84 years at Examination 1 of the Multi-Ethnic Study of Atherosclerosis (18.4% white, 53.1% Hispanics, and 28.5% African American). LTL was determined by using quantitative polymerase chain reaction, and SS was measured with the Enhancing Recovery in Coronary Heart Disease SS inventory.<br><br>RESULTS: Across the entire sample, SS was not associated with LTL (p=.87) after adjusting for demographic (age, sex, race/ethnicity, socioeconomic status), age&#xd7;sex, age&#xd7;race, health (body mass index, diabetes, pulse pressure), and life-style factors (smoking, physical activity, diet); however, the interaction term age (dichotomized)&#xd7;SS was significant (p=.001). Stratification by age group revealed a positive association between SS (score range, 5-25) and LTL in the older (65-84 years; B[SE]=.005[.002]; p=.007) but not younger participants (45-64 years; p=.12) after adjusting for covariates.<br><br>CONCLUSIONS: These results from a racially/ethnically diverse community sample of men and women provide initial evidence that low SS is associated with shorter LTL in adults aged 65 years and older and is consistent with the hypothesis that social environment may contribute to rates of cellular aging, particularly in late life.},
}
@article {pmid23363843,
year = {2013},
author = {Zhou, J and Richardson, M and Reddy, V and Menon, M and Barrack, ER and Reddy, GP and Kim, SH},
title = {Structural and functional association of androgen receptor with telomeres in prostate cancer cells.},
journal = {Aging},
volume = {5},
number = {1},
pages = {3-17},
pmid = {23363843},
issn = {1945-4589},
mesh = {Androgen Antagonists/pharmacology ; Anilides/pharmacology ; Cell Line, Tumor ; Chromatin/metabolism ; Humans ; Male ; Nitriles/pharmacology ; Prostatic Neoplasms/*metabolism ; Receptors, Androgen/*metabolism ; Telomere/*metabolism ; Tosyl Compounds/pharmacology ; Transcription, Genetic ; },
abstract = {Telomeres protect the ends of linear chromosomes from being recognized as damaged DNA, and telomere stability is required for genome stability. Here we demonstrate that telomere stability in androgen receptor (AR)-positive LNCaP human prostate cancer cells is dependent on AR and androgen, as AR inactivation by AR antagonist bicalutamide (Casodex), AR-knockdown, or androgen-depletion caused telomere dysfunction, and the effect of androgen-depletion or Casodex was blocked by the addition of androgen. Notably, neither actinomycin D nor cycloheximide blocked the DNA damage response to Casodex, indicating that the role of AR in telomere stability is independent of its role in transcription. We also demonstrate that AR is a component of telomeres, as AR-bound chromatin contains telomeric DNA, and telomeric chromatin contains AR. Importantly, AR inactivation by Casodex caused telomere aberrations, including multiple abnormal telomere signals, remindful of a fragile telomere phenotype that has been described previously to result from defective telomere DNA replication. We suggest that AR plays an important role in telomere stability and replication of telomere DNA in prostate cancer cells, and that AR inactivation-mediated telomere dysfunction may contribute to genomic instability and progression of prostate cancer cells.},
}
@article {pmid23360839,
year = {2013},
author = {Mathur, S and Ardestani, A and Parker, B and Cappizzi, J and Polk, D and Thompson, PD},
title = {Telomere length and cardiorespiratory fitness in marathon runners.},
journal = {Journal of investigative medicine : the official publication of the American Federation for Clinical Research},
volume = {61},
number = {3},
pages = {613-615},
doi = {10.2310/JIM.0b013e3182814cc2},
pmid = {23360839},
issn = {1708-8267},
mesh = {Adult ; *Athletes ; Demography ; Exercise ; Female ; Granulocytes/metabolism ; Heart/*physiology ; Humans ; Male ; Middle Aged ; Physical Fitness/*physiology ; *Respiration ; Running/*physiology ; Sedentary Behavior ; Telomere/genetics/*metabolism ; },
abstract = {BACKGROUND AND AIM: Physical exercise up-regulates telomere-stabilizing proteins in mice, suggesting that physical activity affects telomere length. Several human studies assessing the relationship between physical activity, measured by health or activity surveys, and telomere length have produced conflicting results. The present study sought to explore the association between telomere length and physical fitness measured objectively as maximal oxygen uptake in endurance-trained athletes and sedentary controls.<br><br>METHODS: Seventeen marathon runners and 15 age- and sex-matched healthy, sedentary control subjects participated in the study. Medical history, demographic information, maximal oxygen uptake (VO2 max), and peripheral blood lymphocyte telomere length were measured in all subjects. Statistical analysis was performed to examine the relationship between telomere length and measured variables.<br><br>RESULTS: Athletes and sedentary controls had similar lymphocyte (0.97 &#xb1; 0.20 vs 1.01 &#xb1; 0.18; P = 0.6) and granulocyte (0.89 &#xb1; 0.11 vs 0.89 &#xb1; 0.12; P = 0.9) telomere lengths. Linear regression analysis showed age as the only variable significantly associated with telomere length (P = 0.007). There was no correlation between VO2 max and telomere length.<br><br>CONCLUSION: In a cohort of healthy adult athletes and sedentary controls, there was no association between physical activity measured by VO2 max and peripheral blood lymphocyte and granulocyte telomere length.},
}
@article {pmid23358853,
year = {2013},
author = {Castro-Vega, LJ and Jouravleva, K and Liu, WY and Martinez, C and Gestraud, P and Hupé, P and Servant, N and Albaud, B and Gentien, D and Gad, S and Richard, S and Bacchetti, S and Londoño-Vallejo, A},
title = {Telomere crisis in kidney epithelial cells promotes the acquisition of a microRNA signature retrieved in aggressive renal cell carcinomas.},
journal = {Carcinogenesis},
volume = {34},
number = {5},
pages = {1173-1180},
doi = {10.1093/carcin/bgt029},
pmid = {23358853},
issn = {1460-2180},
mesh = {Carcinoma, Renal Cell/*genetics/*pathology ; Cell Line, Tumor ; Chromosomal Instability/genetics ; DNA Damage/genetics ; Epithelial Cells/pathology ; Epithelial-Mesenchymal Transition/genetics ; HEK293 Cells ; Humans ; Kidney Neoplasms/*genetics/*pathology ; MicroRNAs/*genetics ; Telomere/*genetics ; Transcription, Genetic/genetics ; },
abstract = {Telomere shortening is a major source of chromosome instability (CIN) at early stages during carcinogenesis. However, the mechanisms through which telomere-driven CIN (T-CIN) contributes to the acquisition of tumor phenotypes remain uncharacterized. We discovered that human epithelial kidney cells undergoing T-CIN display massive microRNA (miR) expression changes that are not related to local losses or gains. This widespread miR deregulation encompasses a miR-200-dependent epithelial-to-mesenchymal transition (EMT) that confers to immortalized pre-tumoral cells phenotypic traits of metastatic potential. Remarkably, a miR signature of these cells, comprising a downregulation of miRs with conserved expression in kidney, was retrieved in poorly differentiated aggressive renal cell carcinomas. Our results reveal an unanticipated connection between telomere crisis and the activation of the EMT program that occurs at pre-invasive stages of epithelial cancers, through mechanisms that involve miR deregulation. Thus, this study provides a new rational into how telomere instability contributes to the acquisition of the malignant phenotype.},
}
@article {pmid23347616,
year = {2013},
author = {Oganesian, L and Karlseder, J},
title = {5' C-rich telomeric overhangs are an outcome of rapid telomere truncation events.},
journal = {DNA repair},
volume = {12},
number = {3},
pages = {238-245},
pmid = {23347616},
issn = {1568-7856},
support = {P30 CA014195/CA/NCI NIH HHS/United States ; R01 GM087476/GM/NIGMS NIH HHS/United States ; GM087476/GM/NIGMS NIH HHS/United States ; P30 CA014195-38/CA/NCI NIH HHS/United States ; },
mesh = {Base Composition ; Cell Line, Tumor ; DNA Damage ; DNA Repair ; DNA, Intergenic ; DNA-Binding Proteins/metabolism ; Fibroblasts/metabolism ; Genome, Human ; Humans ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Werner Syndrome/metabolism ; },
abstract = {A subset of human tumors ensures indefinite telomere length maintenance by activating a telomerase-independent mechanism known as Alternative Lengthening of Telomeres (ALT). Most tumor cells of ALT origin share a constellation of unique characteristics, which include large stores of extra-chromosomal telomeric material, chronic telomere dysfunction and a peculiar enrichment in chromosome ends with 5' C-rich overhangs. Here we demonstrate that acute telomere de-protection and the subsequent DNA damage signal are not sufficient to facilitate formation of 5' C-overhangs at the chromosome end. Rather chromosome ends bearing 5' C-overhangs are a by-product of rapid cleavage events, processing of which occurs independently of the DNA damage response and is partly mediated through the XRCC3 endonuclease.},
}
@article {pmid23346961,
year = {2013},
author = {Boonekamp, JJ and Simons, MJ and Hemerik, L and Verhulst, S},
title = {Telomere length behaves as biomarker of somatic redundancy rather than biological age.},
journal = {Aging cell},
volume = {12},
number = {2},
pages = {330-332},
doi = {10.1111/acel.12050},
pmid = {23346961},
issn = {1474-9726},
mesh = {Aged ; Aged, 80 and over ; Biomarkers/analysis ; Blood Pressure ; Body Mass Index ; Cholesterol/blood ; Computer Simulation ; Humans ; Leukocytes/chemistry ; *Life Expectancy ; *Longevity ; Middle Aged ; *Models, Statistical ; Telomere/*chemistry ; *Telomere Homeostasis ; },
abstract = {Biomarkers of aging are essential to predict mortality and aging-related diseases. Paradoxically, age itself imposes a limitation on the use of known biomarkers of aging because their associations with mortality generally diminish with age. How this pattern arises is, however, not understood. With meta-analysis we show that human leucocyte telomere length (TL) predicts mortality, and that this mortality association diminishes with age, as found for other biomarkers of aging. Subsequently, we demonstrate with simulation models that this observation cannot be reconciled with the popular hypothesis that TL is proportional to biological age. Using the reliability theory of aging, we instead propose that TL is a biomarker of somatic redundancy, the body's capacity to absorb damage, which fits the observed pattern well. We discuss to what extent diminishing redundancy with age may also explain the observed diminishing mortality modulation with age of other biomarkers of aging. Considering diminishing somatic redundancy as the causal agent of aging may critically advance our understanding of the aging process, and improve predictions of life expectancy and vulnerability to aging-related diseases.},
}
@article {pmid23343176,
year = {2013},
author = {Gu, BW and Mason, P},
title = {Telomere 3' overhang and disease.},
journal = {Leukemia &amp; lymphoma},
volume = {54},
number = {7},
pages = {1347-1348},
doi = {10.3109/10428194.2013.769538},
pmid = {23343176},
issn = {1029-2403},
mesh = {Asian People/*genetics ; Female ; Humans ; Leukemia, Myeloid, Acute/*genetics ; Male ; *Mutation ; Telomerase/*genetics ; Telomere/*genetics ; },
}
@article {pmid23342266,
year = {2012},
author = {Butler, KS and Hines, WC and Heaphy, CM and Griffith, JK},
title = {Coordinate regulation between expression levels of telomere-binding proteins and telomere length in breast carcinomas.},
journal = {Cancer medicine},
volume = {1},
number = {2},
pages = {165-175},
pmid = {23342266},
issn = {2045-7634},
mesh = {Adult ; Aged ; Aged, 80 and over ; Breast Neoplasms/genetics/*metabolism ; Carcinoma/genetics/*metabolism ; Cell Line, Tumor ; Dexamethasone/metabolism ; Female ; Humans ; MCF-7 Cells ; Middle Aged ; NF-kappa B/metabolism ; Promoter Regions, Genetic ; RNA, Messenger/biosynthesis ; Shelterin Complex ; Telomerase/genetics/metabolism ; Telomere/*genetics ; *Telomere Homeostasis ; Telomere-Binding Proteins/*biosynthesis/genetics/metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; },
abstract = {Telomere dysregulation occurs in both the in situ and invasive stages of many carcinomas, including breast. Knockout experiments have identified several telomere-associated proteins required for proper telomere function and maintenance, including telomere repeat-binding factor 1 and 2 (TRF1 and TRF2), protection of telomeres (POT1), and TRF1-interacting nuclear factor 2 (TIN2). Using telomere content assays and quantitative reverse transcription-polymerase chain reaction (RT-PCR), we examined the relationship between telomere length and the mRNA levels of telomere-associated proteins in breast tumors. The levels of TRF2, TRF1, TIN2, and POT1 mRNA, but not telomerase reverse transcriptase (TERT) RNA, are inversely correlated with telomere content in breast tumors. Significant associations were identified between the mRNA levels of TRF1, TIN2, and POT1; however, there were no significant associations with the mRNA levels of TRF2 or TERT. These associations suggest that a complex transcriptional program coordinately regulates the expression of these mRNAs. We examined the promoter regions of the telomere-associated proteins to identify transcription factors consistent with the observed patterns of presumed coordinate expression. We demonstrated in human breast cancer cell lines that expressions of TRF1, TIN2, and POT1 are upregulated by dexamethasone, suggesting activation of the glucocorticoid receptor, whereas TERT, TRF2, TRF1, TIN2, and POT1 are upregulated by tumor necrosis factor-α (TNF-α), suggesting activation of the nuclear factor kappa B transcription factor. These findings link telomere content in breast tumors to the coordinate expression of several telomere-associated proteins previously shown to be negative regulators of telomere length in cell lines. The results further suggest a possible link between the expressions of the telomere-associated proteins and mediators of stress and inflammation.Telomere content assays and quantitative RT-PCR demonstrate that the levels of TRF2, TRF1, TIN2, and POT1 mRNA, but not telomerase reverse transcriptase (TERT) RNA, are inversely correlated with telomere content in breast tumors. Within human breast cancer cell lines, expressions of TRF1, TIN2, and POT1 are upregulated by dexamethasone, suggesting activation of the glucocorticoid receptor, whereas TERT, TRF2, TRF1, TIN2, and POT1 are upregulated by TNF-α, suggesting activation of the NFκB transcription factor. These findings link telomere content in breast tumors to the expression of several telomere-associated proteins previously shown to be negative regulators of telomere length in cell lines and suggest a link between the expressions of the telomere-associated proteins and mediators of stress and inflammation.},
}
@article {pmid23341363,
year = {2013},
author = {Qian, D and Zhang, B and He, LR and Cai, MY and Mai, SJ and Liao, YJ and Liu, YH and Lin, MC and Bian, XW and Zeng, YX and Huang, JJ and Kung, HF and Xie, D},
title = {The telomere/telomerase binding factor PinX1 is a new target to improve the radiotherapy effect of oesophageal squamous cell carcinomas.},
journal = {The Journal of pathology},
volume = {229},
number = {5},
pages = {765-774},
doi = {10.1002/path.4163},
pmid = {23341363},
issn = {1096-9896},
mesh = {Animals ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Carcinoma, Squamous Cell/genetics/metabolism/mortality/pathology/*therapy ; Cell Cycle Proteins ; Cell Line, Tumor ; *Chemoradiotherapy ; Cisplatin/administration &amp; dosage ; Dose-Response Relationship, Drug ; Dose-Response Relationship, Radiation ; Drug Resistance, Neoplasm ; Esophageal Neoplasms/genetics/metabolism/mortality/pathology/*therapy ; Female ; Fluorouracil/administration &amp; dosage ; Humans ; Immunohistochemistry ; Male ; Mice ; Mice, Nude ; Middle Aged ; Mitosis/drug effects/radiation effects ; RNA Interference ; Survival Analysis ; Telomerase/metabolism ; Time Factors ; Transfection ; Treatment Outcome ; Tumor Suppressor Proteins/genetics/*metabolism ; Xenograft Model Antitumor Assays ; },
abstract = {Chemoradiotherapy (CRT) is a standard treatment for oesophageal squamous cell carcinoma (ESCC) in its advanced stages. The telomerase/telomere interacting protein PinX1 contributes to telomere maintenance, tumourigenicity, and influences the DNA damage agent-induced apoptotic response in telomerase-positive cancer cells. However, the clinical and biological significance of PinX1 in human ESCCs remains unclear. We examined the expression dynamics of PinX1 by immunohistochemistry in a learning cohort (n = 98) and a validation cohort (n = 59) of ESCC patients treated with definite chemoradiotherapy (CRT). A series of in vivo and in vitro assays were performed to elucidate the effect of PinX1 on ESCC cells' CRT response and underlying mechanisms. Knockdown of PinX1 did not affect ESCC cells' chemosensitivities to 5-fluorouracil and cisplatin, but substantially increased ESCC cells' therapeutic efficacy of radiation both in vitro and in vivo. Ectopic overexpression of PinX1 dramatically enhanced ESCC cells' resistance to radiotherapy. Furthermore, we demonstrated that PinX1 resistance to radiotherapy (RT) was attributed to PinX1 maintaining telomere stability, reducing ESCC cell death by RT-induced mitosis catastrophe (MC). High expression of Pinx1 correlated positively with ESCC's resistance to CRT, and was a strong and independent predictor for short disease-specific survival (DSS) of ESCC patients. Our data suggest that PinX1 could serve as a novel predictor for a CRT response to ESCC patients, and the pathway of PinX1-mediated telomere stability might represent a new target to improve the RT effect of ESCC.},
}
@article {pmid23341124,
year = {2013},
author = {Samassekou, O and Hébert, J and Mai, S and Yan, J},
title = {Nuclear remodeling of telomeres in chronic myeloid leukemia.},
journal = {Genes, chromosomes &amp; cancer},
volume = {52},
number = {5},
pages = {495-502},
doi = {10.1002/gcc.22046},
pmid = {23341124},
issn = {1098-2264},
mesh = {Case-Control Studies ; Cell Nucleus/genetics/*metabolism ; Cell Nucleus Size ; Genomic Instability ; Humans ; In Situ Hybridization, Fluorescence ; Interphase ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*genetics/pathology ; Microscopy, Fluorescence ; Telomere/genetics/*metabolism ; Tumor Cells, Cultured ; },
abstract = {Chronic myeloid leukemia (CML) is a hematologic cancer characterized by the proliferation of myeloid cells and the translocation between chromosomes 9 and 22, [t(9;22)(q34.1;q11.2)]. At the chronic phase (CP), CML cells present longer telomeres than at the other clinical phases, display arm-specific maintenance of individual telomere lengths, and are chromosomally stable. We asked whether an alteration of nuclear organization of telomeres, which is associated with genomic instability, occurs in CML cells at the CP. We used fluorescent in situ hybridization of telomeres combined with three-dimensional (3D) quantification to study the nuclear telomeric architecture of CML cells at the CP. We found that cells can exhibit high telomere numbers, different telomere distributions, and alterations in peripheral or central nuclear location of telomeres. Also, we show that CML cells can be categorized in two groups according to the number of their telomere aggregates (TAs). We propose that the presence of high TAs in some samples is associated with the increased genomic instability and could be an indication of the clinical transitional phase. Also, alterations of nuclear organization of telomeres at the CP confirm that nuclear remodeling of telomeres can occur at an early clinical stage of a cancer.},
}
@article {pmid23338150,
year = {2013},
author = {Qin, X and Qi, B and Zhao, B},
title = {Alternative lengthening of telomeres is induced by telomerase inhibitors in Barrett's esophageal cells.},
journal = {Oncology reports},
volume = {29},
number = {4},
pages = {1399-1404},
doi = {10.3892/or.2013.2238},
pmid = {23338150},
issn = {1791-2431},
mesh = {Apoptosis/drug effects ; Barrett Esophagus/*genetics/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Transformation, Neoplastic ; Enzyme Inhibitors/pharmacology ; Humans ; In Situ Hybridization, Fluorescence ; RNA, Small Interfering/genetics ; Sister Chromatid Exchange/genetics ; Telomerase/antagonists &amp; inhibitors/genetics/*metabolism ; Telomere/*genetics ; *Telomere Homeostasis/drug effects/genetics ; },
abstract = {A crucial step in the path to the malignant transformation of cells and tumor formation is immortalization, which essentially depends on telomere maintenance. The aim of this study was to investigate the role of telomerase in the progression of Barrett's esophagus. Telomerase activity was measured in Barrett's cells using terminal restriction fragment (TRF) analysis. Telomere length was measured using Q-FISH analysis. Furthermore, the telomere recombination events were detected between sister chromatids using chromosome orientation FISH (CO-FISH). There was a reduction in telomerase activity in the CP-A cells transduced with MT-hTER/47A+siRNA, which led to an almost complete disappearance of telomerase activity. The telomere length of the CP-A cells transduced with MT-hTER/47A+siRNA was slightly shorter compared to that of the untransduced cells. The telomerase-inhibited cells were morphologically indistinguishable from those untransduced and WT-hter-transduced cells. In the control cells, the growth rate was between 0.9 to 1.1 with the population doubling per day. Although the transduction of the telomerase inhibitors in the CP-A cells did not cause a significant reduction in cell growth, these transduced cells grew generally slower compared with the control cells. The heterogeneous telomere length was also be detected in the telomerase-inhibited CP-A cells. However, the telomere length remained homogeneous in the control cells. The metaphase of the CP-A cells transduced with MT-hTER/47A+siRNA demonstrated 70% heterogeneous telomeres. In addition, no increased recombination was observed between sister chromatids in the transduced CP-A cells compared with the control cells. Our findings suggest that an alternative lengthening of telomeres (ALT) may be induced by telomerase inhibitors in CP-A cells. Therefore, telomerase inhibitors may exhibit high potency in the treatment of esophageal adenocarcinoma arising from Barrett's esophagus.},
}
@article {pmid23337086,
year = {2013},
author = {Ichikawa, Y and Kagawa, W and Saito, K and Chikashige, Y and Haraguchi, T and Hiraoka, Y and Kurumizaka, H},
title = {Purification and characterization of the fission yeast telomere clustering factors, Bqt1 and Bqt2.},
journal = {Protein expression and purification},
volume = {88},
number = {2},
pages = {207-213},
doi = {10.1016/j.pep.2013.01.006},
pmid = {23337086},
issn = {1096-0279},
mesh = {Amino Acid Sequence ; Escherichia coli/genetics ; Gene Expression ; Genetic Vectors/genetics ; Molecular Sequence Data ; Protein Multimerization ; Recombinant Fusion Proteins/chemistry/genetics/isolation &amp; purification ; Saccharomyces cerevisiae Proteins/chemistry/genetics/isolation &amp; purification ; Schizosaccharomyces/chemistry/*genetics ; Schizosaccharomyces pombe Proteins/chemistry/*genetics/*isolation &amp; purification ; Small Ubiquitin-Related Modifier Proteins/chemistry/genetics/isolation &amp; purification ; Solubility ; Telomere-Binding Proteins/chemistry/*genetics/*isolation &amp; purification ; },
abstract = {During meiosis, chromosomes adopt a bouquet arrangement, which is widely conserved among eukaryotes. This arrangement is assumed to play an important role in the normal progression of meiosis, by mediating the proper pairing of homologous chromosomes. In Schizosaccharomyces pombe, the complex of Bqt1 and Bqt2 plays a key role in telomere clustering and the subsequent bouquet arrangement of chromosomes during early meiotic prophase. Bqt1 and Bqt2 are part of a multi-protein complex that mediates the attachment of the telomere to the nuclear membrane. However, the structural details of the complex are needed to clarify the mechanism of telomere clustering. To enable biophysical studies of Bqt1 and Bqt2, we established a purification procedure for the Schizosaccharomyces japonicus Bqt1-Bqt2 complex, which is closely related to the S. pombe Bqt1-Bqt2 complex. A co-expression vector, in which one of the expressed subunits is fused to a removable SUMO tag, yielded high amounts of the proteins in the soluble fraction. The solubility of the Bqt1-Bqt2 complex after the removal of the SUMO tag was maintained by including CHAPS, a nondenaturing, zwitterionic detergent, in the purification buffers. These procedures enabled us to rapidly purify the stable Bqt1-Bqt2 complex. The co-purified Bqt1 and Bqt2 proteins formed a stable heterodimer, consistent with results from in vivo studies showing the requirement of both proteins for the bouquet arrangement. The expression and purification procedures established here will facilitate further biophysical studies of the Bqt1-Bqt2 complex.},
}
@article {pmid23335786,
year = {2013},
author = {Almeida, H and Godinho Ferreira, M},
title = {Spontaneous telomere to telomere fusions occur in unperturbed fission yeast cells.},
journal = {Nucleic acids research},
volume = {41},
number = {5},
pages = {3056-3067},
pmid = {23335786},
issn = {1362-4962},
mesh = {Chromosomal Instability ; Chromosomes, Fungal/genetics/metabolism ; DNA End-Joining Repair ; Gene Fusion ; Neoplasms/genetics ; Schizosaccharomyces/*genetics/metabolism ; Schizosaccharomyces pombe Proteins/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomeres protect eukaryotic chromosomes from illegitimate end-to-end fusions. When this function fails, dicentric chromosomes are formed, triggering breakage-fusion-bridge cycles and genome instability. How efficient is this protection mechanism in normal cells is not fully understood. We created a positive selection assay aimed at capturing chromosome-end fusions in Schizosaccharomyces pombe. We placed telomere sequences with a head to head arrangement in an intron of a selectable marker contained on a plasmid. By linearizing the plasmid between the telomere sequences, we generated a stable mini-chromosome that fails to express the reporter gene. Whenever the ends of the mini-chromosome join, the marker gene is reconstituted and fusions are captured by direct selection. Using telomerase mutants, we recovered several fusion events that lacked telomere sequences. The end-joining reaction involved specific homologous subtelomeric sequences capable of forming hairpins, suggestive of ssDNA stabilization prior to fusing. These events occurred via microhomology-mediated end-joining (MMEJ)/single-strand annealing (SSA) repair and also required MRN/Ctp1. Strikingly, we were able to capture spontaneous telomere-to-telomere fusions in unperturbed cells. Similar to disruption of the telomere regulator Taz1/TRF2, end-joining reactions occurred via non-homologous end-joining (NHEJ) repair. Thus, telomeres undergo fusions prior to becoming critically short, possibly through transient deprotection. These dysfunction events induce chromosome instability and may underlie early tumourigenesis.},
}
@article {pmid23335335,
year = {2013},
author = {Gupta, A and Sharma, S and Reichenbach, P and Marjavaara, L and Nilsson, AK and Lingner, J and Chabes, A and Rothstein, R and Chang, M},
title = {Telomere length homeostasis responds to changes in intracellular dNTP pools.},
journal = {Genetics},
volume = {193},
number = {4},
pages = {1095-1105},
pmid = {23335335},
issn = {1943-2631},
support = {GM67055/GM/NIGMS NIH HHS/United States ; R37 GM050237/GM/NIGMS NIH HHS/United States ; R01 GM067055/GM/NIGMS NIH HHS/United States ; R01 GM050237/GM/NIGMS NIH HHS/United States ; GM50237/GM/NIGMS NIH HHS/United States ; },
mesh = {Nucleotides/*metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/metabolism ; *Telomere Homeostasis ; Telomere Shortening ; },
abstract = {Telomeres, the ends of linear eukaryotic chromosomes, shorten due to incomplete DNA replication and nucleolytic degradation. Cells counteract this shortening by employing a specialized reverse transcriptase called telomerase, which uses deoxyribonucleoside triphosphates (dNTPs) to extend telomeres. Intracellular dNTP levels are tightly regulated, and perturbation of these levels is known to affect DNA synthesis. We examined whether altering the levels of the dNTP pools or changing the relative ratios of the four dNTPs in Saccharomyces cerevisiae would affect the length of the telomeres. Lowering dNTP levels leads to a modest shortening of telomeres, while increasing dNTP pools has no significant effect on telomere length. Strikingly, altering the ratio of the four dNTPs dramatically affects telomere length homeostasis, both positively and negatively. Specifically, we find that intracellular deoxyguanosine triphosphate (dGTP) levels positively correlate with both telomere length and telomerase nucleotide addition processivity in vivo. Our findings are consistent with in vitro data showing dGTP-dependent stimulation of telomerase activity in multiple organisms and suggest that telomerase activity is modulated in vivo by dGTP levels.},
}
@article {pmid23333817,
year = {2013},
author = {Müezzinler, A and Zaineddin, AK and Brenner, H},
title = {A systematic review of leukocyte telomere length and age in adults.},
journal = {Ageing research reviews},
volume = {12},
number = {2},
pages = {509-519},
doi = {10.1016/j.arr.2013.01.003},
pmid = {23333817},
issn = {1872-9649},
mesh = {Age Factors ; Aged ; Aged, 80 and over ; Aging/genetics ; Cross-Sectional Studies ; Humans ; Leukocytes/*physiology ; Linear Models ; Longitudinal Studies ; Middle Aged ; Telomere Homeostasis/*physiology ; *Telomere Shortening ; },
abstract = {OBJECTIVE: To provide a systematic review of the relationship between age and leukocyte telomere length (LTL) in adults.<br><br>METHODS: Relevant studies were identified by a systematic search of Medline, EMBASE and ISI Web of Knowledge databases. Key data, such as age and LTL, were extracted from the studies along with correlation coefficients and yearly attrition rates where available. Obtained data were used to calculate weighted means and correlation coefficients.<br><br>RESULTS: Overall, 124 cross-sectional studies and 5 longitudinal studies were identified. A statistically significant inverse correlation between mean age and mean LTL across cross-sectional studies was observed for both absolute (r=-0.338, p<0.0001) and relative LTL (r=-0.295, p=0.0088). From mean LTL and ages, a yearly telomere loss of 24.7 base pairs (BP)/year was estimated by weighted linear regression. Weighted means of within study correlation of age and TL and yearly telomere loss rate estimates from cross-sectional studies were also in a similar order of magnitude (-0.380 and 21.91 BP/year). The few longitudinal studies reported somewhat higher mean telomere loss rates (between 32.2 and 45.5 BP/year).<br><br>CONCLUSION: While a decrease of LTL with age is out of question, data on variation of the decrease according to sex, age and other potential determinants especially from longitudinal data are still sparse.},
}
@article {pmid23329068,
year = {2013},
author = {Ballew, BJ and Yeager, M and Jacobs, K and Giri, N and Boland, J and Burdett, L and Alter, BP and Savage, SA},
title = {Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita.},
journal = {Human genetics},
volume = {132},
number = {4},
pages = {473-480},
pmid = {23329068},
issn = {1432-1203},
support = {ZIA CP010144/ImNIH/Intramural NIH HHS/United States ; ZIA CP010144-13/ImNIH/Intramural NIH HHS/United States ; N02-CP-91026/CP/NCI NIH HHS/United States ; N02CP11019/CP/NCI NIH HHS/United States ; },
mesh = {Adult ; Child ; Child, Preschool ; DNA Helicases/*genetics/metabolism ; Dyskeratosis Congenita/enzymology/*genetics ; Exome ; Family ; Female ; *Germ-Line Mutation ; Humans ; Infant ; Male ; *Mutation, Missense ; Protein Structure, Tertiary ; Telomere/enzymology/genetics ; },
abstract = {Dyskeratosis congenita (DC) is an inherited bone marrow failure and cancer predisposition syndrome caused by aberrant telomere biology. The classic triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia is diagnostic of DC, but substantial clinical heterogeneity exists; the clinically severe variant Hoyeraal Hreidarsson syndrome (HH) also includes cerebellar hypoplasia, severe immunodeficiency, enteropathy, and intrauterine growth retardation. Germline mutations in telomere biology genes account for approximately one-half of known DC families. Using exome sequencing, we identified mutations in RTEL1, a helicase with critical telomeric functions, in two families with HH. In the first family, two siblings with HH and very short telomeres inherited a premature stop codon from their mother who has short telomeres. The proband from the second family has HH and inherited a premature stop codon in RTEL1 from his father and a missense mutation from his mother, who also has short telomeres. In addition, inheritance of only the missense mutation led to very short telomeres in the proband's brother. Targeted sequencing identified a different RTEL1 missense mutation in one additional DC proband who has bone marrow failure and short telomeres. Both missense mutations affect the helicase domain of RTEL1, and three in silico prediction algorithms suggest that they are likely deleterious. The nonsense mutations both cause truncation of the RTEL1 protein, resulting in loss of the PIP box; this may abrogate an important protein-protein interaction. These findings implicate a new telomere biology gene, RTEL1, in the etiology of DC.},
}
@article {pmid23326560,
year = {2013},
author = {Toutain, J and Prochazkova-Carlotti, M and Cappellen, D and Jarne, A and Chevret, E and Ferrer, J and Idrissi, Y and Pelluard, F and Carles, D and Maugey-Laulon, B and Lacombe, D and Horovitz, J and Merlio, JP and Saura, R},
title = {Reduced placental telomere length during pregnancies complicated by intrauterine growth restriction.},
journal = {PloS one},
volume = {8},
number = {1},
pages = {e54013},
pmid = {23326560},
issn = {1932-6203},
mesh = {Adult ; Chorionic Villi Sampling ; Female ; *Fetal Growth Retardation/physiopathology ; Gene Dosage ; Humans ; In Situ Hybridization, Fluorescence ; Placenta/*cytology/physiopathology ; *Placental Insufficiency/genetics/physiopathology ; Pregnancy ; Pregnancy Complications/physiopathology ; RNA/genetics ; Telomerase/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {OBJECTIVES: Recent studies have shown that telomere length was significantly reduced in placentas collected at delivery from pregnancies complicated by intrauterine growth restriction secondary to placental insufficiency. Placental telomere length measurement during ongoing pregnancies complicated by intrauterine growth restriction has never been reported. This was the main objective of our study.<br><br>METHODS: In our center, late chorionic villus samplings were performed between 18 and 37 weeks of amenorrhea in 24 subjects with severe intrauterine growth restriction (cases) and in 28 subjects with other indications for prenatal diagnosis (controls). Placental insufficiency was assessed by histo-pathological examination. Relative measurement of telomere length was carried out prospectively by quantitative Fluorescent In Situ Hybridization using fluorescent Peptide Nucleic Acid probes on interphase nuclei obtained from long-term cultured villi and with an automated epifluorescent microscope. A quantitative Polymerase Chain Reaction technique was performed to confirm the quantitative Fluorescent In Situ Hybridization results. The number of copies of gene loci encoding the RNA template (hTERC) and the catalytic subunit (hTERT) of the enzyme complex telomerase were also estimated in these placentas by Fluorescent In Situ Hybridization.<br><br>RESULTS: Mean fluorescence intensity of telomere probes estimated by quantitative Fluorescent In Situ Hybridization was significantly less for cases compared to controls (p<0.001). This result indicated that mean telomere length was significantly reduced in placentas during pregnancies complicated by intrauterine growth restriction. Reduced telomere length was confirmed by the quantitative Polymerase Chain Reaction technique. No copy number variation of the hTERC and hTERT loci was noticed for cases, or for controls.<br><br>CONCLUSION: This study clearly demonstrates a reduction of placental telomere length in ongoing pregnancies (from 18 to 37 weeks of amenorrhea) complicated by severe intrauterine growth restriction secondary to placental insufficiency.},
}
@article {pmid23323942,
year = {2013},
author = {Zhang, W and Chen, Y and Wang, Y and Liu, P and Zhang, M and Zhang, C and Hu, FB and Hui, R},
title = {Short telomere length in blood leucocytes contributes to the presence of atherothrombotic stroke and haemorrhagic stroke and risk of post-stroke death.},
journal = {Clinical science (London, England : 1979)},
volume = {125},
number = {1},
pages = {27-36},
doi = {10.1042/CS20120691},
pmid = {23323942},
issn = {1470-8736},
mesh = {Adult ; Aged ; Carotid Arteries/pathology ; Carotid Artery Diseases/pathology ; Case-Control Studies ; China/epidemiology ; Cohort Studies ; Female ; Humans ; Leukocytes/*pathology ; Male ; Middle Aged ; Plaque, Atherosclerotic/pathology ; Stroke/mortality/*pathology ; Telomere/*pathology ; *Telomere Shortening ; },
abstract = {Inter-individual differences in biological aging could affect susceptibility to stroke. To date, the relationship between stroke and telomere shortening remain inconclusive; and sparse data are available for haemorrhagic stroke. A Chinese case-control study was conducted, comprising 1756 cases (767 atherothrombosis, 503 lacunar infarction and 486 haemorrhagic strokes) and 1801 controls. Stroke patients were prospectively followed up for a median of 4.5 (range, 0.1-6.0) years. Individuals with shorter telomere length had a higher presence of atherothrombotic stroke {multivariate OR (odds ratio) 1.37 [95% CI (confidence interval), 1.06-1.77]; P=0.015}
or haemorrhagic stroke [multivariate OR 1.48 (95% CI, 1.08-2.02); P=0.016] in comparison of the lowest to highest tertile of telomere length. Particularly, in subjects with a family history of stroke, there was a significant 2.55-fold increased presence of atherothrombotic stroke (95% CI, 1.87-3.48; Ptrend<0.0001) and a 2.33-fold increased presence of haemorrhagic stroke (95% CI, 1.62-3.36; Ptrend<0.0001). During the follow-up, 338 recurrent strokes and 312 deaths (181 from stroke or coronary heart disease and 131 from other causes) were documented. Associations with stroke recurrence were not observed in the follow-up patients, whereas atherothrombotic stroke cases with shorter telomeres had 69% increased risk of post-stroke death [relative risk, 1.69 (95% CI, 1.07-2.67); P=0.02]. Finally, we compared telomere lengths in 12 paired samples of circulating leucocytes and carotid atherosclerotic plaques from patients undergoing carotid endarterectomy; there was a positive correlation between vessel wall tissue and leucocyte telomere length. In conclusion, shorter telomere length may serve as a potential marker for the presence of atherothrombotic and haemorrhagic stroke and for the risk of post-stroke death.},
}
@article {pmid23321625,
year = {2013},
author = {Broer, L and Codd, V and Nyholt, DR and Deelen, J and Mangino, M and Willemsen, G and Albrecht, E and Amin, N and Beekman, M and de Geus, EJ and Henders, A and Nelson, CP and Steves, CJ and Wright, MJ and de Craen, AJ and Isaacs, A and Matthews, M and Moayyeri, A and Montgomery, GW and Oostra, BA and Vink, JM and Spector, TD and Slagboom, PE and Martin, NG and Samani, NJ and van Duijn, CM and Boomsma, DI},
title = {Meta-analysis of telomere length in 19,713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect.},
journal = {European journal of human genetics : EJHG},
volume = {21},
number = {10},
pages = {1163-1168},
pmid = {23321625},
issn = {1476-5438},
support = {//British Heart Foundation/United Kingdom ; //Department of Health/United Kingdom ; //Wellcome Trust/United Kingdom ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Case-Control Studies ; Female ; Humans ; Inheritance Patterns ; Male ; Middle Aged ; *Paternal Age ; *Pedigree ; Telomere/*genetics ; Telomere Shortening/*genetics ; Twins/genetics ; },
abstract = {Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19,713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64-0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother-offspring (r=0.42; P-value=3.60 × 10(-61)) than father-offspring correlation (r=0.33; P-value=7.01 × 10(-5)), and a significant positive association with paternal age at offspring birth (β=0.005; P-value=7.01 × 10(-5)). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10(-30)) was seen, which appeared stronger in older spouse pairs (mean age ≥55 years; r=0.31; P-value=4.27 × 10(-23)) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10(-10)). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.},
}
@article {pmid23321015,
year = {2013},
author = {Taka, T and Huang, L and Wongnoppavich, A and Tam-Chang, SW and Lee, TR and Tuntiwechapikul, W},
title = {Telomere shortening and cell senescence induced by perylene derivatives in A549 human lung cancer cells.},
journal = {Bioorganic &amp; medicinal chemistry},
volume = {21},
number = {4},
pages = {883-890},
doi = {10.1016/j.bmc.2012.12.020},
pmid = {23321015},
issn = {1464-3391},
mesh = {Cell Line, Tumor ; Cell Proliferation/drug effects ; Cellular Senescence/drug effects ; Down-Regulation/drug effects ; G-Quadruplexes ; Humans ; Imides/*chemistry/pharmacology ; Lung Neoplasms/metabolism/pathology ; Perylene/*analogs &amp; derivatives/chemistry/pharmacology ; Promoter Regions, Genetic ; Telomerase/antagonists &amp; inhibitors/genetics/metabolism ; Telomere/*metabolism ; Telomere Shortening/drug effects ; },
abstract = {Cancer cells evade replicative senescence by re-expressing telomerase, which maintains telomere length and hence chromosomal integrity. Telomerase inhibition would lead cancer cells to senesce and therefore prevent cancer cells from growing indefinitely. G-quadruplex ligands can attenuate telomerase activity by inducing G-quadruplex formation at the 3'-overhang of telomere and at the human telomerase reverse transcriptase (hTERT) promoter; the former prevents telomerase from accessing the telomere, and the latter acts as a transcriptional silencer. The present investigation found that perylene derivatives PM2 and PIPER induced G-quadruplex formation from both telomeric DNA and the hTERT promoter region in vitro. Further, TRAP assay showed that these compounds inhibited telomerase in a dose-dependent manner. When A549 human lung cancer cells were treated with these compounds, hTERT expression was down-regulated. Moreover, the crude protein extract from these treated cells exhibited less telomerase activity. In the long-term treatment of A549 lung cancer cells with sub-cytotoxic dose of these perylenes, telomere shortening, reduction of cell proliferation and tumorigenicity, and cell senescence were observed. The results of this study indicate that perylene derivatives warrant further consideration as effective agents for cancer therapy.},
}
@article {pmid23319366,
year = {2013},
author = {Tasaka, K and Yokoyama, N and Nodono, H and Hoshi, M and Matsumoto, M},
title = {Innate sexuality determines the mechanisms of telomere maintenance.},
journal = {The International journal of developmental biology},
volume = {57},
number = {1},
pages = {69-72},
doi = {10.1387/ijdb.120114mm},
pmid = {23319366},
issn = {1696-3547},
mesh = {Animals ; Cell Division ; Longevity ; Planarians/cytology/*physiology ; Reproduction/physiology ; Reproduction, Asexual/*physiology ; Sexuality ; Telomere ; *Telomere Homeostasis ; },
abstract = {Recently, telomere length has been shown to be differentially regulated in asexually and sexually reproducing planarians. In addition, it was found that asexual worms maintain telomere length somatically during reproduction by fission or when regeneration is induced by amputation, whereas sexual worms only achieve telomere elongation through sexual reproduction. We have established an experimental bioassay system to induce switching from asexual to sexual reproduction in planarians, that is, sexualization. In this study, the relationship between the reproductive mode and telomere maintenance was investigated using innate asexually reproducing worms, innate sexually reproducing worms, and experimentally sexualized worms. Here, we show that innate asexual planarians maintain telomere length during cell division and that innate sexual planarians exhibit telomere shortening. However, experimental sexualized worms maintain telomere length during cell division. These results indicate that innate sexuality is linked to the mechanism of telomere maintenance.},
}
@article {pmid23312805,
year = {2013},
author = {Grandin, N and Charbonneau, M},
title = {RPA provides checkpoint-independent cell cycle arrest and prevents recombination at uncapped telomeres of Saccharomyces cerevisiae.},
journal = {DNA repair},
volume = {12},
number = {3},
pages = {212-226},
doi = {10.1016/j.dnarep.2012.12.002},
pmid = {23312805},
issn = {1568-7856},
mesh = {*Cell Cycle Checkpoints ; DNA, Fungal/genetics ; DNA, Single-Stranded/genetics ; Microbial Viability/genetics ; Mutation, Missense ; *Recombination, Genetic ; Replication Protein A/*genetics/metabolism/physiology ; Saccharomyces cerevisiae/*genetics/growth &amp; development/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism/physiology ; Spores, Fungal/genetics/metabolism ; Telomere/*genetics ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Replication Protein A (RPA) is an evolutionary conserved essential complex with single-stranded DNA binding properties that has been implicated in numerous DNA transactions. At damaged telomeres, Saccharomyces cerevisiae RPA recruits the Mec1-Ddc2 module of the DNA damage checkpoint network, its only known function in DNA damage signaling. Here, we describe rfa1 mutants (rfa1-1, rfa1-9, rfa1-10, rfa1-11 and rfa1-12) that are proficient in this checkpoint but nevertheless exhibit deregulation of cell cycle control upon telomere uncapping induced by the cdc13-1 mutation. Overriding of this damage-induced checkpoint-independent cell cycle block in the rfa1 mutants was suppressed following genetic inactivation of either TEL1 or EST2/telomerase. Altogether, our results suggest that a previously non-suspected function of RPA is to block cell cycle progression upon telomere uncapping using a yet unidentified pathway that functions in a Mec1-Ddc2-independent manner. We propose that in the rfa1 mutants, ill-masking of uncapped telomeres provokes inappropriate access of Tel1 and inappropriate functioning of telomerase, which, by yet unknown mechanisms, allows cell division to take place in spite of the block established by the DNA damage checkpoint. In the present study, we also observed that upon telomere uncapping, rfa1-12, but not the other studied rfa1 mutants, triggered telomeric recombination in the presence of functional telomerase. In conclusion, the present study identifies a novel pathway of telomere end protection that utilizes a previously unsuspected function of RPA at the telomeres.},
}
@article {pmid23312029,
year = {2013},
author = {Cohn, M},
title = {OB Fold Contributes to Telomere Maintenance.},
journal = {Structure (London, England : 1993)},
volume = {21},
number = {1},
pages = {3-4},
doi = {10.1016/j.str.2012.12.005},
pmid = {23312029},
issn = {1878-4186},
abstract = {The essential Cdc13 protein is part of the trimeric CST complex that confers genome stability by binding to and protecting yeast telomeres. In this issue of Structure, Mason and colleagues characterize an OB fold domain of Cdc13 (named OB2) and propose that homo-dimerization of OB2 is required for proper assembly of the CST complex and telomere maintenance.},
}
@article {pmid23307865,
year = {2013},
author = {Neumann, AA and Watson, CM and Noble, JR and Pickett, HA and Tam, PP and Reddel, RR},
title = {Alternative lengthening of telomeres in normal mammalian somatic cells.},
journal = {Genes &amp; development},
volume = {27},
number = {1},
pages = {18-23},
pmid = {23307865},
issn = {1549-5477},
mesh = {Animals ; B-Lymphocytes/cytology ; Breeding ; Cell Line ; Chimera/genetics ; Chromosomes/genetics/metabolism ; Embryonic Stem Cells/cytology/metabolism ; Female ; Genotyping Techniques ; Keratinocytes/cytology/metabolism/*physiology ; Male ; Mammals ; Mice ; Mice, Inbred C57BL ; Spermatocytes/cytology/physiology ; Staining and Labeling ; T-Lymphocytes/cytology ; Telomere Homeostasis/*genetics ; },
abstract = {Some cancers use alternative lengthening of telomeres (ALT), a mechanism whereby new telomeric DNA is synthesized from a DNA template. To determine whether normal mammalian tissues have ALT activity, we generated a mouse strain containing a DNA tag in a single telomere. We found that the tagged telomere was copied by other telomeres in somatic tissues but not the germline. The tagged telomere was also copied by other telomeres when introgressed into CAST/EiJ mice, which have telomeres more similar in length to those of humans. We conclude that ALT activity occurs in normal mouse somatic tissues.},
}
@article {pmid23307557,
year = {2013},
author = {Her, YR and Chung, IK},
title = {p300-mediated acetylation of TRF2 is required for maintaining functional telomeres.},
journal = {Nucleic acids research},
volume = {41},
number = {4},
pages = {2267-2283},
pmid = {23307557},
issn = {1362-4962},
mesh = {Acetylation ; Amino Acid Substitution ; Cell Line ; Cell Proliferation ; DNA Damage ; Humans ; Protein Structure, Tertiary ; Proteolysis ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/chemistry/genetics/*metabolism ; Ubiquitin/metabolism ; p300-CBP Transcription Factors/*metabolism ; },
abstract = {The human telomeric protein TRF2 is required to protect chromosome ends by facilitating their organization into the protective capping structure. Post-translational modifications of TRF2 such as phosphorylation, ubiquitination, SUMOylation, methylation and poly(ADP-ribosyl)ation have been shown to play important roles in telomere function. Here we show that TRF2 specifically interacts with the histone acetyltransferase p300, and that p300 acetylates the lysine residue at position 293 of TRF2. We also report that p300-mediated acetylation stabilizes the TRF2 protein by inhibiting its ubiquitin-dependent proteolysis and is required for efficient telomere binding of TRF2. Furthermore, overexpression of the acetylation-deficient mutant, K293R, induces DNA-damage response foci at telomeres, thereby leading to induction of impaired cell growth, cellular senescence and altered cell cycle distribution. A small but significant number of metaphase chromosomes show no telomeric signals at chromatid ends, suggesting an aberrant telomere structure. These findings demonstrate that acetylation of TRF2 by p300 plays a crucial role in the maintenance of functional telomeres as well as in the regulation of the telomere-associated DNA-damage response, thus providing a new route for modulating telomere protection function.},
}
@article {pmid23303789,
year = {2013},
author = {Long, X and Parks, JW and Bagshaw, CR and Stone, MD},
title = {Mechanical unfolding of human telomere G-quadruplex DNA probed by integrated fluorescence and magnetic tweezers spectroscopy.},
journal = {Nucleic acids research},
volume = {41},
number = {4},
pages = {2746-2755},
pmid = {23303789},
issn = {1362-4962},
support = {R01 GM095850/GM/NIGMS NIH HHS/United States ; GM095850-02/GM/NIGMS NIH HHS/United States ; DGE 0809125//PHS HHS/United States ; },
mesh = {DNA/*chemistry ; Fluorescence Resonance Energy Transfer/*methods ; *G-Quadruplexes ; Humans ; Magnets ; Telomere/*chemistry ; },
abstract = {Single-molecule techniques facilitate analysis of mechanical transitions within nucleic acids and proteins. Here, we describe an integrated fluorescence and magnetic tweezers instrument that permits detection of nanometer-scale DNA structural rearrangements together with the application of a wide range of stretching forces to individual DNA molecules. We have analyzed the force-dependent equilibrium and rate constants for telomere DNA G-quadruplex (GQ) folding and unfolding, and have determined the location of the transition state barrier along the well-defined DNA-stretching reaction coordinate. Our results reveal the mechanical unfolding pathway of the telomere DNA GQ is characterized by a short distance (<1 nm) to the transition state for the unfolding reaction. This mechanical unfolding response reflects a critical contribution of long-range interactions to the global stability of the GQ fold, and suggests that telomere-associated proteins need only disrupt a few base pairs to destabilize GQ structures. Comparison of the GQ unfolded state with a single-stranded polyT DNA revealed the unfolded GQ exhibits a compacted non-native conformation reminiscent of the protein molten globule. We expect the capacity to interrogate macromolecular structural transitions with high spatial resolution under conditions of low forces will have broad application in analyses of nucleic acid and protein folding.},
}
@article {pmid23302541,
year = {2013},
author = {Sanders, JL and Newman, AB},
title = {Telomere length in epidemiology: a biomarker of aging, age-related disease, both, or neither?.},
journal = {Epidemiologic reviews},
volume = {35},
number = {1},
pages = {112-131},
pmid = {23302541},
issn = {1478-6729},
support = {F30 AG038093/AG/NIA NIH HHS/United States ; 1F30-AG038093/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*genetics ; Animals ; Atherosclerosis/*epidemiology/genetics ; Biomarkers ; Genetic Markers ; Humans ; Leukocytes/*metabolism ; Mice ; *Oxidative Stress ; Sex Factors ; Telomere/*metabolism ; White People/genetics ; },
abstract = {Telomeres are nucleoprotein caps flanking DNA. They are shortened by cell division and oxidative stress and are lengthened by the enzyme telomerase and DNA exchange during mitosis. Short telomeres induce cellular senescence. As an indicator of oxidative stress and senescence (2 processes thought to be fundamental to aging), telomere length is hypothesized to be a biomarker of aging. This hypothesis has been tested for more than a decade with epidemiologic study methods. In cross-sectional studies, researchers have investigated whether leukocyte telomere length (LTL) is associated with demographic, behavioral, and health variables. In prospective studies, baseline LTL has been used to predict mortality and occasionally other adverse health outcomes. Conflicting data have generated heated debate about the value of LTL as a biomarker of overall aging. In this review, we address the epidemiologic data on LTL and demonstrate that shorter LTL is associated with older age, male gender, Caucasian race, and possibly atherosclerosis; associations with other markers of health are equivocal. We discuss the reasons for discrepancy across studies, including a detailed review of methods for measuring telomere length as they apply to epidemiology. Finally, we conclude with questions about LTL as a biomarker of aging and how epidemiology can be used to answer these questions.},
}
@article {pmid23300766,
year = {2012},
author = {Østhus, IB and Sgura, A and Berardinelli, F and Alsnes, IV and Brønstad, E and Rehn, T and Støbakk, PK and Hatle, H and Wisløff, U and Nauman, J},
title = {Telomere length and long-term endurance exercise: does exercise training affect biological age? A pilot study.},
journal = {PloS one},
volume = {7},
number = {12},
pages = {e52769},
pmid = {23300766},
issn = {1932-6203},
mesh = {Adult ; Aged ; *Aging ; Cross-Sectional Studies ; Humans ; Male ; Muscle, Skeletal/metabolism ; Oxygen Consumption ; Physical Endurance ; Physical Fitness ; Pilot Projects ; Running ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Telomeres are potential markers of mitotic cellular age and are associated with physical ageing process. Long-term endurance training and higher aerobic exercise capacity (VO(2max)) are associated with improved survival, and dynamic effects of exercise are evident with ageing. However, the association of telomere length with exercise training and VO(2max) has so far been inconsistent. Our aim was to assess whether muscle telomere length is associated with endurance exercise training and VO(2max) in younger and older people.<br><br>METHODS: Twenty men; 10 young (22-27 years) and 10 old (66-77 years), were studied in this cross-sectional study. Five out of 10 young adults and 5 out of 10 older were endurance athletes, while other halves were exercising at a medium level of activity. Mean telomere length was measured as telomere/single copy gene-ratio (T/S-ratio) using quantitative real time polymerase chain reaction. VO(2max) was measured directly running on a treadmill.<br><br>RESULTS: Older endurance trained athletes had longer telomere length compared with older people with medium activity levels (T/S ratio 1.12&#xb1;0.1 vs. 0.92&#xb1;0.2, p&#x200a;=&#x200a;0.04). Telomere length of young endurance trained athletes was not different than young non-athletes (1.47&#xb1;0.2 vs. 1.33&#xb1;0.1, p&#x200a;=&#x200a;0.12). Overall, there was a positive association between T/S ratio and VO(2max) (r&#x200a;=&#x200a;0.70, p&#x200a;=&#x200a;0.001). Among endurance trained athletes, we found a strong correlation between VO(2max) and T/S ratio (r&#x200a;=&#x200a;0.78, p&#x200a;=&#x200a;0.02). However, corresponding association among non-athlete participants was relatively weak (r&#x200a;=&#x200a;0.58, p&#x200a;=&#x200a;0.09).<br><br>CONCLUSION: Our data suggest that VO(2max) is positively associated with telomere length, and we found that long-term endurance exercise training may provide a protective effect on muscle telomere length in older people.},
}
@article {pmid23300679,
year = {2012},
author = {Bodelon, C and Pfeiffer, RM and Bollati, V and Debbache, J and Calista, D and Ghiorzo, P and Fargnoli, MC and Bianchi-Scarra, G and Peris, K and Hoxha, M and Hutchinson, A and Burdette, L and Burke, L and Fang, S and Tucker, MA and Goldstein, AM and Lee, JE and Wei, Q and Savage, SA and Yang, XR and Amos, C and Landi, MT},
title = {On the interplay of telomeres, nevi and the risk of melanoma.},
journal = {PloS one},
volume = {7},
number = {12},
pages = {e52466},
pmid = {23300679},
issn = {1932-6203},
support = {P50 CA093459/CA/NCI NIH HHS/United States ; 2P50CA093459/CA/NCI NIH HHS/United States ; CA 5558 - 01A2)/CA/NCI NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Case-Control Studies ; Disease Progression ; Dysplastic Nevus Syndrome/complications/pathology ; Environmental Exposure/adverse effects/statistics &amp; numerical data ; Female ; Genetic Predisposition to Disease/genetics ; Humans ; Male ; Melanoma/*complications/epidemiology/ethnology/*genetics ; Middle Aged ; Nevus/*complications/pathology ; Pigmentation ; Polymorphism, Single Nucleotide ; Risk Factors ; Skin Neoplasms/*complications/pathology ; Sunlight/adverse effects ; Telomere/*genetics ; Young Adult ; },
abstract = {The relationship between telomeres, nevi and melanoma is complex. Shorter telomeres have been found to be associated with many cancers and with number of nevi, a known risk factor for melanoma. However, shorter telomeres have also been found to decrease melanoma risk. We performed a systematic analysis of telomere-related genes and tagSNPs within these genes, in relation to the risk of melanoma, dysplastic nevi, and nevus count combining data from four studies conducted in Italy. In addition, we examined whether telomere length measured in peripheral blood leukocytes is related to the risk of melanoma, dysplastic nevi, number of nevi, or telomere-related SNPs. A total of 796 cases and 770 controls were genotyped for 517 SNPs in 39 telomere-related genes genotyped with a custom-made array. Replication of the top SNPs was conducted in two American populations consisting of 488 subjects from 53 melanoma-prone families and 1,086 cases and 1,024 controls from a case-control study. We estimated odds ratios for associations with SNPs and combined SNP P-values to compute gene region-specific, functional group-specific, and overall P-value using an adaptive rank-truncated product algorithm. In the Mediterranean population, we found suggestive evidence that RECQL4, a gene involved in genome stability, RTEL1, a gene regulating telomere elongation, and TERF2, a gene implicated in the protection of telomeres, were associated with melanoma, the presence of dysplastic nevi and number of nevi, respectively. However, these associations were not found in the American samples, suggesting variable melanoma susceptibility for these genes across populations or chance findings in our discovery sample. Larger studies across different populations are necessary to clarify these associations.},
}
@article {pmid23300477,
year = {2013},
author = {Lue, NF and Zhou, R and Chico, L and Mao, N and Steinberg-Neifach, O and Ha, T},
title = {The telomere capping complex CST has an unusual stoichiometry, makes multipartite interaction with G-Tails, and unfolds higher-order G-tail structures.},
journal = {PLoS genetics},
volume = {9},
number = {1},
pages = {e1003145},
pmid = {23300477},
issn = {1553-7404},
support = {GM062631/GM/NIGMS NIH HHS/United States ; GM065367/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; R01 GM062631/GM/NIGMS NIH HHS/United States ; R01 GM065367/GM/NIGMS NIH HHS/United States ; },
mesh = {Candida albicans/genetics/metabolism ; Candida glabrata/*genetics/metabolism ; *Cell Cycle Proteins/genetics/metabolism ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; DNA Replication ; Fungal Proteins/*chemistry/*genetics ; Protein Binding ; Protein Folding ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/genetics ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/*chemistry/*genetics/metabolism ; },
abstract = {The telomere-ending binding protein complex CST (Cdc13-Stn1-Ten1) mediates critical functions in both telomere protection and replication. We devised a co-expression and affinity purification strategy for isolating large quantities of the complete Candida glabrata CST complex. The complex was found to exhibit a 2∶4∶2 or 2∶6∶2 stoichiometry as judged by the ratio of the subunits and the native size of the complex. Stn1, but not Ten1 alone, can directly and stably interact with Cdc13. In gel mobility shift assays, both Cdc13 and CST manifested high-affinity and sequence-specific binding to the cognate telomeric repeats. Single molecule FRET-based analysis indicates that Cdc13 and CST can bind and unfold higher order G-tail structures. The protein and the complex can also interact with non-telomeric DNA in the absence of high-affinity target sites. Comparison of the DNA-protein complexes formed by Cdc13 and CST suggests that the latter can occupy a longer DNA target site and that Stn1 and Ten1 may contact DNA directly in the full CST-DNA assembly. Both Stn1 and Ten1 can be cross-linked to photo-reactive telomeric DNA. Mutating residues on the putative DNA-binding surface of Candida albicans Stn1 OB fold domain caused a reduction in its crosslinking efficiency in vitro and engendered long and heterogeneous telomeres in vivo, indicating that the DNA-binding activity of Stn1 is required for telomere protection. Our data provide insights on the assembly and mechanisms of CST, and our robust reconstitution system will facilitate future biochemical analysis of this important complex.},
}
@article {pmid23299958,
year = {2013},
author = {Nandakumar, J and Cech, TR},
title = {Finding the end: recruitment of telomerase to telomeres.},
journal = {Nature reviews. Molecular cell biology},
volume = {14},
number = {2},
pages = {69-82},
pmid = {23299958},
issn = {1471-0080},
support = {/HHMI_/Howard Hughes Medical Institute/United States ; K99 CA167644/CA/NCI NIH HHS/United States ; R01 GM099705/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromosomes/*chemistry/metabolism ; Humans ; Models, Biological ; Models, Molecular ; Protein Binding/physiology ; Saccharomyces cerevisiae/genetics/metabolism ; Schizosaccharomyces/genetics/metabolism ; Shelterin Complex ; Telomerase/*metabolism ; Telomere/chemistry/genetics/*metabolism ; Telomere-Binding Proteins ; },
abstract = {Telomeres, the ends of linear eukaryotic chromosomes, are characterized by the presence of multiple repeats of a short DNA sequence. This telomeric DNA is protected from illicit repair by telomere-associated proteins, which in mammals form the shelterin complex. Replicative polymerases are unable to synthesize DNA at the extreme ends of chromosomes, but in unicellular eukaryotes such as yeast and in mammalian germ cells and stem cells, telomere length is maintained by a ribonucleoprotein enzyme known as telomerase. Recent work has provided insights into the mechanisms of telomerase recruitment to telomeres, highlighting the contribution of telomere-associated proteins, including TPP1 in humans, Ccq1 in Schizosaccharomyces pombe and Cdc13 and Ku70-Ku80 in Saccharomyces cerevisiae.},
}
@article {pmid23296662,
year = {2013},
author = {Nakamura, AJ},
title = {Methods for the assessment of telomere status.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {965},
number = {},
pages = {233-242},
doi = {10.1007/978-1-62703-239-1_15},
pmid = {23296662},
issn = {1940-6029},
mesh = {Chromosomes, Human/genetics ; Histones/metabolism ; Humans ; Image Processing, Computer-Assisted ; Immunohistochemistry ; In Situ Hybridization, Fluorescence/*methods ; Metaphase/genetics ; Telomere/*genetics ; },
abstract = {Most methods for examining telomere functionality have relied on measurements of telomeric DNA by hybridization or quantitative PCR. While these techniques yield measures of telomeric DNA length, they generate whole-population results. However, telomeric DNA lengths on different chromatids even in the same cell are usually heterogeneous. Also, these measurements do not reveal whether a particular telomere contains the critical minimum DNA length to be functional. Therefore, in order to gain a more complete knowledge of cellular health, an alternative method that reveals the functional status of each individual telomere is needed. Based on the fact that a dysfunctional telomere induces a DNA damage response, we developed a novel technique which combines a DNA damage marker with fluorescence in situ hybridization (FISH) of telomeric DNA on metaphase chromosomes to assess the functional status of individual telomeres. This technique reveals not only whether the telomeric DNA in each chromatid is significantly shortened, but also whether the telomere has induced a DNA damage response, i.e., has become dysfunctional. We describe here in detail the protocols for simultaneous assessment of telomere length and functionality.},
}
@article {pmid23295325,
year = {2013},
author = {Tomita, K and Bez, C and Fennell, A and Cooper, JP},
title = {A single internal telomere tract ensures meiotic spindle formation.},
journal = {EMBO reports},
volume = {14},
number = {3},
pages = {252-260},
pmid = {23295325},
issn = {1469-3178},
support = {12097/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Chromosomes, Fungal/metabolism ; *Meiosis ; Schizosaccharomyces/genetics/metabolism ; Schizosaccharomyces pombe Proteins/metabolism ; Shelterin Complex ; Spindle Apparatus/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Contact between telomeres and the fission yeast spindle pole body during meiotic prophase is crucial for subsequent spindle assembly, but the feature of telomeres that confers their ability to promote spindle formation remains mysterious. Here we show that while strains harbouring circular chromosomes devoid of telomere repeat tracts undergo aberrant meiosis with defective spindles, the insertion of a single internal telomere repeat stretch rescues the spindle defects. Moreover, the telomeric overhang-binding protein Pot1 is dispensable for rescue of spindle formation. Hence, an inherent feature of the double-strand telomeric region endows telomeres with the capacity to promote spindle formation.},
}
@article {pmid23293769,
year = {2012},
author = {Deng, Z and Wang, Z and Lieberman, PM},
title = {Telomeres and viruses: common themes of genome maintenance.},
journal = {Frontiers in oncology},
volume = {2},
number = {},
pages = {201},
pmid = {23293769},
issn = {2234-943X},
support = {R01 CA117830/CA/NCI NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; },
abstract = {Genome maintenance mechanisms actively suppress genetic instability associated with cancer and aging. Some viruses provoke genetic instability by subverting the host's control of genome maintenance. Viruses have their own specialized strategies for genome maintenance, which can mimic and modify host cell processes. Here, we review some of the common features of genome maintenance utilized by viruses and host chromosomes, with a particular focus on terminal repeat (TR) elements. The TRs of cellular chromosomes, better known as telomeres, have well-established roles in cellular chromosome stability. Cellular telomeres are themselves maintained by viral-like mechanisms, including self-propagation by reverse transcription, recombination, and retrotransposition. Viral TR elements, like cellular telomeres, are essential for viral genome stability and propagation. We review the structure and function of viral repeat elements and discuss how they may share telomere-like structures and genome protection functions. We consider how viral infections modulate telomere regulatory factors for viral repurposing and can alter normal host telomere structure and chromosome stability. Understanding the common strategies of viral and cellular genome maintenance may provide new insights into viral-host interactions and the mechanisms driving genetic instability in cancer.},
}
@article {pmid23292711,
year = {2013},
author = {Kapoor, S},
title = {Leukocyte telomere length and colorectal cancer risk.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {22},
number = {1},
pages = {175},
doi = {10.1158/1055-9965.EPI-12-1148},
pmid = {23292711},
issn = {1538-7755},
mesh = {Breast Neoplasms/epidemiology/genetics ; Colorectal Neoplasms/epidemiology/*genetics ; Female ; Genetic Predisposition to Disease/*epidemiology ; Humans ; Leukocytes ; Male ; Risk Assessment ; Sensitivity and Specificity ; Telomere/*genetics ; Urinary Bladder Neoplasms/epidemiology/genetics ; },
}
@article {pmid23288511,
year = {2013},
author = {Stout, GJ and Blasco, MA},
title = {Telomere length and telomerase activity impact the UV sensitivity syndrome xeroderma pigmentosum C.},
journal = {Cancer research},
volume = {73},
number = {6},
pages = {1844-1854},
doi = {10.1158/0008-5472.CAN-12-3125},
pmid = {23288511},
issn = {1538-7445},
mesh = {Animals ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Knockout ; Neoplasms, Radiation-Induced/genetics ; Telomerase/*metabolism ; *Telomere ; *Ultraviolet Rays ; Xeroderma Pigmentosum/*enzymology/*genetics ; },
abstract = {Xeroderma pigmentosum (XP), a UV-sensitivity syndrome characterized by skin hyperpigmentation, premature aging, and increased skin cancer, is caused by defects in the nucleotide excision repair (NER) pathway. XP shares phenotypical characteristics with telomere-associated diseases like Dyskeratosis congenita and mouse models with dysfunctional telomeres, including mice deficient for telomerase (Terc(-/-) mice). Thus, we investigated a hypothesized role for telomerase and telomere dysfunction in the pathobiology of XP by comparing Xpc(-/-)-mutant mice and Xpc(-/-)G1-G3Terc(-/-) double-mutant mice and exposed them to UV radiation. Chronically UV-exposed Xpc(-/-) skin displayed shorter telomeres on an average compared with wild-type skin. Strikingly, this effect was reversed by an additional deficiency in the telomerase. Moreover, aberrantly long telomeres were observed in the double-mutant mice. Telomere lengthening in the absence of telomerase suggested activation of the alternative lengthening of telomeres (ALT) in the UV-exposed skin of the double mutants. Mechanistic investigations revealed an elevated susceptibility for UV-induced p53 patches, known to represent precursor lesions of carcinomas, in Xpc(-/-)G1-G3Terc(-/-) mice where a high number of UV-induced skin tumors occurred that were characterized by aggressive growth. Taken together, our results establish a role for xeroderma pigmentosum, complementation group C (XPC) in telomere stability, particularly upon UV exposure. In absence of telomerase, critically short telomeres in XP mutants seem to aggravate this pathology, associated with an increased tumor incidence, by activating the ALT pathway of telomere lengthening.},
}
@article {pmid23279657,
year = {2013},
author = {Jonassaint, NL and Guo, N and Califano, JA and Montgomery, EA and Armanios, M},
title = {The gastrointestinal manifestations of telomere-mediated disease.},
journal = {Aging cell},
volume = {12},
number = {2},
pages = {319-323},
pmid = {23279657},
issn = {1474-9726},
support = {R01 CA160433/CA/NCI NIH HHS/United States ; T32 DK007632/DK/NIDDK NIH HHS/United States ; R01CA160433/CA/NCI NIH HHS/United States ; T32DK007632/DK/NIDDK NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; Enterocolitis/diagnosis/pathology/*physiopathology ; Esophageal Stenosis/diagnosis/pathology/*physiopathology ; Female ; Humans ; Infant ; Intestinal Mucosa/pathology/*physiopathology ; Malabsorption Syndromes/diagnosis/pathology/*physiopathology ; Male ; *Registries ; Telomere/*pathology ; Telomere Homeostasis ; },
abstract = {Defects in telomere maintenance genes cause pathological telomere shortening, and manifest in syndromes which have prominent phenotypes in tissues of high turnover: the skin and bone marrow. Because the gastrointestinal (GI) epithelium is highly proliferative, we sought to determine whether telomere syndromes cause GI disease, and to define its prevalence, spectrum, and natural history. We queried subjects in the Johns Hopkins Telomere Syndrome Registry for evidence of luminal GI disease. In sixteen percent of Registry subjects (6 of 38), there was a history of significant GI pathology, and 43 additional cases were identified in the literature. Esophageal stenosis, enteropathy, and enterocolitis were the recurrent findings. In the intestinal mucosa, there was striking villous atrophy, extensive apoptosis, and anaphase bridging pointing to regenerative defects in the epithelial compartment. GI disease was often the first and most severe manifestation of telomere disease in young children. These findings indicate that telomere dysfunction disrupts the epithelial integrity in the human GI tract manifesting in recognizable disease processes. A high index of suspicion should facilitate diagnosis and management.},
}
@article {pmid23276906,
year = {2013},
author = {Draskovic, I and Londono Vallejo, A},
title = {Telomere recombination and alternative telomere lengthening mechanisms.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {18},
number = {1},
pages = {1-20},
doi = {10.2741/4084},
pmid = {23276906},
issn = {2768-6698},
mesh = {Animals ; DNA Helicases/metabolism ; DNA Methylation/physiology ; Exodeoxyribonucleases/metabolism ; Genomic Instability ; Heterochromatin/metabolism ; Humans ; Mice ; RecQ Helicases/metabolism ; Recombination, Genetic ; Shelterin Complex ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; Telomere Shortening ; Telomere-Binding Proteins/physiology ; Werner Syndrome Helicase ; },
abstract = {Telomeres are nucleoprotein structures at the ends of linear chromosomes that protect them from being recognized as DNA double stranded breaks. Telomeres shorten with every cell division and in the absence of the checkpoint mechanisms critical telomere shortening leads to chromosome end fusions and genomic instability. Cancer cells achieve immortality by engaging in one of the two known mechanisms for telomere maintenance: elongation by telomerase or through recombination. Recombination based elongation of telomeres, also known as alternative lengthening of telomeres or ALT, is prevalent among cancers of mesenchymal origin. However, the conditions favoring ALT emergence are not known. Here we will discuss possible players in ALT mechanisms, including recruitment of telomeres to recombination centers, alterations of telomere associated proteins and modifications at the level of chromatin that could generate recombination permissive conditions at telomeres.},
}
@article {pmid25003004,
year = {2013},
author = {Stadler, G and King, OD and Robin, JD and Shay, JW and Wright, WE},
title = {Facioscapulohumeral muscular dystrophy: Are telomeres the end of the story?.},
journal = {Rare diseases (Austin, Tex.)},
volume = {1},
number = {},
pages = {e26142},
pmid = {25003004},
issn = {2167-5511},
support = {R01 AG001228/AG/NIA NIH HHS/United States ; U54 HD060848/HD/NICHD NIH HHS/United States ; },
abstract = {Facioscapulohumeral muscular dystrophy (FSHD) is a progressive myopathy with a relatively late age of onset (usually in the late teens) compared with Duchenne and many other muscular dystrophies. The current FSHD disease model postulates that contraction of the D4Z4 array at chromosome 4q35 leads to a more open chromatin conformation in that region and allows transcription of the DUX4 gene. DUX4 mRNA is stable only when transcribed from certain haplotypes that contain a polyadenylation signal. DUX4 protein is hypothesized to cause FSHD by mediating cytotoxicity and impairing skeletal muscle differentiation. We recently showed in a cell culture model that DUX4 expression is regulated by telomere length, suggesting that telomere shortening during aging may be partially responsible for the delayed onset and progressive nature of FSHD. We here put our data in the context of other recent findings arguing that progressive telomere shortening may play a critical role in FSHD but is not the whole story and that the current disease model needs additional refinement.},
}
@article {pmid23275564,
year = {2013},
author = {Oh, S and Wang, Y and Zimbric, J and Hendrickson, EA},
title = {Human LIGIV is synthetically lethal with the loss of Rad54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction.},
journal = {Nucleic acids research},
volume = {41},
number = {3},
pages = {1734-1749},
pmid = {23275564},
issn = {1362-4962},
support = {CA154461/CA/NCI NIH HHS/United States ; T32 AG029796/AG/NIA NIH HHS/United States ; R01 GM088351/GM/NIGMS NIH HHS/United States ; GM088351/GM/NIGMS NIH HHS/United States ; R01 CA154461/CA/NCI NIH HHS/United States ; },
mesh = {Antigens, Nuclear/genetics ; Cell Line, Tumor ; Cell Proliferation ; Chromatids ; *Chromosome Aberrations ; DNA Damage ; *DNA End-Joining Repair ; DNA Helicases/*genetics ; DNA Ligase ATP ; DNA Ligases/genetics/metabolism/*physiology ; DNA-Binding Proteins/genetics ; Gene Targeting ; Genomic Instability ; Humans ; Ku Autoantigen ; Mutation ; Nuclear Proteins/*genetics ; Recombination, Genetic ; Recombinational DNA Repair ; Telomere/*physiology ; Telomere Homeostasis ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Classic non-homologous end joining (C-NHEJ) is the predominant DNA double-strand break repair pathway in humans. Although seven genes Ku70, Ku86, DNA-PK(cs), Artemis, DNA Ligase IV (LIGIV), X-ray cross-complementing group 4 and XRCC4-like factor are required for C-NHEJ, several of them also have ancillary functions. For example, Ku70:Ku86 possesses an essential telomere maintenance activity. In contrast, LIGIV is believed to function exclusively in C-NHEJ. Moreover, a viable LIGIV-null human B-cell line and LIGIV-reduced patient cell lines have been described. Together, these observations suggest that LIGIV (and hence C-NHEJ), albeit important, is nonetheless dispensable, whereas Ku70:Ku86 and telomere maintenance are essential. To confirm this hypothesis, we inactivated LIGIV in the epithelial human cell line, HCT116. The resulting LIGIV-null cell line was viable, verifying that the gene and C-NHEJ are not essential. However, functional inactivation of RAD54B, a key homologous recombination factor, in the LIGIV-null background yielded no viable clones, suggesting that the combined absence of RAD54B/homologous recombination and C-NHEJ is synthetically lethal. Finally, we demonstrate that LIGIV is differentially required for certain chromosome fusion events induced by telomere dysfunction-used for those owing to the overexpression of a dominant negative version of telomere recognition factor 2, but not used for those owing to absence of Ku70:Ku86.},
}
@article {pmid23273986,
year = {2013},
author = {Kalmbach, KH and Fontes Antunes, DM and Dracxler, RC and Knier, TW and Seth-Smith, ML and Wang, F and Liu, L and Keefe, DL},
title = {Telomeres and human reproduction.},
journal = {Fertility and sterility},
volume = {99},
number = {1},
pages = {23-29},
pmid = {23273986},
issn = {1556-5653},
support = {UL1 RR029893/RR/NCRR NIH HHS/United States ; 1UL1RR029893/RR/NCRR NIH HHS/United States ; },
mesh = {Animals ; Cellular Senescence/physiology ; Female ; Humans ; Male ; Mice ; Models, Animal ; Oocytes/physiology ; Reproduction/*physiology ; *Sex Characteristics ; Spermatozoa/physiology ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; Telomere Shortening/*physiology ; },
abstract = {Telomeres mediate biologic aging in organisms as diverse as plants, yeast, and mammals. We propose a telomere theory of reproductive aging that posits telomere shortening in the female germ line as the primary driver of reproductive aging in women. Experimental shortening of telomeres in mice, which normally do not exhibit appreciable oocyte aging, and which have exceptionally long telomeres, recapitulates the aging phenotype of human oocytes. Telomere shortening in mice reduces synapsis and chiasmata, increases embryo fragmentation, cell cycle arrest, apoptosis, spindle dysmorphologies, and chromosome abnormalities. Telomeres are shorter in the oocytes from women undergoing in vitro fertilization, who then produce fragmented, aneuploid embryos that fail to implant. In contrast, the testes are replete with spermatogonia that can rejuvenate telomere reserves throughout the life of the man by expressing telomerase. Differences in telomere dynamics across the life span of men and women may have evolved because of the difference in the inherent risks of aging on reproduction between men and women. Additionally, growing evidence links altered telomere biology to endometriosis and gynecologic cancers, thus future studies should examine the role of telomeres in pathologies of the reproductive tract.},
}
@article {pmid23273548,
year = {2012},
author = {Pauliny, A and Larsson, K and Blomqvist, D},
title = {Telomere dynamics in a long-lived bird, the barnacle goose.},
journal = {BMC evolutionary biology},
volume = {12},
number = {},
pages = {257},
pmid = {23273548},
issn = {1471-2148},
mesh = {Age Factors ; Aging/*genetics ; Animals ; Female ; Geese/*genetics ; Longevity/*genetics ; Male ; Telomere/*genetics ; Telomere Shortening/genetics ; Time Factors ; },
abstract = {BACKGROUND: Theories of ageing predict a trade-off between metabolism, reproduction, and maintenance. Species with low investment in early reproduction are thus expected to be able to evolve more efficient maintenance and repair mechanisms, allowing for a longer potential life span (intrinsic longevity). The erosion of telomeres, the protective caps at the ends of linear chromosomes, plays an important role in cellular and organismal senescence, signalling the onset of age-related disease due to accumulation of unrepaired somatic damage. Using extensive longitudinal data from a long-term study of a natural population of barnacle geese Branta leucopsis, we investigated individual rates of telomere length changes over two years in 34 birds between 0 and 22 years of age, covering almost 80% of the species' lifespan.<br><br>RESULTS: We show that telomeres in this long-lived bird are very well maintained, as theoretically expected, with an average loss rate of only 5 base pairs per year among adults. We thus found no significant relationship between change in telomere length and age. However, telomeres tended to shorten at a faster pace in juveniles compared to adults. For the first time, we demonstrate a faster telomere attrition rate in females compared to males. We found no correlation between telomere loss rate and adult survival or change in body mass.<br><br>CONCLUSIONS: Our results add further support for a link between longevity and telomere maintenance, and highlight the complexities of telomere dynamics in natural populations.},
}
@article {pmid23270390,
year = {2012},
author = {Botha, M and Grace, L and Bugarith, K and Russell, VA and Kidd, M and Seedat, S and Hemmings, SM},
title = {The impact of voluntary exercise on relative telomere length in a rat model of developmental stress.},
journal = {BMC research notes},
volume = {5},
number = {},
pages = {697},
pmid = {23270390},
issn = {1756-0500},
mesh = {Animals ; Anxiety, Separation/etiology/*genetics/psychology ; *Behavior, Animal ; Cognition ; Disease Models, Animal ; Hippocampus/*metabolism ; Male ; Maze Learning ; Memory ; *Physical Exertion ; Prefrontal Cortex/*metabolism ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction ; Running ; Stress, Psychological/etiology/*genetics/psychology ; Telomere/*metabolism ; *Telomere Homeostasis ; *Volition ; },
abstract = {BACKGROUND: Exposure to early adverse events can result in the development of later psychopathology, and is often associated with cognitive impairment. This may be due to accelerated cell aging, which can be catalogued by attritioned telomeres. Exercise enhances neurogenesis and has been proposed to buffer the effect of psychological stress on telomere length. This study aimed to investigate the impact of early developmental stress and voluntary exercise on telomere length in the ventral hippocampus (VH) and prefrontal cortex (PFC) of the rat. Forty-five male Sprague-Dawley rats were categorised into four groups: maternally separated runners (MSR), maternally separated non-runners (MSnR), non-maternally separated runners (nMSR) and non-maternally separated non-runners (nMSnR). Behavioural analyses were conducted to assess anxiety-like behaviour and memory performance in the rats, after which relative telomere length was measured using qPCR.<br><br>RESULTS: Maternally separated (MS) rats exhibited no significant differences in either anxiety levels or memory performance on the elevated-plus maze and the open field compared to non-maternally separated rats at 49 days of age. Exercised rats displayed increased levels of anxiety on the day that they were removed from the cages with attached running wheels, as well as improved spatial learning and temporal recognition memory compared to non-exercised rats. Exploratory post-hoc analyses revealed that maternally separated non-exercised rats exhibited significantly longer telomere length in the VH compared to those who were not maternally separated; however, exercise appeared to cancel this effect since there was no difference in VH telomere length between maternally separated and non-maternally separated runners.<br><br>CONCLUSIONS: The increased telomere length in the VH of maternally separated non-exercised rats may be indicative of reduced cellular proliferation, which could, in turn, indicate hippocampal dysfunction. This effect on telomere length was not observed in exercised rats, indicating that voluntary exercise may buffer against the progressive changes in telomere length caused by alterations in maternal care early in life. In future, larger sample sizes will be needed to validate results obtained in the present study and obtain a more accurate representation of the effect that psychological stress and voluntary exercise have on telomere length.},
}
@article {pmid23268632,
year = {2012},
author = {Valls-Bautista, C and Piñol-Felis, C and Reñé-Espinet, JM and Buenestado-García, J and Viñas-Salas, J},
title = {Telomeric repeat factor 1 protein levels correlates with telomere length in colorectal cancer.},
journal = {Revista espanola de enfermedades digestivas},
volume = {104},
number = {10},
pages = {530-536},
doi = {10.4321/s1130-01082012001000005},
pmid = {23268632},
issn = {1130-0108},
mesh = {Aged ; Aged, 80 and over ; Blotting, Southern ; Blotting, Western ; Colorectal Neoplasms/*pathology/ultrastructure ; Female ; Humans ; Intestinal Mucosa/chemistry/pathology ; Male ; Middle Aged ; Nucleic Acid Amplification Techniques ; Telomere/pathology/*ultrastructure ; Telomeric Repeat Binding Protein 1/*blood ; },
abstract = {BACKGROUND: colorectal cancer is the third cancer cause of death in Spain. It is important to investigate new tumoral markers for early diagnosis, disease monitoring and prevention strategies. Telomeres protect the chromosome from degradation by nucleases and endto-end fusion. The progressive loss of the telomeric ends of chromosomes is an important mechanism in the timing of human cellular aging. Telomeric Repeat Factor 1 (TRF1) is a protein that binds at telomere ends.<br><br>PURPOSE: to measure the concentrations of TRF1 and the relationships among telomere length, telomerase activity, and TRF1 levels in tumor and normal colorectal mucosa.<br><br>METHOD: from normal and tumoral samples of 83 patients who underwent surgery for colorectal cancer we analyzed TRF1 protein concentration by Western Blot, telomerase activity, by the fluorescent-telomeric repeat amplification protocol assay and telomere length by Southern Blot.<br><br>RESULTS: high levels of TRF1 were observed in 68.7% of tumor samples, while the majority of normal samples (59%) showed negative or weak TRF1 concentrations. Among the tumor samples, telomere length was significantly associated with TRF1 protein levels (p = 0.023).<br><br>CONCLUSIONS: a relationship was found between telomere length and TRF1 abundance protein in tumor samples, which means that TRF1 is an important factor in the tumor progression and maybe a diagnostic factor.},
}
@article {pmid23268483,
year = {2013},
author = {Rode, L and Bojesen, SE and Weischer, M and Vestbo, J and Nordestgaard, BG},
title = {Short telomere length, lung function and chronic obstructive pulmonary disease in 46,396 individuals.},
journal = {Thorax},
volume = {68},
number = {5},
pages = {429-435},
doi = {10.1136/thoraxjnl-2012-202544},
pmid = {23268483},
issn = {1468-3296},
mesh = {Adult ; Aged ; DNA/*analysis ; Denmark/epidemiology ; Female ; Forced Expiratory Volume/*genetics ; Humans ; Male ; Middle Aged ; Polymerase Chain Reaction ; Prevalence ; Pulmonary Disease, Chronic Obstructive/epidemiology/*genetics/physiopathology ; Retrospective Studies ; *Telomere ; Vital Capacity/*genetics ; },
abstract = {BACKGROUND: A previous case-control study of 100 individuals found that short telomere length was associated with a 28-fold increased risk of chronic obstructive pulmonary disease (COPD).<br><br>OBJECTIVES: To test the hypothesis that short telomere length is associated with reduced lung function and an increased risk of COPD.<br><br>METHODS: Observational study of 46 396 individuals from the Danish general population.<br><br>MEASUREMENTS: Leucocyte telomere length and spirometry were measured. COPD was defined using either fixed forced expiratory volume in 1 s (FEV&#x2081;)/forced vital capacity (FVC) ratio <0.70 as suggested by the Global initiative for chronic Obstructive Lung Disease (GOLD) or FEV&#x2081;/FVC below the lower limit of normal (LLN).<br><br>RESULTS: Telomere length decreased significantly with increasing age (p<10(-300)). FEV&#x2081;, FVC and FEV1/FVC decreased with decreasing telomere length quartiles (p trend: 5 &#xd7; 10(-51), 5 &#xd7; 10(-35) and 6 &#xd7; 10(-137), respectively), but the associations attenuated after age and multivariable adjustment. The risk of COPD increased with decreasing telomere length quartile (p trend: p=7 &#xd7; 10(-92) for GOLD; p=8 &#xd7; 10(-44) for FEV&#x2081;/FVC below LLN), but associations also attenuated after adjustment. Unadjusted and multivariable adjusted OR for shortest versus longest telomere length quartiles were 2.06 (95% CI 1.91 to 2.22) and 1.15 (95% CI 1.06 to 1.25) for GOLD and 1.73 (95% CI 1.60 to 1.88) and 1.19 (95% CI 1.09 to 1.30) for FEV&#x2081;/FVC below LLN, respectively. Per 1000 base pairs decrease in telomere length, the multivariable adjusted OR was 1.07 (95% CI 1.03 to 1.10) for GOLD and 1.07 (95% CI 1.03 to 1.11) for FEV&#x2081;/FVC below LLN.<br><br>CONCLUSIONS: Short telomere length is associated with decreased lung function and with increased risk of COPD, but the associations are markedly attenuated after adjustment. Our data support a modest correlation between telomere length and the lung function indices examined.},
}
@article {pmid23268311,
year = {2013},
author = {Rezazadeh, S},
title = {On BLM helicase in recombination-mediated telomere maintenance.},
journal = {Molecular biology reports},
volume = {40},
number = {4},
pages = {3049-3064},
pmid = {23268311},
issn = {1573-4978},
mesh = {Aging ; Bloom Syndrome/complications/enzymology/*genetics ; DNA Breaks, Double-Stranded ; DNA Repair/genetics ; DNA Replication/genetics ; Humans ; Neoplasms/complications/*genetics/pathology ; RecQ Helicases/chemistry/*genetics ; Recombination, Genetic ; Telomerase/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Bloom syndrome (BS) is an extremely rare, autosomal recessive genetic syndrome of humans. Patients with BS are predisposed to almost all forms of cancer and also display premature aging phenotypes. These patients are diagnosed in the clinics by hyper-recombination phenotype that is manifested by high rates of sister chromatid exchange. The gene mutated in BS, designated BLM, lies on chromosome 15q26.1 and encodes a RecQ-like ATP-dependent 3'-5' helicase, which functions in DNA double-strand break repair processes such as non-homologous end joining, homologous recombination-mediated repair, resolution of stalled replication forks and synthesis-dependent strand annealing, although its precise functions at the telomeres are speculative. Recently it has been suggested that the BLM helicase may play important roles in Telomerase-independent forms of telomere elongation or alternative lengthening of telomeres (ALT). A mechanism that although provides cells with a window of opportunity to save ends of their chromosomes, puts these Telomerase (-/-) cells under continuous stress. BLM localization within ALT-associated PML nuclear bodies in telomerase-negative immortalized cell lines and its interaction with the telomere-specific proteins strengthens that suggestion. Here, I begin by outlining features common to all RecQ helicases. I, then, survey evidences that implicate possible roles of BLM helicase in this recombination-mediated mechanism of telomere elongation.},
}
@article {pmid23262106,
year = {2012},
author = {Xie, BT and Ji, GZ and Kong, QR and Mao, J and Shi, YQ and Liu, SC and Wu, ML and Wang, J and Liu, L and Liu, ZH},
title = {[Telomere lengthening by trichostatin A treatment in cloned pigs].},
journal = {Yi chuan = Hereditas},
volume = {34},
number = {12},
pages = {1583-1590},
doi = {10.3724/sp.j.1005.2012.01583},
pmid = {23262106},
issn = {0253-9772},
mesh = {Animals ; Animals, Genetically Modified ; Blastocyst/cytology/drug effects/metabolism ; Cloning, Organism ; Hydroxamic Acids/*pharmacology ; Swine/embryology/*genetics/metabolism ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*drug effects ; },
abstract = {Telomeres are repeated GC rich sequences at the end of chromosomes, and shorten with each cell division due to DNA end replication problem. Previously, reprogrammed somatic cells of cloned animals display variable telomere elongation. However, it was reported that the cloned animals including Dolly do not reset telomeres and show premature aging. In this study, we investigated telomere function in cloned or transgenic cloned pigs, including the cloned Northeast Min pigs, eGFP, Mx, and PGC1α transgenic cloned pigs, and found that the telomere lengths of cloned pigs were significantly shorter than the nuclear donor adult fibroblasts and age-matched noncloned pigs (P<0.05), indicating that nuclear reprogramming did not restore cellular age of donor cells after somatic cell nuclear transfer (SCNT). Trichostatin A (TSA), an inhibitor of histone deacetylase, has proven to enhance the efficiency of nuclear reprogramming in several species. In order to test whether TSA also can effectively enhance reprogramming of telomeres, TSA (40 nmol/L) was used to treat porcine cloned embryos at 1-cell stage for 24 h. Consistent with previous reports, the developmental rate of SCNT embryos to the blastocyst stage was significantly increased compared with those of the control group (16.35% vs. 27.09%, 21.60% vs. 34.90%, P<0.05). Notably, the telomere length of cloned porcine blastocysts was also significantly elongated (P<0.05). Although TSA did not improve the cloning efficiency (1.3% vs. 1.7%, TSA vs. control), the telomere lengths of cloned pig-lets were significantly longer compared with those of the control group and the donor fibroblasts (P<0.05). In conclusion, telomeres have not been effectively restored by SCNT in pigs but TSA can effectively lengthen the telomere lengths of cloned pigs.},
}
@article {pmid23260664,
year = {2012},
author = {Fick, LJ and Fick, GH and Li, Z and Cao, E and Bao, B and Heffelfinger, D and Parker, HG and Ostrander, EA and Riabowol, K},
title = {Telomere length correlates with life span of dog breeds.},
journal = {Cell reports},
volume = {2},
number = {6},
pages = {1530-1536},
doi = {10.1016/j.celrep.2012.11.021},
pmid = {23260664},
issn = {2211-1247},
support = {//Canadian Institutes of Health Research/Canada ; //Intramural NIH HHS/United States ; },
mesh = {Animals ; *Breeding ; Dogs ; Female ; Humans ; Leukocytes, Mononuclear/cytology/metabolism ; Longevity/*physiology ; Male ; Species Specificity ; Telomere/genetics/*metabolism ; },
abstract = {Telomeric DNA repeats are lost as normal somatic cells replicate. When telomeres reach a critically short length, a DNA damage signal is initiated, inducing cell senescence. Some studies have indicated that telomere length correlates with mortality, suggesting that telomere length contributes to human life span; however, other studies report no correlation, and thus the issue remains controversial. Domestic dogs show parallels in telomere biology to humans, with similar telomere length, telomere attrition, and absence of somatic cell telomerase activity. Using this model, we find that peripheral blood mononuclear cell (PBMC) telomere length is a strong predictor of average life span among 15 different breeds (p < 0.0001), consistent with telomeres playing a role in life span determination. Dogs lose telomeric DNA ~10-fold faster than humans, which is similar to the ratio of average life spans between these species. Breeds with shorter mean telomere lengths show an increased probability of death from cardiovascular disease, which was previously correlated with short telomere length in humans.},
}
@article {pmid23260663,
year = {2012},
author = {Crabbe, L and Cesare, AJ and Kasuboski, JM and Fitzpatrick, JA and Karlseder, J},
title = {Human telomeres are tethered to the nuclear envelope during postmitotic nuclear assembly.},
journal = {Cell reports},
volume = {2},
number = {6},
pages = {1521-1529},
pmid = {23260663},
issn = {2211-1247},
support = {P30 CA014195-38/CA/NCI NIH HHS/United States ; T32 CA009370/CA/NCI NIH HHS/United States ; GM087476/GM/NIGMS NIH HHS/United States ; 5T32CA009370-29/CA/NCI NIH HHS/United States ; R01 GM087476/GM/NIGMS NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; HeLa Cells ; Humans ; Membrane Proteins/genetics/*metabolism ; Mice ; Microtubule-Associated Proteins/genetics/*metabolism ; Mitosis/*physiology ; Nuclear Envelope/genetics/*metabolism ; Nuclear Proteins/genetics/*metabolism ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Telomeres are essential for nuclear organization in yeast and during meiosis in mice. Exploring telomere dynamics in living human cells by advanced time-lapse confocal microscopy allowed us to evaluate the spatial distribution of telomeres within the nuclear volume. We discovered an unambiguous enrichment of telomeres at the nuclear periphery during postmitotic nuclear assembly, whereas telomeres were localized more internally during the rest of the cell cycle. Telomere enrichment at the nuclear rim was mediated by physical tethering of telomeres to the nuclear envelope, most likely via specific interactions between the shelterin subunit RAP1 and the nuclear envelope protein Sun1. Genetic interference revealed a critical role in cell-cycle progression for Sun1 but no effect on telomere positioning for RAP1. Our results shed light on the dynamic relocalization of human telomeres during the cell cycle and suggest redundant pathways for tethering telomeres to the nuclear envelope.},
}
@article {pmid23260199,
year = {2013},
author = {Gocha, AR and Nuovo, G and Iwenofu, OH and Groden, J},
title = {Human sarcomas are mosaic for telomerase-dependent and telomerase-independent telomere maintenance mechanisms: implications for telomere-based therapies.},
journal = {The American journal of pathology},
volume = {182},
number = {1},
pages = {41-48},
pmid = {23260199},
issn = {1525-2191},
support = {P30 CA016058/CA/NCI NIH HHS/United States ; R01 CA117898/CA/NCI NIH HHS/United States ; CA-117898/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Bone Neoplasms/genetics/pathology ; DNA, Neoplasm/genetics ; Female ; Humans ; Male ; Microscopy, Confocal ; Middle Aged ; Osteosarcoma/enzymology/genetics/pathology ; Sarcoma/enzymology/*genetics/pathology ; Telomerase/*genetics/metabolism ; Telomere Homeostasis/*genetics ; Young Adult ; },
abstract = {Telomere shortening necessitates that tumor cells activate a telomere maintenance mechanism (TMM) to support immortalization. Although most tumor cells activate expression of the enzyme telomerase, some cells elongate telomeres in a telomerase-independent manner, termed alternative lengthening of telomeres (ALT). Previous studies have evaluated the presence of telomerase or ALT mechanisms or both in a variety of tumor types. Our studies also show that TMMs are not mutually exclusive in some tumors. In contrast, our IHC analyses of human sarcomas identified a subset of tumors with some cells containing ALT-associated PML bodies, a hallmark of ALT, and separate cells expressing telomerase in the same tumor. By using a second set of human osteosarcomas, we merged IHC and biochemical analyses to characterize more fully the tumor TMM. The IHC data reveal the presence of both telomerase- and ALT-positive tumor cells in samples that demonstrate characteristics of both telomerase and ALT in biochemical assays. These assays, which measure telomere length and telomerase activity of tumor extracts, are conventionally used to classify tumor TMM. Our results suggest that TMM is not a single or perhaps static characteristic of some tumors and that TMM heterogeneity should be considered in tumor stratification. Furthermore, clinical interest in telomere-based therapies may necessitate accurate characterization of tumor TMM before treatment to maximize therapeutic efficacy.},
}
@article {pmid23258416,
year = {2013},
author = {Robertson, T and Batty, GD and Der, G and Fenton, C and Shiels, PG and Benzeval, M},
title = {Is socioeconomic status associated with biological aging as measured by telomere length?.},
journal = {Epidemiologic reviews},
volume = {35},
number = {1},
pages = {98-111},
pmid = {23258416},
issn = {1478-6729},
support = {MC_U130059821/MRC_/Medical Research Council/United Kingdom ; MC_UU_12017/7/MRC_/Medical Research Council/United Kingdom ; MC_UP_A540_1021/MRC_/Medical Research Council/United Kingdom ; MC_U130059823/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; SPHSU2/CSO_/Chief Scientist Office/United Kingdom ; },
mesh = {Aging/*genetics ; Biomarkers ; Educational Status ; Genetic Markers ; Humans ; *Social Class ; Telomere/*metabolism ; },
abstract = {It has been hypothesized that one way in which lower socioeconomic status (SES) affects health is by increasing the rate of biological aging. A widely used marker of biological aging is telomere length. Telomeres are structures at the ends of chromosomes that erode with increasing cell proliferation and genetic damage. We aimed to identify, through systematic review and meta-analysis, whether lower SES (greater deprivation) is associated with shorter telomeres. Thirty-one articles, including 29 study populations, were identified. We conducted 3 meta-analyses to compare the telomere lengths of persons of high and low SES with regard to contemporaneous SES (12 study populations from 10 individual articles), education (15 study populations from 14 articles), and childhood SES (2 study populations from 2 articles). For education, there was a significant difference in telomere length between persons of high and low SES in a random-effects model (standardized mean difference (SMD) = 0.060, 95% confidence interval (CI): 0.002, 0.118; P = 0.042), although a range of sensitivity analyses weakened this association. There was no evidence for an association between telomere length and contemporaneous SES (SMD = 0.104, 95% CI: -0.027, 0.236; P = 0.119) or childhood SES (SMD = -0.037, 95% CI: -0.143, 0.069; P = 0.491). These results suggest weak evidence for an association between SES (as measured by education) and biological aging (as measured by telomere length), although there was a lack of consistent findings across the SES measures investigated here.},
}
@article {pmid23252341,
year = {2013},
author = {Ishizuka, T and Xu, Y and Komiyama, M},
title = {A chemistry-based method to detect individual telomere length at a single chromosome terminus.},
journal = {Journal of the American Chemical Society},
volume = {135},
number = {1},
pages = {14-17},
doi = {10.1021/ja308481c},
pmid = {23252341},
issn = {1520-5126},
mesh = {Cells, Cultured ; Chromosomes/*chemistry/genetics ; DNA/*chemistry/genetics ; HEK293 Cells ; HeLa Cells ; Humans ; Telomere/*chemistry/genetics ; },
abstract = {The understanding of telomeres is expected to provide major insights into genome stability, cancer, and telomere-related diseases. In recent years, there have been considerable improvements in the technologies available to determine the length of telomeres of human chromosomes; however, the present methods for measuring telomere length are fraught with shortcomings that have limited their use. Here we describe a method for detection of individual telomere lengths (DITL) that uses a chemistry-based approach that accurately measures the telomere lengths from individual chromosomes. The method was successfully used to determine telomere DNA by breaking in the target sequence and producing a "real telomere fragment." The DITL approach involves cleavage of the sequence adjacent to the telomere followed by resolution of the telomere length at the nucleotide level of a single chromosome. Comparison of the DITL method and the traditional terminal restriction fragment (TRF) analysis indicates that the DITL approach appears to be promising for the quantification of telomere repeats in each chromosome and the detection of accurate telomere lengths that can be missed using TRF analysis.},
}
@article {pmid23243283,
year = {2013},
author = {Jebaraj, BM and Kienle, D and Lechel, A and Mertens, D and Heuberger, M and Ott, G and Rosenwald, A and Barth, TF and Möller, P and Zenz, T and Döhner, H and Stilgenbauer, S},
title = {Telomere length in mantle cell lymphoma.},
journal = {Blood},
volume = {121},
number = {7},
pages = {1184-1187},
doi = {10.1182/blood-2012-08-452649},
pmid = {23243283},
issn = {1528-0020},
mesh = {Adult ; Aged ; Aged, 80 and over ; B-Lymphocytes/pathology ; Case-Control Studies ; Chromosome Aberrations ; Humans ; Immunoglobulin Heavy Chains/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics/immunology/pathology ; Lymphoma, Mantle-Cell/*genetics/immunology/pathology ; Middle Aged ; Mutation ; Prognosis ; Telomere/*genetics/pathology ; Telomere Shortening/genetics ; },
abstract = {Telomere shortening is of pathogenic and prognostic importance in cancers. In the present study, we analyzed telomere length in 73 mantle cell lymphoma (MCL), 55 chronic lymphocytic leukemia (CLL), and 20 normal B-cell samples using quantitative PCR (Q-PCR) to study its association with disease characteristics and outcome. Telomere length was found to be highly variable in MCL (range, 2.2-13.8 kb; median, 4.3 kb). Telomere dysfunction in MCL was evident from comparison with normal B cells (median, 7.5 kb), but had no significant association with any biologic or clinical feature. This was in contrast to CLL, in which a significant correlation of short telomeres with poor prognostic subgroups was confirmed. There was a trend toward an increased number of genomic aberrations with shortening of telomeres in MCL. No difference in survival was observed between the groups with short and long telomeres, indicating that, as opposed to CLL, telomere length is not of prognostic relevance in MCL.},
}
@article {pmid23241441,
year = {2012},
author = {Ji, G and Liu, K and Okuka, M and Liu, N and Liu, L},
title = {Association of telomere instability with senescence of porcine cells.},
journal = {BMC cell biology},
volume = {13},
number = {},
pages = {36},
pmid = {23241441},
issn = {1471-2121},
mesh = {Animals ; Base Sequence ; Cells, Cultured ; *Cellular Senescence ; Genomic Instability ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Real-Time Polymerase Chain Reaction ; Swine ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Telomeres are essential for the maintenance of genomic stability, and telomere dysfunction leads to cellular senescence, carcinogenesis, aging, and age-related diseases in humans. Pigs have become increasingly important large animal models for preclinical tests and study of human diseases, and also may provide xeno-transplantation sources. Thus far, Southern blot analysis has been used to estimate average telomere lengths in pigs. Telomere quantitative fluorescence in situ hybridization (Q-FISH), however, can reveal status of individual telomeres in fewer cells, in addition to quantifying relative telomere lengths, and has been commonly used for study of telomere function of mouse and human cells. We attempted to investigate telomere characteristics of porcine cells using telomere Q-FISH method.<br><br>RESULTS: The average telomere lengths in porcine cells measured by Q-FISH correlated with those of quantitative real-time PCR method (qPCR) or telomere restriction fragments (TRFs) by Southern blot analysis. Unexpectedly, we found that porcine cells exhibited high incidence of telomere doublets revealed by Q-FISH method, coincided with increased frequency of cellular senescence. Also, telomeres shortened during subculture of various porcine primary cell types. Interestingly, the high frequency of porcine telomere doublets and telomere loss was associated with telomere dysfunction-induced foci (TIFs). The incidence of TIFs, telomere doublets and telomere loss increased with telomere shortening and cellular senescence during subculture.<br><br>CONCLUSION: Q-FISH method using telomere PNA probe is particularly useful for characterization of porcine telomeres. Porcine cells exhibit high frequency of telomere instability and are susceptible to telomere damage and replicative senescence.},
}
@article {pmid23240911,
year = {2013},
author = {Diker-Cohen, T and Uziel, O and Szyper-Kravitz, M and Shapira, H and Natur, A and Lahav, M},
title = {The effect of chemotherapy on telomere dynamics: clinical results and possible mechanisms.},
journal = {Leukemia &amp; lymphoma},
volume = {54},
number = {9},
pages = {2023-2029},
doi = {10.3109/10428194.2012.757765},
pmid = {23240911},
issn = {1029-2403},
mesh = {Adult ; Aged ; Antineoplastic Agents/administration &amp; dosage/*pharmacology/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/pharmacology/therapeutic use ; Case-Control Studies ; Female ; Fluorouracil/administration &amp; dosage ; Hematopoietic Stem Cells/drug effects/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Karyotype ; Male ; Middle Aged ; Neoplasms/drug therapy/genetics/metabolism ; Telomere/*drug effects/genetics/metabolism ; Vidarabine/administration &amp; dosage/analogs &amp; derivatives ; },
abstract = {Telomeres are the chromosomal end components, and their length in hematopoietic stem cells correlates with the bone marrow proliferative reserve. There are few data regarding telomere dynamics in hematopoietic stem cells after exposure to chemotherapy. We show that the attrition of telomeres after cytotoxic treatment correlates with the intensity of chemotherapy. Using cytotoxic drugs with differential effects on hematopoietic stem cells, our data imply that chemotherapy-induced telomere shortening results from direct damage to hematopoietic stem cells and/or the induction of proliferative stress on bone marrow while sparing repopulating stem cells. These results gain importance considering the current long survival of patients with cancer.},
}
@article {pmid23239407,
year = {2013},
author = {Qi, A and Zhou, H and Zhou, Z and Huang, X and Ma, L and Wang, H and Yang, Y and Zhang, D and Li, H and Ren, R and Yang, R},
title = {Telomerase activity increased and telomere length shortened in peripheral blood cells from patients with immune thrombocytopenia.},
journal = {Journal of clinical immunology},
volume = {33},
number = {3},
pages = {577-585},
pmid = {23239407},
issn = {1573-2592},
mesh = {Adult ; Aged ; Antigens, CD19/metabolism ; CD4 Antigens/metabolism ; CD8 Antigens/metabolism ; Enzyme Activation ; Female ; Humans ; Leukocytes, Mononuclear/metabolism ; Lymphocytes/metabolism ; Male ; Middle Aged ; Prognosis ; Purpura, Thrombocytopenic, Idiopathic/diagnosis/*genetics/*metabolism ; Risk Factors ; Telomerase/*metabolism ; *Telomere Shortening ; Young Adult ; },
abstract = {OBJECTIVES: To evaluate the telomere/telomerase system and its clinical significance in immune thrombocytopenia (ITP) patients.<br><br>METHODS: A total of 237 ITP patients, 20 SLE patients and 200 age-and sex-matched healthy controls were included in this study. CD4(+), CD8(+) and CD19(+) lymphocytes were purified by magnetic beads sorting from peripheral blood of 37 active chronic ITP patients and 22 age-and sex-matched healthy controls. Telomerase activity was assayed by Telo TTAGGG Telomerase PCR ELISA KIT. The relative telomere length of peripheral blood mononuclear cell (PBMC) was measured by a quantitative polymerase chain reaction-based method (Q-PCR) from 200 ITP patients and 178 age-and sex-matched healthy controls.<br><br>RESULTS: Telomerase activity was increased in CD4(+), CD8(+) and CD19(+) lymphocytes from ITP patients compared to those from healthy controls (p&#x2009;=&#x2009;0.000). The level of telomerase activity in CD19(+) lymphocyte was higher than those in CD4(+) and CD8(+) lymphocytes. Telomerase activity of CD19+ lymphocytes had a modest negative correlation with platelet count in ITP patients (p&#x2009;=&#x2009;0.042). The relative telomere length of PBMC in ITP patients was significantly shorter than that in the healthy controls (p&#x2009;=&#x2009;0.002). Telomere length of PBMC in active ITP patients was significantly shorter than that in the controls (p&#x2009;=&#x2009;0.000) and a tendency to be shorter even in inactive ITP patients (p&#x2009;=&#x2009;0.065). Moreover, the telomere length in refractory and non-refractory ITP patients were both significantly shorter than that in the controls (p&#x2009;=&#x2009;0.025; p&#x2009;=&#x2009;0.000). However no significant difference in telomere length of PBMC was found between refractory ITP patients and non-refractory ITP patients (p&#x2009;=&#x2009;0.234).<br><br>CONCLUSION: An abnormal regulating telomere/telomerase system might be involved in the pathogenesis of ITP. Further studies may elucidate whether the telomere length could be considered as a predictive biomarker for the prognosis of ITP.},
}
@article {pmid23236272,
year = {2012},
author = {Richards, DM and Greer, E and Martin, AC and Moore, G and Shaw, PJ and Howard, M},
title = {Quantitative dynamics of telomere bouquet formation.},
journal = {PLoS computational biology},
volume = {8},
number = {12},
pages = {e1002812},
pmid = {23236272},
issn = {1553-7358},
support = {BBS/E/J/00000315/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/J007188/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/J004588/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BBS/E/J/000C0637/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BBS/E/J/00000128/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Chromosomes, Plant ; Genes, Plant ; Hybridization, Genetic ; Models, Theoretical ; Secale/*genetics ; *Telomere ; Triticum/*genetics ; },
abstract = {The mechanism by which homologous chromosomes pair during meiosis, as a prelude to recombination, has long been mysterious. At meiosis, the telomeres in many organisms attach to the nuclear envelope and move together to form the telomere bouquet, perhaps to facilitate the homologous search. It is believed that diffusion alone is not sufficient to account for the formation of the bouquet, and that some directed movement is also required. Here we consider the formation of the telomere bouquet in a wheat-rye hybrid both experimentally and using mathematical modelling. The large size of the wheat nucleus and wheat's commercial importance make chromosomal pairing in wheat a particularly interesting and important process, which may well shed light on pairing in other organisms. We show that, prior to bouquet formation, sister chromatid telomeres are always attached to a hemisphere of the nuclear membrane and tend to associate in pairs. We study a mutant lacking the Ph1 locus, a locus ensuring correct homologous chromosome pairing, and discover that bouquet formation is delayed in the wild type compared to the mutant. Further, we develop a mathematical model of bouquet formation involving diffusion and directed movement, where we show that directed movement alone is sufficient to explain bouquet formation dynamics.},
}
@article {pmid23232110,
year = {2014},
author = {Endo, M and Kimura, K and Kuwayama, T and Monji, Y and Iwata, H},
title = {Effect of estradiol during culture of bovine oocyte-granulosa cell complexes on the mitochondrial DNA copies of oocytes and telomere length of granulosa cells.},
journal = {Zygote (Cambridge, England)},
volume = {22},
number = {4},
pages = {431-439},
doi = {10.1017/S0967199412000603},
pmid = {23232110},
issn = {1469-8730},
mesh = {Animals ; Cattle ; Cells, Cultured ; *DNA, Mitochondrial ; Estradiol/*pharmacology ; Female ; Granulosa Cells/*drug effects ; Oocytes/*drug effects/physiology ; Telomere/*drug effects ; },
abstract = {During the development of oocytes from early antral follicles (EAFs) to antral follicles (AFs), the mitochondrial DNA copy number (Mt DNA number) increases, and granulosa cells markedly proliferate. This study examined the effect of supplementation of culture medium with estradiol-17β (E2) on the in vitro growth of oocytes, and increases in the Mt DNA number, and telomere length during the in vitro culture of oocytes derived from EAFs (0.4-0.7 mm in diameter). The E2 supplementation improved antrum formation and the ratio of oocytes reaching the metaphase II (MII) stage, and there was a significant difference in these values between addition E2 concentrations of 10 μg/ml and 0.1 μg/ml. When the oocytes were cultured in the medium containing 10 μg/ml E2, the Mt DNA number determined by real-time polymerase chain reaction (PCR) significantly increased, and the ratio of the Mt DNA number at the end of culture to the Mt DNA number at the beginning of the culture was greatly different among cows, and could be predicted by the degree of the difference between the Mt DNA number of oocytes derived from EAFs and that of oocytes derived from AFs (3-6 mm in diameter). When oocytes were cultured for 16 days in a medium containing 10 μg/ml E2 or 0.1 μg/ml E2, the Mt DNA number of oocytes grown in vitro did not differ, but the telomere length of the granulosa cells was significantly greater in the 10 μg/ml E2 group than in the 0.1 μg/ml group. In conclusion, E2 supplementation in culture medium improved the growth of oocytes derived from EAFs, and a high E2 concentration increased the telomere length of the granulosa cells.},
}
@article {pmid23229897,
year = {2012},
author = {Conomos, D and Stutz, MD and Hills, M and Neumann, AA and Bryan, TM and Reddel, RR and Pickett, HA},
title = {Variant repeats are interspersed throughout the telomeres and recruit nuclear receptors in ALT cells.},
journal = {The Journal of cell biology},
volume = {199},
number = {6},
pages = {893-906},
pmid = {23229897},
issn = {1540-8140},
mesh = {Base Sequence ; Binding Sites ; COUP Transcription Factor II/*metabolism ; Cell Line ; Humans ; Mutation ; Nuclear Receptor Subfamily 2, Group C, Member 2/*metabolism ; Protein Binding/genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Sequence Analysis, DNA ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Telomeres in cells that use the recombination-mediated alternative lengthening of telomeres (ALT) pathway elicit a DNA damage response that is partly independent of telomere length. We therefore investigated whether ALT telomeres contain structural abnormalities that contribute to ALT activity. Here we used next generation sequencing to analyze the DNA content of ALT telomeres. We discovered that variant repeats were interspersed throughout the telomeres of ALT cells. We found that the C-type (TCAGGG) variant repeat predominated and created a high-affinity binding site for the nuclear receptors COUP-TF2 and TR4. Nuclear receptors were directly recruited to telomeres and ALT-associated characteristics were induced after incorporation of the C-type variant repeat by a mutant telomerase. We propose that the presence of variant repeats throughout ALT telomeres results from recombination-mediated telomere replication and spreading of variant repeats from the proximal regions of the telomeres and that the consequent binding of nuclear receptors alters the architecture of telomeres to facilitate further recombination.},
}
@article {pmid23226680,
year = {2012},
author = {Luke-Glaser, S and Poschke, H and Luke, B},
title = {Getting in (and out of) the loop: regulating higher order telomere structures.},
journal = {Frontiers in oncology},
volume = {2},
number = {},
pages = {180},
pmid = {23226680},
issn = {2234-943X},
abstract = {The DNA at the ends of linear chromosomes (the telomere) folds back onto itself and forms an intramolecular lariat-like structure. Although the telomere loop has been implicated in the protection of chromosome ends from nuclease-mediated resection and unscheduled DNA repair activities, it potentially poses an obstacle to the DNA replication machinery during S-phase. Therefore, the coordinated regulation of telomere loop formation, maintenance, and resolution is required in order to establish a balance between protecting the chromosome ends and promoting their duplication prior to cell division. Until recently, the only factor known to influence telomere looping in human cells was TRF2, a component of the shelterin complex. Recent work in yeast and mouse cells has uncovered additional regulatory factors that affect the loop structure at telomeres. In the following "perspective" we outline what is known about telomere looping and highlight the latest results regarding the regulation of this chromosome end structure. We speculate about how the manipulation of the telomere loop may have therapeutic implications in terms of diseases associated with telomere dysfunction and uncontrolled proliferation.},
}
@article {pmid23226558,
year = {2012},
author = {Kozlitina, J and Garcia, CK},
title = {Red blood cell size is inversely associated with leukocyte telomere length in a large multi-ethnic population.},
journal = {PloS one},
volume = {7},
number = {12},
pages = {e51046},
pmid = {23226558},
issn = {1932-6203},
support = {R01 HL093096/HL/NHLBI NIH HHS/United States ; UL1 TR000451/TR/NCATS NIH HHS/United States ; UL1 TR001105/TR/NCATS NIH HHS/United States ; },
mesh = {Demography ; Erythrocyte Count ; *Erythrocyte Indices ; *Ethnicity ; Female ; Hemoglobins/metabolism ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Telomere/*metabolism ; *Telomere Homeostasis ; Texas ; },
abstract = {Although mutations in the genes encoding either the protein or RNA component of telomerase have been found in patients with various blood disorders, the impact of telomere length on hematopoiesis is less well understood for subjects from the general population. Here we have measured telomere lengths of genomic DNA isolated from circulating leukocytes of 3157 subjects, ranging from 18 to 85 years of age, enrolled in a large multiethnic population based study, the Dallas Heart Study 2. Shorter telomere lengths are marginally associated with lower red blood cell counts in this cohort, but are significantly associated with larger mean red blood cell size (as measured by the MCV), increased red blood cell distribution width (RDW), higher hemoglobin levels and lower platelet counts, even after correction for age, gender and ethnicity (p-values of <0.0001, <0.0001, 0.0009 and 0.0016, respectively). In a multiple regression model we find that telomere length is a significant covariate of MCV (p = 7.6 × 10(-8)), independent of age, ethnicity, BMI, current smoking, alcohol consumption, iron or homocysteine levels. The effect of telomere length on MCV variation is comparable to the effect of smoking or alcohol consumption and is more significant in older individuals (p = 9.2 × 10(-7) for >50 years vs. p = 0.0006 for <50 years of age). To our knowledge, this is the first report of an association between telomere length and red cell size in a large urban US population and suggests a biologic mechanism for macrocytosis of aging.},
}
@article {pmid23222450,
year = {2013},
author = {Bauch, C and Becker, PH and Verhulst, S},
title = {Telomere length reflects phenotypic quality and costs of reproduction in a long-lived seabird.},
journal = {Proceedings. Biological sciences},
volume = {280},
number = {1752},
pages = {20122540},
pmid = {23222450},
issn = {1471-2954},
mesh = {Animals ; Charadriiformes/*physiology ; Clutch Size ; DNA/blood ; Female ; Genetic Fitness ; Germany ; *Longevity ; Male ; *Reproduction ; Seasons ; Stress, Physiological ; *Telomere Shortening ; },
abstract = {Telomere length is associated with cellular senescence, lifestyle and ageing. Short telomeres indicate poor health in humans and reduced life expectancy in several bird species, but little is known about telomeres in relation to phenotypic quality in wild animals. We investigated telomere lengths in erythrocytes of known-age common terns (Sterna hirundo), a migratory seabird, in relation to arrival date and reproductive performance. Cross-sectional data revealed that, independent of age, individuals with short telomeres performed better: they arrived and reproduced earlier in the season and had more chicks in the nest. The latter effect was stronger the older the brood and stronger in males, which do most of the chick provisioning. Longitudinal data confirmed this pattern: compared with birds that lost their brood, birds that raised chicks beyond the 10th nestling day experienced higher telomere attrition from one year to the next. However, more detailed analysis revealed that the least and most successful individuals lost the fewest base pairs compared with birds with intermediate success. Our results suggest that reproductive success is achieved at the expense of telomeres, but that individual heterogeneity in susceptibility to such detrimental effects is important, as indicated by low telomere loss in the most successful birds.},
}
@article {pmid23220250,
year = {2012},
author = {Berardinelli, F and Nieri, D and Sgura, A and Tanzarella, C and Antoccia, A},
title = {Telomere loss, not average telomere length, confers radiosensitivity to TK6-irradiated cells.},
journal = {Mutation research},
volume = {740},
number = {1-2},
pages = {13-20},
doi = {10.1016/j.mrfmmm.2012.11.004},
pmid = {23220250},
issn = {0027-5107},
mesh = {Cell Line ; Humans ; Lymphocytes/*radiation effects ; Radiation Tolerance/*genetics ; Telomerase/metabolism ; Telomere Homeostasis/radiation effects ; Telomere Shortening/*radiation effects ; },
abstract = {Many and varied are the proposed mechanisms that lead to resistance to ionizing radiation treatment. Among them, an inverse relationship between telomere length and radioresistance has been recently advanced. Investigating such a relationship in TK6 lymphoblasts, we found that clones originating from cells survived to 4Gy of X-rays showed a significantly higher telomere length when compared with clones grown from untreated cells. The lengthening observed was not attributable to a radiation-induced increase in telomerase activity, as demonstrated by TRAP assay performed in the dose range of 1-10Gy. Given the evidence that TK6 whole population was characterized by heterogeneity in cellular mean telomere length and telomere loss, we tested the hypothesis that a process of selection may favour cells with longer telomeres (more radioresistant cells) following exposure to irradiation. In order to do this 15 independent TK6 clones were selected and characterized for telomere length and loss on the basis of q-FISH and flow-FISH analysis. Among the screened clones four characterized by long telomeres and four characterized by short telomeres were tested for their radiosensitivity by means of clonogenic assay. The results obtained showed that, in our experimental conditions (cellular model, radiation doses) no significant correlation was observed between radiosensitivity and mean telomere lengths, whereas a positive correlation was observed with respect to telomere loss. Overall, these results indicate that telomere loss and not mean telomere length plays a critical role in the phenomenon of radiosensitivity/radioresistance.},
}
@article {pmid23219603,
year = {2013},
author = {Gocha, ARS and Harris, J and Groden, J},
title = {Alternative mechanisms of telomere lengthening: permissive mutations, DNA repair proteins and tumorigenic progression.},
journal = {Mutation research},
volume = {743-744},
number = {},
pages = {142-150},
pmid = {23219603},
issn = {0027-5107},
support = {M01 RR008084/RR/NCRR NIH HHS/United States ; R01 CA117898/CA/NCI NIH HHS/United States ; UL1 TR000090/TR/NCATS NIH HHS/United States ; CA117898/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Transformation, Neoplastic/*genetics/metabolism ; *DNA Repair ; Disease Progression ; Humans ; *Mutation ; Neoplasms/enzymology/*genetics/metabolism/pathology ; Telomerase/*genetics/metabolism ; Telomere/*genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {Telomeres protect chromosome termini to maintain genomic stability and regulate cellular lifespan. Maintenance of telomere length is required for neoplastic cells after the acquisition of mutations that deregulate cell cycle control and increase cellular proliferation, and can occur through expression of the enzyme telomerase or in a telomerase-independent manner termed alternative lengthening of telomeres (ALT). The precise mechanisms that govern the activation of ALT or telomerase in tumor cells are unknown, although cellular origin may favor one or the other mechanisms. ALT pathways are incompletely understood to date; however, recent publications have increasingly broadened our understanding of how ALT is activated, how it proceeds, and how it influences tumor growth. Specific mutational events influence ALT activation, as mutations in genes that suppress recombination and/or alterations in the regulation of telomerase expression are associated with ALT. Once engaged, ALT uses DNA repair proteins to maintain telomeres in the absence of telomerase; experiments that manipulate the expression of specific proteins in cells using ALT are illuminating some of its mechanisms. Furthermore, ALT may influence tumor growth, as experimental and clinical data suggest that telomerase expression may favor tumor progression. This review summarizes recent findings in mammalian cells and models, as well as clinical data, that identify the genetic mutations permissive to ALT, the DNA repair proteins involved in ALT mechanisms and the importance of telomere maintenance mechanisms for tumor progression. A comprehensive understanding of the mechanisms that permit tumor cell immortalization will be important for identifying novel therapeutic targets in cancer.},
}
@article {pmid23218933,
year = {2013},
author = {Aulinas, A and Santos, A and Valassi, E and Mato, E and Crespo, I and Resmini, E and Roig, O and Bell, O and Webb, SM},
title = {[Telomeres, aging and Cushing's syndrome: are they related?].},
journal = {Endocrinologia y nutricion : organo de la Sociedad Espanola de Endocrinologia y Nutricion},
volume = {60},
number = {6},
pages = {329-335},
doi = {10.1016/j.endonu.2012.10.002},
pmid = {23218933},
issn = {1579-2021},
mesh = {Cellular Senescence/*physiology ; Cushing Syndrome/*etiology/therapy ; Humans ; Telomere/*physiology ; },
abstract = {Cushing's syndrome is due to excess cortisol secretion and is associated to increased mortality and severe morbidity that are not fully reversible despite biochemical control. The syndrome consists of a set of systemic manifestations similar to those found in aging. Chronic stress, which also causes hyperstimulation of the hypothalamic-pituitary-adrenal axis, has been related to accelerated telomere shortening, oxidative damage, and cell aging. Although premature aging in patients with Cushing's syndrome could be related to environmental factors, the possibility that chronic exposure to hypercortisolism causes telomere shortening, and thus premature aging, cannot be ruled out. This review discusses the available evidence supporting a link between Cushing's syndrome and cell aging.},
}
@article {pmid23211840,
year = {2013},
author = {Pereira, B and Ferreira, MG},
title = {Sowing the seeds of cancer: telomeres and age-associated tumorigenesis.},
journal = {Current opinion in oncology},
volume = {25},
number = {1},
pages = {93-98},
doi = {10.1097/CCO.0b013e32835b6358},
pmid = {23211840},
issn = {1531-703X},
mesh = {Aging/genetics/*physiology ; Animals ; *Cell Transformation, Neoplastic/genetics ; Humans ; *Neoplasms/enzymology/genetics ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {PURPOSE OF REVIEW: Advances in the health system and medical sciences are continuously pushing the barrier of life-expectancy. As a consequence, humans are being increasingly afflicted by age-associated diseases, such as cancer. The challenge now lies in understanding the mechanisms underlying ageing in order to reduce the lifetime risk for cancer.<br><br>RECENT FINDINGS: In long-lived mammals, telomere length and restriction of telomerase activity are important barriers preventing the uncontrolled cell division. Absence of telomerase dictates the continuous telomere erosion with each cell division, thus restraining the proliferation of incipient tumour cells. However, recent findings have revealed the unintended consequences of telomere control of cell division. Cells with short telomeres accumulate in older individuals increasing the risk of telomere depletion. Loss of telomere protection results in tetraploidization and genomic instability characteristic of epithelial cancers. Additionally, telomere shortening blocks cell proliferation and induces cell senescence. Senescent cells secrete proinflammatory factors and reactive oxygen species that increase the likelihood of cellular transformation and create the perfect soil for cancer development.<br><br>SUMMARY: Telomere shortening thus provides an example of antagonist pleiotropy, in which a beneficial characteristic that acts during the reproductive years of an organism may, later in life, contain the seed to its demise.},
}
@article {pmid23209831,
year = {2012},
author = {Huusko, TJ and Santaniemi, M and Kakko, S and Taskinen, P and Ukkola, O and Kesäniemi, YA and Savolainen, MJ and Salonurmi, T},
title = {Long telomeres in blood leukocytes are associated with a high risk of ascending aortic aneurysm.},
journal = {PloS one},
volume = {7},
number = {11},
pages = {e50828},
pmid = {23209831},
issn = {1932-6203},
mesh = {Aged ; Aortic Aneurysm/*genetics ; Female ; Humans ; Leukocytes/*metabolism ; Logistic Models ; Male ; Middle Aged ; Risk Factors ; Telomere/*genetics ; },
abstract = {Ascending aortic aneurysm is a connective tissue disorder. Even though multiple novel gene mutations have been identified, risk profiling and diagnosis before rupture still represent a challenge. There are studies demonstrating shorter telomere lengths in the blood leukocytes of abdominal aortic aneurysm patients. The aim of this study was to measure whether relative telomere lengths are changed in the blood leukocytes of ascending aortic aneurysm patients. We also studied the expression of telomerase in aortic tissue samples of ascending aortic aneurysms. Relative lengths of leukocyte telomeres were determined from blood samples of patients with ascending aortic aneurysms and compared with healthy controls. Telomerase expression, both at the level of mRNA and protein, was quantified from the aortic tissue samples. Mean relative telomere length was significantly longer in ascending aortic aneurysm blood samples compared with controls (T/S ratio 0.87 vs. 0.61, p<0.001). Expressions of telomerase mRNA and protein were elevated in the aortic aneurysm samples (p<0.05 and p<0.01). Our study reveals a significant difference in the mean length of blood leukocyte telomeres in ascending aortic aneurysm and controls. Furthermore, expression of telomerase, the main compensating factor for telomere loss, is elevated at both the mRNA and protein level in the samples of aneurysmal aorta. Further studies will be needed to confirm if this change in telomere length can serve as a tool for assessing the risk of ascending aortic aneurysm.},
}
@article {pmid23207109,
year = {2013},
author = {Garcia-Rizo, C and Fernandez-Egea, E and Miller, BJ and Oliveira, C and Justicia, A and Griffith, JK and Heaphy, CM and Bernardo, M and Kirkpatrick, B},
title = {Abnormal glucose tolerance, white blood cell count, and telomere length in newly diagnosed, antidepressant-naïve patients with depression.},
journal = {Brain, behavior, and immunity},
volume = {28},
number = {},
pages = {49-53},
pmid = {23207109},
issn = {1090-2139},
support = {G0001354/MRC_/Medical Research Council/United Kingdom ; R01 DK069265/DK/NIDDK NIH HHS/United States ; R25 GM060201/GM/NIGMS NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adult ; Blood Glucose/analysis ; Case-Control Studies ; Depressive Disorder, Major/immunology/*physiopathology ; Female ; *Glucose Tolerance Test ; Humans ; Interview, Psychological ; *Leukocyte Count ; Lymphocyte Count ; Male ; Psychiatric Status Rating Scales ; Telomere Shortening/*physiology ; },
abstract = {Chronic mood disorders have been associated with a shortened telomere, a marker of increased mortality rate and aging, and impaired cellular immunity. However, treatment may confound these relationships. We examined the relationship of glucose tolerance, white blood cell count and telomere length to depression in newly diagnosed, antidepressant-naïve patients. Subjects with major depression (n=15), and matched healthy control subjects (n=70) underwent a two-hour oral glucose tolerance test and evaluation of blood cell count and telomere content. The depression group had significantly higher two-hour glucose concentrations and a lower lymphocyte count than control subjects (respective means [SD] for two-hour glucose were 125.0mg/dL [67.9] vs 84.6 [25.6] (p<.001); for lymphocyte count 2.1×10(9)/L [0.6] vs 2.5×10(9)/L [0.7] p=.028). Telomere content was significantly shortened in the depression group (87.9 [7.6]) compared to control subjects (101.0 [14.3]; p<0.01). Abnormal glucose tolerance, lymphopenia and a shortened telomere are present early in the course of depression independently of the confounding effect of antidepressant treatment, supporting the concept of major depression as an accelerated aging disease.},
}
@article {pmid23206469,
year = {2012},
author = {Ma, HM and Liu, W and Zhang, P and Yuan, XY},
title = {Human skin fibroblast telomeres are shortened after ultraviolet irradiation.},
journal = {The Journal of international medical research},
volume = {40},
number = {5},
pages = {1871-1877},
doi = {10.1177/030006051204000526},
pmid = {23206469},
issn = {1473-2300},
mesh = {Cell Survival/radiation effects ; Cells, Cultured ; Cellular Senescence/radiation effects ; Child ; Fibroblasts/*physiology/radiation effects ; Humans ; Male ; Skin/cytology ; Telomere/*metabolism/radiation effects ; Telomere Shortening/*radiation effects ; *Ultraviolet Rays ; },
abstract = {OBJECTIVE: Telomere length was used as a biomarker of cell senescence to explore the role of telomere shortening in photoageing induced by ultraviolet A (UVA) light.<br><br>METHODS: Real-time polymerase chain reaction was used to determine telomere length in cultured human fibroblasts of different generations and after exposure to UVA at doses up to 10 000 mJ/cm(2). Twoway analysis of variance was used to determine whether passaging or UVA was the main factor contributing to telomere shortening.<br><br>RESULTS: In nonirradiated cells, telomere length was inversely related to cell generation number. In fibroblasts exposed to UVA at a dose of 1000 or 10 000 mJ/cm(2), telomere length was significantly shorter than that of nonirradiated controls and was negatively related to UVA dose.<br><br>CONCLUSIONS: Telomere length and subsequent cell viability may be affected by UVA irradiation. DNA damage caused by UVA irradiation may initiate the photoageing process and telomeres may be a useful new target for attempts to prevent photoageing.},
}
@article {pmid23201774,
year = {2013},
author = {Cardus, A and Uryga, AK and Walters, G and Erusalimsky, JD},
title = {SIRT6 protects human endothelial cells from DNA damage, telomere dysfunction, and senescence.},
journal = {Cardiovascular research},
volume = {97},
number = {3},
pages = {571-579},
pmid = {23201774},
issn = {1755-3245},
mesh = {Aorta/cytology/metabolism ; Cell Proliferation ; Cells, Cultured ; Cellular Senescence/*physiology ; DNA Damage/*physiology ; Endothelium, Vascular/*cytology/*metabolism ; Homeostasis/physiology ; Humans ; Intercellular Adhesion Molecule-1/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Plasminogen Activator Inhibitor 1/metabolism ; RNA Interference/physiology ; Sirtuins/deficiency/genetics/*metabolism ; Telomere/*physiology ; Umbilical Veins/cytology/metabolism ; },
abstract = {AIMS: Although endothelial cell senescence is known to play an important role in the development of cardiovascular pathologies, mechanisms that attenuate this process have not been extensively investigated. The aim of this study was to investigate whether SIRT6, a member of the sirtuin family of NAD(+)-dependent protein deacetylases/ADP-ribosyltransferases, protects endothelial cells from premature senescence and dysfunction, and if so which is its mode of action.<br><br>METHODS AND RESULTS: mRNA expression analysis demonstrated comparable levels of SIRT1 and SIRT6 transcripts in endothelial cells derived from different vascular beds and significantly higher levels of SIRT6 in these cells relative to those in haematopoietic progenitor cells. SIRT6 depletion by RNA interference in human umbilical vein endothelial cells (HUVEC) and aortic endothelial cells reduced cell proliferation, increased the fraction of senescence-associated-&#x3b2;-galactosidase-positive cells, and diminished the ability of the cells to form tubule networks on Matrigel. Further examination of SIRT6-depleted HUVEC demonstrated higher intercellular-adhesion molecule-1 (ICAM-1) and plasminogen-activator inhibitor-1 mRNA, lower levels of endothelial nitric oxide synthase mRNA and protein, higher ICAM-1 surface expression, and up-regulation of p21. Fluorescence microscopy of SIRT6-depleted HUVEC stained with anti-phospho-histone H2A.X and anti-telomere-repeat-binding-factor-1 antibodies showed evidence of increased nuclear DNA damage and the formation of telomere dysfunction-induced foci.<br><br>CONCLUSION: This work demonstrates that the presence of SIRT6 in endothelial cells confers protection from telomere and genomic DNA damage, thus preventing a decrease in replicative capacity and the onset of premature senescence. These findings suggest that SIRT6 may be important to maintain endothelial homeostatic functions and delay vascular ageing.},
}
@article {pmid23201158,
year = {2013},
author = {Steffens, JP and Masi, S and D'Aiuto, F and Spolidorio, LC},
title = {Telomere length and its relationship with chronic diseases - new perspectives for periodontal research.},
journal = {Archives of oral biology},
volume = {58},
number = {2},
pages = {111-117},
doi = {10.1016/j.archoralbio.2012.09.009},
pmid = {23201158},
issn = {1879-1506},
mesh = {Aging/*physiology ; Chronic Disease ; Humans ; Periodontal Diseases/*physiopathology ; *Telomere Shortening ; },
abstract = {OBJECTIVE: The ageing process is accompanied by a variety of cellular modifications, and telomere shortening is a common finding. Large epidemiological studies have reported an association between shorter telomere length in peripheral leukocytes and several inflammatory diseases of the elderly including diabetes, atherosclerosis and, recently, periodontitis. The primary aim of this study was to critically discuss available evidence regarding the potential mechanisms relating shorter telomeres to periodontitis.<br><br>DESIGN: A narrative literature review was performed to report evidence relating shorter telomeres to the ageing process and inflammation. Then, we searched MEDLINE (1950 to May 2012) and ISI WEB OF SCIENCE (1950 to May 2012) databases for the combination of the terms 'telomere' and 'periodontitis'.<br><br>RESULTS: Although these associations suggest a possible role of telomere attrition in the onset or evolution of chronic inflammatory diseases, only two studies addressed the relationship between telomere length and periodontitis.<br><br>CONCLUSION: We suggest that the chronic inflammatory burden observed in people with chronic periodontitis could represent the driver of telomere shortening. However, further evidence is needed to confirm whether inflammation is the cause or the consequence of the shorter leukocyte telomere length observed in people with periodontitis.},
}
@article {pmid23200710,
year = {2013},
author = {Entringer, S and Epel, ES and Lin, J and Buss, C and Shahbaba, B and Blackburn, EH and Simhan, HN and Wadhwa, PD},
title = {Maternal psychosocial stress during pregnancy is associated with newborn leukocyte telomere length.},
journal = {American journal of obstetrics and gynecology},
volume = {208},
number = {2},
pages = {134.e1-7},
pmid = {23200710},
issn = {1097-6868},
support = {R01 HD-041663/HD/NICHD NIH HHS/United States ; R01 HD-060628/HD/NICHD NIH HHS/United States ; R01 HD-052732/HD/NICHD NIH HHS/United States ; R01 HD041663/HD/NICHD NIH HHS/United States ; R01 HD052732/HD/NICHD NIH HHS/United States ; R01 HD065825/HD/NICHD NIH HHS/United States ; R01 HD060628/HD/NICHD NIH HHS/United States ; P01 HD-047609/HD/NICHD NIH HHS/United States ; P01 HD047609/HD/NICHD NIH HHS/United States ; HD-065825/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Birth Weight ; Blotting, Southern ; Female ; Fetal Blood/cytology ; Gestational Age ; Humans ; Infant, Newborn ; Leukocytes, Mononuclear/*ultrastructure ; Polymerase Chain Reaction ; Pregnancy ; Pregnancy Complications/*psychology ; Prospective Studies ; Risk Factors ; Sex Factors ; Stress, Psychological/*psychology ; *Telomere Homeostasis ; Young Adult ; },
abstract = {OBJECTIVE: In adults, one of the major determinants of leukocyte telomere length (LTL), a predictor of age-related diseases and mortality, is cumulative psychosocial stress exposure. More recently we reported that exposure to maternal psychosocial stress during intrauterine life is associated with LTL in young adulthood. The objective of the present study was to determine how early in life this effect of stress on LTL is apparent by quantifying the association of maternal psychosocial stress during pregnancy with newborn telomere length.<br><br>STUDY DESIGN: In a prospective study of N = 27 mother-newborn dyads maternal pregnancy-specific stress was assessed in early gestation and cord blood peripheral blood mononuclear cells were subsequently collected and analyzed for LTL measurement.<br><br>RESULTS: After accounting for the effects of potential determinants of newborn LTL (gestational age at birth, weight, sex, and exposure to antepartum obstetric complications), there was a significant, independent, linear effect of pregnancy-specific stress on newborn LTL that accounted for 25% of the variance in adjusted LTL (&#x3b2; = -0.099; P = .04).<br><br>CONCLUSION: Our finding provides the first preliminary evidence in human beings that maternal psychological stress during pregnancy may exert a "programming" effect on the developing telomere biology system that is already apparent at birth, as reflected by the setting of newborn LTL.},
}
@article {pmid23199912,
year = {2012},
author = {Burnecki, K and Kepten, E and Janczura, J and Bronshtein, I and Garini, Y and Weron, A},
title = {Universal algorithm for identification of fractional Brownian motion. A case of telomere subdiffusion.},
journal = {Biophysical journal},
volume = {103},
number = {9},
pages = {1839-1847},
pmid = {23199912},
issn = {1542-0086},
mesh = {*Algorithms ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Green Fluorescent Proteins/genetics/metabolism ; Humans ; Motion ; Movement ; Recombinant Fusion Proteins/genetics/metabolism ; Stochastic Processes ; Telomere/chemistry/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; },
abstract = {We present a systematic statistical analysis of the recently measured individual trajectories of fluorescently labeled telomeres in the nucleus of living human cells. The experiments were performed in the U2OS cancer cell line. We propose an algorithm for identification of the telomere motion. By expanding the previously published data set, we are able to explore the dynamics in six time orders, a task not possible earlier. As a result, we establish a rigorous mathematical characterization of the stochastic process and identify the basic mathematical mechanisms behind the telomere motion. We find that the increments of the motion are stationary, Gaussian, ergodic, and even more chaotic--mixing. Moreover, the obtained memory parameter estimates, as well as the ensemble average mean square displacement reveal subdiffusive behavior at all time spans. All these findings statistically prove a fractional Brownian motion for the telomere trajectories, which is confirmed by a generalized p-variation test. Taking into account the biophysical nature of telomeres as monomers in the chromatin chain, we suggest polymer dynamics as a sufficient framework for their motion with no influence of other models. In addition, these results shed light on other studies of telomere motion and the alternative telomere lengthening mechanism. We hope that identification of these mechanisms will allow the development of a proper physical and biological model for telomere subdynamics. This array of tests can be easily implemented to other data sets to enable quick and accurate analysis of their statistical characteristics.},
}
@article {pmid23199575,
year = {2012},
author = {Baicharoen, S and Arsaithamkul, V and Hirai, Y and Hara, T and Koga, A and Hirai, H},
title = {In situ hybridization analysis of gibbon chromosomes suggests that amplification of alpha satellite DNA in the telomere region is confined to two of the four genera.},
journal = {Genome},
volume = {55},
number = {11},
pages = {809-812},
doi = {10.1139/gen-2012-0123},
pmid = {23199575},
issn = {1480-3321},
mesh = {Animals ; Chromosomes/*genetics ; DNA, Satellite/*genetics ; Heterochromatin/genetics ; Hylobates/*genetics ; In Situ Hybridization, Fluorescence/*methods ; Phylogeny ; Species Specificity ; Telomere/genetics ; },
abstract = {The siamang (Symphalangus syndactylus), a species of the family Hylobatidae (gibbons), carries large blocks of constitutive heterochromatin in the telomere region of chromosomes. We recently found that alpha satellite DNA constitutes these heterochromatin blocks as a main component. Alpha satellite DNA, tandem repeat sequences of 171-bp repeat units, is a major component of centromeres in primates. In addition to the siamang, the white-cheeked gibbon (Nomascus leucogenys) was previously found to carry the alpha satellite DNA in the telomere region, although not as large a scale as the siamang. Gibbons comprise four genera: Hoolock, Hylobates, Nomascus, and Symphalangus. Here, we report that the amplification of alpha satellite DNA in the telomere region is probably confined to two genera: Nomascus and Symphalangus. We examined one species of Hoolock and four species of Hylobates and obtained evidence against such an amplification event in these species. The phylogenetic relationship of the four gibbon genera remains unclear. One simple explanation for the current distribution of the telomere region alpha satellite DNA would be that Nomascus and Symphalangus are relatively closely related and the amplification occurred in their common ancestor.},
}
@article {pmid23194454,
year = {2012},
author = {Dang-Nguyen, TQ and Haraguchi, S and Akagi, S and Somfai, T and Kaneda, M and Watanabe, S and Kikuchi, K and Tajima, A and Nagai, T},
title = {Telomere elongation during morula-to-blastocyst transition in cloned porcine embryos.},
journal = {Cellular reprogramming},
volume = {14},
number = {6},
pages = {514-519},
doi = {10.1089/cell.2012.0045},
pmid = {23194454},
issn = {2152-4998},
mesh = {Animals ; Blastocyst/cytology/*metabolism ; *Cloning, Organism ; Female ; Morula/cytology/*metabolism ; Swine ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Although telomeres are elongated during morula-to-blastocyst transition in cloned embryos, it is still unknown whether donor cell types have any effect on this elongation. In the present study, we examined the changes of telomere length during morula-to-blastocyst transition in cloned porcine embryos using different types of donor cells. Porcine embryonic stem-like cells (pESLCs), porcine cumulus cells (PCs), and porcine embryonic fibroblasts at passages 7 and 10 (PEF7s and PEF10s, respectively) were used as donor cells. Telomere lengths of pESLCs (35.8±1.5 kb), PCs (24.4±0.5 kb), PEF7s (18.7±0.6 kb), and PEF10s (17.2±0.1 kb) were significantly different. In contrast, telomere length in morulae derived from pESLCs (18.2±0.3 kb), PC (17.8±0.7 kb), PEF7 (18.5±0.3 kb), and PEF10 (18.4±0.4 kb) did not differ significantly. Likewise, telomeres in blastocysts derived from pESLCs (22.3±1.5 kb), PCs (23.5±2.6 kb), PEF7s (20.2±1.0 kb), and PEF10s (20.9±1.0 kb) had similar lengths. However, telomeres in blastocysts were significant longer (p<0.05) compared with morulae in each group. Relative telomerase activities of morulae derived from pESLCs (4.2±0.4), PCs (4.0±0.5), PEF7s (5.1±0.4), and PEF10s (4.9±0.4) were significantly lower (p<0.01) than those of blastocysts derived from pESLCs (8.2±1.1), PCs (8.6±0.6), PEF7s (12.5±2.9), and PEF10s (8.3±1.1). In conclusion, the telomere elongation in cloned pig embryos that occurred during morula-to-blastocyst transition may be related to the rise of telomerase activity. The telomere elongation may also be independent of the type and telomere length of the donor cell.},
}
@article {pmid23193277,
year = {2013},
author = {Jullien, L and Mestre, M and Roux, P and Gire, V},
title = {Eroded human telomeres are more prone to remain uncapped and to trigger a G2 checkpoint response.},
journal = {Nucleic acids research},
volume = {41},
number = {2},
pages = {900-911},
pmid = {23193277},
issn = {1362-4962},
mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/metabolism ; Cells, Cultured ; Cellular Senescence ; DNA Damage ; DNA-Binding Proteins/metabolism ; Fibroblasts/metabolism ; G2 Phase ; G2 Phase Cell Cycle Checkpoints/*genetics ; Humans ; Mitosis ; Protein Serine-Threonine Kinases/metabolism ; Retinoblastoma Protein/metabolism ; Telomere/metabolism ; *Telomere Shortening ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins/metabolism ; },
abstract = {Telomeres cap the ends of chromosomes and regulate the replicative life span of human somatic cells. Telomere function is lost upon critical shortening and a p53-dependent checkpoint that detects altered telomere states at the G1/S transition was proposed to act as a regulator of the telomere damage response. We show that telomerase-negative human fibroblasts spend more time in G2 phase as they approach senescence and this delay is associated with manifestations of telomere dysfunction and the triggering of an ATM/ATR-dependent DNA damage signal. This correlates with a partial release of telomeric proteins TRF1 and TRF2. Analysis of the consequences of TRF1 and TRF2 depletion or over-expression of mutated versions revealed that telomere uncapping or telomere replication stress also led to DNA damage signalling in G2. Progression through mitosis of these cells was associated with signs of incomplete telomere terminal processing. We also observed an increase in sister chromatid-type telomere aberrations in senescing fibroblasts indicating that defects of telomere post-replicative events increased as cells age. Our results link a post-replicative damage response at eroded telomeres to G2 arrest signalling and challenge the current paradigm that the checkpoint response to short telomeres occurs primarily at the G1/S transition in human cells.},
}
@article {pmid23192708,
year = {2013},
author = {Khaw, AK and Hande, MP and Kalthur, G and Hande, MP},
title = {Curcumin inhibits telomerase and induces telomere shortening and apoptosis in brain tumour cells.},
journal = {Journal of cellular biochemistry},
volume = {114},
number = {6},
pages = {1257-1270},
doi = {10.1002/jcb.24466},
pmid = {23192708},
issn = {1097-4644},
mesh = {Antineoplastic Agents, Phytogenic/metabolism/*pharmacology ; Apoptosis/*drug effects ; Brain Neoplasms ; Cell Line, Tumor ; Cell Membrane/metabolism ; Cell Proliferation/drug effects ; Cell Shape/drug effects ; Curcumin/metabolism/*pharmacology ; Cyclin E/genetics/metabolism ; DNA Damage ; Down-Regulation/drug effects ; Drug Screening Assays, Antitumor ; E2F1 Transcription Factor/genetics/metabolism ; G2 Phase Cell Cycle Checkpoints ; Gene Expression/drug effects ; Humans ; Inhibitory Concentration 50 ; Oncogene Proteins/genetics/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Telomerase/genetics/*metabolism ; Telomere Shortening/*drug effects ; bcl-2-Associated X Protein/genetics/metabolism ; },
abstract = {Curcumin, a polyphenolic compound isolated from Curcuma longa (Turmeric) is widely used in traditional Ayurvedic medicine. Its potential therapeutic effects on a variety of diseases have long been known. Though anti-tumour effects of curcumin have been reported earlier, its mode of action and telomerase inhibitory effects are not clearly determined in brain tumour cells. In the present study, we demonstrate that curcumin binds to cell surface membrane and infiltrates into cytoplasm to initiate apoptotic events. Curcumin treatment has resulted in higher cytotoxicity in the cells that express telomerase enzyme, highlighting its potential as an anticancer agent. Curcumin induced growth inhibition and cell cycle arrest at G2/M phase in the glioblastoma and medulloblastoma cells used in the study. Gene and protein expression analyses revealed that curcumin down-regulated CCNE1, E2F1 and CDK2 and up-regulated the expression of PTEN genes resulting in growth arrest at G2/M phase. Curcumin-induced apoptosis is found to be associated with increased caspase-3/7 activity and overexpression of Bax. In addition, down-regulation of Bcl2 and survivin was observed in curcumin-treated cells. Besides these effects, we found curcumin to be inhibiting telomerase activity and down-regulating hTERT mRNA expression leading to telomere shortening. We conclude that telomerase inhibitory effects of curcumin underscore its use in adjuvant cancer therapy.},
}
@article {pmid23192261,
year = {2012},
author = {Khan, S and Chuturgoon, AA and Naidoo, DP},
title = {Telomeres and atherosclerosis.},
journal = {Cardiovascular journal of Africa},
volume = {23},
number = {10},
pages = {563-571},
pmid = {23192261},
issn = {1680-0745},
mesh = {Animals ; Apoptosis ; Atherosclerosis/*diagnosis/*genetics/physiopathology ; Biomarkers/metabolism ; Cellular Senescence ; Endothelium, Vascular/*pathology/physiopathology ; Humans ; Prognosis ; Risk Factors ; Telomere/*physiology ; *Telomere Homeostasis ; Telomere Shortening ; },
abstract = {In humans and other multicellular organisms that have an extended lifespan, the leading causes of death are atherosclerotic cardiovascular disease and cancer. Experimental and clinical evidence indicates that these age-related disorders are linked through dysregulation of telomere homeostasis. Telomeres are DNA protein structures located at the terminal end of chromosomes and shorten with each cycle of cell replication, thereby reflecting the biological age of an organism. Critically shortened telomeres provoke cellular senescence and apoptosis, impairing the function and viability of a cell. The endothelial cells within atherosclerotic plaques have been shown to display features of cellular senescence. Studies have consistently demonstrated an association between shortened telomere length and coronary artery disease (CAD). Several of the CAD risk factors and particularly type 2 diabetes are linked to telomere shortening and cellular senescence. Our interest in telomere biology was prompted by the high incidence of premature CAD and diabetes in a subset of our population, and the hypothesis that these conditions are premature-ageing syndromes. The assessment of telomere length may serve as a better predictor of cardiovascular risk and mortality than currently available risk markers, and anti-senescence therapy targeting the telomere complex is emerging as a new strategy in the treatment of atherosclerosis. We review the evidence linking telomere biology to atherosclerosis and discuss methods to preserve telomere length.},
}
@article {pmid23188080,
year = {2012},
author = {Reis, CC and Batista, S and Ferreira, MG},
title = {The fission yeast MRN complex tethers dysfunctional telomeres for NHEJ repair.},
journal = {The EMBO journal},
volume = {31},
number = {24},
pages = {4576-4586},
pmid = {23188080},
issn = {1460-2075},
mesh = {Cell Survival/physiology ; Chromosomal Proteins, Non-Histone/metabolism ; DNA End-Joining Repair/*physiology ; DNA Primers/genetics ; Electrophoresis, Gel, Pulsed-Field ; Exodeoxyribonucleases/metabolism ; G1 Phase/*physiology ; Multiprotein Complexes/*metabolism ; Polymerase Chain Reaction ; Schizosaccharomyces ; Schizosaccharomyces pombe Proteins/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/deficiency ; },
abstract = {Telomeres protect the natural ends of chromosomes from being repaired as deleterious DNA breaks. In fission yeast, absence of Taz1 (homologue of human TRF1 and TRF2) renders telomeres vulnerable to DNA repair. During the G1 phase, when non-homologous end joining (NHEJ) is upregulated, taz1Δ cells undergo telomere fusions with consequent loss of viability. Here, we show that disruption of the fission yeast MRN (Rad23(MRE11)-Rad50-Nbs1) complex prevents NHEJ at telomeres and, as a result, rescues taz1Δ lethality in G1. Neither Tel1(ATM) activation nor 5'-end resection was required for telomere fusion. Nuclease activity of Rad32(MRE11) was also dispensable for NHEJ. Mutants unable to coordinate metal ions required for nuclease activity were proficient in NHEJ repair. In contrast, Rad32(MRE11) mutations that affect binding and/or positioning of DNA ends leaving the nuclease function largely unaffected also impaired NHEJ at telomeres and restored the viability of taz1Δ in G1. Consistently, MRN structural integrity but not nuclease function is also required for NHEJ of independent DNA ends in a novel split-molecule plasmid assay. Thus, MRN acts to tether unlinked DNA ends, allowing for efficient NHEJ.},
}
@article {pmid23186115,
year = {2013},
author = {Tian, L and Weizmann, Y},
title = {Real-time detection of telomerase activity using the exponential isothermal amplification of telomere repeat assay.},
journal = {Journal of the American Chemical Society},
volume = {135},
number = {5},
pages = {1661-1664},
doi = {10.1021/ja309198j},
pmid = {23186115},
issn = {1520-5126},
mesh = {*Enzyme Assays ; HeLa Cells ; Humans ; *Nucleic Acid Amplification Techniques ; Telomerase/*genetics/metabolism ; Telomere/*genetics/metabolism ; Terminal Repeat Sequences/*genetics ; Time Factors ; },
abstract = {As crucial pieces in the puzzle of cancer and human aging, telomeres and telomerase are indispensable in modern biology. Here we describe a novel exponential isothermal amplification of telomere repeat (EXPIATR) assay--a sensitive, simple, and reliable in vitro method for measuring telomerase activity in cell extracts. Through a strategically designed path of nucleic acid isothermal amplifications, EXPIATR abandons the expensive thermal cycling protocol and achieves ultrafast detection: telomerase activity equivalent to a single HeLa cancer cell can be detected in ∼25 min.},
}
@article {pmid23185534,
year = {2012},
author = {Bower, K and Napier, CE and Cole, SL and Dagg, RA and Lau, LM and Duncan, EL and Moy, EL and Reddel, RR},
title = {Loss of wild-type ATRX expression in somatic cell hybrids segregates with activation of Alternative Lengthening of Telomeres.},
journal = {PloS one},
volume = {7},
number = {11},
pages = {e50062},
pmid = {23185534},
issn = {1932-6203},
mesh = {Adaptor Proteins, Signal Transducing/*genetics/metabolism ; Cell Fusion ; Co-Repressor Proteins ; DNA Helicases/*genetics/metabolism ; Female ; *Gene Expression Regulation ; Humans ; Hybrid Cells/*metabolism/pathology ; Male ; Molecular Chaperones ; Nuclear Proteins/*genetics/metabolism ; Repressor Proteins/*genetics/metabolism ; Signal Transduction ; Telomerase/genetics/metabolism ; *Telomere ; Telomere Homeostasis/genetics ; X-linked Nuclear Protein ; },
abstract = {Alternative Lengthening of Telomeres (ALT) is a non-telomerase mechanism of telomere lengthening that occurs in about 10% of cancers overall and is particularly common in astrocytic brain tumors and specific types of sarcomas. Somatic cell hybridization analyses have previously shown that normal telomerase-negative fibroblasts and telomerase-positive immortalized cell lines contain repressors of ALT activity, indicating that activation of ALT results from loss of one or more unidentified repressors. More recently, ATRX or DAXX was shown to be mutated both in tumors with telomere lengths suggestive of ALT activity and in ALT cell lines. Here, an ALT cell line was separately fused to each of four telomerase-positive cell lines, and four or five independent hybrid lines from each fusion were examined for expression of ATRX and DAXX and for telomere lengthening mechanism. The hybrid lines expressed either telomerase or ALT, with the other mechanism being repressed. DAXX was expressed normally in all parental cell lines and in all of the hybrids. ATRX was expressed normally in each of the four telomerase-positive parental cell lines and in every telomerase-positive hybrid line, and was abnormal in the ALT parental cells and in all but one of the ALT hybrids. This correlation between ALT activity and loss of ATRX expression is consistent with ATRX being a repressor of ALT.},
}
@article {pmid23185405,
year = {2012},
author = {Teyssier, JR and Chauvet-Gelinier, JC and Ragot, S and Bonin, B},
title = {Up-regulation of leucocytes genes implicated in telomere dysfunction and cellular senescence correlates with depression and anxiety severity scores.},
journal = {PloS one},
volume = {7},
number = {11},
pages = {e49677},
pmid = {23185405},
issn = {1932-6203},
mesh = {Adult ; Aging ; Anxiety/*genetics/metabolism ; Biomarkers ; Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p16/biosynthesis ; DNA/genetics ; DNA Damage ; Depression/*genetics/metabolism ; Depressive Disorder, Major/genetics ; Female ; *Gene Expression Regulation ; Humans ; Leukocytes/*cytology ; Middle Aged ; Oxygen/chemistry ; Stathmin/genetics ; Telomere/*ultrastructure ; *Up-Regulation ; },
abstract = {BACKGROUND: Major depressive disorder (MDD) is frequently associated with chronic medical illness responsible of increased disability and mortality. Inflammation and oxidative stress are considered to be the major mediators of the allostatic load, and has been shown to correlate with telomere erosion in the leucocytes of MDD patients, leading to the model of accelerated aging. However, the significance of telomere length as an exclusive biomarker of aging has been questioned on both methodological and biological grounds. Furthermore, telomeres significantly shorten only in patients with long lasting MDD. Sensitive and dynamic functional biomarkers of aging would be clinically useful to evaluate the somatic impact of MDD.<br><br>METHODOLOGY: To address this issue we have measured in the blood leucocytes of MDD patients (N=17) and controls (N=16) the expression of two genes identified as robust biomarkers of human aging and telomere dysfunction: p16(INK4a) and STMN1. We have also quantified the transcripts of genes involved in the repair of oxidative DNA damage at telomeres (OGG1), telomere regulation and elongation (TERT), and in the response to biopsychological stress (FOS and DUSP1).<br><br>RESULTS: The OGG1, p16(INK4a), and STMN1 gene were significantly up-regulated (25 to 100%) in the leucocytes of MDD patients. Expression of p16(INK4a) and STMN1 was directly correlated with anxiety scores in the depression group, and that of p16(INK4a), STMN and TERT with the depression and anxiety scores in the combined sample (MDD plus controls). Furthermore, we identified a unique correlative pattern of gene expression in the leucocytes of MDD subjects.<br><br>CONCLUSIONS: Expression of p16(INK4) and STMN1 is a promising biomarker for future epidemiological assessment of the somatic impact of depressive and anxious symptoms, at both clinical and subclinical level in both depressive patients and general population.},
}
@article {pmid23184978,
year = {2012},
author = {Wang, F and Tang, ML and Zeng, ZX and Wu, RY and Xue, Y and Hao, YH and Pang, DW and Zhao, Y and Tan, Z},
title = {Telomere- and telomerase-interacting protein that unfolds telomere G-quadruplex and promotes telomere extension in mammalian cells.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {109},
number = {50},
pages = {20413-20418},
pmid = {23184978},
issn = {1091-6490},
mesh = {Alternative Splicing ; Animals ; Base Sequence ; Binding Sites/genetics ; Cell Line ; DNA, Complementary/chemistry/genetics/metabolism ; *G-Quadruplexes ; HeLa Cells ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/chemistry/genetics/*metabolism ; Humans ; Liver/metabolism ; Male ; Mice ; Models, Biological ; Nucleic Acid Conformation ; RNA, Messenger/genetics/metabolism ; RNA, Small Interfering/genetics ; Rats ; Recombinant Proteins/chemistry/genetics/metabolism ; Telomerase/antagonists &amp; inhibitors/genetics/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*physiology ; },
abstract = {Telomere extension by telomerase is essential for chromosome stability and cell vitality. Here, we report the identification of a splice variant of mammalian heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2), hnRNP A2*, which binds telomeric DNA and telomerase in vitro. hnRNP A2* colocalizes with telomerase in Cajal bodies and at telomeres. In vitro assays show that hnRNP A2* actively unfolds telomeric G-quadruplex DNA, exposes 5 nt of the 3' telomere tail and substantially enhances the catalytic activity and processivity of telomerase. The expression level of hnRNP A2* in tissues positively correlates with telomerase activity, and overexpression of hnRNP A2* leads to telomere elongation in vivo. Thus, hnRNP A2* plays a positive role in unfolding telomere G-quadruplexes and in enhancing telomere extension by telomerase.},
}
@article {pmid23181431,
year = {2013},
author = {Wu, Y and DiMaggio, PA and Perlman, DH and Zakian, VA and Garcia, BA},
title = {Novel phosphorylation sites in the S. cerevisiae Cdc13 protein reveal new targets for telomere length regulation.},
journal = {Journal of proteome research},
volume = {12},
number = {1},
pages = {316-327},
pmid = {23181431},
issn = {1535-3907},
support = {GM43265/GM/NIGMS NIH HHS/United States ; R01 GM043265/GM/NIGMS NIH HHS/United States ; DP2OD007447/OD/NIH HHS/United States ; F32 GM093490/GM/NIGMS NIH HHS/United States ; R01 GM026938/GM/NIGMS NIH HHS/United States ; DP2 OD007447/OD/NIH HHS/United States ; },
mesh = {Cell Cycle/genetics ; DNA Replication/genetics ; Mutation ; Phosphorylation ; Saccharomyces cerevisiae/cytology/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; Tandem Mass Spectrometry ; *Telomerase/deficiency/genetics/metabolism ; *Telomere/genetics/metabolism ; *Telomere Homeostasis ; *Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {The S. cerevisiae Cdc13 is a multifunctional protein with key roles in regulation of telomerase, telomere end protection, and conventional telomere replication, all of which are cell cycle-regulated processes. Given that phosphorylation is a key mechanism for regulating protein function, we identified sites of phosphorylation using nano liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS). We also determined phosphorylation abundance on both wild type (WT) and a telomerase deficient form of Cdc13, encoded by the cdc13-2 allele, in both G1 phase cells, when telomerase is not active, and G2/M phase cells, when it is. We identified 21 sites of in vivo phosphorylation, of which only five had been reported previously. In contrast, phosphorylation of two in vitro targets of the ATM-like Tel1 kinase, S249 and S255, was not detected. This result helps resolve conflicting data on the importance of phosphorylation of these residues in telomerase recruitment. Multiple residues showed differences in their cell cycle pattern of modification. For example, phosphorylation of S314 was significantly higher in the G2/M compared to the G1 phase and in WT versus mutant Cdc13, and a S314D mutation negatively affected telomere length. Our findings provide new targets in a key telomerase regulatory protein for modulation of telomere dynamics.},
}
@article {pmid23180556,
year = {2013},
author = {Shi, J and Sun, F and Peng, L and Li, B and Liu, L and Zhou, C and Han, J and Zhang, L and Zhou, L and Zhang, X and Pu, H and Tong, L and Yuan, Q and Song, X and Yang, M},
title = {Leukocyte telomere length-related genetic variants in 1p34.2 and 14q21 loci contribute to the risk of esophageal squamous cell carcinoma.},
journal = {International journal of cancer},
volume = {132},
number = {12},
pages = {2799-2807},
doi = {10.1002/ijc.27959},
pmid = {23180556},
issn = {1097-0215},
mesh = {Adult ; Aged ; Alleles ; Carcinoma, Squamous Cell/*genetics ; Case-Control Studies ; *Chromosomes, Human, Pair 1 ; *Chromosomes, Human, Pair 14 ; Esophageal Neoplasms/*genetics ; Esophageal Squamous Cell Carcinoma ; Female ; Gene Frequency ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genotype ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; Reproducibility of Results ; Telomere/*genetics ; },
abstract = {Short leukocyte telomere length has been associated with significantly increased risk of esophageal cancer. A previous genome-wide association study demonstrated that four SNPs (rs398652 on 14q21, rs621559 on 1p34.2, rs6028466 on 20q11.22 and rs654128 on 6q22.1) were associated with leukocyte telomere length in Caucasians. However, the role of these genetic variants on esophageal squamous cell carcinoma (ESCC) susceptibility is still unknown. Therefore, we investigated whether these polymorphisms have impact on leukocyte telomere length and the risk of ESCC in Chinese. After measuring leukocyte telomere length of 550 healthy individuals, we observed that both rs621559 and rs398652 genetic variants are significantly associated with leukocyte telomere length. On the basis of analyzing 1550 ESCC patients and frequency-matched 1620 controls from 4 medical centers in China, we found that 0.71-fold decreased risk of ESCC is associated with the rs621559 AA genotype compared with the rs621559 GG genotype (p = 5.9 × 10(-6)). We also detected a moderately increased OR for ESCC that was associated with the 14q21 rs398652 G allele (p = 6.5 × 10(-4)). It has been shown that both rs621559 and rs398652 polymorphisms were significantly associated with ESCC risk in additive, recessive or dominant genetic models. Stratified analyses demonstrated that these associations were more pronounced in males. Our results highlight the complexity of genetic regulation of telomere length and further support the important role of telomere in carcinogenesis.},
}
@article {pmid23179801,
year = {2013},
author = {Thilagavathi, J and Kumar, M and Mishra, SS and Venkatesh, S and Kumar, R and Dada, R},
title = {Analysis of sperm telomere length in men with idiopathic infertility.},
journal = {Archives of gynecology and obstetrics},
volume = {287},
number = {4},
pages = {803-807},
doi = {10.1007/s00404-012-2632-8},
pmid = {23179801},
issn = {1432-0711},
mesh = {Case-Control Studies ; *DNA Fragmentation ; Humans ; Infertility, Male/metabolism/*pathology ; Male ; Pilot Projects ; Reactive Oxygen Species/metabolism ; Semen/metabolism ; Spermatozoa/*pathology ; Telomere/*pathology ; },
abstract = {PURPOSE: Telomeres are multifunctional nucleoprotein domains with hexanucleotide tandem repeat (5' TTAGGG 3') sequences, which cap the chromosome ends. However, the role of telomere and its length in sperm with regard to fertility remains unknown.<br><br>METHODS: In this pilot study, we analyzed 32 idiopathic infertile men and 25 controls for sperm telomere length by quantitative polymerase chain reaction (Q-PCR), and correlated it with sperm DNA fragmentation index (DFI) and reactive oxygen species (ROS) levels.<br><br>RESULTS: The relative sperm mean telomere length (T/S) of infertile men was found to be significantly lower (p < 0.005) when compared to controls (0.674 &#xb1; 0.028 vs. 0.699 &#xb1; 0.030). None of the sperm parameters such as sperm count, forward motility, morphology, ROS, and DFI were found to correlate with the sperm telomere length.<br><br>CONCLUSION: Shorter telomeres in sperm may be one of the causative factors responsible for male infertility, but further detailed studies are needed to confirm these findings.},
}
@article {pmid23178942,
year = {2013},
author = {D'Souza, Y and Lauzon, C and Chu, TW and Autexier, C},
title = {Regulation of telomere length and homeostasis by telomerase enzyme processivity.},
journal = {Journal of cell science},
volume = {126},
number = {Pt 2},
pages = {676-687},
doi = {10.1242/jcs.119297},
pmid = {23178942},
issn = {1477-9137},
support = {MOP86672//Canadian Institutes of Health Research/Canada ; },
mesh = {Animals ; HEK293 Cells ; Homeostasis ; Humans ; Rabbits ; Telomerase/genetics/*metabolism ; Telomere/metabolism ; *Telomere Homeostasis ; },
abstract = {Telomerase is a ribonucleoprotein consisting of a catalytic subunit, the telomerase reverse transcriptase (TERT), and an integrally associated RNA that contains a template for the synthesis of short repetitive G-rich DNA sequences at the ends of telomeres. Telomerase can repetitively reverse transcribe its short RNA template, acting processively to add multiple telomeric repeats onto the same DNA substrate. The contribution of enzyme processivity to telomere length regulation in human cells is not well characterized. In cancer cells, under homeostatic telomere length-maintenance conditions, telomerase acts processively, whereas under nonequilibrium conditions, telomerase acts distributively on the shortest telomeres. To investigate the role of increased telomerase processivity on telomere length regulation in human cells with limited lifespan that are dependent on human TERT for lifespan extension and immortalization, we mutated the leucine at position 866 in the reverse transcriptase C motif of human TERT to a tyrosine (L866Y), which is the amino acid found at the equivalent position in HIV-1 reverse transcriptase. We report that, similar to the previously reported gain-of-function Tetrahymena telomerase mutant (L813Y), the human telomerase variant displays increased processivity. Human TERT-L866Y, like wild-type human TERT, can immortalize and extend the lifespan of limited-lifespan cells. Moreover, cells expressing human TERT-L866Y display heterogenous telomere lengths, telomere elongation, multiple telomeric signals indicative of fragile sites and replicative stress, and an increase in short telomeres, which is accompanied by telomere trimming events. Our results suggest that telomere length and homeostasis in human cells may be regulated by telomerase enzyme processivity.},
}
@article {pmid23178129,
year = {2012},
author = {Berman, AJ and Cech, TR},
title = {SnapShot: telomeres and telomerase.},
journal = {Cell},
volume = {151},
number = {5},
pages = {1138-1138.e1},
doi = {10.1016/j.cell.2012.11.008},
pmid = {23178129},
issn = {1097-4172},
mesh = {Animals ; Cell Proliferation ; Humans ; Telomerase/chemistry/*metabolism ; Telomere/chemistry/*metabolism ; Yeasts/metabolism ; },
}
@article {pmid23177925,
year = {2013},
author = {Mason, M and Wanat, JJ and Harper, S and Schultz, DC and Speicher, DW and Johnson, FB and Skordalakes, E},
title = {Cdc13 OB2 dimerization required for productive Stn1 binding and efficient telomere maintenance.},
journal = {Structure (London, England : 1993)},
volume = {21},
number = {1},
pages = {109-120},
pmid = {23177925},
issn = {1878-4186},
support = {R01 AG021521/AG/NIA NIH HHS/United States ; R01 GM088332/GM/NIGMS NIH HHS/United States ; T32 CA009171/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Amino Acid Substitution ; Cell Cycle Proteins/*metabolism ; Crystallography, X-Ray ; DNA, Fungal/chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Secondary ; Saccharomyces cerevisiae/growth &amp; development/*metabolism ; Saccharomyces cerevisiae Proteins/*chemistry/genetics/*metabolism ; Telomere/metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/*chemistry/genetics/*metabolism ; },
abstract = {Cdc13 is an essential yeast protein required for telomere length regulation and genome stability. It does so via its telomere-capping properties and by regulating telomerase access to the telomeres. The crystal structure of the Saccharomyces cerevisiae Cdc13 domain located between the recruitment and DNA binding domains reveals an oligonucleotide-oligosaccharide binding fold (OB2) with unusually long loops extending from the core of the protein. These loops are involved in extensive interactions between two Cdc13 OB2 folds leading to stable homodimerization. Interestingly, the functionally impaired cdc13-1 mutation inhibits OB2 dimerization. Biochemical assays indicate OB2 is not involved in telomeric DNA or Stn1 binding. However, disruption of the OB2 dimer in full-length Cdc13 affects Cdc13-Stn1 association, leading to telomere length deregulation, increased temperature sensitivity, and Stn1 binding defects. We therefore propose that dimerization of the OB2 domain of Cdc13 is required for proper Cdc13, Stn1, Ten1 (CST) assembly and productive telomere capping.},
}
@article {pmid23167566,
year = {2013},
author = {Barrett, EL and Burke, TA and Hammers, M and Komdeur, J and Richardson, DS},
title = {Telomere length and dynamics predict mortality in a wild longitudinal study.},
journal = {Molecular ecology},
volume = {22},
number = {1},
pages = {249-259},
doi = {10.1111/mec.12110},
pmid = {23167566},
issn = {1365-294X},
mesh = {Aging/*genetics ; Animals ; Female ; Genetic Variation ; Longevity/genetics ; Longitudinal Studies ; Male ; Songbirds/*genetics ; *Telomere Shortening ; },
abstract = {Explaining variation in life expectancy between individuals of the same age is fundamental to our understanding of population ecology and life history evolution. Variation in the length and rate of loss of the protective telomere chromosome caps has been linked to cellular lifespan. Yet, the extent to which telomere length and dynamics predict organismal lifespan in nature is still contentious. Using longitudinal samples taken from a closed population of Acrocephalus sechellensis (Seychelles warblers) studied for over 20 years, we describe the first study into life-long adult telomere dynamics (1-17 years) and their relationship to mortality under natural conditions (n = 204 individuals). We show that telomeres shorten with increasing age and body mass, and that shorter telomeres and greater rates of telomere shortening predicted future mortality. Our results provide the first clear and unambiguous evidence of a relationship between telomere length and mortality in the wild, and substantiate the prediction that telomere length and shortening rate can act as an indicator of biological age further to chronological age when exploring life history questions in natural conditions.},
}
@article {pmid23166646,
year = {2012},
author = {Kingma, EM and de Jonge, P and van der Harst, P and Ormel, J and Rosmalen, JG},
title = {The association between intelligence and telomere length: a longitudinal population based study.},
journal = {PloS one},
volume = {7},
number = {11},
pages = {e49356},
pmid = {23166646},
issn = {1932-6203},
mesh = {Age Factors ; Cellular Senescence/*physiology ; Cohort Studies ; Female ; Humans ; Intelligence/*genetics ; Intelligence Tests ; Leukocytes/physiology ; Life Style ; Linear Models ; Male ; Middle Aged ; Polymerase Chain Reaction ; Prospective Studies ; Sex Factors ; Socioeconomic Factors ; Telomere Shortening/*physiology ; },
abstract = {Low intelligence has been associated with poor health and mortality, but underlying mechanisms remain obscure. We hypothesized that low intelligence is associated with accelerated biological ageing as reflected by telomere length; we suggested potential mediation of this association by unhealthy behaviors and low socioeconomic position. The study was performed in a longitudinal population-based cohort study of 895 participants (46.8% males). Intelligence was measured with the Generalized Aptitude-Test Battery at mean age 52.8 years (33-79 years, SD=11.3). Leukocyte telomere length was measured by PCR. Lifestyle and socioeconomic factors were assessed using written self-report measures. Linear regression analyses, adjusted for age, sex, and telomere length measured at the first assessment wave (T1), showed that low intelligence was associated with shorter leukocyte telomere length at approximately 2 years follow-up (beta= .081, t=2.160, p= .031). Nearly 40% of this association was explained by an unhealthy lifestyle, while low socioeconomic position did not add any significant mediation. Low intelligence may be a risk factor for accelerated biological ageing, thereby providing an explanation for its association with poor health and mortality.},
}
@article {pmid23165206,
year = {2012},
author = {Tazumi, A and Masukata, H},
title = {Telomere-binding proteins play roles in control of replication timing.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {11},
number = {24},
pages = {4492-4493},
pmid = {23165206},
issn = {1551-4005},
mesh = {Animals ; DNA Replication/genetics/*physiology ; Humans ; Models, Biological ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Comment on: Tazumi A, et al. Genes Dev 2012; 26:2050-62.},
}
@article {pmid23162608,
year = {2012},
author = {Puterman, E and Epel, E},
title = {An intricate dance: Life experience, multisystem resiliency, and rate of telomere decline throughout the lifespan.},
journal = {Social and personality psychology compass},
volume = {6},
number = {11},
pages = {807-825},
pmid = {23162608},
issn = {1751-9004},
support = {K99 HL109247/HL/NHLBI NIH HHS/United States ; R01 AG030424/AG/NIA NIH HHS/United States ; R01 HL108821/HL/NHLBI NIH HHS/United States ; },
abstract = {Accumulation of life stressors predicts accelerated development and progression of diseases of aging. Telomere length, the DNA-based biomarker indicating cellular aging, is a mechanism of disease development, and is shortened in a dose response fashion by duration and severity of life stressor exposures. Telomere length captures the interplay between genetics, life experiences and psychosocial and behavioral factors. Over the past several years, psychological stress resilience, healthy lifestyle factors, and social connections have been associated with longer telomere length and it appears that these factors can protect individuals from stress-induced telomere shortening. In the current review, we highlight these findings, and illustrate that combining these `multisystem resiliency' factors may strengthen our understanding of aging, as these powerful factors are often neglected in studies of aging. In naturalistic studies, the effects of chronic stress exposure on biological pathways are rarely main effects, but rather a complex interplay between adversity and resiliency factors. We suggest that chronic stress effects can be best understood by directly testing if the deleterious effects of stress on biological aging processes, in this case the cell allostasis measure of telomere shortening, are mitigated in individuals with high levels of multisystem resiliency. Without attending to such interactions, stress effects are often masked and missed. Taking account of the cluster of positive buffering factors that operate across the lifespan will take us a step further in understanding healthy aging. While these ideas are applied to the telomere length literature for illustration, the concept of multisystem resiliency might apply to aging broadly, from cellular to systemic health.},
}
@article {pmid23161153,
year = {2013},
author = {Cai, Z and Yan, LJ and Ratka, A},
title = {Telomere shortening and Alzheimer's disease.},
journal = {Neuromolecular medicine},
volume = {15},
number = {1},
pages = {25-48},
pmid = {23161153},
issn = {1559-1174},
mesh = {Aged ; Alzheimer Disease/drug therapy/etiology/*genetics/metabolism/pathology/psychology ; Amyloid beta-Peptides/metabolism ; Animals ; Chronic Disease ; Cognition Disorders/etiology/genetics ; Humans ; Inflammation/complications/metabolism ; Mice ; Mice, Transgenic ; Models, Biological ; Molecular Targeted Therapy ; Nerve Degeneration ; Nerve Tissue Proteins/metabolism ; Oxidative Stress ; Phosphorylation ; Protein Processing, Post-Translational ; Telomere/*ultrastructure ; tau Proteins/metabolism ; },
abstract = {Telomeres, at the ends of chromosomes and strands of genetic material, become shorter as cells divide in the process of aging. Telomere length has been considered as a biological marker of age. Telomere length shortening has also been evidenced as the causable role in age-related neurodegenerative diseases, including Alzheimer's disease (AD). It has been demonstrated that telomere shortening has been associated with cognitive impairment, amyloid pathology and hyper-phosphorylation of tau in AD and plays an important role in the pathogenesis of AD via the mechanism of oxidative stress and inflammation. However, it seems that there is no relationship between telomere shortening and AD. Therefore, it is essential for further clarification of telomere-related pathogenesis in AD.},
}
@article {pmid23157242,
year = {2013},
author = {Yan, S and Han, B and Wu, Y and Zhou, D and Zhao, Y},
title = {Telomerase gene mutation screening and telomere overhang detection in Chinese patients with acute myeloid leukemia.},
journal = {Leukemia &amp; lymphoma},
volume = {54},
number = {7},
pages = {1437-1441},
doi = {10.3109/10428194.2012.729834},
pmid = {23157242},
issn = {1029-2403},
mesh = {Adolescent ; Adult ; Aged ; Asian People/*genetics ; China ; DNA Mutational Analysis ; Female ; Humans ; Leukemia, Myeloid, Acute/*genetics ; Male ; Middle Aged ; *Mutation ; Risk Factors ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Shortening ; Young Adult ; },
abstract = {Loss-of-function mutations in telomerase complex genes reduce telomerase activity, and can clinically manifest as bone marrow failure disease, which predisposes to acute myeloid leukemia (AML). Telomerase dysfunction also leads to short telomeric overhang, which is a crucial telomeric structural component, and potentially results in chromosome instability. We screened variants in telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) genes, and investigated the 3'-overhang length in bone marrow samples from 72 Chinese patients with AML (61 de novo, 11 secondary, excluding M3), aged 13-77. Cytogenetics, disease severity and short-term survival were evaluated. Three TERT mutations (n896G>A, n1079C>G and n1451G>C) were identified. Mutation carriers had short overhangs and a poor prognosis. We found that overhang lengths were much shorter in AML compared to normal controls (p < 0.001). Short overhangs were related to a high percentage of karyotype abnormalities and poor prognosis (73.8% in short overhang group vs. 30% in normal group, p=0.001). Multivariant analysis showed that overhang length, age and unfavorable chromosome abnormalities served as independent prognostic markers in AML (Cox regression, p=0.001). These data raise the possibility that short overhang length may predict poor prognosis in patients with AML. These findings would have to be confirmed in large, prospective studies.},
}
@article {pmid23146029,
year = {2013},
author = {Castaldo, I and Vergara, P and Pinelli, M and Filla, A and De Michele, G and Cocozza, S and Monticelli, A},
title = {Can telomere shortening in human peripheral blood leukocytes serve as a disease biomarker of Friedreich's ataxia?.},
journal = {Antioxidants &amp; redox signaling},
volume = {18},
number = {11},
pages = {1303-1306},
pmid = {23146029},
issn = {1557-7716},
mesh = {Adult ; Biomarkers ; Case-Control Studies ; Female ; Friedreich Ataxia/*diagnosis/*genetics ; Humans ; Leukocytes/*metabolism ; Male ; *Telomere Shortening ; Young Adult ; },
abstract = {Enhanced oxidative stress and inflammation contribute to telomere erosion. Friedreich's ataxia is a neurodegenerative disorder caused by a reduction in frataxin expression that results in mitochondrial dysfunction and oxidative damage. Furthermore, frataxin deficiency induces a strong activation of inflammatory genes and neuronal death. We investigated telomere length (TL) in peripheral blood leukocytes of 37 patients with Friedreich's ataxia and 36 controls. We noted a significant telomere shortening in patients with Friedreich's ataxia compared to healthy controls (p=0.03). We also found a correlation between TL and disease duration (p=0.001). Our observations lead to the hypothesis that the TL of human peripheral blood leukocytes may serve as a biomarker of Friedreich's ataxia that could be used as an outcome measure in clinical trials.},
}
@article {pmid23145125,
year = {2012},
author = {Russo, A and Palumbo, L and Fornengo, C and Di Gaetano, C and Ricceri, F and Guarrera, S and Critelli, R and Anselmino, M and Piazza, A and Gaita, F and Bergerone, S and Matullo, G},
title = {Telomere length variation in juvenile acute myocardial infarction.},
journal = {PloS one},
volume = {7},
number = {11},
pages = {e49206},
pmid = {23145125},
issn = {1932-6203},
mesh = {Adult ; Age Factors ; Case-Control Studies ; Cohort Studies ; Coronary Artery Disease/complications/genetics ; Diabetes Complications/complications/genetics ; Genetic Markers ; *Genetic Variation ; Humans ; Hypercholesterolemia/complications/genetics ; Hypertension/complications/genetics ; Middle Aged ; Myocardial Infarction/complications/*genetics ; Prospective Studies ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Leukocyte telomere length (LTL) provides a potential marker of biological age, closely related to the endothelial dysfunction and consequently to the atherosclerotic process. To investigate the relationship between the LTL and the risk of premature acute myocardial infarction and to evaluate the predictive value of LTL on the onset of major cardiovascular events, 199 patients from 18 to 48 years old with first diagnosis of acute myocardial infarction were enrolled and were matched with 190 controls for sex and age (± 1 year). Clinical data and coronary artery disease were evaluated at enrollment and at follow up. LTL was measured at enrollment using a quantitative PCR-based method. No significant differences were observed in LTL between cases and controls (p = 0.20) and with the presence of coronary artery disease in patients (p = 0.47). Hypercholesterolemic cases presented LTL significantly longer than cases without hypercholesterolemia (t/s: 0.82 ± 0.16 p = 0.79 and t/s norm: 0.79 ± 0.19 p = 0.01), as confirmed in multivariate regression analysis (p = 0.005, β = 0.09). Furthermore, multivariate regression analysis showed LTL significantly shorter in hypertensive cases than in normotensive cases (p = 0.04, β = -0.07). One hundred seventy-one cases (86%) ended the average follow up of 9 ± 5 years, 92 (54%) presented a major cardiovascular event. At multivariate regression analysis the LTL detected at enrollment did not represent a predictive factor of major cardiovascular events nor it significantly impacted with cumulative events. Based on present cohort of young Italian patients, the LTL did not represent a marker of acute myocardial infarction nor had a predictive role at medium term follow up.},
}
@article {pmid23144701,
year = {2012},
author = {Jackowska, M and Hamer, M and Carvalho, LA and Erusalimsky, JD and Butcher, L and Steptoe, A},
title = {Short sleep duration is associated with shorter telomere length in healthy men: findings from the Whitehall II cohort study.},
journal = {PloS one},
volume = {7},
number = {10},
pages = {e47292},
pmid = {23144701},
issn = {1932-6203},
support = {G0601647//Medical Research Council/United Kingdom ; RG/05/006//British Heart Foundation/United Kingdom ; //Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Aged ; Cohort Studies ; Educational Status ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Self Report ; Sex Factors ; Sleep/*genetics ; Telomere/*genetics ; Telomere Shortening/*genetics ; Time Factors ; },
abstract = {BACKGROUND: Shorter telomere length and poor sleep are more prevalent at older ages, but their relationship is uncertain. This study explored associations between sleep duration and telomere length in a sample of healthy middle and early old age people.<br><br>METHODS: Participants were 434 men and women aged 63.3 years on average drawn from the Whitehall II cohort study. Sleep duration was measured by self-report.<br><br>RESULTS: There was a linear association between sleep duration and leukocyte telomere length in men but not in women (P = 0.035). Men reporting shorter sleep duration had shorter telomeres, independently of age, body mass index, smoking, educational attainment, current employment, cynical hostility scores and depressive symptoms. Telomeres were on average 6% shorter in men sleeping 5 hours or fewer compared with those sleeping more than 7 hours per night.<br><br>CONCLUSION: This study adds to the growing literature relating sleep duration with biomarkers of aging, and suggests that shortening of telomeres might reflect mechanisms through which short sleep contributes to pathological conditions in older men.},
}
@article {pmid23142704,
year = {2013},
author = {Carroll, JE and Diez-Roux, AV and Adler, NE and Seeman, TE},
title = {Socioeconomic factors and leukocyte telomere length in a multi-ethnic sample: findings from the multi-ethnic study of atherosclerosis (MESA).},
journal = {Brain, behavior, and immunity},
volume = {28},
number = {},
pages = {108-114},
pmid = {23142704},
issn = {1090-2139},
support = {R01 HL101161/HL/NHLBI NIH HHS/United States ; N01 HC095167/HC/NHLBI NIH HHS/United States ; T32-MH19925/MH/NIMH NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; N01 HC095161/HC/NHLBI NIH HHS/United States ; N01 HC095164/HC/NHLBI NIH HHS/United States ; N01-HC 95159/HC/NHLBI NIH HHS/United States ; T32 MH019925/MH/NIMH NIH HHS/United States ; N01 HC095169/HC/NHLBI NIH HHS/United States ; N01 HC095165/HC/NHLBI NIH HHS/United States ; N01 HC095168/HC/NHLBI NIH HHS/United States ; N01 HC095163/HC/NHLBI NIH HHS/United States ; N01 HC095162/HC/NHLBI NIH HHS/United States ; N01 HC095159/HC/NHLBI NIH HHS/United States ; N01 HC095166/HC/NHLBI NIH HHS/United States ; N01 HC095160/HC/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; N01-HC 95169/HC/NHLBI NIH HHS/United States ; },
mesh = {Black or African American/*statistics &amp; numerical data ; Aged ; Aged, 80 and over ; Atherosclerosis/*ethnology/immunology/physiopathology ; Biomarkers/metabolism ; Educational Status ; Family Characteristics ; Female ; Hispanic or Latino/*statistics &amp; numerical data ; Humans ; Income/statistics &amp; numerical data ; Leukocytes/*physiology ; Longitudinal Studies ; Male ; Middle Aged ; Risk Factors ; Socioeconomic Factors ; Telomere Shortening/*physiology ; White People/*statistics &amp; numerical data ; },
abstract = {Previous findings have linked lower socioeconomic status (SES) with elevated morbidity and mortality. Leukocyte telomere length (LTL), which also has been associated with age-related disease morbidity and mortality, is a marker of aging at the cellular level, making it a valuable early biomarker of risk and an indicator of biological age. It is hypothesized that SES will be associated with LTL, indicating that SES influences disease risk by accelerating biological aging. In the present sample we test for associations of childhood SES and adult SES (i.e. education, income, home ownership) with LTL, and examine whether these associations vary by racial/ethnic group. Analyses on 963 subjects (18.7% White, 53% Hispanics, and 28.5% African American) from the stress ancillary study of the multi-ethnic study of atherosclerosis revealed a significant difference in LTL between home owners and renters in Hispanic and White participants (p<.05), but not amongst African Americans (p=.98). There were no linear associations of adult education or family income with LTL, however, there was an inverse association between father's education and LTL (p=.03). These findings suggest that for Whites and Hispanics renting vs. owning a home is associated with an older biological age; however we did not replicate previous findings linking education with LTL.},
}
@article {pmid23142664,
year = {2012},
author = {Wang, F and Stewart, JA and Kasbek, C and Zhao, Y and Wright, WE and Price, CM},
title = {Human CST has independent functions during telomere duplex replication and C-strand fill-in.},
journal = {Cell reports},
volume = {2},
number = {5},
pages = {1096-1103},
pmid = {23142664},
issn = {2211-1247},
support = {F32GM097833/GM/NIGMS NIH HHS/United States ; GM041803/GM/NIGMS NIH HHS/United States ; R01 GM041803/GM/NIGMS NIH HHS/United States ; AGO1228//PHS HHS/United States ; F32 GM097833/GM/NIGMS NIH HHS/United States ; T32CA117846/CA/NCI NIH HHS/United States ; T32 CA117846/CA/NCI NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; },
mesh = {DNA/metabolism ; DNA Polymerase I/metabolism ; DNA Replication ; G2 Phase ; HCT116 Cells ; HeLa Cells ; Humans ; RNA Interference ; RNA, Small Interfering/metabolism ; S Phase ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; },
abstract = {Human CST (CTC1-STN1-TEN1) is an RPA-like complex that is needed for efficient replication through the telomere duplex and genome-wide replication restart after fork stalling. Here, we show that STN1/CST has a second function in telomere replication during G-overhang maturation. Analysis of overhang structure after STN1 depletion revealed normal kinetics for telomerase-mediated extension in S phase but a delay in subsequent overhang shortening. This delay resulted from a defect in C-strand fill-in. Short telomeres exhibited the fill-in defect but normal telomere duplex replication, indicating that STN1/CST functions independently in these processes. Our work also indicates that the requirement for STN1/CST in telomere duplex replication correlates with increasing telomere length and replication stress. Our results provide direct evidence that STN1/CST participates in C-strand fill-in. They also demonstrate that STN1/CST participates in two mechanistically separate steps during telomere replication and identify CST as a replication factor that solves diverse replication-associated problems.},
}
@article {pmid23135002,
year = {2012},
author = {Sfeir, A},
title = {Telomeres at a glance.},
journal = {Journal of cell science},
volume = {125},
number = {Pt 18},
pages = {4173-4178},
pmid = {23135002},
issn = {1477-9137},
support = {R01 DK102562/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Cell Transformation, Neoplastic/metabolism/pathology ; DNA Replication ; Humans ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
}
@article {pmid23133674,
year = {2012},
author = {Fujita, I and Tanaka, M and Kanoh, J},
title = {Identification of the functional domains of the telomere protein Rap1 in Schizosaccharomyces pombe.},
journal = {PloS one},
volume = {7},
number = {11},
pages = {e49151},
pmid = {23133674},
issn = {1932-6203},
mesh = {Binding Sites ; Chromatin/chemistry/metabolism ; DNA/chemistry ; G1 Phase ; Gene Silencing ; Genetic Variation ; Meiosis ; Mutation ; Protein Structure, Tertiary ; Schizosaccharomyces/*metabolism ; Schizosaccharomyces pombe Proteins/chemistry/*physiology ; Shelterin Complex ; Telomere/*ultrastructure ; Telomere-Binding Proteins/chemistry/*physiology ; Two-Hybrid System Techniques ; },
abstract = {The telomere at the end of a linear chromosome plays crucial roles in genome stability. In the fission yeast Schizosaccharomyces pombe, the Rap1 protein, one of the central players at the telomeres, associates with multiple proteins to regulate various telomere functions, such as the maintenance of telomere DNA length, telomere end protection, maintenance of telomere heterochromatin, and telomere clustering in meiosis. The molecular bases of the interactions between Rap1 and its partners, however, remain largely unknown. Here, we describe the identification of the interaction domains of Rap1 with its partners. The Bqt1/Bqt2 complex, which is required for normal meiotic progression, Poz1, which is required for telomere length control, and Taz1, which is required for the recruitment of Rap1 to telomeres, bind to distinct domains in the C-terminal half of Rap1. Intriguingly, analyses of a series of deletion mutants for rap1(+) have revealed that the long N-terminal region (1-456 a.a. [amino acids]) of Rap1 (full length: 693 a.a.) is not required for telomere DNA length control, telomere end protection, and telomere gene silencing, whereas the C-terminal region (457-693 a.a.) containing Poz1- and Taz1-binding domains plays important roles in those functions. Furthermore, the Bqt1/Bqt2- and Taz1-binding domains are essential for normal spore formation after meiosis. Our results suggest that the C-terminal half of Rap1 is critical for the primary telomere functions, whereas the N-terminal region containing the BRCT (BRCA1 C-terminus) and Myb domains, which are evolutionally conserved among the Rap1 family proteins, does not play a major role at the telomeres.},
}
@article {pmid23133583,
year = {2012},
author = {Shaffer, JA and Epel, E and Kang, MS and Ye, S and Schwartz, JE and Davidson, KW and Kirkland, S and Honig, LS and Shimbo, D},
title = {Depressive symptoms are not associated with leukocyte telomere length: findings from the Nova Scotia Health Survey (NSHS95), a population-based study.},
journal = {PloS one},
volume = {7},
number = {10},
pages = {e48318},
pmid = {23133583},
issn = {1932-6203},
support = {HL-084034/HL/NHLBI NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; T32HL007854-16/HL/NHLBI NIH HHS/United States ; P50AG008702/AG/NIA NIH HHS/United States ; P01 HL088117/HL/NHLBI NIH HHS/United States ; K24 HL084034/HL/NHLBI NIH HHS/United States ; R01 HL091099/HL/NHLBI NIH HHS/United States ; T32 HL007854/HL/NHLBI NIH HHS/United States ; T32 HP10260//PHS HHS/United States ; HL-091099/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Algorithms ; Depressive Disorder/*blood/diagnosis/epidemiology ; Female ; Humans ; Leukocytes/*cytology/ultrastructure ; Male ; Middle Aged ; Models, Statistical ; Nova Scotia ; Risk ; Risk Factors ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Premature shortening of leukocyte telomere length has been proposed as a novel mechanism by which depression may confer increased risk of adverse cardiovascular events. Prior studies demonstrating associations of depression and depressive symptoms with shorter leukocyte telomere length were small, included selected psychiatric outpatients, were based on convenience samples, and/or adjusted for a limited number of possible confounding factors.<br><br>METHODS AND FINDINGS: We examined the associations of depressive symptoms, probable depressive disorder, and specific depressive symptom clusters, as assessed by the Center for Epidemiological Studies--Depression (CES-D) scale, with leukocyte telomere length, measured by using a real-time PCR method, in 2,225 apparently healthy participants from the 1995 Nova Scotia Health Survey population-based study. The mean age was 48.2 &#xb1; 18.9 years; 49.9% of participants were female; and the mean CES-D score was 7.4 &#xb1; 7.9. The mean telomere length was 5,301 &#xb1; 587 base pairs. In an unadjusted model, depressive symptoms were significantly associated with longer leukocyte telomere length (B = 27.6 base pairs per standard deviation increase in CES-D, 95% confidence interval [CI] = 3.1-52.1, p = 0.027). This association was no longer significant after adjustment for age and sex (B = 9.5, 95% CI = -14.6-33.6, p = 0.44) or after further adjustment for body mass index, Framingham risk score and previous history of ischemic heart disease (all p's &#x2265; 0.37). Neither probable depressive disorder nor specific depressive symptom clusters were independently associated with leukocyte telomere length.<br><br>CONCLUSIONS: Concurrent depressive symptoms were not associated with leukocyte telomere length in a large, representative, population-based study.},
}
@article {pmid23133400,
year = {2012},
author = {Xu, J and McEachern, MJ},
title = {Long telomeres produced by telomerase-resistant recombination are established from a single source and are subject to extreme sequence scrambling.},
journal = {PLoS genetics},
volume = {8},
number = {11},
pages = {e1003017},
pmid = {23133400},
issn = {1553-7404},
support = {R01 GM061645/GM/NIGMS NIH HHS/United States ; GM 61645/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Mismatch Repair/genetics ; *Kluyveromyces/cytology/genetics ; *Recombination, Genetic ; Sequence Deletion ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis ; Telomere Shortening/*genetics ; },
abstract = {Considerable evidence now supports the idea that the moderate telomere lengthening produced by recombinational telomere elongation (RTE) in a Kluyveromyces lactis telomerase deletion mutant occurs through a roll-and-spread mechanism. However, it is unclear whether this mechanism can account for other forms of RTE that produce much longer telomeres such as are seen in human alternative lengthening of telomere (ALT) cells or in the telomerase-resistant type IIR "runaway" RTE such as occurs in the K. lactis stn1-M1 mutant. In this study we have used mutationally tagged telomeres to examine the mechanism of RTE in an stn1-M1 mutant both with and without telomerase. Our results suggest that the establishment stage of the mutant state in newly generated stn1-M1 ter1-Δ mutants surprisingly involves a first stage of sudden telomere shortening. Our data also show that, as predicted by the roll-and-spread mechanism, all lengthened telomeres in a newly established mutant cell commonly emerge from a single telomere source. However, in sharp contrast to the RTE of telomerase deletion survivors, we show that the RTE of stn1-M1 ter1-Δ cells produces telomeres whose sequences undergo continuous intense scrambling via recombination. While telomerase was not necessary for the long telomeres in stn1-M1 cells, its presence during their establishment was seen to interfere with the amplification of repeats via recombination, a result consistent with telomerase retaining its ability to add repeats during active RTE. Finally, we observed that the presence of active mismatch repair or telomerase had important influences on telomeric amplification and/or instability.},
}
@article {pmid23127607,
year = {2012},
author = {Henriques, CM and Ferreira, MG},
title = {Consequences of telomere shortening during lifespan.},
journal = {Current opinion in cell biology},
volume = {24},
number = {6},
pages = {804-808},
doi = {10.1016/j.ceb.2012.09.007},
pmid = {23127607},
issn = {1879-0410},
mesh = {Aging/*genetics ; Animals ; Biological Clocks ; Cell Division ; Cellular Senescence/genetics ; Humans ; Models, Animal ; Telomerase/metabolism ; Telomere/genetics/metabolism ; *Telomere Shortening/genetics ; },
abstract = {Telomerase expression is restricted in human cells and so telomeres shorten throughout our lives, providing a tumour suppressor mechanism that limits cell proliferation. As a trade-off, continuous telomere erosion results in replicative senescence and contributes to ageing. Recently, telomerase therapies were proposed as a valid approach to rescue degenerative phenotypes caused by telomere dysfunction. However, systemic effects initiated by short telomeres may prove dominant in limiting tissue renewal in the whole organism. Most of our knowledge of telomere biology derives from mouse models that do not rely on telomere exhaustion for controlling cell proliferation and tissue homeostasis. In order to understand the impact of telomere shortening in natural ageing, we need to investigate animal models that, like humans, have evolved to have telomere length as a cell division clock.},
}
@article {pmid23125966,
year = {2012},
author = {Li, B},
title = {Telomere components as potential therapeutic targets for treating microbial pathogen infections.},
journal = {Frontiers in oncology},
volume = {2},
number = {},
pages = {156},
pmid = {23125966},
issn = {2234-943X},
support = {R01 AI066095/AI/NIAID NIH HHS/United States ; },
abstract = {In a number of microbial pathogens that undergoes antigenic variation to evade the host's immune attack, genes encoding surface antigens are located at subtelomeric loci, and recent studies have revealed that telomere components play important roles in regulation of surface antigen expression in several of these pathogens, indicating that telomeres play critical roles in microbial pathogen virulence regulation. Importantly, although telomere protein components and their functions are largely conserved from protozoa to mammals, telomere protein homologs in microbial pathogens and humans have low sequence homology. Therefore, pathogen telomere components are potential drug targets for therapeutic approaches because first, most telomere proteins are essential for pathogens' survival, and second, disruption of pathogens' antigenic variation mechanism would facilitate host's immune system to clear the infection.},
}
@article {pmid23124483,
year = {2013},
author = {Hao, XD and Yang, Y and Song, X and Zhao, XK and Wang, LD and He, JD and Kong, QP and Tang, NL and Zhang, YP},
title = {Correlation of telomere length shortening with TP53 somatic mutations, polymorphisms and allelic loss in breast tumors and esophageal cancer.},
journal = {Oncology reports},
volume = {29},
number = {1},
pages = {226-236},
doi = {10.3892/or.2012.2098},
pmid = {23124483},
issn = {1791-2431},
mesh = {Breast Neoplasms/*genetics/pathology ; Esophageal Neoplasms/*genetics/pathology ; Female ; Genomic Instability ; Humans ; *Loss of Heterozygosity ; Mutation/*genetics ; Polymorphism, Genetic/*genetics ; Prognosis ; Telomere/*genetics ; Telomere Shortening ; Tumor Suppressor Protein p53/*genetics ; },
abstract = {Genomic instability caused by telomere erosion is an important mechanism of tumorigenesis. p53 plays a key role in cellular senescence and/or apoptosis associated with telomere erosion which positions p53 as a guard against tumorigenesis. The present study was undertaken to investigate the potential interactions between p53 functional mutations, polymorphisms, allelic loss and telomere erosion in 126 breast tumor patients and 68 esophageal cancer patients. Telomere length (TL) was measured by real-time quantitative PCR. Somatic mutations, polymorphisms and allelic loss in the TP53 gene were detected by direct sequencing of both tumor and normal tissue samples. Our results showed that telomeres were significantly shorter in tumors with somatic p53 mutations compared with tumors with wild-type p53 in both breast tumors (P=0.007) and esophageal cancer (P=0.001). Telomeres of patients with minor genotype CC of rs12951053 and GG of rs1042522 were significantly shorter compared to patients with other genotypes of this single nucleotide polymorphism in esophageal cancer tissue. Furthermore, TP53 allelic loss was detected and significantly associated with somatic mutations in both types of tumor tissues. These findings suggest that somatic p53 mutations, rs12951053 genotype CC and rs1042522 genotype GG contribute to erosion of telomeres, and TP53 allelic loss may be one of the representations of chromosomal instability caused by telomere erosion combined with somatic p53 mutations. These results support that the TP53 gene has a strong interaction with TL erosion in tumorigenesis.},
}
@article {pmid23114548,
year = {2012},
author = {Guan, JZ and Guan, WP and Maeda, T and Makino, N},
title = {Different levels of hypoxia regulate telomere length and telomerase activity.},
journal = {Aging clinical and experimental research},
volume = {24},
number = {3},
pages = {213-217},
doi = {10.1007/BF03325250},
pmid = {23114548},
issn = {1720-8319},
mesh = {Cells, Cultured ; Endothelial Cells/metabolism ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Hypoxia/*genetics/*metabolism ; Telomerase/*metabolism ; Telomere/*genetics/*metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {This study was designed to identify changes in telomere length and telomerase activity in human umbilical vein endothelial cells (HUVECs) exposed to various levels of hypoxia. Mild hypoxia (10%, 15% oxygen) increased telomere length, which did not appear to change under severe hypoxia (1% oxygen). Telomerase activity in HUVECs correlated inversely with oxygen concentration. Endothelial cell telomere elongation with telomerase activation in conditions of mild hypoxia was demonstrated in this study. High telomerase activity may contribute to hypoxia-related telomere elongation. The best cell growth and longest telomere length were observed at 10% O(2), and this percentage may therefore be the optimal level for maintaining vascular endothelial cells. In addition, elevated telomerase activity maintains telomere length within normal range in conditions of severe hypoxia (1% O(2)). The telomere length distribution in HUVECs under hypoxia seems to be regulated by a balance between telomere attrition by hypoxia and telomere elongation by enhanced telomerase activity acting on telomeres, perhaps in a telomere-length dependent manner.},
}
@article {pmid23113342,
year = {2012},
author = {Zhdanova, NS and Minina, IuM and Rubtsov, NB},
title = {[Mammalian telomere biology].},
journal = {Molekuliarnaia biologiia},
volume = {46},
number = {4},
pages = {539-555},
pmid = {23113342},
issn = {0026-8984},
mesh = {Animals ; Cell Cycle/genetics ; Cell Transformation, Neoplastic/genetics ; Cellular Senescence/genetics ; Chromosome Structures/genetics ; Genomic Instability ; Humans ; Neoplasms/enzymology/*genetics ; Telomerase/genetics/*metabolism ; Telomere/*physiology ; Telomere Shortening ; Telomere-Binding Proteins/*physiology ; },
abstract = {Review is devoted to detailed consideration of the functioning in normal and immortal cells of one of the main chromosomal regions, telomeres, being dynamic nucleoprotein structures that cap the ends of eukaryotic chromosomes, protecting them from degradation and end-to-end fusion. The role of telomeres in maintenance of genome stability and cell division was also analyzed. Telomere function depends on many interrelated parameters such as telomerase activity, status of the telomere safety complex shelterin and telomere associated proteins (factors of replication, recombination, and reparation of DNA breaks, and so on). We have focused on mechanisms of telomere length control in normal and immortal cells as well as in cells containing active telomerase and cells wherein it is absent. We have analyzed the features attributed to alternative telomere lengthening, namely in view of recently discovered additional mechanism of telomere shortening by trimming of t-cycles. We have viewed a possibility of expression in normal mammalian cells of both telomerase dependent and recombinational ways of telomere length control and the role of shelterin proteins in choice of the one of them as the dominant way. The role oftelomeres in spatial organization of nucleus, in mitosis and meiosis has been also considered. Diversity of telomere organization in mammalians including unusual telomeres in Iberian shrews has been discussed.},
}
@article {pmid23112344,
year = {2012},
author = {Entringer, S and Buss, C and Wadhwa, PD},
title = {Prenatal stress, telomere biology, and fetal programming of health and disease risk.},
journal = {Science signaling},
volume = {5},
number = {248},
pages = {pt12},
doi = {10.1126/scisignal.2003580},
pmid = {23112344},
issn = {1937-9145},
support = {R01 HD060628/HD/NICHD NIH HHS/United States ; },
mesh = {Aging/*metabolism/pathology ; Animals ; Cellular Senescence ; Disease Susceptibility/etiology/*metabolism/physiopathology ; Female ; Humans ; Male ; Pregnancy ; Prenatal Exposure Delayed Effects/*metabolism/physiopathology ; *Stress, Physiological ; Telomere/*metabolism ; },
abstract = {A substantial body of epidemiological, clinical, cellular, and molecular evidence converges to suggest that conditions during the intrauterine period of life play a critical role in developmental programming to influence subsequent health and susceptibility for common, complex disorders. Elucidation of the biological mechanisms underlying these effects is an area of considerable interest and investigation, and it is important to determine whether these mechanisms are distinct for different health outcomes or whether there are some common underlying pathways that may account for the effects of disparate prenatal and early postnatal conditions on various health and disease risk phenotypes. We propose that telomere biology may represent a common underlying mechanism connecting fetal programming and subsequent health outcomes. It appears that the initial establishment of telomere length and regulation of telomere homeostasis may be plastic and receptive to the influence of intrauterine and other early life conditions. Moreover, telomere homeostasis in various cell types may serve as a fundamental integrator and regulator of processes underlying cell genomic integrity and function, aging, and senescence over the life span. We advance the hypothesis that context- and time-inappropriate exposures to various forms of physiological stress (maternal-placental-fetal endocrine aberrations and immune, inflammatory, and oxidative stresses) during the intrauterine period of development may alter or program the telomere biology system in a manner that accelerates cellular dysfunction, aging, and disease susceptibility over the life span.},
}
@article {pmid23108080,
year = {2013},
author = {Aslan, R and Bektas, A and Bedir, A and Alacam, H and Aslan, MS and Nar, R and Yildirim, B and Goren, I and Ecemis, O and Ustaoglu, M and Goren, F and Okuyucu, A},
title = {Helicobacter pylori eradication increases telomere length in gastric mucosa.},
journal = {Hepato-gastroenterology},
volume = {60},
number = {123},
pages = {601-604},
doi = {10.5754/hge12691},
pmid = {23108080},
issn = {0172-6390},
mesh = {Adult ; Anti-Bacterial Agents/*therapeutic use ; Biopsy ; Case-Control Studies ; Chi-Square Distribution ; Drug Therapy, Combination ; Enzyme-Linked Immunosorbent Assay ; Female ; Gastric Mucosa/*drug effects/metabolism/microbiology ; Helicobacter Infections/diagnosis/*drug therapy/microbiology ; Helicobacter pylori/*drug effects ; Humans ; Male ; Middle Aged ; Polymerase Chain Reaction ; Predictive Value of Tests ; Proton Pump Inhibitors/*therapeutic use ; Telomerase/metabolism ; Telomere/*metabolism/microbiology ; *Telomere Homeostasis ; Time Factors ; Treatment Outcome ; },
abstract = {BACKGROUND/AIMS: Our purpose in this study was to analyze telomere length and telomerase activity before and after eradication treatment in gastric mucosa in patients positive for H. pylori.<br><br>METHODOLOGY: There were two groups: a control group (n=17) and a study group (n=21). For H. pylori eradication, the patients were administrated proton pump inhibitor (PPI) + clarithromycin + amoxicillin or PPI + metronidazole + tetracycline + bismuth for 14 days. Telomere length was analyzed with RT-PCR and telomerase activity with PCR-ELISA on biopsy specimens from the antrum. The result p<0.05 was considered significant.<br><br>RESULTS: Prior to eradication, there was no significant difference between telomere lengths of the patient and control groups (2481.2&#xb1;1823 and 2958.9&#xb1;1345.7 bp, p=0.11, respectively). The telomere length of the study group became longer after eradication (before 2481.2&#xb1;1823bp, after 3766.3&#xb1;1608.8bp, p=0.01). Telomerase activity was not detected in either the patient or the control group.<br><br>CONCLUSIONS: An increase in telomere length was observed with H. pylori eradication. This finding may indicate the importance of H. pylori eradication to avoid the development of gastric cancer.},
}
@article {pmid23108000,
year = {2012},
author = {Bansal, N and Whooley, MA and Regan, M and McCulloch, CE and Ix, JH and Epel, E and Blackburn, E and Lin, J and Hsu, CY},
title = {Association between kidney function and telomere length: the heart and soul study.},
journal = {American journal of nephrology},
volume = {36},
number = {5},
pages = {405-411},
pmid = {23108000},
issn = {1421-9670},
support = {K24 DK92291/DK/NIDDK NIH HHS/United States ; R01 HL079235/HL/NHLBI NIH HHS/United States ; R01 HL096851/HL/NHLBI NIH HHS/United States ; 1R01HL096851/HL/NHLBI NIH HHS/United States ; K23 DK088865/DK/NIDDK NIH HHS/United States ; K24 DK092291/DK/NIDDK NIH HHS/United States ; },
mesh = {Aged ; Coronary Disease/physiopathology ; Female ; Humans ; Kidney/*physiopathology ; Kidney Function Tests ; Longitudinal Studies ; Male ; Middle Aged ; Telomere/*ultrastructure ; *Telomere Shortening ; },
abstract = {BACKGROUND: Telomere attrition is a novel risk factor for cardiovascular disease. Studies of telomere length in relation to kidney function are limited. We explored the association of kidney function with telomere length and telomere shortening.<br><br>METHODS: The Heart and Soul Study is a longitudinal study of patients with stable coronary heart disease. Measures of baseline kidney function included: serum creatinine, creatinine-derived estimated glomerular filtration rate (eGFR(CKD-EPI)), 24-hour urine measured creatinine clearance, cystatin C, cystatin C-derived estimated glomerular filtration rate (eGFRcys) and urine albumin to creatinine ratio. Telomere length was measured from peripheral blood leukocytes at baseline (n = 954) and 5 years later (n = 608). Linear regression models were used to test the association of kidney function with (i) baseline telomere length and (ii) change in telomere length over 5 years.<br><br>RESULTS: At baseline, mean eGFR(CKD-EPI) was 72.6 (&#xb1;21.5) ml/min/1.73 m(2), eGFRcys was 71.0 (&#xb1;23.1) ml/min/1.73 m(2) and ACR was 8.6 (&#xb1;12.3) mg/g. Only lower baseline eGFR(CKD-EPI) was associated with shorter baseline telomere length (9.1 (95% CI 1.2-16.9) fewer base pairs for every 5 ml/min/1.73 m(2) lower eGFR(CKD-EPI)). Lower baseline eGFR(CKD-EPI) (and all other measures of kidney function) predicted more rapid telomere shortening (10.8 (95% CI 4.3-17.3) decrease in base pairs over 5 years for every 5 ml/min/1.73 m(2) lower eGFR(CKD-EPI)). After adjustment for age, these associations were no longer statistically significant.<br><br>CONCLUSIONS: In patients with coronary heart disease, reduced kidney function is associated with (i) shorter baseline telomere length and (ii) more rapid telomere shortening over 5 years; however, these associations are entirely explained by older age.},
}
@article {pmid23103865,
year = {2012},
author = {Nandakumar, J and Bell, CF and Weidenfeld, I and Zaug, AJ and Leinwand, LA and Cech, TR},
title = {The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity.},
journal = {Nature},
volume = {492},
number = {7428},
pages = {285-289},
pmid = {23103865},
issn = {1476-4687},
support = {R01 GM029090/GM/NIGMS NIH HHS/United States ; R01GM099705/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; K99CA167644/CA/NCI NIH HHS/United States ; R01GM29090/GM/NIGMS NIH HHS/United States ; R01 GM099705/GM/NIGMS NIH HHS/United States ; K99 CA167644/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line ; HEK293 Cells ; HeLa Cells ; Humans ; Models, Molecular ; Mutation ; Protein Binding ; Protein Structure, Tertiary ; Shelterin Complex ; Telomerase/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {Human chromosome ends are capped by shelterin, a protein complex that protects the natural ends from being recognized as sites of DNA damage and also regulates the telomere-replicating enzyme, telomerase. Shelterin includes the heterodimeric POT1-TPP1 protein, which binds the telomeric single-stranded DNA tail. TPP1 has been implicated both in recruiting telomerase to telomeres and in stimulating telomerase processivity (the addition of multiple DNA repeats after a single primer-binding event). Determining the mechanisms of these activities has been difficult, especially because genetic perturbations also tend to affect the essential chromosome end-protection function of TPP1 (refs 15-17). Here we identify separation-of-function mutants of human TPP1 that retain full telomere-capping function in vitro and in vivo, yet are defective in binding human telomerase. The seven separation-of-function mutations map to a patch of amino acids on the surface of TPP1, the TEL patch, that both recruits telomerase to telomeres and promotes high-processivity DNA synthesis, indicating that these two activities are manifestations of the same molecular interaction. Given that the interaction between telomerase and TPP1 is required for telomerase function in vivo, the TEL patch of TPP1 provides a new target for anticancer drug development.},
}
@article {pmid23097341,
year = {2012},
author = {Franceschin, M and Rizzo, A and Casagrande, V and Salvati, E and Alvino, A and Altieri, A and Ciammaichella, A and Iachettini, S and Leonetti, C and Ortaggi, G and Porru, M and Bianco, A and Biroccio, A},
title = {Aromatic core extension in the series of N-cyclic bay-substituted perylene G-quadruplex ligands: increased telomere damage, antitumor activity, and strong selectivity for neoplastic over healthy cells.},
journal = {ChemMedChem},
volume = {7},
number = {12},
pages = {2144-2154},
doi = {10.1002/cmdc.201200348},
pmid = {23097341},
issn = {1860-7187},
mesh = {Antineoplastic Agents/*chemistry/*pharmacology ; Cell Line ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Damage/drug effects ; G-Quadruplexes/*drug effects ; Humans ; Neoplasms/drug therapy/genetics ; Perylene/*analogs &amp; derivatives/*pharmacology ; Polycyclic Compounds/*chemistry/*pharmacology ; Telomere/chemistry/genetics ; },
abstract = {Based on previous work on both perylene and coronene derivatives as G-quadruplex binders, a novel chimeric compound was designed: N,N'-bis[2-(1-piperidino)-ethyl]-1-(1-piperidinyl)-6-[2-(1-piperidino)-ethyl]-benzo[ghi]perylene-3,4:9,10-tetracarboxylic diimide (EMICORON), having one piperidinyl group bound to the perylene bay area (positions 1, 12 and 6, 7 of the aromatic core), sufficient to guarantee good selectivity, and an extended aromatic core able to increase the stacking interactions with the terminal tetrad of the G-quadruplex. The obtained "chimera" molecule, EMICORON, rapidly triggers extensive DNA damage of telomeres, associated with the delocalization of telomeric protein protection of telomeres 1 (POT1), and efficiently limits the growth of both telomerase-positive and -negative tumor cells. Notably, the biological effects of EMICORON are more potent than those of the previously described perylene derivative (PPL3C), and more interestingly, EMICORON appears to be detrimental to transformed and tumor cells, while normal fibroblasts expressing telomerase remain unaffected. These results identify a new promising G-quadruplex ligand, structurally and biologically similar on one side to coronene and on the other side to a bay-monosubstituted perylene, that warrants further studies.},
}
@article {pmid23094159,
year = {2012},
author = {Hallows, SE and Regnault, TR and Betts, DH},
title = {The long and short of it: the role of telomeres in fetal origins of adult disease.},
journal = {Journal of pregnancy},
volume = {2012},
number = {},
pages = {638476},
pmid = {23094159},
issn = {2090-2735},
mesh = {Adult ; Biomarkers/metabolism ; Cardiovascular Diseases/*etiology/genetics ; Diabetes Mellitus, Type 2/*etiology/genetics ; Female ; Fetal Growth Retardation/enzymology/etiology/genetics/*physiopathology ; Humans ; Male ; Ovum/physiology ; Placenta/enzymology/physiopathology ; Placental Insufficiency/enzymology/genetics/*physiopathology ; Pregnancy ; Prenatal Exposure Delayed Effects/*etiology/genetics ; Spermatozoa/physiology ; Telomerase/metabolism ; Telomere/*physiology ; Telomere Shortening/physiology ; },
abstract = {Placental insufficiency, maternal malnutrition, and other causes of intrauterine growth restriction (IUGR) can significantly affect short-term growth and long-term health. Following IUGR, there is an increased risk for cardiovascular disease and Type 2 Diabetes. The etiology of these diseases is beginning to be elucidated, and premature aging or cellular senescence through increased oxidative stress and DNA damage to telomeric ends may be initiators of these disease processes. This paper will explore the areas where telomere and telomerase biology can have significant effects on various tissues in the body in IUGR outcomes.},
}
@article {pmid23093543,
year = {2012},
author = {Skinner, HG and Gangnon, RE and Litzelman, K and Johnson, RA and Chari, ST and Petersen, GM and Boardman, LA},
title = {Telomere length and pancreatic cancer: a case-control study.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {21},
number = {11},
pages = {2095-2100},
pmid = {23093543},
issn = {1538-7755},
support = {P50CA102701/CA/NCI NIH HHS/United States ; R01 CA132718/CA/NCI NIH HHS/United States ; P30 CA014520/CA/NCI NIH HHS/United States ; P30DK084567/DK/NIDDK NIH HHS/United States ; K07 CA109361/CA/NCI NIH HHS/United States ; P30 DK084567/DK/NIDDK NIH HHS/United States ; R01 CA 132718/CA/NCI NIH HHS/United States ; P50 CA102701/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Case-Control Studies ; Female ; Humans ; Leukocytes/ultrastructure ; Male ; Pancreatic Neoplasms/blood/*genetics ; Risk Factors ; Telomere/genetics/*ultrastructure ; Telomere Shortening/genetics ; },
abstract = {BACKGROUND: Telomeres, the ends of chromosomes, are critical for maintaining genomic stability and grow shorter with age. Shortened telomeres in pancreatic tissue play a key role in the pathogenesis of pancreatic cancer, and shorter telomeres in peripheral blood leukocytes (PBL) have been associated with increased risk for several cancer types. We hypothesized that shorter blood telomeres are associated with higher risk for pancreatic cancer.<br><br>METHODS: Telomere length was measured in PBLs using quantitative real-time PCR in 499 cases with pancreatic cancer and 963 cancer-free controls from the Mayo Clinic. ORs and confidence intervals (CI) were computed using logistic generalized additive models (GAM) adjusting for multiple variables.<br><br>RESULTS: In multivariable adjusted models, we observed a significant nonlinear association between telomere length in peripheral blood samples and the risk for pancreatic cancer. Risk was lower among those with longer telomeres compared with shorter telomeres across a range from the 1st percentile to 90th percentile of telomere length. There was also some evidence for higher risk among those with telomeres in the longest extreme.<br><br>CONCLUSIONS: Short telomeres in peripheral blood are associated with an increased risk for pancreatic cancer across most of the distribution of length, but extremely long telomeres may also be associated with higher risk.<br><br>IMPACT: Although the temporality of this relationship is unknown, telomere length may be useful as either a marker of pancreatic cancer risk or of the presence of undetected pancreatic cancer. If telomere shortening precedes cancer incidence, interventions to preserve telomere length may be an effective strategy to prevent pancreatic cancer.},
}
@article {pmid23087363,
year = {2012},
author = {De Meyer, T and Van Daele, CM and De Buyzere, ML and Denil, S and De Bacquer, D and Segers, P and Cooman, L and De Backer, GG and Gillebert, TC and Bekaert, S and Rietzschel, ER and , },
title = {No shorter telomeres in subjects with a family history of cardiovascular disease in the Asklepios study.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {32},
number = {12},
pages = {3076-3081},
doi = {10.1161/ATVBAHA.112.300341},
pmid = {23087363},
issn = {1524-4636},
mesh = {Adult ; Belgium/epidemiology ; Cardiovascular Diseases/*epidemiology/*ethnology ; Family Health ; Female ; Humans ; Leukocytes, Mononuclear/ultrastructure ; Longitudinal Studies ; Male ; Middle Aged ; Pedigree ; Prevalence ; Telomere/*ultrastructure ; },
abstract = {OBJECTIVE: Shorter telomere length is associated with the occurrence of cardiovascular events, but the question of causality is complicated by the intertwined effects of inheritance, aging, and lifestyle factors on both telomere length and cardiovascular disease (CVD). Some studies indicated that healthy offspring of coronary artery disease patients exhibited shorter telomeres than subjects without a family history. Importantly, this result would imply that inheritance of shorter telomeres is a primary abnormality associated with an increased risk of CVD, the so-called Telomere Hypothesis of CVD. Therefore, we aimed at further validating the latter results in the large, population-representative Asklepios Study.<br><br>METHODS AND RESULTS: Peripheral blood leukocyte telomere length was measured using telomere restriction fragment analysis in the young to middle-aged (&#x2248; 35-55 years old) Asklepios study population, free from overt CVD, and could be successfully combined with data from the Asklepios Family History Database for 2136 subjects. No shorter telomere length could be found in healthy subjects with a family history of CVD compared with those without.<br><br>CONCLUSIONS: These findings cast serious doubt on the hypothesis that telomere length is shorter in families with an increased risk of CVD and do not support the Telomere Hypothesis of CVD.},
}
@article {pmid23086976,
year = {2012},
author = {Arat, N&#xd6; and Griffith, JD},
title = {Human Rap1 interacts directly with telomeric DNA and regulates TRF2 localization at the telomere.},
journal = {The Journal of biological chemistry},
volume = {287},
number = {50},
pages = {41583-41594},
pmid = {23086976},
issn = {1083-351X},
support = {R01 ES013773/ES/NIEHS NIH HHS/United States ; R01 GM031819/GM/NIGMS NIH HHS/United States ; ES3773/ES/NIEHS NIH HHS/United States ; GM31819/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA/*chemistry/genetics/metabolism ; Humans ; Multiprotein Complexes/*chemistry/genetics/metabolism ; Protein Binding/physiology ; Recombinant Proteins/chemistry/genetics/metabolism ; Shelterin Complex ; Telomere/*chemistry/genetics/metabolism ; Telomere-Binding Proteins/*chemistry/genetics/metabolism ; Telomeric Repeat Binding Protein 2/*chemistry/genetics/metabolism ; },
abstract = {The TRF2-Rap1 complex suppresses non-homologous end joining and interacts with DNAPK-C to prevent end joining. We previously demonstrated that hTRF2 is a double strand telomere binding protein that forms t-loops in vitro and recognizes three- and four-way junctions independent of DNA sequence. How the DNA binding characteristics of hTRF2 to DNA is altered in the presence of hRap1 however is not known. Here we utilized EM and quantitative gel retardation to characterize the DNA binding properties of hRap1 and the TRF2-Rap1 complex. Both gel filtration chromatography and mass analysis from two-dimensional projections showed that the TRF2-Rap1 complex exists in solution and binds to DNA as a complex consisting of four monomers each of hRap1 and hTRF2. EM revealed for the first time that hRap1 binds to DNA templates in the absence of hTRF2 with a preference for double strand-single strand junctions in a sequence independent manner. When hTRF2 and hRap1 are in a complex, its affinity for ds telomeric sequences is 2-fold higher than TRF2 alone and more than 10-fold higher for telomeric 3' ends. This suggests that as hTRF2 recruits hRap1 to telomeric sequences, hRap1 alters the affinity of hTRF2 and its binding preference on telomeric DNA. Moreover, the TRF2-Rap1 complex has higher ability to re-model telomeric DNA than either component alone. This finding underlies the importance of complex formation between hRap1 and hTRF2 for telomere function and end protection.},
}
@article {pmid23082874,
year = {2013},
author = {Salvi, JS and Chan, JN and Pettigrew, C and Liu, TT and Wu, JD and Mekhail, K},
title = {Enforcement of a lifespan-sustaining distribution of Sir2 between telomeres, mating-type loci, and rDNA repeats by Rif1.},
journal = {Aging cell},
volume = {12},
number = {1},
pages = {67-75},
doi = {10.1111/acel.12020},
pmid = {23082874},
issn = {1474-9726},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {DNA, Ribosomal/*genetics/metabolism ; Gene Expression Regulation, Fungal ; Genes, Mating Type, Fungal ; Repressor Proteins/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/*metabolism ; Sirtuin 2/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Transcription, Genetic ; },
abstract = {Telomere dysfunction is linked with genome instability and premature aging. Roles for sirtuin proteins at telomeres are thought to promote lifespan in yeast and mammals. However, replicative lifespan of the budding yeast Saccharomyces cerevisiae shortens upon deletion of Rif1, a protein that limits the recruitment of the sirtuin histone deacetylase Sir2 to telomeres. Here we show that Rif1 maintains replicative lifespan by ultimately stabilizing another age-related chromosomal domain harboring the ribosomal DNA (rDNA) repeats. Deletion of Rif1 increases Sir2 localization to telomeres and the silent mating-type loci, while releasing a pool of the histone deacetylase from the intergenic spacer 1 (IGS1) of rDNA. This is accompanied by a disruption of IGS1 silent chromatin assembly and increases in aberrant recombination within rDNA repeats. Lifespan defects linked with Rif1 deletion are abolished if rDNA repeats are forcibly stabilized via deletion of the replication fork-blocking protein Fob1. In addition, Sir2 overexpression prevents Rif1 deletion from disrupting Sir2 at IGS1 and shortening lifespan. Moreover, subjecting cells lacking Rif1 to caloric restriction increases IGS1 histone deacetylation and lifespan, while uncovering novel genetic interactions between RIF1 and SIR2. Our data indicate that Rif1 maintains lifespan-sustaining levels of Sir2 at rDNA by preventing excessive recruitment of the histone deacetylase to telomeric and silent mating-type loci. As sirtuin histone deacetylases, such as Sir2 or mammalian SIRT6, each operate at multiple age-related loci, we propose that factors limiting the localization of sirtuins to certain age-related loci can promote lifespan-sustaining roles of these sirtuins elsewhere in the genome.},
}
@article {pmid23082138,
year = {2012},
author = {Zhang, W and Chen, Y and Yang, X and Fan, J and Mi, X and Wang, J and Zhang, C and Hu, FB and Hui, R},
title = {Functional haplotypes of the hTERT gene, leukocyte telomere length shortening, and the risk of peripheral arterial disease.},
journal = {PloS one},
volume = {7},
number = {10},
pages = {e47029},
pmid = {23082138},
issn = {1932-6203},
mesh = {Female ; Genetic Association Studies ; *Genetic Predisposition to Disease ; Haplotypes/*genetics ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Peripheral Arterial Disease/*genetics ; Polymorphism, Single Nucleotide/genetics ; Promoter Regions, Genetic/genetics ; Risk Factors ; Telomerase/*genetics ; Telomere Shortening/*genetics ; Transcription, Genetic ; },
abstract = {BACKGROUND: The development of peripheral arterial disease (PAD) is heterogeneous even in the presence of similar risk factors. Our aim was to determine whether inter-individual differences in leukocyte telomere length contribute to the susceptibility of PAD.<br><br>METHODS: A total of 485 patients with PAD (defined by the ankle-brachial index) and 970 age- and gender-matched controls were recruited from seven rural communities in Henan Province in China. The relative leukocyte telomere length was determined by a quantitative PCR-based method. Two common promoter variants of the hTERT gene were genotyped to assess their effects on telomere length and the risk of PAD. In vivo luciferase assay was performed to study the transcriptional activity.<br><br>RESULTS: After adjustment for vascular risk factors and genetic variants in the hTERT gene, individuals in the lowest and middle tertiles of telomere length had a significantly higher risk of PAD than did those in the highest tertile (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.29-2.49 in the middle tertile; 3.15, 95%CI 2.31-4.29 in the lowest tertile). Haplotype analysis using the 2 variants (rs2735940 and rs2853669) showed that subjects with the at-risk C-C haplotype had shorter telomere length than those individuals with the T-T haplotype and consistently had 1.30-fold (OR 1.30, 95%CI 1.06-1.58; P=0.005) increased risk for PAD. The C-C haplotype had 43% lowered transcription activity of hTERT promoter (P<0.001).<br><br>CONCLUSION: The associations between the functional haplotype of hTERT gene and telomere length and the risk of atherosclerotic PAD suggested that mean leukocyte telomere length may independently serve as a potential predictor of PAD.},
}
@article {pmid23077078,
year = {2013},
author = {Fyhrquist, F and Eriksson, A and Saijonmaa, O and Nordestgaard, BG and Kontula, K and de Faire, U and Ibsen, H and Kjeldsen, S and Os, I and Dahlöf, B},
title = {Telomere length is associated with ACE I/D polymorphism in hypertensive patients with left ventricular hypertrophy.},
journal = {Journal of the renin-angiotensin-aldosterone system : JRAAS},
volume = {14},
number = {3},
pages = {227-234},
doi = {10.1177/1470320312460292},
pmid = {23077078},
issn = {1752-8976},
mesh = {Aged ; Aged, 80 and over ; Female ; *Genetic Predisposition to Disease ; Humans ; Hypertension/*complications/enzymology/genetics ; Hypertrophy, Left Ventricular/complications/enzymology/*genetics ; INDEL Mutation/*genetics ; Linear Models ; Male ; Middle Aged ; Multivariate Analysis ; Peptidyl-Dipeptidase A/*genetics ; *Polymorphism, Genetic ; Risk Factors ; Telomere Homeostasis/*genetics ; },
abstract = {INTRODUCTION: Short telomeres are often associated with cardiovascular risk factors and age-related diseases, while the angiotensin converting enzyme (ACE) gene insertion/deletion polymorphism (DD, ID, II) has shown such associations less consistently. We hypothesized that telomere length and association of telomere length with cardiovascular risk is affected by ACE (I/D) genotype.<br><br>METHODS: We measured leucocyte telomere length (LTL) by Southern blot and analysed ACE I/D genotypes in 1249 subjects with hypertension and left ventricular hypertrophy (LVH). We examined interactions of ACE I/D genotype with LTL and cardiovascular risk.<br><br>RESULTS: Mean LTL in DD or ID genotype was shorter (8.15 and 8.14 kb, respectively), than in II genotype (8.27 kb, p=0.0005). This difference was significant in the younger subjects (55-64 years, p=0.02) but not in the older group (65-80 years, p=0.56). In DD but not I/D or II genotype, proportion of short telomeres (<5 kb) was related to Framingham risk score.<br><br>CONCLUSIONS: Shorter LTL in genotypes DD or ID suggests a negative effect of the D allele on telomere length. Homozygocity for the D allele appears to strengthen the association of telomere length with increased cardiovascular risk in elderly hypertensive subjects with LVH.},
}
@article {pmid23076733,
year = {2012},
author = {Guilherme, RS and Klein, E and Venner, C and Hamid, AB and Bhatt, S and Melaragno, MI and Volleth, M and Polityko, A and Kulpanovich, A and Kosyakova, N and Liehr, T},
title = {Human ring chromosomes and small supernumerary marker chromosomes-do they have telomeres?.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {20},
number = {7},
pages = {825-835},
pmid = {23076733},
issn = {1573-6849},
mesh = {*Chromosome Aberrations ; *Genetic Markers ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; *Ring Chromosomes ; Sequence Analysis, DNA ; Telomere/*genetics ; },
abstract = {Ring chromosomes and small supernumerary marker chromosomes (sSMC) are enigmatic types of derivative chromosomes, in which the telomeres are thought to play a crucial role in their formation and stabilization. Considering that there are only a few studies that evaluate the presence of telomeric sequences in ring chromosomes and on sSMC, here, we analyzed 14 ring chromosomes and 29 sSMC for the presence of telomeric sequences through fluorescence in situ hybridization (FISH). The results showed that ring chromosomes can actually fall into two groups: the ones with or without telomeres. Additionally, telomeric signals were detectable at both ends of centric and neocentric sSMC with inverted duplication shape, as well as in complex sSMC. Apart from that, generally both ring- and centric minute-shaped sSMC did not present telomeric sequences neither detectable by FISH nor by a second protein-directed immunohistochemical approach. However, the fact that telomeres are absent does not automatically mean that the sSMC has a ring shape, as often deduced in the previous literature. Overall, the results obtained by FISH studies directed against telomeres need to be checked carefully by other approaches.},
}
@article {pmid23073262,
year = {2012},
author = {Tiainen, AM and Männistö, S and Blomstedt, PA and Moltchanova, E and Perälä, MM and Kaartinen, NE and Kajantie, E and Kananen, L and Hovatta, I and Eriksson, JG},
title = {Leukocyte telomere length and its relation to food and nutrient intake in an elderly population.},
journal = {European journal of clinical nutrition},
volume = {66},
number = {12},
pages = {1290-1294},
doi = {10.1038/ejcn.2012.143},
pmid = {23073262},
issn = {1476-5640},
mesh = {Aged ; Cohort Studies ; Cross-Sectional Studies ; *Diet ; Diet Surveys ; Dietary Fats/*adverse effects ; *Energy Intake ; Fatty Acids/*adverse effects ; Female ; Humans ; Leukocytes/*drug effects/ultrastructure ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Surveys and Questionnaires ; Telomere/*drug effects/ultrastructure ; *Vegetables ; },
abstract = {BACKGROUND/OBJECTIVES: Shorter leukocyte telomere length (LTL) is associated with several chronic diseases, but only a few studies have assessed the association between dietary factors and LTL. Our objective was to study the association between fats, fruits, vegetables and LTL in a cross-sectional study design. We hypothesized that intakes of fruits and vegetables would be positively associated with LTL and that intakes of fats, and especially saturated fatty acids (SFAs), would be negatively associated with LTL.<br><br>SUBJECTS/METHODS: LTL was measured by quantitative real-time polymerase chain reaction in 1942 men and women aged 57-70 years from the Helsinki Birth Cohort Study. We assessed the whole diet by a validated semiquantitative 128-item food-frequency questionnaire.<br><br>RESULTS: In general, there were only a few significant results. However, total fat and SFA intake (P=0.04 and 0.01, respectively) were inversely associated with LTL in men adjusting for age and energy intake. In women, vegetable intake was positively associated with LTL (P=0.05). Men consuming the most butter and least fruits had significantly shorter telomeres than those consuming the lowest amounts of butter and highest amounts of fruits (P=0.05). We found no association between LTL and body mass index, waist-hip ratio, smoking, physical activity or educational attainment.<br><br>CONCLUSIONS: In this cross-sectional study of elderly men and women, there were only a few statistically significant effects of diet, but in general they support the hypothesis that fat and vegetable intakes were associated with LTL.},
}
@article {pmid23066103,
year = {2012},
author = {Weuts, A and Voet, T and Verbeeck, J and Lambrechts, N and Wirix, E and Schoonjans, L and Danloy, S and Marynen, P and Froyen, G},
title = {Telomere length homeostasis and telomere position effect on a linear human artificial chromosome are dictated by the genetic background.},
journal = {Nucleic acids research},
volume = {40},
number = {22},
pages = {11477-11489},
pmid = {23066103},
issn = {1362-4962},
mesh = {Animals ; Cells, Cultured ; Chromatin/metabolism ; *Chromosomal Position Effects ; *Chromosomes, Artificial, Human ; Cricetinae ; DNA Methylation ; Humans ; Mice ; Mice, Inbred BALB C ; Telomere/*physiology ; *Telomere Homeostasis ; },
abstract = {Telomere position effect (TPE) is the influence of telomeres on subtelomeric epigenetic marks and gene expression. Previous studies suggested that TPE depends on genetic background. As these analyses were performed on different chromosomes, cell types and species, it remains unclear whether TPE represents a chromosome-rather than genetic background-specific regulation. We describe the development of a Linear Human Artificial Chromosome (L-HAC) as a new tool for telomere studies. The L-HAC was generated through the Cre-loxP-mediated addition of telomere ends to an existing circular HAC (C-HAC). As it can be transferred to genetically distinct cell lines and animal models the L-HAC enables the study of TPE in an unprecedented manner. The HAC was relocated to four telomerase-positive cell lines via microcell-mediated chromosome transfer and subsequently to mice via blastocyst injection of L-HAC(+)-ES-cells. We could show consistent genetic background-dependent adaptation of telomere length and telomere-associated de novo subtelomeric DNA methylation in mouse ES-R1 cells as well as in mice. Expression of the subtelomeric neomycin gene was inversely correlated with telomere length and subtelomeric methylation. We thus provide a new tool for functional telomere studies and provide strong evidence that telomere length, subtelomeric chromatin marks and expression of subtelomeric genes are genetic background dependent.},
}
@article {pmid23065897,
year = {2014},
author = {Jeon, HS and Choi, YY and Choi, JE and Lee, WK and Lee, E and Yoo, SS and Lee, SY and Lee, J and Cha, SI and Kim, CH and Park, JY},
title = {Telomere length of tumor tissues and survival in patients with early stage non-small cell lung cancer.},
journal = {Molecular carcinogenesis},
volume = {53},
number = {4},
pages = {272-279},
doi = {10.1002/mc.21972},
pmid = {23065897},
issn = {1098-2744},
mesh = {Base Sequence ; Carcinoma, Non-Small-Cell Lung/*genetics/pathology ; DNA Primers ; Humans ; Lung Neoplasms/*genetics ; Polymerase Chain Reaction ; *Survival Analysis ; *Telomere ; },
abstract = {Telomere shortening leads to genomic instability that drives oncogenesis through the activation of telomerase and the generation of other mutations necessary for tumor progression. This study was conducted to determine the impact of telomere shortening on the survival of patients with early stage non-small cell lung cancer (NSCLC). Relative telomere length in tumor tissues was measured by quantitative polymerase chain reaction in 164 patients with surgically resected NSCLC. The association between telomere length and overall survival (OS) and disease-free survival (DFS) was analyzed. When the patients were categorized into quartiles based on telomere length, those patients with the 1st quartile (shortest) of telomere length had a significantly worse OS and DFS compared to patients with the 2nd to the 4th quartiles of telomere length (adjusted hazard ratio for OS = 2.67, 95% confidence interval = 1.50-4.75, P = 0.001; and adjusted hazard ratio for DFS = 1.92, 95% confidence interval = 1.17-3.14, P = 0.01). An association between telomere length and survival outcome was more pronounced in squamous cell carcinomas than adenocarcinomas (P-value of test for homogeneity for OS and DFS = 0.05 and 0.02, respectively). Telomere length of tumor tissues is an independent prognostic factor in patients with surgically resected early stage NSCLC.},
}
@article {pmid23065534,
year = {2012},
author = {Hartwig, FP and Nedel, F and Collares, TV and Tarquinio, SB and Nör, JE and Demarco, FF},
title = {Telomeres and tissue engineering: the potential roles of TERT in VEGF-mediated angiogenesis.},
journal = {Stem cell reviews and reports},
volume = {8},
number = {4},
pages = {1275-1281},
pmid = {23065534},
issn = {2629-3277},
mesh = {Animals ; Cellular Senescence ; *Gene Expression Regulation, Enzymologic ; Humans ; *Neovascularization, Physiologic ; *Signal Transduction ; Telomerase/*biosynthesis ; Telomere/*metabolism ; Tissue Engineering/*methods ; Vascular Endothelial Growth Factor A/*metabolism ; },
abstract = {Telomeres are protective structures located at the end of eukaryotic chromosomes which are shortened after each cell division, leading to senescence. Telomerase activity prevents telomere shortening by reverse transcription catalyzed by the subunit called TERT (telomerase reverse transcriptase). TERT expression has shown interesting cellular properties, which may be appealing for tissue engineering, such as the enhancement of cell proliferation and differentiation abilities in vitro. Despite some evidence for playing these roles in VEGF (vascular endothelial growth factor)-mediated angiogenesis, it is still unclear whether TERT can contribute to this essential event to generate functional organs. This review suggests a hypothesis that TERT and VEGF potentially regulates the transcriptional expression of each other, which would give new perspectives in the roles of telomerase in regulating several cellular processes, and also contributing for a better comprehension of the molecular mechanisms underlying VEGF signaling (both paracrine and autocrine). In general, based on the literature revised, it is possible to conclude that TERT is a potential VEGF enhancer; however, it is necessary to elaborate methodological approaches to explore this potential and to assess the potential benefits on tissue engineering approaches.},
}
@article {pmid23065374,
year = {2013},
author = {Ferrandon, S and Saultier, P and Carras, J and Battiston-Montagne, P and Alphonse, G and Beuve, M and Malleval, C and Honnorat, J and Slatter, T and Hung, N and Royds, J and Rodriguez-Lafrasse, C and Poncet, D},
title = {Telomere profiling: toward glioblastoma personalized medicine.},
journal = {Molecular neurobiology},
volume = {47},
number = {1},
pages = {64-76},
pmid = {23065374},
issn = {1559-1182},
mesh = {Brain Neoplasms/*genetics/*therapy ; Cell Line, Tumor ; Glioblastoma/*genetics/*therapy ; Heavy Ion Radiotherapy ; Humans ; Photons ; *Precision Medicine ; Radiation Tolerance ; Shelterin Complex ; Survival Analysis ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins ; },
abstract = {Despite a standard of care combining surgery, radiotherapy (RT), and temozolomide chemotherapy, the average overall survival (OS) of glioblastoma patients is only 15 months, and even far lower when the patient cannot benefit from this combination. Therefore, there is a strong need for new treatments, such as new irradiation techniques. Against this background, carbon ion hadrontherapy, a new kind of irradiation, leads to a greater biological response of the tumor, while minimizing adverse effects on healthy tissues in comparison with RT. As carbon ion hadrontherapy is restricted to RT-resistant patients, photon irradiation resistance biomarkers are needed. Long telomeres and high telomerase activity have been widely associated with photon radioresistance in other cancers. Moreover, telomere protection, telomere function, and telomere length (TL) also depend on the shelterin protein complex (TRF1, TRF2, TPP1, POT1, TIN2, and hRAP1). We thus decided to evaluate an enlarged telomeric status (TL, telomerase catalytic subunit, and the shelterin component expression level) as a potential radioresistance biomarker in vitro using cellular models and ex vivo using patient tumor biopsies. In addition, nothing was known about the role of telomeres in carbon ion response. We thus evaluated telomeric status after both types of irradiation. We report here a significant correlation between TL and the basal POT1 expression level and photon radioresistance, in vitro, and a significant increase in the OS of patients with long telomeres or a high POT1 level, in vivo. POT1 expression was predictive of patient response irrespective of the TL. Strikingly, these correlations were lost, in vitro, when considering carbon irradiation. We thus propose (1) a model of the implications of telomeric damage in the cell response to both types of irradiation and (2) assessment of the POT1 expression level and TL using patient tumor biopsies to identify radioresistant patients who could benefit from carbon hadrontherapy.},
}
@article {pmid23061048,
year = {2012},
author = {Muraki, K and Nyhan, K and Han, L and Murnane, JP},
title = {Mechanisms of telomere loss and their consequences for chromosome instability.},
journal = {Frontiers in oncology},
volume = {2},
number = {},
pages = {135},
pmid = {23061048},
issn = {2234-943X},
support = {R01 CA120205/CA/NCI NIH HHS/United States ; },
abstract = {The ends of chromosomes in mammals, called telomeres, are composed of a 6-bp repeat sequence, TTAGGG, which is added on by the enzyme telomerase. In combination with a protein complex called shelterin, these telomeric repeat sequences form a cap that protects the ends of chromosomes. Due to insufficient telomerase expression, telomeres shorten gradually with each cell division in human somatic cells, which limits the number of times they can divide. The extensive cell division involved in cancer cell progression therefore requires that cancer cells must acquire the ability to maintain telomeres, either through expression of telomerase, or through an alternative mechanism involving recombination. It is commonly thought that the source of many chromosome rearrangements in cancer cells is a result of the extensive telomere shortening that occurs prior to the expression of telomerase. However, despite the expression of telomerase, tumor cells can continue to show chromosome instability due to telomere loss. Dysfunctional telomeres in cancer cells can result from oncogene-induced replication stress, which results in double-strand breaks (DSBs) at fragile sites, including telomeres. DSBs near telomeres are especially prone to chromosome rearrangements, because telomeric regions are deficient in DSB repair. The deficiency in DSB repair near telomeres is also an important mechanism for ionizing radiation-induced replicative senescence in normal human cells. In addition, DSBs near telomeres can result in chromosome instability in mouse embryonic stem cells, suggesting that telomere loss can contribute to heritable chromosome rearrangements. Consistent with this possibility, telomeric regions in humans are highly heterogeneous, and chromosome rearrangements near telomeres are commonly involved in human genetic disease. Understanding the mechanisms of telomere loss will therefore provide important insights into both human cancer and genetic disease.},
}
@article {pmid23061047,
year = {2012},
author = {Chiodi, I and Mondello, C},
title = {Telomere-independent functions of telomerase in nuclei, cytoplasm, and mitochondria.},
journal = {Frontiers in oncology},
volume = {2},
number = {},
pages = {133},
pmid = {23061047},
issn = {2234-943X},
abstract = {Telomerase canonical activity at telomeres prevents telomere shortening, allowing chromosome stability and cellular proliferation. To perform this task, the catalytic subunit (telomerase reverse transcriptase, TERT) of the enzyme works as a reverse transcriptase together with the telomerase RNA component (TERC), adding telomeric repeats to DNA molecule ends. Growing evidence indicates that, besides the telomeric-DNA synthesis activity, TERT has additional functions in tumor development and is involved in many different biological processes, among which cellular proliferation, gene expression regulation, and mitochondrial functionality. TERT has been shown to act independently of TERC in the Wnt-β-catenin signaling pathway, regulating the expression of Wnt target genes, which play a role in development and tumorigenesis. Moreover, TERT RNA-dependent RNA polymerase activity has been found, leading to the genesis of double-stranded RNAs that act as precursor of silencing RNAs. In mitochondria, a TERT TERC-independent reverse transcriptase activity has been described that could play a role in the protection of mitochondrial integrity. In this review, we will discuss some of the extra-telomeric functions of telomerase.},
}
@article {pmid23060172,
year = {2012},
author = {Blackburn, EH and Epel, ES},
title = {Telomeres and adversity: Too toxic to ignore.},
journal = {Nature},
volume = {490},
number = {7419},
pages = {169-171},
pmid = {23060172},
issn = {1476-4687},
mesh = {Animals ; Genetic Predisposition to Disease/psychology ; Humans ; Life Change Events ; Stress, Psychological/*genetics ; Telomere/*genetics/pathology ; },
}
@article {pmid23052336,
year = {2012},
author = {Lamm, N and Bsoul, S and Kabaha, MM and Tzfati, Y},
title = {"Poisoning" yeast telomeres distinguishes between redundant telomere capping pathways.},
journal = {Chromosoma},
volume = {121},
number = {6},
pages = {613-627},
pmid = {23052336},
issn = {1432-0886},
mesh = {Cell Cycle Checkpoints/genetics ; Cloning, Molecular ; DNA End-Joining Repair/genetics ; Fungal Proteins/genetics/*metabolism ; Kluyveromyces/cytology/*genetics/metabolism ; Recombinant Fusion Proteins/genetics/metabolism ; Recombination, Genetic ; Repetitive Sequences, Nucleic Acid ; Telomerase/genetics/metabolism ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Tetrahymena/genetics ; },
abstract = {In most eukaryotes, telomeres are composed of tandem arrays of species-specific DNA repeats ending with a G-rich 3' overhang. In budding yeast, Cdc13 binds this overhang and recruits Ten1-Stn1 and the telomerase protein Est1 to protect (cap) and elongate the telomeres, respectively. To dissect and study the various pathways employed to cap and maintain the telomere end, we engineered telomerase to incorporate Tetrahymena telomeric repeats (G4T2) onto the telomeres of the budding yeast Kluyveromyces lactis. These heterologous repeats caused telomere-telomere fusions, cell cycle arrest at G2/M, and severely reduced viability--the hallmarks of telomere uncapping. Fusing Cdc13 or Est1 to universal minicircle sequence binding protein (UMSBP), a small protein that binds the single-stranded G4T2 repeats, rescued the cell viability and restored telomere capping, but not telomerase-mediated telomere maintenance. Surprisingly, Cdc13-UMSBP-mediated telomere capping was dependent on the homologous recombination factor Rad52, while Est1-UMSBP was not. Thus, our results distinguish between two, redundant, telomere capping pathways.},
}
@article {pmid23050056,
year = {2012},
author = {Harris, HR and Vivo, ID and Titus, LJ and Vitonis, AF and Wong, JY and Cramer, DW and Terry, KL},
title = {Genetic variation in telomere maintenance genes in relation to ovarian cancer survival.},
journal = {International journal of molecular epidemiology and genetics},
volume = {3},
number = {3},
pages = {252-261},
pmid = {23050056},
issn = {1948-1756},
support = {P50 CA105009/CA/NCI NIH HHS/United States ; R01 CA054419/CA/NCI NIH HHS/United States ; },
abstract = {Telomeres are repetitive non-coding DNA sequences at the ends of chromosomes that provide protection against chromosomal instability. Telomere length and stability are influenced by proteins, including telomerase which is partially encoded by the TERT gene. Genetic variation in the TERT gene is associated with ovarian cancer risk, and predicts survival in lung cancer and glioma. We investigated whether genetic variation in five telomere maintenance genes was associated with survival among 1480 cases of invasive epithelial ovarian cancer in the population-based New England Case-Control Study. Cox proportional hazard models were used to calculate hazard ratios and 95% confidence intervals. Overall we observed no significant associations between SNPs in telomere maintenance genes and mortality using a significance threshold of p=0.001. However, we observed some suggestive associations in subgroup analyses. Future studies with larger populations may further our understanding of what role telomeres play in ovarian cancer survival.},
}
@article {pmid23050049,
year = {2012},
author = {Pellatt, AJ and Wolff, RK and Lundgreen, A and Cawthon, R and Slattery, ML},
title = {Genetic and lifestyle influence on telomere length and subsequent risk of colon cancer in a case control study.},
journal = {International journal of molecular epidemiology and genetics},
volume = {3},
number = {3},
pages = {184-194},
pmid = {23050049},
issn = {1948-1756},
support = {R01 CA048998/CA/NCI NIH HHS/United States ; U01 CA048998/CA/NCI NIH HHS/United States ; },
abstract = {BACKGROUND: Telomeres cap the ends of chromosomes and help maintain genomic stability and integrity. Telomere length (TL) has been linked to a number of diseases, including a variety of cancers; however, the association between TL and risk for colorectal cancer is unclear.<br><br>METHODS: We investigate the association between genetic, diet, and lifestyle factors and TL and the association between TL and colorectal cancer using data from a population-based case-control study of colon (249 cases and 371 controls) and rectal cancer (276 cases and 372 controls) conducted in Utah. DNA samples came from immortalized cell lines for colon cancer and directly from whole blood for rectal cancer. We genotyped 11 single nucleotide polymorphisms in five genes associated with telomeres, TERT, MEN1, MRE11A, RECQL5, and TNKS.<br><br>RESULTS: TL was measured using quantitative PCR. TERT rs2853676 (p=0.044) and RECQL5 rs820152 (p=0.001) were associated with TL at <0.05 level of significance. After adjusting for age and sex, BMI and cigarette smoking were significantly inversely associated with TL among controls. Use of aspirin/NSAIDs interacted significantly with TERT rs10069690 and rs2242652 to alter TL. Longer TL was significantly associated with reduced colon cancer risk after adjusting for age and sex (OR = 0.94 95% confidence intervals 0.89-0.99 per decile of TL). Further adjustment for BMI and cigarette smoking attenuated the association so that it was no longer significant.<br><br>CONCLUSIONS: In summary several genetic and lifestyle factors were observed to influence TL. These factors also appear to confound associations between TL and colon cancer.},
}
@article {pmid23049977,
year = {2012},
author = {Bender, HS and Murchison, EP and Pickett, HA and Deakin, JE and Strong, MA and Conlan, C and McMillan, DA and Neumann, AA and Greider, CW and Hannon, GJ and Reddel, RR and Graves, JA},
title = {Extreme telomere length dimorphism in the Tasmanian devil and related marsupials suggests parental control of telomere length.},
journal = {PloS one},
volume = {7},
number = {9},
pages = {e46195},
pmid = {23049977},
issn = {1932-6203},
support = {P30 CA045508/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; In Situ Hybridization ; Marsupialia/*genetics ; Sex Chromosomes/genetics ; Telomere/*genetics ; Telomere Homeostasis/genetics ; },
abstract = {Telomeres, specialised structures that protect chromosome ends, play a critical role in preserving chromosome integrity. Telomere dynamics in the Tasmanian devil (Sarcophilus harrisii) are of particular interest in light of the emergence of devil facial tumour disease (DFTD), a transmissible malignancy that causes rapid mortality and threatens the species with extinction. We used fluorescent in situ hybridisation to investigate telomere length in DFTD cells, in healthy Tasmanian devils and in four closely related marsupial species. Here we report that animals in the Order Dasyuromorphia have chromosomes characterised by striking telomere length dimorphism between homologues. Findings in sex chromosomes suggest that telomere length dimorphism may be regulated by events in the parental germlines. Long telomeres on the Y chromosome imply that telomere lengthening occurs during spermatogenesis, whereas telomere diminution occurs during oogenesis. Although found in several somatic cell tissue types, telomere length dimorphism was not found in DFTD cancer cells, which are characterised by uniformly short telomeres. This is, to our knowledge, the first report of naturally occurring telomere length dimorphism in any species and suggests a novel strategy of telomere length control. Comparative studies in five distantly related marsupials and a monotreme indicate that telomere dimorphism evolved at least 50 million years ago.},
}
@article {pmid23045155,
year = {2012},
author = {Carulli, L and Dei Cas, A and Nascimbeni, F},
title = {Synchronous cryptogenic liver cirrhosis and idiopathic pulmonary fibrosis: a clue to telomere involvement.},
journal = {Hepatology (Baltimore, Md.)},
volume = {56},
number = {5},
pages = {2001-2003},
doi = {10.1002/hep.26089},
pmid = {23045155},
issn = {1527-3350},
mesh = {Diabetes Mellitus, Type 2/complications ; Fatal Outcome ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/complications/*genetics ; Liver Cirrhosis/complications/*genetics ; Middle Aged ; Pedigree ; Polymorphism, Genetic ; Telomerase/*genetics ; },
}
@article {pmid23042912,
year = {2012},
author = {Ludlow, AT and Lima, LC and Wang, J and Hanson, ED and Guth, LM and Spangenburg, EE and Roth, SM},
title = {Exercise alters mRNA expression of telomere-repeat binding factor 1 in skeletal muscle via p38 MAPK.},
journal = {Journal of applied physiology (Bethesda, Md. : 1985)},
volume = {113},
number = {11},
pages = {1737-1746},
pmid = {23042912},
issn = {1522-1601},
support = {AG000268/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Calcimycin/pharmacology ; Calcium/metabolism ; Calcium Ionophores/pharmacology ; Cell Line ; DNA-Binding Proteins/genetics/metabolism ; Down-Regulation ; Enzyme Activation ; Female ; MAP Kinase Signaling System ; Mice ; Mice, Inbred C57BL ; *Muscle Contraction ; Muscle Fibers, Skeletal/drug effects/enzymology ; Muscle, Skeletal/drug effects/*enzymology ; Phosphorylation ; *Physical Exertion ; RNA, Messenger/*metabolism ; Shelterin Complex ; Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 1/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Time Factors ; p38 Mitogen-Activated Protein Kinases/*metabolism ; },
abstract = {Telomeres protect chromosome ends and shorten with age in most tissues. Integral to the maintenance of telomeres is the protein complex shelterin. The gene expression regulation of shelterin proteins to physiological stressors is not understood in vivo. We have recently reported increased telomere-repeat binding factor 1 (TRF1) protein expression and longer telomere length in skeletal muscle of sedentary compared with chronically active mice. These provocative observations led us to examine the effects of acute physiological stress on shelterin expression in vivo in mice and to further define potential mechanisms associated with gene regulation of shelterin. Three groups of female C57Bl/6 mice were studied: one control group and two groups that underwent a 30-min treadmill running bout and were killed either immediately following or 1-h after the exercise. Following the exercise bout, mRNA expression of Trf1 was significantly reduced in the plantaris muscle, and this reduction was paralleled by significant increases in p38 MAPK phosphorylation. To determine if p38 mediated the decreases in Trf1 mRNA expression, C2C12 myotubes were treated with the calcium ionophore, A23187. In response to the A23187, Trf1 gene expression was significantly reduced, coupled with significant increases in p38 phosphorylation, similar to in vivo data. C2C12 myotubes pretreated with a p38 inhibitor (SB-202190) prevented the A23187-induced decrease in Trf1 mRNA expression, indicating a link between Trf1 gene expression and p38 MAPK activation. While it is too early to definitively report the effect of exercise on telomere biology in rodents or humans, these data provide important mechanistic insights into the paradoxical telomere shortening that occurs in skeletal muscle in response to chronic exercise in mice.},
}
@article {pmid23037760,
year = {2012},
author = {Ishikawa, F},
title = {[Telomere dysfunction in cancer progression].},
journal = {[Rinsho ketsueki] The Japanese journal of clinical hematology},
volume = {53},
number = {10},
pages = {1849-1856},
pmid = {23037760},
issn = {0485-1439},
mesh = {Animals ; Chromosomes/enzymology/genetics ; DNA Replication Timing ; Disease Progression ; Humans ; Neoplasms/genetics/*metabolism/pathology ; Telomerase/antagonists &amp; inhibitors/metabolism ; *Telomere ; },
}
@article {pmid23035035,
year = {2013},
author = {Raymond, AR and Norton, GR and Sareli, P and Woodiwiss, AJ and Brooksbank, RL},
title = {Relationship between average leucocyte telomere length and the presence or severity of idiopathic dilated cardiomyopathy in black Africans.},
journal = {European journal of heart failure},
volume = {15},
number = {1},
pages = {54-60},
doi = {10.1093/eurjhf/hfs147},
pmid = {23035035},
issn = {1879-0844},
mesh = {Adult ; Black People/*genetics ; Cardiomyopathy, Dilated/ethnology/*genetics/physiopathology ; Female ; Humans ; *Leukocytes ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Severity of Illness Index ; Stroke Volume ; Telomere/*genetics ; *Ventricular Function, Left ; },
abstract = {AIMS: A reduced average leucocyte telomere length is associated with ischaemic heart failure. Whether this relationship represents a cause or consequence of heart failure or is attributed to associated risk factors and coronary artery disease is uncertain. We evaluated if average leucocyte telomere length is associated with idiopathic dilated cardiomyopathy (IDC) or its severity.<br><br>METHODS AND RESULTS: We compared average leucocyte telomere length in 223 patients with heart failure due to IDC and 227 healthy controls of black African ancestry. We also evaluated the relationship between average leucocyte telomere length and left ventricular ejection fraction (LVEF). LVEF was determined using echocardiography and radionuclide multiple-gated acquisition (MUGA) scan in patients with IDC. Relative leucocyte telomere length (T/S) was measured using a quantitative real-time polymerase chain reaction assay. Log T/S was negatively correlated with age in patients with IDC (P = 0.0007) and in controls (P = 0.030), and with alcohol consumption (P = 0.032) and regular smoking (P = 0.021) in patients with IDC. Log T/S did not differ between IDC and control groups either before (P = 0.11) or after (IDC = 0.071 &#xb1; 0.187, control = 0.071 &#xb1; 0.187, P = 0.99) adjustments for confounders. Log T/S was not associated with echocardiographic (P = 0.47) or MUGA (P = 0.99) LVEF or LV end-diastolic diameter (LVEDD) (P = 0.34) in patients with IDC. With adjustments for age, sex, alcohol consumption, and smoking, log T/S was similarly not associated with echocardiographic (P = 0.60) or MUGA (P = 0.91) LVEF or LVEDD (P = 0.53) in patients with IDC.<br><br>CONCLUSIONS: Average relative leucocyte telomere length is not associated with IDC or its severity in groups of black African ancestry.},
}
@article {pmid23032416,
year = {2013},
author = {Tendeiro, R and Albuquerque, AS and Foxall, RB and Cavaleiro, R and Soares, RS and Baptista, AP and Soares, MV and Gomes, P and Sousa, AE},
title = {Preserved CD4 T-cell telomere length during long-lasting HIV-2 infection.},
journal = {AIDS (London, England)},
volume = {27},
number = {2},
pages = {289-292},
doi = {10.1097/QAD.0b013e32835ab234},
pmid = {23032416},
issn = {1473-5571},
mesh = {Adult ; CD4 Lymphocyte Count ; CD4-Positive T-Lymphocytes/*immunology ; Cohort Studies ; Female ; HIV Infections/*immunology ; HIV-1/*immunology ; HIV-2/*immunology ; Humans ; Linear Models ; Male ; Middle Aged ; Telomere/*immunology ; Time Factors ; },
abstract = {HIV-2 infection features a much slower course than HIV-1 infection, often asymptomatic for over 20 years, without antiretroviral therapy (ART). Nevertheless, CD4 T cells progressively decline, in direct correlation with immune activation and cell cycling. We report, for the first time, preserved telomere length within naive and memory CD4 subsets in prolonged HIV-2 infection despite the increased CD4 turnover.},
}
@article {pmid23031395,
year = {2012},
author = {Hassett, AL and Epel, E and Clauw, DJ and Harris, RE and Harte, SE and Kairys, A and Buyske, S and Williams, DA},
title = {Pain is associated with short leukocyte telomere length in women with fibromyalgia.},
journal = {The journal of pain},
volume = {13},
number = {10},
pages = {959-969},
doi = {10.1016/j.jpain.2012.07.003},
pmid = {23031395},
issn = {1528-8447},
support = {R01 AR050044/AR/NIAMS NIH HHS/United States ; },
mesh = {Adult ; Cellular Senescence/genetics ; Female ; Fibromyalgia/*genetics/metabolism/physiopathology ; Humans ; Leukocytes/*metabolism ; Middle Aged ; Pain/*genetics/metabolism/physiopathology ; Pain Measurement ; Pain Threshold/physiology ; Telomere/*genetics/metabolism ; },
abstract = {UNLABELLED: Telomere length, considered a measure of biological aging, is linked to morbidity and mortality. Psychosocial factors associated with shortened telomeres are also common in chronic pain; yet, little is known about telomere length in pain populations. Leukocyte telomere length was evaluated in 66 women with fibromyalgia and 22 healthy female controls. Participants completed questionnaires and a subgroup of fibromyalgia patients underwent quantitative sensory testing (QST; n = 12) and neuroimaging (n = 12). Telomere length was measured using the quantitative polymerase chain reaction method. Although patients had shorter telomere length than controls, the difference was not statistically significant. However, higher levels of pain within fibromyalgia were associated with shorter telomere length (P = .039). When pain and depression were combined, patients categorized as high-pain/high-depression had an age-adjusted telomere length 265 base pairs shorter than those with low-pain/low-depression (P = .043), a difference consistent with approximately 6 years of chronological aging. In the subset tested, telomere length was also related to pain threshold and pain sensitivity, as well as gray matter volume, such that patients with shorter telomeres were more sensitive to evoked pain and had less gray matter in brain regions associated with pain processing (eg, primary somatosensory cortex). These preliminary data support a relationship between pain and telomere length.<br><br>PERSPECTIVE: Our findings support a link between premature cellular aging and chronic pain. These preliminary data imply that chronic pain is a more serious condition than has typically been recognized in terms of bodily aging.},
}
@article {pmid23028820,
year = {2012},
author = {Der, G and Batty, GD and Benzeval, M and Deary, IJ and Green, MJ and McGlynn, L and McIntyre, A and Robertson, T and Shiels, PG},
title = {Is telomere length a biomarker for aging: cross-sectional evidence from the west of Scotland?.},
journal = {PloS one},
volume = {7},
number = {9},
pages = {e45166},
pmid = {23028820},
issn = {1932-6203},
support = {MC_U130059821/MRC_/Medical Research Council/United Kingdom ; MC_US_A540_0080/MRC_/Medical Research Council/United Kingdom ; G0700704/MRC_/Medical Research Council/United Kingdom ; MC_UP_A540_1021/MRC_/Medical Research Council/United Kingdom ; MC_U130059823/MRC_/Medical Research Council/United Kingdom ; //Wellcome Trust/United Kingdom ; SPHSU2/CSO_/Chief Scientist Office/United Kingdom ; },
mesh = {Adolescent ; Adult ; Aged ; Aging/*genetics ; Biomarkers ; Cognition/physiology ; Cross-Sectional Studies ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Predictive Value of Tests ; Principal Component Analysis ; Scotland ; Telomere/*chemistry/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: The search for biomarkers of aging (BoAs) has been largely unsuccessful to-date and there is widespread skepticism about the prospects of finding any that satisfy the criteria developed by the American Federation of Aging Research. This may be because the criteria are too strict or because a composite measure might be more appropriate. Telomere length has attracted a great deal of attention as a candidate BoA. We investigate whether it meets the criteria to be considered as a single biomarker of aging, and whether it makes a useful contribution to a composite measure.<br><br>Using data from a large population based study, we show that telomere length is associated with age, with several measures of physical and cognitive functioning that are related to normal aging, and with three measures of overall health. In the majority of cases, telomere length adds predictive power to that of age, although it was not nearly as good a predictor overall. We used principal components analysis to form two composites from the measures of functioning, one including telomere length and the other not including it. These composite BoAs were better predictors of the health outcomes than chronological age. There was little difference between the two composites.<br><br>CONCLUSIONS: Telomere length does not satisfy the strict criteria for a BoA, but does add predictive power to that of chronological age. Equivocal results from previous studies might be due to lack of power or the choice of measures examined together with a focus on single biomarkers. Composite biomarkers of aging have the potential to outperform age and should be considered for future research in this area.},
}
@article {pmid23028367,
year = {2012},
author = {Poschke, H and Dees, M and Chang, M and Amberkar, S and Kaderali, L and Rothstein, R and Luke, B},
title = {Rif2 promotes a telomere fold-back structure through Rpd3L recruitment in budding yeast.},
journal = {PLoS genetics},
volume = {8},
number = {9},
pages = {e1002960},
pmid = {23028367},
issn = {1553-7404},
support = {R01 GM050237/GM/NIGMS NIH HHS/United States ; R37 GM050237/GM/NIGMS NIH HHS/United States ; GM50237/GM/NIGMS NIH HHS/United States ; },
mesh = {Acetylation ; Chromatin/genetics ; Chromosomes/genetics ; *Histone Deacetylases/genetics/metabolism ; Lysine/genetics/metabolism ; Mutation ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomere/*genetics ; *Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Using a genome-wide screening approach, we have established the genetic requirements for proper telomere structure in Saccharomyces cerevisiae. We uncovered 112 genes, many of which have not previously been implicated in telomere function, that are required to form a fold-back structure at chromosome ends. Among other biological processes, lysine deacetylation, through the Rpd3L, Rpd3S, and Hda1 complexes, emerged as being a critical regulator of telomere structure. The telomeric-bound protein, Rif2, was also found to promote a telomere fold-back through the recruitment of Rpd3L to telomeres. In the absence of Rpd3 function, telomeres have an increased susceptibility to nucleolytic degradation, telomere loss, and the initiation of premature senescence, suggesting that an Rpd3-mediated structure may have protective functions. Together these data reveal that multiple genetic pathways may directly or indirectly impinge on telomere structure, thus broadening the potential targets available to manipulate telomere function.},
}
@article {pmid23022483,
year = {2012},
author = {Vera, E and Bernardes de Jesus, B and Foronda, M and Flores, JM and Blasco, MA},
title = {The rate of increase of short telomeres predicts longevity in mammals.},
journal = {Cell reports},
volume = {2},
number = {4},
pages = {732-737},
doi = {10.1016/j.celrep.2012.08.023},
pmid = {23022483},
issn = {2211-1247},
mesh = {Animals ; Humans ; *Longevity ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Aberrantly short telomeres result in decreased longevity in both humans and mice with defective telomere maintenance. Normal populations of humans and mice present high interindividual variation in telomere length, but it is unknown whether this is associated with their lifespan potential. To address this issue, we performed a longitudinal telomere length study along the lifespan of wild-type and transgenic telomerase reverse transcriptase mice. We found that mouse telomeres shorten ∼100 times faster than human telomeres. Importantly, the rate of increase in the percentage of short telomeres, rather than the rate of telomere shortening per month, was a significant predictor of lifespan in both mouse cohorts, and those individuals who showed a higher rate of increase in the percentage of short telomeres were also the ones with a shorter lifespan. These findings demonstrate that short telomeres have a direct impact on longevity in mammals, and they highlight the importance of performing longitudinal telomere studies to predict longevity.},
}
@article {pmid23020852,
year = {2012},
author = {Sullivan, LB and Santos, JH and Chandel, NS},
title = {Mitochondria and telomeres: the promiscuous roles of TIN2.},
journal = {Molecular cell},
volume = {47},
number = {6},
pages = {823-824},
doi = {10.1016/j.molcel.2012.09.006},
pmid = {23020852},
issn = {1097-4164},
support = {T32 GM008061/GM/NIGMS NIH HHS/United States ; },
abstract = {Telomeric proteins are best known for their role in maintenance of telomere function. In this issue, Chen et al. (2012) demonstrate that the telomeric protein TIN2 can specifically localize to the mitochondria, where it can regulate metabolism and ROS production.},
}
@article {pmid23020808,
year = {2013},
author = {Maeda, T and Nakamura, K and Atsumi, K and Hirakawa, M and Ueda, Y and Makino, N},
title = {Radiation-associated changes in the length of telomeres in peripheral leukocytes from inpatients with cancer.},
journal = {International journal of radiation biology},
volume = {89},
number = {2},
pages = {106-109},
doi = {10.3109/09553002.2013.734945},
pmid = {23020808},
issn = {1362-3095},
mesh = {Aged ; Aged, 80 and over ; Carcinoma, Hepatocellular/genetics/radiotherapy ; Case-Control Studies ; DNA, Neoplasm/genetics ; Female ; Humans ; Leukocytes/*radiation effects ; Liver Neoplasms/genetics/radiotherapy ; Lung Neoplasms/genetics/radiotherapy ; Male ; Middle Aged ; Neoplasms/*genetics/*radiotherapy ; Prostatic Neoplasms/genetics/radiotherapy ; Radiation Tolerance/genetics ; Radiotherapy Dosage ; Rectal Neoplasms/genetics/radiotherapy ; Telomere Homeostasis/*radiation effects ; Telomere Shortening/radiation effects ; Thyroid Neoplasms/genetics/radiotherapy ; },
abstract = {PURPOSE: The telomere length of somatic cells shortens with age and with other endogenous and exogenous pathogenic factors. However, the effects of radiation therapy on telomere DNA of non-cancer tissue have not been thoroughly investigated. This study analyzed the telomere length of inpatients with cancer treated with radiation therapy to see whether the telomere lengths change in response to therapeutic radiation.<br><br>MATERIALS AND METHODS: Twenty-five patients were enrolled in the study. The patients had lung cancer, prostate cancer, thyroid cancer, hepatoma, or rectal cancer. They received radiation therapy with a dose range of 15-74 Gy. The telomere lengths and telomere length distribution in peripheral leukocytes were analyzed by using a Southern blot-based method.<br><br>RESULTS: The telomere length and the telomere length distribution of the peripheral leukocytes did not change after radiation therapy. However, there was a significant proportional decrease in the short telomere fraction (< 4.4 kb) per day and per Gy.<br><br>CONCLUSIONS: This observation suggested that the telomere length distribution of peripheral leukocytes could be affected by radiation therapy, and that the effect of radiation tends to appear in cells with short telomeres. Radiation therapy-associated somatic telomere length change within a short range of time, about three months or shorter, can be detected by analyzing the mean telomere length and telomere length distribution.},
}
@article {pmid23019197,
year = {2012},
author = {Tuo, B and Ju, Z and Riederer, B and Engelhardt, R and Manns, MP and Rudolph, KL and Seidler, U},
title = {Telomere shortening is associated with reduced duodenal HCOFormula secretory but normal gastric acid secretory capacity in aging mice.},
journal = {American journal of physiology. Gastrointestinal and liver physiology},
volume = {303},
number = {12},
pages = {G1312-21},
doi = {10.1152/ajpgi.00035.2012},
pmid = {23019197},
issn = {1522-1547},
mesh = {Aging/*physiology ; Animals ; Bicarbonates/*metabolism ; Duodenum/*physiopathology ; Gastric Acid/*metabolism ; Intestinal Mucosa/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Telomere Shortening/*physiology ; },
abstract = {The incidence of duodenal ulcer, especially Helicobacter pylori-negative duodenal ulcer, strongly increases with age. In humans, telomere length shortening is considered to be one critical factor in cellular senescence and organ survival. In this study, we compared basal and stimulated gastric acid and duodenal HCO(3)(-) secretory rates in aged late-generation (G(3)) telomerase-deficient (mTERC(-/-)) mice, which are characterized by severe telomere dysfunction due to the inability to elongate telomeres during cell division. We found that basal and forskolin-stimulated HCO(3)(-) secretion and short-circuit current (I(sc)) in isolated duodenal mucosa of G(3) mTERC(-/-) mice were markedly reduced compared with age-matched wild-type mice. In contrast, basal and forskolin-stimulated acid secretory rates in isolated G(3) mTERC(-/-) gastric mucosa were not significantly altered. Correspondingly, duodenal mucosa of G(3) mTERC(-/-) mice showed slimming and shortening of villi, whereas gastric mucosal histology was not significantly altered. However, the ratios of cystic fibrosis transmembrane conductance regulator (CFTR) and solute-linked carrier 26 gene family (Slc26a6) mRNA expression in relation to cytokeratin-18 were not altered in duodenal mucosa. The further knockout of p21, which is a downstream effector of telomere shortening-induced senescence, rescued villus atrophy of duodenal mucosa, and basal and forskolin-stimulated duodenal HCO(3)(-) secretion and I(sc) in mTERC(-/-) p21(-/-) double-knockout mice were not different from wild-type controls. In conclusion, genetic ablation of telomerase resulted in p21-dependent duodenal mucosal atrophy and reduced duodenal HCO(3)(-) secretory capacity, whereas gastric morphology and acid secretory function were preserved. This suggests that telomere shortening during aging may result in an imbalance between aggressive and protective secretions against duodenal mucosa and thus predispose to ulcer formation.},
}
@article {pmid23018532,
year = {2013},
author = {Dang-Nguyen, TQ and Haraguchi, S and Furusawa, T and Somfai, T and Kaneda, M and Watanabe, S and Akagi, S and Kikuchi, K and Tajima, A and Nagai, T},
title = {Downregulation of histone methyltransferase genes SUV39H1 and SUV39H2 increases telomere length in embryonic stem-like cells and embryonic fibroblasts in pigs.},
journal = {The Journal of reproduction and development},
volume = {59},
number = {1},
pages = {27-32},
pmid = {23018532},
issn = {1348-4400},
mesh = {Animals ; Cell Line ; DNA Methylation ; DNA Primers/genetics ; Embryonic Stem Cells/*cytology ; Epigenesis, Genetic ; Fibroblasts/*cytology ; *Gene Expression Regulation, Developmental ; Gene Knockdown Techniques ; Histone Methyltransferases ; Histone-Lysine N-Methyltransferase/genetics/*metabolism ; Histones/metabolism ; RNA Interference ; Swine ; Telomere/*ultrastructure ; },
abstract = {Telomere is a nucleoprotein structure at the ends of chromosomes that helps to protect the ends of chromosomes from being fused with other chromosomes. Knockout of histone methyltransferases Suv39h1 and Suv39h2 increases the telomere length in murine cells, whereas downregulation of SUV39H1 and SUV39H2 genes decreases the telomere length in human cells, suggesting that telomere biology is different among mammalian species. However, epigenetic regulation of the telomere has not been studied in mammals other than the human and mouse. In the present study, the effect of knockdown of SUV39H1 and SUV39H2 genes on telomere length was examined in porcine embryonic stem-like cells (pESLCs) and porcine embryonic fibroblasts (PEFs). The telomeres in SUV39H1 and SUV39H2 knockdown (SUV39KD) pESLCs (37.1 ± 0.9 kb) were longer (P<0.05) compared with those of the control (33.0 ± 0.7 kb). Similarly, SUV39KD PEFs had longer telomeres (22.1 ± 0.4 kb; P<0.05) compared with the control (17.8 ± 1.1 kb). Telomerase activities were not different between SUV39KD pESLCs (10.4 ± 1.7) and the control (10.1 ± 1.7) or between SUV39KD PEFs (1.0 ± 0.3) and the control (1.0 ± 0.4), suggesting that telomerase activities did not contribute to the telomere elongation in SUV39KD pESLCs and SUV39KD PEFs. Relative levels of trimethylation of histone H3 lysine 9 and expressions of DNMT1, DNMT3A and DNMT3B were decreased in SUV39KD cells, suggesting that telomere lengthening in SUV39KD pESLCs and SUV39KD PEFs might be not only related to the loss of histone modification marks but also linked to the decrease in DNA methyltransferase in pigs.},
}
@article {pmid23012368,
year = {2012},
author = {Xu, Y and Ishizuka, T and Yang, J and Ito, K and Katada, H and Komiyama, M and Hayashi, T},
title = {Oligonucleotide models of telomeric DNA and RNA form a Hybrid G-quadruplex structure as a potential component of telomeres.},
journal = {The Journal of biological chemistry},
volume = {287},
number = {50},
pages = {41787-41796},
pmid = {23012368},
issn = {1083-351X},
mesh = {DNA/*chemistry/metabolism ; Humans ; Oligonucleotides/*chemistry/metabolism ; RNA/*chemistry/metabolism ; Telomere/*chemistry/metabolism ; },
abstract = {Telomeric repeat-containing RNA, a non-coding RNA molecule, has recently been found in mammalian cells. The detailed structural features and functions of the telomeric RNA at human chromosome ends remain unclear, although this RNA molecule may be a key component of the telomere machinery. In this study, using model human telomeric DNA and RNA sequences, we demonstrated that human telomeric RNA and DNA oligonucleotides form a DNA-RNA G-quadruplex. We next employed chemistry-based oligonucleotide probes to mimic the naturally formed telomeric DNA-RNA G-quadruplexes in living cells, suggesting that the process of DNA-RNA G-quadruplex formation with oligonucleotide models of telomeric DNA and RNA could occur in cells. Furthermore, we investigated the possible roles of this DNA-RNA G-quadruplex. The formation of the DNA-RNA G-quadruplex causes a significant increase in the clonogenic capacity of cells and has an effect on inhibition of cellular senescence. Here, we have used a model system to provide evidence about the formation of G-quadruplex structures involving telomeric DNA and RNA sequences that have the potential to provide a protective capping structure for telomere ends.},
}
@article {pmid23011128,
year = {2012},
author = {Chen, Y and Qu, K and Zhao, C and Wu, L and Ren, J and Wang, J and Qu, X},
title = {Insights into the biomedical effects of carboxylated single-wall carbon nanotubes on telomerase and telomeres.},
journal = {Nature communications},
volume = {3},
number = {},
pages = {1074},
pmid = {23011128},
issn = {2041-1723},
mesh = {Cell Line, Tumor ; Cell Proliferation ; Chromatin Immunoprecipitation ; G-Quadruplexes/drug effects ; HeLa Cells ; Humans ; Nanotubes, Carbon/*chemistry ; Protein Binding ; Protein Stability ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Both human telomeric G-rich and C-rich DNA have been considered as specific drug targets for cancer therapy. However, due to i-motif structure instability and lack of specific binding agents, it remains unclear whether stabilization of telomeric i-motif can inhibit telomerase activity. Single-walled carbon nanotubes (SWNTs) have been reported as the first ligand that can selectively stabilize human telomeric i-motif DNA. Here we report that SWNTs can inhibit telomerase activity through stabilization of i-motif structure. The persistence of i-motif and the concomitant G-quadruplex eventually leads to telomere uncapping and displaces telomere-binding proteins from telomere. The dysfunctional telomere triggers DNA damage response and elicits upregulation of p16 and p21 proteins. This is the first example that SWNTs can inhibit telomerase activity and interfere with the telomere functions in cancer cells. These results provide new insights into understanding the biomedical effects of SWNTs and the biological importance of i-motif DNA.},
}
@article {pmid23010778,
year = {2012},
author = {Deng, Z and Wang, Z and Stong, N and Plasschaert, R and Moczan, A and Chen, HS and Hu, S and Wikramasinghe, P and Davuluri, RV and Bartolomei, MS and Riethman, H and Lieberman, PM},
title = {A role for CTCF and cohesin in subtelomere chromatin organization, TERRA transcription, and telomere end protection.},
journal = {The EMBO journal},
volume = {31},
number = {21},
pages = {4165-4178},
pmid = {23010778},
issn = {1460-2075},
support = {R21 CA143349/CA/NCI NIH HHS/United States ; F31HG006395/HG/NHGRI NIH HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; R01 HD042026/HD/NICHD NIH HHS/United States ; T32GM008216/GM/NIGMS NIH HHS/United States ; F31 HG006395/HG/NHGRI NIH HHS/United States ; R01CA140652/CA/NCI NIH HHS/United States ; P30 CA10815/CA/NCI NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; R21CA143349/CA/NCI NIH HHS/United States ; R01HD042026/HD/NICHD NIH HHS/United States ; T32 GM008216/GM/NIGMS NIH HHS/United States ; },
mesh = {CCCTC-Binding Factor ; Cell Cycle Proteins/genetics/*metabolism ; Cells, Cultured ; Chromatin/*genetics ; Chromatin Immunoprecipitation ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; CpG Islands/genetics ; DNA-Binding Proteins/*genetics ; Electrophoretic Mobility Shift Assay ; Fluorescent Antibody Technique ; *Gene Expression Regulation ; Humans ; Luciferases/metabolism ; Neoplasms/genetics/pathology ; Nuclear Proteins/genetics/metabolism ; Phosphoproteins/genetics/metabolism ; Promoter Regions, Genetic/genetics ; RNA Polymerase II/genetics/metabolism ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Repressor Proteins/genetics/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*genetics ; Transcription Factors/*genetics ; *Transcription, Genetic ; Cohesins ; },
abstract = {The contribution of human subtelomeric DNA and chromatin organization to telomere integrity and chromosome end protection is not yet understood in molecular detail. Here, we show by ChIP-Seq that most human subtelomeres contain a CTCF- and cohesin-binding site within ∼1-2 kb of the TTAGGG repeat tract and adjacent to a CpG-islands implicated in TERRA transcription control. ChIP-Seq also revealed that RNA polymerase II (RNAPII) was enriched at sites adjacent to the CTCF sites and extending towards the telomere repeat tracts. Mutation of CTCF-binding sites in plasmid-borne promoters reduced transcriptional activity in an orientation-dependent manner. Depletion of CTCF by shRNA led to a decrease in TERRA transcription, and a loss of cohesin and RNAPII binding to the subtelomeres. Depletion of either CTCF or cohesin subunit Rad21 caused telomere-induced DNA damage foci (TIF) formation, and destabilized TRF1 and TRF2 binding to the TTAGGG proximal subtelomere DNA. These findings indicate that CTCF and cohesin are integral components of most human subtelomeres, and important for the regulation of TERRA transcription and telomere end protection.},
}
@article {pmid23010453,
year = {2013},
author = {Mazzotti, DR and Tufik, S and Andersen, ML},
title = {A stepforward in understanding the association between social attainment and health disparities: evidence from late life telomere length and educational level.},
journal = {Brain, behavior, and immunity},
volume = {27},
number = {1},
pages = {13-14},
doi = {10.1016/j.bbi.2012.09.005},
pmid = {23010453},
issn = {1090-2139},
mesh = {Educational Status ; *Health Status Disparities ; Humans ; Leukocytes ; *Social Class ; Telomere Homeostasis ; *Telomere Shortening ; },
}
@article {pmid23010452,
year = {2013},
author = {Kiecolt-Glaser, JK and Epel, ES and Belury, MA and Andridge, R and Lin, J and Glaser, R and Malarkey, WB and Hwang, BS and Blackburn, E},
title = {Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial.},
journal = {Brain, behavior, and immunity},
volume = {28},
number = {},
pages = {16-24},
pmid = {23010452},
issn = {1090-2139},
support = {AG038621/AG/NIA NIH HHS/United States ; CA16058/CA/NCI NIH HHS/United States ; UL1RR025755/RR/NCRR NIH HHS/United States ; R01 AG038621/AG/NIA NIH HHS/United States ; UL1 RR025755/RR/NCRR NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; AG029562/AG/NIA NIH HHS/United States ; R01 AG029562/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Cellular Senescence/drug effects ; Depression/physiopathology ; Dietary Supplements ; Double-Blind Method ; Fatty Acids, Omega-3/blood/*therapeutic use ; Female ; Humans ; Leukocytes/*drug effects ; Male ; Middle Aged ; Oxidative Stress/*drug effects ; Telomerase/drug effects/metabolism ; Telomere Shortening/*drug effects ; },
abstract = {Shorter telomeres have been associated with poor health behaviors, age-related diseases, and early mortality. Telomere length is regulated by the enzyme telomerase, and is linked to exposure to proinflammatory cytokines and oxidative stress. In our recent randomized controlled trial, omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation lowered the concentration of serum proinflammatory cytokines. This study assessed whether n-3 PUFA supplementation also affected leukocyte telomere length, telomerase, and oxidative stress. In addition to testing for group differences, changes in the continuous n-6:n-3 PUFA ratio were assessed to account for individual differences in adherence, absorption, and metabolism. The double-blind four-month trial included 106 healthy sedentary overweight middle-aged and older adults who received (1) 2.5g/day n-3 PUFAs, (2) l.25g/day n-3 PUFAs, or (3) placebo capsules that mirrored the proportions of fatty acids in the typical American diet. Supplementation significantly lowered oxidative stress as measured by F2-isoprostanes (p=0.02). The estimated geometric mean log-F2-isoprostanes values were 15% lower in the two supplemented groups compared to placebo. Although group differences for telomerase and telomere length were nonsignificant, changes in the n-6:n-3 PUFA plasma ratios helped clarify the intervention's impact: telomere length increased with decreasing n-6:n-3 ratios, p=0.02. The data suggest that lower n-6:n-3 PUFA ratios can impact cell aging. The triad of inflammation, oxidative stress, and immune cell aging represents important pre-disease mechanisms that may be ameliorated through nutritional interventions. This translational research broadens our understanding of the potential impact of the n-6:n-3 PUFA balance. ClinicalTrials.gov identifier: NCT00385723.},
}
@article {pmid23010295,
year = {2012},
author = {Perez-Rivera, JA and Pabon-Osuna, P and Cieza-Borrella, C and Martin-Herrero, F and Gonzalez-Porras, JR and Gonzalez-Sarmiento, R},
title = {Prognostic value of telomere length in acute coronary syndrome.},
journal = {Mechanisms of ageing and development},
volume = {133},
number = {11-12},
pages = {695-697},
doi = {10.1016/j.mad.2012.09.003},
pmid = {23010295},
issn = {1872-6216},
mesh = {Acute Coronary Syndrome/diagnosis/*metabolism ; Aged ; Aging ; Cardiovascular Diseases/metabolism ; Cellular Senescence ; Humans ; Male ; Middle Aged ; Models, Biological ; Polymerase Chain Reaction/methods ; Polymorphism, Genetic ; Prognosis ; Telomerase/genetics/metabolism ; Telomere/*ultrastructure ; Time Factors ; },
abstract = {Telomere and telomerase are involved in cellular and organismal ageing and have been related to human diseases. Coronary artery disease is one of the most common age-related health problems in developed countries. Nevertheless, the specific role of cellular ageing in this process is still unclear. In this study, we analyze the possible prognostic value of telomere length and telomerase polymorphisms in a population of 150 middle aged males (mean age 62 ± 7) admitted for acute coronary syndrome who were followed up for more than 600 days. Peripheral blood samples were obtained and relative and comparative qPCR was used to measure telomere length and real time PCR to study the polymorphisms. Two prognostic combined events were defined. Long telomere length was revealed as an independent predictor (protector) of combined event presentation during long term follow up in our patients.},
}
@article {pmid23009101,
year = {2013},
author = {He, M and Bian, B and Gesuwan, K and Gulati, N and Zhang, L and Nilubol, N and Kebebew, E},
title = {Telomere length is shorter in affected members of families with familial nonmedullary thyroid cancer.},
journal = {Thyroid : official journal of the American Thyroid Association},
volume = {23},
number = {3},
pages = {301-307},
pmid = {23009101},
issn = {1557-9077},
support = {//Intramural NIH HHS/United States ; },
mesh = {Adult ; Carcinoma/*genetics/metabolism ; Carcinoma, Papillary ; Case-Control Studies ; Cohort Studies ; Female ; Gene Dosage ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Middle Aged ; Pedigree ; Polymerase Chain Reaction ; RNA, Messenger/metabolism ; Shelterin Complex ; Surveys and Questionnaires ; Telomerase/genetics ; Telomere/*ultrastructure ; Telomere-Binding Proteins/genetics ; Thyroid Cancer, Papillary ; Thyroid Neoplasms/*genetics/metabolism ; Thyroidectomy ; Tripeptidyl-Peptidase 1 ; },
abstract = {BACKGROUND: The theory that short telomere length and genetic defects in maintaining telomere length are associated with familial nonmedullary thyroid cancer (FNMTC) is controversial. Thus, the aim of this study was to determine whether telomere length and genes involved in maintaining telomere length are altered in FNMTC.<br><br>METHODS: Blood samples were collected from 44 members (13 affected and 31 unaffected) of six families with FNMTC and from 60 controls. Quantitative polymerase chain reaction (Q-PCR) and reverse transcription PCR were performed to analyze relative telomere length (RTL), gene copy number, and mRNA expression of telomerase reverse transcriptase (hTERT), telomere repeat binding factor 1 (TRF1), telomere repeat binding factor 2 (TRF2), repressor activator protein 1 (RAP1), TRF1 interacting nuclear factor 2 (TIN2), tripeptidyl peptidase 1 (TPP1), and protection of telomere 1 (POT1).<br><br>RESULTS: Affected members had shorter RTL, as compared with unaffected members (0.98 vs. 1.23, p<0.01). There was no significant difference in hTERT, TRF1, TRF2, RAP1, TIN2, TPP1, and POT1 gene copy number or mRNA expression between affected and unaffected members.<br><br>CONCLUSIONS: RTL is shorter in affected members with FNMTC but is not associated with altered copy number or expression in hTERT, TRF1, TRF2, RAP1, TIN2, TPP1, and POT1. The small differences in RTL preclude the utility of RTL as a marker for FNMTC in at-risk individuals.},
}
@article {pmid23006819,
year = {2013},
author = {Lu, W and Zhang, Y and Liu, D and Songyang, Z and Wan, M},
title = {Telomeres-structure, function, and regulation.},
journal = {Experimental cell research},
volume = {319},
number = {2},
pages = {133-141},
pmid = {23006819},
issn = {1090-2422},
support = {CA133249/CA/NCI NIH HHS/United States ; GM081627/GM/NIGMS NIH HHS/United States ; P30CA125123/CA/NCI NIH HHS/United States ; P01 GM081627/GM/NIGMS NIH HHS/United States ; P30 HD024064/HD/NICHD NIH HHS/United States ; P30 CA125123/CA/NCI NIH HHS/United States ; P30HD024064/HD/NICHD NIH HHS/United States ; R01 GM095599/GM/NIGMS NIH HHS/United States ; R01 CA133249/CA/NCI NIH HHS/United States ; GM095599/GM/NIGMS NIH HHS/United States ; },
mesh = {Cyclin-Dependent Kinase Inhibitor p16/metabolism ; DNA/chemistry/metabolism ; G-Quadruplexes ; Humans ; Protein Binding ; Telomere/*chemistry/genetics/*metabolism ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {In mammals, maintenance of the linear chromosome ends (or telomeres) involves faithful replication of genetic materials and protection against DNA damage signals, to ensure genome stability and integrity. These tasks are carried out by the telomerase holoenzyme and a unique nucleoprotein structure in which an array of telomere-associated proteins bind to telomeric DNA to form special protein/DNA complexes. The telomerase complex, which is comprised of telomeric reverse transcriptase (TERT), telomeric RNA component (TERC), and other assistant factors, is responsible for adding telomeric repeats to the ends of chromosomes. Without proper telomere maintenance, telomere length will shorten with successive round of DNA replication due to the so-called end replication problem. Aberrant regulation of telomeric proteins and/or telomerase may lead to abnormalities that can result in diseases such as dyskeratosis congenita (DC) and cancers. Understanding the mechanisms that regulate telomere homeostasis and the factors that contribute to telomere dysfunction should aid us in developing diagnostic and therapeutic tools for these diseases.},
}
@article {pmid23001564,
year = {2012},
author = {Mangino, M and Hwang, SJ and Spector, TD and Hunt, SC and Kimura, M and Fitzpatrick, AL and Christiansen, L and Petersen, I and Elbers, CC and Harris, T and Chen, W and Srinivasan, SR and Kark, JD and Benetos, A and El Shamieh, S and Visvikis-Siest, S and Christensen, K and Berenson, GS and Valdes, AM and Viñuela, A and Garcia, M and Arnett, DK and Broeckel, U and Province, MA and Pankow, JS and Kammerer, C and Liu, Y and Nalls, M and Tishkoff, S and Thomas, F and Ziv, E and Psaty, BM and Bis, JC and Rotter, JI and Taylor, KD and Smith, E and Schork, NJ and Levy, D and Aviv, A},
title = {Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans.},
journal = {Human molecular genetics},
volume = {21},
number = {24},
pages = {5385-5394},
pmid = {23001564},
issn = {1460-2083},
support = {N01-HC-25195/HC/NHLBI NIH HHS/United States ; UL1TR000124/TR/NCATS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; AG-15928/AG/NIA NIH HHS/United States ; 1R01AG032098-01A1/AG/NIA NIH HHS/United States ; N01-HC-85086/HC/NHLBI NIH HHS/United States ; AG-027058/AG/NIA NIH HHS/United States ; R01AG21593/AG/NIA NIH HHS/United States ; R01AG20132/AG/NIA NIH HHS/United States ; HD-062783/HD/NICHD NIH HHS/United States ; N01-HC-85239/HC/NHLBI NIH HHS/United States ; HL54472/HL/NHLBI NIH HHS/United States ; HL105756/HL/NHLBI NIH HHS/United States ; N01AG62101/AG/NIA NIH HHS/United States ; HL54515/HL/NHLBI NIH HHS/United States ; R01 AG016592/AG/NIA NIH HHS/United States ; HL087652/HL/NHLBI NIH HHS/United States ; UL1 TR000124/TR/NCATS NIH HHS/United States ; AG-20098/AG/NIA NIH HHS/United States ; HL055673/HL/NHLBI NIH HHS/United States ; N01-HC-35129/HC/NHLBI NIH HHS/United States ; N01 HC-55222/HC/NHLBI NIH HHS/United States ; HL54496/HL/NHLBI NIH HHS/United States ; 1 R01 HL80698-01/HL/NHLBI NIH HHS/United States ; N01-HC-75150/HC/NHLBI NIH HHS/United States ; N01 HC-15103/HC/NHLBI NIH HHS/United States ; HHSN268200782096C/HG/NHGRI NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; HL54473/HL/NHLBI NIH HHS/United States ; AG-16592/AG/NIA NIH HHS/United States ; DK063491/DK/NIDDK NIH HHS/United States ; N01-HC-45133/HC/NHLBI NIH HHS/United States ; N01-HC-85079/HC/NHLBI NIH HHS/United States ; N01AG62103/AG/NIA NIH HHS/United States ; HL080295/HL/NHLBI NIH HHS/United States ; N01AG62106/AG/NIA NIH HHS/United States ; HL54495/HL/NHLBI NIH HHS/United States ; HD-061437/HD/NICHD NIH HHS/United States ; R01AG030678/AG/NIA NIH HHS/United States ; AG 023629/AG/NIA NIH HHS/United States ; HL54471/HL/NHLBI NIH HHS/United States ; HL54509/HL/NHLBI NIH HHS/United States ; K24 CA169004/CA/NCI NIH HHS/United States ; },
mesh = {Genome-Wide Association Study ; Humans ; Kruppel-Like Transcription Factors ; Telomere/metabolism ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10(-11)) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.},
}
@article {pmid22997064,
year = {2013},
author = {Li, H and Hilmarsen, HT and Hossain, MB and Björk, J and Hansteen, IL and Albin, M and Furu Skjelbred, C and Broberg, K},
title = {Telomere length and LINE1 methylation is associated with chromosomal aberrations in peripheral blood.},
journal = {Genes, chromosomes &amp; cancer},
volume = {52},
number = {1},
pages = {1-10},
doi = {10.1002/gcc.22000},
pmid = {22997064},
issn = {1098-2264},
mesh = {Adult ; *Chromosome Aberrations ; Cohort Studies ; *DNA Methylation ; Humans ; Leukocytes, Mononuclear/*ultrastructure ; *Long Interspersed Nucleotide Elements ; Male ; Middle Aged ; Norway ; Statistics, Nonparametric ; Telomere/chemistry/*genetics ; Young Adult ; },
abstract = {The frequency of chromosomal aberrations in peripheral blood predicts a probable cancer risk. The individual telomere length and methylation of repetitive elements may be susceptibility factors for chromosomal aberrations. A cohort of healthy Norwegian men (N = 364) recruited during 1980-1999 were analyzed for chromosomal aberrations in phytohemagglutinin-stimulated lymphocytes from peripheral blood. Chromosome-type or chromatid-type aberrations were scored. DNA was extracted from slides cytogenetically analyzed and relative average telomere length and methylation of LINE1 repeats were determined by quantitative polymerase chain reaction and bisulfite pyrosequencing, respectively. Information about individuals with malignant tumors (N = 49) diagnosed after chromosomal aberrations testing until end of 2008 was obtained and two matched controls per case were used in a nested case-control analysis. Shorter relative telomere length and higher methylation of LINE1 were associated with higher frequency of total chromosomal aberrations (β = -0.76, P = 0.022; and β = 0.042, P = 0.048, respectively; age-adjusted ordinal regression). The telomere length was stronger associated with chromosome-type (β = -1.00, P = 0.006) than with chromatid-type aberrations (β = -0.49, P = 0.115). The LINE1 methylation was stronger associated with chromatid-type (β = 0.062, P = 0.003) than with chromosome-type aberrations (β = 0.018, P = 0.41). Telomere length [individuals with short telomeres odds ratio (OR) = 0.87, 95% confidence interval (CI) 0.38-2.0], LINE1 (individuals with high methylation OR = 1.04, 95% CI 0.43-2.5) and chromosomal aberrations (individuals with high frequency OR = 1.6, 95% CI 0.63-3.9) at baseline did not predict cancer risk, but the conclusions were hampered by low statistical precision. The results suggest that shorter telomere length and higher LINE1 methylation in peripheral blood lymphocytes are predisposition factors for increased frequency of chromosomal aberrations.},
}
@article {pmid22992703,
year = {2012},
author = {Field, MC and Horn, D and Alsford, S and Koreny, L and Rout, MP},
title = {Telomeres, tethers and trypanosomes.},
journal = {Nucleus (Austin, Tex.)},
volume = {3},
number = {6},
pages = {478-486},
pmid = {22992703},
issn = {1949-1042},
support = {U54 RR022220/RR/NCRR NIH HHS/United States ; U54 GM103511/GM/NIGMS NIH HHS/United States ; R21 AI096069/AI/NIAID NIH HHS/United States ; 082813/WT_/Wellcome Trust/United Kingdom ; 093010/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Cell Nucleus/metabolism ; Chromosomes/metabolism ; Fungi/metabolism ; Gene Silencing ; Heterochromatin/metabolism ; Histones/metabolism ; Lamins/metabolism ; Nuclear Envelope/metabolism ; Nuclear Pore Complex Proteins/metabolism ; Telomere/*metabolism ; Trypanosoma/*metabolism ; },
abstract = {Temporal and spatial organization of the nucleus is critical for the control of transcription, mRNA processing and the assembly of ribosomes. This includes the occupancy of specific territories by mammalian chromosomes, the presence of subnuclear compartments such as the nucleolus and Cajal bodies and the division of chromatin between active and inactive states. These latter are commonly associated with the location of DNA within euchromatin and heterochromatin respectively; critically these distinctions arise through modifications to chromatin-associated proteins, including histones, as well as the preferential localization of heterochromatin at the nuclear periphery. Most research on nuclear organization has focused on metazoa and fungi; however, recent technical advances have made more divergent eukaryotes accessible to study, with some surprising results. For example, the organization of heterochromatin is mediated in metazoan nuclei in large part by lamins, the prototypical intermediate filament proteins. Despite the presence of heterochromatin, detected both biochemically and by EM in most eukaryotic organisms, until this year lamins were thought to be restricted to metazoan taxa, and the proteins comprising the lamina in other lineages were unknown. Recent work indicates the presence of lamin orthologs in amoeba, while trypanosomatids possess a large coiled-coil protein, NUP-1, that performs functions analogous to lamins. These data indicate that the presence of a nuclear lamina is substantially more widespread than previously thought, with major implications for the evolution of eukaryotic gene expression mechanisms. We discuss these and other recent findings on the organization of nuclei in diverse organisms, and the implications of these findings for the evolutionary origin of eukaryotes.},
}
@article {pmid22991129,
year = {2012},
author = {Shalev, I},
title = {Early life stress and telomere length: investigating the connection and possible mechanisms: a critical survey of the evidence base, research methodology and basic biology.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {34},
number = {11},
pages = {943-952},
pmid = {22991129},
issn = {1521-1878},
support = {R01 HD061298/HD/NICHD NIH HHS/United States ; HD061298/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; *Data Collection ; Humans ; Quality of Life ; Research Design ; Stress, Psychological/*genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {How can adverse experiences in early life, such as maltreatment, exert such powerful negative effects on health decades later? The answer may lie in changes to DNA. New research suggests that exposure to stress can accelerate the erosion of DNA segments called telomeres. Shorter telomere length correlates with chronological age and also disease morbidity and mortality. Thus, telomere erosion is a potential mechanism linking childhood stress to health problems later in life. However, an array of mechanistic, methodological, and basic biological questions must be addressed in order to translate telomere discoveries into clinical applications for monitoring health and predicting disease risk. This paper covers the current state of the science and lays out new research directions.},
}
@article {pmid22990653,
year = {2012},
author = {Garg, MB and Lincz, LF and Adler, K and Scorgie, FE and Ackland, SP and Sakoff, JA},
title = {Predicting 5-fluorouracil toxicity in colorectal cancer patients from peripheral blood cell telomere length: a multivariate analysis.},
journal = {British journal of cancer},
volume = {107},
number = {9},
pages = {1525-1533},
pmid = {22990653},
issn = {1532-1827},
mesh = {Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/*adverse effects/blood/pharmacokinetics/therapeutic use ; Cohort Studies ; Colorectal Neoplasms/blood/*drug therapy/genetics ; Female ; Fluorouracil/administration &amp; dosage/*adverse effects/blood/pharmacokinetics ; Humans ; Leucovorin/administration &amp; dosage/adverse effects/blood ; Leukocytes, Mononuclear/*ultrastructure ; Male ; Middle Aged ; Multivariate Analysis ; Telomere/*metabolism/pathology ; },
abstract = {BACKGROUND: Identifying various pretreatment factors that predict chemotherapy-induced toxicity in colorectal cancer (CRC) patients undergoing treatment for their disease is crucial to optimising patient care.<br><br>METHODS: Seventy-three patients received adjuvant 5-fluorouracil (5FU)/leucovorin using either the Mayo Clinic (n=42) or a weekly schedule (n=31) and evaluated for clinical toxicity. Pretreatment blood analysis included measures of plasma uracil and dihydrouracil, peripheral blood mononuclear cell (PBMNC) telomere length (TL), standard biochemistry and cell differential analysis. On the first day of treatment 5FU-pharmacokinetic variables of area under the curve, half life and clearance were also measured. These variables together with age and gender were used in univariate and multivariate analysis as predictors of clinical toxicity.<br><br>RESULTS: For the Mayo schedule the primary toxicities were neutropenia (69%), mucositis (58%) and leukopenia (46%), with 70% of patients presenting with haematological toxicity &#x2265;grade 1 (neutropenia and/or leukopenia). Multivariate analysis showed that haematological toxicity was predicted by short TL, high platelet lymphocyte ratio (PLR) and low neutrophil count (R(2)=0.38, P<0.0006), whereas mucositis was predicted by age, TL and PLR (R(2)=0.34, P<0.001). For the weekly schedule diarrhoea predominated (16%), with female gender as the only predictive factor. Although measures of uracil metabolism correlated well with 5FU metabolism (r=0.45-0.49), they did not indicate abnormal pyrimidine metabolism in this cohort and not surprisingly failed to predict for 5FU toxicity.<br><br>CONCLUSION: Short TL of PBMNC and an increased PLR were strong predictors of mucositis and haematological toxicity in CRC patients undergoing 5FU treatment in the adjuvant setting.},
}
@article {pmid22989712,
year = {2012},
author = {Mendez-Bermudez, A and Hidalgo-Bravo, A and Cotton, VE and Gravani, A and Jeyapalan, JN and Royle, NJ},
title = {The roles of WRN and BLM RecQ helicases in the Alternative Lengthening of Telomeres.},
journal = {Nucleic acids research},
volume = {40},
number = {21},
pages = {10809-10820},
pmid = {22989712},
issn = {1362-4962},
support = {C17992/A8641//Cancer Research UK/United Kingdom ; G0500336//Medical Research Council/United Kingdom ; },
mesh = {Base Sequence ; Cell Line ; Down-Regulation ; Exodeoxyribonucleases/*physiology ; Humans ; Male ; Middle Aged ; Minisatellite Repeats ; Molecular Sequence Data ; Mutation ; RecQ Helicases/metabolism/*physiology ; Telomere/chemistry ; *Telomere Homeostasis ; Werner Syndrome Helicase ; },
abstract = {Approximately 10% of all cancers, but a higher proportion of sarcomas, use the recombination-based alternative lengthening of telomeres (ALT) to maintain telomeres. Two RecQ helicase genes, BLM and WRN, play important roles in homologous recombination repair and they have been implicated in telomeric recombination activity, but their precise roles in ALT are unclear. Using analysis of sequence variation present in human telomeres, we found that a WRN- ALT+ cell line lacks the class of complex telomere mutations attributed to inter-telomeric recombination in other ALT+ cell lines. This suggests that WRN facilitates inter-telomeric recombination when there are sequence differences between the donor and recipient molecules or that sister-telomere interactions are suppressed in the presence of WRN and this promotes inter-telomeric recombination. Depleting BLM in the WRN- ALT+ cell line increased the mutation frequency at telomeres and at the MS32 minisatellite, which is a marker of ALT. The absence of complex telomere mutations persisted in BLM-depleted clones, and there was a clear increase in sequence homogenization across the telomere and MS32 repeat arrays. These data indicate that BLM suppresses unequal sister chromatid interactions that result in excessive homogenization at MS32 and at telomeres in ALT+ cells.},
}
@article {pmid22987637,
year = {2012},
author = {Tazumi, A and Fukuura, M and Nakato, R and Kishimoto, A and Takenaka, T and Ogawa, S and Song, JH and Takahashi, TS and Nakagawa, T and Shirahige, K and Masukata, H},
title = {Telomere-binding protein Taz1 controls global replication timing through its localization near late replication origins in fission yeast.},
journal = {Genes &amp; development},
volume = {26},
number = {18},
pages = {2050-2062},
pmid = {22987637},
issn = {1549-5477},
mesh = {Base Sequence ; DNA Replication/*physiology ; DNA, Fungal/genetics/metabolism ; DNA-Binding Proteins/metabolism ; Molecular Sequence Data ; Protein Binding ; Protein Transport ; Replication Origin/physiology ; Schizosaccharomyces/genetics/metabolism/*physiology ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {In eukaryotes, the replication of chromosome DNA is coordinated by a replication timing program that temporally regulates the firing of individual replication origins. However, the molecular mechanism underlying the program remains elusive. Here, we report that the telomere-binding protein Taz1 plays a crucial role in the control of replication timing in fission yeast. A DNA element located proximal to a late origin in the chromosome arm represses initiation from the origin in early S phase. Systematic deletion and substitution experiments demonstrated that two tandem telomeric repeats are essential for this repression. The telomeric repeats recruit Taz1, a counterpart of human TRF1 and TRF2, to the locus. Genome-wide analysis revealed that Taz1 regulates about half of chromosomal late origins, including those in subtelomeres. The Taz1-mediated mechanism prevents Dbf4-dependent kinase (DDK)-dependent Sld3 loading onto the origins. Our results demonstrate that the replication timing program in fission yeast uses the internal telomeric repeats and binding of Taz1.},
}
@article {pmid22985462,
year = {2012},
author = {Najdekrova, L and Siroky, J},
title = {NBS1 plays a synergistic role with telomerase in the maintenance of telomeres in Arabidopsis thaliana.},
journal = {BMC plant biology},
volume = {12},
number = {},
pages = {167},
pmid = {22985462},
issn = {1471-2229},
mesh = {Anaphase ; Arabidopsis/cytology/enzymology/*genetics/growth &amp; development ; Arabidopsis Proteins/genetics/*metabolism ; Cell Cycle Proteins/genetics/*metabolism ; Chromosomal Instability ; Chromosomes, Plant/genetics/metabolism ; Cytogenetic Analysis ; DNA Repair ; DNA-Binding Proteins/genetics/metabolism ; Flowers/cytology/genetics/metabolism ; Germination ; In Situ Hybridization, Fluorescence ; MRE11 Homologue Protein ; Meiosis ; Nuclear Proteins/genetics/*metabolism ; Plant Cells/enzymology/metabolism ; Protein Interaction Mapping ; Seeds/genetics/growth &amp; development/metabolism ; Self-Fertilization ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomere Homeostasis ; },
abstract = {BACKGROUND: Telomeres, as elaborate nucleo-protein complexes, ensure chromosomal stability. When impaired, the ends of linear chromosomes can be recognised by cellular repair mechanisms as double-strand DNA breaks and can be healed by non-homologous-end-joining activities to produce dicentric chromosomes. During cell divisions, particularly during anaphase, dicentrics can break, thus producing naked chromosome tips susceptible to additional unwanted chromosome fusion. Many telomere-building protein complexes are associated with telomeres to ensure their proper capping function. It has been found however, that a number of repair complexes also contribute to telomere stability.<br><br>RESULTS: We used Arabidopsis thaliana to study the possible functions of the DNA repair subunit, NBS1, in telomere homeostasis using knockout nbs1 mutants. The results showed that although NBS1-deficient plants were viable, lacked any sign of developmental aberration and produced fertile seeds through many generations upon self-fertilisation, plants also missing the functional telomerase (double mutants), rapidly, within three generations, displayed severe developmental defects. Cytogenetic inspection of cycling somatic cells revealed a very early onset of massive genome instability. Molecular methods used for examining the length of telomeres in double homozygous mutants detected much faster telomere shortening than in plants deficient in telomerase gene alone.<br><br>CONCLUSIONS: Our findings suggest that NBS1 acts in concert with telomerase and plays a profound role in plant telomere renewal.},
}
@article {pmid22985061,
year = {2013},
author = {Maeda, T and Guan, JZ and Koyanagi, M and Makino, N},
title = {Telomerase activity and telomere length distribution in vascular endothelial cells in a short-term culture under the presence of hydrogen peroxide.},
journal = {Geriatrics &amp; gerontology international},
volume = {13},
number = {3},
pages = {774-782},
doi = {10.1111/j.1447-0594.2012.00936.x},
pmid = {22985061},
issn = {1447-0594},
mesh = {Blotting, Western ; Cells, Cultured ; Endothelial Cells/cytology/*metabolism ; *Gene Expression Regulation ; Humans ; Hydrogen Peroxide/*pharmacology ; *Oxidative Stress ; RNA/*genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/biosynthesis/*genetics ; Telomere/*genetics/metabolism ; },
abstract = {AIM: The aim of this study was to assess the biological effects of oxidative stress on human vascular endothelial cells.<br><br>METHODS: The telomeric changes and the alterations of the expression of telomere-associated proteins in human umbilical venous endothelial cells (HUVEC) cultured in the presence of hydrogen peroxide (H2 O2) were analyzed.<br><br>RESULTS: During the culture, the cell growth rate decreased, whereas the telomerase activity of the surviving cells increased. As the H2 O2 level increased, long telomeres decreased proportionally, thus resulting in a telomere length distribution that was rich in short telomeres. These observations suggested that H2 O2 -affected endothelial cells bear telomeric features similar to those of aged cells. In contrast, the expression of telomere-associated proteins, TRF1 and TRF2, showed different changes. TRF1 increased in relation to H2 O2 concentration, whereas TRF2 showed no significant change. The surviving cells exposed to H2 O2 showed a H2 O2 -dose dependent increase in telomerase activity, whereas the telomere protein and RNA components were only elevated in low concentrations of H2 O2 .<br><br>CONCLUSIONS: The increase in telomerase activity and TRF1 protein expression of vascular endothelial cell might show an aspect of cellular protective reaction against oxygen stress.},
}
@article {pmid22984146,
year = {2012},
author = {Kajantie, E and Pietiläinen, KH and Wehkalampi, K and Kananen, L and Räikkönen, K and Rissanen, A and Hovi, P and Kaprio, J and Andersson, S and Eriksson, JG and Hovatta, I},
title = {No association between body size at birth and leucocyte telomere length in adult life--evidence from three cohort studies.},
journal = {International journal of epidemiology},
volume = {41},
number = {5},
pages = {1400-1408},
doi = {10.1093/ije/dys127},
pmid = {22984146},
issn = {1464-3685},
mesh = {Aged ; Aging/*metabolism ; Birth Weight/*physiology ; Body Weights and Measures ; Cohort Studies ; Female ; Humans ; Infant, Newborn ; Leukocytes/*cytology ; Male ; Middle Aged ; Sex Factors ; Socioeconomic Factors ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Shorter leucocyte telomere length (LTL) is a promising marker of biological ageing. It is predicted by cumulative adverse conditions throughout life course, but few studies have data from the prenatal period when most developmental processes and cell replication take place. We studied whether body size at birth and underlying factors including severely preterm birth predict LTL in adult life.<br><br>METHODS: We used data from following three cohorts: (i) 1894 subjects (age: 56-69 years) from the Helsinki Birth Cohort Study (HBCS), representing normal variation in fetal growth; (ii) the Helsinki Study of Very Low Birth Weight Adults encompassing 164 subjects born preterm at very low birthweight (<1500 g; representing extreme pre- and neonatal conditions) and 170 term-born controls (18-27 years) and (iii) 248 twins (23-31 years) from the FinnTwin16 cohort, allowing comparisons between twin pairs. Relative telomere length was measured from leucocytes by real-time quantitative polymerase chain reaction.<br><br>RESULTS: Shorter LTL was associated with higher age in HBCS and among men in the Helsinki Study of Very Low Birth Weight Adults and with lower childhood socio-economic status in HBCS and FinnTwin16. LTL was not associated with weight, length or gestational age at birth in any cohort. LTL was similar in very-low-birthweight and control subjects.<br><br>CONCLUSIONS: LTL is unlikely to be a useful marker of a mechanism linking body size at birth with individual differences in ageing in the general population.},
}
@article {pmid22981835,
year = {2013},
author = {Adler, N and Pantell, MS and O'Donovan, A and Blackburn, E and Cawthon, R and Koster, A and Opresko, P and Newman, A and Harris, TB and Epel, E},
title = {Educational attainment and late life telomere length in the Health, Aging and Body Composition Study.},
journal = {Brain, behavior, and immunity},
volume = {27},
number = {1},
pages = {15-21},
pmid = {22981835},
issn = {1090-2139},
support = {T32 MH019391/MH/NIMH NIH HHS/United States ; R01-AG028050/AG/NIA NIH HHS/United States ; N01-AG-6-2101/AG/NIA NIH HHS/United States ; N01-AG-6-2103/AG/NIA NIH HHS/United States ; R01-NR012459/NR/NINR NIH HHS/United States ; R01 NR012459/NR/NINR NIH HHS/United States ; N01-AG-6-2106/AG/NIA NIH HHS/United States ; R01 AG028050/AG/NIA NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; },
mesh = {*Health Status Disparities ; Humans ; *Social Class ; *Telomere Shortening ; },
abstract = {Morbidity and mortality are greater among socially disadvantaged racial/ethnic groups and those of lower socioeconomic status (SES). Greater chronic stress exposure in disadvantaged groups may contribute to this by accelerating cellular aging, indexed by shorter age-adjusted telomere length. While studies consistently relate shorter leukocyte telomere length (LTL) to stress, the few studies, mostly from the UK, examining associations of LTL with SES have been mixed. The current study examined associations between educational attainment and LTL among 2599 high-functioning black and white adults age 70-79 from the Health, Aging and Body Composition Study. Multiple regression analyses tested associations of race/ethnicity, educational attainment and income with LTL, adjusting for potential confounders. Those with only a high school education had significantly shorter mean LTL (4806 basepairs) than those with post-high school education (4926 basepairs; B=125, SE=47.6, p=.009). A significant interaction of race and education (B=207.8, SE=98.7, p=.035) revealed more beneficial effects of post-high school education for blacks than for whites. Smokers had shorter LTL than non-smokers, but the association of education and LTL remained significant when smoking was covaried (B=119.7, SE=47.6, p=.012). While higher income was associated with longer LTL, the effect was not significant (p>.10). This study provides the first demonstration of an association between educational attainment and LTL in a US population where higher education appears to have a protective effect against telomere shortening, particularly in blacks.},
}
@article {pmid22981568,
year = {2012},
author = {Brown, DE and Dechow, CD and Liu, WS and Harvatine, KJ and Ott, TL},
title = {Hot topic: association of telomere length with age, herd, and culling in lactating Holsteins.},
journal = {Journal of dairy science},
volume = {95},
number = {11},
pages = {6384-6387},
doi = {10.3168/jds.2012-5593},
pmid = {22981568},
issn = {1525-3198},
mesh = {Age Factors ; Animals ; Cattle/*physiology ; Dairying/*methods ; Female ; Lactation/*physiology ; Multiplex Polymerase Chain Reaction/veterinary ; Telomere Shortening/*physiology ; beta-Globins/analysis ; },
abstract = {Telomere length variation may provide a quantitative measure of the effects of dairy management and selection practices on animal stress and welfare. The objective of this study was to evaluate the association between telomere length in Holstein cattle with age, herd, and survival. A multiplex quantitative PCR (qPCR) procedure was utilized to estimate telomere length for 201 Holstein cows from 10 herds following DNA extraction from blood. Primers were designed to amplify a 79-bp telomere product and a 144-bp product of a standard reference gene (β-globin). Both primer sets were included in the same reaction well to enable the analysis of relative quantity (qT) of telomere product compared with β-globin product. Triplicate samples were run for each cow, and mixed models were used to analyze the qPCR results. Younger cows were significantly associated with higher qT, and significant variation was observed among herds for qT. Cows with short telomeres were more likely to be culled in the subsequent year than cows with above-average telomere lengths. Multiplex qPCR provides a cost-effective method of assessing telomere length. Variation in telomere length might provide insights into how management practices and genetic selection influence cow stress and physiological responses to stress.},
}
@article {pmid22980747,
year = {2012},
author = {Joksic, I and Vujic, D and Guc-Scekic, M and Leskovac, A and Petrovic, S and Ojani, M and Trujillo, JP and Surralles, J and Zivkovic, M and Stankovic, A and Slijepcevic, P and Joksic, G},
title = {Dysfunctional telomeres in primary cells from Fanconi anemia FANCD2 patients.},
journal = {Genome integrity},
volume = {3},
number = {1},
pages = {6},
pmid = {22980747},
issn = {2041-9414},
abstract = {BACKGROUND: Fanconi anemia (FA) is characterized by sensitivity to DNA cross-linking agents, mild cellular, and marked clinical radio sensitivity. In this study we investigated telomeric abnormalities of non-immortalized primary cells (lymphocytes and fibroblasts) derived from FA patients of the FA-D2 complementation group, which provides a more accurate physiological assessment than is possible with transformed cells or animal models.<br><br>RESULTS: We analyzed telomere length, telomere dysfunction-induced foci (TIFs), sister chromatid exchanges (SCE), telomere sister chromatid exchanges (T-SCE), apoptosis and expression of shelterin components TRF1 and TRF2. FANCD2 lymphocytes exhibited multiple types of telomeric abnormalities, including premature telomere shortening, increase in telomeric recombination and aberrant telomeric structures ranging from fragile to long-string extended telomeres. The baseline incidence of SCE in FANCD2 lymphocytes was reduced when compared to control, but in response to diepoxybutane (DEB) the 2-fold higher rate of SCE was observed. In contrast, control lymphocytes showed decreased SCE incidence in response to DEB treatment. FANCD2 fibroblasts revealed a high percentage of TIFs, decreased expression of TRF1 and invariable expression of TRF2. The percentage of TIFs inversely correlated with telomere length, emphasizing that telomere shortening is the major reason for the loss of telomere capping function. Upon irradiation, a significant decrease of TIFs was observed at all recovery times. Surprisingly, a considerable percentage of TIF positive cells disappeared at the same time when incidence of &#x3b3;-H2AX foci was maximal. Both FANCD2 leucocytes and fibroblasts appeared to die spontaneously at higher rate than control. This trend was more evident upon irradiation; the percentage of leucocytes underwent apoptosis was 2.59- fold higher than that in control, while fibroblasts exhibited a 2- h delay before entering apoptosis.<br><br>CONCLUSION: The results of our study showed that primary cells originating from FA-D2 patients display shorten telomeres, elevated incidence of T-SCEs and high frequency of TIFs. Disappearance of TIFs in early response to irradiation represent distinctive feature of FANCD2 cells that should be examined further.},
}
@article {pmid22971476,
year = {2012},
author = {Li, D and Yuan, Q and Wang, W},
title = {The role of telomeres in musculoskeletal diseases.},
journal = {The Journal of international medical research},
volume = {40},
number = {4},
pages = {1242-1250},
doi = {10.1177/147323001204000403},
pmid = {22971476},
issn = {1473-2300},
mesh = {Animals ; Base Sequence ; Bone Neoplasms/enzymology/*genetics ; Humans ; Osteoarthritis/enzymology/*genetics ; Osteoporosis/enzymology/*genetics ; Osteosarcoma/enzymology/*genetics ; Telomerase/genetics/metabolism/physiology ; Telomere/*genetics/metabolism/physiology ; },
abstract = {The telomeric region of repetitive DNA sequences at the end of chromosomes prevents end-to-end fusion of chromosome terminals and deterioration of the doublestrand free ends. Because of the 'end-replication problem', telomeres shorten with each round of cell division, resulting in cell senescence. The enzyme telomerase compensates for telomere shortening by elongating telomeric sequences, thereby prolonging the lifespan of the cell. Studies of articular cartilage and bone tissues have indicated that telomere shortening limits normal cell function and proliferation, while the telomere maintenance mechanisms of osteosarcoma cells facilitate escape from cell death and promote immortality. This article reviews the literature on this topic and provides an extensive discussion of the basic molecular biology and roles of telomeres and telomerase in musculoskeletal diseases such as osteoarthritis, osteoporosis and osteosarcoma. Findings to date suggest that telomeres and telomerase may become novel therapeutic targets for the diagnosis, treatment and prevention of musculoskeletal disorders.},
}
@article {pmid22970196,
year = {2012},
author = {Shen, J and Terry, MB and Liao, Y and Gurvich, I and Wang, Q and Senie, RT and Santella, RM},
title = {Genetic variation in telomere maintenance genes, telomere length and breast cancer risk.},
journal = {PloS one},
volume = {7},
number = {9},
pages = {e44308},
pmid = {22970196},
issn = {1932-6203},
support = {U01 CA069398/CA/NCI NIH HHS/United States ; U01 CA69398/CA/NCI NIH HHS/United States ; P30 CA013696/CA/NCI NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; P30 CA13696/CA/NCI NIH HHS/United States ; R03 CA125768/CA/NCI NIH HHS/United States ; },
mesh = {Breast Neoplasms/*genetics/*pathology ; Case-Control Studies ; Family ; Female ; *Genetic Predisposition to Disease ; *Genetic Variation ; Humans ; Logistic Models ; Middle Aged ; New York ; Registries ; Risk Factors ; Siblings ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: Telomeres at the ends of eukaryotic chromosomes play a critical role in maintaining the integrity and stability of the genome and participate in the initiation of DNA damage/repair responses.<br><br>METHODS: We performed a case-control study to evaluate the role of three SNPs (TERT-07, TERT-54 and POT1-03) in telomere maintenance genes previously found to be significantly associated with breast cancer risk. We used sister-sets obtained from the New York site of the Breast Cancer Family Registry (BCFR). Among the 313 sister-sets, there were 333 breast cancer cases and 409 unaffected sisters who were evaluated in the current study. We separately applied conditional logistic regression and generalized estimating equations (GEE) models to evaluate associations between the three SNPs and breast cancer risk within sister-sets. We examined the associations between genotype, covariates and telomere length among unaffected sisters using a GEE model.<br><br>RESULTS: We found no significant associations between the three SNPs in telomere maintenance genes and breast cancer risk by both conditional logistic regression and GEE models, nor were these SNPs significantly related to telomere length. Among unaffected sisters, shortened telomeres were statistically significantly correlated with never hormone replacement therapy (HRT) use. Increased duration of HRT use was significantly associated with reduced telomere length. The means of telomere length were 0.77 (SD = 0.35) for never HRT use, 0.67 (SD = 0.29) for HRT use < 5 yrs and 0.59 (SD = 0.24) for HRT use &#x2265; 5 yrs after adjusting for age of blood donation and race and ethnicity.<br><br>CONCLUSIONS: We found that exogenous hormonal exposure was inversely associated with telomere length. No significant associations between genetic variants and telomere length or breast cancer risk were observed. These findings provide initial evidence to understand hormonal exposure in the regulation of telomere length and breast cancer risk but need replication in prospective studies.},
}
@article {pmid22965356,
year = {2012},
author = {Armanios, M and Blackburn, EH},
title = {The telomere syndromes.},
journal = {Nature reviews. Genetics},
volume = {13},
number = {10},
pages = {693-704},
pmid = {22965356},
issn = {1471-0064},
support = {R01 CA160433/CA/NCI NIH HHS/United States ; R21 HL104345/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Genetic Association Studies ; Genetic Diseases, Inborn/*genetics ; Genetic Predisposition to Disease ; Humans ; Models, Biological ; Quantitative Trait, Heritable ; Syndrome ; Telomere/*genetics/metabolism/pathology/physiology ; },
abstract = {There has been mounting evidence of a causal role for telomere dysfunction in a number of degenerative disorders. Their manifestations encompass common disease states such as idiopathic pulmonary fibrosis and bone marrow failure. Although these disorders seem to be clinically diverse, collectively they comprise a single syndrome spectrum defined by the short telomere defect. Here we review the manifestations and unique genetics of telomere syndromes. We also discuss their underlying molecular mechanisms and significance for understanding common age-related disease processes.},
}
@article {pmid22964711,
year = {2012},
author = {Huang, C and Dai, X and Chai, W},
title = {Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in.},
journal = {Cell research},
volume = {22},
number = {12},
pages = {1681-1695},
pmid = {22964711},
issn = {1748-7838},
support = {R15 GM099008/GM/NIGMS NIH HHS/United States ; R21 AG041375/AG/NIA NIH HHS/United States ; R15GM099008/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line ; Cellular Senescence ; DNA Polymerase I/metabolism ; DNA, Single-Stranded/metabolism ; Down-Regulation ; G2 Phase ; HeLa Cells ; Humans ; RNA Interference ; RNA, Small Interfering/metabolism ; S Phase ; Telomere/*metabolism ; Telomere-Binding Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; },
abstract = {Telomere maintenance is critical for genome stability. The newly-identified Ctc1/Stn1/Ten1 complex is important for telomere maintenance, though its precise role is unclear. We report here that depletion of hStn1 induces catastrophic telomere shortening, DNA damage response, and early senescence in human somatic cells. These phenotypes are likely due to the essential role of hStn1 in promoting efficient replication of lagging-strand telomeric DNA. Downregulation of hStn1 accumulates single-stranded G-rich DNA specifically at lagging-strand telomeres, increases telomere fragility, hinders telomere DNA synthesis, as well as delays and compromises telomeric C-strand synthesis. We further show that hStn1 deficiency leads to persistent and elevated association of DNA polymerase α (polα) to telomeres, suggesting that hStn1 may modulate the DNA synthesis activity of polα rather than controlling the loading of polα to telomeres. Additionally, our data suggest that hStn1 is unlikely to be part of the telomere capping complex. We propose that the hStn1 assists DNA polymerases to efficiently duplicate lagging-strand telomeres in order to achieve complete synthesis of telomeric DNA, therefore preventing rapid telomere loss.},
}
@article {pmid22959349,
year = {2012},
author = {Fujita, I and Nishihara, Y and Tanaka, M and Tsujii, H and Chikashige, Y and Watanabe, Y and Saito, M and Ishikawa, F and Hiraoka, Y and Kanoh, J},
title = {Telomere-nuclear envelope dissociation promoted by Rap1 phosphorylation ensures faithful chromosome segregation.},
journal = {Current biology : CB},
volume = {22},
number = {20},
pages = {1932-1937},
doi = {10.1016/j.cub.2012.08.019},
pmid = {22959349},
issn = {1879-0445},
mesh = {CDC2 Protein Kinase/metabolism ; Cell Cycle/genetics ; Chromosome Segregation/*physiology ; Mitosis ; Nuclear Envelope/genetics/*metabolism ; Phosphorylation ; Protein Structure, Tertiary ; Schizosaccharomyces/*genetics/metabolism ; Schizosaccharomyces pombe Proteins/*metabolism ; Shelterin Complex ; Spindle Apparatus/genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Efficient chromosomal movements are important for the fidelity of chromosome segregation during mitosis; however, movements are constrained during interphase by tethering of multiple domains to the nuclear envelope (NE). Higher eukaryotes undergo open mitosis accompanied by NE breakdown, enabling chromosomes to be released from the NE, whereas lower eukaryotes undergo closed mitosis, in which NE breakdown does not occur. Although the chromosomal movements in closed mitosis are thought to be restricted compared to open mitosis, the cells overcome this problem by an unknown mechanism that enables accurate chromosome segregation. Here, we report the spatiotemporal regulation of telomeres in Schizosaccharomyces pombe closed mitosis. We found that the telomeres, tethered to the NE during interphase, are transiently dissociated from the NE during mitosis. This dissociation from the NE is essential for accurate chromosome segregation because forced telomere tethering to the NE causes frequent chromosome loss. The phosphorylation of the telomere protein Rap1 during mitosis, primarily by Cdc2, impedes the interaction between Rap1 and Bqt4, a nuclear membrane protein, thereby inducing telomere dissociation from the NE. We propose that the telomere dissociation from the NE promoted by Rap1 phosphorylation is critical for the fidelity of chromosome segregation in closed mitosis.},
}
@article {pmid22954451,
year = {2012},
author = {Olsen, MT and Bérubé, M and Robbins, J and Palsbøll, PJ},
title = {Empirical evaluation of humpback whale telomere length estimates; quality control and factors causing variability in the singleplex and multiplex qPCR methods.},
journal = {BMC genetics},
volume = {13},
number = {},
pages = {77},
pmid = {22954451},
issn = {1471-2156},
mesh = {Animals ; DNA Primers/metabolism ; Humpback Whale/*genetics/metabolism ; Quality Control ; Real-Time Polymerase Chain Reaction/*standards ; Reference Standards ; Telomere/*genetics/metabolism ; },
abstract = {BACKGROUND: Telomeres, the protective cap of chromosomes, have emerged as powerful markers of biological age and life history in model and non-model species. The qPCR method for telomere length estimation is one of the most common methods for telomere length estimation, but has received recent critique for being too error-prone and yielding unreliable results. This critique coincides with an increasing awareness of the potentials and limitations of the qPCR technique in general and the proposal of a general set of guidelines (MIQE) for standardization of experimental, analytical, and reporting steps of qPCR. In order to evaluate the utility of the qPCR method for telomere length estimation in non-model species, we carried out four different qPCR assays directed at humpback whale telomeres, and subsequently performed a rigorous quality control to evaluate the performance of each assay.<br><br>RESULTS: Performance differed substantially among assays and only one assay was found useful for telomere length estimation in humpback whales. The most notable factors causing these inter-assay differences were primer design and choice of using singleplex or multiplex assays. Inferred amplification efficiencies differed by up to 40% depending on assay and quantification method, however this variation only affected telomere length estimates in the worst performing assays.<br><br>CONCLUSION: Our results suggest that seemingly well performing qPCR assays may contain biases that will only be detected by extensive quality control. Moreover, we show that the qPCR method for telomere length estimation can be highly precise and accurate, and thus suitable for telomere measurement in non-model species, if effort is devoted to optimization at all experimental and analytical steps. We conclude by highlighting a set of quality controls which may serve for further standardization of the qPCR method for telomere length estimation, and discuss some of the factors that may cause variation in qPCR experiments.},
}
@article {pmid22953000,
year = {2012},
author = {Milliman, EJ and Yadav, N and Chen, YC and Muddukrishna, B and Karunanithi, S and Yu, MC},
title = {Recruitment of Rpd3 to the telomere depends on the protein arginine methyltransferase Hmt1.},
journal = {PloS one},
volume = {7},
number = {8},
pages = {e44656},
pmid = {22953000},
issn = {1932-6203},
mesh = {Acetylation ; Chromatin Immunoprecipitation ; Epistasis, Genetic ; Gene Silencing ; Genes, Synthetic/genetics ; Genetic Testing ; Genome, Fungal/genetics ; Histone Deacetylases/genetics/*metabolism ; Histones/metabolism ; Methylation ; Mutation/genetics ; Protein Binding ; Protein Subunits/metabolism ; Protein-Arginine N-Methyltransferases/genetics/*metabolism ; Repressor Proteins/genetics/*metabolism ; Saccharomyces cerevisiae/*enzymology/genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/metabolism ; Sirtuin 2/metabolism ; Telomere/*metabolism ; },
abstract = {In the yeast Saccharomyces cerevisiae, the establishment and maintenance of silent chromatin at the telomere requires a delicate balance between opposing activities of histone modifying enzymes. Previously, we demonstrated that the protein arginine methyltransferase Hmt1 plays a role in the formation of yeast silent chromatin. To better understand the nature of the Hmt1 interactions that contribute to this phenomenon, we carried out a systematic reverse genetic screen using a null allele of HMT1 and the synthetic genetic array (SGA) methodology. This screen revealed interactions between HMT1 and genes encoding components of the histone deacetylase complex Rpd3L (large). A double mutant carrying both RPD3 and HMT1 deletions display increased telomeric silencing and Sir2 occupancy at the telomeric boundary regions, when comparing to a single mutant carrying Hmt1-deletion only. However, the dual rpd3/hmt1-null mutant behaves like the rpd3-null single mutant with respect to silencing behavior, indicating that RPD3 is epistatic to HMT1. Mutants lacking either Hmt1 or its catalytic activity display an increase in the recruitment of histone deacetylase Rpd3 to the telomeric boundary regions. Moreover, in such loss-of-function mutants the levels of acetylated H4K5, which is a substrate of Rpd3, are altered at the telomeric boundary regions. In contrast, the level of acetylated H4K16, a target of the histone deacetylase Sir2, was increased in these regions. Interestingly, mutants lacking either Rpd3 or Sir2 display various levels of reduction in dimethylated H4R3 at these telomeric boundary regions. Together, these data provide insight into the mechanism whereby Hmt1 promotes the proper establishment and maintenance of silent chromatin at the telomeres.},
}
@article {pmid22952882,
year = {2012},
author = {Ujvari, B and Pearse, AM and Taylor, R and Pyecroft, S and Flanagan, C and Gombert, S and Papenfuss, AT and Madsen, T and Belov, K},
title = {Telomere dynamics and homeostasis in a transmissible cancer.},
journal = {PloS one},
volume = {7},
number = {8},
pages = {e44085},
pmid = {22952882},
issn = {1932-6203},
support = {//Medical Research Council/United Kingdom ; },
mesh = {Animals ; Cell Line, Tumor ; DNA Copy Number Variations/genetics ; Enzyme Assays ; Geography ; Marsupialia/*genetics ; Neoplasms/genetics/*veterinary ; Polymorphism, Restriction Fragment Length ; Repetitive Sequences, Nucleic Acid/genetics ; Tasmania ; Telomerase/genetics/metabolism ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/genetics/metabolism ; Time Factors ; Up-Regulation/genetics ; },
abstract = {BACKGROUND: Devil Facial Tumour Disease (DFTD) is a unique clonal cancer that threatens the world's largest carnivorous marsupial, the Tasmanian devil (Sarcophilus harrisii) with extinction. This transmissible cancer is passed between individual devils by cell implantation during social interactions. The tumour arose in a Schwann cell of a single devil over 15 years ago and since then has expanded clonally, without showing signs of replicative senescence; in stark contrast to a somatic cell that displays a finite capacity for replication, known as the "Hayflick limit".<br><br>In the present study we investigate the role of telomere length, measured as Telomere Copy Number (TCN), and telomerase and shelterin gene expression, as well as telomerase activity in maintaining hyperproliferation of Devil Facial Tumour (DFT) cells. Our results show that DFT cells have short telomeres. DFTD TCN does not differ between geographic regions or between strains. However, TCN has increased over time. Unlimited cell proliferation is likely to have been achieved through the observed up-regulation of the catalytic subunit of telomerase (TERT) and concomitant activation of telomerase. Up-regulation of the central component of shelterin, the TRF1-intercating nuclear factor 2 (TINF2) provides DFT a mechanism for telomere length homeostasis. The higher expression of both TERT and TINF2 may also protect DFT cells from genomic instability and enhance tumour proliferation.<br><br>CONCLUSIONS/SIGNIFICANCE: DFT cells appear to monitor and regulate the length of individual telomeres: i.e. shorter telomeres are elongated by up-regulation of telomerase-related genes; longer telomeres are protected from further elongation by members of the shelterin complex, which may explain the lack of spatial and strain variation in DFT telomere copy number. The observed longitudinal increase in gene expression in DFT tissue samples and telomerase activity in DFT cell lines might indicate a selection for more stable tumours with higher proliferative potential.},
}
@article {pmid22952449,
year = {2012},
author = {Hovel-Miner, GA and Boothroyd, CE and Mugnier, M and Dreesen, O and Cross, GA and Papavasiliou, FN},
title = {Telomere length affects the frequency and mechanism of antigenic variation in Trypanosoma brucei.},
journal = {PLoS pathogens},
volume = {8},
number = {8},
pages = {e1002900},
pmid = {22952449},
issn = {1553-7374},
support = {R01 AI021729/AI/NIAID NIH HHS/United States ; R01 AI085973/AI/NIAID NIH HHS/United States ; AI21729/AI/NIAID NIH HHS/United States ; AI085973/AI/NIAID NIH HHS/United States ; },
mesh = {Antigenic Variation/*genetics ; DNA, Protozoan/genetics ; Gene Conversion ; Gene Duplication ; *Genetic Variation ; Humans ; Phenotype ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; Telomere Homeostasis/genetics ; Trypanosoma brucei brucei/*genetics/immunology/metabolism ; Variant Surface Glycoproteins, Trypanosoma/*genetics/immunology/metabolism ; },
abstract = {Trypanosoma brucei is a master of antigenic variation and immune response evasion. Utilizing a genomic repertoire of more than 1000 Variant Surface Glycoprotein-encoding genes (VSGs), T. brucei can change its protein coat by "switching" from the expression of one VSG to another. Each active VSG is monoallelically expressed from only one of approximately 15 subtelomeric sites. Switching VSG expression occurs by three predominant mechanisms, arguably the most significant of which is the non-reciprocal exchange of VSG containing DNA by duplicative gene conversion (GC). How T. brucei orchestrates its complex switching mechanisms remains to be elucidated. Recent work has demonstrated that an exogenous DNA break in the active site could initiate a GC based switch, yet the source of the switch-initiating DNA lesion under natural conditions is still unknown. Here we investigated the hypothesis that telomere length directly affects VSG switching. We demonstrate that telomerase deficient strains with short telomeres switch more frequently than genetically identical strains with long telomeres and that, when the telomere is short, switching preferentially occurs by GC. Our data supports the hypothesis that a short telomere at the active VSG expression site results in an increase in subtelomeric DNA breaks, which can initiate GC based switching. In addition to their significance for T. brucei and telomere biology, the findings presented here have implications for the many diverse pathogens that organize their antigenic genes in subtelomeric regions.},
}
@article {pmid22951603,
year = {2013},
author = {Yen, YC and Lung, FW},
title = {Older adults with higher income or marriage have longer telomeres.},
journal = {Age and ageing},
volume = {42},
number = {2},
pages = {234-239},
pmid = {22951603},
issn = {1468-2834},
mesh = {Age Factors ; Aged ; Aging/*genetics ; Cross-Sectional Studies ; Female ; Humans ; *Income ; Leukocytes/*metabolism ; Linear Models ; Male ; *Marital Status ; Multivariate Analysis ; Polymerase Chain Reaction ; Residence Characteristics ; Surveys and Questionnaires ; Taiwan ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {BACKGROUND: telomere length has been used to represent biological ageing and is found to be associated with various physiological, psychological and social factors.<br><br>OBJECTIVE: to explore the effects of income and marriage on leucocyte telomere length in a representative sample of older adults.<br><br>DESIGN AND SUBJECTS: cross-sectional analysis among 298 adults, aged 65-74, randomly selected from the community by census.<br><br>METHODS: telomere length was measured by quantitative PCR. Participants provided information on sociodemographics, physical illness and completed questionnaires rating mental state and perceived neighbourhood experience.<br><br>RESULTS: telomere length was negatively associated with lower income [coefficient -0.141 (95% CI: -0.244 to -0.020), P = 0.021] and positively associated with the marital status [coefficient 0.111 (95% CI: -0.008 to 0.234), P = 0.067] when controlling for gender, age, educational level, physical diseases (including diabetes, hypertension, cardiovascular diseases, cerebrovascular disease and Parkinson's disease), depressive symptoms, minor mental symptoms, cognitive impairment and perceived neighbourhood experience (including social support, perceived security and public facilities).<br><br>CONCLUSIONS: these results indicate that older adults with higher income or being married have longer telomeres when other sociodemographics, physical diseases, mental status and neighbourhood experience are adjusted.},
}
@article {pmid22948043,
year = {2012},
author = {Peffault de Latour, R and Calado, RT and Busson, M and Abrams, J and Adoui, N and Robin, M and Larghero, J and Dhedin, N and Xhaard, A and Clave, E and Charron, D and Toubert, A and Loiseau, P and Socié, G and Young, NS},
title = {Age-adjusted recipient pretransplantation telomere length and treatment-related mortality after hematopoietic stem cell transplantation.},
journal = {Blood},
volume = {120},
number = {16},
pages = {3353-3359},
pmid = {22948043},
issn = {1528-0020},
support = {//Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Child ; Child, Preschool ; Female ; Graft vs Host Disease/mortality ; HLA Antigens/metabolism ; Hematologic Neoplasms/genetics/*mortality/therapy ; Hematopoietic Stem Cell Transplantation/*mortality ; Humans ; Infant ; Male ; Middle Aged ; Neoplasm Recurrence, Local/mortality ; Siblings ; Survival Rate ; *Telomere Homeostasis ; Transplantation Conditioning/*mortality ; Transplantation, Homologous ; Young Adult ; },
abstract = {Telomere attrition induces cell senescence and apoptosis. We hypothesized that age-adjusted pretransplantation telomere length might predict treatment-related mortality (TRM) after hematopoietic stem cell transplantation (HSCT). Between 2000 and 2005, 178 consecutive patients underwent HSCT from HLA-identical sibling donors after myeloablative conditioning regimens, mainly for hematologic malignancies (n = 153). Blood lymphocytes' telomere length was measured by real-time quantitative PCR before HSCT. Age-adjusted pretransplantation telomere lengths were analyzed for correlation with clinical outcomes. After age adjustment, patients' telomere-length distribution was similar among all 4 quartiles except for disease stage. There was no correlation between telomere length and engraftment, GVHD, or relapse. The overall survival was 62% at 5 years (95% confidence interval [CI], 54-70). After a median follow-up of 51 months (range, 1-121 months), 43 patients died because of TRM. The TRM rate inversely correlated with telomere length. TRM in patients in the first (lowest telomere length) quartile was significantly higher than in patients with longer telomeres (P = .017). In multivariate analysis, recipients' age (hazard ratio, 1.1; 95% CI, .0-1.1; P = .0001) and age-adjusted telomere length (hazard ratio, 0.4; 95% CI; 0.2-0.8; P = .01) were independently associated with TRM. In conclusion, age-adjusted recipients' telomere length is an independent biologic marker of TRM after HSCT.},
}
@article {pmid22947495,
year = {2012},
author = {Cesare, AJ and Karlseder, J},
title = {A three-state model of telomere control over human proliferative boundaries.},
journal = {Current opinion in cell biology},
volume = {24},
number = {6},
pages = {731-738},
pmid = {22947495},
issn = {1879-0410},
support = {P30 CA014195-38/CA/NCI NIH HHS/United States ; T32 CA009370/CA/NCI NIH HHS/United States ; GM087476/GM/NIGMS NIH HHS/United States ; 5T32CA009370-29/CA/NCI NIH HHS/United States ; R01 GM087476/GM/NIGMS NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Differentiation ; *Cell Proliferation ; Cellular Senescence/*genetics ; Humans ; M Phase Cell Cycle Checkpoints ; *Models, Biological ; Neoplasms/genetics/pathology ; Stress, Physiological ; Telomere/*genetics/*metabolism/pathology ; },
abstract = {Intrinsic limits on cellular proliferation in human somatic tissue serves as a tumor suppressor mechanism by restricting cell growth in aged cells with accrued pre-cancerous mutations. This is accompanied by the potential cost of restricting regenerative capacity and contributing to cellular and organismal aging. Emerging data support a model where telomere erosion controls proliferative boundaries through the progressive change of telomere structure from a protected state, through two distinct states of telomere deprotection. In this model telomeres facilitate a controlled permanent cell cycle arrest with a stable diploid genome during differentiation and may serve as an epigenetic sensor of general stress in DNA metabolism processes.},
}
@article {pmid22947336,
year = {2012},
author = {Díaz de la Guardia, R and Catalina, P and Panero, J and Elosua, C and Pulgarin, A and López, MB and Ayllón, V and Ligero, G and Slavutsky, I and Leone, PE},
title = {Expression profile of telomere-associated genes in multiple myeloma.},
journal = {Journal of cellular and molecular medicine},
volume = {16},
number = {12},
pages = {3009-3021},
pmid = {22947336},
issn = {1582-4934},
mesh = {14-3-3 Proteins/genetics/metabolism ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; Chromosomal Instability ; Embryonic Stem Cells/metabolism ; Female ; Gene Expression Profiling ; HSP70 Heat-Shock Proteins/genetics/metabolism ; Heterogeneous-Nuclear Ribonucleoproteins/genetics/metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Leukemia, Plasma Cell/genetics/metabolism ; Male ; Mitochondrial Proteins/genetics/metabolism ; Monoclonal Gammopathy of Undetermined Significance/genetics/metabolism ; Multiple Myeloma/*genetics/*metabolism ; Plasma Cells/metabolism ; Proto-Oncogene Proteins/genetics/metabolism ; Proto-Oncogene Proteins p21(ras) ; Retinoblastoma Protein/genetics/metabolism ; Ribonucleoproteins, Small Nucleolar/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics ; Transcriptome ; ras Proteins/genetics/metabolism ; },
abstract = {To further contribute to the understanding of multiple myeloma, we have focused our research interests on the mechanisms by which tumour plasma cells have a higher survival rate than normal plasma cells. In this article, we study the expression profile of genes involved in the regulation and protection of telomere length, telomerase activity and apoptosis in samples from patients with monoclonal gammopathy of undetermined significance, smouldering multiple myeloma, multiple myeloma (MM) and plasma cell leukaemia (PCL), as well as several human myeloma cell lines (HMCLs). Using conventional cytogenetic and fluorescence in situ hybridization studies, we identified a high number of telomeric associations (TAs). Moreover, telomere length measurements by terminal restriction fragment (TRF) assay showed a shorter mean TRF peak value, with a consistent correlation with the number of TAs. Using gene expression arrays and quantitative PCR we identified the hTERT gene together with 16 other genes directly involved in telomere length maintenance: HSPA9, KRAS, RB1, members of the Small nucleolar ribonucleoproteins family, A/B subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins, and 14-3-3 family. The expression levels of these genes were even higher than those in human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), which have unlimited proliferation capacity. In conclusion, the gene signature suggests that MM tumour cells are able to maintain stable short telomere lengths without exceeding the short critical length, allowing cell divisions to continue. We propose that this could be a mechanism contributing to MM tumour cells expansion in the bone marrow (BM).},
}
@article {pmid22946492,
year = {2013},
author = {Akhtar, N and Anand, V and Verma, KK and Sharma, A},
title = {Augmented telomerase activity and reduced telomere length in parthenium-induced contact dermatitis.},
journal = {Journal of the European Academy of Dermatology and Venereology : JEADV},
volume = {27},
number = {10},
pages = {1222-1227},
doi = {10.1111/j.1468-3083.2012.04691.x},
pmid = {22946492},
issn = {1468-3083},
mesh = {Adult ; Aged ; Biomarkers/metabolism ; CD4-Positive T-Lymphocytes/metabolism/pathology/ultrastructure ; CD8-Positive T-Lymphocytes/metabolism/pathology/ultrastructure ; Case-Control Studies ; Dermatitis, Contact/*metabolism/*pathology ; Female ; Humans ; Leukocytes, Mononuclear/metabolism/pathology/ultrastructure ; Male ; Middle Aged ; Parthenogenesis ; Plant Extracts/*adverse effects ; Prognosis ; Telomerase/*metabolism ; Telomere/ultrastructure ; *Telomere Shortening ; },
abstract = {BACKGROUND: Parthenium dermatitis is a common chronic inflammatory disease with activated T lymphocytes that recognize the antigens, which leads to proliferation and differentiation. Telomeres and telomerase play an important role in the regulation of life span of the cell. Telomere length maintained by telomerase, are specialized repeats present at the end of chromosomes which protect it from degradation, end-to-end fusion and are important for integrity of chromosomes.<br><br>OBJECTIVES: The aim of this study was to measure telomerase activity and telomere length in Peripheral blood mononuclear cell (PBMC), CD4(+) and CD8(+) T lymphocytes from parthenium dermatitis patients.<br><br>METHODS: The study includes 50 patients of parthenium dermatitis confirmed by patch testing and 50 healthy controls. Telomerase activity was measured using the telomere repeat amplification protocol using PCR-ELISA kit. Telomere length was measured by using Telo TAGGG Telomere Length Assay Kit.<br><br>RESULTS: Significantly elevated levels of telomerase activity was observed in PBMC, CD4(+) and CD8(+) T cells of parthenium dermatitis patients as compared with healthy controls. However, significantly reduced telomere length in PBMC, CD4(+) and CD8(+) T cells have been found in patients than healthy subjects, but there was no difference between CD4(+) and CD8(+) T cells in patients.<br><br>CONCLUSION: This study might have provided insight into the role of telomerase in parthenium dermatitis that is characterized by the recruitment of T lymphocytes, which play an important role in this inflammatory disease. The augmented telomerase activity and reduced terminal restriction fragment length might be explored as a potential diagnostic/prognostic marker for parthenium dermatitis in future.},
}
@article {pmid22941386,
year = {2012},
author = {Gomez, DE and Armando, RG and Farina, HG and Menna, PL and Cerrudo, CS and Ghiringhelli, PD and Alonso, DF},
title = {Telomere structure and telomerase in health and disease (review).},
journal = {International journal of oncology},
volume = {41},
number = {5},
pages = {1561-1569},
pmid = {22941386},
issn = {1791-2423},
mesh = {Animals ; Cell Transformation, Neoplastic/genetics/metabolism ; Humans ; Mammals ; Neoplasms/genetics/metabolism ; Telomerase/*metabolism ; Telomere/*chemistry ; Telomere Homeostasis/*physiology ; },
abstract = {Telomerase is the enzyme responsible for maintenance of the length of telomeres by addition of guanine-rich repetitive sequences. Telomerase activity is exhibited in gametes and stem and tumor cells. In human somatic cells, proliferation potential is strictly limited and senescence follows approximately 50-70 cell divisions. In most tumor cells, on the contrary, replication potential is unlimited. The key role in this process of the system of the telomere length maintenance with involvement of telomerase is still poorly studied. Undoubtedly, DNA polymerase is not capable of completely copying DNA at the very ends of chromosomes; therefore, approximately 50 nucleotides are lost during each cell cycle, which results in gradual telomere length shortening. Critically short telomeres cause senescence, following crisis and cell death. However, in tumor cells the system of telomere length maintenance is activated. Much work has been done regarding the complex telomere/telomerase as a unique target, highly specific in cancer cells. Telomeres have additional proteins that regulate the binding of telomerase. Telomerase, also associates with a number of proteins forming the sheltering complex having a central role in telomerase activity. This review focuses on the structure and function of the telomere/telomerase complex and its altered behavior leading to disease, mainly cancer. Although telomerase therapeutics are not approved yet for clinical use, we can assume that based on the promising in vitro and in vivo results and successful clinical trials, it can be predicted that telomerase therapeutics will be utilized soon in the combat against malignancies and degenerative diseases. The active search for modulators is justified, because the telomere/telomerase system is an extremely promising target offering possibilities to decrease or increase the viability of the cell for therapeutic purposes.},
}
@article {pmid22940768,
year = {2012},
author = {Prescott, J and Du, M and Wong, JY and Han, J and De Vivo, I},
title = {Paternal age at birth is associated with offspring leukocyte telomere length in the nurses' health study.},
journal = {Human reproduction (Oxford, England)},
volume = {27},
number = {12},
pages = {3622-3631},
pmid = {22940768},
issn = {1460-2350},
support = {CA139586/CA/NCI NIH HHS/United States ; CA065725/CA/NCI NIH HHS/United States ; CA87969/CA/NCI NIH HHS/United States ; HL088521/HL/NHLBI NIH HHS/United States ; CA49449/CA/NCI NIH HHS/United States ; CA133914/CA/NCI NIH HHS/United States ; ES01664/ES/NIEHS NIH HHS/United States ; CA132175/CA/NCI NIH HHS/United States ; CA132190/CA/NCI NIH HHS/United States ; CA140790/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Case-Control Studies ; Cohort Studies ; Female ; Humans ; Leukocytes/*physiology ; Male ; Menopause ; Middle Aged ; Parturition ; *Paternal Age ; *Social Class ; Telomere/*genetics ; },
abstract = {STUDY QUESTION: Is the association between paternal age at birth and offspring leukocyte telomere length (LTL) an artifact of early life socioeconomic status (SES)?<br><br>SUMMARY ANSWER: Indicators of early life SES did not alter the relationship between paternal age at birth and offspring LTL among a population of white female nurses.<br><br>WHAT IS KNOWN ALREADY: Telomere length is considered a highly heritable trait. Recent studies report a positive correlation between paternal age at birth and offspring LTL. Maternal age at birth has also been positively associated with offspring LTL, but may stem from the strong correlation with paternal age at birth.<br><br>The Nurses' Health Study (NHS) is an ongoing prospective cohort study of 121 700 female registered nurses who were enrolled in 1976. Great effort goes into maintaining a high degree of follow-up among our cohort participants (>95% of potential person-years). In 1989-1990, a subset of 32 826 women provided blood samples from which we selected participants for several nested case-control studies of telomere length and incident chronic disease. We used existing LTL data on a total of 4250 disease-free women who also reported maternal and paternal age at birth for this study.<br><br>Nested case-control studies of stroke, myocardial infarction, cancers of the breast, endometrium, skin, pancreas and colon, as well as colon adenoma, were conducted within the blood sub-cohort. Each study used the following study design: for each case of a disease diagnosed after blood collection, a risk-set sampling scheme was used to select from one to three controls from the remaining participants in the blood sub-cohort who were free of that disease when the case was diagnosed. Controls were matched to cases by age at blood collection (&#xb1; 1 year), date of blood collection (&#xb1; 3 months), menopausal status, recent postmenopausal hormone use at blood collection (within 3 months, except for the myocardial infarction case-control study), as well as other factors carefully chosen for each individual study. The current analysis was limited to healthy controls. We also included existing LTL data from a small random sample of women participating in a cognitive sub-study. LTL was measured using the quantitative PCR-based method. Exposure and covariate information are extracted from biennial questionnaires completed by the participants.<br><br>We found a strong association between paternal age at birth and participant LTL (P = 1.6 &#xd7; 10(-5)) that remained robust after controlling for indicators of early life SES. Maternal age at birth showed a weak inverse association with participant LTL after adjusting for age at blood collection and paternal age at birth (P = 0.01). We also noted a stronger association between paternal age at birth and participant LTL among premenopausal than among postmenopausal women (P(interaction) = 0.045). However, this observation may be due to chance as premenopausal women represented only 12.6% (N = 535) of the study population and LTL was not correlated with age at menopause, total or estrogen-only hormone therapy (HT) use suggesting that changes in in vivo estrogen exposure do not influence telomere length regulation.<br><br>The women in our study are not representative of the general US female population, with an underrepresentation of non-white and low social class groups. Although the interaction was not significant, we noted that the paternal age at birth association with offspring LTL appeared weaker among women whose parents did not own their home at the time of the participant's birth. As telomere dynamics may differ among individuals who are most socioeconomically deprived, SES indicators may have more of an influence on the relationship between paternal age at birth and offspring LTL in such populations.<br><br>As of yet, our and prior studies have not identified childhood or adult characteristics that confound the paternal age at birth association with offspring LTL, supporting the hypothesis that offspring may inherit the longer telomeres found in sperm of older men. The biological implications of the paternal age effect are unknown. A recent theory proposed that the inheritance of longer telomere from older men may be an adaptive signal of reproductive lifespan, while another theory links telomere length attrition to female reproductive senescence. However, we are unaware of any data to substantiate a relationship between paternal age at birth and daughter's fertility. Generalizability of our study results to other white female populations is supported by prior reports of paternal age at birth and offspring telomere length. Furthermore, a confounding relationship between paternal or maternal age at birth and SES was not observed in a study of SES and telomere length.<br><br>This work was supported by the National Institutes of Health (grants numbers: CA87969, CA49449, CA065725, CA132190, CA139586, HL088521, CA140790, CA133914, CA132175, ES01664 to M.D.); and by the American Health Association Foundation. We have no competing interests to declare.},
}
@article {pmid22937179,
year = {2012},
author = {Knecht, H and Kongruttanachok, N and Sawan, B and Brossard, J and Prévost, S and Turcotte, E and Lichtensztejn, Z and Lichtensztejn, D and Mai, S},
title = {Three-dimensional Telomere Signatures of Hodgkin- and Reed-Sternberg Cells at Diagnosis Identify Patients with Poor Response to Conventional Chemotherapy.},
journal = {Translational oncology},
volume = {5},
number = {4},
pages = {269-277},
pmid = {22937179},
issn = {1936-5233},
abstract = {In classic Hodgkin lymphoma (HL) the malignant mononuclear Hodgkin (H) and multinuclear Reed-Sternberg (RS) cells are characterized by a distinct three-dimensional nuclear telomere organization with shortening of the telomere length and the formation of telomeric aggregates. We asked if the severity of these telomere changes correlates with the clinical behavior of the disease. We retrospectively evaluated three-dimensional telomere organization by quantitative fluorescent in situ hybridization (Q-FISH) of diagnostic biopsies from 16 patients who were good responders and compared them with 16 diagnostic biopsies of 10 patients with refractory or relapsing HL (eight initial biopsies, four confirming progressions, and four confirming relapses). The H cells from patients with refractory/relapsing disease contained a significantly higher percentage of very small telomeres (P = .027) and telomere aggregates (P = .032) compared with H cells of patients entering rapid remission. These differences were even more significant (P = .002 and P = .013, respectively) when comparing the eight initial diagnostic biopsies of refractory/relapsing HL with diagnostic biopsies of eight patients with ongoing long-lasting remission (mean of 47 months). This specific three-dimensional telomere Q-FISH signature identifies these highly aggressive mononuclear H cells at the first diagnostic biopsy and thus may offer a new molecular marker to optimize initial treatment.},
}
@article {pmid22934675,
year = {2013},
author = {Xu, L and Li, S and Stohr, BA},
title = {The role of telomere biology in cancer.},
journal = {Annual review of pathology},
volume = {8},
number = {},
pages = {49-78},
doi = {10.1146/annurev-pathol-020712-164030},
pmid = {22934675},
issn = {1553-4014},
support = {K08 CA134552/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Transformation, Neoplastic/*genetics/metabolism/pathology ; Humans ; Neoplasms/enzymology/*genetics/pathology ; Telomerase/genetics/metabolism ; Telomere/genetics/metabolism/*physiology ; Telomere Homeostasis ; },
abstract = {Telomere biology plays a critical and complex role in the initiation and progression of cancer. Although telomere dysfunction resulting from replicative attrition constrains tumor growth by engaging DNA-damage signaling pathways, it can also promote tumorigenesis by causing oncogenic chromosomal rearrangements. Expression of the telomerase enzyme enables telomere-length homeostasis and allows tumor cells to escape the antiproliferative barrier posed by short telomeres. Telomeres and telomerase also function independently of one another. Recent work has suggested that telomerase promotes cell growth through pathways unrelated to telomere maintenance, and a subset of tumors elongate telomeres through telomerase-independent mechanisms. In an effort to exploit the integral link between telomere biology and cancer growth, investigators have developed several telomerase-based therapeutic strategies, which are currently in clinical trials. Here, we broadly review the state of the field with a particular focus on recent developments of interest.},
}
@article {pmid22928904,
year = {2013},
author = {Thilagavathi, J and Venkatesh, S and Dada, R},
title = {Telomere length in reproduction.},
journal = {Andrologia},
volume = {45},
number = {5},
pages = {289-304},
doi = {10.1111/and.12008},
pmid = {22928904},
issn = {1439-0272},
mesh = {Female ; Humans ; Male ; Reproduction/genetics/physiology ; Spermatogenesis/genetics ; Spermatozoa/physiology ; TATA Box Binding Protein-Like Proteins ; Telomere/*physiology/ultrastructure ; },
abstract = {Telomeres, noncoding hexameric tandem repeats located at the ends of chromosomes, maintain chromosome stability and genome integrity. These guanine-rich repeats are highly conserved during evolution, and their role is dependent on their length and structure. They have multiple functions, including regulating the reproductive lifespan by mediating synapsis and homologous recombination of the chromosomes. Short telomeres result in meiotic arrest, segregation abnormalities and dysjunction, which lead to an increased incidence of aneuploid germ cells. In addition, shortened telomeres in men result in apoptosis of germ cells, whereas, in women, they result in meiotic arrest. In somatic cells, telomere shortening occurs at each consecutive round of replication, which induces senescence in vitro and in vivo. However there is a 2-fold elongation of telomeres during spermatogenesis. Spermatozoa, are terminally differentiated cells, have longer telomeres than spermatogonia and pachytene spermatocytes. In addition to genetic factors, lifestyle factors and psychological stress also play crucial role in modulating telomere length. Because not much is known about its role in reproduction, we focused this review on the function, structure and length dynamics of the telomere in the reproductive process.},
}
@article {pmid22928601,
year = {2013},
author = {Nguyen, DN and Heaphy, CM and de Wilde, RF and Orr, BA and Odia, Y and Eberhart, CG and Meeker, AK and Rodriguez, FJ},
title = {Molecular and morphologic correlates of the alternative lengthening of telomeres phenotype in high-grade astrocytomas.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {23},
number = {3},
pages = {237-243},
pmid = {22928601},
issn = {1750-3639},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing/metabolism ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Astrocytoma/*pathology/ultrastructure ; Brain Neoplasms/*pathology/ultrastructure ; Child ; Child, Preschool ; Co-Repressor Proteins ; DNA Helicases/metabolism ; Female ; Follow-Up Studies ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Infant ; Kaplan-Meier Estimate ; Male ; Microarray Analysis ; Middle Aged ; Molecular Chaperones ; Nuclear Proteins/metabolism ; Phenotype ; Survival Analysis ; Telomere/*pathology/ultrastructure ; X-linked Nuclear Protein ; Young Adult ; },
abstract = {Recent studies suggest that the telomere maintenance mechanism known as alternative lengthening of telomeres (ALT) is relatively more common in specific glioma subsets and strongly associated with ATRX mutations. We retrospectively examined 116 high-grade astrocytomas (32 pediatric glioblastomas, 65 adult glioblastomas, 19 anaplastic astrocytomas) with known ALT status using tissue microarrays to identify associations with molecular and phenotypic features. Immunohistochemistry was performed using antibodies against ATRX, DAXX, p53 and IDH1(R132H) mutant protein. EGFR amplification was evaluated by fluorescence in situ hybridization (FISH). Almost half of fibrillary and gemistocytic astrocytomas (44%) demonstrated ALT. Conversely all gliosarcomas (n = 4), epithelioid (n = 2), giant cell (n = 2) and adult small cell astrocytomas (n = 7) were ALT negative. The ALT phenotype was positively correlated with the presence of round cells (P = 0.002), microcysts (P < 0.0002), IDH1 mutant protein (P < 0.0001), ATRX protein loss (P < 0.0001), strong P53 immunostaining (P < 0.0001) and absence of EGFR amplification (P = 0.004). There was no significant correlation with DAXX expression. We conclude that ALT represents a specific phenotype in high-grade astrocytomas with distinctive pathologic and molecular features. Future studies are required to clarify the clinical and biological significance of ALT in high-grade astrocytomas.},
}
@article {pmid22925423,
year = {2012},
author = {Yong, JW and Yeo, X and Khan, MM and Lee, MB and Hande, MP},
title = {Stable expression of promyelocytic leukaemia (PML) protein in telomerase positive MCF7 cells results in alternative lengthening of telomeres phenotype.},
journal = {Genome integrity},
volume = {3},
number = {1},
pages = {5},
pmid = {22925423},
issn = {2041-9414},
abstract = {BACKGROUND: Cancer cells can employ telomerase or the alternative lengthening of telomeres (ALT) pathway for telomere maintenance. Cancer cells that use the ALT pathway exhibit distinct phenotypes such as heterogeneous telomeres and specialised Promyelocytic leukaemia (PML) nuclear foci called APBs. In our study, we used wild-type PML and a PML mutant, in which the coiled-coil domain is deleted (PML C/C-), to investigate how these proteins can affect telomere maintenance pathways in cancer cells that use either the telomerase or ALT pathway.<br><br>RESULTS: Stable over-expression of both types of PML does not affect the telomere maintenance in the ALT cells. We report novel observations in PML over-expressed telomerase-positive MCF7 cells: 1) APBs are detected in telomerase-positive MCF7 cells following over-expression of wild-type PML and 2) rapid telomere elongation is observed in MCF7 cells that stably express either wild-type PML or PML C/C-. We also show that the telomerase activity in MCF7 cells can be affected depending on the type of PML protein over-expressed.<br><br>CONCLUSION: Our data suggests that APBs might not be essential for the ALT pathway as MCF7 cells that do not contain APBs exhibit long telomeres. We propose that wild-type PML can either definitively dominate over telomerase or enhance the activity of telomerase, and PML C/C- can allow for the co-existence of both telomerase and ALT pathways. Our findings add another dimension in the study of telomere maintenance as the expression of PML alone (wild-type or otherwise) is able to change the dynamics of the telomerase pathway.},
}
@article {pmid22923525,
year = {2013},
author = {Lau, LM and Dagg, RA and Henson, JD and Au, AY and Royds, JA and Reddel, RR},
title = {Detection of alternative lengthening of telomeres by telomere quantitative PCR.},
journal = {Nucleic acids research},
volume = {41},
number = {2},
pages = {e34},
pmid = {22923525},
issn = {1362-4962},
mesh = {Cell Line, Tumor ; DNA, Neoplasm/analysis ; Humans ; Neoplasms/*genetics ; Oligonucleotide Probes ; Polymerase Chain Reaction/*methods ; Telomere/chemistry ; *Telomere Homeostasis ; },
abstract = {Alternative lengthening of telomeres (ALT) is one of the two known telomere length maintenance mechanisms that are essential for the unlimited proliferation potential of cancer cells. Existing methods for detecting ALT in tumors require substantial amounts of tumor material and are labor intensive, making it difficult to study prevalence and prognostic significance of ALT in large tumor cohorts. Here, we present a novel strategy utilizing telomere quantitative PCR to diagnose ALT. The protocol is more rapid than conventional methods and scrutinizes two distinct characteristics of ALT cells concurrently: long telomeres and the presence of C-circles (partially double-stranded circles of telomeric C-strand DNA). Requiring only 30 ng of genomic DNA, this protocol will facilitate large-scale studies of ALT in tumors and can be readily adopted by clinical laboratories.},
}
@article {pmid22923044,
year = {2012},
author = {Anderson, MZ and Baller, JA and Dulmage, K and Wigen, L and Berman, J},
title = {The three clades of the telomere-associated TLO gene family of Candida albicans have different splicing, localization, and expression features.},
journal = {Eukaryotic cell},
volume = {11},
number = {10},
pages = {1268-1275},
pmid = {22923044},
issn = {1535-9786},
support = {R01 AI075096/AI/NIAID NIH HHS/United States ; AI075096-03S1/AI/NIAID NIH HHS/United States ; },
mesh = {Candida albicans/*genetics/metabolism ; Cell Nucleus/metabolism ; Fungal Proteins/*genetics/metabolism ; Introns ; Mediator Complex/genetics/metabolism ; Mitochondria/metabolism ; *Multigene Family ; Phylogeny ; Protein Subunits/genetics/metabolism ; RNA Splicing ; Telomere-Binding Proteins/*genetics/metabolism ; Transcription, Genetic ; },
abstract = {Candida albicans grows within a wide range of host niches, and this adaptability enhances its success as a commensal and as a pathogen. The telomere-associated TLO gene family underwent a recent expansion from one or two copies in other CUG clade members to 14 expressed copies in C. albicans. This correlates with increased virulence and clinical prevalence relative to those of other Candida clade species. The 14 expressed TLO gene family members have a conserved Med2 domain at the N terminus, suggesting a role in general transcription. The C-terminal half is more divergent, distinguishing three clades: clade α and clade β have no introns and encode proteins that localize primarily to the nucleus; clade γ sometimes undergoes splicing, and the gene products localize within the mitochondria as well as the nuclei. Additionally, TLOα genes are generally expressed at much higher levels than are TLOγ genes. We propose that expansion of the TLO gene family and the predicted role of Tlo proteins in transcription regulation provide C. albicans with the ability to adapt rapidly to the broad range of different environmental niches within the human host.},
}
@article {pmid22922742,
year = {2012},
author = {Arnoult, N and Van Beneden, A and Decottignies, A},
title = {Telomere length regulates TERRA levels through increased trimethylation of telomeric H3K9 and HP1α.},
journal = {Nature structural &amp; molecular biology},
volume = {19},
number = {9},
pages = {948-956},
pmid = {22922742},
issn = {1545-9985},
mesh = {Base Sequence ; Cell Line, Tumor ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/*metabolism ; Down-Regulation ; *Gene Silencing ; Histones/*metabolism ; Humans ; Methylation ; Methyltransferases/metabolism ; RNA, Untranslated/chemistry/*genetics/metabolism ; Repressor Proteins/metabolism ; Telomere/chemistry/genetics/*metabolism ; },
abstract = {Gene silencing by the repressive telomeric chromatin environment, referred to as telomere position effect (TPE), has been well characterized in yeast and depends on telomere length. However, proof of its existence at native human chromosome ends has remained elusive, mainly owing to the paucity of genes near telomeres. The discovery of TERRAs, the telomeric noncoding RNAs transcribed from subtelomeric promoters, paved the way to probing for telomere-length impact on physiological TPE. Using cell lines of various origins, we show that telomere elongation consistently represses TERRA expression. Repression is mediated by increased trimethylated H3K9 density at telomeres and by heterochromatin protein HP1α, with no detectable spreading of the marks beyond the telomeric tract, restricting human TPE to telomere transcription. Our data further support the existence of a negative-feedback mechanism in which longer TERRA molecules repress their own transcription upon telomere elongation.},
}
@article {pmid22917110,
year = {2012},
author = {Li, H and Engström, K and Vahter, M and Broberg, K},
title = {Arsenic exposure through drinking water is associated with longer telomeres in peripheral blood.},
journal = {Chemical research in toxicology},
volume = {25},
number = {11},
pages = {2333-2339},
pmid = {22917110},
issn = {1520-5010},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Arsenic/*adverse effects/metabolism/urine ; Blood Cells/*drug effects/metabolism ; Child ; Drinking Water/*chemistry ; *Environmental Exposure ; Female ; Gene Expression Profiling ; Genotype ; Humans ; Middle Aged ; Telomerase/genetics/metabolism ; Telomere/*drug effects/genetics ; Young Adult ; },
abstract = {Inorganic arsenic is a strong carcinogen, possibly by interaction with the telomere length. The aim of the study was to evaluate how chronic arsenic exposure from drinking water as well as the arsenic metabolism efficiency affect the individual telomere length and the expression of telomere-related genes. Two hundred two women with a wide range in exposure to arsenic via drinking water (3.5-200 μg/L) were recruited. Concentrations of arsenic metabolites in urine [inorganic arsenic (iAs), methylarsonic acid (MMA), and dimethylarsinic acid (DMA)] were measured. The relative telomere length in blood was measured by quantitative real-time polymerase chain reaction. Genotyping (N = 172) for eight SNPs in AS3MT and gene expression of telomere-related genes (in blood; N = 90) were performed. Urinary arsenic (sum of metabolites) was positively associated with telomere length (β = 0.65 × 10(-4), 95% CI = 0.031 × 10(-4)-1.3 × 10(-4), adjusted for age and BMI). Individuals with above median fractions of iAs and MMA showed significantly longer telomeres by increasing urinary arsenic (β = 1.0 × 10(-4), 95% CI = 0.21 × 10(-4)-1.8 × 10(-4) at high % iAs; β = 0.88 × 10(-4) 95% CI = 0.12 × 10(-4)-1.6 × 10(-4) at high % MMA) than those below the median (p = 0.80 and 0.44, respectively). Similarly, carriers of the slow and more toxic metabolizing AS3MT haplotype showed stronger positive associations between arsenic exposure and telomere length, as compared to noncarriers (interaction urinary arsenic and haplotype p = 0.025). Urinary arsenic was positively correlated with the expression of telomerase reverse transcriptase (TERT, Spearman r = 0.22, p = 0.037), but no association was found between TERT expression and telomere length. Arsenic in drinking water influences the telomere length, and this may be a mechanism for its carcinogenicity. A faster and less toxic arsenic metabolism diminishes arsenic-related telomere elongation.},
}
@article {pmid22916246,
year = {2012},
author = {Maeda, J and Yurkon, CR and Fujisawa, H and Kaneko, M and Genet, SC and Roybal, EJ and Rota, GW and Saffer, ER and Rose, BJ and Hanneman, WH and Thamm, DH and Kato, TA},
title = {Genomic instability and telomere fusion of canine osteosarcoma cells.},
journal = {PloS one},
volume = {7},
number = {8},
pages = {e43355},
pmid = {22916246},
issn = {1932-6203},
mesh = {Animals ; Chromosomes/metabolism ; Dogs ; Genomic Instability/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Osteosarcoma/*genetics ; Telomere/*genetics ; },
abstract = {Canine osteosarcoma (OSA) is known to present with highly variable and chaotic karyotypes, including hypodiploidy, hyperdiploidy, and increased numbers of metacentric chromosomes. The spectrum of genomic instabilities in canine OSA has significantly augmented the difficulty in clearly defining the biological and clinical significance of the observed cytogenetic abnormalities. In this study, eight canine OSA cell lines were used to investigate telomere fusions by fluorescence in situ hybridization (FISH) using a peptide nucleotide acid probe. We characterized each cell line by classical cytogenetic studies and cellular phenotypes including telomere associated factors and then evaluated correlations from this data. All eight canine OSA cell lines displayed increased abnormal metacentric chromosomes and exhibited numerous telomere fusions and interstitial telomeric signals. Also, as evidence of unstable telomeres, colocalization of γ-H2AX and telomere signals in interphase cells was observed. Each cell line was characterized by a combination of data representing cellular doubling time, DNA content, chromosome number, metacentric chromosome frequency, telomere signal level, cellular radiosensitivity, and DNA-PKcs protein expression level. We have also studied primary cultures from 10 spontaneous canine OSAs. Based on the observation of telomere aberrations in those primary cell cultures, we are reasonably certain that our observations in cell lines are not an artifact of prolonged culture. A correlation between telomere fusions and the other characteristics analyzed in our study could not be identified. However, it is important to note that all of the canine OSA samples exhibiting telomere fusion utilized in our study were telomerase positive. Pending further research regarding telomerase negative canine OSA cell lines, our findings may suggest telomere fusions can potentially serve as a novel marker for canine OSA.},
}
@article {pmid22915504,
year = {2012},
author = {Cottage, CT and Neidig, L and Sundararaman, B and Din, S and Joyo, AY and Bailey, B and Gude, N and Hariharan, N and Sussman, MA},
title = {Increased mitotic rate coincident with transient telomere lengthening resulting from pim-1 overexpression in cardiac progenitor cells.},
journal = {Stem cells (Dayton, Ohio)},
volume = {30},
number = {11},
pages = {2512-2522},
pmid = {22915504},
issn = {1549-4918},
support = {RC1 HL100891/HL/NHLBI NIH HHS/United States ; R01 HL105759/HL/NHLBI NIH HHS/United States ; R37 HL091102/HL/NHLBI NIH HHS/United States ; R21 HL102714/HL/NHLBI NIH HHS/United States ; R01 HL067245/HL/NHLBI NIH HHS/United States ; P01 HL085577/HL/NHLBI NIH HHS/United States ; R21 HL104544/HL/NHLBI NIH HHS/United States ; R01 HL113656/HL/NHLBI NIH HHS/United States ; R21 HL102613/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Cardiotoxins/pharmacology ; Cell Proliferation ; Cell Survival ; Cells, Cultured ; Doxorubicin/pharmacology ; Enzyme Activation ; Gene Expression ; Green Fluorescent Proteins/biosynthesis/genetics ; Mice ; *Mitosis ; Myocardium/*cytology ; Phosphorylation ; Protein Binding ; Protein Interaction Mapping ; Protein Processing, Post-Translational ; Proto-Oncogene Proteins c-myc/antagonists &amp; inhibitors/metabolism ; Proto-Oncogene Proteins c-pim-1/genetics/*metabolism ; Regenerative Medicine ; Stem Cells/enzymology/metabolism/*physiology ; Telomerase/metabolism ; *Telomere Homeostasis/drug effects ; Thiazoles/pharmacology ; },
abstract = {Cardiac regeneration following myocardial infarction rests with the potential of c-kit+ cardiac progenitor cells (CPCs) to repopulate damaged myocardium. The ability of CPCs to reconstitute the heart is restricted by patient age and disease progression. Increasing CPC proliferation, telomere length, and survival will improve the ability of autologous CPCs to be successful in myocardial regeneration. Prior studies have demonstrated enhancement of myocardial regeneration by engineering CPCs to express Pim-1 kinase, but cellular and molecular mechanisms for Pim-1-mediated effects on CPCs remain obscure. We find CPCs rapidly expand following overexpression of cardioprotective kinase Pim-1 (CPCeP), however, increases in mitotic rate are short-lived as late passage CPCePs proliferate similar to control CPCs. Telomere elongation consistent with a young phenotype is observed following Pim-1 modification of CPCeP; in addition, telomere elongation coincides with increased telomerase expression and activity. Interestingly, telomere length and telomerase activity normalize after several rounds of passaging, consistent with the ability of Pim-1 to transiently increase mitosis without resultant oncogenic transformation. Accelerating mitosis in CPCeP without immortalization represents a novel strategy to expand the CPC population in order to improve their therapeutic efficacy.},
}
@article {pmid22911335,
year = {2012},
author = {Cui, Y and Cai, Q and Qu, S and Chow, WH and Wen, W and Xiang, YB and Wu, J and Rothman, N and Yang, G and Shu, XO and Gao, YT and Zheng, W},
title = {Association of leukocyte telomere length with colorectal cancer risk: nested case-control findings from the Shanghai Women's Health Study.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {21},
number = {10},
pages = {1807-1813},
pmid = {22911335},
issn = {1538-7755},
support = {P30 CA068485/CA/NCI NIH HHS/United States ; R37 CA070867/CA/NCI NIH HHS/United States ; R37 CA 070867/CA/NCI NIH HHS/United States ; P30 CA68485/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Case-Control Studies ; China ; Colorectal Neoplasms/etiology/*genetics ; Female ; Humans ; Leukocytes/*ultrastructure ; Middle Aged ; Prospective Studies ; Risk ; *Telomere ; *Women's Health ; },
abstract = {BACKGROUND: Telomeres are specialized chromatin structures essential for maintenance of chromosomal integrity and stability. Abnormal alteration of telomere length has been linked to several cancers; however, epidemiologic evidence about the association of telomere length with colorectal cancer risk has been conflicting.<br><br>METHODS: We conducted a nested case-control study to evaluate the association between telomere length and colorectal cancer risk using peripheral blood samples collected before cancer diagnosis. The study included 441 women with incident colorectal cancer and 549 matched controls. Monochrome multiplex quantitative PCR was applied to measure relative telomere length. Multiple logistic regressions were used to derive adjusted OR with 95% confidence intervals (CI) as the measure of association between telomere length and subsequent colorectal cancer risk.<br><br>RESULTS: A U-shaped association was observed between telomere length and colorectal cancer risk (test for nonlinearity P = 0.0112). Women with telomere length in the third quintile (40th-60th percentiles) had the lowest risk of colorectal cancer, and the risks were elevated with a shorter or longer telomere length. This U-shaped association did not statistically differ for colon cancer and rectum cancer.<br><br>CONCLUSIONS AND IMPACT: Our prospective study revealed a U-shaped association between telomere length in peripheral blood cells and colorectal cancer risk. Our findings provide strong evidence that both very short and very long telomeres are associated with increased risk of colorectal cancer.},
}
@article {pmid22904069,
year = {2012},
author = {Batenburg, NL and Mitchell, TR and Leach, DM and Rainbow, AJ and Zhu, XD},
title = {Cockayne Syndrome group B protein interacts with TRF2 and regulates telomere length and stability.},
journal = {Nucleic acids research},
volume = {40},
number = {19},
pages = {9661-9674},
pmid = {22904069},
issn = {1362-4962},
mesh = {Cell Line ; Cockayne Syndrome/*genetics ; DNA Helicases/analysis/genetics/*metabolism ; DNA Repair Enzymes/analysis/genetics/*metabolism ; Humans ; Mutation ; Poly-ADP-Ribose Binding Proteins ; RNA, Long Noncoding/metabolism ; Telomerase/metabolism ; Telomere/chemistry ; *Telomere Homeostasis ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {The majority of Cockayne syndrome (CS) patients carry a mutation in Cockayne Syndrome group B (CSB), a large nuclear protein implicated in DNA repair, transcription and chromatin remodeling. However, whether CSB may play a role in telomere metabolism has not yet been characterized. Here, we report that CSB physically interacts with TRF2, a duplex telomeric DNA binding protein essential for telomere protection. We find that CSB localizes at a small subset of human telomeres and that it is required for preventing the formation of telomere dysfunction-induced foci (TIF) in CS cells. We find that CS cells or CSB knockdown cells accumulate telomere doublets, the suppression of which requires CSB. We find that overexpression of CSB in CS cells promotes telomerase-dependent telomere lengthening, a phenotype that is associated with a decrease in the amount of telomere-bound TRF1, a negative mediator of telomere length maintenance. Furthermore, we show that CS cells or CSB knockdown cells exhibit misregulation of TERRA, a large non-coding telomere repeat-containing RNA important for telomere maintenance. Taken together, these results suggest that CSB is required for maintaining the homeostatic level of TERRA, telomere length and integrity. These results further imply that CS patients carrying CSB mutations may be defective in telomere maintenance.},
}
@article {pmid22902537,
year = {2012},
author = {Lee-Soety, JY and Jones, J and MacGibeny, MA and Remaly, EC and Daniels, L and Ito, A and Jean, J and Radecki, H and Spencer, S},
title = {Yeast hnRNP-related proteins contribute to the maintenance of telomeres.},
journal = {Biochemical and biophysical research communications},
volume = {426},
number = {1},
pages = {12-17},
pmid = {22902537},
issn = {1090-2104},
support = {R15 AG035257/AG/NIA NIH HHS/United States ; },
mesh = {Cellular Senescence/genetics ; DNA/metabolism ; DNA, Single-Stranded/metabolism ; Heterogeneous Nuclear Ribonucleoprotein A1 ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B ; Heterogeneous-Nuclear Ribonucleoproteins/genetics/*metabolism ; Humans ; Nuclear Cap-Binding Protein Complex/genetics/*metabolism ; Nuclear Proteins/genetics/*metabolism ; RNA-Binding Proteins/genetics/*metabolism ; Saccharomyces cerevisiae/genetics/metabolism/*physiology ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/*physiology ; *Telomere Homeostasis ; },
abstract = {Telomeres protect the ends of linear chromosomes, which if eroded to a critical length can become uncapped and lead to replicative senescence. Telomerase maintains telomere length in some cells, but inappropriate expression facilitates the immortality of cancer cells. Recently, proteins involved in RNA processing and ribosome assembly, such as hnRNP (heterogeneous nuclear ribonucleoprotein) A1, have been found to participate in telomere maintenance in mammals. The Saccharomyces cerevisiae protein Npl3 shares significant amino acid sequence similarities with hnRNP A1. We found that deleting NPL3 accelerated the senescence of telomerase null cells. The highly conserved RNA recognition motifs (RRM) in Npl3 appear to be important for preventing faster senescence. Npl3 preferentially binds telomere sequences in vitro, suggesting that Npl3 may affect telomeres directly. Despite similarities between the two proteins, human hnRNP A1 is unable to complement the lack of Npl3 to rescue accelerated senescence in tlc1 npl3 cells. Deletion of CBC2, which encodes another hnRNP-related protein that associates with Npl3, also accelerates senescence. Potential mechanisms by which hnRNP-related proteins maintain telomeres are discussed.},
}
@article {pmid22901253,
year = {2012},
author = {Tümpel, S and Rudolph, KL},
title = {The role of telomere shortening in somatic stem cells and tissue aging: lessons from telomerase model systems.},
journal = {Annals of the New York Academy of Sciences},
volume = {1266},
number = {},
pages = {28-39},
doi = {10.1111/j.1749-6632.2012.06547.x},
pmid = {22901253},
issn = {1749-6632},
mesh = {Animals ; Cell Cycle Checkpoints ; Cellular Senescence/genetics/physiology ; Humans ; Mice ; Models, Genetic ; Phenotype ; Stem Cell Niche ; Stem Cells/*metabolism ; Telomere Shortening/*genetics ; },
abstract = {The analysis of model systems has broadened our understanding of telomere-related aging processes. Telomerase-deficient mouse models have demonstrated that telomere dysfunction impairs tissue renewal capacity and shortens lifespan. Telomere shortening limits cell proliferation by activating checkpoints that induce replicative senescence or apoptosis. These checkpoints protect against an accumulation of genomically instable cells and cancer initiation. However, the induction of these checkpoints can also limit organ homeostasis, regeneration, and survival during aging and in the context of diseases. The decline in tissue regeneration in response to telomere shortening has been related to impairments in stem cell function. Telomere dysfunction impairs stem cell function by activation of cell-intrinsic checkpoints and by the induction of alterations in the micro- and macro-environment of stem cells. In this review, we discuss the current knowledge about the impact of telomere shortening on disease stages induced by replicative cell aging as indicated by studies on telomerase model systems.},
}
@article {pmid22901085,
year = {2012},
author = {Voillemot, M and Hine, K and Zahn, S and Criscuolo, F and Gustafsson, L and Doligez, B and Bize, P},
title = {Effects of brood size manipulation and common origin on phenotype and telomere length in nestling collared flycatchers.},
journal = {BMC ecology},
volume = {12},
number = {},
pages = {17},
pmid = {22901085},
issn = {1472-6785},
mesh = {Animals ; Body Size ; *Clutch Size ; Female ; Linear Models ; Male ; *Phenotype ; Songbirds/*genetics ; Telomere/*genetics ; },
abstract = {BACKGROUND: Evidence is accumulating that telomere length is a good predictor of life expectancy, especially early in life, thus calling for determining the factors that affect telomere length at this stage. Here, we investigated the relative influence of early growth conditions and origin (genetics and early maternal effects) on telomere length of collared flycatchers (Ficedula albicollis) at fledging. We experimentally transferred hatchlings among brood triplets to create reduced, control (i.e. unchanged final nestling number) and enlarged broods.<br><br>RESULTS: Although our treatment significantly affected body mass at fledging, we found no evidence that increased sibling competition affected nestling tarsus length and telomere length. However, mixed models showed that brood triplets explained a significant part of the variance in body mass (18%) and telomere length (19%), but not tarsus length (13%), emphasizing that unmanipulated early environmental factors influenced telomere length. These models also revealed low, but significant, heritability of telomere length (h(2) = 0.09). For comparison, the heritability of nestling body mass and tarsus length was 0.36 and 0.39, respectively, which was in the range of previously published estimates for those two traits in this species.<br><br>CONCLUSION: Those findings in a wild bird population demonstrate that telomere length at the end of the growth period is weakly, but significantly, determined by genetic and/or maternal factors taking place before hatching. However, we found no evidence that the brood size manipulation experiment, and by extension the early growth conditions, influenced nestling telomere length. The weak heritability of telomere length suggests a close association with fitness in natural populations.},
}
@article {pmid22899577,
year = {2013},
author = {Walne, AJ and Bhagat, T and Kirwan, M and Gitiaux, C and Desguerre, I and Leonard, N and Nogales, E and Vulliamy, T and Dokal, IS},
title = {Mutations in the telomere capping complex in bone marrow failure and related syndromes.},
journal = {Haematologica},
volume = {98},
number = {3},
pages = {334-338},
pmid = {22899577},
issn = {1592-8721},
support = {/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Anemia, Aplastic ; Bone Marrow Diseases ; Bone Marrow Failure Disorders ; Dyskeratosis Congenita/diagnosis/*genetics ; Female ; Hemoglobinuria, Paroxysmal/diagnosis/*genetics ; Heterozygote ; Humans ; Male ; *Mutation ; Pedigree ; Registries ; Telomere/metabolism ; Telomere Shortening ; Telomere-Binding Proteins/*genetics ; },
abstract = {Dyskeratosis congenita and its variants have overlapping phenotypes with many disorders including Coats plus, and their underlying pathology is thought to be one of defective telomere maintenance. Recently, biallelic CTC1 mutations have been described in patients with syndromes overlapping Coats plus. CTC1, STN1 and TEN1 are part of the telomere-capping complex involved in maintaining telomeric structural integrity. Based on phenotypic overlap we screened 73 genetically uncharacterized patients with dyskeratosis congenita and related bone marrow failure syndromes for mutations in this complex. Biallelic CTC1 mutations were identified in 6 patients but none in either STN1 or TEN1. We have expanded the phenotypic spectrum associated with CTC1 mutations and report that intracranial and retinal abnormalities are not a defining feature, as well as showing that the effect of these mutations on telomere length is variable. The study also demonstrates the lack of disease-causing mutations in other components of the telomere-capping complex.},
}
@article {pmid22898896,
year = {2012},
author = {Lipinski, D and Zeyland, J and Szalata, M and Plawski, A and Jarmuz, M and Jura, J and Korcz, A and Smorag, Z and Pienkowski, M and Slomski, R},
title = {Expression of human growth hormone in the milk of transgenic rabbits with transgene mapped to the telomere region of chromosome 7q.},
journal = {Journal of applied genetics},
volume = {53},
number = {4},
pages = {435-442},
pmid = {22898896},
issn = {2190-3883},
mesh = {Animals ; Animals, Genetically Modified/genetics/*metabolism ; Chromosome Mapping/*methods ; Chromosomes, Mammalian ; Female ; Gene Expression Regulation ; Human Growth Hormone/*biosynthesis/genetics ; Humans ; Immunoradiometric Assay ; In Situ Hybridization, Fluorescence ; Male ; Mammary Glands, Animal/chemistry ; Milk/*chemistry ; Milk Proteins/genetics ; Promoter Regions, Genetic ; Rabbits ; Rats ; Telomere/*genetics ; *Transgenes ; },
abstract = {The advent of transgenic technology has provided methods for the production of pharmaceuticals by the isolation of these proteins from transgenic animals. The mammary gland has been focused on as a bioreactor, since milk is easily collected from lactating animals and protein production can be expressed at very high levels, including hormones and enzymes. We demonstrate here the expression pattern of recombinant human growth hormone (rhGH) in transgenic rabbits carrying hGH genomic sequences driven by the rat whey acidic protein (WAP) promoter. The transgene was mapped to the q26-27 telomere region of chromosome 7q by fluorescence in situ hybridization (FISH). Nearly 30 % of the F1 generation demonstrated the presence of transgene. The recombinant growth hormone was detected in the milk of the transgenic rabbit females, but not in serum, up to the level of 10 μg/ml. Ectopic expression of the transgene in the brain, heart, kidney, liver, and salivary gland was not observed, indicating that a short sequence of rat WAP promoter (969 bp) contained essential sequences directing expression exclusively to the mammary gland. The biological activity of recombinant growth hormone was measured by immunoreactivity and the capability to stimulate growth of the hormone-dependent Nb211 cell line.},
}
@article {pmid22895432,
year = {2012},
author = {David, R},
title = {Telomeres: Preventing unauthorized entry.},
journal = {Nature reviews. Molecular cell biology},
volume = {13},
number = {9},
pages = {538},
pmid = {22895432},
issn = {1471-0080},
}
@article {pmid22893980,
year = {2012},
author = {Holliday, R},
title = {Telomeres and telomerase: the commitment theory of cellular ageing revisited.},
journal = {Science progress},
volume = {95},
number = {Pt 2},
pages = {199-205},
pmid = {22893980},
issn = {0036-8504},
mesh = {Animals ; Cell Enlargement ; Cell Proliferation ; Cellular Senescence/*physiology ; Fibroblasts/cytology/*physiology ; Humans ; *Models, Biological ; Models, Statistical ; Telomerase/*metabolism ; Telomere/*physiology ; },
abstract = {It is not always realised that separate fibroblast populations of the same strain have very different lifespans, that is, over a million-fold range. This is best documented for human strains WI-38 and MRC-5. There is evidence that it is the molecular clock of telomere shortening which determines the growth potential of these cells. However, if a clock is set and runs its course one would expect parallel cultures to have similar lifespans. The commitment theory of fibroblast ageing proposes that commitment occurs during early cell divisions with a given probability and after that there is then a constant number of divisions until growth ceases. This constant number could be determined by the gradual loss of telomeres. The stochastic feature of the theory is the probability of the loss of the last uncommitted cells or the youngest committed cells. These cells have the longest lifespan and will give rise to the final population.},
}
@article {pmid22893708,
year = {2012},
author = {Sexton, AN and Youmans, DT and Collins, K},
title = {Specificity requirements for human telomere protein interaction with telomerase holoenzyme.},
journal = {The Journal of biological chemistry},
volume = {287},
number = {41},
pages = {34455-34464},
pmid = {22893708},
issn = {1083-351X},
support = {R01 HL079585/HL/NHLBI NIH HHS/United States ; R01HL079585/HL/NHLBI NIH HHS/United States ; },
mesh = {Cell Line ; Holoenzymes/genetics/metabolism ; Humans ; Protein Binding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; *Repetitive Sequences, Nucleic Acid ; Shelterin Complex ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Human telomeres are maintained by the enzyme telomerase, which uses a template within its integral RNA subunit (hTR) and telomerase reverse transcriptase protein (TERT) to accomplish the synthesis of single-stranded DNA repeats. Many questions remain unresolved about the cellular regulation of telomerase subunits and the fully assembled telomerase holoenzyme, including the basis for the specificity of binding and acting on telomeres. Previous studies have revealed that the telomere protein TPP1 is necessary for stable TERT and hTR association with telomeres in vivo. Here, we expand the biochemical characterization and understanding of TPP1 interaction with TERT and the catalytically active telomerase holoenzyme. Using extracts from human cells, we show that TPP1 interacts sequence-specifically with TERT when TERT is assembled into holoenzyme context. In holoenzyme context, the TERT N-terminal domain mediates a TPP1 interaction. Assays of stable subunit complexes purified after their cellular assembly suggest that other telomere proteins do not necessarily influence TPP1 association with telomerase holoenzyme or alter its impact on elongation processivity. We show that a domain of recombinant TPP1 comprised of an oligonucleotide/oligosaccharide binding fold recapitulates the full-length protein interaction specificity for the TERT N-terminal domain assembled into telomerase holoenzyme. By global analysis of TPP1 side chain requirements for holoenzyme association, we demonstrate a selective requirement for the amino acids in one surface-exposed protein loop. Our results reveal the biochemical determinants of a sequence-specific TPP1-TERT interaction in human cells, with implications for the mechanisms of TPP1 function in recruiting telomerase subunits to telomeres and in promoting telomere elongation.},
}
@article {pmid22891313,
year = {2012},
author = {Tanaka, H and Abe, S and Huda, N and Tu, L and Beam, MJ and Grimes, B and Gilley, D},
title = {Telomere fusions in early human breast carcinoma.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {109},
number = {35},
pages = {14098-14103},
pmid = {22891313},
issn = {1091-6490},
mesh = {Breast/cytology ; Breast Neoplasms/*genetics/pathology ; Carcinoma in Situ/genetics/pathology ; Carcinoma, Ductal/*genetics/pathology ; Female ; Fibroblasts/cytology ; Foreskin/cytology ; Gene Expression Regulation, Neoplastic/*genetics ; Genomic Instability/genetics ; Humans ; Male ; Neoplasm Staging ; Retroelements/*genetics ; Telomerase/genetics ; Telomere/*genetics ; Tissue Banks ; },
abstract = {Several lines of evidence suggest that defects in telomere maintenance play a significant role in the initiation of genomic instability during carcinogenesis. Although the general concept of defective telomere maintenance initiating genomic instability has been acknowledged, there remains a critical gap in the direct evidence of telomere dysfunction in human solid tumors. To address this topic, we devised a multiplex PCR-based assay, termed TAR (telomere-associated repeat) fusion PCR, to detect and analyze chromosome end-to-end associations (telomere fusions) within human breast tumor tissue. Using TAR fusion PCR, we found that human breast lesions, but not normal breast tissues from healthy volunteers, contained telomere fusions. Telomere fusions were detected at similar frequencies during early ductal carcinoma in situ and in the later invasive ductal carcinoma stage. Our results provide direct evidence that telomere fusions are present in human breast tumor tissue and suggest that telomere dysfunction may be an important component of the genomic instability observed in this cancer. Development of this robust method that allows identification of these genetic aberrations (telomere fusions) is anticipated to be a valuable tool for dissecting mechanisms of telomere dysfunction.},
}
@article {pmid22890305,
year = {2012},
author = {Yatsenko, SA and Hixson, P and Roney, EK and Scott, DA and Schaaf, CP and Ng, YT and Palmer, R and Fisher, RB and Patel, A and Cheung, SW and Lupski, JR},
title = {Human subtelomeric copy number gains suggest a DNA replication mechanism for formation: beyond breakage-fusion-bridge for telomere stabilization.},
journal = {Human genetics},
volume = {131},
number = {12},
pages = {1895-1910},
pmid = {22890305},
issn = {1432-1203},
support = {M01 RR000188/RR/NCRR NIH HHS/United States ; P30 HD024064/HD/NICHD NIH HHS/United States ; R01 NS058529/NS/NINDS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Base Sequence ; Child ; Child, Preschool ; Chromosome Deletion ; Chromosomes, Human, Pair 9/genetics/metabolism ; Comparative Genomic Hybridization ; Craniofacial Abnormalities/*genetics/*metabolism ; DNA Breaks ; *DNA Copy Number Variations ; DNA Replication/*genetics ; Female ; Genomic Instability ; Heart Defects, Congenital/*genetics/*metabolism ; Histone-Lysine N-Methyltransferase/genetics ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; Intellectual Disability/*genetics/*metabolism ; Male ; *Models, Genetic ; Telomere/*genetics/metabolism ; },
abstract = {Constitutional deletions of distal 9q34 encompassing the EHMT1 (euchromatic histone methyltransferase 1) gene, or loss-of-function point mutations in EHMT1, are associated with the 9q34.3 microdeletion syndrome, also known as Kleefstra syndrome [MIM#610253]. We now report further evidence for genomic instability of the subtelomeric 9q34.3 region as evidenced by copy number gains of this genomic interval that include duplications, triplications, derivative chromosomes and complex rearrangements. Comparisons between the observed shared clinical features and molecular analyses in 20 subjects suggest that increased dosage of EHMT1 may be responsible for the neurodevelopmental impairment, speech delay, and autism spectrum disorders revealing the dosage sensitivity of yet another chromatin remodeling protein in human disease. Five patients had 9q34 genomic abnormalities resulting in complex deletion-duplication or duplication-triplication rearrangements; such complex triplications were also observed in six other subtelomeric intervals. Based on the specific structure of these complex genomic rearrangements (CGR) a DNA replication mechanism is proposed confirming recent findings in Caenorhabditis elegans telomere healing. The end-replication challenges of subtelomeric genomic intervals may make them particularly prone to rearrangements generated by errors in DNA replication.},
}
@article {pmid22885005,
year = {2012},
author = {Chen, LY and Zhang, Y and Zhang, Q and Li, H and Luo, Z and Fang, H and Kim, SH and Qin, L and Yotnda, P and Xu, J and Tu, BP and Bai, Y and Songyang, Z},
title = {Mitochondrial localization of telomeric protein TIN2 links telomere regulation to metabolic control.},
journal = {Molecular cell},
volume = {47},
number = {6},
pages = {839-850},
pmid = {22885005},
issn = {1097-4164},
support = {CA133249/CA/NCI NIH HHS/United States ; R21 NS072777/NS/NINDS NIH HHS/United States ; GM081627/GM/NIGMS NIH HHS/United States ; P01 DK059820/DK/NIDDK NIH HHS/United States ; P30CA125123/CA/NCI NIH HHS/United States ; P01 GM081627/GM/NIGMS NIH HHS/United States ; P30 HD024064/HD/NICHD NIH HHS/United States ; P30 CA125123/CA/NCI NIH HHS/United States ; P30HD024064/HD/NICHD NIH HHS/United States ; R01 CA112403/CA/NCI NIH HHS/United States ; R01 CA133249/CA/NCI NIH HHS/United States ; GM095599/GM/NIGMS NIH HHS/United States ; 1R21NS072777/NS/NINDS NIH HHS/United States ; DK058242/DK/NIDDK NIH HHS/United States ; R01 DK058242/DK/NIDDK NIH HHS/United States ; R01 GM095599/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenosine Triphosphate/metabolism ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Glycolysis/genetics ; Humans ; Mitochondria/*metabolism ; Oxidative Phosphorylation ; Oxygen Consumption ; Protein Binding ; Protein Processing, Post-Translational ; Protein Sorting Signals ; RNA Interference ; RNA, Small Cytoplasmic ; Reactive Oxygen Species/metabolism ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {Both mitochondria, which are metabolic powerhouses, and telomeres, which help maintain genomic stability, have been implicated in cancer and aging. However, the signaling events that connect these two cellular structures remain poorly understood. Here, we report that the canonical telomeric protein TIN2 is also a regulator of metabolism. TIN2 is recruited to telomeres and associates with multiple telomere regulators including TPP1. TPP1 interacts with TIN2 N terminus, which contains overlapping mitochondrial and telomeric targeting sequences, and controls TIN2 localization. We have found that TIN2 is posttranslationally processed in mitochondria and regulates mitochondrial oxidative phosphorylation. Reducing TIN2 expression by RNAi knockdown inhibited glycolysis and reactive oxygen species (ROS) production and enhanced ATP levels and oxygen consumption in cancer cells. These results suggest a link between telomeric proteins and metabolic control, providing an additional mechanism by which telomeric proteins regulate cancer and aging.},
}
@article {pmid22884422,
year = {2012},
author = {Savolainen, K and Räikkönen, K and Kananen, L and Kajantie, E and Hovatta, I and Lahti, M and Lahti, J and Pesonen, AK and Heinonen, K and Eriksson, JG},
title = {History of mental disorders and leukocyte telomere length in late adulthood: the Helsinki Birth Cohort Study (HBCS).},
journal = {Journal of psychiatric research},
volume = {46},
number = {10},
pages = {1346-1353},
doi = {10.1016/j.jpsychires.2012.07.005},
pmid = {22884422},
issn = {1879-1379},
mesh = {Aged ; Antidepressive Agents/pharmacology/therapeutic use ; Cohort Studies ; Female ; Finland/epidemiology ; Humans ; Leukocytes/drug effects/*physiology ; Male ; Mental Disorders/drug therapy/*genetics/*pathology ; Middle Aged ; Psychiatric Status Rating Scales ; Psychotropic Drugs/pharmacology/therapeutic use ; Retrospective Studies ; Telomere/drug effects/*pathology ; Telomere Homeostasis/drug effects/*physiology ; },
abstract = {Shorter leukocyte telomere length (LTL) has been linked with mental disorders and with other manifestations of chronic non-communicable diseases. Mental disorders are associated with increased morbidity and premature mortality. It remains unclear if shorter LTL characterizes patients who have been diagnosed with mental disorders in the past, and who have survived till late adulthood. 1051 women and 905 men of the Helsinki Birth Cohort Study participated in this study. LTL was measured by using the real-time quantitative PCR method for subjects and patients at the mean age of 61.5 years. Patients with a mental disorder severe enough to warrant hospitalization (n = 116) were identified by their case records in the Finnish Hospital Discharge Register and the use of psychotropic medication by reimbursement entitlements or prescription fills (n = 665) data in the Finnish Social Insurance Register. Participants hospitalized for any mental or substance use disorders had longer LTL than non-hospitalized controls (p-values < 0.042). Moreover, only those any mental disorder patients who had psychotropic medication use had longer LTL than non-hospitalized controls (p = 0.02). Adjustment for a number of covariates did not attenuate the association. Our findings suggest that shorter LTL may not be an intrinsic feature of mental disorders. Future research is needed to elucidate if psychotropic medication is involved in leukocyte telomere length maintenance in subjects with mental disorders.},
}
@article {pmid22879408,
year = {2012},
author = {Wellinger, RJ and Zakian, VA},
title = {Everything you ever wanted to know about Saccharomyces cerevisiae telomeres: beginning to end.},
journal = {Genetics},
volume = {191},
number = {4},
pages = {1073-1105},
pmid = {22879408},
issn = {1943-2631},
support = {MOP97874/CAPMC/CIHR/Canada ; R01&#x2019;S GM43265/GM/NIGMS NIH HHS/United States ; R01 GM043265/GM/NIGMS NIH HHS/United States ; R37 GM026938/GM/NIGMS NIH HHS/United States ; MOP110982/CAPMC/CIHR/Canada ; R01 GM026938/GM/NIGMS NIH HHS/United States ; GM026938/GM/NIGMS NIH HHS/United States ; },
mesh = {Saccharomyces cerevisiae/*genetics/*metabolism ; Telomere/*physiology ; },
abstract = {The mechanisms that maintain the stability of chromosome ends have broad impact on genome integrity in all eukaryotes. Budding yeast is a premier organism for telomere studies. Many fundamental concepts of telomere and telomerase function were first established in yeast and then extended to other organisms. We present a comprehensive review of yeast telomere biology that covers capping, replication, recombination, and transcription. We think of it as yeast telomeres--soup to nuts.},
}
@article {pmid22878603,
year = {2013},
author = {Véronèse, L and Tournilhac, O and Callanan, M and Prie, N and Kwiatkowski, F and Combes, P and Chauvet, M and Davi, F and Gouas, L and Verrelle, P and Guièze, R and Vago, P and Bay, JO and Tchirkov, A},
title = {Telomeres and chromosomal instability in chronic lymphocytic leukemia.},
journal = {Leukemia},
volume = {27},
number = {2},
pages = {490-493},
doi = {10.1038/leu.2012.194},
pmid = {22878603},
issn = {1476-5551},
mesh = {Aged ; Biomarkers, Tumor/*genetics ; *Chromosomal Instability ; DNA, Neoplasm/genetics ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia, Lymphocytic, Chronic, B-Cell/classification/*genetics ; Male ; Neoplasm Staging ; Prognosis ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; Shelterin Complex ; Telomerase/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; Telomeric Repeat Binding Protein 1/genetics ; Telomeric Repeat Binding Protein 2/genetics ; },
}
@article {pmid22877856,
year = {2013},
author = {Hoen, PW and Rosmalen, JG and Schoevers, RA and Huzen, J and van der Harst, P and de Jonge, P},
title = {Association between anxiety but not depressive disorders and leukocyte telomere length after 2 years of follow-up in a population-based sample.},
journal = {Psychological medicine},
volume = {43},
number = {4},
pages = {689-697},
doi = {10.1017/S0033291712001766},
pmid = {22877856},
issn = {1469-8978},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/physiology ; Alcohol Drinking/epidemiology ; Antidepressive Agents/therapeutic use ; Anxiety Disorders/*epidemiology/pathology ; Biomarkers ; Cohort Studies ; Depressive Disorder/*epidemiology/pathology ; Educational Status ; Female ; Health Behavior ; Humans ; Interview, Psychological ; Leukocytes/*ultrastructure ; Life Change Events ; Linear Models ; Male ; Middle Aged ; Multiplex Polymerase Chain Reaction/methods ; Smoking/epidemiology ; Stress, Psychological/*epidemiology ; Telomere/*ultrastructure ; *Telomere Shortening ; Time Factors ; },
abstract = {BACKGROUND: Telomere length is considered an emerging marker of biological aging. Depression and anxiety are associated with excess mortality risk but the mechanisms remain obscure. Telomere length might be involved because it is associated with psychological distress and mortality. The aim of this study was to test whether anxiety and depressive disorders predict telomere length over time in a large population-based sample. Method All analyses were performed in a longitudinal study in a general population cohort of 974 participants. The Composite International Diagnostic Interview (CIDI) was used to measure the presence of anxiety and depressive disorders. Telomere length was measured using monochrome multiplex polymerase chain reaction (PCR) at approximately 2 years of follow-up. We used linear multivariable regression models to evaluate the association between anxiety and depressive disorders and telomere length, adjusting for adverse life events, lifestyle factors, educational level and antidepressant use.<br><br>RESULTS: The presence of anxiety disorders predicted shorter telomeres at follow-up (&#x3b2; = -0.073, t = -2.302, p = 0.022). This association was similar after controlling for adverse life events, lifestyle factors, educational level and antidepressant use (&#x3b2; = -0.077, t = -2.144, p = 0.032). No association was found between depressive disorders and shorter telomeres at follow-up (&#x3b2; = 0.010, t = 0.315, p = 0.753).<br><br>CONCLUSIONS: This study found that anxiety disorders predicted shorter telomere length at follow-up in a general population cohort. The association was not explained by adverse life events, lifestyle factors, educational level and antidepressant use. How anxiety disorders might lead to accelerated telomere shortening and whether this might be a mediator explaining the excess mortality risk associated with anxiety deserve further investigation.},
}
@article {pmid22875407,
year = {2012},
author = {Strandberg, TE and Strandberg, AY and Saijonmaa, O and Tilvis, RS and Pitkälä, KH and Fyhrquist, F},
title = {Association between alcohol consumption in healthy midlife and telomere length in older men. The Helsinki Businessmen Study.},
journal = {European journal of epidemiology},
volume = {27},
number = {10},
pages = {815-822},
pmid = {22875407},
issn = {1573-7284},
mesh = {Age Factors ; Aged ; Alcohol Drinking/adverse effects/*epidemiology ; Finland/epidemiology ; Health Status ; Humans ; Male ; Middle Aged ; Prospective Studies ; Telomere Shortening/*drug effects ; },
abstract = {There are scarce data of alcohol consumption and telomere length, an indicator of biological age. In 1974, detailed alcohol consumption was available for a socioeconomically homogenous cohort of middle-aged men (The Helsinki Businessmen Study). Their alcohol use, divided into 5 groups (zero, 1-98, 99-196, 197-490, >490 g/week) has been repeatedly assessed until old age. In 2002/2003, leukocyte telomere length (LTL) and the proportion of short telomeres (less than 5 kilobases) were measured in a random subcohort of 499 men (mean age 76 years) using the Southern blot. Age-adjusted mean LTL in the 5 midlife alcohol consumption groups were 8.33, 8.24, 8.12, 8.13, and 7.87 kilobases, respectively (P < 0.001). The respective proportions (%) for short telomeres were 11.24, 11.52, 11.89, 12.08, and 13.47 (P = 0.004). The differences remained after further adjustments (ever smoking, body mass index, cholesterol, perceived fitness) for LTL (P = 0.03) and tended to remain for proportion of short telomeres (P = 0.07). Neither LTL, nor proportion of short telomeres, were associated with contemporary alcohol consumption groups in old age. Even minor alcohol consumption in midlife was significantly associated with shorter telomere length in old age. The differences represent an up to 10 year gap in biological age between zero and highest consumption.},
}
@article {pmid22872811,
year = {2012},
author = {Rubtsova, MP and Vasilkova, DP and Malyavko, AN and Naraikina, YV and Zvereva, MI and Dontsova, OA},
title = {Telomere lengthening and other functions of telomerase.},
journal = {Acta naturae},
volume = {4},
number = {2},
pages = {44-61},
pmid = {22872811},
issn = {2075-8251},
abstract = {Telomerase is an enzyme that maintains the length of the telomere. The telomere length specifies the number of divisions a cell can undergo before it finally dies (i.e. the proliferative potential of cells). For example, telomerase is activated in embryonic cell lines and the telomere length is maintained at a constant level; therefore, these cells have an unlimited fission potential. Stem cells are characterized by a lower telomerase activity, which enables only partial compensation for the shortening of telomeres. Somatic cells are usually characterized by the absence of telomerase activity. Telomere shortening leads to the attainment of the Hayflick limit, the transition of cells to a state of senescence. The cells subsequently enter a state of crisis, accompanied by massive cell death. The surviving cells become cancer cells, which are capable both of dividing indefinitely and maintaining telomere length (usually with the aid of telomerase). Telomerase is a reverse transcriptase. It consists of two major components: telomerase RNA (TER) and reverse transcriptase (TERT). TER is a non-coding RNA, and it contains the region which serves as a template for telomere synthesis. An increasing number of articles focussing on the alternative functions of telomerase components have recently started appearing. The present review summarizes data on the structure, biogenesis, and functions of telomerase.},
}
@article {pmid22871736,
year = {2012},
author = {Dai, X and Huang, C and Chai, W},
title = {CDK1 differentially regulates G-overhang generation at leading- and lagging-strand telomeres in telomerase-negative cells in G2 phase.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {11},
number = {16},
pages = {3079-3086},
pmid = {22871736},
issn = {1551-4005},
support = {R15 GM099008/GM/NIGMS NIH HHS/United States ; R21 AG041375/AG/NIA NIH HHS/United States ; R15GM099008/GM/NIGMS NIH HHS/United States ; },
mesh = {2-Aminopurine/analogs &amp; derivatives/pharmacology ; CDC2 Protein Kinase/antagonists &amp; inhibitors/*metabolism ; Chromatin Immunoprecipitation ; DNA/genetics/metabolism ; DNA Polymerase I/metabolism ; DNA Replication ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Flow Cytometry ; *G2 Phase ; HeLa Cells ; Humans ; Quinolines/pharmacology ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; Thiazoles/pharmacology ; },
abstract = {Human telomeres contain single-stranded 3' G-overhangs that function in telomere end protection and telomerase action. Previously we have demonstrated that multiple steps involving C-strand end resection, telomerase elongation and C-strand fill-in contribute to G-overhang generation in telomerase-positive cancer cells. However, how G-overhangs are generated in telomerase-negative human somatic cells is unknown. Here, we report that C-strand fill-in is present at lagging-strand telomeres in telomerase-negative human cells but not at leading-strand telomeres, suggesting that C-strand fill-in is independent of telomerase extension of G-strand. We further show that while cyclin-dependent kinase 1 (CDK1) positively regulates C-strand fill-in, CDK1 unlikely regulates G-overhang generation at leading-strand telomeres. In addition, DNA polymerase α (Polα) association with telomeres is not altered upon CDK1 inhibition, suggesting that CDK1 does not control the loading of Polα to telomeres during fill-in. In summary, our results reveal that G-overhang generation at leading- and lagging-strand telomeres are regulated by distinct mechanisms in human cells.},
}
@article {pmid22871507,
year = {2012},
author = {Hou, L and Wang, S and Dou, C and Zhang, X and Yu, Y and Zheng, Y and Avula, U and Hoxha, M and Díaz, A and McCracken, J and Barretta, F and Marinelli, B and Bertazzi, PA and Schwartz, J and Baccarelli, AA},
title = {Air pollution exposure and telomere length in highly exposed subjects in Beijing, China: a repeated-measure study.},
journal = {Environment international},
volume = {48},
number = {},
pages = {71-77},
pmid = {22871507},
issn = {1873-6750},
support = {P30 ES000002/ES/NIEHS NIH HHS/United States ; R21 ES020010/ES/NIEHS NIH HHS/United States ; R21ES020010/ES/NIEHS NIH HHS/United States ; ES00002/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; Air Pollution/*statistics &amp; numerical data ; Biomarkers/blood ; Cardiovascular Diseases/epidemiology/metabolism ; China ; Female ; Humans ; Inhalation Exposure/*statistics &amp; numerical data ; Male ; Middle Aged ; Particulate Matter/analysis ; Reactive Oxygen Species/metabolism ; Telomere/*physiology ; Telomere Shortening/*physiology ; },
abstract = {BACKGROUND: Ambient particulate matter (PM) exposure has been associated with short- and long-term effects on cardiovascular disease (CVD). Telomere length (TL) is a biomarker of CVD risk that is modified by inflammation and oxidative stress, two key pathways for PM effects. Whether PM exposure modifies TL is largely unexplored.<br><br>OBJECTIVES: To investigate effects of PM on blood TL in a highly-exposed population.<br><br>METHODS: We measured blood TL in 120 blood samples from truck drivers and 120 blood samples from office workers in Beijing, China. We measured personal PM(2.5) and Elemental Carbon (EC, a tracer of traffic particles) using light-weight monitors. Ambient PM(10) was obtained from local monitoring stations. We used covariate-adjusted regression models to estimate percent changes in TL per an interquartile-range increase in exposure.<br><br>RESULTS: Covariate-adjusted TL was higher in drivers (mean=0.87, 95%CI: 0.74; 1.03) than in office workers (mean=0.79, 95%CI: 0.67; 0.93; p=0.001). In all participants combined, TL increased in association with personal PM(2.5) (+5.2%, 95%CI: 1.5; 9.1; p=0.007), personal EC (+4.9%, 95%CI: 1.2; 8.8; p=0.01), and ambient PM(10) (+7.7%, 95%CI: 3.7; 11.9; p<0.001) on examination days. In contrast, average ambient PM(10) over the 14 days before the examinations was significantly associated with shorter TL (-9.9%, 95%CI: -17.6; -1.5; p=0.02).<br><br>CONCLUSIONS: Short-term exposure to ambient PM is associated with increased blood TL, consistent with TL roles during acute inflammatory responses. Longer exposures may shorten TL as expected after prolonged pro-oxidant exposures. The observed TL alterations may participate in the biological pathways of short- and long-term PM effects.},
}
@article {pmid22865299,
year = {2012},
author = {Riegert-Johnson, DL and Boardman, LA and Crook, JE and Thomas, CS and Johnson, RA and Roberts, ME},
title = {Shorter peripheral blood telomeres are a potential biomarker for patients with advanced colorectal adenomas.},
journal = {The International journal of biological markers},
volume = {27},
number = {4},
pages = {e375-80},
pmid = {22865299},
issn = {1724-6008},
support = {R01 CA132718/CA/NCI NIH HHS/United States ; CA 132718/CA/NCI NIH HHS/United States ; },
mesh = {Adenoma/blood/*genetics/pathology ; Adult ; Aged ; Biomarkers, Tumor/blood/*genetics ; Colonoscopy/methods ; Colorectal Neoplasms/blood/*genetics/pathology ; Female ; Humans ; Leukocytes/ultrastructure ; Male ; Middle Aged ; Retrospective Studies ; Telomere/metabolism/*ultrastructure ; },
abstract = {BACKGROUND: Colorectal cancer (CRC) can be prevented by the early detection and removal of advanced adenomas (AAs) by colonoscopy. Our aim was to evaluate peripheral blood leukocyte (PBL) telomere length as a potential biomarker for the presence of AAs.<br><br>METHODS: PBL telomere length was measured in patients with AAs (n=35), in a control group of similarly aged patients who had a normal colonoscopy (n=145) and in a separate population group with no history of cancer, again similarly aged (n=495). Telomere measurements were performed using a quantitative PCR assay and reported as ratios of telomere and single copy gene measurements.<br><br>RESULTS: Telomere lengths tended to be lower in patients with AAs than in patients in the normal colonoscopy group (p<0.001) as well as those in the population group (p=0.011). A telomere/single copy gene ratio of 0.5 was found to have an estimated 94% sensitivity and a 56% specificity for AAs; a combination of sensitivity and specificity for which a value of >0.5 would reduce the odds of a patient having AAs by a factor of 0.11 (the negative likelihood ratio). Thirty three percent of individuals in the population group tested above this cutoff and could be considered at low risk for AAs.<br><br>CONCLUSIONS: PBL telomeres are shortened in patients with colorectal neoplasia, suggesting that PBL telomere length could be a promising non-invasive blood biomarker to pre-screen for risk of AAs prior to colonoscopy.},
}
@article {pmid22863775,
year = {2012},
author = {Stewart, JA and Wang, F and Chaiken, MF and Kasbek, C and Chastain, PD and Wright, WE and Price, CM},
title = {Human CST promotes telomere duplex replication and general replication restart after fork stalling.},
journal = {The EMBO journal},
volume = {31},
number = {17},
pages = {3537-3549},
pmid = {22863775},
issn = {1460-2075},
support = {P30 ES010126/ES/NIEHS NIH HHS/United States ; AG01228/AG/NIA NIH HHS/United States ; F32GM097833/GM/NIGMS NIH HHS/United States ; T32 CA117846/CA/NCI NIH HHS/United States ; GM041803/GM/NIGMS NIH HHS/United States ; ES018918/ES/NIEHS NIH HHS/United States ; R01 GM041803/GM/NIGMS NIH HHS/United States ; F32 GM097833/GM/NIGMS NIH HHS/United States ; R21 ES018918/ES/NIEHS NIH HHS/United States ; P30ES010126/ES/NIEHS NIH HHS/United States ; T32CA117846/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; *DNA Replication ; Gene Knockdown Techniques ; Genomic Instability ; Humans ; Telomere/*metabolism ; Telomere-Binding Proteins/*genetics ; Telomeric Repeat Binding Protein 1/genetics ; },
abstract = {Mammalian CST (CTC1-STN1-TEN1) associates with telomeres and depletion of CTC1 or STN1 causes telomere defects. However, the function of mammalian CST remains poorly understood. We show here that depletion of CST subunits leads to both telomeric and non-telomeric phenotypes associated with DNA replication defects. Stable knockdown of CTC1 or STN1 increases the incidence of anaphase bridges and multi-telomeric signals, indicating genomic and telomeric instability. STN1 knockdown also delays replication through the telomere indicating a role in replication fork passage through this natural barrier. Furthermore, we find that STN1 plays a novel role in genome-wide replication restart after hydroxyurea (HU)-induced replication fork stalling. STN1 depletion leads to reduced EdU incorporation after HU release. However, most forks rapidly resume replication, indicating replisome integrity is largely intact and STN1 depletion has little effect on fork restart. Instead, STN1 depletion leads to a decrease in new origin firing. Our findings suggest that CST rescues stalled replication forks during conditions of replication stress, such as those found at natural replication barriers, likely by facilitating dormant origin firing.},
}
@article {pmid22863003,
year = {2012},
author = {Zhong, FL and Batista, LF and Freund, A and Pech, MF and Venteicher, AS and Artandi, SE},
title = {TPP1 OB-fold domain controls telomere maintenance by recruiting telomerase to chromosome ends.},
journal = {Cell},
volume = {150},
number = {3},
pages = {481-494},
pmid = {22863003},
issn = {1097-4172},
support = {T32 CA009302/CA/NCI NIH HHS/United States ; 5T32 CA09302/CA/NCI NIH HHS/United States ; R01 CA125453/CA/NCI NIH HHS/United States ; R01 AG033747/AG/NIA NIH HHS/United States ; CA125453/CA/NCI NIH HHS/United States ; CA111691/CA/NCI NIH HHS/United States ; R01 CA111691/CA/NCI NIH HHS/United States ; AG033747/AG/NIA NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Cell Line ; Cell Line, Tumor ; Coiled Bodies/metabolism ; Humans ; Idiopathic Pulmonary Fibrosis/genetics/metabolism ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/metabolism ; Sequence Alignment ; Shelterin Complex ; Telomerase/chemistry/genetics/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*chemistry/genetics/*metabolism ; },
abstract = {Telomere synthesis in cancer cells and stem cells involves trafficking of telomerase to Cajal bodies, and telomerase is thought to be recruited to telomeres through interactions with telomere-binding proteins. Here, we show that the OB-fold domain of the telomere-binding protein TPP1 recruits telomerase to telomeres through an association with the telomerase reverse transcriptase TERT. When tethered away from telomeres and other telomere-binding proteins, the TPP1 OB-fold domain is sufficient to recruit telomerase to a heterologous chromatin locus. Expression of a minimal TPP1 OB-fold inhibits telomere maintenance by blocking access of telomerase to its cognate binding site at telomeres. We identify amino acids required for the TPP1-telomerase interaction, including specific loop residues within the TPP1 OB-fold domain and individual residues within TERT, some of which are mutated in a subset of pulmonary fibrosis patients. These data define a potential interface for telomerase-TPP1 interaction required for telomere maintenance and implicate defective telomerase recruitment in telomerase-related disease.},
}
@article {pmid22863000,
year = {2012},
author = {Noël, JF and Wellinger, RJ},
title = {Exposing secrets of telomere-telomerase encounters.},
journal = {Cell},
volume = {150},
number = {3},
pages = {453-454},
doi = {10.1016/j.cell.2012.07.015},
pmid = {22863000},
issn = {1097-4172},
abstract = {In order for telomeres to remain functional and stable, they must rendezvous with the enzyme telomerase in a productive manner. In human cells, this interaction is mediated by Cajal bodies as matchmaker, and now Zhong et al. reveal molecular determinants that establish good chemistry between the two partners.},
}
@article {pmid22855827,
year = {2012},
author = {Nelson, AD and Shippen, DE},
title = {Blunt-ended telomeres: an alternative ending to the replication and end protection stories.},
journal = {Genes &amp; development},
volume = {26},
number = {15},
pages = {1648-1652},
pmid = {22855827},
issn = {1549-5477},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; R01-GM065383/GM/NIGMS NIH HHS/United States ; },
mesh = {Arabidopsis/*metabolism ; Chromosomes, Plant/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres ensure the complete replication of genetic material while simultaneously distinguishing the chromosome terminus from a double-strand break. A prevailing theme in telomere biology is that the two chromosome ends are symmetrical. Both terminate in a single-strand 3' extension, and the 3' extension is crucial for telomere end protection. In this issue of Genes &amp; Development, Kazda and colleagues (pp. 1703-1713) challenge this paradigm using a series of elegant biochemical and genetic assays to demonstrate that half of the chromosomes in flowering plants are blunt-ended. This discovery reveals unanticipated complexity in telomeric DNA processing and a novel mode of chromosome end protection.},
}
@article {pmid22855562,
year = {2012},
author = {Garrels, W and Kues, WB and Herrmann, D and Holler, S and Baulain, U and Niemann, H},
title = {Ectopic expression of human telomerase RNA component results in increased telomerase activity and elongated telomeres in bovine blastocysts.},
journal = {Biology of reproduction},
volume = {87},
number = {4},
pages = {95},
doi = {10.1095/biolreprod.112.100198},
pmid = {22855562},
issn = {1529-7268},
mesh = {Animals ; Animals, Genetically Modified ; Blastocyst/*metabolism ; Cattle/*embryology/genetics/metabolism ; Cells, Cultured ; Embryo, Mammalian ; Enzyme Activation/genetics ; Gene Expression Regulation, Developmental/physiology ; Humans ; RNA/*genetics/metabolism ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Transfection ; Up-Regulation/genetics/physiology ; },
abstract = {Telomeres play an important role in aging, and are critical for the regenerative capacity of mammalian cells. The holoenzyme telomerase rebuilds telomeres and is composed of two components, the catalytic protein telomerase reverse transcriptase (TERT) and the telomerase RNA (TERC). TERC is ubiquitously expressed in somatic cells and is thought to have no regulatory effects on telomerase activity. Transgenic expression of human TERT (hTERT) in bovine somatic and embryonic cells extends telomere length and enhances telomerase activity. To obtain further insight into the regulatory capacity of the two telomerase components, we have studied the ability of hTERC and hTERT to increase telomerase activity and telomere length in bovine embryos. Expression plasmids for the human RNA component (hTERC) and/or the catalytic subunit of human telomerase (hTERT), respectively, were injected into the cytoplasm of in vitro-produced bovine zygotes. Ectopic expression of hTERC increased telomerase activity and telomere length in bovine blastocysts. Coexpression of hTERT and hTERC did not result in further telomere elongation when compared to the hTERC group. These data indicate that TERC is one of the limiting factors of telomerase activity in bovine blastocysts, and further establish bovine preimplantation embryos as a useful model to modulate telomere length with impact for basic embryology and derivation of pluripotent cells.},
}
@article {pmid22855559,
year = {2012},
author = {Vaquero-Sedas, MI and Luo, C and Vega-Palas, MA},
title = {Analysis of the epigenetic status of telomeres by using ChIP-seq data.},
journal = {Nucleic acids research},
volume = {40},
number = {21},
pages = {e163},
pmid = {22855559},
issn = {1362-4962},
mesh = {Arabidopsis/genetics/metabolism ; Chromatin/chemistry/*metabolism ; Chromatin Immunoprecipitation ; *Epigenesis, Genetic ; Histones/metabolism ; Oryza/genetics/metabolism ; Sequence Analysis, DNA ; Telomere/chemistry/*metabolism ; },
abstract = {The chromatin structure of eukaryotic telomeres plays an essential role in telomere functions. However, their study might be impaired by the presence of interstitial telomeric sequences (ITSs), which have a widespread distribution in different model systems. We have developed a simple approach to study the chromatin structure of Arabidopsis telomeres independently of ITSs by analyzing ChIP-seq data. This approach could be used to study the chromatin structure of telomeres in some other eukaryotes. The analysis of ChIP-seq experiments revealed that Arabidopsis telomeres have higher density of histone H3 than centromeres, which might reflects their short nucleosomal organization. These experiments also revealed that Arabidopsis telomeres have lower levels of heterochromatic marks than centromeres (H3K9(Me2) and H3K27(Me)), higher levels of some euchromatic marks (H3K4(Me2) and H3K9Ac) and similar or lower levels of other euchromatic marks (H3K4(Me3), H3K36(Me2), H3K36(Me3) and H3K18Ac). Interestingly, the ChIP-seq experiments also revealed that Arabidopsis telomeres exhibit high levels of H3K27(Me3), a repressive mark that associates with many euchromatic genes. The epigenetic profile of Arabidopsis telomeres is closely related to the previously defined chromatin state 2. This chromatin state is found in 23% of Arabidopsis genes, many of which are repressed or lowly expressed. At least, in part, this scenario is similar in rice.},
}
@article {pmid22850665,
year = {2012},
author = {Wu, XJ and Zhu, JW and Lu, ZF and Xue, D},
title = {Local Artemis dysfunction may be one molecular mechanism for androgenetic alopecia via telomere shortening.},
journal = {Medical hypotheses},
volume = {79},
number = {4},
pages = {554},
doi = {10.1016/j.mehy.2012.07.011},
pmid = {22850665},
issn = {1532-2777},
mesh = {Alopecia/*etiology/genetics/pathology/physiopathology ; DNA-Binding Proteins ; Endonucleases ; Hair Follicle/pathology/physiopathology ; Humans ; Models, Theoretical ; Nuclear Proteins/genetics/*physiology ; Telomere Shortening/genetics/physiology ; },
}
@article {pmid22848695,
year = {2012},
author = {Luke-Glaser, S and Luke, B},
title = {The Mph1 helicase can promote telomere uncapping and premature senescence in budding yeast.},
journal = {PloS one},
volume = {7},
number = {7},
pages = {e42028},
pmid = {22848695},
issn = {1932-6203},
mesh = {DEAD-box RNA Helicases/genetics/*metabolism ; DNA Breaks, Double-Stranded ; DNA End-Joining Repair/genetics ; DNA Replication/genetics ; DNA, Fungal/biosynthesis/genetics ; DNA, Single-Stranded/biosynthesis/genetics ; Gene Expression Regulation, Fungal ; Mutation ; Saccharomyces cerevisiae/*cytology/enzymology/*genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/*genetics ; },
abstract = {Double strand breaks (DSBs) can be repaired via either Non-Homologous End Joining (NHEJ) or Homology directed Repair (HR). Telomeres, which resemble DSBs, are refractory to repair events in order to prevent chromosome end fusions and genomic instability. In some rare instances telomeres engage in Break-Induced Replication (BIR), a type of HR, in order to maintain telomere length in the absence of the enzyme telomerase. Here we have investigated how the yeast helicase, Mph1, affects DNA repair at both DSBs and telomeres. We have found that overexpressed Mph1 strongly inhibits BIR at internal DSBs however allows it to proceed at telomeres. Furthermore, while overexpressed Mph1 potently inhibits NHEJ at telomeres it has no effect on NHEJ at DSBs within the chromosome. At telomeres Mph1 is able to promote telomere uncapping and the accumulation of ssDNA, which results in premature senescence in the absence of telomerase. We propose that Mph1 is able to direct repair towards HR (thereby inhibiting NHEJ) at telomeres by remodeling them into a nuclease-sensitive structure, which promotes the accumulation of a recombinogenic ssDNA intermediate. We thus put forward that Mph1 is a double-edge sword at the telomere, it prevents NHEJ, but promotes senescence in cells with dysfunctional telomeres by increasing the levels of ssDNA.},
}
@article {pmid22848311,
year = {2011},
author = {Zhang, Y and Cai, L and Wei, RX and Hu, H and Jin, W and Zhu, XB},
title = {Different expression of alternative lengthening of telomere (ALT)-associated proteins/mRNAs in osteosarcoma cell lines.},
journal = {Oncology letters},
volume = {2},
number = {6},
pages = {1327-1332},
pmid = {22848311},
issn = {1792-1074},
abstract = {Tumors, including osteosarcoma (OS), are capable of evading senescence and cell death, which is caused by telomere loss with cell division. Alternative lengthening of telomeres (ALT) is considered as the main telomere maintenance mechanism in OS. In this study, we investigated the expression of ALT-associated proteins and mRNAs in human OS cell lines. Western blotting was used to detect the protein expression in OS cell lines, while the expression of mRNA was determined by reverse-transcriptase PCR and quantitative real-time PCR analysis. Whole-genome expression arrays were used to analyze the expression of all the mRNAs involved in telomere maintenance mechanisms (TMMs) including human telomerase reverse transcriptase, promyelocytic leukemia proteins and other related proteins. OS and normal cell lines do not express telomerase reverse transcriptase (hTERT) as a key subunit of telomerase, although they show varying levels of ALT-associated proteins and mRNAs such as PML, Rad52, MRE11 and FEN1 by Western blotting and quantitative real-time PCR analysis. A number of mRNAs that play essential roles in ALT are expressed more in OS cell lines than in the osteoblast cell line, as shown by whole-genome expression arrays. In conclusion, OS cell lines maintain their telomere length primarily through the ALT mechanism. There are numerous other proteins that regulate this process in OS; therefore, anti-ALT therapy may be a more effective method to treat OS than anti-telomerase therapy.},
}
@article {pmid22844639,
year = {2012},
author = {Dubruille, R and Marais, GA and Loppin, B},
title = {Repeated evolution of testis-specific new genes: the case of telomere-capping genes in Drosophila.},
journal = {International journal of evolutionary biology},
volume = {2012},
number = {},
pages = {708980},
pmid = {22844639},
issn = {2090-052X},
abstract = {Comparative genome analysis has allowed the identification of various mechanisms involved in gene birth. However, understanding the evolutionary forces driving new gene origination still represents a major challenge. In particular, an intriguing and not yet fully understood trend has emerged from the study of new genes: many of them show a testis-specific expression pattern, which has remained poorly understood. Here we review the case of such a new gene, which involves a telomere-capping gene family in Drosophila. hiphop and its testis-specific paralog K81 are critical for the protection of chromosome ends in somatic cells and male gametes, respectively. Two independent functional studies recently proposed that these genes evolved under a reproductive-subfunctionalization regime. The 2011 release of new Drosophila genome sequences from the melanogaster group of species allowed us to deepen our phylogenetic analysis of the hiphop/K81 family. This work reveals an unsuspected dynamic of gene birth and death within the group, with recurrent duplication events through retroposition mechanisms. Finally, we discuss the plausibility of different evolutionary scenarios that could explain the diversification of this gene family.},
}
@article {pmid22844525,
year = {2012},
author = {Robertson, T and Batty, GD and Der, G and Green, MJ and McGlynn, LM and McIntyre, A and Shiels, PG and Benzeval, M},
title = {Is telomere length socially patterned? Evidence from the West of Scotland Twenty-07 Study.},
journal = {PloS one},
volume = {7},
number = {7},
pages = {e41805},
pmid = {22844525},
issn = {1932-6203},
support = {MC_U130059821/MRC_/Medical Research Council/United Kingdom ; MC_US_A540_0080/MRC_/Medical Research Council/United Kingdom ; MC_US_A540_0056/MRC_/Medical Research Council/United Kingdom ; MC_UP_A540_1021/MRC_/Medical Research Council/United Kingdom ; MC_U130059823/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; SPHSU2/CSO_/Chief Scientist Office/United Kingdom ; },
mesh = {Adolescent ; Adult ; Aged ; Cohort Studies ; Educational Status ; Female ; Humans ; Male ; Middle Aged ; Scotland ; *Social Class ; Telomere/*genetics ; *Telomere Shortening ; Time Factors ; Young Adult ; },
abstract = {Lower socioeconomic status (SES) is strongly associated with an increased risk of morbidity and premature mortality, but it is not known if the same is true for telomere length, a marker often used to assess biological ageing. The West of Scotland Twenty-07 Study was used to investigate this and consists of three cohorts aged approximately 35 (N = 775), 55 (N = 866) and 75 years (N = 544) at the time of telomere length measurement. Four sets of measurements of SES were investigated: those collected contemporaneously with telomere length assessment, educational markers, SES in childhood and SES over the preceding twenty years. We found mixed evidence for an association between SES and telomere length. In 35-year-olds, many of the education and childhood SES measures were associated with telomere length, i.e. those in poorer circumstances had shorter telomeres, as was intergenerational social mobility, but not accumulated disadvantage. A crude estimate showed that, at the same chronological age, social renters, for example, were nine years (biologically) older than home owners. No consistent associations were apparent in those aged 55 or 75. There is evidence of an association between SES and telomere length, but only in younger adults and most strongly using education and childhood SES measures. These results may reflect that childhood is a sensitive period for telomere attrition. The cohort differences are possibly the result of survival bias suppressing the SES-telomere association; cohort effects with regard different experiences of SES; or telomere possibly being a less effective marker of biological ageing at older ages.},
}
@article {pmid22842784,
year = {2012},
author = {Thanasoula, M and Escandell, JM and Suwaki, N and Tarsounas, M},
title = {ATM/ATR checkpoint activation downregulates CDC25C to prevent mitotic entry with uncapped telomeres.},
journal = {The EMBO journal},
volume = {31},
number = {16},
pages = {3398-3410},
pmid = {22842784},
issn = {1460-2075},
support = {17201/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*metabolism ; Cell Line ; *Cytokinesis ; DNA-Binding Proteins/*metabolism ; Gene Expression Profiling ; *Gene Expression Regulation ; Humans ; Models, Biological ; Protein Serine-Threonine Kinases/*metabolism ; Telomere/*metabolism ; Tumor Suppressor Proteins/*metabolism ; cdc25 Phosphatases/*biosynthesis ; },
abstract = {Shelterin component TRF2 prevents ATM activation, while POT1 represses ATR signalling at telomeres. Here, we investigate the mechanism of G2/M arrest triggered by telomeres uncapped through TRF2 or POT1 inhibition in human cells. We find that telomere damage-activated ATR and ATM phosphorylate p53, as well as CHK1 and CHK2, thus activating two independent pathways to prevent progression into mitosis with uncapped telomeres. Surprisingly, telomere damage targets the CDC25C phosphatase for proteasome degradation in G2/M. CHK1/CHK2-dependent phosphorylation of CDC25C at Ser 216 is required for CDC25C nuclear export and destruction, which in turn acts to sustain the G2/M arrest elicited by TRF2- or POT1-depleted telomeres. In addition, CDC25C is transcriptionally downregulated by p53 in response to telomere damage. These mechanisms are distinct from the canonical DNA damage response to ionizing radiation, which triggers cell-cycle arrest through CDC25A destruction. Thus, dysfunctional telomeres promote ATM/ATR-dependent degradation of CDC25C phosphatase to block mitotic entry, thereby preventing telomere dysfunction-driven genomic instability.},
}
@article {pmid22835139,
year = {2012},
author = {Kagawa, Y},
title = {From clock genes to telomeres in the regulation of the healthspan.},
journal = {Nutrition reviews},
volume = {70},
number = {8},
pages = {459-471},
doi = {10.1111/j.1753-4887.2012.00504.x},
pmid = {22835139},
issn = {1753-4887},
mesh = {Aryl Hydrocarbon Receptor Nuclear Translocator/genetics ; Circadian Clocks/*genetics/physiology ; Circadian Rhythm/*genetics/physiology ; Energy Metabolism/*genetics/physiology ; Gene Expression Regulation/genetics ; Humans ; Telomere ; Transcription, Genetic/genetics ; },
abstract = {Biological clocks are classified into oscillatory (clock genes) and unidirectional hourglass clocks (telomeres). Clock genes align behavioral and biochemical processes with the day/night cycle. Telomeres, the repeated series of DNA sequences that cap the ends of chromosomes, become shorter during cell division. Shortened telomeres have been documented in various pathological states associated with aging. Human activity is driven by NADH and ATP produced from nutrients, and the resulting NAD and AMP play a predominant role in energy regulation. Caloric restriction increases both AMP and NAD and is known to extend the healthspan (healthy lifespan) of animals. Silent information regulator T1 (SIRT1), the NAD-dependent deacetylase, attenuates telomere shortening, while peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a master modulator of gene expression, is phosphorylated by AMP kinase and deacetylated by SIRT1. Thus, PGC-1α is a key component of the circadian oscillator that integrates the mammalian clock and energy metabolism. Reactive oxygen species produced in clock mutants result in telomere shortening. The circadian rhythms produced by clock genes and lifestyle factors are ultimately controlled by the human brain and drive homeostatic and hedonic feeding and daily activity.},
}
@article {pmid22833748,
year = {2012},
author = {Shakirov, EV and Shippen, DE},
title = {Selaginella moellendorffii telomeres: conserved and unique features in an ancient land plant lineage.},
journal = {Frontiers in plant science},
volume = {3},
number = {},
pages = {161},
pmid = {22833748},
issn = {1664-462X},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; },
abstract = {Telomeres, the essential terminal regions of linear eukaryotic chromosomes, consist of G-rich DNA repeats bound by a plethora of associated proteins. While the general pathways of telomere maintenance are evolutionarily conserved, individual telomere complex components show remarkable variation between eukaryotic lineages and even within closely related species. The recent genome sequencing of the lycophyte Selaginella moellendorffii and the availability of an ever-increasing number of flowering plant genomes provides a unique opportunity to evaluate the molecular and functional evolution of telomere components from the early evolving non-seed plants to the more developmentally advanced angiosperms. Here we analyzed telomere sequence in S. moellendorffii and found it to consist of TTTAGGG repeats, typical of most plants. Telomere tracts in S. moellendorffii range from 1 to 5.5 kb, closely resembling Arabidopsis thaliana. We identified several S. moellendorffii genes encoding sequence homologs of proteins involved in telomere maintenance in other organisms, including CST complex components and the telomere-binding proteins, POT1 and the TRFL family. Notable sequence similarities and differences were uncovered among the telomere-related genes in some of the plant lineages. Taken together, the data indicate that comparative analysis of the telomere complex in early diverging land plants such as S. moellendorffii and green algae will yield important insights into the evolution of telomeres and their protein constituents.},
}
@article {pmid22832159,
year = {2012},
author = {Taboski, MA and Sealey, DC and Dorrens, J and Tayade, C and Betts, DH and Harrington, L},
title = {Long telomeres bypass the requirement for telomere maintenance in human tumorigenesis.},
journal = {Cell reports},
volume = {1},
number = {2},
pages = {91-98},
pmid = {22832159},
issn = {2211-1247},
support = {R01-AG024398/AG/NIA NIH HHS/United States ; R01 AG024398/AG/NIA NIH HHS/United States ; MOP-86453/CAPMC/CIHR/Canada ; R01 AG024398-05/AG/NIA NIH HHS/United States ; 092076/WT_/Wellcome Trust/United Kingdom ; 84637/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Biocatalysis ; Cell Line, Tumor ; Cell Transformation, Neoplastic/*genetics ; Humans ; Mice ; Mutation/genetics ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Despite the importance of telomere maintenance in cancer cell survival via the elongation of telomeres by telomerase reverse transcriptase (TERT) or alternative lengthening of telomeres (ALT), it had not been tested directly whether telomere maintenance is dispensable for human tumorigenesis. We engineered human tumor cells containing loxP-flanked hTERT to enable extensive telomere elongation prior to complete hTERT excision. Despite unabated telomere erosion, hTERT-excised cells formed tumors in mice and proliferated in vitro for up to 1 year. Telomerase reactivation or ALT was not observed, and the eventual loss of telomeric signal coincided with loss of tumorigenic potential and cell viability. Crisis was averted via the reintroduction of active but not inactive hTERT. Thus, telomere maintenance is dispensable for human tumorigenesis when telomere reserves are long. Yet, despite telomere instability and the presence of oncogenic RAS, human tumors remain susceptible to crisis induced by critically short telomeres.},
}
@article {pmid22831981,
year = {2013},
author = {Price, LH and Kao, HT and Burgers, DE and Carpenter, LL and Tyrka, AR},
title = {Telomeres and early-life stress: an overview.},
journal = {Biological psychiatry},
volume = {73},
number = {1},
pages = {15-23},
pmid = {22831981},
issn = {1873-2402},
support = {R01 MH068767/MH/NIMH NIH HHS/United States ; R01 MH083704/MH/NIMH NIH HHS/United States ; },
mesh = {Aging/genetics ; Humans ; Mental Disorders/*genetics ; Stress, Psychological/*genetics ; Telomere/*metabolism ; Telomere Shortening/*genetics ; },
abstract = {The long-term sequelae of adverse early-life experiences have long been a focus in psychiatry, with a historic neurobiological emphasis on physiological systems that are demonstrably stress-responsive, such as the hypothalamic-pituitary-adrenal axis and neuroimmune function. However, there has been increasing recognition in the general medical literature that such sequelae might encompass more pervasive alterations in health status and physiology. Recent findings in telomere biology have suggested a new avenue for exploring the adverse health effects of childhood maltreatment. Telomere length in proliferative tissues declines with cell replication and the effect can be accelerated by such factors as inflammation, oxidative stress, radiation, and toxins. Reduced telomere length, as a proxy for cellular aging, has been associated with numerous chronic somatic diseases that are generally considered to be diseases of aging, such as diabetes, cancer, and heart disease. More recently, shorter telomeres have been demonstrated in several psychiatric conditions, particularly depression. Sustained psychosocial stress of a variety of types in adulthood appears to be associated with shorter telomeres. Now, emerging work suggests a robust, and perhaps dose-dependent, relationship with early-life stress. These findings present new opportunities to reconceptualize the complex relationships between experience, physical and psychiatric disease, and aging.},
}
@article {pmid22829774,
year = {2012},
author = {Lovejoy, CA and Li, W and Reisenweber, S and Thongthip, S and Bruno, J and de Lange, T and De, S and Petrini, JH and Sung, PA and Jasin, M and Rosenbluh, J and Zwang, Y and Weir, BA and Hatton, C and Ivanova, E and Macconaill, L and Hanna, M and Hahn, WC and Lue, NF and Reddel, RR and Jiao, Y and Kinzler, K and Vogelstein, B and Papadopoulos, N and Meeker, AK and , },
title = {Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway.},
journal = {PLoS genetics},
volume = {8},
number = {7},
pages = {e1002772},
pmid = {22829774},
issn = {1553-7404},
support = {R13 CA162528/CA/NCI NIH HHS/United States ; R01 GM049046/GM/NIGMS NIH HHS/United States ; F32GM090437/GM/NIGMS NIH HHS/United States ; CA076027/CA/NCI NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; R01 GM056888/GM/NIGMS NIH HHS/United States ; R37 CA043460/CA/NCI NIH HHS/United States ; R37 GM059413/GM/NIGMS NIH HHS/United States ; R01 AG023145/AG/NIA NIH HHS/United States ; GM049046/GM/NIGMS NIH HHS/United States ; F32 GM090437/GM/NIGMS NIH HHS/United States ; R01 CA076027/CA/NCI NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing/genetics/metabolism ; Chromatin Assembly and Disassembly/genetics ; Co-Repressor Proteins ; DNA Breaks, Double-Stranded ; DNA Damage/genetics ; DNA Helicases/*genetics/metabolism ; DNA Repair/genetics ; G2 Phase Cell Cycle Checkpoints/genetics ; Genomic Instability ; HeLa Cells ; *Histones/genetics/metabolism ; Homologous Recombination ; Humans ; Molecular Chaperones ; Nuclear Proteins/*genetics/metabolism ; Signal Transduction ; Telomerase/genetics ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics ; X-linked Nuclear Protein ; },
abstract = {The Alternative Lengthening of Telomeres (ALT) pathway is a telomerase-independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized cell lines. ALT is thought to involve templated extension of telomeres through homologous recombination, but the genetic or epigenetic changes that unleash ALT are not known. Recently, mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 were found to correlate with features of ALT in pancreatic neuroendocrine cancers, pediatric glioblastomas, and other tumors of the central nervous system, suggesting that these mutations might contribute to the activation of the ALT pathway in these cancers. We have taken a comprehensive approach to deciphering ALT by applying genomic, molecular biological, and cell biological approaches to a panel of 22 ALT cell lines, including cell lines derived in vitro. Here we show that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT-immortalized cell lines. In addition, ALT is associated with extensive genome rearrangements, marked micronucleation, defects in the G2/M checkpoint, and altered double-strand break (DSB) repair. These attributes will facilitate the diagnosis and treatment of ALT positive human cancers.},
}
@article {pmid22829448,
year = {2012},
author = {You, NC and Chen, BH and Song, Y and Lu, X and Chen, Y and Manson, JE and Kang, M and Howard, BV and Margolis, KL and Curb, JD and Phillips, LS and Stefanick, ML and Tinker, LF and Liu, S},
title = {A prospective study of leukocyte telomere length and risk of type 2 diabetes in postmenopausal women.},
journal = {Diabetes},
volume = {61},
number = {11},
pages = {2998-3004},
pmid = {22829448},
issn = {1939-327X},
support = {N01-WH-32115/WH/WHI NIH HHS/United States ; N01-WH-32113/WH/WHI NIH HHS/United States ; N01-WH-42110/WH/WHI NIH HHS/United States ; R21-DK-084452/DK/NIDDK NIH HHS/United States ; N01-WH-42132/WH/WHI NIH HHS/United States ; N01-WH-42111/WH/WHI NIH HHS/United States ; R21 DK084452/DK/NIDDK NIH HHS/United States ; N01-WH-42119/WH/WHI NIH HHS/United States ; N01-WH-44221/WH/WHI NIH HHS/United States ; N01-WH-42112/WH/WHI NIH HHS/United States ; N01-WH-32119/WH/WHI NIH HHS/United States ; N01-WH-42117/WH/WHI NIH HHS/United States ; N01-WH-32112/WH/WHI NIH HHS/United States ; N01WH22110/WH/WHI NIH HHS/United States ; N01-WH-32118/WH/WHI NIH HHS/United States ; N01-WH-42114/WH/WHI NIH HHS/United States ; N01-WH-32105/WH/WHI NIH HHS/United States ; N01-WH-42125/WH/WHI NIH HHS/United States ; N01-WH-42126/WH/WHI NIH HHS/United States ; N01-WH-32102/WH/WHI NIH HHS/United States ; N01-WH-42120/WH/WHI NIH HHS/United States ; N01-WH-42131/WH/WHI NIH HHS/United States ; N01-WH-42121/WH/WHI NIH HHS/United States ; N01-WH-42115/WH/WHI NIH HHS/United States ; N01-WH-42113/WH/WHI NIH HHS/United States ; N01-WH-42124/WH/WHI NIH HHS/United States ; N01-WH-42107/WH/WHI NIH HHS/United States ; N01-WH-42116/WH/WHI NIH HHS/United States ; N01-WH-42109/WH/WHI NIH HHS/United States ; N01-WH-32101/WH/WHI NIH HHS/United States ; N01-WH-32108/WH/WHI NIH HHS/United States ; N01-WH-42130/WH/WHI NIH HHS/United States ; N01-WH-32111/WH/WHI NIH HHS/United States ; N01-WH-42122/WH/WHI NIH HHS/United States ; N01-WH-32106/WH/WHI NIH HHS/United States ; N01-WH-32122/WH/WHI NIH HHS/United States ; N01-WH-32100/WH/WHI NIH HHS/United States ; N01-WH-42123/WH/WHI NIH HHS/United States ; N01-WH-42108/WH/WHI NIH HHS/United States ; N01-WH-22110/WH/WHI NIH HHS/United States ; N01-WH-24152/WH/WHI NIH HHS/United States ; N01-WH-42129/WH/WHI NIH HHS/United States ; N01-WH-42118/WH/WHI NIH HHS/United States ; N01-WH-32109/WH/WHI NIH HHS/United States ; },
mesh = {Aged ; Cohort Studies ; Diabetes Mellitus, Type 2/blood/epidemiology/ethnology/*genetics ; Female ; Follow-Up Studies ; Genetic Association Studies ; Humans ; Leukocytes/*metabolism ; Mendelian Randomization Analysis ; Middle Aged ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; Postmenopause ; Prospective Studies ; Risk Factors ; Shelterin Complex ; *Telomere Shortening ; Telomere-Binding Proteins/genetics/metabolism ; United States/epidemiology ; },
abstract = {Telomere length (TL) has been implicated in the pathogenesis of age-related disorders. However, there are no prospective studies directly investigating the role of TL and relevant genes in diabetes development. In the multiethnic Women's Health Initiative, we identified 1,675 incident diabetes case participants in 6 years of follow-up and 2,382 control participants matched by age, ethnicity, clinical center, time of blood draw, and follow-up duration. Leukocyte TL at baseline was measured using quantitative PCR, and Mendelian randomization analysis was conducted to test whether TL is causally associated with diabetes risk. After adjustment for matching and known diabetes risk factors, odds ratios per 1-kilobase increment were 1.00 (95% CI 0.90-1.11) in whites, 0.95 (0.85-1.06) in blacks, 0.96 (0.79-1.17) in Hispanics, and 0.88 (0.70-1.10) in Asians. Of the 80 single nucleotide polymorphisms (SNPs) in nine genes involved in telomere regulation, 14 SNPs were predictive of TL, but none were significantly associated with diabetes risk. Using ethnicity-specific SNPs as randomization instruments, we observed no statistically significant association between TL and diabetes risk (P = 0.52). Although leukocyte TL was weakly associated with diabetes risk, this association was not independent of known risk factors. These prospective findings indicate limited clinical utility of TL in diabetes risk stratification among postmenopausal women.},
}
@article {pmid22827974,
year = {2012},
author = {Biegler, KA and Anderson, AK and Wenzel, LB and Osann, K and Nelson, EL},
title = {Longitudinal change in telomere length and the chronic stress response in a randomized pilot biobehavioral clinical study: implications for cancer prevention.},
journal = {Cancer prevention research (Philadelphia, Pa.)},
volume = {5},
number = {10},
pages = {1173-1182},
pmid = {22827974},
issn = {1940-6215},
support = {R01CA11836/CA/NCI NIH HHS/United States ; T32 CA009054/CA/NCI NIH HHS/United States ; 5T32 CA09054-32/CA/NCI NIH HHS/United States ; R21CA098794/CA/NCI NIH HHS/United States ; R01 CA118136/CA/NCI NIH HHS/United States ; R21 CA098794/CA/NCI NIH HHS/United States ; P30 CA062203/CA/NCI NIH HHS/United States ; P30CA062203/CA/NCI NIH HHS/United States ; },
mesh = {Female ; Flow Cytometry ; Humans ; Immunophenotyping ; In Situ Hybridization, Fluorescence ; Leukocytes, Mononuclear/metabolism ; Longitudinal Studies ; Middle Aged ; Monocytes/cytology/metabolism ; Pilot Projects ; *Quality of Life ; Stress, Psychological/*genetics ; T-Lymphocytes/immunology/metabolism ; Telomere Homeostasis/*genetics ; Uterine Cervical Neoplasms/genetics/*prevention &amp; control/psychology ; },
abstract = {Shortened telomere length is associated with increased cancer incidence and mortality. Populations experiencing chronic stress have accelerated telomere shortening. In this exploratory study, we examined associations between longitudinal changes in patient reported outcomes (PRO) of psychologic distress and peripheral blood mononuclear cell (PBMC) telomere length to test the hypothesis that modulation of the chronic stress response would also modulate telomere dynamics. Archived PBMC specimens (N = 22) were analyzed from a completed and reported randomized, longitudinal trial that showed a psychosocial telephone counseling intervention improved quality of life (QOL) and modulated stress-associated biomarkers in cervical cancer survivors. PROs and biospecimens were collected at baseline and 4 months postenrollment. Telomere length of archived PBMCs was evaluated using the flow-FISH assay. Longitudinal changes in psychologic distress, measured by the Brief Symptom Inventory-18, were significantly associated with increased telomere length within the CD14(+) (monocyte) population (r = -0.46, P = 0.043); a similar trend was observed for the CD14(-) population. Longitudinal changes in telomere length of the CD14(-) subset, primarily T lymphocytes, were associated with longitudinal increases in the naive T-cell population (r = 0.49, P = 0.052). Alterations in the chronic stress response were associated with modulation of telomere length in PBMCs, with evidence for mobilization of "younger" cells from progenitor populations. These data provide preliminary support for the (i) capacity to modulate the chronic stress response and the associated accelerated telomere shortening, (ii) inclusion of telomere length in the biobehavioral paradigm, and (iii) potential link between the chronic stress response and biologic mechanisms responsible for genomic integrity and carcinogenesis.},
}
@article {pmid22827962,
year = {2012},
author = {Monickaraj, F and Gokulakrishnan, K and Prabu, P and Sathishkumar, C and Anjana, RM and Rajkumar, JS and Mohan, V and Balasubramanyam, M},
title = {Convergence of adipocyte hypertrophy, telomere shortening and hypoadiponectinemia in obese subjects and in patients with type 2 diabetes.},
journal = {Clinical biochemistry},
volume = {45},
number = {16-17},
pages = {1432-1438},
doi = {10.1016/j.clinbiochem.2012.07.097},
pmid = {22827962},
issn = {1873-2933},
mesh = {Adipocytes/*physiology ; Adiponectin/blood/deficiency/genetics ; Adult ; Case-Control Studies ; Cell Size ; Diabetes Mellitus, Type 2/blood/genetics/*pathology ; Female ; Humans ; Hypertrophy/blood/genetics/pathology ; Intra-Abdominal Fat/pathology ; Male ; Metabolism, Inborn Errors/blood/genetics/*pathology ; Middle Aged ; Obesity/blood/genetics/*pathology ; Risk Factors ; Subcutaneous Fat/pathology ; *Telomere Shortening ; Thiobarbituric Acid Reactive Substances/metabolism ; },
abstract = {OBJECTIVE: Although telomere shortening has been linked with type 2 diabetes and most variables of adiposity, a shortcoming of such studies is the measurement of telomere length in leukocytes. Therefore, we tested the association among adipocyte cell size, telomere length (both subcutaneous and visceral adipose tissue) and systemic levels of adiponectin in obese subjects and patients with type 2 diabetes compared to control subjects.<br><br>METHODS: Human subcutaneous and visceral adipose tissues were obtained from the subjects who have undergone bariatric surgery or other abdominal surgeries. The study groups comprised: i) control subjects, ii) type 2 diabetes patients, iii) obese subjects without diabetes and iv) obese subjects with diabetes. Adipocyte cell size was measured by histological staining. Adiponectin levels were measured by ELISA. Telomere length was determined by Real-time PCR and lipid peroxidation was assessed by fluorimetry.<br><br>RESULTS: Compared to control subjects, adipocyte size (both subcutaneous and visceral) from obese, diabetic and obese-diabetic subjects was significantly larger [p<0.001]. Individuals with adipose hypertrophy also exhibited shortened telomeres and hypoadiponectinemia. Pearson correlation analysis revealed that both visceral and subcutaneous fat cell size showed a positive correlation with FBS, HbA1c, HOMA-IR, LDL, total cholesterol, triglycerides and negatively correlated with HDL and adiponectin. Regression analysis revealed that the association between shortened telomeres and hypoadiponectinemia was lost when adjusted for adipocyte cell size.<br><br>CONCLUSION: Adipocyte hypertrophy appears to be strongly associated with shortened telomeres, hypoadiponectinemia and poor glycemic and lipid control. Interestingly, these molecular alterations seen in lean diabetics reflect a state of 'metabolic obesity'.},
}
@article {pmid22827042,
year = {2012},
author = {Smirnova, TIu and Runov, AL and Vonskiĭ, MS and Spivak, DL and Zakharchuk, AG and Mikhel'son, VM and Spivak, IM},
title = {[Telomere length in the population of long-lived persons of North-West region of Russia].},
journal = {Tsitologiia},
volume = {54},
number = {5},
pages = {439-445},
pmid = {22827042},
issn = {0041-3771},
mesh = {Aged ; Aged, 80 and over ; Female ; Geriatric Assessment ; Humans ; Longevity/*genetics ; Male ; Middle Aged ; Peptidyl-Dipeptidase A/genetics ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Psychological Tests ; Receptor, Serotonin, 5-HT2A/genetics ; Regression Analysis ; Russia ; Serotonin Plasma Membrane Transport Proteins/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; },
abstract = {Interdisciplinary study of telomere length, polymorphism of genes of renin-angiotensin (ACE) and serotonin (5HTR2A and 5HTTPR) systems in population of aged and old inhabitants of the North-West of Russia was conducted, in their relations to data from clinical and geriatric anamnesis, and psychological functioning. Regular link between telomere length and respondent's age was demonstrated in subgroups of old respondents and long-livers, by method of factor analysis.},
}
@article {pmid22826121,
year = {2012},
author = {Morimoto, A and Shibuya, H and Zhu, X and Kim, J and Ishiguro, K and Han, M and Watanabe, Y},
title = {A conserved KASH domain protein associates with telomeres, SUN1, and dynactin during mammalian meiosis.},
journal = {The Journal of cell biology},
volume = {198},
number = {2},
pages = {165-172},
pmid = {22826121},
issn = {1540-8140},
mesh = {Amino Acid Sequence ; Animals ; Cell Cycle Proteins/*metabolism ; Conserved Sequence ; Cytoskeletal Proteins ; Dynactin Complex ; HeLa Cells ; Humans ; Male ; *Meiosis ; Membrane Proteins/*metabolism ; Mice ; Mice, Inbred C57BL ; Microtubule-Associated Proteins/*metabolism ; Molecular Sequence Data ; Nuclear Proteins/*metabolism ; Protein Structure, Tertiary ; Spermatocytes/metabolism ; Telomere/*metabolism ; Testis/metabolism ; },
abstract = {In yeasts and worms, KASH (Klarsicht/ANC-1/Syne/homology) domain and SUN (Sad-1/UNC-84) domain nuclear envelope (NE) proteins play a crucial role in meiotic chromosome movement and homologue pairing. However, although the vertebrate SUN domain protein SUN1 is involved in these processes, its partner has remained identified. Based on subcellular localization screening in mouse spermatocytes, we identified a novel germ cell-specific protein, KASH5, that localized exclusively at telomeres from the leptotene to diplotene stages in both spermatocytes and oocytes. KASH5 possesses hitherto unknown KASH-related sequences that directly interacted with SUN1 and mediated telomere localization. Thus, KASH5 is a mammalian meiosis-specific KASH domain protein. We show that meiotic chromosome movement depended on microtubules and that KASH5 interacted with the microtubule-associated dynein-dynactin complex. These results suggest that KASH5 connects the telomere-associated SUN1 protein to the cytoplasmic force-generating mechanism involved in meiotic chromosome movement. Our study strongly suggests that the meiotic homologue-pairing mechanism mediated by the SUN-KASH NE bridge is highly conserved among eukaryotes.},
}
@article {pmid22825311,
year = {2012},
author = {Honig, LS and Kang, MS and Schupf, N and Lee, JH and Mayeux, R},
title = {Association of shorter leukocyte telomere repeat length with dementia and mortality.},
journal = {Archives of neurology},
volume = {69},
number = {10},
pages = {1332-1339},
pmid = {22825311},
issn = {1538-3687},
support = {P50 AG008702/AG/NIA NIH HHS/United States ; UL1 RR024156/RR/NCRR NIH HHS/United States ; P01 AG007232/AG/NIA NIH HHS/United States ; P50AG008702/AG/NIA NIH HHS/United States ; R01AG037212/AG/NIA NIH HHS/United States ; P01AG007232/AG/NIA NIH HHS/United States ; R01 AG037212/AG/NIA NIH HHS/United States ; UL1RR024156/RR/NCRR NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Apolipoproteins E/genetics ; *Dementia/genetics/mortality/pathology ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Residence Characteristics ; Survival Analysis ; Telomere/*metabolism ; *Telomere Shortening/genetics ; },
abstract = {BACKGROUND: Shortening of chromosomal telomeres is a consequence of cell division and is a biological factor related to cellular aging and potentially to more rapid organismal biological aging.<br><br>OBJECTIVE: To determine whether shorter telomere length (TL), as measured in human blood samples, is associated with the development of Alzheimer disease and mortality.<br><br>DESIGN: We studied available stored leukocyte DNA from a community-based study of aging using realtime polymerase chain reaction analysis to determine mean TL in our modification of a method measuring the ratio of telomere sequence to single-copy gene sequence.<br><br>SETTING: A multiethnic community-based study of aging and dementia.<br><br>PARTICIPANTS: One thousand nine hundred eighty-three subjects 65 years or older. Mean (SD) age at blood draw was 78.3 (6.9) years; at death, 86.0 (7.4) years. Median follow-up for mortality was 9.3 years; 190 (9.6%) developed incident dementia.<br><br>RESULTS: The TL was inversely related to age and shorter in men than women. Persons dying during follow-up had a shorter TL compared with survivors (mean [SD], 6218 [819] vs 6491 [881] base pairs [bp] [P.001]), even after adjustment for age, sex, education, and apolipoprotein E genotype. Individuals who developed dementia had significantly shorter TL (mean [SD], 6131 [798] bp for prevalent cases and 6315 [817] bp for incident cases) compared with those remaining dementia-free (6431 [864] bp). Cox-regression analyses showed that shorter TL was a risk for earlier onset of dementia (P=.05), but stratified analyses for sex showed that this association of age at onset of dementia with shorter TL was significant in women only.<br><br>CONCLUSION: Our findings suggest that shortened leukocyte TL is associated with risks for dementia and mortality and may therefore be a marker of biological aging.},
}
@article {pmid22824788,
year = {2013},
author = {Huang, J and Okuka, M and Lu, W and Tsibris, JC and McLean, MP and Keefe, DL and Liu, L},
title = {Telomere shortening and DNA damage of embryonic stem cells induced by cigarette smoke.},
journal = {Reproductive toxicology (Elmsford, N.Y.)},
volume = {35},
number = {},
pages = {89-95},
doi = {10.1016/j.reprotox.2012.07.003},
pmid = {22824788},
issn = {1873-1708},
mesh = {Animals ; Apoptosis/drug effects ; Cadmium/*toxicity ; Cells, Cultured ; *DNA Damage ; Embryonic Stem Cells/*drug effects/metabolism ; Mice ; Mice, Inbred C57BL ; Smoke/*adverse effects ; Telomere Shortening ; Nicotiana ; Tobacco Smoke Pollution/*adverse effects ; },
abstract = {Embryonic stem cells (ESCs) provide a valuable in vitro model for testing toxicity of chemicals and environmental contaminants including cigarette smoke. Mouse ESCs were acutely or chronically exposed to smoke components, cigarette smoke condensate (CSC), or cadmium, an abundant component of CSC, and then evaluated for their self-renewal, apoptosis, DNA damage and telomere function. Acute exposure of ESCs to high dose of CSC or cadmium increased DNA damage and apoptosis. Yet, ESCs exhibited a remarkable capacity to recover following absence of exposure. Chronic exposure of ESCs to low dose of CSC or cadmium resulted in shorter telomeres and DNA damage. Together, acute exposure of ESCs to CSC or cadmium causes immediate cell death and reduces pluripotency, while chronic exposure of ESCs to CSC or cadmium leads to DNA damage and telomere shortening. Notably, a sub-proportion of ESCs during passages is selected to resist to smoke-induced oxidative damage to telomeres.},
}
@article {pmid22816089,
year = {2012},
author = {Kozhevnikov, VS and Borisov, VI and Korolkova, OY and Kozlov, VA},
title = {Telomere lengthening in CD8(+)cells in polyclonal in vitro stimulation is associated with an increase in protein content of catalytic subunit of telomerase (hTERT).},
journal = {Bulletin of experimental biology and medicine},
volume = {153},
number = {2},
pages = {226-228},
doi = {10.1007/s10517-012-1682-z},
pmid = {22816089},
issn = {1573-8221},
mesh = {CD4-CD8 Ratio ; CD4-Positive T-Lymphocytes/cytology/immunology/*metabolism ; CD8-Positive T-Lymphocytes/cytology/*immunology/*metabolism ; Cells, Cultured ; Humans ; *Lymphocyte Activation ; Telomerase/*metabolism ; *Telomere Homeostasis ; },
abstract = {Culturing of polyclonally activated T lymphocytes for 7 days in vitro leads to telomere lengthening in CD8(+), but not CD4(+)lymphocytes. Under these conditions, CD8(+)lymphocytes more intensively express telomerase catalytic subunit protein (hTERT) and divide more often than CD4(+)lymphocytes. It changes the ratio of CD4(+)and CD8(+)subpopulations in favor of the latter by the end of culturing.},
}
@article {pmid22815702,
year = {2012},
author = {Côté, HC and Soudeyns, H and Thorne, A and Alimenti, A and Lamarre, V and Maan, EJ and Sattha, B and Singer, J and Lapointe, N and Money, DM and Forbes, J and , and Wong, J and Bitnun, A and Samson, L and Brophy, J and Burdge, D and Pick, N and van Schalkwyk, J and Montaner, J and Harris, M and Janssen, P},
title = {Leukocyte telomere length in HIV-infected and HIV-exposed uninfected children: shorter telomeres with uncontrolled HIV viremia.},
journal = {PloS one},
volume = {7},
number = {7},
pages = {e39266},
pmid = {22815702},
issn = {1932-6203},
support = {HET-85515//Canadian Institutes of Health Research/Canada ; MOP-79331//Canadian Institutes of Health Research/Canada ; YSH-80511//Canadian Institutes of Health Research/Canada ; },
mesh = {Adolescent ; Anti-HIV Agents/pharmacology ; Child ; Child, Preschool ; Environmental Exposure/*adverse effects ; Female ; HIV Infections/blood/genetics/*pathology/prevention &amp; control ; Humans ; Infant ; Leukocytes/*drug effects/*pathology ; Linear Models ; Male ; Pregnancy ; Reverse Transcriptase Inhibitors/pharmacology ; Telomerase/antagonists &amp; inhibitors ; Telomere/*drug effects/genetics/*pathology ; Viremia/blood/genetics/*pathology/prevention &amp; control ; Young Adult ; },
abstract = {OBJECTIVES: Nucleoside reverse transcriptase inhibitors (NRTIs) used in HIV antiretroviral therapy can inhibit human telomerase reverse transcriptase. We therefore investigated whether in utero or childhood exposure to NRTIs affects leukocyte telomere length (LTL), a marker of cellular aging.<br><br>METHODS: In this cross-sectional CARMA cohort study, we investigated factors associated with LTL in HIV-1-infected (HIV(+)) children (n&#x200a;=&#x200a;94), HIV-1-exposed uninfected (HEU) children who were exposed to antiretroviral therapy (ART) perinatally (n&#x200a;=&#x200a;177), and HIV-unexposed uninfected (HIV(-)) control children (n&#x200a;=&#x200a;104) aged 0-19 years. Univariate followed by multivariate linear regression models were used to examine relationships of explanatory variables with LTL for: a) all subjects, b) HIV(+)/HEU children only, and c) HIV(+) children only.<br><br>RESULTS: After adjusting for age and gender, there was no difference in LTL between the 3 groups, when considering children of all ages together. In multivariate models, older age and male gender were associated with shorter LTL. For the HIV(+) group alone, having a detectable HIV viral load was also strongly associated with shorter LTL (p&#x200a;=&#x200a;0.007).<br><br>CONCLUSIONS: In this large study, group rates of LTL attrition were similar for HIV(+), HEU and HIV(-) children. No associations between children's LTL and their perinatal ART exposure or HIV status were seen in linear regression models. However, the association between having a detectable HIV viral load and shorter LTL suggests that uncontrolled HIV viremia rather than duration of ART exposure may be associated with acceleration of blood telomere attrition.},
}
@article {pmid22815473,
year = {2012},
author = {Visacka, K and Hofr, C and Willcox, S and Necasova, I and Pavlouskova, J and Sepsiova, R and Wimmerova, M and Simonicova, L and Nosek, J and Fajkus, J and Griffith, JD and Tomaska, L},
title = {Synergism of the two Myb domains of Tay1 protein results in high affinity binding to telomeres.},
journal = {The Journal of biological chemistry},
volume = {287},
number = {38},
pages = {32206-32215},
pmid = {22815473},
issn = {1083-351X},
support = {R01 ES013773/ES/NIEHS NIH HHS/United States ; R01 GM031819/GM/NIGMS NIH HHS/United States ; GM 31819/GM/NIGMS NIH HHS/United States ; ES 03773/ES/NIEHS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Anisotropy ; Biophysics/methods ; Calorimetry/methods ; Chromosome Mapping ; Evolution, Molecular ; Fungal Proteins/*chemistry/metabolism ; Humans ; Kinetics ; Microscopy, Fluorescence/methods ; Molecular Sequence Data ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-myb/*chemistry ; Saccharomyces cerevisiae/metabolism ; Sequence Homology, Amino Acid ; Telomere/ultrastructure ; Telomeric Repeat Binding Protein 1/*chemistry ; Thermodynamics ; Yarrowia/*metabolism ; },
abstract = {Double-stranded regions of the telomeres are recognized by proteins containing Myb-like domains conferring specificity toward telomeric repeats. Although biochemical and structural studies revealed basic molecular principles involved in DNA binding, relatively little is known about evolutionary pathways leading to various types of Myb domain-containing proteins in divergent species of eukaryotes. Recently we identified a novel type of telomere-binding protein YlTay1p from the yeast Yarrowia lipolytica containing two Myb domains (Myb1, Myb2) very similar to the Myb domain of mammalian TRF1 and TRF2. In this study we prepared mutant versions of YlTay1p lacking Myb1, Myb2, or both Myb domains and found that YlTay1p carrying either Myb domain exhibits preferential affinity to both Y. lipolytica (GGGTTAGTCA)(n) and human (TTAGGG)(n) telomeric sequences. Quantitative measurements of the protein binding to telomeric DNA revealed that the presence of both Myb domains is required for a high affinity of YlTay1p to either telomeric repeat. Additionally, we performed detailed thermodynamic analysis of the YlTay1p interaction with its cognate telomeric DNA, which is to our knowledge the first energetic description of a full-length telomeric-protein binding to DNA. Interestingly, when compared with human TRF1 and TRF2 proteins, YlTay1p exhibited higher affinity not only for Y. lipolytica telomeres but also for human telomeric sequences. The duplication of the Myb domain region in YlTay1p thus produces a synergistic effect on its affinity toward the cognate telomeric sequence, alleviating the need for homodimerization observed in TRF-like proteins possessing a single Myb domain.},
}
@article {pmid22810623,
year = {2012},
author = {Kazda, A and Zellinger, B and Rössler, M and Derboven, E and Kusenda, B and Riha, K},
title = {Chromosome end protection by blunt-ended telomeres.},
journal = {Genes &amp; development},
volume = {26},
number = {15},
pages = {1703-1713},
pmid = {22810623},
issn = {1549-5477},
support = {Y 418/FWF_/Austrian Science Fund FWF/Austria ; },
mesh = {Arabidopsis/*metabolism ; Arabidopsis Proteins/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes, Plant/*metabolism ; DNA Helicases/metabolism ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/metabolism ; Exodeoxyribonucleases/metabolism ; Recombination, Genetic ; Telomere/*metabolism ; },
abstract = {Single-stranded telomeric DNA protrusions are considered to be evolutionarily conserved structural elements essential for chromosome end protection. Their formation at telomeres replicated by the leading strand mechanism is thought to involve poorly understood post-replicative processing of blunt ends. Unexpectedly, we found that angiosperm plants contain blunt-ended and short (1- to 3-nucleotide) G-overhang-containing telomeres that are stably retained in post-mitotic tissues, revealing a novel mechanism of chromosome end protection. The integrity of blunt-ended telomeres depends on the Ku70/80 heterodimer but not on another telomere capping protein, STN1. Curiously, Ku-depleted telomeres are fully functional. They are resected by exonuclease 1, promoting intrachromatid recombination, which may facilitate formation of an alternative capping structure. These data challenge the view that telomeres require ssDNA protrusions for forming a functional capping structure and demonstrate flexibility in solutions to the chromosome end protection problem.},
}
@article {pmid22808278,
year = {2012},
author = {Plot, V and Criscuolo, F and Zahn, S and Georges, JY},
title = {Telomeres, age and reproduction in a long-lived reptile.},
journal = {PloS one},
volume = {7},
number = {7},
pages = {e40855},
pmid = {22808278},
issn = {1932-6203},
mesh = {Animals ; Clutch Size ; DNA/blood ; Female ; French Guiana ; Longevity/*physiology ; Models, Biological ; Reproduction/physiology ; Telomere/*metabolism ; Telomere Homeostasis ; Turtles/blood/*physiology ; },
abstract = {A major interest has recently emerged in understanding how telomere shortening, mechanism triggering cell senescence, is linked to organism ageing and life history traits in wild species. However, the links between telomere length and key history traits such as reproductive performances have received little attention and remain unclear to date. The leatherback turtle Dermochelys coriacea is a long-lived species showing rapid growth at early stages of life, one of the highest reproductive outputs observed in vertebrates and a dichotomised reproductive pattern related to migrations lasting 2 or 3 years, supposedly associated with different environmental conditions. Here we tested the prediction of blood telomere shortening with age in this species and investigated the relationship between blood telomere length and reproductive performances in leatherback turtles nesting in French Guiana. We found that blood telomere length did not differ between hatchlings and adults. The absence of blood telomere shortening with age may be related to an early high telomerase activity. This telomere-restoring enzyme was formerly suggested to be involved in preventing early telomere attrition in early fast-growing and long-lived species, including squamate reptiles. We found that within one nesting cycle, adult females having performed shorter migrations prior to the considered nesting season had shorter blood telomeres and lower reproductive output. We propose that shorter blood telomeres may result from higher oxidative stress in individuals breeding more frequently (i.e., higher costs of reproduction) and/or restoring more quickly their body reserves in cooler feeding areas during preceding migration (i.e., higher foraging costs). This first study on telomeres in the giant leatherback turtle suggests that blood telomere length predicts not only survival chances, but also reproductive performances. Telomeres may therefore be a promising new tool to evaluate individual reproductive quality which could be useful in such species of conservation concern.},
}
@article {pmid22808180,
year = {2012},
author = {Okereke, OI and Prescott, J and Wong, JY and Han, J and Rexrode, KM and De Vivo, I},
title = {High phobic anxiety is related to lower leukocyte telomere length in women.},
journal = {PloS one},
volume = {7},
number = {7},
pages = {e40516},
pmid = {22808180},
issn = {1932-6203},
support = {R03 CA139586/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA082838/CA/NCI NIH HHS/United States ; R01 HL088521/HL/NHLBI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; K08 AG029813/AG/NIA NIH HHS/United States ; R01 CA49449/CA/NCI NIH HHS/United States ; R01 CA065725/CA/NCI NIH HHS/United States ; P01 CA87969/CA/NCI NIH HHS/United States ; R01 HL034594/HL/NHLBI NIH HHS/United States ; R03 CA132190/CA/NCI NIH HHS/United States ; K07 CA140790/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Anxiety Disorders/*genetics ; Body Mass Index ; Female ; Humans ; Least-Squares Analysis ; Leukocytes/*metabolism ; Middle Aged ; Paternal Age ; Smoking/genetics ; Telomere Homeostasis/*genetics ; },
abstract = {BACKGROUND: Chronic psychological distress has been linked to shorter telomeres, an indication of accelerated aging. Yet, little is known about relations of anxiety to telomeres. We examined whether a typically chronic form of anxiety--phobic anxiety--is related to telomere length.<br><br>Relative telomere lengths (RTLs) in peripheral blood leukocytes were measured by quantitative real-time polymerase chain reaction among 5,243 women (aged 42-69 years) who: were participants in the Nurses' Health Study; were controls in prior case-control studies of telomeres and disease, or randomly selected healthy participants in a cognitive function sub-study; had completed the Crown-Crisp phobic index proximal to blood collection. Adjusted least-squares mean RTLs (z-scores) were calculated across phobic categories. Higher phobic anxiety was generally associated with lower RTLs (age-adjusted p-trend = 0.09); this association was similar after adjustment for confounders--paternal age-at-birth, smoking, body mass index (BMI) and physical activity (p-trend = 0.15). Notably, a threshold was identified. Among women with Crown-Crisp<6 points, the multivariable-adjusted least-squares mean RTL z-score = 0.02 standard units; however, among the most phobic women (Crown-Crisp &#x2265; 6), the multivariable-adjusted least-squares mean RTL z-score = -0.09 standard units (mean difference = -0.10 standard units; p = 0.02). The magnitude of this difference was comparable to that for women 6 years apart in age. Finally, effect modification by BMI, smoking and paternal age was observed: associations were stronger among highly phobic women with BMI &#x2265; 25 kg/m(2), without smoking history, or born to fathers aged &#x2265; 40 years.<br><br>CONCLUSIONS/SIGNIFICANCE: In this large, cross-sectional study high phobic anxiety was associated with shorter telomeres. These results point toward prospective investigations relating anxiety to telomere length change.},
}
@article {pmid22808115,
year = {2012},
author = {Ahola, K and Sirén, I and Kivimäki, M and Ripatti, S and Aromaa, A and Lönnqvist, J and Hovatta, I},
title = {Work-related exhaustion and telomere length: a population-based study.},
journal = {PloS one},
volume = {7},
number = {7},
pages = {e40186},
pmid = {22808115},
issn = {1932-6203},
support = {G19/35/MRC_/Medical Research Council/United Kingdom ; G0100222/MRC_/Medical Research Council/United Kingdom ; G8802774/MRC_/Medical Research Council/United Kingdom ; G0902037/MRC_/Medical Research Council/United Kingdom ; RG/07/008/23674/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Adult ; Aging/genetics ; Fatigue ; Female ; Finland ; Humans ; Leukocytes ; Male ; Middle Aged ; Stress, Psychological/*genetics ; Telomere Homeostasis/*genetics ; Work/*psychology ; },
abstract = {BACKGROUND: Psychological stress is suggested to accelerate the rate of biological aging. We investigated whether work-related exhaustion, an indicator of prolonged work stress, is associated with accelerated biological aging, as indicated by shorter leukocyte telomeres, that is, the DNA-protein complexes that cap chromosomal ends in cells.<br><br>METHODS: We used data from a representative sample of the Finnish working-age population, the Health 2000 Study. Our sample consisted of 2911 men and women aged 30-64. Work-related exhaustion was assessed using the Maslach Burnout Inventory--General Survey. We determined relative leukocyte telomere length using a quantitative real-time polymerase chain reaction (PCR) -based method.<br><br>RESULTS: After adjustment for age and sex, individuals with severe exhaustion had leukocyte telomeres on average 0.043 relative units shorter (standard error of the mean 0.016) than those with no exhaustion (p = 0.009). The association between exhaustion and relative telomere length remained significant after additional adjustment for marital and socioeconomic status, smoking, body mass index, and morbidities (adjusted difference 0.044 relative units, standard error of the mean 0.017, p = 0.008).<br><br>CONCLUSIONS: These data suggest that work-related exhaustion is related to the acceleration of the rate of biological aging. This hypothesis awaits confirmation in a prospective study measuring changes in relative telomere length over time.},
}
@article {pmid22805138,
year = {2012},
author = {Touzot, F and Le Guen, T and de Villartay, JP and Revy, P},
title = {[Dyskeratosis congenita: short telomeres are not the rule].},
journal = {Medecine sciences : M/S},
volume = {28},
number = {6-7},
pages = {618-624},
doi = {10.1051/medsci/2012286015},
pmid = {22805138},
issn = {0767-0974},
mesh = {DNA Replication/genetics/physiology ; Dyskeratosis Congenita/diagnosis/etiology/*genetics ; Fetal Growth Retardation/diagnosis/genetics ; Humans ; Intellectual Disability/diagnosis/genetics ; Microcephaly/diagnosis/genetics ; Models, Biological ; Ribonucleoproteins/metabolism/physiology ; Telomerase/genetics/metabolism ; Telomere/genetics/metabolism/*physiology ; },
abstract = {Telomeres are nucleoprotein structures at the end of linear chromosomes. Their length, structure, and integrity are regulated by the telomerase complex, the shelterins and components of the DNA damage response. In human subjects, defects in telomere maintenance are responsible for Dyskeratosis Congenita (DC), a rare genetic disorder characterized by aplastic anaemia, premature aging and predisposition to cancer. Recent data from the study of patients with Hoyeraal-Hreidarsson syndrome, a severe variant of DC, demonstrate the great molecular heterogeneity of this disease. While most cases of DC are associated with defects in factors involved in telomere length regulation, some severe forms of the disease seem to be rather associated with defects in telomere replication and protection.},
}
@article {pmid22796264,
year = {2012},
author = {Sidibe, A and Hamon, F and Largy, E and Gomez, D and Teulade-Fichou, MP and Trentesaux, C and Riou, JF},
title = {Effects of a halogenated G-quadruplex ligand from the pyridine dicarboxamide series on the terminal sequence of XpYp telomere in HT1080 cells.},
journal = {Biochimie},
volume = {94},
number = {12},
pages = {2559-2568},
doi = {10.1016/j.biochi.2012.07.003},
pmid = {22796264},
issn = {1638-6183},
mesh = {Base Composition/drug effects/genetics ; Base Sequence ; Bromine/chemistry/metabolism ; Cell Line ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA/*chemistry/genetics/metabolism ; Fluorescence Resonance Energy Transfer ; *G-Quadruplexes ; HCT116 Cells ; Halogenation ; Humans ; Ligands ; Pyridines/*chemistry/metabolism/pharmacology ; Quinolines/*chemistry/metabolism/pharmacology ; RNA Interference ; Shelterin Complex ; Spectrometry, Mass, Electrospray Ionization ; Telomere/*chemistry/genetics/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Non-canonical four-stranded structures called G-quadruplexes can form among telomere repeats during its replication. Small molecule ligands able to interact and to stabilize G-quadruplexes were shown to disrupt the binding of essential telomeric components, such as POT1 and to trigger a telomeric dysfunction associated with a delayed growth arrest in tumor cells. We describe here the chemical synthesis and the G-quadruplex binding properties of three halogenated analogs of the 360A ligand that belongs to the 2,6 pyridine dicarboxamide series. 360A is now commonly used as a benchmark both for biophysical and cellular assays as this compound was shown to display a potent affinity and selectivity for telomeric G-quadruplex DNA over duplex DNA and to induce delayed growth inhibition in HT1080 tumor cell line. Two biophysical assays indicate that, in most cases, the presence of the halogen atom seems to slightly improve the interaction with the telomeric quadruplex. For stability reasons, the bromo derivative (360A-Br) was selected for the cellular assays. Since POT1 participates to the fine tuning of the C-strand end resection during telomere replication, we investigated the effect of 360A-Br to alter the terminal nucleotide composition of XpYp telomere in HT1080 cells using C-STELA. HT1080 cells treated for up to 24 days with 360A-Br presented some minor but significant variations of C-strand terminal nucleotide composition, also observed with a partial siRNA depletion of POT1. The relevance of these minor modifications of the telomeric C-strand resection induced by 360A-Br in HT1080 cells are discussed.},
}
@article {pmid22793690,
year = {2012},
author = {Chen, LY and Lingner, J},
title = {AUF1/HnRNP D RNA binding protein functions in telomere maintenance.},
journal = {Molecular cell},
volume = {47},
number = {1},
pages = {1-2},
doi = {10.1016/j.molcel.2012.06.031},
pmid = {22793690},
issn = {1097-4164},
abstract = {In this issue of Molecular Cell, Pont et al. (2012) show that AUF1/hnRNP D promotes TERT transcription, which is required for telomere maintenance in mice.},
}
@article {pmid22792358,
year = {2012},
author = {Kim, S and Parks, CG and Xu, Z and Carswell, G and DeRoo, LA and Sandler, DP and Taylor, JA},
title = {Association between genetic variants in DNA and histone methylation and telomere length.},
journal = {PloS one},
volume = {7},
number = {7},
pages = {e40504},
pmid = {22792358},
issn = {1932-6203},
support = {Z01 ES044005//Intramural NIH HHS/United States ; Z01 ES049033//Intramural NIH HHS/United States ; },
mesh = {Adult ; Aged ; Alleles ; Carbon/metabolism ; DNA Damage ; DNA Methylation ; Female ; *Genetic Variation ; Genotype ; Histones/*metabolism ; Humans ; Methylation ; Middle Aged ; Polymorphism, Single Nucleotide ; Signal Transduction ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomere length, a biomarker of aging and age-related diseases, exhibits wide variation between individuals. Common genetic variation may explain some of the individual differences in telomere length. To date, however, only a few genetic variants have been identified in the previous genome-wide association studies. As emerging data suggest epigenetic regulation of telomere length, we investigated 72 single nucleotide polymorphisms (SNPs) in 46 genes that involve DNA and histone methylation as well as telomerase and telomere-binding proteins and DNA damage response. Genotyping and quantification of telomere length were performed in blood samples from 989 non-Hispanic white participants of the Sister Study, a prospective cohort of women aged 35-74 years. The association of each SNP with logarithmically-transformed relative telomere length was estimated using multivariate linear regression. Six SNPs were associated with relative telomere length in blood cells with p-values<0.05 (uncorrected for multiple comparisons). The minor alleles of BHMT rs3733890 G>A (p = 0.041), MTRR rs2966952 C>T (p = 0.002) and EHMT2 rs558702 G>A (p = 0.008) were associated with shorter telomeres, while minor alleles of ATM rs1801516 G>A (p = 0.031), MTR rs1805087 A>G (p = 0.038) and PRMT8 rs12299470 G>A (p = 0.019) were associated with longer telomeres. Five of these SNPs are located in genes coding for proteins involved in DNA and histone methylation. Our results are consistent with recent findings that chromatin structure is epigenetically regulated and may influence the genomic integrity of telomeric region and telomere length maintenance. Larger studies with greater coverage of the genes implicated in DNA methylation and histone modifications are warranted to replicate these findings.},
}
@article {pmid22792222,
year = {2012},
author = {Pearce, MS and Mann, KD and Martin-Ruiz, C and Parker, L and White, M and von Zglinicki, T and Adams, J},
title = {Childhood growth, IQ and education as predictors of white blood cell telomere length at age 49-51 years: the Newcastle Thousand Families Study.},
journal = {PloS one},
volume = {7},
number = {7},
pages = {e40116},
pmid = {22792222},
issn = {1932-6203},
support = {G0900686/MRC_/Medical Research Council/United Kingdom ; /BHF_/British Heart Foundation/United Kingdom ; /CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Adult ; *Birth Weight ; Child ; Child Development ; Child, Preschool ; *Educational Status ; England ; Female ; Humans ; Infant ; Infant, Newborn ; *Intelligence ; Life Style ; Longitudinal Studies ; Male ; Middle Aged ; *Telomere ; },
abstract = {BACKGROUND: Telomere length is emerging as a potential factor in the pathogenesis of cardiovascular disease. We investigated whether birth weight, infant growth, childhood cognition and adult height, as well as a range of lifestyle, socio-economic and educational factors, were associated with white blood cell telomere length at age 49-51 years.<br><br>METHODS: The study included 318 members of the Newcastle Thousand Families Study, a prospectively followed birth cohort which includes all individuals born in Newcastle, England in May and June 1947, who attended for clinical examination at age 49-51 years, and had telomere length successfully measured using real-time PCR analyses of DNA extracted from peripheral blood mononuclear cells.<br><br>RESULTS: No association was found between birth weight and later telomere length. However, associations were seen with other factors from early life. Education level was the only predictor in males, while telomere length in females was associated with gestational age at birth, childhood growth and childhood IQ.<br><br>CONCLUSIONS: While these findings may be due to chance, in particular where differing associations were seen between males and females, they do provide evidence of early life associations with telomere length much later in life. Our findings of sex differences in the education association may reflect the sex differences in achieved education levels in this generation where few women went to university regardless of their intelligence. Our findings do not support the concept of telomere length being on the pathway between very early growth and later disease risk.},
}
@article {pmid22792162,
year = {2012},
author = {McLaughlan, JM and Liti, G and Sharp, S and Maslowska, A and Louis, EJ},
title = {Apparent ploidy effects on silencing are post-transcriptional at HML and telomeres in Saccharomyces cerevisiae.},
journal = {PloS one},
volume = {7},
number = {7},
pages = {e39044},
pmid = {22792162},
issn = {1932-6203},
support = {//Wellcome Trust/United Kingdom ; BB/F015216/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; WT084507/WT_/Wellcome Trust/United Kingdom ; C6950/A9435/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Chromatin/genetics/metabolism ; Diploidy ; *Gene Expression Regulation, Fungal ; *Gene Silencing ; Genes, Mating Type, Fungal ; Genes, Reporter ; *Ploidies ; Promoter Regions, Genetic ; *Quantitative Trait Loci ; *RNA Processing, Post-Transcriptional ; Saccharomyces cerevisiae/*genetics/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Telomere/*genetics/metabolism ; Transcription, Genetic ; },
abstract = {The repression of genes in regions of heterochromatin is known as transcriptional silencing. It occurs in a wide range of organisms and can have importance in adaptation to the environment, developmental changes and disease. The model organism Saccharomyces cerevisiae has been used for many years to study transcriptional silencing, but until recently no study has been made in relation to ploidy. The aim of this work was to compare transcriptional silencing in haploids and diploids at both telomeres and the hidden mating-type (HM) loci. Transcriptional silencing was assayed, by growth on 5-fluoroorotic acid (5-FOA) media or by flow cytometry, on strains where a telomere or HM locus was marked. RNA levels were measured by quantitative RT-PCR to confirm that effects were transcriptional. 5-FOA assays and flow cytometry were consistent with transcriptional silencing at telomeres and at HML being reduced as ploidy increases which agreed with conclusions in previous publications. However, QRT-PCR revealed that transcriptional silencing was unaffected by ploidy and thus protein levels were increasing independently of RNA levels. At telomere XI left (XI-L), changes in protein level were strongly influenced by mating-type, whereas at HML mating-type had much less influence. The post-transcriptional effects seen in this study, illustrate the often ignored need to measure RNA levels when assaying transcriptional silencing in Saccharomyces cerevisiae.},
}
@article {pmid22790277,
year = {2012},
author = {Müller, S and Sanders, DA and Di Antonio, M and Matsis, S and Riou, JF and Rodriguez, R and Balasubramanian, S},
title = {Pyridostatin analogues promote telomere dysfunction and long-term growth inhibition in human cancer cells.},
journal = {Organic &amp; biomolecular chemistry},
volume = {10},
number = {32},
pages = {6537-6546},
pmid = {22790277},
issn = {1477-0539},
support = {11961/CRUK_/Cancer Research UK/United Kingdom ; 12488/CRUK_/Cancer Research UK/United Kingdom ; BB/G008337/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Aminoquinolines/chemistry/*pharmacology ; Antineoplastic Agents/chemistry/*pharmacology ; Base Sequence ; Cell Line, Tumor ; Cell Survival/drug effects ; G-Quadruplexes/drug effects ; Humans ; Models, Biological ; Molecular Sequence Data ; Molecular Structure ; Picolinic Acids/chemistry/*pharmacology ; Static Electricity ; Telomere/*drug effects ; },
abstract = {The synthesis, biophysical and biological evaluation of a series of G-quadruplex interacting small molecules based on a N,N'-bis(quinolinyl)pyridine-2,6-dicarboxamide scaffold is described. The synthetic analogues were evaluated for their ability to stabilize telomeric G-quadruplex DNA, some of which showed very high stabilization potential associated with high selectivity over double-stranded DNA. The compounds exhibited growth arrest of cancer cells with detectable selectivity over normal cells. Long-time growth arrest was accompanied by senescence, where telomeric dysfunction is a predominant mechanism together with the accumulation of restricted DNA damage sites in the genome. Our data emphasize the potential of a senescence-mediated anticancer therapy through the use of G-quadruplex targeting small molecules based on the molecular framework of pyridostatin.},
}
@article {pmid22784978,
year = {2012},
author = {Harbo, M and Koelvraa, S and Serakinci, N and Bendix, L},
title = {Telomere dynamics in human mesenchymal stem cells after exposure to acute oxidative stress.},
journal = {DNA repair},
volume = {11},
number = {9},
pages = {774-779},
doi = {10.1016/j.dnarep.2012.06.003},
pmid = {22784978},
issn = {1568-7856},
mesh = {Cell Line ; Cellular Senescence/drug effects/genetics ; DNA Damage ; Genes, Reporter ; Humans ; Hydrogen Peroxide/pharmacology ; Mesenchymal Stem Cells/drug effects/*metabolism ; *Oxidative Stress ; Telomere/drug effects/metabolism ; Telomere Homeostasis/drug effects ; *Telomere Shortening ; beta-Galactosidase/genetics ; },
abstract = {A gradual shortening of telomeres due to replication can be measured using the standard telomere restriction fragments (TRF) assay and other methods by measuring the mean length of all the telomeres in a cell. In contrast, stress-induced telomere shortening, which is believed to be just as important for causing cellular senescence, cannot be measured properly using these methods. Stress-induced telomere shortening caused by, e.g. oxidative damage happens in a stochastic manner leaving just a few single telomeres critically short. It is now possible to visualize these few ultra-short telomeres due to the advantages of the newly developed Universal single telomere length assay (STELA), and we therefore believe that this method should be considered the method of choice when measuring the length of telomeres after exposure to oxidative stress. In order to test our hypothesis, cultured human mesenchymal stem cells, either primary or hTERT immortalized, were exposed to sub-lethal doses of hydrogen peroxide, and the short term effect on telomere dynamics was monitored by Universal STELA and TRF measurements. Both telomere measures were then correlated with the percentage of senescent cells estimated by senescence-associated β-galactosidase staining. The exposure to acute oxidative stress resulted in an increased number of ultra-short telomeres, which correlated strongly with the percentage of senescent cells, whereas a correlation between mean telomere length and the percentage of senescent cells was absent. Based on the findings in the present study, it seems reasonable to conclude that Universal STELA is superior to TRF in detecting telomere damage caused by exposure to oxidative stress. The choice of method should therefore be considered carefully in studies examining stress-related telomere shortening as well as in the emerging field of lifestyle studies involving telomere length measurements.},
}
@article {pmid22782639,
year = {2012},
author = {Aston, KI and Hunt, SC and Susser, E and Kimura, M and Factor-Litvak, P and Carrell, D and Aviv, A},
title = {Divergence of sperm and leukocyte age-dependent telomere dynamics: implications for male-driven evolution of telomere length in humans.},
journal = {Molecular human reproduction},
volume = {18},
number = {11},
pages = {517-522},
pmid = {22782639},
issn = {1460-2407},
support = {AG30678/AG/NIA NIH HHS/United States ; MH059114/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aging/*genetics ; Biological Evolution ; Blotting, Southern ; DNA Replication ; Humans ; *Inheritance Patterns ; Leukocytes/cytology/*metabolism ; Male ; Middle Aged ; Organ Specificity ; Paternal Age ; Spermatozoa/cytology/*metabolism ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {Telomere length (TL) dynamics in vivo are defined by TL and its age-dependent change, brought about by cell replication. Leukocyte TL (LTL), which reflects TL in hematopoietic stem cells (HSCs), becomes shorter with age. In contrast, sperm TL, which reflects TL in the male germ cells, becomes longer with age. Moreover, offspring of older fathers display longer LTL. Thus far, no study has examined LTL and sperm TL relations with age in the same individuals, nor considered their implications for the paternal age at conception (PAC) effect on offspring LTL. We report that in 135 men (mean age: 34.4 years; range: 18-68 years) on average, LTL became shorter by 19 bp/year (r = -0.3; P = 0.0004), while sperm TL became longer by 57 bp/year (r = 0.32; P = 0.0002). Based on previously reported replication rates of HSCs and male germ cells, we estimate that HSCs lose 26 bp per replication. However, male germ cells gain only 2.48 bp per replication. As TL is inherited in an allele-specific manner, the magnitude of the PAC effect on the offspring's LTL should be approximately half of age-dependent sperm-TL elongation. When we compared the PAC effect data from previous studies with sperm-TL data from this study, the result was consistent with this prediction. As older paternal age is largely a feature of contemporary humans, we suggest that there may be progressive elongation of TL in future generations. In this sense, germ cell TL dynamics could be driving the evolution of TL in modern humans and perhaps telomere-related diseases in the general population.},
}
@article {pmid22775391,
year = {2012},
author = {Aini, W and Miyagawa-Hayashino, A and Tsuruyama, T and Hashimoto, S and Sumiyoshi, S and Ozeki, M and Tamaki, K and Uemoto, S and Haga, H},
title = {Telomere shortening and karyotypic alterations in hepatocytes in long-term transplanted human liver allografts.},
journal = {Transplant international : official journal of the European Society for Organ Transplantation},
volume = {25},
number = {9},
pages = {956-966},
doi = {10.1111/j.1432-2277.2012.01523.x},
pmid = {22775391},
issn = {1432-2277},
mesh = {Adolescent ; Aneuploidy ; Biopsy ; Child ; Child, Preschool ; Female ; Follow-Up Studies ; Graft Survival ; Hepatitis/complications/etiology ; Hepatocytes/*pathology ; Humans ; Immunosuppressive Agents ; In Situ Hybridization, Fluorescence ; Infant ; Karyotyping ; Liver Failure/*genetics/*therapy ; Liver Transplantation/*methods ; Male ; Multivariate Analysis ; Telomere/*ultrastructure ; Transplantation, Homologous ; Treatment Outcome ; },
abstract = {The long-term fate of aged liver allografts in young recipients who received grafts from older donors is unknown. We evaluated graft aging by analyzing hepatocytic telomere length and karyotypic changes. Seventeen pediatric individuals who underwent living-donor liver transplantation for congenital biliary diseases were selected. At a median of 10.4 years post-transplant, ten had tolerated grafts with weaned off immunosuppressants, and seven had idiopathic post-transplantation hepatitis. Fluorescence in situ hybridization was used to evaluate the telomere signal intensity (TI) and karyotypic changes. First, we measured predictive age-dependent TI decline with regression analysis of donor livers. The mean TI at the earliest (within a year) and latest biopsies was significantly lower than the predicted TI of the studied allografts. With univariate analysis, a higher abnormal karyotype ratio in the donor liver was correlated with development of idiopathic post-transplantation hepatitis. With multivariate analysis that included clinical parameters, a greater TI decline at the earliest biopsy was correlated with the development of idiopathic post-transplantation hepatitis. In conclusion, graft aging as measured by TI decline and donor abnormal karyotype ratio was associated with idiopathic post-transplantation hepatitis of long-term transplanted liver allografts.},
}
@article {pmid22772478,
year = {2012},
author = {Ballen, C and Healey, M and Wilson, M and Tobler, M and Olsson, M},
title = {Predictors of telomere content in dragon lizards.},
journal = {Die Naturwissenschaften},
volume = {99},
number = {8},
pages = {661-664},
pmid = {22772478},
issn = {1432-1904},
mesh = {Animals ; Australia ; Female ; Lizards/*genetics ; Superoxides/analysis ; Telomere/*genetics ; Telomere Shortening ; },
abstract = {Telomeres shorten as a consequence of DNA replication, in particular in cells with low production of telomerase and perhaps in response to physiological stress from exposure to reactive oxygen species, such as superoxide. This process of telomere attrition is countered by innate antioxidation, such as via the production of superoxide dismutase. We studied the inheritance of telomere length in the Australian painted dragon lizard (Ctenophorus pictus) and the extent to which telomere length covaries with mass-corrected maternal reproductive investment, which reflects the level of circulating yolk precursor and antioxidant, vitellogenin. Our predictors of offspring telomere length explained 72 % of telomere variation (including interstitial telomeres if such are present). Maternal telomere length and reproductive investment were positively influencing offspring telomere length in our analyses, whereas flow cytometry-estimated superoxide level was negatively impacting offspring telomere length. We suggest that the effects of superoxide on hatchling telomere shortening may be partly balanced by transgenerational effects of vitellogenin antioxidation.},
}
@article {pmid22770844,
year = {2012},
author = {Sibille, KT and Witek-Janusek, L and Mathews, HL and Fillingim, RB},
title = {Telomeres and epigenetics: potential relevance to chronic pain.},
journal = {Pain},
volume = {153},
number = {9},
pages = {1789-1793},
pmid = {22770844},
issn = {1872-6623},
support = {UL1 RR029890/RR/NCRR NIH HHS/United States ; UL1 TR000064/TR/NCATS NIH HHS/United States ; P30 AG028740/AG/NIA NIH HHS/United States ; R01 AG033906/AG/NIA NIH HHS/United States ; R01 CA134736/CA/NCI NIH HHS/United States ; U01 DE017018/DE/NIDCR NIH HHS/United States ; AG0333906 07S1/AG/NIA NIH HHS/United States ; NIH/CA134736/CA/NCI NIH HHS/United States ; KL2 TR000065/TR/NCATS NIH HHS/United States ; },
mesh = {Chronic Pain/*genetics ; DNA Methylation/physiology ; Epigenesis, Genetic/*genetics ; *Gene-Environment Interaction ; Histones/metabolism ; Humans ; Leukocytes, Mononuclear/metabolism ; Telomere/*metabolism ; Telomere Homeostasis/genetics ; Telomere Shortening/genetics ; },
}
@article {pmid22762309,
year = {2012},
author = {Sabatino, L and Picano, E and Andreassi, MG},
title = {Telomere shortening and ionizing radiation: a possible role in vascular dysfunction?.},
journal = {International journal of radiation biology},
volume = {88},
number = {11},
pages = {830-839},
doi = {10.3109/09553002.2012.709307},
pmid = {22762309},
issn = {1362-3095},
mesh = {Animals ; Humans ; *Models, Cardiovascular ; *Models, Genetic ; Telomere/*genetics/*radiation effects ; Telomere Shortening/*genetics/*radiation effects ; Vascular Diseases/etiology/*genetics ; },
abstract = {PURPOSE: In recent years, growing epidemiological evidence has linked ionizing radiation exposure to cardiovascular atherosclerotic disease. However, there are still major gaps in the knowledge of the molecular mechanisms of radiation-induced vascular disease, especially for low-dose levels. Telomeres, repetitive DNA sequences of (TTAGGG)(n) located at the ends of eukaryotic chromosomes, play a role in regulating vascular aging, and shorter leukocyte telomere length has been demonstrated to predict cardiovascular disease and mortality. There is also evidence supporting the crucial role of telomeres in the formation of chromosome and chromatid aberrations induced by ionizing radiation.<br><br>CONCLUSIONS: The purpose of the present paper is to review the recent advances in the biological mechanisms determining telomere length erosion after ionizing radiation exposure as well as to examine the hypothesis that telomere shortening may be the crucial mediator leading to detrimental vascular effects after ionizing radiation exposure.},
}
@article {pmid22760118,
year = {2012},
author = {Stower, H},
title = {Telomeres: stem cells, cancer and telomerase linked by WNT.},
journal = {Nature reviews. Molecular cell biology},
volume = {13},
number = {8},
pages = {480},
pmid = {22760118},
issn = {1471-0080},
}
@article {pmid22759813,
year = {2012},
author = {Silva-Sousa, R and López-Panadѐs, E and Casacuberta, E},
title = {Drosophila telomeres: an example of co-evolution with transposable elements.},
journal = {Genome dynamics},
volume = {7},
number = {},
pages = {46-67},
doi = {10.1159/000337127},
pmid = {22759813},
issn = {1660-9263},
mesh = {Animals ; Chromosome Mapping ; Drosophila/*genetics ; Drosophila Proteins/*genetics ; Epigenesis, Genetic ; Evolution, Molecular ; Gene Products, gag/*genetics ; *Genome, Insect ; Models, Genetic ; Retroelements/*genetics ; Species Specificity ; Telomere/*genetics ; Telomere Homeostasis/genetics ; },
abstract = {Telomeres have a DNA component composed of repetitive sequences. In most eukaryotes these repeats are very similar in length and sequence and are maintained by a highly conserved specialized cellular enzyme, telomerase. Some exceptions of the telomerase mechanism exist in eukaryotes of which the most studied are concentrated in insects, and from these, Drosophila species stand out in particular. The alternative mechanism of telomere maintenance in Drosophila is based on targeted transposition of 3 very special non-LTR retrotransposons, HeT-A, TART and TAHRE. The fingerprint of the co-evolution between the Drosophila genome and the telomeric retrotransposons is visible in special features of both. In this chapter, we will review the main aspects of Drosophila telomeres and the telomere retrotransposons that explain how this alternative mechanism works, is regulated, and evolves. By going through the different aspects of this symbiotic relationship, we will try to unravel which have been the necessary changes at Drosophila telomeres in order to exert their telomeric function analogously to telomerase telomeres, and also which particularities have been maintained in order to preserve the retrotransposon personality of HeT-A, TART and TAHRE. Drosophila telomeres constitute a remarkable variant that reminds us how exceptions should be treasured in order to widen our knowledge in any particular biological mechanism.},
}
@article {pmid22759812,
year = {2012},
author = {Silvestre, DC and Londoño-Vallejo, A},
title = {Telomere dynamics in mammals.},
journal = {Genome dynamics},
volume = {7},
number = {},
pages = {29-45},
doi = {10.1159/000337128},
pmid = {22759812},
issn = {1660-9263},
mesh = {Animals ; Chromatin/genetics ; DNA/*genetics ; DNA Damage/genetics ; DNA Repair/*genetics ; Genetic Heterogeneity ; Genomic Instability ; Humans ; Mammals ; Protein Subunits/genetics ; Shelterin Complex ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/genetics ; },
abstract = {Telomeres are specialized structures found at the end of linear chromosomes. Telomere structure and functions are conserved throughout evolution and are essential for genome stability, preventing chromosome ends from being recognized as damaged DNA and from being fused or degraded by the DNA repair machinery. The structure of telomeres is intrinsically dynamic and affected by multiple processes that impact their length and nucleoprotein composition, thus leading to functional and structural heterogeneity. We review here the most significant facets of telomere metabolism and its dynamics, with an emphasis on human biology.},
}
@article {pmid22754337,
year = {2012},
author = {Zhang, X and Wu, X and Tang, W and Luo, Y},
title = {Loss of p16(Ink4a) function rescues cellular senescence induced by telomere dysfunction.},
journal = {International journal of molecular sciences},
volume = {13},
number = {5},
pages = {5866-5877},
pmid = {22754337},
issn = {1422-0067},
mesh = {Animals ; Cells, Cultured ; *Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p16/deficiency/*genetics ; DNA Damage ; Doxorubicin/*pharmacology ; Embryo, Mammalian/cytology ; Fibroblasts/*cytology/drug effects ; Gene Expression Regulation, Developmental ; Gene Knock-In Techniques ; Mice ; RecQ Helicases/*deficiency/genetics ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Tumor Suppressor Protein p53/metabolism ; Werner Syndrome Helicase ; },
abstract = {p16(Ink4a) is a tumor suppressor and a marker for cellular senescence. Previous studies have shown that p16(Ink4a) plays an important role in the response to DNA damage signals caused by telomere dysfunction. In this study, we crossed Wrn(-/-) and p16(Ink4a-/-) mice to knock out the p16(Ink4a) function in a Wrn null background. Growth curves showed that loss of p16(Ink4a) could rescue the growth barriers that are observed in Wrn(-/-) mouse embryonic fibroblasts (MEFs). By challenging the MEFs with the global genotoxin doxorubicin, we showed that loss of p16(Ink4a) did not dramatically affect the global DNA damage response of Wrn(-/-) MEFs induced by doxorubicin. However, in response to telomere dysfunction initiated by the telomere damaging protein TRF2(ΔBΔM), loss of p16(Ink4a) could partially overcome the DNA damage response by disabling p16(Ink4a) up-regulation and reducing the accumulation of γ-H2AX that is observed in Wrn(-/-) MEFs. Furthermore, in response to TRF2(ΔBΔM) overexpression, Wrn(-/-) MEFs senesced within several passages. In contrast, p16(Ink4a-/-) and p16(Ink4a-/-)Wrn(-/-) MEFs could continuously grow and lose expression of the exogenous TRF2(ΔBΔM) in their late passages. In summary, our data suggest that in the context of telomere dysfunction, loss of p16(Ink4a) function could prevent cells from senescence. These results shed light on the anti-aging strategy through regulation of p16(Ink4a) expression.},
}
@article {pmid22752289,
year = {2012},
author = {Yanowsky, K and Barroso, A and Osorio, A and Urioste, M and Benitez, J and Martinez-Delgado, B},
title = {Mutational analysis of telomere genes in BRCA1/2-negative breast cancer families with very short telomeres.},
journal = {Breast cancer research and treatment},
volume = {134},
number = {3},
pages = {1337-1343},
doi = {10.1007/s10549-012-2141-2},
pmid = {22752289},
issn = {1573-7217},
mesh = {Adult ; Aged ; Breast Neoplasms/*genetics ; DNA Mutational Analysis ; Family ; Female ; *Genes, BRCA1 ; *Genes, BRCA2 ; Genetic Predisposition to Disease ; Humans ; Middle Aged ; *Mutation ; Ovarian Neoplasms/genetics ; Telomere/*genetics ; *Telomere Shortening ; Tripeptidyl-Peptidase 1 ; },
abstract = {A majority of the familial breast cancer cases are not explained by mutations in the best-known high susceptibility genes BRCA1 and BRCA2. Since there is a link between DNA repair and telomere maintenance mechanisms, we have investigated for the first time the role of telomere genes in breast cancer predisposition. By a combination of DHPLC and direct sequencing, we screened for sequence variation in 14 telomere-related genes which included telomerase and shelterin complexes in index cases from 50 BRCA1/2-negative families previously characterized to have very short telomere length in peripheral blood leukocytes. Clear pathogenic changes were not detected in any of the genes analyzed. Most of the changes were non-coding variants and only nine corresponded to coding variants located in TPP1, TINF2, NHP2, TNKS, and RAD54B genes; although only two corresponded to coding missense changes leading to aminoacid changes in genes NHP2 and RAD54B. However, functional prediction analysis and control population studies of both variants ruled out its possible pathogenic role. Our results discard a major contribution of telomere-specific genes in hereditary breast cancer.},
}
@article {pmid22751425,
year = {2012},
author = {Stower, H},
title = {Telomeres: stem cells, cancer and telomerase linked by WNT.},
journal = {Nature reviews. Genetics},
volume = {13},
number = {8},
pages = {521},
pmid = {22751425},
issn = {1471-0064},
}
@article {pmid24970147,
year = {2012},
author = {Baldo, V and Liang, J and Wang, G and Zhou, H},
title = {Preserving Yeast Genetic Heritage through DNA Damage Checkpoint Regulation and Telomere Maintenance.},
journal = {Biomolecules},
volume = {2},
number = {4},
pages = {505-523},
pmid = {24970147},
issn = {2218-273X},
support = {R01 GM080469/GM/NIGMS NIH HHS/United States ; },
abstract = {In order to preserve genome integrity, extrinsic or intrinsic DNA damages must be repaired before they accumulate in cells and trigger other mutations and genome rearrangements. Eukaryotic cells are able to respond to different genotoxic stresses as well as to single DNA double strand breaks (DSBs), suggesting highly sensitive and robust mechanisms to detect lesions that trigger a signal transduction cascade which, in turn, controls the DNA damage response (DDR). Furthermore, cells must be able to distinguish natural chromosomal ends from DNA DSBs in order to prevent inappropriate checkpoint activation, DDR and chromosomal rearrangements. Since the original discovery of RAD9, the first DNA damage checkpoint gene identified in Saccharomyces cerevisiae, many genes that have a role in this pathway have been identified, including MRC1, MEC3, RAD24, RAD53, DUN1, MEC1 and TEL1. Extensive studies have established most of the genetic basis of the DNA damage checkpoint and uncovered its different functions in cell cycle regulation, DNA replication and repair, and telomere maintenance. However, major questions concerning the regulation and functions of the DNA damage checkpoint remain to be answered. First, how is the checkpoint activity coupled to DNA replication and repair? Second, how do cells distinguish natural chromosome ends from deleterious DNA DSBs? In this review we will examine primarily studies performed using Saccharomyces cerevisiae as a model system.},
}
@article {pmid24358832,
year = {2012},
author = {Chaudari, A and Huberman, JA},
title = {Identification of two telomere-proximal fission yeast DNA replication origins constrained by nearby cis-acting sequences to replicate in late S phase.},
journal = {F1000Research},
volume = {1},
number = {},
pages = {58},
pmid = {24358832},
issn = {2046-1402},
support = {P30 CA016056/CA/NCI NIH HHS/United States ; R01 CA095908/CA/NCI NIH HHS/United States ; R01 GM070566/GM/NIGMS NIH HHS/United States ; },
abstract = {Telomeres of the fission yeast, Schizosaccharomyces pombe, are known to replicate in late S phase, but the reasons for this late replication are not fully understood. We have identified two closely-spaced DNA replication origins, 5.5 to 8 kb upstream from the telomere itself. These are the most telomere-proximal of all the replication origins in the fission yeast genome. When located by themselves in circular plasmids, these origins fired in early S phase, but if flanking sequences closer to the telomere were included in the circular plasmid, then replication was restrained to late S phase - except in cells lacking the replication-checkpoint kinase, Cds1. We conclude that checkpoint-dependent late replication of telomere-associated sequences is dependent on nearby cis-acting sequences, not on proximity to the physical end of a linear chromosome.},
}
@article {pmid23905037,
year = {2011},
author = {La Torre, D and Aguennouz, M and Conti, A and Giusa, M and Raffa, G and Abbritti, RV and Germano', A and Angileri, FF},
title = {Potential clinical role of telomere length in human glioblastoma.},
journal = {Translational medicine @ UniSa},
volume = {1},
number = {},
pages = {243-270},
pmid = {23905037},
issn = {2239-9747},
abstract = {Glioblastoma Multiforme (GBM) is the most common and lethal of human primary central nervous system (CNS) tumors. Due to the tumour's intrinsic clinical and molecular heterogeneity, choice of initial treatment, prediction of survival, stratification of patients, prediction and monitoring of response to therapy, represent some of the greatest challenges in the management of GBM patients. Patients, despite optimal surgery, radiation and chemotherapy, still have a median survival of 14-16 months. A reason for this dismal prognosis is because of the relative inaccuracy of current prognostic markers, so far based on clinical or pathological variables. Molecular markers that effectively predict response to therapy and survival outcomes are limited. Consequently, there is a strong need to develop novel and independent markers of prognosis. Ideal biomarkers for solid tumors would serve one or more important functions. Telomeres, guanine-rich tandem DNA repeats of the chromosomal end, provide chromosomal stability, regulates important cellular processes, and seem to be implicated in human carcinogenesis. Recently, telomeres have been shown either to be associated with clinical markers of disease progression or to be independent markers of cancer prognosis in solid tumours, including GBM. Nevertheless, a corresponding comprehensive discussion of these promising developments in brain tumours has not yet been available in the literature. Therefore, here we reviewed studies focused on the assessment of telomeric length in brain tumours with the aim to emphasized those findings indicating a potential clinical role of telomeres in GBM. With the aim to enhance the awareness of the potential clinical role of telomeres' length information in GBM, using a southern blot analysis, telomeric length in excised tumour samples was analyzed. Moreover, an attempt to correlated telomere length with patients' overall survival, was also performed. The findings here reviewed shows some contradictory results, due to different tissues used as controls, but mainly to cellular and molecular heterogeneity in GBMs that drive molecular mechanisms controlling telomere length, included telomerase and Alternative Lengthening of Telomeres (ALT), through multiple mechanisms. However, overall these studies, including our own, are consistent with the hypothesis that GBMs' telomeres were always shorter when compared with Normal Brain Tissue (NBT), and together with higher telomerase activity seem to be associated with malignancy and poor outcome; while tumours with ALT phenotype have longer telomeres, "less malignant" behaviour and better prognosis. We conclude that, although not entirely consistent in the type of telomere alteration, i.e., attrition vs. elongation, and unclear on the underlying mechanisms, multiple studies in brain tumours have shown that telomere dysfunctions are associated with parameters of clinical outcome in patients with GBMs and therefore will be part of novel risk assessment and prognostic modalities for patients with these still dismal disease.},
}
@article {pmid22881202,
year = {2010},
author = {Olofsson, P},
title = {Can telomere shortening explain sigmoidal growth curves?.},
journal = {Journal of biological dynamics},
volume = {4},
number = {6},
pages = {527-538},
doi = {10.1080/17513750903377442},
pmid = {22881202},
issn = {1751-3766},
mesh = {Cell Proliferation ; Microbial Viability ; Models, Biological ; Saccharomyces cerevisiae/*cytology/metabolism ; Telomere/genetics/*metabolism ; *Telomere Shortening ; },
abstract = {A general branching process model is proposed to describe the shortening of telomeres in eukaryotic chromosomes. The model is flexible and incorporates many special cases to be found in the literature. In particular, we show how telomere shortening can give rise to sigmoidal growth curves, an idea first expressed by Portugal et al. [A computational model for telomere-dependent cell-replicative aging, BioSystems 91 (2008), pp. 262-267]. We also demonstrate how other types of growth curves arise if telomere shortening is mitigated by other cellular processes. We compare our results with published data sets from the biological literature.},
}
@article {pmid22966305,
year = {2010},
author = {Pai, RB and Pai, SB and Yang, L and Joshi, HC},
title = {Abundance of a distinct cluster of telomere t-stumps in advanced breast cancer cell line.},
journal = {Oncology letters},
volume = {1},
number = {2},
pages = {339-343},
pmid = {22966305},
issn = {1792-1074},
support = {R01 CA095317/CA/NCI NIH HHS/United States ; },
abstract = {Breast tumors are the second major cause of cancer-related death in women worldwide. These tumors are aggressive, leading to metastatic cancers that are heterogeneous in nature, with numerous subtypes. The basal-like tumor subtype invariably shows unfavorable prognosis and is often characterized by the lack of estrogen, progesterone and HER2 receptors. These cancer types do not respond to the current targeted therapies. Therefore, the need for the discovery of novel diagnostic markers/therapeutic targets is of paramount importance. Immortalization of breast tumor cells leading to advanced stage cancer is one of the pivotal steps in breast cancer and telomeres/telomerase play a critical role in this process. Using single telomere length analysis, cell lines with a basal-like phenotype encompassing immortalized/non-tumorigenic MCF10A and invasive/metastatic MCF10CA1 along with the MCF-7 cell line were examined for the presence of a unique class of telomere t-stumps. Telomerase activity, protein levels of telomerase and bulk telomere lengths were assessed in the above-mentioned cell lines. This is the first study describing the existence of a distinct class of extremely short telomeres termed 't-stumps' in breast cancer cell lines. The cell lines MCF10A and MCF10CA1 showed distinct telomeric bands in the molecular size range of 100-1,000 bp, whereas the MCF-7 cell line showed very low levels of t-stumps. Of note is that only the highly invasive/metastatic cancer cell line MCF10CA1 exhibited an abundance of a cluster of t-stumps with a size distribution range of 500-700 bp. These unique t-stumps observed in the advanced breast cancer cell line may serve as a novel diagnostic marker and also form a key molecular target for novel anticancer therapy.},
}
@article {pmid23604406,
year = {1999},
author = {Takubo, K and Nakamura, K and Izumiyama, N and Sawabe, M and Arai, T and Esaki, Y and Tanaka, Y and Mafune, K and Fujiwara, M and Kammori, M and Sasajima, K},
title = {Telomere shortening with aging in human esophageal mucosa.},
journal = {Age},
volume = {22},
number = {3},
pages = {95-99},
pmid = {23604406},
abstract = {Progressive telomere shortening with aging was studied using normal esophageal mucosal specimens from 177 human subjects aged between 0 and 102 years (yrs). We observed age-related shortening of the telomere, at a rate of 60 base pairs (bp) per year (yr). The mean telomere length of 12 neonates was 15.2 kilobase pairs (kbp) and that of 2 centenarians was 9.3 kbp. Mean (±SD) telomere lengths were 14.9±1.3, 14.0±1.8, 10.1±3.7, 10.4±3.3 and 9.5±3.1 kbp for the age groups less than 2 yrs, 2-20 yrs, 21-60 yrs, 61-80 yrs and 81-102 yrs, respectively. The variation in telomere length among individuals in the same age group was greater for the 3 older groups than for the 2 younger groups, as shown by the SDs. Furthermore, older individuals had greater telomere length variation than younger individuals, based on the lengths of DNA digested smears. Although the telomere length decreased significantly with aging at the rate of 60 bp per yr, differences in the mean telomere lengths between the 3 older age groups were not significant. Rapid shortening occurred in the young generations and there was no further substantial decrease in the esophageal mucosa after 60 yrs of age. Compared to the very rapid renewal rate of the esophageal epithelial cells, the annual reduction rate in telomere length was very low. These findings support the hypothesis that germ cells in the esophageal epithelium have a mechanism to lengthen telomeres.},
}
@article {pmid23604397,
year = {1999},
author = {Cowell, JK},
title = {Telomeres and telomerase in ageing and cancer.},
journal = {Age},
volume = {22},
number = {2},
pages = {59-64},
pmid = {23604397},
abstract = {Telomeres lie at the ends of human chromosomes and contain long tandem repeats of a simple nucleotide sequence. Because DNA replication cannot proceed to the very end of chromosomes, copies of these repeats are lost at each cell division. If the telomeres shorten below a critical length, the cells will eventually die as a result of genomic instability. Aging cells usually avoid death by entering senescence before the critical telomere length is reached. Malignantly transformed, immortal cells overcome senescence but they must still avoid the final, critical shortening of telomeres to survive. In the vast majority of cases, tumor cells achieve this by activating the telomerase enzyme, a ribonucleoprotein complex which repairs the end of chromosomes and prevents telomere shortening. Normal mortal cells do not normally express telomerase, although some stem cell populations which must regenerate thought the life span of the organism, retain enzyme activity. Cellular senescence can be overcome by inducing telomerase expression in mortal cells, firmly establishing the role of telomere length in the senescence signaling pathway. In tumor cells, the evidence of a role for telomerase in immortality is still largely correlative, with 80-90% of tumors expressing telomerase activity. To establish whether telomerase activity is important in maintaining the malignant phenotype, attempts have been made to inactivate it in tumor cells, using a variety of approaches, where there is evidence that disrupting telomerase function can result in the induction of apoptosis. The background and implications of these observations is discussed.},
}
@article {pmid24169979,
year = {1995},
author = {Galasso, I and Schmidt, T and Pignone, D and Heslop-Harrison, JS},
title = {The molecular cytogenetics of Vigna unguiculata (L.) Walp: the physical organization and characterization of 18s-5.8s-25s rRNA genes, 5s rRNA genes, telomere-like sequences, and a family of centromeric repetitive DNA sequences.},
journal = {TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik},
volume = {91},
number = {6-7},
pages = {928-935},
pmid = {24169979},
issn = {0040-5752},
abstract = {A knowledge of genome organization is important for understanding how genomes function and evolve, and provide information likely to be useful in plant breeding programmes involving hybridization and genetic manipulation. Molecular techniques, including in situ hybridization, molecular cloning and DNA sequencing, are proving valuable tools to investigate the structure, organization, and diversity of chromosomes in agricultural crops. Heterologous labelled 18 s-5.8 s-25 s (pTa71) and 5 s rDNAs (pTa794) were used for in situ hybridization on Vigna unguiculata (L.) Walp. chromosomes. Hybridization with 18 s-5.8 s-25 s rRNA gene probes occurred at the same chromosomal sites which were positive to the CMA fluorochrome. Silver staining of nucleolar-organizing regions indicated that all the rDNA sites detected using the 18 s-5.8 s-25 s rRNA gene probe possessed active genes. Degenerate telomeric repeats gave hybridization signals at the telomeres of most chromosomes and no intercalary sites were detected at metaphase; the sequences appear to have no preferential distribution in interphase nuclei. A repetitive DraI family from V. unguiculata was cloned (pVuKB1) and characterized. The DraI repeat is 488 nucleotides long, AT rich (74%), and hybridized on all chromosomes in the centromeric areas. The presence of this sequence family was investigated by Southern hybridization in different Vigna species and other Leguminoseae. It was only detected in V. unguiculata, and hence represents a species-specific DNA sequence.},
}
@article {pmid22747954,
year = {2012},
author = {Antoniou, KM and Margaritopoulos, GA and Proklou, A and Karagiannis, K and Lasithiotaki, I and Soufla, G and Kastrinaki, MC and Spandidos, DA and Papadaki, HA and Siafakas, NM},
title = {Investigation of Telomerase/Telomeres system in Bone Marrow Mesenchymal Stem Cells derived from IPF and RA-UIP.},
journal = {Journal of inflammation (London, England)},
volume = {9},
number = {1},
pages = {27},
pmid = {22747954},
issn = {1476-9255},
abstract = {OBJECTIVE: Idiopathic Pulmonary Fibrosis and Rheumatoid Arthritis associated usual interstitial pneumonia seem to have the same poor outcome as there is not an effective treatment. The aim of the study is to explore the reparative ability of bone marrow mesenchymal stem cells by evaluating the system telomerase/telomeres and propose a novel therapeutic approach.<br><br>METHODS: BM-MSCs were studied in 6 IPF patients, 7 patients with RA-UIP and 6 healthy controls. We evaluated the telomere length as well as the mRNA expression of both components of telomerase (human telomerase reverse transcriptase, h-TERT and RNA template complementary to the telomeric loss DNA, h-TERC).<br><br>RESULTS: We found that BM-MSCs from IPF, RA-UIP cases do not present smaller telomere length than the controls (p&#x2009;=&#x2009;0.170). There was no significant difference regarding the expression of both h-TERT and h-TERC genes between patients and healthy controls (p&#x2009;=&#x2009;0.107 and p&#x2009;=&#x2009;0.634 respectively).<br><br>CONCLUSIONS: We demonstrated same telomere length and telomerase expression in BM-MSCs of both IPF and RA-UIP which could explain similarities in pathogenesis and prognosis. Maintenance of telomere length in these cells could have future implication in cell replacement treatment with stem cells of these devastating lung disorders.},
}
@article {pmid22747879,
year = {2012},
author = {Ahmad, S and Heraclides, A and Sun, Q and Elgzyri, T and Rönn, T and Ling, C and Isomaa, B and Eriksson, KF and Groop, L and Franks, PW and Hansson, O},
title = {Telomere length in blood and skeletal muscle in relation to measures of glycaemia and insulinaemia.},
journal = {Diabetic medicine : a journal of the British Diabetic Association},
volume = {29},
number = {10},
pages = {e377-81},
pmid = {22747879},
issn = {1464-5491},
support = {K99 HL098459/HL/NHLBI NIH HHS/United States ; R00 HL098459/HL/NHLBI NIH HHS/United States ; K99HL098459/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Blood Glucose/genetics/*metabolism ; Body Mass Index ; Diabetes Mellitus, Type 2/*genetics/*metabolism/physiopathology ; Fasting/blood ; Glycated Hemoglobin/*metabolism ; Humans ; Insulin/*blood ; Insulin Resistance ; Leukocytes/*metabolism/pathology ; Male ; Muscle, Skeletal/*metabolism ; Real-Time Polymerase Chain Reaction ; Telomere/genetics/*pathology ; },
abstract = {AIMS: Skeletal muscle is a major metabolic organ and plays important roles in glucose metabolism, insulin sensitivity and insulin action. Muscle telomere length reflects the myocyte's exposure to harmful environmental factors. Leukocyte telomere length is considered a marker of muscle telomere length and is used in epidemiologic studies to assess associations with ageing-related diseases where muscle physiology is important. However, the extent to which leucocyte and muscle telomere length are correlated is unknown, as are their relative correlations with glucose and insulin concentrations. The purpose of this study was to determine the extent of these relationships.<br><br>METHODS: Leucocyte and muscle telomere length were measured by quantitative real-time polymerase chain reaction in participants from the Malm&#xf6; Exercise Intervention (n = 27) and the Prevalence, Prediction and Prevention of Diabetes-Botnia studies (n = 31). Participants in both studies were free from Type 2 diabetes. We assessed the association between leucocyte telomere length, muscle telomere length and metabolic traits using Spearmen correlations and multivariate linear regression. Bland-Altman analysis was used to assess agreement between leucocyte and muscle telomere length.<br><br>RESULTS: In age-, study-, diabetes family history- and sex-adjusted models, leucocyte and muscle telomere length were positively correlated (r = 0.39, 95% CI 0.15-0.59). Leucocyte telomere length was inversely associated with 2-h glucose concentrations (r = -0.58, 95% CI -1.0 to -0.16), but there was no correlation between muscle telomere length and 2-h glucose concentrations (r = 0.05, 95% CI -0.35 to 0.46) or between leucocyte or muscle telomere length with other metabolic traits.<br><br>CONCLUSIONS: In summary, the current study supports the use of leucocyte telomere length as a proxy for muscle telomere length in epidemiological studies of Type 2 diabetes aetiology.},
}
@article {pmid22728163,
year = {2012},
author = {Li, P and Hou, M and Lou, F and Björkholm, M and Xu, D},
title = {Telomere dysfunction induced by chemotherapeutic agents and radiation in normal human cells.},
journal = {The international journal of biochemistry &amp; cell biology},
volume = {44},
number = {9},
pages = {1531-1540},
doi = {10.1016/j.biocel.2012.06.020},
pmid = {22728163},
issn = {1878-5875},
mesh = {Antineoplastic Agents/adverse effects ; Cell Proliferation/drug effects/radiation effects ; Down-Regulation/drug effects ; Doxorubicin/adverse effects ; Etoposide/adverse effects ; Fibroblasts/cytology/*drug effects/metabolism/*radiation effects ; Gamma Rays/*adverse effects ; Gene Expression Regulation, Enzymologic/drug effects/radiation effects ; Humans ; RNA, Messenger/genetics/metabolism ; Shelterin Complex ; T-Lymphocytes/cytology/*drug effects/metabolism/*radiation effects ; Telomerase/genetics ; Telomere/*drug effects/genetics/metabolism/*radiation effects ; Telomere Shortening/drug effects/radiation effects ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {The number of long-term survivors of patients with various malignancies (>5 years) is increasing mainly owing to advances in cancer therapeutics, but long-term side effects of the cancer treatment in this population have emerged as an important health and socio-economical issue. Telomeres and telomerase are known to be essential for regulation of cellular life-span and maintenance of genomic stability, and earlier studies have demonstrated that cancer patients who receive chemotherapy have shorter telomeres in their blood cells, indicating accelerated telomere erosion and a potential contribution of telomere loss to late side-effects. Little is currently known about the effect of chemotherapeutic agents and radiation on telomere dynamics including potential effects on telomere length, structure, function, telomerase activity, and telomere shelterin proteins in normal human cells. In the present study, we had addressed this issue experimentally. The treatment of normal human T lymphocytes and fibroblasts with chemotherapeutic agents doxorubicin (DOX) or etoposide (VP16) led to significant shortening of telomeres, down-regulation of telomerase activity, and diminished expression of telomerase reverse transcriptase (hTERT) and the telomere binding proteins TPP1 and POT1. More importantly, telomere dysfunction was observed in cells treated with DOX or VP16. Furthermore, all the above alterations were similarly found in the cells receiving γ-irradiation. Taken together, both chemotherapy and radiotherapy significantly impair telomere maintenance and function in normal human cells. Conceivably telomere dysfunction causes shortened life-span and genomic instability of normal human cells, and thereby contributes to tissue/organ damage and secondary malignancies in long-term survivors of cancer.},
}
@article {pmid22727244,
year = {2012},
author = {Londoño-Vallejo, JA and Wellinger, RJ},
title = {Telomeres and telomerase dance to the rhythm of the cell cycle.},
journal = {Trends in biochemical sciences},
volume = {37},
number = {9},
pages = {391-399},
doi = {10.1016/j.tibs.2012.05.004},
pmid = {22727244},
issn = {0968-0004},
mesh = {Animals ; *Cell Cycle ; Cell Nucleus/enzymology ; Humans ; Ribonucleoproteins/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {The stability of the ends of linear eukaryotic chromosomes is ensured by functional telomeres, which are composed of short, species-specific direct repeat sequences. The maintenance of telomeres depends on a specialized ribonucleoprotein (RNP) called telomerase. Both telomeres and telomerase are dynamic entities with different physical behaviors and, given their substrate-enzyme relation, they must establish a productive interaction. Regulatory mechanisms controlling this interaction are key missing elements in our understanding of telomere functions. Here, we review the dynamic properties of telomeres and the maturing telomerase RNPs, and summarize how tracking the timing of their dance during the cell cycle will yield insights into chromosome stability mechanisms. Cancer cells often display loss of genome integrity; therefore, these issues are of particular interest for our understanding of cancer initiation or progression.},
}
@article {pmid22724077,
year = {2012},
author = {Guan, JZ and Guan, WP and Maeda, T and Makino, N},
title = {The Subtelomere of Short Telomeres is Hypermethylated in Alzheimer's Disease.},
journal = {Aging and disease},
volume = {3},
number = {2},
pages = {164-170},
pmid = {22724077},
issn = {2152-5250},
abstract = {Telomere shortening has been reported to be related to oxidative stress (OS) associated with the aging process and aging-associated diseases, including Alzheimer's disease (AD). We measured the methylated and non-methylated telomere lengths in the peripheral blood mononuclear cells of 34 AD patients and 49 healthy controls by a Southern blotting analysis, using methylation-sensitive and - insensitive restriction enzyme isoschizomers, MspI and HpaII. AD patients bore normal mean telomere lengths and had an unchanged distribution of the telomere length in peripheral leukocytes. However, the subtelomeres in the shortest telomeres were relatively more methylated in AD patients of both genders, compared with age-matched controls. We observed that the pathogenesis of AD was associated with the epigenetic condition of the subtelomere, but not on the overall telomere length and distribution. The relative elevation of subtelomeric methylation of short telomeres in peripheral blood leukocytes may be a characteristic of AD. This implies that leukocytes containing short telomeres with less methylated subtelomeres tend to be removed faster from the peripheral blood in AD patients.},
}
@article {pmid22719262,
year = {2012},
author = {Pfeiffer, V and Lingner, J},
title = {TERRA promotes telomere shortening through exonuclease 1-mediated resection of chromosome ends.},
journal = {PLoS genetics},
volume = {8},
number = {6},
pages = {e1002747},
pmid = {22719262},
issn = {1553-7404},
support = {232812/ERC_/European Research Council/International ; },
mesh = {Aldose-Ketose Isomerases/genetics ; Base Sequence ; Chromosomes/*genetics ; Exodeoxyribonucleases/genetics/metabolism ; Gene Expression Regulation, Fungal ; Molecular Sequence Data ; Promoter Regions, Genetic ; RNA, Untranslated/genetics/metabolism ; Repetitive Sequences, Nucleic Acid/genetics ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/genetics ; Telomerase/genetics/metabolism ; Telomere/*genetics ; *Telomere Shortening ; Transcription Initiation Site ; *Transcription, Genetic ; },
abstract = {The long noncoding telomeric repeat containing RNA (TERRA) is expressed at chromosome ends. TERRA upregulation upon experimental manipulation or in ICF (immunodeficiency, centromeric instability, facial anomalies) patients correlates with short telomeres. To study the mechanism of telomere length control by TERRA in Saccharomyces cerevisiae, we mapped the transcriptional start site of TERRA at telomere 1L and inserted a doxycycline regulatable promoter upstream. Induction of TERRA transcription led to telomere shortening of 1L but not of other chromosome ends. TERRA interacts with the Exo1-inhibiting Ku70/80 complex, and deletion of EXO1 but not MRE11 fully suppressed the TERRA-mediated short telomere phenotype in presence and absence of telomerase. Thus TERRA transcription facilitates the 5'-3' nuclease activity of Exo1 at chromosome ends, providing a means to regulate the telomere shortening rate. Thereby, telomere transcription can regulate cellular lifespan through modulation of chromosome end processing activities.},
}
@article {pmid22713142,
year = {2012},
author = {Fyhrquist, F and Saijonmaa, O},
title = {Telomere length and cardiovascular aging.},
journal = {Annals of medicine},
volume = {44 Suppl 1},
number = {},
pages = {S138-42},
doi = {10.3109/07853890.2012.660497},
pmid = {22713142},
issn = {1365-2060},
mesh = {Aging/*genetics ; Alcoholism/physiopathology ; Biomarkers ; Cardiovascular Diseases/genetics ; Cardiovascular Physiological Phenomena/*genetics ; Diet ; Humans ; *Leukocytes ; Life Style ; Smoking/physiopathology ; Stress, Psychological/physiopathology ; *Telomere Homeostasis ; },
abstract = {Telomeres are located at the end of chromosomes. They are composed of repetitive TTAGGG tandem repeats and associated proteins of crucial importance for telomere function. Telomeric DNA is shortened by each cell division until a critical length is achieved and the cell enters senescence and eventually apoptosis. Telomeres are therefore considered a 'biological clock' of the cell. Telomerase adds nucleotides to telomeric DNA thereby contributing to telomere maintenance, genomic stability, functions, and proliferative capacity of the cell. In certain rare forms of progeria, point mutations within the telomere lead to accelerated telomere attrition and premature aging. Endogenous factors causing telomere shortening are aging, inflammation, and oxidative stress. Leukocyte telomere length (LTL) shortening is inhibited by estrogen and endogenous antioxidants. Accelerated telomere attrition is associated with cardiovascular risk factors such as age, gender, obesity, smoking, sedentary life-style, excess alcohol intake, and even mental stress. Cardiovascular (CV) diseases and CV aging are usually but not invariably associated with shorter telomeres than in healthy subjects. LTL appears to be a biomarker of CV aging, reflecting the cumulative burden of endogenous and exogenous factors negatively affecting LTL. Whether accelerated telomere shortening is cause or consequence of CV aging and disease is not clear.},
}
@article {pmid22712556,
year = {2012},
author = {Sreesankar, E and Senthilkumar, R and Bharathi, V and Mishra, RK and Mishra, K},
title = {Functional diversification of yeast telomere associated protein, Rif1, in higher eukaryotes.},
journal = {BMC genomics},
volume = {13},
number = {},
pages = {255},
pmid = {22712556},
issn = {1471-2164},
mesh = {Animals ; Carrier Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Computational Biology ; DNA Damage ; Drosophila Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Drosophila melanogaster/metabolism ; Evolution, Molecular ; HeLa Cells ; Humans ; Phylogeny ; Protein Binding ; Protein Phosphatase 1/chemistry/metabolism ; RNA Interference ; RNA, Small Interfering/metabolism ; Repressor Proteins/classification/*genetics/metabolism ; Retroelements ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/classification/*genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/classification/*genetics/metabolism ; },
abstract = {BACKGROUND: Telomeres are nucleoprotein complexes at the end of linear eukaryotic chromosomes which maintain the genome integrity by regulating telomere length, preventing recombination and end to end fusion events. Multiple proteins associate with telomeres and function in concert to carry out these functions. Rap1 interacting factor 1 (Rif1), was identified as a protein involved in telomere length regulation in yeast. Rif1 is conserved upto mammals but its function has diversified from telomere length regulation to maintenance of genome integrity.<br><br>RESULTS: We have carried out detailed bioinformatic analyses and identified Rif1 homologues in 92 organisms from yeast to human. We identified Rif1 homologues in Drosophila melanogaster, even though fly telomeres are maintained by a telomerase independent pathway. Our analysis shows that Drosophila Rif1 (dRif1) sequence is phylogenetically closer to the one of vertebrates than yeast and has identified a few Rif1 specific motifs conserved through evolution. This includes a Rif1 family specific conserved region within the HEAT repeat domain and a motif involved in protein phosphatase1 docking. We show that dRif1 is nuclear localized with a prominent heterochromatin association and unlike human Rif1, it does not respond to DNA damage by localizing to damaged sites. To test the evolutionary conservation of dRif1 function, we expressed the dRif1 protein in yeast and HeLa cells. In yeast, dRif1 did not perturb yeast Rif1 (yRif1) functions; and in HeLa cells it did not colocalize with DNA damage foci.<br><br>CONCLUSIONS: Telomeres are maintained by retrotransposons in all Drosophila species and consequently, telomerase and many of the telomere associated protein homologues are absent, including Rap1, which is the binding partner of Rif1. We found that a homologue of yRif1 protein is present in fly and dRif1 has evolutionarily conserved motifs. Functional studies show that dRif1 responds differently to DNA damage, implying that dRif1 may have a different function and this may be conserved in other organisms as well.},
}
@article {pmid22704416,
year = {2012},
author = {Chen, C and Chi, HY and Yu, ZH and Chen, JL},
title = {[Effects of Chinese herbal medicine Shoushen Granule on telomere length and telomerase activity of peripheral white blood cells and vascular cells in rats with atherosclerosis].},
journal = {Zhong xi yi jie he xue bao = Journal of Chinese integrative medicine},
volume = {10},
number = {6},
pages = {667-673},
doi = {10.3736/jcim20120611},
pmid = {22704416},
issn = {1672-1977},
mesh = {Animals ; Atherosclerosis/*blood/*drug therapy/pathology ; Blood Cells/*drug effects/enzymology ; Drugs, Chinese Herbal/*pharmacology ; Male ; Rats ; Rats, Sprague-Dawley ; Telomerase/*blood ; Telomere/*drug effects ; },
abstract = {OBJECTIVE: To observe the effects of Shoushen Granule, a compound traditional Chinese herbal medicine, on telomere length and telomerase activity in peripheral leukocytes and vascular cells, artery wall lesions and blood lipid in a Sprague-Dawley (SD) rat model of atherosclerosis.<br><br>METHODS: Forty SD rats were randomly divided into normal control group, model group, Shoushen Granule group and Western medicine group with 10 in each group. The rat model of atherosclerosis was established by high-fat diet and vitamin D3 loading. The model group was given gastric perfusion of double distilled water; The Shoushen Granule group and the Western medicine group were respectively given gastric perfusion of Shoushen Granule and pravastatin. After 12 weeks, pathological changes of abdominal aorta were determined by hematoxylin and eosin staining. Biochemical colorimetric method was used to detect the contents of total cholesterol (TC), triacylglycerol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol (LDL-C) in serum of the rats. Telomere length and telomerase activity in peripheral leukocytes and vascular cells of the rats were tested by quantitative real-time polymerase chain reaction method.<br><br>RESULTS: When compared with the model group, atherosclerosis lesions of the arterial wall were significantly improved in the Shoushen Granule group. In addition, both TC and LDL-C levels in the Shoushen Granule group were decreased significantly compared with the model group (P<0.01). Besides, not only telomerase activity but also telomere length in peripheral leukocytes (P<0.01) and vascular cells (P<0.05) were increased significantly as compared to those in the model group. However, there was no significant difference between the Shoushen Granule group and the normal control group (P>0.05).<br><br>CONCLUSION: Shoushen Granule improves the atherosclerosis lesions in rats, and the mechanism may be related to regulating telomere length and telomerase activity.},
}
@article {pmid22704123,
year = {2012},
author = {Su, CH and Chu, WC and Lan, KH and Li, CP and Chao, Y and Lin, HC and Lee, SD and Tsai, YC and Lee, WP},
title = {Gemcitabine causes telomere attrition by stabilizing TRF2.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {48},
number = {18},
pages = {3465-3474},
doi = {10.1016/j.ejca.2012.04.015},
pmid = {22704123},
issn = {1879-0852},
mesh = {Antimetabolites, Antineoplastic/*pharmacology ; Cell Division/drug effects ; Chromatin Immunoprecipitation ; DNA, Neoplasm/metabolism ; DNA-Binding Proteins/physiology ; Deoxycytidine/*analogs &amp; derivatives/pharmacology ; Endonucleases/physiology ; Gene Expression Regulation, Neoplastic/drug effects ; Half-Life ; HeLa Cells/drug effects ; Humans ; In Vitro Techniques ; Neoplasm Proteins/chemistry/*drug effects/genetics/physiology ; Polymorphism, Restriction Fragment Length ; Protein Binding ; Protein Interaction Mapping ; Protein Processing, Post-Translational/drug effects ; Protein Stability ; Recombinant Fusion Proteins/biosynthesis ; Telomere/*drug effects/ultrastructure ; Telomeric Repeat Binding Protein 2/chemistry/*drug effects/genetics/physiology ; Ubiquitination/drug effects ; Up-Regulation/drug effects ; Gemcitabine ; },
abstract = {Gemcitabine is an effective anti-cancer agent against solid tumors. The pharmacological mechanism of gemcitabine is known as incorporation into DNA and thereby inhibition of DNA synthesis. When used in metronomic chemotherapy of cancer, the agent may inhibit angiogenesis. It is still uncertain whether the agent can inhibit tumor growth by a mechanism other than DNA incorporation. In this report, we show that gemcitabine causes telomere shortening by stabilizing TRF2 that is required for XPF-dependent telomere loss. Overexpression of TRF2 in the absence of gemcitabine also causes telomere shortening with simultaneous association of TRF2 with XPF/ERCC1. Our study provides a new mechanism by which gemcitabine exerts its anti-tumor activity.},
}
@article {pmid22700908,
year = {2012},
author = {Shay, JW and Reddel, RR and Wright, WE},
title = {Cancer. Cancer and telomeres--an ALTernative to telomerase.},
journal = {Science (New York, N.Y.)},
volume = {336},
number = {6087},
pages = {1388-1390},
doi = {10.1126/science.1222394},
pmid = {22700908},
issn = {1095-9203},
support = {C06 RR030414/RR/NCRR NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Antineoplastic Agents/therapeutic use ; Drug Resistance, Neoplasm ; Homologous Recombination ; Humans ; Molecular Targeted Therapy ; Neoplasms/enzymology/*genetics/therapy ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/*metabolism/ultrastructure ; *Telomere Homeostasis ; },
}
@article {pmid22698402,
year = {2012},
author = {Davoli, T and de Lange, T},
title = {Telomere-driven tetraploidization occurs in human cells undergoing crisis and promotes transformation of mouse cells.},
journal = {Cancer cell},
volume = {21},
number = {6},
pages = {765-776},
pmid = {22698402},
issn = {1878-3686},
support = {R01 CA160924/CA/NCI NIH HHS/United States ; CA160924/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle Checkpoints/genetics ; Cell Line ; Cell Transformation, Neoplastic/*genetics ; Cells, Cultured ; *DNA Damage ; Epithelial Cells/metabolism ; Fibroblasts/cytology/metabolism ; Flow Cytometry ; Humans ; Immunoblotting ; In Situ Hybridization, Fluorescence ; Karyotype ; Mammary Glands, Human/cytology ; Mice ; Mitosis/genetics ; RNA Interference ; Retinoblastoma Protein/genetics/metabolism ; Telomere/*genetics ; *Tetraploidy ; Time Factors ; Tumor Suppressor Protein p53/genetics/metabolism ; },
abstract = {Human cancers with a subtetraploid karyotype are thought to originate from tetraploid precursors, but the cause of tetraploidization is unknown. We previously documented endoreduplication in mouse cells with persistent telomere dysfunction or genome-wide DNA damage. We now report that endoreduplication and mitotic failure occur during telomere crisis in human fibroblasts and mammary epithelial cells and document the role of p53 and Rb in repressing tetraploidization. Using an inducible system to generate transient telomere damage, we show that telomere-driven tetraploidization enhances the tumorigenic transformation of mouse cells. Similar to human solid cancers, the resulting tumors evolved subtetraploid karyotypes. These data establish that telomere-driven tetraploidization is induced by critically short telomeres and has the potential to promote tumorigenesis in early cancerous lesions.},
}
@article {pmid22698395,
year = {2012},
author = {Varetti, G and Pellman, D},
title = {"Two" much of a good thing: telomere damage-induced genome doubling drives tumorigenesis.},
journal = {Cancer cell},
volume = {21},
number = {6},
pages = {712-714},
doi = {10.1016/j.ccr.2012.05.033},
pmid = {22698395},
issn = {1878-3686},
support = {R01 GM083299/GM/NIGMS NIH HHS/United States ; },
abstract = {Data from human tumors and mouse models suggest that tetraploidy, one example of polyploidy, can promote tumorigenesis. In this issue of Cancer Cell, Davoli and De Lange make important connections between tetraploidy, tumorigenesis, and telomere crisis-a common event during the development of human cancers.},
}
@article {pmid22689985,
year = {2012},
author = {Eisenberg, DT and Hayes, MG and Kuzawa, CW},
title = {Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {109},
number = {26},
pages = {10251-10256},
pmid = {22689985},
issn = {1091-6490},
support = {P30 ES010126/ES/NIEHS NIH HHS/United States ; RR20649/RR/NCRR NIH HHS/United States ; R24 HD042828/HD/NICHD NIH HHS/United States ; ES10126/ES/NIEHS NIH HHS/United States ; P20 RR020649/RR/NCRR NIH HHS/United States ; },
mesh = {Humans ; Intergenerational Relations ; Male ; *Paternal Age ; *Reproduction ; *Telomere ; },
abstract = {Telomeres are repeating DNA sequences at the ends of chromosomes that protect and buffer genes from nucleotide loss as cells divide. Telomere length (TL) shortens with age in most proliferating tissues, limiting cell division and thereby contributing to senescence. However, TL increases with age in sperm, and, correspondingly, offspring of older fathers inherit longer telomeres. Using data and samples from a longitudinal study from the Philippines, we first replicate the finding that paternal age at birth is associated with longer TL in offspring (n = 2,023, P = 1.84 × 10(-6)). We then show that this association of paternal age with offspring TL is cumulative across multiple generations: in this sample, grandchildren of older paternal grandfathers at the birth of fathers have longer telomeres (n = 234, P = 0.038), independent of, and additive to, the association of their father's age at birth with TL. The lengthening of telomeres predicted by each year that the father's or grandfather's reproduction are delayed is equal to the yearly shortening of TL seen in middle-age to elderly women in this sample, pointing to potentially important impacts on health and the pace of senescent decline in tissues and systems that are cell-replication dependent. This finding suggests a mechanism by which humans could extend late-life function as average age at reproduction is delayed within a lineage.},
}
@article {pmid22689059,
year = {2013},
author = {Akbay, EA and Peña, CG and Ruder, D and Michel, JA and Nakada, Y and Pathak, S and Multani, AS and Chang, S and Castrillon, DH},
title = {Cooperation between p53 and the telomere-protecting shelterin component Pot1a in endometrial carcinogenesis.},
journal = {Oncogene},
volume = {32},
number = {17},
pages = {2211-2219},
pmid = {22689059},
issn = {1476-5594},
support = {U01CA141576/CA/NCI NIH HHS/United States ; R01 CA137181/CA/NCI NIH HHS/United States ; U01 CA141576/CA/NCI NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; R01CA129037/CA/NCI NIH HHS/United States ; R01CA137181/CA/NCI NIH HHS/United States ; NCI CA016672/CA/NCI NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; },
mesh = {Aneuploidy ; Animals ; Carcinoma, Endometrioid/genetics/metabolism/pathology ; Cell Transformation, Neoplastic/genetics/metabolism ; DNA Breaks, Double-Stranded ; DNA-Binding Proteins/genetics/*metabolism ; Disease Models, Animal ; Endometrial Neoplasms/genetics/metabolism/pathology ; Female ; Humans ; Mice ; Mice, Transgenic ; Shelterin Complex ; *Telomere Homeostasis ; Telomere-Binding Proteins ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/genetics/*metabolism ; },
abstract = {Type II endometrial cancer (EMCA) represents only 10% of all EMCAs, but accounts for 40% of EMCA-related mortality. Previous studies of human tumors have shown an association between Type II tumors and damaged telomeres. We hypothesized that the lack of murine Type II EMCA models is due to the extremely long telomeres in laboratory mouse strains. We previously showed that telomerase-null mice with critically short telomeres developed endometrial lesions histologically resembling endometrial intraepithelial carcinoma (EIC), the accepted precursor for Type II EMCA. However, these mice did not develop invasive endometrial adenocarcinoma, and instead succumbed prematurely to multi-organ failure. Here, we modeled critical telomere attrition by conditionally inactivating Pot1a, a component of the shelterin complex that stabilizes telomeres, within endometrial epithelium. Inactivation of Pot1a by itself did not stimulate endometrial carcinogenesis, and did not result in detectable DNA damage or apoptosis in endometrium. However, simultaneous inactivation of Pot1a and p53 resulted in EIC-like lesions by 9 months indistinguishable from those seen in late generation telomerase-null mice. These lesions progressed to invasive endometrial adenocarcinomas as early as 9 months of age with metastatic disease in 100% of the animals by 15 months. These tumors were poorly differentiated endometrial adenocarcinomas with prominent nuclear atypia, resembling human Type II cancers. Furthermore, these tumors were aneuploid with double-stranded DNA breaks and end-to-end telomere fusions and most were tetraploid or near-tetraploid. These studies lend further support to the hypothesis that telomeric instability has a critical role in Type II endometrial carcinogenesis and provides an intriguing in-vivo correlate to recent studies implicating telomere-dependent tetraploidization as an important mechanism in carcinogenesis.},
}
@article {pmid22687638,
year = {2012},
author = {Lobetti-Bodoni, C and Ferrero, D and Genuardi, E and Passera, R and Bernocco, E and Sia, D and Grignani, G and Crisà, E and Monitillo, L and Rocci, A and Drandi, D and Giai, V and Zanni, M and Boi, M and Isaia, G and Barbero, D and Lunghi, M and Abruzzese, E and Radaelli, F and Pini, M and Pregno, P and Carlo-Stella, C and Gaidano, G and Boccadoro, M and Ladetto, M},
title = {Telomere loss in Philadelphia-negative hematopoiesis after successful treatment of chronic myeloid leukemia: evidence for premature aging of the myeloid compartment.},
journal = {Mechanisms of ageing and development},
volume = {133},
number = {7},
pages = {479-488},
doi = {10.1016/j.mad.2012.05.007},
pmid = {22687638},
issn = {1872-6216},
mesh = {Adult ; Aged ; Aged, 80 and over ; *Aging, Premature/etiology/metabolism/physiopathology ; Follow-Up Studies ; *Hematopoiesis ; Humans ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism/physiopathology/therapy ; Male ; Middle Aged ; *Philadelphia Chromosome ; Telomere/*metabolism ; },
abstract = {Telomere shortening, a well-known marker of aging and cellular stress, occurs under several conditions in the hematopoietic compartment, including aplastic anemia and following iatrogenic noxae. We decided to verify whether pathological telomere erosion also arises in restored Philadelphia-negative (Ph-negative) hematopoiesis following successful treatment of chronic myeloid leukemia (CML). Eighty-one CML patients in complete cytogenetic remission were compared to 76 age-matched healthy subjects. Myeloid cells of CML patients had shorter telomeres than controls (6521 bp vs 7233 bp, p<0.001). This difference was specific for the myeloid compartment, since it was not observed in lymphoid cells (6774 bp vs 6909 bp, p=0.620). Acquired Ph-negative cytogenetic abnormalities (p=0.010), lack of complete molecular remission (p=0.016) and age (p=0.013) were independent predictors of telomere shortening. Telomere dynamics were assessed over a median follow-up period of 22 months. We documented accelerated non-physiological ongoing telomere shortening in 17/59 CML patients (28%). Patients experiencing grade 2-4 hematological toxicity, during CML remission possessed significantly shorter telomeres compared to those lacking toxicity (p=0.005 for any toxicity, p=0.007 for anemia). CML patients suffer from significant and often ongoing telomere stress resulting in premature and selective aging of the myeloid compartment which might have long-term consequences on function and integrity of Ph-negative hematopoiesis.},
}
@article {pmid22683684,
year = {2012},
author = {Vera, E and Blasco, MA},
title = {Beyond average: potential for measurement of short telomeres.},
journal = {Aging},
volume = {4},
number = {6},
pages = {379-392},
pmid = {22683684},
issn = {1945-4589},
mesh = {Aging/*genetics ; Blotting, Southern ; *Genetic Techniques ; Humans ; In Situ Hybridization, Fluorescence ; Polymorphism, Restriction Fragment Length ; Real-Time Polymerase Chain Reaction ; Telomere/*ultrastructure ; },
abstract = {The length of telomeres, and in particular the abundance of short telomeres, has been proposed as a biomarker of aging and of general health status. A wide variety of studies show the association of short telomeres with age related pathologies and cancer, as well as with lifespan and mortality. These facts highlight the importance of measuring telomere length in human populations and by using reliable methods to uncover the association between telomere length and human disease. This review discusses the advantages and drawbacks of current telomere length measurement methods. Most of these methods provide mean telomere length values per cell or per sample and very few of them are able to measure the abundance of short telomeres, which are the ones indicative of telomere dysfunction. The information provided by each method and their suitability for different studies is discussed here.},
}
@article {pmid22679311,
year = {2012},
author = {Masi, S and Nightingale, CM and Day, IN and Guthrie, P and Rumley, A and Lowe, GD and von Zglinicki, T and D'Aiuto, F and Taddei, S and Klein, N and Salpea, K and Cook, DG and Humphries, SE and Whincup, PH and Deanfield, JE},
title = {Inflammation and not cardiovascular risk factors is associated with short leukocyte telomere length in 13- to 16-year-old adolescents.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {32},
number = {8},
pages = {2029-2034},
doi = {10.1161/ATVBAHA.112.250589},
pmid = {22679311},
issn = {1524-4636},
support = {G0601625/MRC_/Medical Research Council/United Kingdom ; RG/08/008/25291/BHF_/British Heart Foundation/United Kingdom ; G0900686/MRC_/Medical Research Council/United Kingdom ; CH/03/002/15570/BHF_/British Heart Foundation/United Kingdom ; 051187/Z/97/A/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Adolescent ; C-Reactive Protein/analysis ; Cardiovascular Diseases/*etiology ; Female ; Humans ; Inflammation/blood/*genetics ; Leukocytes/*physiology ; Male ; Risk Factors ; *Telomere ; },
abstract = {OBJECTIVE: Short leukocyte telomere length (LTL) is associated with cardiovascular (CV) disease in adulthood. However, the biological basis of this association remains unclear. We sought to define early determinants of the association between CV disease and LTL in an adolescent population.<br><br>METHODS AND RESULTS: One thousand eighty adolescents, aged 13 to 16 years and participating in the Ten Towns Heart Health Study, provided blood samples for DNA extraction and measurement of a range of CV risk factors. LTL was measured by real-time polymerase chain reaction. LTL was inversely associated with age (P=0.04), longer in females than in males (P=0.03), and longer in South Asians than in white Europeans (P=0.01). No associations were found between LTL and traditional CV risk factors. There was a significant and inverse association between LTL and inflammatory markers, including C-reactive protein (P<0.001) and fibrinogen (P=0.001). The associations between LTL and inflammatory markers were not affected by multiple adjustments for behavioral and metabolic factors.<br><br>CONCLUSIONS: High levels of inflammation are associated with shorter LTL from early adolescence; traditional CV risk factors have little association with LTL in adolescence. Inflammation in early life may play a causal role in the adult association between short LTL and CV disease.},
}
@article {pmid22676944,
year = {2012},
author = {Armstrong, EJ and Xing, L and Zhang, J and Zheng, Y and Shunk, KA and Yeh, RW and Farzaneh-Far, R and Yu, B and Jang, IK},
title = {Association between leukocyte telomere length and drug-eluting stent strut coverage by optical coherence tomography.},
journal = {Journal of the American College of Cardiology},
volume = {59},
number = {24},
pages = {2218-2219},
doi = {10.1016/j.jacc.2012.03.028},
pmid = {22676944},
issn = {1558-3597},
mesh = {Aged ; Coronary Angiography ; Coronary Restenosis/diagnosis ; *Drug-Eluting Stents ; Female ; Humans ; Leukocytes/*cytology ; Male ; Middle Aged ; Telomere/*physiology ; *Tomography, Optical Coherence ; },
}
@article {pmid22675460,
year = {2012},
author = {Sun, Q and Shi, L and Prescott, J and Chiuve, SE and Hu, FB and De Vivo, I and Stampfer, MJ and Franks, PW and Manson, JE and Rexrode, KM},
title = {Healthy lifestyle and leukocyte telomere length in U.S. women.},
journal = {PloS one},
volume = {7},
number = {5},
pages = {e38374},
pmid = {22675460},
issn = {1932-6203},
support = {HL34594/HL/NHLBI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; CA4449/CA/NCI NIH HHS/United States ; R01 CA082838/CA/NCI NIH HHS/United States ; R01 HL034594/HL/NHLBI NIH HHS/United States ; K99 HL098459/HL/NHLBI NIH HHS/United States ; R01 HL088521/HL/NHLBI NIH HHS/United States ; CA87969/CA/NCI NIH HHS/United States ; HL088521/HL/NHLBI NIH HHS/United States ; K99HL098459/HL/NHLBI NIH HHS/United States ; CA82838/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Case-Control Studies ; Female ; Humans ; Leukocytes/*metabolism ; *Life Style ; Middle Aged ; Prospective Studies ; Risk Factors ; *Telomere ; United States ; },
abstract = {CONTEXT: Whether a healthy lifestyle may be associated with longer telomere length is largely unknown.<br><br>OBJECTIVES: To examine healthy lifestyle practices, which are primary prevention measures against major age-related chronic diseases, in relation to leukocyte telomere length.<br><br>DESIGN AND SETTING: Cross-sectional analysis in the Nurses' Health Study (NHS).<br><br>PARTICIPANTS: The population consisted of 5,862 women who participated in multiple prospective case-control studies within the NHS cohort. Z scores of leukocyte telomere length were derived within each case-control study. Based on prior work, we defined low-risk or healthy categories for five major modifiable factors assessed in 1988 or 1990: non-current smoking, maintaining a healthy body weight (body mass index in 18.5-24.9 kg/m(2)), engaging in regular moderate or vigorous physical activities (&#x2265;150 minutes/week), drinking alcohol in moderation (1 drink/week to <2 drinks/day), and eating a healthy diet (Alternate Healthy Eating Index score in top 50%). We calculated difference (%) of the z scores contrasting low-risk groups with reference groups to evaluate the association of interest.<br><br>RESULTS: Although none of the individual low-risk factors was significantly associated with larger leukocyte telomere length z scores, we observed a significant, positive relationship between the number of low-risk factors and the z scores. In comparison with women who had zero low-risk factors (1.9% of the total population) and were, therefore, considered the least healthy group, the leukocyte telomere length z scores were 16.4%, 22.1%, 28.7%, 22.6%, and 31.2% (P for trend&#x200a;=&#x200a;0.015) higher for women who had 1 to 5 low-risk factors, respectively.<br><br>CONCLUSIONS: Adherence to a healthy lifestyle, defined by major modifiable risk factors, was associated with longer telomere length in leukocytes.},
}
@article {pmid22673587,
year = {2012},
author = {Garber, K},
title = {At loose ends: telomere theories of aging and cancer begin to converge.},
journal = {Journal of the National Cancer Institute},
volume = {104},
number = {11},
pages = {803-806},
doi = {10.1093/jnci/djs271},
pmid = {22673587},
issn = {1460-2105},
mesh = {Aging/*genetics ; Animals ; *Cell Transformation, Neoplastic/genetics/metabolism ; Disease Progression ; Enzyme Inhibitors/pharmacology ; Evidence-Based Medicine ; Humans ; *Mitochondria/genetics/metabolism/pathology ; Neoplasms/*genetics ; *Telomerase/antagonists &amp; inhibitors/metabolism ; *Telomere/chemistry/metabolism/pathology ; },
}
@article {pmid22672906,
year = {2012},
author = {Leman, AR and Dheekollu, J and Deng, Z and Lee, SW and Das, MM and Lieberman, PM and Noguchi, E},
title = {Timeless preserves telomere length by promoting efficient DNA replication through human telomeres.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {11},
number = {12},
pages = {2337-2347},
pmid = {22672906},
issn = {1551-4005},
support = {P30CA10815/CA/NCI NIH HHS/United States ; F31 AG035480/AG/NIA NIH HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; R01GM077604/GM/NIGMS NIH HHS/United States ; R01CA140652/CA/NCI NIH HHS/United States ; R01 GM077604/GM/NIGMS NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; F31AG035480/AG/NIA NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Cell Line, Tumor ; DNA Damage ; *DNA Replication ; HEK293 Cells ; HeLa Cells ; Humans ; Intracellular Signaling Peptides and Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Protein Binding ; RNA Interference ; RNA, Small Interfering/metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {A variety of telomere protection programs are utilized to preserve telomere structure. However, the complex nature of telomere maintenance remains elusive. The Timeless protein associates with the replication fork and is thought to support efficient progression of the replication fork through natural impediments, including replication fork block sites. However, the mechanism by which Timeless regulates such genomic regions is not understood. Here, we report the role of Timeless in telomere length maintenance. We demonstrate that Timeless depletion leads to telomere shortening in human cells. This length maintenance is independent of telomerase, and Timeless depletion causes increased levels of DNA damage, leading to telomere aberrations. We also show that Timeless is associated with Shelterin components TRF1 and TRF2. Timeless depletion slows telomere replication in vitro, and Timeless-depleted cells fail to maintain TRF1-mediated accumulation of replisome components at telomeric regions. Furthermore, telomere replication undergoes a dramatic delay in Timeless-depleted cells. These results suggest that Timeless functions together with TRF1 to prevent fork collapse at telomere repeat DNA and ensure stable maintenance of telomere length and integrity.},
}
@article {pmid22672282,
year = {2012},
author = {Imbert, I and Botto, JM and Farra, CD and Domloge, N},
title = {Modulation of telomere binding proteins: a future area of research for skin protection and anti-aging target.},
journal = {Journal of cosmetic dermatology},
volume = {11},
number = {2},
pages = {162-166},
doi = {10.1111/j.1473-2165.2012.00611.x},
pmid = {22672282},
issn = {1473-2165},
mesh = {Humans ; Skin/*enzymology/metabolism ; *Skin Aging ; Skin Physiological Phenomena ; Telomerase/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomere shortening is considered as one of the main characteristics of cellular aging by limiting cellular division. Besides the fundamental advances through the discoveries of telomere and telomerase, which were recognized by a Nobel Prize, telomere protection remains an essential area of research. Recently, it was evidenced that studying the cross-talks between the proteins associated with telomere should provide a better understanding of the mechanistic basis for telomere-associated aging phenotypes. In this review, we discuss the current knowledge on telomere shortening, telomerase activity, and the essential role of telomere binding proteins in telomere stabilization and telomere-end protection. This review highlights the capacity of telomere binding proteins to limit cellular senescence and to maintain skin tissue homeostasis, which is of key importance to reduce accelerated tissue aging. Future studies addressing telomere protection and limitation of DNA damage response in human skin should include investigations on telomere binding proteins. As little is known about the expression of telomere binding proteins in human skin and modulation of their expression with aging, it remains an interesting field of skin research and a key area for future skin protection and anti-aging developments.},
}
@article {pmid22669075,
year = {2012},
author = {Koga, A and Hirai, Y and Hara, T and Hirai, H},
title = {Repetitive sequences originating from the centromere constitute large-scale heterochromatin in the telomere region in the siamang, a small ape.},
journal = {Heredity},
volume = {109},
number = {3},
pages = {180-187},
pmid = {22669075},
issn = {1365-2540},
mesh = {Animals ; Base Sequence ; Centromere/chemistry/*genetics ; Chromosome Banding ; DNA, Satellite/genetics ; Female ; Heterochromatin/chemistry/*genetics ; Hylobates/classification/*genetics ; Male ; Molecular Sequence Data ; Phylogeny ; Primates/classification/genetics ; *Repetitive Sequences, Nucleic Acid ; Sequence Homology, Nucleic Acid ; Telomere/chemistry/*genetics ; },
abstract = {Chromosomes of the siamang Symphalangus syndactylus (a small ape) carry large-scale heterochromatic structures at their ends. These structures look similar, by chromosome C-banding, to chromosome-end heterochromatin found in chimpanzee, bonobo and gorilla (African great apes), of which a major component is tandem repeats of 32-bp-long, AT-rich units. In the present study, we identified repetitive sequences that are a major component of the siamang heterochromatin. Their repeat units are 171 bp in length, and exhibit sequence similarity to alpha satellite DNA, a major component of the centromeres in primates. Thus, the large-scale heterochromatic structures have different origins between the great apes and the small ape. The presence of alpha satellite DNA in the telomere region has previously been reported in the white-cheeked gibbon Nomascus leucogenys, another small ape species. There is, however, a difference in the size of the telomere-region alpha satellite DNA, which is far larger in the siamang. It is not known whether the sequences of these two species (of different genera) have a common origin because the phylogenetic relationship of genera within the small ape family is still not clear. Possible evolutionary scenarios are discussed.},
}
@article {pmid22668817,
year = {2012},
author = {Kim, JH and Ko, JH and Lee, DC and Lim, I and Bang, H},
title = {Habitual physical exercise has beneficial effects on telomere length in postmenopausal women.},
journal = {Menopause (New York, N.Y.)},
volume = {19},
number = {10},
pages = {1109-1115},
doi = {10.1097/gme.0b013e3182503e97},
pmid = {22668817},
issn = {1530-0374},
mesh = {Adiponectin/blood ; Aged ; Blood Pressure/physiology ; Body Mass Index ; Cholesterol, HDL/blood ; Cross-Sectional Studies ; DNA Primers/chemistry ; Exercise/*physiology ; Female ; Humans ; Insulin/blood ; Leukocytes, Mononuclear/ultrastructure ; Middle Aged ; Postmenopause/*physiology ; Real-Time Polymerase Chain Reaction ; Sedentary Behavior ; Telomere Homeostasis/*physiology ; },
abstract = {OBJECTIVE: It has been reported that women benefit from the maintenance of telomere length by estrogen. Exercise may favorably influence telomere length, although results are inconsistent regarding the duration and type of exercise and the cell type used to measure telomere length. The purpose of this study was to investigate the relationship between habitual physical exercise and telomere length in peripheral blood mononuclear cells (PBMCs) in postmenopausal women. Postmenopausal women were chosen as study participants because they are typically estrogen deficient.<br><br>METHODS: This experimental-control, cross-sectional study included 44 healthy, nondiabetic, nonsmoking, postmenopausal women. Habitual exercisers and sedentary participants were matched for age and body mass index. Body weight, height, blood pressure, and waist and hip circumference were measured. Mitochondrial DNA copy number and telomere length in PBMCs were determined, and biochemical tests were performed. Habitual physical exercise was defined as combined aerobic and resistance exercise performed for at least 60 minutes per session more than three times a week for more than 12 months.<br><br>RESULTS: The mean age of all participants was 58.11 &#xb1; 6.84 years, and participants in the habitual exercise group had been exercising more than three times per week for an average of 19.23 &#xb1; 5.15 months. Serum triglyceride levels (P = 0.01), fasting insulin concentrations (P < 0.01), and homeostasis model assessment of insulin resistance (P < 0.01) were significantly lower and high-density lipoprotein cholesterol levels (P < 0.01), circulating adiponectin (P < 0.01), mitochondrial DNA copy number (P < 0.01), and telomere length (P < 0.01) were significantly higher in the habitual exercise group than in the sedentary group. In a stepwise multiple regression analysis, habitual exercise (&#x3b2; = 0.522, P < 0.01) and adiponectin levels (&#x3b2; = 0.139, P = 0.03) were the independent factors associated with the telomere length of PBMCs in postmenopausal women.<br><br>CONCLUSIONS: Habitual physical exercise is associated with greater telomere length in postmenopausal women. This finding suggests that habitual physical exercise in postmenopausal women may reduce telomere attrition.},
}
@article {pmid22668000,
year = {2012},
author = {Das, B and Saini, D and Seshadri, M},
title = {No evidence of telomere length attrition in newborns from high level natural background radiation areas in Kerala coast, south west India.},
journal = {International journal of radiation biology},
volume = {88},
number = {9},
pages = {642-647},
doi = {10.3109/09553002.2012.699135},
pmid = {22668000},
issn = {1362-3095},
mesh = {Adult ; *Background Radiation ; Female ; Humans ; India ; Infant, Newborn ; Male ; Telomere/*radiation effects ; },
abstract = {PURPOSE: The tandemly repeated hexamers (TTAGGG)n present at the telomeric ends protect the human genome from a variety of environmental exposures including ionizing radiation. In order to find out the effect of chronic low dose radiation exposure, we have determined telomere length among newborns from high level natural radiation areas (HLNRA) of the Kerala coast in South west India.<br><br>METHODOLOGY: Umbilical cord blood samples were collected from 128 newborns from HLNRA and 43 newborns from normal level natural radiation areas (NLNRA) and genomic DNA was isolated using a salt precipitation method. The mean telomere length was determined using SYBR green-based real time quantitative Polymerase chain reaction (qPCR), where telomere gene specific (T) and single copy gene specific (S) primers were used. The average of telomere versus single copy gene (T/S) ratio was calculated which was proportional to telomere length of each individual.<br><br>RESULTS: The mean relative telomere length was found to be 1.03&#x2009;&#xb1;&#x2009;0.01 (95% CI, 0.99-1.05) and 1.10&#x2009;&#xb1;&#x2009;0.03 (95% CI, 1.04-1.17) in HLNRA and NLNRA newborns, respectively (P >&#x2009;0.05). Based on the level of background radiation dose, samples were divided into four groups, i.e., NLNRA: <&#x2009;1.50 mGy/year and three HNLRA groups: 1.51-3.00 mGy/year, 3.01-5.00 mGy/year, and >&#x2009;5.00 mGy/year. The mean relative telomere length in these groups were found to be 1.10&#x2009;&#xb1;&#x2009;0.03 (95% CI, 1.03-1.17), 0.98&#x2009;&#xb1;&#x2009;0.01 (95% CI, 0.95-1.01), 1.05&#x2009;&#xb1;&#x2009;0.02 (95% CI, 1.01-1.10) and 1.07&#x2009;&#xb1;&#x2009;0.03 (95% CI, 1.04-1.10), respectively. No significant difference was observed between the mean telomere length of male and female newborns.<br><br>CONCLUSIONS: The elevated level of natural chronic background radiation prevailing in Kerala coast did not show any significant effect on telomere length of newborns. To our knowledge, this is the first report on newborn telomere length from a high level natural radiation area.},
}
@article {pmid22664510,
year = {2012},
author = {Math, MV},
title = {Prehypertension associated with dyslipidaemia in young adults - life-style &amp; telomeres.},
journal = {The Indian journal of medical research},
volume = {135},
number = {4},
pages = {565-566},
pmid = {22664510},
issn = {0971-5916},
mesh = {Cardiovascular Diseases/*epidemiology ; Dyslipidemias/*epidemiology ; Humans ; Military Personnel/*statistics &amp; numerical data ; Obesity, Abdominal/*epidemiology ; Overweight/*epidemiology ; Prehypertension/*epidemiology ; },
}
@article {pmid22661914,
year = {2012},
author = {Aubert, G and Baerlocher, GM and Vulto, I and Poon, SS and Lansdorp, PM},
title = {Collapse of telomere homeostasis in hematopoietic cells caused by heterozygous mutations in telomerase genes.},
journal = {PLoS genetics},
volume = {8},
number = {5},
pages = {e1002696},
pmid = {22661914},
issn = {1553-7404},
support = {R01 GM094146/GM/NIGMS NIH HHS/United States ; RMF-92093/CAPMC/CIHR/Canada ; R01GM094146/GM/NIGMS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; *Aging ; Cell Death/genetics ; Cellular Senescence/genetics ; Child ; Child, Preschool ; Granulocytes/cytology ; *Hematopoietic Stem Cells/cytology ; Heterozygote ; Humans ; Infant ; Lymphocytes/cytology ; Middle Aged ; *Mutation ; RNA/*genetics ; *Sex Characteristics ; Telomerase/*genetics ; Telomere/genetics ; *Telomere Homeostasis/genetics ; Young Adult ; },
abstract = {Telomerase activity is readily detectable in extracts from human hematopoietic stem and progenitor cells, but appears unable to maintain telomere length with proliferation in vitro and with age in vivo. We performed a detailed study of the telomere length by flow FISH analysis in leukocytes from 835 healthy individuals and 60 individuals with reduced telomerase activity. Healthy individuals showed a broad range in average telomere length in granulocytes and lymphocytes at any given age. The average telomere length declined with age at a rate that differed between age-specific breakpoints and between cell types. Gender differences between leukocyte telomere lengths were observed for all cell subsets studied; interestingly, this trend could already be detected at birth. Heterozygous carriers for mutations in either the telomerase reverse transcriptase (hTERT) or the telomerase RNA template (hTERC) gene displayed striking and comparable telomere length deficits. Further, non-carrier relatives of such heterozygous individuals had somewhat shorter leukocyte telomere lengths than expected; this difference was most profound for granulocytes. Failure to maintain telomere homeostasis as a result of partial telomerase deficiency is thought to trigger cell senescence or cell death, eventually causing tissue failure syndromes. Our data are consistent with these statements and suggest that the likelihood of similar processes occurring in normal individuals increases with age. Our work highlights the essential role of telomerase in the hematopoietic system and supports the notion that telomerase levels in hematopoietic cells, while limiting and unable to prevent overall telomere shortening, are nevertheless crucial to maintain telomere homeostasis with age.},
}
@article {pmid22661228,
year = {2012},
author = {Chow, TT and Zhao, Y and Mak, SS and Shay, JW and Wright, WE},
title = {Early and late steps in telomere overhang processing in normal human cells: the position of the final RNA primer drives telomere shortening.},
journal = {Genes &amp; development},
volume = {26},
number = {11},
pages = {1167-1178},
pmid = {22661228},
issn = {1549-5477},
support = {R01 AG001228/AG/NIA NIH HHS/United States ; AG01228/AG/NIA NIH HHS/United States ; },
mesh = {*DNA Replication ; Fibroblasts/cytology ; Foreskin/cytology ; G2 Phase ; HeLa Cells ; Humans ; Male ; RNA ; S Phase ; Telomere/metabolism ; *Telomere Shortening ; },
abstract = {Telomere overhangs are essential for telomere end protection and telomerase extension, but how telomere overhangs are generated is unknown. Leading daughter strands synthesized by conventional semiconservation DNA replication are initially blunt, while lagging daughter strands are shorter by at least the size of the final RNA primer, which is thought to be located at extreme chromosome ends. We developed a variety of new approaches to define the steps in the processing of these overhangs. We show that the final lagging RNA primer is not terminal but is randomly positioned ~70-100 nucleotides from the ends and is not removed for more than an hour. This identifies an important intrinsic step in replicative aging. Telomeric termini are processed in two distinct phases. During the early phase, which occupies 1-2 h following replication of the duplex telomeric DNA, several steps occur on both leading and lagging daughters. Leading telomere processing remains incomplete until late S/G2, when the C-terminal nucleotide is specified-referred to as the late phase. These observations suggest the presence of previously unsuspected complexes and signaling events required for the replication of the ends of human chromosomes.},
}
@article {pmid22661225,
year = {2012},
author = {Lundblad, V},
title = {Telomere end processing: unexpected complexity at the end game.},
journal = {Genes &amp; development},
volume = {26},
number = {11},
pages = {1123-1127},
pmid = {22661225},
issn = {1549-5477},
support = {R37 AG011728/AG/NIA NIH HHS/United States ; R37 AG11728/AG/NIA NIH HHS/United States ; },
mesh = {*DNA Replication ; Humans ; Male ; *Telomere Shortening ; },
abstract = {Most human cells lack telomerase, the enzyme that elongates telomeres. The resulting telomere erosion eventually limits cell proliferation and tissue renewal, thereby impacting age-dependent pathologies. In this issue of Genes &amp; Development, a technical tour-de-force by Chow and colleagues (pp. 1167-1178) reveals a highly choreographed sequence of events that processes newly replicated chromosome ends into mature telomeres. This sheds new light on an underappreciated contribution to telomere dynamics that may be as important as telomerase in dictating the correlation between life span and telomere length.},
}
@article {pmid22654677,
year = {2012},
author = {Lee, CY and Conrad, MN and Dresser, ME},
title = {Meiotic chromosome pairing is promoted by telomere-led chromosome movements independent of bouquet formation.},
journal = {PLoS genetics},
volume = {8},
number = {5},
pages = {e1002730},
pmid = {22654677},
issn = {1553-7404},
support = {R01 GM087516/GM/NIGMS NIH HHS/United States ; GM087516/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics ; Cell Nucleus ; Centromere/genetics ; Chromosome Pairing/*genetics ; Chromosome Segregation/genetics ; In Situ Hybridization, Fluorescence ; *Meiosis/genetics ; Membrane Proteins/genetics ; Mutation ; Nuclear Proteins/genetics ; Prophase/genetics ; *Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/genetics ; *Telomere/genetics ; },
abstract = {Chromosome pairing in meiotic prophase is a prerequisite for the high fidelity of chromosome segregation that haploidizes the genome prior to gamete formation. In the budding yeast Saccharomyces cerevisiae, as in most multicellular eukaryotes, homologous pairing at the cytological level reflects the contemporaneous search for homology at the molecular level, where DNA double-strand broken ends find and interact with templates for repair on homologous chromosomes. Synapsis (synaptonemal complex formation) stabilizes pairing and supports DNA repair. The bouquet stage, where telomeres have formed a transient single cluster early in meiotic prophase, and telomere-promoted rapid meiotic prophase chromosome movements (RPMs) are prominent temporal correlates of pairing and synapsis. The bouquet has long been thought to contribute to the kinetics of pairing, but the individual roles of bouquet and RPMs are difficult to assess because of common dependencies. For example, in budding yeast RPMs and bouquet both require the broadly conserved SUN protein Mps3 as well as Ndj1 and Csm4, which link telomeres to the cytoskeleton through the intact nuclear envelope. We find that mutants in these genes provide a graded series of RPM activity: wild-type>mps3-dCC>mps3-dAR>ndj1Δ>mps3-dNT = csm4Δ. Pairing rates are directly correlated with RPM activity even though only wild-type forms a bouquet, suggesting that RPMs promote homologous pairing directly while the bouquet plays at most a minor role in Saccharomyces cerevisiae. A new collision trap assay demonstrates that RPMs generate homologous and heterologous chromosome collisions in or before the earliest stages of prophase, suggesting that RPMs contribute to pairing by stirring the nuclear contents to aid the recombination-mediated homology search.},
}
@article {pmid22652771,
year = {2012},
author = {Frias, C and Pampalona, J and Genesca, A and Tusell, L},
title = {Telomere dysfunction and genome instability.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {17},
number = {6},
pages = {2181-2196},
doi = {10.2741/4044},
pmid = {22652771},
issn = {2768-6698},
mesh = {Animals ; Cell Proliferation ; Cellular Senescence/genetics ; DNA Breaks, Double-Stranded ; DNA Damage ; DNA Repair ; *Genomic Instability ; Humans ; Mice ; Models, Genetic ; Neoplasms/genetics ; Shelterin Complex ; Telomerase/metabolism ; Telomere/*genetics/*metabolism ; Telomere Homeostasis ; Telomere Shortening ; Telomere-Binding Proteins/metabolism ; },
abstract = {The nucleoprotein complexes that cap the very ends of the eukaryotic chromosomes, named telomeres, are indispensable for cell viability. Telomeric DNA shortens in each cell division until it cannot exert end-protective functions in human somatic cells. Additionally, several proteins have been described to play a key role in telomere homeostasis preventing chromosome extremities to be recognized as double-stranded breaks (DSBs). When telomeres become dysfunctional, either through excessive shortening or due to defects in the proteins that form its structure, they trigger p53/pRb pathways what limits proliferative lifespan. Impairment of telomere function together with a compromised senescence/apoptosis response leads to chromosome instability. Fusions between dysfunctional telomeres or even between dysfunctional telomeres and DSBs can initiate breakage-fusion-bridge (BFB) cycles. Initially, telomere fusions were proposed to cause only structural abnormalities. Nevertheless, changes in chromosome number have also emerged as a possible consequence of alterations in end capping. Here we review the main aspects of telomeres and telomere-based chromosome instability, highlighting why they have been proposed as a driving force for tumourigenesis.},
}
@article {pmid22651378,
year = {2012},
author = {Lannan, FM and Mamajanov, I and Hud, NV},
title = {Human telomere sequence DNA in water-free and high-viscosity solvents: G-quadruplex folding governed by Kramers rate theory.},
journal = {Journal of the American Chemical Society},
volume = {134},
number = {37},
pages = {15324-15330},
doi = {10.1021/ja303499m},
pmid = {22651378},
issn = {1520-5126},
mesh = {DNA/*genetics ; *G-Quadruplexes ; Humans ; Kinetics ; Models, Theoretical ; *Solvents ; *Telomere ; *Viscosity ; },
abstract = {Structures formed by human telomere sequence (HTS) DNA are of interest due to the implication of telomeres in the aging process and cancer. We present studies of HTS DNA folding in an anhydrous, high viscosity deep eutectic solvent (DES) comprised of choline choride and urea. In this solvent, the HTS DNA forms a G-quadruplex with the parallel-stranded ("propeller") fold, consistent with observations that reduced water activity favors the parallel fold, whereas alternative folds are favored at high water activity. Surprisingly, adoption of the parallel structure by HTS DNA in the DES, after thermal denaturation and quick cooling to room temperature, requires several months, as opposed to less than 2 min in an aqueous solution. This extended folding time in the DES is, in part, due to HTS DNA becoming kinetically trapped in a folded state that is apparently not accessed in lower viscosity solvents. A comparison of times required for the G-quadruplex to convert from its aqueous-preferred folded state to its parallel fold also reveals a dependence on solvent viscosity that is consistent with Kramers rate theory, which predicts that diffusion-controlled transitions will slow proportionally with solvent friction. These results provide an enhanced view of a G-quadruplex folding funnel and highlight the necessity to consider solvent viscosity in studies of G-quadruplex formation in vitro and in vivo. Additionally, the solvents and analyses presented here should prove valuable for understanding the folding of many other nucleic acids and potentially have applications in DNA-based nanotechnology where time-dependent structures are desired.},
}
@article {pmid22645309,
year = {2012},
author = {Xu, J and McEachern, MJ},
title = {Maintenance of very long telomeres by recombination in the Kluyveromyces lactis stn1-M1 mutant involves extreme telomeric turnover, telomeric circles, and concerted telomeric amplification.},
journal = {Molecular and cellular biology},
volume = {32},
number = {15},
pages = {2992-3008},
pmid = {22645309},
issn = {1098-5549},
support = {R01 GM061645/GM/NIGMS NIH HHS/United States ; GM 61645/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA, Circular/genetics ; DNA, Fungal/genetics/metabolism ; DNA-Binding Proteins/biosynthesis/genetics ; Fungal Proteins/biosynthesis/genetics ; Gene Dosage ; Genetic Variation ; Kluyveromyces/*genetics/metabolism ; Rad51 Recombinase/metabolism ; Telomere/genetics/*metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Some cancers utilize the recombination-dependent process of alternative lengthening of telomeres (ALT) to maintain long heterogeneous telomeres. Here, we studied the recombinational telomere elongation (RTE) of the Kluyveromyces lactis stn1-M1 mutant. We found that the total amount of the abundant telomeric DNA in stn1-M1 cells is subject to rapid variation and that it is likely to be primarily extrachromosomal. Rad50 and Rad51, known to be required for different RTE pathways in Saccharomyces cerevisiae, were not essential for the production of either long telomeres or telomeric circles in stn1-M1 cells. Circles of DNA containing telomeric repeats (t-circles) either present at the point of establishment of long telomeres or introduced later into stn1-M1 cells each led to the formation of long tandem arrays of the t-circle's sequence, which were incorporated at multiple telomeres. These tandem arrays were extraordinarily unstable and showed evidence of repeated rounds of concerted amplification. Our results suggest that the maintenance of telomeres in the stn1-M1 mutant involves extreme turnover of telomeric sequences from processes including both large deletions and the copying of t-circles.},
}
@article {pmid22643218,
year = {2012},
author = {Günes, C and Rudolph, KL},
title = {Telomere dysfunction puts the brakes on oncogene-induced cancers.},
journal = {The EMBO journal},
volume = {31},
number = {13},
pages = {2833-2834},
pmid = {22643218},
issn = {1460-2075},
mesh = {Cellular Senescence/*physiology ; Humans ; Oncogenes/*physiology ; Telomere/*physiology ; },
abstract = {EMBO J 31 13, 2839–2851 (2012); published online May 08 2012 Senescence represents a major tumour suppressor checkpoint activated by telomere dysfunction or cellular stress factors such as oncogene activation. In this issue of The EMBO Journal, Suram et al (2012) reveal a surprising interconnection between oncogene activation and telomere dysfunction induced senescence. The study supports an alternative model of tumour suppression, indicating that oncogene-induced accumulation of telomeric DNA damage contributes to the induction of senescence in telomerase-negative tumours.},
}
@article {pmid22641345,
year = {2012},
author = {Hsu, JK and Lin, T and Tsai, RY},
title = {Nucleostemin prevents telomere damage by promoting PML-IV recruitment to SUMOylated TRF1.},
journal = {The Journal of cell biology},
volume = {197},
number = {5},
pages = {613-624},
pmid = {22641345},
issn = {1540-8140},
mesh = {GTP-Binding Proteins/*metabolism ; HEK293 Cells ; Humans ; Nuclear Proteins/*metabolism ; Sumoylation ; Telomere/*metabolism/pathology ; Telomeric Repeat Binding Protein 1/*metabolism ; },
abstract = {Continuously dividing cells must be protected from telomeric and nontelomeric DNA damage in order to maintain their proliferative potential. Here, we report a novel telomere-protecting mechanism regulated by nucleostemin (NS). NS depletion increased the number of telomere damage foci in both telomerase-active (TA(+)) and alternative lengthening of telomere (ALT) cells and decreased the percentage of damaged telomeres associated with ALT-associated PML bodies (APB) and the number of APB in ALT cells. Mechanistically, NS could promote the recruitment of PML-IV to SUMOylated TRF1 in TA(+) and ALT cells. This event was stimulated by DNA damage. Supporting the importance of NS and PML-IV in telomere protection, we demonstrate that loss of NS or PML-IV increased the frequency of telomere damage and aberration, reduced telomeric length, and perturbed the TRF2(ΔBΔM)-induced telomeric recruitment of RAD51. Conversely, overexpression of either NS or PML-IV protected ALT and TA(+) cells from telomere damage. This work reveals a novel mechanism in telomere protection.},
}
@article {pmid22634377,
year = {2012},
author = {Walker, JR and Zhu, XD},
title = {Post-translational modifications of TRF1 and TRF2 and their roles in telomere maintenance.},
journal = {Mechanisms of ageing and development},
volume = {133},
number = {6},
pages = {421-434},
doi = {10.1016/j.mad.2012.05.002},
pmid = {22634377},
issn = {1872-6216},
support = {MOP-86620//Canadian Institutes of Health Research/Canada ; MSH-76599//Canadian Institutes of Health Research/Canada ; },
mesh = {Animals ; Humans ; Mice ; Phosphorylation ; *Protein Processing, Post-Translational ; Protein-Arginine N-Methyltransferases/physiology ; Rats ; Sumoylation/physiology ; *Telomere Homeostasis ; Telomeric Repeat Binding Protein 1/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; Ubiquitination/physiology ; },
abstract = {Telomeres, heterochromatic structures, found at the ends of linear eukaryotic chromosomes, function to protect natural chromosome ends from nucleolytic attack. Human telomeric DNA is bound by a telomere-specific six-subunit protein complex, termed shelterin/telosome. The shelterin subunits TRF1 and TRF2 bind in a sequence-specific manner to double-stranded telomeric DNA, providing a vital platform for recruitment of additional shelterin proteins as well as non-shelterin factors crucial for the maintenance of telomere length and structure. Both TRF1 and TRF2 are engaged in multiple roles at telomeres including telomere protection, telomere replication, sister telomere resolution and telomere length maintenance. Regulation of TRF1 and TRF2 in these various processes is controlled by post-translational modifications, at times in a cell-cycle-dependent manner, affecting key functions such as DNA binding, dimerization, localization, degradation and interactions with other proteins. Here we review the post-translational modifications of TRF1 and TRF2 and discuss the mechanisms by which these modifications contribute to the function of these two proteins.},
}
@article {pmid22633956,
year = {2012},
author = {Dehé, PM and Rog, O and Ferreira, MG and Greenwood, J and Cooper, JP},
title = {Taz1 enforces cell-cycle regulation of telomere synthesis.},
journal = {Molecular cell},
volume = {46},
number = {6},
pages = {797-808},
doi = {10.1016/j.molcel.2012.04.022},
pmid = {22633956},
issn = {1097-4164},
support = {//Cancer Research UK/United Kingdom ; },
mesh = {DNA Replication ; Humans ; Schizosaccharomyces/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {The dramatic telomerase-dependent overelongation of telomeres in cells lacking Taz1 (ortholog of human TRF1/TRF2) or Rap1 implicates these proteins in restraint of telomerase activity. However, the modes by which these proteins regulate telomerase remain mysterious. Here we show that the mechanisms underlying excessive telomerase activity differ markedly between taz1Δ and rap1Δ strains. Despite allowing elevated telomerase access, rap1Δ telomeres are processed and synthesized in a cell-cycle-constrained manner similar to that of wild-type cells. In contrast, taz1Δ telomeres are processed with little cell-cycle dependency and recruit telomerase over an abnormally wide range of cell-cycle stages. Furthermore, although taz1Δ telomeres experience transient attrition mediated by replication fork stalling, this is balanced not only by temporal expansion of the telomerase activity period, but also by markedly increased recruitment of telomerase and its accessory factor Est1, suggesting that stalled forks generate robust substrates for telomerase.},
}
@article {pmid22633954,
year = {2012},
author = {Pont, AR and Sadri, N and Hsiao, SJ and Smith, S and Schneider, RJ},
title = {mRNA decay factor AUF1 maintains normal aging, telomere maintenance, and suppression of senescence by activation of telomerase transcription.},
journal = {Molecular cell},
volume = {47},
number = {1},
pages = {5-15},
pmid = {22633954},
issn = {1097-4164},
support = {R01 GM085693/GM/NIGMS NIH HHS/United States ; T32 AI007180/AI/NIAID NIH HHS/United States ; R01 GM085693-03/GM/NIGMS NIH HHS/United States ; R01 CA095099/CA/NCI NIH HHS/United States ; T32 T32AI007180/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Animals, Newborn ; Anticipation, Genetic/genetics ; Cells, Cultured ; Cellular Senescence/*genetics ; DNA Damage ; Embryo, Mammalian/cytology/metabolism ; Female ; Fibroblasts/cytology/metabolism ; Heterogeneous Nuclear Ribonucleoprotein D0 ; Heterogeneous-Nuclear Ribonucleoprotein D/deficiency/*genetics/metabolism ; Immunoblotting ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Knockout ; Microscopy, Confocal ; Promoter Regions, Genetic/genetics ; Protein Binding ; RNA Stability/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*genetics ; Telomere/*genetics ; *Transcriptional Activation ; },
abstract = {Inflammation is associated with DNA damage, cellular senescence, and aging. Cessation of the inflammatory cytokine response is mediated in part through cytokine mRNA degradation facilitated by RNA-binding proteins, including AUF1. We report a major function of AUF1-it activates telomerase expression, suppresses cellular senescence, and maintains normal aging. AUF1-deficient mice undergo striking telomere erosion, markedly increased DNA damage responses at telomere ends, pronounced cellular senescence, and rapid premature aging that increases with successive generations, which can be rescued in AUF1 knockout mice and their cultured cells by resupplying AUF1 expression. AUF1 binds and strongly activates the transcription promoter for telomerase catalytic subunit Tert. In addition to directing inflammatory cytokine mRNA decay, AUF1 destabilizes cell-cycle checkpoint mRNAs, preventing cellular senescence. Thus, a single gene, AUF1, links maintenance of telomere length and normal aging to attenuation of inflammatory cytokine expression and inhibition of cellular senescence.},
}
@article {pmid22626625,
year = {2012},
author = {Weng, NP},
title = {Telomeres and immune competency.},
journal = {Current opinion in immunology},
volume = {24},
number = {4},
pages = {470-475},
pmid = {22626625},
issn = {1879-0372},
support = {Z01 AG000756-10/ImNIH/Intramural NIH HHS/United States ; ZIA AG000756-14/ImNIH/Intramural NIH HHS/United States ; ZIA AG000756-12/ImNIH/Intramural NIH HHS/United States ; Z01 AG000756-11/ImNIH/Intramural NIH HHS/United States ; ZIA AG000756-13/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Animals ; Humans ; Immune System/*physiology ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; },
abstract = {Telomeres are essential for the integrity of chromosomes and for cellular replication. Attrition of telomeres occurs during DNA replication owing to the inability of conventional DNA polymerase to replicate chromosomal termini and the insufficient compensation for telomere loss by telomerase, an enzyme that synthesizes telomeric DNA. A number of genetic defects have been described in humans and in animal models that cause accelerated telomere attrition, in turn leading to severe phenotypes of hematopoietic and other proliferating cells. Telomere length, most frequently measured as an average value in heterogeneous peripheral blood leukocyte populations in humans, has been associated with a wide range of health conditions and diseases of immune and non-immune cells. Here, I review recent studies of telomere length dynamics with particular relevance to immune function.},
}
@article {pmid22622044,
year = {2012},
author = {Wanat, JJ and Johnson, FB},
title = {Telomere stability and carcinogenesis: an off-again, on-again relationship.},
journal = {The Journal of clinical investigation},
volume = {122},
number = {6},
pages = {1962-1965},
pmid = {22622044},
issn = {1558-8238},
support = {R01 AG021521/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Apoptosis ; *Cell Cycle Checkpoints ; Cell Transformation, Neoplastic/*metabolism ; *Chromosomal Instability ; Liver Neoplasms/*enzymology ; RNA/*metabolism ; Telomerase/*metabolism ; Telomere/*enzymology ; },
abstract = {Previous studies in mice have demonstrated antagonistic effects of telomerase loss on carcinogenesis. Telomere attrition can promote genome instability, thereby stimulating initiation of early-stage cancers, but can also inhibit tumorigenesis by promoting permanent cell growth arrest or death. Human cancers likely develop in cell lineages with low levels of telomerase, leading to telomere losses in early lesions, followed by subsequent activation of telomerase. Mouse models constitutively lacking telomerase have thus not addressed how telomere losses within telomerase-proficient cells have an impact on carcinogenesis. Using a novel transgenic mouse model, Begus-Nahrmann et al. demonstrate in this issue of the JCI that transient telomere dysfunction in telomerase-proficient animals is a potent stimulus of tumor formation.},
}
@article {pmid22622037,
year = {2012},
author = {Begus-Nahrmann, Y and Hartmann, D and Kraus, J and Eshraghi, P and Scheffold, A and Grieb, M and Rasche, V and Schirmacher, P and Lee, HW and Kestler, HA and Lechel, A and Rudolph, KL},
title = {Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis.},
journal = {The Journal of clinical investigation},
volume = {122},
number = {6},
pages = {2283-2288},
pmid = {22622037},
issn = {1558-8238},
mesh = {Animals ; *Apoptosis ; *Cell Cycle Checkpoints ; Cell Transformation, Neoplastic/genetics/*metabolism/pathology ; *Chromosomal Instability ; DNA Damage ; Liver Neoplasms/*enzymology/genetics/metabolism ; Mice ; Mice, Knockout ; RNA/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/*enzymology/genetics ; },
abstract = {Telomere shortening limits the proliferative capacity of a cell, but perhaps surprisingly, shortening is also known to be associated with increased rates of tumor initiation. A current hypothesis suggests that telomere dysfunction increases tumor initiation by induction of chromosomal instability, but that initiated tumors need to reactivate telomerase for genome stabilization and tumor progression. This concept has not been tested in vivo, since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis in a mouse model of inducible telomere dysfunction on a telomerase-proficient background, in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and in WT mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell-cycle arrest, and apoptosis in telomerase-deficient liver tumors. Together, these data provide in vivo evidence that transient telomere dysfunction during early or late stages of tumorigenesis promotes chromosomal instability and carcinogenesis in telomerase-proficient mice.},
}
@article {pmid22621437,
year = {2012},
author = {Wang, H and Chen, Q and Lee, SH and Choi, Y and Johnson, FB and Pignolo, RJ},
title = {Impairment of osteoblast differentiation due to proliferation-independent telomere dysfunction in mouse models of accelerated aging.},
journal = {Aging cell},
volume = {11},
number = {4},
pages = {704-713},
pmid = {22621437},
issn = {1474-9726},
support = {R01 AG021521/AG/NIA NIH HHS/United States ; R01 AG028873/AG/NIA NIH HHS/United States ; R01AG028873/AG/NIA NIH HHS/United States ; },
mesh = {Aging, Premature/enzymology/*genetics/*pathology ; Animals ; Cell Differentiation/genetics ; Cellular Senescence/genetics/physiology ; Disease Models, Animal ; Female ; Male ; Mesenchymal Stem Cells/enzymology/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Osteoblasts/enzymology/*pathology ; Osteoporosis/enzymology/genetics/pathology ; RecQ Helicases/deficiency/genetics ; Signal Transduction ; Telomerase/deficiency/genetics ; Telomere Homeostasis/*genetics ; Werner Syndrome Helicase ; },
abstract = {We undertook genetic and nongenetic approaches to investigate the relationship between telomere maintenance and osteoblast differentiation, as well as to uncover a possible link between a known mediator of cellular aging and senile bone loss. Using mouse models of disrupted telomere maintenance molecules, including mutants in the Werner helicase (Wrn(-/-)), telomerase (Terc(-/-)), and Wrn(-/-) Terc(-/-) double mutants predisposed to accelerated bone loss, we measured telomere dysfunction-induced foci (TIFs) and markers of osteoblast differentiation in mesenchymal progenitor cells (MPCs). We found that telomere maintenance is directly and significantly related to osteoblast differentiation, with dysfunctional telomeres associated with impaired differentiation independent of proliferation state. Telomere-mediated defects in osteoblast differentiation are associated with increased p53/p21 expression and concomitant reduction in RUNX2. Conversely, MPCs from p53(-/-) mice do not have substantial telomere dysfunction and spontaneously differentiate into osteoblasts. These results suggest that critical telomere dysfunction may be a prominent mechanism for age-related osteoporosis and limits MPC differentiation into bone-forming cells via the p53/p21 pathway.},
}
@article {pmid22617877,
year = {2012},
author = {Maicher, A and Kastner, L and Luke, B},
title = {Telomeres and disease: enter TERRA.},
journal = {RNA biology},
volume = {9},
number = {6},
pages = {843-849},
doi = {10.4161/rna.20330},
pmid = {22617877},
issn = {1555-8584},
mesh = {Animals ; Chromosomes/metabolism ; Humans ; Neoplasms/genetics/metabolism ; Progeria/genetics/metabolism ; RNA, Long Noncoding/*genetics/metabolism/physiology ; Telomere/*genetics/metabolism/physiology ; Telomere Homeostasis/*genetics ; Transcription, Genetic ; },
abstract = {Telomere function is tightly regulated in order to maintain chromosomal stability. When telomeres become dysfunctional, the replicative capacity of cells diminishes and cellular senescence ensues. This can lead to impaired tissue replenishment and eventually degenerative disorders, referred to as telomere syndromes. Cancer can also develop as a result of the genomic instability associated with telomere dysfunction. TERRA (TElomeric Repeat containing RNA) is a long non-coding transcript that stems from sub-telomeric regions and continues into the telomeric tract and is therefore a hybrid of both sub-telomeric and telomeric sequence. In general, increased TERRA transcription is associated with telomere shortening and compromised telomere function. Here we will briefly outline the general principles behind telomere dysfunction-associated diseases. Furthermore, we will discuss the few known links that exist between telomere transcription (TERRA) and disease. Finally, we will speculate on how the understanding, and eventual manipulation, of TERRA transcription could potentially be used in terms of therapeutic strategies.},
}
@article {pmid22617386,
year = {2012},
author = {Kupiec, M and Weisman, R},
title = {TOR links starvation responses to telomere length maintenance.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {11},
number = {12},
pages = {2268-2271},
doi = {10.4161/cc.20401},
pmid = {22617386},
issn = {1551-4005},
mesh = {DNA-Binding Proteins/metabolism ; Humans ; Repressor Proteins/metabolism ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Schizosaccharomyces/metabolism ; TOR Serine-Threonine Kinases/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; Transcription Factors/metabolism ; },
abstract = {Telomeres are nucleoprotein structures that protect the ends of eukaryotic chromosomes and play important roles in ensuring the genome's integrity. Telomere length is maintained by complex mechanisms that ensure length homeostasis. Recent work has linked telomere length maintenance to the Tor protein kinases, which are central regulators of cellular growth. Here we summarize these results, which suggest a link between nutrient availability, telomere length maintenance and chronological lifespan.},
}
@article {pmid22614020,
year = {2013},
author = {Rybanska, I and Ishaq, O and Chou, J and Prakash, M and Bakhsheshian, J and Huso, DL and Franco, S},
title = {PARP1 and DNA-PKcs synergize to suppress p53 mutation and telomere fusions during T-lineage lymphomagenesis.},
journal = {Oncogene},
volume = {32},
number = {14},
pages = {1761-1771},
pmid = {22614020},
issn = {1476-5594},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Apoptosis ; Blotting, Western ; Cell Proliferation ; Cell Transformation, Neoplastic/*pathology ; Cesium Radioisotopes ; Chromosome Aberrations ; DNA/genetics ; DNA-Activated Protein Kinase/*physiology ; DNA-Binding Proteins/*physiology ; Female ; Genomic Instability ; Immunoenzyme Techniques ; In Situ Hybridization, Fluorescence ; Lymphoma/*etiology/metabolism/pathology ; Male ; Mice ; Mice, Knockout ; Mutation/*genetics ; Nuclear Proteins/*physiology ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases/*physiology ; Radiation Tolerance/genetics ; Real-Time Polymerase Chain Reaction ; Telomere/*physiology ; Thymocytes/metabolism/pathology ; Translocation, Genetic ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/*genetics ; },
abstract = {Poly(ADP-ribose) polymerase 1 (PARP1) interacts genetically with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to suppress early-onset T-lineage lymphomas in the mouse, but the underlying mechanisms have remained unknown. To address this question, we analyzed a series of lymphomas arising in PARP1(-/-)/DNA-PKcs(-/-) (P1(-/-)/D(-/-)) mice. We found that, despite defective V(D)J recombination, P1(-/-)/D(-/-) lymphomas lacked clonal reciprocal translocations involving antigen-receptor loci. Instead, tumor cells were characterized by aneuploidy driven by two main mechanisms: p53 inactivation and abnormal chromosome disjunction due to telomere fusions (TFs). Aberrant accumulation of p53 was observed in 13/19 (68.4%) lymphomas. Sequence analysis revealed five p53 mutations: three missense point mutations (one transition in exon 8 and two transversions in exons 5 and 8, respectively), one in-frame 5-11 microindel in exon 7 and a 410-bp deletion encompassing exons 5-8, resulting in a truncated protein. Analysis of tumor metaphases using sequential telomere fluorescent in-situ hybridization and spectral karyotyping revealed that nine out of nine lymphomas contained TFs. Mutant but not wild-type p53 status was associated with frequent clonal and nonclonal TFs, suggesting that p53 normally limits the extent of telomere dysfunction during transformation. Chromosomes involved in TFs were more likely to be aneuploid than chromosomes not involved in TFs in the same metaphases, regardless of the p53 status, indicating that TFs promote aneuploidy via a mechanism that is distinct from p53 loss. Finally, analysis of radiation responses in P1(-/-)/D(-/-), and control primary cells and tissues indicates that loss of PARP1 increases in vivo radiosensitivity and genomic instability in DNA-PKcs-deficient mice without impairing p53 stabilization and effector functions, suggesting a more severe defect in double-strand break (DSB) repair in double mutants. Together, our findings uncover defective DSB repair leading to tumor suppressor inactivation and abnormal segregation of fused chromosomes as two novel mechanisms promoting tumorigenesis in thymocytes lacking PARP1 and DNA-PKcs.},
}
@article {pmid22606980,
year = {2012},
author = {Al-Attas, OS and Al-Daghri, NM and Alokail, MS and Alkharfy, KM and Alfadda, AA and McTernan, P and Gibson, GC and Sabico, SB and Chrousos, GP},
title = {Circulating leukocyte telomere length is highly heritable among families of Arab descent.},
journal = {BMC medical genetics},
volume = {13},
number = {},
pages = {38},
pmid = {22606980},
issn = {1471-2350},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Arabs/*genetics ; Blood Glucose/genetics ; Body Mass Index ; Child ; Child, Preschool ; Cross-Sectional Studies ; Female ; Humans ; Infant ; Leukocytes ; Lipids/blood ; Male ; Middle Aged ; Saudi Arabia/epidemiology ; Telomere/*genetics ; Young Adult ; },
abstract = {BACKGROUND: Telomere length, an indicator of ageing and longevity, has been correlated with several biomarkers of cardiometabolic disease in both Arab children and adults. It is not known, however, whether or not telomere length is a highly conserved inheritable trait in this homogeneous cohort, where age-related diseases are highly prevalent. As such, the aim of this study was to address the inheritability of telomere length in Saudi families and the impact of cardiometabolic disease biomarkers on telomere length.<br><br>METHODS: A total of 119 randomly selected Saudi families (123 adults and 131 children) were included in this cross-sectional study. Anthropometrics were obtained and fasting blood samples were taken for routine analyses of fasting glucose and lipid profile. Leukocyte telomere length was determined using quantitative real time PCR.<br><br>RESULTS: Telomere length was highly heritable as assessed by a parent-offspring regression [h2 = 0.64 (p = 0.0006)]. Telomere length was modestly associated with BMI (R(2) 0.07; p-value 0.0087), total cholesterol (R(2) 0.08; p-value 0.0033), and LDL-cholesterol (R(2) 0.15; p-value 3 x 10(-5)) after adjustments for gender, age and age within generation.<br><br>CONCLUSION: The high heritability of telomere length in Arab families, and the associations of telomere length with various cardiometabolic parameters suggest heritable genetic fetal and/or epigenetic influences on the early predisposition of Arab children to age-related diseases and accelerated ageing.},
}
@article {pmid22595804,
year = {2012},
author = {Zhang, W and Tian, Y and Chen, JJ and Zhao, W and Yu, X},
title = {A postulated role of p130 in telomere maintenance by human papillomavirus oncoprotein E7.},
journal = {Medical hypotheses},
volume = {79},
number = {2},
pages = {178-180},
doi = {10.1016/j.mehy.2012.04.028},
pmid = {22595804},
issn = {1532-2777},
mesh = {Cell Transformation, Neoplastic/*genetics ; Crk-Associated Substrate Protein/*genetics ; Female ; Humans ; *Models, Biological ; *Models, Genetic ; Papillomavirus E7 Proteins/*genetics ; Telomere/*genetics ; Uterine Cervical Neoplasms/*genetics ; },
abstract = {High-risk human papillomaviruses (HR-HPVs) infections is highly associated with the development of cervical cancer. It is now recognized that telomere length maintenance or extension is indispensable for carcinogenesis. The early oncoproteins E6 and E7 are the main malignant transformation factors of HR-HPVs and they maintain telomeres by different mechanisms, of which E6 protein activating telomerase is well documented. Reports showed that E7 protein utilized an alternative lengthen of telomere (ALT) mechanism to restore telomere length, yet the underlying molecular basis remains largely unknown. We propose that degradation of tumor suppressor pRb family member p130 plays an essential role in E7-regulated telomere extension by ALT. ALT is a mechanism based on homologous recombination (HR) between telomere sister chromatids, and a number of proteins involved in the HR pathway, such as MRN [MRE11 (meiotic recombination 11)-Rad50-NBS1 (Nijmegen breakage syndrome 1)] complex are required for the ALT pathway. Rb family member p130 could inhibit ALT by interacting with Rad50, while HPV E7 could activate ALT by degrading p130. We will make E7 mutants which are defective in p130 degradation to test whether these cells have a limited life span. Besides, immunofluorescence assay will show an ALT-related promyelocytic leukemia (PML) body (APBs) in E7-expressing cells. Although cervical cancer usually has high telomerase activities since the expressing of HPV E6, the anti-telomerase therapy will be unavailable for cervical cancer since it may activate E7-induced ALT. Our hypothesis not only enrich the knowledge of the regulation of ALT, but also indicate that p130 may serve as a potential suppressor of ALT, and gene therapy of p130 may be used in cervical cancers.},
}
@article {pmid22593209,
year = {2012},
author = {Uringa, EJ and Lisaingo, K and Pickett, HA and Brind'Amour, J and Rohde, JH and Zelensky, A and Essers, J and Lansdorp, PM},
title = {RTEL1 contributes to DNA replication and repair and telomere maintenance.},
journal = {Molecular biology of the cell},
volume = {23},
number = {14},
pages = {2782-2792},
pmid = {22593209},
issn = {1939-4586},
support = {/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Cells, Cultured ; DNA/genetics ; DNA Damage ; DNA Helicases/*genetics/*metabolism ; *DNA Repair ; *DNA Replication ; Embryonic Stem Cells/cytology/metabolism ; Female ; Gene Knock-In Techniques ; Genomic Instability ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Sister Chromatid Exchange ; Telomerase/metabolism ; Telomere/*physiology ; *Telomere Homeostasis ; },
abstract = {Telomere maintenance and DNA repair are important processes that protect the genome against instability. mRtel1, an essential helicase, is a dominant factor setting telomere length in mice. In addition, mRtel1 is involved in DNA double-strand break repair. The role of mRtel1 in telomere maintenance and genome stability is poorly understood. Therefore we used mRtel1-deficient mouse embryonic stem cells to examine the function of mRtel1 in replication, DNA repair, recombination, and telomere maintenance. mRtel1-deficient mouse embryonic stem cells showed sensitivity to a range of DNA-damaging agents, highlighting its role in replication and genome maintenance. Deletion of mRtel1 increased the frequency of sister chromatid exchange events and suppressed gene replacement, demonstrating the involvement of the protein in homologous recombination. mRtel1 localized transiently at telomeres and is needed for efficient telomere replication. Of interest, in the absence of mRtel1, telomeres in embryonic stem cells appeared relatively stable in length, suggesting that mRtel1 is required to allow extension by telomerase. We propose that mRtel1 is a key protein for DNA replication, recombination, and repair and efficient elongation of telomeres by telomerase.},
}
@article {pmid22592955,
year = {2012},
author = {Jenkins, EC and Ye, L and Velinov, M and Krinsky-McHale, SJ and Zigman, WB and Schupf, N and Silverman, WP},
title = {Mild cognitive impairment identified in older individuals with Down syndrome by reduced telomere signal numbers and shorter telomeres measured in microns.},
journal = {American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics},
volume = {159B},
number = {5},
pages = {598-604},
pmid = {22592955},
issn = {1552-485X},
support = {P01 HD035897/HD/NICHD NIH HHS/United States ; R01-HD37425/HD/NICHD NIH HHS/United States ; R01-AG014673/AG/NIA NIH HHS/United States ; P30-HD024061/HD/NICHD NIH HHS/United States ; P01-HD35897/HD/NICHD NIH HHS/United States ; UL1 RR024922/RR/NCRR NIH HHS/United States ; P30 HD024061/HD/NICHD NIH HHS/United States ; R01 AG014673/AG/NIA NIH HHS/United States ; R01 HD037425/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Centromere/metabolism ; Chromosomes, Human, Pair 1/genetics ; Chromosomes, Human, Pair 21/genetics ; Cognitive Dysfunction/*complications/*genetics ; Down Syndrome/*complications/*genetics ; Female ; Humans ; Interphase ; Light ; Male ; Metaphase ; Middle Aged ; Peptide Nucleic Acids/metabolism ; Telomere/*metabolism ; Telomere Shortening/*genetics ; },
abstract = {Previously, we established that short-term T lymphocyte cultures from people with Down syndrome (DS) and dementia (Alzheimer's disease) had shorter telomeres than did those from age- and sex-matched people with DS only, quantified as significantly reduced numbers of signals of peptide nucleic acid (PNA) telomere probes in whole metaphases [Jenkins et al. (2008); Neurosci Lett 440:340-343] as well as reduced telomere probe light intensity values in interphases [Jenkins et al. (2010); Neurobiol Aging 31:765-771]. We now describe shorter telomere length in adults with DS and mild cognitive impairment (MCI) compared to age- and sex-matched individuals with DS without MCI. Telomere length is quantified by reduced telomere signal numbers and shorter chromosome 1 telomeres measured in micrometers (microns). These findings were in agreement with quantitative light intensity measurements of chromosome 1 and chromosome 21 PNA telomere probes with and without the use of a "normalizing ratio" involving the fluorescence exhibited by a PNA probe for centromere 2, and with the use of light intensity measurements of interphase preparations. Most importantly, the distributions of chromosome 1 telomere lengths (in microns) were completely non-overlapping for adults with and without MCI, indicating that this measure has great promise as a biomarker for MCI as well as dementia in this population.},
}
@article {pmid22588366,
year = {2012},
author = {Sahin, E and DePinho, RA},
title = {Axis of ageing: telomeres, p53 and mitochondria.},
journal = {Nature reviews. Molecular cell biology},
volume = {13},
number = {6},
pages = {397-404},
pmid = {22588366},
issn = {1471-0080},
support = {R01 CA084628/CA/NCI NIH HHS/United States ; },
mesh = {Aging/*physiology ; Animals ; Humans ; *Metabolic Networks and Pathways ; Mitochondria/*metabolism ; Models, Biological ; Telomere/*metabolism ; Tumor Suppressor Protein p53/*metabolism ; },
abstract = {Progressive DNA damage and mitochondrial decline are both considered to be prime instigators of natural ageing. Traditionally, these two pathways have been viewed largely in isolation. However, recent studies have revealed a molecular circuit that directly links DNA damage to compromised mitochondrial biogenesis and function via p53. This axis of ageing may account for both organ decline and disease development associated with advanced age and could illuminate a path for the development of relevant therapeutics.},
}
@article {pmid22584221,
year = {2012},
author = {Zhang, B and Suer, S and Livak, F and Adediran, S and Vemula, A and Khan, MA and Ning, Y and Hussain, A},
title = {Telomere and microtubule targeting in treatment-sensitive and treatment-resistant human prostate cancer cells.},
journal = {Molecular pharmacology},
volume = {82},
number = {2},
pages = {310-321},
doi = {10.1124/mol.111.076752},
pmid = {22584221},
issn = {1521-0111},
support = {R25 GM055036/GM/NIGMS NIH HHS/United States ; R25 GM078441/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Docetaxel ; Drug Delivery Systems/*methods ; Drug Resistance, Neoplasm/drug effects/*physiology ; Humans ; Male ; Microtubules/drug effects/*metabolism ; Paclitaxel/administration &amp; dosage/metabolism ; Prostatic Neoplasms/drug therapy/*metabolism ; Taxoids/administration &amp; dosage/metabolism ; Telomere/drug effects/*metabolism ; Treatment Outcome ; },
abstract = {Modulating telomere dynamics may be a useful strategy for targeting prostate cancer cells, because they generally have short telomeres. Because a plateau has been reached in the development of taxane-based treatments for prostate cancer, this study was undertaken to evaluate the relative efficacy of targeting telomeres and microtubules in taxane-sensitive, taxane-resistant, androgen-sensitive, and androgen-insensitive prostate cancer cells. Paclitaxel- and docetaxel-resistant DU145 cells were developed and their underlying adaptive responses were evaluated. Telomere dynamics and the effects of targeting telomeres with sodium meta-arsenite (KML001) (an agent undergoing early clinical trials), including combinations with paclitaxel and docetaxel, were evaluated in parental and drug-resistant cells. The studies were extended to androgen-sensitive LNCaP cells and androgen-insensitive LNCaP/C81 cells. Both P-glycoprotein (Pgp)-dependent and non-Pgp-dependent mechanisms of resistance were recruited within the same population of DU145 cells with selection for drug resistance. Wild-type DU145 cells have a small side population (SP) (0.4-1.2%). The SP fraction increased with increasing drug resistance, which was correlated with enhanced expression of Pgp but not breast cancer resistance protein. Telomere dynamics remained unchanged in taxane-resistant cells, which retained sensitivity to KML001. Furthermore, KML001 targeted SP and non-SP fractions, inducing DNA damage signaling in both fractions. KML001 induced telomere erosion, decreased telomerase gene expression, and was highly synergistic with the taxanes in wild-type and drug-resistant DU145 cells. This synergism extended to androgen-sensitive and androgen-insensitive LNCaP cells under basal and androgen-deprived conditions. These studies demonstrate that KML001 plus docetaxel and KML001 plus paclitaxel represent highly synergistic drug combinations that should be explored further in the different disease states of prostate cancer.},
}
@article {pmid22580562,
year = {2012},
author = {Imam, T and Jitratkosol, MH and Soudeyns, H and Sattha, B and Gadawski, I and Maan, E and Forbes, JC and Alimenti, A and Lapointe, N and Lamarre, V and Money, DM and Côté, HC and , },
title = {Leukocyte telomere length in HIV-infected pregnant women treated with antiretroviral drugs during pregnancy and their uninfected infants.},
journal = {Journal of acquired immune deficiency syndromes (1999)},
volume = {60},
number = {5},
pages = {495-502},
doi = {10.1097/QAI.0b013e31825aa89c},
pmid = {22580562},
issn = {1944-7884},
support = {HET-85515//Canadian Institutes of Health Research/Canada ; YSH-80511//Canadian Institutes of Health Research/Canada ; },
mesh = {Adolescent ; Adult ; Anti-Retroviral Agents/administration &amp; dosage/*adverse effects ; Female ; HIV Infections/*drug therapy/immunology ; Humans ; Infant ; Infant, Newborn ; Leukocytes/*drug effects/physiology ; Male ; Pregnancy ; Pregnancy Complications, Infectious/*drug therapy/immunology ; Retrospective Studies ; Telomerase/antagonists &amp; inhibitors ; Telomere/*drug effects ; Young Adult ; },
abstract = {OBJECTIVES: HIV disease can lead to accelerated telomere attrition, although certain drugs used as part of antiretroviral therapy (ART) can inhibit telomerase reverse transcriptase activity. This could in turn lead to shorter telomeres. We hypothesized that HIV and ART exposure would be associated with shorter leukocyte telomere length (TL) in exposed mother/infant pairs compared with controls.<br><br>METHODS: In these retrospective and prospective observational cohort studies, TL was evaluated in peripheral blood leukocytes obtained from HIV-infected pregnant women treated with ART and their uninfected infants, and compared with HIV untreated (retrospective cohort) or HIV mothers and their infants (prospective cohort).<br><br>RESULTS: In HIV-infected ART-exposed mothers, leukocyte TL was not significantly shorter than that in HIV untreated mothers or HIV controls, nor was their infants' TL significantly different. Cord blood of ART-exposed infants exhibited TL shorter than that from infants born to HIV-negative mothers. Placenta also showed evidence of shorter TL after adjustment for relevant covariates. Factors associated with shorter maternal and infant TL included smoking and the use of drugs of addiction in pregnancy.<br><br>CONCLUSIONS: These results suggest that maternal HIV infection or exposure to ART has minimal effect on infant leukocyte TL, a reassuring finding. In contrast, tissues that express higher telomerase activity such as umbilical cord blood and placenta appear comparatively more affected by ART. Smoking and the use of drugs of addiction have a negative impact on maternal and infant leukocyte TL, possibly through oxidative telomere damage.},
}
@article {pmid22579284,
year = {2012},
author = {Vannier, JB and Pavicic-Kaltenbrunner, V and Petalcorin, MI and Ding, H and Boulton, SJ},
title = {RTEL1 dismantles T loops and counteracts telomeric G4-DNA to maintain telomere integrity.},
journal = {Cell},
volume = {149},
number = {4},
pages = {795-806},
doi = {10.1016/j.cell.2012.03.030},
pmid = {22579284},
issn = {1097-4172},
support = {11581/CRUK_/Cancer Research UK/United Kingdom ; /CAPMC/CIHR/Canada ; },
mesh = {Animals ; DNA Helicases/*metabolism ; DNA Replication ; Fibroblasts/metabolism ; *G-Quadruplexes ; Mice ; Nucleic Acid Conformation ; Recombinases/metabolism ; Telomere/*metabolism ; },
abstract = {T loops and telomeric G-quadruplex (G4) DNA structures pose a potential threat to genome stability and must be dismantled to permit efficient telomere replication. Here we implicate the helicase RTEL1 in the removal of telomeric DNA secondary structures, which is essential for preventing telomere fragility and loss. In the absence of RTEL1, T loops are inappropriately resolved by the SLX4 nuclease complex, resulting in loss of the telomere as a circle. Depleting SLX4 or blocking DNA replication abolished telomere circles (TCs) and rescued telomere loss in RTEL1(-/-) cells but failed to suppress telomere fragility. Conversely, stabilization of telomeric G4-DNA or loss of BLM dramatically enhanced telomere fragility in RTEL1-deficient cells but had no impact on TC formation or telomere loss. We propose that RTEL1 performs two distinct functions at telomeres: it disassembles T loops and also counteracts telomeric G4-DNA structures, which together ensure the dynamics and stability of the telomere.},
}
@article {pmid22577349,
year = {2012},
author = {Kuzyk, A and Mai, S},
title = {Selected telomere length changes and aberrant three-dimensional nuclear telomere organization during fast-onset mouse plasmacytomas.},
journal = {Neoplasia (New York, N.Y.)},
volume = {14},
number = {4},
pages = {344-351},
pmid = {22577349},
issn = {1476-5586},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Animals ; Cell Nucleus/*genetics/ultrastructure ; Disease Models, Animal ; Imaging, Three-Dimensional ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Inbred BALB C ; Plasmacytoma/*genetics/*ultrastructure ; Telomere/genetics/*pathology ; Telomere Homeostasis/*genetics ; Translocation, Genetic ; },
abstract = {Mouse plasmacytoma (PCT) can develop within 45 days when induced by a v-abl/myc replication-deficient retrovirus. This fast-onset PCT development is always associated with trisomy of cytoband E2 of mouse chromosome 11 (11E2). Trisomy of 11E2 was identified as the sole aberration in all fast-onset mouse PCTs in [T38HxBALB/c]N congenic mice, with a reciprocal translocation between chromosome X and 11 (rcpT(X;11)) (Genes Cancer 2010;1:847-858). Using this mouse model, we have now examined the overall and individual telomere lengths in fast-onset PCTs compared with normal B cells using two-dimensional and three-dimensional quantitative fluorescent in situ hybridization of telomeres. We found fast-onset PCTs to have a significantly different three-dimensional telomere profile, compared with primary B cells of wild-type littermates with and without rcpT(X;11) (P < .0001 and P = .006, respectively). Our data also indicate for primary PCT cells, from the above mouse strain, that the translocation chromosome carrying 11E2 is the only chromosome with telomere lengthening (P = 4 x 10(-16)). This trend is not seen for T(X;11) in primary B cells of control [T38HxBALB/c]N mice with the rcpT(X;11). This finding supports the concept of individual telomere lengthening of chromosomes that are functionally important for the tumorigenic process.},
}
@article {pmid22576367,
year = {2012},
author = {Barefield, C and Karlseder, J},
title = {The BLM helicase contributes to telomere maintenance through processing of late-replicating intermediate structures.},
journal = {Nucleic acids research},
volume = {40},
number = {15},
pages = {7358-7367},
pmid = {22576367},
issn = {1362-4962},
support = {R01 GM087476/GM/NIGMS NIH HHS/United States ; AG025837/AG/NIA NIH HHS/United States ; GM087476/GM/NIGMS NIH HHS/United States ; P30 CA014195-38/CA/NCI NIH HHS/United States ; },
mesh = {Cell Cycle ; Cell Line ; Chromosome Aberrations ; Chromosomes, Human/ultrastructure ; *DNA Replication ; Exodeoxyribonucleases/antagonists &amp; inhibitors ; Humans ; RecQ Helicases/analysis/antagonists &amp; inhibitors/*metabolism ; Telomere/*enzymology/physiology ; Telomere Homeostasis ; Telomeric Repeat Binding Protein 1/antagonists &amp; inhibitors ; Werner Syndrome Helicase ; },
abstract = {Werner's syndrome (WS) and Bloom's syndrome (BS) are cancer predisposition disorders caused by loss of function of the RecQ helicases WRN or BLM, respectively. BS and WS are characterized by replication defects, hyperrecombination events and chromosomal aberrations, which are hallmarks of cancer. Inefficient replication of the G-rich telomeric strand contributes to chromosome aberrations in WS cells, demonstrating a link between WRN, telomeres and genomic stability. Herein, we provide evidence that BLM also contributes to chromosome-end maintenance. Telomere defects (TDs) are observed in BLM-deficient cells at an elevated frequency, which is similar to cells lacking a functional WRN helicase. Loss of both helicases exacerbates TDs and chromosome aberrations, indicating that BLM and WRN function independently in telomere maintenance. BLM localization, particularly its recruitment to telomeres, changes in response to replication dysfunction, such as in WRN-deficient cells or after aphidicolin treatment. Exposure to replication challenge causes an increase in decatenated deoxyribonucleic acid (DNA) structures and late-replicating intermediates (LRIs), which are visible as BLM-covered ultra-fine bridges (UFBs) in anaphase. A subset of UFBs originates from telomeric DNA and their frequency correlates with telomere replication defects. We propose that the BLM complex contributes to telomere maintenance through its activity in resolving LRIs.},
}
@article {pmid22575867,
year = {2012},
author = {de Wilde, RF and Heaphy, CM and Maitra, A and Meeker, AK and Edil, BH and Wolfgang, CL and Ellison, TA and Schulick, RD and Molenaar, IQ and Valk, GD and Vriens, MR and Borel Rinkes, IH and Offerhaus, GJ and Hruban, RH and Matsukuma, KE},
title = {Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors.},
journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},
volume = {25},
number = {7},
pages = {1033-1039},
pmid = {22575867},
issn = {1530-0285},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing/*biosynthesis ; Adenoma/etiology/metabolism/pathology ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Neuroendocrine/etiology/*metabolism/pathology ; Co-Repressor Proteins ; DNA Helicases/*biosynthesis ; Female ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Molecular Chaperones ; Multiple Endocrine Neoplasia Type 1/complications ; Nuclear Proteins/*biosynthesis ; Pancreatic Neoplasms/etiology/*metabolism/pathology ; Phenotype ; Telomere/metabolism/*pathology ; X-linked Nuclear Protein ; Young Adult ; },
abstract = {Approximately 45% of sporadic well-differentiated pancreatic neuroendocrine tumors harbor mutations in either ATRX (alpha thalassemia/mental retardation X-linked) or DAXX (death domain-associated protein). These novel tumor suppressor genes encode nuclear proteins that interact with one another and function in chromatin remodeling at telomeric and peri-centromeric regions. Mutations in these genes are associated with loss of their protein expression and correlate with the alternative lengthening of telomeres phenotype. Patients with multiple endocrine neoplasia-1 (MEN-1) syndrome, genetically defined by a germ line mutation in the MEN1 gene, are predisposed to developing pancreatic neuroendocrine tumors and thus represent a unique model for studying the timing of ATRX and DAXX inactivation in pancreatic neuroendocrine tumor development. We characterized ATRX and DAXX protein expression by immunohistochemistry and telomere status by telomere-specific fluorescence in situ hybridization in 109 well-differentiated pancreatic neuroendocrine lesions from 28 MEN-1 syndrome patients. The study consisted of 47 neuroendocrine microadenomas (<0.5 cm), 50 pancreatic neuroendocrine tumors (≥0.5 cm), and 12 pancreatic neuroendocrine tumor lymph node metastases. Expression of ATRX and DAXX was intact in all 47 microadenomas, and none showed the alternative lengthening of telomeres phenotype. ATRX and/or DAXX expression was lost in 3 of 50 (6%) pancreatic neuroendocrine tumors. In all three of these, tumor size was ≥3 cm, and loss of ATRX and/or DAXX expression correlated with the alternative lengthening of telomeres phenotype. Concurrent lymph node metastases were present for two of the three tumors, and each metastasis displayed the same changes as the primary tumor. These findings establish the existence of ATRX and DAXX defects and the alternative lengthening of telomeres phenotype in pancreatic neuroendocrine tumors in the context of MEN-1 syndrome. The observation that ATRX and DAXX defects and the alternative lengthening of telomeres phenotype occurred only in pancreatic neuroendocrine tumors measuring ≥3 cm and their lymph node metastases suggests that these changes are late events in pancreatic neuroendocrine tumor development.},
}
@article {pmid22573130,
year = {2012},
author = {Nilsson, PM},
title = {Impact of vascular aging on cardiovascular disease: the role of telomere biology.},
journal = {Journal of hypertension},
volume = {30 Suppl},
number = {},
pages = {S9-12},
doi = {10.1097/HJH.0b013e328353e512},
pmid = {22573130},
issn = {1473-5598},
mesh = {Aging/*physiology ; Blood Vessels/*physiology/physiopathology ; Cardiovascular Diseases/genetics/*physiopathology ; Female ; Humans ; Male ; Risk Factors ; *Telomere ; },
abstract = {Cardiovascular risk increases with chronological as well as biological aging, and one marker of this might be telomere length. The telomere cap is located at the end of the DNA helix and serves to protect its end. This is an evolutionary adaptation which has resulted in stabilization of the DNA strand within the chromosome. During the life course, telomeres tend to shorten in most cells, with the exception of germ line cells and cells that do not undergo cell division, as well as cancer cells. Telomeres are typically shorter in men than in women and continue to shorten over the life-span. In certain conditions this shortening is enhanced, especially in the presence of cardiovascular risk factors. There is evidence to suggest that telomere length could be a potential marker of early vascular aging in individuals with a burden of cardiovascular risk factors that might speed up the aging process.},
}
@article {pmid22572954,
year = {2012},
author = {Chung, I and Osterwald, S and Deeg, KI and Rippe, K},
title = {PML body meets telomere: the beginning of an ALTernate ending?.},
journal = {Nucleus (Austin, Tex.)},
volume = {3},
number = {3},
pages = {263-275},
pmid = {22572954},
issn = {1949-1042},
mesh = {Cell Nucleus Division ; Humans ; Intranuclear Inclusion Bodies/metabolism ; Leukemia, Promyelocytic, Acute/*metabolism/pathology ; Small Ubiquitin-Related Modifier Proteins/metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {The unlimited proliferation potential of cancer cells requires the maintenance of their telomeres. This is frequently accomplished by reactivation of telomerase. However, in a significant fraction of tumors an alternative lengthening of telomeres (ALT) mechanism is active. The molecular mechanism of the ALT pathway remains elusive. In particular, the role of characteristic complexes of promyelocytic leukemia nuclear bodies (PML-NBs) with telomeres, the ALT-associated PML-NBs (APBs), is currently under investigation. Here, we review recent findings on the assembly, structure and functions of APBs. It is discussed how genomic aberrations in ALT-positive cancer cells could result in the formation of APBs and in ALT activity. We conclude that they are important functional intermediates in what is considered the canonical ALT pathway and discuss deregulations of cellular pathways that contribute to the emergence of the ALT phenotype.},
}
@article {pmid22570622,
year = {2012},
author = {Pampalona, J and Frías, C and Genescà, A and Tusell, L},
title = {Progressive telomere dysfunction causes cytokinesis failure and leads to the accumulation of polyploid cells.},
journal = {PLoS genetics},
volume = {8},
number = {4},
pages = {e1002679},
pmid = {22570622},
issn = {1553-7404},
mesh = {Acid Phosphatase/metabolism ; Anaphase/genetics ; Bleomycin/pharmacology ; Cell Line ; Chromatin/genetics/metabolism ; *Chromosomal Instability ; Cytokinesis/*genetics ; DNA Breaks, Double-Stranded/drug effects ; Humans ; In Situ Hybridization, Fluorescence ; Isoenzymes/metabolism ; Mammary Glands, Human/cytology/metabolism ; *Polyploidy ; Tartrate-Resistant Acid Phosphatase ; *Telomerase/genetics/metabolism ; *Telomere/genetics/pathology ; Telomere Shortening/genetics ; },
abstract = {Most cancer cells accumulate genomic abnormalities at a remarkably rapid rate, as they are unable to maintain their chromosome structure and number. Excessively short telomeres, a known source of chromosome instability, are observed in early human-cancer lesions. Besides telomere dysfunction, it has been suggested that a transient phase of polyploidization, in most cases tetraploidization, has a causative role in cancer. Proliferation of tetraploids can gradually generate subtetraploid lineages of unstable cells that might fire the carcinogenic process by promoting further aneuploidy and genomic instability. Given the significance of telomere dysfunction and tetraploidy in the early stages of carcinogenesis, we investigated whether there is a connection between these two important promoters of chromosomal instability. We report that human mammary epithelial cells exhibiting progressive telomere dysfunction, in a pRb deficient and wild-type p53 background, fail to complete the cytoplasmatic cell division due to the persistence of chromatin bridges in the midzone. Flow cytometry together with fluorescence in situ hybridization demonstrated an accumulation of binucleated polyploid cells upon serial passaging cells. Restoration of telomere function through hTERT transduction, which lessens the formation of anaphase bridges by recapping the chromosome ends, rescued the polyploid phenotype. Live-cell imaging revealed that these polyploid cells emerged after abortive cytokinesis due to the persistence of anaphase bridges with large intervening chromatin in the cleavage plane. In agreement with a primary role of anaphase bridge intermediates in the polyploidization process, treatment of HMEC-hTERT cells with bleomycin, which produces chromatin bridges through illegimitate repair, resulted in tetraploid binucleated cells. Taken together, we demonstrate that human epithelial cells exhibiting physiological telomere dysfunction engender tetraploid cells through interference of anaphase bridges with the completion of cytokinesis. These observations shed light on the mechanisms operating during the initial stages of human carcinogenesis, as they provide a link between progressive telomere dysfunction and tetraploidy.},
}
@article {pmid22570605,
year = {2012},
author = {Penfold, CA and Brown, PE and Lawrence, ND and Goldman, AS},
title = {Modeling meiotic chromosomes indicates a size dependent contribution of telomere clustering and chromosome rigidity to homologue juxtaposition.},
journal = {PLoS computational biology},
volume = {8},
number = {5},
pages = {e1002496},
pmid = {22570605},
issn = {1553-7358},
support = {BB/D01042X/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Chromosome Pairing/*genetics ; Chromosomes, Fungal/*genetics ; Humans ; Meiosis/*genetics ; Models, Chemical ; *Models, Genetic ; Models, Molecular ; Saccharomyces cerevisiae/chemistry/*genetics/ultrastructure ; Sequence Homology, Nucleic Acid ; Structure-Activity Relationship ; Telomere/chemistry/*genetics/ultrastructure ; },
abstract = {Meiosis is the cell division that halves the genetic component of diploid cells to form gametes or spores. To achieve this, meiotic cells undergo a radical spatial reorganisation of chromosomes. This reorganisation is a prerequisite for the pairing of parental homologous chromosomes and the reductional division, which halves the number of chromosomes in daughter cells. Of particular note is the change from a centromere clustered layout (Rabl configuration) to a telomere clustered conformation (bouquet stage). The contribution of the bouquet structure to homologous chromosome pairing is uncertain. We have developed a new in silico model to represent the chromosomes of Saccharomyces cerevisiae in space, based on a worm-like chain model constrained by attachment to the nuclear envelope and clustering forces. We have asked how these constraints could influence chromosome layout, with particular regard to the juxtaposition of homologous chromosomes and potential nonallelic, ectopic, interactions. The data support the view that the bouquet may be sufficient to bring short chromosomes together, but the contribution to long chromosomes is less. We also find that persistence length is critical to how much influence the bouquet structure could have, both on pairing of homologues and avoiding contacts with heterologues. This work represents an important development in computer modeling of chromosomes, and suggests new explanations for why elucidating the functional significance of the bouquet by genetics has been so difficult.},
}
@article {pmid22569128,
year = {2012},
author = {Suram, A and Kaplunov, J and Patel, PL and Ruan, H and Cerutti, A and Boccardi, V and Fumagalli, M and Di Micco, R and Mirani, N and Gurung, RL and Hande, MP and d'Adda di Fagagna, F and Herbig, U},
title = {Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions.},
journal = {The EMBO journal},
volume = {31},
number = {13},
pages = {2839-2851},
pmid = {22569128},
issn = {1460-2075},
support = {GGP08183/TI_/Telethon/Italy ; R01 CA136533/CA/NCI NIH HHS/United States ; R01CA136533/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line ; Cell Transformation, Neoplastic/drug effects/genetics ; Cellular Senescence/drug effects/genetics/*physiology ; DNA Replication/drug effects/genetics/physiology ; Humans ; Oncogenes/drug effects/genetics/*physiology ; Protein Synthesis Inhibitors/pharmacology ; Puromycin/pharmacology ; Signal Transduction/drug effects/genetics/physiology ; Telomere/drug effects/genetics/*physiology ; },
abstract = {In normal human somatic cells, telomere dysfunction causes cellular senescence, a stable proliferative arrest with tumour suppressing properties. Whether telomere dysfunction-induced senescence (TDIS) suppresses cancer growth in humans, however, is unknown. Here, we demonstrate that multiple and distinct human cancer precursor lesions, but not corresponding malignant cancers, are comprised of cells that display hallmarks of TDIS. Furthermore, we demonstrate that oncogenic signalling, frequently associated with initiating cancer growth in humans, dramatically affected telomere structure and function by causing telomeric replication stress, rapid and stochastic telomere attrition, and consequently telomere dysfunction in cells that lack hTERT activity. DNA replication stress induced by drugs also resulted in telomere dysfunction and cellular senescence in normal human cells, demonstrating that telomeric repeats indeed are hypersensitive to DNA replication stress. Our data reveal that TDIS, accelerated by oncogene-induced DNA replication stress, is a biological response of cells in human cancer precursor lesions and provide strong evidence that TDIS is a critical tumour suppressing mechanism in humans.},
}
@article {pmid22564429,
year = {2012},
author = {Paviolo, NS and Quiroga, IY and Castrogiovanni, DC and Bianchi, MS and Bolzán, AD},
title = {Telomere instability is present in the progeny of mammalian cells exposed to bleomycin.},
journal = {Mutation research},
volume = {734},
number = {1-2},
pages = {5-11},
doi = {10.1016/j.mrfmmm.2012.04.008},
pmid = {22564429},
issn = {0027-5107},
mesh = {Adipose Tissue/cytology/drug effects ; Animals ; Antibiotics, Antineoplastic/*toxicity ; Bleomycin/*toxicity ; Cell Line ; Chromosome Aberrations/*chemically induced ; Mutagens/*toxicity ; Rats ; Rats, Sprague-Dawley ; Telomere/*drug effects ; Time Factors ; },
abstract = {We analyzed the chromosomal aberrations involving telomeres in the progeny of mammalian cells exposed to the radiomimetic compound bleomycin (BLM) in order to determine if this antineoplastic drug induces long-term telomere instability. To this end, rat cells (ADIPO-P2 cell line, derived from adipose cells from Sprague-Dawley rat) were treated with a single concentration of BLM (2.5 μg/ml), and chromosomal aberrations were analyzed 18 h and 10 days after treatment by using PNA-FISH with a pan-telomeric probe [(TTAGGG)n repeats]. Cytogenetic analysis revealed a higher frequency of aberrations at 18 h and 10 days after treatment in BLM-exposed cultures vs. untreated cultures, although the yield of BLM-induced aberrations 10 days after treatment decreased about 25% compared with the one at 18 h after treatment. Moreover, the level of telomerase activity in BLM-treated cells compared with that of untreated control cells was significantly higher at 10 days after treatment, but did not differ at 18 h after treatment. These data indicate that in terms of unstable aberrations, the in vitro clastogenic effect of BLM on ADIPO-P2 cells persists for at least 10 days after exposure. In addition, our data demonstrate, for the first time, that BLM-induced telomere instability in mammalian cells (cytogenetically detectable as incomplete chromosome elements and telomere FISH signal loss and duplication) persists for several generations after exposure. Moreover, the appearance of telomere fusions in BLM-exposed cells 10 days after treatment suggests that this compound can induce delayed telomere instability. The increase in telomerase activity in BLM-exposed cells 10 days after treatment is accompanied by the presence of aberrations directly related to telomere dysfunction. This fact suggests that telomerase is not directly involved in BLM-induced telomere instability.},
}
@article {pmid22564407,
year = {2012},
author = {Tanrikulu-Kucuk, S and Ademoglu, E},
title = {Dietary restriction of amino acids other than methionine prevents oxidative damage during aging: involvement of telomerase activity and telomere length.},
journal = {Life sciences},
volume = {90},
number = {23-24},
pages = {924-928},
doi = {10.1016/j.lfs.2012.04.024},
pmid = {22564407},
issn = {1879-0631},
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Aging ; Amino Acids/*administration &amp; dosage ; Animals ; DNA Damage/drug effects ; DNA, Mitochondrial/drug effects/metabolism ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Dietary Proteins/*administration &amp; dosage ; Liver/drug effects/metabolism ; Male ; Methionine/administration &amp; dosage ; Oxidative Stress/*drug effects ; Protein Carbonylation/drug effects ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {AIMS: It has been suggested that variations in the proportions of some dietary amino acids can slow down aging. In this study, the influence of amino acids other than methionine on aging was investigated.<br><br>MAIN METHODS: Rats were fed either with normal (ND) or except methionine, protein restricted diet (PREMD) for 4 months and oxygen radical production, oxidative protein and DNA damage along with telomere length and telomerase activity were evaluated in the liver.<br><br>KEY FINDINGS: Except mitochondrial superoxide production rate, feeding with PREMD significantly decreased the oxygen radical production rate and protein carbonyl levels in the homogenate and mitochondria of 16-month-old rats. Feeding with PREMD prevented 8-OHdG formation in mitochondrial DNA but not in the genomic DNA. Although liver telomerase activities of rats receiving either ND or PREMD seemed to have some variations, these did not reach a statistical significance. Feeding with PREMD conserved the telomere length in the liver. The telomere length of 8- and 16-month-old rats fed PREMD was similar, 16-month-old rats fed ND had telomeres shortened by 36% (p<0.05).<br><br>SIGNIFICANCE: Long-term restriction of the amino acids other than methionine may decrease oxygen radical generation and oxidative damage of cellular constituents, and may also prevent telomere shortening in rat liver.},
}
@article {pmid22561920,
year = {2012},
author = {de Vos-Houben, JM and Ottenheim, NR and Kafatos, A and Buijsse, B and Hageman, GJ and Kromhout, D and Giltay, EJ},
title = {Telomere length, oxidative stress, and antioxidant status in elderly men in Zutphen and Crete.},
journal = {Mechanisms of ageing and development},
volume = {133},
number = {6},
pages = {373-377},
doi = {10.1016/j.mad.2012.04.003},
pmid = {22561920},
issn = {1872-6216},
mesh = {Aged ; Aged, 80 and over ; Greece/epidemiology ; Humans ; Leukocytes/ultrastructure ; Male ; Netherlands/epidemiology ; *Oxidative Stress ; Serum Albumin/analysis ; Telomere/*genetics ; Uric Acid/blood ; },
abstract = {The incidence of chronic diseases such as cardiovascular diseases is lower in Mediterranean Southern Europe than Northern Europe. This may be due to a lower level of oxidative stress and a higher antioxidant status in people living around the Mediterranean Sea. Oxidative stress may influence the rate of shortening of telomeres, the nucleoprotein structures at the ends of chromosomes. We compared leukocyte telomere length (LTL) in elderly men from Northern and Southern Europe and investigated the possible relationship between LTL and indicators of oxidative stress and antioxidant status. We examined 143 elderly Dutch men (mean age 83.9 years) and 109 Greek elderly men (mean age 84.6 years) and found that the Greek men had significantly longer telomeres (geometric mean 4.95 kbp, 95% confidence interval (CI): 4.71-5.23 kbp) compared to the men from the Netherlands (4.76 kbp, 95% CI: 4.55-4.98 kbp; P=0.001). Age was inversely associated with LTL (β=-0.10, P=0.31 in Cretan men and β=-0.19, P=0.02 in Dutch men). In all men LTL was not related to indicators of oxidative stress and plasma antioxidants. However, the endogenous antioxidants serum albumin (β=0.18, P=0.007) and uric acid (β=0.13, P=0.045) were positively associated with LTL. The age-adjusted difference between Crete and Zutphen was reduced by 25% after adjustment for serum albumin and uric acid. We conclude that Greek elderly men have significantly longer LTL compared to Dutch counterparts. The endogenous antioxidants albumin and uric acid were positively associated with longer telomeres.},
}
@article {pmid22561906,
year = {2012},
author = {Kim, SH and Barrack, ER and Reddy, GP},
title = {Telomerase turns telomere dysfunction from bad to worse.},
journal = {Asian journal of andrology},
volume = {14},
number = {5},
pages = {665-666},
pmid = {22561906},
issn = {1745-7262},
}
@article {pmid22561093,
year = {2012},
author = {Fan, Y and Dai, Y and Cheng, Q and Zhang, G and Zhang, D and Fang, P and Wu, H and Bai, L and Deng, Z and Qin, Z},
title = {A self-ligation method for PCR-sequencing the telomeres of Streptomyces and Mycobacterium linear replicons.},
journal = {Journal of microbiological methods},
volume = {90},
number = {2},
pages = {105-107},
doi = {10.1016/j.mimet.2012.04.012},
pmid = {22561093},
issn = {1872-8359},
mesh = {Cloning, Molecular/*methods ; Ligation/*methods ; Mycobacterium/*genetics ; Polymerase Chain Reaction/*methods ; *Replicon ; Sequence Analysis, DNA/methods ; Streptomyces/*genetics ; *Telomere ; },
abstract = {Actinomycete species from many genera often harbor linear plasmids and some contain linear chromosomes. A self-ligation and PCR-sequencing method was developed for identifying three novel telomere sequences of linear plasmids of Streptomyces and Mycobacterium. This and four previously described methods for actinomycetes telomere cloning and sequencing are discussed.},
}
@article {pmid22558207,
year = {2012},
author = {Farnung, BO and Brun, CM and Arora, R and Lorenzi, LE and Azzalin, CM},
title = {Telomerase efficiently elongates highly transcribing telomeres in human cancer cells.},
journal = {PloS one},
volume = {7},
number = {4},
pages = {e35714},
pmid = {22558207},
issn = {1932-6203},
mesh = {Cell Line, Tumor ; DNA (Cytosine-5-)-Methyltransferase 1 ; DNA (Cytosine-5-)-Methyltransferases/deficiency/genetics ; Fibroblasts/cytology/metabolism ; Humans ; Plasmids ; Primary Cell Culture ; RNA, Untranslated/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics ; *Transcription, Genetic ; Transfection ; DNA Methyltransferase 3B ; },
abstract = {RNA polymerase II transcribes the physical ends of linear eukaryotic chromosomes into a variety of long non-coding RNA molecules including telomeric repeat-containing RNA (TERRA). Since TERRA discovery, advances have been made in the characterization of TERRA biogenesis and regulation; on the contrary its associated functions remain elusive. Most of the biological roles so far proposed for TERRA are indeed based on in vitro experiments carried out using short TERRA-like RNA oligonucleotides. In particular, it has been suggested that TERRA inhibits telomerase activity. We have exploited two alternative cellular systems to test whether TERRA and/or telomere transcription influence telomerase-mediated telomere elongation in human cancer cells. In cells lacking the two DNA methyltransferases DNMT1 and DNMT3b, TERRA transcription and steady-state levels are greatly increased while telomerase is able to elongate telomeres normally. Similarly, telomerase can efficiently elongate transgenic inducible telomeres whose transcription has been experimentally augmented. Our data challenge the current hypothesis that TERRA functions as a general inhibitor of telomerase and suggest that telomere length homeostasis is maintained independently of TERRA and telomere transcription.},
}
@article {pmid22558169,
year = {2012},
author = {Lee, J and Sandford, AJ and Connett, JE and Yan, J and Mui, T and Li, Y and Daley, D and Anthonisen, NR and Brooks-Wilson, A and Man, SF and Sin, DD},
title = {The relationship between telomere length and mortality in chronic obstructive pulmonary disease (COPD).},
journal = {PloS one},
volume = {7},
number = {4},
pages = {e35567},
pmid = {22558169},
issn = {1932-6203},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Adult ; Aging/*genetics ; Case-Control Studies ; Female ; Humans ; Leukocytes, Mononuclear/metabolism ; Longitudinal Studies ; Lung Neoplasms/blood/*genetics/mortality ; Male ; Middle Aged ; Polymerase Chain Reaction ; Pulmonary Disease, Chronic Obstructive/blood/*genetics/mortality ; Respiratory Function Tests ; Risk Factors ; Smoking ; Survival Analysis ; Telomere/chemistry/*genetics ; Telomere Homeostasis/genetics ; },
abstract = {Some have suggested that chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging. Aging is characterized by shortening of telomeres. The relationship of telomere length to important clinical outcomes such as mortality, disease progression and cancer in COPD is unknown. Using quantitative polymerase chain reaction (qPCR), we measured telomere length of peripheral leukocytes in 4,271 subjects with mild to moderate COPD who participated in the Lung Health Study (LHS). The subjects were followed for approximately 7.5 years during which time their vital status, FEV(1) and smoking status were ascertained. Using multiple regression methods, we determined the relationship of telomere length to cancer and total mortality in these subjects. We also measured telomere length in healthy "mid-life" volunteers and patients with more severe COPD. The LHS subjects had significantly shorter telomeres than those of healthy "mid-life" volunteers (p<.001). Compared to individuals in the 4(th) quartile of relative telomere length (i.e. longest telomere group), the remaining participants had significantly higher risk of cancer mortality (Hazard ratio, HR, 1.48; p = 0.0324) and total mortality (HR, 1.29; p = 0.0425). Smoking status did not make a significant difference in peripheral blood cells telomere length. In conclusion, COPD patients have short leukocyte telomeres, which are in turn associated increased risk of total and cancer mortality. Accelerated aging is of particular relevance to cancer mortality in COPD.},
}
@article {pmid22556254,
year = {2012},
author = {Sfeir, A and de Lange, T},
title = {Removal of shelterin reveals the telomere end-protection problem.},
journal = {Science (New York, N.Y.)},
volume = {336},
number = {6081},
pages = {593-597},
pmid = {22556254},
issn = {1095-9203},
support = {R01 GM049046/GM/NIGMS NIH HHS/United States ; AG016642/AG/NIA NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; R01 CA076027/CA/NCI NIH HHS/United States ; GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Antigens, Nuclear/genetics/metabolism ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle ; Cell Cycle Proteins/metabolism ; Cells, Cultured ; Chromosomal Proteins, Non-Histone/metabolism ; DNA Breaks, Double-Stranded ; DNA End-Joining Repair ; DNA Ligase ATP ; DNA Ligases/metabolism ; DNA Repair ; DNA-Binding Proteins/genetics/metabolism ; Homologous Recombination ; Ku Autoantigen ; Mice ; Mice, Knockout ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases/metabolism ; Poly-ADP-Ribose Binding Proteins ; Protein Serine-Threonine Kinases/metabolism ; Signal Transduction ; Telomere/*metabolism/ultrastructure ; *Telomere Homeostasis ; Telomere-Binding Proteins/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Tumor Suppressor Proteins/metabolism ; Tumor Suppressor p53-Binding Protein 1 ; Xenopus Proteins ; },
abstract = {The telomere end-protection problem is defined by the aggregate of DNA damage signaling and repair pathways that require repression at telomeres. To define the end-protection problem, we removed the whole shelterin complex from mouse telomeres through conditional deletion of TRF1 and TRF2 in nonhomologous end-joining (NHEJ) deficient cells. The data reveal two DNA damage response pathways not previously observed upon deletion of individual shelterin proteins. The shelterin-free telomeres are processed by microhomology-mediated alternative-NHEJ when Ku70/80 is absent and are attacked by nucleolytic degradation in the absence of 53BP1. The data establish that the end-protection problem is specified by six pathways [ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3 related) signaling, classical-NHEJ, alt-NHEJ, homologous recombination, and resection] and show how shelterin acts with general DNA damage response factors to solve this problem.},
}
@article {pmid22556055,
year = {2012},
author = {Armanios, M},
title = {An emerging role for the conserved telomere component 1 (CTC1) in human genetic disease.},
journal = {Pediatric blood &amp; cancer},
volume = {59},
number = {2},
pages = {209-210},
doi = {10.1002/pbc.24200},
pmid = {22556055},
issn = {1545-5017},
mesh = {Dyskeratosis Congenita/*genetics ; Female ; Humans ; Mutation/*genetics ; Retinal Telangiectasis/*genetics ; Telomere-Binding Proteins/*genetics ; },
}
@article {pmid22555600,
year = {2012},
author = {Jacobs, JJ},
title = {Fusing telomeres with RNF8.},
journal = {Nucleus (Austin, Tex.)},
volume = {3},
number = {2},
pages = {143-149},
pmid = {22555600},
issn = {1949-1042},
mesh = {Animals ; Chromosomal Instability/genetics ; DNA Damage/genetics ; Genome/genetics ; Humans ; Telomere/*genetics ; Ubiquitin-Protein Ligases/*metabolism ; },
abstract = {DNA repair activities at DNA double-strand breaks (DSBs) are under control of regulatory ubiquitylation events governed by the RNF8 and RNF168 ubiquitin-ligases. Defects in this regulatory mechanism, as with mutation of other key DNA damage-response factors, lead to genomic instability and cancer, presumably due to impaired repair of DNA lesions. Recent work revealed that RNF8 and RNF168 also play critical roles at natural chromosome ends, when no longer adequately shielded by telomeres. In contrast to repair of DSBs being needed to maintain genome integrity, repair activities at telomeres create chromosome end-to-end fusions that threaten genome integrity. Upon cell division these telomere fusions give rise to genomic alterations and instability via chromosomal missegregration and initiation of breakage-fusion-bridge cycles. Here, I discuss the role of RNF8 at natural chromosome ends and its (potential) consequences.},
}
@article {pmid22553368,
year = {2012},
author = {Maicher, A and Kastner, L and Dees, M and Luke, B},
title = {Deregulated telomere transcription causes replication-dependent telomere shortening and promotes cellular senescence.},
journal = {Nucleic acids research},
volume = {40},
number = {14},
pages = {6649-6659},
pmid = {22553368},
issn = {1362-4962},
mesh = {*Cellular Senescence ; *DNA Replication ; Gene Deletion ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/genetics ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics ; Sirtuin 2/genetics ; Telomerase/genetics ; Telomere/*genetics ; *Telomere Shortening ; *Transcription, Genetic ; },
abstract = {Telomeres are transcribed into non-coding TElomeric Repeat containing RNAs (TERRA). We have employed a transcriptionally inducible telomere to investigate how telomere transcription affects telomere function in Saccharomyces cerevisiae. We report that telomere shortening resulting from high levels of telomere transcription stems from a DNA replication-dependent loss of telomere tracts, which can occur independent of both telomerase inhibition and homologous recombination. We show that in order for telomere loss to occur, transcription must pass through the telomere tract itself producing a TERRA molecule. We demonstrate that increased telomere transcription of a single telomere leads to a premature cellular senescence in the absence of a telomere maintenance mechanism (telomerase and homology directed repair). Similar rapid senescence and telomere shortening are also seen in sir2Δ cells with compromised telomere maintenance, where TERRA levels are increased at natural telomeres. These data suggest that telomere transcription must be tightly controlled to prevent telomere loss and early onset senescence.},
}
@article {pmid22553213,
year = {2012},
author = {Murphy, SP and Bass, HW},
title = {The maize (Zea mays) desynaptic (dy) mutation defines a pathway for meiotic chromosome segregation, linking nuclear morphology, telomere distribution and synapsis.},
journal = {Journal of cell science},
volume = {125},
number = {Pt 15},
pages = {3681-3690},
doi = {10.1242/jcs.108290},
pmid = {22553213},
issn = {1477-9137},
mesh = {Cell Nucleus/*genetics ; *Chromosome Segregation ; Genetic Linkage ; In Situ Hybridization, Fluorescence ; Meiosis/*genetics ; *Mutation ; Synapses/*genetics ; Telomere/genetics/*metabolism ; Zea mays/*genetics/ultrastructure ; },
abstract = {Meiosis involves a dramatic reorganization of the genetic material, along with changes in the architecture of the nucleoplasm and cytoplasm. In the opisthokonts, nuclear envelope and meiotic chromosome behavior are coordinated by forces generated in the cytoplasm and transferred to the nucleus by the nuclear-envelope protein linkers SUN and KASH. During meiotic prophase I, the telomere bouquet arrangement has roles in interhomolog recognition, pairing, synapsis, interlock resolution and homologous chromosome recombination. The maize desynaptic (dy) mutant is defective in homologous chromosome synapsis, recombination, telomere-nuclear envelope interactions and chromosome segregation. A detailed three-dimensional cytological analysis of dy revealed telomere misplacement during the bouquet stage, synaptic irregularities, nuclear envelope distortion and chromosome bridges at anaphase I. Using linkage and B-A translocation mapping, we placed dy on the long arm of chromosome 3, genetic bin 3.06. SSR marker analysis narrowed the mapping interval to 9 cM. Candidate genes in this region include a PM3-type SUN domain protein, ZmSUN3. No obvious genetic lesions were found in the ZmSUN3 allele of dy, but a conspicuous splice variant, ZmSUN3-sv1, was observed in mRNA from dy. The variant message is predicted to result in the synthesis of a truncated ZmSUN3 protein lacking two C-terminal transmembrane domains. Other potential candidate genes relevant to the documented phenotypes were also considered. In summary, this study reveals that dy causes disruption of a central meiotic pathway connecting nuclear envelope integrity to telomere localization and synapsis during meiotic prophase.},
}
@article {pmid22551349,
year = {2013},
author = {Immonen, I and Seitsonen, S and Saionmaa, O and Fyhrquist, F},
title = {Leucocyte telomere length in age-related macular degeneration.},
journal = {Acta ophthalmologica},
volume = {91},
number = {5},
pages = {453-456},
doi = {10.1111/j.1755-3768.2012.02427.x},
pmid = {22551349},
issn = {1755-3768},
mesh = {Aged ; Blotting, Southern ; DNA/*genetics ; Female ; Fluorescein Angiography ; Fundus Oculi ; *Genetic Predisposition to Disease ; Genotype ; Humans ; Leukocytes/*chemistry ; Macular Degeneration/blood/*genetics/pathology ; Male ; *Polymorphism, Single Nucleotide ; Retina/*pathology ; *Telomere ; },
abstract = {PURPOSE: To evaluate the association between telomere length and age-related macular degeneration (AMD).<br><br>METHODS: Circulating leucocyte telomere length and the proportion of telomeres <5 kb were analysed in blood DNA samples taken from 121 patients with exudative AMD (83%), large drusen (14%) or central geographic atrophy (3%). Controls consisted of 77 age-matched subjects without AMD. The AMD status was assessed by a masked analysis of fundus photographs or angiographs. Telomere length was measured by Southern blotting.<br><br>RESULTS: Mean (SD) telomere length was 7.76 kb (0.68) in AMD patients and 7.83 (0.69) in controls (p = 0.485). The corresponding proportions of telomeres <5 kb were 10.60 (2.76) and 10.05 (2.64) (p = 0.197). In this material, there was no correlation between telomere length and age, gender or smoking status. There were no differences between the major AMD risk single-nucleotide polymorphisms (SNPs) of the CFH, HTRA1 or C3 genes, expect for somewhat longer telomeres in controls with the C3 risk SNP. There were no differences in telomere length between patients with drusen or exudative AMD.<br><br>CONCLUSIONS: Telomere length is not associated with exudative AMD or high-risk drusen.},
}
@article {pmid22547822,
year = {2012},
author = {Cheng, C and Shtessel, L and Brady, MM and Ahmed, S},
title = {Caenorhabditis elegans POT-2 telomere protein represses a mode of alternative lengthening of telomeres with normal telomere lengths.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {109},
number = {20},
pages = {7805-7810},
pmid = {22547822},
issn = {1091-6490},
support = {R01 GM066228/GM/NIGMS NIH HHS/United States ; R56 GM066228/GM/NIGMS NIH HHS/United States ; GM066228/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Caenorhabditis elegans/genetics/metabolism/*physiology ; Caenorhabditis elegans Proteins/*metabolism ; Indoles ; Mutation/genetics ; Polymorphism, Restriction Fragment Length ; Telomerase/genetics ; Telomere Homeostasis/*physiology ; Telomere-Binding Proteins/deficiency/*metabolism ; },
abstract = {Canonical telomere repeats at chromosome termini can be maintained by a telomerase-independent pathway termed alternative lengthening of telomeres (ALT). Human cancers that survive via ALT can exhibit long and heterogeneous telomeres, although many telomerase-negative tumors possess telomeres of normal length. Here, we report that Caenorhabditis elegans telomerase mutants that survived via ALT possessed either long or normal telomere lengths. Most ALT strains displayed end-to-end chromosome fusions, suggesting that critical telomere shortening occurred before or concomitant with ALT. ALT required the 9-1-1 DNA damage response complex and its clamp loader, HPR-17. Deficiency for the POT-2 telomere binding protein promoted ALT in telomerase mutants, overcame the requirement for the 9-1-1 complex in ALT, and promoted ALT with normal telomere lengths. We propose that telomerase-deficient human tumors with normal telomere lengths could represent a mode of ALT that is facilitated by telomere capping protein dysfunction.},
}
@article {pmid22545238,
year = {2011},
author = {Shpiz, S and Kalmykova, A},
title = {Role of piRNAs in the Drosophila telomere homeostasis.},
journal = {Mobile genetic elements},
volume = {1},
number = {4},
pages = {274-278},
pmid = {22545238},
issn = {2159-2543},
abstract = {Drosophila telomeres are maintained as a result of transpositions of specialized telomeric retrotransposons. The abundance of telomeric retroelement transcripts, as well as the frequency of their transpositions onto the chromosome ends, is controlled by a PIWI-interacting RNA (piRNA) pathway. In our recent report, we demonstrate strong evidence of piRNA-mediated transcriptional silencing of telomeric repeats in the Drosophila germline. Telomerase-generated repeats serve as a platform for recruiting specialized DNA-binding proteins which are involved in chromosome end protection and in the telomere length control. No specific proteins are known to bind to heterogeneous long sequences of the Drosophila telomeric retrotransposons. The importance of the piRNA silencing mechanism in the formation of telomeric chromatin along the region of the retrotransposon array will be discussed. We propose that Drosophila telomeric retrotransposon HeT-A serves as a template for the piRNA-mediated assembly of the specific protein complex, which is functionally similar to the recruiting of the DNA-binding telomeric proteins by the telomerase-generated repeats. The role of the piRNA pathway components in the assembly of the telomere capping complex was recently unveiled. Taken together, these data elucidate the importance of the piRNA pathway in the Drosophila telomere homeostasis.},
}
@article {pmid22545052,
year = {2012},
author = {Siddiqa, A and Cavazos, D and Chavez, J and Long, L and Marciniak, RA},
title = {Modulation of telomeres in alternative lengthening of telomeres type I like human cells by the expression of werner protein and telomerase.},
journal = {Journal of oncology},
volume = {2012},
number = {},
pages = {806382},
pmid = {22545052},
issn = {1687-8469},
abstract = {The alternative lengthening of telomeres (ALT) is a recombination-based mechanism of telomere maintenance activated in 5-20% of human cancers. In Saccharomyces cerevisiae, survivors that arise after inactivation of telomerase can be classified as type I or type II ALT. In type I, telomeres have a tandem array structure, with each subunit consisting of a subtelomeric Y' element and short telomere sequence. Telomeres in type II have only long telomere repeats and require Sgs1, the S. cerevisiae RecQ family helicase. We previously described the first human ALT cell line, AG11395, that has a telomere structure similar to type I ALT yeast cells. This cell line lacks the activity of the Werner syndrome protein, a human RecQ helicase. The telomeres in this cell line consist of tandem repeats containing SV40 DNA, including the origin of replication, and telomere sequence. We investigated the role of the SV40 origin of replication and the effects of Werner protein and telomerase on telomere structure and maintenance in AG11395 cells. We report that the expression of Werner protein facilitates the transition in human cells of ALT type I like telomeres to type II like telomeres in some aspects. These findings have implications for the diagnosis and treatment of cancer.},
}
@article {pmid22544908,
year = {2012},
author = {Hsu, M and Yu, EY and Sprušanský, O and McEachern, MJ and Lue, NF},
title = {Functional analysis of the single Est1/Ebs1 homologue in Kluyveromyces lactis reveals roles in both telomere maintenance and rapamycin resistance.},
journal = {Eukaryotic cell},
volume = {11},
number = {7},
pages = {932-942},
pmid = {22544908},
issn = {1535-9786},
support = {R01 GM062631/GM/NIGMS NIH HHS/United States ; NIH GM-062631/GM/NIGMS NIH HHS/United States ; R01 GM061645/GM/NIGMS NIH HHS/United States ; NIH GM 61645/GM/NIGMS NIH HHS/United States ; GM062631-08S1/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Antifungal Agents/*pharmacology ; Base Sequence ; *Drug Resistance, Fungal ; Fungal Proteins/genetics/*metabolism ; Kluyveromyces/classification/drug effects/*enzymology/genetics ; Molecular Sequence Data ; Phylogeny ; RNA/genetics/metabolism ; Sirolimus/*pharmacology ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Est1 and Ebs1 in Saccharomyces cerevisiae are paralogous proteins that arose through whole-genome duplication and that serve distinct functions in telomere maintenance and translational regulation. Here we present our functional analysis of the sole Est1/Ebs1 homologue in the related budding yeast Kluyveromyces lactis (named KlEst1). We show that similar to other Est1s, KlEst1 is required for normal telomere maintenance in vivo and full telomerase primer extension activity in vitro. KlEst1 also associates with telomerase RNA (Ter1) and an active telomerase complex in cell extracts. Both the telomere maintenance and the Ter1 association functions of KlEst1 require its N-terminal domain but not its C terminus. Analysis of clusters of point mutations revealed residues in both the N-terminal TPR subdomain and the downstream helical subdomain (DSH) that are important for telomere maintenance and Ter1 association. A UV cross-linking assay was used to establish a direct physical interaction between KlEst1 and a putative stem-loop in Ter1, which also requires both the TPR and DSH subdomains. Moreover, similar to S. cerevisiae Ebs1 (ScEbs1) (but not ScEst1), KlEst1 confers rapamycin sensitivity and may be involved in nonsense-mediated decay. Interestingly, unlike telomere regulation, this apparently separate function of KlEst1 requires its C-terminal domain. Our findings provide insights on the mechanisms and evolution of Est1/Ebs1 homologues in budding yeast and present an attractive model system for analyzing members of this multifunctional protein family.},
}
@article {pmid22544226,
year = {2012},
author = {Polanská, E and Dobšáková, Z and Dvořáčková, M and Fajkus, J and Štros, M},
title = {HMGB1 gene knockout in mouse embryonic fibroblasts results in reduced telomerase activity and telomere dysfunction.},
journal = {Chromosoma},
volume = {121},
number = {4},
pages = {419-431},
pmid = {22544226},
issn = {1432-0886},
mesh = {Animals ; Cell Line ; Chromosome Aberrations ; DNA Damage ; DNA Fragmentation ; DNA Replication ; Down-Regulation ; Fibroblasts/*cytology/metabolism ; *Gene Knockout Techniques ; HMGB1 Protein/*genetics/metabolism ; HMGB2 Protein/genetics/metabolism ; Histones/genetics/metabolism ; In Situ Hybridization, Fluorescence ; Mice ; Microscopy, Fluorescence ; RNA/*genetics/metabolism ; Telomerase/*genetics/metabolism ; Telomere/metabolism/pathology ; },
abstract = {Telomere repeats are added onto chromosome ends by telomerase, consisting of two main core components: a catalytic protein subunit (telomerase reverse trancriptase, TERT), and an RNA subunit (telomerase RNA, TR). Here, we report for the first time evidence that HMGB1 (a chromatin-associated protein in mammals, acting as a DNA chaperone in transcription, replication, recombination, and repair) can modulate cellular activity of mammalian telomerase. Knockout of the HMGB1 gene (HMGB1 KO) in mouse embryonic fibroblasts (MEFs) results in chromosomal abnormalities, enhanced colocalization of γ-H2AX foci at telomeres, and a moderate shortening of telomere lengths. HMGB1 KO MEFs also exhibit significantly (>5-fold) lower telomerase activity than the wild-type MEFs. Correspondingly, enhanced telomerase activity is observed upon overexpression of HMGB1 in MEFs. HMGB1 physically interacts with both TERT and TR, as well as with active telomerase complex in vitro. However, direct interaction of HMGB1 with telomerase is most likely not accountable for the observed higher telomerase activity in HMGB1-containing cells, as revealed from the inability of purified HMGB1 protein to stimulate telomerase activity in vitro. While no transcriptional silencing of TERT is observed in HMGB1 KO MEFs, levels of TR are diminished (~3-fold), providing possible explanation for the observed lower telomerase activity in HMGB1 KO cells. Interestingly, knockout of the HMGB2 gene elevates telomerase activity (~3-fold) in MEFs, suggesting that the two closely related proteins of the HMGB family, HMGB1 and HMGB2, have opposite effects on telomerase activity in the cell. The ability of HMGB1 to modulate cellular activity of telomerase and to maintain telomere integrity can help to understand some aspects of the protein involvement in chromosome stability and cancer.},
}
@article {pmid22539756,
year = {2012},
author = {Moslehi, J and DePinho, RA and Sahin, E},
title = {Telomeres and mitochondria in the aging heart.},
journal = {Circulation research},
volume = {110},
number = {9},
pages = {1226-1237},
pmid = {22539756},
issn = {1524-4571},
support = {R01 CA084628/CA/NCI NIH HHS/United States ; R01CA84628/CA/NCI NIH HHS/United States ; U01 CA141508/CA/NCI NIH HHS/United States ; K08 HL097031/HL/NHLBI NIH HHS/United States ; K08HL097031/HL/NHLBI NIH HHS/United States ; 1U01CA141508-01/CA/NCI NIH HHS/United States ; },
mesh = {Age Factors ; Aging/*genetics/pathology ; Animals ; Cardiovascular Diseases/*genetics/metabolism/pathology ; Carrier Proteins/metabolism ; Energy Metabolism ; Heat-Shock Proteins/metabolism ; Humans ; Mitochondria, Heart/*metabolism/pathology ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; RNA-Binding Proteins ; Signal Transduction ; Telomerase/metabolism ; Telomere/*metabolism/ultrastructure ; *Telomere Shortening ; Transcription Factors/metabolism ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Studies in humans and in mice have highlighted the importance of short telomeres and impaired mitochondrial function in driving age-related functional decline in the heart. Although telomere and mitochondrial dysfunction have been viewed mainly in isolation, recent studies in telomerase-deficient mice have provided evidence for an intimate link between these two processes. Telomere dysfunction induces a profound p53-dependent repression of the master regulators of mitochondrial biogenesis and function, peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and PGC-1β in the heart, which leads to bioenergetic compromise due to impaired oxidative phosphorylation and ATP generation. This telomere-p53-PGC mitochondrial/metabolic axis integrates many factors linked to heart aging including increased DNA damage, p53 activation, mitochondrial, and metabolic dysfunction and provides a molecular basis of how dysfunctional telomeres can compromise cardiomyocytes and stem cell compartments in the heart to precipitate cardiac aging.},
}
@article {pmid22539657,
year = {2012},
author = {Wu, Y and Liu, Y and Ni, N and Bao, B and Zhang, C and Lu, L},
title = {High lead exposure is associated with telomere length shortening in Chinese battery manufacturing plant workers.},
journal = {Occupational and environmental medicine},
volume = {69},
number = {8},
pages = {557-563},
doi = {10.1136/oemed-2011-100478},
pmid = {22539657},
issn = {1470-7926},
mesh = {Body Burden ; China ; Hazardous Substances/*adverse effects/blood/urine ; Humans ; Industry ; Lead/*adverse effects/blood/urine ; Lead Poisoning/blood/*genetics/urine ; Leukocytes/ultrastructure ; Models, Biological ; Multivariate Analysis ; Occupational Diseases/blood/*genetics/urine ; Occupational Exposure/*adverse effects/analysis ; Occupations ; *Telomere ; *Telomere Shortening ; Time Factors ; },
abstract = {OBJECTIVES: Critically shortening of telomere length caused by various factors including environmental pollutants results in genome instability and age-associated diseases. Lead is one of the ubiquitous environmental and occupational pollutants, potentially affecting public health even at a low level. However, it is still unclear whether lead exposure affects telomere length. This study aims to investigate the association between lead exposure and peripheral white blood cell telomere length (PWBTL) in Chinese battery manufacturing plant workers.<br><br>METHODS: Lead levels in blood (BLL) and urine (ULL) were evaluated using flame atomic absorption spectrometry and lead mobilisation test for body lead burden (BLB) assessment, respectively. Quantitative PCR was employed to determine relative PWBTL. Univariate and multivariate analyses were performed to examine the associations of telomere length and other variables.<br><br>RESULTS: PWBTL averaged 1.76 (telomere/single-copy gene of albumin, T/S) in 144 battery plant workers. Significantly shorter PWBTL was observed in the workers with abnormal BLL and/or ULL than those with normal ones (1.66&#xb1;0.63 vs 1.91&#xb1;0.46, p=0.010). In all workers, PWBTL was in negative correlations with BLL, ULL, time working at the plant (working length) and body mass index. A strong inverse correlation was observed between PWBTL and BLB (r=-0.70, p<0.0001) in those with abnormal BLL and ULL. GLMSELECT model showed in the subgroup of inpatient workers, working length and BLB were significantly in inverse associations with PWBTL, while BLL was in weak positive association with PWBTL.<br><br>CONCLUSIONS: These findings suggest that PWBTL shortening is associated with long-term lead exposure and that PWBTL may be one of the targets damaged by lead toxicity.},
}
@article {pmid22539583,
year = {2012},
author = {Cantara, S and Pisu, M and Frau, DV and Caria, P and Dettori, T and Capezzone, M and Capuano, S and Vanni, R and Pacini, F},
title = {Telomere abnormalities and chromosome fragility in patients affected by familial papillary thyroid cancer.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {97},
number = {7},
pages = {E1327-31},
doi = {10.1210/jc.2011-2096},
pmid = {22539583},
issn = {1945-7197},
mesh = {Adult ; Aged ; Carcinoma ; Carcinoma, Papillary ; Case-Control Studies ; Cells, Cultured ; Chromosome Breakage ; Chromosome Fragility/*genetics ; Cytogenetic Analysis ; Family ; Female ; Gene Dosage ; Gene Frequency ; Genetic Predisposition to Disease ; Humans ; Male ; Metaphase/genetics ; Middle Aged ; Telomerase/genetics ; Telomere/*metabolism/pathology ; Thyroid Cancer, Papillary ; Thyroid Neoplasms/*genetics/metabolism ; },
abstract = {INTRODUCTION: Genomic instability has been proposed to play a role in cancer development and can occur through different mechanisms including telomere association and telomere loss. Studies carried out in our unit have demonstrated that familial papillary thyroid cancer (fPTC) patients display an imbalance, at the germinal level, in telomere-telomerase complex.<br><br>AIM: We aimed to verify whether familial fPTC patients show an increased spontaneous chromosome fragility.<br><br>METHODS: To this purpose, we compared telomeric fusions and associations as well as other chromosomal fragility features by conventional and molecular cytogenetic analyses, in phytohemagglutinin stimulated T-lymphocytes from fPTC patients, unaffected family members, sporadic papillary thyroid cancer patients, and healthy subjects.<br><br>RESULTS: We demonstrate that fPTC patients have a significant increase in spontaneous telomeric associations and telomeric fusions compared with healthy subjects and sporadic cases in the frame of an otherwise common spontaneous chromosome fragility pattern. A quantitative fluorescence in situ hybridization analysis demonstrates that familial cases display a significant decrease in the telomeric peptide nucleic acid-fluorescence in situ hybridization signal intensity in the metaphase chromosome. Moreover, three copies of the hTERT gene were found only in familial cases, although the result was not statistically significant.<br><br>CONCLUSIONS: These results contribute in defining familial thyroid cancer as a clinical entity characterized by an altered telomere stability, which may be associated with the predisposition to develop the familial form of thyroid cancer.},
}
@article {pmid22539396,
year = {2012},
author = {Melin, BS and Nordfjäll, K and Andersson, U and Roos, G},
title = {hTERT cancer risk genotypes are associated with telomere length.},
journal = {Genetic epidemiology},
volume = {36},
number = {4},
pages = {368-372},
doi = {10.1002/gepi.21630},
pmid = {22539396},
issn = {1098-2272},
mesh = {Adult ; Aged ; Cohort Studies ; Female ; *Genetic Predisposition to Disease ; Genetic Variation ; *Genotype ; Humans ; Male ; Middle Aged ; Models, Statistical ; Neoplasms/*genetics ; Polymorphism, Genetic ; Polymorphism, Single Nucleotide ; Regression Analysis ; Risk ; Telomerase/*genetics/metabolism ; Telomere/*ultrastructure ; },
abstract = {Telomere biology is associated with cancer initiation and prognosis. Collected data suggest that blood cell telomere length (TL) can change over time, which may be related to development of common disorders, such as cardiovascular diseases and cancer. Recently, single nucleotide polymorphisms in the region of the human telomerase reverse transcriptase (hTERT) gene were associated with various malignancies, including glioma, lung and urinary bladder cancer, and telomerase RNA gene hTERC genotypes were recently linked to TL. In the present study a hypothetical association between identified genotypes in hTERT and hTERC genes and TL were investigated. We analyzed 21 polymorphisms, covering 90% of the genetic variance, in the hTERT gene, two genetic variants in hTERC, and relative TL(RTL) at average age 50 and 60 in 959 individuals with repeated blood samples. Mean RTL at age 60 was associated with four genetic variants of the hTERT gene (rs2736100, rs2853672, rs2853677, and rs2853676), two of which reported to be associated with cancer risk. Two alleles (rs12696304, rs16847897) near the hTERC gene were confirmed as also being associated with RTL at age 60. Our data suggest that hTERT and hTERC genotypes have an impact on TL of potential relevance and detectable first at higher ages, which gives us further insight to the complex regulation of TL.},
}
@article {pmid22533425,
year = {2012},
author = {Balistreri, CR and Pisano, C and Merlo, D and Fattouch, K and Caruso, M and Incalcaterra, E and Colonna-Romano, G and Candore, G},
title = {Is the mean blood leukocyte telomere length a predictor for sporadic thoracic aortic aneurysm? Data from a preliminary study.},
journal = {Rejuvenation research},
volume = {15},
number = {2},
pages = {170-173},
doi = {10.1089/rej.2011.1273},
pmid = {22533425},
issn = {1557-8577},
mesh = {Aged ; Aging ; Aortic Aneurysm, Thoracic/blood/*physiopathology ; Case-Control Studies ; Cellular Senescence/genetics ; DNA/genetics ; DNA Damage ; Female ; Humans ; Leukocytes/*cytology ; Male ; Middle Aged ; Recombination, Genetic ; Telomere/*ultrastructure ; Vascular Diseases/metabolism ; },
abstract = {Telomeres have been postulated as a universal clock that shortens in parallel with cellular aging. They are specialized DNA-protein structures at the ends of chromosome with remarkable functions--preventing their recognition as double-stranded DNA breaks, protecting their recombination and degradation, and avoiding a DNA damage cellular response. Telomere shortening is currently considered the best aging marker, but is also a predictor for age-related diseases, including cardiovascular diseases. Biological age clearly seems to be a better predictor of vascular risk rather than chronological age. This concept is supported by key assumptions that peripheral blood leukocyte telomere content accurately reflects that of the vascular wall and its decrease is associated with premature vascular disease. Thus, we are analyzing whether the mean of blood leukocyte telomere length might also be a predictor for sporadic thoracic aortic aneurysm (S-TAA). The preliminary results seem to be promising. Shorter telomeres were detected in patients than in controls. Thus, mean of blood leukocyte telomere length could contribute to identify individuals at S-TAA risk.},
}
@article {pmid22531781,
year = {2012},
author = {Gu, P and Min, JN and Wang, Y and Huang, C and Peng, T and Chai, W and Chang, S},
title = {CTC1 deletion results in defective telomere replication, leading to catastrophic telomere loss and stem cell exhaustion.},
journal = {The EMBO journal},
volume = {31},
number = {10},
pages = {2309-2321},
pmid = {22531781},
issn = {1460-2075},
support = {R15 CA132090/CA/NCI NIH HHS/United States ; R15GM099008/GM/NIGMS NIH HHS/United States ; R15 GM099008/GM/NIGMS NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; R15CA132090/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; *DNA Replication ; *Gene Deletion ; Mice ; Mice, Knockout ; Stem Cells/*physiology ; Telomere/*metabolism ; Telomere-Binding Proteins/*genetics/*metabolism ; },
abstract = {The proper maintenance of telomeres is essential for genome stability. Mammalian telomere maintenance is governed by a number of telomere binding proteins, including the newly identified CTC1-STN1-TEN1 (CST) complex. However, the in vivo functions of mammalian CST remain unclear. To address this question, we conditionally deleted CTC1 from mice. We report here that CTC1 null mice experience rapid onset of global cellular proliferative defects and die prematurely from complete bone marrow failure due to the activation of an ATR-dependent G2/M checkpoint. Acute deletion of CTC1 does not result in telomere deprotection, suggesting that mammalian CST is not involved in capping telomeres. Rather, CTC1 facilitates telomere replication by promoting efficient restart of stalled replication forks. CTC1 deletion results in increased loss of leading C-strand telomeres, catastrophic telomere loss and accumulation of excessive ss telomere DNA. Our data demonstrate an essential role for CTC1 in promoting efficient replication and length maintenance of telomeres.},
}
@article {pmid22530730,
year = {2012},
author = {Biotti, D and Aho, S and Béjot, Y and Giroud, M and Caillier, M and Ragot, S and Osseby, GV and Moreau, T and Teyssier, JR},
title = {Leukocyte telomere length: a focus on cerebrovascular events.},
journal = {Rejuvenation research},
volume = {15},
number = {3},
pages = {274-280},
doi = {10.1089/rej.2011.1243},
pmid = {22530730},
issn = {1557-8577},
mesh = {Aged ; Cerebrovascular Disorders/blood/epidemiology/*metabolism/*pathology ; Demography ; Female ; Homocysteine/blood ; Humans ; Leukocytes/*metabolism ; Male ; *Telomere Homeostasis ; Triglycerides/blood ; },
abstract = {Telomeres are specialized DNA structures located at the ends of chromosomes. Their length is reduced at each cell cycle, especially when the cumulative burden of oxidative stress is high. The purpose of this study was to determine the associations between telomere length and clinical and biological risk factors in ischemic stroke patients. A total of 215 stroke patients hospitalized in the Dijon, France, stroke unit were prospectively and continuously included from January to September, 2004. The telomere length measured from peripheral blood leukocytes--leukocyte telomere length (LTL)--was determined by real-time quantitative polymerase chain reaction. The results were compared with clinical and biological variables of interest collected at admission to find significant associations. Possible relationships between LTL and stroke subtypes were evaluated. A multiple regression that included all the variables significantly associated (p<0.20) with LTL in univariate analysis and age and subtypes of stroke confirmed a significant association with age (p<0.001), homocysteinemia (p=0,049), and levels of both antiphospholipid antibodies (p=0.019) and triglycerides (p=0.007). Linearity was verified and confirmed for each variable. The subtype of stroke did not significantly affect telomere length. We were able to highlight significant associations between LTL and certain cerebrovascular risk factors in a general population of stroke patients. These associations did not depend on the ischemic stroke subtype.},
}
@article {pmid22527105,
year = {2012},
author = {Shen, J and Gammon, MD and Terry, MB and Bradshaw, PT and Wang, Q and Teitelbaum, SL and Neugut, AI and Santella, RM},
title = {Genetic polymorphisms in telomere pathway genes, telomere length, and breast cancer survival.},
journal = {Breast cancer research and treatment},
volume = {134},
number = {1},
pages = {393-400},
pmid = {22527105},
issn = {1573-7217},
support = {P30 ES010126/ES/NIEHS NIH HHS/United States ; U01 CA066572/CA/NCI NIH HHS/United States ; P30ES009089/ES/NIEHS NIH HHS/United States ; U01CA/ES66572/CA/NCI NIH HHS/United States ; R03CA125768/CA/NCI NIH HHS/United States ; P30ES10126/ES/NIEHS NIH HHS/United States ; R03 CA125768/CA/NCI NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; },
mesh = {Breast Neoplasms/*genetics/mortality/pathology ; Cell Cycle Proteins ; Female ; Genetic Association Studies ; Humans ; Kaplan-Meier Estimate ; Neoplasm Invasiveness ; *Polymorphism, Single Nucleotide ; Proportional Hazards Models ; Sequence Analysis, DNA ; Shelterin Complex ; Telomerase/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; Telomeric Repeat Binding Protein 2/genetics ; Tumor Suppressor Proteins/genetics ; },
abstract = {The impact of genetic variants in telomere pathway genes on telomere length and breast cancer survival remains unclear. We hypothesized that telomere length and genetic variants of telomere pathway genes are associated with survival among breast cancer patients. A population-based cohort study of 1,026 women diagnosed with a first primary breast cancer was conducted to examine telomere length and 52 genetic variants of 9 telomere pathway genes. Adjusted Cox regression analysis was employed to examine associations between telomere length, genetic variants and all-cause and breast cancer-specific mortality. Longer telomere length was significantly correlated with all-cause mortality in the subgroup with HER-2/neu negative tumors (HR=1.90, 95% CI: 1.12-3.22). Carrying the PINX1-33 (rs2277130) G-allele was significantly associated with increased all-cause mortality (HR=1.45, 95% CI: 1.06-1.98). Three SNPs (TERF2-03 rs35439397, TERT-14 rs2853677, and TERT-67 rs2853669) were significantly associated with reduced all-cause mortality. A similar reduced trend for breast cancer-specific mortality was observed for carrying the TERT-14 (rs2853677) T-allele (HR=0.57, 95% CI: 0.39-0.84), while carrying the POT1-18 (rs1034794) T-allele significantly increased breast cancer-specific mortality (HR=1.48, 95% CI: 1.00-2.19). However, none of the associations remained significant after correction for multiple tests. A significant dose-response effect was observed with increased number of unfavorable alleles/genotypes (PINX1-33 G-allele, POT1-18 T-allele, TERF2-03 GG, TERT-14 CC, and TERT-67 TT genotypes) and decreased survival. These data suggest that unfavorable genetic variants in telomere pathway genes may help to predict breast cancer survival.},
}
@article {pmid22525489,
year = {2013},
author = {Shalev, I and Moffitt, TE and Sugden, K and Williams, B and Houts, RM and Danese, A and Mill, J and Arseneault, L and Caspi, A},
title = {Exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: a longitudinal study.},
journal = {Molecular psychiatry},
volume = {18},
number = {5},
pages = {576-581},
pmid = {22525489},
issn = {1476-5578},
support = {R24 HD065563/HD/NICHD NIH HHS/United States ; MH077874/MH/NIMH NIH HHS/United States ; R01 HD077482/HD/NICHD NIH HHS/United States ; R01 MH077874/MH/NIMH NIH HHS/United States ; G9806489/MRC_/Medical Research Council/United Kingdom ; HD061298/HD/NICHD NIH HHS/United States ; G1002190/MRC_/Medical Research Council/United Kingdom ; R01 HD061298/HD/NICHD NIH HHS/United States ; R01 AG032282/AG/NIA NIH HHS/United States ; P2C HD065563/HD/NICHD NIH HHS/United States ; AG032282/AG/NIA NIH HHS/United States ; },
mesh = {Age Factors ; Body Mass Index ; Child ; Child, Preschool ; Crime Victims/*psychology ; Female ; Humans ; Longitudinal Studies ; Male ; Parent-Child Relations ; Social Class ; Telomere/*genetics/*pathology ; *Telomere Homeostasis ; Twin Studies as Topic ; United Kingdom ; Violence/*psychology ; },
abstract = {There is increasing interest in discovering mechanisms that mediate the effects of childhood stress on late-life disease morbidity and mortality. Previous studies have suggested one potential mechanism linking stress to cellular aging, disease and mortality in humans: telomere erosion. We examined telomere erosion in relation to children's exposure to violence, a salient early-life stressor, which has known long-term consequences for well-being and is a major public-health and social-welfare problem. In the first prospective-longitudinal study with repeated telomere measurements in children while they experienced stress, we tested the hypothesis that childhood violence exposure would accelerate telomere erosion from age 5 to age 10 years. Violence was assessed as exposure to maternal domestic violence, frequent bullying victimization and physical maltreatment by an adult. Participants were 236 children (49% females; 42% with one or more violence exposures) recruited from the Environmental-Risk Longitudinal Twin Study, a nationally representative 1994-1995 birth cohort. Each child's mean relative telomere length was measured simultaneously in baseline and follow-up DNA samples, using the quantitative PCR method for T/S ratio (the ratio of telomere repeat copy numbers to single-copy gene numbers). Compared with their counterparts, the children who experienced two or more kinds of violence exposure showed significantly more telomere erosion between age-5 baseline and age-10 follow-up measurements, even after adjusting for sex, socioeconomic status and body mass index (B=-0.052, s.e.=0.021, P=0.015). This finding provides support for a mechanism linking cumulative childhood stress to telomere maintenance, observed already at a young age, with potential impact for life-long health.},
}
@article {pmid22524803,
year = {2012},
author = {Feng, TB and Cai, LM and Qian, KQ and Qi, CJ},
title = {Reduced telomere length in colorectal carcinomas.},
journal = {Asian Pacific journal of cancer prevention : APJCP},
volume = {13},
number = {2},
pages = {443-446},
doi = {10.7314/apjcp.2012.13.2.443},
pmid = {22524803},
issn = {2476-762X},
mesh = {Colorectal Neoplasms/*genetics/mortality/*pathology ; Cyclooxygenase 2/*genetics ; Disease Progression ; Female ; Humans ; Male ; Neoplasm Grading ; Neoplasm Metastasis ; Neoplasm Staging ; Prognosis ; Survival Rate ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Shortening/*genetics ; Tumor Suppressor Protein p53/*genetics ; },
abstract = {PURPOSE: Telomeres play a key role in the maintenance of chromosome integrity and stability, and telomere shortening is involved in initiation and progression of malignancies. The aim of this study was to determine whether telomere length is associated with the colorectal carcinoma.<br><br>PATIENTS AND METHODS: A total of 148 colorectal cancer (CRC) samples and corresponding adjacent non-cancerous tissues were evaluated for telomere length, P53 mutation, and cyclooxygenase-2 (COX-2) mutation detected by fluorescent immunohistochemistry. Telomere length was estimated by real-time PCR. Samples with a T/S>1.0 have an average telomere length greater than that of the standard DNA; samples with a T/S<1.0 have an average telomere length shorter than that of the standard DNA.<br><br>RESULTS: Telomeres were shorter in CRCs than in adjacent tissues, regardless of tumor stage and grade, site, or genetic alterations (P=0.004). Telomere length in CRCs also had differences with COX-2 status (P=0.004), but did not differ with P53 status (P=0.101), tumor progression (P=0.244), gender (P=0.542), and metastasis (0.488). There was no clear trend between T/S optimal cut-off values (<1 or > 1) and colorectal tumor progression, metastasis, gender, P53 and COX-2 status.<br><br>CONCLUSION: These findings suggesting that telomere shortening is associated with colorectal carcinogenesis but does not differ with tumor progression, gender, and metastasis.},
}
@article {pmid22507770,
year = {2012},
author = {Young, NS},
title = {Bone marrow failure and the new telomere diseases: practice and research.},
journal = {Hematology (Amsterdam, Netherlands)},
volume = {17 Suppl 1},
number = {},
pages = {S18-21},
doi = {10.1179/102453312X13336169155132},
pmid = {22507770},
issn = {1607-8454},
mesh = {Adult ; Anemia, Aplastic/genetics/pathology ; Bone Marrow/metabolism/pathology ; Bone Marrow Diseases/genetics/*pathology ; Chromosomal Instability ; Dyskeratosis Congenita/genetics/pathology ; Humans ; Mutation ; Neoplasms/genetics/pathology ; Telomerase/genetics/metabolism ; Telomere/*genetics/*pathology ; },
abstract = {The telomeropathies are a newly described group of human diseases based on the genetics and molecular biology of the telomeres, the ends of chromosomes. Telomeres are repeated hexanucleotides and their associated proteins; the protect chromosomes from recognition as damaged DNA, and their inevitable gradual loss with DNA replication is harmless as they are noncoding. However, when telomeres become critically short in a cell, senescence, apoptosis, or, rarely malignant transformation results. In individuals with mutations in genes involved in telomere repair, especially the enzymatic telomerase complex, telomere attrition is accelerated. Severe deficiencies result in dyskeratosis congenita, a congenital aplastic anemia with associated mucocutaneous abnormalities. Mutations in TERT, the catalytic component, and TERC, the RNA template, can behave as risk factors for the development of bone marrow failure, pulmonary fibrosis, and hepatic cirrhosis. Both penetrance and organ specificity are variable and not well understood. Chromosome instability is a result of critical shortening of telomeres and cancer. For example, short telomeres are the major prognostic risk factor for clonal evolution to myelodysplasia and acute leukemia. Practically, hematologists need to recognize the multisystem presentation of telomere disease, implications for outcomes, and options for therapy.},
}
@article {pmid22517724,
year = {2012},
author = {Pettigrew, KA and Armstrong, RN and Colyer, HA and Zhang, SD and Rea, IM and Jones, RE and Baird, DM and Mills, KI},
title = {Differential TERT promoter methylation and response to 5-aza-2'-deoxycytidine in acute myeloid leukemia cell lines: TERT expression, telomerase activity, telomere length, and cell death.},
journal = {Genes, chromosomes &amp; cancer},
volume = {51},
number = {8},
pages = {768-780},
doi = {10.1002/gcc.21962},
pmid = {22517724},
issn = {1098-2264},
support = {//Biotechnology and Biological Sciences Research Council/United Kingdom ; //Cancer Research UK/United Kingdom ; },
mesh = {Aged, 80 and over ; Antimetabolites, Antineoplastic/pharmacology ; Azacitidine/*analogs &amp; derivatives/pharmacology ; Cell Death/drug effects/genetics ; Cell Line, Tumor ; CpG Islands ; *DNA Methylation ; Decitabine ; Female ; Gene Expression Regulation, Neoplastic ; HL-60 Cells ; Humans ; Leukemia, Myeloid, Acute/*drug therapy/*genetics/metabolism/pathology ; Male ; Promoter Regions, Genetic ; Telomerase/biosynthesis/genetics/*metabolism ; Telomere/*genetics ; U937 Cells ; },
abstract = {The catalytic subunit of human telomerase (TERT) is highly expressed in cancer cells, and correlates with complex cytogenetics and disease severity in acute myeloid leukemia (AML). The TERT promoter is situated within a large CpG island, suggesting that expression is methylation-sensitive. Studies suggest a correlation between hypermethylation and TERT overexpression. We investigated the relationship between TERT promoter methylation and expression and telomerase activity in human leukemia and lymphoma cell lines. DAC-induced demethylation and cell death were observed in all three cell lines, as well as telomere shortening in HL-60 cells. DAC treatment reduced TERT expression and telomerase activity in OCI/AML3 and HL-60 cells, but not in U937 cells. Control U937 cells expressed lower levels of TERT mRNA, carried a highly methylated TERT core promoter, and proved more resistant to DAC-induced repression of TERT expression and cell death. AML patients had significantly lower methylation levels at several CpGs than "well elderly" individuals. This study, the first to investigate the relationship between TERT methylation and telomerase activity in leukemia cells, demonstrated a differential methylation pattern and response to DAC in three AML cell lines. We suggest that, although DAC treatment reduces TERT expression and telomerase activity, this is unlikely to occur via direct demethylation of the TERT promoter. However, further investigations on the regions spanning CpGs 7-12 and 14-16 may reveal valuable information regarding transcriptional regulation of TERT.},
}
@article {pmid22516689,
year = {2012},
author = {Venturini, L and Daidone, MG and Motta, R and Cimino-Reale, G and Hoare, SF and Gronchi, A and Folini, M and Keith, WN and Zaffaroni, N},
title = {Telomere maintenance mechanisms in malignant peripheral nerve sheath tumors: expression and prognostic relevance.},
journal = {Neuro-oncology},
volume = {14},
number = {6},
pages = {736-744},
pmid = {22516689},
issn = {1523-5866},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; DNA Copy Number Variations/genetics ; Fluorescent Antibody Technique, Indirect ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Nerve Sheath Neoplasms/*genetics/mortality/pathology ; Neurofibromatosis 1/*genetics/mortality/pathology ; Prognosis ; Survival Rate ; Telomerase/*genetics/metabolism ; *Telomere Homeostasis ; Young Adult ; },
abstract = {This study investigated the prevalence and the prognostic relevance of the 2 known telomere maintenance mechanisms (TMMs), telomerase activity (TA) and alternative lengthening of telomeres (ALT), in malignant peripheral nerve sheath tumors (MPNST). In 57 specimens from 49 patients with MPNST (35 sporadic, 14 neurofibromatosis type 1-related), TA was determined using the telomeric repeat amplification protocol, and ALT was detected by assaying ALT-associated promyelocytic leukemia bodies (APB) and terminal restriction fragment (TRF) length distribution. TA or ALT (defined on the basis of APB) alone was found in 24.6% or 26.3% of the lesions, respectively, whereas 6 cases (10.5%) were TA+/ALT+. A concordance between APB and TRF results in defining the ALT status was observed in 44 of 57 cases (77.2%; P < .0001). TA was more frequently expressed in samples from patients with neurofibromatosis type 1 than in those with sporadic disease (60% vs 29.4%, P = 0.087). In the overall series, TA proved to be prognostic for 5-year disease-specific death (hazard ratio, 3.78; 95% confidence interval [CI], 1.60-8.95; P = .002), even when adjusted for the presence of neurofibromatosis type 1 (hazard ratio, 4.22; 95% CI, 1.804-9.874; P = .001) and margin status after surgery (hazard ratio, 5.78; 95% CI, 2.19-15.26; P < .001). Conversely, ALT did not significantly affect clinical outcome of MPNST using either APB expression (hazard ratio, 1.25; 95% CI 0.54-2.89; P = 0.605) or TRF distribution (hazard ratio, 0.57; 95% CI, 0.17-1.96; P = .375) as the detection approach. Our results indicate for the first time that both TMMs, TA and ALT, are present in MPNST and differentially affect patient prognosis.},
}
@article {pmid22514726,
year = {2012},
author = {Cafueri, G and Parodi, F and Pistorio, A and Bertolotto, M and Ventura, F and Gambini, C and Bianco, P and Dallegri, F and Pistoia, V and Pezzolo, A and Palombo, D},
title = {Endothelial and smooth muscle cells from abdominal aortic aneurysm have increased oxidative stress and telomere attrition.},
journal = {PloS one},
volume = {7},
number = {4},
pages = {e35312},
pmid = {22514726},
issn = {1932-6203},
mesh = {Aortic Aneurysm, Abdominal/*genetics/*metabolism ; Case-Control Studies ; DNA Damage/genetics ; Endothelial Cells/*metabolism ; Fluorescent Antibody Technique ; Humans ; In Situ Hybridization, Fluorescence ; In Vitro Techniques ; Lymphocytes/metabolism ; Muscle, Smooth, Vascular/cytology ; Myocytes, Smooth Muscle/*metabolism ; Oxidative Stress/*physiology ; Telomere/genetics/*metabolism ; },
abstract = {BACKGROUND: Abdominal aortic aneurysm (AAA) is a complex multi-factorial disease with life-threatening complications. AAA is typically asymptomatic and its rupture is associated with high mortality rate. Both environmental and genetic risk factors are involved in AAA pathogenesis. Aim of this study was to investigate telomere length (TL) and oxidative DNA damage in paired blood lymphocytes, aortic endothelial cells (EC), vascular smooth muscle cells (VSMC), and epidermal cells from patients with AAA in comparison with matched controls.<br><br>METHODS: TL was assessed using a modification of quantitative (Q)-FISH in combination with immunofluorescence for CD31 or &#x3b1;-smooth muscle actin to detect EC and VSMC, respectively. Oxidative DNA damage was investigated by immunofluorescence staining for 7, 8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG).<br><br>RESULTS AND CONCLUSIONS: Telomeres were found to be significantly shortened in EC, VSMC, keratinocytes and blood lymphocytes from AAA patients compared to matched controls. 8-oxo-dG immunoreactivity, indicative of oxidative DNA damage, was detected at higher levels in all of the above cell types from AAA patients compared to matched controls. Increased DNA double strand breaks were detected in AAA patients vs controls by nuclear staining for &#x3b3;-H2AX histone. There was statistically significant inverse correlation between TL and accumulation of oxidative DNA damage in blood lymphocytes from AAA patients. This study shows for the first time that EC and VSMC from AAA have shortened telomeres and oxidative DNA damage. Similar findings were obtained with circulating lymphocytes and keratinocytes, indicating the systemic nature of the disease. Potential translational implications of these findings are discussed.},
}
@article {pmid22508511,
year = {2012},
author = {Martínez, P and Flores, JM and Blasco, MA},
title = {53BP1 deficiency combined with telomere dysfunction activates ATR-dependent DNA damage response.},
journal = {The Journal of cell biology},
volume = {197},
number = {2},
pages = {283-300},
pmid = {22508511},
issn = {1540-8140},
support = {232854/ERC_/European Research Council/International ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/*metabolism ; Checkpoint Kinase 1 ; Chromosomal Proteins, Non-Histone/deficiency/genetics/*metabolism ; DNA Breaks, Double-Stranded ; DNA Damage ; *DNA End-Joining Repair ; DNA-Binding Proteins/deficiency/genetics/*metabolism ; Homologous Recombination ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Phosphorylation ; Protein Kinases/metabolism ; Protein Serine-Threonine Kinases/*metabolism ; Telomere/*metabolism/pathology ; Telomeric Repeat Binding Protein 1/deficiency/genetics/metabolism ; Telomeric Repeat Binding Protein 2 ; Tumor Suppressor Proteins/*metabolism ; Tumor Suppressor p53-Binding Protein 1 ; },
abstract = {TRF1 protects mammalian telomeres from fusion and fragility. Depletion of TRF1 leads to telomere fusions as well as accumulation of γ-H2AX foci and activation of both the ataxia telangiectasia mutated (ATM)- and the ataxia telangiectasia and Rad3 related (ATR)-mediated deoxyribonucleic acid (DNA) damage response (DDR) pathways. 53BP1, which is also present at dysfunctional telomeres, is a target of ATM that accumulates at DNA double-strand breaks and favors nonhomologous end-joining (NHEJ) repair over ATM-dependent resection and homology-directed repair (homologous recombination [HR]). To address the role of 53BP1 at dysfunctional telomeres, we generated mice lacking TRF1 and 53BP1. 53BP1 deficiency significantly rescued telomere fusions in mouse embryonic fibroblasts (MEFs) lacking TRF1, but they showed evidence of a switch from the NHEJ- to HR-mediated repair of uncapped telomeres. Concomitantly, double-mutant MEFs showed evidence of hyperactivation of the ATR-dependent DDR. In intact mice, combined 53BP1/TRF1 deficiency in stratified epithelia resulted in earlier onset of DNA damage and increased CHK1 phosphorylation during embryonic development, leading to aggravation of skin phenotypes.},
}
@article {pmid22508510,
year = {2012},
author = {Drosopoulos, WC and Kosiyatrakul, ST and Yan, Z and Calderano, SG and Schildkraut, CL},
title = {Human telomeres replicate using chromosome-specific, rather than universal, replication programs.},
journal = {The Journal of cell biology},
volume = {197},
number = {2},
pages = {253-266},
pmid = {22508510},
issn = {1540-8140},
support = {R01 GM045751/GM/NIGMS NIH HHS/United States ; 5R01-GM045751/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Chromosomes, Human/metabolism ; DNA/metabolism ; DNA Replication/*physiology ; Embryonic Stem Cells/*metabolism ; HeLa Cells ; Heterochromatin ; Humans ; Telomere/*metabolism ; },
abstract = {Telomeric and adjacent subtelomeric heterochromatin pose significant challenges to the DNA replication machinery. Little is known about how replication progresses through these regions in human cells. Using single molecule analysis of replicated DNA (SMARD), we delineate the replication programs-i.e., origin distribution, termination site location, and fork rate and direction-of specific telomeres/subtelomeres of individual human chromosomes in two embryonic stem (ES) cell lines and two primary somatic cell types. We observe that replication can initiate within human telomere repeats but was most frequently accomplished by replisomes originating in the subtelomere. No major delay or pausing in fork progression was detected that might lead to telomere/subtelomere fragility. In addition, telomeres from different chromosomes from the same cell type displayed chromosome-specific replication programs rather than a universal program. Importantly, although there was some variation in the replication program of the same telomere in different cell types, the basic features of the program of a specific chromosome end appear to be conserved.},
}
@article {pmid22506016,
year = {2012},
author = {Wikgren, M and Karlsson, T and Lind, J and Nilbrink, T and Hultdin, J and Sleegers, K and Van Broeckhoven, C and Roos, G and Nilsson, LG and Nyberg, L and Adolfsson, R and Norrback, KF},
title = {Longer leukocyte telomere length is associated with smaller hippocampal volume among non-demented APOE ε3/ε3 subjects.},
journal = {PloS one},
volume = {7},
number = {4},
pages = {e34292},
pmid = {22506016},
issn = {1932-6203},
mesh = {Age Factors ; Aged ; Alleles ; Apolipoprotein E3/*genetics ; Apolipoprotein E4/genetics ; Atrophy/genetics/pathology ; Biomarkers/metabolism ; Cell Proliferation ; Cognition ; Female ; Hippocampus/pathology/*physiology ; Humans ; Leukocytes/*physiology/ultrastructure ; Male ; Memory, Episodic ; Middle Aged ; Neurogenesis/genetics ; Telomere/*genetics ; },
abstract = {Telomere length shortens with cellular division, and leukocyte telomere length is used as a marker for systemic telomere length. The hippocampus hosts adult neurogenesis and is an important structure for episodic memory, and carriers of the apolipoprotein E ε4 allele exhibit higher hippocampal atrophy rates and differing telomere dynamics compared with non-carriers. The authors investigated whether leukocyte telomere length was associated with hippocampal volume in 57 cognitively intact subjects (29 ε3/ε3 carriers; 28 ε4 carriers) aged 49-79 yr. Leukocyte telomere length correlated inversely with left (r(s) = -0.465; p = 0.011), right (r(s) = -0.414; p = 0.025), and total hippocampus volume (r(s) = -0.519; p = 0.004) among APOE ε3/ε3 carriers, but not among ε4 carriers. However, the ε4 carriers fit with the general correlation pattern exhibited by the ε3/ε3 carriers, as ε4 carriers on average had longer telomeres and smaller hippocampi compared with ε3/ε3 carriers. The relationship observed can be interpreted as long telomeres representing a history of relatively low cellular proliferation, reflected in smaller hippocampal volumes. The results support the potential of leukocyte telomere length being used as a biomarker for tapping functional and structural processes of the aging brain.},
}
@article {pmid22504828,
year = {2012},
author = {Verma, S and Tachtatzis, P and Penrhyn-Lowe, S and Scarpini, C and Jurk, D and Von Zglinicki, T and Coleman, N and Alexander, GJ},
title = {Sustained telomere length in hepatocytes and cholangiocytes with increasing age in normal liver.},
journal = {Hepatology (Baltimore, Md.)},
volume = {56},
number = {4},
pages = {1510-1520},
doi = {10.1002/hep.25787},
pmid = {22504828},
issn = {1527-3350},
support = {G0900686/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adolescent ; Adult ; Aged ; Aging/*genetics ; Bile Ducts/*cytology/physiology ; Cells, Cultured ; Cellular Senescence/*genetics ; Child, Preschool ; Female ; Hepatocytes/metabolism/*physiology ; Humans ; In Situ Hybridization, Fluorescence ; Kupffer Cells/cytology/physiology ; Liver/*pathology ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction/methods ; Reference Values ; Reproducibility of Results ; Risk Assessment ; Sampling Studies ; Sensitivity and Specificity ; Telomere/*genetics/physiology ; Telomere Shortening/genetics ; Young Adult ; },
abstract = {UNLABELLED: Telomeres, a validated biomarker of aging, comprise multiple nucleotide repeats capping chromosomes that shorten with each cell cycle until a critical length is achieved, precipitating cell senescence. Only two previous studies focused on the effect of aging in "normal" liver tissue, but these studies were compromised by small sample size, limited age range, tissue derived from individuals with an increased risk of senescence, and the use of liver homogenates. We developed a robust large-volume, four-color quantitative fluorescent in situ hybridization technique to measure telomere length in large numbers of hepatocytes, Kupffer cells, hepatic stellate cells, CD4-positive and CD8-positive lymphocytes, and cholangiocytes. Following validation against the gold standard (Southern blotting), the technique was applied to normal archived paraffin-embedded liver tissue obtained following reperfusion of implanted donor liver. We studied 73 highly selected donors aged 5-79 years with a short medical illness preceding death and no history of liver disease, reperfusion injury, or steatosis and normal graft function 1-year posttransplantation. Cholangiocytes had significantly longer telomeres compared with all other intrahepatic lineages over a wide age range (P < 0.05). Age-related telomere attrition was restricted to sinusoidal cells (i.e., Kupffer cells [P = 0.0054] and stellate cells [P = 0.0001]). Cholangiocytes and hepatocytes showed no age-related telomere shortening.<br><br>CONCLUSION: In normal liver and over a broad age range, cholangiocytes have longer telomeres than all other intrahepatic lineages. Age-related telomere length decline is restricted to Kupffer cells and stellate cells.},
}
@article {pmid22503908,
year = {2012},
author = {Dlouha, D and Pitha, J and Lanska, V and Hubacek, JA},
title = {Association between FTO 1st intron tagging variant and telomere length in middle aged females. 3PMFs study.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {413},
number = {15-16},
pages = {1222-1225},
doi = {10.1016/j.cca.2012.03.025},
pmid = {22503908},
issn = {1873-3492},
mesh = {Alpha-Ketoglutarate-Dependent Dioxygenase FTO ; Body Mass Index ; Female ; Gene Frequency ; Humans ; Introns ; Menopause/genetics ; Middle Aged ; Polymorphism, Single Nucleotide ; Proteins/*genetics ; Subcutaneous Fat ; *Telomere ; },
abstract = {The FTO gene plays an important role in the determination of body weight and BMI and it has been suspected of being associated with all-cause mortality, cardiovascular disease, cancer and end stage renal disease, but the causal mechanism of these effects is still unknown. One of the possibilities is the potential association with telomere length. Telomeres are repetitive DNA-sequences located at the ends of eukaryotic chromosomes' length of which is reduced in all somatic cells during ageing. Out of the 908 females (3PMFs study), in 783 females both FTO 1st intron tagging polymorphism (G>T, rs17817449) and the relative telomere length were successfully analysed. The relative telomere length was calculated as the ratio of telomere repeats to single-copy gene copies. The frequencies of the FTO genotypes were similar to other populations (GG=18.3%, GT=49.1% and TT=32.6%). We have detected, that the relative telomere length was significantly shorter (P<0.02, P<0.01 after adjustment for age, BMI, waist and subcutaneous fat), in carriers of at least one FTO risky (G) allele (0.85±0.39) in comparison to the carriers of the protective TT genotype (0.93±0.48). We have demonstrated that the FTO variant could be associated with the relative telomere length. Whether this represents a causality of association between the FTO variant and the non-communicable diseases needs to be further analysed.},
}
@article {pmid22500192,
year = {2012},
author = {Calado, R and Young, N},
title = {Telomeres in disease.},
journal = {F1000 medicine reports},
volume = {4},
number = {},
pages = {8},
pmid = {22500192},
issn = {1757-5931},
abstract = {Telomeres and telomere repair are basic molecular features of cells possessing linear DNA chromosomes and defects in them result in various diseases. This review examines recent advances in understanding these diseases, particularly at a molecular level, and in relating telomere dysfunction to clinical diseases. We also discuss the potential role of telomere elongation as a therapy in diseases, and more controversially, the prevention/reversal of aging.},
}
@article {pmid22493726,
year = {2012},
author = {Hovatta, I and de Mello, VD and Kananen, L and Lindström, J and Eriksson, JG and Ilanne-Parikka, P and Keinänen-Kiukaanniemi, S and Peltonen, M and Tuomilehto, J and Uusitupa, M},
title = {Leukocyte telomere length in the Finnish Diabetes Prevention Study.},
journal = {PloS one},
volume = {7},
number = {4},
pages = {e34948},
pmid = {22493726},
issn = {1932-6203},
mesh = {Aged ; Aging/*blood/genetics ; Diabetes Mellitus, Type 2/*blood/complications/epidemiology/prevention &amp; control ; Diet, Fat-Restricted ; *Exercise ; Female ; Finland ; Glucose Intolerance ; Humans ; Insulin/blood ; Insulin Resistance ; Leukocytes/cytology/*metabolism ; Life Style ; Longitudinal Studies ; Male ; Middle Aged ; Obesity/*blood/complications/epidemiology/prevention &amp; control ; Telomere/*genetics ; Telomere Homeostasis/genetics ; Telomere Shortening/genetics ; },
abstract = {Leukocyte telomere length (TL) is considered a biomarker for biological aging. Shortened TL has been observed in many complex diseases, including type 2 diabetes (T2DM). Lifestyle intervention studies, e.g. the Diabetes Prevention Study (DPS), have shown a decrease in the incidence of T2DM by promoting healthy lifestyles in individuals with impaired glucose tolerance (IGT). Our aim was to study in the DPS the influence of the lifestyle intervention on TL. TL was measured by quantitative PCR-based method at two time points (N = 334 and 343) on average 4.5 years apart during the active intervention and post-intervention follow-up. TL inversely correlated with age. Our main finding was that TL increased in about two thirds of the individuals both in the intervention and in the control groups during follow-up; TL increased most in individuals with the shortest TL at the first measurement. TL was not associated with development of T2DM, nor did lifestyle intervention have an effect on TL. No association between insulin secretion or insulin resistance indices and TL was observed. We did not detect an association between TL and development of T2DM in the DPS participants. It could be due to all participants being overweight and having IGT at baseline, both of which have been found to be independently associated with shorter leukocyte TL in some earlier studies. TL had no substantial role in worsening of glucose tolerance in people with IGT. Our study confirms that leukocyte TL can increase with time even in obese people with impaired glucose metabolism.},
}
@article {pmid22493152,
year = {2012},
author = {Martinez-Delgado, B and Yanowsky, K and Inglada-Perez, L and de la Hoya, M and Caldes, T and Vega, A and Blanco, A and Martin, T and Gonzalez-Sarmiento, R and Blasco, M and Robledo, M and Urioste, M and Song, H and Pharoah, P and Benitez, J},
title = {Shorter telomere length is associated with increased ovarian cancer risk in both familial and sporadic cases.},
journal = {Journal of medical genetics},
volume = {49},
number = {5},
pages = {341-344},
doi = {10.1136/jmedgenet-2012-100807},
pmid = {22493152},
issn = {1468-6244},
support = {10124/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Adult ; Case-Control Studies ; DNA/analysis/blood ; Female ; Genetic Predisposition to Disease/epidemiology/*genetics ; Humans ; Leukocytes, Mononuclear ; Logistic Models ; Middle Aged ; Ovarian Neoplasms/epidemiology/*genetics ; Real-Time Polymerase Chain Reaction ; Risk Factors ; Spain/epidemiology ; Telomere/*genetics ; Telomere Shortening/genetics ; },
abstract = {BACKGROUND: Alterations in telomere maintenance mechanisms leading to short telomeres underlie different genetic disorders of ageing and cancer predisposition syndromes. It is known that short telomeres and subsequent genomic instability contribute to malignant transformation, and it is therefore likely that people with shorter telomeres are at higher risk for different types of cancer. Recently, the authors demonstrated that the genes BRCA1 and BRCA2 are modifiers of telomere length (TL) in familial breast cancer. The present study analysed TL in peripheral blood leucocytes of hereditary and sporadic ovarian cancer cases, as well as in female controls, to evaluate whether TL contributes to ovarian cancer risk.<br><br>METHODS: TL was measured by quantitative PCR in 178 sporadic and 168 hereditary ovarian cases (46 BRCA1, 12 BRCA2, and 110 BRCAX) and compared to TL in 267 controls.<br><br>RESULTS: Both sporadic and hereditary cases showed significantly shorter age adjusted TLs than controls. Unconditional logistic regression analysis revealed an association between TL and ovarian cancer risk with a significant interaction with age (p<0.001). Risk was higher in younger women and progressively decreased with age, with the highest OR observed in women under 30 years of age (OR 1.56, 95% CI 1.34 to 1.81; p=1.0&#xd7;10(-18)).<br><br>CONCLUSION: These findings indicate that TL could be a risk factor for early onset ovarian cancer.},
}
@article {pmid22493064,
year = {2012},
author = {Antão, JM and Mason, JM and Déjardin, J and Kingston, RE},
title = {Protein landscape at Drosophila melanogaster telomere-associated sequence repeats.},
journal = {Molecular and cellular biology},
volume = {32},
number = {12},
pages = {2170-2182},
pmid = {22493064},
issn = {1098-5549},
support = {R01 GM043901/GM/NIGMS NIH HHS/United States ; R37 GM048405/GM/NIGMS NIH HHS/United States ; GM43901/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromatin/chemistry/*genetics ; Chromatin Immunoprecipitation ; Drosophila Proteins/*analysis/genetics ; Drosophila melanogaster/*genetics ; Humans ; Proteomics/*methods ; Repetitive Sequences, Amino Acid ; Sequence Analysis ; Telomere/chemistry/*genetics ; },
abstract = {The specific set of proteins bound at each genomic locus contributes decisively to regulatory processes and to the identity of a cell. Understanding of the function of a particular locus requires the knowledge of what factors interact with that locus and how the protein composition changes in different cell types or during the response to internal and external signals. Proteomic analysis of isolated chromatin segments (PICh) was developed as a tool to target, purify, and identify proteins associated with a defined locus and was shown to allow the purification of human telomeric chromatin. Here we have developed this method to identify proteins that interact with the Drosophila telomere-associated sequence (TAS) repeats. Several of the purified factors were validated as novel TAS-bound proteins by chromatin immunoprecipitation, and the Brahma complex was confirmed as a dominant modifier of telomeric position effect through the use of a genetic test. These results offer information on the efficacy of applying the PICh protocol to loci with sequence more complex than that found at human telomeres and identify proteins that bind to the TAS repeats, which might contribute to TAS biology and chromatin silencing.},
}
@article {pmid22490525,
year = {2012},
author = {Arasaradnam, R and Nwokolo, CU},
title = {Epiphenomenon of telomere lengths: lessons from ulcerative colitis.},
journal = {Gut},
volume = {61},
number = {10},
pages = {1516},
doi = {10.1136/gutjnl-2012-302102},
pmid = {22490525},
issn = {1468-3288},
mesh = {Colorectal Neoplasms/*genetics ; Female ; *Genetic Predisposition to Disease ; Humans ; Male ; *Polymorphism, Single Nucleotide ; RNA/*genetics ; Telomerase/*genetics ; Telomere/*chemistry ; },
}
@article {pmid22489017,
year = {2012},
author = {Jenkins, EC and Tassone, F and Ye, L and Hoogeveen, AT and Brown, WT and Hagerman, RJ and Hagerman, PJ},
title = {Reduced telomere length in individuals with FMR1 premutations and full mutations.},
journal = {American journal of medical genetics. Part A},
volume = {158A},
number = {5},
pages = {1060-1065},
pmid = {22489017},
issn = {1552-4833},
support = {P30 HD002274/HD/NICHD NIH HHS/United States ; R01 NS044299/NS/NINDS NIH HHS/United States ; HD036071/HD/NICHD NIH HHS/United States ; R01 HD036071/HD/NICHD NIH HHS/United States ; HD02274/HD/NICHD NIH HHS/United States ; UL1 RR024922/RR/NCRR NIH HHS/United States ; RL1 AG032119/AG/NIA NIH HHS/United States ; NS044299/NS/NINDS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Case-Control Studies ; Child, Preschool ; Fragile X Mental Retardation Protein/*genetics ; Humans ; Light ; Male ; Middle Aged ; Molecular Probe Techniques ; *Mutation ; Repetitive Sequences, Nucleic Acid ; T-Lymphocytes/ultrastructure ; Telomere/*pathology ; Young Adult ; },
abstract = {We reported previously that 10 older men (66.4 ± 4.6 years) with premutation alleles (55-200 CGG repeats) of the FMR1 gene, with or without FXTAS, had decreased telomere length when compared to sex- and age-matched controls. Extending our use of light intensity measurements from a telomere probe hybridized to interphase preparations, we have now found shortened telomeres in 9 younger male premutation carriers (31.7 ± 17.6 years). We have also shown decreased telomere length in T lymphocytes from 6 male individuals (12.0 ± 1.8 years) with full mutation FMR1 alleles (>200 CGG repeats). These findings support our hypothesis that reduced telomere length is a component of the sub-cellular pathology of FMR1-associated disorders. The experimental approach involved pair-wise comparisons of light intensity values of 20 cells from an individual with either premutation or full mutation CGG-repeat expansions relative to an equivalent number of cells from a sex- and age-matched control. In addition, we demonstrated reduced telomere size in T-lymphocyte cultures from eight individuals with the FMR1 premutation using six different measures. Four relied on detection of light intensity differences, and two involved measuring the whole chromosome, including the telomere, in microns. This new approach confirmed our findings with light intensity measurements and demonstrated the feasibility of direct linear measurements for detecting reductions in telomere size. We have thus confirmed our hypothesis that reduced telomere length is associated with both premutation and full mutation-FMR1 alleles and have demonstrated that direct measurements of telomere length can reliably detect such reductions.},
}
@article {pmid22476886,
year = {2012},
author = {Ziegler, P and Schrezenmeier, H and Akkad, J and Brassat, U and Vankann, L and Panse, J and Wilop, S and Balabanov, S and Schwarz, K and Martens, UM and Brümmendorf, TH},
title = {Telomere elongation and clinical response to androgen treatment in a patient with aplastic anemia and a heterozygous hTERT gene mutation.},
journal = {Annals of hematology},
volume = {91},
number = {7},
pages = {1115-1120},
doi = {10.1007/s00277-012-1454-x},
pmid = {22476886},
issn = {1432-0584},
mesh = {Androgens/*therapeutic use ; Anemia, Aplastic/diagnosis/*drug therapy/genetics/metabolism ; Heterozygote ; Humans ; Male ; Middle Aged ; Mutation ; Telomerase/*genetics ; Telomere/*metabolism ; Treatment Outcome ; },
abstract = {Telomere length (TL) both reflects and limits the replicative life span of normal somatic cells. As a consequence, critically shortened telomeres are associated with a variety of disease states. Telomere attrition can be counteracted by a nucleoprotein complex containing telomerase. Mutations in subunits of telomerase, telomerase-binding proteins as well as in members of the shelterin complex have been described both in inherited and acquired bone marrow failure syndromes. Here, we report on a patient with acquired aplastic anemia and a nonsynonymous variation of codon 1062 of the hTERT gene (p.Ala1062Thr) whose substantial and maintained hematologic response to long-term androgen treatment (including complete transfusion independence) was paralleled by a significant and continued increase in TL in multilineage peripheral blood cells. To our knowledge, this represents the first case of sustained telomere elongation in hematopoietic stem cells induced by a pharmacological approach in vivo (141 words).},
}
@article {pmid22474429,
year = {2012},
author = {Harte, AL and da Silva, NF and Miller, MA and Cappuccio, FP and Kelly, A and O'Hare, JP and Barnett, AH and Al-Daghri, NM and Al-Attas, O and Alokail, M and Sabico, S and Tripathi, G and Bellary, S and Kumar, S and McTernan, PG},
title = {Telomere length attrition, a marker of biological senescence, is inversely correlated with triglycerides and cholesterol in South Asian males with type 2 diabetes mellitus.},
journal = {Experimental diabetes research},
volume = {2012},
number = {},
pages = {895185},
pmid = {22474429},
issn = {1687-5303},
mesh = {Aging/blood/ethnology/*genetics ; Asian People/*genetics ; Blood Glucose/genetics ; Cholesterol/*blood ; Cohort Studies ; Diabetes Mellitus, Type 2/blood/ethnology/*genetics ; Genetic Predisposition to Disease ; Humans ; Insulin/blood ; Insulin Resistance/genetics ; Male ; Middle Aged ; Telomere Shortening ; Triglycerides/*blood ; },
abstract = {South Asians have a higher risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) than white Caucasians, for a given BMI. Premature biological ageing, assessed by reduction in telomere length (TL), may be mediated by factors resulting from altered metabolic profiles associated with obesity. We hypothesise that ethnicity and metabolic status represent detrimental factors contributing to premature biological ageing. Therefore we assessed TL in two South Asian, age and BMI-matched cohorts [T2DM (n = 142) versus non-T2DM (n = 76)] to determine the effects of BMI, gender, lipid and CVD profile on biological ageing. Genomic DNA was obtained from the UKADS cohort; biochemical and anthropometric data was collected and TL was measured by quantitative real-time PCR. Our findings indicated a gender-specific effect with reduced TL in T2DM men compared with non-T2DM men (P = 0.006). Additionally, in T2DM men, TL was inversely correlated with triglycerides and total cholesterol (r = -0.419, P < 0.01; r = -0.443, P < 0.01). In summary, TL was reduced amongst South Asian T2DM men and correlated with triglycerides and total cholesterol. This study highlights enhanced biological ageing among South Asian, T2DM men, which appears to be tracked by changes in lipids and BMI, suggesting that raised lipids and BMI may directly contribute to premature ageing.},
}
@article {pmid22471856,
year = {2012},
author = {Wan, S and Hann, HW and Myers, RE and Fu, X and Hann, RS and Kim, SH and Tang, H and Xing, J and Yang, H},
title = {Telomere length in circulating serum DNA as a novel non-invasive biomarker for cirrhosis: a nested case-control analysis.},
journal = {Liver international : official journal of the International Association for the Study of the Liver},
volume = {32},
number = {8},
pages = {1233-1241},
doi = {10.1111/j.1478-3231.2012.02801.x},
pmid = {22471856},
issn = {1478-3231},
support = {R03 CA153099/CA/NCI NIH HHS/United States ; R21 CA159047/CA/NCI NIH HHS/United States ; CA159074/CA/NCI NIH HHS/United States ; CA153099/CA/NCI NIH HHS/United States ; },
mesh = {Carcinoma, Hepatocellular/epidemiology/*genetics ; Case-Control Studies ; DNA/blood ; Female ; Genetic Markers ; Humans ; Liver Cirrhosis/epidemiology/*genetics ; Liver Neoplasms/*genetics/metabolism ; Male ; Middle Aged ; Precancerous Conditions/epidemiology/*genetics ; Predictive Value of Tests ; ROC Curve ; Retrospective Studies ; Risk Factors ; Telomere/*genetics ; },
abstract = {BACKGROUND &amp; AIMS: Previous studies have indicated that telomere length is associated with altered risk of various tumours including hepatitis B virus (HBV)-related hepatocellular carcinoma. However, the association between telomere length and the risk of cirrhosis has not been reported.<br><br>METHODS: In this nested case-control study, we used real-time quantitative PCR to determine the relative telomere length (RTL) in serum DNA samples from 100 HBV-related cirrhosis cases and 100 frequency-matched HBV controls, and evaluated the associations between RTL and cirrhosis risk by logistic regression analyses.<br><br>RESULTS: We found that cirrhotic cases had a significantly longer RTL (median, 0.36; range, 0.08-1.87) than non-cirrhotic controls (median, 0.20; range, 0.05-1.11) (P&#xa0;<&#xa0;0.0001). Compared with subjects with short RTL, those with long RTL had a significantly increased cirrhosis risk [odds ratio, 2.76, 95% confidence interval, 1.50-5.10; P&#xa0;=&#xa0;0.001]. Quartile analysis further indicated a dose-response effect for this association. Compared with patients with the lowest quartile of RTL, the cirrhosis risk for those with the second, third and highest quartile of RTL was 2.68 (0.91-7.87, P&#xa0;=&#xa0;0.073), 3.37 (1.32-10.54, P&#xa0;=&#xa0;0.013) and 6.64 (2.41-18.32, P&#xa0;<&#xa0;0.0001) respectively (P(trend) <0.0001). Moreover, the area under the receiver operating characteristic curve increased from 0.60 (epidemiological variables) to 0.72 (epidemiological variables plus RTL), with statistically significant difference assessed by bootstrap analysis.<br><br>CONCLUSIONS: Our study presents the first epidemiological evidence that RTL in serum DNA could potentially be used as a simple, inexpensive and non-invasive marker of cirrhosis risk, a finding that warrants further investigations in independent retrospective and prospective populations.},
}
@article {pmid22465657,
year = {2012},
author = {Jenkins, EC and Ye, L and Silverman, WP},
title = {Does the cryogenic freezing process cause shorter telomeres?.},
journal = {Cryobiology},
volume = {65},
number = {1},
pages = {72-73},
pmid = {22465657},
issn = {1090-2392},
support = {P01 HD035897/HD/NICHD NIH HHS/United States ; R01-HD37425/HD/NICHD NIH HHS/United States ; P30 HD024061/HD/NICHD NIH HHS/United States ; R01-AG014673/AG/NIA NIH HHS/United States ; P01 HD035897-19/HD/NICHD NIH HHS/United States ; P01-HD35897/HD/NICHD NIH HHS/United States ; R01 AG014673/AG/NIA NIH HHS/United States ; R01 HD037425/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Aged ; Female ; Freezing ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; T-Lymphocytes/metabolism ; Telomere/genetics/metabolism/*physiology ; *Telomere Shortening ; },
abstract = {We have observed evidence of increased telomere shortening in short-term T-lymphocyte cultures following freezing and thawing of the original inoculum obtained by ficoll-paque gradient centrifugation, compared to T-lymphocytes that were cultured immediately without freezing and thawing from the same blood sample from 3 female and 3 male adults. Because freezing may have similar effects on other cell types, and because telomere shortening may only manifest its effects after many years or decades, we suggest there is a pressing need for evaluation of the effects of freezing on any cells envisioned for clinical applications, including embryo implantation.},
}
@article {pmid22465532,
year = {2012},
author = {De Felice, B and Nappi, C and Zizolfi, B and Guida, M and Di Spiezio Sardo, A and Bifulco, G and Guida, M},
title = {Telomere shortening in women resident close to waste landfill sites.},
journal = {Gene},
volume = {500},
number = {1},
pages = {101-106},
doi = {10.1016/j.gene.2012.03.040},
pmid = {22465532},
issn = {1879-0038},
mesh = {Air Pollution ; *Environmental Exposure ; Female ; Humans ; Italy ; Leukocytes, Mononuclear/metabolism ; Oxidative Stress ; Pregnancy ; *Refuse Disposal ; Telomerase/genetics ; Telomere Shortening/*drug effects ; },
abstract = {Several studies demonstrate links between environmental stress and index of reduced health, including risk factors for cardiovascular disease, reduced immune function and cancer risks. We investigated the hypothesis that pollution, as an environmental stress, impacts health by modulating the rate of cellular aging in healthy pregnant women. Our research looked at the effects that illegal waste sites have on the localized population of pregnant women in Campania, Italy. As is often the case in illegal dumping, the effects on the population are often seen well before knowing what specific agents in the soil and water are responsible. Here we provide evidence that the pollution in this region is significantly associated with higher oxidative stress, shorter telomere length and lower telomerase activity, which are known determinants of cell senescence and aging-related meiotic dysfunction in women, in peripheral blood mononuclear cells from healthy pregnant women, subjected to therapeutic abortion in the second trimester of pregnancy. These findings may have implications for understanding how, at the cellular level, environmental stress may promote earlier onset of age-related diseases.},
}
@article {pmid22460582,
year = {2012},
author = {Le Chalony, C and Hoffschir, F and Gauthier, LR and Gross, J and Biard, DS and Boussin, FD and Pennaneach, V},
title = {Partial complementation of a DNA ligase I deficiency by DNA ligase III and its impact on cell survival and telomere stability in mammalian cells.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {69},
number = {17},
pages = {2933-2949},
pmid = {22460582},
issn = {1420-9071},
mesh = {Animals ; Blotting, Western ; Cell Survival ; Cells, Cultured ; Chromatin/genetics ; Colony-Forming Units Assay ; DNA Damage/genetics ; DNA Ligase ATP ; DNA Ligases/antagonists &amp; inhibitors/*physiology ; DNA Repair ; DNA Replication ; DNA-Binding Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Embryo, Mammalian/*cytology/enzymology ; Fibroblasts/*cytology/enzymology ; Fluorescent Antibody Technique ; Genetic Complementation Test ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Knockout ; Mitosis/*physiology ; Poly-ADP-Ribose Binding Proteins ; RNA, Small Interfering/genetics ; Sister Chromatid Exchange/genetics ; Telomere/*chemistry/genetics ; X-ray Repair Cross Complementing Protein 1 ; Xenopus Proteins ; },
abstract = {DNA ligase I (LigI) plays a central role in the joining of strand interruptions during replication and repair. In our current study, we provide evidence that DNA ligase III (LigIII) and XRCC1, which form a complex that functions in single-strand break repair, are required for the proliferation of mammalian LigI-depleted cells. We show from our data that in cells with either dysfunctional LigI activity or depleted of this enzyme, both LigIII and XRCC1 are retained on the chromatin and accumulate at replication foci. We also demonstrate that the LigI and LigIII proteins cooperate to inhibit sister chromatid exchanges but that only LigI prevents telomere sister fusions. Taken together, these results suggest that in cells with dysfunctional LigI, LigIII contributes to the ligation of replication intermediates but not to the prevention of telomeric instability.},
}
@article {pmid22458992,
year = {2012},
author = {Rackley, S and Pao, M and Seratti, GF and Giri, N and Rasimas, JJ and Alter, BP and Savage, SA},
title = {Neuropsychiatric conditions among patients with dyskeratosis congenita: a link with telomere biology?.},
journal = {Psychosomatics},
volume = {53},
number = {3},
pages = {230-235},
pmid = {22458992},
issn = {1545-7206},
support = {N02CP11019/CP/NCI NIH HHS/United States ; N02CP65501/CP/NCI NIH HHS/United States ; N02CP65504/CP/NCI NIH HHS/United States ; ZIA CP010144-11//Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Anemia, Aplastic ; Bone Marrow Diseases ; Bone Marrow Failure Disorders ; Child ; Comorbidity ; Diagnostic and Statistical Manual of Mental Disorders ; Dyskeratosis Congenita/*epidemiology/genetics/psychology ; Early Diagnosis ; Germ-Line Mutation/genetics ; Hemoglobinuria, Paroxysmal/*epidemiology/genetics ; Humans ; Male ; Mental Disorders/*epidemiology ; Middle Aged ; Pilot Projects ; Prospective Studies ; Telomere/enzymology/*genetics ; Young Adult ; },
abstract = {BACKGROUND: Dyskeratosis congenita (DC), an inherited bone marrow failure syndrome (IBMFS), is caused by defects in telomere biology, which result in very short germline telomeres. Telomeres, long nucleotide repeats and a protein complex at chromosome ends, are essential for chromosomal stability. Several association studies suggest that short telomeres are associated with certain psychiatric disorders, including mood disorders and schizophrenia. There are two cases in the literature of schizophrenia and DC occurring as co-morbid conditions. We noted that many patients with DC in our cohort had neuropsychiatric conditions.<br><br>METHODS: Subjects were participants in NCI's IBMFS prospective cohort study. Psychiatric evaluation was incorporated into our clinical assessment in January 2009. Fourteen DC or DC-like patients, including six children, were evaluated in this study through in person interview by either a psychiatrist specialized in psychosomatic medicine or a child and adolescent psychiatrist.<br><br>RESULTS: Three of the six pediatric subjects and five of the eight adults had a neuropsychiatric condition such as a mood, anxiety, or adjustment disorder, intellectual disability, attention deficit hyperactivity disorder, or pervasive developmental disorders. The lifetime occurrence of any of these disorders in our study was 83% in pediatric subjects and 88% in adults. Notably, the literature reports neuropsychiatric conditions in 25% and 38% in chronically ill children and adults, respectively.<br><br>CONCLUSION: This pilot study suggests that patients with DC may have higher rates of neuropsychiatric conditions than the general population or other chronically ill individuals. This potential link between very short telomeres and neuropsychiatric conditions warrants further study.},
}
@article {pmid22456777,
year = {2012},
author = {Zekry, D and Krause, KH and Irminger-Finger, I and Graf, CE and Genet, C and Vitale, AM and Michel, JP and Gold, G and Herrmann, FR},
title = {Telomere length, comorbidity, functional, nutritional and cognitive status as predictors of 5 years post hospital discharge survival in the oldest old.},
journal = {The journal of nutrition, health &amp; aging},
volume = {16},
number = {3},
pages = {225-230},
pmid = {22456777},
issn = {1760-4788},
mesh = {Aged, 80 and over ; Aging/*physiology ; Biomarkers ; Body Mass Index ; Cognition Disorders/mortality ; Comorbidity ; Female ; Flow Cytometry ; Geriatric Assessment ; *Health Status ; Humans ; Leukocytes/*cytology ; Male ; *Nutritional Status ; Obesity/mortality ; Patient Discharge/*statistics &amp; numerical data ; Prospective Studies ; Survival Analysis ; Telomere/ultrastructure ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Telomere length has been considered in many cross-sectional studies as a biomarker of aging. However the association between shorter telomeres with lower survival at advanced ages remains a controversial issue. This association could reflect the impact of other health conditions than a direct biological effect.<br><br>OBJECTIVE: To test whether leukocyte telomere length is associated with 5-year survival beyond the impact of other risk factors of mortality like comorbidity, functional, nutritional and cognitive status.<br><br>DESIGN: Prospective study.<br><br>SETTING AND PARTICIPANTS: A population representative sample of 444 patients (mean age 85 years; 74% female) discharged from the acute geriatric hospital of Geneva University Hospitals (January-December 2004), since then 263 (59.2%) had died (December 2009).<br><br>MEASUREMENTS: Telomere length in leukocytes by flow cytometry.<br><br>RESULTS: In univariate model, telomere length at baseline and cognitive status were not significantly associated with mortality even when adjusting for age (R&#xb2;=9.5%) and gender (R&#xb2;=1.9%). The best prognostic predictor was the geriatric index of comorbidity (GIC) (R&#xb2;=8.8%; HR=3.85) followed by more dependence in instrumental (R&#xb2;=5.9%; HR=3.85) and based (R&#xb2;=2.3%; HR=0.84) activities of daily living and lower albumin levels (R&#xb2;=1.5%; HR=0.97). Obesity (BMI>30: R&#xb2;=1.6%; HR=0.55) was significantly associated with a two-fold decrease in the risk of mortality compared to BMI between 20-25. When all independent variables were entered in a full multiple Cox regression model (R&#xb2;=21.4%), the GIC was the strongest risk predictor followed by the nutritional and functional variables.<br><br>CONCLUSION: Neither telomeres length nor the presence of dementia are predictors of survival whereas the weight of multiple comorbidity conditions, nutritional and functional impairment are significantly associated with 5-year mortality in the oldest old.},
}
@article {pmid22449406,
year = {2012},
author = {Burnett-Hartman, AN and Fitzpatrick, AL and Kronmal, RA and Psaty, BM and Jenny, NS and Bis, JC and Tracy, RP and Kimura, M and Aviv, A},
title = {Telomere-associated polymorphisms correlate with cardiovascular disease mortality in Caucasian women: the Cardiovascular Health Study.},
journal = {Mechanisms of ageing and development},
volume = {133},
number = {5},
pages = {275-281},
pmid = {22449406},
issn = {1872-6216},
support = {M01-RR00425/RR/NCRR NIH HHS/United States ; N01-HC-85085/HC/NHLBI NIH HHS/United States ; N01 HC075150/HC/NHLBI NIH HHS/United States ; N01-HC-85081/HC/NHLBI NIH HHS/United States ; N01 HC015103/HC/NHLBI NIH HHS/United States ; R56 AG020098/AG/NIA NIH HHS/United States ; AG-027058/AG/NIA NIH HHS/United States ; N01-HC-85082/HC/NHLBI NIH HHS/United States ; M01 RR000425/RR/NCRR NIH HHS/United States ; DK063491/DK/NIDDK NIH HHS/United States ; N01-HC-85079/HC/NHLBI NIH HHS/United States ; R01 AG015928/AG/NIA NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; AG-20098/AG/NIA NIH HHS/United States ; R01 HL080698/HL/NHLBI NIH HHS/United States ; N01HC55222/HL/NHLBI NIH HHS/United States ; N01-HC-85086/HC/NHLBI NIH HHS/United States ; N01HC85086/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; N01 HC-55222/HC/NHLBI NIH HHS/United States ; N01-HC-85083/HC/NHLBI NIH HHS/United States ; N01-HC-75150/HC/NHLBI NIH HHS/United States ; N01-HC-85080/HC/NHLBI NIH HHS/United States ; R01 AG020098/AG/NIA NIH HHS/United States ; N01HC75150/HL/NHLBI NIH HHS/United States ; N01-HC-85239/HC/NHLBI NIH HHS/United States ; AG-023629/AG/NIA NIH HHS/United States ; N01HC85079/HL/NHLBI NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; R01 AG027058/AG/NIA NIH HHS/United States ; N01 HC045133/HC/NHLBI NIH HHS/United States ; N01 HC035129/HC/NHLBI NIH HHS/United States ; R56 AG023629/AG/NIA NIH HHS/United States ; N01-HC-85084/HC/NHLBI NIH HHS/United States ; R01 HL80698-01/HL/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Cardiovascular Diseases/*genetics/*mortality ; Cohort Studies ; Female ; Humans ; Leukocytes ; Male ; *Polymorphism, Genetic ; Polymorphism, Single Nucleotide ; RNA/genetics ; Risk ; Sex Factors ; Telomerase/genetics ; Telomere/*genetics ; White People/*genetics/*statistics &amp; numerical data ; },
abstract = {Leukocyte telomere length (LTL) is linked to cardiovascular disease (CVD); however, it is unclear if LTL has an etiologic role in CVD. To gain insight into the LTL and CVD relationship, a cohort study of CVD mortality and single nucleotide polymorphisms (SNPs) in OBFC1 and TERC, genes related to LTL, was conducted among 3271 Caucasian participants ages ≥65 years enrolled 1989-1990 in the Cardiovascular Health Study. Leukocyte DNA was genotyped for SNPs in OBFC1 (rs4387287 and rs9419958) and TERC (rs3772190) that were previously associated with LTL through genome-wide association studies. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The OBFC1 SNPs were in linkage disequilibrium (r(2)=0.99), and both SNPs were similarly associated with CVD mortality in women. For women, there was a decreased risk of CVD death associated with the minor allele (rs4387287), HR=0.7; 95% CI: 0.5-0.9 (CC vs. AC) and HR=0.5; 95% CI: 0.20-1.4 (CC vs. AA) (P-trend <0.01). For men there was no association, HR=1.0; 95% CI: 0.7-1.3 (CC vs. AC) and HR=1.7; 95% CI: 0.8-3.6 (CC vs. AA) (P-trend=0.64). These findings support the hypothesis that telomere biology and associated genes may play a role in CVD-related death, particularly among women.},
}
@article {pmid22448247,
year = {2012},
author = {Yu, TY and Wang, CY and Lin, JJ},
title = {Depleting components of the THO complex causes increased telomere length by reducing the expression of the telomere-associated protein Rif1p.},
journal = {PloS one},
volume = {7},
number = {3},
pages = {e33498},
pmid = {22448247},
issn = {1932-6203},
mesh = {Blotting, Northern ; DNA-Binding Proteins/genetics/metabolism ; *Gene Expression Regulation, Fungal ; Immunoblotting ; Mutation/genetics ; Nuclear Proteins/*genetics/metabolism ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Repressor Proteins/genetics/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Saccharomyces cerevisiae/*genetics/growth &amp; development/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/*metabolism ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/genetics/*metabolism ; Transcription Factors/*genetics/metabolism ; Transcription, Genetic ; },
abstract = {Telomere length is regulated mostly by proteins directly associated with telomeres. However, genome-wide analysis of Saccharomyces cerevisiae mutants has revealed that deletion of Hpr1p, a component of the THO complex, also affects telomere length. The THO complex comprises four protein subunits, namely, Tho2p, Hpr1p, Mft1p, and Thp2p. These subunits interplay between transcription elongation and co-transcriptional assembly of export-competent mRNPs. Here we found that the deletion of tho2 or hpr1 caused telomere lengthening by ∼50-100 bps, whereas that of mft1 or thp2 did not affect telomere length. Since the THO complex functions in transcription elongation, we analyzed the expression of telomere-associated proteins in mutants depleted of complex components. We found that both the mRNA and protein levels of RIF1 were decreased in tho2 and hpr1 cells. RIF1 encodes a 1917-amino acid polypeptide that is involved in regulating telomere length and the formation of telomeric heterochromatin. Hpr1p and Tho2p appeared to affect telomeres through Rif1p, as increased Rif1p levels suppressed the telomere lengthening in tho2 and hpr1 cells. Moreover, yeast cells carrying rif1 tho2 or rif1 hpr1 double mutations showed telomere lengths and telomere silencing effects similar to those observed in the rif1 mutant. Thus, we conclude that mutations of components of the THO complex affect telomere functions by reducing the expression of a telomere-associated protein, Rif1p.},
}
@article {pmid22446319,
year = {2012},
author = {Starnes, JH and Thornbury, DW and Novikova, OS and Rehmeyer, CJ and Farman, ML},
title = {Telomere-targeted retrotransposons in the rice blast fungus Magnaporthe oryzae: agents of telomere instability.},
journal = {Genetics},
volume = {191},
number = {2},
pages = {389-406},
pmid = {22446319},
issn = {1943-2631},
mesh = {Amino Acid Sequence ; Base Sequence ; *Genomic Instability ; Lolium/microbiology ; Magnaporthe/*genetics/isolation &amp; purification ; Mitosis/genetics ; Molecular Sequence Data ; Mutagenesis, Insertional ; Oryza/microbiology ; Plant Diseases/microbiology ; Repetitive Sequences, Nucleic Acid ; *Retroelements ; Sequence Homology, Nucleic Acid ; *Telomere ; },
abstract = {The fungus Magnaporthe oryzae is a serious pathogen of rice and other grasses. Telomeric restriction fragments in Magnaporthe isolates that infect perennial ryegrass (prg) are hotspots for genomic rearrangement and undergo frequent, spontaneous alterations during fungal culture. The telomeres of rice-infecting isolates are very stable by comparison. Sequencing of chromosome ends from a number of prg-infecting isolates revealed two related non-LTR retrotransposons (M. oryzae Telomeric Retrotransposons or MoTeRs) inserted in the telomere repeats. This contrasts with rice pathogen telomeres that are uninterrupted by other sequences. Genetic evidence indicates that the MoTeR elements are responsible for the observed instability. MoTeRs represent a new family of telomere-targeted transposons whose members are found exclusively in fungi.},
}
@article {pmid22446318,
year = {2012},
author = {Beaucher, M and Zheng, XF and Amariei, F and Rong, YS},
title = {Multiple pathways suppress telomere addition to DNA breaks in the Drosophila germline.},
journal = {Genetics},
volume = {191},
number = {2},
pages = {407-417},
pmid = {22446318},
issn = {1943-2631},
support = {//Intramural NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Carrier Proteins/metabolism ; Cell Death ; Chromosomes ; *DNA Breaks, Double-Stranded ; DNA End-Joining Repair ; DNA Transposable Elements ; DNA-Binding Proteins/metabolism ; Drosophila/*genetics/metabolism ; Drosophila Proteins/metabolism ; Female ; Germ Cells/metabolism ; Male ; Mutation ; Protein Serine-Threonine Kinases/metabolism ; Recombinational DNA Repair ; Telomere/*genetics/*metabolism ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Telomeres protect chromosome ends from being repaired as double-strand breaks (DSBs). Just as DSB repair is suppressed at telomeres, de novo telomere addition is suppressed at the site of DSBs. To identify factors responsible for this suppression, we developed an assay to monitor de novo telomere formation in Drosophila, an organism in which telomeres can be established on chromosome ends with essentially any sequence. Germline expression of the I-SceI endonuclease resulted in precise telomere formation at its cut site with high efficiency. Using this assay, we quantified the frequency of telomere formation in different genetic backgrounds with known or possible defects in DNA damage repair. We showed that disruption of DSB repair factors (Rad51 or DNA ligase IV) or DSB sensing factors (ATRIP or MDC1) resulted in more efficient telomere formation. Interestingly, partial disruption of factors that normally regulate telomere protection (ATM or NBS) also led to higher frequencies of telomere formation, suggesting that these proteins have opposing roles in telomere maintenance vs. establishment. In the ku70 mutant background, telomere establishment was preceded by excessive degradation of DSB ends, which were stabilized upon telomere formation. Most strikingly, the removal of ATRIP caused a dramatic increase in telomeric retrotransposon attachment to broken ends. Our study identifies several pathways that suppress telomere addition at DSBs, paving the way for future mechanistic studies.},
}
@article {pmid22444598,
year = {2012},
author = {Fu, X and Wan, S and Hann, HW and Myers, RE and Hann, RS and Au, J and Chen, B and Xing, J and Yang, H},
title = {Relative telomere length: a novel non-invasive biomarker for the risk of non-cirrhotic hepatocellular carcinoma in patients with chronic hepatitis B infection.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {48},
number = {7},
pages = {1014-1022},
pmid = {22444598},
issn = {1879-0852},
support = {R21 CA159047/CA/NCI NIH HHS/United States ; CA152703/CA/NCI NIH HHS/United States ; R03 CA153099-01/CA/NCI NIH HHS/United States ; R21 CA159047-01/CA/NCI NIH HHS/United States ; R03 CA153099/CA/NCI NIH HHS/United States ; R03 CA153099-02/CA/NCI NIH HHS/United States ; R21 CA159047-02/CA/NCI NIH HHS/United States ; CA153099/CA/NCI NIH HHS/United States ; },
mesh = {*Biomarkers ; Carcinoma, Hepatocellular/blood/complications/*genetics ; Case-Control Studies ; Female ; Hepatitis B, Chronic/blood/complications/*genetics ; Humans ; Liver Neoplasms/blood/complications/*genetics ; Male ; Middle Aged ; Risk Factors ; Serum/*chemistry ; *Telomere Homeostasis ; },
abstract = {BACKGROUND AND AIMS: Telomere length has emerged as a promising risk predictor of various cancers including hepatocellular carcinoma (HCC). However, the majority of studies in this area measured telomere length in hepatocytes and one in lymphocytes with conflicting results. Moreover, no studies have been reported on using circulating DNA telomere length as a non-invasive HCC biomarker.<br><br>METHODS: We conducted a nested case-control study to determine the relative telomere length (RTL) in serum DNA from 140 hepatitis B virus (HBV)-related HCC cases and 280 frequency-matched cancer-free HBV controls.<br><br>RESULTS: Cases had a significantly longer RTL (median, 0.31; range, 0.02-2.31) than controls (median, 0.20; range, 0.01-1.60) (P = 0.003). Consistently, longer RTLs conferred a significantly increased HCC risk compared to short RTLs in a univariate logistic regression analysis (odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.02-2.33, P = 0.038). This association attenuated after multivariate adjustment (OR = 1.40, 95% CI = 0.90-2.19, P = 0.132). In a quartile analysis, a significant dose-response relationship was noted in univariate analysis (P(trend) = 0.017) which was again attenuated in multivariate analysis (P(trend) = 0.079). Further analyses revealed that the significant association between serum RTL and HCC risk was evident in non-cirrhotic (OR = 3.54, 95% CI 1.58-7.93 P = 0.002), but not cirrhotic (OR = 0.95, 95% CI 0.55-1.64, P = 0.860) HBV patients. Moreover, the significantly increased HCC risk conferred by cirrhosis was modulated by RTL with a significant interaction effect (P(interaction) = 0.013).<br><br>CONCLUSIONS: RTL in circulating cell-free serum DNA could potentially be used as a novel non-invasive biomarker for non-cirrhotic HCC. Prospective cohort studies are warranted to validate this finding and assess its clinical significance in HCC prevention.},
}
@article {pmid22440628,
year = {2012},
author = {Xu, L and Xu, Z and Shang, Y and Feng, S and Zhou, X},
title = {Structural polymorphism of human telomere G-quadruplex induced by a pyridyl carboxamide molecule.},
journal = {Bioorganic &amp; medicinal chemistry letters},
volume = {22},
number = {8},
pages = {2988-2992},
doi = {10.1016/j.bmcl.2012.02.030},
pmid = {22440628},
issn = {1464-3405},
mesh = {Base Sequence ; Circular Dichroism ; *G-Quadruplexes/drug effects ; Humans ; Kinetics ; Molecular Sequence Data ; Molecular Structure ; Pyridines/*chemistry/pharmacology ; Telomere/*chemistry/drug effects ; Thermodynamics ; },
abstract = {In this work, we described a kinetically slow (hour-scale) but thermodynamically favored G-quadruplex conversion induced by a pyridyl carboxamide molecule. This slow transition was observed through CD spectra and gels, and its final stable parallel conformation was identified by 2-aminopurine experiments. Kinetic experiments indicated that this slow process was a first-order reaction, implying it was a unimolecular conversion. Quite distinctly from other reported ligand-driven G-quadruplex conformation alteration, this slow conversion reveals a novel insight into G-quadruplex polymorphism, in accordance with the behavior of human telomere G-quadruplex in a molecular crowding environment in K(+) solution, further enriching the known structural polymorphism of human telomere DNA and providing new consideration for drug design based on G-quadruplexes.},
}
@article {pmid22436739,
year = {2012},
author = {Schuldt, A},
title = {Telomeres: The perils of peripheral damage.},
journal = {Nature reviews. Molecular cell biology},
volume = {13},
number = {4},
pages = {208-209},
pmid = {22436739},
issn = {1471-0080},
}
@article {pmid22433952,
year = {2012},
author = {Peuscher, MH and Jacobs, JJ},
title = {Posttranslational control of telomere maintenance and the telomere damage response.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {11},
number = {8},
pages = {1524-1534},
doi = {10.4161/cc.19847},
pmid = {22433952},
issn = {1551-4005},
mesh = {Chromatin/metabolism ; DNA Damage ; *DNA Repair ; Genomic Instability ; Humans ; *Protein Processing, Post-Translational ; Sumoylation ; Telomere/*metabolism ; Ubiquitination ; },
abstract = {Telomeres help maintain genome integrity by protecting natural chromosome ends from being recognized as damaged DNA. When telomeres become dysfunctional, they limit replicative lifespan and prevent outgrowth of potentially cancerous cells by activating a DNA damage response that forces cells into senescence or apoptosis. On the other hand, chromosome ends devoid of proper telomere protection are subject to DNA repair activities that cause end-to-end fusions and, when cells divide, extensive genomic instability that can promote cancer. While telomeres represent unique chromatin structures with important roles in cancer and aging, we have limited understanding of the way telomeres and the response to their malfunction are controlled at the level of chromatin. Accumulating evidence indicates that different types of posttranslational modifications act in both telomere maintenance and the response to telomere uncapping. Here, we discuss the latest insights on posttranslational control of telomeric chromatin, with emphasis on ubiquitylation and SUMOylation events.},
}
@article {pmid22433385,
year = {2012},
author = {Fernández-Marcelo, T and Morán, A and de Juan, C and Pascua, I and Head, J and Gómez, A and Hernando, F and López-Asenjo, JA and Hernández, S and Sánchez-Pernaute, A and Torres, AJ and Benito, M and Iniesta, P},
title = {Differential expression of senescence and cell death factors in non-small cell lung and colorectal tumors showing telomere attrition.},
journal = {Oncology},
volume = {82},
number = {3},
pages = {153-164},
doi = {10.1159/000335678},
pmid = {22433385},
issn = {1423-0232},
mesh = {Adenocarcinoma/genetics/metabolism/pathology ; Aged ; Aging/*genetics ; Biomarkers, Tumor/genetics ; Carcinoma, Large Cell/genetics/metabolism/pathology ; Carcinoma, Non-Small-Cell Lung/*genetics/metabolism/pathology ; Carcinoma, Squamous Cell/genetics/metabolism/pathology ; Cell Death/*genetics ; Colon/metabolism ; Colorectal Neoplasms/*genetics/metabolism/pathology ; Female ; Gene Expression Profiling ; Humans ; Lung/metabolism ; Lung Neoplasms/*genetics/metabolism/pathology ; Male ; Oligonucleotide Array Sequence Analysis ; Prognosis ; Rectum/metabolism ; Telomerase/genetics/metabolism ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {OBJECTIVE: The main aim of this work is to investigate the expression of factors related to senescence and cell death pathways in non-small cell lung cancers (NSCLCs) and colorectal cancers (CRCs) in relation to telomere status.<br><br>METHODS: We analyzed 158 tissue samples, 36 NSCLCs, 43 CRCs, and their corresponding control tissues obtained from patients submitted to surgery. Telomere function was evaluated by determining telomerase activity and telomere length. Expression of factors related to senescence, cell death pathways, transformation and tumorigenesis was investigated using arrays. Results were validated by real-time quantitative PCR.<br><br>RESULTS: Considering tumors with telomere shortening, expression for BNIP3, DAPK1, NDRG1, EGFR, and CDKN2A was significantly higher in NSCLC than in CRC, whereas TP53 was overexpressed in CRC with respect to NSCLC. Moreover, compared to nontumor samples, DAPK1, GADD45A, SHC1, and TP53 were downregulated in the group of NSCLCs with telomere shortening, and no significant differences were found in CRC.<br><br>CONCLUSIONS: In NSCLC, the failure of pathways which involve factors such as DAPK1, GADD45A, SHC1, and TP53, in response to short telomeres, could promote tumor progression. In CRC, the viability of these pathways in response to short telomeres could contribute to limiting tumorigenesis.},
}
@article {pmid22431479,
year = {2012},
author = {Bhupatiraju, C and Saini, D and Patkar, S and Deepak, P and Das, B and Padma, T},
title = {Association of shorter telomere length with essential hypertension in Indian population.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {24},
number = {4},
pages = {573-578},
doi = {10.1002/ajhb.22264},
pmid = {22431479},
issn = {1520-6300},
mesh = {Adult ; Aged ; Biomarkers ; Female ; Fluorescent Dyes/chemistry ; Humans ; Hypertension/*genetics ; India ; Leukocytes/cytology/*pathology ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Telomere/*genetics/*pathology ; },
abstract = {OBJECTIVES: Essential hypertension is known to be associated with growth, development, and aging of humans. Telomeres are specialized nucleoprotein complexes consisting of tandem repeats of DNA sequences (TTAGGG)n that serve as protective caps of human chromosomes. Telomere length is considered as a biomarker of aging in somatic cells. In the present investigation, leukocyte telomere length was determined among hypertensive and normal individuals to find out the association, if any, with hypertension.<br><br>MATERIALS AND METHODS: Venous blood samples were collected from normal and hypertensive individuals with written informed consent approved by ethic committee of Department of Genetics, Osmania University Hyderabad, India. Genomic DNA was isolated from blood samples of 98 normal (age range: 30-70 years, mean age: 51.01 &#xb1; 10.12 years) and 96 hypertensive individuals (age range: 35-75 years, mean age: 49.18 &#xb1; 6.46 years). Using a SYBR green-based real time quantitative PCR relative telomere length was determined among these individuals.<br><br>RESULTS: The relative telomere length (T/S ratio) in hypertensive individuals was observed to be 0.91 &#xb1; 0.16 which was significantly different (P < 0.001) from normal individuals where the relative telomere length was 0.99 &#xb1; 0.13. No significant difference was observed between relative telomere length of male and female individuals, although there is negative correlation between age and telomere length was observed in both normal and hypertensive individuals. The systolic and diastolic blood pressure was negatively correlated with relative telomere length, though not significant.<br><br>CONCLUSION: Shorter telomere length is associated with hypertensive individuals in Indian population.},
}
@article {pmid22427862,
year = {2012},
author = {Gissot, M and Walker, R and Delhaye, S and Huot, L and Hot, D and Tomavo, S},
title = {Toxoplasma gondii chromodomain protein 1 binds to heterochromatin and colocalises with centromeres and telomeres at the nuclear periphery.},
journal = {PloS one},
volume = {7},
number = {3},
pages = {e32671},
pmid = {22427862},
issn = {1932-6203},
mesh = {Cell Division/*physiology ; Cell Nucleus/*metabolism/physiology ; Centromere/*metabolism ; Heterochromatin/*metabolism ; Protozoan Proteins/*metabolism ; Telomere/*metabolism ; Toxoplasma/metabolism/*physiology ; },
abstract = {BACKGROUND: Apicomplexan parasites are responsible for some of the most deadly parasitic diseases afflicting humans, including malaria and toxoplasmosis. These obligate intracellular parasites exhibit a complex life cycle and a coordinated cell cycle-dependant expression program. Their cell division is a coordinated multistep process. How this complex mechanism is organised remains poorly understood.<br><br>METHODS AND FINDINGS: In this study, we provide evidence for a link between heterochromatin, cell division and the compartmentalisation of the nucleus in Toxoplasma gondii. We characterised a T. gondii chromodomain containing protein (named TgChromo1) that specifically binds to heterochromatin. Using ChIP-on-chip on a genome-wide scale, we report TgChromo1 enrichment at the peri-centromeric chromatin. In addition, we demonstrate that TgChromo1 is cell-cycle regulated and co-localised with markers of the centrocone. Through the loci-specific FISH technique for T. gondii, we confirmed that TgChromo1 occupies the same nuclear localisation as the peri-centromeric sequences.<br><br>CONCLUSION: We propose that TgChromo1 may play a role in the sequestration of chromosomes at the nuclear periphery and in the process of T. gondii cell division.},
}
@article {pmid22426229,
year = {2012},
author = {Hewitt, G and Jurk, D and Marques, FD and Correia-Melo, C and Hardy, T and Gackowska, A and Anderson, R and Taschuk, M and Mann, J and Passos, JF},
title = {Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence.},
journal = {Nature communications},
volume = {3},
number = {},
pages = {708},
pmid = {22426229},
issn = {2041-1723},
support = {BB/H022384/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Aging/genetics/*physiology ; Animals ; Cell Division ; Cell Line ; Chromatin Immunoprecipitation ; *DNA Damage ; DNA Repair ; DNA Replication ; Gastrointestinal Tract/cytology ; Humans ; In Situ Hybridization, Fluorescence ; Liver/cytology ; Male ; Mice ; Mice, Inbred C57BL ; *Oxidative Stress/genetics ; Telomerase/genetics/metabolism ; Telomere/metabolism ; Telomere Shortening/genetics/*physiology ; },
abstract = {Telomeres are specialized nucleoprotein structures, which protect chromosome ends and have been implicated in the ageing process. Telomere shortening has been shown to contribute to a persistent DNA damage response (DDR) during replicative senescence, the irreversible loss of division potential of somatic cells. Similarly, persistent DDR foci can be found in stress-induced senescence, although their nature is not understood. Here we show, using immuno-fluorescent in situ hybridization and ChIP, that up to half of the DNA damage foci in stress-induced senescence are located at telomeres irrespective of telomerase activity. Moreover, live-cell imaging experiments reveal that all persistent foci are associated with telomeres. Finally, we report an age-dependent increase in frequencies of telomere-associated foci in gut and liver of mice, occurring irrespectively of telomere length. We conclude that telomeres are important targets for stress in vitro and in vivo and this has important consequences for the ageing process.},
}
@article {pmid22425636,
year = {2012},
author = {Xu, Y and Komiyama, M},
title = {Structure, function and targeting of human telomere RNA.},
journal = {Methods (San Diego, Calif.)},
volume = {57},
number = {1},
pages = {100-105},
doi = {10.1016/j.ymeth.2012.02.015},
pmid = {22425636},
issn = {1095-9130},
mesh = {Circular Dichroism ; Crystallography, X-Ray ; *G-Quadruplexes ; Humans ; *Ligands ; Magnetic Resonance Spectroscopy ; Nucleic Acid Conformation ; RNA/*chemistry ; Telomere/*chemistry ; },
abstract = {Human telomeres play an important role in critical processes underlying genome stability, cancer, and aging. For a long time, telomeres have been considered transcriptionally silent. A recent finding demonstrated that telomere DNA is transcribed into telomeric repeat-containing RNA (referred to as TERRA) in mammalian cells. The existence of TERRA RNA may reveal a new level of regulation and protection of chromosome ends that could promote valuable insight into fundamental biological processes such as cancer and aging. Revealing the structure and function of telomere RNA will be essential for understanding telomere biology and telomere-related diseases. NMR and X-ray crystallography have demonstrated that human telomere RNA forms G-quadruplex structures. More recently, human telomere RNA is suggested to form a G-quadruplex dimer in the living cells by employing a light-switching probe. The proposed structures may be a valuable target for anticancer agents directed against telomeres. This review highlights the structures and topologies for telomere RNA G-quadruplex and recent efforts in the design of telomere RNA G-quadruplex ligands. The future challenges in the field are outlined.},
}
@article {pmid22421147,
year = {2012},
author = {Pickett, HA and Reddel, RR},
title = {The role of telomere trimming in normal telomere length dynamics.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {11},
number = {7},
pages = {1309-1315},
doi = {10.4161/cc.19632},
pmid = {22421147},
issn = {1551-4005},
mesh = {Aging/genetics ; Animals ; Cell Division ; Chromosomes, Mammalian/genetics/physiology ; DNA/genetics ; DNA Repair ; Humans ; Mice ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; Telomere Shortening/*genetics ; },
abstract = {Telomeres consist of repetitive DNA and associated proteins that protect chromosome ends from illicit DNA repair. It is well known that telomeric DNA is progressively eroded during cell division, until telomeres become too short and the cell stops dividing. There is a second mode of telomere shortening, however, which is a regulated form of telomere rapid deletion (TRD) termed telomere trimming that is reviewed here. Telomere trimming appears to involve resolution of recombination intermediate structures, which shortens the telomere by release of extrachromosomal telomeric DNA. This has been detected in human and in mouse cells and occurs both in somatic and germline cells, where it sets an upper limit on telomere length and contributes to a length equilibrium set-point in cells that have a telomere elongation mechanism. Telomere trimming thus represents an additional mechanism of telomere length control that contributes to normal telomere dynamics and cell proliferative potential.},
}
@article {pmid22417715,
year = {2012},
author = {Borras, M and Panizo, S and Sarró, F and Valdivielso, JM and Fernandez, E},
title = {Assessment of the potential role of active vitamin D treatment in telomere length: a case-control study in hemodialysis patients.},
journal = {Clinical therapeutics},
volume = {34},
number = {4},
pages = {849-856},
doi = {10.1016/j.clinthera.2012.02.016},
pmid = {22417715},
issn = {1879-114X},
mesh = {Case-Control Studies ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Telomere/*drug effects ; Vitamin D/pharmacology/*therapeutic use ; },
abstract = {BACKGROUND: Telomeres are special chromatin sequences located at the end of eukaryotic chromosomes, protecting these regions from recombination and degradation. Previous studies have reported a decrease in telomere length on white blood cells from hemodialysis (HD) patients, which suggests premature senescence. Active vitamin D treatment has been reported to have an effect on telomere length and beneficial effects on HD patients, but the mechanisms are unknown.<br><br>OBJECTIVE: Our aim was to assess the potential protective role of active vitamin D treatment on telomere length in peripheral mononuclear cells (PBMC) from HD patients.<br><br>METHODS: A retrospective case-control study of 62 stable HD patients and 60 healthy sex-matched controls was undertaken. Telomere length was measured in PBMC by Southern blot. After telomere length measurement, 5 control samples that did not reach quality-control standards were excluded. Standard epidemiological and biochemical parameters were recorded. Blood biochemistries were performed at the Biochemistry Department of the University Hospital Arnau de Vilanova in Lleida, Spain, using standard routine techniques. Differences in telomere length were analyzed using Student's t test. Multiple regression analysis examined the independent contribution of the factors that significantly affected telomere length in the bivariate analysis.<br><br>RESULTS: HD patients presented shorter telomere length in PBMC, independent of age and sex (mean [SD] 8.8 [1.5] kbp vs 10.5 [2.9] kbp; P = 0.0001). Multivariate regression analysis of the HD subgroup suggested that patients under active vitamin D treatment have greater telomere length in PBMC than untreated patients (9.5 [0.2] kbp vs 8.4 [0.2] kbp; P = 0.003).<br><br>CONCLUSIONS: HD patients were observed to have decreased PBMC telomere length compared with healthy controls. HD patients treated with active vitamin D compounds had greater PBMC telomere length than untreated patients. Prospective studies are required to assess the potential role of active vitamin D treatment in PBMC telomere length.},
}
@article {pmid22415954,
year = {2012},
author = {von Zglinicki, T},
title = {Will your telomeres tell your future?.},
journal = {BMJ (Clinical research ed.)},
volume = {344},
number = {},
pages = {e1727},
doi = {10.1136/bmj.e1727},
pmid = {22415954},
issn = {1756-1833},
support = {G0601333/MRC_/Medical Research Council/United Kingdom ; G0900686/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aging/*genetics ; Biomarkers ; Cardiovascular Diseases/genetics ; Cataract/genetics ; Dementia/genetics ; Diabetes Mellitus/genetics ; Gene-Environment Interaction ; Humans ; Life Style ; Research ; Risk Factors ; Telomere/*metabolism ; *Telomere Shortening ; },
}
@article {pmid22415365,
year = {2012},
author = {Remeseiro, S and Cuadrado, A and Carretero, M and Martínez, P and Drosopoulos, WC and Cañamero, M and Schildkraut, CL and Blasco, MA and Losada, A},
title = {Cohesin-SA1 deficiency drives aneuploidy and tumourigenesis in mice due to impaired replication of telomeres.},
journal = {The EMBO journal},
volume = {31},
number = {9},
pages = {2076-2089},
pmid = {22415365},
issn = {1460-2075},
support = {R01 GM045751/GM/NIGMS NIH HHS/United States ; GM045751/GM/NIGMS NIH HHS/United States ; },
mesh = {*Aneuploidy ; Animals ; Carcinogens ; Cell Cycle Proteins/*deficiency/genetics ; Cell Line ; Chromatids/metabolism ; Chromosomal Proteins, Non-Histone/*deficiency/genetics ; Chromosome Segregation ; Diethylnitrosamine ; Fibrosarcoma/chemically induced/genetics/pathology ; Liver Neoplasms/chemically induced/genetics/pathology ; Male ; Methylcholanthrene ; Mice ; Mice, Knockout ; Neoplasms, Experimental/chemically induced/genetics/pathology ; Protein Subunits/*deficiency/genetics ; Sister Chromatid Exchange ; Telomere/*metabolism ; Cohesins ; },
abstract = {Cohesin is a protein complex originally identified for its role in sister chromatid cohesion, although increasing evidence portrays it also as a major organizer of interphase chromatin. Vertebrate cohesin consists of Smc1, Smc3, Rad21/Scc1 and either stromal antigen 1 (SA1) or SA2. To explore the functional specificity of these two versions of cohesin and their relevance for embryonic development and cancer, we generated a mouse model deficient for SA1. Complete ablation of SA1 results in embryonic lethality, while heterozygous animals have shorter lifespan and earlier onset of tumourigenesis. SA1-null mouse embryonic fibroblasts show decreased proliferation and increased aneuploidy as a result of chromosome segregation defects. These defects are not caused by impaired centromeric cohesion, which depends on cohesin-SA2. Instead, they arise from defective telomere replication, which requires cohesion mediated specifically by cohesin-SA1. We propose a novel mechanism for aneuploidy generation that involves impaired telomere replication upon loss of cohesin-SA1, with clear implications in tumourigenesis.},
}
@article {pmid22411737,
year = {2012},
author = {Monickaraj, F and Aravind, S and Gokulakrishnan, K and Sathishkumar, C and Prabu, P and Prabu, D and Mohan, V and Balasubramanyam, M},
title = {Accelerated aging as evidenced by increased telomere shortening and mitochondrial DNA depletion in patients with type 2 diabetes.},
journal = {Molecular and cellular biochemistry},
volume = {365},
number = {1-2},
pages = {343-350},
pmid = {22411737},
issn = {1573-4919},
mesh = {Adiponectin/blood ; Adult ; *Aging ; Biomarkers/blood ; Blood Glucose ; Body Mass Index ; DNA, Mitochondrial/*genetics ; Diabetes Mellitus, Type 2/blood/genetics/*physiopathology ; Female ; Humans ; Lipids/blood ; Logistic Models ; Male ; Middle Aged ; Odds Ratio ; Oxidative Stress ; Risk Factors ; *Telomere Shortening ; Thiobarbituric Acid Reactive Substances ; },
abstract = {Although shortened telomeres were shown associated with several risk factors of diabetes, there is lack of data on their relationship with mitochondrial dysfunction. Therefore, we compared the relationship between telomere length and mitochondrial DNA (mtDNA) content in patients with type 2 diabetes mellitus (T2DM; n = 145) and in subjects with normal glucose tolerance (NGT; n = 145). Subjects were randomly recruited from the Chennai Urban Rural Epidemiology Study. mtDNA content and telomere length were assessed by Real-Time PCR. Malonodialdehyde, a marker of lipid peroxidation was measured by thiobarbituric acid reactive substances (TBARS) using fluorescence methodology. Adiponectin levels were measured by radioimmunoassay. Oxidative stress as determined by lipid peroxidation (TBARS) was significantly (p < 0.001) higher in patients with T2DM compared to NGT subjects. In contrast, the mean telomere length, adiponectin and mtDNA content were significantly (p < 0.001) lower in patients with T2DM compared to NGT subjects. Telomere length was positively correlated with adiponectin, HDL, mtDNA content and good glycemic/lipid control and negatively correlated with adiposity and insulin resistance. On regression analysis, shortened telomeres showed significant association with T2DM even after adjusting for waist circumference, insulin resistance, triglyceride, HDL, adiponectin, mtDNA &amp; TBARS. mtDNA depletion showed significant association with T2DM after adjusting for waist circumference and adiponectin but lost its significance when further adjusted for telomere length, TBARS and insulin resistance. Our study emphasizes the clustering of accelerated aging features viz., shortened telomeres, decreased mtDNA content, hypoadiponectinemia, low HDL, and increased oxidative stress in Asian Indian type 2 diabetes patients.},
}
@article {pmid22410593,
year = {2012},
author = {Rizzo, A and Salvati, E and Biroccio, A},
title = {Methods of studying telomere damage induced by quadruplex-ligand complexes.},
journal = {Methods (San Diego, Calif.)},
volume = {57},
number = {1},
pages = {93-99},
doi = {10.1016/j.ymeth.2012.02.010},
pmid = {22410593},
issn = {1095-9130},
mesh = {Cellular Senescence/drug effects ; *DNA/chemistry/pharmacology ; DNA Damage/drug effects ; *G-Quadruplexes ; Humans ; *Ligands ; *Telomerase/antagonists &amp; inhibitors/chemistry ; *Telomere/chemistry/drug effects ; },
abstract = {The burgeoning knowledge about the structure of telomeres and the roles of various factors involved in telomere maintenance provides several possible targets for pharmacological intervention. To date the area that has received major attention regarding drug discovery is the targeting the telomeric G-quadruplex (G4) structure. G4 ligands were initially designed to counteract telomerase action at telomeres. Surprisingly, their antiproliferative effects can occur in telomerase negative cells and follow kinetics, which cannot be merely explained by telomere shortening, suggesting that these compounds affect other pathways, not necessarily related to telomere biology. Impressively, it has been shown that polyaromatic compounds featuring end-stacking binding properties trigger a strong DNA damage response at telomeres. This is typical of the telomere deprotection occurring during cellular senescence or upon telomere injury. It emerged that the G4-interacting agents are more than simple telomerase inhibitors and that their direct target is rather telomere than telomerase. This review summarizes the most valid experimental approaches for studying the pharmacological telomere damage induced by G4-ligand complexes.},
}
@article {pmid22409744,
year = {2012},
author = {Khalaf, D and Ye, L and Shil, AB},
title = {Telomere length and high-density lipoprotein cholesterol.},
journal = {Journal of the American Geriatrics Society},
volume = {60},
number = {3},
pages = {599},
doi = {10.1111/j.1532-5415.2011.03856.x},
pmid = {22409744},
issn = {1532-5415},
mesh = {Aging/*genetics ; Cholesterol/*blood ; Humans ; Male ; Telomere Shortening/*genetics ; },
}
@article {pmid22407014,
year = {2012},
author = {Hayashi, MT and Cesare, AJ and Fitzpatrick, JA and Lazzerini-Denchi, E and Karlseder, J},
title = {A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest.},
journal = {Nature structural &amp; molecular biology},
volume = {19},
number = {4},
pages = {387-394},
pmid = {22407014},
issn = {1545-9985},
support = {T32 CA009370/CA/NCI NIH HHS/United States ; P30 CA014195-38/CA/NCI NIH HHS/United States ; AG025837/AG/NIA NIH HHS/United States ; R01 GM087476/GM/NIGMS NIH HHS/United States ; P30CA014195-38/CA/NCI NIH HHS/United States ; GM087476/GM/NIGMS NIH HHS/United States ; R01 AG025837/AG/NIA NIH HHS/United States ; R01 AG025837-04/AG/NIA NIH HHS/United States ; 5T32CA009370-29/CA/NCI NIH HHS/United States ; R01 GM087476-03/GM/NIGMS NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins ; Aurora Kinase B ; Aurora Kinases ; *Cell Cycle Checkpoints/drug effects ; Cell Cycle Proteins/metabolism ; Cell Line ; Cells, Cultured ; *DNA Damage ; DNA-Binding Proteins/metabolism ; G1 Phase/drug effects ; Humans ; *Mitosis/drug effects ; Protein Serine-Threonine Kinases/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Tubulin Modulators/pharmacology ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins/metabolism ; Up-Regulation ; },
abstract = {Telomere shortening and disruption of telomeric components are pathways that induce telomere deprotection. Here we describe another pathway, in which prolonged mitotic arrest induces damage signals at telomeres in human cells. Exposure to microtubule drugs, kinesin inhibitors, proteasome inhibitors or the disruption of proper chromosome cohesion resulted in the formation of damage foci at telomeres. Induction of mitotic telomere deprotection coincided with dissociation of TRF2 from telomeres, telomeric 3'-overhang degradation and ATM activation, and deprotection could be suppressed by TRF2 overexpression or inhibition of Aurora B kinase. Normal cells that escaped from prolonged mitotic arrest halted in the following G1 phase, whereas cells lacking p53 continued to cycle and became aneuploid. We propose a telomere-dependent mitotic-duration monitoring system that reacts to improper progression through mitosis.},
}
@article {pmid22396899,
year = {2011},
author = {Hohensinner, PJ and Goronzy, JJ and Weyand, CM},
title = {Telomere dysfunction, autoimmunity and aging.},
journal = {Aging and disease},
volume = {2},
number = {6},
pages = {524-537},
pmid = {22396899},
issn = {2152-5250},
support = {R01 HL117913/HL/NHLBI NIH HHS/United States ; },
abstract = {Immune aging is associated with loss of critical immune functions, such as host protection from infection and malignancy. Unexpectedly, immunosenescence also renders the host susceptible to inflammation, which may translate into tissue-damaging disease as the senescent immune system loses its ability to maximize inflammatory protection while minimizing inflammatory injury. On the other hand, chronic inflammation associated with immune-mediated disease represents a profound stress factor for the immune system, affecting cellular turn-over, replication and exhaustion. Immune cell longevity is tightly connected to the functional integrity of telomeres which are regulated by cell multiplication, exposure to oxidative stress and DNA repair mechanisms. Lymphocytes are amongst the few cell types that can actively elongate telomeres through the action of telomerase. In patients with the autoimmune disease rheumatoid arthritis (RA), telomerase deficiency is associated with prematurity of immune aging. Patients with RA have other defects in DNA repair mechanisms, including the kinase Ataxia telangiectasia mutated (ATM), critically involved in the repair of DNA double strand breaks. ATM deficiency in RA shortens lymphocyte survival. Dynamics of telomeric length and structure are beginning to be understood and have distinct patterns in different autoimmune diseases, suggesting a multitude of molecular mechanisms defining the interface between chronic immune stimulation and progressive aging of the immune system.},
}
@article {pmid22395986,
year = {2012},
author = {Pucciarelli, S and Rampazzo, E and Briarava, M and Maretto, I and Agostini, M and Digito, M and Keppel, S and Friso, ML and Lonardi, S and De Paoli, A and Mescoli, C and Nitti, D and De Rossi, A},
title = {Telomere-specific reverse transcriptase (hTERT) and cell-free RNA in plasma as predictors of pathologic tumor response in rectal cancer patients receiving neoadjuvant chemoradiotherapy.},
journal = {Annals of surgical oncology},
volume = {19},
number = {9},
pages = {3089-3096},
doi = {10.1245/s10434-012-2272-z},
pmid = {22395986},
issn = {1534-4681},
mesh = {Adenocarcinoma/*blood/therapy ; Adult ; Aged ; Aged, 80 and over ; Area Under Curve ; Biomarkers, Tumor/*blood ; Carcinoembryonic Antigen/blood ; Chemoradiotherapy, Adjuvant ; Female ; Humans ; Logistic Models ; Male ; Middle Aged ; Multivariate Analysis ; RNA/*blood ; ROC Curve ; Rectal Neoplasms/*blood/therapy ; Retrospective Studies ; Telomerase/*blood ; Treatment Outcome ; },
abstract = {PURPOSE: To investigate whether the plasma levels of cell-free RNA (cfRNA) and telomere-specific reverse transcriptase mRNA (hTERT) are associated with tumor response in rectal cancer patients who received preoperative chemoradiotherapy (pCRT).<br><br>METHODS: Patients who underwent pCRT for rectal cancer and for whom baseline and paired post-pCRT blood samples were available were studied. On the basis of tumor regression score, patients were classified as having response or having no response. Clinical variables and plasma levels of cfRNA and hTERT before and after the pCRT were evaluated. The association between each predictor and tumor response was assessed by univariate and multivariate analyses.<br><br>RESULTS: Of 98 eligible patients, 45 were determined to respond to therapy, and 53 did not respond to therapy. In univariate analysis, gender (P = 0.040), baseline levels of cfRNA (P = 0.026), post-pCRT levels of both hTERT and cfRNA (P < 0.0001 and P = 0.001, respectively), and the difference between the post- and pre-pCRT levels of both hTERT and cfRNA (P = 0.009 and P = 0.001, respectively) were found to be significant predictors of tumor response. In multivariate analysis, using variables that were available before pCRT, cfRNA levels and gender independently predicted the tumor response, while in multivariate analysis, which used all of the variables available before the surgical procedure, the post-pCRT levels of cfRNA and the difference between the post- and pre-pCRT levels of cfRNA independently predicted tumor response.<br><br>CONCLUSIONS: Plasma levels of cfRNA and hTERT are promising markers of tumor response to pCRT for rectal cancer.},
}
@article {pmid22395926,
year = {2012},
author = {Shiels, PG},
title = {CDKN2A might be better than telomere length in determining individual health status.},
journal = {BMJ (Clinical research ed.)},
volume = {344},
number = {},
pages = {e1415},
doi = {10.1136/bmj.e1415},
pmid = {22395926},
issn = {1756-1833},
mesh = {Aging/*genetics ; Genetic Testing/*methods ; Humans ; *Telomere ; },
}
@article {pmid22391099,
year = {2012},
author = {Zakian, VA},
title = {Telomeres: the beginnings and ends of eukaryotic chromosomes.},
journal = {Experimental cell research},
volume = {318},
number = {12},
pages = {1456-1460},
pmid = {22391099},
issn = {1090-2422},
support = {R01 GM043265/GM/NIGMS NIH HHS/United States ; R01 GM043265-22/GM/NIGMS NIH HHS/United States ; R37 GM026938/GM/NIGMS NIH HHS/United States ; R37 GM026938-30/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromosomes/*chemistry/genetics/metabolism/ultrastructure ; Eukaryota/*genetics ; History, 20th Century ; History, 21st Century ; Humans ; Molecular Biology/history ; Telomere/chemistry/metabolism/*physiology ; },
abstract = {The ends of eukaryotic chromosomes are called telomeres. This article provides a short history of telomere and telomerase research starting with the pioneering work of Muller and McClintock through the molecular era of telomere biology. These studies culminated in the 2009 Nobel Prize in Medicine. Critical findings that moved the field forward and that suggest directions for future research are emphasized.},
}
@article {pmid22390679,
year = {2012},
author = {Sheng, X and Zhang, L and Luo, D and Tong, N and Wang, M and Fang, Y and Li, J and Zhang, Z},
title = {A common variant near TERC and telomere length are associated with susceptibility to childhood acute lymphoblastic leukemia in Chinese.},
journal = {Leukemia &amp; lymphoma},
volume = {53},
number = {9},
pages = {1688-1692},
doi = {10.3109/10428194.2012.671482},
pmid = {22390679},
issn = {1029-2403},
mesh = {Asian People/genetics ; Case-Control Studies ; Child ; China ; Chromosomes, Human, Pair 3/genetics ; Female ; Gene Frequency ; Genetic Predisposition to Disease/*genetics ; Genotype ; Humans ; Logistic Models ; Male ; Multivariate Analysis ; Odds Ratio ; Polymorphism, Single Nucleotide ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/ethnology/*genetics ; RNA/*genetics ; Risk Factors ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {Telomeres are involved in maintaining chromosomal stability, cellular immortality and tumorigenesis. A recent genome-wide association study has identified an association between telomere length and two common variants (rs12696304 and rs16847897) at 3q26 that includes TERC. We hypothesized that the two variants and relative telomere length (RTL) would be predictors of the risk of childhood acute lymphoblastic leukemia (ALL). A case-control study of 570 cases and 673 cancer-free controls among Chinese children was performed. We found that there was a protective relationship between the second and third quartiles of RTL and risk of ALL [adjusted odds ratio (OR) with 95% confidence interval (95% CI) by quartile: 0.65 (0.47-0.91), 0.56 (0.40-0.79)], compared with the first quartile (shortest) RTL. Moreover, rs16847897 CG genotype increased the risk of childhood ALL by 29% compared with the CC genotype. Our findings indicate that extreme telomere length may be a potential predictor for future risk of ALL, and TERC rs16847897 may contribute to the development of childhood ALL.},
}
@article {pmid22389464,
year = {2012},
author = {Ludlow, AT and Witkowski, S and Marshall, MR and Wang, J and Lima, LC and Guth, LM and Spangenburg, EE and Roth, SM},
title = {Chronic exercise modifies age-related telomere dynamics in a tissue-specific fashion.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {67},
number = {9},
pages = {911-926},
pmid = {22389464},
issn = {1758-535X},
support = {T32 AG000268/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*genetics/physiology ; Animals ; Base Sequence ; DNA Primers/genetics ; DNA Repair ; Female ; Gene Expression ; Liver/metabolism ; Male ; Mice ; Muscle, Skeletal/metabolism ; Myocardium/metabolism ; Physical Exertion/*genetics/physiology ; Telomerase/metabolism ; Telomere Shortening/*genetics/physiology ; Telomeric Repeat Binding Protein 1/metabolism ; Tissue Distribution ; },
abstract = {We evaluated the impact of long-term exercise on telomere dynamics in wild-derived short telomere mice (CAST/Ei) over 1 year. We observed significant telomere shortening in liver and cardiac tissues in sedentary 1-year-old mice compared with young (8 weeks) baseline mice that were attenuated in exercised 1-year-old animals. In contrast, skeletal muscle exhibited significant telomere shortening in exercise mice compared with sedentary and young mice. Telomerase enzyme activity was increased in skeletal muscle of exercise compared with sedentary animals but was similar in cardiac and liver tissues. We observed significant age-related decreases in expression of telomere-related genes that were attenuated by exercise in cardiac and skeletal muscle but not liver. Protein content of TRF1 was significantly increased in plantaris muscle with age. In summary, long-term exercise altered telomere dynamics, slowing age-related decreases in telomere length in cardiac and liver tissue but contributing to shortening in exercised skeletal muscle.},
}
@article {pmid22387016,
year = {2012},
author = {Polvi, A and Linnankivi, T and Kivelä, T and Herva, R and Keating, JP and Mäkitie, O and Pareyson, D and Vainionpää, L and Lahtinen, J and Hovatta, I and Pihko, H and Lehesjoki, AE},
title = {Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts.},
journal = {American journal of human genetics},
volume = {90},
number = {3},
pages = {540-549},
pmid = {22387016},
issn = {1537-6605},
support = {RC2 HL102926/HL/NHLBI NIH HHS/United States ; HL-102924/HL/NHLBI NIH HHS/United States ; RC2 HL102924/HL/NHLBI NIH HHS/United States ; HL-102926/HL/NHLBI NIH HHS/United States ; HL-102925/HL/NHLBI NIH HHS/United States ; RC2 HL103010/HL/NHLBI NIH HHS/United States ; HL-102923/HL/NHLBI NIH HHS/United States ; 098051/WT_/Wellcome Trust/United Kingdom ; RC2 HL102923/HL/NHLBI NIH HHS/United States ; UC2 HL102926/HL/NHLBI NIH HHS/United States ; UC2 HL103010/HL/NHLBI NIH HHS/United States ; HL-103010/HL/NHLBI NIH HHS/United States ; UC2 HL102923/HL/NHLBI NIH HHS/United States ; UC2 HL102924/HL/NHLBI NIH HHS/United States ; RC2 HL102925/HL/NHLBI NIH HHS/United States ; UC2 HL102925/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age of Onset ; Amino Acid Sequence ; Calcification, Physiologic/*genetics ; Cerebral Small Vessel Diseases/*genetics/metabolism/pathology ; Child ; Child, Preschool ; Cysts/*genetics/metabolism/pathology ; Exome ; Exons ; Female ; Heterozygote ; Humans ; Infant ; Infant, Newborn ; Male ; Molecular Sequence Data ; *Mutation ; Pedigree ; Phenotype ; Sequence Analysis, DNA/methods ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics ; Young Adult ; },
abstract = {Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is a rare multisystem disorder characterized by extensive intracranial calcifications and cysts, leukoencephalopathy, and retinal vascular abnormalities. Additional features include poor growth, skeletal and hematological abnormalities, and recurrent gastrointestinal bleedings. Autosomal-recessive inheritance has been postulated. The pathogenesis of CRMCC is unknown, but its phenotype has key similarities with Revesz syndrome, which is caused by mutations in TINF2, a gene encoding a member of the telomere protecting shelterin complex. After a whole-exome sequencing approach in four unrelated individuals with CRMCC, we observed four recessively inherited compound heterozygous mutations in CTC1, which encodes the CTS telomere maintenance complex component 1. Sanger sequencing revealed seven more compound heterozygous mutations in eight more unrelated affected individuals. Two individuals who displayed late-onset cerebral findings, a normal fundus appearance, and no systemic findings did not have CTC1 mutations, implying that systemic findings are an important indication for CTC1 sequencing. Of the 11 mutations identified, four were missense, one was nonsense, two resulted in in-frame amino acid deletions, and four were short frameshift-creating deletions. All but two affected individuals were compound heterozygous for a missense mutation and a frameshift or nonsense mutation. No individuals with two frameshift or nonsense mutations were identified, which implies that severe disturbance of CTC1 function from both alleles might not be compatible with survival. Our preliminary functional experiments did not show evidence of severely affected telomere integrity in the affected individuals. Therefore, determining the underlying pathomechanisms associated with deficient CTC1 function will require further studies.},
}
@article {pmid22386580,
year = {2013},
author = {Savela, S and Saijonmaa, O and Strandberg, TE and Koistinen, P and Strandberg, AY and Tilvis, RS and Pitkälä, KH and Miettinen, TA and Fyhrquist, F},
title = {Physical activity in midlife and telomere length measured in old age.},
journal = {Experimental gerontology},
volume = {48},
number = {1},
pages = {81-84},
doi = {10.1016/j.exger.2012.02.003},
pmid = {22386580},
issn = {1873-6815},
mesh = {Adult ; Aging/*genetics/physiology ; Blotting, Southern ; Follow-Up Studies ; Humans ; Leukocytes/ultrastructure ; Male ; Middle Aged ; Motor Activity/*genetics/physiology ; Telomere Homeostasis/*physiology ; Telomere Shortening/physiology ; },
abstract = {Physical activity has been associated with alterations in telomere length, a potential indicator of biological aging, but several inconsistencies exist. Our aim was to investigate the associations between physical activity in midlife and leukocyte telomere length (LTL) measured in old age in the Helsinki Businessmen Study, Finland. At entry, in 1974, 782 men (mean age 47) completed a questionnaire about their physical activity and this was collapsed into 3 categories: low (n=148), moderate (n=398) and high physical activity (n=236, 7 of whom had a competitive activity level). After 29-year follow-up in 2003, mean LTL and the proportion of short (<5 kB) telomeres were measured from DNA samples of a random subcohort of survivors (n=204, mean age 76) using the Southern blot technique. Adjusted for age, body mass index (BMI), cholesterol and smoking in 1974, the moderate physical activity group had longer mean LTL (8.27 kB, SE 0.05) than the low (8.10 kB, SE 0.07), or high (8.10 kB, SE 0.05) physical activity groups (P=0.03 between groups). Conversely, the proportion of short telomeres was lowest in the moderate physical activity group (11.35%, SE 0.25), and higher in the high (12.39%, SE 0.29), and the low physical activity (12.21%, SE 0.39) groups (P=0.02 between groups). We conclude that the results of this observational cohort study give support to the idea that both low and high physical activity is in the long-term associated with factors shortening LTL.},
}
@article {pmid22384354,
year = {2011},
author = {Brown, AN and Lauter, N and Vera, DL and McLaughlin-Large, KA and Steele, TM and Fredette, NC and Bass, HW},
title = {QTL Mapping and Candidate Gene Analysis of Telomere Length Control Factors in Maize (Zea mays L.).},
journal = {G3 (Bethesda, Md.)},
volume = {1},
number = {6},
pages = {437-450},
pmid = {22384354},
issn = {2160-1836},
abstract = {Telomere length is a quantitative trait important for many cellular functions. Failure to regulate telomere length contributes to genomic instability, cellular senescence, cancer, and apoptosis in humans, but the functional significance of telomere regulation in plants is much less well understood. To gain a better understanding of telomere biology in plants, we used quantitative trait locus (QTL) mapping to identify genetic elements that control telomere length variation in maize (Zea mays L.). For this purpose, we measured the median and mean telomere lengths from 178 recombinant inbred lines of the IBM mapping population and found multiple regions that collectively accounted for 33-38% of the variation in telomere length. Two-way analysis of variance revealed interaction between the quantitative trait loci at genetic bin positions 2.09 and 5.04. Candidate genes within these and other significant QTL intervals, along with select genes known a priori to regulate telomere length, were tested for correlations between expression levels and telomere length in the IBM population and diverse inbred lines by quantitative real-time PCR. A slight but significant positive correlation between expression levels and telomere length was observed for many of the candidate genes, but Ibp2 was a notable exception, showing instead a negative correlation. A rad51-like protein (TEL-MD_5.04) was strongly supported as a candidate gene by several lines of evidence. Our results highlight the value of QTL mapping plus candidate gene expression analysis in a genetically diverse model system for telomere research.},
}
@article {pmid22384331,
year = {2011},
author = {Chang, HY and Lawless, C and Addinall, SG and Oexle, S and Taschuk, M and Wipat, A and Wilkinson, DJ and Lydall, D},
title = {Genome-wide analysis to identify pathways affecting telomere-initiated senescence in budding yeast.},
journal = {G3 (Bethesda, Md.)},
volume = {1},
number = {3},
pages = {197-208},
pmid = {22384331},
issn = {2160-1836},
support = {075294/WT_/Wellcome Trust/United Kingdom ; BB/C008200/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/F006063/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/F023545/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
abstract = {In telomerase-deficient yeast cells, like equivalent mammalian cells, telomeres shorten over many generations until a period of senescence/crisis is reached. After this, a small fraction of cells can escape senescence, principally using recombination-dependent mechanisms. To investigate the pathways that affect entry into and recovery from telomere-driven senescence, we combined a gene deletion disrupting telomerase (est1Δ) with the systematic yeast deletion collection and measured senescence characteristics in high-throughput assays. As expected, the vast majority of gene deletions showed no strong effects on entry into/exit from senescence. However, around 200 gene deletions behaving similarly to a rad52Δest1Δ archetype (rad52Δ affects homologous recombination) accelerated entry into senescence, and such cells often could not recover growth. A smaller number of strains similar to a rif1Δest1Δ archetype (rif1Δ affects proteins that bind telomeres) accelerated entry into senescence but also accelerated recovery from senescence. Our genome-wide analysis identifies genes that affect entry into and/or exit from telomere-initiated senescence and will be of interest to those studying telomere biology, replicative senescence, cancer, and ageing. Our dataset is complementary to other high-throughput studies relevant to telomere biology, genetic stability, and DNA damage responses.},
}
@article {pmid22379092,
year = {2012},
author = {Shamay, M and Liu, J and Li, R and Liao, G and Shen, L and Greenway, M and Hu, S and Zhu, J and Xie, Z and Ambinder, RF and Qian, J and Zhu, H and Hayward, SD},
title = {A protein array screen for Kaposi's sarcoma-associated herpesvirus LANA interactors links LANA to TIP60, PP2A activity, and telomere shortening.},
journal = {Journal of virology},
volume = {86},
number = {9},
pages = {5179-5191},
pmid = {22379092},
issn = {1098-5514},
support = {R21CA138163/CA/NCI NIH HHS/United States ; R01 GM076102/GM/NIGMS NIH HHS/United States ; U54 RR020839/RR/NCRR NIH HHS/United States ; U54 GM103520/GM/NIGMS NIH HHS/United States ; P01CA113239/CA/NCI NIH HHS/United States ; RR020839/RR/NCRR NIH HHS/United States ; GM076102/GM/NIGMS NIH HHS/United States ; R21 CA138163/CA/NCI NIH HHS/United States ; P30CA006973/CA/NCI NIH HHS/United States ; P01 CA113239/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; },
mesh = {Antigens, Viral/genetics/*metabolism ; Cell Line ; Gene Expression ; HMGA Proteins/metabolism ; HMGB1 Protein/metabolism ; Histone Acetyltransferases/*metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Lysine Acetyltransferase 5 ; Nuclear Proteins/genetics/*metabolism ; Protein Array Analysis ; Protein Binding ; Protein Phosphatase 2/*metabolism ; Replication Protein A/metabolism ; Telomere/metabolism ; *Telomere Shortening/genetics ; Telomeric Repeat Binding Protein 1/metabolism ; Xeroderma Pigmentosum Group A Protein/metabolism ; },
abstract = {The Kaposi's sarcoma-associated herpesvirus (KSHV) LANA protein functions in latently infected cells as an essential participant in KSHV genome replication and as a driver of dysregulated cell growth. To identify novel LANA protein-cell protein interactions that could contribute to these activities, we performed a proteomic screen in which purified, adenovirus-expressed Flag-LANA protein was incubated with an array displaying 4,192 nonredundant human proteins. Sixty-one interacting cell proteins were consistently detected. LANA interactions with high-mobility group AT-hook 1 (HMGA1), HMGB1, telomeric repeat binding factor 1 (TRF1), xeroderma pigmentosum complementation group A (XPA), pygopus homolog 2 (PYGO2), protein phosphatase 2A (PP2A)B subunit, Tat-interactive protein 60 (TIP60), replication protein A1 (RPA1), and RPA2 proteins were confirmed in coimmunoprecipitation assays. LANA-associated TIP60 retained acetyltransferase activity and, unlike human papillomavirus E6 and HIV-1 TAT proteins, LANA did not reduce TIP60 stability. The LANA-bound PP2A B subunit was associated with the PP2A A subunit but not the catalytic C subunit, suggesting a disruption of PP2A phosphatase activity. This is reminiscent of the role of simian virus 40 (SV40) small t antigen. Chromatin immunoprecipitation (ChIP) assays showed binding of RPA1 and RPA2 to the KSHV terminal repeats. Interestingly, LANA expression ablated RPA1 and RPA2 binding to the cell telomeric repeats. In U2OS cells that rely on the alternative mechanism for telomere maintenance, LANA expression had minimal effect on telomere length. However, LANA expression in telomerase immortalized endothelial cells resulted in telomere shortening. In KSHV-infected cells, telomere shortening may be one more mechanism by which LANA contributes to the development of malignancy.},
}
@article {pmid22377634,
year = {2012},
author = {Paschini, M and Toro, TB and Lubin, JW and Braunstein-Ballew, B and Morris, DK and Lundblad, V},
title = {A naturally thermolabile activity compromises genetic analysis of telomere function in Saccharomyces cerevisiae.},
journal = {Genetics},
volume = {191},
number = {1},
pages = {79-93},
pmid = {22377634},
issn = {1943-2631},
support = {P30 CA014195/CA/NCI NIH HHS/United States ; R01 GM055867/GM/NIGMS NIH HHS/United States ; GM55867/GM/NIGMS NIH HHS/United States ; P30-CA014195/CA/NCI NIH HHS/United States ; },
mesh = {Alleles ; Microbial Viability ; Mutagenesis ; Mutation ; Phenotype ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/cytology/*genetics/growth &amp; development/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism ; Telomere/*genetics/*metabolism ; Telomere Shortening ; *Temperature ; },
abstract = {The core assumption driving the use of conditional loss-of-function reagents such as temperature-sensitive mutations is that the resulting phenotype(s) are solely due to depletion of the mutant protein under nonpermissive conditions. However, prior published data, combined with observations presented here, challenge the generality of this assumption at least for telomere biology: for both wild-type yeast and strains bearing null mutations in telomere protein complexes, there is an additional phenotypic consequence when cells are grown above 34°. We propose that this synthetic phenotype is due to a naturally thermolabile activity that confers a telomere-specific defect, which we call the Tmp(-) phenotype. This prompted a re-examination of commonly used cdc13-ts and stn1-ts mutations, which indicates that these alleles are instead hypomorphic mutations that behave as apparent temperature-sensitive mutations due to the additive effects of the Tmp(-) phenotype. We therefore generated new cdc13-ts reagents, which are nonpermissive below 34°, to allow examination of cdc13-depleted phenotypes in the absence of this temperature-dependent defect. A return-to-viability experiment following prolonged incubation at 32°, 34°, and 36° with one of these new cdc13-ts alleles argues that the accelerated inviability previously observed at 36° in cdc13-1 rad9-Δ mutant strains is a consequence of the Tmp(-) phenotype. Although this study focused on telomere biology, viable null mutations that confer inviability at 36° have been identified for multiple cellular pathways. Thus, phenotypic analysis of other aspects of yeast biology may similarly be compromised at high temperatures by pathway-specific versions of the Tmp(-) phenotype.},
}
@article {pmid22376119,
year = {2012},
author = {Xu, Y},
title = {Human telomere RNA: a potential target for ligand recognition.},
journal = {Current pharmaceutical design},
volume = {18},
number = {14},
pages = {2096-2101},
doi = {10.2174/138161212799958378},
pmid = {22376119},
issn = {1873-4286},
mesh = {Drug Design ; *G-Quadruplexes ; Humans ; Ligands ; RNA/*chemistry/physiology ; Telomere/*chemistry/physiology ; },
abstract = {A recent finding demonstrated that telomere DNA is transcribed into telomeric repeat-containing RNA (referred to as TERRA) in mammalian cells. The existence of TERRA RNA may reveal a new level of regulation and protection of chromosome ends that could promote valuable insight into fundamental biological processes such as cancer and aging. Revealing the structure and function of telomere RNA will be essential for understanding telomere biology and telomere-related diseases. In fact, others and we have shown by NMR and x-ray crystallography that human telomere RNA forms G-quadruplex structures. More recently, we found that human telomere RNA forms a G-quadruplex dimer in the living cells by employing a light-switching probe. Recently, researches concerning the telomere RNA G-quadruplexes have made much progress. This review highlights the structures and topologies for telomere RNA G-quadruplex and recent efforts in the design of telomere RNA G-quadruplex ligands; outlines the future challenges in the field.},
}
@article {pmid22376109,
year = {2012},
author = {Juranek, SA and Paeschke, K},
title = {Cell cycle regulation of G-quadruplex DNA structures at telomeres.},
journal = {Current pharmaceutical design},
volume = {18},
number = {14},
pages = {1867-1872},
doi = {10.2174/138161212799958404},
pmid = {22376109},
issn = {1873-4286},
mesh = {*Cell Cycle ; DNA/*chemistry ; *G-Quadruplexes ; Humans ; *Telomere ; Telomere-Binding Proteins/chemistry ; },
abstract = {DNA and RNA regions containing tracts of guanines can form very stable secondary structures called G-quadruplex (G4). Genomic sequences with the potential to form G4 (G4-motifs) are abundant across species. In all analyzed genomes G4 motifs are found near promoter regions and double strand break sites and at telomeres. Telomeres are very G-rich and prone for G4 formation. Therefore they are routinely used in in vitro and in vivo experiments to elucidate the function of G4 structures in telomere metabolism. Recently various labs demonstrated that telomere length maintenance is mediated via G4 structures. Telomere-binding proteins specifically bind to G4 structure and regulate this structure throughout the cell cycle.},
}
@article {pmid22375401,
year = {2011},
author = {Zhou, Y and Jiang, R and Yang, B and Yao, X and Wang, P and Liu, D and Wang, Y},
title = {[Changes of telomere and telomerase in effect of ginsenoside Rg1 to delay hematopoietic stem cell senescence].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {36},
number = {22},
pages = {3172-3175},
pmid = {22375401},
issn = {1001-5302},
mesh = {Cellular Senescence/*drug effects ; Ginsenosides/*pharmacology ; Hematopoietic Stem Cells/*drug effects/physiology ; Telomerase/*metabolism ; Telomere/*drug effects ; },
abstract = {OBJECTIVE: To investigate the roles of telomere and telomerase in the effect of ginsenoside Rg1 to delay hematopoietic stem cell senescence.<br><br>METHOD: Sca-1(+) HSC was isolated by magnetic cell sorting(MACS) and divided into five groups: the control group, the aged model group, the Rg1 group, the Rg1 treated aged group and the Rg1 delayed aged group. The changes of cells were observed by senescence-associated beta-Galactosidase (SA-beta-Gal) staining. Cell cycle assay and culture of mixed hematopoietic progenitor cell were used to investigate the effect of ginsenoside Rg1 to delay Sca-1(+) HSC senescence. Telomere length and telomerase activity were detected by southern blotting and TRAP-PCR-SYBR Green staining.<br><br>RESULT: Compared with aged model group, the percentage of positive cells expressed SA-beta-Gal and the number of cells entered G1 phase were decreased and the number of colony of mixed hematopoietic progenitor was increased. It showed markedly decreased in the shortening of telomere length and reinforcing in the telomerase activity to Rg1 treated aged group and Rg1 delayed aged group. The change of Rg1 delayed aged group was significantly higher than Rg1 treated aged group.<br><br>CONCLUSION: Activation of telomerase and prolonging of telomere length might be involved in the process of ginsenoside Rg1 to delay and treat the senescence of Sca-1(+) HSC.},
}
@article {pmid22374245,
year = {2012},
author = {Guan, JZ and Guan, WP and Maeda, T and Makino, N},
title = {Alteration of telomere length and subtelomeric methylation in human endothelial cell under different levels of hypoxia.},
journal = {Archives of medical research},
volume = {43},
number = {1},
pages = {15-20},
doi = {10.1016/j.arcmed.2012.02.001},
pmid = {22374245},
issn = {1873-5487},
mesh = {Cell Hypoxia ; Cell Proliferation ; Cultured Milk Products ; *DNA Methylation ; Human Umbilical Vein Endothelial Cells/enzymology/*metabolism ; Humans ; Telomerase/metabolism ; *Telomere Homeostasis ; },
abstract = {BACKGROUND AND AIMS: Hypoxia-associated changes of telomeric structure in cell cultures have been analyzed mainly in cancer cells, stem cells, or cells transduced with vectors containing the telomerase gene, but not in somatic cells. The stability of telomere structure has been reported to be associated with subtelomeric methylation status. However, there are no reports of epigenetic alterations of telomeric regions of human somatic cells under hypoxia. This study aims at detecting and analyzing the subtelomeric methylation status in human somatic cells cultured under hypoxia.<br><br>METHODS: Mean telomere length and telomerase activity of human umbilical vein endothelial cells (HUVECs) cultured in hypoxic conditions were measured. Subtelomeric methylation status of these cells was assessed by genomic Southern blot with telomere DNA probe using methylation-sensitive and -insensitive isoschizomers, MspI and HpaII.<br><br>RESULTS: The telomerase activity in HUVECs correlated inversely with the oxygen concentration. Mild hypoxia (10 or 15% oxygen) increased the telomere lengths, whereas the telomere lengths did not appear to change when <1% O(2). The subtelomere of the shortest telomere range was methylated the most at 1% O(2).<br><br>CONCLUSIONS: Subtelomeric hypermethylation of short telomeres at 1% O(2) compared to milder hypoxia implied that the subtelomeric hypermethylation may yield telomere stability and favor the cell survival of short telomere-bearing cells.},
}
@article {pmid22373525,
year = {2012},
author = {Flynn, RL and Chang, S and Zou, L},
title = {RPA and POT1: friends or foes at telomeres?.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {11},
number = {4},
pages = {652-657},
pmid = {22373525},
issn = {1551-4005},
support = {R01 CA129037/CA/NCI NIH HHS/United States ; R01 GM076388/GM/NIGMS NIH HHS/United States ; GM076388/GM/NIGMS NIH HHS/United States ; CA129037/CA/NCI NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle/genetics/physiology ; Cell Cycle Proteins/genetics/metabolism ; Humans ; Models, Biological ; Protein Serine-Threonine Kinases/genetics/metabolism ; Replication Protein A/genetics/*metabolism ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Telomere maintenance in cycling cells relies on both DNA replication and capping by the protein complex shelterin. Two single-stranded DNA (ssDNA)-binding proteins, replication protein A (RPA) and protection of telomere 1 (POT1) play critical roles in DNA replication and telomere capping, respectively. While RPA binds to ssDNA in a non-sequence-specific manner, POT1 specifically recognizes singlestranded TTAGGG telomeric repeats. Loss of POT1 leads to aberrant accumulation of RPA at telomeres and activation of the ataxia telangiectasia and Rad3-related kinase (ATR)-mediated checkpoint response, suggesting that POT1 antagonizes RPA binding to telomeric ssDNA. The requirement for both POT1 and RPA in telomere maintenance and the antagonism between the two proteins raises the important question of how they function in concert on telomeric ssDNA. Two interesting models were proposed by recent studies to explain the regulation of POT1 and RPA at telomeres. Here, we discuss how these models help unravel the coordination, and also the antagonism, between POT1 and RPA during the cell cycle.},
}
@article {pmid22371573,
year = {2012},
author = {Tan, TC and Rahman, R and Jaber-Hijazi, F and Felix, DA and Chen, C and Louis, EJ and Aboobaker, A},
title = {Telomere maintenance and telomerase activity are differentially regulated in asexual and sexual worms.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {109},
number = {11},
pages = {4209-4214},
pmid = {22371573},
issn = {1091-6490},
support = {BB/E01030X/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; G0601133/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Alternative Splicing/genetics ; Animals ; *Gene Expression Regulation ; Germ Cells/metabolism ; In Situ Hybridization ; Molecular Sequence Data ; Planarians/*enzymology/*genetics/growth &amp; development ; RNA Interference ; RNA, Messenger/genetics/metabolism ; Regeneration/genetics ; Reproduction, Asexual/*genetics ; Stem Cells/cytology/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {In most sexually reproducing animals, replication and maintenance of telomeres occurs in the germ line and during early development in embryogenesis through the use of telomerase. Somatic cells generally do not maintain telomere sequences, and these cells become senescent in adults as telomeres shorten to a critical length. Some animals reproduce clonally and must therefore require adult somatic mechanisms for maintaining their chromosome ends. Here we study the telomere biology of planarian flatworms with apparently limitless regenerative capacity fueled by a population of highly proliferative adult stem cells. We show that somatic telomere maintenance is different in asexual and sexual animals. Asexual animals maintain telomere length somatically during reproduction by fission or when regeneration is induced by amputation, whereas sexual animals only achieve telomere elongation through sexual reproduction. We demonstrate that this difference is reflected in the expression and alternate splicing of the protein subunit of the telomerase enzyme. Asexual adult planarian stem cells appear to maintain telomere length over evolutionary timescales without passage through a germ-line stage. The adaptations we observe demonstrate indefinite somatic telomerase activity in proliferating stem cells during regeneration or reproduction by fission, and establish planarians as a pertinent model for studying telomere structure, function, and maintenance.},
}
@article {pmid22369941,
year = {2012},
author = {Xiao, N and Chen, S and Ma, Y and Qiu, J and Tan, JH and Ou, TM and Gu, LQ and Huang, ZS and Li, D},
title = {Interaction of Berberine derivative with protein POT1 affect telomere function in cancer cells.},
journal = {Biochemical and biophysical research communications},
volume = {419},
number = {3},
pages = {567-572},
doi = {10.1016/j.bbrc.2012.02.063},
pmid = {22369941},
issn = {1090-2104},
mesh = {Antineoplastic Agents/chemistry/*metabolism/pharmacology ; Berberine/*analogs &amp; derivatives/metabolism/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chromatin Immunoprecipitation ; Cloning, Molecular ; DNA, Single-Stranded/metabolism ; Drug Design ; Fluorescence Resonance Energy Transfer ; G-Quadruplexes ; Humans ; Ligands ; Neoplasms/genetics/*metabolism ; Recombinant Proteins/genetics/metabolism ; Shelterin Complex ; Telomerase/antagonists &amp; inhibitors ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {The protein POT1 plays an important role in telomere protection, which is related with telomere elongation and cell immortality. The protein has been recognized as a promising drug target for cancer treatment. In the present study, we cloned, overexpressed in Escherichia coli for the first time, and purified recombinant human POT1. The protein was proved to be active through filter binding assay, FRET and CD experiments. In the initial screening for protein binding ligands using SPR, compound Sysu-00692 was found to bind well with the POT1, which was confirmed with EMSA. Its in vivo activity study showed that compound Sysu-00692 could interfere with the binding between human POT1 and the telomeric DNA through chromatin immunoprecipitation. Besides, the compound showed mild inhibition on telomerase and cell proliferation. As we know, compound Sysu-00692 is the first reported POT1-binding ligand, which could serve as a lead compound for further improvement. This work offered a potentially new approach for drug design for the treatment of cancers.},
}
@article {pmid22366562,
year = {2012},
author = {Ponsot, E and Echaniz-Laguna, A and Delis, AM and Kadi, F},
title = {Telomere length and regulatory proteins in human skeletal muscle with and without ongoing regenerative cycles.},
journal = {Experimental physiology},
volume = {97},
number = {6},
pages = {774-784},
doi = {10.1113/expphysiol.2011.063818},
pmid = {22366562},
issn = {1469-445X},
mesh = {Female ; Humans ; Male ; Middle Aged ; Muscle, Skeletal/*metabolism ; Shelterin Complex ; Tankyrases/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; },
abstract = {New insights suggest the existence of telomere regulatory mechanisms in several adult tissues. In this study, we aimed to assess in vivo telomere length and the presence of specific proteins involved in telomere regulation in a model of human skeletal muscle with (patients with dermatomyosis or polymyositis) and without ongoing regenerative events (healthy subjects). Mean (meanTRF) and minimal telomere (miniTRF) lengths and the expression of telomerase, tankyrase 1, TRF2 (telomeric repeat binding factor 2) and POT1 (protection of telomeres 1) were investigated in skeletal muscle samples from 12 patients (MYO) and 13 healthy subjects (CON). There was no significant shortening of telomeres in skeletal muscle from patients compared with control subjects (MYO, meanTRF length 11.0 ± 1.8 kbp and miniTRF length 4.7 ± 0.8 kbp; CON, meanTRF length 10.4 ± 1.1 kbp and miniTRF length 4.6 ± 0.5 kbp). Theoretically, telomere length can be controlled by endogenous mechanisms. Here, we show for the first time that expression levels of telomerase, tankyrase 1, TRF2 and POT1 were, respectively, six-, seven-, three- and fivefold higher in the nuclear fraction of skeletal muscle of MYO compared with CON (P < 0.05). This suggests the existence of endogenous mechanisms allowing for telomere regulation in skeletal muscle with ongoing cycles of degeneration and regeneration and a model where regulatory factors are possibly involved in the protection of skeletal muscle telomeres.},
}
@article {pmid22364520,
year = {2012},
author = {Maeda, T and Guan, JZ and Koyanagi, M and Higuchi, Y and Makino, N},
title = {Aging-associated alteration of telomere length and subtelomeric status in female patients with Parkinson's disease.},
journal = {Journal of neurogenetics},
volume = {26},
number = {2},
pages = {245-251},
doi = {10.3109/01677063.2011.651665},
pmid = {22364520},
issn = {1563-5260},
mesh = {Aging/*genetics ; Analysis of Variance ; Female ; Humans ; Japan ; Middle Aged ; Parkinson Disease/*genetics/physiopathology ; Retrospective Studies ; Telomere/*genetics ; Telomere Shortening/*genetics ; Telomere-Binding Proteins/genetics ; },
abstract = {A telomere is a repetitive DNA structure at chromosomal ends that stabilizes the chromosome structure and prevents harmful end-to-end recombinations. The telomere length of somatic cells becomes shorter with aging because of the "end replication problem." This telomere shortening is accelerated by pathophysiological conditions including daily mental stress. Living with Parkinson's disease (PD) causes physical and mental stress; therefore, the authors hypothesized that the telomere length of somatic cells was shortened excessively in patients with PD. In order to detect PD-associated somatic telomeric alterations, the telomere length and subtelomeric methylation status of peripheral leukocytes of PD patients were assessed by Southern blotting, using methylation-sensitive and -insensitive isoschizomers. The results demonstrated that the peripheral leukocytes of Japanese female patients with PD bore fewer long telomeres and a proportional increase of hypomethylated subtelomeres in short telomeres in comparison with the healthy controls. This study indicates that with the neurodegeneration associated with PD, telomeric and subtelomeric structural alterations occur. These structural telomere alterations most likely occur secondary to the acceleration of aging-associated telomeric changes and the accelerated loss of cells bearing short telomeres.},
}
@article {pmid22364217,
year = {2012},
author = {Tsang, AR and Wyatt, HD and Ting, NS and Beattie, TL},
title = {hTERT mutations associated with idiopathic pulmonary fibrosis affect telomerase activity, telomere length, and cell growth by distinct mechanisms.},
journal = {Aging cell},
volume = {11},
number = {3},
pages = {482-490},
doi = {10.1111/j.1474-9726.2012.00810.x},
pmid = {22364217},
issn = {1474-9726},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Aged, 80 and over ; Aging, Premature/enzymology/genetics/metabolism ; Amino Acid Sequence ; Cell Growth Processes/physiology ; Cell Line ; Fibroblasts/cytology ; Humans ; Idiopathic Pulmonary Fibrosis/*enzymology/*genetics/pathology ; Kidney/cytology ; Molecular Sequence Data ; *Mutation ; Telomerase/*genetics/*metabolism ; },
abstract = {Telomerase is a ribonucleoprotein reverse transcriptase (RT) that synthesizes specific DNA repeats, or telomeric DNA, at the ends of chromosomes. Telomerase is minimally composed of a protein subunit, TERT, and an RNA component, TR. Aberrant telomerase activity has been associated with most human cancers and several premature aging diseases, such as idiopathic pulmonary fibrosis (IPF), a chronic, progressive, and fatal lung disease characterized by alveolar epithelial cell damage and fibrosis. Our study focuses on three hTERT mutations that were identified in a subset of patients with IPF, in which these patients also exhibited shorter telomeres compared with age-matched controls. We characterized how three IPF-associated hTERT mutations, V144M, R865C, and R865H, affected telomerase function both in vitro and in human cells. We demonstrated that the R865 residue is crucial for repeat addition processivity and thus telomere synthesis in telomerase-positive 293 cells and telomerase-negative BJ cells, consistent with its location in the hTERT nucleotide-binding motif. In contrast, while the V144M mutant did not exhibit any biochemical defects, this mutant was unable to elongate telomeres in human cells. As a result, our studies have identified hTERT V144 and R865 as two critical residues required for proper telomerase function in cells. Together, this may explain how inherited hTERT mutations can lead to shortened telomeres in patients with IPF and, thus, provide further insight into the role of naturally occurring telomerase mutations in the pathophysiology of certain age-related disease states.},
}
@article {pmid22363464,
year = {2012},
author = {Chang, J and Dinney, CP and Huang, M and Wu, X and Gu, J},
title = {Genetic variants in telomere-maintenance genes and bladder cancer risk.},
journal = {PloS one},
volume = {7},
number = {2},
pages = {e30665},
pmid = {22363464},
issn = {1932-6203},
support = {CA74880/CA/NCI NIH HHS/United States ; CA127615/CA/NCI NIH HHS/United States ; U01 CA127615/CA/NCI NIH HHS/United States ; R01 CA131335/CA/NCI NIH HHS/United States ; CA131335/CA/NCI NIH HHS/United States ; CA91846/CA/NCI NIH HHS/United States ; P50 CA091846/CA/NCI NIH HHS/United States ; R01 CA074880/CA/NCI NIH HHS/United States ; },
mesh = {Epistasis, Genetic ; Female ; *Genetic Predisposition to Disease ; *Genetic Variation ; Haplotypes/genetics ; Humans ; Logistic Models ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/genetics ; Risk Factors ; Telomere Homeostasis/*genetics ; Urinary Bladder Neoplasms/*genetics ; },
abstract = {Telomeres are critical in maintaining genomic stability. Genetic variants in telomere pathway genes may affect telomere and telomerase function, and subsequently cancer risk. We evaluated 126 SNPs from 10 genes related to telomere regulation in relation to bladder cancer risk. Five SNPs, 4 from TEP1 gene and 1 from PINX1 gene, were found to be highly significant (P<0.01). Out of these, the most significant association was found in rs2228041 of TEP1 (OR 1.66, 95% CI 1.19-2.31) while rs1469557 of PINX1 had a protective effect (OR 0.75, 95% CI 0.61-0.93). Haplotype analysis showed that a TEP1 haplotype consisting of the variant alleles of 7 SNPs exhibited a 2.28 fold increased risk (95% CI 1.13-4.60). We then performed cumulative analysis of multiple risk variants, as well as Classification and Regression Tree (CART) to look for gene-gene interactions. In cumulative effect analysis, the group with 4-5 risk variants had an OR of 2.57 (95% CI = 1.62-4.09) versus the reference group with 0 risk variants. The CART analysis categorized individuals into five subgroups with different bladder cancer risk profiles based on their distinct genotype background. To our knowledge, this is one of the largest, most comprehensive studies on bladder cancer risk concerning telomere-regulating pathway gene SNPs and our results support that genetic variations of telomere maintenance modulate bladder cancer risk individually and jointly.},
}
@article {pmid22361470,
year = {2012},
author = {Monaghan, P},
title = {Telomeres and longevity.},
journal = {Aging},
volume = {4},
number = {2},
pages = {76-77},
pmid = {22361470},
issn = {1945-4589},
mesh = {Aging/physiology ; Animals ; Finches/physiology ; Humans ; Longevity/*physiology ; Species Specificity ; Telomere Homeostasis/*physiology ; },
}
@article {pmid22357912,
year = {2012},
author = {Arora, R and Brun, CM and Azzalin, CM},
title = {Transcription regulates telomere dynamics in human cancer cells.},
journal = {RNA (New York, N.Y.)},
volume = {18},
number = {4},
pages = {684-693},
pmid = {22357912},
issn = {1469-9001},
mesh = {Base Sequence ; Centromere ; DNA Modification Methylases/metabolism ; DNA Primers ; *Gene Expression Regulation, Neoplastic ; HeLa Cells ; Humans ; Neoplasms/*genetics ; Reverse Transcriptase Polymerase Chain Reaction ; *Telomere ; *Transcription, Genetic ; },
abstract = {Telomeres are nucleoprotein structures capping the physical ends of linear eukaryotic chromosomes. Although largely heterochromatic, telomeres are transcribed into telomeric repeat-containing RNA (TERRA) molecules by RNA polymerase II. The functions associated with telomere transcription and TERRA remain ill defined. Here we show that the transcriptional activity of human telomeres directly regulates their movement during interphase. We find that chemical inhibition of global transcription dampens telomere motion, while global stimulation promotes it. Likewise, when DNA methyltransferase enzymes are deleted to augment telomere transcription, we observe increased telomere movement. Finally, using a cell line engineered with a unique transcriptionally inducible telomere, we show that transcription of one specific telomere stimulates only its own dynamics without overtly affecting its stability or its length. We reveal a new and unforeseen function for telomere transcription as a regulator of telomere motion, and speculate on the intriguing possibility that transcription-dependent telomere motion sustains the maintenance of functional and dysfunctional telomeres.},
}
@article {pmid22357613,
year = {2012},
author = {Boltz, KA and Leehy, K and Song, X and Nelson, AD and Shippen, DE},
title = {ATR cooperates with CTC1 and STN1 to maintain telomeres and genome integrity in Arabidopsis.},
journal = {Molecular biology of the cell},
volume = {23},
number = {8},
pages = {1558-1568},
pmid = {22357613},
issn = {1939-4586},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; GM065383/GM/NIGMS NIH HHS/United States ; },
mesh = {Arabidopsis/genetics/metabolism ; Arabidopsis Proteins/*genetics/*metabolism ; Ataxia Telangiectasia Mutated Proteins ; Bleomycin/pharmacology ; Cell Cycle Proteins/genetics/*metabolism ; Chromosomal Proteins, Non-Histone/*metabolism ; DNA Repair ; Genome ; Genomic Instability ; Genotype ; Plants, Genetically Modified ; Protein Serine-Threonine Kinases/*genetics/*metabolism ; Telomerase/metabolism ; Telomere/physiology ; *Telomere Homeostasis ; Telomere Shortening ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {The CTC1/STN1/TEN1 (CST) complex is an essential constituent of plant and vertebrate telomeres. Here we show that CST and ATR (ataxia telangiectasia mutated [ATM] and Rad3-related) act synergistically to maintain telomere length and genome stability in Arabidopsis. Inactivation of ATR, but not ATM, temporarily rescued severe morphological phenotypes associated with ctc1 or stn1. Unexpectedly, telomere shortening accelerated in plants lacking CST and ATR. In first-generation (G1) ctc1 atr mutants, enhanced telomere attrition was modest, but in G2 ctc1 atr, telomeres shortened precipitously, and this loss coincided with a dramatic decrease in telomerase activity in G2 atr mutants. Zeocin treatment also triggered a reduction in telomerase activity, suggesting that the prolonged absence of ATR leads to a hitherto-unrecognized DNA damage response (DDR). Finally, our data indicate that ATR modulates DDR in CST mutants by limiting chromosome fusions and transcription of DNA repair genes and also by promoting programmed cell death in stem cells. We conclude that the absence of CST in Arabidopsis triggers a multifaceted ATR-dependent response to facilitate maintenance of critically shortened telomeres and eliminate cells with severe telomere dysfunction.},
}
@article {pmid22356715,
year = {2011},
author = {Wang, W and Li, ZT and Zhu, HS and Zhao, Y and Wang, LX and Yan, Z and L, IS and Xu, D and Wu, WD and Wu, YJ and Wu, YM},
title = {[The change of telomere protein in BEAS-2B malignant transformation cell induced by coal tar pitch smoke extracts].},
journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases},
volume = {29},
number = {9},
pages = {678-681},
doi = {10.3760/cma.j.issn.1001-9391.2011.09.011},
pmid = {22356715},
issn = {1001-9391},
mesh = {Cell Line ; Cell Transformation, Neoplastic/*metabolism ; Coal Tar/*toxicity ; Epithelial Cells/cytology/metabolism/*pathology ; Humans ; Repetitive Sequences, Nucleic Acid ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {OBJECTIVE: By testing the changes of telomere binding protein in malignant transformation BEAS-2B cells induced by coal tar pitch smoke extracts, to study the role of protection of telomeres 1 (POT1), telomeric repeat binding factor 1 (TRF1) and TRF2 in tumorgenesis that contact with coal tar pitch.<br><br>METHODS: The BEAS-2B cells were induced by coal tar pitch smoke extracts to form malignant transformation cell model in vitro. The gene expression levels of mRNA were assessed by real-time quantitative RT-PCR, the protein expression variations were determined by cell culture overslip of immunohistochemical methods.<br><br>RESULTS: In malignant transformation cells, the mRNA expression level (POT1: 0.63 &#xb1; 0.04, TRF1: 0.36 &#xb1; 0.01) and the protein expression level (POT1: 0.36 &#xb1; 0.05, TRF1: 0.09 &#xb1; 0.03) of POT1 and TRF1 was statistically significant decreased compared to that of BEAS-2B group (mRNA: POT1: 1.00 &#xb1; 0.04, TRF1: 1.01 &#xb1; 0.16; protein: POT1: 0.55 &#xb1; 0.07, TRF1: 0.27 &#xb1; 0.07) and DMSO group (mRNA: POT1: 0.89 &#xb1; 0.12, TRF1: 0.90 &#xb1; 0.08; protein: POT1: 0.55 &#xb1; 0.10, TRF1: 0.26 &#xb1; 0.04) (P < 0.05); mRNA expression level (1.45 &#xb1; 0.07) and the protein expression level (0.88 &#xb1; 0.06) of TRF2 was increased compared to that of BEAS-2B group (mRNA: 1.00 &#xb1; 0.07, protein: 0.48 &#xb1; 0.06) and DMSO group (mRNA: 1.00 &#xb1; 0.06, protein: 0.50 &#xb1; 0.06) (P < 0.05).<br><br>CONCLUSION: The change of gene and protein expression level in POT1, TRF1, and TRF2 involved in the process that evolved into malignant transformation in bronchial epithelial cells BEAS-2B induced by coal tar pitch smoke extracts.},
}
@article {pmid22354991,
year = {2012},
author = {Martina, M and Clerici, M and Baldo, V and Bonetti, D and Lucchini, G and Longhese, MP},
title = {A balance between Tel1 and Rif2 activities regulates nucleolytic processing and elongation at telomeres.},
journal = {Molecular and cellular biology},
volume = {32},
number = {9},
pages = {1604-1617},
pmid = {22354991},
issn = {1098-5549},
mesh = {Alleles ; Cell Nucleus/*metabolism ; DNA Breaks, Double-Stranded ; DNA, Fungal/genetics/metabolism ; Enzyme Activation ; Intracellular Signaling Peptides and Proteins/genetics/*metabolism ; Mutation ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Generation of G-strand overhangs at Saccharomyces cerevisiae yeast telomeres depends primarily on the MRX (Mre11-Rad50-Xrs2) complex, which is also necessary to maintain telomere length by recruiting the Tel1 kinase. MRX physically interacts with Rif2, which inhibits both resection and elongation of telomeres. We provide evidence that regulation of telomere processing and elongation relies on a balance between Tel1 and Rif2 activities. Tel1 regulates telomere nucleolytic processing by promoting MRX activity. In fact, the lack of Tel1 impairs MRX-dependent telomere resection, which is instead enhanced by the Tel1-hy909 mutant variant, which causes telomerase-dependent telomere overelongation. The Tel1-hy909 variant is more robustly associated than wild-type Tel1 to double-strand-break (DSB) ends carrying telomeric repeat sequences. Furthermore, it increases the persistence at a DSB adjacent to telomeric repeats of both MRX and Est1, which in turn likely account for the increased telomere resection and elongation in TEL1-hy909 cells. Strikingly, Rif2 is unable to negatively regulate processing and lengthening at TEL1-hy909 telomeres, indicating that the Tel1-hy909 variant overcomes the inhibitory activity exerted by Rif2 on MRX. Altogether, these findings highlight a primary role of Tel1 in overcoming Rif2-dependent negative regulation of MRX activity in telomere resection and elongation.},
}
@article {pmid22353550,
year = {2012},
author = {Hirai, Y and Masutomi, K and Ishikawa, F},
title = {Kinetics of DNA replication and telomerase reaction at a single-seeded telomere in human cells.},
journal = {Genes to cells : devoted to molecular &amp; cellular mechanisms},
volume = {17},
number = {3},
pages = {186-204},
doi = {10.1111/j.1365-2443.2012.01581.x},
pmid = {22353550},
issn = {1365-2443},
mesh = {Bromodeoxyuridine/chemistry ; Chromatin/chemistry/metabolism ; Chromatin Immunoprecipitation/methods ; *DNA Replication ; DNA, Single-Stranded/*biosynthesis/genetics ; HeLa Cells ; Humans ; Kinetics ; S Phase/genetics ; Telomerase/chemistry/*metabolism ; Telomere/*genetics ; },
abstract = {In most cancer cells, telomerase is activated to elongate telomere DNA, thereby ensuring numerous rounds of cell divisions. It is thus important to understand how telomerase and the replication fork react with telomeres in human cells. However, the highly polymorphic and repetitive nature of the nucleotide sequences in human subtelomeric regions hampers the precise analysis of sequential events taking place at telomeres in S phase. Here, we have established HeLa cells harboring a single-seeded telomere abutted by a unique subtelomere DNA sequence, which has enabled us to specifically focus on the seeded telomere. We have also developed a modified chromatin immunoprecipitation (ChIP) method that uses restriction digestion instead of sonication to fragment chromatin DNA (RES-ChIP), and a method for immunoprecipitating 5-bromo-2'-deoxyuridine (BrdU)-labeled single-stranded DNA by incubating DNA with anti-BrdU antibody in the nondenaturing condition. We have shown that DNA replication of the seeded telomere takes place during a relatively narrow time window in S phase, and telomerase synthesizes telomere DNA after the replication. Moreover, we have demonstrated that the telomerase catalytic subunit TERT associates with telomeres before telomere DNA replication. These results provide a temporal and spatial framework for understanding DNA replication and telomerase reaction at human telomeres.},
}
@article {pmid22348177,
year = {2012},
author = {Sampl, S and Pramhas, S and Stern, C and Preusser, M and Marosi, C and Holzmann, K},
title = {Expression of telomeres in astrocytoma WHO grade 2 to 4: TERRA level correlates with telomere length, telomerase activity, and advanced clinical grade.},
journal = {Translational oncology},
volume = {5},
number = {1},
pages = {56-65},
pmid = {22348177},
issn = {1936-5233},
abstract = {Cancer cells bypass replicative senescence, the major barrier to tumor progression, by using telomerase or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms (TMMs). Correlation between ALT and patient survival was demonstrated for high-grade astrocytomas. Transcription from subtelomeres produces telomeric repeat-containing RNA (TERRA), a natural inhibitor of telomerase activity (TA). This led us to evaluate correlations of TERRA and TMM with tumor grade and outcome in astrocytoma patients. SYBR Green real-time reverse transcription-polymerase chain reaction assays for quantitation of total and chromosome 2p and 18p specific TERRA levels were developed. Tumor samples from 46 patients with astrocytoma grade 2 to 4, tissue controls, and cell lines were assessed. TMMs were evaluated by measuring TA and by detecting long telomeres due to ALT. In glioblastoma multiforme (GBM) grade 4, total TERRA levels were similar to cell lines but 14-, 31-, and 313-fold lower compared with grade 3, grade 2, and nonmalignant tissue, respectively. Total TERRA levels differed from chromosomal levels. Low 2p TERRA levels correlated with dense promoter methylation of subtelomeric CpG islands, indicating that TERRA expression in gliomas may be chromosome specific and epigenetically regulated. Total TERRA levels correlated with diagnosis, with low or absent TA and the presence of ALT, and were tentatively associated with favorable patient prognosis in our cohort (P = .06). TA and short telomeres identified a subset of GBM with a median survival of only 14.8 months. TERRA and TA may be prognostic in astrocytic tumors.},
}
@article {pmid22348044,
year = {2012},
author = {Menon, R and Yu, J and Basanta-Henry, P and Brou, L and Berga, SL and Fortunato, SJ and Taylor, RN},
title = {Short fetal leukocyte telomere length and preterm prelabor rupture of the membranes.},
journal = {PloS one},
volume = {7},
number = {2},
pages = {e31136},
pmid = {22348044},
issn = {1932-6203},
mesh = {Female ; Fetal Blood ; Fetal Membranes, Premature Rupture/etiology/*pathology ; Gestational Age ; Humans ; Leukocytes/*ultrastructure ; Oxidative Stress ; Polymerase Chain Reaction ; Pregnancy ; Premature Birth ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Rupture of the fetal membranes is a common harbinger of imminent labor and delivery. Telomere shortening is a surrogate for oxidative stress (OS) and senescence. Fetal leukocyte and placental membrane DNA telomere lengths were evaluated to determine their association with preterm prelabor rupture of the membranes (pPROM) or spontaneous preterm births with intact membranes (PTB), compared to term birth.<br><br>METHODS: Telomere lengths were quantified in cord blood leukocytes (n = 133) from three major groups: 1) pPROM (n = 28), 2) PTB (n = 69) and 3) uncomplicated full term births (controls, n = 35), using real-time quantitative PCR. Placental membrane specimens (n = 18) were used to correlate fetal leukocyte and placental telomere lengths. Telomere length differences among the groups were analyzed by ANOVA. Pearson correlation coefficients determined relationships between leukocyte and placental membrane telomere lengths.<br><br>RESULTS: In pregnancies with intact membranes, fetal leukocyte telomere length was inversely proportional to gestational age. The mean telomere length decreased as gestation progressed, with the shortest at term. pPROM had telomere lengths (9962 &#xb1; 3124 bp) that were significantly shorter than gestational age-matched PTB (11546 &#xb1; 4348 bp, p = 0.04), but comparable to term births (9011 &#xb1; 2497 bp, p = 0.31). Secondary analyses revealed no effects of race (African American vs. Caucasian) or intraamniotic infection on telomere length. A strong Pearson's correlation was noted between fetal leukocyte and placental membrane telomere lengths (&#x3c1; = 0.77; p<0.01).<br><br>CONCLUSIONS: Fetal leukocyte telomere length is reduced in pPROM compared to PTB but is similar to term births. pPROM represents a placental membrane disease likely mediated by OS-induced senescence.},
}
@article {pmid22343724,
year = {2012},
author = {Ribeyre, C and Shore, D},
title = {Anticheckpoint pathways at telomeres in yeast.},
journal = {Nature structural &amp; molecular biology},
volume = {19},
number = {3},
pages = {307-313},
pmid = {22343724},
issn = {1545-9985},
mesh = {DNA Breaks, Double-Stranded ; DNA, Fungal/genetics ; *G2 Phase Cell Cycle Checkpoints ; Protein Binding ; Rad51 Recombinase/genetics/metabolism ; Repressor Proteins/genetics/metabolism ; Saccharomyces cerevisiae/cytology/*enzymology ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomerase/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Telomeres hide (or 'cap') chromosome ends from DNA-damage surveillance mechanisms that arrest the cell cycle and promote repair, but the checkpoint status of telomeres is not well understood. Here we characterize the response in Saccharomyces cerevisiae to DNA double-strand breaks (DSBs) flanked by varying amounts of telomeric repeat sequences (TG(1-3)). We show that even short arrays of TG(1-3) repeats do not induce G2/M arrest. Both Rif1 and Rif2 are required for capping at short, rapidly elongating ends, yet are largely dispensable for protection of longer telomeric arrays. Rif1 and Rif2 act through parallel pathways to block accumulation of both RPA and Rad24, activators of checkpoint kinase Mec1 (ATR). Finally, we show that Rif function is correlated with an 'anticheckpoint' effect, in which checkpoint recovery at an adjacent unprotected end is stimulated, and we provide insight into the molecular mechanism of this phenomenon.},
}
@article {pmid22343648,
year = {2012},
author = {Ding, H and Chen, C and Shaffer, JR and Liu, L and Xu, Y and Wang, X and Hui, R and Wang, DW},
title = {Telomere length and risk of stroke in Chinese.},
journal = {Stroke},
volume = {43},
number = {3},
pages = {658-663},
doi = {10.1161/STROKEAHA.111.637207},
pmid = {22343648},
issn = {1524-4628},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Asian People ; Brain Ischemia/complications ; Case-Control Studies ; Cerebral Hemorrhage/complications ; China/epidemiology ; Confidence Intervals ; Coronary Disease/complications/pathology ; DNA/genetics ; Female ; Follow-Up Studies ; Humans ; Leukocytes/ultrastructure ; Logistic Models ; Male ; Middle Aged ; Odds Ratio ; Predictive Value of Tests ; Prospective Studies ; Recurrence ; Stroke/epidemiology/etiology/*pathology ; Telomere/*diagnostic imaging/*pathology ; Thrombosis/complications ; Ultrasonography ; },
abstract = {BACKGROUND AND PURPOSE: Accumulating evidence suggests that telomere length is a maker for biological aging of the cardiovascular system. Whether stroke is associated with accelerated biological aging as measured by telomere length has not been conclusively demonstrated. Our aim was to determine whether mean leukocyte telomere length is a predictor for the development of stroke.<br><br>METHODS: The relative telomere length of leukocytes was determined by quantitative polymerase chain reaction in 1309 stroke patients and 1309 age- and sex-matched control subjects as well as 858 stroke patients followed prospectively for 5 years. For each measure, the study sample was divided into quartiles. The associations between the telomere length and risk of stroke as well as poststroke adverse outcomes were determined.<br><br>RESULTS: Mean telomere length was significantly shorter in stroke patients than in control subjects. Shorter telomere length levels were directly associated with a higher risk of stroke in the case/control sample. As compared with the fourth (longest) quartile, the odd ratios [OR] (and 95% confidence intervals [CI]) for ischemic stroke risk were as follows: third quartile, 1.37 (1.04-1.82); second quartile, 1.53 (1.17-2.02); and first quartile, 2.12 (1.62-2.77). Follow-up of the patients from the prospective cohort also showed that shorter telomere length levels were associated with mortality from all causes but not with recurrence of stroke.<br><br>CONCLUSIONS: Shorter telomere length was associated with ischemic stroke and was a strong predictor of poststroke death.},
}
@article {pmid22342531,
year = {2012},
author = {Zhang, L and Rong, YS},
title = {Retrotransposons at Drosophila telomeres: host domestication of a selfish element for the maintenance of genome integrity.},
journal = {Biochimica et biophysica acta},
volume = {1819},
number = {7},
pages = {771-775},
pmid = {22342531},
issn = {0006-3002},
support = {ZIA BC010446-09/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Animals ; Chromosomes, Insect/genetics ; Drosophila/*genetics ; Gene Expression Regulation, Developmental ; Genomic Instability ; Humans ; Mutagenesis, Insertional ; RNA, Messenger/genetics/metabolism ; Repetitive Sequences, Nucleic Acid ; *Retroelements ; Telomere/*genetics ; },
abstract = {Telomere serves two essential functions for the cell. It prevents the recognition of natural chromosome ends as DNA breaks (the end capping function). It counteracts incomplete end replication by adding DNA to the ends of chromosomes (the end elongation function). In most organisms studied, telomerase fulfills the end elongation function. In Drosophila, however, telomere specific retrotransposons have been coerced into performing this essential function for the host. In this review, we focus our discussion on transposition mechanisms and transcriptional regulation of these transposable elements, and present provocative models for the purpose of spurring new interests in the field. This article is part of a Special Issue entitled: Chromatin in time and space.},
}
@article {pmid22341455,
year = {2012},
author = {Ding, Z and Wu, CJ and Jaskelioff, M and Ivanova, E and Kost-Alimova, M and Protopopov, A and Chu, GC and Wang, G and Lu, X and Labrot, ES and Hu, J and Wang, W and Xiao, Y and Zhang, H and Zhang, J and Zhang, J and Gan, B and Perry, SR and Jiang, S and Li, L and Horner, JW and Wang, YA and Chin, L and DePinho, RA},
title = {Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases.},
journal = {Cell},
volume = {148},
number = {5},
pages = {896-907},
pmid = {22341455},
issn = {1097-4172},
support = {R01CA084628/CA/NCI NIH HHS/United States ; K99 CA194289/CA/NCI NIH HHS/United States ; U01 CA141508-04/CA/NCI NIH HHS/United States ; R01 CA084628-20/CA/NCI NIH HHS/United States ; R01 CA084628/CA/NCI NIH HHS/United States ; U01 CA141508/CA/NCI NIH HHS/United States ; U01CA141508/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Bone Neoplasms/secondary ; Cell Line, Tumor ; Crosses, Genetic ; DNA Copy Number Variations ; Disease Models, Animal ; Female ; Genomic Instability ; Humans ; Male ; Mice ; Prostatic Neoplasms/*genetics/*pathology ; Telomerase/*metabolism ; Telomere/*metabolism ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {To determine the role of telomere dysfunction and telomerase reactivation in generating pro-oncogenic genomic events and in carcinoma progression, an inducible telomerase reverse transcriptase (mTert) allele was crossed onto a prostate cancer-prone mouse model null for Pten and p53 tumor suppressors. Constitutive telomerase deficiency and associated telomere dysfunction constrained cancer progression. In contrast, telomerase reactivation in the setting of telomere dysfunction alleviated intratumoral DNA-damage signaling and generated aggressive cancers with rearranged genomes and new tumor biological properties (bone metastases). Comparative oncogenomic analysis revealed numerous recurrent amplifications and deletions of relevance to human prostate cancer. Murine tumors show enrichment of the TGF-β/SMAD4 network, and genetic validation studies confirmed the cooperative roles of Pten, p53, and Smad4 deficiencies in prostate cancer progression, including skeletal metastases. Thus, telomerase reactivation in tumor cells experiencing telomere dysfunction enables full malignant progression and provides a mechanism for acquisition of cancer-relevant genomic events endowing new tumor biological capabilities.},
}
@article {pmid22341437,
year = {2012},
author = {Campbell, PJ},
title = {Telomeres and cancer: from crisis to stability to crisis to stability.},
journal = {Cell},
volume = {148},
number = {4},
pages = {633-635},
pmid = {22341437},
issn = {1097-4172},
support = {088340/WT_/Wellcome Trust/United Kingdom ; 093867/WT_/Wellcome Trust/United Kingdom ; },
abstract = {Telomere attrition unleashes genomic instability, promoting cancer development. Once established, however, the malignant clone often re-establishes genomic stability through overexpression of telomerase. In two papers, one in this issue of Cell and one in the subsequent issue, DePinho and colleagues explore the consequences of telomerase re-expression and its validity as a therapeutic target in mouse models of cancer.},
}
@article {pmid22336916,
year = {2012},
author = {Miller, AS and Balakrishnan, L and Buncher, NA and Opresko, PL and Bambara, RA},
title = {Telomere proteins POT1, TRF1 and TRF2 augment long-patch base excision repair in vitro.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {11},
number = {5},
pages = {998-1007},
pmid = {22336916},
issn = {1551-4005},
support = {R01 ES015052/ES/NIEHS NIH HHS/United States ; R01 GM024441/GM/NIGMS NIH HHS/United States ; GM024441/GM/NIGMS NIH HHS/United States ; ES015052/ES/NIEHS NIH HHS/United States ; },
mesh = {DNA Ligase ATP ; DNA Ligases/metabolism ; DNA Polymerase beta/metabolism ; DNA Repair ; DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism ; Electrophoretic Mobility Shift Assay ; Flap Endonucleases/metabolism ; Humans ; Protein Binding ; Shelterin Complex ; Substrate Specificity ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {Human telomeres consist of multiple tandem hexameric repeats, each containing a guanine triplet. Guanosine-rich clusters are highly susceptible to oxidative base damage, necessitating base excision repair (BER). Previous demonstration of enhanced strand displacement synthesis by the BER component DNA polymerase β in the presence of telomere protein TRF2 suggests that telomeres employ long-patch (LP) BER. Earlier analyses in vitro showed that efficiency of BER reactions is reduced in the DNA-histone environment of chromatin. Evidence presented here indicates that BER is promoted at telomeres. We found that the three proteins that contact telomere DNA, POT1, TRF1 and TRF2, enhance the rate of individual steps of LP-BER and stimulate the complete reconstituted LP-BER pathway. Thought to protect telomere DNA from degradation, these proteins still apparently evolved to allow selective access of repair proteins.},
}
@article {pmid22334142,
year = {2012},
author = {Schuldt, A},
title = {Telomeres: Damage response cut short.},
journal = {Nature reviews. Molecular cell biology},
volume = {13},
number = {3},
pages = {137},
pmid = {22334142},
issn = {1471-0080},
}
@article {pmid22331467,
year = {2012},
author = {Yonekawa, T and Yang, S and Counter, CM},
title = {PinX1 localizes to telomeres and stabilizes TRF1 at mitosis.},
journal = {Molecular and cellular biology},
volume = {32},
number = {8},
pages = {1387-1395},
pmid = {22331467},
issn = {1098-5549},
support = {R01 CA082481/CA/NCI NIH HHS/United States ; R01 CA123031/CA/NCI NIH HHS/United States ; CA123031/CA/NCI NIH HHS/United States ; CA082481/CA/NCI NIH HHS/United States ; },
mesh = {Apoptosis/genetics ; Cell Cycle Proteins ; HeLa Cells ; Humans ; Mitosis/*physiology ; Protein Binding ; Telomere/*metabolism ; Telomere Homeostasis ; Telomeric Repeat Binding Protein 1/genetics/*metabolism ; Tumor Suppressor Proteins/genetics/*metabolism ; },
abstract = {Human telomeres are DNA-protein complexes that cap and protect the ends of chromosomes. The protein PinX1 associates with telomeres through an interaction with the resident double-stranded telomere-binding protein TRF1. PinX1 also binds to and inhibits telomerase, the enzyme responsible for complete replication of telomeric DNA. We now report that endogenous PinX1 associates with telomeres primarily at mitosis. Moreover, knockdown of PinX1 caused delayed mitotic entry and reduced the accumulation of TRF1 on telomeres during this stage of the cell cycle. Taking these findings together, we suggest that one function of PinX1 is to stabilize TRF1 during mitosis, perhaps to promote transition into M phase of the cell cycle.},
}
@article {pmid22330096,
year = {2013},
author = {Novo, CL and Londoño-Vallejo, JA},
title = {Telomeres and the nucleus.},
journal = {Seminars in cancer biology},
volume = {23},
number = {2},
pages = {116-124},
doi = {10.1016/j.semcancer.2012.02.001},
pmid = {22330096},
issn = {1096-3650},
mesh = {Animals ; Cell Nucleus/*genetics/metabolism/physiology/ultrastructure ; Chromatin Assembly and Disassembly/physiology ; DNA Replication/genetics/physiology ; Genomic Instability/physiology ; Humans ; Models, Biological ; Neoplasms/genetics/pathology ; Telomere/chemistry/genetics/metabolism/*physiology ; Telomere Homeostasis/genetics ; },
abstract = {Telomeres are crucial for the maintenance of genome stability through "capping" of chromosome ends to prevent their recognition as double-strand breaks, thus avoiding end-to-end fusions or illegitimate recombination [1-3]. Similar to other genomic regions, telomeres participate to the nuclear architecture while being highly mobile. The interaction of telomeres with nuclear domains or compartments greatly differs not only between organisms but also between cells within the same organism. It is also expected that biological processes like replication, repair or telomere elongation impact the distribution of chromosome extremities within the nucleus, as they probably do with other regions of the genome. Pathological processes such as cancer induce profound changes in the nuclear architecture, which also affects telomere dynamics and spatial organization. Here we will expose our present knowledge on the relationship between telomeres and nuclear architecture and on how this relationship is affected by normal or abnormal telomere metabolisms.},
}
@article {pmid22327932,
year = {2012},
author = {Jiao, J and Kang, JX and Tan, R and Wang, J and Zhang, Y},
title = {Multiplex time-reducing quantitative polymerase chain reaction assay for determination of telomere length in blood and tissue DNA.},
journal = {Analytical and bioanalytical chemistry},
volume = {403},
number = {1},
pages = {157-166},
doi = {10.1007/s00216-012-5783-3},
pmid = {22327932},
issn = {1618-2650},
mesh = {Animals ; Base Sequence ; DNA/blood/*genetics/metabolism ; DNA Primers ; Mice ; Polymerase Chain Reaction/*methods ; Reproducibility of Results ; *Telomere ; },
abstract = {In this paper we describe a multiplex time-reducing quantitative polymerase chain reaction (qPCR) method for determination of telomere length. This multiplex qPCR assay enables two pairs of primers to simultaneously amplify telomere and single copy gene (albumin) templates, thus reducing analysis time and labor compared with the previously established singleplex assay. The chemical composition of the master mix and primers for the telomere and albumin were systematically optimized. The thermal cycling program was designed to ensure complete separation of the melting processes of the telomere and albumin. Semi-log standard curves of DNA concentration versus cycle threshold (C (t)) were established, with a linear relationship over an 81-fold DNA concentration range. The well-performed intra-assay (RSD range 2.4-4.7%) and inter-assay (RSD range: 3.1-5.0%) reproducibility were demonstrated to ensure measurement stability. Using wild-type, Lewis lung carcinoma and H22 liver carcinoma C57BL/6 mouse models, significantly different telomere lengths among different DNA samples were not observed in wild-type mice. However, the relative telomere lengths of the tumor DNA in the two strains of tumor-bearing mice were significantly shorter than the lengths in the surrounding non-tumor DNA of tumor-bearing mice and the tissue DNA of wild-type mice. These results suggest that the shortening of telomere lengths may be regarded as an important indicator for cancer control and prevention. Quantification of telomere lengths was further confirmed by the traditional Southern blotting method. This method could be successfully used to reduce the time needed for rapid, precise measurement of telomere lengths in biological samples.},
}
@article {pmid22323752,
year = {2012},
author = {Jicha, GA},
title = {Comment: Telomeres in AD--the long and the short of it.},
journal = {Neurology},
volume = {78},
number = {8},
pages = {574},
doi = {10.1212/WNL.0b013e318247cce3},
pmid = {22323752},
issn = {1526-632X},
mesh = {Alzheimer Disease/*diagnosis/*enzymology ; Chitinases/*cerebrospinal fluid ; Female ; Humans ; Male ; },
}
@article {pmid22323451,
year = {2012},
author = {Aalbers, AM and Kajigaya, S and van den Heuvel-Eibrink, MM and van der Velden, VH and Calado, RT and Young, NS},
title = {Human telomere disease due to disruption of the CCAAT box of the TERC promoter.},
journal = {Blood},
volume = {119},
number = {13},
pages = {3060-3063},
pmid = {22323451},
issn = {1528-0020},
support = {//Intramural NIH HHS/United States ; },
mesh = {Adult ; Anemia, Aplastic/genetics ; Binding Sites/genetics ; Case-Control Studies ; Dyskeratosis Congenita/genetics ; HEK293 Cells ; HeLa Cells ; Humans ; Leukemia, Myeloid, Acute/genetics ; Liver Cirrhosis/genetics ; Male ; Mutation/physiology ; NFI Transcription Factors/*metabolism ; Pedigree ; Promoter Regions, Genetic/*genetics ; Pulmonary Fibrosis/genetics ; RNA/*genetics/metabolism ; Telomerase/*genetics/metabolism ; Telomere/genetics/*pathology ; },
abstract = {Mutations in the coding region of telomerase complex genes can result in accelerated telomere attrition and human disease. Manifestations of telomere disease include the bone marrow failure syndromes dyskeratosis congenita and aplastic anemia, acute myeloid leukemia, liver cirrhosis, and pulmonary fibrosis. Here, we describe a mutation in the CCAAT box (GCAAT) of the TERC gene promoter in a family in which multiple members had typical features of telomeropathy. The genetic alteration in this critical regulatory sequence resulted in reduced reporter gene activity and absent binding of transcription factor NF-Y, likely responsible for reduced TERC levels, decreased telomerase activity, and short telomeres. This is the first description of a pathogenic mutation in the highly conserved CCAAT box and the first instance of a mutation in the promoter region of TERC producing a telomeropathy. We propose that current mutation-screening strategies should include gene promoter regions for the diagnosis of telomere diseases. This clinical trial was registered at www.clinicaltrials.gov as #NCT00071045.},
}
@article {pmid22319045,
year = {2012},
author = {Shen, Q and Zhao, X and Yu, L and Zhang, Z and Zhou, D and Kan, M and Zhang, D and Cao, L and Xing, Q and Yang, Y and Xu, H and He, L and Liu, Y},
title = {Association of leukocyte telomere length with type 2 diabetes in mainland Chinese populations.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {97},
number = {4},
pages = {1371-1374},
doi = {10.1210/jc.2011-1562},
pmid = {22319045},
issn = {1945-7197},
mesh = {Age Factors ; Aged ; Case-Control Studies ; China ; Diabetes Mellitus, Type 2/ethnology/*genetics/*metabolism ; Ethnicity ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Oxidative Stress ; Polymerase Chain Reaction ; Reproducibility of Results ; Retrospective Studies ; Sex Characteristics ; Telomere/metabolism ; *Telomere Shortening ; Urban Health/ethnology ; },
abstract = {CONTEXT: Telomeres are structures at the ends of eukaryotic chromosomes. They help maintain genomic stability. High oxidative stress can lead to accelerated telomere shortening, which causes premature cell senescence. This is implicated in the development of type 2 diabetes (T2D). For this reason, we hypothesize that telomere shortening can characterize T2D.<br><br>METHODS: We investigated the association between leukocyte telomere length (LTL) and T2D in a retrospective case-control study with a sample of 4016 Chinese Han subjects (1936 unrelated T2D cases and 2080 controls). Logistic regression analysis was performed to evaluate the association between LTL and T2D, adjusted for age and gender. Multivariate linear regression analysis was used to test for any association of LTL with a number of clinical, demographic, and diabetes-associated variables.<br><br>RESULTS: Telomere repeat length (T)/copy number of a single-copy gene (S) ratios (T/S) of LTL were found to be significantly shorter in T2D cases [1.00 T/S, 95% confidence interval (CI) = 0.99-1.02] compared with controls (1.08 T/S, 95% CI = 1.06-1.09) over a wide age range (odds ratio of diabetes for a 1-U decrease in ln-transformed TL = 1.52; 95% CI = 1.23-1.88; P = 0.0001).<br><br>CONCLUSION: Our research demonstrates association between shorter LTL and T2D in a population from mainland China. Our study suggests that shorter LTL might be associated with T2D in a manner independent of smoking and drinking habits or the time of T2D onset time.},
}
@article {pmid22318909,
year = {2012},
author = {Liu, HQ and An, JZ and Liu, J and Yang, YF and Zhang, HX and Zhao, BY and Li, JB and Yang, HS and Chen, ZN and Xing, JL},
title = {Leukocyte telomere length predicts overall survival in hepatocellular carcinoma treated with transarterial chemoembolization.},
journal = {Carcinogenesis},
volume = {33},
number = {5},
pages = {1040-1045},
pmid = {22318909},
issn = {1460-2180},
mesh = {Carcinoma, Hepatocellular/*blood/genetics/*mortality/therapy ; Chemoembolization, Therapeutic/methods ; China/epidemiology ; Female ; Humans ; Leukocytes/metabolism/*ultrastructure ; Liver Neoplasms/*blood/genetics/*mortality/therapy ; Male ; Middle Aged ; Multivariate Analysis ; Prognosis ; Real-Time Polymerase Chain Reaction ; Survival Rate ; T-Lymphocytes/metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {Previous studies have reported that telomere length in peripheral blood leukocytes can predict the clinical outcome of several cancers. However, whether leukocyte telomere length is associated with the prognosis of hepatocellular carcinoma (HCC) remains to be determined. In this study, relative telomere length (RTL) in peripheral blood leukocytes was measured using a real-time PCR-based method for 269 HCC patients treated with transarterial chemoembolization (TACE) from two independent hospitals. The association between RTL and the overall survival (OS) of HCC was analyzed. The immunological function of the HCC patients with different leukocyte RTLs was evaluated. Multivariate analyses indicated that long leukocyte RTL was significantly associated with poor OS of HCC patients, with a hazard ratio of 2.04 (95% confidence interval, 1.46-2.86; P < 0.001). Kaplan-Meier analyses showed a significant difference of median survival time between patients with long and short RTL (log rank P < 0.001). Fluorescence-activated cell sorting analyses showed that the long RTL group had a significantly increased percentage of CD4(+)CD25(+)FOXP3(+) Treg in CD4(+) T cells compared with short RTL group (P = 0.002). In conclusion, our results suggest that leukocyte RTL may serve as an independent prognostic marker for HCC patients treated with TACE.},
}
@article {pmid22318437,
year = {2012},
author = {McCartney, M},
title = {Would you like your telomeres tested?.},
journal = {BMJ (Clinical research ed.)},
volume = {344},
number = {},
pages = {e681},
doi = {10.1136/bmj.e681},
pmid = {22318437},
issn = {1756-1833},
mesh = {Aging/*genetics ; Communications Media ; Genetic Testing/*methods ; Humans ; Life Style ; Mass Screening/methods ; *Telomere ; },
}
@article {pmid22314626,
year = {2012},
author = {Huber, M and Treszl, A and Wehland, M and Winther, I and Zergibel, I and Reibis, R and Bolbrinker, J and Stoll, M and Schönfelder, G and Wegscheider, K and Völler, H and Kreutz, R},
title = {Genetic variants implicated in telomere length associated with left ventricular function in patients with hypertension and cardiac organ damage.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {90},
number = {9},
pages = {1059-1067},
pmid = {22314626},
issn = {1432-1440},
mesh = {Adaptor Proteins, Signal Transducing/genetics ; Aged ; Aging ; Alleles ; Cardiovascular Diseases/*complications/*genetics/pathology/physiopathology ; Cohort Studies ; Cytoskeletal Proteins/genetics ; Echocardiography ; Female ; Genotype ; Heart Ventricles/pathology/physiopathology ; Humans ; Hypertension/*complications/*genetics ; Leukocytes/*metabolism/pathology ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Real-Time Polymerase Chain Reaction ; Telomere/*genetics/pathology ; Ventricular Function, Left ; },
abstract = {Telomere length has emerged as a biological correlate for ageing, which in turn is a risk factor for the manifestation of cardiovascular diseases. This study investigated the relation between leucocyte telomere length (LTL) and its genetic background to cardiac structure and function in patients with arterial hypertension. We analysed a cohort of 1,106 treated hypertensive patients (83.3% males; mean age, 57.9 ± 9.8 years) with an ejection fraction (EF) over 40% and documented cardiovascular disease or target organ damage. LTL and genotypes of single nucleotide polymorphisms (SNPs), previously implicated in LTL, were determined by real-time PCR. The mean left ventricular mass index (LVMI) and EF were 51.8 ± 21.0 g/H2.7 and 61.1 ± 9.6%, respectively. In multivariate adjusted analysis, a 1.5-fold LTL was positively related with a 2.2% increase of LVMI (CI = 0.1% to 4.2%, p = 0.044) and an absolute increase in EF of 0.6% (CI = 0.1% to 1.1%, p = 0.028). One SNP near TERC (rs16847897) showed a significant absolute difference in EF dependent on allele status (rs16847897, G allele 2.7%; CI = 0.7% to 4.6%; p raw = 0.008, p mt = 0.048, after adjustment for multiple testing). This applied also for two SNPs in BICD1 (rs2630578, C allele −1.8%; CI = −2.8% to −0.7%; p raw = 0.002, p mt = 0.018; rs1151026, G allele −1.9%, CI = −3.0% to −0.8%; p raw < 0.001, p mt = 0.002) with the extension that a frequent haplotype in BICD1 showed an absolute −1.8% (CI = −3.0% to −0.7%; p raw = 0.002, p mt = 0.008) lower EF compared with those lacking this haplotype. Our results point to a role of genetic variants recently implicated in LTL for left ventricular function in hypertensive patients.},
}
@article {pmid22311140,
year = {2012},
author = {Sanada, Y and Aida, J and Kawano, Y and Nakamura, K and Shimomura, N and Ishikawa, N and Arai, T and Poon, SS and Yamada, N and Okada, N and Wakiya, T and Hayashida, M and Saito, T and Egami, S and Hishikawa, S and Ihara, Y and Urahashi, T and Mizuta, K and Yasuda, Y and Kawarasaki, H and Takubo, K},
title = {Hepatocellular telomere length in biliary atresia measured by Q-FISH.},
journal = {World journal of surgery},
volume = {36},
number = {4},
pages = {908-916},
pmid = {22311140},
issn = {1432-2323},
mesh = {Biliary Atresia/*genetics/pathology/*surgery ; Child ; Child, Preschool ; Female ; Hepatocytes/*pathology ; Humans ; *In Situ Hybridization, Fluorescence ; Infant ; Liver/*pathology ; Liver Transplantation ; Male ; *Telomere Shortening ; },
abstract = {BACKGROUND: Liver transplantation for biliary atresia is indicated whenever a Kasai portoenterostomy is considered unfeasible. However, the timing of liver transplantation in biliary atresia has not been precisely defined. Excessive shortening of hepatocellular telomeres may occur in patients with biliary atresia, and therefore, telomere length could be a predictor of hepatocellular reserve capacity.<br><br>METHODS: Hepatic tissues were obtained from 20 patients with biliary atresia who underwent LT and 10 age-matched autopsied individuals (mean age, 1.7 and 1.2&#xa0;years, respectively). Telomere lengths were measured by Southern blotting and quantitative fluorescence in situ hybridization using the normalized telomere-centromere ratio. The correlation between the normalized telomere-centromere ratio for the hepatocytes in biliary atresia and the pediatric end-stage liver disease score was analyzed.<br><br>RESULTS: The median terminal restriction fragment length of the hepatic tissues in biliary atresia was not significantly different from that of the control (p&#xa0;=&#xa0;0.425), whereas the median normalized telomere-centromere ratio of hepatocytes in biliary atresia was significantly smaller than that of the control (p&#xa0;<&#xa0;0.001). Regression analysis demonstrated a negative correlation of the normalized telomere-centromere ratio with the pediatric end-stage liver disease score in biliary atresia (p&#xa0;<&#xa0;0.001).<br><br>CONCLUSIONS: Telomere length analysis using quantitative fluorescence in situ hybridization could be an objective indicator of hepatocellular reserve capacity in patients with biliary atresia, and excessive telomere shortening supports the early implementation of liver transplantation.},
}
@article {pmid22306869,
year = {2012},
author = {Wang, W and Wang, SS and Li, H and Wang, N},
title = {[Telomere biology of the chicken].},
journal = {Yi chuan = Hereditas},
volume = {34},
number = {1},
pages = {19-26},
doi = {10.3724/sp.j.1005.2012.00019},
pmid = {22306869},
issn = {0253-9772},
mesh = {Animals ; Chickens/genetics/*metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres, the nucleoprotein "caps" protecting the ends of linear chromosomes, are maintained by telomerase. Telomeres have important roles in maintaining genomic stability and preventing senescence or oncogenesis. Chicken is a classical model animal for genetic and developmental studies. With further development of chicken genomics, great progress has been made in research of chicken telomere and telomerase. This review describes recent advances and future research directions in chicken telomere biology.},
}
@article {pmid22304389,
year = {2012},
author = {Cantara, S and Capuano, S and Capezzone, M and Benigni, M and Pisu, M and Marchisotta, S and Pacini, F},
title = {Lack of mutations of the telomerase RNA component in familial papillary thyroid cancer with short telomeres.},
journal = {Thyroid : official journal of the American Thyroid Association},
volume = {22},
number = {4},
pages = {363-368},
doi = {10.1089/thy.2011.0109},
pmid = {22304389},
issn = {1557-9077},
mesh = {Alleles ; Carcinoma, Papillary/*genetics/*pathology ; Chromatography, High Pressure Liquid ; DNA, Neoplasm/genetics ; GTPase-Activating Proteins/genetics ; Gene Dosage ; Genotype ; Humans ; Mutation/*genetics ; Point Mutation/genetics ; Polymorphism, Single Nucleotide ; RNA/*genetics ; RNA, Messenger/genetics ; Shelterin Complex ; Telomerase/*genetics ; Telomere/*genetics/*ultrastructure ; Telomere-Binding Proteins/genetics/metabolism ; Thyroid Neoplasms/*genetics/*pathology ; },
abstract = {BACKGROUND: The occurrence of familial papillary thyroid cancer (FPTC) is well established but no susceptibility genes for this disease have been discovered. Our group has recently demonstrated that patients with FPTC have shorter telomeres, not associated with mutations in telomerase reverse transcriptase, gene than patients with sporadic papillary thyroid cancer (SPTC), healthy subjects (HS), and unaffected family members (UFMs). Several diseases, however, have short telomeres associated with mutations in the telomerase RNA component (TERC) gene or in the shelterin complex (POT1, RAP1, TIN2, TPP1, TRF1, and TRF2) genes. The objective of the present study was to verify whether short telomeres observed in FPTC patients were related to mutations in TERC or shelterin genes.<br><br>METHODS: Sixty-six patients with FPTC, 46 UFMs, 111 patients with SPTC, and 153 HS were analyzed by polymerase chain reaction followed by denaturing high performance liquid chromatography analysis and direct sequencing for the presence of TERC or shelterin gene mutations. When present, single-nucleotide polymorphisms were tested by &#x3c7;(2) analysis at the genotypic, allelic, and haplotypic levels.<br><br>RESULTS: The entire sequence of the TERC gene was analyzed with particular attention to known mutations known to be associated with short telomeres. All samples appeared to be homozygous wild type for A-771G, C-99G, G305A, G322A, C323T, C408G, G450A, T467C, G508A, A514G, G623A, and C727G substitutions and for the 378&#x394;&#x2192;3' deletion in the TERC gene. In addition, upon analysis of all samples for shelterin proteins, we observed a significant decrease in POT1 and RAP1 protein expression in the blood of FPTC patients compared with SPTC subjects. However, no mutations or polymorphisms were found when in the coding sequences of both genes.<br><br>CONCLUSIONS: To our knowledge this is the first study of TERC mutations or alterations in the shelterin complex in relation to FPTC. Shorter telomeres observed in FPTC are not linked to mutations or polymorphisms in TERC, POT1, or RAP1 genes.},
}
@article {pmid22302936,
year = {2012},
author = {Yamazaki, H and Tarumoto, Y and Ishikawa, F},
title = {Tel1(ATM) and Rad3(ATR) phosphorylate the telomere protein Ccq1 to recruit telomerase and elongate telomeres in fission yeast.},
journal = {Genes &amp; development},
volume = {26},
number = {3},
pages = {241-246},
pmid = {22302936},
issn = {1549-5477},
mesh = {Cell Cycle Proteins/metabolism ; Checkpoint Kinase 2 ; Mutation ; Phosphorylation ; Protein Kinases/metabolism ; Protein Serine-Threonine Kinases/*metabolism ; Schizosaccharomyces/*enzymology/genetics ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Telomerase/*metabolism ; Telomere/enzymology/*metabolism ; },
abstract = {In fission yeast, the DNA damage sensor kinases Tel1(ATM) and Rad3(ATR) exist at telomeres and are required for telomere maintenance, but the biological role they play at telomeres is not known. Here we show that the telomere protein Ccq1 is phosphorylated at Thr 93 (threonine residue at amino acid 93) by Tel1(ATM) and Rad3(ATR) both in vitro and in vivo. A ccq1 mutant in which alanine was substituted for Thr 93 failed to recruit telomerase to telomeres and showed gradual shortening of telomeres. These results indicate that the direct phosphorylation of Ccq1 Thr 93 by Tel1 and Rad3 is involved in the recruitment of telomerase to elongate telomeres.},
}
@article {pmid22302075,
year = {2012},
author = {Du, M and Prescott, J and Kraft, P and Han, J and Giovannucci, E and Hankinson, SE and De Vivo, I},
title = {Physical activity, sedentary behavior, and leukocyte telomere length in women.},
journal = {American journal of epidemiology},
volume = {175},
number = {5},
pages = {414-422},
pmid = {22302075},
issn = {1476-6256},
support = {P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA49449/CA/NCI NIH HHS/United States ; T32 CA09001/CA/NCI NIH HHS/United States ; T32 CA009001/CA/NCI NIH HHS/United States ; R01 HL088521/HL/NHLBI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; R01 ES001664/ES/NIEHS NIH HHS/United States ; R01 CA082838/CA/NCI NIH HHS/United States ; T32 ES01664/ES/NIEHS NIH HHS/United States ; P01 CA87969/CA/NCI NIH HHS/United States ; R01 HL034594/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Case-Control Studies ; Cross-Sectional Studies ; Exercise/*physiology ; Female ; Health Surveys ; Humans ; Least-Squares Analysis ; Leukocytes/*physiology ; Linear Models ; Middle Aged ; Motor Activity/physiology ; Polymerase Chain Reaction ; Prospective Studies ; *Sedentary Behavior ; Self Report ; Telomere/*chemistry ; *Telomere Shortening/physiology ; },
abstract = {Leukocyte telomere length (LTL) is a potential indicator of cellular aging; however, its relation to physical activity and sedentary behavior is unclear. The authors examined cross-sectionally associations among activity, sedentary behavior, and LTL among 7,813 women aged 43-70 years in the Nurses' Health Study. Participants self-reported activity by questionnaire in 1988 and 1992 and sedentary behavior in 1992. Telomere length in peripheral blood leukocytes, collected in 1989-1990, was measured by quantitative polymerase chain reaction. The least-squares mean telomere length (z-score) was calculated after adjustment for age and other potential confounders. For total activity, moderately or highly active women had a 0.07-standard deviation (SD) increase in LTL (2-sided P(trend) = 0.02) compared with those least active. Greater moderate- or vigorous-intensity activity was also associated with increased LTL (SD = 0.11 for 2-4 vs. <1 hour/week and 0.04 for ≥7 vs. <1 hour/week; 2-sided P(trend) = 0.02). Specifically, calisthenics or aerobics was associated with increased LTL (SD = 0.10 for ≥2.5 vs. 0 hours/week; 2-sided P(trend) = 0.04). Associations remained after adjustment for body mass index. Other specific activities and sitting were unassociated with LTL. Although associations were modest, these findings suggest that even moderate amounts of activity may be associated with longer telomeres, warranting further investigation in large prospective studies.},
}
@article {pmid22293459,
year = {2012},
author = {O'Donovan, A and Tomiyama, AJ and Lin, J and Puterman, E and Adler, NE and Kemeny, M and Wolkowitz, OM and Blackburn, EH and Epel, ES},
title = {Stress appraisals and cellular aging: a key role for anticipatory threat in the relationship between psychological stress and telomere length.},
journal = {Brain, behavior, and immunity},
volume = {26},
number = {4},
pages = {573-579},
pmid = {22293459},
issn = {1090-2139},
support = {MH64110-01A1/MH/NIMH NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; AG030424/AG/NIA NIH HHS/United States ; R56 AG030424-01A1/AG/NIA NIH HHS/United States ; P30 AI027763/AI/NIAID NIH HHS/United States ; R56 AG030424-02/AG/NIA NIH HHS/United States ; R56 AG030424/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Caregivers/*psychology ; Case-Control Studies ; Cellular Senescence/*physiology ; Female ; Humans ; Middle Aged ; Risk Factors ; Stress, Psychological/*metabolism ; Surveys and Questionnaires ; Telomere Homeostasis/*physiology ; Telomere Shortening/*physiology ; },
abstract = {Chronic psychological stress is a risk factor for multiple diseases of aging. Accelerated cellular aging as indexed by short telomere length has emerged as a potential common biological mechanism linking various forms of psychological stress and diseases of aging. Stress appraisals determine the degree and type of biological stress responses and altered stress appraisals may be a common psychological mechanism linking psychological stress and diseases of aging. However, no previous studies have examined the relationship between stress appraisals and telomere length. We exposed chronically stressed female caregivers and non-caregiving controls (N=50; M age=62.14±6.10) to a standardized acute laboratory stressor and measured their anticipatory and retrospective threat and challenge appraisals of the stressor. We hypothesized that threat and challenge appraisals would be associated with shorter and longer telomere length respectively, and that chronic caregiving stress would influence telomere length through altered stress appraisals. Higher anticipatory threat appraisals were associated with shorter age-adjusted telomere length (β=-.32, p=.03), but challenge appraisals and retrospective threat appraisals showed no independent association with telomere length. Caregivers reported significantly higher anticipatory (β=-.36, p=.006) and retrospective (β=-.29, p=.03) threat appraisals than controls, but similar challenge appraisals. Although there was no significant main effect of caregiver status on telomere length, caregiving had a significant indirect effect on telomere length through anticipatory threat appraisals. Exaggerated anticipatory threat appraisals may be a common and modifiable psychological mechanism of psychological stress effects on cellular aging.},
}
@article {pmid22289863,
year = {2012},
author = {Hector, RE and Ray, A and Chen, BR and Shtofman, R and Berkner, KL and Runge, KW},
title = {Mec1p associates with functionally compromised telomeres.},
journal = {Chromosoma},
volume = {121},
number = {3},
pages = {277-290},
pmid = {22289863},
issn = {1432-0886},
support = {UL1 RR024989/RR/NCRR NIH HHS/United States ; R01 AG019960/AG/NIA NIH HHS/United States ; F32 AG022743/AG/NIA NIH HHS/United States ; R01 GM050752/GM/NIGMS NIH HHS/United States ; T32 HD007104/HD/NICHD NIH HHS/United States ; },
mesh = {Cell Proliferation ; DNA-Binding Proteins/genetics/metabolism ; Exodeoxyribonucleases/genetics/metabolism ; Intracellular Signaling Peptides and Proteins/genetics/*metabolism ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {In many organisms, telomere DNA consists of simple sequence repeat tracts that are required to protect the chromosome end. In the yeast Saccharomyces cerevisiae, tract maintenance requires two checkpoint kinases of the ATM family, Tel1p and Mec1p. Previous work has shown that Tel1p is recruited to functional telomeres with shorter repeat tracts to promote telomerase-mediated repeat addition, but the role of Mec1p is unknown. We found that Mec1p telomere association was detected as cells senesced when telomere function was compromised by extreme shortening due to either the loss of telomerase or the double-strand break binding protein Ku. Exonuclease I effects the removal of the 5' telomeric strand, and eliminating it prevented both senescence and Mec1p telomere association. Thus, in contrast to Tel1p, Mec1p associates with short, functionally compromised telomeres.},
}
@article {pmid22288427,
year = {2012},
author = {Kume, K and Kikukawa, M and Hanyu, H and Takata, Y and Umahara, T and Sakurai, H and Kanetaka, H and Ohyashiki, K and Ohyashiki, JH and Iwamoto, T},
title = {Telomere length shortening in patients with dementia with Lewy bodies.},
journal = {European journal of neurology},
volume = {19},
number = {6},
pages = {905-910},
doi = {10.1111/j.1468-1331.2011.03655.x},
pmid = {22288427},
issn = {1468-1331},
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Aged ; Aged, 80 and over ; Deoxyguanosine/analogs &amp; derivatives/urine ; Female ; Humans ; Lewy Bodies/pathology/*ultrastructure ; Lewy Body Disease/*pathology/urine ; Male ; Severity of Illness Index ; Statistics as Topic ; Telomere/*pathology ; },
abstract = {BACKGROUND AND PURPOSE: Shortened telomere length has been considered to be associated with various age-related diseases, especially in dementia such as Alzheimer's disease and vascular dementia. However, changes in telomere length in dementia with Lewy bodies (DLB) remain unclear. To elucidate these changes, we set out to determine telomere length in peripheral leukocytes as well as the level of urinary 8-hydroxy-deoxyguanosine (8-OHdG) as a marker of oxidative stress in DLB.<br><br>METHODS: Blood samples were obtained from 33 patients with a clinical diagnosis of probable DLB and 35 age-matched, non-demented elderly controls (NEC). Telomere length was assessed by quantitative real-time polymerase chain reaction of genomic DNA extracted from leukocytes, whereas oxidative stress was assessed on the basis of urine 8-OHdG level, which was measured using high-performance liquid chromatography.<br><br>RESULTS: Telomere length was significantly shorter in the DLB group than in the NEC group. Urinary 8-OHdG levels were significantly higher in the DLB group than in the NEC group. There was a negative correlation between telomere length and age in the DLB group; however, there were no significant relationships between telomere length and clinical findings including disease duration, severity of cognitive decline, presence or absence of fluctuation in cognitive function, visual hallucinations, and Parkinsonism. In both groups, the correlation between telomere length and urinary 8-OHdG levels was not significant.<br><br>CONCLUSIONS: These findings indicate that the etiopathology of DLB is considered to be an accelerated aging process.},
}
@article {pmid22286818,
year = {2012},
author = {Jia, G and Su, L and Singhal, S and Liu, X},
title = {Emerging roles of SIRT6 on telomere maintenance, DNA repair, metabolism and mammalian aging.},
journal = {Molecular and cellular biochemistry},
volume = {364},
number = {1-2},
pages = {345-350},
pmid = {22286818},
issn = {1573-4919},
mesh = {Aging/genetics/*metabolism ; Animals ; Autophagy/genetics ; DNA Repair/*genetics ; Humans ; Mammals/genetics ; NF-kappa B/genetics/*metabolism ; Signal Transduction ; Sirtuins/*genetics/*metabolism ; Telomere/*genetics/metabolism/ultrastructure ; },
abstract = {With the characterization of Sir2 gene in yeast aging, its mammalian homologs Sirtuins 1–7 have been attracting attention from scientists with various research backgrounds. Among Sirtuins, SIRT1 is the most extensively studied. Recent progress on mammalian Sirtuins has shown that SIRT6 as a histone deacetylase may also play a critical role in regulating mammalian aging. This review summarizes recent advances on SIRT6 as a key modulator of telomere structure, DNA repair, metabolism, and NF-kappa B pathway in aging. In addition, we discuss the challenges that remain to be studied in SIRT6 biology.},
}
@article {pmid22284665,
year = {2012},
author = {Song, Z and Zhang, J and Ju, Z and Rudolph, KL},
title = {Telomere dysfunctional environment induces loss of quiescence and inherent impairments of hematopoietic stem cell function.},
journal = {Aging cell},
volume = {11},
number = {3},
pages = {449-455},
doi = {10.1111/j.1474-9726.2012.00802.x},
pmid = {22284665},
issn = {1474-9726},
mesh = {Animals ; Cell Growth Processes/physiology ; Cells, Cultured ; Cellular Senescence/physiology ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/cytology/*physiology ; Mice ; Mice, Knockout ; Telomerase/deficiency ; Telomere/*physiology ; },
abstract = {Previous studies have shown that telomere dysfunction induces alteration in the systemic (circulatory) environment impairing the differentiation of hematopoietic stem cells (HSCs) but these defects can be reverted by re-exposing HSCs to an environment with functional telomeres. In contrast, HSC intrinsic telomere dysfunction induces permanent and irreversible limitations in the repopulation capacity partially depending on the induction of checkpoints such as cell cycle arrest, differentiation, or apoptosis. It is currently unknown whether telomere dysfunctional environment can induce irreversible, cell intrinsic defects impairing the function of HSCs. Here, we analyzed the functional reserves of murine, wild-type HSCs with intact telomeres that were transiently exposed to a telomere dysfunctional environment (late generation telomerase knockout mice) or to an environment with functional telomeres (wild-type mice). The study shows that the telomere dysfunctional environment leads to irreversible impairments in the repopulation capacity of wild-type HSCs. The telomere dysfunctional environment impaired the maintenance of HSC quiescent. Moreover, the study shows that alterations in the systemic (circulatory) environment rather than the bone stromal niche induce loss of stem cell quiescence and irreversible deficiencies of HSCs exposed to a telomere dysfunctional environment.},
}
@article {pmid22281704,
year = {2012},
author = {Kibe, R and Zhang, S and Guo, D and Marrero, L and Tsien, F and Rodriguez, P and Khan, S and Zieske, A and Huang, J and Li, W and Durum, SK and Iwakuma, T and Cui, Y},
title = {IL-7Rα deficiency in p53null mice exacerbates thymocyte telomere erosion and lymphomagenesis.},
journal = {Cell death and differentiation},
volume = {19},
number = {7},
pages = {1139-1151},
pmid = {22281704},
issn = {1476-5403},
support = {P20RR021970/RR/NCRR NIH HHS/United States ; P20 RR020152/RR/NCRR NIH HHS/United States ; P20RR020152/RR/NCRR NIH HHS/United States ; P20 RR021970/RR/NCRR NIH HHS/United States ; R01 CA112065/CA/NCI NIH HHS/United States ; CA112065/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Differentiation ; Cell Line ; Chromosomal Instability ; DNA Damage ; DNA-Binding Proteins/metabolism ; Interleukin-7/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Receptors, Interleukin-7/genetics/*metabolism ; Shelterin Complex ; Signal Transduction ; Telomere/*metabolism ; Telomere-Binding Proteins ; Thymocytes/cytology/*metabolism ; Tumor Suppressor Protein p53/deficiency/genetics/*metabolism ; },
abstract = {Interleukin-7 (IL-7) is an essential T-cell survival cytokine. IL-7 receptor (IL-7Rα) deficiency severely impairs T-cell development due to substantial apoptosis. We hypothesized that IL-7Rα(null)-induced apoptosis is partially contributed by an elevated p53 activity. To investigate the genetic association of IL-7/IL-7Rα signaling with the p53 pathway, we generated IL-7Rα(null)p53(null) (DKO) mice. DKO mice exhibited a marked reduction of apoptosis in developing T cells and an augmented thymic lymphomagenesis with telomere erosions and exacerbated chromosomal anomalies, including chromosome duplications, breaks, and translocations. In particular, Robertsonian translocations, in which telocentric chromosomes fuse at the centromeric region, and a complete loss of telomeres at the fusion site occurred frequently in DKO thymic lymphomas. Cellular and molecular investigations revealed that IL-7/IL-7Rα signaling withdrawal diminished the protein synthesis of protection of telomere 1 (POT1), a subunit of telomere protective complex shelterin, leading to telomere erosion and the activation of the p53 pathway. Blockade of IL-7/IL-7Rα signaling in IL-7-dependent p53(null) cells reduced POT1 expression and caused telomere and chromosome abnormalities similar to those observed in DKO lymphomas. This study underscores a novel function of IL-7/IL-7Rα during T-cell development in regulating telomere integrity via POT1 expression and provides new insights into cytokine-mediated survival signals and T-cell lymphomagenesis.},
}
@article {pmid22269209,
year = {2012},
author = {Hou, L and Zhang, X and Gawron, AJ and Liu, J},
title = {Surrogate tissue telomere length and cancer risk: shorter or longer?.},
journal = {Cancer letters},
volume = {319},
number = {2},
pages = {130-135},
doi = {10.1016/j.canlet.2012.01.028},
pmid = {22269209},
issn = {1872-7980},
mesh = {Humans ; Neoplasms/*genetics ; Risk Factors ; Specimen Handling ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Telomeres play a critical role in chromosome stability. Telomere length (TL) shortening is a risk factor for cancers. Measuring TL in surrogate tissues that can be easily collected may provide a potential tool for early detection of cancers. A number of studies on surrogate tissue TL and cancer risks have been conducted and results are inconsistent, including positive, negative, or null associations. In this article, we reviewed the published data on surrogate tissue TL in relation to cancer risks, discussed the possible reasons for the differences in the results and future directions and challenges for this line of research.},
}
@article {pmid22268496,
year = {2012},
author = {Xu, C and Cheng, Z and Yu, W},
title = {Construction of rice mini-chromosomes by telomere-mediated chromosomal truncation.},
journal = {The Plant journal : for cell and molecular biology},
volume = {70},
number = {6},
pages = {1070-1079},
doi = {10.1111/j.1365-313X.2012.04916.x},
pmid = {22268496},
issn = {1365-313X},
mesh = {Chromosomes, Artificial/*genetics ; Chromosomes, Plant/*genetics ; Genetic Engineering/*methods ; Oryza/*genetics ; Telomere/*genetics ; Transformation, Genetic ; Transgenes ; },
abstract = {Telomere truncation has been shown to be an efficient technology for the creation of mini-chromosomes that can be used as artificial chromosome platforms for genetic engineering. Artificial chromosome-based genetic engineering is considered to be superior to the existing techniques of randomized gene integration by Agrobacterium or biolistic-mediated genetic transformation. It organizes multiple transgenes as a unique genetic linkage block for subsequent manipulations in breeding. Telomere truncation technology relies on three components: the telomere sequence that mediates chromosomal truncation, a selection marker that allows the selection of transgenic events, and a site-specific recombination system that can be used to accept future genes into the mini-chromosome by gene targeting. These elements are usually pre-assembled before transformation, a process that is both time and labor consuming. We found in this research that the three elements could be mixed to transform plant cells in a biolistic transformation, and produced efficient chromosomal truncations and mini-chromosomes in rice. This system will allow rapid construction of mini-chromosomes with a flexible selection of resistant markers, site-specific recombination systems and other desirable elements. In addition, a rice telotrisomic line was used as the starting material for chromosomal truncations. Mini-chromosomes from the truncations of both the telocentric chromosome and other chromosomes were recovered. The mini-chromosomes remained stable during 2 years of subculture. The construction of mini-chromosomes in rice, an economically important crop, will provide a platform for future artificial chromosome-based genetic engineering of rice for stacking multiple genes.},
}
@article {pmid22267287,
year = {2012},
author = {Terry, KL and Tworoger, SS and Vitonis, AF and Wong, J and Titus-Ernstoff, L and De Vivo, I and Cramer, DW},
title = {Telomere length and genetic variation in telomere maintenance genes in relation to ovarian cancer risk.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {21},
number = {3},
pages = {504-512},
pmid = {22267287},
issn = {1538-7755},
support = {R01 CA049449-19/CA/NCI NIH HHS/United States ; R01CA54419/CA/NCI NIH HHS/United States ; R01CA49449/CA/NCI NIH HHS/United States ; P50 CA105009/CA/NCI NIH HHS/United States ; P01 CA087969-11/CA/NCI NIH HHS/United States ; P01CA876969/CA/NCI NIH HHS/United States ; R01 CA054419/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; P50 CA105009-05/CA/NCI NIH HHS/United States ; P50CA105009/CA/NCI NIH HHS/United States ; R01 CA054419-15/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Biomarkers, Tumor/blood/*genetics ; Case-Control Studies ; DNA, Neoplasm/genetics ; Female ; Follow-Up Studies ; Genetic Predisposition to Disease ; Humans ; Middle Aged ; Ovarian Neoplasms/blood/*genetics ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide/*genetics ; Prognosis ; Risk Factors ; Telomerase/blood/*genetics ; Telomere/*genetics ; },
abstract = {BACKGROUND: Telomeres protect chromosomal ends, shorten with cellular division, and signal cellular senescence, but unchecked telomere attrition can lead to telomere dysfunction, upregulation of telomerase, and carcinogenesis. Shorter telomeres in peripheral blood leukocytes (PBL) have been associated with elevated cancer risk. Furthermore, genetic variants in and around the TERT gene have been implicated in carcinogenesis.<br><br>METHODS: We measured relative telomere length (RTL) in PBLs of 911 cases and 948 controls from the New England case-control (NECC) study, a population-based study of ovarian cancer. In addition, we assessed germ line genetic variation in five telomere maintenance genes among 2,112 cases and 2,456 controls from the NECC study and the Nurses' Health Study, a prospective cohort study. ORs and 95% CIs were estimated by logistic regression.<br><br>RESULTS: Overall, we observed no differences in telomere length between cases and controls. Compared with women with RTL in the longest tertile, women with RTL in the shortest tertile had no increase in risk (OR = 1.01, 95% CI: 0.80-1.28). However, several SNPs in the TERT gene, including rs2736122, rs4246742, rs4975605, rs10069690, rs2736100, rs2853676, and rs7726159, were significantly associated with ovarian cancer risk. We observed a significant gene-level association between TERT and ovarian cancer risk (P = 0.00008).<br><br>CONCLUSION: Our observations suggest that genetic variation in the TERT gene may influence ovarian cancer risk, but the association between average telomere length in PBLs and ovarian cancer remains unclear.<br><br>IMPACT: The role of telomeres in ovarian carcinogenesis remains unsettled and warrants further investigation.},
}
@article {pmid22267198,
year = {2012},
author = {Anderson, BH and Kasher, PR and Mayer, J and Szynkiewicz, M and Jenkinson, EM and Bhaskar, SS and Urquhart, JE and Daly, SB and Dickerson, JE and O'Sullivan, J and Leibundgut, EO and Muter, J and Abdel-Salem, GM and Babul-Hirji, R and Baxter, P and Berger, A and Bonafé, L and Brunstom-Hernandez, JE and Buckard, JA and Chitayat, D and Chong, WK and Cordelli, DM and Ferreira, P and Fluss, J and Forrest, EH and Franzoni, E and Garone, C and Hammans, SR and Houge, G and Hughes, I and Jacquemont, S and Jeannet, PY and Jefferson, RJ and Kumar, R and Kutschke, G and Lundberg, S and Lourenço, CM and Mehta, R and Naidu, S and Nischal, KK and Nunes, L and Ounap, K and Philippart, M and Prabhakar, P and Risen, SR and Schiffmann, R and Soh, C and Stephenson, JB and Stewart, H and Stone, J and Tolmie, JL and van der Knaap, MS and Vieira, JP and Vilain, CN and Wakeling, EL and Wermenbol, V and Whitney, A and Lovell, SC and Meyer, S and Livingston, JH and Baerlocher, GM and Black, GC and Rice, GI and Crow, YJ},
title = {Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus.},
journal = {Nature genetics},
volume = {44},
number = {3},
pages = {338-342},
pmid = {22267198},
issn = {1546-1718},
support = {HL-102923/HL/NHLBI NIH HHS/United States ; HL-102924/HL/NHLBI NIH HHS/United States ; HL-102925/HL/NHLBI NIH HHS/United States ; HL-102926/HL/NHLBI NIH HHS/United States ; HL-103010/HL/NHLBI NIH HHS/United States ; },
mesh = {Abnormalities, Multiple/*genetics ; Base Sequence ; Flow Cytometry ; Genetic Predisposition to Disease/*genetics ; Histones/metabolism ; Molecular Sequence Data ; Retinal Telangiectasis/*genetics/pathology ; Sequence Analysis, DNA/methods ; Telomere/*pathology ; Telomere-Binding Proteins/*genetics ; },
abstract = {Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.},
}
@article {pmid22266933,
year = {2012},
author = {Lee, YK and Park, NH and Lee, H},
title = {Prognostic value of alternative lengthening of telomeres-associated biomarkers in uterine sarcoma and uterine carcinosarcoma.},
journal = {International journal of gynecological cancer : official journal of the International Gynecological Cancer Society},
volume = {22},
number = {3},
pages = {434-441},
doi = {10.1097/IGC.0b013e31823ca017},
pmid = {22266933},
issn = {1525-1438},
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/*genetics/metabolism/physiology ; Carcinosarcoma/*diagnosis/genetics ; Female ; Humans ; Middle Aged ; Predictive Value of Tests ; Prognosis ; Retrospective Studies ; Sarcoma/*diagnosis/genetics ; Telomerase/metabolism ; Telomere Homeostasis/*physiology ; Tumor Cells, Cultured ; Uterine Neoplasms/*diagnosis/genetics ; Young Adult ; },
abstract = {OBJECTIVE: A subset of cancer cells maintains telomere lengths in a telomerase-independent manner known as the alternative lengthening of telomeres (ALT). The goal of this study was to evaluate the frequency of ALT in uterine sarcoma and carcinosarcoma and to assess its association with clinical parameters.<br><br>METHODS: Retrospectively collected paraffin blocks from 41 patients with uterine sarcomas and carcinosarcomas were analyzed for ALT-associated promyelocytic leukemia bodies (APBs), which are a significant feature of ALT cells, using combined immunofluorescence and telomere fluorescence in situ hybridization. In addition, a C-circle assay and human telomerase reverse transcriptase immunohistochemistry were performed to support these results.<br><br>RESULTS: The APB assay and C-circle assay indicated that 46.3% (19/41 cases) and 36.4% (8/22 cases) of sarcomas of the uterus, respectively, were positive for ALT. Alternative lengthening of telomerase positivity was correlated with high-grade uterine sarcoma and parameters indicative of an aggressive tumor, such as tumor size (P = 0.033) and mitotic index (P = 0.001); ALT positivity was negatively correlated with human telomerase reverse transcriptase reactivity (P = 0.036). In a survival analysis, the presence of APBs was found to be a poor prognostic factor for disease-free survival (P = 0.018) and overall survival (P = 0.021).<br><br>CONCLUSIONS: Alternative lengthening of telomeres is a prevalent mechanism in uterine sarcomas and carcinosarcomas and is associated with the aggressiveness of the tumor and tumor progression. Importantly, ALT positivity is an indicator of poor prognosis for patients with uterine sarcoma and carcinosarcoma.},
}
@article {pmid22266654,
year = {2012},
author = {McKerlie, M and Lin, S and Zhu, XD},
title = {ATM regulates proteasome-dependent subnuclear localization of TRF1, which is important for telomere maintenance.},
journal = {Nucleic acids research},
volume = {40},
number = {9},
pages = {3975-3989},
pmid = {22266654},
issn = {1362-4962},
support = {MOP-86620//Canadian Institutes of Health Research/Canada ; MSH-76599//Canadian Institutes of Health Research/Canada ; },
mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle ; Cell Cycle Proteins/*metabolism ; Cell Line ; Cell Nucleus/chemistry/enzymology/*metabolism ; DNA-Binding Proteins/*metabolism ; Humans ; Mutation ; Phosphorylation ; Proteasome Endopeptidase Complex/*metabolism ; Proteasome Inhibitors ; Protein Serine-Threonine Kinases/*metabolism ; Telomerase/metabolism ; Telomere/chemistry ; *Telomere Homeostasis ; Telomeric Repeat Binding Protein 1/analysis/genetics/*metabolism ; Tumor Suppressor Proteins/*metabolism ; },
abstract = {Ataxia telangiectasia mutated (ATM), a PI-3 kinase essential for maintaining genomic stability, has been shown to regulate TRF1, a negative mediator of telomerase-dependent telomere extension. However, little is known about ATM-mediated TRF1 phosphorylation site(s) in vivo. Here, we report that ATM phosphorylates S367 of TRF1 and that this phosphorylation renders TRF1 free of chromatin. We show that phosphorylated (pS367)TRF1 forms distinct non-telomeric subnuclear foci and that these foci occur predominantly in S and G2 phases, implying that their formation is cell cycle regulated. We show that phosphorylated (pS367)TRF1-containing foci are sensitive to proteasome inhibition. We find that a phosphomimic mutation of S367D abrogates TRF1 binding to telomeric DNA and renders TRF1 susceptible to protein degradation. In addition, we demonstrate that overexpressed TRF1-S367D accumulates in the subnuclear domains containing phosphorylated (pS367)TRF1 and that these subnuclear domains overlap with nuclear proteasome centers. Taken together, these results suggest that phosphorylated (pS367)TRF1-containing foci may represent nuclear sites for TRF1 proteolysis. Furthermore, we show that TRF1 carrying the S367D mutation is unable to inhibit telomerase-dependent telomere lengthening or to suppress the formation of telomere doublets and telomere loss in TRF1-depleted cells, suggesting that S367 phosphorylation by ATM is important for the regulation of telomere length and stability.},
}
@article {pmid22257826,
year = {2012},
author = {Harbo, M and Bendix, L and Bay-Jensen, AC and Graakjaer, J and Søe, K and Andersen, TL and Kjaersgaard-Andersen, P and Koelvraa, S and Delaisse, JM},
title = {The distribution pattern of critically short telomeres in human osteoarthritic knees.},
journal = {Arthritis research &amp; therapy},
volume = {14},
number = {1},
pages = {R12},
pmid = {22257826},
issn = {1478-6362},
mesh = {Aged ; Arthroplasty, Replacement, Knee ; Cellular Senescence/genetics ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Knee Joint/*metabolism/pathology/surgery ; Middle Aged ; Osteoarthritis, Knee/*genetics/pathology/surgery ; Severity of Illness Index ; Telomere/*genetics ; *Telomere Shortening ; },
abstract = {INTRODUCTION: Telomere shortening is associated with a number of common age-related diseases. A role of telomere shortening in osteoarthritis (OA) has been suggested, mainly based on the assessment of mean telomere length in ex vivo expanded chondrocytes. We addressed this role directly in vivo by using a newly developed assay, which measures specifically the load of ultra-short single telomeres (below 1,500 base pairs), that is, the telomere subpopulation believed to promote cellular senescence.<br><br>METHODS: Samples were obtained from human OA knees at two distances from the central lesion site. Each sample was split into three: one was used for quantification of ultra-short single telomeres through the Universal single telomere length assay (STELA), one for histological Mankin grading of OA, and one for mean telomere length measurement through quantitative fluorescence in situ hybridization (Q-FISH) as well as for assessment of senescence through quantification of senescence-associated heterochromatin foci (SAHF).<br><br>RESULTS: The load of ultra-short telomeres as well as mean telomere length was significantly associated with proximity to lesions, OA severity, and senescence level. The degree of significance was higher when assessed through load of ultra-short telomeres per cell compared with mean telomere length.<br><br>CONCLUSIONS: These in vivo data, especially the quantification of ultra-short telomeres, stress a role of telomere shortening in human OA.},
}
@article {pmid22250043,
year = {2012},
author = {Slatter, TL and Tan, X and Yuen, YC and Gunningham, S and Ma, SS and Daly, E and Packer, S and Devenish, C and Royds, JA and Hung, NA},
title = {The alternative lengthening of telomeres pathway may operate in non-neoplastic human cells.},
journal = {The Journal of pathology},
volume = {226},
number = {3},
pages = {509-518},
doi = {10.1002/path.2981},
pmid = {22250043},
issn = {1096-9896},
mesh = {Adult ; Aged ; Aged, 80 and over ; Case-Control Studies ; Cells, Cultured ; DNA/analysis ; Endothelial Cells/*pathology ; Epithelial Cells/*pathology ; Humans ; Middle Aged ; Neoplasms/pathology ; Nuclear Proteins/metabolism ; Promyelocytic Leukemia Protein ; Stromal Cells/*pathology ; Telomere/genetics/*pathology ; Telomere Homeostasis/*physiology ; Transcription Factors/metabolism ; Tumor Suppressor Proteins/metabolism ; Young Adult ; },
abstract = {The alternative lengthening of telomeres (ALT) mechanism represents an alternative to the enzyme telomerase in the maintenance of mammalian telomeres in 25-60% of sarcomas and a minority of carcinomas (about 5-15%). ALT-positive cells are distinguished by long and heterogeneous telomere length distributions by terminal restriction fragment (TRF) Southern blotting. Another diagnostic marker of ALT is discrete nuclear co-localized signals of telomeric DNA and the promyelocytic leukaemia protein (PML), referred to as ALT-associated PML bodies (APBs). Recently, we detected smaller sized co-localized PML and telomere DNA (APB-like) bodies in endothelial cells adjacent to astrocytoma tumour cells in situ. In this study, we examined a wide variety of non-neoplastic tissues, and report that co-localized signals of PML and telomere DNA are present in endothelial, stromal, and some epithelial cells. Co-localized signals of PML and telomere DNA showed an increased frequency in non-neoplastic cells with DNA damage. These results suggest that a mechanism similar to that in ALT-positive tumours also operates in non-neoplastic cells, which may be activated by DNA damage.},
}
@article {pmid22244753,
year = {2012},
author = {Lewis, KA and Wuttke, DS},
title = {Telomerase and telomere-associated proteins: structural insights into mechanism and evolution.},
journal = {Structure (London, England : 1993)},
volume = {20},
number = {1},
pages = {28-39},
pmid = {22244753},
issn = {1878-4186},
support = {F32 GM093528/GM/NIGMS NIH HHS/United States ; R01 GM059414/GM/NIGMS NIH HHS/United States ; GM093528/GM/NIGMS NIH HHS/United States ; GM059414/GM/NIGMS NIH HHS/United States ; },
mesh = {*Evolution, Molecular ; Humans ; *Models, Molecular ; *Protein Structure, Tertiary ; Species Specificity ; Telomerase/*chemistry/metabolism ; Telomere-Binding Proteins/*chemistry/metabolism ; },
abstract = {Recent advances in our structural understanding of telomerase and telomere-associated proteins have contributed significantly to elucidating the molecular mechanisms of telomere maintenance. The structures of telomerase TERT domains have provided valuable insights into how experimentally identified conserved motifs contribute to the telomerase reverse transcriptase reaction. Additionally, structures of telomere-associated proteins in a variety of organisms have revealed that, across evolution, telomere-maintenance mechanisms employ common structural elements. For example, the single-stranded 3' overhang of telomeric DNA is specifically and tightly bound by an OB-fold in nearly all species, including ciliates (TEBP and Pot1a), fission yeast (SpPot1), budding yeast (Cdc13), and humans (hPOT1). Structures of the yeast Cdc13, Stn1, and Ten1 proteins demonstrated that telomere maintenance is regulated by a complex that bears significant similarity to the RPA heterotrimer. Similarly, proteins that specifically bind double-stranded telomeric DNA in divergent species use homeodomains to execute their functions (human TRF1 and TRF2 and budding yeast ScRap1). Likewise, the conserved protein Rap1, which is found in budding yeast, fission yeast, and humans, contains a structural motif that is known to be critical for protein-protein interaction. In addition to revealing the common underlying themes of telomere maintenance, structures have also elucidated the specific mechanisms by which many of these proteins function, including identifying a telomere-specific domain in Stn1 and how the human TRF proteins avoid heterodimerization. In this review, we summarize the high-resolution structures of telomerase and telomere-associated proteins and discuss the emergent common structural themes among these proteins. We also address how these high-resolution structures complement biochemical and cellular studies to enhance our understanding of telomere maintenance and function.},
}
@article {pmid22237065,
year = {2012},
author = {Kark, JD and Goldberger, N and Kimura, M and Sinnreich, R and Aviv, A},
title = {Energy intake and leukocyte telomere length in young adults.},
journal = {The American journal of clinical nutrition},
volume = {95},
number = {2},
pages = {479-487},
pmid = {22237065},
issn = {1938-3207},
support = {AG030678/AG/NIA NIH HHS/United States ; AG20132/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aging/genetics/*physiology ; Base Pairing ; Biomarkers ; Blotting, Southern ; Cross-Sectional Studies ; *Diet ; Diet Surveys ; *Energy Intake ; Fatty Acids, Unsaturated/*pharmacology ; Female ; Humans ; Leukocytes/*ultrastructure ; Linear Models ; Longitudinal Studies ; Male ; Multivariate Analysis ; Sex Factors ; Smoking ; Statistics, Nonparametric ; Surveys and Questionnaires ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Dietary energy restriction in mammals, particularly at a young age, extends the life span. Leukocyte telomere length (LTL) is thought to be a bioindicator of aging in humans. High n-6 (omega-6) PUFA intake may accelerate LTL attrition.<br><br>OBJECTIVE: We determined whether lower energy and higher PUFA intakes in young adulthood are associated with shorter LTL in cross-sectional and longitudinal analyses.<br><br>DESIGN: In a longitudinal observational study (405 men, 204 women), diet was determined at baseline by a semiquantitative food-frequency questionnaire, and LTL was determined by Southern blots at mean ages of 30.1 y (baseline) and 43.2 y (follow-up). Spearman correlations and multivariable linear regression were used.<br><br>RESULTS: Baseline energy intake was inversely associated with follow-up LTL in men (standardized &#x3b2; = -0.171, P = 0.0005) but not in women (P = 0.039 for sex interaction). The difference in men between the highest and lowest quintiles of energy was 244 base pairs (bp) (95% CI: 59, 429 bp) and between extreme quintiles of LTL was 440 kcal (95% CI: 180, 700 kcal). Multivariable adjustment modestly attenuated the association (&#x3b2; = -0.157, P = 0.002). Inverse associations, which were noted for all macronutrients, were strongest for the unsaturated fatty acids. In multivariable models including energy and the macronutrients (as percentage of energy), the significant inverse energy-LTL association (but not the PUFA-LTL association) persisted. The energy-LTL association was restricted to never smokers (standardized &#x3b2; = -0.259, P = 0.0008; P = 0.050 for the smoking &#xd7; calorie interaction).<br><br>CONCLUSIONS: The inverse calorie intake-LTL association is consistent with trial data showing beneficial effects of calorie restriction on aging biomarkers. Further exploration of energy intake and LTL dynamics in the young is needed.},
}
@article {pmid22233151,
year = {2012},
author = {Jones, CH and Pepper, C and Baird, DM},
title = {Telomere dysfunction and its role in haematological cancer.},
journal = {British journal of haematology},
volume = {156},
number = {5},
pages = {573-587},
doi = {10.1111/j.1365-2141.2011.09022.x},
pmid = {22233151},
issn = {1365-2141},
support = {//Cancer Research UK/United Kingdom ; },
mesh = {Acute Disease ; Bone Marrow Diseases/genetics ; Disease Progression ; Genomic Instability ; Hematologic Neoplasms/*genetics ; Humans ; Leukemia/genetics ; Lymphoma, B-Cell/genetics ; Multiple Myeloma/genetics ; Prognosis ; Telomere/*physiology ; Telomere Shortening/genetics ; },
abstract = {Observations in human tumours, as well as mouse models, have indicated that telomere dysfunction may be a key event driving genomic instability and disease progression in many solid tumour types. In this scenario, telomere shortening ultimately results in telomere dysfunction, fusion and genomic instability, creating the large-scale rearrangements that are characteristic of these tumours. It is now becoming apparent that this paradigm may also apply to haematological malignancies; indeed these conditions have provided some of the most convincing evidence of telomere dysfunction in any malignancy. Telomere length has been shown in several malignancies to provide clinically useful prognostic information, implicating telomere dysfunction in disease progression. In these malignancies extreme telomere shortening, telomere dysfunction and fusion have all been documented and correlate with the emergence of increased genomic complexity. Telomeres may therefore represent both a clinically useful prognostic tool and a potential target for therapeutic intervention.},
}
@article {pmid22232932,
year = {2011},
author = {Grach, AA},
title = {[The role of alternative lengthening of telomeres mechanisms in carcinogenesis and prospects for using an anti-telomerase drugs in malignant tumors treatment].},
journal = {Tsitologiia},
volume = {53},
number = {10},
pages = {759-771},
pmid = {22232932},
issn = {0041-3771},
mesh = {Antineoplastic Agents/*therapeutic use ; Cancer Vaccines/therapeutic use ; Carcinoma/genetics/immunology/pathology/prevention &amp; control/*therapy ; Cell Transformation, Neoplastic/drug effects/immunology/metabolism ; Enzyme Inhibitors/*therapeutic use ; Humans ; Sarcoma/genetics/immunology/pathology/prevention &amp; control/*therapy ; Telomerase/*antagonists &amp; inhibitors/genetics/metabolism ; Telomere/*drug effects/immunology/metabolism ; Telomere Homeostasis/*drug effects ; },
abstract = {The review analyzes telomere lengthening mechanisms in cancer cells of two different tumor types--carcinomas and sarcomas. Basic attention is given to sarcomas which cells lengthen their telomeres through alternative mechanisms for lengthening telomeres (ALT). The features of ALT mechanisms functioning in these cells have been examined in detail. Moreover, the actually existing anti-telomerase drugs and their efficiency in carcinomas treatment were analyzed. The experimental data showing that, contrary to theoretical expectations, activation of ALT was not observed on a background of such anti-telomerase, are presented. This portends a good prognosis in the treatment of the patients with carcinoma. Finally, on the basis of the data analyzed the candidates for a role of targets are proposed for development of anti-ALT antineoplastic therapy. Expected efficiency and toxicity of such drugs are considered in detail.},
}
@article {pmid22232671,
year = {2012},
author = {Heidinger, BJ and Blount, JD and Boner, W and Griffiths, K and Metcalfe, NB and Monaghan, P},
title = {Telomere length in early life predicts lifespan.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {109},
number = {5},
pages = {1743-1748},
pmid = {22232671},
issn = {1091-6490},
mesh = {Animals ; Finches/*genetics ; *Life Expectancy ; *Telomere ; },
abstract = {The attrition of telomeres, the ends of eukaryote chromosomes, is thought to play an important role in cell deterioration with advancing age. The observed variation in telomere length among individuals of the same age is therefore thought to be related to variation in potential longevity. Studies of this relationship are hampered by the time scale over which individuals need to be followed, particularly in long-lived species where lifespan variation is greatest. So far, data are based either on simple comparisons of telomere length among different age classes or on individuals whose telomere length is measured at most twice and whose subsequent survival is monitored for only a short proportion of the typical lifespan. Both approaches are subject to bias. Key studies, in which telomere length is tracked from early in life, and actual lifespan recorded, have been lacking. We measured telomere length in zebra finches (n = 99) from the nestling stage and at various points thereafter, and recorded their natural lifespan (which varied from less than 1 to almost 9 y). We found telomere length at 25 d to be a very strong predictor of realized lifespan (P < 0.001); those individuals living longest had relatively long telomeres at all points at which they were measured. Reproduction increased adult telomere loss, but this effect appeared transient and did not influence survival. Our results provide the strongest evidence available of the relationship between telomere length and lifespan and emphasize the importance of understanding factors that determine early life telomere length.},
}
@article {pmid22229928,
year = {2012},
author = {Uchino, BN and Cawthon, RM and Smith, TW and Light, KC and McKenzie, J and Carlisle, M and Gunn, H and Birmingham, W and Bowen, K},
title = {Social relationships and health: is feeling positive, negative, or both (ambivalent) about your social ties related to telomeres?.},
journal = {Health psychology : official journal of the Division of Health Psychology, American Psychological Association},
volume = {31},
number = {6},
pages = {789-796},
pmid = {22229928},
issn = {1930-7810},
support = {R21 AG029239-01A1/AG/NIA NIH HHS/United States ; C06 RR011234/RR/NCRR NIH HHS/United States ; R21 AG029239/AG/NIA NIH HHS/United States ; UL1-RR025764/RR/NCRR NIH HHS/United States ; UL1 RR025764/RR/NCRR NIH HHS/United States ; },
mesh = {Aged ; *Emotions ; Female ; *Health Status ; Humans ; *Interpersonal Relations ; Male ; Middle Aged ; Telomere/*ultrastructure ; Telomere Shortening ; },
abstract = {OBJECTIVES: The quality of one's personal relationships has been linked to morbidity and mortality across different diseases. As a result, it is important to examine more integrative mechanisms that might link relationships across diverse physical health outcomes. In this study, we examine associations between relationships and telomeres that predict general disease risk. These questions are pursued in the context of a more comprehensive model of relationships that highlights the importance of jointly considering positive and negative aspects of social ties.<br><br>METHOD: One hundred thirty-six individuals from a community sample (ages 48 to 77 years) completed the social relationships index, which allows a determination of relationships that differ in their positive and negative substrates (i.e., ambivalent, supportive, aversive, indifferent). Telomere length was determined from peripheral blood mononuclear cells via quantitative polymerase chain reaction.<br><br>RESULTS: Participants who had a higher number of ambivalent ties in their social networks evidenced shorter telomeres. These results were independent of other relationship types (e.g., supportive) and standard control variables (e.g., age, health behaviors, and medication use). Gender moderated the links between ambivalent ties and telomere length, with these associations seen primarily in women. Follow-up analyses revealed that the links between ambivalent ties and telomeres were primarily due to friendships, parents, and social acquaintances.<br><br>CONCLUSION: Consistent with epidemiological findings, these data highlight a novel and integrative biological mechanism by which social ties may affect health across diseases and further suggest the importance of incorporating positivity and negativity in the study of specific relationships and physical health.},
}
@article {pmid22227188,
year = {2012},
author = {Rozario, D and Siede, W},
title = {Saccharomyces cerevisiae Tel2 plays roles in TORC signaling and telomere maintenance that can be mutationally separated.},
journal = {Biochemical and biophysical research communications},
volume = {417},
number = {4},
pages = {1182-1187},
doi = {10.1016/j.bbrc.2011.12.103},
pmid = {22227188},
issn = {1090-2104},
mesh = {Cell Cycle Proteins/*metabolism ; Mutagenesis ; Phosphatidylinositol 3-Kinase/metabolism ; Phosphatidylinositol 3-Kinases/*metabolism ; Point Mutation ; Saccharomyces cerevisiae/drug effects/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Signal Transduction ; Sirolimus/pharmacology ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {The evolutionary conserved Tel2 protein appears to function as a co-chaperone required for the activity of phosphatidylinositol 3-kinase-like protein kinases (PIKKs). Since Saccharomyces cerevisiae Tel2 is essential for viability and only a single point mutant (Tel2-1) had been characterized so far, the possible range of phenotypes associated with Tel2 mutations was unknown. We used random in vitro mutagenesis and plasmid shuffling to create additional point mutants. No significant sensitivity towards DNA damaging agents or hydroxyurea was evident, indicating that Tel2 is not required for Mec1 function. However, as frequent novel phenotypes, we detected slow growth or enhanced lethality in response to rapamycin that could be correlated with lower level and activity of Tor1 or of both Tor1 and Tor2, respectively. The newly isolated mutant with the most severe phenotype, Tel2-13, is comprised of 8 amino acid changes. Two mutated residues of Tel2-13 near the N-terminus and close to Tel2-1 are sufficient for shortened telomeres whereas multiple mutations within the C-terminal two thirds of the protein are required for enhanced rapamycin lethality. Our findings demonstrate separation of function explainable by differential binding of Tel2 to its PIKK substrates Tel1 or Tor1/Tor2 and thus a critical contribution of Tel2 to the interface that links various PIKKs to this chaperone complex.},
}
@article {pmid22217714,
year = {2011},
author = {Ilyenko, I and Lyaskivska, O and Bazyka, D},
title = {Analysis of relative telomere length and apoptosis in humans exposed to ionising radiation.},
journal = {Experimental oncology},
volume = {33},
number = {4},
pages = {235-238},
pmid = {22217714},
issn = {2312-8852},
mesh = {Apoptosis/*radiation effects ; Chernobyl Nuclear Accident ; Humans ; In Situ Hybridization, Fluorescence ; K562 Cells ; Leukocytes, Mononuclear/radiation effects ; Lymphocyte Count ; Middle Aged ; Myelodysplastic Syndromes/etiology/genetics ; *Radiation, Ionizing ; Telomere/*radiation effects ; Telomere Homeostasis/*radiation effects ; },
abstract = {BACKGROUND: Ionizing radiation could modify lymphocyte function via oxidative damage, DNA breaks, and resulting changes of proliferation, apoptosis and cellular senescence, where telomeres may play a critical role.<br><br>AIM: To study the effect of low-dose irradiation on the telomere length and apoptosis rates in peripheral blood lymphocytes of irradiated persons.<br><br>PATIENTS AND METHODS: A study was performed on 83 peripheral blood samples from the Chornobyl clean-up workers, radiation workers exposed under the professional limits at construction works at the "Shelter" object and healthy controls. Bone marrow leukocyte telomere length was estimated in 15 patients with myelodysplastic syndrome secondary to low-dose radiation exposure and 12 age-standardized healthy donors. Relative telomere length was studied by the combination of a fluorescence hybridization in situ with PNA probe and flow cytometry, apoptosis - by Annexin-V test.<br><br>RESULTS: A significant relative telomere length decrease has been demonstrated in Chornobyl clean-up workers compared to healthy donors (13.2 &#xb1; 0.69 and 18.6 &#xb1; 0.73 respectively, p < 0.05), and a tendency (p < 0.1) in radiation workers. At doses over professional limits an inverse dependency is demonstrated between the relative telomere length and a number of lymphocytes in early stage of apoptosis. In MDS group a tendency of telomere elongation was demonstrated in bone marrow granulocytes in RAEB-t and RAEB as comparing with RA.<br><br>CONCLUSION: This study shows telomere shortening after low-dose irradiation and preservation of these changes even 20 years after exposure. Apoptosis induction is possible by the telomere region changes at least in individuals with shorter telomeres. Apoptosis decrease in MDS clonal transformation is associated with a substantially longer telomeres.},
}
@article {pmid22217197,
year = {2012},
author = {Imsoonthornruksa, S and Sangmalee, A and Srirattana, K and Parnpai, R and Ketudat-Cairns, M},
title = {Development of intergeneric and intrageneric somatic cell nuclear transfer (SCNT) cat embryos and the determination of telomere length in cloned offspring.},
journal = {Cellular reprogramming},
volume = {14},
number = {1},
pages = {79-87},
doi = {10.1089/cell.2011.0054},
pmid = {22217197},
issn = {2152-4998},
mesh = {Animals ; Cats/*embryology/*genetics ; Cloning, Organism/*methods ; DNA, Intergenic/*genetics ; Embryo Transfer ; Embryo, Mammalian/ultrastructure ; Embryonic Development/*genetics ; Female ; Fibroblasts/cytology ; In Vitro Techniques ; Male ; Models, Animal ; *Nuclear Transfer Techniques ; Oocytes/cytology ; Pregnancy ; Pregnancy Outcome ; Telomere/*ultrastructure ; },
abstract = {Somatic cell nuclear transfer (SCNT) holds potential as a useful tool for agricultural and biomedical applications. In vitro development of marbled cat intergeneric SCNT reconstructed into domestic cat cytoplast revealed that cloned, marbled cat embryo development was blocked at the morula stage. No pregnancies resulted from the transfer of one- to eight-cell stage embryos into domestic cat surrogate mothers. This suggested that abnormalities occurred in the cloned marbled cat embryos, which may be associated with incomplete reprogramming during early embryo development. Two pregnancies were established in surrogate mothers that received cloned domestic cat embryos, but SCNT offspring developed abnormally. Some specific phenotypes that were observed included incomplete abdominal wall disclosure, improper fetal development. In addition, some of the fetuses were mummified or stillbirths. The two live births died within 5 days. Telomere lengths of cloned kittens as determined by qualtitative polymerase chain reaction (qPCR) were inconclusive: some were found to be shorter, longer, or the same as donor control cells. Our findings support the hypothesis that telomere lengths do not govern the health of these cloned animals. A lack of complete reprogramming may lead to developmental failure and the abnormalities observed in cloned offspring.},
}
@article {pmid22215813,
year = {2012},
author = {Webb, CJ and Zakian, VA},
title = {Schizosaccharomyces pombe Ccq1 and TER1 bind the 14-3-3-like domain of Est1, which promotes and stabilizes telomerase-telomere association.},
journal = {Genes &amp; development},
volume = {26},
number = {1},
pages = {82-91},
pmid = {22215813},
issn = {1549-5477},
support = {P30 CA072720/CA/NCI NIH HHS/United States ; R01 GM043265/GM/NIGMS NIH HHS/United States ; GM043265/GM/NIGMS NIH HHS/United States ; },
mesh = {14-3-3 Proteins/metabolism ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Models, Molecular ; Protein Binding ; Protein Stability ; Protein Structure, Tertiary ; RNA ; Schizosaccharomyces/enzymology/*metabolism ; Schizosaccharomyces pombe Proteins/chemistry/genetics/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {The telomerase protein Est1 exists in multiple organisms, including Schizosaccharomyces pombe, humans, and Saccharomyces cerevisiae, but its function has only been closely examined in S. cerevisiae, where it is a recruiter/activator of telomerase. Here, we demonstrate that S. pombe Est1 was required for the telomere association of the telomerase holoenzyme, suggesting that it too has a recruitment role. Its association with telomeres was dependent on Trt1, the catalytic subunit, and Ccq1, a telomeric protein. Surprisingly, Est1 telomere binding was only partially dependent on TER1, the telomerase RNA, even though Est1 bound nucleotides 415-507 of TER1. A ter1-Δ415-507 strain had short telomeres and very low Est1 and Trt1 telomere association in late S phase but did not senesce. An unbiased search for mutations that reduced Est1-TER1 interaction identified mutations only in the Est1 14-3-3-like domain, a phosphoserine-binding motif, the first example of a 14-3-3-like domain with RNA-binding activity. These mutations also reduced Est1-Ccq1 binding. One such mutant prevented Est1 telomere association and caused telomere loss and slow senescence, similar to ccq1Δ. We propose that the Est1-Ccq1 interaction is critical for telomerase recruitment, while the Est1-TER1 interaction acts downstream from Ccq1-mediated recruitment to stabilize the holoenzyme at the telomere.},
}
@article {pmid22212477,
year = {2012},
author = {Allsopp, R},
title = {Telomere length and iPSC re-programming: survival of the longest.},
journal = {Cell research},
volume = {22},
number = {4},
pages = {614-615},
pmid = {22212477},
issn = {1748-7838},
mesh = {*Cell Differentiation ; Enzyme Activation ; Humans ; Pluripotent Stem Cells/*cytology/metabolism ; RNA/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; *Telomere Homeostasis/genetics ; Transcription Factors/genetics/metabolism ; },
}
@article {pmid22210444,
year = {2012},
author = {Senthilkumar, PK and Robertson, LW and Ludewig, G},
title = {PCB153 reduces telomerase activity and telomere length in immortalized human skin keratinocytes (HaCaT) but not in human foreskin keratinocytes (NFK).},
journal = {Toxicology and applied pharmacology},
volume = {259},
number = {1},
pages = {115-123},
pmid = {22210444},
issn = {1096-0333},
support = {P42 ES013661-02/ES/NIEHS NIH HHS/United States ; P42 ES013661-05/ES/NIEHS NIH HHS/United States ; P30 ES005605/ES/NIEHS NIH HHS/United States ; P42 ES013661-04/ES/NIEHS NIH HHS/United States ; P42 ES013661-03/ES/NIEHS NIH HHS/United States ; P42 ES013661-07/ES/NIEHS NIH HHS/United States ; P42 ES013661/ES/NIEHS NIH HHS/United States ; P42 ES013661-06/ES/NIEHS NIH HHS/United States ; },
mesh = {Cell Culture Techniques ; Cell Cycle/drug effects ; Cell Line ; Cell Survival/drug effects ; DNA/genetics ; Dose-Response Relationship, Drug ; Environmental Pollutants/*toxicity ; Enzyme Activation ; Foreskin/*drug effects/enzymology/ultrastructure ; Humans ; Keratinocytes/*drug effects/enzymology/ultrastructure ; Male ; Oxidative Stress/drug effects ; Polychlorinated Biphenyls/*toxicity ; Superoxides/metabolism ; Telomerase/*metabolism ; Telomere Shortening/*drug effects/genetics ; },
abstract = {Polychlorinated biphenyls (PCBs), ubiquitous environmental pollutants, are characterized by long term-persistence in the environment, bioaccumulation, and biomagnification in the food chain. Exposure to PCBs may cause various diseases, affecting many cellular processes. Deregulation of the telomerase and the telomere complex leads to several biological disorders. We investigated the hypothesis that PCB153 modulates telomerase activity, telomeres and reactive oxygen species resulting in the deregulation of cell growth. Exponentially growing immortal human skin keratinocytes (HaCaT) and normal human foreskin keratinocytes (NFK) were incubated with PCB153 for 48 and 24days, respectively, and telomerase activity, telomere length, superoxide level, cell growth, and cell cycle distribution were determined. In HaCaT cells exposure to PCB153 significantly reduced telomerase activity, telomere length, cell growth and increased intracellular superoxide levels from day 6 to day 48, suggesting that superoxide may be one of the factors regulating telomerase activity, telomere length and cell growth compared to untreated control cells. Results with NFK cells showed no shortening of telomere length but reduced cell growth and increased superoxide levels in PCB153-treated cells compared to untreated controls. As expected, basal levels of telomerase activity were almost undetectable, which made a quantitative comparison of treated and control groups impossible. The significant down regulation of telomerase activity and reduction of telomere length by PCB153 in HaCaT cells suggest that any cell type with significant telomerase activity, like stem cells, may be at risk of premature telomere shortening with potential adverse health effects for the affected organism.},
}
@article {pmid22210159,
year = {2012},
author = {Movérare-Skrtic, S and Johansson, P and Mattsson, N and Hansson, O and Wallin, A and Johansson, JO and Zetterberg, H and Blennow, K and Svensson, J},
title = {Leukocyte telomere length (LTL) is reduced in stable mild cognitive impairment but low LTL is not associated with conversion to Alzheimer's disease: a pilot study.},
journal = {Experimental gerontology},
volume = {47},
number = {2},
pages = {179-182},
doi = {10.1016/j.exger.2011.12.005},
pmid = {22210159},
issn = {1873-6815},
mesh = {Aged ; Aging/*genetics ; Alzheimer Disease/cerebrospinal fluid/*diagnosis/etiology ; Amyloid beta-Peptides/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Case-Control Studies ; Cognitive Dysfunction/cerebrospinal fluid/complications/*genetics ; Female ; Follow-Up Studies ; Humans ; *Leukocytes ; Male ; Neuropsychological Tests ; Peptide Fragments/cerebrospinal fluid ; Pilot Projects ; Telomere/genetics ; *Telomere Shortening/genetics ; tau Proteins/cerebrospinal fluid ; },
abstract = {Leukocyte telomere length (LTL) is associated with the aging process and may be related to cognitive aging. Previous studies have shown conflicting results whether LTL is affected in patients with Alzheimer's disease (AD). In this pilot study, we investigated LTL in a well-defined homogeneous mono-center population. Sixty consecutive patients admitted for cognitive impairment to a memory clinic were recruited. The participants included patients with AD or mild cognitive impairment (MCI) diagnosed with AD upon follow-up (n=32), patients with stable MCI (n=13), patients with other dementias diagnosed at primary evaluation or upon follow-up (n=15), and healthy controls (n=20). LTL was determined using a quantitative PCR assay. Patients with AD had similar LTL as healthy controls. Patients with stable MCI had reduced LTL both compared to AD patients (p=0.02) and controls (p=0.008). Subanalyses within the AD group showed that patients with MCI that later converted to AD had similar LTL as patients with clinical diagnosis of AD at primary evaluation and healthy controls whereas the LTL was longer compared to the stable MCI group (p=0.02). There were no correlations between LTL and the core AD biomarkers Aβ(1-42), T-tau and P-tau. In conclusion, in this pilot study, patients with AD or MCI that later converted to AD had similar LTL as healthy controls. Patients with stable MCI that did not progress to dementia had reduced LTL compared to controls, which might suggest a more marked biological aging as a cause of the cognitive symptoms in this group.},
}
@article {pmid22203190,
year = {2012},
author = {Dewar, JM and Lydall, D},
title = {Similarities and differences between "uncapped" telomeres and DNA double-strand breaks.},
journal = {Chromosoma},
volume = {121},
number = {2},
pages = {117-130},
pmid = {22203190},
issn = {1432-0886},
support = {075294//Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Cell Cycle Proteins/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; *DNA Breaks, Double-Stranded ; DNA Helicases/genetics/metabolism ; DNA Repair/genetics/*physiology ; Exodeoxyribonucleases/metabolism ; Mammals ; *Models, Biological ; Multiprotein Complexes/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Saccharomycetales ; Telomere/*genetics ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomeric DNA is present at the ends of eukaryotic chromosomes and is bound by telomere "capping" proteins, which are the (Cdc13-Stn1-Ten1) CST complex, Ku (Yku70-Yku80), and Rap1-Rif1-Rif2 in budding yeast. Inactivation of any of these complexes causes telomere "uncapping," stimulating a DNA damage response (DDR) that frequently involves resection of telomeric DNA and stimulates cell cycle arrest. This is presumed to occur because telomeres resemble one half of a DNA double-strand break (DSB). In this review, we outline the DDR that occurs at DSBs and compare it to the DDR occurring at uncapped telomeres, in both budding yeast and metazoans. We give particular attention to the resection of DSBs in budding yeast by Mre11-Xrs2-Rad50 (MRX), Sgs1/Dna2, and Exo1 and compare their roles at DSBs and uncapped telomeres. We also discuss how resection uncapped telomeres in budding yeast is promoted by the by 9-1-1 complex (Rad17-Mec3-Ddc1), to illustrate how analysis of uncapped telomeres can serve as a model for the DDR elsewhere in the genome. Finally, we discuss the role of the helicase Pif1 and its requirement for resection of uncapped telomeres, but not DSBs. Pif1 has roles in DNA replication and mammalian and plant CST complexes have been identified and have roles in global genome replication. Based on these observations, we suggest that while the DDR at uncapped telomeres is partially due to their resemblance to a DSB, it may also be partially due to defective DNA replication. Specifically, we propose that the budding yeast CST complex has dual roles to inhibit a DSB-like DDR initiated by Exo1 and a replication-associated DDR initiated by Pif1. If true, this would suggest that the mammalian CST complex inhibits a Pif1-dependent DDR.},
}
@article {pmid22202040,
year = {2012},
author = {Choudhary, B and Karande, AA and Raghavan, SC},
title = {Telomere and telomerase in stem cells: relevance in ageing and disease.},
journal = {Frontiers in bioscience (Scholar edition)},
volume = {4},
number = {1},
pages = {16-30},
doi = {10.2741/248},
pmid = {22202040},
issn = {1945-0524},
mesh = {Animals ; Cellular Senescence/physiology ; Humans ; Stem Cells/cytology/*enzymology/*ultrastructure ; Telomerase/genetics/metabolism/*physiology ; Telomere/genetics/metabolism/*physiology ; },
abstract = {Telomeres, at the end of chromosomes provide genomic stability. During embryonic development, telomerase, a reverse transcriptase elongates the ends of the DNA. In somatic cells, the activity of telomerase decreases after birth leading to shortening of telomere with cell division, which thereby triggers senescence. In embryonic stem cells and germ cells, telomere length is maintained. In adults, the tissue specific stem cells have telomerase activity, but it is not enough to maintain the length of telomere. The stem cells also undergo the process of ageing but it is delayed as compared to the somatic cells. Studies on the genetic disorder, dyskeratosis congenital, caused by mutations in the human telomerase, reiterate the importance of telomere maintenance in human stem cells. This review covers the role of telomere and telomerase in stem cells and their relevance in disease and ageing.},
}
@article {pmid22201831,
year = {2012},
author = {Longhese, MP and Anbalagan, S and Martina, M and Bonetti, D},
title = {The role of shelterin in maintaining telomere integrity.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {17},
number = {5},
pages = {1715-1728},
doi = {10.2741/4014},
pmid = {22201831},
issn = {2768-6698},
mesh = {DNA Damage ; DNA Repair ; Humans ; Shelterin Complex ; *Telomere ; Telomere-Binding Proteins/*physiology ; },
abstract = {The ends of eukaryotic chromosomes need to be protected from detection as DNA double strand breaks by the DNA damage response pathways. Failure to do so would have devastating consequences for genome integrity. Packaging of chromosome ends into protective structures called telomeres prevents checkpoint activation and DNA repair/recombination activities. Several studies on a variety of organisms have revealed that protein complexes with specificity for telomeric DNA protect chromosome ends from being recognized as DNA double-strand breaks and regulate telomere maintenance by the telomerase. In this review, we will discuss the consequences of telomere dysfunction and our understanding of how telomere integrity is maintained.},
}
@article {pmid22199369,
year = {2012},
author = {Weischer, M and Bojesen, SE and Cawthon, RM and Freiberg, JJ and Tybjærg-Hansen, A and Nordestgaard, BG},
title = {Short telomere length, myocardial infarction, ischemic heart disease, and early death.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {32},
number = {3},
pages = {822-829},
doi = {10.1161/ATVBAHA.111.237271},
pmid = {22199369},
issn = {1524-4636},
mesh = {Adult ; Age Factors ; Aged ; Aging/genetics ; Denmark/epidemiology ; Female ; Follow-Up Studies ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Myocardial Infarction/*genetics/*mortality ; Myocardial Ischemia/*genetics/*mortality ; Phenotype ; Proportional Hazards Models ; Prospective Studies ; Real-Time Polymerase Chain Reaction ; Risk Assessment ; Risk Factors ; *Telomere Shortening ; Time Factors ; },
abstract = {OBJECTIVE: We tested the hypothesis that short telomere length is associated with increased risk of myocardial infarction, ischemic heart disease, and early death.<br><br>METHODS AND RESULTS: We measured leukocyte telomere length in 2 prospective studies of 19 838 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Participants were followed for up to 19 years for incident myocardial infarction (n=929), ischemic heart disease (n=2038), and death (n=4342). Follow-up was 100% complete. Telomere length decreased linearly with increasing age in women and men in both studies (P=7&#xd7;10(-74) to P=3&#xd7;10(-125)). Multifactorially adjusted hazard ratios were 1.10 (95% CI 1.01-1.19) for myocardial infarction, 1.06 (1.00-1.11) for ischemic heart disease, and 1.09 (1.05-1.13) for early death per 1000-base pair decrease in telomere length. The multifactorially adjusted hazard ratios for the shortest versus the longest decile of telomere length were 1.49 (1.07-2.07) for myocardial infarction, 1.24 (1.01-1.53) for ischemic heart disease, and 1.25 (1.07-1.46) for early death.<br><br>CONCLUSION: Short telomere length is associated with only modestly increased risk of myocardial infarction, ischemic heart disease, and early death.},
}
@article {pmid22187435,
year = {2012},
author = {Min, J and Choi, ES and Hwang, K and Kim, J and Sampath, S and Venkitaraman, AR and Lee, H},
title = {The breast cancer susceptibility gene BRCA2 is required for the maintenance of telomere homeostasis.},
journal = {The Journal of biological chemistry},
volume = {287},
number = {7},
pages = {5091-5101},
pmid = {22187435},
issn = {1083-351X},
support = {G0600332/MRC_/Medical Research Council/United Kingdom ; G0700651/MRC_/Medical Research Council/United Kingdom ; G1001521/MRC_/Medical Research Council/United Kingdom ; MC_U105359877/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; BRCA2 Protein/genetics/*metabolism ; Cells, Cultured ; Chromosome Aberrations ; DNA Damage/physiology ; Fibroblasts/cytology/*metabolism ; Homeostasis/*physiology ; Humans ; Mice ; Mice, Knockout ; S Phase/*physiology ; Sister Chromatid Exchange/physiology ; Telomere/genetics/*metabolism ; },
abstract = {Inactivating mutations in the breast cancer susceptibility gene BRCA2 cause gross chromosomal rearrangements. Chromosome structural instability in the absence of BRCA2 is thought to result from defective homology-directed DNA repair. Here, we show that BRCA2 links the fidelity of telomere maintenance with genetic integrity. Absence of BRCA2 resulted in signs of dysfunctional telomeres, such as telomere shortening, erosions, and end fusions in proliferating mouse fibroblasts. BRCA2 localized to the telomeres in S phase in an ATR-dependent manner, and its absence resulted in the accumulation of common fragile sites, particularly at the G-rich lagging strand, and increased the telomere sister chromatid exchange in unchallenged cells. The incidence of common fragile sites and telomere sister chromatid exchange increased markedly after treatment with replication inhibitors. Congruently, telomere-induced foci were frequently observed in the absence of Brca2, denoting activation of the DNA damage response and abnormal chromosome end joining. These telomere end fusions constituted a significant portion of chromosome aberrations in Brca2-deficient cells. Our results suggest that BRCA2 is required for telomere homeostasis and may be particularly important for the replication of G-rich telomeric lagging strands.},
}
@article {pmid22186032,
year = {2012},
author = {Tzanetakou, IP and Katsilambros, NL and Benetos, A and Mikhailidis, DP and Perrea, DN},
title = {"Is obesity linked to aging?": adipose tissue and the role of telomeres.},
journal = {Ageing research reviews},
volume = {11},
number = {2},
pages = {220-229},
doi = {10.1016/j.arr.2011.12.003},
pmid = {22186032},
issn = {1872-9649},
mesh = {Adipose Tissue/immunology/*metabolism/pathology ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics/immunology/metabolism/pathology ; Animals ; Cellular Senescence ; Child ; Child, Preschool ; Female ; Humans ; Inflammation Mediators/*metabolism ; Male ; Middle Aged ; Obesity/*genetics/immunology/metabolism/pathology ; *Oxidative Stress ; Telomere/*metabolism ; *Telomere Shortening ; Young Adult ; },
abstract = {Obesity is a condition in which excess or abnormal fat accumulation may present with adverse effects on health and decreased life expectancy. Increased body weight and adipose tissue accumulation amplifies the risk of developing various age-related diseases, such as cardiovascular disease, type 2 diabetes mellitus, musculoskeletal disorders, respiratory diseases and certain types of cancer. This imbalance in body composition and body weight is now recognized as a state of increased oxidative stress and inflammation for the organism. Increasing oxidative stress and inflammation affect telomeres. Telomeres are specialized DNA-protein structures found at the ends of eukaryotic chromosomes and serve as markers of biological aging rate. They also play a critical role in maintaining genomic integrity and are involved in age-related metabolic dysfunction. Erosion of telomeres is hazardous to healthy cells, as it is a known mechanism of premature cellular senescence and loss of longevity. The association of telomeres and oxidative stress is evident in cultured somatic cells in vitro, where oxidative stress enhances the process of erosion with each cycle of replication. Shorter telomeres have been associated with increasing body mass index, increased adiposity, and more recently with increasing waist to hip ratio and visceral excess fat accumulation. Furthermore, many of the metabolic imbalances of obesity (e.g. glycemic, lipidemic, etc.) give rise to organ dysfunction in a way that resembles the accelerated aging process. This article is a non-systematic review of the evidence linking obesity and accelerated aging processes as they are regulated by telomeres.},
}
@article {pmid22184006,
year = {2012},
author = {Wang, F and Yin, Y and Ye, X and Liu, K and Zhu, H and Wang, L and Chiourea, M and Okuka, M and Ji, G and Dan, J and Zuo, B and Li, M and Zhang, Q and Liu, N and Chen, L and Pan, X and Gagos, S and Keefe, DL and Liu, L},
title = {Molecular insights into the heterogeneity of telomere reprogramming in induced pluripotent stem cells.},
journal = {Cell research},
volume = {22},
number = {4},
pages = {757-768},
pmid = {22184006},
issn = {1748-7838},
support = {R01 DK054369/DK/NIDDK NIH HHS/United States ; 2 R01 DK054369/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Cell Differentiation/genetics ; Cells, Cultured ; Cellular Reprogramming ; Embryonic Stem Cells/*cytology/metabolism ; Fibroblasts/cytology ; Gene Expression ; In Situ Hybridization, Fluorescence ; Induced Pluripotent Stem Cells/*cytology/metabolism ; Mice ; Recombination, Genetic/genetics ; Telomerase/deficiency/*genetics/*metabolism ; Telomere/*genetics/metabolism ; Telomere Homeostasis/*genetics ; Transcription Factors/genetics/metabolism ; },
abstract = {Rejuvenation of telomeres with various lengths has been found in induced pluripotent stem cells (iPSCs). Mechanisms of telomere length regulation during induction and proliferation of iPSCs remain elusive. We show that telomere dynamics are variable in mouse iPSCs during reprogramming and passage, and suggest that these differences likely result from multiple potential factors, including the telomerase machinery, telomerase-independent mechanisms and clonal influences including reexpression of exogenous reprogramming factors. Using a genetic model of telomerase-deficient (Terc(-/-) and Terc(+/-)) cells for derivation and passages of iPSCs, we found that telomerase plays a critical role in reprogramming and self-renewal of iPSCs. Further, telomerase maintenance of telomeres is necessary for induction of true pluripotency while the alternative pathway of elongation and maintenance by recombination is also required, but not sufficient. Together, several aspects of telomere biology may account for the variable telomere dynamics in iPSCs. Notably, the mechanisms employed to maintain telomeres during iPSC reprogramming are very similar to those of embryonic stem cells. These findings may also relate to the cloning field where these mechanisms could be responsible for telomere heterogeneity after nuclear reprogramming by somatic cell nuclear transfer.},
}
@article {pmid22178899,
year = {2012},
author = {Surtees, PG and Wainwright, NW and Pooley, KA and Luben, RN and Khaw, KT and Easton, DF and Dunning, AM},
title = {Educational attainment and mean leukocyte telomere length in women in the European Prospective Investigation into Cancer (EPIC)-Norfolk population study.},
journal = {Brain, behavior, and immunity},
volume = {26},
number = {3},
pages = {414-418},
doi = {10.1016/j.bbi.2011.11.009},
pmid = {22178899},
issn = {1090-2139},
support = {G0300128/MRC_/Medical Research Council/United Kingdom ; C8197/A10123/CRUK_/Cancer Research UK/United Kingdom ; G9502233/MRC_/Medical Research Council/United Kingdom ; G0401527/MRC_/Medical Research Council/United Kingdom ; C865/A2883/CRUK_/Cancer Research UK/United Kingdom ; G1000143/MRC_/Medical Research Council/United Kingdom ; 11022/CRUK_/Cancer Research UK/United Kingdom ; C1287/A9540/CRUK_/Cancer Research UK/United Kingdom ; 10118/CRUK_/Cancer Research UK/United Kingdom ; 14136/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Cross-Sectional Studies ; Educational Status ; England ; Female ; Humans ; Leukocytes/*physiology ; Middle Aged ; *Social Class ; Telomere Shortening ; },
abstract = {BACKGROUND: Telomere length has been postulated as a marker of biological aging. Recent evidence has suggested that educational attainment but not social class is associated with telemore length.<br><br>METHODS: We investigated the associations between educational attainment, social class and relative mean telomere length in an ethnically homogeneous population of 4441 women, aged 41-80 years. Mean telomere length was measured using high-throughput quantitative Real Time PCR.<br><br>RESULTS: Educational attainment (p=0.015) but not social class (p=0.61) was associated with mean telomere length in these data. This association was independent of social class and of systolic blood pressure, high-density lipoprotein cholesterol, cigarette smoking, body mass index, glycated hemoglobin, plasma vitamin C and physical activity (p=0.014), and was not attenuated through additional adjustment for measures of social adversity, including those experienced during childhood (p=0.006).<br><br>CONCLUSIONS: Our results, at least for women, provide support for the findings previously reported in this journal that lower educational attainment, but not social class, is associated with shorter telomere length.},
}
@article {pmid22178633,
year = {2012},
author = {Hochstrasser, T and Marksteiner, J and Humpel, C},
title = {Telomere length is age-dependent and reduced in monocytes of Alzheimer patients.},
journal = {Experimental gerontology},
volume = {47},
number = {2},
pages = {160-163},
pmid = {22178633},
issn = {1873-6815},
mesh = {Aged ; *Aging/genetics/pathology ; Alzheimer Disease/blood/*diagnosis/*genetics/pathology/physiopathology ; Analysis of Variance ; Austria ; Case-Control Studies ; Enzyme-Linked Immunosorbent Assay ; Female ; Genetic Markers ; Humans ; Male ; *Monocytes/pathology ; Neuropsychological Tests ; Precision Medicine ; *Telomere/genetics ; *Telomere Shortening ; },
abstract = {Telomeres are regions of repetitive DNA at the end of eukaryotic chromosomes, which prevent chromosomal instability. Telomere shortening is linked to age-related disease including Alzheimer's disease (AD) and has been reported to be reduced in leukocytes of AD patients. The aim of the present study was to measure telomere length in monocytes of patients with AD or mild cognitive impairment (MCI) compared to healthy subjects. Our data show significant shorter telomere length in AD patients (6.6±0.2kb; p=0.05) compared to controls (7.3±0.2kb). Telomere length of MCI patients did not differ compared to healthy subjects (7.0±0.2kb). We observe a strong correlation between telomere length and age (p=0.01, r=-0.38), but no association between telomere length and Mini-Mental State Examination score. In conclusion, the telomere length is age-dependent in monocytes and decreased in AD patients, which could mean that the AD pathology may contribute to telomere length shortening. The high variability of telomere lengths in individuals suggests that it will not be useful as a general biomarker for AD. However, it could become a biomarker in personalized long-term monitoring of an individuals' health.},
}
@article {pmid22178426,
year = {2012},
author = {Kroenke, CH and Pletcher, MJ and Lin, J and Blackburn, E and Adler, N and Matthews, K and Epel, E},
title = {Telomerase, telomere length, and coronary artery calcium in black and white men in the CARDIA study.},
journal = {Atherosclerosis},
volume = {220},
number = {2},
pages = {506-512},
doi = {10.1016/j.atherosclerosis.2011.10.041},
pmid = {22178426},
issn = {1879-1484},
mesh = {Adolescent ; Adult ; Black or African American/*genetics ; Chi-Square Distribution ; Coronary Angiography/methods ; Coronary Artery Disease/diagnostic imaging/enzymology/ethnology/*genetics ; Cross-Sectional Studies ; Disease Progression ; Humans ; Incidence ; Leukocytes/*enzymology ; Linear Models ; Longitudinal Studies ; Male ; Middle Aged ; Multivariate Analysis ; Odds Ratio ; Prevalence ; Risk Assessment ; Risk Factors ; Telomerase/*blood ; Telomere/*metabolism ; *Telomere Shortening ; Time Factors ; Tomography, X-Ray Computed ; United States/epidemiology ; Up-Regulation ; Vascular Calcification/diagnostic imaging/enzymology/ethnology/*genetics ; White People/*genetics ; Young Adult ; },
abstract = {OBJECTIVE: To evaluate whether telomerase activity, measured in circulating blood leukocytes, might be associated with prevalent atherosclerosis, or predict future coronary artery disease risk.<br><br>METHODS AND RESULTS: We examined associations of telomerase activity levels measured at year 15 in the Coronary Artery Risk Development in Young Adults (CARDIA) Study with prevalent coronary artery calcium (CAC), progressive CAC at year 20, and incident CAC between years 15 and 20, in 440 black and white men aged 33-45 years. Telomere length was also measured in a subset of participants (N=129). In multivariate-adjusted analysis, higher quartiles of telomerase were cross-sectionally associated with greater odds of prevalent CAC at year 15 (quartile 2: OR=1.32, 95% CI: 0.54-3.23; quartile 3: OR=1.40, 95% CI: 0.60-3.30; quartile 4: OR=3.27, 95% CI: 1.39-7.71 compared with quartile 1, p-continuous=0.012) and progressive CAC at year 20, but telomerase was not significantly associated with incidence of newly detectable CAC. Higher telomerase activity levels predicted greater CAC progression at year 20 among persons with short telomere length; low telomerase and short TL predicted less CAC progression.<br><br>CONCLUSION: Telomerase activity in leukocytes was associated with calcified atherosclerotic plaque, and was also a predictor of advancing plaque among persons with short telomeres.},
}
@article {pmid22171676,
year = {2011},
author = {Fernández-Moreno, M and Tamayo, M and Soto-Hermida, A and Mosquera, A and Oreiro, N and Fernández-López, C and Fernández, JL and Rego-Pérez, I and Blanco, FJ},
title = {mtDNA haplogroup J modulates telomere length and nitric oxide production.},
journal = {BMC musculoskeletal disorders},
volume = {12},
number = {},
pages = {283},
pmid = {22171676},
issn = {1471-2474},
mesh = {Adult ; Aged ; Aged, 80 and over ; Case-Control Studies ; Cells, Cultured ; Chondrocytes/*metabolism ; Colorimetry ; DNA, Mitochondrial/*genetics ; Female ; Genetic Predisposition to Disease ; *Haplotypes ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Multivariate Analysis ; Nitric Oxide/*metabolism ; Nitric Oxide Synthase Type II/metabolism ; Osteoarthritis, Hip/diagnosis/*genetics/*metabolism ; *Oxidative Stress ; Phenotype ; Polymerase Chain Reaction ; Regression Analysis ; Spain ; Telomere/*metabolism ; Telomere Shortening ; Young Adult ; },
abstract = {BACKGROUND: Oxidative stress due to the overproduction of nitric oxide (NO) and other oxygen reactive species (ROS), play a main role in the initiation and progression of the OA disease and leads to the degeneration of mitochondria. Therefore, the goal of this work is to describe the difference in telomere length of peripheral blood leukocytes (PBLs) and Nitric Oxide (NO) production between mitochondrial DNA (mtDNA) haplogroup J and non-J carriers, as indirect approaches of oxidative stress.<br><br>METHODS: The telomere length of PBL was analyzed in DNA samples from 166 healthy controls (114 J and 52 non-J) and 79 OA patients (41 J and 38 non-J) by means of a validated qPCR method. The NO production was assessed in 7 carriers of the haplogroup J and 27 non-J carriers, by means of the colorimetric reaction of the Griess reagent in supernatants of cultured chondrocytes. Inducible nitric oxide synthase (iNOS) mRNA from these samples was analyzed by qPCR. Appropiated statistical analyses were performed<br><br>RESULTS: Carriers of the haplogroup J showed a significantly longer telomere length of PBLs than non-J carriers, regardless of age, gender and diagnosis (p = 0.025). Cultured chondrocytes carrying the mtDNA haplogroup J also showed a lower NO production than non-J carriers (p = 0.043). No significant correlations between age and telomore length of PBLs were detected neither for carriers of the haplogroup J nor for non-J carriers. A strong positive correlation between NO production and iNOS expression was also observed (correlation coefficient = 0.791, p < 0.001).<br><br>CONCLUSION: The protective effect of the mtDNA haplogroup J in the OA disease arise from a lower oxidative stress in carriers of this haplogroup, since this haplogroup is related to lower NO production and hence longer telomere length of PBLs too.},
}
@article {pmid22169538,
year = {2011},
author = {Ungar, L and Harari, Y and Toren, A and Kupiec, M},
title = {Tor complex 1 controls telomere length by affecting the level of Ku.},
journal = {Current biology : CB},
volume = {21},
number = {24},
pages = {2115-2120},
doi = {10.1016/j.cub.2011.11.024},
pmid = {22169538},
issn = {1879-0445},
mesh = {Caloric Restriction ; DNA-Binding Proteins/*metabolism ; GATA Transcription Factors/metabolism ; Glutathione Peroxidase/metabolism ; Neoplasms/drug therapy ; Prions/metabolism ; RNA-Binding Proteins/metabolism ; Saccharomyces cerevisiae/cytology/drug effects/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Signal Transduction ; Sirolimus/*pharmacology ; Species Specificity ; Telomere/*metabolism ; *Telomere Shortening ; Transcription Factors/genetics/*metabolism ; },
abstract = {Telomeres are specialized DNA-protein structures at the ends of eukaryotic chromosomes. Telomeric DNA is synthesized by telomerase, which is expressed only at the early stages of development [1, 2]. To become malignant, any cell has to be able to replenish telomeres [3]. Thus, understanding how telomere length is monitored has significant medical implications, especially in the fields of aging and cancer. In yeast, telomerase is constitutively active. A large network of genes participates in controlling telomere length [4-8]. Tor1 and Tor2 (targets of rapamycin [9]) are two similar kinases that regulate cell growth [10]. Both can be found as part of the TOR complex 1 (TORC1 [11]), which coordinates the response to nutrient starvation and is sensitive to rapamycin [12]. The rapamycin-insensitive TOR complex 2 (TORC2) contains only Tor2 and regulates actin cytoskeleton polarization [13]. Here we provide evidence for a role of TORC1 in telomere shortening upon starvation in yeast cells. The TORC1 signal is transduced by the Gln3/Gat1/Ure2 pathway, which controls the levels of the Ku heterodimer, a telomere regulator. We discuss the potential implications for the usage of rapamycin as a therapeutic agent against cancer and the effect that calorie restriction may have on telomere length.},
}
@article {pmid22161642,
year = {2012},
author = {Hou, YY and Toh, MT and Wang, X},
title = {NBS1 deficiency promotes genome instability by affecting DNA damage signaling pathway and impairing telomere integrity.},
journal = {Cell biochemistry and function},
volume = {30},
number = {3},
pages = {233-242},
doi = {10.1002/cbf.1840},
pmid = {22161642},
issn = {1099-0844},
mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*deficiency/genetics/metabolism ; *DNA Damage ; DNA-Binding Proteins/genetics/metabolism ; *Genomic Instability ; Humans ; Nijmegen Breakage Syndrome/*genetics/*metabolism ; Nuclear Proteins/*deficiency/genetics ; Protein Serine-Threonine Kinases/genetics/metabolism ; Telomere/*metabolism ; Telomere Shortening ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Tumor Suppressor Proteins/genetics/metabolism ; },
abstract = {Studies revealed that Nijmegen Breakage Syndrome protein 1 (NBS1) plays an important role in maintaining genome stability, but the underlying mechanism is controversial and elusive. Our results using clinical samples showed that NBS1 was involved in ataxia-telangiectasia mutated (ATM)-dependent pathway. NBS1 deficiency severely affected the phosphorylation of ATM as well as its downstream targets. BrdU proliferation assay revealed a delay of NBS cells in inhibiting DNA synthesis after Doxorubicin (Dox) treatment. In addition, under higher concentrations of Dox, NBS cells exhibited a much lower level of apoptosis compared to their normal counterparts, indicating a resistance to Dox treatment. Accelerated telomere shortening was also observed in NBS fibroblasts, consistent with an early onset of cellular replicative senescence in vitro. This abnormality may be due to the shelterin protein telomeric binding factor 2 (TRF2) which was found to be upregulated in NBS fibroblasts. The dysregulation of telomere shortening rate and of TRF2 expression level leads to telomere fusions and cellular aneuploidy in NBS cells. Collectively, our results suggest a possible mechanism that NBS1 deficiency simultaneously affects ATM-dependent DNA damage signaling and TRF2-regulated telomere maintenance, which synergistically lead to genomic abnormalities.},
}
@article {pmid22158468,
year = {2011},
author = {Amiard, S and Depeiges, A and Allain, E and White, CI and Gallego, ME},
title = {Arabidopsis ATM and ATR kinases prevent propagation of genome damage caused by telomere dysfunction.},
journal = {The Plant cell},
volume = {23},
number = {12},
pages = {4254-4265},
pmid = {22158468},
issn = {1532-298X},
mesh = {Arabidopsis/enzymology/*genetics ; Arabidopsis Proteins/*genetics/metabolism ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*genetics/metabolism ; Cell Death ; Cell Nucleus/genetics/metabolism ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; Chromosomes, Plant/genetics/metabolism ; DNA Damage ; Enzyme Activation ; Genome, Plant ; Genomic Instability ; Phosphatidylinositol 3-Kinases/genetics/metabolism ; Phosphorylation ; Plant Cells/metabolism ; Plant Roots/genetics/metabolism ; Protein Serine-Threonine Kinases/*genetics/metabolism ; Signal Transduction ; Telomere/*genetics/metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {The ends of linear eukaryotic chromosomes are hidden in nucleoprotein structures called telomeres, and loss of the telomere structure causes inappropriate repair, leading to severe karyotypic and genomic instability. Although it has been shown that DNA damaging agents activate a DNA damage response (DDR), little is known about the signaling of dysfunctional plant telomeres. We show that absence of telomerase in Arabidopsis thaliana elicits an ATAXIA-TELANGIECTASIA MUTATED (ATM) and ATM AND RAD3-RELATED (ATR)-dependent DDR at telomeres, principally through ATM. By contrast, telomere dysfunction induces an ATR-dependent response in telomeric Conserved telomere maintenance component1 (Ctc1)-Suppressor of cdc thirteen (Stn1)-Telomeric pathways in association with Stn1 (CST)-complex mutants. These results uncover a new role for the CST complex in repressing the ATR-dependent DDR pathway in plant cells and show that plant cells use two different DNA damage surveillance pathways to signal telomere dysfunction. The absence of either ATM or ATR in ctc1 and stn1 mutants significantly enhances developmental and genome instability while reducing stem cell death. These data thus give a clear illustration of the action of ATM/ATR-dependent programmed cell death in maintaining genomic integrity through elimination of genetically unstable cells.},
}
@article {pmid22157895,
year = {2011},
author = {Kaul, Z and Cesare, AJ and Huschtscha, LI and Neumann, AA and Reddel, RR},
title = {Five dysfunctional telomeres predict onset of senescence in human cells.},
journal = {EMBO reports},
volume = {13},
number = {1},
pages = {52-59},
pmid = {22157895},
issn = {1469-3178},
mesh = {Cells, Cultured ; Cellular Senescence/*genetics ; DNA Damage ; Humans ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Replicative senescence is accompanied by a telomere-specific DNA damage response (DDR). We found that DDR+ telomeres occur spontaneously in early-passage normal human cells and increase in number with increasing cumulative cell divisions. DDR+ telomeres at replicative senescence retain TRF2 and RAP1 proteins, are not associated with end-to-end fusions and mostly result from strand-independent, postreplicative dysfunction. On the basis of the calculated number of DDR+ telomeres in G1-phase cells just before senescence and after bypassing senescence by inactivation of wild-type p53 function, we conclude that the accrual of five telomeres in G1 that are DDR+ but nonfusogenic is associated with p53-dependent senescence.},
}
@article {pmid22157893,
year = {2011},
author = {Price, CM},
title = {Telomere flip-flop: an unfolding passage to senescence.},
journal = {EMBO reports},
volume = {13},
number = {1},
pages = {5-6},
pmid = {22157893},
issn = {1469-3178},
support = {R01 GM041803/GM/NIGMS NIH HHS/United States ; R01 GM088728/GM/NIGMS NIH HHS/United States ; GM088728/GM/NIGMS NIH HHS/United States ; GM041803/GM/NIGMS NIH HHS/United States ; },
mesh = {Cellular Senescence/*genetics ; Humans ; Telomere/*metabolism ; },
}
@article {pmid22157096,
year = {2012},
author = {Houghtaling, BR and Canudas, S and Smith, S},
title = {A role for sister telomere cohesion in telomere elongation by telomerase.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {11},
number = {1},
pages = {19-25},
pmid = {22157096},
issn = {1551-4005},
support = {R01 CA116352/CA/NCI NIH HHS/United States ; },
mesh = {Binding Sites ; Cell Line, Tumor ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/metabolism ; Dyskeratosis Congenita/enzymology/metabolism/pathology ; Humans ; Mutation ; Protein Binding ; S Phase ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere Homeostasis ; Telomere Shortening ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Telomere length homeostasis is achieved by a balance of telomere shortening caused by DNA replication and nucleolytic attack and telomere lengthening by telomerase. The importance of telomere length maintenance to human health is best illustrated by dyskeratosis congenita (DC) a disease of telomere shortening caused by mutations in telomerase subunits. DC patients suffer stem cell depletion and die of bone marrow stem cell failure. Recently a new class of particularly severe DC patients was found to harbor mutations in the shelterin subunit TIN2. The DC-TIN2 mutations were clustered in small domain of unknown function. In a recently published study we showed that the DC mutation cluster in TIN2 harbored a binding site for heterochromatin protein 1 (HP1) and further, that HP1 binding to TIN2 was required for sister telomere cohesion in S phase and for telomere length maintenance by telomerase. We briefly review and discuss the implications of our findings in this Extra View, and present some new data that may shed light on how sister telomere cohesion could influence telomere elongation by telomerase.},
}
@article {pmid22152484,
year = {2011},
author = {Gallardo, F and Laterreur, N and Cusanelli, E and Ouenzar, F and Querido, E and Wellinger, RJ and Chartrand, P},
title = {Live cell imaging of telomerase RNA dynamics reveals cell cycle-dependent clustering of telomerase at elongating telomeres.},
journal = {Molecular cell},
volume = {44},
number = {5},
pages = {819-827},
doi = {10.1016/j.molcel.2011.09.020},
pmid = {22152484},
issn = {1097-4164},
support = {89768-1//Canadian Institutes of Health Research/Canada ; MOP97874/CAPMC/CIHR/Canada ; MOP89768/CAPMC/CIHR/Canada ; },
mesh = {Cell Cycle ; Cell Survival ; Microscopy, Confocal ; RNA/analysis/*metabolism ; Saccharomyces cerevisiae/*cytology/*enzymology/metabolism ; Telomerase/analysis/*metabolism ; Telomere/chemistry/*metabolism ; Thermodynamics ; },
abstract = {The telomerase, which is composed of both protein and RNA, maintains genome stability by replenishing telomeric repeats at the ends of chromosomes. Here, we use live-cell imaging to follow yeast telomerase RNA dynamics and recruitment to telomeres in single cells. Tracking of single telomerase particles revealed a diffusive behavior and transient association with telomeres in G1 and G2 phases of the cell cycle. Interestingly, concurrent with telomere elongation in late S phase, a subset of telomerase enzyme clusters and stably associates with few telomeres. Our data show that this clustering represents elongating telomerase and it depends on regulators of telomerase at telomeres (MRX, Tel1, Rif1/2, and Cdc13). Furthermore, the assay revealed premature telomere elongation in G1 in a rif1/2 strains, suggesting that Rif1/2 act as cell-cycle dependent negative regulators of telomerase. We propose that telomere elongation is organized around a local and transient accumulation of several telomerases on a few telomeres.},
}
@article {pmid22152194,
year = {2011},
author = {Sapir, E and Gozaly-Chianea, Y and Al-Wahiby, S and Ravindran, S and Yasaei, H and Slijepcevic, P},
title = {Effects of BRCA2 deficiency on telomere recombination in non-ALT and ALT cells.},
journal = {Genome integrity},
volume = {2},
number = {},
pages = {9},
pmid = {22152194},
issn = {2041-9414},
abstract = {BACKGROUND: Recent studies suggest that BRCA2 affects telomere maintenance. Interestingly, anti cancer treatments that involve BRCA2 and telomerase individually are currently being explored. In the light of the above recent studies their combinatorial targeting may be justified in the development of future treatments. In order to investigate effects of BRCA2 that can be explored for this combinatorial targeting we focused on the analysis of recombination rates at telomeres by monitoring T-SCEs (Telomere Sister Chromatid Exchanges).<br><br>RESULTS: We observed a significant increase in T-SCE frequencies in four BRCA2 defective human cell lines thus suggesting that BRCA2 suppresses recombination at telomeres. To test this hypothesis further we analyzed T-SCE frequencies in a set of Chinese hamster cell lines with or without functional BRCA2. Our results indicate that introduction of functional BRCA2 normalizes frequencies of T-SCEs thus supporting the notion that BRCA2 suppresses recombination at telomeres. Given that ALT (Alternative Lengthening of Telomeres) positive cells maintain telomeres by recombination we investigated the effect of BRCA2 depletion in these cells. Our results show that this depletion causes a dramatic reduction in T-SCE frequencies in ALT positive cells, but not in non-ALT cells.<br><br>CONCLUSION: BRCA2 suppresses recombination at telomeres in cells that maintain them by conventional mechanisms. Furthermore, BRCA2 depletion in ALT positive cells reduces high levels of T-SCEs normally found in these cells. Our results could be potentially important for refining telomerase-based anti-cancer therapies.},
}
@article {pmid22151982,
year = {2011},
author = {Gao, J and Zhang, J and Long, Y and Lu, X},
title = {Expression of telomere binding proteins in gastric cancer and correlation with clinicopathological parameters.},
journal = {Asia-Pacific journal of clinical oncology},
volume = {7},
number = {4},
pages = {339-345},
doi = {10.1111/j.1743-7563.2011.01437.x},
pmid = {22151982},
issn = {1743-7563},
mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Reverse Transcriptase Polymerase Chain Reaction ; Shelterin Complex ; Stomach Neoplasms/enzymology/genetics/*metabolism/pathology ; Telomerase/metabolism ; Telomere-Binding Proteins/*biosynthesis/genetics/metabolism ; Telomeric Repeat Binding Protein 1/biosynthesis/genetics/metabolism ; Telomeric Repeat Binding Protein 2/biosynthesis/genetics/metabolism ; },
abstract = {AIM: The aim of this study was to investigate the expression of telomere repeat binding factor 1 (TRF1), TRF2 and protection of telomeres 1 (POT1) in gastric cancer and their relationships with clinicopathological features and telomerase activity.<br><br>METHODS: In total 36 gastric cancer tissue and paired adjacent normal tissue were analyzed. The mRNA expression of telomere binding proteins TRF1, TRF2 and POT1 were measured using quantitative reverse transcription polymerase chain reaction, and telomerase activity was assessed by the telomeric repeat amplification protocol/enzyme linked immunosorbent assay method.<br><br>RESULTS: The expression of POT1 was significantly higher in tumor tissue than in adjacent normal tissue (P < 0.001). Levels of TRF2 mRNA were significantly higher in bigger tumors (diameter &#x2265; 5 cm) than in small tumors (diameter < 5 cm) (P = 0.043). POT1 mRNA transcription levels were higher in tumors with lymph nodes metastases than in those without lymph nodes metastases (P = 0.048). POT1 expression was significantly correlated with tumor stage (P = 0.008). A higher level of expression of POT1 was observed in late-stage tumors (III, IV) than in early stage tumors (I, II). Telomerase activity was significantly higher in gastric cancers than in corresponding normal tissue (P < 0.001). Moreover, POT1 expression was significantly positive correlated with telomerase activity (r = 0.572, P < 0.01).<br><br>CONCLUSION: POT1 was overexpressed in gastric cancer and may be associated with stomach carcinogenesis and gastric cancer progression.},
}
@article {pmid22143823,
year = {2012},
author = {Ivanković, M and Cukušić Kalajžić, A and Skrobot Vidaček, N and Franić Šimić, I and Davidović Mrsić, S and Rubelj, I},
title = {Human Xp/Yp telomere analysis by Southern-STELA.},
journal = {Biogerontology},
volume = {13},
number = {2},
pages = {203-213},
doi = {10.1007/s10522-011-9368-x},
pmid = {22143823},
issn = {1573-6768},
mesh = {Blotting, Southern/*methods ; Cells, Cultured ; *Chromosomes, Human, X ; *Chromosomes, Human, Y ; Fibroblasts/metabolism ; Humans ; *In Situ Hybridization, Fluorescence ; Metaphase ; Nucleic Acid Probes ; Peptide Nucleic Acids ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {Telomeres are specialized structures designed to protect the ends of linear chromosomes. They are dynamic structures such that in normal somatic cells they constantly shorten as cell division progresses. There is compelling evidence that telomere shortening leads to cell senescence, a process perceived as the main cause of aging in higher mammals. Therefore, the features of telomere shortening are of great importance in understanding cell senescence and aging in general. By identifying unique subtelomeric regions, large enough to produce strong chemiluminescent signals, we have provided a new tool for Southern blot analysis of individual human Xp/Yp telomeres. We extend these results with quantitative fluorescence in situ hybridization using peptide nucleic acid probe (PNA Q-FISH) analysis of telomeres on the Y chromosome. Our results demonstrates unequal shortening dynamics between the p and q telomeres.},
}
@article {pmid22139912,
year = {2012},
author = {Tankimanova, M and Capper, R and Letsolo, BT and Rowson, J and Jones, RE and Britt-Compton, B and Taylor, AM and Baird, DM},
title = {Mre11 modulates the fidelity of fusion between short telomeres in human cells.},
journal = {Nucleic acids research},
volume = {40},
number = {6},
pages = {2518-2526},
pmid = {22139912},
issn = {1362-4962},
support = {C17199/A13490//Cancer Research UK/United Kingdom ; C1799/A5603//Cancer Research UK/United Kingdom ; C1799/A6932//Cancer Research UK/United Kingdom ; },
mesh = {Ataxia Telangiectasia/genetics ; Cell Line ; DNA-Binding Proteins/genetics/*physiology ; Humans ; MRE11 Homologue Protein ; Mutation ; Repetitive Sequences, Nucleic Acid ; Sequence Deletion ; Telomere/*chemistry/metabolism ; },
abstract = {The loss of telomere function can result in the fusion of telomeres with other telomeric loci, or non-telomeric double-stranded DNA breaks. Sequence analysis of fusion events between short dysfunctional telomeres in human cells has revealed that fusion is characterized by a distinct molecular signature consisting of extensive deletions and micro-homology at the fusion points. This signature is consistent with alternative error-prone end-joining processes. We have examined the role that Mre11 may play in the fusion of short telomeres in human cells; to do this, we have analysed telomere fusion events in cells derived from ataxia-telangiectasia-like disorder (ATLD) patients that exhibit hypomorphic mutations in MRE11. The telomere dynamics of ATLD fibroblasts were indistinguishable from wild-type fibroblasts and they were proficient in the fusion of short telomeres. However, we observed a high frequency of insertion of DNA sequences at the fusion points that created localized sequence duplications. These data indicate that Mre11 plays a role in the fusion of short dysfunctional telomeres in human cells and are consistent with the hypothesis that as part of the MRN complex it serves to stabilize the joining complex, thereby controlling the fidelity of the fusion reaction.},
}
@article {pmid22138576,
year = {2011},
author = {Sperka, T and Song, Z and Morita, Y and Nalapareddy, K and Guachalla, LM and Lechel, A and Begus-Nahrmann, Y and Burkhalter, MD and Mach, M and Schlaudraff, F and Liss, B and Ju, Z and Speicher, MR and Rudolph, KL},
title = {Puma and p21 represent cooperating checkpoints limiting self-renewal and chromosomal instability of somatic stem cells in response to telomere dysfunction.},
journal = {Nature cell biology},
volume = {14},
number = {1},
pages = {73-79},
pmid = {22138576},
issn = {1476-4679},
mesh = {Animals ; Apoptosis/genetics ; Apoptosis Regulatory Proteins/*genetics/metabolism ; Cell Cycle Checkpoints/*genetics ; Cell Growth Processes/genetics ; *Chromosomal Instability ; Cyclin-Dependent Kinase Inhibitor p21/*genetics/metabolism ; DNA Damage ; Mice ; Mice, Inbred C57BL ; NIH 3T3 Cells ; Stem Cells/metabolism/*physiology ; Telomere/*genetics/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; Tumor Suppressor Proteins/*genetics/metabolism ; Up-Regulation ; },
abstract = {The tumour suppressor p53 activates Puma-dependent apoptosis and p21-dependent cell-cycle arrest in response to DNA damage. Deletion of p21 improved stem-cell function and organ maintenance in progeroid mice with dysfunctional telomeres, but the function of Puma has not been investigated in this context. Here we show that deletion of Puma improves stem- and progenitor-cell function, organ maintenance and lifespan of telomere-dysfunctional mice. Puma deletion impairs the clearance of stem and progenitor cells that have accumulated DNA damage as a consequence of critically short telomeres. However, further accumulation of DNA damage in these rescued progenitor cells leads to increasing activation of p21. RNA interference experiments show that upregulation of p21 limits proliferation and evolution of chromosomal imbalances of Puma-deficient stem and progenitor cells with dysfunctional telomeres. These results provide experimental evidence that p53-dependent apoptosis and cell-cycle arrest act in cooperating checkpoints limiting tissue maintenance and evolution of chromosomal instability at stem- and progenitor-cell levels in response to telomere dysfunction. Selective inhibition of Puma-dependent apoptosis can result in temporary improvements in maintenance of telomere-dysfunctional organs.},
}
@article {pmid22138440,
year = {2012},
author = {Tomiyama, AJ and O'Donovan, A and Lin, J and Puterman, E and Lazaro, A and Chan, J and Dhabhar, FS and Wolkowitz, O and Kirschbaum, C and Blackburn, E and Epel, E},
title = {Does cellular aging relate to patterns of allostasis? An examination of basal and stress reactive HPA axis activity and telomere length.},
journal = {Physiology &amp; behavior},
volume = {106},
number = {1},
pages = {40-45},
pmid = {22138440},
issn = {1873-507X},
support = {K08 MH064110/MH/NIMH NIH HHS/United States ; K08 MH064110-01A1/MH/NIMH NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; K08 MH64110-01A1/MH/NIMH NIH HHS/United States ; },
mesh = {Aged ; Allostasis/*physiology ; Area Under Curve ; Body Mass Index ; Caregivers/psychology ; Cellular Senescence/*physiology ; Circadian Rhythm/physiology ; Data Interpretation, Statistical ; Dementia ; Female ; Humans ; Hydrocortisone/metabolism/urine ; Hypothalamo-Hypophyseal System/*physiopathology ; Saliva/metabolism ; Social Environment ; Stress, Psychological/*physiopathology ; Telomere/*physiology/ultrastructure ; Telomere Shortening/*physiology ; },
abstract = {Long-term exposure to stress and its physiological mediators, in particular cortisol, may lead to impaired telomere maintenance. In this study, we examine if greater cortisol responses to an acute stressor and/or dysregulated patterns of daily cortisol secretion are associated with shorter telomere length. Twenty-three postmenopausal women comprising caregivers for dementia partners (n=14) and age- and BMI-matched non-caregivers provided home sampling of cortisol-saliva samples at waking, 30 min after waking, and bedtime, and a 12-hour overnight urine collection. They were also exposed to an acute laboratory stressor throughout which they provided saliva samples. Peripheral blood mononuclear cells were isolated from a fasting blood sample and assayed for telomere length. As hypothesized, greater cortisol responses to the acute stressor were associated with shorter telomeres, as were higher overnight urinary free cortisol levels and flatter daytime cortisol slopes. While robust physiological responses to acute stress serve important functions, the long-term consequences of frequent high stress reactivity may include accelerated telomere shortening.},
}
@article {pmid22138403,
year = {2012},
author = {Woo, SR and Park, JE and Juhn, KM and Ju, YJ and Jeong, J and Kang, CM and Yun, HJ and Yun, MY and Shin, HJ and Joo, HY and Park, ER and Park, IC and Hong, SH and Hwang, SG and Kim, H and Cho, MH and Kim, SH and Park, GH and Lee, KH},
title = {Cells with dysfunctional telomeres are susceptible to reactive oxygen species hydrogen peroxide via generation of multichromosomal fusions and chromosomal fragments bearing telomeres.},
journal = {Biochemical and biophysical research communications},
volume = {417},
number = {1},
pages = {204-210},
doi = {10.1016/j.bbrc.2011.11.086},
pmid = {22138403},
issn = {1090-2104},
mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Division ; Chromosome Aberrations/*chemically induced ; G2 Phase ; Hydrogen Peroxide/*pharmacology ; Mice ; Mice, Mutant Strains ; RNA/genetics ; Telomerase/genetics ; Telomere/genetics/*metabolism ; },
abstract = {During genotoxic stress, reactive oxygen species hydrogen peroxide (H(2)O(2)) is a prime mediator of the DNA damage response. Telomeres function both to assist in DNA damage repair and to inhibit chromosomal end-to-end fusion. Here, we show that telomere dysfunction renders cells susceptible to H(2)O(2), via generation of multichromosomal fusion and chromosomal fragments. H(2)O(2) caused formation of multichromosomal end-to-end fusions involving more than three chromosomes, preferentially when telomeres were erosive. Interestingly, extensive chromosomal fragmentation (yielding small-sized fragments) occurred only in cells exhibiting such multichromosomal fusions. Telomeres were absent from fusion points, being rather present in the small fragments, indicating that H(2)O(2) cleaves chromosomal regions adjacent to telomeres. Restoration of telomere function or addition of the antioxidant N-acetylcysteine prevented development of chromosomal aberrations and rescued the observed hypersensitivity to H(2)O(2). Thus, chromosomal regions adjacent to telomeres become sensitive to reactive oxygen species hydrogen peroxide when telomeres are dysfunctional, and are cleaved to produce multichromosomal fusions and small chromosomal fragments bearing the telomeres.},
}
@article {pmid22136229,
year = {2012},
author = {Soerensen, M and Thinggaard, M and Nygaard, M and Dato, S and Tan, Q and Hjelmborg, J and Andersen-Ranberg, K and Stevnsner, T and Bohr, VA and Kimura, M and Aviv, A and Christensen, K and Christiansen, L},
title = {Genetic variation in TERT and TERC and human leukocyte telomere length and longevity: a cross-sectional and longitudinal analysis.},
journal = {Aging cell},
volume = {11},
number = {2},
pages = {223-227},
pmid = {22136229},
issn = {1474-9726},
support = {P01 AG008761/AG/NIA NIH HHS/United States ; P01 AG008761-10/AG/NIA NIH HHS/United States ; R01 AG030678/AG/NIA NIH HHS/United States ; R01 AG030678-01A2/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Female ; *Genetic Variation ; Genotype ; Humans ; Leukocytes/*metabolism ; *Longevity ; Longitudinal Studies ; Male ; RNA/*genetics ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {Telomerase is of key importance for telomere maintenance, and variants of the genes encoding its major subunits, telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), are candidates for interindividual variation in telomere length. Recently, the two SNPs rs3772190 and rs12696304 in the TERC locus were reported to be associated with leukocyte telomere length (LTL) in two genome-wide association studies, while one haplotype of TERT (rs2853669, rs2736098, rs33954691, and rs2853691) has been reported to be associated with both LTL and longevity in a candidate gene study. In this study, we investigated the two TERC and four TERT SNPs in middle-aged, old, and oldest-old Danes (58-100 years) and their association with LTL (n = 864) and longevity (n = 1069). Furthermore, data on 11 TERT tagging SNPs in 1089 oldest-old and 736 middle-aged Danes were investigated with respect to longevity. For all SNPs, the association with longevity was investigated using both a cross-sectional and a longitudinal approach. Applying an additive model, we found association of LTL with the minor TERC alleles of rs3772190 (A) and rs12696304 (G), such that a shorter LTL was seen in rs3772190 A carriers (regression coefficient = -0.08, P = 0.011) and in male rs12696304 G carriers (regression coefficient = -0.13, P = 0.014). No TERT variations showed association. Moreover, the A allele of rs3772190 (TERC) was found to be associated with longevity [hazard rate (AG + AA) = 1.31, P = 0.006]. No associations with longevity were observed for the TERT SNPs or haplotypes. Our study, thus, indicates that TERC is associated with both LTL and longevity in humans.},
}
@article {pmid22135295,
year = {2012},
author = {Kar, A and Saha, D and Purohit, G and Singh, A and Kumar, P and Yadav, VK and Kumar, P and Thakur, RK and Chowdhury, S},
title = {Metastases suppressor NME2 associates with telomere ends and telomerase and reduces telomerase activity within cells.},
journal = {Nucleic acids research},
volume = {40},
number = {6},
pages = {2554-2565},
pmid = {22135295},
issn = {1362-4962},
mesh = {Cell Line, Tumor ; Chromatin Immunoprecipitation ; High-Throughput Nucleotide Sequencing ; Humans ; NM23 Nucleoside Diphosphate Kinases/*metabolism ; Nucleotide Motifs ; Repetitive Sequences, Amino Acid ; Telomerase/*metabolism ; Telomere/chemistry/*metabolism ; Telomere Homeostasis ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Analysis of chromatin-immunoprecipitation followed by sequencing (ChIP-seq) usually disregards sequence reads that do not map within binding positions (peaks). Using an unbiased approach, we analysed all reads, both that mapped and ones that were not included as part of peaks. ChIP-seq experiments were performed in human lung adenocarcinoma and fibrosarcoma cells for the metastasis suppressor non-metastatic 2 (NME2). Surprisingly, we identified sequence reads that uniquely represented human telomere ends in both cases. In vivo presence of NME2 at telomere ends was validated using independent methods and as further evidence we found intranuclear association of NME2 and the telomere repeat binding factor 2. Most remarkably, results demonstrate that NME2 associates with telomerase and reduces telomerase activity in vitro and in vivo, and sustained NME2 expression resulted in reduced telomere length in aggressive human cancer cells. Anti-metastatic function of NME2 has been demonstrated in human cancers, however, mechanisms are poorly understood. Together, findings reported here suggest a novel role for NME2 as a telomere binding protein that can alter telomerase function and telomere length. This presents an opportunity to investigate telomere-related interactions in metastasis suppression.},
}
@article {pmid22133767,
year = {2012},
author = {Pavlaki, KI and Kastrinaki, MC and Klontzas, M and Velegraki, M and Mavroudi, I and Papadaki, HA},
title = {Abnormal telomere shortening of peripheral blood mononuclear cells and granulocytes in patients with chronic idiopathic neutropenia.},
journal = {Haematologica},
volume = {97},
number = {5},
pages = {743-750},
pmid = {22133767},
issn = {1592-8721},
mesh = {Adult ; Aged ; Case-Control Studies ; Cohort Studies ; DNA/genetics ; Female ; Granulocytes/*pathology ; Humans ; Leukocytes, Mononuclear/*pathology ; Male ; Middle Aged ; Neutropenia/*genetics/*pathology ; Real-Time Polymerase Chain Reaction ; Telomerase/genetics ; *Telomere Shortening ; },
abstract = {BACKGROUND: Chronic idiopathic neutropenia is characterized by immune-mediated suppression of neutrophil production. Because patients with immune-mediated bone marrow failure syndromes display age-inappropriate telomere shortening in leukocytes, we investigated telomere lengths in peripheral blood mononuclear cells and granulocytes of patients with chronic idiopathic neutropenia.<br><br>DESIGN AND METHODS: We studied 37 patients with chronic idiopathic neutropenia and 68 age- and sex-matched healthy controls. Relative telomere length and telomerase reverse transcriptase expression were assessed by a quantitative real time polymerase chain reaction. Telomerase activity was determined by a polymerase chain reaction-based immunoassay.<br><br>RESULTS: The mean relative telomere values of peripheral blood mononuclear cells and granulocytes were significantly lower in patients compared to controls, and significantly lower than expected on the basis of the age-adjusted healthy control distribution. The difference in the relative telomere lengths between patients and controls in both peripheral blood mononuclear cells and granulocytes was prominent in those under the age of 50 years. Contrary to the peripheral blood mononuclear cells, in which an inverse correlation was observed between relative telomere values and age, no significant correlation was noted between granulocyte telomere values and patient age. A significant correlation was observed between individual relative telomere values and absolute neutrophil counts. There was no difference in expression of telomerase reverse transcriptase in peripheral blood mononuclear cells between patients and controls but telomerase activity was identified at a significantly higher frequency in controls than in patients. No correlation was found between telomerase activity or telomerase reverse transcriptase expression and relative telomere lengths of peripheral blood mononuclear cells.<br><br>CONCLUSIONS: Patients with chronic idiopathic neutropenia display age-inappropriate telomere shortening of peripheral blood cells and low telomerase activity in peripheral blood mononuclear cells. A compensatory increased proliferation of bone marrow hematopoietic progenitor cells in association with lymphocyte replicative exhaustion probably account for these abnormalities.},
}
@article {pmid22130795,
year = {2012},
author = {Fukunaga, K and Hirano, Y and Sugimoto, K},
title = {Subtelomere-binding protein Tbf1 and telomere-binding protein Rap1 collaborate to inhibit localization of the Mre11 complex to DNA ends in budding yeast.},
journal = {Molecular biology of the cell},
volume = {23},
number = {2},
pages = {347-359},
pmid = {22130795},
issn = {1939-4586},
support = {R01 CA148939/CA/NCI NIH HHS/United States ; R01 GM073876/GM/NIGMS NIH HHS/United States ; GM073876/GM/NIGMS NIH HHS/United States ; CA148939/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; DNA, Fungal/*metabolism ; DNA-Binding Proteins/*metabolism ; Endodeoxyribonucleases/*metabolism ; Exodeoxyribonucleases/*metabolism ; Molecular Sequence Data ; Repressor Proteins/metabolism ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/*metabolism ; Transcription Factors/*metabolism ; },
abstract = {Chromosome ends, known as telomeres, have to be distinguished from DNA double-strand breaks that activate DNA damage checkpoints. In budding yeast, the Mre11-Rad50-Xrs2 (MRX) complex associates with DNA ends and promotes checkpoint activation. Rap1 binds to double-stranded telomeric regions and recruits Rif1 and Rif2 to telomeres. Rap1 collaborates with Rif1 and Rif2 and inhibits MRX localization to DNA ends. This Rap1-Rif1-Rif2 function becomes attenuated at shortened telomeres. Here we show that Rap1 acts together with the subtelomere-binding protein Tbf1 and inhibits MRX localization to DNA ends. The placement of a subtelomeric sequence or TTAGGG repeats together with a short telomeric TG repeat sequence inhibits MRX accumulation at nearby DNA ends in a Tbf1-dependent manner. Moreover, tethering of both Tbf1 and Rap1 proteins decreases MRX and Tel1 accumulation at nearby DNA ends. This Tbf1- and Rap1-dependent pathway operates independently of Rif1 or Rif2 function. Depletion of Tbf1 protein stimulates checkpoint activation in cells containing short telomeres but not in cells containing normal-length telomeres. These data support a model in which Tbf1 and Rap1 collaborate to maintain genomic stability of short telomeres.},
}
@article {pmid22129501,
year = {2011},
author = {Yan, J and Yang, Y and Chen, C and Peng, J and Ding, H and Wen Wang, D},
title = {Short leukocyte telomere length is associated with aortic dissection.},
journal = {Internal medicine (Tokyo, Japan)},
volume = {50},
number = {23},
pages = {2871-2875},
doi = {10.2169/internalmedicine.50.5958},
pmid = {22129501},
issn = {1349-7235},
mesh = {Adult ; Aged ; Aortic Dissection/*diagnostic imaging/genetics ; Aortic Aneurysm/*diagnostic imaging/genetics ; Female ; Humans ; Leukocytes/*physiology ; Male ; Middle Aged ; Radiography ; Risk Factors ; Telomere/genetics/*pathology ; *Telomere Shortening ; },
abstract = {BACKGROUND: Aortic dissection is an age-related and lethal vascular disease. Aging, which is associated with degeneration, is the major risk factor of aortic dissection. Telomeres are specialized DNA structures located at the end of eukaryotic chromosomes, the telomere length could be considered as an index of vascular aging. The purpose of present study was undertaken to investigate the relationship between the leukocyte telomere length and aortic dissection.<br><br>METHODS AND RESULTS: Seventy-two patients with aortic dissection and seventy-two sex- and age-matched subjects without vascular diseases were collected. Leukocyte telomere length ratio (T/S ratio) was measured using a quantitative PCR method and analyzed. A significantly shorter leukocyte telomere length in the patients with aortic dissection was found compared to the controls, [median 1.02 (interquartile range {IQR}
:0.83-1.37) vs median 1.63 [IQR: 1.18-2.51), p<0.001]. The telomere length in the control group showed a trend of inverse correlation with age (r=-0.226, p=0.056), however, there was no significant correlation in aortic dissection (r=0.062, p=0.607). The short leukocyte telomere length was associated with aortic dissection, even after adjustment for other risk factor (OR=0.214, 95% CI: 0.085-0.537).<br><br>CONCLUSION: Leukocyte telomere length could be an independent predictor of aortic dissection. Measurement of the leukocyte telomere length may be valuable for patients with a high risk of aortic dissection.},
}
@article {pmid22122732,
year = {2012},
author = {Aida, J and Kobayashi, T and Saku, T and Yamaguchi, M and Shimomura, N and Nakamura, K and Ishikawa, N and Maruyama, S and Cheng, J and Poon, SS and Sawabe, M and Arai, T and Takubo, K},
title = {Short telomeres in an oral precancerous lesion: Q-FISH analysis of leukoplakia.},
journal = {Journal of oral pathology &amp; medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology},
volume = {41},
number = {5},
pages = {372-378},
doi = {10.1111/j.1600-0714.2011.01120.x},
pmid = {22122732},
issn = {1600-0714},
mesh = {Adult ; Aged ; Carcinoma, Squamous Cell/genetics/*pathology ; *Chromosomal Instability ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Keratosis ; Leukoplakia, Oral/genetics/*pathology ; Male ; Middle Aged ; Mouth Neoplasms/genetics/*pathology/prevention &amp; control ; Precancerous Conditions/genetics/pathology ; *Telomere Shortening ; },
abstract = {OBJECTIVES: A precancerous condition is a lesion that, if left untreated, leads to cancer or can be induced to become malignant. In the oral region, leukoplakia is a lesion that has been regarded as precancerous. In cases of oral carcinoma, we have frequently noticed that a type of leukoplakia histologically demonstrating hyper-orthokeratosis and mild atypia (ortho-keratotic dysplasia; OKD) is often associated with carcinoma, either synchronously or metachronously. Therefore, we consider OKD-type leukoplakia to be a true precancerous lesion.<br><br>MATERIALS AND METHODS: In an attempt to clarify the relationship between OKD as a precancerous condition in the oral mucosa and telomere length, we estimated telomere lengths in this type of leukoplakia using quantitative fluorescence in situ hybridization, and also quantified the frequency of anaphase-telophase bridges (ATBs) in comparison with squamous cell carcinoma in situ (CIS) and the background tissues of CIS and OKD.<br><br>RESULTS: Ortho-keratotic dysplasia was frequently associated with squamous cell carcinoma (45.0%) and showed significantly shorter telomeres than normal control epithelium, CIS, or the background of CIS or OKD. The frequency of ATBs was much higher in OKD than in control epithelium or CIS.<br><br>CONCLUSION: Ortho-keratotic dysplasia appears to be frequently associated with carcinoma, chromosomal instability, and excessively shortened telomeres, not only in the lesion itself but also in the surrounding background. Therefore, when this type of leukoplakia is recognized in the oral region, strict follow-up for oral squamous cell carcinoma is necessary, focusing not only on the areas of leukoplakia, but also the surrounding background.},
}
@article {pmid22122049,
year = {2010},
author = {Wong, LH},
title = {Epigenetic regulation of telomere chromatin integrity in pluripotent embryonic stem cells.},
journal = {Epigenomics},
volume = {2},
number = {5},
pages = {639-655},
doi = {10.2217/epi.10.49},
pmid = {22122049},
issn = {1750-192X},
mesh = {Chromatin/genetics/*physiology ; DNA Methylation/genetics/*physiology ; Embryonic Stem Cells/*physiology ; Epigenesis, Genetic/genetics/*physiology ; Histones/*metabolism ; Humans ; Pluripotent Stem Cells/*physiology ; Shelterin Complex ; Telomere/genetics/*physiology ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomeres are protective chromosomal structures highly conserved from primitive organisms to humans. The evolutionary conservation of telomere DNA implicates the importance of telomeric structure for basic cellular functions. Loss of telomere function causes chromosomal fusion, activation of DNA damage checkpoint responses, genome instability and impaired stem cell function. In human cells, the telomeric chromatin consists of TTAGGG repeats associated with a complex of proteins known as Shelterin. It is also organized in nucleosomes enriched with epigenetic modifications of 'closed' or 'silenced' chromatin states, including DNA hypermethylation and trimethylation of H3K9 and H4K20. These heterochromatin marks serve as a higher-order level of control of telomere length and structural integrity. Recent studies have shown that the telomere nucleosome in pluripotent embryonic stem cells is characterized by a more 'open' chromatin state that switches to become more repressive during differentiation. Conversely, the reprogramming of adult somatic cells into induced pluripotent cells results in the switch in telomeric chromatin from a repressive to a more open embryonic stem cell-like state, coupled with the restoration of telomere length. These findings indicate that telomeric chromatin is dynamic and reprogrammable, and has a fundamental role in the maintenance of embryonic stem cell pluripotency.},
}
@article {pmid22117889,
year = {2012},
author = {Geiger, S and Le Vaillant, M and Lebard, T and Reichert, S and Stier, A and LE Maho, Y and Criscuolo, F},
title = {Catching-up but telomere loss: half-opening the black box of growth and ageing trade-off in wild king penguin chicks.},
journal = {Molecular ecology},
volume = {21},
number = {6},
pages = {1500-1510},
doi = {10.1111/j.1365-294X.2011.05331.x},
pmid = {22117889},
issn = {1365-294X},
mesh = {Aging/*physiology ; Animals ; Body Weight ; Female ; Male ; Oxidative Stress ; Spheniscidae/*growth &amp; development/*physiology ; Telomere ; *Telomere Shortening ; },
abstract = {One of the reasons for animals not to grow as fast as they potentially could is that fast growth has been shown to be associated with reduced lifespan. However, we are still lacking a clear description of the reality of growth-dependent modulation of ageing mechanisms in wild animals. Using the particular growth trajectory of small king penguin chicks naturally exhibiting higher-than-normal growth rate to compensate for the winter break, we tested whether oxidative stress and telomere shortening are related to growth trajectories. Plasma antioxidant defences, oxidative damage levels and telomere length were measured at the beginning and at the end of the post-winter growth period in three groups of chicks (small chicks, which either passed away or survived the growth period, and large chicks). Small chicks that died early during the growth period had the highest level of oxidative damage and the shortest telomere lengths prior to death. Here, we show that small chicks that grew faster did it at the detriment of body maintenance mechanisms as shown by (i) higher oxidative damage and (ii) accelerated telomere loss. Our study provides the first evidence for a mechanistic link between growth and ageing rates under natural conditions.},
}
@article {pmid22117085,
year = {2012},
author = {Smith, DR and Kayal, E and Yanagihara, AA and Collins, AG and Pirro, S and Keeling, PJ},
title = {First complete mitochondrial genome sequence from a box jellyfish reveals a highly fragmented linear architecture and insights into telomere evolution.},
journal = {Genome biology and evolution},
volume = {4},
number = {1},
pages = {52-58},
pmid = {22117085},
issn = {1759-6653},
support = {U54 MD007584/MD/NIMHD NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cubozoa/*genetics ; DNA Fragmentation ; DNA, Mitochondrial/*genetics ; *Evolution, Molecular ; Gene Conversion ; *Genome, Mitochondrial ; Mitochondria/genetics ; Molecular Sequence Data ; Recombination, Genetic ; Telomere/*genetics ; },
abstract = {Animal mitochondrial DNAs (mtDNAs) are typically single circular chromosomes, with the exception of those from medusozoan cnidarians (jellyfish and hydroids), which are linear and sometimes fragmented. Most medusozoans have linear monomeric or linear bipartite mitochondrial genomes, but preliminary data have suggested that box jellyfish (cubozoans) have mtDNAs that consist of many linear chromosomes. Here, we present the complete mtDNA sequence from the winged box jellyfish Alatina moseri (the first from a cubozoan). This genome contains unprecedented levels of fragmentation: 18 unique genes distributed over eight 2.9- to 4.6-kb linear chromosomes. The telomeres are identical within and between chromosomes, and recombination between subtelomeric sequences has led to many genes initiating or terminating with sequences from other genes (the most extreme case being 150 nt of a ribosomal RNA containing the 5' end of nad2), providing evidence for a gene conversion-based model of telomere evolution. The silent-site nucleotide variation within the A. moseri mtDNA is among the highest observed from a eukaryotic genome and may be associated with elevated rates of recombination.},
}
@article {pmid22113349,
year = {2013},
author = {Deelen, J and Uh, HW and Monajemi, R and van Heemst, D and Thijssen, PE and Böhringer, S and van den Akker, EB and de Craen, AJ and Rivadeneira, F and Uitterlinden, AG and Westendorp, RG and Goeman, JJ and Slagboom, PE and Houwing-Duistermaat, JJ and Beekman, M},
title = {Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 signaling and telomere maintenance pathways.},
journal = {Age (Dordrecht, Netherlands)},
volume = {35},
number = {1},
pages = {235-249},
pmid = {22113349},
issn = {1574-4647},
mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Genome-Wide Association Study ; Genotype ; Humans ; Insulin/genetics/*metabolism ; Insulin-Like Growth Factor I/*genetics ; Longevity/*genetics ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; Signal Transduction/genetics ; Telomere ; },
abstract = {In genome-wide association studies (GWAS) of complex traits, single SNP analysis is still the most applied approach. However, the identified SNPs have small effects and provide limited biological insight. A more appropriate approach to interpret GWAS data of complex traits is to analyze the combined effect of a SNP set grouped per pathway or gene region. We used this approach to study the joint effect on human longevity of genetic variation in two candidate pathways, the insulin/insulin-like growth factor (IGF-1) signaling (IIS) pathway and the telomere maintenance (TM) pathway. For the analyses, we used genotyped GWAS data of 403 unrelated nonagenarians from long-lived sibships collected in the Leiden Longevity Study and 1,670 younger population controls. We analyzed 1,021 SNPs in 68 IIS pathway genes and 88 SNPs in 13 TM pathway genes using four self-contained pathway tests (PLINK set-based test, Global test, GRASS and SNP ratio test). Although we observed small differences between the results of the different pathway tests, they showed consistent significant association of the IIS and TM pathway SNP sets with longevity. Analysis of gene SNP sets from these pathways indicates that the association of the IIS pathway is scattered over several genes (AKT1, AKT3, FOXO4, IGF2, INS, PIK3CA, SGK, SGK2, and YWHAG), while the association of the TM pathway seems to be mainly determined by one gene (POT1). In conclusion, this study shows that genetic variation in genes involved in the IIS and TM pathways is associated with human longevity.},
}
@article {pmid22111838,
year = {2011},
author = {Piñeyro, D and López-Panadès, E and Lucena-Pérez, M and Casacuberta, E},
title = {Transcriptional analysis of the HeT-A retrotransposon in mutant and wild type stocks reveals high sequence variability at Drosophila telomeres and other unusual features.},
journal = {BMC genomics},
volume = {12},
number = {},
pages = {573},
pmid = {22111838},
issn = {1471-2164},
mesh = {Animals ; Drosophila Proteins/*genetics ; Drosophila melanogaster/*genetics ; Female ; Gene Products, gag/*genetics ; *Genetic Variation ; Male ; Mutation ; *Retroelements ; Sequence Analysis, DNA ; Telomere/*genetics ; },
abstract = {BACKGROUND: Telomere replication in Drosophila depends on the transposition of a domesticated retroelement, the HeT-A retrotransposon. The sequence of the HeT-A retrotransposon changes rapidly resulting in differentiated subfamilies. This pattern of sequence change contrasts with the essential function with which the HeT-A is entrusted and brings about questions concerning the extent of sequence variability, the telomere contribution of different subfamilies, and whether wild type and mutant Drosophila stocks show different HeT-A scenarios.<br><br>RESULTS: A detailed study on the variability of HeT-A reveals that both the level of variability and the number of subfamilies are higher than previously reported. Comparisons between GIII, a strain with longer telomeres, and its parental strain Oregon-R indicate that both strains have the same set of HeT-A subfamilies. Finally, the presence of a highly conserved splicing pattern only in its antisense transcripts indicates a putative regulatory, functional or structural role for the HeT-A RNA. Interestingly, our results also suggest that most HeT-A copies are actively expressed regardless of which telomere and where in the telomere they are located.<br><br>CONCLUSIONS: Our study demonstrates how the HeT-A sequence changes much faster than previously reported resulting in at least nine different subfamilies most of which could actively contribute to telomere extension in Drosophila. Interestingly, the only significant difference observed between Oregon-R and GIII resides in the nature and proportion of the antisense transcripts, suggesting a possible mechanism that would in part explain the longer telomeres of the GIII stock.},
}
@article {pmid22110834,
year = {2011},
author = {Ly, H},
title = {Telomere dynamics in induced pluripotent stem cells: Potentials for human disease modeling.},
journal = {World journal of stem cells},
volume = {3},
number = {10},
pages = {89-95},
pmid = {22110834},
issn = {1948-0210},
abstract = {Recent advances in reprograming somatic cells from normal and diseased tissues into induced pluripotent stem cells (iPSCs) provide exciting possibilities for generating renewed tissues for disease modeling and therapy. However, questions remain on whether iPSCs still retain certain markers (e.g. aging) of the original somatic cells that could limit their replicative potential and utility. A reliable biological marker for measuring cellular aging is telomere length, which is maintained by a specialized form of cellular polymerase known as telomerase. Telomerase is composed of the cellular reverse transcriptase protein, its integral RNA component, and other cellular proteins (e.g. dyskerin). Mutations in any of these components of telomerase can lead to a severe form of marrow deficiency known as dyskeratosis congenita (DC). This review summarizes recent findings on the effect of cellular reprograming via iPS of normal or DC patient-derived tissues on telomerase function and consequently on telomere length maintenance and cellular aging. The potentials and challenges of using iPSCs in a clinical setting will also be discussed.},
}
@article {pmid22110763,
year = {2011},
author = {Watabe-Rudolph, M and Begus-Nahrmann, Y and Lechel, A and Rolyan, H and Scheithauer, MO and Rettinger, G and Thal, DR and Rudolph, KL},
title = {Telomere shortening impairs regeneration of the olfactory epithelium in response to injury but not under homeostatic conditions.},
journal = {PloS one},
volume = {6},
number = {11},
pages = {e27801},
pmid = {22110763},
issn = {1932-6203},
mesh = {Aging/genetics/metabolism/pathology ; Animals ; Cell Proliferation/drug effects ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Gene Knockout Techniques ; Homeostasis/drug effects/genetics ; Mice ; Olfactory Mucosa/drug effects/*injuries/pathology/*physiopathology ; Regeneration/drug effects/*genetics ; *Telomere Shortening/drug effects ; },
abstract = {Atrophy of the olfactory epithelium (OE) associated with impaired olfaction and dry nose represents one of the most common phenotypes of human aging. Impairment in regeneration of a functional olfactory epithelium can also occur in response to injury due to infection or nasal surgery. These complications occur more frequently in aged patients. Although age is the most unifying risk factor for atrophic changes and functional decline of the olfactory epithelium, little is known about molecular mechanisms that could influence maintenance and repair of the olfactory epithelium. Here, we analyzed the influence of telomere shortening (a basic mechanism of cellular aging) on homeostasis and regenerative reserve in response to chemical induced injury of the OE in late generation telomere knockout mice (G3 mTerc(-/-)) with short telomeres compared to wild type mice (mTerc(+/+)) with long telomeres. The study revealed no significant influence of telomere shortening on homeostatic maintenance of the OE during mouse aging. In contrast, the regenerative response to chemical induced injury of the OE was significantly impaired in G3 mTerc(-/-) mice compared to mTerc(+/+) mice. Seven days after chemical induced damage, G3 mTerc(-/-) mice exhibited significantly enlarged areas of persisting atrophy compared to mTerc(+/+) mice (p = 0.031). Telomere dysfunction was associated with impairments in cell proliferation in the regenerating epithelium. Deletion of the cell cycle inhibitor, Cdkn1a (p21) rescued defects in OE regeneration in telomere dysfunctional mice. Together, these data indicate that telomere shortening impairs the regenerative capacity of the OE by impairing cell cycle progression in a p21-dependent manner. These findings could be relevant for the impairment in OE function in elderly people.},
}
@article {pmid22108242,
year = {2012},
author = {Hirt, BV and Wattis, JA and Preston, SP and Laughton, CA},
title = {The effects of a telomere destabilizing agent on cancer cell-cycle dynamics--integrated modelling and experiments.},
journal = {Journal of theoretical biology},
volume = {295},
number = {},
pages = {9-22},
doi = {10.1016/j.jtbi.2011.10.038},
pmid = {22108242},
issn = {1095-8541},
mesh = {Acridines/administration &amp; dosage/*pharmacology ; Antineoplastic Agents/administration &amp; dosage/*pharmacology ; Cell Cycle/drug effects ; Cell Death/drug effects ; Colorectal Neoplasms/*drug therapy/genetics/pathology ; DNA, Neoplasm/metabolism ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical/methods ; HCT116 Cells ; Humans ; *Models, Biological ; Telomerase/*antagonists &amp; inhibitors ; Telomere/drug effects ; },
abstract = {The pentacyclic acridinium salt RHPS4 displays anti-tumour properties in vitro as well as in vivo and is potentially cell-cycle specific. We have collected experimental data and formulated a compartmental model using ordinary differential equations to investigate how the compound affects cells in each stage of the cell cycle. In addition to a control case in which no drug was used, we treated colorectal cancer cells with three different concentrations of the drug and fitted simulations from our models to experimental observations. We found that RHPS4 caused a concentration-dependent, marked cell death in treated cells, which is best modelled by allowing the rate parameters corresponding to cell death to be sigmoidal functions of time. We have shown that the model is "identifiable", meaning that, at least in principle, the parameter values can be determined from observable quantities. We find that at low concentrations RHPS4 primarily affects the cells in the G(2)/M phase, and that the drug has a delayed effect with the delay decreasing at larger doses. Since the drug diffuses into the nucleus, the observed delayed effect of the compound is unexpected and is a novel finding of our research into this compound.},
}
@article {pmid22101936,
year = {2011},
author = {Rai, R and Li, JM and Zheng, H and Lok, GT and Deng, Y and Huen, MS and Chen, J and Jin, J and Chang, S},
title = {The E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protection.},
journal = {Nature structural &amp; molecular biology},
volume = {18},
number = {12},
pages = {1400-1407},
pmid = {22101936},
issn = {1545-9985},
support = {R01 CA092312/CA/NCI NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes, Mammalian/metabolism ; DNA Damage ; DNA-Binding Proteins/metabolism ; Histones/metabolism ; Mice ; Protein Interaction Mapping ; Protein Stability ; Telomere/*chemistry ; Telomere-Binding Proteins ; Tumor Suppressor p53-Binding Protein 1 ; Ubiquitin-Protein Ligases/analysis/chemistry/*physiology ; Ubiquitination ; },
abstract = {The mammalian shelterin component TPP1 has essential roles in telomere maintenance and, together with POT1, is required for the repression of DNA damage signaling at telomeres. Here we show that in Mus musculus, the E3 ubiquitin ligase Rnf8 localizes to uncapped telomeres and promotes the accumulation of DNA damage proteins 53Bp1 and γ-H2ax. In the absence of Rnf8, Tpp1 is unstable, resulting in telomere shortening and chromosome fusions through the alternative nonhomologous end-joining (A-NHEJ) repair pathway. The Rnf8 RING-finger domain is essential for Tpp1 stability and retention at telomeres. Rnf8 physically interacts with Tpp1 to generate Ubc13-dependent Lys63 polyubiquitin chains that stabilize Tpp1 at telomeres. The conserved Tpp1 residue Lys233 is important for Rnf8-mediated Tpp1 ubiquitylation and localization to telomeres. Thus, Tpp1 is a newly identified substrate for Rnf8, indicating a previously unrecognized role for Rnf8 in telomere end protection.},
}
@article {pmid22101932,
year = {2011},
author = {Moser, BA and Chang, YT and Kosti, J and Nakamura, TM},
title = {Tel1ATM and Rad3ATR kinases promote Ccq1-Est1 interaction to maintain telomeres in fission yeast.},
journal = {Nature structural &amp; molecular biology},
volume = {18},
number = {12},
pages = {1408-1413},
pmid = {22101932},
issn = {1545-9985},
support = {R01 GM078253/GM/NIGMS NIH HHS/United States ; R01 GM078253-06/GM/NIGMS NIH HHS/United States ; GM078253/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/chemistry/metabolism/*physiology ; Checkpoint Kinase 2 ; Models, Genetic ; Models, Molecular ; Mutation ; Phosphorylation ; Protein Interaction Mapping ; Protein Kinases/chemistry/metabolism/*physiology ; Protein Serine-Threonine Kinases/chemistry/metabolism/*physiology ; Protein Structure, Tertiary ; Schizosaccharomyces/*enzymology ; Schizosaccharomyces pombe Proteins/chemistry/*metabolism/*physiology ; Telomerase/chemistry/*metabolism ; Telomere/*metabolism ; },
abstract = {The evolutionarily conserved shelterin complex has been shown to play both positive and negative roles in telomerase regulation in mammals and fission yeast. Although shelterin prevents the checkpoint kinases ATM and ATR from fully activating DNA damage responses at telomeres in mammalian cells, those kinases also promote telomere maintenance. In fission yeast, cells lacking both Tel1 (ATM ortholog) and Rad3 (ATR ortholog) fail to recruit telomerase to telomeres and survive by circularizing chromosomes. However, the critical telomere substrate(s) of Tel1(ATM) and Rad3(ATR) was unknown. Here we show that phosphorylation of the shelterin subunit Ccq1 on Thr93, redundantly mediated by Tel1(ATM) and/or Rad3(ATR), is essential for telomerase association with telomeres. In addition, we show that the telomerase subunit Est1 interacts directly with the phosphorylated Thr93 of Ccq1 to ensure telomere maintenance. The shelterin subunits Taz1, Rap1 and Poz1 (previously established inhibitors of telomerase) were also found to negatively regulate Ccq1 phosphorylation. These findings establish Tel1(ATM)/Rad3(ATR)-dependent Ccq1 Thr93 phosphorylation as a critical regulator of telomere maintenance in fission yeast.},
}
@article {pmid22100639,
year = {2012},
author = {Armanios, M and Price, C},
title = {Telomeres and disease: an overview.},
journal = {Mutation research},
volume = {730},
number = {1-2},
pages = {1-2},
doi = {10.1016/j.mrfmmm.2011.11.005},
pmid = {22100639},
issn = {0027-5107},
mesh = {Disease/*genetics ; Humans ; Telomere/*physiology ; },
}
@article {pmid22100521,
year = {2012},
author = {Harrington, L},
title = {Haploinsufficiency and telomere length homeostasis.},
journal = {Mutation research},
volume = {730},
number = {1-2},
pages = {37-42},
doi = {10.1016/j.mrfmmm.2011.11.004},
pmid = {22100521},
issn = {0027-5107},
support = {092076/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Gene Dosage ; *Haploinsufficiency ; Humans ; Mice ; Models, Animal ; Mutation ; Telomerase/metabolism ; Telomere/*genetics ; *Telomere Homeostasis ; },
abstract = {In humans, autosomal dominant or X-linked disease can arise through a phenomenon termed haploinsufficiency, where one remaining wild-type allele is insufficient for function. In model organisms, the impact of heterozygosity can be tested directly with engineered mutant alleles or in a hemizygous state where the expression of one allele is abrogated completely. This review will focus on haploinsufficiency as it relates to telomerase and telomere length maintenance and, citing selected examples in various model organisms, it will discuss how the problem of gene dosage relates to telomere function in normal and diseased states.},
}
@article {pmid22099311,
year = {2011},
author = {Takai, KK and Kibe, T and Donigian, JR and Frescas, D and de Lange, T},
title = {Telomere protection by TPP1/POT1 requires tethering to TIN2.},
journal = {Molecular cell},
volume = {44},
number = {4},
pages = {647-659},
pmid = {22099311},
issn = {1097-4164},
support = {R37 GM049046-20/GM/NIGMS NIH HHS/United States ; R01 GM049046/GM/NIGMS NIH HHS/United States ; AG016642/AG/NIA NIH HHS/United States ; R56 AG016642/AG/NIA NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; R01 AG016642-14/AG/NIA NIH HHS/United States ; GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/metabolism ; DNA Damage ; *DNA Repair ; DNA, Single-Stranded/chemistry/genetics/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; *Gene Expression ; HeLa Cells ; Humans ; Mice ; Mice, Knockout ; Protein Binding/genetics ; Recombinant Proteins/genetics/metabolism ; Shelterin Complex ; Signal Transduction/*genetics ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; },
abstract = {To prevent ATR activation, telomeres deploy the single-stranded DNA binding activity of TPP1/POT1a. POT1a blocks the binding of RPA to telomeres, suggesting that ATR is repressed through RPA exclusion. However, comparison of the DNA binding affinities and abundance of TPP1/POT1a and RPA indicates that TPP1/POT1a by itself is unlikely to exclude RPA. We therefore analyzed the central shelterin protein TIN2, which links TPP1/POT1a (and POT1b) to TRF1 and TRF2 on the double-stranded telomeric DNA. Upon TIN2 deletion, telomeres lost TPP1/POT1a, accumulated RPA, elicited an ATR signal, and showed all other phenotypes of POT1a/b deletion. TIN2 also affected the TRF2-dependent repression of ATM kinase signaling but not to TRF2-mediated inhibition of telomere fusions. Thus, while TIN2 has a minor contribution to the repression of ATM by TRF2, its major role is to stabilize TPP1/POT1a on the ss telomeric DNA, thereby allowing effective exclusion of RPA and repression of ATR signaling.},
}
@article {pmid22096847,
year = {2011},
author = {Bin, P and Leng, SG and Cheng, J and Duan, HW and Pan, ZF and Dai, YF and Niu, Y and Liu, QJ and Chen, H and Liu, Q and Zheng, YX},
title = {[Association between polymorphisms of metabolic genes and telomere length in workers exposed to polycyclic aromatic hydrocarbon].},
journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases},
volume = {29},
number = {6},
pages = {401-404},
pmid = {22096847},
issn = {1001-9391},
mesh = {Adult ; Case-Control Studies ; Cytochrome P-450 CYP1A1/genetics ; DNA/genetics ; DNA Damage ; Female ; Genotype ; Humans ; Male ; Middle Aged ; *Occupational Exposure ; Polycyclic Aromatic Hydrocarbons/*toxicity ; *Polymorphism, Single Nucleotide ; Telomere/*genetics ; Young Adult ; },
abstract = {OBJECTIVE: To investigate the association between the polymorphisms of metabolic genes and telomere length of genomic DNA in peripheral blood of workers exposed to polycyclic aromatic hydrocarbons (PAHs).<br><br>METHODS: One hundred and forty five coke-oven workers exposed to PAHs and sixty eight non-exposed medical staffs were recruited in this study. Urinary 1-hydroxypyrene (1-OHP) served as the internal exposure dose of PAHs for all subjects. Relative telomere length (RTL) of genomic DNA in peripheral blood was used as telomere length and measured by real-time PCR. Polymorphisms of metabolic genes were detected by PCR-based methods.<br><br>RESULTS: Compared with control group, the exposure group shown a decreased RTL (1.10 +/- 0.75 vs 1.43 +/- 1.06, P < 0.05). In the coke-oven workers, after adjusting the sex, age, cigarettes per day and urinary 1-OHP, RTL (1.25 +/- 0.93) of workers with CT genotype at the CYP1A1 3801 T > C was significantly longer than that (0.93 +/- 0.51) of workers with TT genotype (P < 0.05). RTL (0.90 +/- 0.58) of individuals with the Tyr/His genotype at mEH Tyr113His was significantly shorter than that (1.24 +/- 0.90) of individuals with the Tyr/Tyr genotype (P < 0.05). RTL (1.02 +/- 0.64) of individuals with the CT genotype at AHR rs10250822 was significantly shorter than that (1.36 +/- 1.14) of individuals with the CC genotype (P < 0.05). RTL (0.93 +/- 0.54) of individuals with the AT genotype at AHR rs10247158 was significantly shorter than that (1.19 +/- 0.84) of individuals with the AA genotype (P < 0.05).<br><br>CONCLUSION: The results of present study suggested that PAHs exposure could induce the shorted RTL, CYP1A1, mEH, AHR polymorphisms might influence the change of telomere length of genomic DNA in peripheral blood of workers exposed to PAHs.},
}
@article {pmid22096513,
year = {2011},
author = {Krauss, J and Farzaneh-Far, R and Puterman, E and Na, B and Lin, J and Epel, E and Blackburn, E and Whooley, MA},
title = {Physical fitness and telomere length in patients with coronary heart disease: findings from the Heart and Soul Study.},
journal = {PloS one},
volume = {6},
number = {11},
pages = {e26983},
pmid = {22096513},
issn = {1932-6203},
mesh = {Aged ; Aged, 80 and over ; Coronary Disease/*genetics ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/metabolism ; Logistic Models ; Male ; Middle Aged ; Physical Fitness/*physiology ; Telomere/*genetics ; },
abstract = {BACKGROUND: Short telomere length (TL) is an independent predictor of mortality in patients with coronary heart disease (CHD). However, the relationship between physical fitness and TL has not been explored in these patients.<br><br>METHODS: In a cross sectional study of 944 outpatients with stable CHD, we performed exercise treadmill testing, assessed self-reported physical activity, and measured leukocyte TL using a quantitative PCR assay. We used generalized linear models to calculate mean TL (T/S ratio), and logistic regression models to compare the proportion of patients with short TL (defined as the lowest quartile), among participants with low, medium and high physical fitness, based on metabolic equivalent tasks achieved (METs).<br><br>RESULTS: 229 participants had low physical fitness (<5 METS), 334 had moderate physical fitness (5-7 METS), and 381 had high physical fitness (>7 METS). Mean &#xb1; T/S ratio ranged from 0.86&#xb1;0.21 (5349&#xb1;3781 base pairs) in those with low physical fitness to 0.95&#xb1;0.23 (5566&#xb1;3829 base pairs) in those with high physical fitness (p<.001). This association remained strong after adjustment for numerous patient characteristics, including measures of cardiac disease severity and physical inactivity (p&#x200a;=&#x200a;0.005). Compared with participants with high physical fitness, those with low physical fitness had 2-fold greater odds of having TL in the lowest quartile (OR 2.39, 95% CI 1.60-3.55; p<.001). This association was similar after multivariable adjustment (OR 1.94, 95%CI, 1.18-3.20; p&#x200a;=&#x200a;0.009). Self-reported physical inactivity was associated with shorter TL in unadjusted analyses, but not after multivariable adjustment.<br><br>CONCLUSIONS: We found that worse objectively-assessed physical fitness is associated with shorter leukocyte telomere length in patients with CHD. The clinical implications of this association deserve further study.},
}
@article {pmid22091521,
year = {2011},
author = {Strandberg, TE and Saijonmaa, O and Fyhrquist, F and Tilvis, RS and Strandberg, AY and Miettinen, TA and Pitkälä, KH and Salomaa, V},
title = {Telomere length in old age and cholesterol across the life course.},
journal = {Journal of the American Geriatrics Society},
volume = {59},
number = {10},
pages = {1979-1981},
doi = {10.1111/j.1532-5415.2011.03610_13.x},
pmid = {22091521},
issn = {1532-5415},
mesh = {Adult ; Aged ; Aging/*genetics ; Body Mass Index ; Cholesterol/*blood ; Cholesterol, HDL/blood ; Cholesterol, LDL/blood ; Cohort Studies ; Finland ; Humans ; Hypercholesterolemia/blood/mortality ; Leukocytes/metabolism ; Male ; Mathematical Computing ; Middle Aged ; Smoking/blood ; Survival Analysis ; Telomere Shortening/*genetics ; },
}
@article {pmid22086874,
year = {2013},
author = {Bojovic, B and Crowe, DL},
title = {Dysfunctional telomeres promote genomic instability and metastasis in the absence of telomerase activity in oncogene induced mammary cancer.},
journal = {Molecular carcinogenesis},
volume = {52},
number = {2},
pages = {103-117},
doi = {10.1002/mc.21834},
pmid = {22086874},
issn = {1098-2744},
mesh = {Animals ; Female ; Gene Expression Regulation, Neoplastic ; *Genes, erbB-2 ; *Genomic Instability ; Humans ; Lung Neoplasms/genetics/pathology/secondary ; Mammary Neoplasms, Experimental/enzymology/*genetics/*pathology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Proto-Oncogene Mas ; RNA/genetics/metabolism ; Telomerase/genetics/*metabolism ; *Telomere ; },
abstract = {Telomerase is a ribonucleoprotein that maintains the ends of chromosomes (telomeres). In normal cells lacking telomerase activity, telomeres shorten with each cell division because of the inability to completely synthesize the lagging strand. Critically shortened telomeres elicit DNA damage responses and limit cellular division and lifespan, providing an important tumor suppressor function. Most human cancer cells express telomerase which contributes significantly to the tumor phenotype. In human breast cancer, telomerase expression is predictive of clinical outcomes such as lymph node metastasis and survival. In mouse models of mammary cancer, telomerase expression is also upregulated. Telomerase overexpression resulted in spontaneous mammary tumor development in aged female mice. Increased mammary cancer also was observed when telomerase deficient mice were crossed with p53 null mutant animals. However, the effects of telomerase and telomere length on oncogene driven mammary cancer have not been completely characterized. To address these issues we characterized neu proto-oncogene driven mammary tumor formation in G1 Terc-/- (telomerase deficient with long telomeres), G3 Terc-/- (telomerase deficient with short telomeres), and Terc+/+ mice. Telomerase deficiency reduced the number of mammary tumors and increased tumor latency regardless of telomere length. Decreased tumor formation correlated with increased apoptosis in Terc deficient tumors. Short telomeres dramatically increased lung metastasis which correlated with increased genomic instability, and specific alterations in DNA copy number and gene expression. We concluded that short telomeres promote metastasis in the absence of telomerase activity in neu oncogene driven mammary tumors.},
}
@article {pmid22080935,
year = {2012},
author = {Kapusi, E and Ma, L and Teo, CH and Hensel, G and Himmelbach, A and Schubert, I and Mette, MF and Kumlehn, J and Houben, A},
title = {Telomere-mediated truncation of barley chromosomes.},
journal = {Chromosoma},
volume = {121},
number = {2},
pages = {181-190},
pmid = {22080935},
issn = {1432-0886},
mesh = {Agrobacterium ; Chromosomes, Plant/*genetics ; DNA Primers/genetics ; DNA, Bacterial/genetics ; *Gene Transfer Techniques ; Genetic Engineering/*methods ; Hordeum/*genetics ; In Situ Hybridization, Fluorescence ; Plasmids/genetics ; Polymerase Chain Reaction ; Telomere/*genetics ; Transformation, Genetic/genetics ; },
abstract = {Engineered minichromosomes offer an enormous opportunity to plant biotechnology as they have the potential to simultaneously transfer and stably express multiple genes. Following a top-down approach, we truncated endogenous chromosomes in barley (Hordeum vulgare) by Agrobacterium-mediated transfer of T-DNA constructs containing telomere sequences. Blocks of Arabidopsis-like telomeric repeats were inserted into a binary vector suitable for stable transformation. After transfer of these constructs into immature embryos of diploid and tetraploid barley, chromosome truncation by T-DNA-induced de novo formation of telomeres could be confirmed by fluorescent in situ hybridisation, primer extension telomere repeat amplification and DNA gel blot analysis in regenerated plants. Telomere seeding connected to chromosome truncation was found in tetraploid plants only, indicating that genetic redundancy facilitates recovery of shortened chromosomes. Truncated chromosomes were transmissible in sexual reproduction, but were inherited at rates lower than expected according to Mendelian rules.},
}
@article {pmid22078571,
year = {2012},
author = {Touzot, F and Gaillard, L and Vasquez, N and Le Guen, T and Bertrand, Y and Bourhis, J and Leblanc, T and Fischer, A and Soulier, J and de Villartay, JP and Revy, P},
title = {Heterogeneous telomere defects in patients with severe forms of dyskeratosis congenita.},
journal = {The Journal of allergy and clinical immunology},
volume = {129},
number = {2},
pages = {473-82, 482.e1-3},
doi = {10.1016/j.jaci.2011.09.043},
pmid = {22078571},
issn = {1097-6825},
support = {249816/ERC_/European Research Council/International ; },
mesh = {Child, Preschool ; DNA/genetics ; DNA Repair ; Dyskeratosis Congenita/genetics/*metabolism/pathology ; Female ; Fetal Growth Retardation/genetics/*metabolism/pathology ; Fibroblasts/enzymology/*metabolism/pathology ; Humans ; Infant ; Intellectual Disability/genetics/*metabolism/pathology ; Male ; Microcephaly/genetics/*metabolism/pathology ; Phenotype ; Sequence Analysis, DNA ; Telomerase/metabolism ; Telomere/*metabolism/pathology ; Telomere-Binding Proteins/genetics ; },
abstract = {BACKGROUND: Telomeres represent the tips of linear chromosomes. In human subjects telomere maintenance deficiency leads to dyskeratosis congenita (DC), a rare genetic disorder characterized by progressive bone marrow failure, accelerated aging, and cancer predisposition. Hoyeraal-Hreidarsson syndrome (HH) is a severe variant of DC in which an early onset of bone marrow failure leading to combined immunodeficiency is associated with microcephaly, cerebellar hypoplasia, and growth retardation.<br><br>OBJECTIVES: Limited information is available on the cellular and molecular phenotypes of cells from patients with HH. We analyzed fibroblasts and whole blood cells from 5 patients with HH, 3 of them of unknown molecular origin.<br><br>METHODS: Telomere length, cellular senescence rate, telomerase activity, telomeric aberration, and DNA repair pathways were investigated.<br><br>RESULTS: Although patients' cells exhibit dysfunctional telomeres, sharp differences in the telomeric aberrations and telomere lengths were noted among these patients. In some patients the dysfunctional telomere phenotype was unprecedented and associated with either normal telomere length or with telomeric aberrations akin to fragile telomeres. This result is of particular importance because the molecular diagnosis of these patients is primarily based on telomere length, which therefore misses a subset of patients with telomere dysfunction.<br><br>CONCLUSION: These observations provide the notions that (1)&#xa0;various telomere defects can lead to similar clinical features, (2) telomere dysfunction in cells from patients with DC/HH is not always associated with short telomeres, and (3) additional factors, likely involved in telomere protection rather than in length regulation, are responsible for a subset of DC/HH.},
}
@article {pmid22072619,
year = {2012},
author = {Zhou, X and Meeker, AK and Makambi, KH and Kosti, O and Kallakury, BV and Sidawy, MK and Loffredo, CA and Zheng, YL},
title = {Telomere length variation in normal epithelial cells adjacent to tumor: potential biomarker for breast cancer local recurrence.},
journal = {Carcinogenesis},
volume = {33},
number = {1},
pages = {113-118},
pmid = {22072619},
issn = {1460-2180},
support = {P30 CA51008/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Biomarkers, Tumor ; Breast Neoplasms/*genetics/pathology ; Case-Control Studies ; Epithelial Cells/*ultrastructure ; Female ; Humans ; Middle Aged ; Neoplasm Recurrence, Local/*genetics/pathology ; Stromal Cells/ultrastructure ; *Telomere ; },
abstract = {A better understanding of the risk of local recurrence (LR) will facilitate therapeutic decision making in the management of early breast cancers. In the present study, we investigated whether telomere length in the normal breast epithelial cells surrounding the tumor is predictive of breast cancer LR; 152 women who were diagnosed with breast cancer at the Lombardi Comprehensive Cancer Center were included in this nested case-control study. Cases (patients had LR) and controls (patients had no LR) were matched on year of surgery, age at diagnosis and type of surgery. Telomere fluorescent in situ hybridization was used to determine the telomere length using formalin fixed paraffin-embedded breast tissues. Small telomere length variation (TLV), defined as the coefficient variation of telomere lengths among examined cells, in normal epithelial cells adjacent to the tumor was significantly associated with a 5-fold (95% confidence interval = 1.2-22.2) increased risk of breast cancer LR. When the subjects were categorized into quartiles, a significant inverse dose-response relationship was observed with lowest versus highest quartile odds ratio of 15.3 (P(trend) = 0.012). Patients who had large TLV had significantly better 10 year recurrence free survival rate compared with patients who had small TLV (80 versus 33%). The present study revealed that TLV in normal epithelial cells adjacent to tumor is a strong predictor of breast cancer LR. If confirmed by future studies, TLV in normal epithelial cells adjacent to tumor has the potential to become a promising biomarker for predicting breast cancer LR after breast conserving surgery.},
}
@article {pmid22072607,
year = {2012},
author = {Haussmann, MF and Longenecker, AS and Marchetto, NM and Juliano, SA and Bowden, RM},
title = {Embryonic exposure to corticosterone modifies the juvenile stress response, oxidative stress and telomere length.},
journal = {Proceedings. Biological sciences},
volume = {279},
number = {1732},
pages = {1447-1456},
pmid = {22072607},
issn = {1471-2954},
mesh = {Animals ; Biological Evolution ; Cellular Senescence/drug effects ; Chick Embryo/*drug effects/physiology ; Corticosterone/*administration &amp; dosage ; Female ; Hypothalamo-Hypophyseal System/drug effects ; Models, Biological ; Oxidative Stress/drug effects ; Pituitary-Adrenal System/drug effects ; Stress, Physiological/drug effects ; Telomere Homeostasis/drug effects ; },
abstract = {Early embryonic exposure to maternal glucocorticoids can broadly impact physiology and behaviour across phylogenetically diverse taxa. The transfer of maternal glucocorticoids to offspring may be an inevitable cost associated with poor environmental conditions, or serve as a maternal effect that alters offspring phenotype in preparation for a stressful environment. Regardless, maternal glucocorticoids are likely to have both costs and benefits that are paid and collected over different developmental time periods. We manipulated yolk corticosterone (cort) in domestic chickens (Gallus domesticus) to examine the potential impacts of embryonic exposure to maternal stress on the juvenile stress response and cellular ageing. Here, we report that juveniles exposed to experimentally increased cort in ovo had a protracted decline in cort during the recovery phase of the stress response. All birds, regardless of treatment group, shifted to oxidative stress during an acute stress response. In addition, embryonic exposure to cort resulted in higher levels of reactive oxygen metabolites and an over-representation of short telomeres compared with the control birds. In many species, individuals with higher levels of oxidative stress and shorter telomeres have the poorest survival prospects. Given this, long-term costs of glucocorticoid-induced phenotypes may include accelerated ageing and increased mortality.},
}
@article {pmid22066540,
year = {2011},
author = {Cauët, E},
title = {Unique hole-trapping property of the human telomere sequence.},
journal = {Journal of biomolecular structure &amp; dynamics},
volume = {29},
number = {3},
pages = {557-561},
doi = {10.1080/07391102.2011.10507405},
pmid = {22066540},
issn = {1538-0254},
mesh = {Base Sequence ; Guanine/chemistry ; Humans ; Nucleic Acid Conformation ; *Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; },
abstract = {The hypothetical protection of genes from oxidative damage provided by the G-rich telomeric overhangs located at the end of chromosomes, which consist, in humans, of single strands of TTAGGG sequence repeats, is investigated here. First principle Moller-Plesset perturbation theory calculations reveal that the TTAGGG human telomere sequence is particularly prone to oxidation and can act as a profound hole trap as deep as a sequence of five consecutive guanines. In addition, we show that the sequence dependence is very important and that modifications in the human telomeric sequence can induce crucial changes in the electronic structure of the sequence, with concomitant increase of the ionization energy. These theoretical results provide, for the first time, quantitative data indicating a high and unique efficiency of the human telomeric sequence as a trap in long-range hole migration which will aid in the design of subsequent experiments.},
}
@article {pmid22065550,
year = {2011},
author = {Malan, S and Hemmings, S and Kidd, M and Martin, L and Seedat, S},
title = {Investigation of telomere length and psychological stress in rape victims.},
journal = {Depression and anxiety},
volume = {28},
number = {12},
pages = {1081-1085},
doi = {10.1002/da.20903},
pmid = {22065550},
issn = {1520-6394},
mesh = {Adolescent ; Adult ; Depressive Disorder, Major/*etiology/genetics/pathology ; Female ; Humans ; Leukocytes/metabolism/pathology ; Polymerase Chain Reaction ; Rape/*psychology ; Stress Disorders, Post-Traumatic/*etiology/genetics ; Telomere/*metabolism ; Young Adult ; },
abstract = {BACKGROUND: Women are at an increased risk of depression and other mental health problems following rape. Various etiological factors for depression, including predisposing genetic factors, have been identified. Telomeres are repetitive nucleoprotein structures located at chromosomal ends that protect them from premature degradation. Telomeres reduce in length with each cell division, resulting in cellular senescence and apoptosis.<br><br>METHODS: Relative quantification of telomeric repeats using qPCR was performed to investigate whether shorter relative leukocyte telomere length (LTL) in a cohort of 64 rape victims was associated with resilience, the development of rape trauma-related major depressive disorder (MDD) or the development of posttraumatic stress disorder (PTSD) after 3 months.<br><br>RESULTS: Out of the 64 participants, 23 participants were diagnosed with MDD at baseline and 31 after 3 months. Nine participants were diagnosed with PTSD (MDD and PTSD specifically related to the trauma). No significant associations were observed between relative LTL and resilience or the development of MDD at either baseline or after 3 months in this cohort. However, a marginally significant association was evident between relative LTL and PTSD status.<br><br>CONCLUSIONS: The significant association between relative LTL and PTSD suggests that shorter relative LTL might have acted as a predisposing factor in the development of PTSD after a severely traumatic event. The results of this study indicate that telomere shortening may be an important marker of PTSD risk, with implications for early intervention and timely treatment, and as such warrant replication in a larger cohort.},
}
@article {pmid22064443,
year = {2011},
author = {Brault, ME and Autexier, C},
title = {ALTered telomeres in response to telomere dysfunction.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {10},
number = {22},
pages = {3807-3809},
doi = {10.4161/cc.10.22.18188},
pmid = {22064443},
issn = {1551-4005},
mesh = {Chromatin/ultrastructure ; Homologous Recombination ; Humans ; Models, Genetic ; Neoplasms/genetics ; Telomerase/*physiology ; Telomere/metabolism/*physiology ; Tumor Cells, Cultured ; },
}
@article {pmid22058290,
year = {2012},
author = {Zeng, XL and Thumati, NR and Fleisig, HB and Hukezalie, KR and Savage, SA and Giri, N and Alter, BP and Wong, JM},
title = {The accumulation and not the specific activity of telomerase ribonucleoprotein determines telomere maintenance deficiency in X-linked dyskeratosis congenita.},
journal = {Human molecular genetics},
volume = {21},
number = {4},
pages = {721-729},
pmid = {22058290},
issn = {1460-2083},
support = {MOP-81094/CAPMC/CIHR/Canada ; N02CP65501/CP/NCI NIH HHS/United States ; N02CP11019/CP/NCI NIH HHS/United States ; N02CP65504/CP/NCI NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; },
mesh = {Biocatalysis ; Cell Cycle Proteins/*genetics/metabolism ; Cell Line ; Dyskeratosis Congenita/enzymology/*genetics/*metabolism/pathology ; Fibroblasts/enzymology/metabolism/pathology ; Gene Expression ; Genotype ; Holoenzymes/isolation &amp; purification/metabolism ; Humans ; Mutant Proteins/genetics/metabolism ; Mutation ; Nuclear Proteins/*genetics/metabolism ; Nucleotide Motifs ; RNA/genetics/metabolism ; RNA Stability ; Telomerase/genetics/isolation &amp; purification/*metabolism ; Telomere/*genetics/*metabolism ; Telomere Homeostasis ; },
abstract = {X-linked dyskeratosis congenita (X-DC) is caused by mutations in the housekeeping nucleolar protein dyskerin. Amino acid changes associated with X-DC are remarkably heterogeneous. Peripheral mononuclear blood cells and fibroblasts isolated from X-DC patients harbor lower steady-state telomerase RNA (TER) levels and shorter telomeres than healthy age-matched controls. Previously, we showed that retroviral expression of recombinant TER, together with expression of recombinant telomerase reverse transcriptase, restored telomere maintenance and proliferative capacity in X-DC patient cells. Using rare X-DC isoforms (ΔL37 and A386T dyskerin), we showed that telomere maintenance defects observed in X-DC are solely due to decreased steady-state levels of TER. Disease-associated reductions in steady-state TER levels cause deficiencies in telomere maintenance. Here, we confirm these findings in other primary X-DC patient cell lines coding for the most common (A353V dyskerin) and more clinically severe (K314R and A353V dyskerin) X-DC isoforms. Using cell lines derived from these patients, we also examined the steady-state levels of other hinge-ACA motif RNAs and did not find differences in their in vivo accumulations. We show, for the first time, that purified telomerase holoenzyme complexes from different X-DC cells have normal catalytic activity. Our data confirm that dyskerin promotes TER stability in vivo, endorsing the development of TER supplementation strategies for the treatment of X-DC.},
}
@article {pmid22058220,
year = {2012},
author = {Alter, BP and Rosenberg, PS and Giri, N and Baerlocher, GM and Lansdorp, PM and Savage, SA},
title = {Telomere length is associated with disease severity and declines with age in dyskeratosis congenita.},
journal = {Haematologica},
volume = {97},
number = {3},
pages = {353-359},
pmid = {22058220},
issn = {1592-8721},
support = {HHSN261200655001C//PHS HHS/United States ; R01 GM094146/GM/NIGMS NIH HHS/United States ; R01GM094146/GM/NIGMS NIH HHS/United States ; RMF-92093/CAPMC/CIHR/Canada ; /ImNIH/Intramural NIH HHS/United States ; N02-CP-91026/CP/NCI NIH HHS/United States ; RMF-92093//PHS HHS/United States ; N02CP11019/CP/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aging/*genetics ; Child ; Child, Preschool ; Disease Progression ; Dyskeratosis Congenita/diagnosis/*genetics ; Female ; Humans ; Infant ; Infant, Newborn ; Longitudinal Studies ; Male ; Middle Aged ; *Telomere Shortening ; Young Adult ; },
abstract = {BACKGROUND: Dyskeratosis congenita is a cancer-prone bone marrow failure syndrome caused by aberrations in telomere biology.<br><br>DESIGN AND METHODS: We studied 65 patients with dyskeratosis congenita and 127 unaffected relatives. Telomere length was measured by automated multicolor flow fluorescence in situ hybridization in peripheral blood leukocyte subsets. We age-adjusted telomere length using Z-scores (standard deviations from the mean for age).<br><br>RESULTS: We confirmed that telomere lengths below the first percentile for age are very sensitive and specific for the diagnosis of dyskeratosis congenita. We provide evidence that lymphocytes alone and not granulocytes may suffice for clinical screening, while lymphocyte subsets may be required for challenging cases, including identification of silent carriers. We show for the first time using flow fluorescence in situ hybridization that the shortest telomeres are associated with severe variants (Hoyeraal-Hreidarsson and Revesz syndromes), mutations in DKC1, TINF2, or unknown genes, and moderate or severe aplastic anemia. In the first longitudinal follow up of dyskeratosis congenita patients, we demonstrate that telomere lengths decline with age, in contrast to the apparent stable telomere length observed in cross-sectional data.<br><br>CONCLUSIONS: Telomere length by flow fluorescence in situ hybridization is an important diagnostic test for dyskeratosis congenita; age-adjusted values provide a quantitative measure of disease severity (clinical subset, mutated gene, and degree of bone marrow failure). Patients with dyskeratosis congenita have accelerated telomere shortening. This study is registered at www.clinicaltrials.gov (identifier: NCT00027274).},
}
@article {pmid22055018,
year = {2012},
author = {Wikgren, M and Maripuu, M and Karlsson, T and Nordfjäll, K and Bergdahl, J and Hultdin, J and Del-Favero, J and Roos, G and Nilsson, LG and Adolfsson, R and Norrback, KF},
title = {Short telomeres in depression and the general population are associated with a hypocortisolemic state.},
journal = {Biological psychiatry},
volume = {71},
number = {4},
pages = {294-300},
doi = {10.1016/j.biopsych.2011.09.015},
pmid = {22055018},
issn = {1873-2402},
mesh = {*Adrenal Insufficiency/etiology/metabolism/physiopathology ; Adult ; Aged ; C-Reactive Protein/metabolism ; *Depressive Disorder, Major/complications/metabolism/pathology/physiopathology ; Female ; Humans ; Hydrocortisone/*metabolism ; Hypothalamo-Hypophyseal System/metabolism/physiopathology ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Pituitary-Adrenal System/metabolism/physiopathology ; Psychiatric Status Rating Scales ; Statistics as Topic ; *Stress, Psychological/complications/metabolism/pathology/physiopathology ; Surveys and Questionnaires ; Telomere/*pathology ; },
abstract = {BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in stress regulation, and leukocyte telomere length (TL) has been suggested to represent a cumulative measure of stress. Depression is intimately related with stress and frequently exhibits a dysregulated HPA axis. We aimed to study the relationships between TL and biological and psychological facets of stress in recurrent major depressive disorder and controls.<br><br>METHODS: Leukocyte TL was measured in 91 subjects with recurrent major depressive disorder and 451 control subjects. Stress was assessed from both a biological perspective, by assessing HPA axis function with a weight-adjusted very-low-dose dexamethasone suppression test (DST), and a psychological perspective, with self-report questionnaires.<br><br>RESULTS: TL was shorter among patients compared with control subjects (277 base pairs, p = .001). Overall, short TL was associated with a hypocortisolemic state (low post-DST cortisol and high percentage of cortisol reduction after the DST) among both patients and control subjects but more pronounced among patients. This state, which was overrepresented among patients, was characterized by high familial loading of affective disorders among patients (p = .001) and high C-reactive protein levels among control subjects (p = .040). TL was also inversely associated with stress measured with the Perceived Stress Questionnaire (r(s) = -.258, p = .003).<br><br>CONCLUSIONS: Short TL is associated with depression and hypocortisolism. Because hypocortisolism has been shown to develop from chronic stress exposure, our findings corroborate the concept of TL as a cumulative measure of stress and provide novel insights into the detrimental role of stress in depressive illness and the general population.},
}
@article {pmid22050065,
year = {2011},
author = {Hoffmann, J and Spyridopoulos, I},
title = {Telomere length in cardiovascular disease: new challenges in measuring this marker of cardiovascular aging.},
journal = {Future cardiology},
volume = {7},
number = {6},
pages = {789-803},
doi = {10.2217/fca.11.55},
pmid = {22050065},
issn = {1744-8298},
mesh = {Aging/*genetics ; Cardiovascular Diseases/*genetics ; Genetic Markers/*genetics ; Humans ; Oxidative Stress/genetics ; Telomere/*genetics ; },
abstract = {Atherosclerosis is an age-related systemic disease characterized by systemic oxidative stress and low grade chronic inflammation. Various types of leukocytes play an important role within this process. Telomeres, the ends of chromosomes, shorten during each and every cell division and have therefore been regarded as a cellular clock. Telomere dysfunction has been implicated in aging and senescence, and shorter leukocyte telomere length (LTL) has been demonstrated to predict cardiovascular disease and mortality. However, although LTL can predict cardiovascular events in population studies, a number of factors have prevented its broad use as a surrogate end point, such as serum levels of LDL cholesterol. In this article we will provide an overview of telomere biology and telomere dynamics of different leukocyte populations, and we will also discuss pitfalls in the methodology of LTL quantification, in context with landmark studies, which measured LTL in cardiovascular disease. Finally, we will attempt to critically assess and explain the shortcomings of LTL as a biomarker and identify further research avenues that require further investigation before telomere length can be implemented as an individual biomarker for cardiovascular aging. From this it becomes evident that LTL can be susceptible to methodological errors affecting longitudinal reproducibility. LTL is generally confounded at least by genetic factors, population variation and leukocyte composition.},
}
@article {pmid22046530,
year = {2011},
author = {Prather, AA and Puterman, E and Lin, J and O'Donovan, A and Krauss, J and Tomiyama, AJ and Epel, ES and Blackburn, EH},
title = {Shorter leukocyte telomere length in midlife women with poor sleep quality.},
journal = {Journal of aging research},
volume = {2011},
number = {},
pages = {721390},
pmid = {22046530},
issn = {2090-2212},
abstract = {Background. Accumulating evidence supports leukocyte telomere length (LTL) as a biological marker of cellular aging. Poor sleep is a risk factor for age-related disease; however, the extent to which sleep accounts for variation in LTL is unknown. Methods. The present study examined associations of self-reported sleep duration, onset latency, and subjective quality with LTL in a community-dwelling sample of 245 healthy women in midlife (aged 49-66 years). Results. While sleep duration and onset latency were unrelated to LTL, women reporting poorer sleep quality displayed shorter LTL (r = 0.14, P = 0.03), independent of age, BMI, race, and income (b = 55.48, SE = 27.43, P = 0.04). When analyses were restricted to participants for whom sleep patterns were chronic, poorer sleep quality predicted shorter LTL independent of covariates and perceived psychological stress. Conclusions. This study provides the first evidence that poor sleep quality explains significant variation in LTL, a marker of cellular aging.},
}
@article {pmid22046342,
year = {2011},
author = {Royds, JA and Al Nadaf, S and Wiles, AK and Chen, YJ and Ahn, A and Shaw, A and Bowie, S and Lam, F and Baguley, BC and Braithwaite, AW and MacFarlane, MR and Hung, NA and Slatter, TL},
title = {The CDKN2A G500 allele is more frequent in GBM patients with no defined telomere maintenance mechanism tumors and is associated with poorer survival.},
journal = {PloS one},
volume = {6},
number = {10},
pages = {e26737},
pmid = {22046342},
issn = {1932-6203},
mesh = {Adult ; Aged ; Alleles ; Biomarkers ; Cyclin-Dependent Kinase Inhibitor p16/*genetics ; Female ; Gene Frequency ; Genetic Variation ; Glioblastoma/*genetics/*mortality ; Humans ; Isocitrate Dehydrogenase/genetics ; Male ; Middle Aged ; Prognosis ; Survival Analysis ; Telomerase ; Telomere ; },
abstract = {Prognostic markers for glioblastoma multiforme (GBM) are important for patient management. Recent advances have identified prognostic markers for GBMs that use telomerase or the alternative lengthening of telomeres (ALT) mechanism for telomere maintenance. Approximately 40% of GBMs have no defined telomere maintenance mechanism (NDTMM), with a mixed survival for affected individuals. This study examined genetic variants in the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene that encodes the p16(INK4a) and p14(ARF) tumor suppressors, and the isocitrate dehydrogenase 1 (IDH1) gene as potential markers of survival for 40 individuals with NDTMM GBMs (telomerase negative and ALT negative by standard assays), 50 individuals with telomerase, and 17 individuals with ALT positive tumors. The analysis of CDKN2A showed NDTMM GBMs had an increased minor allele frequency for the C500G (rs11515) polymorphism compared to those with telomerase and ALT positive GBMs (p = 0.002). Patients with the G500 allele had reduced survival that was independent of age, extent of surgery, and treatment. In the NDTMM group G500 allele carriers had increased loss of CDKN2A gene dosage compared to C500 homozygotes. An analysis of IDH1 mutations showed the R132H mutation was associated with ALT positive tumors, and was largely absent in NDTMM and telomerase positive tumors. In the ALT positive tumors cohort, IDH1 mutations were associated with a younger age for the affected individual. In conclusion, the G500 CDKN2A allele was associated with NDTMM GBMs from older individuals with poorer survival. Mutations in IDH1 were not associated with NDTMM GBMs, and instead were a marker for ALT positive tumors in younger individuals.},
}
@article {pmid22045740,
year = {2011},
author = {Meng, L and Hsu, JK and Zhu, Q and Lin, T and Tsai, RY},
title = {Nucleostemin inhibits TRF1 dimerization and shortens its dynamic association with the telomere.},
journal = {Journal of cell science},
volume = {124},
number = {Pt 21},
pages = {3706-3714},
pmid = {22045740},
issn = {1477-9137},
support = {R01 CA113750/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line ; Dimerization ; GTP-Binding Proteins/genetics/*metabolism ; Humans ; Nuclear Proteins/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/*chemistry/genetics/*metabolism ; },
abstract = {TRF1 is a key component of the telomere-capping complex and binds double-strand telomeric DNA as homodimers. So far, it is not clear whether TRF1 dimerization coincides with its telomere binding or is actively controlled before it binds the telomere, and in the latter case, how this event might affect its telomere association. We previously found that TRF1 dimerization and its telomere binding can be increased by GNL3L, which is the vertebrate paralogue of nucleostemin (NS). Here, we show that NS and GNL3L bind TRF1 directly but competitively through two separate domains of TRF1. In contrast to GNL3L, NS prevents TRF1 dimerization through a mechanism not determined by its ability to displace TRF1-bound GNL3L. Furthermore, NS is capable of shortening the dynamic association of TRF1 with the telomere in normal and TRF2(ΔBΔM)-induced telomere-damaged cells without affecting the amount of telomere-bound TRF1 proteins in vivo. Importantly, NS displays a protective function against the formation of telomere-dysfunction-induced foci. This work demonstrates that TRF1 dimerization is actively and oppositely regulated by NS and GNL3L extrachromosomally. Changing the relative amount of TRF1 monomers versus dimers in the nucleoplasm might affect the dynamic association of TRF1 with the telomere and the repair of damaged telomeres.},
}
@article {pmid22045732,
year = {2011},
author = {Chung, I and Leonhardt, H and Rippe, K},
title = {De novo assembly of a PML nuclear subcompartment occurs through multiple pathways and induces telomere elongation.},
journal = {Journal of cell science},
volume = {124},
number = {Pt 21},
pages = {3603-3618},
doi = {10.1242/jcs.084681},
pmid = {22045732},
issn = {1477-9137},
mesh = {Cell Line, Tumor ; Humans ; Intranuclear Inclusion Bodies/*metabolism ; Intranuclear Space/*metabolism ; Leukemia, Promyelocytic, Acute/genetics/*metabolism ; Nuclear Proteins/genetics/*metabolism ; Promyelocytic Leukemia Protein ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Transcription Factors/genetics/*metabolism ; Tumor Suppressor Proteins/genetics/*metabolism ; },
abstract = {Telomerase-negative tumor cells use an alternative lengthening of telomeres (ALT) pathway that involves DNA recombination and repair to maintain their proliferative potential. The cytological hallmark of this process is the accumulation of promyelocytic leukemia (PML) nuclear protein at telomeric DNA to form ALT-associated PML bodies (APBs). Here, the de novo formation of a telomeric PML nuclear subcompartment was investigated by recruiting APB protein components. We show that functionally distinct proteins were able to initiate the formation of bona fide APBs with high efficiency in a self-organizing and self-propagating manner. These included: (1) PML and Sp100 as the constituting components of PML nuclear bodies, (2) telomere repeat binding factors 1 and 2 (TRF1 and TRF2, respectively), (3) the DNA repair protein NBS1 and (4) the SUMO E3 ligase MMS21, as well as the isolated SUMO1 domain, through an interacting domain of another protein factor. By contrast, the repair factors Rad9, Rad17 and Rad51 were less efficient in APB nucleation but were recruited to preassembled APBs. The artificially created APBs induced telomeric extension through a DNA repair mechanism, as inferred from their colocalization with sites of non-replicative DNA synthesis and histone H2A.X phosphorylation, and an increase of the telomere repeat length. These activities were absent after recruitment of the APB factors to a pericentric locus and establish APBs as functional intermediates of the ALT pathway.},
}
@article {pmid22039056,
year = {2012},
author = {Ghosh, AK and Rossi, ML and Singh, DK and Dunn, C and Ramamoorthy, M and Croteau, DL and Liu, Y and Bohr, VA},
title = {RECQL4, the protein mutated in Rothmund-Thomson syndrome, functions in telomere maintenance.},
journal = {The Journal of biological chemistry},
volume = {287},
number = {1},
pages = {196-209},
pmid = {22039056},
issn = {1083-351X},
support = {//Intramural NIH HHS/United States ; },
mesh = {Aphidicolin/pharmacology ; Base Sequence ; DNA/biosynthesis/chemistry/metabolism ; DNA Replication/drug effects ; Exodeoxyribonucleases/metabolism ; Gene Knockdown Techniques ; HeLa Cells ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Molecular Sequence Data ; Mutant Proteins/genetics/*metabolism ; *Mutation ; Nucleic Acid Conformation/drug effects ; Protein Transport/drug effects ; RNA, Small Interfering/genetics ; RecQ Helicases/deficiency/genetics/*metabolism ; Rothmund-Thomson Syndrome/*genetics/metabolism/pathology ; Telomere/drug effects/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; Tumor Suppressor p53-Binding Protein 1 ; Werner Syndrome Helicase ; },
abstract = {Telomeres are structures at the ends of chromosomes and are composed of long tracks of short tandem repeat DNA sequences bound by a unique set of proteins (shelterin). Telomeric DNA is believed to form G-quadruplex and D-loop structures, which presents a challenge to the DNA replication and repair machinery. Although the RecQ helicases WRN and BLM are implicated in the resolution of telomeric secondary structures, very little is known about RECQL4, the RecQ helicase mutated in Rothmund-Thomson syndrome (RTS). Here, we report that RTS patient cells have elevated levels of fragile telomeric ends and that RECQL4-depleted human cells accumulate fragile sites, sister chromosome exchanges, and double strand breaks at telomeric sites. Further, RECQL4 localizes to telomeres and associates with shelterin proteins TRF1 and TRF2. Using recombinant proteins we showed that RECQL4 resolves telomeric D-loop structures with the help of shelterin proteins TRF1, TRF2, and POT1. We also found a novel functional synergistic interaction of this protein with WRN during D-loop unwinding. These data implicate RECQL4 in telomere maintenance.},
}
@article {pmid22033273,
year = {2011},
author = {Hofmann, JN and Baccarelli, A and Schwartz, K and Davis, FG and Ruterbusch, JJ and Hoxha, M and McCarthy, BJ and Savage, SA and Wacholder, S and Rothman, N and Graubard, BI and Colt, JS and Chow, WH and Purdue, MP},
title = {Risk of renal cell carcinoma in relation to blood telomere length in a population-based case-control study.},
journal = {British journal of cancer},
volume = {105},
number = {11},
pages = {1772-1775},
pmid = {22033273},
issn = {1532-1827},
support = {P30 ES000002/ES/NIEHS NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Carcinoma, Renal Cell/*blood/*genetics ; Case-Control Studies ; Child ; Child, Preschool ; Female ; Humans ; Hypertension/genetics ; Infant ; Infant, Newborn ; Kidney Neoplasms/*blood/*genetics ; Male ; Middle Aged ; Multivariate Analysis ; Risk Factors ; Telomere/*genetics ; United States ; Young Adult ; },
abstract = {BACKGROUND: There are few known risk factors for renal cell carcinoma (RCC). Two small hospital-based case-control studies suggested an association between short blood telomere length (TL) and increased RCC risk.<br><br>METHODS: We conducted a large population-based case-control study in two metropolitan regions of the United States comparing relative TL in DNA derived from peripheral blood samples from 891 RCC cases and 894 controls. Odds ratios and 95% confidence intervals were estimated using unconditional logistic regression in both unadjusted and adjusted models.<br><br>RESULTS: Median TL was 0.85 for both cases and controls (P=0.40), and no differences in RCC risk by quartiles of TL were observed. Results of analyses stratified by age, sex, race, tumour stage, and time from RCC diagnosis to blood collection were similarly null. In multivariate analyses among controls, increasing age and history of hypertension were associated with shorter TL (P<0.001 and P=0.07, respectively), and African Americans had longer TL than Caucasians (P<0.001).<br><br>CONCLUSION: These data do not support the hypothesis that blood TL is associated with RCC. This population-based case-control study is, to our knowledge, the largest investigation to date of TL and RCC.},
}
@article {pmid22028319,
year = {2011},
author = {Nan, H and Du, M and De Vivo, I and Manson, JE and Liu, S and McTiernan, A and Curb, JD and Lessin, LS and Bonner, MR and Guo, Q and Qureshi, AA and Hunter, DJ and Han, J},
title = {Shorter telomeres associate with a reduced risk of melanoma development.},
journal = {Cancer research},
volume = {71},
number = {21},
pages = {6758-6763},
pmid = {22028319},
issn = {1538-7445},
support = {CA87969/CA/NCI NIH HHS/United States ; N01WH32108-9/WH/WHI NIH HHS/United States ; CA49449/CA/NCI NIH HHS/United States ; N01WH42107-26/WH/WHI NIH HHS/United States ; R01 CA122838/CA/NCI NIH HHS/United States ; N01WH32122/WH/WHI NIH HHS/United States ; N01WH32105-6/WH/WHI NIH HHS/United States ; N01WH32111-13/WH/WHI NIH HHS/United States ; T32 ES016645/ES/NIEHS NIH HHS/United States ; R01 CA122838-02/CA/NCI NIH HHS/United States ; U01 CA049449/CA/NCI NIH HHS/United States ; N01WH22110/WH/WHI NIH HHS/United States ; N01WH24152/WH/WHI NIH HHS/United States ; N01WH42129-32/WH/WHI NIH HHS/United States ; R03 CA133914-02/CA/NCI NIH HHS/United States ; R01 CA137365/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R03 CA133914/CA/NCI NIH HHS/United States ; N01WH32119/WH/WHI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; N01WH32100-2/WH/WHI NIH HHS/United States ; N01WH32118/WH/WHI NIH HHS/United States ; CA133914/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; CA055075/CA/NCI NIH HHS/United States ; N01WH32115/WH/WHI NIH HHS/United States ; CA122838/CA/NCI NIH HHS/United States ; N01WH44221/WH/WHI NIH HHS/United States ; },
mesh = {Aged ; Case-Control Studies ; Cohort Studies ; Female ; Hair Color ; Humans ; Leukocytes/ultrastructure ; Male ; Melanoma/blood/*epidemiology/genetics ; Middle Aged ; Prospective Studies ; Risk ; Risk Factors ; Single-Blind Method ; Skin Neoplasms/blood/*epidemiology/genetics ; Telomere/*ultrastructure ; White People ; },
abstract = {Epidemiologic studies have linked shortened telomeres with the development of many cancers. However, recent studies have suggested that longer telomeres may lead to prolonged senescence in melanocytes, providing increased opportunity for malignant transformation. We therefore examined whether shorter prediagnostically measured relative telomere length in peripheral blood leukocytes (PBL) was associated with a decreased risk of cutaneous melanoma. Telomere length in prospectively collected PBLs was measured in incident melanoma cases and age-matched controls selected from participants in three large prospective cohorts: the Women's Health Initiative Observational Study (WHI-OS), the Health Professionals Follow-up Study (HPFS), and the Nurses' Health Study (NHS). Shorter telomere lengths were associated with decreased risk of melanoma in each cohort. The P(trend) across quartiles was 0.03 in the WHI-OS and 0.008 in the HPFS. When combining these two datasets with published data in the NHS (P(trend), 0.09), compared with individuals in the fourth quartile (the longest telomere lengths), those in the first quartile had an OR of 0.43 (95% CI: 0.28-0.68; P(trend), 0.0003). Unlike findings for other tumors, shorter telomeres were significantly associated with a decreased risk of melanoma in this study, suggesting a unique role of telomeres in melanoma development.},
}
@article {pmid22022767,
year = {2012},
author = {Olivieri, F and Mazzanti, I and Abbatecola, AM and Recchioni, R and Marcheselli, F and Procopio, AD and Antonicelli, R},
title = {Telomere/Telomerase system: a new target of statins pleiotropic effect?.},
journal = {Current vascular pharmacology},
volume = {10},
number = {2},
pages = {216-224},
doi = {10.2174/157016112799305076},
pmid = {22022767},
issn = {1875-6212},
mesh = {Aged ; Aged, 80 and over ; Animals ; Cellular Senescence/drug effects ; DNA Damage/drug effects ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology ; Leukocytes/drug effects/metabolism ; Telomerase/*drug effects/metabolism ; Telomere/*drug effects/metabolism ; Telomere Shortening/drug effects ; },
abstract = {Statins are well established drugs for primary and secondary prevention of coronary artery disease (CAD). Despite the well-known ability of statins to lower cholesterol, it is now clear that clinical benefits are also substantially higher than expected and several clinical trials, like JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial) have indicated that such clinical effects are independent of cholesterol reduction. These cholesterol-independent actions have been named "pleiotropic effects" and include: anti-oxidation and anti-inflammatory effects, modulation of immune activation, stabilization of atherosclerotic plaque, decreased platelet activation, inhibition of cardiac hypertrophy, reduction of cytokine-mediated vascular smooth muscle cell (VSMC) proliferation and improvement of endothelial function. Recently, additional pleiotropic effects of statins on "cellular senescence" have been seen in different cell types, including endothelial progenitor cells (EPC), endothelial cells (EC), VSMC and chondrocytes. At the molecular level, the effect of statins on cellular senescence could be mediated by their interaction with the telomere/telomerase system. Recent evidence suggests that the anti-aging effects of statins are linked to their ability to inhibit telomere shortening by reducing either directly and indirectly oxidative telomeric DNA damage, as well as by a telomere capping proteins dependent mechanism. In this review, we discuss the pleiotropic effects of statins, focusing on the telomere/telomerase system. We will also present our current findings regarding leukocyte telomere length in very old people with myocardial infarction on statin therapy.},
}
@article {pmid22022429,
year = {2011},
author = {Marión, RM and Schotta, G and Ortega, S and Blasco, MA},
title = {Suv4-20h abrogation enhances telomere elongation during reprogramming and confers a higher tumorigenic potential to iPS cells.},
journal = {PloS one},
volume = {6},
number = {10},
pages = {e25680},
pmid = {22022429},
issn = {1932-6203},
support = {232854/ERC_/European Research Council/International ; },
mesh = {Animals ; Cell Proliferation ; Cell Transformation, Neoplastic/*genetics ; Cellular Reprogramming/*genetics ; Chromatin/metabolism ; Chromosome Aberrations ; Histone-Lysine N-Methyltransferase/*metabolism ; Induced Pluripotent Stem Cells/*enzymology/*pathology ; Mice ; Mice, Inbred C57BL ; RNA/metabolism ; Telomere/*metabolism ; Teratoma/pathology ; },
abstract = {Reprogramming of adult differentiated cells to induced pluripotent stem cells (iPS) cells has been achieved by over-expression of specific transcription factors. Nuclear reprogramming induces a series of profound changes at the telomeres of the parental differentiated cells, including a telomerase-dependent telomere elongation and the remodeling of telomeric chromatin. In particular, iPS cells show a decreased density of H4K20me3 heterochromatic mark at telomeres compared to the parental cells. Suv4-20h1 and Suv4-20h2 histone methytransferases (HMTases) are responsible for the trimethylation of H4K20 at telomeres, as cells deficient for both HMTases show decreased levels of H4K20me3 at telomeric chromatin. Here, we set to address the role of the Suv4-20h enzymes in telomere reprogramming by generating bona-fide iPS cells from mouse embryonic fibroblasts (MEFs) double null for both HMTases (Suv4-20dn MEFs). We found that Suv4-20h deficiency enhances telomere elongation during reprogramming without altering their ability to protect the chromosome ends or the efficiency of reprogramming. Moreover, teratomas generated from Suv4-20dn iPS cells also have elongated telomeres and an increased growth rate when compared to wild-type controls. These results indicate that abrogation of Suv4-20h enzymes and loss of heterochromatic mark H4K20me3 at telomeric heterochromatin facilitates telomere reprogramming and provides an increased tumorigenic potential to the resulting iPS cells.},
}
@article {pmid22020438,
year = {2011},
author = {Clemente-Blanco, A and Sen, N and Mayan-Santos, M and Sacristán, MP and Graham, B and Jarmuz, A and Giess, A and Webb, E and Game, L and Eick, D and Bueno, A and Merkenschlager, M and Aragón, L},
title = {Cdc14 phosphatase promotes segregation of telomeres through repression of RNA polymerase II transcription.},
journal = {Nature cell biology},
volume = {13},
number = {12},
pages = {1450-1456},
pmid = {22020438},
issn = {1476-4679},
support = {MC_U120027516/MRC_/Medical Research Council/United Kingdom ; MC_U120074328/MRC_/Medical Research Council/United Kingdom ; U.1200.01.001(74328)/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Cell Cycle Proteins/antagonists &amp; inhibitors/*genetics/*metabolism ; DNA, Ribosomal Spacer/genetics ; Gene Silencing/*physiology ; Interphase/genetics ; Mitosis/genetics ; Phosphorylation/genetics ; Protein Tyrosine Phosphatases/antagonists &amp; inhibitors/*genetics/*metabolism ; RNA Polymerase II/antagonists &amp; inhibitors/*genetics ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/cytology/enzymology/*metabolism ; Saccharomyces cerevisiae Proteins/antagonists &amp; inhibitors/*genetics/*metabolism ; Suppression, Genetic/physiology ; Telomere/enzymology/*metabolism ; Transcription, Genetic/*physiology ; },
abstract = {Kinases and phosphatases regulate messenger RNA synthesis through post-translational modification of the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II (ref. 1). In yeast, the phosphatase Cdc14 is required for mitotic exit(2,3) and for segregation of repetitive regions(4). Cdc14 is also a subunit of the silencing complex RENT (refs 5,6), but no roles in transcriptional repression have been described. Here we report that inactivation of Cdc14 causes silencing defects at the intergenic spacer sequences of ribosomal genes during interphase and at Y' repeats in subtelomeric regions during mitosis. We show that the role of Cdc14 in silencing is independent of the RENT deacetylase subunit Sir2. Instead, Cdc14 acts directly on RNA polymerase II by targeting CTD phosphorylation at Ser 2 and Ser 5. We also find that the role of Cdc14 as a CTD phosphatase is conserved in humans. Finally, telomere segregation defects in cdc14 mutants(4) correlate with the presence of subtelomeric Y' elements and can be rescued by transcriptional inhibition of RNA polymerase II.},
}
@article {pmid22019938,
year = {2011},
author = {Bendix, L and Gade, MM and Staun, PW and Kimura, M and Jeune, B and Hjelmborg, JV and Aviv, A and Christensen, K},
title = {Leukocyte telomere length and physical ability among Danish twins age 70+.},
journal = {Mechanisms of ageing and development},
volume = {132},
number = {11-12},
pages = {568-572},
pmid = {22019938},
issn = {1872-6216},
support = {P01 AG008761/AG/NIA NIH HHS/United States ; R01 AG030678/AG/NIA NIH HHS/United States ; R01 AG030678-01A2/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/genetics/*physiology/*psychology ; Cognition/physiology ; Cohort Studies ; Denmark ; Female ; Humans ; Leukocytes/ultrastructure ; Longitudinal Studies ; Male ; Mental Status Schedule ; Models, Biological ; Physical Fitness/*physiology ; Telomere/ultrastructure ; Telomere Shortening/*physiology ; Twins, Dizygotic ; Twins, Monozygotic ; },
abstract = {Leukocyte telomere length (LTL) shortens with age and is potentially a biomarker of human aging. We examined the relation of LTL with physical ability and cognitive function in 548 same-sex twins from the Longitudinal Study of Aging Danish Twins. LTL was measured by Southern blots of the terminal restriction fragments (TRF). Physical ability was evaluated using a self reported scale of 11 questions, while cognitive function was scored by MMSE and a cognitive composite score sensitive to age-related decline. A random intercept model revealed a positive, significant association between LTL and physical ability. For every unit increase in physical ability score, LTL increased by 0.066 kb (p = 0.01), equal to approximately three years of age-dependent LTL shortening. A matched case-co-twin design showed that the group consisting of the twins from each pair with the longer LTL also displayed better physical ability (p < 0.01). Moreover, the intra-pair difference in LTL was associated with intra-pair difference in physical ability (p < 0.01), confirming the association. However, we found no association between cognitive function and LTL. The LTL-physical ability association in the elderly provides further support to the premise that LTL is an index of somatic fitness in the narrow context of human physical health.},
}
@article {pmid22019625,
year = {2012},
author = {Bodvarsdottir, SK and Steinarsdottir, M and Bjarnason, H and Eyfjord, JE},
title = {Dysfunctional telomeres in human BRCA2 mutated breast tumors and cell lines.},
journal = {Mutation research},
volume = {729},
number = {1-2},
pages = {90-99},
doi = {10.1016/j.mrfmmm.2011.10.002},
pmid = {22019625},
issn = {0027-5107},
mesh = {Alleles ; BRCA2 Protein/*genetics/*metabolism ; Breast Neoplasms/*genetics ; Cell Line, Tumor ; Chromosome Aberrations ; Female ; Gene Frequency ; Heterozygote ; Histones/genetics/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Sister Chromatid Exchange ; Telomere/*genetics/metabolism ; },
abstract = {In the present study the possible involvement of telomeres in chromosomal instability of breast tumors and cell lines from BRCA2 mutation carriers was examined. Breast tumors from BRCA2 mutation carriers showed significantly higher frequency of chromosome end-to-end fusions (CEFs) than tumors from non-carriers despite normal telomere DNA content. Frequent CEFs were also found in four different BRCA2 heterozygous breast epithelial cell lines, occasionally with telomere signal at the fusion point, indicating telomere capping defects. Extrachromosomal telomeric repeat (ECTR) DNA was frequently found scattered around metaphase chromosomes and interstitial telomere sequences (ITSs) were also common. Telomere sister chromatid exchanges (T-SCEs), characteristic of cells using alternative lengthening of telomeres (ALT), were frequently detected in all heterozygous BRCA2 cell lines as well as the two ALT positive cell lines tested. Even though T-SCE frequency was similar in BRCA2 heterozygous and ALT positive cell lines they differed in single telomere signal loss and ITSs. Chromatid type alterations were more prominent in the BRCA2 heterozygous cell lines that may have propensity for telomere based chromosome healing. Telomere dysfunction-induced foci (TIFs) formation, identified by co-localization of telomeres and γ-H2AX, supported telomere associated DNA damage response in BRCA2 heterozygous cell lines. TIFs were found in interphase nuclei, at chromosome ends, ITSs and ECTR DNA. In conclusion, our results suggest that BRCA2 has an important role in telomere stabilization by repressing CEFs through telomere capping and the prevention of telomere loss by replication stabilization.},
}
@article {pmid22017543,
year = {2011},
author = {Ji, X and Chen, J and Sun, H and Zhou, H and Xiang, J and Peng, A and Tang, Y and Zhao, C},
title = {The interaction of telomere DNA G-quadruplex with three bis-benzyltetrahydroisoquinoline alkaloids.},
journal = {Nucleic acid therapeutics},
volume = {21},
number = {6},
pages = {415-422},
doi = {10.1089/nat.2011.0311},
pmid = {22017543},
issn = {2159-3345},
mesh = {Alkaloids/administration &amp; dosage/*analysis/*chemistry ; Benzylisoquinolines/administration &amp; dosage/analysis/chemistry ; Cell Cycle Checkpoints/*drug effects ; Cell Survival/*drug effects ; Cells, Cultured ; Epithelial Cells ; G-Quadruplexes/*drug effects ; Humans ; Molecular Structure ; Telomere/*chemistry ; },
abstract = {Telomeres are important multifunctional nucleoprotein structures located at the ends of eukaryotic chromosomes. Telomerase regulates telomere elongation, and its activity is associated with tumorigenesis. Because the activity of telomerase can be inhibited by G-quadruplex (G4) formation (a four-stranded DNA with stacks of G-quartets formed by four guanines in a planar structure), the role of G4 in cancer therapy has attracted many research interests. We studied the effects of three natural alkaloids-tetrandrine, fangchinoline, and berbamine-on the stability and formation of telomere DNA G4 with circular dichroism melting spectroscopy (melting-CD), variable temperature ultraviolet (melting-UV), proton nuclear magnetic resonance spectroscopy ((1)H NMR), and molecular docking, and examined the relationships among the alkaloid structure and their activities. We further investigated their cytotoxicity with the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT) and flow cytometry (FCM). The results demonstrated that alkaloids increased G4 stability and induced its formation, which added structure diversity of G4-ligands. The results showed that -OH at R(1), -OCH(3) at R(2), and [Formula: see text] at R(3) had higher stability than other substituent groups for these alkaloids. We also found a transition of antiparallel to parallel G4 as the temperature increased. The result indicated the possible advantage of parallel G4 in adversity. In addition, the alkaloids demonstrated a moderate cytotoxicity and proved to be cell cycle blocker in the G(1) phase. These alkaloids have revealed promising potentials to be the agents for antitumor therapy.},
}
@article {pmid22017444,
year = {2012},
author = {Aviv, A and Levy, D},
title = {Telomeres, atherosclerosis, and the hemothelium: the longer view.},
journal = {Annual review of medicine},
volume = {63},
number = {},
pages = {293-301},
pmid = {22017444},
issn = {1545-326X},
support = {AG030678/AG/NIA NIH HHS/United States ; R01 AG030678/AG/NIA NIH HHS/United States ; AG16592/AG/NIA NIH HHS/United States ; R01 AG020132/AG/NIA NIH HHS/United States ; AG020132/AG/NIA NIH HHS/United States ; R01 AG016592/AG/NIA NIH HHS/United States ; Z01 HL006001-02//Intramural NIH HHS/United States ; Z99 HL999999//Intramural NIH HHS/United States ; Z01 HL006001-01//Intramural NIH HHS/United States ; },
mesh = {Atherosclerosis/epidemiology/pathology/*physiopathology ; Endothelium, Vascular/pathology/*physiology ; Hematopoietic Stem Cells/pathology/*physiology ; Humans ; *Models, Biological ; Risk Factors ; Telomere/pathology/*physiology ; },
abstract = {The model we propose to explain the links between atherosclerosis and telomere dynamics (birth telomere length and its age-dependent shortening) in leukocytes takes cues from three facts: atherosclerosis is a disease of the vascular endothelium; the hematopoietic system and the vascular endothelium share a common embryonic origin; interindividual variation in leukocyte telomere length (LTL) in the general population has a genetic explanation. The model posits that LTL dynamics mirror telomere dynamics in hematopoietic stem cells (HSCs), where telomere length is an index of HSC reserves. Diminished HSC reserves at birth, their accelerated attrition rate afterward, or both are are reflected in shortened LTL during adulthood-a phenomenon that confers increased risk for atherosclerosis. We explain how telomere length in HSCs serves as both a biomarker of atherosclerosis and a determinant of its development. Our model comes down to this proposition: Shortened LTL predicts increased atherosclerotic risk because the injurious component of atherosclerosis exceeds the repair capacity of HSC reserves, which largely depend on HSC telomere length.},
}
@article {pmid22016362,
year = {2012},
author = {Takata, Y and Kikukawa, M and Hanyu, H and Koyama, S and Shimizu, S and Umahara, T and Sakurai, H and Iwamoto, T and Ohyashiki, K and Ohyashiki, JH},
title = {Association between ApoE phenotypes and telomere erosion in Alzheimer's disease.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {67},
number = {4},
pages = {330-335},
doi = {10.1093/gerona/glr185},
pmid = {22016362},
issn = {1758-535X},
mesh = {Adult ; Aged ; Aged, 80 and over ; Alzheimer Disease/*genetics ; Apolipoproteins E/*genetics/metabolism ; Female ; Heterozygote ; Homozygote ; Humans ; Male ; Middle Aged ; Severity of Illness Index ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {Although several reports suggest that Alzheimer's disease (AD) is associated with shortened telomere length, the clinical relevance of this has not yet been fully elucidated. This study was conducted to clarify the correlation of telomere length with clinical characteristics and ApoE phenotypes in 74 AD patients. Telomere length was determined from genomic DNA extracted from whole blood by quantitative real-time polymerase chain reaction. We found no significant difference in telomere length between the AD and non-dementia elderly control (n = 35) groups. Furthermore, no significant correlation was found among telomere length and the severity of cognitive decline and disease duration, age, or gender difference. However, telomere length was significantly shorter in AD patients with the ApoE4 homozygote than in those with the ApoE4 heterozygote (p < .001) and noncarriers (p < .001). These findings suggest that shortened telomere length may be associated with the ApoE4 homozygote in AD patients.},
}
@article {pmid22015685,
year = {2011},
author = {Shay, JW and Wright, WE},
title = {Role of telomeres and telomerase in cancer.},
journal = {Seminars in cancer biology},
volume = {21},
number = {6},
pages = {349-353},
pmid = {22015685},
issn = {1096-3650},
support = {P50 CA070907/CA/NCI NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Neoplasms/*genetics ; Neoplastic Stem Cells/enzymology ; Telomerase/*metabolism ; *Telomere ; },
abstract = {There is mounting evidence for the existence of an important relationship between telomeres and telomerase and cellular aging and cancer. Normal human cells progressively lose telomeres with each cell division until a few short telomeres become uncapped leading to a growth arrest known as replicative aging. In the absence of genomic alterations these cells do not die but remain quiescent producing a different constellation of proteins compared to young quiescent cells. Upon specific genetic and epigenetic alterations, normal human cells bypass replicative senescence and continue to proliferate until many telomere ends become uncapped leading to a phenomenon known as crisis. In crisis cells have critically shortened telomeres but continue to attempt to divide leading to significant cell death (apoptosis) and progressive genomic instability. Rarely, a human cell escapes crisis and these cells almost universally express the ribonucleoprotein, telomerase, and maintain stable but short telomeres. The activation of telomerase may be thought of as a mechanism to slow down the rate genomic instability due to dysfunctional telomeres. While telomerase does not drive the oncogenic process, it is permissive and required for the sustain growth of most advanced cancers. Since telomerase is not expressed in most normal human cells, this has led to the development of targeted telomerase cancer therapeutic approaches that are presently in advanced clinical trials.},
}
@article {pmid22015233,
year = {2011},
author = {Björck, M and Ravn, H and Nilsson, TK and Wanhainen, A and Nilsson, PM},
title = {Blood cell telomere length among patients with an isolated popliteal artery aneurysm and those with multiple aneurysm disease.},
journal = {Atherosclerosis},
volume = {219},
number = {2},
pages = {946-950},
doi = {10.1016/j.atherosclerosis.2011.09.034},
pmid = {22015233},
issn = {1879-1484},
mesh = {Aged ; Analysis of Variance ; Aneurysm/blood/diagnostic imaging/*genetics/surgery ; Aortic Aneurysm, Abdominal/blood/diagnostic imaging/*genetics/surgery ; Female ; *Femoral Artery/diagnostic imaging/surgery ; Genetic Markers ; Humans ; Iliac Aneurysm/blood/diagnostic imaging/*genetics/surgery ; Male ; *Popliteal Artery/diagnostic imaging/surgery ; Real-Time Polymerase Chain Reaction ; Registries ; Sweden ; Telomere/*metabolism ; *Telomere Shortening ; Ultrasonography ; },
abstract = {OBJECTIVES: Short relative telomere length (RTL) is associated with vascular ageing, inflammation and cardiovascular risk factors. Previous studies have reported an association between abdominal aortic aneurysm and short RTL. The presence of atherosclerosis among patients with aneurysm disease may, however, be a confounder. The aim was to explore the associations between short RTL and aneurysm disease, by comparing patients with isolated popliteal artery aneurysms with those having multiple aneurysms.<br><br>DESIGN AND PATIENTS: DNA was retrieved from 183 patients with popliteal artery aneurysm (PAA). They were all examined with ultrasound at the time of blood-sampling, and had a total of 423 aneurysms (range 1-7, mean 2.3/patient).<br><br>METHODS: TL was measured with Real-Time PCR, RTL was calculated by comparing with three reference populations.<br><br>RESULTS: Patients with bilateral PAAs had a mean RTL of 0.985 vs. 1.038 with unilateral PAAs (P = 0.326). Patients with abdominal aortic aneurysm had RTL 1.035, vs. 0.999 without (P = 0.513). No difference was seen with or without femoral or iliac aneurysms. Fifty-six patients with isolated PAA at surgery and at re-examination had RTL 0.974, vs. 1.033 who had >1 aneurysm (P = 0.308). RTL was not associated with the number of aneurysms at re-examination (P = 0.727, one-way ANOVA). There was a trend towards shorter RTL among active smokers (0.93 vs. 1.04, P = 0.066).<br><br>CONCLUSIONS: No association between short RTL and multiple aneurysm disease was found. The previously reported association between AAA and short RTL may be secondary to cardiovascular risk factors, rather than by aneurysm disease.},
}
@article {pmid22011238,
year = {2011},
author = {Sealey, DC and Kostic, AD and LeBel, C and Pryde, F and Harrington, L},
title = {The TPR-containing domain within Est1 homologs exhibits species-specific roles in telomerase interaction and telomere length homeostasis.},
journal = {BMC molecular biology},
volume = {12},
number = {},
pages = {45},
pmid = {22011238},
issn = {1471-2199},
support = {84637//Wellcome Trust/United Kingdom ; G0800081//Medical Research Council/United Kingdom ; },
mesh = {Humans ; Protein Binding ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/chemistry/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/*chemistry/genetics/*metabolism ; Species Specificity ; Telomerase/*chemistry/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {BACKGROUND: The first telomerase-associated protein (Est1) was isolated in yeast due to its essential role in telomere maintenance. The human counterparts EST1A, EST1B, and EST1C perform diverse functions in nonsense-mediated mRNA decay (NMD), telomere length homeostasis, and telomere transcription. Although Est1 and EST1A/B interact with the catalytic subunit of yeast and human telomerase (Est2 and TERT, respectively), the molecular determinants of these interactions have not been elaborated fully.<br><br>RESULTS: To investigate the functional conservation of the EST1 protein family, we performed protein-protein interaction mapping and structure-function analysis. The domain in hEST1A most conserved between species, containing a TPR (tricotetrapeptide repeat), was sufficient for interaction of hEST1A with multiple fragments of hTERT including the N-terminus. Two mutations within the hTERT N-terminus that perturb in vivo function (NAAIRS(92), NAAIRS(122)) did not affect this protein interaction. ScEst1 hybrids containing the TPR of hEST1A, hEST1B, or hEST1C were expressed in yeast strains lacking EST1, yet they failed to complement senescence. Point mutations within and outside the cognate ScEst1 TPR, chosen to disrupt a putative protein interaction surface, resulted in telomere lengthening or shortening without affecting recruitment to telomeres.<br><br>CONCLUSIONS: These results identify a domain encompassing the TPR of hEST1A as an hTERT interaction module. The TPR of S. cerevisiae Est1 is required for telomerase-mediated telomere length maintenance in a manner that appears separable from telomere recruitment. Discrete residues in or adjacent to the TPR of Est1 also regulate telomere length homeostasis.},
}
@article {pmid22008383,
year = {2012},
author = {Vorlícková, M and Tomasko, M and Sagi, AJ and Bednarova, K and Sagi, J},
title = {8-oxoguanine in a quadruplex of the human telomere DNA sequence.},
journal = {The FEBS journal},
volume = {279},
number = {1},
pages = {29-39},
doi = {10.1111/j.1742-4658.2011.08396.x},
pmid = {22008383},
issn = {1742-4658},
mesh = {Circular Dichroism ; DNA/*chemistry/*genetics ; Guanine/*analogs &amp; derivatives/chemistry ; Humans ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Nucleic Acid Conformation ; Potassium/*chemistry ; Telomere/*chemistry ; Thermodynamics ; },
abstract = {8-Oxoguanine is a ubiquitous oxidative base lesion. We report here on the effect of this lesion on the structure and stability of quadruplexes formed by the human telomeric DNA sequence 5'-dG(3)(TTAG(3))(3) in NaCl and KCl. CD, PAGE and absorption-based thermodynamic stability data showed that replacement of any of the tetrad-forming guanines by 8-oxoguanine did not hinder the formation of monomolecular, antiparallel quadruplexes in NaCl. The modified quadruplexes were, however, destabilized in both salts, the extent of this depending on the position of the lesion. These results and the results of previous studies on guanine-to-adenine exchanges and guanine abasic lesions in the same quadruplex show a noticeable trend: it is not the type of the lesion but the position of the modification that determines the effect on the conformation and stability of the quadruplex. The type of lesion only governs the extent of changes, such as of destabilization. Most sensitive sites were found in the middle tetrad of the three-tetrad quadruplex, and the smallest alterations were observed if guanines of the terminal tetrad with the diagonal TTA loop were substituted, although even these substitutions brought about unfavorable enthalpic changes. Interestingly, the majority of these base-modified quadruplexes did not adopt the rearranged folding induced in the unmodified dG(3)(TTAG(3))(3) by potassium ions, an observation that could imply biological relevance of the results.},
}
@article {pmid22006845,
year = {2012},
author = {Tsai, HH and Shu, HW and Yang, CC and Chen, CW},
title = {Translesion-synthesis DNA polymerases participate in replication of the telomeres in Streptomyces.},
journal = {Nucleic acids research},
volume = {40},
number = {3},
pages = {1118-1130},
pmid = {22006845},
issn = {1362-4962},
mesh = {Actinobacteria/genetics ; Alkylation ; Chromosomes, Bacterial/chemistry ; Conjugation, Genetic ; DNA/metabolism ; DNA Damage ; DNA Polymerase III/classification/genetics/*physiology ; DNA Polymerase beta/classification/genetics/*physiology ; DNA Repair ; *DNA Replication ; Gene Deletion ; Gene Duplication ; Gene Transfer, Horizontal ; Phylogeny ; Plasmids/biosynthesis ; Streptomyces/*enzymology/*genetics ; Synteny ; Telomere/*metabolism ; Ultraviolet Rays ; },
abstract = {Linear chromosomes and linear plasmids of Streptomyces are capped by terminal proteins that are covalently bound to the 5'-ends of DNA. Replication is initiated from an internal origin, which leaves single-stranded gaps at the 3'-ends. These gaps are patched by terminal protein-primed DNA synthesis. Streptomyces contain five DNA polymerases: one DNA polymerase I (Pol I), two DNA polymerases III (Pol III) and two DNA polymerases IV (Pol IV). Of these, one Pol III, DnaE1, is essential for replication, and Pol I is not required for end patching. In this study, we found the two Pol IVs (DinB1 and DinB2) to be involved in end patching. dinB1 and dinB2 could not be co-deleted from wild-type strains containing a linear chromosome, but could be co-deleted from mutant strains containing a circular chromosome. The resulting ΔdinB1 ΔdinB2 mutants supported replication of circular but not linear plasmids, and exhibited increased ultraviolet sensitivity and ultraviolet-induced mutagenesis. In contrast, the second Pol III, DnaE2, was not required for replication, end patching, or ultraviolet resistance and mutagenesis. All five polymerase genes are relatively syntenous in the Streptomyces chromosomes, including a 4-bp overlap between dnaE2 and dinB2. Phylogenetic analysis showed that the dinB1-dinB2 duplication occurred in a common actinobacterial ancestor.},
}
@article {pmid22005790,
year = {2012},
author = {Calado, RT and Cooper, JN and Padilla-Nash, HM and Sloand, EM and Wu, CO and Scheinberg, P and Ried, T and Young, NS},
title = {Short telomeres result in chromosomal instability in hematopoietic cells and precede malignant evolution in human aplastic anemia.},
journal = {Leukemia},
volume = {26},
number = {4},
pages = {700-707},
pmid = {22005790},
issn = {1476-5551},
support = {ZIA HL006089-03//Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; *Aged ; Aged, 80 and over ; Anemia, Aplastic/complications/*genetics ; Aneuploidy ; Cell Transformation, Neoplastic/*genetics ; Child ; Child, Preschool ; *Chromosomal Instability ; Female ; Hematopoietic System/*metabolism ; Humans ; Male ; Middle Aged ; *Telomere Shortening ; },
abstract = {In cell and animal models, telomere erosion promotes chromosomal instability via breakage-fusion-bridge cycles, contributing to the early stages of tumorigenesis. However, evidence involving short telomeres in cancer development in humans is scarce, epidemiological and indirect. Here we directly implicate telomere shortening as a critical molecular event for malignant evolution in aplastic anemia (AA). Patients' telomere lengths at diagnosis of AA, while comparable to age-matched controls, inversely correlated with the probability of developing a cytogenetically abnormal clone. A significantly increased number of telomere signal-free chromosomal ends and chromosomal numerical and structural abnormalities were observed in bone marrow cells of patients with shorter telomeres in comparison with patients with longer telomeres and healthy subjects. The proportion of monosomy-7 cells in the bone marrow at diagnosis of AA inversely correlated with telomere length, years before the emergence of an autonomous and clinically detectable abnormal clone. Marrow cells of clinically healthy individuals carrying loss-of-function telomerase mutations and with extremely short telomeres also showed chromosomal instability in vitro. These results provide the first clinical direct evidence in humans that short telomeres in hematopoietic cells are dysfunctional, mediate chromosomal instability and predispose to malignant transformation in a human disease.},
}
@article {pmid22005719,
year = {2012},
author = {Njajou, OT and Cawthon, RM and Blackburn, EH and Harris, TB and Li, R and Sanders, JL and Newman, AB and Nalls, M and Cummings, SR and Hsueh, WC},
title = {Shorter telomeres are associated with obesity and weight gain in the elderly.},
journal = {International journal of obesity (2005)},
volume = {36},
number = {9},
pages = {1176-1179},
pmid = {22005719},
issn = {1476-5497},
support = {UL1 TR000005/TR/NCATS NIH HHS/United States ; N01-AG-6-2103/AG/NIA NIH HHS/United States ; R25 CA112355/CA/NCI NIH HHS/United States ; R25 CA112355-06/CA/NCI NIH HHS/United States ; N1AG62103A/AG/NIA NIH HHS/United States ; R01 AG023692-05/AG/NIA NIH HHS/United States ; R01 AG023692/AG/NIA NIH HHS/United States ; N1AG62101A/AG/NIA NIH HHS/United States ; N01-AG-6-2101/AG/NIA NIH HHS/United States ; K01 AG022782/AG/NIA NIH HHS/United States ; N01 AG062106/AG/NIA NIH HHS/United States ; N01-AG-6-2106/AG/NIA NIH HHS/United States ; K01 AG022782-05/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Cohort Studies ; Cross-Sectional Studies ; Female ; Humans ; Male ; Obesity/epidemiology/*genetics ; Phenotype ; Prospective Studies ; Risk Factors ; Telomere/*genetics ; United States/epidemiology ; Weight Gain/*genetics ; },
abstract = {OBJECTIVE: Obesity and shorter telomeres are commonly associated with elevated risk for age-related diseases and mortality. Whether telomere length (TL) may be associated with obesity or variations in adiposity is not well established. Therefore, we set out to test the hypothesis that TL may be a risk factor for increased adiposity using data from a large population-based cohort study.<br><br>DESIGN: Levels of adiposity were assessed in six ways (obesity status, body mass index (BMI), the percentage of body fat or % body fat, leptin, visceral and subcutaneous fat mass) in 2721 elderly subjects (42% black and 58% white). Associations between TL measured in leukocytes at baseline and adiposity traits measured at baseline, and three of these traits after 7 years of follow-up were tested using regression models adjusting for important covariates. Additionally, we look at weight changes and relative changes in BMI and % body fat between baseline and follow-up.<br><br>RESULTS: At baseline, TL was negatively associated with % body fat (&#xdf;=-0.35&#xb1;0.09, P=0.001) and subcutaneous fat (&#xdf;=-2.66&#xb1;1.07, P=0.01), and positively associated with leptin after adjusting for % body fat (&#xdf;=0.32&#xb1;0.14, P=0.001), but not with obesity, BMI or visceral fat. Prospective analyses showed that longer TL was associated with positive percent change between baseline and 7-year follow-up for both BMI (&#xdf;=0.48&#xb1;0.20, P=0.01) and % body fat (&#xdf;=0.42&#xb1;0.23, P=0.05).<br><br>CONCLUSION: Our study suggests that shorter TL may be a risk factor for increased adiposity. Coupling with previous reports on their reversed roles, the relationship between adiposity and TL may be complicated and may warrant more prospective studies.},
}
@article {pmid22002246,
year = {2011},
author = {Shah, S and Henriksen, MA},
title = {A novel disrupter of telomere silencing 1-like (DOT1L) interaction is required for signal transducer and activator of transcription 1 (STAT1)-activated gene expression.},
journal = {The Journal of biological chemistry},
volume = {286},
number = {48},
pages = {41195-41204},
pmid = {22002246},
issn = {1083-351X},
mesh = {Cell Line ; Gene Expression Regulation/*physiology ; Histone-Lysine N-Methyltransferase ; Histones/genetics/metabolism ; Humans ; Interferon Regulatory Factor-1/biosynthesis/genetics ; Methyltransferases/genetics/*metabolism ; Peptide Mapping ; Protein Structure, Tertiary ; Response Elements/physiology ; STAT1 Transcription Factor/genetics/*metabolism ; Transcription, Genetic/*physiology ; },
abstract = {JAK-STAT-activated gene expression is both rapid and transient and requires dynamic post-translational modification of the chromatin template. Previously, we showed that following IFN-γ treatment, trimethylation of histone H3 at lysine 79 (H3K79me3) is rapidly and highly induced in the 5'-end of the STAT1-dependent gene interferon regulatory factor 1 (IRF1), but the role of this histone modification was unexplored. Here we report that DOT1L, the non-SET domain containing methyltransferase that modifies Lys-79, is localized across IRF1 in the uninduced state and is not further recruited by IFN-γ induction. RNAi-mediated depletion of DOT1L prevents the induction of H3K79me3 and lowers the transcription of IRF1 2-fold, as expected. Surprisingly, STAT1 binding to its DNA recognition element near the IRF1 promoter is diminished 2-fold in the DOT1L-depleted cell line. In vivo and in vitro protein interaction assays reveal a DOT1L-STAT1 interaction. Domain mapping identifies the middle region of DOT1L (amino acids 580-1183) as the STAT1 interaction domain. Overexpression of the DOT1L STAT1 interaction domain represses IRF1 transcription (2-fold) and interferes with STAT1 DNA binding at IRF1 and endogenous DOT1L histone methyltransferase activity. Collectively, our findings reveal a novel STAT1-DOT1L interaction that is required for the regulation JAK-STAT-inducible gene expression.},
}
@article {pmid22000973,
year = {2013},
author = {Sheng, R and Gu, ZL and Xie, ML},
title = {Epigallocatechin gallate, the major component of polyphenols in green tea, inhibits telomere attrition mediated cardiomyocyte apoptosis in cardiac hypertrophy.},
journal = {International journal of cardiology},
volume = {162},
number = {3},
pages = {199-209},
doi = {10.1016/j.ijcard.2011.07.083},
pmid = {22000973},
issn = {1874-1754},
mesh = {Animals ; Apoptosis/drug effects/physiology ; Cardiomegaly/*drug therapy/pathology ; Catechin/*analogs &amp; derivatives/isolation &amp; purification/pharmacology/therapeutic use ; Male ; Myocytes, Cardiac/*drug effects/pathology ; Polyphenols/isolation &amp; purification/pharmacology/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; *Tea ; Telomere/*drug effects/pathology ; },
abstract = {BACKGROUND: Telomere signaling plays a role in regulating cardiomyocyte apoptosis during cardiac dysfunction. In this study, we investigated the effects of epigallocatechin gallate (EGCG), the major component of polyphenols in green tea, on telomere dependent apoptotic signal in pressure overload cardiac hypertrophy.<br><br>METHODS AND RESULTS: Cardiac hypertrophy in rats was established by abdominal aortic constriction (AC). EGCG 50, 100 mg/kg, quercetin (Que) 100mg/kg, captopril (Cap) 50mg/kg, losartan (Los) 30 mg/kg and carvedilol (Carv) 30 mg/kg was intragastrically administered for 6 weeks. Three, five and 7 weeks after aortic constriction, the heart weight indices increased progressively. Malondialdehyde (MDA) contents progressively increased, while superoxide dismutase (SOD) activities decreased. Progressive cardiomyocyte apoptosis and telomere attrition were also found. Although no significant alteration of telomerase reverse transcriptase (TERT) mRNA was found till 7 weeks after aortic constriction, progressive upregulation of p53, c-myc and downregulation of bcl-2, telomere repeat-binding factor 2(TRF(2)) were seen. EGCG, quercetin, captopril, losartan and carvedilol markedly reduced heart weight indices and apoptotic cardiomyocyte in hypertrophic myocardium, but they had different effects on apoptotic related proteins bcl-2, p53 and c-myc. EGCG, quercetin and carvedilol, have potent antioxidant effects as evidenced by reduction of MDA contents and resumption of SOD activities. EGCG, quercetin and carvedilol could prevent telomere attrition and telomere repeat-binding factor 2 (TRF(2)) loss remarkably, whereas captopril and losartan had no effect on oxidative stress and telomere signal.<br><br>CONCLUSIONS: Pressure overload induced cardiac hypertrophy initiates oxidative stress, induces telomere repeat-binding factor 2 loss and accelerates telomere shortening in hypertrophic myocardium. EGCG, quercetin and carvedilol with potent antioxidant effect, may inhibit cardiac myocyte apoptosis by preventing telomere shortening and telomere repeat-binding factor 2 (TRF(2)) loss.},
}
@article {pmid21997949,
year = {2011},
author = {Fonseca Guerra, C and Zijlstra, H and Paragi, G and Bickelhaupt, FM},
title = {Telomere structure and stability: covalency in hydrogen bonds, not resonance assistance, causes cooperativity in guanine quartets.},
journal = {Chemistry (Weinheim an der Bergstrasse, Germany)},
volume = {17},
number = {45},
pages = {12612-12622},
doi = {10.1002/chem.201102234},
pmid = {21997949},
issn = {1521-3765},
mesh = {Algorithms ; *G-Quadruplexes ; Hydrogen Bonding ; *Models, Molecular ; Molecular Structure ; Telomere/*chemistry ; },
abstract = {We show that the cooperative reinforcement between hydrogen bonds in guanine quartets is not caused by resonance-assisted hydrogen bonding (RAHB). This follows from extensive computational analyses of guanine quartets (G(4)) and xanthine quartets (X(4)) based on dispersion-corrected density functional theory (DFT-D). Our investigations cover the situation of quartets in the gas phase, in aqueous solution as well as in telomere-like stacks. A new mechanism for cooperativity between hydrogen bonds in guanine quartets emerges from our quantitative Kohn-Sham molecular orbital (MO) and corresponding energy decomposition analyses (EDA). Our analyses reveal that the intriguing cooperativity originates from the charge separation that goes with donor-acceptor orbital interactions in the σ-electron system, and not from the strengthening caused by resonance in the π-electron system. The cooperativity mechanism proposed here is argued to apply, beyond the present model systems, also to other hydrogen bonds that show cooperativity effects.},
}
@article {pmid21994403,
year = {2011},
author = {Liu, Z and Ma, H and Wei, S and Li, G and Sturgis, EM and Wei, Q},
title = {Telomere length and TERT functional polymorphisms are not associated with risk of squamous cell carcinoma of the head and neck.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {20},
number = {12},
pages = {2642-2645},
pmid = {21994403},
issn = {1538-7755},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; P50 CA097007/CA/NCI NIH HHS/United States ; R01 ES011740/ES/NIEHS NIH HHS/United States ; P50 CA097007-09/CA/NCI NIH HHS/United States ; R01 CA131274-03/CA/NCI NIH HHS/United States ; CA 16672/CA/NCI NIH HHS/United States ; P30 CA023100/CA/NCI NIH HHS/United States ; R01 ES011740-09/ES/NIEHS NIH HHS/United States ; R01 ES 11740-07/ES/NIEHS NIH HHS/United States ; CA 131274-01/CA/NCI NIH HHS/United States ; R01 CA131274/CA/NCI NIH HHS/United States ; },
mesh = {Carcinoma, Squamous Cell/*genetics/metabolism ; Female ; Genetic Predisposition to Disease ; Genotype ; Head and Neck Neoplasms/*genetics/metabolism ; Humans ; Male ; Middle Aged ; Polymorphism, Genetic ; Squamous Cell Carcinoma of Head and Neck ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {BACKGROUND: Recent studies reported associations of the relative telomere length (RTL) and TERT variants with risk of several cancers, which have not been comprehensively investigated in squamous cell carcinoma of the head and neck (SCCHN).<br><br>METHODS: We detected RTL in peripheral blood lymphocytes and genotyped six selected functional single-nucleotide polymorphisms (SNP) of the TERT gene in 888 SCCHN cases and 885 cancer-free controls of non-Hispanic whites.<br><br>RESULTS: Overall, we did not observe significant associations between RTL and SCCHN risk (adjusted OR = 0.97; 95% CI = 0.80-1.17 for below versus above the median; P(trend) = 0.618) nor between the six TERT SNPs and SCCHN risk. We also found no associations between RTL and TERT SNPs.<br><br>CONCLUSIONS: Our results suggest that RTL and TERT functional polymorphisms may not play a major role in the etiology of SCCHN. Large prospective studies are needed to validate our findings.<br><br>IMPACT: Although our results suggest no association among RTL, TERT functional polymorphisms, and SCCHN risk, this study may contribute to future meta-analysis.},
}
@article {pmid21993820,
year = {2011},
author = {Eisenstein, M},
title = {Telomeres: All's well that ends well.},
journal = {Nature},
volume = {478},
number = {7368},
pages = {S13-5},
pmid = {21993820},
issn = {1476-4687},
mesh = {Aging/genetics ; Animals ; DNA Replication ; *Disease ; Dyskeratosis Congenita/genetics ; Humans ; Nobel Prize ; Telomerase/genetics/metabolism ; Telomere/*genetics/*physiology ; Tumor Suppressor Protein p53/deficiency/metabolism ; },
}
@article {pmid21989238,
year = {2011},
author = {Raffa, GD and Ciapponi, L and Cenci, G and Gatti, M},
title = {Terminin: a protein complex that mediates epigenetic maintenance of Drosophila telomeres.},
journal = {Nucleus (Austin, Tex.)},
volume = {2},
number = {5},
pages = {383-391},
doi = {10.4161/nucl.2.5.17873},
pmid = {21989238},
issn = {1949-1042},
mesh = {Animals ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; Drosophila ; Drosophila Proteins/genetics/*metabolism ; Epigenesis, Genetic ; Nuclear Proteins/genetics/*metabolism ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {In most organisms, telomeres are extended by telomerase and contain GC-rich repeats. Drosophila telomeres are elongated by occasional transposition of specialized retroelements rather than telomerase activity, and are assembled independently of the sequence of the DNA termini. Recent work has shown that Drosophila telomeres are capped by a complex, we call terminin, which includes HOAP, HipHop, Moi and Ver; these are fast-evolving proteins that prevent telomere fusion, directly interact with each other, and appear to localize and function only at telomeres. With the possible exception of Ver that contains an OB fold domain structurally similar to the Stn1 OB fold, none of the terminin proteins is evolutionarily conserved outside the Drosophila species. Human telomeres are protected by the shelterin complex, which comprises six proteins that bind chromosome ends in a sequence-dependent manner. Shelterin subunits are not fast-evolving proteins and are not conserved in flies, but localize and function only at telomeres like the terminin components. Based on these findings, we propose that concomitant with telomerase loss Drosophila rapidly evolved terminin to bind chromosome ends in a sequence-independent fashion, and that terminin is functionally analogous to shelterin.},
}
@article {pmid21987532,
year = {2011},
author = {Merle, P and Evrard, B and Petitjean, A and Lehn, JM and Teulade-Fichou, MP and Chautard, E and De Cian, A and Guittat, L and Tran, PL and Mergny, JL and Verrelle, P and Tchirkov, A},
title = {Telomere targeting with a new G4 ligand enhances radiation-induced killing of human glioblastoma cells.},
journal = {Molecular cancer therapeutics},
volume = {10},
number = {10},
pages = {1784-1795},
doi = {10.1158/1535-7163.MCT-10-0664},
pmid = {21987532},
issn = {1538-8514},
mesh = {Adult ; Brain Neoplasms/*drug therapy/genetics/pathology/*radiotherapy ; Cell Growth Processes/drug effects/radiation effects ; Cell Line, Tumor ; Combined Modality Therapy ; DNA Damage ; Female ; G-Quadruplexes ; Glioblastoma/*drug therapy/genetics/pathology/*radiotherapy ; Humans ; Ligands ; Mesylates/chemistry/pharmacology ; Pyrimidines/chemistry/*pharmacology ; Radiation-Sensitizing Agents/*pharmacology ; Telomerase/biosynthesis/genetics ; Telomere/*drug effects/metabolism/*radiation effects ; },
abstract = {The aim of this study was to test in vitro the efficacy of TAC, an original G-quadruplex ligand, as a potential radiosensitizing agent for glioblastoma multiforme (GBM). Two human radioresistant telomerase-positive GBM cell lines (SF763 and SF767) were analyzed, with and without TAC treatment, for telomere length, cell proliferation, apoptosis, cell-cycle distribution, gene expression, cytogenetic aberrations, clonogenic survival assay, 53BP1 immunofluorescence staining, and γH2AX phosphorylation. We found that low concentrations of TAC (0.5 and 1 μmol/L) inhibited the proliferation of GBM cells in a concentration-dependent manner after only 1 week of treatment, with minimal effects on cell cycle and apoptosis. TAC treatment had no visible effect on average telomere length but modified expression levels of telomere-related genes (hTERT, TRF1, and TRF2) and induced concentration-dependent DNA damage response and dicentric chromosomes. Survival curves analysis showed that exposure to nontoxic, subapoptotic concentrations of TAC enhanced radiation-induced killing of GBM cells. Analysis of DNA repair after irradiation revealed delayed repair kinetics in GBM cells treated with TAC. Furthermore, the combined treatment (TAC and radiation) significantly increased the frequency of chromosomal aberrations as compared with radiation alone. These findings provide the first evidence that exposure to a G4 ligand radiosensitizes human glioblastoma cells and suggest the prospect of future therapeutic applications.},
}
@article {pmid21986843,
year = {2012},
author = {Britt-Compton, B and Lin, TT and Ahmed, G and Weston, V and Jones, RE and Fegan, C and Oscier, DG and Stankovic, T and Pepper, C and Baird, DM},
title = {Extreme telomere erosion in ATM-mutated and 11q-deleted CLL patients is independent of disease stage.},
journal = {Leukemia},
volume = {26},
number = {4},
pages = {826-830},
doi = {10.1038/leu.2011.281},
pmid = {21986843},
issn = {1476-5551},
support = {C17199/A5603//Cancer Research UK/United Kingdom ; },
mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*genetics ; *Chromosome Deletion ; *Chromosomes, Human, Pair 11 ; DNA Breaks, Double-Stranded ; DNA-Binding Proteins/*genetics ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/pathology ; *Mutation ; Neoplasm Staging ; Protein Serine-Threonine Kinases/*genetics ; *Telomere Homeostasis ; Tumor Suppressor Proteins/*genetics ; },
}
@article {pmid21984947,
year = {2011},
author = {Kim, S and Sandler, DP and Carswell, G and Weinberg, CR and Taylor, JA},
title = {Reliability and short-term intra-individual variability of telomere length measurement using monochrome multiplexing quantitative PCR.},
journal = {PloS one},
volume = {6},
number = {9},
pages = {e25774},
pmid = {21984947},
issn = {1932-6203},
support = {Z01 ES044005/ImNIH/Intramural NIH HHS/United States ; Z01 ES049033/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; Multiplex Polymerase Chain Reaction ; Real-Time Polymerase Chain Reaction ; Telomere/*genetics ; },
abstract = {BACKGROUND: Studies examining the association between telomere length and cancer risk have often relied on measurement of telomere length from a single blood draw using a real-time PCR technique. We examined the reliability of telomere length measurement using sequential samples collected over a 9-month period.<br><br>METHODS AND FINDINGS: Relative telomere length in peripheral blood was estimated using a single tube monochrome multiplex quantitative PCR assay in blood DNA samples from 27 non-pregnant adult women (aged 35 to 74 years) collected in 7 visits over a 9-month period. A linear mixed model was used to estimate the components of variance for telomere length measurements attributed to variation among women and variation between time points within women. Mean telomere length measurement at any single visit was not significantly different from the average of 7 visits. Plates had a significant systematic influence on telomere length measurements, although measurements between different plates were highly correlated. After controlling for plate effects, 64% of the remaining variance was estimated to be accounted for by variance due to subject. Variance explained by time of visit within a subject was minor, contributing 5% of the remaining variance.<br><br>CONCLUSION: Our data demonstrate good short-term reliability of telomere length measurement using blood from a single draw. However, the existence of technical variability, particularly plate effects, reinforces the need for technical replicates and balancing of case and control samples across plates.},
}
@article {pmid21983177,
year = {2012},
author = {Zou, YS and Ouahchi, K and Lu, Y and Liu, W and Christensen, T and Schappert, J and Saleki, R},
title = {Jumping translocations of 3q21 in an acute monocytic leukemia (M5) patient reveal mechanisms of multistage telomere shortening in pathogenesis of AML.},
journal = {Leukemia research},
volume = {36},
number = {1},
pages = {e31-3},
doi = {10.1016/j.leukres.2011.09.004},
pmid = {21983177},
issn = {1873-5835},
mesh = {Aged ; Cell Transformation, Neoplastic/genetics ; *Chromosomes, Human, Pair 3/genetics ; Genetic Predisposition to Disease ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia, Monocytic, Acute/*genetics ; Male ; Signal Transduction/genetics ; Telomere Shortening/*genetics ; *Translocation, Genetic ; },
}
@article {pmid21981562,
year = {2012},
author = {Yu, EY},
title = {Telomeres and telomerase in Candida albicans.},
journal = {Mycoses},
volume = {55},
number = {3},
pages = {e48-59},
doi = {10.1111/j.1439-0507.2011.02123.x},
pmid = {21981562},
issn = {1439-0507},
mesh = {Animals ; Candida albicans/*enzymology/*genetics ; Candidiasis/*microbiology ; Fungal Proteins/genetics/*metabolism ; Humans ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are the nucleoprotein structures at the ends of linear chromosomes and maintain the genomic integrity through multiple cell divisions. Telomeres protect the chromosome ends from degradation, end-to-end fusion and abnormal recombination and they also promote the end replication. The budding yeast Saccharomyces cerevisiae is the most well-studied model system with regard to telomere and telomerase regulation. Recently, the opportunistic fungal pathogen Candida albicans has emerged as an attractive model system for investigating telomere biology. Candida underwent rapid evolutionary divergence with respect to telomere sequences. Concomitant with the evolutionary divergence of telomere sequences, telomere repeat binding factors and telomerase components have also evolved, leading to differences in their functions and domain structures. Thus, the comparative analysis of the telomeres and telomerase-related factors in the budding yeast has provided a better understanding on both conserved and variable aspects of telomere regulation. In this review, I will discuss telomeres and telomerase-related factors and their functions in telomere and telomerase regulation in C. albicans.},
}
@article {pmid21981348,
year = {2012},
author = {Gadalla, SM and Katki, HA and Shebl, FM and Giri, N and Alter, BP and Savage, SA},
title = {The relationship between DNA methylation and telomere length in dyskeratosis congenita.},
journal = {Aging cell},
volume = {11},
number = {1},
pages = {24-28},
pmid = {21981348},
issn = {1474-9726},
support = {N02CP11019/CP/NCI NIH HHS/United States ; N02CP65501/CP/NCI NIH HHS/United States ; N02CP65504/CP/NCI NIH HHS/United States ; ZIA CP010190-05//Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Animals ; Case-Control Studies ; Cell Cycle Proteins/genetics ; Child ; Child, Preschool ; *DNA Methylation ; Dyskeratosis Congenita/*genetics/metabolism ; Epigenesis, Genetic ; Female ; Humans ; Long Interspersed Nucleotide Elements/genetics ; Male ; Mice ; Middle Aged ; Molecular Chaperones ; Mutation ; Nuclear Proteins/genetics ; RNA/genetics ; Skin/*metabolism/pathology ; Telomerase/genetics ; Telomere/*genetics ; Telomere Homeostasis ; Telomere-Binding Proteins/*genetics ; },
abstract = {The regulation of telomere length (TL) is a complex process, requiring the telomerase enzyme complex and numerous regulatory proteins. Epigenetic regulation may also be important in telomere maintenance. Specifically, methylation at subtelomeres is associated with changes in TL in vitro and in mouse models. Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by exceedingly short telomeres and mutations in telomere biology genes. To understand the interaction between methylation and TL in humans, we measured LINE-1, pericentromeric (NBL2), and subtelomeric (D4Z4) methylation in peripheral blood DNA derived from 40 patients with DC and 51 mutation-negative relatives. Pearson's correlation coefficient and linear regression models were used to evaluate the relationship between age-standardized lymphocyte TL measured by flow FISH and % DNA methylation. No differences in % subtelomeric, LINE-1, or pericentromeric methylation between patients with DC and relatives were noted except for an increase in % subtelomeric methylation in DC patients with a telomerase-complex mutation (TERC, TERT, DKC1, or TCAB1) (63.0% in DC vs. 61.8% in relatives, P = 0.03). Positive correlations between TL and DNA methylation at LINE-1 (r = 0.39, P = 0.01) and subtelomeric (r = 0.32, P = 0.05) sites were present in patients with DC. The positive correlation between TL and % LINE-1 methylation was restricted to TINF2 mutations. In contrast, statistically nonsignificant inverse correlations between TL and % LINE-1 (r = -0.17), subtelomeric (r = -0.20) were present in unaffected relatives. This study suggests an interaction between TL and both subtelomeric and LINE-1 methylation, which may be altered based on mutation status of telomere biology genes.},
}
@article {pmid21972126,
year = {2012},
author = {Kim, S and Bi, X and Czarny-Ratajczak, M and Dai, J and Welsh, DA and Myers, L and Welsch, MA and Cherry, KE and Arnold, J and Poon, LW and Jazwinski, SM},
title = {Telomere maintenance genes SIRT1 and XRCC6 impact age-related decline in telomere length but only SIRT1 is associated with human longevity.},
journal = {Biogerontology},
volume = {13},
number = {2},
pages = {119-131},
pmid = {21972126},
issn = {1573-6768},
support = {P01AG017553/AG/NIA NIH HHS/United States ; P01AG022064/AG/NIA NIH HHS/United States ; P01 AG017553-05/AG/NIA NIH HHS/United States ; P01 AG017553/AG/NIA NIH HHS/United States ; P01 AG022064/AG/NIA NIH HHS/United States ; P01 AG022064-06/AG/NIA NIH HHS/United States ; },
mesh = {3' Flanking Region ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Antigens, Nuclear/*genetics/metabolism ; Case-Control Studies ; DNA-Binding Proteins/*genetics/metabolism ; Female ; Gene Frequency ; Genotype ; Georgia ; Humans ; Ku Autoantigen ; Lod Score ; Longevity/*genetics ; Louisiana ; Male ; Middle Aged ; Multivariate Analysis ; Odds Ratio ; Phenotype ; *Polymorphism, Single Nucleotide ; Proportional Hazards Models ; Sirtuin 1/*genetics/metabolism ; Survival Analysis ; Telomere/*metabolism ; *Telomere Shortening ; Young Adult ; },
abstract = {Leukocyte telomere length is widely considered a biomarker of human age and in many studies indicative of health or disease. We have obtained quantitative estimates of telomere length from blood leukocytes in a population sample, confirming results of previous studies that telomere length significantly decreases with age. Telomere length was also positively associated with several measures of healthy aging, but this relationship was dependent on age. We screened two genes known to be involved in telomere maintenance for association with the age-related decline in telomere length observed in our population to identify candidate longevity-associated genes. A single-nucleotide polymorphism located in the SIRT1 gene and another in the 3' flanking region of XRCC6 had significant effects on telomere length. At each bi-allelic locus, the minor variant was associated with longer telomeres, though the mode of inheritance fitting best differed between the two genes. No statistical interaction was detected for telomere length between the SIRT1 and XRCC6 variants or between these polymorphisms and age. The SIRT1 locus was significantly associated with longevity (P < 0.003). The frequency of the minor allele was higher in long-lived cases than in young controls, which coincides with the protective role of the minor variant for telomere length. In contrast, the XRCC6 variant was not associated with longevity. Furthermore, it did not affect the association of SIRT1 with exceptional survival. The association of the same variant of SIRT1 with longevity was near significant (P < 0.07) in a second population. These results suggest a potential role of SIRT1 in linking telomere length and longevity. Given the differences between this gene and XRCC6, they point to the distinct impact that alternate pathways of telomere maintenance may have on aging and exceptional survival.},
}
@article {pmid21963168,
year = {2012},
author = {O'Callaghan, NJ and Toden, S and Bird, AR and Topping, DL and Fenech, M and Conlon, MA},
title = {Colonocyte telomere shortening is greater with dietary red meat than white meat and is attenuated by resistant starch.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {31},
number = {1},
pages = {60-64},
doi = {10.1016/j.clnu.2011.09.003},
pmid = {21963168},
issn = {1532-1983},
mesh = {Animals ; Cattle ; Chickens ; Colon/physiopathology ; Cooking ; DNA Damage ; Dietary Carbohydrates/administration &amp; dosage ; Dietary Fiber/administration &amp; dosage ; Male ; Malondialdehyde/analysis/metabolism ; *Meat ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Regression Analysis ; Sequence Analysis, DNA ; Starch/*administration &amp; dosage ; *Telomere Shortening ; },
abstract = {BACKGROUND &amp; AIMS: Population studies indicate that greater red meat consumption increases colorectal cancer risk while dietary fibre is protective. Previous work in rats showed that diets high in protein, including red meat, increase colonocyte DNA strand breaks and that this effect is attenuated by resistant starches (RS). Telomeres are long hexamer repeats that protect against spontaneous DNA damage which would lead to chromosomal instability. Telomere shortening is associated with greater risk of colorectal cancer. The current study aimed to determine the effects of cooked red and white meat intake on colonocyte telomere length in rats and whether dietary RS modified their effects.<br><br>METHODS: After four weeks of feeding cooked beef or chicken at 15, 25 and 35% of diet with or without RS, colonocyte telomere length was measured.<br><br>RESULTS: Telomere length decreased in proportion to red meat content of the diet. A similar trend was observed in the white meat group. Colonocyte telomere shortening due to increased dietary meat was attenuated by the inclusion of RS.<br><br>CONCLUSION: These data support previous findings of increased colonocyte DNA damage with greater red and white meat intake and also the protective effect of dietary fibre.},
}
@article {pmid21962402,
year = {2011},
author = {Saliques, S and Teyssier, JR and Vergely, C and Lorgis, L and Lorin, J and Farnier, M and Donzel, A and Sicard, P and Berchoud, J and Lagrost, AC and Touzery, C and Ragot, S and Cottin, Y and Rochette, L and Zeller, M},
title = {Circulating leukocyte telomere length and oxidative stress: a new target for statin therapy.},
journal = {Atherosclerosis},
volume = {219},
number = {2},
pages = {753-760},
doi = {10.1016/j.atherosclerosis.2011.09.011},
pmid = {21962402},
issn = {1879-1484},
mesh = {Aged ; Aged, 80 and over ; Chi-Square Distribution ; DNA Glycosylases/genetics ; Dyslipidemias/blood/complications/*drug therapy/genetics ; Female ; Genetic Markers ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use ; Leukocytes/*drug effects/metabolism ; Linear Models ; Logistic Models ; Male ; Middle Aged ; Myocardial Infarction/blood/genetics/*prevention &amp; control ; Oxidative Stress/*drug effects ; Propensity Score ; Proto-Oncogene Proteins c-fos/genetics ; RNA, Messenger/blood ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Risk Assessment ; Risk Factors ; Telomere/*drug effects/metabolism ; },
abstract = {OBJECTIVES: We investigated the relationship between prior statin therapy and leukocyte telomere length (LTL), as well as their interaction with potential new biomarkers of oxidative deoxyribonucleic acid (DNA) lesions and reactive oxygen species-induced inflammation.<br><br>METHODS AND RESULTS: From patients admitted for an acute myocardial infarction, LTL was assessed by quantitative polymerase chain reaction (Q-PCR), and leukocyte Finkel-Biskis-Jinkins osteosarcoma (FOS) and 8-oxoguanine DNA glycosylase (OGG1) messenger ribonucleic acid (mRNA) levels were measured by retrotranscription Q-PCR. Patients under prior chronic statin therapy were compared with patients without statin therapy. Although patients on statin therapy were older, their mean LTL was longer than patients not under statin therapy (1.29 &#xb1; 0.11 vs. 1.25 &#xb1; 0.11 T/S ratio, p = 0.008). In contrast, FOS and OGG1 mRNA levels were similar for the 2 groups. LTL decreased with increasing age, FOS, and OGG1 mRNA levels. Statin therapy remained associated with longer LTL, even after adjustment for confounding factors (p = 0.001), and in younger patients (&#x2264; 64 y). Even in groups matched for propensity scores for statin use, LTL was markedly longer in patients under statin therapy.<br><br>CONCLUSIONS: Our observational study showed that statin therapy was associated with longer LTL. These data bring to light opportunities to identify new targets for early primary preventive treatment strategies. Moreover, our study raised FOS and OGG1 as new relevant biomarkers of LTL.},
}
@article {pmid21950380,
year = {2011},
author = {Horvath, MP},
title = {Structural anatomy of telomere OB proteins.},
journal = {Critical reviews in biochemistry and molecular biology},
volume = {46},
number = {5},
pages = {409-435},
pmid = {21950380},
issn = {1549-7798},
support = {R01 GM067994/GM/NIGMS NIH HHS/United States ; R01 GM067994-05/GM/NIGMS NIH HHS/United States ; GM067994/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Crystallography, X-Ray ; DNA/*biosynthesis/chemistry ; DNA, Single-Stranded/chemistry ; Eukaryota/genetics/*metabolism ; Molecular Sequence Data ; Phylogeny ; Protein Conformation ; Protein Folding ; Protein Structure, Tertiary ; Replication Protein A/*chemistry ; Telomere/*chemistry ; Telomere-Binding Proteins/*chemistry ; },
abstract = {Telomere DNA-binding proteins protect the ends of chromosomes in eukaryotes. A subset of these proteins are constructed with one or more OB folds and bind with G+T-rich single-stranded DNA found at the extreme termini. The resulting DNA-OB protein complex interacts with other telomere components to coordinate critical telomere functions of DNA protection and DNA synthesis. While the first crystal and NMR structures readily explained protection of telomere ends, the picture of how single-stranded DNA becomes available to serve as primer and template for synthesis of new telomere DNA is only recently coming into focus. New structures of telomere OB fold proteins alongside insights from genetic and biochemical experiments have made significant contributions towards understanding how protein-binding OB proteins collaborate with DNA-binding OB proteins to recruit telomerase and DNA polymerase for telomere homeostasis. This review surveys telomere OB protein structures alongside highly comparable structures derived from replication protein A (RPA) components, with the goal of providing a molecular context for understanding telomere OB protein evolution and mechanism of action in protection and synthesis of telomere DNA.},
}
@article {pmid21945241,
year = {2012},
author = {Stewart, JA and Chaiken, MF and Wang, F and Price, CM},
title = {Maintaining the end: roles of telomere proteins in end-protection, telomere replication and length regulation.},
journal = {Mutation research},
volume = {730},
number = {1-2},
pages = {12-19},
pmid = {21945241},
issn = {0027-5107},
support = {R01 GM088728-04/GM/NIGMS NIH HHS/United States ; T32 CA117846/CA/NCI NIH HHS/United States ; GM041803/GM/NIGMS NIH HHS/United States ; R01 GM088728/GM/NIGMS NIH HHS/United States ; R01 GM041803/GM/NIGMS NIH HHS/United States ; GM088728/GM/NIGMS NIH HHS/United States ; F32 GM097833/GM/NIGMS NIH HHS/United States ; T32 CA117846-04/CA/NCI NIH HHS/United States ; R01 GM041803-21/GM/NIGMS NIH HHS/United States ; F32 GM097833-01/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Replication ; Genomic Instability ; Models, Molecular ; Shelterin Complex ; Telomerase/metabolism ; Telomere/*physiology ; *Telomere Homeostasis ; Telomere Shortening ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Chromosome end protection is essential to protect genome integrity. Telomeres, tracts of repetitive DNA sequence and associated proteins located at the chromosomal terminus, serve to safeguard the ends from degradation and unwanted double strand break repair. Due to the essential nature of telomeres in protecting the genome, a number of unique proteins have evolved to ensure that telomere length and structure are preserved. The inability to properly maintain telomeres can lead to diseases such as dyskeratosis congenita, pulmonary fibrosis and cancer. In this review, we will discuss the known functions of mammalian telomere-associated proteins, their role in telomere replication and length regulation and how these processes relate to genome instability and human disease.},
}
@article {pmid21945094,
year = {2011},
author = {Reynolds, GE and Gao, Q and Miller, D and Snow, BE and Harrington, LA and Murnane, JP},
title = {PIF1 disruption or NBS1 hypomorphism does not affect chromosome healing or fusion resulting from double-strand breaks near telomeres in murine embryonic stem cells.},
journal = {DNA repair},
volume = {10},
number = {11},
pages = {1164-1173},
pmid = {21945094},
issn = {1568-7856},
support = {R01 ES008427/ES/NIEHS NIH HHS/United States ; R01 ES008427-11/ES/NIEHS NIH HHS/United States ; R01 AG02398/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cell Cycle Proteins/*genetics/metabolism ; *Chromosome Aberrations ; *DNA Breaks, Double-Stranded ; DNA Helicases/*genetics/metabolism ; DNA-Binding Proteins ; Embryonic Stem Cells/*metabolism ; Female ; Gene Knockout Techniques ; Male ; Mice ; Mice, Transgenic ; Molecular Sequence Data ; Nuclear Proteins/*genetics/metabolism ; Sequence Alignment ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {Telomerase serves to maintain telomeric repeat sequences at the ends of chromosomes. However, telomerase can also add telomeric repeat sequences at DNA double-strand breaks (DSBs), a process called chromosome healing. Here, we employed a method of inducing DSBs near telomeres to query the role of two proteins, PIF1 and NBS1, in chromosome healing in mammalian cells. PIF1 was investigated because the PIF1 homolog in Saccharomyces cerevisiae inhibits chromosome healing, as shown by a 1000-fold increase in chromosome in PIF1-deficient cells. NBS1 was investigated because the functional homolog of NBS1 in S. cerevisiae, Xrs2, is part of the Mre11/Rad50/Xrs2 complex that is required for chromosome healing due to its role in the processing of DSBs and recruitment of telomerase. We found that disruption of mPif1 had no detectable effect on the frequency of chromosome healing at DSBs near telomeres in murine embryonic stem cells. Moreover, the Nbs1(ΔB) hypomorph, which is defective in the processing of DSBs, also had no detectable effect on the frequency of chromosome healing, DNA degradation, or gross chromosome rearrangements (GCRs) that result from telomeric DSBs. Although we cannot rule out small changes in chromosome healing using this system, it is clear from our results that knockout of PIF1 or the Nbs1(ΔB) hypomorph does not result in large differences in chromosome healing in murine cells. These results represent the first genetic assessment of the role of these proteins in chromosome healing in mammals, and suggest that murine cells have evolved mechanisms to ensure the functional redundancy of Pif1 or Nbs1 in the regulation of chromosome healing.},
}
@article {pmid21934123,
year = {2012},
author = {Sanders, JL and Fitzpatrick, AL and Boudreau, RM and Arnold, AM and Aviv, A and Kimura, M and Fried, LF and Harris, TB and Newman, AB},
title = {Leukocyte telomere length is associated with noninvasively measured age-related disease: The Cardiovascular Health Study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {67},
number = {4},
pages = {409-416},
pmid = {21934123},
issn = {1758-535X},
support = {AG-021593/AG/NIA NIH HHS/United States ; P30 AG024827/AG/NIA NIH HHS/United States ; 5-P30-AG-024827/AG/NIA NIH HHS/United States ; R01-HL-80698-01/HL/NHLBI NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; AG-020132/AG/NIA NIH HHS/United States ; N01-HC-35129/HC/NHLBI NIH HHS/United States ; N01-HC-55222/HC/NHLBI NIH HHS/United States ; N01-HC-75150/HC/NHLBI NIH HHS/United States ; N01-HC-85086/HC/NHLBI NIH HHS/United States ; N01-HC-15103/HC/NHLBI NIH HHS/United States ; R01-AG-023629/AG/NIA NIH HHS/United States ; N01-HC-45133/HC/NHLBI NIH HHS/United States ; N01-HC-85079/HC/NHLBI NIH HHS/United States ; },
mesh = {Black or African American/genetics ; Aged ; Aged, 80 and over ; Cardiovascular Diseases/*genetics ; Carotid Intima-Media Thickness ; Chronic Disease ; Cystatin C/blood ; Female ; Humans ; Leukocytes/*physiology ; Lung/physiology ; Male ; Middle Aged ; *Telomere Homeostasis ; White People/genetics ; },
abstract = {BACKGROUND: Most studies of leukocyte telomere length (LTL) focus on diagnosed disease in one system. A more encompassing depiction of health is disease burden, defined here as the sum of noninvasively measured markers of structure or function in different organ systems. We determined if (a) shorter LTL is associated with greater age-related disease burden and (b) shorter LTL is less strongly associated with disease in individual systems or diagnosed chronic conditions (cardiovascular disease, stroke, pulmonary disease, diabetes, kidney disease, arthritis, or depression).<br><br>METHODS: LTL was measured by Southern blots of terminal restriction fragment length. Age-related disease was measured noninvasively and included carotid intima-media thickness, lung vital capacity, white matter grade, cystatin-C, and fasting glucose; each graded 0 (best tertile), 1 (middle tertile), or 2 (worst tertile) and summed (0 to 10) to estimate disease burden. Of 419 participants randomly selected for LTL measurement, 236 had disease burden assessed (mean [SD] age 74.2 [4.9] years, 42.4% male, 86.8% white, and 13.2% black).<br><br>RESULTS: Mean (SD) LTL was 6,312 (615) bp, and disease score was 4.7 (2.1) points. An SD higher disease score (&#x3b2; [SE] = -132 [47] bp, p < .01), age (&#x3b2; [SE] = -107 [46], p = .02) or carotid thickness (&#x3b2; [SE] = -95 [40] bp, p = .02) was associated with shorter LTL, but diagnosed conditions or number of conditions were not associated with LTL. Disease score attenuated the effect of age on LTL by 35%.<br><br>CONCLUSION: LTL was associated with a characterization of age-related disease burden across multiple physiologic systems, which was comparable to, but independent of, its association with age.},
}
@article {pmid21933855,
year = {2012},
author = {Rampazzo, E and Bonaldi, L and Trentin, L and Visco, C and Keppel, S and Giunco, S and Frezzato, F and Facco, M and Novella, E and Giaretta, I and Del Bianco, P and Semenzato, G and De Rossi, A},
title = {Telomere length and telomerase levels delineate subgroups of B-cell chronic lymphocytic leukemia with different biological characteristics and clinical outcomes.},
journal = {Haematologica},
volume = {97},
number = {1},
pages = {56-63},
pmid = {21933855},
issn = {1592-8721},
mesh = {ADP-ribosyl Cyclase 1/metabolism ; Adult ; Aged ; Aged, 80 and over ; Chromosome Aberrations ; Female ; Humans ; Immunoglobulin Heavy Chains/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/classification/*genetics/*metabolism/mortality ; Male ; Middle Aged ; Mutation ; Prognosis ; Survival Analysis ; Telomerase/genetics/*metabolism ; *Telomere Homeostasis ; Transcription, Genetic ; ZAP-70 Protein-Tyrosine Kinase/metabolism ; },
abstract = {BACKGROUND: B-cell chronic lymphocytic leukemia is a clinically heterogeneous disease; some patients rapidly progress and die within a few years of diagnosis, whereas others have a long life expectancy with minimal or no treatment. Telomere length and telomerase levels have been proposed as prognostic factors; however, very few cases have been characterized for both parameters and no study has analyzed the prognostic value of the telomere/telomerase profile.<br><br>DESIGN AND METHODS: One hundred and seventy-three cases of chronic lymphocytic leukemia were characterized for telomere lengths and telomerase levels by real-time polymerase chain reaction. Data were correlated with established prognostic markers, IGVH mutational status and chromosomal aberrations, and clinical outcome.<br><br>RESULTS: Telomere lengths were inversely correlated with telomerase levels (r(s) = -0.213; P = 0.012), and most of the cases of chronic lymphocytic leukemia with high levels (above median) of telomerase had short (below median) telomeres (P = 0.0001). Telomerase levels were higher and telomeres were shorter in unmutated IGVH cases than in mutated IGVH ones (P<0.0001). Chronic lymphocytic leukemias with 11q, 17p deletion or 12 trisomy had significantly higher levels of telomerase and shorter telomeres than those with no chromosomal aberration or the sole 13q deletion (P < 0.001). Telomere length/telomerase level profiles identified subgroups of patients with different clinical outcomes (P < 0.0001), even within the subsets of chronic lymphocytic leukemia defined by IGVH mutational status or chromosomal aberrations. Short telomere/high telomerase profile was independently associated with more rapid disease progression.<br><br>CONCLUSIONS: Comprehensive analyses of telomeres, telomerase, chromosomal aberrations, and IGVH mutational status delineate groups of chronic lymphocytic leukemias with distinct biological characteristics and clinical outcomes. The telomere/telomerase profile may be particularly useful in refining the prognosis of chronic lymphocytic leukemia patients with mutated IGVH and no high-risk chromosomal aberrations.},
}
@article {pmid21931702,
year = {2011},
author = {Vulliamy, TJ and Kirwan, MJ and Beswick, R and Hossain, U and Baqai, C and Ratcliffe, A and Marsh, J and Walne, A and Dokal, I},
title = {Differences in disease severity but similar telomere lengths in genetic subgroups of patients with telomerase and shelterin mutations.},
journal = {PloS one},
volume = {6},
number = {9},
pages = {e24383},
pmid = {21931702},
issn = {1932-6203},
support = {//Wellcome Trust/United Kingdom ; 085937/Z/08/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; Humans ; Infant ; Middle Aged ; Mutation/*genetics ; *Severity of Illness Index ; Shelterin Complex ; Telomerase/*genetics ; *Telomere Homeostasis ; Telomere-Binding Proteins/*genetics ; Young Adult ; },
abstract = {The bone marrow failure syndrome dyskeratosis congenita (DC) has been considered to be a disorder of telomere maintenance in which disease features arise due to accelerated shortening of telomeres. By screening core components of the telomerase and shelterin complexes in patients with DC and related bone marrow failure syndromes we have identified 24 novel mutations: 11 in the RNA component of telomerase (TERC), 8 in the reverse transcriptase component (TERT), 4 in dyskerin (DKC1) and 1 in TRF1-interacting nuclear factor 2 (TINF2). This has prompted us to review these genetic subtypes in terms of telomere length, telomerase activity and clinical presentation among 194 genetically characterised index cases recruited onto the registry in London. While those with DKC1 and TINF2 mutations present at a younger age and have more disease features than those with TERC or TERT mutations, there is no difference in telomere length between these groups. There is no difference in the age of onset and numbers of disease features seen in those with TERC and TERT mutations despite the fact that the latter show higher levels of telomerase activity in vitro. The incidence of aplastic anaemia is greater in patients with TERC or TINF2 mutations compared to patients with DKC1 mutations, and cancer incidence is highest in patients with TERC mutations. These data are the first to provide robust comparisons between different genetic subtypes of telomerase and shelterin mutations (the "telomereopathies") and clearly demonstrate that disease severity is not explained by telomere length alone.},
}
@article {pmid21930799,
year = {2011},
author = {Drissi, R and Wu, J and Hu, Y and Bockhold, C and Dome, JS},
title = {Telomere shortening alters the kinetics of the DNA damage response after ionizing radiation in human cells.},
journal = {Cancer prevention research (Philadelphia, Pa.)},
volume = {4},
number = {12},
pages = {1973-1981},
pmid = {21930799},
issn = {1940-6215},
support = {CA87903/CA/NCI NIH HHS/United States ; R01 CA087903-03/CA/NCI NIH HHS/United States ; R01 CA087903/CA/NCI NIH HHS/United States ; R21 CA111347-01A1/CA/NCI NIH HHS/United States ; CA111347/CA/NCI NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; },
mesh = {Acetylation/radiation effects ; Ataxia Telangiectasia Mutated Proteins ; Blotting, Western ; Cell Cycle Proteins/metabolism ; Chromatin/*genetics ; DNA Damage/*radiation effects ; DNA Methylation/radiation effects ; DNA Repair/radiation effects ; DNA-Binding Proteins/metabolism ; Fluorescent Antibody Technique ; HeLa Cells ; Histones/metabolism ; Humans ; Immunoprecipitation ; Kinetics ; Phosphorylation/radiation effects ; Protein Serine-Threonine Kinases/metabolism ; Radiation Tolerance ; *Radiation, Ionizing ; Telomerase/metabolism ; Telomere/*genetics ; Telomere Shortening/*radiation effects ; Tumor Suppressor Proteins/metabolism ; },
abstract = {Studies of telomerase-deficient mice and human cell lines have showed that telomere shortening enhances sensitivity to ionizing radiation (IR). The molecular basis for this observation remains unclear. To better understand the connection between telomere shortening and radiation sensitivity, we evaluated components of the DNA damage response pathway in normal human fibroblasts with short and long telomeres. Late-passage cells with short telomeres showed enhanced sensitivity to IR compared with early-passage cells with longer telomeres. Compared with early-passage cells, late-passage cells had a higher baseline level of phosphorylated H2AX protein (γH2AX) before IR but diminished peak levels of H2AX phosphorylation after treatment with IR. Both the appearance and disappearance of γH2AX foci were delayed in late-passage cells, indicative of delayed DNA repair. In contrast to the situation with H2AX, ATM and p53 phosphorylation kinetics were similar in early- and late-passage cells, but phosphorylation of the chromatin-bound ATM targets SMC1 and NBS1 was delayed in late-passage cells. Because impaired phosphorylation associated with short telomeres was restricted to chromatin-bound ATM targets, chromatin structure was assessed. DNA from cells with short telomeres was more resistant to digestion with micrococcal nuclease, indicative of compacted chromatin. Moreover, cells with short telomeres showed histone acetylation and methylation profiles consistent with heterochromatin. Together our data suggest a model in which short telomeres induce chromatin structure changes that limit access of activated ATM to its downstream targets on the chromatin, thereby providing a potential explanation for the increased radiation sensitivity seen with telomere shortening.},
}
@article {pmid21930512,
year = {2012},
author = {Peng, J and Zhou, JQ},
title = {The tail-module of yeast Mediator complex is required for telomere heterochromatin maintenance.},
journal = {Nucleic acids research},
volume = {40},
number = {2},
pages = {581-593},
pmid = {21930512},
issn = {1362-4962},
mesh = {Acetylation ; Gene Silencing ; Heterochromatin/chemistry/*metabolism ; Histones/metabolism ; Mediator Complex/genetics/*metabolism ; Mutation ; Protein Subunits/genetics/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Shelterin Complex ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/metabolism ; Sirtuin 2/metabolism ; Telomere/enzymology/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/metabolism ; Transcription Factors/metabolism ; },
abstract = {Eukaryotic chromosome ends have a DNA-protein complex structure termed telomere. Integrity of telomeres is essential for cell proliferation. Genome-wide screenings for telomere length maintenance genes identified several components of the transcriptional regulator, the Mediator complex. Our work provides evidence that Mediator is involved in telomere length regulation and telomere heterochromatin maintenance. Tail module of Mediator is required for telomere silencing by promoting or stabilizing Sir protein binding and spreading on telomeres. Mediator binds on telomere and may be a component of telomeric chromatin. Our study reveals a specific role of Mediator complex at the heterochromatic telomere and this function is specific to telomeres as it has no effect on the HMR locus.},
}
@article {pmid21925300,
year = {2011},
author = {Genescà, A and Pampalona, J and Frías, C and Domínguez, D and Tusell, L},
title = {Role of telomere dysfunction in genetic intratumor diversity.},
journal = {Advances in cancer research},
volume = {112},
number = {},
pages = {11-41},
doi = {10.1016/B978-0-12-387688-1.00002-8},
pmid = {21925300},
issn = {2162-5557},
mesh = {*Chromosomal Instability ; Humans ; Neoplasms/*genetics/*pathology ; Telomere/*genetics/*pathology ; },
abstract = {Most solid tumors are unable to maintain the stability of their genomes at the chromosome level. Indeed, cancer cells display highly rearranged karyotypes containing translocations, amplifications, deletions, and gains and losses of whole chromosomes, which reshuffle steadily. This chromosomal instability most likely occurs early in the development of cancer, and may represent an important step in promoting the multiple genetic changes required for the initiation and/or progression of the disease. Different mechanisms may underlie chromosome instability in cancer cells, but a prominent role for telomeres, the tip of linear chromosomes, has been determined. Telomeres are ribonucleoprotein structures that prevent natural chromosome ends being recognized as DNA double-strand breaks, by adopting a loop structure. Loss of telomere function appears from either alteration on telomere-binding proteins or from the progressive telomere shortening that normally occurs under physiological conditions in the majority of cells in tissues. Importantly, unmasked telomeres may either trigger the senescent phenotype that has been linked to the aging process or may initiate the chromosome instability needed for cancer development, depending on the integrity of the DNA damage checkpoint responses. Telomere dysfunction contributes to chromosome instability through end-to-end chromosome fusions entering breakage-fusion-bridge (BFB) cycles. Resolution of chromatin bridge intermediates is likely to contribute greatly to the generation of segmental chromosome amplification events, unbalanced chromosome rearrangements, and whole chromosome aneuploidy. Noteworthy is the fact that telomere length heterogeneity among individuals may directly influence the scrambling of the genome at tumor initiation. However, reiterated BFB cycles would randomly reorganize the cell karyotype, thus increasing the genetic diversity that characterizes tumor cells. Even though a direct link is still lacking, multiple evidence lead one to believe that telomere dysfunction directly contributes to cancer development in humans. The expansion of highly unstable cells due to telomere dysfunction enhances the genetic diversity needed to fuel specific mutations that may promote cell immortalization and the acquisition of a tumor phenotype.},
}
@article {pmid21920955,
year = {2012},
author = {Turbill, C and Smith, S and Deimel, C and Ruf, T},
title = {Daily torpor is associated with telomere length change over winter in Djungarian hamsters.},
journal = {Biology letters},
volume = {8},
number = {2},
pages = {304-307},
pmid = {21920955},
issn = {1744-957X},
mesh = {Animals ; *Body Temperature Regulation ; Cold Temperature ; Cricetinae ; Female ; Hot Temperature ; Motor Activity ; Phodopus/*physiology ; Photoperiod ; Polymerase Chain Reaction ; Seasons ; Telomere/chemistry ; *Telomere Homeostasis ; },
abstract = {Ageing can progress at different rates according to an individual's physiological state. Natural hypothermia, including torpor and hibernation, is a common adaptation of small mammals to survive intermittent or seasonal declines in environmental conditions. In addition to allowing energy savings, hypothermia and torpor have been associated with retarded ageing and increased longevity. We tested the hypothesis that torpor use slows ageing by measuring changes in the relative telomere length (RTL) of Djungarian hamsters, Phodopus sungorus, a highly seasonal rodent using spontaneous daily torpor, over 180 days of exposure to a short-day photoperiod and warm (approx. 20°C) or cold (approx. 9°C) air temperatures. Multi-model inference showed that change in RTL within individuals was best explained by positive effects of frequency of torpor use, particularly at low body temperatures, as well as the change in body mass and initial RTL. Telomere dynamics have been linked to future survival and proposed as an index of rates of biological ageing. Our results therefore support the hypothesis that daily torpor is associated with physiological changes that increase somatic maintenance and slow the processes of ageing.},
}
@article {pmid21917112,
year = {2011},
author = {Benetos, A and Kimura, M and Labat, C and Buchoff, GM and Huber, S and Labat, L and Lu, X and Aviv, A},
title = {A model of canine leukocyte telomere dynamics.},
journal = {Aging cell},
volume = {10},
number = {6},
pages = {991-995},
pmid = {21917112},
issn = {1474-9726},
support = {R01 AG030678/AG/NIA NIH HHS/United States ; R01 AG030678-04/AG/NIA NIH HHS/United States ; AG030678/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Blotting, Southern ; Body Weight ; DNA/analysis ; Dogs ; Female ; Genetic Variation ; Humans ; Leukocytes/metabolism ; Longevity/*genetics ; Male ; Models, Biological ; Muscle, Skeletal/metabolism ; Subcutaneous Fat/metabolism ; Telomere/chemistry/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Recent studies have found associations of leukocyte telomere length (TL) with diseases of aging and with longevity. However, it is unknown whether birth leukocyte TL or its age-dependent attrition--the two factors that determine leukocyte TL dynamics--explains these associations because acquiring this information entails monitoring individuals over their entire life course. We tested in dogs a model of leukocyte TL dynamics, based on the following premises: (i) TL is synchronized among somatic tissues; (ii) TL in skeletal muscle, which is largely postmitotic, is a measure of TL in early development; and (iii) the difference between TL in leukocytes and muscle (ΔLMTL) is the extent of leukocyte TL shortening since early development. Using this model, we observed in 83 dogs (ages, 4-42 months) no significant change with age in TLs of skeletal muscle and a shorter TL in leukocytes than in skeletal muscle (P<0.0001). Age explained 43% of the variation in ΔLMTL (P<0.00001), but only 6% of the variation in leukocyte TL (P=0.035) among dogs. Accordingly, muscle TL and ΔLMTL provide the two essential factors of leukocyte TL dynamics in the individual dog. When applied to humans, the partition of the contribution of leukocyte TL during early development vs. telomere shortening afterward might provide information about whether the individual's longevity is calibrated to either one or both factors that define leukocyte TL dynamics.},
}
@article {pmid21915807,
year = {2011},
author = {Gleichmann, U and Gleichmann, US and Gleichmann, S},
title = {[From cardiovascular prevention to anti-aging medicine: influence on telomere and cell aging].},
journal = {Deutsche medizinische Wochenschrift (1946)},
volume = {136},
number = {38},
pages = {1913-1916},
doi = {10.1055/s-0031-1286363},
pmid = {21915807},
issn = {1439-4413},
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Cardiovascular Diseases/*genetics/*prevention &amp; control ; Cellular Senescence/*genetics ; Child ; Child, Preschool ; Controlled Clinical Trials as Topic ; Enzyme Activation/genetics ; Humans ; Infant ; Infant, Newborn ; Life Expectancy ; Middle Aged ; Risk Factors ; Telomerase/genetics ; Telomere/*genetics ; Young Adult ; },
abstract = {The most important cardiovascular risk factors (hypercholesterolemia , hypertension, diabetes, chronic stress, physical inactivity, smoking, adipositas) were evaluated in the second half of the last century using placebo controlled trials. The mechanismen of action was not fully understood or remained unclear. In some studies not only the risk of atherosclerosis was reduced but life expectancy was improved. The length of telomeres is influenced by many of the cardiovascular risk factors and is a biomarker of age. Reduced telomere length are found in higher age, atherosclerosis, hypertension, adipositas, diabetes, smoking, physical inactivity, heart failure, maltreatment in childhood, exposure to traffic pollution, chronic infection, single life and dementia. A positive effect on telomerase and telomere length is found with increased physical activity, statins for treatment of hypercholesterolemia, and higher blood levels of omega-3 fatty acids. The probable mechanismen for this is an activation of telomerase activity. Many of the cardiovascular risk factors influence the cellular DNA by telomere shortening. These effects could be reduced by life style measures with prudent diet and drugs for good somatic fitness and healthy aging. By this mechanism cardiovascular prevention not only reduces the risk of atherosclerosis but also improves life exspectancy by anti-aging effects.},
}
@article {pmid21914494,
year = {2011},
author = {Borssén, M and Cullman, I and Norén-Nyström, U and Sundström, C and Porwit, A and Forestier, E and Roos, G},
title = {hTERT promoter methylation and telomere length in childhood acute lymphoblastic leukemia: associations with immunophenotype and cytogenetic subgroup.},
journal = {Experimental hematology},
volume = {39},
number = {12},
pages = {1144-1151},
doi = {10.1016/j.exphem.2011.08.014},
pmid = {21914494},
issn = {1873-2399},
mesh = {Adolescent ; Bone Marrow Cells/ultrastructure ; Child ; Child, Preschool ; Chromosome Aberrations ; Cohort Studies ; *DNA Methylation ; Female ; *Gene Expression Regulation, Leukemic ; Humans ; Immunophenotyping ; Infant ; Male ; Oncogene Proteins, Fusion/genetics ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics/pathology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/classification/*genetics/pathology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics/pathology ; Promoter Regions, Genetic/*genetics ; RNA, Messenger/genetics ; RNA, Neoplasm/genetics ; Telomerase/*genetics ; Telomere/*ultrastructure ; },
abstract = {Telomere maintenance, important for long-term cell survival and malignant transformation, is directed by a multitude of factors, including epigenetic mechanisms, and has been implicated in outcomes for patients with leukemia. In the present study, the objective was to investigate the biological and clinical significance of telomere length and promoter methylation of the human telomerase reverse transcriptase gene in childhood acute lymphoblastic leukemia. A cohort of 169 childhood acute lymphoblastic leukemias was investigated for telomere length, human telomerase reverse transcriptase gene promoter methylation status, genomic aberrations, immunophenotype, and clinical outcomes. Methylation of the core promoter of the human telomerase reverse transcriptase (hTERT) gene was demonstrated in 24% of diagnostic samples, with a significant difference between B-cell precursor (n = 130) and T-cell acute lymphoblastic leukemia (ALL) (n = 17) cases (18% and 72%, respectively; p < 0.001). No remission sample demonstrated hTERT promoter methylation (n = 40). Within the B-cell precursor group, t(12;21)(p13;q22) [ETV6/RUNX1] cases (n = 19) showed a much higher frequency of hTERT methylation than high-hyperdiploid (51-61 chromosomes) ALL (n = 44) (63% and 7%, respectively; p < 0.001). hTERT messenger RNA levels were negatively associated with methylation status and, in the t(12;21) group, methylated cases had shorter telomeres (p = 0.017). In low-risk B-cell precursor patients (n = 101), long telomeres indicated a worse prognosis. The collected data from the present study indicate that the telomere biology in childhood ALL has clinical implications and reflects molecular differences between diverse ALL subgroups.},
}
@article {pmid21903926,
year = {2011},
author = {Zhang, P and Casaday-Potts, R and Precht, P and Jiang, H and Liu, Y and Pazin, MJ and Mattson, MP},
title = {Nontelomeric splice variant of telomere repeat-binding factor 2 maintains neuronal traits by sequestering repressor element 1-silencing transcription factor.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {108},
number = {39},
pages = {16434-16439},
pmid = {21903926},
issn = {1091-6490},
support = {ZIA AG000378-04//Intramural NIH HHS/United States ; },
mesh = {Animals ; Brain/growth &amp; development/metabolism ; *Gene Silencing ; Humans ; Molecular Sequence Data ; Neurons/*cytology ; Repressor Proteins/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; *Telomere ; Telomere-Binding Proteins/genetics/*physiology ; Transcription Factors/*metabolism ; },
abstract = {Telomere repeat-binding factor 2 (TRF2) is critical for telomere integrity in dividing stem and somatic cells, but its role in postmitotic neurons is unknown. Apart from protecting telomeres, nuclear TRF2 interacts with the master neuronal gene-silencer repressor element 1-silencing transcription factor (REST), and disruption of this interaction induces neuronal differentiation. Here we report a developmental switch from the expression of TRF2 in proliferating neural progenitor cells to expression of a unique short nontelomeric isoform of TRF2 (TRF2-S) as neurons establish a fully differentiated state. Unlike nuclear TRF2, which enhances REST-mediated gene repression, TRF2-S is located in the cytoplasm where it sequesters REST, thereby maintaining the expression of neuronal genes, including those encoding glutamate receptors, cell adhesion, and neurofilament proteins. In neurons, TRF2-S-mediated antagonism of REST nuclear activity is greatly attenuated by either overexpression of TRF2 or administration of the excitatory amino acid kainic acid. Overexpression of TRF2-S rescues kainic acid-induced REST nuclear accumulation and its gene-silencing effects. Thus, TRF2-S acts as part of a unique developmentally regulated molecular switch that plays critical roles in the maintenance and plasticity of neurons.},
}
@article {pmid21903669,
year = {2011},
author = {Pickett, HA and Henson, JD and Au, AY and Neumann, AA and Reddel, RR},
title = {Normal mammalian cells negatively regulate telomere length by telomere trimming.},
journal = {Human molecular genetics},
volume = {20},
number = {23},
pages = {4684-4692},
doi = {10.1093/hmg/ddr402},
pmid = {21903669},
issn = {1460-2083},
mesh = {Animals ; Chromosomes, Mammalian/genetics/*metabolism ; DNA, Circular/metabolism ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/metabolism ; HeLa Cells ; Homologous Recombination ; Humans ; Lymphocyte Activation/immunology ; Male ; Mammals ; Mice ; Models, Biological ; Organ Specificity ; Spermatozoa/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {In human cancer cells with telomeres that have been over-lengthened by exogenous telomerase activity, telomere shortening can occur by a process that generates circles of double-stranded telomeric DNA (t-circles). Here, we demonstrate that this telomeretrimming process occurs in cells of the male germline and in normal lymphocytes following mitogen-stimulated upregulation of telomerase activity. Mouse tissues also contain abundant t-circles, suggesting that telomere trimming also contributes to telomere length regulation in mice. In cancer cells and stimulated lymphocytes, the mechanism involves the XRCC3 homologous recombination (HR) protein and generates single-stranded C-rich telomeric DNA. This suggests that, in addition to the well-documented gradual telomere attrition that accompanies cellular replication, there is also a more rapid form of negative telomere length control in normal mammalian cells, which most likely involves HR-mediated removal of telomere loops in the form of t-circles. We therefore propose that this telomere trimming mechanism is an additional factor in the balance between telomere lengthening and telomere shortening in normal human germline and somatic cells that may prevent excessive lengthening by processes such as telomerase activity.},
}
@article {pmid21902801,
year = {2011},
author = {Barrett, EL and Richardson, DS},
title = {Sex differences in telomeres and lifespan.},
journal = {Aging cell},
volume = {10},
number = {6},
pages = {913-921},
doi = {10.1111/j.1474-9726.2011.00741.x},
pmid = {21902801},
issn = {1474-9726},
mesh = {Animals ; Female ; Germ Cells/cytology ; Hormones/*genetics ; Humans ; *Life Expectancy ; Longevity/*genetics ; Male ; Oxidative Stress ; Sex Characteristics ; Sex Factors ; Telomere/chemistry/*metabolism ; *Telomere Shortening ; },
abstract = {Males and females often age at different rates resulting in longevity 'gender gaps', where one sex outlives the other. Why the sexes have different lifespans is an age-old question, still fiercely debated today. One cellular process related to lifespan, which is known to differ according to sex, is the rate at which the protective telomere chromosome caps are lost. In humans, men have shorter lifespans and greater telomere shortening. This has led to speculation in the medical literature that sex-specific telomere shortening is one cause of sex-specific mortality. However, telomere shortening may be a cause for and/or a consequence of the processes that govern survival, and to infer general principles from single-taxon studies may be misleading. Here, we review recent work on telomeres in a variety of animal taxa, including those with reverse sexual lifespan dimorphism (i.e., where males live longer), to establish whether sex-specific survival is generally associated with sex differences in telomere dynamics. By doing this, we attempt to tease apart the potential underlying causes for sex differences in telomere lengths in humans and highlight targets for future research across all taxa.},
}
@article {pmid21901113,
year = {2011},
author = {Kwan, EX and Foss, E and Kruglyak, L and Bedalov, A},
title = {Natural polymorphism in BUL2 links cellular amino acid availability with chronological aging and telomere maintenance in yeast.},
journal = {PLoS genetics},
volume = {7},
number = {8},
pages = {e1002250},
pmid = {21901113},
issn = {1553-7404},
support = {CA103728-03/CA/NCI NIH HHS/United States ; T32 CA009229/CA/NCI NIH HHS/United States ; 2P30AG013280-16/AG/NIA NIH HHS/United States ; CA129132/CA/NCI NIH HHS/United States ; P20 CA103728/CA/NCI NIH HHS/United States ; R01 CA129132/CA/NCI NIH HHS/United States ; T32 CA09229/CA/NCI NIH HHS/United States ; P30 AG013280/AG/NIA NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing/*genetics/*metabolism ; Aging/*genetics ; Amino Acid Sequence ; Amino Acid Transport Systems/genetics/metabolism ; Amino Acids/genetics/*metabolism ; Molecular Sequence Data ; Polymorphism, Genetic ; Quantitative Trait Loci ; Repressor Proteins/genetics/metabolism ; Ribonucleotide Reductases/genetics/metabolism ; S Phase/genetics ; Saccharomyces cerevisiae/genetics/*metabolism/physiology ; Saccharomyces cerevisiae Proteins/*genetics/*metabolism ; Telomere/*genetics ; Transcription Factors/genetics/metabolism ; Ubiquitin-Protein Ligase Complexes/genetics/metabolism ; },
abstract = {Aging and longevity are considered to be highly complex genetic traits. In order to gain insight into aging as a polygenic trait, we employed an outbred Saccharomyces cerevisiae model, generated by crossing a vineyard strain RM11 and a laboratory strain S288c, to identify quantitative trait loci that control chronological lifespan. Among the major loci that regulate chronological lifespan in this cross, one genetic linkage was found to be congruent with a previously mapped locus that controls telomere length variation. We found that a single nucleotide polymorphism in BUL2, encoding a component of an ubiquitin ligase complex involved in trafficking of amino acid permeases, controls chronological lifespan and telomere length as well as amino acid uptake. Cellular amino acid availability changes conferred by the BUL2 polymorphism alter telomere length by modulating activity of a transcription factor Gln3. Among the GLN3 transcriptional targets relevant to this phenotype, we identified Wtm1, whose upregulation promotes nuclear retention of ribonucleotide reductase (RNR) components and inhibits the assembly of the RNR enzyme complex during S-phase. Inhibition of RNR is one of the mechanisms by which Gln3 modulates telomere length. Identification of a polymorphism in BUL2 in this outbred yeast population revealed a link among cellular amino acid availability, chronological lifespan, and telomere length control.},
}
@article {pmid21900503,
year = {2011},
author = {Linger, BR and Morin, GB and Price, CM},
title = {The Pot1a-associated proteins Tpt1 and Pat1 coordinate telomere protection and length regulation in Tetrahymena.},
journal = {Molecular biology of the cell},
volume = {22},
number = {21},
pages = {4161-4170},
pmid = {21900503},
issn = {1939-4586},
support = {R01 GM088728/GM/NIGMS NIH HHS/United States ; T32 CA117846/CA/NCI NIH HHS/United States ; GM088728/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatography, Affinity ; Cloning, Molecular ; Immunoprecipitation ; Multiprotein Complexes/metabolism ; Organisms, Genetically Modified ; Protein Binding ; Protozoan Proteins/genetics/isolation &amp; purification/*metabolism ; Recombinant Fusion Proteins/genetics/isolation &amp; purification/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; Tetrahymena thermophila/*genetics/growth &amp; development/metabolism ; },
abstract = {We have identified two new telomere proteins, Tpt1 and Pat1, from the ciliate Tetrahymena thermophila. Although Tetrahymena telomerase is well characterized, only one telomere protein had previously been identified. This was the G-overhang binding-protein Pot1a. Tpt1 and Pat1 were isolated as Pot1a binding partners and shown to localize to telomeres. As Tpt1 and Pat1 were both found to be essential, conditional cell lines were generated to explore their function. Tpt1 depletion caused a rapid growth arrest and telomere elongation in the absence of cell division. The phenotype was similar to that seen after Pot1a depletion suggesting that Tpt1 and Pot1a function together to regulate telomere length and prevent telomere deprotection. In contrast, Pat1 depletion had a modest effect on cell growth but caused progressive telomere shortening similar to that observed upon TERT depletion. Thus Pat1 appears to be needed for telomerase to maintain the chromosome terminus. Analysis of Pot1a-Tpt1-Pat1 complex formation using purified proteins indicated that Tpt1 interacts directly with Pot1a while Pat1 interacts with Tpt1. Our results indicate that Tpt1 is the Tetrahymena equivalent of mammalian TPP1, Schizosaccharomyces pombe Tpz1, and Oxytricha nova TEBPβ.},
}
@article {pmid21900378,
year = {2011},
author = {Jendrzejewski, J and Tomsic, J and Lozanski, G and Labanowska, J and He, H and Liyanarachchi, S and Nagy, R and Ringel, MD and Kloos, RT and Heerema, NA and de la Chapelle, A},
title = {Telomere length and telomerase reverse transcriptase gene copy number in patients with papillary thyroid carcinoma.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {96},
number = {11},
pages = {E1876-80},
pmid = {21900378},
issn = {1945-7197},
support = {P01 CA124570/CA/NCI NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; P01CA124570/CA/NCI NIH HHS/United States ; P30CA16058/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Carcinoma, Papillary/*genetics/pathology ; Female ; Gene Dosage ; Humans ; Male ; Middle Aged ; RNA, Messenger/genetics ; Telomerase/*genetics ; Telomere/genetics/*pathology ; Thyroid Neoplasms/*genetics/pathology ; },
abstract = {CONTEXT: The family risk ratio for papillary thyroid carcinoma (PTC) is among the highest of all cancers. Collectively, familial cases (fPTC) and sporadic cases (sPTC) are not known to show molecular differences. However, one study reported that telomeres were markedly shorter and the telomerase reverse transcriptase (TERT) gene was amplified and up-regulated in germline DNA from patients with fPTC compared with sPTC.<br><br>OBJECTIVE: The aim of this study was to evaluate telomere length and TERT gene amplification and expression in blood samples of fPTC and sPTC patients in a genetically distinct population from the previous study.<br><br>DESIGN: In 42 fPTC and 65 sPTC patients, quantitative real-time PCR was employed to measure the relative telomere length (RTL) and TERT gene copy number and RNA level. To validate the results using alternative methods, we further studied a subset of the original cohort consisting of randomly chosen fPTC (n = 10) and sPTC (n = 14) patients and controls (n = 21) by assessing both telomere length by flow fluorescent in situ hybridization and TERT gene expression by quantitative real-time PCR.<br><br>RESULTS: RTL and TERT gene copy number did not differ between fPTC and sPTC (P = 0.957 and P = 0.998, respectively). The mean RTL and TERT gene expression were not significantly different among the groups of the validation series (P = 0.169 and P = 0.718, respectively).<br><br>CONCLUSION: Our data show no difference between familial and sporadic PTC with respect to telomere length, TERT copy number, or expression in our cohort. Further investigations in additional cohorts of patients are desirable.},
}
@article {pmid21892132,
year = {2011},
author = {Franks, I},
title = {Colorectal cancer: Telomere length and risk of CRC.},
journal = {Nature reviews. Gastroenterology &amp; hepatology},
volume = {8},
number = {9},
pages = {475},
pmid = {21892132},
issn = {1759-5053},
}
@article {pmid21888887,
year = {2011},
author = {Heaphy, CM and Subhawong, AP and Hong, SM and Goggins, MG and Montgomery, EA and Gabrielson, E and Netto, GJ and Epstein, JI and Lotan, TL and Westra, WH and Shih, IeM and Iacobuzio-Donahue, CA and Maitra, A and Li, QK and Eberhart, CG and Taube, JM and Rakheja, D and Kurman, RJ and Wu, TC and Roden, RB and Argani, P and De Marzo, AM and Terracciano, L and Torbenson, M and Meeker, AK},
title = {Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes.},
journal = {The American journal of pathology},
volume = {179},
number = {4},
pages = {1608-1615},
pmid = {21888887},
issn = {1525-2191},
support = {P50 CA058236/CA/NCI NIH HHS/United States ; P50 CA88843/CA/NCI NIH HHS/United States ; P50 CA098252/CA/NCI NIH HHS/United States ; P50 CA58236/CA/NCI NIH HHS/United States ; R01 CA113669/CA/NCI NIH HHS/United States ; T32 CA067751/CA/NCI NIH HHS/United States ; P50 CA088843/CA/NCI NIH HHS/United States ; R01 NS055089/NS/NINDS NIH HHS/United States ; P50 CA062924/CA/NCI NIH HHS/United States ; P50 CA62924/CA/NCI NIH HHS/United States ; P50 CA058184/CA/NCI NIH HHS/United States ; },
mesh = {Female ; Humans ; Male ; Neoplasms/*classification/*pathology ; Telomere/*metabolism ; *Telomere Homeostasis ; },
abstract = {Approximately 10% to 15% of human cancers lack detectable telomerase activity, and a subset of these maintain telomere lengths by the telomerase-independent telomere maintenance mechanism termed alternative lengthening of telomeres (ALT). The ALT phenotype, relatively common in subtypes of sarcomas and astrocytomas, has rarely been reported in epithelial malignancies. However, the prevalence of ALT has not been thoroughly assessed across all cancer types. We therefore comprehensively surveyed the ALT phenotype in a broad range of human cancers. In total, two independent sets comprising 6110 primary tumors from 94 different cancer subtypes, 541 benign neoplasms, and 264 normal tissue samples were assessed by combined telomere-specific fluorescence in situ hybridization and immunofluorescence labeling for PML protein. Overall, ALT was observed in 3.73% (228/6110) of all tumor specimens, but was not observed in benign neoplasms or normal tissues. This is the first report of ALT in carcinomas arising from the bladder, cervix, endometrium, esophagus, gallbladder, kidney, liver, and lung. Additionally, this is the first report of ALT in medulloblastomas, oligodendrogliomas, meningiomas, schwannomas, and pediatric glioblastoma multiformes. Previous studies have shown associations between ALT status and prognosis in some tumor types; thus, further studies are warranted to assess the potential prognostic significance and unique biology of ALT-positive tumors. These findings may have therapeutic consequences, because ALT-positive cancers are predicted to be resistant to anti-telomerase therapies.},
}
@article {pmid21886818,
year = {2011},
author = {Chico, L and Ciudad, T and Hsu, M and Lue, NF and Larriba, G},
title = {The Candida albicans Ku70 modulates telomere length and structure by regulating both telomerase and recombination.},
journal = {PloS one},
volume = {6},
number = {8},
pages = {e23732},
pmid = {21886818},
issn = {1932-6203},
support = {R01 GM069507/GM/NIGMS NIH HHS/United States ; GM069507/GM/NIGMS NIH HHS/United States ; },
mesh = {Antigens, Nuclear/genetics/*physiology ; Candida albicans/*genetics ; DNA Repair ; DNA-Binding Proteins/genetics/*physiology ; Genotype ; Ku Autoantigen ; Mutation ; *Recombination, Genetic ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {The heterodimeric Ku complex has been shown to participate in DNA repair and telomere regulation in a variety of organisms. Here we report a detailed characterization of the function of Ku70 in the diploid fungal pathogen Candida albicans. Both ku70 heterozygous and homozygous deletion mutants have a wild-type colony and cellular morphology, and are not sensitive to MMS or UV light. Interestingly, we observed complex effects of KU70 gene dosage on telomere lengths, with the KU70/ku70 heterozygotes exhibiting slightly shorter telomeres, and the ku70 null strain exhibiting long and heterogeneous telomeres. Analysis of combination mutants suggests that the telomere elongation in the ku70 null mutant is due mostly to unregulated telomerase action. In addition, elevated levels of extrachromosomal telomeric circles were detected in the null mutant, consistent with activation of aberrant telomeric recombination. Altogether, our observations point to multiple mechanisms of the Ku complex in telomerase regulation and telomere protection in C. albicans, and reveal interesting similarities and differences in the mechanisms of the Ku complex in disparate systems.},
}
@article {pmid21886188,
year = {2011},
author = {David, R},
title = {Telomeres: Fusing with RNF8.},
journal = {Nature reviews. Molecular cell biology},
volume = {12},
number = {10},
pages = {624},
pmid = {21886188},
issn = {1471-0080},
}
@article {pmid21885626,
year = {2011},
author = {Amsellem, V and Gary-Bobo, G and Marcos, E and Maitre, B and Chaar, V and Validire, P and Stern, JB and Noureddine, H and Sapin, E and Rideau, D and Hue, S and Le Corvoisier, P and Le Gouvello, S and Dubois-Randé, JL and Boczkowski, J and Adnot, S},
title = {Telomere dysfunction causes sustained inflammation in chronic obstructive pulmonary disease.},
journal = {American journal of respiratory and critical care medicine},
volume = {184},
number = {12},
pages = {1358-1366},
doi = {10.1164/rccm.201105-0802OC},
pmid = {21885626},
issn = {1535-4970},
mesh = {Adult ; Animals ; Case-Control Studies ; Endothelium, Vascular/*ultrastructure ; Female ; Humans ; Inflammation/*pathology ; Least-Squares Analysis ; Male ; Matched-Pair Analysis ; Mice ; Mice, Knockout ; Prospective Studies ; Pulmonary Disease, Chronic Obstructive/*pathology ; Smoking/adverse effects ; *Telomere Shortening ; },
abstract = {RATIONALE: Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation of unknown pathogenesis.<br><br>OBJECTIVES: To investigate whether telomere dysfunction and senescence of pulmonary vascular endothelial cells (P-ECs) induce inflammation in COPD.<br><br>METHODS: Prospective comparison of patients with COPD and age- and sex-matched control smokers. Investigation of mice null for telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes.<br><br>MEASUREMENTS AND MAIN RESULTS: In situ lung specimen studies showed a higher percentage of senescent P-ECs stained for p16 and p21 in patients with COPD than in control subjects. Cultured P-ECs from patients with COPD exhibited early replicative senescence, with decreased cell-population doublings, a higher percentage of &#x3b2;-galactosidase-positive cells, reduced telomerase activity, shorter telomeres, and higher p16 and p21 mRNA levels at an early cell passage compared with control subjects. Senescent P-ECs released cytokines and mediators: the levels of IL-6, IL-8, monocyte chemotactic protein (MCP)-1, Hu-GRO, and soluble intercellular adhesion molecule (sICAM)-1 were elevated in the media of P-ECs from patients compared with control subjects at an early cell passage, in proportion to the senescent P-EC increase and telomere shortening. Up-regulation of MCP-1 and sICAM-1 led to increased monocyte adherence and migration. The elevated MCP-1, IL-8, Hu-GRO&#x3b1;, and ICAM-1 levels measured in lungs from patients compared with control subjects correlated with P-EC senescence criteria and telomere length. In Tert(-/-) and/or Terc(-/-) mouse lungs, levels of the corresponding cytokines (MCP-1, IL-8, Hu-GRO&#x3b1;, and ICAM-1) were also altered, despite the absence of external stimuli and in proportion to telomere dysfunction.<br><br>CONCLUSIONS: Telomere dysfunction and premature P-EC senescence are major processes perpetuating lung inflammation in COPD.},
}
@article {pmid21881852,
year = {2011},
author = {Ragno, M and Pianese, L and Pinelli, M and Silvestri, S and Cacchiò, G and Di Marzio, F and Scarcella, M and Coretti, F and Altamura, F and Monticelli, A and Castaldo, I},
title = {Shorter telomeres in patients with cerebral autosomal dominant arteriopathy and leukoencephalopathy (CADASIL).},
journal = {Neurogenetics},
volume = {12},
number = {4},
pages = {337-343},
pmid = {21881852},
issn = {1364-6753},
mesh = {Adult ; Aged ; Aged, 80 and over ; CADASIL/*genetics ; Female ; Humans ; Male ; Middle Aged ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {CADASIL is a hereditary systemic vasculopathy which affects mainly small cerebral arteries and is caused by mutations in the Notch3 gene. Misfolding of Notch3 is linked to endoplasmic reticulum stress and increased reactive oxygen species, which may result in dysfunction of endothelial cells, inflammation and ischemia. Oxidative stress and inflammation may induce a rapid telomere shortening in peripheral blood leukocytes (PBLs). The aim of this study was to assess the telomere length in PBLs from 29 patients with a genetic diagnosis of CADASIL by using a modified quantitative real-time polymerase chain reaction based assay. PBL telomere length was significantly shorter in CADASIL patients (T/S ratio = 0.17, 95% CI, 0.14-0.20) than in the controls (T/S ratio = 0.31, 95% CI, 0.27-0.35, t-test p < 0.001). Moreover, patients with functional dependence displayed shorter telomeres than those with functional independence (p = 0.039). Our data provide the first evidence that PBL telomere length is shortened in CADASIL disease, and this may be a systemic oxidative stress indicator in CADASIL patients, providing a possible biomarker of disease progression and for future therapeutic strategies.},
}
@article {pmid21881613,
year = {2011},
author = {Wolinsky, H},
title = {Testing time for telomeres. Telomere length can tell us something about disease susceptibility and ageing, but are commercial tests ready for prime time?.},
journal = {EMBO reports},
volume = {12},
number = {9},
pages = {897-900},
pmid = {21881613},
issn = {1469-3178},
mesh = {*Aging/genetics ; Biomarkers ; Disease Susceptibility ; Humans ; Longevity/genetics ; Molecular Diagnostic Techniques/*methods ; Telomere/*genetics/physiology/ultrastructure ; },
}
@article {pmid21880373,
year = {2011},
author = {Elvsåshagen, T and Vera, E and Bøen, E and Bratlie, J and Andreassen, OA and Josefsen, D and Malt, UF and Blasco, MA and Boye, B},
title = {The load of short telomeres is increased and associated with lifetime number of depressive episodes in bipolar II disorder.},
journal = {Journal of affective disorders},
volume = {135},
number = {1-3},
pages = {43-50},
doi = {10.1016/j.jad.2011.08.006},
pmid = {21880373},
issn = {1573-2517},
mesh = {Adult ; Aging/genetics ; Bipolar Disorder/*genetics/psychology ; Case-Control Studies ; Cross-Sectional Studies ; Depression/*genetics/psychology ; Depressive Disorder/genetics ; Diagnostic and Statistical Manual of Mental Disorders ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes, Mononuclear ; Longitudinal Studies ; Male ; Mental Disorders/genetics ; Telomere ; *Telomere Shortening ; Time Factors ; },
abstract = {BACKGROUND: It has recently been hypothesized that bipolar disorders are associated with accelerated aging. Telomere dysfunction, a biomarker of aging, is determined by the load of short telomeres, rather than by the mean telomere length. To our knowledge, the load of short telomeres has not been reported in any psychiatric disorder. The aims of the study were to examine the load of short telomeres and the mean telomere length and their relationships with illness duration and lifetime number of depressive episodes in bipolar II disorder (BD-II).<br><br>METHODS: Twenty-eight patients (mean age=34.8 &#xb1; 7.7) with a DSM-IV diagnosis of BD-II and 28 healthy control subjects (mean age=34.8 &#xb1; 9.2) matched for age, sex, and education participated. The load of short telomeres (percentage of telomeres <3 kilobases) and mean telomere length in peripheral blood mononuclear cells were measured using high-throughput quantitative fluorescence in situ hybridization.<br><br>RESULTS: The load of short telomeres was significantly increased in patients with BD-II relative to healthy controls and may represent 13 years of accelerated aging. The load of short telomeres and the mean telomere length were associated with lifetime number of depressive episodes, but not with illness duration.<br><br>LIMITATIONS: Modest sample size and cross-sectional design.<br><br>CONCLUSIONS: Our results suggest that BD-II is associated with an increased load of short telomeres. Depressive episode-related stress may accelerate telomere shortening and aging. However, longitudinal studies are needed to fully clarify telomere shortening and its relationship with clinical variables in BD-II.},
}
@article {pmid21878343,
year = {2012},
author = {Lin, J and Epel, E and Blackburn, E},
title = {Telomeres and lifestyle factors: roles in cellular aging.},
journal = {Mutation research},
volume = {730},
number = {1-2},
pages = {85-89},
doi = {10.1016/j.mrfmmm.2011.08.003},
pmid = {21878343},
issn = {0027-5107},
mesh = {Aging/genetics ; Cellular Senescence/*genetics ; Diet ; Humans ; Leukocytes/ultrastructure ; *Life Style ; Stress, Psychological/*genetics/metabolism ; Telomere/*genetics ; *Telomere Homeostasis ; Temperament ; },
abstract = {Recent research has demonstrated that telomere maintenance might be a key integrating point for the cumulative effects of genetic, environmental and lifestyle factors on aging and aging-related diseases. It is timely to 'take stock' of where this work has led the field. This review summarizes studies that have examined associations between lifestyle factors and telomere length and telomerase activity. In most of the studies described in this chapter, telomere length was measured in leukocytes (LTL) or peripheral blood mononuclear cells (PBMCs), taken from blood draws from the study subjects. Much of this chapter focuses on psychological stress, a widespread factor often intimately tied in with lifestyle or behavioral factors that in turn are related to risks of clinical diseases. Together, these findings suggest that cellular aging is linked to a range of influences, with an individual's life events and lifestyle parameters playing significant roles. Lastly, we propose possible biochemical mechanisms that mediate these associations and discuss future directions.},
}
@article {pmid21876736,
year = {2011},
author = {Wong, LS and Huzen, J and de Boer, RA and van Gilst, WH and van Veldhuisen, DJ and van der Harst, P},
title = {Telomere length of circulating leukocyte subpopulations and buccal cells in patients with ischemic heart failure and their offspring.},
journal = {PloS one},
volume = {6},
number = {8},
pages = {e23118},
pmid = {21876736},
issn = {1932-6203},
mesh = {Adult ; Aged ; Antigens, CD34/metabolism ; Case-Control Studies ; Female ; Heart Failure/*complications/*pathology ; Humans ; Leukocytes/*pathology ; Male ; Middle Aged ; Mouth/metabolism/*pathology ; Myocardial Ischemia/*complications/*pathology ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: We aimed to find support for the hypothesis that telomere length (TL) is causally involved in the pathogenesis of ischemic heart failure (IHF). We measured TL in IHF patients and their high-risk offspring and determined whether mean leukocyte TL reflects TL in CD34+ progenitor. We additionally measured TL of offspring of patients and controls to examine heritability throughout different cell types.<br><br>METHODS AND RESULTS: TL was measured by qPCR in overall leukocytes, CD34+ progenitor cells, mononuclear cells (MNCs), and buccal cells in 27 IHF patients, 24 healthy controls and 60 offspring. TL in IHF patients was shorter than healthy controls in leukocytes (p&#x200a;=&#x200a;0.002), but not in CD34+ cells (p&#x200a;=&#x200a;0.39), MNCs (p&#x200a;=&#x200a;0.31) or buccal cells (p&#x200a;=&#x200a;0.19). Offspring of IHF patients had shorter TL in leukocytes than offspring of healthy subjects (p&#x200a;=&#x200a;0.04) but not in other cell types. Controls and offspring showed a good within person correlation between leukocytes and CD34+ cells (r 0.562; p&#x200a;=&#x200a;0.004 and r 0.602; p&#x200a;=&#x200a;0.001, respectively). In IHF patients and offspring the correlation among cell types was blunted. Finally, we found strong correlations between parent and offspring TL in all four cell types.<br><br>CONCLUSIONS: Reduced leukocyte TL in offspring of IHF subjects suggests a potential causal link of TL in ischemic heart disease. However, this causality is unlikely to originate from exhaustion of TL in CD34+ progenitor or MNC cells as their lengths are not well captured by overall leukocyte TL. Additionally, we found strong correlations between parent and offspring TL in all examined cell types, suggesting high heritability of TL among cell types.},
}
@article {pmid21873590,
year = {2011},
author = {De Meyer, T},
title = {Telomere length integrates psychological factors in the successful aging story, but what about the biology?.},
journal = {Psychosomatic medicine},
volume = {73},
number = {7},
pages = {524-527},
doi = {10.1097/PSY.0b013e31822ed876},
pmid = {21873590},
issn = {1534-7796},
mesh = {Adrenal Cortex/*physiology ; Autonomic Nervous System/*physiology ; Coronary Artery Disease/*physiopathology ; Depressive Disorder, Major/*physiopathology ; Female ; Humans ; Leukocytes/*physiology ; Male ; Mouth Mucosa/*cytology ; Telomere/*physiology ; },
}
@article {pmid21873585,
year = {2011},
author = {Kroenke, CH and Epel, E and Adler, N and Bush, NR and Obradovic, J and Lin, J and Blackburn, E and Stamperdahl, JL and Boyce, WT},
title = {Autonomic and adrenocortical reactivity and buccal cell telomere length in kindergarten children.},
journal = {Psychosomatic medicine},
volume = {73},
number = {7},
pages = {533-540},
pmid = {21873585},
issn = {1534-7796},
support = {R21 MH070950-02/MH/NIMH NIH HHS/United States ; MH 070950-02/MH/NIMH NIH HHS/United States ; },
mesh = {Adrenal Cortex/*physiology ; Aging/physiology ; Anxiety/physiopathology ; Arrhythmia, Sinus/physiopathology ; Autonomic Nervous System/*physiology ; Child ; Child, Preschool ; Depression/physiopathology ; Female ; Heart Rate/physiology ; Humans ; Hydrocortisone/analysis ; Male ; Mouth Mucosa/*cytology/physiology ; Real-Time Polymerase Chain Reaction ; Saliva/chemistry ; Stress, Psychological/physiopathology ; Telomere/*physiology ; },
abstract = {OBJECTIVE: To examine associations between autonomic nervous system and adrenocortical reactivity to laboratory stressors and buccal cell telomere length (BTL) in children.<br><br>METHODS: The study sample comprised 78 children, aged 5 to 6 years, from a longitudinal cohort study of kindergarten social hierarchies, biologic responses to adversity, and child health. Buccal cell samples and reactivity measures were collected in the spring of the kindergarten year. BTL was measured by real-time polymerase chain reaction, as the telomere-to-single-copy gene ratio. Parents provided demographic information; parents and teachers reported children's internalizing and externalizing behavior problems. Components of children's autonomic (heart rate, respiratory sinus arrhythmia [RSA], and preejection period [PEP]) and adrenocortical (salivary cortisol) responses were monitored during standardized laboratory challenges. We examined relationships between reactivity, internalizing and externalizing behaviors, and BTL, adjusted for age, race, and sex.<br><br>RESULTS: Heart rate and cortisol reactivity were inversely related to BTL, PEP was positively related to BTL, and RSA was unrelated to BTL. Internalizing behaviors were also inversely related to BTL (standardized &#x3b2; = -0.33, p = .004). Split at the median of reactivity parameters, children with high sympathetic activation (decreasing PEP), and parasympathetic withdrawal (decreasing RSA) did not differ with regard to BTL. However, children with both this profile and high cortisol reactivity (n = 12) had significantly shorter BTL (0.80 versus 1.00; &#x3c7;&#xb2; = 7.6, p = .006), compared with other children.<br><br>CONCLUSIONS: The combination of autonomic and adrenocortical reactivity was associated with shorter BTL in children. These data suggest that psychophysiological processes may influence, and that BTL may be a useful marker of, early biologic aging.},
}
@article {pmid21873561,
year = {2011},
author = {Xiao, F and Zheng, X and Cui, M and Shi, G and Chen, X and Li, R and Song, Z and Rudolph, KL and Chen, B and Ju, Z},
title = {Telomere dysfunction-related serological markers are associated with type 2 diabetes.},
journal = {Diabetes care},
volume = {34},
number = {10},
pages = {2273-2278},
pmid = {21873561},
issn = {1935-5548},
mesh = {Acetylglucosaminidase/blood ; Age Factors ; Diabetes Mellitus, Type 2/*blood/*genetics/pathology ; Humans ; Ion Channels/genetics ; Mitochondrial Proteins/genetics ; Peptide Elongation Factor 1/blood ; Real-Time Polymerase Chain Reaction ; Stathmin/blood ; Telomere/*genetics/*pathology ; Uncoupling Protein 2 ; },
abstract = {OBJECTIVE: Recent studies have identified a set of serological markers for telomere dysfunction and DNA damage. The relevance of these serological markers in type 2 diabetes remains elusive. We investigated the association of serological markers (elongation factor 1α [EF-1α], stathmin, and N-acetyl-glucosaminidase) with leukocyte telomere length, a functional variant of uncoupling protein-2 (UCP2), and susceptibility of type 2 diabetes.<br><br>RESEARCH DESIGN AND METHODS: A total of 930 patients and 867 control subjects were recruited to examine the association between leukocyte telomere length, UCP2 variant (-886G>A), recently identified serological markers, and type 2 diabetes. Telomere length was determined by a quantitative real-time PCR-based assay. EF-1&#x3b1;, stathmin, and C-reactive proteins were measured by enzyme-linked immunosorbent assays. N-acetyl-glucosaminidase was measured by an enzyme activity assay. The UCP2 variant was determined by PCR and restriction enzyme digestion.<br><br>RESULTS: The average telomere length of type 2 diabetic patients was significantly shorter than that of control subjects. Serological N-acetyl-glucosaminidase correlates with both age and telomere length and was significantly higher in patients than in control subjects. Neither EF-1&#x3b1; nor stathmin showed significant difference between patients and control subjects. The UCP2-886G>A variant correlated with type 2 diabetes status but did not correlate with telomere length or the serological markers. Multivariate analysis showed that higher serological N-acetyl-glucosaminidase, shorter telomeres, and the UCP2-886G>A variant are independent risk factors for type 2 diabetes.<br><br>CONCLUSIONS: Serological N-acetyl-glucosaminidase, telomere length, and the UCP2-886G>A variant are independent risk factors for type 2 diabetes. Serological N-acetyl-glucosaminidase correlates with telomere length but not with the UCP2-886G>A variant.},
}
@article {pmid21873233,
year = {2011},
author = {Varela, E and Schneider, RP and Ortega, S and Blasco, MA},
title = {Different telomere-length dynamics at the inner cell mass versus established embryonic stem (ES) cells.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {108},
number = {37},
pages = {15207-15212},
pmid = {21873233},
issn = {1091-6490},
support = {232854/ERC_/European Research Council/International ; },
mesh = {Animals ; Blastocyst/cytology/*metabolism ; Cell Aggregation ; Cell Line ; Cell Proliferation ; Cell Separation ; Embryonic Stem Cells/cytology/*metabolism ; Heterochromatin/metabolism ; Mice ; Mice, Inbred C57BL ; Octamer Transcription Factor-3/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; },
abstract = {Murine embryonic stem (ES) cells have unusually long telomeres, much longer than those in embryonic tissues. Here we address whether hyper-long telomeres are a natural property of pluripotent stem cells, such as those present at the blastocyst inner cell mass (ICM), or whether it is a characteristic acquired by the in vitro expansion of ES cells. We find that ICM cells undergo telomere elongation during the in vitro derivation of ES-cell lines. In vivo analysis shows that the hyper-long telomeres of morula-injected ES cells remain hyper-long at the blastocyst stage and longer than telomeres of the blastocyst ICM. Telomere lengthening during derivation of ES-cell lines is concomitant with a decrease in heterochromatic marks at telomeres. We also found increased levels of the telomere repeat binding factor 1 (TRF1) telomere-capping protein in cultured ICM cells before telomere elongation occurs, coinciding with expression of pluripotency markers. These results suggest that high TRF1 levels are present in pluripotent cells, most likely to ensure proficient capping of the newly synthesized telomeres. These results highlight a previously unnoticed difference between ICM cells at the blastocyst and ES cells, and suggest that abnormally long telomeres in ES cells are likely to result from continuous telomere lengthening of proliferating ICM cells locked at an epigenetic state associated to pluripotency.},
}
@article {pmid21870178,
year = {2012},
author = {Rius-Ottenheim, N and Houben, JM and Kromhout, D and Kafatos, A and van der Mast, RC and Zitman, FG and Geleijnse, JM and Hageman, GJ and Giltay, EJ},
title = {Telomere length and mental well-being in elderly men from the Netherlands and Greece.},
journal = {Behavior genetics},
volume = {42},
number = {2},
pages = {278-286},
pmid = {21870178},
issn = {1573-3297},
mesh = {Aged ; Aged, 80 and over ; Aging/*genetics/*psychology ; Cohort Studies ; Depression/*genetics/psychology ; Greece ; Humans ; Leukocytes/metabolism ; Male ; *Mental Health ; Netherlands ; Neuropsychological Tests ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres, repetitive DNA sequences that promote chromosomal stability, have been related to different measures of mental well-being and self-rated health, but mainly in women during adulthood. We aimed to investigate whether accelerated telomere shortening is associated with poor mental well-being and poor self-rated health in community-dwelling elderly men. Leukocyte telomere length was measured using quantitative PCR in two different samples of 203 elderly men (mean age 78 years) from the Netherlands in 1993, and 123 elderly men (mean age 84 years) from Greece in 2000. We also obtained follow-up data in 2000 from 144 Dutch subjects, of whom 75 had paired telomere length data in 1993 and 2000. Mental well-being was conceptualized as dispositional optimism, depressive symptoms, cognitive functioning, and loneliness. Linear regression analyses were used to study the association between telomere length, measures of mental well being, and self-rated health, while adjusting for potential confounders. In cross-sectional analyses, leukocyte telomere length was not associated with measures of mental well-being and self-rated health, neither in the Netherlands nor in Greece. Also, the rate of leukocyte telomere shortening (mean decrease: 0.28 kbp over 7 years) in the 75 Dutch participants with longitudinal data was not associated with changes in different measures of mental well-being and self-rated health. Thus, our results provide no support for a relationship between leukocyte telomere length and mental well-being in elderly community-dwelling men.},
}
@article {pmid21867906,
year = {2011},
author = {McCarthy, A},
title = {Taking stock of telomere length at telome health.},
journal = {Chemistry &amp; biology},
volume = {18},
number = {8},
pages = {937-938},
doi = {10.1016/j.chembiol.2011.08.004},
pmid = {21867906},
issn = {1879-1301},
mesh = {*Genetic Techniques ; Health ; Humans ; Nobel Prize ; Telomere/*chemistry ; },
}
@article {pmid21866390,
year = {2011},
author = {Majerová, E and Fojtová, M and Mozgová, I and Bittová, M and Fajkus, J},
title = {Hypomethylating drugs efficiently decrease cytosine methylation in telomeric DNA and activate telomerase without affecting telomere lengths in tobacco cells.},
journal = {Plant molecular biology},
volume = {77},
number = {4-5},
pages = {371-380},
pmid = {21866390},
issn = {1573-5028},
mesh = {Adenine/*analogs &amp; derivatives/pharmacology ; Cells, Cultured ; Cytidine/*analogs &amp; derivatives/pharmacology ; DNA Methylation/drug effects ; DNA, Plant/chemistry/*drug effects ; Enzyme Activation/drug effects ; Epigenesis, Genetic ; Nucleosomes/drug effects/physiology ; Plant Proteins/genetics/metabolism ; Telomerase/*metabolism ; Telomere/chemistry/*drug effects/metabolism ; Nicotiana/cytology/*drug effects/genetics/metabolism ; Transcription, Genetic/drug effects ; },
abstract = {Telomere homeostasis is regulated at multiple levels, including the local chromatin structure of telomeres and subtelomeres. Recent reports demonstrated that a decrease in repressive chromatin marks, such as levels of cytosine methylation in subtelomeric regions, results in telomere elongation in mouse cells. Here we show that a considerable fraction of cytosines is methylated not only in subtelomeric, but also in telomeric DNA of tobacco BY-2 cells. Drug-induced hypomethylation (demonstrated at subtelomeric, telomeric, and global DNA levels) results in activation of telomerase. However, in contrast to mouse cells, the decrease in 5-methylcytosine levels and upregulation of telomerase do not result in any changes of telomere lengths. These results demonstrate the involvement of epigenetic mechanisms in the multilevel process of regulation of telomerase activity in plant cells and, at the same time, they indicate that changes in telomerase activity can be overridden by other factors governing telomere length stability.},
}
@article {pmid21865371,
year = {2011},
author = {Capezzone, M and Cantara, S and Marchisotta, S and Busonero, G and Formichi, C and Benigni, M and Capuano, S and Toti, P and Pazaitou-Panayiotou, K and Caruso, G and Carli, AF and Palummo, N and Pacini, F},
title = {Telomere length in neoplastic and nonneoplastic tissues of patients with familial and sporadic papillary thyroid cancer.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {96},
number = {11},
pages = {E1852-6},
doi = {10.1210/jc.2011-1003},
pmid = {21865371},
issn = {1945-7197},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Papillary/*genetics/pathology ; Female ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Telomere/genetics/*pathology ; Thyroid Gland/*pathology ; Thyroid Neoplasms/*genetics/pathology ; },
abstract = {INTRODUCTION: Many studies have found an association between altered telomere length (TL), both attrition or elongation, and cancer phenotype. Recently, we have reported that patients with the familial form of papillary thyroid cancer (FPTC) have short telomeres in blood leucocytes.<br><br>AIM: To evaluate relative TL (RTL) at somatic level in neoplastic and nonneoplastic tissues of patients with FPTC (n = 30) and sporadic PTC (n = 46).<br><br>METHODS: RTL was measured by quantitative PCR in neoplastic thyroid tissues, in the corresponding nontumor thyroid tissues (normal contralateral thyroid), and in other extrathyroidal tissues (lymph nodes, muscles, or buccal mucosa). RTL was also measured in adenomas and hyperplastic nodules. In a subset of samples, telomerase expression was measured by quantitative PCR.<br><br>RESULTS: Mean &#xb1; SD RTL of FPTC patients was short in neoplastic thyroid tissues (0.87 &#xb1; 0.2) with no difference from the normal contralateral thyroid tissues (0.85 &#xb1; 0.11) and extrathyroidal tissues (0.85 &#xb1; 0.31). On the contrary, in patients with sporadic PTC, the mean &#xb1; SD RTL in the neoplastic tissues (1.73 &#xb1; 0.63) was significantly shorter than that found in normal contralateral tissues (2.58 &#xb1; 0.89) and extrathyroidal tissues (2.5 &#xb1; 0.86). For all tissue samples (cancer, normal thyroid, and nonthyroidal tissues) the mean &#xb1; SD RTL of familial cases was shorter (P < 0.0001) than that found in tissues from sporadic PTC. RTL of FPTC was also lower (P < 0.0001) than that of 23 follicular adenomas (1.6 &#xb1; 0.7) and 24 hyperplastic nodules (2.2 &#xb1; 0.9).<br><br>CONCLUSIONS: Our results demonstrate that short telomeres are a consistent feature of PTC, which in familial cases, is not restricted to the tumor tissue. This finding suggests that FPTC has a distinct, heritable, genetic background.},
}
@article {pmid21865325,
year = {2011},
author = {Canudas, S and Houghtaling, BR and Bhanot, M and Sasa, G and Savage, SA and Bertuch, AA and Smith, S},
title = {A role for heterochromatin protein 1γ at human telomeres.},
journal = {Genes &amp; development},
volume = {25},
number = {17},
pages = {1807-1819},
pmid = {21865325},
issn = {1549-5477},
support = {R01 CA116352/CA/NCI NIH HHS/United States ; N02CP65501/CP/NCI NIH HHS/United States ; N02CP11019/CP/NCI NIH HHS/United States ; N02CP65504/CP/NCI NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Cell Line ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/*metabolism ; Dyskeratosis Congenita/genetics ; HeLa Cells ; Humans ; Male ; Molecular Sequence Data ; Mutation/genetics ; Protein Binding/genetics ; S Phase/genetics ; Shelterin Complex ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/metabolism ; },
abstract = {Human telomere function is mediated by shelterin, a six-subunit complex that is required for telomere replication, protection, and cohesion. TIN2, the central component of shelterin, has binding sites to three subunits: TRF1, TRF2, and TPP1. Here we identify a fourth partner, heterochromatin protein 1γ (HP1γ), that binds to a conserved canonical HP1-binding motif, PXVXL, in the C-terminal domain of TIN2. We show that HP1γ localizes to telomeres in S phase, where it is required to establish/maintain cohesion. We further demonstrate that the HP1-binding site in TIN2 is required for sister telomere cohesion and can impact telomere length maintenance by telomerase. Remarkably, the PTVML HP1-binding site is embedded in the recently identified cluster of mutations in TIN2 that gives rise to dyskeratosis congenita (DC), an inherited bone marrow failure syndrome caused by defects in telomere maintenance. We show that DC-associated mutations in TIN2 abrogate binding to HP1γ and that DC patient cells are defective in sister telomere cohesion. Our data indicate a novel requirement for HP1γ in the establishment/maintenance of cohesion at human telomeres and, furthermore, may provide insight into the mechanism of pathogenesis in TIN2-mediated DC.},
}
@article {pmid21860014,
year = {2011},
author = {Smith, DL and Mattison, JA and Desmond, RA and Gardner, JP and Kimura, M and Roth, GS and Ingram, DK and Allison, DB and Aviv, A},
title = {Telomere dynamics in rhesus monkeys: no apparent effect of caloric restriction.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {66},
number = {11},
pages = {1163-1168},
pmid = {21860014},
issn = {1758-535X},
support = {P30 AI027767/AI/NIAID NIH HHS/United States ; T32 DK062710/DK/NIDDK NIH HHS/United States ; AG 020132/AG/NIA NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; P30 DK056336/DK/NIDDK NIH HHS/United States ; AG 021593/AG/NIA NIH HHS/United States ; },
mesh = {Adipose Tissue/cytology ; Animals ; Blotting, Southern ; *Caloric Restriction ; Female ; Leukocytes/cytology ; Macaca mulatta ; Male ; Muscle, Skeletal/cytology ; Skin/cytology ; Telomere/*physiology/*ultrastructure ; },
abstract = {The role of telomere attrition in limiting the replicative capacity of cells in culture is well established. In humans, epidemiologic evidence suggests telomere length (TL) in leukocytes is highly variable at birth and inversely related to age. Although calorie restriction (CR) significantly increases life span in most rodent models, its association with TL is unknown. Using linear regression analysis, TLs (as measured by Southern blot analysis) of skeletal muscle (a postmitotic tissue that largely represents early development TL), fat, leukocytes, and skin were tested for effects of age, sex, and diet in 48 control and 23 calorie restriction rhesus monkeys. After controlling for the individual's muscle mean TL, differences between leukocytes muscle and skin muscle were significantly associated with age (p = .002; p = .002) and sex (p = .003; p = .042), but not calorie restriction (p = .884; p = .766). Despite an age-dependent shortening of TL in leukocytes and skin, calorie restriction did not significantly affect TL dynamics in these samples.},
}
@article {pmid21857671,
year = {2011},
author = {Peuscher, MH and Jacobs, JJ},
title = {DNA-damage response and repair activities at uncapped telomeres depend on RNF8.},
journal = {Nature cell biology},
volume = {13},
number = {9},
pages = {1139-1145},
pmid = {21857671},
issn = {1476-4679},
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/metabolism ; Cells, Cultured ; Chromatin/genetics/metabolism ; *DNA Damage ; *DNA Repair ; DNA-Binding Proteins/genetics/*metabolism ; Embryo, Mammalian/cytology ; Fibroblasts/cytology/metabolism ; Genomic Instability ; HEK293 Cells ; Histones/metabolism ; Humans ; Immunoblotting ; In Situ Hybridization, Fluorescence ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Mice ; Mice, Knockout ; Phosphorylation ; Protein Serine-Threonine Kinases/genetics/metabolism ; RNA Interference ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Tumor Suppressor Proteins/genetics/metabolism ; Tumor Suppressor p53-Binding Protein 1 ; Ubiquitin-Protein Ligases/genetics/*metabolism ; Ubiquitination ; },
abstract = {Loss of telomere protection causes natural chromosome ends to become recognized by DNA-damage response and repair proteins. These events result in ligation of chromosome ends with dysfunctional telomeres, thereby causing chromosomal aberrations on cell division. The control of these potentially dangerous events at deprotected chromosome ends with their unique telomeric chromatin configuration is poorly understood. In particular, it is unknown to what extent bulky modification of telomeric chromatin is involved. Here we show that uncapped telomeres accumulate ubiquitylated histone H2A in a manner dependent on the E3 ligase RNF8. The ability of RNF8 to ubiquitylate telomeric chromatin is associated with its capacity to facilitate accumulation of both 53BP1 and phospho-ATM at uncapped telomeres and to promote non-homologous end-joining of deprotected chromosome ends. In line with the detrimental effect of RNF8 on uncapped telomeres, depletion of RNF8, as well as of the E3 ligase RNF168, reduces telomere-induced genome instability. This indicates that, besides suppressing tumorigenesis by mediating repair of DNA double-strand breaks, RNF8 and RNF168 might enhance cancer development by aggravating telomere-induced genome instability.},
}
@article {pmid21857007,
year = {2012},
author = {Marcon, F and Siniscalchi, E and Crebelli, R and Saieva, C and Sera, F and Fortini, P and Simonelli, V and Palli, D},
title = {Diet-related telomere shortening and chromosome stability.},
journal = {Mutagenesis},
volume = {27},
number = {1},
pages = {49-57},
pmid = {21857007},
issn = {1464-3804},
mesh = {Antioxidants/administration &amp; dosage ; Biomarkers/analysis ; *Chromosomal Instability ; *Diet ; Female ; Genotype ; Humans ; Life Style ; Lymphocytes/pathology ; Male ; Micronucleus Tests ; Micronutrients/administration &amp; dosage ; Middle Aged ; Oxidative Stress/drug effects ; Sequence Analysis, DNA ; Smoking/adverse effects ; Surveys and Questionnaires ; Telomere/pathology ; *Telomere Shortening ; Vegetables ; beta Carotene/administration &amp; dosage ; },
abstract = {Recent evidences have highlighted an influence of micronutrients in the maintenance of telomere length (TL). In order to explore whether diet-related telomere shortening had any physiological relevance and was accompanied by significant damage in the genome, in the present study, TL was assessed by terminal restriction fragment (TRF) analysis in peripheral blood lymphocytes of 56 healthy subjects for which detailed information on dietary habits was available and data were compared \with the incidence of nucleoplasmic bridges (NPBs), a marker of chromosomal instability related to telomere dysfunction visualised with the cytokinesis-blocked micronucleus assay. To increase the capability to detect even slight impairment of telomere function, the incidence of NPBs was also evaluated on cells exposed in vitro to ionising radiation. Care was taken to control for potential confounding factors that might influence TL, viz. age, hTERT genotype and smoking status. Data showed that higher consumption of vegetables was related with significantly higher mean TL (P = 0.013); in particular, the analysis of the association between micronutrients and mean TL highlighted a significant role of antioxidant intake, especially beta-carotene, on telomere maintenance (P = 0.004). However, the diet-related telomere shortening did not result in associated increased spontaneous or radiation-induced NPBs. The distribution of TRFs was also analysed and a slight prevalence of radiation-induced NPBs (P = 0.03) was observed in subjects with higher amount of very short TRFs (<2 kb). The relative incidence of very short TRFs was positively associate with ageing (P = 0.008) but unrelated to vegetables consumption and daily intake of micronutrients, suggesting that the degree of telomere erosion related with low dietary intake of antioxidants observed in this study was not so extensive to lead to chromosome instability.},
}
@article {pmid21857006,
year = {2012},
author = {Bolzán, AD},
title = {Chromosomal aberrations involving telomeres and interstitial telomeric sequences.},
journal = {Mutagenesis},
volume = {27},
number = {1},
pages = {1-15},
doi = {10.1093/mutage/ger052},
pmid = {21857006},
issn = {1464-3804},
mesh = {Animals ; Centromere/genetics ; Chromatids/genetics ; Chromosome Disorders/genetics ; *Chromosome Duplication ; DNA/genetics ; Humans ; In Situ Hybridization, Fluorescence/methods ; Mutagens ; Repetitive Sequences, Nucleic Acid ; Sequence Analysis, DNA ; Sister Chromatid Exchange ; Telomere/*genetics ; },
abstract = {Telomeres are specialised nucleoproteic complexes localised at the physical ends of linear eukaryotic chromosomes that maintain their stability and integrity. In vertebrate chromosomes, the DNA component of telomeres is constituted by (TTAGGG)n repeats, which can be localised at the terminal regions of chromosomes (true telomeres) or at intrachromosomal sites (interstitial telomeric sequences or ITSs, located at the centromeric region or between the centromere and the telomere). In the past two decades, the use of molecular cytogenetic techniques has led to a new spectrum of spontaneous and clastogen-induced chromosomal aberrations being identified, involving telomeres and ITSs. Some aberrations involve the chromosome ends and, indirectly, the telomeric repeats located at the terminal regions of chromosomes (true telomeres). A second type of aberrations directly involves the telomeric sequences located at the chromosome ends. Finally, there is a third class of aberrations that specifically involves the ITSs. The aims of this review are to provide a detailed description of these aberrations and to summarise the available data regarding their induction by physical and chemical mutagens.},
}
@article {pmid21853136,
year = {2011},
author = {Liang, G and Schernhammer, E and Qi, L and Gao, X and De Vivo, I and Han, J},
title = {Associations between rotating night shifts, sleep duration, and telomere length in women.},
journal = {PloS one},
volume = {6},
number = {8},
pages = {e23462},
pmid = {21853136},
issn = {1932-6203},
support = {P01 CA087969/CA/NCI NIH HHS/United States ; R03 CA133914/CA/NCI NIH HHS/United States ; CA87969/CA/NCI NIH HHS/United States ; CA49449/CA/NCI NIH HHS/United States ; CA133914/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; U01 CA049449/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aging/blood ; Female ; Humans ; Middle Aged ; Sleep/*physiology ; Telomere/*metabolism ; *Telomere Homeostasis ; Work Schedule Tolerance/*physiology ; },
abstract = {BACKGROUND: Telomere length has been proposed as a marker of aging. However, our knowledge of lifestyle risk factors determining telomere length is limited.<br><br>METHODS: We evaluated the associations between years of rotating night shifts, self-reported sleep duration, and telomere length in 4,117 female participants from the Nurses' Health Study. Telomere length in peripheral blood leukocytes was determined by Real-Time PCR assay. Information on rotating night shifts and sleep duration was collected via questionnaires prior to blood collection. We used multivariable linear regression to investigate the associations between rotating night shifts, sleep duration, and telomere length.<br><br>RESULTS: Compared with women in the category (9 hours), those in the lowest category of sleep duration (&#x2264;6 hours) had a 0.12 unit decrease in z score after adjustment for age, BMI and cigarette smoking (equivalent to 9-year telomere attrition, P for trend &#x200a;=&#x200a;0.05). Significant positive association between sleep duration and telomere length was seen among women under age of 50 (P for trend &#x200a;=&#x200a;0.004), but not among those over 50 (P for trend &#x200a;=&#x200a;0.33) (P for interaction &#x200a;=&#x200a;0.005). In addition, we observed that women with a longer history of rotating night shifts tended to have shorter telomere length, but this relation was not statistically significant (P for trend &#x200a;=&#x200a;0.36).<br><br>CONCLUSION: We found that sleep duration was positively associated with telomere length among women under 50 years old. Further research is needed to confirm the observed associations.},
}
@article {pmid21847107,
year = {2011},
author = {Tennen, RI and Bua, DJ and Wright, WE and Chua, KF},
title = {SIRT6 is required for maintenance of telomere position effect in human cells.},
journal = {Nature communications},
volume = {2},
number = {},
pages = {433},
pmid = {21847107},
issn = {2041-1723},
support = {AG01228/AG/NIA NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; K08 AG028961/AG/NIA NIH HHS/United States ; 1018438-142-PABCA//PHS HHS/United States ; R01 AG028867/AG/NIA NIH HHS/United States ; },
mesh = {Chromatin/genetics/metabolism ; Gene Silencing ; HeLa Cells ; Humans ; Sirtuins/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {In Saccharomyces cerevisiae, the repressive chromatin environment at telomeres gives rise to telomere position effect (TPE), the epigenetic silencing of telomere-proximal genes. Chromatin-modifying factors that control TPE in yeast have been extensively studied, and, among these, the lifespan regulator and silencing protein Sir2 has a pivotal role. In contrast, the factors that generate and maintain silent telomeric chromatin in human cells remain largely unknown. Here we show that the Sir2 family member SIRT6 is required for maintenance of TPE in human cells. RNAi-mediated depletion of SIRT6 abrogates silencing of both an integrated telomeric transgene and an endogenous telomere-proximal gene. Moreover, enhanced telomeric silencing in response to telomere elongation is associated with increased repressive chromatin marks, and this heterochromatic milieu is lost in SIRT6-deficient cells. Together, these findings establish a new role for SIRT6 in regulating an ageing-associated epigenetic silencing process and provide new mechanistic insight into chromatin silencing at telomeres.},
}
@article {pmid21846102,
year = {2011},
author = {Chen, CY and Wang, Q and Liu, JQ and Hao, YH and Tan, Z},
title = {Contribution of telomere G-quadruplex stabilization to the inhibition of telomerase-mediated telomere extension by chemical ligands.},
journal = {Journal of the American Chemical Society},
volume = {133},
number = {38},
pages = {15036-15044},
doi = {10.1021/ja204326w},
pmid = {21846102},
issn = {1520-5126},
mesh = {Carbazoles/chemistry/*pharmacology ; Dose-Response Relationship, Drug ; *G-Quadruplexes ; Humans ; Indoles/chemistry/*pharmacology ; Ligands ; Organometallic Compounds/chemistry/*pharmacology ; Pyridinium Compounds/chemistry/*pharmacology ; Structure-Activity Relationship ; Telomerase/*antagonists &amp; inhibitors/genetics/metabolism ; Telomere/*chemistry ; },
abstract = {Inhibition of telomerase activity through stabilizing telomere G-quadruplex with small chemical ligands is emerging as a novel strategy for cancer therapy. For the large number of ligands that have been reported to inhibit telomerase activity, it is difficult to validate the contribution of G-quadruplex stabilization to the overall inhibition. Using a modified telomere repeat amplification protocol (TRAP) method to differentiate the telomere G-quadruplex independent effect from dependent ones, we analyzed several ligands that have high affinity and/or selectivity to telomere G-quadruplex. Our results show that these ligands effectively inhibited telomerase activity in the absence of telomere G-quadruplex. The expected G-quadruplex-dependent inhibition was only obvious for the cationic ligands at low K(+) concentration, but it dramatically decreased at physiological concentration of K(+). These observations demonstrate that the ligands are much more than G-quadruplex stabilizers with a strong G-quadruplex-irrelevant off-target effect. They inhibit telomerase via multiple pathways in which stabilization of telomere G-quadruplex may only make a minor or neglectable contribution under physiologically relevant conditions depending on the stability of telomere G-quadruplex under ligand-free conditions.},
}
@article {pmid21844336,
year = {2011},
author = {Park, S and Patterson, EE and Cobb, J and Audhya, A and Gartenberg, MR and Fox, CA},
title = {Palmitoylation controls the dynamics of budding-yeast heterochromatin via the telomere-binding protein Rif1.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {108},
number = {35},
pages = {14572-14577},
pmid = {21844336},
issn = {1091-6490},
support = {R01 GM56890/GM/NIGMS NIH HHS/United States ; GM56890/GM/NIGMS NIH HHS/United States ; R01 GM051402/GM/NIGMS NIH HHS/United States ; F31 GM078746/GM/NIGMS NIH HHS/United States ; R01 GM056890/GM/NIGMS NIH HHS/United States ; T32 GM007133/GM/NIGMS NIH HHS/United States ; 5 T32 GM07133/GM/NIGMS NIH HHS/United States ; GM078746/GM/NIGMS NIH HHS/United States ; R01 GM088151/GM/NIGMS NIH HHS/United States ; GM51402/GM/NIGMS NIH HHS/United States ; },
mesh = {Acylation ; Acyltransferases/physiology ; Heterochromatin/*metabolism ; Lipoylation ; Repressor Proteins/*physiology ; Saccharomyces cerevisiae Proteins/*physiology ; Saccharomycetales/*genetics ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics ; Telomere ; Telomere-Binding Proteins/*physiology ; },
abstract = {The posttranslational addition of palmitate to cysteines occurs ubiquitously in eukaryotic cells, where it functions in anchoring target proteins to membranes and in vesicular trafficking. Here we show that the Saccharomyces cerevisiae palmitoyltransferase Pfa4 enhanced heterochromatin formation at the cryptic mating-type loci HMR and HML via Rif1, a telomere regulatory protein. Acylated Rif1 was detected in extracts from wild-type but not pfa4Δ mutant cells. In a pfa4Δ mutant, Rif1-GFP dispersed away from foci positioned at the nuclear periphery into the nucleoplasm. Sir3-GFP distribution was also perturbed, indicating a change in the nuclear dynamics of heterochromatin proteins. Genetic analyses indicated that PFA4 functioned upstream of RIF1. Surprisingly, the pfa4Δ mutation had only mild effects on telomeric regulation, suggesting Rif1's roles at HM loci and telomeres were more complexly related than previously thought. These data supported a model in which Pfa4-dependent palmitoylation of Rif1 anchored it to the inner nuclear membrane, influencing its role in heterochromatin dynamics.},
}
@article {pmid21830498,
year = {2011},
author = {Viidik, A},
title = {[The long way towards selling telomere lengths?].},
journal = {Lakartidningen},
volume = {108},
number = {24-25},
pages = {1288-1289},
pmid = {21830498},
issn = {0023-7205},
mesh = {Aging ; Chronic Disease ; *Cytological Techniques ; Disease Susceptibility ; Humans ; In Situ Hybridization, Fluorescence ; Polymerase Chain Reaction ; Telomerase/metabolism ; *Telomere/physiology/ultrastructure ; },
}
@article {pmid21829595,
year = {2011},
author = {O'Bryan, JM and Potts, JA and Bonkovsky, HL and Mathew, A and Rothman, AL and , },
title = {Extended interferon-alpha therapy accelerates telomere length loss in human peripheral blood T lymphocytes.},
journal = {PloS one},
volume = {6},
number = {8},
pages = {e20922},
pmid = {21829595},
issn = {1932-6203},
support = {M01RR-00042/RR/NCRR NIH HHS/United States ; N01-DK-9-2324/DK/NIDDK NIH HHS/United States ; U19 AI057319/AI/NIAID NIH HHS/United States ; 1 UL1 RR024986/RR/NCRR NIH HHS/United States ; N01-DK-9-2321/DK/NIDDK NIH HHS/United States ; U19AI057319/AI/NIAID NIH HHS/United States ; P01 AI049320/AI/NIAID NIH HHS/United States ; M01 RR006192/RR/NCRR NIH HHS/United States ; M01 RR000633/RR/NCRR NIH HHS/United States ; UL1 RR024982/RR/NCRR NIH HHS/United States ; N01-DK-9-2326/DK/NIDDK NIH HHS/United States ; N01-DK-9-2323/DK/NIDDK NIH HHS/United States ; M01 RR000042/RR/NCRR NIH HHS/United States ; UL1 RR024986/RR/NCRR NIH HHS/United States ; 1 UL1RR024982-01/RR/NCRR NIH HHS/United States ; N01-DK-9-2325/DK/NIDDK NIH HHS/United States ; M01 RR000043/RR/NCRR NIH HHS/United States ; T32 AI007349/AI/NIAID NIH HHS/United States ; M01RR-00633/RR/NCRR NIH HHS/United States ; M01RR-00043/RR/NCRR NIH HHS/United States ; M01RR-06192/RR/NCRR NIH HHS/United States ; },
mesh = {Alanine Transaminase/blood ; Antigens, CD/immunology ; Aspartate Aminotransferases/blood ; Drug Therapy, Combination ; Flow Cytometry ; Hepatitis C/*drug therapy ; Humans ; In Situ Hybridization, Fluorescence ; Interferon-alpha/administration &amp; dosage/*therapeutic use ; Ribavirin/administration &amp; dosage/*therapeutic use ; T-Lymphocytes/immunology/*ultrastructure ; *Telomere ; Viral Load ; },
abstract = {BACKGROUND: Type I interferons have pleiotropic effects on host cells, including inhibiting telomerase in lymphocytes and antiviral activity. We tested the hypothesis that long-term interferon treatment would result in significant reduction in average telomere length in peripheral blood T lymphocytes.<br><br>METHODS/PRINCIPAL FINDINGS: Using a flow cytometry-based telomere length assay on peripheral blood mononuclear cell samples from the Hepatitis-C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study, we measured T cell telomere lengths at screening and at months 21 and 45 in 29 Hepatitis-C virus infected subjects. These subjects had failed to achieve a sustained virologic response following 24 weeks of pegylated-interferon-alpha plus ribavirin treatment and were subsequently randomized to either a no additional therapy group or a maintenance dose pegylated-IFN&#x3b1; group for an additional 3.5 years. Significant telomere loss in na&#xef;ve T cells occurred in the first 21 months in the interferon-alpha group. Telomere losses were similar in both groups during the final two years. Expansion of CD8(+)CD45RA(+)CD57(+) memory T cells and an inverse correlation of alanine aminotransferase levels with na&#xef;ve CD8(+) T cell telomere loss were observed in the control group but not in the interferon-alpha group. Telomere length at screening inversely correlated with Hepatitis-C viral load and body mass index.<br><br>CONCLUSIONS/SIGNIFICANCE: Sustained interferon-alpha treatment increased telomere loss in na&#xef;ve T cells, and inhibited the accumulation of T cell memory expansions. The durability of this effect and consequences for immune senescence need to be defined.},
}
@article {pmid21829450,
year = {2011},
author = {Wang, CY and Hua, CY and Hsu, HE and Hsu, CL and Tseng, HY and Wright, DE and Hsu, PH and Jen, CH and Lin, CY and Wu, MY and Tsai, MD and Kao, CF},
title = {The C-terminus of histone H2B is involved in chromatin compaction specifically at telomeres, independently of its monoubiquitylation at lysine 123.},
journal = {PloS one},
volume = {6},
number = {7},
pages = {e22209},
pmid = {21829450},
issn = {1932-6203},
mesh = {Acetylation ; Biomarkers/metabolism ; Blotting, Western ; *Chromatin Assembly and Disassembly ; Chromatin Immunoprecipitation ; Fluorescent Antibody Technique ; Gene Expression Profiling ; Heterochromatin/genetics ; Histones/chemistry/*metabolism ; Lysine/chemistry/*metabolism ; Nucleosomes/genetics ; Oligonucleotide Array Sequence Analysis ; RNA, Fungal/genetics ; RNA, Messenger/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Saccharomyces cerevisiae/genetics/growth &amp; development/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/*metabolism ; Telomere/*physiology ; Ubiquitin/*metabolism ; Ubiquitination ; },
abstract = {Telomeric heterochromatin assembly in budding yeast propagates through the association of Silent Information Regulator (SIR) proteins with nucleosomes, and the nucleosome array has been assumed to fold into a compacted structure. It is believed that the level of compaction and gene repression within heterochromatic regions can be modulated by histone modifications, such as acetylation of H3 lysine 56 and H4 lysine 16, and monoubiquitylation of H2B lysine 123. However, it remains unclear as to whether or not gene silencing is a direct consequence of the compaction of chromatin. Here, by investigating the role of the carboxy-terminus of histone H2B in heterochromatin formation, we identify that the disorderly compaction of chromatin induced by a mutation at H2B T122 specifically hinders telomeric heterochromatin formation. H2B T122 is positioned within the highly conserved AVTKY motif of the αC helix of H2B. Heterochromatin containing the T122E substitution in H2B remains inaccessible to ectopic dam methylase with dramatically increased mobility in sucrose gradients, indicating a compacted chromatin structure. Genetic studies indicate that this unique phenotype is independent of H2B K123 ubiquitylation and Sir4. In addition, using ChIP analysis, we demonstrate that telomere structure in the mutant is further disrupted by a defect in Sir2/Sir3 binding and the resulting invasion of euchromatic histone marks. Thus, we have revealed that the compaction of chromatin per se is not sufficient for heterochromatin formation. Instead, these results suggest that an appropriately arrayed chromatin mediated by H2B C-terminus is required for SIR binding and the subsequent formation of telomeric chromatin in yeast, thereby identifying an intrinsic property of the nucleosome that is required for the establishment of telomeric heterochromatin. This requirement is also likely to exist in higher eukaryotes, as the AVTKY motif of H2B is evolutionarily conserved.},
}
@article {pmid21829373,
year = {2011},
author = {Martinez-Delgado, B and Yanowsky, K and Inglada-Perez, L and Domingo, S and Urioste, M and Osorio, A and Benitez, J},
title = {Genetic anticipation is associated with telomere shortening in hereditary breast cancer.},
journal = {PLoS genetics},
volume = {7},
number = {7},
pages = {e1002182},
pmid = {21829373},
issn = {1553-7404},
mesh = {Adolescent ; Adult ; Age of Onset ; Aged ; *Anticipation, Genetic ; BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; Breast Neoplasms/epidemiology/*genetics ; Female ; Heterozygote ; Humans ; Middle Aged ; Mutation/genetics ; Pedigree ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {There is increasing evidence suggesting that short telomeres and subsequent genomic instability contribute to malignant transformation. Telomere shortening has been described as a mechanism to explain genetic anticipation in dyskeratosis congenita and Li-Fraumeni syndrome. Since genetic anticipation has been observed in familial breast cancer, we aimed to study telomere length in familial breast cancer patients and hypothesized that genetic defects causing this disease would affect telomere maintenance resulting in shortened telomeres. Here, we first investigated age anticipation in mother-daughter pairs with breast cancer in 623 breast cancer families, classified as BRCA1, BRCA2, and BRCAX. Moreover, we analyzed telomere length in DNA from peripheral blood leukocytes by quantitative PCR in a set of 198 hereditary breast cancer patients, and compared them with 267 control samples and 71 sporadic breast cancer patients. Changes in telomere length in mother-daughter pairs from breast cancer families and controls were also evaluated to address differences through generations. We demonstrated that short telomeres characterize hereditary but not sporadic breast cancer. We have defined a group of BRCAX families with short telomeres, suggesting that telomere maintenance genes might be susceptibility genes for breast cancer. Significantly, we described that progressive telomere shortening is associated with earlier onset of breast cancer in successive generations of affected families. Our results provide evidence that telomere shortening is associated with earlier age of cancer onset in successive generations, suggesting that it might be a mechanism of genetic anticipation in hereditary breast cancer.},
}
@article {pmid21829167,
year = {2011},
author = {Chawla, R and Redon, S and Raftopoulou, C and Wischnewski, H and Gagos, S and Azzalin, CM},
title = {Human UPF1 interacts with TPP1 and telomerase and sustains telomere leading-strand replication.},
journal = {The EMBO journal},
volume = {30},
number = {19},
pages = {4047-4058},
pmid = {21829167},
issn = {1460-2075},
mesh = {Cell Cycle ; Cell Line ; Cell Nucleus/metabolism ; HeLa Cells ; Humans ; Models, Biological ; Proteome ; Proteomics ; RNA Helicases ; Shelterin Complex ; Telomerase/genetics/*metabolism ; Telomere/*genetics/ultrastructure ; Telomere-Binding Proteins ; Trans-Activators/*genetics ; },
abstract = {Eukaryotic up-frameshift 1 (UPF1) is a nucleic acid-dependent ATPase and 5'-to-3' helicase, best characterized for its roles in cytoplasmic RNA quality control. We previously demonstrated that human UPF1 binds to telomeres in vivo and its depletion leads to telomere instability. Here, we show that UPF1 is present at telomeres at least during S and G2/M phases and that UPF1 association with telomeres is stimulated by the phosphoinositide 3-kinase (PI3K)-related protein kinase ataxia telangiectasia mutated and Rad3-related (ATR) and by telomere elongation. UPF1 physically interacts with the telomeric factor TPP1 and with telomerase. Akin to UPF1 binding to telomeres, this latter interaction is mediated by ATR. Moreover, the ATPase activity of UPF1 is required to prevent the telomeric defects observed upon UPF1 depletion, and these defects stem predominantly from inefficient telomere leading-strand replication. Our results portray a scenario where UPF1 orchestrates crucial aspects of telomere biology, including telomere replication and telomere length homeostasis.},
}
@article {pmid21824912,
year = {2011},
author = {Aviv, A and Hunt, SC and Lin, J and Cao, X and Kimura, M and Blackburn, E},
title = {Impartial comparative analysis of measurement of leukocyte telomere length/DNA content by Southern blots and qPCR.},
journal = {Nucleic acids research},
volume = {39},
number = {20},
pages = {e134},
pmid = {21824912},
issn = {1362-4962},
support = {AG030678/AG/NIA NIH HHS/United States ; AG18734/AG/NIA NIH HHS/United States ; AG20132/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; *Blotting, Southern ; DNA/*analysis ; Female ; Humans ; Leukocytes/chemistry ; Male ; Middle Aged ; *Polymerase Chain Reaction ; Reproducibility of Results ; Telomere/*chemistry ; *Telomere Homeostasis ; },
abstract = {Telomere length/DNA content has been measured in epidemiological/clinical settings with the goal of testing a host of hypotheses related to the biology of human aging, but often the conclusions of these studies have been inconsistent. These inconsistencies may stem from various reasons, including the use of different telomere length measurement techniques. Here, we report the first impartial evaluation of measurements of leukocyte telomere length by Southern blot of the terminal restriction fragments and quantitative PCR (qPCR) of telomere DNA content, expressed as the ratio of telomeric product (T)/single copy gene (S) product. Blind measurements on the same samples from 50 donors were performed in two independent laboratories on two different occasions. Both the qPCR and Southern blots displayed highly reproducible results as shown by r values > 0.9 for the correlations between results obtained by either method on two occasions. The inter-assay CV measurement for the qPCR was 6.45%, while that of the Southern blots was 1.74%. The relation between the results generated by Southern blots versus those generated by qPCR deviated from linearity. We discuss the ramifications of these findings with regard to measurements of telomere length/DNA content in epidemiological/clinical circumstances.},
}
@article {pmid21824757,
year = {2013},
author = {Dei Cas, A and Spigoni, V and Franzini, L and Preti, M and Ardigò, D and Derlindati, E and Metra, M and Monti, LD and Dell'Era, P and Gnudi, L and Zavaroni, I},
title = {Lower endothelial progenitor cell number, family history of cardiovascular disease and reduced HDL-cholesterol levels are associated with shorter leukocyte telomere length in healthy young adults.},
journal = {Nutrition, metabolism, and cardiovascular diseases : NMCD},
volume = {23},
number = {3},
pages = {272-278},
doi = {10.1016/j.numecd.2011.04.005},
pmid = {21824757},
issn = {1590-3729},
mesh = {Adult ; Biomarkers/blood ; Blood Pressure ; C-Reactive Protein/analysis/metabolism ; Cardiovascular Diseases/*genetics ; Cholesterol, HDL/*blood ; Cross-Sectional Studies ; Endothelial Cells/cytology ; Female ; Humans ; Leukocytes/*pathology/ultrastructure ; Linear Models ; Male ; Middle Aged ; Plasminogen Activator Inhibitor 1/blood ; Real-Time Polymerase Chain Reaction ; Risk Factors ; Stem Cells/*cytology/metabolism ; Telomere/*pathology/ultrastructure ; Triglycerides/blood ; Uric Acid/blood ; },
abstract = {BACKGROUND AND AIMS: Leukocyte telomere length (LTL) is a novel marker of cardiovascular (CV) risk. The aim of the study was to investigate the major determinants of LTL in a healthy young population at very low CV risk.<br><br>METHODS AND RESULTS: LTL was determined in 82 healthy subjects (49M/33F; age37 &#xb1; 9yrs), normotensive and not taking any medication with different family history of cardiovascular disease (CVD) (24yes/58no). Fasting blood samples were drawn in all subjects for the determination of lipid profile, high sensitive C-reactive protein, uric acid, Plasminogen Activator Inhibitor-1 (PAI-1), LTL and Endothelial Progenitor Cell (EPC) number. LTL was assessed with a specific real-time PCR reaction in leukocyte DNA samples. LTL resulted inversely correlated with family history of CVD (t = 2.70; p = 0.009), age (r = -0.238; p = 0.032), waist circumference (r = -0.256; p = 0.02), triglycerides (r = -0.218; p = 0.049), PAI-1 (r = -0.288; p = 0.009) and directly correlated with HDL-cholesterol (r = 0.316; p = 0.004) and EPC number (r = 0.358; p = 0.002). At a multivariate analysis, family history of CVD (p = 0.013), EPC count (p = 0.003), and HDL-cholesterol (p = 0.017) were independently associated with LTL (r = 0.62).<br><br>CONCLUSION: LTL is independently associated to CV risk factors also in healthy young adults.},
}
@article {pmid21824049,
year = {2012},
author = {Murillo-Ortiz, B and Albarrán-Tamayo, F and Arenas-Aranda, D and Benítez-Bribiesca, L and Malacara-Hernández, JM and Martínez-Garza, S and Hernández-González, M and Solorio, S and Garay-Sevilla, ME and Mora-Villalpando, C},
title = {Telomere length and type 2 diabetes in males, a premature aging syndrome.},
journal = {The aging male : the official journal of the International Society for the Study of the Aging Male},
volume = {15},
number = {1},
pages = {54-58},
doi = {10.3109/13685538.2011.593658},
pmid = {21824049},
issn = {1473-0790},
mesh = {Aging, Premature/*physiopathology ; Diabetes Mellitus, Type 2/blood/genetics/*physiopathology ; Disease Progression ; Humans ; Interleukin-6/blood ; Lipid Peroxidation ; Lipids/blood ; Male ; Middle Aged ; Oxidative Stress/physiology ; Syndrome ; Telomere Homeostasis/physiology ; Telomere Shortening/*physiology ; Tumor Necrosis Factor-alpha/blood ; },
abstract = {BACKGROUND: Increased telomere shortening has been demonstrated in several diseases including type 2 diabetes. However, it is not known whether telomere length changes during the course of type 2 diabetes.<br><br>OBJECTIVE: To determine telomere length at different stages of type 2 diabetes, including early and late stages.<br><br>METHODS: A total of 93 males with type 2 diabetes and 10 years or more since original diagnosis; 96 males with less than one year of diagnosis; 98 age matched healthy males. Telomere length was estimated by means of real-time polymerase chain reaction. Fasting venous blood samples were obtained for measurement of lipid peroxidation and inflammation markers.<br><br>RESULTS: We found a greater telomere shortening in group (A) with type 2 diabetes of 10 years or more since original diagnosis, compared with the control group (C) of healthy males (5.4 vs 9.6 Kb) (p = 0.04) and with group B (5.4 vs 8.7 kb) (p = 0.05). With regard to inflammatory markers TNF-&#x3b1;, malondialdehyde peroxidation and adiponectin we found significant differences.<br><br>CONCLUSION: Telomere shortening increases with the duration of diabetes. The time of exhibition suggests in parallel that the progressive increase of inflammation and/or oxidative stress plays a direct role in telomere shortening.},
}
@article {pmid21822217,
year = {2011},
author = {Horigome, C and Okada, T and Shimazu, K and Gasser, SM and Mizuta, K},
title = {Ribosome biogenesis factors bind a nuclear envelope SUN domain protein to cluster yeast telomeres.},
journal = {The EMBO journal},
volume = {30},
number = {18},
pages = {3799-3811},
pmid = {21822217},
issn = {1460-2075},
mesh = {Carrier Proteins/*metabolism ; DNA, Fungal/*metabolism ; Membrane Proteins/*metabolism ; Nuclear Proteins/*metabolism ; Protein Binding ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/metabolism ; Telomere/*metabolism ; },
abstract = {Two interacting ribosome biogenesis factors, Ebp2 and Rrs1, associate with Mps3, an essential inner nuclear membrane protein. Both are found in foci along the nuclear periphery, like Mps3, as well as in the nucleolus. Temperature-sensitive ebp2 and rrs1 mutations that compromise ribosome biogenesis displace the mutant proteins from the nuclear rim and lead to a distorted nuclear shape. Mps3 is known to contribute to the S-phase anchoring of telomeres through its interaction with the silent information regulator Sir4 and yKu. Intriguingly, we find that both Ebp2 and Rrs1 interact with the C-terminal domain of Sir4, and that conditional inactivation of either ebp2 or rrs1 interferes with both the clustering and silencing of yeast telomeres, while telomere tethering to the nuclear periphery remains intact. Importantly, expression of an Ebp2-Mps3 fusion protein in the ebp2 mutant suppresses the defect in telomere clustering, but not its defects in growth or ribosome biogenesis. Our results suggest that the ribosome biogenesis factors Ebp2 and Rrs1 cooperate with Mps3 to mediate telomere clustering, but not telomere tethering, by binding Sir4.},
}
@article {pmid21822057,
year = {2011},
author = {Vaquero-Sedas, MI and Vega-Palas, MA},
title = {On the chromatin structure of eukaryotic telomeres.},
journal = {Epigenetics},
volume = {6},
number = {9},
pages = {1055-1058},
pmid = {21822057},
issn = {1559-2308},
mesh = {Arabidopsis/chemistry/*genetics ; Base Sequence ; Chromatin/*chemistry/genetics ; Chromatin Assembly and Disassembly ; Chromatin Immunoprecipitation/methods ; Chromosome Aberrations ; Chromosomes/chemistry/genetics ; Telomere/*chemistry/genetics ; },
abstract = {Telomeres prevent chromosome fusions and degradation by exonucleases and are implicated in DNA repair, homologous recombination, chromosome pairing and segregation. All these functions of telomeres require the integrity of their chromatin structure, which has been traditionally considered as heterochromatic. In agreement with this idea, different studies have reported that telomeres associate with heterochromatic marks. However, these studies addressed simultaneously the chromatin structures of telomeres and subtelomeric regions or the chromatin structure of telomeres and Interstitial Telomeric Sequences (ITSs). The independent analysis of Arabidopsis telomeres, subtelomeric regions and ITSs has allowed the discovery of euchromatic telomeres. In Arabidopsis, whereas subtelomeric regions and ITSs associate with heterochromatic marks, telomeres exhibit euchromatic features. We think that this scenario could be found in other model systems if the chromatin organizations of telomeres, subtelomeric regions and ITSs are independently analyzed.},
}
@article {pmid21822009,
year = {2011},
author = {O'Hare, TH and Delany, ME},
title = {Molecular and cellular evidence for the alternative lengthening of telomeres (ALT) mechanism in chicken.},
journal = {Cytogenetic and genome research},
volume = {135},
number = {1},
pages = {65-78},
pmid = {21822009},
issn = {1424-859X},
mesh = {Animals ; Cell Line ; Cell Proliferation ; Chick Embryo ; Chickens/*genetics/metabolism ; Cytogenetics/*methods ; DNA/analysis/genetics ; Fibroblasts/cytology/metabolism ; Fluorescent Antibody Technique ; Gene Expression ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Polymerase Chain Reaction ; RNA, Messenger/analysis ; Telomerase/*deficiency/genetics ; Telomere/chemistry/*metabolism ; Telomeric Repeat Binding Protein 2/*genetics/metabolism ; Transfection ; Tumor Suppressor Proteins/*genetics/metabolism ; },
abstract = {Telomere maintenance is an important genetic mechanism controlling cellular proliferation. Normally, telomeres are maintained by telomerase which is downregulated upon cellular differentiation in most somatic cell lineages. Telomerase activity is upregulated in immortalized cells and cancers to support an infinite lifespan and uncontrolled cell growth; however, some immortalized and transformed cells lack telomerase activity. Telomerase-negative tumors and immortalized cells utilize an alternative mechanism for maintaining telomeres termed alternative lengthening of telomeres (ALT). This research explored evidence for the ALT pathway in chicken cell lines by studying nontransformed immortalized cell lines (DF-1 and OU2) and comparing them to a normal (mortal) cell line and a transformed cell line (DT40). The research consisted of molecular and cellular analyses including profiling of telomeric DNA (array sizing and total content), telomerase activity, and expression of genes involved in the telomerase, recombination, and ALT pathways. In addition, an immunofluorescence analysis for an ALT marker, i.e. ALT-associated promyelocytic leukemia bodies (APBs), was conducted. Evidence for ALT was observed in the telomerase-negative immortalized cell lines. Additionally, the APB marker was also found in the other cell systems. The attributes of the chicken provide an additional vertebrate model for investigation of the ALT pathway.},
}
@article {pmid21818333,
year = {2011},
author = {Shiels, PG and McGlynn, LM and MacIntyre, A and Johnson, PC and Batty, GD and Burns, H and Cavanagh, J and Deans, KA and Ford, I and McConnachie, A and McGinty, A and McLean, JS and Millar, K and Sattar, N and Tannahill, C and Velupillai, YN and Packard, CJ},
title = {Accelerated telomere attrition is associated with relative household income, diet and inflammation in the pSoBid cohort.},
journal = {PloS one},
volume = {6},
number = {7},
pages = {e22521},
pmid = {21818333},
issn = {1932-6203},
support = {MC_U130059821/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Biomarkers/metabolism ; Cohort Studies ; *Diet ; *Family Characteristics ; Female ; Housing ; Humans ; *Income ; Inflammation/*pathology ; Interleukin-6/metabolism ; Life Style ; Male ; Middle Aged ; Regression Analysis ; Telomere/*metabolism ; },
abstract = {BACKGROUND: It has previously been hypothesized that lower socio-economic status can accelerate biological ageing, and predispose to early onset of disease. This study investigated the association of socio-economic and lifestyle factors, as well as traditional and novel risk factors, with biological-ageing, as measured by telomere length, in a Glasgow based cohort that included individuals with extreme socio-economic differences.<br><br>METHODS: A total of 382 blood samples from the pSoBid study were available for telomere analysis. For each participant, data was available for socio-economic status factors, biochemical parameters and dietary intake. Statistical analyses were undertaken to investigate the association between telomere lengths and these aforementioned parameters.<br><br>RESULTS: The rate of age-related telomere attrition was significantly associated with low relative income, housing tenure and poor diet. Notably, telomere length was positively associated with LDL and total cholesterol levels, but inversely correlated to circulating IL-6.<br><br>CONCLUSIONS: These data suggest lower socio-economic status and poor diet are relevant to accelerated biological ageing. They also suggest potential associations between elevated circulating IL-6, a measure known to predict cardiovascular disease and diabetes with biological ageing. These observations require further study to tease out potential mechanistic links.},
}
@article {pmid21818122,
year = {2012},
author = {Ha, GH and Kim, HS and Go, H and Lee, H and Seimiya, H and Chung, DH and Lee, CW},
title = {Tankyrase-1 function at telomeres and during mitosis is regulated by Polo-like kinase-1-mediated phosphorylation.},
journal = {Cell death and differentiation},
volume = {19},
number = {2},
pages = {321-332},
pmid = {21818122},
issn = {1476-5403},
mesh = {Adenosine Diphosphate Ribose/metabolism ; Cell Cycle Proteins/*metabolism ; Enzyme Stability ; HeLa Cells ; Humans ; *Mitosis ; Mutation/genetics ; Phosphorylation ; Protein Binding ; Protein Serine-Threonine Kinases/*metabolism ; Proto-Oncogene Proteins/*metabolism ; Spindle Apparatus/metabolism ; Tankyrases/*metabolism ; Telomere/*enzymology ; Polo-Like Kinase 1 ; },
abstract = {Telomere length is critical for chromosome stability that affects cell proliferation and survival. Telomere elongation by telomerase is inhibited by the telomeric protein, TRF1. Tankyrase-1 (TNKS1) poly(ADP-ribosyl)ates TRF1 and releases TRF1 from telomeres, thereby allowing access of telomerase to the telomeres. TNKS1-mediated poly(ADP-ribosyl)ation also appears to be crucial for regulating the mitotic cell cycle. In searching for proteins that interact with polo-like kinase-1 (Plk1) by using complex proteomics, we identified TNKS1 as a novel Plk1-binding protein. Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends. Taken together, our results provide evidence of a novel molecular mechanism in which phosphorylation of TNKS1 by Plk1 may help regulate mitotic spindle assembly and promote telomeric chromatin maintenance.},
}
@article {pmid21817835,
year = {2011},
author = {Miyashita, N and Kubo, Y and Yonai, M and Kaneyama, K and Saito, N and Sawai, K and Minamihashi, A and Suzuki, T and Kojima, T and Nagai, T},
title = {Cloned cows with short telomeres deliver healthy offspring with normal-length telomeres.},
journal = {The Journal of reproduction and development},
volume = {57},
number = {5},
pages = {636-642},
doi = {10.1262/jrd.11-017a},
pmid = {21817835},
issn = {1348-4400},
mesh = {Age Factors ; Animals ; Animals, Newborn/*genetics ; Cattle/*genetics/physiology ; Cells, Cultured ; *Cloning, Organism/veterinary ; Delivery, Obstetric/veterinary ; Embryo Transfer/veterinary ; Female ; Health ; Nuclear Transfer Techniques/veterinary ; Pregnancy ; *Pregnancy, Animal ; Telomere Homeostasis/genetics/*physiology ; Telomere Shortening/genetics/*physiology ; },
abstract = {Dolly, the first mammal cloned from a somatic cell, had shorter telomeres than age-matched controls and died at an early age because of disease. To investigate longevity and lifetime performance in cloned animals, we produced cloned cows with short telomeres using oviductal epithelial cells as donor cells. At 5 years of age, despite the presence of short telomeres, all cloned cows delivered multiple healthy offspring following artificial insemination with conventionally processed spermatozoa from noncloned bulls, and their milk production was comparable to that of donor cows. Moreover, this study revealed that the offspring had normal-length telomeres in their leukocytes and major organs. Thus, cloned animals have normal functional germ lines, and therefore germ line function can completely restore telomere lengths in clone gametes by telomerase activity, resulting in healthy offspring with normal-length telomeres.},
}
@article {pmid21815629,
year = {2011},
author = {Altschuler, SE and Dickey, TH and Wuttke, DS},
title = {Schizosaccharomyces pombe protection of telomeres 1 utilizes alternate binding modes to accommodate different telomeric sequences.},
journal = {Biochemistry},
volume = {50},
number = {35},
pages = {7503-7513},
pmid = {21815629},
issn = {1520-4995},
support = {GM065103/GM/NIGMS NIH HHS/United States ; R01 GM059414/GM/NIGMS NIH HHS/United States ; GM-059414/GM/NIGMS NIH HHS/United States ; R01 GM059414-11/GM/NIGMS NIH HHS/United States ; T32 GM065103/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites/genetics ; Conserved Sequence/genetics ; DNA-Binding Proteins/chemistry/genetics/metabolism ; Protein Binding/genetics ; Protein Structure, Tertiary/genetics ; Schizosaccharomyces/*chemistry/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/*chemistry/genetics/*metabolism ; Shelterin Complex ; Telomere-Binding Proteins/*chemistry/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/*chemistry/genetics/*metabolism ; },
abstract = {The ends of eukaryotic chromosomes consist of long tracts of repetitive GT-rich DNA with variable sequence homogeneity between and within organisms. Telomeres terminate in a conserved 3'-ssDNA overhang that, regardless of sequence variability, is specifically and tightly bound by proteins of the telomere-end protection family. The high affinity ssDNA-binding activity of S. pombe Pot1 protein (SpPot1) is conferred by a DNA-binding domain consisting of two subdomains, Pot1pN and Pot1pC. Previous work has shown that Pot1pN binds a single repeat of the core telomere sequence (GGTTAC) with exquisite specificity, while Pot1pC binds an extended sequence of nine nucleotides (GGTTACGGT) with modest specificity requirements. We find that full-length SpPot1 binds the composite 15mer, (GGTTAC)(2)GGT, and a shorter two-repeat 12mer, (GGTTAC)(2), with equally high affinity (<3 pM), but with substantially different kinetic and thermodynamic properties. The binding mode of the SpPot1/15mer complex is more stable than that of the 12mer complex, with a 2-fold longer half-life and increased tolerance to nucleotide and amino acid substitutions. Our data suggest that SpPot1 protection of heterogeneous telomeres is mediated through 5'-sequence recognition and the use of alternate binding modes to maintain high affinity interaction with the G-strand, while simultaneously discriminating against the complementary strand.},
}
@article {pmid21813766,
year = {2011},
author = {Entringer, S and Epel, ES and Kumsta, R and Lin, J and Hellhammer, DH and Blackburn, EH and Wüst, S and Wadhwa, PD},
title = {Stress exposure in intrauterine life is associated with shorter telomere length in young adulthood.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {108},
number = {33},
pages = {E513-8},
pmid = {21813766},
issn = {1091-6490},
support = {P01 HD047609/HD/NICHD NIH HHS/United States ; R01 HD065825/HD/NICHD NIH HHS/United States ; R01 HD-065825/HD/NICHD NIH HHS/United States ; R01 HD-06028/HD/NICHD NIH HHS/United States ; R01 HD060628/HD/NICHD NIH HHS/United States ; P01 HD-047609/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Case-Control Studies ; Female ; Humans ; Infant, Newborn ; Male ; Mothers/psychology ; Pregnancy ; Pregnancy Complications/*psychology ; *Prenatal Exposure Delayed Effects ; Risk ; *Stress, Psychological ; *Telomere ; Young Adult ; },
abstract = {Leukocyte telomere length (LTL) is a predictor of age-related disease onset and mortality. The association in adults of psychosocial stress or stress biomarkers with LTL suggests telomere biology may represent a possible underlying mechanism linking stress and health outcomes. It is, however, unknown whether stress exposure in intrauterine life can produce variations in LTL, thereby potentially setting up a long-term trajectory for disease susceptibility. We, therefore, as a first step, tested the hypothesis that stress exposure during intrauterine life is associated with shorter telomeres in adult life after accounting for the effects of other factors on LTL. LTL was assessed in 94 healthy young adults. Forty-five subjects were offspring of mothers who had experienced a severe stressor in the index pregnancy (prenatal stress group; PSG), and 49 subjects were offspring of mothers who had a healthy, uneventful index pregnancy (comparison group; CG). Prenatal stress exposure was a significant predictor of subsequent adult telomere length in the offspring (178-bp difference between prenatal stress and CG; d = 0.41 SD units; P < 0.05). The effect was substantially unchanged after adjusting for potential confounders (subject characteristics, birth weight percentile, and early-life and concurrent stress level), and was more pronounced in women (295-bp difference; d = 0.68 SD units; P < 0.01). To the best of our knowledge, this study provides the first evidence in humans of an association between prenatal stress exposure and subsequent shorter telomere length. This observation may help shed light on an important biological pathway underlying the developmental origins of adult health and disease risk.},
}
@article {pmid21810973,
year = {2011},
author = {Elena, C and Rumi, E and Portolan, M and Della Porta, MG and Pascutto, C and Passamonti, F},
title = {Flow-FISH evaluation of telomere length in Philadelphia-negative myeloproliferative neoplasms.},
journal = {Haematologica},
volume = {96},
number = {8},
pages = {1236-1238},
pmid = {21810973},
issn = {1592-8721},
mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Myeloproliferative Disorders/*diagnosis/*genetics ; Telomere/*genetics ; Telomere Homeostasis ; Young Adult ; },
}
@article {pmid21799512,
year = {2012},
author = {Göhring, G and Lange, K and Hofmann, W and Nielsen, KV and Hellström-Lindberg, E and Roy, L and Morgan, M and Kreipe, H and Büsche, G and Giagounidis, A and Schlegelberger, B},
title = {Telomere shortening, clonal evolution and disease progression in myelodysplastic syndrome patients with 5q deletion treated with lenalidomide.},
journal = {Leukemia},
volume = {26},
number = {2},
pages = {356-358},
doi = {10.1038/leu.2011.193},
pmid = {21799512},
issn = {1476-5551},
mesh = {Antineoplastic Agents/*therapeutic use ; *Chromosome Deletion ; *Chromosomes, Human, Pair 5 ; Disease Progression ; Humans ; Lenalidomide ; Myelodysplastic Syndromes/drug therapy/*genetics ; *Telomere ; Thalidomide/*analogs &amp; derivatives/therapeutic use ; },
}
@article {pmid21794951,
year = {2011},
author = {Hudson, G and Faini, D and Stutt, A and Eccles, M and Robinson, L and Burn, DJ and Chinnery, PF},
title = {No evidence of substantia nigra telomere shortening in Parkinson's disease.},
journal = {Neurobiology of aging},
volume = {32},
number = {11},
pages = {2107.e3-5},
pmid = {21794951},
issn = {1558-1497},
support = {J-0804/PUK_/Parkinson's UK/United Kingdom ; G0900652/MRC_/Medical Research Council/United Kingdom ; NEWBRC-2007-1/DH_/Department of Health/United Kingdom ; G0400074/MRC_/Medical Research Council/United Kingdom ; 071095/WT_/Wellcome Trust/United Kingdom ; G-0618/PUK_/Parkinson's UK/United Kingdom ; G0502157/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Case-Control Studies ; Female ; Humans ; Male ; *Monocytes ; Parkinson Disease/*genetics/physiopathology ; Substantia Nigra/*physiopathology ; *Telomere Shortening ; },
abstract = {Telomeres are repetitive tracts of DNA which protect chromosomal integrity. Increased oxidative stress leads to shorter telomeres, which have been associated with several late-onset human diseases. Given independent evidence of oxidative stress and Parkinson's disease (PD), and conflicting reports of the role of telomere length in PD, we measured telomere length in both PD peripheral blood monocytes and in substantia nigra from affected individuals and controls. We confirmed previous findings of a paradoxically longer telomere length in blood from PD patients, but found no difference in telomere length in substantia nigra. Confounding factors provide a likely explanation for the findings in blood, and possibly the reduced frequency of cigarette smoking in PD patients. We conclude that telomere shortening is unlikely to be involved in the pathogenesis of PD.},
}
@article {pmid21793842,
year = {2011},
author = {Moores, CJ and Fenech, M and O'Callaghan, NJ},
title = {Telomere dynamics: the influence of folate and DNA methylation.},
journal = {Annals of the New York Academy of Sciences},
volume = {1229},
number = {},
pages = {76-88},
doi = {10.1111/j.1749-6632.2011.06101.x},
pmid = {21793842},
issn = {1749-6632},
mesh = {Animals ; Cell Cycle ; Cellular Senescence ; Chromatin/metabolism ; *DNA Methylation ; DNA Repair ; Folic Acid/*metabolism ; Humans ; Telomere/*metabolism ; },
abstract = {Since the suggestion of their existence, a wealth of literature on telomere biology has emerged aimed at solving the DNA end-underreplication problem identified by Olovnikov in 1971. Telomere shortening/dysfunction is now recognized as increasing degenerative disease risk. Recent studies have suggested that both dietary patterns and individual micronutrients--including folate--can influence telomere length and function. Folate is an important dietary vitamin required for DNA synthesis, repair, and one-carbon metabolism within the cell. However, the potential mechanisms by which folate deficiency directly or indirectly affects telomere biology has not yet been reviewed comprehensively. The present review summarizes recent published knowledge and identifies the residual knowledge gaps. Specifically, this review addresses whether it is plausible that folate deficiency may (1) cause accelerated telomere shortening, (2) intrinsically affect telomere function, and/or (3) cause increased telomere-end fusions and subsequent breakage-fusion-bridge cycles in the cell.},
}
@article {pmid21791163,
year = {2013},
author = {Goto, H and Iwata, H and Takeo, S and Nisinosono, K and Murakami, S and Monji, Y and Kuwayama, T},
title = {Effect of bovine age on the proliferative activity, global DNA methylation, relative telomere length and telomerase activity of granulosa cells.},
journal = {Zygote (Cambridge, England)},
volume = {21},
number = {3},
pages = {256-264},
doi = {10.1017/S0967199411000499},
pmid = {21791163},
issn = {1469-8730},
mesh = {Age Factors ; Animals ; Cattle ; Cell Proliferation ; Cytosine/metabolism ; *DNA Methylation ; Female ; Granulosa Cells/*cytology/metabolism/*physiology ; Ovarian Follicle/cytology/physiology ; Ovary/cytology ; Telomerase/*metabolism ; Telomere/metabolism/*physiology ; },
abstract = {Granulosa cells influence the growth and acquisition of the developmental competence of oocytes. We investigated the effects of ageing on the proliferative activity, global genomic DNA methylation, relative telomere length and telomerase activity of bovine granulosa cells. The proliferative activity of cells was examined by bromodeoxyuridine (BrdU) assay, genomic DNA methylation was examined by enzyme-linked immunosorbent assay (ELISA), and relative telomere length and telomerase activity were examined by real-time polymerase chain reaction. We first compared the proliferative activity of the granulosa cells of the medium follicles between in dominant phase ovaries and growth phase ovaries. We observed that the proliferative activity of the granulosa cells of dominant phase ovaries was significantly lower than those of growth phase ovaries. In addition, the proliferative activity of granulosa cells was inversely associated with follicular size. Based on the results, we used granulosa cells harvested from the medium follicles (3-5 mm in diameter) on the surfaces of the dominant phase ovaries collected from cows at a slaughterhouse. The proliferative activity of the granulosa cells harvested from the ovaries of old cows (N = 8; average age 165.1 months) was lower than that of the cells from young cows (N = 8; average age 30.9 months). Global loss of cytosine methylation was detected in the granulosa cells of old cows (N = 12; average age 141.0 months) compared with young cows (N = 15; average age 27.4 months). Although the relative telomere lengths of cumulus cells were similar in the two age groups, the relative telomere lengths and telomerase activity of the granulosa cells from old cows (N = 17 and 9; average age, 164.6 and 151.3 months, respectively) tended to be shorter than those of the cells from young cows (N = 17 and 10; average age 30.6 and 28.1 months, respectively); however, this difference was not significant p = 0.09 and 0.053, respectively). In conclusion, the proliferative activity and genomic global DNA methylation significantly decreased, and the relative telomere lengths and telomerase activity of granulosa cells tended to be shorter with the age of donor cows.},
}
@article {pmid21788988,
year = {2011},
author = {Agarwal, S and Daley, GQ},
title = {Telomere dynamics in dyskeratosis congenita: the long and the short of iPS.},
journal = {Cell research},
volume = {21},
number = {8},
pages = {1157-1160},
pmid = {21788988},
issn = {1748-7838},
support = {K08 HL089150/HL/NHLBI NIH HHS/United States ; },
mesh = {Dyskeratosis Congenita/*genetics/physiopathology ; Humans ; Induced Pluripotent Stem Cells/cytology/*metabolism ; Mutation ; RNA/metabolism ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Transcription Factors/metabolism ; },
}
@article {pmid21788649,
year = {2011},
author = {Surtees, PG and Wainwright, NW and Pooley, KA and Luben, RN and Khaw, KT and Easton, DF and Dunning, AM},
title = {Life stress, emotional health, and mean telomere length in the European Prospective Investigation into Cancer (EPIC)-Norfolk population study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {66},
number = {11},
pages = {1152-1162},
doi = {10.1093/gerona/glr112},
pmid = {21788649},
issn = {1758-535X},
support = {G0300128/MRC_/Medical Research Council/United Kingdom ; 11022/CRUK_/Cancer Research UK/United Kingdom ; C8197/A10123/CRUK_/Cancer Research UK/United Kingdom ; G1000143/MRC_/Medical Research Council/United Kingdom ; G9502233/MRC_/Medical Research Council/United Kingdom ; G0401527/MRC_/Medical Research Council/United Kingdom ; C865/A2883/CRUK_/Cancer Research UK/United Kingdom ; C1287/A9540/CRUK_/Cancer Research UK/United Kingdom ; 10118/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Cellular Senescence/genetics ; Child ; Child Abuse/psychology ; Female ; Humans ; Life Change Events ; *Mental Health ; Middle Aged ; Polymerase Chain Reaction ; Stress, Psychological/genetics/*physiopathology ; Telomere/chemistry/*ultrastructure ; Telomere Homeostasis/genetics/*physiology ; },
abstract = {We investigated the association between psychological stress, emotional health, and relative mean telomere length in an ethnically homogeneous population of 4,441 women, aged 41-80 years. Mean telomere length was measured using high-throughput quantitative real-time polymerase chain reaction. Social adversity exposure and emotional health were assessed through questionnaire and covariates through direct measurement and questionnaire. This study found evidence that adverse experiences during childhood may be associated with shorter telomere length. This finding remained after covariate adjustment and showed evidence of a dose-response relationship with increasing number of reported childhood difficulties associated with decreasing relative mean telomere length. No associations were observed for any of the other summary measures of social adversity and emotional health considered. These results extend and provide support for some previous findings concerning the association of adverse experience and emotional health histories with shorter telomere length in adulthood. Replication of these findings in longitudinal studies is now essential.},
}
@article {pmid21781041,
year = {2011},
author = {Ortega, LM and Hengartner, CJ and Vega, LR},
title = {Nonradioactive method to detect native single-stranded G-tails on yeast telomeres using a modified Southern blot protocol.},
journal = {BioTechniques},
volume = {50},
number = {6},
pages = {407-410},
doi = {10.2144/000113687},
pmid = {21781041},
issn = {1940-9818},
support = {3SC2CA138567-02S1/CA/NCI NIH HHS/United States ; 5R25 GM059244/GM/NIGMS NIH HHS/United States ; 5SC2CA138567/CA/NCI NIH HHS/United States ; 5T34 GM08021/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Blotting, Southern/*methods ; DNA, Fungal/*chemistry/genetics/metabolism ; DNA, Single-Stranded/*chemistry/genetics/metabolism ; Digoxigenin/chemistry ; Nucleic Acid Hybridization ; Oligonucleotide Probes/genetics/metabolism ; Saccharomyces cerevisiae/genetics ; Sensitivity and Specificity ; Telomere/*chemistry/genetics ; },
abstract = {Because of their low abundance and short length, telomeric single-stranded extensions have not traditionally been assessed by Southern blot analysis. Instead, most methods have relied on hybridizing radioactively labeled oligonucleotide probes to electrophoresed DNA within agarose gels. Here we describe a rapid and nonradioactive Southern blot-derived method to transfer and detect telomeric single-stranded G-rich overhangs (G-tails) under nondenaturing (native) conditions, using Saccharomyces cerevisiae DNA. Restriction enzyme-digested chromosomal DNA is separated by agarose gel electrophoresis, transferred onto a charged membrane by electroblotting under nondenaturing conditions, and probed with a digoxigenin (DIG)-labeled oligonucleotide. Compared with the prolonged film exposure required to detect radioactive probes, detection of short single-strand G-tails with this method takes mere minutes. Furthermore, following detection of the single-stranded G-tails, the DNA on the membrane can be denatured and reprobed using conventional hybridization and detection methods.},
}
@article {pmid21777611,
year = {2011},
author = {Fernández, S and Eritja, R and Aviñó, A and Jaumot, J and Gargallo, R},
title = {Influence of pH, temperature and the cationic porphyrin TMPyP4 on the stability of the i-motif formed by the 5'-(C3TA2)4-3' sequence of the human telomere.},
journal = {International journal of biological macromolecules},
volume = {49},
number = {4},
pages = {729-736},
doi = {10.1016/j.ijbiomac.2011.07.004},
pmid = {21777611},
issn = {1879-0003},
mesh = {Base Sequence ; Cations ; Humans ; Hydrogen-Ion Concentration ; Least-Squares Analysis ; Multivariate Analysis ; *Nucleotide Motifs ; Porphyrins/*chemistry ; Spectrum Analysis ; Telomere/*chemistry/*genetics ; *Temperature ; },
abstract = {The influence of pH, temperature and the cationic porphyrin TMPyP4 on the conformational equilibria of the cytosine-rich strand of the human telomeric sequence 5'-(C(3)TA(2))(4)-3', as well as those of the sequence 5'-(C(3)TT(2))(4)-3', was studied. The presence of adenine bases at the loops causes the formation of two different intramolecular i-motif structures with a pH-transition midpoint around 4.6, which stability is lower than the i-motif formed by the sequence 5'-(C(3)TT(2))(4)-3'. The stoichiometries of the complexes formed by these i-motif structures with TMPyP4 are also influenced by the presence of adenine at the loops.},
}
@article {pmid21776017,
year = {2011},
author = {Nilsson, PM},
title = {Telomeres and cardiovascular disease: new perspectives in hypertension.},
journal = {Journal of human hypertension},
volume = {25},
number = {12},
pages = {703-704},
doi = {10.1038/jhh.2011.69},
pmid = {21776017},
issn = {1476-5527},
mesh = {Cardiovascular Diseases/*epidemiology ; Diabetes Mellitus, Type 2/*epidemiology ; Female ; Humans ; Hypertension/*pathology ; Hypertrophy, Left Ventricular/*pathology ; Leukocytes/*pathology ; Male ; Telomere/*pathology ; },
}
@article {pmid21773671,
year = {2012},
author = {Gauthier, LR and Granotier, C and Hoffschir, F and Etienne, O and Ayouaz, A and Desmaze, C and Mailliet, P and Biard, DS and Boussin, FD},
title = {Rad51 and DNA-PKcs are involved in the generation of specific telomere aberrations induced by the quadruplex ligand 360A that impair mitotic cell progression and lead to cell death.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {69},
number = {4},
pages = {629-640},
pmid = {21773671},
issn = {1420-9071},
mesh = {Anaphase ; *Apoptosis ; Cell Line ; DNA End-Joining Repair ; DNA-Activated Protein Kinase/antagonists &amp; inhibitors/genetics/*metabolism ; *G-Quadruplexes ; Homologous Recombination ; Humans ; Ligands ; Metaphase ; Mitosis/*genetics ; Nuclear Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Pyridines/*pharmacology ; Quinolines/*pharmacology ; RNA Interference ; RNA, Small Interfering/metabolism ; Rad51 Recombinase/antagonists &amp; inhibitors/genetics/*metabolism ; *Telomere/metabolism/pathology ; },
abstract = {Functional telomeres are protected from non-homologous end-joining (NHEJ) and homologous recombination (HR) DNA repair pathways. Replication is a critical period for telomeres because of the requirement for reconstitution of functional protected telomere conformations, a process that involves DNA repair proteins. Using knockdown of DNA-PKcs and Rad51 expression in three different cell lines, we demonstrate the respective involvement of NHEJ and HR in the formation of telomere aberrations induced by the G-quadruplex ligand 360A during or after replication. HR contributed to specific chromatid-type aberrations (telomere losses and doublets) affecting the lagging strand telomeres, whereas DNA-PKcs-dependent NHEJ was responsible for sister telomere fusions as a direct consequence of G-quadruplex formation and/or stabilization induced by 360A on parental telomere G strands. NHEJ and HR activation at telomeres altered mitotic progression in treated cells. In particular, NHEJ-mediated sister telomere fusions were associated with altered metaphase-anaphase transition and anaphase bridges and resulted in cell death during mitosis or early G1. Collectively, these data elucidate specific molecular and cellular mechanisms triggered by telomere targeting by the G-quadruplex ligand 360A, leading to cancer cell death.},
}
@article {pmid21769957,
year = {2011},
author = {Venturini, L and Daidone, MG and Motta, R and Collini, P and Spreafico, F and Terenziani, M and Piva, L and Radice, P and Perotti, D and Zaffaroni, N},
title = {Telomere maintenance in Wilms tumors: first evidence for the presence of alternative lengthening of telomeres mechanism.},
journal = {Genes, chromosomes &amp; cancer},
volume = {50},
number = {10},
pages = {823-829},
doi = {10.1002/gcc.20903},
pmid = {21769957},
issn = {1098-2264},
mesh = {Adolescent ; Adult ; Aged ; Cell Line, Tumor ; Child ; Child, Preschool ; Electrophoresis, Gel, Pulsed-Field ; Humans ; In Situ Hybridization, Fluorescence ; Kidney Neoplasms/enzymology/*genetics/pathology ; Male ; Microscopy, Fluorescence ; Middle Aged ; Neoplasm Staging ; Nucleic Acid Amplification Techniques ; Telomerase/genetics/*metabolism ; Telomere/chemistry/*metabolism ; Telomere Homeostasis ; Wilms Tumor/enzymology/*genetics/pathology ; },
abstract = {Unlimited proliferative potential is a hallmark of cancer, and can be achieved through the activation of telomere maintenance mechanisms (TMMs). Most tumors activate telomerase, but a significant minority, mainly of mesenchymal origin, uses a recombination-based, alternative lengthening of telomeres (ALT) mechanism. We investigated the presence of ALT in 34 Wilms tumor (WT) samples from 30 patients by using two approaches: (i) the detection of ALT-associated promyelocytic leukemia (PML) nuclear bodies (APBs) by combined PML immunofluorescence and telomere fluorescence in situ hybridization and (ii) the assessment of terminal restriction fragment (TRF) length distribution by pulsed field gel electrophoresis. In parallel, telomerase activity (TA) was determined by the telomeric repeat amplification protocol (TRAP) assay. Based on APB expression, ALT was detectable in five samples as the sole TMM and in six samples in association with telomerase. Seventeen samples only expressed TA and in six cases no known TMM was appreciable. Results of TRF length distribution were available in 32 cases, and a concordance between APB and TRF data in defining the ALT phenotype was found in 26/32 cases (81%). The study provides the first evidence of the presence of ALT in WT, and indicates that in a small but defined fraction of cases (about 15%) ALT is the only TMM that supports the development of WT.},
}
@article {pmid21764192,
year = {2011},
author = {Gadalla, SM and Savage, SA},
title = {Telomere biology in hematopoiesis and stem cell transplantation.},
journal = {Blood reviews},
volume = {25},
number = {6},
pages = {261-269},
pmid = {21764192},
issn = {1532-1681},
support = {ZIA CP010144//Intramural NIH HHS/United States ; },
mesh = {Animals ; *Hematopoiesis ; Hematopoietic Stem Cells/cytology/metabolism ; Humans ; *Stem Cell Transplantation ; Telomere/*genetics/metabolism/*pathology ; *Telomere Shortening ; },
abstract = {Telomeres are long (TTAGGG)(n) nucleotide repeats and an associated protein complex located at the end of the chromosomes. They shorten with every cell division and, thus are markers for cellular aging, senescence, and replicative capacity. Telomere dysfunction is linked to several bone marrow disorders, including dyskeratosis congenita, aplastic anemia, myelodysplastic syndrome, and hematopoietic malignancies. Hematopoietic stem cell transplantation (HSCT) provides an opportunity in which to study telomere dynamics in a high cell proliferative environment. Rapid telomere shortening of donor cells occurs in the recipient shortly after HSCT; the degree of telomere attrition does not appear to differ by graft source. As expected, telomeres are longer in recipients of grafts with longer telomeres (e.g., cord blood). Telomere attrition may play a role in, or be a marker of, long term outcome after HSCT, but these data are limited. In this review, we discuss telomere biology in normal and abnormal hematopoiesis, including HSCT.},
}
@article {pmid21763693,
year = {2011},
author = {Wan, Y and Chen, W and Xing, J and Tan, J and Li, B and Chen, H and Lin, Z and Chiang, JH and Saleem, RA},
title = {Transcriptome profiling reveals a novel role for trichostatin A in antagonizing histone chaperone Chz1 mediated telomere anti-silencing.},
journal = {FEBS letters},
volume = {585},
number = {15},
pages = {2519-2525},
doi = {10.1016/j.febslet.2011.06.036},
pmid = {21763693},
issn = {1873-3468},
mesh = {*Gene Expression Profiling ; Gene Expression Regulation, Fungal/drug effects ; Gene Silencing/drug effects ; Histone Chaperones/*antagonists &amp; inhibitors ; Histone Deacetylases ; Hydroxamic Acids/*pharmacology ; Saccharomyces cerevisiae Proteins/*antagonists &amp; inhibitors ; Telomere/*genetics ; Transcription, Genetic ; },
abstract = {The histone chaperones play an important role in chromatin assembly and disassembly during replication and transcription. We have assessed the global roles of histone chaperones in Saccharomyces cerevisiae. Microarray transcriptional analyzes indicate that histone chaperones have their own specific target genes, and various histone chaperones have partially overlapping functions during transcriptional regulation. The histone deacetylase inhibitor TSA and histone chaperones Asf1, Vps75 and Rtt106 can function in parallel pathways to regulate transcription. Moreover, TSA can specifically antagonize histone chaperone Chz1-mediated telomere anti-silencing. This study demonstrates that a mutual cross-talk mechanism exists between histone chaperones and histone deacetylation in transcriptional regulation.},
}
@article {pmid21763260,
year = {2011},
author = {Wang, Y and Meeker, AK and Kowalski, J and Tsai, HL and Somervell, H and Heaphy, C and Sangenario, LE and Prasad, N and Westra, WH and Zeiger, MA and Umbricht, CB},
title = {Telomere length is related to alternative splice patterns of telomerase in thyroid tumors.},
journal = {The American journal of pathology},
volume = {179},
number = {3},
pages = {1415-1424},
pmid = {21763260},
issn = {1525-2191},
support = {R21 CA137550/CA/NCI NIH HHS/United States ; },
mesh = {Alternative Splicing/*physiology ; Humans ; In Situ Hybridization, Fluorescence ; ROC Curve ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*metabolism ; Telomere/metabolism/*pathology ; Telomere Homeostasis/physiology ; Thyroid Neoplasms/*enzymology/pathology ; },
abstract = {Telomere dysfunction and aberrant telomerase expression play important roles in tumorigenesis. In thyroid tumors, three possibly inhibitory splice variants of the active full-length isoform of human telomerase reverse transcriptase (hTERT) may be expressed. These variants might regulate telomerase activity and telomere length because it is the fraction of the full-length isoform, rather than the total transcript level, that correlates with enzymatic activity. Telomerase reactivation may be critical in the early stages of tumorigenesis, when progressive telomere shortening may be limiting cell viability. The aim of this study was to investigate the relationship between telomere length and hTERT splice variant expression patterns in benign and well-differentiated malignant thyroid tumors. Telomere lengths of 61 thyroid tumors were examined by fluorescence in situ hybridization, comparing tumors with adjacent normal thyroid tissue on the same slide. Expression patterns of hTERT splice variants were evaluated by quantitative and nested RT-PCR. Telomere length was inversely correlated with percentage of full-length hTERT expression rather than with total hTERT expression levels. Short telomeres and high fractions of full-length hTERT transcripts were associated with follicular and papillary thyroid carcinomas, whereas long telomeres and low levels of full-length hTERT were associated with benign thyroid nodules. Intermediate levels of full-length hTERT and telomere length were found in follicular variant of papillary thyroid carcinomas and follicular adenomas.},
}
@article {pmid21762422,
year = {2011},
author = {Smith, DR and Lee, RW},
title = {Nucleotide diversity of the colorless green alga Polytomella parva (Chlorophyceae, Chlorophyta): high for the mitochondrial telomeres, surprisingly low everywhere else.},
journal = {The Journal of eukaryotic microbiology},
volume = {58},
number = {5},
pages = {471-473},
doi = {10.1111/j.1550-7408.2011.00569.x},
pmid = {21762422},
issn = {1550-7408},
mesh = {Chlorophyta/*genetics ; Evolution, Molecular ; *Genetic Variation ; Genome, Mitochondrial ; Mitochondria/*genetics ; Molecular Sequence Data ; Telomere/*genetics ; },
abstract = {Silent-site nucleotide diversity data (π(silent)) can provide insights into the forces driving genome evolution. Here we present π(silent) statistics for the mitochondrial and nuclear DNAs of Polytomella parva, a nonphotosynthetic green alga with a highly reduced, linear fragmented mitochondrial genome. We show that this species harbors very little genetic diversity, with the exception of the mitochondrial telomeres, which have an excess of polymorphic sites. These data are compared with previously published π(silent) values from the mitochondrial and nuclear genomes of the model species Chlamydomonas reinhardtii and Volvox carteri, which are close relatives of P. parva, and are used to understand the modes and tempos of genome evolution within green algae.},
}
@article {pmid21757622,
year = {2011},
author = {Alder, JK and Guo, N and Kembou, F and Parry, EM and Anderson, CJ and Gorgy, AI and Walsh, MF and Sussan, T and Biswal, S and Mitzner, W and Tuder, RM and Armanios, M},
title = {Telomere length is a determinant of emphysema susceptibility.},
journal = {American journal of respiratory and critical care medicine},
volume = {184},
number = {8},
pages = {904-912},
pmid = {21757622},
issn = {1535-4970},
support = {R21 HL104345/HL/NHLBI NIH HHS/United States ; K08 CA118416/CA/NCI NIH HHS/United States ; HL104345/HL/NHLBI NIH HHS/United States ; CA118416/CA/NCI NIH HHS/United States ; R01 ES016285/ES/NIEHS NIH HHS/United States ; P50 HL073994/HL/NHLBI NIH HHS/United States ; HL073994/HL/NHLBI NIH HHS/United States ; },
mesh = {Age Factors ; Animals ; Bone Marrow Transplantation ; DNA Damage ; Female ; Fluorescent Antibody Technique ; *Genetic Predisposition to Disease ; Idiopathic Pulmonary Fibrosis/enzymology/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Pulmonary Emphysema/*chemically induced/enzymology/*genetics/surgery ; Real-Time Polymerase Chain Reaction ; Respiratory Function Tests ; Reverse Transcriptase Polymerase Chain Reaction ; Smoke/*adverse effects ; Telomerase/deficiency/*genetics ; Telomere/*chemistry ; Nicotiana/*adverse effects ; },
abstract = {RATIONALE: Germline mutations in the enzyme telomerase cause telomere shortening, and have their most common clinical manifestation in age-related lung disease that manifests as idiopathic pulmonary fibrosis. Short telomeres are also a unique heritable trait that is acquired with age.<br><br>OBJECTIVES: We sought to understand the mechanisms by which telomerase deficiency contributes to lung disease.<br><br>METHODS: We studied telomerase null mice with short telomeres.<br><br>MEASUREMENTS AND MAIN RESULTS: Although they have no baseline histologic defects, when mice with short telomeres are exposed to chronic cigarette smoke, in contrast with controls, they develop emphysematous air space enlargement. The emphysema susceptibility did not depend on circulating cell genotype, because mice with short telomeres developed emphysema even when transplanted with wild-type bone marrow. In lung epithelium, cigarette smoke exposure caused additive DNA damage to telomere dysfunction, which limited their proliferative recovery, and coincided with a failure to down-regulate p21, a mediator of cellular senescence, and we show here, a determinant of alveolar epithelial cell cycle progression. We also report early onset of emphysema, in addition to pulmonary fibrosis, in a family with a germline deletion in the Box H domain of the RNA component of telomerase.<br><br>CONCLUSIONS: Our data indicate that short telomeres lower the threshold of cigarette smoke-induced damage, and implicate telomere length as a genetic susceptibility factor in emphysema, potentially contributing to its age-related onset in humans.},
}
@article {pmid21756922,
year = {2012},
author = {Prescott, J and Wentzensen, IM and Savage, SA and De Vivo, I},
title = {Epidemiologic evidence for a role of telomere dysfunction in cancer etiology.},
journal = {Mutation research},
volume = {730},
number = {1-2},
pages = {75-84},
pmid = {21756922},
issn = {0027-5107},
support = {CA082838/CA/NCI NIH HHS/United States ; R01 CA134958/CA/NCI NIH HHS/United States ; R01 CA134958-02/CA/NCI NIH HHS/United States ; R01 CA065725/CA/NCI NIH HHS/United States ; R01 CA082838/CA/NCI NIH HHS/United States ; R01 CA082838-01/CA/NCI NIH HHS/United States ; CA134958/CA/NCI NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; R01 CA065725-10/CA/NCI NIH HHS/United States ; CA65725/CA/NCI NIH HHS/United States ; },
mesh = {Cell Transformation, Neoplastic/genetics ; Cellular Senescence ; *Epidemiologic Methods ; Genomic Instability ; Humans ; Neoplasms/*genetics ; *Research Design ; Risk Assessment ; Telomere/*physiology ; *Telomere Shortening ; },
abstract = {Telomeres, the dynamic nucleoprotein structures at the ends of linear chromosomes, maintain the genomic integrity of a cell. Telomere length shortens with age due to the incomplete replication of DNA ends with each cell division as well as damage incurred by oxidative stress. Patterns of telomere shortening, genomic instability, and telomerase expression in many cancer tissues compared to adjacent normal tissue implicate telomere crisis as a common crucial event in malignant transformation. In order to understand the role of telomere length in cancer etiology, most epidemiologic studies have measured average telomere length of peripheral blood or buccal cell DNA as a surrogate tissue biomarker of telomere dysfunction and cancer risk. In this review, we present the results from epidemiologic investigations conducted of telomere length and cancer risk. We note differences in reported associations based on study design, which may be due to biases intrinsic to retrospective studies. Finally, we conclude with study design considerations as future investigations are needed to elucidate the relationship between telomere length and a number of cancer sites.},
}
@article {pmid21753158,
year = {2011},
author = {Maxwell, F and McGlynn, LM and Muir, HC and Talwar, D and Benzeval, M and Robertson, T and Roxburgh, CS and McMillan, DC and Horgan, PG and Shiels, PG},
title = {Telomere attrition and decreased fetuin-A levels indicate accelerated biological aging and are implicated in the pathogenesis of colorectal cancer.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {17},
number = {17},
pages = {5573-5581},
doi = {10.1158/1078-0432.CCR-10-3271},
pmid = {21753158},
issn = {1557-3265},
support = {MC_UP_A540_1021/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aged ; Aged, 80 and over ; *Aging/genetics ; Biomarkers, Tumor/analysis ; Calcium/metabolism ; Colorectal Neoplasms/*blood/genetics/*pathology ; DNA/blood ; Female ; Humans ; Leukocytes/pathology ; Male ; Middle Aged ; Oxidation-Reduction ; Rectal Neoplasms/blood/genetics/pathology ; Risk Factors ; Telomere/*ultrastructure ; *Telomere Shortening ; alpha-2-HS-Glycoprotein/*analysis ; },
abstract = {PURPOSE: Increasing chronological age is a risk factor for many types of cancer including colorectal. An understanding of the biology of aging and factors which regulate it may provide insight into cancer pathogenesis. The role of telomere biology in both the cancer and aging process could prove useful in this regard.<br><br>EXPERIMENTAL DESIGN: Using quantitative PCR, we determined telomere length in the peripheral blood leukocytes of 64 colorectal cancer (CRC) patients and 1,348 controls. We also measured telomere length in 32 colorectal tumor samples and matched normal tissue. We aimed to assess whether telomere lengths were reflected in circulating mediators of inflammation and redox control factors, including fetuin-A, a circulating modulator of calcium homeostasis.<br><br>RESULTS: CRC patients had shorter telomeres [adjusted mean ratio of relative telomere repeat copy number to single-copy gene number (RelT/S) = 0.61] compared with chronologically older controls (mean age = 75, adjusted mean RelT/S = 0.70; ANCOVA, P = 0.004). Telomere length in tumor tissue [median = 0.43, interquartile range (IQR) = 0.40] was significantly shorter than adjacent normal tissue (median = 0.65, IQR = 0.28; P = 0.004). Patients with low fetuin-A levels were shown to have significantly shorter telomeres (P = 0.041). Patients with rectal tumors had significantly higher levels of fetuin-A than those with colonic tumors (P = 0.045).<br><br>CONCLUSIONS: We have observed that patients with CRC display clear evidence of telomere attrition compared with controls. This is congruent with accelerated biological aging in the pathogenesis of CRC. An imbalance in redox control mechanisms and calcium homeostasis may be a contributing factor to telomere dynamics in our patients. Furthermore, fetuin-A levels can be used to distinguish between colon and rectal cancers.},
}
@article {pmid21745483,
year = {2012},
author = {Nelson, ND and Bertuch, AA},
title = {Dyskeratosis congenita as a disorder of telomere maintenance.},
journal = {Mutation research},
volume = {730},
number = {1-2},
pages = {43-51},
pmid = {21745483},
issn = {0027-5107},
support = {R01 GM077509/GM/NIGMS NIH HHS/United States ; R01 GM077509-04/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics ; Dyskeratosis Congenita/*genetics ; Genes, Dominant ; Genes, X-Linked ; Humans ; Mutation ; Nuclear Proteins/genetics ; Telomerase/genetics/metabolism ; Telomere Homeostasis ; *Telomere Shortening ; Telomere-Binding Proteins/genetics ; },
abstract = {Since 1998, there have been great advances in our understanding of the pathogenesis of dyskeratosis congenita (DC), a rare inherited bone marrow failure and cancer predisposition syndrome with prominent mucocutaneous abnormalities and features of premature aging. DC is now characterized molecularly by the presence of short age-adjusted telomeres. Mutations in seven genes have been unequivocally associated with DC, each with a role in telomere length maintenance. These observations, combined with knowledge that progressive telomere shortening can impose a proliferative barrier on dividing cells and contribute to chromosome instability, have led to the understanding that extreme telomere shortening drives the clinical features of DC. However, some of the genes implicated in DC encode proteins that are also components of H/ACA-ribonucleoprotein enzymes, which are responsible for the post-translational modification of ribosomal and spliceosomal RNAs, raising the question whether alterations in these activities play a role in the pathogenesis of DC. In addition, recent reports suggest that some cases of DC may not be characterized by short age-adjusted telomeres. This review will highlight our current knowledge of the telomere length defects in DC and the factors involved in its development.},
}
@article {pmid21745249,
year = {2011},
author = {Teo, CH and Ma, L and Kapusi, E and Hensel, G and Kumlehn, J and Schubert, I and Houben, A and Mette, MF},
title = {Induction of telomere-mediated chromosomal truncation and stability of truncated chromosomes in Arabidopsis thaliana.},
journal = {The Plant journal : for cell and molecular biology},
volume = {68},
number = {1},
pages = {28-39},
doi = {10.1111/j.1365-313X.2011.04662.x},
pmid = {21745249},
issn = {1365-313X},
mesh = {Agrobacterium ; Aneuploidy ; Arabidopsis/*genetics ; Centromere/metabolism ; Chromosomal Instability/*genetics ; Chromosome Segregation/genetics ; Chromosomes, Artificial/genetics ; Chromosomes, Plant/*genetics/metabolism ; DNA, Bacterial ; DNA, Plant/genetics ; Gene Transfer Techniques ; In Situ Hybridization, Fluorescence ; Models, Molecular ; Molecular Sequence Data ; Plants, Genetically Modified ; Plasmids ; Telomere/*metabolism ; Terminal Repeat Sequences/*genetics ; Transformation, Genetic ; },
abstract = {Minichromosomes possess functional centromeres and telomeres and thus should be stably inherited. They offer an enormous opportunity to plant biotechnology as they have the potential to simultaneously transfer and stably express multiple genes. Segregating independently of host chromosomes, they provide a platform for accelerating plant breeding. Following a top-down approach, we truncated endogenous chromosomes in Arabidopsis thaliana by Agrobacterium-mediated transfer of T-DNA constructs containing telomere sequences. Blocks of A. thaliana telomeric repeats were inserted into a binary vector suitable for stable transformation. After transfer of these constructs into the natural tetraploid A. thaliana accession Wa-1, chromosome truncation by T-DNA-induced de novo formation of telomeres could be confirmed by DNA gel blot analysis, PCR (polymerase chain reaction), and fluorescence in situ hybridisation. The addition of new telomere repeats in this process could start alternatively from within the T-DNA-derived telomere repeats or from adjacent sequences close to the right border of the T-DNA. Truncated chromosomes were transmissible in sexual reproduction, but were inherited at rates lower than expected according to Mendelian rules.},
}
@article {pmid21743457,
year = {2011},
author = {Hang, LE and Liu, X and Cheung, I and Yang, Y and Zhao, X},
title = {SUMOylation regulates telomere length homeostasis by targeting Cdc13.},
journal = {Nature structural &amp; molecular biology},
volume = {18},
number = {8},
pages = {920-926},
pmid = {21743457},
issn = {1545-9985},
support = {R01 GM080670-04/GM/NIGMS NIH HHS/United States ; R01GM080670/GM/NIGMS NIH HHS/United States ; R01 GM043265/GM/NIGMS NIH HHS/United States ; /CAPMC/CIHR/Canada ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 GM080670/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites ; Cell Cycle Proteins/chemistry/metabolism ; Epistasis, Genetic ; Homeostasis ; Phosphorylation ; S Phase ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; Sumoylation ; Telomere/*metabolism ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {Telomere length homeostasis is an important aspect of telomere biology. Here, we show that SUMOylation limits telomere length and targets multiple telomere proteins in Saccharomyces cerevisiae. A main target is Cdc13, which both positively and negatively regulates telomerase and confers end protection. We demonstrate that Cdc13 SUMOylation restrains telomerase functions by promoting Cdc13 interaction with the telomerase inhibitor Stn1 without affecting end protection. Mutation of the Cdc13 SUMOylation site (cdc13-snm) lengthens telomeres and reduces the Stn1 interaction, whereas Cdc13-SUMO fusion has the opposite effects. cdc13-snm's effect on telomere length is epistatic with stn1, but not with yku70, tel1 or est1 alleles, and is suppressed by Stn1 overexpression. Cdc13 SUMOylation peaks in early-mid S phase, prior to its known Cdk1-mediated phosphorylation, and the two modifications act antagonistically, suggesting that the opposite roles of Cdc13 in telomerase regulation can be separated temporally and regulated by distinct modifications.},
}
@article {pmid21741697,
year = {2011},
author = {Pérez-Cerezales, S and Gutiérrez-Adán, A and Martínez-Páramo, S and Beirão, J and Herráez, MP},
title = {Altered gene transcription and telomere length in trout embryo and larvae obtained with DNA cryodamaged sperm.},
journal = {Theriogenology},
volume = {76},
number = {7},
pages = {1234-1245},
doi = {10.1016/j.theriogenology.2011.05.028},
pmid = {21741697},
issn = {1879-3231},
mesh = {Animals ; Cryopreservation/methods/*veterinary ; *DNA Damage ; Female ; Larva/genetics ; Male ; *Spermatozoa ; Telomere/*metabolism/ultrastructure ; *Transcription, Genetic ; Trout/*embryology/genetics/growth &amp; development ; },
abstract = {Sperm cryopreservation could entail DNA damage, promoting base oxidization and strand breaks. In a previous work we showed that trout DNA damaged sperm is able to fertilize leading to embryo loss when the repair system of the oocyte is inhibited. Here we have analysed the later effects on embryo and larvae of fertilizing trout oocytes with cryopreserved DNA-damaged spermatozoa. Fish have weak sperm selection mechanisms, are very prolific and have external embryo development, being convenient models for this type of study. We cryopreserved rainbow trout semen using extenders containing egg yolk or their low density lipoprotein fraction to obtain samples with different degrees of DNA damage. DNA fragmentation was evaluated using the Comet assay and telomere length using quantitative-PCR. Fertilization trials were performed and the transcription at different developmental stages of telomerase reverse transcriptase (Tert) and eight genes related with embryo growth and development (Igf1, Igf2, Igfr1a, Igfr1b, Gh1, Gh2, Ins1 and Ins2) were analyzed using quantitative-PCR in surviving embryos and larvae. Results showed an increase in sperm DNA fragmentation after both cryopreservation procedures as well as a decrease in sperm telomere length. Larvae obtained with damaged sperm showed longer telomeres and Tert overexpression. The transcription of the analyzed genes in these embryos and larvae was also modified with respect to the control, most of them as an increase at hatch. We conclude that fertilization with cryopreserved DNA-damaged spermatozoa significantly affects offspring performance, detectable as an increase in telomere length as well as some alterations in gene expression in surviving embryo and larvae.},
}
@article {pmid21738835,
year = {2011},
author = {Diotti, R and Loayza, D},
title = {Shelterin complex and associated factors at human telomeres.},
journal = {Nucleus (Austin, Tex.)},
volume = {2},
number = {2},
pages = {119-135},
pmid = {21738835},
issn = {1949-1042},
mesh = {Animals ; Base Sequence ; Chromosomes, Human/genetics/*metabolism ; Humans ; Neoplasms/genetics/metabolism ; Nucleotide Motifs/genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {The processes regulating telomere function have major impacts on fundamental issues in human cancer biology. First, active telomere maintenance is almost always required for full oncogenic transformation of human cells, through cellular immortalization by endowment of an infinite replicative potential. Second, the attrition that telomeres undergo upon replication is responsible for the finite replicative life span of cells in culture, a process called senescence, which is of paramount importance for tumor suppression in vivo. The process of telomere-based senescence is intimately coupled to the induction of a DNA damage response emanating from telomeres, which can be elicited by both the ATM and ATR dependent pathways. At telomeres, the shelterin complex is constituted by a group of six proteins which assembles quantitatively along the telomere tract, and imparts both telomere maintenance and telomere protection. Shelterin is known to regulate the action of telomerase, and to prevent inappropriate DNA damage responses at chromosome ends, mostly through inhibition of ATM and ATR. The roles of shelterin have increasingly been associated with transient interactions with downstream factors that are not associated quantitatively or stably with telomeres. Here, some of the important known interactions between shelterin and these associated factors and their interplay to mediate telomere functions are reviewed.},
}
@article {pmid21738493,
year = {2011},
author = {Treff, NR and Su, J and Taylor, D and Scott, RT},
title = {Telomere DNA deficiency is associated with development of human embryonic aneuploidy.},
journal = {PLoS genetics},
volume = {7},
number = {6},
pages = {e1002161},
pmid = {21738493},
issn = {1553-7404},
mesh = {*Aneuploidy ; Blastocyst/metabolism ; Cell Line, Tumor ; Embryo, Mammalian/metabolism ; Embryonic Development/*genetics ; Female ; Gene Expression Regulation, Developmental ; Genome, Human/genetics ; HeLa Cells ; Humans ; Jurkat Cells ; K562 Cells ; Oocytes/metabolism ; Telomere/*genetics ; },
abstract = {Aneuploidy represents the most prevalent form of genetic instability found in human embryos and is the leading genetic cause of miscarriage and developmental delay in newborns. Telomere DNA deficiency is associated with genomic instability in somatic cells and may play a role in development of aneuploidy commonly found in female germ cells and human embryos. To test this hypothesis, we developed a method capable of quantifying telomere DNA in parallel with 24-chromosome aneuploidy screening from the same oocyte or embryo biopsy. Aneuploid human polar bodies possessed significantly less telomere DNA than euploid polar bodies from sibling oocytes (-3.07 fold, P = 0.016). This indicates that oocytes with telomere DNA deficiency are prone to aneuploidy development during meiosis. Aneuploid embryonic cells also possessed significantly less telomere DNA than euploid embryonic cells at the cleavage stage (-2.60 fold, P = 0.002) but not at the blastocyst stage (-1.18 fold, P = 0.340). The lack of a significant difference at the blastocyst stage was found to be due to telomere DNA normalization between the cleavage and blastocyst stage of embryogenesis and not due to developmental arrest of embryos with short telomeres. Heterogeneity in telomere length within oocytes may provide an opportunity to improve the treatment of infertility through telomere-based selection of oocytes and embryos with reproductive competence.},
}
@article {pmid21737157,
year = {2013},
author = {Olivieri, F and Antonicelli, R and Recchioni, R and Mariotti, S and Marcheselli, F and Lisa, R and Spazzafumo, L and Galeazzi, R and Caraceni, D and Testa, R and Latini, R and Procopio, AD},
title = {Telomere/telomerase system impairment in circulating angiogenic cells of geriatric patients with heart failure.},
journal = {International journal of cardiology},
volume = {164},
number = {1},
pages = {99-105},
doi = {10.1016/j.ijcard.2011.06.091},
pmid = {21737157},
issn = {1874-1754},
mesh = {Aged ; Aged, 80 and over ; *Cells ; Female ; Heart Failure/*blood ; Humans ; Male ; *Neovascularization, Physiologic ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {BACKGROUND: The functional characteristics of circulating angiogenic cells (CACs) are impaired in congestive heart failure (CHF) patients, suggesting that CAC dysfunction could contribute to CHF pathogenesis. However, the underlying mechanisms are only partly unraveled. No data are currently available regarding telomere/telomerase system in CACs of CHF patients.<br><br>METHODS: CACs were obtained from 80 subjects: 40 healthy control subjects (CTR) [median age (IQR), 80 (76-85 yrs)] and 40 patients affected by post-ischemic cardiomyopathy CHF [median age (IQR), 82 (77-89)]. CAC and leukocyte telomere length, assessed as T/S ratio, and telomerase (TERT) activity were determined in all the enrolled subjects. Specificity and sensitivity of CAC and leukocyte T/S in discriminating between CHF and CTR were evaluated using Receiver Operator Characteristic (ROC) curve analysis and reported as AUC values. CD34+/VEGFR2+ number and pro-inflammatory cytokines plasma levels, such as IL-6 and TNF-&#x3b1;, were also measured.<br><br>RESULTS: CAC T/S and TERT activity were significantly reduced in CHF patients compared to CTR subjects. In leukocytes, only a significant T/S reduction was observed. AUC values were higher for CAC T/S with respect to leukocyte T/S (AUC=0.89, and AUC=0.73, P<0.01, respectively). In multivariate analysis, leukocyte T/S, CAC T/S, CAC TERT activity and NT-proBNP levels were confirmed as parameters significantly associated with CHF. CD34+/VEGFR2+ number, IL-6 and TNF-&#x3b1; plasma levels were significantly increased in CHF patients.<br><br>CONCLUSIONS: CACs from CHF patients are characterized by telomere/telomerase system impairment, providing new insight into the clinical relevance of CACs in CHF pathogenesis.},
}
@article {pmid21735056,
year = {2012},
author = {Ishikawa, N and Nakamura, K and Izumiyama, N and Aida, J and Sawabe, M and Arai, T and Kishimoto, H and Fujiwara, M and Ishii, A and Takubo, K},
title = {Telomere length dynamics in the human pituitary gland: robust preservation throughout adult life to centenarian age.},
journal = {Age (Dordrecht, Netherlands)},
volume = {34},
number = {4},
pages = {795-804},
pmid = {21735056},
issn = {1574-4647},
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Aging/*genetics ; Analysis of Variance ; Autopsy ; Blotting, Southern ; Child ; Child, Preschool ; Female ; Humans ; Immunohistochemistry ; Infant ; Male ; Middle Aged ; Pituitary Gland/*metabolism/*pathology ; Polymorphism, Restriction Fragment Length ; Sampling Studies ; Telomere/genetics/*ultrastructure ; Telomere Homeostasis/*physiology ; Young Adult ; },
abstract = {Many studies have demonstrated the association between telomere length in mitotic cells and aging, but the relationship between telomere length in post-mitotic cells and aging in human populations has remained largely unclear. In this study, we assessed the dynamics of telomere length (terminal restriction fragment length-TRF) in normal pituitary glands obtained at autopsy from 65 patients aged between 0 and 100 years. The initial length (the value for neonatal pituitary) was 14.2 ± 1.1 kbp (mean of the median TRF value ± SD), being the longest among those for other systemic organs. The annual telomere reduction rates for pituitary (21 bp) were equivalent to or below the lowest values for various cells and tissues. Hence, comparison of TRF lengths among organs revealed that the pituitary gland retained longer telomeres than most other organs throughout life. The median TRF value showed a significant decrease between newborns and the 61-75 age group, but then leveled off or increased slightly in advanced age groups. These data indicate that innate telomere length is highly conserved in the pituitary and suggest that pituitary telomere length provides a good basic indicator for studies of telomere biology.},
}
@article {pmid21734364,
year = {2011},
author = {Sukenik-Halevy, R and Biron-Shental, T and Sharony, R and Fejgin, MD and Amiel, A},
title = {Telomeres in trisomy 21 amniocytes.},
journal = {Cytogenetic and genome research},
volume = {135},
number = {1},
pages = {12-18},
doi = {10.1159/000329714},
pmid = {21734364},
issn = {1424-859X},
mesh = {Amniocentesis ; Amniotic Fluid/*cytology ; Case-Control Studies ; Cell Culture Techniques ; Cytogenetics/*methods ; Dementia/diagnosis/genetics/pathology ; *Down Syndrome/diagnosis/genetics/pathology ; Female ; Fluorescent Antibody Technique ; *Gene Dosage ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Leukemia/diagnosis/genetics/pathology ; Pregnancy ; *Prenatal Diagnosis ; RNA/*genetics ; Risk Factors ; Software ; Telomerase/*genetics ; Telomere/chemistry ; },
abstract = {Individuals with trisomy 21 have an increased risk of developing leukemia and premature dementia. They also have a higher rate of telomere loss. The aim of the study was to compare telomere length and the hTERC gene copy number, which encodes the telomerase RNA subunit, in amniocytes of trisomy 21 conceptions and normal pregnancies. A quantitative fluorescence-in-situ protocol (Q-FISH) was used to compare telomere length in amniocytes cultured from 11 trisomy 21 conceptions and from 14 normal pregnancies. Quantification was conducted using novel computer software. Fluorescence in situ hybridization (FISH) was used to assess the percentage of cells with additional copies of hTERC. We found that the immunofluorescence intensity, which represents telomere length, was significantly lower in amniocytes from trisomy 21 conceptions compared to the control group. The trisomy 21 group had a higher number of cells with additional copies of hTERC. This observation could be one of the cytogenetic parameters that represent a state of genetic instability and might play a role in the pathomechanism of typical features of Down syndrome, such as dementia and malignancy.},
}
@article {pmid21732567,
year = {2011},
author = {Sell, C},
title = {Ku circles the telomere?.},
journal = {Aging},
volume = {3},
number = {4},
pages = {344-345},
pmid = {21732567},
issn = {1945-4589},
mesh = {Antigens, Nuclear/*chemistry/*metabolism ; Cell Line ; DNA/chemistry/metabolism ; DNA-Binding Proteins/*chemistry/*metabolism ; Humans ; Ku Autoantigen ; Nucleic Acid Conformation ; Protein Subunits/chemistry/metabolism ; Telomere/*metabolism ; },
}
@article {pmid21732565,
year = {2011},
author = {Brosh, RM},
title = {Put on your thinking cap: G-quadruplexes, helicases, and telomeres.},
journal = {Aging},
volume = {3},
number = {4},
pages = {332-335},
pmid = {21732565},
issn = {1945-4589},
mesh = {Animals ; DNA/chemistry/genetics/metabolism ; DNA Helicases/*metabolism ; *G-Quadruplexes ; Humans ; Substrate Specificity ; Telomere/chemistry/genetics/*metabolism ; },
}
@article {pmid21732564,
year = {2011},
author = {Ishikawa, N and Nakamura, K and Izumiyama-Shimomura, N and Aida, J and Ishii, A and Goto, M and Ishikawa, Y and Asaka, R and Matsuura, M and Hatamochi, A and Kuroiwa, M and Takubo, K},
title = {Accelerated in vivo epidermal telomere loss in Werner syndrome.},
journal = {Aging},
volume = {3},
number = {4},
pages = {417-429},
pmid = {21732564},
issn = {1945-4589},
mesh = {Adult ; Aging/genetics ; Asian People/genetics ; Cells, Cultured ; Epidermal Cells ; Epidermis/pathology/*physiology ; Female ; Humans ; Male ; Telomere/*pathology ; Werner Syndrome/*genetics/pathology ; },
abstract = {Many data pertaining to the accelerated telomere loss in cultured cells derived from Werner syndrome (WS), a representative premature aging syndrome, have been accumulated. However, there have been no definitive data on in vivo telomere shortening in WS patients. In the present study, we measured terminal restriction fragment (TRF) lengths of 10 skin samples collected from extremities of 8 WS patients aged between 30 and 61 years that had been surgically amputated because of skin ulceration, and estimated the annual telomere loss. Whereas the values of TRF length in younger WS patients (in their thirties) were within the normal range, those in older WS patients were markedly shorter relative to non‐WS controls. Regression analyses indicated that the TRF length in WS was significantly shorter than that in controls (p < 0.001). Furthermore, we found that TRF lengths in muscle adjacent to the examined epidermis were also significantly shorter than those of controls (p = 0.047). These data demonstrate for the first time that in vivo telomere loss is accelerated in systemic organs of WS patients, suggesting that abnormal telomere erosion is one of the major causes of early onset of age‐related symptoms and a predisposition to sarcoma and carcinoma in WS.},
}
@article {pmid21732364,
year = {2012},
author = {Zahnreich, S and Krunic, D and Melnikova, L and Szejka, A and Drossel, B and Sabatier, L and Durante, M and Ritter, S and Fournier, C},
title = {Duplicated chromosomal fragments stabilize shortened telomeres in normal human IMR-90 cells before transition to senescence.},
journal = {Journal of cellular physiology},
volume = {227},
number = {5},
pages = {1932-1940},
doi = {10.1002/jcp.22921},
pmid = {21732364},
issn = {1097-4652},
mesh = {Cell Line ; Cellular Senescence/*physiology ; *Chromosome Duplication ; Chromosomes, Human/*metabolism ; Cytogenetic Analysis ; Fibroblasts/cytology/physiology ; Humans ; In Situ Hybridization, Fluorescence/methods ; Telomere/*metabolism ; },
abstract = {To assess why during in vitro aging of fibroblasts the maintenance of chromosomal stability is effective or occasionally fails, a detailed cytogenetic analysis was performed in normal human IMR-90 fetal lung fibroblasts. The onset of senescence was inferred from proliferation activity, expression pattern of cell cycle regulating proteins, activity of β-galactosidase, and morphological features. Over the period of proliferation, a moderate increase of non-transmissible structural chromosomal aberrations was observed. In addition, using fluorescence in situ hybridization (mFISH and mBAND) techniques, we detected clonally expanding translocations in up to 70% of the analyzed metaphases, all involving one homolog of chromosome 9 as an acceptor. Notably, chromosomes are randomly involved as donor-chromosomes of the translocated terminal acentric fragments. These fragments result from duplication because the donor chromosomes are apparently unchanged. Interstitial telomeric signals were detectable at fusion sites, most likely belonging to chromosome 9. Quantitative fluorescence in situ hybridization (QFISH) detecting telomere sequences, followed by mFISH technique revealed that already in young cells the respective telomeres of one chromosome 9 were particularly short. For the first time, we have observed dysfunctional telomeres of one specific chromosome in normal human cells that have been stabilized by duplicated terminal sequences.},
}
@article {pmid21731707,
year = {2011},
author = {Xin, ZT and Carroll, KA and Kumar, N and Song, K and Ly, H},
title = {Transcriptional activation of TINF2, a gene encoding the telomere-associated protein TIN2, by Sp1 and NF-κB factors.},
journal = {PloS one},
volume = {6},
number = {6},
pages = {e21333},
pmid = {21731707},
issn = {1932-6203},
support = {UL1RR025008/RR/NCRR NIH HHS/United States ; P30 CA138292/CA/NCI NIH HHS/United States ; UL1 TR000454/TR/NCATS NIH HHS/United States ; T32 GM008490/GM/NIGMS NIH HHS/United States ; P30CA138292/CA/NCI NIH HHS/United States ; UL1 RR025008/RR/NCRR NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Binding Sites ; Cell Line ; Cloning, Molecular ; Drosophila ; Gene Expression Regulation ; HeLa Cells ; Humans ; Luciferases/metabolism ; Mice ; Mutation/genetics ; NF-kappa B/*metabolism ; Promoter Regions, Genetic/genetics ; Protein Binding ; Reproducibility of Results ; Sp1 Transcription Factor/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*genetics/metabolism ; Transcription, Genetic ; Transcriptional Activation/*genetics ; },
abstract = {The expression of the telomere-associated protein TIN2 has been shown to be essential for early embryonic development in mice and for development of a variety of human malignancies. Recently, germ-line mutations in TINF2, which encodes for the TIN2 protein, have been identified in a number of patients with bone-marrow failure syndromes. Yet, the molecular mechanisms that regulate TINF2 expression are largely unknown. To elucidate the mechanisms involved in human TINF2 regulation, we cloned a 2.7 kb genomic DNA fragment containing the putative promoter region and, through deletion analysis, identified a 406 bp region that functions as a minimal promoter. This promoter proximal region is predicted to contain several putative Sp1 and NF-κB binding sites based on bioinformatic analysis. Direct binding of the Sp1 and NF-κB transcription factors to the TIN2 promoter sequence was demonstrated by electrophoretic mobility shift assay (EMSA) and/or chromatin immunoprecipitation (ChIP) assays. Transfection of a plasmid carrying the Sp1 transcription factor into Sp-deficient SL2 cells strongly activated TIN2 promoter-driven luciferase reporter expression. Similarly, the NF-κB molecules p50 and p65 were found to strongly activate luciferase expression in NF-κB knockout MEFs. Mutating the predicted transcription factor binding sites effectively reduced TIN2 promoter activity. Various known chemical inhibitors of Sp1 and NF-κB could also strongly inhibit TIN2 transcriptional activity. Collectively, our results demonstrate the important roles that Sp1 and NF-κB play in regulating the expression of the human telomere-binding protein TIN2, which can shed important light on its possible role in causing various forms of human diseases and cancers.},
}
@article {pmid21731055,
year = {2012},
author = {Mirabello, L and Yeager, M and Chowdhury, S and Qi, L and Deng, X and Wang, Z and Hutchinson, A and Savage, SA},
title = {Worldwide genetic structure in 37 genes important in telomere biology.},
journal = {Heredity},
volume = {108},
number = {2},
pages = {124-133},
pmid = {21731055},
issn = {1365-2540},
support = {HHSN261200800001C/RC/CCR NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; Z01 CP010190-02/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Gene Frequency ; Genetic Variation ; Genetics, Population ; *Genome, Human ; HapMap Project ; Haplotypes ; Humans ; Polymorphism, Single Nucleotide ; Proteins/*genetics ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres form the ends of eukaryotic chromosomes and are vital in maintaining genetic integrity. Telomere dysfunction is associated with cancer and several chronic diseases. Patterns of genetic variation across individuals can provide keys to further understanding the evolutionary history of genes. We investigated patterns of differentiation and population structure of 37 telomere maintenance genes among 53 worldwide populations. Data from 898 unrelated individuals were obtained from the genome-wide scan of the Human Genome Diversity Panel (HGDP) and from 270 unrelated individuals from the International HapMap Project at 716 single-nucleotide polymorphism (SNP) loci. We additionally compared this gene set to HGDP data at 1396 SNPs in 174 innate immunity genes. The majority of the telomere biology genes had low to moderate haplotype diversity (45-85%), high ancestral allele frequencies (>60%) and low differentiation (FST<0.10). Heterozygosity and differentiation were significantly lower in telomere biology genes compared with the innate immunity genes. There was evidence of evolutionary selection in ACD, TERF2IP, NOLA2, POT1 and TNKS in this data set, which was consistent in HapMap 3. TERT had higher than expected levels of haplotype diversity, likely attributable to a lack of linkage disequilibrium, and a potential cancer-associated SNP in this gene, rs2736100, varied substantially in genotype frequency across major continental regions. It is possible that the genes under selection could influence telomere biology diseases. As a group, there appears to be less diversity and differentiation in telomere biology genes than in genes with different functions, possibly due to their critical role in telomere maintenance and chromosomal stability.},
}
@article {pmid21730353,
year = {2011},
author = {Sekulovic, S and Gylfadottir, V and Vulto, I and Gasparetto, M and Even, Y and Brookes, C and Smith, C and Eaves, CJ and Lansdorp, PM and Rossi, FM and Humphries, RK},
title = {Prolonged self-renewal activity unmasks telomerase control of telomere homeostasis and function of mouse hematopoietic stem cells.},
journal = {Blood},
volume = {118},
number = {7},
pages = {1766-1773},
pmid = {21730353},
issn = {1528-0020},
support = {MOP82382/CAPMC/CIHR/Canada ; HL065430/HL/NHLBI NIH HHS/United States ; MOP38075/CAPMC/CIHR/Canada ; R01 HL065430/HL/NHLBI NIH HHS/United States ; GMH79042/CAPMC/CIHR/Canada ; },
mesh = {Animals ; Cell Proliferation ; *DNA Damage ; Gene Deletion ; Gene Expression Regulation ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/cytology/*enzymology/metabolism ; Histones/genetics ; Mice ; Mice, Inbred C57BL ; Telomerase/genetics/*metabolism ; *Telomere ; },
abstract = {Strategies for expanding hematopoietic stem cells (HSCs) could have significant utility for transplantation-based therapies. However, deleterious consequences of such manipulations remain unknown. Here we examined the impact of HSC self-renewal divisions in vitro and in vivo on their subsequent regenerative and continuing ability to sustain blood cell production in the absence of telomerase. HSC expansion in vitro was obtained using a NUP98-HOXA10hd transduction strategy and, in vivo, using a serial transplant protocol. We observed ~ 10kb telomere loss in leukocytes produced in secondary mice transplanted with HSCs regenerated in primary recipients of NUP98-HOXA10hd-transduced and in vitro-expanded Tert(-/-) HSCs 6 months before. The second generation leukocytes also showed elevated expression of γH2AX (relative to control) indicative of greater accumulating DNA damage. In contrast, significant telomere shortening was not detected in leukocytes produced from freshly isolated, serially transplanted wild-type (WT) or Tert(-/-) HSCs, suggesting that HSC replication posttransplant is not limited by telomere shortening in the mouse. These findings document a role of telomerase in telomere homeostasis, and in preserving HSC functional integrity on prolonged self-renewal stimulation.},
}
@article {pmid21730239,
year = {2011},
author = {Willeit, P and Willeit, J and Kloss-Brandstätter, A and Kronenberg, F and Kiechl, S},
title = {Fifteen-year follow-up of association between telomere length and incident cancer and cancer mortality.},
journal = {JAMA},
volume = {306},
number = {1},
pages = {42-44},
doi = {10.1001/jama.2011.901},
pmid = {21730239},
issn = {1538-3598},
support = {RG/08/014/24067/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Adult ; Aged ; C-Reactive Protein/analysis ; Female ; Follow-Up Studies ; Humans ; Incidence ; Italy/epidemiology ; Leukocytes ; Male ; Middle Aged ; Neoplasms/blood/*mortality ; Prospective Studies ; Telomere/*ultrastructure ; },
}
@article {pmid21722804,
year = {2011},
author = {Carbonari, M and Cibati, M and Sette, N and Catizone, A and Fiorilli, M},
title = {Measurement of telomere length using PNA probe by cytometry.},
journal = {Methods in cell biology},
volume = {103},
number = {},
pages = {189-202},
doi = {10.1016/B978-0-12-385493-3.00008-5},
pmid = {21722804},
issn = {0091-679X},
mesh = {Base Sequence ; Carbocyanines/analysis/metabolism ; DNA/*chemistry/genetics ; Flow Cytometry/*methods ; Fluorescent Dyes/analysis/metabolism ; Formamides/chemistry ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Microscopy, Confocal ; Molecular Sequence Data ; Nucleic Acid Probes/*analysis/chemical synthesis ; Peptide Nucleic Acids/*analysis/chemical synthesis ; Ploidies ; T-Lymphocytes/chemistry/*pathology ; Telomerase/metabolism ; Telomere/*chemistry/genetics ; Tumor Cells, Cultured ; },
abstract = {Peptide nucleic acid (PNA) probes hybridize to denatured telomeric sequences in cells permeabilized in hot formamide. In reported protocols, the hybridization was conducted in solutions with high formamide concentrations to avoid the DNA renaturation that can hamper binding of the oligo-PNA probe to specific sequences. We postulated that telomeric DNA, confined in the nuclear microvolume, is not able to properly renature after hot formamide denaturation. Therefore, to improve hybridization conditions between the probe and the target sequences, it might be possible to add probe to sample after the complete removal of formamide.},
}
@article {pmid21720548,
year = {2011},
author = {Svenson, U and Nordfjäll, K and Baird, D and Roger, L and Osterman, P and Hellenius, ML and Roos, G},
title = {Blood cell telomere length is a dynamic feature.},
journal = {PloS one},
volume = {6},
number = {6},
pages = {e21485},
pmid = {21720548},
issn = {1932-6203},
support = {06-0914/AICR_/Worldwide Cancer Research/United Kingdom ; /CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Adult ; Aged ; Blood Cells/*metabolism ; Blood Donors ; Child, Preschool ; Female ; Humans ; Infant ; Male ; Middle Aged ; Telomere/*metabolism ; },
abstract = {There is a considerable heterogeneity in blood cell telomere length (TL) for individuals of similar age and recent studies have revealed that TL changes by time are dependent on TL at baseline. TL is partly inherited, but results from several studies indicate that e.g. life style and/or environmental factors can affect TL during life. Collectively, these studies imply that blood cell TL might fluctuate during a life time and that the actual TL at a defined time point is the result of potential regulatory mechanism(s) and environmental factors. We analyzed relative TL (RTL) in subsequent blood samples taken six months apart from 50 individuals and found significant associations between RTL changes and RTL at baseline. Individual RTL changes per month were more pronounced than the changes recorded in a previously studied population analyzed after 10 years' follow up. The data argues for an oscillating TL pattern which levels out at longer follow up times. In a separate group of five blood donors, a marked telomere loss was demonstrated within a six month period for one donor where after TL was stabilized. PCR determined RTL changes were verified by Southern blotting and STELA (single telomere elongation length analysis). The STELA demonstrated that for the donor with a marked telomere loss, the heterogeneity of the telomere distribution decreased considerably, with a noteworthy loss of the largest telomeres. In summary, the collected data support the concept that individual blood cell telomere length is a dynamic feature and this will be important to recognize in future studies of human telomere biology.},
}
@article {pmid21719641,
year = {2011},
author = {Heaphy, CM and de Wilde, RF and Jiao, Y and Klein, AP and Edil, BH and Shi, C and Bettegowda, C and Rodriguez, FJ and Eberhart, CG and Hebbar, S and Offerhaus, GJ and McLendon, R and Rasheed, BA and He, Y and Yan, H and Bigner, DD and Oba-Shinjo, SM and Marie, SK and Riggins, GJ and Kinzler, KW and Vogelstein, B and Hruban, RH and Maitra, A and Papadopoulos, N and Meeker, AK},
title = {Altered telomeres in tumors with ATRX and DAXX mutations.},
journal = {Science (New York, N.Y.)},
volume = {333},
number = {6041},
pages = {425},
pmid = {21719641},
issn = {1095-9203},
support = {P50 NS020023/NS/NINDS NIH HHS/United States ; R01 CA113669-06/CA/NCI NIH HHS/United States ; R01 CA121113-01/CA/NCI NIH HHS/United States ; R01 CA140316-01A1/CA/NCI NIH HHS/United States ; R01 CA140316/CA/NCI NIH HHS/United States ; P50 NS020023-28/NS/NINDS NIH HHS/United States ; R01 NS055089-01A2/NS/NINDS NIH HHS/United States ; P01 CA134292-01A1/CA/NCI NIH HHS/United States ; R37 CA011898/CA/NCI NIH HHS/United States ; R01 NS055089/NS/NINDS NIH HHS/United States ; P50 CA062924/CA/NCI NIH HHS/United States ; R37 CA011898-41/CA/NCI NIH HHS/United States ; R01 CA121113/CA/NCI NIH HHS/United States ; P01 CA134292/CA/NCI NIH HHS/United States ; R01 CA113669/CA/NCI NIH HHS/United States ; P50 CA062924-06/CA/NCI NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing/*genetics/metabolism ; Carcinoma, Neuroendocrine/*genetics/pathology/physiopathology ; Cell Nucleus/metabolism ; Central Nervous System Neoplasms/*genetics/pathology/physiopathology ; Chromatin Assembly and Disassembly ; Co-Repressor Proteins ; DNA Helicases/*genetics/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Molecular Chaperones ; Mutant Proteins/genetics/metabolism ; Mutation ; Nuclear Proteins/*genetics/metabolism ; Pancreatic Neoplasms/*genetics/pathology/physiopathology ; Phenotype ; Telomere/*physiology/ultrastructure ; X-linked Nuclear Protein ; },
abstract = {The proteins encoded by ATRX and DAXX participate in chromatin remodeling at telomeres and other genomic sites. Because inactivating mutations of these genes are common in human pancreatic neuroendocrine tumors (PanNETs), we examined the telomere status of these tumors. We found that 61% of PanNETs displayed abnormal telomeres that are characteristic of a telomerase-independent telomere maintenance mechanism termed ALT (alternative lengthening of telomeres). All of the PanNETs exhibiting these abnormal telomeres had ATRX or DAXX mutations or loss of nuclear ATRX or DAXX protein. ATRX mutations also correlate with abnormal telomeres in tumors of the central nervous system. These data suggest that an alternative telomere maintenance function may operate in human tumors with alterations in the ATRX or DAXX genes.},
}
@article {pmid21719360,
year = {2011},
author = {Stacey, M and Fox, P and Buescher, S and Kolb, J},
title = {Nanosecond pulsed electric field induced cytoskeleton, nuclear membrane and telomere damage adversely impact cell survival.},
journal = {Bioelectrochemistry (Amsterdam, Netherlands)},
volume = {82},
number = {2},
pages = {131-134},
doi = {10.1016/j.bioelechem.2011.06.002},
pmid = {21719360},
issn = {1878-562X},
mesh = {Cell Line ; Cell Survival ; Cytoskeleton/*ultrastructure ; Electricity ; *Electroporation ; HeLa Cells ; Humans ; Jurkat Cells ; Nuclear Envelope/*ultrastructure ; Telomere/*ultrastructure ; },
abstract = {We investigated the effects of nanosecond pulsed electric fields (nsPEF) on three human cell lines and demonstrated cell shrinkage, breakdown of the cytoskeleton, nuclear membrane and chromosomal telomere damage. There was a differential response between cell types coinciding with cell survival. Jurkat cells showed cytoskeleton, nuclear membrane and telomere damage that severely impacted cell survival compared to two adherent cell lines. Interestingly, disruption of the actin cytoskeleton in adherent cells prior to nsPEF exposure significantly reduced cell survival. We conclude that nsPEF applications are able to induce damage to the cytoskeleton and nuclear membrane. Telomere sequences, regions that tether and stabilize DNA to the nuclear membrane, are severely compromised as measured by a pan-telomere probe. Internal pore formation following nsPEF applications has been described as a factor in induced cell death. Here we suggest that nsPEF induced physical changes to the cell in addition to pore formation need to be considered as an alternative method of cell death. We suggest nsPEF electrochemical induced depolymerization of actin filaments may account for cytoskeleton and nuclear membrane anomalies leading to sensitization.},
}
@article {pmid21717459,
year = {2012},
author = {Zane, L and Sibon, D and Capraro, V and Galia, P and Karam, M and Delfau-Larue, MH and Gilson, E and Gessain, A and Gout, O and Hermine, O and Mortreux, F and Wattel, E},
title = {HTLV-1 positive and negative T cells cloned from infected individuals display telomerase and telomere genes deregulation that predominate in activated but untransformed CD4+ T cells.},
journal = {International journal of cancer},
volume = {131},
number = {4},
pages = {821-833},
doi = {10.1002/ijc.26270},
pmid = {21717459},
issn = {1097-0215},
mesh = {Base Sequence ; CD4-Positive T-Lymphocytes/*virology ; Clone Cells ; DNA Primers ; HTLV-I Infections/*enzymology/genetics/immunology ; Homeostasis ; Human T-lymphotropic virus 1/*isolation &amp; purification ; Humans ; Lymphocyte Activation ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Shelterin Complex ; Telomerase/*genetics ; *Telomere ; Telomere-Binding Proteins ; Transcription, Genetic ; Transcriptome ; },
abstract = {Untransformed HTLV-1 positive CD4(+) cells from infected individuals are selected for expressing tax and displaying morphological features consistent with telomere dysfunctions. We show that in resting HTLV-1 positive CD4(+) cells cloned from patients, hTERT expression parallels tax expression and cell cycling. Upon activation, these cells dramatically augment tax expression, whereas their increase in telomerase activity is about 20 times lower than that of their uninfected counterpart. Activated HTLV-1 positive CD4(+) but not uninfected CD4(+) or CD8(+) clones also repress the transcription of TRF1, TPP1, TANK1, POT1, DNA-PKc and Ku80. Both infected and uninfected lymphocytes from infected individuals shared common telomere gene deregulations toward a pattern consistent with premature senescence. ATLL cells displayed the highest telomerase activity (TA) whereas recovered a telomere gene transcriptome close to that of normal CD4(+) cells. In conclusion HTLV-1-dependent telomere modulations seem involved in clonal expansion, immunosuppression, tumor initiation and progression.},
}
@article {pmid21712819,
year = {2011},
author = {McKerlie, M and Zhu, XD},
title = {Cyclin B-dependent kinase 1 regulates human TRF1 to modulate the resolution of sister telomeres.},
journal = {Nature communications},
volume = {2},
number = {},
pages = {371},
pmid = {21712819},
issn = {2041-1723},
support = {31758-1/CAPMC/CIHR/Canada ; 69077-2/CAPMC/CIHR/Canada ; },
mesh = {CDC2 Protein Kinase/*metabolism ; Cells, Cultured ; Chromatids/genetics/*physiology ; Chromatin Immunoprecipitation ; Cyclin B/*metabolism ; Electrophoretic Mobility Shift Assay ; Humans ; In Situ Hybridization, Fluorescence ; In Situ Nick-End Labeling ; Microscopy, Fluorescence ; Mutagenesis, Site-Directed ; Phosphorylation ; Telomere/genetics/*physiology ; Telomeric Repeat Binding Protein 1/*metabolism ; Threonine/metabolism ; },
abstract = {Cyclin B-Cdk1 is a key mediator of mitotic entry; however, little is known about its role in the separation of sister chromatids. Here we report that upon mitotic entry, Cdk1 specifically phosphorylates threonine 371 of TRF1, a telomere binding protein implicated in the regulation of sister telomere cohesion. Such phosphorylation is removed in late mitosis when Cdk1 activity is inhibited, indicative of a tight regulation of T371 phosphorylation. We show that T371 phosphorylation by Cdk1 keeps TRF1 free of chromatin and this phosphorylation is associated with loss of telomere-bound TRF1 and TIN2, and a reduction in telomere heterochromatin. We find that a phosphomimic mutation at T371 of TRF1 induces telomere deprotection, resulting in telomere loss and the formation of telomere fusions, whereas a non-phosphorylatable substitution of T371 blocks sister telomere resolution, promotes micronuclei formation and impairs cell proliferation. Our work suggests that Cdk1 controls TRF1 association with telomeres to facilitate temporal telomere de-protection, which is essential for sister telomere resolution.},
}
@article {pmid21710574,
year = {2012},
author = {Mirsaidi, A and Kleinhans, KN and Rimann, M and Tiaden, AN and Stauber, M and Rudolph, KL and Richards, PJ},
title = {Telomere length, telomerase activity and osteogenic differentiation are maintained in adipose-derived stromal cells from senile osteoporotic SAMP6 mice.},
journal = {Journal of tissue engineering and regenerative medicine},
volume = {6},
number = {5},
pages = {378-390},
doi = {10.1002/term.440},
pmid = {21710574},
issn = {1932-7005},
mesh = {Adipose Tissue/*metabolism/pathology ; Aging/*metabolism/pathology ; Animals ; Bone Marrow Cells/*metabolism/pathology ; Mice ; Mice, Mutant Strains ; Osteoporosis/*metabolism/pathology ; Stem Cells/*metabolism/pathology ; Stromal Cells/metabolism/pathology ; Telomerase/*metabolism ; Telomere/*metabolism/pathology ; },
abstract = {Adipose tissue provides for a rich and easily accessible source of multipotent stromal cells and thus offers the potential for autologous cell-based therapy for a number of degenerative diseases. Senile osteoporosis is characterized by a reduction in bone quality, which is associated with inadequacies in bone marrow stromal cell (BMSC) differentiation. In the present study, we have characterized adipose-derived stromal cells (ASCs) isolated from aged osteoporotic mice and evaluated their suitability as a source of osteogenic precursor cells. Significant reductions in both tibia bone quality and telomere length in liver tissue were observed in the senescence-accelerated mouse prone 6 strain (SAMP6), as compared to the control age-matched senescence-accelerated mouse resistant 1 strain (SAMR1), thus confirming osteoporosis and accelerated ageing traits in this model. ASCs isolated from inguinal fat expressed mesenchymal surface markers and were capable of differentiating along the osteoblast, adipocyte and chondrocyte lineages. Telomere length was not compromised in ASCs from SAMP6 mice but was actually found to be significantly increased as compared to control SAMR1 mice. Furthermore, ASCs from both strains were comparable in terms of telomerase activity, p21 mRNA expression, SA-β-gal activity and proliferative capacity. The overall osteogenic and adipogenic potential of ASCs was comparable between SAMP6 and SAMR1 strains, as determined by quantitative molecular, biochemical and histological analyses. In conclusion, adipose tissue may represent a promising autologous cell source for the development of novel bone regenerative therapeutic strategies in the treatment of age-related osteoporosis.},
}
@article {pmid21709411,
year = {2011},
author = {Samassekou, O and Yan, J},
title = {Polymorphism in a human chromosome-specific interstitial telomere-like sequence at 22q11.2.},
journal = {Cytogenetic and genome research},
volume = {134},
number = {3},
pages = {174-181},
doi = {10.1159/000328862},
pmid = {21709411},
issn = {1424-859X},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Base Sequence ; Case-Control Studies ; Child ; Child, Preschool ; *Chromosomes, Human, Pair 22 ; DNA Primers ; DiGeorge Syndrome/genetics ; Female ; Humans ; Male ; Middle Aged ; Polymerase Chain Reaction ; *Polymorphism, Genetic ; *Telomere ; Young Adult ; },
abstract = {Interstitial telomeric sequences (ITSs) are common in human. We previously reported the presence of an ITS at 22q11.2 which is in the vicinity of the genomically unstable region involved in 22q11 rearrangements. Recently, we studied the molecular status of the ITS 22q11.2 in the normal population. The amplification of an ITS at 22q11.2 showed different patterns ranging from 1-4 kb, confirming the highly polymorphic nature of this sequence. The linkage analysis of the ITS at 22q11.2 in members of 10 different families demonstrated a strong relation between offspring and parents. In contrast, the study of a DiGeorge case and his 2 parents revealed the presence of a novel allele probably inherited from the father. These results open an avenue for the use of this sequence as an allelic marker, and its implication in 22q11.2-related pathogenesis.},
}
@article {pmid21708826,
year = {2012},
author = {Jones, AM and Beggs, AD and Carvajal-Carmona, L and Farrington, S and Tenesa, A and Walker, M and Howarth, K and Ballereau, S and Hodgson, SV and Zauber, A and Bertagnolli, M and Midgley, R and Campbell, H and Kerr, D and Dunlop, MG and Tomlinson, IP},
title = {TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres.},
journal = {Gut},
volume = {61},
number = {2},
pages = {248-254},
pmid = {21708826},
issn = {1468-3288},
support = {K/OPR/2/2/D333/CSO_/Chief Scientist Office/United Kingdom ; MC_U127527198/MRC_/Medical Research Council/United Kingdom ; G1001799/MRC_/Medical Research Council/United Kingdom ; P30 CA008748/CA/NCI NIH HHS/United States ; 090532//Wellcome Trust/United Kingdom ; CZB/4/449/CSO_/Chief Scientist Office/United Kingdom ; G0000657-53203/MRC_/Medical Research Council/United Kingdom ; 12076/CRUK_/Cancer Research UK/United Kingdom ; 090532/Z/09/Z/WT_/Wellcome Trust/United Kingdom ; C348/A12076/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Adenoma/genetics ; Aged ; Carcinoma/genetics ; Case-Control Studies ; Colorectal Neoplasms/*genetics ; Female ; *Genetic Predisposition to Disease ; Genotyping Techniques ; HCT116 Cells ; Humans ; Leukocytes ; Male ; Middle Aged ; Polymerase Chain Reaction ; *Polymorphism, Single Nucleotide ; RNA/*genetics ; Retrospective Studies ; Telomerase/*genetics ; Telomere/*chemistry/genetics ; },
abstract = {BACKGROUND AND AIMS: Shorter telomeres have been associated with increased risk of malignancy, including colorectal cancer (CRC). Telomere length is heritable and may be an intermediate phenotype linked to genetic susceptibility to CRC.<br><br>METHODS: In a large sample, the study investigated whether candidate single nucleotide polymorphisms (SNP) in 'telomere biology' genes were associated with telomere length in leucocytes. SNP associated with an increased risk of CRC were searched for separately.<br><br>RESULTS: Carriers of the common allele at SNP rs10936599, near the telomerase RNA component (TERC) locus, had significantly longer telomeres. It was independently found that the same rs10936599 allele was associated with increased risk of both CRC and colorectal adenomas. Neither telomere length nor CRC risk was associated with variation near telomerase reverse transcriptase or other telomere biology genes. In silico analysis showed that SNP rs2293607 was strongly correlated with rs10936599, mapped within TERC transcripts, had a predicted effect on messenger RNA folding and lay at a reported transcription factor binding site. TERC mRNA were expressed, differing only at the alleles of rs2293607, in CRC cell line HCT116. The long-telomere/CRC-risk allele was associated with higher levels of TERC mRNA and the formation of longer telomeres.<br><br>CONCLUSIONS: Common genetic variation at TERC is associated with both longer telomeres and an increased risk of CRC, a potential mechanism being reduced levels of cell senescence or death. This finding is somewhat paradoxical, given retrospective studies reporting that CRC cases have shorter telomeres than controls. One possibility is that that association actually results from poorer survival in patients with longer telomeres.},
}
@article {pmid21706060,
year = {2012},
author = {Doyle, KR and Mitchell, MA and Roberts, CL and James, S and Johnson, JE and Zhou, Y and von Mehren, M and Lev, D and Kipling, D and Broccoli, D},
title = {Validating a gene expression signature proposed to differentiate liposarcomas that use different telomere maintenance mechanisms.},
journal = {Oncogene},
volume = {31},
number = {2},
pages = {265-6; author reply 267-8},
pmid = {21706060},
issn = {1476-5594},
mesh = {*Gene Expression ; Humans ; Liposarcoma/*genetics/pathology ; *Telomere ; },
}
@article {pmid21697896,
year = {2011},
author = {Fyhrquist, F and Silventoinen, K and Saijonmaa, O and Kontula, K and Devereux, RB and de Faire, U and Os, I and Dahlöf, B},
title = {Telomere length and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study.},
journal = {Journal of human hypertension},
volume = {25},
number = {12},
pages = {711-718},
doi = {10.1038/jhh.2011.57},
pmid = {21697896},
issn = {1476-5527},
mesh = {Aged ; Aged, 80 and over ; Antihypertensive Agents/pharmacology/therapeutic use ; Atenolol/pharmacology/therapeutic use ; Blood Pressure/drug effects/physiology ; Cardiovascular Diseases/*epidemiology ; Comorbidity ; Diabetes Mellitus, Type 2/*epidemiology ; Female ; Follow-Up Studies ; Humans ; Hypertension/drug therapy/epidemiology/*pathology ; Hypertrophy, Left Ventricular/epidemiology/*pathology ; Leukocytes/*pathology/ultrastructure ; Losartan/pharmacology/therapeutic use ; Male ; Middle Aged ; Risk Factors ; Telomere/*pathology/ultrastructure ; Treatment Outcome ; },
abstract = {Short telomeres are associated with aging and age-related diseases. Our aim was to determine whether short leukocyte telomere length is associated with risk factors and cardiovascular diseases in a high-risk hypertensive population. We measured leukocyte telomere lengths at recruitment in 1271 subjects with hypertension and left ventricular hypertrophy (LVH) participating in the Lifestyle Interventions and Independence for Elders (LIFE) study. At baseline, short mean telomere length was associated with coronary artery disease in males (odds ratio (OR) 0.61, 95% confidence interval (CI) 0.39-0.95), and transient ischemic attack in females (OR 0.62 95% CI 0.39-0.99). Proportion of short telomeres (shorter than 5 kb) was associated with Framingham risk score (r=0.07, P<0.05), cerebrovascular disease (OR 1.18, 95% CI 1.01-1.15) and type 2 diabetes in men (OR 1.07, 95% CI 1.02-1.11). During follow-up, proportion of short telomeres was associated with combined cardiovascular mortality, stroke or angina pectoris (hazard ratio 1.04, 95% CI 1.01-1.07). Telomere length was not associated with smoking, body mass index, pulse pressure or self-reported use of alcohol. Our data suggest that reduced leukocyte telomere length is associated with cardiovascular risk factors and diseases as well as type 2 diabetes, and is a predictor of cardiovascular disease in elderly patients with hypertension and LVH.},
}
@article {pmid21697500,
year = {2011},
author = {Strandberg, TE and Saijonmaa, O and Tilvis, RS and Pitkälä, KH and Strandberg, AY and Miettinen, TA and Fyhrquist, F},
title = {Association of telomere length in older men with mortality and midlife body mass index and smoking.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {66},
number = {7},
pages = {815-820},
doi = {10.1093/gerona/glr064},
pmid = {21697500},
issn = {1758-535X},
mesh = {Adult ; Aged ; Aging/*genetics ; Blotting, Southern ; *Body Mass Index ; Cardiovascular Diseases/etiology/*genetics/mortality ; DNA/*analysis/genetics ; Finland/epidemiology ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Overweight/etiology/*genetics/mortality ; Retrospective Studies ; Risk Factors ; Smoking/*adverse effects/genetics/mortality ; Surveys and Questionnaires ; Survival Rate/trends ; Telomere/*chemistry/genetics ; Time Factors ; },
abstract = {BACKGROUND: Leukocyte telomere length has been taken as a measure of biological age but several inconsistencies exist.<br><br>METHODS: We investigated associations between leukocyte telomere length in old age, midlife risk factors, and mortality. The Helsinki Businessmen Study (a cohort of mainly business executives, born 1919-1934) had baseline assessments of cardiovascular risk factors including body mass index between 1964 and 1973 at a mean age of 40. Leukocyte telomere length and proportion of short telomeres were measured from DNA samples collected in 2002-2003 (n = 622, mean age 78 years). Body mass index and smoking in old age were assessed from questionnaires. Total mortality was verified from registers through January 2010. Main outcome measures were relationships between telomeres, body mass index, smoking, and mortality.<br><br>RESULTS: Leukocyte telomere length and notably proportion of short telomeres (<5kb) in old age were significantly (p =. 008 after full adjustments) and in a graded manner associated with midlife overweight and smoking. The associations were independent of age and cardiovascular risk factors including postload glucose. Associations with body mass index and smoking were nonsignificant in old age, and telomere length did not predict 7-year total mortality.<br><br>CONCLUSIONS: We conclude that smoking and overweight in midlife, irrespective of glucose, cholesterol and blood pressure, are related to shorter leukocyte telomeres in old men. Telomere length in old age did not predict total mortality possibly due to competing causes.},
}
@article {pmid21695195,
year = {2011},
author = {Ma, H and Zhou, Z and Wei, S and Liu, Z and Pooley, KA and Dunning, AM and Svenson, U and Roos, G and Hosgood, HD and Shen, M and Wei, Q},
title = {Shortened telomere length is associated with increased risk of cancer: a meta-analysis.},
journal = {PloS one},
volume = {6},
number = {6},
pages = {e20466},
pmid = {21695195},
issn = {1932-6203},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; R01 CA131274/CA/NCI NIH HHS/United States ; R01 ES011740/ES/NIEHS NIH HHS/United States ; },
mesh = {Confidence Intervals ; *Genetic Predisposition to Disease ; Humans ; Neoplasms/*genetics ; Odds Ratio ; Publication Bias ; Risk Factors ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Telomeres play a key role in the maintenance of chromosome integrity and stability, and telomere shortening is involved in initiation and progression of malignancies. A series of epidemiological studies have examined the association between shortened telomeres and risk of cancers, but the findings remain conflicting.<br><br>METHODS: A dataset composed of 11,255 cases and 13,101 controls from 21 publications was included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and the relative telomere length. Heterogeneity among studies and their publication bias were further assessed by the &#x3c7;(2)-based Q statistic test and Egger's test, respectively.<br><br>RESULTS: The results showed that shorter telomeres were significantly associated with cancer risk (OR&#x200a;=&#x200a;1.35, 95% CI&#x200a;=&#x200a;1.14-1.60), compared with longer telomeres. In the stratified analysis by tumor type, the association remained significant in subgroups of bladder cancer (OR&#x200a;=&#x200a;1.84, 95% CI&#x200a;=&#x200a;1.38-2.44), lung cancer (OR&#x200a;=&#x200a;2.39, 95% CI&#x200a;=&#x200a;1.18-4.88), smoking-related cancers (OR&#x200a;=&#x200a;2.25, 95% CI&#x200a;=&#x200a;1.83-2.78), cancers in the digestive system (OR&#x200a;=&#x200a;1.69, 95% CI&#x200a;=&#x200a;1.53-1.87) and the urogenital system (OR&#x200a;=&#x200a;1.73, 95% CI&#x200a;=&#x200a;1.12-2.67). Furthermore, the results also indicated that the association between the relative telomere length and overall cancer risk was statistically significant in studies of Caucasian subjects, Asian subjects, retrospective designs, hospital-based controls and smaller sample sizes. Funnel plot and Egger's test suggested that there was no publication bias in the current meta-analysis (P&#x200a;=&#x200a;0.532).<br><br>CONCLUSIONS: The results of this meta-analysis suggest that the presence of shortened telomeres may be a marker for susceptibility to human cancer, but single larger, well-design prospective studies are warranted to confirm these findings.},
}
@article {pmid21693493,
year = {2011},
author = {Zhou, JG and Qing, YF and Yang, QB and Xie, WG and Zhao, MC},
title = {Changes in the expression of telomere maintenance genes might play a role in the pathogenesis of systemic lupus erythematosus.},
journal = {Lupus},
volume = {20},
number = {8},
pages = {820-828},
doi = {10.1177/0961203310397964},
pmid = {21693493},
issn = {1477-0962},
mesh = {Adult ; Antigens, Nuclear/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Female ; Humans ; Ki-67 Antigen/genetics/metabolism ; Ku Autoantigen ; Leukocytes, Mononuclear/physiology ; Lupus Erythematosus, Systemic/*genetics/pathology/*physiopathology ; MRE11 Homologue Protein ; Male ; Middle Aged ; RNA, Messenger/genetics/*metabolism ; Shelterin Complex ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Young Adult ; },
abstract = {Previous studies demonstrated that telomerase activity increased while telomere length shortened in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE). This study aimed to examine the changes of telomere maintenance genes and their clinical significance in SLE. The mRNA level of telomeric proteins in PBMCs, including shelterin complex (TRF1, TRF2, POT1, TPP1, TIN2 and hRAP1), a set of multifunctional proteins involved in telomere maintenance (MRE11, KU80 and RPA1), and Ki67, was measured using real-time quantitative PCR in 56 SLE patients (36 treated and 20 untreated; 32 with renal involvement and 24 without renal involvement) and 46 healthy subjects (controls). The expression of TPP1, TIN2, POT1 and KU80 was significantly reduced while that of TRF2 and MRE11 increased in SLE patients (p < 0.05, respectively); significant difference was not found in the expression of TRF1, hRAP1, RPA1 and Ki67 (p > 0.05, respectively). The expression of TRF2, MRE11 and Ki67 was much higher in untreated SLE patients than in controls or treated SLE patients (p < 0.05, respectively); the expression of hRAP1 was much higher in SLE patients with renal involvement than in controls or SLE patients without renal involvement (p < 0.05, respectively). Significant positive correlation was found between level of KU80 and C3, TPP1 and TIN2, TPP1 and POT1, while significant negative correlation was found between KU80 and serum total globulins, TIN2 and RF, TPP1 and SLEDAI score (p < 0.05, respectively). In conclusion, altered expression of telomere maintenance genes might be involved in the pathogenesis of SLE. Further study in expression and functions of telomeric proteins would be needed.},
}
@article {pmid21692845,
year = {2011},
author = {Testa, R and Olivieri, F and Sirolla, C and Spazzafumo, L and Rippo, MR and Marra, M and Bonfigli, AR and Ceriello, A and Antonicelli, R and Franceschi, C and Castellucci, C and Testa, I and Procopio, AD},
title = {Leukocyte telomere length is associated with complications of type 2 diabetes mellitus.},
journal = {Diabetic medicine : a journal of the British Diabetic Association},
volume = {28},
number = {11},
pages = {1388-1394},
doi = {10.1111/j.1464-5491.2011.03370.x},
pmid = {21692845},
issn = {1464-5491},
mesh = {Adult ; Aged ; Aged, 80 and over ; Analysis of Variance ; Cross-Sectional Studies ; Diabetes Mellitus, Type 2/complications/*genetics/physiopathology ; Diabetic Angiopathies/etiology/*genetics/physiopathology ; Diabetic Nephropathies/*genetics/physiopathology ; Disease Progression ; Female ; Humans ; *Leukocytes/pathology ; Male ; Middle Aged ; Predictive Value of Tests ; Real-Time Polymerase Chain Reaction ; Risk Factors ; Telomere/*genetics/pathology ; },
abstract = {OBJECTIVE: The key goal of diabetes management is to prevent complications. While the patho-physiological mechanisms responsible for diabetes complications have been extensively studied, at present it is impossible to predict which patient with diabetes could develop complications. In recent years, the role of leukocyte telomere length in the pathogenesis of cardiovascular disease and Type 2 diabetes has been investigated. However, studies aiming to investigate the role of telomeres in the development and progression of Type 2 diabetes, as well as diabetic complications, are still lacking. As a consequence, this study aimed to verify whether leukocyte telomere length is associated with the presence and the number of diabetic complications in a sample of patients with Type 2 diabetes.<br><br>METHODS: This is a cross-sectional study. Nine hundred and one subjects were enrolled, including 501 patients with Type 2 diabetes, of whom 284 had at least one complication and 217 were without complications, and 400 control subjects. Leukocyte telomere length was measured by quantitative real-time PCR.<br><br>RESULTS: Patients with diabetes complications had significantly shorter leukocyte telomere length than both patients without diabetes complications and healthy control subjects. Moreover, among patients with diabetes complications, leukocyte telomere length became significantly and gradually shorter with the increasing number of diabetes complications. The magnitude of the effect of the decrease of the abundance of telomeric template vs. a single-copy gene length (T/S ratio) on complications is described by the estimated odds ratio OR=5.44 (95%CI 3.52-8.42).<br><br>CONCLUSIONS: The results of the study support the hypothesis that telomere attrition may be a marker associated with the presence and the number of diabetic complications.},
}
@article {pmid21689668,
year = {2012},
author = {Singh, DK and Ghosh, AK and Croteau, DL and Bohr, VA},
title = {RecQ helicases in DNA double strand break repair and telomere maintenance.},
journal = {Mutation research},
volume = {736},
number = {1-2},
pages = {15-24},
pmid = {21689668},
issn = {0027-5107},
support = {Z01 AG000726-16//Intramural NIH HHS/United States ; },
mesh = {*DNA Breaks, Double-Stranded ; *DNA Repair ; Genomic Instability ; Humans ; Oxidative Stress ; RecQ Helicases/*metabolism ; Telomere/*physiology ; },
abstract = {Organisms are constantly exposed to various environmental insults which could adversely affect the stability of their genome. To protect their genomes against the harmful effect of these environmental insults, organisms have evolved highly diverse and efficient repair mechanisms. Defective DNA repair processes can lead to various kinds of chromosomal and developmental abnormalities. RecQ helicases are a family of evolutionarily conserved, DNA unwinding proteins which are actively engaged in various DNA metabolic processes, telomere maintenance and genome stability. Bacteria and lower eukaryotes, like yeast, have only one RecQ homolog, whereas higher eukaryotes including humans possess multiple RecQ helicases. These multiple RecQ helicases have redundant and/or non-redundant functions depending on the types of DNA damage and DNA repair pathways. Humans have five different RecQ helicases and defects in three of them cause autosomal recessive diseases leading to various kinds of cancer predisposition and/or aging phenotypes. Emerging evidence also suggests that the RecQ helicases have important roles in telomere maintenance. This review mainly focuses on recent knowledge about the roles of RecQ helicases in DNA double strand break repair and telomere maintenance which are important in preserving genome integrity.},
}
@article {pmid21689454,
year = {2011},
author = {Broadbent, KM and Park, D and Wolf, AR and Van Tyne, D and Sims, JS and Ribacke, U and Volkman, S and Duraisingh, M and Wirth, D and Sabeti, PC and Rinn, JL},
title = {A global transcriptional analysis of Plasmodium falciparum malaria reveals a novel family of telomere-associated lncRNAs.},
journal = {Genome biology},
volume = {12},
number = {6},
pages = {R56},
pmid = {21689454},
issn = {1474-760X},
support = {T32 AI007638/AI/NIAID NIH HHS/United States ; 1DP2OD00667-01/OD/NIH HHS/United States ; },
mesh = {Base Sequence ; Binding Sites/genetics ; Chromosomes ; Gene Expression Regulation, Developmental ; Genes, Protozoan ; Genetic Loci ; Genome, Protozoan ; Humans ; Molecular Sequence Data ; Oligonucleotide Array Sequence Analysis ; Open Reading Frames/genetics ; Plasmodium falciparum/*genetics/metabolism ; Pseudogenes ; RNA, Untranslated/*genetics/*metabolism ; Sequence Alignment ; Telomere/*metabolism ; Transcription Factors/metabolism ; Transcription, Genetic ; *Transcriptome ; },
abstract = {BACKGROUND: Mounting evidence suggests a major role for epigenetic feedback in Plasmodium falciparum transcriptional regulation. Long non-coding RNAs (lncRNAs) have recently emerged as a new paradigm in epigenetic remodeling. We therefore set out to investigate putative roles for lncRNAs in P. falciparum transcriptional regulation.<br><br>RESULTS: We used a high-resolution DNA tiling microarray to survey transcriptional activity across 22.6% of the P. falciparum strain 3D7 genome. We identified 872 protein-coding genes and 60 putative P. falciparum lncRNAs under developmental regulation during the parasite's pathogenic human blood stage. Further characterization of lncRNA candidates led to the discovery of an intriguing family of lncRNA telomere-associated repetitive element transcripts, termed lncRNA-TARE. We have quantified lncRNA-TARE expression at 15 distinct chromosome ends and mapped putative transcriptional start and termination sites of lncRNA-TARE loci. Remarkably, we observed coordinated and stage-specific expression of lncRNA-TARE on all chromosome ends tested, and two dominant transcripts of approximately 1.5 kb and 3.1 kb transcribed towards the telomere.<br><br>CONCLUSIONS: We have characterized a family of 22 telomere-associated lncRNAs in P. falciparum. Homologous lncRNA-TARE loci are coordinately expressed after parasite DNA replication, and are poised to play an important role in P. falciparum telomere maintenance, virulence gene regulation, and potentially other processes of parasite chromosome end biology. Further study of lncRNA-TARE and other promising lncRNA candidates may provide mechanistic insight into P. falciparum transcriptional regulation.},
}
@article {pmid21684834,
year = {2011},
author = {Rajpar, S and Guittat, L and Mergny, JL},
title = {[Telomeres: a Nobel Prize at the beginning… of the end].},
journal = {Bulletin du cancer},
volume = {98},
number = {9},
pages = {999-1009},
doi = {10.1684/bdc.2011.1378},
pmid = {21684834},
issn = {1769-6917},
mesh = {Aging/genetics ; Animals ; Cell Proliferation ; Genomic Instability ; Humans ; Mice ; Neoplasms/enzymology/*genetics/therapy ; *Nobel Prize ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {The 2009 Nobel Prize for Physiology and Medicine was awarded to Elizabeth H. Blackburn, Carol W. Greider and Jack K. Szostak for their work on telomeres and telomerase. This prize acknowledges their pionneering discoveries on chromosomal extremities. Telomeres are the nucleoproteic complexes that may be found at the ends of linear chromosomes. They are essential for genomic stability and are involved in aging and tumorogenesis.},
}
@article {pmid21683470,
year = {2011},
author = {Moriguchi, R and Ohata, K and Kanahama, K and Takahashi, H and Nishiyama, M and Kanayama, Y},
title = {Suppression of telomere-binding protein gene expression represses seed and fruit development in tomato.},
journal = {Journal of plant physiology},
volume = {168},
number = {16},
pages = {1927-1933},
doi = {10.1016/j.jplph.2011.05.009},
pmid = {21683470},
issn = {1618-1328},
mesh = {Chromosomes, Plant/genetics ; DNA, Antisense/genetics ; DNA, Complementary/genetics ; DNA, Plant/genetics ; Flowers/genetics/growth &amp; development/physiology ; Fruit/genetics/*growth &amp; development/physiology ; Gene Expression/genetics ; Gene Expression Regulation, Plant/genetics ; Solanum lycopersicum/cytology/genetics/growth &amp; development/*physiology ; Meristem/cytology ; Ovule/physiology ; Plant Leaves/genetics/metabolism ; Plant Proteins/genetics/metabolism ; Plants, Genetically Modified ; Pollen/physiology ; Seeds/genetics/*growth &amp; development/physiology ; Stress, Physiological ; Suppression, Genetic/*genetics ; Telomere-Binding Proteins/*genetics/metabolism ; Temperature ; },
abstract = {Tomato (Solanum lycopersicum L.) plants were transformed with an antisense construct of a cDNA encoding tomato telomere-binding protein (LeTBP1) to describe the role of a telomere-binding protein at the whole plant level. Fruit size decreased corresponding to the degree of suppression of LeTBP1 expression. This inhibition of fruit development was likely due to a decrease in the number of seeds in the LeTBP1 antisense plants. Pollen fertility and pollen germination rate decreased in accordance with the degree of suppression of LeTBP1 expression. Ovule viability was also reduced in the LeTBP1 antisense plants. Although plant height was somewhat reduced in the antisense plants compared to the control plants, the number and weight of leaves were unaffected by LeTBP1 suppression. The number and morphology of flowers were also normal in the antisense plants. These indicate that reduced fertility in the antisense plants is not an indirect effect of altered vegetative growth. LeTBP1 expression was sensitive to temperature stress in wild-type plants. We conclude that LeTBP1 plays a critical role in seed and fruit development rather than vegetative growth and flower formation.},
}
@article {pmid21680897,
year = {2011},
author = {Calvert, PA and Liew, TV and Gorenne, I and Clarke, M and Costopoulos, C and Obaid, DR and O'Sullivan, M and Shapiro, LM and McNab, DC and Densem, CG and Schofield, PM and Braganza, D and Clarke, SC and Ray, KK and West, NE and Bennett, MR},
title = {Leukocyte telomere length is associated with high-risk plaques on virtual histology intravascular ultrasound and increased proinflammatory activity.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {31},
number = {9},
pages = {2157-2164},
doi = {10.1161/ATVBAHA.111.229237},
pmid = {21680897},
issn = {1524-4636},
support = {RG/04/001/BHF_/British Heart Foundation/United Kingdom ; G0800784/MRC_/Medical Research Council/United Kingdom ; PG/08/008/BHF_/British Heart Foundation/United Kingdom ; FS/09/005/26845/BHF_/British Heart Foundation/United Kingdom ; G1000847/MRC_/Medical Research Council/United Kingdom ; FS/10/025/28196/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Cellular Senescence ; Coronary Artery Disease/diagnostic imaging/*etiology/immunology ; Cytokines/metabolism ; Humans ; Inflammation/*etiology ; Leukocytes/*metabolism ; Lymphocytes/immunology ; Plaque, Atherosclerotic/diagnostic imaging/*etiology/immunology ; Risk ; Risk Factors ; *Telomere ; *Ultrasonography, Interventional ; },
abstract = {OBJECTIVE: Leukocyte telomere length (LTL), a marker of cellular senescence, is inversely associated with cardiovascular events. However, whether LTL reflects plaque extent or unstable plaques, and the mechanisms underlying any association are unknown.<br><br>METHODS AND RESULTS: One hundred seventy patients with stable angina or acute coronary syndrome referred for percutaneous coronary intervention underwent 3-vessel virtual histology intravascular ultrasound; 30 372 mm of intravascular ultrasound pullback and 1096 plaques were analyzed. LTL was not associated with plaque volume but was associated with calcified thin-capped fibroatheroma (OR, 1.24; CI, 1.01-1.53; P=0.039) and total fibroatheroma numbers (OR, 1.19; CI, 1.02-1.39; P=0.027). Monocytes from coronary artery disease patients showed increased secretion of proinflammatory cytokines. To mimic leukocyte senescence, we disrupted telomeres and binding and expression of the telomeric protein protection of telomeres protein-1, inducing DNA damage. Telomere disruption increased monocyte secretion of monocyte chemoattractant protein-1, IL-6, and IL-1&#x3b2; and oxidative burst, similar to that seen in coronary artery disease patients, and lymphocyte secretion of IL-2 and reduced lymphocyte IL-10.<br><br>CONCLUSIONS: Shorter LTL is associated with high-risk plaque morphology on virtual histology intravascular ultrasound but not total 3-vessel plaque burden. Monocytes with disrupted telomeres show increased proinflammatory activity, which is also seen in coronary artery disease patients, suggesting that telomere shortening promotes high-risk plaque subtypes by increasing proinflammatory activity.},
}
@article {pmid21677878,
year = {2011},
author = {Samassekou, O and Li, H and Hébert, J and Ntwari, A and Wang, H and Cliché, CG and Bouchard, E and Huang, S and Yan, J},
title = {Chromosome arm-specific long telomeres: a new clonal event in primary chronic myelogenous leukemia cells.},
journal = {Neoplasia (New York, N.Y.)},
volume = {13},
number = {6},
pages = {550-560},
pmid = {21677878},
issn = {1476-5586},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Base Sequence ; *Chromosome Aberrations ; Chromosomes, Human, Pair 11/genetics ; Chromosomes, Human, Pair 15/genetics ; Chromosomes, Human, Pair 18/genetics ; Chromosomes, Human, Pair 7/genetics ; Female ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*genetics/pathology ; Male ; Middle Aged ; Telomere/*genetics ; Young Adult ; },
abstract = {Previous studies demonstrated that critically shortened telomere lengths correlate with the chromosome instability in carcinogenesis. However, little has been noticed regarding the correlation of long telomeres at specific chromosomes with malignant disorders. We studied relative telomere lengths (RTLs) for individual chromosomes using the quantitative fluorescence in situ hybridization technique in a cohort of 32 patients with chronic myeloid leukemia (CML) and 32 normal samples. We found that telomeres at some specific chromosome arms remain well maintained or even lengthened in a high frequency (27/32) of leukemia cases. In particular, 10 chromosome arms, 4q, 5p, 7q, 11p, 13p, 13q, 14p, 15p, 18p, and Xp, with long telomeres were consistently identified in different samples, and six of them (4q, 5p, 13p, 13q, 14p, and Xp) with relatively long telomeres were also observed in normal samples, but they appeared in lower occurrence rate and shorter RTL than in CML samples. Our results strongly indicate the presence of a special leukemia cell population, or a clone, originated from a common progenitor that is characterized with chromosome arm-specific long telomeres. We suggest that relatively long telomeres located at key chromosomes could be preferentially maintained or further elongated during the early stage of malignant transformation.},
}
@article {pmid21672962,
year = {2011},
author = {Rolyan, H and Scheffold, A and Heinrich, A and Begus-Nahrmann, Y and Langkopf, BH and Hölter, SM and Vogt-Weisenhorn, DM and Liss, B and Wurst, W and Lie, DC and Thal, DR and Biber, K and Rudolph, KL},
title = {Telomere shortening reduces Alzheimer's disease amyloid pathology in mice.},
journal = {Brain : a journal of neurology},
volume = {134},
number = {Pt 7},
pages = {2044-2056},
doi = {10.1093/brain/awr133},
pmid = {21672962},
issn = {1460-2156},
mesh = {Age Factors ; Alzheimer Disease/*pathology ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Animals ; Aspartic Acid Endopeptidases/metabolism ; Bromodeoxyuridine/metabolism ; Calcium-Binding Proteins/metabolism ; Cell Cycle/genetics ; Cerebral Cortex/*pathology ; Cognition Disorders/etiology/genetics ; Disease Models, Animal ; Doublecortin Domain Proteins ; Hippocampus/*pathology ; Maze Learning/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microfilament Proteins/metabolism ; Microglia/pathology ; Microscopy, Electron, Transmission/methods ; Microtubule-Associated Proteins/metabolism ; Neurogenesis/genetics ; Neurons/pathology/physiology/*ultrastructure ; Neuropeptides/metabolism ; Plaque, Amyloid/*pathology ; Presenilin-1/metabolism ; Synapses/ultrastructure ; Telomerase/deficiency ; Telomere/genetics/*pathology/ultrastructure ; },
abstract = {Alzheimer's disease is a neurodegenerative disorder of the elderly and advancing age is the major risk factor for Alzheimer's disease development. Telomere shortening represents one of the molecular causes of ageing that limits the proliferative capacity of cells, including neural stem cells. Studies on telomere lengths in patients with Alzheimer's disease have revealed contrary results and the functional role of telomere shortening on brain ageing and Alzheimer's disease is not known. Here, we have investigated the effects of telomere shortening on adult neurogenesis and Alzheimer's disease progression in mice. The study shows that aged telomerase knockout mice with short telomeres (G3Terc-/-) exhibit reduced dentate gyrus neurogenesis and loss of neurons in hippocampus and frontal cortex, associated with short-term memory deficit in comparison to mice with long telomere reserves (Terc+/+). In contrast, telomere shortening improved the spatial learning ability of ageing APP23 transgenic mice, a mouse model for Alzheimer's disease. Telomere shortening was also associated with an activation of microglia in ageing amyloid-free brain. However, in APP23 transgenic mice, telomere shortening reduced both amyloid plaque pathology and reactive microgliosis. Together, these results provide the first experimental evidence that telomere shortening, despite impairing adult neurogenesis and maintenance of post-mitotic neurons, can slow down the progression of amyloid plaque pathology in Alzheimer's disease, possibly involving telomere-dependent effects on microglia activation.},
}
@article {pmid21671044,
year = {2011},
author = {Ju, Z and Zhang, J and Gao, Y and Cheng, T},
title = {Telomere dysfunction and cell cycle checkpoints in hematopoietic stem cell aging.},
journal = {International journal of hematology},
volume = {94},
number = {1},
pages = {33-43},
pmid = {21671044},
issn = {1865-3774},
mesh = {Cell Cycle Checkpoints/*physiology ; *Cellular Senescence ; Hematopoietic Stem Cells/*physiology ; Humans ; Regeneration ; Telomere/*pathology ; },
abstract = {Stem cells are believed to be closely associated with tissue degeneration during aging. Studies of human genetic diseases and gene-targeted animal models have provided evidence that functional decline of telomeres and deregulation of cell cycle checkpoints contribute to the aging process of tissue stem cells. Telomere dysfunction can induce DNA damage response via key cell cycle checkpoints, leading to cellular senescence or apoptosis depending on the tissue type and developmental stage of a specific stem cell compartment. Telomerase mutation and telomere shortening have been observed in a variety of hematological disorders, such as dyskeratosis congenital, aplastic anemia, myelodysplastic syndromes and leukemia, in which the hematopoietic stem cells (HSC) are a major target during the pathogenesis. Moreover, telomere dysfunction is able to induce both cell-intrinsic checkpoints and environmental factors limiting the self-renewal capacity and differentiation potential of HSCs. Crucial components in the cascade of DNA damage response, including ataxia telangiectasia mutated, CHK2, p53, p21 and p16/p19(ARF), play important roles in HSC maintenance and self-renewal in the scenarios of both sufficient telomere reserve and dysfunctional telomere. Therefore, a further understanding of the molecular mechanisms underlying HSC aging may help identity new therapeutic targets for stem cell-based regenerative medicine.},
}
@article {pmid21670498,
year = {2011},
author = {Cao, K and Blair, CD and Faddah, DA and Kieckhaefer, JE and Olive, M and Erdos, MR and Nabel, EG and Collins, FS},
title = {Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts.},
journal = {The Journal of clinical investigation},
volume = {121},
number = {7},
pages = {2833-2844},
pmid = {21670498},
issn = {1558-8238},
support = {R00 AG029761/AG/NIA NIH HHS/United States ; R00AG029761/AG/NIA NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; },
mesh = {Aging/physiology ; Animals ; Cells, Cultured ; Cellular Senescence/*physiology ; Fibroblasts/cytology/*physiology ; Humans ; Lamin Type A/genetics/metabolism ; Nuclear Proteins/genetics/*metabolism ; Progeria/genetics/physiopathology ; Protein Precursors/genetics/*metabolism ; Telomerase/genetics ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/genetics ; },
abstract = {Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disease, is caused by a point mutation in the lamin A gene (LMNA). This mutation constitutively activates a cryptic splice donor site, resulting in a mutant lamin A protein known as progerin. Recent studies have demonstrated that progerin is also produced at low levels in normal human cells and tissues. However, the cause-and-effect relationship between normal aging and progerin production in normal individuals has not yet been determined. In this study, we have shown in normal human fibroblasts that progressive telomere damage during cellular senescence plays a causative role in activating progerin production. Progressive telomere damage was also found to lead to extensive changes in alternative splicing in multiple other genes. Interestingly, elevated progerin production was not seen during cellular senescence that does not entail telomere shortening. Taken together, our results suggest a synergistic relationship between telomere dysfunction and progerin production during the induction of cell senescence, providing mechanistic insight into how progerin may participate in the normal aging process.},
}
@article {pmid21667174,
year = {2011},
author = {Monti, V and Giusti, M and Bizzaro, D and Manicardi, GC and Mandrioli, M},
title = {Presence of a functional (TTAGG)(n) telomere-telomerase system in aphids.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {19},
number = {5},
pages = {625-633},
pmid = {21667174},
issn = {1573-6849},
mesh = {Animals ; Aphids/classification/enzymology/*genetics ; Base Sequence ; Chromosomes, Insect/genetics ; Gene Expression Profiling ; Gene Expression Regulation, Enzymologic ; Humans ; In Situ Hybridization, Fluorescence ; *Repetitive Sequences, Nucleic Acid ; Reverse Transcriptase Polymerase Chain Reaction ; Species Specificity ; Synteny ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {The structure of the telomeres of four aphid species (Acyrthosiphon pisum, Megoura viciae, Myzus persicae and Rhopalosiphum padi) was evaluated by Southern blotting and fluorescent in situ hybridization, revealing that each chromosomal end consists of a (TTAGG)(n) repeat. The presence of a telomerase coding gene has been verified successively in the A. pisum genome, revealing that aphid telomerase shares sequence identity ranging from 12% to 18% with invertebrate and vertebrate homologues, and possesses the two main domains involved in telomerase activity. Interestingly, telomerase expression has been verified in different somatic tissues suggesting that, in aphids, telomerase activity is not as restricted as in human cells. The study of telomeres in a M. persicae strain with a variable chromosome number showed that aphid telomerase can initiate the de novo synthesis of telomere sequences at internal breakpoints, resulting in the stabilization of chromosomal fragments.},
}
@article {pmid21666682,
year = {2011},
author = {Ferreira, HC and Luke, B and Schober, H and Kalck, V and Lingner, J and Gasser, SM},
title = {The PIAS homologue Siz2 regulates perinuclear telomere position and telomerase activity in budding yeast.},
journal = {Nature cell biology},
volume = {13},
number = {7},
pages = {867-874},
pmid = {21666682},
issn = {1476-4679},
support = {232812/ERC_/European Research Council/International ; },
mesh = {DNA Helicases/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Microscopy, Fluorescence ; Mutation ; Nuclear Envelope/*enzymology ; Protein Processing, Post-Translational ; Recombinant Fusion Proteins/metabolism ; Saccharomyces cerevisiae/*enzymology/genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Sumoylation ; Telomerase/*metabolism ; Telomere/*enzymology ; Time Factors ; },
abstract = {Budding yeast telomeres are reversibly bound at the nuclear envelope through two partially redundant pathways that involve the Sir2/3/4 silencing complex and the Yku70/80 heterodimer. To better understand how this is regulated, we studied the role of SUMOylation in telomere anchoring. We find that the PIAS-like SUMO E3 ligase Siz2 sumoylates both Yku70/80 and Sir4 in vivo and promotes telomere anchoring to the nuclear envelope. Remarkably, loss of Siz2 also provokes telomere extension in a telomerase-dependent manner that is epistatic with loss of the helicase Pif1. Consistent with our previously documented role for telomerase in anchorage, normal telomere anchoring in siz2 Δ is restored by PIF1 deletion. By live-cell imaging of a critically short telomere, we show that telomeres shift away from the nuclear envelope when elongating. We propose that SUMO-dependent association with the nuclear periphery restrains bound telomerase, whereas active elongation correlates with telomere release.},
}
@article {pmid21666348,
year = {2011},
author = {Konishi, K and Yonai, M and Kaneyama, K and Ito, S and Matsuda, H and Yoshioka, H and Nagai, T and Imai, K},
title = {Relationships of survival time, productivity and cause of death with telomere lengths of cows produced by somatic cell nuclear transfer.},
journal = {The Journal of reproduction and development},
volume = {57},
number = {5},
pages = {572-578},
doi = {10.1262/jrd.10-174a},
pmid = {21666348},
issn = {1348-4400},
mesh = {Animals ; Animals, Genetically Modified/*genetics/*physiology ; *Cattle/genetics/physiology ; Cause of Death ; Data Collection ; Efficiency/*physiology ; Female ; Follow-Up Studies ; Longevity/genetics/*physiology ; *Nuclear Transfer Techniques/adverse effects/veterinary ; Pregnancy ; Survival/physiology ; Telomere Homeostasis/*physiology ; Time Factors ; },
abstract = {The reproductive ability, milk-producing capacity, survival time and relationships of these parameters with telomere length were investigated in 4 groups of cows produced by somatic cell nuclear transfer (SCNT). Each group was produced using the same donor cells (6 Holstein (1H), 3 Holstein (2H), 4 Jersey (1J) and 5 Japanese Black (1B) cows). As controls, 47 Holstein cows produced by artificial insemination were used. The SCNT cows were artificially inseminated, and multiple deliveries were performed after successive rounds of breeding and conception. No correlation was observed between the telomere length and survival time in the SCNT cows. Causes of death of SCNT cows included accidents, accident-associated infections, inappropriate management, acute mastitis and hypocalcemia. The lifetime productivity of SCNT cows was superior to those of the controls and cell donor cows. All SCNT beef cows with a relatively light burden of lactation remained alive and showed significantly prolonged survival time compared with the cows in the SCNT dairy breeds. These results suggest that the lifetime productivity of SCNT cows was favorable, and their survival time was more strongly influenced by environmental burdens, such as pregnancy, delivery, lactation and feeding management, than by the telomere length.},
}
@article {pmid21666075,
year = {2011},
author = {Basenko, E and Topcu, Z and McEachern, MJ},
title = {Recombination can either help maintain very short telomeres or generate longer telomeres in yeast cells with weak telomerase activity.},
journal = {Eukaryotic cell},
volume = {10},
number = {8},
pages = {1131-1142},
pmid = {21666075},
issn = {1535-9786},
support = {R01 GM061645/GM/NIGMS NIH HHS/United States ; R01GM061645/GM/NIGMS NIH HHS/United States ; },
mesh = {Fungal Proteins/genetics/*metabolism ; Gene Knockout Techniques ; Kluyveromyces/enzymology/*genetics/growth &amp; development ; Rad52 DNA Repair and Recombination Protein/genetics ; *Recombination, Genetic ; Sequence Deletion ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Yeast mutants lacking telomerase are able to elongate their telomeres through processes involving homologous recombination. In this study, we investigated telomeric recombination in several mutants that normally maintain very short telomeres due to the presence of a partially functional telomerase. The abnormal colony morphology present in some mutants was correlated with especially short average telomere length and with a requirement for RAD52 for indefinite growth. Better-growing derivatives of some of the mutants were occasionally observed and were found to have substantially elongated telomeres. These telomeres were composed of alternating patterns of mutationally tagged telomeric repeats and wild-type repeats, an outcome consistent with amplification occurring via recombination rather than telomerase. Our results suggest that recombination at telomeres can produce two distinct outcomes in the mutants we studied. In occasional cells, recombination generates substantially longer telomeres, apparently through the roll-and-spread mechanism. However, in most cells, recombination appears limited to helping to maintain very short telomeres. The latter outcome likely represents a simplified form of recombinational telomere maintenance that is independent of the generation and copying of telomeric circles.},
}
@article {pmid21666001,
year = {2011},
author = {Eckardt, NA},
title = {De novo telomere formation in Arabidopsis tetraploids.},
journal = {The Plant cell},
volume = {23},
number = {6},
pages = {2008},
pmid = {21666001},
issn = {1532-298X},
mesh = {Arabidopsis/*genetics/*metabolism ; Chromosomes, Plant/*metabolism ; Humans ; Telomere/*metabolism ; },
}
@article {pmid21665207,
year = {2011},
author = {Zee, RY and Ridker, PM and Chasman, DI},
title = {Genetic variants of 11 telomere-pathway gene loci and the risk of incident type 2 diabetes mellitus: the Women's Genome Health Study.},
journal = {Atherosclerosis},
volume = {218},
number = {1},
pages = {144-146},
pmid = {21665207},
issn = {1879-1484},
support = {R01 HL043851/HL/NHLBI NIH HHS/United States ; CA-047988/CA/NCI NIH HHS/United States ; R01 HL080467-05/HL/NHLBI NIH HHS/United States ; HL-043851/HL/NHLBI NIH HHS/United States ; R01 CA047988/CA/NCI NIH HHS/United States ; R01 HL043851-10/HL/NHLBI NIH HHS/United States ; HL-080467/HL/NHLBI NIH HHS/United States ; R01 CA047988-21/CA/NCI NIH HHS/United States ; R01 HL080467/HL/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Cohort Studies ; Diabetes Mellitus, Type 2/*blood/genetics ; Female ; *Genetic Variation ; Genome, Human ; Genotype ; Haplotypes ; Humans ; Middle Aged ; Polymorphism, Single Nucleotide ; Proportional Hazards Models ; Risk ; Telomere/*ultrastructure ; },
abstract = {OBJECTIVE: Leukocyte telomere length shortening has recently been associated with type 2 diabetes mellitus (T2D). Whether this observation was modulated by genetic variation within the telomere-pathway genes remains elusive. To date, no prospective epidemiological data on the relationship of telomere-pathway gene variation with T2D are available.<br><br>METHODS: The association between 150 tagging-SNPs (tSNPs) of 11 telomere-pathway genes (TERC, UCP1, TERT, POT1, TNKS, TERF1, TNKS2, TEP1, ACD, TERF2 and TERF2IP) and incident T2D was investigated in 22,715 Caucasian female participants of the prospective Women's Genome Health Study. All were free of known cardiovascular disease, cancer and diabetes at baseline. During a 13-year follow-up period, 1445 participants developed an incident T2D. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and T2D risk assuming an additive genetic model. Haplotype block analysis was also performed.<br><br>RESULTS: A total of eleven tSNPs within TERF1, TNKS, TEP1, ACD, and TERF2 were associated with T2D risk (all p-uncorrected <0.050). Further investigation using the haplotype-block analysis again revealed an association of several prespecified haplotypes of TERF1, and TEP1 with T2D risk (all p-uncorrected <0.040).<br><br>CONCLUSION: If corroborated in other prospective studies, the present findings suggest that genetic variation within the telomere-pathway gene loci examined may be useful predictor for T2D risk assessment.},
}
@article {pmid21663926,
year = {2012},
author = {Aubert, G and Hills, M and Lansdorp, PM},
title = {Telomere length measurement-caveats and a critical assessment of the available technologies and tools.},
journal = {Mutation research},
volume = {730},
number = {1-2},
pages = {59-67},
pmid = {21663926},
issn = {0027-5107},
support = {R01 GM094146/GM/NIGMS NIH HHS/United States ; GMH79042//PHS HHS/United States ; MOP38075/CAPMC/CIHR/Canada ; },
mesh = {Biotechnology ; Flow Cytometry/methods ; *Genetic Techniques ; Humans ; In Situ Hybridization, Fluorescence/methods ; Polymerase Chain Reaction ; Polymorphism, Restriction Fragment Length ; Telomere/*chemistry ; Weights and Measures ; },
abstract = {Studies of telomeres and telomere biology often critically rely on the detection of telomeric DNA and measurements of the length of telomere repeats in either single cells or populations of cells. Several methods are available that provide this type of information and it is often not clear what method is most appropriate to address a specific research question. The major variables that need to be considered are the material that is or can be made available and the accuracy of measurements that is required. The goal of this review is to provide a comprehensive summary of the most commonly used methods and discuss the advantages and disadvantages of each. Methods that start with genomic DNA include telomere restriction fragment (TRF) length analysis, PCR amplification of telomere repeats relative to a single copy gene by Q-PCR or MMQPCR and single telomere length analysis (STELA), a PCR-based approach that accurately measures the full spectrum of telomere lengths from individual chromosomes. A different set of methods relies on fluorescent in situ hybridization (FISH) to detect telomere repeats in individual cells or chromosomes. By including essential calibration steps and appropriate controls these methods can be used to measure telomere repeat length or content in chromosomes and cells. Such methods include quantitative FISH (Q-FISH) and flow FISH which are based on digital microscopy and flow cytometry, respectively. Here the basic principles of various telomere length measurement methods are described and their strengths and weaknesses are highlighted. Some recent developments in telomere length analysis are also discussed. The information in this review should facilitate the selection of the most suitable method to address specific research question about telomeres in either model organisms or human subjects.},
}
@article {pmid21660686,
year = {2011},
author = {Ma, W and Westmoreland, J and Nakai, W and Malkova, A and Resnick, MA},
title = {Characterizing resection at random and unique chromosome double-strand breaks and telomere ends.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {745},
number = {},
pages = {15-31},
pmid = {21660686},
issn = {1940-6029},
support = {R01 GM084242/GM/NIGMS NIH HHS/United States ; Z01 ES065073//Intramural NIH HHS/United States ; },
mesh = {Blotting, Southern ; *DNA Breaks, Double-Stranded ; DNA Repair/genetics ; Electrophoresis, Gel, Pulsed-Field ; Plant Proteins/metabolism ; Radiation, Ionizing ; Single-Strand Specific DNA and RNA Endonucleases/metabolism ; Telomere/*genetics ; },
abstract = {Resection of DNA double-strand break (DSB) ends, which results in 3(') single-stranded tails, is an early event of DSB repair and can be a critical determinant in choice of repair pathways and eventual genome stability. Current techniques for examining resection are restricted to model in vivo systems with defined substrates (i.e., HO-endonuclease targets). We present here a robust assay that can analyze not only the resection of site-specific DSBs which typically have "clean" double-strand ends but also random "dirty-ended" DSBs such as those generated by ionizing radiation and chemotherapeutic agents. The assay is based on our finding that yeast chromosomes with single-stranded DNA tails caused by resection are less mobile during pulsed-field gel electrophoresis (PFGE) than those without a tail. In combination with the use of a circular chromosome and enzymatic trimming of single-stranded DNA, resection of random DSBs can be easily detected and analyzed. This mobility-shift assay provides a unique opportunity to examine the mechanisms of resection, early events in DSB repair, as well as factors involved in pathway regulation.},
}
@article {pmid21659533,
year = {2011},
author = {Talley, JM and DeZwaan, DC and Maness, LD and Freeman, BC and Friedman, KL},
title = {Stimulation of yeast telomerase activity by the ever shorter telomere 3 (Est3) subunit is dependent on direct interaction with the catalytic protein Est2.},
journal = {The Journal of biological chemistry},
volume = {286},
number = {30},
pages = {26431-26439},
pmid = {21659533},
issn = {1083-351X},
support = {T32 HL007121/HL/NHLBI NIH HHS/United States ; GM080393/GM/NIGMS NIH HHS/United States ; T32 GM008554/GM/NIGMS NIH HHS/United States ; R01 GM080393/GM/NIGMS NIH HHS/United States ; T32 GM08554/GM/NIGMS NIH HHS/United States ; },
mesh = {Mutation ; Protein Binding ; Protein Structure, Tertiary ; Recombinant Proteins/genetics/metabolism ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/genetics/*metabolism ; },
abstract = {Telomerase is a multisubunit enzyme that maintains genome stability through its role in telomere replication. Although the Est3 protein is long recognized as an essential telomerase component, how it associates with and functions in the telomerase complex has remained enigmatic. Here we provide the first evidence of a direct interaction between Saccharomyces cerevisiae Est3p and the catalytic protein subunit (Est2p) by demonstrating that recombinant Est3p binds the purified telomerase essential N-terminal (TEN) domain of Est2p in vitro. Mutations in a small cluster of amino acids predicted to lie on the surface of Est3p disrupt this interaction with Est2p, reduce assembly of Est3p with telomerase in vivo, and cause telomere shortening and senescence. We also show that recombinant Est3p stimulates telomerase activity above basal levels in vitro in a manner dependent on the Est2p TEN domain interaction. Together, these results define a direct binding interaction between Est3p and Est2p and reconcile the effect of S. cerevisiae Est3p with previous experiments showing that Est3p homologs in related yeast species influence telomerase activity. Additionally, it contributes functional support to the idea that Est3p is structurally related to the mammalian shelterin protein, TPP1, which also influences telomerase activity through interaction with the Est2p homolog, TERT.},
}
@article {pmid21656736,
year = {2011},
author = {Printz, C},
title = {New insights into telomeres, stress, and cancer risk.},
journal = {Cancer},
volume = {117},
number = {12},
pages = {2585},
doi = {10.1002/cncr.26259},
pmid = {21656736},
issn = {1097-0142},
mesh = {Humans ; Neoplasms/*etiology ; Risk ; Stress, Psychological/*complications ; Telomerase/*physiology ; Telomere ; },
}
@article {pmid21655359,
year = {2011},
author = {Kawashima, M and Kawakita, T and Maida, Y and Kamoi, M and Ogawa, Y and Shimmura, S and Masutomi, K and Tsubota, K},
title = {Comparison of telomere length and association with progenitor cell markers in lacrimal gland between Sjögren syndrome and non-Sjögren syndrome dry eye patients.},
journal = {Molecular vision},
volume = {17},
number = {},
pages = {1397-1404},
pmid = {21655359},
issn = {1090-0535},
mesh = {Adult ; Aged ; Aging/genetics ; Asian People/genetics ; Biomarkers/analysis ; GTP-Binding Proteins/genetics/*metabolism ; Gene Expression ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Lacrimal Apparatus/*metabolism/pathology ; Membrane Proteins/genetics/*metabolism ; Microscopy, Electron, Transmission ; Middle Aged ; Nuclear Proteins/genetics/*metabolism ; Repetitive Sequences, Nucleic Acid ; Sjogren's Syndrome/*genetics/pathology ; Stem Cells/cytology/*metabolism ; Xerophthalmia/*genetics/pathology ; },
abstract = {PURPOSE: Indicators of aging such as disruption of telomeric function due to shortening may be more frequent in dysfunctional lacrimal gland. The aims of this study were to 1) determine the viability of quantitative fluorescence in situ hybridization of telomeres (telo-FISH) for the assessment of telomere length in lacrimal gland in Sjögren and non- Sjögren syndrome patients; and 2) investigate the relationship between progenitor cell markers and telomere length in both groups.<br><br>METHODS: Quantitative fluorescence in situ hybridization with a peptide nucleic acid probe complementary to the telomere repeat sequence was performed on frozen sections from human lacrimal gland tissues. The mean fluorescence intensity of telomere spots was automatically quantified by image analysis as relative telomere length in lacrimal gland epithelial cells. Immunostaining for p63, nucleostemin, ATP-binding cassette, sub-family G, member 2 (ABCG2), and nestin was also performed.<br><br>RESULTS: Telomere intensity in the Sj&#xf6;gren syndrome group (6,785.0&#xb1;455) was significantly lower than that in the non-Sj&#xf6;gren syndrome group (7,494.7&#xb1;477; p=0.02). Among the samples from the non-Sj&#xf6;gren syndrome group, immunostaining revealed that p63 was expressed in 1-3 acinar cells in each acinar unit and continuously in the basal layer of duct cells. In contrast, in the Sj&#xf6;gren syndrome group, p63 and nucleostemin showed a lower level of expression. ABCG2 was expressed in acinar cells in both sjogren and non-Sjogren syndrome.<br><br>CONCLUSIONS: The results of this study indicate that 1) telo-FISH is a viable method of assessing telomere length in lacrimal gland, and 2) telomere length in Sj&#xf6;gren syndrome is shorter and associated with lower levels of expression of p63 and nucleostemin than in non-Sj&#xf6;gren syndrome.},
}
@article {pmid21655087,
year = {2011},
author = {Kurzhals, RL and Titen, SW and Xie, HB and Golic, KG},
title = {Chk2 and p53 are haploinsufficient with dependent and independent functions to eliminate cells after telomere loss.},
journal = {PLoS genetics},
volume = {7},
number = {6},
pages = {e1002103},
pmid = {21655087},
issn = {1553-7404},
support = {R01 GM065604/GM/NIGMS NIH HHS/United States ; T32 GM007464/GM/NIGMS NIH HHS/United States ; R01 GM65604/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Apoptosis/genetics ; Cellular Senescence ; Checkpoint Kinase 2 ; Drosophila/*genetics ; Drosophila Proteins/*genetics/metabolism ; Genes, p53/*genetics ; Haplotypes/*genetics ; Protein Serine-Threonine Kinases/*genetics/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {The mechanisms that cells use to monitor telomere integrity, and the array of responses that may be induced, are not fully defined. To date there have been no studies in animals describing the ability of cells to survive and contribute to adult organs following telomere loss. We developed assays to monitor the ability of somatic cells to proliferate and differentiate after telomere loss. Here we show that p53 and Chk2 limit the growth and differentiation of cells that lose a telomere. Furthermore, our results show that two copies of the genes encoding p53 and Chk2 are required for the cell to mount a rapid wildtype response to a missing telomere. Finally, our results show that, while Chk2 functions by activating the p53-dependent apoptotic cascade, Chk2 also functions independently of p53 to limit survival. In spite of these mechanisms to eliminate cells that have lost a telomere, we find that such cells can make a substantial contribution to differentiated adult tissues.},
}
@article {pmid21653196,
year = {2011},
author = {Nelson, AD and Lamb, JC and Kobrossly, PS and Shippen, DE},
title = {Parameters affecting telomere-mediated chromosomal truncation in Arabidopsis.},
journal = {The Plant cell},
volume = {23},
number = {6},
pages = {2263-2272},
pmid = {21653196},
issn = {1532-298X},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; GM-065383/GM/NIGMS NIH HHS/United States ; GM-800052/GM/NIGMS NIH HHS/United States ; },
mesh = {Arabidopsis/*genetics/*metabolism ; Arabidopsis Proteins/genetics/metabolism ; Chromosomes, Plant/*metabolism ; DNA Breaks, Double-Stranded ; DNA Repair ; Genome, Plant ; Humans ; Repetitive Sequences, Nucleic Acid ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Tetraploidy ; },
abstract = {Conversion of a double-strand break into a telomere is a dangerous, potentially lethal event. However, little is known about the mechanism and control of de novo telomere formation (DNTF). DNTF can be instigated by the insertion of a telomere repeat array (TRA) into the host genome, which seeds the formation of a new telomere, resulting in chromosome truncation. Such events are rare and concentrated at chromosome ends. Here, we introduce tetraploid Arabidopsis thaliana as a robust genetic model for DNTF. Transformation of a 2.6-kb TRA into tetraploid plants resulted in a DNTF efficiency of 56%, fivefold higher than in diploid plants and 50-fold higher than in human cells. DNTF events were recovered across the entire genome, indicating that genetic redundancy facilitates recovery of DNTF events. Although TRAs as short as 100 bp seeded new telomeres, these tracts were unstable unless they were extended above a 1-kb size threshold. Unexpectedly, DNTF efficiency increased in plants lacking telomerase, and DNTF rates were lower in plants null for Ku70 or Lig4, components of the nonhomologous end-joining repair pathway. We conclude that multiple competing pathways modulate DNTF, and that tetraploid Arabidopsis will be a powerful model for elucidating the molecular details of these processes.},
}
@article {pmid21648092,
year = {2012},
author = {Osterwald, S and Wörz, S and Reymann, J and Sieckmann, F and Rohr, K and Erfle, H and Rippe, K},
title = {A three-dimensional colocalization RNA interference screening platform to elucidate the alternative lengthening of telomeres pathway.},
journal = {Biotechnology journal},
volume = {7},
number = {1},
pages = {103-116},
doi = {10.1002/biot.201000474},
pmid = {21648092},
issn = {1860-7314},
mesh = {Cell Cycle/genetics ; Cell Line, Tumor ; Gene Knockdown Techniques/methods ; HeLa Cells ; Humans ; Imaging, Three-Dimensional/*methods ; Intranuclear Inclusion Bodies/genetics/metabolism ; Leukemia, Promyelocytic, Acute/genetics/metabolism ; Microscopy, Confocal/*methods ; Microscopy, Fluorescence/*methods ; Nuclear Proteins/genetics/metabolism ; *RNA Interference ; Signal Transduction/genetics ; Telomerase/genetics/metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {A high-content colocalization RNA interference screen based on automatic three-color confocal fluorescence microscopy was developed to analyze the alternative lengthening of telomeres (ALT) pathway. Via this pathway telomerase-negative cancer cells can maintain their telomeres and with it their unlimited proliferative potential. A hallmark of ALT cells is the colocalization of promyelocytic leukemia (PML) nuclear bodies with telomeres to form ALT-associated PML nuclear bodies (APBs). In our screen, the presence of APBs was used as a marker to identify proteins required for the ALT mechanism. A cell-based assay and an automatic confocal image acquisition procedure were established. Using automatic image analysis based on 3D parametric intensity models to identify APBs, we conducted an unbiased and quantitative analysis of nine different candidate genes. A comparison with the literature and manual analysis of the gene knockdown demonstrates the reliability of our approach. It extends the available repertoire of high-content screening to studies of cellular colocalizations and allows the identification of candidate genes for the ALT mechanism that represent possible targets for cancer therapy.},
}
@article {pmid21647296,
year = {2011},
author = {Shtessel, L and Ahmed, S},
title = {Telomere dysfunction in human bone marrow failure syndromes.},
journal = {Nucleus (Austin, Tex.)},
volume = {2},
number = {1},
pages = {24-29},
pmid = {21647296},
issn = {1949-1042},
support = {R01 GM066228/GM/NIGMS NIH HHS/United States ; R56 GM066228/GM/NIGMS NIH HHS/United States ; },
mesh = {Anemia, Aplastic ; Bone Marrow Diseases ; Bone Marrow Failure Disorders ; DNA Repair Enzymes/metabolism ; Exodeoxyribonucleases ; Hemoglobinuria, Paroxysmal/metabolism/*pathology ; Humans ; Inhibitor of Apoptosis Proteins/metabolism ; Nuclear Proteins/metabolism ; Telomerase/metabolism ; Telomere/*metabolism/pathology ; },
abstract = {Approximately 90% of all human cancers, in which some deregulation of cell cycle arrest or programmed cell death has occurred, express telomerase, a ribonucleoprotein whose activity is normally turned off in healthy somatic tissues. Additionally, small populations of self-renewing stem cells, such as hematopoietic stem cells, skin and hair follicle basal layer cells and intestinal basal crypt cells, have been shown to retain telomerase activity. Conversely, hereditary defects that result in shortened telomeres in humans have been shown to manifest most often as bone marrow failure or pulmonary fibrosis, along with a myriad of other symptoms, likely due to the loss of the stem and/or progenitor cells of affected tissues. The aim of this review is to highlight our knowledge of the mechanisms of telomere maintenance that contribute to the pathology of human disease caused by dysfunctional telomere homeostasis. Specifically, a new role for the SNM1B/Apollo nuclease in the pathologies of Hoyeraal-Hreidarsson syndrome will be discussed.},
}
@article {pmid21645396,
year = {2011},
author = {Lu, L and Zhang, C and Zhu, G and Irwin, M and Risch, H and Menato, G and Mitidieri, M and Katsaros, D and Yu, H},
title = {Telomerase expression and telomere length in breast cancer and their associations with adjuvant treatment and disease outcome.},
journal = {Breast cancer research : BCR},
volume = {13},
number = {3},
pages = {R56},
pmid = {21645396},
issn = {1465-542X},
mesh = {Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/pharmacology ; Apoptosis ; Breast Neoplasms/*drug therapy/genetics/mortality ; Cell Division/genetics ; Chemotherapy, Adjuvant ; Female ; Humans ; Middle Aged ; Tamoxifen/pharmacology/therapeutic use ; Telomerase/*metabolism ; Telomere/*physiology ; *Telomere Homeostasis ; Treatment Outcome ; },
abstract = {INTRODUCTION: Telomere length plays important roles in maintaining genome stability and regulating cell replication and death. Telomerase has functions not only to extend telomere length but also to repair DNA damage. Studies have shown that telomerase may increase cancer cell resistance to DNA-damaging anticancer agents; tamoxifen may suppress telomerase expression in breast cancer cells. This study aimed to investigate the role of telomere length and telomerase activity in breast cancer prognosis.<br><br>METHODS: qPCR and qRT-PCR were used to analyze telomere length and telomerase expression, respectively, in tumor samples of 348 breast cancer patients. Cox regression analysis was performed to examine telomere length and telomerase expression in association with disease-free survival and cause-specific mortality.<br><br>RESULTS: Telomere length had no relation to tumor features or disease outcomes. Telomerase expression was detected in 53% of tumors. Larger tumors or aggressive disease were more likely to have telomerase expression. Among patients treated with chemotherapy, high telomerase was found to be associated with increased risk of death (hazard ratio (HR) = 3.15; 95% CI: 1.34 to 7.40) and disease recurrence (HR = 2.04; 95% CI: 0.96 to 4.30) regardless of patient age, disease stage, tumor grade, histological type or hormone receptor status. Patients treated with endocrine therapy had different results regarding telomerase: high telomerase appeared to be associated with better survival outcomes. Telomerase expression made no survival difference in patients who received both chemotherapy and endocrine therapy.<br><br>CONCLUSIONS: Overall, telomerase expression was not associated with disease outcome, but this finding may be masked by adjuvant treatment. Patients with high telomerase expression responded poorly to chemotherapy in terms of disease-free and overall survival, but fared better if treated with endocrine therapy.},
}
@article {pmid21643930,
year = {2011},
author = {Kim, S and Sandler, DP and Carswell, G and De Roo, LA and Parks, CG and Cawthon, R and Weinberg, CR and Taylor, JA},
title = {Telomere length in peripheral blood and breast cancer risk in a prospective case-cohort analysis: results from the Sister Study.},
journal = {Cancer causes &amp; control : CCC},
volume = {22},
number = {7},
pages = {1061-1066},
pmid = {21643930},
issn = {1573-7225},
support = {Z01 ES049033-12//Intramural NIH HHS/United States ; },
mesh = {Adult ; Aged ; Blood Cells/*metabolism ; Breast Neoplasms/blood/*etiology/metabolism ; Carcinoma/blood/*etiology/metabolism ; Case-Control Studies ; Cohort Studies ; Female ; Humans ; Middle Aged ; Prospective Studies ; *Siblings ; Telomere/genetics/*metabolism ; },
abstract = {OBJECTIVE: Telomeres are required for maintaining genomic integrity and may play a role in carcinogenesis. Some, but not all, epidemiologic studies have found that short telomeres in leukocytes are associated with an increased risk of breast cancer. To further elucidate this potential association, we examined telomere length in relation to breast cancer risk in prospectively collected blood samples from the Sister Study, a cohort of women aged 35-74 years who have a sister with breast cancer.<br><br>METHODS: We performed a case-cohort analysis comparing incident breast cancer cases (n = 342) with a subcohort (n = 735), randomly selected from 29,026 participants, enrolled by June 1, 2007. Relative telomere length in peripheral blood cells was estimated using a single-tube monochrome multiplex quantitative PCR assay.<br><br>RESULTS: No association was observed between telomere length and breast cancer risk. Compared with the longest quartile, hazard ratios (HR) associated with the second, third, and the shortest quartile were 0.91 [95% confidence interval (95% CI): 0.62-1.34], 1.11 (95% CI: 0.77-1.60), and 0.93 (95% CI: 0.64-1.35), respectively. Subgroup analyses by menopausal status, invasiveness, or estrogen receptor status of breast cancer did not reveal evidence of association between telomere length in blood cells and subsequent breast cancer risk.<br><br>CONCLUSIONS: This prospective investigation does not support telomere length in blood cells as a biomarker for breast cancer risk.},
}
@article {pmid21643006,
year = {2012},
author = {Zhang, B and Qian, D and Ma, HH and Jin, R and Yang, PX and Cai, MY and Liu, YH and Liao, YJ and Deng, HX and Mai, SJ and Zhang, H and Zeng, YX and Lin, MC and Kung, HF and Xie, D and Huang, JJ},
title = {Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation.},
journal = {Oncogene},
volume = {31},
number = {1},
pages = {1-12},
doi = {10.1038/onc.2011.214},
pmid = {21643006},
issn = {1476-5594},
mesh = {Anthracyclines/*pharmacology ; Cell Cycle Proteins ; Cell Line, Tumor ; DNA Damage ; Humans ; Proteasome Endopeptidase Complex/physiology ; Telomerase/*physiology ; Telomere/*drug effects ; Tumor Suppressor Proteins/*metabolism ; *Ubiquitination ; },
abstract = {Telomere maintenance is essential for cancer growth. Induction of telomere dysfunction, for example, by inhibition of telomeric proteins or telomerase, has been shown to strongly enhance cancer cells' sensitivity to chemotherapies. However, it is not clear whether modulations of telomere maintenance constitute cancer cellular responses to chemotherapies. Furthermore, the manner in which anti-cancer drugs affect telomere function remains unknown. In this study, we show that anthracyclines, a class of anti-cancer drugs widely used in clinical cancer treatments, have an active role in triggering telomere dysfunction specifically in telomerase-positive cancer cells. Anthracyclines interrupt telomere maintenance by telomerase through the downregulation of PinX1, a protein factor responsible for targeting telomerase onto telomeres, thereby inhibiting telomerase association with telomeres. We further demonstrate that anthracyclines downregulate PinX1 by inducing this protein degradation through the ubiquitin-proteasome-dependent pathway. Our data not only reveal a novel action for anthracyclines as telomerase functional inhibitors but also provide a clue for the development of novel anti-cancer drugs based on telomerase/telomere targeting, which is actively investigated by many current studies.},
}
@article {pmid21642670,
year = {2011},
author = {Hampton, T},
title = {Studies probe role of telomere length in predicting, modulating cancer risk.},
journal = {JAMA},
volume = {305},
number = {22},
pages = {2278-2279},
doi = {10.1001/jama.2011.772},
pmid = {21642670},
issn = {1538-3598},
mesh = {Female ; Genetic Predisposition to Disease ; Humans ; Male ; Neoplasms/*epidemiology/genetics ; Predictive Value of Tests ; Prognosis ; Risk ; Stress, Psychological ; Telomere/*diagnostic imaging ; Ultrasonography ; Urinary Bladder Neoplasms/epidemiology/genetics ; },
}
@article {pmid21638208,
year = {2011},
author = {Jeon, BG and Kumar, BM and Kang, EJ and Ock, SA and Lee, SL and Kwack, DO and Byun, JH and Park, BW and Rho, GJ},
title = {Characterization and comparison of telomere length, telomerase and reverse transcriptase activity and gene expression in human mesenchymal stem cells and cancer cells of various origins.},
journal = {Cell and tissue research},
volume = {345},
number = {1},
pages = {149-161},
doi = {10.1007/s00441-011-1191-9},
pmid = {21638208},
issn = {1432-0878},
mesh = {Adipogenesis/genetics ; Adolescent ; Adult ; Biomarkers/metabolism ; Cell Line, Tumor ; Cell Lineage ; Cell Membrane/metabolism ; Female ; *Gene Expression Regulation ; Gene Expression Regulation, Neoplastic ; Humans ; Mesenchymal Stem Cells/*enzymology ; Neoplasms/*enzymology/*genetics ; Osteogenesis/genetics ; RNA, Messenger/genetics/metabolism ; Telomerase/*genetics/metabolism ; Telomere/*metabolism ; Transcription, Genetic ; },
abstract = {We have characterized and compared the telomere length, telomerase, reverse transcriptase (RT) activity and expression of genes implicated in cancer and in pluripotency, in human mesenchymal stem cells (MSCs) derived from dental papilla tissue, umbilical cord matrix and adipose tissue and in cancer cells (MDA-MB-231, U-87 MG, and MCF-7). MRC-5 fetal fibroblasts and adult muscle cells were used as somatic cell controls. Telomere length was significantly (P<0.05) higher in MSCs and somatic cells (7.2-9.3 kb) than in cancer cell lines (3.9-6 kb). However, the relative telomerase activity (RTA) in the cancer cell lines was significantly (P<0.05) higher than that of MSCs and somatic cells. RTA tended to be slightly higher in MSCs but no significant differences were observed between some cancer cells and MSCs. However, RTA was not detected in somatic cells. Although differentially displayed, the expression of genes related to cancer (BCL-2, p53, NF-κB, TGF-β, VEGF) and transcription and pluripotency (OCT4, NANOG, STAT3, REX1) were commonly observed in MSCs and cancer cells. Thus, endogenous non-telomerase RTA might be a potential biological marker or regulator among MSCs and cancer cells. Further, by sharing the biological and molecular markers of self-renewal and proliferation with cancer cells, MSCs might play a contributory role as tissue resident stem cells in tumor development.},
}
@article {pmid21635204,
year = {2011},
author = {Rollison, DE and Epling-Burnette, PK and Park, JY and Lee, JH and Park, H and Jonathan, K and Cole, AL and Painter, JS and Guerrier, M and Meléndez-Santiago, J and Fulp, W and Komrokji, R and Lancet, J and List, AF},
title = {Telomere length in myelodysplastic syndromes.},
journal = {Leukemia &amp; lymphoma},
volume = {52},
number = {8},
pages = {1528-1536},
pmid = {21635204},
issn = {1029-2403},
support = {P20 CA103676/CA/NCI NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; R01 CA129952/CA/NCI NIH HHS/United States ; R01CA129952/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Antigens, CD19/blood ; Case-Control Studies ; Female ; Flow Cytometry ; Gene Frequency ; Genotype ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes/metabolism ; Lewis X Antigen/blood ; Logistic Models ; Male ; Middle Aged ; *Mutation ; Myelodysplastic Syndromes/enzymology/*genetics/pathology ; Paint/poisoning ; Pesticides/poisoning ; Polymerase Chain Reaction ; Saliva/metabolism ; Telomerase/*genetics ; Telomere/drug effects/*genetics ; Young Adult ; },
abstract = {The relationship between telomere length (TL) and predisposition to myelodysplastic syndromes (MDS) remains unclear. We compared peripheral blood leukocyte (PBL) TL among cases of histologically confirmed MDS (n = 65) who were treatment-naive with no prior cancer history to age-matched controls (n = 63). Relative TL was measured in PBLs and saliva by quantitative polymerase chain reaction (PCR) and in CD15+ and CD19+ cells by flow cytometry-fluorescence in situ hybridization (flow-FISH). Human telomerase reverse transcriptase gene (hTERT) mutations were assessed by PCR. After adjustment for age and sex, relative TLs were reduced in PBLs (p = 0.02), CD15+ (p = 0.01), CD19+ (p = 0.25), and saliva (p = 0.13) in MDS cases versus controls, although only the PBL and CD15+ results were statistically significant. Among MDS cases, CD15+ and CD19+ cell TLs were positively correlated (p = 0.03). PBL TL was reduced among those occupationally exposed to paints and pesticides, but was not associated with hTERT genotype. Future studies are needed to further investigate constitutional telomere attrition as a possible predisposing factor for MDS.},
}
@article {pmid21625008,
year = {2011},
author = {Burgio, G and Cipressa, F and Ingrassia, AM and Cenci, G and Corona, DF},
title = {The histone deacetylase Rpd3 regulates the heterochromatin structure of Drosophila telomeres.},
journal = {Journal of cell science},
volume = {124},
number = {Pt 12},
pages = {2041-2048},
doi = {10.1242/jcs.078261},
pmid = {21625008},
issn = {1477-9137},
support = {TCR09002/TI_/Telethon/Italy ; },
mesh = {Animals ; Drosophila Proteins/*metabolism ; Drosophila melanogaster/*genetics/metabolism ; Epigenomics ; Heterochromatin/*metabolism ; Histone Deacetylase 1/*metabolism ; Male ; Polytene Chromosomes ; Telomere/*metabolism ; },
abstract = {Telomeres are specialized structures at the end of eukaryotic chromosomes that are required to preserve genome integrity, chromosome stability and nuclear architecture. Telomere maintenance and function are established epigenetically in several eukaryotes. However, the exact chromatin enzymatic modifications regulating telomere homeostasis are poorly understood. In Drosophila melanogaster, telomere length and stability are maintained through the retrotransposition of specialized telomeric sequences and by the specific loading of protecting capping proteins, respectively. Here, we show that the loss of the essential and evolutionarily conserved histone deacetylase Rpd3, the homolog of mammalian HDAC1, causes aberrant telomeric fusions on polytene chromosome ends. Remarkably, these telomere fusion defects are associated with a marked decrease of histone H4 acetylation, as well as an accumulation of heterochromatic epigenetic marks at telomeres, including histone H3K9 trimethylation and the heterochromatic protein HP2. Our work suggests that Drosophila telomere structure is epigenetically regulated by the histone deacetylase Rpd3.},
}
@article {pmid21622673,
year = {2011},
author = {Den Elzen, WP and Martin-Ruiz, C and von Zglinicki, T and Westendorp, RG and Kirkwood, TB and Gussekloo, J},
title = {Telomere length and anaemia in old age: results from the Newcastle 85-plus Study and the Leiden 85-plus Study.},
journal = {Age and ageing},
volume = {40},
number = {4},
pages = {494-500},
pmid = {21622673},
issn = {1468-2834},
support = {MR/J50001X/1/MRC_/Medical Research Council/United Kingdom ; G0500997/MRC_/Medical Research Council/United Kingdom ; G0500997/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; G0601333/MRC_/Medical Research Council/United Kingdom ; AG06354/AG/NIA NIH HHS/United States ; },
mesh = {Age Factors ; Aged, 80 and over ; *Aging/blood/genetics ; Anemia/blood/*genetics ; Chi-Square Distribution ; Cross-Sectional Studies ; England ; Female ; Genetic Predisposition to Disease ; Humans ; Linear Models ; Male ; Netherlands ; Polymerase Chain Reaction ; Risk Assessment ; Risk Factors ; Telomere/*metabolism ; },
abstract = {BACKGROUND: reduced telomere length in blood cells has been associated with increased risk of multiple age-related diseases and is widely regarded as a general biomarker of ageing. Therefore, it is important to know both the extent and limitations of this association. We investigated the relation between telomere length and anaemia in two independent cohorts, with the prior expectation of adding anaemia to the list of conditions for which telomere reduction is a risk factor.<br><br>PARTICIPANTS AND METHODS: the present study is embedded in the Newcastle 85-plus Study and Leiden 85-plus Study, two population-based studies of inhabitants of Newcastle and North Tyneside, UK (n = 749) and Leiden, the Netherlands (n = 658) aged 85 and over. High-molecular-weight DNA was isolated from full fresh blood (Newcastle) and peripheral blood mononuclear cells samples (Leiden). Telomere length was measured as abundance of telomeric template versus a single gene by quantitative real-time polymerase chain reaction. Anaemia was defined according to World Health Organization criteria.<br><br>RESULTS: in both studies, no differences in median telomere length were observed between participants with anaemia and participants without anaemia (Newcastle: 2,846 bp (interquartile range (IQR) 2,433-3,630) versus 2,920 bp (IQR 2,425-3,570), P = 0.63; Leiden: 4,136 bp (IQR 3,879-4,428) versus 4,167 bp (IQR 3,893-4,501), P = 0.41). Telomere length also did not correlate with any other haematological parameter in both men and women.<br><br>CONCLUSIONS: in contrast to other age-related diseases, telomere length is not associated with anaemia or any other haematological parameter in older individuals in the general population.},
}
@article {pmid21619941,
year = {2012},
author = {Downs, KP and Shen, Y and Pasquali, A and Beldorth, I and Savage, M and Gallier, K and Garcia, T and Booth, RE and Walter, RB},
title = {Characterization of telomeres and telomerase expression in Xiphophorus.},
journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP},
volume = {155},
number = {1},
pages = {89-94},
pmid = {21619941},
issn = {1532-0456},
support = {R24 OD011120/OD/NIH HHS/United States ; R24 RR024790/RR/NCRR NIH HHS/United States ; R24 RR024790-05/RR/NCRR NIH HHS/United States ; R24-RR024790/RR/NCRR NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animal Structures/metabolism/radiation effects ; Animals ; Blotting, Southern/methods ; Chimera/genetics/metabolism ; Cyprinodontiformes/*genetics/metabolism ; Female ; Fish Proteins/genetics/metabolism ; Gene Expression Regulation ; Male ; Molecular Sequence Data ; Real-Time Polymerase Chain Reaction ; Sequence Alignment ; Skin/radiation effects ; Species Specificity ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere Shortening ; Ultraviolet Rays/adverse effects ; },
abstract = {Research investigating telomere lengths and telomerase expression in vertebrates has progressively become important due to the association of these two biological endpoints with cellular aging and cancer in humans. Studies that rely upon the traditional use of laboratory mice have been faced with limitations largely due to inbred mice possessing large telomeres and ubiquitous expression of telomerase. Recently, a number of small fish species have been shown to provide potentially informative models for examining the role of telomeres and telomerase within intact vertebrate animals. Xiphophorus fishes represent a new world live-bearing genus that has not previously been assessed for telomere length or telomerase expression. To add to the knowledge base of telomere and telomerase biology in vertebrates we assessed telomere length and telomerase expression among several species of Xiphophorus. The telomere lengths in several organs (gill, brain, eyes, testis, ovary and liver) in three species (Xiphophorus hellerii, Xiphophorus maculatus, Xiphophorus couchianus) and also in F(1) interspecies hybrids were approximately 2-6 kb. This size was consistent within the same organs of the same species, as well as between species and F(1) hybrids. Despite possessing relatively short telomere lengths compared to humans, the consistency of size among Xiphophorus species and organs may allow experimental detection of telomere shortening. The relative expression of telomerase reverse transcriptase (TERT) was determined by quantitative real-time PCR. Expression levels of TERT was measured in seven organs (ovary, testis, liver, gill, brain, heart, skin) from X. maculatus, X. hellerii and in control and ultraviolet light (UVB) exposed skin samples from X. maculatus, X. hellerii, and F(1) interspecies hybrids. TERT gene expression was significantly higher in ovary and testis, while all other organs showed low relative TERT expression. Detectable increases in TERT expression were found in skin samples upon UVB exposure. Our findings suggest that Xiphophorus may serve as a suitable model for future studies investigating the association of telomere length and telomerase expression in regard to aging and disease.},
}
@article {pmid21615055,
year = {2011},
author = {Ruiz-Gómez, MJ},
title = {Telomere instability caused by subtelomeric Y' amplification and rearrangements in Saccharomyces cerevisiae (ku70 tel1 and ku70 rad50) double mutants.},
journal = {Indian journal of experimental biology},
volume = {49},
number = {5},
pages = {324-331},
pmid = {21615055},
issn = {0019-5189},
mesh = {Chromosomal Instability/genetics ; Chromosomes, Fungal/genetics ; DNA-Binding Proteins/genetics ; Gene Amplification ; Gene Rearrangement ; Genes, Fungal ; Intracellular Signaling Peptides and Proteins/genetics ; Mutation ; Protein Serine-Threonine Kinases/genetics ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/genetics ; Telomere/*genetics ; },
abstract = {Telomeres solve the end-replication problem. Previous results suggested a relation between Yku70/80 and proteins Tell and Rad50 in telomere stabilization. Inactivation of any of these genes lead to a shortening of telomeres, while in ku70 tell or ku70 rad50 double mutants a drastic amplification of Y' elements was found. The biological significance of this observation is not clear. To further characterize Y' amplification 25 strains and isolates of S. cerevisiae were analyzed. As expected, amplification was seen in yku70 tel1 and yku70 rad50 double mutants, but not in other strains. The extent of Y' amplification was also tested to determine if excessive numbers of Y' repeats appear. A variation in chromosome lengths within the population of cells has been found. Hybridisation study indicated that chromosomes only increase in length in these double mutants, but never get shorter. A high degree of variability was observed in single cell clones, in spite of their close relationship, indicating that alterations in subtelomeric regions are not stable but occur continuously in these mutants. Therefore, these genes are essential to chromosome stability.},
}
@article {pmid21606440,
year = {2011},
author = {Peres, J},
title = {Telomere research offers insight on stress-disease link.},
journal = {Journal of the National Cancer Institute},
volume = {103},
number = {11},
pages = {848-850},
doi = {10.1093/jnci/djr214},
pmid = {21606440},
issn = {1460-2105},
mesh = {Aging/genetics ; Animals ; Breast Neoplasms/genetics/psychology/therapy ; Cellular Senescence/*genetics ; *Counseling ; *Exercise ; Female ; Humans ; Neoplasms/enzymology/*genetics/psychology/*therapy ; Psychophysiology/trends ; Quality of Life ; Stress, Psychological/*complications/etiology ; Telomere/*genetics ; Uterine Cervical Neoplasms/genetics/psychology/therapy ; },
}
@article {pmid21605571,
year = {2012},
author = {Gourronc, FA and Klingelhutz, AJ},
title = {Therapeutic opportunities: telomere maintenance in inducible pluripotent stem cells.},
journal = {Mutation research},
volume = {730},
number = {1-2},
pages = {98-105},
pmid = {21605571},
issn = {0027-5107},
support = {R01 AG027388/AG/NIA NIH HHS/United States ; R01 AG027388-05/AG/NIA NIH HHS/United States ; AG027388/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Cell Differentiation ; *Cellular Reprogramming ; Dyskeratosis Congenita/genetics/pathology ; Enzyme Activation ; Epigenesis, Genetic ; Humans ; Induced Pluripotent Stem Cells/enzymology/*transplantation ; Mice ; Telomerase/*metabolism ; Telomere/metabolism ; *Telomere Homeostasis ; },
abstract = {It has been demonstrated that exogenous expression of a combination of transcription factors can reprogram differentiated cells such as fibroblasts and keratinocytes into what have been termed induced pluripotent stem (iPS) cells. These iPS cells are capable of differentiating into all the tissue lineages when placed in the right environment and, in the case of mouse cells, can generate chimeric mice and be transmitted through the germline. Safer and more efficient methods of reprogramming are rapidly being developed. Clearly, iPS cells present a number of exciting possibilities, including disease modeling and therapy. A major question is whether the nuclei of iPS cells are truly rejuvenated or whether they might retain some of the marks of aging from the cells from which they were derived. One measure of cellular aging is the telomere. In this regard, recent studies have demonstrated that telomeres in iPS cells may be rejuvenated. They are not only elongated by reactivated telomerase but they are also epigenetically modified to be similar but not identical to embryonic stem cells. Upon differentiation, the derivative cells turn down telomerase, the telomeres begin to shorten again, and the telomeres and the genome are returned to an epigenetic state that is similar to normal differentiated somatic cells. While these preliminary telomere findings are promising, the overall genomic integrity of reprogrammed cells may still be problematic and further studies are needed to examine the safety and feasibility of using iPS cells in regenerative medicine applications.},
}
@article {pmid21605287,
year = {2011},
author = {Kobayashi, T},
title = {How does genome instability affect lifespan?: roles of rDNA and telomeres.},
journal = {Genes to cells : devoted to molecular &amp; cellular mechanisms},
volume = {16},
number = {6},
pages = {617-624},
pmid = {21605287},
issn = {1365-2443},
mesh = {Cellular Senescence/genetics ; DNA, Ribosomal/*genetics/*metabolism ; Genomic Instability/*genetics ; Saccharomyces cerevisiae/genetics/metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {The genome is composed not only of genes but also of several noncoding functional elements (NOCs/ncFE, here I use NOCs), such as transcriptional promoters, enhancers, replication origins, centromeres and telomeres. rDNA has both gene and NOC characteristics. Thus, the rDNA encodes ribosomal RNAs, components of the ribosomes, that account for approximately 80% of the total RNA in a cell. However, rDNA may also act as a NOC with respect to cellular senescence by limiting the number of times a cell can divide. Here, I discuss how rDNA might function as a NOC to influence life span in a manner analogous to telomeres.},
}
@article {pmid21602933,
year = {2011},
author = {O'Donovan, A and Pantell, MS and Puterman, E and Dhabhar, FS and Blackburn, EH and Yaffe, K and Cawthon, RM and Opresko, PL and Hsueh, WC and Satterfield, S and Newman, AB and Ayonayon, HN and Rubin, SM and Harris, TB and Epel, ES and , },
title = {Cumulative inflammatory load is associated with short leukocyte telomere length in the Health, Aging and Body Composition Study.},
journal = {PloS one},
volume = {6},
number = {5},
pages = {e19687},
pmid = {21602933},
issn = {1932-6203},
support = {UL1 TR000005/TR/NCATS NIH HHS/United States ; AG-6-2101/AG/NIA NIH HHS/United States ; R01 AG021918/AG/NIA NIH HHS/United States ; AG-6-2103/AG/NIA NIH HHS/United States ; AG-6-2106/AG/NIA NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; AG021918/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aging ; Biomarkers ; C-Reactive Protein ; Humans ; Inflammation/*pathology ; Interleukin-6/analysis ; Leukocytes/*ultrastructure ; Odds Ratio ; Telomere/*ultrastructure ; Tumor Necrosis Factor-alpha/analysis ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) is an emerging marker of biological age. Chronic inflammatory activity is commonly proposed as a promoter of biological aging in general, and of leukocyte telomere shortening in particular. In addition, senescent cells with critically short telomeres produce pro-inflammatory factors. However, in spite of the proposed causal links between inflammatory activity and LTL, there is little clinical evidence in support of their covariation and interaction.<br><br>To address this issue, we examined if individuals with high levels of the systemic inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-&#x3b1; (TNF-&#x3b1;) and C-reactive protein (CRP) had increased odds for short LTL. Our sample included 1,962 high-functioning adults who participated in the Health, Aging and Body Composition Study (age range: 70-79 years). Logistic regression analyses indicated that individuals with high levels of either IL-6 or TNF-&#x3b1; had significantly higher odds for short LTL. Furthermore, individuals with high levels of both IL-6 and TNF-&#x3b1; had significantly higher odds for short LTL compared with those who had neither high (OR&#x200a;=&#x200a;0.52, CI&#x200a;=&#x200a;0.37-0.72), only IL-6 high (OR&#x200a;=&#x200a;0.57, CI&#x200a;=&#x200a;0.39-0.83) or only TNF-&#x3b1; high (OR&#x200a;=&#x200a;0.67, CI&#x200a;=&#x200a;0.46-0.99), adjusting for a wide variety of established risk factors and potential confounds. In contrast, CRP was not associated with LTL.<br><br>CONCLUSIONS/SIGNIFICANCE: Results suggest that cumulative inflammatory load, as indexed by the combination of high levels of IL-6 and TNF-&#x3b1;, is associated with increased odds for short LTL. In contrast, high levels of CRP were not accompanied by short LTL in this cohort of older adults. These data provide the first large-scale demonstration of links between inflammatory markers and LTL in an older population.},
}
@article {pmid21602826,
year = {2011},
author = {Batista, LF and Pech, MF and Zhong, FL and Nguyen, HN and Xie, KT and Zaug, AJ and Crary, SM and Choi, J and Sebastiano, V and Cherry, A and Giri, N and Wernig, M and Alter, BP and Cech, TR and Savage, SA and Reijo Pera, RA and Artandi, SE},
title = {Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells.},
journal = {Nature},
volume = {474},
number = {7351},
pages = {399-402},
pmid = {21602826},
issn = {1476-4687},
support = {T32 CA009302/CA/NCI NIH HHS/United States ; U01 HL100397/HL/NHLBI NIH HHS/United States ; R01 CA125453-05/CA/NCI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; RC1 HL100361-01/HL/NHLBI NIH HHS/United States ; R01 CA111691/CA/NCI NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; R01 CA125453/CA/NCI NIH HHS/United States ; R01 AG033747-02/AG/NIA NIH HHS/United States ; R01 AG033747/AG/NIA NIH HHS/United States ; R01 CA111691-05/CA/NCI NIH HHS/United States ; RC1 HL100361/HL/NHLBI NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics/metabolism ; Cell Division ; Cellular Reprogramming ; Dyskeratosis Congenita/*genetics/*pathology ; Fibroblasts ; Gene Expression Regulation ; Humans ; Induced Pluripotent Stem Cells/*metabolism/*pathology ; Molecular Chaperones ; Nuclear Proteins/genetics/metabolism ; RNA/genetics ; Telomerase/genetics/metabolism ; Telomere/enzymology/genetics/metabolism/*pathology ; },
abstract = {The differentiation of patient-derived induced pluripotent stem cells (iPSCs) to committed fates such as neurons, muscle and liver is a powerful approach for understanding key parameters of human development and disease. Whether undifferentiated iPSCs themselves can be used to probe disease mechanisms is uncertain. Dyskeratosis congenita is characterized by defective maintenance of blood, pulmonary tissue and epidermal tissues and is caused by mutations in genes controlling telomere homeostasis. Short telomeres, a hallmark of dyskeratosis congenita, impair tissue stem cell function in mouse models, indicating that a tissue stem cell defect may underlie the pathophysiology of dyskeratosis congenita. Here we show that even in the undifferentiated state, iPSCs from dyskeratosis congenita patients harbour the precise biochemical defects characteristic of each form of the disease and that the magnitude of the telomere maintenance defect in iPSCs correlates with clinical severity. In iPSCs from patients with heterozygous mutations in TERT, the telomerase reverse transcriptase, a 50% reduction in telomerase levels blunts the natural telomere elongation that accompanies reprogramming. In contrast, mutation of dyskerin (DKC1) in X-linked dyskeratosis congenita severely impairs telomerase activity by blocking telomerase assembly and disrupts telomere elongation during reprogramming. In iPSCs from a form of dyskeratosis congenita caused by mutations in TCAB1 (also known as WRAP53), telomerase catalytic activity is unperturbed, yet the ability of telomerase to lengthen telomeres is abrogated, because telomerase mislocalizes from Cajal bodies to nucleoli within the iPSCs. Extended culture of DKC1-mutant iPSCs leads to progressive telomere shortening and eventual loss of self-renewal, indicating that a similar process occurs in tissue stem cells in dyskeratosis congenita patients. These findings in iPSCs from dyskeratosis congenita patients reveal that undifferentiated iPSCs accurately recapitulate features of a human stem cell disease and may serve as a cell-culture-based system for the development of targeted therapeutics.},
}
@article {pmid21600224,
year = {2012},
author = {Aviv, A},
title = {Genetics of leukocyte telomere length and its role in atherosclerosis.},
journal = {Mutation research},
volume = {730},
number = {1-2},
pages = {68-74},
pmid = {21600224},
issn = {0027-5107},
support = {AG21593/AG/NIA NIH HHS/United States ; R01 AG020132/AG/NIA NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; R01 AG021593-05/AG/NIA NIH HHS/United States ; R01 AG030678-04/AG/NIA NIH HHS/United States ; R01 AG020132-04/AG/NIA NIH HHS/United States ; AG20132/AG/NIA NIH HHS/United States ; R01 AG030678/AG/NIA NIH HHS/United States ; AG30678/AG/NIA NIH HHS/United States ; },
mesh = {Aging/genetics ; Atherosclerosis/*genetics ; Hematopoietic Stem Cells/chemistry ; Humans ; Leukocytes/*chemistry ; Longevity/genetics ; Paternal Age ; Telomere/genetics/*ultrastructure ; Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Humans display a large inter-individual variation in leukocyte telomere length (LTL), which is influenced by heredity, sex, race/ethnicity, paternal age at conception and environmental exposures. LTL dynamics (birth LTL and its age-dependent attrition thereafter) mirror telomere dynamics in hematopoietic stem cells (HSCs). LTL at birth is evidently a major determinant of LTL throughout the human lifespan, such that individuals endowed with short (or long) LTL at birth probably have short (or long) LTL later in life. Therefore, the associations of short LTL with atherosclerosis and with diminished survival in the elderly may relate to short birth LTL, accelerated age-dependent LTL attrition, or both. The mechanisms underlying these associations are still not well understood, but they stem in part from genetic factors in control of telomere maintenance and the rate of HSC replication.},
}
@article {pmid21599212,
year = {2011},
author = {Kepten, E and Bronshtein, I and Garini, Y},
title = {Ergodicity convergence test suggests telomere motion obeys fractional dynamics.},
journal = {Physical review. E, Statistical, nonlinear, and soft matter physics},
volume = {83},
number = {4 Pt 1},
pages = {041919},
doi = {10.1103/PhysRevE.83.041919},
pmid = {21599212},
issn = {1550-2376},
mesh = {Animals ; Cell Nucleus/*physiology/*ultrastructure ; Computer Simulation ; Diffusion ; Humans ; *Models, Biological ; Models, Statistical ; Telomere/*physiology/*ultrastructure ; },
abstract = {Anomalous diffusion, observed in many biological processes, is a generalized description of a wide variety of processes, all obeying the same law of mean-square displacement. Identifying the basic mechanisms of these observations is important for deducing the nature of the biophysical systems measured. We implement a previously suggested method for distinguishing between fractional Langevin dynamics, fractional Brownian motion, and continuous time random walk based on the ergodic nature of the data. We apply the method together with the recently suggested P-variation test and the displacement correlation to the lately measured dynamics of telomeres in the nucleus of mammalian cells and find strong evidence that the telomeres motion obeys fractional dynamics. The ergodic dynamics are observed experimentally to fit fractional Brownian or Langevin dynamics.},
}
@article {pmid21597035,
year = {2011},
author = {Hoen, PW and de Jonge, P and Na, BY and Farzaneh-Far, R and Epel, E and Lin, J and Blackburn, E and Whooley, MA},
title = {Depression and leukocyte telomere length in patients with coronary heart disease: data from the Heart and Soul Study.},
journal = {Psychosomatic medicine},
volume = {73},
number = {7},
pages = {541-547},
pmid = {21597035},
issn = {1534-7796},
support = {R01 HL079235/HL/NHLBI NIH HHS/United States ; R01 HL079235-01A1/HL/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Biomarkers/metabolism ; Chi-Square Distribution ; Coronary Artery Disease/mortality/*physiopathology/psychology ; Depressive Disorder, Major/mortality/*physiopathology ; Female ; Humans ; Leukocytes/*physiology ; Linear Models ; Logistic Models ; Male ; Middle Aged ; Prospective Studies ; Psychiatric Status Rating Scales ; Telomere/*physiology ; },
abstract = {OBJECTIVE: Shortened telomere length has been associated with mortality in patients with coronary heart disease (CHD) and is considered as an emerging marker of biologic age. Whether depression is associated with telomere length or trajectory has not been evaluated in patients with CHD.<br><br>METHODS: In a prospective cohort study, we measured leukocyte telomere length in 952 participants with stable CHD at baseline and in 608 of these participants after 5 years of follow-up. The presence of major depressive disorder in the past month was assessed using the computerized diagnostic interview schedule at baseline. We used linear and logistic regression models to evaluate the association of depression with baseline and 5-year change in leukocyte telomere length.<br><br>RESULTS: Of the 952 participants, 206 (22%) had major depression at baseline. After the adjustment for age and sex, the patients with current major depressive disorder had shorter baseline telomere length than those without depression (mean [standard error] = 0.86 [0.02] versus 0.90 [0.01]; p = .02). This association was similar (but no longer statistically significant) after adjustment for body mass index, smoking, diabetes, left ventricular ejection fraction, statin use, antidepressant use, physical inactivity, and anxiety (0.85 [0.02] versus 0.89 [0.01], p = .06). Depression was not predictive of 5-year change in telomere length after adjustment for the mentioned covariates and baseline telomere length.<br><br>CONCLUSIONS: Depression is associated with reduced leukocyte telomere length in patients with CHD but does not predict 5-year change in telomere length. Future research is necessary to elucidate the potential mechanisms underlying the association between depression and telomere length.},
}
@article {pmid21593138,
year = {2011},
author = {Bojovic, B and Crowe, DL},
title = {Telomere dysfunction promotes metastasis in a TERC null mouse model of head and neck cancer.},
journal = {Molecular cancer research : MCR},
volume = {9},
number = {7},
pages = {901-913},
pmid = {21593138},
issn = {1557-3125},
support = {R03 DE014283-02/DE/NIDCR NIH HHS/United States ; DE14283/DE/NIDCR NIH HHS/United States ; },
mesh = {Animals ; Carcinoma, Squamous Cell/genetics/*secondary ; Gene Expression Profiling ; Genomic Instability ; Head and Neck Neoplasms/genetics/*pathology ; Humans ; Mice ; Mice, Inbred C57BL ; Neoplasm Metastasis ; Neoplasms, Experimental/genetics/*pathology ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {Squamous cell carcinoma arises from highly proliferative basal layer epithelial cells, which normally divide for a short time before detaching from the basement membrane and undergoing terminal differentiation. Basal layer cells in stratified epithelia express the reverse transcriptase known as telomerase. Most human cells do not express telomerase and therefore are subject to loss of telomeric DNA with age due to the inability of lagging strand synthesis to completely replicate chromosomal ends. Late generation telomerase deficient mice exhibit signs of premature aging including reduced function of proliferating cellular compartments. We examined development of squamous cell carcinoma in a telomerase deficient murine background with long and short telomeres. G1 Terc-/- mice (long telomeres) had fewer lymph node metastases, which correlated with increased numbers of apoptotic cells in these tumors compared with wild-type mice. However, G5 Terc-/- mice with short telomeres had increased metastatic tumor burden similar to wild type mice. This increased metastasis correlated with genomic instability and aneuploidy in tumor cells from G5 Terc-/- mice. A number of similarities with human SCC were noted in the mouse model, and dramatic differences in global gene expression profiles were shown between primary and metastatic tumors. We concluded that telomere shortening promotes metastatic tumor development in a Terc null mouse model of head and neck cancer.},
}
@article {pmid21592086,
year = {2011},
author = {Kljajevic, V},
title = {From cell to cognition: can changes in telomere length indicate patterns of cognitive aging?.},
journal = {Clinical science (London, England : 1979)},
volume = {121},
number = {7},
pages = {313-314},
doi = {10.1042/CS20110227},
pmid = {21592086},
issn = {1470-8736},
mesh = {Aging/*genetics ; Humans ; Telomere/*physiology ; },
}
@article {pmid21590410,
year = {2011},
author = {Farman, ML},
title = {Targeted cloning of fungal telomeres.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {722},
number = {},
pages = {11-31},
doi = {10.1007/978-1-61779-040-9_2},
pmid = {21590410},
issn = {1940-6029},
mesh = {Blotting, Southern ; Chromosomes, Fungal/*genetics/metabolism ; Cloning, Molecular/*methods ; DNA Restriction Enzymes/metabolism ; DNA, Fungal/genetics ; Genes, Fungal ; Hypocreales/classification/*genetics/physiology ; Telomere/*genetics ; },
abstract = {Telomeres are the sequences that form the ends of eukaryotic chromosomes and are essential structures that confer genome stability and guide chromosome behavior. In addition, the terminal regions of the chromosomes tend to house genes with predicted roles in ecological adaptation. Unfortunately, however, most fungal genome assemblies contain very few telomeres and, therefore, the identities of genes residing near the chromosome ends are often unknown. In an effort to develop a complete understanding of the organization and gene content of chromosome ends in a number of fungi, we developed efficient methods for the identification and targeted cloning of telomeres. This chapter describes the basic steps and shows exemplary results from the targeted cloning of Epichloë festucae telomeres.},
}
@article {pmid21586494,
year = {2012},
author = {Insel, KC and Merkle, CJ and Hsiao, CP and Vidrine, AN and Montgomery, DW},
title = {Biomarkers for cognitive aging part I: telomere length, blood pressure and cognition among individuals with hypertension.},
journal = {Biological research for nursing},
volume = {14},
number = {2},
pages = {124-132},
pmid = {21586494},
issn = {1552-4175},
support = {P20 NR007794/NR/NINR NIH HHS/United States ; R03 NR010010/NR/NINR NIH HHS/United States ; R03 NR010010-01/NR/NINR NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; *Aging ; Antihypertensive Agents/therapeutic use ; *Blood Pressure ; *Cognition ; Female ; Humans ; Hypertension/drug therapy/genetics/*physiopathology/*psychology ; Male ; Middle Aged ; Patient Compliance ; Real-Time Polymerase Chain Reaction ; *Telomere ; },
abstract = {Chronological age is used as a marker for age-associated changes in cognitive function. However, there is great interindividual variability in cognitive ability among people of the same age. Physiological age rather than chronological age should be more closely associated with age-related cognitive changes because these changes are not universal and are likely dependent on several factors in addition to the number of years lived. Cognitive function is associated with successful self-management, and a biological marker that reflects physiological age and is associated with cognitive function could be used to identify risk for failure to self-manage. The purpose of this study was to investigate the association between telomere length, a known biomarker of age; blood pressure; cognitive assessments; and adherence to antihypertensive medication among community-dwelling middle-aged and older adults. The authors administered a battery of cognitive assessments to 42 participants (M = 69 years of age), collected blood samples, and isolated peripheral blood mononuclear leukocytes for genomic DNA. The authors determined relative telomere length using Cawthon's method for real-time quantitative polymerase chain reaction (RT-qPCR) and measured medication adherence using an electronic medication monitoring system (MEMS by Aardex) over 8 weeks. Findings indicate that telomere length was inversely associated with systolic blood pressure (r = -.38, p < .01) and diastolic blood pressure (r = -.42, p < .01) but not with cognitive assessments or adherence. The authors discuss the nonsignificant findings between telomere length and cognitive assessments including the potential modifying role of gender.},
}
@article {pmid21577215,
year = {2012},
author = {Drury, SS and Theall, K and Gleason, MM and Smyke, AT and De Vivo, I and Wong, JY and Fox, NA and Zeanah, CH and Nelson, CA},
title = {Telomere length and early severe social deprivation: linking early adversity and cellular aging.},
journal = {Molecular psychiatry},
volume = {17},
number = {7},
pages = {719-727},
pmid = {21577215},
issn = {1476-5578},
support = {R01 ES020447/ES/NIEHS NIH HHS/United States ; R01 MH091363/MH/NIMH NIH HHS/United States ; R21 MH094688/MH/NIMH NIH HHS/United States ; },
mesh = {Cellular Senescence/*genetics/*physiology ; Child ; *Child, Institutionalized ; Child, Preschool ; Female ; Foster Home Care ; Humans ; Infant ; Male ; *Psychosocial Deprivation ; Randomized Controlled Trials as Topic ; Sex Characteristics ; Telomere Homeostasis/*genetics ; Telomere Shortening/*genetics ; Time Factors ; },
abstract = {Accelerated telomere length attrition has been associated with psychological stress and early adversity in adults; however, no studies have examined whether telomere length in childhood is associated with early experiences. The Bucharest Early Intervention Project is a unique randomized controlled trial of foster care placement compared with continued care in institutions. As a result of the study design, participants were exposed to a quantified range of time in institutional care, and represented an ideal population in which to examine the association between a specific early adversity, institutional care and telomere length. We examined the association between average relative telomere length, telomere repeat copy number to single gene copy number (T/S) ratio and exposure to institutional care quantified as the percent of time at baseline (mean age 22 months) and at 54 months of age that each child lived in the institution. A significant negative correlation between T/S ratio and percentage of time was observed. Children with greater exposure to institutional care had significantly shorter relative telomere length in middle childhood. Gender modified this main effect. The percentage of time in institutional care at baseline significantly predicted telomere length in females, whereas the percentage of institutional care at 54 months was strongly predictive of telomere length in males. This is the first study to demonstrate an association between telomere length and institutionalization, the first study to find an association between adversity and telomere length in children, and contributes to the growing literature linking telomere length and early adversity.},
}
@article {pmid21575746,
year = {2011},
author = {Costenbader, KH and Prescott, J and Zee, RY and De Vivo, I},
title = {Immunosenescence and rheumatoid arthritis: does telomere shortening predict impending disease?.},
journal = {Autoimmunity reviews},
volume = {10},
number = {9},
pages = {569-573},
pmid = {21575746},
issn = {1873-0183},
support = {R01 AR059073/AR/NIAMS NIH HHS/United States ; R01 AR059073-01/AR/NIAMS NIH HHS/United States ; NIAMSR01//PHS HHS/United States ; AR059073/AR/NIAMS NIH HHS/United States ; },
mesh = {Arthritis, Rheumatoid/diagnosis/*genetics/*immunology/physiopathology ; Humans ; Prognosis ; Risk Factors ; Telomere/*genetics ; },
abstract = {The pathogenesis of RA, a disabling autoimmune disease, is incompletely understood. Early in the development of RA there appears to be loss of immune homeostasis and regulation, and premature immunosenescence. While identification of risk factors and understanding of the phases of RA pathogenesis are advancing, means of accurately predicting an individual's risk of developing RA are currently lacking. Telomere length has been proposed as a potential new biomarker for the development of RA that could enhance prediction of this serious disease. Studies examining telomere length in relation to RA have found that telomere erosion appears to proceed more rapidly in subjects with RA than in healthy controls, and that telomere lengths are shorter in those with the RA-risk HLA-shared epitope genes. These studies have been small, however, with retrospective or cross-sectional designs. The potential role of telomere shortening as an independent biomarker for future RA risk, perhaps strongly genetically determined by HLA-SE genes, after controlling for known risk factors such as smoking, body mass index and immunosuppressant medication use, as well as systemic inflammation, is an unanswered question.},
}
@article {pmid21575645,
year = {2012},
author = {Murnane, JP},
title = {Telomere dysfunction and chromosome instability.},
journal = {Mutation research},
volume = {730},
number = {1-2},
pages = {28-36},
pmid = {21575645},
issn = {0027-5107},
support = {R01 CA120205/CA/NCI NIH HHS/United States ; R01 CA120205-05/CA/NCI NIH HHS/United States ; CA120205/CA/NCI NIH HHS/United States ; },
mesh = {*Chromosomal Instability ; DNA Breaks, Double-Stranded ; Humans ; Neoplasms/genetics ; Recombinational DNA Repair ; Telomerase/metabolism ; Telomere/*genetics/metabolism ; *Telomere Shortening ; Telomere-Binding Proteins/metabolism ; Translocation, Genetic ; },
abstract = {The ends of chromosomes are composed of a short repeat sequence and associated proteins that together form a cap, called a telomere, that keeps the ends from appearing as double-strand breaks (DSBs) and prevents chromosome fusion. The loss of telomeric repeat sequences or deficiencies in telomeric proteins can result in chromosome fusion and lead to chromosome instability. The similarity between chromosome rearrangements resulting from telomere loss and those found in cancer cells implicates telomere loss as an important mechanism for the chromosome instability contributing to human cancer. Telomere loss in cancer cells can occur through gradual shortening due to insufficient telomerase, the protein that maintains telomeres. However, cancer cells often have a high rate of spontaneous telomere loss despite the expression of telomerase, which has been proposed to result from a combination of oncogene-mediated replication stress and a deficiency in DSB repair in telomeric regions. Chromosome fusion in mammalian cells primarily involves nonhomologous end joining (NHEJ), which is the major form of DSB repair. Chromosome fusion initiates chromosome instability involving breakage-fusion-bridge (B/F/B) cycles, in which dicentric chromosomes form bridges and break as the cell attempts to divide, repeating the process in subsequent cell cycles. Fusion between sister chromatids results in large inverted repeats on the end of the chromosome, which amplify further following additional B/F/B cycles. B/F/B cycles continue until the chromosome acquires a new telomere, most often by translocation of the end of another chromosome. The instability is not confined to a chromosome that loses its telomere, because the instability is transferred to the chromosome donating a translocation. Moreover, the amplified regions are unstable and form extrachromosomal DNA that can reintegrate at new locations. Knowledge concerning the factors promoting telomere loss and its consequences is therefore important for understanding chromosome instability in human cancer.},
}
@article {pmid21574432,
year = {2011},
author = {Grach, AA},
title = {[Mechanisms of alternative lengthening of telomeres].},
journal = {TSitologiia i genetika},
volume = {45},
number = {2},
pages = {69-81},
pmid = {21574432},
issn = {0564-3783},
mesh = {Animals ; Humans ; *RNA/genetics/metabolism ; *Recombination, Genetic ; *Telomerase/genetics/metabolism ; Telomere/genetics/*ultrastructure ; },
abstract = {The review considers mechanisms of an alternative lengthening of telomeres (ALT) which possess the second after telomerase but not less important place in telomere length regulation. The general data about ALT are shown. An alternative lengthening of telomeres in normal and cancer cell lines are characterized. Special attention is given to the features of recombinational and retrotranspositional mechanisms of ALT.},
}
@article {pmid21574023,
year = {2011},
author = {Bayne, S and Li, H and Jones, ME and Pinto, AR and van Sinderen, M and Drummond, A and Simpson, ER and Liu, JP},
title = {Estrogen deficiency reversibly induces telomere shortening in mouse granulosa cells and ovarian aging in vivo.},
journal = {Protein &amp; cell},
volume = {2},
number = {4},
pages = {333-346},
pmid = {21574023},
issn = {1674-8018},
mesh = {46, XX Disorders of Sex Development/drug therapy/*genetics/metabolism ; Aging/*genetics/metabolism ; Animals ; Aromatase/deficiency/*genetics/metabolism ; Cell Proliferation/drug effects ; Estrogen Replacement Therapy ; *Estrogens/deficiency/pharmacology ; Female ; Gene Expression ; Genes, myc/genetics ; Granulosa Cells/drug effects/*metabolism/pathology ; Gynecomastia/drug therapy/*genetics/metabolism ; Humans ; Infertility, Male/drug therapy/*genetics/metabolism ; Metabolism, Inborn Errors/drug therapy/*genetics/metabolism ; Mice ; Mice, Knockout ; Proto-Oncogene Mas ; Telomerase/genetics/*metabolism ; Telomere/*chemistry/metabolism/pathology ; },
abstract = {Estrogen is implicated as playing an important role in aging and tumorigenesis of estrogen responsive tissues; however the mechanisms underlying the mitogenic actions of estrogen are not fully understood. Here we report that estrogen deficiency in mice caused by targeted disruption of the aromatase gene results in a significant inhibition of telomerase maintenance of telomeres in mouse ovaries in a tissue-specific manner. The inhibition entails a significant shortening of telomeres and compromised proliferation in the follicular granulosa cell compartment of ovary. Gene expression analysis showed decreased levels of proto-oncogene c-Myc and the telomerase catalytic subunit, telomerase reverse transcriptase (TERT), in response to estrogen deficiency. Estrogen replacement therapy led to increases in TERT gene expression, telomerase activity, telomere length and ovarian tissue growth, thereby reinstating ovary development to normal in four weeks. Our data demonstrate for the first time that telomere maintenance is the primary mechanism mediating the mitogenic effect of estrogen on ovarian granulosa cell proliferation by upregulating the genes of c-Myc and TERT in vivo. Estrogen deficiency or over-activity may cause ovarian tissue aging or tumorigenesis, respectively, through estrogen regulation of telomere remodeling.},
}
@article {pmid21573139,
year = {2011},
author = {Tuzon, CT and Wu, Y and Chan, A and Zakian, VA},
title = {The Saccharomyces cerevisiae telomerase subunit Est3 binds telomeres in a cell cycle- and Est1-dependent manner and interacts directly with Est1 in vitro.},
journal = {PLoS genetics},
volume = {7},
number = {5},
pages = {e1002060},
pmid = {21573139},
issn = {1553-7404},
support = {R01 GM043265/GM/NIGMS NIH HHS/United States ; GM43265/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle/*physiology ; Glycine/chemistry/metabolism ; Phosphorylation ; Protein Binding ; Proto-Oncogene Proteins c-myc/chemistry/metabolism ; Saccharomyces cerevisiae/enzymology/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomerase is a telomere dedicated reverse transcriptase that replicates the very ends of eukaryotic chromosomes. Saccharomyces cerevisiae telomerase consists of TLC1 (the RNA template), Est2 (the catalytic subunit), and two accessory proteins, Est1 and Est3, that are essential in vivo for telomerase activity but are dispensable for catalysis in vitro. Est1 functions in both recruitment and activation of telomerase. The association of Est3 with telomeres occurred largely in late S/G2 phase, the time when telomerase acts and Est1 telomere binding occurs. Est3 telomere binding was Est1-dependent. This dependence is likely due to a direct interaction between the two proteins, as purified recombinant Est1 and Est3 interacted in vitro. Est3 abundance was neither cell cycle-regulated nor Est1-dependent. Est3 was the most abundant of the three Est proteins (84.3±13.3 molecules per cell versus 71.1±19.2 for Est1 and 37.2±6.5 for Est2), so its telomere association and/or activity is unlikely to be limited by its relative abundance. Est2 and Est1 telomere binding was unaffected by the absence of Est3. Taken together, these data indicate that Est3 acts downstream of both Est2 and Est1 and that the putative activation function of Est1 can be explained by its role in recruiting Est3 to telomeres.},
}
@article {pmid21573004,
year = {2011},
author = {Prescott, J and Kraft, P and Chasman, DI and Savage, SA and Mirabello, L and Berndt, SI and Weissfeld, JL and Han, J and Hayes, RB and Chanock, SJ and Hunter, DJ and De Vivo, I},
title = {Genome-wide association study of relative telomere length.},
journal = {PloS one},
volume = {6},
number = {5},
pages = {e19635},
pmid = {21573004},
issn = {1932-6203},
support = {CA065725/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 HL043851/HL/NHLBI NIH HHS/United States ; CA87969/CA/NCI NIH HHS/United States ; CA49449/CA/NCI NIH HHS/United States ; R01 CA065725/CA/NCI NIH HHS/United States ; R01 CA047988/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; U01 HL069757/HL/NHLBI NIH HHS/United States ; U01-CA98233/CA/NCI NIH HHS/United States ; R03 CA133914/CA/NCI NIH HHS/United States ; HL69757/HL/NHLBI NIH HHS/United States ; CA133914/CA/NCI NIH HHS/United States ; CA047988/CA/NCI NIH HHS/United States ; U01 CA098233/CA/NCI NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; T32 CA009001/CA/NCI NIH HHS/United States ; U19 HL069757/HL/NHLBI NIH HHS/United States ; U01 CA049449/CA/NCI NIH HHS/United States ; T32 CA 09001/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Female ; Genetic Loci/genetics ; *Genome-Wide Association Study ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/genetics ; Reproducibility of Results ; Telomere/*metabolism ; },
abstract = {Telomere function is essential to maintaining the physical integrity of linear chromosomes and healthy human aging. The probability of forming proper telomere structures depends on the length of the telomeric DNA tract. We attempted to identify common genetic variants associated with log relative telomere length using genome-wide genotyping data on 3,554 individuals from the Nurses' Health Study and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial that took part in the National Cancer Institute Cancer Genetic Markers of Susceptibility initiative for breast and prostate cancer. After genotyping 64 independent SNPs selected for replication in additional Nurses' Health Study and Women's Genome Health Study participants, we did not identify genome-wide significant loci; however, we replicated the inverse association of log relative telomere length with the minor allele variant [C] of rs16847897 at the TERC locus (per allele β = -0.03, P = 0.003) identified by a previous genome-wide association study. We did not find evidence for an association with variants at the OBFC1 locus or other loci reported to be associated with telomere length. With this sample size we had >80% power to detect β estimates as small as ±0.10 for SNPs with minor allele frequencies of ≥0.15 at genome-wide significance. However, power is greatly reduced for β estimates smaller than ±0.10, such as those for variants at the TERC locus. In general, common genetic variants associated with telomere length homeostasis have been difficult to detect. Potential biological and technical issues are discussed.},
}
@article {pmid21570985,
year = {2011},
author = {Grasman, J and Salomons, HM and Verhulst, S},
title = {Stochastic modeling of length-dependent telomere shortening in Corvus monedula.},
journal = {Journal of theoretical biology},
volume = {282},
number = {1},
pages = {1-6},
doi = {10.1016/j.jtbi.2011.04.026},
pmid = {21570985},
issn = {1095-8541},
mesh = {Animals ; Crows/*genetics ; DNA Damage ; Oxidative Stress ; Poisson Distribution ; *Stochastic Processes ; *Telomere ; },
abstract = {It was recently shown that, within individuals, longer telomeres shorten at a higher rate. This explorative study deals with a mathematical model of this process. It is a nonlinear differential equation describing length-dependent decrease that can be linked to a Poisson process. The model also takes in account telomere shortening due to the end replication problem. Parameters are fitted using data from samples of red blood cells of free-living juvenile corvids. The Poisson process can be related to oxidative stress causing DNA strand breaks. The shortest telomeres in a genome are the best predictors of survival, and one can therefore hypothesize on functional grounds that short telomeres should be better protected by some control mechanism in the cellular system. However, the present study shows that such a mechanism is not required to explain length-dependent telomere shortening: agents of telomere shortening such as oxidative stress with a certain strength modeled by a Poisson process with an appropriately chosen parameter suffice to generate the observed pattern.},
}
@article {pmid21554499,
year = {2011},
author = {Muraki, K and Nabetani, A and Nishiyama, A and Ishikawa, F},
title = {Essential roles of Xenopus TRF2 in telomere end protection and replication.},
journal = {Genes to cells : devoted to molecular &amp; cellular mechanisms},
volume = {16},
number = {6},
pages = {728-739},
doi = {10.1111/j.1365-2443.2011.01520.x},
pmid = {21554499},
issn = {1365-2443},
mesh = {Amino Acid Sequence ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/metabolism ; Cell Nucleus/genetics/metabolism ; Chromatin/metabolism ; DNA Replication/*genetics ; DNA-Binding Proteins/metabolism ; Gene Order ; Molecular Sequence Data ; Protein Serine-Threonine Kinases/metabolism ; Sequence Alignment ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; Tumor Suppressor Proteins/metabolism ; Xenopus/*genetics/*metabolism ; Xenopus Proteins/metabolism ; },
abstract = {TRF1 and TRF2 are double-stranded (ds) telomere DNA-binding proteins and the core members of shelterin, a complex that provides the structural and functional basis of telomere functions. We have reported that unlike mammalian TRF1 that constitutively binds to chromatin, Xenopus TRF1 (xTRF1) associates with mitotic chromatin but dissociates from interphase chromatin reconstituted in Xenopus egg extracts. This finding raised the possibility that xTRF1 and Xenopus TRF2 (xTRF2) contribute to telomere functions in a manner different from mammalian TRF1 and TRF2. Here, we focused on the role of xTRF2. We prepared chromatin reconstituted in egg extracts immunodepleted for xTRF2. Compared to mock-depleted nuclei, DNA damage response at telomeres was activated, and bulk DNAs were poorly replicated in xTRF2-depleted nuclei. The replication defect was rescued by inactivating ATR through the addition of anti-ATR neutralizing antibody, suggesting that ATR plays a role in the defect. Interestingly, the bulk DNA replication defect, but not the DNA damage response at telomeres, was rescued by supplementing the xTRF2-depleted extracts with recombinant xTRF2 (rTRF2). We propose that xTRF2 is required for both efficient replication of bulk DNA and protection from the activation of the DNA damage checkpoints pathway, and that those two functions are mechanistically separable.},
}
@article {pmid21553437,
year = {2011},
author = {},
title = {Telomeres and health. Keeping your DNA happy.},
journal = {Mayo Clinic health letter (English ed.)},
volume = {29},
number = {3},
pages = {7},
pmid = {21553437},
issn = {0741-6245},
mesh = {*DNA ; Humans ; Inflammation/pathology ; Oxidative Stress/physiology ; Telomere/*pathology ; },
}
@article {pmid21553025,
year = {2011},
author = {Roberts, AR and Blewitt, ME and Youngson, NA and Whitelaw, E and Chong, S},
title = {Reduced dosage of the modifiers of epigenetic reprogramming Dnmt1, Dnmt3L, SmcHD1 and Foxo3a has no detectable effect on mouse telomere length in vivo.},
journal = {Chromosoma},
volume = {120},
number = {4},
pages = {377-385},
pmid = {21553025},
issn = {1432-0886},
mesh = {Animals ; Chromosomal Proteins, Non-Histone/deficiency/*genetics ; DNA (Cytosine-5-)-Methyltransferase 1 ; DNA (Cytosine-5-)-Methyltransferases/deficiency/*genetics ; DNA Methylation ; Electrophoresis, Agar Gel ; Embryo, Mammalian ; *Epigenomics ; Female ; Forkhead Box Protein O3 ; Forkhead Transcription Factors/deficiency/*genetics ; Gene Dosage ; Histone Methyltransferases ; Histone-Lysine N-Methyltransferase/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Pregnancy ; Restriction Mapping ; Telomere/*chemistry/genetics ; },
abstract = {Studies carried out in cultured cells have implicated modifiers of epigenetic reprogramming in the regulation of telomere length, reporting elongation in cells that were null for DNA methyltransferase DNA methyltransferase 1 (Dnmt1), both de novo DNA methyltransferases, Dnmt3a and Dnmt3b or various histone methyltransferases. To investigate this further, we assayed telomere length in whole embryos or adult tissue from mice carrying mutations in four different modifiers of epigenetic reprogramming: Dnmt1, DNA methyltransferase 3-like, structural maintenance of chromosomes hinge domain containing 1, and forkhead box O3a. Terminal restriction fragment analysis was used to compare telomere length in homozygous mutants, heterozygous mutants and wild-type littermates. Contrary to expectation, we did not detect overall lengthening in the mutants, raising questions about the role of epigenetic processes in telomere length in vivo.},
}
@article {pmid21549308,
year = {2011},
author = {Zhao, Y and Abreu, E and Kim, J and Stadler, G and Eskiocak, U and Terns, MP and Terns, RM and Shay, JW and Wright, WE},
title = {Processive and distributive extension of human telomeres by telomerase under homeostatic and nonequilibrium conditions.},
journal = {Molecular cell},
volume = {42},
number = {3},
pages = {297-307},
pmid = {21549308},
issn = {1097-4164},
support = {AG01228/AG/NIA NIH HHS/United States ; F31GM087949/GM/NIGMS NIH HHS/United States ; R01 CA104676/CA/NCI NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; F31 GM087949/GM/NIGMS NIH HHS/United States ; R01 AG001228-31/AG/NIA NIH HHS/United States ; CA104676/CA/NCI NIH HHS/United States ; },
mesh = {Blotting, Western ; Cell Line, Tumor ; Coiled Bodies/metabolism ; G1 Phase ; Gene Expression Regulation, Enzymologic/drug effects ; HeLa Cells ; *Homeostasis ; Humans ; Models, Genetic ; Oligonucleotides/pharmacology ; RNA Interference ; Reverse Transcriptase Polymerase Chain Reaction ; S Phase ; Telomerase/antagonists &amp; inhibitors/genetics/*metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {Specific information about how telomerase acts in vivo is necessary for understanding telomere dynamics in human tumor cells. Our results imply that, under homeostatic telomere length-maintenance conditions, only one molecule of telomerase acts at each telomere during every cell division and processively adds ∼60 nt to each end. In contrast, multiple molecules of telomerase act at each telomere when telomeres are elongating (nonequilibrium conditions). Telomerase extension is less processive during the first few weeks following the reversal of long-term treatment with the telomerase inhibitor Imetelstat (GRN163L), a time when Cajal bodies fail to deliver telomerase RNA to telomeres. This result implies that processing of telomerase by Cajal bodies may affect its processivity. Overexpressed telomerase is also less processive than the endogenously expressed telomerase. These findings reveal two major distinct extension modes adopted by telomerase in vivo.},
}
@article {pmid21541185,
year = {2011},
author = {Makpol, S and Durani, LW and Chua, KH and Mohd Yusof, YA and Ngah, WZ},
title = {Tocotrienol-rich fraction prevents cell cycle arrest and elongates telomere length in senescent human diploid fibroblasts.},
journal = {Journal of biomedicine &amp; biotechnology},
volume = {2011},
number = {},
pages = {506171},
pmid = {21541185},
issn = {1110-7251},
mesh = {Cell Cycle/*drug effects ; Cell Shape/drug effects ; Cells, Cultured ; Cellular Senescence/*drug effects ; Chemical Fractionation ; Comet Assay ; DNA Damage ; *Diploidy ; Fibroblasts/*cytology/drug effects/enzymology/*metabolism ; Humans ; Staining and Labeling ; Telomerase/metabolism ; Telomere/*metabolism ; Tocotrienols/*pharmacology ; beta-Galactosidase/metabolism ; },
abstract = {This study determined the molecular mechanisms of tocotrienol-rich fraction (TRF) in preventing cellular senescence of human diploid fibroblasts (HDFs). Primary culture of HDFs at various passages were incubated with 0.5 mg/mL TRF for 24 h. Telomere shortening with decreased telomerase activity was observed in senescent HDFs while the levels of damaged DNA and number of cells in G(0)/G(1) phase were increased and S phase cells were decreased. Incubation with TRF reversed the morphology of senescent HDFs to resemble that of young cells with decreased activity of SA-β-gal, damaged DNA, and cells in G(0)/G(1) phase while cells in the S phase were increased. Elongated telomere length and restoration of telomerase activity were observed in TRF-treated senescent HDFs. These findings confirmed the ability of tocotrienol-rich fraction in preventing HDFs cellular ageing by restoring telomere length and telomerase activity, reducing damaged DNA, and reversing cell cycle arrest associated with senescence.},
}
@article {pmid21540175,
year = {2011},
author = {Parks, CG and DeRoo, LA and Miller, DB and McCanlies, EC and Cawthon, RM and Sandler, DP},
title = {Employment and work schedule are related to telomere length in women.},
journal = {Occupational and environmental medicine},
volume = {68},
number = {8},
pages = {582-589},
pmid = {21540175},
issn = {1470-7926},
support = {Z01 ES044005/ImNIH/Intramural NIH HHS/United States ; Z01 ES044005-10/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging/genetics ; Biomarkers/urine ; Cross-Sectional Studies ; *Employment ; Epinephrine/urine ; Female ; Humans ; Leukocytes/ultrastructure ; Middle Aged ; Occupational Diseases/genetics/urine ; Socioeconomic Factors ; Stress, Psychological/genetics/urine ; Telomere/*ultrastructure ; Time Factors ; Work Schedule Tolerance/*physiology ; },
abstract = {OBJECTIVES: To examine the association of employment and work schedule with shorter DNA telomeres, a marker of cellular ageing and disease risk factor, and consider whether differences were related to health, behaviours and sociodemographic factors, or varied by stress levels or menopausal status.<br><br>METHODS: This cross-sectional analysis of 608 women aged 35-74 in the Sister Study examined determinants of relative telomere length (rTL) measured by quantitative PCR in leucocyte DNA. Age-adjusted regression models estimated base pair (bp) rTL differences for current and lifetime schedule characteristics (ie, part-time, full-time or overtime hours; multiple jobs; irregular hours; shiftwork; work at night). Covariates included race, smoking, perceived stress, sleep, physical activity, health and menopausal status, education, marital status, live births, children under 18, measured body mass index and urinary stress hormones.<br><br>RESULTS: Compared with non-employed women with moderate or substantial past work histories (n=190), those currently working full-time (n=247; median 40 h/week) had a shorter rTL, an age-adjusted difference of -329 bp (95% CI -110 to -548). Longer-duration full-time work was also associated with shorter rTL (age-adjusted difference of -472 bp, 95% CI -786 to -158 for 20+ vs 1-5 years). Findings were not explained by health and demographic covariates. However, rTL differences for working at least full-time were greater in women with higher stress and epinephrine levels.<br><br>CONCLUSIONS: Current and long-term full-time work were associated with shorter rTL, with differences of similar magnitude to smoking and history of heart disease or diabetes. Longitudinal data with specific stress measures are needed to further evaluate the impact of work schedule on rTL.},
}
@article {pmid21538690,
year = {2011},
author = {Mendez-Bermudez, A and Royle, NJ},
title = {Deficiency in DNA mismatch repair increases the rate of telomere shortening in normal human cells.},
journal = {Human mutation},
volume = {32},
number = {8},
pages = {939-946},
doi = {10.1002/humu.21522},
pmid = {21538690},
issn = {1098-1004},
support = {C17992/A8641//Cancer Research UK/United Kingdom ; G0500336//Medical Research Council/United Kingdom ; //Wellcome Trust/United Kingdom ; },
mesh = {Base Sequence ; Cell Line ; Cell Line, Tumor ; DNA Mismatch Repair/*genetics ; Down-Regulation/genetics ; Female ; Fetus ; Fibroblasts/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Infant, Newborn ; Male ; Microsatellite Instability ; Molecular Sequence Data ; MutS Homolog 2 Protein/deficiency/*genetics ; Mutation/genetics ; RNA, Small Interfering/genetics/metabolism ; Sequence Alignment ; Telomere/*genetics/*metabolism ; },
abstract = {DNA mismatch repair (MMR) is essential for genome stability and inheritance of a mutated MMR gene, most frequently MSH2 or MLH1, results in cancer predisposition known as Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC). Tumors that arise through MMR deficiency show instability at simple tandem repeat loci (STRs) throughout the genome, known as microsatellite instability (MSI). The STR instability is dominated by errors that accumulate during replication in the absence of effective MMR. In this study we show that there is a high level of instability within telomeric DNA with a tendency toward deletions in tumor-derived MMR defective cell lines. We downregulated MSH2 expression in a normal fibroblast cell line and isolated four clones, with differing levels of MSH2 depletion. The telomere-shortening rate was measured at the Xp/Yp, 12q, and 17p telomeres in the MSH2 depleted and three control clones. Interestingly the mean telomere-shortening rate in the clones with MSH2 depletion was significantly greater than in the control clones. This is the first demonstration that MSH2 deficiency alone can lead to accelerated telomere shortening in normal human cells.},
}
@article {pmid21537919,
year = {2012},
author = {Li, J and He, S and Zhang, L and Hu, Y and Yang, F and Ma, L and Huang, J and Li, L},
title = {Telomere and 45S rDNA sequences are structurally linked on the chromosomes in Chrysanthemum segetum L.},
journal = {Protoplasma},
volume = {249},
number = {1},
pages = {207-215},
pmid = {21537919},
issn = {1615-6102},
mesh = {Base Sequence ; Cell Nucleus/genetics/metabolism ; Chromosomes, Plant/*genetics ; Chrysanthemum/*genetics/metabolism ; Cloning, Molecular ; Conserved Sequence ; DNA Primers/genetics/metabolism ; DNA, Ribosomal/genetics/metabolism ; Escherichia coli/genetics/metabolism ; Homologous Recombination ; In Situ Hybridization, Fluorescence ; Interphase ; Metaphase ; Molecular Sequence Data ; RNA, Ribosomal/*genetics/metabolism ; Sequence Analysis, DNA ; Telomere/*genetics/metabolism ; },
abstract = {Some reports have shown that nucleolar organizer regions are located at the telomeric region and have a structural connection with telomeres at the cellular level in many organisms. In this study, we found that all 45S ribosomal DNA (rDNA) signals were located at telomeric regions on the chromosomes in Chrysanthemum segetum L., and the 45S rDNA showed distinct signal patterns on different metaphase chromosome spreads. The bicolor fluorescence in situ hybridization experiment on the extended fibers revealed that telomere repeats were structurally connected with or interspersed into rDNA sequences. The close cytological structure relation between rDNA and telomere sequences led us to use PCR with combinations of the telomere primer and the rDNA primer to obtain some fragments, which were flanked by different rDNA and telomere primer sequences. One representative clone CHS2 contains closely connected rDNA and telomere sequences, suggesting that the telomere sequence invaded into the conserved rDNA sequence. In addition, the sequences of some PCR clones were flanked by the single telomeric primer sequence or the rDNA primer sequence. These results suggested that homologous recombination occurred between tandem repeat units of rDNA sequences or telomere repeats at the chromosome terminus.},
}
@article {pmid21537398,
year = {2011},
author = {Mirabello, L and Richards, EG and Duong, LM and Yu, K and Wang, Z and Cawthon, R and Berndt, SI and Burdett, L and Chowdhury, S and Teshome, K and Douglass, C and Savage, SA and , },
title = {Telomere length and variation in telomere biology genes in individuals with osteosarcoma.},
journal = {International journal of molecular epidemiology and genetics},
volume = {2},
number = {1},
pages = {19-29},
pmid = {21537398},
issn = {1948-1756},
support = {HHSN261200800001C/RC/CCR NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; },
abstract = {Osteosarcoma, the most common primary bone tumor, occurs most frequently in adolescents. Chromosomal aneuploidy is common in osteosarcoma cells, suggesting underlying chromosomal instability. Telomeres, located at chromosome ends, are essential for genomic stability; several studies have suggested that germline telomere length (TL) is associated with cancer risk. We hypothesized that TL and/or common genetic variation in telomere biology genes may be associated with risk of osteosarcoma. We investigated TL in peripheral blood DNA and 713 single nucleotide polymorphisms (SNPs) from 39 telomere biology genes in 98 osteosarcoma cases and 69 orthopedic controls. For the genotyping component, we added 1363 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer ScreeningTrial. Short TL was not associated with osteosarcoma risk overall (OR 1.39, P=0.67), although there was a statistically significant association in females (OR 4.35, 95% Cl 1.20-15.74, P=0.03). Genotype analyses identified seven SNPs in TERF1 significantly associated with osteosarcoma risk after Bonferroni correction by gene. These SNPs were highly linked and associated with a reduced risk of osteosarcoma (OR 0.48-0.53, P=0.0001-0.0006). We also investigated associations between TL and telomere gene SNPs in osteosarcoma cases and orthopedic controls. Several SNPs were associated with TL prior to Bonferroni correction; one SNP in NOLA2 and one in MEN1 were marginally non-significant after correction (P(adj)=0.057 and 0.066, respectively). This pilot-study suggests that females with short telomeres may be at increased risk of osteosarcoma, and that SNPs in TERF1 are inversely associated with osteosarcoma risk.},
}
@article {pmid21536423,
year = {2011},
author = {Li, Y and Li, X and Ji, X and Li, X},
title = {Formation of G-quadruplex-hemin DNAzyme based on human telomere elongation and its application in telomerase activity detection.},
journal = {Biosensors &amp; bioelectronics},
volume = {26},
number = {10},
pages = {4095-4098},
doi = {10.1016/j.bios.2011.03.041},
pmid = {21536423},
issn = {1873-4235},
mesh = {Biosensing Techniques/*methods ; *DNA, Catalytic ; *G-Quadruplexes ; Gold ; HeLa Cells ; *Hemin ; Humans ; Luminescent Measurements ; Metal Nanoparticles ; Telomerase/*analysis ; Telomere/chemistry ; },
abstract = {In the present study, a chemiluminescence method for sensitive detection of human telomerase activity was developed based on the formation of G-quadruplex-hemin DNAzyme. In the presence of telomerase, the telomerase substrate (TS) primer elongated and a long single-strand DNA containing the telomere repeat units (TTAGGG)n was formed. When K(+) was introduced, the telomere repeat units could form G-quadruplex and then combined with hemin to form DNAzymes which could stimulate the generation of chemiluminescence (CL) in the presence of luminol and H(2)O(2). The amount of telomerase elongation product was controlled by the content of telomerase extracted from HeLa cells, so the amount of DNAzymes and the intensity of chemiluminescence signal were all related to the number of HeLa cells. Using this simple method, the telomerase activity extracted from 100 cultured cancer cells could be detected without the polymerase chain reaction (PCR) amplification of telomerase elongated product.},
}
@article {pmid21536122,
year = {2011},
author = {Steptoe, A and Hamer, M and Butcher, L and Lin, J and Brydon, L and Kivimäki, M and Marmot, M and Blackburn, E and Erusalimsky, JD},
title = {Educational attainment but not measures of current socioeconomic circumstances are associated with leukocyte telomere length in healthy older men and women.},
journal = {Brain, behavior, and immunity},
volume = {25},
number = {7},
pages = {1292-1298},
doi = {10.1016/j.bbi.2011.04.010},
pmid = {21536122},
issn = {1090-2139},
support = {G0100222/MRC_/Medical Research Council/United Kingdom ; RG/10/005/28296/BHF_/British Heart Foundation/United Kingdom ; G0902037/MRC_/Medical Research Council/United Kingdom ; RG/07/008/23674/BHF_/British Heart Foundation/United Kingdom ; G19/35/MRC_/Medical Research Council/United Kingdom ; G8802774/MRC_/Medical Research Council/United Kingdom ; G0601647/MRC_/Medical Research Council/United Kingdom ; RG/05/006/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Aging/*metabolism ; Body Mass Index ; Educational Status ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Smoking ; Social Class ; Socioeconomic Factors ; *Telomere Homeostasis ; *Telomere Shortening ; },
abstract = {Low socioeconomic status (SES) may be associated with accelerated biological aging, but findings relating SES with telomere length have been inconsistent. We tested the hypotheses that shorter telomere length and telomerase activity would be related more robustly to education, an early life indicator of socioeconomic position, than to current indicators of socioeconomic circumstances. Healthy men and women aged 53-76 years from the Whitehall II epidemiological cohort provided blood samples from which telomere length was assessed in 448 and telomerase activity in 416. Educational attainment was classified into four levels, while household income and grade of employment were measured as indicators of current socioeconomic circumstances. Age, gender, blood pressure, glycated hemoglobin, high density lipoprotein cholesterol, smoking, body mass index and physical activity were included as covariates. We found that lower educational attainment was associated with shorter telomere length after controlling statistically for biological and behavioral covariates. Neither household income nor employment grade was related to telomere length. The association between telomere length and education remained significant after adjusting for current socioeconomic circumstances. In men, highest levels of telomerase activity were found in the lowest education group. We conclude that low SES defined in terms of education but not current socioeconomic circumstances is associated with shortened telomeres. Low educational attainment may be an indicator of long-term SES trajectories, and be associated with accumulated allostatic load resulting in telomere shortening. Education may also promote problem-solving skills leading to reduced biological stress responsivity, with favorable consequences for biological aging.},
}
@article {pmid21530622,
year = {2011},
author = {Senthilkumar, PK and Klingelhutz, AJ and Jacobus, JA and Lehmler, H and Robertson, LW and Ludewig, G},
title = {Airborne polychlorinated biphenyls (PCBs) reduce telomerase activity and shorten telomere length in immortal human skin keratinocytes (HaCat).},
journal = {Toxicology letters},
volume = {204},
number = {1},
pages = {64-70},
pmid = {21530622},
issn = {1879-3169},
support = {P42 ES013661-02/ES/NIEHS NIH HHS/United States ; P42 ES013661]/ES/NIEHS NIH HHS/United States ; P42 ES013661-05/ES/NIEHS NIH HHS/United States ; P30 ES005605/ES/NIEHS NIH HHS/United States ; P42 ES013661-04/ES/NIEHS NIH HHS/United States ; P42 ES013661-03/ES/NIEHS NIH HHS/United States ; P42 ES013661-07/ES/NIEHS NIH HHS/United States ; P42 ES013661/ES/NIEHS NIH HHS/United States ; P42 ES013661-06/ES/NIEHS NIH HHS/United States ; },
mesh = {Air Pollutants/adverse effects/pharmacology ; Cell Cycle/drug effects ; Cell Line ; Dose-Response Relationship, Drug ; Humans ; Keratinocytes/*drug effects ; Polychlorinated Biphenyls/*adverse effects/pharmacology ; Telomerase/*drug effects/metabolism ; Telomere/*drug effects ; },
abstract = {PCBs, a group of 209 individual congeners, are ubiquitous environmental pollutants and classified as probable human carcinogens. One major route of exposure is by inhalation of these industrial compounds, possibly daily from inner city air and/or indoor air in contaminated buildings. Hallmarks of aging and carcinogenesis are changes in telomere length and telomerase activity. We hypothesize that semi-volatile PCBs, like those found in inner city air, are capable of disrupting telomerase activity and altering telomere length. To explore this possibility, we exposed human skin keratinocytes to a synthetic Chicago Airborne Mixture (CAM) of PCBs, or the prominent airborne PCB congeners, PCB28 or PCB52 for up to 48 days and determined telomerase activity, telomere length, cell proliferation, and cell cycle distribution. PCBs 28, 52 and CAM significantly reduced telomerase activity from days 18-48. Telomere length was shortened by PCB 52 from day 18 and PCB 28 and CAM from days 30 on. All PCBs decreased cell proliferation from day 18; only PCB 52 produced a small increase of cells in G0/G1 of the cell cycle. This significant inhibition of telomerase activity and reduction of telomere length by PCB congeners suggest a potential mechanism by which these compounds could lead to accelerated aging and cancer.},
}
@article {pmid21527554,
year = {2011},
author = {Chen, J and Zhang, B and Wong, N and Lo, AW and To, KF and Chan, AW and Ng, MH and Ho, CY and Cheng, SH and Lai, PB and Yu, J and Ng, HK and Ling, MT and Huang, AL and Cai, XF and Ko, BC},
title = {Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth.},
journal = {Cancer research},
volume = {71},
number = {12},
pages = {4138-4149},
doi = {10.1158/0008-5472.CAN-10-4274},
pmid = {21527554},
issn = {1538-7445},
mesh = {Apoptosis ; Carcinoma, Hepatocellular/genetics/*pathology ; Cell Line, Tumor ; *Cell Proliferation ; Cellular Senescence ; Doxorubicin/pharmacology ; *Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; Liver Neoplasms/genetics/*pathology ; Shelterin Complex ; Sirtuin 1/analysis/*physiology ; Telomerase/analysis/physiology ; *Telomere ; Telomere-Binding Proteins/analysis/physiology ; Tumor Suppressor Protein p53/physiology ; Up-Regulation ; },
abstract = {Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. Treatment of HCC is complicated by the fact that the disease is often diagnosed at an advanced stage when it is no longer amenable to curative surgery, and current systemic chemotherapeutics are mostly inefficacious. Sirtuin 1 (SIRT1) is a class III histone deacetylase that is implicated in gene regulations and stress resistance. In this study, we found that SIRT1 is essential for the tumorigenesis of HCC. We showed that although SIRT1 was expressed at very low levels in normal livers, it was overexpressed in HCC cell lines and in a subset of HCC. Tissue microarray analysis of HCC and adjacent nontumoral liver tissues revealed a positive correlation between the expression levels of SIRT1 and advancement in tumor grades. Downregulation of SIRT1 consistently suppressed the proliferation of HCC cells via the induction of cellular senescence or apoptosis. SIRT1 silencing also caused telomere dysfunction-induced foci and nuclear abnormality that were clearly associated with reduced expressions of telomerase reverse transcriptase (TERT), and PTOP, which is a member of the shelter in complex. Ectopic expression of either TERT or PTOP in SIRT1-depleted cells significantly restored cell proliferation. There was also a positive correlation between the level of induction of SIRT1 and TERT [corrected] in human HCC. Finally, SIRT1-silencing sensitized HCC cells to doxorubicin treatment. Together, our findings reveal a novel function for SIRT1 in telomere maintenance of HCC, and they rationalize the clinical exploration of SIRT1 inhibitors for HCC therapy.},
}
@article {pmid21526170,
year = {2011},
author = {Olsson, M and Pauliny, A and Wapstra, E and Uller, T and Schwartz, T and Blomqvist, D},
title = {Sex differences in sand lizard telomere inheritance: paternal epigenetic effects increases telomere heritability and offspring survival.},
journal = {PloS one},
volume = {6},
number = {4},
pages = {e17473},
pmid = {21526170},
issn = {1932-6203},
mesh = {Animals ; Animals, Newborn ; *Epigenesis, Genetic ; Female ; Inheritance Patterns/*genetics ; Lizards/*genetics/growth &amp; development ; Male ; Regression, Psychology ; *Sex Characteristics ; Survival Analysis ; Telomere/*genetics ; },
abstract = {BACKGROUND: To date, the only estimate of the heritability of telomere length in wild populations comes from humans. Thus, there is a need for analysis of natural populations with respect to how telomeres evolve.<br><br>Here, we show that telomere length is heritable in free-ranging sand lizards, Lacerta agilis. More importantly, heritability estimates analysed within, and contrasted between, the sexes are markedly different; son-sire heritability is much higher relative to daughter-dam heritability. We assess the effect of paternal age on Telomere Length (TL) and show that in this species, paternal age at conception is the best predictor of TL in sons. Neither paternal age per se at blood sampling for telomere screening, nor corresponding age in sons impact TL in sons. Processes maintaining telomere length are also associated with negative fitness effects, most notably by increasing the risk of cancer and show variation across different categories of individuals (e.g. males vs. females). We therefore tested whether TL influences offspring survival in their first year of life. Indeed such effects were present and independent of sex-biased offspring mortality and offspring malformations.<br><br>CONCLUSIONS/SIGNIFICANCE: TL show differences in sex-specific heritability with implications for differences between the sexes with respect to ongoing telomere selection. Paternal age influences the length of telomeres in sons and longer telomeres enhance offspring survival.},
}
@article {pmid21526145,
year = {2011},
author = {Baker, AM and Fu, Q and Hayward, W and Victoria, S and Pedroso, IM and Lindsay, SM and Fletcher, TM},
title = {The telomere binding protein TRF2 induces chromatin compaction.},
journal = {PloS one},
volume = {6},
number = {4},
pages = {e19124},
pmid = {21526145},
issn = {1932-6203},
support = {F31 GM075427/GM/NIGMS NIH HHS/United States ; F31-GM75427-01/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chickens ; Chromatin/*metabolism ; *Chromatin Assembly and Disassembly ; DNA/metabolism ; HeLa Cells ; Humans ; Microscopy, Atomic Force ; Mutant Proteins/metabolism ; Nucleosomes/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Static Electricity ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/chemistry/*metabolism ; },
abstract = {Mammalian telomeres are specialized chromatin structures that require the telomere binding protein, TRF2, for maintaining chromosome stability. In addition to its ability to modulate DNA repair activities, TRF2 also has direct effects on DNA structure and topology. Given that mammalian telomeric chromatin includes nucleosomes, we investigated the effect of this protein on chromatin structure. TRF2 bound to reconstituted telomeric nucleosomal fibers through both its basic N-terminus and its C-terminal DNA binding domain. Analytical agarose gel electrophoresis (AAGE) studies showed that TRF2 promoted the folding of nucleosomal arrays into more compact structures by neutralizing negative surface charge. A construct containing the N-terminal and TRFH domains together altered the charge and radius of nucleosomal arrays similarly to full-length TRF2 suggesting that TRF2-driven changes in global chromatin structure were largely due to these regions. However, the most compact chromatin structures were induced by the isolated basic N-terminal region, as judged by both AAGE and atomic force microscopy. Although the N-terminal region condensed nucleosomal array fibers, the TRFH domain, known to alter DNA topology, was required for stimulation of a strand invasion-like reaction with nucleosomal arrays. Optimal strand invasion also required the C-terminal DNA binding domain. Furthermore, the reaction was not stimulated on linear histone-free DNA. Our data suggest that nucleosomal chromatin has the ability to facilitate this activity of TRF2 which is thought to be involved in stabilizing looped telomere structures.},
}
@article {pmid21525130,
year = {2011},
author = {Kimura, M and Aviv, A},
title = {Measurement of telomere DNA content by dot blot analysis.},
journal = {Nucleic acids research},
volume = {39},
number = {12},
pages = {e84},
pmid = {21525130},
issn = {1362-4962},
support = {AG030678/AG/NIA NIH HHS/United States ; AG20132/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Blotting, Southern ; DNA/*analysis ; Humans ; *Molecular Probe Techniques ; Telomere/*chemistry ; },
abstract = {Telomeres play a central role in human cancer, cardiovascular aging and possibly longevity. However, present methods to measure telomere length are fraught with shortcomings that limit their use. Here, we describe a novel method to measure the relative telomere DNA content by dot blot analysis. In each dot, the DNA content is measured by a DNA stain (Dx) and the telomeric DNA content is measured with a telomeric probe (T). The T normalized for Dx (T/Dx) of each dot is a measure of telomere content. The method requires ∼20 ng of DNA per assay. Moreover, the T/Dx data are highly correlated linearly with mean telomere lengths derived from Southern blots of the terminal restriction fragments (r > 0.96, P < 0.0001). The method is also simple to use, has a relatively low interassay coefficient of variation (<6%), retains its precision in moderately degraded DNA and can be forged for high throughput analysis. The method might help researchers and clinicians alike in understanding risks for and extent of human diseases.},
}
@article {pmid21519191,
year = {2011},
author = {Sheppard, SA and Savinova, T and Loayza, D},
title = {TRIP6 and LPP, but not Zyxin, are present at a subset of telomeres in human cells.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {10},
number = {11},
pages = {1726-1730},
pmid = {21519191},
issn = {1551-4005},
support = {G12 RR003037/RR/NCRR NIH HHS/United States ; RR003037/RR/NCRR NIH HHS/United States ; },
mesh = {ATPases Associated with Diverse Cellular Activities ; Adaptor Proteins, Signal Transducing/*analysis/metabolism ; Cell Line ; Cytoskeletal Proteins/*analysis/metabolism ; DNA Damage ; Humans ; LIM Domain Proteins/*analysis/metabolism ; Proteasome Endopeptidase Complex ; Protein Binding ; Shelterin Complex ; Telomere/*chemistry/metabolism ; Telomere-Binding Proteins/metabolism ; Transcription Factors/*analysis/metabolism ; Zyxin/*analysis/metabolism ; },
abstract = {The protection of chromosome ends requires the inhibition of DNA damage responses at telomeres. This inhibition is exerted in great part by the shelterin complex, known to prevent inappropriate ATM and ATR activation. The molecular mechanisms by which shelterin protects telomeres are incompletely understood. Recently, we have implicated for the first time a class of molecules, LIM domain proteins, in telomere protection. This protection occurred through interaction with shelterin, possibly through POT1, and required the pair of LIM proteins TRIP6 and LPP, themselves part of the Zyxin family. The domain similarity between TRIP6, LPP and Zyxin led us to ask whether the latter also interacted with telomeres. Here, we show that there is specificity in the association of LIM proteins with telomeres: Zyxin, despite a high degree of similarity with TRIP6 and LPP, was not detected at telomeres, nor found in a complex with shelterin. TRIP6 and LPP, however, were detected by immunofluorescence at a small subset of telomeres, perhaps those that are critically short. We speculate that specific LIM proteins are part of complex events occurring in the context of the telomere dysfunction response, and possibly at play during the induction of senescence.},
}
@article {pmid21518433,
year = {2011},
author = {Ramaiah, MJ and Pushpavalli, S and Krishna, GR and Sarma, P and Mukhopadhyay, D and Kamal, A and Bhadra, U and Bhadra, MP},
title = {Chalcone-imidazolone conjugates induce apoptosis through DNA damage pathway by affecting telomeres.},
journal = {Cancer cell international},
volume = {11},
number = {},
pages = {11},
pmid = {21518433},
issn = {1475-2867},
abstract = {BACKGROUND: Breast cancer is one of the most prevalent cancers in the world and more than one million women are diagnosed leading to 410,000 deaths every year. In our previous studies new chalcone-imidazolone conjugates were prepared and evaluated for their anticancer activity in a panel of 53 human tumor cell lines and the lead compounds identified were 6 and 8. This prompted us to investigate the mechanism of apoptotic event.<br><br>RESULTS: Involvement of pro-apoptotic protein (Bax), active caspase-9 and cleavage of retinoblastoma protein was studied. Interestingly, the compounds caused upregulation of p21, check point proteins (Chk1, Chk2) and as well as their phosphorylated forms which are known to regulate the DNA damage pathway. Increased p53BP1 foci by immunolocalisation studies and TRF1 suggested the possible involvement of telomere and associated proteins in the apoptotic event. The telomeric protein such as TRF2 which is an important target for anticancer therapy against human breast cancer was extensively studied along with proteins involved in proper functioning of telomeres.<br><br>CONCLUSIONS: The apoptotic proteins such as Bax, active caspase-9 and cleaved RB are up-regulated in the compound treated cells revealing the apoptotic nature of the compounds. Down regulation of TRF2 and upregulation of the TRF1 as well as telomerase assay indicated the decrease in telomeric length revealing telomeric dysfunction and thereby controlling the rapid rate of cell proliferation. In summary, chalcone-imidazolone conjugates displayed significant DNA damage activity particularly at telomeres and caused both apoptosis and senescence-like growth arrest which suggested that these compounds have potential activity against breast carcinoma.},
}
@article {pmid21518243,
year = {2011},
author = {Gomes, NM and Ryder, OA and Houck, ML and Charter, SJ and Walker, W and Forsyth, NR and Austad, SN and Venditti, C and Pagel, M and Shay, JW and Wright, WE},
title = {Comparative biology of mammalian telomeres: hypotheses on ancestral states and the roles of telomeres in longevity determination.},
journal = {Aging cell},
volume = {10},
number = {5},
pages = {761-768},
pmid = {21518243},
issn = {1474-9726},
support = {P50 CA070907/CA/NCI NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; AG01228/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*physiology ; Animals ; Body Size ; Cell Cycle Checkpoints ; Cell Division ; Cell Line ; Enzyme Repression ; Evolution, Molecular ; Fibroblasts/cytology/metabolism ; Genetic Vectors ; Humans ; *Longevity ; Mammals ; Oxidation-Reduction ; Phenotype ; Phylogeny ; Regression Analysis ; Telomerase/genetics/*metabolism ; Telomere/genetics/metabolism/*physiology ; Telomere Shortening ; Transfection ; },
abstract = {Progressive telomere shortening from cell division (replicative aging) provides a barrier for human tumor progression. This program is not conserved in laboratory mice, which have longer telomeres and constitutive telomerase. Wild species that do/do not use replicative aging have been reported, but the evolution of different phenotypes and a conceptual framework for understanding their uses of telomeres is lacking. We examined telomeres/telomerase in cultured cells from > 60 mammalian species to place different uses of telomeres in a broad mammalian context. Phylogeny-based statistical analysis reconstructed ancestral states. Our analysis suggested that the ancestral mammalian phenotype included short telomeres (< 20 kb, as we now see in humans) and repressed telomerase. We argue that the repressed telomerase was a response to a higher mutation load brought on by the evolution of homeothermy. With telomerase repressed, we then see the evolution of replicative aging. Telomere length inversely correlated with lifespan, while telomerase expression co-evolved with body size. Multiple independent times smaller, shorter-lived species changed to having longer telomeres and expressing telomerase. Trade-offs involving reducing the energetic/cellular costs of specific oxidative protection mechanisms (needed to protect < 20 kb telomeres in the absence of telomerase) could explain this abandonment of replicative aging. These observations provide a conceptual framework for understanding different uses of telomeres in mammals, support a role for human-like telomeres in allowing longer lifespans to evolve, demonstrate the need to include telomere length in the analysis of comparative studies of oxidative protection in the biology of aging, and identify which mammals can be used as appropriate model organisms for the study of the role of telomeres in human cancer and aging.},
}
@article {pmid21512015,
year = {2011},
author = {Leslie, M},
title = {Cell biology. Are telomere tests ready for prime time?.},
journal = {Science (New York, N.Y.)},
volume = {332},
number = {6028},
pages = {414-415},
doi = {10.1126/science.332.6028.414},
pmid = {21512015},
issn = {1095-9203},
mesh = {*Aging ; *Chronic Disease ; *Cytological Techniques ; Diagnostic Services ; *Disease Susceptibility ; Female ; Health Behavior ; Humans ; In Situ Hybridization, Fluorescence ; Life Style ; Male ; Polymerase Chain Reaction ; Telomere/*physiology/*ultrastructure ; },
}
@article {pmid21507503,
year = {2011},
author = {Shen, M and Cawthon, R and Rothman, N and Weinstein, SJ and Virtamo, J and Hosgood, HD and Hu, W and Lim, U and Albanes, D and Lan, Q},
title = {A prospective study of telomere length measured by monochrome multiplex quantitative PCR and risk of lung cancer.},
journal = {Lung cancer (Amsterdam, Netherlands)},
volume = {73},
number = {2},
pages = {133-137},
pmid = {21507503},
issn = {1872-8332},
support = {N01 CN045165/CN/NCI NIH HHS/United States ; N01RC37004/RC/CCR NIH HHS/United States ; ZIA CP010195-05/ImNIH/Intramural NIH HHS/United States ; N01-RC-45035/RC/CCR NIH HHS/United States ; },
mesh = {Aged ; Case-Control Studies ; Chromosomal Instability ; Cohort Studies ; Genetic Markers ; Humans ; Leukocytes/metabolism ; Lung Neoplasms/etiology/*genetics ; Male ; Middle Aged ; Odds Ratio ; Polymerase Chain Reaction ; Prospective Studies ; Risk Factors ; Smoking/adverse effects ; Statistics, Nonparametric ; Telomere/*metabolism ; },
abstract = {PURPOSE: Telomere length plays an important role in chromosomal stability and tumorigenesis, and its measurement in peripheral white blood cell DNA may be a predictor of the development of lung cancer.<br><br>EXPERIMENTAL DESIGN: Using a new method - monochrome multiplex quantitative PCR - which reduces measurement variability, we compared telomere length relative to standard DNA in white blood cell DNA in 229 incident male lung cancer cases and 229 matched controls within the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of male smokers.<br><br>RESULTS: Median (10th, 90th percentile) telomere length was 1.13 (0.86, 1.45) in cases and 1.08 (0.85, 1.38) in controls (P=0.038). Telomere length was inversely associated with pack-years of smoking (Spearman's correlation r=-0.16, P=0.02) among controls. Compared to subjects with shorter telomere length (&#x2264;median), subjects with greater telomere length (>median) had a 1.6-fold (95% CI, 1.06-2.36) increased risk of lung cancer. There was a significant linear relationship between quartiles of telomere length and risk of lung cancer (odds ratios (95% confidence intervals) by quartile: 1.00, 0.98 (0.55-1.73), 1.62 (0.95-2.77), and 1.50 (0.84-2.68); P(trend)=0.05). In addition, subgroup analysis showed that greater telomere length was associated with an increased risk of lung cancer among longer-term smokers (>38 years) (OR, 1.90; 95% CI, 1.00-3.59) but not among shorter-term smokers (&#x2264;38 years) (OR, 1.08; 95% CI, 0.56-2.11) (P(interaction)=0.01).<br><br>CONCLUSIONS: Our results suggest that greater telomere length may be associated with higher risk of lung cancer among male smokers.},
}
@article {pmid21504833,
year = {2011},
author = {Oganesian, L and Karlseder, J},
title = {Mammalian 5' C-rich telomeric overhangs are a mark of recombination-dependent telomere maintenance.},
journal = {Molecular cell},
volume = {42},
number = {2},
pages = {224-236},
pmid = {21504833},
issn = {1097-4164},
support = {R01 AG025837-05/AG/NIA NIH HHS/United States ; R01 GM087476-01A1/GM/NIGMS NIH HHS/United States ; R01 AG025837-03/AG/NIA NIH HHS/United States ; GM087476/GM/NIGMS NIH HHS/United States ; R01 GM087476-02/GM/NIGMS NIH HHS/United States ; AG025837/AG/NIA NIH HHS/United States ; R01 GM087476/GM/NIGMS NIH HHS/United States ; R01 AG025837/AG/NIA NIH HHS/United States ; R01 AG025837-04/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Base Composition ; Chromosomes, Human/chemistry/metabolism/*ultrastructure ; Cytosine ; DNA, Single-Stranded/chemistry/metabolism/*ultrastructure ; DNA-Binding Proteins/genetics/metabolism ; Electrophoresis, Gel, Two-Dimensional ; Exonucleases/metabolism ; HeLa Cells ; Humans ; Mice ; Nucleic Acid Conformation ; RNA Interference ; Rad51 Recombinase/genetics/metabolism ; Rad52 DNA Repair and Recombination Protein/genetics/metabolism ; *Recombination, Genetic ; Telomere/chemistry/metabolism/*ultrastructure ; Transfection ; },
abstract = {Recent evidence for 5'-cytosine (C)-rich overhangs at the telomeres of the nematode Caenorhabditis elegans provided the impetus to re-examine the end structure of mammalian telomeres. Two-dimensional (2D) gel electrophoresis, single telomere-length analysis (STELA), and strand-specific exonuclease assays revealed the presence of a 5'-C-rich overhang at the telomeres of human and mouse chromosomes. C-overhangs were prominent in G1/S arrested as well as terminally differentiated cells, indicating that they did not represent replication intermediates. C-rich overhangs were far more prevalent in tumor cells engaged in the alternative lengthening of telomeres (ALT) pathway of telomere maintenance, which relies on the homologous recombination (HR) machinery. Transient siRNA-based depletion of the HR-specific proteins RAD51, RAD52, and XRCC3 resulted in changes in C-overhang levels, implicating the involvement of 5'-C-overhangs in the HR-dependent pathway of telomere maintenance.},
}
@article {pmid21499239,
year = {2011},
author = {Kuhn, E and Meeker, AK and Visvanathan, K and Gross, AL and Wang, TL and Kurman, RJ and Shih, IeM},
title = {Telomere length in different histologic types of ovarian carcinoma with emphasis on clear cell carcinoma.},
journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},
volume = {24},
number = {8},
pages = {1139-1145},
pmid = {21499239},
issn = {1530-0285},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma, Clear Cell/*genetics/mortality/*pathology ; Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Image Interpretation, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Kaplan-Meier Estimate ; Microscopy, Fluorescence ; Middle Aged ; Neoplasm Staging ; Ovarian Neoplasms/*genetics/mortality/*pathology ; Prognosis ; Telomere/*ultrastructure ; Tissue Array Analysis ; Young Adult ; },
abstract = {Ovarian carcinoma is composed of a heterogeneous group of tumors with distinct clinico-pathological and molecular features. Alteration of telomerase activity has been reported in ovarian tumors but the pattern of telomere length in their specific histological subtypes has not been reported. In this study, we performed quantitative telomere fluorescence in situ hybridization on a total of 219 ovarian carcinomas including 106 high-grade serous carcinomas, 26 low-grade serous carcinomas, 56 clear cell carcinomas and 31 low-grade endometrioid carcinomas. The mean relative telomere length of carcinoma to stromal cells was calculated as a telomere index. This index was significantly higher in clear cell carcinoma compared with the other histologic types (P=0.007). Overall there was no association between the telomere index and mortality, but when stratified by histologic types, the hazard ratio for death among women with clear cell carcinoma with a telomere index >1 was significantly increased at 4.93 (95% CI 1.64-14.86, P=0.005) when compared with those with a telomere index ≤1. In conclusion, our results provide new evidence that telomere length significantly differs by histologic type in ovarian carcinoma. Specifically, clear cell carcinomas have longer mean relative telomere lengths compared with the other histologic types and longer telomeres in clear cell carcinoma are associated with increased mortality suggesting that aberrations in telomere length may have an important role in the development and progression of this neoplasm.},
}
@article {pmid21499016,
year = {2011},
author = {Maeda, T and Oyama, J and Sasaki, M and Nishiyama, Y and Kudo, Y and Yamori, T and Nakazono, T and Arima, T and Makino, N},
title = {The physical ability of elderly female Japanese patients with cerebrovascular disease correlates with telomere length in their peripheral blood leukocytes.},
journal = {Aging clinical and experimental research},
volume = {23},
number = {1},
pages = {22-28},
doi = {10.1007/BF03324949},
pmid = {21499016},
issn = {1594-0667},
mesh = {*Activities of Daily Living ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Asian People ; Cerebrovascular Disorders/*genetics ; Female ; Humans ; *Leukocytes, Mononuclear/metabolism ; Male ; Middle Aged ; Sex Characteristics ; *Telomere ; },
abstract = {BACKGROUND AND AIMS: The telomere length of peripheral blood leukocytes has been reported to be inversely correlated with many kinds of pathophysiological conditions. However, correlations between telomere length in peripheral blood leukocytes and patients' physical ability are not known.<br><br>METHODS: To address this problem, the physical ability of patients with cerebrovascular disease admitted to the chronic disease ward of Kyushu University Hospital was assessed with the Barthel index (BI) and the telomere length of their peripheral blood leukocytes was determined.<br><br>RESULTS AND CONCLUSIONS: Women exhibited a significant correlation between the Barthel score and the expression of long telomeres (>9.4 Kb), in contrast with men who revealed no such correlation. The physical ability of older women was positively correlated with the lengths of their somatic telomeres. Among the BI items, the scores of more difficult physical performances tended to correlate with the presence of terminal restriction fragments longer than 9.4 Kb.},
}
@article {pmid21497268,
year = {2011},
author = {Dereure, O},
title = {[Mutations of C16orf57 gene have been identified in the poikiloderma-neutropenia syndrome and in a specific subset of congenital dyskeratosis with normal-length telomeres].},
journal = {Annales de dermatologie et de venereologie},
volume = {138},
number = {4},
pages = {362-363},
doi = {10.1016/j.annder.2011.01.026},
pmid = {21497268},
issn = {0151-9638},
mesh = {Chromosomes, Human, Pair 16/*genetics ; Dyskeratosis Congenita/diagnosis/*genetics ; Genetic Association Studies ; Genetic Variation/genetics ; Homozygote ; Humans ; Mutation/*genetics ; Open Reading Frames/*genetics ; Rothmund-Thomson Syndrome/diagnosis/*genetics ; Telomere/*genetics ; },
}
@article {pmid21495473,
year = {2011},
author = {Singer, T},
title = {My, what long telomeres you have.},
journal = {Scientific American},
volume = {304},
number = {4},
pages = {22},
doi = {10.1038/scientificamerican0411-22a},
pmid = {21495473},
issn = {0036-8733},
mesh = {Aging/*genetics ; Humans ; Telomere/*ultrastructure ; },
}
@article {pmid21493920,
year = {2011},
author = {Finkel, T},
title = {Telomeres and mitochondrial function.},
journal = {Circulation research},
volume = {108},
number = {8},
pages = {903-904},
pmid = {21493920},
issn = {1524-4571},
support = {ZIA HL006037-03//Intramural NIH HHS/United States ; },
}
@article {pmid21490951,
year = {2011},
author = {Addinall, SG and Holstein, EM and Lawless, C and Yu, M and Chapman, K and Banks, AP and Ngo, HP and Maringele, L and Taschuk, M and Young, A and Ciesiolka, A and Lister, AL and Wipat, A and Wilkinson, DJ and Lydall, D},
title = {Quantitative fitness analysis shows that NMD proteins and many other protein complexes suppress or enhance distinct telomere cap defects.},
journal = {PLoS genetics},
volume = {7},
number = {4},
pages = {e1001362},
pmid = {21490951},
issn = {1553-7404},
support = {BBF0235451/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; 075294/WT_/Wellcome Trust/United Kingdom ; BB/F006039/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; B/C008200/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/F023545/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Gene Expression Regulation, Fungal ; Models, Biological ; Mutation/genetics ; RNA Stability/genetics ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomere/genetics/*metabolism/*pathology ; Telomere-Binding Proteins/genetics/*metabolism ; Temperature ; Transcription Factors/*metabolism ; },
abstract = {To better understand telomere biology in budding yeast, we have performed systematic suppressor/enhancer analyses on yeast strains containing a point mutation in the essential telomere capping gene CDC13 (cdc13-1) or containing a null mutation in the DNA damage response and telomere capping gene YKU70 (yku70Δ). We performed Quantitative Fitness Analysis (QFA) on thousands of yeast strains containing mutations affecting telomere-capping proteins in combination with a library of systematic gene deletion mutations. To perform QFA, we typically inoculate 384 separate cultures onto solid agar plates and monitor growth of each culture by photography over time. The data are fitted to a logistic population growth model; and growth parameters, such as maximum growth rate and maximum doubling potential, are deduced. QFA reveals that as many as 5% of systematic gene deletions, affecting numerous functional classes, strongly interact with telomere capping defects. We show that, while Cdc13 and Yku70 perform complementary roles in telomere capping, their genetic interaction profiles differ significantly. At least 19 different classes of functionally or physically related proteins can be identified as interacting with cdc13-1, yku70Δ, or both. Each specific genetic interaction informs the roles of individual gene products in telomere biology. One striking example is with genes of the nonsense-mediated RNA decay (NMD) pathway which, when disabled, suppress the conditional cdc13-1 mutation but enhance the null yku70Δ mutation. We show that the suppressing/enhancing role of the NMD pathway at uncapped telomeres is mediated through the levels of Stn1, an essential telomere capping protein, which interacts with Cdc13 and recruitment of telomerase to telomeres. We show that increased Stn1 levels affect growth of cells with telomere capping defects due to cdc13-1 and yku70Δ. QFA is a sensitive, high-throughput method that will also be useful to understand other aspects of microbial cell biology.},
}
@article {pmid21489410,
year = {2011},
author = {O'Donovan, A and Epel, E and Lin, J and Wolkowitz, O and Cohen, B and Maguen, S and Metzler, T and Lenoci, M and Blackburn, E and Neylan, TC},
title = {Childhood trauma associated with short leukocyte telomere length in posttraumatic stress disorder.},
journal = {Biological psychiatry},
volume = {70},
number = {5},
pages = {465-471},
pmid = {21489410},
issn = {1873-2402},
support = {R01 MH073978-01/MH/NIMH NIH HHS/United States ; K23 HL 094765-01/HL/NHLBI NIH HHS/United States ; 5R34MH077667-03/MH/NIMH NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; R34 MH077667/MH/NIMH NIH HHS/United States ; R01 MH073978-02/MH/NIMH NIH HHS/United States ; R01 MH073978/MH/NIMH NIH HHS/United States ; R34 MH077667-03/MH/NIMH NIH HHS/United States ; R01 MH073978-03/MH/NIMH NIH HHS/United States ; R01 MH073978-04/MH/NIMH NIH HHS/United States ; K23 HL094765-01/HL/NHLBI NIH HHS/United States ; K23 HL094765/HL/NHLBI NIH HHS/United States ; 5R01MH073978-04/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Adult Survivors of Child Abuse/*psychology ; Biomarkers/blood ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Stress Disorders, Post-Traumatic/blood/complications/*genetics ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with increased risk for age-related diseases and early mortality. An accelerated rate of biological aging could contribute to this increased risk. To investigate, we assessed leukocyte telomere length (LTL), an emerging marker of biological age, in men and women with and without PTSD. We also examined childhood trauma, a risk factor for both PTSD and short LTL, as a potential contributor to short LTL in PTSD.<br><br>METHODS: Participants included 43 adults with chronic PTSD (n = 18 with multiple categories of childhood trauma) and 47 control subjects (none with multiple categories of childhood trauma) (mean age = 30.55, SD = 7.44). Exclusion criteria included physical illness, medication use, obesity, alcohol or substance abuse, and pregnancy. Structured clinical interviews were conducted to assess PTSD and other psychiatric disorders and childhood trauma exposure. LTL was measured with a quantitative polymerase chain reaction method.<br><br>RESULTS: As predicted, participants with PTSD had shorter age-adjusted LTL than control subjects. Exposure to childhood trauma was also associated with short LTL. In fact, childhood trauma seemed to account for the PTSD group difference in LTL; only participants with PTSD and exposure to multiple categories of childhood trauma had significantly shorter LTL than control subjects.<br><br>CONCLUSIONS: Childhood trauma is associated with short LTL in individuals with PTSD. Chronic exposure to the psychobiological sequelae of childhood trauma could increase risk for PTSD and short LTL. Thus, the lasting psychological impact of exposure to trauma in childhood might be accompanied by equally enduring changes at the molecular level.},
}
@article {pmid21486373,
year = {2011},
author = {Olsson, M and Pauliny, A and Wapstra, E and Uller, T and Schwartz, T and Miller, E and Blomqvist, D},
title = {Sexual differences in telomere selection in the wild.},
journal = {Molecular ecology},
volume = {20},
number = {10},
pages = {2085-2099},
doi = {10.1111/j.1365-294X.2011.05085.x},
pmid = {21486373},
issn = {1365-294X},
mesh = {Animals ; Female ; Lizards/*genetics ; Male ; *Sex Characteristics ; Telomere/*genetics ; },
abstract = {Telomere length is restored primarily through the action of the reverse transcriptase telomerase, which may contribute to a prolonged lifespan in some but not all species and may result in longer telomeres in one sex than the other. To what extent this is an effect of proximate mechanisms (e.g. higher stress in males, higher oestradiol/oestrogen levels in females), or is an evolved adaptation (stronger selection for telomere length in one sex), usually remains unknown. Sand lizard (Lacerta agilis) females have longer telomeres than males and better maintain telomere length through life than males do. We also show that telomere length more strongly contributes to life span and lifetime reproductive success in females than males and that telomere length is under sexually diversifying selection in the wild. Finally, we performed a selection analysis with number of recruited offspring into the adult population as a response variable with telomere length, life span and body size as predictor variables. This showed significant differences in selection pressures between the sexes with strong ongoing selection in females, with these three predictors explaining 63% of the variation in recruitment. Thus, the sexually dimorphic telomere dynamics with longer telomeres in females is a result of past and ongoing selection in sand lizards. Finally, we compared the results from our selection analyses based on Telometric-derived data to the results based on data generated by the software ImageJ. ImageJ resulted in shorter average telomere length, but this difference had virtually no qualitative effect on the patterns of ongoing selection.},
}
@article {pmid21478459,
year = {2011},
author = {Martínez-A, C and van Wely, KH},
title = {Centromere fission, not telomere erosion, triggers chromosomal instability in human carcinomas.},
journal = {Carcinogenesis},
volume = {32},
number = {6},
pages = {796-803},
pmid = {21478459},
issn = {1460-2180},
mesh = {Centromere/*genetics ; *Chromosomal Instability ; Humans ; Neoplasms/*genetics/*pathology ; Telomere/*genetics ; },
abstract = {The majority of sporadic carcinomas suffer from a kind of genetic instability in which chromosome number changes occur together with segmental defects. This means that changes involving intact chromosomes accompany breakage-induced alterations. Whereas the causes of aneuploidy are described in detail, the origins of chromosome breakage in sporadic carcinomas remain disputed. The three main pathways of chromosomal instability (CIN) proposed until now (random breakage, telomere fusion and centromere fission) are largely based on animal models and in vitro experiments, and recent studies revealed several discrepancies between animal models and human cancer. Here, we discuss how the experimental systems translate to human carcinomas and compare the theoretical breakage products to data from patient material and cancer cell lines. The majority of chromosomal defects in human carcinomas comprises pericentromeric breaks that are captured by healthy telomeres, and only a minor proportion of chromosome fusions can be attributed to telomere erosion or random breakage. Centromere fission, not telomere erosion, is therefore the most probably trigger of CIN and early carcinogenesis. Similar centromere-telomere fusions might drive a subset of congenital defects and evolutionary chromosome changes.},
}
@article {pmid21474994,
year = {2011},
author = {Lee, YW and Kim, WT},
title = {Roles of NtGTBP1 in telomere stability.},
journal = {Plant signaling &amp; behavior},
volume = {6},
number = {4},
pages = {523-525},
pmid = {21474994},
issn = {1559-2324},
mesh = {Genomic Instability/genetics/*physiology ; Models, Biological ; Plant Proteins/genetics/*metabolism ; RNA Interference/physiology ; Recombination, Genetic/genetics ; Telomere ; Telomere-Binding Proteins/genetics/*metabolism ; Nicotiana/genetics/*metabolism ; },
abstract = {Telomeres are protective nucleoprotein structures at the ends of linear eukaryotic chromosomes. In contrast to double-stranded-specific telomere-binding proteins, the cellular roles of single-stranded-specific telomeric proteins are not well understood in higher plants. Three highly conserved tobacco G-strand-specific telomere-binding protein paralogs (NtGTBP1, NtGTBP2, and NtGTBP3) were identified and characterized. All three NtGTBPs were able to bind specifically to the plant single-stranded telomeric repeat elements in vitro with similar affinities. Suppression of NtGTBP1 by means of the RNAi-mediated gene knock-down method resulted in developmental defects in transgenic tobacco plants accompanied by lengthened telomeres, extra-chromosomal telomeric circles, and abnormal anaphase bridges. These results suggest that the down-regulation of NtGTBP1 results in genome instability. NtGTBP1 prevented in vitro strand invasion, a prerequisite process for inter-chromosomal telomeric recombination. Therefore, tobacco NtGTBP1 is one of the essential factors for telomere stability. Because abnormal telomeric elongation and recombination due to the suppression of NtGTBP1 are reminiscent of the recombinational telomere lengthening mechanism that purportedly operates in telomerase negative cancer cells, it is of interest to investigate whether telomeric recombination is associated with cell death in animal systems.},
}
@article {pmid21468560,
year = {2011},
author = {Feng, X and Wang, L and Li, Y},
title = {Change of telomere length in angiotensin II-induced human glomerular mesangial cell senescence and the protective role of losartan.},
journal = {Molecular medicine reports},
volume = {4},
number = {2},
pages = {255-260},
doi = {10.3892/mmr.2011.436},
pmid = {21468560},
issn = {1791-3004},
mesh = {Angiotensin II/*pharmacology ; Blotting, Western ; Cell Cycle/drug effects ; Cellular Senescence/*drug effects ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Flow Cytometry ; Humans ; Losartan/*pharmacology ; Mesangial Cells/*cytology/*drug effects/enzymology ; Protective Agents/*pharmacology ; Telomere/*metabolism ; Tumor Suppressor Protein p53/metabolism ; beta-Galactosidase/metabolism ; },
abstract = {Telomeres are DNA repeats at the ends of linear chromosomes in eukaryotic cells; they form cap-like specialized structures at chromosome ends to protect them from digestion and degradation. With each cell division, somatic cell telomeres progressively wear and shorten, leading to cell senescence. Various environmental factors, such as oxidative stress and inflammation, can accelerate telomere shortening. The renin angiotensin system seems to be the key mechanism involved in aging. Our previous studies demonstrated that treatment of human glomerular mesangial cells (GMCs) with angiotensin II (AngII) caused cell senescence. It is important to understand whether AngII accelerates telomere shortening in GMCs and further promotes aging. Therefore, this study was designed to investigate the change in telomere length in AngII-induced GMC senescence and the role of the AngII receptor antagonist losartan in delaying this process. The cells were synchronized and divided into a normal control group, an AngII group (AngII, 10[-6] mol/l) and an AngII + losartan group (losartan, 10[-5] mol/l), and were then cultured for 72 h. The telomere lengths were analyzed by Southern blot analysis, cell morphology was monitored, the cell cycle and β-galactosidase staining were determined, and the expression of P53 and P21 proteins was assessed by Western blotting. Compared with the control group, the AngII group exhibited a markedly reduced telomere length, cell cycle arrest, enhanced β-galactosidase staining, and elevated expression of P53 and P21. The AngII + losartan group displayed longer telomere lengths, further reduced β-galactosidase staining and decreased P53 and P21 expression compared to the AngII group. This study confirms that AngII induces the shortening of telomere lengths, P53 and P21 expression, cell cycle arrest, and the resulting cell senescence in GMCs. In addition, losartan significantly reduced telomere shortening and cell senescence.},
}
@article {pmid21467229,
year = {2011},
author = {Wentzensen, IM and Mirabello, L and Pfeiffer, RM and Savage, SA},
title = {The association of telomere length and cancer: a meta-analysis.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {20},
number = {6},
pages = {1238-1250},
pmid = {21467229},
issn = {1538-7755},
support = {Z01 CP010190-02/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Case-Control Studies ; Chromosomal Instability ; Humans ; Neoplasms/*genetics ; Prospective Studies ; Retrospective Studies ; Risk Factors ; Telomere/*genetics ; },
abstract = {BACKGROUND: Telomeres shorten with each cell division and are essential for chromosomal stability. Short telomeres in surrogate tissues (e.g., blood cells) are associated with increased cancer risk in several case-control studies, but findings are inconsistent in prospective studies.<br><br>METHODS: We systematically reviewed studies published prior to August 30, 2010, on the association between telomere length (TL) in surrogate tissues and cancer. There were 27 reports on 13 cancers and/or incident cancer investigating this association. The majority, 16, were retrospective case--control studies, 11 were prospective studies. Meta-analyses were conducted to determine ORs and 95% CIs for these studies.<br><br>RESULTS: Studies on bladder, esophageal, gastric, head and neck, ovarian, renal, and overall incident cancer found associations between short telomeres and these cancers. Non-Hodgkin lymphoma, breast, lung, and colorectal cancer reports were inconsistent. Single studies on endometrial, prostate, and skin cancers were null. In a random-effects meta-analysis, short TL was significantly associated with cancer in retrospective studies (pooled OR for the shortest TL quartile compared with the longest: 2.9, 95% CI: 1.75-4.8, P < 0.0001). The pooled OR for prospective studies was 1.16 (95% CI: 0.87-1.54, P = 0.32). All studies combined yielded a pooled OR of 1.96 (95% CI: 1.37-2.81, P = 0.0001) for the association of short TL and cancer.<br><br>CONCLUSION AND IMPACT: There is suggestive evidence that short surrogate tissue TL is associated with cancer; the strongest evidence exists for bladder, esophageal, gastric, and renal cancers. Additional prospective studies with consistent methodology are needed to confirm this hypothesis.},
}
@article {pmid21465749,
year = {2010},
author = {McCracken, J and Baccarelli, A and Hoxha, M and Dioni, L and Melly, S and Coull, B and Suh, H and Vokonas, P and Schwartz, J},
title = {Annual ambient black carbon associated with shorter telomeres in elderly men: Veterans Affairs Normative Aging Study.},
journal = {Environmental health perspectives},
volume = {118},
number = {11},
pages = {1564-1570},
pmid = {21465749},
issn = {1552-9924},
support = {R01 ES015172/ES/NIEHS NIH HHS/United States ; P01 ES009825/ES/NIEHS NIH HHS/United States ; P30 ES000002/ES/NIEHS NIH HHS/United States ; ES014663/ES/NIEHS NIH HHS/United States ; ES-0002/ES/NIEHS NIH HHS/United States ; ES009825/ES/NIEHS NIH HHS/United States ; R01-ES015172/ES/NIEHS NIH HHS/United States ; R01 ES014663/ES/NIEHS NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging ; Air Pollutants/*analysis ; Air Pollution/*statistics &amp; numerical data ; Biomarkers/chemistry ; Cardiovascular Diseases/epidemiology ; Environmental Monitoring/methods ; Epidemiological Monitoring ; Humans ; Inhalation Exposure/analysis/statistics &amp; numerical data ; Linear Models ; Male ; Middle Aged ; Risk Factors ; Soot/*analysis ; Telomere/*genetics ; Veterans/*statistics &amp; numerical data ; },
abstract = {BACKGROUND: Telomere length reflects biological age and is inversely associated with risk of cardiovascular disease (CVD). Ambient air pollution is associated with CVD, but its effect on telomere length is unknown.<br><br>OBJECTIVE: We investigated whether ambient black carbon (BC), a marker for traffic-related particles, is associated with telomere length in the Normative Aging Study (NAS).<br><br>METHODS: Among 165 never-smoking men from the NAS, leukocyte telomere length (LTL) was measured repeatedly approximately every 3 years from 1999 through 2006 using quantitative real-time polymerase chain reaction (qRT-PCR). BC concentration at their residences during the year before each LTL measurement was estimated based on a spatiotemporal model calibrated with BC measurements from 82 locations within the study area.<br><br>RESULTS: The median [interquartile range (IQR)] annual moving-average BC concentration was 0.32 (0.20-0.45) microg/m3. LTL, expressed as population-standardized ratio of telomere repeat to single-copy gene copy numbers, had a geometric mean (geometric SD) of 1.25 (1.42). We used linear mixed-effects models including random subject intercepts and adjusted for several potential confounders. We used inverse probability of response weighting to adjust for potential selection bias due to loss to follow-up. An IQR increase in annual BC (0.25 microg/m3) was associated with a 7.6% decrease (95% confidence interval, -12.8 to -2.1) in LTL. We found evidence of effect modification, with a stronger association among subjects > or = 75 years of age compared with younger participants (p = 0.050) and statin medications appearing protective of the effects of BC on LTL (p = 0.050).<br><br>CONCLUSIONS: Telomere attrition, linked to biological aging, may be associated with long-term exposures to airborne particles, particularly those rich in BC, which are primarily related to automobile traffic.},
}
@article {pmid21465324,
year = {2011},
author = {Paul, M and Murray, V},
title = {The sequence selectivity of DNA-targeted 9-aminoacridine cisplatin analogues in a telomere-containing DNA sequence.},
journal = {Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry},
volume = {16},
number = {5},
pages = {735-743},
pmid = {21465324},
issn = {1432-1327},
mesh = {Aminacrine/*chemistry ; Antineoplastic Agents/*chemistry/*pharmacology ; Base Sequence ; Cisplatin/*analogs &amp; derivatives/*pharmacology ; DNA/*chemistry/metabolism ; Humans ; Intercalating Agents/*chemistry ; Molecular Sequence Data ; Neoplasms/drug therapy ; Telomere/drug effects ; },
abstract = {In this study, the detailed DNA sequence specificity of four acridine Pt complexes was examined and compared with that of cisplatin. The DNA sequence specificity was determined in a telomere-containing DNA sequence using a polymerase stop assay, with a fluorescent primer and an automated capillary DNA sequencer. The Pt compounds included an acridine intercalating moiety that was modified to give a 9-aminoacridine derivative, a 7-methoxy-9-aminoacridine derivative, a 7-fluoro-9-aminoacridine derivative and a 9-ethanolamine-acridine derivative. Compared with cisplatin, the DNA sequence specificity was most altered for the 7-methoxy-9-aminoacridine compound, followed by the 9-aminoacridine derivative, the 7-fluoro-9-aminoacridine compound and the 9-ethanolamine-acridine derivative. The DNA sequence selectivity for the four acridine Pt complexes was shifted away from runs of consecutive guanines towards single guanine bases, especially 5'-GA dinucleotides and sequences that contained 5'-CG. The sequence specificity was examined in telomeric and non-telomeric DNA sequences. Although it was found that telomeric DNA sequences were extensively damaged by the four acridine Pt complexes, there was no extra preference for telomeric sequences.},
}
@article {pmid21464209,
year = {2011},
author = {Strong, MA and Vidal-Cardenas, SL and Karim, B and Yu, H and Guo, N and Greider, CW},
title = {Phenotypes in mTERT[+]/[-] and mTERT[-]/[-] mice are due to short telomeres, not telomere-independent functions of telomerase reverse transcriptase.},
journal = {Molecular and cellular biology},
volume = {31},
number = {12},
pages = {2369-2379},
pmid = {21464209},
issn = {1098-5549},
support = {R01 AG027406/AG/NIA NIH HHS/United States ; R01AG027406/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Body Weight ; Humans ; Mice ; Mice, Inbred C57BL ; *Mice, Knockout ; Mutation ; *Phenotype ; RNA/genetics/metabolism ; Signal Transduction/physiology ; Survival Rate ; Syndrome ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; Wnt Proteins/genetics/metabolism ; },
abstract = {Telomerase is essential for telomere length maintenance. Mutations in either of the two core components of telomerase, telomerase RNA (TR) or the catalytic protein component telomerase reverse transcriptase (TERT), cause the genetic disorders dyskeratosis congenita, pulmonary fibrosis, and other degenerative diseases. Overexpression of the TERT protein has been reported to have telomere length-independent roles, including regulation of the Wnt signaling pathway. To examine the phenotypes of TERT haploinsufficiency and determine whether loss of function of TERT has effects other than those associated with telomere shortening, we characterized both mTERT[+]/[-] and mTERT[-]/[-] mice on the CAST/EiJ genetic background. Phenotypic analysis showed a loss of tissue renewal capacity with progressive breeding of heterozygous mice that was indistinguishable from that of mTR-deficient mice. mTERT[-]/[-] mice, from heterozygous mTERT[+]/[-] mouse crosses, were born at the expected Mendelian ratio (26.5%; n = 1,080 pups), indicating no embryonic lethality of this genotype. We looked for, and failed to find, hallmarks of Wnt deficiency in various adult and embryonic tissues, including those of the lungs, kidneys, brain, and skeleton. Finally, mTERT[-]/[-] cells showed wild-type levels of Wnt signaling in vitro. Thus, while TERT overexpression in some settings may activate the Wnt pathway, loss of function in a physiological setting has no apparent effects on Wnt signaling. Our results indicate that both TERT and TR are haploinsufficient and that their deficiency leads to telomere shortening, which limits tissue renewal. Our studies imply that hypomorphic loss-of-function alleles of hTERT and hTR should cause a similar disease spectrum in humans.},
}
@article {pmid21461822,
year = {2011},
author = {Wang, F and Lei, M},
title = {Human telomere POT1-TPP1 complex and its role in telomerase activity regulation.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {735},
number = {},
pages = {173-187},
doi = {10.1007/978-1-61779-092-8_17},
pmid = {21461822},
issn = {1940-6029},
support = {GM 083015-01/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; Shelterin Complex ; Telomerase/chemistry/isolation &amp; purification/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/isolation &amp; purification/*metabolism ; },
abstract = {Telomeres, the specialized DNA-protein complexes found at the termini of all linear eukaryotic -chromosomes, protect chromosomes from degradation and end-to-end fusion. The protection of telomeres 1 (POT1) protein binds the single-stranded overhang at the ends of chromosomes in diverse eukaryotes. It is essential for chromosome end-protection and involved in telomere length regulation. TPP1 is a previously identified binding partner of POT1 that has been proposed to form part of a -six-protein shelterin complex at telomeres. Through structural and biochemical studies, we have -demonstrated that human TPP1 is the missing human homolog of the β subunit of protozoan telomere end-binding-protein-complex (TEBPα-TEBPβ). Therefore, capping of telomeres by a TEBPα-TEBPβ/POT1-TPP1 dimer is more evolutionarily conserved than that had been expected. In addition, we also discovered that the human POT1-TPP1 complex is a processivity factor for telomerase.},
}
@article {pmid21461820,
year = {2011},
author = {Ma, W},
title = {Analysis of telomere proteins by Chromatin Immunoprecipitation (ChIP).},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {735},
number = {},
pages = {151-159},
doi = {10.1007/978-1-61779-092-8_15},
pmid = {21461820},
issn = {1940-6029},
mesh = {Chromatin Immunoprecipitation/*methods ; DNA/analysis/genetics/isolation &amp; purification ; HeLa Cells ; Humans ; Telomerase/analysis/genetics ; Telomere/*metabolism ; Telomere-Binding Proteins/*analysis/genetics ; },
abstract = {Telomere Chromatin Immunoprecipitation (ChIP) is an experimental method used to determine whether proteins are associated with telomere DNA inside the nucleus of cells or tissues. Telomere-associated proteins are covalently cross-linked to telomere DNA, and then immunoprecipitated using a specific antibody for the protein. This method has become one of the most indispensable tools for unraveling the protein complexes that associate with the telomeres.},
}
@article {pmid21461819,
year = {2011},
author = {Rai, R and Chang, S},
title = {Probing the telomere damage response.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {735},
number = {},
pages = {145-150},
pmid = {21461819},
issn = {1940-6029},
support = {R01 CA129037/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; DNA/genetics/metabolism ; *DNA Damage ; DNA Repair ; Fibroblasts ; HEK293 Cells ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; Retroviridae/physiology ; Telomere/*genetics/metabolism/*pathology ; Tripeptidyl-Peptidase 1 ; },
abstract = {Telomere dysfunctions, rendered through replicative attrition of telomeric DNA or due to the inhibition of shelterin components, are recognized as DNA double-stranded breaks (DSBs) by the DNA damage repair (DDR) pathway. This leads to the activation of DNA damage checkpoint sensors, including the Mre11-Rad50-Nbs1 (MRN) complex, γ-H2AX and 53BP1, the ATM and ATR signal-transducing kinases and downstream effectors, including Chk1, Chk2, and p53. Robust DNA damage response signals at dysfunctional telomeres, achieved by the complete deletion of TRF2 or by expressing dominant negative mutant TPP1(ΔRD), can be detected by their association with γ-H2AX and 53BP1 forming "telomere dysfunction induced foci (TIFs)." Induction of TIFs at telomeres provides an opportunity to quantify the extent of telomere dysfunction and monitor the signaling pathways.},
}
@article {pmid21461818,
year = {2011},
author = {Multani, AS and Chang, S},
title = {Cytogenetic analysis of telomere dysfunction.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {735},
number = {},
pages = {139-143},
pmid = {21461818},
issn = {1940-6029},
support = {R01 AG028888/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; Cytogenetic Analysis/*methods ; DNA Breaks, Double-Stranded ; DNA Repair ; Fibroblasts/cytology/metabolism ; In Situ Hybridization, Fluorescence ; Mice ; Recombination, Genetic ; Telomere/*genetics/metabolism/*pathology ; },
abstract = {Dysfunctional telomeres arising either through natural attrition due to telomerase deficiency or by the removal of telomere binding proteins are recognized as double stranded breaks (DSBs). Repair of DSBs is crucial for the maintenance of genome stability. In mammals, DSBs are repaired by either error prone nonhomologous end joining (NHEJ) or error free homologous recombination (HR) and can be visualized as chromosomal fusions.},
}
@article {pmid21461812,
year = {2011},
author = {Zhao, Y and Shay, JW and Wright, WE},
title = {Telomere terminal G/C strand synthesis: measuring telomerase action and C-rich fill-in.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {735},
number = {},
pages = {63-75},
pmid = {21461812},
issn = {1940-6029},
support = {R01 AG001228/AG/NIA NIH HHS/United States ; },
mesh = {Cytosine/*metabolism ; DNA/chemistry/genetics ; Guanine/*metabolism ; HeLa Cells ; Humans ; Repetitive Sequences, Nucleic Acid/genetics ; Sequence Analysis, DNA/*methods ; Telomerase/*metabolism ; Telomere/chemistry/genetics/*metabolism ; },
abstract = {Telomerase is present in most human cancers, and proliferative stem cells including germline cells. Telomerase plays an essential role in tumorigenesis by maintaining/elongating telomeric DNA, and thus preventing the telomere shortening that results in replicative senescence. Understanding telomerase action in vivo has important implication for both cancer and aging, but there are not robust methods for monitoring telomerase action. By combining a series of cell biological and biochemical approaches, and taking advantage of the enzyme DSN that specifically cuts double-stranded DNA and releases the telomeric overhangs, we have developed a method to monitor telomerase action during one cell cycle. Here, we describe this method using HeLa carcinoma cells as an example.},
}
@article {pmid21461811,
year = {2011},
author = {Tahara, H},
title = {Telomere G-overhang length measurement method 2: G-tail telomere HPA.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {735},
number = {},
pages = {55-61},
doi = {10.1007/978-1-61779-092-8_6},
pmid = {21461811},
issn = {1940-6029},
mesh = {DNA/genetics ; Guanine/*analysis/metabolism ; Humans ; Luminescent Measurements/methods ; Nucleic Acid Hybridization/*methods ; Staining and Labeling ; Telomere/*chemistry/genetics/*metabolism ; },
abstract = {Both telomere length and telomere G-tail length are altered in human diseases such as cancer and -age-related disease. While most methods for the measurement of G-tail and telomere length require electrophoresis, centrifugation, radioisotope labeling, and autoradiography, G-tail telomere HPA provides a convenient and useful tool for the examination of G-tail length with a high-throughput platform using genomic DNA or cell lysate. G-tail telomere HPA may be applicable for clinical diagnostics as well as drug target screening.},
}
@article {pmid21461810,
year = {2011},
author = {Zhao, Y and Shay, JW and Wright, WE},
title = {Telomere G-overhang length measurement method 1: the DSN method.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {735},
number = {},
pages = {47-54},
pmid = {21461810},
issn = {1940-6029},
support = {R01 AG001228/AG/NIA NIH HHS/United States ; },
mesh = {Base Sequence ; DNA, Single-Stranded/genetics/metabolism ; Deoxyribonucleases/*metabolism ; Guanine/*analysis/metabolism ; Humans ; Repetitive Sequences, Nucleic Acid/genetics ; Telomere/*chemistry/genetics/*metabolism ; },
abstract = {Telomeres terminate in 3' single-stranded G-overhangs that function in telomere end protection and telomerase action. An accurate measurement of overhang length is challenging due to the presence of many kilobases of double-stranded telomere DNA. Here, a simple method is described that utilizes duplex-specific nuclease (DSN) to digest all genomic DNA including telomeres, leaving the single-stranded overhangs intact. The telomere single-strand G-rich overhang length can then be determined by Southern blot-based assays.},
}
@article {pmid21461809,
year = {2011},
author = {Ourliac-Garnier, I and Londoño-Vallejo, A},
title = {Telomere strand-specific length analysis by fluorescent in situ hybridization (Q-CO-FISH).},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {735},
number = {},
pages = {33-46},
doi = {10.1007/978-1-61779-092-8_4},
pmid = {21461809},
issn = {1940-6029},
mesh = {Cells, Cultured ; DNA Replication ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Telomere/*chemistry/metabolism ; },
abstract = {The implementation of quantitative approaches in telomere chromosome-oriented FISH (telomeric CO-FISH) allows the assessment of the relative efficiency of lagging versus leading strand telomere replication and thus provides information on the implicated mechanisms. Here, we describe a simple method for telomere strand-specific analyses and discuss its potential applications.},
}
@article {pmid21461808,
year = {2011},
author = {Ourliac-Garnier, I and Londoño-Vallejo, A},
title = {Telomere length analysis by quantitative fluorescent in situ hybridization (Q-FISH).},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {735},
number = {},
pages = {21-31},
doi = {10.1007/978-1-61779-092-8_3},
pmid = {21461808},
issn = {1940-6029},
mesh = {Cells, Cultured ; Chromosomes/chemistry ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Telomere/*chemistry/metabolism ; },
abstract = {Length is a functional parameter of telomeres, the nucleoprotein structures that protect chromosome ends. The availability of highly specific, high-affinity probes for telomeric repeated sequences allowed the development of quantitative approaches aimed at measuring telomere length directly on chromosomes or in interphase nuclei. Here, we describe a general method for telomere quantitative FISH on metaphase chromosomes and discuss its most common applications in research.},
}
@article {pmid21461807,
year = {2011},
author = {Liu, D},
title = {Analysis of average telomere length in cultured human cells.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {735},
number = {},
pages = {13-19},
doi = {10.1007/978-1-61779-092-8_2},
pmid = {21461807},
issn = {1940-6029},
mesh = {Cells, Cultured ; Eukaryotic Cells/chemistry/enzymology/metabolism ; Humans ; Telomerase/chemistry/metabolism ; Telomere/*chemistry/genetics/*metabolism ; Telomere-Binding Proteins/chemistry/metabolism ; },
abstract = {Telomeres play an important role in ensuring the integrity of the genome. Telomere shortening can lead to the loss of genetic information and trigger DNA damage responses. Cultured mammalian cells have served as critical model systems for studying the function of telomere binding proteins and telomerase. Tremendous heterogeneity can be observed both between species and within a single cell line population. Here, we describe the assay that analyzes the average length of telomeres in cultured cells (TRF analysis).},
}
@article {pmid21461806,
year = {2011},
author = {Songyang, Z},
title = {Introduction to telomeres and telomerase.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {735},
number = {},
pages = {1-11},
doi = {10.1007/978-1-61779-092-8_1},
pmid = {21461806},
issn = {1940-6029},
mesh = {Animals ; Disease ; Humans ; Signal Transduction ; Telomerase/chemistry/*metabolism ; Telomere/chemistry/genetics/*metabolism ; },
abstract = {Telomeres are ends of chromosomes that play an important part in the biology of eukaryotic cells. Through the coordinated action of the telomerase and networks of other proteins and factors, the length and integrity of telomeres are maintained to prevent telomere dysfunction that has been linked to senescence, aging, diseases, and cancer. The tools and assays being used to study telomeres are being broadened, which has allowed us to derive a more detailed, high-resolution picture of the various players and pathways at work at the telomeres.},
}
@article {pmid21460395,
year = {2011},
author = {Gu, J and Chen, M and Shete, S and Amos, CI and Kamat, A and Ye, Y and Lin, J and Dinney, CP and Wu, X},
title = {A genome-wide association study identifies a locus on chromosome 14q21 as a predictor of leukocyte telomere length and as a marker of susceptibility for bladder cancer.},
journal = {Cancer prevention research (Philadelphia, Pa.)},
volume = {4},
number = {4},
pages = {514-521},
pmid = {21460395},
issn = {1940-6215},
support = {CA74880/CA/NCI NIH HHS/United States ; CA127615/CA/NCI NIH HHS/United States ; R01 CA131335/CA/NCI NIH HHS/United States ; CA121197/CA/NCI NIH HHS/United States ; R01 CA131335-04/CA/NCI NIH HHS/United States ; R01 CA121197-04/CA/NCI NIH HHS/United States ; R01 CA111922/CA/NCI NIH HHS/United States ; CA131335/CA/NCI NIH HHS/United States ; CA91846/CA/NCI NIH HHS/United States ; P50 CA091846/CA/NCI NIH HHS/United States ; P50 CA091846-10/CA/NCI NIH HHS/United States ; R01 CA074880/CA/NCI NIH HHS/United States ; U01 CA127615-04/CA/NCI NIH HHS/United States ; U01 CA127615/CA/NCI NIH HHS/United States ; R01 CA074880-10/CA/NCI NIH HHS/United States ; R01 CA121197/CA/NCI NIH HHS/United States ; },
mesh = {Biomarkers, Tumor/blood/*genetics ; Case-Control Studies ; Chromosomes, Human, Pair 14/*genetics ; *Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; Hematologic Tests ; Humans ; *Leukocytes ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*genetics ; Urinary Bladder Neoplasms/*genetics ; },
abstract = {Telomeres play a critical role in maintaining genome integrity. Telomere shortening is associated with the risk of many aging-related diseases. Classic twin studies have shown that genetic components may contribute up to 80% of the heritability of telomere length. In the study we report here that we used a multistage genome-wide association study to identify genetic determinants of telomere length. The mean telomere length in peripheral blood leukocytes was measured by quantitative real-time PCR. We first analyzed 300,000 single-nucleotide polymorphisms (SNPs) in 459 healthy controls, finding 15,120 SNPs associated with telomere length at P < 0.05. We then validated these SNPs in two independent populations comprising 890 and 270 healthy controls, respectively. Four SNPs, including rs398652 on 14q21, were associated with telomere length across all three populations (pooled P values of <10(-5)). The variant alleles of these SNPs were associated with longer telomere length. We then analyzed the association of these SNPs with the risk of bladder cancer in a large case-control study. The variant allele of rs398652 was associated with a significantly reduced risk of bladder cancer (odds ratio = 0.81; 95% confidence interval, 0.67-0.97; P = 0.025), consistent with the correlation of this variant allele with longer telomeres. We then conducted a mediation analysis to examine whether the association between rs398652 and reduced bladder cancer risk is mediated by telomere length, finding that telomere length was a significant mediator of the relationship between rs398652 and bladder cancer (P = 0.013), explaining 14% of the effect. In conclusion, we found that the SNP rs398652 on 14q21 was associated with longer telomere length and a reduced risk of bladder cancer and that a portion of the effect of this SNP on bladder cancer risk was mediated by telomere length.},
}
@article {pmid21460394,
year = {2011},
author = {Blackburn, EH},
title = {Walking the walk from genes through telomere maintenance to cancer risk.},
journal = {Cancer prevention research (Philadelphia, Pa.)},
volume = {4},
number = {4},
pages = {473-475},
doi = {10.1158/1940-6207.CAPR-11-0066},
pmid = {21460394},
issn = {1940-6215},
support = {R01 CA096840/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; *Genetic Predisposition to Disease ; Humans ; Neoplasms/*genetics ; *Polymorphism, Single Nucleotide ; Risk Factors ; Telomere/*genetics/metabolism ; Urinary Bladder Neoplasms/genetics ; },
abstract = {Recent studies have shown associations between human population single-nucleotide polymorphisms (SNP) and white blood cell telomere shortness; independently, telomere shortness has been associated with higher risks of various cancers. However, no single previous study simultaneously linked a given SNP both with telomere length and reduced risk of cancer. In this issue of the journal (beginning on page 514), Gu and colleagues report four new SNPs associated, in three cohorts, with telomere length. One of these SNPs predicted risk for bladder cancer, an effect partially mediated by telomere length. Interventions that could forestall telomere shortening should be explored for their potential to reduce cancer risks.},
}
@article {pmid21460122,
year = {2011},
author = {Jackson, SR and Lee, J and Reddy, R and Williams, GN and Kikuchi, A and Freiberg, Y and Warburton, D and Driscoll, B},
title = {Partial pneumonectomy of telomerase null mice carrying shortened telomeres initiates cell growth arrest resulting in a limited compensatory growth response.},
journal = {American journal of physiology. Lung cellular and molecular physiology},
volume = {300},
number = {6},
pages = {L898-909},
pmid = {21460122},
issn = {1522-1504},
support = {HL44977/HL/NHLBI NIH HHS/United States ; R01 HL065352/HL/NHLBI NIH HHS/United States ; R01S HL44060/HL/NHLBI NIH HHS/United States ; P01 HL60231/HL/NHLBI NIH HHS/United States ; GM096195/GM/NIGMS NIH HHS/United States ; R01 GM096195/GM/NIGMS NIH HHS/United States ; },
mesh = {*Aging ; Animals ; Body Weight ; *Cell Proliferation ; DNA Damage ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Organ Size ; *Pneumonectomy ; Pulmonary Alveoli/*cytology/metabolism ; Signal Transduction ; Stem Cells ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {Telomerase mutations and significantly shortened chromosomal telomeres have recently been implicated in human lung pathologies. Natural telomere shortening is an inevitable consequence of aging, which is also a risk factor for development of lung disease. However, the impact of shortened telomeres and telomerase dysfunction on the ability of lung cells to respond to significant challenge is still largely unknown. We have previously shown that lungs of late generation, telomerase null B6.Cg-Terc(tm1Rdp) mice feature alveolar simplification and chronic stress signaling at baseline, a phenocopy of aged lung. To determine the role telomerase plays when the lung is challenged, B6.Cg-Terc(tm1Rdp) mice carrying shortened telomeres and wild-type controls were subjected to partial pneumonectomy. We found that telomerase activity was strongly induced in alveolar epithelial type 2 cells (AEC2) of the remaining lung immediately following surgery. Eighty-six percent of wild-type animals survived the procedure and exhibited a burst of early compensatory growth marked by upregulation of proliferation, stress response, and DNA repair pathways in AEC2. In B6.Cg-Terc(tm1Rdp) mice carrying shortened telomeres, response to pneumonectomy was characterized by decreased survival, diminished compensatory lung growth, attenuated distal lung progenitor cell response, persistent DNA damage, and cell growth arrest. Overall, survival correlated strongly with telomere length. We conclude that functional telomerase and properly maintained telomeres play key roles in both long-term survival and the early phase of compensatory lung growth following partial pneumonectomy.},
}
@article {pmid21458587,
year = {2011},
author = {Arbuckle, JH and Medveczky, PG},
title = {The molecular biology of human herpesvirus-6 latency and telomere integration.},
journal = {Microbes and infection},
volume = {13},
number = {8-9},
pages = {731-741},
pmid = {21458587},
issn = {1769-714X},
support = {R01 CA111196/CA/NCI NIH HHS/United States ; R01 CA111196-04S1/CA/NCI NIH HHS/United States ; R01 CA111196-05/CA/NCI NIH HHS/United States ; 5R01CA111196/CA/NCI NIH HHS/United States ; },
mesh = {Herpesvirus 6, Human/genetics/*physiology ; Host-Pathogen Interactions ; Humans ; Roseolovirus Infections/*virology ; Telomere/*physiology ; Virus Integration ; Virus Latency ; },
abstract = {The genomes of herpesviruses establish latency as a circular episome. However, Human herpesvirus-6 (HHV-6) has been shown to specifically integrate into the telomeres of chromosomes during latency and vertically transmit through the germ-line. This review will focus on the telomere integration of HHV-6, the potential viral and cellular genes that mediate integration, and the clinical impact on the host.},
}
@article {pmid21449049,
year = {2011},
author = {Kakui, Y and Sato, M and Tanaka, K and Yamamoto, M},
title = {A novel fission yeast mei4 mutant that allows efficient synchronization of telomere dispersal and the first meiotic division.},
journal = {Yeast (Chichester, England)},
volume = {28},
number = {6},
pages = {467-479},
doi = {10.1002/yea.1851},
pmid = {21449049},
issn = {1097-0061},
mesh = {Amino Acid Sequence ; Gene Deletion ; *Meiosis ; Molecular Sequence Data ; Mutant Proteins/genetics/metabolism ; Mutation, Missense ; Schizosaccharomyces/*genetics/*growth &amp; development/radiation effects ; Schizosaccharomyces pombe Proteins/*genetics/*metabolism ; Telomere/*metabolism ; Temperature ; },
abstract = {The progression of meiosis is controlled by a number of gene-expression systems in the fission yeast Schizosaccharomyces pombe. A forkhead-type transcription factor Mei4 activates a number of genes essential for progression from the middle to late stages of meiosis, which include meiosis I, meiosis II and sporulation. The mei4-deletion mutant (mei4Δ) arrests after meiotic prophase and does not enter meiosis I. To further analyse the Mei4 function, we isolated novel temperature-sensitive mei4 alleles. The two alleles isolated in the initial screen turned out to contain a substitution at N136 in the forkhead DNA-binding domain. Among site-directed mutants that carried a point mutation at this position, the mei4-N136A mutant showed the most severe temperature sensitivity. The mei4-N136A mutant arrested before meiosis I at the restrictive temperature, as did the mei4Δ mutant. In fission yeast, the telomeres are clustered at the spindle pole body (SPB) in meiotic prophase and disperse from it at the onset of meiosis I. The mei4Δ mutant was found to arrest with its telomeres clustered at the SPB, demonstrating a role for Mei4 in telomere dispersion. The mei4-N136A mutant also arrested with clustered telomeres at the restrictive temperature, and the clustering was synchronously resolved after a temperature down-shift, indicating that mei4-N136A is a reversible allele. Hence, the mei4-N136A mutant will be a unique tool to synchronize the meiotic cell cycle from meiosis I onwards and may facilitate analyses of cellular activities occurring during meiosis I.},
}
@article {pmid21448457,
year = {2011},
author = {Wolkowitz, OM and Mellon, SH and Epel, ES and Lin, J and Dhabhar, FS and Su, Y and Reus, VI and Rosser, R and Burke, HM and Kupferman, E and Compagnone, M and Nelson, JC and Blackburn, EH},
title = {Leukocyte telomere length in major depression: correlations with chronicity, inflammation and oxidative stress--preliminary findings.},
journal = {PloS one},
volume = {6},
number = {3},
pages = {e17837},
pmid = {21448457},
issn = {1932-6203},
support = {R01 MH083784/MH/NIMH NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; R01-MH083784/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Aged ; Case-Control Studies ; Chronic Disease ; Demography ; Depressive Disorder, Major/blood/diagnosis/*genetics/*pathology ; Female ; Humans ; Inflammation/blood/complications/*pathology ; Interleukin-6/blood ; Leukocytes/*metabolism ; Male ; Middle Aged ; *Oxidative Stress ; Sex Characteristics ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Depression is associated with an unusually high rate of aging-related illnesses and early mortality. One aspect of "accelerated aging" in depression may be shortened leukocyte telomeres. When telomeres critically shorten, as often occurs with repeated mitoses or in response to oxidation and inflammation, cells may die. Indeed, leukocyte telomere shortening predicts early mortality and medical illnesses in non-depressed populations. We sought to determine if leukocyte telomeres are shortened in Major Depressive Disorder (MDD), whether this is a function of lifetime depression exposure and whether this is related to putative mediators, oxidation and inflammation.<br><br>METHODOLOGY: Leukocyte telomere length was compared between 18 unmedicated MDD subjects and 17 controls and was correlated with lifetime depression chronicity and peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio) and inflammation (IL-6). Analyses were controlled for age and sex.<br><br>PRINCIPAL FINDINGS: The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere length was significantly inversely correlated with lifetime depression exposure, even after controlling for age (p<0.05). Average telomere length in the depressed subjects who were above the median of lifetime depression exposure (&#x2265;9.2 years' cumulative duration) was 281 base pairs shorter than that in controls (p<0.05), corresponding to approximately seven years of "accelerated cell aging." Telomere length was inversely correlated with oxidative stress in the depressed subjects (p<0.01) and in the controls (p<0.05) and with inflammation in the depressed subjects (p<0.05).<br><br>CONCLUSIONS: These preliminary data indicate that accelerated aging at the level of leukocyte telomeres is proportional to lifetime exposure to MDD. This might be related to cumulative exposure to oxidative stress and inflammation in MDD. This suggest that telomere shortening does not antedate depression and is not an intrinsic feature. Rather, telomere shortening may progress in proportion to lifetime depression exposure.},
}
@article {pmid21442903,
year = {2011},
author = {Egorov, EE and Zelenin, AV},
title = {[Racing for cell immortality, telomeres, telomerase, and the measure of health (a reflection on the award of the 2009 Demidov Prize in the field of biology given to Alexeĭ Matveevich Olovnikov)].},
journal = {Ontogenez},
volume = {42},
number = {1},
pages = {62-66},
pmid = {21442903},
issn = {0475-1450},
mesh = {Animals ; *Awards and Prizes ; Cell Biology/*history ; Cellular Senescence/*physiology ; History, 20th Century ; History, 21st Century ; Humans ; Russia ; Telomerase/*metabolism ; Telomere/*metabolism ; },
}
@article {pmid21441915,
year = {2011},
author = {Chang, M and Dittmar, JC and Rothstein, R},
title = {Long telomeres are preferentially extended during recombination-mediated telomere maintenance.},
journal = {Nature structural &amp; molecular biology},
volume = {18},
number = {4},
pages = {451-456},
pmid = {21441915},
issn = {1545-9985},
support = {T32 GM008798-11/GM/NIGMS NIH HHS/United States ; CA009503/CA/NCI NIH HHS/United States ; R37 GM050237-19/GM/NIGMS NIH HHS/United States ; R01 GM050237/GM/NIGMS NIH HHS/United States ; T32 GM008798/GM/NIGMS NIH HHS/United States ; GM50237/GM/NIGMS NIH HHS/United States ; R37 GM050237/GM/NIGMS NIH HHS/United States ; T32 CA009503-24/CA/NCI NIH HHS/United States ; T32 CA009503/CA/NCI NIH HHS/United States ; GM008798/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line ; Humans ; *Recombination, Genetic ; Saccharomyces cerevisiae/genetics ; *Telomere ; },
abstract = {Most human somatic cells do not express telomerase. Consequently, with each cell division their telomeres progressively shorten until replicative senescence is induced. Around 15% of human cancers maintain their telomeres using telomerase-independent, recombination-based mechanisms that are collectively termed 'alternative lengthening of telomeres' (ALT). In the yeast Saccharomyces cerevisiae, ALT cells are referred to as 'survivors'. One type of survivor (type II) resembles human ALT cells in that both are defined by the amplification of telomeric repeats. We analyzed recombination-mediated telomere extension events at individual telomeres in telomerase-negative yeast during the formation of type II survivors and found that long telomeres were preferentially extended. Furthermore, senescent cells with long telomeres were more efficient at bypassing senescence by the type II pathway. We speculate that telomere length may be important in determining whether cancer cells use telomerase or ALT to bypass replicative senescence.},
}
@article {pmid21441540,
year = {2011},
author = {Wang, Q and Liu, JQ and Chen, Z and Zheng, KW and Chen, CY and Hao, YH and Tan, Z},
title = {G-quadruplex formation at the 3' end of telomere DNA inhibits its extension by telomerase, polymerase and unwinding by helicase.},
journal = {Nucleic acids research},
volume = {39},
number = {14},
pages = {6229-6237},
pmid = {21441540},
issn = {1362-4962},
mesh = {DNA/chemistry ; DNA Polymerase I/*metabolism ; *G-Quadruplexes ; RecQ Helicases/*metabolism ; Telomerase/*metabolism ; Telomere/*chemistry/metabolism ; },
abstract = {Telomere G-quadruplex is emerging as a promising anti-cancer target due to its inhibition to telomerase, an enzyme expressed in more than 85% tumors. Telomerase-mediated telomere extension and some other reactions require a free 3' telomere end in single-stranded form. G-quadruplex formation near the 3' end of telomere DNA can leave a 3' single-stranded tail of various sizes. How these terminal structures affect reactions at telomere end is not clear. In this work, we studied the 3' tail size-dependence of telomere extension by either telomerase or the alternative lengthening of telomere (ALT) mechanism as well as telomere G-quadruplex unwinding. We show that these reactions require a minimal tail of 8, 12 and 6 nt, respectively. Since we have shown that G-quadruplex tends to form at the farthest 3' distal end of telomere DNA leaving a tail of no more than 5 nt, these results imply that G-quadruplex formation may play a role in regulating reactions at the telomere ends and, as a result, serve as effective drug target for intervening telomere function.},
}
@article {pmid21441303,
year = {2011},
author = {Lian, HY and Robertson, ED and Hiraga, S and Alvino, GM and Collingwood, D and McCune, HJ and Sridhar, A and Brewer, BJ and Raghuraman, MK and Donaldson, AD},
title = {The effect of Ku on telomere replication time is mediated by telomere length but is independent of histone tail acetylation.},
journal = {Molecular biology of the cell},
volume = {22},
number = {10},
pages = {1753-1765},
pmid = {21441303},
issn = {1939-4586},
support = {18926//PHS HHS/United States ; C1445/A10817//Cancer Research UK/United Kingdom ; C1445/A2571//Cancer Research UK/United Kingdom ; G0600774//Medical Research Council/United Kingdom ; },
mesh = {Acetylation ; Acetyltransferases/*metabolism ; Base Sequence ; Cell Cycle ; Cell Cycle Proteins/metabolism ; Chromosomes, Fungal/genetics/metabolism ; *DNA Replication ; DNA-Binding Proteins/genetics/*metabolism ; Histones/*metabolism ; Protein Processing, Post-Translational ; Protein Serine-Threonine Kinases/metabolism ; Replication Origin ; Repressor Proteins/metabolism ; Saccharomyces cerevisiae/*physiology ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Sequence Deletion ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/metabolism ; Time Factors ; },
abstract = {DNA replication in Saccharomyces cerevisiae proceeds according to a temporal program. We have investigated the role of the telomere-binding Ku complex in specifying late replication of telomere-proximal sequences. Genome-wide analysis shows that regions extending up to 80 kb from telomeres replicate abnormally early in a yku70 mutant. We find that Ku does not appear to regulate replication time by binding replication origins directly, nor is its effect on telomere replication timing mediated by histone tail acetylation. We show that Ku instead regulates replication timing through its effect on telomere length, because deletion of the telomerase regulator Pif1 largely reverses the short telomere defect of a yku70 mutant and simultaneously rescues its replication timing defect. Consistent with this conclusion, deleting the genome integrity component Elg1 partially rescued both length and replication timing of yku70 telomeres. Telomere length-mediated control of replication timing requires the TG(1-3) repeat-counting component Rif1, because a rif1 mutant replicates telomeric regions early, despite having extended TG(1-3) tracts. Overall, our results suggest that the effect of Ku on telomere replication timing results from its impact on TG(1-3) repeat length and support a model in which Rif1 measures telomere repeat length to ensure that telomere replication timing is correctly programmed.},
}
@article {pmid21441231,
year = {2011},
author = {Solorio, S and Murillo-Ortíz, B and Hernández-González, M and Guillén-Contreras, J and Arenas-Aranda, D and Solorzano-Zepeda, FJ and Ruiz-Avila, R and Mora-Villalpando, C and de la Roca-Chiapas, JM and Malacara-Hernández, JM},
title = {Association between telomere length and C-reactive protein and the development of coronary collateral circulation in patients with coronary artery disease.},
journal = {Angiology},
volume = {62},
number = {6},
pages = {467-472},
doi = {10.1177/0003319710398007},
pmid = {21441231},
issn = {1940-1574},
mesh = {C-Reactive Protein/*physiology ; Case-Control Studies ; *Collateral Circulation ; Coronary Artery Disease/*genetics/*physiopathology ; Female ; Humans ; Male ; Middle Aged ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Coronary collateral circulation is a stabilizer factor in myocardial ischemia. We attempted to establish a link between collateral circulation, C-reactive protein (CRP), and telomere shortening.<br><br>PATIENTS AND METHODS: A case-control study was performed in patients with (group A) and without (group B) coronary collaterals using coronariography. The patients were males, CRP levels and telomere length in circulating leucocytes were measured; Student t test and logistic regression were used to analyze the data.<br><br>RESULTS: The study included 40 patients aged 53.9 &#xb1; 7.0 years (20 per group). Group A exhibited lower CRP levels (2.76 &#xb1; 3.34 vs 4.04 &#xb1; 3.38; P = .004); whereas telomere length was shorter in group B (2.3 &#xb1; 6.9 kb vs 6.1 &#xb1; 5.9 kb; P < .0001).<br><br>CONCLUSIONS: Collateral circulation was associated with telomere shortening and elevation of CRP levels.},
}
@article {pmid21437559,
year = {2011},
author = {Watfa, G and Dragonas, C and Brosche, T and Dittrich, R and Sieber, CC and Alecu, C and Benetos, A and Nzietchueng, R},
title = {Study of telomere length and different markers of oxidative stress in patients with Parkinson's disease.},
journal = {The journal of nutrition, health &amp; aging},
volume = {15},
number = {4},
pages = {277-281},
pmid = {21437559},
issn = {1760-4788},
mesh = {Aged ; Aging/*physiology ; Biomarkers/analysis ; Case-Control Studies ; Female ; Glutathione/blood ; Humans ; Male ; *Oxidative Stress ; Parkinson Disease/*genetics ; Superoxide Dismutase/metabolism ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Many studies have shown that short telomere length (TL) is associated with high oxidative stress and various age-related diseases. Parkinson's disease (PD) is an age-related disease, and although its pathogenic mechanism is uncertain, oxidative stress is believed to be implicated in this pathology. The aim of this case-control study was to assess both TL and the different markers of oxidative stress in elderly patients with PD compared to age control subjects.<br><br>METHODS: 20 PD patients and 15 age-matched controls, >65 years were studied. TL was measured by Southern blotting from DNA samples extracted from white blood cells. Superoxide dismutase (SOD) activity and plasma levels of total glutathione and protein carbonyls were determined.<br><br>RESULTS: There was a trend for lower TL in PD patients: 6.06 &#xb1; 0.81 kb in PD versus 6.45 &#xb1; 0.73 kb in controls (p = 0.08). No significant difference was found between the two groups in terms of oxidative stress markers. In controls, age was the main determinant of telomere shortening (r = -0.547; p = 0.03) whereas, in PD patients, telomere shortening was mainly dependent on plasmatic concentrations of carbonyl proteins (r= -0.544; p=0.044). In PD patients, a negative association was observed between plasma carbonyl protein levels and SOD activity (r= -0.622, p=0.004).<br><br>CONCLUSIONS: In PD, TL is shorter in presence of high oxidative stress as measured by carbonyl protein levels. The absence of telomere attrition with age among patients with PD could reflect a telomere regulation by mechanisms other than age.},
}
@article {pmid21437267,
year = {2011},
author = {Anbalagan, S and Bonetti, D and Lucchini, G and Longhese, MP},
title = {Rif1 supports the function of the CST complex in yeast telomere capping.},
journal = {PLoS genetics},
volume = {7},
number = {3},
pages = {e1002024},
pmid = {21437267},
issn = {1553-7404},
mesh = {Cell Cycle/genetics ; Cell Survival/genetics ; DNA Damage/genetics ; DNA, Single-Stranded/metabolism ; Mutation/genetics ; Repressor Proteins/genetics/*metabolism ; Saccharomyces cerevisiae/cytology/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Telomere integrity in budding yeast depends on the CST (Cdc13-Stn1-Ten1) and shelterin-like (Rap1-Rif1-Rif2) complexes, which are thought to act independently from each other. Here we show that a specific functional interaction indeed exists among components of the two complexes. In particular, unlike RIF2 deletion, the lack of Rif1 is lethal for stn1ΔC cells and causes a dramatic reduction in viability of cdc13-1 and cdc13-5 mutants. This synthetic interaction between Rif1 and the CST complex occurs independently of rif1Δ-induced alterations in telomere length. Both cdc13-1 rif1Δ and cdc13-5 rif1Δ cells display very high amounts of telomeric single-stranded DNA and DNA damage checkpoint activation, indicating that severe defects in telomere integrity cause their loss of viability. In agreement with this hypothesis, both DNA damage checkpoint activation and lethality in cdc13 rif1Δ cells are partially counteracted by the lack of the Exo1 nuclease, which is involved in telomeric single-stranded DNA generation. The functional interaction between Rif1 and the CST complex is specific, because RIF1 deletion does not enhance checkpoint activation in case of CST-independent telomere capping deficiencies, such as those caused by the absence of Yku or telomerase. Thus, these data highlight a novel role for Rif1 in assisting the essential telomere protection function of the CST complex.},
}
@article {pmid21436892,
year = {2011},
author = {Granick, M and Kimura, M and Kim, S and Daniali, L and Cao, X and Herbig, U and Aviv, A},
title = {Telomere dynamics in keloids.},
journal = {Eplasty},
volume = {11},
number = {},
pages = {e15},
pmid = {21436892},
issn = {1937-5719},
abstract = {OBJECTIVE: Little is known about telomere dynamics in keloids. As keloid formation is dependent on cell replication, in theory telomeres should be shorter in keloids than in normal skin. We examined this concept in the present study.<br><br>METHODS: We measured by Southern blot analysis telomere length in keloids and in adjacent normal skin of 16 individuals. When available, we also measured telomere length in blood (leukocytes) and subcutaneous fat.<br><br>RESULTS: Telomere length was highly variable among individuals but highly correlated among tissues (cells) within the individual. The mean telomere length in the keloids was longer than that in the adjacent normal skin and displayed a length gradient, with the mean length of telomeres shorter just below the epidermis and longer at the base of the keloids. No apparent telomerase activity was detected in the keloids.<br><br>CONCLUSIONS: Our findings suggest a transient activation of telomerase, the reverse transcriptase that prevents telomere shortening, probably during the early phase of keloid formation. The activation of telomerase serves to maintain (or even elongate) telomere length in the keloid. However, telomerase activity is repressed in the fully developed keloid.},
}
@article {pmid21429730,
year = {2011},
author = {Paul, L},
title = {Diet, nutrition and telomere length.},
journal = {The Journal of nutritional biochemistry},
volume = {22},
number = {10},
pages = {895-901},
doi = {10.1016/j.jnutbio.2010.12.001},
pmid = {21429730},
issn = {1873-4847},
mesh = {Animals ; DNA/chemistry ; DNA Methylation ; DNA Repair ; Diet ; Humans ; Nutritional Status/*physiology ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {The ends of human chromosomes are protected by DNA-protein complexes termed telomeres, which prevent the chromosomes from fusing with each other and from being recognized as a double-strand break by DNA repair proteins. Due to the incomplete replication of linear chromosomes by DNA polymerase, telomeric DNA shortens with repeated cell divisions until the telomeres reach a critical length, at which point the cells enter senescence. Telomere length is an indicator of biological aging, and dysfunction of telomeres is linked to age-related pathologies like cardiovascular disease, Parkinson disease, Alzheimer disease and cancer. Telomere length has been shown to be positively associated with nutritional status in human and animal studies. Various nutrients influence telomere length potentially through mechanisms that reflect their role in cellular functions including inflammation, oxidative stress, DNA integrity, DNA methylation and activity of telomerase, the enzyme that adds the telomeric repeats to the ends of the newly synthesized DNA.},
}
@article {pmid21429128,
year = {2011},
author = {Dunshea, G and Duffield, D and Gales, N and Hindell, M and Wells, RS and Jarman, SN},
title = {Telomeres as age markers in vertebrate molecular ecology.},
journal = {Molecular ecology resources},
volume = {11},
number = {2},
pages = {225-235},
doi = {10.1111/j.1755-0998.2010.02976.x},
pmid = {21429128},
issn = {1755-0998},
mesh = {*Aging ; Animals ; Biomarkers/analysis/metabolism ; Humans ; Telomere/chemistry/genetics/*metabolism ; Vertebrates/genetics/*growth &amp; development/*metabolism ; },
abstract = {Chronological age is a fundamental and yet elusive variable in studies of many wild animals. Telomeres are nucleoprotein structures on the ends of chromosomes that change size throughout the life of many animals and because of this property have been advocated as a means to estimate age. In this review, we assess the existing and potential application of using telomeres for age estimation. We argue that there are conceptual and statistical inconsistencies in previous studies and that the basis for telomere change over time is not well understood and affected by several intrinsic and extrinsic process unrelated to chronological time. Furthermore, these processes are likely to vary spatially and temporally for animal populations. We conclude that the current data suggest telomeres should not be used for age estimation. If telomere-based age estimation is to be used, more work in understanding variability in key processes affecting telomere dynamics and rigorous substantiation via blind testing is needed.},
}
@article {pmid21427752,
year = {2011},
author = {Haussmann, MF and Salomons, HM and Verhulst, S},
title = {Telomere measurement tools: Telometric produces biased estimates of telomere length.},
journal = {Heredity},
volume = {107},
number = {4},
pages = {371},
pmid = {21427752},
issn = {1365-2540},
mesh = {Animals ; Computational Biology/*instrumentation/standards ; Genetic Techniques/*instrumentation/standards ; Humans ; *Software ; Telomere/*chemistry/*genetics/metabolism ; },
}
@article {pmid21426483,
year = {2011},
author = {Bernardes de Jesus, B and Schneeberger, K and Vera, E and Tejera, A and Harley, CB and Blasco, MA},
title = {The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence.},
journal = {Aging cell},
volume = {10},
number = {4},
pages = {604-621},
pmid = {21426483},
issn = {1474-9726},
support = {232854/ERC_/European Research Council/International ; },
mesh = {Animals ; Anticarcinogenic Agents/*pharmacology ; Astragalus propinquus/chemistry ; DNA Damage ; Diet ; Embryo, Mammalian/cytology ; Female ; Fibroblasts/drug effects/metabolism ; Mice ; Mice, Inbred C57BL ; Neoplasms/genetics/metabolism/*prevention &amp; control ; RNA/genetics/metabolism ; Telomerase/genetics/*metabolism ; Telomere/*drug effects/metabolism/ultrastructure ; },
abstract = {Here, we show that a small-molecule activator of telomerase (TA-65) purified from the root of Astragalus membranaceus is capable of increasing average telomere length and decreasing the percentage of critically short telomeres and of DNA damage in haploinsufficient mouse embryonic fibroblasts (MEFs) that harbor critically short telomeres and a single copy of the telomerase RNA Terc gene (G3 Terc(+/-) MEFs). Importantly, TA-65 does not cause telomere elongation or rescue DNA damage in similarly treated telomerase-deficient G3 Terc(-/-) littermate MEFs. These results indicate that TA-65 treatment results in telomerase-dependent elongation of short telomeres and rescue of associated DNA damage, thus demonstrating that TA-65 mechanism of action is through the telomerase pathway. In addition, we demonstrate that TA-65 is capable of increasing mouse telomerase reverse transcriptase levels in some mouse tissues and elongating critically short telomeres when supplemented as part of a standard diet in mice. Finally, TA-65 dietary supplementation in female mice leads to an improvement of certain health-span indicators including glucose tolerance, osteoporosis and skin fitness, without significantly increasing global cancer incidence.},
}
@article {pmid21425407,
year = {2011},
author = {Silvestre, DC and Pineda, JR and Hoffschir, F and Studler, JM and Mouthon, MA and Pflumio, F and Junier, MP and Chneiweiss, H and Boussin, FD},
title = {Alternative lengthening of telomeres in human glioma stem cells.},
journal = {Stem cells (Dayton, Ohio)},
volume = {29},
number = {3},
pages = {440-451},
doi = {10.1002/stem.600},
pmid = {21425407},
issn = {1549-4918},
mesh = {Adult ; Aged ; Animals ; Brain Neoplasms/genetics/metabolism/*pathology ; Female ; Glioma/genetics/metabolism/*pathology ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Mice, Transgenic ; Middle Aged ; Neoplastic Stem Cells/*metabolism/pathology ; Telomere/genetics/*metabolism ; Transplantation, Heterologous ; Tumor Cells, Cultured ; },
abstract = {Cancer stem cells are increasingly recognized as major therapeutic targets. We report here the isolation of glioma stem cells (GSCs) maintaining telomere length through a telomerase-independent mechanism known as alternative lengthening of telomeres (ALTs). TG20 cells were isolated from a glioblastoma multiforme, which had the ALT phenotype. They have no detectable telomerase activity and extremely long and heterogeneous telomeres colocalizing with promyelocytic leukemia bodies. The cancer stem cell potential of TG20 cells was confirmed based on their expression of neural stem cell markers, their capacity of in vitro long-term proliferation and to form intracranial tumors in immune-deficient mice. Interestingly, we found that both in vitro and in vivo TG20 cells were significantly more resistant to ionizing radiation than GSCs with telomerase activity. Analysis of DNA damage foci, DNA double-strand breaks repair, and chromosome instability suggest that radiation resistance was related to interference of ALT pathway with DNA damage response. Therefore, our data show for the first time that the ALT pathway can confer to cancer stem cells the capacity to sustain long-term proliferation as telomerase activity and importantly may also affect treatment efficiency. TG20 cells are thus the first cellular model of GSCs displaying ALT and should prove to be useful for the development of specific treatment strategies.},
}
@article {pmid21423765,
year = {2011},
author = {Guo, N and Parry, EM and Li, LS and Kembou, F and Lauder, N and Hussain, MA and Berggren, PO and Armanios, M},
title = {Short telomeres compromise β-cell signaling and survival.},
journal = {PloS one},
volume = {6},
number = {3},
pages = {e17858},
pmid = {21423765},
issn = {1932-6203},
support = {K08 CA118416/CA/NCI NIH HHS/United States ; T32 GM007309/GM/NIGMS NIH HHS/United States ; GM007309/GM/NIGMS NIH HHS/United States ; CA118416/CA/NCI NIH HHS/United States ; R01 AG027406/AG/NIA NIH HHS/United States ; T32 DK007632/DK/NIDDK NIH HHS/United States ; AG27406/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Calcium Signaling/drug effects ; Cell Survival/drug effects ; Cellular Senescence/drug effects ; Diabetes Mellitus/epidemiology/etiology ; Dyskeratosis Congenita/complications ; Endoplasmic Reticulum/drug effects/pathology ; Gene Expression Regulation/drug effects ; Glucose/pharmacology ; Glucose Tolerance Test ; Humans ; Incidence ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/drug effects/*metabolism/*pathology ; Mice ; Mitochondria/drug effects/metabolism ; *Signal Transduction/drug effects/genetics ; Stress, Physiological/drug effects ; Telomere/*pathology ; },
abstract = {The genetic factors that underlie the increasing incidence of diabetes with age are poorly understood. We examined whether telomere length, which is inherited and known to shorten with age, plays a role in the age-dependent increased incidence of diabetes. We show that in mice with short telomeres, insulin secretion is impaired and leads to glucose intolerance despite the presence of an intact β-cell mass. In ex vivo studies, short telomeres induced cell-autonomous defects in β-cells including reduced mitochondrial membrane hyperpolarization and Ca(2+) influx which limited insulin release. To examine the mechanism, we looked for evidence of apoptosis but found no baseline increase in β-cells with short telomeres. However, there was evidence of all the hallmarks of senescence including slower proliferation of β-cells and accumulation of p16(INK4a). Specifically, we identified gene expression changes in pathways which are essential for Ca(2+)-mediated exocytosis. We also show that telomere length is additive to the damaging effect of endoplasmic reticulum stress which occurs in the late stages of type 2 diabetes. This additive effect manifests as more severe hyperglycemia in Akita mice with short telomeres which had a profound loss of β-cell mass and increased β-cell apoptosis. Our data indicate that short telomeres can affect β-cell metabolism even in the presence of intact β-cell number, thus identifying a novel mechanism of telomere-mediated disease. They implicate telomere length as a determinant of β-cell function and diabetes pathogenesis.},
}
@article {pmid21423281,
year = {2011},
author = {Gaeta, RT and Danilova, TV and Zhao, C and Masonbrink, RE and McCaw, ME and Birchler, JA},
title = {Recovery of a telomere-truncated chromosome via a compensating translocation in maize.},
journal = {Genome},
volume = {54},
number = {3},
pages = {184-195},
doi = {10.1139/G10-108},
pmid = {21423281},
issn = {1480-3321},
mesh = {Blotting, Southern ; Chromosomes, Plant/*genetics ; Gene Expression Profiling ; Genetic Engineering/*methods ; In Situ Hybridization, Fluorescence ; Inheritance Patterns/genetics ; Karyotyping ; Pollen/genetics ; Telomere/*genetics ; Transgenes/genetics ; Translocation, Genetic/*genetics ; Zea mays/*genetics ; },
abstract = {Maize-engineered minichromosomes are easily recovered from telomere-truncated B chromosomes but are rarely recovered from A chromosomes. B chromosomes lack known genes, and their truncation products are tolerated and transmitted during meiosis. In contrast, deficiency gametes resulting from truncated A chromosomes prevent their transmission. We report here a de novo compensating translocation that permitted recovery of a large truncation of chromosome 1 in maize. The truncation (trunc-1) and translocation with chromosome 6 (super-6) occurred during telomere-mediated truncation experiments and were characterized using single-gene fluorescent in situ hybridization (FISH) probes. The truncation contained a transgene signal near the end of the broken chromosome and transmitted together with the compensating translocation as a heterozygote to approximately 41%-55% of progeny. Transmission as an addition chromosome occurred in ~15% of progeny. Neither chromosome transmitted through pollen. Transgene expression (Bar) cosegregated with trunc-1 transcriptionally and phenotypically. Meiosis in T1 plants revealed eight bivalents and one tetravalent chain composed of chromosome 1, trunc-1, chromosome 6, and super-6 in diplotene and diakinesis. Our data suggest that de novo compensating translocations allow recovery of truncated A chromosomes by compensating deficiency in female gametes and by affecting chromosome pairing and segregation. The truncated chromosome can be maintained as an extra chromosome or together with the super-6 as a heterozygote.},
}
@article {pmid21421482,
year = {2011},
author = {LIN, L and LI, TP},
title = {[Alteration of telomere length of the peripheral white blood cells in patients with obstructive sleep apnea syndrome].},
journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University},
volume = {31},
number = {3},
pages = {457-460},
pmid = {21421482},
issn = {1673-4254},
mesh = {Adult ; Case-Control Studies ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Sleep Apnea, Obstructive/*blood ; Telomere/*metabolism ; },
abstract = {OBJECTIVE: To study the alteration of telomere length of the peripheral white blood cells in patients with obstructive sleep apnea syndrome (OSAS) and explore its significance.<br><br>METHODS: The DNA was extracted from the peripheral white blood cells of 11 patients with OSAS and 10 normal subjects matched for age and gender, and the T/S ratio was measured by fluorescence quantitative PCR.<br><br>RESULTS: The T/S ratio in the peripheral white blood cells of patients with OSAS was obviously lower than that of the normal subjects (P<0.05).<br><br>CONCLUSION: The reduction in the telomere length in the peripheral blood cells suggests a possible relationship between OSAS pathogenesis and telomere length, and hypoxemia and hypercapnia make accelerate telomere shortening and promote cell apoptosis.},
}
@article {pmid21415081,
year = {2011},
author = {Parry, EM and Alder, JK and Lee, SS and Phillips, JA and Loyd, JE and Duggal, P and Armanios, M},
title = {Decreased dyskerin levels as a mechanism of telomere shortening in X-linked dyskeratosis congenita.},
journal = {Journal of medical genetics},
volume = {48},
number = {5},
pages = {327-333},
pmid = {21415081},
issn = {1468-6244},
support = {T32 GM007309/GM/NIGMS NIH HHS/United States ; T32GM007309/GM/NIGMS NIH HHS/United States ; T32 GM007814/GM/NIGMS NIH HHS/United States ; K08 CA118416/CA/NCI NIH HHS/United States ; K08CA118416/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Cell Cycle Proteins/genetics/*metabolism ; Child ; Dyskeratosis Congenita/*genetics/*metabolism/mortality/pathology ; Genetic Linkage/genetics ; Humans ; Infant ; Infant, Newborn ; Male ; Mutation/genetics ; Nuclear Proteins/genetics/*metabolism ; Pedigree ; Phenotype ; Pulmonary Fibrosis/genetics/metabolism/pathology ; RNA/genetics/metabolism ; Regulatory Elements, Transcriptional/genetics ; Telomerase/genetics/metabolism ; Telomere/*genetics/*metabolism ; X Chromosome Inactivation/genetics ; },
abstract = {Dyskeratosis congenita (DC) is a premature ageing syndrome characterised by short telomeres. An X-linked form of DC is caused by mutations in DKC1 which encodes dyskerin, a telomerase component that is essential for telomerase RNA stability. However, mutations in DKC1 are identifiable in only half of X-linked DC families. A four generation family with pulmonary fibrosis and features of DC was identified. Affected males showed the classic mucocutaneous features of DC and died prematurely from pulmonary fibrosis. Although there were no coding sequence or splicing variants, genome wide linkage analysis of 16 individuals across four generations identified significant linkage at the DKC1 locus, and was accompanied by reduced dyskerin protein levels in affected males. Decreased dyskerin levels were associated with compromised telomerase RNA levels and very short telomeres. These data identify decreased dyskerin levels as a novel mechanism of DC, and indicate that intact dyskerin levels, in the absence of coding mutations, are critical for telomerase RNA stability and for in vivo telomere maintenance.},
}
@article {pmid21407256,
year = {2011},
author = {Smith, S and Turbill, C and Penn, DJ},
title = {Chasing telomeres, not red herrings, in evolutionary ecology.},
journal = {Heredity},
volume = {107},
number = {4},
pages = {372-373},
pmid = {21407256},
issn = {1365-2540},
mesh = {Animals ; *Biological Evolution ; Ecology ; Fishes/*genetics/metabolism ; Telomere/*chemistry/*genetics/metabolism ; },
}
@article {pmid21407239,
year = {2011},
author = {David, R},
title = {Ageing: Mitochondria and telomeres come together.},
journal = {Nature reviews. Molecular cell biology},
volume = {12},
number = {4},
pages = {204},
pmid = {21407239},
issn = {1471-0080},
}
@article {pmid21403893,
year = {2011},
author = {Ludlow, AT and Roth, SM},
title = {Physical activity and telomere biology: exploring the link with aging-related disease prevention.},
journal = {Journal of aging research},
volume = {2011},
number = {},
pages = {790378},
pmid = {21403893},
issn = {2090-2212},
support = {T32 AG000268/AG/NIA NIH HHS/United States ; },
abstract = {Physical activity is associated with reduced risk of several age-related diseases as well as with increased longevity in both rodents and humans. Though these associations are well established, evidence of the molecular and cellular factors associated with reduced disease risk and increased longevity resulting from physical activity is sparse. A long-standing hypothesis of aging is the telomere hypothesis: as a cell divides, telomeres shorten resulting eventually in replicative senescence and an aged phenotype. Several reports have recently associated telomeres and telomere-related proteins to diseases associated with physical inactivity and aging including cardiovascular disease, insulin resistance, and hypertension. Interestingly several reports have also shown that longer telomeres are associated with higher physical activity levels, indicating a potential mechanistic link between physical activity, reduced age-related disease risk, and longevity. The primary purpose of this review is to discuss the potential importance of physical activity in telomere biology in the context of inactivity- and age-related diseases. A secondary purpose is to explore potential mechanisms and important avenues for future research in the field of telomeres and diseases associated with physical inactivity and aging.},
}
@article {pmid21399640,
year = {2011},
author = {Smith, JS and Chen, Q and Yatsunyk, LA and Nicoludis, JM and Garcia, MS and Kranaster, R and Balasubramanian, S and Monchaud, D and Teulade-Fichou, MP and Abramowitz, L and Schultz, DC and Johnson, FB},
title = {Rudimentary G-quadruplex-based telomere capping in Saccharomyces cerevisiae.},
journal = {Nature structural &amp; molecular biology},
volume = {18},
number = {4},
pages = {478-485},
pmid = {21399640},
issn = {1545-9985},
support = {T32 GM07229/GM/NIGMS NIH HHS/United States ; P01 AG031862-03/AG/NIA NIH HHS/United States ; A5709/CRUK_/Cancer Research UK/United Kingdom ; T32 GM007229/GM/NIGMS NIH HHS/United States ; T32 GM008216-22/GM/NIGMS NIH HHS/United States ; P01 AG031862/AG/NIA NIH HHS/United States ; T32 GM008216/GM/NIGMS NIH HHS/United States ; P01 AG031862-02/AG/NIA NIH HHS/United States ; R01 AG021521/AG/NIA NIH HHS/United States ; },
mesh = {Base Sequence ; DNA Primers ; *G-Quadruplexes ; Saccharomyces cerevisiae/*genetics ; *Telomere ; },
abstract = {Telomere capping conceals chromosome ends from exonucleases and checkpoints, but the full range of capping mechanisms is not well defined. Telomeres have the potential to form G-quadruplex (G4) DNA, although evidence for telomere G4 DNA function in vivo is limited. In budding yeast, capping requires the Cdc13 protein and is lost at nonpermissive temperatures in cdc13-1 mutants. Here, we use several independent G4 DNA-stabilizing treatments to suppress cdc13-1 capping defects. These include overexpression of three different G4 DNA binding proteins, loss of the G4 DNA unwinding helicase Sgs1, or treatment with small molecule G4 DNA ligands. In vitro, we show that protein-bound G4 DNA at a 3' overhang inhibits 5'→3' resection of a paired strand by exonuclease I. These findings demonstrate that, at least in the absence of full natural capping, G4 DNA can play a positive role at telomeres in vivo.},
}
@article {pmid21396170,
year = {2011},
author = {Jeon, BG and Kang, EJ and Kumar, BM and Maeng, GH and Ock, SA and Kwack, DO and Park, BW and Rho, GJ},
title = {Comparative analysis of telomere length, telomerase and reverse transcriptase activity in human dental stem cells.},
journal = {Cell transplantation},
volume = {20},
number = {11-12},
pages = {1693-1705},
doi = {10.3727/096368911X565001},
pmid = {21396170},
issn = {1555-3892},
mesh = {Adipocytes/cytology ; Adolescent ; Bone Marrow Cells/cytology ; Cell Differentiation ; Cells, Cultured ; Dental Papilla/cytology ; Dental Pulp/cytology ; Dental Sac/*cytology ; Female ; Humans ; Mesenchymal Stem Cells/cytology/enzymology/metabolism ; Osteocytes/cytology ; RNA-Directed DNA Polymerase/*metabolism ; Stem Cells/cytology/enzymology/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Stem cells from dental tissues have been isolated and established for tooth regenerative applications. However, basic characterization on their biological properties still needs to be investigated before employing them for effective clinical trials. In this study, we compared the telomere length, relative telomerase activity (RTA), and relative reverse transcriptase activity (RRA) as well as the surface antigen profile and mesenchymal differentiation ability in human dental papilla stem cells (DPaSCs), dental pulp stem cells (DPuSCs), and dental follicle stem cells (DFSCs) with mesenchymal stem cells (MSCs) derived from bone marrow. Dental stem cells (DSCs) were strongly positive for cell surface markers, such as CD44 and CD90. However, slightly lower expression of CD105 was observed in DPaSCs and DPuSCs compared to DFSCs and MSCs. Following specific induction, DPaSCs, DFSCs, and MSCs were successfully differentiated into adipocytes and osteocytes. However, DPuSCS, in particular, were able to differentiate into adipocytes but failed to induce into osteogenic differentiation. Further, all DSCs, MSCs, and MRC-5 fibroblasts as control were investigated for telomere length by nonradioactive chemiluminescent assay, RTA by relative-quantitative telomerase repeat amplification protocol (RQ-TRAP), and RRA by PCR-based assay. Mean telomere lengths in DPaSCs, DPuSCs, DFSCs, and MSCs was ∼11 kb, and the values did not differ significantly (p < 0.05) among the cells analyzed. RTA levels in DPaSCs were significantly (p < 0.05) higher than in MSCs, DPuSCs, DFSCs, and MRC-5 fibroblasts and among DSCs, DFSCs showed a significantly (p < 0.05) lower RTA. Moreover, RRA levels were significantly (p < 0.05) higher in DPaSCs, DPuSCs, and MSCs than in DFSCs. Based on these observations, we conclude that among DSCs, DPaSCs possessed ideal characteristics on telomere length, telomerase activity and reverse transcriptase (RTase) activity, and may serve as suitable alternative candidates for regenerative medicine.},
}
@article {pmid21394098,
year = {2011},
author = {Kamranvar, SA and Masucci, MG},
title = {The Epstein-Barr virus nuclear antigen-1 promotes telomere dysfunction via induction of oxidative stress.},
journal = {Leukemia},
volume = {25},
number = {6},
pages = {1017-1025},
pmid = {21394098},
issn = {1476-5551},
mesh = {Cell Line, Tumor ; *Cell Transformation, Viral ; Chromosome Aberrations ; DNA Repair ; Epstein-Barr Virus Nuclear Antigens/*physiology ; Herpesvirus 4, Human/*physiology ; Histones/metabolism ; Humans ; *Oxidative Stress ; Phosphorylation ; Reactive Oxygen Species ; Telomere/*pathology ; },
abstract = {The Epstein-Barr virus (EBV) nuclear antigen (EBNA)-1 promotes the accumulation of chromosomal aberrations in malignant B cells by inducing oxidative stress. Here we report that this phenotype is associated with telomere dysfunction. Stable or conditional expression of EBNA1 induced telomere abnormalities including loss or gain of telomere signals, telomere fusion and heterogeneous length of telomeres. This was accompanied by the accumulation of extrachromosomal telomeres, telomere dysfunction-induced foci (TIFs) containing phosphorylated histone H2AX and the DNA damage response protein 53BP1, telomere-associated promyelocytic leukemia nuclear bodies (APBs), telomeric-sister chromatid exchanges and displacement of the shelterin protein TRF2. The induction of TIFs and APBs was inhibited by treatment with scavengers of reactive oxygen species (ROS) that also promoted the relocalization of TRF2 at telomeres. These findings highlight a novel mechanism by which EBNA1 may promote malignant transformation and tumor progression.},
}
@article {pmid21391375,
year = {2010},
author = {Shukla, S and Acharya, S and Rajput, D and Vagha, S and Grover, S},
title = {Telomere--the twilight to immortality.},
journal = {The Journal of the Association of Physicians of India},
volume = {58},
number = {},
pages = {553-560},
pmid = {21391375},
issn = {0004-5772},
mesh = {Aging/physiology ; Antineoplastic Agents/pharmacology ; Cell Division/genetics/physiology ; *Cell Survival ; Cellular Senescence/*genetics/physiology ; *DNA Replication ; Humans ; Neoplasms/*genetics/ultrastructure ; Telomerase/*metabolism ; Telomere/*physiology ; },
abstract = {Besides forming a very important component of the chromosome, the telomeres have extremely significant modes of action and functions, right from maintaining a basic infrastructure and integrity of the chromosome vis a vis the other chromosomes, telomeres are responsible for the cell divisions and replicative senescence of the cell. The number of mitotic divisions which a cell will go through in its life span while passing through the cell cycle is governed inturn by these telomeres, the crux of the entire functioning of these chromosomal components suggests that they are the ticking clocks of the cell and when they diminish or are worn out so does the cell reach it's senility at the fag end of it's replicative life--resulting fate being--the cell is sent to it's grave yard (the final destination). Clinical implications include--regulation of cell life spans, regulating the cell's replicative behavior and it's utility in forming cells which usually are impossible to divide or replicate, telomeres regulate the cloning process,the telomeres play a major role in predicting the fate of a neoplastic cell and finally enhancing the life span of a single cell, the organ, the body as a whole by enzymes which expand the telomeres--the telomerase.},
}
@article {pmid21388492,
year = {2011},
author = {Yoo, HH and Chung, IK},
title = {Requirement of DDX39 DEAD box RNA helicase for genome integrity and telomere protection.},
journal = {Aging cell},
volume = {10},
number = {4},
pages = {557-571},
doi = {10.1111/j.1474-9726.2011.00696.x},
pmid = {21388492},
issn = {1474-9726},
mesh = {Cell Line, Tumor ; DEAD-box RNA Helicases/genetics/*metabolism ; DNA Damage ; *Genome, Human ; Humans ; RNA Splicing ; RNA, Small Interfering/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; },
abstract = {Human chromosome ends associate with shelterin, a six-protein complex that protects telomeric DNA from being recognized as sites of DNA damage. The shelterin subunit TRF2 has been implicated in the protection of chromosome ends by facilitating their organization into the protective capping structure and by associating with several accessory proteins involved in various DNA transactions. Here we describe the characterization of DDX39 DEAD-box RNA helicase as a novel TRF2-interacting protein. DDX39 directly interacts with the telomeric repeat binding factor homology domain of TRF2 via the FXLXP motif (where X is any amino acid). DDX39 is also found in association with catalytically competent telomerase in cell lysates through an interaction with hTERT but has no effect on telomerase activity. Whereas overexpression of DDX39 in telomerase-positive human cancer cells led to progressive telomere elongation, depletion of endogenous DDX39 by small hairpin RNA (shRNA) resulted in telomere shortening. Furthermore, depletion of DDX39 induced DNA-damage response foci at internal genome as well as telomeres as evidenced by telomere dysfunction-induced foci. Some of the metaphase chromosomes showed no telomeric signal at chromatid ends, suggesting an aberrant telomere structure. Our findings suggest that DDX39, in addition to its role in mRNA splicing and nuclear export, is required for global genome integrity as well as telomere protection and represents a new pathway for telomere maintenance by modulating telomere length homeostasis.},
}
@article {pmid21387278,
year = {2011},
author = {Bozzao, C and Lastella, P and Ponz de Leon, M and Pedroni, M and Di Gregorio, C and D'Ovidio, FD and Resta, N and Prete, F and Guanti, G and Stella, A},
title = {Analysis of telomere dynamics in peripheral blood cells from patients with Lynch syndrome.},
journal = {Cancer},
volume = {117},
number = {18},
pages = {4325-4335},
doi = {10.1002/cncr.26022},
pmid = {21387278},
issn = {1097-0142},
mesh = {Adaptor Proteins, Signal Transducing/*genetics ; Adult ; Age of Onset ; Aged ; Colorectal Neoplasms, Hereditary Nonpolyposis/blood/*genetics ; DNA Mismatch Repair/*genetics ; Female ; Heterozygote ; Humans ; Male ; Middle Aged ; MutL Protein Homolog 1 ; MutS Homolog 2 Protein/*genetics ; Mutation ; Nuclear Proteins/*genetics ; Pedigree ; Telomere/*pathology ; },
abstract = {BACKGROUND: In patients with Lynch syndrome, germline mutations in DNA mismatch repair (MMR) genes cause a high risk of developing a broad spectrum of cancers. To date, the management of patients with Lynch syndrome has represented a major challenge because of large variations in age at cancer onset. Several factors, including genetic anticipation, have been proposed to explain this phenotypic heterogeneity, but the molecular mechanisms remain unknown. Telomere shortening is a common event in tumorigenesis and also has been observed in different familial cancers. In this study, the authors investigated the possibility of a relation between telomere length and cancer onset in patients with Lynch syndrome.<br><br>METHODS: The mean telomere length was measured using quantitative polymerase chain reaction in peripheral blood samples from a control group of 50 individuals, from 31 unaffected mutation carriers, and from 43 affected patients, and the results were correlated with both gene mutation and cancer occurrence. In affected patients, telomere attrition was correlated with age at cancer onset. In all patients, a t test was used to assess the linearity of the regression.<br><br>RESULTS: A significant correlation between telomere length and age was observed in both affected and unaffected mutation carriers (P = .0016 and P = .004, respectively) and in mutS homolog 2 (MSH2) mutation carriers (P = .0002) but not in mutL homolog 1 (MLH1) mutation carriers. Telomere attrition was correlated significantly with age at onset in MSH2 carriers (P = .004), whereas an opposite trend toward longer telomeres in patients with delayed onset was observed in MLH1 carriers.<br><br>CONCLUSIONS: The current data suggested that telomere dynamics differ between MLH1 and MSH2 mutation carriers. It is possible that subtle, gene-specific mechanisms can be linked to cancer onset and anticipation in patients with Lynch syndrome.},
}
@article {pmid21387275,
year = {2011},
author = {Liu, J and Yang, Y and Zhang, H and Zhao, S and Liu, H and Ge, N and Yang, H and Xing, JL and Chen, Z},
title = {Longer leukocyte telomere length predicts increased risk of hepatitis B virus-related hepatocellular carcinoma: a case-control analysis.},
journal = {Cancer},
volume = {117},
number = {18},
pages = {4247-4256},
doi = {10.1002/cncr.26015},
pmid = {21387275},
issn = {1097-0142},
mesh = {Aged ; Alcohol Drinking ; Carcinoma, Hepatocellular/complications/*genetics ; Case-Control Studies ; Female ; Hepatitis B/*complications ; Humans ; Leukocytes/ultrastructure ; Liver Neoplasms/complications/*genetics ; Male ; Middle Aged ; Risk Factors ; Smoking ; Telomere/*pathology ; },
abstract = {BACKGROUND: Convincing evidence has indicated that an alteration in telomere length is involved in tumorigenesis. In epidemiologic studies, a strong correlation also has been observed consistently between relative telomere length (RTL) in peripheral blood leukocytes (PBLs) and susceptibility of many cancers. However, whether leukocyte RTL can be used as a predictor of risk for hepatocellular carcinoma (HCC) remains to be determined.<br><br>METHODS: The RTL in PBLs was determined by measuring the telomere repeat copy number to single-copy gene number ratio in each sample compared with a reference DNA sample using a polymerase chain reaction-based method in this case-control study. The study participants included 240 patients with HCC (cases), a group of 240 healthy individuals (controls), and 120 noncancer controls with chronic liver disease (CLD).<br><br>RESULTS: HCC cases exhibited a significantly longer RTL (median, 0.57; range, 0.21-3.3) than CLD controls (median, 0.46; range, 0.15-1.99; P < .001) and healthy controls (median, 0.39; range, 0.13-2.69; P < .001). Compared with individuals who had short RTL, individuals who had long RTL had a significantly increased risk of HCC when either healthy controls (adjusted odds ratio [OR], 7.28; 95% confidence interval, 4.46-11.88) or CLD controls (adjusted OR, 2.86; 95% confidence interval, 1.74-4.70) were used as the reference group. A significant dose-response relation was observed between HCC risk and long RTL (P(trend) < .001 for both control groups). In addition, there was a significantly positive RTL correlation between PBLs and normal liver tissues (r = 0.78; P < .001) or cirrhotic liver tissues (r = 0.67; P = .001). Furthermore, a significant joint effect on the risk of HCC was noted between RTL and smoking status or alcohol use.<br><br>CONCLUSIONS: The current study produced the first epidemiologic evidence linking long RTL in PBLs to an increased risk of HCC. The authors concluded that these findings warrant further investigation in other populations.},
}
@article {pmid21386659,
year = {2011},
author = {Dubruille, R and Loppin, B},
title = {Epigenetic maintenance of telomere identity in Drosophila: buckle up for the sperm ride.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {10},
number = {7},
pages = {1037-1042},
doi = {10.4161/cc.10.7.15071},
pmid = {21386659},
issn = {1551-4005},
mesh = {Animals ; Chromatin Assembly and Disassembly/*genetics ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; Drosophila/genetics/metabolism ; Drosophila Proteins/genetics/metabolism ; Epigenesis, Genetic/*genetics ; Fertilization/*genetics/physiology ; Male ; Spermatogenesis/*genetics/physiology ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {A critical function of telomeres is to prevent the ligation of chromosome ends by DNA repair enzymes. In most eukaryotes, telomeric DNA consists in large arrays of G-rich tandem repeats that are recognized by DNA binding capping proteins. Drosophila telomeres are unusual as they lack short tandem repeats. However, Drosophila capping proteins can bind chromosome extremities in a DNA sequence-independent manner. This epigenetic protection of fly telomeres has been essentially studied in somatic cells where capping proteins such as HOAP or HP1 are essential in preventing chromosome end-to-end fusions. HipHop and K81 are two recently identified paralogous capping proteins with complementary expression patterns. While HipHop is involved in telomere capping in somatic cells, K81 has specialized in the protection of telomeres in post-meiotic male germ cells. Remarkably, K81 is required for the stabilization of HOAP and HP1 at telomeres during the massive paternal chromatin remodeling that occurs during spermiogenesis and at fertilization. We thus propose that the maintenance of capping proteins at Drosophila sperm telomeres is crucial for the transmission of telomere identity to the diploid zygote. :},
}
@article {pmid21385798,
year = {2012},
author = {Humphreys, J and Epel, ES and Cooper, BA and Lin, J and Blackburn, EH and Lee, KA},
title = {Telomere shortening in formerly abused and never abused women.},
journal = {Biological research for nursing},
volume = {14},
number = {2},
pages = {115-123},
pmid = {21385798},
issn = {1552-4175},
support = {UL1 RR024131/RR/NCRR NIH HHS/United States ; UL1 RR024131-02/RR/NCRR NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Base Sequence ; Biomarkers ; Case-Control Studies ; DNA Primers ; *Domestic Violence ; Female ; Humans ; Middle Aged ; Polymerase Chain Reaction ; *Telomere ; Young Adult ; },
abstract = {Recent studies suggest that chronic psychological stress may accelerate aging at the cellular level. Telomeres are protective components that stabilize the ends of chromosomes and modulate cellular aging. Women exposed to intimate partner violence (IPV) experience chronic stress and report worse health. The purpose of this exploratory study was to examine telomeric DNA length in women who have experienced chronic stress related to IPV. We hypothesized that IPV exposure would be associated with shorter telomere length. The investigation used a cross-sectional design to study telomere length in women with a history of IPV exposure and control women who reported no prior exposure to IPV. Advertisements and public notices were used to recruit a convenience sample of healthy women. Mean leukocyte telomere length was measured in DNA samples from peripheral blood mononuclear cells (PBMCs) by a quantitative polymerase chain reaction assay (qPCR). Telomere length was significantly shorter in the 61 formerly abused women compared to the 41 controls (t = 2.4, p = .02). Length of time in the abusive relationship and having children were associated with telomere length after controlling for age and body mass index (BMI) (F(2, 99) = 10.23, p < .001). Numerous studies suggest that women who experience IPV have poorer overall health. It is often presumed that the stress of IPV may be causing greater morbidity. Findings from this descriptive study suggest a link between IPV exposure, duration of IPV-related stress, and telomere length molecular mechanisms that regulate cellular aging.},
}
@article {pmid21385157,
year = {2011},
author = {Mehdipour, P and Kheirollahi, M and Mehrazin, M and Kamalian, N and Atri, M},
title = {Evolutionary hypothesis of telomere length in primary breast cancer and brain tumour patients: a tracer for genomic-tumour heterogeneity and instability.},
journal = {Cell biology international},
volume = {35},
number = {9},
pages = {915-925},
doi = {10.1042/CBI20100560},
pmid = {21385157},
issn = {1095-8355},
mesh = {Aged ; Brain Neoplasms/*genetics ; Breast Neoplasms/*genetics ; Evolution, Molecular ; Female ; Fluorescent Antibody Technique ; *Genetic Heterogeneity ; *Genome, Human ; *Genomic Instability ; Genomics ; Humans ; Middle Aged ; Telomere/*metabolism/ultrastructure ; Telomere Homeostasis/genetics ; },
abstract = {It was previously reported that tumour samples had shorter telomeres than the surrounding normal tissue. Hereby, the initial sign of correlation between malignant tissue and telomere behaviour could be noticed. Bridging knowledge between germ and somatic cells could facilitate understanding cellular evolution. The aim of our investigation was to provide evidence for the evolutionary hypothesis of TL (telomere length) in primary BC (breast cancer) and BTs (brain tumours), which might be applied as a prognostic and/or predictive marker. DNA extraction from the frozen tissues was performed using high pure PCR template preparation kit. Standard protocol of Telo TTAGGG Telomere Length Assay kit, a non-radioactive chemiluminescent assay, was used. The protein expression in extracted cells was analysed by immunofluorescence. We also detected telomerase activity. The G/T (genomic/tumour ratio) for TL in two groups of patients affected with primary BC and primary BT revealed significant differences in both BC patients (P = 0.025) and in BTs (P = 0.001). The pattern of telomere signals by Q-FISH (quantitative fluorescent in situ hybridization) show that in all samples, except one, SI (signal intensity) has been significantly decreased in tissue related to blood, either in BC patients or in patients with BTs (0.041≥P≥0.001). However, the data achieved by Q-FISH support the results of Southern blot. These data reflect a significant diversity either in BC or in BT patients, providing evidence for the evolutionary hypothesis of TL in cancer development and progression.},
}
@article {pmid21383184,
year = {2011},
author = {Gao, G and Cheng, Y and Wesolowska, N and Rong, YS},
title = {Paternal imprint essential for the inheritance of telomere identity in Drosophila.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {108},
number = {12},
pages = {4932-4937},
pmid = {21383184},
issn = {1091-6490},
support = {//Intramural NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; Chromatin Assembly and Disassembly/*physiology ; Chromosomes, Insect/genetics/*metabolism ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster ; Embryo, Nonmammalian ; Evolution, Molecular ; *Genomic Imprinting ; Male ; Sperm Maturation/*physiology ; Telomere/genetics/*metabolism ; },
abstract = {Chromatin remodeling during sperm maturation could erase epigenetic landmarks on the paternal genome, creating a challenge for its reestablishment on fertilization. Here, we show that selective retention of a chromosomal protein in mature sperm protects the identity of paternal telomeres in Drosophila. The ms(3)k81 (k81) gene is a duplication of hiphop that encodes a telomeric protein. Although HipHop protects telomeres in somatic cells, K81 is produced exclusively in males and localizes to telomeres in postmitotic cells, including mature sperm. In embryos fathered by k81 mutants, the maternal supplies fail to reestablish a protective cap on paternal telomeres, leading to their fusions. These fusions hinder the segregation of the paternal genome and result in haploid embryos with maternal chromosomes. The functional divergence between hiphop and k81 manifests not only in their expression patterns but also in the protein functions that they encode. By swapping the two coding regions, we show that K81 can replace HipHop for somatic protection; however, HipHop cannot replace K81 in the germ line to specify telomere identity, because HipHop ectopically expressed in the testis is removed from chromatin during sperm maturation. HipHop lacks a short motif in K81 that is essential for K81 to survive the remodeling process. We show that the combined functions of HipHop and K81 are likely fulfilled by the single ancestral hiphop locus in other Drosophila species, supporting the hypothesis that the evolutionary process of subfunctionalization was responsible for the preservation of the hiphop-k81 duplicate.},
}
@article {pmid21383055,
year = {2011},
author = {Kaufer, BB and Jarosinski, KW and Osterrieder, N},
title = {Herpesvirus telomeric repeats facilitate genomic integration into host telomeres and mobilization of viral DNA during reactivation.},
journal = {The Journal of experimental medicine},
volume = {208},
number = {3},
pages = {605-615},
pmid = {21383055},
issn = {1540-9538},
support = {R01 CA127238/CA/NCI NIH HHS/United States ; 5R01CA127238/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Chickens/genetics/virology ; DNA, Viral/*genetics/physiology ; Herpesviridae/genetics/*physiology ; Herpesvirus 2, Gallid/genetics/physiology ; Marek Disease/genetics/virology ; Mutation/genetics/physiology ; Repetitive Sequences, Nucleic Acid/*genetics/physiology ; Telomere/*genetics/physiology ; Virus Activation/*genetics/physiology ; Virus Integration/*genetics/physiology ; },
abstract = {Some herpesviruses, particularly lymphotropic viruses such as Marek's disease virus (MDV) and human herpesvirus 6 (HHV-6), integrate their DNA into host chromosomes. MDV and HHV-6, among other herpesviruses, harbor telomeric repeats (TMRs) identical to host telomeres at either end of their linear genomes. Using MDV as a natural virus-host model, we show that herpesvirus TMRs facilitate viral genome integration into host telomeres and that integration is important for establishment of latency and lymphoma formation. Integration into host telomeres also aids in reactivation from the quiescent state of infection. Our results and the presence of TMRs in many herpesviruses suggest that integration mediated by viral TMRs is a conserved mechanism, which ensures faithful virus genome maintenance in host cells during cell division and allows efficient mobilization of dormant viral genomes. This finding is of particular importance as reactivation is critical for virus spread between susceptible individuals and is necessary for continued herpesvirus evolution and survival.},
}
@article {pmid21382885,
year = {2011},
author = {Sanders, JL and Iannaccone, A and Boudreau, RM and Conley, YP and Opresko, PL and Hsueh, WC and Cummings, SR and Cawthon, RM and Harris, TB and Nalls, MA and Kritchevsky, SB and Newman, AB and , },
title = {The association of cataract with leukocyte telomere length in older adults: defining a new marker of aging.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {66},
number = {6},
pages = {639-645},
pmid = {21382885},
issn = {1758-535X},
support = {P30 AG024827/AG/NIA NIH HHS/United States ; 5U19AG023122-05/AG/NIA NIH HHS/United States ; N01-AG-6-2101/AG/NIA NIH HHS/United States ; K23 EY000409/EY/NEI NIH HHS/United States ; N01-AG-6-2103/AG/NIA NIH HHS/United States ; N01 AG62101/AG/NIA NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; N01-AG-6-2106/AG/NIA NIH HHS/United States ; N01 AG62103/AG/NIA NIH HHS/United States ; N01 AG62106/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; *Aging ; Biomarkers ; Cataract ; Cataract Extraction/statistics &amp; numerical data ; Female ; Humans ; Leukocytes/*ultrastructure ; Male ; *Telomere ; },
abstract = {Lens transparency, or the magnitude of cataract severity, is a potential in vivo marker of aging distinguishable from diagnosed cataract. To explore lens transparency as a marker of aging, we determined its association with leukocyte telomere length (LTL) measured with quantitative polymerase chain reaction. Cataract severity was directly measured in 259 participants, and prevalent cataract and incident cataract surgery were ascertained in 2,750 participants of the Health, Aging, and Body Composition Study. LTL was unassociated with clinical cataract outcomes. Six of 259 had successfully aged lenses and a mean LTL of 5,700 bp, whereas 253/259 with poorly aged lenses had a mean LTL of 4,770 bp. Participants with a 1,000 bp greater mean LTL had nearly half the odds of any cataract (odds ratio = 0.47, 95% confidence interval 0.22-1.02) after adjustment. Lens transparency might be associated with longer LTL in community-dwelling older adults and should be investigated further as a possible biomarker of aging.},
}
@article {pmid21372300,
year = {2011},
author = {Huzen, J and Peeters, W and de Boer, RA and Moll, FL and Wong, LS and Codd, V and de Kleijn, DP and de Smet, BJ and van Veldhuisen, DJ and Samani, NJ and van Gilst, WH and Pasterkamp, G and van der Harst, P},
title = {Circulating leukocyte and carotid atherosclerotic plaque telomere length: interrelation, association with plaque characteristics, and restenosis after endarterectomy.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {31},
number = {5},
pages = {1219-1225},
doi = {10.1161/ATVBAHA.110.217158},
pmid = {21372300},
issn = {1524-4636},
mesh = {Aged ; Carotid Stenosis/blood/genetics/immunology/pathology/*surgery ; Case-Control Studies ; Chi-Square Distribution ; Endarterectomy, Carotid/*adverse effects ; Female ; Humans ; Immunohistochemistry ; Leukocytes/*immunology ; Linear Models ; Logistic Models ; Male ; Netherlands ; Odds Ratio ; Polymerase Chain Reaction ; Recurrence ; Risk Assessment ; Risk Factors ; Telomere/*ultrastructure ; Time Factors ; Treatment Outcome ; },
abstract = {OBJECTIVE: Shorter leukocyte telomeres are associated with atherosclerosis and predict future heart disease. The goal of the present study was to determine whether leukocyte telomere length is related to atherosclerotic plaque telomere length and whether it is associated with plaque characteristics or recurrence of disease.<br><br>METHODS AND RESULTS: Telomere length was measured by real-time quantitative polymerase chain reaction in atherosclerotic plaques and leukocytes in patients with carotid atherosclerosis undergoing carotid endarterectomy (n=684) and of leukocytes in age- and gender-balanced subjects without clinical atherosclerosis (n=780). Leukocyte telomere length was shorter in patients versus controls (0.99 [interquartile range (IQR): 0.79 to 1.26] versus 1.06 [0.80 to 1.39]; P=0.0007). Plaque telomeres were longer than leukocyte telomeres (1.42 [IQR: 1.21 to 1.77] versus 1.01 [IQR: 0.75 to 1.34]; P<1.00&#xd7;10(-6)) and independent of age. Leukocyte and plaque telomere length were only weakly correlated (correlation coefficient r2=0.04, P=0.03). Patients, whose plaques showed marked macrophage infiltration and large lipid core, had longer plaque telomeres (1.61 [IQR: 1.32 to 2.04] versus 1.40 [IQR: 1.15 to 1.57]; P=0.006) and shorter leukocyte telomeres (0.88 [IQR: 0.75 to 1.20] versus 1.03 [IQR: 0.83 to 1.34]; P=0.02). Plaque telomere length was associated with restenosis 1 year after endarterectomy (OR 1.58&#xb1;0.206; P=0.026 per SD decrease of plaque telomere length).<br><br>CONCLUSIONS: Leukocyte telomere length is associated with the presence of atherosclerotic carotid plaques but is not a proxy for local plaque telomere length. Plaque telomere length is related to plaque characteristics and development of restenosis following endarterectomy.},
}
@article {pmid21371125,
year = {2011},
author = {Buckingham, EM and Klingelhutz, AJ},
title = {The role of telomeres in the ageing of human skin.},
journal = {Experimental dermatology},
volume = {20},
number = {4},
pages = {297-302},
pmid = {21371125},
issn = {1600-0625},
support = {R01 AG027388/AG/NIA NIH HHS/United States ; R01AG27388/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Humans ; Oxidative Stress ; Skin/physiopathology ; Skin Aging/genetics/*physiology ; Telomerase/genetics/*physiology ; Telomere/enzymology/genetics/*physiology ; },
abstract = {Skin is a self-renewing tissue that is required to go through extensive proliferation throughout the lifespan of an organism. Telomere shortening acts as a mitotic clock that prevents aberrant proliferation such as cancer. A consequence of this protection is cellular senescence and ageing. The telomerase enzyme complex maintains telomere length in germline cells and in cancer cells. Telomerase is also active in certain somatic cells such as those in the epidermis but is almost undetectable in the dermis. Increasing evidence indicates that telomerase plays a significant role in maintenance of skin function and proliferation. Mutations in telomerase component genes in the disease dyskeratosis congenita result in numerous epidermal abnormalities. Studies also indicate that telomerase activity in epidermal stem cells might have roles that go beyond telomere elongation. Telomeres in skin cells may be particularly susceptible to accelerated shortening because of both proliferation and DNA-damaging agents such as reactive oxygen species. Skin might present an accessible tissue for manipulation of telomerase activity and telomere length with the potential of ameliorating skin diseases associated with ageing.},
}
@article {pmid21369674,
year = {2011},
author = {Maeda, T and Oyama, JI and Sasaki, M and Arima, T and Makino, N},
title = {The correlation between the clinical laboratory data and the telomere length in peripheral blood leukocytes of Japanese female patients with hypertension.},
journal = {The journal of nutrition, health &amp; aging},
volume = {15},
number = {3},
pages = {240-244},
pmid = {21369674},
issn = {1760-4788},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*blood ; Amlodipine/therapeutic use ; Antihypertensive Agents/therapeutic use ; Blotting, Southern ; Creatinine/blood ; Cross-Sectional Studies ; Female ; Humans ; Hypertension/blood/drug therapy/*genetics ; Japan ; Leukocytes ; Methylation ; Middle Aged ; Telomere/*chemistry/genetics ; },
abstract = {OBJECTIVE: This study investigated the correlation between the chronological age, telomere length in peripheral blood leukocytes and blood laboratory data of female patients with mild hypertension to identify laboratory data that reflect the biological aging of individuals.<br><br>DESIGN: Cross-sectional population-based study.<br><br>SETTING: Outpatient clinic of the Department of Cardiovascular, Respiratory, and Geriatric Medicine Kyushu University Hospital at Beppu in Japan.<br><br>PARTICIPANTS: Outpatients with mild hypertension treated with a low dose of amlodipine.<br><br>MEASUREMENTS: The laboratory data of female patients were collected and the telomere length parameters in their peripheral blood leukocytes were determined by Southern blotting. Any correlations between the laboratory data and the telomere length parameters were assessed.<br><br>RESULTS: The patients showed a positive correlation between the telomere length and the high density lipoprotein, albumin, creatinine, hemoglobin levels, red blood cell counts, and a negative correlation with the globulin level. The extent of subtelomeric methylation of long telomeres tended to correlate negatively with the telomeric attrition. Only the creatinine level correlated with subtelomeric methylation, but not with telomeric length.<br><br>CONCLUSION: HDL and the albumin/globulin ratio were potential indicators for individual somatic genomic aging. Creatinine may therefore be a useful indicator for a predisposition for telomeric attrition.},
}
@article {pmid21369534,
year = {2011},
author = {O'Callaghan, NJ and Fenech, M},
title = {A quantitative PCR method for measuring absolute telomere length.},
journal = {Biological procedures online},
volume = {13},
number = {},
pages = {3},
pmid = {21369534},
issn = {1480-9222},
abstract = {We describe a simple and reproducible method to measure absolute telomere length (aTL) using quantitative real-time polymerase chain reaction (qPCR). This method is based on the Cawthon method for relative measurement of telomere length (TL) but modified by introducing an oligomer standard to measure aTL. The method describes the oligomer standards, the generation of the standard curve and the calculations required to calculate aTL from the qPCR data. The necessary controls and performance characteristics of the assay are described in detail and compared relative to other methods for measuring TL. Typical results for this assay for a variety of human tissue samples are provided as well as a troubleshooting schedule. This method allows high throughput measurement of aTL using small amounts of DNA making it amenable for molecular epidemiological studies. Compared to the traditional relative TL qPCR assays, the aTL method described in this protocol enables a more direct comparison of results between experiments within and between laboratories.},
}
@article {pmid21365170,
year = {2011},
author = {Nzietchueng, R and Elfarra, M and Nloga, J and Labat, C and Carteaux, JP and Maureira, P and Lacolley, P and Villemot, JP and Benetos, A},
title = {Telomere length in vascular tissues from patients with atherosclerotic disease.},
journal = {The journal of nutrition, health &amp; aging},
volume = {15},
number = {2},
pages = {153-156},
pmid = {21365170},
issn = {1760-4788},
mesh = {Aged ; Aged, 80 and over ; Aging/pathology ; Arteriosclerosis/blood ; Atherosclerosis/blood/*pathology ; Biomarkers/blood ; Case-Control Studies ; Female ; Humans ; Male ; Middle Aged ; Oxidative Stress ; Plaque, Atherosclerotic/blood/*pathology ; Risk Factors ; Telomere/*chemistry ; },
abstract = {OBJECTIVES: The present study was aimed at evaluating telomere length in blood and in different vascular tissues with or without atheroma, in 3 groups of subjects: a group of atherosclerotic subjects who underwent surgery (Atherosclerosis-Surgery), a second group of subjects with asymptomatic atherosclerotic carotid plaques but who did not undergo cardiovascular surgery (Atherosclerosis-No surgery), and a third group of subjects without atherosclerotic disease (Controls). The main objective was to determine if there is in vivo regulation of telomere length in situ by atherosclerotic lesions.<br><br>METHODS: A total of 84 subjects (mean age 69 &#xb1; 8 years) were studied. Blood and arterial tissue telomere lengths were determined by Southern blotting. Personal medical history (diabetes, hypertension, cardiovascular disease, dyslipidemia), family medical history, drug intake, and lifestyle were evaluated in the entire population through the use of a questionnaire.<br><br>RESULTS AND CONCLUSION: Arterial segments which did not develop atherosclerosis such as the saphenous vein and internal mammary artery, had longer telomere length than aortic segments. On the other hand, telomere length was shorter in aortic tissues which presented atherosclerotic lesions compared to corresponding tissues without atherosclerotic lesions. These results also suggest tissue regulation of telomere size by local factors likely related to oxidative stress responses.},
}
@article {pmid21364961,
year = {2011},
author = {von Figura, G and Wagner, M and Nalapareddy, K and Hartmann, D and Kleger, A and Guachalla, LM and Rolyan, H and Adler, G and Rudolph, KL},
title = {Regeneration of the exocrine pancreas is delayed in telomere-dysfunctional mice.},
journal = {PloS one},
volume = {6},
number = {2},
pages = {e17122},
pmid = {21364961},
issn = {1932-6203},
mesh = {Animals ; Cell Division/genetics ; Cellular Senescence/genetics ; DNA Damage/genetics/physiology ; Mice ; Mice, Knockout ; Pancreas, Exocrine/metabolism/*physiology ; RNA/genetics ; Regeneration/*genetics/physiology ; Telomerase/*genetics/metabolism/physiology ; Telomere/genetics/*metabolism/pathology/physiology ; Time Factors ; Tumor Suppressor Protein p53/genetics/metabolism/physiology ; },
abstract = {INTRODUCTION: Telomere shortening is a cell-intrinsic mechanism that limits cell proliferation by induction of DNA damage responses resulting either in apoptosis or cellular senescence. Shortening of telomeres has been shown to occur during human aging and in chronic diseases that accelerate cell turnover, such as chronic hepatitis. Telomere shortening can limit organ homeostasis and regeneration in response to injury. Whether the same holds true for pancreas regeneration in response to injury is not known.<br><br>METHODS: In the present study, pancreatic regeneration after acute cerulein-induced pancreatitis was studied in late generation telomerase knockout mice with short telomeres compared to telomerase wild-type mice with long telomeres.<br><br>RESULTS: Late generation telomerase knockout mice exhibited impaired exocrine pancreatic regeneration after acute pancreatitis as seen by persistence of metaplastic acinar cells and markedly reduced proliferation. The expression levels of p53 and p21 were not significantly increased in regenerating pancreas of late generation telomerase knockout mice compared to wild-type mice.<br><br>CONCLUSION: Our results indicate that pancreatic regeneration is limited in the context of telomere dysfunction without evidence for p53 checkpoint activation.},
}
@article {pmid21364951,
year = {2011},
author = {Horn, T and Robertson, BC and Will, M and Eason, DK and Elliott, GP and Gemmell, NJ},
title = {Inheritance of telomere length in a bird.},
journal = {PloS one},
volume = {6},
number = {2},
pages = {e17199},
pmid = {21364951},
issn = {1932-6203},
mesh = {Aging/genetics/metabolism ; Animals ; Birds/genetics/physiology ; Female ; Heredity ; Inheritance Patterns/genetics/*physiology ; Male ; Psittaciformes/*genetics/physiology ; Sex Characteristics ; Telomere/*genetics/metabolism ; },
abstract = {Telomere dynamics are intensively studied in human ageing research and epidemiology, with many correlations reported between telomere length and age-related diseases, cancer and death. While telomere length is influenced by environmental factors there is also good evidence for a strong heritable component. In human, the mode of telomere length inheritance appears to be paternal and telomere length differs between sexes, with females having longer telomeres than males. Genetic factors, e.g. sex chromosomal inactivation, and non-genetic factors, e.g. antioxidant properties of oestrogen, have been suggested as possible explanations for these sex-specific telomere inheritance and telomere length differences. To test the influence of sex chromosomes on telomere length, we investigated inheritance and sex-specificity of telomere length in a bird species, the kakapo (Strigops habroptilus), in which females are the heterogametic sex (ZW) and males are the homogametic (ZZ) sex. We found that, contrary to findings in humans, telomere length was maternally inherited and also longer in males. These results argue against an effect of sex hormones on telomere length and suggest that factors associated with heterogamy may play a role in telomere inheritance and sex-specific differences in telomere length.},
}
@article {pmid21363920,
year = {2011},
author = {Risques, RA and Lai, LA and Himmetoglu, C and Ebaee, A and Li, L and Feng, Z and Bronner, MP and Al-Lahham, B and Kowdley, KV and Lindor, KD and Rabinovitch, PS and Brentnall, TA},
title = {Ulcerative colitis-associated colorectal cancer arises in a field of short telomeres, senescence, and inflammation.},
journal = {Cancer research},
volume = {71},
number = {5},
pages = {1669-1679},
pmid = {21363920},
issn = {1538-7445},
support = {R01 CA068124/CA/NCI NIH HHS/United States ; K07 CA137136/CA/NCI NIH HHS/United States ; R01 DK056924-02/DK/NIDDK NIH HHS/United States ; P30 AG13280/AG/NIA NIH HHS/United States ; DK56924/DK/NIDDK NIH HHS/United States ; P01 AG001751/AG/NIA NIH HHS/United States ; P30 AG013280-05/AG/NIA NIH HHS/United States ; R01 DK056924/DK/NIDDK NIH HHS/United States ; P30 AG013280/AG/NIA NIH HHS/United States ; P20 CA103728-01/CA/NCI NIH HHS/United States ; K07 CA137136-01A1/CA/NCI NIH HHS/United States ; P20 CA103728/CA/NCI NIH HHS/United States ; R01 CA068124-15/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Cell Transformation, Neoplastic ; Cellular Senescence/*physiology ; Colitis, Ulcerative/genetics/metabolism/*pathology ; Colorectal Neoplasms/etiology/genetics/*pathology ; Cyclin-Dependent Kinase Inhibitor p16 ; Disease Progression ; Humans ; Immunohistochemistry ; Inflammation/genetics/metabolism/*pathology ; Middle Aged ; Neoplasm Proteins/biosynthesis ; Polymerase Chain Reaction ; Precancerous Conditions/genetics/metabolism/*pathology ; Telomere/*genetics ; Tumor Suppressor Protein p53/biosynthesis ; Young Adult ; },
abstract = {Inflammation plays a role in the progression to cancer and it is linked to the presence of senescent cells. Ulcerative colitis (UC) is a chronic inflammatory disease that predisposes to colorectal cancer. Tumorigenesis in this setting is associated with telomere shortening that can be observed in the nondysplastic epithelium of UC patients with high-grade dysplasia (HGD) or cancer (UC progressors). We hypothesized that a preneoplastic field of inflammation, telomere shortening, and senescence underlies tumor progression in UC progressors. Multiple biopsies of varying histologic grade were collected along the colon of nine UC progressors and analyzed for telomere length, DNA damage, senescence, p53, p16, and chronic and acute inflammation. Twenty biopsies from four UC nonprogressors and twenty-one biopsies from control individuals without UC were also analyzed. Short telomeres and increased DNA damage, senescence, and infiltrating leukocytes were observed in biopsies located less than 10 cm from HGD or cancer. Low-grade dysplasia (LGD) had the shortest telomeres along with the highest levels of senescence and infiltrating leukocytes, whereas HGD biopsies showed the opposite pattern. The expression of p16 and p53 was low in nondysplastic biopsies but progressively increased in LGD and HGD. In addition, high levels of infiltrating leukocytes were associated with telomere shortening, senescence, and reduced p53 expression. These results suggest that dysplasia arises in a preneoplastic field of chronic inflammation, which leads to telomere shortening, DNA damage, and senescence. Our findings argue that senescence acts as a tumor suppressor mechanism that is abrogated during the transition from LGD to HGD in UC.},
}
@article {pmid21359861,
year = {2012},
author = {Mu, Y and Zhang, Q and Mei, L and Liu, X and Yang, W and Yu, J},
title = {Telomere shortening occurs early during gastrocarcinogenesis.},
journal = {Medical oncology (Northwood, London, England)},
volume = {29},
number = {2},
pages = {893-898},
pmid = {21359861},
issn = {1559-131X},
mesh = {Adenocarcinoma/*genetics/pathology ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Signet Ring Cell/*genetics/pathology ; DNA/genetics ; Female ; Gastric Mucosa/metabolism ; *Gene Expression Regulation, Neoplastic ; Humans ; Male ; Middle Aged ; Neoplasm Grading ; Neoplasm Invasiveness ; Neoplasm Staging ; Prognosis ; Real-Time Polymerase Chain Reaction ; Stomach/pathology ; Stomach Neoplasms/*genetics/pathology ; Telomere/*genetics ; Telomere Shortening/*genetics ; Young Adult ; },
abstract = {When telomeres are shortened to a critical length, they will initiate chromosomal instability (CIN) and may finally cause tumorigenesis. The purpose of the present study was to evaluate the shortened telomere as a potential biomarker for tumorigenesis in gastric carcinoma. The telomeres in matched cancer and adjacent noncancer mucosa samples from 86 gastric carcinoma patients were measured by real-time polymerase chain reaction (PCR). According to the International Union Against Cancer (UICC), tumor stages were classified into four groups: stage I (n = 23), stage II (n = 20), stage III (n = 23), and stage IV (n = 20). Telomere length decreased with aging in both adjacent noncancer mucosa and cancer tissue (r = -0.261 (P = 0.008) and r = -0.27 (P = 0.012), respectively). The telomere length of UICC stage I tumors was significantly shorter than the average telomere length in adjacent noncancer mucosa (P = 0.023). Telomere length increased gradually with increasing UICC stage (P = 0.032). The telomere length of UICC stage IV tumors was significantly longer, when compared to that in noncancer mucosa (P = 0.019) and stage I tumors (P = 0.002). In summary, telomere length undergoes shortening in early stage gastric carcinoma and lengthening in advanced gastric carcinoma. Additionally, telomere shortening may initiate the tumorigenesis of gastric carcinoma.},
}
@article {pmid21357660,
year = {2011},
author = {Matsui-Hirai, H and Hayashi, T and Yamamoto, S and Ina, K and Maeda, M and Kotani, H and Iguchi, A and Ignarro, LJ and Hattori, Y},
title = {Dose-dependent modulatory effects of insulin on glucose-induced endothelial senescence in vitro and in vivo: a relationship between telomeres and nitric oxide.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {337},
number = {3},
pages = {591-599},
doi = {10.1124/jpet.110.177584},
pmid = {21357660},
issn = {1521-0103},
mesh = {Aging/metabolism ; Animals ; Aorta ; Atherosclerosis/physiopathology ; Cells, Cultured ; Cellular Senescence/drug effects ; Diabetes Mellitus, Experimental/*drug therapy ; Dose-Response Relationship, Drug ; Endothelial Cells/cytology/*drug effects/metabolism ; Endothelium, Vascular/cytology/*drug effects/metabolism ; Glucose ; Humans ; Hypoglycemic Agents/metabolism/*pharmacology ; Insulin/*pharmacology/physiology ; Nitric Oxide/*metabolism ; Nitric Oxide Synthase Type III/genetics/metabolism ; RNA, Small Interfering/genetics ; Rats ; Telomerase/metabolism ; Telomere/*physiology ; Umbilical Veins/drug effects/metabolism ; beta-Galactosidase/metabolism ; },
abstract = {The elderly are prone to postprandial hyperglycemia that increases their cardiovascular risk. Although insulin therapy is necessary to treat diabetes, high plasma concentrations of insulin may cause the development of atherosclerosis and accelerate endothelial senescence. We assumed that high glucose causes stress-induced premature senescence and replicative senescence and examined the regulatory role of insulin in endothelial senescence and functions under different glucose conditions. Exposure of human endothelial cells to high glucose (22 mM) for 3 days increased senescence-associated-β-galactosidase activity, a senescence marker, and decreased telomerase activity, a replicative senescence marker. Physiological concentrations of insulin preserved telomere length and delayed endothelial senescence under high-glucose conditions. The effect of insulin under high-glucose conditions was associated with reduced reactive oxygen species and increased nitric oxide (NO). Small interfering RNA targeting endothelial NO synthase reduced the antisenescence effects of insulin. Physiological concentrations of insulin also reversed high glucose-induced increases in p53 and vascular cell adhesion molecule-1 and decreases in senescence marker protein-30. On the other hand, when insulin was given at any concentrations under normal glucose or at high concentrations under high glucose, its ability to promote cellular senescence was unrelated to endothelial NO. Finally, streptozotocin-induced diabetes showed more senescent cells in the aortic endothelium of aged rats compared with age-matched control and insulin-treated animals. Conclusively, the regulatory effects of insulin on endothelial senescence were modulated by the glucose environment. These data may help explain insulin's complicated roles in atherosclerosis in the elderly.},
}
@article {pmid21357377,
year = {2011},
author = {Liang, G and Qureshi, AA and Guo, Q and De Vivo, I and Han, J},
title = {No association between telomere length in peripheral blood leukocytes and the risk of nonmelanoma skin cancer.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {20},
number = {5},
pages = {1043-1045},
pmid = {21357377},
issn = {1538-7755},
support = {R03 CA133914-02/CA/NCI NIH HHS/United States ; R03 CA133914/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; CA87969/CA/NCI NIH HHS/United States ; CA49449/CA/NCI NIH HHS/United States ; CA133914/CA/NCI NIH HHS/United States ; U01 CA049449/CA/NCI NIH HHS/United States ; R01 CA137365/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; CA055075/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Carcinoma, Basal Cell/blood/*etiology/pathology ; Carcinoma, Squamous Cell/blood/*etiology/pathology ; Case-Control Studies ; Cohort Studies ; DNA, Neoplasm/blood/genetics ; Follow-Up Studies ; Humans ; Leukocytes/*pathology ; Male ; Middle Aged ; Nurses/statistics &amp; numerical data ; Polymerase Chain Reaction ; Prognosis ; Prospective Studies ; Risk Factors ; Skin Neoplasms/blood/*etiology/pathology ; Telomere/*genetics ; },
abstract = {BACKGROUND: Recent reports have shown that telomere length was associated with the risk of various cancers, but the results have been inconsistent.<br><br>METHODS: We prospectively evaluated the association of telomere length in peripheral blood leukocytes with the risk of skin squamous cell carcinoma (SCC) in 241 cases and 241 controls within the Health Professionals Follow-up Study (HPFS), and the risk of skin basal cell carcinoma (BCC) in 623 cases and 1,943 controls within the Nurses' Health Study (NHS).<br><br>RESULTS: No significant association was observed between telomere length and risk of SCC (longest quartile vs. shortest quartile, OR = 1.09, 95%CI: 0.62-1.93, P = 0.81). Null findings were also observed between telomere length and risk of BCC in 2 independent sets (OR = 0.96, 95%CI: 0.49-1.87, P = 0.83; and OR = 0.91, 95%CI: 0.66-1.25, P = 0.39).<br><br>CONCLUSION: We found no evidence that telomere length in peripheral blood leukocytes was associated with risk of nonmelanoma skin cancer.<br><br>IMPACT: Our prospective study suggests that telomere length in peripheral blood leukocytes is less likely to play a substantial role in nonmelanoma skin cancer development.},
}
@article {pmid21355072,
year = {2011},
author = {Biroccio, A and Porru, M and Rizzo, A and Salvati, E and D'Angelo, C and Orlandi, A and Passeri, D and Franceschin, M and Stevens, MF and Gilson, E and Beretta, G and Zupi, G and Pisano, C and Zunino, F and Leonetti, C},
title = {DNA damage persistence as determinant of tumor sensitivity to the combination of Topo I inhibitors and telomere-targeting agents.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {17},
number = {8},
pages = {2227-2236},
doi = {10.1158/1078-0432.CCR-10-3033},
pmid = {21355072},
issn = {1557-3265},
mesh = {Acridines/administration &amp; dosage/pharmacology ; Animals ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Apoptosis/drug effects ; Camptothecin/administration &amp; dosage/analogs &amp; derivatives/pharmacology ; Cell Cycle/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Colonic Neoplasms/*drug therapy/metabolism/pathology ; *DNA Damage ; Drug Synergism ; G-Quadruplexes/drug effects ; HCT116 Cells ; HT29 Cells ; Humans ; Irinotecan ; Male ; Mice ; Mice, Nude ; Telomere/drug effects/genetics/metabolism ; Topoisomerase I Inhibitors/administration &amp; dosage/pharmacology ; Treatment Outcome ; *Xenograft Model Antitumor Assays ; },
abstract = {PURPOSE: We previously reported that the G-quadruplex (G4) ligand RHPS4 potentiates the antitumor activity of camptothecins both in vitro and in tumor xenografts. The present study aims at investigating the mechanisms involved in this specific drug interaction.<br><br>EXPERIMENTAL DESIGN: Combination index test was used to evaluate the interaction between G4 ligands and standard or novel Topo I inhibitors. Chromatin immunoprecipitation was performed to study the presence at telomeres of various types of topisomerase, while immunolabeling experiments were performed to measure the activation of DNA damage both in vitro and in tumor xenografts.<br><br>RESULTS: We report that integration of the Topo I inhibitor SN-38, but not the Topo II poison doxorubicin with telomere-based therapy is strongly effective and the sequence of drug administration is critical in determining the synergistic interaction, impairing the cell ability to recover from drug-induced cytotoxicity. The synergistic effect of this combination was also observed by using novel camptothecins and, more interestingly, mice treated with ST1481/RHPS4 combination showed an inhibition and delay of tumor growth as well as an increased survival. The study of the mechanism(s) revealed that treatment with G4 ligands increased Topo I at the telomeres and the functional relevance of this observation was directly assessed by showing that standard and novel camptothecins stabilized DNA damage both in vitro and in xenografts.<br><br>CONCLUSIONS: Our results demonstrate an outstanding efficacy of Topo I inhibitors/G4 ligands combination, which likely reflects an enhanced and persistent activation of DNA damage response as a critical determinant of the therapeutic improvement.},
}
@article {pmid21354438,
year = {2011},
author = {Arbeev, KG and Hunt, SC and Kimura, M and Aviv, A and Yashin, AI},
title = {Leukocyte telomere length, breast cancer risk in the offspring: the relations with father's age at birth.},
journal = {Mechanisms of ageing and development},
volume = {132},
number = {4},
pages = {149-153},
pmid = {21354438},
issn = {1872-6216},
support = {U01 HL56564/HL/NHLBI NIH HHS/United States ; U01 HL67897/HL/NHLBI NIH HHS/United States ; R01 AG020132/AG/NIA NIH HHS/United States ; U01 HL067895-04/HL/NHLBI NIH HHS/United States ; U01 HL067901/HL/NHLBI NIH HHS/United States ; U01 HL067900/HL/NHLBI NIH HHS/United States ; U01 HL67900/HL/NHLBI NIH HHS/United States ; U01 HL056568-04/HL/NHLBI NIH HHS/United States ; U01 HL67898/HL/NHLBI NIH HHS/United States ; U01 HL067902-04/HL/NHLBI NIH HHS/United States ; R01AG020132/AG/NIA NIH HHS/United States ; U01 HL67899/HL/NHLBI NIH HHS/United States ; U01 HL056567-04/HL/NHLBI NIH HHS/United States ; U01 HL56565/HL/NHLBI NIH HHS/United States ; U01 HL067897/HL/NHLBI NIH HHS/United States ; U01 HL067893/HL/NHLBI NIH HHS/United States ; R01AG027019/AG/NIA NIH HHS/United States ; U01 HL056563-04/HL/NHLBI NIH HHS/United States ; R01 AG030612-04/AG/NIA NIH HHS/United States ; U01 HL056567/HL/NHLBI NIH HHS/United States ; U01 HL67896/HL/NHLBI NIH HHS/United States ; U01 HL067900-04/HL/NHLBI NIH HHS/United States ; U01 HL067896/HL/NHLBI NIH HHS/United States ; U01 HL56566/HL/NHLBI NIH HHS/United States ; R01AG030612/AG/NIA NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; U01 HL067898-04/HL/NHLBI NIH HHS/United States ; U01 HL56569/HL/NHLBI NIH HHS/United States ; U01 HL056569-04/HL/NHLBI NIH HHS/United States ; U01 HL067898/HL/NHLBI NIH HHS/United States ; U01 HL056566-04/HL/NHLBI NIH HHS/United States ; U01 HL067894/HL/NHLBI NIH HHS/United States ; U01 HL067896-04/HL/NHLBI NIH HHS/United States ; U01 HL067897-04/HL/NHLBI NIH HHS/United States ; U01 HL67895/HL/NHLBI NIH HHS/United States ; R01 AG027019/AG/NIA NIH HHS/United States ; R01 AG021593-05/AG/NIA NIH HHS/United States ; U01 HL56568/HL/NHLBI NIH HHS/United States ; U01 HL067894-04/HL/NHLBI NIH HHS/United States ; U01 HL067895/HL/NHLBI NIH HHS/United States ; U01 HL067901-04/HL/NHLBI NIH HHS/United States ; R01 AG030612/AG/NIA NIH HHS/United States ; U01 HL067899/HL/NHLBI NIH HHS/United States ; U01 HL067893-04/HL/NHLBI NIH HHS/United States ; U01 AG023746/AG/NIA NIH HHS/United States ; U01 HL56567/HL/NHLBI NIH HHS/United States ; U01 HL056564-04/HL/NHLBI NIH HHS/United States ; R01 AG020132-04/AG/NIA NIH HHS/United States ; U01 HL56563/HL/NHLBI NIH HHS/United States ; U01 HL056565-04/HL/NHLBI NIH HHS/United States ; U01 HL67902/HL/NHLBI NIH HHS/United States ; U01 HL67893/HL/NHLBI NIH HHS/United States ; R01 AG027019-04/AG/NIA NIH HHS/United States ; R01AG021593/AG/NIA NIH HHS/United States ; U01 HL067902/HL/NHLBI NIH HHS/United States ; U01 HL67894/HL/NHLBI NIH HHS/United States ; U01 HL067899-04/HL/NHLBI NIH HHS/United States ; U01 HL67901/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Breast Neoplasms/*diagnosis/genetics ; Cohort Studies ; Female ; Genetic Predisposition to Disease ; Humans ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Paternal Age ; Proportional Hazards Models ; Risk ; Telomere/*ultrastructure ; },
abstract = {Recent studies have reported that leukocyte telomere length (LTL) is longer in offspring of older fathers. Longer telomeres might increase cancer risk. We examined the relation of father's age at the birth of the offspring (FAB) with LTL in the offspring in 2177 participants of the Family Heart Study and the probability of developing breast cancer in 1405 women from the Framingham Heart Study (offspring cohort). For each year of increase in FAB (adjusted for mother's age at birth), LTLs in the daughters and sons were longer by 19.4bp and 12.2bp, respectively (p<0.0001). Daughters of older fathers were less likely to stay free of breast cancer compared to daughters of younger fathers in empirical (p=0.014) and Cox regression analyses (p=0.0012) adjusted for relevant covariates. We conclude that older fathers endow their offspring with a longer LTL and their daughters with increased susceptibility to breast cancer. These independent observations cannot provide evidence for a causal relationship, mediated by telomere length, between FAB and increased breast cancer risk in daughters. However, with couples delaying having children in today's society, studies exploring the LTL association with increased breast cancer risk in daughters of older fathers might be timely and relevant.},
}
@article {pmid21352473,
year = {2011},
author = {Heaphy, CM and Meeker, AK},
title = {The potential utility of telomere-related markers for cancer diagnosis.},
journal = {Journal of cellular and molecular medicine},
volume = {15},
number = {6},
pages = {1227-1238},
pmid = {21352473},
issn = {1582-4934},
mesh = {Biomarkers/analysis ; Breast Neoplasms/*diagnosis/genetics/pathology ; Chemistry Techniques, Analytical ; Disease Progression ; Female ; Gene Expression Regulation, Neoplastic ; Genomic Instability ; Humans ; Male ; Minisatellite Repeats ; Prostatic Neoplasms/*diagnosis/genetics/pathology ; Shelterin Complex ; Telomerase/genetics/*metabolism ; Telomere/*metabolism/pathology ; Telomere-Binding Proteins/*genetics/metabolism ; Up-Regulation ; },
abstract = {The role telomeres and telomerase play in the initiation and progression of human cancers has been extensively evaluated. Telomeres are nucleoprotein complexes comprising the hexanucleotide DNA repeat sequence, TTAGGG and numerous telomere-associated proteins, including the six member Shelterin complex. The main function of the telomere is to stabilize the ends of the chromosomes. However, through multiple mechanisms, telomeres can become dysfunctional, which may drive genomic instability leading to the development of cancer. The majority of human cancers maintain, or actively lengthen, telomeres through up-regulation of the reverse transcriptase telomerase. Because there are significant differences in telomere length and telomerase activity between malignant and non-malignant tissues, many investigations have assessed the potential to utilize these molecular markers for cancer diagnosis. Here, we critically evaluate whether measurements of telomere lengths and telomerase levels may be clinically utilized as diagnostic markers in solid tumours, with emphasis on breast and prostate cancer as representative examples. Future directions focusing on the direct detection of dysfunctional telomeres are explored. New markers for telomere dysfunction may eventually prove clinically useful.},
}
@article {pmid21351086,
year = {2011},
author = {Pavanello, S and Hoxha, M and Dioni, L and Bertazzi, PA and Snenghi, R and Nalesso, A and Ferrara, SD and Montisci, M and Baccarelli, A},
title = {Shortened telomeres in individuals with abuse in alcohol consumption.},
journal = {International journal of cancer},
volume = {129},
number = {4},
pages = {983-992},
pmid = {21351086},
issn = {1097-0215},
support = {P30 ES000002/ES/NIEHS NIH HHS/United States ; P30 ES000002-48/ES/NIEHS NIH HHS/United States ; ES000002/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; Aged ; Alcohol Dehydrogenase/*genetics ; Alcohol-Induced Disorders/*etiology ; Alcoholism/*genetics ; Case-Control Studies ; Genotype ; Humans ; Male ; Middle Aged ; Polymorphism, Genetic/*genetics ; Telomere/*genetics ; },
abstract = {Alcohol abuse leads to earlier onset of aging-related diseases, including cancer at multiple sites. Shorter telomere length (TL) in peripheral blood leucocytes (PBLs), a marker of biological aging, has been associated with alcohol-related cancer risks. Whether alcohol abusers exhibit accelerated biological aging, as reflected in PBL-TL, has never been examined. To investigated the effect of alcohol abuse on PBL-TL and its interaction with alcohol metabolic genotypes, we examined 200 drunk-driving traffic offenders diagnosed as alcohol abusers as per the Diagnostic and Statistical Manual of Mental Disorders [DSM-IV-TR] and enrolled in a probation program, and 257 social drinkers (controls). We assessed alcohol intake using self-reported drink-units/day and conventional alcohol abuse biomarkers (serum γ-glutamyltrasferase [GGT] and mean corpuscular volume of erythrocytes [MCV]). We used multivariable models to compute TL geometric means (GM) adjusted for age, smoking, BMI, diet, job at elevated risk of accident, genotoxic exposures. TL was nearly halved in alcohol abusers compared with controls (GMs 0.42 vs. 0.87 relative T/S ratio; p<0.0001) and decreased in relation with increasing drink-units/day (p-trend=0.003). Individuals drinking >4 drink-units/day had substantially shorter TL than those drinking ≤4 drink-units/day (GMs 0.48 vs. 0.61 T/S, p=0.002). Carriers of the common ADH1B*1/*1 (rs1229984) genotype were more likely to be abusers (p=0.008), reported higher drink-units/day (p=0.0003), and exhibited shorter TL (p<0.0001). The rs698 ADH1C and rs671 ALDH2 polymorphisms were not associated with TL. The decrease in PBL-TL modulated by the alcohol metabolic genotype ADH1B*1/*1 may represent a novel mechanism potentially related to alcohol carcinogenesis in alcohol abusers.},
}
@article {pmid21350437,
year = {2011},
author = {Fernández-Real, JM and Moreno-Navarrete, JM and Ortega, F and Ricart, W},
title = {Decreased serum creatinine concentration is associated with short telomeres of adipose tissue cells.},
journal = {Obesity (Silver Spring, Md.)},
volume = {19},
number = {7},
pages = {1511-1514},
doi = {10.1038/oby.2011.31},
pmid = {21350437},
issn = {1930-739X},
mesh = {Adipocytes/*ultrastructure ; Adult ; Biomarkers ; Body Mass Index ; Cellular Senescence ; Creatinine/*blood ; Diabetes Mellitus, Type 2/epidemiology ; Female ; Glomerular Filtration Rate ; Humans ; Hypertension/etiology ; Male ; Middle Aged ; Obesity/*blood/*pathology/physiopathology ; Oxidative Stress ; Risk Factors ; Spain/epidemiology ; Subcutaneous Fat, Abdominal/pathology ; Telomere/*ultrastructure ; },
abstract = {Decreased serum creatinine concentration has been recently described to constitute a new risk factor of type 2 diabetes. Increased free radicals have been consistently associated with decreased serum creatinine and with cellular senescence. Telomere length is considered as a biological marker for senescence. We aimed to study the association of telomere length with serum creatinine. Telomere length of subcutaneous adipose tissue cells was measured in a sample of obese and nonobese subjects (n = 49). Telomere length of subcutaneous adipose tissue cells was positively associated with serum creatinine (r = 0.40, P = 0.004), i.e., the lower the telomere length, the lower the serum creatinine, but not with glomerular filtration rate (GFR). In addition, telomere length was negatively associated with BMI (r = -0.45, P = 0.001) and systolic blood pressure (r = -0.41, P = 0.003). In a multiple linear regression analysis, BMI (P = 0.005), systolic blood pressure (P = 0.01) and telomere length (P = 0.03) independently contributed to 37% of serum creatinine variance after controlling for sex and age. In conclusion, the association of serum creatinine with a marker of cellular senescence suggests an underlying mechanism influencing both decreased serum creatinine and increased risk of type 2 diabetes.},
}
@article {pmid21349907,
year = {2011},
author = {Buxton, JL and Walters, RG and Visvikis-Siest, S and Meyre, D and Froguel, P and Blakemore, AI},
title = {Childhood obesity is associated with shorter leukocyte telomere length.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {96},
number = {5},
pages = {1500-1505},
pmid = {21349907},
issn = {1945-7197},
support = {WT088431MA//Wellcome Trust/United Kingdom ; },
mesh = {Adolescent ; Blood Pressure/physiology ; Body Height/physiology ; Body Weight/physiology ; Child ; Child, Preschool ; Cholesterol/blood ; Cholesterol, HDL/blood ; Cohort Studies ; DNA/genetics ; Female ; Humans ; Leukocytes/*pathology/ultrastructure ; Male ; Obesity/genetics/*pathology ; Puberty/physiology ; Reverse Transcriptase Polymerase Chain Reaction ; Sex Characteristics ; Telomere/genetics/*pathology/ultrastructure ; },
abstract = {CONTEXT: Obesity in adults is associated with shorter mean leukocyte telomere length (LTL), a marker of biological age that is also associated with age-related conditions including cardiovascular disease and type 2 diabetes. However, studies of childhood obesity and LTL have proved inconclusive.<br><br>OBJECTIVE: The objective of the study was to clarify the relationship between telomere length and childhood obesity by measuring the average LTL in a large case-control cohort.<br><br>PARTICIPANTS AND METHODS: LTL was measured in 793 French children aged 2-17 yr (471 with early onset obesity and 322 nonobese controls) using multiplex quantitative real-time PCR. The average LTL in the two groups was compared, and the relationships between telomere length and selected anthropometric and biochemical measurements were examined.<br><br>RESULTS: Obese children had a mean LTL that was 23.9% shorter than that of nonobese children (P < 0.0001). Telomere length was inversely associated with age (R = -0.17, P = 0.002 in controls; R = -0.15, P = 0.001 in cases), log weight (R= -0.13, P = 0.017 in controls; R = -0.16, P = 0.0004 in cases), and height (R = -0.15, P = 0.008 in controls; R = -0.17, P = 0.0002 in cases). The mean LTL of girls and boys was not significantly different in either the cases or controls or in the group overall.<br><br>CONCLUSION: Obese girls and boys have significantly shorter leukocyte telomeres than their nonobese counterparts, a finding that highlights a potentially deleterious impact of early onset obesity on future health.},
}
@article {pmid21348850,
year = {2011},
author = {Peška, V and Schrumpfová, PP and Fajkus, J},
title = {Using the telobox to search for plant telomere binding proteins.},
journal = {Current protein &amp; peptide science},
volume = {12},
number = {2},
pages = {75-83},
doi = {10.2174/138920311795684968},
pmid = {21348850},
issn = {1875-5550},
mesh = {Amino Acid Sequence ; Cestrum/metabolism ; DNA/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Molecular Sequence Data ; Phylogeny ; Plant Proteins/chemistry/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Telobox is a Myb-related DNA-binding domain which is present in a number of yeast, plant and animal proteins. Its capacity to bind preferentially double-stranded telomeric DNA has been used in numerous studies to search for candidate telomeric proteins in various organisms, including plants. Here we provide an overview of these studies with a special emphasis on plants, where a specific subfamily of the proteins possessing the N-terminally positioned telobox is present in addition to more common C-terminal telobox proteins. We further demonstrate the presence of a telobox protein (CpTBP1) in Cestrum parqui, a plant lacking typical telomeres and telomerase. The protein shows nuclear localisation and association with chromatin. The role of this protein in ancestral and current telomere structure is discussed in the evolutionary context. Altogether, the present overview shows the importance of the telobox domain in a search for candidate telomere proteins but at the same time warns against oversimplified identification of any telobox protein with telomere structure without appropriate evidence of its telomeric localisation and function.},
}
@article {pmid21348849,
year = {2011},
author = {Amiard, S and White, C and Gallego, ME},
title = {Recombination proteins and telomere stability in plants.},
journal = {Current protein &amp; peptide science},
volume = {12},
number = {2},
pages = {84-92},
doi = {10.2174/138920311795684931},
pmid = {21348849},
issn = {1875-5550},
mesh = {Chromosomes, Plant/metabolism ; DNA Damage ; *DNA Repair ; Genome, Plant ; Plant Proteins/genetics/*metabolism ; *Recombination, Genetic ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Repair of DNA damage is essential for the maintenance of the integrity and transmission of the genome in development and reproduction. Telomeres are nucleoprotein structures which protect the ends of (linear) eukaryotic chromosomes. Telomere dysfunction results in loss of this protection and the telomeres being recognised as DNA damage by the cellular DNA Damage Repair and Response (DDR) machinery, leading to senescence or cell death. Telomeric homeostasis is thus tightly controlled and many specific and non-specific proteins are involved in its regulation. Among these, DNA damage and Repair proteins contribute both to the recognition of telomere dysfunction and more surprisingly, are directly implicated in telomere homeostasis itself. Plants offer a great opportunity to study these mechanisms due to the fact that many key DNA repair and recombination proteins are non-essential in plants, in contrast to vertebrates. In the following text, after a brief summary of the current state of knowledge on telomere-specific proteins in plants, we review the DDR processes and the related proteins implicated in plant telomere stability. We focus specifically on telomere signalling and on recombination events induced by unprotected telomeres, at the origin of genome rearrangements and instability when telomere function is affected.},
}
@article {pmid21348847,
year = {2011},
author = {Schrumpfová, PP and Fojtová, M and Mokroš, P and Grasser, KD and Fajkus, J},
title = {Role of HMGB proteins in chromatin dynamics and telomere maintenance in Arabidopsis thaliana.},
journal = {Current protein &amp; peptide science},
volume = {12},
number = {2},
pages = {105-111},
doi = {10.2174/138920311795684922},
pmid = {21348847},
issn = {1875-5550},
mesh = {Arabidopsis/*metabolism ; Arabidopsis Proteins/*metabolism ; Chromatin/chemistry/*metabolism ; Epigenomics ; HMGB Proteins/*metabolism ; HMGB1 Protein/*metabolism ; Telomere/*metabolism ; },
abstract = {Chromosome stability is conditioned by functional chromatin structure of chromosome ends - telomeres. Organisation and regulation of telomere maintenance represent a complex process whose details still remain enigmatic, especially in plants. Several telomere-binding or telomere-associated proteins and distinct epigenetic marks have been shown to influence telomere length and telomerase activity. HMGB proteins play important role in dynamic changes of chromatin structure and are involved in regulation of cellular processes of key importance, such as replication, transcription, recombination and DNA-repair. HMGB proteins in plants are more diversified than in other eukaryotes. Here, we summarise the roles of plant HMGB proteins in regulation of chromatin structure and dynamics and report on the newly identified role of AtHMGB1 protein in the regulation of plant telomere length. Astonishingly, contrary to mice mHMGB1 homologue, AtHMGB1 does not affect telomerase activity and AtHMGB1 loss or overexpression does not cause any obvious changes in chromatin architecture.},
}
@article {pmid21348272,
year = {2010},
author = {Sugimoto, K},
title = {[Telomere maintenance by DNA damage response machinery].},
journal = {Seikagaku. The Journal of Japanese Biochemical Society},
volume = {82},
number = {12},
pages = {1145-1150},
pmid = {21348272},
issn = {0037-1017},
mesh = {Animals ; Apoptosis ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle ; Cell Cycle Proteins/physiology ; DNA Breaks, Double-Stranded ; DNA Damage/*genetics ; DNA Repair ; DNA Replication ; DNA-Binding Proteins/physiology ; Humans ; Protein Binding ; Protein Serine-Threonine Kinases/physiology ; Signal Transduction ; Telomere/*physiology ; Tumor Suppressor Proteins/physiology ; },
}
@article {pmid21347393,
year = {2011},
author = {Anchelin, M and Murcia, L and Alcaraz-Pérez, F and García-Navarro, EM and Cayuela, ML},
title = {Behaviour of telomere and telomerase during aging and regeneration in zebrafish.},
journal = {PloS one},
volume = {6},
number = {2},
pages = {e16955},
pmid = {21347393},
issn = {1932-6203},
mesh = {Aging/*genetics ; Animals ; Biomarkers/metabolism ; Female ; Gene Expression Regulation, Developmental ; Humans ; NF-kappa B/metabolism ; Promoter Regions, Genetic ; Proto-Oncogene Proteins c-myc/metabolism ; Regeneration/*genetics ; Telomerase/genetics/*metabolism ; Telomere/*genetics ; Telomere Shortening ; Zebrafish/*genetics/growth &amp; development/metabolism/*physiology ; Zebrafish Proteins/genetics/*metabolism ; },
abstract = {Telomere length and telomerase activity are important factors in the pathobiology of human diseases. Age-related diseases and premature aging syndromes are characterized by short telomeres, which can compromise cell viability, whereas tumour cells can prevent telomere loss by aberrantly upregulating telomerase. The zebrafish (Danio rerio) offers multiple experimental manipulation advantages over other vertebrate models and, therefore, it has been recently considered as a potential model for aging, cancer, and regeneration studies. However, it has only partially been exploited to shed light on these fundamental biological processes. The aim of this study was, therefore, to investigate telomere length and telomerase expression and activity in different strains of zebrafish obtained from different stock centres to determine whether they undergo any changes during aging and regeneration. We found that although both telomerase expression and telomere length increased from embryo to adulthood stages, they drastically declined in aged fish despite telomerase activity was detected in different tissues of old fish. In addition, we observed a weaker upregulation of telomerase expression in regenerating fins of old fish, which well correlates with their impaired regeneration capacity. Strikingly, telomeres were elongated or maintained during the fin regeneration process at all ages and after repeated amputations, likely to support high cell proliferation rates. We conclude that the expression of telomerase and telomere length are closely related during the entire life cycle of the fish and that these two parameters can be used as biomarkers of aging in zebrafish. Our results also reveal a direct relationship between the expression of telomerase, telomere length and the efficiency of tissue regeneration.},
}
@article {pmid21347226,
year = {2011},
author = {Jiang, WQ and Nguyen, A and Cao, Y and Chang, AC and Reddel, RR},
title = {HP1-mediated formation of alternative lengthening of telomeres-associated PML bodies requires HIRA but not ASF1a.},
journal = {PloS one},
volume = {6},
number = {2},
pages = {e17036},
pmid = {21347226},
issn = {1932-6203},
mesh = {Active Transport, Cell Nucleus ; Animals ; Cell Cycle Proteins/deficiency/genetics/*metabolism ; Cell Nucleolus/metabolism ; Cell Nucleus/*metabolism ; Cellular Senescence ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/*metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Gene Knockdown Techniques ; HeLa Cells ; Histone Chaperones/deficiency/genetics/*metabolism ; Humans ; Molecular Chaperones ; *Telomere Homeostasis ; Transcription Factors/deficiency/genetics/*metabolism ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Approximately 10% of cancers use recombination-mediated Alternative Lengthening of Telomeres (ALT) instead of telomerase to prevent telomere shortening. A characteristic of cells that utilize ALT is the presence of ALT-associated PML nuclear bodies (APBs) containing (TTAGGG)n DNA, telomere binding proteins, DNA recombination proteins, and heterochromatin protein 1 (HP1). The function of APBs is unknown and it is possible that they are functionally heterogeneous. Most ALT cells lack functional p53, and restoration of the p53/p21 pathway in these cells results in growth arrest/senescence and a substantial increase in the number of large APBs that is dependent on two HP1 isoforms, HP1α and HP1γ. Here we investigated the mechanism of HP1-mediated APB formation, and found that histone chaperones, HIRA and ASF1a, are present in APBs following activation of the p53/p21 pathway in ALT cells. HIRA and ASF1a were also found to colocalize inside PML bodies in normal fibroblasts approaching senescence, providing evidence for the existence of a senescence-associated ASF1a/HIRA complex inside PML bodies, consistent with a role for these proteins in induction of senescence in both normal and ALT cells. Moreover, knockdown of HIRA but not ASF1a significantly reduced p53-mediated induction of large APBs, with a concomitant reduction of large HP1 foci. We conclude that HIRA, in addition to its physical and functional association with ASF1a, plays a unique, ASF1a-independent role, which is required for the localization of HP1 to PML bodies and thus for APB formation.},
}
@article {pmid21346783,
year = {2011},
author = {Martínez, P and Blasco, MA},
title = {Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins.},
journal = {Nature reviews. Cancer},
volume = {11},
number = {3},
pages = {161-176},
pmid = {21346783},
issn = {1474-1768},
mesh = {Aging/genetics/metabolism ; Animals ; Gene Expression Regulation ; Humans ; Neoplasms/genetics/metabolism ; Protein Binding ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Mammalian telomeres are formed by tandem repeats of the TTAGGG sequence, which are progressively lost with each round of cell division. Telomere protection requires a minimal length of TTAGGG repeats to allow the binding of shelterin, which prevents the activation of a DNA damage response (DDR) at chromosome ends. Telomere elongation is carried out by telomerase. Telomerase can also act as a transcriptional modulator of the Wnt-β-catenin signalling pathway and has RNA-dependent RNA polymerase activity. Dysfunctional telomeres can lead to either cancer or ageing pathologies depending on the integrity of the DDR. This Review discusses the role of telomeric proteins in cancer and ageing through modulating telomere length and protection, as well as regulating gene expression by binding to non-telomeric sites.},
}
@article {pmid21341274,
year = {2011},
author = {Pitiyage, GN and Slijepcevic, P and Gabrani, A and Chianea, YG and Lim, KP and Prime, SS and Tilakaratne, WM and Fortune, F and Parkinson, EK},
title = {Senescent mesenchymal cells accumulate in human fibrosis by a telomere-independent mechanism and ameliorate fibrosis through matrix metalloproteinases.},
journal = {The Journal of pathology},
volume = {223},
number = {5},
pages = {604-617},
doi = {10.1002/path.2839},
pmid = {21341274},
issn = {1096-9896},
mesh = {Adolescent ; Adult ; Aged ; Cell Proliferation ; Cells, Cultured ; Cellular Senescence/genetics/physiology ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; DNA Damage ; Disease Progression ; Fibroblasts/metabolism/pathology ; Humans ; Matrix Metalloproteinase 1/metabolism ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinases/*physiology ; Mesenchymal Stem Cells/metabolism/*pathology/physiology ; Middle Aged ; Mitochondria/physiology ; Oral Submucous Fibrosis/genetics/metabolism/*pathology ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; Telomere/physiology ; Young Adult ; },
abstract = {Fibrosis can occur in many organs, where it is a debilitating and preneoplastic condition. The senescence of activated fibroblasts has been proposed to ameliorate fibrosis via the innate immune system but its role in humans has not been investigated. The availability of oral submucous fibrosis (OSMF) biopsies at different stages of disease progression allowed us to test the hypothesis that senescent fibroblasts accumulate with the progression of human fibrosis in vivo, and also to examine the mechanism of senescence. We tested the hypothesis that senescent cells may ameliorate fibrosis by increasing the secretion of matrix metalloproteinases (MMPs). We have used a combination of in situ immunodetection techniques, drug treatments, fluorescence-activated cell sorting and enzyme-linked absorbance assays on tissue samples and fibroblast cultures. We report a novel panning technique, based on fibronectin adhesion rates, to enrich and deplete senescent cells from fibroblast populations. Senescent fibroblasts, as determined by the presence of senescence-associated heterochromatic foci, accumulated with OSMF progression (R(2) = 0.98) and possessed a reduced replicative lifespan in vitro. Unlike wounds, however, OSMF fibroblasts were quiescent in vivo and consistent with this observation, possessed functional telomeres of normal length. Senescence was associated in vivo and in vitro with oxidative damage, DNA damage foci and p16(INK4A) accumulation and required the production of reactive oxygen species (ROS), perhaps from damaged mitochondria, but not the continuous presence of the disease stimulus (areca nut and tobacco), the tissue environment or other cell types. Depletion of OSMF fibroblasts of senescent cells showed that these cells accounted for 25-83 times more MMP-1 and -2 than their pre-senescent counterparts. The results show that the accumulation of senescent fibroblasts in human fibrosis occurs by a telomere-independent mechanism involving ROS and may locally ameliorate the condition by the increased expression of MMPs prior to clearance by the immune system.},
}
@article {pmid21332117,
year = {2011},
author = {Maruyama, Y and Matsushita, T and Ueoka, R and Hirata, F},
title = {Solvent and salt effects on structural stability of human telomere.},
journal = {The journal of physical chemistry. B},
volume = {115},
number = {10},
pages = {2408-2416},
doi = {10.1021/jp1096019},
pmid = {21332117},
issn = {1520-5207},
mesh = {Base Sequence ; DNA/chemistry/genetics ; Humans ; Models, Molecular ; Nucleic Acid Conformation ; Potassium Chloride/pharmacology ; Sodium Chloride/*pharmacology ; Solutions ; Solvents/*pharmacology ; Telomere/*chemistry/*drug effects/genetics ; Thermodynamics ; Water/chemistry ; },
abstract = {The free energy and the solvation structures of the G-quadruplex telomeric DNA in pure water and in the 0.1 M aqueous solutions of sodium and potassium chlorides are calculated on the basis of the 3D-RISM theory. To find the most stable structure of each G-quadruplex in the aqueous solutions, the free energy is minimized in the solutions on the basis of the quasi-Newton method using the analytical derivative of the solvation free energy obtained from 3D-RISM. In pure water, the chair-type conformation was found to be the most stable structure, which is followed by basket-, hybrid-, and propeller-type structures in the order. It is clarified that the order of the stability is determined essentially by the solvation free energy, not by the conformational energy. The order of the stability changes in 0.1 M NaCl solutions from that in pure water. The basket-type structure becomes the most stable one in the electrolyte solution. The theoretical finding is consistent with the experimental observation due to NMR. The reversed order of the conformational stability was attributed to the salt effect, especially, to that from the Na(+) ions bound at interstrand spaces of DNA. Concerning the conformational stability in KCl solutions, which has not been clarified yet by experiments, our results predict that the order is not changed from that in pure water; that is, the chair-type is the most stable one. The finding suggests that the effect of the potassium ion upon the structure is not so strong as the sodium ion to change the order of the stability determined in pure water. The result is consistent with our finding for RDFs of the ions bound at the interstrand spaces in DNA, which indicates clearly that the affinity of K(+) to the binding site is weaker than that of Na(+).},
}
@article {pmid21328702,
year = {2011},
author = {Suda, M and Uno, Y and Mori, Y and Matsuda, Y and Nakamura, M},
title = {Molecular cytogenetic characterization of telomere-specific repetitive DNA sequences in Rana rugosa.},
journal = {Journal of experimental zoology. Part A, Ecological genetics and physiology},
volume = {315},
number = {4},
pages = {222-231},
doi = {10.1002/jez.668},
pmid = {21328702},
issn = {1932-5231},
mesh = {Amino Acid Sequence ; Animals ; Aspartate Aminotransferases/*genetics ; Centromere/*genetics ; Chromosome Mapping ; Cloning, Molecular ; Cytogenetics ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Ranidae/*genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; Sex Chromosomes/*genetics ; Telomere/*genetics ; },
abstract = {We performed a molecular cloning of the glutamic oxaloacetic transaminase (GOT1) gene from R. rugosa, and determined its chromosomal location. This gene was reportedly localized near the sex-determining region of the ZW sex chromosomes in the frog Buergeria buergeri; however, the GOT1 gene was mapped to the distal end of chromosome 9 in R. rugosa using a GOT1 cDNA FISH probe. This was also the case when a 46.3 kb genomic clone containing exon 8 and 9 and the 3'-neighboring region of the GOT1 gene, designated clone B, was used as probe. However, weak signals were also detected at the telomeric ends of other autosomes and the Z sex chromosome, and near the centromeric region of the W sex chromosome. To intensify the signals, we used eight internal fragments in clone B and applied them to chromosome mapping. Consequently, only two fragments containing repeated sequence blocks produced hybridization signals; those signals were observed on autosomes and ZW sex chromosomes. The 3'-neighboring region contained two types of repeated sequence elements: a 41 bp element, designated 41-REL, localized to telomeric ends of autosomes and a 31 bp element, designated 31-REL, localized to telomeric ends of all autosomes and the ZW sex chromosomes, and also near the centromere on the W long arm. The results collectively suggest that the two repeated sequence elements were independently amplified around the chromosomal telomeres in R. rugosa, indicating that they will be useful cytogenetic markers for studying karyotypic evolution-especially the W chromosome differentiation-in this species.},
}
@article {pmid21327090,
year = {2010},
author = {Chikashige, Y and Haraguchi, T and Hiraoka, Y},
title = {Nuclear envelope attachment is not necessary for telomere function in fission yeast.},
journal = {Nucleus (Austin, Tex.)},
volume = {1},
number = {6},
pages = {481-486},
pmid = {21327090},
issn = {1949-1042},
mesh = {Amino Acid Sequence ; Cytoskeleton ; Molecular Sequence Data ; Nuclear Envelope/*metabolism ; Prophase ; Schizosaccharomyces/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Sequence Alignment ; Telomere/*metabolism/physiology ; Telomere-Binding Proteins/metabolism ; },
abstract = {Inner nuclear membrane (INM) proteins can be important for positioning chromosomes within the nucleus. Little is known about INM proteins in the fission yeast Schizossacharomayces pombe. Telomeres are the most obvious chromosomal sites that are anchored to the nuclear envelope in this organism. A group of proteins that tether telomeres to the spindle-pole body (SPB) during meiotic prophase, such as Bqt1, Bqt2 and Sad1, has been identified previously, but proteins for anchoring telomeres to the nuclear envelope in vegetative cells have not been identified until recently. A recent report demonstrates that Bqt3 and Bqt4 are INM proteins that affect nuclear positioning of telomeres in vegetative cells, and consequently affect the telomere clustering in meiotic prophase. Interestingly, in the absence of Bqt4, telomeres are separated from the nuclear envelope but telomere silencing and telomere length are properly regulated. An important implication of these results is that the functional integrity of telomeres is maintained independently of their connection to the nuclear envelope.},
}
@article {pmid21327073,
year = {2010},
author = {Li, B},
title = {A newly discovered role of telomeres in an ancient organism.},
journal = {Nucleus (Austin, Tex.)},
volume = {1},
number = {3},
pages = {260-263},
pmid = {21327073},
issn = {1949-1042},
support = {R01 AI066095/AI/NIAID NIH HHS/United States ; },
mesh = {Alleles ; Chromatin Assembly and Disassembly/genetics ; Gene Expression Regulation/genetics ; Gene Silencing ; Humans ; Microbiology ; Telomere/*genetics ; Trypanosoma brucei brucei/*genetics ; Variant Surface Glycoproteins, Trypanosoma/genetics ; Virulence/genetics ; },
abstract = {Trypanosoma brucei expresses Variant Surface Glycoprotein (VSG) genes in a strictly monoallelic fashion in its mammalian hosts, and the regulation of this important virulence mechanism has been the research focus for decades. Telomere position effect (TPE), an epigenetic phenomenon, has been proposed to play a critical role in VSG regulation, yet no telomeric protein was identified whose disruption led to VSG derepression. We recently identified tbRAP1 as an intrinsic component of the T. brucei telomere complex and a major regulator for silencing VSG expression sites (ESs). Knockdown of tbRAP1 led to derepression of all ES-linked VSGs but not VSGs located elsewhere, and resulted in stronger derepression of telomere-proximal genes than telomere-distal genes. This tapered silencing pattern further argues that telomere integrity plays a key role in tbRAP1-dependent silencing and for the first time provides direct evidence indicating that telomeres are important for VSG expression regulation. Whether chromatin remodeling is important for tbRAP1-mediated silencing as in classical TPE will also be discussed.},
}
@article {pmid21326947,
year = {2010},
author = {Lisby, M and Teixeira, T and Gilson, E and Géli, V},
title = {The fate of irreparable DNA double-strand breaks and eroded telomeres at the nuclear periphery.},
journal = {Nucleus (Austin, Tex.)},
volume = {1},
number = {2},
pages = {158-161},
pmid = {21326947},
issn = {1949-1042},
mesh = {Cell Nucleus/*genetics/metabolism ; *DNA Breaks, Double-Stranded ; *DNA Repair ; Saccharomyces cerevisiae/*cytology/enzymology/*genetics/metabolism ; Telomerase/deficiency ; Telomere/*genetics/metabolism ; },
}
@article {pmid21321788,
year = {2011},
author = {Li, H and Jönsson, BA and Lindh, CH and Albin, M and Broberg, K},
title = {N-nitrosamines are associated with shorter telomere length.},
journal = {Scandinavian journal of work, environment &amp; health},
volume = {37},
number = {4},
pages = {316-324},
doi = {10.5271/sjweh.3150},
pmid = {21321788},
issn = {1795-990X},
mesh = {Adult ; Air Pollutants, Occupational/*poisoning ; Carbon Disulfide/poisoning ; Chromosome Aberrations/*chemically induced ; Cross-Sectional Studies ; Female ; Humans ; Male ; Manufactured Materials ; Middle Aged ; Nitrosamines/*poisoning ; Occupational Exposure/*adverse effects ; Polycyclic Aromatic Hydrocarbons/poisoning ; Rubber ; Sweden/epidemiology ; Telomere/*drug effects/metabolism ; Toluidines/poisoning ; Young Adult ; },
abstract = {OBJECTIVES: Telomeres are critical to maintain the integrity of the chromosomes, and telomere abnormalities are important features of carcinogenesis. Telomere length differs among individuals due to genetic and environmental factors. Aiming to examine the relationship between DNA-damaging agents and average telomere length in peripheral blood, we conducted a cross-sectional study among 157 workers working in the rubber industry in Sweden.<br><br>METHODS: N-nitrosamines were measured in air by personal sampling on Thermosorb/N tubes and analyzed by liquid chromatography tandem mass spectrometry (LC/MS/MS) for 60 individuals. Based on a similar working situation, the exposure was estimated for all workers. Polycyclic aromatic hydrocarbons (PAH) were measured as the metabolite 1-hydroxypyrene (1-HP) in urine by LC. Carbon disulphide (CS2) was measured as the metabolite 2-thiothiazolidine-4-carboxylic acid (TTCA) in urine by LC/MS/MS. Toluidines (orto-, meta-, and para-) were measured in urine by gas chromatography (GC)/MS. The average telomere length in peripheral blood was determined by quantitative polymerase chain reaction (PCR).<br><br>RESULTS: There was a reduction in telomere length with increasing exposure to N-nitrosamines in air [measured (N=60) N-nitrosamines &#x3b2;-coefficient= -10, (95% confidence interval [95% CI] -17- -1.9) P=0.016; estimated (N=157) N-nitrosamines &#x3b2;-coefficient = -5.3, (95% CI -9.5- -0.97) P=0.016]. Also, there were negative associations between para-toluidine [&#x3b2;-coefficient= -0.031 (95% CI -0.055- -0.0063) P=0.014], as well as age &#x3b2;-coefficient= -0.005 (95% CI -0.007- -0.002) P=0.001] and telomere length. There were no strong associations between other exposures and telomere length nor did smoking modify the effect.<br><br>CONCLUSION: N-nitrosamines exposure may lead to telomere shortening.},
}
@article {pmid21320523,
year = {2011},
author = {Shlush, LI and Skorecki, KL and Itzkovitz, S and Yehezkel, S and Segev, Y and Shachar, H and Berkovitz, R and Adir, Y and Vulto, I and Lansdorp, PM and Selig, S},
title = {Telomere elongation followed by telomere length reduction, in leukocytes from divers exposed to intense oxidative stress--implications for tissue and organismal aging.},
journal = {Mechanisms of ageing and development},
volume = {132},
number = {3},
pages = {123-130},
doi = {10.1016/j.mad.2011.01.005},
pmid = {21320523},
issn = {1872-6216},
support = {GMH79042//Canadian Institutes of Health Research/Canada ; MOP38075//Canadian Institutes of Health Research/Canada ; },
mesh = {Adult ; Aging/*metabolism ; Cohort Studies ; *Diving ; Enzyme Activation ; Humans ; Leukocytes/*metabolism ; Male ; *Oxidative Stress ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {Many cross-sectional studies have tried to assess the in vivo effect of oxidative stress on organismal aging in general and on telomere length dynamics specifically. Here we followed telomere length dynamics over a 12-month interval, in divers exposed to intense hyperbaric oxygen in comparison with an age-matched control group. Both groups were exposed to extreme physical activity, as well. Among the divers following the oxidative stress, significant telomere elongation was observed in granulocytes and naïve T cells, but not in memory T cells and B cells. Telomere length in granulocytes was mildly elongated in the control group as well, a finding that may relate to the extreme physical activity to which they were exposed. While telomere elongation in naïve T cells may be attributed to telomerase activation, we suggest that in granulocytes the elongation results from undifferentiated hematopoietic cells carrying longer telomeres that repopulate the peripheral hematopoietic compartment. This event might be accompanied by enhanced cell division within the repopulating pool. Since the aging of mammalian tissues can be attributed in part to the reduction in the replicative potential of self renewing cells, enhanced cell turnover under conditions of hyperbaric oxidative stress might be directly relevant to tissue and organismal aging.},
}
@article {pmid21319603,
year = {2010},
author = {Omura, Y and Chen, Y and Lermand, O and Jones, M and Duvvi, H and Shimotsuura, Y},
title = {Effects of transcutaneous electrical stimulation (1 pulse/sec) through custom-made disposable surface electrodes covering Omura's ST36 area of both legs on normal cell telomeres, oncogen C-fosAb2, integrin alpha5beta1, chlamydia trachomatis, etc. in breast cancer &amp; alzheimer patients.},
journal = {Acupuncture &amp; electro-therapeutics research},
volume = {35},
number = {3-4},
pages = {147-185},
doi = {10.3727/036012910803860922},
pmid = {21319603},
issn = {0360-1293},
mesh = {*Acupuncture Points ; Aged ; Alzheimer Disease/genetics/metabolism/*therapy ; Breast Neoplasms/genetics/metabolism/*therapy ; Chlamydia Infections/genetics/metabolism/microbiology/*therapy ; Chlamydia trachomatis/genetics/isolation &amp; purification ; Electrodes ; Female ; Humans ; Integrin alpha5beta1/genetics/*metabolism ; Leg ; Male ; Proto-Oncogene Proteins c-fos/genetics/*metabolism ; Telomere/genetics/*metabolism ; *Transcutaneous Electric Nerve Stimulation/instrumentation ; },
abstract = {Our previous study indicated that when extremely reduced normal cell (NC) telomeres in various cancer patients are increased over 500 ng BDORT units, abnormally high cancer cell telomeres and cancer-related markers such as Oncogen C-fosAb2 (Onco.)&amp; Integrin alpha5beta1 (Integ.), &amp; 8-OH-dG as well as bacterial &amp; viral infections, mercury, asbestos, chromium, &amp; beta-amyloid (1-42) markedly reduced due to improved circulation &amp; excretion of these substances in urine. Since 1995, we have been using press-needle stimulation of Omura's ST36 with 200x press-release procedure 4x a day, with significant improvements in various cancer patients. In this study, Transcutaneous Electrical Stimulation (TES) at 60 pulses/min, which is close to patient's heart rate, was given between Omura's ST36 of both legs of the breast cancer &amp; Alzheimer's patients. After about 10 minutes of TES, NC telomeres increased from 1 yg (= 10-24 g) to 500-525 ng; Integ. reduced from 85-75 ng to 0.5 ng &amp; Chlamydia trachomatis (CT) reduced from 4500-3500 ng to 0.5 ng. An additional 10 minutes TES increased NC telomeres to 800-875 ng, while Integ. reduced to 0.5 yg &amp; CT became less than 0.1 yg. After a total 30 minutes of TES, NC telomeres increased to 1000-1200ng BDORT units, with decreases in Integ. and Onco. to less than 0.1 yg. CT reduced to << 0.1 yg. About 24 hours later, NC telomeres were still 300 ng &amp; both Integ. and Onco. were 2.5 ng. CT was approximately 20 ng. In Alzheimer patient, abnormally high beta-Amyloid (1-42) of 7-12 ng markedly reduced to within normal value of less than 1.5 ng by 20-30 min TES. Stimulation beyond 30 minutes gradually reduced NC telomeres. TES pulse rate of 4 pulses/sec for the same patient initially increased NC telomere up to 750-950 ng BDORT units within 20 minutes, but when stimulation continued more than 20 min, NC telomeres rapidly reduced to -150 ng in less than 10 min of TES with reduced beneficial effects.},
}
@article {pmid21319260,
year = {2011},
author = {Lundberg, G and Sehic, D and Länsberg, JK and Øra, I and Frigyesi, A and Castel, V and Navarro, S and Piqueras, M and Martinsson, T and Noguera, R and Gisselsson, D},
title = {Alternative lengthening of telomeres--an enhanced chromosomal instability in aggressive non-MYCN amplified and telomere elongated neuroblastomas.},
journal = {Genes, chromosomes &amp; cancer},
volume = {50},
number = {4},
pages = {250-262},
doi = {10.1002/gcc.20850},
pmid = {21319260},
issn = {1098-2264},
mesh = {Adult ; Anaphase ; Cell Line, Tumor ; Child ; Child, Preschool ; *Chromosomal Instability ; Female ; Gene Amplification ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; Infant, Newborn ; Male ; N-Myc Proto-Oncogene Protein ; Neuroblastoma/*genetics/pathology ; Nuclear Proteins/genetics ; Oncogene Proteins/genetics ; Telomerase/metabolism ; Telomere/*genetics ; Young Adult ; },
abstract = {Telomere length alterations are known to cause genomic instability and influence clinical course in several tumor types, but have been little investigated in neuroblastoma (NB), one of the most common childhood tumors. In the present study, telomere-dependent chromosomal instability and telomere length were determined in six NB cell lines and fifty tumor biopsies. The alternative lengthening of telomeres (ALT) pathway was assayed by scoring ALT-associated promyelocytic leukemia (PML) bodies (APBs). We found a reduced probability of overall survival for tumors with increased telomere length compared to cases with reduced or unchanged telomere length. In non-MYCN amplified tumors, a reduced or unchanged telomere length was associated with 100% overall survival. Tumor cells with increased telomere length had an elevated frequency of APBs, consistent with activation of the ALT pathway. The vast majority of tumor biopsies and cell lines exhibited an elevated rate of anaphase bridges, suggesting telomere-dependent chromosomal instability. This was more pronounced in tumors with increased telomere length. In cell lines, there was a close correlation between lack of telomere-protective TTAGGG-repeats, anaphase bridging, and remodeling of oncogene sequences. Thus, telomere-dependent chromosomal instability is highly prevalent in NB, and may contribute to the complexity of genomic alterations as well as therapy resistance in the absence of MYCN amplification and in this tumor type.},
}
@article {pmid21319253,
year = {2011},
author = {Eisenberg, DT and Salpea, KD and Kuzawa, CW and Hayes, MG and Humphries, SE and , },
title = {Substantial variation in qPCR measured mean blood telomere lengths in young men from eleven European countries.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {23},
number = {2},
pages = {228-231},
doi = {10.1002/ajhb.21126},
pmid = {21319253},
issn = {1520-6300},
support = {RG/08/008/25291/BHF_/British Heart Foundation/United Kingdom ; FS/06/053/BHF_/British Heart Foundation/United Kingdom ; RG2005/014/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Adolescent ; Adult ; Blood Cells/*cytology ; Case-Control Studies ; Cohort Studies ; Europe ; Humans ; Male ; Myocardial Infarction/ethnology/*genetics ; Polymerase Chain Reaction ; Telomere/*genetics ; White People/classification/genetics ; Young Adult ; },
abstract = {OBJECTIVES: Telomeres, repetitive DNA sequences found at the ends of chromosomes, shorten with age in proliferating human tissues and are implicated in senescence. Previous studies suggest that shorter telomeres impair immune and cardiovascular function and result in increased mortality. Although few, prior studies have documented ethnic/population differences in human telomere lengths. The nature and cause(s) of these population differences remain poorly understood.<br><br>METHODS: Here, we extend the work of Salpea et al. (2008) by reporting variation in mean blood telomere lengths (BTL) from 765 individuals from 14 study centers across 11 European countries. Subjects are male students (ages 18&#x2013;28), half of whom had fathers with myocardial infarction before 55 and the remainder age-matched controls. Controlling for age and case&#x2013;control status, telomere lengths averaged 10.20 kilobases (interpolated from qPCR measures) across study centers and ranged from 5.10 kilobases in Naples, Italy to 18.64 kilobases in Ghent, Belgium--a greater than threefold difference across populations. These population level differences in BTLs were neither explained by national level measures of population genetic structure nor by national level ecological analysis of indices of infection/economic status.<br><br>CONCLUSIONS: These findings suggest considerable population variation in BTL in Europe that is not obviously a result of broad measures of population structure or infection/economic exposure measured in early life or in adulthood.Studying telomere dynamics in a wider variety of populations, and with greater attention to life-cycle dynamics, will be important to help elucidate the causes and possible consequences of human population variation in telomere length.},
}
@article {pmid21319244,
year = {2011},
author = {Eisenberg, DT},
title = {An evolutionary review of human telomere biology: the thrifty telomere hypothesis and notes on potential adaptive paternal effects.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {23},
number = {2},
pages = {149-167},
doi = {10.1002/ajhb.21127},
pmid = {21319244},
issn = {1520-6300},
mesh = {*Adaptation, Physiological ; Aging ; *Biological Evolution ; *Energy Metabolism ; Genotype ; Humans ; Male ; Models, Biological ; Neoplasms/genetics ; *Paternal Age ; Phenotype ; Selection, Genetic ; Telomerase/metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {Telomeres, repetitive DNA sequences found at the ends of linear chromosomes, play a role in regulating cellular proliferation, and shorten with increasing age in proliferating human tissues. The rate of age-related shortening of telomeres is highest early in life and decreases with age. Shortened telomeres are thought to limit the proliferation of cells and are associated with increased morbidity and mortality. Although natural selection is widely assumed to operate against long telomeres because they entail increased cancer risk, the evidence for this is mixed. Instead, here it is proposed that telomere length is primarily limited by energetic constraints. Cell proliferation is energetically expensive, so shorter telomeres should lead to a thrifty phenotype. Shorter telomeres are proposed to restrain adaptive immunity as an energy saving mechanism. Such a limited immune system, however, might also result in chronic infections, inflammatory stress, premature aging, and death--a more "disposable soma." With an increased reproductive lifespan, the fitness costs of premature aging are higher and longer telomeres will be favored by selection. Telomeres exhibit a paternal effect whereby the offspring of older fathers have longer telomeres due to increased telomere lengths of sperm with age. This paternal effect is proposed to be an adaptive signal of the expected age of male reproduction in the environment offspring are born into. The offspring of lineages of older fathers will tend to have longer, and thereby less thrifty, telomeres, better preparing them for an environment with higher expected ages at reproduction.},
}
@article {pmid21310811,
year = {2011},
author = {Chen, W and Kimura, M and Kim, S and Cao, X and Srinivasan, SR and Berenson, GS and Kark, JD and Aviv, A},
title = {Longitudinal versus cross-sectional evaluations of leukocyte telomere length dynamics: age-dependent telomere shortening is the rule.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {66},
number = {3},
pages = {312-319},
pmid = {21310811},
issn = {1758-535X},
support = {AG-16592/AG/NIA NIH HHS/United States ; HD-061437/HD/NICHD NIH HHS/United States ; HD-062783/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Aging/*physiology ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/*physiology ; Longitudinal Studies ; Male ; Middle Aged ; Telomere/*physiology ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) is considered a biomarker of human aging and based on cross-sectional studies it shortens with age. However, longitudinal studies reported that many adults display LTL lengthening.<br><br>METHODS: Using Southern blots, we compared cross-sectional rates of age-related LTL change across a &#x223c;20 year age range with those based on longitudinal evaluations in three surveys (S1, S2, and S3) with three time intervals: S1-S2 (5.8 years), S2-S3 (6.6 years), and S1-S3 (12.4 years). Hierarchical linear modeling was used to explore LTL dynamics using LTL data from S1, S2, and S3.<br><br>RESULTS: Cross-sectionally, mean LTL shortenings were 24.6, 25.4, and 23.6 bp/y at S1, S2, and S3, respectively. Longitudinally, more variation was observed in the rate of LTL change during the shorter than longer follow-up periods. Furthermore, using simple differences in LTL, 14.4% and 10.7% of individuals displayed LTL lengthening during S1-S2 and S2-S3, respectively, but only 1.5% during S1-S3 (p < 0.001). The estimated mean rate of LTL shortening based on averaging empirical Bayes' estimates of LTL from a parsimonious hierarchical linear modeling model was 31 bp/y with a range from 23 to 47 bp/y with none of the participants showing LTL lengthening over the average 12.4 years of follow-up.<br><br>CONCLUSIONS: As aging displays a unidirectional progression, it is unlikely that LTL elongates with age. LTL elongation in longitudinal studies primarily reflects measurement errors of LTL in relation to the duration of follow-up periods.},
}
@article {pmid21310705,
year = {2011},
author = {Zanni, GR and Wick, JY},
title = {Telomeres: unlocking the mystery of cell division and aging.},
journal = {The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists},
volume = {26},
number = {2},
pages = {78-90},
doi = {10.4140/TCP.n.2011.78},
pmid = {21310705},
issn = {2331-0936},
mesh = {Adult ; Aging/genetics/metabolism/*physiology ; Animals ; Cell Division/genetics/physiology ; DNA Replication ; Humans ; Male ; Mice ; Telomerase/genetics/metabolism ; Telomere/genetics/metabolism/*physiology ; },
abstract = {Telomeres are DNA sequences that cap the ends of chromosomes, protecting them from fraying and fusing together during replication. During replication, telomeres lose some of their genetic material but are repaired by the ribonucleoprotein telomerase. Both telomeres and telomerase are linked to cell senescence and apoptosis, and research suggests they play key roles in aging, cancer, hereditary syndromes, and chronic diseases. Several theories of aging are reviewed along with the potential impact of telomerase in developing new treatments.},
}
@article {pmid21307849,
year = {2011},
author = {Sahin, E and Colla, S and Liesa, M and Moslehi, J and Müller, FL and Guo, M and Cooper, M and Kotton, D and Fabian, AJ and Walkey, C and Maser, RS and Tonon, G and Foerster, F and Xiong, R and Wang, YA and Shukla, SA and Jaskelioff, M and Martin, ES and Heffernan, TP and Protopopov, A and Ivanova, E and Mahoney, JE and Kost-Alimova, M and Perry, SR and Bronson, R and Liao, R and Mulligan, R and Shirihai, OS and Chin, L and DePinho, RA},
title = {Telomere dysfunction induces metabolic and mitochondrial compromise.},
journal = {Nature},
volume = {470},
number = {7334},
pages = {359-365},
pmid = {21307849},
issn = {1476-4687},
support = {R01 DK035914/DK/NIDDK NIH HHS/United States ; U24 DK-59635/DK/NIDDK NIH HHS/United States ; U24 DK059635/DK/NIDDK NIH HHS/United States ; R01 DK063356/DK/NIDDK NIH HHS/United States ; P30 DK046200/DK/NIDDK NIH HHS/United States ; R01 DK089185/DK/NIDDK NIH HHS/United States ; P30 DK079638/DK/NIDDK NIH HHS/United States ; P30DK079638/DK/NIDDK NIH HHS/United States ; R01 CA084628/CA/NCI NIH HHS/United States ; R01 DK056690/DK/NIDDK NIH HHS/United States ; },
mesh = {Adenosine Triphosphate/biosynthesis ; Aging/metabolism/pathology ; Animals ; Cardiomyopathies/chemically induced/metabolism/pathology/physiopathology ; Cell Proliferation ; DNA, Mitochondrial/analysis ; Doxorubicin/toxicity ; Gluconeogenesis ; Hematopoietic Stem Cells/metabolism/pathology ; Liver/cytology/metabolism ; Mice ; Mitochondria/*metabolism/*pathology ; Myocardium/cytology/metabolism ; RNA/genetics ; Reactive Oxygen Species/metabolism ; Telomerase/deficiency/genetics ; Telomere/enzymology/genetics/*metabolism/*pathology ; Transcription Factors/antagonists &amp; inhibitors/metabolism ; Tumor Suppressor Protein p53/deficiency/genetics/metabolism ; },
abstract = {Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1α and PGC-1β, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1α expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1α and PGC-1β promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.},
}
@article {pmid21307825,
year = {2011},
author = {Sandhu, R and Li, B},
title = {Examination of the telomere G-overhang structure in Trypanosoma brucei.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {47},
pages = {},
pmid = {21307825},
issn = {1940-087X},
support = {R01 AI066095/AI/NIAID NIH HHS/United States ; AI066095/AI/NIAID NIH HHS/United States ; },
mesh = {Electrophoresis, Gel, Pulsed-Field ; Guanine/physiology ; Nucleic Acid Hybridization ; Nucleotides/genetics ; Telomere/*genetics ; Trypanosoma brucei brucei/*genetics ; },
abstract = {The telomere G-overhang structure has been identified in many eukaryotes including yeast, vertebrates, and Trypanosoma brucei. It serves as the substrate for telomerase for de novo telomere DNA synthesis and is therefore important for telomere maintenance. T. brucei is a protozoan parasite that causes sleeping sickness in humans and nagana in cattle. Once infected mammalian host, T. brucei cell regularly switches its surface antigen to evade the host's immune attack. We have recently demonstrated that the T. brucei telomere structure plays an essential role in regulation of surface antigen gene expression, which is critical for T. brucei pathogenesis. However, T. brucei telomere structure has not been extensively studied due to the limitation of methods for analysis of this specialized structure. We have now successfully adopted the native in-gel hybridization and ligation-mediated primer extension methods for examination of the telomere G-overhang structure and an adaptor ligation method for determination of the telomere terminal nucleotide in T. brucei cells. Here, we will describe the protocols in detail and compare their different advantages and limitations.},
}
@article {pmid21304559,
year = {2011},
author = {Shen, Q and Zhang, Z and Yu, L and Cao, L and Zhou, D and Kan, M and Li, B and Zhang, D and He, L and Liu, Y},
title = {Common variants near TERC are associated with leukocyte telomere length in the Chinese Han population.},
journal = {European journal of human genetics : EJHG},
volume = {19},
number = {6},
pages = {721-723},
pmid = {21304559},
issn = {1476-5438},
support = {R01 AA022701/AA/NIAAA NIH HHS/United States ; },
mesh = {Age Factors ; Aged ; Alleles ; Asian People/*genetics ; Case-Control Studies ; China ; DNA Fingerprinting ; Diabetes Mellitus/epidemiology/*genetics ; Female ; Gene Dosage ; Genome-Wide Association Study/*methods ; Genotype ; Humans ; Leukocytes/*chemistry/cytology ; Linear Models ; Longevity/genetics ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; Sex Factors ; Telomerase/*genetics ; Telomere/*chemistry/genetics ; },
abstract = {A recent genome-wide association study has identified an association between leukocyte telomere length (LTL) and a locus at 3q26 that includes TERC. In order to evaluate the effects of the SNPs rs12696304 and rs16847897 near TERC in the population of mainland China, we conducted an association study of LTL focusing on these two candidate SNPs in a sample of 4016 Chinese Han individuals. Multiple linear regression analyses were performed to evaluate the association of LTL with each SNP adjusted for age, gender and diabetes status. In the study, we confirmed the association of SNP rs12696304 and rs16847897 near TERC with LTL in the Chinese Han population (P ∼ 4.5 × 10(-3) and 9.5 × 10(-5), respectively). Each copy of the major allele of rs12696304 and rs16847897 was associated with a shorter mean telomere length of 0.024 and 0.031 T/S respectively, which is equivalent to about 3 and 4 years of average age-related telomere attrition. Our short report confirmed the effects of SNPs near TERC on LTL in the Chinese Han population for the first time.},
}
@article {pmid21301727,
year = {2011},
author = {Xu, Y},
title = {Chemistry in human telomere biology: structure, function and targeting of telomere DNA/RNA.},
journal = {Chemical Society reviews},
volume = {40},
number = {5},
pages = {2719-2740},
doi = {10.1039/c0cs00134a},
pmid = {21301727},
issn = {1460-4744},
mesh = {DNA/*chemistry/metabolism ; G-Quadruplexes ; Humans ; Neoplasms/therapy ; Nucleosides/chemistry/therapeutic use ; Peptides/chemistry/therapeutic use ; RNA/*chemistry/metabolism ; Small Molecule Libraries/chemistry/therapeutic use ; Telomerase/*chemistry/metabolism ; Telomere/*chemistry/metabolism ; },
abstract = {Telomeres are present at the ends of all eukaryotic chromosomes. Human telomeres play an important role in critical processes underlying genome stability, cancer, and aging, and their importance was recognized via the award of the 2009 Nobel Prize in Physiology or Medicine. Chemistry has made vast and almost unparalleled contributions to telomere biology. This critical review highlights the contributions of chemistry in human telomeres and summarizes the significant development of human telomere biology. First, I provide an overview of the advances in understanding of the structures and functions of human telomeres. Second, I focus on the current efforts on developing various chemical approaches to targeting human telomeres and telomerase for the treatment of cancer. Third, studies on a newly discovered telomeric repeat-containing RNA are discussed in detail. Last, future challenges in the field are outlined, including perspectives of both chemistry and biology (412 references).},
}
@article {pmid21301156,
year = {2010},
author = {Maeda, T and Makino, N},
title = {[Correlations between clinical laboratory data and telomere length in the leukocytes of patients with hypertension].},
journal = {Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics},
volume = {47},
number = {6},
pages = {573-577},
doi = {10.3143/geriatrics.47.573},
pmid = {21301156},
issn = {0300-9173},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/genetics ; Female ; Humans ; Hypertension/*blood/*genetics ; Leukocytes/*ultrastructure ; Middle Aged ; Telomere/*ultrastructure ; },
abstract = {AIM: We investigated the correlation between age, telomere length of peripheral blood leukocytes and blood laboratory data of women with mild hypertension, to identify laboratory data that may reflect the biological aging process of individuals.<br><br>METHODS: The subjects were women with mild hypertension who were being treated with a low dose of amlodipine and who regularly visited the outpatient clinic of the Department of Cardiovascular, Respiratory, and Geriatric Medicine at Kyushu University Hospital. The laboratory data of patients were collected and the telomere length parameters in their peripheral blood leukocytes were determined by Southern blotting. We assessed the laboratory data and the telomere length parameters to determine any correlations.<br><br>RESULTS: The telomere length of the patients correlated positively with high-density lipoprotein cholesterol, albumin, hemoglobin levels and red blood cell counts, but negatively with globulin levels.<br><br>CONCLUSION: Among the analyzed laboratory data, the albumin/globulin rates were the best candidate indicators for individual somatic genomic aging.},
}
@article {pmid21300849,
year = {2011},
author = {Ruault, M and De Meyer, A and Loïodice, I and Taddei, A},
title = {Clustering heterochromatin: Sir3 promotes telomere clustering independently of silencing in yeast.},
journal = {The Journal of cell biology},
volume = {192},
number = {3},
pages = {417-431},
pmid = {21300849},
issn = {1540-8140},
support = {210508/ERC_/European Research Council/International ; },
mesh = {Binding Sites ; Gene Expression Regulation, Fungal ; *Gene Silencing ; Heterochromatin/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Shelterin Complex ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/*genetics/metabolism ; Sirtuin 2/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Transcription Factors/genetics/metabolism ; },
abstract = {A general feature of the nucleus is the organization of repetitive deoxyribonucleic acid sequences in clusters concentrating silencing factors. In budding yeast, we investigated how telomeres cluster in perinuclear foci associated with the silencing complex Sir2-Sir3-Sir4 and found that Sir3 is limiting for telomere clustering. Sir3 overexpression triggers the grouping of telomeric foci into larger foci that relocalize to the nuclear interior and correlate with more stable silencing in subtelomeric regions. Furthermore, we show that Sir3's ability to mediate telomere clustering can be separated from its role in silencing. Indeed, nonacetylable Sir3, which is unable to spread into subtelomeric regions, can mediate telomere clustering independently of Sir2-Sir4 as long as it is targeted to telomeres by the Rap1 protein. Thus, arrays of Sir3 binding sites at telomeres appeared as the sole requirement to promote trans-interactions between telomeres. We propose that similar mechanisms involving proteins able to oligomerize account for long-range interactions that impact genomic functions in many organisms.},
}
@article {pmid21300409,
year = {2011},
author = {Mansour, H and Chowdari, K and Fathi, W and Elassy, M and Ibrahim, I and Wood, J and Bamne, M and Tobar, S and Yassin, A and Salah, H and Elsayed, H and Eissa, A and El-Boraie, H and Ibrahim, NE and Elsayed, M and El-Bahaei, W and Gomaa, Z and El-Chennawi, F and Nimgaonkar, VL},
title = {Does telomere length mediate associations between inbreeding and increased risk for bipolar I disorder and schizophrenia?.},
journal = {Psychiatry research},
volume = {188},
number = {1},
pages = {129-132},
doi = {10.1016/j.psychres.2011.01.010},
pmid = {21300409},
issn = {0165-1781},
support = {MH63420/MH/NIMH NIH HHS/United States ; TW006949/TW/FIC NIH HHS/United States ; TW007997/TW/FIC NIH HHS/United States ; },
mesh = {Adult ; Analysis of Variance ; Bipolar Disorder/epidemiology/*genetics ; Case-Control Studies ; Egypt/epidemiology ; Female ; Genetic Predisposition to Disease ; Humans ; *Inbreeding ; Linear Models ; Male ; Risk Factors ; Schizophrenia/epidemiology/*genetics ; Telomere/*genetics ; Young Adult ; },
abstract = {We have recently found that consanguinity is a risk factor for bipolar I disorder (BP1) and schizophrenia (SZ) in Egypt. Inbreeding has been associated with increased cellular stress and impaired physiological function in plants and animals. Previous studies have reported that telomere length (TL), an index of oxidative stress and cellular senescence is significantly reduced among patients with SZ or mood disorders compared with control individuals. Hence we evaluated TL as a possible mediator of the observed association between consanguinity and BP1/SZ risk. Patients with BP1 (n=108), or SZ (n=60) were compared with screened adult controls in separate experiments. TL was estimated using a quantitative PCR (qPCR) based assay. The inbreeding coefficient/consanguinity rate was estimated in two ways: using 64 DNA polymorphisms ('DNA-based' rate); and from family history data ('self report'). Significant correlation between TL and DNA based inbreeding was not observed overall, though suggestive trends were present among the SZ cases. No significant case-control differences in TL were found after controlling for demographic variables. In conclusion, reduced TL may not explain a significant proportion of observed associations between consanguinity and risk for BP1/SZ.},
}
@article {pmid21300019,
year = {2011},
author = {Yamasuji, M and Shibata, T and Kabashima, T and Kai, M},
title = {Chemiluminescence detection of telomere DNA in human cells on a membrane by using fluorescein-5-isothiocyanate-labeled primers.},
journal = {Analytical biochemistry},
volume = {413},
number = {1},
pages = {50-54},
doi = {10.1016/j.ab.2011.01.047},
pmid = {21300019},
issn = {1096-0309},
mesh = {Base Sequence ; Cells, Cultured ; DNA/*analysis ; DNA Primers/*chemistry ; Fluorescein-5-isothiocyanate/*chemistry ; Humans ; Luminescent Measurements/*methods ; Mouth Mucosa/cytology ; Polymerase Chain Reaction/methods ; Telomere/*chemistry ; },
abstract = {Telomere DNA is related to cell aging and cancer genesis because the telomeric region of DNA sequences at chromosome ends are shortened with cell divisions. Therefore, a sensitive and specific detection method is required for the telomere DNA. Here we propose a chemiluminescence (CL)-based method for the sensitive detection of telomere DNA in human cells. In this study, the telomere DNA was amplified by polymerase chain reaction (PCR) using special forward and reverse primers labeled with fluorescein-5-isothiocyanate (FITC) at the 5' end, and then the FITC-containing PCR products were detected by CL reaction with 3,4,5-trimethoxyphenylglyoxal (TMPG) after electrophoresis followed by Southern blot onto a nylon membrane. The TMPG reagent specifically reacted with guanine moiety in DNA at room temperature and provided CL intensities. The CL intensities from the PCR products could be enhanced approximately 10-fold using FITC-labeled primers as compared with those using nonlabeled primers. The detection limit of the PCR products with the proposed method was 0.3 ng on the membrane. The developed CL method could quantitatively determine the telomere DNA in a small number of human cells (∼350) and gave approximately 10 times higher sensitivity than a conventional fluorescence-based method.},
}
@article {pmid21297001,
year = {2011},
author = {Nitta, E and Yamashita, M and Hosokawa, K and Xian, M and Takubo, K and Arai, F and Nakada, S and Suda, T},
title = {Telomerase reverse transcriptase protects ATM-deficient hematopoietic stem cells from ROS-induced apoptosis through a telomere-independent mechanism.},
journal = {Blood},
volume = {117},
number = {16},
pages = {4169-4180},
doi = {10.1182/blood-2010-08-297390},
pmid = {21297001},
issn = {1528-0020},
mesh = {*Aging ; Animals ; *Apoptosis ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*genetics/metabolism ; Cellular Senescence ; DNA-Binding Proteins/*genetics/metabolism ; Gene Deletion ; Hematopoietic Stem Cells/*cytology/metabolism ; Mice ; Mice, Inbred C57BL ; Protein Serine-Threonine Kinases/*genetics/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/metabolism ; Tumor Suppressor Proteins/*genetics/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; },
abstract = {Telomerase reverse transcriptase (TERT) contributes to the prevention of aging by a largely unknown mechanism that is unrelated to telomere lengthening. The current study used ataxia-telangiectasia mutated (ATM) and TERT doubly deficient mice to evaluate the contributions of 2 aging-regulating molecules, TERT and ATM, to the aging process. ATM and TERT doubly deficient mice demonstrated increased progression of aging and had shorter lifespans than ATM-null mice, while TERT alone was insufficient to affect lifespan. ATM-TERT doubly null mice show in vivo senescence, especially in hematopoietic tissues, that was dependent on p16(INK4a) and p19(ARF), but not on p21. As their HSCs show decreased stem cell activities, accelerated aging seen in these mice has been attributed to impaired stem cell function. TERT-deficient HSCs are characterized by reactive oxygen species (ROS) fragility, which has been suggested to cause stem cell impairment during aging, and apoptotic HSCs are markedly increased in these mice. p38MAPK activation was indicated to be partially involved in ROS-induced apoptosis in TERT-null HSCs, and BCL-2 is suggested to provide a part of the protective mechanisms of HSCs by TERT. The current study demonstrates that TERT mitigates aging by protecting HSCs under stressful conditions through telomere length-independent mechanisms.},
}
@article {pmid21295115,
year = {2011},
author = {Devore, EE and Prescott, J and De Vivo, I and Grodstein, F},
title = {Relative telomere length and cognitive decline in the Nurses' Health Study.},
journal = {Neuroscience letters},
volume = {492},
number = {1},
pages = {15-18},
pmid = {21295115},
issn = {1872-7972},
support = {AG15424/AG/NIA NIH HHS/United States ; R01 AG015424-01A1/AG/NIA NIH HHS/United States ; F32 AG031633-03/AG/NIA NIH HHS/United States ; R01 CA040356-15/CA/NCI NIH HHS/United States ; R01 CA040356/CA/NCI NIH HHS/United States ; F32 AG031633/AG/NIA NIH HHS/United States ; CA40356/CA/NCI NIH HHS/United States ; R01 AG015424/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aging/*genetics/*metabolism/*psychology ; Cognition Disorders/*genetics ; Female ; Gene Dosage ; Health Surveys ; Humans ; Middle Aged ; Telomere/metabolism/*ultrastructure ; },
abstract = {Telomeres are short DNA repeats on the ends of mammalian chromosomes, which can undergo incomplete replication leading to gradual shortening with each cell cycle. Age and oxidative stress are contributors to telomere shortening; thus, telomere length may be a composite measure of biologic aging, and a potential predictor of health status in older adults. We evaluated whether relative telomere length (the proportion of telomere repeat copy number to single gene copy number, using a real-time PCR method) predicts cognitive decline measured ten years later among ∼ 2000 older participants in the Nurses' Health Study (NHS). Mixed linear regression was used to evaluate mean differences in cognitive decline according to telomere length. After adjustment for potential confounders, we found that decreasing telomere length was associated with more cognitive decline, although associations were modest (e.g. for a global score, averaging all six tests in our cognitive battery, mean difference=0.03 standard units per SD increase in telomere length; p=0.04). The magnitude of these estimates was similar to the differences we find in this cohort for women one year apart in age (e.g. the differences that we observe between women who are 73 versus 74 years of age); thus, our results suggest that telomere length is not a particularly powerful marker of impending cognitive decline.},
}
@article {pmid21289018,
year = {2011},
author = {Fitzpatrick, AL and Kronmal, RA and Kimura, M and Gardner, JP and Psaty, BM and Jenny, NS and Tracy, RP and Hardikar, S and Aviv, A},
title = {Leukocyte telomere length and mortality in the Cardiovascular Health Study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {66},
number = {4},
pages = {421-429},
pmid = {21289018},
issn = {1758-535X},
support = {N01-HC-85085/HC/NHLBI NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; N01-HC-85081/HC/NHLBI NIH HHS/United States ; N01-HC-85086/HC/NHLBI NIH HHS/United States ; N01-HC-85082/HC/NHLBI NIH HHS/United States ; N01-HC-35129/HC/NHLBI NIH HHS/United States ; N01 HC-55222/HC/NHLBI NIH HHS/United States ; 1 R01 HL80698-01/HL/NHLBI NIH HHS/United States ; N01-HC-85083/HC/NHLBI NIH HHS/United States ; N01-HC-75150/HC/NHLBI NIH HHS/United States ; N01-HC-85080/HC/NHLBI NIH HHS/United States ; N01 HC-15103/HC/NHLBI NIH HHS/United States ; N01-HC-45133/HC/NHLBI NIH HHS/United States ; N01-HC-85079/HC/NHLBI NIH HHS/United States ; N01-HC-85084/HC/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*genetics ; Body Mass Index ; Cardiovascular Diseases/*mortality ; *Cause of Death ; Comorbidity ; Coronary Disease/mortality ; Diabetes Mellitus/epidemiology ; Female ; Humans ; Hypertension/epidemiology ; Leukocytes/metabolism ; Longitudinal Studies ; Male ; Prospective Studies ; Smoking/epidemiology ; Stroke/mortality ; Telomere/*genetics ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) is related to diseases of aging, but studies of mortality have been inconsistent.<br><br>METHODS: We evaluated LTL in relation to total mortality and specific cause of death in 1,136 participants of the Cardiovascular Health Study who provided blood samples in 1992-1993 and survived through 1997-1998. LTL was measured by Southern blots of the terminal restriction fragments. Cause of death was classified by a committee of physicians reviewing death certificates, medical records, and informant interviews.<br><br>RESULTS: A total of 468 (41.2%) deaths occurred over 6.1 years of follow-up in participants with mean age of 73.9 years (SD 4.7), 65.4% female, and 14.8% African American. Although increased age and male gender were associated with shorter LTLs, African Americans had significantly longer LTLs independent of age and sex (p < .001). Adjusted for age, sex, and race, persons with the shortest quartile of LTL were 60% more likely to die during follow-up than those within the longest quartile (hazard ratio: 1.61, 95% confidence interval: 1.22-2.12, p = .001). The association remained after adjustment for cardiovascular disease risk factors. Evaluations of cause of death found LTL to be related to deaths due to an infectious disease etiology (hazard ratio: 2.80, 95% confidence interval: 1.32-5.94, p = .007), whereas a borderline association was found for cardiac deaths (hazard ratio: 1.82, 95% confidence interval: 0.95-3.49, p = .07) in adjusted models. Risk estimates for deaths due to cancer, dementia, and ischemic stroke were not significant.<br><br>CONCLUSION: These data weakly corroborate prior findings of associations between LTL and mortality in the elderly.},
}
@article {pmid21288186,
year = {2011},
author = {Folini, M and Venturini, L and Cimino-Reale, G and Zaffaroni, N},
title = {Telomeres as targets for anticancer therapies.},
journal = {Expert opinion on therapeutic targets},
volume = {15},
number = {5},
pages = {579-593},
doi = {10.1517/14728222.2011.556621},
pmid = {21288186},
issn = {1744-7631},
mesh = {Animals ; G-Quadruplexes/drug effects ; Humans ; Neoplasms/*drug therapy/*genetics ; Telomerase/antagonists &amp; inhibitors ; Telomere/*drug effects/physiology ; Telomeric Repeat Binding Protein 2/antagonists &amp; inhibitors ; },
abstract = {INTRODUCTION: The limitless replicative potential of cancer cells relies on telomere integrity (which is guaranteed by a complex interaction between several specialized proteins and telomeric DNA) and the activation of specific mechanisms for telomere length maintenance. Two mechanisms are currently known in human cancer, namely telomerase activity and the alternative lengthening of telomere pathway.<br><br>EXPERT OPINION: In this review, we summarize the available data concerning the therapeutic strategies proposed thus far and the current challenges posed for the development of innovative telomere-based therapeutic approaches with broad-spectrum anticancer activity and for their translation into the clinical setting.<br><br>AREAS COVERED: Due to their essential role in tumor cell proliferation, telomere maintenance mechanisms have become extremely attractive targets for the development of new anticancer interventions. Although numerous efforts have been made to identify specific approaches to interfere with telomere maintenance mechanisms in human cancers, the only molecule currently tested in clinical trials is the oligonucleotide GRN163L. However, a growing body of evidence suggests that interfering with telomeres, through the direct targeting of telomeric G-quadruplex structures, may be a valuable antitumor therapeutic strategy, independent of the specific telomere maintenance mechanism operating in the tumor.},
}
@article {pmid21287751,
year = {2010},
author = {Dahlman, D and Fyhrquist, F and Nilsson, PM},
title = {[Telomeres, aging and life style--research with contradictory finding].},
journal = {Lakartidningen},
volume = {107},
number = {48},
pages = {3053-3055},
pmid = {21287751},
issn = {0023-7205},
mesh = {Aged ; *Aging/genetics/physiology ; Biomedical Research ; Cardiovascular Diseases/etiology/genetics ; Genetic Predisposition to Disease ; Humans ; Life Style ; Risk Factors ; Telomerase/metabolism ; *Telomere/drug effects/genetics/physiology ; },
}
@article {pmid21287551,
year = {2011},
author = {Visentini, M and Cagliuso, M and Conti, V and Carbonari, M and Mancaniello, D and Cibati, M and Siciliano, G and Giorda, E and Keller, B and Warnatz, K and Fiorilli, M and Quinti, I},
title = {Telomere-dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency.},
journal = {European journal of immunology},
volume = {41},
number = {3},
pages = {854-862},
doi = {10.1002/eji.201040862},
pmid = {21287551},
issn = {1521-4141},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; B-Lymphocytes/*immunology/pathology ; Calcium Signaling/immunology ; Case-Control Studies ; Cellular Senescence/immunology ; Common Variable Immunodeficiency/classification/etiology/*immunology/pathology ; Female ; Humans ; Lymphocyte Activation ; Male ; Middle Aged ; Receptors, Complement 3d/metabolism ; T-Lymphocytes/*immunology/pathology ; Telomere/genetics/*pathology ; Young Adult ; },
abstract = {A subset of patients with common variable immunodeficiency (CVID), group 1a of the Freiburg classification, is characterized by increased B cells expressing low levels of CD21 (CD21(low)), lymphoproliferation and autoimmunity. The CD21(low) B cells have been shown to be profoundly anergic, and defects of BCR-mediated calcium signaling and of T cells have been described in CVID 1a. We found that also the classical naïve B cells from CVID 1a patients, but not from CVID non-1a patients, proliferated poorly. The B cells of CVID 1a patients had a reduced capacity to divide reminiscent of the proliferative arrest associated with replicative senescence. Thus, we investigated whether lymphocyte dysfunction in CVID 1a was related to telomere-dependent replicative senescence, and found that both the B and the T cells from CVID 1a patients had significantly shorter telomeres compared with B and T cells from CVID non-1a patients. Telomere lengths in B and T cells were significantly correlated, indicating that the rate of telomere attrition in lymphocytes is an individual characteristic of CVID patients. Our findings suggest that telomere-dependent replicative senescence contributes to the immune dysfunction of CVID 1a patients, and may provide an important clue for a better understanding of the pathogenesis of CVID.},
}
@article {pmid21287134,
year = {2011},
author = {Arora, R and Brun, CM and Azzalin, CM},
title = {TERRA: Long Noncoding RNA at Eukaryotic Telomeres.},
journal = {Progress in molecular and subcellular biology},
volume = {51},
number = {},
pages = {65-94},
doi = {10.1007/978-3-642-16502-3_4},
pmid = {21287134},
issn = {0079-6484},
mesh = {Eukaryota/genetics ; Humans ; RNA Polymerase II/genetics ; *RNA, Long Noncoding ; *Telomere ; },
abstract = {Telomeres protect the ends of linear eukaryotic chromosomes from being recognized as DNA double-stranded breaks, thereby maintaining the stability of our genome. The highly heterochromatic nature of telomeres had, for a long time, reinforced the idea that telomeres were transcriptionally silent. Since a few years, however, we know that DNA-dependent RNA polymerase II transcribes telomeric DNA into TElomeric Repeat-containing RNA (TERRA) molecules in a large variety of eukaryotes. In this chapter, we summarize the current knowledge of telomere structure and function and extensively review data accumulated on TERRA biogenesis and regulation. We also discuss putative functions of TERRA in preserving telomere stability and propose future directions for research encompassing this novel and exciting aspect of telomere biology.},
}
@article {pmid21283131,
year = {2011},
author = {Huang, J and Wang, F and Okuka, M and Liu, N and Ji, G and Ye, X and Zuo, B and Li, M and Liang, P and Ge, WW and Tsibris, JC and Keefe, DL and Liu, L},
title = {Association of telomere length with authentic pluripotency of ES/iPS cells.},
journal = {Cell research},
volume = {21},
number = {5},
pages = {779-792},
pmid = {21283131},
issn = {1748-7838},
mesh = {Animals ; Cell Line ; Embryonic Stem Cells/*metabolism/pathology ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Induced Pluripotent Stem Cells/*metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Telomerase/deficiency/metabolism ; Telomere/*metabolism ; Teratoma/pathology ; Transcription, Genetic ; },
abstract = {Telomerase and telomeres are important for indefinite replication of stem cells. Recently, telomeres of somatic cells were found to be reprogrammed to elongate in induced pluripotent stem cells (iPSCs). The role of telomeres in developmental pluripotency in vivo of embryonic stem cells (ESCs) or iPSCs, however, has not been directly addressed. We show that ESCs with long telomeres exhibit authentic developmental pluripotency, as evidenced by generation of complete ESC pups as well as germline-competent chimeras, the most stringent tests available in rodents. ESCs with short telomeres show reduced teratoma formation and chimera production, and fail to generate complete ESC pups. Telomere lengths are highly correlated (r > 0.8) with the developmental pluripotency of ESCs. Short telomeres decrease the proliferative rate or capacity of ESCs, alter the expression of genes related to telomere epigenetics, down-regulate genes important for embryogenesis and disrupt germ cell differentiation. Moreover, iPSCs with longer telomeres generate chimeras with higher efficiency than those with short telomeres. Our data show that functional telomeres are essential for the developmental pluripotency of ESCs/iPSCs and suggest that telomere length may provide a valuable marker to evaluate stem cell pluripotency, particularly when the stringent tests are not feasible.},
}
@article {pmid21280624,
year = {2011},
author = {Casagrande, V and Salvati, E and Alvino, A and Bianco, A and Ciammaichella, A and D'Angelo, C and Ginnari-Satriani, L and Serrilli, AM and Iachettini, S and Leonetti, C and Neidle, S and Ortaggi, G and Porru, M and Rizzo, A and Franceschin, M and Biroccio, A},
title = {N-cyclic bay-substituted perylene G-quadruplex ligands have selective antiproliferative effects on cancer cells and induce telomere damage.},
journal = {Journal of medicinal chemistry},
volume = {54},
number = {5},
pages = {1140-1156},
doi = {10.1021/jm1013665},
pmid = {21280624},
issn = {1520-4804},
mesh = {Antineoplastic Agents/*chemical synthesis/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; DNA Damage ; Drug Screening Assays, Antitumor ; Fluorescence Resonance Energy Transfer ; *G-Quadruplexes ; Histones/metabolism ; Humans ; Ligands ; Perylene/*analogs &amp; derivatives/*chemical synthesis/pharmacology ; Phosphorylation ; Piperidines/*chemical synthesis/pharmacology ; Spectrometry, Mass, Electrospray Ionization ; Structure-Activity Relationship ; Telomere/*drug effects ; },
abstract = {A series of bay-substituted perylene derivatives is reported as a new class of G-quadruplex ligands. The synthesized compounds have differing N-cyclic substituents on the bay area and differing side chains on the perylene major axis. ESI-MS and FRET measurements highlighted the strongest quadruplex binders in this series and those showing the highest quadruplex/duplex selectivity. Several biological assays were performed on these compounds, which showed that compound 5 (PPL3C) triggered a DNA damage response in transformed cells with the formation of telomeric foci containing phosphorylated γ-H2AX and 53BP1. This effect mainly occurred in replicating cells and was consistent with Pot1 dissociation. Compound 5 does not induce telomere damage in normal cells, which are unaffected by treatment with the compound, suggesting that this agent preferentially kills cancer cells. These results reinforce the notion that G-quadruplex binding compounds can act as broad inhibitors of telomere-related processes and have potential as selective antineoplastic drugs.},
}
@article {pmid21271986,
year = {2011},
author = {Zhu, H and Belcher, M and van der Harst, P},
title = {Healthy aging and disease: role for telomere biology?.},
journal = {Clinical science (London, England : 1979)},
volume = {120},
number = {10},
pages = {427-440},
pmid = {21271986},
issn = {1470-8736},
support = {HL85817/HL/NHLBI NIH HHS/United States ; },
mesh = {Aging/*genetics ; Cardiovascular Diseases/genetics ; Chronic Disease ; Diabetes Mellitus/genetics ; Humans ; Stem Cells/physiology ; Telomerase/physiology ; Telomere/*physiology/ultrastructure ; },
abstract = {Aging is a biological process that affects most cells, organisms and species. Human aging is associated with increased susceptibility to a variety of chronic diseases, including cardiovascular disease, Type 2 diabetes, neurological diseases and cancer. Despite the remarkable progress made during the last two decades, our understanding of the biology of aging remains incomplete. Telomere biology has recently emerged as an important player in the aging and disease process.},
}
@article {pmid21270748,
year = {2010},
author = {Gerashchenko, BI},
title = {At a crossroads of cancer risk and aging: the role of telomeres.},
journal = {Experimental oncology},
volume = {32},
number = {4},
pages = {224-227},
pmid = {21270748},
issn = {2312-8852},
mesh = {Aging/*genetics ; Cellular Senescence/*genetics ; Humans ; Life Expectancy ; Neoplasms/*genetics ; Risk Factors ; *Telomere ; },
abstract = {The risk of overall cancer inevitably increases with advancing age. The cancer incidence rate is not constant within the human life span (it exponentially increases with advancing age). Aging itself is a complex biological process with a poorly understood mechanism of its regulation. The aging process, as evidenced from the survey of the chances for death for the large cohort of people of various age groups, manifests probably due to a progressive accumulation of diverse adverse changes that increase the risk of death. While an increase of cancer risk due to aging cannot be fully explained, the length of telomeres (biomarker of aging) appears to be important to predict this risk. Cellular senescence, which is believed to be associated with dysfunctional (shortened) telomeres, may contribute to the aging of a whole organism. Here, based on recent literature data, we investigate the possible link between telomere dysfunction associated cellular senescence and tumorigenesis.},
}
@article {pmid21266744,
year = {2011},
author = {Horikawa, I and Fujita, K and Harris, CC},
title = {p53 governs telomere regulation feedback too, via TRF2.},
journal = {Aging},
volume = {3},
number = {1},
pages = {26-32},
pmid = {21266744},
issn = {1945-4589},
mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/metabolism ; DNA Damage ; DNA-Binding Proteins/genetics/metabolism ; Feedback, Physiological ; Humans ; Nuclear Proteins/genetics/metabolism ; Protein Serine-Threonine Kinases/genetics/metabolism ; Signal Transduction ; Telomerase/metabolism ; Telomere/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; Tumor Suppressor Proteins/genetics/metabolism ; Ubiquitin-Protein Ligases/genetics/metabolism ; },
abstract = {p53 takes critical part in a number of positive and negative feedback loops to regulate carcinogenesis, aging and other biological processes. Uncapped or dysfunctional telomeres are an endogenous DNA damage that activates ATM kinase (ataxia telangiectasia mutated) and then p53 to induce cellular senescence or apoptosis. Our recent study shows that p53, a downstream effector of the telomere damage signaling, also functions upstream of the telomere‐capping protein complex by inhibiting one of its components, TRF2 (telomeric repeat binding factor 2). Since TRF2 inhibition leads to ATM activation, a novel positive feedback loop exists to amplify uncapped telomere‐induced, p53‐mediated cellular responses. Siah1 (seven in absentia homolog 1), a p53‐inducible E3 ubiquitin ligase, plays a key role in this feedback regulation by targeting TRF2 for ubiquitination and proteasomal degradation. Biological significance and therapeutic implications of this study are discussed.},
}
@article {pmid21265009,
year = {2011},
author = {Klewes, L and Höbsch, C and Katzir, N and Rourke, D and Garini, Y and Mai, S},
title = {Novel automated three-dimensional genome scanning based on the nuclear architecture of telomeres.},
journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology},
volume = {79},
number = {2},
pages = {159-166},
doi = {10.1002/cyto.a.21012},
pmid = {21265009},
issn = {1552-4930},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Animals ; Cell Line, Tumor ; Cell Nucleus/genetics/ultrastructure ; Genome ; Imaging, Three-Dimensional/*methods ; In Situ Hybridization, Fluorescence/methods ; Interphase/genetics ; Lymphocytes/ultrastructure ; Male ; Mice ; Microscopy/*methods ; Neoplasms/genetics/ultrastructure ; Plasmacytoma/ultrastructure ; Sensitivity and Specificity ; Telomere/genetics/*ultrastructure ; },
abstract = {Telomeres, the end of chromosomes, are organized in a nonoverlapping fashion and form microterritories in nuclei of normal cells. Previous studies have shown that normal and tumor cell nuclei differ in their 3D telomeric organization. The differences include a change in the spatial organization of the telomeres, in telomere numbers and sizes and in the presence of telomeric aggregates. Previous attempts to identify the above parameters of 3D telomere organization were semi-automated. Here we describe the automation of 3D scanning for telomere signatures in interphase nuclei based on three-dimensional fluorescent in situ hybridization (3D-FISH) and, for the first time, define its sensitivity in tumor cell detection. The data were acquired with a high-throughput scanning/acquisition system that allows to measure cells and acquire 3D images of nuclei at high resolution with 40 × or 60 × oil and at a speed of 10,000-15,000 cells h(-1) , depending on the cell density on the slides. The automated scanning, TeloScan, is suitable for large series of samples and sample sizes. We define the sensitivity of this automation for tumor cell detection. The data output includes 3D telomere positions, numbers of telomeric aggregates, telomere numbers, and telomere signal intensities. We were able to detect one aberrant cell in 1,000 normal cells. In conclusions, we are able to detect tumor cells based on 3D architectural profiles of the genome. This new tool could, in the future, assist in patient diagnosis, in the detection of minimal residual disease, in the analysis of treatment response and in treatment decisions.},
}
@article {pmid21264070,
year = {2010},
author = {Makino, N and Sasaki, M and Maeda, T and Mimori, K},
title = {Telomere biology in cardiovascular disease - role of insulin sensitivity in diabetic hearts.},
journal = {Experimental and clinical cardiology},
volume = {15},
number = {4},
pages = {e128-33},
pmid = {21264070},
issn = {1918-1515},
abstract = {The present study examined telomere biology in the context of insulin sensitivity in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a type 2 diabetic animal model. To improve insulin sensitivity, pioglitazone (PG; 10 mg/kg/day) was administered to OLETF rats between 20 weeks and 40 weeks of age, and the effects of the treatment were compared with those in untreated OLETF rats or control Long-Evans Tokushima Otsuka rats. The homeostasis model assessment of insulin resistance index significantly increased in OLETF rats, but decreased in PG-treated OLETF rats. Telomere lengths were not shortened in heart tissues of OLETF rats; however, telomerase activity was decreased in heart tissues of OLETF rats. Messenger RNA expression for both telomerase reverse transcriptase and telomere repeat binding factor 2 was downregulated in the hearts of OLETF rats. Protein expression of phosphorylated Akt, insulin-like growth factor and endothelial nitric oxide synthase were all reduced in OLETF rats. The changes observed in OLETF rats were inhibited by PG treatment. Myocardial fibrosis was less extensive and diastolic dysfunction improved in PG-treated OLETF rats versus untreated OLETF rats. These findings suggest that improving insulin sensitivity via the activation of peroxisome proliferator-activated receptor-gamma may exert regulatory effects on cardiac telomere biology, and may have desirable morphological and functional effects on the diabetic heart.},
}
@article {pmid21261810,
year = {2011},
author = {Herbert, BS},
title = {The impact of telomeres and telomerase in cellular biology and medicine: it's not the end of the story.},
journal = {Journal of cellular and molecular medicine},
volume = {15},
number = {1},
pages = {1-2},
pmid = {21261810},
issn = {1582-4934},
mesh = {Animals ; Cell Biology ; Humans ; Medicine ; Telomerase/*metabolism ; Telomere/*metabolism ; },
}
@article {pmid21258621,
year = {2010},
author = {Trudeau, MA and Wong, JM},
title = {Genetic Variations in Telomere Maintenance, with Implications on Tissue Renewal Capacity and Chronic Disease Pathologies.},
journal = {Current pharmacogenomics and personalized medicine},
volume = {8},
number = {1},
pages = {7-24},
pmid = {21258621},
issn = {1875-6921},
support = {81094/CAPMC/CIHR/Canada ; 81094//PHS HHS/United States ; },
abstract = {Premature loss of telomere repeats underlies the pathologies of inherited bone marrow failure syndromes. Over the past decade, researchers have mapped genetic lesions responsible for the accelerated loss of telomere repeats. Haploinsufficiencies in the catalytic core components of the telomere maintenance enzyme telomerase, as well as genetic defects in telomerase holoenzyme components responsible for enzyme stability, have been linked to hematopoietic failure pathologies. Frequencies of these disease-associated alleles in human populations are low. Accordingly, the diseases themselves are rare. On the other hand, single nucleotide polymorphisms of telomerase enzyme components are found with much higher frequencies, with several non-synonymous SNP alleles observed in 2-4% of the general population. Importantly, recent advents of molecular diagnostic techniques have uncovered links between telomere length maintenance deficiencies and an increasing number of pathologies unrelated to the hematopoietic system. In these cases, short telomere length correlates to tissue renewal capacities and predicts clinical progression and disease severity. To the authors of this review, these new discoveries imply that even minor genetic defects in telomere maintenance can culminate in the premature failure of tissue compartments with high renewal rates. In this review, we discuss the biology and molecules of telomere maintenance, and the pathologies associated with an accelerated loss of telomeres, along with their etiologies. We also discuss single nucleotide polymorphisms of key telomerase components and their association with tissue renewal deficiency syndromes and other pathologies. We suggest that inter-individual variability in telomere maintenance capacity could play a significant role in chronic inflammatory diseases, and that this is not yet fully appreciated in the translational research of pharmacogenomics and personalized medicine.},
}
@article {pmid21250944,
year = {2011},
author = {Li, S},
title = {Cell-cycle-dependent telomere elongation by telomerase in budding yeast.},
journal = {Bioscience reports},
volume = {31},
number = {3},
pages = {169-177},
doi = {10.1042/BSR20100095},
pmid = {21250944},
issn = {1573-4935},
mesh = {Cell Cycle ; Saccharomycetales/*cytology/*enzymology ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are essential for the stability and complete replication of linear chromosomes. Telomere elongation by telomerase counteracts the telomere shortening due to the incomplete replication of chromosome ends by DNA polymerase. Telomere elongation is cell-cycle-regulated and coupled to DNA replication during S-phase. However, the molecular mechanisms that underlie such cell-cycle-dependent telomere elongation by telomerase remain largely unknown. Several aspects of telomere replication in budding yeast, including the modulation of telomere chromatin structure, telomere end processing, recruitment of telomere-binding proteins and telomerase complex to telomere as well as the coupling of DNA replication to telomere elongation during cell cycle progression will be discussed, and the potential roles of Cdk (cyclin-dependent kinase) in these processes will be illustrated.},
}
@article {pmid21242650,
year = {2011},
author = {Dateki, S and Fukami, M and Tanaka, Y and Sasaki, G and Moriuchi, H and Ogata, T},
title = {Identification of chromosome 15q26 terminal deletion with telomere sequences and its bearing on genotype-phenotype analysis.},
journal = {Endocrine journal},
volume = {58},
number = {3},
pages = {155-159},
doi = {10.1507/endocrj.k10e-251},
pmid = {21242650},
issn = {1348-4540},
mesh = {Adolescent ; *Chromosome Deletion ; Chromosomes, Human, Pair 13/*genetics ; Female ; *Genetic Association Studies ; Growth Disorders/genetics ; Heart Septal Defects, Ventricular/genetics ; Humans ; Intellectual Disability/genetics ; Receptor, IGF Type 1/genetics ; Telomere/*genetics ; },
abstract = {We report a de novo heterozygous 5,013,940 bp terminal deletion of chromosome 15q26 in a 13 9/12 -year-old Japanese girl with short stature (-3.9 SD), mild mental retardation, and ventricular septal defect (VSD). This terminal deletion involved IGF1R but not NR2F2, and was associated with an addition of telomere repeat sequences (TTAGGG) at the end of the truncated chromosome. The results provide further support for the notion that terminal deletions are healed by de novo addition of telomere sequences essential for chromosome stability and DNA replication. Furthermore, while growth failure and mental retardation are primarily explained by loss of IGF1R, the occurrence of VSD might suggest the existence of a cardiac anomaly gene, other than the candidate cardiac anomaly gene NR2F2, in the deleted region.},
}
@article {pmid21239767,
year = {2010},
author = {Young, NS},
title = {Telomere biology and telomere diseases: implications for practice and research.},
journal = {Hematology. American Society of Hematology. Education Program},
volume = {2010},
number = {},
pages = {30-35},
pmid = {21239767},
issn = {1520-4383},
support = {Z01 HL002315-21/ImNIH/Intramural NIH HHS/United States ; Z01 HL002315-22/ImNIH/Intramural NIH HHS/United States ; Z01 HL002315-23/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Animals ; *Biomedical Research ; Disease/*genetics ; Humans ; *Medicine ; Neoplasms/genetics ; Telomere/*metabolism ; },
abstract = {The recent recognition of genetic defects in telomeres and telomere repair in multiple human diseases has practical implications for hematologists and oncologists and their patients; consequences for future clinical research in hematology and other subspecialties; and even importance in the interpretation of animal experiments involving cell propagation. Telomere diseases include constitutional marrow failure as dyskeratosis congenita, some apparently acquired aplastic anemia, myelodysplasia and acute myeloid leukemia; pulmonary fibrosis; and hepatic nodular regenerative hyperplasia and cirrhosis. Accelerated telomere attrition is a likely pathophysiology of cancer arising from chronic inflammation. Telomerase can be modulated by sex hormones, which may explain the activity of androgens in marrow failure. Measurement of telomere length of peripheral blood leukocytes is a simple screening clinical assay. Detection of a mutation in a patient has implications for therapy, prognosis, monitoring, and genetic counseling. For research in hematology and oncology, telomere biology could be assessed as a risk for secondary malignancies and in graft-versus-host disease, for progression in a variety of blood cancers, and as potentially modifiable by hormone replacement strategies.},
}
@article {pmid21234654,
year = {2011},
author = {Farrag, W and Eid, M and El-Shazly, S and Abdallah, M},
title = {Angiotensin II type 1 receptor gene polymorphism and telomere shortening in essential hypertension.},
journal = {Molecular and cellular biochemistry},
volume = {351},
number = {1-2},
pages = {13-18},
pmid = {21234654},
issn = {1573-4919},
mesh = {Adult ; Base Sequence ; Case-Control Studies ; DNA Primers ; Female ; Gene Frequency ; Humans ; Hypertension/*genetics ; Male ; Middle Aged ; Polymerase Chain Reaction ; *Polymorphism, Genetic ; Polymorphism, Restriction Fragment Length ; Receptor, Angiotensin, Type 1/*genetics ; *Telomere ; },
abstract = {Several genetic studies were carried out among hypertensive patients to assess allelic association at the 1166 position of the 3' untranslated region of angiotensin II type 1 receptor gene. In addition, attempts have also been made to find out whether telomere length attrition is associated with hypertension. The main aim of this study was to examine the association of A1166C polymorphism of angiotensin II type 1 receptor and telomere length with essential hypertension in Egyptian people. Angiotensin II type 1 genotyping and relative telomere length were investigated by PCR in 40 patients of essential hypertension and 15 healthy controls. The homozygous AA1166 allele frequency was 92.8% among the studied subjects. There was no intergroup variation in A allele frequency in normotensive group. The frequency of homozygous A allele was significantly higher in hypertensive than normotensive subjects (97.5 and 80%, respectively) with higher frequencies in male patients. The average telomere length ratio was significantly shorter in hypertensive than in normal subjects (1.08 ± 0.3 and 1.54 ± 0.18, respectively). No correlation was observed between telomere length ratio and body mass index. This study suggests that the homozygous A1166 allele of angiotensin II type 1 and short telomeres may be predisposing factors for essential hypertension in Egyptians and may be involved in the pathogenesis of the disease. Further strategies for treating high-risk patients could result in prevention or delay of end organ damage.},
}
@article {pmid21222203,
year = {2010},
author = {Marión, RM and Blasco, MA},
title = {Telomeres and telomerase in adult stem cells and pluripotent embryonic stem cells.},
journal = {Advances in experimental medicine and biology},
volume = {695},
number = {},
pages = {118-131},
doi = {10.1007/978-1-4419-7037-4_9},
pmid = {21222203},
issn = {0065-2598},
mesh = {Adult ; Cellular Reprogramming ; Embryonic Stem Cells/cytology ; Humans ; Pluripotent Stem Cells/cytology ; *Telomerase/genetics ; *Telomere/metabolism ; },
abstract = {Telomerase expression is silenced in most adult somatic tissues with the exception of adult stem cell (SC) compartments, which have the property of having the longest telomeres within a given tissue. Adult SC compartments suffer from telomere shortening associated with organismal aging until telomeres reach a critically short length, which is sufficient to impair SC mobilization and tissue regeneration. p53 is essential to prevent that adult SC carrying telomere damage contribute to tissue regeneration, indicating a novel role for p53 in SC behavior and therefore in the maintenance of tissue fitness and tumor protection. Reprogramming of adult differentiated cells to a more pluripotent state has been achieved by various means, including somatic cell nuclear transfer and, more recently, by over expression of specific transcription factors to generate the so-called induced pluripotent stem (iPS) cells. Recent work has demonstrated that telomeric chromatin is remodeled and telomeres are elongated by telomerase during nuclear reprogramming. These findings suggest that the structure of telomeric chromatin is dynamic and controlled by epigenetic programs associated with the differentiation potential of cells, which are reversed by reprogramming. This chapter will focus on the current knowledge of the role of telomeres and telomerase in adult SC, as well as during nuclear reprograming to generate pluripotent embryonic-like stem cells from adult differentiated cells.},
}
@article {pmid21220516,
year = {2011},
author = {Tong, XJ and Li, QJ and Duan, YM and Liu, NN and Zhang, ML and Zhou, JQ},
title = {Est1 protects telomeres and inhibits subtelomeric y'-element recombination.},
journal = {Molecular and cellular biology},
volume = {31},
number = {6},
pages = {1263-1274},
pmid = {21220516},
issn = {1098-5549},
mesh = {DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/genetics/metabolism ; G-Quadruplexes ; Gene Deletion ; Mutation ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {In the budding yeast Saccharomyces cerevisiae, the structure and function of telomeres are maintained by binding proteins, such as Cdc13-Stn1-Ten1 (CST), Yku, and the telomerase complex. Like CST and Yku, telomerase also plays a role in telomere protection or capping. Unlike CST and Yku, however, the underlying molecular mechanism of telomerase-mediated telomere protection remains unclear. In this study, we employed both the CDC13-EST1 fusion gene and the separation-of-function allele est1-D514A to elucidate that Est1 provided a telomere protection pathway that was independent of both the CST and Yku pathways. Est1's ability to convert single-stranded telomeric DNA into a G quadruplex was required for telomerase-mediated telomere protection function. Additionally, Est1 maintained the integrity of telomeres by suppressing the recombination of subtelomeric Y' elements. Our results demonstrate that one major functional role that Est1 brings to the telomerase complex is the capping or protection of telomeres.},
}
@article {pmid21217703,
year = {2011},
author = {Chen, Y and Rai, R and Zhou, ZR and Kanoh, J and Ribeyre, C and Yang, Y and Zheng, H and Damay, P and Wang, F and Tsujii, H and Hiraoka, Y and Shore, D and Hu, HY and Chang, S and Lei, M},
title = {A conserved motif within RAP1 has diversified roles in telomere protection and regulation in different organisms.},
journal = {Nature structural &amp; molecular biology},
volume = {18},
number = {2},
pages = {213-221},
pmid = {21217703},
issn = {1545-9985},
support = {R01 AG028888/AG/NIA NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; R01 GM083015/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Cells, Cultured ; Crystallography, X-Ray ; Fungal Proteins/chemistry/genetics/metabolism ; HeLa Cells ; Humans ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Nuclear Magnetic Resonance, Biomolecular ; Protein Binding ; Protein Interaction Domains and Motifs ; Saccharomycetales/chemistry/genetics/metabolism ; Schizosaccharomyces/chemistry/genetics/metabolism ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/*chemistry/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/chemistry/genetics/metabolism ; },
abstract = {Repressor activator protein 1 (RAP1) is the most highly conserved telomere protein. It is involved in protecting chromosome ends in fission yeast and promoting gene silencing in Saccharomyces cerevisiae, whereas it represses homology-directed recombination at telomeres in mammals. To understand how RAP1 has such diverse functions at telomeres, we solved the crystal or solution structures of the RAP1 C-terminal (RCT) domains of RAP1 from multiple organisms in complex with their respective protein-binding partners. Our analysis establishes RAP1(RCT) as an evolutionarily conserved protein-protein interaction module. In mammalian and fission yeast cells, this module interacts with TRF2 and Taz1, respectively, targeting RAP1 to chromosome ends for telomere protection. In contrast, S. cerevisiae RAP1 uses its RCT domain to recruit Sir3 to telomeres to mediate gene silencing. Together, our results show that, depending on the organism, the evolutionarily conserved RAP1 RCT motif has diverse functional roles at telomeres.},
}
@article {pmid21215935,
year = {2011},
author = {Blumenstiel, J},
title = {Telomeres: a new means to an end.},
journal = {Current biology : CB},
volume = {21},
number = {1},
pages = {R32-4},
doi = {10.1016/j.cub.2010.11.054},
pmid = {21215935},
issn = {1879-0445},
mesh = {Animals ; Biological Evolution ; Chromatin ; Drosophila/*genetics/*physiology ; Female ; *Gene Duplication ; Male ; Ovum/cytology ; Spermatozoa/cytology ; *Telomere ; },
abstract = {Gene duplication provides an important evolutionary mechanism for functional diversification. A new study in Drosophila indicates that gene duplication has allowed telomere protection to be partitioned between the soma and the specialized chromatin environment of sperm.},
}
@article {pmid21212735,
year = {2011},
author = {Kitada, T and Schleker, T and Sperling, AS and Xie, W and Gasser, SM and Grunstein, M},
title = {γH2A is a component of yeast heterochromatin required for telomere elongation.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {10},
number = {2},
pages = {293-300},
pmid = {21212735},
issn = {1551-4005},
support = {R01 GM042421/GM/NIGMS NIH HHS/United States ; R01 GM042421-21/GM/NIGMS NIH HHS/United States ; GM42421/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Division ; Chromatin Immunoprecipitation ; Gene Silencing ; Heterochromatin/*metabolism ; Histones/genetics/*metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Mutation ; Protein Serine-Threonine Kinases/metabolism ; S Phase ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Telomere/*metabolism/physiology ; Telomere-Binding Proteins/metabolism ; },
abstract = {Histones of heterochromatin are deacetylated in yeast and methylated in more complex eukaryotes to regulate heterochromatin structure and gene silencing. Here, we report that histone H2A phosphorylated at serine 129 (γH2A) in Saccharomyces cerevisiae is a conceptually new type of heterochromatin modification that functions downstream of silent chromatin assembly. We show that γH2A is enriched throughout yeast telomeric and silent mating locus (HM) heterochromatin where γH2A results from the action of kinases Tel1 and Mec1. Interestingly, mutation of γH2A has no apparent effect on the binding of Sir (silent information regulator) complex or on gene silencing. In contrast, deletion of SIR3 abolishes the formation of γH2A at heterochromatin. To address the function of γH2A, we used a Δrif1 mutant strain in which telomeres are excessively elongated to show that γH2A is required for the optimal recruitment of Cdc13, a regulator of telomere elongation, and for telomere elongation itself. Thus, a histone modification that parallels Sir3 protein binding is shown here to be dispensable for the formation of a silent structure but is important for a crucial heterochromatin-specific downstream function in telomere homeostasis.},
}
@article {pmid21211774,
year = {2011},
author = {Bernardes de Jesus, B and Blasco, MA},
title = {Aging by telomere loss can be reversed.},
journal = {Cell stem cell},
volume = {8},
number = {1},
pages = {3-4},
doi = {10.1016/j.stem.2010.12.013},
pmid = {21211774},
issn = {1875-9777},
abstract = {Recently in Nature, Jaskelioff et al. (2010) demonstrated that multiple aging phenotypes in a mouse model of accelerated telomere loss can be reversed within 4 weeks of reactivating telomerase. This raises the major question of whether physiological aging, likely caused by a combination of molecular defects, may also be reversible.},
}
@article {pmid21209389,
year = {2010},
author = {de Lange, T},
title = {How shelterin solves the telomere end-protection problem.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {75},
number = {},
pages = {167-177},
doi = {10.1101/sqb.2010.75.017},
pmid = {21209389},
issn = {1943-4456},
support = {OD000379/OD/NIH HHS/United States ; AG016642/AG/NIA NIH HHS/United States ; CA076027/CA/NCI NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; GM049046/GM/NIGMS NIH HHS/United States ; R01 CA076027/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Base Sequence ; Cell Cycle Proteins/metabolism ; DNA Repair/genetics ; DNA-Binding Proteins/metabolism ; Humans ; Mice ; Models, Biological ; Molecular Sequence Data ; Protein Serine-Threonine Kinases/metabolism ; Recombination, Genetic ; Telomere/*metabolism ; Telomere-Binding Proteins/chemistry/*metabolism ; Tumor Suppressor Proteins/metabolism ; },
abstract = {The symphony of the human genome concludes with a long Gregorian chant of TTAGGG repeats. This monotonous coda represents one of the most complex problems in chromosome biology: the question of how cells distinguish their natural chromosome ends from double-strand breaks elsewhere in the genome. McClintock's classic finding of chromosome breakage-fusion-bridge cycles, first reported by her at one of the early Cold Spring Harbor Laboratory Symposia (the ninth), served as a prelude to this question. The 75th Cold Spring Harbor Laboratory Symposium marks the completion of a series of mouse gene deletion experiments that revealed DNA-damage-response pathways that threaten chromosome ends and how the components of the telomeric shelterin complex prevent activation of these pathways.},
}
@article {pmid21209253,
year = {2011},
author = {Wills, LP and Schnellmann, RG},
title = {Telomeres and telomerase in renal health.},
journal = {Journal of the American Society of Nephrology : JASN},
volume = {22},
number = {1},
pages = {39-41},
doi = {10.1681/ASN.2010060662},
pmid = {21209253},
issn = {1533-3450},
support = {DK062028/DK/NIDDK NIH HHS/United States ; DK071997/DK/NIDDK NIH HHS/United States ; ES012878/ES/NIEHS NIH HHS/United States ; GM084147/GM/NIGMS NIH HHS/United States ; T32 CA119945-04/CA/NCI NIH HHS/United States ; },
mesh = {Aging/physiology ; Apoptosis/physiology ; Chronic Disease ; Disease Progression ; Humans ; Kidney/pathology/physiopathology ; Kidney Diseases/*physiopathology ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {The role of telomeres and telomerase in human biology has been studied since the early 1990s because telomere attrition is implicated in various diseases including cardiovascular dysfunction, carcinogenesis, and the progression of acute kidney injury. Telomeric length is a reliable indicator of intrinsic biologic age and a surrogate for the mitotic clock. Because the prevalence of chronic kidney disease increases with age, telomere length and telomerase activity may play a role in its progression.},
}
@article {pmid21209122,
year = {2011},
author = {Savage, SA and Giri, N and Jessop, L and Pike, K and Plona, T and Burdett, L and Alter, BP},
title = {Sequence analysis of the shelterin telomere protection complex genes in dyskeratosis congenita.},
journal = {Journal of medical genetics},
volume = {48},
number = {4},
pages = {285-288},
doi = {10.1136/jmg.2010.082727},
pmid = {21209122},
issn = {1468-6244},
support = {//Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; Dyskeratosis Congenita/*genetics ; Female ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Sequence Analysis, DNA ; Shelterin Complex ; Telomere/genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {BACKGROUND: Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterised by dystrophic nails, abnormal skin pigmentation and oral leukoplakia. Patients are at very high risk of cancer and other medical problems. They have exceedingly short telomeres for their age and approximately 60% have a germline mutation in a gene important in telomere biology (DKC1, TERC, TERT, TINF2, NOP10, or NHP2). The shelterin complex consists of six proteins encoded by TINF2, ACD, POT1, TERF1, TERF2 and TERF2IP, which are essential for telomeric stability. TINF2 mutations are present in 11-25% of patients with DC.<br><br>METHODS: Bi-directional sequence analysis was conducted of all exons, intron-exon boundaries and the proximal promoter of the other five shelterin genes to determine whether mutations in these genes were associated with DC. Sixteen mutation-negative patients, nine with DC and seven patients with short telomeres and bone marrow failure, were evaluated.<br><br>RESULTS: Two variants were identified, ACD Ex1+189 G&#x2192;A and TERF1 Ex9+59 G&#x2192;A, which were each present in one patient and a healthy parent but absent in 364 controls. Three other variants were rare (<1%) but present in both patients and controls.<br><br>DISCUSSION: These data suggest that except for TINF2, mutations in shelterin genes are not a common cause of DC.},
}
@article {pmid21208905,
year = {2011},
author = {Castelo-Branco, P and Zhang, C and Lipman, T and Fujitani, M and Hansford, L and Clarke, I and Harley, CB and Tressler, R and Malkin, D and Walker, E and Kaplan, DR and Dirks, P and Tabori, U},
title = {Neural tumor-initiating cells have distinct telomere maintenance and can be safely targeted for telomerase inhibition.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {17},
number = {1},
pages = {111-121},
doi = {10.1158/1078-0432.CCR-10-2075},
pmid = {21208905},
issn = {1557-3265},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Animals ; Cell Line ; Cell Proliferation ; Glioma/enzymology/metabolism/*therapy ; Humans ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Neoplastic Stem Cells/*metabolism ; Neural Crest ; Neural Stem Cells/*metabolism ; Neuroblastoma/enzymology/metabolism/*therapy ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/*metabolism ; },
abstract = {PURPOSE: Cancer recurrence is one of the major setbacks in oncology. Maintaining telomeres is essential for sustaining the limitless replicative potential of such cancers. Because telomerase is thought to be active in all tumor cells and normal stem cells, telomerase inhibition may be nonspecific and have detrimental effects on tissue maintenance and development by affecting normal stem cell self-renewal.<br><br>METHODS: We examined telomerase activity, telomere maintenance, and stem cell maturation in tumor subpopulations from freshly resected gliomas, long-term, primary, neural tumor-initiating cells (TIC) and corresponding normal stem cell lines. We then tested the efficacy of the telomerase inhibitor Imetelstat on propagation and self-renewal capacity of TIC and normal stem cells in vitro and in vivo.<br><br>RESULTS: Telomerase was undetectable in the majority of tumor cells and specific to the TIC subpopulation that possessed critically short telomeres. In contrast, normal tissue stem cells had longer telomeres and undetectable telomerase activity and were insensitive to telomerase inhibition, which results in proliferation arrest, cell maturation, and DNA damage in neural TIC. Significant survival benefit and late tumor growth arrest of neuroblastoma TIC were observed in a xenograft model (P = 0.02). Furthermore, neural TIC exhibited irreversible loss of self-renewal and stem cell capabilities even after cessation of treatment in vitro and in vivo.<br><br>CONCLUSIONS: TIC exhaustion with telomerase inhibition and lack of telomerase dependency in normal stem cells add new dimensions to the telomere hypothesis and suggest that targeting TIC with telomerase inhibitors may represent a specific and safe therapeutic approach for tumors of neural origin.},
}
@article {pmid21203871,
year = {2011},
author = {Sellmann, L and de Beer, D and Bartels, M and Opalka, B and Nückel, H and Dührsen, U and Dürig, J and Seifert, M and Siemer, D and Küppers, R and Baerlocher, GM and Röth, A},
title = {Telomeres and prognosis in patients with chronic lymphocytic leukaemia.},
journal = {International journal of hematology},
volume = {93},
number = {1},
pages = {74-82},
pmid = {21203871},
issn = {1865-3774},
mesh = {Disease-Free Survival ; Female ; Humans ; Immunoglobulin Heavy Chains/*genetics ; Immunoglobulin Variable Region/*genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/metabolism/*mortality/pathology/therapy ; Male ; *Mutation ; Retrospective Studies ; Survival Rate ; Telomere/*genetics ; },
abstract = {In the present study, telomere length, telomerase activity, the mutation load of immunoglobulin variable heavy chain (IGHV) genes, and established prognostic factors were investigated in 78 patients with chronic lymphocytic leukaemia (CLL) to determine the impact of telomere biology on the pathogenesis of CLL. Telomere length was measured by an automated multi-colour flow-FISH, and an age-independent delta telomere length (ΔTL) was calculated. CLL with unmutated IGHV genes was associated with shorter telomeres (p = 0.002). Furthermore, we observed a linear correlation between the frequency of IGHV gene mutations and elongation of telomeres (r = 0.509, p < 0.001). With respect to prognosis, a threshold ΔTL of -4.2 kb was the best predictor for progression-free and overall survival. ΔTL was not significantly altered over time or with therapy. The correlation between the mutational load in IGHV genes and the ΔTL in CLL might reflect the initial telomere length of the putative cell of origin (pre- versus post-germinal center B cells). In conclusion, the ΔTL is a reliable prognostic marker for patients with CLL. Short telomeres and high telomerase activity as occurs in some patients with CLL with a worse prognosis might be an ideal target for treatment with telomerase inhibitors.},
}
@article {pmid21199492,
year = {2012},
author = {Vulliamy, T and Beswick, R and Kirwan, MJ and Hossain, U and Walne, AJ and Dokal, I},
title = {Telomere length measurement can distinguish pathogenic from non-pathogenic variants in the shelterin component, TIN2.},
journal = {Clinical genetics},
volume = {81},
number = {1},
pages = {76-81},
pmid = {21199492},
issn = {1399-0004},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Adolescent ; Adult ; Aged ; Amino Acid Sequence ; Amino Acid Substitution ; Child ; Child, Preschool ; Chromosomes, Human, Pair 7/genetics/metabolism ; DNA Mutational Analysis ; Dyskeratosis Congenita/diagnosis/*genetics/metabolism/pathology ; Female ; Fetal Growth Retardation/diagnosis/genetics/metabolism ; Frameshift Mutation ; Genome, Human ; Humans ; Infant ; Intellectual Disability/diagnosis/genetics/metabolism ; Male ; Microcephaly/diagnosis/genetics/metabolism ; Middle Aged ; Molecular Sequence Data ; Mutation, Missense ; Phenotype ; Sequence Alignment ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {Dyskeratosis congenita (DC) is a heterogeneous bone marrow failure syndrome with seven disease-causing genes identified to date, six of which are linked to telomere maintenance. Mutations in one of these genes (TINF2), which encodes a component of the shelterin complex, are associated with particularly short telomeres. Among the 224 consecutive patients with different forms of bone marrow failure (46 with DC, 122 with aplastic anaemia and 57 with some features of DC), we have identified 16 new families with variants in exon 6 of the TINF2 gene, eight of which are novel. We observe that the phenotype associated with these mutations extends to a severe early presentation, not always classified as DC. In addition, we see that some of the variants identified are not associated with short telomeres and are also found in asymptomatic individuals. In the absence of any direct functional assay, the data indicates that the telomere length measurement can inform us as to which variants in TINF2 are pathogenic and which may be non-pathogenic.},
}
@article {pmid21199331,
year = {2011},
author = {Bilsland, AE and Cairney, CJ and Keith, WN},
title = {Targeting the telomere and shelterin complex for cancer therapy: current views and future perspectives.},
journal = {Journal of cellular and molecular medicine},
volume = {15},
number = {2},
pages = {179-186},
pmid = {21199331},
issn = {1582-4934},
support = {//Cancer Research UK/United Kingdom ; },
mesh = {Apoptosis ; Cellular Senescence ; DNA Damage ; Enzyme Inhibitors/*therapeutic use ; Humans ; Molecular Targeted Therapy ; Neoplasms/*therapy ; Shelterin Complex ; Telomerase/antagonists &amp; inhibitors/genetics/metabolism ; Telomere/*metabolism ; Telomere Homeostasis ; *Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Aberrant telomere homeostasis is essential for cell immortality, enabling cells to evade telomere dependent senescence. Disruption of telomere structure and function in cancer cells is highly toxic as shown by detailed pre-clinical evaluation of telomerase inhibitors. Under telomerase inhibition, cells must divide sufficiently frequently to allow one or more telomeres to shorten to an unprotected length. Functioning telomeres are disguised from the DNA damage machinery by DNA remodelling and other activities of the telomere binding complex shelterin. Direct interference with shelterin has been shown to result in cell killing and small molecules directly targeting telomere DNA also have anti-tumour effects partially dependent on shelterin disruption. However, shelterin components have not generally been regarded as therapeutic targets in their own right. In this review, we explore the possibilities for therapeutic targeting of the shelterin complex.},
}
@article {pmid21196166,
year = {2011},
author = {Pinto, AR and Li, H and Nicholls, C and Liu, JP},
title = {Telomere protein complexes and interactions with telomerase in telomere maintenance.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {16},
number = {1},
pages = {187-207},
doi = {10.2741/3683},
pmid = {21196166},
issn = {2768-6698},
mesh = {Alternative Splicing ; Animals ; DNA/metabolism ; DNA-Activated Protein Kinase/metabolism ; Humans ; Multiprotein Complexes/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Shelterin Complex ; Telomerase/*physiology ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomeres are the termini of linear chromosomes. They are composed of DNA and DNA-binding proteins critical for maintaining chromosome integrity and cellular function. Telomere binding proteins regulate the structure and function of telomeres through the formation of different complexes with telomeric DNA. Double- and single-stranded telomeric DNA binding protein complexes have shared and unique functions that regulate telomere homeostasis. Recent studies have shown that telomerase interacts with several telomere-binding protein complexes including shelterin, CST, DNA-dependent protein kinase (DNA-PK) and MRN. The present review describes the recognised telomere-binding protein complexes, sub-complex exchanges and inter-complex molecular interactions. It also discusses the evidence suggesting that telomerase reverse transcriptase (TERT) switches between different complexes. Studies of the telomere protein inter-complex interactions and the switching of components between complexes provide insight into their fundamental roles of programming telomere length and configuration, and thus cell proliferative potential.},
}
@article {pmid21195167,
year = {2011},
author = {Masi, S and Salpea, KD and Li, K and Parkar, M and Nibali, L and Donos, N and Patel, K and Taddei, S and Deanfield, JE and D'Aiuto, F and Humphries, SE},
title = {Oxidative stress, chronic inflammation, and telomere length in patients with periodontitis.},
journal = {Free radical biology &amp; medicine},
volume = {50},
number = {6},
pages = {730-735},
doi = {10.1016/j.freeradbiomed.2010.12.031},
pmid = {21195167},
issn = {1873-4596},
support = {RG/08/008/25291/BHF_/British Heart Foundation/United Kingdom ; FS/06/053/BHF_/British Heart Foundation/United Kingdom ; RG2008/08/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Adult ; C-Reactive Protein/analysis ; Female ; Humans ; *Leukocytes ; Male ; Middle Aged ; *Oxidative Stress ; Periodontitis/*pathology/*physiopathology ; Polymerase Chain Reaction ; Reactive Oxygen Species/analysis ; Telomere/*ultrastructure ; },
abstract = {The aim of this study was to determine leukocyte telomere length (LTL) in individuals with periodontitis and controls, exploring its relationship with systemic inflammation and oxidative stress. Five hundred sixty-three participants were recruited for this case-control study: 356 subjects with and 207 subjects without periodontitis. LTL was measured by a qPCR technique from leukocytes' DNA. Global measures of oxidative stress (reactive oxygen metabolites) and biological antioxidant potential in plasma were performed together with high-sensitivity assays for C-reactive protein (CRP). Leukocyte counts and lipid profiles were performed using standard biochemistry. Cases had higher levels of CRP (2.1±3.7mg/L vs 1.3±5.4mg/L, P<0.001) and reactive oxygen metabolites (378.1±121.1 U Carr vs 277.4±108.6 U Carr, P<0.001) compared to controls. Overall, cases had shorter LTL with respect to controls (1.23±0.42 vs 1.12±0.31T/S ratio, P=0.006), independent of age, gender, ethnicity, and smoking habit. When divided by subgroup of periodontal diagnosis (chronic, n=285; aggressive, n=71), only chronic cases displayed shorter LTL (P=0.01). LTL was negatively correlated with age (P=0.001; R=-0.2), oxidative stress (P=0.008; R=-0.2), and severity of periodontitis (P=0.003; R=-0.2) in both the whole population and the subgroups (cases and controls). We conclude that shorter telomere lengths are associated with a diagnosis of periodontitis and their measures correlate with the oxidative stress and severity of disease.},
}
@article {pmid21194798,
year = {2012},
author = {Harris, SE and Martin-Ruiz, C and von Zglinicki, T and Starr, JM and Deary, IJ},
title = {Telomere length and aging biomarkers in 70-year-olds: the Lothian Birth Cohort 1936.},
journal = {Neurobiology of aging},
volume = {33},
number = {7},
pages = {1486.e3-8},
doi = {10.1016/j.neurobiolaging.2010.11.013},
pmid = {21194798},
issn = {1558-1497},
support = {G0601333/MRC_/Medical Research Council/United Kingdom ; G0700704/84698/MRC_/Medical Research Council/United Kingdom ; G0700704/84698/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Aged ; Aging/*genetics/physiology/psychology ; Biomarkers/blood ; C-Reactive Protein/metabolism ; Child ; Cohort Studies ; Female ; Humans ; Male ; Scotland/epidemiology ; Sex Characteristics ; Telomere/*genetics ; Telomere Homeostasis/genetics ; },
abstract = {Telomeres are nucleo-protein complexes at the end of eukaryotic chromosomes. They shorten each time a somatic cell replicates and this shortening is modulated by the effects of oxidative stress. Previous studies have associated telomere length with a number of age-related outcomes and it is hypothesized to be a quantitative indicator of aging. We tested this hypothesis in a cohort of ∼1000 relatively healthy 70-year-old Scots (the Lothian Birth Cohort of 1936: LBC1936) on whom we have measures of cognition, physical health and associated traits, and social class. Telomeres were significantly longer in males than females (p < 0.0001). Longer telomeres were associated, in females only, with higher general cognitive ability scores (p = 0.022) and lower C-reactive protein levels (p = 0.014). Telomere length was not associated with any of the other measured cognitive, physical, or social traits. In conclusion we find little evidence that telomere length is a significant biomarker of normal aging in important cognitive and physical domains.},
}
@article {pmid21190904,
year = {2011},
author = {Noël, JF and Wellinger, RJ},
title = {Abrupt telomere losses and reduced end-resection can explain accelerated senescence of Smc5/6 mutants lacking telomerase.},
journal = {DNA repair},
volume = {10},
number = {3},
pages = {271-282},
doi = {10.1016/j.dnarep.2010.11.010},
pmid = {21190904},
issn = {1568-7856},
support = {MOP 12616//Canadian Institutes of Health Research/Canada ; },
mesh = {Cell Cycle Proteins/*genetics/metabolism ; Cell Proliferation ; Chromosome Breakage ; DNA Replication/genetics ; DNA, Fungal/biosynthesis/genetics ; DNA-Binding Proteins/metabolism ; *Mutation ; Recombination, Genetic/genetics ; SUMO-1 Protein/metabolism ; Saccharomyces cerevisiae/*cytology/enzymology/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Telomerase/*deficiency ; Telomere/*genetics ; Telomere-Binding Proteins/metabolism ; },
abstract = {The highly conserved Structural Maintenance of Chromosome (SMC) proteins are crucial for the formation of three essential complexes involved in high fidelity chromosome transmission during cell division. Recently, the Smc5/6 complex has been reported to be important for telomere maintenance in yeast and also in cancerous human ALT cells, where it could function in a homologous recombination-based (HR) telomere maintenance pathway. Here, we investigate the possible roles of the budding yeast Smc5/6 complex in maintaining appropriate chromosome end-structures allowing cell survival in absence of telomerase. The results show that cells harbouring mutant alleles of genes encoding Smc5/6-complex proteins rapidly stop growing after telomerase loss. Furthermore, this telomerase-induced growth arrest is much more pronounced as compared to cultures with a functional Smc5/6-complex. Bulk telomere sequence loss is not increased in the mutant cells and the evidence suggests that Smc5/6 slows senescence through a partially HR-independent pathway. We propose that in yeast, the Smc5/6-complex is required for efficient and timely termination of DNA replication and repair at telomeres to avoid stochastic telomere loss during cell division. Consistent with this hypothesis, sequencing of telomeres from telomerase-positive smc5/6 mutant cells revealed a higher frequency of telomere breakage events. Finally, the results also show that on dysfunctional telomeres, the generation of 3'-single stranded DNA is impaired, suggesting that the complex may also participate in the formation of single-stranded overhangs which are thought to be the substrates for telomere repeat replenishment in the absence of telomerase.},
}
@article {pmid21189492,
year = {2010},
author = {Savage, SA and Bertuch, AA},
title = {The genetics and clinical manifestations of telomere biology disorders.},
journal = {Genetics in medicine : official journal of the American College of Medical Genetics},
volume = {12},
number = {12},
pages = {753-764},
pmid = {21189492},
issn = {1530-0366},
support = {ZIA CP010190-07//Intramural NIH HHS/United States ; },
mesh = {Chromosome Disorders/*genetics/*pathology ; Genetic Predisposition to Disease ; Humans ; Inheritance Patterns/genetics ; Mutation ; Telomerase/genetics/metabolism ; Telomere/*genetics/*pathology ; },
abstract = {Telomere biology disorders are a complex set of illnesses defined by the presence of very short telomeres. Individuals with classic dyskeratosis congenita have the most severe phenotype, characterized by the triad of nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. More significantly, these individuals are at very high risk of bone marrow failure, cancer, and pulmonary fibrosis. A mutation in one of six different telomere biology genes can be identified in 50–60% of these individuals. DKC1, TERC, TERT, NOP10, and NHP2 encode components of telomerase or a telomerase-associated factor and TINF2, a telomeric protein. Progressively shorter telomeres are inherited from generation to generation in autosomal dominant dyskeratosis congenita, resulting in disease anticipation. Up to 10% of individuals with apparently acquired aplastic anemia or idiopathic pulmonary fibrosis also have short telomeres and mutations in TERC or TERT. Similar findings have been seen in individuals with liver fibrosis or acute myelogenous leukemia. This report reviews basic aspects of telomere biology and telomere length measurement, and the clinical and genetic features of those disorders that constitute our current understanding of the spectrum of illness caused by defects in telomere biology. We also suggest a grouping schema for the telomere disorders.},
}
@article {pmid21187476,
year = {2010},
author = {Matsuo, T and Shimose, S and Kubo, T and Fujimori, J and Yasunaga, Y and Ochi, M},
title = {Alternative lengthening of telomeres as a prognostic factor in malignant fibrous histiocytomas of bone.},
journal = {Anticancer research},
volume = {30},
number = {12},
pages = {4959-4962},
pmid = {21187476},
issn = {1791-7530},
mesh = {Adult ; Aged ; Bone Neoplasms/*genetics/metabolism ; Female ; Histiocytoma, Malignant Fibrous/*genetics/metabolism ; Humans ; Male ; Middle Aged ; Prognosis ; RNA, Messenger/biosynthesis/genetics ; Telomerase/biosynthesis/genetics/metabolism ; Telomere/*genetics ; Young Adult ; },
abstract = {BACKGROUND: Malignant fibrous histiocytoma (MFH) of bone is a rare primary malignant neoplasm. Recent studies indicate a positive correlation between the telomere maintenance mechanism and tumour aggressiveness in sarcomas. This study was undertaken to analyse the clinical significance of telomere factors in primary tumour samples from patients with MFHs of bone.<br><br>MATERIALS AND METHODS: Telomerase activity was measured in ten bone MFH specimens using a PCR-based TRAP assay. Telomere length was assessed using gel hybridisation. Quantitative detection of human telomerase reverse transcriptase (hTERT) was performed by real-time PCR.<br><br>RESULTS: Telomerase activity and hTERT expression were detectable in 100% of tumour samples and 50% of tumour samples had evidence of engagement of the alternative lengthening of telomere (ALT) mechanisms. ALT was a significant prognostic risk factor (p = 0.0316).<br><br>CONCLUSION: This study suggests that the presence of ALT telomere maintenance mechanisms indicates a poor prognosis for bone MFH patients.},
}
@article {pmid21187328,
year = {2010},
author = {Palacios, JA and Herranz, D and De Bonis, ML and Velasco, S and Serrano, M and Blasco, MA},
title = {SIRT1 contributes to telomere maintenance and augments global homologous recombination.},
journal = {The Journal of cell biology},
volume = {191},
number = {7},
pages = {1299-1313},
pmid = {21187328},
issn = {1540-8140},
support = {232854/ERC_/European Research Council/International ; },
mesh = {Acetylation ; Aging/genetics ; Animals ; Centromere/genetics/metabolism ; Chromosome Fragility/genetics ; Chromosomes/genetics/metabolism ; DNA Damage/genetics ; DNA Methylation/genetics ; Embryo, Mammalian/cytology ; Fibroblasts/metabolism ; Gene Expression/genetics ; Histone Deacetylases/metabolism ; Histones/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Kidney/metabolism ; Liver/metabolism ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Knockout ; Protein Binding/genetics ; RNA/genetics ; Recombination, Genetic/*genetics ; Sirtuin 1/*genetics ; Sister Chromatid Exchange/genetics ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Yeast Sir2 deacetylase is a component of the silent information regulator (SIR) complex encompassing Sir2/Sir3/Sir4. Sir2 is recruited to telomeres through Rap1, and this complex spreads into subtelomeric DNA via histone deacetylation. However, potential functions at telomeres for SIRT1, the mammalian orthologue of yeast Sir2, are less clear. We studied both loss of function (SIRT1 deficient) and gain of function (SIRT1(super)) mouse models. Our results indicate that SIRT1 is a positive regulator of telomere length in vivo and attenuates telomere shortening associated with aging, an effect dependent on telomerase activity. Using chromatin immunoprecipitation assays, we find that SIRT1 interacts with telomeric repeats in vivo. In addition, SIRT1 overexpression increases homologous recombination throughout the entire genome, including telomeres, centromeres, and chromosome arms. These findings link SIRT1 to telomere biology and global DNA repair and provide new mechanistic explanations for the known functions of SIRT1 in protection from DNA damage and some age-associated pathologies.},
}
@article {pmid21181890,
year = {2010},
author = {Zhang, J and Ju, Z},
title = {Telomere, DNA damage, and oxidative stress in stem cell aging.},
journal = {Birth defects research. Part C, Embryo today : reviews},
volume = {90},
number = {4},
pages = {297-307},
doi = {10.1002/bdrc.20190},
pmid = {21181890},
issn = {1542-9768},
mesh = {Apoptosis/genetics ; Cellular Senescence/*genetics ; *DNA Damage ; Hematopoietic Stem Cells/cytology ; Humans ; Neoplasms/genetics ; Oxidative Stress/*genetics ; Stem Cells/cytology/*physiology ; *Telomere ; },
abstract = {"Stem cell aging" is a novel concept that developed together with the advances of stem cell biology, especially the sophisticated prospectively isolation and characterization of multipotent somatic tissue stem cells. Although being immortal in principle, stem cells can also undergo aging processes and potentially contribute to organismal aging. The impact of an age-dependent decline of stem cell function weighs differently in organs with high or low rates of cell turnover. Nonetheless, most of the organ systems undergo age-dependent loss of homeostasis and functionality, and emerging evidence showed that this has to do with the aging of resident stem cells in the organ systems. The mechanisms of stem cell aging and its real contribution to human aging remain to be defined. Many antitumor mechanisms protect potential malignant transformation of stem cell by inducing apoptosis or senescence but simultaneously provoke stem cell aging. In this review, we try to discuss several concept of stem cell aging and summarize recent progression on the molecular mechanisms of stem cell aging.},
}
@article {pmid21181527,
year = {2011},
author = {Xu, C and Yu, W},
title = {Telomere truncation in plants.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {701},
number = {},
pages = {113-130},
doi = {10.1007/978-1-61737-957-4_6},
pmid = {21181527},
issn = {1940-6029},
mesh = {*Chromosomes, Plant ; Rhizobium/genetics ; *Telomere ; *Transformation, Genetic ; Zea mays/*genetics ; },
abstract = {Telomeres are highly repetitive sequences at the ends of chromosomes that act as protection structure for chromosome stability. The integration of telomere sequences into the genome by genetic transformation can create chromosome instability because the integrated telomere sequences tend to form de novo telomeres at the site of integration. Thus, telomere repeats can be used to generate minichromosomes by telomere-mediated chromosome truncation in both plants and animals for chromosome studies as well as the applications in genetic engineering as engineered minichromosomes or artificial chromosomes. This protocol describes the procedure for telomere truncation of maize chromosomes by genetic transformation of telomere-containing constructs by both Agrobacterium- and biolistic-mediated transformations.},
}
@article {pmid21179579,
year = {2010},
author = {Khurana, JS and Xu, J and Weng, Z and Theurkauf, WE},
title = {Distinct functions for the Drosophila piRNA pathway in genome maintenance and telomere protection.},
journal = {PLoS genetics},
volume = {6},
number = {12},
pages = {e1001246},
pmid = {21179579},
issn = {1553-7404},
support = {R01 HD049116/HD/NICHD NIH HHS/United States ; R01HD049116/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Argonaute Proteins ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster/cytology/embryology/genetics/*metabolism ; *Genome, Insect ; Meiosis ; Peptide Initiation Factors/genetics/*metabolism ; RNA Helicases/genetics/*metabolism ; RNA, Small Interfering/genetics/metabolism ; Signal Transduction ; Telomere/genetics/*metabolism ; },
abstract = {Transposons and other selfish DNA elements can be found in all phyla, and mobilization of these elements can compromise genome integrity. The piRNA (PIWI-interacting RNA) pathway silences transposons in the germline, but it is unclear if this pathway has additional functions during development. Here we show that mutations in the Drosophila piRNA pathway genes, armi, aub, ago3, and rhi, lead to extensive fragmentation of the zygotic genome during the cleavage stage of embryonic divisions. Additionally, aub and armi show defects in telomere resolution during meiosis and the cleavage divisions; and mutations in lig-IV, which disrupt non-homologous end joining, suppress these fusions. By contrast, lig-IV mutations enhance chromosome fragmentation. Chromatin immunoprecipitation studies show that aub and armi mutations disrupt telomere binding of HOAP, which is a component of the telomere protection complex, and reduce expression of a subpopulation of 19- to 22-nt telomere-specific piRNAs. Mutations in rhi and ago3, by contrast, do not block HOAP binding or production of these piRNAs. These findings uncover genetically separable functions for the Drosophila piRNA pathway. The aub, armi, rhi, and ago3 genes silence transposons and maintain chromosome integrity during cleavage-stage embryonic divisions. However, the aub and armi genes have an additional function in assembly of the telomere protection complex.},
}
@article {pmid21178172,
year = {2011},
author = {Iqbal, K and Kues, WA and Baulain, U and Garrels, W and Herrmann, D and Niemann, H},
title = {Species-specific telomere length differences between blastocyst cell compartments and ectopic telomere extension in early bovine embryos by human telomerase reverse transcriptase.},
journal = {Biology of reproduction},
volume = {84},
number = {4},
pages = {723-733},
doi = {10.1095/biolreprod.110.087205},
pmid = {21178172},
issn = {1529-7268},
mesh = {Animals ; Base Sequence ; Blastocyst/cytology/*metabolism ; Blastocyst Inner Cell Mass/cytology/metabolism ; Cattle ; Cell Compartmentation ; DNA Methylation ; DNA Primers/genetics ; Embryonic Development ; Female ; Green Fluorescent Proteins/genetics/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; Pregnancy ; Recombinant Proteins/genetics/metabolism ; Species Specificity ; Telomerase/genetics/*metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {The enzyme telomerase is active in germ cells and is critically involved in maintenance of telomere length in successive generations. In preimplantation mammalian embryos, telomerase activity is present from the morula stage onward and is associated with an increase in telomere length in blastocysts. Herein, we show that telomere length regulation in murine and bovine blastocysts differed between trophectodermal and inner cell mass cells in a species-specific manner. Ectopic expression of human telomerase reverse transcriptase (TERT) in bovine embryos increased telomerase activity and in turn increased telomere length. Transient expression of human TERT could be targeted to the 4-cell to morula stages and to the morula to blastocyst stages using unmodified and cytosine-methylated expression plasmids, respectively. Introduction of human TERT constructs in bovine embryos resulted in functional telomerase expression and effective telomere elongation, allowing us to study the effects on embryonic development. Ultimately, these studies may lead to a large-animal model for telomere regulation and aging.},
}
@article {pmid21177376,
year = {2011},
author = {Zappulla, DC and Goodrich, KJ and Arthur, JR and Gurski, LA and Denham, EM and Stellwagen, AE and Cech, TR},
title = {Ku can contribute to telomere lengthening in yeast at multiple positions in the telomerase RNP.},
journal = {RNA (New York, N.Y.)},
volume = {17},
number = {2},
pages = {298-311},
pmid = {21177376},
issn = {1469-9001},
support = {GM28039/GM/NIGMS NIH HHS/United States ; R00 GM080400-04/GM/NIGMS NIH HHS/United States ; K99 GM080400-01/GM/NIGMS NIH HHS/United States ; R00 GM080400-05/GM/NIGMS NIH HHS/United States ; R00 GM080400-03/GM/NIGMS NIH HHS/United States ; R01 GM028039/GM/NIGMS NIH HHS/United States ; R00 GM080400/GM/NIGMS NIH HHS/United States ; K99 GM080400/GM/NIGMS NIH HHS/United States ; R00 GM80400/GM/NIGMS NIH HHS/United States ; K99 GM80400/GM/NIGMS NIH HHS/United States ; K99 GM080400-02/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites ; DNA-Binding Proteins/*chemistry/metabolism ; Kinetics ; Models, Biological ; RNA/*chemistry/metabolism ; RNA, Fungal/chemistry/metabolism ; Ribonucleoproteins/*chemistry/metabolism ; Saccharomyces cerevisiae Proteins/*chemistry/metabolism ; Telomerase/*chemistry/metabolism ; Telomere/chemistry/metabolism ; },
abstract = {Unlike ribonucleoprotein complexes that have a highly ordered overall architecture, such as the ribosome, yeast telomerase appears to be much more loosely constrained. Here, we investigate the importance of positioning of the Ku subunit within the 1157-nt yeast telomerase RNA (TLC1). Deletion of the 48-nt Ku-binding hairpin in TLC1 RNA (tlc1Δ48) reduces telomere length, survival of cells with gross chromosomal rearrangements, and de novo telomere addition at a broken chromosome end. To test the function of Ku at novel positions in the telomerase RNP, we reintroduced its binding site into tlc1Δ48 RNA at position 446 or 1029. We found that Ku bound to these repositioned sites in vivo and telomere length increased slightly, but statistically significantly. The ability of telomerase to promote survival of cells with gross chromosomal rearrangements by healing damaged chromosome arms was also partially restored, whereas the kinetics of DNA addition to a specific chromosome break was delayed. Having two Ku sites in TLC1 caused progressive hyperelongation of a variable subset of telomeres, consistent with Ku's role in telomerase recruitment to chromosome ends. The number of Ku-binding sites in TLC1 contributed to telomerase RNA abundance in vivo but was only partially responsible for telomere length phenotypes. Thus, telomerase RNA levels and telomere length regulation can be modulated by the number of Ku sites in telomerase RNA. Furthermore, there is substantial flexibility in the relative positioning of Ku in the telomerase RNP for native telomere length maintenance, although not as much flexibility as for the essential Est1p subunit.},
}
@article {pmid21176960,
year = {2011},
author = {Brugat, T and Nguyen-Khac, F and Merle-Béral, H and Delic, J},
title = {Concomitant telomere shortening, acquisition of multiple chromosomal aberrations and in vitro resistance to apoptosis in a single case of progressive CLL.},
journal = {Leukemia research},
volume = {35},
number = {5},
pages = {e37-40},
doi = {10.1016/j.leukres.2010.11.026},
pmid = {21176960},
issn = {1873-5835},
mesh = {Apoptosis/genetics/*physiology ; Cells, Cultured ; *Chromosome Aberrations ; Disease Progression ; *Drug Resistance, Neoplasm/genetics ; Fatal Outcome ; Follow-Up Studies ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/*pathology ; Telomere/*genetics/metabolism/pathology ; },
}
@article {pmid21176396,
year = {2011},
author = {Ho, JH and Chen, YF and Ma, WH and Tseng, TC and Chen, MH and Lee, OK},
title = {Cell contact accelerates replicative senescence of human mesenchymal stem cells independent of telomere shortening and p53 activation: roles of Ras and oxidative stress.},
journal = {Cell transplantation},
volume = {20},
number = {8},
pages = {1209-1220},
doi = {10.3727/096368910X546562},
pmid = {21176396},
issn = {1555-3892},
mesh = {Adenosine Triphosphate/biosynthesis ; Adolescent ; Adult ; Antioxidants/metabolism ; Bone Marrow Cells/cytology ; Cell Adhesion ; Cell Cycle Checkpoints ; Cells, Cultured ; *Cellular Senescence ; Connexin 43/metabolism ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; G1 Phase ; Humans ; Intracellular Space/metabolism ; Mesenchymal Stem Cells/*cytology/enzymology ; Middle Aged ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Resting Phase, Cell Cycle ; *Telomere Shortening ; Time Factors ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation ; Young Adult ; ras Proteins/*metabolism ; },
abstract = {Mesenchymal stem cells (MSCs) are of great therapeutic potentials due to their multilineage differentiation capabilities. Before transplantation, in vitro culture expansion of MSCs is necessary to get desired cell number. We observed that cell contact accelerated replicative senescence during such process. To confirm the finding as well as to investigate the underlying mechanisms, we cultured both human bone marrow- and umbilical cord blood-derived MSCs under noncontact culture (subculture performed at 60-70% of confluence), or contact culture (cell passage performed at 100% of confluence). It was found that MSCs reached cellular senescence earlier in contact culture, and the doubling time was significantly prolonged. Marked increase of senescence-associated β-galactosidase-positive staining was also observed as a result of cell contact. Cell cycle analysis revealed increased frequency of cell cycle arrest after contact culture. It was noted, however, that the telomere length was not altered during contact-induced acceleration of senescence. Moreover, cell cycle checkpoint regulator P53 expression was not affected by cell contact. Marked increase in intracellular reactive oxygen species (ROS) and a concomitant decrease in the activities of antioxidative enzymes were also observed during contact-induced senescence. Importantly, increased p16(INK4a) following Ras upregulation was found after contact culture. Taken together, cell contact induced accelerated senescence of MSCs, which is telomere shortening and p53 independent. ROS accumulation due to defective ROS clearance function together with Ras and p16(INK4a) upregulation play an important role in contact-induced senescence of MSCs. Overconfluence should therefore be avoided during in vitro culture expansion of MSCs in order to maintain their qualities for clinical application purposes. The contact-induced senescence model reported in this study will serve as a useful model system that allows further study of the molecular mechanisms of senescence in MSCs.},
}
@article {pmid21176337,
year = {2010},
author = {Zhan, Y and Feng, R and Yi, ZS and Song, LL and Wang, Q and Xu, M and Wei, YQ},
title = {Simultaneous analysis of telomere length and cell surface antigen in leukemia by multicolor Flow-FISH.},
journal = {Zhongguo shi yan xue ye xue za zhi},
volume = {18},
number = {6},
pages = {1395-1401},
pmid = {21176337},
issn = {1009-2137},
mesh = {Adolescent ; Adult ; Aged ; Antigens, Surface/analysis ; Female ; Flow Cytometry ; Humans ; *In Situ Hybridization, Fluorescence ; Leukemia/*genetics/*immunology ; Male ; Middle Aged ; Neoplasm, Residual/genetics/immunology ; Recurrence ; Remission Induction ; Telomere/*genetics ; Young Adult ; },
abstract = {This study was purposed to explore the feasibility of simultaneous analysis of telomere length and cell surface antigen by multicolor Flow-FISH to assess minimal residual disease (MRD) in leukemia. The telomere length in 34 leukemia patients versus 20 normal controls was compared by using Flow-FISH, and the relationship between telomere length and therapeutic effect and prognosis was analyzed preliminarily. As for those patients with follow-up samples, the changes of telomere length combined with surface antigen in different courses of disease were observed by multicolor Flow-FISH. The results indicated that the telomere length of de novo patients was significantly shorter than that of controls except the patients in chronic myeloid leukemia-chronic phase (CML-CP). The shorter telomere, the lower complete remission (CR) rates were observed in acute leukemia cases and the shorter duration of CP before onset of blast phase (BP) occurred in CML cases. The acute leukemia patients showed longer telomere and fewer cells expressed the related antigen after CR. The telomere length of cases with continued CR remained at normal level during remission, and there was no increased expression of the specific antigen. However, the telomere of relapsed cases shortened again after relapse with elevated specific antigen expression. In the relapsed cases, the telomere of related antigen positive cells shortened ahead of telomere length change of the whole cells and morphologic change of bone marrow cells. It is concluded that analysis of telomere length by flow-FISH manifests the significance for monitoring disease conditions, estimating prognosis and guiding therapy in all kinds of leukemia. The simultaneous analysis of telomere length and cell surface antigen by multicolor flow-FISH may monitor abnormal clone or clonal evolution to predict recurrence more sensitively and specifically, and may provide a promising and widely applicable method for monitoring MRD in leukemia.},
}
@article {pmid21172147,
year = {2010},
author = {Li, P and Tong, Y and Mao, M},
title = {[Relationship between telomere/telomerase and the developmental origins of metabolic syndrome].},
journal = {Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics},
volume = {12},
number = {12},
pages = {1008-1012},
pmid = {21172147},
issn = {1008-8830},
mesh = {Humans ; Metabolic Syndrome ; *Telomerase/metabolism ; *Telomere ; },
}
@article {pmid21171996,
year = {2010},
author = {Gaspin, C and Rami, JF and Lescure, B},
title = {Distribution of short interstitial telomere motifs in two plant genomes: putative origin and function.},
journal = {BMC plant biology},
volume = {10},
number = {},
pages = {283},
pmid = {21171996},
issn = {1471-2229},
mesh = {3' Untranslated Regions/genetics ; 5' Flanking Region/genetics ; 5' Untranslated Regions/genetics ; Arabidopsis/*genetics ; Base Sequence ; Gene Expression Regulation, Plant ; Genes, Plant/genetics ; Genome, Plant/*genetics ; Molecular Sequence Data ; Oryza/*genetics ; Promoter Regions, Genetic/genetics ; Regulatory Sequences, Nucleic Acid/genetics ; Ribosomal Proteins/genetics ; Telomere/*genetics ; },
abstract = {BACKGROUND: Short interstitial telomere motifs (telo boxes) are short sequences identical to plant telomere repeat units. They are observed within the 5' region of several genes over-expressed in cycling cells. In synergy with various cis-acting elements, these motifs participate in the activation of expression. Here, we have analysed the distribution of telo boxes within Arabidopsis thaliana and Oryza sativa genomes and their association with genes involved in the biogenesis of the translational apparatus.<br><br>RESULTS: Our analysis showed that the distribution of the telo box (AAACCCTA) in different genomic regions of A. thaliana and O. sativa is not random. As is also the case for plant microsatellites, they are preferentially located in the 5' flanking regions of genes, mainly within the 5' UTR, and distributed as a gradient along the direction of transcription. As previously reported in Arabidopsis, a conserved topological association of telo boxes with site II or TEF cis-acting elements is observed in almost all promoters of genes encoding ribosomal proteins in O. sativa. Such a conserved promoter organization can be found in other genes involved in the biogenesis of the translational machinery including rRNA processing proteins and snoRNAs. Strikingly, the association of telo boxes with site II motifs or TEF boxes is conserved in promoters of genes harbouring snoRNA clusters nested within an intron as well as in the 5' flanking regions of non-intronic snoRNA genes. Thus, the search for associations between telo boxes and site II motifs or TEF box in plant genomes could provide a useful tool for characterizing new cryptic RNA pol II promoters.<br><br>CONCLUSIONS: The data reported in this work support the model previously proposed for the spreading of telo boxes within plant genomes and provide new insights into a putative process for the acquisition of microsatellites in plants. The association of telo boxes with site II or TEF cis-acting elements appears to be an essential feature of plant genes involved in the biogenesis of ribosomes and clearly indicates that most plant snoRNAs are RNA pol II products.},
}
@article {pmid21171086,
year = {2011},
author = {Aida, J and Yokoyama, A and Izumiyama, N and Nakamura, K and Ishikawa, N and Poon, SS and Fujiwara, M and Sawabe, M and Matsuura, M and Arai, T and Takubo, K},
title = {Alcoholics show reduced telomere length in the oesophagus.},
journal = {The Journal of pathology},
volume = {223},
number = {3},
pages = {410-416},
doi = {10.1002/path.2817},
pmid = {21171086},
issn = {1096-9896},
mesh = {Adult ; Aged ; Aged, 80 and over ; Alcoholism/*genetics/pathology ; Biopsy ; Case-Control Studies ; Esophagoscopy ; Esophagus/*pathology ; Female ; Humans ; In Situ Hybridization, Fluorescence/methods ; Male ; Middle Aged ; Mucous Membrane/pathology ; Telomere/*pathology ; },
abstract = {Telomeres are repetitive G-rich DNA sequences located at the ends of chromosomes. Chromosomal and genomic instability due to telomere dysfunction plays an important role in carcinogenesis. To study telomere shortening in the oesophageal epithelium of alcoholics, we measured the telomere lengths of basal and parabasal cells in comparison with those of non-alcoholics using Q-FISH and our original software, Tissue Telo, and also assessed histological inflammation. Telomeres in basal cells were significantly shorter in alcoholics than in age-matched normal controls. Prominent histological findings of chronic inflammation were not evident in either alcoholics or non-alcoholics. Our finding that telomeres in the oesophageal epithelium are shorter in alcoholics than in non-alcoholics indicates that telomere shortening may be associated with the frequent occurrence of squamous cell carcinoma in alcoholics. Further studies to clarify the reason for the large annual loss of telomere length with rapid turnover or lower telomerase activity in the oesophageal epithelium of alcoholics will be necessary.},
}
@article {pmid21169126,
year = {2011},
author = {Dioni, L and Hoxha, M and Nordio, F and Bonzini, M and Tarantini, L and Albetti, B and Savarese, A and Schwartz, J and Bertazzi, PA and Apostoli, P and Hou, L and Baccarelli, A},
title = {Effects of short-term exposure to inhalable particulate matter on telomere length, telomerase expression, and telomerase methylation in steel workers.},
journal = {Environmental health perspectives},
volume = {119},
number = {5},
pages = {622-627},
pmid = {21169126},
issn = {1552-9924},
support = {P30 ES000002/ES/NIEHS NIH HHS/United States ; RC1 ES018461-02/ES/NIEHS NIH HHS/United States ; RC1 ES018461/ES/NIEHS NIH HHS/United States ; RC1 ES018461-01/ES/NIEHS NIH HHS/United States ; 5P30ES000002/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; Humans ; Inhalation ; Male ; Methylation/drug effects ; Middle Aged ; Occupational Exposure/adverse effects ; Particulate Matter/*toxicity ; *Steel ; Telomerase/*metabolism ; Telomere/*drug effects ; },
abstract = {BACKGROUND: Shortened leukocyte telomere length (LTL) is a marker of cardiovascular risk that has been recently associated with long-term exposure to ambient particulate matter (PM). However, LTL is increased during acute inflammation and allows for rapid proliferation of inflammatory cells. Whether short-term exposure to proinflammatory exposures such as PM increases LTL has never been evaluated.<br><br>OBJECTIVES: We investigated the effects of acute exposure to metal-rich PM on blood LTL, as well as molecular mechanisms contributing to LTL regulation in a group of steel workers with high PM exposure.<br><br>METHODS: We measured LTL, as well as mRNA expression and promoter DNA methylation of the telomerase catalytic enzyme gene [human telomerase reverse transcriptase (hTERT)] in blood samples obtained from 63 steel workers on the first day of a workweek (baseline) and after 3 days of work (postexposure).<br><br>RESULTS: LTL was significantly increased in postexposure (mean &#xb1; SD, 1.43 &#xb1; 0.51) compared with baseline samples (1.23 &#xb1; 0.28, p-value < 0.001). Postexposure LTL was positively associated with PM&#x2081;&#x2080; (&#x3b2; = 0.30, p-value = 0.002 for 90th vs. 10th percentile exposure) and PM&#x2081; (&#x3b2; = 0.29, p-value = 0.042) exposure levels in regression models adjusting for multiple covariates. hTERT expression was lower in postexposure samples (1.31 &#xb1; 0.75) than at baseline (1.68 &#xb1; 0.86, p-value < 0.001), but the decrease in hTERT expression did not show a dose-response relationship with PM. We found no exposure-related differences in the methylation of any of the CpG sites investigated in the hTERT promoter.<br><br>CONCLUSIONS: Short-term exposure to PM caused a rapid increase in blood LTL. The LTL increase did not appear to be mediated by PM-related changes in hTERT expression and methylation.},
}
@article {pmid21156783,
year = {2011},
author = {Berardinelli, F and Antoccia, A and Cherubini, R and De Nadal, V and Gerardi, S and Tanzarella, C and Sgura, A},
title = {Telomere alterations and genomic instability in long-term cultures of normal human fibroblasts irradiated with X rays and protons.},
journal = {Radiation protection dosimetry},
volume = {143},
number = {2-4},
pages = {274-278},
doi = {10.1093/rpd/ncq486},
pmid = {21156783},
issn = {1742-3406},
mesh = {Cell Line ; Chromosomal Instability/*genetics/*radiation effects ; Dose-Response Relationship, Radiation ; Humans ; Photons ; Radiation Dosage ; Telomere/*genetics/*radiation effects/ultrastructure ; X-Rays ; },
abstract = {Telomeres are the end of linear chromosomes, responsible for chromosome stability and cell viability. It is well known that radiations are able to induce chromosome instability but it has not yet been investigated whether telomere structure is affected by the radiation exposure and if radiations with different quality act in a different way on telomeres. The effect of radiations with different quality on telomere structure and chromosome instability was analysed in human primary fibroblasts exposed to X rays or low-energy protons (28.5 keV μm(-1)). Telomere length was evaluated at different harvesting times from 24 h up to 360 h (15 days), whereas chromosome instability was evaluated in terms of sister chromatid exchanges (SCEs) (48 h from irradiation) and chromosome painting (360 h from irradiation). Results indicated a delayed telomere lengthening 360 h after X-ray treatment, whereas protons were able to induce such a lengthening shortly from irradiation as well as at longer harvesting times. Data obtained from chromosome instability analysis indicated an increase of SCE frequency only after proton irradiation, but, on the contrary, at the longer harvesting time chromosome painting analysis displayed a higher frequency of aberrations after X-ray treatment, suggesting a role of selective process against highly damaged cells.},
}
@article {pmid21149347,
year = {2011},
author = {Giltay, EJ and Hageman, GJ and Kromhout, D},
title = {Spurious association between telomere length reduction over time and baseline telomere length.},
journal = {International journal of epidemiology},
volume = {40},
number = {3},
pages = {839-40; author reply 840-1},
doi = {10.1093/ije/dyq235},
pmid = {21149347},
issn = {1464-3685},
mesh = {Aging/*genetics ; Female ; Humans ; Male ; *Mortality ; *Smoking ; Telomere/*chemistry ; },
}
@article {pmid21148804,
year = {2011},
author = {Kiecolt-Glaser, JK and Gouin, JP and Weng, NP and Malarkey, WB and Beversdorf, DQ and Glaser, R},
title = {Childhood adversity heightens the impact of later-life caregiving stress on telomere length and inflammation.},
journal = {Psychosomatic medicine},
volume = {73},
number = {1},
pages = {16-22},
pmid = {21148804},
issn = {1534-7796},
support = {CA16058/CA/NCI NIH HHS/United States ; R21 AG025732/AG/NIA NIH HHS/United States ; UL1 RR025755-04/RR/NCRR NIH HHS/United States ; P30 CA016058-25/CA/NCI NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; AG025732/AG/NIA NIH HHS/United States ; UL1RR025755/RR/NCRR NIH HHS/United States ; R21 AG025732-02/AG/NIA NIH HHS/United States ; R21 AG025732-02S1/AG/NIA NIH HHS/United States ; UL1 RR025755/RR/NCRR NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adult ; Adult Survivors of Child Abuse/*psychology ; Aged ; Body Mass Index ; Caregivers/*psychology ; Cellular Senescence ; Child ; Child Abuse/psychology ; Depression/blood/*diagnosis ; Female ; Humans ; Inflammation/*diagnosis/psychology ; Interleukin-6/blood ; Leukocytes, Mononuclear/physiology ; *Life Change Events ; Male ; Psychoneuroimmunology ; Risk Factors ; Stress, Psychological/blood/*diagnosis/psychology ; Surveys and Questionnaires ; Telomere/genetics/physiology ; Tumor Necrosis Factor-alpha/blood ; },
abstract = {OBJECTIVE: To address the question of whether childhood abuse and other adversities have lasting, detectable consequences for inflammation and cell aging late in life, and whether the effects are large enough to be discernible beyond that of a major chronic stressor, dementia family caregiving. Previous research on the physical health consequences of childhood abuse and other adversities has been based on data from young or middle-aged adults.<br><br>METHOD: In this community sample of 132 healthy older adults (mean age = 69.70 years; standard deviation = 10.14), including 58 dementia family caregivers and 74 non-caregivers, blood samples were analyzed for interleukin (IL)-6, tumor necrosis factor (TNF)-&#x3b1;, and telomere length, a measure of cell aging. Depressive symptoms were assessed by the Center for Epidemiological Studies Depression Scale.<br><br>RESULTS: After controlling for age, caregiving status, gender, body mass index, exercise, and sleep, the presence of multiple childhood adversities was related to both heightened IL-6 (0.37 &#xb1; 0.03 log10 pg/mL versus 0.44 &#xb1; 0.03 log10 pg/mL) and shorter telomeres (6.51 &#xb1; 0.17 Kb versus 5.87 &#xb1; 0.20 Kb), compared with the absence of adversity; the telomere difference could translate into a 7- to 15-year difference in life span. Abuse was associated with heightened IL-6 and TNF-&#x3b1; levels; for TNF-&#x3b1;, this relationship was magnified in caregivers compared with controls. Moreover, abuse and caregiving status were associated significantly and independently with higher levels of depressive symptoms.<br><br>CONCLUSIONS: Adverse childhood events are related to continued vulnerability among older adults, enhancing the impact of chronic stressors. Childhood adversities cast a very long shadow.},
}
@article {pmid21148753,
year = {2011},
author = {Bechard, LH and Jamieson, N and McEachern, MJ},
title = {Recombination can cause telomere elongations as well as truncations deep within telomeres in wild-type Kluyveromyces lactis cells.},
journal = {Eukaryotic cell},
volume = {10},
number = {2},
pages = {226-236},
pmid = {21148753},
issn = {1535-9786},
support = {R01 GM061645/GM/NIGMS NIH HHS/United States ; GM 61645/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Gene Deletion ; Humans ; Kluyveromyces/cytology/*genetics/metabolism ; Meiosis/genetics ; Rad52 DNA Repair and Recombination Protein/genetics ; *Recombination, Genetic ; Restriction Mapping ; Sequence Deletion ; Telomere/genetics/*metabolism ; },
abstract = {In this study, we examined the role of recombination at the telomeres of the yeast Kluyveromyces lactis. We demonstrated that an abnormally long and mutationally tagged telomere was subject to high rates of telomere rapid deletion (TRD) that preferentially truncated the telomere to near-wild-type size. Unlike the case in Saccharomyces cerevisiae, however, there was not a great increase in TRD in meiosis. About half of mitotic TRD events were associated with deep turnover of telomeric repeats, suggesting that telomeres were often cleaved to well below normal length prior to being reextended by telomerase. Despite its high rate of TRD, the long telomere showed no increase in the rate of subtelomeric gene conversion, a highly sensitive test of telomere dysfunction. We also showed that the long telomere was subject to appreciable rates of becoming elongated substantially further through a recombinational mechanism that added additional tagged repeats. Finally, we showed that the deep turnover that occurs within normal-length telomeres was diminished in the absence of RAD52. Taken together, our results suggest that homologous recombination is a significant process acting on both abnormally long and normally sized telomeres in K. lactis.},
}
@article {pmid21145579,
year = {2010},
author = {Sacco, A and Mourkioti, F and Tran, R and Choi, J and Llewellyn, M and Kraft, P and Shkreli, M and Delp, S and Pomerantz, JH and Artandi, SE and Blau, HM},
title = {Short telomeres and stem cell exhaustion model Duchenne muscular dystrophy in mdx/mTR mice.},
journal = {Cell},
volume = {143},
number = {7},
pages = {1059-1071},
pmid = {21145579},
issn = {1097-4172},
support = {R37 AG009521/AG/NIA NIH HHS/United States ; U01 HL100397/HL/NHLBI NIH HHS/United States ; AG020961/AG/NIA NIH HHS/United States ; R01 AG009521-25/AG/NIA NIH HHS/United States ; AG009521/AG/NIA NIH HHS/United States ; R01 AG020961/AG/NIA NIH HHS/United States ; R01 AG009521/AG/NIA NIH HHS/United States ; R01 HL096113/HL/NHLBI NIH HHS/United States ; R01 AG020961-08/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Cell Proliferation ; *Disease Models, Animal ; Dystrophin/metabolism ; Humans ; *Mice ; Mice, Inbred mdx ; Muscular Dystrophy, Animal/genetics ; Muscular Dystrophy, Duchenne/*genetics ; Prejudice ; Stem Cells/*metabolism ; Telomere/*metabolism ; },
abstract = {In Duchenne muscular dystrophy (DMD), dystrophin mutation leads to progressive lethal skeletal muscle degeneration. For unknown reasons, dystrophin deficiency does not recapitulate DMD in mice (mdx), which have mild skeletal muscle defects and potent regenerative capacity. We postulated that human DMD progression is a consequence of loss of functional muscle stem cells (MuSC), and the mild mouse mdx phenotype results from greater MuSC reserve fueled by longer telomeres. We report that mdx mice lacking the RNA component of telomerase (mdx/mTR) have shortened telomeres in muscle cells and severe muscular dystrophy that progressively worsens with age. Muscle wasting severity parallels a decline in MuSC regenerative capacity and is ameliorated histologically by transplantation of wild-type MuSC. These data show that DMD progression results, in part, from a cell-autonomous failure of MuSC to maintain the damage-repair cycle initiated by dystrophin deficiency. The essential role of MuSC function has therapeutic implications for DMD.},
}
@article {pmid21144828,
year = {2011},
author = {Park, JE and Woo, SR and Kang, CM and Juhn, KM and Ju, YJ and Shin, HJ and Joo, HY and Park, ER and Park, IC and Hong, SH and Hwang, SG and Lee, JK and Kim, HK and Cho, MH and Park, GH and Lee, KH},
title = {Paclitaxel stimulates chromosomal fusion and instability in cells with dysfunctional telomeres: implication in multinucleation and chemosensitization.},
journal = {Biochemical and biophysical research communications},
volume = {404},
number = {2},
pages = {615-621},
doi = {10.1016/j.bbrc.2010.12.018},
pmid = {21144828},
issn = {1090-2104},
mesh = {Animals ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis ; Cell Cycle ; *Chromosomal Instability ; Chromosomes, Mammalian/*drug effects/genetics/metabolism ; Drug Resistance, Neoplasm/*genetics ; Mice ; Paclitaxel/*pharmacology ; Telomere/genetics/*metabolism ; Tubulin Modulators/*pharmacology ; },
abstract = {The anticancer effect of paclitaxel is attributable principally to irreversible promotion of microtubule stabilization and is hampered upon development of chemoresistance by tumor cells. Telomere shortening, and eventual telomere erosion, evoke chromosomal instability, resulting in particular cellular responses. Using telomerase-deficient cells derived from mTREC-/-p53-/- mice, here we show that, upon telomere erosion, paclitaxel propagates chromosomal instability by stimulating chromosomal end-to-end fusions and delaying the development of multinucleation. The end-to-end fusions involve both the p- and q-arms in cells in which telomeres are dysfunctional. Paclitaxel-induced chromosomal fusions were accompanied by prolonged G2/M cell cycle arrest, delayed multinucleation, and apoptosis. Telomere dysfunctional cells with mutlinucleation eventually underwent apoptosis. Thus, as telomere erosion proceeds, paclitaxel stimulates chromosomal fusion and instability, and both apoptosis and chemosensitization eventually develop.},
}
@article {pmid21144060,
year = {2010},
author = {Knecht, H and Brüderlein, S and Wegener, S and Lichtensztejn, D and Lichtensztejn, Z and Lemieux, B and Möller, P and Mai, S},
title = {3D nuclear organization of telomeres in the Hodgkin cell lines U-HO1 and U-HO1-PTPN1: PTPN1 expression prevents the formation of very short telomeres including "t-stumps".},
journal = {BMC cell biology},
volume = {11},
number = {},
pages = {99},
pmid = {21144060},
issn = {1471-2121},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Apoptosis ; Cell Line ; G2 Phase ; Hodgkin Disease/enzymology/metabolism/*pathology ; Humans ; Imaging, Three-Dimensional ; In Situ Hybridization, Fluorescence ; Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics/*metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reed-Sternberg Cells/metabolism/*ultrastructure ; STAT5 Transcription Factor/metabolism ; Telomerase/metabolism ; Telomere/chemistry/metabolism/*ultrastructure ; Tumor Suppressor Proteins/metabolism ; },
abstract = {BACKGROUND: In cancer cells the three-dimensional (3D) telomere organization of interphase nuclei into a telomeric disk is heavily distorted and aggregates are found. In Hodgkin's lymphoma quantitative FISH (3D Q-FISH) reveals a major impact of nuclear telomere dynamics during the transition form mononuclear Hodgkin (H) to diagnostic multinuclear Reed-Sternberg (RS) cells. In vitro and in vivo formation of RS-cells is associated with the increase of very short telomeres including "t-stumps", telomere loss, telomeric aggregate formation and the generation of "ghost nuclei".<br><br>RESULTS: Here we analyze the 3D telomere dynamics by Q-FISH in the novel Hodgkin cell line U-HO1 and its non-receptor protein-tyrosine phosphatase N1 (PTPN1) stable transfectant U-HO1-PTPN1, derived from a primary refractory Hodgkin's lymphoma. Both cell lines show equally high telomerase activity but U-HO1-PTPN differs from U-HO1 by a three times longer doubling time, low STAT5A expression, accumulation of RS-cells (p < 0.0001) and a fourfold increased number of apoptotic cells.As expected, multinuclear U-HO1-RS-cells and multinuclear U-HO1-PTPN1-RS-cells differ from their mononuclear H-precursors by their nuclear volume (p < 0.0001), the number of telomeres (p < 0.0001) and the increase in telomere aggregates (p < 0.003). Surprisingly, U-HO1-RS cells differ from U-HO1-PTPN1-RS-cells by a highly significant increase of very short telomeres including "t-stumps" (p < 0.0001).<br><br>CONCLUSION: Abundant RS-cells without additional very short telomeres including "t-stumps", high rate of apoptosis, but low STAT5A expression, are hallmarks of the U-HO1-PTPN1 cell line. These characteristics are independent of telomerase activity. Thus, PTPN1 induced dephosphorylation of STAT5 with consecutive lack of Akt/PKB activation and cellular arrest in G&#x2082;, promoting induction of apoptosis, appears as a possible pathogenetic mechanism deserving further experimental investigation.},
}
@article {pmid21142655,
year = {2010},
author = {Pepper, C and Baird, DM},
title = {Shortened telomeres: a driving force behind leukemia?.},
journal = {Future oncology (London, England)},
volume = {6},
number = {11},
pages = {1681-1686},
doi = {10.2217/fon.10.135},
pmid = {21142655},
issn = {1744-8301},
mesh = {Animals ; *Genomic Instability ; Humans ; Leukemia/*genetics/metabolism ; Mutation ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; },
}
@article {pmid21130233,
year = {2010},
author = {Teyssier, JR and Ragot, S and Donzel, A and Chauvet-Gelinier, JC},
title = {[Telomeres in the brain cortex of depressive patients].},
journal = {L'Encephale},
volume = {36},
number = {6},
pages = {491-494},
doi = {10.1016/j.encep.2010.04.004},
pmid = {21130233},
issn = {0013-7006},
mesh = {Adult ; Affective Disorders, Psychotic/*genetics/mortality/pathology ; Age Factors ; Apoptosis/*genetics ; Cause of Death ; Depressive Disorder, Major/*genetics/mortality/pathology ; Female ; France ; Humans ; Leukocytes/pathology ; Male ; Middle Aged ; Occipital Lobe/*pathology ; Polymerase Chain Reaction ; Reference Values ; Suicide/psychology ; Telomere/*genetics ; },
abstract = {BACKGROUND: Telomeres are complex structures formed by the end of the DNA molecule at the tip of chromosomal arms. The telomeric sequence, which results from the repetition of the hexanucleotide TTAGGG, is partly single strand and is associated with more than ten proteins, including the enzyme telomerase. Because of the characteristics of the DNA replication process, only telomerase is able to elongate the telomeric sequence. Since the telomerase gene is repressed in virtually all the somatic cells, telomeres progressively shorten at each S phase of the cell cycle, and this shortening is accelerated by oxidative stress. A critically shortened telomere activates the genetic program of cell senescence and/or apoptosis. The telomere length measured in peripheral blood leucocytes is considered a reliable marker of biological age, mortality risk and exposure to various pathological conditions, including cardiovascular disease, dementia and metabolic syndrome. Telomere erosion has been observed in psychiatric disorders including schizophrenia and mood disorders, suggesting an accelerated aging of 10 to 20 years. Whether this peripheral dynamic is reflected by a similar pattern in the brain remains unknown. To address this issue, we have measured the telomere length in the occipital DNA cortex of 24 patients with major depressive disorder and 12 controls (donated by the Stanley Research Institute).<br><br>METHODOLOGY: The mean telomere length has been evaluated by a real time quantitative PCR technique, which amplified the telomere sequence and a reference single copy sequence. Results have been expressed by the ratios of Ct obtained for the two amplification curves.<br><br>RESULTS: The mean Ct values were strictly identical (0.79 &#xb1; 0.001) and the 36 PCR curves were coincident.<br><br>DISCUSSION: This study demonstrates for the first time that there is no shortening of telomeres in the cortex of patients with depressive disorder. Previous results have shown that in normal tissues telomeres length is inversely correlated to age, even in non proliferating tissues, but that the change is minimal in the brain. Thus, although consistent evidence for the role of a systemic and brain inflammation associated oxidative stress in depression has been provided, it must be concluded that the cerebral state of telomeres is not affected by the mechanism operating in the leucocytes. This observation raises the issue of the relation between the psychiatric pathological process and the peripheral telomere marker. It suggests the existence of specific telomere stabilizing factors in the cortex cells.},
}
@article {pmid21127712,
year = {2010},
author = {Jiang, H and Chen, W and Qu, L and Chen, Y and He, Q and Wang, H and Wu, J and Shou, Z and Ju, Z and Chen, J},
title = {ELISA for aging biomarkers induced by telomere dysfunction in human plasma.},
journal = {Journal of biomedicine &amp; biotechnology},
volume = {2010},
number = {},
pages = {121947},
pmid = {21127712},
issn = {1110-7251},
mesh = {Adult ; Antimicrobial Cationic Peptides ; Biomarkers/*blood ; Cathelicidins/*blood ; Cellular Senescence/*physiology ; Enzyme-Linked Immunosorbent Assay/*methods ; Female ; Humans ; Male ; Middle Aged ; Polymerase Chain Reaction ; Specimen Handling ; Statistics, Nonparametric ; Telomere/chemistry/*genetics ; },
abstract = {BACKGROUND: We identified cathelicidin related antimicrobial protein (CRAMP) secreted from telomere dysfunctional bone marrow cells of late generation telomerase knockout mice (G4mTerc(-/-)), increased in blood and various tissues. It can represented human aging and disease. The main aim of this study is to investigate the sensitive direct enzyme-linked immunosorbent assay (ELISA) method to analyze the human aging and disease in plasma and the detailed methods to quantify the direct ELISA of these aging biomarkers.<br><br>METHODS: Telomere lengths of 50 healthy persons are measured with real-time PCR in blood cells. Plasma samples from all subjects are analyzed using direct ELISA.<br><br>RESULTS: From 25 years old person to 78 years, the telomere length becomes shorter during aging. In blood plasma, the expression levels of CRAMP increases during human aging. There is the reverse correspondence between the telomere length and the plasma CRAMP level. We also find that the fresh plasma, the frozen plasma which thawed less than 3 times, and the plasma kept in the room temperature less than 3 hours are better for the ELISA analyze of CRAMP in the plasma.<br><br>CONCLUSION: This CRAMP ELISA could become a powerful tool for investigating the relationship between human aging and telomere length shortening.},
}
@article {pmid21126532,
year = {2011},
author = {Mattarocci, S and D'Ambrosio, E and Tafaro, L and Somma, V and Zannino, G and Marigliano, V and Ascenzioni, F and Cimino-Reale, G},
title = {Erosion of telomeric 3'-overhangs in white blood cells of aged subjects with high frequency of very short telomeres.},
journal = {Mechanisms of ageing and development},
volume = {132},
number = {1-2},
pages = {27-32},
doi = {10.1016/j.mad.2010.11.002},
pmid = {21126532},
issn = {1872-6216},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*blood/*genetics/pathology ; Base Sequence ; Cell Proliferation ; Cellular Senescence/genetics ; Child ; Child, Preschool ; DNA/blood/genetics ; DNA Probes/genetics ; Humans ; Infant ; Leukocytes/*metabolism/*pathology ; Middle Aged ; Tandem Repeat Sequences ; Telomere/*genetics/*pathology ; Young Adult ; },
abstract = {After extended proliferation, cells enter a state of replicative quiescence that is probably due to progressive telomere shortening. It is supposed that changes in telomere structure eventually expose the chromosome ends to undesired recombination events and thus promote cell senescence. The telomeric 3'-overhang is crucial for efficient chromosome capping, but its specific role in telomere shortening and in triggering the senescence program is uncertain. We have addressed this issue by measuring the 3'-overhangs of a human tissue cells aging in vivo. The 3'-overhangs were analyzed in blood samples from 41 individuals aged 91-106 years and 89 individuals ranging from 6 months to 85 years. We found that the overall 3'-overhang length did not significantly change with age, but did, however, find extensively eroded 3'-overhangs in 3 subjects of the 91-106 years cohort and one 61 years old subject affected with Down syndrome. These subjects had 3'-overhang length distributions skewed towards shorter tails, the shortest overall telomere lengths and the highest frequencies of very short telomeres. These data raise the possibility that during ageing very short telomeres with very poor 3'-overhangs can reach a critical point for functional telomeres.},
}
@article {pmid21122064,
year = {2011},
author = {Sampathi, S and Chai, W},
title = {Telomere replication: poised but puzzling.},
journal = {Journal of cellular and molecular medicine},
volume = {15},
number = {1},
pages = {3-13},
pmid = {21122064},
issn = {1582-4934},
support = {R15 CA132090/CA/NCI NIH HHS/United States ; R15 CA132090-01/CA/NCI NIH HHS/United States ; R15CA132090/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; *DNA Replication ; Humans ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {Faithful replication of chromosomes is essential for maintaining genome stability. Telomeres, the chromosomal termini, pose quite a challenge to replication machinery due to the complexity in their structures and sequences. Efficient and complete replication of chromosomes is critical to prevent aberrant telomeres as well as to avoid unnecessary loss of telomere DNA. Compelling evidence supports the emerging picture of synergistic actions between DNA replication proteins and telomere protective components in telomere synthesis. This review discusses the actions of various replication and telomere-specific binding proteins that ensure accurate telomere replication and their roles in telomere maintenance and protection.},
}
@article {pmid21120634,
year = {2011},
author = {Sarzotti-Kelsoe, M and Daniell, XG and Whitesides, JF and Buckley, RH},
title = {The long and the short of telomeres in bone marrow recipient SCID patients.},
journal = {Immunologic research},
volume = {49},
number = {1-3},
pages = {44-48},
pmid = {21120634},
issn = {1559-0755},
support = {R01 AI047605/AI/NIAID NIH HHS/United States ; R01 AI047605-10/AI/NIAID NIH HHS/United States ; R21 AI047605/AI/NIAID NIH HHS/United States ; AI47605/AI/NIAID NIH HHS/United States ; },
mesh = {Adult ; Antigens, CD/analysis/blood ; *Bone Marrow Transplantation ; Cell Proliferation ; Flow Cytometry ; Humans ; Precursor Cells, T-Lymphoid ; Receptors, Antigen, T-Cell/genetics ; Severe Combined Immunodeficiency/blood/*genetics/therapy ; *T-Lymphocytes/immunology/metabolism/transplantation ; Telomere/*genetics/metabolism ; Transplantation ; },
abstract = {Telomeres are noncoding DNA regions at the end of the chromosomes that are crucial for genome stability. Since telomere length decreases with cell division, they can be used as a signature of cell proliferation history. T-cell reconstitution in severe combined immunodeficiency (SCID) subjects, recipients of T-cell-depleted, allogeneic-related bone marrow cells, is due to the development and maturation of donor T-cell precursors in the infant's vestigial thymus and to homeostatic proliferation of mature T cells in the peripheral organs. Since T-cell function, thymic output, and T-cell clonal diversity are maintained long term in these patients, we investigated whether donor T-cell engraftment resulted in increased telomere shortening. Our study of seven SCID patients, following successful bone marrow transplantation, demonstrates that the patients' peripheral T cells did not exhibit greater than normal telomere shortening.},
}
@article {pmid21119197,
year = {2011},
author = {Soohoo, CY and Shi, R and Lee, TH and Huang, P and Lu, KP and Zhou, XZ},
title = {Telomerase inhibitor PinX1 provides a link between TRF1 and telomerase to prevent telomere elongation.},
journal = {The Journal of biological chemistry},
volume = {286},
number = {5},
pages = {3894-3906},
pmid = {21119197},
issn = {1083-351X},
support = {R01 CA122434/CA/NCI NIH HHS/United States ; R01CA122434/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acids ; Binding Sites ; Cell Cycle Proteins ; *Homeostasis ; Humans ; Protein Binding ; Protein Transport ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; Tumor Suppressor Proteins/*metabolism ; },
abstract = {Telomere maintenance is essential for protecting chromosome ends. Aberrations in telomere length have been implicated in cancer and aging. Telomere elongation by human telomerase is inhibited in cis by the telomeric protein TRF1 and its associated proteins. However, the link between TRF1 and inhibition of telomerase elongation of telomeres remains elusive because TRF1 has no direct effect on telomerase activity. We have previously identified one Pin2/TRF1-interacting protein, PinX1, that has the unique property of directly binding and inhibiting telomerase catalytic activity (Zhou, X. Z., and Lu, K. P. (2001) Cell 107, 347-359). However, nothing is known about the role of the PinX1-TRF1 interaction in the regulation of telomere maintenance. By identifying functional domains and key amino acid residues in PinX1 and TRF1 responsible for the PinX1-TRF1 interaction, we show that the TRF homology domain of TRF1 interacts with a minimal 20-amino acid sequence of PinX1 via hydrophilic and hydrophobic interactions. Significantly, either disrupting this interaction by mutating the critical Leu-291 residue in PinX1 or knocking down endogenous TRF1 by RNAi abolishes the ability of PinX1 to localize to telomeres and to inhibit telomere elongation in cells even though neither has any effect on telomerase activity per se. Thus, the telomerase inhibitor PinX1 is recruited to telomeres by TRF1 and provides a critical link between TRF1 and telomerase inhibition to prevent telomere elongation and help maintain telomere homeostasis.},
}
@article {pmid21118998,
year = {2011},
author = {Brault, ME and Autexier, C},
title = {Telomeric recombination induced by dysfunctional telomeres.},
journal = {Molecular biology of the cell},
volume = {22},
number = {2},
pages = {179-188},
pmid = {21118998},
issn = {1939-4586},
support = {MOP-81215//Canadian Institutes of Health Research/Canada ; },
mesh = {Ataxia Telangiectasia Mutated Proteins ; Breast Neoplasms ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; DNA, Circular/biosynthesis ; DNA-Binding Proteins/metabolism ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Intracellular Signaling Peptides and Proteins/metabolism ; Mutation ; Protein Serine-Threonine Kinases/metabolism ; *Recombination, Genetic ; Sister Chromatid Exchange ; Telomerase/*biosynthesis/genetics ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; Tumor Suppressor Proteins/metabolism ; Tumor Suppressor p53-Binding Protein 1 ; },
abstract = {Telomere maintenance is essential for cellular immortality, and most cancer cells maintain their telomeres through the enzyme telomerase. Telomeres and telomerase represent promising anticancer targets. However, 15% of cancer cells maintain their telomeres through alternative recombination-based mechanisms, and previous analyses showed that recombination-based telomere maintenance can be activated after telomerase inhibition. We determined whether telomeric recombination can also be promoted by telomere dysfunction. We report for the first time that telomeric recombination can be induced in human telomerase-positive cancer cells with dysfunctional telomeres.},
}
@article {pmid21118150,
year = {2010},
author = {Tusell, L and Pampalona, J and Soler, D and Frías, C and Genescà, A},
title = {Different outcomes of telomere-dependent anaphase bridges.},
journal = {Biochemical Society transactions},
volume = {38},
number = {6},
pages = {1698-1703},
doi = {10.1042/BST0381698},
pmid = {21118150},
issn = {1470-8752},
mesh = {Adult ; Anaphase/*genetics ; Animals ; Chromatin/chemistry/genetics/metabolism ; *Chromosomal Instability ; *Chromosome Aberrations ; Chromosome Segregation ; Humans ; Neoplasms/genetics ; Telomere/*chemistry/genetics/*metabolism ; },
abstract = {Chromosomal instability occurs early in the development of cancer and may represent an important step in promoting the multiple genetic changes required for the initiation and/or progression of the disease. Telomere erosion is one of the factors that contribute to chromosome instability through end-to-end chromosome fusions entering BFB (breakage-fusion-bridge) cycles. Uncapped chromosomes with short dysfunctional telomeres represent an initiating substrate for both pre- and post-replicative joining, which leads to unstable chromosome rearrangements prone to bridge at mitotic anaphase. Resolution of chromatin bridge intermediates is likely to contribute greatly to the generation of segmental chromosome amplification events, unbalanced chromosome rearrangements and whole chromosome aneuploidy. Accordingly, telomere-driven instability generates highly unstable genomes that could promote cell immortalization and the acquisition of a tumour phenotype.},
}
@article {pmid21116649,
year = {2011},
author = {Nan, H and Qureshi, AA and Prescott, J and De Vivo, I and Han, J},
title = {Genetic variants in telomere-maintaining genes and skin cancer risk.},
journal = {Human genetics},
volume = {129},
number = {3},
pages = {247-253},
pmid = {21116649},
issn = {1432-1203},
support = {CA082838/CA/NCI NIH HHS/United States ; R01 CA122838-01A2/CA/NCI NIH HHS/United States ; R03 CA133914/CA/NCI NIH HHS/United States ; 5T32 CA 09001/CA/NCI NIH HHS/United States ; R01 CA122838/CA/NCI NIH HHS/United States ; CA132190/CA/NCI NIH HHS/United States ; CA122838/CA/NCI NIH HHS/United States ; R01 CA082838/CA/NCI NIH HHS/United States ; CA133914/CA/NCI NIH HHS/United States ; R03 CA132190/CA/NCI NIH HHS/United States ; T32 CA009001/CA/NCI NIH HHS/United States ; },
mesh = {Cohort Studies ; Female ; Genetic Predisposition to Disease ; *Genetic Variation ; Genome-Wide Association Study ; Humans ; Melanoma/epidemiology/*genetics ; Neoplasms, Basal Cell/epidemiology/*genetics ; Neoplasms, Squamous Cell/epidemiology/*genetics ; Polymorphism, Single Nucleotide ; Prospective Studies ; Retrospective Studies ; Risk ; Skin Neoplasms/epidemiology/*genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomeric Repeat Binding Protein 1/genetics ; },
abstract = {Telomere-related genes play an important role in maintaining the integrity of the telomeric structure that protects chromosome ends, and telomere dysfunction may lead to tumorigenesis. We evaluated the associations between 39 SNPs, including 38 tag-SNPs in telomere-related genes (TERT, TRF1, TRF2, TNKS2, and POT1) and one SNP (rs401681) in the TERT-CLPTM1L locus which has been identified as a susceptibility locus to skin cancer in the previous GWAS, and the risk of skin cancer in a case-control study of Caucasians nested within the Nurses' Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 870 controls. Of the 39 SNPs evaluated, ten showed a nominal significant association with the risk of at least one type of skin cancer. After correction for multiple testing within each gene, two SNPs in the TERT gene (rs2853676 and rs2242652) and one SNP in the TRF1 gene (rs2981096) showed significant associations with the risk of melanoma. Also, the SNP rs401681 in the TERT-CLPTM1L locus was replicated for the association with melanoma risk. The additive odds ratio (OR) [95% confidence interval (95% CI)] of these four SNPs (rs2853676[T], rs2242652[A], rs2981096[G], and rs401681[C]) for the risk of melanoma was 1.43 (1.14-1.81), 1.50 (1.14-1.98), 1.87 (1.19-2.91), and 0.73 (0.59-0.91), respectively. Moreover, we found that the rs401681[C] was associated with shorter relative telomere length (P for trend, 0.05). We did not observe significant associations for SCC or BCC risk. Our study provides evidence for the contribution of genetic variants in the telomere-maintaining genes to melanoma susceptibility.},
}
@article {pmid21115533,
year = {2011},
author = {Donate, LE and Blasco, MA},
title = {Telomeres in cancer and ageing.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {366},
number = {1561},
pages = {76-84},
pmid = {21115533},
issn = {1471-2970},
mesh = {Aging/*genetics ; Animals ; Disease Models, Animal ; Epigenomics ; Humans ; Mice ; Mice, Knockout ; Neoplasms/*genetics ; Telomere/genetics/*physiology ; Tripeptidyl-Peptidase 1 ; },
abstract = {Telomeres protect the chromosome ends from unscheduled DNA repair and degradation. Telomeres are heterochromatic domains composed of repetitive DNA (TTAGGG repeats) bound to an array of specialized proteins. The length of telomere repeats and the integrity of telomere-binding proteins are both important for telomere protection. Furthermore, telomere length and integrity are regulated by a number of epigenetic modifications, thus pointing to higher order control of telomere function. In this regard, we have recently discovered that telomeres are transcribed generating long, non-coding RNAs, which remain associated with the telomeric chromatin and are likely to have important roles in telomere regulation. In the past, we showed that telomere length and the catalytic component of telomerase, Tert, are critical determinants for the mobilization of stem cells. These effects of telomerase and telomere length on stem cell behaviour anticipate the premature ageing and cancer phenotypes of telomerase mutant mice. Recently, we have demonstrated the anti-ageing activity of telomerase by forcing telomerase expression in mice with augmented cancer resistance. Shelterin is the major protein complex bound to mammalian telomeres; however, its potential relevance for cancer and ageing remained unaddressed to date. To this end, we have generated mice conditionally deleted for the shelterin proteins TRF1, TPP1 and Rap1. The study of these mice demonstrates that telomere dysfunction, even if telomeres are of a normal length, is sufficient to produce premature tissue degeneration, acquisition of chromosomal aberrations and initiation of neoplastic lesions. These new mouse models, together with the telomerase-deficient mouse model, are valuable tools for understanding human pathologies produced by telomere dysfunction.},
}
@article {pmid21113083,
year = {2010},
author = {Gramatges, MM and Bertuch, AA},
title = {Measuring relative telomere length: is tissue an issue?.},
journal = {Aging},
volume = {2},
number = {11},
pages = {756-757},
pmid = {21113083},
issn = {1945-4589},
support = {K12 CA090433/CA/NCI NIH HHS/United States ; },
mesh = {Biomarkers/metabolism ; Cellular Senescence/*genetics ; Humans ; Phenotype ; Telomere/genetics/*metabolism ; },
}
@article {pmid21113082,
year = {2010},
author = {Gadalla, SM and Cawthon, R and Giri, N and Alter, BP and Savage, SA},
title = {Telomere length in blood, buccal cells, and fibroblasts from patients with inherited bone marrow failure syndromes.},
journal = {Aging},
volume = {2},
number = {11},
pages = {867-874},
pmid = {21113082},
issn = {1945-4589},
support = {//Intramural NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Anemia, Aplastic ; Anemia, Diamond-Blackfan/genetics ; Bone Marrow Diseases ; Bone Marrow Failure Disorders ; Cheek ; Child ; Dyskeratosis Congenita/genetics ; Female ; Fibroblasts/cytology/*physiology ; Hemoglobinuria, Paroxysmal/genetics ; Humans ; Male ; Mouth Mucosa/*cytology ; Telomere/*genetics/metabolism ; Young Adult ; },
abstract = {Telomeres, the nucleotide repeats and protein complex at chromosome ends, are required for chromosomal stability and are important markers of aging. Patients with dyskeratosis congenita (DC), an inherited bone marrow failure syndrome (IBMFS), have mutations in telomere biology genes, and very short telomeres. There are limited data on intra-individual telomere length (TL) variability in DC and related disorders. We measured relative TL by quantitative-PCR in blood, buccal cells, and fibroblasts from 21 patients with an IBMFS (5 Diamond-Blackfan anemia, 6 DC, 6 Fanconi anemia, and 4 Shwachman-Diamond syndrome). As expected, TL in patients with DC was significantly (p<0.01) shorter in all tissues compared with other IBMFS. In all disorders combined, the median Q-PCR TL was longer in fibroblast and buccal cells than in blood (overall T/S ratio=1.42 and 1.16 vs. 1.05, p=0.001, 0.006, respectively). Although the absolute values varied, statistically significant intra-individual correlations in TL were present in IBMFS patients: blood and fibroblast (r=0.66, p=0.002), blood and buccal cells (r=0.74, p<0.0001), and fibroblast and buccal cells (r=0.65, p=0.004). These data suggest that relative TL is tissue-independent in DC and possibly in the other IBMFS.},
}
@article {pmid21112850,
year = {2010},
author = {Chen, M and McLeskey, SW},
title = {Telomere-based cancer treatment: emerging targeted therapies.},
journal = {Clinical journal of oncology nursing},
volume = {14},
number = {6},
pages = {720-726},
doi = {10.1188/10.CJON.720-726},
pmid = {21112850},
issn = {1538-067X},
mesh = {Antineoplastic Agents/pharmacology/*therapeutic use ; Humans ; In Situ Hybridization, Fluorescence ; Neoplasms/*drug therapy/enzymology/genetics ; Telomerase/antagonists &amp; inhibitors/metabolism ; Telomere/*drug effects ; },
abstract = {Chemotherapy and radiation therapy are standard care in cancer treatment; however, both have numerous adverse side effects because they affect healthy as well as cancerous cells. The side effects, including decreased white blood cell count, nausea, hair loss, and fatigue, can be severe enough that patients may decide to forgo treatment. Targeted therapies are treatments that focus on specific molecules in cancerous cells and avoid disruption of healthy cells. Telomeres, the ends of chromosomes, are possible targets. In healthy cells, telomeres become shorter with each cell division, limiting the number of divisions that a normal cell can undergo. Many cancer cells have telomerase activity, which rebuilds telomeres after each cell division and confers immortality to cancer cells. Telomerase is an enzyme normally present to a significant degree only in the cells of developing fetuses. Treatments that target the telomerase enzyme itself or the chromosomal telomeres are being developed and tested in early clinical trials. This article focuses on several approaches to telomere-targeted therapy.},
}
@article {pmid21109027,
year = {2011},
author = {De Meyer, T and Rietzschel, ER and De Buyzere, ML and Van Criekinge, W and Bekaert, S},
title = {Telomere length and cardiovascular aging: the means to the ends?.},
journal = {Ageing research reviews},
volume = {10},
number = {2},
pages = {297-303},
doi = {10.1016/j.arr.2010.11.001},
pmid = {21109027},
issn = {1872-9649},
mesh = {Aging/*genetics ; Biomarkers/analysis ; Cardiovascular Diseases/*genetics ; Humans ; Inflammation Mediators/analysis ; Life Style ; Oxidative Stress/genetics ; Risk Factors ; Telomerase/metabolism ; Telomere/genetics/*ultrastructure ; },
abstract = {Epidemiologic and other evidence clearly indicates that peripheral blood leukocyte telomere length, a systemic marker for biological aging, can be useful as a cardiovascular aging biomarker. Although telomere biology might yield new insights into the underlying molecular biology of vascular aging and even radically improve current cardiovascular risk stratification, the specific nature of the association between telomere length and cardiovascular disease still remains to be elucidated. Here, we review several candidate hypotheses and critically review supporting and contesting scientific evidence for the underlying theories. For each hypothesis, we discuss the potential implications. We conclude that the most promising theory is based on an acceleration of the telomere attrition rate due to cardiovascular aging related factors, possibly complemented by telomere mediated hematopoietic senescence.},
}
@article {pmid21108926,
year = {2011},
author = {Pradhan, SK and Dasgupta, D and Basu, G},
title = {Human telomere d[(TTAGGG)4] undergoes a conformational transition to the Na+-form upon binding with sanguinarine in presence of K+.},
journal = {Biochemical and biophysical research communications},
volume = {404},
number = {1},
pages = {139-142},
doi = {10.1016/j.bbrc.2010.11.081},
pmid = {21108926},
issn = {1090-2104},
mesh = {Antineoplastic Agents/chemistry/*metabolism ; Base Sequence ; Benzophenanthridines/chemistry/*metabolism ; *G-Quadruplexes ; Humans ; Isoquinolines/chemistry/*metabolism ; Nuclear Magnetic Resonance, Biomolecular ; Potassium/chemistry/*metabolism ; Sodium/chemistry/*metabolism ; Telomere/chemistry/*metabolism ; },
abstract = {Guanine-rich telomeric sequences fold into G-quadruplex conformation and are known to bind a variety of ligands including potential drug candidates. By means of CD spectroscopy and fluorescence lifetime measurements we demonstrate that putative anticancer therapeutic sanguinarine (SGR) exhibits two distinct interactions with human telomere d[(TTAGGG)(4)] (H24) in presence of K(+). Up to about 1:2 M ratio of H24:SGR (10 μM H24), two molecules of SGR bind H24. Above this molar ratio, SGR induces a conformational transition in H24 from the K(+)-form to the Na(+)-form. The demonstration of SGR-induced conformational transition in a G-quadruplex formed by a human telomeric sequence could provide new insights into interaction of drugs with quadruplex DNA structure.},
}
@article {pmid21102320,
year = {2011},
author = {Shammas, MA},
title = {Telomeres, lifestyle, cancer, and aging.},
journal = {Current opinion in clinical nutrition and metabolic care},
volume = {14},
number = {1},
pages = {28-34},
pmid = {21102320},
issn = {1473-6519},
support = {R01CA124929/CA/NCI NIH HHS/United States ; R01 CA125711-04/CA/NCI NIH HHS/United States ; R01 CA124929/CA/NCI NIH HHS/United States ; R01 CA125711/CA/NCI NIH HHS/United States ; R01CA125711/CA/NCI NIH HHS/United States ; },
mesh = {Aging/*physiology ; Diet ; Exercise ; Humans ; *Life Style ; *Longevity ; Neoplasms/*physiopathology ; Obesity/complications ; Stress, Physiological ; *Telomere ; },
abstract = {PURPOSE OF REVIEW: There has been growing evidence that lifestyle factors may affect the health and lifespan of an individual by affecting telomere length. The purpose of this review was to highlight the importance of telomeres in human health and aging and to summarize possible lifestyle factors that may affect health and longevity by altering the rate of telomere shortening.<br><br>RECENT FINDINGS: Recent studies indicate that telomere length, which can be affected by various lifestyle factors, can affect the pace of aging and onset of age-associated diseases.<br><br>SUMMARY: Telomere length shortens with age. Progressive shortening of telomeres leads to senescence, apoptosis, or oncogenic transformation of somatic cells, affecting the health and lifespan of an individual. Shorter telomeres have been associated with increased incidence of diseases and poor survival. The rate of telomere shortening can be either increased or decreased by specific lifestyle factors. Better choice of diet and activities has great potential to reduce the rate of telomere shortening or at least prevent excessive telomere attrition, leading to delayed onset of age-associated diseases and increased lifespan. This review highlights the role of telomeres in aging and describes the lifestyle factors which may affect telomeres, human health, and aging.},
}
@article {pmid21097466,
year = {2011},
author = {Uringa, EJ and Youds, JL and Lisaingo, K and Lansdorp, PM and Boulton, SJ},
title = {RTEL1: an essential helicase for telomere maintenance and the regulation of homologous recombination.},
journal = {Nucleic acids research},
volume = {39},
number = {5},
pages = {1647-1655},
pmid = {21097466},
issn = {1362-4962},
support = {GMH79042//Canadian Institutes of Health Research/Canada ; MOP38075//Canadian Institutes of Health Research/Canada ; //Cancer Research UK/United Kingdom ; },
mesh = {Animals ; DNA Helicases/*physiology ; Meiosis/genetics ; Mice ; Mitosis/genetics ; *Recombination, Genetic ; Telomere/*metabolism ; },
abstract = {Telomere maintenance and DNA repair are crucial processes that protect the genome against instability. RTEL1, an essential iron-sulfur cluster-containing helicase, is a dominant factor that controls telomere length in mice and is required for telomere integrity. In addition, RTEL1 promotes synthesis-dependent strand annealing to direct DNA double-strand breaks into non-crossover outcomes during mitotic repair and in meiosis. Here, we review the role of RTEL1 in telomere maintenance and homologous recombination and discuss models linking RTEL1's enzymatic activity to its function in telomere maintenance and DNA repair.},
}
@article {pmid21093267,
year = {2010},
author = {Dubruille, R and Orsi, GA and Delabaere, L and Cortier, E and Couble, P and Marais, GA and Loppin, B},
title = {Specialization of a Drosophila capping protein essential for the protection of sperm telomeres.},
journal = {Current biology : CB},
volume = {20},
number = {23},
pages = {2090-2099},
doi = {10.1016/j.cub.2010.11.013},
pmid = {21093267},
issn = {1879-0445},
mesh = {Animals ; Animals, Genetically Modified ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster/*genetics/*metabolism ; Epigenesis, Genetic ; Female ; Male ; Multigene Family ; Phylogeny ; Recombinant Fusion Proteins/genetics/metabolism ; Spermatozoa/*physiology ; Telomere/*metabolism ; },
abstract = {BACKGROUND: A critical function of telomeres is to prevent fusion of chromosome ends by the DNA repair machinery. In Drosophila somatic cells, assembly of the protecting capping complex at telomeres notably involves the recruitment of HOAP, HP1, and their recently identified partner, HipHop. We previously showed that the hiphop gene was duplicated before the radiation of the melanogaster subgroup of species, giving birth to K81, a unique paternal effect gene specifically expressed in the male germline.<br><br>RESULTS: Here we show that K81 specifically associates with telomeres during spermiogenesis, along with HOAP and HP1, and is retained on paternal chromosomes until zygote formation. In K81 mutant testes, capping proteins are not maintained at telomeres in differentiating spermatids, resulting in the transmission of uncapped paternal chromosomes that fail to properly divide during the first zygotic mitosis. Despite the apparent similar capping roles of K81 and HipHop in their respective domain of expression, we demonstrate by in vivo reciprocal complementation analyses that they are not interchangeable. Strikingly, HipHop appeared to be unable to maintain capping proteins at telomeres during the global chromatin remodeling of spermatid nuclei.<br><br>CONCLUSIONS: Our data demonstrate that K81 is essential for the maintenance of capping proteins at telomeres in postmeiotic male germ cells. In species of the melanogaster subgroup, HipHop and K81 have not only acquired complementary expression domains, they have also functionally diverged following the gene duplication event. We propose that K81 specialized in the maintenance of telomere protection in the highly peculiar chromatin environment of differentiating male gametes.},
}
@article {pmid21087016,
year = {2010},
author = {Miller, MC and Buscaglia, R and Chaires, JB and Lane, AN and Trent, JO},
title = {Hydration is a major determinant of the G-quadruplex stability and conformation of the human telomere 3' sequence of d(AG3(TTAG3)3).},
journal = {Journal of the American Chemical Society},
volume = {132},
number = {48},
pages = {17105-17107},
doi = {10.1021/ja105259m},
pmid = {21087016},
issn = {1520-5126},
support = {CA113735-01/CA/NCI NIH HHS/United States ; GM077422/GM/NIGMS NIH HHS/United States ; P20RR018733/RR/NCRR NIH HHS/United States ; },
mesh = {Base Sequence ; DNA/*chemistry/genetics ; *G-Quadruplexes ; Humans ; Nucleic Acid Denaturation ; Solutions ; Solvents/*chemistry ; Telomere/*genetics ; Transition Temperature ; },
abstract = {The factors that determine the conformation and stability of G-quadruplex forming sequences remain poorly understood. Here we demonstrate the influence of cosolvents on the conformation and stability of the human telomeric sequence d(A(GGGTTA)3GGG)) in both K(+) and Na(+) containing solutions using a combination of circular dichroism, NMR, and thermodynamics. Molecular crowding arguments have previously been used to suggest that the parallel quadruplex form may be biologically relevant. However, the small cosolvents previously used, PEG 200 and 400, are actually dehydrating agents. We have used acetonitrile as a non-hydrogen-bonding dehydrating agent; similar conformational transitions were observed in K(+) solution. Moreover, NMR analysis shows that the resulting structure contains non-anti guanine glycosyl torsion angles suggesting that the conformation present in acetonitrile is not identical to the all-parallel crystal structure, despite the supposed parallel type CD spectrum.},
}
@article {pmid21088221,
year = {2010},
author = {George, JA and Traverse, KL and DeBaryshe, PG and Kelley, KJ and Pardue, ML},
title = {Evolution of diverse mechanisms for protecting chromosome ends by Drosophila TART telomere retrotransposons.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {107},
number = {49},
pages = {21052-21057},
pmid = {21088221},
issn = {1091-6490},
support = {R01 GM050315/GM/NIGMS NIH HHS/United States ; R56 GM050315/GM/NIGMS NIH HHS/United States ; GM50315/GM/NIGMS NIH HHS/United States ; },
mesh = {5' Flanking Region/*genetics ; Animals ; Biological Evolution ; *Chromosomes ; Drosophila/*genetics ; Drosophila Proteins/*genetics ; Drosophila melanogaster/genetics ; Promoter Regions, Genetic ; Retroelements/*genetics ; Telomere/*genetics ; Transcription, Genetic ; },
abstract = {The retrotransposons HeT-A, TART, and TAHRE, which maintain Drosophila telomeres, transpose specifically onto chromosome ends to form long arrays that extend the chromosome and compensate for terminal loss. Because they transpose by target-primed reverse transcription, each element is oriented so that its 5' end serves as the extreme end of the chromosome until another element transposes to occupy the terminal position. Thus 5' sequences are at risk for terminal erosion while the element is at the chromosome end. Here we report that TART elements in Drosophila melanogaster and Drosophila virilis show species-specific innovations in promoter architecture that buffer loss of sequence exposed at chromosome ends. The two elements have evolved different ways to effect this protection. The D. virilis TART (TART(vir)) promoter is found in the 3' UTR of the element directly upstream of the element transcribed. Transcription starts within the upstream element so that a "Tag" of extra sequence is added to the 5' end of the newly transcribed RNA. This Tag provides expendable sequence to buffer end erosion of essential 5' sequence after the RNA is reverse transcribed onto the chromosome. In contrast, the D. melanogaster TART (TART(mel)) promoter initiates transcription deep within the 5' UTR, but the element is able to replace and extend the 5' UTR sequence by copying sequence from its 3' UTR, we believe while being reverse transcribed onto the chromosome end. Astonishingly, end-protection in TART(vir) and HeT-A(mel) are essentially identical (using Tags), whereas HeT-A(vir) is clearly protected from end erosion by an as-yet-unspecified program.},
}
@article {pmid21085125,
year = {2010},
author = {Kimura, M and Stone, RC and Hunt, SC and Skurnick, J and Lu, X and Cao, X and Harley, CB and Aviv, A},
title = {Measurement of telomere length by the Southern blot analysis of terminal restriction fragment lengths.},
journal = {Nature protocols},
volume = {5},
number = {9},
pages = {1596-1607},
pmid = {21085125},
issn = {1750-2799},
support = {5F30AG032858/AG/NIA NIH HHS/United States ; R01AG20132/AG/NIA NIH HHS/United States ; F30 AG032858/AG/NIA NIH HHS/United States ; R01AG021593/AG/NIA NIH HHS/United States ; R01AG030678/AG/NIA NIH HHS/United States ; },
mesh = {*Blotting, Southern ; Epidemiologic Studies ; *Genetic Techniques ; Humans ; Restriction Mapping ; Telomere/*genetics ; },
abstract = {In this protocol we describe a method to obtain telomere length parameters using Southern blots of terminal restriction fragments (TRFs). We use this approach primarily for epidemiological studies that examine leukocyte telomere length. However, the method can be adapted for telomere length measurements in other cells whose telomere lengths are within its detection boundaries. After extraction, DNA is inspected for integrity, digested, resolved by gel electrophoresis, transferred to a membrane, hybridized with labeled probes and exposed to X-ray film using chemiluminescence. Although precise and highly accurate, the method requires a considerable amount of DNA (3 μg per sample) and it measures both the canonical and noncanonical components of telomeres. The method also provides parameters of telomere length distribution in each DNA sample, which are useful in answering questions beyond those focusing on the mean length of telomeres in a given sample. A skilled technician can measure TRF length in ∼130 samples per week.},
}
@article {pmid21080812,
year = {2010},
author = {Mainous, AG and Diaz, VA},
title = {Telomere length as a risk marker for cardiovascular disease: the next big thing?.},
journal = {Expert review of molecular diagnostics},
volume = {10},
number = {8},
pages = {969-971},
doi = {10.1586/erm.10.69},
pmid = {21080812},
issn = {1744-8352},
mesh = {Aging ; Cardiovascular Diseases/*genetics ; *Genetic Markers ; Humans ; Polymorphism, Single Nucleotide ; Risk Factors ; *Telomere ; },
}
@article {pmid21080476,
year = {2011},
author = {Lee, M and Martin, H and Firpo, MA and Demerath, EW},
title = {Inverse association between adiposity and telomere length: The Fels Longitudinal Study.},
journal = {American journal of human biology : the official journal of the Human Biology Council},
volume = {23},
number = {1},
pages = {100-106},
pmid = {21080476},
issn = {1520-6300},
support = {R01 HD012252/HD/NICHD NIH HHS/United States ; R03 AG023251/AG/NIA NIH HHS/United States ; R03 AG023251-02/AG/NIA NIH HHS/United States ; R01 HD12252/HD/NICHD NIH HHS/United States ; },
mesh = {Abdominal Fat/*pathology ; Adiposity ; Adult ; Aging/pathology ; Apolipoproteins B ; Blood Pressure ; *Body Fat Distribution ; Body Mass Index ; Cardiovascular Diseases/etiology ; Child ; Fasting ; Glucose/metabolism ; Humans ; Ohio ; Telomere/*ultrastructure ; Waist Circumference ; White People ; },
abstract = {OBJECTIVES: To assess the relationship between telomere length and adiposity, using dual-energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI), in addition to conventional anthropometric proxies including body mass index (BMI) and cardiovascular disease risk factors.<br><br>METHODS: A cross-sectional sample of 309 non-Hispanic white participants in the Fels Longitudinal Study aged 8 to 80 yr (52% female) was included. Average telomere length was measured by quantitative PCR.<br><br>RESULTS: Telomere length was negatively correlated with age (r = -0.32, P < 0.0001) and had numerous significant correlations with established cardiovascular disease risk factors including waist circumference (r = -0.33), apolipoprotein B (r = -0.26), systolic blood pressure (r = -0.28), and fasting serum glucose (r = -0.15); all P < 0.0025. In backward selection linear regression models of telomere length, adiposity measures were consistently retained in the best models; BMI, waist circumference, hip circumference, total body fat, and visceral adipose tissue volume were all inversely associated with telomere length at the nominal P < 0.05 level or lower, independent of age, sex, systolic blood pressure, and fasting serum lipid, lipoprotein, and glucose concentrations. The negative association of BMI with telomere length was stronger among younger than older participants (P for interaction, 0.03).<br><br>CONCLUSIONS: Individuals with higher total and abdominal adiposity have lower telomere length, a marker of cellular senescence, suggesting obesity may hasten the aging process. Longitudinal studies are required to establish the causal association of early life adiposity with biological aging.},
}
@article {pmid21076401,
year = {2010},
author = {Badie, S and Escandell, JM and Bouwman, P and Carlos, AR and Thanasoula, M and Gallardo, MM and Suram, A and Jaco, I and Benitez, J and Herbig, U and Blasco, MA and Jonkers, J and Tarsounas, M},
title = {BRCA2 acts as a RAD51 loader to facilitate telomere replication and capping.},
journal = {Nature structural &amp; molecular biology},
volume = {17},
number = {12},
pages = {1461-1469},
pmid = {21076401},
issn = {1545-9985},
support = {2005NOV57/BCN_/Breast Cancer Now/United Kingdom ; A6444/CRUK_/Cancer Research UK/United Kingdom ; A8935/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Animals ; BRCA2 Protein/genetics/metabolism/*physiology ; Cells, Cultured ; Chromatin Immunoprecipitation ; DNA Repair ; G2 Phase ; Gene Deletion ; Genomic Instability ; Mice ; Rad51 Recombinase/antagonists &amp; inhibitors/genetics/*metabolism ; S Phase ; Telomere/chemistry/*metabolism ; },
abstract = {The tumor suppressor protein BRCA2 is a key component of the homologous recombination pathway of DNA repair, acting as the loader of RAD51 recombinase at sites of double-strand breaks. Here we show that BRCA2 associates with telomeres during the S and G2 phases of the cell cycle and facilitates the loading of RAD51 onto telomeres. Conditional deletion of Brca2 and inhibition of Rad51 in mouse embryonic fibroblasts (MEFs), but not inactivation of Brca1, led to shortening of telomeres and accumulation of fragmented telomeric signals--a hallmark of telomere fragility that is associated with replication defects. These findings suggest that BRCA2-mediated homologous recombination reactions contribute to the maintenance of telomere length by facilitating telomere replication and imply that BRCA2 has an essential role in maintaining telomere integrity during unchallenged cell proliferation. Mouse mammary tumors that lacked Brca2 accumulated telomere dysfunction-induced foci. Human breast tumors in which BRCA2 was mutated had shorter telomeres than those in which BRCA1 was mutated, suggesting that the genomic instability in BRCA2-deficient tumors was due in part to telomere dysfunction.},
}
@article {pmid21076183,
year = {2010},
author = {Mulder, H},
title = {Is shortening of telomeres the missing link between aging and the Type 2 Diabetes epidemic?.},
journal = {Aging},
volume = {2},
number = {10},
pages = {634-636},
pmid = {21076183},
issn = {1945-4589},
mesh = {Aging/*metabolism ; Animals ; Blood Glucose/metabolism ; Diabetes Mellitus, Type 2/*epidemiology/*etiology/genetics/pathology ; Humans ; Insulin/metabolism ; Insulin-Secreting Cells/metabolism/pathology ; Islets of Langerhans/metabolism/pathology ; Mice ; Models, Biological ; RNA/genetics ; Risk Factors ; Telomerase/deficiency/genetics ; Telomere/*metabolism ; },
abstract = {The world is facing an impending epidemic of diabetes [1]. Diabetes occurs in two forms - Type 1 and Type 2. These are separate entities, although they share an elevation of fasting plasma glucose (≥7.0 mM or 126 mg/dl) as the only required diagnostic criterion. The diabetes epidemic can be attributed to Type 2 Diabetes. Historically, Type 2 Diabetes has been a disease of the aged population. Recently, a drift in the incidence is observed, with younger individuals developing Type 2 Diabetes.},
}
@article {pmid21076181,
year = {2010},
author = {Chang, S},
title = {The telomere protein tankyrase 1 regulates DNA damage responses at telomeres.},
journal = {Aging},
volume = {2},
number = {10},
pages = {639-642},
pmid = {21076181},
issn = {1945-4589},
support = {R01 CA129037/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cellular Senescence/physiology ; DNA Repair/*physiology ; DNA-Activated Protein Kinase/metabolism ; Humans ; Mice ; Neoplasms/genetics/metabolism ; Nuclear Proteins/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Processing, Post-Translational/physiology ; Sister Chromatid Exchange/physiology ; Tankyrases/*physiology ; Telomere/genetics/*metabolism ; },
abstract = {The proliferative potential of eukaryotic cells is critically dependent upon the maintenance of functional telomeres, the protein-DNA complexes that cap the ends of chromosomes. A paper published in this issue of Aging describes that the telomere protein tankyrase 1 regulates DNA damage responses at telomeres.},
}
@article {pmid21074124,
year = {2010},
author = {Saliques, S and Zeller, M and Lorin, J and Lorgis, L and Teyssier, JR and Cottin, Y and Rochette, L and Vergely, C},
title = {Telomere length and cardiovascular disease.},
journal = {Archives of cardiovascular diseases},
volume = {103},
number = {8-9},
pages = {454-459},
doi = {10.1016/j.acvd.2010.08.002},
pmid = {21074124},
issn = {1875-2128},
mesh = {Animals ; Cardiovascular Diseases/*genetics/metabolism/pathology ; Cellular Senescence ; Endothelium, Vascular/metabolism/pathology ; Gene Expression Regulation ; *Genetic Markers ; Humans ; Myocytes, Cardiac/metabolism/pathology ; Oxidative Stress ; Telomere/*metabolism ; },
abstract = {Telomeres are structures composed of deoxyribonucleic acid repeats that protect the end of chromosomes, but shorten with each cell division. They have been the subject of many studies, particularly in the field of oncology, and more recently their role in the onset, development and prognosis of cardiovascular disease has generated considerable interest. It has already been shown that these structures may deteriorate at the beginning of the atherosclerotic process, in the onset and development of arterial hypertension or during myocardial infarction, in which their length may be a predictor of outcome. As telomere length by its nature is a marker of cell senescence, it is of particular interest when studying the lifespan and fate of endothelial cells and cardiomyocytes, especially so because telomere length seems to be regulated by various factors notably certain cardiovascular risk factors, such as smoking, sex and obesity that are associated with high levels of oxidative stress. To gain insights into the links between telomere length and cardiovascular disease, and to assess the usefulness of telomere length as a new marker of cardiovascular risk, it seems essential to review the considerable amount of data published recently on the subject.},
}
@article {pmid21071395,
year = {2011},
author = {Vaquero-Sedas, MI and Gámez-Arjona, FM and Vega-Palas, MA},
title = {Arabidopsis thaliana telomeres exhibit euchromatic features.},
journal = {Nucleic acids research},
volume = {39},
number = {6},
pages = {2007-2017},
pmid = {21071395},
issn = {1362-4962},
mesh = {Arabidopsis/enzymology/*genetics ; Arabidopsis Proteins/physiology ; DNA Methylation ; DNA, Plant/metabolism ; DNA-Binding Proteins/physiology ; Epigenesis, Genetic ; Euchromatin/*chemistry ; Histone Methyltransferases ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/chemistry/metabolism ; Telomere/*chemistry ; Transcription Factors/physiology ; },
abstract = {Telomere function is influenced by chromatin structure and organization, which usually involves epigenetic modifications. We describe here the chromatin structure of Arabidopsis thaliana telomeres. Based on the study of six different epigenetic marks we show that Arabidopsis telomeres exhibit euchromatic features. In contrast, subtelomeric regions and telomeric sequences present at interstitial chromosomal loci are heterochromatic. Histone methyltransferases and the chromatin remodeling protein DDM1 control subtelomeric heterochromatin formation. Whereas histone methyltransferases are required for histone H3K9(2Me) and non-CpG DNA methylation, DDM1 directs CpG methylation but not H3K9(2Me) or non-CpG methylation. These results argue that both kinds of proteins participate in different pathways to reinforce subtelomeric heterochromatin formation.},
}
@article {pmid21070964,
year = {2010},
author = {Gong, Y and de Lange, T},
title = {A Shld1-controlled POT1a provides support for repression of ATR signaling at telomeres through RPA exclusion.},
journal = {Molecular cell},
volume = {40},
number = {3},
pages = {377-387},
pmid = {21070964},
issn = {1097-4164},
support = {OD000379/OD/NIH HHS/United States ; R01 AG016642-13/AG/NIA NIH HHS/United States ; DP1 OD000379-05/OD/NIH HHS/United States ; AG016642/AG/NIA NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; DP1 OD000379/OD/NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*metabolism ; Cytoprotection/drug effects ; DNA Damage ; DNA-Binding Proteins/*metabolism ; Enzyme Activation/drug effects ; HEK293 Cells ; Humans ; Interphase/drug effects ; Mice ; Morpholines/*pharmacology ; Protein Serine-Threonine Kinases/*metabolism ; RNA, Small Interfering/metabolism ; Replication Protein A/*metabolism ; Repressor Proteins/*metabolism ; Shelterin Complex ; Signal Transduction/*drug effects ; Telomere/*metabolism ; Telomere-Binding Proteins ; },
abstract = {We previously proposed that POT1 prevents ATR signaling at telomeres by excluding RPA from the single-stranded TTAGGG repeats. Here, we use a Shld1-stabilized degron-POT1a fusion (DD-POT1a) to study the telomeric ATR kinase response. In the absence of Shld1, DD-POT1a degradation resulted in rapid and reversible activation of the ATR pathway in G1 and S/G2. ATR signaling was abrogated by shRNAs to ATR and TopBP1, but shRNAs to the ATM kinase or DNA-PKcs did not affect the telomere damage response. Importantly, ATR signaling in G1 and S/G2 was reduced by shRNAs to RPA. In S/G2, RPA was readily detectable at dysfunctional telomeres, and both POT1a and POT1b were required to exclude RPA and prevent ATR activation. In G1, the accumulation of RPA at dysfunctional telomeres was strikingly less, and POT1a was sufficient to repress ATR signaling. These results support an RPA exclusion model for the repression of ATR signaling at telomeres.},
}
@article {pmid21069314,
year = {2011},
author = {Takahashi, S and Nakajima, Y and Imaizumi, T and Furuta, Y and Ohshiro, Y and Abe, K and Yamada, RH and Kera, Y},
title = {Development of an autonomously replicating linear vector of the yeast Cryptococcus humicola by using telomere-like sequence repeats.},
journal = {Applied microbiology and biotechnology},
volume = {89},
number = {4},
pages = {1213-1221},
doi = {10.1007/s00253-010-2985-5},
pmid = {21069314},
issn = {1432-0614},
mesh = {Cryptococcus/*genetics ; *DNA Replication ; Gene Dosage ; Genetic Engineering/methods ; *Genetic Vectors ; Genetics, Microbial/methods ; Repetitive Sequences, Nucleic Acid ; Telomere ; Transformation, Genetic ; },
abstract = {The yeast Cryptococcus humicola has several attractive properties for practical applications such as in bioremediation and as a source of industrially useful enzymes and compounds. We have developed an autonomously replicating vector of C. humicola to improve its properties. We initially tried to isolate an autonomously replicating sequence (ARS) from genomic DNA by transformation using a genomic DNA library. We obtained a candidate plasmid vector harboring an ARS that gave high transformation efficiency. Southern blot analysis of transformants revealed the autonomous replication of the introduced vector in some transformants. However, the vector was not only variously altered in length but also linearized. PCR analysis indicated that a telomere-like sequence repeat (TTAGGGGG)(n) was added to the termini of linearized vector. Thus, we constructed an autonomously replicating linear vector having ten repeats of the telomere-like sequence at both ends. The vector transformed the yeast cells with high transformation efficiency (3230 CFU/μg of DNA), which was approximately 25-fold higher than that of a control vector lacking the repeats, and was autonomously replicated at a roughly constant size. The copy number was estimated to be less than one copy, and Ura(+) mitotic stability varied widely among the transformants and was related to plasmid segregation efficiency.},
}
@article {pmid21067315,
year = {2011},
author = {Wang, YY and Chen, AF and Wang, HZ and Xie, LY and Sui, KX and Zhang, QY},
title = {Association of shorter mean telomere length with large artery stiffness in patients with coronary heart disease.},
journal = {The aging male : the official journal of the International Society for the Study of the Aging Male},
volume = {14},
number = {1},
pages = {27-32},
doi = {10.3109/13685538.2010.529196},
pmid = {21067315},
issn = {1473-0790},
mesh = {Adult ; Aged ; C-Reactive Protein/metabolism ; Case-Control Studies ; Coronary Artery Disease/diagnostic imaging/*genetics/pathology ; Coronary Vessels/diagnostic imaging/*pathology ; Elasticity ; Humans ; Inflammation ; Male ; Middle Aged ; Oxidative Stress ; Reference Values ; Reverse Transcriptase Polymerase Chain Reaction ; Risk Factors ; Telomere/*genetics ; Ultrasonography ; },
abstract = {BACKGROUND: Accumulating evidence implicates leukocyte telomere length (LTL) shortening as a potential risk predictor for cardiovascular disease. Arterial stiffness chronicles the cumulative burden of cardiovascular disease risk factors. Therefore, the capacity of LTL to predict arterial stiffness was examined.<br><br>METHODS: A total of 275 unrelated Chinese males: 163 patients with coronary artery disease (CAD) and 112 healthy controls, 40-73 years of age were included in this study. The relative telomere length of leukocytes was determined by a real-time fluorescence quantitative polymerase chain reaction (PCR). Large artery stiffness was measured with carotid-femoral pulse wave velocity (PWV).<br><br>RESULTS: The relative telomere length (T/S) ratio was significantly shorter in patients with CAD (0.79 +/- 0.26) than in control subjects (1.08 +/- 0.22) (p<0.001). The correlation between LTL and PWV in patients with CAD was stronger than that in the controls (r= -0.467, r(2)=0.227, p<0.001 for patients with CAD versus r= -0.223; r(2)=0.050; p=0.018 for controls). The log(e)-transformed T/S ratio was inversely correlated with age (r= -0.345; p<0.001), PWV (r= -0.326; p<0.001) and C-reactive protein (r= -0.133; p=0.027).<br><br>CONCLUSIONS: The data show an association of leukocyte telomere length shortening with increased arterial stiffness and cardiovascular burden, suggesting that telomere length is a biomarker of large artery elasticity and CAD. Further studies are warranted to study the role of LTL dynamics in the pathogenesis of atherosclerosis.},
}
@article {pmid21061623,
year = {2010},
author = {Zhdanova, NS and Minina, IuM and Karamysheva, TV and Rubtsov, NB and Londono-Vallejo, JA},
title = {[The structure of long telomeres in chromosomes of the Iberian shrew].},
journal = {Genetika},
volume = {46},
number = {9},
pages = {1222-1225},
pmid = {21061623},
issn = {0016-6758},
mesh = {Animals ; Chromosome Mapping ; Chromosomes, Mammalian/*ultrastructure ; In Situ Hybridization, Fluorescence ; Shrews/*genetics ; Telomere/*ultrastructure ; },
abstract = {It is shown that the size, localization, and structure of telomeres in the Iberian shrew (Sorex granarius) are not characteristic of mammals. In this species, long telomeres of an average size of 213 kb are localized on the short arms of all 32 acrocentrics; ribosomal blocks and active nucleolus-organizing regions (NORs) were also discovered there. At the remaining chromosome ends the average size of telomeres is 3.8 kb. However, in a closely related species, Sorex araneus, all telomeres have size similar to that of human telomeres, i.e., 6.8-15.2 kb. Despite the fact that some long telomeres contain ribosomal repeats in addition to telomeric ones, the long telomeres have preserved asymmetry of G- and C-rich strands as in functional telomeres. It is probable that long telomeres were formed in meiosis at the stage of chromosome bouquet as a result of global reorganization of the chromosome ends. The provoking factors for such reorganization might be the fission of several metacentrics and the necessity of telomerization of the resulting acrocentrics.},
}
@article {pmid21057524,
year = {2010},
author = {McGee, JS and Phillips, JA and Chan, A and Sabourin, M and Paeschke, K and Zakian, VA},
title = {Reduced Rif2 and lack of Mec1 target short telomeres for elongation rather than double-strand break repair.},
journal = {Nature structural &amp; molecular biology},
volume = {17},
number = {12},
pages = {1438-1445},
pmid = {21057524},
issn = {1545-9985},
support = {R01 GM043265/GM/NIGMS NIH HHS/United States ; R01 GM043265-22/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding, Competitive ; *DNA Breaks, Double-Stranded ; *DNA Repair ; DNA Replication ; Endodeoxyribonucleases/metabolism ; Exodeoxyribonucleases/metabolism ; Histones/metabolism ; Intracellular Signaling Peptides and Proteins/genetics/metabolism/*physiology ; Mutation ; Protein Serine-Threonine Kinases/genetics/metabolism/*physiology ; Replication Protein A/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/genetics/metabolism/*physiology ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/metabolism/*physiology ; },
abstract = {Telomerase in Saccharomyces cerevisiae binds and preferentially elongates short telomeres, and this process requires the checkpoint kinase Tel1. Here we show that the Mre11 complex bound preferentially to short telomeres, which could explain the preferential binding of Tel1 to these ends. Compared to wild-type length telomeres, short telomeres generated by incomplete replication had low levels of the telomerase inhibitory protein Rif2. Moreover, in the absence of Rif2, Tel1 bound equally well to short and wild-type length telomeres, suggesting that low Rif2 content marks short telomeres for preferential elongation. In congenic strains, a double-strand break bound at least 140 times as much Mec1 in the first cell cycle after breakage as did a short telomere in the same time frame. Binding of replication protein A was also much lower at short telomeres. The absence of Mec1 at short telomeres could explain why they do not trigger a checkpoint-mediated cell-cycle arrest.},
}
@article {pmid21057505,
year = {2010},
author = {Fujita, K and Horikawa, I and Mondal, AM and Jenkins, LM and Appella, E and Vojtesek, B and Bourdon, JC and Lane, DP and Harris, CC},
title = {Positive feedback between p53 and TRF2 during telomere-damage signalling and cellular senescence.},
journal = {Nature cell biology},
volume = {12},
number = {12},
pages = {1205-1212},
pmid = {21057505},
issn = {1476-4679},
support = {A7874/CRUK_/Cancer Research UK/United Kingdom ; Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; },
mesh = {*Cellular Senescence ; Fibroblasts ; Gene Knockdown Techniques ; Humans ; Nuclear Proteins/genetics/metabolism ; *Signal Transduction ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; Tumor Suppressor Protein p53/*metabolism ; Ubiquitin-Protein Ligases/genetics/metabolism ; },
abstract = {The telomere-capping complex shelterin protects functional telomeres and prevents the initiation of unwanted DNA-damage-response pathways. At the end of cellular replicative lifespan, uncapped telomeres lose this protective mechanism and DNA-damage signalling pathways are triggered that activate p53 and thereby induce replicative senescence. Here, we identify a signalling pathway involving p53, Siah1 (a p53-inducible E3 ubiquitin ligase) and TRF2 (telomere repeat binding factor 2; a component of the shelterin complex). Endogenous Siah1 and TRF2 were upregulated and downregulated, respectively, during replicative senescence with activated p53. Experimental manipulation of p53 expression demonstrated that p53 induces Siah1 and represses TRF2 protein levels. The p53-dependent ubiquitylation and proteasomal degradation of TRF2 are attributed to the E3 ligase activity of Siah1. Knockdown of Siah1 stabilized TRF2 and delayed the onset of cellular replicative senescence, suggesting a role for Siah1 and TRF2 in p53-regulated senescence. This study reveals that p53, a downstream effector of telomere-initiated damage signalling, also functions upstream of the shelterin complex.},
}
@article {pmid21057458,
year = {2011},
author = {Heaphy, CM and Subhawong, AP and Gross, AL and Konishi, Y and Kouprina, N and Argani, P and Visvanathan, K and Meeker, AK},
title = {Shorter telomeres in luminal B, HER-2 and triple-negative breast cancer subtypes.},
journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},
volume = {24},
number = {2},
pages = {194-200},
pmid = {21057458},
issn = {1530-0285},
support = {K07 CA111948/CA/NCI NIH HHS/United States ; P50 CA88843/CA/NCI NIH HHS/United States ; K07 CA111948-01A1/CA/NCI NIH HHS/United States ; T32 CA067751/CA/NCI NIH HHS/United States ; P50 CA088843/CA/NCI NIH HHS/United States ; },
mesh = {Breast Neoplasms/*genetics/metabolism/pathology ; Carcinoma/*genetics/metabolism/pathology ; Female ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Prognosis ; Receptor, ErbB-2/genetics ; Receptors, Estrogen/genetics/metabolism ; Receptors, Progesterone/genetics/metabolism ; Telomere/*genetics/metabolism/pathology ; Tissue Array Analysis ; Tumor Suppressor Protein p53/genetics ; },
abstract = {Telomeres are nucleoprotein structures that protect chromosome ends from degradation and recombination. Cancers often have critically shortened telomeres, contributing to genomic instability. Many of these tumors activate telomerase to stabilize telomeric ends and achieve a capacity for unlimited replication. Telomere shortening has been reported in in situ and invasive carcinomas, including breast, and has been associated with disease recurrence after surgical resection. However, previous studies have not evaluated breast cancer subtypes. The objective of this study was to evaluate telomere lengths in different subtypes of breast cancer. Breast carcinomas (n=103) identified between 2001 and 2010 from patients seen at the Johns Hopkins Hospital were categorized into luminal A (n=18), luminal B (n=28), HER-2-positive (n=20) and triple-negative carcinomas (n=37) based on tumor characteristics. Telomere lengths were assessed directly at the single cell level by fluorescence in situ hybridization, and patient groups were compared using Fisher's exact tests. ER-negative status (P=0.022), PR-negative status (P=0.008), HER-2-positive status (P=0.023) and p53-positive status (P=0.022) were associated with shorter telomere length. A larger proportion of luminal A cancers had normal or long telomere lengths as compared with luminal B cases (P=0.002), HER-2-positive cases (P=0.011) or triple-negative cases (P=0.0003). Luminal B, HER-2-positive and triple-negative cases did not differ significantly. Telomere length was shorter in more aggressive subtypes, such as luminal B, HER-2-positive and triple-negative tumors, suggesting that tumor telomere length may have utility as a prognostic and/or risk marker for breast cancer.},
}
@article {pmid21056083,
year = {2011},
author = {Capraro, V and Zane, L and Poncet, D and Perol, D and Galia, P and Preudhomme, C and Bonnefoy-Berard, N and Gilson, E and Thomas, X and El-Hamri, M and Chelghoun, Y and Michallet, M and Wattel, E and Mortreux, F and Sibon, D},
title = {Telomere deregulations possess cytogenetic, phenotype, and prognostic specificities in acute leukemias.},
journal = {Experimental hematology},
volume = {39},
number = {2},
pages = {195-202.e2},
doi = {10.1016/j.exphem.2010.10.008},
pmid = {21056083},
issn = {1873-2399},
mesh = {Antineoplastic Agents/therapeutic use ; Biomarkers, Tumor/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; *Leukemia, Myeloid, Acute/drug therapy/genetics/physiopathology ; *Phenotype ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics/physiopathology ; Prognosis ; Survival Analysis ; Telomerase/*metabolism ; Telomere/*genetics/*metabolism ; Tumor Cells, Cultured ; },
abstract = {OBJECTIVE: Telomeres are protected by tightly regulated factors and elongated by telomerase. Short and/or deprotected chromosomes are recombinogenic and thereby cancer prone.<br><br>MATERIALS AND METHODS: Together with the quantification of telomerase activity (TA), measuring telomere length (TL) and expression of the genes that govern telomere protection and elongation are useful for assessing telomere homeostasis.<br><br>RESULTS: By these means we demonstrate that TL, hTERT, and TA are in the order acute myelogenous leukemia (AML) > T-cell acute lymphoblastic leukemia (T-ALL) > B-cell acute lymphoblastic leukemia (B-ALL) > T-ALL > AML, and B-ALL > AML > T-ALL. AML0 and AML3 display the lowest amounts of hTERT transcripts, and ALL and AML cells with cytogenetic abnormalities possess the shortest telomeres. hTERT expression includes phenotype-specific RNA maturation and correlates with TA but not with TL. A wide ratio of TA to hTERT expression between leukemia subtypes suggests phenotype-specific hTERT post-transcriptional deregulations. B- and T-ALL overexpress Ku70 and Pinx1, T-ALL PTOP and RAP1, and B-ALL TRF2, the expression of which is significantly higher in cases with abnormal karyotype. hTERT transcription and TL correlate with response to intensive chemotherapy, and hTERT and RAD50 are independent prognostic factors for survival.<br><br>CONCLUSIONS: Each leukemia subtype possesses specific telomere dysregulations that rely on phenotype, karyotype, response to treatment, and survival.},
}
@article {pmid21055130,
year = {2010},
author = {Bin, P and Leng, SG and Cheng, J and Pan, ZF and Duan, HW and Dai, YF and Li, HS and Niu, Y and Liu, QJ and Liu, Q and Zheng, YX},
title = {[Association between telomere length and occupational polycyclic aromatic hydrocarbons exposure].},
journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]},
volume = {44},
number = {6},
pages = {535-538},
pmid = {21055130},
issn = {0253-9624},
mesh = {Adult ; Benzene ; Case-Control Studies ; Coke ; *DNA Damage ; Female ; Humans ; Male ; Occupational Exposure/*adverse effects/analysis ; Polycyclic Aromatic Hydrocarbons/*adverse effects/analysis ; Pyrenes/analysis ; Telomere/*drug effects/genetics ; },
abstract = {OBJECTIVE: To explore the association between polycyclic aromatic hydrocarbons (PAHs) exposure and telomere length (TL), so as to investigate the effective biomarkers to evaluate the genetic damage in peripheral blood of workers exposed to PAHs.<br><br>METHODS: The exposure group consisted of 145 coke-oven workers (including 30 top-oven workers, 76 side-oven workers and 39 bottom-oven workers), and the non-exposure control group comprised 68 medical staffs. At 6 hours after the weekend duty shift, the samples of urine and 1 ml venous blood were collected from each subject. Airborne benzene-soluble matter (BSM) and particulate-phase B(a)P in the working environment of coke-oven and controls were sampled and analyzed. The concentration of urinary 1-hydroxypyrene (1-OHPyr) was determined. A real-time PCR method was used to determine the relative telomere length (RTL) of genomic DNA in peripheral blood. The relationship between the RTL and external exposure of PAHs, the potential factors which might have influence on TL were analyzed.<br><br>RESULTS: The medians of air BSM and particulate-phase B(a)P were higher in coke-oven (BSM: 328.6 &#xb5;g/m(3); B(a)P: 926.9 ng/m(3)) than those in control working environment (BSM:97.8 &#xb5;g/m(3); B(a)P: 49.1 ng/m(3)). The level of 1-OHPyr among coke-oven workers was significantly higher than that of non-exposed group (12.2 &#xb5;mol/mol Cr vs 0.7 &#xb5;mol/mol Cr; t = 26.971, P < 0.01). RTL in coke-oven workers were significantly shorter than those of controls (1.10 &#xb1; 0.75 vs 1.43 &#xb1; 1.06; t = 2.263, P = 0.026), and after adjusting for cigarettes per day and urinary 1-OHPyr, the significant difference was still observed (F(adju) = 5.496, P(adju) = 0.020). Stratification analysis found that RTL among the male and non-drinking groups in coke-oven workers were shorter than those the same sex and alcohol using status in controls (1.08 &#xb1; 0.73 vs 1.51 &#xb1; 1.10, F = 9.212, P = 0.003; 0.96 &#xb1; 0.38 vs 1.26 &#xb1; 0.46, F = 6.484, P = 0.012). Significant correlation between RTL and age was found (r = -0.284, P = 0.019) in non-exposure group.<br><br>CONCLUSION: PAH-exposure has effect on TL of genomic DNA in peripheral blood, which is mainly observed in the male and non-drinking groups between PAH-exposed workers and controls. It indicates that TL of genomic DNA in peripheral blood might be an effective biomarker as PAH-induced genetic damage.},
}
@article {pmid21053332,
year = {2010},
author = {Hartmann, N and Boehner, M and Groenen, F and Kalb, R},
title = {Telomere length of patients with major depression is shortened but independent from therapy and severity of the disease.},
journal = {Depression and anxiety},
volume = {27},
number = {12},
pages = {1111-1116},
doi = {10.1002/da.20749},
pmid = {21053332},
issn = {1520-6394},
mesh = {Adult ; Age Factors ; Aged ; Antidepressive Agents/*therapeutic use ; Blotting, Southern ; Combined Modality Therapy ; Depressive Disorder, Major/diagnosis/*drug therapy/*genetics/psychology ; Dose-Response Relationship, Drug ; Electroconvulsive Therapy ; Female ; Humans ; Male ; Middle Aged ; Polymorphism, Restriction Fragment Length/*genetics ; Reference Values ; Telomere/*genetics ; Young Adult ; },
abstract = {BACKGROUND: Shortened telomere length has been observed in a variety of diseases. Our objective was to analyze mean telomere length of patients with major depressive disorder. A key question was whether telomere length varies in different groups of depressive patients.<br><br>METHODS: We obtained blood samples from patients with major depressive disorder (n = 54) and healthy subjects (n = 20). We isolated genomic DNA and measured mean telomere length using telomere restriction fragments and Southern blotting. We grouped patients according to the therapy they received including total antidepressant dose.<br><br>RESULTS: Mean telomere length of the entire patient group (7.20 &#xb1; 0.61 kb) was significantly shorter than in the control group (7.55 &#xb1; 0.54 kb). We observed no significant difference in telomere length among the different patient groups, but each of these patient groups had significantly shorter telomeres than the healthy subjects. Further analysis revealed no significant association between telomere length and illness duration and between telomere length and the severity of depression, as determined by the Hamilton score.<br><br>CONCLUSION: These results provide further evidence that major depressive disorder is associated with shortened telomeres. However, differences in the applied therapy, the duration of illness, or the severity of depression do not seem to have any influence on telomere length.},
}
@article {pmid21045806,
year = {2010},
author = {Dewar, JM and Lydall, D},
title = {Pif1- and Exo1-dependent nucleases coordinate checkpoint activation following telomere uncapping.},
journal = {The EMBO journal},
volume = {29},
number = {23},
pages = {4020-4034},
pmid = {21045806},
issn = {1460-2075},
support = {075294//Wellcome Trust/United Kingdom ; BB/F006012/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; BB/F006039/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {*DNA Breaks, Double-Stranded ; DNA Helicases/*metabolism ; DNA Repair ; Exodeoxyribonucleases/*metabolism ; Mutation ; Saccharomyces cerevisiae/enzymology/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Essential telomere 'capping' proteins act as a safeguard against ageing and cancer by inhibiting the DNA damage response (DDR) and regulating telomerase recruitment, thus distinguishing telomeres from double-strand breaks (DSBs). Uncapped telomeres and unrepaired DSBs can both stimulate a potent DDR, leading to cell cycle arrest and cell death. Using the cdc13-1 mutation to conditionally 'uncap' telomeres in budding yeast, we show that the telomere capping protein Cdc13 protects telomeres from the activity of the helicase Pif1 and the exonuclease Exo1. Our data support a two-stage model for the DDR at uncapped telomeres; Pif1 and Exo1 resect telomeric DNA <5 kb from the chromosome end, stimulating weak checkpoint activation; resection is extended >5 kb by Exo1 and full checkpoint activation occurs. Cdc13 is also crucial for telomerase recruitment. However, cells lacking Cdc13, Pif1 and Exo1, do not senesce and maintain their telomeres in a manner dependent upon telomerase, Ku and homologous recombination. Thus, attenuation of the DDR at uncapped telomeres can circumvent the need for otherwise-essential telomere capping proteins.},
}
@article {pmid21044950,
year = {2011},
author = {Lee, OH and Kim, H and He, Q and Baek, HJ and Yang, D and Chen, LY and Liang, J and Chae, HK and Safari, A and Liu, D and Songyang, Z},
title = {Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells.},
journal = {Molecular &amp; cellular proteomics : MCP},
volume = {10},
number = {2},
pages = {M110.001628},
pmid = {21044950},
issn = {1535-9484},
support = {CA133249/CA/NCI NIH HHS/United States ; GM081627/GM/NIGMS NIH HHS/United States ; P30CA125123/CA/NCI NIH HHS/United States ; P01 GM081627/GM/NIGMS NIH HHS/United States ; P30 HD024064/HD/NICHD NIH HHS/United States ; P30 CA125123/CA/NCI NIH HHS/United States ; P30HD024064/HD/NICHD NIH HHS/United States ; R01 CA133249/CA/NCI NIH HHS/United States ; },
mesh = {Bacterial Proteins/*chemistry ; Flow Cytometry/methods ; Genetic Complementation Test ; Genome ; Humans ; Luminescent Proteins/*chemistry ; Protein Interaction Mapping ; Proteins/chemistry ; Proteome ; Retroviridae/genetics ; Shelterin Complex ; Signal Transduction ; Telomere/*ultrastructure ; Telomere-Binding Proteins/chemistry ; Ubiquitin/chemistry ; Ubiquitin-Protein Ligases/chemistry ; },
abstract = {Detection of low-affinity or transient interactions can be a bottleneck in our understanding of signaling networks. To address this problem, we developed an arrayed screening strategy based on protein complementation to systematically investigate protein-protein interactions in live human cells, and performed a large-scale screen for regulators of telomeres. Maintenance of vertebrate telomeres requires the concerted action of members of the Telomere Interactome, built upon the six core telomeric proteins TRF1, TRF2, RAP1, TIN2, TPP1, and POT1. Of the ∼12,000 human proteins examined, we identified over 300 proteins that associated with the six core telomeric proteins. The majority of the identified proteins have not been previously linked to telomere biology, including regulators of post-translational modifications such as protein kinases and ubiquitin E3 ligases. Results from this study shed light on the molecular niche that is fundamental to telomere regulation in humans, and provide a valuable tool to investigate signaling pathways in mammalian cells.},
}
@article {pmid21040099,
year = {2010},
author = {Silver, TD and Moore, CE and Archibald, JM},
title = {Nucleomorph ribosomal DNA and telomere dynamics in chlorarachniophyte algae.},
journal = {The Journal of eukaryotic microbiology},
volume = {57},
number = {6},
pages = {453-459},
doi = {10.1111/j.1550-7408.2010.00511.x},
pmid = {21040099},
issn = {1550-7408},
support = {ROP85016//Canadian Institutes of Health Research/Canada ; },
mesh = {Cercozoa/*cytology/*genetics ; DNA, Protozoan/chemistry/genetics ; DNA, Ribosomal/*genetics ; Gene Order ; Genes, rRNA/*genetics ; Molecular Sequence Data ; Operon ; Sequence Analysis, DNA ; *Telomere ; },
abstract = {Chlorarachniophytes are enigmatic marine unicellular algae that acquired photosynthesis by secondary endosymbiosis. Chlorarachniophytes are unusual in that the nucleus of the engulfed algal cell (a green alga) persists in a miniaturized form, termed a nucleomorph. The nucleomorph genome of the model chlorarachniophyte, Bigelowiella natans CCMP621, is 373 kilobase pairs (kbp) in size, the smallest nuclear genome characterized to date. The B. natans nucleomorph genome is composed of three chromosomes, each with canonical eukaryotic telomeres and sub-telomeric ribosomal DNA (rDNA) operons transcribed away from the chromosome end. Here we present the complete rDNA operon and telomeric region from the nucleomorph genome of Lotharella oceanica CCMP622, a newly characterized chlorarachniophyte strain with a genome ∼610 kbp in size, significantly larger than all other known chlorarachniophytes. We show that the L. oceanica rDNA operon is in the opposite chromosomal orientation to that of B. natans. Furthermore, we determined the rDNA operon orientation of five additional chlorarachniophyte strains, the majority of which possess the same arrangement as L. oceanica, with the exception of Chlorarachnion reptans and those very closely related to B. natans. It is thus possible that the ancestral rDNA operon orientation of the chlorarachniophyte nucleomorph genome might have been the same as in the independently evolved, red algal-derived, nucleomorph genomes of cryptophytes. A U2 small nuclear RNA gene was found adjacent to the telomere in Gymnochlora stellata CCMP2057 and Chlorarachnion sp. CCMP2014. This feature may represent a useful evolutionary character for inferring the relationships among extant lineages.},
}
@article {pmid21039993,
year = {2010},
author = {Carbonari, M and Mancaniello, D and Cibati, M and Catizone, A and Fiorilli, M},
title = {Improved procedure for the measurement of telomere length in whole cells by PNA probe and flow cytometry.},
journal = {Cell proliferation},
volume = {43},
number = {6},
pages = {553-561},
pmid = {21039993},
issn = {1365-2184},
mesh = {B-Lymphocytes/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Flow Cytometry/*methods ; Formamides/pharmacology ; Humans ; In Situ Hybridization, Fluorescence ; Nucleic Acid Denaturation/drug effects ; Oligonucleotide Probes/*chemistry ; Peptide Nucleic Acids/*chemistry ; T-Lymphocytes/drug effects ; Telomere/drug effects/*physiology ; },
abstract = {OBJECTIVES: Peptide nucleic acid (PNA) probes hybridize to denatured telomeric sequences in cells permeabilized in hot formamide. In reported protocols, the hybridization was conducted in solutions with high formamide concentrations to avoid the DNA renaturation that can hamper binding of the oligo-PNA probe to specific sequences. We postulated that telomeric DNA, confined in the nuclear microvolume, is not able to properly renature after hot formamide denaturation. Therefore, to improve hybridization conditions between the probe and the target sequences, it might be possible to add probe to sample after the complete removal of formamide.<br><br>MATERIALS AND METHODS: After telomeric DNA denaturation in hot formamide solution and several washes to remove the ionic solvent, cells were hybridized overnight at room temperature with human telomere-specific PNA probe conjugated with Cy5 fluorochrome, Cy5-OO-(CCCTAA)(3) . After stringency washes and staining with ethidium bromide, the cells were analysed by flow cytometry and by using a confocal microscope.<br><br>RESULTS: Using three continuous cell lines, different in DNA content and telomere length, and resting human peripheral blood T and B lymphocytes, we demonstrated that the oligo-PNA probe hybridized to telomeric sequences after complete removal of formamide and that in the preserved nucleus, telomeric sequence denaturation is irreversible.<br><br>CONCLUSION: According to our experience, oligo-PNA binding results is efficient, specific and proportional to telomere length. These, our original findings, can form the technological basis of actual in situ hybridization on preserved whole cells.},
}
@article {pmid21039041,
year = {2010},
author = {Looi, LM and Cheah, PL and Ng, MH and Yip, CH and Mun, KS and Rahman, NA},
title = {Comparison of telomere length and telomerase activation between breast fibroadenoma and infiltrating ductal carcinoma in Malaysian women.},
journal = {Asian Pacific journal of cancer prevention : APJCP},
volume = {11},
number = {3},
pages = {713-716},
pmid = {21039041},
issn = {2476-762X},
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/blood ; Breast/metabolism/*pathology ; Breast Neoplasms/genetics/metabolism/*pathology ; Carcinoma, Ductal, Breast/genetics/metabolism/*pathology ; Case-Control Studies ; Enzyme-Linked Immunosorbent Assay ; Female ; Fibroadenoma/genetics/metabolism/*pathology ; Humans ; Middle Aged ; Polymerase Chain Reaction ; Prognosis ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {A study was initiated to explore possible differences in handling telomere attrition in the most common lignant and benign tumours of the breast in Malaysian women. Infiltrating ductal carcinoma (IDC) and fibroadenoma (FA) represented the malignant and benign prototypes respectively. 29 IDC, 28 FA and 22 benign non-lesional control (BNL) breast tissue samples were analysed for telomerase activation using a Telomerase PCR ELISA kit (Boehringer Mannheim). In addition, 23 IDC, 12 FA and 14 BNL were subjected to telomere length determination with a TeloTAGGG Telomere Length Assay Kit (Roche Diagnostic GmbH, Germany), following digestion of genomic DNA by frequently cutting restriction enzymes RsaI and HinfI. Mean telomerase activity in IDC (A450nm=0.3338), but not FA (A450nm=0.0003) was significantly raised (p<0.05) compared with BNL (A450nm=0.0031). Similarly IDC (1.2 kb), but not FA (2.2 kb), showed significant telomere shortening (p<0.05) relative to BNL (2.9 kb). The findings imply that telomere attrition and telomerase activation differ between malignant and benign tumours of the breast and may be important for targeted therapy.},
}
@article {pmid21037379,
year = {2010},
author = {Dregalla, RC and Zhou, J and Idate, RR and Battaglia, CL and Liber, HL and Bailey, SM},
title = {Regulatory roles of tankyrase 1 at telomeres and in DNA repair: suppression of T-SCE and stabilization of DNA-PKcs.},
journal = {Aging},
volume = {2},
number = {10},
pages = {691-708},
pmid = {21037379},
issn = {1945-4589},
mesh = {Adenosine Diphosphate/analogs &amp; derivatives/pharmacology ; Antigens, Nuclear/genetics/metabolism ; Benzamides/pharmacology ; Biocatalysis/drug effects ; Cell Death/radiation effects ; Cell Line, Transformed ; Cell Line, Tumor ; Chromones/pharmacology ; Chromosomal Instability/genetics ; Chromosome Aberrations/radiation effects ; DNA Repair/*physiology ; DNA-Activated Protein Kinase/analysis/antagonists &amp; inhibitors/genetics/*metabolism ; DNA-Binding Proteins/genetics/metabolism ; Electrophoresis, Polyacrylamide Gel ; Enzyme Inhibitors/pharmacology ; Fibroblasts/metabolism/radiation effects ; Gene Expression/genetics ; Glycoside Hydrolases/antagonists &amp; inhibitors ; Heterocyclic Compounds, 3-Ring/pharmacology ; Humans ; Ku Autoantigen ; Models, Biological ; Morpholines/pharmacology ; Mutation/drug effects/radiation effects ; Nuclear Proteins/analysis/antagonists &amp; inhibitors/genetics/*metabolism ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Proteasome Inhibitors ; Protein Processing, Post-Translational/*physiology ; Pyrrolidines/pharmacology ; RNA, Small Interfering/genetics ; Sister Chromatid Exchange/*physiology ; Tankyrases/antagonists &amp; inhibitors/*physiology ; Telomere/genetics/*metabolism ; },
abstract = {Intrigued by the dynamics of the seemingly contradictory yet integrated cellular responses to the requisites of preserving telomere integrity while also efficiently repairing damaged DNA, we investigated roles of the telomere associated poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) tankyrase 1 in both telomere function and the DNA damage response following exposure to ionizing radiation. Tankyrase 1 siRNA knockdown in human cells significantly elevated recombination specifically within telomeres, a phenotype with the potential of accelerating cellular senescence. Additionally, depletion of tankyrase 1 resulted in concomitant and rapid reduction of the nonhomologous end-joining protein DNA-PKcs, while Ku86 and ATM protein levels remained unchanged; DNA-PKcs mRNA levels were also unaffected. We found that the requirement of tankyrase 1 for DNA-PKcs protein stability reflects the necessity of its PARP enzymatic activity. We also demonstrated that depletion of tankyrase 1 resulted in proteasome-mediated DNA-PKcs degradation, explaining the associated defective damage response observed; i.e., increased sensitivity to ionizing radiation-induced cell killing, mutagenesis, chromosome aberration and telomere fusion. We provide the first evidence for regulation of DNA-PKcs by tankyrase 1 PARP activity and taken together, identify roles of tankyrase 1 with implications not only for DNA repair and telomere biology, but also for cancer and aging.},
}
@article {pmid21037079,
year = {2010},
author = {Slatter, T and Gifford-Garner, J and Wiles, A and Tan, X and Chen, YJ and MacFarlane, M and Sullivan, M and Royds, J and Hung, N},
title = {Pilocytic astrocytomas have telomere-associated promyelocytic leukemia bodies without alternatively lengthened telomeres.},
journal = {The American journal of pathology},
volume = {177},
number = {6},
pages = {2694-2700},
pmid = {21037079},
issn = {1525-2191},
support = {//Cancer Research UK/United Kingdom ; },
mesh = {Adolescent ; Adult ; Astrocytoma/*genetics/*metabolism/pathology ; Brain Neoplasms/*genetics/*metabolism/pathology ; Child ; Disease Progression ; Humans ; Inclusion Bodies/metabolism ; Middle Aged ; Neoplasm Staging ; Nuclear Proteins/*metabolism ; Promyelocytic Leukemia Protein ; Telomere/chemistry/genetics/*metabolism ; Transcription Factors/*metabolism ; Tumor Suppressor Proteins/*metabolism ; Young Adult ; },
abstract = {Telomere maintenance by either telomerase activity or the recombination-mediated alternative lengthening of telomeres (ALT) mechanism is a hallmark of cancer. Tumors that use ALT as their telomere maintenance mechanism are characterized by long telomeres of great heterogeneity in length and by specific nuclear structures of co-localized promyelocytic leukemia protein and telomere DNA, called ALT-associated promyelocytic leukemia bodies (APBs). Recent advances have revealed a direct role for APBs in telomere recombination in ALT-positive cells. In this study, we investigated the possibility that APBs could occur before the long 'alternatively' lengthened telomeres arise, particularly in low-grade tumors. We measured APBs, telomere length, and telomerase activity in 64 astrocytomas inclusive of grade 1-4 tumors. Almost all grade 1-3 tumors (93%) were APB-positive using published criteria. Grade 2-3 APB-positive tumors also had long telomeres and were confirmed as ALT positive. However, grade 1 tumors lacked long telomeres and were therefore classified as ALT negative, but positive for telomere-associated promyelocytic leukemia bodies (TPB). This is the first report of a TPB-positive but ALT-negative tumor, and suggests that low-grade tumors have the foundation for recombinational telomere repair, as in ALT. Further work is warranted to characterize the TPB-positive phenotype in other early malignancies, as well as to determine whether TPBs predispose to telomere maintenance by ALT.},
}
@article {pmid21034675,
year = {2010},
author = {Kouniavsky, G and Zeiger, MA},
title = {The role of telomeres and telomerase in endocrine tumors.},
journal = {Discovery medicine},
volume = {10},
number = {53},
pages = {340-347},
pmid = {21034675},
issn = {1944-7930},
mesh = {Adenoma/*etiology/genetics/metabolism ; Animals ; Carcinoma/*etiology/genetics/metabolism ; Endocrine Gland Neoplasms/*etiology/genetics/metabolism ; Humans ; Telomerase/genetics/metabolism/*physiology ; Telomere/genetics/metabolism/*physiology ; },
abstract = {The enzyme, telomerase, is a reverse transcriptase that synthesizes the telomeric ends of linear chromosomes and compensate for the shortened telomere, thereby immortalizing the cell. It is present at the blastocyst stage of embryological development, low or undetectable in most somatic cells, and activated in cancer. Because of its strong association with cancer cell immortalization and proliferation, numerous attempts have been made to capitalize on its diagnostic, prognostic, and therapeutic potential. Herein we discuss the role of telomerase in normal, benign, and cancerous endocrine tissues.},
}
@article {pmid21031437,
year = {2011},
author = {Joshua, AM and Shen, E and Yoshimoto, M and Marrano, P and Zielenska, M and Evans, AJ and Van der Kwast, T and Squire, JA},
title = {Topographical analysis of telomere length and correlation with genomic instability in whole mount prostatectomies.},
journal = {The Prostate},
volume = {71},
number = {7},
pages = {778-790},
doi = {10.1002/pros.21294},
pmid = {21031437},
issn = {1097-0045},
mesh = {Biomarkers, Tumor/metabolism ; Chromosome Aberrations ; Chromosomes, Human, Pair 7 ; Chromosomes, Human, Pair 8 ; DNA, Neoplasm/analysis ; *Genomic Instability ; Humans ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Ki-67 Antigen/metabolism ; Male ; Malondialdehyde/metabolism ; Oxidative Stress ; Prostatectomy ; Prostatic Intraepithelial Neoplasia/*genetics/metabolism/pathology ; Prostatic Neoplasms/*genetics/metabolism/pathology ; *Telomere ; },
abstract = {BACKGROUND: Many critical events in prostatic carcinogenesis appear to relate to the emergence of genomic instability. Characteristic genomic abnormalities such as 8p loss, 8q gain, trisomy 7, and PTEN microdeletions may provide selective advantages to increase neoplastic transformation. Evidence suggests that telomere dysfunction is a plausible mechanism for some of these abnormalities on the basis of the break-fusion-bridge cycle that can lead to manifestations of genomic instability.<br><br>METHODS: In this study, we correlate telomere length measured by quantitative FISH in various prostatic histologies with markers of genomic instability and immunohistochemical measures of proliferation and oxidative stress.<br><br>RESULTS: We find that telomere shortening is correlated with abnormalities on chromosome 8, but not with trisomy 7 or abnormalities of the PTEN locus. There are associations with C-MYC aberrations in stroma with greater proximity to cancer and a correlation between telomere length in a number of prostatic histologies and the adjacent stroma, suggesting the importance of microenvironmental effects on telomere maintenance in the prostate. This finding was also supported by the finding of the correlation between telomere attrition and the levels of oxidative stress as measured by malondialdehyde staining in HPIN lesions close to cancer.<br><br>CONCLUSIONS: Telomere attrition in the prostate gland is associated with particular genomic aberrations that contribute to the genomic instability characteristic of prostatic carcinogenesis. Correlations between various histologies and adjacent stroma telomere length suggest it is also may reveal microenvironmental effects within the prostate gland. Oxidative stress may contribute to telomere attrition in HPIN close to cancer.},
}
@article {pmid21030466,
year = {2011},
author = {Mather, KA and Jorm, AF and Parslow, RA and Christensen, H},
title = {Is telomere length a biomarker of aging? A review.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {66},
number = {2},
pages = {202-213},
doi = {10.1093/gerona/glq180},
pmid = {21030466},
issn = {1758-535X},
mesh = {Aging/genetics/*metabolism ; Animals ; Biomarkers/metabolism ; Cellular Senescence/genetics ; *Cognition ; Humans ; Longitudinal Studies ; Male ; Mice ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres, the DNA-protein structures located at the ends of chromosomes, have been proposed to act as a biomarker of aging. In this review, the human evidence that telomere length is a biomarker of aging is evaluated. Although telomere length is implicated in cellular aging, the evidence suggesting telomere length is a biomarker of aging in humans is equivocal. More studies examining the relationships between telomere length and mortality and with measures that decline with "normal" aging in community samples are required. These studies would benefit from longitudinal measures of both telomere length and aging-related parameters.},
}
@article {pmid21028832,
year = {2010},
author = {Wang, Q and Ma, L and Hao, YH and Tan, Z},
title = {Folding equilibrium constants of telomere G-quadruplexes in free state or associated with proteins determined by isothermal differential hybridization.},
journal = {Analytical chemistry},
volume = {82},
number = {22},
pages = {9469-9475},
doi = {10.1021/ac102168m},
pmid = {21028832},
issn = {1520-6882},
mesh = {Base Sequence ; Digoxin/immunology ; *G-Quadruplexes ; Humans ; Immunoglobulin Fab Fragments/immunology/metabolism ; Nucleic Acid Hybridization/*methods ; Proteins/*metabolism ; Telomere/*chemistry/genetics/*metabolism ; },
abstract = {Guanine rich (G-rich) nucleic acids form G-quadruplex structures that are implicated in many biological processes, pharmaceutical applications, and molecular machinery. The folding equilibrium constant (K(F)) of the G-quadruplex not only determines its stability and competition against duplex formation in genomic DNA but also defines its recognition by proteins and drugs and technical specifications. The K(F) is most conveniently derived from thermal melting analysis that has so far yielded extremely diversified results for the human telomere G-quadruplex. Melting analysis cannot be used for nucleic acids associated with proteins, thus has difficulty to study how protein association affects the folding equilibrium of G-quadruplex structure. In this work, we established an isothermal differential hybridization (IDH) method that is able to determine the K(F) of G-quadruplex, either alone or associated with proteins. Using this method, we studied the folding equilibrium of the core sequence G(3)(T(2)AG(3))(3) from vertebrate telomere in K(+) and Na(+) solutions and how it is affected by proteins associated at its adjacent regions. Our results show that the K(F) obtained for the free G-quadruplex is within 1 order of magnitude of most of those obtained by melting analysis and protein binding beside a G-quadruplex can dramatically destabilize the G-quadruplex.},
}
@article {pmid20980239,
year = {2011},
author = {Martins-Taylor, K and Sharma, U and Rozario, T and Holmes, SG},
title = {H2A.Z (Htz1) controls the cell-cycle-dependent establishment of transcriptional silencing at Saccharomyces cerevisiae telomeres.},
journal = {Genetics},
volume = {187},
number = {1},
pages = {89-104},
pmid = {20980239},
issn = {1943-2631},
mesh = {Cell Cycle/*genetics ; Cell Cycle Proteins/metabolism ; Chromatin Assembly and Disassembly/genetics ; Chromosomal Proteins, Non-Histone/metabolism ; Euchromatin/genetics/metabolism ; *Gene Silencing ; Heterochromatin/genetics/metabolism ; Histone Acetyltransferases/metabolism ; Histones/*metabolism ; Saccharomyces cerevisiae/*cytology/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/metabolism ; Telomere/*genetics ; Time Factors ; Transcription, Genetic/*genetics ; },
abstract = {The establishment of transcriptional silencing in Saccharomyces cerevisiae requires progression through the cell cycle. We have previously found that transit through M-phase is necessary and sufficient to establish silencing at telomeres following induction of the Sir3 silencing factor. In this study we find that halting cell-cycle progression in either G(1) or at the beginning of M-phase limits the ability of Sir3 to associate with a telomere-linked reporter gene and prevents the changes in histone modifications associated with gene repression. Deletion of genes coding for the histone variant H2A.Z (Htz1 in yeast) and histone acetyltransferase Sas2 abolish the cell-cycle progression requirement for the establishment of silencing. Cells blocked in telophase (but not at metaphase) are also able to establish silencing. We show that H2A.Z binds to the promoter of our telomere-linked reporter gene and that this binding diminishes in silenced cells. Finally, we observe a specific displacement of H2A.Z from chromatin in telophase-blocked cells, regardless of the silencing status of the reporter gene. These results suggest that the requirement for M-phase in the establishment of silencing may reflect a cell-cycle regulated relaxation of heterochromatin barriers.},
}
@article {pmid20979881,
year = {2010},
author = {Gao, YY and Luo, D and Zhou, BR and Li, W and Min, W and Lin, BJ},
title = {[Mechanism of telomere shortening in photoaging model induced by 8-methoxypsoralen and ultraviolet A].},
journal = {Zhonghua yi xue za zhi},
volume = {90},
number = {24},
pages = {1698-1702},
pmid = {20979881},
issn = {0376-2491},
mesh = {Cell Line/drug effects/radiation effects ; Cellular Senescence/*drug effects/*radiation effects ; Fibroblasts/cytology/drug effects/radiation effects ; Humans ; Methoxsalen/*pharmacology ; Oxidative Stress ; Telomere/*drug effects/*radiation effects ; *Ultraviolet Rays ; },
abstract = {OBJECTIVE: To investigate the mechanism of telomere shortening through 8-methoxypsoralen (8-MOP) and subsequent ultraviolet A (UVA) irradiation-induced photoaging model in human dermal fibroblasts (HDFs).<br><br>METHODS: Photoaging model was established by 8-MOP + UVA in skin HDFs. Flow cytometer, enzyme cytochemistry, immunofluorescence, Western blot and Real-time PCR were employed.<br><br>RESULTS: The percentage of G1 blockage of 8-MOP + UVA group were higher than that of control group at 24, 48, 72 h and 7 d (61.4% +/- 1.5% vs. 32.8% +/- 1.5%, 69.5% +/- 2.2% vs. 44.9% +/- 2.3%, 88.2% +/- 1.6% vs. 59.8% +/- 1.4%, 90.7% +/- 2.5% vs. 68.5% +/- 2.6%, all P < 0.01). The expression of SA-beta-Gal of 8-MOP + UVA group were higher than that of control group at 24, 48, 72 h and 7 d (34.87% +/- 0.59% vs. 7.11% +/- 0.78%, 59.38% +/- 0.46% vs. 10.57% +/- 0.47%, 72.46% +/- 0.98% vs. 11.67% +/- 0.87%, 94.33% +/- 0.13% vs. 12.04% +/- 0.12%, all P < 0.01). 8-MOP + UVA treatment could significantly aggravate the oxidative DNA damages, the percentage of 8-oxo-dG positive cell of 8-MOP + UVA group (95.78% +/- 0.14%) were significantly higher than that of control group (7.69% +/- 0.09%, P < 0.01), 8-MOP group (9.76% +/- 0.11%, P < 0.01) and UVA group (35.29% +/- 0.14%, P < 0.05). 8-MOP + UVA treatment could accelerate the telomere shortening ,the relative length of telomere of 8-MOP + UVA group were 2.57 +/- 0.05 lower than that of control group (6.63 +/- 0.12, P < 0.01). The levels of P53, P21(WAF-1) and P16(INK-4a) of 8-MOP + UVA group were higher than that of control group (3.00 +/- 0.88 vs. 0.54 +/- 0.10, 2.50 +/- 0.51 vs. 0.42 +/- 0.06, 2.21 +/- 0.34 vs. 0.38 +/- 0.05, all P < 0.01).<br><br>CONCLUSION: 8-MOP + UVA-induced photoaging of HDFs can be mediated though the regulation of telomere and subsequent P53-dependent signaling pathways.},
}
@article {pmid20976265,
year = {2010},
author = {Mokry, J and Soukup, T and Micuda, S and Karbanova, J and Visek, B and Brcakova, E and Suchanek, J and Bouchal, J and Vokurkova, D and Ivancakova, R},
title = {Telomere attrition occurs during ex vivo expansion of human dental pulp stem cells.},
journal = {Journal of biomedicine &amp; biotechnology},
volume = {2010},
number = {},
pages = {673513},
pmid = {20976265},
issn = {1110-7251},
mesh = {Adolescent ; Adult ; Antigens, CD/metabolism ; Cell Count ; Cell Proliferation ; Cells, Cultured ; Chondrogenesis ; Colony-Forming Units Assay ; DNA ; Dental Pulp/*cytology ; Female ; Flow Cytometry ; Humans ; Immunohistochemistry ; Kinetics ; Male ; Microscopy, Phase-Contrast ; Multipotent Stem Cells/cytology/metabolism ; Osteogenesis ; Reference Standards ; Stem Cells/*cytology/metabolism ; Telomere/*pathology ; Time Factors ; Young Adult ; },
abstract = {We provide a detailed characteristic of stem cells isolated and expanded from the human dental pulp. Dental pulp stem cells express mesenchymal cell markers STRO-1, vimentin, CD29, CD44, CD73, CD90, CD166, and stem cell markers Sox2, nestin, and nucleostemin. They are multipotent as shown by their osteogenic and chondrogenic potential. We measured relative telomere length in 11 dental pulp stem cell lines at different passages by quantitative real-time PCR. Despite their large proliferative capacity, stable viability, phenotype, and genotype over prolonged cultivation, human dental pulp stem cells suffer from progressive telomere shortening over time they replicate in vitro. Relative telomere length (T/S) was inversely correlated with cumulative doubling time. Our findings indicate that excessive ex vivo expansion of adult stem cells should be reduced at minimum to avoid detrimental effects on telomere maintenance and measurement of telomere length should become a standard when certificating the status and replicative age of stem cells prior therapeutic applications.},
}
@article {pmid20975208,
year = {2010},
author = {Mason, M and Skordalakes, E},
title = {Insights into Cdc13 dependent telomere length regulation.},
journal = {Aging},
volume = {2},
number = {10},
pages = {731-734},
pmid = {20975208},
issn = {1945-4589},
support = {R01 GM088332/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites ; Cell Survival/physiology ; DNA/metabolism ; DNA Polymerase I/metabolism ; DNA Primase/metabolism ; Protein Binding/physiology ; Protein Interaction Domains and Motifs/physiology ; Saccharomyces cerevisiae/*physiology ; Saccharomyces cerevisiae Proteins/chemistry/*physiology ; Telomerase/metabolism ; Telomere/*physiology ; Telomere-Binding Proteins/chemistry/*physiology ; },
abstract = {Cdc13 is a single stranded telomere binding protein that specifically localizes to the telomere ends of budding yeasts and is essential for cell viability. It caps the ends of chromosomes thus preventing chromosome end-to-end fusions and exonucleolytic degradation, events that could lead to genomic instability and senescence, the hallmark of aging. Cdc13 is also involved in telomere length regulation by recruiting or preventing access of telomerase to the telomeric overhang. Recruitment of telomerase to the telomeres for G-strand extension is required for continuous cell division, while preventing its access to the telomeres through capping the chromosome ends prevents mitotic events that could lead to cell immortality, the hall mark of carcinogenesis. Cdc13 and its putative homologues human CTC1 and POT1 are therefore key to many biological processes directly associated with life extension and cancer prevention and can be viewed as an ideal target for cancer and age related therapies.},
}
@article {pmid20965155,
year = {2011},
author = {Lin, J and Kroenke, CH and Epel, E and Kenna, HA and Wolkowitz, OM and Blackburn, E and Rasgon, NL},
title = {Greater endogenous estrogen exposure is associated with longer telomeres in postmenopausal women at risk for cognitive decline.},
journal = {Brain research},
volume = {1379},
number = {},
pages = {224-231},
pmid = {20965155},
issn = {1872-6240},
support = {M01 RR000070-44/RR/NCRR NIH HHS/United States ; R01 AG022008-03/AG/NIA NIH HHS/United States ; R01 AG022008-04/AG/NIA NIH HHS/United States ; R13 AG032903-01A1/AG/NIA NIH HHS/United States ; R01 AG022008-01/AG/NIA NIH HHS/United States ; R01 AG022008-05/AG/NIA NIH HHS/United States ; R01 AG022008-05S1/AG/NIA NIH HHS/United States ; R01 AG022008-05S2/AG/NIA NIH HHS/United States ; R01 AG022008-02/AG/NIA NIH HHS/United States ; M01 RR000070/RR/NCRR NIH HHS/United States ; M01 RR-00070/RR/NCRR NIH HHS/United States ; R01 AG022008/AG/NIA NIH HHS/United States ; R13 AG032903/AG/NIA NIH HHS/United States ; R01 AG22008/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Cognition Disorders/*blood/*psychology ; Estrogen Replacement Therapy/methods ; Estrogens/adverse effects/*blood ; Female ; Humans ; Longitudinal Studies ; Middle Aged ; Postmenopause/*blood/drug effects/*psychology ; Risk Factors ; Telomere/*physiology ; },
abstract = {Longer duration of reproductive years of life and thus greater exposure to endogenous estrogen may be associated with a lower risk of age-related diseases in women. The present study examined the relationship between estimated endogenous estrogen exposure and telomere length (TL) and telomerase activity, two biomarkers of cellular aging, in a sample of postmenopausal women at risk for cognitive decline. Telomere length was measured using a quantitative PCR method and telomerase activity by TRAP (Telomere-Repeats Amplification Protocol) assay in peripheral blood mononuclear cells (PBMCs). Study subjects were 53 postmenopausal women (35 with natural and 18 with surgical menopause) receiving hormone therapy (HT) for at least one year or longer. Length of reproductive years of life, computed as the difference between age at menopause and age at menarche, was used as a proxy of duration of exposure to endogenous estrogen. Length of time on HT was the measure used for duration of exogenous estrogen exposure. We found that longer endogenous estrogen exposure was associated with greater TL (standardized β=0.06, Wald χ(2)=3.7, p=0.04) and with lower telomerase activity (standardized β=-0.09, Wald χ(2)=5.0, p=0.03). Length of reproductive years was also inversely associated with the combination of short TL and high telomerase (OR=0.78, 95% CI: 0.63, 0.97, p=0.02). Length of HT use was not associated with TL or telomerase activity in this study. The results suggest that the endogenous estrogens may be associated with deceleration of cellular aging. This is the first study to examine associations between endogenous estrogens, telomere length and telomerase activity.},
}
@article {pmid20961747,
year = {2011},
author = {Yang, Q and Zhao, J and Zhou, N and Ye, Z and Li, G},
title = {Electrochemical sensing telomere-bending motions caused by hTRF1.},
journal = {Biosensors &amp; bioelectronics},
volume = {26},
number = {5},
pages = {2228-2231},
doi = {10.1016/j.bios.2010.09.039},
pmid = {20961747},
issn = {1873-4235},
mesh = {Biosensing Techniques/*instrumentation ; Conductometry/*instrumentation ; Elastic Modulus ; Equipment Design ; Equipment Failure Analysis ; Protein Binding ; Protein Interaction Mapping/*instrumentation/methods ; Telomere/*chemistry/ultrastructure ; Telomeric Repeat Binding Protein 1/*chemistry/ultrastructure ; },
abstract = {It has been reported that human telomeric repeat binding factor 1 (hTRF1) may cause telomeric DNA bent; however there is no direct evidence, thus controversy still exists. In this work, the interaction between hTRF1 and a simulated telomeric DNA was investigated by using electrochemical method. While the telomeric DNA was immobilized on a gold electrode surface, a guanine-quadruplex-hemin complex was linked at the end of the DNA to serve as an electrochemical signal reporter. If hTRF1 made the telomeric tracts bent, electrochemical response from "off" to "on" could be observed. Therefore, this electrochemical method could give direct evidence whether hTRF1 binding to telomeric DNA would induce a shallow distortion of the DNA molecules, and a new way to explore the structural information of telomere was also proposed in this paper.},
}
@article {pmid20956286,
year = {2011},
author = {Zheng, YL and Zhou, X and Loffredo, CA and Shields, PG and Sun, B},
title = {Telomere deficiencies on chromosomes 9p, 15p, 15q and Xp: potential biomarkers for breast cancer risk.},
journal = {Human molecular genetics},
volume = {20},
number = {2},
pages = {378-386},
pmid = {20956286},
issn = {1460-2083},
support = {R01 CA132996/CA/NCI NIH HHS/United States ; P30 CA51008/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Breast Neoplasms/*genetics ; Case-Control Studies ; Chromosomal Instability ; *Chromosomes, Human, Pair 15 ; *Chromosomes, Human, Pair 9 ; *Chromosomes, Human, X ; Female ; *Genetic Markers ; Genetic Predisposition to Disease ; Humans ; Middle Aged ; Risk Factors ; Telomere/*genetics ; },
abstract = {Although telomere dysfunction is a characteristic of breast cancer cells, the relationship between deficiency on individual chromosomal telomeres in normal somatic cells and breast cancer risk has not been characterized. A case-control study was conducted to examine the associations between individual lengths of 92 telomeres in the human genome and the risk of breast cancer in 204 newly diagnosed breast cancer patients and 236 healthy controls. Chromosome arm-specific telomere lengths were measured by telomere quantitative fluorescent in situ hybridization. Unconditional logistic regression was used to estimate the risk associations. This genome-wide screen identified that shorter telomere lengths on chromosomes Xp and 15p were associated with breast cancer risk in pre-menopausal women, with adjusted odds ratios (aORs) of 2.5 (95% CI = 1.3, 4.8) and 2.6 (1.3, 5.0), respectively. The study also revealed that greater length differences between homologous telomeres on chromosomes 9p, 15p and 15q were associated with breast cancer risk in pre-menopausal women, with aORs of 4.6 (2.3, 9.2), 3.1 (1.6, 6.0) and 2.8 (1.4, 5.4), respectively. When the subjects were categorized into quartiles, a dose-response relationship was observed for all of the above telomeres (P-for-trend ≤ 0.005). This study revealed that telomere deficiencies on chromosomes 9p, 15p, 15q and Xp were associated with breast cancer risk in pre-menopausal women. If confirmed in future studies, chromosomal arm-specific telomeres are likely to be a useful panel of blood-based biomarkers for breast cancer risk assessment, given their strong associations with breast cancer risk.},
}
@article {pmid20952810,
year = {2010},
author = {Blagoev, KB and Goodwin, EH and Bailey, SM},
title = {Telomere sister chromatid exchange and the process of aging.},
journal = {Aging},
volume = {2},
number = {10},
pages = {727-730},
pmid = {20952810},
issn = {1945-4589},
mesh = {Aging/genetics ; Animals ; Antioxidants/pharmacology ; Bloom Syndrome/genetics ; *Cell Proliferation ; Cellular Senescence/*physiology ; Computer Simulation ; Exodeoxyribonucleases/genetics ; Humans ; Models, Biological ; Neoplasms/genetics ; RecQ Helicases/genetics ; Sister Chromatid Exchange/drug effects/*physiology/radiation effects ; Skin Aging/genetics/radiation effects ; Telomere/genetics/*metabolism ; Werner Syndrome/genetics ; Werner Syndrome Helicase ; },
abstract = {Telomeres are a hotspot for sister chromatid exchange (T-SCE). Any biological consequence of this form of instability remained obscure until quantitative modeling revealed a link between elevated T-SCE rates and accelerated cellular replicative senescence. This work strongly suggests that progressive telomere erosion is not the only determinant of replicative capacity; instead, T-SCE need to be considered as an independent factor controlling colony growth and senescence. Additionally high T-SCE rates have been observed in cells with deficiencies in WRN and BLM, the genes that are defective in Werner's and Bloom's syndromes, implying a connection to premature aging. In this Research Perspective we will explore some of the implications this recent work has for human health.},
}
@article {pmid20952394,
year = {2010},
author = {Briffotaux, J and Kobryn, K},
title = {Preventing broken Borrelia telomeres: ResT couples dual hairpin telomere formation with product release.},
journal = {The Journal of biological chemistry},
volume = {285},
number = {52},
pages = {41010-41018},
pmid = {20952394},
issn = {1083-351X},
support = {MOP 79344//Canadian Institutes of Health Research/Canada ; },
mesh = {Bacterial Proteins ; Borrelia/*enzymology/genetics ; DNA, Bacterial/genetics/*metabolism ; DNA, Cruciform/genetics/*metabolism ; Endodeoxyribonucleases ; Telomere/genetics/*metabolism ; },
abstract = {Spirochetes of the genus Borrelia include the tick-transmitted causative agents of Lyme disease and relapsing fever. They possess unusual genomes composed mainly of linear replicons terminated by closed DNA hairpins. Hairpin telomeres are formed from inverted repeat replicated telomere junctions (rTels) by the telomere resolvase ResT. ResT uses a reaction mechanism similar to that of the type IB topoisomerases and tyrosine recombinases. ResT can catalyze three distinct reactions: telomere resolution, telomere fusion, and Holliday junction (HJ) formation. HJ formation is known to occur only in the context of a synapsed pair of rTels. To test whether telomere resolution was synapsis-dependent, we performed experiments with rTel substrates immobilized on streptavidin-coated beads. We report that telomere resolution by ResT is synapsis-independent, indicating that alternative complexes are formed for telomere resolution and HJ formation. We also present evidence that dual hairpin telomere formation precedes product release. This mechanism of telomere resolution prevents the appearance of broken telomeres. We compare and contrast this mechanism with that proposed for TelK, the telomere resolvase of ϕKO2.},
}
@article {pmid20950384,
year = {2010},
author = {Cross, JA and Temple, RC and Hughes, JC and Dozio, NC and Brennan, C and Stanley, K and Murphy, HR and Fowler, D and Hughes, DA and Sampson, MJ},
title = {Cord blood telomere length, telomerase activity and inflammatory markers in pregnancies in women with diabetes or gestational diabetes.},
journal = {Diabetic medicine : a journal of the British Diabetic Association},
volume = {27},
number = {11},
pages = {1264-1270},
doi = {10.1111/j.1464-5491.2010.03099.x},
pmid = {20950384},
issn = {1464-5491},
support = {PDF/01/036/DH_/Department of Health/United Kingdom ; },
mesh = {Adult ; Biomarkers/blood ; DNA Damage/*genetics ; Diabetes Mellitus, Type 1/blood/*genetics ; Diabetes Mellitus, Type 2/blood/*genetics ; Diabetes, Gestational/blood/*genetics ; Female ; *Fetal Blood ; Humans ; Infant, Newborn ; Pregnancy ; Pregnancy in Diabetics/blood/*genetics ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {AIMS: We tested the hypothesis that diabetes during pregnancy leads to chromosomal DNA damage and telomere attrition in the feto placental unit and cord blood, and provides evidence for intrauterine programming towards a senescent phenotype in the offspring.<br><br>METHODS: We obtained cord blood from pregnant women with pregestational Type 1 diabetes (n=26), Type 2 diabetes (n=20) or gestational diabetes (n=71), and control subjects without diabetes (n=45, n=76 and n=81, respectively) matched for maternal and gestational age. We measured cord blood mononuclear cell telomere length, telomerase activity (a reverse transcriptase that limits telomere attrition), and concentrations of insulin, high-sensitivity C-reactive protein (hs-CRP) and soluble intercellular adhesion molecule-1 (sICAM-1).<br><br>RESULTS: We found no significant differences between groups in cord blood telomere length in any nucleated cell type, or in hs-CRP or sICAM-1 concentrations, but telomerase activity was higher in cord blood from Type 1 (P<0.05) and gestational diabetes pregnancies (P<0.05), but not in Type 2 diabetes pregnancies. There were no significant relationships between glycaemic control, cord blood telomere length, telomerase activity or inflammatory markers in any group.<br><br>CONCLUSIONS: We found no difference in cord blood telomere length in pregnancies of women with diabetes compared with control subjects, but higher cord blood telomerase activity in Type 1 and gestational diabetes. This may reflect upregulated telomere reverse transcriptase in response to in utero oxidative DNA and telomere damage. These observations are relevant to the hypothesis that diabetes during pregnancy leads to in utero preprogramming towards senescence in the offspring.},
}
@article {pmid20947477,
year = {2010},
author = {Perona, R},
title = {The Nobel Prize in physiology or medicine 2009 "for telomere biology" and its relevance to cancer and related diseases.},
journal = {Clinical &amp; translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico},
volume = {12},
number = {10},
pages = {647-649},
pmid = {20947477},
issn = {1699-3055},
mesh = {Animals ; Genetics/*history ; History, 20th Century ; History, 21st Century ; Humans ; Neoplasms/*genetics ; *Nobel Prize ; Telomere/*physiology ; },
}
@article {pmid20942452,
year = {2010},
author = {Markus, TZ and Daube, SS and Naaman, R},
title = {Cooperative effect in the electronic properties of human telomere sequence.},
journal = {The journal of physical chemistry. B},
volume = {114},
number = {43},
pages = {13897-13903},
doi = {10.1021/jp1064038},
pmid = {20942452},
issn = {1520-5207},
mesh = {Adenine ; Base Sequence ; DNA/chemistry/genetics ; *Electrons ; Humans ; Photoelectron Spectroscopy ; Telomere/*chemistry/*genetics ; },
abstract = {The contribution of sequence elements of human telomere DNA to the interaction of DNA with electrons has been analyzed. By applying wavelength dependent low-energy photoelectron transmission and two-photon photoemission spectroscopy, we investigated the density of states of DNA oligomers with partial sequence elements of the human telomere assembled as monolayers on gold. The findings demonstrate the role of the resonance states in the DNA in accepting electrons and the effect of the sequence on these states. When guanine (G) bases are clustered together, the resonance negative ion state is stabilized, as compared to oligomers containing the same number of G bases but distributed within the sequence. The electron-capturing probability of the human telomere-like oligomer, a sequence with an additional single adenine (A) base adjacent to the G cluster, is dramatically enhanced compared to the other oligomers studied, most likely due to the enhancement of the density of states near the highest occupied molecular orbital.},
}
@article {pmid20937668,
year = {2011},
author = {Nabetani, A and Ishikawa, F},
title = {Alternative lengthening of telomeres pathway: recombination-mediated telomere maintenance mechanism in human cells.},
journal = {Journal of biochemistry},
volume = {149},
number = {1},
pages = {5-14},
doi = {10.1093/jb/mvq119},
pmid = {20937668},
issn = {1756-2651},
mesh = {Acid Anhydride Hydrolases ; Animals ; Cell Cycle Proteins/physiology ; DNA/*metabolism ; DNA Helicases/physiology ; DNA Repair Enzymes/physiology ; DNA, Cruciform/metabolism ; DNA-Binding Proteins/physiology ; Humans ; MRE11 Homologue Protein ; Nuclear Proteins/metabolism/physiology ; *Recombination, Genetic ; Shelterin Complex ; Telomerase/biosynthesis ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/physiology ; Telomeric Repeat Binding Protein 2/physiology ; },
abstract = {Unlimitedly proliferating cells need to acquire the telomere DNA maintenance mechanism, to counteract possible shortening through multiple rounds of replication and segregation of linear chromosomes. Most human cancer cells express telomerase whereas the other cells utilize the alternative lengthening of telomeres (ALT) pathway to elongate telomere DNA. It is suggested that ALT depends on the recombination between telomere repetitive DNAs. However, the molecular details remain unknown. Recent studies have provided evidence of special structures of telomere DNA and genes essential for the phenotypes of ALT cells. The molecular models of the ALT pathway should be validated to elucidate recombination-mediated telomere maintenance and promote the applications to anti-cancer therapy.},
}
@article {pmid20937264,
year = {2011},
author = {Zee, RY and Ridker, PM and Chasman, DI},
title = {Genetic variants in eleven telomere-associated genes and the risk of incident cardio/cerebrovascular disease: The Women's Genome Health Study.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {412},
number = {1-2},
pages = {199-202},
pmid = {20937264},
issn = {1873-3492},
support = {R01 HL043851/HL/NHLBI NIH HHS/United States ; CA-047988/CA/NCI NIH HHS/United States ; R01 CA047988-20/CA/NCI NIH HHS/United States ; R01 HL080467-05/HL/NHLBI NIH HHS/United States ; HL-043851/HL/NHLBI NIH HHS/United States ; R01 HL080467/HL/NHLBI NIH HHS/United States ; R01 CA047988/CA/NCI NIH HHS/United States ; R01 HL043851-10/HL/NHLBI NIH HHS/United States ; HL-080467/HL/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Cardiovascular Diseases/*genetics ; Cerebrovascular Disorders/*genetics ; Cohort Studies ; Female ; Genetic Predisposition to Disease/*genetics ; Genome, Human/*genetics ; *Health ; Humans ; Middle Aged ; *Polymorphism, Single Nucleotide ; Regression Analysis ; Telomere/*genetics ; },
abstract = {BACKGROUND: Candidate genes associated with telomere length maintenance, an important molecular marker for biological aging, represent potential risk predictors for cardiovascular disease (CVD). To date, no prospective data are available.<br><br>METHODS: The associations between 154 tag-single nucleotide polymorphisms (tSNPs) of 11 telomere-associated candidate genes (TERT, POT1, TNKS, TERF1, TNKS2, UCP2, TEP1, ACD, TERF2, TERF2IP, and TERC) were investigated in 23,294 Caucasian participants of the Women's Genome Health Study. All were free of known CVD and cancer at baseline. The primary outcome measure was a composite CVD end point (incident ischemic stroke, myocardial infarction (MI), or death due to ischemic CVD); other measures were incident MI and ischemic stroke. During follow-up, 1178 total incident CVD, 315 incident MI cases, and 323 incident ischemic stroke events were identified. Multivariable Cox regression analysis and a haplotype-based approach were performed to investigate the relationship between genotypes/haplotypes and CVD risk, assuming an additive model.<br><br>RESULTS: In a marker-by-marker analysis, 7 (TEP1, TNKS, and ACD), 11 (TEP1, ACD, and TERT), and 24 (TEP1, TNKS, TERT, TERF2IP, TNKS2, and UCP2) SNPs were associated-at the level of p < 0.05-with the total CVD, MI, and ischemic stroke risk, respectively. Further analysis using a haplotype-based approach showed similar findings. Although none remained significant after the correction of multiple testing, the false discovery rate analysis revealed 28% of the nominally significant SNPs with true associations in relation to ischemic stroke risk.<br><br>CONCLUSIONS: The present large prospective study encourages further investigation of the biological role of telomere-associated pathway genes in the pathogenesis and early assessment of vascular events.},
}
@article {pmid20931867,
year = {2010},
author = {Yang, Y and Dai, Y and Chen, Z and Qin, Z},
title = {[Cloning and analysis of the telomeres of five Streptomyces linear plasmids].},
journal = {Wei sheng wu xue bao = Acta microbiologica Sinica},
volume = {50},
number = {8},
pages = {1008-1013},
pmid = {20931867},
issn = {0001-6209},
mesh = {Base Sequence ; Cloning, Molecular ; Molecular Sequence Data ; *Plasmids ; Soil Microbiology ; Streptomyces/*genetics ; *Telomere ; },
abstract = {OBJECTIVE: Streptomyces strains were isolated from soil samples of Tibet, five small linear plasmids were detected by pulsed-field gel electrophoresis.<br><br>OBJECTIVE: Cloning, sequencing and analysis of telomeres of these plasmids.<br><br>METHODS: The telomeres were cloned by a modified procedure--"alkaline treatment and enzyme digestion in gels".<br><br>RESULTS: Telomeres of five linear plasmids were cloned and sequenced. Compared with the typical Streptomyces telomeres, the newly identified telomeres contained multiple palindromes, but some could not "fold-back" of their first conserved palindrome I with the internal palindromes to form a "super-hairpin", and palindromes of some telomeres did not contain the 3-nt "loop".<br><br>CONCLUSION: New telomere sequences were cloned by a modified procedure. Both folding-back of the telomere palindromes and 3-nt loop of palindromes varied among telomeres.},
}
@article {pmid20927532,
year = {2011},
author = {Scherthan, H and Sfeir, A and de Lange, T},
title = {Rap1-independent telomere attachment and bouquet formation in mammalian meiosis.},
journal = {Chromosoma},
volume = {120},
number = {2},
pages = {151-157},
pmid = {20927532},
issn = {1432-0886},
support = {R01 GM049046/GM/NIGMS NIH HHS/United States ; AG016642/AG/NIA NIH HHS/United States ; R56 AG016642/AG/NIA NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; GM049046/GM/NIGMS NIH HHS/United States ; R01 AG016642-12/AG/NIA NIH HHS/United States ; R37 GM049046-19/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Female ; Male ; *Meiosis ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microtubule-Associated Proteins/genetics/metabolism ; Nuclear Envelope/genetics/*metabolism ; Protein Binding ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Attachment of telomeres to the nuclear envelope (NE) and their clustering in a chromosomal bouquet during meiotic prophase I is an evolutionary conserved event that promotes chromosome pairing and recombination. In fission yeast, bouquet formation fails when the telomeric protein Rap1 is absent or when the telomeric protein Taz1 fails to recruit Rap1 to telomeres. The mammalian Rap1 orthologue is a component of the shelterin complex and localises to telomeres through an interaction with a Taz1-like telomeric DNA binding factor, TRF2. Here, we investigated the role of mammalian Rap1 in meiotic telomere attachment and clustering by analysing spermatogenesis in Rap1-deficient mice. The results establish that the meiotic three-dimensional nuclear architecture and recombination are not affected by the absence of Rap1. Furthermore, Rap1-deficient meiotic telomeres assemble the SUN1 nuclear membrane protein, attach to the NE, and undergo bouquet formation indistinguishable from the wild-type setting. Thus, the role of Rap1 in meiosis is not conserved between fission yeast and mammals, suggesting that mammals have alternative modes for connecting telomeres to SUN proteins on the meiotic nuclear envelope.},
}
@article {pmid20926045,
year = {2010},
author = {Bendix, L and Kølvraa, S},
title = {[The role of telomeres in aging-related disease].},
journal = {Ugeskrift for laeger},
volume = {172},
number = {40},
pages = {2752-2755},
pmid = {20926045},
issn = {1603-6824},
mesh = {Aging/*genetics ; Cellular Senescence/genetics ; Genetic Therapy ; Humans ; Morbidity ; Mortality ; Telomerase/genetics/metabolism/physiology ; Telomere/genetics/*physiology ; },
abstract = {Telomeres are specialized DNA structures, protecting the ends of linear chromosomes. The association between telomeres and cellular aging is well-established, and it has been shown that there is a negative correlation between telomere length and chronological age for many types of human tissue. On the other hand, the association between telomere length and mortality is poor. Nevertheless, it has been suggested that telomeres may play a role in the development of many aging-related diseases. This has led to attempts to develop telomere-elongating treatment.},
}
@article {pmid20926044,
year = {2010},
author = {Bendix, L and Kølvraa, S},
title = {[The role of telomeres in cancer].},
journal = {Ugeskrift for laeger},
volume = {172},
number = {40},
pages = {2748-2751},
pmid = {20926044},
issn = {1603-6824},
mesh = {Cell Transformation, Neoplastic/genetics ; Cellular Senescence/genetics ; Chromosomal Instability/genetics ; Humans ; Neoplasms/enzymology/etiology/*genetics/therapy ; Prognosis ; Telomerase/genetics/physiology ; Telomere/genetics/*physiology ; },
abstract = {Telomeres are a double-edged sword when it comes to cancer. On one hand, telomeres limit the cells' ability to divide and thereby restrict the uninhibited growth seen in cancer. On the other hand, short telomeres can initiate the chromosome instability that characterizes cancer. Diseases with the combination of short telomeres and high cancer risk are seen, but until now the use of telomeres as predictors of cancer has, in general, been unsuccessful. Telomeres and telomerase play an important role in further cancer development. Researchers are trying to exploit this in the development of new cancer therapies.},
}
@article {pmid20926043,
year = {2010},
author = {Bendix, L and Kølvraa, S},
title = {[Telomeres and telomerase].},
journal = {Ugeskrift for laeger},
volume = {172},
number = {40},
pages = {2745-2748},
pmid = {20926043},
issn = {1603-6824},
mesh = {Aging/genetics ; Biomedical Research/history ; Cellular Senescence/genetics ; DNA Damage/genetics ; Genetics/history ; History, 20th Century ; Humans ; Neoplasms/enzymology/genetics ; Telomerase/genetics/*physiology ; Telomere/genetics/*physiology ; },
abstract = {In 2009 the Nobel Prize in Medicine was awarded to EH Blackburn, CW Greider and JW Szostak for their work on "How chromosomes are protected by telomeres and the enzyme telomerase". Telomeres are specialized DNA structures localized at the end of linear chromosomes. Telomeres are known as the biological clock of the cell, since they shorten with each cell division. Telomerase can elongate telomeres. Telomeres protect chromosome ends against being recognized as double stranded DNA breaks, and are thought to be a guard against cancer. It has furthermore been suggested that telomeres may play a role in aging and age-related diseases.},
}
@article {pmid20926042,
year = {2010},
author = {Bohr, VA},
title = {[Telomeres--the beginning and the end].},
journal = {Ugeskrift for laeger},
volume = {172},
number = {40},
pages = {2744},
pmid = {20926042},
issn = {1603-6824},
mesh = {Aging/genetics ; Biomedical Research ; Cellular Senescence/genetics ; Humans ; Neoplasms/genetics ; *Telomere/genetics/physiology ; },
}
@article {pmid20924736,
year = {2011},
author = {Ozsarlak-Sozer, G and Kerry, Z and Gokce, G and Oran, I and Topcu, Z},
title = {Oxidative stress in relation to telomere length maintenance in vascular smooth muscle cells following balloon angioplasty.},
journal = {Journal of physiology and biochemistry},
volume = {67},
number = {1},
pages = {35-42},
pmid = {20924736},
issn = {1877-8755},
mesh = {Angioplasty, Balloon/*adverse effects ; Animals ; Arteries/anatomy &amp; histology/drug effects/injuries ; Atherosclerosis/pathology ; Buthionine Sulfoximine/pharmacology ; Cell Proliferation/drug effects ; Glutathione/blood/drug effects ; Glutathione Disulfide/blood/drug effects ; Glutathione Peroxidase/blood/drug effects ; Hyperplasia/pathology ; Muscle, Smooth, Vascular/drug effects/injuries/*metabolism/*pathology ; Myocytes, Smooth Muscle/*drug effects/pathology ; *Oxidative Stress ; Rabbits ; Taurine/pharmacology ; Telomere/drug effects/*pathology ; Tunica Intima/drug effects/pathology ; Vascular System Injuries/*etiology/prevention &amp; control ; },
abstract = {Telomeres are specialized DNA-protein complexes found at the tips of linear chromosomes. In this study, we investigated the effects of oxidative stress on telomeric length distribution of proliferating vascular smooth muscle cells following balloon injury in single or combined treatment of rabbits with either buthionine sulfoximine or taurine. Exposure to oxidative stress increased the balloon injury whereas taurine treatment significantly diminished L-buthionine-sulfoximine-related intimal hyperplasia. Our results also showed that both variables had a significant influence on mean telomeric length distribution.},
}
@article {pmid20924398,
year = {2010},
author = {Monaghan, P},
title = {Crossing the great divide: telomeres and ecology.},
journal = {Heredity},
volume = {105},
number = {6},
pages = {574-575},
doi = {10.1038/hdy.2010.120},
pmid = {20924398},
issn = {1365-2540},
mesh = {Aging/genetics/*metabolism ; Animals ; Biological Evolution ; *Ecology ; Humans ; Telomere/genetics/*metabolism ; },
}
@article {pmid20923774,
year = {2010},
author = {Kramara, J and Willcox, S and Gunisova, S and Kinsky, S and Nosek, J and Griffith, JD and Tomaska, L},
title = {Tay1 protein, a novel telomere binding factor from Yarrowia lipolytica.},
journal = {The Journal of biological chemistry},
volume = {285},
number = {49},
pages = {38078-38092},
pmid = {20923774},
issn = {1083-351X},
support = {55005622/HHMI/Howard Hughes Medical Institute/United States ; R01 ES013773/ES/NIEHS NIH HHS/United States ; R01 GM031819/GM/NIGMS NIH HHS/United States ; ES013773/ES/NIEHS NIH HHS/United States ; GM31819/GM/NIGMS NIH HHS/United States ; R56 ES013773/ES/NIEHS NIH HHS/United States ; TW005654/TW/FIC NIH HHS/United States ; R03 TW005654/TW/FIC NIH HHS/United States ; },
mesh = {Basidiomycota/genetics/metabolism ; DNA, Fungal/genetics/*metabolism ; Dimerization ; Fungal Proteins/genetics/*metabolism ; Humans ; Schizosaccharomyces/genetics/metabolism ; Sequence Homology, Amino Acid ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Yarrowia/genetics/*metabolism ; },
abstract = {Inspection of the complete genome of the yeast Yarrowia lipolytica for the presence of genes encoding homologues of known telomere-binding proteins surprisingly revealed no counterparts of typical yeast Myb domain-containing telomeric factors including Rap1 or Taz1. Instead, we identified a gene, YALIOD10923g, encoding a protein containing two Myb domains, exhibiting a high degree of similarity to the Myb domain of human telomeric proteins TRF1 and TRF2 and homologous to an essential fission yeast protein Mug152 whose expression is elevated during meiosis. The protein, which we named Tay1p (telomere-associated in Yarrowia lipolytica 1), was purified for biochemical studies. Using a model Y. lipolytica telomere, we demonstrate that the protein preferentially binds to Y. lipolytica telomeric tracts. Tay1p binds along the telomeric tract as dimers and larger oligomers, and it is able to remodel the telomeric DNA into both looped structures and synaptic complexes of two model telomere DNAs. The ability of Tay1p to induce dimerization of telomeres in vitro goes in line with its oligomeric nature, where each oligomer can employ several Myb domains to form intermolecular telomere clusters. We also provide experimental evidence that Tay1p may be associated with Y. lipolytica telomeres in vivo. Together with its homologues from Schizosaccharomyces pombe and several basidiomycetous fungi (Sánchez-Alonso, P., and Guzman, P. (2008) Fungal Genet. Biol. 45, S54-S62), Tay1p constitutes a novel family of putative telomeric factors whose analysis may be instrumental in understanding the function and evolution of double-stranded DNA telomeric proteins.},
}
@article {pmid20890289,
year = {2010},
author = {O'Sullivan, RJ and Kubicek, S and Schreiber, SL and Karlseder, J},
title = {Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres.},
journal = {Nature structural &amp; molecular biology},
volume = {17},
number = {10},
pages = {1218-1225},
pmid = {20890289},
issn = {1545-9985},
support = {R01 GM069525-05/GM/NIGMS NIH HHS/United States ; R01 GM06525/GM/NIGMS NIH HHS/United States ; R01 AG025837-03/AG/NIA NIH HHS/United States ; R01 GM069525/GM/NIGMS NIH HHS/United States ; R01 GM087476/GM/NIGMS NIH HHS/United States ; R01 GM069525-04/GM/NIGMS NIH HHS/United States ; R01 AG025837/AG/NIA NIH HHS/United States ; R01 AG025837-04/AG/NIA NIH HHS/United States ; },
mesh = {Bleomycin/toxicity ; Cell Line ; Cellular Senescence/*physiology ; Chromatin/*metabolism ; Chromatin Immunoprecipitation ; *DNA Damage ; DNA Replication ; Epigenesis, Genetic ; Fibroblasts/cytology/drug effects/*metabolism ; Histones/*biosynthesis ; Humans ; Methylation ; Nuclear Proteins/biosynthesis/genetics ; Oncogene Proteins, Viral/physiology ; Papillomavirus E7 Proteins/physiology ; Protein Processing, Post-Translational ; Repressor Proteins/physiology ; Retinoblastoma Protein/physiology ; Telomere/*physiology ; Tumor Suppressor Protein p53/physiology ; mRNA Cleavage and Polyadenylation Factors/biosynthesis/genetics ; },
abstract = {During replicative aging of primary cells morphological transformations occur, the expression pattern is altered and chromatin changes globally. Here we show that chronic damage signals, probably caused by telomere processing, affect expression of histones and lead to their depletion. We investigated the abundance and cell cycle expression of histones and histone chaperones and found defects in histone biosynthesis during replicative aging. Simultaneously, epigenetic marks were redistributed across the phases of the cell cycle and the DNA damage response (DDR) machinery was activated. The age-dependent reprogramming affected telomeric chromatin itself, which was progressively destabilized, leading to a boost of the telomere-associated DDR with each successive cell cycle. We propose a mechanism in which changes in the structural and epigenetic integrity of telomeres affect core histones and their chaperones, enforcing a self-perpetuating pathway of global epigenetic changes that ultimately leads to senescence.},
}
@article {pmid20890110,
year = {2010},
author = {Ghosh, AS and Tergaonkar, V},
title = {Telomeres and inflammation: Rap1 joins the ends?.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {9},
number = {19},
pages = {3834-3835},
doi = {10.4161/cc.9.19.13383},
pmid = {20890110},
issn = {1551-4005},
mesh = {Animals ; Inflammation/*genetics ; Multiprotein Complexes/metabolism ; NF-kappa B/metabolism ; Signal Transduction/physiology ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; rap1 GTP-Binding Proteins/*metabolism ; },
}
@article {pmid20890109,
year = {2010},
author = {Fink, LS and Lerner, CA and Torres, PF and Sell, C},
title = {Ku80 facilitates chromatin binding of the telomere binding protein, TRF2.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {9},
number = {18},
pages = {3798-3806},
pmid = {20890109},
issn = {1551-4005},
support = {R01 AG022443/AG/NIA NIH HHS/United States ; T32 CA009035/CA/NCI NIH HHS/United States ; AG022443/AG/NIA NIH HHS/United States ; },
mesh = {Antigens, Nuclear/genetics/*metabolism ; Chromatin/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Dimerization ; Fibroblasts/metabolism ; Humans ; Ku Autoantigen ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; RNA Interference ; Telomere/metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {The Ku70/80 heterodimer is central to non-homologous end joining repair of DNA double-strand breaks and the Ku80 gene appears to be essential for human but not rodent cell survival. The Ku70/80 heterodimer is located at telomeres but its precise function in telomere maintenance is not known. In order to examine the role of Ku80 beyond DNA repair in more detail, we have taken a knockdown approach using a human fibroblast strain. Following targeted Ku80 knockdown, telomere defects are observed and the steady state levels of the TRF2 protein are reduced. Inhibitor studies indicate that this loss of TRF2 is mediated by the proteasome and degradation of TRF2 following Ku depletion appears to involve a decrease in chromatin binding of TRF2, suggesting that the Ku heterodimer enhances TRF2 chromatin association and that non-chromatin bound TRF2 is targeted to the proteasome.},
}
@article {pmid20889650,
year = {2011},
author = {Houben, JM and Giltay, EJ and Rius-Ottenheim, N and Hageman, GJ and Kromhout, D},
title = {Telomere length and mortality in elderly men: the Zutphen Elderly Study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {66},
number = {1},
pages = {38-44},
doi = {10.1093/gerona/glq164},
pmid = {20889650},
issn = {1758-535X},
mesh = {Aged ; Aged, 80 and over ; Biomarkers ; Humans ; Leukocytes/metabolism ; Male ; *Mortality ; Proportional Hazards Models ; Prospective Studies ; *Telomere ; },
abstract = {Telomere shortening is a marker of aging and therefore telomere length might be related to disease progression and survival. To address these questions, we measured leukocyte telomere length (LTL) in male participants from the Zutphen Elderly Study. LTL was measured by quantitative polymerase chain reaction in 203 men: mean aged 78 years in 1993 and 75 surviving participants mean aged 83 years in 2000. During 7 years of follow-up, 105 men died. Cox proportional hazards models were used to estimate hazard ratios for all-cause and cause-specific mortality. We found that LTL declined with a mean of 40.2 bp/year, and LTL values measured in 1993 and 2000 correlated significantly (r = .51, p < .001). Longer telomeres at baseline were not predictive for all-cause mortality, cardiovascular mortality, or cancer mortality. These results suggest that LTL decreases with increasing age and that LTL is not related to mortality in men aged more than 70 years.},
}
@article {pmid20886614,
year = {2010},
author = {Hannes, F and Van Houdt, J and Quarrell, OW and Poot, M and Hochstenbach, R and Fryns, JP and Vermeesch, JR},
title = {Telomere healing following DNA polymerase arrest-induced breakages is likely the main mechanism generating chromosome 4p terminal deletions.},
journal = {Human mutation},
volume = {31},
number = {12},
pages = {1343-1351},
doi = {10.1002/humu.21368},
pmid = {20886614},
issn = {1098-1004},
mesh = {Base Sequence ; *Chromosome Breakage ; *Chromosome Deletion ; Chromosomes, Human, Pair 4/*genetics ; Computational Biology ; DNA-Directed DNA Polymerase/*metabolism ; Humans ; Molecular Sequence Data ; Regulatory Sequences, Nucleic Acid/genetics ; Sequence Analysis, DNA ; Telomere/*genetics ; },
abstract = {Constitutional developmental disorders are frequently caused by terminal chromosomal deletions. The mechanisms and/or architectural features that might underlie those chromosome breakages remain largely unexplored. Because telomeres are the vital DNA protein complexes stabilizing linear chromosomes against chromosome degradation, fusion, and incomplete replication, those terminal-deleted chromosomes acquired new telomeres either by telomere healing or by telomere capture. To unravel the mechanisms leading to chromosomal breakage and healing, we sequenced nine chromosome 4p terminal deletion boundaries. A computational analysis of the breakpoint flanking region, including 12 previously published pure terminal breakage sites, was performed in order to identify architectural features that might be involved in this process. All terminal 4p truncations were likely stabilized by telomerase-mediated telomere healing. In the majority of breakpoints multiple genetic elements have a potential to induce secondary structures and an enrichment in replication stalling site motifs were identified. These findings suggest DNA replication stalling-induced chromosome breakage during early development is the first mechanistic step leading toward terminal deletion syndromes.},
}
@article {pmid20885959,
year = {2010},
author = {Njajou, OT and Blackburn, EH and Pawlikowska, L and Mangino, M and Damcott, CM and Kwok, PY and Spector, TD and Newman, AB and Harris, TB and Cummings, SR and Cawthon, RM and Shuldiner, AR and Valdes, AM and Hsueh, WC},
title = {A common variant in the telomerase RNA component is associated with short telomere length.},
journal = {PloS one},
volume = {5},
number = {9},
pages = {e13048},
pmid = {20885959},
issn = {1932-6203},
support = {U19 AG023122/AG/NIA NIH HHS/United States ; R25 CA112355/CA/NCI NIH HHS/United States ; K01 AG022782/AG/NIA NIH HHS/United States ; N01 AG-6-2103/AG/NIA NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 AG023692/AG/NIA NIH HHS/United States ; N01 AG-6-2106/AG/NIA NIH HHS/United States ; N01 AG-6-2101/AG/NIA NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics/metabolism ; Body Composition ; Cohort Studies ; Female ; *Genetic Variation ; Humans ; Male ; Middle Aged ; Osteoporosis/*genetics/metabolism ; Polymorphism, Single Nucleotide ; RNA/*genetics/metabolism ; Telomerase/*genetics/metabolism ; Telomere/genetics/*metabolism ; Twins/genetics/metabolism ; White People/genetics ; Young Adult ; },
abstract = {BACKGROUND: Telomeres shorten as cells divide. This shortening is compensated by the enzyme telomerase. We evaluated the effect of common variants in the telomerase RNA component (TERC) gene on telomere length (TL) in the population-based Health Aging and Body Composition (Health ABC) Study and in two replication samples (the TwinsUK Study and the Amish Family Osteoporosis Study, AFOS).<br><br>METHODOLOGY: Five variants were identified in the TERC region by sequence analysis and only one SNP was common (rs2293607, G/A). The frequency of the G allele was 0.26 and 0.07 in white and black, respectively. Testing for association between TL and rs2293607 was performed using linear regression models or variance component analysis conditioning on relatedness among subjects.<br><br>RESULTS: The adjusted mean TL was significantly shorter in 665 white carriers of the G allele compared to 887 non-carriers from the Health ABC Study (4.69&#xb1;0.05 kbp vs. 4.86&#xb1;0.04 kbp, measured by quantitative PCR, p&#x200a;=&#x200a;0.005). This association was replicated in another white sample from the TwinsUK Study (6.90&#xb1;0.03 kbp in 301 carriers compared to 7.06&#xb1;0.03 kbp in 395 non-carriers, measured by Southern blots, p&#x200a;=&#x200a;0.009). A similar pattern of association was observed in whites from the family-based AFOS and blacks from the Health ABC cohort, although not statistically significant, possibly due to the lower allele frequency in these populations. Combined analysis using 2,953 white subjects from 3 studies showed a significant association between TL and rs2293607 (&#x3b2;&#x200a;=&#x200a;-0.19&#xb1;0.04 kbp, p&#x200a;=&#x200a;0.001).<br><br>CONCLUSION: Our study shows a significant association between a common variant in TERC and TL in humans, suggesting that TERC may play a role in telomere homeostasis.},
}
@article {pmid20883122,
year = {2010},
author = {Moskovtsev, SI and Willis, J and White, J and Mullen, JB},
title = {Disruption of telomere-telomere interactions associated with DNA damage in human spermatozoa.},
journal = {Systems biology in reproductive medicine},
volume = {56},
number = {6},
pages = {407-412},
doi = {10.3109/19396368.2010.502587},
pmid = {20883122},
issn = {1939-6376},
mesh = {Chromatin/ultrastructure ; *DNA Fragmentation ; Humans ; In Situ Hybridization, Fluorescence ; Infertility, Male/*genetics ; Male ; Spermatozoa/*physiology ; Telomere/*physiology/ultrastructure ; },
abstract = {Telomeres play a fundamental role in the organization of the sperm nucleus resulting in the looped chromosome configuration and non-random positioning of chromosomes. Telomeres localize in the nuclear periphery and interact dynamically by forming dimers and tetramers. The purpose of this study was to evaluate the relationship of telomere interactions to DNA damage, a factor known to adversely influence male fertility. Telomeres were localized by fluorescence in situ hybridization (FISH) using human chromosome pan-telomeric probe in ten samples with low and ten samples with high sperm DNA damage. The samples with a low DNA fragmentation index (DFI) had a mean number of telomere signals of 21.7±1.9 compared to a mean of 26.5±3.4 signals in the samples with a high DFI (p<.005). The percentage of cells with a typical telomere distribution of ≤23 telomere-telomere dimers was observed in 70.8%±15.6 samples with a low DFI compared to 44.2%±22.4 in samples with a high DFI (p<.05). These results suggest that sperm DNA damage is associated with disruption of the normal telomere-telomere interactions leading to possible loss of the looped chromosome configuration. Improperly packed and organized sperm chromatin might have a high probability of disrupting the extremely structured sequence of sperm chromosome deposition, activation, and processing by the oocyte at the time of fertilization. These results might provide additional information on the nature of sperm DNA damage and the role of such damage on fertilization and development of the zygote.},
}
@article {pmid20877309,
year = {2011},
author = {Sun, J and Yang, Y and Wan, K and Mao, N and Yu, TY and Lin, YC and DeZwaan, DC and Freeman, BC and Lin, JJ and Lue, NF and Lei, M},
title = {Structural bases of dimerization of yeast telomere protein Cdc13 and its interaction with the catalytic subunit of DNA polymerase α.},
journal = {Cell research},
volume = {21},
number = {2},
pages = {258-274},
pmid = {20877309},
issn = {1748-7838},
support = {T32 HL007121/HL/NHLBI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; DK074270/DK/NIDDK NIH HHS/United States ; R01 GM062631/GM/NIGMS NIH HHS/United States ; R01 GM083015/GM/NIGMS NIH HHS/United States ; R01 DK074270/DK/NIDDK NIH HHS/United States ; GM062631/GM/NIGMS NIH HHS/United States ; GM 083015-01/GM/NIGMS NIH HHS/United States ; },
mesh = {Catalytic Domain ; Crystallography, X-Ray ; DNA Polymerase I/*chemistry/metabolism ; Dimerization ; Mutation ; Protein Binding ; Protein Structure, Tertiary ; Replication Protein A/metabolism ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/*chemistry/genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*chemistry/genetics/metabolism ; },
abstract = {Budding yeast Cdc13-Stn1-Ten1 (CST) complex plays an essential role in telomere protection and maintenance, and has been proposed to be a telomere-specific replication protein A (RPA)-like complex. Previous genetic and structural studies revealed a close resemblance between Stn1-Ten1 and RPA32-RPA14. However, the relationship between Cdc13 and RPA70, the largest subunit of RPA, has remained unclear. Here, we report the crystal structure of the N-terminal OB (oligonucleotide/oligosaccharide binding) fold of Cdc13. Although Cdc13 has an RPA70-like domain organization, the structures of Cdc13 OB folds are significantly different from their counterparts in RPA70, suggesting that they have distinct evolutionary origins. Furthermore, our structural and biochemical analyses revealed unexpected dimerization by the N-terminal OB fold and showed that homodimerization is probably a conserved feature of all Cdc13 proteins. We also uncovered the structural basis of the interaction between the Cdc13 N-terminal OB fold and the catalytic subunit of DNA polymerase α (Pol1), and demonstrated a role for Cdc13 dimerization in Pol1 binding. Analysis of the phenotypes of mutants defective in Cdc13 dimerization and Cdc13-Pol1 interaction revealed multiple mechanisms by which dimerization regulates telomere lengths in vivo. Collectively, our findings provide novel insights into the mechanisms and evolution of Cdc13.},
}
@article {pmid20874798,
year = {2011},
author = {Valls, C and Piñol, C and Reñé, JM and Buenestado, J and Viñas, J},
title = {Telomere length is a prognostic factor for overall survival in colorectal cancer.},
journal = {Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland},
volume = {13},
number = {11},
pages = {1265-1272},
doi = {10.1111/j.1463-1318.2010.02433.x},
pmid = {20874798},
issn = {1463-1318},
mesh = {Adenocarcinoma/*genetics/*mortality/pathology ; Aged ; Blotting, Southern ; Colorectal Neoplasms/*genetics/*mortality/pathology ; *DNA, Neoplasm ; Female ; Humans ; Kaplan-Meier Estimate ; Lymphatic Metastasis ; Male ; Multivariate Analysis ; Neoplasm Metastasis ; Neoplasm Staging ; Prognosis ; Proportional Hazards Models ; *Telomere Homeostasis ; },
abstract = {AIM: The aim of this study was to determine whether telomere length is an independent prognostic factor for the prevention and survival of colorectal cancer.<br><br>METHOD: Terminal restriction fragment (TRF) length was determined by Southern blot in tumours and paired normal tissue samples from 147 patients with sporadic colorectal cancer who had undergone surgery. The TRF length ratio (TRFLR) was determined as the ratio between the length of the patient's tumour and normal tissue.The classification and regression tree technique was used to determine optimal cut-off values (&#x2264; 1 or > 1).<br><br>RESULTS: Mean TRF length was 6.79 Kbp (1.19-13.99) in tumour tissue and 7.81 Kbp (3.63-15.70) in normal mucosa (P < 0.001). Mean TRFLR was 0.88. Telomere length and telomere length ratio were not correlated with any clinicopathological factors. In univariate analysis, overall survival was related to N stage (lymph node +/-; P = 0.002), TNM classification (P = 0.019) and TRFLR (&#x2264; 1 or > 1; P = 0.014). In multivariate analysis, overall survival was significantly associated with TRFLR and N stage. Colorectal cancer patients with TRFLR &#x2264; 1 and negative lymph node involvement had a higher overall survival rate.<br><br>CONCLUSION: Telomere length ratio is an independent prognostic factor for survival in colorectal cancer patients, and the telomere lengths in the normal and tumour mucosa of the same patient present with parallel behaviour.},
}
@article {pmid20871595,
year = {2011},
author = {Hong, SM and Heaphy, CM and Shi, C and Eo, SH and Cho, H and Meeker, AK and Eshleman, JR and Hruban, RH and Goggins, M},
title = {Telomeres are shortened in acinar-to-ductal metaplasia lesions associated with pancreatic intraepithelial neoplasia but not in isolated acinar-to-ductal metaplasias.},
journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},
volume = {24},
number = {2},
pages = {256-266},
pmid = {20871595},
issn = {1530-0285},
support = {P50 CA102701-08/CA/NCI NIH HHS/United States ; R01-CA120432/CA/NCI NIH HHS/United States ; R01 CA097075-02/CA/NCI NIH HHS/United States ; P50 CA062924-12/CA/NCI NIH HHS/United States ; P50 CA102701/CA/NCI NIH HHS/United States ; R01 CA120432-05/CA/NCI NIH HHS/United States ; P50-CA62924/CA/NCI NIH HHS/United States ; R01 CA097075/CA/NCI NIH HHS/United States ; R01-CA97075/CA/NCI NIH HHS/United States ; P50 CA062924/CA/NCI NIH HHS/United States ; R01 CA120432/CA/NCI NIH HHS/United States ; R01 CA097075-08/CA/NCI NIH HHS/United States ; P50 CA062924-14/CA/NCI NIH HHS/United States ; },
mesh = {Analysis of Variance ; Carcinoma in Situ/*genetics/pathology ; Humans ; In Situ Hybridization, Fluorescence ; Metaplasia/genetics/pathology ; Pancreas/*pathology ; Pancreatic Neoplasms/*genetics/pathology ; Telomere/*pathology ; },
abstract = {Telomeres protect against chromosomal breakage, fusion, and interchromosome bridges during cell division. Shortened telomeres have been observed in the lowest grade of pancreatic intraepithelial neoplasia (PanIN). Genetically engineered mouse models of pancreatic neoplasia develop acinar-to-ductal metaplasia prior to the development of PanIN, suggesting that acinar-to-ductal metaplasias can be an early precursor lesion to pancreatic cancer. Some human PanINs are associated with acinar-to-ductal metaplasias, and it has been suggested that these acinar-to-ductal metaplasias arise as a consequence of growth of adjacent PanINs. As the earliest known genetic lesions of PanINs is shortened telomeres, we compared the telomere lengths of acinar-to-ductal metaplasia lesions, PanINs, and adjacent normal cells of human pancreata to determine whether acinar-to-ductal metaplasias could be precursors to PanIN. We used quantitative fluorescent in situ hybridization to measure the telomere length of cells from pancreatic lesions and adjacent normal pancreata from 22 patients, including 20 isolated acinar-to-ductal metaplasias, 13 PanINs associated with acinar-to-ductal metaplasias, and 12 PanINs. Normalized mean telomere fluorescence was significantly different among the cell types analyzed; 12.6 ± 10.2 units in normal acinar cells, 10.2 ± 6.4 in ductal cells, 8.4 ± 5.9 in fibroblasts, 9.4 ± 7.3 in isolated acinar-to-ductal metaplasias, 4.1 ± 2.9 in PanIN-associated acinar-to-ductal metaplasias, and 1.6 ± 1.9 in PanINs, respectively (P<0.001, ANOVA with randomized block design). Telomeres were significantly shorter in PanIN-associated acinar-to-ductal metaplasias (P<0.05, post hoc Duncan test) and in PanINs (P<0.05), than in normal cells, or isolated acinar-to-ductal metaplasias. Thus, shortened telomeres are found in PanIN-associated acinar-to-ductal metaplasias, but not in isolated acinar-to-ductal metaplasia lesions. These results indicate that isolated acinar-to-ductal metaplasias are not a precursor to PanIN, and support the hypothesis that PanIN-associated acinar-to-ductal metaplasias arise secondary to PanIN lesions.},
}
@article {pmid20864561,
year = {2010},
author = {Kushner, EJ and Weil, BR and MacEneaney, OJ and Morgan, RG and Mestek, ML and Van Guilder, GP and Diehl, KJ and Stauffer, BL and DeSouza, CA},
title = {Human aging and CD31+ T-cell number, migration, apoptotic susceptibility, and telomere length.},
journal = {Journal of applied physiology (Bethesda, Md. : 1985)},
volume = {109},
number = {6},
pages = {1756-1761},
pmid = {20864561},
issn = {1522-1601},
support = {HL-076434/HL/NHLBI NIH HHS/United States ; HL-077450/HL/NHLBI NIH HHS/United States ; RR-00051/RR/NCRR NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Aged ; Aging/genetics/*immunology/metabolism/pathology ; *Apoptosis/genetics ; Cardiovascular Diseases/genetics/*immunology/metabolism/pathology ; Caspase 3/metabolism ; Cell Separation/methods ; Chemokine CXCL12/metabolism ; *Chemotaxis ; Cytochromes c/metabolism ; Flow Cytometry ; Humans ; Lymphocyte Count ; Male ; Middle Aged ; Platelet Endothelial Cell Adhesion Molecule-1/*analysis ; Risk Factors ; T-Lymphocyte Subsets/*immunology/pathology ; T-Lymphocytes/*immunology/pathology ; Telomerase/metabolism ; Telomere/*metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Young Adult ; },
abstract = {CD31(+) T cells, or so-called "angiogenic T cells," have been shown to demonstrate vasculoprotective and neovasculogenic qualities. The influence of age on CD31(+) T-cell number and function is unclear. We tested the hypothesis that circulating CD31(+) T-cell number and migratory capacity are reduced, apoptotic susceptibility is heightened, and telomere length is shortened with advancing age in adult humans. Thirty-six healthy, sedentary men were studied: 12 young (25 ± 1 yr), 12 middle aged (46 ± 1 yr), and 12 older (64 ± 2 yr). CD31(+) T cells were isolated from peripheral blood samples by magnetic-activated cell sorting. The number of circulating CD31(+) T cells (fluorescence-activated cell sorting analysis) was lower (P < 0.01) in older (24% of CD3(+) cells) compared with middle-aged (38% of CD3(+) cells) and young (40% of CD3(+) cells) men. Migration (Boyden chamber) to both VEGF and stromal cell-derived factor-1α was markedly blunted (P < 0.05) in cells harvested from middle-aged [306.1 ± 45 and 305.6 ± 46 arbitrary units (AU), respectively] and older (231 ± 65 and 235 ± 62 AU, respectively) compared with young (525 ± 60 and 570 ± 62 AU, respectively) men. CD31(+) T cells from middle-aged and older men demonstrated greater apoptotic susceptibility, as staurosporine-stimulated intracellular caspase-3 activation was ∼ 40% higher (P < 0.05) than young. There was a progressive age-related decline in CD31(+) T-cell telomere length (young: 10,706 ± 220 bp; middle-aged: 10,179 ± 251 bp; and older: 9,324 ± 192 bp). Numerical and functional impairments in this unique T-cell subpopulation may contribute to diminished angiogenic potential and greater cardiovascular risk with advancing age.},
}
@article {pmid20860686,
year = {2010},
author = {Monaghan, P},
title = {Telomeres and life histories: the long and the short of it.},
journal = {Annals of the New York Academy of Sciences},
volume = {1206},
number = {},
pages = {130-142},
doi = {10.1111/j.1749-6632.2010.05705.x},
pmid = {20860686},
issn = {1749-6632},
mesh = {Animals ; Biological Evolution ; *Evolution, Molecular ; Genetic Fitness ; Histones/*metabolism ; Humans ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres are repetitive DNA sequences at the ends of eukaryote chromosomes. Telomere loss limits the number of times cells can divide and is intimately involved in cell loss and renewal. Average telomere length in cell samples generally declines with donor age but shows substantial intraspecific variation. Telomeres are potentially of great interest to evolutionary biologists since the balance of fitness costs and benefits associated with loss and restoration is linked to the biology of life span. Most telomere research is done in the context of human disease. Recently, however, there has been a burgeoning of interest in telomere dynamics in healthy organisms. The extent to which variation in telomere loss might be involved in the evolution of life histories, and constrain or underpin life history trade-offs, is a growing field of research. I discuss what we do and do not know about the links between telomere length and life histories and the extent to which variations in telomere length and loss rate are useful indicators of aging-related changes and/or the biological state of individuals.},
}
@article {pmid20858879,
year = {2010},
author = {Scheinberg, P and Cooper, JN and Sloand, EM and Wu, CO and Calado, RT and Young, NS},
title = {Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia.},
journal = {JAMA},
volume = {304},
number = {12},
pages = {1358-1364},
pmid = {20858879},
issn = {1538-3598},
support = {Z99 HL999999/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adult ; Anemia, Aplastic/blood/drug therapy/*genetics/pathology ; *Cell Transformation, Neoplastic ; *Chromosomal Instability ; Cohort Studies ; Female ; Humans ; Immunosuppressive Agents/therapeutic use ; Leukocytes/ultrastructure ; Male ; Prognosis ; Recurrence ; Survival Analysis ; Telomere/*ultrastructure ; Treatment Outcome ; },
abstract = {CONTEXT: Critically short telomeres produce apoptosis, cell senescence, and chromosomal instability in tissue culture and animal models. Variations in telomere length have been reported in severe aplastic anemia but their clinical significance is unknown.<br><br>OBJECTIVE: To investigate the relationship between telomere length and clinical outcomes in severe aplastic anemia.<br><br>DESIGN, SETTING, AND PATIENTS: Single institution analysis of 183 patients with severe aplastic anemia who were treated in sequential prospective protocols at the National Institutes of Health from 2000 to 2008. The pretreatment leukocyte age-adjusted telomere length of patients with severe aplastic anemia consecutively enrolled in immunosuppression protocols with antithymocyte globulin plus cyclosporine for correlation with clinical outcomes were analyzed.<br><br>MAIN OUTCOME MEASURES: Hematologic response, relapse, clonal evolution, and survival.<br><br>RESULTS: There was no relationship between hematologic response and telomere length with response rates of 56.5% of 46 patients in the first, 54.3% of 46 in the second, 60% of 45 in the third, and 56.5% of 46 in the fourth quartiles. Multivariate analysis demonstrated that telomere length was associated with relapse, clonal evolution, and mortality. Evaluated as a continuous variable, telomere length inversely correlated with the probability of hematologic relapse (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.03-0.69; P = .01). The probability of clonal evolution was higher in patients in the first quartile (24.5%; 95% CI, 8.7%-37.5%) than in quartiles 2 through 4 (8.4%; 95% CI, 3.2%-13.3%; P = .009), and evolution to monosomy 7 or complex cytogenetics was more common in the first quartile (18.8%; 95% CI, 3.5%-31.6%) [corrected] than in quartiles 2 through 4 (4.5%; 95% CI, 0.5%-8.2%; P = .002) [corrected]. Survival between these 2 groups differed, with 66% (95% CI, 52.9%-82.5%) surviving 6 years in the first quartile compared with 83.8% (95% CI, 77.3%-90.9%) in quartiles 2 through 4 (P = .008).<br><br>CONCLUSION: In a cohort of patients with severe aplastic anemia receiving immunosuppressive therapy, telomere length was unrelated to response but was associated with risk of relapse, clonal evolution, and overall survival.},
}
@article {pmid20857414,
year = {2011},
author = {Knecht, H and Mai, S},
title = {3D imaging of telomeres and nuclear architecture: An emerging tool of 3D nano-morphology-based diagnosis.},
journal = {Journal of cellular physiology},
volume = {226},
number = {4},
pages = {859-867},
doi = {10.1002/jcp.22425},
pmid = {20857414},
issn = {1097-4652},
mesh = {Centrosome/metabolism ; Chromosome Segregation ; Diagnostic Imaging/*methods ; Humans ; Nanotechnology/*methods ; Neoplasms/*diagnosis/genetics/pathology ; Telomere/*metabolism ; },
abstract = {Patient samples are evaluated by experienced pathologists whose diagnosis guides treating physicians. Pathological diagnoses are complex and often assisted by the application of specific tissue markers. However, cases still exist where pathologists cannot distinguish between closely related entities or determine the aggressiveness of the disease they identify under the microscope. This is due to the absence of reliable markers that define diagnostic subgroups in several cancers. Three-dimensional (3D) imaging of nuclear telomere signatures is emerging as a new tool that may change this situation offering new opportunities to the patients. This article will review current and future avenues in the assessment of diagnostic patient samples.},
}
@article {pmid20855079,
year = {2011},
author = {Zhu, H and Wang, X and Gutin, B and Davis, CL and Keeton, D and Thomas, J and Stallmann-Jorgensen, I and Mooken, G and Bundy, V and Snieder, H and van der Harst, P and Dong, Y},
title = {Leukocyte telomere length in healthy Caucasian and African-American adolescents: relationships with race, sex, adiposity, adipokines, and physical activity.},
journal = {The Journal of pediatrics},
volume = {158},
number = {2},
pages = {215-220},
pmid = {20855079},
issn = {1097-6833},
support = {HL85817/HL/NHLBI NIH HHS/United States ; R01 HL064157/HL/NHLBI NIH HHS/United States ; R21 HL085817/HL/NHLBI NIH HHS/United States ; R21 HL085817-02/HL/NHLBI NIH HHS/United States ; R01 HL077230/HL/NHLBI NIH HHS/United States ; HL64157/HL/NHLBI NIH HHS/United States ; HL77230/HL/NHLBI NIH HHS/United States ; },
mesh = {Adipokines/*blood ; Adiposity/*ethnology/*genetics ; Adolescent ; Black or African American/genetics ; Anthropometry ; Body Mass Index ; Cross-Sectional Studies ; Female ; Genetic Predisposition to Disease/epidemiology ; Health Status ; Humans ; Leukocytes ; Motor Activity/*physiology ; Obesity/ethnology/genetics ; Polymerase Chain Reaction/methods ; Risk Assessment ; Sensitivity and Specificity ; Sex Factors ; Telomere/*genetics ; White People/genetics ; },
abstract = {OBJECTIVE: To examine the relationships of race, sex, adiposity, adipokines, and physical activity to telomere length in adolescents.<br><br>STUDY DESIGN: Leukocyte telomere length (T/S ratio) was assessed cross-sectionally in 667 adolescents (aged 14-18 years; 48% African-Americans; 51% girls) using a quantitative polymerase chain reaction method. Generalized estimating equations analyses were performed.<br><br>RESULTS: Telomere length was greater in the African-American adolescents than in the Caucasian adolescents (age- and sex-adjusted T/S ratio &#xb1; SE, 1.32 &#xb1; 0.01 vs 1.27 &#xb1; 0.01: P = .014) and greater in girls than in boys (age- and race-adjusted T/S ratio &#xb1; SE, 1.31 &#xb1; 0.01 vs 1.27 &#xb1; 0.01; P = .007). None of the adiposity or adipokine measures explained a significant proportion of the variance in telomere length. Vigorous physical activity was positively associated with telomere length (adjusted R(2) = 0.019; P = .009) and accounted for 1.9% of the total variance only in girls.<br><br>CONCLUSIONS: This study, conducted in a biracial adolescent cohort, demonstrated that (1) race and sex differences in telomere length have already emerged during adolescence; (2) adiposity and adipokines are not associated with telomere length at this age; and (3) the antiaging effect of vigorous physical activity may begin in youth, especially in girls.},
}
@article {pmid20847205,
year = {2010},
author = {Ladetto, M},
title = {Telomere disrupts, CLL progresses.},
journal = {Blood},
volume = {116},
number = {11},
pages = {1821-1822},
doi = {10.1182/blood-2010-07-291443},
pmid = {20847205},
issn = {1528-0020},
}
@article {pmid20846433,
year = {2010},
author = {Weng, D and Cunin, MC and Song, B and Price, BD and Eller, MS and Gilchrest, BA and Calderwood, SK and Gong, J},
title = {Radiosensitization of mammary carcinoma cells by telomere homolog oligonucleotide pretreatment.},
journal = {Breast cancer research : BCR},
volume = {12},
number = {5},
pages = {R71},
pmid = {20846433},
issn = {1465-542X},
mesh = {Animals ; Apoptosis/drug effects/radiation effects ; Cell Line, Tumor ; Cell Proliferation/drug effects/radiation effects ; Cellular Senescence/drug effects/radiation effects ; Combined Modality Therapy ; Comet Assay ; DNA Damage/drug effects/radiation effects ; Female ; Galactosides/analysis ; Histones/metabolism ; In Situ Nick-End Labeling ; Mammary Neoplasms, Animal/*radiotherapy ; Mice ; Mice, Inbred C57BL ; Oligonucleotides/*pharmacology ; Phosphorylation/radiation effects ; Radiation Tolerance/*drug effects ; Radiation, Ionizing ; Radiation-Sensitizing Agents/*pharmacology/therapeutic use ; Telomere/genetics ; },
abstract = {INTRODUCTION: Ionizing radiation (IR) is a widely used approach to cancer therapy, ranking second only to surgery in rate of utilization. Responses of cancer patients to radiotherapy depend in part on the intrinsic radiosensitivity of the tumor cells. Thus, promoting tumor cell sensitivity to IR could significantly enhance the treatment outcome and quality of life for patients.<br><br>METHODS: Mammary tumor cells were treated by a 16-base phosphodiester-linked oligonucleotide homologous to the telomere G-rich sequence TTAGGG (T-oligo: GGTTAGGTGTAGGTTT) or a control-oligo (the partial complement, TAACCCTAACCCTAAC) followed by IR. The inhibition of tumor cell growth in vitro was assessed by cell counting and clonogenic cell survival assay. The tumorigenesis of tumor cells after various treatments was measured by tumor growth in mice. The mechanism underlying the radiosensitization by T-oligo was explored by immunouorescent determination of phosphorylated histone H2AX (&#x3b3;H2AX) foci, &#x3b2;-galactosidase staining, comet and Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) assays. The efficacy of the combined treatment was assessed in a spontaneous murine mammary tumor model.<br><br>RESULTS: Pretreatment of tumor cells with T-oligo for 24 hours in vitro enhanced both senescence and apoptosis of irradiated tumor cells and reduced clonogenic potential. Radiosensitization by T-oligo was associated with increased formation and/or delayed resolution of &#x3b3;H2AX DNA damage foci and fragmented DNA. T-oligo also caused radiosensitization in two in vivo mammary tumor models. Indeed, combined T-oligo and IR-treatment in vivo led to a substantial reduction in tumor growth. Of further significance, treatment with T-oligo and IR led to synergistic inhibition of the growth of spontaneous mammary carcinomas. Despite these profound antitumor properties, T-oligo and IR caused no detectable side effects under our experimental conditions.<br><br>CONCLUSIONS: Pretreatment with T-oligo sensitizes mammary tumor cells to radiation in both in vitro and in vivo settings with minimal or no normal tissue side effects.},
}
@article {pmid20844067,
year = {2010},
author = {Kang, JX},
title = {Differential effects of omega-6 and omega-3 fatty acids on telomere length.},
journal = {The American journal of clinical nutrition},
volume = {92},
number = {5},
pages = {1276-7; author reply 1277},
doi = {10.3945/ajcn.110.000463},
pmid = {20844067},
issn = {1938-3207},
mesh = {Cross-Sectional Studies ; Fatty Acids, Omega-3/*pharmacology ; Fatty Acids, Omega-6/*pharmacology ; Humans ; Telomere/*drug effects/ultrastructure ; },
}
@article {pmid20843367,
year = {2010},
author = {Mather, KA and Jorm, AF and Anstey, KJ and Milburn, PJ and Easteal, S and Christensen, H},
title = {Cognitive performance and leukocyte telomere length in two narrow age-range cohorts: a population study.},
journal = {BMC geriatrics},
volume = {10},
number = {},
pages = {62},
pmid = {20843367},
issn = {1471-2318},
mesh = {Adult ; Age Factors ; Aged ; Aging/*physiology ; Cognition/*physiology ; Cognition Disorders/diagnosis/physiopathology ; Cohort Studies ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/*physiology ; Longitudinal Studies ; Male ; Middle Aged ; *Population Surveillance/methods ; Psychomotor Performance/*physiology ; Telomere/*physiology ; },
abstract = {BACKGROUND: Cognitive function and telomere length both decline with age. A correlation between these two measures would suggest that they may be influenced by the same underlying age-related biological process. Several studies suggest telomere length may be positively correlated with cognitive performance but the evidence is equivocal. In this report, the relationships between telomere length and cognitive performance at Wave 2 and cognitive change from Wave 1 to Wave 2 are assessed in two narrow age-range population cohorts.<br><br>METHODS: We tested the hypothesis that leukocyte telomere length correlates positively with cognitive performance and cognitive decline in two community cohorts of middle-aged (n = 351, 44-49 years) and older (n = 295, 64-70 years) adults, who participated in two waves of a longitudinal study undertaken in the Canberra-Queanbeyan region of Australia. Telomere length was estimated at Wave 2. Cognitive performance was measured using the Symbol Digit Modalities Test, the immediate recall test of the California Verbal Learning Test, reaction time (simple &amp; choice) and the Trails Test Part B.<br><br>RESULTS: Cross-sectionally at Wave 2, telomere length correlated with Symbol Digit Modalities Test scores (men) and simple reaction time (women) for the older cohort only, although the latter finding was in the opposite direction to that hypothesised. Telomere length measured at Wave 2 was not associated with cognitive change from Wave 1 to Wave 2 for either cohort, except for two associations of small magnitude (immediate recall in the older cohort, choice reaction time in older women), which were also in the contrary direction to that predicted.<br><br>CONCLUSIONS: These results do not give strong support to the hypothesis that leukocyte telomere length is associated with either levels of cognitive performance or age-related cognitive change.},
}
@article {pmid20841475,
year = {2010},
author = {Stewart, SA and Bertuch, AA},
title = {The role of telomeres and telomerase in cancer research.},
journal = {Cancer research},
volume = {70},
number = {19},
pages = {7365-7371},
pmid = {20841475},
issn = {1538-7445},
support = {R01 GM077509/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Humans ; Mice ; Neoplasms/drug therapy/*enzymology/*genetics ; Telomerase/antagonists &amp; inhibitors/*metabolism ; Telomere/*genetics ; },
abstract = {The fourth AACR Special Conference on The Role of Telomeres and Telomerase in Cancer Research was held February 27 to March 2, 2010 in Fort Worth, TX. The meeting was organized to bring together those interested in the basic molecular mechanisms that govern telomere dynamics and stability with those interested in the clinical implications of telomere dysfunction and the use of telomeres and telomerase as therapeutic targets. The meeting was extremely successful as evidenced by the attendance and quality of the presentations. Indeed, several important themes emerged including (a) the intricate connection between the DNA replication and repair machineries in basic telomere replication and stability, (b) the complex interplay between the telomere-specific shelterin components and DNA repair proteins, (c) the nontelomeric functions of TERT in numerous cell types including stem cells, (d) a growing appreciation for the connection that exists between telomere maintenance deficiency states and diverse conditions such as idiopathic pulmonary fibrosis and hematopoietic malignancies, and (e) the successful progression of agents targeting telomerase directly and immunologically to phase III clinical trials. Evident at the meeting was the vibrant energy that permeates the telomere field and the important biological and medical findings that it continues to yield.},
}
@article {pmid20839490,
year = {2010},
author = {Simpson, RJ and Cosgrove, C and Chee, MM and McFarlin, BK and Bartlett, DB and Spielmann, G and O'Connor, DP and Pircher, H and Shiels, PG},
title = {Senescent phenotypes and telomere lengths of peripheral blood T-cells mobilized by acute exercise in humans.},
journal = {Exercise immunology review},
volume = {16},
number = {},
pages = {40-55},
pmid = {20839490},
issn = {1077-5552},
mesh = {Adult ; Cell Differentiation/immunology ; Cell Movement/*immunology ; Cell Separation ; Cellular Senescence/*immunology ; *Exercise ; Flow Cytometry ; Humans ; Lectins, C-Type/biosynthesis/immunology ; Male ; Phenotype ; Receptors, Immunologic ; Reverse Transcriptase Polymerase Chain Reaction ; T-Lymphocyte Subsets/*cytology/immunology/metabolism ; T-Lymphocytes/*cytology/immunology/metabolism ; Telomere/immunology/*metabolism ; Trans-Activators/biosynthesis/immunology ; },
abstract = {Acute bouts of aerobic exercise are known to mobilize antigen-experienced CD8+ T-cells expressing the cell surface marker of senescence, KLRG1, into the blood. It is not known; however if this is due to a selective mobilization of terminally differentiated T-cells (i.e., KLRG1 +/CD28-/CD57+) or a population of effector memory T-cells (i.e., KLRG1+/CD28+/CD57-) that have not reached terminal differentiation. The aim of this study was to further characterize KLRG1 + T-cells mobilized by acute exercise by assessing the co-expression of KLRG1 with CD28 or CD57 and to determine telomere lengths in the CD4+ and CD8+ T-cell subsets. Nine moderately trained male subjects completed an exhaustive treadmill running protocol at 80%. Blood lymphocytes isolated before, immediately after and 1h after exercise were labelled with antibodies against KLRG1, CD28 or CD57, CD4 or CD8 and CD3 for 4-color flow cytometry analysis. Telomere lengths in CD3+, CD4+ and CD8+ T-cells were determined using Q-PCR. The relative proportion of KLRG1 + cells among the CD8+ T-cells increased by 40% immediately after exercise, returning to baseline 1h later. This was due to a mobilization of KLRG1+/CD28- (61% increase), KLRG1+/CD57+ (56% increase) and to a lesser extent, KLRG1+/CD57- cells (24% increase). Telomeres in CD8+ T-cells displayed an increased relative length immediately after exercise, whereas no change occurred for CD4+ or the overall CD3+ T-cells. In conclusion, the increased frequency of KLRG1 +/CD8+ T-cells in blood after acute exercise is predominantly due to a selective mobilization of terminally differentiated T-cells. The increased relative telomere length in CD8+ T-cells after exercise might indicate that KLRG1+ cells mobilized by exercise are under stress or aberrant signaling-induced senescence (STASIS). We postulate that a frequent mobilization of these cells by acute exercise might eventually allow naïve T-cells to occupy the "vacant" immune space and increase the naïve T-cell repertoire.},
}
@article {pmid20837709,
year = {2010},
author = {Mitchell, MT and Smith, JS and Mason, M and Harper, S and Speicher, DW and Johnson, FB and Skordalakes, E},
title = {Cdc13 N-terminal dimerization, DNA binding, and telomere length regulation.},
journal = {Molecular and cellular biology},
volume = {30},
number = {22},
pages = {5325-5334},
pmid = {20837709},
issn = {1098-5549},
support = {R01 GM088332/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; DNA/genetics/*metabolism ; Dimerization ; Humans ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Protein Binding ; *Protein Structure, Quaternary ; *Protein Structure, Tertiary ; Saccharomyces cerevisiae Proteins/*chemistry/genetics/*metabolism ; Sequence Alignment ; Telomere/*metabolism ; Telomere-Binding Proteins/*chemistry/genetics/*metabolism ; },
abstract = {The essential yeast protein Cdc13 facilitates chromosome end replication by recruiting telomerase to telomeres, and together with its interacting partners Stn1 and Ten1, it protects chromosome ends from nucleolytic attack, thus contributing to genome integrity. Although Cdc13 has been studied extensively, the precise role of its N-terminal domain (Cdc13N) in telomere length regulation remains unclear. Here we present a structural, biochemical, and functional characterization of Cdc13N. The structure reveals that this domain comprises an oligonucleotide/oligosaccharide binding (OB) fold and is involved in Cdc13 dimerization. Biochemical data show that Cdc13N weakly binds long, single-stranded, telomeric DNA in a fashion that is directly dependent on domain oligomerization. When introduced into full-length Cdc13 in vivo, point mutations that prevented Cdc13N dimerization or DNA binding caused telomere shortening or lengthening, respectively. The multiple DNA binding domains and dimeric nature of Cdc13 offer unique insights into how it coordinates the recruitment and regulation of telomerase access to the telomeres.},
}
@article {pmid20837174,
year = {2010},
author = {Kulikowski, LD and Yoshimoto, M and da Silva Bellucco, FT and Belangero, SI and Christofolini, DM and Pacanaro, AN and Bortolai, A and Smith, Mde A and Squire, JA and Melaragno, MI},
title = {Cytogenetic molecular delineation of a terminal 18q deletion suggesting neo-telomere formation.},
journal = {European journal of medical genetics},
volume = {53},
number = {6},
pages = {404-407},
doi = {10.1016/j.ejmg.2010.08.007},
pmid = {20837174},
issn = {1878-0849},
mesh = {Adolescent ; *Chromosome Deletion ; *Chromosomes, Human, Pair 18 ; Comparative Genomic Hybridization/*methods ; Female ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Intellectual Disability/genetics ; Karyotyping ; Repetitive Sequences, Nucleic Acid/genetics ; Telomere/*genetics/metabolism ; },
abstract = {Deletion of the long arm of chromosome 18 is one of the most common segmental aneusomies compatible with life and usually involves a deletion of the terminal chromosomal region. However, the mechanisms implicated in the stabilization of terminal deletions are not well understood. In this study, we analyzed a girl with moderate mental retardation who had a cytogenetically visible terminal 18q deletion. In order to characterize the breakpoint in the terminal 18q region, we used fluorescence In situ hybridization (FISH) with bacterial artificial chromosomes (BACs) and pan-telomeric probes and also the array technique based on comparative genomic hybridization (array-CGH). FISH with pan-telomeric probes revealed no signal in the terminal region of the deleted chromosome, indicating the absence of normal telomere repeat (TTAGGG)n sequences in 18q. We suggest that neo-telomere formation by chromosome healing was involved in the repair and stabilization of this terminal deletion.},
}
@article {pmid20833238,
year = {2011},
author = {Effros, RB},
title = {Telomere/telomerase dynamics within the human immune system: effect of chronic infection and stress.},
journal = {Experimental gerontology},
volume = {46},
number = {2-3},
pages = {135-140},
pmid = {20833238},
issn = {1873-6815},
support = {R01 AG023720-01A1/AG/NIA NIH HHS/United States ; R01 AI060362-01/AI/NIAID NIH HHS/United States ; R01 AG023720-05/AG/NIA NIH HHS/United States ; AI 060362/AI/NIAID NIH HHS/United States ; R01 AI060362-05/AI/NIAID NIH HHS/United States ; AG 023720/AG/NIA NIH HHS/United States ; R01 AG023720/AG/NIA NIH HHS/United States ; R01 AI060362/AI/NIAID NIH HHS/United States ; },
mesh = {Aging/*immunology ; Cell Proliferation ; Humans ; Immune System/*metabolism ; T-Lymphocytes/*physiology ; Telomerase/*metabolism ; Telomere/*metabolism ; Virus Diseases/immunology ; Virus Latency ; },
abstract = {Aging of the immune system is a major factor responsible for the increased severity of infections, reduced responses to vaccines, and higher cancer incidence in the elderly. A major category of stressors that contribute to the alterations within the T lymphocyte compartment is the family of herpes viruses. These viruses, usually acquired early in life, persist for many decades and drive certain T cells to the end stage of replicative senescence, which is characterized by a variety of phenotypic and functional changes, including altered cytokine profile, resistance to apoptosis, and shortened telomeres. Indeed, high proportions of senescent CD8 (cytotoxic) T lymphocytess are associated with latent cytomegalovirus (CMV) infection in the elderly, and are part of a cluster of immune biomarkers that are associated with early mortality. Similar cells accumulate at younger ages in persons chronically infected with HIV-1. In addition to persistent viral infection, psychological stress as well as oxidative stress can also contribute to the generation of senescent dysfunctional T lymphocytes. Strategies such as cell culture manipulation of replicative senescence, as well as lifestyle and stress reduction techniques are discussed in terms of possible approaches to enhance immune function in older persons. This review highlights the importance of using humans in studies on immunosenescence and telomere/telomerase dynamics, since model organisms employed in other facets of aging research are not subject to the particular factors that cause the striking age-related reconfiguration of the human immune system.},
}
@article {pmid20832719,
year = {2010},
author = {Giraud-Panis, MJ and Teixeira, MT and Géli, V and Gilson, E},
title = {CST meets shelterin to keep telomeres in check.},
journal = {Molecular cell},
volume = {39},
number = {5},
pages = {665-676},
doi = {10.1016/j.molcel.2010.08.024},
pmid = {20832719},
issn = {1097-4164},
mesh = {Cyclin B/genetics/*metabolism ; DNA Replication/*physiology ; DNA, Fungal/genetics/*metabolism ; Multiprotein Complexes/genetics/metabolism ; Saccharomycetales/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Telomere protection in budding yeast requires the heterotrimer named CST (for Cdc13-Stn1-Ten1). Recent data show that CST components are conserved and required for telomere stability in a wide range of eukaryotes, even those utilizing the shelterin complex to protect their telomeres. A common function of these proteins might be to stimulate priming at the C-strand gap that remains after telomerase elongation, replication termination, and terminal processing. In light of the budding yeast situation, another conserved function of CST might well be the regulation of telomerase. The cohabitation at telomeres of CST and shelterin components highlights the complexity of telomere biology.},
}
@article {pmid20829797,
year = {2010},
author = {Carneiro, T and Khair, L and Reis, CC and Borges, V and Moser, BA and Nakamura, TM and Ferreira, MG},
title = {Telomeres avoid end detection by severing the checkpoint signal transduction pathway.},
journal = {Nature},
volume = {467},
number = {7312},
pages = {228-232},
pmid = {20829797},
issn = {1476-4687},
support = {06-0396/AICR_/Worldwide Cancer Research/United Kingdom ; R01 GM078253/GM/NIGMS NIH HHS/United States ; R01 GM078253-04/GM/NIGMS NIH HHS/United States ; GM078253/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle ; DNA Damage ; *DNA Repair ; Schizosaccharomyces/cytology/*genetics/*metabolism ; Schizosaccharomyces pombe Proteins/metabolism ; *Signal Transduction ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomeres protect the normal ends of chromosomes from being recognized as deleterious DNA double-strand breaks. Recent studies have uncovered an apparent paradox: although DNA repair is prevented, several proteins involved in DNA damage processing and checkpoint responses are recruited to telomeres in every cell cycle and are required for end protection. It is currently not understood how telomeres prevent DNA damage responses from causing permanent cell cycle arrest. Here we show that fission yeast (Schizosaccharomyces pombe) cells lacking Taz1, an orthologue of human TRF1 and TRF2 (ref. 2), recruit DNA repair proteins (Rad22(RAD52) and Rhp51(RAD51), where the superscript indicates the human orthologue) and checkpoint sensors (RPA, Rad9, Rad26(ATRIP) and Cut5/Rad4(TOPBP1)) to telomeres. Despite this, telomeres fail to accumulate the checkpoint mediator Crb2(53BP1) and, consequently, do not activate Chk1-dependent cell cycle arrest. Artificially recruiting Crb2(53BP1) to taz1Δ telomeres results in a full checkpoint response and cell cycle arrest. Stable association of Crb2(53BP1) to DNA double-strand breaks requires two independent histone modifications: H4 dimethylation at lysine 20 (H4K20me2) and H2A carboxy-terminal phosphorylation (γH2A). Whereas γH2A can be readily detected, telomeres lack H4K20me2, in contrast to internal chromosome locations. Blocking checkpoint signal transduction at telomeres requires Pot1 and Ccq1, and loss of either Pot1 or Ccq1 from telomeres leads to Crb2(53BP1) foci formation, Chk1 activation and cell cycle arrest. Thus, telomeres constitute a chromatin-privileged region of the chromosomes that lack essential epigenetic markers for DNA damage response amplification and cell cycle arrest. Because the protein kinases ATM and ATR must associate with telomeres in each S phase to recruit telomerase, exclusion of Crb2(53BP1) has a critical role in preventing telomeres from triggering cell cycle arrest.},
}
@article {pmid20829796,
year = {2010},
author = {Jain, D and Hebden, AK and Nakamura, TM and Miller, KM and Cooper, JP},
title = {HAATI survivors replace canonical telomeres with blocks of generic heterochromatin.},
journal = {Nature},
volume = {467},
number = {7312},
pages = {223-227},
pmid = {20829796},
issn = {1476-4687},
support = {//Cancer Research UK/United Kingdom ; },
mesh = {Animals ; Cell Cycle Proteins/metabolism ; Chromosomes, Fungal/*metabolism ; Drosophila melanogaster/metabolism ; *Heterochromatin ; Histone-Lysine N-Methyltransferase ; Humans ; Methyltransferases/metabolism ; Rad51 Recombinase/metabolism ; Schizosaccharomyces/*genetics/*metabolism ; Schizosaccharomyces pombe Proteins/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {The notion that telomeres are essential for chromosome linearity stems from the existence of two chief dangers: inappropriate DNA damage response (DDR) reactions that mistake natural chromosome ends for double-strand DNA breaks (DSBs), and the progressive loss of DNA from chromosomal termini due to the end replication problem. Telomeres avert the former peril by binding sequence-specific end-protection factors that control the access of DDR activities. The latter threat is tackled by recruiting telomerase, a reverse transcriptase that uses an integral RNA subunit to template the addition of telomere repeats to chromosome ends. Here we describe an alternative mode of linear chromosome maintenance in which canonical telomeres are superseded by blocks of heterochromatin. We show that in the absence of telomerase, Schizosaccharomyces pombe cells can survive telomere sequence loss by continually amplifying and rearranging heterochromatic sequences. Because the heterochromatin assembly machinery is required for this survival mode, we have termed it 'HAATI' (heterochromatin amplification-mediated and telomerase-independent). HAATI uses the canonical end-protection protein Pot1 (ref. 4) and its interacting partner Ccq1 (ref. 5) to preserve chromosome linearity. The data suggest a model in which Ccq1 is recruited by the amplified heterochromatin and provides an anchor for Pot1, which accomplishes its end-protection function in the absence of its cognate DNA-binding sequence. HAATI resembles the chromosome end-maintenance strategy found in Drosophila melanogaster, which lacks specific telomere sequences but nonetheless assembles terminal heterochromatin structures that recruit end-protection factors. These findings reveal a previously unrecognized mode by which cancer cells might escape the requirement for telomerase activation, and offer a tool for studying genomes that sustain unusually high levels of heterochromatinization.},
}
@article {pmid20828816,
year = {2011},
author = {Spanoudakis, E and Bazdiara, I and Pantelidou, D and Kotsianidis, I and Papadopoulos, V and Margaritis, D and Xanthopoulidis, G and Moustakidis, E and Mantzourani, S and Bourikas, G and Tsatalas, C},
title = {Dynamics of telomere's length and telomerase activity in Philadelphia chromosome negative myeloproliferative neoplasms.},
journal = {Leukemia research},
volume = {35},
number = {4},
pages = {459-464},
doi = {10.1016/j.leukres.2010.07.042},
pmid = {20828816},
issn = {1873-5835},
mesh = {Bone Marrow Cells/enzymology/metabolism ; Cells, Cultured ; Gene Expression ; Humans ; In Situ Hybridization, Fluorescence ; Janus Kinase 2/genetics ; Mutation ; Myeloproliferative Disorders/drug therapy/*enzymology/*genetics ; Philadelphia Chromosome ; Prognosis ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/genetics/*metabolism ; Telomere/*genetics ; },
abstract = {Telomere exhaustion and increased telomerase activity are associated with the acquisition of aggressive molecular events in a variety of haematological malignancies. In Philadelphia chromosome negative myeloproliferative neoplasms (Ph(neg)MPN's), telomere dynamics during clonal evolution of these diseases have not yet been fully elucidated. Herein we demonstrated that telomere shortening is a global phenomenon in Ph(neg)MPN's, irrespective of disease phenotype, treatment administration and JAK2V617F mutational status but the presence of additional cytogenetic abnormalities further affects them. Consistent with the above finding, TA was upregulated in CD34+ haemopoietic progenitors from almost all Ph(neg)MPN subgroups compared to healthy donors. Moreover, TL below the cut-off value of 27% could predict disease progression in Ph(neg)MPN patients (PFS at 5 years 39% vs 81%). Thus, TL emerges as a new prognostic marker in Ph(neg)MPN, reflecting probably the genetic instability of highly proliferating MPN clones.},
}
@article {pmid20826803,
year = {2010},
author = {Williams, TL and Levy, DL and Maki-Yonekura, S and Yonekura, K and Blackburn, EH},
title = {Characterization of the yeast telomere nucleoprotein core: Rap1 binds independently to each recognition site.},
journal = {The Journal of biological chemistry},
volume = {285},
number = {46},
pages = {35814-35824},
pmid = {20826803},
issn = {1083-351X},
support = {//Howard Hughes Medical Institute/United States ; },
mesh = {Algorithms ; Base Sequence ; Binding Sites/genetics ; Chromosomes, Fungal/genetics/metabolism ; DNA, Fungal/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism/ultrastructure ; Microscopy, Electron, Transmission ; Nucleoproteins/genetics/metabolism/ultrastructure ; Protein Binding ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism/ultrastructure ; Sequence Homology, Nucleic Acid ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism/ultrastructure ; Transcription Factors/genetics/*metabolism/ultrastructure ; },
abstract = {At the core of Saccharomyces cerevisiae telomeres is an array of tandem telomeric DNA repeats bound site-specifically by multiple Rap1 molecules. There, Rap1 orchestrates the binding of additional telomere-associated proteins and negatively regulates both telomere fusion and length homeostasis. Using electron microscopy, viscosity, and light scattering measurements, we show that purified Rap1 is a monomer in solution that adopts a ringlike or C shape with a central cavity. Rap1 could orchestrate telomere function by binding multiple telomere array sites through either cooperative or independent mechanisms. To determine the mechanism, we analyze the distribution of Rap1 monomers on defined telomeric DNA arrays. This analysis clearly indicates that Rap1 binds independently to each nonoverlapping site in an array, regardless of the spacing between sites, the total number of sites, the affinity of the sites for Rap1, and over a large concentration range. Previous experiments have not clearly separated the effects of affinity from repeat spacing on telomere function. We clarify these results by testing in vivo the function of defined telomere arrays containing the same Rap1 binding site separated by spacings that were previously defined as low or high activity. We find that Rap1 binding affinity in vitro correlates with the ability of telomeric repeat arrays to regulate telomere length in vivo. We suggest that Rap1 binding to multiple sites in a telomere array does not, by itself, promote formation of a more energetically stabile complex.},
}
@article {pmid20824134,
year = {2010},
author = {Brennan, SK and Wang, Q and Tressler, R and Harley, C and Go, N and Bassett, E and Huff, CA and Jones, RJ and Matsui, W},
title = {Telomerase inhibition targets clonogenic multiple myeloma cells through telomere length-dependent and independent mechanisms.},
journal = {PloS one},
volume = {5},
number = {9},
pages = {},
pmid = {20824134},
issn = {1932-6203},
support = {K23CA107040/CA/NCI NIH HHS/United States ; P01 CA015396/CA/NCI NIH HHS/United States ; R01 CA127574/CA/NCI NIH HHS/United States ; P01CA015396/CA/NCI NIH HHS/United States ; K23 CA107040/CA/NCI NIH HHS/United States ; R01CA127574/CA/NCI NIH HHS/United States ; R01 CA127574-05/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Differentiation ; Cell Line, Tumor ; *Cell Proliferation ; Clone Cells ; Down-Regulation ; Humans ; Mice ; Mice, SCID ; Multiple Myeloma/*enzymology/metabolism/*physiopathology ; Neoplastic Stem Cells/cytology/enzymology/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; Tumor Cells, Cultured ; },
abstract = {BACKGROUND: Plasma cells constitute the majority of tumor cells in multiple myeloma (MM) but lack the potential for sustained clonogenic growth. In contrast, clonotypic B cells can engraft and recapitulate disease in immunodeficient mice suggesting they serve as the MM cancer stem cell (CSC). These tumor initiating B cells also share functional features with normal stem cells such as drug resistance and self-renewal potential. Therefore, the cellular processes that regulate normal stem cells may serve as therapeutic targets in MM. Telomerase activity is required for the maintenance of normal adult stem cells, and we examined the activity of the telomerase inhibitor imetelstat against MM CSC. Moreover, we carried out both long and short-term inhibition studies to examine telomere length-dependent and independent activities.<br><br>Human MM CSC were isolated from cell lines and primary clinical specimens and treated with imetelstat, a specific inhibitor of the reverse transcriptase activity of telomerase. Two weeks of exposure to imetelstat resulted in a significant reduction in telomere length and the inhibition of clonogenic MM growth both in vitro and in vivo. In addition to these relatively long-term effects, 72 hours of imetelstat treatment inhibited clonogenic growth that was associated with MM CSC differentiation based on expression of the plasma cell antigen CD138 and the stem cell marker aldehyde dehydrogenase. Short-term treatment of MM CSC also decreased the expression of genes typically expressed by stem cells (OCT3/4, SOX2, NANOG, and BMI1) as revealed by quantitative real-time PCR.<br><br>CONCLUSIONS: Telomerase activity regulates the clonogenic growth of MM CSC. Moreover, reductions in MM growth following both long and short-term telomerase inhibition suggest that it impacts CSC through telomere length-dependent and independent mechanisms.},
}
@article {pmid20821774,
year = {2010},
author = {Blackburn, EH},
title = {Telomeres and telomerase: the means to the end (Nobel lecture).},
journal = {Angewandte Chemie (International ed. in English)},
volume = {49},
number = {41},
pages = {7405-7421},
doi = {10.1002/anie.201002387},
pmid = {20821774},
issn = {1521-3773},
support = {R01 CA096840/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; DNA/chemistry/*metabolism ; History, 20th Century ; History, 21st Century ; Humans ; Nobel Prize ; Telomerase/chemistry/*metabolism ; Telomere/chemistry/*metabolism ; },
}
@article {pmid20817935,
year = {2011},
author = {Mainous, AG and Everett, CJ and Diaz, VA and Baker, R and Mangino, M and Codd, V and Samani, NJ},
title = {Leukocyte telomere length and marital status among middle-aged adults.},
journal = {Age and ageing},
volume = {40},
number = {1},
pages = {73-78},
pmid = {20817935},
issn = {1468-2834},
support = {UL1 RR029882/RR/NCRR NIH HHS/United States ; 5M01RR001070-31/RR/NCRR NIH HHS/United States ; },
mesh = {Adult ; Aging/ethnology/*physiology ; Biomarkers ; Black People/ethnology ; Cross-Sectional Studies ; Female ; Health Status ; Humans ; Leukocytes/physiology/*ultrastructure ; Life Style ; Longevity/physiology ; Male ; *Marital Status ; Middle Aged ; South Carolina ; Telomere/physiology/*ultrastructure ; White People/ethnology ; },
abstract = {BACKGROUND: being unmarried is associated with worse health and increased mortality risk. Telomere length has emerged as a marker for biological ageing but it is unclear how telomere length relates to marital status.<br><br>OBJECTIVE: to examine the relationship between telomere length and marital status in a sample of middle-aged adults.<br><br>DESIGN AND SUBJECTS: cross-sectional analysis among 321 adults aged 40-64 years.<br><br>METHODS: telomere length was measured by PCR (T/S ratio). Participants provided information on healthy lifestyle activities including smoking, alcohol use, diet, exercise, obesity as well as social support.<br><br>RESULTS: participants married or living with a partner had a mean T/S ratio of 1.70 and those widowed, divorced, separated or never married had a mean T/S ratio of 1.58 in a model adjusted for age, gender and race/ethnicity (P < 0.001). When the analysis was further adjusted for diet, alcohol consumption, exercise, smoking, social support, poverty and obesity, persons married or living with a partner had a higher mean T/S ratio of 1.69 than their unmarried counterparts (1.59) (P = 0.004).<br><br>CONCLUSIONS: these results indicate that unmarried individuals have shorter telomeres. This relationship between marital status and telomere length is independent of presumed benefits of marriage such as social support and a healthier lifestyle.},
}
@article {pmid20817924,
year = {2010},
author = {Walne, AJ and Vulliamy, T and Beswick, R and Kirwan, M and Dokal, I},
title = {Mutations in C16orf57 and normal-length telomeres unify a subset of patients with dyskeratosis congenita, poikiloderma with neutropenia and Rothmund-Thomson syndrome.},
journal = {Human molecular genetics},
volume = {19},
number = {22},
pages = {4453-4461},
pmid = {20817924},
issn = {1460-2083},
support = {085937//Wellcome Trust/United Kingdom ; },
mesh = {Case-Control Studies ; Consanguinity ; DNA Mutational Analysis ; Dyskeratosis Congenita/*genetics ; Female ; GTPase-Activating Proteins ; Genetic Linkage ; Homozygote ; Humans ; Male ; Mutation ; Neutropenia/*genetics ; Nuclear Proteins/*genetics ; Pigmentation Disorders/*genetics ; Polymorphism, Single Nucleotide ; Rothmund-Thomson Syndrome/*genetics ; Telomere/*genetics/metabolism ; },
abstract = {Dyskeratosis congenita (DC) is an inherited poikiloderma which in addition to the skin abnormalities is typically associated with nail dystrophy, leucoplakia, bone marrow failure, cancer predisposition and other features. Approximately 50% of DC patients remain genetically uncharacterized. All the DC genes identified to date are important in telomere maintenance. To determine the genetic basis of the remaining cases of DC, we undertook linkage analysis in 20 families and identified a common candidate gene region on chromosome 16 in a subset of these. This region included the C16orf57 gene recently identified to be mutated in poikiloderma with neutropenia (PN), an inherited poikiloderma displaying significant clinical overlap with DC. Analysis of the C16orf57 gene in our uncharacterized DC patients revealed homozygous mutations in 6 of 132 families. In addition, three of six families previously classified as Rothmund-Thomson syndrome (RTS-a poikiloderma that is sometimes confused with PN) were also found to have homozygous C16orf57 mutations. Given the role of the previous DC genes in telomere maintenance, telomere length was analysed in these patients and found to be comparable to age-matched controls. These findings suggest that mutations in C16orf57 unify a distinct set of families which clinically can be categorized as DC, PN or RTS. This study also highlights the multi-system nature (wider than just poikiloderma and neutropenia) of the clinical features of affected individuals (and therefore house-keeping function of C16orf57), a possible role for C16orf57 in apoptosis, as well as a distinct difference from previously characterized DC patients because telomere length was normal.},
}
@article {pmid20817007,
year = {2010},
author = {Takubo, K and Aida, J and Izumiyama, N and Ishikawa, N and Fujiwara, M and Poon, SS and Kondo, H and Kammori, M and Matsuura, M and Sawabe, M and Arai, T and Baird, DM and Nakamura, K},
title = {Chromosomal instability and telomere lengths of each chromosomal arm measured by Q-FISH in human fibroblast strains prior to replicative senescence.},
journal = {Mechanisms of ageing and development},
volume = {131},
number = {10},
pages = {614-624},
doi = {10.1016/j.mad.2010.08.007},
pmid = {20817007},
issn = {1872-6216},
mesh = {Adult ; Aged ; Anaphase/physiology ; Cell Line ; Cellular Senescence/*physiology ; *Chromosomal Instability ; Chromosomes, Human, Pair 21/genetics/*metabolism ; Chromosomes, Human, X/genetics/*metabolism ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Telomere/genetics/*metabolism ; },
abstract = {We monitored the telomere lengths and chromosomal instability characteristics of fibroblasts at different population doubling levels (PDLs) to gain further insight into the role of telomere shortening in chromosomal instability. We used 7 normal diploid human fibroblast strains (TIG-1, 3, 7, 103, 104, 112, and 114) and a quantitative fluorescence in situ hybridization method to measure telomere lengths of the p- and q-arms of individual chromosomes. We also enumerated morphologic signs of chromosomal instability, including fusion or loss of chromosomes, and anaphase bridges. In strains TIG-1, 3, 7, 103, and 114 at the late (phase 3) stage (≧40PDLs), 29 (96.6%) of 30 fusions were associated with one or both of the chromosomal arms that bear significantly shorter telomeres in those populations. In TIG-1 at 62PDL, 6 fusions were associated with Xq (n=3), 21q (n=3), and other (n=6) chromosomes. Xq and 21q had significantly shorter telomeres, and anaphase bridges were often associated with chromosomes X and/or 21 (74.6%). Our results indicate that chromosomes having excessively shortened telomeres at late PDLs begin to show features of instability such as fusions and anaphase bridges.},
}
@article {pmid20814240,
year = {2010},
author = {Reddy, S and Li, B and Comai, L},
title = {Processing of human telomeres by the Werner syndrome protein.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {9},
number = {16},
pages = {3137-3138},
pmid = {20814240},
issn = {1551-4005},
support = {R01 AG023873/AG/NIA NIH HHS/United States ; R01 AG023873-05/AG/NIA NIH HHS/United States ; R01 AG034156/AG/NIA NIH HHS/United States ; R01 AG034156-01A1/AG/NIA NIH HHS/United States ; },
mesh = {Antigens, Nuclear/metabolism ; DNA-Binding Proteins/metabolism ; Exodeoxyribonucleases/*metabolism ; Humans ; Ku Autoantigen ; RecQ Helicases/*metabolism ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; Werner Syndrome Helicase ; },
}
@article {pmid20811689,
year = {2010},
author = {Zhang, H and Yang, MH and Zhao, JJ and Chen, L and Yu, ST and Tang, XD and Fang, DC and Yang, SM},
title = {Inhibition of tankyrase 1 in human gastric cancer cells enhances telomere shortening by telomerase inhibitors.},
journal = {Oncology reports},
volume = {24},
number = {4},
pages = {1059-1065},
doi = {10.3892/or.2010.1059},
pmid = {20811689},
issn = {1791-2431},
mesh = {Blotting, Southern ; Blotting, Western ; Cell Line, Tumor ; Enzyme Inhibitors/pharmacology ; Enzyme-Linked Immunosorbent Assay ; Humans ; Reverse Transcriptase Polymerase Chain Reaction ; Stomach Neoplasms/*enzymology/*genetics ; Tankyrases/*metabolism ; Telomerase/*metabolism ; Telomere/drug effects/*metabolism ; Transfection ; },
abstract = {Telomere stability is believed to be related to aging and tumorigenesis. Besides telomerase, telomere length is also regulated by several telomere-specific binding proteins. Tankyrase 1, a telomeric poly(ADP-ribose) polymerase (PARP), elongates telomere length by inhibiting TRF1 binding to telomeres. In order to study the synergistic action of tankyrase 1 and telomerase in the maintenance of telomere length in mammalian cells, we constructed anti-sense tankyrase 1 (aTNKS) eukaryotic expression vectors and then transfected them into the SGC-7901 human gastric cancer cell line, as well as SGC-7901 cells that had been transfected with antisense hTR (7901-ahTR) and antisense hTERT (7901-ahTERT) with DOTAP liposomes. The activity of telomerase, telomere length and telomerase-associated protein activities were measure by TRAP-ELISA, Southern blot and western blot analysis, respectively, in aTNKS transfected and untransfected cells. The results demonstrated that telomere length was significantly shorter in cells with concomitant tankyrase 1 and telomerase inhibition than by either tankyrase 1 or telomerase inhibition alone, in SGC-7901 cells. We also found that aTNKS had no effect on telomerase activity. These results reveal that inhibition of tankyrase 1 could shorten telomere length and play a synergistic role with telomerase inhibitors in telomere length shortening in the SGC-7901 gastric cancer cell line. Co-inhibition of tankyrase 1 and telomerase activity may be a rational strategy for telomere-directed gastric cancer therapeutics.},
}
@article {pmid20811636,
year = {2010},
author = {Giannone, RJ and McDonald, HW and Hurst, GB and Shen, RF and Wang, Y and Liu, Y},
title = {The protein network surrounding the human telomere repeat binding factors TRF1, TRF2, and POT1.},
journal = {PloS one},
volume = {5},
number = {8},
pages = {e12407},
pmid = {20811636},
issn = {1932-6203},
support = {//Intramural NIH HHS/United States ; },
mesh = {Cell Line ; Chromatography, Liquid ; Humans ; Mass Spectrometry ; Protein Binding ; Shelterin Complex ; Telomere-Binding Proteins/*metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {Telomere integrity (including telomere length and capping) is critical in overall genomic stability. Telomere repeat binding factors and their associated proteins play vital roles in telomere length regulation and end protection. In this study, we explore the protein network surrounding telomere repeat binding factors, TRF1, TRF2, and POT1 using dual-tag affinity purification in combination with multidimensional protein identification technology liquid chromatography--tandem mass spectrometry (MudPIT LC-MS/MS). After control subtraction and data filtering, we found that TRF2 and POT1 co-purified all six members of the telomere protein complex, while TRF1 identified five of six components at frequencies that lend evidence towards the currently accepted telomere architecture. Many of the known TRF1 or TRF2 interacting proteins were also identified. Moreover, putative associating partners identified for each of the three core components fell into functional categories such as DNA damage repair, ubiquitination, chromosome cohesion, chromatin modification/remodeling, DNA replication, cell cycle and transcription regulation, nucleotide metabolism, RNA processing, and nuclear transport. These putative protein-protein associations may participate in different biological processes at telomeres or, intriguingly, outside telomeres.},
}
@article {pmid20808892,
year = {2010},
author = {Ngo, HP and Lydall, D},
title = {Survival and growth of yeast without telomere capping by Cdc13 in the absence of Sgs1, Exo1, and Rad9.},
journal = {PLoS genetics},
volume = {6},
number = {8},
pages = {e1001072},
pmid = {20808892},
issn = {1553-7404},
support = {075294/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Cell Cycle Proteins/genetics/*metabolism ; Exodeoxyribonucleases/genetics/*metabolism ; *Microbial Viability ; RecQ Helicases/genetics/*metabolism ; Saccharomyces cerevisiae/genetics/*growth &amp; development/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Maintenance of telomere capping is absolutely essential to the survival of eukaryotic cells. Telomere capping proteins, such as Cdc13 and POT1, are essential for the viability of budding yeast and mammalian cells, respectively. Here we identify, for the first time, three genetic modifications that allow budding yeast cells to survive without telomere capping by Cdc13. We found that simultaneous inactivation of Sgs1, Exo1, and Rad9, three DNA damage response (DDR) proteins, is sufficient to allow cell division in the absence of Cdc13. Quantitative amplification of ssDNA (QAOS) was used to show that the RecQ helicase Sgs1 plays an important role in the resection of uncapped telomeres, especially in the absence of checkpoint protein Rad9. Strikingly, simultaneous deletion of SGS1 and the nuclease EXO1, further reduces resection at uncapped telomeres and together with deletion of RAD9 permits cell survival without CDC13. Pulsed-field gel electrophoresis studies show that cdc13-1 rad9Delta sgs1Delta exo1Delta strains can maintain linear chromosomes despite the absence of telomere capping by Cdc13. However, with continued passage, the telomeres of such strains eventually become short and are maintained by recombination-based mechanisms. Remarkably, cdc13Delta rad9Delta sgs1Delta exo1Delta strains, lacking any Cdc13 gene product, are viable and can grow indefinitely. Our work has uncovered a critical role for RecQ helicases in limiting the division of cells with uncapped telomeres, and this may provide one explanation for increased tumorigenesis in human diseases associated with mutations of RecQ helicases. Our results reveal the plasticity of the telomere cap and indicate that the essential role of telomere capping is to counteract specific aspects of the DDR.},
}
@article {pmid20805671,
year = {2010},
author = {Yamaguchi, H and Dan, K},
title = {[Bone marrow failure due to telomere associated gene mutation].},
journal = {[Rinsho ketsueki] The Japanese journal of clinical hematology},
volume = {51},
number = {8},
pages = {646-653},
pmid = {20805671},
issn = {0485-1439},
mesh = {Animals ; Cell Cycle Proteins/genetics ; Dyskeratosis Congenita/*genetics/pathology/therapy ; Genes, Dominant ; Genes, Recessive ; Genes, X-Linked ; Hematopoietic Stem Cell Transplantation ; Humans ; Mice ; *Mutation ; Nuclear Proteins/genetics ; Oxymetholone/therapeutic use ; RNA/genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; Transplantation Conditioning ; Vidarabine/analogs &amp; derivatives/therapeutic use ; },
}
@article {pmid20803084,
year = {2010},
author = {Yoo, HH and Kwon, C and Chung, IK},
title = {An Arabidopsis splicing RNP variant STEP1 regulates telomere length homeostasis by restricting access of nuclease and telomerase.},
journal = {Molecules and cells},
volume = {30},
number = {3},
pages = {279-283},
doi = {10.1007/s10059-010-0115-y},
pmid = {20803084},
issn = {0219-1032},
mesh = {Arabidopsis ; Arabidopsis Proteins/*metabolism ; Chloroplast Proteins ; Deoxyribonucleases/metabolism ; Plant Proteins/*metabolism ; Protein Binding ; Protein Isoforms/*metabolism ; *Protein Splicing ; Protein Structure, Tertiary/physiology ; Ribonucleoproteins/*metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {Telomere is an essential DNA-protein complex composed of repetitive DNA and binding proteins to protect the chromosomal ends in eukaryotes. Telomere length is regulated by a specialized RNA-dependent DNA polymerase, telomerase and associated proteins. We show here a potential role of STEP1 that was previously isolated by affinity chromatography in controlling telomere length. While STEP1 requires both RNA-binding domains for telomere binding and subsequent DNA protection, it requires only one RBD to interact with telomerase. The differential telomerase inhibitory activity depending on STEP1 concentrations may suggest that STEP1 contributes to controlling telomere length homeostasis, likely by limiting the accessibility of nuclease or telomerase to telomeric DNA.},
}
@article {pmid20802535,
year = {2010},
author = {Castedo, M and Vitale, I and Kroemer, G},
title = {A novel source of tetraploid cancer cell precursors: telomere insufficiency links aging to oncogenesis.},
journal = {Oncogene},
volume = {29},
number = {44},
pages = {5869-5872},
doi = {10.1038/onc.2010.392},
pmid = {20802535},
issn = {1476-5594},
mesh = {Aged ; Aging/*pathology ; *Cell Transformation, Neoplastic ; DNA Damage ; Humans ; *Polyploidy ; S Phase ; *Telomere ; },
abstract = {Epithelial cancers of the elderly are caused by a combination of telomere dysfunction and the mutational invalidation of major tumor suppressors including p53. A recent article published in Cell by Davoli et al. shows that the simultaneous elimination of p53 and telomerase causes a state of chronic DNA damage that results in tetraploidization through endoreplication, that is, two consecutive S phases that are not separated by mitosis. As tetraploid cells represent a metastable intermediate between normal diploidy and cancer-associated aneuploidy, this novel route to tetraploidization may constitute (one of) the functional link(s) between aging and carcinogenesis.},
}
@article {pmid20802516,
year = {2010},
author = {Salvati, E and Scarsella, M and Porru, M and Rizzo, A and Iachettini, S and Tentori, L and Graziani, G and D'Incalci, M and Stevens, MF and Orlandi, A and Passeri, D and Gilson, E and Zupi, G and Leonetti, C and Biroccio, A},
title = {PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy.},
journal = {Oncogene},
volume = {29},
number = {47},
pages = {6280-6293},
doi = {10.1038/onc.2010.344},
pmid = {20802516},
issn = {1476-5594},
mesh = {Acridines/metabolism/pharmacology/therapeutic use ; Animals ; Antineoplastic Agents/*metabolism/*pharmacology/therapeutic use ; DNA Damage ; DNA Repair/drug effects ; Drug Synergism ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; G-Quadruplexes/*drug effects ; HCT116 Cells ; HT29 Cells ; Humans ; Male ; Mice ; Poly(ADP-ribose) Polymerases/*metabolism ; Protein Transport/drug effects ; Telomere/*drug effects/enzymology/*genetics ; Xenograft Model Antitumor Assays ; },
abstract = {New anti-telomere strategies represent important goals for the development of selective cancer therapies. In this study, we reported that uncapped telomeres, resulting from pharmacological stabilization of quadruplex DNA by RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate), trigger specific recruitment and activation of poly-adenosine diphosphate (ADP) ribose polymerase I (PARP1) at the telomeres, forming several ADP-ribose polymers that co-localize with the telomeric repeat binding factor 1 protein and are inhibited by selective PARP(s) inhibitors or PARP1-specific small interfering RNAs. The knockdown of PARP1 prevents repairing of RHPS4-induced telomere DNA breaks, leading to increases in chromosome abnormalities and eventually to the inhibition of tumor cell growth both in vitro and in xenografts. More interestingly, the integration of a TOPO1 inhibitor on the combination treatment proved to have a high therapeutic efficacy ensuing a complete regression of the tumor as well as a significant increase in overall survival and cure of mice even when treatments started at a very late stage of tumor growth. Overall, this work reveals the unexplored link between the PARP1 and G-quadruplex ligands and demonstrates the excellent efficacy of a multi-component strategy based on the use of PARP inhibitors in telomere-based therapy.},
}
@article {pmid20798328,
year = {2010},
author = {Lee, YW and Kim, WT},
title = {Tobacco GTBP1, a homolog of human heterogeneous nuclear ribonucleoprotein, protects telomeres from aberrant homologous recombination.},
journal = {The Plant cell},
volume = {22},
number = {8},
pages = {2781-2795},
pmid = {20798328},
issn = {1532-298X},
mesh = {Anaphase ; Cells, Cultured ; DNA, Plant/genetics ; Gene Knockdown Techniques ; Genomic Instability ; Heterogeneous-Nuclear Ribonucleoproteins/genetics/metabolism ; Phylogeny ; Plant Proteins/genetics/*metabolism ; Plants, Genetically Modified/genetics/metabolism ; *Recombination, Genetic ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Nicotiana/*genetics/metabolism ; },
abstract = {Telomeres are nucleoprotein complexes essential for the integrity of eukaryotic chromosomes. Cellular roles of single-stranded telomeric DNA binding proteins have been extensively described in yeast and animals, but our knowledge about plant single-strand telomeric factors is rudimentary. Here, we investigated Nicotiana tabacum G-strand-specific single-stranded telomere binding proteins (GTBPs), homologs of a human heterogeneous nuclear ribonucleoprotein. GTBPs bound specifically to the plant single-stranded (TTTAGGG)(4) telomeric repeat element in vitro and were associated with telomeric sequences in tobacco BY-2 suspension cells. Transgenic plants (35S:RNAi-GTBP1), in which GTBP1 was suppressed, exhibited severe developmental anomalies. In addition, the chromosomes of 35S:RNAi-GTBP1 cells displayed elongated telomeres, frequent formation of extrachromosomal telomeric circles, and numerous abnormal anaphase bridges, indicating that GTBP1 knockdown tobacco plants experienced genome instability. GTBP1 inhibited strand invasion, an initial step in interchromosomal homologous recombination. We propose that GTBP1 plays a critical role in telomere structure and function by preventing aberrant interchromosomal telomeric homologous recombination in tobacco.},
}
@article {pmid20798040,
year = {2010},
author = {Hagelstrom, RT and Blagoev, KB and Niedernhofer, LJ and Goodwin, EH and Bailey, SM},
title = {Hyper telomere recombination accelerates replicative senescence and may promote premature aging.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {107},
number = {36},
pages = {15768-15773},
pmid = {20798040},
issn = {1091-6490},
support = {R01 ES016114/ES/NIEHS NIH HHS/United States ; ES16114/ES/NIEHS NIH HHS/United States ; },
mesh = {Aging, Premature/*genetics/pathology ; Animals ; *Cell Division ; Cells, Cultured ; DNA-Binding Proteins/genetics ; Endonucleases/genetics ; Exodeoxyribonucleases/genetics ; Humans ; Mice ; RecQ Helicases/genetics ; *Recombination, Genetic ; Sister Chromatid Exchange ; *Telomere ; Werner Syndrome Helicase ; },
abstract = {Werner syndrome and Bloom syndrome result from defects in the RecQ helicases Werner (WRN) and Bloom (BLM), respectively, and display premature aging phenotypes. Similarly, XFE progeroid syndrome results from defects in the ERCC1-XPF DNA repair endonuclease. To gain insight into the origin of cellular senescence and human aging, we analyzed the dependence of sister chromatid exchange (SCE) frequencies on location [i.e., genomic (G-SCE) vs. telomeric (T-SCE) DNA] in primary human fibroblasts deficient in WRN, BLM, or ERCC1-XPF. Consistent with our other studies, we found evidence of elevated T-SCE in telomerase-negative but not telomerase-positive backgrounds. In telomerase-negative WRN-deficient cells, T-SCE-but not G-SCE-frequencies were significantly increased compared with controls. In contrast, SCE frequencies were significantly elevated in BLM-deficient cells irrespective of genome location. In ERCC1-XPF-deficient cells, neither T- nor G-SCE frequencies differed from controls. A theoretical model was developed that allowed an in silico investigation into the cellular consequences of increased T-SCE frequency. The model predicts that in cells with increased T-SCE, the onset of replicative senescence is dramatically accelerated even though the average rate of telomere loss has not changed. Premature cellular senescence may act as a powerful tumor-suppressor mechanism in telomerase-deficient cells with mutations that cause T-SCE levels to rise. Furthermore, T-SCE-driven premature cellular senescence may be a factor contributing to accelerated aging in Werner and Bloom syndromes, but not XFE progeroid syndrome.},
}
@article {pmid20797622,
year = {2010},
author = {Sarthy, JF and Baumann, P},
title = {Apollo-taking the lead in telomere protection.},
journal = {Molecular cell},
volume = {39},
number = {4},
pages = {489-491},
doi = {10.1016/j.molcel.2010.08.018},
pmid = {20797622},
issn = {1097-4164},
abstract = {The single-stranded overhangs at the ends of telomeres are thought to be critical for telomere maintenance, but how they are generated has been largely unclear. Two studies (one in this issue of Molecular Cell, Wu et al., 2010) have now implicated the Apollo nuclease in maintaining the overhang specifically at those telomeres generated by leading-strand DNA synthesis.},
}
@article {pmid20739078,
year = {2010},
author = {Hoare, M and Das, T and Alexander, G},
title = {Ageing, telomeres, senescence, and liver injury.},
journal = {Journal of hepatology},
volume = {53},
number = {5},
pages = {950-961},
doi = {10.1016/j.jhep.2010.06.009},
pmid = {20739078},
issn = {1600-0641},
mesh = {*Aging ; Animals ; Carcinoma, Hepatocellular/genetics ; *Cellular Senescence ; Chronic Disease ; DNA Damage ; Hepatocytes/pathology ; Humans ; Liver Diseases/*etiology/genetics/metabolism ; Liver Neoplasms/genetics ; Oxidative Stress ; Signal Transduction ; *Telomere ; Tumor Suppressor Protein p53/physiology ; },
abstract = {Populations in developed countries continue to grow older and an understanding of the ageing process to allow healthy ageing carries important medical implications. Older individuals are more susceptible to most acquired liver disorders and more vulnerable to the consequences of liver disease. Accordingly, age is a critical determinant of outcome for hepatitis C virus infection and liver transplantation. In this review we describe changes in the ageing liver and discuss mechanisms of senescence at the cellular level. In particular, we focus on mechanisms by which inflammation, oxidative stress, and oncogenic stress accelerate cellular senescence. In the setting of chronic hepatic injury and inflammation, cellular senescence functions as an essential stress-response mechanism to limit the proliferation of damaged cells and reduce the risk of malignancy, but this benefit is achieved at the expense of senescence-related organ dysfunction. The dual role of cell senescence in chronic liver disease will make this an intriguing but challenging area for future clinical interventions.},
}
@article {pmid20736972,
year = {2010},
author = {Horn, T and Robertson, BC and Gemmell, NJ},
title = {The use of telomere length in ecology and evolutionary biology.},
journal = {Heredity},
volume = {105},
number = {6},
pages = {497-506},
doi = {10.1038/hdy.2010.113},
pmid = {20736972},
issn = {1365-2540},
mesh = {Aging/genetics/*metabolism ; Animals ; *Biological Evolution ; Biomarkers/analysis/metabolism ; Ecology ; Humans ; Telomere/genetics/*metabolism ; },
abstract = {The measurement of telomere length (TL) is a genetic tool that is beginning to be employed widely in ecological and evolutionary studies as marker of age and fitness. The adoption of this approach has been accelerated by the development of telomere quantitative PCR, which enables the screening of large numbers of samples with little effort. However, the measurement and interpretation of TL change need to be done with a necessary level of rigour that has thus far often been missing where this approach has been employed in an ecological and evolutionary context. In this article, we critically review the literature available on the relationship between TL, age and fitness. We seek to familiarize geneticists, ecologists and evolutionary biologists with the shortcomings of the methods and the most common mistakes made while analysing TL. Prevention of these mistakes will ensure accuracy, reproducibility and comparability of TL studies in different species and allow the identification of ecological and evolutionary principles behind TL dynamics.},
}
@article {pmid20734798,
year = {2010},
author = {Mikhel'son, VM and Gamaleî, IA},
title = {[Telomere shortening is the main mechanism of natural and radiation aging].},
journal = {Radiatsionnaia biologiia, radioecologiia},
volume = {50},
number = {3},
pages = {269-275},
pmid = {20734798},
issn = {0869-8031},
mesh = {Aging/*physiology/*radiation effects ; Animals ; Cellular Senescence/physiology ; Humans ; Radiation, Ionizing ; Reactive Oxygen Species/*metabolism ; Telomere/*metabolism ; },
abstract = {Adduced proofs of the telomere shortening are the main or even the sole mechanism of the natural and radiation aging. All apparent contradictions, primary, the absence of exact inverse correlation between residual telomere length and the donor age are explained within the frames of the telomere theory. We try to explain in what way telomere shortening might be the cause of aging and longevity restriction. We also show the inability of the oxidative theory to explain a number of indisputable facts easily explained by the telomere theory, such as unlimited growth of tumor sells or why a new-born child starts to age from zero level rather than the level reached by the cells of his parents at the moment of conception. We postulate that if oxidative damage was entirely absent, telomeres would, nevertheless, shorten with each mitotic cycle because such is the mechanism of DNA replication, and aging would be in progress, which we invariantly observe in the presence of any antioxidants. But if telomeres do not shorten, as happens in transformed cells because telomerase works there, aging does cease and the transformed cells show no senescence. We also observe it in spite of the damaging effect of reactive oxygen species which may be even more than in normal cells.},
}
@article {pmid20732797,
year = {2010},
author = {Samassekou, O and Gadji, M and Drouin, R and Yan, J},
title = {Sizing the ends: normal length of human telomeres.},
journal = {Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft},
volume = {192},
number = {5},
pages = {284-291},
doi = {10.1016/j.aanat.2010.07.005},
pmid = {20732797},
issn = {1618-0402},
mesh = {Cell Cycle/genetics ; Cell Division ; Chromosomes, Human/metabolism ; DNA/chemistry ; Humans ; Telomerase/metabolism ; Telomere/chemistry/*metabolism ; },
abstract = {The ends of human chromosomes are constituted of telomeres, a nucleoprotein complex. They are mainly formed by the entanglement of repeat DNA and telomeric and non-telomeric proteins. Telomeric sequences are lost in each cell division and this loss happens in vitro as well as in vivo. The diminution of telomere length over the cell cycle has led to the consideration of telomeres as a 'mitotic clock'. Telomere lengths are heterogeneous because they differ among tissues, cells, and chromosome arms. Cell proliferation capacity, cellular environment, and epigenetic factors are some elements that affect this telomere heterogeneity. Also, genetic and environmental factors modulate the difference in telomere lengths between individuals. Telomere length is regulated by telomere structure, telomerase, the enzyme that elongates the 3'-end of telomeres, and alternative lengthening of telomeres (ALT) used exclusively in immortalized and cancer cells. The understanding of telomere length dynamic in the normal population is essential to develop a deeper insight into the role of telomere function in pathological settings.},
}
@article {pmid20726715,
year = {2010},
author = {Zhou, FX and Xiong, J and Luo, ZG and Dai, J and Yu, HJ and Liao, ZK and Lei, H and Xie, CH and Zhou, YF},
title = {cDNA expression analysis of a human radiosensitive-radioresistant cell line model identifies telomere function as a hallmark of radioresistance.},
journal = {Radiation research},
volume = {174},
number = {5},
pages = {550-557},
doi = {10.1667/RR1657.1},
pmid = {20726715},
issn = {1938-5404},
mesh = {Cell Cycle/genetics/radiation effects ; Cell Line, Tumor ; Cell Proliferation/radiation effects ; *Gene Expression Profiling ; Humans ; *Oligonucleotide Array Sequence Analysis ; Radiation Tolerance/*genetics/*radiation effects ; Telomerase/metabolism ; Telomere/*metabolism/*radiation effects ; },
abstract = {To achieve a more complete understanding of the molecular mechanisms underlying tumor radioresistance, we established a radioresistant cell line from the human larynx squamous cell carcinoma cell line Hep-2 after long-term radiation induction. The biological features of the resulting cell lines were characterized. cDNA microarray technology was used to measure the alterations of gene expression in the radioresistant cells. We found that certain genes associated with DNA repair, cell cycle, apoptosis, etc. were significantly changed. In particular, genes related to telomeres, such as POT1, were significantly altered. Radioresistant cells had higher telomerase activity and longer telomeres than their parental cells. Our research suggests that telomere function is a novel hallmark of cellular radiosensitivity, and the mechanistic link between telomere maintenance and radiosensitivity may involve the genes and pathways we implicated in this study.},
}
@article {pmid20724388,
year = {2010},
author = {Palmer, JM and Mallaredy, S and Perry, DW and Sanchez, JF and Theisen, JM and Szewczyk, E and Oakley, BR and Wang, CCC and Keller, NP and Mirabito, PM},
title = {Telomere position effect is regulated by heterochromatin-associated proteins and NkuA in Aspergillus nidulans.},
journal = {Microbiology (Reading, England)},
volume = {156},
number = {Pt 12},
pages = {3522-3531},
pmid = {20724388},
issn = {1465-2080},
support = {1 R01 AL065728-01//PHS HHS/United States ; R01 GM031837/GM/NIGMS NIH HHS/United States ; R01GM031837/GM/NIGMS NIH HHS/United States ; P01GM084077/GM/NIGMS NIH HHS/United States ; P01 GM084077/GM/NIGMS NIH HHS/United States ; },
mesh = {Antigens, Nuclear/genetics/*metabolism ; Aspergillus nidulans/genetics/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Fungal Proteins/genetics/*metabolism ; *Gene Expression Regulation, Fungal ; Gene Silencing ; Heterochromatin/genetics/*metabolism ; Ku Autoantigen ; Telomere/genetics/*metabolism ; },
abstract = {Gene-silencing mechanisms are being shown to be associated with an increasing number of fungal developmental processes. Telomere position effect (TPE) is a eukaryotic phenomenon resulting in gene repression in areas immediately adjacent to telomere caps. Here, TPE is shown to regulate expression of transgenes on the left arm of chromosome III and the right arm of chromosome VI in Aspergillus nidulans. Phenotypes found to be associated with transgene repression included reduction in radial growth and the absence of sexual spores; however, these pleiotropic phenotypes were remedied when cultures were grown on media with appropriate supplementation. Simple radial growth and ascosporogenesis assays provided insights into the mechanism of TPE, including a means to determine its extent. These experiments revealed that the KU70 homologue (NkuA) and the heterochromatin-associated proteins HepA, ClrD and HdaA were partially required for transgene silencing. This study indicates that TPE extends at least 30&amp;emsp14;kb on chromosome III, suggesting that this phenomenon may be important for gene regulation in subtelomeric regions of A. nidulans.},
}
@article {pmid20723641,
year = {2010},
author = {Diaz, VA and Mainous, AG and Everett, CJ and Schoepf, UJ and Codd, V and Samani, NJ},
title = {Effect of healthy lifestyle behaviors on the association between leukocyte telomere length and coronary artery calcium.},
journal = {The American journal of cardiology},
volume = {106},
number = {5},
pages = {659-663},
doi = {10.1016/j.amjcard.2010.04.018},
pmid = {20723641},
issn = {1879-1913},
support = {5M01RR001070-31/RR/NCRR NIH HHS/United States ; //British Heart Foundation/United Kingdom ; },
mesh = {Adult ; Body Mass Index ; Calcinosis/*epidemiology/genetics/psychology ; Coronary Artery Disease/*epidemiology/genetics/psychology ; Cross-Sectional Studies ; Diet ; Exercise ; Female ; *Health Behavior ; Humans ; Leukocytes/*physiology ; *Life Style ; Male ; Middle Aged ; Social Support ; Telomere/*genetics ; },
abstract = {The telomere length is an indicator of biologic aging, and shorter telomeres have been associated with coronary artery calcium (CAC), a validated indicator of coronary atherosclerosis. It is unclear, however, whether healthy lifestyle behaviors affect the relation between telomere length and CAC. In a sample of subjects aged 40 to 64 years with no previous diagnosis of coronary heart disease, stroke, diabetes mellitus, or cancer (n = 318), healthy lifestyle behaviors of greater fruit and vegetable consumption, lower meat consumption, exercise, being at a healthy weight, and the presence of social support were examined to determine whether they attenuated the association between a shorter telomere length and the presence of CAC. Logistic regression analyses controlling for age, gender, race/ethnicity, and Framingham risk score revealed that the relation between having shorter telomeres and the presence of CAC was attenuated in the presence of high social support, low meat consumption, and high fruit and vegetable consumption. Those with shorter telomeres and these characteristics were not significantly different from those with longer telomeres. Conversely, the subjects with shorter telomeres and less healthy lifestyles had a significantly increased risk of the presence of CAC: low fruit and vegetable consumption (odds ratio 3.30, 95% confidence interval 1.61 to 6.75), high meat consumption (odds ratio 3.33, 95% confidence interval 1.54 to 7.20), and low social support (odds ratio 2.58, 95% confidence interval 1.24 to 5.37). Stratification by gender yielded similar results for men; however, among women, only fruit and vegetable consumption attenuated the shorter telomere length and CAC relation. In conclusion, the results of the present study suggest that being involved in healthy lifestyle behaviors might attenuate the association between shorter telomere length and coronary atherosclerosis, as identified using CAC.},
}
@article {pmid20716926,
year = {2010},
author = {Makpol, S and Abidin, AZ and Sairin, K and Mazlan, M and Top, GM and Ngah, WZ},
title = {gamma-Tocotrienol prevents oxidative stress-induced telomere shortening in human fibroblasts derived from different aged individuals.},
journal = {Oxidative medicine and cellular longevity},
volume = {3},
number = {1},
pages = {35-43},
pmid = {20716926},
issn = {1942-0994},
mesh = {Adult ; Cell Survival/drug effects ; Cells, Cultured ; Chromans/*pharmacology ; Enzyme Activation/drug effects ; Fibroblasts/*drug effects/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Inhibitory Concentration 50 ; Oxidative Stress/*drug effects ; Telomerase/metabolism ; Telomere/*metabolism ; Vitamin E/*analogs &amp; derivatives/pharmacology ; Young Adult ; },
abstract = {The effects of palm gamma-tocotrienol (GGT) on oxidative stress-induced cellular ageing was investigated in normal human skin fibroblast cell lines derived from different age groups; young (21-year-old, YF), middle (40-year-old, MF) and old (68-year-old, OF). Fibroblast cells were treated with gamma-tocotrienol for 24 hours before or after incubation with IC50 dose of H2O2 for 2 hours. Changes in cell viability, telomere length and telomerase activity were assessed using the MTS assay (Promega, USA), Southern blot analysis and telomere repeat amplification protocol respectively. Results showed that treatment with different concentrations of gamma-tocotrienol increased fibroblasts viability with optimum dose of 80 microM for YF and 40 microM for both MF and OF. At higher concentrations, gamma-tocotrienol treatment caused marked decrease in cell viability with IC50 value of 200 microM (YF), 300 microM (MF) and 100 microM (OF). Exposure to H2O2 decreased cell viability in dose dependent manner, shortened telomere length and reduced telomerase activity in all age groups. The IC50 of H2O2 was found to be; YF (700 microM), MF (400 microM) and OF (100 microM). Results showed that viability increased significantly (p < 0.05) when cells were treated with 80 microM and 40 microM gamma-tocotrienol prior or after H2O2-induced oxidative stress in all age groups. In YF and OF, pretreatment with gamma-tocotrienol prevented shortening of telomere length and reduction in telomerase activity. In MF, telomerase activity increased while no changes in telomere length was observed. However, post-treatment of gamma-tocotrienol did not exert any significant effects on telomere length and telomerase activity. Thus, these data suggest that gamma-tocotrienol protects against oxidative stress-induced cellular ageing by modulating the telomere length possibly via telomerase.},
}
@article {pmid20711355,
year = {2010},
author = {Stimpson, KM and Song, IY and Jauch, A and Holtgreve-Grez, H and Hayden, KE and Bridger, JM and Sullivan, BA},
title = {Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes.},
journal = {PLoS genetics},
volume = {6},
number = {8},
pages = {},
pmid = {20711355},
issn = {1553-7404},
support = {R01 GM069514/GM/NIGMS NIH HHS/United States ; R01 GM098500/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line ; Centromere/genetics/*metabolism ; Chromosomes, Human/*genetics/metabolism ; DNA, Satellite/genetics/metabolism ; Humans ; Telomere/*genetics/*metabolism ; },
abstract = {Genome rearrangement often produces chromosomes with two centromeres (dicentrics) that are inherently unstable because of bridge formation and breakage during cell division. However, mammalian dicentrics, and particularly those in humans, can be quite stable, usually because one centromere is functionally silenced. Molecular mechanisms of centromere inactivation are poorly understood since there are few systems to experimentally create dicentric human chromosomes. Here, we describe a human cell culture model that enriches for de novo dicentrics. We demonstrate that transient disruption of human telomere structure non-randomly produces dicentric fusions involving acrocentric chromosomes. The induced dicentrics vary in structure near fusion breakpoints and like naturally-occurring dicentrics, exhibit various inter-centromeric distances. Many functional dicentrics persist for months after formation. Even those with distantly spaced centromeres remain functionally dicentric for 20 cell generations. Other dicentrics within the population reflect centromere inactivation. In some cases, centromere inactivation occurs by an apparently epigenetic mechanism. In other dicentrics, the size of the alpha-satellite DNA array associated with CENP-A is reduced compared to the same array before dicentric formation. Extra-chromosomal fragments that contained CENP-A often appear in the same cells as dicentrics. Some of these fragments are derived from the same alpha-satellite DNA array as inactivated centromeres. Our results indicate that dicentric human chromosomes undergo alternative fates after formation. Many retain two active centromeres and are stable through multiple cell divisions. Others undergo centromere inactivation. This event occurs within a broad temporal window and can involve deletion of chromatin that marks the locus as a site for CENP-A maintenance/replenishment.},
}
@article {pmid20711342,
year = {2010},
author = {Gurung, RL and Lim, SN and Khaw, AK and Soon, JF and Shenoy, K and Mohamed Ali, S and Jayapal, M and Sethu, S and Baskar, R and Hande, MP},
title = {Thymoquinone induces telomere shortening, DNA damage and apoptosis in human glioblastoma cells.},
journal = {PloS one},
volume = {5},
number = {8},
pages = {e12124},
pmid = {20711342},
issn = {1932-6203},
mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Benzoquinones/*pharmacology ; Brain/cytology/drug effects/metabolism/pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cytochromes c/metabolism ; *DNA Damage ; DNA Repair/drug effects ; DNA-Activated Protein Kinase/metabolism ; Dose-Response Relationship, Drug ; Gene Expression Regulation, Neoplastic/drug effects ; Glioblastoma/genetics/*pathology ; Humans ; Nuclear Proteins/metabolism ; Telomerase/metabolism ; Telomere/*drug effects/genetics/metabolism ; bcl-2-Associated X Protein/metabolism ; },
abstract = {BACKGROUND: A major concern of cancer chemotherapy is the side effects caused by the non-specific targeting of both normal and cancerous cells by therapeutic drugs. Much emphasis has been placed on discovering new compounds that target tumour cells more efficiently and selectively with minimal toxic effects on normal cells.<br><br>The cytotoxic effect of thymoquinone, a component derived from the plant Nigella sativa, was tested on human glioblastoma and normal cells. Our findings demonstrated that glioblastoma cells were more sensitive to thymoquinone-induced antiproliferative effects. Thymoquinone induced DNA damage, cell cycle arrest and apoptosis in the glioblastoma cells. It was also observed that thymoquinone facilitated telomere attrition by inhibiting the activity of telomerase. In addition to these, we investigated the role of DNA-PKcs on thymoquinone mediated changes in telomere length. Telomeres in glioblastoma cells with DNA-PKcs were more sensitive to thymoquinone mediated effects as compared to those cells deficient in DNA-PKcs.<br><br>CONCLUSIONS/SIGNIFICANCE: Our results indicate that thymoquinone induces DNA damage, telomere attrition by inhibiting telomerase and cell death in glioblastoma cells. Telomere shortening was found to be dependent on the status of DNA-PKcs. Collectively, these data suggest that thymoquinone could be useful as a potential chemotherapeutic agent in the management for brain tumours.},
}
@article {pmid20709788,
year = {2010},
author = {Motwani, T and Doris, R and Holmes, SG and Flory, MR},
title = {Ccq1p and the condensin proteins Cut3p and Cut14p prevent telomere entanglements in the fission yeast Schizosaccharomyces pombe.},
journal = {Eukaryotic cell},
volume = {9},
number = {10},
pages = {1612-1621},
pmid = {20709788},
issn = {1535-9786},
mesh = {Chromosomes, Fungal/genetics ; *Mitosis ; Schizosaccharomyces/cytology/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {The Schizosaccharomyces pombe telomere-associated protein Ccq1p has previously been shown to participate in telomerase recruitment, heterochromatin formation, and suppression of checkpoint activation. Here we characterize a critical role for Ccq1p in mitotic transit. We show that mitotic cells lacking Ccq1p lose minichromosomes at high frequencies but that conditional knockdown of Ccq1p expression results in telomere bridging within one cell cycle. Elevating Ccq1p expression resolves the telomere entanglements caused by decreased Taz1p activity. Ccq1p affects telomere resolution in the absence of changes in telomere size, indicating a role for Ccq1p that is independent of telomere length regulation. Using affinity purification, we identify the condensin proteins Cut3p and Cut14p as candidate Ccq1p interactors in this activity. Condensin loss-of-function disrupts Ccq1p telomeric localization and normal intertelomere clustering, while condensin overexpression relieves the chromosome segregation defects associated with conditional Ccq1p knockdown. These data suggest that Ccq1p and condensins collaborate to mediate resolution of telomeres in mitosis and regulate intertelomeric clustering during interphase.},
}
@article {pmid20709332,
year = {2010},
author = {Zekry, D and Herrmann, FR and Irminger-Finger, I and Graf, C and Genet, C and Vitale, AM and Michel, JP and Gold, G and Krause, KH},
title = {Telomere length and ApoE polymorphism in mild cognitive impairment, degenerative and vascular dementia.},
journal = {Journal of the neurological sciences},
volume = {299},
number = {1-2},
pages = {108-111},
doi = {10.1016/j.jns.2010.07.019},
pmid = {20709332},
issn = {1878-5883},
mesh = {Aged ; Aged, 80 and over ; Alleles ; Alzheimer Disease/diagnosis/*genetics ; Analysis of Variance ; Apolipoproteins E/*genetics ; Cognition Disorders/diagnosis/*genetics ; Dementia, Vascular/diagnosis/*genetics ; Female ; Flow Cytometry ; Gene Frequency ; Humans ; In Situ Hybridization ; Logistic Models ; Longitudinal Studies ; Male ; Neuropsychological Tests ; Polymorphism, Genetic ; Telomere/*genetics ; },
abstract = {BACKGROUND: Clarifying the aetiology of dementia is of crucial importance in the management of patients as well as for research purposes but it is not always possible clinically. Therefore the identification of biological markers should complement clinical approaches. Telomere shortening is emerging as an important mechanism in vascular aging and the pathogenesis of hypertension and atherosclerosis. Thus, telomere length could be a potential candidate to accurately separate vascular from degenerative cognitive impairment.<br><br>OBJECTIVES: To evaluate the usefulness of telomere length alone or combined with ApoE polymorphism in diagnosing mild cognitive impairment (MCI) and in differentiating Alzheimer's disease (AD) from vascular (VaD) and mixed dementia (MD).<br><br>METHODS: Telomere length in peripheral blood lymphocytes was performed by flow cytometry in 439 patients (mean age, 85.1 years): 204 cognitively normal, 187 demented patients: 80 AD, 86 MD, and 21 with VaD; and 48 patients with MCI. Simple and multiple ordered logistic regressions were used to predict the risk of dementia from telomere length, ApoE polymorphism and age.<br><br>RESULTS: ApoE&#x3b5;4 was statistically associated with patients with dementia (p<0.001) compared to cognitively normal or MCI patients; but not with the aetiologies of dementia (AD, VaD and MD) (p=0.385). No significant differences in telomere length were found among patients with different aetiologies or severities of dementia. In the global model, the combination of telomere length and ApoE polymorphism did not confer a significantly higher dementia risk (OR=0.95, 95% CI=0.69-1.32; p=0.784) than APOE&#x3b5;4 alone (OR=2.12, 95% CI=1.15-3.9; p=0.016).<br><br>CONCLUSION: This longitudinal study in very old patients provided no evidence suggesting that telomere length alone could be used to distinguish between the different types of dementia or MCI, nor combined with the ApoE polymorphism.},
}
@article {pmid20699390,
year = {2010},
author = {Mozgová, I and Mokros, P and Fajkus, J},
title = {Dysfunction of chromatin assembly factor 1 induces shortening of telomeres and loss of 45S rDNA in Arabidopsis thaliana.},
journal = {The Plant cell},
volume = {22},
number = {8},
pages = {2768-2780},
pmid = {20699390},
issn = {1532-298X},
mesh = {Arabidopsis/*genetics/metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Chromatin Assembly Factor-1/genetics/*metabolism ; Chromatin Assembly and Disassembly ; DNA, Plant/genetics/metabolism ; DNA, Ribosomal/genetics/metabolism ; Gene Expression Regulation, Plant ; Mutagenesis, Insertional ; Mutation ; RNA, Ribosomal/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Chromatin Assembly Factor 1 (CAF1) is a three-subunit H3/H4 histone chaperone responsible for replication-dependent nucleosome assembly. It is composed of CAC 1-3 in yeast; p155, p60, and p48 in humans; and FASCIATA1 (FAS1), FAS2, and MULTICOPY SUPPRESSOR OF IRA1 in Arabidopsis thaliana. We report that disruption of CAF1 function by fas mutations in Arabidopsis results in telomere shortening and loss of 45S rDNA, while other repetitive sequences (5S rDNA, centromeric 180-bp repeat, CACTA, and Athila) are unaffected. Substantial telomere shortening occurs immediately after the loss of functional CAF1 and slows down at telomeres shortened to median lengths around 1 to 1.5 kb. The 45S rDNA loss is progressive, leaving 10 to 15% of the original number of repeats in the 5th generation of mutants affecting CAF1, but the level of the 45S rRNA transcripts is not altered in these mutants. Increasing severity of the fas phenotype is accompanied by accumulation of anaphase bridges, reduced viability, and plant sterility. Our results show that appropriate replication-dependent chromatin assembly is specifically required for stable maintenance of telomeres and 45S rDNA.},
}
@article {pmid20698892,
year = {2011},
author = {Babizhayev, MA and Yegorov, YE},
title = {Smoking and health: association between telomere length and factors impacting on human disease, quality of life and life span in a large population-based cohort under the effect of smoking duration.},
journal = {Fundamental &amp; clinical pharmacology},
volume = {25},
number = {4},
pages = {425-442},
doi = {10.1111/j.1472-8206.2010.00866.x},
pmid = {20698892},
issn = {1472-8206},
mesh = {Cohort Studies ; Disease/*etiology ; Humans ; *Longevity ; Oxidative Stress ; *Quality of Life ; Smoking/*adverse effects/epidemiology ; *Telomere Shortening ; },
abstract = {Reactive oxygen species (ROS) are of primary importance as they cause damage to lipids, proteins, and DNA either endogenously by cellular mechanism, or through exogenous exposure to environmental injury factors, including oxidation insult factors, such as tobacco smoke. Currently 46.3 million adults (25.7 percent of the population) are smokers. This includes 24 million men (28.1 percent of the total) and more than 22 million women (23.5 percent). The prevalence is highest among persons 25-44 years of age. Cigarette smokers have a higher risk of developing several chronic disorders. These include fatty buildups in arteries, several types of cancer and chronic obstructive pulmonary disease (lung problems). As peripheral leukocytes have been the main target of human telomere research, most of what is known about human telomere dynamics in vivo is based on these cells. Leukocyte telomere length (TL) is a complex trait that is shaped by genetic, epigenetic, and environmental determinants. In this article, we consider that smoking modifies leukocyte TL in humans and contributes to its variability among individuals, although the smoking effect on TL and its relation with other metabolic indices may accelerate biological aging and development of smoking-induced chronic diseases in a large human population-based cohorts with smoking behavior. Recent studies confirmed that individuals with shorter telomeres present a higher prevalence of arterial lesions and higher risk of cardiovascular disease mortality. This study originally suggests that efficient therapeutic protection of TL and structure in response to stresses that are known to reduce TL, such as oxidative damage or inflammation associated with tobacco smoking, would lead to better telomere maintenance. Recently, we have discovered the potential use of telomere-restorative imidazole-containing dipeptide (non-hydrolized carnosine, carcinine) based therapy for better survival of smokers. We conclude that a better therapeutic or nutritional maintenance of TL may confer healthy aging in smokers and exceptional longevity in regularly ROS-exposed human survivors.},
}
@article {pmid20697207,
year = {2010},
author = {Price, CM and Boltz, KA and Chaiken, MF and Stewart, JA and Beilstein, MA and Shippen, DE},
title = {Evolution of CST function in telomere maintenance.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {9},
number = {16},
pages = {3157-3165},
pmid = {20697207},
issn = {1551-4005},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; F32 CA117846/CA/NCI NIH HHS/United States ; T32 CA117846/CA/NCI NIH HHS/United States ; GM041803/GM/NIGMS NIH HHS/United States ; F32 GM093635/GM/NIGMS NIH HHS/United States ; R01 GM088728/GM/NIGMS NIH HHS/United States ; GM065383/GM/NIGMS NIH HHS/United States ; R01 GM041803/GM/NIGMS NIH HHS/United States ; GM088728/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/chemistry/*metabolism ; Chromosomal Proteins, Non-Histone/chemistry/*metabolism ; Evolution, Molecular ; Humans ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {Telomeres consist of an elaborate, higher-order DNA architecture, and a suite of proteins that provide protection for the chromosome terminus by blocking inappropriate recombination and nucleolytic attack. In addition, telomeres facilitate telomeric DNA replication by physical interactions with telomerase and the lagging strand replication machinery. The prevailing view has been that two distinct telomere capping complexes evolved, shelterin in vertebrates and a trimeric complex comprised of Cdc13, Stn1 and Ten1 (CST) in yeast. The recent discovery of a CST-like complex in plants and humans raises new questions about the composition of telomeres and their regulatory mechanisms in multicellular eukaryotes. In this review we discuss the evolving functions and interactions of CST components and their contributions to chromosome end protection and DNA replication.},
}
@article {pmid20691626,
year = {2010},
author = {Zambre, VP and Murumkar, PR and Giridhar, R and Yadav, MR},
title = {Development of highly predictive 3D-QSAR CoMSIA models for anthraquinone and acridone derivatives as telomerase inhibitors targeting G-quadruplex DNA telomere.},
journal = {Journal of molecular graphics &amp; modelling},
volume = {29},
number = {2},
pages = {229-239},
doi = {10.1016/j.jmgm.2010.07.003},
pmid = {20691626},
issn = {1873-4243},
mesh = {Acridines/chemistry/*pharmacology ; Acridones ; Anthraquinones/chemistry/*pharmacology ; Enzyme Inhibitors/chemistry/*pharmacology ; G-Quadruplexes/*drug effects ; Humans ; *Models, Molecular ; *Quantitative Structure-Activity Relationship ; Reproducibility of Results ; Telomerase/*antagonists &amp; inhibitors ; Telomere/chemistry/*drug effects/enzymology ; },
abstract = {G-quadruplex structures of DNA represent a potentially useful target for anticancer drugs. Telomerase enzyme, involved in immortalization of cancer cells is inhibited by stabilization of G-quadruplex at the ends of chromosomes. Anthraquinone and acridone derivatives are promising G-quadruplex ligands as telomerase inhibitors. So far, optimization of these ligands remained hampered due to the lack of creditable quantitative structure-activity relationships. To understand the structural basis of anthraquinone and acridone derivatives, a predictive 3D-QSAR model has been developed for the first time for telomerase inhibitory activity of G4 ligands, employing comparative molecular similarity indices analysis (CoMSIA). Considering the proposition that the basic nitrogens in these compounds should exist in protonated form at physiological pH the protonated forms of the reported compounds were analyzed and investigated. The QSAR model from conformational template Conf1 exhibited best correlative and predictive properties. The actual predictive abilities of the QSAR model were thoroughly validated through an external validation test set of compounds. The statistics indicate a significantly high prediction power of the best model (r(2), 0.721), supporting the proposed molecular mechanism of DNA G-quadruplex ligands.},
}
@article {pmid20686699,
year = {2010},
author = {Bhattacharjee, RN and Banerjee, B and Akira, S and Hande, MP},
title = {Telomere-mediated chromosomal instability triggers TLR4 induced inflammation and death in mice.},
journal = {PloS one},
volume = {5},
number = {7},
pages = {e11873},
pmid = {20686699},
issn = {1932-6203},
mesh = {Animals ; Blotting, Western ; Chromosomal Instability/genetics/*physiology ; Electrophoretic Mobility Shift Assay ; In Situ Hybridization ; Inflammation/genetics/*metabolism/mortality ; Interleukin-6/metabolism ; Mice ; RNA ; Telomerase ; Telomere/genetics/*metabolism ; Toll-Like Receptor 4/*metabolism ; Tumor Necrosis Factor-alpha/metabolism ; },
abstract = {BACKGROUND: Telomeres are essential to maintain chromosomal stability. Cells derived from mice lacking telomerase RNA component (mTERC-/- mice) display elevated telomere-mediated chromosome instability. Age-dependent telomere shortening and associated chromosome instability reduce the capacity to respond to cellular stress occurring during inflammation and cancer. Inflammation is one of the important risk factors in cancer progression. Controlled innate immune responses mediated by Toll-like receptors (TLR) are required for host defense against infection. Our aim was to understand the role of chromosome/genome instability in the initiation and maintenance of inflammation.<br><br>We examined the function of TLR4 in telomerase deficient mTERC-/- mice harbouring chromosome instability which did not develop any overt immunological disorder in pathogen-free condition or any form of cancers at this stage. Chromosome instability was measured in metaphase spreads prepared from wildtype (mTERC+/+), mTERC+/- and mTERC-/- mouse splenocytes. Peritoneal and/or bone marrow-derived macrophages were used to examine the responses of TLR4 by their ability to produce inflammatory mediators TNFalpha and IL6. Our results demonstrate that TLR4 is highly up-regulated in the immune cells derived from telomerase-null (mTERC-/-) mice and lipopolysaccharide, a natural ligand for TLR4 stabilises NF-kappaB binding to its promoter by down-regulating ATF-3 in mTERC-/- macrophages.<br><br>CONCLUSIONS/SIGNIFICANCE: Our findings implied that background chromosome instability in the cellular level stabilises the action of TLR4-induced NF-kappaB action and sensitises cells to produce excess pro-inflammatory mediators. Chromosome/genomic instability data raises optimism for controlling inflammation by non-toxic TLR antagonists among high-risk groups.},
}
@article {pmid20682311,
year = {2010},
author = {Dehé, PM and Cooper, JP},
title = {Fission yeast telomeres forecast the end of the crisis.},
journal = {FEBS letters},
volume = {584},
number = {17},
pages = {3725-3733},
doi = {10.1016/j.febslet.2010.07.045},
pmid = {20682311},
issn = {1873-3468},
support = {//Cancer Research UK/United Kingdom ; },
mesh = {Ataxia Telangiectasia/genetics ; Cell Cycle/genetics ; DNA Damage/genetics ; DNA-Binding Proteins/genetics/metabolism ; Heterochromatin/genetics ; Humans ; Meiosis/genetics ; RNA/genetics ; RNA, Fungal/genetics ; Recombination, Genetic ; Schizosaccharomyces/*genetics ; Telomerase/genetics ; Telomere/*genetics/*physiology ; },
abstract = {Recent years have placed fission yeast at the forefront of telomere research, as this organism combines a high level of conservation with human telomeres and precise genetic manipulability. Here we highlight some of the latest knowledge of fission yeast telomere maintenance and dysfunction, and illustrate how principles arising from fission yeast research are raising novel questions about telomere plasticity and function in all eukaryotes.},
}
@article {pmid20679394,
year = {2010},
author = {Raffa, GD and Raimondo, D and Sorino, C and Cugusi, S and Cenci, G and Cacchione, S and Gatti, M and Ciapponi, L},
title = {Verrocchio, a Drosophila OB fold-containing protein, is a component of the terminin telomere-capping complex.},
journal = {Genes &amp; development},
volume = {24},
number = {15},
pages = {1596-1601},
pmid = {20679394},
issn = {1549-5477},
support = {GGP07200/TI_/Telethon/Italy ; },
mesh = {Amino Acid Sequence ; Animals ; Chromosomal Proteins, Non-Histone/metabolism ; Drosophila Proteins/chemistry/*genetics/isolation &amp; purification/*metabolism ; Drosophila melanogaster/*genetics/*metabolism ; Gene Expression Regulation ; Models, Molecular ; Mutation/genetics ; Nuclear Proteins/genetics/metabolism ; Protein Binding ; Protein Folding ; Protein Structure, Tertiary ; Sequence Alignment ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/chemistry/*genetics/isolation &amp; purification/*metabolism ; },
abstract = {Drosophila telomeres are elongated by transposition of specialized retroelements rather than telomerase activity, and are assembled independently of the terminal DNA sequence. Drosophila telomeres are protected by terminin, a complex that includes the HOAP (Heterochromatin Protein 1/origin recognition complex-associated protein) and Moi (Modigliani) proteins and shares the properties of human shelterin. Here we show that Verrocchio (Ver), an oligonucleotide/oligosaccharide-binding (OB) fold-containing protein related to Rpa2/Stn1, interacts physically with HOAP and Moi, is enriched only at telomeres, and prevents telomere fusion. These results indicate that Ver is a new terminin component; we speculate that, concomitant with telomerase loss, Drosophila evolved terminin to bind chromosome ends independently of the DNA sequence.},
}
@article {pmid20679357,
year = {2010},
author = {Al-Attas, OS and Al-Daghri, NM and Alokail, MS and Alfadda, A and Bamakhramah, A and Sabico, S and Pritlove, D and Harte, A and Tripathi, G and McTernan, PG and Kumar, S and Chrousos, G},
title = {Adiposity and insulin resistance correlate with telomere length in middle-aged Arabs: the influence of circulating adiponectin.},
journal = {European journal of endocrinology},
volume = {163},
number = {4},
pages = {601-607},
pmid = {20679357},
issn = {1479-683X},
mesh = {Adiponectin/*blood ; Adiposity/genetics/*physiology ; Adolescent ; Adult ; Aged ; Arabs/*genetics ; Body Mass Index ; Cross-Sectional Studies ; Female ; Humans ; Insulin Resistance/genetics/*physiology ; Male ; Middle Aged ; Telomere/*genetics ; Young Adult ; },
abstract = {OBJECTIVE: Studies in obesity have implicated adipocytokines in the development of insulin resistance, which in turn may lead to accelerated aging. In this study, we determined associations of chromosomal telomere length (TL) to markers of obesity and insulin resistance in middle-aged adult male and female Arabs with and without diabetes mellitus type 2 (DMT2).<br><br>DESIGN AND METHODS: One hundred and ninety-three non-diabetic and DMT2 subjects without complications (97 males and 96 females) participated in this cross-sectional study. Clinical data, as well as fasting blood samples, were collected. Serum glucose and lipid profile were determined using routine laboratory methods. Serum insulin, leptin, adiponectin, resistin, tumor necrosis factor-&#x3b1;, and PAI-1 were quantified using customized multiplex assay kits. High sensitive C-reactive protein (hsCRP) and angiotensin II (ANG II) were measured using ELISAs. Circulating leukocyte TL was examined by quantitative real-time PCR.<br><br>RESULTS: Circulating chromosomal leukocyte TL had significant inverse associations with body mass index (BMI), systolic blood pressure, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), low-density lipoprotein (LDL)- and total cholesterol, ANG II and hsCRP levels. Adiponectin, BMI, systolic blood pressure, and LDL cholesterol predicted 47% of the variance in TL (P<0.0001). HOMA-IR was the most significant predictor for TL in males, explaining 35% of the variance (P=0.01). In females, adiponectin accounted for 28% of the variance in TL (P=0.01).<br><br>CONCLUSION: Obesity and insulin resistance are associated with chromosomal TL among adult Arabs. Evidence of causal relations needs further investigation. The positive association of adiponectin to TL has clinical implications as to the possible protective effects of this hormone from accelerated aging.},
}
@article {pmid20678755,
year = {2010},
author = {Glass, D and Parts, L and Knowles, D and Aviv, A and Spector, TD},
title = {No correlation between childhood maltreatment and telomere length.},
journal = {Biological psychiatry},
volume = {68},
number = {6},
pages = {e21-2; author reply e23-4},
pmid = {20678755},
issn = {1873-2402},
support = {G0900339/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; },
mesh = {Child ; *Child Abuse ; Humans ; Leukocytes/ultrastructure ; Sample Size ; Sex Offenses ; Telomere/*ultrastructure ; Twin Studies as Topic ; },
}
@article {pmid20678254,
year = {2010},
author = {Yasaei, H and Slijepcevic, P},
title = {Defective Artemis causes mild telomere dysfunction.},
journal = {Genome integrity},
volume = {1},
number = {1},
pages = {3},
pmid = {20678254},
issn = {2041-9414},
abstract = {BACKGROUND: Repair of DNA double strand breaks by non-homologous end joining (NHEJ) requires several proteins including Ku, DNA-PKcs, Artemis, XRCC4, Ligase IV and XLF. Two of these proteins, namely Ku and DNA-PKcs, are also involved in maintenance of telomeres, chromosome end-structures. In contrast, cells defective in Ligase IV and XRCC4 do not show changes in telomere length or function suggesting that these proteins are not involved in telomere maintenance. Since a mouse study indicated that defective Artemis may cause telomere dysfunction we investigated the effects of defective Artemis on telomere maintenance in human cells.<br><br>RESULTS: We observed significantly elevated frequencies of telomeric fusions in two primary fibroblast cell lines established from Artemis defective patients relative to the control cell line. The frequencies of telomeric fusions increased after exposure of Artemis defective cells to ionizing radiation. Furthermore, we observed increased incidence of DNA damage at telomeres in Artemis defective cells that underwent more than 32 population doublings using the TIF (Telomere dysfunction Induced Foci) assay. We have also inhibited the expression levels of DNA-PKcs in Artemis defective cell lines by either using synthetic inhibitor (IC86621) or RNAi and observed their greater sensitivity to telomere dysfunction relative to control cells.<br><br>CONCLUSION: These results suggest that defective Artemis causes a mild telomere dysfunction phenotype in human cell lines.},
}
@article {pmid20674573,
year = {2010},
author = {Flores, I and Blasco, MA},
title = {The role of telomeres and telomerase in stem cell aging.},
journal = {FEBS letters},
volume = {584},
number = {17},
pages = {3826-3830},
doi = {10.1016/j.febslet.2010.07.042},
pmid = {20674573},
issn = {1873-3468},
mesh = {Adult ; Aging/physiology ; Cell Division ; Cellular Senescence/*physiology ; Chromosomal Instability/genetics ; DNA Damage/genetics ; DNA Replication ; Homeostasis ; Humans ; Neoplasms/prevention &amp; control ; Neurodegenerative Diseases/pathology/prevention &amp; control ; Pluripotent Stem Cells/physiology ; Stem Cells/cytology/enzymology/pathology/*physiology ; Telomerase/*metabolism ; Telomere/*physiology/ultrastructure ; },
abstract = {Stem cells regenerate our bodies. In a similar manner to match ignition, stem cell "ignition" has to be precisely tuned to avoid uncontrolled proliferation as may occur in tumors or, inversely, the lack of proliferation as happens in degenerative disorders. During the last years it has become evident that telomeres and telomerase are main components of the stem cell "ignition" mechanism, providing a way to restrain cancer and delay aging.},
}
@article {pmid20674190,
year = {2010},
author = {Baydar, DE and Ozen, H and Geyik, PO and Gurel, B},
title = {Can telomere alterations predict biochemical recurrence in prostate adenocarcinoma? A preliminary study.},
journal = {Pathology, research and practice},
volume = {206},
number = {10},
pages = {700-704},
doi = {10.1016/j.prp.2010.05.009},
pmid = {20674190},
issn = {1618-0631},
mesh = {Adenocarcinoma/*genetics/mortality/pathology/surgery ; Aged ; Disease-Free Survival ; Humans ; In Situ Hybridization, Fluorescence ; Kaplan-Meier Estimate ; Logistic Models ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; Neoplasm Staging ; Pilot Projects ; Proportional Hazards Models ; Prostate-Specific Antigen/blood ; Prostatectomy ; Prostatic Neoplasms/*genetics/mortality/pathology/surgery ; Risk Assessment ; Risk Factors ; Telomere/*metabolism ; Time Factors ; Tissue Array Analysis ; Treatment Outcome ; },
abstract = {Telomeres function in human somatic tissues to stabilize chromosome ends. Telomere shortening can be one of the ways that cause chromosomal instability in the pathogenesis of prostatic carcinoma. In the current study, we evaluated telomere length (TL) in normal and malignant prostate tissues, and its association with prognostic factors and with time to biochemical tumor recurrence. Tissue microarrays constructed from paraffin blocks from radical prostatectomy specimens containing 61 randomly selected cases were used. Sections were hybridized with a Cy3-labeled telomere-specific peptide nucleic acid probe. TL, proportional to probe fluorescence intensity, was visually evaluated. Statistical analysis was done to relate TL clinical and pathological prognostic variables. The majority (49/61) of prostate cancers displayed abnormally short telomeres. Univariate analysis revealed inverse correlation between telomere shortening in tumor and Gleason scores (p=0.017). Multivariate analyses pointed to TL as an independent predictor in addition to serum pre-operative PSA for reduced biochemical progression-free survival (p=0.035). Telomere shortening is a common alteration in prostatic adenocarcinoma. Normal or long telomeres are rarely seen and, when present, seem to provide a growth advantage for the tumor as being an advocate for poor differentiation.},
}
@article {pmid20670897,
year = {2010},
author = {Stohr, BA and Xu, L and Blackburn, EH},
title = {The terminal telomeric DNA sequence determines the mechanism of dysfunctional telomere fusion.},
journal = {Molecular cell},
volume = {39},
number = {2},
pages = {307-314},
pmid = {20670897},
issn = {1097-4164},
support = {P50 CA058207-140015/CA/NCI NIH HHS/United States ; CA58205/CA/NCI NIH HHS/United States ; K08 CA134552/CA/NCI NIH HHS/United States ; P50 CA058207/CA/NCI NIH HHS/United States ; R01 CA096840/CA/NCI NIH HHS/United States ; K08 CA134552-01A1/CA/NCI NIH HHS/United States ; R01 CA096840-06/CA/NCI NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/metabolism ; Cell Line, Tumor ; Chromatids/genetics/*metabolism ; Chromosomes, Human/genetics/*metabolism ; DNA-Binding Proteins/genetics/metabolism ; *Genomic Instability ; Humans ; Mutation ; Protein Serine-Threonine Kinases/genetics/metabolism ; *Tandem Repeat Sequences ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Tumor Suppressor Proteins/genetics/metabolism ; },
abstract = {Mammalian telomeres consist of tandem DNA repeats that bind protective protein factors collectively termed shelterins. Telomere disruption typically results in genome instability induced by telomere fusions. The mechanism of telomere fusion varies depending on the means of telomere disruption. Here, we investigate telomere fusions caused by overexpression of mutant telomerases that add mutated telomeric repeats, thereby compromising shelterin binding to telomeric termini. While all mutant telomeric sequences tested induced heterodicentric chromosome fusions in ATM-competent cells, only those mutant repeat sequences with significant self complementarity induced ATM-independent sister chromatid and isodicentric chromosome fusions. Thus, once a telomere becomes dysfunctional, the terminal telomeric sequence itself determines the fate of that telomere. These results suggest that annealing of self-complementary DNA sequence engages an alternative telomere fusion pathway in human cells, and provide one explanation for the conspicuous lack of self complementarity in the majority of known naturally occurring eukaryotic telomeric sequences.},
}
@article {pmid20663741,
year = {2010},
author = {Souiden, Y and Bouraoui, A and Chaieb, K and Mahdouani, K},
title = {[Telomeres and telomerase as targeted therapies in cancer treatment].},
journal = {Bulletin du cancer},
volume = {97},
number = {9},
pages = {1087-1104},
doi = {10.1684/bdc.2010.1155},
pmid = {20663741},
issn = {1769-6917},
mesh = {Cell Division/physiology ; Cellular Senescence/physiology ; Enzyme Inhibitors/therapeutic use ; Forecasting ; G-Quadruplexes ; Genetic Therapy/methods ; Humans ; Immunotherapy/methods ; Neoplasm Proteins/physiology ; Neoplasms/*drug therapy/enzymology/genetics ; Oligonucleotides/therapeutic use ; Oligonucleotides, Antisense/therapeutic use ; RNA ; *RNA Interference ; RNA Processing, Post-Transcriptional ; RNA, Catalytic/therapeutic use ; RNA, Long Noncoding ; RNA, Untranslated/antagonists &amp; inhibitors ; Reverse Transcriptase Inhibitors/therapeutic use ; Telomerase/*antagonists &amp; inhibitors/metabolism/physiology ; *Telomere/chemistry/genetics/immunology ; Telomeric Repeat Binding Protein 1/physiology ; Telomeric Repeat Binding Protein 2/physiology ; Transcription, Genetic ; },
abstract = {Advances in chromosome dynamics have increased our understanding of the significant role of telomeres and telomerase in cancer. Telomerase is expressed in almost all cancer cells but is inactive in most normal somatic cells. Therefore, telomerase is an important target for the design of therapeutic agents that might have minimal side effects. Herein, we evaluate current approaches to telomerase/telomere-targeted therapy, discuss the benefits and disadvantages, and speculate on the future direction of telomerase inhibitors as cancer therapeutics.},
}
@article {pmid20660518,
year = {2010},
author = {Kuznetsova, T and Codd, V and Brouilette, S and Thijs, L and González, A and Jin, Y and Richart, T and van der Harst, P and Díez, J and Staessen, JA and Samani, NJ},
title = {Association between left ventricular mass and telomere length in a population study.},
journal = {American journal of epidemiology},
volume = {172},
number = {4},
pages = {440-450},
doi = {10.1093/aje/kwq142},
pmid = {20660518},
issn = {1476-6256},
support = {//British Heart Foundation/United Kingdom ; },
mesh = {Adult ; Aged ; Female ; Follow-Up Studies ; Humans ; Hypertension/physiopathology ; Hypertrophy, Left Ventricular/diagnostic imaging/*physiopathology ; Male ; Middle Aged ; Predictive Value of Tests ; Surveys and Questionnaires ; Telomere/*physiology ; Ultrasonography ; },
abstract = {Experimental studies have implicated telomere dynamics in cardiomyocyte size and replication potential; shorter telomeres mark attenuated proliferation and increased apoptosis. The authors examined whether this translates into an impact of telomere length (TL) on left ventricular (LV) mass in the general population. In 334 randomly selected Flemish participants (mean age = 46.5 years; 52.5% women), they measured TL in circulating leukocytes using quantitative polymerase chain reaction, expressing it as telomere/genomic DNA ratio (T/S). After a median 7.4 years of follow-up (interquartile range, 6.2-8.5) during 1996-2007, they measured LV mass by echocardiography. In multivariable-adjusted analyses accounting for sex, age, body weight and height, systolic blood pressure, and antihypertensive drug use, LV mass and LV mass index significantly increased with mean leukocyte TL in the entire population and in the 198 normotensive subjects. For a 1-standard-deviation increment in T/S ratio, LV mass (mean = 170 g) and LV mass index (mean = 92 g/m(2)) increased by 5.20 g (P = 0.003) and 2.70 g/m(2) (P = 0.004), respectively, in all subjects and by 8.03 g (P = 0.0001) and 3.74 g/m(2) (P = 0.0007) in normotensive subjects. There were corresponding associations with LV wall thicknesses (P < 0.007) but not LV internal diameter (P = 0.26) in normotensive subjects. Longer mean leukocyte TL is associated with increased LV mass, particularly in normotensive subjects. This association could have a biologic basis related to the role of TL in determining cardiomyocyte size and replication potential.},
}
@article {pmid20655915,
year = {2010},
author = {Gomes, NM and Shay, JW and Wright, WE},
title = {Telomere biology in Metazoa.},
journal = {FEBS letters},
volume = {584},
number = {17},
pages = {3741-3751},
pmid = {20655915},
issn = {1873-3468},
support = {R01 AG001228/AG/NIA NIH HHS/United States ; R01 AG001228-30/AG/NIA NIH HHS/United States ; AG01228/AG/NIA NIH HHS/United States ; },
mesh = {Aging/physiology ; Amphibians/genetics/metabolism ; Animals ; Arthropods/enzymology/genetics ; Base Sequence ; Conserved Sequence ; Fishes/genetics/metabolism ; Molecular Sequence Data ; Mutation ; Nematoda/enzymology/genetics ; Neoplasms/genetics/prevention &amp; control ; Reptiles/genetics/metabolism ; Telomerase/metabolism ; Telomere/*genetics ; },
abstract = {In this review we present critical overview of some of the available literature on the fundamental biology of telomeres and telomerase in Metazoan. With the exception of Nematodes and Arthropods, the (TTAGGG)(n) sequence is conserved in most Metazoa. Available data show that telomerase-based end maintenance is a very ancient mechanism in unicellular and multicellular organisms. In invertebrates, fish, amphibian, and reptiles persistent telomerase activity in somatic tissues might allow the maintenance of the extensive regenerative potentials of these species. Telomerase repression among birds and many mammals suggests that, as humans, they may use replicative aging as a tumor protection mechanism.},
}
@article {pmid20655466,
year = {2010},
author = {Ye, J and Lenain, C and Bauwens, S and Rizzo, A and Saint-Léger, A and Poulet, A and Benarroch, D and Magdinier, F and Morere, J and Amiard, S and Verhoeyen, E and Britton, S and Calsou, P and Salles, B and Bizard, A and Nadal, M and Salvati, E and Sabatier, L and Wu, Y and Biroccio, A and Londoño-Vallejo, A and Giraud-Panis, MJ and Gilson, E},
title = {TRF2 and apollo cooperate with topoisomerase 2alpha to protect human telomeres from replicative damage.},
journal = {Cell},
volume = {142},
number = {2},
pages = {230-242},
doi = {10.1016/j.cell.2010.05.032},
pmid = {20655466},
issn = {1097-4172},
mesh = {Antigens, Neoplasm/*metabolism ; Cellular Senescence ; DNA Damage ; DNA Repair Enzymes/*metabolism ; *DNA Replication ; DNA Topoisomerases, Type II/*metabolism ; DNA-Binding Proteins/*metabolism ; Exodeoxyribonucleases ; Humans ; Nuclear Proteins/*metabolism ; Protein Structure, Tertiary ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {Human telomeres are protected from DNA damage by a nucleoprotein complex that includes the repeat-binding factor TRF2. Here, we report that TRF2 regulates the 5' exonuclease activity of its binding partner, Apollo, a member of the metallo-beta-lactamase family that is required for telomere integrity during S phase. TRF2 and Apollo also suppress damage to engineered interstitial telomere repeat tracts that were inserted far away from chromosome ends. Genetic data indicate that DNA topoisomerase 2alpha acts in the same pathway of telomere protection as TRF2 and Apollo. Moreover, TRF2, which binds preferentially to positively supercoiled DNA substrates, together with Apollo, negatively regulates the amount of TOP1, TOP2alpha, and TOP2beta at telomeres. Our data are consistent with a model in which TRF2 and Apollo relieve topological stress during telomere replication. Our work also suggests that cellular senescence may be caused by topological problems that occur during the replication of the inner portion of telomeres.},
}
@article {pmid20655310,
year = {2010},
author = {de Lange, T},
title = {Telomere biology and DNA repair: enemies with benefits.},
journal = {FEBS letters},
volume = {584},
number = {17},
pages = {3673-3674},
doi = {10.1016/j.febslet.2010.07.030},
pmid = {20655310},
issn = {1873-3468},
support = {R01 GM049046/GM/NIGMS NIH HHS/United States ; AG016642/AG/NIA NIH HHS/United States ; GM049046/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Damage/genetics ; *DNA Repair ; DNA Replication ; Genetic Diseases, Inborn/enzymology/genetics ; Humans ; Telomerase/metabolism ; Telomere/genetics/*physiology ; },
}
@article {pmid20655309,
year = {2010},
author = {Lamarche, BJ and Orazio, NI and Weitzman, MD},
title = {The MRN complex in double-strand break repair and telomere maintenance.},
journal = {FEBS letters},
volume = {584},
number = {17},
pages = {3682-3695},
pmid = {20655309},
issn = {1873-3468},
support = {R01 AI067952-05/AI/NIAID NIH HHS/United States ; R01 CA097093/CA/NCI NIH HHS/United States ; R01 CA097093-08/CA/NCI NIH HHS/United States ; R01 AI051686-05/AI/NIAID NIH HHS/United States ; T32 CA009523/CA/NCI NIH HHS/United States ; CA097093/CA/NCI NIH HHS/United States ; R01 AI051686/AI/NIAID NIH HHS/United States ; AI067952/AI/NIAID NIH HHS/United States ; AI051686/AI/NIAID NIH HHS/United States ; R01 AI067952/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; DNA Breaks, Double-Stranded ; DNA Damage/*genetics ; DNA Repair/*genetics ; Genome ; Humans ; Mice ; Models, Animal ; Mutation ; Nijmegen Breakage Syndrome/genetics ; Sequence Deletion/genetics ; Signal Transduction ; Telomere/*genetics ; },
abstract = {Genomes are subject to constant threat by damaging agents that generate DNA double-strand breaks (DSBs). The ends of linear chromosomes need to be protected from DNA damage recognition and end-joining, and this is achieved through protein-DNA complexes known as telomeres. The Mre11-Rad50-Nbs1 (MRN) complex plays important roles in detection and signaling of DSBs, as well as the repair pathways of homologous recombination (HR) and non-homologous end-joining (NHEJ). In addition, MRN associates with telomeres and contributes to their maintenance. Here, we provide an overview of MRN functions at DSBs, and examine its roles in telomere maintenance and dysfunction.},
}
@article {pmid20653999,
year = {2010},
author = {Gancarcíková, M and Zemanová, Z and Brezinová, J and Berková, A and Vcelíková, S and Smigová, J and Michalová, K},
title = {The role of telomeres and telomerase complex in haematological neoplasia: the length of telomeres as a marker of carcinogenesis and prognosis of disease.},
journal = {Prague medical report},
volume = {111},
number = {2},
pages = {91-105},
pmid = {20653999},
issn = {1214-6994},
mesh = {Animals ; Biomarkers, Tumor/analysis ; Hematologic Neoplasms/diagnosis/genetics/*physiopathology ; Hematopoietic Stem Cells/physiology ; Humans ; Prognosis ; Telomerase/genetics/*physiology ; Telomere/genetics/*physiology ; },
abstract = {Human telomeres (discovery of telomere structure and function has been recently awarded The Nobel Prize) consist of approximately 5-12 kb of tandem repeated sequences (TTAGGG)n and associated proteins capping chromosome ends which prevent degradation, loss of genetic information, end-to-end fusion, senescence and apoptosis. Due to the end-replication problem, telomere repeats are lost with each cell division, eventually leading to genetic instability and cellular senescence when telomeres become critically short. Stabilization of the telomeric DNA through telomerase activation, unique reverse transcriptase, or activation of the alternative mechanism of telomere maintenance is essential if the cells are to survive and proliferate indefinitely. Telomerase is expressed during early development and remains fully active in specific germline cells, but is undetectable in most normal somatic cells. High level of telomerase activity is detected in almost 90% of human tumours and immortalized cell lines. The hematopoietic compartment may develop genetic instability as a consequence of telomere erosion, resulting in aplastic anaemia (AA) and increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Genetic instability associated with telomere dysfunction (i.e. short telomeres) is an early event in carcinogenesis. The molecular cytogenetic method telomere/centromere fluorescence in situ hybridization (T/C-FISH) can be used to characterize the telomere length of hematopoietic cells. This review describes recent advances in the molecular characterization of telomere system, the regulation of telomerase activity in cancer pathogenesis and shows that the telomeric length could be a potential clinical marker of hematologic neoplasia and prognosis of disease.},
}
@article {pmid20652008,
year = {2010},
author = {Coleman, C and Levine, D and Kishore, R and Qin, G and Thorne, T and Lambers, E and Sasi, SP and Yaar, M and Gilchrest, BA and Goukassian, DA},
title = {Inhibition of melanoma angiogenesis by telomere homolog oligonucleotides.},
journal = {Journal of oncology},
volume = {2010},
number = {},
pages = {928628},
pmid = {20652008},
issn = {1687-8469},
abstract = {Telomere homolog oligonucleotides (T-oligos) activate an innate telomere-based program that leads to multiple anticancer effects. T-oligos act at telomeres to initiate signaling through the Werner protein and ATM kinase. We wanted to determine if T-oligos have antiangiogenic effects. We found that T-oligo-treated human melanoma (MM-AN) cells had decreased expression of vascular endothelial growth factor (VEGF), VEGF receptor 2, angiopoeitin-1 and -2 and decreased VEGF secretion. T-oligos activated the transcription factor E2F1 and inhibited the activity of the angiogenic transcription factor, HIF-1alpha. T-oligos inhibited EC tubulogenesis and total tumor microvascular density matrix invasion by MM-AN cells and ECs in vitro. In melanoma SCID xenografts, two systemic T-oligo injections decreased by 60% (P < .004) total tumor microvascular density and the functional vessels density by 80% (P < .002). These findings suggest that restriction of tumor angiogenesis is among the host's innate telomere-based anticancer responses and provide further evidence that T-oligos may offer a powerful new approach for melanoma treatment.},
}
@article {pmid20651253,
year = {2010},
author = {Lewis, PW and Elsaesser, SJ and Noh, KM and Stadler, SC and Allis, CD},
title = {Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {107},
number = {32},
pages = {14075-14080},
pmid = {20651253},
issn = {1091-6490},
support = {R37 GM053512/GM/NIGMS NIH HHS/United States ; GM53512/GM/NIGMS NIH HHS/United States ; GM53122/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Carrier Proteins/metabolism/*physiology ; *Chromatin Assembly and Disassembly ; Co-Repressor Proteins ; DNA Helicases/*metabolism ; Embryonic Stem Cells ; Heterochromatin ; Histone Chaperones/*metabolism ; Histones/*metabolism ; Intracellular Signaling Peptides and Proteins/metabolism/*physiology ; Mice ; Molecular Chaperones ; Multiprotein Complexes ; Nuclear Proteins/*metabolism/*physiology ; Nucleosomes/metabolism ; Protein Binding ; *Telomere ; X-linked Nuclear Protein ; },
abstract = {The histone variant H3.3 is implicated in the formation and maintenance of specialized chromatin structure in metazoan cells. H3.3-containing nucleosomes are assembled in a replication-independent manner by means of dedicated chaperone proteins. We previously identified the death domain associated protein (Daxx) and the alpha-thalassemia X-linked mental retardation protein (ATRX) as H3.3-associated proteins. Here, we report that the highly conserved N terminus of Daxx interacts directly with variant-specific residues in the H3.3 core. Recombinant Daxx assembles H3.3/H4 tetramers on DNA templates, and the ATRX-Daxx complex catalyzes the deposition and remodeling of H3.3-containing nucleosomes. We find that the ATRX-Daxx complex is bound to telomeric chromatin, and that both components of this complex are required for H3.3 deposition at telomeres in murine embryonic stem cells (ESCs). These data demonstrate that Daxx functions as an H3.3-specific chaperone and facilitates the deposition of H3.3 at heterochromatin loci in the context of the ATRX-Daxx complex.},
}
@article {pmid20644899,
year = {2010},
author = {Panero, J and Arbelbide, J and Fantl, DB and Rivello, HG and Kohan, D and Slavutsky, I},
title = {Altered mRNA expression of telomere-associated genes in monoclonal gammopathy of undetermined significance and multiple myeloma.},
journal = {Molecular medicine (Cambridge, Mass.)},
volume = {16},
number = {11-12},
pages = {471-478},
pmid = {20644899},
issn = {1528-3658},
mesh = {Adult ; Aged ; Aged, 80 and over ; Bone Marrow/metabolism ; Female ; Gene Expression Regulation ; Humans ; Male ; Middle Aged ; Multiple Myeloma/*genetics ; Paraproteinemias/*genetics ; RNA, Messenger/genetics/metabolism ; Tankyrases/*metabolism ; Telomerase/metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {In this study, we explored changes in the expression of the telomere maintenance genes, TRF1, TRF2 and TANK1 in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Results were correlated with human telomerase reverse transcriptase (hTERT) expression, telomere length (TL) and clinicopathological characteristics. Bone marrow (BM) samples from 132 patients, 64 with MGUS and 68 with MM, were studied. Real-time quantitative reverse transcription-polymerase chain reaction was used to quantify gene expression. TL was evaluated by terminal restriction fragment length analysis. MGUS patients showed increased TRF1 levels (P = 0.006) and lower expression of TRF2 (P = 0.005) and TANK1 (P = 0.003) compared with MM patients. For hTERT analysis, patients were divided into three groups by use of receiver operating characteristics: low (group I [GI]), intermediate (group II [GII]) and high (group III [GIII]) expression. We observed increasing expression of TRF2 and TANK1 from GI to GIII in MGUS and MM, with differences for both genes in MM (P < 0.01) and for TRF2 in MGUS (P < 0.01). GIII patients with the highest telomerase expression had the shortest TL. In both entities, a positive association between TRF2-TANK1, TRF2-hTERT and TANK1-hTERT (P ≤ 0.01) was observed. In MM, the percentage of BM infiltration and Ki-67 index were positively associated with TRF2, TANK1 and hTERT expression (P ≤ 0.03) and negatively with TL (P = 0.02), whereas lactate dehydrogenase was significantly correlated with TRF2 mRNA (P = 0.008). Our findings provide the first evidence of a modification in the expression of telomeric proteins in plasma cell disorders, and suggest that mechanisms other than telomerase activation are involved in TL maintenance in these pathologies.},
}
@article {pmid20643102,
year = {2010},
author = {Skoláková, P and Bednárová, K and Vorlícková, M and Sagi, J},
title = {Quadruplexes of human telomere dG(3)(TTAG(3))(3) sequences containing guanine abasic sites.},
journal = {Biochemical and biophysical research communications},
volume = {399},
number = {2},
pages = {203-208},
doi = {10.1016/j.bbrc.2010.07.055},
pmid = {20643102},
issn = {1090-2104},
mesh = {Base Sequence ; Circular Dichroism ; *G-Quadruplexes ; Guanine/*chemistry ; Humans ; *Nucleic Acid Conformation ; Potassium/chemistry ; Sodium/chemistry ; Telomere/*chemistry ; },
abstract = {This study was performed to evaluate how the loss of a guanine base affects the structure and stability of the three-tetrad G-quadruplex of 5'-dG(3)(TTAG(3))(3), the basic quadruplex-forming unit of the human telomere DNA. None of the 12 possible abasic sites hindered the formation of quadruplexes, but all reduced the thermodynamic stability of the parent quadruplex in both NaCl and KCl. The base loss did not change the Na(+)-stabilized intramolecular antiparallel architecture, based on CD spectra, but held up the conformational change induced in dG(3)(TTAG(3))(3) in physiological concentration of KCl. The reduced stability and the inhibited conformational transitions observed here in vitro for the first time may predict that unrepaired abasic sites in G-quadruplexes could lead to changes in the chromosome's terminal protection in vivo.},
}
@article {pmid20639858,
year = {2010},
author = {Dai, X and Huang, C and Bhusari, A and Sampathi, S and Schubert, K and Chai, W},
title = {Molecular steps of G-overhang generation at human telomeres and its function in chromosome end protection.},
journal = {The EMBO journal},
volume = {29},
number = {16},
pages = {2788-2801},
pmid = {20639858},
issn = {1460-2075},
support = {R15 CA132090/CA/NCI NIH HHS/United States ; R15 CA132090-01/CA/NCI NIH HHS/United States ; R15 GM099008/GM/NIGMS NIH HHS/United States ; R15CA132090/CA/NCI NIH HHS/United States ; },
mesh = {CDC2 Protein Kinase/antagonists &amp; inhibitors/metabolism ; *Cell Cycle ; Cell Line ; DNA Damage ; HeLa Cells ; Humans ; Nucleotides/metabolism ; Telomerase/*metabolism ; Telomere/chemistry/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomeric G-overhangs are required for the formation of the protective telomere structure and telomerase action. However, the mechanism controlling G-overhang generation at human telomeres is poorly understood. Here, we show that G-overhangs can undergo cell cycle-regulated changes independent of telomerase activity. G-overhangs at lagging telomeres are lengthened in S phase and then shortened in late S/G2 because of C-strand fill-in, whereas the sizes of G-overhangs at leading telomeres remain stable throughout S phase and are lengthened in G2/M. The final nucleotides at measurable C-strands are precisely defined throughout the cell cycle, indicating that C-strand resection is strictly regulated. We demonstrate that C-strand fill-in is mediated by DNA polymerase alpha (polalpha) and controlled by cyclin-dependent kinase 1 (CDK1). Inhibition of CDK1 leads to accumulation of lengthened G-overhangs and induces telomeric DNA damage response. Furthermore, depletion of hStn1 results in elongation of G-overhangs and an increase in telomeric DNA damage. Our results suggest that G-overhang generation at human telomeres is regulated by multiple tightly controlled processes and C-strand fill-in is under the control of polalpha and CDK1.},
}
@article {pmid20639300,
year = {2010},
author = {Eerola, J and Kananen, L and Manninen, K and Hellström, O and Tienari, PJ and Hovatta, I},
title = {No evidence for shorter leukocyte telomere length in Parkinson's disease patients.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {65},
number = {11},
pages = {1181-1184},
doi = {10.1093/gerona/glq125},
pmid = {20639300},
issn = {1758-535X},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/physiology ; Case-Control Studies ; Chi-Square Distribution ; Female ; Humans ; Leukocytes/*ultrastructure ; Linear Models ; Male ; Middle Aged ; Parkinson Disease/*genetics/physiopathology ; Phenotype ; Telomere/*ultrastructure ; },
abstract = {Telomeres constitute the protective ends of chromosomes. They become shorter after each cell division, and therefore, telomere length is considered as an indicator of cellular aging. Interestingly, both inflammation and oxidative stress, which play a role in the etiology of Parkinson's disease (PD), may accelerate telomere shortening. Furthermore, it has been suggested that leukocyte telomere shortening may be accelerated in PD. To replicate the earlier findings, we analyzed telomere length of peripheral blood leukocytes in a sample of 131 PD patients (aged 66.8 ± 9.7 years) and 115 controls (aged 65.4 ± 9.8 years) from Finland. As expected, age associated significantly with telomere length (p = .01). However, telomere length did not differ significantly between PD patients and controls (p = .54). Furthermore, extremely short telomeres were not more frequent in PD patients than in controls, as suggested in an earlier study. Our results do not support the concept of accelerated leukocyte telomere shortening in PD.},
}
@article {pmid20638489,
year = {2010},
author = {Ghosh, S and Majumder, P and Pradhan, SK and Dasgupta, D},
title = {Mechanism of interaction of small transcription inhibitors with DNA in the context of chromatin and telomere.},
journal = {Biochimica et biophysica acta},
volume = {1799},
number = {10-12},
pages = {795-809},
doi = {10.1016/j.bbagrm.2010.06.008},
pmid = {20638489},
issn = {0006-3002},
mesh = {Animals ; Antineoplastic Agents/*chemistry/pharmacology ; Chromatin/*metabolism ; DNA/*metabolism ; Enzyme Inhibitors/*chemistry/pharmacology ; Humans ; Telomere/*metabolism ; Transcription, Genetic/*drug effects ; },
abstract = {Small molecules from natural and synthetic sources have long been employed as human drugs. The transcription inhibitory potential of one class of these molecules has paved their use as anticancer drugs. The principal mode of action of these molecules is via reversible interaction with genomic DNA, double and multiple stranded. In this article we have revisited the mechanism of the interaction in the context of chromatin and telomere. The established modes of association of these molecules with double helical DNA provide a preliminary mechanism of their transcription inhibitory potential, but the scenario assumes a different dimension when the genomic DNA is associated with proteins in the transcription apparatus of both prokaryotic and eukaryotic organisms. We have discussed this altered scenario as a prelude to understand the chemical biology of their action in the cell. For the telomeric quadruplex DNA, we have reviewed the mechanism of their association with the quadruplex and resultant cellular consequence.},
}
@article {pmid20637196,
year = {2010},
author = {Paeschke, K and McDonald, KR and Zakian, VA},
title = {Telomeres: structures in need of unwinding.},
journal = {FEBS letters},
volume = {584},
number = {17},
pages = {3760-3772},
pmid = {20637196},
issn = {1873-3468},
support = {R01 GM043265/GM/NIGMS NIH HHS/United States ; R01 GM043265-20/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA/genetics/metabolism ; DNA Helicases/genetics/metabolism ; DNA Replication ; Fanconi Anemia Complementation Group Proteins/genetics/metabolism ; Humans ; RecQ Helicases/genetics/metabolism ; Recombination, Genetic ; Saccharomyces cerevisiae/genetics/metabolism ; Sequence Alignment ; Telomere/*chemistry/genetics ; Transcription, Genetic ; },
abstract = {Telomeres protect the ends of eukaryotic chromosomes from being recognized and processed as double strand breaks. In most organisms, telomeric DNA is highly repetitive with a high GC-content. Moreover, the G residues are concentrated in the strand running 3'-5' from the end of the chromosome towards its center. This G-rich strand is extended to form a 3' single-stranded tail that can form unusual secondary structures such as T-loops and G-quadruplex DNA. Both the duplex repeats and the single-stranded G-tail are assembled into stable protein-DNA complexes. The unique architecture, high GC content, and multi-protein association create particularly stable protein-DNA complexes that are a challenge for replication, recombination, and transcription. Helicases utilize the energy of nucleotide hydrolysis to unwind base paired nucleic acids and, in some cases, to displace proteins from them. The telomeric functions of helicases from the RecQ, Pifl, FANCJ, and DNA2 families are reviewed in this article. We summarize data showing that perturbation of their telomere activities can lead to telomere dysfunction and genome instability and in some cases human disease.},
}
@article {pmid20634563,
year = {2010},
author = {Sheppard, SA and Loayza, D},
title = {LIM-domain proteins TRIP6 and LPP associate with shelterin to mediate telomere protection.},
journal = {Aging},
volume = {2},
number = {7},
pages = {432-444},
pmid = {20634563},
issn = {1945-4589},
support = {G12 RR003037/RR/NCRR NIH HHS/United States ; RR003037/RR/NCRR NIH HHS/United States ; },
mesh = {ATPases Associated with Diverse Cellular Activities ; Adaptor Proteins, Signal Transducing/*metabolism ; Cytoskeletal Proteins/*metabolism ; DNA Damage ; DNA-Binding Proteins/physiology ; Humans ; LIM Domain Proteins ; Proteasome Endopeptidase Complex ; Protein Binding ; Shelterin Complex ; *Telomere/pathology/physiology ; Telomere-Binding Proteins/*metabolism/physiology ; Transcription Factors/*metabolism ; Yeasts/genetics ; },
abstract = {POT1 is the single stranded telomeric overhang binding protein, and is part of the shelterin complex, a group of six proteins essential for proper telomere function. The reduction or abrogation of POT1 DNA binding activity in mammalian cells results in telomere elongation, or activation of the ATR DNA damage response at telomeres. Therefore, overhang binding represents the functionally relevant activity of POT1. To better understand the roles of POT1, we sought to isolate proteins that interact with the DNA binding domain of the protein. A yeast two-hybrid screen was implemented using a C-terminal truncation termed POT1DeltaC, retaining the DNA binding domain. This screen yielded a partial cDNA corresponding to TRIP6, a member of the LIM domain protein family. TRIP6 could co-immunoprecipitate with POT1, TRF2 and TIN2 in human cells, arguing for association with the whole shelterin complex, and was detected at telomeres by ChIP. TRIP6 depletion by siRNA led to the induction of telomere dysfunction induced foci (TIFs), indicating a role in telomere protection. A closely related LIM domain protein, LPP, was also found at telomeres and was also important for repressing the DNA damage response. We propose that TRIP6 and LPP are both required for telomere protection.},
}
@article {pmid20632849,
year = {2010},
author = {West, MD and Vaziri, H},
title = {Back to immortality: the restoration of embryonic telomere length during induced pluripotency.},
journal = {Regenerative medicine},
volume = {5},
number = {4},
pages = {485-488},
doi = {10.2217/rme.10.51},
pmid = {20632849},
issn = {1746-076X},
mesh = {Animals ; Cellular Senescence/*physiology ; Embryo, Mammalian/cytology/*physiology ; Humans ; Induced Pluripotent Stem Cells/*physiology ; Telomere/*physiology ; },
}
@article {pmid20629093,
year = {2011},
author = {Ponsot, E and Langberg, H and Krogsgaard, MR and Kjaer, M and Kadi, F},
title = {Telomere length of anterior crucial ligament after rupture: similar telomere length in injured and noninjured ACL portions.},
journal = {Journal of orthopaedic research : official publication of the Orthopaedic Research Society},
volume = {29},
number = {1},
pages = {79-83},
doi = {10.1002/jor.21201},
pmid = {20629093},
issn = {1554-527X},
mesh = {Adolescent ; Adult ; *Anterior Cruciate Ligament Injuries ; Female ; Humans ; Male ; Rupture ; *Telomere ; Wound Healing ; },
abstract = {The regeneration of ligaments following injury is a slow process compared to the healing of many other tissues and the underlying mechanisms remain unknown. The purpose of the study was to evaluate the proliferative potential of ligaments by assessing telomere length within three distinct parts of human anterior cruciate ligament (ACL) obtained during ACL reconstruction: the macroscopically injured proximal part and macroscopically noninjured mid- and distal portions in eight subjects (age 28 ± 8 years). The mean telomere length in ACL was within normal range of values usually reported for other tissues indicating that the endogenous machinery responsible for the proliferative potential of ligament is not implicated in its poor healing capacity. The three ACL parts showed similar mean TRF lengths (distal part: 11.5 ± 0.8 kbp, mid-portion: 11.8 ± 1.2 kbp, proximal part: 11.9 ± 1.6 kbp) and there was no relationship between mean telomere length in ACL and the healing duration after rupture. This implies that despite the occurrence of ligament repair including a phase of intense cell proliferation the proliferative potential of ruptured ACL is not impaired. This knowledge is important for scientists and clinicians aiming to understand the mechanisms behind the low healing capacity of ligament.},
}
@article {pmid20628356,
year = {2010},
author = {Vodenicharov, MD and Laterreur, N and Wellinger, RJ},
title = {Telomere capping in non-dividing yeast cells requires Yku and Rap1.},
journal = {The EMBO journal},
volume = {29},
number = {17},
pages = {3007-3019},
pmid = {20628356},
issn = {1460-2075},
support = {12616//Canadian Institutes of Health Research/Canada ; },
mesh = {Cell Cycle Proteins/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes, Fungal/*metabolism ; DNA, Fungal/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Gene Knockout Techniques ; Microbial Viability ; Saccharomyces cerevisiae/*physiology ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; Transcription Factors/*metabolism ; },
abstract = {The assembly of a protective cap onto the telomeres of eukaryotic chromosomes suppresses genomic instability through inhibition of DNA repair activities that normally process accidental DNA breaks. We show here that the essential Cdc13-Stn1-Ten1 complex is entirely dispensable for telomere protection in non-dividing cells. However, Yku and Rap1 become crucially important for this function in these cells. After inactivation of Yku70 in G1-arrested cells, moderate but significant telomere degradation occurs. As the activity of cyclin-dependent kinases (CDK) promotes degradation, these results suggest that Yku stabilizes G1 telomeres by blocking the access of CDK1-independent nucleases to telomeres. The results indeed show that both Exo1 and the Mre11/Rad50/Xrs2 complex are required for telomeric resection after Yku loss in non-dividing cells. Unexpectedly, both asynchronously growing and quiescent G0 cells lacking Rap1 display readily detectable telomere degradation, suggesting an earlier unanticipated function for this protein in suppression of nuclease activities at telomeres. Together, our results show a high flexibility of the telomeric cap and suggest that distinct configurations may provide for efficient capping in dividing versus non-dividing cells.},
}
@article {pmid20626135,
year = {2010},
author = {Salamanca-Gómez, F},
title = {[Telomeres and pathology of the skin].},
journal = {Gaceta medica de Mexico},
volume = {146},
number = {2},
pages = {160-161},
pmid = {20626135},
issn = {0016-3813},
mesh = {Dyskeratosis Congenita/*genetics ; Humans ; *Telomere ; },
}
@article {pmid20590834,
year = {2010},
author = {Takubo, K and Aida, J and Izumiyama-Shimomura, N and Ishikawa, N and Sawabe, M and Kurabayashi, R and Shiraishi, H and Arai, T and Nakamura, K},
title = {Changes of telomere length with aging.},
journal = {Geriatrics &amp; gerontology international},
volume = {10 Suppl 1},
number = {},
pages = {S197-206},
doi = {10.1111/j.1447-0594.2010.00605.x},
pmid = {20590834},
issn = {1447-0594},
mesh = {Aging/*physiology ; Blotting, Southern ; Breast/cytology ; Female ; Flow Cytometry ; Gastric Mucosa/cytology ; Humans ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence/methods ; Stomach/cytology ; Telomere/chemistry/genetics/*physiology/ultrastructure ; Tongue/cytology ; },
abstract = {We reviewed our methodology and results of telomere measurements, with reference to telomere length and aging. Human tissues always showed telomere shortening with age, except for the brain and myocardium. Yearly rates of telomere length reduction in various tissues were mostly within the range 20-60 bp, and thus compatible with that expected from only one round of mitosis. It was suggested that when telomeres were found to be longer in any specific organ in a given individual, then the other organs in that individual would also have longer telomeres. Using the quantitative fluorescence in situ hybridization (Q-FISH) method for telomere measurement, we were able to measure the telomere lengths of various cell types within tissues. Here we summarize the results obtained for various cell types in the stomach, tongue and breast. Our Q-FISH method using our original software program "Tissue Telo" is excellent for measuring telomere lengths using tissue sections and PNA probes.},
}
@article {pmid20625812,
year = {2011},
author = {Diehl, MC and Idowu, MO and Kimmelshue, KN and York, TP and Jackson-Cook, CK and Turner, KC and Holt, SE and Elmore, LW},
title = {Elevated TRF2 in advanced breast cancers with short telomeres.},
journal = {Breast cancer research and treatment},
volume = {127},
number = {3},
pages = {623-630},
pmid = {20625812},
issn = {1573-7217},
support = {K01 CA105050/CA/NCI NIH HHS/United States ; R01 ES012074/ES/NIEHS NIH HHS/United States ; R01 ES12074/ES/NIEHS NIH HHS/United States ; KO1 CA105050-01A131/CA/NCI NIH HHS/United States ; },
mesh = {Blotting, Western ; Breast Neoplasms/*genetics/*pathology ; Carcinoma, Intraductal, Noninfiltrating/genetics/pathology ; Cell Line, Tumor ; DNA-Binding Proteins/genetics/metabolism ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Protein Array Analysis ; RNA, Messenger/analysis ; Telomere/*pathology ; Telomeric Repeat Binding Protein 2/biosynthesis/*genetics ; },
abstract = {Telomere repeat binding factor 2 (TRF2) binds directly to telomeres and preserves the structural integrity of chromosome ends. In vitro models suggest that expression of TRF2 protein increases during mammary cancer progression. However, a recent study has reported that TRF2 mRNA levels tend to be lower in clinical specimens of malignant breast tissue. Here, we conduct the first large-scale investigation to assess the levels and cellular localization of the TRF2 protein in normal, pre-malignant and malignant breast tissues. Breast tissue arrays, containing normal, ductal carcinoma in situ (DCIS) and invasive carcinoma specimens, were used to assess the expression and localization of TRF2 protein. Telomere lengths were semi-quantitatively measured using a pantelomeric peptide nucleic acid probe. A mixed effects modeling approach was used to assess the relationship between TRF2 expression and telomeric signal scores across disease states or clinical staging. We demonstrate that TRF2 is exclusively nuclear with a trend toward lower expression with increased malignancy. More case-to-case variability of TRF2 immunostaining intensity was noted amongst the invasive carcinomas than the other disease groups. Invasive carcinomas also displayed variable telomere lengths while telomeres in normal mammary epithelium were generally longer. Statistical analyses revealed that increased TRF2 immunostaining intensity in invasive carcinomas is associated with shorter telomeres and shorter telomeres correlate with a higher TNM stage. All immortalized and cancer cell lines within the array displayed strong, nuclear TRF2 expression. Our data indicate that elevated expression of TRF2 is not a frequent occurrence during the transformation of breast cancer cells in vivo, but higher levels of this telomere-binding protein may be important for protecting advanced cancer cells with critically short telomeres. Our findings also reinforce the concept that serially propagated cancer cells, although tumor-derived, may not model all types of authentic tumors especially those demonstrating genetic heterogeneity.},
}
@article {pmid20625380,
year = {2010},
author = {Liu, NN and Han, TX and Du, LL and Zhou, JQ},
title = {A genome-wide screen for Schizosaccharomyces pombe deletion mutants that affect telomere length.},
journal = {Cell research},
volume = {20},
number = {8},
pages = {963-965},
doi = {10.1038/cr.2010.107},
pmid = {20625380},
issn = {1748-7838},
mesh = {Genome, Fungal ; Schizosaccharomyces/*genetics ; *Sequence Deletion ; Telomere/chemistry/*metabolism ; },
}
@article {pmid20622870,
year = {2010},
author = {Teo, H and Ghosh, S and Luesch, H and Ghosh, A and Wong, ET and Malik, N and Orth, A and de Jesus, P and Perry, AS and Oliver, JD and Tran, NL and Speiser, LJ and Wong, M and Saez, E and Schultz, P and Chanda, SK and Verma, IM and Tergaonkar, V},
title = {Telomere-independent Rap1 is an IKK adaptor and regulates NF-kappaB-dependent gene expression.},
journal = {Nature cell biology},
volume = {12},
number = {8},
pages = {758-767},
pmid = {20622870},
issn = {1476-4679},
mesh = {Animals ; Apoptosis/genetics/physiology ; Blotting, Western ; Cell Line ; Cell Line, Tumor ; Chromatin Immunoprecipitation ; Chromatography, Gel ; HeLa Cells ; Humans ; I-kappa B Kinase/genetics/*metabolism ; Immunohistochemistry ; Immunoprecipitation ; Kaplan-Meier Estimate ; Mice ; NF-kappa B/genetics/*metabolism ; Phosphorylation/genetics/physiology ; Polymerase Chain Reaction ; Protein Binding/genetics/physiology ; RNA, Small Interfering ; Shelterin Complex ; Telomere-Binding Proteins/genetics/*metabolism ; Tissue Array Analysis ; },
abstract = {We describe a genome-wide gain-of-function screen for regulators of NF-kappaB, and identify Rap1 (Trf2IP), as an essential modulator of NF-kappaB-mediated pathways. NF-kappaB is induced by ectopic expression of Rap1, whereas its activity is inhibited by Rap1 depletion. In addition to localizing on telomeres, mammalian Rap1 forms a complex with IKKs (IkappaB kinases), and is crucial for the ability of IKKs to be recruited to, and phosphorylate, the p65 subunit of NF-kappaB to make it transcriptionally competent. Rap1-mutant mice display defective NF-kappaB activation and are resistant to endotoxic shock. Furthermore, levels of Rap1 are positively regulated by NF-kappaB, and human breast cancers with NF-kappaB hyperactivity show elevated levels of cytoplasmic Rap1. Similar to inhibiting NF-kappaB, knockdown of Rap1 sensitizes breast cancer cells to apoptosis. These results identify the first cytoplasmic role of Rap1 and provide a mechanism through which it regulates an important signalling cascade in mammals, independent of its ability to regulate telomere function.},
}
@article {pmid20622869,
year = {2010},
author = {Martinez, P and Thanasoula, M and Carlos, AR and Gómez-López, G and Tejera, AM and Schoeftner, S and Dominguez, O and Pisano, DG and Tarsounas, M and Blasco, MA},
title = {Mammalian Rap1 controls telomere function and gene expression through binding to telomeric and extratelomeric sites.},
journal = {Nature cell biology},
volume = {12},
number = {8},
pages = {768-780},
pmid = {20622869},
issn = {1476-4679},
support = {232854/ERC_/European Research Council/International ; /CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Animals ; Binding Sites/genetics/physiology ; Body Weight/genetics/physiology ; Cell Line ; Cell Proliferation ; Chromatin Immunoprecipitation ; DNA Methylation ; Flow Cytometry ; Fluorescent Antibody Technique ; Gene Expression Regulation/genetics/physiology ; Humans ; Immunoblotting ; Immunoprecipitation ; Mice ; Mice, Knockout ; Protein Binding ; Reverse Transcriptase Polymerase Chain Reaction ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Rap1 is a component of the shelterin complex at mammalian telomeres, but its in vivo role in telomere biology has remained largely unknown to date. Here we show that Rap1 deficiency is dispensable for telomere capping but leads to increased telomere recombination and fragility. We generated cells and mice deleted for Rap1; mice with Rap1 deletion in stratified epithelia were viable but had shorter telomeres and developed skin hyperpigmentation in adulthood. By performing chromatin immunoprecipitation coupled with ultrahigh-throughput sequencing, we found that Rap1 binds to both telomeres and to extratelomeric sites through the (TTAGGG)(2) consensus motif. Extratelomeric Rap1-binding sites were enriched at subtelomeric regions, in agreement with preferential deregulation of subtelomeric genes in Rap1-deficient cells. More than 70% of extratelomeric Rap1-binding sites were in the vicinity of genes, and 31% of the genes deregulated in Rap1-null cells contained Rap1-binding sites, suggesting a role for Rap1 in transcriptional control. These findings place a telomere protein at the interface between telomere function and transcriptional regulation.},
}
@article {pmid20620955,
year = {2010},
author = {Faure, V and Coulon, S and Hardy, J and Géli, V},
title = {Cdc13 and telomerase bind through different mechanisms at the lagging- and leading-strand telomeres.},
journal = {Molecular cell},
volume = {38},
number = {6},
pages = {842-852},
doi = {10.1016/j.molcel.2010.05.016},
pmid = {20620955},
issn = {1097-4164},
mesh = {Endodeoxyribonucleases/metabolism ; Exodeoxyribonucleases/metabolism ; Protein Binding ; Saccharomyces cerevisiae/*metabolism/ultrastructure ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Lagging-strand and leading-strand synthesis of chromosomes generates two structurally distinct ends at the telomeres. Based on sequence bias of yeast telomeres that contain a 250-300 bp array of C(1-3)A/ TG(1-3) repeats, we developed a method allowing us to distinguish which of the two daughter telomeres chromosome end-binding proteins bind to at the end of S phase. The single-stranded DNA-binding protein Cdc13 and the telomerase subunits Est1 and Est2 can bind to the two daughter telomeres, but only their binding to the leading-strand telomere depends on the Mre11/Rad50/Xrs2 (MRX) complex involved in both telomeric 5' nucleolytic resection and telomerase recruitment at short telomeres. Consistently, the MRX complex is mainly found to bind to the leading-strand telomere. Our results indicate that Cdc13 can bind to the telomeric template for lagging-strand replication. Since mre11-deficient strains have markedly short telomeres, telomere elongation by telomerase is likely to occur mainly at the leading-strand telomere.},
}
@article {pmid20620949,
year = {2010},
author = {Dewar, JM and Lydall, D},
title = {Telomere replication: Mre11 leads the way.},
journal = {Molecular cell},
volume = {38},
number = {6},
pages = {777-779},
doi = {10.1016/j.molcel.2010.06.003},
pmid = {20620949},
issn = {1097-4164},
support = {075294/WT_/Wellcome Trust/United Kingdom ; },
abstract = {In this issue of Molecular Cell, Faure et al. (2010) establish a critical role for the Mre11 complex in the recruitment of telomerase to leading- but not lagging-strand telomeres of budding yeast.},
}
@article {pmid20619976,
year = {2010},
author = {Biron-Shental, T and Sukenik Halevy, R and Goldberg-Bittman, L and Kidron, D and Fejgin, MD and Amiel, A},
title = {Telomeres are shorter in placental trophoblasts of pregnancies complicated with intrauterine growth restriction (IUGR).},
journal = {Early human development},
volume = {86},
number = {7},
pages = {451-456},
doi = {10.1016/j.earlhumdev.2010.06.002},
pmid = {20619976},
issn = {1872-6232},
mesh = {Female ; Fetal Growth Retardation/etiology/*genetics ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Placental Insufficiency/*genetics ; Pregnancy ; Telomere/*ultrastructure ; Trophoblasts/*ultrastructure ; },
abstract = {OBJECTIVE: Telomeres are nucleoprotein structures located at the termini of chromosomes, and protect them from fusion and degradation. Telomeres are progressively shortened with each mitotic cycle and by environmental factors. We hypothesized that antepartum stress can lead to accelerated telomere shortening in placental trophoblasts, and plays a role in intrauterine growth restriction (IUGR).<br><br>METHODS: Placental biopsies were derived from 16 pregnancies complicated with IUGR and from 13 uncomplicated pregnancies. Fluorescence-in-situ protocol was used to determine telomere length. Immunohistochemistry for hTERT was performed to assess telomerase activity. Clinical and histopathological characteristics were collected to ensure that IUGR was secondary to placental insufficiency. Fluorescence-in-situ-hybridization was used to rule out aneuploidy as a reason for shortened telomeres.<br><br>RESULTS: The number and intensity of telomeres staining and telomerase activity were significantly lower in the IUGR placentas. No aneuploidy was detected for the chromosomes checked in the placental biopsies.<br><br>CONCLUSIONS: Telomeres are shorter in trophoblasts of IUGR placentas.},
}
@article {pmid20619712,
year = {2010},
author = {Wu, P and van Overbeek, M and Rooney, S and de Lange, T},
title = {Apollo contributes to G overhang maintenance and protects leading-end telomeres.},
journal = {Molecular cell},
volume = {39},
number = {4},
pages = {606-617},
pmid = {20619712},
issn = {1097-4164},
support = {F30 AG034744/AG/NIA NIH HHS/United States ; R01 GM049046/GM/NIGMS NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; F30AG034744/AG/NIA NIH HHS/United States ; GM49046/GM/NIGMS NIH HHS/United States ; GM07739/GM/NIGMS NIH HHS/United States ; CA76027/CA/NCI NIH HHS/United States ; R01 CA076027/CA/NCI NIH HHS/United States ; T32 GM007739/GM/NIGMS NIH HHS/United States ; R01 CA076027-13/CA/NCI NIH HHS/United States ; R37 GM049046-19/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Motifs ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/metabolism ; Cell Line ; DNA Damage ; *DNA Replication ; DNA-Binding Proteins/metabolism ; Enzyme Activation ; Exodeoxyribonucleases ; Fibroblasts/*enzymology ; G2 Phase ; Gene Fusion ; Genotype ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mutation ; Nucleic Acid Conformation ; Phenotype ; Protein Serine-Threonine Kinases/metabolism ; RNA Interference ; S Phase ; Telomere/chemistry/*metabolism ; Telomere-Binding Proteins/chemistry/deficiency/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; Time Factors ; Tumor Suppressor Proteins/metabolism ; },
abstract = {Mammalian telomeres contain a single-stranded 3' overhang that is thought to mediate telomere protection. Here we identify the TRF2-interacting factor Apollo as a nuclease that contributes to the generation/maintenance of this overhang. The function of mouse Apollo was determined using Cre-mediated gene deletion, complementation with Apollo mutants, and the TRF2-F120A mutant that cannot bind Apollo. Cells lacking Apollo activated the ATM kinase at their telomeres in S phase and showed leading-end telomere fusions. These telomere dysfunction phenotypes were accompanied by a reduction in the telomeric overhang signal. The telomeric functions of Apollo required its TRF2-interaction and nuclease motifs. Thus, TRF2 recruits the Apollo nuclease to process telomere ends synthesized by leading-strand DNA synthesis, thereby creating a terminal structure that avoids ATM activation and resists end-joining. These data establish that the telomeric overhang is required for the protection of telomeres from the DNA damage response.},
}
@article {pmid20619302,
year = {2010},
author = {Napier, CE and Veas, LA and Kan, CY and Taylor, LM and Yuan, J and Wen, VW and James, A and O'Brien, TA and Lock, RB and MacKenzie, KL},
title = {Mild hyperoxia limits hTR levels, telomerase activity, and telomere length maintenance in hTERT-transduced bone marrow endothelial cells.},
journal = {Biochimica et biophysica acta},
volume = {1803},
number = {10},
pages = {1142-1153},
doi = {10.1016/j.bbamcr.2010.06.010},
pmid = {20619302},
issn = {0006-3002},
mesh = {Blotting, Western ; Bone Marrow Cells/cytology/metabolism ; Cell Hypoxia ; Cell Proliferation ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Endothelial Cells/cytology/drug effects/*metabolism ; Genetic Vectors/genetics ; Humans ; Hydroxylamines/pharmacology ; Oxidative Stress ; RNA/genetics/*metabolism ; Retroviridae/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; Transduction, Genetic ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Reactivation of telomerase in endothelial cells (ECs) may be an effective approach to the treatment of vascular disorders associated with telomere attrition and EC senescence. However, overexpression of human telomerase reverse transcriptase (hTERT) does not prevent net telomere loss in ECs grown in standard culture medium with exposure to atmospheric oxygen (21% O(2)). Since these culture conditions are hyperoxic relative to normal tissue in vivo, where oxygen tension is estimated to be 1%-6%, we examined the effects of reduced exposure to oxidative stress (OS) on telomere length maintenance in hTERT-transduced bone marrow endothelial (BMhTERT) cells. Propagation of BMhTERT cells in the free radical scavenger, tert-butylhydroxylamine (tBN), and/or in 5% O(2) increased telomerase enzyme activity and facilitated telomere length maintenance. The enhancement of telomerase activity correlated with higher levels of the telomerase RNA component (hTR). We also investigated the role of the telomere binding protein, TRF1, in telomere length regulation under alternate OS conditions. Inhibition of TRF1 function had no effect on telomere length in BMhTERT cells grown under standard culture conditions. However, alleviation of OS by growth in tBN plus 5% O(2), elevated hTR levels, enhanced telomerase enzyme activity, and enabled progressive telomere lengthening. The direct impact of hTR levels on telomerase-mediated telomere lengthening was demonstrated by overexpression of hTR. BMhTERT cells transduced with hTR exhibited very high telomerase enzyme activity and underwent dramatic telomere lengthening under standard culture conditions. Overall, these results demonstrate that hTR levels are reduced by mild hyperoxia and limit telomerase-mediated telomere lengthening in hTERT-transduced ECs.},
}
@article {pmid20618815,
year = {2010},
author = {Ren, H and Collins, V and Fernandez, F and Quinlan, S and Griffiths, L and Choo, KH},
title = {Shorter telomere length in peripheral blood cells associated with migraine in women.},
journal = {Headache},
volume = {50},
number = {6},
pages = {965-972},
doi = {10.1111/j.1526-4610.2010.01693.x},
pmid = {20618815},
issn = {1526-4610},
mesh = {Adolescent ; Adult ; Aged ; Female ; Humans ; Leukocytes, Mononuclear ; Middle Aged ; Migraine Disorders/*genetics ; Polymerase Chain Reaction ; Regression Analysis ; Telomere/*genetics ; White People ; },
abstract = {OBJECTIVE: To evaluate relative telomere length of female migraine patients.<br><br>BACKGROUND: Migraine is a debilitating disorder affecting 6-28% of the population. Studies on the mechanisms of migraine have demonstrated genetic causes but the pathophysiology and subcellular effects of the disease remain poorly understood. Shortened telomere length is associated with age-related or chronic diseases, and induced stresses. Migraine attacks may impart significant stress on cellular function, thus this study investigates a correlation between shortening of telomeres and migraine.<br><br>METHODS: Relative telomere length was measured using a previously described quantitative polymerase chain reaction method. A regression analysis was performed to assess differences in mean relative telomere length between migraine patients and healthy controls.<br><br>RESULTS: The leukocyte telomeres of a cohort of 142 Caucasian female migraine subjects aged 18-77 years and 143 matched 17-77-year-old healthy control Caucasian women were examined. A significantly shorter relative telomere length was observed in the migraine group compared with the control group after adjusting for age and body mass index (P = .001). In addition, age of onset was observed to associate with the loss of relative telomere length, especially at early age of onset (<17 years old). No association was observed between relative telomere length and the severity and frequency of migraine attacks and the duration of migraine.<br><br>CONCLUSION: Telomeres are shorter in migraine patients and there is more variation in telomere length in migraine patients.},
}
@article {pmid20616147,
year = {2010},
author = {Shin, JY and Choi, YY and Jeon, HS and Hwang, JH and Kim, SA and Kang, JH and Chang, YS and Jacobs, DR and Park, JY and Lee, DH},
title = {Low-dose persistent organic pollutants increased telomere length in peripheral leukocytes of healthy Koreans.},
journal = {Mutagenesis},
volume = {25},
number = {5},
pages = {511-516},
doi = {10.1093/mutage/geq035},
pmid = {20616147},
issn = {1464-3804},
mesh = {*Asian People ; Dichlorodiphenyl Dichloroethylene/blood ; *Environmental Monitoring ; Environmental Pollutants/*blood ; Female ; *Health ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Organic Chemicals/*blood ; Polychlorinated Biphenyls/blood ; Republic of Korea ; Statistics, Nonparametric ; Telomere/*metabolism ; },
abstract = {Although shortened telomeres have been found in many cancers, elongated telomere length has been observed as an early response after low-dose treatment with various chemical carcinogens in vitro and animal experiments, suggesting low-dose exposure to carcinogenic chemicals may function as a tumour promoter at the very early stage of carcinogenesis in humans. This cross-sectional study was performed to examine whether low-dose exposure to persistent organic pollutants (POPs), lipophilic xenobiotics that mainly bioaccumulate in adipose tissue, is associated with telomere length of peripheral blood leukocytes in apparently healthy persons. Telomere length was measured using quantitative polymerase chain reaction method in 84 apparently healthy Koreans. Among various POPs, serum concentrations of organochlorine (OC) pesticides, polychlorinated biphenyls (PCBs) and polybrominated diphenylethers were measured. Most OC pesticides and PCBs were positively and significantly associated with telomere length with correlation coefficients from about +0.25 to +0.35. The strongest associations were observed with p,p'-dichlorodiphenyldichloroethylene, PCB99, PCB153, PCB180, PCB183 and PCB187. When we examined adjusted means of telomere length by quintiles of POPs, the steeper increases of telomere length tended to be observed within relatively lower ranges of POPs. Besides serum concentrations of POPs, none of the other variables studied, including age, were associated with telomere length in this study. We found that telomere length was increasing across low doses of exposure to POPs in which the majority of study subjects were found, suggesting that low-dose POPs may act as a tumour promoter in carcinogenesis in humans.},
}
@article {pmid20606397,
year = {2010},
author = {Yu, S and Graf, WD},
title = {Telomere capture as a frequent mechanism for stabilization of the terminal chromosomal deletion associated with inverted duplication.},
journal = {Cytogenetic and genome research},
volume = {129},
number = {4},
pages = {265-274},
doi = {10.1159/000315887},
pmid = {20606397},
issn = {1424-859X},
mesh = {*Chromosome Deletion ; *Chromosome Inversion ; Chromosomes, Human, Pair 13 ; Chromosomes, Human, Pair 5 ; Chromosomes, Human, Pair 8 ; *Gene Duplication ; Humans ; Nucleic Acid Hybridization ; Telomere/*genetics ; },
abstract = {We report 4 interstitial inverted duplications with associated terminal deletions (inv dup del) involving the short arms of chromosomes 5 and 8, and the long arm of chromosome 13 by microarray-based comparative genomic hybridization (aCGH) combined with chromosome banding (GTG banding) and fluorescence in situ hybridization (FISH) analyses. Formation of the intermediate dicentric chromosomes in 3 of them occurred through breakage-fusion-bridge cycle mechanism (U-type exchange mechanism) and in the fourth one it occurred through the mediation of the inverted low-copy repeats on chromosome 8p23.1. Two of these 4 inv dup del were confirmed and a third one was suspected to be associated with telomere capture for the healing of the terminal deletions. These findings indicate that a telomere capture mechanism is frequently used for stabilizing the broken chromosome ends in this type of genomic rearrangements. In addition, the inv dup del(13) represents the first observation of inv dup del on chromosome 13 in humans, the inv dup del(5) represents the first observation of inv dup del(5p) with an associated telomere capture, and unique features of the remaining two inv dup del(8p) were also discussed.},
}
@article {pmid20606151,
year = {2010},
author = {Willeit, P and Willeit, J and Mayr, A and Weger, S and Oberhollenzer, F and Brandstätter, A and Kronenberg, F and Kiechl, S},
title = {Telomere length and risk of incident cancer and cancer mortality.},
journal = {JAMA},
volume = {304},
number = {1},
pages = {69-75},
doi = {10.1001/jama.2010.897},
pmid = {20606151},
issn = {1538-3598},
mesh = {Adult ; Aged ; Female ; Humans ; Italy/epidemiology ; Leukocytes ; Male ; Middle Aged ; Neoplasms/*mortality ; Polymerase Chain Reaction ; Prospective Studies ; Risk ; Telomere/*ultrastructure ; },
abstract = {CONTEXT: Telomeres are essential to preserve the integrity of the genome. Critically short telomeres lead to replicative cell senescence and chromosomal instability and may thereby increase cancer risk.<br><br>OBJECTIVE: To determine the association between baseline telomere length and incident cancer and cancer mortality.<br><br>Leukocyte telomere length was measured by quantitative polymerase chain reaction in 787 participants free of cancer at baseline in 1995 from the prospective, population-based Bruneck Study in Italy.<br><br>MAIN OUTCOME MEASURES: Incident cancer and cancer mortality over a follow-up period of 10 years (1995-2005 with a follow-up rate of 100%).<br><br>RESULTS: A total of 92 of 787 participants (11.7%) developed cancer (incidence rate, 13.3 per 1000 person-years). Short telomere length at baseline was associated with incident cancer independently of standard cancer risk factors (multivariable hazard ratio [HR] per 1-SD decrease in log(e)-transformed telomere length, 1.60; 95% confidence interval [CI], 1.30-1.98; P < .001). Compared with participants in the longest telomere length group, the multivariable HR for incident cancer was 2.15 (95% CI, 1.12-4.14) in the middle length group and 3.11 (95% CI, 1.65-5.84) in the shortest length group (P < .001). Incidence rates were 5.1 (95% CI, 2.9-8.7) per 1000 person-years in the longest telomere length group, 14.2 (95% CI, 10.0-20.1) per 1000 person-years in the middle length group, and 22.5 (95% CI, 16.9-29.9) per 1000 person-years in the shortest length group. The association equally applied to men and women and emerged as robust under a variety of circumstances. Furthermore, short telomere length was associated with cancer mortality (multivariable HR per 1-SD decrease in log(e)-transformed telomere length, 2.13; 95% CI, 1.58-2.86; P < .001) and individual cancer subtypes with a high fatality rate.<br><br>CONCLUSION: In this study population, there was a statistically significant inverse relationship between telomere length and both cancer incidence and mortality.},
}
@article {pmid20605919,
year = {2010},
author = {Benson, EK and Lee, SW and Aaronson, SA},
title = {Role of progerin-induced telomere dysfunction in HGPS premature cellular senescence.},
journal = {Journal of cell science},
volume = {123},
number = {Pt 15},
pages = {2605-2612},
pmid = {20605919},
issn = {1477-9137},
support = {T32 GM008553/GM/NIGMS NIH HHS/United States ; R01 CA085681/CA/NCI NIH HHS/United States ; 5R24 CA095823-04/CA/NCI NIH HHS/United States ; 1 S10 RR0 9145-01/RR/NCRR NIH HHS/United States ; R24 CA095823/CA/NCI NIH HHS/United States ; P01CA80058/CA/NCI NIH HHS/United States ; T32 CA078207/CA/NCI NIH HHS/United States ; P01 CA080058/CA/NCI NIH HHS/United States ; },
mesh = {Aging, Premature/genetics/physiopathology ; Cell Line ; Cellular Senescence/genetics/*physiology ; Chromatin Immunoprecipitation ; DNA Damage/genetics/physiology ; Flow Cytometry ; Humans ; Immunoblotting ; Lamin Type A ; Microscopy, Confocal ; Nuclear Proteins/genetics/*metabolism ; Progeria/genetics/*metabolism ; Protein Precursors/genetics/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/genetics/physiology ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature-aging syndrome caused by a dominant mutation in the gene encoding lamin A, which leads to an aberrantly spliced and processed protein termed progerin. Previous studies have shown that progerin induces early senescence associated with increased DNA-damage signaling and that telomerase extends HGPS cellular lifespan. We demonstrate that telomerase extends HGPS cellular lifespan by decreasing progerin-induced DNA-damage signaling and activation of p53 and Rb pathways that otherwise mediate the onset of premature senescence. We show further that progerin-induced DNA-damage signaling is localized to telomeres and is associated with telomere aggregates and chromosomal aberrations. Telomerase amelioration of DNA-damage signaling is relatively rapid, requires both its catalytic and DNA-binding functions, and correlates in time with the acquisition by HGPS cells of the ability to proliferate. All of these findings establish that HGPS premature cellular senescence results from progerin-induced telomere dysfunction.},
}
@article {pmid20605447,
year = {2010},
author = {Park, M and Bruice, TC},
title = {Development of potential anticancer agents that target the telomere sequence.},
journal = {Bioorganic &amp; medicinal chemistry letters},
volume = {20},
number = {13},
pages = {3982-3986},
doi = {10.1016/j.bmcl.2010.04.089},
pmid = {20605447},
issn = {1464-3405},
mesh = {Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology ; Base Sequence ; DNA/chemical synthesis/chemistry/*pharmacology ; DNA, Neoplasm/chemistry/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Guanidines/chemical synthesis/chemistry/*pharmacology ; Humans ; Molecular Structure ; Nucleic Acid Conformation ; Oligodeoxyribonucleotides/chemical synthesis/chemistry/*pharmacology ; Stereoisomerism ; Structure-Activity Relationship ; Telomerase/antagonists &amp; inhibitors ; Telomere/*drug effects/*genetics ; },
abstract = {The immortality of cancer cells is due to the relatively high concentration of telomerase enzyme that maintains the telomere sequence during cell division. Human telomeric DNA consists of repeats of the sequence d(5'-TTAGGG-3'). Deoxyribonucleic guanidine (DNG) is a DNA analog in which positively charged guanidine [-NH-C(NH2+)-NH-] replaces the negatively charged phosphodiester of DNA. The synthesized DNG hexamer AgAgTgCgCpC and dodecamer AgAgTgCgCgCAgAgTgCgCpC are complementary to the non-coding telomere sequence d(5'-TTAGGG-3'). We have found that binding of the complementary DNG hexamer to the telomere is favored over that of DNA telomere by 10(2.5)-fold and binding the dodecamer with 2-mismatched DNA is favored by 10(5)-fold. We have shown that DNG binding to RNA is favored over binding to DNA. A complementary complex of DNG with RNA at the active site of telomerase enzyme would be very stable.},
}
@article {pmid20603667,
year = {2010},
author = {Pu, F and Wang, C and Hu, D and Huang, Z and Ren, J and Wang, S and Qu, X},
title = {Logic gates and pH sensing devices based on a supramolecular telomere DNA/conjugated polymer system.},
journal = {Molecular bioSystems},
volume = {6},
number = {10},
pages = {1928-1932},
doi = {10.1039/c004215c},
pmid = {20603667},
issn = {1742-2051},
mesh = {Base Sequence ; DNA/*chemistry ; DNA Primers ; Fluorescence Resonance Energy Transfer ; *Hydrogen-Ion Concentration ; Polymers/*chemistry ; *Telomere ; },
abstract = {A conceptually new class of telomere DNA/conjugated polymer system has been constructed to enable sensing of pH changes and create robust logic gates capable of multiplex logic operations. It combines the advantages of quadruplex-duplex conversion and efficient energy transfer from the polymer to the DNA binding molecule. The system is simple in design, fast in operation, and allows the detection of pH changes with high accuracy and sensitivity. In addition, the approach could be adopted for the investigation of other biomolecular conformational changes upon binding to their targets. More importantly, the present logic operations showed advantages over other nucleic acid-based logic gates: (1) The system does not require any CP modification or oligonucleotide labeling, which offers the advantages of simplicity and cost efficiency. (2) The reversibility of the switch makes the logic gates feasible to realize system reset. (3) The system could be implemented to perform multiple logic functions by using distinct input signals.},
}
@article {pmid20601686,
year = {2010},
author = {Pitt, CW and Cooper, JP},
title = {Pot1 inactivation leads to rampant telomere resection and loss in one cell cycle.},
journal = {Nucleic acids research},
volume = {38},
number = {20},
pages = {6968-6975},
pmid = {20601686},
issn = {1362-4962},
support = {//Cancer Research UK/United Kingdom ; },
mesh = {Alleles ; Cell Cycle/*genetics ; DNA Damage ; Phenotype ; S Phase ; Schizosaccharomyces pombe Proteins/genetics/*physiology ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*physiology ; },
abstract = {Removal of the conserved telomere protein, Pot1, confers the immediate loss of fission yeast telomeres. This drastic phenotype has established the centrality of Pot1 for telomere maintenance but prohibited elucidation of the intermediate steps leading to telomere loss. To circumvent this problem, we have generated a conditional allele, pot1-1. We show that loss of Pot1 function during G1 leads to rapid telomere erosion during the ensuing S/G2 period. Precipitous telomere loss depends upon S-phase progression and is preceded by 5' telomeric resection. Telomere loss is accompanied by ATR- and Chk1-mediated checkpoint activation, but is not caused by checkpoint arrest.},
}
@article {pmid20600576,
year = {2010},
author = {Kimura, M and Gazitt, Y and Cao, X and Zhao, X and Lansdorp, PM and Aviv, A},
title = {Synchrony of telomere length among hematopoietic cells.},
journal = {Experimental hematology},
volume = {38},
number = {10},
pages = {854-859},
pmid = {20600576},
issn = {1873-2399},
support = {R01 AG020132/AG/NIA NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; GMH79042/CAPMC/CIHR/Canada ; R01AG21593/AG/NIA NIH HHS/United States ; R01AG20132/AG/NIA NIH HHS/United States ; MOP38075/CAPMC/CIHR/Canada ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; *Aging ; Antigens, CD34/blood ; Child ; Child, Preschool ; Female ; Fetal Blood/cytology/metabolism ; Flow Cytometry ; Fluorescent Antibody Technique ; Granulocytes/metabolism ; Hematopoietic Stem Cells/*metabolism ; Humans ; Infant ; Infant, Newborn ; Leukocytes/*metabolism ; Male ; Middle Aged ; T-Lymphocytes/metabolism ; Telomere/*genetics ; Young Adult ; },
abstract = {OBJECTIVE: Little is known about the relationship of telomere length among leukocyte subsets and cells up the hematopoietic hierarchy. This information is relevant because telomere dynamics in granulocytes were postulated to mirror those of hematopoietic stem cells (HSCs).<br><br>MATERIALS AND METHODS: In newborn umbilical cord blood (UCB), we examined the relationships of telomere length in hematopoietic progenitor cells (HPCs) (CD34(+)CD45(-)) with those in T lymphocytes and granulocytes. In addition, we correlated telomere length in granulocytes with those in whole leukocyte samples of individuals ranging in age from birth to 100 years.<br><br>RESULTS: In the UCB, we found strong correlations of telomere length in HPCs with telomere length in T lymphocytes (r ranging from 0.882 to 0.935; p ranging from 0.0038 to 0.0007) and in granulocytes (r = 0.930; p = 0.0072). At birth, strong correlations were also observed between telomere length in granulocytes and those in all leukocytes (r = 0.979; p = 0.0003). Throughout the human lifespan, the relationship between telomere length in granulocytes and that in all leukocytes was r > 0.980 and p < 0.0001.<br><br>CONCLUSIONS: Robust synchrony exists among leukocyte subsets throughout the human lifespan; individuals with relatively long (or short) telomeres in one leukocyte subset have long (or short) telomeres in other leukocyte subsets. Moreover, telomere length in leukocytes reflects its length in cells up the hematopoietic hierarchy, i.e., HPCs and, by inference, HSCs. Strong links have been found by many studies between leukocyte telomere length and a host of aging-related diseases. Our findings suggest, therefore, that these links might be traced to telomere dynamics in HSCs.},
}
@article {pmid20600003,
year = {2010},
author = {Wellinger, RJ},
title = {When the caps fall off: responses to telomere uncapping in yeast.},
journal = {FEBS letters},
volume = {584},
number = {17},
pages = {3734-3740},
doi = {10.1016/j.febslet.2010.06.031},
pmid = {20600003},
issn = {1873-3468},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Cell Cycle/genetics ; Chromosomal Instability/genetics ; Chromosomes, Fungal/genetics ; DNA Damage/genetics ; DNA Repair/genetics ; Genomic Instability/genetics ; RNA Caps/*genetics ; Telomere/*genetics ; Yeasts/cytology/*genetics ; },
abstract = {Telomeres protect the ends of linear chromosomes from activities that cause sequence losses or challenge chromosome integrity. Furthermore, these ends must be hidden from detection by the DNA damage recognition and response pathways. In particular, they must not fuse with each other. These fundamental and very first functions attributed to telomeres are also summarized with the term 'chromosome capping'. However, telomeres can become uncapped and the foremost cellular responses to such events aim to restore genome stability in the most conservative fashion possible. I will provide an outline of cellular responses to uncapping in budding yeast and briefly discuss the reverse, namely avoidance mechanisms that prevent telomere formation at inappropriate places.},
}
@article {pmid20599933,
year = {2010},
author = {Hájek, M and Cvilink, V and Votruba, I and Holý, A and Mertlíková-Kaiserová, H},
title = {Distinct modulation of telomere length in two T-lymphoblastic leukemia cell lines by cytotoxic nucleoside phosphonates PMEG and PMEDAP.},
journal = {European journal of pharmacology},
volume = {643},
number = {1},
pages = {6-12},
doi = {10.1016/j.ejphar.2010.06.006},
pmid = {20599933},
issn = {1879-0712},
mesh = {Adenine/*analogs &amp; derivatives/pharmacology ; Antineoplastic Agents/*pharmacology ; Cell Culture Techniques ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Electrophoresis, Polyacrylamide Gel ; Guanine/*analogs &amp; derivatives/pharmacology ; Humans ; In Situ Hybridization, Fluorescence ; Organophosphorus Compounds/*pharmacology ; Proto-Oncogene Proteins c-myc/*biosynthesis ; RNA/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/antagonists &amp; inhibitors/*biosynthesis ; Telomere/*drug effects ; Time Factors ; },
abstract = {We have previously shown that PMEG diphosphate (PMEGpp) and PMEDAP diphosphate (PMEDAPpp) inhibit the enzymatic activity of human telomerase in a cell-free assay. Here, we investigated the ability of PMEG and PMEDAP to induce telomere shortening and telomerase inhibition at both transcriptional and activity level in T-lymphoblastic leukemia cells CCRF-CEM and MOLT-4. At defined time points (3days and 9weeks), the telomerase activity and relative levels of hTERT and c-myc mRNA were determined using real-time RT-PCR. Telomere length was measured by the flow-FISH method. Both PMEDAP and PMEG induced telomere shortening in CCRF-CEM cells after 9weeks of exposure by 50% and 20%, respectively, without major impairment of telomerase activity. The effect of the tested compounds on telomere length in MOLT-4 cells was the opposite, with telomere elongation by 50% and 40% after 9-week treatment with PMEDAP and PMEG, respectively. At this time point, telomerase activity in MOLT-4 cells appeared to be slightly higher than that of CCRF-CEM cells, nevertheless no correlation between telomerase activity and telomere length was found. Both compounds down-regulated the expression of hTERT and c-myc mRNA in CCRF-CEM and MOLT-4 cells at 72h in a concentration-dependent manner while prolonged exposure to PMEG or PMEDAP for 9weeks had weaker effects. In conclusion, PMEDAP and PMEG are able to modulate telomere length in leukemic cells and this effect is cell-type specific. It is neither due to direct telomerase inhibition nor impairment of hTERT expression and it is likely to be telomerase-independent.},
}
@article {pmid20597107,
year = {2010},
author = {Mirabello, L and Yu, K and Kraft, P and De Vivo, I and Hunter, DJ and Prescott, J and Wong, JY and Chatterjee, N and Hayes, RB and Savage, SA},
title = {The association of telomere length and genetic variation in telomere biology genes.},
journal = {Human mutation},
volume = {31},
number = {9},
pages = {1050-1058},
pmid = {20597107},
issn = {1098-1004},
support = {Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adult ; Aged ; False Positive Reactions ; Female ; *Genetic Association Studies ; Genetic Predisposition to Disease ; *Genetic Variation ; Humans ; Inheritance Patterns/genetics ; Male ; Middle Aged ; Models, Genetic ; Neoplasms/genetics ; Polymorphism, Single Nucleotide/genetics ; Signal Transduction/genetics ; Telomere/*genetics/*metabolism ; },
abstract = {Telomeres cap chromosome ends and are critical for genomic stability. Many telomere-associated proteins are important for telomere length maintenance. Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in genes encoding telomere-associated proteins (RTEL1 and TERT-CLPTM1) as markers of cancer risk. We conducted an association study of telomere length and 743 SNPs in 43 telomere biology genes. Telomere length in peripheral blood DNA was determined by Q-PCR in 3,646 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and Nurses' Health Study. We investigated associations by SNP, gene, and pathway (functional group). We found no associations between telomere length and SNPs in TERT-CLPTM1L or RTEL1. Telomere length was not significantly associated with specific functional groups. Thirteen SNPs from four genes (MEN1, MRE11A, RECQL5, and TNKS) were significantly associated with telomere length. The strongest findings were in MEN1 (gene-based P=0.006), menin, which associates with the telomerase promoter and may negatively regulate telomerase. This large association study did not find strong associations with telomere length. The combination of limited diversity and evolutionary conservation suggest that these genes may be under selective pressure. More work is needed to explore the role of genetic variants in telomere length regulation.},
}
@article {pmid20588252,
year = {2010},
author = {Rai, R and Zheng, H and He, H and Luo, Y and Multani, A and Carpenter, PB and Chang, S},
title = {The function of classical and alternative non-homologous end-joining pathways in the fusion of dysfunctional telomeres.},
journal = {The EMBO journal},
volume = {29},
number = {15},
pages = {2598-2610},
pmid = {20588252},
issn = {1460-2075},
support = {R01 AG028888/AG/NIA NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; R21 AI076747/AI/NIAID NIH HHS/United States ; 5R21-AI076747-01/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Antigens, Nuclear/metabolism ; Cells, Cultured ; Chromosomal Proteins, Non-Histone ; *DNA Repair ; DNA-Binding Proteins/deficiency/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/deficiency/genetics/metabolism ; Ku Autoantigen ; Mice ; Mice, Knockout ; Shelterin Complex ; *Telomere ; Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 2/metabolism ; Tumor Suppressor p53-Binding Protein 1 ; },
abstract = {Repair of DNA double-stranded breaks (DSBs) is crucial for the maintenance of genome stability. DSBs are repaired by either error prone non-homologous end-joining (NHEJ) or error-free homologous recombination. NHEJ precedes either by a classic, Lig4-dependent process (C-NHEJ) or an alternative, Lig4-independent one (A-NHEJ). Dysfunctional telomeres arising either through natural attrition due to telomerase deficiency or by removal of telomere-binding proteins are recognized as DSBs. In this report, we studied which end-joining pathways are required to join dysfunctional telomeres. In agreement with earlier studies, depletion of Trf2 resulted in end-to-end chromosome fusions mediated by the C-NHEJ pathway. In contrast, removal of Tpp1-Pot1a/b initiated robust chromosome fusions that are mediated by A-NHEJ. C-NHEJ is also dispensable for the fusion of naturally shortened telomeres. Our results reveal that telomeres engage distinct DNA repair pathways depending on how they are rendered dysfunctional, and that A-NHEJ is a major pathway to process dysfunctional telomeres.},
}
@article {pmid20580855,
year = {2010},
author = {Belloni, P and Latini, P and Palitti, F},
title = {Relationship between spontaneous or radiation-induced apoptosis and telomere shortening in G(0) human lymphocytes.},
journal = {Mutation research},
volume = {701},
number = {2},
pages = {118-122},
doi = {10.1016/j.mrgentox.2010.05.011},
pmid = {20580855},
issn = {0027-5107},
mesh = {Adult ; Apoptosis/*genetics/*radiation effects ; Cell Survival ; Cells, Cultured ; Female ; *Genes, p53 ; Humans ; Lymphocytes/*radiation effects ; Male ; Resting Phase, Cell Cycle ; Telomere/*radiation effects ; X-Rays ; },
abstract = {To examine the correlation between spontaneous or radiation-induced apoptosis and telomere shortening, G(0) human peripheral blood lymphocytes were irradiated with X-rays and analyzed for viability, apoptosis, and telomere length. Part of the lymphocytes was kept under liquid-holding conditions for 48 h, and then loaded onto Ficoll-Paque medium to separate apoptotic (high-density) from normal (normal-density) cells. Then all samples were examined for the same three end-points. To determine whether expression of p53 influences the telomere shortening associated with a spontaneous or radiation-induced apoptotic process, the lymphocytes were also analyzed for expression of p53 at 0 and 48 h recovery times (non-irradiated and irradiated samples) and after 2 weeks in liquid-holding conditions (non-irradiated sample). After 48 h in liquid-holding, the p53-dependent apoptotic lymphocytes in the irradiated cultures presented shortened telomeres. After a 2-week recovery time, non-irradiated cells showed a p53-dependent spontaneous apoptosis, but no telomere shortening. These results demonstrate that radiation-induced apoptosis correlates with shortened telomeres in G(0) human lymphocytes. Spontaneous and radiation-induced apoptosis are dependent on expression of p53. In contrast, p53 may not play an effective role in telomere shortening, because spontaneous apoptosis did not correlate with telomere shortening. As most tumours are compromised with respect to p53 function, our findings on the role of p53 in telomere shortening may prove critical for applying therapeutic modalities in the clinic, and may facilitate the design of agents that selectively disrupt telomere integrity in tumour cells.},
}
@article {pmid20580716,
year = {2010},
author = {Eckert-Boulet, N and Lisby, M},
title = {Regulation of homologous recombination at telomeres in budding yeast.},
journal = {FEBS letters},
volume = {584},
number = {17},
pages = {3696-3702},
doi = {10.1016/j.febslet.2010.05.037},
pmid = {20580716},
issn = {1873-3468},
mesh = {Cell Cycle Proteins/genetics/metabolism ; Chromosomes, Fungal/genetics ; Conserved Sequence ; DNA Damage/genetics ; DNA Repair/genetics ; DNA, Fungal/genetics ; DNA-Directed DNA Polymerase/metabolism ; Expressed Sequence Tags/metabolism ; *Recombination, Genetic ; Saccharomycetales/*genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Homologous recombination is suppressed at normal length telomere sequences. In contrast, telomere recombination is allowed when telomeres erode in the absence of telomerase activity or as a consequence of nucleolytic degradation or incomplete replication. Here, we review the mechanisms that contribute to regulating mitotic homologous recombination at telomeres and the role of these mechanisms in signalling short telomeres in the budding yeast Saccharomyces cerevisiae.},
}
@article {pmid20580356,
year = {2010},
author = {Watson, JM and Riha, K},
title = {Comparative biology of telomeres: where plants stand.},
journal = {FEBS letters},
volume = {584},
number = {17},
pages = {3752-3759},
pmid = {20580356},
issn = {1873-3468},
support = {Y 418/FWF_/Austrian Science Fund FWF/Austria ; },
mesh = {Animals ; Base Sequence ; Caenorhabditis elegans/genetics ; DNA/genetics ; DNA, Plant/genetics ; Diptera/genetics/physiology ; Genes, Essential ; Models, Molecular ; *Plant Physiological Phenomena ; Plant Proteins/genetics/metabolism ; Plants/enzymology/*genetics ; Protein Conformation ; Telomerase/genetics/metabolism ; Telomere/*genetics ; Telomeric Repeat Binding Protein 1/chemistry/genetics/metabolism ; },
abstract = {Telomeres are essential structures at the ends of eukaryotic chromosomes. Work on their structure and function began almost 70 years ago in plants and flies, continued through the Nobel Prize winning work on yeast and ciliates, and goes on today in many model and non-model organisms. The basic molecular mechanisms of telomeres are highly conserved throughout evolution, and our current understanding of how telomeres function is a conglomeration of insights gained from many different species. This review will compare the current knowledge of telomeres in plants with other organisms, with special focus on the functional length of telomeric DNA, the search for TRF homologs, the family of POT1 proteins, and the recent discovery of members of the CST complex.},
}
@article {pmid20579263,
year = {2010},
author = {De Vos, WH and Joss, GH and Haffmans, W and Hoebe, RA and Manders, EM and Van Oostveldt, P},
title = {Four-dimensional telomere analysis in recordings of living human cells acquired with controlled light exposure microscopy.},
journal = {Journal of microscopy},
volume = {238},
number = {3},
pages = {254-264},
doi = {10.1111/j.1365-2818.2009.03350.x},
pmid = {20579263},
issn = {1365-2818},
mesh = {Cell Line, Tumor ; Cell Nucleus/*chemistry ; Chromosomes, Human/*ultrastructure ; Endothelial Cells/chemistry ; Humans ; Imaging, Three-Dimensional/*methods ; Microscopy, Video/*methods ; Telomere/*ultrastructure ; },
abstract = {Telomeres are the complex end structures that confer functional integrity and positional stability to human chromosomes. Telomere research has long been dominated by length measurements and biochemical analyses. Recently, interest has shifted towards the role of their three-dimensional organization and dynamics within the nuclear volume. In the mammalian interphase nucleus, there is increasing evidence for a telomeric configuration that is non-random and is cell cycle and cell type dependent. This has functional implications for genome stability. Objective and reproducible representation of the spatiotemporal organization of telomeres, under different experimental conditions, requires quantification by reliable automated image processing techniques. In this paper, we describe methods for quantitative telomere analysis in cell nuclei of living human cells expressing telomere-binding fusion proteins. We present a toolbox for determining telomere positions within the nucleus with subresolution accuracy and tracking telomeres in 4D controlled light exposure microscopy (CLEM) recordings. The use of CLEM allowed for durable imaging and thereby improved segmentation performance considerably. With minor modifications, the underlying algorithms can be expanded to the analysis of other intranuclear features, such as nuclear bodies or DNA double stranded break foci.},
}
@article {pmid20579170,
year = {2010},
author = {Risques, RA and Arbeev, KG and Yashin, AI and Ukraintseva, SV and Martin, GM and Rabinovitch, PS and Oshima, J},
title = {Leukocyte telomere length is associated with disability in older u.s. Population.},
journal = {Journal of the American Geriatrics Society},
volume = {58},
number = {7},
pages = {1289-1298},
pmid = {20579170},
issn = {1532-5415},
support = {R24 CA078088-13/CA/NCI NIH HHS/United States ; P01AG008761/AG/NIA NIH HHS/United States ; R24 CA078088/CA/NCI NIH HHS/United States ; R01AG028259/AG/NIA NIH HHS/United States ; R01AG030612/AG/NIA NIH HHS/United States ; P01 AG008761/AG/NIA NIH HHS/United States ; R01 AG030612/AG/NIA NIH HHS/United States ; P30 AG013280/AG/NIA NIH HHS/United States ; R01 AG028259/AG/NIA NIH HHS/United States ; P30 AG013280-10/AG/NIA NIH HHS/United States ; R24CA78088/CA/NCI NIH HHS/United States ; P01 AG001751/AG/NIA NIH HHS/United States ; P30AG13280/AG/NIA NIH HHS/United States ; },
mesh = {*Activities of Daily Living ; Age Factors ; Aged ; Aged, 80 and over ; Biomarkers/blood ; Cross-Sectional Studies ; Disability Evaluation ; Female ; Geriatric Assessment ; Humans ; Leukocytes/*physiology ; Male ; Predictive Value of Tests ; Retrospective Studies ; Sex Factors ; Socioeconomic Factors ; Telomere/*genetics ; },
abstract = {OBJECTIVES: To determine whether mean leukocyte telomere length (LTL) serves as a biomarker of disability assessed according to activities of daily living (ADLs) and what factors may modify this relationship.<br><br>DESIGN: Retrospective cross-sectional study.<br><br>SETTING: A subset of the National Long Term Care Survey (NTLCS), a Medicare-based U.S. population longitudinal study focused on trends of overall health and functional status in older adults.<br><br>PARTICIPANTS: Six hundred and twenty-four individuals from the 1999 wave of the NTLCS cohort.<br><br>MEASUREMENTS: Relative LTL determined according to quantitative polymerase chain reaction. LTL has previously been shown to correlate with common age-related disorders and mortality, as well as with socioeconomic status.<br><br>RESULTS: A sex difference in LTL was observed but not age-dependent shortening or association with socioeconomic status. LTL was associated with disability and functional status assessed according to ADLs. The association between ADLs and LTL was stronger in subjects without diabetes mellitus, whereas associations were not seen when only subjects with diabetes mellitus were analyzed. Associations between LTL and cardiovascular disease (CVD) and cancer were also present in the group without diabetes mellitus but not in the group with diabetes mellitus.<br><br>CONCLUSION: These findings support the concept that LTL is a biomarker of overall well-being that is predictive of disability of older individuals in the U.S. population. Diabetes mellitus plays an important role as a modifier of the association between LTL and disability, CVD, and cancer. These associations have clinical implications because of the potential predictive value of LTL and deserve further investigation.},
}
@article {pmid20578200,
year = {2010},
author = {Rossi, D and Bodoni, CL and Zucchetto, A and Rasi, S and De Paoli, L and Fangazio, M and Rossi, FM and Ladetto, M and Gattei, V and Gaidano, G},
title = {Low CD49d expression and long telomere identify a chronic lymphocytic leukemia subset with highly favourable outcome.},
journal = {American journal of hematology},
volume = {85},
number = {8},
pages = {619-622},
doi = {10.1002/ajh.21756},
pmid = {20578200},
issn = {1096-8652},
mesh = {Aged ; Biomarkers ; Biomarkers, Tumor ; Chromosome Aberrations ; Disease-Free Survival ; Female ; Follow-Up Studies ; Gene Rearrangement, B-Lymphocyte, Heavy Chain ; Genes, p53 ; Genomic Instability ; Humans ; Integrin alpha4/*analysis/biosynthesis ; Leukemia, Lymphocytic, Chronic, B-Cell/blood/*genetics/mortality ; Male ; Middle Aged ; Prognosis ; Proportional Hazards Models ; Telomere/*ultrastructure ; ZAP-70 Protein-Tyrosine Kinase/blood ; },
}
@article {pmid20577265,
year = {2010},
author = {Nalapareddy, K and Choudhury, AR and Gompf, A and Ju, Z and Ravipati, S and Leucht, T and Lechel, A and Rudolph, KL},
title = {CHK2-independent induction of telomere dysfunction checkpoints in stem and progenitor cells.},
journal = {EMBO reports},
volume = {11},
number = {8},
pages = {619-625},
pmid = {20577265},
issn = {1469-3178},
mesh = {Animals ; Cell Cycle/physiology ; Cellular Senescence/physiology ; Checkpoint Kinase 2 ; DNA Damage ; Fibroblasts/cytology/physiology ; Humans ; Intestinal Mucosa/metabolism ; Intestines/cytology ; Mice ; Mice, Knockout ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Stem Cells/cytology/*physiology ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {Telomere shortening limits the proliferation of primary human fibroblasts by the induction of senescence, which is mediated by ataxia telangiectasia mutated-dependent activation of p53. Here, we show that CHK2 deletion impairs the induction of senescence in mouse and human fibroblasts. By contrast, CHK2 deletion did not improve the stem-cell function, organ maintenance and lifespan of telomere dysfunctional mice and did not prevent the induction of p53/p21, apoptosis and cell-cycle arrest in telomere dysfunctional progenitor cells. Together, these results indicate that CHK2 mediates the induction of senescence in fibroblasts, but is dispensable for the induction of telomere dysfunction checkpoints at the stem and progenitor cell level in vivo.},
}
@article {pmid20573647,
year = {2010},
author = {Turner, S and Wong, HP and Rai, J and Hartshorne, GM},
title = {Telomere lengths in human oocytes, cleavage stage embryos and blastocysts.},
journal = {Molecular human reproduction},
volume = {16},
number = {9},
pages = {685-694},
pmid = {20573647},
issn = {1460-2407},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Blastocyst/*metabolism ; Cleavage Stage, Ovum/*metabolism ; Embryo Culture Techniques ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Microscopy, Fluorescence ; Oocytes/*metabolism ; Signal Processing, Computer-Assisted ; Telomere/*metabolism/ultrastructure ; },
abstract = {Telomeres are repeated sequences that protect the ends of chromosomes and harbour DNA repair proteins. Telomeres shorten during each cell division in the absence of telomerase. When telomere length becomes critically short, cell senescence occurs. Telomere length therefore reflects both cellular ageing and capacity for division. We have measured telomere length in human germinal vesicle (GV) oocytes and preimplantation embryos, by quantitative fluorescence in situ hybridization (Q-FISH), providing baseline data towards our hypothesis that telomere length is a marker of embryo quality. The numbers of fluorescent foci suggest that extensive clustering of telomeres occurs in mature GV stage oocytes, and in preimplantation embryos. When calculating average telomere length by assuming that each signal presents one telomere, the calculated telomere length decreased from the oocyte to the cleavage stages, and increased between the cleavage stages and the blastocyst (11.12 versus 8.43 versus 12.22 kb, respectively, P < 0.001). Other methods of calculation, based upon expected maximum and minimum numbers of telomeres, confirm that telomere length in blastocysts is significantly longer than cleavage stages. Individual blastomeres within an embryo showed substantial variation in calculated average telomere length. This study implies that telomere length changes according to the stage of preimplantation embryo development.},
}
@article {pmid20570912,
year = {2010},
author = {Pooley, KA and Tyrer, J and Shah, M and Driver, KE and Leyland, J and Brown, J and Audley, T and McGuffog, L and Ponder, BA and Pharoah, PD and Easton, DF and Dunning, AM},
title = {No association between TERT-CLPTM1L single nucleotide polymorphism rs401681 and mean telomere length or cancer risk.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {19},
number = {7},
pages = {1862-1865},
pmid = {20570912},
issn = {1538-7755},
support = {10124/CRUK_/Cancer Research UK/United Kingdom ; 11021/CRUK_/Cancer Research UK/United Kingdom ; A10119/CRUK_/Cancer Research UK/United Kingdom ; A10123/CRUK_/Cancer Research UK/United Kingdom ; 10118/CRUK_/Cancer Research UK/United Kingdom ; 11022/CRUK_/Cancer Research UK/United Kingdom ; A10124/CRUK_/Cancer Research UK/United Kingdom ; 19275/CRUK_/Cancer Research UK/United Kingdom ; A9540/CRUK_/Cancer Research UK/United Kingdom ; 10119/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; Breast Neoplasms/enzymology/genetics ; Case-Control Studies ; Colorectal Neoplasms/enzymology/genetics ; Female ; Genetic Predisposition to Disease ; Genetic Variation ; Humans ; Male ; Melanoma/enzymology/genetics ; Membrane Proteins/*genetics ; Middle Aged ; Neoplasm Proteins/*genetics ; Neoplasms/enzymology/*genetics ; Polymorphism, Single Nucleotide ; Risk Factors ; Telomerase/*genetics ; Telomere/chemistry/*genetics/pathology ; Young Adult ; },
abstract = {BACKGROUND: A recent study reported genetic variants in the TERT-CLPTM1L locus that were associated with mean telomere length, and with risk of multiple cancers.<br><br>METHODS: We evaluated the association between single nucleotide polymorphism (SNP) rs401681 (C > T) and mean telomere length, using quantitative real-time PCR, in blood-extracted DNA collected from 11,314 cancer-free participants from the Sisters in Breast Screening study, the Melanoma and Pigmented Lesions Evaluative Study melanoma family study, and the SEARCH Breast, Colorectal, Melanoma studies. We also examined the relationship between rs401618 genotype and susceptibility to breast cancer (6,800 cases and 6,608 controls), colorectal cancer (2,259 cases and 2,181 controls), and melanoma (787 cases and 999 controls).<br><br>RESULTS: The "per T allele" change in mean telomere length (DeltaCt), adjusted for age, study plate, gender, and family was 0.001 [95% confidence intervals (CI), 0.01-0.02; P trend = 0.61]. The "per T allele" odds ratio for each cancer was 1.01 for breast cancer (95% CI, 0.96-1.06; P trend = 0.64), 1.02 for colorectal cancer (95% CI, 0.94-1.11; P trend = 0.66), and 0.99 for melanoma (95% CI, 0.84-1.15; P trend = 0.87).<br><br>CONCLUSIONS: We found no evidence that this SNP was associated with mean telomere length, or with risk of breast cancer, colorectal cancer, or melanoma.<br><br>IMPACT: Our results indicate that the observed associations between rs401681 and several cancer types might be weaker than previously described. The lack of an association in our study between this SNP and mean telomere length suggests that any association with cancer risk at this locus is not mediated through TERT.},
}
@article {pmid20569234,
year = {2010},
author = {Wheaton, K and Muir, J and Ma, W and Benchimol, S},
title = {BTG2 antagonizes Pin1 in response to mitogens and telomere disruption during replicative senescence.},
journal = {Aging cell},
volume = {9},
number = {5},
pages = {747-760},
doi = {10.1111/j.1474-9726.2010.00601.x},
pmid = {20569234},
issn = {1474-9726},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Cell Proliferation ; Cells, Cultured ; *Cellular Senescence ; Fibroblasts/cytology/metabolism ; Humans ; Immediate-Early Proteins/genetics/*metabolism ; Mitogens/*metabolism ; NIMA-Interacting Peptidylprolyl Isomerase ; Peptidylprolyl Isomerase/*metabolism ; Signal Transduction ; Telomere/*metabolism ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins/genetics/*metabolism ; },
abstract = {Cellular senescence limits the replicative capacity of normal cells and acts as an intrinsic barrier that protects against the development of cancer. Telomere shortening-induced replicative senescence is dependent on the ATM-p53-p21 pathway but additional genes likely contribute to senescence. Here, we show that the p53-responsive gene BTG2 plays an essential role in replicative senescence. Similar to p53 and p21 depletion, BTG2 depletion in human fibroblasts leads to an extension of cellular lifespan, and ectopic BTG2 induces senescence independently of p53. The anti-proliferative function of BTG2 during senescence involves its stabilization in response to telomere dysfunction followed by serum-dependent binding and relocalization of the cell cycle regulator prolyl isomerase Pin1. Pin1 inhibition leads to senescence in late-passage cells, and ectopic Pin1 expression rescues cells from BTG2-induced senescence. The neutralization of Pin1 by BTG2 provides a critical mechanism to maintain senescent arrest in the presence of mitogenic signals in normal primary fibroblasts.},
}
@article {pmid20564052,
year = {2010},
author = {Sagi, J and Renciuk, D and Tomasko, M and Vorlícková, M},
title = {Quadruplexes of human telomere DNA analogs designed to contain G:A:G:A, G:G:A:A, and A:A:A:A tetrads.},
journal = {Biopolymers},
volume = {93},
number = {10},
pages = {880-886},
doi = {10.1002/bip.21481},
pmid = {20564052},
issn = {0006-3525},
mesh = {Base Sequence ; Circular Dichroism ; DNA/*chemistry/*genetics ; Dimethyl Sulfoxide/metabolism ; Electrophoresis, Polyacrylamide Gel ; *G-Quadruplexes ; Humans ; Molecular Sequence Data ; Nucleic Acid Denaturation ; Potassium ; Sodium ; Solutions ; Telomere/*chemistry/*genetics ; Temperature ; },
abstract = {Replacement of two to four guanines by adenines in the human telomere DNA repeat dG3(TTAG3)3 did not hinder the formation of quadruplexes if the substitutions took place in the terminal tetrad bridged by the diagonal loop of the intramolecular antiparallel three-tetrad scaffold, as proved by CD and PAGE in both Na+ and K+ solutions. Thermodynamic data showed that, in Na+ solution, the dG3(TTAG3)3 quadruplex was destabilized, the least by the two G:A:G:A tetrads, the most by the G:G:A:A tetrad in which the adenosines replaced syn-guanosines. In physiological K+ solution, the highest destabilization was caused by the 4A tetrad. In K+, only the unmodified dG3(TTAG3)3 quadruplex rearranged into a K+-dependent quadruplex form, none of the multiple adenine-modified structures did so. This may imply biological consequences for nonrepaired A-for-G mutations.},
}
@article {pmid20561403,
year = {2010},
author = {Hou, YQ and Xu, W and Miao, KR and Qiao, C and Zhu, HY and Zhu, DX and Zhuang, Y and Wu, YJ and Wang, JN and Li, JY},
title = {[Prognostic significance of telomere length in patients with chronic lymphocytic leukemia].},
journal = {Zhongguo shi yan xue ye xue za zhi},
volume = {18},
number = {3},
pages = {570-574},
pmid = {20561403},
issn = {1009-2137},
mesh = {ADP-ribosyl Cyclase 1/metabolism ; Adult ; Aged ; Aged, 80 and over ; Case-Control Studies ; Female ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics/*metabolism ; Male ; Middle Aged ; Mutation ; Prognosis ; Telomere/chemistry/*genetics/*metabolism ; ZAP-70 Protein-Tyrosine Kinase/metabolism ; },
abstract = {This study was aimed to explore the prognostic significance of telomere length in patients with chronic lymphocytic leukemia (CLL) and to analyze relation of telomere length with Binet stage, IgVH mutation status, CD38, ZAP-70 expression as well as other clinical features. 35 CLL patients who contained 80% or more tumor cells in the peripheral blood or bone marrow samples were selected as objects studied, while 13 healthy donors were served as normal controls. The telomere relative length was detected by using a real-time fluorescent quantitative polymerase chain reaction method (qPCR); the expression of CD38 and ZAP-70 protein were detected by flow cytometry, the IgVH mutation was detected by multiplex PCR. The results showed that the mean telomere relative length in CLL patients and normal controls were 0.384 and 0.443 respectively, but the difference between them was not significant (p > 0.05). The telomere length was significantly correlated with Binet stages and IgVH mutation status. Patients in Binet stage B and C showed significantly shorter telomeres than those in Binet stage A (p = 0.001). Mean telomere relative lengths in patients without IgVH mutation were shorter than those in patients with IgVH mutation (p = 0.015). No relation of telomere length with sex, age, ZAP-70 protein and CD38 were found (p > 0.05). It is concluded that telomere length may have a prognostic significance for CLL patients. Combining telomere length and IgVH mutation status may achieve a better prognostic subclassification for CLL patients.},
}
@article {pmid20560902,
year = {2010},
author = {Song, Z and von Figura, G and Liu, Y and Kraus, JM and Torrice, C and Dillon, P and Rudolph-Watabe, M and Ju, Z and Kestler, HA and Sanoff, H and Lenhard Rudolph, K},
title = {Lifestyle impacts on the aging-associated expression of biomarkers of DNA damage and telomere dysfunction in human blood.},
journal = {Aging cell},
volume = {9},
number = {4},
pages = {607-615},
pmid = {20560902},
issn = {1474-9726},
support = {R01 AG024379/AG/NIA NIH HHS/United States ; R01 AG024379-06/AG/NIA NIH HHS/United States ; AG024379/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*blood ; Biomarkers/*blood ; Body Mass Index ; Cellular Senescence ; *DNA Damage ; Exercise ; Humans ; *Life Style ; Regression Analysis ; Smoking/blood ; T-Lymphocytes/metabolism ; Telomere/*metabolism ; },
abstract = {Cellular aging is characterized by telomere shortening, which can lead to uncapping of chromosome ends (telomere dysfunction) and activation of DNA damage responses. There is some evidence that DNA damage accumulates during human aging and that lifestyle factors contribute to the accumulation of DNA damage. Recent studies have identified a set of serum markers that are induced by telomere dysfunction and DNA damage, and these markers showed an increased expression in blood during human aging. Here, we investigated the influence of lifestyle factors (such as exercise, smoking, body mass) on the aging-associated expression of serum markers of DNA damage (CRAMP, EF-1alpha, stathmin, n-acetyl-glucosaminidase and chitinase) in comparison with other described markers of cellular aging (p16(INK4a) upregulation and telomere shortening) in human peripheral blood. The study shows that lifestyle factors have an age-independent impact on the expression level of biomarkers of DNA damage. Smoking and increased body mass indices were associated with elevated levels of biomarkers of DNA damage independent of the age of the individuals. In contrast, exercise was associated with an age-independent reduction in the expression of biomarkers of DNA damage in human blood. The expression of biomarkers of DNA damage correlated positively with p16(INK4a) expression and negatively with telomere length in peripheral blood T-lymphocytes. Together, these data provide experimental evidence that both aging and lifestyle impact on the accumulation of DNA damage during human aging.},
}
@article {pmid20560346,
year = {2010},
author = {Yang, Y and Zhong, L and Tian, X and Cheng, Q and Chen, Z and Qin, Z},
title = {[Cloning and identification of telomere and internal origin of the endophytic Streptomyces linear plasmid pYY8L from Allium fistulosum].},
journal = {Wei sheng wu xue bao = Acta microbiologica Sinica},
volume = {50},
number = {4},
pages = {452-458},
pmid = {20560346},
issn = {0001-6209},
mesh = {Allium/*genetics ; Cloning, Molecular ; Conjugation, Genetic/*genetics ; DNA, Bacterial/analysis/genetics ; Molecular Sequence Data ; Plasmids/*genetics ; Replication Origin/*genetics ; Streptomyces/*genetics ; Telomere/*genetics/metabolism ; },
abstract = {UNLABELLED: Strain 36R-2-1B was isolated from Allium fistulosum and identified as Streptomyces spp., harboring an approximate 280 kb linear plasmid designated pYY8L.<br><br>OBJECTIVE: Cloning, sequencing and analysis of telomere and internal replication origin of pYY8L.<br><br>METHODS: pYY8L telomere was cloned by a modified procedure--"alkaline treatment and enzyme digestion in gel". The internal replication origin of pYY8L was cloned by construction of a cosmid library and then subcloning.<br><br>RESULTS: An approximate 280 kb DNA band (pYY8L) of strain 36R-2-1B was detected by pulsed-field gel electrophoresis. The 152-bp telomere, containing six small palindromes and potentially forming complicated secondary structure, was cloned and sequenced. The replication origin of pYY8L was initially cloned on a cosmid and then sub-cloned as a 4891-bp autonomous replication sequence. This sequence was predicted to contain six genes, two of them resembling replication genes of Streptomyces linear plasmid SCP1, but their adjacent iterons were different.<br><br>CONCLUSION: New telomere and internal replication origin of Streptomyces linear plasmid pYY8L were cloned and identified. This is the first example of report on telomere and replication genes of linear plasmid from endophytic Streptomyces.},
}
@article {pmid20553906,
year = {2010},
author = {Sheng, R and Gu, ZL and Xie, ML and Zhou, WX and Guo, CY},
title = {Epigallocatechin gallate protects H9c2 cardiomyoblasts against hydrogen dioxides- induced apoptosis and telomere attrition.},
journal = {European journal of pharmacology},
volume = {641},
number = {2-3},
pages = {199-206},
doi = {10.1016/j.ejphar.2010.05.054},
pmid = {20553906},
issn = {1879-0712},
mesh = {Animals ; Antioxidants/metabolism/pharmacology ; Apoptosis/*drug effects ; Cardiotonic Agents/*pharmacology ; Catechin/*analogs &amp; derivatives/pharmacology ; Cell Line ; Cells, Cultured ; DNA Fragmentation/drug effects ; Dose-Response Relationship, Drug ; Embryo, Mammalian ; Flavonoids/chemistry ; Hydrogen Peroxide/metabolism/*pharmacology ; Myoblasts, Cardiac/*cytology/metabolism/ultrastructure ; Myocytes, Cardiac/*drug effects/metabolism ; Oxidative Stress/drug effects ; Phenols/chemistry ; Polyphenols ; Rats ; Signal Transduction/drug effects ; Telomere/*metabolism ; Time Factors ; },
abstract = {Epigallocatechin gallate (EGCG), the major component of polyphenols in green tea, has recently attracted considerable attention for its cardioprotective effects. Telomere signalling plays a role in regulating cardiomyocyte apoptosis during cardiac dysfunction. The purpose of this study was to investigate the effects of EGCG on oxidative stress-induced apoptosis and telomere attrition in cardiomyocytes. H9c2 cells were incubated with EGCG, 50 and 100 mg/l, for 24 h. Apoptosis induced by 200 micromol/l hydrogen dioxide (H(2)O(2)) was analyzed by DAPI nuclear staining, electron microscopy, electrophoresis of DNA fragments and flow cytometry. When H9c2 cells were incubated with H(2)O(2) for 12-24 h, the intracellular and extracellular H(2)O(2) concentrations were not affected by the presence of EGCG. Chromatin condensation, DNA fragmentation and apoptotic body formation were observed in H(2)O(2)-induced injury. Flow cytometry analysis showed that the apoptotic rate increased remarkably. EGCG significantly inhibited H(2)O(2)-induced apoptotic morphological changes and apoptotic rate. When H9c2 cells were incubated with H(2)O(2), the telomere length shortened and the protein expression of telomere repeat-binding factor 2 (TRF(2)) decreased gradually, while the protein levels of p53 and p21 increased. EGCG significantly inhibited telomere attrition, TRF(2) loss and p53, p21 upregulation induced by H(2)O(2). These results suggested that EGCG might suppress oxidative stress-induced cardiomyocyte apoptosis through inhibiting telomere dependent apoptotic pathway.},
}
@article {pmid20551906,
year = {2010},
author = {Lam, YC and Akhter, S and Gu, P and Ye, J and Poulet, A and Giraud-Panis, MJ and Bailey, SM and Gilson, E and Legerski, RJ and Chang, S},
title = {SNMIB/Apollo protects leading-strand telomeres against NHEJ-mediated repair.},
journal = {The EMBO journal},
volume = {29},
number = {13},
pages = {2230-2241},
pmid = {20551906},
issn = {1460-2075},
support = {R01 AG028888/AG/NIA NIH HHS/United States ; R01 CA052461/CA/NCI NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; CA05246/CA/NCI NIH HHS/United States ; },
mesh = {Aminopeptidases/metabolism ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/metabolism ; Chromosomes/metabolism ; DNA Damage ; *DNA Repair ; DNA-Binding Proteins/metabolism ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism ; Embryo, Mammalian/cytology ; Exodeoxyribonucleases ; Fibroblasts/*metabolism ; Mice ; Mice, Knockout ; Protein Serine-Threonine Kinases/metabolism ; Serine Proteases/metabolism ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Tripeptidyl-Peptidase 1 ; Tumor Suppressor Proteins/metabolism ; },
abstract = {Progressive telomere attrition or deficiency of the protective shelterin complex elicits a DNA damage response as a result of a cell's inability to distinguish dysfunctional telomeric ends from DNA double-strand breaks. SNMIB/Apollo is a shelterin-associated protein and a member of the SMN1/PSO2 nuclease family that localizes to telomeres through its interaction with TRF2. Here, we generated SNMIB/Apollo knockout mouse embryo fibroblasts (MEFs) to probe the function of SNMIB/Apollo at mammalian telomeres. SNMIB/Apollo null MEFs exhibit an increased incidence of G2 chromatid-type fusions involving telomeres created by leading-strand DNA synthesis, reflective of a failure to protect these telomeres after DNA replication. Mutations within SNMIB/Apollo's conserved nuclease domain failed to suppress this phenotype, suggesting that its nuclease activity is required to protect leading-strand telomeres. SNMIB/Apollo(-/-)ATM(-/-) MEFs display robust telomere fusions when Trf2 is depleted, indicating that ATM is dispensable for repair of uncapped telomeres in this setting. Our data implicate the 5'-3' exonuclease function of SNM1B/Apollo in the generation of 3' single-stranded overhangs at newly replicated leading-strand telomeres to protect them from engaging the non-homologous end-joining pathway.},
}
@article {pmid20551483,
year = {2010},
author = {Saharia, A and Teasley, DC and Duxin, JP and Dao, B and Chiappinelli, KB and Stewart, SA},
title = {FEN1 ensures telomere stability by facilitating replication fork re-initiation.},
journal = {The Journal of biological chemistry},
volume = {285},
number = {35},
pages = {27057-27066},
pmid = {20551483},
issn = {1083-351X},
support = {T32 GM007067/GM/NIGMS NIH HHS/United States ; T32 GM007067-35/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle/physiology ; DNA/genetics/*metabolism ; DNA Replication/*physiology ; Flap Endonucleases/genetics/*metabolism ; HeLa Cells ; Humans ; RecQ Helicases/genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres are terminal repetitive DNA sequences whose stability requires the coordinated actions of telomere-binding proteins and the DNA replication and repair machinery. Recently, we demonstrated that the DNA replication and repair protein Flap endonuclease 1 (FEN1) is required for replication of lagging strand telomeres. Here, we demonstrate for the first time that FEN1 is required for efficient re-initiation of stalled replication forks. At the telomere, we find that FEN1 depletion results in replicative stress as evidenced by fragile telomere expression and sister telomere loss. We show that FEN1 participation in Okazaki fragment processing is not required for efficient telomere replication. Instead we find that FEN1 gap endonuclease activity, which processes DNA structures resembling stalled replication forks, and the FEN1 interaction with the RecQ helicases are vital for telomere stability. Finally, we find that FEN1 depletion neither impacts cell cycle progression nor in vitro DNA replication through non-telomeric sequences. Our finding that FEN1 is required for efficient replication fork re-initiation strongly suggests that the fragile telomere expression and sister telomere losses observed upon FEN1 depletion are the direct result of replication fork collapse. Together, these findings suggest that other nucleases compensate for FEN1 loss throughout the genome during DNA replication but fail to do so at the telomere. We propose that FEN1 maintains stable telomeres by facilitating replication through the G-rich lagging strand telomere, thereby ensuring high fidelity telomere replication.},
}
@article {pmid20549820,
year = {2010},
author = {Prescott, J and McGrath, M and Lee, IM and Buring, JE and De Vivo, I},
title = {Telomere length and genetic analyses in population-based studies of endometrial cancer risk.},
journal = {Cancer},
volume = {116},
number = {18},
pages = {4275-4282},
pmid = {20549820},
issn = {0008-543X},
support = {CA082838/CA/NCI NIH HHS/United States ; R01 HL043851/HL/NHLBI NIH HHS/United States ; CA49449/CA/NCI NIH HHS/United States ; R01 CA047988-20/CA/NCI NIH HHS/United States ; R03 CA121362/CA/NCI NIH HHS/United States ; R01 CA082838/CA/NCI NIH HHS/United States ; CA047988/CA/NCI NIH HHS/United States ; CA121362/CA/NCI NIH HHS/United States ; R01 CA047988/CA/NCI NIH HHS/United States ; CA132190/CA/NCI NIH HHS/United States ; R01 HL043851-10/HL/NHLBI NIH HHS/United States ; R03 CA132190/CA/NCI NIH HHS/United States ; K12HD051959-01/HD/NICHD NIH HHS/United States ; T32 CA009001/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; 5T32CA09001/CA/NCI NIH HHS/United States ; K12 HD051959/HD/NICHD NIH HHS/United States ; U01 CA049449/CA/NCI NIH HHS/United States ; },
mesh = {Case-Control Studies ; Endometrial Neoplasms/*genetics ; Female ; *Genetic Predisposition to Disease ; Humans ; Middle Aged ; Polymorphism, Single Nucleotide ; Population Surveillance ; Risk ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Telomeres are protective structures at the ends of linear chromosomes, regulated by a host of associated proteins. When telomeres become dysfunctional, genomic instability ensues. The vast majority of cells undergo apoptosis, although a rare cell may survive and become tumorigenic.<br><br>METHODS: The authors used conditional logistic regression to examine relative telomere length in peripheral blood leukocytes, genetic variants at telomere maintenance gene loci (TERT, TNKS2, POT1, TERF1, TERF2), and endometrial cancer risk in case-control studies nested within the Nurses' Health Study and the Women's Health Study.<br><br>RESULTS: Relative telomere length was significantly inversely correlated with body mass index and weight gain since age 18 years. The authors did not observe a relationship between relative telomere length and endometrial cancer risk. Women in the shortest quartile had a multivariate-adjusted odds ratio (OR) of 1.20 (95% confidence interval [95% CI], 0.73-1.96; P for trend = .37) compared with women in the longest quartile. The authors found an elevation in endometrial cancer risk among women carrying at least 1 minor allele of RS2736122 (TERT; OR, 1.18; 95% CI, 1.01-1.38) or RS12412538 (TNKS2; OR, 1.16; 95% CI, 1.00-1.34).<br><br>CONCLUSIONS: Relative telomere length was not associated with endometrial cancer risk. Other aspects of telomere maintenance remain to be explored.},
}
@article {pmid20549676,
year = {2012},
author = {Dolcetti, R and De Rossi, A},
title = {Telomere/telomerase interplay in virus-driven and virus-independent lymphomagenesis: pathogenic and clinical implications.},
journal = {Medicinal research reviews},
volume = {32},
number = {2},
pages = {233-253},
doi = {10.1002/med.20211},
pmid = {20549676},
issn = {1098-1128},
mesh = {B-Lymphocytes/enzymology ; Cell Transformation, Neoplastic/genetics ; Humans ; Leukemia-Lymphoma, Adult T-Cell/virology ; Lymphoma/*etiology/virology ; T-Lymphocytes/enzymology ; Telomerase/antagonists &amp; inhibitors/biosynthesis/*physiology ; Telomere/*physiology ; Telomere Shortening ; },
abstract = {Telomerase is a ribonucleoprotein complex critically involved in extending and maintaining telomeres. Unlike the majority of somatic cells, in which hTERT and telomerase activity are generally silent, normal lymphocytes show transient physiological hTERT expression and telomerase activity according to their differentiation/activation status. During lymphomagenesis, induction of persistent telomerase expression and activity may occur before or after telomere shortening, as a consequence of the different mechanisms through which transforming factors/agents may activate telomerase. Available data indicate that the timing of telomerase activation may allow the distinction of two different lymphomagenetic models: (i) an early activation of telomerase via exogenous regulators of hTERT, along with an increased lymphocyte growth and a subsequent selection of cells with increased transforming potential may characterize several virus-related lymphoid malignancies; (ii) a progressive shortening of telomeres, leading to genetic instability which favors a subsequent activation of telomerase via endogenous regulators may occur in most virus-unrelated lymphoid tumors. These models may have clinically relevant implications, particularly for the tailoring of therapeutic strategies targeting telomerase.},
}
@article {pmid20548962,
year = {2010},
author = {Vrbsky, J and Akimcheva, S and Watson, JM and Turner, TL and Daxinger, L and Vyskot, B and Aufsatz, W and Riha, K},
title = {siRNA-mediated methylation of Arabidopsis telomeres.},
journal = {PLoS genetics},
volume = {6},
number = {6},
pages = {e1000986},
pmid = {20548962},
issn = {1553-7404},
mesh = {Arabidopsis/*genetics ; Chromatin/genetics ; Chromosomes, Plant ; *DNA Methylation ; Gene Expression Regulation, Plant ; Mutation ; RNA, Small Interfering/*genetics ; *Telomere ; Transcription, Genetic ; },
abstract = {Chromosome termini form a specialized type of heterochromatin that is important for chromosome stability. The recent discovery of telomeric RNA transcripts in yeast and vertebrates raised the question of whether RNA-based mechanisms are involved in the formation of telomeric heterochromatin. In this study, we performed detailed analysis of chromatin structure and RNA transcription at chromosome termini in Arabidopsis. Arabidopsis telomeres display features of intermediate heterochromatin that does not extensively spread to subtelomeric regions which encode transcriptionally active genes. We also found telomeric repeat-containing transcripts arising from telomeres and centromeric loci, a portion of which are processed into small interfering RNAs. These telomeric siRNAs contribute to the maintenance of telomeric chromatin through promoting methylation of asymmetric cytosines in telomeric (CCCTAAA)(n) repeats. The formation of telomeric siRNAs and methylation of telomeres relies on the RNA-dependent DNA methylation pathway. The loss of telomeric DNA methylation in rdr2 mutants is accompanied by only a modest effect on histone heterochromatic marks, indicating that maintenance of telomeric heterochromatin in Arabidopsis is reinforced by several independent mechanisms. In conclusion, this study provides evidence for an siRNA-directed mechanism of chromatin maintenance at telomeres in Arabidopsis.},
}
@article {pmid20547081,
year = {2010},
author = {Butt, HZ and Atturu, G and London, NJ and Sayers, RD and Bown, MJ},
title = {Telomere length dynamics in vascular disease: a review.},
journal = {European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery},
volume = {40},
number = {1},
pages = {17-26},
doi = {10.1016/j.ejvs.2010.04.012},
pmid = {20547081},
issn = {1532-2165},
mesh = {Evidence-Based Medicine ; Genetic Predisposition to Disease ; Humans ; Phenotype ; Risk Assessment ; Risk Factors ; Telomere/*metabolism ; Vascular Diseases/*genetics/pathology ; },
abstract = {INTRODUCTION: Telomeres are specialised DNA-protein complexes which cap the ends of linear chromosomes serving to maintain DNA integrity during cell division. Telomere length naturally shortens with successive cell divisions and represents a cellular marker of biological age. This paper aims to provide an overview of telomere biology and review the evidence for any association between vascular surgical conditions and short telomere length.<br><br>METHODS: A systematic review of the literature was performed using the search terms 'telomere' and 'vascular'.<br><br>RESULTS: Considerable associations between a shorter mean telomere length and coronary heart disease have been observed. This finding extends to vascular disease risk factors including age, sex, smoking, obesity, hypertension and diabetes. Vascular diseases including abdominal aortic aneurysm, peripheral vascular disease and carotid disease were also associated with shorter telomere lengths but evidence was limited to a small number of studies. There were no reports of short telomere length associated with varicose veins or arterio-venous malformations suggesting a novel area for further investigation.<br><br>CONCLUSION: Multiple associations between short telomere length and vascular disease characterised by atherosclerosis suggest a possible link between telomere attrition and disease mechanisms. Further studies are warranted to validate and define the role of telomeres in vascular disease pathogenesis.},
}
@article {pmid20545697,
year = {2010},
author = {Chen, W and Xiao, BK and Liu, JP and Chen, SM and Tao, ZZ},
title = {Alternative lengthening of telomeres in hTERT-inhibited laryngeal cancer cells.},
journal = {Cancer science},
volume = {101},
number = {8},
pages = {1769-1776},
doi = {10.1111/j.1349-7006.2010.01611.x},
pmid = {20545697},
issn = {1349-7006},
mesh = {Animals ; Cell Line, Tumor ; Cell Survival ; Humans ; In Situ Hybridization, Fluorescence ; Laryngeal Neoplasms/*genetics/pathology ; Mice ; Neoplasm Invasiveness ; Proteomics ; RNA Interference ; Spectrometry, Mass, Electrospray Ionization ; Telomerase/antagonists &amp; inhibitors/*physiology ; *Telomere ; },
abstract = {In most human malignancies, telomere homeostasis is maintained by the reactivation of telomerase. While inhibiting telomerase provides a novel approach to the treatment of many cancers, telomere maintenance can occur in the absence of telomerase activity by the alternative lengthening of telomeres (ALT) mechanism. Therefore, it must be determined if inhibiting telomerase selects for cancer cells that activate ALT. Here, we report that Hep-2 cells that survived anti-telomerase treatments showed sustained proliferation in culture with down-regulated human telomerase reverse transcriptase (hTERT) expression and significantly enhanced levels of ALT-specific promyelocytic leukemia (PML) bodies. Analysis of the telomere lengthening kinetics also demonstrated elevated telomeric sister-chromatid exchange (T-SCE) in surviving Hep-2 cells, consistent with their long and heterogeneous telomeres. Similar to ALT cells, the surviving cells showed evidence of ALT telomere homeostasis. Furthermore, proteomic analysis identified several proteins differentially expressed between the untreated Hep-2 cells and surviving cells that may provide new insight for understanding these two telomere maintenance mechanisms. Thus, the findings in this study may help to improve telomerase-based therapy for cancer.},
}
@article {pmid20542034,
year = {2010},
author = {Henson, JD and Reddel, RR},
title = {Assaying and investigating Alternative Lengthening of Telomeres activity in human cells and cancers.},
journal = {FEBS letters},
volume = {584},
number = {17},
pages = {3800-3811},
doi = {10.1016/j.febslet.2010.06.009},
pmid = {20542034},
issn = {1873-3468},
mesh = {Carcinoma/enzymology/genetics ; Cell Line, Tumor ; DNA Primers/genetics ; DNA, Circular/genetics ; Humans ; Microsatellite Instability ; Neoplasms/enzymology/*genetics ; Prognosis ; Radionuclide Imaging ; Sarcoma/diagnostic imaging/genetics ; Sister Chromatid Exchange/genetics ; Telomerase/deficiency/genetics/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Alternative Lengthening of Telomeres (ALT) activity can be deduced from the presence of telomere length maintenance in the absence of telomerase activity. More convenient assays for ALT utilize phenotypic markers of ALT activity, but only a few of these assays are potentially definitive. Here we assess each of the current ALT assays and their implications for understanding the ALT mechanism. We also review the clinical situations where availability of an ALT activity assay would be advantageous. The prevalence of ALT ranges from 25% to 60% in sarcomas and 5% to 15% in carcinomas. Patients with many of these types of ALT[+] tumors have a poor prognosis.},
}
@article {pmid20538902,
year = {2010},
author = {Shiels, PG},
title = {Improving precision in investigating aging: why telomeres can cause problems.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {65},
number = {8},
pages = {789-791},
doi = {10.1093/gerona/glq095},
pmid = {20538902},
issn = {1758-535X},
mesh = {Adult ; Aged ; *Aging ; Biomarkers ; Blotting, Southern ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Humans ; Middle Aged ; *Telomere ; },
abstract = {A host of recent publications has highlighted a growing number of discrepancies between small-scale laboratory-based studies and larger clinical and epidemiological studies, using telomere length as a bio-aging marker for physical, sociological, and psychological parameters in their respective cohorts. These discrepancies may be rooted in differing telomere length measurement methods and their application. This leads to the question of just how robust telomere length is as a biomarker of aging and whether measurement of CDKN2A levels offers a better alternative. The latter has already provided reproducible data from a small number of clinical studies and in one proven better than telomere length determination in predicting organ function. It seems prudent to address the use of these markers, alone or in combination, in multicentre double-blinded studies, using standardized methodologies and reagents, in order to identify the most appropriate marker and method for investigating bio-aging.},
}
@article {pmid20538793,
year = {2010},
author = {Lin, TT and Letsolo, BT and Jones, RE and Rowson, J and Pratt, G and Hewamana, S and Fegan, C and Pepper, C and Baird, DM},
title = {Telomere dysfunction and fusion during the progression of chronic lymphocytic leukemia: evidence for a telomere crisis.},
journal = {Blood},
volume = {116},
number = {11},
pages = {1899-1907},
doi = {10.1182/blood-2010-02-272104},
pmid = {20538793},
issn = {1528-0020},
support = {C17199/A5603//Cancer Research UK/United Kingdom ; C1799/A6932//Cancer Research UK/United Kingdom ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; B-Lymphocytes/metabolism/pathology ; Base Sequence ; Cell Proliferation ; *Chromosome Deletion ; Chromosomes, Human, Pair 17/genetics ; Chromosomes, Human, X/genetics ; Chromosomes, Human, Y/genetics ; Comparative Genomic Hybridization ; Disease Progression ; Gene Expression Profiling ; Gene Expression Regulation, Leukemic ; Genomic Instability ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/metabolism/pathology ; Middle Aged ; Molecular Sequence Data ; Prognosis ; Repetitive Sequences, Nucleic Acid/genetics ; *Sequence Deletion ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {We performed single-molecule telomere length and telomere fusion analysis in patients at different stages of chronic lymphocytic leukemia (CLL). Our work identified the shortest telomeres ever recorded in primary human tissue, reinforcing the concept that there is significant cell division in CLL. Furthermore, we provide direct evidence that critical telomere shortening, dysfunction, and fusion contribute to disease progression. The frequency of short telomeres and fusion events increased with advanced disease, but importantly these were also found in a subset of early-stage patient samples, indicating that these events can precede disease progression. Sequence analysis of fusion events isolated from persons with the shortest telomeres revealed limited numbers of repeats at the breakpoint, subtelomeric deletion, and microhomology. Array-comparative genome hybridization analysis of persons displaying evidence of telomere dysfunction revealed large-scale genomic rearrangements that were concentrated in the telomeric regions; this was not observed in samples with longer telomeres. The telomere dynamics observed in CLL B cells were indistinguishable from that observed in cells undergoing crisis in culture after abrogation of the p53 pathway. Taken together, our data support the concept that telomere erosion and subsequent telomere fusion are critical in the progression of CLL and that this paradigm may extend to other malignancies.},
}
@article {pmid20536547,
year = {2010},
author = {Amiel, T and Sharony, R and Goldberg-Bittman, L and Biron-Shental, T and Fejgin, MD and Amiel, A},
title = {Telomere aggregates in amniocytes with karyotype of balanced chromosomal rearrangements.},
journal = {Hereditas},
volume = {147},
number = {2},
pages = {90-93},
doi = {10.1111/j.1601-5223.2009.02170.x},
pmid = {20536547},
issn = {1601-5223},
mesh = {Amniotic Fluid/*metabolism ; *Chromosome Aberrations ; In Situ Hybridization, Fluorescence ; Karyotyping ; *Telomere ; },
abstract = {Telomeres are TTAGGG repetitions at the ends of chromosomes. Functioning telomeres are essential for normal segregation and maintenance of chromosomes during mitotic and meiotic divisions. Dysfunctional telomeres support the survival of aneuploid cells, a characteristic of many human malignancies. In contrast to the non-overlapping nature of telomeres in normal nuclei, telomeres of tumor nuclei tend to form aggregates. In this study, our objective was to evaluate the number of telomere aggregates (TAs) in karyotype-balanced structural rearrangements. This is an additional parameter of genetic instability, which might suggest a possible increased risk for diseases related to genomic instability, such as cancer. Twenty-six amniotic fluid cell cultures were established following genetic amniocentesis. Telomere FISH protocol was applied to the samples. Telomere aggregates were counted using a 2D microscope. The results were statistically tested by analysis of variance (ANOVA) and Kruskal-Wallis tests. More telomere aggregates in the structural balanced rearrangements were found in both study groups (balanced translocations and inversions) compared to the control group (P < 0.05). The persistence of TAs in cells is probably related to Breakage-Bridge-Fusion (BBF) cycles, a mechanism of TAs described by Muller and McClintock, resulting in end-to-end fusion that contributes to the onset of genomic instability. BBF cycles contribute to deletions, gene amplification, non-reciprocal translocations, and overall genetic changes associated with tumor genesis. According to our studies, the individuals who are carriers of balanced structural chromosomal rearrangements show some of the genetic instability parameters that appear in other circumstances, such as premalignant and malignant conditions.},
}
@article {pmid20535033,
year = {2010},
author = {McDonald, KL and McDonnell, J and Muntoni, A and Henson, JD and Hegi, ME and von Deimling, A and Wheeler, HR and Cook, RJ and Biggs, MT and Little, NS and Robinson, BG and Reddel, RR and Royds, JA},
title = {Presence of alternative lengthening of telomeres mechanism in patients with glioblastoma identifies a less aggressive tumor type with longer survival.},
journal = {Journal of neuropathology and experimental neurology},
volume = {69},
number = {7},
pages = {729-736},
doi = {10.1097/NEN.0b013e3181e576cf},
pmid = {20535033},
issn = {1554-6578},
mesh = {Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents, Alkylating/therapeutic use ; Cohort Studies ; Dacarbazine/analogs &amp; derivatives/therapeutic use ; Female ; Glioblastoma/drug therapy/genetics/metabolism/*pathology ; Humans ; International Cooperation ; Isocitrate Dehydrogenase/genetics ; Male ; Middle Aged ; Mutation/genetics ; Proportional Hazards Models ; Retrospective Studies ; Survival Analysis ; Telomerase ; Telomere/genetics/*pathology/*ultrastructure ; Temozolomide ; Young Adult ; },
abstract = {Patients with glioblastoma (GBM) have variable clinical courses, but the factors that underlie this heterogeneity are not understood. To determine whether the presence of the telomerase-independent alternative lengthening of telomeres (ALTs) mechanism is a significant prognostic factor for survival, we performed a retrospective analysis of 573 GBM patients. The presence of ALT was identified in paraffin sections using a combination of immunofluorescence for promyelocytic leukemia body and telomere fluorescence in situ hybridization. Alternative lengthening of telomere was present in 15% of the GBM patients. Patients with ALT had longer survival that was independent of age, surgery, and other treatments. Mutations in isocitrate dehydrogenase (IDH1mut) 1 frequently accompanied ALT, and in the presence of both molecular events, there was significantly longer overall survival. These data suggest that most ALT+ tumors may be less aggressive proneural GBMs, and the better prognosis may relate to the set of genetic changes associated with this tumor subtype. Despite improved overall survival of patients treated with the addition of chemotherapy to radiotherapy and surgery, ALT and chemotherapy independently provided a survival advantage, but these factors were not found to be additive. These results suggest a critical need for developing new therapies to target these specific GBM subtypes.},
}
@article {pmid20532978,
year = {2010},
author = {Wong, LS and van der Harst, P and de Boer, RA and Huzen, J and van Gilst, WH and van Veldhuisen, DJ},
title = {Aging, telomeres and heart failure.},
journal = {Heart failure reviews},
volume = {15},
number = {5},
pages = {479-486},
pmid = {20532978},
issn = {1573-7322},
mesh = {Aging/*pathology ; Disease Progression ; Heart Failure/*enzymology/genetics ; Humans ; Myocytes, Cardiac/enzymology ; Prognosis ; Risk Factors ; Telomerase/*genetics/metabolism ; Telomere/enzymology/*genetics ; },
abstract = {During normal aging, the heart undergoes functional, morphological and cellular changes. Although aging per se does not lead to the expression of heart failure, it is likely that age-associated changes lower the threshold for the manifestation of signs and symptoms of heart failure. In patients, the susceptibility, age of onset and pace of progression of heart failure are highly variable. The presence of conventional risk factors cannot completely explain this variability. Accumulation of DNA damage and telomere attrition results in an increase in cellular senescence and apoptosis, resulting in a decrease in the number and function of cells, contributing to the overall tissue and organ dysfunction. Biological aging, characterized by reduced telomere length, provides an explanation for the highly interindividual variable threshold to express the clinical syndrome of heart failure at some stage during life. In this review, we will elaborate on the current knowledge of aging of the heart, telomere biology and its potential role in the development of heart failure.},
}
@article {pmid20523895,
year = {2010},
author = {Lydeard, JR and Lipkin-Moore, Z and Jain, S and Eapen, VV and Haber, JE},
title = {Sgs1 and exo1 redundantly inhibit break-induced replication and de novo telomere addition at broken chromosome ends.},
journal = {PLoS genetics},
volume = {6},
number = {5},
pages = {e1000973},
pmid = {20523895},
issn = {1553-7404},
support = {R01 GM076020/GM/NIGMS NIH HHS/United States ; GM76020/GM/NIGMS NIH HHS/United States ; GM20056/GM/NIGMS NIH HHS/United States ; R37 GM020056/GM/NIGMS NIH HHS/United States ; R01 GM020056/GM/NIGMS NIH HHS/United States ; T32 GM007122/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; *Chromosomes, Fungal ; DNA Primers ; DNA Replication ; Exodeoxyribonucleases/*physiology ; Gene Conversion ; Genes, Fungal ; Polymerase Chain Reaction ; RecQ Helicases/*physiology ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/*physiology ; *Telomere ; Translocation, Genetic ; },
abstract = {In budding yeast, an HO endonuclease-inducible double-strand break (DSB) is efficiently repaired by several homologous recombination (HR) pathways. In contrast to gene conversion (GC), where both ends of the DSB can recombine with the same template, break-induced replication (BIR) occurs when only the centromere-proximal end of the DSB can locate homologous sequences. Whereas GC results in a small patch of new DNA synthesis, BIR leads to a nonreciprocal translocation. The requirements for completing BIR are significantly different from those of GC, but both processes require 5' to 3' resection of DSB ends to create single-stranded DNA that leads to formation of a Rad51 filament required to initiate HR. Resection proceeds by two pathways dependent on Exo1 or the BLM homolog, Sgs1. We report that Exo1 and Sgs1 each inhibit BIR but have little effect on GC, while overexpression of either protein severely inhibits BIR. In contrast, overexpression of Rad51 markedly increases the efficiency of BIR, again with little effect on GC. In sgs1Delta exo1Delta strains, where there is little 5' to 3' resection, the level of BIR is not different from either single mutant; surprisingly, there is a two-fold increase in cell viability after HO induction whereby 40% of all cells survive by formation of a new telomere within a few kb of the site of DNA cleavage. De novo telomere addition is rare in wild-type, sgs1Delta, or exo1Delta cells. In sgs1Delta exo1Delta, repair by GC is severely inhibited, but cell viability remains high because of new telomere formation. These data suggest that the extensive 5' to 3' resection that occurs before the initiation of new DNA synthesis in BIR may prevent efficient maintenance of a Rad51 filament near the DSB end. The severe constraint on 5' to 3' resection, which also abrogates activation of the Mec1-dependent DNA damage checkpoint, permits an unprecedented level of new telomere addition.},
}
@article {pmid20523746,
year = {2010},
author = {Bonetti, D and Clerici, M and Anbalagan, S and Martina, M and Lucchini, G and Longhese, MP},
title = {Shelterin-like proteins and Yku inhibit nucleolytic processing of Saccharomyces cerevisiae telomeres.},
journal = {PLoS genetics},
volume = {6},
number = {5},
pages = {e1000966},
pmid = {20523746},
issn = {1553-7404},
mesh = {DNA Damage ; Hydrolysis ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/*physiology ; *Telomere ; },
abstract = {Eukaryotic cells distinguish their chromosome ends from accidental DNA double-strand breaks (DSBs) by packaging them into protective structures called telomeres that prevent DNA repair/recombination activities. Here we investigate the role of key telomeric proteins in protecting budding yeast telomeres from degradation. We show that the Saccharomyces cerevisiae shelterin-like proteins Rif1, Rif2, and Rap1 inhibit nucleolytic processing at both de novo and native telomeres during G1 and G2 cell cycle phases, with Rif2 and Rap1 showing the strongest effects. Also Yku prevents telomere resection in G1, independently of its role in non-homologous end joining. Yku and the shelterin-like proteins have additive effects in inhibiting DNA degradation at G1 de novo telomeres, where Yku plays the major role in preventing initiation, whereas Rif1, Rif2, and Rap1 act primarily by limiting extensive resection. In fact, exonucleolytic degradation of a de novo telomere is more efficient in yku70Delta than in rif2Delta G1 cells, but generation of ssDNA in Yku-lacking cells is limited to DNA regions close to the telomere tip. This limited processing is due to the inhibitory action of Rap1, Rif1, and Rif2, as their inactivation allows extensive telomere resection not only in wild-type but also in yku70Delta G1 cells. Finally, Rap1 and Rif2 prevent telomere degradation by inhibiting MRX access to telomeres, which are also protected from the Exo1 nuclease by Yku. Thus, chromosome end degradation is controlled by telomeric proteins that specifically inhibit the action of different nucleases.},
}
@article {pmid20520834,
year = {2010},
author = {Kananen, L and Surakka, I and Pirkola, S and Suvisaari, J and Lönnqvist, J and Peltonen, L and Ripatti, S and Hovatta, I},
title = {Childhood adversities are associated with shorter telomere length at adult age both in individuals with an anxiety disorder and controls.},
journal = {PloS one},
volume = {5},
number = {5},
pages = {e10826},
pmid = {20520834},
issn = {1932-6203},
mesh = {Adult ; Aging/metabolism/pathology ; Anxiety Disorders/*complications ; Case-Control Studies ; Child ; Child Abuse/*psychology ; Humans ; *Life Change Events ; Socioeconomic Factors ; Stress, Psychological/complications ; Telomere/*metabolism ; },
abstract = {Accelerated leukocyte telomere shortening has been previously associated to self-perceived stress and psychiatric disorders, including schizophrenia and mood disorders. We set out to investigate whether telomere length is affected in patients with anxiety disorders in which stress is a known risk factor. We also studied the effects of childhood and recent psychological distress on telomere length. We utilized samples from the nationally representative population-based Health 2000 Survey that was carried out between 2000-2001 in Finland to assess major public health problems and their determinants. We measured the relative telomere length of the peripheral blood cells by quantitative real-time PCR from 321 individuals with DSM-IV anxiety disorder or subthreshold diagnosis and 653 matched controls aged 30-87 years, who all had undergone the Composite International Diagnostic Interview. While telomere length did not differ significantly between cases and controls in the entire cohort, the older half of the anxiety disorder patients (48-87 years) exhibited significantly shorter telomeres than healthy controls of the same age (P = 0.013). Interestingly, shorter telomere length was also associated with a greater number of reported childhood adverse life events, among both the anxiety disorder cases and controls (P = 0.005). Childhood chronic or serious illness was the most significantly associated single event affecting telomere length at the adult age (P = 0.004). Self-reported current psychological distress did not affect telomere length. Our results suggest that childhood stress might lead to accelerated telomere shortening seen at the adult age. This finding has potentially important implications supporting the view that childhood adversities might have a considerable impact on well being later in life.},
}
@article {pmid20520771,
year = {2010},
author = {Puterman, E and Lin, J and Blackburn, E and O'Donovan, A and Adler, N and Epel, E},
title = {The power of exercise: buffering the effect of chronic stress on telomere length.},
journal = {PloS one},
volume = {5},
number = {5},
pages = {e10837},
pmid = {20520771},
issn = {1932-6203},
support = {P30 AI027763/AI/NIAID NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; P30AI027763/AI/NIAID NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Exercise/*physiology ; Female ; Humans ; Middle Aged ; Motor Activity ; Sedentary Behavior ; Stress, Psychological/*metabolism ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Chronic psychological stress is associated with detrimental effects on physical health, and may operate in part through accelerated cell aging, as indexed by shorter telomeres at the ends of chromosomes. However, not all people under stress have distinctly short telomeres, and we examined whether exercise can serve a stress-buffering function. We predicted that chronic stress would be related to short telomere length (TL) in sedentary individuals, whereas in those who exercise, stress would not have measurable effects on telomere shortening.<br><br>63 healthy post-menopausal women underwent a fasting morning blood draw for whole blood TL analysis by a quantitative polymerase chain reaction method. Participants completed the Perceived Stress Scale (Cohen et al., 1983), and for three successive days reported daily minutes of vigorous activity. Participants were categorized into two groups-sedentary and active (those getting Centers for Disease Control-recommended daily amount of activity). The likelihood of having short versus long telomeres was calculated as a function of stress and exercise group, covarying age, BMI and education. Logistic regression analyses revealed a significant moderating effect of exercise. As predicted, among non-exercisers a one unit increase in the Perceived Stress Scale was related to a 15-fold increase in the odds of having short telomeres (p<.05), whereas in exercisers, perceived stress appears to be unrelated to TL (B = -.59, SE = .78, p = .45).<br><br>DISCUSSION: Vigorous physical activity appears to protect those experiencing high stress by buffering its relationship with TL. We propose pathways through which physical activity acts to buffer stress effects.},
}
@article {pmid20519782,
year = {2010},
author = {Beattie, TL and Lees-Miller, SP},
title = {Unraveling the roles of WRN and DNA-PKcs at telomeres.},
journal = {Aging},
volume = {2},
number = {5},
pages = {257-258},
pmid = {20519782},
issn = {1945-4589},
mesh = {Calcium-Binding Proteins/*genetics/metabolism ; Exodeoxyribonucleases/*genetics/metabolism ; Humans ; RecQ Helicases/*genetics/metabolism ; Telomere/*genetics/metabolism ; Werner Syndrome Helicase ; },
}
@article {pmid20519779,
year = {2010},
author = {Wu, RT and Cheng, WH},
title = {New insight into telomere maintenance.},
journal = {Aging},
volume = {2},
number = {5},
pages = {255-256},
pmid = {20519779},
issn = {1945-4589},
mesh = {Aging/*genetics ; Humans ; Longevity/*genetics ; Telomere/*genetics ; },
}
@article {pmid20518743,
year = {2010},
author = {Moraes, AS and Mondin, M and Beletti, ME and Aguiar-Perecin, ML and Guaraldo, AM and Mello, ML},
title = {Age-related association of rDNA and telomeres with the nuclear matrix in mouse hepatocytes.},
journal = {Cell biology international},
volume = {34},
number = {9},
pages = {925-931},
doi = {10.1042/CBI20090457},
pmid = {20518743},
issn = {1095-8355},
mesh = {Aging/*metabolism ; Animals ; Base Sequence ; Cell Fractionation ; Chromatin/metabolism ; DNA/metabolism ; DNA, Ribosomal/*metabolism ; Hepatocytes/cytology/*metabolism ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Nuclear Matrix/*metabolism ; Telomere/*metabolism ; },
abstract = {Transcribed sequences have been suggested to be associated with the nuclear matrix, differing from non-transcribing sequences, which have been reported to be contained in DNA loops. However, although a dozen of genes have their expression level affected by aging, data on chromatin-nuclear matrix interactions under this physiological condition are still scarce. In the present study, liver imprints from young, adult and old mice were subjected to FISH (fluorescence in situ hybridization) for 45S rDNA and telomeric sequences, with or without a lysis treatment to produce extended chromatin fibres. There was an increased amount of 45S rDNA sequences located in DNA loops as the animals grow older, while telomeric sequences were always observed in DNA loops irrespective of the animal age. We assume that active rRNA genes associate with the nuclear matrix, while DNA loops contain silent sequences. Transcription of each 45S rDNA repeat unit is suggested to be dependent on its interaction with the nuclear matrix.},
}
@article {pmid20517159,
year = {2010},
author = {Ning, X and Yang, S and Wang, R and Zhang, R and Guo, L and Tie, J and Cheng, Y and Wang, G and Wan, S and Fang, D},
title = {POT1 deficiency alters telomere length and telomere-associated gene expression in human gastric cancer cells.},
journal = {European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP)},
volume = {19},
number = {5},
pages = {345-351},
doi = {10.1097/CEJ.0b013e32833b4812},
pmid = {20517159},
issn = {1473-5709},
mesh = {Adenocarcinoma/*genetics/metabolism ; Cell Survival ; Gene Expression ; Humans ; RNA, Small Interfering/genetics/metabolism ; Shelterin Complex ; Stomach Neoplasms/*genetics/metabolism ; Tankyrases/genetics ; Telomerase/genetics ; Telomere/*genetics/*ultrastructure ; Telomere-Binding Proteins/*deficiency ; Telomeric Repeat Binding Protein 1/genetics ; Telomeric Repeat Binding Protein 2/genetics ; Tumor Cells, Cultured ; },
abstract = {Telomeres are the end structures of linear chromosomes in eukaryotic cells. The integrity of a telomere is essential for the overall stability of the chromosome. The human protection of telomeres 1 (hPOT1) protein, a single-stranded telomeric DNA binding protein, plays an important role in telomere protection and telomere length regulation. Here, we show that the loss of hPOT1 by RNA interference in BGC823 (poorly differentiated human gastric adenocarcinoma) cells leads to an increase in multinucleated giant cells, a decrease in cell proliferation and colony formation, induction of senescence and apoptosis, shortened telomere length, upregulation of the TRF1 gene and downregulation of the TRF2, tankyrase1 and hTERT genes. These results suggest that the loss of hPOT1 results in a decrease in the viability of BGC823 cells; hPOT1 regulates telomere length positively and has an influence on the expression of other telomere-associated genes in the cells.},
}
@article {pmid20515974,
year = {2010},
author = {Shakirov, EV and Perroud, PF and Nelson, AD and Cannell, ME and Quatrano, RS and Shippen, DE},
title = {Protection of Telomeres 1 is required for telomere integrity in the moss Physcomitrella patens.},
journal = {The Plant cell},
volume = {22},
number = {6},
pages = {1838-1848},
pmid = {20515974},
issn = {1532-298X},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; GM065383/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Bryopsida/*genetics/metabolism ; DNA, Plant/genetics ; DNA, Single-Stranded/metabolism ; Gene Deletion ; Genetic Complementation Test ; Genomic Instability ; Molecular Sequence Data ; Plant Proteins/genetics/*metabolism ; Sequence Alignment ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {In vertebrates, the single-stranded telomeric DNA binding protein Protection of Telomeres 1 (POT1) shields chromosome ends and prevents them from eliciting a DNA damage response. By contrast, Arabidopsis thaliana encodes two divergent full-length POT1 paralogs that do not exhibit telomeric DNA binding in vitro and have evolved to mediate telomerase regulation instead of chromosome end protection. To further investigate the role of POT1 in plants, we established the moss Physcomitrella patens as a new model for telomere biology and a counterpoint to Arabidopsis. The sequence and architecture of the telomere tract is similar in P. patens and Arabidopsis, but P. patens harbors only a single-copy POT1 gene. Unlike At POT1 proteins, Pp POT1 efficiently bound single-stranded telomeric DNA in vitro. Deletion of the P. patens POT1 gene resulted in the rapid onset of severe developmental defects and sterility. Although telomerase activity levels were unperturbed, telomeres were substantially shortened, harbored extended G-overhangs, and engaged in end-to-end fusions. We conclude that the telomere capping function of POT1 is conserved in early diverging land plants but is subsequently lost in Arabidopsis.},
}
@article {pmid20515788,
year = {2010},
author = {Nawrot, TS and Staessen, JA and Holvoet, P and Struijker-Boudier, HA and Schiffers, P and Van Bortel, LM and Fagard, RH and Gardner, JP and Kimura, M and Aviv, A},
title = {Telomere length and its associations with oxidized-LDL, carotid artery distensibility and smoking.},
journal = {Frontiers in bioscience (Elite edition)},
volume = {2},
number = {3},
pages = {1164-1168},
doi = {10.2741/e176},
pmid = {20515788},
issn = {1945-0508},
support = {AG020132/AG/NIA NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Carotid Arteries/*pathology ; Cohort Studies ; Female ; Humans ; Lipoproteins, LDL/*blood ; Male ; Middle Aged ; Smoking/*genetics ; *Telomere ; },
abstract = {Oxidative stress is a key factor driving the aging of cells and arteries. Studies suggest that white blood cell (WBC) telomere length is an index of systemic aging. We, therefore, investigated the association between WBC telomere length and oxidized-LDL, and vascular aging, expressed by the distensibility of the carotid artery. We studied a random population sample of 216 non-smokers and 89, smokers. In all subjects, age and gender- adjusted telomere length was inversely correlated with plasma oxidized-LDL (regression coefficient = -0.656 kb/mg/dL; p=0.0006). Independent of gender, age and mean blood pressure, carotid distensibility increased with telomere length (2.33+/- 1.18 10-3/kPa/kb; p=0.05) but decreased with higher plasma levels of oxidized LDL (-10.7+/- 3.91 10-3/kPa/ mg/dL; p=0.006). Adjusted for gender and age, smokers' telomere length was shorter (6.72 vs 6.91 kb; p=0.014) and plasma oxidized-LDL level higher (0.52 vs 0.46 mg/dL; p=0.03) than in non-smokers. Higher level of oxidized-LDL, is associated with shorter WBC telomeres and increased stiffness of the carotid artery. Smoking is marked by increased oxidative stress in concert with shortened WBC telomere length.},
}
@article {pmid20515744,
year = {2010},
author = {Subramanian, L and Nakamura, TM},
title = {To fuse or not to fuse: how do checkpoint and DNA repair proteins maintain telomeres?.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {15},
number = {3},
pages = {1105-1118},
pmid = {20515744},
issn = {2768-6698},
support = {R01 GM078253/GM/NIGMS NIH HHS/United States ; R01 GM078253-04/GM/NIGMS NIH HHS/United States ; GM078253/GM/NIGMS NIH HHS/United States ; },
mesh = {Acid Anhydride Hydrolases ; Animals ; DNA Damage ; *DNA Repair ; DNA Repair Enzymes/*metabolism ; DNA Replication ; DNA-Binding Proteins/*metabolism ; Humans ; MRE11 Homologue Protein ; Protein Binding ; Telomerase/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {DNA damage checkpoint and DNA repair mechanisms play critical roles in the stable maintenance of genetic information. Various forms of DNA damage that arise inside cells due to common errors in normal cellular processes, such as DNA replication, or due to exposure to various DNA damaging agents, must be quickly detected and repaired by checkpoint signaling and repair factors. Telomeres, the natural ends of linear chromosomes, share many features with undesired "broken" DNA, and are recognized and processed by various DNA damage checkpoint and DNA repair proteins. However, their modes of action at telomeres must be altered from their actions at other DNA damage sites to avoid telomere fusions and permanent cell cycle arrest. Interestingly, accumulating evidence indicates that DNA damage checkpoint and DNA repair proteins are essential for telomere maintenance. In this article, we review our current knowledge on various mechanisms by which DNA damage checkpoint and DNA repair proteins are modulated at telomeres and how they might contribute to telomere maintenance in eukaryotes.},
}
@article {pmid20515735,
year = {2010},
author = {Babizhayev, MA and Yegorov, YE},
title = {Telomere attrition in lens epithelial cells - a target for N-acetylcarnosine therapy.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {15},
number = {3},
pages = {934-956},
doi = {10.2741/3655},
pmid = {20515735},
issn = {2768-6698},
mesh = {Aged ; Animals ; Carnosine/*analogs &amp; derivatives/therapeutic use ; Cataract/genetics/physiopathology/*prevention &amp; control ; Disease Models, Animal ; Humans ; Lens, Crystalline/cytology/*drug effects/metabolism ; Telomere/*drug effects/genetics ; Vision, Ocular/drug effects ; Visual Acuity/drug effects ; },
abstract = {The lens epithelium is especially vulnerable to oxidative stress. The erosion and shortening of telomeres in human lens epithelial cells in the lack of telomerase activity has been recognized as a primary cause of premature lens senescence phenotype that trigger human cataractogenesis. Carnosine, released ophthalmically from N-acetylcarnosine prodrug lubricant eye drops , at physiological concentration might remarkably reduce the rate of telomere shortening in the lens cells subjected to oxidative stress in the lack of efficient antioxidant lens protection. The data of visual functions (visual acuity, glare sensitivity) in older adult subjects and older subjects with cataract treated with 1% N-acetylcarnosine lubricant eye drops showed significant improvement as compared, by contrast with the control group which showed generally no improvement in visual functions, with no difference from baseline in visual acuity and glare sensitivity readings. Prevention of cellular senescence with ophthalmic prodrug N-acetylcarnosine may be a novel therapeutic target in a management of cataract, basic preventive health care and in arresting of after-cataract following extracapsular cataract extraction.},
}
@article {pmid20514214,
year = {2009},
author = {Capezzone, M and Marchisotta, S and Cantara, S and Pacini, F},
title = {Telomeres and thyroid cancer.},
journal = {Current genomics},
volume = {10},
number = {8},
pages = {526-533},
pmid = {20514214},
issn = {1875-5488},
abstract = {Telomeres are specialized structures at the ends of chromosomes, consisting of hundreds of repeated hexanucleotides (TTAGGG)n. Genetic integrity is partly maintained by the architecture of telomeres and it is gradually lost as telomeres progressively shorten with each cell replication, due to incomplete lagging DNA strand synthesis and oxidative damage. Telomerase is a reverse transcriptase enzyme that counteracts telomere shortening by adding telomeric repeats to the G-rich strand. It is composed of a telomerase RNA component and a protein component, telomerase reverse transcriptase. In the absence of telomerase or when the activity of the enzyme is low compared to the replicative erosion, apoptosis is triggered. Patients who have inherited genetic defects in telomere maintenance seem to have an increased risk of developing familial benign diseases or malignant diseases. At the somatic level, telomerase is reactivated in the majority of human carcinomas, suggesting that telomerase reactivation is a critical step for cancerogenesis.In sporadic thyroid carcinoma telomerase activity is detectable in nearly 50% of thyroid cancer tissues and some authors proposed that the detection of telomerase activity may be used for differentiating between benign and malignant thyroid tumours. Recently a germline alteration of telomere-telomerase complex has been identified in patients with familial papillary thyroid cancer, characterized by short telomeres and increased expression and activity of telomerase compared to patients with sporadic papillary thyroid cancer.In this report, we will review the role of telomere-telomerase complex in sporadic and familial thyroid cancer.},
}
@article {pmid20513435,
year = {2010},
author = {Preti, M and Ribeyre, C and Pascali, C and Bosio, MC and Cortelazzi, B and Rougemont, J and Guarnera, E and Naef, F and Shore, D and Dieci, G},
title = {The telomere-binding protein Tbf1 demarcates snoRNA gene promoters in Saccharomyces cerevisiae.},
journal = {Molecular cell},
volume = {38},
number = {4},
pages = {614-620},
doi = {10.1016/j.molcel.2010.04.016},
pmid = {20513435},
issn = {1097-4164},
mesh = {Base Sequence ; Computational Biology ; Conserved Sequence ; DNA-Binding Proteins/genetics/*metabolism ; Molecular Sequence Data ; Promoter Regions, Genetic/*genetics ; RNA, Small Nucleolar/*genetics ; Saccharomyces cerevisiae/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Transcription Factors/genetics/*metabolism ; },
abstract = {Small nucleolar RNAs (snoRNAs) play a key role in ribosomal RNA biogenesis, yet factors controlling their expression are unknown. We found that the majority of Saccharomyces snoRNA promoters display an aRCCCTaa sequence motif at the upstream border of a TATA-containing nucleosome-free region. Genome-wide ChIP-seq analysis showed that these motifs are bound by Tbf1, a telomere-binding protein known to recognize mammalian-like T(2)AG(3) repeats at subtelomeric regions. Tbf1 has over 100 additional promoter targets, including several other genes involved in ribosome biogenesis and the TBF1 gene itself. Tbf1 is required for full snoRNA expression, yet it does not influence nucleosome positioning at snoRNA promoters. In contrast, Tbf1 contributes to nucleosome exclusion at non-snoRNA promoters, where it selectively colocalizes with the Tbf1-interacting zinc-finger proteins Vid22 and Ygr071c. Our data show that, besides the ribosomal protein gene regulator Rap1, a second telomere-binding protein also functions as a transcriptional regulator linked to yeast ribosome biogenesis.},
}
@article {pmid20508208,
year = {2010},
author = {Willeit, P and Willeit, J and Brandstätter, A and Ehrlenbach, S and Mayr, A and Gasperi, A and Weger, S and Oberhollenzer, F and Reindl, M and Kronenberg, F and Kiechl, S},
title = {Cellular aging reflected by leukocyte telomere length predicts advanced atherosclerosis and cardiovascular disease risk.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {30},
number = {8},
pages = {1649-1656},
doi = {10.1161/ATVBAHA.110.205492},
pmid = {20508208},
issn = {1524-4636},
mesh = {Aged ; Aged, 80 and over ; Atherosclerosis/complications/*genetics/pathology ; Austria ; Cellular Senescence/*genetics ; Disease Progression ; Female ; Humans ; Leukocytes/*pathology ; Linear Models ; Logistic Models ; Male ; Middle Aged ; Myocardial Infarction/*genetics/pathology ; Phenotype ; Proportional Hazards Models ; Prospective Studies ; Risk Assessment ; Risk Factors ; Stroke/*genetics/pathology ; *Telomere ; Time Factors ; },
abstract = {OBJECTIVE: To determine the association between leukocyte telomere length (TL) and atherosclerosis and its clinical sequelae stroke and myocardial infarction.<br><br>METHODS AND RESULTS: Within the scope of the prospective population-based Bruneck Study, leukocyte TL was measured by quantitative polymerase chain reaction in 800 women and men aged 45 to 84 years (in 1995). The manifestation of cardiovascular disease (CVD) (1995-2005) and the progression of atherosclerosis (1995-2000) were carefully assessed. The TL was shorter in men than in women (age-adjusted mean [95% CI], 1.41 [1.33 to 1.49] versus 1.55 [1.47 to 1.62]; P=0.02) and inversely correlated to age (r=-0.22, P<0.001) and family history of CVD (P=0.03). Participants with CVD events during follow-up (n=88) had significantly shorter telomeres (age- and sex-adjusted mean [95% CI], 1.25 [1.08 to 1.42] versus 1.51 [1.45 to 1.57]; P<0.001). In multivariable Cox models, baseline TL emerged as a significant and independent risk predictor for the composite CVD end point and its individual components (myocardial infarction and stroke); however, this was not the case for de novo stable angina and intermittent claudication. Subjects in the top and bottom TL tertile group differed in their CVD risk by a factor of 2.72 (95% CI, 1.41 to 5.28), which is the risk ratio attributable to a 13.9-year difference in chronological age. Remarkably, in our atherosclerosis progression model, TL was strongly associated with advanced, but not early, atherogenesis. All findings were consistent in women and men.<br><br>CONCLUSIONS: Our findings indicate a differential role of telomere shortening in the various stages of atherosclerosis, with preferential involvement in advanced vessel pathology and acute vascular syndromes.},
}
@article {pmid20505337,
year = {2010},
author = {Khair, L and Chang, YT and Subramanian, L and Russell, P and Nakamura, TM},
title = {Roles of the checkpoint sensor clamp Rad9-Rad1-Hus1 (911)-complex and the clamp loaders Rad17-RFC and Ctf18-RFC in Schizosaccharomyces pombe telomere maintenance.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {9},
number = {11},
pages = {2237-2248},
pmid = {20505337},
issn = {1551-4005},
support = {GM59447/GM/NIGMS NIH HHS/United States ; GM078253/GM/NIGMS NIH HHS/United States ; R01 GM059447/GM/NIGMS NIH HHS/United States ; R01 GM078253/GM/NIGMS NIH HHS/United States ; R01 GM078253-04/GM/NIGMS NIH HHS/United States ; CA77325/CA/NCI NIH HHS/United States ; R01 CA077325/CA/NCI NIH HHS/United States ; },
mesh = {Alleles ; Carrier Proteins/metabolism/physiology ; Cell Cycle Proteins/metabolism/physiology ; Checkpoint Kinase 2 ; DNA/chemistry ; DNA-Binding Proteins/metabolism/physiology ; Endonucleases/metabolism/physiology ; Protein Kinases/metabolism/physiology ; Protein Serine-Threonine Kinases/metabolism/physiology ; Protein Structure, Tertiary ; Schizosaccharomyces/*metabolism ; Schizosaccharomyces pombe Proteins/metabolism/*physiology ; Telomere/*metabolism ; Transcription Factors/metabolism/physiology ; },
abstract = {While telomeres must provide mechanisms to prevent DNA repair and DNA damage checkpoint factors from fusing chromosome ends and causing permanent cell cycle arrest, these factors associate with functional telomeres and play critical roles in the maintenance of telomeres. Previous studies have established that Tel1 (ATM) and Rad3 (ATR) kinases play redundant but essential roles for telomere maintenance in fission yeast. In addition, the Rad9-Rad1-Hus1 (911) and Rad17-RFC complexes work downstream of Rad3 (ATR) in fission yeast telomere maintenance. Here, we investigated how 911, Rad17-RFC and another RFC-like complex Ctf18-RFC contribute to telomere maintenance in fission yeast cells lacking Tel1 and carrying a novel hypomorphic allele of rad3 (DBD-rad3), generated by the fusion between the DNA binding domain (DBD) of the fission yeast telomere capping protein Pot1 and Rad3. Our investigations have uncovered a surprising redundancy for Rad9 and Hus1 in allowing Rad1 to contribute to telomere maintenance in DBD-rad3 tel1 cells. In addition, we found that Rad17-RFC and Ctf18-RFC carry out redundant telomere maintenance functions in DBD-rad3 tel1 cells. Since checkpoint sensor proteins are highly conserved, genetic redundancies uncovered here may be relevant to telomere maintenance and detection of DNA damage in other eukaryotes.},
}
@article {pmid20504835,
year = {2011},
author = {Woo, J and Tang, NL and Suen, E and Leung, J},
title = {Shorter telomere length is associated with greater decrease in ankle-brachial index in elderly Chinese women but not men.},
journal = {Angiology},
volume = {62},
number = {1},
pages = {87-91},
doi = {10.1177/0003319710371618},
pmid = {20504835},
issn = {1940-1574},
mesh = {Aged ; *Ankle Brachial Index ; China ; Female ; Humans ; Male ; Sex Characteristics ; *Telomere/ultrastructure ; },
abstract = {Telomere shortening has been shown to contribute to the pathogenesis of atherosclerosis directly or through influencing cardiovascular risk factors. We examined telomere length (TL) and change in ankle-brachial index (ABI) over 5 years in a Chinese population aged 65 years and older living in the community. Telomere length was determined using the quantitative polymerase chain reaction (PCR) method in 976 men and 1030 women. Ankle-brachial index was measured using Doppler ultrasound. Analysis of covariance was used to examine the relationship between quartiles of TL and baseline ABI values as well as percentage change in ABI, adjusting for confounders. Women had longer TL and lower ABI values compared with men, and there was a significant trend for an inverse association between TL and percentage decline in ABI after adjustment for confounders. No significant association was observed in men. The findings support the association between TL and markers of atherosclerosis in older women but not men.},
}
@article {pmid20502709,
year = {2010},
author = {Diaz de Leon, A and Cronkhite, JT and Katzenstein, AL and Godwin, JD and Raghu, G and Glazer, CS and Rosenblatt, RL and Girod, CE and Garrity, ER and Xing, C and Garcia, CK},
title = {Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations.},
journal = {PloS one},
volume = {5},
number = {5},
pages = {e10680},
pmid = {20502709},
issn = {1932-6203},
support = {K23 RR020632/RR/NCRR NIH HHS/United States ; R01 HL093096/HL/NHLBI NIH HHS/United States ; R01HL093096/HL/NHLBI NIH HHS/United States ; K23RR020632/RR/NCRR NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Family ; Female ; Heterozygote ; Humans ; Male ; Middle Aged ; Mutation/*genetics ; Pedigree ; Phenotype ; Pulmonary Fibrosis/diagnostic imaging/*enzymology/*genetics/physiopathology ; Radiography ; Respiratory Function Tests ; Smoking ; Telomerase/*genetics ; Telomere/*metabolism ; Young Adult ; },
abstract = {BACKGROUND: Telomerase is an enzyme that catalyzes the addition of nucleotides on the ends of chromosomes. Rare loss of function mutations in the gene that encodes the protein component of telomerase (TERT) have been described in patients with idiopathic pulmonary fibrosis (IPF). Here we examine the telomere lengths and pulmonary fibrosis phenotype seen in multiple kindreds with heterozygous TERT mutations.<br><br>METHODS AND FINDINGS: We have identified 134 individuals with heterozygous TERT mutations from 21 unrelated families. Available medical records, surgical lung biopsies and radiographs were evaluated retrospectively. Genomic DNA isolated from circulating leukocytes has been used to measure telomere lengths with a quantitative PCR assay. We find that telomere lengths of TERT mutation carriers decrease in an age-dependent manner and show progressive shortening with successive generations of mutation inheritance. Family members without TERT mutations have a shorter mean telomere length than normal, demonstrating epigenetic inheritance of shortened telomere lengths in the absence of an inherited TERT mutation. Pulmonary fibrosis is an age-dependent phenotype not seen in mutation carriers less than 40 years of age but found in 60% of men 60 years or older; its development is associated with environmental exposures including cigarette smoking. A radiographic CT pattern of usual interstitial pneumonia (UIP), which is consistent with a diagnosis of IPF, is seen in 74% of cases and a pathologic pattern of UIP is seen in 86% of surgical lung biopsies. Pulmonary fibrosis associated with TERT mutations is progressive and lethal with a mean survival of 3 years after diagnosis. Overall, TERT mutation carriers demonstrate reduced life expectancy, with a mean age of death of 58 and 67 years for males and females, respectively.<br><br>CONCLUSIONS: A subset of pulmonary fibrosis, like dyskeratosis congenita, bone marrow failure, and liver disease, represents a "telomeropathy" caused by germline mutations in telomerase and characterized by short telomere lengths. Family members within kindreds who do not inherit the TERT mutation have shorter telomere lengths than controls, demonstrating epigenetic inheritance of a shortened parental telomere length set-point.},
}
@article {pmid20493859,
year = {2010},
author = {Baumann, P and Price, C},
title = {Pot1 and telomere maintenance.},
journal = {FEBS letters},
volume = {584},
number = {17},
pages = {3779-3784},
pmid = {20493859},
issn = {1873-3468},
support = {R01 GM041803-21/GM/NIGMS NIH HHS/United States ; GM041803/GM/NIGMS NIH HHS/United States ; R01 GM088728-03/GM/NIGMS NIH HHS/United States ; R01 GM088728/GM/NIGMS NIH HHS/United States ; R01 GM041803/GM/NIGMS NIH HHS/United States ; GM088728/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Animals ; Fungal Proteins/genetics ; Gene Duplication ; Genes, Protozoan ; Humans ; Mice ; Nematoda/genetics ; Plants/genetics ; Saccharomyces cerevisiae/genetics ; Shelterin Complex ; Telomerase/genetics/metabolism ; Telomere/genetics/*physiology ; Telomere-Binding Proteins/*genetics ; Yeasts/genetics ; },
abstract = {Proteins that specifically bind the single-stranded overhang at the ends of telomeres have been identified in a wide range of eukaryotes and play pivotal roles in chromosome end protection and telomere length regulation. Here we summarize recent findings regarding the functions of POT1 proteins in vertebrates and discuss the functional evolution of POT1 proteins following gene duplication in protozoa, plants, nematodes and mice.},
}
@article {pmid20493857,
year = {2010},
author = {Shay, JW and Wright, WE},
title = {Telomeres and telomerase in normal and cancer stem cells.},
journal = {FEBS letters},
volume = {584},
number = {17},
pages = {3819-3825},
pmid = {20493857},
issn = {1873-3468},
support = {P50 CA070907/CA/NCI NIH HHS/United States ; P50 CA127297/CA/NCI NIH HHS/United States ; CA70907/CA/NCI NIH HHS/United States ; CA127297/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Division ; Cellular Senescence/physiology ; DNA Damage ; Humans ; Models, Biological ; Neoplastic Stem Cells/cytology/*enzymology/physiology ; Stem Cells/cytology/enzymology/physiology ; Telomerase/genetics/*metabolism ; Telomere/*metabolism/ultrastructure ; Templates, Genetic ; },
abstract = {Differences between normal adult tissue stem cells and cancer stem/initiating cells remain poorly defined. For example, it is controversial if cancer stem cells can become fully quiescent, require a stem cell niche, are better at repairing DNA damage than the bulk of the cancer cells, and if and how they regulate symmetric versus asymmetric cell divisions. This minireview will not only provide our personal views to address some of these outstanding questions, but also present evidence that an understanding of telomere dynamics and telomerase activity in normal and cancer stem cells may provide additional insights into how tumors are initiated, and how they should be monitored and treated.},
}
@article {pmid20493811,
year = {2010},
author = {Tejera, AM and Stagno d'Alcontres, M and Thanasoula, M and Marion, RM and Martinez, P and Liao, C and Flores, JM and Tarsounas, M and Blasco, MA},
title = {TPP1 is required for TERT recruitment, telomere elongation during nuclear reprogramming, and normal skin development in mice.},
journal = {Developmental cell},
volume = {18},
number = {5},
pages = {775-789},
pmid = {20493811},
issn = {1878-1551},
support = {232854/ERC_/European Research Council/International ; /CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Animals ; Cell Nucleus/*physiology ; Gene Deletion ; Hair Follicle/pathology ; Hyperpigmentation/genetics/pathology ; Mice ; Mice, Knockout ; Morphogenesis ; Reference Values ; Sister Chromatid Exchange ; Skin/*growth &amp; development ; Skin Diseases/genetics/pathology ; *Skin Physiological Phenomena ; Telomerase/*metabolism ; Telomere/physiology ; Telomere-Binding Proteins ; },
abstract = {The TPP1/ACD protein (hereafter TPP1) is a component of the shelterin complex at mammalian telomeres. Here we find that Tpp1-deficient mouse embryonic fibroblasts (MEFs) show increased chromosomal instability including sister chromatid fusions and chromosomes with multitelomeric signals related to telomere fragility. Tpp1 deletion decreases both TERT (the telomerase catalytic subunit) binding to telomeres in MEFs and telomerase function at chromosome ends in vivo. Abrogation of Tpp1 abolished net telomere elongation in the context of nuclear reprogramming of MEFs into induced pluripotent stem cells, whereas Tpp1 deletion in stratified epithelia of Tpp1(Delta/Delta)K5-Cre mice resulted in perinatal death, severe skin hyperpigmentation, and impaired hair follicle morphogenesis. p53 deficiency rescues skin hyperpigmentation and hair growth in these mice, indicating that p53 restricts proliferation of Tpp1-deficient cells. These results suggest a telomere-capping model where TPP1 protects telomere integrity and regulates telomerase recruitment to telomeres, thereby preventing early occurrence of degenerative pathologies.},
}
@article {pmid20493300,
year = {2010},
author = {Gou, XC and Liu, J and Zhang, HL},
title = {Monitoring human telomere DNA hybridization and G-quadruplex formation using gold nanorods.},
journal = {Analytica chimica acta},
volume = {668},
number = {2},
pages = {208-214},
doi = {10.1016/j.aca.2010.04.027},
pmid = {20493300},
issn = {1873-4324},
mesh = {Biosensing Techniques ; Circular Dichroism ; DNA/chemistry ; *G-Quadruplexes ; Gold ; Humans ; Limit of Detection ; *Metal Nanoparticles ; Nucleic Acid Conformation ; *Nucleic Acid Hybridization ; Spectrometry, Fluorescence ; Spectrum Analysis ; Surface Plasmon Resonance ; *Telomere/chemistry ; },
abstract = {A facile and multi-response strategy for studying the transformations of human telomere DNA from single strand (ss) to double strand (ds) and G-quadruplex has been established by using positively charged gold nanorod (AuNR) as an optical label. The conformation change information of the telomere DNA was transferred into multiple optical signals, including changes in fluorescence emission, near infrared (NIR) absorption, plasma resonance light scattering (PRLS) and dynamic light scattering (DLS) response. The formations of dsDNA and G-quadruplex DNA induced fluorescence quenching of dye on DNA, and were accompanied by the intensity decrease and blue shift of the longitudinal absorption peak of AuNRs. Meanwhile, PRLS and DLS results revealed slightly increased AuNR aggregation due to increased charge density of dsDNA and G-quadruplex DNA as compared to ssDNA. Control experiment suggests that the AuNR-based assay is highly sequence specific; and the high sensitivity allows the study of human telomere DNA at a concentration as low as 58 nM.},
}
@article {pmid20485567,
year = {2010},
author = {Wang, Z and Rhee, DB and Lu, J and Bohr, CT and Zhou, F and Vallabhaneni, H and de Souza-Pinto, NC and Liu, Y},
title = {Characterization of oxidative guanine damage and repair in mammalian telomeres.},
journal = {PLoS genetics},
volume = {6},
number = {5},
pages = {e1000951},
pmid = {20485567},
issn = {1553-7404},
support = {//Intramural NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; Fluorescent Antibody Technique, Indirect ; Guanine/*chemistry ; Guanosine/*analogs &amp; derivatives/chemistry ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Oxidation-Reduction ; Oxidative Stress ; Recombination, Genetic ; Sister Chromatid Exchange ; *Telomere ; },
abstract = {8-oxo-7,8-dihydroguanine (8-oxoG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) are among the most common oxidative DNA lesions and are substrates for 8-oxoguanine DNA glycosylase (OGG1)-initiated DNA base excision repair (BER). Mammalian telomeres consist of triple guanine repeats and are subject to oxidative guanine damage. Here, we investigated the impact of oxidative guanine damage and its repair by OGG1 on telomere integrity in mice. The mouse cells were analyzed for telomere integrity by telomere quantitative fluorescence in situ hybridization (telomere-FISH), by chromosome orientation-FISH (CO-FISH), and by indirect immunofluorescence in combination with telomere-FISH and for oxidative base lesions by Fpg-incision/Southern blot assay. In comparison to the wild type, telomere lengthening was observed in Ogg1 null (Ogg1(-/-)) mouse tissues and primary embryonic fibroblasts (MEFs) cultivated in hypoxia condition (3% oxygen), whereas telomere shortening was detected in Ogg1(-/-) mouse hematopoietic cells and primary MEFs cultivated in normoxia condition (20% oxygen) or in the presence of an oxidant. In addition, telomere length abnormalities were accompanied by altered telomere sister chromatid exchanges, increased telomere single- and double-strand breaks, and preferential telomere lagging- or G-strand losses in Ogg1(-/-) mouse cells. Oxidative guanine lesions were increased in telomeres in Ogg1(-/-) mice with aging and primary MEFs cultivated in 20% oxygen. Furthermore, oxidative guanine lesions persisted at high level in Ogg1(-/-) MEFs after acute exposure to hydrogen peroxide, while they rapidly returned to basal level in wild-type MEFs. These findings indicate that oxidative guanine damage can arise in telomeres where it affects length homeostasis, recombination, DNA replication, and DNA breakage repair. Our studies demonstrate that BER pathway is required in repairing oxidative guanine damage in telomeres and maintaining telomere integrity in mammals.},
}
@article {pmid20485519,
year = {2010},
author = {Chung, WH and Zhu, Z and Papusha, A and Malkova, A and Ira, G},
title = {Defective resection at DNA double-strand breaks leads to de novo telomere formation and enhances gene targeting.},
journal = {PLoS genetics},
volume = {6},
number = {5},
pages = {e1000948},
pmid = {20485519},
issn = {1553-7404},
support = {R01 GM084242/GM/NIGMS NIH HHS/United States ; R01 GM080600-04/GM/NIGMS NIH HHS/United States ; R01 GM080600/GM/NIGMS NIH HHS/United States ; GM080600/GM/NIGMS NIH HHS/United States ; GM084242-01/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; *DNA Damage ; DNA Repair ; DNA, Single-Stranded/genetics ; Electrophoresis, Gel, Pulsed-Field ; *Gene Targeting ; Recombination, Genetic ; *Telomere ; },
abstract = {The formation of single-stranded DNA (ssDNA) at double-strand break (DSB) ends is essential in repair by homologous recombination and is mediated by DNA helicases and nucleases. Here we estimated the length of ssDNA generated during DSB repair and analyzed the consequences of elimination of processive resection pathways mediated by Sgs1 helicase and Exo1 nuclease on DSB repair fidelity. In wild-type cells during allelic gene conversion, an average of 2-4 kb of ssDNA accumulates at each side of the break. Longer ssDNA is formed during ectopic recombination or break-induced replication (BIR), reflecting much slower repair kinetics. This relatively extensive resection may help determine sequences involved in homology search and prevent recombination within short DNA repeats next to the break. In sgs1Delta exo1Delta mutants that form only very short ssDNA, allelic gene conversion decreases 5-fold and DSBs are repaired by BIR or de novo telomere formation resulting in loss of heterozygosity. The absence of the telomerase inhibitor, PIF1, increases de novo telomere pathway usage to about 50%. Accumulation of Cdc13, a protein recruiting telomerase, at the break site increases in sgs1Delta exo1Delta, and the requirement of the Ku complex for new telomere formation is partially bypassed. In contrast to this decreased and alternative DSB repair, the efficiency and accuracy of gene targeting increases dramatically in sgs1Delta exo1Delta cells, suggesting that transformed DNA is very stable in these mutants. Altogether these data establish a new role for processive resection in the fidelity of DSB repair.},
}
@article {pmid20484032,
year = {2010},
author = {Murnane, JP},
title = {Telomere loss as a mechanism for chromosome instability in human cancer.},
journal = {Cancer research},
volume = {70},
number = {11},
pages = {4255-4259},
pmid = {20484032},
issn = {1538-7445},
support = {R01 CA120205/CA/NCI NIH HHS/United States ; R01 CA120205-05/CA/NCI NIH HHS/United States ; CA120205/CA/NCI NIH HHS/United States ; },
mesh = {*Chromosomal Instability ; DNA Breaks, Double-Stranded ; DNA Repair ; Humans ; Neoplasms/*genetics ; Telomere/*genetics ; },
abstract = {Cancer cells commonly have a high rate of telomere loss, even when expressing telomerase, contributing to chromosome instability and tumor cell progression. This review addresses the hypothesis that this high rate of telomere loss results from a combination of four factors. The first factor is an increase in the frequency of double-strand breaks (DSB) at fragile sites in cancer cells due to replication stress. The second factor is that telomeres are fragile sites. The third factor is that subtelomeric regions are highly sensitive to DSBs, so that DSBs near telomeres have an increased probability of resulting in chromosome instability. The fourth factor is that cancer cells may be deficient in chromosome healing, the de novo addition of telomeres to the sites of DSBs, a mechanism that prevents chromosome instability resulting from DSBs near telomeres. Understanding these factors and how they influence telomere loss will provide important insights into the mechanisms of chromosome instability and the development of novel approaches for anti-cancer therapy. Cancer Res; 70(11); 4255-9. (c)2010 AACR.},
}
@article {pmid20479256,
year = {2010},
author = {Touzot, F and Callebaut, I and Soulier, J and Gaillard, L and Azerrad, C and Durandy, A and Fischer, A and de Villartay, JP and Revy, P},
title = {Function of Apollo (SNM1B) at telomere highlighted by a splice variant identified in a patient with Hoyeraal-Hreidarsson syndrome.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {107},
number = {22},
pages = {10097-10102},
pmid = {20479256},
issn = {1091-6490},
support = {249816/ERC_/European Research Council/International ; },
mesh = {*Alternative Splicing ; Amino Acid Sequence ; Base Sequence ; Cells, Cultured ; Cellular Senescence/genetics/physiology ; Child, Preschool ; Conserved Sequence ; DNA/genetics ; DNA Damage ; DNA Repair ; DNA Repair Enzymes/*genetics/*metabolism ; Dyskeratosis Congenita/*genetics/*metabolism/pathology ; Exodeoxyribonucleases ; Exons ; Female ; Fibroblasts/metabolism ; Genetic Complementation Test ; Humans ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Nuclear Proteins/*genetics/*metabolism ; Protein Isoforms/genetics/metabolism ; Sequence Homology, Amino Acid ; Sequence Homology, Nucleic Acid ; Syndrome ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres, the protein-DNA complexes at the ends of linear chromosomes, are protected and regulated by the shelterin molecules, the telomerase complex, and other accessory factors, among which is Apollo, a DNA repair factor of the beta-lactamase/beta-CASP family. Impaired telomere protection in humans causes dyskeratosis congenita and Hoyeraal-Hreidarsson (HH) syndrome, characterized by premature aging, bone marrow failure, and immunodeficiency. We identified a unique Apollo splice variant (designated Apollo-Delta) in fibroblasts from a patient with HH syndrome. Apollo-Delta generates a dominant negative form of Apollo lacking the telomeric repeat-binding factor homology (TRFH)-binding motif (TBM) required for interaction with the shelterin TRF2 at telomeres. Apollo-Delta hampers the proper replication of telomeres, leading to major telomeric dysfunction and cellular senescence, but maintains its DNA interstrand cross-link repair function in the whole genome. These results identify Apollo as a crucial actor in telomere maintenance in vivo, independent of its function as a general DNA repair factor.},
}
@article {pmid20479226,
year = {2010},
author = {Chiang, YJ and Calado, RT and Hathcock, KS and Lansdorp, PM and Young, NS and Hodes, RJ},
title = {Telomere length is inherited with resetting of the telomere set-point.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {107},
number = {22},
pages = {10148-10153},
pmid = {20479226},
issn = {1091-6490},
support = {//Intramural NIH HHS/United States ; },
mesh = {Anemia, Aplastic/genetics ; Animals ; Crosses, Genetic ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Mutant Strains ; Models, Genetic ; Mutation ; Pedigree ; Phenotype ; Telomerase/genetics ; Telomere/*genetics/*ultrastructure ; },
abstract = {We have studied models of telomerase haploinsufficiency in humans and mice to analyze regulation of telomere length and the significance of "set points" in inheritance of telomere length. In three families with clinical syndromes associated with short telomeres resulting from haploinsufficient mutations in TERT, the gene encoding telomerase reverse transcriptase, we asked whether restoration of normal genotypes in offspring of affected individuals would elongate inherited short telomeres. Telomeres were shorter than normal in some but not all genotypically normal offspring of telomerase-mutant parents or grandparents. Analysis of these findings was complicated by heterogeneity of telomere length among individuals, as well as by the admixing of telomeres inherited from affected parents with those inherited from unaffected ("wild-type" TERT) parents. To understand further the inheritance of telomere length, we established a shortened-telomere mouse model. When Tert(+/-) heterozygous mice were successively cross-bred through 17 generations, telomere length shortened progressively. The late-generation Tert(+/-) mice were intercrossed to produce genotypically wild-type Tert(+/+) mice, for which telomere length was characterized. Strikingly, telomere length in these Tert(+/+) mice was not longer than that of their Tert(+/-) parents. Moreover, when successive crosses were carried out among these short-telomere Tert(+/+) offspring mice, telomere length was stable, with no elongation up to six generations. This breeding strategy therefore has established a mouse strain, B6.ST (short telomeres), with C57BL/6 genotype and stable short telomeres. These findings suggest that the set point of telomere lengths of offspring is determined by the telomere lengths of their parents in the presence of normal expression of telomerase.},
}
@article {pmid20478660,
year = {2010},
author = {Stindl, R and Stindl, W},
title = {Vanishing honey bees: Is the dying of adult worker bees a consequence of short telomeres and premature aging?.},
journal = {Medical hypotheses},
volume = {75},
number = {4},
pages = {387-390},
doi = {10.1016/j.mehy.2010.04.003},
pmid = {20478660},
issn = {1532-2777},
mesh = {Aging/immunology/*physiology ; Animals ; *Bees ; Colony Collapse/*genetics ; Longevity ; Regeneration/*physiology ; Seasons ; Telomere/*genetics/immunology ; },
abstract = {Einstein is often quoted to have said that without the bee, mankind would have but 4years to live. It is highly unlikely that he made this comment, which was even mentioned in a Lancet article on honey bees. However, the current vanishing of the bees can have serious consequences for human health, because 35% of the human diet is thought to benefit from pollination. Colony collapse disorder (CCD) in honey bees is characterized by the rapid decline of the adult bee population, leaving the brood and the queen poorly or completely unattended, with no dead bodies in or around the hive. A large study found no evidence that the presence or amount of any individual pesticide or infectious agent occurred more frequently or abundantly in CCD-affected colonies. The growing consensus is that honey bees are suffering from comprised immune systems, which allow various infectious pathogens to invade. The question remains, what causes immunosuppression in many colonies of Apis mellifera in North America and Europe? Telomeres are protective DNA structures located at eukaryotic chromosome tips that shorten in the somatic tissues of animals with age. Lifelong tissue regeneration takes place in Apis mellifera, and worker bees have been shown to senesce. In humans, a vast amount of literature has accumulated on exhausted telomere reserves causing impaired tissue regeneration and age-associated diseases, specifically cancer and immunosuppression. Therefore, we propose a new causative mechanism for the vanishing of the bees: critically short telomeres in long-lived winter bees. We term this the telomere premature aging syndrome.},
}
@article {pmid20473888,
year = {2011},
author = {Oh, BK and Um, TH and Choi, GH and Park, YN},
title = {Frequent changes in subtelomeric DNA methylation patterns and its relevance to telomere regulation during human hepatocarcinogenesis.},
journal = {International journal of cancer},
volume = {128},
number = {4},
pages = {857-868},
doi = {10.1002/ijc.25398},
pmid = {20473888},
issn = {1097-0215},
mesh = {Carcinoma, Hepatocellular/*genetics/*pathology ; Cell Transformation, Neoplastic/*pathology ; Chromosomes, Human, Pair 18/genetics ; Chromosomes, Human, Pair 21/genetics ; Chromosomes, Human, Pair 7/genetics ; *DNA Methylation ; DNA, Neoplasm/genetics ; Humans ; Liver Neoplasms/*genetics/*pathology ; Polymerase Chain Reaction ; Prognosis ; Telomere/*genetics ; },
abstract = {Subtelomeric chromatin modifications are important regulators of telomere length. We examined the subtelomeric DNA methylation status of 7q, 8q, 17q, 18p, 21q and XpYp in 32 pairs of hepatocellular carcinomas (HCCs) and their adjacent non-HCCs via methylation-specific PCR (quantified as methylation ratio). In addition, 10q was subjected to bisulfite-genomic-sequencing. Telomere length was determined by Southern hybridization. In all cases, the relationship between methylation ratio and telomere length was determined. High levels of methylation ratio were found on chromosomes 7q, 18p and XpYp, whereas 8q 17q and 21q were less methylated in both HCCs and non-HCCs. Compared to non-HCCs, HCCs exhibited a higher methylation ratio on 18p and 21q, and a wider distribution of methylation ratio on 7q, 21q and 10q (p < 0.05). The methylation ratio of 18p and of 21q was negatively and positively correlated with telomere length of HCCs, respectively (p < 0.05). We evaluated changes in methylation pattern between non-HCCs and HCCs. Out of 185 sites, hypermethylation changes from non-HCC to HCC were found at 47 sites and hypomethylation changes at 31 sites. Changes in methylation pattern were observed at three to four sites among six chromosomal sites in 15 patients (47%). There was a tendency toward hypomethylation changes at 7q (p = 0.013) and hypermethylation changes at 21q (p = 0.057) when telomere lengthened from non-HCCs to HCCs. In summary, subtelomeric methylation patterns dynamically changed during hepatocarcinogenesis. Subtelomeric methylation at certain regions was related to telomere lengthening or shortening, suggesting an association between subtelomeric chromatin structure and telomere length regulation in human hepatocarcinogenesis.},
}
@article {pmid20464436,
year = {2010},
author = {Cysewski, P and Czeleń, P},
title = {Structural and energetic consequences of oxidation of d(ApGpGpGpTpT) telomere repeat unit in complex with TRF1 protein.},
journal = {Journal of molecular modeling},
volume = {16},
number = {11},
pages = {1797-1807},
pmid = {20464436},
issn = {0948-5023},
mesh = {Base Sequence ; Molecular Conformation ; Molecular Sequence Data ; Oxidation-Reduction ; Protein Binding ; Purines/metabolism ; Regression Analysis ; Repetitive Sequences, Nucleic Acid/*genetics ; Telomere/*chemistry/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/*chemistry/*metabolism ; Thermodynamics ; },
abstract = {The configuration hyperspace of canonical and oxidized 14-mers of B-DNA comprising telomere repeat units d(ApGpGpGpTpT) was sampled over 40 ns via molecular dynamic (MD) simulations. The energetic and structural consequences of TRF1 binding to telomere B-DNA were compared with non-complexed systems. Energetic properties of analyzed pairs, di- and tri-nucleotide steps occurring in central telomere repeat unit were estimated by means of advanced quantum chemistry computations including not only BSSE corrections, electron correlation contributions but also non-negligible many-body terms. These data along with bases pair and base step parameters distributions allow for quantization of consequences of oxidation and/or TRF1 binding to telomere repeat units. Occurrence of 8-oxoguanine in central telomeric triad (CTT) is the source of high stiffness if compared to non-modified oligomer. The origin of this property comes from significantly alteration of intermolecular interactions introduced by 8-oxoguanine. The increased stability observed for base-base interactions are accumulated and characterizes also di- and tri-nucleotides. The observed changes in the intermolecular interactions originate from structural alterations imposed by TRF1 binding to canonical and oxidized telomere B-DNA. First and most direct consequence of TRF1 binding to oxidized telomere repeat unit is alteration of shift-slide correlations if compared to canonical system. This in turn leads to large differences in purine-purine overlapping in oxidized structures. Thus, oxidized telomere B-DNA double strands are sensitive to interactions with protein ligands and numerous structural and energetic changes are imposed on base pairs forming CTT.},
}
@article {pmid20462651,
year = {2010},
author = {Hoare, M and Gelson, WT and Das, A and Fletcher, JM and Davies, SE and Curran, MD and Vowler, SL and Maini, MK and Akbar, AN and Alexander, GJ},
title = {CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection.},
journal = {Journal of hepatology},
volume = {53},
number = {2},
pages = {252-260},
pmid = {20462651},
issn = {1600-0641},
support = {G0801213/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Antiviral Agents/*therapeutic use ; Biopsy ; CD4-Positive T-Lymphocytes/*pathology ; Case-Control Studies ; Female ; *Hepacivirus ; Hepatitis C, Chronic/diagnosis/*drug therapy/*pathology ; Humans ; Liver/pathology ; Liver Cirrhosis/*pathology ; Male ; Middle Aged ; Phenotype ; Prognosis ; Regression Analysis ; Severity of Illness Index ; Telomere/*pathology ; Treatment Outcome ; },
abstract = {BACKGROUND &amp; AIMS: Increasing age is associated with impaired immune function and in chronic HCV infection specifically, with progressive fibrosis, liver failure, HCC and impaired responses to antiviral therapy. T-lymphocyte telomere length declines with age. We hypothesised that shorter T-lymphocyte telomere length would be associated with poor clinical outcome in HCV infection.<br><br>METHODS: Circulating T-lymphocyte telomere length, an objective measure of immune senescence, was measured by flow-FISH in 135 HCV-RNA-positive, treatment-na&#xef;ve patients and 41 healthy controls in relation to clinical outcome.<br><br>RESULTS: Shorter CD4+CD45RO+ T-lymphocyte telomeres were associated with severe fibrosis (p=0.003), independent of male sex (p=0.04), CMV positivity (p=0.003), previous HBV infection (p=0.007), and age (p=ns) in viraemic patients compared to controls. There were inverse correlations between CD4+CD45RO+ telomere length and fibrosis stage (p<0.001), portal tract inflammatory grade (p=0.035), prothrombin time (p<0.001) and bilirubin (p=0.001). One hundred and twenty-four viraemic individuals were followed prospectively to a composite endpoint of death, hepatic decompensation or HCC. Independent of age, those with shorter CD4+CD45RO+ telomeres were less likely to be complication free after 2-years than those with longer telomeres (86% versus 96%, p=0.009) with an age-adjusted hazard ratio of 0.93 (0.90-0.96). In addition, CD4+CD45RO+ telomere length predicted successful antiviral therapy (p=0.001) independent of other factors.<br><br>CONCLUSIONS: CD4+ T-lymphocyte telomere length, independent of age, was related to inflammatory grade, fibrosis stage, laboratory indices of severity, subsequent hepatic decompensation and treatment outcome in patients with chronic HCV infection.},
}
@article {pmid20459667,
year = {2010},
author = {da Silva, MS and Perez, AM and da Silveira, Rde C and de Moraes, CE and Siqueira-Neto, JL and Freitas, Lde H and Cano, MI},
title = {The Leishmania amazonensis TRF (TTAGGG repeat-binding factor) homologue binds and co-localizes with telomeres.},
journal = {BMC microbiology},
volume = {10},
number = {},
pages = {136},
pmid = {20459667},
issn = {1471-2180},
mesh = {Amino Acid Sequence ; Blotting, Western ; Chromatin Immunoprecipitation ; Cloning, Molecular ; In Situ Hybridization, Fluorescence ; Leishmania mexicana/*chemistry/*physiology ; Molecular Sequence Data ; Polymerase Chain Reaction ; Protein Binding ; Protozoan Proteins/*analysis/*genetics ; Sequence Alignment ; Sequence Homology, Amino Acid ; Telomere/*chemistry ; Telomere-Binding Proteins/*analysis/*genetics ; Telomeric Repeat Binding Protein 1/genetics ; Telomeric Repeat Binding Protein 2/genetics ; },
abstract = {BACKGROUND: Telomeres are specialized structures at the end of chromosomes essential for maintaining genome stability and cell viability. The importance of telomeric proteins for telomere maintenance has increased our interest in the identification of homologues within the genus Leishmania. The mammalian TRF1 and TRF2 proteins, for example, bind double-stranded telomeres via a Myb-like DNA-binding domain and are involved with telomere length regulation and chromosome end protection. In addition, TRF2 can modulate the activity of several enzymes and influence the conformation of telomeric DNA. In this work, we identified and characterized a Leishmania protein (LaTRF) homologous to both mammalian TRF1 and TRF2.<br><br>RESULTS: LaTRF was cloned using a PCR-based strategy. ClustalW and bl2seq sequence analysis showed that LaTRF shared sequence identity with the Trypanosoma brucei TRF (TbTRF) protein and had the same degree of sequence similarities with the dimerization (TRFH) and the canonical DNA-binding Myb-like domains of both mammalian TRFs. LaTRF was predicted to be an 82.5 kDa protein, indicating that it is double the size of the trypanosome TRF homologues. Western blot and indirect immunofluorescence combined with fluorescence in situ hybridization showed that LaTRF, similarly to hTRF2, is a nuclear protein that also associates with parasite telomeres. Native and full length LaTRF and a mutant bearing the putative Myb-like domain expressed in bacteria bound double-stranded telomeric DNA in vitro. Chromatin immunoprecipitation showed that LaTRF interacted specifically with telomeres in vivo.<br><br>CONCLUSION: The nuclear localization of LaTRF, its association and co-localization with parasite telomeres and its high identity with TbTRF protein, support the hypothesis that LaTRF is a Leishmania telomeric protein.},
}
@article {pmid20456367,
year = {2010},
author = {Waki, K and Anno, K and Ono, T and Ide, T and Chayama, K and Tahara, H},
title = {Establishment of functional telomerase immortalized human hepatocytes and a hepatic stellate cell line for telomere-targeting anticancer drug development.},
journal = {Cancer science},
volume = {101},
number = {7},
pages = {1678-1685},
doi = {10.1111/j.1349-7006.2010.01576.x},
pmid = {20456367},
issn = {1349-7006},
mesh = {Antineoplastic Agents/pharmacology/toxicity ; Cell Division ; Cell Line, Tumor ; Fetus ; Gene Amplification ; Hepatic Stellate Cells/drug effects/*enzymology ; Hepatocytes/drug effects/*enzymology/virology ; Humans ; Oxazoles/pharmacology/toxicity ; RNA/genetics/isolation &amp; purification ; RNA, Messenger/genetics ; Retroviridae/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/drug effects/*genetics/metabolism ; Telomere/drug effects/*physiology/ultrastructure ; Transduction, Genetic ; },
abstract = {We previously reported that the telomere-targeting drug telomestatin induces apoptosis accompanied by G-tail reduction and dissociation of binding protein TRF2 from telomeres in cancer cell lines but not normal or human telomerase reverse transcriptase (hTERT)-immortalized cells. Because telomere-targeting drugs induce growth arrest in normal cells at higher doses, their development is dependent on the ability to predict toxicity before in vivo use, but no models for this are available. Here, we established two new cell lines, telomerase immortalized human fetal hepatocytes, Hc3716-hTERT, and telomerase immortalized hepatic stellate cells, NPC-hTERT. Examinations showed that Hc3716-hTERT maintained normal mammalian cell morphology, cell growth, albumin expression, and wild-type p53 responsiveness, whereas NPC-hTERT maintained hepatic stellate-like morphology, expression of hepatic stellate markers, alpha-smooth muscle actin, and secretion of type I collagen, an extracellular matrix protein. Given our finding that telomere G-tail length in Hc3716 cells was decreased in senescence and increased by hTERT infection, we next examined the effect of high-dose telomestatin-induced telomere dysfunction and G-tail shortening on cellular functions in Hc3716-hTERT cells. Interestingly, telomestatin decreased expression of cytochrome P450 (CYP) family members CYP3A3/4, CYP3A5, and CYP3A7, mRNA and induced albumin expression at both mRNA and protein levels. These gene expression responses to telomestatin were similar to those of the normal parental cell Hc3716. These established cell lines thus represent the first model for predicting the side-effects of telomere-targeting drugs in normal cells, and should be powerful tools in the development of these drugs.},
}
@article {pmid20455255,
year = {2010},
author = {Takubo, K and Fujita, M and Izumiyama, N and Nakamura, K and Ishikawa, N and Poon, SS and Fujiwara, M and Sawabe, M and Matsuura, M and Grabsch, H and Arai, T and Aida, J},
title = {Q-FISH analysis of telomere and chromosome instability in the oesophagus with and without squamous cell carcinoma in situ.},
journal = {The Journal of pathology},
volume = {221},
number = {2},
pages = {201-209},
doi = {10.1002/path.2704},
pmid = {20455255},
issn = {1096-9896},
mesh = {Aged ; Aged, 80 and over ; Carcinoma in Situ/*genetics/pathology ; Carcinoma, Squamous Cell/*genetics/pathology ; Case-Control Studies ; Chromosomal Instability/*genetics ; Esophageal Neoplasms/*genetics/pathology ; Female ; Humans ; In Situ Hybridization, Fluorescence/methods ; Male ; Middle Aged ; Telomere/*genetics/pathology ; Tumor Cells, Cultured ; },
abstract = {Chromosomal and genomic instability due to telomere dysfunction is known to play an important role in carcinogenesis. To study telomere dysfunction in the surrounding background epithelium of squamous cell carcinoma in situ (CIS) of the oesophagus, we measured telomere lengths of basal and parabasal cells of epithelia with and without CIS using quantitative fluorescence in situ hybridization (Q-FISH) and our original software, Tissue Telo. Additionally, we assessed histological inflammation and the anaphase bridge index. In non-cancerous epithelium, telomeres in basal cells were significantly longer than those in parabasal cells, whereas CIS showed a homogeneous telomere pattern in the basal and parabasal cells. Telomeres in basal and parabasal cells were significantly shorter in the background with CIS than in epithelium from age-matched normal controls. Significant negative correlation was observed between the normalized telomere : centromere ratio (reflected telomere length) and the anaphase bridge index in non-cancerous epithelia from both normal controls and the CIS background with no histological inflammation. These findings indicate that tissue stem cells may be located among basal cells, and that telomere length distribution in component cell types differs between CIS and non-cancerous epithelium. We have demonstrated conclusively that oesophageal CIS arises from epithelium with short telomeres and chromosomal instability in the absence of histological inflammation.},
}
@article {pmid20454512,
year = {2010},
author = {Lafferty-Whyte, K and Bilsland, A and Hoare, SF and Burns, S and Zaffaroni, N and Cairney, CJ and Keith, WN},
title = {TCEAL7 inhibition of c-Myc activity in alternative lengthening of telomeres regulates hTERT expression.},
journal = {Neoplasia (New York, N.Y.)},
volume = {12},
number = {5},
pages = {405-414},
pmid = {20454512},
issn = {1476-5586},
support = {//Cancer Research UK/United Kingdom ; },
mesh = {Cell Line, Tumor ; *Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Humans ; Immunoprecipitation ; Nuclear Proteins/genetics/*metabolism ; Promoter Regions, Genetic ; Proto-Oncogene Proteins c-myc/genetics/*metabolism ; RNA, Small Interfering ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*biosynthesis/genetics ; Telomere/*metabolism/pathology ; Transcriptional Activation ; Transfection ; },
abstract = {Replicative senescence forms a major barrier to tumor progression. Cancer cells bypass this by using one of the two known telomere maintenance mechanisms: telomerase or the recombination-based alternative lengthening of telomeres (ALT) mechanism. The molecular details of ALT are currently poorly understood. We have previously shown that telomerase is actively repressed through complex networks of kinase, gene expression, and chromatin regulation. In this study, we aimed to gain further understanding of the role of kinases in the regulation of telomerase expression in ALT cells. Using a whole human kinome small interfering RNA (siRNA) screen, we highlighted 106 kinases whose expression is linked to human telomerase reverse transcriptase (hTERT) promoter activity. Network modeling of transcriptional regulation implicated c-Myc as a key regulator of the 106 kinase hits. Given our previous observations of lower c-Myc activity in ALT cells, we further explored its potential to regulate telomerase expression in ALT. We found increased c-Myc binding at the hTERT promoter in telomerase-positive compared with ALT cells, although no expression differences in c-Myc, Mad, or Max were observed between ALT and telomerase-positive cells that could explain decreased c-Myc activity in ALT. Instead, we found increased expression of the c-Myc competitive inhibitor TCEAL7 in ALT cells and tumors and that alteration of TCEAL7 expression levels in ALT and telomerase-positive cells affects hTERT expression. Lower c-Myc activity in ALT may therefore be obtained through TCEAL7 regulation. Thus, TCEAL7 may present an interesting novel target for cancer therapy, which warrants further investigation.},
}
@article {pmid20453489,
year = {2011},
author = {Maeda, T and Oyama, J and Higuchi, Y and Nishiyama, Y and Kudo, Y and Yamori, T and Nakazono, T and Arima, T and Mimori, K and Makino, N},
title = {The physical ability of Japanese female elderly with cerebrovascular disease correlates with the telomere length and subtelomeric methylation status in their peripheral blood leukocytes.},
journal = {Gerontology},
volume = {57},
number = {2},
pages = {137-143},
doi = {10.1159/000314633},
pmid = {20453489},
issn = {1423-0003},
mesh = {Aged ; Aged, 80 and over ; Aging/*genetics ; Asian People/genetics ; Cerebrovascular Disorders/ethnology/*genetics/rehabilitation ; Chronic Disease ; DNA Methylation/*genetics ; Female ; Hospitalization/statistics &amp; numerical data ; Humans ; Leukocytes/physiology ; Motor Activity/*genetics ; Restriction Mapping ; Telomere/*genetics ; },
abstract = {BACKGROUND: The telomere length and subtelomeric methylated status of peripheral blood leukocytes have been reported to be correlated with many kinds of pathophysiological conditions. However, the correlation between the telomeric parameters and patients' physical ability is not known.<br><br>OBJECTIVE: This study aims to study how telomeric parameters, including telomere length and the subtelomeric methylation status of peripheral blood leukocytes, are associated with the physical inability of patients with cerebrovascular disease and its improvement by inpatient rehabilitation.<br><br>METHODS: The physical ability of female patients with cerebrovascular disease admitted in the chronic disease ward of Kyushu University Hospital was assessed using the Barthel index, and the telomeric parameters in their peripheral blood leukocytes were determined by Southern blotting with methylation-sensitive and -insensitive isoschizomers.<br><br>RESULTS: The patients revealed a significant correlation between Barthel score and the mean telomere length and expression of long telomeres (> 9.4 kb). Improvement of the Barthel index of patients during admission was correlated not to telomere length, but to subtelomeric hypermethylation of long telomeres.<br><br>CONCLUSIONS: The physical ability of patients was positively correlated with the lengths of their somatic telomeres, and the recovery potential of physical ability was associated with the subtelomeric hypermethylated status stabilizing long telomeric structure.},
}
@article {pmid20442874,
year = {2010},
author = {Rochette, PJ and Brash, DE},
title = {Human telomeres are hypersensitive to UV-induced DNA Damage and refractory to repair.},
journal = {PLoS genetics},
volume = {6},
number = {4},
pages = {e1000926},
pmid = {20442874},
issn = {1553-7404},
support = {R01 CA055737/CA/NCI NIH HHS/United States ; CA55737/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; DNA/*radiation effects ; *DNA Damage ; *DNA Repair ; Female ; Humans ; Telomere/*metabolism/*radiation effects ; Ultraviolet Rays/*adverse effects ; },
abstract = {Telomeric repeats preserve genome integrity by stabilizing chromosomes, a function that appears to be important for both cancer and aging. In view of this critical role in genomic integrity, the telomere's own integrity should be of paramount importance to the cell. Ultraviolet light (UV), the preeminent risk factor in skin cancer development, induces mainly cyclobutane pyrimidine dimers (CPD) which are both mutagenic and lethal. The human telomeric repeat unit (5'TTAGGG/CCCTAA3') is nearly optimal for acquiring UV-induced CPD, which form at dipyrimidine sites. We developed a ChIP-based technique, immunoprecipitation of DNA damage (IPoD), to simultaneously study DNA damage and repair in the telomere and in the coding regions of p53, 28S rDNA, and mitochondrial DNA. We find that human telomeres in vivo are 7-fold hypersensitive to UV-induced DNA damage. In double-stranded oligonucleotides, this hypersensitivity is a property of both telomeric and non-telomeric repeats; in a series of telomeric repeat oligonucleotides, a phase change conferring UV-sensitivity occurs above 4 repeats. Furthermore, CPD removal in the telomere is almost absent, matching the rate in mitochondria known to lack nucleotide excision repair. Cells containing persistent high levels of telomeric CPDs nevertheless proliferate, and chronic UV irradiation of cells does not accelerate telomere shortening. Telomeres are therefore unique in at least three respects: their biophysical UV sensitivity, their prevention of excision repair, and their tolerance of unrepaired lesions. Utilizing a lesion-tolerance strategy rather than repair would prevent double-strand breaks at closely-opposed excision repair sites on opposite strands of a damage-hypersensitive repeat.},
}
@article {pmid20436780,
year = {2010},
author = {Geronimus, AT and Hicken, MT and Pearson, JA and Seashols, SJ and Brown, KL and Cruz, TD},
title = {Do US Black Women Experience Stress-Related Accelerated Biological Aging?: A Novel Theory and First Population-Based Test of Black-White Differences in Telomere Length.},
journal = {Human nature (Hawthorne, N.Y.)},
volume = {21},
number = {1},
pages = {19-38},
pmid = {20436780},
issn = {1936-4776},
support = {T32 AG000221-18/AG/NIA NIH HHS/United States ; T32 AG000221/AG/NIA NIH HHS/United States ; P30 AG012846-15/AG/NIA NIH HHS/United States ; R01 AG032632/AG/NIA NIH HHS/United States ; U01 NR004061/NR/NINR NIH HHS/United States ; U01 AG017719/AG/NIA NIH HHS/United States ; R01 AG032632-01A1/AG/NIA NIH HHS/United States ; P20 AG012846/AG/NIA NIH HHS/United States ; R01 AG032632-02/AG/NIA NIH HHS/United States ; P30 AG012846/AG/NIA NIH HHS/United States ; R24 HD041028/HD/NICHD NIH HHS/United States ; },
abstract = {We hypothesize that black women experience accelerated biological aging in response to repeated or prolonged adaptation to subjective and objective stressors. Drawing on stress physiology and ethnographic, social science, and public health literature, we lay out the rationale for this hypothesis. We also perform a first population-based test of its plausibility, focusing on telomere length, a biomeasure of aging that may be shortened by stressors. Analyzing data from the Study of Women's Health Across the Nation (SWAN), we estimate that at ages 49-55, black women are 7.5 years biologically "older" than white women. Indicators of perceived stress and poverty account for 27% of this difference. Data limitations preclude assessing objective stressors and also result in imprecise estimates, limiting our ability to draw firm inferences. Further investigation of black-white differences in telomere length using large-population-based samples of broad age range and with detailed measures of environmental stressors is merited.},
}
@article {pmid20436270,
year = {2010},
author = {DeZwaan, DC and Freeman, BC},
title = {Is there a telomere-bound 'EST' telomerase holoenzyme?.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {9},
number = {10},
pages = {1913-1917},
doi = {10.4161/cc.9.10.11536},
pmid = {20436270},
issn = {1551-4005},
support = {DK074270/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Humans ; Models, Biological ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Eukaryotic linear chromosomes culminate in nucleoprotein structures designated telomeres. The terminal telomeric DNA consists of tandem repeats of a G-rich motif that is established and maintained by the action of the specialized reverse transcriptase telomerase. In addition to the core enzyme, effective replication of telomeric DNA requires a number of regulatory factors. In budding yeast, four components identified in the seminal Ever Shorter Telomere (EST) genetic screens constitute the keystone proteins that sustain telomeric DNA. Importantly, the EST proteins appear to be structurally conserved from yeast to human. The mechanism of telomerase recruitment and regulation, with an emphasis on the EST proteins, are discussed in this review.},
}
@article {pmid20435169,
year = {2010},
author = {Georgin-Lavialle, S and Aouba, A and Mouthon, L and Londono-Vallejo, JA and Lepelletier, Y and Gabet, AS and Hermine, O},
title = {The telomere/telomerase system in autoimmune and systemic immune-mediated diseases.},
journal = {Autoimmunity reviews},
volume = {9},
number = {10},
pages = {646-651},
doi = {10.1016/j.autrev.2010.04.004},
pmid = {20435169},
issn = {1873-0183},
mesh = {Aging, Premature/genetics ; Animals ; Apoptosis ; Autoimmune Diseases/*genetics ; Cellular Senescence/genetics/*immunology ; DNA Damage ; Enzyme Activation ; Humans ; Telomerase/genetics/*metabolism ; Telomere/genetics/*immunology ; },
abstract = {Telomeres are specialized nucleoproteic structures that cap and protect the ends of chromosomes. They can be elongated by the telomerase enzyme, but in telomerase negative cells, telomeres shorten after each cellular division because of the end replicating problem. This phenomenon leads ultimately to cellular senescence, conferring to the telomeres a role of biological clock. Oxidative stress, inflammation and increased cell renewal are supplementary environmental factors that accelerate age-related telomere shortening. Similar to other types of DNA damage, very short/dysfunctional telomeres activate a DNA response pathway leading to different outcomes: DNA repair, cell senescence or apoptosis. During the last 10 years, studies on the telomere/telomerase system in autoimmune and/or systemic immune-mediated diseases have revealed its involvement in relevant physiopathological processes. Here, we present a literature review of telomere and telomerase homeostasis in systemic inflammatory diseases including systemic lupus erythematosus, rheumatoid arthritis and granulomatous diseases. The available data indicate that both telomerase activity and telomere length are modified in various systemic immune-mediated diseases and appear to be connected with premature immunosenescence. Studies on the telomere/telomerase system open new research avenues for the basic understanding and for therapeutic approaches of these pathologies.},
}
@article {pmid20431479,
year = {2010},
author = {Kuhn, E and Meeker, A and Wang, TL and Sehdev, AS and Kurman, RJ and Shih, IeM},
title = {Shortened telomeres in serous tubal intraepithelial carcinoma: an early event in ovarian high-grade serous carcinogenesis.},
journal = {The American journal of surgical pathology},
volume = {34},
number = {6},
pages = {829-836},
pmid = {20431479},
issn = {1532-0979},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; },
mesh = {Carcinoma in Situ/*genetics/pathology ; Cystadenocarcinoma, Serous/*genetics/pathology ; Fallopian Tube Neoplasms/*genetics/pathology ; Female ; Fluorescent Antibody Technique ; Humans ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Neoplasm Staging ; Ovarian Neoplasms/*genetics/pathology ; Telomere/*genetics/pathology ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Short telomeres are one of the main genetic manifestations in human cancer, as they have been shown to play an important role in inducing chromosomal instability and in contributing to tumor progression. The purpose of this study was to determine if changes in telomere length occur in serous tubal intraepithelial carcinoma (STIC), the putative precursor of "ovarian" high-grade serous carcinoma (HGSC). Twenty-two STICs from 15 patients with concurrent but discrete HGSCs were analyzed for telomere length on formalin-fixed, paraffin-embedded sections by conducting p53 immunofluorescence to assist in identifying STICs and telomere-specific FISH. Telomere length (short, long, or no change) in STICs was compared with HGSCs using normal fallopian tube epithelium and stromal cells as controls. We found that STICs had the shortest telomeres, as 18 (82%) of 22 STICs had short telomeres, whereas only 2 (9%) showed no change and 2 (9%) had long telomeres compared with the normal-looking tubal epithelium. In contrast, among 12 paired HGSCs and STICs, 6 HGSCs showed an increase in telomere length, one showed a decrease in length and 5 did not show any change when compared with their matched STICs, although, such as STICs, the majority of HGSCs had shorter telomeres than the associated normal tubal epithelial cells. These differences in telomere length between normal tubal epithelial cells and STICs, and between STICs and HGSCs were statisticaly significant (P<0.05). In conclusion, the finding of short telomeres, which have been shown to be one of the earliest molecular changes in carcinogenesis, in a vast majority of STICs provides further support to the proposal that STICs are precursors of HGSC and opens new areas of research in elucidating the early events of ovarian high-grade serous carcinogenesis.},
}
@article {pmid20431348,
year = {2010},
author = {Ju, X},
title = {New roles of hRAD21 in alternative lengthening of telomeres in cancer genesis.},
journal = {Cancer biology &amp; therapy},
volume = {9},
number = {12},
pages = {984-985},
doi = {10.4161/cbt.9.12.12044},
pmid = {20431348},
issn = {1555-8576},
mesh = {Cell Cycle Proteins/genetics/metabolism ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; DNA-Binding Proteins ; Humans ; Nuclear Proteins/genetics/*metabolism ; Phosphoproteins/genetics/*metabolism ; Promyelocytic Leukemia Protein ; *Recombination, Genetic ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Transcription Factors ; Tumor Suppressor Proteins ; Cohesins ; },
}
@article {pmid20430605,
year = {2010},
author = {Barceló, A and Piérola, J and López-Escribano, H and de la Peña, M and Soriano, JB and Alonso-Fernández, A and Ladaria, A and Agustí, A},
title = {Telomere shortening in sleep apnea syndrome.},
journal = {Respiratory medicine},
volume = {104},
number = {8},
pages = {1225-1229},
doi = {10.1016/j.rmed.2010.03.025},
pmid = {20430605},
issn = {1532-3064},
mesh = {Age Factors ; Case-Control Studies ; Female ; Humans ; Male ; Middle Aged ; Oxidative Stress/genetics/*physiology ; Risk Factors ; Severity of Illness Index ; Sleep Apnea Syndromes/genetics/*physiopathology ; Telomere/*pathology ; },
abstract = {BACKGROUND: Telomere length (TL) in circulating leukocytes relates to the chronological age of the individual but it is believed to reflect also the cumulative burden of oxidative stress and inflammation over the life-time. Shortening of TL has been reported in several chronic conditions characterized by oxidative stress and inflammation, such as diabetes and atherosclerosis. Because these conditions also occur in patients with Obstructive Sleep Apnea Syndrome (OSAS), we hypothesized that TL would be reduced in patients with OSAS.<br><br>METHODS: We compared TL in 256 patients with OSAS and 148 controls without OSAS. We also investigated if TL was related to the severity of OSAS, the presence of metabolic disorders and/or cardiovascular risk factors in these patients.<br><br>RESULTS: TL was significantly shorter in patients with OSAS than in controls (p<0.001). This difference persisted after adjustment for age, body mass index, cholesterol, triglycerides, glucose, and uric acid levels, smoking status and the presence of arterial hypertension (p=0.018). TL was not related to the severity of OSAS as assessed by the apnea-hypopnea index, nocturnal oxygen saturation and daytime sleepiness.<br><br>CONCLUSIONS: TL in circulating leukocytes is shorter in patients with OSAS than subjects without OSAS. The mechanism of this observation is unresolved since it appears independent of chronological age, the severity of OSAS and/or the presence of cardiovascular or metabolic alterations but the potential utility of TL as a biomarker of increased cardiovascular risk in these patients justifies further studies.},
}
@article {pmid20427319,
year = {2010},
author = {Fakhoury, J and Marie-Egyptienne, DT and Londoño-Vallejo, JA and Autexier, C},
title = {Telomeric function of mammalian telomerases at short telomeres.},
journal = {Journal of cell science},
volume = {123},
number = {Pt 10},
pages = {1693-1704},
doi = {10.1242/jcs.063636},
pmid = {20427319},
issn = {1477-9137},
support = {MOP86672//Canadian Institutes of Health Research/Canada ; },
mesh = {Animals ; Cell Line, Tumor ; Cloning, Molecular ; DNA/*biosynthesis ; Fibroblasts/*metabolism/pathology ; Gene Expression Regulation, Enzymologic ; Humans ; Mice ; Protein Multimerization ; Species Specificity ; Substrate Specificity ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Transgenes/genetics ; },
abstract = {Telomerase synthesizes telomeric sequences and is minimally composed of a reverse transcriptase (RT) known as TERT and an RNA known as TR. We reconstituted heterologous mouse (m) and human (h) TERT-TR complexes and chimeric mTERT-hTERT-hTR complexes in vitro and in immortalized human alternative lengthening of telomere (ALT) cells. Our data suggest that species-specific determinants of activity, processivity and telomere function map not only to the TR but also to the TERT component. The presence of hTERT-hTR, but not heterologous TERT-TR complexes or chimeric mTERT-hTERT-hTR complexes, significantly reduced the percentage of chromosomes without telomeric signals in ALT cells. Moreover, heterologous and chimeric complexes were defective in recruitment to telomeres. Our results suggest a requirement for several hTERT domains and interaction with multiple proteins for proper recruitment of telomerase to the shortest telomeres in human ALT cells. Late-passage mTERT(-/-) mouse embryonic stem (ES) cells ectopically expressing hTERT or mTERT harboured fewer chromosome ends without telomeric signals and end-to-end fusions than typically observed in late-passage mTERT(-/-) ES cells. The ability of hTERT to function at mouse telomeres and the inability of mTERT to function at human telomeres suggest that mechanisms regulating the recruitment and activity of hTERT at mouse telomeres might be less stringent than the mechanisms regulating mTERT at human telomeres.},
}
@article {pmid20426626,
year = {2010},
author = {Zee, RY and Castonguay, AJ and Barton, NS and Ridker, PM},
title = {Relative leukocyte telomere length and risk of incident ischemic stroke in men: a prospective, nested case-control approach.},
journal = {Rejuvenation research},
volume = {13},
number = {4},
pages = {411-414},
pmid = {20426626},
issn = {1557-8577},
support = {CA-40360/CA/NCI NIH HHS/United States ; CA-34944/CA/NCI NIH HHS/United States ; HL-34595/HL/NHLBI NIH HHS/United States ; HL-26490/HL/NHLBI NIH HHS/United States ; R01 CA097193-08/CA/NCI NIH HHS/United States ; R01 CA097193-07/CA/NCI NIH HHS/United States ; CA-97193/CA/NCI NIH HHS/United States ; R01 CA097193-06A1/CA/NCI NIH HHS/United States ; R01 CA097193/CA/NCI NIH HHS/United States ; R01 CA097193-05/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Brain Ischemia/*genetics ; Case-Control Studies ; Double-Blind Method ; Humans ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Placebos ; Prospective Studies ; Stroke/*genetics ; *Telomere ; },
abstract = {Recent data have implicated telomere-length shortening as potential risk predictor for vascular diseases, including stroke. However, to date, prospective epidemiological data are scarce in relation to ischemic stroke risk. Using leukocyte DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we examined the relationship of leukocyte telomere repeat copy number to single gene copy number (TSR), using a quantitative polymerase chain reaction protocol, amongst 259 white males who subsequently developed an ischemic stroke and amongst an equal number of age- and smoking-matched white males who remained free of reported vascular disease during follow up (controls). The observed TSRs were inversely correlated with age in the controls (p < 0.0001). However, the observed TSRs were similar between cases and controls (p = 0.92). In a multivariable adjusted analysis, no evidence was found for an association of the TSRs with ischemic stroke risk (odds ratio [OR] = 1.100, 95% confidence interval [CI], 0.506-2.392, p = 0.811). The present investigation has shown no evidence for an association of relative leukocyte telomere length with risk of incident ischemic stroke. More importantly, our present findings require replication/confirmation in future large, prospective studies.},
}
@article {pmid20424183,
year = {2010},
author = {Brugat, T and Nguyen-Khac, F and Grelier, A and Merle-Béral, H and Delic, J},
title = {Telomere dysfunction-induced foci arise with the onset of telomeric deletions and complex chromosomal aberrations in resistant chronic lymphocytic leukemia cells.},
journal = {Blood},
volume = {116},
number = {2},
pages = {239-249},
doi = {10.1182/blood-2009-12-257618},
pmid = {20424183},
issn = {1528-0020},
mesh = {Adult ; Aged ; Aged, 80 and over ; Apoptosis/genetics ; Chromatin Immunoprecipitation ; Chromosome Aberrations ; Drug Resistance, Neoplasm/*genetics ; Female ; Fluorescent Antibody Technique ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/*pathology ; Male ; Middle Aged ; Prognosis ; Telomere/*genetics/*pathology ; },
abstract = {In somatic cells, eroded telomeres can induce DNA double-strand break signaling, leading to a form of replicative senescence or apoptosis, both of which are barriers to tumorigenesis. However, cancer cells might display telomere dysfunctions which in conjunction with defects in DNA repair and apoptosis, enables them to circumvent these pathways. Chronic lymphocytic leukemia (CLL) cells exhibit telomere dysfunction, and a subset of these cells are resistant to DNA damage-induced apoptosis and display short telomeres. We show here that these cells exhibit significant resection of their protective telomeric 3' single-stranded overhangs and an increased number of telomere-induced foci containing gammaH2AX and 53BP1. Chromatin immunoprecipitation and immunofluorescence experiments demonstrated increased levels of telomeric Ku70 and phospho-S2056-DNA-PKcs, 2 essential components of the mammalian nonhomologous end-joining DNA repair system. Notably, these CLL cells display deletions of telomeric signals on one or 2 chromatids in parallel with 11q22 deletions, or with 13q14 deletions associated with another chromosomal aberration or with a complex karyotype. Taken together, our results indicate that a subset of CLL cells from patients with an unfavorable clinical outcome harbor a novel type of chromosomal aberration resulting from telomere dysfunction.},
}
@article {pmid20421929,
year = {2010},
author = {Arnoult, N and Schluth-Bolard, C and Letessier, A and Drascovic, I and Bouarich-Bourimi, R and Campisi, J and Kim, SH and Boussouar, A and Ottaviani, A and Magdinier, F and Gilson, E and Londoño-Vallejo, A},
title = {Replication timing of human telomeres is chromosome arm-specific, influenced by subtelomeric structures and connected to nuclear localization.},
journal = {PLoS genetics},
volume = {6},
number = {4},
pages = {e1000920},
pmid = {20421929},
issn = {1553-7404},
mesh = {Cell Line ; Cell Nucleus/*metabolism ; Chromosomes/metabolism ; *DNA Replication ; Humans ; S Phase ; Telomerase/metabolism ; Telomere/*chemistry/metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {The mechanisms governing telomere replication in humans are still poorly understood. To fill this gap, we investigated the timing of replication of single telomeres in human cells. Using in situ hybridization techniques, we have found that specific telomeres have preferential time windows for replication during the S-phase and that these intervals do not depend upon telomere length and are largely conserved between homologous chromosomes and between individuals, even in the presence of large subtelomeric segmental polymorphisms. Importantly, we show that one copy of the 3.3 kb macrosatellite repeat D4Z4, present in the subtelomeric region of the late replicating 4q35 telomere, is sufficient to confer both a more peripheral localization and a later-replicating property to a de novo formed telomere. Also, the presence of beta-satellite repeats next to a newly created telomere is sufficient to delay its replication timing. Remarkably, several native, non-D4Z4-associated, late-replicating telomeres show a preferential localization toward the nuclear periphery, while several early-replicating telomeres are associated with the inner nuclear volume. We propose that, in humans, chromosome arm-specific subtelomeric sequences may influence both the spatial distribution of telomeres in the nucleus and their replication timing.},
}
@article {pmid20421597,
year = {2010},
author = {Joseph, IS and Kumari, A and Bhattacharyya, MK and Gao, H and Li, B and Lustig, AJ},
title = {An mre11 mutation that promotes telomere recombination and an efficient bypass of senescence.},
journal = {Genetics},
volume = {185},
number = {3},
pages = {761-770},
pmid = {20421597},
issn = {1943-2631},
support = {R01 AI066095/AI/NIAID NIH HHS/United States ; R01 GM069943/GM/NIGMS NIH HHS/United States ; R56 GM069943/GM/NIGMS NIH HHS/United States ; },
mesh = {Blotting, Southern ; *Cellular Senescence ; Endodeoxyribonucleases/*genetics ; Exodeoxyribonucleases/*genetics ; Mutation/*genetics ; Rad52 DNA Repair and Recombination Protein/genetics ; *Recombination, Genetic ; Saccharomyces cerevisiae/*genetics/growth &amp; development/metabolism ; Saccharomyces cerevisiae Proteins/*genetics ; Telomerase/metabolism ; Telomere/*genetics ; },
abstract = {Preventing the formation of dysfunctional telomeres is essential for genomic stability. In most organisms, the ribo-nucleoprotein reverse transcriptase telomerase is responsible for telomere GT-strand elongation. However, in telomerase-negative cells, low-frequency recombination mechanisms can avert lethality by elongating critically short telomeres. This study focuses on the involvement of the budding yeast Mre11 in telomere recombination and homeostasis. We have identified a novel allele of MRE11, mre11-A470T, that, in telomerase-positive cells, confers a semidominant decrease in telomere size and a recessive defect in telomere healing. In addition, mutant cells lack normal telomere size homeostasis. Telomerase-negative mre11-A470T cells display a Rad51-dependent bypass of replicative senescence via induction of a highly efficient type I-related recombination pathway termed type IA. The type IA pathway involves an amplification of subtelomeric Y' elements, coupled with elongated and more heterogeneous telomere tracts relative to the short telomere size of type I survivors. The data have led us to propose the involvement of break-induced replication in telomere expansion. The differing phenotypes elicited by the mre11-A470T mutants in telomerase-positive and telomerase-negative cells have also led us to speculate that the telomere end structure may be modified differentially in mre11-A470T cells, directing the telomere into specific pathways.},
}
@article {pmid20421499,
year = {2010},
author = {Levy, D and Neuhausen, SL and Hunt, SC and Kimura, M and Hwang, SJ and Chen, W and Bis, JC and Fitzpatrick, AL and Smith, E and Johnson, AD and Gardner, JP and Srinivasan, SR and Schork, N and Rotter, JI and Herbig, U and Psaty, BM and Sastrasinh, M and Murray, SS and Vasan, RS and Province, MA and Glazer, NL and Lu, X and Cao, X and Kronmal, R and Mangino, M and Soranzo, N and Spector, TD and Berenson, GS and Aviv, A},
title = {Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {107},
number = {20},
pages = {9293-9298},
pmid = {20421499},
issn = {1091-6490},
mesh = {Cohort Studies ; Genome-Wide Association Study ; Genotype ; Humans ; Leukocytes/chemistry/*physiology ; Polymorphism, Single Nucleotide/genetics ; Receptors, CXCR4/genetics/*physiology ; Telomere/genetics/*physiology ; Telomere-Binding Proteins/genetics/*physiology ; },
abstract = {Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P < 5 x 10(-8)). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.},
}
@article {pmid20416088,
year = {2010},
author = {Harville, EW and Williams, MA and Qiu, CF and Mejia, J and Risques, RA},
title = {Telomere length, pre-eclampsia, and gestational diabetes.},
journal = {BMC research notes},
volume = {3},
number = {},
pages = {113},
pmid = {20416088},
issn = {1756-0500},
abstract = {BACKGROUND: Telomere length is a marker of cumulative damage to the cell, and has been associated with cardiovascular disease, hypertension, and diabetes.<br><br>FINDINGS: The association of telomere length with pre-eclampsia and gestational diabetes mellitus (GDM) was examined in a nested case-control study. Circulating leukocyte telomere length was measured by Quantitative-PCR. Mean and median telomere length among cases and controls was compared, and logistic regression was used to model the outcomes as a function of tertile telomere length, with control for effects of potential confounders. Mean telomere length in pre-eclampsia cases was 0.77 (SD 0.14), in GDM cases was 0.73 (SD 0.10), and in controls was 0.74 (SD 0.14). The adjusted odds ratio comparing the highest tertile to the lowest for pre-eclampsia was 0.92 (0.15-5.46), and for gestational diabetes was 0.65 (0.13-3.34).<br><br>CONCLUSIONS: Further study is necessary to determine if telomere length is associated with these pregnancy complications.},
}
@article {pmid20413788,
year = {2010},
author = {Zielke, S and Bodnar, A},
title = {Telomeres and telomerase activity in scleractinian corals and Symbiodinium spp.},
journal = {The Biological bulletin},
volume = {218},
number = {2},
pages = {113-121},
doi = {10.1086/BBLv218n2p113},
pmid = {20413788},
issn = {1939-8697},
mesh = {Alveolata/*enzymology/*genetics ; Animals ; Anthozoa/*enzymology/*genetics ; Nucleic Acid Amplification Techniques ; Polymorphism, Restriction Fragment Length ; Repetitive Sequences, Nucleic Acid ; Sequence Analysis, DNA ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are the repetitive sequences of DNA and associated proteins that cap the ends of eukaryotic chromosomes and play an essential role in maintaining chromosome stability. Compromised telomeres can lead to cell cycle arrest, senescence, apoptosis, or genetic instability, whereas maintenance of telomeres can endow cells with the capacity for indefinite self-renewal. Telomere integrity is maintained in most cells by the activity of telomerase, a ribonucleoprotein that can catalyze the addition of repeat sequences onto chromosome ends. Using the telomeric repeat amplification protocol (TRAP) assay, we detected telomerase activity in host nuclear extracts prepared from two scleractinian corals, Madracis auretenra and Madracis decactis, and also in cultured Symbiodinium, the symbiotic algae that live within corals. Sequencing the TRAP reaction products indicated that the telomeric DNA repeat sequence was TTAGGG for coral and TTTAGGG for Symbiodinium. Using this sequence information, we estimated telomere lengths by terminal restriction fragment (TRF) analysis to be greater than 19 kb for several species of coral and their associated Symbiodinium. Maintenance of coral telomeres by telomerase activity may be a mechanism that confers continuous growth and reproductive plasticity to these long-lived organisms.},
}
@article {pmid20413528,
year = {2010},
author = {Mather, KA and Jorm, AF and Milburn, PJ and Tan, X and Easteal, S and Christensen, H},
title = {No associations between telomere length and age-sensitive indicators of physical function in mid and later life.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {65},
number = {8},
pages = {792-799},
doi = {10.1093/gerona/glq050},
pmid = {20413528},
issn = {1758-535X},
mesh = {Adult ; Aged ; *Aging ; Biomarkers ; Humans ; Middle Aged ; Motor Activity ; Polymerase Chain Reaction ; Systole ; *Telomere ; },
abstract = {Telomere length, which declines with age, has been hypothesized to act as an indicator of biological aging. If it fulfills this purpose, shorter telomere length should correlate with age-related loss of physical function, independent of age. In this cross-sectional Australian population study, the associations between peripheral blood leukocyte telomere length and age-sensitive indicators of physical function (lung function, blood pressure, and grip strength) were examined in two narrow age range cohorts aged 44-49 years (n = 351) and 64-70 years (n = 295). Telomere length was correlated with systolic blood pressure but only for women of the younger cohort and in the opposite direction to that expected (partial r = .181, p = .017). This evidence does not provide support for the hypothesis that telomere length is related to age-associated changes in physical function.},
}
@article {pmid20412312,
year = {2011},
author = {Babizhayev, MA and Vishnyakova, KS and Yegorov, YE},
title = {Telomere-dependent senescent phenotype of lens epithelial cells as a biological marker of aging and cataractogenesis: the role of oxidative stress intensity and specific mechanism of phospholipid hydroperoxide toxicity in lens and aqueous.},
journal = {Fundamental &amp; clinical pharmacology},
volume = {25},
number = {2},
pages = {139-162},
doi = {10.1111/j.1472-8206.2010.00829.x},
pmid = {20412312},
issn = {1472-8206},
mesh = {Aged ; Aging ; Animals ; Aqueous Humor/metabolism ; Biomarkers/metabolism ; Cataract/*pathology ; Cellular Senescence ; Epithelial Cells/metabolism/pathology ; Humans ; Lens, Crystalline/metabolism/*pathology ; Lipid Peroxides/metabolism ; Oxidative Stress ; Telomere/*metabolism ; },
abstract = {Cataract formation represents a serious problem in the elderly and has a large impact on healthcare budget. Aging and cataract formation are relatively complex phenomena, both in vivo and in vitro. Telomeres are special structures at the end of chromosomes. They shorten during each round of replication, and this has been characterized as a mitotic counting mechanism. Our review analysis in this work shows that the rate of telomere shortening in human lens epithelial cells during aging and cataract formation is modulated by oxidative stress as well as by differences in antioxidative defense capacity of the normal and cataractous crystalline lenses. Presented in this review studies suggest that telomere shortening in human lens cells and increased oxidative stress are the result of the peroxidative damage to the lens cell membranes and biomolecules induced in the lack of reductive detoxification of phospholipid hydroperoxides as the triggering mechanism of cataractogenesis. Lipid peroxidation (LPO) is a causative factor of cataract. The increased concentrations of primary molecular LPO products (diene conjugates, lipid hydroperoxides) and end fluorescent LPO products were detected in the lipid moieties of the aqueous humor samples obtained from patients with senile and complicated cataracts when compared to normal donors. The progressive accumulation of oxidative damage may act as an important mechanism for organism aging and cataractogenesis. The oxidative stress form and intensity might determine the lens senescence rate and cataract type, making efforts in the cataract prevention challenge more complex. The analyzed challenge in this work is that the reduction in telomere shortening rate and damages in telomeric DNA make an important contribution to the anticataract and life-extension effect of carnosine administered systemically in the formulations stabilizing a dipeptide from the enzymatic hydrolysis with carnosinase, or topically administered to the eye with carnosine ophthalmic prodrug N-acetylcarnosine and lubricant formulations thereof including corneal absorption promoters. Telomere length in the human crystalline lens cells is a reflection of aging, cataractogenesis, and lifespan in biogerontological studies.},
}
@article {pmid20404094,
year = {2010},
author = {Abreu, E and Aritonovska, E and Reichenbach, P and Cristofari, G and Culp, B and Terns, RM and Lingner, J and Terns, MP},
title = {TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo.},
journal = {Molecular and cellular biology},
volume = {30},
number = {12},
pages = {2971-2982},
pmid = {20404094},
issn = {1098-5549},
support = {232812/ERC_/European Research Council/International ; F31 GM087949/GM/NIGMS NIH HHS/United States ; R01 CA104676/CA/NCI NIH HHS/United States ; F31GM087949/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatin Immunoprecipitation ; DNA Damage ; HeLa Cells ; Humans ; Protein Binding ; Protein Structure, Secondary ; Protein Transport ; Shelterin Complex ; Telomerase/*metabolism ; Telomere/*enzymology ; Telomere-Binding Proteins/chemistry/deficiency/*metabolism ; },
abstract = {Recruitment to telomeres is a pivotal step in the function and regulation of human telomerase; however, the molecular basis for recruitment is not known. Here, we have directly investigated the process of telomerase recruitment via fluorescence in situ hybridization (FISH) and chromatin immunoprecipitation (ChIP). We find that depletion of two components of the shelterin complex that is found at telomeres--TPP1 and the protein that tethers TPP1 to the complex, TIN2--results in a loss of telomerase recruitment. On the other hand, we find that the majority of the observed telomerase association with telomeres does not require POT1, the shelterin protein that links TPP1 to the single-stranded region of the telomere. Deletion of the oligonucleotide/oligosaccharide binding fold (OB-fold) of TPP1 disrupts telomerase recruitment. In addition, while loss of TPP1 results in the appearance of DNA damage factors at telomeres, the DNA damage response per se does not account for the telomerase recruitment defect observed in the absence of TPP1. Our findings indicate that TIN2-anchored TPP1 plays a major role in the recruitment of telomerase to telomeres in human cells and that recruitment does not depend on POT1 or interaction of the shelterin complex with the single-stranded region of the telomere.},
}
@article {pmid20404006,
year = {2010},
author = {Lantuejoul, S and Raynaud, C and Salameire, D and Gazzeri, S and Moro-Sibilot, D and Soria, JC and Brambilla, C and Brambilla, E},
title = {Telomere maintenance and DNA damage responses during lung carcinogenesis.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {16},
number = {11},
pages = {2979-2988},
doi = {10.1158/1078-0432.CCR-10-0142},
pmid = {20404006},
issn = {1557-3265},
mesh = {Adenocarcinoma/*genetics/metabolism ; Adenocarcinoma, Bronchiolo-Alveolar/*genetics/metabolism ; Ataxia Telangiectasia Mutated Proteins ; Carcinoma, Squamous Cell/genetics ; Cell Cycle Proteins/metabolism ; Checkpoint Kinase 2 ; *DNA Damage ; DNA-Binding Proteins/metabolism ; Disease Progression ; Histones/metabolism ; Hyperplasia/pathology ; Immunohistochemistry ; Lung/metabolism/pathology ; Lung Neoplasms/*genetics/metabolism ; Precancerous Conditions/*genetics/metabolism ; Protein Serine-Threonine Kinases/metabolism ; Telomere/*ultrastructure ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; Tumor Suppressor Proteins/metabolism ; },
abstract = {PURPOSE: Telomere shortening is an early event in bronchial carcinogenesis, preceding P53/Rb pathway inactivation and telomerase reactivation, and leading to DNA damage responses (DDR). As their inactivation in cancer increases genetic instability, our objective was to identify the chronology of telomere machinery critical events for malignant progression.<br><br>EXPERIMENTAL DESIGN: We have evaluated telomere length by fluorescence in situ hybridization and analyzed DDR proteins p-CHK2, p-ATM, and p-H2AX, and telomeric maintenance proteins TRF1 and TRF2 expression by immunohistochemistry in normal bronchial/bronchiolar epithelium, and in 109 bronchial preneoplastic lesions, in comparison with 32 squamous invasive carcinoma (SCC), and in 27 atypical alveolar hyperplasia (AAH) in comparison with 6 adenocarcinoma in situ (AIS; formerly bronchiolo-alveolar carcinoma) and 24 invasive adenocarcinoma (ADC).<br><br>RESULTS: Telomere length critically shortened at bronchial metaplasia stage to increase gradually from dysplasia to invasive SCC; in bronchiolo-alveolar lesions, telomere length decreased from normal to AIS and increased from stage I to II to stage III to IV ADC. Expression of TRF1 and TRF2 increased progressively from dysplasia to SCC and from AAH to invasive ADC. The expression of concomitant DDR proteins increased significantly from low- to high-grade dysplasia and from AAH to AIS and stage I to II ADC. P-CHK2 and p-H2AX expressions were highly correlated and both decreased, along with p-ATM, in SCC and advanced ADC.<br><br>CONCLUSION: Telomere attrition occurs at the earliest stage of lung carcinogenesis as an initiating event, preceding TRF1 and TRF2 overexpression for telomere stabilization. In contrast, dismiss of DDR, through p-H2AX and p-CHK2 downregulation, represents a late progressing event associated with SCC and ADC progression.},
}
@article {pmid20403221,
year = {2010},
author = {Chen, W and Chen, SM and Yu, Y and Xiao, BK and Huang, ZW and Tao, ZZ},
title = {Telomerase inhibition alters telomere maintenance mechanisms in laryngeal squamous carcinoma cells.},
journal = {The Journal of laryngology and otology},
volume = {124},
number = {7},
pages = {778-783},
doi = {10.1017/S0022215109992854},
pmid = {20403221},
issn = {1748-5460},
mesh = {Carcinoma, Squamous Cell/genetics/*metabolism ; Cell Line, Tumor ; DNA-Binding Proteins/analysis ; Humans ; In Situ Hybridization, Fluorescence ; Laryngeal Neoplasms/genetics/*metabolism ; Neoplasm Proteins/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*antagonists &amp; inhibitors/genetics ; Telomere/*physiology ; Transfection ; },
abstract = {BACKGROUND AND PURPOSE: Telomere length must be maintained throughout cancer cell progression and proliferation. In most tumours, telomerase activity maintains telomere length. Therefore, telomerase is a target for cancer treatments. However, some cancer cells maintain telomere length through an alternative mechanism termed 'alternative lengthening of telomeres'. To determine how telomerase inhibition relates to the initiation of the alternative lengthening of telomeres pathway, we investigated telomerase activity and telomere maintenance in Hep-2 cells with and without reduced telomerase activity.<br><br>MATERIALS AND METHODS: We investigated telomerase activity levels in a normal Hep-2 cell line and in residual cells following telomerase inhibition treatment. Additionally, we looked for expression of a marker protein for the alternative lengthening of telomeres mechanism.<br><br>RESULTS AND CONCLUSIONS: In the residual cells, telomerase activity was eliminated. However, these cells had higher levels of the alternative lengthening of telomeres biomarker, suggesting an alternative mechanism for telomere maintenance following telomerase inhibition. These results could have a major impact on the design of new cancer treatments.},
}
@article {pmid20403043,
year = {2010},
author = {Nakajima, T and Nakashima, T and Okada, Y and Jo, M and Nishikawa, T and Mitsumoto, Y and Katagishi, T and Kimura, H and Itoh, Y and Kagawa, K and Yoshikawa, T},
title = {Nuclear size measurement is a simple method for the assessment of hepatocellular aging in non-alcoholic fatty liver disease: Comparison with telomere-specific quantitative FISH and p21 immunohistochemistry.},
journal = {Pathology international},
volume = {60},
number = {3},
pages = {175-183},
doi = {10.1111/j.1440-1827.2009.02504.x},
pmid = {20403043},
issn = {1440-1827},
mesh = {Adult ; Cell Nucleus/metabolism/*pathology ; *Cell Nucleus Size ; Cell Proliferation ; Cellular Senescence/*genetics ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Fatty Liver/genetics/metabolism/*pathology ; Female ; Hepatocytes/metabolism/*pathology ; Humans ; Immunohistochemistry/methods ; In Situ Hybridization, Fluorescence/methods ; Liver/metabolism/*pathology ; Male ; Statistics, Nonparametric ; Telomere/metabolism/pathology ; },
abstract = {Telomere-specific quantitative fluorescent in situ hybridization (Q-FISH) accurately evaluates hepatocellular aging on histological sections, but it requires appropriate tissue processing. To establish a more simple method for the assessment of hepatocellular aging, the usefulness of nuclear size measurement was clarified using biopsy liver samples from 64 patients with non-alcoholic fatty liver disease (NAFLD), a model for oxidative stress-associated hepatocellular aging, and 11 control individuals. Relative telomere intensity (RTI) was measured on Q-FISH, and the relative nuclear size (RNS) was calculated as the average nuclear size of the hepatocytes divided by that of lymphocytes. In normal individuals and NAFLD patients, the RTI and RNS were negatively correlated. The degree of nuclear enlargement in NAFLD patients was larger than that in normal individuals with the same telomere length, possibly reflecting telomere-independent senescence. In NAFLD patients with RNS >2.0, the regenerative responses, indicated by the ratio of Ki-67-positive index to serum alanine aminotransferase level, were significantly reduced. The RNS positively correlated with the p21 expression, another marker of senescence. This all indicates that nuclear enlargement progresses in parallel with reduced regenerative responses, telomere shortening, and p21 upregulation. Nuclear size measurement is an effective method for estimation of hepatocellular aging.},
}
@article {pmid20399262,
year = {2010},
author = {Swanberg, SE and O'Hare, TH and Robb, EA and Robinson, CM and Chang, H and Delany, ME},
title = {Telomere biology of the chicken: a model for aging research.},
journal = {Experimental gerontology},
volume = {45},
number = {9},
pages = {647-654},
doi = {10.1016/j.exger.2010.04.002},
pmid = {20399262},
issn = {1873-6815},
mesh = {Aging/*physiology ; Animals ; Cell Line ; Cell Line, Tumor ; Chick Embryo/physiology ; Chickens/genetics/*physiology ; Female ; Fibroblasts/physiology ; Humans ; Male ; Mice ; Models, Animal ; Sex Chromosomes/physiology ; Species Specificity ; Telomerase/genetics/metabolism ; Telomere/*physiology ; },
abstract = {Division-dependent telomere shortening correlating with age triggers senescence on a cellular level and telomere dysfunction can facilitate oncogenesis. Therefore, the study of telomere biology is critical to the understanding of aging and cancer. The domestic chicken, a classic model for the study of developmental biology, possesses a telomere genome with highly conserved aspects and distinctive features which make it uniquely suited for the study of telomere maintenance mechanisms, their function and dysfunction. The purpose of this review is to highlight the chicken as a model for aging research, specifically as a model for telomere and telomerase research, and to increase its utility as such by describing developments in the study of chicken telomeres and telomerase in the context of related research in human and mouse.},
}
@article {pmid20398917,
year = {2010},
author = {Hjelmborg, JV and Nzietchueng, R and Kimura, M and Gardner, JP and Bladbjerg, EM and Christensen, K and Aviv, A and Benetos, A},
title = {Leukocyte telomere length is inversely correlated with plasma Von Willebrand factor.},
journal = {Thrombosis research},
volume = {125},
number = {6},
pages = {e339-42},
doi = {10.1016/j.thromres.2010.03.006},
pmid = {20398917},
issn = {1879-2472},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Blood Coagulation ; Cohort Studies ; Data Collection ; Female ; Humans ; Leukocytes/*cytology ; Male ; Middle Aged ; Regression Analysis ; Sex Factors ; Telomere/*ultrastructure ; von Willebrand Factor/*analysis ; },
abstract = {INTRODUCTION: Leukocyte telomere length (LTL) is short, while the plasma level of Von Willebrand (VWF) is high in persons with atherosclerosis. Moreover, both short LTLs and high VWF levels are observed in individuals who display risks for atherosclerosis, including hypertension, obesity, insulin resistance, cigarette smoking and low socio-economic status. We examined the association between LTL and VWF plasma levels to test the hypothesis that high levels of VWF promote an increase in the turnover of blood cells, including leukocytes. Such a process would heighten the rate of age-dependent LTL attrition, ultimately resulting in shortened LTL.<br><br>METHODS: We studied 3 cohorts: the ADELAHYDE study (age 60-87years), the ERA study (age 41-88years) and the Longitudinal Study of Aging Danish Twins (LSADT) (age 73-94years).<br><br>RESULTS: Multiple regression analysis with LTL as the dependent variable, and age, sex and VWF as the independent variables showed that LTL was inversely correlated with VWF in the ADELAHYDE (beta=-0.125, p<0.001) and the ERA study (beta=-0.148, p=0.010). The LSADT displayed VWF x age interaction, which was incorporated into the model, showing that LTL was also inversely correlated with VWF (beta=-0.057, p=0.04).<br><br>CONCLUSIONS: The inverse relationship between LTL and VWF, observed in 3 different populations, suggests that LTL might be linked to the coagulative status of the individual. Further research will be required to confirm our observations and their clinical ramifications.},
}
@article {pmid20398377,
year = {2010},
author = {Castle, JC and Biery, M and Bouzek, H and Xie, T and Chen, R and Misura, K and Jackson, S and Armour, CD and Johnson, JM and Rohl, CA and Raymond, CK},
title = {DNA copy number, including telomeres and mitochondria, assayed using next-generation sequencing.},
journal = {BMC genomics},
volume = {11},
number = {},
pages = {244},
pmid = {20398377},
issn = {1471-2164},
mesh = {Animals ; Carcinoid Tumor/*genetics ; Cell Line, Tumor ; *DNA Copy Number Variations ; Female ; Humans ; Lung Neoplasms/*genetics ; Male ; Mice ; Mitochondria/*genetics ; Sequence Analysis, DNA/methods ; *Telomere ; },
abstract = {BACKGROUND: DNA copy number variations occur within populations and aberrations can cause disease. We sought to develop an improved lab-automatable, cost-efficient, accurate platform to profile DNA copy number.<br><br>RESULTS: We developed a sequencing-based assay of nuclear, mitochondrial, and telomeric DNA copy number that draws on the unbiased nature of next-generation sequencing and incorporates techniques developed for RNA expression profiling. To demonstrate this platform, we assayed UMC-11 cells using 5 million 33 nt reads and found tremendous copy number variation, including regions of single and homogeneous deletions and amplifications to 29 copies; 5 times more mitochondria and 4 times less telomeric sequence than a pool of non-diseased, blood-derived DNA; and that UMC-11 was derived from a male individual.<br><br>CONCLUSION: The described assay outputs absolute copy number, outputs an error estimate (p-value), and is more accurate than array-based platforms at high copy number. The platform enables profiling of mitochondrial levels and telomeric length. The assay is lab-automatable and has a genomic resolution and cost that are tunable based on the number of sequence reads.},
}
@article {pmid20395204,
year = {2010},
author = {Pooley, KA and Sandhu, MS and Tyrer, J and Shah, M and Driver, KE and Luben, RN and Bingham, SA and Ponder, BA and Pharoah, PD and Khaw, KT and Easton, DF and Dunning, AM},
title = {Telomere length in prospective and retrospective cancer case-control studies.},
journal = {Cancer research},
volume = {70},
number = {8},
pages = {3170-3176},
pmid = {20395204},
issn = {1538-7445},
support = {10124/CRUK_/Cancer Research UK/United Kingdom ; 11021/CRUK_/Cancer Research UK/United Kingdom ; A10119/CRUK_/Cancer Research UK/United Kingdom ; G0401527/MRC_/Medical Research Council/United Kingdom ; MC_U105630924/MRC_/Medical Research Council/United Kingdom ; A10123/CRUK_/Cancer Research UK/United Kingdom ; 10118/CRUK_/Cancer Research UK/United Kingdom ; 11022/CRUK_/Cancer Research UK/United Kingdom ; C1287/A9540/CRUK_/Cancer Research UK/United Kingdom ; A10124/CRUK_/Cancer Research UK/United Kingdom ; 19275/CRUK_/Cancer Research UK/United Kingdom ; A9540/CRUK_/Cancer Research UK/United Kingdom ; 10119/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Adolescent ; Adult ; Aged ; Breast Neoplasms/blood/*genetics ; Case-Control Studies ; Cohort Studies ; Colorectal Neoplasms/*genetics ; Female ; Humans ; Middle Aged ; Odds Ratio ; Prospective Studies ; Retrospective Studies ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*ultrastructure ; },
abstract = {Previous studies have reported that shorter mean telomere length in lymphocytes was associated with increased susceptibility to common diseases of aging, and may be predictive of cancer risk. However, most analyses have examined retrospectively collected case-control studies. Mean telomere length was measured using high-throughput quantitative real-time PCR. Blood for DNA extraction was collected after cancer diagnosis in the East Anglian SEARCH Breast (2,243 cases and 2,181 controls) and SEARCH Colorectal (2,249 cases and 2,161 controls) studies. Prospective case-control studies were conducted for breast cancer (199 cases) and colorectal cancer (185 cases), nested within the EPIC-Norfolk cohort. Blood was collected at least 6 months prior to diagnosis, and was matched to DNA from two cancer-free controls per case. In the retrospective SEARCH studies, the age-adjusted odds ratios for shortest (Q4) versus longest (Q1) quartile of mean telomere length was 15.5 [95% confidence intervals (CI), 11.6-20.8; p-het = 5.7 x 10(-75)], with a "per quartile" P-trend = 2.1 x 10(-80) for breast cancer; and 2.14 (95% CI, 1.77-2.59; p-het = 7.3 x 10(-15)), with a per quartile P-trend = 1.8 x 10(-13) for colorectal cancer. In the prospective EPIC study, the comparable odds ratios (Q4 versus Q1) were 1.58 (95% CI, 0.75-3.31; p-het = 0.23) for breast cancer and 1.13 (95% CI, 0.54-2.36; p-het = 0.75) for colorectal cancer risk. Mean telomere length was shorter in retrospectively collected cases than in controls but the equivalent association was markedly weaker in the prospective studies. This suggests that telomere shortening largely occurs after diagnosis, and therefore, might not be of value in cancer prediction.},
}
@article {pmid20395015,
year = {2012},
author = {Wikgren, M and Karlsson, T and Nilbrink, T and Nordfjäll, K and Hultdin, J and Sleegers, K and Van Broeckhoven, C and Nyberg, L and Roos, G and Nilsson, LG and Adolfsson, R and Norrback, KF},
title = {APOE ε4 is associated with longer telomeres, and longer telomeres among ε4 carriers predicts worse episodic memory.},
journal = {Neurobiology of aging},
volume = {33},
number = {2},
pages = {335-344},
doi = {10.1016/j.neurobiolaging.2010.03.004},
pmid = {20395015},
issn = {1558-1497},
mesh = {Adult ; Aged ; Apolipoprotein E4/*genetics/*metabolism ; Biomarkers/metabolism ; Brain/*physiopathology ; Female ; Heterozygote ; Humans ; Male ; *Memory, Episodic ; Middle Aged ; Statistics as Topic ; Telomere/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Both leukocyte telomere length and the apolipoprotein ε4 allele have been associated with mortality, cardiovascular disease, cognition, and dementia. The authors investigated whether leukocyte telomere length was associated with APOE genotype or cognitive abilities in the context of APOE genotype. The setting for this cross-sectional study was 427 nondemented individuals aged 41-81 yr. The authors found that ε4 carriers overall exhibited significantly longer telomeres compared with non-carriers (difference of 268 bp, p = 0.001). This difference was greatest at the lower limit of the age span and nonsignificant at the upper limit, which translated into a significantly higher telomere attrition rate (p = 0.049) among ε4 carriers (37 bp/years) compared with non-carriers (21 bp/year). Further, longer telomeres among ε4 carriers significantly predicted worse performance on episodic memory tasks. No significant associations were found on tasks tapping semantic and visuospatial ability, or among ε3/ε3 carriers. In conclusion, APOE ε4 carriers had longer telomeres compared with non-carriers, but higher rate of attrition. Among them, longer telomeres predicted worse performance on episodic memory tasks. These observations suggest that the ε4 allele is associated with abnormal cell turnover of functional and possibly clinical significance.},
}
@article {pmid20391046,
year = {2010},
author = {Ocampo, C},
title = {Telomere talk: the nutrition connection.},
journal = {Journal of nutrition for the elderly},
volume = {29},
number = {1},
pages = {110-111},
doi = {10.1080/01639360903574775},
pmid = {20391046},
issn = {1540-8566},
mesh = {Aging/genetics ; Cellular Senescence/*genetics ; Humans ; *Telomere ; },
}
@article {pmid20386541,
year = {2010},
author = {Rampazzo, E and Bertorelle, R and Serra, L and Terrin, L and Candiotto, C and Pucciarelli, S and Del Bianco, P and Nitti, D and De Rossi, A},
title = {Relationship between telomere shortening, genetic instability, and site of tumour origin in colorectal cancers.},
journal = {British journal of cancer},
volume = {102},
number = {8},
pages = {1300-1305},
pmid = {20386541},
issn = {1532-1827},
mesh = {Adult ; Aged ; Aged, 80 and over ; Colorectal Neoplasms/*genetics/*pathology ; Female ; *Genomic Instability ; Humans ; Intestinal Mucosa/ultrastructure ; Male ; Middle Aged ; Telomerase/antagonists &amp; inhibitors/metabolism ; Telomere/*pathology ; },
abstract = {BACKGROUND: Telomeres, located at chromosome ends, are progressively shortened during each cell cycle by replication-dependent loss of DNA termini. Although maintenance of telomere length is critical for cell-replicative potential and tumourigenesis, the erosion of telomeres can lead to genetic instability, a pivotal mechanism in the neoplastic process.<br><br>PATIENTS AND METHODS: A total of 118 colorectal cancer (CRC) samples (53 right-colon, 30 left-colon, and 35 rectal tumours) and corresponding adjacent non-cancerous tissues were evaluated for telomere length, p53 mutation, and microsatellite instability (MSI). Telomere length was estimated by real-time PCR.<br><br>RESULTS: Telomeres were significantly shorter in CRCs than in adjacent tissues, regardless of tumour stage and grade, site, or genetic alterations (P<0.0001). Moreover, in normal tissues, but not in tumours, telomere length inversely correlated with age (r=-0.24, P=0.017). Telomere length in CRCs did not differ with tumour progression or p53 status; however, in CRCs carrying the wild-type p53, telomeres were significantly shorter in tumours with MSI than in those with stable microsatellites (P=0.027). Furthermore, telomere length differed according to tumour location, being longer in rectal cancers (P=0.03).<br><br>CONCLUSIONS: These findings suggest that telomere shortening is a key initial event in colorectal carcinogenesis. The extent of telomere erosion is related to tumour origin site and may be influenced by the mismatch repair pathway.},
}
@article {pmid20383691,
year = {2010},
author = {Maubaret, CG and Salpea, KD and Jain, A and Cooper, JA and Hamsten, A and Sanders, J and Montgomery, H and Neil, A and Nair, D and Humphries, SE and , },
title = {Telomeres are shorter in myocardial infarction patients compared to healthy subjects: correlation with environmental risk factors.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {88},
number = {8},
pages = {785-794},
pmid = {20383691},
issn = {1432-1440},
support = {RG/08/008/25291/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Age Factors ; Case-Control Studies ; Cohort Studies ; Coronary Disease/*genetics ; Environment ; Europe ; Female ; Humans ; Hyperlipoproteinemia Type II/genetics ; Leukocytes/*pathology ; Life Style ; Male ; Middle Aged ; Myocardial Infarction/epidemiology/*genetics ; Risk Factors ; Sex Factors ; Telomere/*pathology ; United Kingdom ; },
abstract = {Shorter telomeres have been reported in premature myocardial infarction (MI) patients. Our work aimed at confirming the association of shorter telomere with MI in two case-control studies and in familial hypercholesterolemia (FH) patients with coronary heart disease (CHD). The HIFMECH study compared 598 white male patients (<60 years) who survived a first MI and 653 age-matched controls from North and South Europe. Additionally, from the UK, 413 coronary artery bypass graft (CABG) patients and two groups of 367 and 94 FH patients, of whom 145 and 17 respectively had premature CHD, were recruited. Leukocyte telomere length (LTL) was measured using a real-time polymerase chain reaction-based method. In HIFMECH, LTL was significantly shorter in subjects from the North (7.99 kb, SD 4.51) compared to the South (8.27 kb, SD 4.14; p = 0.02) and in cases (7.85 kb, SD 4.01) compared to controls (8.04 kb, SD 4.46; p = 0.04). In the CABG study, LTL was significantly shorter (6.89 kb, SD 4.14) compared to the HIFMECH UK controls (7.53, SD 5.29; p = 0.007). In both samples of FH patients, LTL was shorter in those with CHD (overall 8.68 kb, SD 4.65) compared to the non-CHD subjects (9.23 kb, SD 4.83; p = 0.012). Apart from a consistent negative correlation with age, LTL was not associated across studies with any measured CHD risk factors. The present data confirms that subjects with CHD have shorter telomeres than controls and extends this to those with monogenic and polygenic forms of CHD.},
}
@article {pmid20381605,
year = {2010},
author = {Huang, J and Okuka, M and McLean, M and Keefe, DL and Liu, L},
title = {Telomere susceptibility to cigarette smoke-induced oxidative damage and chromosomal instability of mouse embryos in vitro.},
journal = {Free radical biology &amp; medicine},
volume = {48},
number = {12},
pages = {1663-1676},
doi = {10.1016/j.freeradbiomed.2010.03.026},
pmid = {20381605},
issn = {1873-4596},
mesh = {Animals ; Antioxidants/pharmacology ; Apoptosis/physiology ; Cadmium/toxicity ; Chromosomal Instability/*drug effects ; Embryo, Mammalian ; Embryonic Development/*drug effects ; In Situ Hybridization, Fluorescence ; In Situ Nick-End Labeling ; In Vitro Techniques ; Metals, Heavy/toxicity ; Mice ; Microscopy, Fluorescence ; Oxidative Stress/drug effects/physiology ; Reactive Oxygen Species/metabolism ; Smoke/adverse effects ; Smoking/*adverse effects ; Telomere/*drug effects ; Nicotiana/adverse effects/chemistry ; },
abstract = {Cigarette smoke is associated with high risk of lung, cardiovascular, and degenerative diseases, reduced fertility, and possibly the health of newborns. Cigarette smoke contains many components and exerts its genotoxicity in part by generating reactive oxidative stress. Telomeres consist of repeated 'G' rich sequences and associated proteins located at the chromosomal ends that maintain chromosomal integrity. We tested the hypothesis that telomere shortening and dysfunction are implicated in smoke associated oxidative damage and chromosomal instability using early mouse embryos in vitro and short-telomere mouse model. Mouse embryos exposed to smoke components, cigarette smoke condensate (CSC) at the concentration of 0.02 mg/ml continuously or 0.1mg/ml for 20 h, or cadmium at 5-100 microM, exhibited increased oxidative stress and telomere shortening and loss, associated with chromosomal instability, apoptosis, and compromised embryo cleavage and development. Remarkably, reduction of oxidative stress by an antioxidant N-acetyl-L-cysteine (NAC) greatly reduced these toxicities. Notably, cadmium led to more severe oxidative damage and telomere dysfunction, which could be more effectively rescued by antioxidant treatment, than did CSC. Moreover, short telomeres predisposed embryos to smoke component-induced oxidative damage. These data further extend our understanding of mechanisms underlying smoke-induced oxidative damage to include telomere dysfunction and chromosomal instability.},
}
@article {pmid20381338,
year = {2010},
author = {Egli, M and Pallan, PS},
title = {The many twists and turns of DNA: template, telomere, tool, and target.},
journal = {Current opinion in structural biology},
volume = {20},
number = {3},
pages = {262-275},
pmid = {20381338},
issn = {1879-033X},
support = {R01 GM055237/GM/NIGMS NIH HHS/United States ; R01 GM055237-13/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA/*chemistry/genetics/metabolism ; DNA Adducts/chemistry/genetics/metabolism ; G-Quadruplexes ; Humans ; Metals/metabolism ; Nanostructures/chemistry ; Telomere/*chemistry/genetics ; },
abstract = {If any proof were needed of DNA's versatile roles and use, it is certainly provided by the numerous depositions of new three-dimensional (3D) structures to the coordinate databanks (PDB, NDB) over the last two years. Quadruplex motifs involving G-repeats, adducted sequences and oligo-2'-deoxynucleotides (ODNs) with bound ligands are particularly well represented. In addition, structures of chemically modified DNAs (CNAs) and artificial analogs are yielding insight into stability, pairing properties, and dynamics, including those of the native nucleic acids. Besides being of significance for establishing diagnostic tools and in the analysis of protein-DNA interactions, chemical modification in conjunction with investigations of the structural consequences may yield novel nucleic acid-based therapeutics. DNA's predictable and highly specific pairing behavior makes it the material of choice for constructing 3D-nanostructures of defined architecture. Recently the first examples of DNA nanoparticle and self-assembled 3D-crystals were reported. Although the structures discussed in this review are all based either on X-ray crystallography or solution NMR, small angle X-ray scattering (SAXS), and cryoEM are proving to be useful approaches for the characterization of nanoscale DNA architecture.},
}
@article {pmid20375491,
year = {2011},
author = {Watson, JM and Riha, K},
title = {Telomeres, aging, and plants: from weeds to Methuselah - a mini-review.},
journal = {Gerontology},
volume = {57},
number = {2},
pages = {129-136},
doi = {10.1159/000310174},
pmid = {20375491},
issn = {1423-0003},
support = {Y 418/FWF_/Austrian Science Fund FWF/Austria ; },
mesh = {Aged ; Aging/*genetics ; Animals ; Genomics ; Humans ; Longevity/*genetics ; Plant Weeds/*genetics ; Telomere/*genetics ; Trees/*genetics ; },
abstract = {The process of aging affects most, if not all, living creatures, from single celled yeast to multi-cellular mammals and plants. The DNA end-replication problem along with the tissue-limited expression of telomerase led to the telomere hypothesis of aging, where limits on cellular proliferation are genetically encoded in the lengths of a cell's telomeres. Support for this hypothesis has been found in several organisms, from worms to mice to humans. While development, and therefore the process of aging, is quite different between plants and animals, telomere biology between these organisms is fundamentally the same. Do telomeres, then, also play the role of a molecular clock in plants? In this review, we explore the current knowledge of the relationship between telomeres and aging in plants in three specific cases: leaf senescence, aging of perennials and seed longevity.},
}
@article {pmid20373057,
year = {2011},
author = {Kheirollahi, M and Mehrazin, M and Kamalian, N and Mehdipour, P},
title = {Alterations of telomere length in human brain tumors.},
journal = {Medical oncology (Northwood, London, England)},
volume = {28},
number = {3},
pages = {864-870},
pmid = {20373057},
issn = {1559-131X},
mesh = {Astrocytoma/metabolism/pathology ; Blotting, Southern ; Brain Neoplasms/*metabolism/pathology ; Ependymoma/metabolism/pathology ; Female ; Humans ; Male ; Meningioma/metabolism/pathology ; Telomere/*metabolism/pathology ; },
abstract = {Telomeres at the ends of human chromosomes consist of tandem hexametric (TTAGGG)n repeats, which protect them from degradation. At each cycle of cell division, most normal somatic cells lose approximately 50-100 bp of the terminal telomeric repeat DNA. Precise prediction of growth and estimation of the malignant potential of brain tumors require additional markers. DNA extraction was performed from the 51 frozen tissues, and a non-radioactive chemiluminescent assay was used for Southern blotting. One sample t-test shows highly significant difference in telomere length in meningioma and astrocytoma with normal range. According to our results, higher grades of meningioma and astrocytoma tumors show more heterogeneity in telomere length, and also it seems shortening process of telomeres is an early event in brain tumors.},
}
@article {pmid20371347,
year = {2010},
author = {Davoli, T and Denchi, EL and de Lange, T},
title = {Persistent telomere damage induces bypass of mitosis and tetraploidy.},
journal = {Cell},
volume = {141},
number = {1},
pages = {81-93},
pmid = {20371347},
issn = {1097-4172},
support = {DP1 OD000379/OD/NIH HHS/United States ; DP1 OD000379-05/OD/NIH HHS/United States ; },
mesh = {Anaphase-Promoting Complex-Cyclosome ; Aneuploidy ; Animals ; Cadherins/metabolism ; Cell Cycle Proteins/metabolism ; Cell Line ; DNA Damage ; Embryo, Mammalian/cytology ; Humans ; Mice ; *Mitosis ; Neoplasms/*genetics ; *Ploidies ; Telomere/*genetics ; Ubiquitin-Protein Ligase Complexes/metabolism ; },
abstract = {Tetraploidization has been proposed as an intermediate step toward aneuploidy in human cancer but a general mechanism for the induction of tetraploidy during tumorigenesis is lacking. We report that tetraploidization occurs in p53-deficient cells experiencing a prolonged DNA damage signal due to persistent telomere dysfunction. Live-cell imaging revealed that these cells have an extended G2 due to ATM/ATR- and Chk1/Chk2-mediated inhibition of Cdk1/CyclinB and eventually bypass mitosis. Despite their lack of mitosis, the cells showed APC/Cdh1-dependent degradation of the replication inhibitor geminin, followed by accumulation of Cdt1, which is required for origin licensing. Cells then entered a second S phase resulting in whole-genome reduplication and tetraploidy. Upon restoration of telomere protection, these tetraploid cells resumed cell division cycles and proliferated. These observations suggest a general mechanism for the induction of tetraploidization in the early stages of tumorigenesis when telomere dysfunction can result from excessive telomere shortening.},
}
@article {pmid20369246,
year = {2010},
author = {Fojtová, M and Wong, JT and Dvorácková, M and Yan, KT and Sýkorová, E and Fajkus, J},
title = {Telomere maintenance in liquid crystalline chromosomes of dinoflagellates.},
journal = {Chromosoma},
volume = {119},
number = {5},
pages = {485-493},
pmid = {20369246},
issn = {1432-0886},
mesh = {Chromatin/genetics/metabolism ; Chromosomes/genetics/*metabolism/ultrastructure ; DNA Breaks ; DNA Replication/genetics ; DNA, Protozoan/genetics ; Dinoflagellida/*genetics/growth &amp; development/metabolism/ultrastructure ; Liquid Crystals ; Repetitive Sequences, Nucleic Acid ; Telomerase/metabolism ; Telomere/genetics/*metabolism/ultrastructure ; },
abstract = {The organisation of dinoflagellate chromosomes is exceptional among eukaryotes. Their genomes are the largest in the Eukarya domain, chromosomes lack histones and may exist in liquid crystalline state. Therefore, the study of the structural and functional properties of dinoflagellate chromosomes is of high interest. In this work, we have analysed the telomeres and telomerase in two Dinoflagellata species, Karenia papilionacea and Crypthecodinium cohnii. Active telomerase, synthesising exclusively Arabidopsis-type telomere sequences, was detected in cell extracts. The terminal position of TTTAGGG repeats was determined by in situ hybridisation and BAL31 digestion methods and provides evidence for the linear characteristic of dinoflagellate chromosomes. The length of telomeric tracts, 25-80 kb, is the largest among unicellular eukaryotic organisms to date. Both the presence of long arrays of perfect telomeric repeats at the ends of dinoflagellate chromosomes and the existence of active telomerase as the primary tool for their high-fidelity maintenance demonstrate the general importance of these structures throughout eukaryotes. We conclude that whilst chromosomes of dinoflagellates are unique in many aspects of their structure and composition, their telomere maintenance follows the most common scenario.},
}
@article {pmid20363058,
year = {2010},
author = {Georgin-Lavialle, S and Aouba, A and Lepelletier, Y and Gabet, AS and Hermine, O},
title = {[Telomeres and telomerase: relevance and future prospects in systemic lupus erythematosus].},
journal = {La Revue de medecine interne},
volume = {31},
number = {5},
pages = {345-352},
doi = {10.1016/j.revmed.2009.09.032},
pmid = {20363058},
issn = {1768-3122},
mesh = {Apoptosis/genetics ; Biomarkers/metabolism ; Cellular Senescence/genetics ; Humans ; Lupus Erythematosus, Systemic/diagnosis/enzymology/*metabolism/physiopathology/therapy ; Oxidative Stress/genetics ; Prognosis ; Risk Factors ; Severity of Illness Index ; Telomerase/*biosynthesis ; Telomere/*metabolism ; },
abstract = {Telomeres are specialized structures that cap and protect the end of chromosomes. Telomeres progressively shorten after each cellular division unless an enzyme, the telomerase, counteracts. Telomeres are implicated in cellular senescence, acting like a biological clock. Telomere length and telomerase activity are important in the physiopathology of cancer. In the past years, research has focused on them in order to find new therapeutic targets. Yet, oxidative stress, inflammation and increased leucocytes renewal are major environmental factors associated with telomeres shortening acceleration and thus in concordance with biological age. Thus, telomeric erosion induces cell apoptosis; indeed, apoptotic cell clearance is impaired in systemic lupus. Considering these elements and data resulting from oncology, telomere/telomerase couple was studied during the last decade in systemic lupus erythematosus. The objective was to know if this couple could have an implication in the physiopathology of this disease. A systematic review of literature is proposed about telomere and/or telomerase in systemic lupus erythematosus in order to discuss their physiopathological implication. Among 273 tested patients, telomere seems to be eroded and telomerase activity insufficiently increased but correlated to the activity of the disease. The analysis of telomere length and telomerase activity could be useful as prognosis factor or disease activity index. Telomere erosion could reflect an accelerated replicative senescence of the immune system. The role of the regulator T lymphocytes has not yet been precised. Standardized studies on larger population could be realized in systemic lupus and open new avenues of research and/or therapy based upon the telomere/telomerase biology.},
}
@article {pmid20360388,
year = {2010},
author = {Pobiega, S and Marcand, S},
title = {Dicentric breakage at telomere fusions.},
journal = {Genes &amp; development},
volume = {24},
number = {7},
pages = {720-733},
pmid = {20360388},
issn = {1549-5477},
mesh = {Centromere/genetics ; *Chromosome Breakage ; Chromosomes, Fungal/*genetics ; Mitosis/genetics ; Saccharomyces cerevisiae/*genetics ; Telomere/*genetics ; },
abstract = {Nonhomologous end-joining (NHEJ) inhibition at telomeres ensures that native chromosome ends do not fuse together. But the occurrence and consequences of rare telomere fusions are not well understood. It is notably unclear whether a telomere fusion could be processed to restore telomere ends. Here we address the behavior of individual dicentrics formed by telomere fusion in the yeast Saccharomyces cerevisiae. Our approach was to first stabilize and amplify fusions between two chromosomes by temporarily inactivating one centromere. Next we analyzed dicentric breakage following centromere reactivation. Unexpectedly, dicentrics often break at the telomere fusions during progression through mitosis, a process that restores the parental chromosomes. This unforeseen result suggests a rescue pathway able to process telomere fusions and to back up NHEJ inhibition at telomeres.},
}
@article {pmid20359340,
year = {2010},
author = {Yoshitake, K and Aoyagi, H and Fujiwara, H},
title = {Creation of a novel telomere-cutting endonuclease based on the EN domain of telomere-specific non-long terminal repeat retrotransposon, TRAS1.},
journal = {Mobile DNA},
volume = {1},
number = {1},
pages = {13},
pmid = {20359340},
issn = {1759-8753},
abstract = {BACKGROUND: The ends of chromosomes, termed telomeres consist of repetitive DNA. The telomeric sequences shorten with cell division and, when telomeres are critically abbreviated, cells stop proliferating. However, in cancer cells, by the expression of telomerase which elongates telomeres, the cells can continue proliferating. Many approaches for telomere shortening have been pursued in the past, but to our knowledge, cutting telomeres in vivo has not so far been demonstrated. In addition, there is lack of information on the cellular effects of telomere shortening in human cells.<br><br>RESULTS: Here, we created novel chimeric endonucleases to cut telomeres by fusing the endonuclease domain (TRAS1EN) of the silkworm's telomere specific non-long terminal repeat retrotransposon TRAS1 to the human telomere-binding protein, TRF1. An in vitro assay demonstrated that the TRAS1EN-TRF1 chimeric endonucleases (T-EN and EN-T) cut the human (TTAGGG)n repeats specifically. The concentration of TRAS1EN-TRF1 chimeric endonucleases necessary for the cleavage of (TTAGGG)n repeats was about 40-fold lower than that of TRAS1EN alone. When TRAS1EN-TRF1 endonucleases were introduced into human U2OS cancer cells using adenovirus vectors, the enzymes localized at telomeres of nuclei, cleaved and shortened the telomeric DNA by double-strand breaks. When human U2OS and HFL-1 fibroblast cells were infected with EN-T recombinant adenovirus, their cellular proliferation was suppressed for about 2 weeks after infection. In contrast, the TRAS1EN mutant (H258A) chimeric endonuclease fused with TRF1 (ENmut-T) did not show the suppression effect. The EN-T recombinant adenovirus induced telomere shortening in U2OS cells, activated the p53-dependent pathway and caused the senescence associated cellular responses, while the ENmut-T construct did not show such effects.<br><br>CONCLUSIONS: A novel TRAS1EN-TRF1 chimeric endonuclease (EN-T) cuts the human telomeric repeats (TTAGGG)n specifically in vitro and in vivo. Thus, the chimeric endonuclease which is expressed from an adenoviral vector can suppress cell proliferation of cancer cells.},
}
@article {pmid20356883,
year = {2010},
author = {Olsson, M and Pauliny, A and Wapstra, E and Blomqvist, D},
title = {Proximate determinants of telomere length in sand lizards (Lacerta agilis).},
journal = {Biology letters},
volume = {6},
number = {5},
pages = {651-653},
pmid = {20356883},
issn = {1744-957X},
mesh = {Animals ; Female ; Lizards/*genetics ; Male ; *Telomere ; },
abstract = {Telomeres are repeat sequences of non-coding DNA that cap the ends of chromosomes and contribute to their stability and the genomic integrity of cells. In evolutionary ecology, the main research target regarding these genomic structures has been their role in ageing and as a potential index of age. However, research on humans shows that a number of traits contribute to among-individual differences in telomere length, in particular traits enhancing cell division and genetic erosion, such as levels of free radicals and stress. In lizards, tail loss owing to predation attempts results in a stress-induced shift to a more cryptic lifestyle. In sand lizard (Lacerta agilis) males, telomere length was compromised by tail regrowth in a body size-related manner, so that small males, which already exhibit more cryptic mating tactics, were less affected than larger males. Tail regrowth just fell short of having a significant relationship with telomere length in females, and so did age in males. In females, there was a significant positive relationship between age and telomere length. We conclude that the proximate effect of compromised antipredation and its associated stress seems to have a more pronounced effect in males than in females and that age-associated telomere dynamics differ between the sexes.},
}
@article {pmid20353271,
year = {2010},
author = {Brezinova, J and Berkova, A and Vcelikova, S and Zemanova, Z and Izakova, S and Sarova, I and Cechova, H and Tajtlova, J and Grosova, L and Lizcova, L and Malinova, E and Zemanova, M and Cmunt, E and Karban, J and Trneny, M and Schwarz, J and Michalova, K},
title = {Telomere length, molecular cytogenetic findings, and immunophenotypic features in previously untreated patients with B-chronic lymphocytic leukemia.},
journal = {Neoplasma},
volume = {57},
number = {3},
pages = {215-221},
doi = {10.4149/neo_2010_03_215},
pmid = {20353271},
issn = {0028-2685},
mesh = {ADP-ribosyl Cyclase 1/analysis ; Adult ; Aged ; Aged, 80 and over ; *Chromosome Aberrations ; Female ; Humans ; Immunoglobulin Heavy Chains/genetics ; Immunoglobulin Variable Region/genetics ; Immunophenotyping ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/immunology/metabolism ; Male ; Middle Aged ; Mutation ; *Telomere ; ZAP-70 Protein-Tyrosine Kinase/analysis ; },
abstract = {UNLABELLED: Telomere length was evaluated by terminal repeat fragment method in 66 previously untreated patients with B-chronic lymphocytic leukemia (B-CLL) to ascertain whether telomere shortening was associated with genomic aberrations, immunoglobulin variable heavy chain (IgVH) mutational status, CD38 and ZAP-70 expression, and telomerase activity. Chromosomal aberrations were present in peripheral blood cells of 73% patients (48/66), no difference in telomere length between patients with good and intermediate prognosis according to cytogenetics was found. Association between telomere length and IgVH mutational status, ZAP-70 and CD38 expression was proved as significantly shorter telomeres in patients with unmutated IgVH status (p=0.01) and ZAP-70 positivity (p=0.01) and CD38 positivity (p=0.05) were detected. Telomerase activity was positive in 11 patients out of 21 examined, correlation between telomere length and telomerase activity was found (p=0.05). Telomere length and telomerase activity in combination with other prognostic parameters complete the risk profile of B-CLL patients and might serve for an easy decision on optimal treatment strategy.<br><br>KEYWORDS: B-chronic lymphocytic leukemia, telomere length, telomerase activity, chromosomal aberrations, prognosis.},
}
@article {pmid20351727,
year = {2010},
author = {Cesare, AJ and Reddel, RR},
title = {Alternative lengthening of telomeres: models, mechanisms and implications.},
journal = {Nature reviews. Genetics},
volume = {11},
number = {5},
pages = {319-330},
pmid = {20351727},
issn = {1471-0064},
mesh = {Animals ; Humans ; Models, Genetic ; Neoplasms/*genetics/metabolism ; Recombination, Genetic ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Unlimited cellular proliferation depends on counteracting the telomere attrition that accompanies DNA replication. In human cancers this usually occurs through upregulation of telomerase activity, but in 10-15% of cancers - including some with particularly poor outcome - it is achieved through a mechanism known as alternative lengthening of telomeres (ALT). ALT, which is dependent on homologous recombination, is therefore an important target for cancer therapy. Although dissection of the mechanism or mechanisms of ALT has been challenging, recent advances have led to the identification of several genes that are required for ALT and the elucidation of the biological significance of some phenotypic markers of ALT. This has enabled development of a rapid assay of ALT activity levels and the construction of molecular models of ALT.},
}
@article {pmid20350810,
year = {2010},
author = {Kashiwazaki, G and Bando, T and Shinohara, K and Minoshima, M and Kumamoto, H and Nishijima, S and Sugiyama, H},
title = {Alkylation of a human telomere sequence by heterotrimeric chlorambucil PI polyamide conjugates.},
journal = {Bioorganic &amp; medicinal chemistry},
volume = {18},
number = {8},
pages = {2887-2893},
doi = {10.1016/j.bmc.2010.03.011},
pmid = {20350810},
issn = {1464-3391},
mesh = {Alkylation ; Antineoplastic Agents, Alkylating/*chemistry/pharmacology ; Base Sequence ; Chlorambucil/*chemistry/pharmacology ; Humans ; Models, Molecular ; Nylons/*chemistry ; Telomere/*metabolism ; },
abstract = {We designed and synthesized human telomere alkylating N-methylpyrrole-N-methylimidazole (PI) polyamide conjugates (1-6). The C-type conjugates 1-3 possessed a chlorambucil moiety at the C terminus, whereas the N-type conjugates 4-6 had one of these moieties at the N terminus. The DNA alkylating activity of these conjugates was evaluated by high-resolution denaturing polyacrylamide gel electrophoresis using a 220bp DNA fragment containing the human telomere repeat sequence 5'-(GGGTTA)(4)-3'/5'-(TAACCC)(4)-3'. C-type conjugates are designed to alkylate the G-rich-strand-containing 5'-GGGTTA-3' and N-type conjugates were designed to alkylate the complementary C-rich strand-containing 5'-TAACCC-3' sequence. The difference between conjugates 1-3 and 4-6 lies in the linker region between the polyamide moiety and chlorambucil. Conjugates 1 and 4 efficiently alkylated the 5'-GGTTAGGGTTA-3' and 5'-CCCTAACCCTAA-3' sequences, respectively, by recognizing 11bp in the presence of distamycin A (Dist), in a heterotrimeric manner: one long alkylating polyamide conjugate (1-6) and two short partners (Dist).},
}
@article {pmid20350645,
year = {2010},
author = {Biron-Shental, T and Sukenik-Halevy, R and Sharon, Y and Goldberg-Bittman, L and Kidron, D and Fejgin, MD and Amiel, A},
title = {Short telomeres may play a role in placental dysfunction in preeclampsia and intrauterine growth restriction.},
journal = {American journal of obstetrics and gynecology},
volume = {202},
number = {4},
pages = {381.e1-7},
doi = {10.1016/j.ajog.2010.01.036},
pmid = {20350645},
issn = {1097-6868},
mesh = {Biopsy ; Cellular Senescence/*genetics ; Female ; Fetal Growth Retardation/*genetics/metabolism/pathology ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Oxidative Stress ; Placenta/pathology/physiopathology ; Placenta Diseases/*genetics/metabolism/pathology ; Pre-Eclampsia/*genetics/metabolism/pathology ; Pregnancy ; Pregnancy Trimester, Third ; Telomerase/genetics/metabolism ; Telomere/metabolism/*pathology ; },
abstract = {OBJECTIVE: Telomeres shorten and aggregate with cellular senescence and oxidative stress. Telomerase and its catalytic component human telomerase reverse-transcriptase regulate telomere length. The pathogenesis of preeclampsia and intrauterine growth restriction involves hypoxic stress. We aimed to assess telomere length in trophoblasts from pregnancies with those complications.<br><br>STUDY DESIGN: Placental specimens from 4 groups of patients were studied: severe preeclampsia, intrauterine growth restriction, preeclampsia combined with intrauterine growth restriction, and uncomplicated (control). Telomere length and human telomerase reverse-transcriptase expression were assessed by using quantitative fluorescence-in-situ protocol and immunohistochemistry.<br><br>RESULTS: Telomere length was significantly lower in preeclampsia, intrauterine growth restriction, and preeclampsia plus intrauterine growth restriction placentas. More aggregates were found in preeclampsia, but not in intrauterine growth restriction placentas. Human telomerase reverse-transcriptase was significantly higher in the controls compared with the other groups.<br><br>CONCLUSION: Telomeres are shorter in placentas from preeclampsia and intrauterine growth restriction pregnancies. Increased telomere aggregate formation in preeclampsia but not in intrauterine growth restriction pregnancies, implies different placental stress-related mechanisms in preeclampsia with or without intrauterine growth restriction.},
}
@article {pmid20347571,
year = {2010},
author = {Watanabe, S and Saitoh, Y and Namba, M and Miwa, N},
title = {Administration with telomeric DNA telomere-like oligonucleotides induces enhancement of telomerase activity and resistance against oxidative stress in telomere reverse transcriptase gene-transfected human fibroblasts.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {64},
number = {8},
pages = {565-571},
doi = {10.1016/j.biopha.2010.02.005},
pmid = {20347571},
issn = {1950-6007},
mesh = {Cell Culture Techniques ; Cell Line ; Cell Survival/drug effects ; DNA/*genetics/ultrastructure ; Enzyme Activation ; Fibroblasts/*drug effects/enzymology ; Humans ; Oligonucleotides/chemistry/*pharmacology ; Oxidative Stress/*drug effects/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/genetics/*metabolism ; Telomere/*genetics/ultrastructure ; Transfection ; },
abstract = {Out of normal human fibroblasts OUMS-36 and three clones (T1, T2 and T3) of telomere reverse transcriptase gene (hTERT)-transfectants, telomere length is in order: T3 >T2 >T1 >>OUMS-36 (young) >>OUMS-36 (old), and telomerase activity is in order: T2 >T3 >T1 >>OUMS-36 (young, old), suggesting that telomere length may be roughly governed by telomerase activity. Telomere-like oligonucleotides [5'- (TTAGGG) (1-3)-3'] (ON mono-/di-/trimer) and a mononucleotide (T:A:G=2:1:3, mol/mol) mixture (MN mix), as candidates for telomerase activators, maintained above 80% of cell viability at marginally higher doses of 2 μM for MN-mix or ON monomer, 1 μM for ON dimmer and 0.67 μM for ON trimer, respectively, in OUMS-36 and T2 cells, and administered for 4 weeks, resulting in no elongation of telomere length in both the cell lines. In contrast, telomerase activity was enhanced by administration with ON mono-/di-/trimer, but not MN mix, in a manner dependent on treatment periods, in T2 transfectants, whereas similar effects were not observed in OUMS-36 parents. The 4-week treatment with ON mono-/di-/trimers, but not MN mix, also suppressed cell-viability diminishment induced by the oxidative-stressor tert-butylhydroperoxide in T2 cells, but scarcely in OUMS-36 cells. Thus, the promoting effects of oligonucleotide [5'-(TTAGGG)(1-3)-3'] on both telomerase enhancement and oxidative-stress resistance can be exerted for telomerase-abundant T2 hTERT-transfectants, but not for telomerase-poor OUMS-36 parents.},
}
@article {pmid20339076,
year = {2010},
author = {Sfeir, A and Kabir, S and van Overbeek, M and Celli, GB and de Lange, T},
title = {Loss of Rap1 induces telomere recombination in the absence of NHEJ or a DNA damage signal.},
journal = {Science (New York, N.Y.)},
volume = {327},
number = {5973},
pages = {1657-1661},
pmid = {20339076},
issn = {1095-9203},
support = {R01 AG016642-09/AG/NIA NIH HHS/United States ; R01 GM049046-11/GM/NIGMS NIH HHS/United States ; R01 GM049046/GM/NIGMS NIH HHS/United States ; R01 AG016642-07/AG/NIA NIH HHS/United States ; R01 GM049046-12/GM/NIGMS NIH HHS/United States ; R01 AG016642-11/AG/NIA NIH HHS/United States ; R01 AG016642-01/AG/NIA NIH HHS/United States ; GM049046/GM/NIGMS NIH HHS/United States ; R37 GM049046-17/GM/NIGMS NIH HHS/United States ; R37 GM049046-16/GM/NIGMS NIH HHS/United States ; R01 AG016642-10/AG/NIA NIH HHS/United States ; R01 AG016642-04/AG/NIA NIH HHS/United States ; R01 GM049046-09/GM/NIGMS NIH HHS/United States ; R37 GM049046-15/GM/NIGMS NIH HHS/United States ; R37 GM049046-13/GM/NIGMS NIH HHS/United States ; AG016642/AG/NIA NIH HHS/United States ; R01 AG016642-06/AG/NIA NIH HHS/United States ; R01 GM049046-08/GM/NIGMS NIH HHS/United States ; R37 GM049046-14/GM/NIGMS NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; R01 AG016642-08/AG/NIA NIH HHS/United States ; R01 GM049046-07/GM/NIGMS NIH HHS/United States ; R01 GM049046-10/GM/NIGMS NIH HHS/United States ; R01 AG016642-02/AG/NIA NIH HHS/United States ; R01 AG016642-03/AG/NIA NIH HHS/United States ; R01 AG016642-05/AG/NIA NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/metabolism ; Cell Proliferation ; Cells, Cultured ; Checkpoint Kinase 2 ; *DNA Damage ; *DNA Repair ; DNA-Binding Proteins/metabolism ; Gene Deletion ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Molecular Sequence Data ; Protein Serine-Threonine Kinases/metabolism ; Recombination, Genetic ; Shelterin Complex ; Signal Transduction ; Sister Chromatid Exchange ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/chemistry/*genetics/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Tumor Suppressor Proteins/metabolism ; },
abstract = {Shelterin is an essential telomeric protein complex that prevents DNA damage signaling and DNA repair at mammalian chromosome ends. Here we report on the role of the TRF2-interacting factor Rap1, a conserved shelterin subunit of unknown function. We removed Rap1 from mouse telomeres either through gene deletion or by replacing TRF2 with a mutant that does not bind Rap1. Rap1 was dispensable for the essential functions of TRF2--repression of ATM kinase signaling and nonhomologous end joining (NHEJ)--and mice lacking telomeric Rap1 were viable and fertile. However, Rap1 was critical for the repression of homology-directed repair (HDR), which can alter telomere length. The data reveal that HDR at telomeres can take place in the absence of DNA damage foci and underscore the functional compartmentalization within shelterin.},
}
@article {pmid20336134,
year = {2010},
author = {Sahin, E and Depinho, RA},
title = {Linking functional decline of telomeres, mitochondria and stem cells during ageing.},
journal = {Nature},
volume = {464},
number = {7288},
pages = {520-528},
pmid = {20336134},
issn = {1476-4687},
support = {R01 CA084628/CA/NCI NIH HHS/United States ; U01 CA084313/CA/NCI NIH HHS/United States ; R01CA84628/CA/NCI NIH HHS/United States ; U01 CA84313/CA/NCI NIH HHS/United States ; },
mesh = {Aging/*pathology ; Animals ; Genome/genetics ; Hematopoietic System/pathology ; Homeostasis/physiology ; Humans ; Mitochondria/enzymology/*pathology ; Phenotype ; Stem Cells/*pathology ; Telomerase/genetics/metabolism ; Telomere/*pathology ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {The study of human genetic disorders and mutant mouse models has provided evidence that genome maintenance mechanisms, DNA damage signalling and metabolic regulation cooperate to drive the ageing process. In particular, age-associated telomere damage, diminution of telomere 'capping' function and associated p53 activation have emerged as prime instigators of a functional decline of tissue stem cells and of mitochondrial dysfunction that adversely affect renewal and bioenergetic support in diverse tissues. Constructing a model of how telomeres, stem cells and mitochondria interact with key molecules governing genome integrity, 'stemness' and metabolism provides a framework for how diverse factors contribute to ageing and age-related disorders.},
}
@article {pmid20336070,
year = {2010},
author = {Zalzman, M and Falco, G and Sharova, LV and Nishiyama, A and Thomas, M and Lee, SL and Stagg, CA and Hoang, HG and Yang, HT and Indig, FE and Wersto, RP and Ko, MS},
title = {Zscan4 regulates telomere elongation and genomic stability in ES cells.},
journal = {Nature},
volume = {464},
number = {7290},
pages = {858-863},
pmid = {20336070},
issn = {1476-4687},
support = {ZIA AG000655-11/ImNIH/Intramural NIH HHS/United States ; ZIA AG000656-11/ImNIH/Intramural NIH HHS/United States ; ZIA AG000700-02/ImNIH/Intramural NIH HHS/United States ; ZIA AG000706-02/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; Cell Proliferation ; Chromosome Aberrations ; Embryonic Stem Cells/cytology/*metabolism/pathology ; Gene Expression Regulation ; Gene Knockdown Techniques ; *Genomic Instability ; Karyotyping ; Meiosis/genetics/physiology ; Mice ; Protein Transport ; Recombination, Genetic/genetics ; Sister Chromatid Exchange/genetics ; Telomere/*genetics/*metabolism ; Transcription Factors/deficiency/genetics/*metabolism ; Up-Regulation ; },
abstract = {Exceptional genomic stability is one of the hallmarks of mouse embryonic stem (ES) cells. However, the genes contributing to this stability remain obscure. We previously identified Zscan4 as a specific marker for two-cell embryo and ES cells. Here we show that Zscan4 is involved in telomere maintenance and long-term genomic stability in ES cells. Only 5% of ES cells express Zscan4 at a given time, but nearly all ES cells activate Zscan4 at least once during nine passages. The transient Zscan4-positive state is associated with rapid telomere extension by telomere recombination and upregulation of meiosis-specific homologous recombination genes, which encode proteins that are colocalized with ZSCAN4 on telomeres. Furthermore, Zscan4 knockdown shortens telomeres, increases karyotype abnormalities and spontaneous sister chromatid exchange, and slows down cell proliferation until reaching crisis by passage eight. Together, our data show a unique mode of genome maintenance in ES cells.},
}
@article {pmid20335598,
year = {2010},
author = {Wallace, DJ},
title = {Telomere diseases.},
journal = {The New England journal of medicine},
volume = {362},
number = {12},
pages = {1150},
doi = {10.1056/NEJMc1000801},
pmid = {20335598},
issn = {1533-4406},
mesh = {Antibodies, Antinuclear ; Autoimmune Diseases/*therapy ; Humans ; T-Lymphocytes/physiology ; Telomerase/deficiency ; Telomere/*immunology ; },
}
@article {pmid20335352,
year = {2010},
author = {Wong, LS and Huzen, J and van der Harst, P and de Boer, RA and Codd, V and Westenbrink, BD and Benus, GF and Voors, AA and van Gilst, WH and Samani, NJ and Jaarsma, T and van Veldhuisen, DJ},
title = {Anaemia is associated with shorter leucocyte telomere length in patients with chronic heart failure.},
journal = {European journal of heart failure},
volume = {12},
number = {4},
pages = {348-353},
doi = {10.1093/eurjhf/hfq007},
pmid = {20335352},
issn = {1879-0844},
mesh = {Aged ; Aged, 80 and over ; Anemia/etiology/*genetics/physiopathology ; Biomarkers ; Case-Control Studies ; Cellular Senescence ; Confidence Intervals ; Disease Progression ; Female ; Heart Failure/complications/*genetics/physiopathology ; Humans ; Leukocytes/*pathology/ultrastructure ; Linear Models ; Logistic Models ; Male ; Middle Aged ; Natriuretic Peptide, Brain ; Odds Ratio ; Prognosis ; Risk Factors ; Stroke Volume ; Telomere/*ultrastructure ; Time Factors ; Ventricular Function, Left ; },
abstract = {AIMS: Anaemia is highly prevalent and associated with poor prognosis in patients with chronic heart failure (CHF). Reduced erythroid proliferation capacity of haematopoietic progenitor cells is associated with reduced telomere length, a marker of cellular ageing. We hypothesize that short telomere length contributes to the susceptibility to develop anaemia in patients with CHF.<br><br>METHODS AND RESULTS: We studied 875 CHF patients, of whom 254 (29%) fulfilled the WHO criteria of anaemia. Telomere length in DNA from peripheral leucocytes was measured with real-time quantitative polymerase chain reaction. Age, gender, and baseline differences adjusted telomere length was correlated with haemoglobin levels (partial r = 0.130; P = 0.011). One standard deviation shorter telomere length was associated with an increased risk of having anaemia [odds ratio (OR), 1.31; 95% confidence interval (CI), 1.12-1.53; P = 0.001]. This observation was not affected by adjustment for potential confounders (OR, 1.38; 95% CI, 1.05-1.81; P = 0.021 after adjustment for age, gender, erythropoietin levels, renal function, left ventricular ejection fraction, age of CHF onset, blood pressure, history of stroke, diabetes, and B-type natriuretic peptide levels).<br><br>CONCLUSION: Shorter telomere length increases the odds of having anaemia in CHF patients. This finding supports the hypothesis that cellular ageing in CHF contributes to the susceptibility to develop anaemia.},
}
@article {pmid20333974,
year = {2010},
author = {Roos, G and Osterman, P},
title = {[The Nobel Prize on the protective function of telomeres can be very useful clinically. Several research targets ahead--not only new cancer therapies].},
journal = {Lakartidningen},
volume = {107},
number = {4},
pages = {190-193},
pmid = {20333974},
issn = {0023-7205},
mesh = {Biomedical Research ; History, 20th Century ; Humans ; Mutation ; Neoplasms/enzymology/genetics/therapy ; *Nobel Prize ; Telomerase/genetics/metabolism/*physiology ; Telomere/chemistry/genetics/*physiology ; },
}
@article {pmid20331440,
year = {2010},
author = {Bendix, L and Horn, PB and Jensen, UB and Rubelj, I and Kolvraa, S},
title = {The load of short telomeres, estimated by a new method, Universal STELA, correlates with number of senescent cells.},
journal = {Aging cell},
volume = {9},
number = {3},
pages = {383-397},
doi = {10.1111/j.1474-9726.2010.00568.x},
pmid = {20331440},
issn = {1474-9726},
mesh = {Cells, Cultured ; *Cellular Senescence ; *Chromosomes, Human/metabolism ; DNA/*analysis/metabolism ; DNA Restriction Enzymes/metabolism ; Female ; *Genetic Techniques ; Humans ; *Telomere/metabolism ; },
abstract = {Short telomeres are thought to trigger senescence, most likely through a single - or a group of few - critically shortened telomeres. Such short telomeres are thought to result from a combination of gradual linear shortening resulting from the end replication problem, reflecting the division history of the cell, superimposed by a more stochastic mechanism, suddenly causing a significant shortening of a single telomere. Previously, studies that have tried to explore the role of critically shortened telomeres have been hampered by methodological problems. With the method presented here, Universal STELA, we have a tool that can directly investigate the relationship between senescence and the load of short telomeres. The method is a variant of the chromosome-specific STELA method but has the advantage that it can demonstrate short telomeres regardless of chromosome. With Universal STELA, we find a strong correlation between the load of short telomeres and cellular senescence. Further we show that the load of short telomeres is higher in senescent cells compared to proliferating cells at the same passage, offering an explanation of premature cell senescence. This new method, Universal STELA, offers some advantages compared to existing methods and can be used to explore many of the unanswered questions in telomere biology including the role that telomeres play in cancer and aging.},
}
@article {pmid20309016,
year = {2010},
author = {Meng, FL and Chen, XF and Hu, Y and Tang, HB and Dang, W and Zhou, JQ},
title = {Sua5p is required for telomere recombination in Saccharomyces cerevisiae.},
journal = {Cell research},
volume = {20},
number = {4},
pages = {495-498},
doi = {10.1038/cr.2010.34},
pmid = {20309016},
issn = {1748-7838},
mesh = {DNA-Binding Proteins/genetics/*metabolism ; Mutation ; *Recombination, Genetic ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; },
}
@article {pmid20303464,
year = {2010},
author = {Zee, RY and Castonguay, AJ and Barton, NS and Germer, S and Martin, M},
title = {Mean leukocyte telomere length shortening and type 2 diabetes mellitus: a case-control study.},
journal = {Translational research : the journal of laboratory and clinical medicine},
volume = {155},
number = {4},
pages = {166-169},
doi = {10.1016/j.trsl.2009.09.012},
pmid = {20303464},
issn = {1878-1810},
mesh = {Case-Control Studies ; Diabetes Mellitus, Type 2/genetics/*metabolism ; Female ; Gene Dosage/genetics ; Humans ; Leukocytes/*metabolism ; Linear Models ; Logistic Models ; Male ; Middle Aged ; Telomere/genetics/*metabolism ; },
abstract = {Recent data have implicated leukocyte telomere length shortening as a potential risk predictor for type 2 diabetes mellitus (T2DM) and its associated phenotypes. However, to date, epidemiologic data are scarce. Using a case-control study from a community-based population sample of the Boston metropolitan area (all whites: 424 controls and 432 cases), we examined the relationship of mean leukocyte telomere repeat copy number to single gene copy number (TSR) and T2DM. Associations of log(e)-transformed TSR with age, race, sex, body mass index (BMI), current smoking status, fasting insulin levels, fasting glucose levels, and hemoglobin A1c (HbA1c) were examined by multivariable linear regression analysis. A logistic regression analysis was performed to evaluate the association of log(e)-transformed TSR with T2DM with or without adjustment for potential confounders. The log(e)-transformed TSR was significantly shorter in the white cases than the white controls (P=0.003). In a multivariable linear regression analysis, an inverse association of log(e)-transformed TSR with BMI was observed (P=0.04). Furthermore, in a multivariable logistic regression analysis, decreased log(e)-transformed TSR was significantly associated with T2DM (adjusted odds ratio=1.748; 95% confidence interval [CI]=1.015-3.012; P=0.044). In summary, the current investigation has shown an association of mean leukocyte telomere length shortening with T2DM in white subjects. If corroborated in other studies, our findings suggest the potential importance of telomere biology in T2DM.},
}
@article {pmid20303463,
year = {2010},
author = {Hamel, FG},
title = {Telomeres and type 2 diabetes.},
journal = {Translational research : the journal of laboratory and clinical medicine},
volume = {155},
number = {4},
pages = {164-165},
doi = {10.1016/j.trsl.2009.12.004},
pmid = {20303463},
issn = {1878-1810},
mesh = {Diabetes Mellitus, Type 2/*metabolism ; Humans ; Reactive Oxygen Species/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; },
}
@article {pmid20299626,
year = {2010},
author = {Kim, J and Lee, S and Bhattacharjee, R and Khalyfa, A and Kheirandish-Gozal, L and Gozal, D},
title = {Leukocyte telomere length and plasma catestatin and myeloid-related protein 8/14 concentrations in children with obstructive sleep apnea.},
journal = {Chest},
volume = {138},
number = {1},
pages = {91-99},
pmid = {20299626},
issn = {1931-3543},
support = {R01 HL065270/HL/NHLBI NIH HHS/United States ; R01 HL086662/HL/NHLBI NIH HHS/United States ; HL-065270/HL/NHLBI NIH HHS/United States ; HL-086662/HL/NHLBI NIH HHS/United States ; },
mesh = {Biomarkers/blood ; Calgranulin A/*blood ; Calgranulin B/*blood ; Child ; Child, Preschool ; Chromogranin A/*blood ; Enzyme-Linked Immunosorbent Assay ; Female ; Genetic Predisposition to Disease ; Humans ; Leukocytes/*physiology ; Male ; Oxidative Stress/*genetics ; Peptide Fragments/*blood ; Polymerase Chain Reaction ; Prognosis ; Severity of Illness Index ; Sleep Apnea, Obstructive/*blood/genetics ; Telomere/*genetics ; },
abstract = {BACKGROUND: Obstructive sleep apnea (OSA) is common in children and leads to multiple end-organ morbidities induced by the cumulative burden of oxidative stress and inflammation. Leukocyte telomere length (LTL) reflects not only chronologic age but also the burden of disease. We hypothesized that LTL would be decreased in children with OSA.<br><br>METHODS: Two hundred thirteen children (mean age, 7.7 +/- 1.4 years) were included after a sleep study and a morning blood sample. LTL was examined by quantitative polymerase chain reaction in a case-control setting involving 111 OSA cases and 102 controls. Myeloid-related protein (MRP) 8/14 and catestatin plasma levels also were assayed using enzyme-linked immunosorbent assay.<br><br>RESULTS: Log LTL was significantly increased and OSA severity dependently increased in children (P = .012), was positively associated with apnea-hypopnea index (AHI) (r = 0.236; P < .01), and was inversely correlated with age (r = -0.145; P < .05). In a multivariate regression model, LTL was independently associated with AHI (beta = 0.28; P = .002) after adjusting for age, sex, BMI z score, and race. Children with OSA exhibited higher BP (P < .05), lower plasma catestatin (P = .009), and higher MRP 8/14 levels (P < .001) than controls. Of note, children with the lowest plasma catestatin levels (< 1.39 ng/mL) had 5.2-fold increased odds of moderate-to-severe OSA (95% CI, 1.19-23.4 ng/mL; P < .05) after adjusting for confounding variables.<br><br>CONCLUSIONS: In pediatric OSA, LTL is longer rather than shorter. Children with OSA have reduced plasma catestatin levels and increased BP along with increased MRP 8/14 levels that exhibit AHI dependencies. Thus, catestatin and MRP 8/14 levels may serve as biomarkers for cardiovascular risk in the context of pediatric OSA. However, the implications of increased LTL in children with OSA remain to be defined.},
}
@article {pmid20238001,
year = {2010},
author = {Zhang, J and Hui, C and Su, L and Xiaoyun, W and Xi, H and Yingchuan, F},
title = {The association between telomere length and sensitivity to apoptosis of HUVEC.},
journal = {Advances in experimental medicine and biology},
volume = {664},
number = {},
pages = {47-53},
doi = {10.1007/978-1-4419-1399-9_6},
pmid = {20238001},
issn = {0065-2598},
mesh = {*Apoptosis/drug effects ; Blotting, Southern ; Cells, Cultured ; Endothelial Cells/*cytology/drug effects/*metabolism ; Free Radicals/pharmacology ; Humans ; Oxidation-Reduction/drug effects ; Telomere/drug effects/*metabolism ; Time Factors ; Umbilical Veins/*cytology ; },
abstract = {OBJECTIVES: To study the association between the mean telomere length (MTL) of human umbilical endothelial cells (HUVEC) and their sensitivity to apoptosis.<br><br>METHODS: Apoptosis of HUVEC was induced by using free hydroxyl radicals. The rate of apoptosis was determined and mean telomere length of HUVEC that were cultured for 1 or 3 months were measured by Southern Blot.<br><br>RESULTS: At 0.2 mmol/l FeSO(4)/0.0001 mmol/l H(2)O(2) free radical concentration, the apoptosis rate was 8.0 and 17.5% and MTL was 4.66 +/- 0.05 and 3.40 +/- 0.46 kb for HUVEC cultured for 1 and 3 months, respectively. At 0.2 mmol/l FeSO(4)/0.005 mmol/l H(2)O(2), apoptosis rates were 17.4 and 36.0% and MTL were 3.67 +/- 0.06 and 2.90 +/- 0.20 kb for HUVEC cultured for 1 and for 3 months, respectively. Control HUVEC had apoptosis rates of 0.5 and 1.0% and MTL of 5.43 +/- 0.45 and 4.57 +/- 0.21 kb for 1 and 3 months, respectively. The MTL and the apoptosis rates in the treatment groups differed significantly from the controls (p <0.05).<br><br>CONCLUSIONS: HUVEC with less culture time or short telomere were sensitive to oxidation stress. Oxidation stress also can enhance the shortening of telomere length.},
}
@article {pmid20237481,
year = {2010},
author = {Varela, E and Blasco, MA},
title = {2009 nobel prize in physiology or medicine: telomeres and telomerase.},
journal = {Oncogene},
volume = {29},
number = {11},
pages = {1561-1565},
doi = {10.1038/onc.2010.15},
pmid = {20237481},
issn = {1476-5594},
mesh = {Aging/genetics/physiology ; Biomedical Research/history ; History, 20th Century ; History, 21st Century ; Medicine ; Neoplasms/enzymology/genetics/pathology ; *Nobel Prize ; Physiology/history ; Stem Cells/cytology/enzymology/metabolism ; Telomerase/*metabolism ; Telomere/*genetics/metabolism ; },
}
@article {pmid20232301,
year = {2010},
author = {Zheng, H and Shen, CJ and Qiu, FY and Zhao, YB and Fu, GS},
title = {Stromal cell-derived factor 1alpha reduces senescence of endothelial progenitor subpopulation in lectin-binding and DiLDL-uptaking cell through telomerase activation and telomere elongation.},
journal = {Journal of cellular physiology},
volume = {223},
number = {3},
pages = {757-763},
doi = {10.1002/jcp.22086},
pmid = {20232301},
issn = {1097-4652},
mesh = {Adult ; Cell Proliferation/drug effects ; Cellular Senescence/*drug effects ; Chemokine CXCL12/*pharmacology ; Colony-Forming Units Assay ; Endothelial Cells/cytology/drug effects/*enzymology ; Enzyme Activation/drug effects ; Female ; Gene Expression Regulation/drug effects ; Humans ; Lectins/*metabolism ; Male ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Binding/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Messenger/genetics/metabolism ; Signal Transduction/drug effects ; Stem Cells/*cytology/drug effects/enzymology ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Recent studies have suggested that reduced endothelial progenitor subpopulation in lectin-binding and DiLDL-uptaking cell (EPC subpopulation) number and activity was associated with EPC subpopulation senescence that involved telomerase activity and telomere length. Stromal cell-derived factor-1alpha (SDF-1alpha) has been shown to augment a variety of cellular functions of EPC subpopulation and subsequently contribute to ischemic neovascularization. Therefore, we investigated whether SDF-1alpha might be able to prevent senescence of EPC subpopulation and also investigated the effects of SDF-1alpha on the telomerase activity and telomere length. EPC subpopulation were isolated from peripheral blood and characterized. After ex vivo prolonged cultivation, EPC subpopulation became senescent as determined by acidic beta-galactosidase staining. SDF-1alpha dose-dependently inhibited the onset of EPC subpopulation senescence. Moreover, SDF-1alpha increased proliferation and colony-forming activity of EPC subpopulation. SDF-1alpha also increased telomerase activity and telomere length, which was accompanied with upregulation of the catalytic subunit, telomerase reverse transcriptase (TERT). Whereas these effects of SDF-1alpha on telomerase activity and expression of hTERT mRNA were significantly attenuated by CXCR4-specific peptide antagonist (AMD3100) and phosphoinositide 3-kinase (PI3K) inhibitor (LY294002). In conclusions, SDF-1alpha delays the onset of EPC subpopulation senescence, which may be related to the activation of telomerase and elongation of telomere length. The inhibition of EPC subpopulation senescence and induction of EPC subpopulation proliferation by SDF-1alpha in vitro may importantly improve the functional activity of EPC subpopulation for potential cell therapy.},
}
@article {pmid20231841,
year = {2010},
author = {Moreno-Navarrete, JM and Ortega, F and Sabater, M and Ricart, W and Fernández-Real, JM},
title = {Telomere length of subcutaneous adipose tissue cells is shorter in obese and formerly obese subjects.},
journal = {International journal of obesity (2005)},
volume = {34},
number = {8},
pages = {1345-1348},
doi = {10.1038/ijo.2010.49},
pmid = {20231841},
issn = {1476-5497},
mesh = {Adipocytes/*ultrastructure ; Cellular Senescence/*genetics ; Female ; Humans ; Male ; Middle Aged ; Obesity/genetics/*metabolism ; Subcutaneous Fat/*cytology ; Telomere/*genetics ; },
abstract = {Obesity and increased fat mass are associated with increased adipocyte proliferation. Telomere length can serve as a biomarker of a cell's biological (vs chronological) age. To gain insight in the physiology of adipose tissue, we aimed to investigate telomere length in subcutaneous adipose tissue in relation to age and obesity. Telomere length was measured in 72 subcutaneous adipose tissue samples from 21 nonobese and 51 obese subjects. Telomere length of subcutaneous adipose tissue cells was negatively associated with body mass index (BMI), systolic blood pressure and fasting triglycerides. After controlling for age, fasting glucose, triglycerides and smoking status, BMI (P=0.009) contributed independently to 16% of telomere length variance. Interestingly, formerly obese patients (n=10) had shorter telomere length than never-obese subjects (n=12) of similar age, sex and BMI (7.1+/-1.3 vs 9.08+/-1.8 kb, P=0.01). In summary, adipose tissue cells from obese subjects show a shorter telomere length. The shorter telomere length of formerly obese subjects suggests that this is an established, irreversible feature of obesity that could contribute to its comorbidities.},
}
@article {pmid20231318,
year = {2010},
author = {Zaug, AJ and Podell, ER and Nandakumar, J and Cech, TR},
title = {Functional interaction between telomere protein TPP1 and telomerase.},
journal = {Genes &amp; development},
volume = {24},
number = {6},
pages = {613-622},
pmid = {20231318},
issn = {1549-5477},
mesh = {Animals ; Cell Line ; Enzyme Activation/genetics ; Humans ; Mice ; Models, Molecular ; Mutation/genetics ; Oryzias ; Protein Structure, Tertiary ; Recombinant Fusion Proteins/metabolism ; Shelterin Complex ; Telomerase/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Human chromosome end-capping and telomerase regulation require POT1 (Protection of Telomeres 1) and TPP1 proteins, which bind to the 3' ssDNA extension of human telomeres. POT1-TPP1 binding to telomeric DNA activates telomerase repeat addition processivity. We now provide evidence that this POT1-TPP1 activation requires specific interactions with telomerase, rather than it being a DNA substrate-specific effect. First, telomerase from the fish medaka, which extends the same telomeric DNA primer as human telomerase, was not activated by human POT1-TPP1. Second, mutation of a conserved glycine, Gly100 in the TEN (telomerase essential N-terminal) domain of TERT, abolished the enhancement of telomerase processivity by POT1-TPP1, in contrast to other single amino acid mutations. Chimeric human-fish telomerases that contained the human TEN domain were active but not stimulated by POT1-TPP1, showing that additional determinants of processivity lie outside the TEN domain. Finally, primers bound to mouse POT1A and human TPP1 were activated for extension by human telomerase, whereas mPOT1A-mTPP1 was most active with mouse telomerase, indicating that these mammalian telomerases have specificity for their respective TPP1 proteins. We suggest that a sequence-specific interaction between TPP1 in the TPP1-POT1-telomeric DNA complex and the G100 region of the TEN domain of TERT is necessary for high-processivity telomerase action.},
}
@article {pmid20228673,
year = {2011},
author = {Babizhayev, MA and Savel'yeva, EL and Moskvina, SN and Yegorov, YE},
title = {Telomere length is a biomarker of cumulative oxidative stress, biologic age, and an independent predictor of survival and therapeutic treatment requirement associated with smoking behavior.},
journal = {American journal of therapeutics},
volume = {18},
number = {6},
pages = {e209-26},
doi = {10.1097/MJT.0b013e3181cf8ebb},
pmid = {20228673},
issn = {1536-3686},
mesh = {Adolescent ; Adult ; Aged ; Aging/*physiology ; Biomarkers ; Cardiovascular Diseases/etiology ; Female ; Free Radicals/*adverse effects ; Humans ; Male ; Middle Aged ; Neoplasms/etiology ; Oxidative Stress/*physiology ; Pulmonary Disease, Chronic Obstructive/etiology ; Smoke/adverse effects ; Smoking/adverse effects/*mortality ; Telomere Homeostasis/*drug effects/physiology ; Telomere Shortening/*drug effects/physiology ; Nicotiana/adverse effects ; Tobacco Products/adverse effects ; Young Adult ; },
abstract = {Globally, tobacco use is associated with 5 million deaths per annum and is regarded as one of the leading causes of premature death. Major chronic disorders associated with smoking include cardiovascular diseases, several types of cancer, and chronic obstructive pulmonary disease (lung problems). Cigarette smoking (CS) generates a cumulative oxidative stress, which may contribute to the pathogenesis of chronic diseases. Mainstream and side stream gas-phase smoke each have about the same concentration of reactive free radical species, about 1 × 10(16) radicals per cigarette (or 5 × 10(14) per puff). This effect is critical in understanding the biologic effects of smoke. Several lines of evidence suggest that cigarette smoke constituents can directly activate vascular reactive oxygen species production. In this work we present multiple evidence that CS provide the important risk factors in many age-related diseases, and is associated with increased cumulative and systemic oxidative stress and inflammation. The cited processes are marked by increased white blood cell (leucocytes, WBCs) turnover. The data suggest an alteration of the circulating WBCs by CS, resulting in increased adherence to endothelial cells. Telomeres are complex DNA-protein structures located at the end of eukaryotic chromosomes. Telomere length shortens with biologic age in all replicating somatic cells. It has been shown that tobacco smoking enhances telomere shortening in circulating human WBCs. Telomere attrition (expressed in WBCs) can serve as a biomarker of the cumulative oxidative stress and inflammation induced by smoking and, consequently, show the pace of biologic aging. We originally propose that patented specific oral formulations of nonhydrolized carnosine and carcinine provide a powerful tool for targeted therapeutic inhibition of cumulative oxidative stress and inflammation and protection of telomere attrition associated with smoking. The longitudinal studies of the clinical population groups described in this study including elderly support the hypothesis that telomere length is a predictor of survival and therapeutic treatment requirement associated with smoking behavior.},
}
@article {pmid20226664,
year = {2010},
author = {Thanasoula, M and Escandell, JM and Martinez, P and Badie, S and Muñoz, P and Blasco, MA and Tarsounas, M},
title = {p53 prevents entry into mitosis with uncapped telomeres.},
journal = {Current biology : CB},
volume = {20},
number = {6},
pages = {521-526},
pmid = {20226664},
issn = {1879-0445},
support = {2005NOV57/BCN_/Breast Cancer Now/United Kingdom ; A8935/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Base Sequence ; Cell Cycle Proteins/physiology ; Cell Line ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p21/deficiency/genetics/physiology ; DNA Damage ; DNA-Binding Proteins/physiology ; HeLa Cells ; Histones/metabolism ; Humans ; Mice ; Mice, Knockout ; Mitosis/genetics/*physiology ; Protein Serine-Threonine Kinases/physiology ; RNA, Small Interfering/genetics ; Telomere/genetics/*physiology ; Tumor Suppressor Protein p53/antagonists &amp; inhibitors/deficiency/genetics/*physiology ; Tumor Suppressor Proteins/physiology ; },
abstract = {Telomeres are protected by capping structures consisting of core protein complexes that bind with sequence specificity to telomeric DNA. In their absence, telomeres trigger a DNA damage response, materialized in accumulation at the telomere of damage response proteins, e.g., phosphorylated histone H2AX (gammaH2AX), into telomere-dysfunction-induced foci. Telomere uncapping occurs transiently in every cell cycle in G2, following DNA replication, but little is known about how protective structures are reassembled or whether this process is controlled by the cell-cycle surveillance machinery. Here, we report that telomere capping is monitored at the G2/M transition by the p53/p21 damage response pathway. Unlike their wild-type counterparts, human and mouse cells lacking p53 or p21 progress into mitosis prematurely with persisting uncapped telomeres. Furthermore, artificially uncapped telomeres delay mitotic entry in a p53- and p21-dependent manner. Uncapped telomeres that persist in mitotic p53-deficient cells are shorter than average and religate to generate end-to-end fusions. These results suggest that a p53-dependent pathway monitors telomere capping after DNA replication and delays G2/M progression in the presence of unprotected telomeres. This mechanism maintains a cell-cycle stage conducive for capping reactions and prevents progression into stages during which uncapped telomeres are prone to deleterious end fusions.},
}
@article {pmid20226199,
year = {2010},
author = {Santiso, R and Tamayo, M and Gosálvez, J and Meseguer, M and Garrido, N and Fernández, JL},
title = {Swim-up procedure selects spermatozoa with longer telomere length.},
journal = {Mutation research},
volume = {688},
number = {1-2},
pages = {88-90},
doi = {10.1016/j.mrfmmm.2010.03.003},
pmid = {20226199},
issn = {0027-5107},
mesh = {*DNA Fragmentation ; Humans ; Male ; *Sperm Motility ; Spermatozoa/*physiology ; Telomere/*physiology ; },
abstract = {Telomere length and sperm DNA fragmentation were determined in sperm samples from 27 patients, using a quantitative PCR (Q-PCR) assay and the Sperm Chromatin Dispersion (SCD) test, respectively. Comparisons of the samples before and after swim-up processing demonstrated that this procedure selects a sperm population with longer average telomere size and lower frequency of sperm cells with fragmented DNA.},
}
@article {pmid20219960,
year = {2010},
author = {Cassidy, A and De Vivo, I and Liu, Y and Han, J and Prescott, J and Hunter, DJ and Rimm, EB},
title = {Associations between diet, lifestyle factors, and telomere length in women.},
journal = {The American journal of clinical nutrition},
volume = {91},
number = {5},
pages = {1273-1280},
pmid = {20219960},
issn = {1938-3207},
support = {CA82838/CA/NCI NIH HHS/United States ; HL34594/HL/NHLBI NIH HHS/United States ; T32 CA 09001/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Body Composition ; Breast Neoplasms/epidemiology/genetics ; Case-Control Studies ; *Diet ; Endometrial Neoplasms/epidemiology/genetics ; Fatty Acids, Unsaturated/blood ; Female ; Humans ; Leukocytes/cytology ; *Life Style ; Middle Aged ; Nutrition Surveys ; Polymerase Chain Reaction ; Repetitive Sequences, Nucleic Acid ; Risk Assessment ; Skin Neoplasms/epidemiology/genetics ; Surveys and Questionnaires ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Leukocyte telomere length is associated with diseases of aging, but there is limited knowledge of diet and lifestyle determinants.<br><br>OBJECTIVE: The objective was to examine cross-sectionally the association between diet, body composition, and lifestyle factors on leukocyte telomere length in women.<br><br>DESIGN: Leukocyte telomere length was measured by quantitative polymerase chain reaction in 2284 female participants from the Nurses' Health Study, who were selected as controls for an investigation of biological predictors of cancer. Diet, lifestyle, and anthropometric data were assessed by questionnaire.<br><br>RESULTS: After multivariate adjustment, dietary fiber intake was positively associated with telomere length (z score), specifically cereal fiber, with an increase of 0.19 units between the lowest and highest quintiles (P = 0.007, P for trend = 0.03). Although total fat intake was not associated with telomere length, polyunsaturated fatty acid intake (-0.26 units, quintile 5 compared with quintile 1: P = 0.002, P for trend = 0.02), specifically linoleic acid intake, was inversely associated with telomere length after multivariate adjustment (-0.32 units; P = 0.001, P for trend = 0.05). Waist circumference was inversely associated with telomere length [0.15-unit difference in z score in a comparison of the highest (> or = 32 in, 81.28 cm) with the lowest (< or = 28 in, 71.12 cm) category (P = 0.01, P for trend = 0.02) in the multivariate model]. We found no association between telomere length and smoking, physical activity, or postmenopausal hormone use.<br><br>CONCLUSION: Although the strength of the associations was modest in this population of middle- and older-age women, our results support the hypothesis that body composition and dietary factors are related to leukocyte telomere length, which is a potential biomarker of chronic disease risk.},
}
@article {pmid20219198,
year = {2010},
author = {Panayiotou, AG and Nicolaides, AN and Griffin, M and Tyllis, T and Georgiou, N and Bond, D and Martin, RM and Hoppensteadt, D and Fareed, J and Humphries, SE},
title = {Leukocyte telomere length is associated with measures of subclinical atherosclerosis.},
journal = {Atherosclerosis},
volume = {211},
number = {1},
pages = {176-181},
doi = {10.1016/j.atherosclerosis.2010.01.037},
pmid = {20219198},
issn = {1879-1484},
support = {RG/08/008/25291/BHF_/British Heart Foundation/United Kingdom ; RG2008/015/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Adult ; Aging ; Atherosclerosis/diagnostic imaging/*pathology ; Carotid Artery Diseases/diagnostic imaging ; Carotid Artery, Common/diagnostic imaging ; Cohort Studies ; Female ; Humans ; Leukocytes/*chemistry ; Male ; Telomere/*chemistry ; Tunica Intima/*diagnostic imaging/pathology ; Ultrasonography ; },
abstract = {AIMS: Our aim was to test the association of mean leukocyte telomere length (LTL) with ultrasonic measures of subclinical atherosclerosis such as intima-media thickness in the common carotid (IMTcc) and sum of plaque areas (SPA) and with serological markers.<br><br>METHODS AND RESULTS: Carotid and femoral bifurcations were scanned in 762 general population volunteers (46% men) over 40. Four features were considered: (a) IMTcc, (b) sum plaque areas of carotid plaques (SPAcar), (c) sum plaque area of common femoral plaques (SPAfem) and (d) sum plaque area (SPA--sum of the plaque areas of the largest plaques present in each of both carotid and femoral bifurcations). Mean LTL was determined with a quantitative real-time PCR-based method. IMTcc was strongly associated with mean LTL both before and after correction for traditional risk factors (B=-0.002; 95% CI=-0.004 to -0.00; p=0.014). In sex-specific analysis, the association was stronger in men (p for sex interaction<0.001). SPAfem was associated with LTL in women before and after correction (B=-0.195; 95% CI=-0.38 to -0.01; p=0.037) (p for sex interaction<0.001). LTL was also associated with age and sex-adjusted levels of hsCRP (p=0.012), sCD40L (p=0.042), homocysteine (p=0.006), creatinine (p=0.02), ApoA1 (p=0.01), Lp(a) (p=0.04) and HOMA-IR (p=0.008).<br><br>CONCLUSIONS: Our results support the telomere hypothesis and highlight potential differences in the biological mechanisms leading to intima-media thickening and/or plaque formation between vascular beds. They may provide insights into a novel treatment of antisenescence to prevent atherosclerosis.},
}
@article {pmid20213664,
year = {2010},
author = {Lobetti-Bodoni, C and Bernocco, E and Genuardi, E and Boccadoro, M and Ladetto, M},
title = {Telomeres and telomerase in normal and malignant B-cells.},
journal = {Hematological oncology},
volume = {28},
number = {4},
pages = {157-167},
doi = {10.1002/hon.937},
pmid = {20213664},
issn = {1099-1069},
mesh = {Aging/genetics ; Animals ; B-Lymphocytes/enzymology/*metabolism/pathology ; Cellular Senescence/genetics ; Humans ; Lymphoma, B-Cell/enzymology/genetics/pathology ; Models, Genetic ; Neoplasms/enzymology/*genetics/pathology ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {The telomeric checkpoint is emerging as a critical sensor of cellular damage, playing a major role in human aging and cancer development. In the meantime, telomere biology is rapidly evolving from a basic discipline to a translational branch, capable of providing major hints for biomarker development, risk assessment and targeted treatment of cancer. These advances have a number of implications in the biology of lymphoid tumours. Moreover, there is considerable interest in the potential role of telomeric dysfunction in the wide array of immunological abnormalities, grouped under the definition of 'immunosenescence'. This review will summarize the impact of recent advances in telomere biology on the physiology and pathology of the B lymphocyte, with special interest in immunosenescence and lymphomagenesis.},
}
@article {pmid21567790,
year = {2010},
author = {Szeberényi, J},
title = {Problem-solving test: Telomere replication.},
journal = {Biochemistry and molecular biology education : a bimonthly publication of the International Union of Biochemistry and Molecular Biology},
volume = {38},
number = {1},
pages = {43-45},
doi = {10.1002/bmb.20372},
pmid = {21567790},
issn = {1539-3429},
abstract = {Terms to be familiar with before you start to solve the test: DNA replication, template, primer, linear DNA, antiparallel orientation, telomere, origin of replication, chromatid, replicon, short tandem repeats, Okazaki fragments, leading strand, lagging strand, ribozyme, promoter, enhancer, terminal transferase, DNA polymerases, reverse transcriptase, RNA polymerase, topoisomerase, retroviral vector, Southern blotting, restriction endonuclease.},
}
@article {pmid21427985,
year = {2010},
author = {Novikova, PIu and Supil'nikova, OV and Novikova, SIu and Khrupina, AS and Ivolgin, DA and Smirnova, NV and Mikhel'son, VM and Khurtsilava, OG and Smolianinov, AB},
title = {[Telomere length of cord blood cells chromosomes as additional quality characteristic of sample for transplantation].},
journal = {Tsitologiia},
volume = {52},
number = {12},
pages = {1045-1048},
pmid = {21427985},
issn = {0041-3771},
mesh = {Cell Line, Tumor ; *Cell Proliferation ; Chromosomes, Human/*metabolism ; *Cord Blood Stem Cell Transplantation ; *Fetal Blood/cytology/metabolism ; Humans ; Quality Control ; *Stem Cells/cytology/metabolism ; Telomere ; *Transplants ; },
abstract = {Telomeres are the ends of the chromosomes and represent repeated DNA sequence and protein complex. Telomeres shorten with each cell division, which limits proliferative potential of cells. There is a great progress in clinical application of telomere length now. Additional characteristic of stem cell proliferation activity estimated by telomere length can be an informative indicator of transplant quality. In this work, we analyzed 14 cord blood samples by flow-FISH, ELISA and gematologycal analisator, and also the number of CD34 + CD45dim cells. Average telomere length of leukocytes fraction CB cells was 20.4-4.9 % respectively the control cells 1301 (T-cell lymphoblastic leukemia).},
}
@article {pmid21160767,
year = {2009},
author = {Frías, C and Morán, A and de Juan, C and Ortega, P and Fernández-Marcelo, T and Sánchez-Pernaute, A and Torres, AJ and Díaz-Rubio, E and Benito, M and Iniesta, P},
title = {Telomere function in colorectal cancer.},
journal = {World journal of gastrointestinal oncology},
volume = {1},
number = {1},
pages = {3-11},
pmid = {21160767},
issn = {1948-5204},
abstract = {Colorectal cancer is the third most common form of cancer and the second leading cause of cancer-related death in the western world. Tumour cells acquire the hallmarks of cancer during the carcinogenic selection process. Cell immortality is one of the principal features acquired during this process which involves the stabilization of telomere length. It is achieved mainly, by telomerase activation. Thus, the discovery of telomeres and telomerase allowed an understanding of the mechanisms by which cells can become immortalized. Different studies have shown that tumour cells have shorter telomeres than nontumour cells and have detected telomerase activity in the majority of tumours. Survival studies have determined that telomere maintenance and telomerase activity are associated with poor prognosis. Taking into account all the results achieved by different groups, quantification and evaluation of telomerase activity and measurement of telomere length may be useful methods for additional biologic and prognostic staging of colorectal carcinoma.},
}
@article {pmid21089501,
year = {2009},
author = {Kanoh, J},
title = {[Regulation of telomere DNA by telomere-specific chromatin structure].},
journal = {Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme},
volume = {54},
number = {4 Suppl},
pages = {514-520},
pmid = {21089501},
issn = {0039-9450},
mesh = {Animals ; Cell Cycle Proteins/physiology ; Chromatin Assembly and Disassembly/*genetics ; Chromosomal Proteins, Non-Histone/physiology ; Chromosomes/genetics ; DNA/*metabolism ; DNA Replication ; Humans ; Multiprotein Complexes ; Protein Binding ; Saccharomyces cerevisiae Proteins/physiology ; Schizosaccharomyces pombe Proteins/physiology ; Shelterin Complex ; Telomerase/physiology ; Telomere/*genetics ; Telomere-Binding Proteins/physiology ; Transcription Factors/physiology ; },
}
@article {pmid20606778,
year = {2009},
author = {Makpol, S and Yaacob, N and Zainuddin, A and Yusof, YA and Ngah, WZ},
title = {Chlorella vulgaris modulates hydrogen peroxide-induced DNA damage and telomere shortening of human fibroblasts derived from different aged individuals.},
journal = {African journal of traditional, complementary, and alternative medicines : AJTCAM},
volume = {6},
number = {4},
pages = {560-572},
pmid = {20606778},
issn = {2505-0044},
mesh = {Adult ; Aged ; Cellular Senescence/physiology ; *Chlorella vulgaris ; Comet Assay ; DNA Damage/*drug effects/genetics ; Dietary Supplements ; Diploidy ; Dose-Response Relationship, Drug ; Female ; Fibroblasts/drug effects/metabolism ; Humans ; Hydrogen Peroxide/*pharmacology ; Male ; Middle Aged ; Oxidative Stress/genetics ; Telomerase/drug effects/genetics/*metabolism ; Telomere/*drug effects/genetics ; Young Adult ; },
abstract = {The objective of this study was to investigate the modulatory effect of Chlorella vulgaris on cultured fibroblast cells derived from young and old aged individuals focusing on DNA damage, telomere length and telomerase activity. Dose-response test of the algal extract on cells in both age groups revealed that optimum viability was observed at a concentration of 50 microg/ml. Results obtained showed that Chlorella vulgaris exhibited protective effects against H(2)O(2)-induced oxidative stress as shown by the reduction in damaged DNA caused by H(2)O(2) treatment (p<0.05) in Chlorella vulgaris pre- and post-treated groups (p<0.05). Pre-treatment of Chlorella vulgaris resulted in a significant decrease in DNA damage suggesting a bioprotective effect against free radical attacks. A decline in DNA damage was observed in post-treated cells which proves Chlorella vulgaris to present bioremediative properties. In cells induced with oxidative stress, telomere length decreased significantly coupled with a concomitant decline of telomerase activity (p<0.05). However, these reductions were prevented with prior and post treatment of Chlorella vulgaris. Therefore, we concluded that Chlorella vulgaris exhibited bioprotective effects especially in cells obtained from young donor but were more bioremediative for cells obtained from old donor as indicated by DNA damage, telomere shortening and reduction in telomerase activity.},
}
@article {pmid20664721,
year = {2008},
author = {Shakirov, EV and Salzberg, SL and Alam, M and Shippen, DE},
title = {Analysis of Carica papaya Telomeres and Telomere-Associated Proteins: Insights into the Evolution of Telomere Maintenance in Brassicales.},
journal = {Tropical plant biology},
volume = {1},
number = {3-4},
pages = {202-215},
pmid = {20664721},
issn = {1935-9756},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; R01 GM083873/GM/NIGMS NIH HHS/United States ; R01 GM083873-06/GM/NIGMS NIH HHS/United States ; },
abstract = {Telomeres are terminal regions of linear eukaryotic chromosomes that are critical for genome stability and continued cell proliferation. The draft assembly of the papaya genome provides an opportunity to analyze and compare the evolution of telomeric DNA sequence composition and telomere maintenance machinery in this and other organisms of the Brassicales Order, which includes Arabidopsis. Here we investigate telomere size and sequence variation at papaya chromosome ends. As with most other plant species, papaya telomeres consist of TTTAGGG repeats. However, in contrast to members of the closely related Brassicaceae family, telomeres in papaya are ~10-fold longer. Sequence analysis reveals that many centromereproximal telomere repeats in papaya harbor nucleotide substitutions and insertions of Gs and Ts. In contrast, we found very few N-to-C substitutions, and even fewer instances of nucleotide deletion, suggesting that a six-nucleotide telomere repeat is not well tolerated. The papaya genome encodes single-copy sequence homologues of several genes involved in telomere maintenance and chromosome end protection, including the Telomerase Reverse Transcriptase (TERT) and Protection Of Telomeres (POT1). Notably, unlike Arabidopsis, which encodes six Telomere Repeat binding Factor-like (TRFL) proteins that bind double-stranded telomere DNA, papaya appears to encode only two such proteins. Thus, the more streamlined genome of papaya will provide an excellent resource for comparative and functional analysis of telomeres in plants.},
}
@article {pmid21887880,
year = {2008},
author = {Ranganath, RM},
title = {Meiotic chromosome pairing and recombination take refuge in the telomeres.},
journal = {Nature reviews. Genetics},
volume = {9},
number = {4},
pages = {318},
doi = {10.1038/nrg2224-c1},
pmid = {21887880},
issn = {1471-0064},
mesh = {Alleles ; *Chromosome Segregation ; Chromosomes, Plant ; *Meiosis ; Oenothera/*genetics ; *Recombination, Genetic ; Sequence Homology, Nucleic Acid ; Telomere/*genetics ; },
}
@article {pmid21585768,
year = {2008},
author = {Haussmann, MF and Mauck, RA},
title = {TECHNICAL ADVANCES: New strategies for telomere-based age estimation.},
journal = {Molecular ecology resources},
volume = {8},
number = {2},
pages = {264-274},
doi = {10.1111/j.1471-8286.2007.01973.x},
pmid = {21585768},
issn = {1755-098X},
abstract = {Telomere dynamics link molecular and cellular mechanisms with organismal processes and therefore may explain variation in a number of important life-history traits. Telomere length has been used to estimate age in free-living populations of animals. Such estimation is a potentially powerful tool in the context of population dynamics and management, as well as the study of life-history trade-offs. The number of studies utilizing telomere restriction fragment assays in the fields of ecology and evolution is steadily growing. However, the field lacks methodological and analytical standardization resulting in considerable variation in telomere length and therefore in the usefulness of these techniques. Here, we illustrate new laboratory and analytical methods to reliably measure telomere length from blood erythrocytes and accurately assess the relationship between telomeres and age. We demonstrate the importance of analysing those telomeres most relevant to age-related studies: the shortest telomeres. We present a reliable method to quickly identify an analysis window (the telomere optimal estimate, TOE) which approaches the optimal window for age estimation. Because the TOE focuses on the shortest telomeres - those telomeres which signal cellular senescence and ageing - TOE can also be used to compare telomeres in age-matched individuals. We also compare constant- and pulsed-field gel electrophoresis to show how each can influence telomere measurement. The use of TOE should provide powerful telomere-based age estimation and enable organismal biologists to readily uncover individual and longitudinal differences with regard to telomere dynamics.},
}
@article {pmid21642143,
year = {2006},
author = {Sykorová, E and Fajkus, J and Mezníková, M and Lim, KY and Neplechová, K and Blattner, FR and Chase, MW and Leitch, AR},
title = {Minisatellite telomeres occur in the family Alliaceae but are lost in Allium.},
journal = {American journal of botany},
volume = {93},
number = {6},
pages = {814-823},
doi = {10.3732/ajb.93.6.814},
pmid = {21642143},
issn = {0002-9122},
abstract = {Although telomere sequences are considered to be highly conserved, there are switch-points in plant telomere evolution that are congruent with species' phylogenies. When Asparagales diverged, the Arabidopsis-type telomeric minisatellite repeat (TTTAGGG)(n) was first replaced by a human-type (TTAGGG)(n) repeat, and both were lost in Allium cepa (Alliaceae). We aimed to discover (1) when this loss occurred during divergence of Alliaceae and, (2) if (TTAGGG)(n) repeats were replaced by other known telomeric minisatellites. Slot-blot hybridization, fluorescent in situ hybridization, BAL31 digestion, asymmetric PCR, and cloning were used to identify and localize candidate telomeric sequences in species of Nothoscordum, Miersia, Ipheion, Tulbaghia, Gethyum, Gilliesia, Leucocoryne, Tristagma, and representatives of the three major Allium clades. Alliaceae genera other than Allium have human (TTAGGG)-type telomeric repeats that form telomeres. In Allium, only Tetrahymena-type (TTGGGG) repeats were ubiquitous in the genome, but they were not localized to telomeres. Likewise, the consensus telomeric repeats in Arabidopsis, human, Bombyx (TTAGG), Chlamydomonas (TTTTAGGG), and Oxytricha (TTTTGGGG) are absent in Allium telomeres. Alliaceae with human-type telomeres share telomere structures with related Asparagales species. We demonstrate that in the Allium ancestor human-type telomeric repeats were lost from telomeres and were not replaced by any investigated alternative minisatellite repeats. However, human and other types of minisatellite telomeric repeats are interspersed in some Allium genomes and their genomic signatures coincide with Allium clades.},
}
@article {pmid20704890,
year = {2005},
author = {Hathcock, KS and Chiang, YJ and Hodes, RJ},
title = {Telomere biology and immune system.},
journal = {Discovery medicine},
volume = {5},
number = {27},
pages = {288-292},
pmid = {20704890},
issn = {1944-7930},
abstract = {Extract: In the 1960s Hayflick reported that normal human somatic cells have a finite replicative capacity and that, after a limited number of cell divisions, cells no longer divide and enter a state termed senescence. Since this observation was made, considerable research energy has focused on identifying molecular pathways that regulate the proliferative capacity of normal somatic (body) cells. One molecular mechanism that has been implicated in the regulation of somatic cell proliferation is mediated by telomeres -- specialized DNA-protein structures that cap the ends of all linear chromosomes. In mammalian cells, telomeres are composed of hexanucleotide repeats (TTAGGG) and a variety of associated proteins. Although all mammalian telomeres are composed of these (TTAGGG) repeats, telomere length varies substantially between different species. The higher order chromatin structure formed by telomeres functions to protect chromosomes ends from degradation and activation of DNA-repair pathways. In the absence of compensatory mechanisms, telomeres shorten progressively with successive rounds of cell division as a result of incomplete replication of telomeric termini, until they reach a critically short length that is no longer protective. Cells that lack protective telomeres fail to proliferate, and they undergo senescence or apoptosis.},
}
@article {pmid20565657,
year = {2005},
author = {Farman, ML and Kim, YS},
title = {Telomere hypervariability in Magnaporthe oryzae.},
journal = {Molecular plant pathology},
volume = {6},
number = {3},
pages = {287-298},
doi = {10.1111/j.1364-3703.2005.00285.x},
pmid = {20565657},
issn = {1364-3703},
abstract = {SUMMARY The gray leaf spot disease of perennial ryegrass and tall fescue is caused by the fungus Magnaporthe oryzae (anamorph = Pyricularia oryzae). A collection of single-copy and repetitive DNA markers was used to investigate genetic diversity among 22 isolates of the gray leaf spot pathogen. The single-copy DNA markers revealed only three polymorphisms among 95 restriction fragments spanning approximately 0.6% of the genome. In addition, Southern hybridization analysis and mating tests revealed that all isolates possessed the MAT1-2 mating-type allele. Fingerprinting of repetitive DNA loci using the Pot2 and MGR583 probes also revealed a high degree of genetic similarity (> 85%) among isolates. These data are consistent with the gray leaf spot pathogens having a recent evolutionary origin. In contrast to the results obtained with probes for internal chromosome loci, a telomere probe revealed that the chromosome ends of the very same isolates are highly divergent, with most isolates sharing less than 20% fingerprint similarity with any other isolate. Telomere mutations arise extremely frequently and changes in telomere fingerprint profiles were readily observed during vegetative growth and among cultures derived from single spores isolated from agar medium and from lesions on perennial ryegrass leaves.},
}
@article {pmid22351265,
year = {2000},
author = {Valenzuela, HF and Effros, RB},
title = {Telomeres and replicative senescence.},
journal = {Methods in molecular medicine},
volume = {38},
number = {},
pages = {63-70},
doi = {10.1385/1-59259-070-5:63},
pmid = {22351265},
issn = {1543-1894},
abstract = {Telomere length measurement can be used both to monitor the proliferation of long-term cultures of somatic cells as well as to determine the replicative history of in vivo-derived cells. The most frequently used technique for telomere length measurement is Southern hybridization (1, 4). The method consists of isolating total genomic DNA, digesting the DNA with restriction enzymes so as to isolate the undigested telomere restriction fragments (TRFs), and separating these fragments by gel electrophoresis. The DNA is denatured and transferred from the gel to a membrane or filter, and the DNA samples are then hybridized to radiolabeled complementary probe. However, when blotting TRF DNA to the membrane, differential transfer may occur owing to inefficient transfer of larger fragments of DNA (>10 kb) to a membrane. As the mean length of the TRF is based on the assumption that the amount of telomeric DNA (TTAGGG repeats) in a given TRF is proportional to the length (3, 4), this would lead to possible error in calculating the mean length of the telomeres. The method that we present here avoids these potential problems by eliminating the membrane blot step altogether and probing the gel directly.},
}
@article {pmid20426563,
year = {1999},
author = {Rufer, N and Brummendorf, TH and Dragowska, V and Shultzer, M and Wadsworth, LD and Lansdorp, PM},
title = {Turnover of stem cells, naive and memory T lymphocytes, estimated from telomere fluorescence measurements.},
journal = {Cytotherapy},
volume = {1},
number = {4},
pages = {342},
doi = {10.1080/0032472031000141274},
pmid = {20426563},
issn = {1465-3249},
mesh = {Age Factors ; Aged ; CD4-Positive T-Lymphocytes/cytology ; CD8-Positive T-Lymphocytes/cytology ; Granulocytes/cytology ; Humans ; *Immunologic Memory ; In Situ Hybridization, Fluorescence ; Lymphocytes/cytology ; Microscopy, Fluorescence/*methods ; Middle Aged ; Stem Cells/*cytology ; T-Lymphocytes/*cytology ; Telomere/*ultrastructure ; },
}
@article {pmid21541632,
year = {1996},
author = {Fiedler, W and Dahse, R and Schlichter, A and Junker, K and Kosmehl, H and Ernst, G and Schubert, J and Claussen, U},
title = {Telomerase activity and telomere length in different areas of renal cell carcinoma.},
journal = {International journal of oncology},
volume = {9},
number = {6},
pages = {1227-1232},
doi = {10.3892/ijo.9.6.1227},
pmid = {21541632},
issn = {1019-6439},
abstract = {Telomerase activity and telomere length were analyzed in a total of 59 surgically removed primary renal cell carcinoma (RCC). The study includes tissue from the centre of the tumor, several different peripheral tumor areas, metastases and secondary tumors. None of the normal renal cortex tissues used as control exhibited telomerase activity. In contrast, telomerase activity was detected in 55 out df 59 (=93%) tested primary RCC. There was no case with intratumoral heterogeneity concerning the telomerase activity status. All metastases and secondary tumors were telomerase-positive. In the four telomerase deficient tumors all measured telomeric repeat fragments were shortened in comparison to the normal tissue. As these patients exhibit no metastases or secondary tumors a less malignant variant of RCC is supposed. There was no correlation between telomerase activity and specific histopathological subtypes of RCC or specific chromosomal aberrations. As telomerase activity is not associated with advanced stages of tumors it may be an important early event in the development of RCC. Thus, telomerase activity may be a prevalent marker for early and late stages of all subtypes of RCC.},
}
@article {pmid21552856,
year = {1995},
author = {Bacchetti, S and Counter, C},
title = {Telomeres and telomerase in human cancer (review).},
journal = {International journal of oncology},
volume = {7},
number = {3},
pages = {423-432},
pmid = {21552856},
issn = {1019-6439},
abstract = {Telomerase has recently come into the limelight as one of the most prevalent tumour markers, due to its nearly ubiquitous presence in malignant tissues and absence from most somatic tissues. The essential role of telomeres in unlimited cell proliferation and that of the enzyme in telomere maintenance have suggested that telomerase inhibitors may be effective in cancer therapy. We provide here a compendium and an evaluation of the available data relating to this hypothesis.},
}
@article {pmid21351687,
year = {1988},
author = {Button, LL and Astell, CR},
title = {DNA fragments isolated from the left end of chromosome III in yeast are repaired to generate functional telomeres.},
journal = {Genome},
volume = {30},
number = {5},
pages = {758-765},
doi = {10.1139/g88-123},
pmid = {21351687},
issn = {0831-2796},
mesh = {Chromosomes, Fungal/*genetics ; DNA Repair/*genetics ; DNA, Fungal/*genetics ; Plasmids/genetics ; Saccharomyces cerevisiae/*genetics ; Telomere/*genetics ; },
abstract = {DNA fragments isolated from the left end of chromosome III in the yeast Saccharomyces cerevisiae are recognized as telomeres in yeast, since plasmids constructed with such fragments are replicated as linear molecules in yeast. The fragments have a 1.18-kb region homologous with the type X regions at yeast telomeres that contain ARS elements that allow the autonomous replication of plasmids in yeast. The X region contains a functional ARS element including the ARS consensus sequence and a distal 200-bp region that enhances ARS function. Distal to the type X region, the fragments have a region of tandemly repeated DNA sequence defined by the formula 5′-C(1–3)A-3′, and designated as the T region at yeast telomeres. Although the terminus of the chromosome was removed in the procedure used to molecularly isolate the left end of chromosome III, the fragments containing the X and T region are recognized as chromosome ends in yeast. Plasmids with inverted repeats of the chromosome III end fragments are resolved in yeast to produce linear plasmids with telomeres that are similar in length and heterogeneity with the natural left end on chromosome III. Fragments with progressive deletions from the distal end of chromosome III were prepared and used to study the X – T region requirements for distinguishing the fragments as telomeres in yeast.},
}
@article {pmid20213319,
year = {2010},
author = {Krüger, AC and Raarup, MK and Nielsen, MM and Kristensen, M and Besenbacher, F and Kjems, J and Birkedal, V},
title = {Interaction of hnRNP A1 with telomere DNA G-quadruplex structures studied at the single molecule level.},
journal = {European biophysics journal : EBJ},
volume = {39},
number = {9},
pages = {1343-1350},
pmid = {20213319},
issn = {1432-1017},
mesh = {Base Sequence ; DNA/*chemistry/genetics/*metabolism ; Electrophoretic Mobility Shift Assay ; Fluorescence Resonance Energy Transfer ; *G-Quadruplexes/drug effects ; Heterogeneous Nuclear Ribonucleoprotein A1 ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/*metabolism/pharmacology ; Protein Binding ; Telomere/*chemistry ; },
abstract = {G-rich telomeric DNA sequences can form G-quadruplex structures. The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and a shortened derivative (UP1) are active in telomere length regulation, and it has been reported that UP1 can unwind G-quadruplex structures. Here, we investigate the interaction of hnRNP A1 with G-quadruplex DNA structures containing the human telomere repeat (TTAGGG) by gel retardation assays, ensemble fluorescence energy transfer (FRET) spectroscopy, and single molecule FRET microscopy. Our biochemical experiments show that hnRNP A1 binds well to the G-quadruplex telomeric DNA. Ensemble and single molecule FRET measurements provide further insight into molecular conformation: the telomeric DNA overhang is found to be in a folded state in the absence of hnRNP A1 and to remain predominantly in a compact state when complexed with hnRNP A1. This finding is in contrast to the previously reported crystal structures of UP1-telomere DNA complexes where the DNA oligo within the protein-DNA complex is in a fully open conformation.},
}
@article {pmid20212315,
year = {2010},
author = {McNees, CJ and Tejera, AM and Martínez, P and Murga, M and Mulero, F and Fernandez-Capetillo, O and Blasco, MA},
title = {ATR suppresses telomere fragility and recombination but is dispensable for elongation of short telomeres by telomerase.},
journal = {The Journal of cell biology},
volume = {188},
number = {5},
pages = {639-652},
pmid = {20212315},
issn = {1540-8140},
support = {232854/ERC_/European Research Council/International ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/*metabolism ; Cells, Cultured ; DNA Damage ; DNA Repair ; Female ; Fibroblasts/cytology/physiology ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Mice, Inbred Strains ; Mice, Knockout ; Protein Serine-Threonine Kinases/genetics/*metabolism ; *Recombination, Genetic ; Survival Rate ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomere shortening caused by incomplete DNA replication is balanced by telomerase-mediated telomere extension, with evidence indicating that the shortest telomeres are preferred substrates in primary cells. Critically short telomeres are detected by the cellular DNA damage response (DDR) system. In budding yeast, the important DDR kinase Tel1 (homologue of ATM [ataxia telangiectasia mutated]) is vital for telomerase recruitment to short telomeres, but mammalian ATM is dispensable for this function. We asked whether closely related ATR (ATM and Rad3 related) kinase, which is important for preventing replicative stress and chromosomal breakage at common fragile sites, might instead fulfill this role. The newly created ATR-deficient Seckel mouse strain was used to examine the function of ATR in telomerase recruitment and telomere function. Telomeres were recently found to resemble fragile sites, and we show in this study that ATR has an important role in the suppression of telomere fragility and recombination. We also find that wild-type ATR levels are important to protect short telomeres from chromosomal fusions but do not appear essential for telomerase recruitment to short telomeres in primary mouse embryonic fibroblasts from the ATR-deficient Seckel mouse model. These results reveal a previously unnoticed role for mammalian ATR in telomere protection and stability.},
}
@article {pmid20212114,
year = {2010},
author = {Arbuckle, JH and Medveczky, MM and Luka, J and Hadley, SH and Luegmayr, A and Ablashi, D and Lund, TC and Tolar, J and De Meirleir, K and Montoya, JG and Komaroff, AL and Ambros, PF and Medveczky, PG},
title = {The latent human herpesvirus-6A genome specifically integrates in telomeres of human chromosomes in vivo and in vitro.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {107},
number = {12},
pages = {5563-5568},
pmid = {20212114},
issn = {1091-6490},
support = {P30 CA077598/CA/NCI NIH HHS/United States ; R01 CA111196/CA/NCI NIH HHS/United States ; 5R01CA111196/CA/NCI NIH HHS/United States ; P30 CA077598-09/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Base Sequence ; Cell Line ; Child ; Chromosomes, Human/*genetics/*virology ; DNA, Viral/blood/genetics ; Female ; Gene Dosage ; Genome, Viral ; Germ Cells/virology ; Herpesvirus 6, Human/*genetics/*pathogenicity/physiology ; Humans ; In Situ Hybridization, Fluorescence ; In Vitro Techniques ; Infectious Disease Transmission, Vertical ; Male ; Middle Aged ; Molecular Sequence Data ; Plasmids/blood/genetics ; Roseolovirus Infections/genetics/transmission/virology ; Telomere/*genetics/*virology ; Virus Activation ; Virus Integration/*genetics ; Virus Replication ; Young Adult ; },
abstract = {Previous research has suggested that human herpesvirus-6 (HHV-6) may integrate into host cell chromosomes and be vertically transmitted in the germ line, but the evidence--primarily fluorescence in situ hybridization (FISH)--is indirect. We sought, first, to definitively test these two hypotheses. Peripheral blood mononuclear cells (PBMCs) were isolated from families in which several members, including at least one parent and child, had unusually high copy numbers of HHV-6 DNA per milliliter of blood. FISH confirmed that HHV-6 DNA colocalized with telomeric regions of one allele on chromosomes 17p13.3, 18q23, and 22q13.3, and that the integration site was identical among members of the same family. Integration of the HHV-6 genome into TTAGGG telomere repeats was confirmed by additional methods and sequencing of the integration site. Partial sequencing of the viral genome identified the same integrated HHV-6A strain within members of families, confirming vertical transmission of the viral genome. We next asked whether HHV-6A infection of naïve cell lines could lead to integration. Following infection of naïve Jjhan and HEK-293 cell lines by HHV-6, the virus integrated into telomeres. Reactivation of integrated HHV-6A virus from individuals' PBMCs as well as cell lines was successfully accomplished by compounds known to induce latent herpesvirus replication. Finally, no circular episomal forms were detected even by PCR. Taken together, the data suggest that HHV-6 is unique among human herpesviruses: it specifically and efficiently integrates into telomeres of chromosomes during latency rather than forming episomes, and the integrated viral genome is capable of producing virions.},
}
@article {pmid20207949,
year = {2010},
author = {Rodriguez-Brenes, IA and Peskin, CS},
title = {Quantitative theory of telomere length regulation and cellular senescence.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {107},
number = {12},
pages = {5387-5392},
pmid = {20207949},
issn = {1091-6490},
support = {P50 GM071558/GM/NIGMS NIH HHS/United States ; P50GM071558/GM/NIGMS NIH HHS/United States ; },
mesh = {Algorithms ; Biophysical Phenomena ; Cell Line ; Cellular Senescence/*physiology ; DNA Damage ; DNA Replication ; HeLa Cells ; Humans ; *Models, Biological ; Stochastic Processes ; Telomere/chemistry/genetics/*physiology ; Telomeric Repeat Binding Protein 2/physiology ; },
abstract = {In normal somatic cells, telomere length shortens with each cell replication. This progressive shortening is associated with cellular senescence and apoptosis. Germ cells, stem cells, and the majority of cancer cells express telomerase, an enzyme that extends telomere length and, when expressed at sufficient levels, can immortalize or extend the life span of a cell line. It is believed that telomeres switch between two states: capped and uncapped. The telomere state determines its accessibility to telomerase and also the onset of senescence. One hypothesis is that the t loop, a large lariat-like structure, represents the capped state. In this paper we model a telomere state on the basis of the biophysics of t-loop formation, allowing us to develop a single mathematical model that accounts for two processes: telomere length regulation for telomerase positive cells and cellular senescence in somatic cells. The model predicts the steady-state length distribution for telomerase positive cells, describes the time evolution of telomere length, and computes the life span of a cell line on the basis of the levels of TRF2 and telomerase expression. The model reproduces a wide range of experimental behavior and fits data from immortal cell lines (HeLa S3 and 293T) and somatic cells (human diploid fibroblasts) well. We conclude that the t loop as the capped state is a quantitatively reasonable model of telomere length regulation and cellular senescence.},
}
@article {pmid20197395,
year = {2010},
author = {Mitchell, MA and Johnson, JE and Pascarelli, K and Beeharry, N and Chiourea, M and Gagos, S and Lev, D and von Mehren, M and Kipling, D and Broccoli, D},
title = {Doxorubicin resistance in a novel in vitro model of human pleomorphic liposarcoma associated with alternative lengthening of telomeres.},
journal = {Molecular cancer therapeutics},
volume = {9},
number = {3},
pages = {682-692},
pmid = {20197395},
issn = {1538-8514},
support = {F32 CA117675/CA/NCI NIH HHS/United States ; R01 CA098087/CA/NCI NIH HHS/United States ; CA006927/CA/NCI NIH HHS/United States ; CA117675/CA/NCI NIH HHS/United States ; R01 CA098087-05/CA/NCI NIH HHS/United States ; CA 098987/CA/NCI NIH HHS/United States ; P30 CA006927/CA/NCI NIH HHS/United States ; },
mesh = {Antineoplastic Agents/pharmacology/therapeutic use ; Cell Line, Tumor ; Chromosome Aberrations/chemically induced ; Cytogenetic Analysis ; Doxorubicin/pharmacology/*therapeutic use ; Drug Resistance, Neoplasm/*genetics ; Gene Expression Profiling ; Genomic Instability/drug effects ; HeLa Cells ; Humans ; Liposarcoma/drug therapy/*genetics/pathology ; Models, Theoretical ; Soft Tissue Neoplasms/drug therapy/*genetics/pathology ; Telomere/*genetics/metabolism ; },
abstract = {Soft tissue sarcomas are a diverse set of fatal human tumors where few agents have demonstrable clinical efficacy, with the standard therapeutic combination of doxorubicin and ifosfamide showing only a 25% to 30% response rate in large multi-institutional trials. Although liposarcomas are the most common histologic form of adult soft tissue sarcomas, research in this area is severely hampered by the lack of experimentally tractable in vitro model systems. To this end, here we describe a novel in vitro model for human pleomorphic liposarcoma. The cell line (LS2) is derived from a pleomorphic liposarcoma that uses the alternative lengthening of telomeres (ALT) mechanism of telomere maintenance, which may be important in modulating the response of this tumor type to DNA-damaging agents. We present detailed baseline molecular and genomic data, including genome-wide copy number and transcriptome profiles, for this model compared with its parental tumor and a panel of liposarcomas covering multiple histologies. The model has retained essentially all of the detectable alterations in copy number that are seen in the parental tumor, and shows molecular karyotypic and expression profiles consistent with pleomorphic liposarcomas. We also show the utility of this model, together with two additional human liposarcoma cell lines, to investigate the relationship between topoisomerase 2A expression and the sensitivity of ALT-positive liposarcomas to doxorubicin. This model, together with its associated baseline data, provides a powerful new tool to develop treatments for this clinically poorly tractable tumor and to investigate the contribution that ALT makes to modulating sensitivity to doxorubicin.},
}
@article {pmid20195488,
year = {2009},
author = {Guachalla, LM and Ju, Z and Koziel, R and von Figura, G and Song, Z and Fusser, M and Epe, B and Jansen-Durr, P and Rudolph, KL},
title = {Sod2 haploinsufficiency does not accelerate aging of telomere dysfunctional mice.},
journal = {Aging},
volume = {1},
number = {3},
pages = {303-315},
pmid = {20195488},
issn = {1945-4589},
mesh = {Aging/*genetics/*metabolism/pathology ; Animals ; Antioxidants/metabolism ; Cellular Senescence ; DNA Damage ; Hematopoietic Stem Cells/physiology ; *Heterozygote ; Longevity ; Mice ; Mice, Knockout ; Mitochondria/physiology ; Oxidative Stress ; *Superoxide Dismutase/deficiency/genetics ; Telomerase/deficiency/genetics ; Telomere/metabolism/*pathology ; },
abstract = {Telomere shortening represents a causal factor of cellular senescence. At the same time, several lines of evidence indicate a pivotal role of oxidative DNA damage for the aging process in vivo. A causal connection between the two observations was suggested by experiments showing accelerated telomere shorting under conditions of oxidative stress in cultured cells, but has never been studied in vivo. We therefore have analysed whether an increase in mitochondrial derived oxidative stress in response to heterozygous deletion of superoxide dismutase (Sod2(+/-)) would exacerbate aging phenotypes in telomere dysfunctional (mTerc(-/-)) mice. Heterozygous deletion of Sod2 resulted in reduced SOD2 protein levels and increased oxidative stress in aging telomere dysfunctional mice, but this did not lead to an increase in basal levels of oxidative nuclear DNA damage, an accumulation of nuclear DNA breaks, or an increased rate of telomere shortening in the mice. Moreover, heterozygous deletion of Sod2 did not accelerate the depletion of stem cells and the impairment in organ maintenance in aging mTerc(-/-) mice. In agreement with these observations, Sod2 haploinsufficiency did not lead to a further reduction in lifespan of mTerc(-/-) mice. Together, these results indicate that a decrease in SOD2-dependent antioxidant defence does not exacerbate aging in the context of telomere dysfunction.},
}
@article {pmid20195387,
year = {2009},
author = {Möller, P and Mayer, S and Mattfeldt, T and Müller, K and Wiegand, P and Brüderlein, S},
title = {Sex-related differences in length and erosion dynamics of human telomeres favor females.},
journal = {Aging},
volume = {1},
number = {8},
pages = {733-739},
pmid = {20195387},
issn = {1945-4589},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics/metabolism ; Child ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Infant, Newborn ; Lymphocytes/metabolism ; Male ; Middle Aged ; Sex Factors ; Telomere/*genetics/metabolism ; Young Adult ; },
abstract = {Telomeres are repetitive DNA sequences at chromosomal ends contributing to genomic integrity. In somatic cells, telomeres are shortened during DNA reduplication. Thus, telomere erosion has been regarded as a biological clock. Applying the telomere/centromere (T/C)-FISH technique to human peripheral blood lymphocytes, we showed that pangenomically, telomere shortening is linear in centenarians and that this attrition is delayed in females. Statistics reveal a greater skewness in telomere length distribution in females. As the morphological correlate, we find abnormally long telomeres distributed at random. This "erratic extensive elongation" (EEE) of telomeres is a hitherto unrecognized phenomenon in non-neoplastic cells, and females are more successful in this respect. As evidenced by endoreduplication, EEE is transmitted to the cells' progeny. The mechanism involved is likely to be the alternative pathway of telomere elongation (ALT), counteracting erosion and already known to operate in neoplastic cells.},
}
@article {pmid20195279,
year = {2010},
author = {Wolinsky, H},
title = {Women and telomeres. Last year's Nobel Prizes for Carol Greider and Elizabeth Blackburn should be encouraging for all female scientists with children.},
journal = {EMBO reports},
volume = {11},
number = {3},
pages = {169-172},
pmid = {20195279},
issn = {1469-3178},
mesh = {Biology/*history ; Career Choice ; Faculty, Medical ; Female ; History, 20th Century ; History, 21st Century ; Humans ; Molecular Biology/history ; Mothers ; *Nobel Prize ; Telomerase/*genetics ; Telomere/*genetics/*ultrastructure ; Women ; },
abstract = {Last year, two eminent female scientists and mothers shared the Nobel Prize for Physiology. Howard Wolinsky explores how their field of telomerase research was shaped and what hope this award to two working mothers offers for other female scientists.},
}
@article {pmid20194442,
year = {2010},
author = {Zhang, W and Durocher, D},
title = {De novo telomere formation is suppressed by the Mec1-dependent inhibition of Cdc13 accumulation at DNA breaks.},
journal = {Genes &amp; development},
volume = {24},
number = {5},
pages = {502-515},
pmid = {20194442},
issn = {1549-5477},
mesh = {*DNA Breaks, Double-Stranded ; DNA Repair/genetics ; DNA, Fungal/*genetics/*metabolism ; Intracellular Signaling Peptides and Proteins/genetics/*metabolism ; Peptidylprolyl Isomerase/metabolism ; Phosphoprotein Phosphatases/metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases/genetics/*metabolism ; *Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/*genetics ; Telomere-Binding Proteins/*metabolism ; },
abstract = {DNA double-strand breaks (DSBs) are a threat to cell survival and genome integrity. In addition to canonical DNA repair systems, DSBs can be converted to telomeres by telomerase. This process, herein termed telomere healing, endangers genome stability, since it usually results in chromosome arm loss. Therefore, cells possess mechanisms that prevent the untimely action of telomerase on DSBs. Here we report that Mec1, the ATR ortholog, couples the detection of DNA ends with the inhibition of telomerase. Mec1 inhibits telomere healing by phosphorylating Cdc13 on its S306 residue, a phosphorylation event that suppresses Cdc13 accumulation at DSBs. Conversely, telomere addition at accidental breaks is promoted by Pph3, the yeast protein phosphatase 4 (PP4). Pph3 is itself modulated by Rrd1, an activator of PP2A family phosphatases. Rrd1 and Pph3 oppose Cdc13 S306 phosphorylation and are necessary for the efficient accumulation of Cdc13 at DNA breaks. These studies therefore identify a mechanism by which the ATR family of kinases enforces genome integrity, and a process that underscores the contribution of Cdc13 to the fate of DNA ends.},
}
@article {pmid20178511,
year = {2010},
author = {Al-Attas, OS and Al-Daghri, N and Bamakhramah, A and Shaun Sabico, S and McTernan, P and Huang, TT},
title = {Telomere length in relation to insulin resistance, inflammation and obesity among Arab youth.},
journal = {Acta paediatrica (Oslo, Norway : 1992)},
volume = {99},
number = {6},
pages = {896-899},
doi = {10.1111/j.1651-2227.2010.01720.x},
pmid = {20178511},
issn = {1651-2227},
mesh = {Blood Pressure ; Child ; Child, Preschool ; Cross-Sectional Studies ; Female ; Humans ; Inflammation/*genetics ; Insulin Resistance/*genetics ; Male ; Obesity/*genetics ; Polymerase Chain Reaction ; Saudi Arabia ; Sex Factors ; Surveys and Questionnaires ; Telomere/*ultrastructure ; Waist Circumference ; },
abstract = {AIM: The aim of this study was to determine the associations of telomere length to markers of obesity, insulin resistance and inflammation in Saudi children.<br><br>METHODS: A total of 69 boys and 79 girls, aged 5-12 years, participated in this cross-sectional study. Anthropometrics were measured. Serum glucose and lipid profile were measured using routine laboratory methods. Serum insulin, leptin, adiponectin, resistin, tumour necrosis factor-alpha and active plasminogen activator inhibitor 1 were quantified using customized multiplex assay kits. C-reactive protein and angiotensin II were quantified using ELISA. Leucocyte telomere length was examined by quantitative real time PCR utilizing IQ cycler.<br><br>RESULTS: Mean telomere length was significantly shorter in obese boys compared with their lean counterparts (p = 0.049), not in girls. It was not associated to insulin resistance, adipocytokines and markers of inflammation. In girls, the significant predictor of telomere length was waist circumference, explaining 24% of variance (p = 0.041) while in boys, systolic blood pressure explained 84% of the variance (p = 0.01).<br><br>CONCLUSION: Childhood obesity in boys corresponds to shorter leucocyte telomere length which is not evident in girls. The association of leucocyte telomere length to blood pressure and waist circumference in children suggests clinical implications as to the contribution of these parameters in premature ageing.},
}
@article {pmid20176738,
year = {2010},
author = {van de Berg, PJ and Griffiths, SJ and Yong, SL and Macaulay, R and Bemelman, FJ and Jackson, S and Henson, SM and ten Berge, IJ and Akbar, AN and van Lier, RA},
title = {Cytomegalovirus infection reduces telomere length of the circulating T cell pool.},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {184},
number = {7},
pages = {3417-3423},
doi = {10.4049/jimmunol.0903442},
pmid = {20176738},
issn = {1550-6606},
support = {//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Antiviral Agents/therapeutic use ; Cell Differentiation/immunology ; Cell Separation ; Cytomegalovirus Infections/genetics/*immunology/pathology ; DNA, Viral/blood ; Flow Cytometry ; Fluorescent Antibody Technique ; Ganciclovir/therapeutic use ; Humans ; In Situ Hybridization, Fluorescence ; Kidney Transplantation/adverse effects/immunology ; Middle Aged ; Polymerase Chain Reaction ; T-Lymphocyte Subsets/immunology/*pathology ; T-Lymphocytes/immunology/*pathology ; Telomere/*pathology/virology ; Viremia/drug therapy ; Young Adult ; },
abstract = {Short telomeres of circulating leukocytes are a risk factor for age-related diseases, such as atherosclerosis, but the exact mechanisms generating variations in telomere length are unknown. We hypothesized that induction of differentiated T cells during chronic CMV infection would affect T cell telomere length. To test this, we measured the amount of differentiated T cells and telomere length of lymphocytes during primary CMV infection as well as CMV-seropositive and -seronegative healthy individuals. After primary CMV infection, we observed an increase in highly differentiated cells that coincided with a steep drop in telomere length. Moreover, we found in a cohort of 159 healthy individuals that telomere shortening was more rapid in CMV-seropositive individuals and correlated with the amount of differentiated T cells in both CD4(+) T cells and CD8(+) T cells. Finally, we found that telomere length measured in blood leukocytes is correlated with lymphocyte telomere length. Thus, CMV infection induces a strong decrease in T cell telomere length, which can be explained by changes in the composition of the circulating lymphocyte pool.},
}
@article {pmid20176474,
year = {2010},
author = {Marión, RM and Blasco, MA},
title = {Telomere rejuvenation during nuclear reprogramming.},
journal = {Current opinion in genetics &amp; development},
volume = {20},
number = {2},
pages = {190-196},
doi = {10.1016/j.gde.2010.01.005},
pmid = {20176474},
issn = {1879-0380},
mesh = {Animals ; Cell Differentiation ; *Cellular Reprogramming ; Epigenesis, Genetic ; Humans ; Induced Pluripotent Stem Cells/cytology/*metabolism ; Models, Genetic ; Telomerase/*metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Reprogramming of adult differentiated cells to a more pluripotent state has been achieved by various means, including somatic cell nuclear transfer (SCNT) and, more recently, by over expression of specific transcription factors to generate the so-called induced pluripotent stem (iPS) cells. Since telomeres play an important role in the maintenance of chromosomal stability associated with continuous cell division, a key question for the quality of the resulting reprogrammed cells was to address whether nuclear reprogramming involves a full rejuvenation of telomeres. Recent work from our group and others demonstrate that telomeres are indeed rejuvenated during nuclear reprogramming. These findings also revealed that the structure of telomeric chromatin is dynamic and controlled by epigenetic programmes, which are reversed by reprogramming.},
}
@article {pmid20172749,
year = {2010},
author = {Atturu, G and Brouilette, S and Samani, NJ and London, NJ and Sayers, RD and Bown, MJ},
title = {Short leukocyte telomere length is associated with abdominal aortic aneurysm (AAA).},
journal = {European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery},
volume = {39},
number = {5},
pages = {559-564},
doi = {10.1016/j.ejvs.2010.01.013},
pmid = {20172749},
issn = {1532-2165},
mesh = {Aged ; Aortic Aneurysm, Abdominal/blood/*genetics ; Case-Control Studies ; Cellular Senescence/genetics ; Chi-Square Distribution ; England ; Female ; Genetic Predisposition to Disease ; Humans ; Leukocytes/*metabolism ; Logistic Models ; Male ; Middle Aged ; Odds Ratio ; Risk Assessment ; Risk Factors ; Telomere/*metabolism ; },
abstract = {OBJECTIVE: Telomeres are specialised DNA structures present at the ends of linear chromosomes, which shorten with each successive cell division and the length of which represents cellular biological age. The aim of this study was to determine the relationship between abdominal aortic aneurysm (AAA) and white cell telomere length.<br><br>METHODS: Peripheral blood samples were collected from 190 patients with AAA and 183 controls. Genomic DNA was extracted from white cells and telomere lengths determined using a chemiluminescence technique.<br><br>RESULTS: The mean white cell telomere length was significantly lower in AAA patients compared to controls (median age 66 years in both groups), with a mean difference of 189 base pairs (bp) (95% confidence interval 77 bp to 301 bp, P=0.005). This relationship between case-control status and mean telomere restriction fragment (TRF) length did not change after adding other risk factors into a multiple regression model. The risk of having AAA doubled in patients with a mean TRF length in the lowest quartile compared to patients with a mean TRF length in the highest quartile (odds ratio 2.30, 95% Confidence Interval 1.28-4.13, P=0.005).<br><br>CONCLUSION: Our data show that patients with AAA have shorter leukocyte telomere length compared to controls. This suggests that vascular biological aging may have a role in the pathogenesis of AAA.},
}
@article {pmid20167271,
year = {2010},
author = {Kiecolt-Glaser, JK and Glaser, R},
title = {Psychological stress, telomeres, and telomerase.},
journal = {Brain, behavior, and immunity},
volume = {24},
number = {4},
pages = {529-530},
pmid = {20167271},
issn = {1090-2139},
support = {CA16058/CA/NCI NIH HHS/United States ; R01 CA131029/CA/NCI NIH HHS/United States ; CA126857/CA/NCI NIH HHS/United States ; R01 AG029562-02/AG/NIA NIH HHS/United States ; UL1RR025755/RR/NCRR NIH HHS/United States ; R21 AT003912/AT/NCCIH NIH HHS/United States ; CA131029/CA/NCI NIH HHS/United States ; R21 AG025732/AG/NIA NIH HHS/United States ; R01 CA126857/CA/NCI NIH HHS/United States ; R21 AG025732-02/AG/NIA NIH HHS/United States ; UL1 RR025755/RR/NCRR NIH HHS/United States ; AT003912/AT/NCCIH NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; R21 AT003912-02/AT/NCCIH NIH HHS/United States ; UL1 RR025755-02/RR/NCRR NIH HHS/United States ; P30 CA016058-32/CA/NCI NIH HHS/United States ; AG029562/AG/NIA NIH HHS/United States ; R01 AG029562/AG/NIA NIH HHS/United States ; R01 CA131029-02/CA/NCI NIH HHS/United States ; R01 CA126857-02/CA/NCI NIH HHS/United States ; },
mesh = {Aging/*metabolism ; Humans ; Psychoneuroimmunology ; Stress, Psychological/genetics/*metabolism ; Telomerase/*metabolism ; Telomere/genetics/*metabolism ; },
}
@article {pmid20164838,
year = {2010},
author = {Agarwal, S and Loh, YH and McLoughlin, EM and Huang, J and Park, IH and Miller, JD and Huo, H and Okuka, M and Dos Reis, RM and Loewer, S and Ng, HH and Keefe, DL and Goldman, FD and Klingelhutz, AJ and Liu, L and Daley, GQ},
title = {Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients.},
journal = {Nature},
volume = {464},
number = {7286},
pages = {292-296},
pmid = {20164838},
issn = {1476-4687},
support = {K08 HL089150/HL/NHLBI NIH HHS/United States ; R01 AG027388-01A2/AG/NIA NIH HHS/United States ; R01AG0227388/AG/NIA NIH HHS/United States ; K08HL089150/HL/NHLBI NIH HHS/United States ; K08 HL089150-01A1/HL/NHLBI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; U01 HL100001/HL/NHLBI NIH HHS/United States ; DP1 OD000256/OD/NIH HHS/United States ; R01 AG027388/AG/NIA NIH HHS/United States ; DP1 OD000256-01/OD/NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle Proteins/genetics ; Cell Line ; Cellular Reprogramming/genetics ; Dyskeratosis Congenita/enzymology/*genetics ; Gene Expression Regulation, Enzymologic ; Humans ; Mice ; Nuclear Proteins/genetics ; *Pluripotent Stem Cells/enzymology ; RNA/genetics/metabolism ; Sequence Deletion/genetics ; Telomerase/genetics/metabolism ; Telomere/*genetics ; Up-Regulation ; },
abstract = {Patients with dyskeratosis congenita (DC), a disorder of telomere maintenance, suffer degeneration of multiple tissues. Patient-specific induced pluripotent stem (iPS) cells represent invaluable in vitro models for human degenerative disorders like DC. A cardinal feature of iPS cells is acquisition of indefinite self-renewal capacity, which is accompanied by induction of the telomerase reverse transcriptase gene (TERT). We investigated whether defects in telomerase function would limit derivation and maintenance of iPS cells from patients with DC. Here we show that reprogrammed DC cells overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal. We discovered that TERC upregulation is a feature of the pluripotent state, that several telomerase components are targeted by pluripotency-associated transcription factors, and that in autosomal dominant DC, transcriptional silencing accompanies a 3' deletion at the TERC locus. Our results demonstrate that reprogramming restores telomere elongation in DC cells despite genetic lesions affecting telomerase, and show that strategies to increase TERC expression may be therapeutically beneficial in DC patients.},
}
@article {pmid20162857,
year = {2010},
author = {Hiraoka, Y and Haraguchi, T},
title = {[Mechanism of chromosome protection by telomere and telomerase].},
journal = {Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme},
volume = {55},
number = {1},
pages = {104-107},
pmid = {20162857},
issn = {0039-9450},
mesh = {Animals ; Base Sequence ; Cell Division ; *Chromosomes ; DNA Replication/genetics ; Humans ; *Nobel Prize ; RNA ; Tandem Repeat Sequences ; Telomerase/genetics/*physiology ; Telomere/genetics/metabolism/*physiology ; },
}
@article {pmid20161752,
year = {2010},
author = {Uziel, O and Beery, E and Dronichev, V and Samocha, K and Gryaznov, S and Weiss, L and Slavin, S and Kushnir, M and Nordenberg, Y and Rabinowitz, C and Rinkevich, B and Zehavi, T and Lahav, M},
title = {Telomere shortening sensitizes cancer cells to selected cytotoxic agents: in vitro and in vivo studies and putative mechanisms.},
journal = {PloS one},
volume = {5},
number = {2},
pages = {e9132},
pmid = {20161752},
issn = {1932-6203},
mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Survival/drug effects ; Cisplatin/pharmacology ; Comet Assay ; DNA Damage ; DNA Repair ; Dose-Response Relationship, Drug ; Female ; Humans ; K562 Cells ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasms/*drug therapy/*genetics/pathology ; Oligonucleotides/pharmacology ; Telomerase/antagonists &amp; inhibitors/genetics/metabolism ; Telomere/*genetics/metabolism ; Xenograft Model Antitumor Assays ; },
abstract = {BACKGROUND: Telomere/telomerase system has been recently recognized as an attractive target for anticancer therapy. Telomerase inhibition results in tumor regression and increased sensitivity to various cytotoxic drugs. However, it has not been fully established yet whether the mediator of these effects is telomerase inhibition per se or telomere shortening resulting from inhibition of telomerase activity. In addition, the characteristics and mechanisms of sensitization to cytotoxic drugs caused by telomerase inhibition has not been elucidated in a systematic manner.<br><br>In this study we characterized the relative importance of telomerase inhibition versus telomere shortening in cancer cells. Sensitization of cancer cells to cytotoxic drugs was achieved by telomere shortening in a length dependent manner and not by telomerase inhibition per se. In our system this sensitization was related to the mechanism of action of the cytotoxic drug. In addition, telomere shortening affected also other cancer cell functions such as migration. Telomere shortening induced DNA damage whose repair was impaired after administration of cisplatinum while doxorubicin or vincristine did not affect the DNA repair. These findings were verified also in in vivo mouse model. The putative explanation underlying the phenotype induced by telomere shortening may be related to changes in expression of various microRNAs triggered by telomere shortening.<br><br>CONCLUSIONS/SIGNIFICANCE: To our best knowledge this is the first study characterizing the relative impact of telomerase inhibition and telomere shortening on several aspects of cancer cell phenotype, especially related to sensitivity to cytotoxic drugs and its putative mechanisms. The microRNA changes in cancer cells upon telomere shortening are novel information. These findings may facilitate the development of telomere based approaches in treatment of cancer.},
}
@article {pmid20157543,
year = {2009},
author = {Lou, Z and Wei, J and Riethman, H and Baur, JA and Voglauer, R and Shay, JW and Wright, WE},
title = {Telomere length regulates ISG15 expression in human cells.},
journal = {Aging},
volume = {1},
number = {7},
pages = {608-621},
pmid = {20157543},
issn = {1945-4589},
support = {R01 AG007992/AG/NIA NIH HHS/United States ; R01 HG000567/HG/NHGRI NIH HHS/United States ; AG07992/AG/NIA NIH HHS/United States ; HG 000567/HG/NHGRI NIH HHS/United States ; },
mesh = {Aged ; Aging/metabolism ; Agrin/genetics ; Antibodies/immunology/pharmacology ; Cell Line ; Cellular Senescence/physiology ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Cytokines/genetics/*metabolism ; DNA Damage/physiology ; Epithelial Cells/metabolism ; Fibroblasts/metabolism ; Gene Expression/genetics ; Gene Expression Regulation/*physiology ; Histones/metabolism ; Humans ; Infant ; Interferon-beta/genetics/immunology ; Middle Aged ; Oligonucleotide Array Sequence Analysis ; RNA Interference ; Signal Transduction/physiology ; Telomerase/genetics/metabolism ; Telomere/*physiology ; Transfection ; Tumor Suppressor Protein p53/genetics ; Ubiquitins/genetics/*metabolism ; Up-Regulation/genetics ; Young Adult ; beta-Galactosidase/metabolism ; },
abstract = {Endogenous genes regulated by telomere length have not previously been identified in human cells. Here we show that telomere length regulates the expression of interferon stimulated gene 15 (ISG15, 1p36.33). ISG15 expression (RNA and protein) increases in human cells with short telomeres, and decreases following the elongation of telomeres by human telomerase reverse transcriptase (hTERT). The short-telomere-dependent up-regulation of ISG15 is not mediated by replicative senescence/DNA damage signaling or type I interferons. In human skin specimens obtained from various aged individuals, ISG15 is up-regulated in a subset of cells in older individuals. Our results demonstrate that endogenous human genes can be regulated by the length of telomeres prior to the onset of DNA damage signals, and suggest the possibility that cell turnover/telomere shortening may provide a mechanism for adjusting cellular physiology. The upregulation of ISG15 with telomere shortening may contribute to chronic inflammatory states associated with human aging.},
}
@article {pmid20157510,
year = {2009},
author = {Nakamura, AJ and Redon, CE and Bonner, WM and Sedelnikova, OA},
title = {Telomere-dependent and telomere-independent origins of endogenous DNA damage in tumor cells.},
journal = {Aging},
volume = {1},
number = {2},
pages = {212-218},
pmid = {20157510},
issn = {1945-4589},
support = {//Intramural NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; *DNA Damage ; Gene Expression Regulation, Neoplastic/drug effects/radiation effects ; Histones/genetics/metabolism ; Humans ; Telomere/*physiology ; },
abstract = {Human tumors and cultured cells contain elevated levels of endogenous DNA damage resulting from telomere dysfunction, replication and transcription errors, reactive oxygen species, and genome instability. However, the contribution of telomere-associated versus telomere-independent endogenous DNA lesions to this damage has never been examined. In this study, we characterized the relative amounts of these two types of DNA damage in five tumor cell lines by noting whether gamma-H2AX foci, generally considered to mark DNA double-strand breaks (DSBs), were on chromosome arms or at chromosome ends. We found that while the numbers of non-telomeric DSBs were remarkably similar in these cultures, considerable variation was detected in the level of telomeric damage. The distinct heterogeneity in the numbers of gamma-H2AX foci in these tumor cell lines was found to be due to foci associated with uncapped telomeres, and the amount of total telomeric damage also appeared to inversely correlate with the telomerase activity present in these cells. These results indicate that damaged telomeres are the major factor accounting for the variability in the amount of DNA DSB damage in tumor cells. This characterization of DNA damage in tumor cells helps clarify the contribution of non-telomeric DSBs and damaged telomeres to major genomic alterations.},
}
@article {pmid20157507,
year = {2009},
author = {Olive, PL},
title = {Endogenous DNA breaks: gammaH2AX and the role of telomeres.},
journal = {Aging},
volume = {1},
number = {2},
pages = {154-156},
pmid = {20157507},
issn = {1945-4589},
mesh = {Animals ; Antineoplastic Agents/pharmacology ; *DNA Breaks, Double-Stranded ; Gene Expression Regulation, Neoplastic/drug effects/radiation effects ; Histones/drug effects/*metabolism ; Humans ; Neoplasms/drug therapy/radiotherapy ; Telomere/*physiology ; },
}
@article {pmid20147462,
year = {2010},
author = {Pennarun, G and Hoffschir, F and Revaud, D and Granotier, C and Gauthier, LR and Mailliet, P and Biard, DS and Boussin, FD},
title = {ATR contributes to telomere maintenance in human cells.},
journal = {Nucleic acids research},
volume = {38},
number = {9},
pages = {2955-2963},
pmid = {20147462},
issn = {1362-4962},
mesh = {Adolescent ; Adult ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/antagonists &amp; inhibitors/genetics/*physiology ; Cells, Cultured ; Child ; Child, Preschool ; Chromosome Aberrations ; Female ; Fibroblasts/chemistry ; Gene Knockdown Techniques ; HeLa Cells ; Humans ; Male ; Middle Aged ; Protein Serine-Threonine Kinases/antagonists &amp; inhibitors/genetics/*physiology ; Pyridines/pharmacology ; Quinolines/pharmacology ; Telomere/*chemistry/drug effects ; },
abstract = {Telomere maintenance is essential to preserve genomic stability and involves several telomere-specific proteins as well as DNA replication and repair proteins. The kinase ATR, which has a crucial function in maintaining genome integrity from yeast to human, has been shown to be involved in telomere maintenance in several eukaryotic organisms, including yeast, Arabidopsis and Drosophila. However, its role in telomere maintenance in mammals remains poorly explored. Here, we report by using telomere-fluorescence in situ hybridization (Telo-FISH) on metaphase chromosomes that ATR deficiency causes telomere instability both in primary human fibroblasts from Seckel syndrome patients and in HeLa cells. The telomere aberrations resulting from ATR deficiency (i.e. sister telomere fusions and chromatid-type telomere aberrations) are mainly generated during and/or after telomere replication, and involve both leading and lagging strand telomeres as shown by chromosome orientation-FISH (CO-FISH). Moreover, we show that ATR deficiency strongly sensitizes cells to the G-quadruplex ligand 360A, enhancing sister telomere fusions and chromatid-type telomere aberrations involving specifically the lagging strand telomeres. Altogether, these data reveal that ATR plays a critical role in telomere maintenance during and/or after telomere replication in human cells.},
}
@article {pmid20142802,
year = {2010},
author = {Knecht, H and Sawan, B and Lichtensztejn, Z and Lichtensztejn, D and Mai, S},
title = {3D Telomere FISH defines LMP1-expressing Reed-Sternberg cells as end-stage cells with telomere-poor 'ghost' nuclei and very short telomeres.},
journal = {Laboratory investigation; a journal of technical methods and pathology},
volume = {90},
number = {4},
pages = {611-619},
doi = {10.1038/labinvest.2010.2},
pmid = {20142802},
issn = {1530-0307},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Adult ; Female ; Hodgkin Disease/*genetics/metabolism/*pathology ; Humans ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Male ; Reed-Sternberg Cells/metabolism/*pathology ; Telomere/*pathology ; Viral Matrix Proteins/analysis ; },
abstract = {In Epstein-Barr virus (EBV) negative Hodgkin's cell lines and classical EBV-negative Hodgkin's lymphoma (HL), Reed-Sternberg cells (RS cells) represent end-stage tumor cells, in which further nuclear division becomes impossible because of sustained telomere loss, shortening and aggregation. However, the three-dimensional (3D) telomere organization in latent membrane protein 1 (LMP1)-expressing RS cells of EBV-associated HL is not known. We performed a 3D telomere analysis after quantitative fluorescent in situ hybridization on 5 mum tissue sections on two LMP1-expressing HL cases and showed highly significant telomere shortening (P<0.0001) and formation of telomere aggregates in RS cells (P<0.0001), when compared with the mononuclear precursor Hodgkin cells (H cells). Telomere-poor or telomere-free 'ghost' nuclei were a regular finding in these RS cells. These nuclei and their telomere content strongly contrasted with the corona of surrounding lymphocytes showing numerous midsized telomere hybridization signals. Both H cells and RS cells of two EBV-negative HL cases analyzed in parallel showed 3D telomere patterns identical to those of LMP1-expressing cases. As a major advance, our 3D nuclear imaging approach allows the visualization of hitherto unknown profound changes in the 3D nuclear telomere organization associated with the transition from LMP1-positive H cells to LMP1-positive RS cells. We conclude that RS cells irrespective of LMP1 expression are end-stage tumor cells in which the extent of their inability to divide further is proportional to the increase of very short telomeres, telomere loss, aggregate formation and the generation of 'ghost' nuclei.},
}
@article {pmid20142254,
year = {2010},
author = {Gramatges, MM and Telli, ML and Balise, R and Ford, JM},
title = {Longer relative telomere length in blood from women with sporadic and familial breast cancer compared with healthy controls.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {19},
number = {2},
pages = {605-613},
doi = {10.1158/1055-9965.EPI-09-0896},
pmid = {20142254},
issn = {1538-7755},
mesh = {Adult ; Breast Neoplasms/*blood/*genetics ; Female ; *Genetic Predisposition to Disease ; Humans ; Middle Aged ; *Telomere ; },
abstract = {Telomeres cap the ends of chromosomes and are composed of a series of noncoding hexamer repeats. Telomeres protect the integrity of DNA coding sequences and are integral to the maintenance of genomic stability. Previous studies have shown an association between shortened lymphocyte telomeres and increased risk for specific cancers. However, the association between telomere length and breast cancer risk is less clear. We examined the relative telomere length (RTL) in blood from women with no personal or family history of cancer (controls) compared with different populations of women with breast cancer and women at high genetic risk for developing breast cancer. RTL was determined as the telomere to single gene copy number ratio assessed by quantitative PCR. Breast cancer cases (low risk, n = 40; high risk, n = 62) had significantly longer RTL compared with unaffected controls (n = 50; mean RTL = 1.11 versus 0.84; P < 0.0001). The assessment of risk by RTL quartile showed an increased risk for breast cancer with each longer quartile, with the most significant risk observed in the longest quartile (odds ratio, 23.3; confidence interval, 4.4-122.3; P < 0.0003). Women without breast cancer but at high risk due to family history (n = 30) also showed longer telomeres than controls (mean RTL = 1.09 versus 0.84; P < 0.0001). Our analysis supports previous findings of longer RTL in breast cancer cases compared with controls, and is the first to observe longer RTL in women without breast cancer identified as high risk based on family history.},
}
@article {pmid20140190,
year = {2010},
author = {Subramanian, L and Nakamura, TM},
title = {A kinase-independent role for the Rad3(ATR)-Rad26(ATRIP) complex in recruitment of Tel1(ATM) to telomeres in fission yeast.},
journal = {PLoS genetics},
volume = {6},
number = {2},
pages = {e1000839},
pmid = {20140190},
issn = {1553-7404},
support = {R01 GM078253/GM/NIGMS NIH HHS/United States ; R01 GM078253-04/GM/NIGMS NIH HHS/United States ; GM078253/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/chemistry/*metabolism ; Checkpoint Kinase 2 ; Chromosomal Proteins, Non-Histone/chemistry/metabolism ; Models, Biological ; Mutation/genetics ; Protein Binding ; Protein Kinases/chemistry/*metabolism ; Protein Serine-Threonine Kinases/*metabolism ; Protein Structure, Tertiary ; Protein Subunits/metabolism ; Schizosaccharomyces/*enzymology ; Schizosaccharomyces pombe Proteins/chemistry/*metabolism ; Telomere/*metabolism ; },
abstract = {ATM and ATR are two redundant checkpoint kinases essential for the stable maintenance of telomeres in eukaryotes. Previous studies have established that MRN (Mre11-Rad50-Nbs1) and ATRIP (ATR Interacting Protein) interact with ATM and ATR, respectively, and recruit their partner kinases to sites of DNA damage. Here, we investigated how Tel1(ATM) and Rad3(ATR) recruitment to telomeres is regulated in fission yeast. Quantitative chromatin immunoprecipitation (ChIP) assays unexpectedly revealed that the MRN complex could also contribute to the recruitment of Tel1(ATM) to telomeres independently of the previously established Nbs1 C-terminal Tel1(ATM) interaction domain. Recruitment of Tel1(ATM) to telomeres in nbs1-c60Delta cells, which lack the C-terminal 60 amino acid Tel1(ATM) interaction domain of Nbs1, was dependent on Rad3(ATR)-Rad26(ATRIP), but the kinase domain of Rad3(ATR) was dispensable. Thus, our results establish that the Rad3(ATR)-Rad26(ATRIP) complex contributes to the recruitment of Tel1(ATM) independently of Rad3(ATR) kinase activity, by a mechanism redundant with the Tel1(ATM) interaction domain of Nbs1. Furthermore, we found that the N-terminus of Nbs1 contributes to the recruitment of Rad3(ATR)-Rad26(ATRIP) to telomeres. In response to replication stress, mammalian ATR-ATRIP also contributes to ATM activation by a mechanism that is dependent on the MRN complex but independent of the C-terminal ATM interaction domain of Nbs1. Since telomere protection and DNA damage response mechanisms are very well conserved between fission yeast and mammalian cells, mammalian ATR-ATRIP may also contribute to the recruitment of ATM to telomeres and to sites of DNA damage independently of ATR kinase activity.},
}
@article {pmid20139977,
year = {2010},
author = {Codd, V and Mangino, M and van der Harst, P and Braund, PS and Kaiser, M and Beveridge, AJ and Rafelt, S and Moore, J and Nelson, C and Soranzo, N and Zhai, G and Valdes, AM and Blackburn, H and Mateo Leach, I and de Boer, RA and Kimura, M and Aviv, A and , and Goodall, AH and Ouwehand, W and van Veldhuisen, DJ and van Gilst, WH and Navis, G and Burton, PR and Tobin, MD and Hall, AS and Thompson, JR and Spector, T and Samani, NJ},
title = {Common variants near TERC are associated with mean telomere length.},
journal = {Nature genetics},
volume = {42},
number = {3},
pages = {197-199},
pmid = {20139977},
issn = {1546-1718},
support = {091746/WT_/Wellcome Trust/United Kingdom ; G0501942/MRC_/Medical Research Council/United Kingdom ; G20234/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Age Factors ; Aging/genetics ; Chromosomes, Human, Pair 3 ; Cohort Studies ; Gene Frequency ; Genome-Wide Association Study ; Humans ; Meta-Analysis as Topic ; *Polymorphism, Single Nucleotide/physiology ; Quantitative Trait Loci ; RNA/*genetics/physiology ; Telomerase/*genetics/physiology ; Telomere/*genetics/metabolism ; Time Factors ; },
abstract = {We conducted genome-wide association analyses of mean leukocyte telomere length in 2,917 individuals, with follow-up replication in 9,492 individuals. We identified an association with telomere length on 3q26 (rs12696304, combined P = 3.72 x 10(-14)) at a locus that includes TERC, which encodes the telomerase RNA component. Each copy of the minor allele of rs12696304 was associated with an approximately 75-base-pair reduction in mean telomere length, equivalent to approximately 3.6 years of age-related telomere-length attrition.},
}
@article {pmid20139621,
year = {2010},
author = {Kobayashi, Y and Sato, K and Kibe, T and Seimiya, H and Nakamura, A and Yukawa, M and Tsuchiya, E and Ueno, M},
title = {Expression of mutant RPA in human cancer cells causes telomere shortening.},
journal = {Bioscience, biotechnology, and biochemistry},
volume = {74},
number = {2},
pages = {382-385},
doi = {10.1271/bbb.90496},
pmid = {20139621},
issn = {1347-6947},
mesh = {Humans ; *Mutation ; Neoplasms/genetics/*pathology ; Replication Protein A/*genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Replication protein A (RPA) binds to single-stranded DNA generated during DNA replication and other processes. The roles of RPA in telomere maintenance have been demonstrated in yeasts, but not in telomerase-positive human cells. In this study, we found that expression of mutant RPA70 in human cells caused telomere shortening, suggesting that RPA is required for telomere-length regulation in human cancer cells.},
}
@article {pmid20137830,
year = {2011},
author = {Aguennouz, M and Vita, GL and Messina, S and Cama, A and Lanzano, N and Ciranni, A and Rodolico, C and Di Giorgio, RM and Vita, G},
title = {Telomere shortening is associated to TRF1 and PARP1 overexpression in Duchenne muscular dystrophy.},
journal = {Neurobiology of aging},
volume = {32},
number = {12},
pages = {2190-2197},
doi = {10.1016/j.neurobiolaging.2010.01.008},
pmid = {20137830},
issn = {1558-1497},
mesh = {Child ; Child, Preschool ; *Gene Expression Regulation ; Humans ; Infant ; Muscular Dystrophy, Duchenne/genetics/*metabolism/pathology ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases/*biosynthesis/genetics ; Quadriceps Muscle/pathology ; Telomere Shortening/*genetics ; Telomeric Repeat Binding Protein 1/*biosynthesis/genetics ; },
abstract = {Telomere shortening is thought to contribute to premature senescence of satellite cells in Duchenne muscular dystrophy (DMD) muscle. Telomeric repeat binding factor-1 (TRF1) and poly (ADP-ribose) polymerase-1 (PARP1) are proteins known to modulate telomerase reverse transcriptase (TERT) activity, which controls telomere elongation. Here we show that an age-dependent telomere shortening occurs in DMD muscles and is associated to overexpression of mRNA and protein levels of TRF1 and PARP1. TERT expression and activity are detectable in normal control muscles and they slightly increase in DMD. This is the first demonstration of TRF1 and PARP1 overexpression in DMD muscles. They can be directly involved in replicative senescence of satellite cells and/or in the pathogenetic cascade through a cross-talk with oxidative stress and inflammatory response. Modulation of these events by TRF1 or PARP1 inhibition might represent a novel strategy for treatment of DMD and other muscular dystrophies.},
}
@article {pmid20137312,
year = {2009},
author = {Liu, B and Han, B and Wang, X and Cui, W and Lin, J and Zhao, YQ},
title = {[Telomere length measurement of 10 Chinese patients with bone marrow failure syndrome.].},
journal = {Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi},
volume = {30},
number = {11},
pages = {758-760},
pmid = {20137312},
issn = {0253-2727},
mesh = {Asian People ; Humans ; Mutation ; Pancytopenia ; *Telomerase/metabolism ; *Telomere/metabolism ; },
abstract = {OBJECTIVE: To measure telomere length of patients with bone marrow failure syndrome (BMFS) and explore the relationship between telomerase gene mutation and telomere shortening.<br><br>METHODS: Blood samples from 10 patients with AA, MDS-RA were collected and performed TERC and TERT gene mutation analysis. Telomere length was measured by Southern blot and compared with normal controls and two patients with MDS-RAEB and AML each.<br><br>RESULTS: Two patients in the 10 BMFS patients had TERC and TERT gene mutations and very short telomeres compared with normal controls and with the 8 BMFS counterparts, the telomere length was less than 50% of that of normal control, and was similar to that of patients with MDS-RAEB and acute myelogenous leukemia, indicating the possibility of malignant transformation. Some BMFS patients with no mutations also had short telomeres.<br><br>CONCLUSIONS: BMFS patients with telomerase gene mutation have very short telomeres, being similar to that of hematological malignancies. Some BMFS patients with no telomerase gene mutations also have short telomere length.},
}
@article {pmid20133733,
year = {2010},
author = {Ehrentraut, S and Weber, JM and Dybowski, JN and Hoffmann, D and Ehrenhofer-Murray, AE},
title = {Rpd3-dependent boundary formation at telomeres by removal of Sir2 substrate.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {107},
number = {12},
pages = {5522-5527},
pmid = {20133733},
issn = {1091-6490},
mesh = {Acetylation ; Euchromatin/genetics/metabolism ; Gene Silencing ; Genes, Fungal ; Heterochromatin/genetics/metabolism ; Histone Acetyltransferases/genetics/metabolism ; Histone Deacetylases/genetics/*metabolism ; Histones/chemistry/metabolism ; Models, Molecular ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/chemistry/genetics/*metabolism ; Sirtuin 2/genetics/*metabolism ; Substrate Specificity ; Telomere/genetics/*metabolism ; },
abstract = {Boundaries between euchromatic and heterochromatic regions until now have been associated with chromatin-opening activities. Here, we identified an unexpected role for histone deacetylation in this process. Significantly, the histone deacetylase (HDAC) Rpd3 was necessary for boundary formation in Saccharomyces cerevisiae. rpd3Delta led to silent information regulator (SIR) spreading and repression of subtelomeric genes. In the absence of a known boundary factor, the histone acetyltransferase complex SAS-I, rpd3Delta caused inappropriate SIR spreading that was lethal to yeast cells. Notably, Rpd3 was capable of creating a boundary when targeted to heterochromatin. Our data suggest a mechanism for boundary formation whereby histone deacetylation by Rpd3 removes the substrate for the HDAC Sir2, so that Sir2 no longer can produce O-acetyl-ADP ribose (OAADPR) by consumption of NAD(+) in the deacetylation reaction. In essence, OAADPR therefore is unavailable for binding to Sir3, preventing SIR propagation.},
}
@article {pmid20127711,
year = {2010},
author = {Mai, S},
title = {Initiation of telomere-mediated chromosomal rearrangements in cancer.},
journal = {Journal of cellular biochemistry},
volume = {109},
number = {6},
pages = {1095-1102},
doi = {10.1002/jcb.22501},
pmid = {20127711},
issn = {1097-4644},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Animals ; Cell Nucleus/genetics ; Genomic Instability/*genetics ; Humans ; Models, Biological ; Neoplasms/*genetics ; Telomere/*genetics ; },
abstract = {Telomeres are the ends of chromosomes and protect them from degradation and fusion. As such, their stability is required for normal cellular function. Telomere dysfunction is found often at the origin of cellular transformation and contributes to the onset of genomic instability, a hallmark of cancer cells. In this article, I discuss current data and concepts on telomere-mediated chromosomal rearrangements in cancer.},
}
@article {pmid20127402,
year = {2010},
author = {Zhang, D and Cheng, L and Craig, DW and Redman, M and Liu, C},
title = {Cerebellar telomere length and psychiatric disorders.},
journal = {Behavior genetics},
volume = {40},
number = {2},
pages = {250-254},
pmid = {20127402},
issn = {1573-3297},
support = {R01 MH080425/MH/NIMH NIH HHS/United States ; R01 MH080425-02/MH/NIMH NIH HHS/United States ; MH080425/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Aged ; Brain/pathology ; Case-Control Studies ; Cerebellum/*pathology ; Female ; Genome-Wide Association Study ; Genotype ; Humans ; Male ; Mental Disorders/*genetics ; Middle Aged ; Oligonucleotide Array Sequence Analysis ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*ultrastructure ; },
abstract = {We tested whether telomere length is altered in the brains of patients diagnosed with major depression (MD), bipolar disorder (BD) and schizophrenia (SZ) by measuring mean telomere length (mTL) with real-time PCR. The samples are cerebellar gray matter from 46 SZ, 46 BP, and 15 MD patients, and 48 healthy controls. We found no difference in mTL between SZ and controls, BD and controls, MD and controls, or all cases and controls; no correlation between mTL and age was observed, either. This suggests that brain gray matter is unlikely to be related to the telomere length shortening reported in blood of psychiatric patients. White matter deserves further investigation as it has been reported to have a different mTL dynamic from gray matter. Since mTL has been reported to be a heritable quantitative trait, we also carried out genome-wide mapping of genetic factors for mTL, treating mTL as a quantitative trait. No association survived correction of multiple testing for the number of SNPs studied. The previously reported rs2630578 (BICD1) association was not replicated. This suggests that telomere length of cerebellar gray matter is determined by multiple loci with "weak effects."},
}
@article {pmid20127252,
year = {2010},
author = {Hu, H and Zhang, Y and Zou, M and Yang, S and Liang, XQ},
title = {Expression of TRF1, TRF2, TIN2, TERT, KU70, and BRCA1 proteins is associated with telomere shortening and may contribute to multistage carcinogenesis of gastric cancer.},
journal = {Journal of cancer research and clinical oncology},
volume = {136},
number = {9},
pages = {1407-1414},
pmid = {20127252},
issn = {1432-1335},
mesh = {Antigens, Nuclear/biosynthesis/*metabolism ; BRCA1 Protein/biosynthesis/*metabolism ; Blotting, Western ; DNA-Binding Proteins/biosynthesis/*metabolism ; Humans ; Immunohistochemistry ; Ku Autoantigen ; Neoplasm Staging ; *Stomach Neoplasms/metabolism/pathology ; Telomerase/biosynthesis/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/biosynthesis/*metabolism ; Telomeric Repeat Binding Protein 1/biosynthesis/*metabolism ; Telomeric Repeat Binding Protein 2/biosynthesis/*metabolism ; },
abstract = {PURPOSE: Telomere dysfunction is believed to be a significant factor in carcinogenesis. To elucidate the carcinogenesis mechanism in gastric cancer, the expression of telomeric proteins and changes in telomere length were investigated during multistage carcinogenesis of gastric cancer.<br><br>METHODS: Tissue samples were obtained during surgical operations from the normal gastric mucosa of 10 patients, the precancerous lesions of 15 patients, the gastric cancer tissues (GC) of 20 patients, and of tumors due to gastric cancer with lymph node metastasis (GCLM) from 5 patients. The expression of TRF1, TRF2, and TIN2 proteins was measured by Western blotting, while the expression of TERT, KU70, and BRCA1 proteins was detected using the immunohistochemical method. The mean telomere length was determined by Southern blotting.<br><br>RESULTS: Compared with normal gastric mucosa tissues, the expression of TRF1, TRF2, and TIN2 proteins was significantly higher in precancerous lesions, GC, and GCLM (P < 0.01). The expression of TRF1, TRF2, and TIN2 proteins was significantly higher in GC and GCLM than in precancerous lesions (P < 0.01). The expression of TERT and Ku70 proteins in precancerous lesions and GC tissues was significantly higher than that in normal gastric mucosa tissues (P < 0.01). The expression of TERT and Ku70 proteins in GC tissues was significantly higher than in precancerous lesions (P < 0.01). In normal gastric mucosa, the BRCA1 protein was primarily located in the cell nucleus. In precancerous lesions and GC, the expression of the BRCA1 protein was apparent in the cell cytoplasm. The mean telomere length in precancerous lesions, GC, and GCLM was significantly shorter than that in normal gastric mucosa tissues (P < 0.05). The mean telomere length in GC and GCLM was significantly shorter than that in precancerous lesions (P < 0.05). The mean telomere length in all tissue samples was inversely correlated with the level of TRF1, TRF2, TIN2, TERT, and Ku70 proteins.<br><br>CONCLUSIONS: Our results suggest that the over-expression of telomeric proteins, TRF1, TRF2, TIN2, TERT, and Ku70, and the transposition of the BRCA1 protein may work together to reduce the telomere length in precancerous lesions and gastric cancer, and could contribute to the multistage carcinogenesis of gastric cancer. These findings offer new insight into the mechanism of carcinogenesis in gastric cancer.},
}
@article {pmid20126476,
year = {2010},
author = {Gadji, M and Fortin, D and Tsanaclis, AM and Garini, Y and Katzir, N and Wienburg, Y and Yan, J and Klewes, L and Klonisch, T and Drouin, R and Mai, S},
title = {Three-dimensional nuclear telomere architecture is associated with differential time to progression and overall survival in glioblastoma patients.},
journal = {Neoplasia (New York, N.Y.)},
volume = {12},
number = {2},
pages = {183-191},
pmid = {20126476},
issn = {1476-5586},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Adult ; Aged ; Brain Neoplasms/mortality/*pathology ; Cell Nucleus/*pathology ; Disease Progression ; Disease-Free Survival ; Female ; Glioblastoma/mortality/*pathology ; Humans ; Image Interpretation, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Prognosis ; Telomere/*pathology ; Young Adult ; },
abstract = {The absence of biological markers allowing for the assessment of the evolution and prognosis of glioblastoma (GBM) is a major impediment to the clinical management of GBM patients. The observed variability in patients' treatment responses and in outcomes implies biological heterogeneity and the existence of unidentified patient categories. Here, we define for the first time three GBM patient categories with distinct and clinically predictive three-dimensional nuclear-telomeric architecture defined by telomere number, size, and frequency of telomeric aggregates. GBM patient samples were examined by three-dimensional fluorescent in situ hybridization of telomeres using two independent three-dimensional telomere-measurement tools (TeloView program [P(1)] and SpotScan system [P(2)]). These measurements identified three patients categories (categories 1-3), displaying significant differences in telomere numbers/nucleus (P(1) = .0275; P(2) <or= .0001), telomere length (P(1) and P(2) = .0275), and number of telomeric aggregates (P(1) = .0464; P(2) <or= .0001). These categories corresponded to patients with long-term, intermediate, and short-term survival, respectively (P = .0393). The time to progression analyses showed significant differences between the three categories (P = .0167). There was a correlation between time to progression, median survival, and nuclear telomere architecture. Our study suggests a link between patient outcome and three-dimensional nuclear-telomere organization and highlights the potential clinical power of telomere signatures as a new prognostic, predictive, and potentially pharmacodynamic biomarker in GBM. Furthermore, novel automated three-dimensional high-throughput scanning as developed here permits to obtain data from 300 nuclei in 20 minutes. This method is applicable to any cell type and scanning application.},
}
@article {pmid20125188,
year = {2010},
author = {O'Sullivan, RJ and Karlseder, J},
title = {Telomeres: protecting chromosomes against genome instability.},
journal = {Nature reviews. Molecular cell biology},
volume = {11},
number = {3},
pages = {171-181},
pmid = {20125188},
issn = {1471-0080},
support = {R01 GM069525-05/GM/NIGMS NIH HHS/United States ; R01 GM06525/GM/NIGMS NIH HHS/United States ; R01 AG025837-03/AG/NIA NIH HHS/United States ; R01 GM069525-03/GM/NIGMS NIH HHS/United States ; R01 AG025837-02/AG/NIA NIH HHS/United States ; R01 GM087476/GM/NIGMS NIH HHS/United States ; R01 GM069525-01/GM/NIGMS NIH HHS/United States ; R01 GM069525-04/GM/NIGMS NIH HHS/United States ; R01 AG025837-01A2/AG/NIA NIH HHS/United States ; R01 GM069525/GM/NIGMS NIH HHS/United States ; R01 AG025837/AG/NIA NIH HHS/United States ; R01 AG025837-04/AG/NIA NIH HHS/United States ; R01 GM069525-02/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; DNA Damage ; DNA Repair ; *Genomic Instability ; Humans ; Models, Biological ; Repetitive Sequences, Nucleic Acid/*genetics ; Telomerase/*metabolism ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {The natural ends of linear chromosomes require unique genetic and structural adaptations to facilitate the protection of genetic material. This is achieved by the sequestration of the telomeric sequence into a protective nucleoprotein cap that masks the ends from constitutive exposure to the DNA damage response machinery. When telomeres are unmasked, genome instability arises. Balancing capping requirements with telomere replication and the enzymatic processing steps that are obligatory for telomere function is a complex problem. Telomeric proteins and their interacting factors create an environment at chromosome ends that inhibits DNA repair; however, the repair machinery is essential for proper telomere function.},
}
@article {pmid20122000,
year = {2009},
author = {Mui, TS and Man, JM and McElhaney, JE and Sandford, AJ and Coxson, HO and Birmingham, CL and Li, Y and Man, SF and Sin, DD},
title = {Telomere length and chronic obstructive pulmonary disease: evidence of accelerated aging.},
journal = {Journal of the American Geriatrics Society},
volume = {57},
number = {12},
pages = {2372-2374},
doi = {10.1111/j.1532-5415.2009.02589.x},
pmid = {20122000},
issn = {1532-5415},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Aged ; Aging/genetics ; Female ; Humans ; Male ; Pulmonary Disease, Chronic Obstructive/*genetics ; Telomere/*ultrastructure ; },
}
@article {pmid20113844,
year = {2010},
author = {Brassesco, MS and Cortez, MA and Valera, ET and Engel, EE and Nogueira-Barbosa, MH and Becker, AP and Tone, LG},
title = {Cytogenetic heterogeneity in biphasic synovial sarcoma associated with telomere instability.},
journal = {Cancer genetics and cytogenetics},
volume = {197},
number = {1},
pages = {86-90},
doi = {10.1016/j.cancergencyto.2009.09.017},
pmid = {20113844},
issn = {1873-4456},
mesh = {*Chromosomes, Human, Pair 18 ; *Chromosomes, Human, X ; Humans ; Middle Aged ; Oncogene Proteins, Fusion/genetics ; Sarcoma, Synovial/*genetics ; *Telomere ; *Translocation, Genetic ; },
}
@article {pmid20112180,
year = {2010},
author = {Makpol, S and Zainuddin, A and Rahim, NA and Yusof, YA and Ngah, WZ},
title = {Alpha-tocopherol modulates hydrogen peroxide-induced DNA damage and telomere shortening of human skin fibroblasts derived from differently aged individuals.},
journal = {Planta medica},
volume = {76},
number = {9},
pages = {869-875},
doi = {10.1055/s-0029-1240812},
pmid = {20112180},
issn = {1439-0221},
mesh = {Age Factors ; Cellular Senescence/*drug effects/genetics ; DNA Damage/*drug effects ; Drug Administration Schedule ; Fibroblasts/drug effects/metabolism ; Humans ; Hydrogen Peroxide ; Oxidative Stress/*drug effects ; Skin/*drug effects/metabolism ; Telomerase/metabolism ; Telomere/*drug effects/ultrastructure ; alpha-Tocopherol/*pharmacology ; },
abstract = {Antioxidants such as vitamin E may act differently on skin cells depending on the age of the skin and the level of oxidative damage induced. The effects of alpha-tocopherol (ATF) on H(2)O(2)-induced DNA damage and telomere shortening of normal human skin fibroblast cells derived from young and old individual donors were determined. Fibroblasts were divided into five groups; untreated control, H(2)O(2)-induced oxidative stress, alpha-tocopherol treatment, and pre- and post-treatment with alpha-tocopherol for H(2)O(2)-induced oxidative stress. Our results showed that H(2)O(2)-induced oxidative stress increased DNA damage, shortened the telomere length and reduced the telomerase activity (p < 0.05) in fibroblasts obtained from young and old donors. Pre- and post-treatment with alpha-tocopherol protected against H(2)O(2)-induced DNA damage in fibroblasts obtained from young individuals (p = 0.005; p = 0.01, respectively). However, in fibroblasts obtained from old individuals, similar protective effects were only seen in cells pretreated with alpha-tocopherol (p = 0.05) but not in the post-treated cells. Protection against H(2)O(2)-induced telomere shortening was observed in fibroblasts obtained from both young and old donors which were pre-treated with alpha-tocopherol (p = 0.009; p = 0.008, respectively). However, similar protective effects against telomere shortening in fibroblasts obtained from both young and old donors were not observed in the post-treated fibroblasts. Protection against H(2)O(2)-induced telomerase activity loss was observed only in fibroblasts obtained from old donors which were pretreated with alpha-tocopherol (p = 0.04) but not in fibroblasts obtained from young donors. Similar protective effects against telomerase activity loss in fibroblasts obtained from both young and old donors were not observed in the post-treated fibroblasts. In conclusion, alpha-tocopherol protected against H(2)O(2)-induced telomere shortening by restoring the telomerase activity. It also modulated H(2)O(2)-induced DNA damage and this modulation was affected by donor age.},
}
@article {pmid20110566,
year = {2010},
author = {Wong, LH and McGhie, JD and Sim, M and Anderson, MA and Ahn, S and Hannan, RD and George, AJ and Morgan, KA and Mann, JR and Choo, KH},
title = {ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells.},
journal = {Genome research},
volume = {20},
number = {3},
pages = {351-360},
pmid = {20110566},
issn = {1549-5469},
mesh = {Adenosine Triphosphatases/chemistry ; Animals ; Chromatin/metabolism/physiology ; Chromatin Assembly and Disassembly ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; Chromosomes/metabolism ; DNA Helicases/genetics/*metabolism ; DNA Replication/genetics/physiology ; Embryonic Stem Cells/metabolism ; Genes ; Histones/genetics/*metabolism ; Humans ; Intellectual Disability/genetics ; Interphase/genetics ; Mental Retardation, X-Linked/genetics ; Mice ; Mutation ; Nuclear Proteins/genetics/*metabolism ; Pluripotent Stem Cells/*metabolism ; Telomere/*metabolism ; X-linked Nuclear Protein ; alpha-Thalassemia/genetics ; },
abstract = {ATRX (alpha thalassemia/mental retardation syndrome X-linked) belongs to the SWI2/SNF2 family of chromatin remodeling proteins. Besides the ATPase/helicase domain at its C terminus, it contains a PHD-like zinc finger at the N terminus. Mutations in the ATRX gene are associated with X-linked mental retardation (XLMR) often accompanied by alpha thalassemia (ATRX syndrome). Although ATRX has been postulated to be a transcriptional regulator, its precise roles remain undefined. We demonstrate ATRX localization at the telomeres in interphase mouse embryonic stem (ES) cells in synchrony with the incorporation of H3.3 during telomere replication at S phase. Moreover, we found that chromobox homolog 5 (CBX5) (also known as heterochromatin protein 1 alpha, or HP1 alpha) is also present at the telomeres in ES cells. We show by coimmunoprecipitation that this localization is dependent on the association of ATRX with histone H3.3, and that mutating the K4 residue of H3.3 significantly diminishes ATRX and H3.3 interaction. RNAi-knockdown of ATRX induces a telomere-dysfunction phenotype and significantly reduces CBX5 enrichment at the telomeres. These findings suggest a novel function of ATRX, working in conjunction with H3.3 and CBX5, as a key regulator of ES-cell telomere chromatin.},
}
@article {pmid20101406,
year = {2010},
author = {Rae, DE and Vignaud, A and Butler-Browne, GS and Thornell, LE and Sinclair-Smith, C and Derman, EW and Lambert, MI and Collins, M},
title = {Skeletal muscle telomere length in healthy, experienced, endurance runners.},
journal = {European journal of applied physiology},
volume = {109},
number = {2},
pages = {323-330},
pmid = {20101406},
issn = {1439-6327},
mesh = {Adult ; *Athletes/statistics &amp; numerical data ; Female ; Humans ; Male ; Middle Aged ; Muscle, Skeletal/*metabolism/pathology ; *Physical Endurance ; Running/*physiology/statistics &amp; numerical data ; Telomere/*metabolism ; },
abstract = {Measuring the DNA telomere length of skeletal muscle in experienced endurance runners may contribute to our understanding of the effects of chronic exposure to endurance exercise on skeletal muscle. This study compared the minimum terminal restriction fragment (TRF) length in the vastus lateralis muscle of 18 experienced endurance runners (mean age: 42 +/- 7 years) to those of 19 sedentary individuals (mean age: 39 +/- 10 years). The runners had covered almost 50,000 km in training and racing over 15 years. Minimum TRF lengths measured in the muscle of both groups were similar (P = 0.805) and within the normal range. Minimum TRF length in the runners, however, was inversely related to their years spent running (r = -0.63, P = 0.007) and hours spent training (r = -0.52, P = 0.035). Therefore, since exposure to endurance running may influence minimum TRF length, and by implication, the proliferative potential of the satellite cells, chronic endurance running may be seen as a stressor to skeletal muscle.},
}
@article {pmid20098422,
year = {2010},
author = {Zhang, ML and Tong, XJ and Fu, XH and Zhou, BO and Wang, J and Liao, XH and Li, QJ and Shen, N and Ding, J and Zhou, JQ},
title = {Yeast telomerase subunit Est1p has guanine quadruplex-promoting activity that is required for telomere elongation.},
journal = {Nature structural &amp; molecular biology},
volume = {17},
number = {2},
pages = {202-209},
pmid = {20098422},
issn = {1545-9985},
mesh = {Cellular Senescence ; Coenzymes/pharmacology ; DNA/*chemistry/*metabolism ; Gene Deletion ; Guanine/*metabolism ; Magnesium/pharmacology ; *Nucleic Acid Conformation ; Saccharomyces cerevisiae/*enzymology ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomerase/deficiency/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are eukaryotic protein-DNA complexes found at the ends of linear chromosomes that are essential for maintaining genome integrity and are implicated in cellular aging and cancer. The guanine (G)-rich strand of telomeric DNA, usually elongated by the telomerase reverse transcriptase, can form a higher-order structure known as a G-quadruplex in vitro and in vivo. Several factors that promote or resolve G-quadruplexes have been identified, but the functional importance of these structures for telomere maintenance is not well understood. Here we show that the yeast telomerase subunit Est1p, known to be involved in telomerase recruitment to telomeres, can convert single-stranded telomeric G-rich DNA into a G-quadruplex structure in vitro in a Mg(2+)-dependent manner. Cells carrying Est1p mutants deficient in G-quadruplex formation in vitro showed gradual telomere shortening and cellular senescence, indicating a positive regulatory role for G-quadruplex in the maintenance of telomere length.},
}
@article {pmid20097687,
year = {2010},
author = {Nittis, T and Guittat, L and LeDuc, RD and Dao, B and Duxin, JP and Rohrs, H and Townsend, RR and Stewart, SA},
title = {Revealing novel telomere proteins using in vivo cross-linking, tandem affinity purification, and label-free quantitative LC-FTICR-MS.},
journal = {Molecular &amp; cellular proteomics : MCP},
volume = {9},
number = {6},
pages = {1144-1156},
pmid = {20097687},
issn = {1535-9484},
support = {P30 CA091842/CA/NCI NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; R21 AG02532/AG/NIA NIH HHS/United States ; P41 RR000954/RR/NCRR NIH HHS/United States ; P41RR000954/RR/NCRR NIH HHS/United States ; UL1RR024992/RR/NCRR NIH HHS/United States ; UL1 RR024992/RR/NCRR NIH HHS/United States ; P30 CA91842/CA/NCI NIH HHS/United States ; },
mesh = {Cell Extracts ; Cell Line ; Chromatography, Affinity/*methods ; Chromatography, Liquid/*methods ; Cross-Linking Reagents/*pharmacology ; Fluorescent Antibody Technique ; Humans ; Immunoblotting ; In Situ Hybridization, Fluorescence ; Mass Spectrometry/*methods ; Nanotechnology ; Recombinant Fusion Proteins/metabolism ; Shelterin Complex ; Staining and Labeling ; Telomere-Binding Proteins/isolation &amp; purification/*metabolism ; },
abstract = {Telomeres are DNA-protein structures that protect chromosome ends from the actions of the DNA repair machinery. When telomeric integrity is compromised, genomic instability ensues. Considerable effort has focused on identification of telomere-binding proteins and elucidation of their functions. To date, protein identification has relied on classical immunoprecipitation and mass spectrometric approaches, primarily under conditions that favor isolation of proteins with strong or long lived interactions that are present at sufficient quantities to visualize by SDS-PAGE. To facilitate identification of low abundance and transiently associated telomere-binding proteins, we developed a novel approach that combines in vivo protein-protein cross-linking, tandem affinity purification, and stringent sequential endoprotease digestion. Peptides were identified by label-free comparative nano-LC-FTICR-MS. Here, we expressed an epitope-tagged telomere-binding protein and utilized a modified chromatin immunoprecipitation approach to cross-link associated proteins. The resulting immunoprecipitant contained telomeric DNA, establishing that this approach captures bona fide telomere binding complexes. To identify proteins present in the immunocaptured complexes, samples were reduced, alkylated, and digested with sequential endoprotease treatment. The resulting peptides were purified using a microscale porous graphite stationary phase and analyzed using nano-LC-FTICR-MS. Proteins enriched in cells expressing HA-FLAG-TIN2 were identified by label-free quantitative analysis of the FTICR mass spectra from different samples and ion trap tandem mass spectrometry followed by database searching. We identified all of the proteins that constitute the telomeric shelterin complex, thus validating the robustness of this approach. We also identified 62 novel telomere-binding proteins. These results demonstrate that DNA-bound protein complexes, including those present at low molar ratios, can be identified by this approach. The success of this approach will allow us to create a more complete understanding of telomere maintenance and have broad applicability.},
}
@article {pmid20096746,
year = {2010},
author = {Gilson, E and Ségal-Bendirdjian, E},
title = {The telomere story or the triumph of an open-minded research.},
journal = {Biochimie},
volume = {92},
number = {4},
pages = {321-326},
doi = {10.1016/j.biochi.2009.12.014},
pmid = {20096746},
issn = {1638-6183},
mesh = {Animals ; Cell Biology/history ; Cellular Senescence/*physiology ; Chromosomes/metabolism ; History, 19th Century ; History, 20th Century ; Humans ; Nobel Prize ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {The Nobel Assembly at Karolinska Institute has decided to award The Nobel Prize in Physiology or Medicine 2009 jointly to Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak for the discovery of "how chromosomes are protected by telomeres and the enzyme telomerase". This discovery had major impacts within the scientific community and led to intense research in this field. All the studies performed are now the bases for future investigations and stimulate the development of potential new therapies.},
}
@article {pmid20088004,
year = {2010},
author = {Pampalona, J and Soler, D and Genescà, A and Tusell, L},
title = {Whole chromosome loss is promoted by telomere dysfunction in primary cells.},
journal = {Genes, chromosomes &amp; cancer},
volume = {49},
number = {4},
pages = {368-378},
doi = {10.1002/gcc.20749},
pmid = {20088004},
issn = {1098-2264},
mesh = {Aneuploidy ; Cells, Cultured ; *Chromosomal Instability ; *Chromosome Deletion ; Chromosome Segregation ; Humans ; In Situ Hybridization, Fluorescence ; Mammary Glands, Human/cytology ; *Models, Genetic ; Statistics, Nonparametric ; Telomere/genetics/metabolism/*physiology ; },
abstract = {Errors in chromosome segregation during mitosis result in aneuploidy, which in humans may play a role in the onset of neoplasia by changing gene dosage. Nearly all solid tumors exhibit genomic instability at the chromosomal level, showing both structural and numerical chromosome abnormalities. Chromosomal instability occurs early in the development of cancer and may represent an important step in the initiation and/or progression of the disease. Telomere integrity appears to be a critical element in the genesis of structural chromosome imbalances, but it is still not clear whether it can also generate numerical chromosome aberrations. We investigated the possible relationship between telomere shortening and aneuploidy formation in human mammary epithelial cells using the cytokinesis-block micronucleus assay combined with fluorescent DNA probes. In this cell system, uncapped chromosomes fuse with each other resulting in dicentric chromosomes, which are known to be a source of new structural chromosome rearrangements. Here, we show that in primary epithelial cells, the chromosomes with short telomeres are more frequently involved in missegregation events than chromosomes of normal telomere length. Whole chromosome aneuploidy occurs through both nondisjunction and anaphase lagging of dicentric chromatids, which suggests that pulling anaphase bridges toward opposite poles can generate the necessary force for detaching a chromosome from the microtubules of one or both spindle poles. Therefore, telomere-driven instability can promote not only the appearance of chromosomal rearrangements but also the appearance of numerical chromosome aberrations that could favor cell immortalization and the acquisition of a tumor phenotype.},
}
@article {pmid20085922,
year = {2010},
author = {Huzen, J and van der Harst, P and de Boer, RA and Lesman-Leegte, I and Voors, AA and van Gilst, WH and Samani, NJ and Jaarsma, T and van Veldhuisen, DJ},
title = {Telomere length and psychological well-being in patients with chronic heart failure.},
journal = {Age and ageing},
volume = {39},
number = {2},
pages = {223-227},
doi = {10.1093/ageing/afp256},
pmid = {20085922},
issn = {1468-2834},
mesh = {Aged ; Aged, 80 and over ; Aging/physiology/psychology ; Chronic Disease ; Cross-Sectional Studies ; *Depression/genetics/psychology ; Female ; Geriatric Assessment ; *Heart Failure/complications/genetics/physiopathology ; Humans ; Male ; Middle Aged ; Polymerase Chain Reaction ; Quality of Life ; Regression Analysis ; Risk Factors ; Surveys and Questionnaires ; Telomere/*genetics/*ultrastructure ; },
abstract = {BACKGROUND: psychological stress and depressive symptoms have been implicated with accelerated ageing and increased progression of diseases. Shorter telomere length indicates a more advanced biological age. It is unknown whether psychological well-being is associated with telomere length in patients with the somatic condition of chronic heart failure (CHF).<br><br>DESIGN: a cross-sectional analysis was used.<br><br>SETTING: patients were admitted to the hospital with signs and symptoms of CHF.<br><br>OBJECTIVE: the study aimed to assess the association between telomere length and psychological well-being in patients with CHF.<br><br>METHODS: telomere length was determined by quantitative polymerase chain reaction in 890 patients with New York Heart Association functional class II to IV CHF. We evaluated the perceived mental health by the validated RAND-36 questionnaire. Depressive symptoms were assessed by the Centre for Epidemiologic Studies Depression scale (CES-D), and the presence of type D personality was evaluated by the DS14.<br><br>RESULTS: a lower perceived mental health on the RAND-36 score was associated with shorter telomere length. Adjustment for age and gender did not change our findings (standardised beta, 0.11; P-value, 0.002). Telomere length was not associated with the CES-D or DS14 score.<br><br>CONCLUSION: decreased perceived mental health is associated with shorter leukocyte telomere length in patients with CHF. Future work should determine whether psychological stress accelerates biological ageing.},
}
@article {pmid20081803,
year = {2010},
author = {Radpour, R and Barekati, Z and Haghighi, MM and Kohler, C and Asadollahi, R and Torbati, PM and Holzgreve, W and Zhong, XY},
title = {Correlation of telomere length shortening with promoter methylation profile of p16/Rb and p53/p21 pathways in breast cancer.},
journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},
volume = {23},
number = {5},
pages = {763-772},
doi = {10.1038/modpathol.2009.195},
pmid = {20081803},
issn = {1530-0285},
mesh = {Breast Neoplasms/*genetics/metabolism/pathology ; Carcinoma, Ductal, Breast/*genetics/metabolism/pathology ; Carcinoma, Lobular/*genetics/metabolism/pathology ; Cell Cycle/genetics ; Cyclin-Dependent Kinase Inhibitor p16 ; Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism ; DNA Methylation/*genetics ; Down-Regulation/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; Mass Spectrometry ; Neoplasm Proteins/genetics/metabolism ; Promoter Regions, Genetic/*genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/genetics ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; },
abstract = {Unregulated cell growth, a major hallmark of cancer, is coupled with telomere shortening. Measurement of telomere length could provide important information on cell replication and proliferation state in cancer tissues. Telomere shortening and its potential correlation with downregulation of cell-cycle regulatory elements were studied by the examination of relative telomere length and methylation status of the TP53, P21 and P16 promoters in tissues from breast cancer patients. Telomere length was measured in 104 samples (52 tumors and paired adjacent normal breast tissues) by quantitative PCR. Methylation profile of selected genes was analyzed in all samples using a matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Our results demonstrated a significant shortening of tumor telomere regions compared with paired adjacent normal tissues (P<0.001). Similarly, telomere lengths were significantly shorter in advanced stage cases and in those with higher histological grades (P<0.05). Telomere shortening in cancer tissues was correlated with a different level of hypermethylation in the TP53, P21 and P16 promoters (r=-0.33, P=0.001; r=-0.70, P<0.0001 and r=-0.71, P<0.0001, respectively). The results suggested that inactivation of p16/Rb and/or p53/p21 pathways by hypermethylation may be linked to critical telomere shortening, leading to genome instability and ultimately to malignant transformation. Thus, telomere shortening and promoter hypermethylation of related genes both might serve as breast cancer biomarkers.},
}
@article {pmid20080237,
year = {2010},
author = {Salpea, KD and Humphries, SE},
title = {Telomere length in atherosclerosis and diabetes.},
journal = {Atherosclerosis},
volume = {209},
number = {1},
pages = {35-38},
pmid = {20080237},
issn = {1879-1484},
support = {FS/06/053/BHF_/British Heart Foundation/United Kingdom ; RG/08/008/25291/BHF_/British Heart Foundation/United Kingdom ; RG2005/014/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Atherosclerosis/genetics/*metabolism ; Base Sequence ; Diabetes Mellitus, Type 2/genetics/*metabolism ; Humans ; Telomere/chemistry/genetics/*metabolism ; },
}
@article {pmid20080170,
year = {2010},
author = {Vidacek, NS and Cukusić, A and Ivanković, M and Fulgosi, H and Huzak, M and Smith, JR and Rubelj, I},
title = {Abrupt telomere shortening in normal human fibroblasts.},
journal = {Experimental gerontology},
volume = {45},
number = {3},
pages = {235-242},
doi = {10.1016/j.exger.2010.01.009},
pmid = {20080170},
issn = {1873-6815},
mesh = {Cells, Cultured ; *Cellular Senescence ; Fibroblasts/*ultrastructure ; Humans ; In Situ Hybridization, Fluorescence ; Microscopy, Electron ; *Telomere ; },
abstract = {Aging is one of the most basic properties of living organisms. Abundant evidence supports the idea that cell senescence underlies organismal aging in higher mammals. Therefore, examining the molecular mechanisms that control cell and replicative senescence is of great interest for biology and medicine. Several discoveries strongly support telomere shortening as the main molecular mechanism that limits the growth of normal cells. Although cultures gradually approach their growth limit, appearance of individual senescent cells is sudden and stochastic. A theoretical model of abrupt telomere shortening has been proposed in order to explain this phenomenon, but until now there was no reliable experimental evidence supporting this idea. Here, we have employed novel methodology to provide evidence for the generation of extrachromosomal circular telomeric DNA as a result of abrupt telomere shortening in normal human fibroblasts. This mechanism ensures heterogeneity in growth potential among individual cells, which is crucial for gradual progression of the aging process.},
}
@article {pmid20079404,
year = {2010},
author = {De Vos, WH and Houben, F and Hoebe, RA and Hennekam, R and van Engelen, B and Manders, EM and Ramaekers, FC and Broers, JL and Van Oostveldt, P},
title = {Increased plasticity of the nuclear envelope and hypermobility of telomeres due to the loss of A-type lamins.},
journal = {Biochimica et biophysica acta},
volume = {1800},
number = {4},
pages = {448-458},
doi = {10.1016/j.bbagen.2010.01.002},
pmid = {20079404},
issn = {0006-3002},
mesh = {Cell Line ; Cell Shape ; *Codon, Nonsense ; Fibroblasts/pathology/*physiology ; Humans ; Immunohistochemistry ; Lamin Type A/deficiency/*genetics ; Nuclear Envelope/*genetics/metabolism ; Nuclear Proteins/genetics/metabolism ; Polymorphism, Single Nucleotide ; Progeria/*genetics/metabolism/pathology ; Protein Precursors/genetics/metabolism ; Reference Values ; Skin/cytology ; Skin Physiological Phenomena ; },
abstract = {BACKGROUND: The nuclear lamina provides structural support to the nucleus and has a central role in defining nuclear organization. Defects in its filamentous constituents, the lamins, lead to a class of diseases collectively referred to as laminopathies. On the cellular level, lamin mutations affect the physical integrity of nuclei and nucleo-cytoskeletal interactions, resulting in increased susceptibility to mechanical stress and altered gene expression.<br><br>METHODS: In this study we quantitatively compared nuclear deformation and chromatin mobility in fibroblasts from a homozygous nonsense LMNA mutation patient and a Hutchinson-Gilford progeria syndrome patient with wild type dermal fibroblasts, based on the visualization of mCitrine labeled telomere-binding protein TRF2 with light-economical imaging techniques and cytometric analyses.<br><br>RESULTS: Without application of external forces, we found that the absence of functional lamin A/C leads to increased nuclear plasticity on the hour and minute time scale but also to increased intranuclear mobility down to the second time scale. In contrast, progeria cells show overall reduced nuclear dynamics. Experimental manipulation (farnesyltransferase inhibition or lamin A/C silencing) confirmed that these changes in mobility are caused by abnormal or reduced lamin A/C expression.<br><br>CONCLUSIONS: These observations demonstrate that A-type lamins affect both nuclear membrane and telomere dynamics.<br><br>GENERAL SIGNIFICANCE: Because of the pivotal role of dynamics in nuclear function, these differences likely contribute to or represent novel mechanisms in laminopathy development.},
}
@article {pmid20075064,
year = {2010},
author = {Wills, LP and Schnellmann, RG},
title = {Telomere shortening and regenerative capacity after acute kidney injury.},
journal = {Journal of the American Society of Nephrology : JASN},
volume = {21},
number = {2},
pages = {202-204},
doi = {10.1681/ASN.2009121270},
pmid = {20075064},
issn = {1533-3450},
support = {DK062028/DK/NIDDK NIH HHS/United States ; DK071997/DK/NIDDK NIH HHS/United States ; ES012878/ES/NIEHS NIH HHS/United States ; GM084147/GM/NIGMS NIH HHS/United States ; T32 CA119945/CA/NCI NIH HHS/United States ; },
mesh = {Acute Kidney Injury/metabolism/*physiopathology ; Animals ; Apoptosis ; Disease Models, Animal ; Humans ; Kidney/pathology/*physiology ; Mice ; Mice, Knockout ; RNA/genetics/metabolism ; Regeneration/*physiology ; Reperfusion Injury/metabolism/physiopathology ; Telomerase/genetics/metabolism ; Telomere/*ultrastructure ; },
}
@article {pmid20072649,
year = {2010},
author = {Silva, AG and Graves, HA and Guffei, A and Ricca, TI and Mortara, RA and Jasiulionis, MG and Mai, S},
title = {Telomere-centromere-driven genomic instability contributes to karyotype evolution in a mouse model of melanoma.},
journal = {Neoplasia (New York, N.Y.)},
volume = {12},
number = {1},
pages = {11-19},
pmid = {20072649},
issn = {1476-5586},
support = {//Canadian Institutes of Health Research/Canada ; },
mesh = {Animals ; Cell Line ; Cell Proliferation ; Centromere/*genetics ; Chromosome Aberrations ; Female ; Gene Expression Regulation, Enzymologic ; *Genomic Instability ; In Situ Hybridization, Fluorescence ; Melanoma, Experimental/*genetics/pathology ; Mice ; Mice, Inbred C57BL ; Reverse Transcriptase Polymerase Chain Reaction ; Spectral Karyotyping ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {Aneuploidy and chromosomal instability (CIN) are hallmarks of most solid tumors. These alterations may result from inaccurate chromosomal segregation during mitosis, which can occur through several mechanisms including defective telomere metabolism, centrosome amplification, dysfunctional centromeres, and/or defective spindle checkpoint control. In this work, we used an in vitro murine melanoma model that uses a cellular adhesion blockade as a transforming factor to characterize telomeric and centromeric alterations that accompany melanocyte transformation. To study the timing of the occurrence of telomere shortening in this transformation model, we analyzed the profile of telomere length by quantitative fluorescent in situ hybridization and found that telomere length significantly decreased as additional rounds of cell adhesion blockages were performed. Together with it, an increase in telomere-free ends and complex karyotypic aberrations were also found, which include Robertsonian fusions in 100% of metaphases of the metastatic melanoma cells. These findings are in agreement with the idea that telomere length abnormalities seem to be one of the earliest genetic alterations acquired in the multistep process of malignant transformation and that telomere abnormalities result in telomere aggregation, breakage-bridge-fusion cycles, and CIN. Another remarkable feature of this model is the abundance of centromeric instability manifested as centromere fragments and centromeric fusions. Taken together, our results illustrate for this melanoma model CIN with a structural signature of centromere breakage and telomeric loss.},
}
@article {pmid20072607,
year = {2010},
author = {Farzaneh-Far, R and Lin, J and Epel, E and Lapham, K and Blackburn, E and Whooley, MA},
title = {Telomere length trajectory and its determinants in persons with coronary artery disease: longitudinal findings from the heart and soul study.},
journal = {PloS one},
volume = {5},
number = {1},
pages = {e8612},
pmid = {20072607},
issn = {1932-6203},
support = {R01 HL079235/HL/NHLBI NIH HHS/United States ; },
mesh = {Base Sequence ; Cohort Studies ; Coronary Artery Disease/*genetics ; DNA Primers ; Humans ; Longitudinal Studies ; Multivariate Analysis ; *Telomere ; },
abstract = {BACKGROUND: Leukocyte telomere length, an emerging marker of biological age, has been shown to predict cardiovascular morbidity and mortality. However, the natural history of telomere length in patients with coronary artery disease has not been studied. We sought to investigate the longitudinal trajectory of telomere length, and to identify the independent predictors of telomere shortening, in persons with coronary artery disease.<br><br>In a prospective cohort study of 608 individuals with stable coronary artery disease, we measured leukocyte telomere length at baseline, and again after five years of follow-up. We used multivariable linear and logistic regression models to identify the independent predictors of leukocyte telomere trajectory. Baseline and follow-up telomere lengths were normally distributed. Mean telomere length decreased by 42 base pairs per year (p<0.001). Three distinct telomere trajectories were observed: shortening in 45%, maintenance in 32%, and lengthening in 23% of participants. The most powerful predictor of telomere shortening was baseline telomere length (OR per SD increase = 7.6; 95% CI 5.5, 10.6). Other independent predictors of telomere shortening were age (OR per 10 years = 1.6; 95% CI 1.3, 2.1), male sex (OR = 2.4; 95% CI 1.3, 4.7), and waist-to-hip ratio (OR per 0.1 increase = 1.4; 95% CI 1.0, 2.0).<br><br>CONCLUSIONS/SIGNIFICANCE: Leukocyte telomere length may increase as well as decrease in persons with coronary artery disease. Telomere length trajectory is powerfully influenced by baseline telomere length, possibly suggesting negative feedback regulation. Age, male sex, and abdominal obesity independently predict telomere shortening. The mechanisms and reversibility of telomeric aging in cardiovascular disease deserve further study.},
}
@article {pmid20069564,
year = {2010},
author = {Uhlírová, R and Horáková, AH and Galiová, G and Legartová, S and Matula, P and Fojtová, M and Varecha, M and Amrichová, J and Vondrácek, J and Kozubek, S and Bártová, E},
title = {SUV39h- and A-type lamin-dependent telomere nuclear rearrangement.},
journal = {Journal of cellular biochemistry},
volume = {109},
number = {5},
pages = {915-926},
doi = {10.1002/jcb.22466},
pmid = {20069564},
issn = {1097-4644},
mesh = {Animals ; DNA-Binding Proteins/metabolism ; Epigenesis, Genetic ; Fibroblasts/metabolism ; Flow Cytometry ; *Gene Rearrangement ; Humans ; Intranuclear Inclusion Bodies/metabolism ; Lamin Type A/*metabolism ; Methyltransferases/*metabolism ; Mice ; Protein Transport ; Repressor Proteins/*metabolism ; Shelterin Complex ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 1/metabolism ; rap1 GTP-Binding Proteins/metabolism ; },
abstract = {Telomeres are specialized chromatin structures that are situated at the end of linear chromosomes and play an important role in cell senescence and immortalization. Here, we investigated whether changes in histone signature influence the nuclear arrangement and positioning of telomeres. Analysis of mouse embryonic fibroblasts revealed that telomeres were organized into specific clusters that partially associated with centromeric clusters. This nuclear arrangement was influenced by deficiency of the histone methyltransferase SUV39h, LMNA deficiency, and the histone deacetylase inhibitor Trichostatin A (TSA). Similarly, nuclear radial distributions of telomeric clusters were preferentially influenced by TSA, which caused relocation of telomeres closer to the nuclear center. Telomeres also co-localized with promyelocytic leukemia bodies (PML). This association was increased by SUV39h deficiency and decreased by LMNA deficiency. These differences could be explained by differing levels of the telomerase subunit, TERT, in SUV39h- and LMNA-deficient fibroblasts. Taken together, our data show that SUV39h and A-type lamins likely play a key role in telomere maintenance and telomere nuclear architecture.},
}
@article {pmid20064545,
year = {2010},
author = {LaRocca, TJ and Seals, DR and Pierce, GL},
title = {Leukocyte telomere length is preserved with aging in endurance exercise-trained adults and related to maximal aerobic capacity.},
journal = {Mechanisms of ageing and development},
volume = {131},
number = {2},
pages = {165-167},
pmid = {20064545},
issn = {1872-6216},
support = {AG006537/AG/NIA NIH HHS/United States ; M01 RR000051/RR/NCRR NIH HHS/United States ; AG000279/AG/NIA NIH HHS/United States ; R01 AG006537/AG/NIA NIH HHS/United States ; R37 AG013038/AG/NIA NIH HHS/United States ; M01 RR000051-441342/RR/NCRR NIH HHS/United States ; M01 RR000051-457882/RR/NCRR NIH HHS/United States ; AG013038/AG/NIA NIH HHS/United States ; R01 AG015897/AG/NIA NIH HHS/United States ; AG031141/AG/NIA NIH HHS/United States ; AG022241/AG/NIA NIH HHS/United States ; RR00051/RR/NCRR NIH HHS/United States ; R01 AG013038/AG/NIA NIH HHS/United States ; R01 AG022241/AG/NIA NIH HHS/United States ; R01 AG006537-22/AG/NIA NIH HHS/United States ; R01 AG031141/AG/NIA NIH HHS/United States ; T32 AG000279/AG/NIA NIH HHS/United States ; AG015897/AG/NIA NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aging/*physiology ; Exercise/*physiology ; Exercise Tolerance ; Humans ; Leukocytes/*cytology ; Male ; Middle Aged ; Oxygen Consumption/*physiology ; Regression Analysis ; Telomere/*physiology ; Young Adult ; },
abstract = {Telomere length (TL), a measure of replicative senescence, decreases with aging, but the factors involved are incompletely understood. To determine if age-associated reductions in TL are related to habitual endurance exercise and maximal aerobic exercise capacity (maximal oxygen consumption, VO(2)max), we studied groups of young (18-32 years; n=15, 7 male) and older (55-72 years; n=15, 9 male) sedentary and young (n=10, 7 male) and older (n=17, 11 male) endurance exercise-trained healthy adults. Leukocyte TL (LTL) was shorter in the older (7059+/-141 bp) vs. young (8407+/-218) sedentary adults (P<0.01). LTL of the older endurance-trained adults (7992+/-169 bp) was approximately 900 bp greater than their sedentary peers (P<0.01) and was not significantly different (P=0.12) from young exercise-trained adults (8579+/-413). LTL was positively related to VO(2)max as a result of a significant association in older adults (r=0.44, P<0.01). Stepwise multiple regression analysis revealed that VO(2)max was the only independent predictor of LTL in the overall group. Our results indicate that LTL is preserved in healthy older adults who perform vigorous aerobic exercise and is positively related to maximal aerobic exercise capacity. This may represent a novel molecular mechanism underlying the "anti-aging" effects of maintaining high aerobic fitness.},
}
@article {pmid20064431,
year = {2009},
author = {Corey, DR},
title = {Telomeres and telomerase: from discovery to clinical trials.},
journal = {Chemistry &amp; biology},
volume = {16},
number = {12},
pages = {1219-1223},
pmid = {20064431},
issn = {1879-1301},
support = {R01 GM073042/GM/NIGMS NIH HHS/United States ; R01 GM073042-05/GM/NIGMS NIH HHS/United States ; NIGMS 73042//PHS HHS/United States ; },
mesh = {Antineoplastic Agents/*chemistry/pharmacology ; Cell Line, Tumor ; Clinical Trials as Topic ; Drug Discovery ; Enzyme Inhibitors/chemistry/pharmacology ; History, 20th Century ; Humans ; Nobel Prize ; Physiology/history ; Telomerase/*antagonists &amp; inhibitors/history/metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are the ends of linear chromosomes. They cannot be fully replicated by standard polymerases and are maintained by the ribonucleoprotein telomerase. Telomeres and telomerase stand at a junction of critical processes underlying chromosome integrity, cancer, and aging, and their importance was recognized by the 2009 Nobel Prize in Physiology or Medicine to Elizabeth Blackburn, Jack Szostak, and Carol Greider. Where will the field go now? What are the prospects for antitelomerase agents as drugs? Nearly 30 years after Szostak and Blackburn's pioneering manuscript on telomere ends, the challenges of discovery remain.},
}
@article {pmid20063167,
year = {2010},
author = {Ghosh, S and Feingold, E and Chakraborty, S and Dey, SK},
title = {Telomere length is associated with types of chromosome 21 nondisjunction: a new insight into the maternal age effect on Down syndrome birth.},
journal = {Human genetics},
volume = {127},
number = {4},
pages = {403-409},
pmid = {20063167},
issn = {1432-1203},
mesh = {Adolescent ; Adult ; Case-Control Studies ; Chromosomes, Human, Pair 21/*genetics ; Cross-Sectional Studies ; Down Syndrome/*genetics ; Female ; Humans ; Infant, Newborn ; Maternal Age ; Meiosis/genetics ; *Nondisjunction, Genetic ; Pregnancy ; Telomere/*genetics ; Young Adult ; },
abstract = {Advanced maternal age is a well-documented risk factor of chromosome 21 nondisjunction in humans, but understanding of this association at the genetic level is still limited. In particular, the state of maternal genetic age is unclear. In the present study, we estimated maternal genetic age by measuring telomere length of peripheral blood lymphocytes among age-matched mothers of children with Down syndrome (cases: N = 75) and mothers of euploid children (controls: N = 75) in an age range of 18-42 years. All blood samples were taken within 1 week of the birth of the child in both cases and controls. The telomere length estimation was performed by restriction digestion--Southern blot hybridization method. We stratified the cases on the basis of centromeric STR genotyping into maternal meiosis I (N = 48) and maternal meiosis II (N = 27) nondisjunction groups and used linear regression to compare telomere length as a function of age in the euploid, meiosis I and meiosis II groups. Our results show that all three groups have similar telomere length on average for younger mothers. As age increases, all groups show telomere loss, but that loss is largest in the meiosis II mother group and smallest in the euploid mother group with the meiosis I mother group in the middle. The regression lines for all three were statistically significantly different from each other (p < 0.001). Our results do not support the theory that younger women who have babies with Down syndrome do so because are 'genetically older' than their chronological age, but we provide the first evidence that older mothers who have babies with Down syndrome are 'genetically older' than controls, who have euploid babies at the same age. We also show for the first time that telomere length attrition may be associated in some way with meiosis I and meiosis II nondisjunction of chromosome 21 and subsequent Down syndrome births at advanced maternal age.},
}
@article {pmid20061350,
year = {2010},
author = {Ehrlenbach, S and Willeit, P and Kiechl, S and Willeit, J and Reindl, M and Schanda, K and Kronenberg, F and Brandstätter, A},
title = {Raising the bar on telomere epidemiology.},
journal = {International journal of epidemiology},
volume = {39},
number = {1},
pages = {308-309},
doi = {10.1093/ije/dyp383},
pmid = {20061350},
issn = {1464-3685},
mesh = {Aging/*genetics ; Humans ; Mortality ; Polymerase Chain Reaction/methods ; Research Design ; Telomere/*genetics ; },
}
@article {pmid20061197,
year = {2010},
author = {Da-Silva, N and Arasaradnam, R and Getliffe, K and Sung, E and Oo, Y and Nwokolo, C},
title = {Altered mRNA expression of telomere binding proteins (TPP1, POT1, RAP1, TRF1 and TRF2) in ulcerative colitis and Crohn's disease.},
journal = {Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver},
volume = {42},
number = {8},
pages = {544-548},
doi = {10.1016/j.dld.2009.12.005},
pmid = {20061197},
issn = {1878-3562},
support = {G0501638/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Azathioprine/therapeutic use ; Biomarkers, Tumor/blood ; Chromosomal Instability/drug effects/genetics ; Colitis, Ulcerative/blood/complications/drug therapy/*genetics ; Colon/pathology ; Colonic Neoplasms/etiology/genetics/pathology ; Crohn Disease/blood/complications/drug therapy/*genetics ; Humans ; Leukocytes, Mononuclear/drug effects/metabolism/ultrastructure ; Lymphocyte Activation/drug effects ; Mesalamine/therapeutic use ; Middle Aged ; RNA, Messenger/*biosynthesis ; Reverse Transcriptase Polymerase Chain Reaction ; Shelterin Complex ; T-Lymphocytes/physiology ; Telomere/pathology/physiology/ultrastructure ; Telomere-Binding Proteins/biosynthesis/*genetics ; Telomeric Repeat Binding Protein 1/biosynthesis/*genetics ; Telomeric Repeat Binding Protein 2/biosynthesis/*genetics ; },
abstract = {AIMS: To determine mRNA expression of telomeric binding proteins in inflammatory bowel disease (IBD), and to note any effects of pharmacotherapy on telomere binding protein expression.<br><br>METHODS: Peripheral blood mononuclear cells (PBMC) obtained from 31 IBD patients and 13 controls were activated with phytohaemagglutinin and purified to yield activated (CD25+) T lymphocytes. TPP1, POT1, RAP1, TRF1 and TRF2 mRNA expression in PBMC and activated T lymphocytes was measured with RT-PCR.<br><br>RESULTS: In activated (CD25+) T lymphocytes, mean TRF2 mRNA levels were lower in both UC (6.6 vs 10, p=0.004) and CD subjects (6.9 vs 10; p=0.004). Similarly. in activated (CD25+) T lymphocytes mean RAP1 mRNA expression was significantly lower in UC subjects (4.5 vs 9.8, p=0.029) but not in CD subjects. In resting PBMC, mean TRF1 mRNA levels were lower in both UC (2.6 vs 3.5; p=0.008) and CD subjects (1.0 vs 3.5; p=0.04). No difference in PBMC and activated (CD25+) T lymphocytes mRNA levels of TPP1 and POT1 were noted in either UC or CD subjects. An association with 5-aminosalicylate therapy (R(2)=0.4) was only detected with RAP1 mRNA expression. TRF2 mRNA expression was inversely associated with disease duration only in UC subjects (p=0.05; R(2)=-0.6).<br><br>CONCLUSIONS: The downregulation of TRF2 and RAP1 mRNA expression in CD25+ T-lymphocytes in IBD suggests that these telomere binding proteins play a role in telomere regulation and may contribute to the telomeric fusions and chromosomal abnormalities observed in UC. These findings may also indicate a systemic process of telomere uncapping which could represent a biomarker for IBD associated cancer risk.},
}
@article {pmid20058805,
year = {2009},
author = {Grach, AA},
title = {[Structural organization of telomeres in various kinds of organisms].},
journal = {Tsitologiia},
volume = {51},
number = {11},
pages = {869-879},
pmid = {20058805},
issn = {0041-3771},
mesh = {Animals ; Plants/genetics ; Saccharomyces cerevisiae/genetics ; Species Specificity ; *Telomere/chemistry/genetics/metabolism ; },
abstract = {The review considers the structure of telomeres, terminal regions of linear of linear chromosomal DNA. Features of nucleotide organization of telomeric DNA in different species are shown. Special attention is given to analysis of functions of separate mammal and Saccharomyces cerevisiae telomere proteins, and their role in telomere length regulation and protection against degradation.},
}
@article {pmid20057362,
year = {2010},
author = {MacEneaney, OJ and Kushner, EJ and Westby, CM and Cech, JN and Greiner, JJ and Stauffer, BL and DeSouza, CA},
title = {Endothelial progenitor cell function, apoptosis, and telomere length in overweight/obese humans.},
journal = {Obesity (Silver Spring, Md.)},
volume = {18},
number = {9},
pages = {1677-1682},
doi = {10.1038/oby.2009.494},
pmid = {20057362},
issn = {1930-739X},
support = {HL076434/HL/NHLBI NIH HHS/United States ; HL077450/HL/NHLBI NIH HHS/United States ; RR00051/RR/NCRR NIH HHS/United States ; },
mesh = {Adult ; Aged ; Apoptosis/drug effects/*physiology ; Caspase 3/*metabolism ; Cell Movement ; Chemokine CXCL12/metabolism ; Cytochromes c/metabolism ; Cytokines/*metabolism ; Endothelial Cells/*physiology ; Enzyme Inhibitors/pharmacology ; Granulocyte Colony-Stimulating Factor/metabolism ; Humans ; Middle Aged ; Obesity/metabolism/*physiopathology ; Plant Lectins/pharmacology ; Staurosporine/pharmacology ; Stem Cells/*physiology ; Telomere ; Vascular Endothelial Growth Factor A/metabolism ; },
abstract = {Excess adiposity is associated with increased cardiovascular morbidity and mortality. Endothelial progenitor cells (EPCs) play an important role in vascular repair. We tested the hypothesis that increased adiposity is associated with EPC dysfunction, characterized by diminished capacity to release angiogenic cytokines, increased apoptotic susceptibility, reduced cell migration, and shorter telomere length. A total of 67 middle-aged and older adults (42-67 years) were studied: 25 normal weight (normal weight; BMI: 18.5-24.9 kg/m(2)) and 42 overweight/obese (overweight/obese; BMI: 25.0-34.9 kg/m(2)). Cells with phenotypic EPC characteristics were isolated from peripheral blood. EPC release of vascular endothelial growth factor (VEGF) and granulocyte colony-stimulating factor (G-CSF) was determined in the absence and presence of phytohemagglutinin (10 microg/ml). Intracellular active caspase-3 and cytochrome c concentrations were determined by immunoassay. Migratory activity of EPCs in response to VEGF (2 ng/ml) and stromal cell-derived factor-1alpha (SDF-1alpha; 10 ng/ml) was determined by Boyden chamber. Telomere length was assessed by Southern hybridization. Phytohemagglutinin-stimulated release of VEGF (90.6 +/- 7.6 vs. 127.2 +/- 11.6 pg/ml) and G-CSF (896.1 +/- 77.4 vs. 1,176.3 +/- 126.3 pg/ml) was ~25% lower (P < 0.05) in EPCs from overweight/obese vs. normal weight subjects. Staurosporine induced a ~30% greater (P < 0.05) increase in active caspase-3 in EPCs from overweight/obese (2.8 +/- 0.2 ng/ml) compared with normal weight (2.2 +/- 0.2) subjects. There were no significant differences in EPC migration to either VEGF or SDF-1alpha. Telomere length did not differ between groups. These results indicate that increased adiposity adversely affects the ability of EPCs to release proangiogenic cytokines and resist apoptosis, potentially compromising their reparative potential.},
}
@article {pmid20057353,
year = {2010},
author = {Gao, G and Walser, JC and Beaucher, ML and Morciano, P and Wesolowska, N and Chen, J and Rong, YS},
title = {HipHop interacts with HOAP and HP1 to protect Drosophila telomeres in a sequence-independent manner.},
journal = {The EMBO journal},
volume = {29},
number = {4},
pages = {819-829},
pmid = {20057353},
issn = {1460-2075},
support = {//Intramural NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; Cell Line ; Chromosomal Proteins, Non-Histone/chemistry/*genetics/*metabolism ; Drosophila/*genetics/*metabolism ; Drosophila Proteins/chemistry/*genetics/*metabolism ; Drosophila melanogaster/genetics/metabolism ; Evolution, Molecular ; Genes, Insect ; Multiprotein Complexes ; Mutation ; Protein Structure, Tertiary ; Protein Subunits ; RNA Interference ; Telomere/*genetics/*metabolism ; },
abstract = {Telomeres prevent chromosome ends from being repaired as double-strand breaks (DSBs). Telomere identity in Drosophila is determined epigenetically with no sequence either necessary or sufficient. To better understand this sequence-independent capping mechanism, we isolated proteins that interact with the HP1/ORC-associated protein (HOAP) capping protein, and identified HipHop as a subunit of the complex. Loss of one protein destabilizes the other and renders telomeres susceptible to fusion. Both HipHop and HOAP are enriched at telomeres, where they also interact with the conserved HP1 protein. We developed a model telomere lacking repetitive sequences to study the distribution of HipHop, HOAP and HP1 using chromatin immunoprecipitation (ChIP). We discovered that they occupy a broad region >10 kb from the chromosome end and their binding is independent of the underlying DNA sequence. HipHop and HOAP are both rapidly evolving proteins yet their telomeric deposition is under the control of the conserved ATM and Mre11-Rad50-Nbs (MRN) proteins that modulate DNA structures at telomeres and at DSBs. Our characterization of HipHop and HOAP reveals functional analogies between the Drosophila proteins and subunits of the yeast and mammalian capping complexes, implicating conservation in epigenetic capping mechanisms.},
}
@article {pmid20057153,
year = {2010},
author = {Ueno, M},
title = {Roles of DNA repair proteins in telomere maintenance.},
journal = {Bioscience, biotechnology, and biochemistry},
volume = {74},
number = {1},
pages = {1-6},
doi = {10.1271/bbb.90682},
pmid = {20057153},
issn = {1347-6947},
mesh = {Animals ; *DNA Repair ; Humans ; Proteins/*metabolism ; RecQ Helicases/metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {Telomeres are protected and maintained by telomere-specific proteins. In addition, proteins involved in DNA repair, such as Mre11-Rad50-Nbs1 complex, RPA, and RecQ helicase, are also involved in telomere maintenance. In this review, the roles of these proteins in telomere maintenance and their functional relationships to the telomere-specific proteins will be discussed.},
}
@article {pmid20057141,
year = {2010},
author = {Matsui, A and Matsuura, A},
title = {Cell size regulation during telomere-directed senescence in Saccharomyces cerevisiae.},
journal = {Bioscience, biotechnology, and biochemistry},
volume = {74},
number = {1},
pages = {195-198},
doi = {10.1271/bbb.90627},
pmid = {20057141},
issn = {1347-6947},
mesh = {Gene Deletion ; Intracellular Signaling Peptides and Proteins/deficiency/genetics/metabolism ; Protein Serine-Threonine Kinases/deficiency/genetics/metabolism ; Qa-SNARE Proteins/genetics/metabolism ; Saccharomyces cerevisiae/*cytology/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {DNA replication without telomerase leads to telomere shortening and induces replicative senescence. We found that in a telomerase-deficient budding yeast mutant, the volume of each telomere-shortened cell increased as its growth capacity decreased, and that this process was associated with changes in vacuolar morphology. Senescence-induced cell expansion required Mec1, a DNA damage-responsive kinase, but not vacuolar SNARE Vam3.},
}
@article {pmid20056655,
year = {2010},
author = {Pisano, S and Leoni, D and Galati, A and Rhodes, D and Savino, M and Cacchione, S},
title = {The human telomeric protein hTRF1 induces telomere-specific nucleosome mobility.},
journal = {Nucleic acids research},
volume = {38},
number = {7},
pages = {2247-2255},
pmid = {20056655},
issn = {1362-4962},
support = {MC_U105184333/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Base Sequence ; DNA/chemistry/metabolism/ultrastructure ; Humans ; Microscopy, Atomic Force ; Nucleosomes/*metabolism ; Telomere/*chemistry ; Telomeric Repeat Binding Protein 1/*metabolism ; },
abstract = {Human telomeres consist of thousands of base pairs of double-stranded TTAGGG repeats, organized by histone proteins into tightly spaced nucleosomes. The double-stranded telomeric repeats are also specifically bound by the telomeric proteins hTRF1 and hTRF2, which are essential for telomere length maintenance and for chromosome protection. An unresolved question is what role nucleosomes play in telomere structure and dynamics and how they interact and/or compete with hTRF proteins. Here we show that hTRF1 specifically induces mobility of telomeric nucleosomes. Moreover, Atomic Force Microscopy (AFM) imaging shows that hTRF1 induces compaction of telomeric DNA only in the presence of a nucleosome, suggesting that this compaction occurs through hTRF1-nucleosome interactions. Our findings reveal an unknown property of hTRF1 that has implications for understanding telomere structure and dynamics.},
}
@article {pmid20056641,
year = {2010},
author = {Shen, J and Gammon, MD and Wu, HC and Terry, MB and Wang, Q and Bradshaw, PT and Teitelbaum, SL and Neugut, AI and Santella, RM},
title = {Multiple genetic variants in telomere pathway genes and breast cancer risk.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {19},
number = {1},
pages = {219-228},
pmid = {20056641},
issn = {1538-7755},
support = {P30 ES010126/ES/NIEHS NIH HHS/United States ; R03 CA125768-02/CA/NCI NIH HHS/United States ; P30 ES009089-11/ES/NIEHS NIH HHS/United States ; U01 CA066572/CA/NCI NIH HHS/United States ; U01 CA066572-08/CA/NCI NIH HHS/United States ; U01CA/ES66572/CA/NCI NIH HHS/United States ; R03CA125768/CA/NCI NIH HHS/United States ; P30ES10126/ES/NIEHS NIH HHS/United States ; R03 CA125768/CA/NCI NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; P30 ES010126-09S19009/ES/NIEHS NIH HHS/United States ; P30ES009089/ES/NIEHS NIH HHS/United States ; },
mesh = {Biomarkers, Tumor/genetics ; Breast Neoplasms/*genetics ; Case-Control Studies ; Female ; *Genetic Predisposition to Disease ; Humans ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; Risk Factors ; Shelterin Complex ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; },
abstract = {PURPOSE: To explore the etiologic role of genetic variants in telomere pathway genes and breast cancer risk.<br><br>METHODS: A population-based case-control study, the Long Island Breast Cancer Study Project, was conducted, and 1,067 cases and 1,110 controls were included in the present study. Fifty-two genetic variants of nine telomere-related genes were genotyped.<br><br>RESULTS: Seven single nucleotide polymorphisms (SNP) showed significant case-control differences at the level of P < 0.05. The top three statistically significant SNPs under a dominant model were TERT-07 (rs2736109), TERT-54 (rs3816659), and POT1-03 (rs33964002). The odds ratios (OR) were 1.56 [95% confidence interval (95% CI), 1.22-1.99] for the TERT-07 G-allele, 1.27 (95% CI, 1.05-1.52) for the TERT-54 T-allele, and 0.79 (95% CI, 0.67-0.95) for the POT1-03 A-allele. TERT-67 (rs2853669) was statistically significant under a recessive model; the OR of the CC genotype was 0.69 (95% CI, 0.69-0.93) compared with the T-allele. However, none of the SNPs retained significance after Bonferroni adjustment for multiple testing at the level of P < 0.001 (0.05/52) except for TERT-07. When restricted to Caucasians (94% of the study subjects), a stronger association for the TERT-07 G-allele was observed with an OR of 1.60 (95% CI, 1.24-2.05; P = 0.0002). No effect modifications were found for variant alleles and menopausal status, telomere length, cigarette smoking, body mass index status, and family history of breast cancer risk.<br><br>CONCLUSIONS: Four SNPs in the TERT and POT1 genes were significantly related with overall breast cancer risk. This initial analysis provides valuable clues for further exploration of the biological role of telomere pathway genes in breast cancer.},
}
@article {pmid20047960,
year = {2010},
author = {Lee, J and Mandell, EK and Rao, T and Wuttke, DS and Lundblad, V},
title = {Investigating the role of the Est3 protein in yeast telomere replication.},
journal = {Nucleic acids research},
volume = {38},
number = {7},
pages = {2279-2290},
pmid = {20047960},
issn = {1362-4962},
support = {R37 AG011728/AG/NIA NIH HHS/United States ; T32 GM008759/GM/NIGMS NIH HHS/United States ; R01 GM059414/GM/NIGMS NIH HHS/United States ; T32 GM142607/GM/NIGMS NIH HHS/United States ; T32 GM08759/GM/NIGMS NIH HHS/United States ; AG11728/AG/NIA NIH HHS/United States ; },
mesh = {DNA, Single-Stranded/metabolism ; Fungal Proteins/genetics/metabolism/*physiology ; Gene Deletion ; Protein Subunits/genetics/metabolism/physiology ; Saccharomyces/*enzymology/genetics ; Telomerase/genetics/metabolism/*physiology ; Telomere/*metabolism ; },
abstract = {The Est3 subunit of yeast telomerase, which adopts a predicted OB-fold, is essential for telomere replication. To assess the possible contributions that Est3 might make to enzyme catalysis, we compared telomerase activity from wild type and est3-Delta strains of Saccharomyces castellii, which revealed that loss of the Est3 subunit results in a 2- to 3-fold decline in nucleotide addition. This effect was not primer-specific, based on assessment of a panel of primers that spanned the template of the S. castellii telomerase RNA. Furthermore, using nuclear magnetic resonance chemical shift perturbation, no chemical shift change was observed at any site in the protein upon addition of single-stranded DNA, arguing against a role for Est3 in recognition of telomeric substrates by telomerase. Addition of exogenous Est3 protein, including mutant Est3 proteins that are severely impaired for telomere replication in vivo, fully restored activity in est3-Delta telomerase reactions. Thus, Est3 performs an in vivo regulatory function in telomere replication, which is distinct from any potential contribution that Est3 might make to telomerase activity.},
}
@article {pmid20047894,
year = {2010},
author = {Weissmann, G},
title = {Radium, telomeres, and ribosomes: glass ceilings break in Stockholm.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {24},
number = {1},
pages = {1-5},
doi = {10.1096/fj.10-0101ufm},
pmid = {20047894},
issn = {1530-6860},
mesh = {History, 20th Century ; History, 21st Century ; *Nobel Prize ; Radium/history ; Research/history ; Ribosomes ; Sweden ; Telomere ; *Women's Rights ; },
}
@article {pmid20044353,
year = {2010},
author = {Xie, M and Podlevsky, JD and Qi, X and Bley, CJ and Chen, JJ},
title = {A novel motif in telomerase reverse transcriptase regulates telomere repeat addition rate and processivity.},
journal = {Nucleic acids research},
volume = {38},
number = {6},
pages = {1982-1996},
pmid = {20044353},
issn = {1362-4962},
mesh = {Amino Acid Motifs ; Amino Acid Sequence ; Conserved Sequence ; DNA Primers ; Humans ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Repetitive Sequences, Nucleic Acid ; Sequence Homology, Amino Acid ; Telomerase/*chemistry/genetics/metabolism ; Telomere/chemistry/*metabolism ; },
abstract = {Telomerase is a specialized reverse transcriptase that adds telomeric DNA repeats onto chromosome termini. Here, we characterize a new telomerase-specific motif, called motif 3, in the catalytic domain of telomerase reverse transcriptase, that is crucial for telomerase function and evolutionally conserved between vertebrates and ciliates. Comprehensive mutagenesis of motif 3 identified mutations that remarkably increase the rate or alter the processivity of telomere repeat addition. Notably, the rate and processivity of repeat addition are affected independently by separate motif 3 mutations. The processive telomerase action relies upon a template translocation mechanism whereby the RNA template and the telomeric DNA strand separate and realign between each repeat synthesis. By analyzing the mutant telomerases reconstituted in vitro and in cells, we show that the hyperactive mutants exhibit higher repeat addition rates and faster enzyme turnovers, suggesting higher rates of strand-separation during template translocation. In addition, the strong correlation between the processivity of the motif 3 mutants and their ability to use an 8 nt DNA primer, suggests that motif 3 facilitates realignment between the telomeric DNA and the template RNA following strand-separation. These findings support motif 3 as a key determinant for telomerase activity and processivity.},
}
@article {pmid20042385,
year = {2009},
author = {Wu, XM and Tang, WR and Luo, Y},
title = {[ALT--alternative lengthening of telomere].},
journal = {Yi chuan = Hereditas},
volume = {31},
number = {12},
pages = {1185-1191},
pmid = {20042385},
issn = {0253-9772},
mesh = {Animals ; Humans ; Leukemia, Promyelocytic, Acute/genetics/metabolism ; Recombination, Genetic ; Telomerase/genetics/metabolism ; Telomere/*chemistry/genetics/*metabolism ; },
abstract = {The maintenance of the length and normal structure of telomeres is highly related to the development of senescence and tumorigenesis. The mechanisms of maintaining telomere are essential for cell growth and the reactivation of these mechanisms is an important step in tumor progression. The mechanism of telomere maintenance might be the reactivation of telomerase. In the case of telomerase deficiency, the mechanisms for maintaining the lengths of telomeres are referred to as alternative lengthening of telomere (ALT). The characteristics of the ALT cells include great heterogeneity of telomere size in individual cells, ALT-associated PML (promyelocytic leukemia) bodies, and evident homologous recombination. The ALT-related proteins and elevated homologous recombination found in ALT cells provide a possible mechanism for the alternative lengthening of telomere. The study of ALT provides a new view of crosstalk between senescence and tumorigenesis.},
}
@article {pmid20040595,
year = {2010},
author = {Khair, L and Subramanian, L and Moser, BA and Nakamura, TM},
title = {Roles of heterochromatin and telomere proteins in regulation of fission yeast telomere recombination and telomerase recruitment.},
journal = {The Journal of biological chemistry},
volume = {285},
number = {8},
pages = {5327-5337},
pmid = {20040595},
issn = {1083-351X},
support = {R01 GM078253/GM/NIGMS NIH HHS/United States ; R01 GM078253-04/GM/NIGMS NIH HHS/United States ; GM078253/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Motifs/physiology ; Amino Acid Sequence ; Cell Cycle Proteins/genetics/metabolism ; Checkpoint Kinase 2 ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; Chromosomes, Fungal/genetics/*metabolism ; Gene Deletion ; Heterochromatin/genetics/*metabolism ; Histone-Lysine N-Methyltransferase ; Methyltransferases/genetics/metabolism ; Protein Kinases/genetics/metabolism ; Recombination, Genetic/*physiology ; Schizosaccharomyces/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/metabolism ; Sequence Deletion ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {When the telomerase catalytic subunit (Trt1/TERT) is deleted, a majority of fission yeast cells survives by circularizing chromosomes. Alternatively, a small minority survives by maintaining telomeric repeats through recombination among telomeres. The recombination-based telomere maintenance in trt1Delta cells is inhibited by the telomere protein Taz1. In addition, catalytically inactive full-length Trt1 (Trt1-CI) and truncated Trt1 lacking the T-motif and reverse transcriptase (RT) domain (Trt1-DeltaT/RT) can strongly inhibit recombination-based survival. Here, we investigated the effects of deleting the heterochromatin proteins Swi6 (HP1 ortholog) and Clr4 (Suv39 family of histone methyltransferases) and the telomere capping complex subunits Poz1 and Ccq1 on Taz1- and Trt1-dependent telomere recombination inhibition. The ability of Taz1 to inhibit telomere recombination did not require Swi6, Clr4, Poz1, or Ccq1. Although Swi6, Clr4, and Poz1 were dispensable for the inhibition of telomere recombination by Trt1-CI, Ccq1 was required for efficient telomere recruitment of Trt1 and Trt1-CI-dependent inhibition of telomere recombination. We also found that Swi6, Clr4, Ccq1, the checkpoint kinase Rad3 (ATR ortholog), and the telomerase regulatory subunit Est1 are all required for Trt1-DeltaT/RT to inhibit telomere recombination. However, because loss of Swi6, Clr4, Rad3, Ccq1, or Est1 did not significantly alter the recruitment efficiency of Trt1-DeltaT/RT to telomeres, these factors are likely to enhance the ability of Trt1-DeltaT/RT to inhibit recombination-based survival by contributing to the negative regulation of telomere recombination.},
}
@article {pmid20037654,
year = {2009},
author = {Das, B and Saini, D and Seshadri, M},
title = {Telomere length in human adults and high level natural background radiation.},
journal = {PloS one},
volume = {4},
number = {12},
pages = {e8440},
pmid = {20037654},
issn = {1932-6203},
mesh = {Adolescent ; Adult ; Age Distribution ; *Background Radiation ; Child ; Confidence Intervals ; Dose-Response Relationship, Radiation ; Female ; Humans ; Male ; Odds Ratio ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Telomere length is considered as a biomarker of aging, stress, cancer. It has been associated with many chronic diseases such as hypertension and diabetes. Although, telomere shortening due to ionizing radiation has been reported in vitro, no in vivo data is available on natural background radiation and its effect on telomere length.<br><br>The present investigation is an attempt to determine the telomere length among human adults residing in high level natural radiation areas (HLNRA) and the adjacent normal level radiation areas (NLNRA) of Kerala coast in Southwest India. Genomic DNA was isolated from the peripheral blood mononuclear cells of 310 individuals (HLNRA: N = 233 and NLNRA: N = 77). Telomere length was determined using real time q-PCR. Both telomere (T) and single copy gene (S) specific primers were used to calculate the relative T/S and expressed as the relative telomere length. The telomere length was determined to be 1.22+/-0.15, 1.12+/-0.15, 1.08+/-0.08, 1.12+/-0.11, respectively, among the four dose groups (</=1.50, 1.51-3.00, 3.01-5.00 and >5.00 mGy per year), which did not show any dose response. The results suggested that the high level natural chronic radiation did not have significant effect on telomere length among young adult population living in HLNRA, which is indicative of better repair of telomeric ends. No significant difference in telomere length was observed between male and female individuals. In the present investigation, although the determination of telomere length was studied among the adults with an age group between 18 to 40 years (mean maternal age: 26.10+/-4.49), a negative correlation was observed with respect to age. However, inter-individual variation was (0.81-1.68) was clearly observed.<br><br>CONCLUSIONS/SIGNIFICANCE: In this preliminary investigation, we conclude that elevated level of natural background radiation has no significant effect on telomere length among the adult population residing in HLNRAs of Kerala coast. To our knowledge, this is the first report from HLNRAs of the world where telomere length was determined on human adults. However, more samples from each background dose group and samples from older population need to be studied to derive firm conclusions.},
}
@article {pmid20036804,
year = {2010},
author = {Huzen, J and de Boer, RA and van Veldhuisen, DJ and van Gilst, WH and van der Harst, P},
title = {The emerging role of telomere biology in cardiovascular disease.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {15},
number = {1},
pages = {35-45},
doi = {10.2741/3604},
pmid = {20036804},
issn = {2768-6698},
mesh = {Aging/*physiology ; Animals ; Cardiovascular Diseases/drug therapy/*genetics/physiopathology ; DNA Repair/drug effects ; Exercise/physiology ; Humans ; Models, Biological ; Telomere/drug effects/*genetics ; },
abstract = {A striking variability exists in the susceptibility, age of onset and pace of progression of cardiovascular diseases. This is inadequately explained by the presence or absence of conventional risk factors. Differences in biological aging might provide an additional component of the observed variability. Telomere length provides a potential marker of an individual's biological age, shorter telomeres reflect a more advanced biological age. Telomere length at birth is mainly determined by genetic factors. Telomere attrition occurs as a consequence of cellular replication and can be accelerated by harmful environmental factors such as oxidative stress. When telomeres reach a critical threshold the cell will enter senescence and becomes dysfunctional. Telomeres are remarkably shorter in patients with aging associated diseases, including coronary artery disease and chronic heart failure. In addition, numerous conventional cardiovascular risk factors are associated with shorter telomere length. If telomeres can be proven to be not only associated but also causally involved in the pathogenesis of cardiovascular disease it might provide exciting new avenues for the development of future preventive and therapeutic strategies.},
}
@article {pmid20031273,
year = {2011},
author = {Yaffe, K and Lindquist, K and Kluse, M and Cawthon, R and Harris, T and Hsueh, WC and Simonsick, EM and Kuller, L and Li, R and Ayonayon, HN and Rubin, SM and Cummings, SR and , },
title = {Telomere length and cognitive function in community-dwelling elders: findings from the Health ABC Study.},
journal = {Neurobiology of aging},
volume = {32},
number = {11},
pages = {2055-2060},
pmid = {20031273},
issn = {1558-1497},
support = {N01 AG062101/AG/NIA NIH HHS/United States ; AG-6-2101/AG/NIA NIH HHS/United States ; AG-6-2103/AG/NIA NIH HHS/United States ; N01 AG062106/AG/NIA NIH HHS/United States ; AG031155/AG/NIA NIH HHS/United States ; K24 AG031155/AG/NIA NIH HHS/United States ; N01 AG062103/AG/NIA NIH HHS/United States ; AG-6-2106/AG/NIA NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; R01 AG021918/AG/NIA NIH HHS/United States ; R01 AG021918-04/AG/NIA NIH HHS/United States ; AG021918/AG/NIA NIH HHS/United States ; K24 AG031155-03/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/genetics/*physiology/psychology ; Cognition/*physiology ; Cognition Disorders/diagnosis/*genetics ; Female ; Follow-Up Studies ; Humans ; Male ; Neuropsychological Tests ; Prospective Studies ; *Telomere ; *Telomere Shortening ; },
abstract = {Telomere shortening is a marker of cellular aging and has been associated with risk of Alzheimer's disease. Few studies have determined if telomere length is associated with cognitive decline in non-demented elders. We prospectively studied 2734 non-demented elders (mean age: 74 years). We measured cognition with the Modified Mini-Mental State Exam (3MS) and Digit Symbol Substitution Test (DSST) repeatedly over 7 years. Baseline telomere length was measured in blood leukocytes and classified by tertile as "short", "medium", or "long". At baseline, longer telomere length was associated with better DSST score (36.4, 34.9 and 34.4 points for long, medium and short, p<0.01) but not for change in score. However, 7-year 3MS change scores were less among those with longer telomere length (-1.7 points vs. -2.5 and -2.9, p=0.01). Findings were similar after multivariable adjustment for age, gender, race, education, assay batch, and baseline score. There was a borderline statistically significant interaction for telomere length and APOE e4 on 3MS change score (p=0.06). Thus, telomere length may serve as a biomarker for cognitive aging.},
}
@article {pmid20030916,
year = {2009},
author = {Ma, L and Wang, J and Jiang, B and Liu, YR and Zhang, B and Chang, NB and Ke, XY},
title = {[Telomere length and telomerase expression activity in mononuclear cells of patients with chronic lymphocytic leukemia].},
journal = {Zhongguo shi yan xue ye xue za zhi},
volume = {17},
number = {6},
pages = {1409-1412},
pmid = {20030916},
issn = {1009-2137},
mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*metabolism/pathology ; Male ; Middle Aged ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {This study was aimed to detect the telomere length and the telomerase expression activity in patients with chronic lymphocytic leukemia (CLL), and investigate their relation to prognosis of CLL. The telomere length and the telomerase expression activity of peripheral blood and / or bone marrow mononuclear cells were examined by Tel-FISH, a semi-quantitative method and by TRAP-ELISA respectively; the expressions of ZAP70 and CD38 were detected by flow cytometry. The results showed that comparing the telomere length in different stages, there was a tendency that the telomere became prolonged when the stage raised up. There was statistical significant difference between Rai stages III-IV and stage 0, Rai stages III-IV and stages I-II, Binet stage C and stage A, Binet stage C and stage B; while no statistical significant difference existed between Rai stage 0 and stages I-II, Binet stage A and stage B. The telomere length in ZAP70 negative group was found similar as in ZAP70 positive group. The telomere length in CD38 positive group was shorter than that in CD38 negative group, but there was no statistical difference between them. Comparing the telomerase expression activity between different stages, there was a tendency that it increased when the stages went up; comparing the telomerase expression activity at different Rai stages, it increased at the higher stages. One case of CLL demonstrated that telomerase expression did not show at remission stage, but was found at relapse stage, which suggested that telomerase expression may relate to prognosis of disease. It is concluded that the telomerase length is in relation to Rai and Binet stage, which was shorter at higher stage than that at lower stage and intermediate stage. It seemed that the telomerase expression activity increased at higher stages. The expression of telomerase in mononuclear cells is stable and not influenced by treatment.},
}
@article {pmid20026586,
year = {2010},
author = {Letsolo, BT and Rowson, J and Baird, DM},
title = {Fusion of short telomeres in human cells is characterized by extensive deletion and microhomology, and can result in complex rearrangements.},
journal = {Nucleic acids research},
volume = {38},
number = {6},
pages = {1841-1852},
pmid = {20026586},
issn = {1362-4962},
support = {C1799/A5603//Cancer Research UK/United Kingdom ; C1799/A6932//Cancer Research UK/United Kingdom ; },
mesh = {Base Sequence ; Cell Line ; DNA/chemistry ; Humans ; Molecular Sequence Data ; Mutation ; Repetitive Sequences, Nucleic Acid ; Sequence Analysis, DNA ; *Sequence Deletion ; Sequence Homology, Nucleic Acid ; Telomere/*chemistry ; },
abstract = {Telomere fusion is an important mutational event that has the potential to lead to large-scale genomic rearrangements of the types frequently observed in cancer. We have developed single-molecule approaches to detect, isolate and characterize the DNA sequence of telomere fusion events in human cells. Using these assays, we have detected complex fusion events that include fusion with interstitial loci adjacent to fragile sites, intra-molecular rearrangements, and fusion events involving the telomeres of both arms of the same chromosome consistent with ring chromosome formation. All fusion events were characterized by the deletion of at least one of the telomeres extending into the sub-telomeric DNA up to 5.6 kb; close to the limit of our assays. The deletion profile indicates that deletion may extend further into the chromosome. Short patches of DNA sequence homology with a G:C bias were observed at the fusion point in 60% of events. The distinct profile that accompanies telomere fusion may be a characteristic of the end-joining processes involved in the fusion event.},
}
@article {pmid20022886,
year = {2010},
author = {Rhee, DB and Wang, Y and Mizesko, M and Zhou, F and Haneline, L and Liu, Y},
title = {FANCC suppresses short telomere-initiated telomere sister chromatid exchange.},
journal = {Human molecular genetics},
volume = {19},
number = {5},
pages = {879-887},
pmid = {20022886},
issn = {1460-2083},
support = {P30 CA82709/CA/NCI NIH HHS/United States ; R01 HL077175/HL/NHLBI NIH HHS/United States ; T32 DK07519/DK/NIDDK NIH HHS/United States ; //Intramural NIH HHS/United States ; },
mesh = {Animals ; Bone Marrow Cells/metabolism ; Fanconi Anemia/genetics ; Fanconi Anemia Complementation Group C Protein/*genetics/metabolism ; Mice ; Mice, Knockout ; Sister Chromatid Exchange/*genetics ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Telomere shortening has been linked to rare human disorders that present with bone marrow failure including Fanconi anemia (FA). FANCC is one of the most commonly mutated FA genes in FA patients and the FANCC subtype tends to have a relatively early onset of bone marrow failure and hematologic malignancies. Here, we studied the role of Fancc in telomere length regulation in mice. Deletion of Fancc (Fancc(-/-)) did not affect telomerase activity, telomere length or telomeric end-capping in a mouse strain possessing intrinsically long telomeres. However, ablation of Fancc did exacerbate telomere attrition when murine bone marrow cells experienced high cell turnover after serial transplantation. When Fancc(-/-) mice were crossed into a telomerase reverse transcriptase heterozygous or null background (Tert(+/-) or Tert(-/-)) with short telomeres, Fancc deficiency led to an increase in the incidence of telomere sister chromatid exchange. In contrast, these phenotypes were not observed in Tert mutant mice with long telomeres. Our data indicate that Fancc deficiency accelerates telomere shortening during high turnover of hematopoietic cells and promotes telomere recombination initiated by short telomeres.},
}
@article {pmid20021886,
year = {2009},
author = {Wang, JJ and Li, SW and Wang, YQ and Wang, Y and Zhong, WX and Zang, XJ},
title = {[Correlations of telomere length changing and pathogeny of keratoconus].},
journal = {[Zhonghua yan ke za zhi] Chinese journal of ophthalmology},
volume = {45},
number = {8},
pages = {724-729},
pmid = {20021886},
issn = {0412-4081},
mesh = {Adolescent ; Adult ; Aging ; Calcium-Binding Proteins/metabolism ; Child ; Corneal Stroma/*metabolism/pathology ; Female ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Keratoconus/*metabolism/pathology ; Male ; Telomere/genetics/*metabolism/pathology ; Young Adult ; beta-Galactosidase/metabolism ; },
abstract = {OBJECTIVE: To study telomere length, senescence-associated-beta-galactosidase (SA-beta-galactosidase) and senescence marker protein-30 (SMP-30) in the stromal cells of keratoconus or normal corneas respectively, aiming finding the association of these indexes with the phenotype of keratoconus.<br><br>METHODS: Experiment research. 37 keratoconus lesions corneas were removed from 32 keratoconus patients who were operated in Shangdong Eye Institute between January 2006 and December 2006, and 20 normal corneas were collected from eye bank. The keratoconus corneas ages were from 13 to 34 years [mean ages (19 + or - 5) years] and the control group consists of 20 normal corneas donor ages from 9 to 30 years [mean ages (19 + or - 4) years]. And there was no statistical difference of ages between keratoconus and normal corneas. Southern blot method was utilized to detect telomere length of genomic DNA. SA-beta-galactosidase was detected by 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-Gal) staining method respectively in keratoconus and normal corneas. Isolated mRNA from keratoconus and normal corneas were reverse-transcribed to cDNA and SMP-30 was detected using PCR with specific primers (sense: 5' ccg tgg atg cct ttg act at 3'; anti-sense: 5' caa ctt cat gc tgct ttg ga 3'). To compare normal corneas and keratoconus corneas by histopathological study. Statistical analysis by t test.<br><br>RESULTS: The telomere length in stromal cells in keratoconus corneas were from 10.29 to 14.12 kb, mean (11.54 + or - 1.41) kb, while that of normal corneas were from 12.64 to 15.32 kb, mean (13.45 + or - 0.99) kb. The difference of telomere length in stromal cells of keratoconus and normal corneas reached a statistical significant level (t = 4.753, P < 0.05). That means the telomere length of keratoconus stroma was shorter than that of normal corneal stroma. Light microscopy revealed that collagen fibers in keratoconus corneal stroma were arranged in an irregular manner. Cells density in keratoconus stroma appeared lower than in normal ones but the decrease was not significant. The staining of SA-beta-galactosidase in the keratoconus section was evident, but there was no staining in the normal corneas. SMP-30 was not detectable with RT-PCR method in either keratoconus or normal corneas.<br><br>CONCLUSION: Telomeres in the keratoconus stromas manifest higher SA-beta-galactosidase than control, implying that improper senescence might be involved in pathogenesis of keratoconus.},
}
@article {pmid20018194,
year = {2010},
author = {Olofsson, P and Bertuch, AA},
title = {Modeling growth and telomere dynamics in Saccharomyces cerevisiae.},
journal = {Journal of theoretical biology},
volume = {263},
number = {3},
pages = {353-359},
pmid = {20018194},
issn = {1095-8541},
support = {R01 GM077509/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle ; *Models, Theoretical ; Saccharomyces cerevisiae/cytology/*genetics/*growth &amp; development ; *Telomere ; },
abstract = {A general branching process is proposed to model a population of cells of the yeast Saccharomyces cerevisiae following loss of telomerase. Previously published experimental data indicate that a population of telomerase-deficient cells regain exponential growth after a period of slowing due to critical telomere shortening. The explanation for this phenomenon is that some cells engage telomerase-independent pathways to maintain telomeres that allow them to become "survivors." Our model takes into account random variation in individual cell cycle times, telomere length, finite replicative lifespan of mother cells, and survivorship. We identify and estimate crucial parameters such as the probability of an individual cell becoming a survivor, and compare our model predictions to experimental data.},
}
@article {pmid20017721,
year = {2010},
author = {Shalaby, T and Hiyama, E and Grotzer, MA},
title = {Telomere maintenance as therapeutic target in embryonal tumours.},
journal = {Anti-cancer agents in medicinal chemistry},
volume = {10},
number = {3},
pages = {196-212},
doi = {10.2174/1871520611009030196},
pmid = {20017721},
issn = {1875-5992},
mesh = {Animals ; Antineoplastic Agents/*therapeutic use ; Child ; Embryo, Mammalian/enzymology ; G-Quadruplexes/drug effects ; Hepatoblastoma/genetics ; Humans ; Medulloblastoma/genetics ; Mice ; Neoplasms, Germ Cell and Embryonal/*drug therapy/physiopathology ; Neuroblastoma/genetics ; Rhabdomyosarcoma/genetics ; Sarcoma, Ewing/genetics ; Telomerase/antagonists &amp; inhibitors/genetics/*physiology ; Telomere/drug effects/*metabolism ; Wilms Tumor/genetics ; },
abstract = {Embryonal tumours most commonly occur in the first few years of life and account for approximately 30% of childhood malignancies. Knowledge of these tumours' genetics has already impacted on their clinical management and further knowledge of their cellular immortalization will hopefully result in novel therapies. The ends of human chromosomes are capped and protected by telomeres; cellular replication, however, causes their loss. A critical length of telomere repeats is required to ensure proper telomere function and avoid the activation of DNA damage pathways that result in senescence and cell death. To proliferate beyond the senescence checkpoint, cells must restore their telomere length. Hence stabilization of telomere is an important step in cell immortalization and carcinogenesis. Telomere maintenance is evident in virtually all types of malignant cells, including embryonal tumours, where either a telomerase-dependent or alternative lengthening of telomeres (ALT) mechanism is employed in order to ensure their limitless replicative potential. For this reason effective strategies targeting telomere maintenance in cancer cells require a combination of telomerase and ALT inhibitors. In this review, we are giving an overview about telomere maintenance in childhood tumours and discussing its potential as a new therapeutic target.},
}
@article {pmid20016274,
year = {2010},
author = {Deng, Z and Campbell, AE and Lieberman, PM},
title = {TERRA, CpG methylation and telomere heterochromatin: lessons from ICF syndrome cells.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {9},
number = {1},
pages = {69-74},
pmid = {20016274},
issn = {1551-4005},
support = {R01 CA093606/CA/NCI NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; CA CA093606/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Centromere/genetics/*metabolism ; CpG Islands/*genetics ; DNA Methylation/genetics/physiology ; Heterochromatin/genetics/*metabolism ; Humans ; Immunologic Deficiency Syndromes/genetics/*metabolism ; Models, Biological ; RNA, Untranslated/genetics/*metabolism ; Repetitive Sequences, Nucleic Acid/*genetics ; Telomere/genetics/*metabolism ; },
abstract = {Self-reinforcing negative feedback loops are commonly observed in biological systems. RNA-mediated negative feedback loops have been described in the formation of heterochromatin at centromeres in fission yeast and the inactive X chromosome in mammalian cells. The telomere repeat-containing RNA (TERRA) has also been implicated in the formation of telomeric heterochromatin through a self-reinforcing negative feedback loop. In cells derived from human ICF syndrome, TERRA levels are abnormally elevated and telomeres are abnormally shortened. We now show that telomere heterochromatin is also abnormal in ICF cells. We propose that ICF cells fail to reinforce the TERRA-dependent negative feedback loop as a result of the inability to establish heterochromatin at subtelomeres. This failure is likely due to the lack of DNMT3b and DNA methylation, which is a genetic lesion associated with ICF syndrome. Failure of this feedback mechanism leads to catastrophic telomere dysfunction and chromosome instability.},
}
@article {pmid20016137,
year = {2010},
author = {Andrews, NP and Fujii, H and Goronzy, JJ and Weyand, CM},
title = {Telomeres and immunological diseases of aging.},
journal = {Gerontology},
volume = {56},
number = {4},
pages = {390-403},
pmid = {20016137},
issn = {1423-0003},
support = {R01 AR41974/AR/NIAMS NIH HHS/United States ; R01 AI044142/AI/NIAID NIH HHS/United States ; R01 AR041974/AR/NIAMS NIH HHS/United States ; R01 EY11916/EY/NEI NIH HHS/United States ; R01 HL117913/HL/NHLBI NIH HHS/United States ; R01 AR42527/AR/NIAMS NIH HHS/United States ; R01 AI108906/AI/NIAID NIH HHS/United States ; R01 AI44142/AI/NIAID NIH HHS/United States ; R01 EY011916/EY/NEI NIH HHS/United States ; R01 AG015043/AG/NIA NIH HHS/United States ; U19 AI057266/AI/NIAID NIH HHS/United States ; R01 AR042527/AR/NIAMS NIH HHS/United States ; R56 AI044142/AI/NIAID NIH HHS/United States ; R01 AG15043/AG/NIA NIH HHS/United States ; U19 AI57266/AI/NIAID NIH HHS/United States ; },
mesh = {Aging/*genetics/*immunology/metabolism/pathology ; Aging, Premature/enzymology/genetics/immunology ; Animals ; Cellular Senescence ; Gene Expression Regulation, Enzymologic ; Humans ; Immune System Diseases/enzymology/*genetics/*immunology ; Inflammation/enzymology/genetics/immunology ; Models, Biological ; T-Lymphocytes/enzymology/immunology/pathology ; Telomerase/genetics/metabolism ; Telomere/enzymology/*genetics/*immunology ; },
abstract = {A defining feature of the eukaryotic genome is the presence of linear chromosomes. This arrangement, however, poses several challenges with regard to chromosomal replication and maintenance. To prevent the loss of coding sequences and to suppress gross chromosomal rearrangements, linear chromosomes are capped by repetitive nucleoprotein structures, called telomeres. Each cell division results in a progressive shortening of telomeres that, below a certain threshold, promotes genome instability, senescence, and apoptosis. Telomeric erosion, maintenance, and repair take center stage in determining cell fate. Cells of the immune system are under enormous proliferative demand, stressing telomeric intactness. Lymphocytes are capable of upregulating telomerase, an enzyme that can elongate telomeric sequences and, thus, prolong cellular lifespan. Therefore, telomere dynamics are critical in preserving immune function and have become a focus for studies of immunosenescence and autoimmunity. In this review, we describe the role of telomeric nucleoproteins in shaping telomere architecture and in suppressing DNA damage responses. We summarize new insights into the regulation of telomerase activity, hereditary disorders associated with telomere dysfunction, the role of telomere loss in immune aging, and the impact of telomere dysfunction in chronic inflammatory disease.},
}
@article {pmid20013183,
year = {2010},
author = {Balasubramanyam, M and Adaikalakoteswari, A and Sameermahmood, Z and Mohan, V},
title = {Biomarkers of oxidative stress: methods and measures of oxidative DNA damage (COMET assay) and telomere shortening.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {610},
number = {},
pages = {245-261},
doi = {10.1007/978-1-60327-029-8_15},
pmid = {20013183},
issn = {1940-6029},
mesh = {Biomarkers/*metabolism ; Blotting, Southern/methods ; Cells, Cultured ; Comet Assay/*methods ; *DNA Damage ; Humans ; Oxidation-Reduction ; *Oxidative Stress ; Reproducibility of Results ; Telomere/*metabolism ; },
abstract = {Oxidative stress is fast becoming the nutritional and medical buzzword for the twenty-first century. The theoretical importance of oxidative stress in diabetes is highlighted by its potential double impact on metabolic dysfunction on one hand and the vascular system on the other hand. The new concept of oxidative stress, being an important trigger in the onset and progression of diabetes and its complications, emphasizes the need for measurement of markers of oxidation to assess the degree of oxidative stress. While we have been routinely measuring biomarkers in our molecular epidemiology projects, here we discuss the utility of two assays, (a) DNA damage assessment by COMET measurement and (b) telomere length measurement. As DNA damage is efficiently repaired by cellular enzymes, its measurement gives a snapshot view of the level of oxidative stress. The protocol allows for measurement of oxidative DNA damage (FPG-sensitive DNA strand breaks). Telomere length measured by Southern blotting technique allows one to estimate the chronic burden of oxidative stress at the molecular level and is now considered as biomarker of biological aging.},
}
@article {pmid20011546,
year = {2009},
author = {Lin, YH and Chang, CC and Wong, CW and Teng, SC},
title = {Recruitment of Rad51 and Rad52 to short telomeres triggers a Mec1-mediated hypersensitivity to double-stranded DNA breaks in senescent budding yeast.},
journal = {PloS one},
volume = {4},
number = {12},
pages = {e8224},
pmid = {20011546},
issn = {1932-6203},
mesh = {Bleomycin/pharmacology ; Cell Cycle/drug effects ; *DNA Breaks, Double-Stranded/drug effects ; Endonucleases/metabolism ; Enzyme Activation/drug effects ; Genetic Complementation Test ; Intracellular Signaling Peptides and Proteins/*metabolism ; Mutation/genetics ; Phenotype ; Plasmids/genetics ; Protein Binding/drug effects ; Protein Serine-Threonine Kinases/*metabolism ; Protein Transport/drug effects ; Rad51 Recombinase/*metabolism ; Rad52 DNA Repair and Recombination Protein/*metabolism ; Saccharomyces cerevisiae/cytology/drug effects/*enzymology ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomerase/metabolism ; Telomere/*enzymology ; Time Factors ; },
abstract = {Telomere maintenance is required for chromosome stability, and telomeres are typically replicated by the action of telomerase. In both mammalian tumor and yeast cells that lack telomerase, telomeres are maintained by an alternative recombination mechanism. Here we demonstrated that the budding yeast Saccharomyces cerevisiae type I survivors derived from telomerase-deficient cells were hypersensitive to DNA damaging agents. Assays to track telomere lengths and drug sensitivity of telomerase-deficient cells from spore colonies to survivors suggested a correlation between telomere shortening and bleomycin sensitivity. Our genetic studies demonstrated that this sensitivity depends on Mec1, which signals checkpoint activation, leading to prolonged cell-cycle arrest in senescent budding yeasts. Moreover, we also observed that when cells equipped with short telomeres, recruitments of homologous recombination proteins, Rad51 and Rad52, were reduced at an HO-endonuclease-catalyzed double-strand break (DSB), while their associations were increased at chromosome ends. These results suggested that the sensitive phenotype may be attributed to the sequestration of repair proteins to compromised telomeres, thus limiting the repair capacity at bona fide DSB sites.},
}
@article {pmid20008939,
year = {2009},
author = {Arnoult, N and Saintome, C and Ourliac-Garnier, I and Riou, JF and Londoño-Vallejo, A},
title = {Human POT1 is required for efficient telomere C-rich strand replication in the absence of WRN.},
journal = {Genes &amp; development},
volume = {23},
number = {24},
pages = {2915-2924},
pmid = {20008939},
issn = {1549-5477},
mesh = {*Cytosine/chemistry ; DNA Replication/*genetics ; Exodeoxyribonucleases/deficiency/*genetics ; Guanine/chemistry ; Humans ; In Situ Hybridization, Fluorescence ; RecQ Helicases/deficiency/*genetics ; Shelterin Complex ; Telomere/*genetics ; Telomere-Binding Proteins/*metabolism ; Werner Syndrome Helicase ; },
abstract = {Mechanisms of telomere replication remain poorly defined. It has been suggested that G-rich telomeric strand replication by lagging mechanisms requires, in a stochastic way, the WRN protein. Here we show that this requirement is more systematic than previously thought. Our data are compatible with a situation in which, in the absence of WRN, DNA synthesis at replication forks is uncoupled, thus allowing replication to continue on the C strand, while single G strands accumulate. We also show that in cells in which both WRN and POT1 are limiting, both G- and C-rich telomeric strands shorten, suggesting a complete replication block. Under this particular condition, expression of a fragment spanning the two POT1-OB (oligonucleotide-binding) fold domains is able to restore C (but not G) strand replication, suggesting that binding of POT1 to the lagging strand allows DNA synthesis uncoupling in the absence of WRN. Furthermore, in vitro experiments indicate that purified POT1 has a higher affinity for the telomeric G-rich strand than purified RPA. We propose a model in which the relative enrichments of POT1 versus RPA on the telomeric lagging strand allows or does not allow uncoupling of DNA synthesis at the replication fork. Our study reveals an unanticipated role for hPOT1 during telomere replication.},
}
@article {pmid20008938,
year = {2009},
author = {Sun, J and Yu, EY and Yang, Y and Confer, LA and Sun, SH and Wan, K and Lue, NF and Lei, M},
title = {Stn1-Ten1 is an Rpa2-Rpa3-like complex at telomeres.},
journal = {Genes &amp; development},
volume = {23},
number = {24},
pages = {2900-2914},
pmid = {20008938},
issn = {1549-5477},
support = {GM 083015-01/GM/NIGMS NIH HHS/United States ; GM069507/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; R01 GM083015/GM/NIGMS NIH HHS/United States ; R01 GM069507/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Fungal Proteins/*chemistry ; *Models, Molecular ; Molecular Sequence Data ; Multiprotein Complexes/chemistry ; Protein Structure, Quaternary ; Sequence Alignment ; Telomere/*chemistry ; Yeasts/*genetics/metabolism ; },
abstract = {In budding yeast, Cdc13, Stn1, and Ten1 form a heterotrimeric complex (CST) that is essential for telomere protection and maintenance. Previous bioinformatics analysis revealed a putative oligonucleotide/oligosaccharide-binding (OB) fold at the N terminus of Stn1 (Stn1N) that shows limited sequence similarity to the OB fold of Rpa2, a subunit of the eukaryotic ssDNA-binding protein complex replication protein A (RPA). Here we present functional and structural analyses of Stn1 and Ten1 from multiple budding and fission yeast. The crystal structure of the Candida tropicalis Stn1N complexed with Ten1 demonstrates an Rpa2N-Rpa3-like complex. In both structures, the OB folds of the two components pack against each other through interactions between two C-terminal helices. The structure of the C-terminal domain of Saccharomyces cerevisiae Stn1 (Stn1C) was found to comprise two related winged helix-turn-helix (WH) motifs, one of which is most similar to the WH motif at the C terminus of Rpa2, again supporting the notion that Stn1 resembles Rpa2. The crystal structure of the fission yeast Schizosaccharomyces pombe Stn1N-Ten1 complex exhibits a virtually identical architecture as the C. tropicalis Stn1N-Ten1. Functional analyses of the Candida albicans Stn1 and Ten1 proteins revealed critical roles for these proteins in suppressing aberrant telomerase and recombination activities at telomeres. Mutations that disrupt the Stn1-Ten1 interaction induce telomere uncapping and abolish the telomere localization of Ten1. Collectively, our structural and functional studies illustrate that, instead of being confined to budding yeast telomeres, the CST complex may represent an evolutionarily conserved RPA-like telomeric complex at the 3' overhangs that works in parallel with or instead of the well-characterized POT1-TPP1/TEBPalpha-beta complex.},
}
@article {pmid20008550,
year = {2010},
author = {Yu, EY and Yen, WF and Steinberg-Neifach, O and Lue, NF},
title = {Rap1 in Candida albicans: an unusual structural organization and a critical function in suppressing telomere recombination.},
journal = {Molecular and cellular biology},
volume = {30},
number = {5},
pages = {1254-1268},
pmid = {20008550},
issn = {1098-5549},
support = {R01 GM069507/GM/NIGMS NIH HHS/United States ; GM-069507/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Base Sequence ; Binding Sites/genetics ; Candida albicans/*genetics/growth &amp; development/*metabolism ; DNA Primers/genetics ; DNA, Fungal/genetics/metabolism ; Evolution, Molecular ; Fungal Proteins/*chemistry/genetics/*metabolism ; Genes, Fungal ; Models, Biological ; Molecular Sequence Data ; Mutation ; Phenotype ; Protein Structure, Tertiary ; *Recombination, Genetic ; Saccharomyces cerevisiae Proteins/chemistry/genetics ; Sequence Homology, Amino Acid ; Sequence Homology, Nucleic Acid ; Shelterin Complex ; Species Specificity ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/*chemistry/genetics/*metabolism ; Transcription Factors/*chemistry/genetics/*metabolism ; },
abstract = {Rap1 (repressor activator protein 1) is a conserved multifunctional protein initially identified as a transcriptional regulator of ribosomal protein genes in Saccharomyces cerevisiae but subsequently shown to play diverse functions at multiple chromosomal loci, including telomeres. The function of Rap1 appears to be evolutionarily plastic, especially in the budding yeast lineages. We report here our biochemical and molecular genetic characterizations of Candida albicans Rap1, which exhibits an unusual, miniaturized domain organization in comparison to the S. cerevisiae homologue. We show that in contrast to S. cerevisiae, C. albicans RAP1 is not essential for cell viability but is critical for maintaining normal telomere length and structure. The rap1 null mutant exhibits drastic telomere-length dysregulation and accumulates high levels of telomere circles, which can be largely attributed to aberrant recombination activities at telomeres. Analysis of combination mutants indicates that Rap1 and other telomere proteins mediate overlapping but nonredundant roles in telomere protection. Consistent with the telomere phenotypes of the mutant, C. albicans Rap1 is localized to telomeres in vivo and recognizes the unusual telomere repeat unit with high affinity and sequence specificity in vitro. The DNA-binding Myb domain of C. albicans Rap1 is sufficient to suppress most of the telomere aberrations observed in the null mutant. Notably, we were unable to detect specific binding of C. albicans Rap1 to gene promoters in vivo or in vitro, suggesting that its functions are more circumscribed in this organism. Our findings provide insights on the evolution and mechanistic plasticity of a widely conserved and functionally critical telomere component.},
}
@article {pmid20008219,
year = {2009},
author = {Calado, RT},
title = {Telomeres and marrow failure.},
journal = {Hematology. American Society of Hematology. Education Program},
volume = {},
number = {},
pages = {338-343},
doi = {10.1182/asheducation-2009.1.338},
pmid = {20008219},
issn = {1520-4383},
mesh = {Acute Disease ; Anemia, Aplastic/diagnosis/genetics/pathology ; Bone Marrow Diseases/diagnosis/genetics/*pathology ; Cell Transformation, Neoplastic ; Cellular Senescence ; Chromosomal Instability ; Chromosome Aberrations ; Chromosomes, Human/*ultrastructure ; Dyskeratosis Congenita/diagnosis/genetics/pathology ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/diagnosis/genetics/pathology ; Leukemia, Myeloid/diagnosis/genetics/pathology ; Male ; Neoplasms/genetics/pathology ; Neoplastic Syndromes, Hereditary/diagnosis/genetics/pathology ; RNA/genetics/physiology ; Shelterin Complex ; Telomerase/genetics/physiology ; Telomere/drug effects/*ultrastructure ; Telomere-Binding Proteins/physiology ; },
abstract = {Telomeres, repeat sequences at the ends of chromosomes, are protective chromosomal structures highly conserved from primitive organisms to humans. Telomeres inevitably shorten with every cell cycle, and telomere attrition has been hypothesized to be fundamental to normal senescence of cells, tissues, and organisms. Molecular mechanisms have evolved to maintain their length and protective function; telomerase (TERT) is a reverse transcriptase enzyme that uses an RNA molecule (TERC) as the template to elongate the 3' ends of telomeres. Shelterin is a collection of DNA-binding proteins that cover and protect telomeres. The recent discovery of inherited mutations in genes that function to repair telomeres as etiologic in a range of human diseases, which have clinical manifestations in diverse tissues, including the hematopoietic tissue, suggests that defects in telomere repair and protection can cause organ failure. Dyskeratosis congenita is the prototype of telomere diseases; it is characterized by bone marrow failure, mucocutaneous abnormalities, pulmonary fibrosis, liver cirrhosis, and increased susceptibility to cancer, including acute myeloid leukemia. Aplastic anemia, acute myeloid leukemia, and idiopathic pulmonary fibrosis also are associated with inherited mutations in telomere repair or protection genes. Additionally, telomere defects associate with predisposition to hematologic malignancy and epithelial tumors. Telomere erosion is abnormally rapid in patients with mutations in telomerase genes but also after hematopoietic stem cell transplant, and telomeres are naturally shorter in older individuals-all conditions associated with higher rates of malignant diseases. In human tissue culture, short telomeres produce end-to-end chromosome fusion, nonreciprocal translocations, and aneuploidy.},
}
@article {pmid20007561,
year = {2009},
author = {Calado, RT and Young, NS},
title = {Telomere diseases.},
journal = {The New England journal of medicine},
volume = {361},
number = {24},
pages = {2353-2365},
pmid = {20007561},
issn = {1533-4406},
support = {Z99 HL999999/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Aging/genetics ; Anemia, Aplastic/genetics ; Animals ; Bone Marrow/pathology ; Cellular Senescence/genetics ; Dyskeratosis Congenita/genetics ; Heart Diseases/genetics ; Humans ; Liver Diseases/genetics/pathology ; Neoplasms/genetics ; Pulmonary Fibrosis/genetics/pathology ; Skin/pathology ; Telomerase/physiology ; Telomere/chemistry/*physiology ; },
}
@article {pmid20006006,
year = {2009},
author = {Onitake, Y and Hiyama, E and Kamei, N and Yamaoka, H and Sueda, T and Hiyama, K},
title = {Telomere biology in neuroblastoma: telomere binding proteins and alternative strengthening of telomeres.},
journal = {Journal of pediatric surgery},
volume = {44},
number = {12},
pages = {2258-2266},
doi = {10.1016/j.jpedsurg.2009.07.046},
pmid = {20006006},
issn = {1531-5037},
mesh = {Adolescent ; Adrenal Gland Neoplasms/genetics/metabolism/mortality ; Blotting, Southern/statistics &amp; numerical data ; Child ; Child, Preschool ; Disease-Free Survival ; Drug Resistance, Neoplasm/genetics ; Flow Cytometry/statistics &amp; numerical data ; Humans ; Mass Screening/statistics &amp; numerical data ; Mediastinal Neoplasms/genetics/metabolism/mortality ; Neuroblastoma/*genetics/mortality ; Ploidies ; Prognosis ; Retroperitoneal Neoplasms/genetics/metabolism/mortality ; Survival Analysis ; Tandem Repeat Sequences/genetics ; Telomerase/genetics/metabolism ; Telomere/genetics/metabolism/*ultrastructure ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {PURPOSE: Neuroblastoma (NBL) shows remarkable biologic heterogeneity, resulting in favorable or unfavorable prognoses. Previously, we reported that most unfavorable NBLs express high telomerase activity to maintain telomere length. Recently, telomere binding proteins (TBPs) and alternative lengthening of telomeres (ALTs) have been identified as key factors of telomere maintenance.<br><br>METHODS: To evaluate the correlation between telomerase activity, telomere length, and the expression levels of TBPs in NBL, we analyzed and quantified these factors in 121 untreated NBLs.<br><br>RESULTS: Shortened and elongated telomeres were detected in 21 (17.3%) and 11 cases (9.0%), respectively, and there was a significant correlation between telomere length and the length of the 3'-overhang. The tumors with shortened or elongated telomeres showed significant lower expression of TBPs, except for RAP1. Although telomerase activity did not correlate with telomere length, 16 of 22 cases with high telomerase activity and 5 of 9 cases (ALT tumors) that showed long telomeres without high telomerase activity resulted in death. High-dose chemotherapy did not have much effect on these deceased ALT cases, but their survival periods were more than 2 years and relatively long compared with the deceased cases with nonelongated telomeres, suggesting that chemoresistance in ALT tumors may be related to slow growth rates.<br><br>CONCLUSIONS: High telomerase activity is a poor prognostic factor in NBL. In the cases without high telomerase activity, those with elongated telomere also showed poor outcomes because of chemoresistance. Therefore, ALT and TBPs may be biomarkers for chemosensitivity in NBL. Thus, a better understanding of telomere biology may help define the characteristics of individual NBLs.},
}
@article {pmid19998444,
year = {2010},
author = {Lange, K and Holm, L and Vang Nielsen, K and Hahn, A and Hofmann, W and Kreipe, H and Schlegelberger, B and Göhring, G},
title = {Telomere shortening and chromosomal instability in myelodysplastic syndromes.},
journal = {Genes, chromosomes &amp; cancer},
volume = {49},
number = {3},
pages = {260-269},
doi = {10.1002/gcc.20737},
pmid = {19998444},
issn = {1098-2264},
mesh = {Anemia/genetics ; Chromosomal Instability/*genetics ; Chromosome Banding/methods ; Chromosomes, Human, Pair 7 ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Metaphase/genetics ; Myelodysplastic Syndromes/*genetics ; Reference Values ; Telomerase/metabolism ; Telomere/*genetics/ultrastructure ; },
abstract = {Telomere shortening and chromosomal instability are believed to play an important role in the development of myeloid neoplasia. So far, published data are only available on the average telomere length in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), but not on the telomere length of individual chromosomes. We used a new technique, telomere/centromere-fluorescence in situ hybridization (T/C-FISH), which combines fluorescence R-banding and FISH using a probe against the telomere repeats to measure the telomere length of each chromosome arm in 78 patients with MDS. In line with the previous results, patients with MDS showed significantly shorter telomeres than those of healthy controls. Telomere lengths did not differ significantly between distinct morphological subtypes of MDS. However, there was a significant difference in telomere length between patients with an isolated monosomy 7 and patients with a normal karyotype (P < 0.05). Notably, patients with an isolated monosomy 7 showed significantly longer telomeres than patients with a normal karyotype in many chromosome arms, among them 7p and 7q. Neo-telomeres were found in two patients with a complex karyotype, in one case at the fusion site of a dic(14;20). Normal and aberrant metaphases of the same patient did not differ in telomere length, thus indicating to telomere shortening as a basic mechanism affecting all hematopoietic cells in patients with MDS. In some MDS subtypes, like MDS with isolated monosomy 7, telomeres may be stabilized and even increase in length because of the activation of telomerase or alternative mechanisms.},
}
@article {pmid19997892,
year = {2010},
author = {Gunaratnam, M and Neidle, S},
title = {An evaluation cascade for G-quadruplex telomere targeting agents in human cancer cells.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {613},
number = {},
pages = {303-313},
doi = {10.1007/978-1-60327-418-0_19},
pmid = {19997892},
issn = {1940-6029},
mesh = {Base Sequence ; Biocatalysis ; Biological Products/metabolism/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA/chemistry/genetics/metabolism ; Enzyme Inhibitors/pharmacology ; Fluorescence Resonance Energy Transfer ; *G-Quadruplexes/drug effects ; Humans ; Inhibitory Concentration 50 ; Neoplasms/*pathology ; Rhodamines/pharmacology ; Staining and Labeling ; Telomerase/antagonists &amp; inhibitors/metabolism ; Telomere/chemistry/genetics/*metabolism ; Time Factors ; beta-Galactosidase/metabolism ; },
abstract = {The targeting of telomerase and telomere maintenance in human cancer cells can be achieved by small molecules that induce the 3'single-stranded ends of telomeric DNA to fold up into four-stranded quadruplex structures that inhibit the action of the telomerase enzyme complex. In this chapter, we describe a series of biochemical, biophysical, and cellular assays that are used to evaluate the activity of new compounds, and so assess whether they are suitable for examination in xenograft models of human cancer. These assays evaluate quadruplex stabilisation properties, short- and long-term cell viability, telomerase enzymatic activity, cellular senescence, and telomere length changes.},
}
@article {pmid19996277,
year = {2009},
author = {Zhou, WJ and Deng, R and Zhang, XY and Feng, GK and Gu, LQ and Zhu, XF},
title = {G-quadruplex ligand SYUIQ-5 induces autophagy by telomere damage and TRF2 delocalization in cancer cells.},
journal = {Molecular cancer therapeutics},
volume = {8},
number = {12},
pages = {3203-3213},
doi = {10.1158/1535-7163.MCT-09-0244},
pmid = {19996277},
issn = {1538-8514},
mesh = {Ataxia Telangiectasia Mutated Proteins ; Autophagy/*drug effects ; Autophagy-Related Protein 5 ; Cell Cycle Proteins/genetics/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; DNA Damage ; DNA-Binding Proteins/genetics/metabolism ; Diamines/*pharmacology ; G-Quadruplexes/drug effects ; HeLa Cells ; Histones/genetics/metabolism ; Humans ; Immunoblotting ; Ligands ; Luminescent Proteins/genetics/metabolism ; Microscopy, Confocal ; Microtubule-Associated Proteins/genetics/metabolism ; Protein Serine-Threonine Kinases/genetics/metabolism ; Quinolines/*pharmacology ; RNA Interference ; Telomere/*drug effects/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; Tumor Suppressor Proteins/genetics/metabolism ; },
abstract = {Agents stabilizing G-quadruplexes have the potential to destroy the functional structure of telomere and could therefore act as antitumor agents. We previously reported that SYUIQ-5 could stabilize G-quadruplex, induce senescence, and inhibit c-myc gene promoter activity. In this study, we showed that SYUIQ-5 inhibited proliferation of CNE2 and HeLa cancer cells, triggered a rapid and potent telomere DNA damage response characterized by the formation of telomeric foci gamma-H2AX, and obviously induced autophagy with the features of increased LC3-II and a punctuated pattern of YFP-LC3 fluorescence. These phenomena may primarily depend on the delocalization of TRF2 from telomere, which was further degraded by proteasomes. Furthermore, overexpression of TRF2 inhibited SYUIQ-5-induced gamma-H2AX expression. Also, ATM was activated following SYUIQ-5 treatment. The pretreatment with ATM inhibitor ku55933 and ATM siRNA effectively reduced the production of gamma-H2AX and LC3-II. ATM knockdown partially antagonized the anticancer effects of SYUIQ-5. Moreover, inhibition of autophagy by short hairpin RNA against the autophagy-related gene ATG5 attenuated the cytotoxicity of SYUIQ-5. These results indicated that SYUIQ-5 triggered potent telomere damage through TRF2 delocalization from telomeres, and eventually induced autophagic cell death in cancer cells. Our findings exhibit a novel mechanism that is responsible for the antitumor effects of SYUIQ-5.},
}
@article {pmid19995905,
year = {2010},
author = {Kibe, T and Osawa, GA and Keegan, CE and de Lange, T},
title = {Telomere protection by TPP1 is mediated by POT1a and POT1b.},
journal = {Molecular and cellular biology},
volume = {30},
number = {4},
pages = {1059-1066},
pmid = {19995905},
issn = {1098-5549},
support = {P30 CA046592/CA/NCI NIH HHS/United States ; AG016642/AG/NIA NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; GM049046/GM/NIGMS NIH HHS/United States ; R01 GM049046/GM/NIGMS NIH HHS/United States ; R01 HD058606/HD/NICHD NIH HHS/United States ; HD058606/HD/NICHD NIH HHS/United States ; CA46592/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/metabolism ; Cell Line ; Chromosome Deletion ; DNA Damage ; DNA-Binding Proteins/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Inbred Strains ; Protein Binding ; RNA Interference ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins ; },
abstract = {Mammalian telomeres are protected by the shelterin complex, which contains single-stranded telomeric DNA binding proteins (POT1a and POT1b in rodents, POT1 in other mammals). Mouse POT1a prevents the activation of the ATR kinase and contributes to the repression of the nonhomologous end-joining pathway (NHEJ) at newly replicated telomeres. POT1b represses unscheduled resection of the 5'-ended telomeric DNA strand, resulting in long 3' overhangs in POT1b KO cells. Both POT1 proteins bind TPP1, forming heterodimers that bind to other proteins in shelterin. Short hairpin RNA (shRNA)-mediated depletion had previously demonstrated that TPP1 contributes to the normal function of POT1a and POT1b. However, these experiments did not establish whether TPP1 has additional functions in shelterin. Here we report on the phenotypes of the conditional deletion of TPP1 from mouse embryo fibroblasts. TPP1 deletion resulted in the release of POT1a and POT1b from chromatin and loss of these proteins from telomeres, indicating that TPP1 is required for the telomere association of POT1a and POT1b but not for their stability. The telomere dysfunction phenotypes associated with deletion of TPP1 were identical to those of POT1a/POT1b DKO cells. No additional telomere dysfunction phenotypes were observed, establishing that the main role of TPP1 is to allow POT1a and POT1b to protect chromosome ends.},
}
@article {pmid19968067,
year = {2009},
author = {Liu, B and Cui, W and Han, B and Wang, X and Lin, J and Zhao, YQ},
title = {[Application of fluorescence in situ hybridization and flow cytometry in the measurement of telomere length in Chinese patients with bone marrow failure syndrome].},
journal = {Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae},
volume = {31},
number = {5},
pages = {547-550},
pmid = {19968067},
issn = {1000-503X},
mesh = {Adolescent ; Adult ; Anemia, Aplastic ; Bone Marrow Diseases ; Bone Marrow Failure Disorders ; Case-Control Studies ; Female ; Flow Cytometry/*methods ; Hemoglobinuria, Paroxysmal/*genetics ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Male ; Middle Aged ; Telomere/*genetics ; Young Adult ; },
abstract = {OBJECTIVE: To measure the telomere length in patients with bone marrow failure syndrome (BMF) using fluorescence in situ hybridization and flow cytometry (Flow-FISH).<br><br>METHODS: Blood samples were collected from 8 patients with BMF. Telomere lengths of mononuclear cells from 8 BMF patients and granulocytes from 3 of these 8 BMF patients (all these 3 patients were suffered from aplastic anemia) were measured using Flow-FISH, and the results were compared with those of normal controls. Telomere lengths were measured by Southern blot in 3 patients, and the results were compared with those obtained from Flow-FISH.<br><br>RESULTS: Among these 8 BMF patients, 5 have decreased telomere length in their mononuclear cells. However, different white cell subgroups, specifically mononucleated cells and granulocytes, have different degree of telomere shortening. In 3 BMF patients who underwent both Flow-FISH and Southern blot, 2 patients had consistent measurement results.<br><br>CONCLUSION: Flow-FISH can be used for the measurement of telomere length in Chinese patients with BMF.},
}
@article {pmid19965646,
year = {2010},
author = {Song, Z and Wang, J and Guachalla, LM and Terszowski, G and Rodewald, HR and Ju, Z and Rudolph, KL},
title = {Alterations of the systemic environment are the primary cause of impaired B and T lymphopoiesis in telomere-dysfunctional mice.},
journal = {Blood},
volume = {115},
number = {8},
pages = {1481-1489},
doi = {10.1182/blood-2009-08-237230},
pmid = {19965646},
issn = {1528-0020},
mesh = {Aging/genetics/metabolism ; Animals ; B-Lymphocytes/cytology/*enzymology ; Epithelium/enzymology ; Hematopoietic Stem Cells/*enzymology/metabolism ; Humans ; Lymphopoiesis/*physiology ; Mice ; Mice, Knockout ; RNA/genetics/*metabolism ; T-Lymphocytes/cytology/*enzymology ; Telomerase/genetics/*metabolism ; Telomere/*enzymology/genetics ; Thymus Gland/enzymology/transplantation ; },
abstract = {There is growing evidence that telomere dysfunction can contribute to human aging. Telomere dysfunction limits lymphopoiesis in aging telomerase knockout (mTerc(-/-)) mice primarily by the induction of stem cell-extrinsic alterations. The relative contribution of alterations in the stem cell niche and the systemic environment to the impairment of lymphopoiesis in response to telomere dysfunction is currently unknown. This study reveals a minor impact of stem cell-intrinsic defects on the impairment of B and T lymphopoiesis in response to telomere dysfunction. The impairment in B and T lymphopoiesis in aging telomere-dysfunctional mice was mainly due to alterations of the systemic environment. Telomere dysfunction had no significant cell-autonomous effects impairing the function of thymic or bone marrow niches in supporting B and T lymphopoiesis. Moreover, age-related alterations in the cellular composition of the thymic epithelium in telomere-dysfunctional mice were rescued by transplantation of the thymus into a wild-type environment; these rejuvenated thymi supported normal T lymphopoiesis in recipient mice. Together, these data place alterations in the systemic environment on top of the hierarchy of events limiting lymphopoiesis in response to telomere dysfunction.},
}
@article {pmid19965504,
year = {2009},
author = {de Lange, T},
title = {How telomeres solve the end-protection problem.},
journal = {Science (New York, N.Y.)},
volume = {326},
number = {5955},
pages = {948-952},
pmid = {19965504},
issn = {1095-9203},
support = {R01 AG016642-09/AG/NIA NIH HHS/United States ; R01 GM049046-11/GM/NIGMS NIH HHS/United States ; R01 GM049046-12/GM/NIGMS NIH HHS/United States ; DP1 OD000379-05/OD/NIH HHS/United States ; R01 AG016642-01/AG/NIA NIH HHS/United States ; R01 CA076027-05A1/CA/NCI NIH HHS/United States ; DP1 OD000379-03/OD/NIH HHS/United States ; R01 CA076027-02/CA/NCI NIH HHS/United States ; R01 AG016642-04/AG/NIA NIH HHS/United States ; R01 CA076027-03/CA/NCI NIH HHS/United States ; R01 GM049046-09/GM/NIGMS NIH HHS/United States ; R37 GM049046-15/GM/NIGMS NIH HHS/United States ; R01 GM049046/GM/NIGMS NIH HHS/United States ; R01 CA076027-06/CA/NCI NIH HHS/United States ; DP1 OD000379-04/OD/NIH HHS/United States ; R01 CA076027-10/CA/NCI NIH HHS/United States ; R01 CA076027-11/CA/NCI NIH HHS/United States ; R01 AG016642-07/AG/NIA NIH HHS/United States ; R01 CA076027-07/CA/NCI NIH HHS/United States ; DP1 OD000379-02/OD/NIH HHS/United States ; R37 GM049046-13/GM/NIGMS NIH HHS/United States ; AG016642/AG/NIA NIH HHS/United States ; CA076027/CA/NCI NIH HHS/United States ; R01 AG016642-11/AG/NIA NIH HHS/United States ; R01 AG016642-06/AG/NIA NIH HHS/United States ; R01 GM049046-08/GM/NIGMS NIH HHS/United States ; DP1 OD000379-01/OD/NIH HHS/United States ; R37 GM049046-14/GM/NIGMS NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; DP1 OD000379/OD/NIH HHS/United States ; R01 AG016642-08/AG/NIA NIH HHS/United States ; GM049046/GM/NIGMS NIH HHS/United States ; R01 CA076027-09/CA/NCI NIH HHS/United States ; R01 CA076027-04/CA/NCI NIH HHS/United States ; R37 GM049046-17/GM/NIGMS NIH HHS/United States ; R01 CA076027/CA/NCI NIH HHS/United States ; R01 GM049046-07/GM/NIGMS NIH HHS/United States ; R01 GM049046-10/GM/NIGMS NIH HHS/United States ; R01 AG016642-02/AG/NIA NIH HHS/United States ; R01 AG016642-03/AG/NIA NIH HHS/United States ; R01 CA076027-12/CA/NCI NIH HHS/United States ; R01 AG016642-05/AG/NIA NIH HHS/United States ; R01 CA076027-08/CA/NCI NIH HHS/United States ; R37 GM049046-16/GM/NIGMS NIH HHS/United States ; R01 CA076027-11S1/CA/NCI NIH HHS/United States ; R01 AG016642-10/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Chromosomes/physiology ; Chromosomes, Mammalian/*physiology/ultrastructure ; Ciliophora/genetics/metabolism ; DNA/biosynthesis/*metabolism ; DNA Damage ; DNA Repair ; DNA-Binding Proteins/metabolism ; Humans ; Repetitive Sequences, Nucleic Acid ; Shelterin Complex ; Signal Transduction ; Telomerase/metabolism ; Telomere/*physiology/ultrastructure ; Telomere-Binding Proteins/*metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; Yeasts/genetics/metabolism ; },
abstract = {The ends of eukaryotic chromosomes have the potential to be mistaken for damaged or broken DNA and must therefore be protected from cellular DNA damage response pathways. Otherwise, cells might permanently arrest in the cell cycle, and attempts to "repair" the chromosome ends would have devastating consequences for genome integrity. This end-protection problem is solved by protein-DNA complexes called telomeres. Studies of mammalian cells have recently uncovered the mechanism by which telomeres disguise the chromosome ends. Comparison to unicellular eukaryotes reveals key differences in the DNA damage response systems that inadvertently threaten chromosome ends. Telomeres appear to be tailored to these variations, explaining their variable structure and composition.},
}
@article {pmid19962994,
year = {2010},
author = {Bowen, AJ and Gonzalez, D and Mullins, JG and Bhatt, AM and Martinez, A and Conlan, RS},
title = {PAH-domain-specific interactions of the Arabidopsis transcription coregulator SIN3-LIKE1 (SNL1) with telomere-binding protein 1 and ALWAYS EARLY2 Myb-DNA binding factors.},
journal = {Journal of molecular biology},
volume = {395},
number = {5},
pages = {937-949},
doi = {10.1016/j.jmb.2009.11.065},
pmid = {19962994},
issn = {1089-8638},
mesh = {Amino Acid Sequence ; Arabidopsis/genetics/*metabolism ; Arabidopsis Proteins/*chemistry/genetics/metabolism ; Base Sequence ; DNA Primers/genetics ; DNA, Plant/genetics/metabolism ; DNA-Binding Proteins/*chemistry/genetics/metabolism ; Genes, Plant ; Models, Molecular ; Molecular Sequence Data ; Multigene Family ; Phylogeny ; Plants, Genetically Modified ; Protein Interaction Domains and Motifs ; Protein Interaction Mapping ; Recombinant Proteins/chemistry/genetics/metabolism ; Sequence Homology, Amino Acid ; Sin3 Histone Deacetylase and Corepressor Complex/*chemistry/genetics/metabolism ; Nicotiana/genetics/metabolism ; Transcription Factors/*chemistry/genetics/metabolism ; Two-Hybrid System Techniques ; },
abstract = {The eukaryotic SIN3 protein is the central component of the evolutionarily conserved multisubunit SIN3 complex that has roles in regulating gene expression and genome stability. Here we characterise the structure of the SIN3 protein in higher plants through the analysis of SNL1 (SIN3-LIKE1), SNL2, SNL3, SNL4, SNL5 and SNL6, a family of six SIN3 homologues in Arabidopsis thaliana. In an Arabidopsis-protoplast beta-glucuronidase reporter gene assay, as well as in a heterologous yeast repression assay, full-length SNL1 was shown to repress transcription in a histone-deacetylase-dependent manner, demonstrating the conserved nature of SIN3 function. Yeast two-hybrid screening identified a number of DNA binding proteins each containing a single Myb domain that included the Arabidopsis ALWAYS EARLY proteins AtALY2 and AtALY3, and two telomere binding proteins AtTBP1 and AtTRP2/TRFL1 as SNL1 partners, suggesting potential functions for SNL1 in development and telomere maintenance. The interaction with telomere-binding protein 1 was found to be mediated through the well-defined paired amphipathic helix domain PAH2. In contrast, the AtALY2 interaction was mediated through the PAH3 domain of SNL1, which is structurally distinct from PAH1 and PAH2, suggesting that evolution of this domain to a more novel structural motif has occurred. These findings support a diverse role of SNL1 in the regulation of transcription and genome stability.},
}
@article {pmid19961392,
year = {2010},
author = {Lee, IM and Lin, J and Castonguay, AJ and Barton, NS and Buring, JE and Zee, RY},
title = {Mean leukocyte telomere length and risk of incident colorectal carcinoma in women: a prospective, nested case-control study.},
journal = {Clinical chemistry and laboratory medicine},
volume = {48},
number = {2},
pages = {259-262},
pmid = {19961392},
issn = {1437-4331},
support = {K07 CA112529-04/CA/NCI NIH HHS/United States ; R01 HL043851/HL/NHLBI NIH HHS/United States ; CA-047988/CA/NCI NIH HHS/United States ; HL-043851/HL/NHLBI NIH HHS/United States ; R01 HL080467-04/HL/NHLBI NIH HHS/United States ; R01 CA047988-18/CA/NCI NIH HHS/United States ; CA112529/CA/NCI NIH HHS/United States ; R01 CA047988/CA/NCI NIH HHS/United States ; R01 HL043851-10/HL/NHLBI NIH HHS/United States ; HL-080467/HL/NHLBI NIH HHS/United States ; R01 HL080467/HL/NHLBI NIH HHS/United States ; K07 CA112529/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Biomarkers, Tumor/genetics ; Case-Control Studies ; Colorectal Neoplasms/*diagnosis/*genetics ; Female ; Genetic Predisposition to Disease ; Humans ; Leukocytes/*metabolism ; Middle Aged ; Predictive Value of Tests ; Prospective Studies ; Risk ; Telomere/*metabolism ; White People/genetics ; },
abstract = {BACKGROUND: To date, no prospective epidemiological data are available, particularly in women, on mean leukocyte telomere length as a risk predictor.<br><br>METHODS: Using leukocyte DNA samples collected at baseline in a prospective cohort of over 28,000 initially healthy women, we examined the relationship between mean leukocyte telomere repeat copy number to single gene copy number (TSR) in 134 incident cases of colorectal carcinoma (CRC), and 357 matched controls; all were Caucasian.<br><br>RESULTS: The observed log(e)-transformed TSRs were similar between cases and controls (p=0.79). Using an adjusted analysis, we found no evidence for an association of the log(e)-TSRs with CRC risk [adjusted odds ratio (OR)=0.943, 95% confidence interval (CI)=0.647-1.376, p=0.762]. Stratified analysis by median follow-up time, or postmenopausal status also showed similar null findings.<br><br>CONCLUSIONS: In concordance with our previous findings in Caucasian men, the present study in Caucasian women found no evidence for an association of mean leukocyte telomere length with risk of incident CRC, further suggesting that leukocyte telomere length may not be a useful indicator for risk assessment.},
}
@article {pmid19959722,
year = {2010},
author = {Westhoff, JH and Schildhorn, C and Jacobi, C and Hömme, M and Hartner, A and Braun, H and Kryzer, C and Wang, C and von Zglinicki, T and Kränzlin, B and Gretz, N and Melk, A},
title = {Telomere shortening reduces regenerative capacity after acute kidney injury.},
journal = {Journal of the American Society of Nephrology : JASN},
volume = {21},
number = {2},
pages = {327-336},
pmid = {19959722},
issn = {1533-3450},
support = {G0601333/MRC_/Medical Research Council/United Kingdom ; G0900686/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Acute Kidney Injury/metabolism/*physiopathology ; Animals ; Apoptosis ; Cell Proliferation ; Connective Tissue Growth Factor/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Disease Models, Animal ; Kidney/pathology/*physiology/surgery ; Male ; Mice ; Mice, Knockout ; Nephrectomy ; RNA/genetics/metabolism ; Regeneration/*physiology ; Reperfusion Injury/metabolism/*physiopathology ; Telomerase/genetics/metabolism ; Telomere/*ultrastructure ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Telomeres of most somatic cells progressively shorten, compromising the regenerative capacity of human tissues during aging and chronic diseases and after acute injury. Whether telomere shortening reduces renal regeneration after acute injury is unknown. Here, renal ischemia-reperfusion injury led to greater impairment of renal function and increased acute and chronic histopathologic damage in fourth-generation telomerase-deficient mice compared with both wild-type and first-generation telomerase-deficient mice. Critically short telomeres, increased expression of the cell-cycle inhibitor p21, and more apoptotic renal cells accompanied the pronounced damage in fourth-generation telomerase-deficient mice. These mice also demonstrated significantly reduced proliferative capacity in tubular, glomerular, and interstitial cells. These data suggest that critical telomere shortening in the kidney leads to increased senescence and apoptosis, thereby limiting regenerative capacity in response to injury.},
}
@article {pmid19956585,
year = {2009},
author = {Suhr, ST and Chang, EA and Rodriguez, RM and Wang, K and Ross, PJ and Beyhan, Z and Murthy, S and Cibelli, JB},
title = {Telomere dynamics in human cells reprogrammed to pluripotency.},
journal = {PloS one},
volume = {4},
number = {12},
pages = {e8124},
pmid = {19956585},
issn = {1932-6203},
mesh = {Aged ; Cell Differentiation ; Cell Line ; Cellular Reprogramming/*genetics ; Fibroblasts/*cytology/*metabolism ; Genetic Vectors/genetics ; Humans ; Induced Pluripotent Stem Cells/*cytology/*metabolism ; Lentivirus/genetics ; Male ; Microscopy, Phase-Contrast ; Phenotype ; Telomere/*metabolism ; Teratoma/pathology ; },
abstract = {BACKGROUND: Human induced pluripotent stem cells (IPSCs) have enormous potential in the development of cellular models of human disease and represent a potential source of autologous cells and tissues for therapeutic use. A question remains as to the biological age of IPSCs, in particular when isolated from older subjects. Studies of cloned animals indicate that somatic cells reprogrammed to pluripotency variably display telomere elongation, a common indicator of cell "rejuvenation."<br><br>We examined telomere lengths in human skin fibroblasts isolated from younger and older subjects, fibroblasts converted to IPSCs, and IPSCs redifferentiated through teratoma formation and explant culture. In IPSCs analyzed at passage five (P5), telomeres were significantly elongated in 6/7 lines by >40% and approximated telomere lengths in human embryonic stem cells (hESCs). In cell lines derived from three IPSC-teratoma explants cultured to P5, two displayed telomeres shortened to lengths similar to input fibroblasts while the third line retained elongated telomeres.<br><br>CONCLUSIONS/SIGNIFICANCE: While these results reveal some heterogeneity in the reprogramming process with respect to telomere length, human somatic cells reprogrammed to pluripotency generally displayed elongated telomeres that suggest that they will not age prematurely when isolated from subjects of essentially any age.},
}
@article {pmid19954519,
year = {2009},
author = {Loney, ER and Inglis, PW and Sharp, S and Pryde, FE and Kent, NA and Mellor, J and Louis, EJ},
title = {Repressive and non-repressive chromatin at native telomeres in Saccharomyces cerevisiae.},
journal = {Epigenetics &amp; chromatin},
volume = {2},
number = {1},
pages = {18},
pmid = {19954519},
issn = {1756-8935},
abstract = {BACKGROUND: In Saccharomyces cerevisiae genes that are located close to a telomere can become transcriptionally repressed by an epigenetic process known as telomere position effect. There is large variation in the level of the telomere position effect among telomeres, with many native ends exhibiting little repression.<br><br>RESULTS: Chromatin analysis, using microccocal nuclease and indirect end labelling, reveals distinct patterns for ends with different silencing states. Differences were observed in the promoter accessibility of a subtelomeric reporter gene and a characteristic array of phased nucleosomes was observed on the centromere proximal side of core X at a repressive end. The silent information regulator proteins 2 - 4, the yKu heterodimer and the subtelomeric core X element are all required for the maintenance of the chromatin structure of repressive ends. However, gene deletions of particular histone modification proteins can eliminate the silencing without the disruption of this chromatin structure.<br><br>CONCLUSION: Our data identifies chromatin features that correlate with the silencing state and indicate that an array of phased nucleosomes is not sufficient for full repression.},
}
@article {pmid19948484,
year = {2009},
author = {Chikashige, Y and Yamane, M and Okamasa, K and Tsutsumi, C and Kojidani, T and Sato, M and Haraguchi, T and Hiraoka, Y},
title = {Membrane proteins Bqt3 and -4 anchor telomeres to the nuclear envelope to ensure chromosomal bouquet formation.},
journal = {The Journal of cell biology},
volume = {187},
number = {3},
pages = {413-427},
pmid = {19948484},
issn = {1540-8140},
mesh = {Chromosomes, Fungal/*metabolism/ultrastructure ; Gene Deletion ; Membrane Proteins/genetics/metabolism/*physiology ; Nuclear Envelope/*metabolism ; Nuclear Proteins/genetics/metabolism/*physiology ; Schizosaccharomyces/genetics/*metabolism/ultrastructure ; Schizosaccharomyces pombe Proteins/genetics/metabolism/*physiology ; Telomere/*metabolism ; },
abstract = {In many organisms, telomeres cluster to form a bouquet arrangement of chromosomes during meiotic prophase. Previously, we reported that two meiotic proteins, Bqt1 and -2, are required for tethering telomeres to the spindle pole body (SPB) during meiotic prophase in fission yeast. This study has further identified two novel, ubiquitously expressed inner nuclear membrane (INM) proteins, Bqt3 and -4, which are required for bouquet formation. We found that in the absence of Bqt4, telomeres failed to associate with the nuclear membranes in vegetative cells and consequently failed to cluster to the SPB in meiotic prophase. In the absence of Bqt3, Bqt4 protein was degraded during meiosis, leading to a phenotype similar to that of the bqt4-null mutant. Collectively, these results show that Bqt4 anchors telomeres to the INM and that Bqt3 protects Bqt4 from protein degradation. Interestingly, the functional integrity of telomeres is maintained even when they are separated from the nuclear envelope in vegetative cells.},
}
@article {pmid19945703,
year = {2010},
author = {Mainous, AG and Codd, V and Diaz, VA and Schoepf, UJ and Everett, CJ and Player, MS and Samani, NJ},
title = {Leukocyte telomere length and coronary artery calcification.},
journal = {Atherosclerosis},
volume = {210},
number = {1},
pages = {262-267},
doi = {10.1016/j.atherosclerosis.2009.10.047},
pmid = {19945703},
issn = {1879-1484},
support = {//British Heart Foundation/United Kingdom ; },
mesh = {Adult ; Age Factors ; Aging/physiology ; Calcinosis/pathology ; Coronary Artery Disease/*pathology ; Female ; Humans ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Risk Factors ; Telomere/*ultrastructure ; },
abstract = {OBJECTIVE: Leukocyte telomere length is representative of biological aging and is associated with clinical coronary artery disease but its association with coronary atherosclerosis is unclear. The objective of this study was to examine the association of telomere length with coronary artery calcification in middle aged adults.<br><br>METHODS: Leukocyte telomere length was measured with a quantitative PCR-based technique and coronary artery calcification (CAC) scoring was performed on a dual-source CT scanner in a sample of 325 adults aged 40-64 years old free of previously diagnosed diabetes, CHD, stroke and cancer. We used logistic regression to determine the association of presence of CAC (Agatston score >0 versus 0) with telomere length adjusted for age, gender, race and metabolic syndrome. Finally, we examined the relation of telomere length to extensiveness of CAC.<br><br>RESULTS: The unadjusted odds ratio of having CAC for the shortest tertile of telomere length versus the longest was 3.39 (95% CI 1.85-6.20). After adjustment for age, race, gender and metabolic syndrome the odds decreased but remained significant (OR 2.36; 95% CI 1.23-4.52). Mean telomere length was significantly shorter with more extensive coronary calcification. The correlation between telomere length and chronological age was r=-0.19 (p<.001) while the correlation between telomere length and arterial age was r=-0.22 (p<.001).<br><br>CONCLUSIONS: In conclusion, telomere length is negatively associated with the presence of coronary atherosclerosis in a low risk cohort free of previously diagnosed CVD.},
}
@article {pmid19944403,
year = {2009},
author = {Armanios, M and Alder, JK and Parry, EM and Karim, B and Strong, MA and Greider, CW},
title = {Short telomeres are sufficient to cause the degenerative defects associated with aging.},
journal = {American journal of human genetics},
volume = {85},
number = {6},
pages = {823-832},
pmid = {19944403},
issn = {1537-6605},
support = {R01 AG027406/AG/NIA NIH HHS/United States ; T32GM007309/GM/NIGMS NIH HHS/United States ; K08 CA118416/CA/NCI NIH HHS/United States ; K08CA118416/CA/NCI NIH HHS/United States ; T32 GM007309/GM/NIGMS NIH HHS/United States ; R01AG27406/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*genetics ; Animals ; B-Lymphocytes/metabolism ; Crosses, Genetic ; Disease Models, Animal ; Dyskeratosis Congenita/genetics ; Female ; Genotype ; Heterozygote ; Immunoglobulin M/metabolism ; Male ; Mice ; Mice, Transgenic ; T-Lymphocytes/metabolism ; Telomerase/genetics/metabolism ; Telomere/*ultrastructure ; },
abstract = {Telomerase function is critical for telomere maintenance. Mutations in telomerase components lead to telomere shortening and progressive bone marrow failure in the premature aging syndrome dyskeratosis congenita. Short telomeres are also acquired with aging, yet the role that they play in mediating age-related disease is not fully known. We generated wild-type mice that have short telomeres. In these mice, we identified hematopoietic and immune defects that resembled those present in dyskeratosis congenita patients. When mice with short telomeres were interbred, telomere length was only incrementally restored, and even several generations later, wild-type mice with short telomeres still displayed degenerative defects. Our findings implicate telomere length as a unique heritable trait that, when short, is sufficient to mediate the degenerative defects of aging, even when telomerase is wild-type.},
}
@article {pmid19944017,
year = {2009},
author = {Hernandez-Caballero, E and Herrera-Gonzalez, NE and Salamanca-Gomez, F and Arenas-Aranda, DJ},
title = {Role of telomere length in subtelomeric gene expression and its possible relation to cellular senescence.},
journal = {BMB reports},
volume = {42},
number = {11},
pages = {747-751},
doi = {10.5483/bmbrep.2009.42.11.747},
pmid = {19944017},
issn = {1976-6696},
mesh = {Adolescent ; Adult ; Aged ; Base Sequence ; Cellular Senescence/*genetics ; Child ; Child, Preschool ; DNA Primers ; *Gene Expression ; Humans ; Infant ; Infant, Newborn ; Middle Aged ; Polymerase Chain Reaction ; *Telomere ; Young Adult ; beta-Galactosidase/genetics ; },
abstract = {Transcriptional silencing of subtelomeric genes is associated with telomere length, which is correlated with age. Long and short telomeres in young and old people, respectively, coincide with gene repression and activation in each case. In addition, differential location of genes with respect to telomeres causes telomere position effect. There is very little evidence of the manner in which age-related telomere length affects the expression of specific human subtelomeric genes. We analyzed the relationship between telomere length and gene expression levels in fibroblasts derived from human donors at ages ranging from 0-70 years. We studied three groups of genes located between 100 and 150 kb, 200 and 250 kb, and > 300 kb away from telomeres. We found that the chromatin modifier-encoding genes Eu-HMTase1, ZMYND11, and RASA3 were overexpressed in adults. Our results suggest that short telomere length-related overexpression of chromatin modifiers could underlie transcriptional changes contributing to cellular senescence.},
}
@article {pmid19943120,
year = {2010},
author = {Tatsuke, T and Sakashita, K and Masaki, Y and Lee, JM and Kawaguchi, Y and Kusakabe, T},
title = {The telomere-specific non-LTR retrotransposons SART1 and TRAS1 are suppressed by Piwi subfamily proteins in the silkworm, Bombyx mori.},
journal = {Cellular &amp; molecular biology letters},
volume = {15},
number = {1},
pages = {118-133},
pmid = {19943120},
issn = {1689-1392},
mesh = {Animals ; Bombyx/*genetics/metabolism ; Cells, Cultured ; RNA Interference ; RNA-Induced Silencing Complex/genetics/*metabolism ; *Retroelements ; Telomere/*chemistry ; Terminal Repeat Sequences ; },
abstract = {The telomere structures in Bombyx mori are thought to be maintained mainly by the transposition of the specialized telomeric retroelements SART and TRAS. The silkworm genome has telomeric TTAGG repeats and telomerase, but this telomerase displays little or no activity. Here, we report that the transcription of the telomeric retroelements SART1 and TRAS1 is suppressed by the silkworm Piwi subfamily proteins BmAgo3 and Siwi. The silkworm Piwi subfamily was found to be expressed predominantly in the gonads and early embryo, as in other model organisms, but in BmN4 cultured cells, these proteins formed granules that were separate from the nuage, which is a different behaviour pattern. The expression of TRAS1 was increased in BmN4 cells when BmAgo3 or Siwi were silenced by RNAi. Our results suggest that B. mori Piwi proteins are involved in regulating the transposition of telomeric retroelements, and that the functional piRNA pathway is conserved in BmN4 cultured cells.},
}
@article {pmid19942858,
year = {2010},
author = {Lu, J and Liu, Y},
title = {Deletion of Ogg1 DNA glycosylase results in telomere base damage and length alteration in yeast.},
journal = {The EMBO journal},
volume = {29},
number = {2},
pages = {398-409},
pmid = {19942858},
issn = {1460-2075},
support = {//Intramural NIH HHS/United States ; },
mesh = {DNA/metabolism ; DNA Glycosylases/*genetics/metabolism ; *Gene Deletion ; Guanine/metabolism ; Oxidation-Reduction ; Protein Binding ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Shelterin Complex ; Telomere/chemistry/*metabolism ; Telomere-Binding Proteins/metabolism ; Transcription Factors/metabolism ; },
abstract = {Telomeres consist of short guanine-rich repeats. Guanine can be oxidized to 8-oxo-7,8-dihydroguanine (8-oxoG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG). 8-oxoguanine DNA glycosylase (Ogg1) repairs these oxidative guanine lesions through the base excision repair (BER) pathway. Here we show that in Saccharomyces cerevisiae ablation of Ogg1p leads to an increase in oxidized guanine level in telomeric DNA. The ogg1 deletion (ogg1Delta) strain shows telomere lengthening that is dependent on telomerase and/or Rad52p-mediated homologous recombination. 8-oxoG in telomeric repeats attenuates the binding of the telomere binding protein, Rap1p, to telomeric DNA in vitro. Moreover, the amount of telomere-bound Rap1p and Rif2p is reduced in ogg1Delta strain. These results suggest that oxidized guanines may perturb telomere length equilibrium by attenuating telomere protein complex to function in telomeres, which in turn impedes their regulation of pathways engaged in telomere length maintenance. We propose that Ogg1p is critical in maintaining telomere length homoeostasis through telomere guanine damage repair, and that interfering with telomere length homoeostasis may be one of the mechanism(s) by which oxidative DNA damage inflicts the genome.},
}
@article {pmid19941821,
year = {2009},
author = {Min, B and Collins, K},
title = {An RPA-related sequence-specific DNA-binding subunit of telomerase holoenzyme is required for elongation processivity and telomere maintenance.},
journal = {Molecular cell},
volume = {36},
number = {4},
pages = {609-619},
pmid = {19941821},
issn = {1097-4164},
support = {R01 GM054198/GM/NIGMS NIH HHS/United States ; R01 GM054198-13/GM/NIGMS NIH HHS/United States ; GM54198/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Chromatography, Affinity ; DNA, Protozoan/*metabolism ; DNA-Binding Proteins/metabolism ; Holoenzymes/*metabolism ; Mass Spectrometry ; Molecular Sequence Data ; Protein Binding ; Protein Subunits/*metabolism ; Recombinant Proteins/metabolism ; Replication Protein A/*chemistry ; Telomerase/*metabolism ; Telomere/*metabolism ; Tetrahymena thermophila/*enzymology ; },
abstract = {Telomerase ribonucleoprotein complexes copy an internal RNA template to synthesize DNA repeats. DNA-interacting subunits other than telomerase reverse transcriptase (TERT) and telomerase RNA (TER) have been hypothesized to account for high repeat addition processivity of telomerase holoenzyme compared to the minimal catalytic RNP. Here, we present the identification of three additional subunits of Tetrahymena thermophila telomerase holoenzyme. Each of seven telomerase proteins is required for telomere maintenance and copurifies active RNP. The catalytic core (p65-TER-TERT) is assembled with a three-protein subcomplex (p75-p45-p19) and two peripheral subunits (p82 and p50). Remarkably, only a p82-enriched subset of the total holoenzyme population is capable of high repeat addition processivity, as shown by p82 immunodepletion and add-back. The RPA-like p82 subunit binds sequence specifically to multiple telomeric repeats. These discoveries establish the existence of a telomerase holoenzyme processivity subunit with sequence-specific DNA binding.},
}
@article {pmid19941413,
year = {2010},
author = {van der Harst, P and de Boer, RA and Samani, NJ and Wong, LS and Huzen, J and Codd, V and Hillege, HL and Voors, AA and van Gilst, WH and Jaarsma, T and van Veldhuisen, DJ},
title = {Telomere length and outcome in heart failure.},
journal = {Annals of medicine},
volume = {42},
number = {1},
pages = {36-44},
doi = {10.3109/07853890903321567},
pmid = {19941413},
issn = {1365-2060},
mesh = {Aged ; Aged, 80 and over ; Atrial Fibrillation/complications/metabolism ; Diabetes Complications/metabolism ; Female ; Heart Failure/*mortality/*physiopathology ; Humans ; Male ; Natriuretic Peptide, Brain/metabolism ; Prognosis ; Stroke/complications/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {BACKGROUND: Telomeres are causally involved in senescence. Senescence is a potential factor in the pathogenesis and progression of heart failure. In heart failure telomeres are shorter, but the prognostic value associated with telomere length has not been defined.<br><br>METHODS: Telomere length was prospectively determined by quantitative polymerase chain reaction in 890 patients with New York Heart Association (NYHA) functional class II to IV heart failure. After 18 months, we examined the association between telomere length and the predefined primary end-point: time to death or hospitalization for heart failure.<br><br>RESULTS: Mean age of the patients was 71 years, 39% were women, 51% were in NYHA class II, and 49% were in class III/IV. A total of 344 patients reached the primary end-point (130 deaths and 214 hospitalizations). Patients with shorter telomeres were at an increased risk of reaching the primary end-point (hazard ratio 1.79; 95% confidence interval (CI) 1.21-2.63). In multivariate analysis shorter telomere length remained associated with a higher risk for death or hospitalization (hazard ratio, 1.74; 95% CI 1.07-2.95) after adjustment for age of heart failure onset, gender, hemoglobin, renal function, and N-terminal pro-B-type natriuretic peptide level, a history of stroke, atrial fibrillation, and diabetes.<br><br>CONCLUSIONS: Shorter length of telomeres predicts the occurrence of death or hospitalization in patients with chronic heart failure.},
}
@article {pmid19938770,
year = {2009},
author = {Eberhard-Metzger, C},
title = {[Nobel Prize in Medicine for discovery of telomeres. Protective caps for the "thread of life"].},
journal = {MMW Fortschritte der Medizin},
volume = {151},
number = {42},
pages = {7},
pmid = {19938770},
issn = {1438-3276},
mesh = {*Genetics ; Humans ; *Nobel Prize ; *Telomere ; },
}
@article {pmid19936723,
year = {2010},
author = {Dong, M and Mürdter, TE and Klotz, U},
title = {Telomeres and telomerase as novel drug targets: reflections on the 2009 Nobel Prize in Physiology or Medicine.},
journal = {European journal of clinical pharmacology},
volume = {66},
number = {1},
pages = {1-3},
pmid = {19936723},
issn = {1432-1041},
mesh = {Animals ; *Drug Delivery Systems ; Humans ; Medicine ; *Nobel Prize ; Physiology ; Telomerase/*physiology ; Telomere/*physiology ; },
}
@article {pmid19935913,
year = {2009},
author = {Bombarová, M and Vítková, M and Spakulová, M and Koubková, B},
title = {Telomere analysis of platyhelminths and acanthocephalans by FISH and Southern hybridization.},
journal = {Genome},
volume = {52},
number = {11},
pages = {897-903},
doi = {10.1139/g09-063},
pmid = {19935913},
issn = {1480-3321},
mesh = {Acanthocephala/*genetics ; Animals ; Base Sequence ; Blotting, Southern ; In Situ Hybridization, Fluorescence ; Platyhelminths/*genetics ; Telomere/*genetics ; },
abstract = {We examined the composition of telomeres in chromosomes of parasitic worms, representatives of the flatworm groups Monogenea and Cestoda (Platyhelminthes), and thorny-headed worms (Syndermata: Acanthocephala) by fluorescence in situ hybridization (FISH) with different telomeric repeat probes. Our results show that the (TTAGGG)n sequence, supposed to be the ancestral telomeric repeat motif of Metazoa, is conserved in Monogenea (Paradiplozoon homoion) and Cestoda (Caryophyllaeus laticeps, Caryophyllaeides fennica, and Nippotaenia mogurndae) but not in Acanthocephala (Pomphorhynchus laevis and Pomphorhynchus tereticollis). In the Pomphorhynchus species, no hybridization signals were obtained with the "nematode" (TTAGGC)n, "arthropod" (TTAGG)n, and bdelloid (TGTGGG)n telomeric probes using FISH with their chromosomes and Southern hybridization with P. laevis DNA. Therefore, we suggest that parasitic Acanthocephala have evolved yet unknown telomeric repeat motifs or different mechanisms of telomere maintenance.},
}
@article {pmid19935656,
year = {2009},
author = {Henson, JD and Cao, Y and Huschtscha, LI and Chang, AC and Au, AY and Pickett, HA and Reddel, RR},
title = {DNA C-circles are specific and quantifiable markers of alternative-lengthening-of-telomeres activity.},
journal = {Nature biotechnology},
volume = {27},
number = {12},
pages = {1181-1185},
pmid = {19935656},
issn = {1546-1696},
mesh = {Biomarkers, Tumor/*genetics ; DNA, Neoplasm/*genetics ; Genetic Markers/*genetics ; Humans ; Osteosarcoma/diagnosis/*genetics ; Telomere/*genetics ; },
abstract = {Alternative lengthening of telomeres (ALT) is likely to be an important target for anticancer treatment as approximately 10% of cancers depend on this telomere maintenance mechanism for continued growth, and inhibition of ALT can cause cellular senescence. However, no ALT inhibitors have been developed for therapeutic use because of the lack of a suitable ALT activity assay and of known ALT-specific target molecules. Here we show that partially single-stranded telomeric (CCCTAA)(n) DNA circles (C-circles) are ALT specific. We provide an assay that is rapidly and linearly responsive to ALT activity and that is suitable for screening for ALT inhibitors. We detect C-circles in blood from ALT(+) osteosarcoma patients, suggesting that the C-circle assay (CC assay) may have clinical utility for diagnosis and management of ALT(+) tumors.},
}
@article {pmid19934287,
year = {2009},
author = {Lan, Q and Cawthon, R and Shen, M and Weinstein, SJ and Virtamo, J and Lim, U and Hosgood, HD and Albanes, D and Rothman, N},
title = {A prospective study of telomere length measured by monochrome multiplex quantitative PCR and risk of non-Hodgkin lymphoma.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {15},
number = {23},
pages = {7429-7433},
pmid = {19934287},
issn = {1557-3265},
support = {Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Aged ; Blotting, Southern ; Case-Control Studies ; Cohort Studies ; Humans ; Leukocytes/metabolism ; Lymphoma, Non-Hodgkin/*diagnosis/*genetics ; Male ; Middle Aged ; Odds Ratio ; Placebos ; Polymerase Chain Reaction/*methods ; Prospective Studies ; Risk ; Telomere/ultrastructure ; alpha-Tocopherol/therapeutic use ; beta Carotene/therapeutic use ; },
abstract = {PURPOSE: Telomere length plays an important role in the maintenance of chromosomal stability and in tumorigenesis. We hypothesized that telomere length in peripheral WBC DNA obtained from healthy individuals would be a predictor of future risk of developing non-Hodgkin lymphoma.<br><br>EXPERIMENTAL DESIGN: Using a new assay to measure relative telomere length, monochrome multiplex quantitative PCR, which strongly correlates with telomere length measured by Southern blot (Spearman r = 0.91, P < 0.0001) and has high precision (coefficient of variation = 7%), we compared telomere length in peripheral WBC DNA in 107 incident male non-Hodgkin lymphoma cases and 107 matched controls within the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort.<br><br>RESULTS: Median (10th, 90th percentile) telomere length was 1.10 (0.79, 1.43) in cases and 1.02 (0.78, 1.26) in controls (P = 0.0017, Wilcoxon sign test). There was a strong dose-response relationship between quartiles of telomere length and risk of non-Hodgkin lymphoma overall [odds ratios (95% confidence intervals) by quartile: 1.0; 1.1 (0.4-2.7); 1.8 (0.7-4.9); and 3.6 (1.4-8.9); P trend = 0.003], and this association was similar across the most common non-Hodgkin lymphoma subtypes present in this study.<br><br>CONCLUSION: These results suggest that longer telomere length may be a potential predictor for future risk of non-Hodgkin lymphoma.},
}
@article {pmid19934285,
year = {2009},
author = {Noy, A},
title = {Telomeres: the long and short of developing non-Hodgkin lymphoma.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {15},
number = {23},
pages = {7114-7115},
doi = {10.1158/1078-0432.CCR-09-2233},
pmid = {19934285},
issn = {1557-3265},
mesh = {Cell Death ; Chromosomes/ultrastructure ; Cohort Studies ; Humans ; Lymphocytes/cytology ; Lymphoma, Non-Hodgkin/*metabolism/pathology ; Male ; Research Design ; Risk ; Smoking ; Telomere/*physiology/ultrastructure ; },
abstract = {Chromosomal integrity is vital to the life span of the dividing cell. Telomeres are tandem sequences at chromosome ends that provide protection for the genetic coding material. Erosion of those ends leads to cell death. Does stabilization promote cancer?},
}
@article {pmid19933847,
year = {2010},
author = {Kulkarni, A and Zschenker, O and Reynolds, G and Miller, D and Murnane, JP},
title = {Effect of telomere proximity on telomere position effect, chromosome healing, and sensitivity to DNA double-strand breaks in a human tumor cell line.},
journal = {Molecular and cellular biology},
volume = {30},
number = {3},
pages = {578-589},
pmid = {19933847},
issn = {1098-5549},
support = {R01 CA120205/CA/NCI NIH HHS/United States ; R01 CA120205-04/CA/NCI NIH HHS/United States ; CA12025/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; *Chromosomal Instability ; *DNA Breaks, Double-Stranded ; DNA Repair/*genetics ; Humans ; Sequence Deletion/*genetics ; Telomere/*metabolism ; },
abstract = {The ends of chromosomes, called telomeres, are composed of a DNA repeat sequence and associated proteins, which prevent DNA degradation and chromosome fusion. We have previously used plasmid sequences integrated adjacent to a telomere to demonstrate that mammalian telomeres suppress gene expression, called telomere position effect (TPE). We have also shown that subtelomeric regions are highly sensitive to double-strand breaks, leading to chromosome instability, and that this instability can be prevented by the addition of a new telomere to the break, a process called chromosome healing. We have now targeted the same plasmid sequences to a site 100 kb from a telomere in a human carcinoma cell line to address the effect of telomere proximity on telomere position effect, chromosome healing, and sensitivity to double-strand breaks. The results demonstrate a substantial decrease in TPE 100 kb from the telomere, demonstrating that TPE is very limited in range. Chromosome healing was also diminished 100 kb from the telomere, consistent with our model that chromosome healing serves as a repair process for restoring lost telomeres. Conversely, the region 100 kb from the telomere was highly sensitive to double-strand breaks, demonstrating that the sensitive region is a relatively large target for ionizing radiation-induced chromosome instability.},
}
@article {pmid19933046,
year = {2009},
author = {Smith, V and Dai, F and Spitz, M and Peters, GJ and Fiebig, HH and Hussain, A and Burger, AM},
title = {Telomerase activity and telomere length in human tumor cells with acquired resistance to anticancer agents.},
journal = {Journal of chemotherapy (Florence, Italy)},
volume = {21},
number = {5},
pages = {542-549},
doi = {10.1179/joc.2009.21.5.542},
pmid = {19933046},
issn = {1973-9478},
mesh = {Antineoplastic Agents/*pharmacology ; Blotting, Western ; Colony-Forming Units Assay ; *Drug Resistance, Neoplasm ; Female ; Glutathione/metabolism ; Humans ; Multidrug Resistance-Associated Proteins/metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; RNA, Messenger/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*metabolism ; Telomere/*genetics ; Tumor Cells, Cultured/drug effects/metabolism ; },
abstract = {Telomeres and telomerase are targets for anticancer drug development and specific inhibitors are currently under clinical investigation. However, it has been reported that standard cytotoxic agents can affect telomere length and telomerase activity suggesting that they also have of a role in drug resistance. in this study, telomere lengths and telomerase activity as well as drug efflux pump expression, glutathione (GSH) levels and polyadenosine-ribose polymerase (PARP) cleavage were assessed in a panel of human tumor cell lines made resistant to vindesine, gemcitabine and cisplatin. these included two lung cancer cell lines resistant to vindesine (LXFL 529L/Vind, LXFA 526L/Vind), a renal cancer cell line (RXF944L/Gem) and an ovarian cancer cell line (AG6000) resistant to gemcitabine, and one resistant to cisplatin (ADDP). The resistant clones were compared to their parental lines and evaluated for cross resistance to other cytotoxic agents. Several drug specific resistance patterns were found, and various complex patterns of cross resistance emerged from some cell lines, but these mechanisms of resistance could not be related to drug efflux pump expression, GSH levels or pARp cleavage. However, all displayed changes in telomerase activity and/or telomere length. Our studies present evidence that telomere maintenance should be taken into consideration in efforts not only to overcome drug resistance, but also to optimize the use of telomere-based therapeutics.},
}
@article {pmid19926595,
year = {2009},
author = {van der Harst, P and de Boer, RA and van Veldhuisen, DJ},
title = {The Nobel Prize for medicine for telomere biology and relevance to heart failure research.},
journal = {European journal of heart failure},
volume = {11},
number = {12},
pages = {1113-1115},
doi = {10.1093/eurjhf/hfp163},
pmid = {19926595},
issn = {1879-0844},
mesh = {Genetics/*history ; Heart Failure/*genetics/physiopathology ; History, 21st Century ; Humans ; *Nobel Prize ; Telomere/genetics/*physiology ; },
}
@article {pmid19923274,
year = {2009},
author = {Ferrón, SR and Marqués-Torrejón, MA and Mira, H and Flores, I and Taylor, K and Blasco, MA and Fariñas, I},
title = {Telomere shortening in neural stem cells disrupts neuronal differentiation and neuritogenesis.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {29},
number = {46},
pages = {14394-14407},
pmid = {19923274},
issn = {1529-2401},
mesh = {Aging/genetics/pathology ; Animals ; Animals, Newborn ; *Cell Differentiation/genetics ; Cells, Cultured ; Fetus ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neurites/enzymology/*pathology ; *Neurogenesis/genetics ; Neurons ; Receptors, Notch/physiology ; Signal Transduction/genetics ; Stem Cells/enzymology/*pathology ; Telomerase/deficiency/genetics ; Telomere/enzymology/*pathology ; Tumor Suppressor Protein p53/physiology ; rho-Associated Kinases/biosynthesis/metabolism ; },
abstract = {Proliferation in the subependymal zone (SEZ) and neurogenesis in the olfactory bulb decline in the forebrain of telomerase-deficient mice. The present work reveals additional effects of telomere shortening on neuronal differentiation, as adult multipotent progenitors with critically short telomeres yield reduced numbers of neurons that, furthermore, exhibit underdeveloped neuritic arbors. Genetic data indicate that the tumor suppressor protein p53 not only mediates the adverse effects of telomere attrition on proliferation and self-renewal but it is also involved in preventing normal neuronal differentiation of adult progenitors with dysfunctional telomeres. Interestingly, progenitor cells with short telomeres obtained from fetal brains do not exhibit any replicative defects but also fail to acquire a fully mature neuritic arbor, demonstrating cell cycle-independent effects of telomeres on neuronal differentiation. The negative effect of p53 on neuritogenesis is mechanistically linked to its cooperation with the Notch pathway in the upregulation of small GTPase RhoA kinases, Rock1 and Rock2, suggesting a potential link between DNA damage and the Notch signaling pathway in the control of neuritogenesis. We also show that telomerase expression is downregulated in the SEZ of aging mice leading to telomere length reductions in neurosphere-forming cells and deficient neurogenesis and neuritogenesis. Our results suggest that age-related deficits could be caused partly by dysfunctional telomeres and demonstrate that p53 is a central modulator of adult neurogenesis, regulating both the production and differentiation of postnatally generated olfactory neurons.},
}
@article {pmid19915151,
year = {2010},
author = {Atzmon, G and Cho, M and Cawthon, RM and Budagov, T and Katz, M and Yang, X and Siegel, G and Bergman, A and Huffman, DM and Schechter, CB and Wright, WE and Shay, JW and Barzilai, N and Govindaraju, DR and Suh, Y},
title = {Evolution in health and medicine Sackler colloquium: Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {107 Suppl 1},
number = {Suppl 1},
pages = {1710-1717},
pmid = {19915151},
issn = {1091-6490},
support = {P41 RR003655/RR/NCRR NIH HHS/United States ; R01 AG007992/AG/NIA NIH HHS/United States ; R01 AG028872/AG/NIA NIH HHS/United States ; R01 AG024391-02/AG/NIA NIH HHS/United States ; RR03655/RR/NCRR NIH HHS/United States ; P30 DK020541/DK/NIDDK NIH HHS/United States ; R01 AG024391-03/AG/NIA NIH HHS/United States ; P60 DK020541/DK/NIDDK NIH HHS/United States ; R01 AG-18728-01A1/AG/NIA NIH HHS/United States ; R01 AG018728/AG/NIA NIH HHS/United States ; R01AG7992/AG/NIA NIH HHS/United States ; R01 AG024391-05/AG/NIA NIH HHS/United States ; R01 AG024391-04/AG/NIA NIH HHS/United States ; P01 AG17242/AG/NIA NIH HHS/United States ; P01 AG027734/AG/NIA NIH HHS/United States ; M01 RR012248/RR/NCRR NIH HHS/United States ; R01 AG024391-01/AG/NIA NIH HHS/United States ; P01 AG017242/AG/NIA NIH HHS/United States ; MO1-RR12248/RR/NCRR NIH HHS/United States ; R01 AG024391/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; *Genetic Variation ; Haplotypes ; Humans ; Lipids/blood ; Longevity/*genetics ; Male ; Middle Aged ; RNA/*genetics ; Telomerase/*genetics ; *Telomere ; },
abstract = {Telomere length in humans is emerging as a biomarker of aging because its shortening is associated with aging-related diseases and early mortality. However, genetic mechanisms responsible for these associations are not known. Here, in a cohort of Ashkenazi Jewish centenarians, their offspring, and offspring-matched controls, we studied the inheritance and maintenance of telomere length and variations in two major genes associated with telomerase enzyme activity, hTERT and hTERC. We demonstrated that centenarians and their offspring maintain longer telomeres compared with controls with advancing age and that longer telomeres are associated with protection from age-related diseases, better cognitive function, and lipid profiles of healthy aging. Sequence analysis of hTERT and hTERC showed overrepresentation of synonymous and intronic mutations among centenarians relative to controls. Moreover, we identified a common hTERT haplotype that is associated with both exceptional longevity and longer telomere length. Thus, variations in human telomerase gene that are associated with better maintenance of telomere length may confer healthy aging and exceptional longevity in humans.},
}
@article {pmid19913048,
year = {2009},
author = {Barbieri, M and Paolisso, G and Kimura, M and Gardner, JP and Boccardi, V and Papa, M and Hjelmborg, JV and Christensen, K and Brimacombe, M and Nawrot, TS and Staessen, JA and Pollak, MN and Aviv, A},
title = {Higher circulating levels of IGF-1 are associated with longer leukocyte telomere length in healthy subjects.},
journal = {Mechanisms of ageing and development},
volume = {130},
number = {11-12},
pages = {771-776},
doi = {10.1016/j.mad.2009.10.002},
pmid = {19913048},
issn = {1872-6216},
support = {AG021593/AG/NIA NIH HHS/United States ; AG20132/AG/NIA NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*physiology ; Female ; Homeostasis ; Humans ; Insulin Resistance ; Insulin-Like Growth Factor I/*analysis ; Leukocytes/*ultrastructure ; Longevity/physiology ; Male ; Middle Aged ; Sex Factors ; Telomere/*ultrastructure ; },
abstract = {Mutations that inhibit the insulin-like growth factor-1 (IGF-1) extend the lifespan of worms, flies and mice. However, it appears that relatively low circulating levels of IGF-1 in humans are associated with aging-related diseases and diminished longevity. As leukocyte telomere length (LTL) is ostensibly a biomarker of human aging, we examined the relationship between LTL and blood IGF-1 in a healthy cohort. Our sample comprised 476 healthy, unrelated Caucasians (208 men and 268 women), aged 16-104 years, living in the West Coast of Southern Italy. We measured LTL by Southern blots and IGF-1 by enzyme-linked immunoassay. Both IGF-1 and LTL diminished with age (IGF-1, r=-0.601, P<0.001; LTL, r=-0.706, P<0.001). Age-adjusted LTL was positively associated with IGF-1 level throughout the age range of the cohort (r=0.270, P<0.001). IGF-1 accounted for about 10% of the inter-individual variation in LTL over and above the effect of age. Our findings suggest that both circulating IGF-1 and LTL are indices of healthy aging in humans. Further research will be necessary to establish whether LTL will ultimately be used in clinical settings as an index of healthy aging.},
}
@article {pmid19911388,
year = {2010},
author = {Bhattacharyya, S and Sandy, A and Groden, J},
title = {Unwinding protein complexes in ALTernative telomere maintenance.},
journal = {Journal of cellular biochemistry},
volume = {109},
number = {1},
pages = {7-15},
pmid = {19911388},
issn = {1097-4644},
support = {R01 CA117898/CA/NCI NIH HHS/United States ; R01 CA117898-02/CA/NCI NIH HHS/United States ; CA-117898/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Humans ; RecQ Helicases/*physiology ; Telomere/chemistry/*physiology ; Telomere-Binding Proteins/*physiology ; },
abstract = {Telomeres are composed of specialized chromatin that includes DNA repair/recombination proteins, telomere DNA-binding proteins and a number of three dimensional nucleic acid structures including G-quartets and D-loops. A number of studies suggest that the BLM and WRN recQ-like helicases play important roles in recombination-mediated mechanisms of telomere elongation or Alternative Lengthening of Telomeres (ALT), processes that maintain/elongate telomeres in the absence of telomerase. BLM and WRN localize within ALT-associated nuclear bodies in telomerase-negative immortalized cell lines and interact with the telomere-specific proteins POT1, TRF1 and TRF2. Helicase activity is modulated by these interactions. BLM functions in DNA double-strand break repair processes such as non-homologous end joining, homologous recombination-mediated repair, resolution of stalled replication forks and synthesis-dependent strand annealing, although its precise functions at the telomeres are speculative. WRN also functions in DNA replication, recombination and repair, and in addition to its helicase domain, includes an exonuclease domain not found in other recQ-like helicases. The biochemical properties of BLM and WRN are, therefore, important in biological processes other than DNA replication, recombination and repair. In this review, we discuss some previous and recent findings of human rec-Q-like helicases and their role in telomere elongation during ALT processes.},
}
@article {pmid19910186,
year = {2010},
author = {Aida, J and Izumo, T and Shimomura, N and Nakamura, K and Ishikawa, N and Matsuura, M and Poon, SS and Fujiwara, M and Sawabe, M and Arai, T and Takubo, K},
title = {Telomere lengths in the oral epithelia with and without carcinoma.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {46},
number = {2},
pages = {430-438},
doi = {10.1016/j.ejca.2009.10.018},
pmid = {19910186},
issn = {1879-0852},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Carcinoma in Situ/genetics/*pathology ; Case-Control Studies ; Chromosomal Instability/*genetics ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Ki-67 Antigen/metabolism ; Middle Aged ; Mouth Mucosa/metabolism ; Telomere/*pathology ; Tongue Neoplasms/genetics/*pathology ; },
abstract = {Aging appears to be intrinsically related to carcinogenesis. Genomic instability due to telomere shortening plays an important role in carcinoma development. In order to clarify telomere dysfunction in carcinoma development, we examined the uninvolved epithelium adjacent to carcinoma in situ (CIS), i.e. background of CIS, and CIS itself, compared to control without carcinoma, using an improved quantitative fluorescence in situ hybridization (Q-FISH) method. We also estimated anaphase bridge (AB), which is inferred to be related to chromosomal instability. In all cell types (basal, parabasal, and suprabasal), mean telomere lengths were significantly shorter in the background than in the control. We also demonstrated increased incidences of AB, not only in CIS, but also in the background and control epithelia with excessively shortened telomeres. Thus we have conclusively demonstrated that CIS arises from epithelium with short telomeres.},
}
@article {pmid19906698,
year = {2010},
author = {Lu, CY and Tsai, CH and Brill, SJ and Teng, SC},
title = {Sumoylation of the BLM ortholog, Sgs1, promotes telomere-telomere recombination in budding yeast.},
journal = {Nucleic acids research},
volume = {38},
number = {2},
pages = {488-498},
pmid = {19906698},
issn = {1362-4962},
support = {R01 GM071268/GM/NIGMS NIH HHS/United States ; R01 GM071268-10A2/GM/NIGMS NIH HHS/United States ; GM071268/GM/NIGMS NIH HHS/United States ; },
mesh = {*DNA Breaks, Double-Stranded ; *DNA Repair ; DNA, Ribosomal/chemistry ; Lysine/metabolism ; RecQ Helicases/chemistry/*metabolism ; *Recombination, Genetic ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; Small Ubiquitin-Related Modifier Proteins/*metabolism ; Telomere/*chemistry ; },
abstract = {BLM and WRN are members of the RecQ family of DNA helicases, and in humans their loss is associated with syndromes characterized by genome instability and cancer predisposition. As the only RecQ DNA helicase in the yeast Saccharomyces cerevisiae, Sgs1 is known to safeguard genome integrity through its role in DNA recombination. Interestingly, WRN, BLM and Sgs1 are all known to be modified by the small ubiquitin-related modifier (SUMO), although the significance of this posttranslational modification remains elusive. Here, we demonstrate that Sgs1 is specifically sumoylated under the stress of DNA double strand breaks. The major SUMO attachment site in Sgs1 is lysine 621, which lies between the Top3 binding domain and the DNA helicase domain. Surprisingly, sumoylation of K621 was found to be uniquely required for Sgs1's role in telomere-telomere recombination. In contrast, sumoylation was dispensable for Sgs1's roles in DNA damage tolerance, supppression of direct repeat and rDNA recombination, and promotion of top3Delta slow growth. Our results demonstrate that although modification by SUMO is a conserved feature of RecQ family DNA helicases, the major sites of modification are located on different domains of the protein in different organisms. We suggest that sumoylation of different domains of RecQ DNA helicases from different organisms contributes to conserved roles in regulating telomeric recombination.},
}
@article {pmid19901520,
year = {2010},
author = {Caslini, C},
title = {Transcriptional regulation of telomeric non-coding RNA: implications on telomere biology, replicative senescence and cancer.},
journal = {RNA biology},
volume = {7},
number = {1},
pages = {18-22},
doi = {10.4161/rna.7.1.10257},
pmid = {19901520},
issn = {1555-8584},
mesh = {Animals ; Cellular Senescence/*genetics ; *Gene Expression Regulation ; Humans ; Neoplasms/*genetics/*pathology ; RNA, Untranslated/*genetics ; Telomere/*genetics/metabolism ; *Transcription, Genetic ; },
abstract = {Telomeres, protective nucleoprotein structures located at the ends of eukaryotic chromosomes and until recently regarded as transcriptionally silent, are now known to be transcribed into non-coding RNA molecules called TERRA. The function(s) of TERRA in telomere metabolism is now the subject of intense study given the implications these may have on fundamental biological processes such as aging and cancer. Here is an overview of what is currently known in the novel field of telomere transcription, with regard to the evidence on the possible role of TERRA in telomeric heterochromatin formation, in the epigenetic protection of telomeres from DNA repair mechanisms, and in the regulation of telomerase activity. The implications of TERRA transcriptional regulation on telomerase activity in cancer cells and on the perception of telomere length and control of replicative senescence in cells devoid of telomere maintenance mechanisms will be discussed.},
}
@article {pmid19898524,
year = {2009},
author = {Moser, BA and Nakamura, TM},
title = {Protection and replication of telomeres in fission yeast.},
journal = {Biochemistry and cell biology = Biochimie et biologie cellulaire},
volume = {87},
number = {5},
pages = {747-758},
pmid = {19898524},
issn = {1208-6002},
support = {R01 GM078253/GM/NIGMS NIH HHS/United States ; R01 GM078253-03/GM/NIGMS NIH HHS/United States ; GM078253/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Replication/*physiology ; Genomic Instability/physiology ; Models, Biological ; Schizosaccharomyces/*genetics/metabolism/physiology ; Schizosaccharomyces pombe Proteins/metabolism/physiology ; Telomerase/metabolism/physiology ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/metabolism/physiology ; },
abstract = {Telomeres, the natural ends of linear chromosomes, must be protected and completely replicated to guarantee genomic stability in eukaryotic cells. However, the protected state of telomeres is not compatible with recruitment of telomerase, an enzyme responsible for extending telomeric G-rich repeats during S-phase; thus, telomeres must undergo switches from a protected state to an accessible state during the cell cycle. In this minireview, we will summarize recent advances in our understanding of proteins involved in the protection and replication of telomeres, and the way these factors are dynamically recruited to telomeres during the cell cycle. We will focus mainly on recent results from fission yeast Schizosaccharomyces pombe, and compare them with results from budding yeast Saccharomyces cerevisiae and mammalian cell studies. In addition, a model for the way in which fission yeast cells replicate telomeres will be presented.},
}
@article {pmid19897748,
year = {2010},
author = {Titen, SW and Golic, KG},
title = {Healing of euchromatic chromosome breaks by efficient de novo telomere addition in Drosophila melanogaster.},
journal = {Genetics},
volume = {184},
number = {1},
pages = {309-312},
pmid = {19897748},
issn = {1943-2631},
support = {R01 GM065604/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Chromosome Breakage ; Chromosome Breakpoints ; *DNA Repair ; Drosophila melanogaster/*genetics ; Euchromatin/*genetics ; Female ; Male ; Telomere/*genetics ; },
abstract = {Previously, we observed that heterochromatic 4 and Y chromosomes that had experienced breakage in the male germline were frequently transmitted to progeny. Their behavior suggested that they carried functional telomeres. Here we show that efficient healing by de novo telomere addition is not unique to heterochromatic breaks.},
}
@article {pmid19896964,
year = {2009},
author = {Lorenzini, A and Johnson, FB and Oliver, A and Tresini, M and Smith, JS and Hdeib, M and Sell, C and Cristofalo, VJ and Stamato, TD},
title = {Significant correlation of species longevity with DNA double strand break recognition but not with telomere length.},
journal = {Mechanisms of ageing and development},
volume = {130},
number = {11-12},
pages = {784-792},
pmid = {19896964},
issn = {1872-6216},
support = {AG20955-03/AG/NIA NIH HHS/United States ; R01 AG020955/AG/NIA NIH HHS/United States ; R01 CA087144-01A1/CA/NCI NIH HHS/United States ; CA877144/CA/NCI NIH HHS/United States ; R01 CA087144-03/CA/NCI NIH HHS/United States ; 5R01AG021521/AG/NIA NIH HHS/United States ; R01 AG022443/AG/NIA NIH HHS/United States ; R01 CA087144-02/CA/NCI NIH HHS/United States ; R01 AG021521/AG/NIA NIH HHS/United States ; AG022443/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aging/*physiology ; Animals ; CHO Cells ; Cats ; Cattle ; Chiroptera ; Cricetinae ; Cricetulus ; DNA/metabolism ; DNA Damage/*physiology ; Dogs ; Embryo, Mammalian ; Fibroblasts/ultrastructure ; Gorilla gorilla ; HeLa Cells ; Horses ; Humans ; Longevity/*physiology ; Lung ; Macaca mulatta ; Male ; Mice ; Nuclear Proteins/metabolism ; Rabbits ; Skin/ultrastructure ; Species Specificity ; Telomere/*ultrastructure ; },
abstract = {The identification of the cellular mechanisms responsible for the wide differences in species lifespan remains one of the major unsolved problems of the biology of aging. We measured the capacity of nuclear protein to recognize DNA double strand breaks (DSBs) and telomere length of skin fibroblasts derived from mammalian species that exhibit wide differences in longevity. Our results indicate DNA DSB recognition increases exponentially with longevity. Further, an analysis of the level of Ku80 protein in human, cow, and mouse suggests that Ku levels vary dramatically between species and these levels are strongly correlated with longevity. In contrast mean telomere length appears to decrease with increasing longevity of the species, although not significantly. These findings suggest that an enhanced ability to bind to DNA ends may be important for longevity. A number of possible roles for increased levels of Ku and DNA-PKcs are discussed.},
}
@article {pmid19896585,
year = {2009},
author = {Lukens, JN and Van Deerlin, V and Clark, CM and Xie, SX and Johnson, FB},
title = {Comparisons of telomere lengths in peripheral blood and cerebellum in Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {5},
number = {6},
pages = {463-469},
pmid = {19896585},
issn = {1552-5279},
support = {P30 AG010124/AG/NIA NIH HHS/United States ; AG 10124/AG/NIA NIH HHS/United States ; R01 AG021521-03/AG/NIA NIH HHS/United States ; R01 AG 021521/AG/NIA NIH HHS/United States ; P30 AG010124-16/AG/NIA NIH HHS/United States ; R01 AG021521/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/genetics/pathology ; Alzheimer Disease/*genetics/*pathology/physiopathology ; Apoptosis/genetics ; Cellular Senescence/genetics ; Cerebellum/metabolism/*pathology ; Female ; Genetic Markers/genetics ; Genetic Predisposition to Disease/*genetics ; Genome, Human/genetics ; Humans ; Leukocytes/metabolism/*pathology ; Longevity/genetics ; Male ; Middle Aged ; Polymerase Chain Reaction ; Predictive Value of Tests ; Risk Factors ; Sensitivity and Specificity ; Telomere/*genetics ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) patients have been reported to have shorter telomeres in peripheral blood leukocytes (PBLs) than age-matched control subjects. However, it is unclear if PBL telomere length reflects brain telomere length, which might play a more direct role in AD pathogenesis. We examined the correlation between PBL and cerebellum telomere length in AD patients, and compared telomere lengths in cerebella from individuals with AD versus age-matched control subjects.<br><br>METHODS: Mean telomere lengths were measured using quantitative telomere polymerase chain reaction of genomic DNA prepared from matched PBL and cerebellum samples from 29 individuals with pathologically confirmed sporadic AD. Telomere length was also measured in cerebellum samples of 30 AD patients versus 22 unaffected age-matched control subjects.<br><br>RESULTS: The PBL and cerebellum telomere lengths were directly correlated in individuals with AD (r = 0.42, P = 0.023). Nonetheless, cerebellum telomere lengths were not significantly different in AD patients and age-matched control subjects.<br><br>CONCLUSIONS: Reduced PBL telomere length in AD might not reflect reduced telomere length in bulk brain tissue, but may be a marker of changes in a subset of brain tissues or other tissues that affect the pathogenesis of AD.},
}
@article {pmid19893630,
year = {2009},
author = {Lund, TC and Glass, TJ and Tolar, J and Blazar, BR},
title = {Expression of telomerase and telomere length are unaffected by either age or limb regeneration in Danio rerio.},
journal = {PloS one},
volume = {4},
number = {11},
pages = {e7688},
pmid = {19893630},
issn = {1932-6203},
mesh = {Age Factors ; Animals ; Blotting, Southern ; Extremities/*pathology ; *Gene Expression Regulation, Enzymologic ; Humans ; Models, Biological ; *Regeneration ; Telomerase/*biosynthesis/metabolism ; Telomere/*ultrastructure ; Time Factors ; Tissue Distribution ; Zebrafish ; },
abstract = {BACKGROUND: The zebrafish is an increasingly popular model for studying many aspects of biology. Recently, ztert, the zebrafish homolog of the mammalian telomerase gene has been cloned and sequenced. In contrast to humans, it has been shown that the zebrafish maintains telomerase activity for much of its adult life and has remarkable regenerative capacity. To date, there has been no longitudinal study to assess whether this retention of telomerase activity equates to the retention of chromosome telomere length through adulthood.<br><br>We have systematically analyzed individual organs of zebrafish with regard to both telomere length and telomerase activity at various time points in its adult life. Heart, gills, kidney, spleen, liver, and intestine were evaluated at 3 months, 6 months, 9 months, and 2 years of age by Southern blot analysis. We found that telomeres do not appreciably shorten throughout the lifespan of the zebrafish in any organ. In addition, there was little difference in telomere lengths between organs. Even when cells were under the highest pressure to divide after fin-clipping experiments, telomere length was unaffected. All aged (2 year old) tissues examined also expressed active amounts of telomerase activity as assessed by TRAP assay.<br><br>CONCLUSIONS/SIGNIFICANCE: In contrast to several other species including humans, the retention of lifelong telomerase and telomeres, as we have reported here, would be necessary in the zebrafish to maintain its tremendous regenerative capacity. The ongoing study of the zebrafish's ability to maintain telomerase activity may be helpful in unraveling the complexity involved in the maintenance (or lack thereof) of telomeres in other species such the mouse or human.},
}
@article {pmid19892797,
year = {2010},
author = {Pavanello, S and Pesatori, AC and Dioni, L and Hoxha, M and Bollati, V and Siwinska, E and Mielzyńska, D and Bolognesi, C and Bertazzi, PA and Baccarelli, A},
title = {Shorter telomere length in peripheral blood lymphocytes of workers exposed to polycyclic aromatic hydrocarbons.},
journal = {Carcinogenesis},
volume = {31},
number = {2},
pages = {216-221},
pmid = {19892797},
issn = {1460-2180},
mesh = {Adult ; Biomarkers/blood ; Case-Control Studies ; DNA Methylation ; Humans ; Lymphocytes/*drug effects ; Male ; Micronuclei, Chromosome-Defective ; Middle Aged ; Occupational Exposure/*adverse effects ; Polycyclic Aromatic Hydrocarbons/*adverse effects ; Polymerase Chain Reaction ; Pyrenes/metabolism ; Telomere/*chemistry ; Young Adult ; },
abstract = {Shorter telomere length (TL) in peripheral blood lymphocytes (PBLs) is predictive of lung cancer risk. Polycyclic aromatic hydrocarbons (PAHs) are established lung carcinogens that cause chromosome instability. Whether PAH exposure and its molecular effects are linked with shorter TL has never been evaluated. In the present study, we investigated the effect of chronic exposure to PAHs on TL measured in PBLs of Polish male non-current smoking cokeoven workers and matched controls. PAH exposure and molecular effects were characterized using measures of internal dose (urinary 1-pyrenol), effective dose [anti-benzo[a]pyrene diolepoxide (anti-BPDE)-DNA adduct], genetic instability (micronuclei, MN) and DNA methylation [p53 promoter and Alu and long interspersed nuclear element-1 (LINE-1) repetitive elements, as surrogate measures of global methylation] in PBLs. TL was measured by real-time polymerase chain reaction. Cokeoven workers were heavily exposed to PAHs (79% exceeded the urinary 1-pyrenol biological exposure index) and exhibited lower TL (P = 0.038) than controls, as well as higher levels of genetic and chromosomal alterations [i.e. anti-BPDE-DNA adduct and MN (P < 0.0001)] and epigenetic changes [i.e. p53 gene-specific promoter and global methylation (P <or= 0.001)]. TL decreased with longer duration of work as cokeoven worker (P = 0.039) and in all subjects with higher levels of anti-BPDE-DNA adduct (P = 0.042), p53 hypomethylation (P = 0.005) and MN (P = 0.009). In multivariate analysis, years of work in cokery (P = 0.008) and p53 hypomethylation (P = 0.001) were the principal determinants of shorter TL. Our results indicate that shorter TL is associated with chronic PAH exposure. The interrelations with other genetic and epigenetic mechanisms in our data suggest that shorter TL could be a central event in PAH carcinogenesis.},
}
@article {pmid19889414,
year = {2010},
author = {Salpea, KD and Talmud, PJ and Cooper, JA and Maubaret, CG and Stephens, JW and Abelak, K and Humphries, SE},
title = {Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation.},
journal = {Atherosclerosis},
volume = {209},
number = {1},
pages = {42-50},
pmid = {19889414},
issn = {1879-1484},
support = {RG/08/008/25291/BHF_/British Heart Foundation/United Kingdom ; FS/06/053/BHF_/British Heart Foundation/United Kingdom ; RG2005/014/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Asian People/genetics ; Cellular Senescence ; Cohort Studies ; Diabetes Mellitus, Type 2/*genetics ; Female ; Heterozygote ; Humans ; Ion Channels/*genetics ; Male ; Middle Aged ; Mitochondria/metabolism ; Mitochondrial Proteins/*genetics ; Oxidative Stress/*genetics ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; Reactive Oxygen Species/metabolism ; Telomere/genetics/*metabolism ; Uncoupling Protein 2 ; White People/genetics ; Young Adult ; },
abstract = {OBJECTIVE: High oxidative stress potentially leads to accelerated telomere shortening and consequent premature cell senescence, implicated in type 2 diabetes (T2D) development. Therefore, we studied the association of leukocyte telomere length (LTL) with the presence of T2D, as well as the effect on the patients' LTL of plasma oxidative stress and of variation in UCP2, a gene involved in the mitochondrial production of reactive oxygen species.<br><br>METHODS: Mean LTL was determined in 569 Caucasian, 103 South Asian and 70 Afro-Caribbean T2D patients aged from 24 to 92 years, 81 healthy Caucasian male students aged from 18 to 28 years and 367 healthy Caucasian men aged from 40 to 61 years by real-time PCR. Plasma total antioxidant status (TAOS) was measured in the T2D patients by a photometric microassay. The patients were also genotyped for the UCP2 functional variants -866G>A and A55V.<br><br>RESULTS: Afro-Carribeans had 510bp longer mean length compared to Caucasians (p<0.0001) and 500bp longer than South Asians (p=0.004). T2D subjects displayed shorter age-adjusted LTL compared to controls [6.94(6.8-7.03) vs. 7.72(7.53-7.9), p<0.001] with subjects in the middle and the lowest tertile of LTL having significantly higher odds ratios for T2D compared to those in the highest tertile [1.50(1.08-2.07) and 5.04(3.63-6.99), respectively, p<0.0001]. In the patients, LTL was correlated negatively with age (r=-0.18, p<0.0001) and positively with TAOS measures (r=0.12, p=0.01) after adjusting for age, while carriers of the UCP2 -866A allele had shorter age-adjusted LTL than common homozygotes [6.86(6.76-6.96)kb vs. 7.03(6.91-7.15)kb, p=0.04].<br><br>CONCLUSION: The present data suggest that shorter LTL is associated with the presence of T2D and this could be partially attributed to the high oxidative stress in these patients. The association of the UCP2 functional promoter variant with the LTL implies a link between mitochondrial production of reactive oxygen species and shorter telomere length in T2D.},
}
@article {pmid19888289,
year = {2009},
author = {Greenwood, J and Cooper, JP},
title = {Trapping Rap1 at the telomere to prevent chromosome end fusions.},
journal = {The EMBO journal},
volume = {28},
number = {21},
pages = {3277-3278},
pmid = {19888289},
issn = {1460-2075},
mesh = {DNA Damage ; Humans ; Shelterin Complex ; *Telomere ; Telomere-Binding Proteins/*metabolism ; },
}
@article {pmid19887628,
year = {2009},
author = {Schoeftner, S and Blanco, R and Lopez de Silanes, I and Muñoz, P and Gómez-López, G and Flores, JM and Blasco, MA},
title = {Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {106},
number = {46},
pages = {19393-19398},
pmid = {19887628},
issn = {1091-6490},
mesh = {Aging, Premature/*genetics/metabolism/pathology ; Animals ; Cell Cycle/genetics ; DNA Damage/*genetics ; Female ; Gene Expression Profiling ; Keratin-15 ; Keratin-5/genetics ; Male ; Mice ; Mice, Transgenic ; Skin/*metabolism/pathology ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Transcription, Genetic ; *X Chromosome Inactivation ; },
abstract = {Telomeres are heterochromatic structures at chromosome ends essential for chromosomal stability. Telomere shortening and the accumulation of dysfunctional telomeres are associated with organismal aging. Using telomerase-deficient TRF2-overexpressing mice (K5TRF2/Terc(-/-)) as a model for accelerated aging, we show that telomere shortening is paralleled by a gradual deregulation of the mammalian transcriptome leading to cumulative changes in a defined set of genes, including up-regulation of the mTOR and Akt survival pathways and down-regulation of cell cycle and DNA repair pathways. Increased DNA damage from dysfunctional telomeres leads to reduced deposition of H3K27me3 onto the inactive X chromosome (Xi), impaired association of the Xi with telomeric transcript accumulations (Tacs), and reactivation of an X chromosome-linked K5TRF2 transgene that is subjected to X-chromosome inactivation in female mice with sufficiently long telomeres. Exogenously induced DNA damage also disrupts Xi-Tacs, suggesting DNA damage at the origin of these alterations. Collectively, these findings suggest that critically short telomeres activate a persistent DNA damage response that alters gene expression programs in a nonstochastic manner toward cell cycle arrest and activation of survival pathways, as well as impacts the maintenance of epigenetic memory and nuclear organization, thereby contributing to organismal aging.},
}
@article {pmid19887512,
year = {2010},
author = {Artandi, SE and DePinho, RA},
title = {Telomeres and telomerase in cancer.},
journal = {Carcinogenesis},
volume = {31},
number = {1},
pages = {9-18},
pmid = {19887512},
issn = {1460-2180},
support = {R01 CA084628/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cellular Senescence ; Dyskeratosis Congenita/enzymology/genetics ; Germ-Line Mutation ; Humans ; Mice ; Mice, Knockout ; Neoplasms/enzymology/*genetics ; Telomerase/genetics/*metabolism ; *Telomere ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Myriad genetic and epigenetic alterations are required to drive normal cells toward malignant transformation. These somatic events commandeer many signaling pathways that cooperate to endow aspiring cancer cells with a full range of biological capabilities needed to grow, disseminate and ultimately kill its host. Cancer genomes are highly rearranged and are characterized by complex translocations and regional copy number alterations that target loci harboring cancer-relevant genes. Efforts to uncover the underlying mechanisms driving genome instability in cancer have revealed a prominent role for telomeres. Telomeres are nucleoprotein structures that protect the ends of eukaryotic chromosomes and are particularly vulnerable due to progressive shortening during each round of DNA replication and, thus, a lifetime of tissue renewal places the organism at risk for increasing chromosomal instability. Indeed, telomere erosion has been documented in aging tissues and hyperproliferative disease states-conditions strongly associated with increased cancer risk. Telomere dysfunction can produce the opposing pathophysiological states of degenerative aging or cancer with the specific outcome dictated by the integrity of DNA damage checkpoint responses. In most advanced cancers, telomerase is reactivated and serves to maintain telomere length and emerging data have also documented the capacity of telomerase to directly regulate cancer-promoting pathways. This review covers the role of telomeres and telomerase in the biology of normal tissue stem/progenitor cells and in the development of cancer.},
}
@article {pmid19887064,
year = {2010},
author = {Tahmaseb, K and Turchi, JJ},
title = {Intrinsic hTRF1 fluorescence quenching reveals details of telomere DNA binding activity: impact of DNA length, structure and position of telomeric repeats.},
journal = {Archives of biochemistry and biophysics},
volume = {493},
number = {2},
pages = {207-212},
pmid = {19887064},
issn = {1096-0384},
support = {R01 CA082741/CA/NCI NIH HHS/United States ; R01 CA082741-08/CA/NCI NIH HHS/United States ; CA82741/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; DNA/chemistry/genetics/*metabolism ; Fluorescence ; Humans ; Kinetics ; Protein Binding/physiology ; Protein Multimerization/*physiology ; Protein Structure, Quaternary/physiology ; Protein Structure, Secondary/physiology ; Protein Structure, Tertiary/physiology ; Repetitive Sequences, Nucleic Acid/*physiology ; Telomere/chemistry/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/chemistry/genetics/*metabolism ; },
abstract = {The myb-DNA binding domain is characterized by a 3-alpha helical bundle and three repeats of this domain drive sequence specific DNA binding of the c-myb transcription factor. Human TRF1 contains a single myb-related domain and as a homodimer, enables the sequence specific binding of telomeric DNA. In this report we provide a kinetic assessment of hTRF1 DNA binding activity. Using intrinsic fluorescence quenching we present evidence that hTRF1 binds to both telomeric and non-telomeric DNA with kinetic discrimination to allow stable binding to telomeric tracts of DNA. The position of telomere repeats does not impact binding though the number of repeats and structure does impact binding. Kinetic analysis of DNA-dependent intrinsic tryptophan fluorescence quenching of hTRF1 revealed a two step binding process that is impacted by telomere repeat length, position, and structure. These data are consistent with existing structural and equilibrium binding data for hTRF1 recognition and binding of telomere DNA.},
}
@article {pmid19884805,
year = {2010},
author = {Raynaud, CM and Hernandez, J and Llorca, FP and Nuciforo, P and Mathieu, MC and Commo, F and Delaloge, S and Sabatier, L and André, F and Soria, JC},
title = {DNA damage repair and telomere length in normal breast, preneoplastic lesions, and invasive cancer.},
journal = {American journal of clinical oncology},
volume = {33},
number = {4},
pages = {341-345},
doi = {10.1097/COC.0b013e3181b0c4c2},
pmid = {19884805},
issn = {1537-453X},
mesh = {Adult ; Aged ; Breast/*cytology/pathology ; Breast Neoplasms/genetics/*pathology ; *DNA Damage ; *DNA Repair ; Female ; Histones/genetics/metabolism ; Humans ; Middle Aged ; Neoplasm Invasiveness ; Precancerous Conditions/genetics/*pathology ; Telomere/genetics/parasitology/*ultrastructure ; },
abstract = {OBJECTIVES: Carcinogenesis is a multistep process involving the accumulation of genetic and molecular abnormalities. It has been suggested that there is a relationship between telomere attrition in the early stages of carcinogenesis and activation of the DNA damage response machinery. We explored telomere length modification and damage response pathway activation at 3 steps of breast carcinogenesis.<br><br>METHODS: We carried out a retrospective immunohistochemical analysis of pathway ataxia telangiectasia mutated (p-ATM) (series 1981) and gamma-H2AX (series 139) levels in normal breast, preneoplastic lesions, and invasive carcinoma. Fluorescent in situ hybridization was used to analyze telomere length at each stage.<br><br>RESULTS: ATM was activated in 45% of normal tissue samples, 70% of preneoplastic lesions, and 14% of breast carcinomas. The increase in ATM activation, between normal tissues and preneoplasia, was not significant (P = 0.095), whereas, ATM repression between preneoplasia and cancer was significant (P = 0.0023). Telomeres in preneoplastic lesions were more frequently shorter than those in normal tissues (P = 0.0116). Finally, telomere lengths were long in 38.9% and very short in 38.9% of breast carcinomas (P = 0.0087 for comparisons with preneoplastic lesions).<br><br>CONCLUSIONS: This study suggests that a major defect in DNA repair occurs between preneoplasia and breast cancer. This defect is associated with changes in telomere length between the preneoplastic and the cancer stage.},
}
@article {pmid19884796,
year = {2009},
author = {Lisby, M and Géli, V},
title = {DNA damage response to eroded telomeres.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {8},
number = {22},
pages = {3617-3618},
doi = {10.4161/cc.8.22.9945},
pmid = {19884796},
issn = {1551-4005},
mesh = {DNA Damage ; DNA Repair/*genetics ; Endodeoxyribonucleases/metabolism ; Exodeoxyribonucleases/metabolism ; Models, Genetic ; Rad52 DNA Repair and Recombination Protein/metabolism ; Recombination, Genetic/*genetics ; S Phase/physiology ; Saccharomyces cerevisiae Proteins/metabolism ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/metabolism ; },
}
@article {pmid19884503,
year = {2009},
author = {Gelinas, AD and Paschini, M and Reyes, FE and Héroux, A and Batey, RT and Lundblad, V and Wuttke, DS},
title = {Telomere capping proteins are structurally related to RPA with an additional telomere-specific domain.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {106},
number = {46},
pages = {19298-19303},
pmid = {19884503},
issn = {1091-6490},
support = {R01 GM083953/GM/NIGMS NIH HHS/United States ; T32 GM008732/GM/NIGMS NIH HHS/United States ; GM083953/GM/NIGMS NIH HHS/United States ; R01 GM059414/GM/NIGMS NIH HHS/United States ; P30 EB009998/EB/NIBIB NIH HHS/United States ; T32 GM-008732/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Motifs ; Cell Cycle Proteins/*chemistry/genetics ; Conserved Sequence ; Crystallography, X-Ray ; Evolution, Molecular ; Protein Structure, Tertiary ; Replication Protein A/*chemistry/genetics ; Saccharomyces cerevisiae Proteins/*chemistry/genetics ; Schizosaccharomyces pombe Proteins/*chemistry/genetics ; Telomere/*metabolism ; Telomere-Binding Proteins/*chemistry/genetics ; },
abstract = {Telomeres must be capped to preserve chromosomal stability. The conserved Stn1 and Ten1 proteins are required for proper capping of the telomere, although the mechanistic details of how they contribute to telomere maintenance are unclear. Here, we report the crystal structures of the C-terminal domain of the Saccharomyces cerevisiae Stn1 and the Schizosaccharomyces pombe Ten1 proteins. These structures reveal striking similarities to corresponding subunits in the replication protein A complex, further supporting an evolutionary link between telomere maintenance proteins and DNA repair complexes. Our structural and in vivo data of Stn1 identify a new domain that has evolved to support a telomere-specific role in chromosome maintenance. These findings endorse a model of an evolutionarily conserved mechanism of DNA maintenance that has developed as a result of increased chromosomal structural complexity.},
}
@article {pmid19881950,
year = {2009},
author = {Samassekou, O and Ntwari, A and Hébert, J and Yan, J},
title = {Individual telomere lengths in chronic myeloid leukemia.},
journal = {Neoplasia (New York, N.Y.)},
volume = {11},
number = {11},
pages = {1146-1154},
pmid = {19881950},
issn = {1476-5586},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*genetics/*pathology ; Male ; Middle Aged ; Telomere/*pathology ; Young Adult ; },
abstract = {Chronic myeloid leukemia (CML) is a neoplasia characterized by proliferation of a myeloid cell lineage and chromosome translocation t(9;22) (q34;q11.2). As in the case of most cancers, the average telomere length in CML cells is shorter than that in normal blood cells. However, there are currently no data available concerning specific individual telomere length in CML. Here, we studied telomere length on each chromosome arm of CML cells. In situ hybridization with peptide nucleic acid probes was performed on CML cells in metaphase. The fluorescence intensity of each specific telomere was converted into kilobases according to the telomere restriction fragment results for each sample. We found differences in telomere length between short arm ends and long arm ends. We observed recurrent telomere length changes as well as telomere length maintenance and elongation in some individual telomeres. We propose a possible involvement of individual telomere length changes to some chromosomal abnormalities in CML. We suggest that individual telomere length maintenance is chromosome arm-specific associated with leukemia cells.},
}
@article {pmid19880356,
year = {2009},
author = {Nnakwe, CC and Altaf, M and Côté, J and Kron, SJ},
title = {Dissection of Rad9 BRCT domain function in the mitotic checkpoint response to telomere uncapping.},
journal = {DNA repair},
volume = {8},
number = {12},
pages = {1452-1461},
pmid = {19880356},
issn = {1568-7856},
support = {R01 GM060443-08/GM/NIGMS NIH HHS/United States ; R01 GM060443-06A2/GM/NIGMS NIH HHS/United States ; R01 GM060443-07/GM/NIGMS NIH HHS/United States ; R01 GM060443/GM/NIGMS NIH HHS/United States ; F31 CA110277/CA/NCI NIH HHS/United States ; R01 GM60443/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Motifs ; Cell Cycle Proteins/chemistry/genetics/*metabolism ; Chromatin/genetics ; DNA Damage ; Humans ; *Mitosis ; Models, Molecular ; Molecular Sequence Data ; Phosphoserine ; Protein Binding ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/chemistry/*cytology/genetics/*metabolism ; Sequence Alignment ; Telomere/*genetics ; },
abstract = {In Saccharomyces cerevisiae, destabilizing telomeres, via inactivation of telomeric repeat binding factor Cdc13, induces a cell cycle checkpoint that arrests cells at the metaphase to anaphase transition--much like the response to an unrepaired DNA double strand break (DSB). Throughout the cell cycle, the multi-domain adaptor protein Rad9 is required for the activation of checkpoint effector kinase Rad53 in response to DSBs and is similarly necessary for checkpoint signaling in response to telomere uncapping. Rad53 activation in G1 and S phase depends on Rad9 association with modified chromatin adjacent to DSBs, which is mediated by Tudor domains binding histone H3 di-methylated at K79 and BRCT domains to histone H2A phosphorylated at S129. Nonetheless, Rad9 Tudor or BRCT mutants can initiate a checkpoint response to DNA damage in nocodazole-treated cells. Mutations affecting di-methylation of H3 K79, or its recognition by Rad9 enhance 5' strand resection upon telomere uncapping, and potentially implicate Rad9 chromatin binding in the checkpoint response to telomere uncapping. Indeed, we report that Rad9 binds to sub-telomeric chromatin, upon telomere uncapping, up to 10 kb from the telomere. Rad9 binding occurred within 30 min after inactivating Cdc13, preceding Rad53 phosphorylation. In turn, Rad9 Tudor and BRCT domain mutations blocked chromatin binding and led to attenuated checkpoint signaling as evidenced by decreased Rad53 phosphorylation and impaired cell cycle arrest. Our work identifies a role for Rad9 chromatin association, during mitosis, in the DNA damage checkpoint response to telomere uncapping, suggesting that chromatin binding may be an initiating event for checkpoints throughout the cell cycle.},
}
@article {pmid19879280,
year = {2010},
author = {Tamayo, M and Mosquera, A and Rego, JI and Fernández-Sueiro, JL and Blanco, FJ and Fernández, JL},
title = {Differing patterns of peripheral blood leukocyte telomere length in rheumatologic diseases.},
journal = {Mutation research},
volume = {683},
number = {1-2},
pages = {68-73},
doi = {10.1016/j.mrfmmm.2009.10.010},
pmid = {19879280},
issn = {0027-5107},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/physiology ; Arthritis, Psoriatic/blood/*genetics/pathology ; Arthritis, Rheumatoid/blood/*genetics/pathology ; Case-Control Studies ; Child ; Child, Preschool ; Humans ; Leukocytes ; Middle Aged ; Osteoporosis/blood/*genetics/pathology ; Polymerase Chain Reaction ; Spondylitis, Ankylosing/blood/*genetics/pathology ; Telomere/*genetics ; Young Adult ; },
abstract = {Telomeres progressively shorten with repeated somatic tissue cell division, their length being an indicator of cellular ageing. Telomeric dysfunction may be implicated in a variety of diseases. We measured mean telomere length in peripheral blood leukocytes (PBL) from patients with various rheumatologic diseases. Mean PBL telomere length was measured using real-time quantitative polymerase chain reaction (Q-PCR) assay in a control population (n=130; age range: 3-94 years) and in subjects diagnosed with rheumatoid arthritis (RA; n=86; age range: 31-82 years), psoriatic arthritis (PA; n=56; age range: 26-79 years) and ankylosing spondylitis (AS; n=59; age range: 21-75 years). These diseases are associated with chronic systemic inflammatory activity. Telomere length was also quantified in subjects with osteoarthritis (OA; n=34; age range: 43-82 years) and osteoporosis (OP; n=35; age range: 59-95 years), diseases without a chronic systemic inflammatory component. Telomere length in OA showed no differences from age-matched controls (p=0.234), but was significantly shorter in OP (p=0.001). Telomere length was significantly longer than controls in RA (p=0.015), PA (p<0.001) and AS (p<0.001). Different patterns in telomere length from PBL are evidenced in rheumatologic pathologies, possibly dependent on the presence or absence of chronic systemic inflammation.},
}
@article {pmid19875981,
year = {2010},
author = {Kozak, ML and Chavez, A and Dang, W and Berger, SL and Ashok, A and Guo, X and Johnson, FB},
title = {Inactivation of the Sas2 histone acetyltransferase delays senescence driven by telomere dysfunction.},
journal = {The EMBO journal},
volume = {29},
number = {1},
pages = {158-170},
pmid = {19875981},
issn = {1460-2075},
support = {P01-AG031862/AG/NIA NIH HHS/United States ; P01 AG031862/AG/NIA NIH HHS/United States ; R01-AG021521/AG/NIA NIH HHS/United States ; R01 AG021521/AG/NIA NIH HHS/United States ; T32 AG000255/AG/NIA NIH HHS/United States ; T32-AG000255/AG/NIA NIH HHS/United States ; },
mesh = {Acetylation ; Epistasis, Genetic ; Gene Deletion ; Genes, Fungal ; Histone Acetyltransferases/antagonists &amp; inhibitors/genetics/*metabolism ; Histones/chemistry/metabolism ; Models, Biological ; Multiprotein Complexes ; Mutation ; Recombination, Genetic ; Saccharomyces cerevisiae/cytology/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Sirtuin 2/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Changes in telomere chromatin have been linked to cellular senescence, but the underlying mechanisms and impact on lifespan are unclear. We found that inactivation of the Sas2 histone acetyltransferase delays senescence in Saccharomyces cerevisiae telomerase (tlc1) mutants through a homologous recombination-dependent mechanism. Sas2 acetylates histone H4 lysine 16 (H4K16), and telomere shortening in tlc1 mutants was accompanied by a selective and Sas2-dependent increase in subtelomeric H4K16 acetylation. Further, mutation of H4 lysine 16 to arginine, which mimics constitutively deacetylated H4K16, delayed senescence and was epistatic to sas2 deletion, indicating that deacetylated H4K16 mediates the delay caused by sas2 deletion. Sas2 normally prevents the Sir2/3/4 heterochromatin complex from leaving the telomere and spreading to internal euchromatic loci. Senescence was delayed by sir3 deletion, but not sir2 deletion, indicating that senescence delay is mediated by release of Sir3 specifically from the telomere repeats. In contrast, sir4 deletion sped senescence and blocked the delay conferred by sas2 or sir3 deletion. We thus show that manipulation of telomere chromatin modulates senescence caused by telomere shortening.},
}
@article {pmid19864453,
year = {2009},
author = {Butts, S and Riethman, H and Ratcliffe, S and Shaunik, A and Coutifaris, C and Barnhart, K},
title = {Correlation of telomere length and telomerase activity with occult ovarian insufficiency.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {94},
number = {12},
pages = {4835-4843},
pmid = {19864453},
issn = {1945-7197},
support = {K12 HD043459/HD/NICHD NIH HHS/United States ; T32 HD040135/HD/NICHD NIH HHS/United States ; K12 HD043459-04/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Anatomy, Cross-Sectional ; Cell Separation ; DNA/genetics/ultrastructure ; Electrophoresis, Polyacrylamide Gel ; Female ; Fertilization in Vitro ; Follicle Stimulating Hormone/blood ; Granulosa Cells/enzymology ; Humans ; Infertility, Female/*enzymology/*pathology ; Ovarian Diseases/*enzymology/epidemiology/*pathology ; Telomerase/genetics/*metabolism ; Telomere/genetics/*ultrastructure ; Young Adult ; },
abstract = {BACKGROUND: Occult ovarian insufficiency is associated with infertility, impaired response to ovarian stimulation, and reduced live birth rates in women treated with assisted reproductive technologies. Although a decline in ovarian follicle number is expected with age, the proximate causes of occult ovarian insufficiency in young women remain poorly understood. Abnormalities in telomere length and telomerase activity in human granulosa cells may serve as molecular markers for this condition.<br><br>METHODS: A cross-sectional study was performed. Subjects (37 yr old or less) undergoing in vitro fertilization were classified as cases of occult ovarian insufficiency or controls with mechanical infertility (male or tubal factor). Granulosa cells were acquired at the time of oocyte retrieval to quantify telomere length and telomerase activity.<br><br>RESULTS: Fifty-four women were enrolled. Human granulosa cell telomerase activity was demonstrated, and lack of granulosa cell telomerase activity was associated with occult ovarian insufficiency (odds ratio, 11.0; 95% confidence interval, 1.3-495.6; P = 0.02). Telomeres were shorter in women with occult ovarian insufficiency than in controls (relative telomere/single copy gene ratio, 1.88 vs. 3.15; P = 0.039).<br><br>CONCLUSIONS: Aberrant telomere homeostasis is associated with occult ovarian insufficiency in young women. This finding is consistent with the presence of telomeric attenuation that has been shown in multiple age-related conditions.},
}
@article {pmid19863817,
year = {2009},
author = {De Felice, B and Wilson, RR and Nacca, M},
title = {Telomere shortening may be associated with human keloids.},
journal = {BMC medical genetics},
volume = {10},
number = {},
pages = {110},
pmid = {19863817},
issn = {1471-2350},
mesh = {Adult ; Blotting, Southern ; Cells, Cultured ; Female ; Fibroblasts/enzymology ; *Genetic Association Studies ; Humans ; Keloid/enzymology/*genetics/metabolism/pathology ; Male ; Oxidative Stress ; Polymorphism, Restriction Fragment Length ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*genetics ; Telomere/*genetics/ultrastructure ; },
abstract = {BACKGROUND: Keloids are benign skin tumors that are the effect of a dysregulated wound-healing process in genetically predisposed patients. They are inherited with an autosomal dominant mode with incomplete clinical penetrance and variable expression. Keloids are characterized by formation of excess scar tissue beyond the boundaries of the wound. The exact etiology is still unknown and there is currently no appropriate treatment for keloid disease.<br><br>METHODS: We analyzed sample tissues were obtained from 20 patients with keloid skin lesions and normal skin was obtained from 20 healthy donors. The telomeres were measured by Terminal Restriction Fragment (TRF) analysis and Real-Time PCR assay. Quantitative Real-Time RT-PCR analysis of hTERT gene expression was performed and intracellular ROS generation was measured.<br><br>RESULTS: In this study, we determined whether telomeric shortening and the expression of human telomerase reverse transcriptase (hTERT) occurs in keloid patients. Using Terminal Restriction Fragment (TRF) analysis and Real-Time PCR assay, we detected a significant telomere shortening of 30% in keloid specimens compared to normal skin. Using quantitative Real-Time RT-PCR, telomerase activity was found absent in the keloid tissues. Moreover, an increase in ROS generation was detected in fibroblasts cell cultures from keloid specimens as more time elapsed compared to fibroblasts from normal skin.<br><br>CONCLUSION: Telomere shortening has been reported in several metabolic and cardiovascular diseases. We found that telomere shortening can also be associated with human keloids. Chronic oxidative stress plays a major role in the pathophysiology of several chronic inflammatory diseases. Here we found increased ROS generation in fibroblasts from keloid fibroblasts cell cultures when compared to normal skin fibroblasts. Hence we conclude that oxidative stress might be an important modulator of telomere loss in keloid because of the absence of active telomerase that counteracts telomere shortening.},
}
@article {pmid19861514,
year = {2009},
author = {Hou, L and Savage, SA and Blaser, MJ and Perez-Perez, G and Hoxha, M and Dioni, L and Pegoraro, V and Dong, LM and Zatonski, W and Lissowska, J and Chow, WH and Baccarelli, A},
title = {Telomere length in peripheral leukocyte DNA and gastric cancer risk.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {18},
number = {11},
pages = {3103-3109},
pmid = {19861514},
issn = {1538-7755},
support = {R01 GM063270/GM/NIGMS NIH HHS/United States ; R01 GM063270-01/GM/NIGMS NIH HHS/United States ; R01GM63270/GM/NIGMS NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adenocarcinoma/epidemiology/*genetics/virology ; Adult ; Aged ; Case-Control Studies ; Cohort Studies ; DNA, Neoplasm/*genetics ; Female ; Fruit ; Helicobacter Infections/genetics/pathology/virology ; Helicobacter pylori/genetics ; Humans ; Leukocytes/*pathology ; Male ; Middle Aged ; Poland/epidemiology ; Polymerase Chain Reaction ; Prognosis ; Risk Factors ; Smoking ; Stomach Neoplasms/epidemiology/*genetics/virology ; Telomere/*ultrastructure ; Vegetables ; Young Adult ; },
abstract = {Telomere length reflects lifetime cumulative oxidative stress from environmental exposures, such as cigarette smoking and chronic inflammation. Shortened telomere length is thought to cause genomic instability and has been associated with several cancers. We examined the association of telomere length in peripheral leukocyte DNA with gastric cancer risk as well as potential confounding factors and risk modifiers for telomere length-related risk. In a population-based study of gastric cancer conducted in a high-risk population in Warsaw, Poland, between 1994 and 1996, we measured relative telomere length in 300 cases and 416 age- and gender-matched controls using quantitative real-time PCR. Among controls, telomeres were significantly shorter in association with aging (P < 0.001), increasing pack-years of cigarette smoking (P = 0.02), decreasing fruit intake (P = 0.04), and Helicobacter pylori positivity (P = 0.03). Gastric cancer cases had significantly shorter telomere length (mean +/- SD relative telomere length, 1.25 +/- 0.34) than controls (1.34 +/- 0.35; P = 0.0008). Gastric cancer risk doubled [odds ratio (OR), 2.04; 95% confidence interval (95% CI), 1.33-3.13] among subjects in the shortest compared with the highest quartile of telomere length (P(trend) < 0.001). Telomere length-associated risks were higher among individuals with the lowest risk profile, those H. pylori-negative (OR, 5.45; 95% CI, 2.10-14.1), nonsmokers (OR, 3.07; 95% CI, 1.71-5.51), and individuals with high intake of fruits (OR, 2.43; 95% CI, 1.46-4.05) or vegetables (OR, 2.39; 95% CI, 1.51-3.81). Our results suggest that telomere length in peripheral leukocyte DNA was associated with H. pylori positivity, cigarette smoking, and dietary fruit intake. Shortened telomeres increased gastric cancer risk in this high-risk Polish population.},
}
@article {pmid19858100,
year = {2010},
author = {Basenko, EY and Cesare, AJ and Iyer, S and Griffith, JD and McEachern, MJ},
title = {Telomeric circles are abundant in the stn1-M1 mutant that maintains its telomeres through recombination.},
journal = {Nucleic acids research},
volume = {38},
number = {1},
pages = {182-189},
pmid = {19858100},
issn = {1362-4962},
support = {R01 GM031819/GM/NIGMS NIH HHS/United States ; GM61645/GM/NIGMS NIH HHS/United States ; GM31819/GM/NIGMS NIH HHS/United States ; ES13773/ES/NIEHS NIH HHS/United States ; },
mesh = {DNA, Circular/analysis/*ultrastructure ; Electrophoresis, Gel, Two-Dimensional ; Kluyveromyces/genetics ; Mutation ; *Recombination, Genetic ; Telomere/*chemistry/ultrastructure ; },
abstract = {Some human cancers maintain their telomeres using the alternative lengthening of telomeres (ALT) mechanism; a process thought to involve recombination. Different types of recombinational telomere elongation pathways have been identified in yeasts. In senescing yeast telomerase deletion (ter1-Delta) mutants with very short telomeres, it has been hypothesized that copying a tiny telomeric circle (t-circle) by a rolling circle mechanism is the key event in telomere elongation. In other cases more closely resembling ALT cells, such as the stn1-M1 mutant of Kluyveromyces lactis, the telomeres appear to be continuously unstable and routinely reach very large sizes. By employing two-dimensional gel electrophoresis and electron microscopy, we show that stn1-M1 cells contain abundant double stranded t-circles ranging from approximately 100 to 30,000 bp in size. We also observed small single-stranded t-circles, specifically composed of the G-rich telomeric strand and tailed circles resembling rolling circle replication intermediates. The t-circles most likely arose from recombination events that also resulted in telomere truncations. The findings strengthen the possibility that t-circles contribute to telomere maintenance in stn1-M1 and ALT cells.},
}
@article {pmid19854361,
year = {2009},
author = {Greider, C},
title = {Carol Greider: unravelling the science of telomeres and telomerase. Interview by Stephen Pincock.},
journal = {Lancet (London, England)},
volume = {374},
number = {9699},
pages = {1413},
doi = {10.1016/S0140-6736(09)61850-X},
pmid = {19854361},
issn = {1474-547X},
mesh = {Career Choice ; *Faculty, Medical ; Humans ; *Molecular Biology ; Nobel Prize ; Telomerase/*genetics ; Telomere/*genetics ; },
}
@article {pmid19854131,
year = {2009},
author = {Surovtseva, YV and Churikov, D and Boltz, KA and Song, X and Lamb, JC and Warrington, R and Leehy, K and Heacock, M and Price, CM and Shippen, DE},
title = {Conserved telomere maintenance component 1 interacts with STN1 and maintains chromosome ends in higher eukaryotes.},
journal = {Molecular cell},
volume = {36},
number = {2},
pages = {207-218},
pmid = {19854131},
issn = {1097-4164},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; GM73169/GM/NIGMS NIH HHS/United States ; R01 GM073169/GM/NIGMS NIH HHS/United States ; GM041803/GM/NIGMS NIH HHS/United States ; R01 GM073169-04/GM/NIGMS NIH HHS/United States ; GM065383/GM/NIGMS NIH HHS/United States ; R01 GM041803/GM/NIGMS NIH HHS/United States ; GM800052/GM/NIGMS NIH HHS/United States ; R01 GM041803-19/GM/NIGMS NIH HHS/United States ; },
mesh = {Anaphase ; Arabidopsis/*metabolism ; Arabidopsis Proteins/*metabolism ; Cell Line, Tumor ; Chromosomal Proteins, Non-Histone/*metabolism ; Chromosomes, Plant/*metabolism ; *Conserved Sequence ; Eukaryotic Cells/*metabolism ; Genomic Instability ; Humans ; In Situ Hybridization, Fluorescence ; Mutation/genetics ; Nucleic Acid Conformation ; Protein Binding ; Recombination, Genetic/genetics ; Telomere/metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Orthologs of the yeast telomere protein Stn1 are present in plants, but other components of the Cdc13/Stn1/Ten1 (CST) complex have only been found in fungi. Here we report the identification of conserved telomere maintenance component 1 (CTC1) in plants and vertebrates. CTC1 encodes an approximately 140 kDa telomere-associated protein predicted to contain multiple OB-fold domains. Arabidopsis mutants null for CTC1 display a severe telomere deprotection phenotype accompanied by a rapid onset of developmental defects and sterility. Telomeric and subtelomeric tracts are dramatically eroded, and chromosome ends exhibit increased G overhangs, recombination, and end-to-end fusions. AtCTC1 both physically and genetically interacts with AtSTN1. Depletion of human CTC1 by RNAi triggers a DNA damage response, chromatin bridges, increased G overhangs, and sporadic telomere loss. These data indicate that CTC1 participates in telomere maintenance in diverse species and that a CST-like complex is required for telomere integrity in multicellular organisms.},
}
@article {pmid19854130,
year = {2009},
author = {Miyake, Y and Nakamura, M and Nabetani, A and Shimamura, S and Tamura, M and Yonehara, S and Saito, M and Ishikawa, F},
title = {RPA-like mammalian Ctc1-Stn1-Ten1 complex binds to single-stranded DNA and protects telomeres independently of the Pot1 pathway.},
journal = {Molecular cell},
volume = {36},
number = {2},
pages = {193-206},
doi = {10.1016/j.molcel.2009.08.009},
pmid = {19854130},
issn = {1097-4164},
mesh = {Animals ; Base Sequence ; DNA, Single-Stranded/*metabolism ; HeLa Cells ; Humans ; Mice ; Molecular Sequence Data ; Multiprotein Complexes/metabolism ; Mutant Proteins/metabolism ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Protein Transport ; Recombinant Proteins ; Replication Protein A/*metabolism ; Sequence Homology, Amino Acid ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {Budding yeast Cdc13, Stn1, and Ten1 form the CST complex to protect telomeres from lethal DNA degradation. It remains unknown whether similar complexes are conserved in higher eukaryotes or not. Here we isolated mammalian STN1 and TEN1 homologs and CTC1 (conserved telomere maintenance component 1). The three proteins contain putative OB-fold domains and form a complex called CST, which binds to single-stranded DNA with high affinity in a sequence-independent manner. CST associates with a fraction of telomeres consistently during the cell cycle, in quiescent cells and Pot1-knockdown cells. It does not colocalize with replication foci in S phase. Significant increases in the abundance of single-stranded G-strand telomeric DNA were observed in Stn1-knockdown cells. We propose that CST is a replication protein A (RPA)-like complex that is not directly involved in conventional DNA replication at forks but plays a role in DNA metabolism frequently required by telomeres.},
}
@article {pmid19854124,
year = {2009},
author = {Wellinger, RJ},
title = {The CST complex and telomere maintenance: the exception becomes the rule.},
journal = {Molecular cell},
volume = {36},
number = {2},
pages = {168-169},
doi = {10.1016/j.molcel.2009.10.001},
pmid = {19854124},
issn = {1097-4164},
mesh = {Animals ; Arabidopsis/metabolism ; Arabidopsis Proteins/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Humans ; Mice ; Models, Biological ; Multiprotein Complexes/*metabolism ; Replication Protein A/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {Telomeres are bound and stabilized by two complexes-CST and shelterin-thought to be species specific and virtually unrelated. In this issue of Molecular Cell, Miyake et al. (2009) and Surovtseva et al. (2009) provide evidence that these complexes coexist and function at telomeres in many species.},
}
@article {pmid19850908,
year = {2009},
author = {Nergadze, SG and Farnung, BO and Wischnewski, H and Khoriauli, L and Vitelli, V and Chawla, R and Giulotto, E and Azzalin, CM},
title = {CpG-island promoters drive transcription of human telomeres.},
journal = {RNA (New York, N.Y.)},
volume = {15},
number = {12},
pages = {2186-2194},
pmid = {19850908},
issn = {1469-9001},
mesh = {Cell Line ; *CpG Islands ; DNA Methylation ; Humans ; Promoter Regions, Genetic ; Telomere/*genetics ; *Transcription, Genetic ; },
abstract = {The longstanding dogma that telomeres, the heterochromatic extremities of linear eukaryotic chromosomes, are transcriptionally silent was overturned by the discovery that DNA-dependent RNA polymerase II (RNAPII) transcribes telomeric DNA into telomeric repeat-containing RNA (TERRA). Here, we show that CpG dinucleotide-rich DNA islands, shared among multiple human chromosome ends, promote transcription of TERRA molecules. TERRA promoters sustain cellular expression of reporter genes, are located immediately upstream of TERRA transcription start sites, and are bound by active RNAPII in vivo. Finally, the identified promoter CpG dinucleotides are methylated in vivo, and cytosine methylation negatively regulates TERRA abundance. The existence of subtelomeric promoters, driving TERRA transcription from independent chromosome ends, supports the idea that TERRA exerts fundamental functions in the context of telomere biology.},
}
@article {pmid19850716,
year = {2010},
author = {Vidal-Cardenas, SL and Greider, CW},
title = {Comparing effects of mTR and mTERT deletion on gene expression and DNA damage response: a critical examination of telomere length maintenance-independent roles of telomerase.},
journal = {Nucleic acids research},
volume = {38},
number = {1},
pages = {60-71},
pmid = {19850716},
issn = {1362-4962},
support = {P01 CA016519/CA/NCI NIH HHS/United States ; P01CA16519/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; *DNA Damage ; Female ; *Gene Expression ; Gene Expression Profiling ; Male ; Mice ; Mice, Knockout ; RNA/genetics/*physiology ; Telomerase/genetics/*physiology ; Telomere/metabolism ; },
abstract = {Telomerase, the essential enzyme that maintains telomere length, contains two core components, TERT and TR. Early studies in yeast and mouse showed that loss of telomerase leads to phenotypes only after several generations, due to telomere shortening. However, recent studies have suggested additional roles for telomerase components in transcription and the response to DNA damage. To examine these potential telomere length maintenance-independent roles of telomerase components, we examined first generation mTR(-/-) and mTERT(-/-) mice with long telomeres. We used gene expression profiling and found no genes that were differentially expressed in mTR(-/-) G1 mice and mTERT(-/-) G1 mice compared with wild-type mice. We also compared the response to DNA damage in mTR(-/-)G1 and mTERT(-/-) G1 mouse embryonic fibroblasts, and found no increase in the response to DNA damage in the absence of either telomerase component compared to wild-type. We conclude that, under physiologic conditions, neither mTR nor mTERT acts as a transcription factor or plays a role in the DNA damage response.},
}
@article {pmid19847201,
year = {2010},
author = {Brugat, T and Gault, N and Baccelli, I and Maës, J and Roborel de Climens, A and Nguyen-Khac, F and Davi, F and Merle-Béral, H and Gilson, E and Goodhardt, M and Delic, J},
title = {Aberrant telomere structure is characteristic of resistant chronic lymphocytic leukaemia cells.},
journal = {Leukemia},
volume = {24},
number = {1},
pages = {246-251},
doi = {10.1038/leu.2009.213},
pmid = {19847201},
issn = {1476-5551},
mesh = {Aged ; Aged, 80 and over ; Apoptosis ; DNA Damage ; Drug Resistance, Neoplasm ; Female ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/*genetics/pathology ; Male ; Middle Aged ; *Telomere ; },
}
@article {pmid19846916,
year = {2009},
author = {Matsuo, T and Shimose, S and Kubo, T and Fujimori, J and Yasunaga, Y and Ochi, M},
title = {Telomeres and telomerase in sarcomas.},
journal = {Anticancer research},
volume = {29},
number = {10},
pages = {3833-3836},
pmid = {19846916},
issn = {1791-7530},
mesh = {Humans ; Sarcoma/*enzymology/*genetics ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres of human tumor cells have two types of telomere maintenance mechanisms by telomerase activation and alternative lengthening of telomeres (ALT). Although over 80% of all carcinomas rely on telomerase activity to maintain stable telomere length, many types of sarcoma elongate telomeres consistent with ALT in the absence of telomerase activity. Recently, the presence of telomerase activity and ALT in several sarcomas was examined extensively, and recent studies indicate a positive correlation between the telomere maintenance mechanism and tumor aggressiveness in several sarcoma types. We reviewed both the activation of telomere maintenance in a variety of common bone and soft tissue sarcoma subtypes, and the consequences of telomere maintenance mechanisms with respect to the clinical characteristics.},
}
@article {pmid19846733,
year = {2009},
author = {Movérare-Skrtic, S and Svensson, J and Karlsson, MK and Orwoll, E and Ljunggren, O and Mellström, D and Ohlsson, C},
title = {Serum insulin-like growth factor-I concentration is associated with leukocyte telomere length in a population-based cohort of elderly men.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {94},
number = {12},
pages = {5078-5084},
doi = {10.1210/jc.2009-1450},
pmid = {19846733},
issn = {1945-7197},
mesh = {Aged ; Aged, 80 and over ; Aging/physiology ; Body Composition/genetics ; Cohort Studies ; DNA/genetics/ultrastructure ; Diabetes Mellitus/genetics ; Humans ; Hypertension/genetics ; Insulin-Like Growth Factor I/*genetics/*metabolism ; Leukocytes/*ultrastructure ; Life Style ; Male ; Odds Ratio ; Population ; Telomerase/genetics ; Telomere/*genetics/*ultrastructure ; },
abstract = {CONTEXT: Both leukocyte telomere length and IGF-I are associated with the aging process. A previous in vitro study suggested that IGF-I may modulate telomerase activity in white blood cells, but little is known whether these two systems interact in vivo.<br><br>PATIENTS AND METHODS: Leukocyte telomere length was determined using a quantitative PCR assay in 2744 elderly men (mean age 75.5 yr, range 69-81 yr) included in the population-based Osteoporotic Fractures in Men-Sweden study. Serum IGF-I concentration was measured using RIA.<br><br>RESULTS: Subjects with a leukocyte telomere length in the lowest tertile group had lower serum IGF-I concentration than subjects in the two tertile groups with longer telomere lengths (P = 0.005). Logistic regression analyses showed that a higher serum IGF-I concentration was associated with a significantly reduced risk of having a leukocyte telomere length in the lowest tertile group and also after adjustment for multiple covariates (P < 0.01). Multivariate linear regression analyses demonstrated that tertile of leukocyte telomere length was positively, whereas age was negatively, associated with serum IGF-I concentration in elderly men.<br><br>CONCLUSIONS: In this large population-based, cross-sectional study, leukocyte telomere length was positively associated with serum IGF-I concentration in elderly men. The mechanisms underlying the association between serum IGF-I concentration and leukocyte telomere length remain to be determined.},
}
@article {pmid19846312,
year = {2010},
author = {Lue, NF},
title = {Plasticity of telomere maintenance mechanisms in yeast.},
journal = {Trends in biochemical sciences},
volume = {35},
number = {1},
pages = {8-17},
pmid = {19846312},
issn = {0968-0004},
support = {GM062631/GM/NIGMS NIH HHS/United States ; GM069507/GM/NIGMS NIH HHS/United States ; R01 GM069507-04/GM/NIGMS NIH HHS/United States ; R01 GM062631/GM/NIGMS NIH HHS/United States ; R01 GM069507/GM/NIGMS NIH HHS/United States ; R01 GM062631-08/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomal Proteins, Non-Histone/metabolism ; Saccharomycetales/classification/*cytology/*genetics/metabolism ; Telomerase/metabolism ; Telomere/chemistry/*metabolism ; },
abstract = {Telomeres, the nucleoprotein structures located at linear eukaryotic chromosomal termini, are essential for chromosome stability and are maintained by the special reverse transcriptase named telomerase. In the Saccharomycotina subphylum of budding yeast, telomere repeat sequences and binding factors, as well as telomerase components, are exceptionally diverse and distinct from those found in other eukaryotes. In this survey, I report a comparative analysis of the domain structures of telomere and telomerase-related factors made possible by the recent sequencing of multiple yeast genomes. This analysis revealed both conserved and variable aspects of telomere maintenance. Based on these findings, I propose a plausible series of evolutionary events in budding yeast to account for its exceptional telomere structural divergence.},
}
@article {pmid19841239,
year = {2009},
author = {Blackburn, E},
title = {Telomeres and Tetrahymena: an interview with Elizabeth Blackburn.},
journal = {Disease models &amp; mechanisms},
volume = {2},
number = {11-12},
pages = {534-537},
doi = {10.1242/dmm.003418},
pmid = {19841239},
issn = {1754-8411},
mesh = {Animals ; Biology/history ; Biomedical Research/methods ; Chromosomes/ultrastructure ; Health Policy ; History, 20th Century ; History, 21st Century ; Humans ; Mentors ; Telomere/*ultrastructure ; Tetrahymena/*metabolism ; },
}
@article {pmid19841238,
year = {2009},
author = {Meznikova, M and Erdmann, N and Allsopp, R and Harrington, LA},
title = {Telomerase reverse transcriptase-dependent telomere equilibration mitigates tissue dysfunction in mTert heterozygotes.},
journal = {Disease models &amp; mechanisms},
volume = {2},
number = {11-12},
pages = {620-626},
pmid = {19841238},
issn = {1754-8411},
support = {/WT_/Wellcome Trust/United Kingdom ; 55005945/HHMI/Howard Hughes Medical Institute/United States ; R01 AG02398/AG/NIA NIH HHS/United States ; 84637/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Apoptosis ; Bone Marrow Cells/cytology ; Disease Models, Animal ; Genotype ; Heterozygote ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; *Mutation ; Saccharomycetales ; Telomerase/*genetics/*metabolism ; Telomere/*ultrastructure ; },
abstract = {Autosomal dominant mutations in telomere-associated factors elicit a disease known as dyskeratosis congenita (DKC), and patients suffer proliferative abnormalities associated with telomere erosion. Mice that are heterozygous for telomerase genes (Tert or Terc, hereafter referred to as mTert and mTerc) are useful models of telomerase haploinsufficiency, but do not strictly mimic DKC. In strains with long telomeres (>60 kbp), animals that are heterozygous for mTert undergo telomere erosion for nine generations and remain phenotypically normal. In an mTerc heterozygous strain with short telomeres (<15 kbp), early mortality arises after five to six generations, but dyskeratosis occurs only upon the further loss of mPot1b. We show that prolonged mTert heterozygosity (for greater than ten generations) did not elicit disease, even upon heterozygote interbreeding, and that telomeres reset to wild-type lengths. This lengthening did not occur in nullizygotes, and short telomeres inherited from mTert null parents were rescued only in heterozygous progeny. In the bone marrow, nullizygotes remained competent for radioprotection for three generations. Thus, gradual telomere erosion in the presence of telomerase may enable subsequent telomere extension, similar to that described in budding yeast. We speculate whether such adaptation occurs in normal human cells (or whether it could be induced in DKC-derived cells), and whether it might mitigate the impact of telomerase inhibition upon stem cells during cancer therapy.},
}
@article {pmid19841137,
year = {2009},
author = {Adelfalk, C and Janschek, J and Revenkova, E and Blei, C and Liebe, B and Göb, E and Alsheimer, M and Benavente, R and de Boer, E and Novak, I and Höög, C and Scherthan, H and Jessberger, R},
title = {Cohesin SMC1beta protects telomeres in meiocytes.},
journal = {The Journal of cell biology},
volume = {187},
number = {2},
pages = {185-199},
pmid = {19841137},
issn = {1540-8140},
support = {R01 GM062517/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle Proteins/*metabolism ; Chromosomal Proteins, Non-Histone/deficiency/*metabolism ; Female ; Male ; *Meiosis ; Mice ; Mice, Knockout ; Microscopy, Electron ; Oocytes/cytology/metabolism ; Spermatocytes/cytology/metabolism ; Telomere/*metabolism ; Cohesins ; },
abstract = {Meiosis-specific mammalian cohesin SMC1beta is required for complete sister chromatid cohesion and proper axes/loop structure of axial elements (AEs) and synaptonemal complexes (SCs). During prophase I, telomeres attach to the nuclear envelope (NE), but in Smc1beta(-/-) meiocytes, one fifth of their telomeres fail to attach. This study reveals that SMC1beta serves a specific role at telomeres, which is independent of its role in determining AE/SC length and loop extension. SMC1beta is necessary to prevent telomere shortening, and SMC3, present in all known cohesin complexes, properly localizes to telomeres only if SMC1beta is present. Very prominently, telomeres in Smc1beta(-/-) spermatocytes and oocytes loose their structural integrity and suffer a range of abnormalities. These include disconnection from SCs and formation of large telomeric protein-DNA extensions, extended telomere bridges between SCs, ring-like chromosomes, intrachromosomal telomeric repeats, and a reduction of SUN1 foci in the NE. We suggest that a telomere structure protected from DNA rearrangements depends on SMC1beta.},
}
@article {pmid19840797,
year = {2009},
author = {Kachouri-Lafond, R and Dujon, B and Gilson, E and Westhof, E and Fairhead, C and Teixeira, MT},
title = {Large telomerase RNA, telomere length heterogeneity and escape from senescence in Candida glabrata.},
journal = {FEBS letters},
volume = {583},
number = {22},
pages = {3605-3610},
doi = {10.1016/j.febslet.2009.10.034},
pmid = {19840797},
issn = {1873-3468},
mesh = {Base Sequence ; Blotting, Southern ; Candida glabrata/enzymology/*genetics/growth &amp; development ; Cell Division ; DNA, Fungal/genetics ; Flow Cytometry ; Gene Deletion ; Molecular Sequence Data ; Mutation ; Nucleic Acid Conformation ; RNA/chemistry/*genetics ; RNA, Fungal/chemistry/*genetics ; Sequence Homology, Nucleic Acid ; Telomerase/chemistry/*genetics ; Telomere/*genetics ; },
abstract = {Telomerase, the key enzyme essential for the maintenance of eukaryotic chromosome ends, contains a reverse transcriptase and an RNA that provides the template for the synthesis of telomeric repeats. Here, we characterize the telomerase subunits in the hemiascomycete yeast Candida glabrata. We propose a secondary structure model for the telomerase RNA that is the largest described to date. Telomerase deletion mutants show a progressive shortening of telomeres and a modest loss of viability. Frequent post-senescence survivors emerge that possess long telomeric repeat tracts. We suggest that the high telomere length heterogeneity accounts for this distinct senescence phenotype.},
}
@article {pmid19840190,
year = {2010},
author = {Ting, AP and Low, GK and Gopalakrishnan, K and Hande, MP},
title = {Telomere attrition and genomic instability in xeroderma pigmentosum type-b deficient fibroblasts under oxidative stress.},
journal = {Journal of cellular and molecular medicine},
volume = {14},
number = {1-2},
pages = {403-416},
pmid = {19840190},
issn = {1582-4934},
mesh = {Adult ; Cellular Senescence/physiology ; DNA Damage ; *DNA Helicases/genetics/metabolism ; DNA Repair ; *DNA-Binding Proteins/genetics/metabolism ; Dose-Response Relationship, Drug ; Female ; Fibroblasts/*cytology/drug effects/*physiology ; *Genomic Instability ; Humans ; Hydrogen Peroxide/pharmacology ; Male ; Oxidants/pharmacology ; *Oxidative Stress ; Telomere/*metabolism ; *Xeroderma Pigmentosum/genetics/metabolism ; },
abstract = {Xeroderma pigmentosum B (XPB/ERCC3/p89) is an ATP-dependent 3'-->5' directed DNA helicase involved in basal RNA transcription and the nucleotide excision repair (NER) pathway. While the role of NER in alleviating oxidative DNA damage has been acknowledged it remains poorly understood. To study the involvement of XPB in repair of oxidative DNA damage, we utilized primary fibroblasts from a patient suffering from XP with Cockayne syndrome and hydrogen peroxide (H(2)O(2)) to induce oxidative stress. Mutant cells retained higher viability and cell cycle dysfunction after H(2)O(2) exposure. Cytokinesis blocked micronucleus assay revealed increased genome instability induced by H(2)O(2). Single cell gel electrophoresis (comet) assay showed that the missense mutation caused a reduced repair capacity for oxidative DNA damage. Mutant fibroblasts also displayed decreased population doubling rate, increased telomere attrition rate and early emergence of senescent characteristics under chronic low dose exposure to H(2)O(2). Fibroblasts from a heterozygous individual displayed intermediate traits in some assays and normal traits in others, indicating possible copy number dependence. The results show that a deficiency in functional XPB paradoxically renders cells more sensitive to the genotoxic effects of oxidative stress while reducing the cytotoxic effects. These findings have implications in the mechanisms of DNA repair, mutagenesis and carcinogenesis and ageing in normal physiological systems.},
}
@article {pmid19839736,
year = {2010},
author = {Wang, P and Zhang, Z and Sun, Y and Liu, X and Tong, T},
title = {The two isomers of HDTIC compounds from Astragali Radix slow down telomere shortening rate via attenuating oxidative stress and increasing DNA repair ability in human fetal lung diploid fibroblast cells.},
journal = {DNA and cell biology},
volume = {29},
number = {1},
pages = {33-39},
doi = {10.1089/dna.2009.0932},
pmid = {19839736},
issn = {1557-7430},
mesh = {Astragalus propinquus/*chemistry ; Cell Line ; Cellular Senescence/drug effects ; DNA Repair/*drug effects ; Dioxolanes/*chemistry/*pharmacology ; *Diploidy ; Female ; Fetus ; Fibroblasts/drug effects/metabolism ; Humans ; Hydrogen Peroxide/toxicity ; Indolizines/*chemistry/*pharmacology ; Lung/cytology/drug effects/embryology ; Oxidative Stress/drug effects ; Plant Roots/*chemistry ; Telomere/*drug effects/genetics/metabolism ; },
abstract = {4-Hydroxy-5-hydroxymethyl-[1,3]dioxolan-2,6'-spirane-5',6',7',8'-tetrahydro-indolizine-3'-carbaldehyde (HDTIC)-1 and HDTIC-2 are two isomers extracted from Astragalus membranaceus (Fisch) Bunge Var. mongholicus (Bge) Hsiao. Our previous study had demonstrated that they could extend the lifespan of human fetal lung diploid fibroblasts (2BS). To investigate the mechanisms of the HDTIC-induced delay of replicative senescence, in this study, we assessed the effects of these two compounds on telomere shortening rate and DNA repair ability in 2BS cells. The telomere shortening rates of the cells cultured with HDTIC-1 or HDTIC-2 were 31.5 and 41.1 bp with each division, respectively, which were much less than that of the control cells (71.1 bp/PD). We also found that 2BS cells pretreated with HDTIC-1 or HDTIC-2 had a significant reduction in DNA damage after exposure to 200 microM H(2)O(2) for 5 min. Moreover, the 100 microM H(2)O(2)-induced DNA damage was significantly repaired after the damaged cells were continually cultured with HDTIC for 1 h. These results suggest that HDTIC compounds slow down the telomere shortening rate of 2BS cells, which is mainly due to the biological properties of the compounds including the reduction of DNA damage and the improvement of DNA repair ability. In addition, the slow down of telomere shortening rate, the reduction of DNA damage, and the improvement of DNA repair ability induced by HDTIC may be responsible for their delay of replicative senescence.},
}
@article {pmid19839711,
year = {2009},
author = {Linger, BR and Price, CM},
title = {Conservation of telomere protein complexes: shuffling through evolution.},
journal = {Critical reviews in biochemistry and molecular biology},
volume = {44},
number = {6},
pages = {434-446},
pmid = {19839711},
issn = {1549-7798},
support = {R01 GM041803-18A1/GM/NIGMS NIH HHS/United States ; T32 CA117846/CA/NCI NIH HHS/United States ; GM041803/GM/NIGMS NIH HHS/United States ; R01 GM088728/GM/NIGMS NIH HHS/United States ; R01 GM041803/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Evolution, Molecular ; Genes, Duplicate ; Humans ; Protein Binding ; Telomere/genetics/metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {The rapid evolution of telomere proteins has hindered identification of orthologs from diverse species and created the impression that certain groups of eukaryotes have largely non-overlapping sets of telomere proteins. However, the recent identification of additional telomere proteins from various model organisms has dispelled this notion by expanding our understanding of the composition, architecture and range of telomere protein complexes present in individual species. It is now apparent that versions of the budding yeast CST complex and mammalian shelterin are present in multiple phyla. While the precise subunit composition and architecture of these complexes vary between species, the general function is often conserved. Despite the overall conservation of telomere protein complexes, there is still considerable species-specific variation, with some organisms having lost a particular subunit or even an entire complex. In some cases, complex components appear to have migrated between the telomere and the telomerase RNP. Finally, gene duplication has created telomere protein paralogs with novel functions. While one paralog may be part of a conserved telomere protein complex and have the expected function, the other paralog may serve in a completely different aspect of telomere biology.},
}
@article {pmid19838219,
year = {2010},
author = {Ruella, M and Rocci, A and Ricca, I and Carniti, C and Bodoni, CL and Ladetto, M and Caracciolo, D and Boccadoro, M and Carlo-Stella, C and Corradini, P and Tarella, C},
title = {Comparative assessment of telomere length before and after hematopoietic SCT: role of grafted cells in determining post-transplant telomere status.},
journal = {Bone marrow transplantation},
volume = {45},
number = {3},
pages = {505-512},
doi = {10.1038/bmt.2009.297},
pmid = {19838219},
issn = {1476-5365},
mesh = {Adult ; Female ; Hematologic Neoplasms/pathology/therapy ; *Hematopoietic Stem Cell Transplantation ; Humans ; Male ; Middle Aged ; Telomere/genetics/*pathology ; Transplantation Conditioning ; Transplantation, Autologous ; Transplantation, Homologous ; Young Adult ; },
abstract = {Our objective was to characterize the role of grafted cells in determining telomere length (TL) after hematopoietic SCT (HSCT). A total of 20 patients undergoing autografts had PBSC collected after two sequential mobilization courses: TL in the first collection was significantly longer than in the second. For their autografts, 10 patients used PBSC from the first collection and 10 from the second. TL was also investigated before and after HSCT and on the graft in 10 allogeneic HSCT. After autografting, patients receiving PBSC from the first collection had BM TL reflecting that of grafted cells (median bp: 7730 on PBSC vs 7610 on post-HSCT BM, P=NS) and significantly longer than TL of the second collection; analogously, patients autografted with PBSC from the second collection had BM TL reflecting that of grafted cells (7360 on PBSC vs 7120 on post-HSCT BM, P=NS) and significantly shorter compared with the first collection. In the allograft setting, eight patients had their pre-transplant TL significantly shorter than donor PBSC (5960 vs 7110; P=0.0005); following HSCT, BM TL (median 7380 bp) was identical to that of the graft (P=NS). We conclude that grafted cells have a major role in determining TL after HSCT.},
}
@article {pmid19838171,
year = {2009},
author = {Makovets, S and Blackburn, EH},
title = {DNA damage signalling prevents deleterious telomere addition at DNA breaks.},
journal = {Nature cell biology},
volume = {11},
number = {11},
pages = {1383-1386},
pmid = {19838171},
issn = {1476-4679},
support = {GM26259/GM/NIGMS NIH HHS/United States ; R01 GM026259-31/GM/NIGMS NIH HHS/United States ; R01 GM026259/GM/NIGMS NIH HHS/United States ; R37 GM026259/GM/NIGMS NIH HHS/United States ; 84637/WT_/Wellcome Trust/United Kingdom ; },
mesh = {*DNA Damage ; Humans ; *Signal Transduction ; Telomerase/metabolism ; *Telomere ; },
abstract = {The response to DNA damage involves regulation of several essential processes to maximize the accuracy of DNA damage repair and cell survival. Telomerase has the potential to interfere with repair by inappropriately adding telomeres to DNA breaks. It was unknown whether cells modulate telomerase in response to DNA damage to increase the accuracy of repair. Here, we report that telomerase action is regulated as a part of the cellular response to DNA double-strand breaks (DSBs). Using yeast, we show that the main ATR/Mec1 DNA damage signalling pathway regulates telomerase action at DSBs. After DNA damage, MEC1-RAD53-DUN1-dependent phosphorylation of the telomerase inhibitor Pif1 occurs. Using a separation of function PIF1 mutation, we show that this phosphorylation is specifically required for the Pif1-mediated telomerase inhibition that takes place at DNA breaks, but not for that at telomeres. Hence DNA damage signalling down-modulates telomerase action at DNA breaks through Pif1 phosphorylation, thus preventing aberrant healing of broken DNA ends by telomerase. These findings uncover a new regulatory mechanism that coordinates competing DNA end-processing activities and thereby promotes DNA repair accuracy and genome integrity.},
}
@article {pmid19837265,
year = {2009},
author = {Sukenik-Halevy, R and Fejgin, M and Kidron, D and Goldberg-Bittman, L and Sharony, R and Biron-Shental, T and Kitay-Cohen, Y and Amiel, A},
title = {Telomere aggregate formation in placenta specimens of pregnancies complicated with pre-eclampsia.},
journal = {Cancer genetics and cytogenetics},
volume = {195},
number = {1},
pages = {27-30},
doi = {10.1016/j.cancergencyto.2009.03.015},
pmid = {19837265},
issn = {1873-4456},
mesh = {Female ; Humans ; Oxidative Stress/genetics ; Paraffin Embedding ; Placenta/metabolism/*ultrastructure ; Pre-Eclampsia/*genetics/metabolism ; Pregnancy ; Risk Factors ; Telomere/metabolism/*ultrastructure ; },
abstract = {Telomeres are specific repetitive DNA sequences that cap and stabilize the ends of chromosomes. Functional telomeres are essential for the normal segregation and maintenance of chromosomes during mitotic and meiotic division. Pre-eclampsia, a pregnancy-specific syndrome of increased blood pressure accompanied by proteinuria, is often associated with growth deficiency in the fetus. Oxidative stress is a major component in the pathophysiology of pre-eclampsia. In contrast to the nonoverlapping nature of telomeres in normal nuclei, telomeres of tumor nuclei tend to form aggregates (TAs) in various numbers and sizes. The formation of TAs represents a stress-related process and is independent of telomere length and telomerase activity. The aim of this study was to evaluate TA formation in paraffin-embedded placentas from pregnancies complicated with pre-eclampsia (study group), compared with placentas from normal pregnancies (control group). There were significantly more TAs in the study group (mean, 8.00 TAs per case) than in the control group (mean, 2.36 TAs per case) (P < 0.01). Pre-eclampsia-related stress may accelerate apoptosis and cell death and lead to placental dysfunction. TAs formation, which has been linked to stress and tumorgenesis is increased in placentas of pre-eclamptic patients.},
}
@article {pmid19837264,
year = {2009},
author = {Hadi, E and Sharony, R and Goldberg-Bittman, L and Biron-Shental, T and Fejgin, M and Amiel, A},
title = {Telomere aggregates in trisomy 21 amniocytes.},
journal = {Cancer genetics and cytogenetics},
volume = {195},
number = {1},
pages = {23-26},
doi = {10.1016/j.cancergencyto.2009.03.003},
pmid = {19837264},
issn = {1873-4456},
mesh = {Amniotic Fluid/cytology/*physiology ; Case-Control Studies ; Cells, Cultured ; Diploidy ; Down Syndrome/*genetics/metabolism ; Female ; Humans ; Microscopy, Fluorescence ; Pregnancy ; Telomere/*ultrastructure ; },
abstract = {Trisomy 21 is the most common chromosomal abnormality among persons with intellectual disability, with a live birth rate of 1 in 800-1,000. As such, this abnormality may serve as a model for human disorders that result from supernumerary copies of a genomic region. Down syndrome carries an increased risk of developing acute leukemia and other malignancies. Telomeres of tumor cells nuclei tend to form aggregates (TA). This study evaluated TA formation in amniocytes from trisomy 21 pregnancies, compared with amniocytes from normal euploid pregnancies. A commercially available peptide nucleic acid telomere kit was used to evaluate TA formation, using two-dimensional fluorescence microscopy. Significantly higher frequencies of TA were found in trisomy 21 amniocytes than in amniocytes from normal pregnancies. The TAs found in trisomy 21 amniocytes apparently represent an additional parameter that reflects the high genetic instability of this syndrome and its recognized predisposition to develop leukemia and other malignancies.},
}
@article {pmid19837074,
year = {2010},
author = {Lin, J and Epel, E and Cheon, J and Kroenke, C and Sinclair, E and Bigos, M and Wolkowitz, O and Mellon, S and Blackburn, E},
title = {Analyses and comparisons of telomerase activity and telomere length in human T and B cells: insights for epidemiology of telomere maintenance.},
journal = {Journal of immunological methods},
volume = {352},
number = {1-2},
pages = {71-80},
pmid = {19837074},
issn = {1872-7905},
support = {RR024131-01/RR/NCRR NIH HHS/United States ; P30AI027763/AI/NIAID NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; P30 AI027763-19/AI/NIAID NIH HHS/United States ; P30 AI027763/AI/NIAID NIH HHS/United States ; UL1 RR024131-01/RR/NCRR NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging/blood/*physiology ; Antigens, CD/biosynthesis ; B-Lymphocytes/*physiology/ultrastructure ; Biomarkers/*analysis ; Cohort Studies ; DNA/*analysis ; Female ; Humans ; Lymphocyte Subsets/*physiology/ultrastructure ; Middle Aged ; T-Lymphocytes/*physiology/ultrastructure ; Telomerase/immunology/*metabolism ; Telomere/physiology/*ultrastructure ; },
abstract = {Telomeres are the DNA-protein complexes that protect the ends of eukaryotic chromosomes. The cellular enzyme telomerase counteracts telomere shortening by adding telomeric DNA. A growing body of literature links shorter telomere length and lower telomerase activity with various age-related diseases and earlier mortality. Thus, leukocyte telomere length (LTL) and telomerase activity are emerging both as biomarkers and contributing factors for age-related diseases. However, no clinical study has directly examined telomerase activity and telomere length in different lymphocyte subtypes isolated from the same donors, which could offer insight into the summary measure of leukocyte telomere maintenance. We report the first quantitative data in humans examining both levels of telomerase activity and telomere length in four lymphocyte subpopulations from the same donors-CD4+, CD8+CD28+ and CD8+CD28- T cells and B cells, as well as total PBMCs-in a cohort of healthy women. We found that B cells had the highest telomerase activity and longest telomere length; CD4+ T cells had slightly higher telomerase activity than CD8+CD28+ T cells, and similar telomere length. Consistent with earlier reports that CD8+CD28- T cells are replicatively senescent cells, they had the lowest telomerase activity and shortest telomere length. In addition, a higher percentage of CD8+CD28- T cells correlated with shorter total PBMC TL (r=-0.26, p=0.05). Interestingly, telomerase activities of CD4+ and CD8+CD28+ T cells from the same individual were strongly correlated (r=0.55, r<0.001), indicating possible common mechanisms for telomerase activity regulation in these two cell subtypes. These data will facilitate the understanding of leukocyte aging and its relationship to human health.},
}
@article {pmid19834903,
year = {2009},
author = {Zimmermann, S and Biniossek, ML and Maurer, C and Münzer, P and Pantic, M and Veelken, H and Martens, UM},
title = {Proteomic profiling in distinct cellular compartments of tumor cells reveals p53-dependent upregulation of S100A6 upon induction of telomere dysfunction.},
journal = {Proteomics},
volume = {9},
number = {22},
pages = {5175-5187},
doi = {10.1002/pmic.200900232},
pmid = {19834903},
issn = {1615-9861},
mesh = {Cell Cycle Proteins/*metabolism ; Cell Line, Tumor ; Gene Expression Profiling ; Humans ; Immunoblotting ; Immunoprecipitation ; *Proteomics ; S100 Calcium Binding Protein A6 ; S100 Proteins/*metabolism ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; *Up-Regulation ; },
abstract = {Telomere dysfunction is evoking a DNA damage response which leads to replicative senescence or apoptosis. Tumor cells feature telomerase, a ribonucleoprotein complex counteracting telomere shortening and proliferation limitation as a prerequisite of immortal cell growth. Recently, we demonstrated the effects of telomerase inhibition on the proteome of tumor cell clones in whole cell lysates by SELDI-TOF-MS profiling and MS/MS protein identification (Zimmermann et al., Proteomics 2009, 9, 521-534). We continued proteomic analyses of such clones after telomerase-inhibition using fractionation of cellular compartments. Among the differentially expressed peaks found in different fractions, a cytoplasmic 10.1 kDa protein upregulated in telomerase-inhibited clones (p<0.0001) was identified by nanoflow-HPLC-MS/MS as S100A6. S100A6 upregulation was confirmed by immunoblotting in telomerase-inhibited HCT-116, A-549, and NCI-H460 clones. S100A6 and other proteins involved in telomere dysfunction were further analyzed in derivative p53(-/-) and p21(-/-) HCT-116 cell lines indicating an overall reduced number of significant changes in these lines compared to wild type HCT-116 cells. In addition, post-translational modification of S100A6 was demonstrated with a potential role in mediating the cellular response to telomere dysfunction. In conclusion, proteomic profiling in distinct cellular compartments led to the identification of a novel p53-dependent biomarker of telomere dysfunction, S100A6.},
}
@article {pmid19834611,
year = {2009},
author = {Ujvari, B and Madsen, T},
title = {Short telomeres in hatchling snakes: erythrocyte telomere dynamics and longevity in tropical pythons.},
journal = {PloS one},
volume = {4},
number = {10},
pages = {e7493},
pmid = {19834611},
issn = {1932-6203},
mesh = {Aging ; Animals ; Animals, Newborn ; Boidae ; Cell Proliferation ; *Cellular Senescence ; Erythrocytes/metabolism ; Female ; Longevity ; Male ; Models, Biological ; Sequence Analysis, DNA ; Sex Factors ; Snakes ; Telomere/*ultrastructure ; Time Factors ; },
abstract = {BACKGROUND: Telomere length (TL) has been found to be associated with life span in birds and humans. However, other studies have demonstrated that TL does not affect survival among old humans. Furthermore, replicative senescence has been shown to be induced by changes in the protected status of the telomeres rather than the loss of TL. In the present study we explore whether age- and sex-specific telomere dynamics affect life span in a long-lived snake, the water python (Liasis fuscus).<br><br>Erythrocyte TL was measured using the Telo TAGGG TL Assay Kit (Roche). In contrast to other vertebrates, TL of hatchling pythons was significantly shorter than that of older snakes. However, during their first year of life hatchling TL increased substantially. While TL of older snakes decreased with age, we did not observe any correlation between TL and age in cross-sectional sampling. In older snakes, female TL was longer than that of males. When using recapture as a proxy for survival, our results do not support that longer telomeres resulted in an increased water python survival/longevity.<br><br>CONCLUSIONS/SIGNIFICANCE: In fish high telomerase activity has been observed in somatic cells exhibiting high proliferation rates. Hatchling pythons show similar high somatic cell proliferation rates. Thus, the increase in TL of this group may have been caused by increased telomerase activity. In older humans female TL is longer than that of males. This has been suggested to be caused by high estrogen levels that stimulate increased telomerase activity. Thus, high estrogen levels may also have caused the longer telomeres in female pythons. The lack of correlation between TL and age among old snakes and the fact that longer telomeres did not appear to affect python survival do not support that erythrocyte telomere dynamics has a major impact on water python longevity.},
}
@article {pmid19828140,
year = {2010},
author = {Tyrka, AR and Price, LH and Kao, HT and Porton, B and Marsella, SA and Carpenter, LL},
title = {Childhood maltreatment and telomere shortening: preliminary support for an effect of early stress on cellular aging.},
journal = {Biological psychiatry},
volume = {67},
number = {6},
pages = {531-534},
pmid = {19828140},
issn = {1873-2402},
support = {R01 NS047209-05/NS/NINDS NIH HHS/United States ; R01 MH068767-04/MH/NIMH NIH HHS/United States ; R01 MH068767/MH/NIMH NIH HHS/United States ; K23 MH067947/MH/NIMH NIH HHS/United States ; K23 MH067947-05/MH/NIMH NIH HHS/United States ; 1 K23 MH067947/MH/NIMH NIH HHS/United States ; R01 MH068767-01/MH/NIMH NIH HHS/United States ; R01 MH070898/MH/NIMH NIH HHS/United States ; R01 NS047209/NS/NINDS NIH HHS/United States ; R01 MH070898-06/MH/NIMH NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Factors ; Body Mass Index ; Cellular Senescence/*genetics ; Child ; Child Abuse/*psychology ; Female ; Humans ; Male ; Middle Aged ; Sex Factors ; Smoking ; Stress, Psychological/*genetics ; Surveys and Questionnaires ; *Telomere ; Young Adult ; },
abstract = {BACKGROUND: Psychological stress and trauma are risk factors for several medical and psychiatric illnesses. Recent studies have implicated advanced cellular aging as a potential mechanism of this association. Telomeres, DNA repeats that cap the ends of chromosomes and promote stability, shorten progressively with each cell division; their length is a marker of biological aging. Based on previous evidence linking psychosocial stress to shorter telomere length, this study was designed to evaluate the effect of childhood adversity on telomere length.<br><br>METHODS: Thirty-one adults with no current or past major Axis I psychiatric disorder participated. Subjects reported on their history of childhood maltreatment and telomere length was measured from DNA extracted from frozen whole blood using quantitative polymerase chain reaction.<br><br>RESULTS: Participants reporting a history of childhood maltreatment had significantly shorter telomeres than those who did not report a history of maltreatment. This finding was not due to effects of age, sex, smoking, body mass index, or other demographic factors. Analysis of subscales showed that both physical neglect and emotional neglect were significantly linked to telomere length.<br><br>CONCLUSIONS: These results extend previous reports linking shortened leukocyte telomere length and caregiver stress to more remote stressful experiences in childhood and suggest that childhood maltreatment could influence cellular aging.},
}
@article {pmid19826452,
year = {2010},
author = {Nordfjäll, K and Svenson, U and Norrback, KF and Adolfsson, R and Roos, G},
title = {Large-scale parent-child comparison confirms a strong paternal influence on telomere length.},
journal = {European journal of human genetics : EJHG},
volume = {18},
number = {3},
pages = {385-389},
pmid = {19826452},
issn = {1476-5438},
mesh = {Adult ; Age Distribution ; Aged ; Child ; *Fathers ; Female ; Humans ; Male ; Middle Aged ; Mothers ; Pedigree ; Sex Characteristics ; Telomere/*metabolism ; },
abstract = {Telomere length is documented to have a hereditary component, and both paternal and X-linked inheritance have been proposed. We investigated blood cell telomere length in 962 individuals with an age range between 0 and 102 years. Telomere length correlations were analyzed between parent-child pairs in different age groups and between grandparent-grandchild pairs. A highly significant correlation between the father's and the child's telomere length was observed (r=0.454, P<0.001), independent of the sex of the offspring (father-son: r=0.465, P<0.001; father-daughter: r=0.484, P<0.001). For mothers, the correlations were weaker (mother-child: r=0.148, P=0.098; mother-son: r=0.080, P=0.561; mother-daughter: r=0.297, P=0.013). A positive telomere length correlation was also observed for grandparent-grandchild pairs (r=0.272, P=0.013). Our findings indicate that fathers contribute significantly stronger to the telomere length of the offspring compared with mothers (P=0.012), but we cannot exclude a maternal influence on the daughter's telomeres. Interestingly, the father-child correlations diminished with increasing age (P=0.022), suggesting that nonheritable factors have an impact on telomere length dynamics during life.},
}
@article {pmid19822671,
year = {2009},
author = {Canudas, S and Smith, S},
title = {Differential regulation of telomere and centromere cohesion by the Scc3 homologues SA1 and SA2, respectively, in human cells.},
journal = {The Journal of cell biology},
volume = {187},
number = {2},
pages = {165-173},
pmid = {19822671},
issn = {1540-8140},
support = {R01 CA116352/CA/NCI NIH HHS/United States ; },
mesh = {Antigens, Nuclear/genetics/*metabolism ; Cell Cycle Proteins/genetics/*metabolism ; Centromere/*metabolism ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; DNA Repair ; DNA Replication ; Genomic Instability ; HeLa Cells ; Humans ; Nuclear Proteins/genetics/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; Cohesins ; },
abstract = {Replicated sister chromatids are held together until mitosis by cohesin, a conserved multisubunit complex comprised of Smc1, Smc3, Scc1, and Scc3, which in vertebrate cells exists as two closely related homologues (SA1 and SA2). Here, we show that cohesin(SA1) and cohesin(SA2) are differentially required for telomere and centromere cohesion, respectively. Cells deficient in SA1 are unable to establish or maintain cohesion between sister telomeres after DNA replication in S phase. The same phenotype is observed upon depletion of the telomeric protein TIN2. In contrast, in SA2-depleted cells telomere cohesion is normal, but centromere cohesion is prematurely lost. We demonstrate that loss of telomere cohesion has dramatic consequences on chromosome morphology and function. In the absence of sister telomere cohesion, cells are unable to repair chromatid breaks and suffer sister telomere loss. Our studies elucidate the functional distinction between the Scc3 homologues in human cells and further reveal an essential role for sister telomere cohesion in genomic integrity.},
}
@article {pmid19822157,
year = {2010},
author = {Pampalona, J and Soler, D and Genescà, A and Tusell, L},
title = {Telomere dysfunction and chromosome structure modulate the contribution of individual chromosomes in abnormal nuclear morphologies.},
journal = {Mutation research},
volume = {683},
number = {1-2},
pages = {16-22},
doi = {10.1016/j.mrfmmm.2009.10.001},
pmid = {19822157},
issn = {0027-5107},
mesh = {Cell Nucleus/*pathology ; *Chromosomal Instability ; Chromosome Painting ; Chromosome Segregation ; *Chromosome Structures ; Chromosomes, Human/*genetics ; Cytokinesis ; Humans ; In Situ Hybridization, Fluorescence ; Mammary Glands, Human/physiology ; Micronuclei, Chromosome-Defective ; Telomere/*physiology ; },
abstract = {The cytokinesis-block micronucleus assay has emerged as a biomarker of chromosome damage relevant to cancer. Although it was initially developed to measure micronuclei, it is also useful for measuring nucleoplasmic bridges and nuclear buds. Abnormal nuclear morphologies are frequently observed in malignant tissues and short-term tumour cell cultures. Changes in chromosome structure and number resulting from chromosome instability are important factors in oncogenesis. Telomeres have become key players in the initiation of chromosome instability related to carcinogenesis by means of breakage-fusion-bridge cycles. To better understand the connection between telomere dysfunction and the appearance of abnormal nuclear morphologies, we have characterised the presence of micronuclei, nucleoplasmic bridges and nuclear buds in human mammary primary epithelial cells. These cells can proliferate beyond the Hayflick limit by spontaneously losing expression of the p16(INK4a) protein. Progressive telomere shortening leads to the loss of the capping function, and the appearance of end-to-end chromosome fusions that can enter into breakage-fusion-bridge cycles generating massive chromosomal instability. In human mammary epithelial cells, different types of abnormal nuclear morphologies were observed, however only nucleoplasmatic bridges and buds increased significantly with population doublings. Fluorescent in situ hybridisation using centromeric and painting specific probes for chromosomes with eroded telomeres has revealed that these chromosomes are preferentially included in the different types of abnormal nuclear morphologies observed, thus reflecting their common origin. Accordingly, real-time imaging of cell divisions enabled us to determine that anaphase bridge resolution was mainly through chromatin breakage and the formation of symmetric buds in daughter nuclei. Few micronuclei emerged in this cell system thus validating the scoring of nucleoplasmic bridges and nuclear buds for measuring chromosome instability in telomere-dysfunction cell environments.},
}
@article {pmid19817785,
year = {2009},
author = {Liew, CW and Holman, A and Kulkarni, RN},
title = {The roles of telomeres and telomerase in beta-cell regeneration.},
journal = {Diabetes, obesity &amp; metabolism},
volume = {11 Suppl 4},
number = {},
pages = {21-29},
doi = {10.1111/j.1463-1326.2009.01103.x},
pmid = {19817785},
issn = {1463-1326},
support = {K99 DK090210/DK/NIDDK NIH HHS/United States ; R01 DK 68721/DK/NIDDK NIH HHS/United States ; R01 DK 67536/DK/NIDDK NIH HHS/United States ; 1RL9EB008539-01/EB/NIBIB NIH HHS/United States ; },
mesh = {Animals ; Cellular Senescence/*physiology ; Diabetes Mellitus/physiopathology ; Humans ; Insulin-Secreting Cells/cytology/*physiology ; Regeneration/*physiology ; Signal Transduction ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {Telomerase is a specialized reverse transcriptase that is responsible for extending and preserving the end of the chromosomes (telomeres). Telomerase plays a key role in regulating the lifespan of mammalian cells and is involved in critical aspects of cellular ageing processes. In this review, we will briefly summarize our current understanding of the functions of telomeres, telomerase and their regulation. Considering that compensatory islet hyperplasia and beta-cell regeneration play important roles in the prevention and/or delay of the onset of overt diabetes, we will also examine current literature regarding the effects of diabetes on telomere shortening and provide insights from our own studies on the role of telomerase in beta-cell regeneration.},
}
@article {pmid19815741,
year = {2009},
author = {Vogel, G and Pennisi, E},
title = {Physiology Nobel. U.S. Researchers recognized for work on telomeres.},
journal = {Science (New York, N.Y.)},
volume = {326},
number = {5950},
pages = {212-213},
doi = {10.1126/science.326_212},
pmid = {19815741},
issn = {1095-9203},
mesh = {Animals ; Disease ; History, 20th Century ; History, 21st Century ; Humans ; *Nobel Prize ; *Telomerase/chemistry/isolation &amp; purification/metabolism ; *Telomere/physiology ; United States ; },
}
@article {pmid19815087,
year = {2010},
author = {Schoeftner, S and Blasco, MA},
title = {Chromatin regulation and non-coding RNAs at mammalian telomeres.},
journal = {Seminars in cell &amp; developmental biology},
volume = {21},
number = {2},
pages = {186-193},
doi = {10.1016/j.semcdb.2009.09.015},
pmid = {19815087},
issn = {1096-3634},
mesh = {Animals ; Chromatin/*genetics/metabolism ; Chromosomes/metabolism ; Epigenesis, Genetic ; Humans ; Mammals/*genetics/metabolism ; RNA/*genetics/metabolism ; Telomere/genetics/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {In eukaryotes, terminal chromosome repeats are bound by a specialized nucleoprotein complex that controls telomere length and protects chromosome ends from DNA repair and degradation. In mammals the "shelterin" complex mediates these central functions at telomeres. In the recent years it has become evident that also the heterochromatic structure of mammalian telomeres is implicated in telomere length regulation. Impaired telomeric chromatin compaction results in a loss of telomere length control. Progressive telomere shortening affects chromatin compaction at telomeric and subtelomeric repeats and activates alternative telomere maintenance mechanisms. Dynamics of chromatin structure of telomeres during early mammalian development and nuclear reprogramming further indicates a central role of telomeric heterochromatin in organismal development. In addition, the recent discovery that telomeres are transcribed, giving rise to UUAGGG-repeat containing TelRNAs/TERRA, opens a new level of chromatin regulation at telomeres. Understanding the links between the epigenetic status of telomeres, TERRA/TelRNA and telomere homeostasis will open new avenues for our understanding of organismal development, cancer and ageing.},
}
@article {pmid19812063,
year = {2009},
author = {Takashi, Y and Kobayashi, Y and Tanaka, K and Tamura, K},
title = {Arabidopsis replication protein A 70a is required for DNA damage response and telomere length homeostasis.},
journal = {Plant &amp; cell physiology},
volume = {50},
number = {11},
pages = {1965-1976},
doi = {10.1093/pcp/pcp140},
pmid = {19812063},
issn = {1471-9053},
mesh = {Arabidopsis/*genetics/metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Cloning, Molecular ; *DNA Breaks, Double-Stranded ; DNA, Bacterial/genetics ; Gene Expression Regulation, Plant ; Mutagenesis, Insertional ; Protein Subunits/genetics/metabolism ; RNA, Plant/genetics ; Replication Protein A/genetics/*metabolism ; Sequence Homology, Amino Acid ; Telomere/*metabolism ; },
abstract = {Replication protein A1 (RPA1/RPA70) forms a heterotrimeric complex together with RPA2/RPA32 and RPA3/RPA14 subunits which plays essential roles in various aspects of DNA metabolism including replication, repair, recombination and telomere maintenance. Compared with RPA70 in yeast and mammals, limited information is available about the factor in plants. In this study, we analyzed the functions of AtRPA70a, which is most similar to human RPA70 among four paralogs in Arabidopsis thaliana. RNA blot analysis showed that AtRPA70a is expressed ubiquitously in plant organs containing differentiated and meristematic tissues, while its expression was up-regulated in response to DNA damage stress. Yeast two-hybrid and co-immunoprecipitation analyses showed that AtRPA70a interacted preferentially with Arabidopsis RPA32a, one of two paralogs. Inactivation of AtRPA70a by T-DNA insertion did not affect growth under normal conditions, but resulted in increased sensitivity to genotoxic agents such as methylmethane sulfonate, bleomycin and hydroxyurea. Terminal restriction fragment analysis revealed that telomere lengths in an AtRPA70a-deficient line were significantly larger than in the wild type, whereas those in the mutant expressing antisense AtTERT (telomerase catalytic subunit gene) were shortened during successive generations. These results demonstrate that AtRPA70a is involved in repair of double-strand DNA breaks and possibly contributes to telomerase-dependent telomere length regulation.},
}
@article {pmid19809492,
year = {2009},
author = {Tomaska, L and Nosek, J and Kramara, J and Griffith, JD},
title = {Telomeric circles: universal players in telomere maintenance?.},
journal = {Nature structural &amp; molecular biology},
volume = {16},
number = {10},
pages = {1010-1015},
pmid = {19809492},
issn = {1545-9985},
support = {55005622/HHMI/Howard Hughes Medical Institute/United States ; R01 ES013773/ES/NIEHS NIH HHS/United States ; GM31819/GM/NIGMS NIH HHS/United States ; R03 TW005654/TW/FIC NIH HHS/United States ; R01 GM031819/GM/NIGMS NIH HHS/United States ; 2-R03-TW005654-04A1/TW/FIC NIH HHS/United States ; ES13773/ES/NIEHS NIH HHS/United States ; P01 CA019014/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Candida/*genetics ; Cell Nucleus/metabolism ; Chromosomes/ultrastructure ; DNA, Fungal/genetics/physiology ; Gene Deletion ; Genetic Techniques ; Genome ; Genome, Fungal ; Mitochondria/*metabolism ; Models, Biological ; Models, Genetic ; Recombination, Genetic ; Retroelements ; Telomere/genetics/*ultrastructure ; },
abstract = {To maintain linear DNA genomes, organisms have evolved numerous means of solving problems associated with DNA ends (telomeres), including telomere-associated retrotransposons, palindromes, hairpins, covalently bound proteins and the addition of arrays of simple DNA repeats. Telomeric arrays can be maintained through various mechanisms such as telomerase activity or recombination. The recombination-dependent maintenance pathways may include telomeric loops (t-loops) and telomeric circles (t-circles). The potential involvement of t-circles in telomere maintenance was first proposed for linear mitochondrial genomes. The occurrence of t-circles in a wide range of organisms, spanning yeasts, plants and animals, suggests the involvement of t-circles in many phenomena including the alternative-lengthening of telomeres (ALT) pathway and telomere rapid deletion (TRD). In this Perspective, we summarize these findings and discuss how t-circles may be related to t-loops and how t-circles may have initiated the evolution of telomeres.},
}
@article {pmid19808762,
year = {2009},
author = {Watts, G},
title = {Nobel medicine prize is won by scientists for work on chromosomal telomeres.},
journal = {BMJ (Clinical research ed.)},
volume = {339},
number = {},
pages = {b4120},
doi = {10.1136/bmj.b4120},
pmid = {19808762},
issn = {1756-1833},
mesh = {Chromosomes/*genetics ; Genetics ; Humans ; *Nobel Prize ; Telomere/*genetics ; },
}
@article {pmid19805416,
year = {2010},
author = {Wu, Y and Zakian, VA},
title = {Identity crisis when telomeres left unprotected.},
journal = {Journal of molecular cell biology},
volume = {2},
number = {1},
pages = {14-16},
pmid = {19805416},
issn = {1759-4685},
support = {R01 GM043265/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; DNA Damage ; DNA Repair ; Humans ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Loss of shelterin components TRF2 or POT1a-TPP1 complex from the chromosome end triggers DNA damage response (DDR) and aberrant DNA repair events. In a recent Nature paper, Chang and colleagues reported that the DNA repair protein Mre11 contributes to multiple events at the uncapped telomere, including ataxia telangiectasia-mutated (ATM)-dependent signaling, processing of the telomeric G-tail and homologous recombination (HR).},
}
@article {pmid19802713,
year = {2010},
author = {Astrup, AS and Tarnow, L and Jorsal, A and Lajer, M and Nzietchueng, R and Benetos, A and Rossing, P and Parving, HH},
title = {Telomere length predicts all-cause mortality in patients with type 1 diabetes.},
journal = {Diabetologia},
volume = {53},
number = {1},
pages = {45-48},
pmid = {19802713},
issn = {1432-0428},
mesh = {Base Pairing ; Cell Division ; DNA/genetics ; Diabetes Mellitus, Type 1/*genetics/*mortality/pathology ; Diabetic Nephropathies/genetics/mortality/physiopathology ; Follow-Up Studies ; Glomerular Filtration Rate ; Glycated Hemoglobin/analysis ; Heart Rate ; Humans ; Predictive Value of Tests ; Prognosis ; Prospective Studies ; Repetitive Sequences, Nucleic Acid ; Telomere/*ultrastructure ; },
abstract = {AIMS/HYPOTHESIS: Type 1 diabetic patients with diabetic nephropathy have increased mortality and morbidity compared with normoalbuminuric patients. Telomere length in proliferative cells is inversely related to the total number of cell divisions, and therefore to biological age. We aimed to evaluate differences in telomere length in patients with type 1 diabetes with or without diabetic nephropathy; we also evaluated the prognostic value of telomere length.<br><br>METHODS: In a prospective follow-up study, 157 type 1 diabetic patients with diabetic nephropathy and a control group of 116 patients with type 1 diabetes and normoalbuminuria were followed for 11.1 years (range 0.2-12.9). Telomere length was measured from DNA samples extracted from white blood cells at baseline.<br><br>RESULTS: The mean telomere length did not differ between patients with or without diabetic nephropathy, and was similar in men and women, but was inversely correlated with age and systolic blood pressure, p < 0.05. When dividing patients into tertiles after telomere length, 36 (37%) patients died in the tertile with the shortest telomere length, 24 (28%) died in the middle tertile, and 15 (17%) of patients in the tertile with the longest telomere length died, log rank test p = 0.017. After adjustment for traditional risk factors, telomere length was still predictive of all-cause mortality.<br><br>CONCLUSIONS/INTERPRETATION: In patients with type 1 diabetes we found no differences in telomere length between patients with or without diabetic nephropathy. We also found that telomere length was associated with all-cause mortality; however, confirmative studies are needed to verify our findings.},
}
@article {pmid19801496,
year = {2009},
author = {Spallarossa, P and Altieri, P and Aloi, C and Garibaldi, S and Barisione, C and Ghigliotti, G and Fugazza, G and Barsotti, A and Brunelli, C},
title = {Doxorubicin induces senescence or apoptosis in rat neonatal cardiomyocytes by regulating the expression levels of the telomere binding factors 1 and 2.},
journal = {American journal of physiology. Heart and circulatory physiology},
volume = {297},
number = {6},
pages = {H2169-81},
doi = {10.1152/ajpheart.00068.2009},
pmid = {19801496},
issn = {1522-1539},
mesh = {Animals ; Animals, Newborn ; Anthracenes/pharmacology ; Antibiotics, Antineoplastic/*toxicity ; Apoptosis/*drug effects ; Benzothiazoles/pharmacology ; Cells, Cultured ; Cellular Senescence/*drug effects ; Checkpoint Kinase 2 ; Cytoskeleton/drug effects/metabolism ; Dose-Response Relationship, Drug ; Doxorubicin/*toxicity ; Imidazoles/pharmacology ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Mitosis/drug effects ; Myocytes, Cardiac/*drug effects/metabolism/pathology ; Phenotype ; Protein Kinase Inhibitors/pharmacology ; Protein Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Pyridines/pharmacology ; RNA Interference ; Rats ; Rats, Sprague-Dawley ; Telomeric Repeat Binding Protein 1/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; Time Factors ; Toluene/analogs &amp; derivatives/pharmacology ; Tumor Suppressor Protein p53/antagonists &amp; inhibitors/metabolism ; bcl-2-Associated X Protein/metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; },
abstract = {Low or high doses of doxorubicin induce either senescence or apoptosis, respectively, in cardiomyocytes. The mechanism by which different doses of doxorubicin may induce different stress-response cellular programs is not well understood. A recent study showed that the level of telomere dysfunction may induce senescence or apoptosis. We investigated the pathways to both apoptosis and senescence in neonatal rat cardiomyocytes and in H9c2 cells exposed to a single pulsed incubation with low or high doses of doxorubicin. High-dose doxorubicin strongly reduces TRF2 expression while enhancing TRF1 expression, and it determines early apoptosis. Low-dose doxorubicin induces downregulation of both TRF2 and TRF1, and it also increases the senescence-associated-beta-galactosidase activity, downregulates the checkpoint kinase Chk2, induces chromosomal abnormalities, and alters the cell cycle. The involvement of TRF1 and TRF2 with apoptosis and senescence was assessed by short interfering RNA interference. The cells maintain telomere dysfunction and a senescent phenotype over time and undergo late death. The increase in the phase>4N and the presence of micronuclei and anaphase bridges indicate that cells die by mitotic catastrophe. p38 modulates TRF2 expression, whereas JNK and cytoplasmic p53 regulate TRF1. Pretreatment with specific inhibitors of MAPKs and p53 may either attenuate the damage induced by doxorubicin or shift the cellular response to stress from senescence to apoptosis. In conclusion, various doses of doxorubicin induce differential regulation of TRF1 and TRF2 through p53 and MAPK, which is responsible for inducing either early apoptosis or senescence and late death due to mitotic catastrophe.},
}
@article {pmid19800890,
year = {2009},
author = {Demarse, NA and Ponnusamy, S and Spicer, EK and Apohan, E and Baatz, JE and Ogretmen, B and Davies, C},
title = {Direct binding of glyceraldehyde 3-phosphate dehydrogenase to telomeric DNA protects telomeres against chemotherapy-induced rapid degradation.},
journal = {Journal of molecular biology},
volume = {394},
number = {4},
pages = {789-803},
pmid = {19800890},
issn = {1089-8638},
support = {R01 CA088932/CA/NCI NIH HHS/United States ; R01 CA088932-08/CA/NCI NIH HHS/United States ; CA88932/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Substitution/genetics ; Antineoplastic Agents/pharmacology ; Binding Sites ; Cell Line, Tumor ; DNA, Single-Stranded/*metabolism ; Deoxycytidine/analogs &amp; derivatives/pharmacology ; Doxorubicin/pharmacology ; Electrophoretic Mobility Shift Assay ; Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+)/genetics/*metabolism ; Humans ; Kinetics ; Mutation, Missense ; Protein Binding ; Telomere/*metabolism ; Gemcitabine ; },
abstract = {Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a glycolytic enzyme that displays several non-glycolytic activities, including the maintenance and/or protection of telomeres. In this study, we determined the molecular mechanism and biological role of the interaction between GAPDH and human telomeric DNA. Using gel-shift assays, we show that recombinant GAPDH binds directly with high affinity (K(d)=45 nM) to a single-stranded oligonucleotide comprising three telomeric DNA repeats, and that nucleotides T1, G5, and G6 of the TTAGGG repeat are essential for binding. The stoichiometry of the interaction is 2:1 (DNA:GAPDH), and GAPDH appears to form a high-molecular-weight complex when bound to the oligonucleotide. Mutation of Asp32 and Cys149, which are localized to the NAD-binding site and the active-site center of GAPDH, respectively, produced mutants that almost completely lost their telomere-binding functions both in vitro and in situ (in A549 human lung cancer cells). Treatment of A549 cells with the chemotherapeutic agents gemcitabine and doxorubicin resulted in increased nuclear localization of expressed wild-type GAPDH, where it protected telomeres against rapid degradation, concomitant with increased resistance to the growth-inhibitory effects of these drugs. The non-DNA-binding mutants of GAPDH also localized to the nucleus when expressed in A549 cells, but did not confer any significant protection of telomeres against chemotherapy-induced degradation or growth inhibition; this occurred without the involvement of caspase activation or apoptosis regulation. Overall, these data demonstrate that GAPDH binds telomeric DNA directly in vitro and may have a biological role in the protection of telomeres against rapid degradation in response to chemotherapeutic agents in A549 human lung cancer cells.},
}
@article {pmid19797335,
year = {2009},
author = {Aviv, A},
title = {Commentary: Raising the bar on telomere epidemiology.},
journal = {International journal of epidemiology},
volume = {38},
number = {6},
pages = {1735-1736},
pmid = {19797335},
issn = {1464-3685},
mesh = {Age Factors ; Aging/*genetics ; Blotting, Southern/methods/*standards ; Humans ; *Mortality ; Polymerase Chain Reaction/methods/*standards ; Predictive Value of Tests ; Reproducibility of Results ; Sensitivity and Specificity ; Survival ; Telomere/*chemistry/genetics ; Twin Studies as Topic ; },
}
@article {pmid19797051,
year = {2009},
author = {Ballal, RD and Saha, T and Fan, S and Haddad, BR and Rosen, EM},
title = {BRCA1 localization to the telomere and its loss from the telomere in response to DNA damage.},
journal = {The Journal of biological chemistry},
volume = {284},
number = {52},
pages = {36083-36098},
pmid = {19797051},
issn = {1083-351X},
support = {R01-CA104546/CA/NCI NIH HHS/United States ; R01-CA80000/CA/NCI NIH HHS/United States ; R01-CA82599/CA/NCI NIH HHS/United States ; R01 CA104546/CA/NCI NIH HHS/United States ; R01 CA082599/CA/NCI NIH HHS/United States ; R01 CA080000/CA/NCI NIH HHS/United States ; },
mesh = {Acid Anhydride Hydrolases ; BRCA1 Protein/genetics/*metabolism ; Cell Line, Tumor ; *DNA Damage ; *DNA Repair ; DNA Repair Enzymes/genetics/*metabolism ; DNA, Neoplasm/genetics/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Gene Expression Regulation, Enzymologic/genetics ; Gene Expression Regulation, Neoplastic/genetics ; Gene Knockdown Techniques ; Humans ; RNA, Small Interfering ; Telomerase/genetics/metabolism ; Telomere/genetics ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Time Factors ; },
abstract = {BRCA1, a tumor suppressor, participates in DNA damage signaling and repair. Previously, we showed that BRCA1 overexpression caused inhibition of telomerase activity and telomere shortening in breast and prostate cancer cells. We now report that BRCA1 knockdown causes increased telomerase reverse transcriptase expression, telomerase activity, and telomere length; but studies utilizing a combination of BRCA1 and telomerase reverse transcriptase small interfering RNAs suggest that BRCA1 also regulates telomere length independently of telomerase. Using telomeric chromatin immunoprecipitation assays, we detected BRCA1 at the telomere and demonstrated time-dependent loss of BRCA1 from the telomere following DNA damage. Further studies suggest that BRCA1 interacts with TRF1 and TRF2 in a DNA-dependent manner and that some of the nuclear BRCA1 colocalizes with TRF1/2. Our findings further suggest that Rad50 is required to localize BRCA1 at the telomere and that the association of BRCA1 with Rad50 does not require DNA. Finally, we found that BRCA1 regulates the length of the 3' G-rich overhang in a manner that is dependent upon Rad50. Our findings suggest that BRCA1 is recruited to the telomere in a Rad50-dependent manner and that BRCA1 may regulate telomere length and stability, in part through its presence at the telomere.},
}
@article {pmid19796246,
year = {2009},
author = {Hills, M and Lansdorp, PM},
title = {Short telomeres resulting from heritable mutations in the telomerase reverse transcriptase gene predispose for a variety of malignancies.},
journal = {Annals of the New York Academy of Sciences},
volume = {1176},
number = {},
pages = {178-190},
doi = {10.1111/j.1749-6632.2009.04565.x},
pmid = {19796246},
issn = {1749-6632},
mesh = {Base Sequence ; *Genetic Predisposition to Disease ; Hematologic Neoplasms/*genetics ; Humans ; Mutation ; Stem Cells/enzymology ; Telomerase/*genetics ; Telomere/*enzymology/*genetics ; },
abstract = {Telomeres are composed of long arrays of TTAGGG repeats and associated proteins that act as a protective cap for chromosome ends. The length of telomere repeats is set in the germline but decreases in somatic cells, primarily as a function of DNA replication. Progressive telomere shortening limits stem cell divisions and probably acts as a tumor suppressor mechanism. Using a sensitive PCR method to detect the length of individual telomere repeats on specific chromosomes, we confirmed that telomere length decreases from primitive to more differentiated human cell types within the hematopoietic hierarchy. Genetic mutations in the components of telomerase (the RNA template sequence hTERC, reverse transcriptase hTERT, and Syskerin DKC1) have recently been implicated in a variety of bone marrow failure syndromes, idiopathic pulmonary fibrosis, and more recently, acute myeloid leukemia (AML). The majority of mutations discovered in AML patients were heritable and resulted in partial loss of telomerase activity, a finding counterintuitive to the requirement of telomerase in cancer cells. We have found heritable hypomorphic TERT mutations in other cancers as well, and we propose that such mutations result in short telomeres and premature loss of stem cells. Loss of normal stem cells could provide strong selection for abnormal cells incapable of responding to DNA damage signals originating from short telomeres. Such cells will have a DNA repair defect resulting in genomic instability and a mutator phenotype. Our findings point to an intimate connection between senescence and cancer and highlight the important role of telomeres in the biology of normal and malignant human cells.},
}
@article {pmid19789987,
year = {2009},
author = {Robertson, HM},
title = {The choanoflagellate Monosiga brevicollis karyotype revealed by the genome sequence: telomere-linked helicase genes resemble those of some fungi.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {17},
number = {7},
pages = {873-882},
pmid = {19789987},
issn = {1573-6849},
mesh = {Choanoflagellata/*enzymology/*genetics ; DNA Helicases/*genetics ; *Genome, Protozoan ; Karyotyping ; Phylogeny ; Sequence Analysis, DNA ; Telomere/*genetics ; },
abstract = {The approximately 42 Mbp assembled genome sequence for the choanoflagellate Monosiga brevicollis reveals that most of the large scaffolds of 300-2,600 kb represent entire chromosomes or chromosome arms. Telomeres are partially assembled at the termini of 37 scaffolds, while another 43 scaffolds end in telomere-associated regions containing distinctive gene sets. Potential centromeric regions were identified on 39 scaffolds. Together, these observations suggest a karyotype of approximately 40 metacentric and submetacentric chromosomes averaging 1 Mbp in size. Genes encoding RecQ family DNA helicases, along with ankyrin-domain proteins and serine/threonine kinases, are associated with most telomeres, a feature shared with some fungi. This telomere-linked helicase gene arrangement might be ancestral to both fungi and choanoflagellates in the super-kingdom Opisthokonta; however, the great lability of telomere architecture suggests that it could also be a convergent feature.},
}
@article {pmid19785508,
year = {2009},
author = {Bull, CF and O'Callaghan, NJ and Mayrhofer, G and Fenech, MF},
title = {Telomere length in lymphocytes of older South Australian men may be inversely associated with plasma homocysteine.},
journal = {Rejuvenation research},
volume = {12},
number = {5},
pages = {341-349},
doi = {10.1089/rej.2009.0868},
pmid = {19785508},
issn = {1557-8577},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; *Aging ; Australia ; Chromosome Aberrations ; Cohort Studies ; Female ; Homocysteine/*blood ; Humans ; Lymphocytes/*metabolism ; Male ; Middle Aged ; Telomere/*ultrastructure ; },
abstract = {Deficiencies in folate (FOL) and vitamin B12 (B12) result in increased chromosomal aberrations, a validated biomarker of cancer risk. Telomeres, the regions of DNA that cap the ends of each chromosome, are critical for maintaining chromosomal stability but the impact of micronutrients on telomere structure and function remains unclear. We hypothesized that telomere length maintenance might be compromised if the status of FOL and B12 was inadequate and plasma homocysteine (HCY) was increased. We investigated the relationship between telomere length in peripheral blood lymphocytes and plasma FOL, B12, and HCY status, and tested whether any such relationship was dependent on age, gender, body mass index, and common polymorphisms in folate metabolism genes. A single blood sample was collected from 43 younger (18-32 years) and 47 older (65-83 years) adults in South Australia. The younger cohort consisted of 18 males and 25 females, whereas the older group included 24 males and 23 females. Telomere length was determined in lymphocytes by flow cytometry. Telomere length in the younger cohort was 11.52% greater than in the older cohort (p = 0.015). In the older cohort, telomere length in females was 12.5% greater than in males (p = 0.028). In older males, there was a significant inverse correlation between telomere length and HCY (r = -0.57, p = 0.004), but this effect was not observed in the younger cohort or in the older female group. These results provide evidence that telomere length of lymphocytes in older men may be adversely affected by HCY in vivo.},
}
@article {pmid19784860,
year = {2010},
author = {Mirabello, L and Garcia-Closas, M and Cawthon, R and Lissowska, J and Brinton, LA and Pepłońska, B and Sherman, ME and Savage, SA},
title = {Leukocyte telomere length in a population-based case-control study of ovarian cancer: a pilot study.},
journal = {Cancer causes &amp; control : CCC},
volume = {21},
number = {1},
pages = {77-82},
pmid = {19784860},
issn = {1573-7225},
support = {R01 CA082838/CA/NCI NIH HHS/United States ; Z01 CP010190-02/ImNIH/Intramural NIH HHS/United States ; CA82838/CA/NCI NIH HHS/United States ; },
mesh = {Case-Control Studies ; Female ; Genetic Predisposition to Disease ; Humans ; Leukocytes/*metabolism ; Middle Aged ; Ovarian Neoplasms/*genetics ; Pilot Projects ; Risk Factors ; Telomere/chemistry/*metabolism ; },
abstract = {OBJECTIVES: Telomeres are structures at chromosome ends that contribute to maintaining genomic integrity. Telomere shortening with repeated cell divisions may lead to genomic instability and carcinogenesis. Studies suggest that shorter telomeres in constitutional DNA are associated with bladder, breast, lung, and renal cancer. Ovarian cancer tissues also have shortened telomeres and increased telomerase activity, suggesting that telomere abnormalities may be related to ovarian cancer.<br><br>METHODS: We investigated leukocyte telomere length in 99 women with serous ovarian adenocarcinoma and 100 age-matched cancer-free controls enrolled in a population-based case-control study.<br><br>RESULTS: Cases tended to have shorter telomeres than controls (P (wilcoxon) = 0.002). Compared to subjects with telomere lengths in the longest tertile, those in the middle and shortest tertiles showed respective age-adjusted odds ratios (95% confidence intervals) of 2.69 (1.23-5.88) and 3.39 (1.54-7.46) (P (trend) = 0.002). Strongest associations were found for subjects with poorly differentiated carcinomas (OR = 4.89, 95% CI 1.93-12.34).<br><br>CONCLUSIONS: This study shows that short leukocyte telomeres are associated with serous ovarian adenocarcinoma. These findings should be confirmed in large, prospective studies.},
}
@article {pmid19773737,
year = {2010},
author = {Diaz, VA and Mainous, AG and Player, MS and Everett, CJ},
title = {Telomere length and adiposity in a racially diverse sample.},
journal = {International journal of obesity (2005)},
volume = {34},
number = {2},
pages = {261-265},
doi = {10.1038/ijo.2009.198},
pmid = {19773737},
issn = {1476-5497},
mesh = {Adiponectin/*blood ; Adult ; Black People/genetics ; Body Composition ; Body Mass Index ; Cross-Sectional Studies ; Female ; Humans ; *Insulin Resistance ; Intra-Abdominal Fat/*anatomy &amp; histology ; Leptin/*blood ; Male ; Middle Aged ; Obesity/blood/ethnology/*genetics ; Tandem Repeat Sequences/genetics ; Telomere/*genetics ; White People/genetics ; },
abstract = {OBJECTIVE: To evaluate the cross-sectional relationship of anthropometric measures (body mass index (BMI) and visceral fat and the adipokines leptin and adiponectin) with telomere length in a racially diverse sample.<br><br>DESIGN: Cross-sectional study of participants recruited from a health science university.<br><br>SUBJECTS: Participants include 317 men and women aged 40-64 years without diagnosed diabetes, cardiovascular disease (defined as coronary heart disease or stroke/transient ischemic attack) or cancer.<br><br>RESULTS: Study participants were 54.9% female, 58% non-Hispanic white (NHW) and 42% non-Hispanic Black (NHB). Of the sample, 76% were either overweight or obese. Linear regressions showed no association between the anthropometric measures (BMI (kg m(-2)), visceral fat (cm(2)), adiponectin (microg ml(-1)), leptin (ng ml(-1)) or adiponectin to leptin ratio (microg ng(-1))) assessed in a continuous manner and telomere length assay ratio, either for the whole sample or when stratified by race or by gender.<br><br>CONCLUSION: This study finds no linear associations between telomere length and several measures of obesity in a sample of NHB and NHW men and women. Further studies are needed to identify factors that influence telomere length in diverse populations.},
}
@article {pmid19773453,
year = {2009},
author = {Choi, JE and Kang, HG and Jang, JS and Choi, YY and Kim, MJ and Kim, JS and Jeon, HS and Lee, WK and Cha, SI and Kim, CH and Kam, S and Jung, TH and Park, JY},
title = {Polymorphisms in telomere maintenance genes and risk of lung cancer.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {18},
number = {10},
pages = {2773-2781},
doi = {10.1158/1055-9965.EPI-09-0323},
pmid = {19773453},
issn = {1538-7755},
mesh = {Aged ; Case-Control Studies ; Female ; Genetic Predisposition to Disease ; Genotype ; Haplotypes ; Humans ; Lung Neoplasms/*genetics ; Male ; Middle Aged ; Neoplasm Staging ; Polymorphism, Genetic ; Risk Factors ; Smoking/genetics ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {This study was conducted to comprehensively evaluate the associations between polymorphisms in telomere maintenance genes (TERT, TRF1, TNKS1, TRF2, RAP1, and POT1) and lung cancer risk. We captured 35 polymorphisms in the genes and determined their frequencies in 27 healthy Koreans. Ten haplotype-tagging polymorphisms were examined in a case-control study that consisted of 720 lung cancer patients and 720 healthy controls. The TERT rs2735940 g.C > T and rs2736098 g.G > A, and TNKS1 rs6985140 g.A > G were significantly associated with the risk of lung cancer. In the haplotype analysis, the TERT rs2735940T/rs2736098A haplotype (ht4) was associated with a significantly increased risk of lung cancer compared with the rs2735940C/rs2736098G haplotype (adjusted odds ratio, 1.26; 95% confidence interval, 1.07-1.50; P = 0.008). When the TERT ht4 and TNKS1 rs6985140G as risk alleles, the risk of lung cancer increased in a dose-dependent manner as the number of risk alleles increased (P(trend) < 0.001). Subjects with two to four risk alleles were at a significantly increased risk of lung cancer (adjusted odds ratio, 1.67; 95% confidence interval, 1.23-2.27; P = 0.001) compared with subjects with zero risk allele. These findings suggest that genetic variants in the TERT and TNKS1 genes contribute to genetic susceptibility to lung cancer.},
}
@article {pmid19773443,
year = {2009},
author = {Garbe, JC and Bhattacharya, S and Merchant, B and Bassett, E and Swisshelm, K and Feiler, HS and Wyrobek, AJ and Stampfer, MR},
title = {Molecular distinctions between stasis and telomere attrition senescence barriers shown by long-term culture of normal human mammary epithelial cells.},
journal = {Cancer research},
volume = {69},
number = {19},
pages = {7557-7568},
pmid = {19773443},
issn = {1538-7445},
support = {U54 CA112970-049003/CA/NCI NIH HHS/United States ; U54 CA112970/CA/NCI NIH HHS/United States ; U54 CA112970-059003/CA/NCI NIH HHS/United States ; R01 CA024844-23/CA/NCI NIH HHS/United States ; U54 CA112970-019003/CA/NCI NIH HHS/United States ; F32 CA108480/CA/NCI NIH HHS/United States ; R01 CA024844-24/CA/NCI NIH HHS/United States ; U54 CA112970-029003/CA/NCI NIH HHS/United States ; U54 CA112970-039003/CA/NCI NIH HHS/United States ; R01 NS045209/NS/NINDS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Cell Growth Processes/drug effects/physiology ; Cells, Cultured ; Culture Media ; DNA Damage ; Epithelial Cells/cytology/drug effects/metabolism/ultrastructure ; Female ; Fibroblasts/cytology/drug effects/metabolism/ultrastructure ; Gene Expression ; Humans ; Mammary Glands, Human/cytology/drug effects/metabolism/*ultrastructure ; Oxytocin/pharmacology ; Protein Biosynthesis ; Telomere/genetics/*metabolism ; Transcription, Genetic ; Young Adult ; },
abstract = {Normal human epithelial cells in culture have generally shown a limited proliferative potential of approximately 10 to 40 population doublings before encountering a stress-associated senescence barrier (stasis) associated with elevated levels of cyclin-dependent kinase inhibitors p16 and/or p21. We now show that simple changes in medium composition can expand the proliferative potential of human mammary epithelial cells (HMEC) initiated as primary cultures to 50 to 60 population doublings followed by p16-positive, senescence-associated beta-galactosidase-positive stasis. We compared the properties of growing and senescent pre-stasis HMEC with growing and senescent post-selection HMEC, that is, cells grown in a serum-free medium that overcame stasis via silencing of p16 expression and that display senescence associated with telomere dysfunction. Cultured pre-stasis populations contained cells expressing markers associated with luminal and myoepithelial HMEC lineages in vivo in contrast to the basal-like phenotype of the post-selection HMEC. Gene transcript and protein expression, DNA damage-associated markers, mean telomere restriction fragment length, and genomic stability differed significantly between HMEC populations at the stasis versus telomere dysfunction senescence barriers. Senescent isogenic fibroblasts showed greater similarity to HMEC at stasis than at telomere dysfunction, although their gene transcript profile was distinct from HMEC at both senescence barriers. These studies support our model of the senescence barriers encountered by cultured HMEC in which the first barrier, stasis, is retinoblastoma-mediated and independent of telomere length, whereas a second barrier (agonescence or crisis) results from telomere attrition leading to telomere dysfunction. Additionally, the ability to maintain long-term growth of genomically stable multilineage pre-stasis HMEC populations can greatly enhance experimentation with normal HMEC.},
}
@article {pmid19772655,
year = {2009},
author = {Das, B and Pawar, N and Saini, D and Seshadri, M},
title = {Genetic association study of selected candidate genes (ApoB, LPL, Leptin) and telomere length in obese and hypertensive individuals.},
journal = {BMC medical genetics},
volume = {10},
number = {},
pages = {99},
pmid = {19772655},
issn = {1471-2350},
mesh = {Adolescent ; Adult ; Aged ; Alleles ; Apolipoproteins B/*genetics ; Child ; Female ; Gene Frequency ; Genetic Markers ; Genetic Predisposition to Disease ; Humans ; Hypertension/*genetics ; India ; Leptin/*genetics ; Lipoproteins, LDL/*genetics ; Male ; Middle Aged ; Obesity/*genetics ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; Telomere/*ultrastructure ; Young Adult ; },
abstract = {BACKGROUND: A genetic study was carried out among obese and hypertensive individuals from India to assess allelic association, if any, at three candidate loci: Apolipoprotein B (ApoB) minisatellite and two tetranucleotide repeat loci; LPL (Lipoprotein lipase) and Leptin. Attempt has also been made to find out whether telomere length attrition is associated with hypertension and obese individuals.<br><br>METHODS: Venous blood samples were collected from 37 normal, 35 obese and 47 hypertensive individuals. Genomic DNA was extracted from peripheral blood mononuclear cells (PBMC) and PCR amplifications were achieved using locus specific primers. Genotyping of ApoB minisatellite was performed using 4% polyacrylamide gel electrophoresis (PAGE) followed by silver staining, whereas LPL and Leptin loci were genotyped using ALF Express DNA sequencer. Telomere length was determined using a recently developed real time based quantitative PCR, where the relative telomere length was determined by calculating the relative ratio of telomere (T) and single copy gene (S) PCR products which is expressed as T/S ratio.<br><br>RESULTS: All the three loci are highly polymorphic, display high heterozygosity and conform to Hardy-Weinberg's equilibrium expectations. ApoB minisatellite displayed 14 alleles, whereas LPL and Leptin tetranucleotide loci were having 9 and 17 alleles, respectively. Interestingly two new alleles (9 and 11 repeats) were detected at ApoB locus for the first time. The alleles at Leptin locus were classified as Class I (lower alleles: 149-200 bp) and Class II alleles (higher alleles: >217 bp). Higher alleles at ApoB (>39 repeats), predominant allele 9 at LPL and alleles 164 bp and 224 bp at Leptin loci have shown allelic association with hypertensive individuals. After adjusting the influence of age and gender, the analysis of co-variance (ANCOVA) revealed the relative telomere length (T/S ratio) in hypertensive individuals to be (1.01 +/- 0.021), which was significantly different (P < 0.001) from obese (1.20 +/- 0.023) and normal (1.22 +/- 0.014) individuals. However, no significant difference in the relative telomere length was observed among male and female individuals, although age related decrease in telomere length was observed in these limited sample size.<br><br>CONCLUSION: The present study revealed that allelic association at ApoB, LPL, Leptin loci and loss of telomere length may have strong genetic association with hypertensive individuals. However, further study on larger sample size is needed to draw firm conclusions.},
}
@article {pmid19772576,
year = {2009},
author = {Hoxha, M and Dioni, L and Bonzini, M and Pesatori, AC and Fustinoni, S and Cavallo, D and Carugno, M and Albetti, B and Marinelli, B and Schwartz, J and Bertazzi, PA and Baccarelli, A},
title = {Association between leukocyte telomere shortening and exposure to traffic pollution: a cross-sectional study on traffic officers and indoor office workers.},
journal = {Environmental health : a global access science source},
volume = {8},
number = {},
pages = {41},
pmid = {19772576},
issn = {1476-069X},
support = {ES015172-01/ES/NIEHS NIH HHS/United States ; },
mesh = {Age Factors ; Aging/genetics ; Air Pollutants/*adverse effects ; Biomarkers/blood ; Cross-Sectional Studies ; Genetic Predisposition to Disease ; Humans ; Inhalation Exposure/*adverse effects ; Leukocytes/*physiology ; Motor Vehicles/*statistics &amp; numerical data ; Polymerase Chain Reaction ; Risk Factors ; Telomere/genetics/*physiology ; Time Factors ; },
abstract = {BACKGROUND: Telomere shortening in blood leukocytes has been associated with increased morbidity and death from cardiovascular disease and cancer, but determinants of shortened telomeres, a molecular feature of biological aging, are still largely unidentified. Traffic pollution has been linked with both cardiovascular and cancer risks, particularly in older subjects. Whether exposure to traffic pollution is associated with telomere shortening has never been evaluated.<br><br>METHODS: We measured leukocyte telomere length (LTL) by real-time PCR in blood DNA from 77 traffic officers exposed to high levels of traffic pollutants and 57 office workers (referents). Airborne benzene and toluene, as tracers for traffic exposure, were measured using personal passive samplers and gas-chromatography/flame-ionization detector analysis. We used covariate-adjusted multivariable models to test the effects of the exposure on LTL and obtain adjusted LTL means and 95% Confidence Intervals (CIs).<br><br>RESULTS: Adjusted mean LTL was 1.10 (95%CI 1.04-1.16) in traffic officers and 1.27 in referents (95%CI 1.20-1.35) [p < 0.001]. LTL decreased in association with age in both traffic officers (p = 0.01) and referents (p = 0.001), but traffic officers had shorter LTL within each age category. Among traffic officers, adjusted mean relative LTL was shorter in individuals working in high (n = 45, LTL = 1.02, 95%CI 0.96-1.09) compared to low traffic intensity (n = 32, LTL = 1.22, 95%CI 1.13-1.31) [p < 0.001]. In the entire study population, LTL decreased with increasing levels of personal exposure to benzene (p = 0.004) and toluene (p = 0.008).<br><br>CONCLUSION: Our results indicate that leukocyte telomere length is shortened in subjects exposed to traffic pollution, suggesting evidence of early biological aging and disease risk.},
}
@article {pmid19770396,
year = {2009},
author = {Spyridopoulos, I and Hoffmann, J and Aicher, A and Brümmendorf, TH and Doerr, HW and Zeiher, AM and Dimmeler, S},
title = {Accelerated telomere shortening in leukocyte subpopulations of patients with coronary heart disease: role of cytomegalovirus seropositivity.},
journal = {Circulation},
volume = {120},
number = {14},
pages = {1364-1372},
doi = {10.1161/CIRCULATIONAHA.109.854299},
pmid = {19770396},
issn = {1524-4539},
mesh = {Adult ; Aged ; CD8-Positive T-Lymphocytes/immunology ; Coronary Disease/*genetics/immunology/*virology ; Cytomegalovirus/*genetics ; Cytomegalovirus Infections/*complications/immunology ; Flow Cytometry ; Granulocytes/physiology ; Humans ; In Situ Hybridization, Fluorescence ; Inflammation/genetics/immunology/physiopathology ; Leukocytes/*physiology ; Male ; Middle Aged ; Monocytes/physiology ; Myocardial Infarction/physiopathology ; Reference Values ; Telomerase/metabolism ; Telomere/*physiology/ultrastructure ; Ventricular Dysfunction, Left/physiopathology ; },
abstract = {BACKGROUND: Shortening of mean telomere length (TL) in white blood cells is correlated with the development of coronary heart disease (CHD) and with increased mortality due to infectious disease. The goal of the present study was to investigate whether telomere shortening in CHD is restricted to specific peripheral blood lymphocyte and/or myeloid cell subpopulations. Results were correlated to TL in CD34+ hematopoietic peripheral blood stem cells and progenitor cells obtained from the same individual patients.<br><br>METHODS AND RESULTS: TL was measured by multicolor flow cytometry-fluorescent in situ hybridization in 12 leukocyte subpopulations after immunomagnetic bead sorting. We investigated TL in 14 young (mean age 25 years) and 13 older (mean age 65 years) healthy male volunteers and in 25 age-matched patients with CHD (mean age 65 years). We show that TL in granulocytes and monocytes mirrors TL of CD34+ peripheral blood stem cells and progenitor cells extremely well (r=0.95, P<0.0001) in patients and in healthy adults. TL was approximately 0.5 kilobases (kb) shorter in leukocytes from patients with CHD than in their age-matched control subjects. This difference was identical for CD34+ peripheral blood stem cells and progenitor cells, monocytes, granulocytes, B lymphocytes, and CD4+ T cells, including their memory and na&#xef;ve subpopulations. Surprisingly, only in cytotoxic CD8+ T lymphocytes, we found a substantially increased TL deficit of 1.0 kb in CHD patients as opposed to control subjects. Further analysis revealed that TL shortening was particularly pronounced in CD8+CD28(-) T cells obtained from cytomegalovirus-seropositive CHD patients, whereas such a difference was not observed in healthy cytomegalovirus-positive as opposed to cytomegalovirus-negative control subjects. Finally, TL shortening of CD8+CD45(RA+) T cells was correlated with the decrease in left ventricular function in CHD patients (r=0.629, P=0.001).<br><br>CONCLUSIONS: Telomere shortening in patients with CHD could potentially be attributed to either inherited TL shortening or acquired accelerated telomere shortening restricted to the hematopoietic system, which affects the baseline TL of all peripheral blood cell populations, including peripheral blood stem cells and progenitor cells. In addition, cytomegalovirus-seropositive patients but not healthy control subjects exhibited further shortening of their cytotoxic T lymphocytes. Surprisingly, TL shortening of CD8+ T lymphocytes in CHD patients demonstrated a very strong correlation with cardiac dysfunction, which suggests a mechanistic link between CHD and immunosenescence.},
}
@article {pmid19766477,
year = {2009},
author = {Varadi, V and Brendle, A and Brandt, A and Johansson, R and Enquist, K and Henriksson, R and Svenson, U and Tavelin, B and Roos, G and Hemminki, K and Lenner, P and Försti, A},
title = {Polymorphisms in telomere-associated genes, breast cancer susceptibility and prognosis.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {45},
number = {17},
pages = {3008-3016},
doi = {10.1016/j.ejca.2009.08.012},
pmid = {19766477},
issn = {1879-0852},
mesh = {Adult ; Aged ; Aged, 80 and over ; Breast Neoplasms/*genetics/pathology ; Epidemiologic Methods ; Female ; Genetic Predisposition to Disease ; Genotype ; Humans ; Middle Aged ; Neoplasm Metastasis ; Neoplasm Staging ; Polymorphism, Single Nucleotide ; Prognosis ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; },
abstract = {Telomeres are essential structures for maintaining chromosomal stability and their length has been reported to correlate with cancer risk and clinical outcome. Single nucleotide polymorphisms (SNPs) in genes encoding telomere-associated proteins could affect telomere length and chromosomal stability by influencing gene expression or protein configuration in the telomeres. Here, we report the results of the first association study on genetic variation in telomere-associated genes and their effect on telomere length, breast cancer (BC) susceptibility and prognosis. We genotyped 14 potentially functional and most informative SNPs in nine telomere-associated genes (TERT, TEP1, TERF1, TERF2, TERF2IP, ACD, POT1, TNKS and TNKS2) in 782 incident BC cases and 1559 matched controls. Relative telomere length (RTL) varied statistically significantly between the genotypes of the SNPs rs446977 (TEP1, p=0.04), rs938886 (TEP1, p=0.04) and rs6990097 (TNKS, p=0.04). However, none of them was associated with BC susceptibility and only rs6990097 correlated with regional lymph node metastasis (odds ratio (OR) 1.38, 95% confidence interval (CI) 1.08-1.77). The strongest association with BC susceptibility was observed for rs3785074 (TERF2, OR 0.51, 95% CI 0.31-0.83) and rs10509637 (TNKS2, OR 1.33, 95% CI 1.08-1.62). Haplotype and diplotype analysis confirmed the association of the TNKS2 gene with BC susceptibility. rs3785074 (TERF2) was additionally associated with histologic grade (OR 1.44, 95% CI 1.08-1.92) and negative oestrogen receptor status (OR 2.93, 95% CI 1.13-7.58). None of the SNPs showed a significant correlation with survival of the breast cancer patients. With these results, none of the SNPs represents any valuable prognostic marker for BC.},
}
@article {pmid19765243,
year = {2010},
author = {Kadi, F and Ponsot, E},
title = {The biology of satellite cells and telomeres in human skeletal muscle: effects of aging and physical activity.},
journal = {Scandinavian journal of medicine &amp; science in sports},
volume = {20},
number = {1},
pages = {39-48},
doi = {10.1111/j.1600-0838.2009.00966.x},
pmid = {19765243},
issn = {1600-0838},
mesh = {Aging/physiology ; Exercise/*physiology ; Humans ; Hypertrophy ; Muscle Fibers, Skeletal/pathology ; Muscle, Skeletal/*physiology ; Oxidative Stress/physiology ; Regeneration/physiology ; Satellite Cells, Skeletal Muscle/*physiology ; Telomere/*physiology ; },
abstract = {The decline in the neuromuscular function affects the physical performance and is a threat for independent living in later life. The age-related decrease in muscle satellite cells observed by the age of 70 can be specific to type II fibers in some muscles. Several studies have shown that different forms of exercise induce the expansion of satellite cell pool in human skeletal muscle of young and elderly. Exercise is a powerful non-pharmacological tool inducing the renewal of the satellite cell pool in skeletal muscles. Skeletal muscle is not a stable tissue as satellite cells are constantly recruited during normal daily activities. Satellite cells and the length of telomeres are important in the context of muscle regeneration. It is likely that the regulation of telomeres in vitro cannot fully mimic the behavior of telomeres in human tissues. New insights suggest that telomeres in skeletal muscle are dynamic structures under the influence of their environment. When satellite cells are heavily recruited for regenerative events as in the skeletal muscle of athletes, telomere length has been found to be either dramatically shortened or maintained and even longer than in non-trained individuals. This suggests the existence of mechanisms allowing the control of telomere length in vivo.},
}
@article {pmid19763176,
year = {2009},
author = {Liti, G and Haricharan, S and Cubillos, FA and Tierney, AL and Sharp, S and Bertuch, AA and Parts, L and Bailes, E and Louis, EJ},
title = {Segregating YKU80 and TLC1 alleles underlying natural variation in telomere properties in wild yeast.},
journal = {PLoS genetics},
volume = {5},
number = {9},
pages = {e1000659},
pmid = {19763176},
issn = {1553-7404},
support = {BB/F015216/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; R01 GM077509/GM/NIGMS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; },
mesh = {*Alleles ; Base Sequence ; Chromosome Mapping ; Chromosome Segregation/*genetics ; Epistasis, Genetic ; Fungal Proteins/*genetics ; Gene Deletion ; Genetic Linkage ; Heterozygote ; Phenotype ; Quantitative Trait Loci/genetics ; Saccharomyces/cytology/*genetics ; Sequence Homology, Nucleic Acid ; Spores, Fungal/genetics ; Telomere/genetics/*metabolism ; },
abstract = {In yeast, as in humans, telomere length varies among individuals and is controlled by multiple loci. In a quest to define the extent of variation in telomere length, we screened 112 wild-type Saccharomyces sensu stricto isolates. We found extensive telomere length variation in S. paradoxus isolates. This phenotype correlated with their geographic origin: European strains were observed to have extremely short telomeres (<150 bp), whereas American isolates had telomeres approximately three times as long (>400 bp). Insertions of a URA3 gene near telomeres allowed accurate analysis of individual telomere lengths and telomere position effect (TPE). Crossing the American and European strains resulted in F1 spores with a continuum of telomere lengths consistent with what would be predicted if many quantitative trait loci (QTLs) were involved in length maintenance. Variation in TPE is similarly quantitative but only weakly correlated with telomere length. Genotyping F1 segregants indicated several QTLs associated with telomere length and silencing variation. These QTLs include likely candidate genes but also map to regions where there are no known genes involved in telomeric properties. We detected transgressive segregation for both phenotypes. We validated by reciprocal hemizygosity that YKU80 and TLC1 are telomere-length QTLs in the two S. paradoxus subpopulations. Furthermore, we propose that sequence divergence within the Ku heterodimer generates negative epistasis within one of the allelic combinations (American-YKU70 and European-YKU80) resulting in very short telomeres.},
}
@article {pmid19763083,
year = {2009},
author = {Sarthy, J and Bae, NS and Scrafford, J and Baumann, P},
title = {Human RAP1 inhibits non-homologous end joining at telomeres.},
journal = {The EMBO journal},
volume = {28},
number = {21},
pages = {3390-3399},
pmid = {19763083},
issn = {1460-2075},
mesh = {DNA/metabolism ; DNA Damage ; *DNA Repair ; DNA-Binding Proteins/metabolism ; Gene Expression ; Genomic Instability ; HeLa Cells ; Humans ; Schizosaccharomyces/metabolism ; Schizosaccharomyces pombe Proteins/metabolism ; Shelterin Complex ; *Telomere ; Telomere-Binding Proteins/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; },
abstract = {Telomeres, the nucleoprotein structures at the ends of linear chromosomes, promote genome stability by distinguishing chromosome termini from DNA double-strand breaks (DSBs). Cells possess two principal pathways for DSB repair: homologous recombination and non-homologous end joining (NHEJ). Several studies have implicated TRF2 in the protection of telomeres from NHEJ, but the underlying mechanism remains poorly understood. Here, we show that TRF2 inhibits NHEJ, in part, by recruiting human RAP1 to telomeres. Heterologous targeting of hRAP1 to telomeric DNA was sufficient to bypass the need for TRF2 in protecting telomeric DNA from NHEJ in vitro. On expanding these studies in cells, we find that recruitment of hRAP1 to telomeres prevents chromosome fusions caused by the loss of TRF2/hRAP1 from chromosome ends despite activation of a DNA damage response. These results provide the first evidence that hRAP1 inhibits NHEJ at mammalian telomeres and identify hRAP1 as a mediator of genome stability.},
}
@article {pmid19757477,
year = {2009},
author = {Xu, Y and Ishizuka, T and Kurabayashi, K and Komiyama, M},
title = {Consecutive formation of G-quadruplexes in human telomeric-overhang DNA: a protective capping structure for telomere ends.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {48},
number = {42},
pages = {7833-7836},
doi = {10.1002/anie.200903858},
pmid = {19757477},
issn = {1521-3773},
mesh = {Base Sequence ; Circular Dichroism ; DNA, Single-Stranded/chemistry/*metabolism ; Fluorescence Resonance Energy Transfer ; *G-Quadruplexes ; Humans ; Hydrolysis ; Microscopy, Atomic Force ; Telomere/chemistry/*metabolism ; },
}
@article {pmid19756717,
year = {2010},
author = {Oeseburg, H and de Boer, RA and van Gilst, WH and van der Harst, P},
title = {Telomere biology in healthy aging and disease.},
journal = {Pflugers Archiv : European journal of physiology},
volume = {459},
number = {2},
pages = {259-268},
pmid = {19756717},
issn = {1432-2013},
mesh = {Aging/*genetics ; Aging, Premature/genetics ; Animals ; Atherosclerosis/genetics ; Cardiovascular Diseases/*genetics ; Cellular Senescence/*genetics ; Coronary Artery Disease/genetics ; Heart Failure/genetics ; Humans ; Neoplasms/*genetics ; Risk Factors ; Telomere/*physiology ; },
abstract = {Aging is a biological process that affects most cells, organisms and species. Telomeres have been postulated as a universal biological clock that shortens in parallel with aging in cells. Telomeres are located at the end of the chromosomes and consist of an evolutionary conserved repetitive nucleotide sequence ranging in length from a few hundred base pairs in yeast till several kilo base pairs in vertebrates. Telomeres associate with shelterin proteins and form a complex protecting the chromosomal deoxyribonucleic acid (DNA) from recognition by the DNA damage-repair system. Due to the "end-replication problem" telomeres shorten with each mitotic cycle resulting in cumulative telomere attrition during aging. When telomeres reach a critical length the cell will not further undergo cell divisions and become senescent or otherwise dysfunctional. Telomere shortening has not only been linked to aging but also to several age associated diseases, including tumorigenesis, coronary artery disease, and heart failure. In the current review, we will discuss the role of telomere biology in relation to aging and aging associated diseases.},
}
@article {pmid19752323,
year = {2009},
author = {Vasan, RS and Demissie, S and Kimura, M and Cupples, LA and White, C and Gardner, JP and Cao, X and Levy, D and Benjamin, EJ and Aviv, A},
title = {Association of leukocyte telomere length with echocardiographic left ventricular mass: the Framingham heart study.},
journal = {Circulation},
volume = {120},
number = {13},
pages = {1195-1202},
pmid = {19752323},
issn = {1524-4539},
support = {N01-HC-25195/HC/NHLBI NIH HHS/United States ; R01 NS017950/NS/NINDS NIH HHS/United States ; N01 HC025195/HC/NHLBI NIH HHS/United States ; R01 NS017950-28/NS/NINDS NIH HHS/United States ; K24 HL004334/HL/NHLBI NIH HHS/United States ; R01HL080124/HL/NHLBI NIH HHS/United States ; 2 K24 HL04334/HL/NHLBI NIH HHS/United States ; R01 AG021593-05/AG/NIA NIH HHS/United States ; 6R01-NS 17950/NS/NINDS NIH HHS/United States ; K24 HL004334-08/HL/NHLBI NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; R01 HL080124/HL/NHLBI NIH HHS/United States ; R01AG021593/AG/NIA NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; R01 HL080124-05/HL/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Blotting, Southern ; Cross-Sectional Studies ; *Echocardiography ; Female ; Humans ; Hypertension/*epidemiology ; *Hypertrophy, Left Ventricular/diagnostic imaging/epidemiology/prevention &amp; control ; Leukocytes/*physiology ; Male ; Massachusetts/epidemiology ; Middle Aged ; Multivariate Analysis ; Oxidative Stress ; Risk Factors ; Telomere/*genetics ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) decreases over the adult life course owing to the cumulative burden of oxidative stress, inflammation, and exposure to vascular risk factors. Left ventricular (LV) mass is a biomarker of long-standing exposure to cardiovascular disease risk factors. We hypothesized that LTL is related inversely to LV mass.<br><br>METHODS AND RESULTS: We related LTL (measured by Southern blot analysis) to echocardiographic LV mass and its components (LV diastolic dimension and LV wall thickness) in 850 Framingham Heart Study participants (mean age 58 years, 58% women) using multivariable linear regression with adjustment for age, sex, height, weight, systolic blood pressure, hypertension treatment, and smoking. Overall, multivariable-adjusted LTL was positively related to LV mass (beta-coefficient per SD increase 0.072; P=0.001), LV wall thickness (beta=0.053; P=0.01), and LV diastolic dimension (beta=0.035; P=0.09). We observed effect modification by hypertension status (P for interaction=0.02 for LV mass); LTL was more strongly associated with LV mass and LV wall thickness in individuals with hypertension (beta-coefficient per SD increment of 0.10 and 0.08, respectively; P<0.01 for both). Participants with hypertension who were in the top quartile of LV mass had LTL that was 250 base pairs longer than those in the lowest quartile (P for trend across quartiles=0.009).<br><br>CONCLUSIONS: In contrast to our expectation, in the present community-based sample, LTL was positively associated with LV mass and wall thickness, especially so in participants with hypertension. These data are consistent with the hypothesis that longer LTL may be a marker of propensity to LV hypertrophy.},
}
@article {pmid19752213,
year = {2009},
author = {Xu, L and Petreaca, RC and Gasparyan, HJ and Vu, S and Nugent, CI},
title = {TEN1 is essential for CDC13-mediated telomere capping.},
journal = {Genetics},
volume = {183},
number = {3},
pages = {793-810},
pmid = {19752213},
issn = {1943-2631},
support = {R01 CA096972/CA/NCI NIH HHS/United States ; R01-CA96972/CA/NCI NIH HHS/United States ; },
mesh = {Blotting, Western ; Cell Division ; Chromatin Immunoprecipitation ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; DNA Polymerase I/genetics/metabolism ; DNA Repair ; DNA, Single-Stranded/genetics ; Exodeoxyribonucleases/genetics/metabolism ; G2 Phase ; Mutation ; Protein Binding ; Rad52 DNA Repair and Recombination Protein/genetics/metabolism ; Saccharomyces cerevisiae/genetics/growth &amp; development/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Temperature ; Two-Hybrid System Techniques ; },
abstract = {Telomere binding proteins protect chromosome ends from degradation and mask chromosome termini from checkpoint surveillance. In Saccharomyces cerevisiae, Cdc13 binds single-stranded G-rich telomere repeats, maintaining telomere integrity and length. Two additional proteins, Ten1 and Stn1, interact with Cdc13 but their contributions to telomere integrity are not well defined. Ten1 is known to prevent accumulation of aberrant single-stranded telomere DNA; whether this results from defective end protection or defective telomere replication is unclear. Here we report our analysis of a new group of ten1 temperature-sensitive (ts) mutants. At permissive temperatures, ten1-ts strains display greatly elongated telomeres. After shift to nonpermissive conditions, however, ten1-ts mutants accumulate extensive telomeric single-stranded DNA. Cdk1 activity is required to generate these single-stranded regions, and deleting the EXO1 nuclease partially suppresses ten1-ts growth defects. This is similar to cdc13-1 mutants, suggesting ten1-ts strains are defective for end protection. Moreover, like Cdc13, our analysis reveals Ten1 promotes de novo telomere addition. Interestingly, in ten1-ts strains at high temperatures, telomeric single-stranded DNA and Rad52-YFP repair foci are strongly induced despite Cdc13 remaining associated with telomeres, revealing Cdc13 telomere binding is not sufficient for end protection. Finally, unlike cdc13-1 mutants, ten1-ts strains display strong synthetic interactions with mutations in the POLalpha complex. These results emphasize that Cdc13 relies on Ten1 to execute its essential function, but leave open the possibility that Ten1 has a Cdc13-independent role in DNA replication.},
}
@article {pmid19749354,
year = {2009},
author = {Kurashina, Y and Liu, X and Kato, C and Inoue, N and Saneyoshi, M and Yamaguchi, T},
title = {Influence of 3'-azido-2',3'-dideoxyguanosine treatment on telomere length in human telomerase-immortalized human fibroblast cells.},
journal = {Nucleic acids symposium series (2004)},
volume = {},
number = {53},
pages = {249-250},
doi = {10.1093/nass/nrp125},
pmid = {19749354},
issn = {1746-8272},
mesh = {Cell Line ; Dideoxynucleosides/*pharmacology ; Enzyme Inhibitors/*pharmacology ; Fibroblasts/drug effects/metabolism ; Humans ; Telomerase/*antagonists &amp; inhibitors/genetics ; Telomere/*drug effects/metabolism ; },
abstract = {In order to study telomerase activation in normal cells, a telomerase-immortalized fibroblast cell line, hTERT-BJ1, treated with a telomerase inhibitor, 3'-azido-2',3'-dideoxyguanosine (AZddG), is considered to be a good model. Long-term treatment with AZddG resulted in telomere shortening from 10-20 kbp to 5-6 kbp in cultured hTERT BJ1 cells. However, the telomere length then stabilized. As expected, removal of AZddG from the culture medium induced telomere lengthening in the cells, suggesting that telomerase activity was recovered upon AZddG removal. The effect of recovery of telomerase activity in hTERT-BJ1 cells will be investigated in future studies.},
}
@article {pmid19749352,
year = {2009},
author = {Kaneda, K and Torigoe, H},
title = {Interaction between tetraplex structure of mouse telomeric DNA and telomeric DNA binding domains of mouse telomere binding protein Pot1.},
journal = {Nucleic acids symposium series (2004)},
volume = {},
number = {53},
pages = {245-246},
doi = {10.1093/nass/nrp123},
pmid = {19749352},
issn = {1746-8272},
mesh = {Animals ; Circular Dichroism ; DNA/*chemistry/metabolism ; DNA-Binding Proteins/chemistry/metabolism ; Fluorescence Resonance Energy Transfer ; *G-Quadruplexes ; Mice ; Protein Interaction Domains and Motifs ; Shelterin Complex ; Telomere/*chemistry ; Telomere-Binding Proteins ; },
abstract = {Mouse telomeric DNA sequence, Tel3.5: 5'-AGGG(T TAGGG)(3)-3', has the ability to form antiparallel tetraplex structure in the presence of Na(+). We examined the interaction between the antiparallel tetraplex structure of Tel3.5 and each of two single-stranded telomeric DNA-binding domains of mouse telomere binding protein Pot1, mPot1OB1 and mPot1OB2. The antiparallel tetraplex of Tel3.5 became unfolded upon the interaction with mPot1OB1. On the other hand, no significant structural change of the antiparallel tetraplex of Tel3.5 was observed upon the interaction with mPot1OB2. Considering that the antiparallel tetraplex inhibits telomerase-mediated telomere elongation, we conclude that the ability of mPot1OB1 to unfold the antiparallel tetraplex of the mouse telomeric DNA is required for telomerase-mediated telomere elongation.},
}
@article {pmid19749261,
year = {2009},
author = {Xu, Y and Suzuki, Y and Kaminaga, K and Komiyama, M},
title = {Molecular basis of human telomere DNA/RNA structure and its potential application.},
journal = {Nucleic acids symposium series (2004)},
volume = {},
number = {53},
pages = {63-64},
doi = {10.1093/nass/nrp032},
pmid = {19749261},
issn = {1746-8272},
mesh = {DNA/*chemistry ; *G-Quadruplexes ; Humans ; RNA, Untranslated/*chemistry ; Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; },
abstract = {Telomeric repeat-containing RNA is a non-coding RNA molecule newly found in mammalian cells. However, structure and function of the telomeric RNA in chromosome ends have not yet been elucidated. Using a combination of NMR, CD and MALDI-TOFMS experiments, we have demonstrated that human telomere RNA can form a parallel G-quadruplex structure. Furthermore, we successfully found for the first time that human telomere DNA and RNA sequence can form a DNA-RNA hybrid type G-quadruplex structure based on click chemistry approach. Telomerase or its telomere DNA substrate is also known to present a specific target in discovering anticancer agents. Recently, we developed a structure-based approach to sequence-specific cleaving of human telomeric DNA by G-quadruplex formation. These results not only provide valuable information to allow understanding of the roles of human telomeric RNA in telomere biology, but also serve as a start step for developing new anti-cancer reagent.},
}
@article {pmid19742304,
year = {2009},
author = {Temime-Smaali, N and Guittat, L and Sidibe, A and Shin-ya, K and Trentesaux, C and Riou, JF},
title = {The G-quadruplex ligand telomestatin impairs binding of topoisomerase IIIalpha to G-quadruplex-forming oligonucleotides and uncaps telomeres in ALT cells.},
journal = {PloS one},
volume = {4},
number = {9},
pages = {e6919},
pmid = {19742304},
issn = {1932-6203},
mesh = {Cell Nucleus/metabolism ; Cell Separation ; Cells, Cultured ; DNA Topoisomerases, Type I/*metabolism ; Flow Cytometry ; *G-Quadruplexes ; Humans ; Ligands ; Models, Biological ; Oligonucleotides/*chemistry ; Oxazoles/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Recombination, Genetic ; Telomere/*metabolism/*ultrastructure ; },
abstract = {In Alternative Lengthening of Telomeres (ALT) cell lines, specific nuclear bodies called APBs (ALT-associated PML bodies) concentrate telomeric DNA, shelterin components and recombination factors associated with telomere recombination. Topoisomerase IIIalpha (Topo III) is an essential telomeric-associated factor in ALT cells. We show here that the binding of Topo III to telomeric G-overhang is modulated by G-quadruplex formation. Topo III binding to G-quadruplex-forming oligonucleotides was strongly inhibited by telomestatin, a potent and specific G-quadruplex ligand. In ALT cells, telomestatin treatment resulted in the depletion of the Topo III/BLM/TRF2 complex and the disruption of APBs and led to the segregation of PML, shelterin components and Topo III. Interestingly, a DNA damage response was observed at telomeres in telomestatin-treated cells. These data indicate the importance of G-quadruplex stabilization during telomere maintenance in ALT cells. The function of TRF2/Topo III/BLM in the resolution of replication intermediates at telomeres is discussed.},
}
@article {pmid19738378,
year = {2009},
author = {Fortin, F and Beaulieu Bergeron, M and Fetni, R and Lemieux, N},
title = {Frequency of chromosome healing and interstitial telomeres in 40 cases of constitutional abnormalities.},
journal = {Cytogenetic and genome research},
volume = {125},
number = {3},
pages = {176-185},
doi = {10.1159/000230002},
pmid = {19738378},
issn = {1424-859X},
mesh = {Chromosomal Instability ; *Chromosome Aberrations ; Chromosome Deletion ; *Chromosomes, Human ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Retrospective Studies ; Ring Chromosomes ; *Telomere ; Translocation, Genetic ; },
abstract = {Human telomeres play a major role in stabilizing chromosome ends and preventing fusions. Chromosomes bearing a broken end are rescued by the acquisition of a new telomeric cap without any subtelomeric sequences being present at the breakpoint, a process referred to as chromosome healing. Conversely, a loss of telomeric function or integrity can lead to the presence of interstitial telomeres at the junction site in translocations or ring chromosomes. In order to determine the frequency at which interstitial telomeres or chromosome healing events are observed in target chromosome abnormalities, we conducted a retrospective FISH study using pan-telomeric and chromosome-specific subtelomeric probes on archival material from 40 cases of terminal deletions, translocations or ring chromosomes. Of the 19 terminal deletions investigated, 17 were negative for the subtelomeric probe specific to the deleted arm despite being positive for the pan-telomeric probe. These 17 cases were thus considered as having been rescued through chromosome healing, suggesting that this process is frequent in terminal deletions. In addition, as 2 of these cases were inherited from a parent bearing the same deletion, chromosomes healed by this process are thus stable through mitosis and meiosis. Regarding the 13 cases of translocations and 8 ring chromosomes, 4 and 2 cases respectively demonstrated pan-telomeric sequences at the interstitial junction point. Furthermore, 2 cases of translocations and 1 ring chromosome had both interstitial pan-telomeres and subtelomeres, whereas 2 other cases of ring chromosomes and 1 case of translocation only showed interstitial subtelomeres. Therefore, interstitial (sub)telomeric sequences in translocations and ring chromosomes are more common than previously thought, as we found a frequency of 43% in this study. Moreover, our results illustrate the necessity of performing FISH with both subtelomeric and pan-telomeric probes when investigating these rearrangements, as the breakpoints can be either in the distal part of the pan-telomeres, or in between the 2 types of sequences.},
}
@article {pmid19735238,
year = {2009},
author = {Epel, E and Daubenmier, J and Moskowitz, JT and Folkman, S and Blackburn, E},
title = {Can meditation slow rate of cellular aging? Cognitive stress, mindfulness, and telomeres.},
journal = {Annals of the New York Academy of Sciences},
volume = {1172},
number = {},
pages = {34-53},
pmid = {19735238},
issn = {1749-6632},
support = {R56-AG030424/AG/NIA NIH HHS/United States ; K08 MH064110-05/MH/NIMH NIH HHS/United States ; K08 MH064110/MH/NIMH NIH HHS/United States ; R56 AG030424-02/AG/NIA NIH HHS/United States ; R56 AG030424/AG/NIA NIH HHS/United States ; },
mesh = {Adaptation, Psychological/physiology ; Cellular Senescence/*genetics ; Cognition/physiology ; Humans ; *Meditation ; Stress, Psychological/*physiopathology ; Telomere/*genetics ; },
abstract = {Understanding the malleable determinants of cellular aging is critical to understanding human longevity. Telomeres may provide a pathway for exploring this question. Telomeres are the protective caps at the ends of chromosomes. The length of telomeres offers insight into mitotic cell and possibly organismal longevity. Telomere length has now been linked to chronic stress exposure and depression. This raises the question of mechanism: How might cellular aging be modulated by psychological functioning? We consider two psychological processes or states that are in opposition to one another-threat cognition and mindfulness-and their effects on cellular aging. Psychological stress cognitions, particularly appraisals of threat and ruminative thoughts, can lead to prolonged states of reactivity. In contrast, mindfulness meditation techniques appear to shift cognitive appraisals from threat to challenge, decrease ruminative thought, and reduce stress arousal. Mindfulness may also directly increase positive arousal states. We review data linking telomere length to cognitive stress and stress arousal and present new data linking cognitive appraisal to telomere length. Given the pattern of associations revealed so far, we propose that some forms of meditation may have salutary effects on telomere length by reducing cognitive stress and stress arousal and increasing positive states of mind and hormonal factors that may promote telomere maintenance. Aspects of this model are currently being tested in ongoing trials of mindfulness meditation.},
}
@article {pmid19734944,
year = {2009},
author = {Jaskelioff, M and Song, W and Xia, J and Liu, C and Kramer, J and Koido, S and Gendler, SJ and Calderwood, SK and Gong, J},
title = {Telomerase deficiency and telomere dysfunction inhibit mammary tumors induced by polyomavirus middle T oncogene.},
journal = {Oncogene},
volume = {28},
number = {48},
pages = {4225-4236},
doi = {10.1038/onc.2009.268},
pmid = {19734944},
issn = {1476-5594},
mesh = {Animals ; Cell Cycle/genetics ; Cell Transformation, Neoplastic/pathology ; Disease Models, Animal ; Female ; Humans ; Mammary Neoplasms, Animal ; Mammary Neoplasms, Experimental/*genetics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic/metabolism ; Mucin-1/genetics ; Oncogenes/*genetics/physiology ; RNA ; Telomerase/*deficiency ; Telomere/*pathology ; },
abstract = {Mice transgenic for MUC1 (mucin 1) and polyomavirus middle T (PyMT) develop mammary carcinomas within 15 weeks with 100% penetrance. PyMT-induced mammary tumorigenesis is closely correlated with robust telomerase expression and activity. To assess the role of telomerase activation and telomere maintenance in mammary carcinoma tumorigenesis, we generated mice expressing MUC1 and PyMT (MMT mice) but deficient in the telomerase RNA component, mTerc, on the C57BL/6 background. Successive generational intercrosses of mTerc(-/-)MMT mice produced cohorts with progressively shorter telomeres that were audited for mammary tumor formation. Relative to MMT (N=14) and G0 mTerc(+/-) female controls (G0=14), mTerc(-/-)MMT females (G1=11, G2=15, G3=15 and G4=5) showed decreased tumor volumes and increased tumor latency-MMT=95.6 days; G0 mTerc(+/-)MMT=98.6 days versus G1, G2, G3 and G4 mTerc(-/-)MMT mice with latencies of 122.6, 138.9, 140.7 and 220.9 days, respectively (controls versus G1-G4, P<0.005). The progressive impairment of lung metastasis was also observed with each successive mTerc(-/-)MMT generation. The impairment of tumorigenesis was associated with decreased proliferation of mammary epithelial and tumor cells and increased apoptosis of tumor cells. Together, these results indicate that, in the setting of viral oncoprotein mammary tumorigenesis, telomerase-dependent telomere maintenance facilitates the formation and metastatic progression of mammary tumors.},
}
@article {pmid19734843,
year = {2009},
author = {Subhawong, AP and Heaphy, CM and Argani, P and Konishi, Y and Kouprina, N and Nassar, H and Vang, R and Meeker, AK},
title = {The alternative lengthening of telomeres phenotype in breast carcinoma is associated with HER-2 overexpression.},
journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},
volume = {22},
number = {11},
pages = {1423-1431},
doi = {10.1038/modpathol.2009.125},
pmid = {19734843},
issn = {1530-0285},
support = {P50 CA088843/CA/NCI NIH HHS/United States ; },
mesh = {Biomarkers, Tumor/genetics/metabolism ; Breast Neoplasms/*genetics/metabolism ; Carcinoma, Ductal, Breast/*genetics/metabolism ; Estrogen Receptor alpha/metabolism ; Female ; Fluorescent Antibody Technique ; Gene Amplification/genetics ; Gene Dosage/*genetics ; Gene Expression Regulation, Neoplastic ; Humans ; In Situ Hybridization, Fluorescence ; Microscopy, Fluorescence ; Middle Aged ; Oligonucleotide Array Sequence Analysis ; Phenotype ; Receptor, ErbB-2/*genetics/metabolism ; Receptors, Progesterone/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Approximately 10-15% of human cancers do not show evidence of telomerase activity, and a subset of these maintain telomere lengths by a recombination-based mechanism termed alternative lengthening of telomeres (ALT). The ALT phenotype, relatively common in certain sarcomas and germ cell tumors, is very rare in carcinomas. In this study we describe evidence for the ALT phenotype in molecular subclasses of breast carcinoma, specifically a subset of cancers with HER-2 overexpression. Tissue microarrays were created from 71 invasive ductal carcinomas of the breast categorized into subclasses, and telomere lengths were directly assessed using fluorescence in situ hybridization with combined promyelocytic leukemia (PML) protein immunofluorescence. The ALT phenotype was identified in 3 of 21 HER-2-positive cases, but in none of the other 50 cases (P=0.023). This is the first direct observation of this mechanism of telomere maintenance in breast carcinoma unrelated to Li-Fraumeni syndrome. The correlation of the ALT phenotype with HER-2 positivity, both of which involve abnormal DNA amplification, suggests a possible common underlying mechanism. This telomere phenotype confers a poor prognosis in some cancers; two of the three cases in our study showed rapid tumor progression, possibly suggesting that it may adversely affect outcome in breast carcinoma as well. As cancers using the ALT pathway are predicted to be resistant to therapies based on telomerase inhibition, these results may have therapeutic consequences.},
}
@article {pmid19729991,
year = {2009},
author = {Gilley, DP},
title = {A two way street: the telomere and the DNA damage response.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {8},
number = {18},
pages = {2855-2856},
doi = {10.4161/cc.8.18.9385},
pmid = {19729991},
issn = {1551-4005},
mesh = {DNA Breaks, Double-Stranded ; *DNA Repair ; DNA Repair Enzymes ; Humans ; Telomere/*physiology ; Telomeric Repeat Binding Protein 2/metabolism ; },
}
@article {pmid19729828,
year = {2009},
author = {Sainger, RN and Shah, FD and Telang, SD and Shah, PM and Patel, PS},
title = {Telomere attrition and telomerase activity are associated with GSTM1 polymorphism in oral cancer.},
journal = {Cancer biomarkers : section A of Disease markers},
volume = {5},
number = {4},
pages = {189-195},
doi = {10.3233/CBM-2009-0103},
pmid = {19729828},
issn = {1875-8592},
mesh = {Adult ; Aged ; Female ; Genotype ; Glutathione Transferase/*genetics ; Humans ; Male ; Middle Aged ; Mouth Neoplasms/*genetics/pathology/ultrastructure ; Polymorphism, Genetic ; Telomerase/*metabolism ; Telomere/*pathology ; },
abstract = {Telomere attrition is an important event during tumorigenesis regulated by factors including oxidative stress, mitochondrial function, DNA adducts etc. Critically short telomeres act as signal for telomerase activity in the cancer cells. To determine whether null genotype of GSTM1 gene has any association with telomere length shortening and telomerase activity, we analyzed telomere length, telomerase activity and GSTM1 polymorphism in oral tissues. We observed that malignant tissues exhibited shorter telomere length. Telomerase activity was observed in about 75% malignant tissues. 40% of the oral cancer patients exhibited GSTM1 polymorphism. Further, shorter telomere lengths were observed in patients having GSTM1 polymorphism. Also, the GSTM1 genotype showed negative correlation with telomerase activity and telomere length. Our study proposes role of GSTM1 polymorphism in telomere attrition and subsequent telomerase activity in the cancer cells. The results are suggestive of possible link between absence of GSTM1 gene and telomere length alterations.},
}
@article {pmid19718028,
year = {2009},
author = {Begus-Nahrmann, Y and Lechel, A and Obenauf, AC and Nalapareddy, K and Peit, E and Hoffmann, E and Schlaudraff, F and Liss, B and Schirmacher, P and Kestler, H and Danenberg, E and Barker, N and Clevers, H and Speicher, MR and Rudolph, KL},
title = {p53 deletion impairs clearance of chromosomal-instable stem cells in aging telomere-dysfunctional mice.},
journal = {Nature genetics},
volume = {41},
number = {10},
pages = {1138-1143},
pmid = {19718028},
issn = {1546-1718},
mesh = {Aging/*physiology ; Animals ; Cell Cycle ; *Chromosomal Instability ; DNA Damage ; *Gene Deletion ; Genome ; Intestinal Mucosa/metabolism ; Intestines/cytology ; Mice ; Mice, Knockout ; Stem Cells/cytology/*metabolism ; Telomere/*genetics ; Tumor Suppressor Protein p53/*deficiency/genetics/metabolism ; },
abstract = {Telomere dysfunction limits the proliferative capacity of human cells and induces organismal aging by activation of p53 and p21. Although deletion of p21 elongates the lifespan of telomere-dysfunctional mice, a direct analysis of p53 in telomere-related aging has been hampered by early tumor formation in p53 knockout mice. Here we analyzed the functional consequences of conditional p53 deletion. Intestinal deletion of p53 shortened the lifespan of telomere-dysfunctional mice without inducing tumor formation. In contrast to p21 deletion, the deletion of p53 impaired the depletion of chromosomal-instable intestinal stem cells in aging telomere-dysfunctional mice. These instable stem cells contributed to epithelial regeneration leading to an accumulation of chromosomal instability, increased apoptosis, altered epithelial cell differentiation and premature intestinal failure. Together, these results provide the first experimental evidence for an organ system in which p53-dependent mechanisms prevent tissue destruction in response to telomere dysfunction by depleting genetically instable stem cells.},
}
@article {pmid19717545,
year = {2009},
author = {Renciuk, D and Kejnovská, I and Skoláková, P and Bednárová, K and Motlová, J and Vorlícková, M},
title = {Arrangements of human telomere DNA quadruplex in physiologically relevant K+ solutions.},
journal = {Nucleic acids research},
volume = {37},
number = {19},
pages = {6625-6634},
pmid = {19717545},
issn = {1362-4962},
mesh = {DNA/chemistry ; Ethanol/pharmacology ; *G-Quadruplexes ; Humans ; Potassium/*chemistry ; Sodium/chemistry ; Telomere/*chemistry ; },
abstract = {The arrangement of the human telomeric quadruplex in physiologically relevant conditions has not yet been unambiguously determined. Our spectroscopic results suggest that the core quadruplex sequence G(3)(TTAG(3))(3) forms an antiparallel quadruplex of the same basket type in solution containing either K(+) or Na(+) ions. Analogous sequences extended by flanking nucleotides form a mixture of the antiparallel and hybrid (3 + 1) quadruplexes in K(+)-containing solutions. We, however, show that long telomeric DNA behaves in the same way as the basic G(3)(TTAG(3))(3) motif. Both G(3)(TTAG(3))(3) and long telomeric DNA are also able to adopt the (3 + 1) quadruplex structure: Molecular crowding conditions, simulated here by ethanol, induced a slow transition of the K(+)-stabilized quadruplex into the hybrid quadruplex structure and then into a parallel quadruplex arrangement at increased temperatures. Most importantly, we demonstrate that the same transitions can be induced even in aqueous, K(+)-containing solution by increasing the DNA concentration. This is why distinct quadruplex structures were detected for AG(3)(TTAG(3))(3) by X-ray, nuclear magnetic resonance and circular dichrosim spectroscopy: Depending on DNA concentration, the human telomeric DNA can adopt the antiparallel quadruplex, the (3 + 1) structure, or the parallel quadruplex in physiologically relevant concentrations of K(+) ions.},
}
@article {pmid19717459,
year = {2009},
author = {Draskovic, I and Arnoult, N and Steiner, V and Bacchetti, S and Lomonte, P and Londoño-Vallejo, A},
title = {Probing PML body function in ALT cells reveals spatiotemporal requirements for telomere recombination.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {106},
number = {37},
pages = {15726-15731},
pmid = {19717459},
issn = {1091-6490},
mesh = {Cell Cycle/genetics/physiology ; Cell Line ; Cell Line, Tumor ; Fluorescent Antibody Technique, Indirect ; Humans ; In Situ Hybridization, Fluorescence ; Intranuclear Space/metabolism ; Nuclear Proteins/*genetics/*metabolism ; Promyelocytic Leukemia Protein ; *Recombination, Genetic ; Telomerase/metabolism ; Telomere/*genetics/*metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; Transcription Factors/*genetics/*metabolism ; Tumor Suppressor Proteins/*genetics/*metabolism ; },
abstract = {Promyelocytic leukemia (PML) bodies (also called ND10) are dynamic nuclear structures implicated in a wide variety of cellular processes. ALT-associated PML bodies (APBs) are specialized PML bodies found exclusively in telomerase-negative tumors in which telomeres are maintained by recombination-based alternative (ALT) mechanisms. Although it has been suggested that APBs are directly implicated in telomere metabolism of ALT cells, their precise role and structure have remained elusive. Here we show that PML bodies in ALT cells associate with chromosome ends forming small, spatially well-defined clusters, containing on average 2-5 telomeres. Using an innovative approach that gently enlarges PML bodies in living cells while retaining their overall organization, we show that this physical enlargement of APBs spatially resolves the single telomeres in the cluster, but does not perturb the potential of the APB to recruit chromosome extremities. We show that telomere clustering in PML bodies is cell-cycle regulated and that unique telomeres within a cluster associate with recombination proteins. Enlargement of APBs induced the accumulation of telomere-telomere recombination intermediates visible on metaphase spreads and connecting heterologous chromosomes. The strand composition of these recombination intermediates indicated that this recombination is constrained to a narrow time window in the cell cycle following replication. These data provide strong evidence that PML bodies are not only a marker for ALT cells but play a direct role in telomere recombination, both by bringing together chromosome ends and by promoting telomere-telomere interactions between heterologous chromosomes.},
}
@article {pmid19716824,
year = {2009},
author = {Britt-Compton, B and Capper, R and Rowson, J and Baird, DM},
title = {Short telomeres are preferentially elongated by telomerase in human cells.},
journal = {FEBS letters},
volume = {583},
number = {18},
pages = {3076-3080},
doi = {10.1016/j.febslet.2009.08.029},
pmid = {19716824},
issn = {1873-3468},
support = {//Cancer Research UK/United Kingdom ; },
mesh = {Alleles ; Cell Line ; Cell Proliferation ; Humans ; Kinetics ; Telomerase/*metabolism ; Telomere/*metabolism/ultrastructure ; },
abstract = {Short telomeres have been shown to be preferentially elongated in both yeast and mouse models. We examined this in human cells, by utilising cells with large allelic telomere length differentials and observing the relative rates of elongation following the expression of hTERT. We observed that short telomeres are gradually elongated in the first 26 PDs of growth, whereas the longer telomeres displayed limited elongation in this period. Telomeres coalesced at similar lengths irrespective of their length prior to the expression of hTERT. These data indicate that short telomeres are marked for gradual elongation to a cell strain specific length threshold.},
}
@article {pmid19716786,
year = {2009},
author = {Deng, Z and Norseen, J and Wiedmer, A and Riethman, H and Lieberman, PM},
title = {TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres.},
journal = {Molecular cell},
volume = {35},
number = {4},
pages = {403-413},
pmid = {19716786},
issn = {1097-4164},
support = {R01 CA093606-07/CA/NCI NIH HHS/United States ; R01 CA093606/CA/NCI NIH HHS/United States ; T32 AI07324-17/AI/NIAID NIH HHS/United States ; T32 AI007324/AI/NIAID NIH HHS/United States ; CA093606/CA/NCI NIH HHS/United States ; },
mesh = {Binding Sites ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosome Aberrations ; DNA Methylation ; HCT116 Cells ; Heterochromatin/*metabolism ; Histones/metabolism ; Humans ; Origin Recognition Complex/*metabolism ; Protein Structure, Tertiary ; RNA Interference ; RNA, Nuclear/*metabolism ; Telomere/*metabolism/ultrastructure ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; Time Factors ; Transfection ; },
abstract = {Telomere-repeat-encoding RNA (referred to as TERRA) has been identified as a potential component of yeast and mammalian telomeres. We show here that TERRA RNA interacts with several telomere-associated proteins, including telomere repeat factors 1 (TRF1) and 2 (TRF2), subunits of the origin recognition complex (ORC), heterochromatin protein 1 (HP1), histone H3 trimethyl K9 (H3 K9me3), and members of the DNA-damage-sensing pathway. siRNA depletion of TERRA caused an increase in telomere dysfunction-induced foci, aberrations in metaphase telomeres, and a loss of histone H3 K9me3 and ORC at telomere repeat DNA. Previous studies found that TRF2 amino-terminal GAR domain recruited ORC to telomeres. We now show that TERRA RNA can interact directly with the TRF2 GAR and ORC1 to form a stable ternary complex. We conclude that TERRA facilitates TRF2 interaction with ORC and plays a central role in telomere structural maintenance and heterochromatin formation.},
}
@article {pmid19714219,
year = {2009},
author = {Moser, BA and Subramanian, L and Khair, L and Chang, YT and Nakamura, TM},
title = {Fission yeast Tel1(ATM) and Rad3(ATR) promote telomere protection and telomerase recruitment.},
journal = {PLoS genetics},
volume = {5},
number = {8},
pages = {e1000622},
pmid = {19714219},
issn = {1553-7404},
support = {R01 GM078253/GM/NIGMS NIH HHS/United States ; R01 GM078253-03/GM/NIGMS NIH HHS/United States ; GM078253/GM/NIGMS NIH HHS/United States ; },
mesh = {Carrier Proteins/genetics/metabolism ; Cell Cycle Proteins/genetics/*metabolism ; Checkpoint Kinase 2 ; DNA-Binding Proteins ; Protein Binding ; Protein Kinases/genetics/*metabolism ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Schizosaccharomyces/enzymology/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {The checkpoint kinases ATM and ATR are redundantly required for maintenance of stable telomeres in diverse organisms, including budding and fission yeasts, Arabidopsis, Drosophila, and mammals. However, the molecular basis for telomere instability in cells lacking ATM and ATR has not yet been elucidated fully in organisms that utilize both the telomere protection complex shelterin and telomerase to maintain telomeres, such as fission yeast and humans. Here, we demonstrate by quantitative chromatin immunoprecipitation (ChIP) assays that simultaneous loss of Tel1(ATM) and Rad3(ATR) kinases leads to a defect in recruitment of telomerase to telomeres, reduced binding of the shelterin complex subunits Ccq1 and Tpz1, and increased binding of RPA and homologous recombination repair factors to telomeres. Moreover, we show that interaction between Tpz1-Ccq1 and telomerase, thought to be important for telomerase recruitment to telomeres, is disrupted in tel1Delta rad3Delta cells. Thus, Tel1(ATM) and Rad3(ATR) are redundantly required for both protection of telomeres against recombination and promotion of telomerase recruitment. Based on our current findings, we propose the existence of a regulatory loop between Tel1(ATM)/Rad3(ATR) kinases and Tpz1-Ccq1 to ensure proper protection and maintenance of telomeres in fission yeast.},
}
@article {pmid19713769,
year = {2009},
author = {Tsai, RY},
title = {Nucleolar modulation of TRF1: a dynamic way to regulate telomere and cell cycle by nucleostemin and GNL3L.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {8},
number = {18},
pages = {2912-2916},
pmid = {19713769},
issn = {1551-4005},
support = {R01 CA113750/CA/NCI NIH HHS/United States ; R01 CA113750-05/CA/NCI NIH HHS/United States ; R01CA113750/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Carrier Proteins/*metabolism ; Cell Cycle ; Cell Nucleolus ; GTP-Binding Proteins/*metabolism ; Humans ; Nuclear Proteins/*metabolism ; Telomere/metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; },
abstract = {Chromosomal ends are protected by a high-order structure called telomere. Maintenance of correct telomere length and structure is critically important for the viability of both dividing and non-dividing cells. Notably, targeted deletion of a component of the multi-protein telomere-capping complex, TRF1 (telomeric repeat binding factor 1), causes lethality at embryonic day 5-6 without apparent telomere deficiency, raising the possibility that TRF1 may also moonlight outside the telomere. Further reinforcing the extra-telomeric tie of TRF1, two studies from our group have reported the findings that TRF1 can be bound and modulated by two nucleolar GTP-binding proteins, nucleostemin (NS) and guanine nucleotide binding protein-like 3-like (GNL3L), which exhibit apparently opposite effects on the protein degradation of TRF1. In particular, GNL3L is able to stabilize TRF1 protein during mitosis and promote the metaphase-to-anaphase transition. This manuscript extends the discussion on how this GNL3L-mediated TRF1 regulation creates a novel dynamic control on telomere and cell cycle, and extrapolates its evolutionary significance by contrasting the activities of NS and GNL3L.},
}
@article {pmid19704012,
year = {2009},
author = {Chang, M and Luke, B and Kraft, C and Li, Z and Peter, M and Lingner, J and Rothstein, R},
title = {Telomerase is essential to alleviate pif1-induced replication stress at telomeres.},
journal = {Genetics},
volume = {183},
number = {3},
pages = {779-791},
pmid = {19704012},
issn = {1943-2631},
support = {GM67055/GM/NIGMS NIH HHS/United States ; /CAPMC/CIHR/Canada ; R01 GM067055/GM/NIGMS NIH HHS/United States ; CA125520/CA/NCI NIH HHS/United States ; R33 CA125520/CA/NCI NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics/metabolism ; Cell Division ; Checkpoint Kinase 2 ; DNA Breaks, Single-Stranded ; DNA Damage ; DNA Helicases/genetics/*metabolism ; DNA Repair ; DNA Replication/*genetics ; Endodeoxyribonucleases/genetics/metabolism ; Exodeoxyribonucleases/genetics/metabolism ; Gene Expression Regulation, Fungal ; Immunoblotting ; Luminescent Proteins/genetics/metabolism ; Microscopy, Fluorescence ; Mutation ; Protein Serine-Threonine Kinases/genetics/metabolism ; Replication Protein A/genetics/metabolism ; Saccharomyces cerevisiae/genetics/growth &amp; development/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/*genetics ; },
abstract = {Pif1, an evolutionarily conserved helicase, negatively regulates telomere length by removing telomerase from chromosome ends. Pif1 has also been implicated in DNA replication processes such as Okazaki fragment maturation and replication fork pausing. We find that overexpression of Saccharomyces cervisiae PIF1 results in dose-dependent growth inhibition. Strong overexpression causes relocalization of the DNA damage response factors Rfa1 and Mre11 into nuclear foci and activation of the Rad53 DNA damage checkpoint kinase, indicating that the toxicity is caused by accumulation of DNA damage. We screened the complete set of approximately 4800 haploid gene deletion mutants and found that moderate overexpression of PIF1, which is only mildly toxic on its own, causes growth defects in strains with mutations in genes involved in DNA replication and the DNA damage response. Interestingly, we find that telomerase-deficient strains are also sensitive to PIF1 overexpression. Our data are consistent with a model whereby increased levels of Pif1 interfere with DNA replication, causing collapsed replication forks. At chromosome ends, collapsed forks result in truncated telomeres that must be rapidly elongated by telomerase to maintain viability.},
}
@article {pmid19696580,
year = {2009},
author = {Ren, F and Li, C and Xi, H and Wen, Y and Huang, K},
title = {Estimation of human age according to telomere shortening in peripheral blood leukocytes of Tibetan.},
journal = {The American journal of forensic medicine and pathology},
volume = {30},
number = {3},
pages = {252-255},
doi = {10.1097/PAF.0b013e318187df8e},
pmid = {19696580},
issn = {1533-404X},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Child ; Child, Preschool ; Ethnicity/*genetics ; Female ; Forensic Genetics/*methods ; Humans ; Infant ; Infant, Newborn ; Leukocytes/*physiology ; Male ; Middle Aged ; Models, Genetic ; Sex Factors ; Telomere/genetics/*physiology ; Tibet ; Young Adult ; },
abstract = {In most normal somatic cells, the terminal restriction fragments (TRF) length and age are inversely correlated, which can be used to determine individual age. However, very little is known about the quantitative relationship between human telomeres and age. The aim of the present study was to investigate age-, gender-, and ethnicity-related changes in telomere length in human peripheral blood leukocytes (PBLs). Changes with age in telomere lengths were assessed by Southern blotting. The results shown that telomeres shorten in human PBLs in an age-dependent manner (r = -0.913, P < 0.01). The formula for age estimation according to telomere shortening was Y = -16.539X + 236.287 (Y: age, year; X: mean TRF length, kb). We analyzed the mean TRF length in males and females and found that males had shorter telomeres than females. Moreover, we compared the TRF length of Tibetan and Han population in China and found that telomere length did not differ between 2 populations. We conclude that estimation of human age according to telomere shortening in PBLs is a novel method especially when there is no morphologic information, furthermore, the gender must be considered when age estimation is carried out based on telomere shortening.},
}
@article {pmid19695733,
year = {2010},
author = {Beisner, J and Dong, M and Taetz, S and Nafee, N and Griese, EU and Schaefer, U and Lehr, CM and Klotz, U and Mürdter, TE},
title = {Nanoparticle mediated delivery of 2'-O-methyl-RNA leads to efficient telomerase inhibition and telomere shortening in human lung cancer cells.},
journal = {Lung cancer (Amsterdam, Netherlands)},
volume = {68},
number = {3},
pages = {346-354},
doi = {10.1016/j.lungcan.2009.07.010},
pmid = {19695733},
issn = {1872-8332},
mesh = {Carcinoma, Non-Small-Cell Lung/genetics/*metabolism/pathology/*therapy ; Cell Line, Tumor ; Fibroblasts/metabolism/pathology ; *Gene Transfer Techniques ; Humans ; Lung Neoplasms/genetics/*metabolism/pathology/*therapy ; Microscopy, Confocal ; Nanoparticles ; Oligodeoxyribonucleotides/*administration &amp; dosage/genetics ; Telomerase/*antagonists &amp; inhibitors/genetics ; Telomere/genetics/pathology ; },
abstract = {A promising approach for treatment of non-small cell lung cancer (NSCLC) is based on the inhibition of telomerase in cancer cells. The antisense oligonucleotide 2'-O-methyl-RNA binding to the RNA component of telomerase acts as a selective telomerase inhibitor. We developed chitosan-coated polylactide-coglycolide (PLGA) nanoparticles to mediate efficient delivery of 2'-O-methyl-RNA into human lung cancer cells. Cellular uptake of the inhibitor mediated by chitosan-coated PLGA nanoparticles was greatly enhanced compared to the uptake of antisense oligonucleotide alone as shown by flow cytometry analysis. Confocal laser scanning microscopy clearly demonstrated internalization of 2'-O-methyl-RNA. 2'-O-methyl-RNA-nanoparticle complexes exhibited nearly no acute cytotoxicity in human lung cancer cells and did not influence the viability of primary tumor lung fibroblasts. Human NSCLC A549 cells treated with 2'-O-methyl-RNA-nanoparticle complexes showed 87% viability compared to untreated control cells. 2'-O-methyl-RNA delivered by nanoparticle complexes inhibited telomerase activity in a sequence-specific manner. During long-term treatment (15 weeks) telomerase activity was continuously reduced by approximately 80%. Furthermore, nanoparticle mediated delivery of 2'-O-methyl-RNA resulted in significant telomere shortening from 5.9kb to 4kb (p=0.008) in A549 cells. In summary, our data demonstrate that nanoparticle mediated delivery of 2'-O-methyl-RNA induces effective telomerase inhibition and telomere shortening in human lung cancer cells and therefore represents a novel and promising strategy for the treatment of lung cancer.},
}
@article {pmid19692585,
year = {2009},
author = {Lim, KW and Alberti, P and Guédin, A and Lacroix, L and Riou, JF and Royle, NJ and Mergny, JL and Phan, AT},
title = {Sequence variant (CTAGGG)n in the human telomere favors a G-quadruplex structure containing a G.C.G.C tetrad.},
journal = {Nucleic acids research},
volume = {37},
number = {18},
pages = {6239-6248},
pmid = {19692585},
issn = {1362-4962},
support = {G0500336/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Calorimetry ; Circular Dichroism ; Electrophoresis, Polyacrylamide Gel ; *G-Quadruplexes ; Genetic Variation ; Humans ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Potassium/chemistry ; Repetitive Sequences, Nucleic Acid ; Spectrophotometry, Ultraviolet ; Telomere/*chemistry ; Thermodynamics ; },
abstract = {Short contiguous arrays of variant CTAGGG repeats in the human telomere are unstable in the male germline and somatic cells, suggesting formation of unusual structures by this repeat type. Here, we report on the structure of an intramolecular G-quadruplex formed by DNA sequences containing four human telomeric variant CTAGGG repeats in potassium solution. Our results reveal a new robust antiparallel G-quadruplex fold involving two G-tetrads sandwiched between a G.C base pair and a G.C.G.C tetrad, which could represent a new platform for drug design targeted to human telomeric DNA.},
}
@article {pmid19687155,
year = {2009},
author = {De Meyer, T and Rietzschel, ER and De Buyzere, ML and Langlois, MR and De Bacquer, D and Segers, P and Van Damme, P and De Backer, GG and Van Oostveldt, P and Van Criekinge, W and Gillebert, TC and Bekaert, S and , },
title = {Systemic telomere length and preclinical atherosclerosis: the Asklepios Study.},
journal = {European heart journal},
volume = {30},
number = {24},
pages = {3074-3081},
doi = {10.1093/eurheartj/ehp324},
pmid = {19687155},
issn = {1522-9645},
mesh = {Adult ; Aged ; Atherosclerosis/*genetics/pathology ; Female ; Humans ; Leukocytes, Mononuclear/*pathology ; Male ; Middle Aged ; Polymorphism, Restriction Fragment Length ; Risk Factors ; Telomere/*pathology ; },
abstract = {AIMS: Peripheral blood leucocyte (PBL) telomere length (TL) is a systemic ageing biomarker and has been proposed to be an independent predictor of cardiovascular disease (CVD). We aimed at providing an explanation for this association by the evaluation of the biomarker value of PBL-TL in preclinical atherosclerosis.<br><br>METHODS AND RESULTS: Peripheral blood leucocyte telomere length was assessed by telomere restriction fragment analysis in 2509 volunteers free from established CVD, aged approximately 35-55 years old, from the Asklepios Study cohort. Intima-media thickness (IMT) and plaque presence were determined by ultrasonography in both left and right carotid and femoral arteries. Peripheral blood leucocyte telomere length was not a significant independent determinant of IMT (P > 0.3) or plaque presence (P > 0.05), in either artery or either sex. In women but not in men, PBL-TL was a weak determinant of combined (carotid or femoral) plaque presence, adjusted for other risk factors (women: P = 0.03, men: P > 0.4). However, even in women presenting plaques, PBL-TL was still longer than in men.<br><br>CONCLUSION: Since systemic TL is not a substantial underlying determinant of preclinical atherosclerosis, the association between CVD and TL cannot be explained by the fact that subjects with shorter inherited TL are predisposed to atherosclerosis.},
}
@article {pmid19685336,
year = {2009},
author = {Scherthan, H},
title = {Analysis of telomere dynamics in mouse spermatogenesis.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {558},
number = {},
pages = {383-399},
doi = {10.1007/978-1-60761-103-5_22},
pmid = {19685336},
issn = {1064-3745},
mesh = {Animals ; Cytogenetic Analysis/*methods ; Male ; Mice ; Spermatogenesis/*genetics/physiology ; Telomere/*metabolism ; },
abstract = {A complex meiotic differentiation program generates genetically diverse haploid cells (gametes or spores) to compensate for the genome doubling that occurs at fertilization. To this end, homologous chromosomes must undergo pairing and recombination before they become partitioned in haploid sets by two consecutive meiotic divisions. Chromosome ends (telomeres) contain a protective complex that is crucial for genomic stability. In meiosis, telomeres become key players in the chromosome pairing process during prophase to the first meiotic division. At the onset of prophase I, telomeres attach to the nuclear envelope, about which they move and transiently cluster in a limited sector of the nuclear periphery. The dynamic clustering of telomeres (bouquet formation) occurs at the onset of the zygotene substage and supports homologue recognition, pairing and telomere DNA metabolism. The following chapter outlines the protocols that have been useful in studies on telomere dynamics and the frequency of earliest prophase I stages in testis suspensions of the mouse, and may be useful to address similar questions in particular mouse mutants that become increasingly available.},
}
@article {pmid19684885,
year = {2009},
author = {Ly, H},
title = {Genetic and environmental factors influencing human diseases with telomere dysfunction.},
journal = {International journal of clinical and experimental medicine},
volume = {2},
number = {2},
pages = {114-130},
pmid = {19684885},
issn = {1940-5901},
support = {P30 AI050409/AI/NIAID NIH HHS/United States ; R24 DK064399/DK/NIDDK NIH HHS/United States ; U54 AI057157/AI/NIAID NIH HHS/United States ; },
abstract = {Both genetic and environmental factors have been implicated in the mechanism underlying the pathogenesis of serious and fatal forms of human blood disorder (acquired aplastic anemia, AA) and lung disease (idiopathic pulmonary fibrosis, IPF). We and other researchers have recently shown that naturally occurring mutations in genes encoding the telomere maintenance complex (telomerase) may predispose patients to the development of AA or IPF. Epidemiological data have shown that environmental factors can also cause and/or exacerbate the pathogenesis of these diseases. The exact mechanisms that these germ-line mutations in telomere maintenance genes coupled with environmental insults lead to ineffective hematopoiesis in AA and lung scarring in IPF are not well understood, however. In this article, we provide a summary of evidence for environmental and genetic factors influencing the diseases. These studies provide important insights into the interplay between environmental and genetic factors leading to human diseases with telomere dysfunction.},
}
@article {pmid19683498,
year = {2009},
author = {Atanassov, BS and Evrard, YA and Multani, AS and Zhang, Z and Tora, L and Devys, D and Chang, S and Dent, SY},
title = {Gcn5 and SAGA regulate shelterin protein turnover and telomere maintenance.},
journal = {Molecular cell},
volume = {35},
number = {3},
pages = {352-364},
pmid = {19683498},
issn = {1097-4164},
support = {AG02888/AG/NIA NIH HHS/United States ; R01 GM067718/GM/NIGMS NIH HHS/United States ; CA129037/CA/NCI NIH HHS/United States ; R01 GM067718-06/GM/NIGMS NIH HHS/United States ; GM067718/GM/NIGMS NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; Chromosome Aberrations ; DNA Breaks, Double-Stranded ; DNA Repair/genetics ; Gene Deletion ; Humans ; Mice ; Models, Biological ; Proteasome Inhibitors ; Protein Stability ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/*metabolism ; Thiolester Hydrolases/genetics/*metabolism ; Ubiquitin Thiolesterase ; p300-CBP Transcription Factors/genetics/metabolism/*physiology ; },
abstract = {Histone acetyltransferases (HATs) play important roles in gene regulation and DNA repair by influencing the accessibility of chromatin to transcription factors and repair proteins. Here, we show that deletion of Gcn5 leads to telomere dysfunction in mouse and human cells. Biochemical studies reveal that depletion of Gcn5 or ubiquitin-specific protease 22 (Usp22), which is another bona fide component of the Gcn5-containing SAGA complex, increases ubiquitination and turnover of TRF1, a primary component of the telomeric shelterin complex. Inhibition of the proteasome or overexpression of USP22 opposes this effect. The USP22 deubiquitinating module requires association with SAGA complexes for activity, and we find that depletion of Gcn5 compromises this association in mammalian cells. Thus, our results indicate that Gcn5 regulates TRF1 levels through effects on Usp22 activity and SAGA integrity.},
}
@article {pmid19680223,
year = {2009},
author = {Germe, T and Miller, K and Cooper, JP},
title = {A non-canonical function of topoisomerase II in disentangling dysfunctional telomeres.},
journal = {The EMBO journal},
volume = {28},
number = {18},
pages = {2803-2811},
pmid = {19680223},
issn = {1460-2075},
support = {//Cancer Research UK/United Kingdom ; },
mesh = {Alleles ; Catalysis ; Chromosomes/ultrastructure ; DNA/chemistry ; DNA Topoisomerases, Type II/*chemistry ; Dimerization ; Escherichia coli/metabolism ; Introns ; Mutagenesis, Site-Directed ; Mutation ; Point Mutation ; Protein Structure, Tertiary ; Schizosaccharomyces/*enzymology/genetics ; Telomere/*ultrastructure ; Temperature ; },
abstract = {The decatenation activity of topoisomerase II (Top2), which is widely conserved within the eukaryotic domain, is essential for chromosomal segregation in mitosis. It is less clear, however, whether Top2 performs the same function uniformly across the whole genome, and whether all its functions rely on decatenation. In the fission yeast, Schizosaccharomyces pombe, telomeres are bound by Taz1, which promotes smooth replication fork progression through the repetitive telomeric sequences. Hence, replication forks stall at taz1 Delta telomeres. This leads to telomeric entanglements at low temperatures (<or=20 degrees C) that cause chromosomal segregation defects and loss of viability. Here, we show that the appearance of entanglements, and the resulting cold sensitivity of taz1 Delta cells, is suppressed by mutated alleles of Top2 that confer slower catalytic turnover. This suppression does not rely on the decatenation activity of Top2. Rather, the enhanced presence of reaction intermediates in which Top2 is clamped around DNA, promotes the removal of telomeric entanglements in vivo, independently of catalytic cycle completion. We propose a model for how the clamped enzyme-DNA complex promotes proper chromosomal segregation.},
}
@article {pmid19679647,
year = {2009},
author = {Martínez, P and Thanasoula, M and Muñoz, P and Liao, C and Tejera, A and McNees, C and Flores, JM and Fernández-Capetillo, O and Tarsounas, M and Blasco, MA},
title = {Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice.},
journal = {Genes &amp; development},
volume = {23},
number = {17},
pages = {2060-2075},
pmid = {19679647},
issn = {1549-5477},
support = {232854/ERC_/European Research Council/International ; /CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Aging/metabolism ; Animals ; Cell Cycle/physiology ; Cell Line ; *Chromosome Fragility ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; DNA Damage/genetics ; E2F1 Transcription Factor/metabolism ; Epidermal Cells ; Epidermis/pathology ; Fibroblasts/cytology/metabolism ; Gene Expression Regulation ; Hyperpigmentation/etiology/genetics ; Mice ; Mice, Knockout ; Mutation/genetics ; Neoplasm Proteins/metabolism ; Neoplasms/genetics ; Protein Deficiency/*complications ; Skin Diseases/*etiology/genetics ; Skin Neoplasms/*etiology/genetics ; Stem Cells/pathology ; Telomere/*genetics ; Telomeric Repeat Binding Protein 1/*deficiency/genetics/*metabolism ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {The telomere repeat-binding factor 1 (TERF1, referred to hereafter as TRF1) is a component of mammalian telomeres whose role in telomere biology and disease has remained elusive. Here, we report on cells and mice conditionally deleted for TRF1. TRF1-deleted mouse embryonic fibroblasts (MEFs) show rapid induction of senescence, which is concomitant with abundant telomeric gamma-H2AX foci and activation of the ATM/ATR downstream checkpoint kinases CHK1 and CHK2. DNA damage foci are rescued by both ATM and ATM/ATR inhibitors, further indicating that both signaling pathways are activated upon TRF1 deletion. Abrogation of the p53 and RB pathways bypasses senescence but leads to chromosomal instability including sister chromatid fusions, chromosome concatenation, and occurrence of multitelomeric signals (MTS). MTS are also elevated in ATR-deficient MEFs or upon treatment with aphidicolin, two conditions known to induce breakage at fragile sites, suggesting that TRF1-depleted telomeres are prone to breakage. To address the impact of these molecular defects in the organism, we deleted TRF1 in stratified epithelia of TRF1(Delta/Delta)K5-Cre mice. These mice die perinatally and show skin hyperpigmentation and epithelial dysplasia, which are associated with induction of telomere-instigated DNA damage, activation of the p53/p21 and p16 pathways, and cell cycle arrest in vivo. p53 deficiency rescues mouse survival but leads to development of squamous cell carcinomas, demonstrating that TRF1 suppresses tumorigenesis. Together, these results demonstrate that dysfunction of a telomere-binding protein is sufficient to produce severe telomeric damage in the absence of telomere shortening, resulting in premature tissue degeneration and development of neoplastic lesions.},
}
@article {pmid19675549,
year = {2009},
author = {Gilchrest, BA and Eller, MS and Yaar, M},
title = {Telomere-mediated effects on melanogenesis and skin aging.},
journal = {The journal of investigative dermatology. Symposium proceedings},
volume = {14},
number = {1},
pages = {25-31},
doi = {10.1038/jidsymp.2009.9},
pmid = {19675549},
issn = {1529-1774},
support = {R01 CA 105156/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cellular Senescence ; DNA Damage ; DNA Repair ; Humans ; Melanins/*biosynthesis ; Models, Biological ; Oligodeoxyribonucleotides/genetics/pharmacology ; Signal Transduction ; Skin Aging/genetics/*physiology/*radiation effects ; Suntan/genetics/*physiology/*radiation effects ; Telomere/genetics/*physiology/*radiation effects ; Ultraviolet Rays/adverse effects ; },
abstract = {UV-induced melanogenesis (tanning) and "premature aging" or photoaging result in large part from DNA damage. This article reviews data tying both phenomena to telomere-based DNA damage signaling and develops a conceptual framework in which both responses may be understood as cancer-avoidance protective mechanisms.Journal of Investigative Dermatology Symposium Proceedings (2009) 14, 25-31; doi:10.1038/jidsymp.2009.9.},
}
@article {pmid19673390,
year = {2009},
author = {Ma, L and Chen, G and Nie, L and Ai, M},
title = {[Effect of Cynomorium songaricum polysaccharide on telomere length in blood and brain of D-galactose-induced senescence mice].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {34},
number = {10},
pages = {1257-1260},
pmid = {19673390},
issn = {1001-5302},
mesh = {Aging/*drug effects ; Animals ; Animals, Newborn ; Brain/drug effects/pathology ; Cellular Senescence/drug effects ; Cynomorium/*chemistry ; Disease Models, Animal ; Drugs, Chinese Herbal/*therapeutic use ; Galactose/pharmacology ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; Polysaccharides/pharmacology/therapeutic use ; Telomere/*drug effects/physiology ; },
abstract = {OBJECTIVE: To study the effects of Cynomorium songaricum polysaccharide (CSP) on telomere length in blood and brain tissues of aged mice in order to provide some evidence for CSP's development and applying in the clinical uses.<br><br>METHOD: Kunming mice were intraperitoneal injected D-galactose (500 mg x kg(-1) x d(-1)) to make the aging models, and different dosages of CSP (20, 40, 80 mg x kg(-1)) were given by gavage for 56 days. The average length of telomere was determined by real-time fluorescence quantitative PCR.<br><br>RESULT: The relative T/S ratio of the group high and middle dosages of CSP in blood were 1.64 +/- 0.36 and 1.33 +/0.28, respectively, and higher than that of the group of senescence 1.01 +/- 0.13 (P < 0.01). Values of the group of high, middle, and low dosages of CSP in brain tissues were 3.34 +/- 0.58, 2.30 +/- 0. 75 and 1.55 +/- 0.58, respectively, and significantly higher than that of the group of senescence 1.04 +/- 0.33 (P < 0.01).<br><br>CONCLUSION: CSP can exert the anti-aging effects by increase telomere length f senescence mice.},
}
@article {pmid19671205,
year = {2010},
author = {Chan, R and Woo, J and Suen, E and Leung, J and Tang, N},
title = {Chinese tea consumption is associated with longer telomere length in elderly Chinese men.},
journal = {The British journal of nutrition},
volume = {103},
number = {1},
pages = {107-113},
doi = {10.1017/S0007114509991383},
pmid = {19671205},
issn = {1475-2662},
mesh = {Aged ; Alcohol Drinking/epidemiology ; Animals ; Anthropometry ; China/epidemiology ; Demography ; Diet ; Dietary Fats ; Educational Status ; Eggs ; Feeding Behavior ; Female ; Fruit ; Health Surveys ; Humans ; Life Expectancy ; Life Style ; Male ; Meat ; Oils ; Smoking/epidemiology ; *Tea ; Telomere/*ultrastructure ; Vegetables ; },
abstract = {Environmental and lifestyle factors that affect oxidative stress and inflammation may influence telomere length (TL). There are limited data to relate the effect of dietary components on TL. The present study examined the association between food groups and TL in a sample of elderly Chinese. In a sample of 2006 Chinese (976 men and 1030 women) aged 65 years and over, TL was measured by quantitative real-time PCR and daily intake of food groups was assessed by a validated FFQ. Linear regression and analysis of covariance were used to examine the association between food group intake and TL, with adjustment for demographic and lifestyle factors. In men, only Chinese tea consumption was significantly associated with TL after adjustment for demographics and lifestyle factors (P = 0.002). Mean difference in TL for those in the highest quartile of Chinese tea consumption (>3 cups/d or >750 ml/d) as compared with those in the lowest quartile of Chinese tea consumption (<or= 0.28 cups/d or <or= 70 ml/d) was 0.46 kb, corresponding to approximately a difference of 5 years of life. In women, intake of fats and oils was borderline and negatively associated with TL after adjustment for demographic and lifestyle factors (P = 0.037). In conclusion, Chinese tea consumption was positively associated with TL in elderly Chinese men.},
}
@article {pmid19669910,
year = {2009},
author = {Cuadrado, A and Golczyk, H and Jouve, N},
title = {A novel, simple and rapid nondenaturing FISH (ND-FISH) technique for the detection of plant telomeres. Potential used and possible target structures detected.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {17},
number = {6},
pages = {755-762},
pmid = {19669910},
issn = {1573-6849},
mesh = {Chromosomes, Plant/*genetics/ultrastructure ; DNA, Plant/*genetics ; In Situ Hybridization, Fluorescence/*methods ; Karyotyping ; Plant Roots/*genetics/growth &amp; development ; Telomere/*genetics ; },
abstract = {We report a new technique-nondenaturing FISH (ND-FISH)-for the rapid detection of plant telomeres without the need for prior denaturation of the chromosomes. In its development, two modified, synthetic oligonucleotides, 21 nt in length, fluorescently labelled at their 5' and 3' ends and complementary to either the cytidine-rich (C(3)TA(3)) or guanosine-rich (T(3)AG(3)) telomeric DNA strands, were used as probes. The high binding affinity of these probes and the short hybridization time required allows the visualization of plant telomeres in less than an hour. In tests, both probes gave strong signals visualized as double spots at both chromosome ends; this was true of both the mitotic and meiotic chromosomes of barley, wheat, rye, maize, Brachypodium distachyon and Rhoeo spathacea. They were also able to detect telomere motifs at certain intercalary sites in the chromosomes of R. spathacea. To investigate the nature of the target structures detected, the chromosomes were treated with RNase A and single strand-specific nuclease S1 before ND-FISH experiments. Signal formation was resistant to standard enzymatic treatment, but sensitive when much higher enzyme concentrations were used. The results are discussed in relation to current knowledge of telomere structure.},
}
@article {pmid19669107,
year = {2009},
author = {von Figura, G and Hartmann, D and Song, Z and Rudolph, KL},
title = {Role of telomere dysfunction in aging and its detection by biomarkers.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {87},
number = {12},
pages = {1165-1171},
pmid = {19669107},
issn = {1432-1440},
mesh = {Adult ; Aged, 80 and over ; *Aging/metabolism/pathology ; Animals ; Biomarkers/*metabolism ; Cellular Senescence/physiology ; DNA Damage ; Gene Expression Regulation ; Humans ; Mice ; Neoplasms/metabolism/pathology/physiopathology ; Proteins/genetics/*metabolism ; Telomerase/genetics/metabolism ; Telomere/metabolism/*pathology ; },
abstract = {Aging is a complex process that has been shown to be linked to accumulation of DNA damage. Telomere shortening represents a cell-intrinsic mechanism leading to DNA damage accumulation and activation of DNA damage checkpoints in aging cells. Activation of DNA damage checkpoints in response to telomere dysfunction results in induction of cellular senescence-a permanent cell cycle arrest. Senescence represents a tumor suppressor mechanism protecting cells from evolution of genomic instability and transformation. As a drawback, telomere shortening may also limit tissue renewal and regenerative capacity of tissues in response to aging and chronic disease. In aged organs, telomere shortening may also increase the cancer risk by initiation of chromosomal instability, loss of proliferative competition of aging stem cells, and selection of aberrant growing clones. Consequently, aged individuals are more susceptible and vulnerable to various diseases and show an increased cancer risk. Recently, proteins were discovered, which are induced by telomere dysfunction and DNA damage. It was shown that these proteins represent new biomarkers of human aging and disease. Here, we review the scientific background and experimental data on these newly discovered biomarkers.},
}
@article {pmid19667076,
year = {2009},
author = {Attwooll, CL and Akpinar, M and Petrini, JH},
title = {The mre11 complex and the response to dysfunctional telomeres.},
journal = {Molecular and cellular biology},
volume = {29},
number = {20},
pages = {5540-5551},
pmid = {19667076},
issn = {1098-5549},
support = {R01 GM056888/GM/NIGMS NIH HHS/United States ; R01 GM059413/GM/NIGMS NIH HHS/United States ; R13 CA162528/CA/NCI NIH HHS/United States ; R01 AG02398/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle Proteins/*metabolism ; Chromosomes, Mammalian/metabolism ; DNA Damage/genetics/physiology ; DNA Repair Enzymes/*metabolism ; DNA-Binding Proteins/*metabolism ; Fibroblasts/cytology/metabolism ; MRE11 Homologue Protein ; Mice ; Nuclear Proteins/*metabolism ; Telomere/*physiology ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {In this study, we examine the telomeric functions of the mammalian Mre11 complex by using hypomorphic Mre11 and Nbs1 mutants (Mre11(ATLD1/ATLD1) and Nbs1(Delta)(B/)(DeltaB), respectively). No telomere shortening was observed in Mre11(ATLD1/ATLD1) cells after extensive passage through culture, and the rate of telomere shortening in telomerase-deficient (Tert(Delta)(/)(Delta)) Mre11(ATLD1/ATLD1) cells was the same as that in Tert(Delta)(/)(Delta) alone. Although telomeres from late-passage Mre11(ATLD1/ATLD1) Tert(Delta)(/)(Delta) cells were as short as those from Tert(Delta)(/)(Delta), the incidence of telomere fusions was reduced. This effect on fusions was also evident upon acute telomere dysfunction in Mre11(ATLD1/ATLD1) and Nbs1(Delta)(B/)(DeltaB) cells rendered Trf2 deficient by cre-mediated TRF2 inactivation than in wild-type cells. The residual fusions formed in Mre11 complex mutant cells exhibited a strong tendency toward chromatid fusions, with an almost complete bias for fusion of telomeres replicated by the leading strand. Finally, the response to acute telomere dysfunction was strongly impaired by Mre11 complex hypomorphism, as the formation of telomere dysfunction-induced DNA damage foci was reduced in both cre-infected Mre11(ATLD1/ATLD1) Trf2(F/)(Delta) and Nbs1(Delta)(B/)(DeltaB) Trf2(F/F) cells. These data indicate that the Mre11 complex influences the cellular response to telomere dysfunction, reminiscent of its influence on the response to interstitial DNA breaks, and suggest that it may promote telomeric DNA end processing during DNA replication.},
}
@article {pmid19667071,
year = {2009},
author = {Dimitrova, N and de Lange, T},
title = {Cell cycle-dependent role of MRN at dysfunctional telomeres: ATM signaling-dependent induction of nonhomologous end joining (NHEJ) in G1 and resection-mediated inhibition of NHEJ in G2.},
journal = {Molecular and cellular biology},
volume = {29},
number = {20},
pages = {5552-5563},
pmid = {19667071},
issn = {1098-5549},
support = {R37 GM049046/GM/NIGMS NIH HHS/United States ; },
mesh = {ATP-Binding Cassette Transporters/*metabolism ; Acid Anhydride Hydrolases ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/*metabolism ; DNA Ligase ATP ; DNA Ligases/genetics/metabolism ; DNA Repair Enzymes/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Fibroblasts/metabolism ; G1 Phase/physiology ; G2 Phase/physiology ; Gene Knockdown Techniques ; Histones/genetics/metabolism ; MRE11 Homologue Protein ; Mice ; Nuclear Proteins/genetics/*metabolism ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Signal Transduction/physiology ; Telomere/*physiology/ultrastructure ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Tumor Suppressor Proteins/genetics/*metabolism ; },
abstract = {Here, we address the role of the MRN (Mre11/Rad50/Nbs1) complex in the response to telomeres rendered dysfunctional by deletion of the shelterin component TRF2. Using conditional NBS1/TRF2 double-knockout MEFs, we show that MRN is required for ATM signaling in response to telomere dysfunction. This establishes that MRN is the only sensor for the ATM kinase and suggests that TRF2 might block ATM signaling by interfering with MRN binding to the telomere terminus, possibly by sequestering the telomere end in the t-loop structure. We also examined the role of the MRN/ATM pathway in nonhomologous end joining (NHEJ) of damaged telomeres. NBS1 deficiency abrogated the telomere fusions that occur in G(1), consistent with the requirement for ATM and its target 53BP1 in this setting. Interestingly, NBS1 and ATM, but not H2AX, repressed NHEJ at dysfunctional telomeres in G(2), specifically at telomeres generated by leading-strand DNA synthesis. Leading-strand telomere ends were not prone to fuse in the absence of either TRF2 or MRN/ATM, indicating redundancy in their protection. We propose that MRN represses NHEJ by promoting the generation of a 3' overhang after completion of leading-strand DNA synthesis. TRF2 may ensure overhang formation by recruiting MRN (and other nucleases) to newly generated telomere ends. The activation of the MRN/ATM pathway by the dysfunctional telomeres is proposed to induce resection that protects the leading-strand ends from NHEJ when TRF2 is absent. Thus, the role of MRN at dysfunctional telomeres is multifaceted, involving both repression of NHEJ in G(2) through end resection and induction of NHEJ in G(1) through ATM-dependent signaling.},
}
@article {pmid19666704,
year = {2009},
author = {Ehrlenbach, S and Willeit, P and Kiechl, S and Willeit, J and Reindl, M and Schanda, K and Kronenberg, F and Brandstätter, A},
title = {Influences on the reduction of relative telomere length over 10 years in the population-based Bruneck Study: introduction of a well-controlled high-throughput assay.},
journal = {International journal of epidemiology},
volume = {38},
number = {6},
pages = {1725-1734},
doi = {10.1093/ije/dyp273},
pmid = {19666704},
issn = {1464-3685},
mesh = {Age Factors ; Aged ; Aged, 80 and over ; Aging/*genetics/physiology ; DNA/chemistry/genetics ; Female ; Genetic Predisposition to Disease ; Humans ; Italy ; Longitudinal Studies ; Male ; Mathematics ; Middle Aged ; *Mortality ; Polymerase Chain Reaction ; Risk Factors ; Sex Factors ; *Smoking/adverse effects ; Telomere/*chemistry/genetics ; },
abstract = {BACKGROUND: Telomeres play a key role in the maintenance of chromosome integrity. Short telomeres are linked to age-associated diseases and cancer. Our aim was to determine the decrease rate of relative telomere length (RTL) over 10 years and whether this rate was influenced by age, sex and smoking behaviour.<br><br>METHODS: We compared RTL in 510 sample pairs from the longitudinal population-based Bruneck Study, which were collected in 1995 and recollected in 2005, and additionally determined RTL from 159 participants who died during follow-up. RTL were determined by a high-throughput real-time PCR assay and by applying a mathematical model.<br><br>RESULTS: The telomeres shortened, on average, by 455 bp over 10 years. The RTL shortening rate was highly correlated with baseline RTL (r = 0.674, P < 0.001). Participants who died within the observed period had considerably shorter telomeres than those who survived (median RTL of 0.98 vs 1.49; P < 0.001). In contrast to previous studies, smoking behaviour had no influence on RTL and on telomere shortening.<br><br>CONCLUSION: This is the first comprehensive longitudinal study of individuals who were, on average, 60 at baseline, and who were re-evaluated 10 years later. Our methodology proved to be a reliable tool for a rapid, accurate and cost-efficient determination of RTL with a low amount of DNA.},
}
@article {pmid19665970,
year = {2009},
author = {Zhao, Y and Sfeir, AJ and Zou, Y and Buseman, CM and Chow, TT and Shay, JW and Wright, WE},
title = {Telomere extension occurs at most chromosome ends and is uncoupled from fill-in in human cancer cells.},
journal = {Cell},
volume = {138},
number = {3},
pages = {463-475},
pmid = {19665970},
issn = {1097-4172},
support = {AG01228/AG/NIA NIH HHS/United States ; P50 CA70907/CA/NCI NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; CA12729701/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; R01 AG001228-29A1/AG/NIA NIH HHS/United States ; P50 CA070907-11/CA/NCI NIH HHS/United States ; },
mesh = {Cell Cycle ; Cell Line, Tumor ; HeLa Cells ; Humans ; S Phase ; Saccharomyces cerevisiae/enzymology ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are thought to be maintained by the preferential recruitment of telomerase to the shortest telomeres. The extension of the G-rich telomeric strand by telomerase is also believed to be coordinated with the complementary synthesis of the C strand by the conventional replication machinery. However, we show that under telomere length-maintenance conditions in cancer cells, human telomerase extends most chromosome ends during each S phase and is not preferentially recruited to the shortest telomeres. Telomerase rapidly extends the G-rich strand following telomere replication but fill-in of the C strand is delayed into late S phase. This late C-strand fill-in is not executed by conventional Okazaki fragment synthesis but by a mechanism using a series of small incremental steps. These findings highlight differences between telomerase actions during steady state versus nonequilibrium conditions and reveal steps in the human telomere maintenance pathway that may provide additional targets for the development of anti-telomerase therapeutics.},
}
@article {pmid19661087,
year = {2009},
author = {Zee, RY and Castonguay, AJ and Barton, NS and Buring, JE},
title = {Mean telomere length and risk of incident colorectal carcinoma: a prospective, nested case-control approach.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {18},
number = {8},
pages = {2280-2282},
pmid = {19661087},
issn = {1538-7755},
support = {CA-40360/CA/NCI NIH HHS/United States ; CA-34944/CA/NCI NIH HHS/United States ; R01 CA040360-17/CA/NCI NIH HHS/United States ; HL-34595/HL/NHLBI NIH HHS/United States ; HL-26490/HL/NHLBI NIH HHS/United States ; R01 CA097193-01/CA/NCI NIH HHS/United States ; R01 HL034595/HL/NHLBI NIH HHS/United States ; R01 CA097193-02/CA/NCI NIH HHS/United States ; R01 CA034944-03/CA/NCI NIH HHS/United States ; R01 CA097193-03/CA/NCI NIH HHS/United States ; R01 CA097193-07/CA/NCI NIH HHS/United States ; R01 CA040360-16/CA/NCI NIH HHS/United States ; R01 HL026490/HL/NHLBI NIH HHS/United States ; R01 CA097193-04/CA/NCI NIH HHS/United States ; R01 CA040360/CA/NCI NIH HHS/United States ; R01 CA097193-06A1/CA/NCI NIH HHS/United States ; R01 HL026490-03/HL/NHLBI NIH HHS/United States ; R01 CA034944/CA/NCI NIH HHS/United States ; R01 CA097193-05/CA/NCI NIH HHS/United States ; CA-97193/CA/NCI NIH HHS/United States ; R01 HL034595-07/HL/NHLBI NIH HHS/United States ; R01 CA040360-14/CA/NCI NIH HHS/United States ; R01 CA097193/CA/NCI NIH HHS/United States ; R01 CA040360-15/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/genetics ; Case-Control Studies ; Colorectal Neoplasms/*genetics ; Humans ; Leukocytes/*physiology ; Male ; Middle Aged ; Polymerase Chain Reaction ; Risk Factors ; Telomere/*genetics ; },
abstract = {Recent studies have shown telomere length shortening in colorectal carcinoma (CRC). However, to date, no prospective, epidemiologic data are available on examining mean leukocyte telomere length as a risk predictor. Using leukocyte DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we examined the relationship of mean telomere repeat copy number to single gene copy number (T/S ratio), using a modified quantitative PCR protocol, among 191 incident CRC cases (all white males), matched to 306 controls by age, smoking status, and length of follow-up. An inverse correlation between T/S ratio and age was observed in our sample population (P = 0.038). However, the T/S ratios were similar between cases and controls (P = 0.650). Furthermore, in a multivariable adjusted analysis, we found no evidence for an association of the observed T/S ratios with CRC risk (adjusted odds ratio, 1.249; 95% confidence interval, 0.863-1.808; P = 0.238). In summary, the present investigation found no evidence for an association of leukocyte mean telomere length with risk of incident CRC and further suggests that leukocyte mean telomere length may not be a useful indicator for risk assessment.},
}
@article {pmid19660449,
year = {2009},
author = {Vlangos, CN and O'Connor, BC and Morley, MJ and Krause, AS and Osawa, GA and Keegan, CE},
title = {Caudal regression in adrenocortical dysplasia (acd) mice is caused by telomere dysfunction with subsequent p53-dependent apoptosis.},
journal = {Developmental biology},
volume = {334},
number = {2},
pages = {418-428},
pmid = {19660449},
issn = {1095-564X},
support = {P30 CA046592/CA/NCI NIH HHS/United States ; R01 HD058606-04/HD/NICHD NIH HHS/United States ; CA46592/CA/NCI NIH HHS/United States ; P60 DK020572/DK/NIDDK NIH HHS/United States ; P30 DK020572/DK/NIDDK NIH HHS/United States ; K08 HD042487/HD/NICHD NIH HHS/United States ; R01 HD058606/HD/NICHD NIH HHS/United States ; DK020572/DK/NIDDK NIH HHS/United States ; K08-HD42487/HD/NICHD NIH HHS/United States ; },
mesh = {Abnormalities, Multiple/embryology/*genetics/pathology ; Adrenal Cortex/*abnormalities/embryology/pathology ; Adrenal Insufficiency/embryology/*genetics/pathology ; Animals ; Apoptosis/*genetics ; Body Patterning/*genetics ; Crosses, Genetic ; Gene Expression Regulation, Developmental ; Genes, Recessive ; Genes, p53 ; Genomic Instability/*genetics ; Gestational Age ; Hindlimb/*abnormalities/embryology/pathology ; Mice ; Mice, Inbred C57BL ; Organ Specificity ; Phenotype ; Shelterin Complex ; Spine/*abnormalities/embryology/pathology ; Tail/*abnormalities/embryology/pathology ; Telomere/*pathology ; Telomere-Binding Proteins ; Tumor Suppressor Protein p53/deficiency/*physiology ; },
abstract = {Adrenocortical dysplasia (acd) is a spontaneous autosomal recessive mouse mutation that exhibits a pleiotropic phenotype with perinatal lethality. Mutant acd embryos have caudal truncation, vertebral segmentation defects, hydronephrosis, and limb hypoplasia, resembling humans with Caudal Regression syndrome. Acd encodes Tpp1, a component of the shelterin complex that maintains telomere integrity, and consequently acd mutant mice have telomere dysfunction and genomic instability. While the association between genomic instability and cancer is well documented, the association between genomic instability and birth defects is unexplored. To determine the relationship between telomere dysfunction and embryonic malformations, we investigated mechanisms leading to the caudal dysgenesis phenotype of acd mutant embryos. We report that the caudal truncation is caused primarily by apoptosis, not altered cell proliferation. We show that the apoptosis and consequent skeletal malformations in acd mutants are dependent upon the p53 pathway by genetic rescue of the limb hypoplasia and vertebral anomalies with p53 null mice. Furthermore, rescue of the acd phenotype by p53 deficiency is a dosage-sensitive process, as acd/acd, p53(-/-) double mutants exhibit preaxial polydactyly. These findings demonstrate that caudal dysgenesis in acd embryos is secondary to p53-dependent apoptosis. Importantly, this study reinforces a significant link between genomic instability and birth defects.},
}
@article {pmid19659180,
year = {2009},
author = {Bronstein, I and Israel, Y and Kepten, E and Mai, S and Shav-Tal, Y and Barkai, E and Garini, Y},
title = {Transient anomalous diffusion of telomeres in the nucleus of mammalian cells.},
journal = {Physical review letters},
volume = {103},
number = {1},
pages = {018102},
doi = {10.1103/PhysRevLett.103.018102},
pmid = {19659180},
issn = {0031-9007},
mesh = {Bone Neoplasms ; Cell Line, Tumor ; Cell Nucleus/*chemistry/genetics ; Diffusion ; Fluorescent Dyes ; Humans ; Indoles ; Models, Chemical ; Osteosarcoma ; Staining and Labeling/methods ; Telomere/*chemistry/genetics ; },
abstract = {We measured individual trajectories of fluorescently labeled telomeres in the nucleus of eukaryotic cells in the time range of 10(-2)-10(4)sec by combining a few acquisition methods. At short times the motion is subdiffusive with r2 approximately talpha and it changes to normal diffusion at longer times. The short times diffusion may be explained by the reptation model and the transient diffusion is consistent with a model of telomeres that are subject to a local binding mechanism with a wide but finite distribution of waiting times. These findings have important biological implications with respect to the genome organization in the nucleus.},
}
@article {pmid19656953,
year = {2009},
author = {Mendez-Bermudez, A and Hills, M and Pickett, HA and Phan, AT and Mergny, JL and Riou, JF and Royle, NJ},
title = {Human telomeres that contain (CTAGGG)n repeats show replication dependent instability in somatic cells and the male germline.},
journal = {Nucleic acids research},
volume = {37},
number = {18},
pages = {6225-6238},
pmid = {19656953},
issn = {1362-4962},
support = {C17992/A8641//Cancer Research UK/United Kingdom ; G0500336//Medical Research Council/United Kingdom ; },
mesh = {Alleles ; DNA Damage ; DNA Replication ; G-Quadruplexes ; *Germ-Line Mutation ; Humans ; Male ; Mutation ; Oligonucleotides/chemistry ; *Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {A number of different processes that impact on telomere length dynamics have been identified but factors that affect the turnover of repeats located proximally within the telomeric DNA are poorly defined. We have identified a particular repeat type (CTAGGG) that is associated with an extraordinarily high mutation rate (20% per gamete) in the male germline. The mutation rate is affected by the length and sequence homogeneity of the (CTAGGG)n array. This level of instability was not seen with other sequence-variant repeats, including the TCAGGG repeat type that has the same composition. Telomeres carrying a (CTAGGG)n array are also highly unstable in somatic cells with the mutation process resulting in small gains or losses of repeats that also occasionally result in the deletion of the whole (CTAGGG)n array. These sequences are prone to quadruplex formation in vitro but adopt a different topology from (TTAGGG)n (see accompanying article). Interestingly, short (CTAGGG)2 oligonucleotides induce a DNA damage response (gammaH2AX foci) as efficiently as (TTAGGG)2 oligos in normal fibroblast cells, suggesting they recruit POT1 from the telomere. Moreover, in vitro assays show that (CTAGGG)n repeats bind POT1 more efficiently than (TTAGGG)n or (TCAGGG)n. We estimate that 7% of human telomeres contain (CTAGGG)n repeats and when present, they create additional problems that probably arise during telomere replication.},
}
@article {pmid19652177,
year = {2009},
author = {Marvin, ME and Griffin, CD and Eyre, DE and Barton, DB and Louis, EJ},
title = {In Saccharomyces cerevisiae, yKu and subtelomeric core X sequences repress homologous recombination near telomeres as part of the same pathway.},
journal = {Genetics},
volume = {183},
number = {2},
pages = {441-51, 1SI-12SI},
pmid = {19652177},
issn = {1943-2631},
mesh = {Chromosome Mapping ; Chromosomes, Fungal/genetics ; DNA, Fungal/*genetics ; DNA-Binding Proteins/genetics ; Genome, Fungal/genetics ; Genomic Instability ; Mutation ; Recombination, Genetic/*genetics ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/genetics ; Signal Transduction/genetics ; Telomere/*genetics ; },
abstract = {Unlike in meiosis where recombination near telomeres is repressed, subtelomeric regions appear to recombine with each other frequently in vegetative cells with no detrimental consequences. To test whether or not such recombination is prevented in the core of chromosomes for maintenance of genome stability, we measured allelic homologous recombination (HR) along chromosome arms and between different ectopic locations. We found that there is an increase of recombination at telomeres in wild-type cells compared with sequences at proximal subtelomeric and interstitial regions of the genome. We also screened for mutations that result in an increase in HR between a telomeric sequence and a more internal sequence, which normally exhibit very low rates of HR. YKU80 was hit most frequently in our screen, and we show that the yKu heterodimer specifically represses HR in the vicinity of telomeres. This repression of HR is not explained solely by the role of yKu in maintaining telomere length, silencing, or tethering to the nuclear periphery. Analysis of mutant strains harboring deleted core X sequences revealed a role for this subtelomeric element in preventing telomeric recombination. Furthermore, core X bestowed this protection as part of the same pathway as yKu. Our findings implicate a role for both yKu and core X in stabilizing the genome against recombination events involving telomeric sequences.},
}
@article {pmid19651898,
year = {2009},
author = {Kendellen, MF and Barrientos, KS and Counter, CM},
title = {POT1 association with TRF2 regulates telomere length.},
journal = {Molecular and cellular biology},
volume = {29},
number = {20},
pages = {5611-5619},
pmid = {19651898},
issn = {1098-5549},
support = {R01 CA082481/CA/NCI NIH HHS/United States ; CA082481/CA/NCI NIH HHS/United States ; },
mesh = {Cell Adhesion Molecules/*metabolism ; Humans ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; rap1 GTP-Binding Proteins/*metabolism ; },
abstract = {Deleting the OB folds encoding the telomeric single-stranded DNA (ssDNA)-binding activity of the human telomeric protein POT1 induces significant telomere elongation, suggesting that at least one critical aspect of the regulation of telomere length is disrupted by this POT1(DeltaOB) mutant protein. POT1 is known to associate with two proteins through the protein interaction domain retained in POT1(DeltaOB)-the telomeric double-stranded DNA-binding protein TRF2 and the telomere-associated protein TPP1. We report that introducing a mutation that reduces association of POT1 with TRF2, but not a mutation that reduces the association with TPP1, abrogates the ability of POT1(DeltaOB) to promote telomere elongation. Mechanistically, expression of POT1(DeltaOB) reduced the association of TRF2 with POT1, RAP1, and TIN2; however, of these proteins, only ectopic expression of POT1 suppressed the telomere elongation induced by POT1(DeltaOB). Lastly, replacing endogenous POT1 with a full-length POT1 mutant defective in the association with TRF2 induced telomere elongation. Thus, we conclude that the association of POT1 with both ssDNA and TRF2 is critical for telomere length homeostasis.},
}
@article {pmid19648609,
year = {2009},
author = {Wan, M and Qin, J and Songyang, Z and Liu, D},
title = {OB fold-containing protein 1 (OBFC1), a human homolog of yeast Stn1, associates with TPP1 and is implicated in telomere length regulation.},
journal = {The Journal of biological chemistry},
volume = {284},
number = {39},
pages = {26725-26731},
pmid = {19648609},
issn = {1083-351X},
mesh = {Blotting, Western ; Cell Line ; Cell Line, Tumor ; DNA, Single-Stranded/metabolism ; Humans ; Immunoprecipitation ; Luminescent Proteins/genetics/metabolism ; Microscopy, Fluorescence ; Protein Binding ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Transfection ; Tripeptidyl-Peptidase 1 ; },
abstract = {The telosome/shelterin, a six-protein complex formed by TRF1, TRF2, RAP1, TIN2, POT1, and TPP1, functions as the core of the telomere interactome, acting as the molecular platform for the assembly of higher order complexes and coordinating cross-talks between various protein subcomplexes. Within the telosome, there are two oligonucleotide- or oligosaccharide-binding (OB) fold-containing proteins, TPP1 and POT1. They can form heterodimers that bind to the telomeric single-stranded DNA, an activity that is central for telomere end capping and telomerase recruitment. Through proteomic analyses, we found that in addition to POT1, TPP1 can associate with another OB fold-containing protein, OBFC1/AAF44. The yeast homolog of OBFC1 is Stn1, which plays a critical role in telomere regulation. We show here that OBFC1/AAF44 can localize to telomeres in human cells and bind to telomeric single-stranded DNA in vitro. Furthermore, overexpression of an OBFC1 mutant resulted in elongated telomeres in human cells, implicating OBFC1/AAF4 in telomere length regulation. Taken together, our studies suggest that OBFC1/AAF44 represents a new player in the telomere interactome for telomere maintenance.},
}
@article {pmid19647509,
year = {2009},
author = {Iglesias, N and Lingner, J},
title = {Related mechanisms for end processing at telomeres and DNA double-strand breaks.},
journal = {Molecular cell},
volume = {35},
number = {2},
pages = {137-138},
doi = {10.1016/j.molcel.2009.07.007},
pmid = {19647509},
issn = {1097-4164},
mesh = {*DNA Breaks, Double-Stranded ; DNA Repair/physiology ; DNA, Fungal/chemistry/genetics ; Models, Genetic ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism/*physiology ; Telomere/chemistry/*genetics ; },
abstract = {In a recent issue of Molecular Cell, Bonetti et al. (2009) identify in the yeast Saccharomyces cerevisiae that the molecular activities that generate 3' overhangs at telomeric DNA ends are the same as those that resect DNA at double-strand breaks.},
}
@article {pmid19643742,
year = {2009},
author = {},
title = {Retraction. Bone morphogenetic protein-7 induces telomerase inhibition, telomere shortening, breast cancer cell senescence, and death via Smad3.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {23},
number = {8},
pages = {2790},
doi = {10.1096/fj.08-119529RET},
pmid = {19643742},
issn = {1530-6860},
}
@article {pmid19636400,
year = {2009},
author = {Carroll, KA and Ly, H},
title = {Telomere dysfunction in human diseases: the long and short of it!.},
journal = {International journal of clinical and experimental pathology},
volume = {2},
number = {6},
pages = {528-543},
pmid = {19636400},
issn = {1936-2625},
support = {P30 AI050409/AI/NIAID NIH HHS/United States ; R24 DK064399/DK/NIDDK NIH HHS/United States ; T32 GM008490/GM/NIGMS NIH HHS/United States ; U54 AI057157/AI/NIAID NIH HHS/United States ; },
abstract = {It has been over one hundred years since the first reported case of dyskeratosis congenita (DC) and over twenty since the discovery of telomerase, an enzyme that adds telomeric DNA repeats to chromosome ends. Emerging evidence suggests that telomere dysfunction plays an important role in the pathogenesis of DC and other human disorders involving tissues that require rapid repair and renewal capacities. Yet we still do not fully understand how mutations in telomere maintenance genes contribute to disease development in affected individuals. In this review, we provide an up-to-date summary of the topic by discussing the results from genetic screens of patients, in vitro mutational analysis of involved molecules, and genetically engineered mouse models. While these data shed important light on the mechanisms underlying disease development, further investigation, particularly in an in vivo setting, is needed.},
}
@article {pmid19633651,
year = {2009},
author = {Deng, Y and Guo, X and Ferguson, DO and Chang, S},
title = {Multiple roles for MRE11 at uncapped telomeres.},
journal = {Nature},
volume = {460},
number = {7257},
pages = {914-918},
pmid = {19633651},
issn = {1476-4687},
support = {P30 CA046592/CA/NCI NIH HHS/United States ; K01 CA124461/CA/NCI NIH HHS/United States ; R01 HL079118/HL/NHLBI NIH HHS/United States ; R01 AG028888-02/AG/NIA NIH HHS/United States ; R01 AG028888/AG/NIA NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; K01CA124461/CA/NCI NIH HHS/United States ; R01 CA129037-02/CA/NCI NIH HHS/United States ; },
mesh = {ATP-Binding Cassette Transporters/genetics/metabolism ; Alleles ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/metabolism ; Cell Line ; Chromosomal Proteins, Non-Histone ; Chromosome Aberrations ; DNA Damage ; DNA Ligase ATP ; DNA Ligases/metabolism ; DNA Repair Enzymes/deficiency/genetics/*metabolism ; DNA-Binding Proteins/deficiency/genetics/*metabolism ; Fibroblasts ; Intracellular Signaling Peptides and Proteins/metabolism ; MRE11 Homologue Protein ; Mice ; Nuclear Proteins/deficiency/genetics/metabolism ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 2/deficiency/metabolism ; Tumor Suppressor Proteins/metabolism ; Tumor Suppressor p53-Binding Protein 1 ; },
abstract = {Progressive telomere attrition or uncapping of the shelterin complex elicits a DNA damage response as a result of a cell's inability to distinguish dysfunctional telomeric ends from DNA double-strand breaks. Telomere deprotection activates both ataxia telangiectasia mutated (ATM) and telangiectasia and Rad3-related (ATR) kinase-dependent DNA damage response pathways, and promotes efficient non-homologous end-joining (NHEJ) of dysfunctional telomeres. The mammalian MRE11-RAD50-NBS1 (MRN; NBS1 is also known as NBN) complex interacts with ATM to sense chromosomal double-strand breaks and coordinate global DNA damage responses. Although the MRN complex accumulates at dysfunctional telomeres, it is not known whether mammalian MRN promotes repair at these sites. Here we address this question by using mouse alleles that either inactivate the entire MRN complex or eliminate only the nuclease activities of MRE11 (ref. 8). We show that cells lacking MRN do not activate ATM when telomeric repeat binding factor 2 (TRF2) is removed from telomeres, and ligase 4 (LIG4)-dependent chromosome end-to-end fusions are markedly reduced. Residual chromatid fusions involve only telomeres generated by leading strand synthesis. Notably, although cells deficient for MRE11 nuclease activity efficiently activate ATM and recruit 53BP1 (also known as TP53BP1) to deprotected telomeres, the 3' telomeric overhang persists to prevent NHEJ-mediated chromosomal fusions. Removal of shelterin proteins that protect the 3' overhang in the setting of MRE11 nuclease deficiency restores LIG4-dependent chromosome fusions. Our data indicate a critical role for the MRN complex in sensing dysfunctional telomeres, and show that in the absence of TRF2, MRE11 nuclease activity removes the 3' telomeric overhang to promote chromosome fusions. MRE11 can also protect newly replicated leading strand telomeres from NHEJ by promoting 5' strand resection to generate POT1a-TPP1-bound 3' overhangs.},
}
@article {pmid19629041,
year = {2009},
author = {Lansdorp, PM},
title = {Telomeres and disease.},
journal = {The EMBO journal},
volume = {28},
number = {17},
pages = {2532-2540},
pmid = {19629041},
issn = {1460-2075},
mesh = {Animals ; DNA Repair ; Disease/*genetics ; Humans ; Neoplasms/genetics/metabolism ; Stem Cells/metabolism ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {The telomeres of most eukaryotes are characterized by guanine-rich repeats synthesized by the reverse transcriptase telomerase. Complete loss of telomerase is tolerated for several generations in most species, but modestly reduced telomerase levels in human beings are implicated in bone marrow failure, pulmonary fibrosis and a spectrum of other diseases including cancer. Differences in telomerase deficiency phenotypes between species most likely reflect a tumour suppressor function of telomeres in long-lived mammals that does not exist as such in short-lived organisms. Another puzzle provided by current observations is that family members with the same genetic defect, haplo-insufficiency for one of the telomerase genes, can present with widely different diseases. Here, the crucial role of telomeres and telomerase in human (stem cell) biology is discussed from a Darwinian perspective. It is proposed that the variable phenotype and penetrance of heritable human telomerase deficiencies result from additional environmental, genetic and stochastic factors or combinations thereof.},
}
@article {pmid19629039,
year = {2009},
author = {Lydall, D},
title = {Taming the tiger by the tail: modulation of DNA damage responses by telomeres.},
journal = {The EMBO journal},
volume = {28},
number = {15},
pages = {2174-2187},
pmid = {19629039},
issn = {1460-2075},
support = {/WT_/Wellcome Trust/United Kingdom ; 075294/WT_/Wellcome Trust/United Kingdom ; BB/C008200/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; /CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {*Cell Cycle ; *DNA Damage ; *DNA Repair ; DNA, Fungal/metabolism ; Fungal Proteins/*metabolism ; Models, Biological ; Saccharomycetales/*physiology ; Telomere/*physiology ; },
abstract = {Telomeres are by definition stable and inert chromosome ends, whereas internal chromosome breaks are potent stimulators of the DNA damage response (DDR). Telomeres do not, as might be expected, exclude DDR proteins from chromosome ends but instead engage with many DDR proteins. However, the most powerful DDRs, those that might induce chromosome fusion or cell-cycle arrest, are inhibited at telomeres. In budding yeast, many DDR proteins that accumulate most rapidly at double strand breaks (DSBs), have important functions in physiological telomere maintenance, whereas DDR proteins that arrive later tend to have less important functions. Considerable diversity in telomere structure has evolved in different organisms and, perhaps reflecting this diversity, different DDR proteins seem to have distinct roles in telomere physiology in different organisms. Drawing principally on studies in simple model organisms such as budding yeast, in which many fundamental aspects of the DDR and telomere biology have been established; current views on how telomeres harness aspects of DDR pathways to maintain telomere stability and permit cell-cycle division are discussed.},
}
@article {pmid19629036,
year = {2009},
author = {Gonzalez-Suarez, I and Redwood, AB and Perkins, SM and Vermolen, B and Lichtensztejin, D and Grotsky, DA and Morgado-Palacin, L and Gapud, EJ and Sleckman, BP and Sullivan, T and Sage, J and Stewart, CL and Mai, S and Gonzalo, S},
title = {Novel roles for A-type lamins in telomere biology and the DNA damage response pathway.},
journal = {The EMBO journal},
volume = {28},
number = {16},
pages = {2414-2427},
pmid = {19629036},
issn = {1460-2075},
mesh = {Animals ; Cell Line ; Cell Nucleus/chemistry/metabolism ; Chromosomal Proteins, Non-Histone ; *DNA Repair ; DNA-Binding Proteins ; Fibroblasts/cytology/metabolism ; Gene Deletion ; Genomic Instability ; Intracellular Signaling Peptides and Proteins/analysis/metabolism ; Lamin Type A/*genetics/*metabolism ; Mice ; Telomere/chemistry/*metabolism ; Tumor Suppressor p53-Binding Protein 1 ; },
abstract = {A-type lamins are intermediate filament proteins that provide a scaffold for protein complexes regulating nuclear structure and function. Mutations in the LMNA gene are linked to a variety of degenerative disorders termed laminopathies, whereas changes in the expression of lamins are associated with tumourigenesis. The molecular pathways affected by alterations of A-type lamins and how they contribute to disease are poorly understood. Here, we show that A-type lamins have a key role in the maintenance of telomere structure, length and function, and in the stabilization of 53BP1, a component of the DNA damage response (DDR) pathway. Loss of A-type lamins alters the nuclear distribution of telomeres and results in telomere shortening, defects in telomeric heterochromatin, and increased genomic instability. In addition, A-type lamins are necessary for the processing of dysfunctional telomeres by non-homologous end joining, putatively through stabilization of 53BP1. This study shows new functions for A-type lamins in the maintenance of genomic integrity, and suggests that alterations of telomere biology and defects in DDR contribute to the pathogenesis of lamin-related diseases.},
}
@article {pmid19629032,
year = {2009},
author = {Schoeftner, S and Blasco, MA},
title = {A 'higher order' of telomere regulation: telomere heterochromatin and telomeric RNAs.},
journal = {The EMBO journal},
volume = {28},
number = {16},
pages = {2323-2336},
pmid = {19629032},
issn = {1460-2075},
mesh = {Animals ; Chromatin/*genetics/metabolism/pathology ; Drosophila/genetics/metabolism ; *Epigenesis, Genetic ; Humans ; RNA/*genetics/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Schizosaccharomyces/genetics/metabolism ; Telomerase/*genetics/metabolism ; Telomere/*genetics/*metabolism/pathology ; },
abstract = {Protection of chromosome ends from DNA repair and degradation activities is mediated by specialized protein complexes bound to telomere repeats. Recently, it has become apparent that epigenetic regulation of the telomeric chromatin template critically impacts on telomere function and telomere-length homeostasis from yeast to man. Across all species, telomeric repeats as well as the adjacent subtelomeric regions carry features of repressive chromatin. Disruption of this silent chromatin environment results in loss of telomere-length control and increased telomere recombination. In turn, progressive telomere loss reduces chromatin compaction at telomeric and subtelomeric domains. The recent discoveries of telomere chromatin regulation during early mammalian development, as well as during nuclear reprogramming, further highlights a central role of telomere chromatin changes in ontogenesis. In addition, telomeres were recently shown to generate long, non-coding RNAs that remain associated to telomeric chromatin and will provide new insights into the regulation of telomere length and telomere chromatin. In this review, we will discuss the epigenetic regulation of telomeres across species, with special emphasis on mammalian telomeres. We will also discuss the links between epigenetic alterations at mammalian telomeres and telomere-associated diseases.},
}
@article {pmid19629031,
year = {2009},
author = {Shore, D and Bianchi, A},
title = {Telomere length regulation: coupling DNA end processing to feedback regulation of telomerase.},
journal = {The EMBO journal},
volume = {28},
number = {16},
pages = {2309-2322},
pmid = {19629031},
issn = {1460-2075},
support = {//Medical Research Council/United Kingdom ; },
mesh = {Animals ; DNA Damage ; DNA Replication ; Humans ; Saccharomyces cerevisiae/enzymology/*genetics ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomerase/*genetics/*metabolism ; Telomere/*chemistry/*metabolism ; },
abstract = {The conventional DNA polymerase machinery is unable to fully replicate the ends of linear chromosomes. To surmount this problem, nearly all eukaryotes use the telomerase enzyme, a specialized reverse transcriptase that utilizes its own RNA template to add short TG-rich repeats to chromosome ends, thus reversing their gradual erosion occurring at each round of replication. This unique, non-DNA templated mode of telomere replication requires a regulatory mechanism to ensure that telomerase acts at telomeres whose TG tracts are too short, but not at those with long tracts, thus maintaining the protective TG repeat 'cap' at an appropriate average length. The prevailing notion in the field is that telomere length regulation is brought about through a negative feedback mechanism that 'counts' TG repeat-bound protein complexes to generate a signal that regulates telomerase action. This review summarizes experiments leading up to this model and then focuses on more recent experiments, primarily from yeast, that begin to suggest how this 'counting' mechanism might work. The emerging picture is that of a complex interplay between the conventional DNA replication machinery, DNA damage response factors, and a specialized set of proteins that help to recruit and regulate the telomerase enzyme.},
}
@article {pmid19627485,
year = {2009},
author = {Saini, N and Srinivasan, R and Chawla, Y and Sharma, S and Chakraborti, A and Rajwanshi, A},
title = {Telomerase activity, telomere length and human telomerase reverse transcriptase expression in hepatocellular carcinoma is independent of hepatitis virus status.},
journal = {Liver international : official journal of the International Association for the Study of the Liver},
volume = {29},
number = {8},
pages = {1162-1170},
doi = {10.1111/j.1478-3231.2009.02082.x},
pmid = {19627485},
issn = {1478-3231},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Hepatocellular/*enzymology/pathology/virology ; Child ; Female ; Gene Expression Regulation, Enzymologic ; Hepacivirus/isolation &amp; purification/physiology ; Hepatitis B virus/isolation &amp; purification/physiology ; Hepatitis Viruses/*isolation &amp; purification/physiology ; Humans ; Liver/enzymology/pathology/virology ; Liver Neoplasms/*enzymology/pathology/virology ; Male ; Middle Aged ; Neoplasm Staging ; RNA, Messenger/metabolism ; Telomerase/genetics/*metabolism ; Telomere/metabolism/*pathology ; Young Adult ; },
abstract = {BACKGROUND: Telomerase expression and the maintenance of a critical telomere length (TL) in cancer initiation indicates that telomere shortening and telomerase expression initiates cancer by induction of chromosomal instability.<br><br>METHODS: Telomerase activity, TL and human telomerase reverse transcriptase (hTERT) expression were investigated in 58 hepatocellular carcinoma (HCC) and 17 chronic hepatitis patients by the telomerase repeat amplification protocol, Southern blotting and reverse transcriptase-polymerase chain reaction.<br><br>RESULTS: Telomerase was positive in 76% of HCC and 11.8% of chronic hepatitis patients (P<0.0001). The mean telomere length (MTL) in HCC was significantly shorter compared with chronic hepatitis (P<0.0001). The MTL was not significantly different in HCC patients with and without cirrhosis (P=0.77). In hepatitis B virus, hepatitis C virus and non-B non-C-related HCC groups, no differences were found in telomerase activity and MTL (P=0.77). hTERT, a regulator of telomerase, was, however, positive in 81% of HCCs. The correlation between telomerase activity and hTERT mRNA expression was statistically significant (P<0.0001). The MTL in telomerase-positive HCC cases was significantly shorter than the MTL in telomerase-negative cases (P<0.0001).<br><br>CONCLUSION: The majority of HCCs exhibited telomerase activity that correlated well with hTERT expression. MTL in HCC was significantly shorter than chronic hepatitis. It was also found that shorter telomeres are present in telomerase-positive HCC cases. However, no correlation was found between telomerase activity and TL with respect to the viral status in HCC.},
}
@article {pmid19626460,
year = {2010},
author = {Song, H and Liu, D and Chen, X and Ying, Z and Zhang, B and Li, F and Lu, H},
title = {Change of season-specific telomere lengths in Ginkgo biloba L.},
journal = {Molecular biology reports},
volume = {37},
number = {2},
pages = {819-824},
pmid = {19626460},
issn = {1573-4978},
mesh = {Chromosomes, Plant/genetics/metabolism ; Germ Cells, Plant/cytology/metabolism/physiology ; Ginkgo biloba/*genetics/growth &amp; development/metabolism ; Models, Theoretical ; *Seasons ; Telomere/*genetics/metabolism ; Time Factors ; Trees/genetics/metabolism ; },
abstract = {Telomeres have lately received considerable attention in the development of tree species. Normal somatic cells have limited replicative capacity and telomeres get shorten with each round of DNA replication. For broad-leaved tree species, to determine what changes happen to their somatic cells in its annual development cycle, an exhaustive research on different ages of gingko trees telomere length changes was carried out. Analysis of changes in leaf telomere lengths in the annual development cycle of Ginkgo biloba L. showed no significant changes (P > 0.05) from April to August, but a dramatic decrease in September and October (P < 0.05). Statistical analyses showed that TRF length of males and females are equal, the p values of the three age groups comparison were all bigger than 0.05. The results showed that specific apoptotic changes occur in the annual development cycle of Ginkgo biloba L.},
}
@article {pmid19622731,
year = {2009},
author = {Indiviglio, SM and Bertuch, AA},
title = {Ku's essential role in keeping telomeres intact.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {106},
number = {30},
pages = {12217-12218},
pmid = {19622731},
issn = {1091-6490},
support = {R01 GM077509/GM/NIGMS NIH HHS/United States ; 1R01GM077509-01A2/GM/NIGMS NIH HHS/United States ; },
mesh = {Antigens, Nuclear/*genetics/metabolism ; Cell Survival ; Chromosome Deletion ; DNA Breaks, Double-Stranded ; DNA-Binding Proteins/*genetics/metabolism ; Exodeoxyribonucleases/metabolism ; Genes, Essential/genetics ; HCT116 Cells ; Humans ; Ku Autoantigen ; Models, Biological ; Mutation ; Protein Binding ; RecQ Helicases/metabolism ; Receptors, Transferrin/metabolism ; Telomere/*genetics/metabolism ; Werner Syndrome Helicase ; },
}
@article {pmid19619548,
year = {2009},
author = {Rudolph, KL and Hartmann, D and Opitz, OG},
title = {Telomere dysfunction and DNA damage checkpoints in diseases and cancer of the gastrointestinal tract.},
journal = {Gastroenterology},
volume = {137},
number = {3},
pages = {754-762},
doi = {10.1053/j.gastro.2009.07.037},
pmid = {19619548},
issn = {1528-0012},
mesh = {Aging/genetics ; Animals ; DNA Damage/*genetics ; Gastrointestinal Diseases/genetics/physiopathology ; Gastrointestinal Neoplasms/*genetics/physiopathology/therapy ; Humans ; Telomere/genetics/*physiology ; },
}
@article {pmid19617699,
year = {2009},
author = {Islam-Faridi, MN and Nelson, CD and DiFazio, SP and Gunter, LE and Tuskan, GA},
title = {Cytogenetic analysis of Populus trichocarpa--ribosomal DNA, telomere repeat sequence, and marker-selected BACs.},
journal = {Cytogenetic and genome research},
volume = {125},
number = {1},
pages = {74-80},
doi = {10.1159/000218749},
pmid = {19617699},
issn = {1424-859X},
mesh = {Arabidopsis/genetics ; Chromosomes, Artificial, Bacterial/genetics ; Chromosomes, Plant/genetics ; Cytogenetic Analysis ; DNA, Plant/*genetics ; DNA, Ribosomal/*genetics ; Genetic Markers ; In Situ Hybridization, Fluorescence ; Populus/classification/*genetics ; Repetitive Sequences, Nucleic Acid ; Species Specificity ; Telomere/genetics ; },
abstract = {The 18S-28S rDNA and 5S rDNA loci in Populus trichocarpa were localized using fluorescent in situ hybridization (FISH). Two 18S-28S rDNA sites and one 5S rDNA site were identified and located at the ends of 3 different chromosomes. FISH signals from the Arabidopsis-type telomere repeat sequence were observed at the distal ends of each chromosome. Six BAC clones selected from 2 linkage groups based on genome sequence assembly (LG-I and LG-VI) were localized on 2 chromosomes, as expected. BACs from LG-I hybridized to the longest chromosome in the complement. All BAC positions were found to be concordant with sequence assembly positions. BAC-FISH will be useful for delineating each of the Populus trichocarpa chromosomes and improving the sequence assembly of this model angiosperm tree species.},
}
@article {pmid19616016,
year = {2009},
author = {Rodríguez, P and Barquinero, JF and Duran, A and Caballín, MR and Ribas, M and Barrios, L},
title = {Cells bearing chromosome aberrations lacking one telomere are selectively blocked at the G2/M checkpoint.},
journal = {Mutation research},
volume = {670},
number = {1-2},
pages = {53-58},
doi = {10.1016/j.mrfmmm.2009.07.003},
pmid = {19616016},
issn = {0027-5107},
mesh = {Adult ; Cell Cycle ; *Chromosome Aberrations ; *G2 Phase ; Humans ; Lymphocytes/*radiation effects ; Male ; *Mitosis ; Radiation, Ionizing ; *Telomere ; },
abstract = {Cell cycle checkpoints are part of the cellular mechanisms to maintain genomic integrity. After ionizing radiation exposure, the cells can show delay or arrest in their progression through the cell cycle, as well as an activation of the DNA repair machinery in order to reduce the damage. The G2/M checkpoint prevents G2 cells entering mitosis until the DNA damage has been reduced. The present study evaluates which G0 radiation-induced chromosome aberrations are negatively selected in the G2/M checkpoint. For this purpose, peripheral blood samples were irradiated at 1 and 3 Gy of gamma-rays, and lymphocytes were cultured for 48 h. Calyculin-A and Colcemid were used to analyze, in the same slide, cells in G2 and M. Chromosome spreads were consecutively analyzed by solid stain, pancentromeric and pantelomeric FISH and mFISH. The results show that the frequency of incomplete chromosome elements, those lacking a telomeric signal at one end, decreases abruptly from G2 to M. This indicates that cells with incomplete chromosome elements can progress from G0 to G2, but at the G2/M checkpoint suffer a strong negative selection.},
}
@article {pmid19615720,
year = {2010},
author = {Treat, EG and Heaphy, CM and Massie, LW and Bisoffi, M and Smith, AY and Davis, MS and Griffith, JK},
title = {Telomere DNA content in prostate biopsies predicts early rise in prostate-specific antigen after radical prostatectomy for prostate cancer.},
journal = {Urology},
volume = {75},
number = {3},
pages = {724-729},
pmid = {19615720},
issn = {1527-9995},
support = {M01-RR00997/RR/NCRR NIH HHS/United States ; M01 RR000997/RR/NCRR NIH HHS/United States ; RR0164880/RR/NCRR NIH HHS/United States ; P30CA118110/CA/NCI NIH HHS/United States ; P20 RR016480-086589/RR/NCRR NIH HHS/United States ; },
mesh = {Aged ; DNA/*analysis ; Humans ; Male ; Middle Aged ; Neoplasm Recurrence, Local/blood ; Predictive Value of Tests ; Prostate/*chemistry/*pathology ; Prostate-Specific Antigen/*blood ; *Prostatectomy ; Prostatic Neoplasms/blood/*surgery ; Retrospective Studies ; Telomere/*genetics ; Time Factors ; },
abstract = {OBJECTIVE: To determine whether measurement of telomere DNA content (TC) in prostate biopsy tissue predicts prostate-specific antigen (PSA) recurrence in men after undergoing radical prostatectomy for prostate cancer.<br><br>METHODS: Slot blot titration assay was used to quantitate TC in archived diagnostic prostate needle biopsy specimens for subjects (n = 103) diagnosed with prostate cancer and who subsequently underwent radical prostatectomy between 1993 and 1997. TC was compared to the clinical outcome measure; PSA recurrence, defined as an increase in PSA > or = 0.2 ng/mL on 2 or more consecutive measurements post-prostatectomy, was observed retrospectively, for a mean follow-up period of 114 months (range, 1-165).<br><br>RESULTS: In the cohort, 46 subjects had a PSA recurrence. In a univariate Cox proportional hazards model, low TC (< 0.3 of standard) demonstrated a significant risk for PSA recurrence (HR = 1.94; 95% CI: 1.02-3.69, P = .04). In a subset analysis of men with biopsy Gleason sum < or = 6 (n = 63; 25 recurrences), a univariate Cox proportional hazards model demonstrated that low TC had a greater risk of PSA recurrence (HR = 4.53; 95% CI: 2.00-10.2, P < .01). In a multivariate Cox proportional hazards model, low TC was also significantly associated with PSA recurrence in this subset after controlling for preoperative PSA levels (HR = 6.62; 95% CI: 2.69-16.3, P < .01).<br><br>CONCLUSIONS: Low TC measured in prostate biopsy tissue predicts early likelihood of post-prostatectomy PSA recurrence in a retrospective analysis, and in men with biopsy Gleason sum < or = 6 disease it is also independent of preoperative PSA level.},
}
@article {pmid19614710,
year = {2010},
author = {Wang, Y and Fang, M and Sun, X and Sun, J},
title = {Telomerase activity and telomere length in acute leukemia: correlations with disease progression, subtypes and overall survival.},
journal = {International journal of laboratory hematology},
volume = {32},
number = {2},
pages = {230-238},
doi = {10.1111/j.1751-553X.2009.01178.x},
pmid = {19614710},
issn = {1751-553X},
mesh = {Adult ; Aged ; Blotting, Southern ; Disease Progression ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Leukemia/classification/*metabolism/*physiopathology ; Male ; Middle Aged ; Polymerase Chain Reaction ; Reference Standards ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {The progressive shortening of telomeres and the activation of telomerase are considered to be one of the important mechanisms in cellular immortalization and disease progression. Bone marrow samples were collected from 148 patients with acute leukemia (AL). Based on the stage of the disease, patients were divided into the newly diagnosed group, the relapsed group and the complete remission (CR) group. telomerase activity (TA) was examined by PCR-ELISA, and telomere length (TL) was examined by Southern blot analyses. TA and TL were analyzed in relation to AL stage and subtype. Five-year survival was analyzed using Kaplan-Meier survival curve. TA in AL patients was higher than healthy individuals. TA level was the highest in the relapsed group, followed by the newly diagnosed group, and then the CR group. TA had no difference between acute nonlymphocytic leukemia (ANLL) group and acute lymphocytic leukemia (ALL) group. But TA in group of subtype M3 was lower than other subtypes of ANLL. TL in AL group was shorter than the control group. TL was the shortest in the relapsed group, followed by the newly diagnosed group, and finally the CR group. TL exhibited an inverse correlation with TA. The group of patients with high TA had a significantly poorer five-year-survival than that of low TA group. TA is elevated and TL is shortened in AL patients. There is a significant inverse correlation between TL and TA. Patients in late-stage disease had shorter TL and higher TA than those in early stages. The shortened TL and elevated TA correlated with disease progression and relapse, and they may serve as prognostic factors for AL patients with poor outcome. M3 subtype is special with relative lower TA and long-lasting survival than other subtypes.},
}
@article {pmid19605693,
year = {2009},
author = {Sebastián, C and Herrero, C and Serra, M and Lloberas, J and Blasco, MA and Celada, A},
title = {Telomere shortening and oxidative stress in aged macrophages results in impaired STAT5a phosphorylation.},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {183},
number = {4},
pages = {2356-2364},
doi = {10.4049/jimmunol.0901131},
pmid = {19605693},
issn = {1550-6606},
mesh = {Animals ; Bone Marrow Cells/immunology/metabolism/pathology ; Cell Proliferation ; Cells, Cultured ; Cellular Senescence/genetics/*immunology ; DNA Damage/immunology ; Macrophages/enzymology/*metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Oxidation-Reduction ; Oxidative Stress/genetics/*immunology ; Phosphorylation/genetics/immunology ; RNA/antagonists &amp; inhibitors/genetics/metabolism ; STAT5 Transcription Factor/antagonists &amp; inhibitors/genetics/*metabolism ; Telomerase/antagonists &amp; inhibitors/deficiency/genetics/metabolism ; Telomere/genetics/*metabolism/*pathology ; },
abstract = {Macrophages are an essential component of both innate and adaptive immunity, and altered function of these cells with aging may play a key role in immunosenescence. To determine the effect of aging on macrophages, we produced bone marrow-derived macrophages in vitro. In these conditions, we analyzed the effect of aging on macrophages without the influence of other cell types that may be affected by aging. We showed that telomeres shorten with age in macrophages leading to a decreased GM-CSF but not M-CSF-dependent proliferation of these cells as a result of decreased phosphorylation of STAT5a. Macrophages from aged mice showed increased susceptibility to oxidants and an accumulation of intracellular reactive oxygen species. In these macrophages STAT5a oxidation was reduced, which led to the decreased phosphorylation observed. Interestingly, the same cellular defects were found in macrophages from telomerase knockout (Terc(-/-)) mice suggesting that telomere loss is the cause for the enhanced oxidative stress, the reduced Stat5a oxidation and phosphorylation and, ultimately, for the impaired GM-CSF-dependent macrophage proliferation.},
}
@article {pmid19603133,
year = {2009},
author = {Wong, LS and van der Harst, P and de Boer, RA and Codd, V and Huzen, J and Samani, NJ and Hillege, HL and Voors, AA and van Gilst, WH and Jaarsma, T and van Veldhuisen, DJ},
title = {Renal dysfunction is associated with shorter telomere length in heart failure.},
journal = {Clinical research in cardiology : official journal of the German Cardiac Society},
volume = {98},
number = {10},
pages = {629-634},
pmid = {19603133},
issn = {1861-0692},
mesh = {Age Factors ; Aged ; Aging/*genetics ; Chronic Disease ; Comorbidity ; Cross-Sectional Studies ; Female ; Glomerular Filtration Rate ; Heart Failure/epidemiology/*genetics/physiopathology ; Humans ; Kidney/*physiopathology ; Kidney Diseases/epidemiology/*genetics/physiopathology ; Linear Models ; Male ; Middle Aged ; Prospective Studies ; Risk Assessment ; Risk Factors ; Stroke Volume ; Telomere/*metabolism ; Ventricular Function, Left ; },
abstract = {BACKGROUND: Renal dysfunction is a frequent comorbidity associated with high mortality in patients with chronic heart failure (CHF). The intrinsic biological age might affect the ability of the kidney to cope with the challenging environment caused by CHF. We explored the association between leukocyte telomere length, a marker for biological age, and renal function in patients with CHF.<br><br>METHODS AND RESULTS: Telomere length was determined by a real-time quantitative polymerase chain reaction in 866 CHF patients. Renal function was estimated with the simplified Modification of Diet in Renal Disease equation. The median age was 74 (interquartile range 64-79) years, 61% male, left ventricular ejection fraction of 30 (23-44)%, and the estimated glomerular filtration rate was 53 (40-68) ml/min/1.73 m(2). Telomere length was associated with renal function (correlation coefficient 0.123, P < 0.001). This relationship remained significant after adjustment for age, gender, age of CHF onset (standardized-beta 0.091, P = 0.007). Also additionally adjusting for the severity of CHF and baseline differences did not change our findings.<br><br>CONCLUSION: The association between shorter leukocyte telomere length and reduced renal function in heart failure suggests that intrinsic biological aging affects the ability of the kidney to cope with the systemic changes evoked by heart failure.},
}
@article {pmid19597487,
year = {2009},
author = {Khadaroo, B and Teixeira, MT and Luciano, P and Eckert-Boulet, N and Germann, SM and Simon, MN and Gallina, I and Abdallah, P and Gilson, E and Géli, V and Lisby, M},
title = {The DNA damage response at eroded telomeres and tethering to the nuclear pore complex.},
journal = {Nature cell biology},
volume = {11},
number = {8},
pages = {980-987},
pmid = {19597487},
issn = {1476-4679},
mesh = {Adaptor Proteins, Signal Transducing/genetics/metabolism ; Cell Cycle Proteins/genetics/metabolism ; Chromatin Immunoprecipitation ; *DNA Damage ; DNA Repair ; DNA, Single-Stranded/genetics ; G2 Phase ; Haploidy ; Luminescent Proteins/genetics/metabolism ; Microscopy, Fluorescence ; Mutation ; Nuclear Pore/*metabolism ; Nuclear Pore Complex Proteins/genetics/metabolism ; Rad52 DNA Repair and Recombination Protein/genetics/metabolism ; Recombinant Fusion Proteins/genetics/metabolism ; Replication Protein A/genetics/metabolism ; S Phase ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {The ends of linear eukaryotic chromosomes are protected by telomeres, which serve to ensure proper chromosome replication and to prevent spurious recombination at chromosome ends. In this study, we show by single cell analysis that in the absence of telomerase, a single short telomere is sufficient to induce the recruitment of checkpoint and recombination proteins. Notably, a DNA damage response at eroded telomeres starts many generations before senescence and is characterized by the recruitment of Cdc13 (cell division cycle 13), replication protein A, DNA damage checkpoint proteins and the DNA repair protein Rad52 into a single focus. Moreover, we show that eroded telomeres, although remaining at the nuclear periphery, move to the nuclear pore complex. Our results link the DNA damage response at eroded telomeres to changes in subnuclear localization and suggest the existence of collapsed replication forks at eroded telomeres.},
}
@article {pmid19597486,
year = {2009},
author = {Abdallah, P and Luciano, P and Runge, KW and Lisby, M and Géli, V and Gilson, E and Teixeira, MT},
title = {A two-step model for senescence triggered by a single critically short telomere.},
journal = {Nature cell biology},
volume = {11},
number = {8},
pages = {988-993},
pmid = {19597486},
issn = {1476-4679},
support = {R01 AG019960/AG/NIA NIH HHS/United States ; R01 GM050752/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle/genetics/physiology ; Cell Division/genetics/physiology ; DNA Nucleotidyltransferases/genetics/metabolism ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; *Models, Biological ; Mutation ; Protein Binding ; Protein Serine-Threonine Kinases/genetics/metabolism ; Rad52 DNA Repair and Recombination Protein/genetics/metabolism ; Saccharomyces cerevisiae/cytology/*genetics/physiology ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Signal Transduction/genetics/physiology ; Spores, Fungal/genetics/physiology ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres protect chromosome ends from fusion and degradation. In the absence of a specific telomere elongation mechanism, their DNA shortens progressively with every round of replication, leading to replicative senescence. Here, we show that telomerase-deficient cells bearing a single, very short telomere senesce earlier, demonstrating that the length of the shortest telomere is a major determinant of the onset of senescence. We further show that Mec1p-ATR specifically recognizes the single, very short telomere causing the accelerated senescence. Strikingly, before entering senescence, cells divide for several generations despite complete erosion of their shortened telomeres. This pre-senescence growth requires RAD52 (radiation sensitive) and MMS1 (methyl methane sulfonate sensitive), and there is no evidence for major inter-telomeric recombination. We propose that, in the absence of telomerase, a very short telomere is first maintained in a pre-signalling state by a RAD52-MMS1-dependent pathway and then switches to a signalling state leading to senescence through a Mec1p-dependent checkpoint.},
}
@article {pmid19596868,
year = {2009},
author = {Lefas, G and Chaconas, G},
title = {High-throughput screening identifies three inhibitor classes of the telomere resolvase from the lyme disease spirochete.},
journal = {Antimicrobial agents and chemotherapy},
volume = {53},
number = {10},
pages = {4441-4449},
pmid = {19596868},
issn = {1098-6596},
mesh = {Animals ; Bacterial Proteins/*antagonists &amp; inhibitors ; Borrelia burgdorferi/*drug effects/*enzymology ; Enzyme Inhibitors/*pharmacology ; Humans ; Lyme Disease/*microbiology ; Recombinases/*antagonists &amp; inhibitors ; },
abstract = {Lyme disease, the most common vector-borne zoonosis in North America, is caused by the spirochetal pathogen Borrelia burgdorferi. The telomere resolvase encoded by this organism (ResT) promotes the formation of covalently closed hairpin ends on the linear DNA molecules of B. burgdorferi through a two-step transesterification. ResT is essential for survival and is therefore an attractive target for the development of highly specific antiborrelial drugs. To identify ResT inhibitors, a novel fluorescence-based high-throughput assay was developed and used to screen a library of 27,520 small-molecule drug-like compounds. Six confirmed inhibitors of ResT, with 50% inhibitory concentrations between 2 and 10 muM, were identified. The inhibitors were characterized further and were grouped into three distinct classes based on their inhibitory features. The high-throughput screening assay developed in this paper, along with the six inhibitory compounds identified, provides a starting point for the future development of novel antiborrelial drugs as well as small-molecule inhibitors that will be helpful for the further dissection of the reaction mechanism.},
}
@article {pmid19596811,
year = {2009},
author = {Rizzo, A and Salvati, E and Porru, M and D'Angelo, C and Stevens, MF and D'Incalci, M and Leonetti, C and Gilson, E and Zupi, G and Biroccio, A},
title = {Stabilization of quadruplex DNA perturbs telomere replication leading to the activation of an ATR-dependent ATM signaling pathway.},
journal = {Nucleic acids research},
volume = {37},
number = {16},
pages = {5353-5364},
pmid = {19596811},
issn = {1362-4962},
mesh = {Acridines/*pharmacology ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*metabolism ; Cell Line ; DNA Damage ; DNA Replication/drug effects ; DNA-Binding Proteins/*metabolism ; G-Quadruplexes/*drug effects ; Humans ; Ligands ; Protein Serine-Threonine Kinases/*metabolism ; Signal Transduction ; Telomere/chemistry/*drug effects/metabolism ; Tumor Suppressor Proteins/*metabolism ; },
abstract = {Functional telomeres are required to maintain the replicative ability of cancer cells and represent putative targets for G-quadruplex (G4) ligands. Here, we show that the pentacyclic acridinium salt RHPS4, one of the most effective and selective G4 ligands, triggers damages in cells traversing S phase by interfering with telomere replication. Indeed, we found that RHPS4 markedly reduced BrdU incorporation at telomeres and altered the dynamic association of the telomeric proteins TRF1, TRF2 and POT1, leading to chromosome aberrations such as telomere fusions and telomere doublets. Analysis of the molecular damage pathway revealed that RHPS4 induced an ATR-dependent ATM signaling that plays a functional role in the cellular response to RHPS4 treatment. We propose that RHPS4, by stabilizing G4 DNA at telomeres, impairs fork progression and/or telomere processing resulting in telomere dysfunction and activation of a replication stress response pathway. The detailed understanding of the molecular mode of action of this class of compounds makes them attractive tools to understand telomere biology and provides the basis for a rational use of G4 ligands for the therapy of cancer.},
}
@article {pmid19596790,
year = {2009},
author = {Ma, Y and Greider, CW},
title = {Kinase-independent functions of TEL1 in telomere maintenance.},
journal = {Molecular and cellular biology},
volume = {29},
number = {18},
pages = {5193-5202},
pmid = {19596790},
issn = {1098-5549},
support = {R01 GM043080/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; Intracellular Signaling Peptides and Proteins/*metabolism ; Mutation/genetics ; Protein Binding ; Protein Serine-Threonine Kinases/*metabolism ; Saccharomyces cerevisiae/*enzymology ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; Telomere/*enzymology ; },
abstract = {TEL1 is important in Saccharomyces cerevisiae telomere maintenance, and its kinase activity is required. Tel1p associates with telomeres in vivo, is enriched at short telomeres, and enhances the binding of telomerase components to short telomeres. However, it is unclear how the kinase activity and telomere association contribute to Tel1p's overall function in telomere length maintenance. To investigate this question, we generated a set of single point mutants and a double point mutant (tel1(KD)) of Tel1p that were kinase deficient and two Xrs2p mutants that failed to bind Tel1p. Using these separation-of-function alleles in a de novo telomere elongation assay, we found, surprisingly, that the tel1(KD) allele and xrs2 C-terminal mutants were both partially functional. Combining the tel1(KD) and xrs2 C-terminal mutants had an additive effect and resembled the TEL1 null (tel1Delta) phenotype. These data indicate that Tel1p has two separate functions in telomere maintenance and that the Xrs2p-dependent recruitment of Tel1p to telomeres plays an important role even in the absence of its kinase activity.},
}
@article {pmid19596784,
year = {2009},
author = {Mitchell, TR and Glenfield, K and Jeyanthan, K and Zhu, XD},
title = {Arginine methylation regulates telomere length and stability.},
journal = {Molecular and cellular biology},
volume = {29},
number = {18},
pages = {4918-4934},
pmid = {19596784},
issn = {1098-5549},
mesh = {Amino Acid Sequence ; Amino Acid Substitution/genetics ; Arginine/*metabolism ; Cell Line ; Cell Proliferation ; Cellular Senescence ; Chromatin Immunoprecipitation ; Humans ; Methylation ; Molecular Sequence Data ; Neoplasms/enzymology/pathology ; Protein Binding ; Protein Structure, Tertiary ; Protein-Arginine N-Methyltransferases/deficiency/metabolism ; Repressor Proteins/metabolism ; Structure-Activity Relationship ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/chemistry/metabolism ; },
abstract = {TRF2, a component of the shelterin complex, functions to protect telomeres. TRF2 contains an N-terminal basic domain rich in glycines and arginines, similar to the GAR motif that is methylated by protein arginine methyltransferases. However, whether arginine methylation regulates TRF2 function has not been determined. Here we report that amino acid substitutions of arginines with lysines in the basic domain of TRF2 induce telomere dysfunction-induced focus formation, leading to induction of cellular senescence. We have demonstrated that cells overexpressing TRF2 lysine mutants accumulate telomere doublets, indicative of telomere instability. We uncovered that TRF2 interacts with PRMT1, and its arginines in the basic domain undergo PRMT1-mediated methylation both in vitro and in vivo. We have shown that loss of PRMT1 induces growth arrest in normal human cells but has no effect on cell proliferation in cancer cells, suggesting that PRMT1 may control cell proliferation in a cell type-specific manner. We found that depletion of PRMT1 in normal human cells results in accumulation of telomere doublets, indistinguishable from overexpression of TRF2 lysine mutants. PRMT1 knockdown in cancer cells upregulates TRF2 association with telomeres, promoting telomere shortening. Taken together, these results suggest that PRMT1 may control telomere length and stability in part through TRF2 methylation.},
}
@article {pmid19596237,
year = {2009},
author = {Sfeir, A and Kosiyatrakul, ST and Hockemeyer, D and MacRae, SL and Karlseder, J and Schildkraut, CL and de Lange, T},
title = {Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication.},
journal = {Cell},
volume = {138},
number = {1},
pages = {90-103},
pmid = {19596237},
issn = {1097-4172},
support = {R01 CA076027-11/CA/NCI NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; R37 GM049046-17/GM/NIGMS NIH HHS/United States ; R01 CA076027/CA/NCI NIH HHS/United States ; R01 AG016642-10/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Aphidicolin ; *Chromosome Fragile Sites ; Chromosomes, Mammalian/metabolism ; *DNA Replication ; Humans ; Metaphase ; Mice ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/*metabolism ; },
abstract = {Telomeres protect chromosome ends through the interaction of telomeric repeats with shelterin, a protein complex that represses DNA damage signaling and DNA repair reactions. The telomeric repeats are maintained by telomerase, which solves the end replication problem. We report that the TTAGGG repeat arrays of mammalian telomeres pose a challenge to the DNA replication machinery, giving rise to replication-dependent defects that resemble those of aphidicolin-induced common fragile sites. Gene deletion experiments showed that efficient duplication of telomeres requires the shelterin component TRF1. Without TRF1, telomeres activate the ATR kinase in S phase and show a fragile-site phenotype in metaphase. Single-molecule analysis of replicating telomeres showed that TRF1 promotes efficient replication of TTAGGG repeats and prevents fork stalling. Two helicases implicated in the removal of G4 DNA structures, BLM and RTEL1, were required to repress the fragile-telomere phenotype. These results identify a second telomere replication problem that is solved by the shelterin component TRF1.},
}
@article {pmid19595717,
year = {2009},
author = {Bonetti, D and Martina, M and Clerici, M and Lucchini, G and Longhese, MP},
title = {Multiple pathways regulate 3' overhang generation at S. cerevisiae telomeres.},
journal = {Molecular cell},
volume = {35},
number = {1},
pages = {70-81},
doi = {10.1016/j.molcel.2009.05.015},
pmid = {19595717},
issn = {1097-4164},
mesh = {Blotting, Southern ; DNA Helicases/genetics/metabolism ; DNA, Fungal/genetics ; DNA, Single-Stranded/chemistry/*genetics ; Endonucleases/genetics/metabolism ; Exodeoxyribonucleases/genetics/metabolism ; Mutation ; Phosphorylation ; RecQ Helicases/genetics/metabolism ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Serine/genetics/metabolism ; Telomere/chemistry/*genetics ; },
abstract = {Generation of 3' G strand overhangs at telomere ends may play a role in regulating telomerase action and occurs by still unclear mechanisms. We show by an inducible short telomere assay that Sae2 and the Sgs1 RecQ helicase control two distinct but partially complementary pathways for nucleolytic processing of S. cerevisiae telomeres, with Sae2 function requiring its serine 267 phosphorylation. No processing activity is detectable in sae2Delta sgs1Delta cells, while the Exo1 exonuclease contributes to telomere end processing and elongation in both sae2Delta and sgs1Delta cells, suggesting that Exo1 telomeric function requires either Sgs1 or Sae2 action. Moreover, Dna2 might also support Sgs1 activity, as it acts redundantly with Exo1, but not with Sgs1. Finally, both length maintenance and G strand overhang generation at native telomeres are affected in sae2Delta sgs1Delta cells, further supporting the notion that Sae2 and Sgs1 combined activities control telomere length by regulating telomere processing.},
}
@article {pmid19594618,
year = {2009},
author = {Cottliar, AS and Panero, J and Pedrazzini, E and Noriega, MF and Narbaitz, M and Rodríguez, A and Slavutsky, I},
title = {Analysis of telomere length in mantle cell lymphoma.},
journal = {European journal of haematology},
volume = {83},
number = {5},
pages = {433-438},
doi = {10.1111/j.1600-0609.2009.01313.x},
pmid = {19594618},
issn = {1600-0609},
mesh = {Adult ; Aged ; Aged, 80 and over ; Chromosomes, Human, Pair 11 ; Chromosomes, Human, Pair 14 ; Female ; Humans ; Lymphoma, Mantle-Cell/diagnosis/*genetics/pathology/therapy ; Male ; Middle Aged ; Oncogene Proteins, Fusion/genetics ; Recurrence ; Sex Factors ; Telomere/*genetics ; Translocation, Genetic/genetics ; },
abstract = {Mantle cell lymphoma (MCL) is a well defined lymphoid neoplasm genetically characterized by the t(11;14)(q13;q32). Telomeres play an essential role in preserving chromosomal integrity and genomic stability; their shortening can lead to telomere dysfunction and chromosomal instability, a critical factor in cancer development. In this study, telomere length (TL) measured by terminal restriction fragments (TRF) assay in DNA samples of tumor cells from 20 patients with MCL was evaluated. Results were correlated with clinical, morphologic and cytogenetic characteristics. In all cases, the presence of the CCND1/IGH@ rearrangement was confirmed by fluorescence in situ hybridization and/or PCR analysis. TL in total MCL patients revealed a mean TRF value (4.51 +/- 0.79 kb) significantly shorter than those observed in controls (7.49 +/- 1.94 kb) (P < 0.001); 30% of patients had TL shorter than 4.0 kb. TRF length was not associated with patients age (P = 0.07; r = 0.17) nor with sex (females: 4.33 +/- 0.51 kb and males: 4.57 +/- 0.85 kb; P = 0.63). No significant differences were found between patients studied at diagnosis (13) (4.44 +/- 0.81 kb) respect to those analyzed at relapse (7) (4.63 +/- 0.82 kb) (P = 0.53). In addition, we compared patients with (4.84 +/- 1.09 kb) and without (4.40 +/- 0.68 kb) complex karyotypes (P = 0.45) and cases with typical morphology (4.48 +/- 0.79 kb) vs. blastoid variant (4.63 +/- 1.04 kb) (P = 0.83), and no significant differences between them were found. Although the number of cases of our series is not large, our results showed that TL reduction in MCL is independent of the clinical characteristics, morphology and karyotype.},
}
@article {pmid19594325,
year = {2009},
author = {O'Callaghan, NJ and Clifton, PM and Noakes, M and Fenech, M},
title = {Weight loss in obese men is associated with increased telomere length and decreased abasic sites in rectal mucosa.},
journal = {Rejuvenation research},
volume = {12},
number = {3},
pages = {169-176},
doi = {10.1089/rej.2008.0819},
pmid = {19594325},
issn = {1557-8577},
mesh = {Adult ; Biopsy ; Body Mass Index ; Caloric Restriction ; Humans ; Intestinal Mucosa/*pathology ; Male ; Middle Aged ; Obesity/*physiopathology ; Rectum/*pathology ; Risk ; Sigmoidoscopy ; Telomere/*ultrastructure ; *Weight Loss ; },
abstract = {Telomere shortening may cause genome instability and is an initiating event in colorectal cancer (CRC). Obesity is associated with reduced telomere length in lymphocytes and is a risk factor for CRC, but the impact of obesity on telomere length in the rectal mucosa is unknown. The purpose of this study was to investigate the effect of weight loss, induced by calorie-restricted diets, on telomere length in the rectal mucosa of obese men. Midrectal biopsies were collected by sigmoidoscopy at three time points (at weeks 0, 12, and 52) during a programmed weight loss intervention. Weight was reduced by an average of 10.6 kg across the study. Telomere length, measured by quantitative real-time PCR (qPCR), was negatively correlated with body mass index (BMI) (r = -0.13, p = 0.05) at baseline (n = 54) and increased at week 12 (four-fold increase) and week 52 (10-fold increase) (analysis of covariance [ANCOVA] p = 0.01, n = 12). Abasic sites in DNA decreased at week 12 (30% decrease) and week 52 (65% decrease) (analysis of variance [ANOVA] p = 0.02). Furthermore, gain of telomere length appeared to be greater if more weight and body fat was lost (r = -0.65, p = 0.01 and r = -0.56, p = 0.01, respectively). These results suggest that weight loss by caloric-restricted diets may contribute to the prevention of telomere shortening and DNA base damage, which are important initiating events in carcinogenesis.},
}
@article {pmid19591275,
year = {2009},
author = {Takubo, K and Nakamura, K and Shimomura, N and Ishikawa, N and Aida, J},
title = {[Telomere].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {67},
number = {7},
pages = {1293-1297},
pmid = {19591275},
issn = {0047-1852},
mesh = {Aging/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Neoplasms/genetics ; Telomere/*physiology ; },
abstract = {We reviewed correlations among telomere length, aging and carcinogenesis. Southern blot analysis showed that telomere shortening occurred with aging in all human tissues except for brain and myocardium. We investigated the telomere lengths of individual cell types in human tissues using a Q-FISH method and an original software package, "Tissue Telo". Q-FISH revealed that in squamous epithelia, NTCR corresponding to telomere length was significantly highest in basal cells and lowest in prickle cells, and that telomere length regressed at a certain rate in each cell type except for fibroblasts. Mean telomere length was significantly less in background tissue squamous epithelia of patients with cancer than in normal controls without cancer. We demonstrated telomere shortening and chromosomal instability in the background and normal control with excessively shortened telomeres. The data suggest that cancer arises from epithelial cells with short telomeres.},
}
@article {pmid19588966,
year = {2009},
author = {Chen, Z and Zheng, KW and Hao, YH and Tan, Z},
title = {Reduced or diminished stabilization of the telomere G-quadruplex and inhibition of telomerase by small chemical ligands under molecular crowding condition.},
journal = {Journal of the American Chemical Society},
volume = {131},
number = {30},
pages = {10430-10438},
doi = {10.1021/ja9010749},
pmid = {19588966},
issn = {1520-5126},
mesh = {Base Sequence ; G-Quadruplexes/*drug effects ; Glycerol/pharmacology ; Humans ; Ligands ; Polyethylene Glycols/pharmacology ; Reverse Transcriptase Inhibitors/*chemistry/metabolism/*pharmacology ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*chemistry/genetics ; Viscosity/drug effects ; Water/metabolism ; },
abstract = {Telomere DNA in human cells shortens during each round of DNA replication. In cancer cells, telomere shortening is compensated by telomerase or the alternative lengthening of telomere (ALT) mechanism to maintain cell division potential. The G-rich strand of telomere DNA can fold into a G-quadruplex structure and disrupt these two processes. Therefore, stabilization of the G-quadruplex by chemical ligands is emerging as a promising anticancer strategy. So far, in vitro studies on such ligands are exclusively carried out in dilute solutions. However, the intracellular environment is highly crowded with biomolecules. How G-quadruplex ligands behave under molecular crowding condition is critical for their in vivo anticancer effect. In this work, we studied several ligands for their ability to stabilize the telomere G-quadruplex and inhibit telomerase under both dilute and crowding conditions. Surprisingly, the ligands became significantly less effective or even lost the ability to stabilize the G-quadruplex and inhibit telomerase under crowding conditions. Our data attributed this consequence to the decreased binding affinity of ligands to the G-quadruplex as a result of reduced water activity and increased viscosity of the medium associated with molecular crowding. This effect is irrelevant to and overweighs the influences from other factors such as the G-quadruplex structure, cation, and ligand species. Our work illustrates a possibility that molecular crowding inside cells may reduce or limit the potency of ligands although they may be effective in dilute solution, thus strongly arguing for the necessity of evaluating ligands under more physiologically relevant conditions and designing drugs with this concern in mind.},
}
@article {pmid19587034,
year = {2009},
author = {Zabala, B and Hammerl, JA and Espejo, RT and Hertwig, S},
title = {The linear plasmid prophage Vp58.5 of Vibrio parahaemolyticus is closely related to the integrating phage VHML and constitutes a new incompatibility group of telomere phages.},
journal = {Journal of virology},
volume = {83},
number = {18},
pages = {9313-9320},
pmid = {19587034},
issn = {1098-5514},
mesh = {Base Sequence ; Chile ; DNA, Viral ; Genome, Viral ; Nucleic Acid Conformation ; *Plasmids ; Prophages/*classification/*genetics/physiology ; Repetitive Sequences, Nucleic Acid ; *Telomere ; Vibrio parahaemolyticus/*virology ; *Virus Integration ; Virus Replication ; },
abstract = {Vibrio parahaemolyticus O3:K6 pandemic strains recovered in Chile frequently possess a 42-kb plasmid which is the prophage of a myovirus. We studied the prototype phage VP58.5 and show that it does not integrate into the host cell chromosome but replicates as a linear plasmid (Vp58.5) with covalently closed ends (telomeres). The Vp58.5 replicon coexists with other plasmid prophages (N15, PY54, and PhiKO2) in the same cell and thus belongs to a new incompatibility group of telomere phages. We determined the complete nucleotide sequence (42,612 nucleotides) of the VP58.5 phage DNA and compared it with that of the plasmid prophage. The two molecules share the same nucleotide sequence but are 35% circularly permuted to each other. In contrast to the hairpin ends of the plasmid, VP58.5 phage DNA contains 5'-protruding ends. The VP58.5 sequence is 92% identical to the sequence of phage VHML, which was reported to integrate into the host chromosome. However, the gene order and termini of the phage DNAs are different. The VHML genome exhibits the same gene order as does the Vp58.5 plasmid. VHML phage DNA has been reported to contain terminal inverted repeats. This repetitive sequence is similar to the telomere resolution site (telRL) of VP58.5 which, after processing by the phage protelomerase, forms the hairpin ends of the Vp58.5 prophage. It is discussed why these closely related phages may be so different in terms of their genome ends and their lifestyle.},
}
@article {pmid19581589,
year = {2009},
author = {Wang, Y and Ghosh, G and Hendrickson, EA},
title = {Ku86 represses lethal telomere deletion events in human somatic cells.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {106},
number = {30},
pages = {12430-12435},
pmid = {19581589},
issn = {1091-6490},
support = {R01 GM069576/GM/NIGMS NIH HHS/United States ; GM069576/GM/NIGMS NIH HHS/United States ; T32 AG029796/AG/NIA NIH HHS/United States ; HL079559/HL/NHLBI NIH HHS/United States ; R01 HL079559/HL/NHLBI NIH HHS/United States ; T32-AG029796/AG/NIA NIH HHS/United States ; },
mesh = {Antigens, Nuclear/*genetics/metabolism ; Blotting, Western ; Cell Survival ; *Chromosome Deletion ; DNA Breaks, Double-Stranded ; DNA-Binding Proteins/*genetics/metabolism ; Dependovirus/genetics ; Electrophoresis/methods ; Fluorescent Antibody Technique ; Gene Targeting/methods ; HCT116 Cells ; Histones/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Ku Autoantigen ; *Mutation ; Telomere/*genetics/metabolism ; Transfection ; },
abstract = {Nonhomologous end joining (NHEJ), a form of DNA double-strand break (DSB) repair, is conserved from bacteria to humans. One essential NHEJ factor is Ku, which consists of a heterodimer of Ku70 and Ku86. In a plethora of model systems, null mutations for Ku70 or Ku86 present with defects in DNA DSB repair, variable(diversity)joining [V(D)J] recombination, and/or telomere maintenance. The complete loss of Ku from bacteria to mice is, however, compatible with viability. In striking contrast, human patients with mutations of either Ku subunit have never been described. Here, we have used recombinant adeno-associated virus-mediated gene targeting to produce a human somatic cell line that expresses a conditionally null allele of Ku86. The induced loss of Ku86 results in cell death accompanied by massive telomere loss in the form of t-circles. Thus, Ku86 is an essential gene in human somatic cells because of its requirement, not in NHEJ or V(D)J recombination, but in telomere maintenance.},
}
@article {pmid19569255,
year = {2009},
author = {Keller, G and Brassat, U and Braig, M and Heim, D and Wege, H and Brümmendorf, TH},
title = {Telomeres and telomerase in chronic myeloid leukaemia: impact for pathogenesis, disease progression and targeted therapy.},
journal = {Hematological oncology},
volume = {27},
number = {3},
pages = {123-129},
doi = {10.1002/hon.901},
pmid = {19569255},
issn = {1099-1069},
mesh = {Animals ; Disease Progression ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy/*enzymology/genetics/pathology ; Telomerase/*antagonists &amp; inhibitors/genetics/*metabolism ; Telomere/*pathology ; },
abstract = {Telomeres are specialized structures localized at the end of human chromosomes. Due to the end replication problem, each cell division results in a loss of telomeric repeats in normal somatic cells. In germ line and stem cells, the multicomponent enzyme telomerase maintains the length of telomere repeats. However, elevated telomerase activity has also been reported in the majority of solid tumours as well as in acute and chronic leukaemia. Chronic myeloid leukaemia (CML) serves as a model disease to study telomere biology in clonal myeloproliferative disorders. In CML, telomere shortening correlates with disease stage, duration of chronic phase (CP), prognosis measured by the Hasford risk score and the response to disease-modifying therapeutics such as the tyrosine kinase inhibitor Imatinib. In addition, telomerase activity (TA) is already increased in CP CML and further upregulated with disease progression to accelerated phase and blast crisis (BC). Furthermore, a correlation of TA with increased genetic instability as well as a shorter survival of the patients has been reported. Here, we review the current state of knowledge of the role of telomere and telomerase biology in CML and discuss the possible impact of novel treatment approaches.},
}
@article {pmid19563389,
year = {2010},
author = {Fyhrquist, F and Tiitu, A and Saijonmaa, O and Forsblom, C and Groop, PH and , },
title = {Telomere length and progression of diabetic nephropathy in patients with type 1 diabetes.},
journal = {Journal of internal medicine},
volume = {267},
number = {3},
pages = {278-286},
doi = {10.1111/j.1365-2796.2009.02139.x},
pmid = {19563389},
issn = {1365-2796},
mesh = {Adult ; Albuminuria/genetics ; Diabetes Mellitus, Type 1/complications/*genetics ; Diabetic Nephropathies/*genetics ; Disease Progression ; Female ; Finland/epidemiology ; Humans ; Leukocytes/ultrastructure ; Male ; Middle Aged ; Predictive Value of Tests ; Telomere/*ultrastructure ; },
abstract = {OBJECTIVES: To determine whether short telomere length of blood leucocytes from patients with type 1 diabetes is associated with or predictive of progression of diabetic nephropathy.<br><br>DESIGN AND METHODS: Two consecutive DNA samples were obtained from 132 patients from the nationwide Finnish Diabetic Nephropathy Study with type 1 diabetes. Control DNA samples were taken from 44 healthy blood donors. Telomere length was measured by Southern blot. Patients were divided into three groups according to their urinary albumin excretion rate (AER): 48 patients with normoalbuminuria (AER < 20 microg min(-1)); seven patients with microalbuminuria (AER > or = 20 microg min(-1) <200 microg min(-1)) and 77 patients with macroalbuminuria (AER > or = 200 microg min(-1)). Progression was defined as a change in albuminuria to a higher level.<br><br>RESULTS: Progression occurred in 21 patients. Progressors had shorter mean telomere length (8.1 +/- 0.7 kb, mean +/- SD; P = 0.017) and higher percentage of short telomeres (32.0 +/- 8%, P = 0.002) than nonprogressors (8.5 +/- 0.7 kb and 27 +/- 7.2%, respectively). Thus, both shorter telomeres (HR = 0.190, 95%CI 0.065-0.558, P = 0.0025) and higher proportion of short telomeres (HR = 1.115, 1.039-1.195, P =0.0023) were independent predictors of diabetic nephropathy. Telomere length was not associated with the degree of albuminuria and was not different in patients with type 1 diabetes compared with healthy controls.<br><br>CONCLUSIONS: Short telomeres are independent predictors of progression of diabetic nephropathy in patients with type 1 diabetes.},
}
@article {pmid19562732,
year = {2009},
author = {Vander Griend, DJ and Konishi, Y and De Marzo, AM and Isaacs, JT and Meeker, AK},
title = {Dual-label centromere and telomere FISH identifies human, rat, and mouse cell contribution to Multispecies recombinant urogenital sinus xenografts.},
journal = {The Prostate},
volume = {69},
number = {14},
pages = {1557-1564},
pmid = {19562732},
issn = {1097-0045},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; T32DK07552/DK/NIDDK NIH HHS/United States ; R01 DK052645/DK/NIDDK NIH HHS/United States ; T32 DK007552/DK/NIDDK NIH HHS/United States ; R01DK52645/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Biomarkers ; Biopsy ; Cell Separation/methods ; Centromere/genetics ; Epithelium/embryology/transplantation ; Female ; Humans ; Immunocompromised Host ; In Situ Hybridization, Fluorescence/*methods ; Male ; Mesoderm/cytology/embryology ; Mice ; Organ Culture Techniques/methods ; Paraffin Embedding ; Pregnancy ; Prostate/*cytology/embryology/*transplantation ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins/genetics ; Species Specificity ; Telomere/genetics ; Transplantation, Heterologous/*methods ; },
abstract = {BACKGROUND: Recombinant xenografts of human cells growing in immunocompromised rodents are widely used for studying stem cell biology, tumor biology, and epithelial to mesenchyme transitions. Of critical importance is the correct interpretation of the cellular composition of such xenografts.<br><br>METHODS: Here we present a rapid and robust method employing protein nucleic acid (PNA) FISH probes to dual-label centromeres and telomeres (Cen/Tel FISH). Such labeling allows unambiguous discrimination between human, mouse, and rat cells in paraffin-embedded tissue sections, providing significant advantages over current methods used to discern human versus rodent cell types.<br><br>RESULTS: Using an in vivo prostatic developmental system where rat embryonic urogenital sinus mesenchyme is recombined with human prostate epithelial organoids and grown in an immunocompromised mouse, Cen/Tel FISH documents that all three species contribute to the development of glandular structures.<br><br>CONCLUSIONS: The method is an indispensable tool to analyze xenograft/host interactions and prevent misinterpretation of data using tissue recombination approaches.},
}
@article {pmid19561077,
year = {2009},
author = {Moriarty, TJ and Chaconas, G},
title = {Identification of the determinant conferring permissive substrate usage in the telomere resolvase, ResT.},
journal = {The Journal of biological chemistry},
volume = {284},
number = {35},
pages = {23293-23301},
pmid = {19561077},
issn = {0021-9258},
support = {78190/CAPMC/CIHR/Canada ; },
mesh = {Amino Acid Sequence ; Bacterial Proteins/*chemistry/genetics/metabolism ; Binding Sites ; Borrelia/chemistry/*enzymology/genetics ; Borrelia burgdorferi/chemistry/*enzymology/genetics ; Molecular Sequence Data ; Recombinases/*chemistry/genetics/metabolism ; Substrate Specificity ; Telomere/chemistry/metabolism ; },
abstract = {Linear genome stability requires specialized telomere replication and protection mechanisms. A common solution to this problem in non-eukaryotes is the formation of hairpin telomeres by telomere resolvases (also known as protelomerases). These enzymes perform a two-step transesterification on replication intermediates to generate hairpin telomeres using an active site similar to that of tyrosine recombinases and type IB topoisomerases. Unlike phage telomere resolvases, the telomere resolvase from the Lyme disease pathogen Borrelia burgdorferi (ResT) is a permissive enzyme that resolves several types of telomere in vitro. However, the ResT region and residues mediating permissive substrate usage have not been identified. The relapsing fever Borrelia hermsii ResT exhibits a more restricted substrate usage pattern than B. burgdorferi ResT and cannot efficiently resolve a Type 2 telomere. In this study, we determined that all relapsing fever ResTs process Type 2 telomeres inefficiently. Using a library of chimeric and mutant B. hermsii/B. burgdorferi ResTs, we mapped the determinants in B. burgdorferi ResT conferring the ability to resolve multiple Type 2 telomeres. Type 2 telomere resolution was dependent on a single proline in the ResT catalytic region that was conserved in all Lyme disease but not relapsing fever ResTs and that is part of a 2-amino acid insertion absent from phage telomere resolvase sequences. The identification of a permissive substrate usage determinant explains the ability of B. burgdorferi ResT to process the 19 unique telomeres found in its segmented genome and will aid further studies on the structure and function of this essential enzyme.},
}
@article {pmid19557187,
year = {2009},
author = {Chen, XF and Meng, FL and Zhou, JQ},
title = {Telomere recombination accelerates cellular aging in Saccharomyces cerevisiae.},
journal = {PLoS genetics},
volume = {5},
number = {6},
pages = {e1000535},
pmid = {19557187},
issn = {1553-7404},
mesh = {Cellular Senescence ; *Recombination, Genetic ; Saccharomyces cerevisiae/genetics/*physiology ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomere/*genetics/physiology ; },
abstract = {Telomeres are nucleoprotein structures located at the linear ends of eukaryotic chromosomes. Telomere integrity is required for cell proliferation and survival. Although the vast majority of eukaryotic species use telomerase as a primary means for telomere maintenance, a few species can use recombination or retrotransposon-mediated maintenance pathways. Since Saccharomyces cerevisiae can use both telomerase and recombination to replicate telomeres, budding yeast provides a useful system with which to examine the evolutionary advantages of telomerase and recombination in preserving an organism or cell under natural selection. In this study, we examined the life span in telomerase-null, post-senescent type II survivors that have employed homologous recombination to replicate their telomeres. Type II recombination survivors stably maintained chromosomal integrity but exhibited a significantly reduced replicative life span. Normal patterns of cell morphology at the end of a replicative life span and aging-dependent sterility were observed in telomerase-null type II survivors, suggesting the type II survivors aged prematurely in a manner that is phenotypically consistent with that of wild-type senescent cells. The shortened life span of type II survivors was extended by calorie restriction or TOR1 deletion, but not by Fob1p inactivation or Sir2p over-expression. Intriguingly, rDNA recombination was decreased in type II survivors, indicating that the premature aging of type II survivors was not caused by an increase in extra-chromosomal rDNA circle accumulation. Reintroduction of telomerase activity immediately restored the replicative life span of type II survivors despite their heterogeneous telomeres. These results suggest that telomere recombination accelerates cellular aging in telomerase-null type II survivors and that telomerase is likely a superior telomere maintenance pathway in sustaining yeast replicative life span.},
}
@article {pmid19556773,
year = {2009},
author = {Roberts, NY and Osman, K and Armstrong, SJ},
title = {Telomere distribution and dynamics in somatic and meiotic nuclei of Arabidopsis thaliana.},
journal = {Cytogenetic and genome research},
volume = {124},
number = {3-4},
pages = {193-201},
doi = {10.1159/000218125},
pmid = {19556773},
issn = {1424-859X},
support = {BB/F002858/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Arabidopsis/*physiology/ultrastructure ; Cell Cycle/physiology ; Cell Nucleus/*physiology/ultrastructure ; Chromosomes, Plant/*physiology/ultrastructure ; Meiosis/*physiology ; Telomere/*physiology/ultrastructure ; },
abstract = {The ends of linear eukaryotic chromosomes are protected by the telomere, a specialised nucleoprotein complex. The primary role of the telomere is to protect the chromosome ends from being degraded or recognised and processed as double strand breaks. Additionally, the telomeres are involved in interphase chromosome organisation and also in chromosome pairing, synapsis and movement during meiotic prophase. The main emphasis of this review is concerned with the distribution and dynamics of the telomeres in the somatic cell and meiocytes of plants, focusing on the model plant Arabidopsis thaliana. In Arabidopsis the telomeres are organised around the nucleolus in both the somatic and meiotic interphase. One of the outstanding questions in meiosis is how homologous chromosomes pair (align) and synapse during meiotic prophase. Recent attention has been paid to the bouquet formation, a nearly universal event, during which the telomeres cluster on the nuclear membrane in early prophase. It has been suggested that because the telomeres are in close proximity this would enhance their pairing and subsequent synapsis of the homologues. In Arabidopsis we observe that the telomeres are paired homologously in early meiosis whilst still arranged around the nucleolus. They are moved to the nuclear membrane preceding synapsis and reveal only a loose clustering, which may represent a transient bouquet. On completion of synapsis the paired telomeres are dispersed and remain attached to the nuclear membrane until diplotene when they dissociate from the nuclear membrane. We also discuss the prospects for live imaging of the telomeres in Arabidopsis.},
}
@article {pmid19556325,
year = {2009},
author = {Woo, J and Suen, EW and Leung, JC and Tang, NL and Ebrahim, S},
title = {Older men with higher self-rated socioeconomic status have shorter telomeres.},
journal = {Age and ageing},
volume = {38},
number = {5},
pages = {553-558},
pmid = {19556325},
issn = {1468-2834},
support = {5R01 AR049439-02/AR/NIAMS NIH HHS/United States ; },
mesh = {Aged ; Aging/*ethnology/*genetics ; *Asian People/ethnology/genetics/statistics &amp; numerical data ; Chronic Disease/ethnology ; Cross-Sectional Studies ; Culture ; Female ; Hong Kong/epidemiology ; Humans ; Male ; Risk Factors ; Sex Distribution ; *Social Class ; Surveys and Questionnaires ; Telomere/*genetics ; },
abstract = {BACKGROUND: previous studies examining the relationship between socioeconomic status and telomere length showed conflicting results, one study finding shorter telomere length in subjects with lower socioeconomic status and one showing no relationship.<br><br>DESIGN: cross-sectional study.<br><br>SETTING: community-living elderly Chinese in Hong Kong.<br><br>OBJECTIVE: this study examines the relationship between self-rated social economic status and telomere length in Hong Kong Chinese men and women aged 65 years and over living in the community.<br><br>SUBJECTS AND METHOD: information was collected from 958 men and 978 women regarding possible confounding factors such as the presence of chronic diseases, smoking, physical activity level, dietary intake and body mass index. Telomere length was measured by quantitative PCR.<br><br>RESULT: in men only, after adjustment for age and other confounding factors, a higher ranking in community standing was associated with shorter telomere length.<br><br>CONCLUSION: men with higher self-rated socioeconomic status have shorter telomeres, possibly mediated through psychosocial rather than lifestyle factors or the presence of chronic disease. There may be cultural ethnic and age-related differences in social determinants of health.},
}
@article {pmid19547752,
year = {2009},
author = {Wise, JL and Crout, RJ and McNeil, DW and Weyant, RJ and Marazita, ML and Wenger, SL},
title = {Human telomere length correlates to the size of the associated chromosome arm.},
journal = {PloS one},
volume = {4},
number = {6},
pages = {e6013},
pmid = {19547752},
issn = {1932-6203},
support = {R01 DE014899/DE/NIDCR NIH HHS/United States ; 5 R01-DE014899/DE/NIDCR NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Factors ; Child ; Child, Preschool ; Chromosomes/physiology/*ultrastructure ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Male ; Middle Aged ; Models, Genetic ; Sex Factors ; Telomere/physiology/*ultrastructure ; },
abstract = {The majority of human telomere length studies have focused on the overall length of telomeres within a cell. In fact, very few studies have examined telomere length for individual chromosome arms. The objective of this study was to examine the relationship between chromosome arm size and the relative length of the associated telomere. Quantitative Fluorescence In Situ Hybridization (Q-FISH) was used to measure the relative telomere length of each chromosome arm in metaphases from cultured lymphocytes of 17 individuals. A statistically significant positive correlation (r = 0.6) was found between telomere length and the size of the associated chromosome arm, which was estimated based on megabase pair measurements from (http://www.ncbi.nlm.nih.gov/projects/mapview/).},
}
@article {pmid19546237,
year = {2009},
author = {Schonbrun, M and Laor, D and López-Maury, L and Bähler, J and Kupiec, M and Weisman, R},
title = {TOR complex 2 controls gene silencing, telomere length maintenance, and survival under DNA-damaging conditions.},
journal = {Molecular and cellular biology},
volume = {29},
number = {16},
pages = {4584-4594},
pmid = {19546237},
issn = {1098-5549},
support = {08-0070/AICR_/Worldwide Cancer Research/United Kingdom ; /CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {CDC2 Protein Kinase/genetics/metabolism ; Cell Survival/*physiology ; *DNA Damage ; DNA Replication ; Enzyme Activation ; Gene Expression Regulation, Fungal ; *Gene Silencing ; Hydroxyurea/pharmacology ; Methyl Methanesulfonate/pharmacology ; Mitosis/drug effects/physiology ; Multiprotein Complexes/metabolism ; Mutagens/pharmacology ; Nucleic Acid Synthesis Inhibitors/pharmacology ; Oligonucleotide Array Sequence Analysis ; Protein Kinases/genetics/*metabolism ; Schizosaccharomyces/cytology/drug effects/*genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {The Target Of Rapamycin (TOR) kinase belongs to the highly conserved eukaryotic family of phosphatidylinositol-3-kinase-related kinases (PIKKs). TOR proteins are found at the core of two distinct evolutionarily conserved complexes, TORC1 and TORC2. Disruption of TORC1 or TORC2 results in characteristically dissimilar phenotypes. TORC1 is a major cell growth regulator, while the cellular roles of TORC2 are not well understood. In the fission yeast Schizosaccharomyces pombe, Tor1 is a component of the TORC2 complex, which is particularly required during starvation and various stress conditions. Our genome-wide gene expression analysis of Deltator1 mutants indicates an extensive similarity with chromatin structure mutants. Consistently, TORC2 regulates several chromatin-mediated functions, including gene silencing, telomere length maintenance, and tolerance to DNA damage. These novel cellular roles of TORC2 are rapamycin insensitive. Cells lacking Tor1 are highly sensitive to the DNA-damaging drugs hydroxyurea (HU) and methyl methanesulfonate, similar to mutants of the checkpoint kinase Rad3 (ATR). Unlike Rad3, Tor1 is not required for the cell cycle arrest in the presence of damaged DNA. Instead, Tor1 becomes essential for dephosphorylation and reactivation of the cyclin-dependent kinase Cdc2, thus allowing reentry into mitosis following recovery from DNA replication arrest. Taken together, our data highlight critical roles for TORC2 in chromatin metabolism and in promoting mitotic entry, most notably after recovery from DNA-damaging conditions. These data place TOR proteins in line with other PIKK members, such as ATM and ATR, as guardians of genome stability.},
}
@article {pmid19545556,
year = {2009},
author = {Zee, RY and Michaud, SE and Ridker, PM},
title = {Mean telomere length and risk of incident venous thromboembolism: a prospective, nested case-control approach.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {406},
number = {1-2},
pages = {148-150},
pmid = {19545556},
issn = {1873-3492},
support = {CA-40360/CA/NCI NIH HHS/United States ; CA-34944/CA/NCI NIH HHS/United States ; HL-34595/HL/NHLBI NIH HHS/United States ; HL-26490/HL/NHLBI NIH HHS/United States ; R01 CA097193-01/CA/NCI NIH HHS/United States ; R01 HL034595/HL/NHLBI NIH HHS/United States ; R01 CA097193-02/CA/NCI NIH HHS/United States ; R01 CA097193-03/CA/NCI NIH HHS/United States ; R01 CA097193-07/CA/NCI NIH HHS/United States ; R01 HL026490/HL/NHLBI NIH HHS/United States ; R01 CA097193-04/CA/NCI NIH HHS/United States ; CA-97193/CA/NCI NIH HHS/United States ; R01 CA040360/CA/NCI NIH HHS/United States ; R01 CA097193-06A1/CA/NCI NIH HHS/United States ; R01 CA097193/CA/NCI NIH HHS/United States ; R01 CA034944/CA/NCI NIH HHS/United States ; R01 CA097193-05/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Case-Control Studies ; Cohort Studies ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Risk ; Venous Thromboembolism/*genetics ; },
abstract = {BACKGROUND: Recent studies have shown telomere-length shortening as a risk predictor for cardiovascular disease. However, to date, no prospective data are available on its potential involvement in venous thromboembolism (VTE).<br><br>METHODS: Using leukocyte DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we examined the relationship of mean telomere repeat copy number to single gene copy number (T/S ratio), using a modified quantitative polymerase chain reaction protocol, amongst 108 White males who subsequently developed a first ever VTE event and amongst an equal number of age- and smoking-matched White males who remained free of vascular events during follow-up (controls).<br><br>RESULTS: An inverse correlation between T/S ratios and age was observed in our controls (p=0.04). However, the T/S ratios were similar between cases and controls (p=0.31). Furthermore, in a multi-variable adjusted analysis, we found no evidence for an association of the observed T/S ratios with VTE risk (odds ratio=1.20; 95%CI=0.58-2.52; p=0.62).<br><br>CONCLUSIONS: The present investigation found no evidence for an association of relative telomere length with risk of incident VTE.},
}
@article {pmid19543829,
year = {2010},
author = {Zheng, YL and Ambrosone, C and Byrne, C and Davis, W and Nesline, M and McCann, SE},
title = {Telomere length in blood cells and breast cancer risk: investigations in two case-control studies.},
journal = {Breast cancer research and treatment},
volume = {120},
number = {3},
pages = {769-775},
pmid = {19543829},
issn = {1573-7217},
support = {P30 CA016056/CA/NCI NIH HHS/United States ; P30 CA051008/CA/NCI NIH HHS/United States ; P30 CA51008/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Breast Neoplasms/blood/*epidemiology/genetics ; Case-Control Studies ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes/*ultrastructure ; Menopause ; Middle Aged ; Polymerase Chain Reaction ; Racial Groups ; Risk Factors ; Smoking/epidemiology ; Socioeconomic Factors ; Telomere/*ultrastructure ; },
abstract = {Telomere dysfunction, which leads to genomic instability, is hypothesized to play a causal role in the development of breast cancer. However, the few epidemiologic studies that assessed the relationship between telomere length in blood cells and breast cancer risk have been inconsistent. We conducted two case-control studies to further understand the role of telomere length and breast cancer risk. Overall telomere lengths were measured by telomere quantitative fluorescent in situ hybridization (TQ-FISH) and telomere quantitative real-time PCR (TQ-PCR). The associations between telomere length in blood leukocytes and risk of breast cancer were examined in two breast cancer case-control studies that were conducted at Roswell Park Cancer Institute (RPCI) and Lombardi Comprehensive Cancer Center (LCCC). Using the 50th percentile value in controls as a cut point, women who had shorter telomere length were not at significantly increased risk of breast cancer compared with women who had longer telomere length in the RPCI study (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 0.84-2.12), in the LCCC study (OR = 1.18, 95% CI = 0.73-1.91), or in the combined RPCI and LCCC studies (OR = 1.23, 95% CI = 0.89-1.71). There was no significant dose-response relationship across quartiles of telomere length and no significant difference when comparing women in the lowest to highest quartile of telomere length. Overall telomere length in blood leukocytes was not significantly associated with the risk of breast cancer.},
}
@article {pmid19540247,
year = {2009},
author = {Gorman, S and Tosetto, M and Lyng, F and Howe, O and Sheahan, K and O'Donoghue, D and Hyland, J and Mulcahy, H and O'Sullivan, J},
title = {Radiation and chemotherapy bystander effects induce early genomic instability events: telomere shortening and bridge formation coupled with mitochondrial dysfunction.},
journal = {Mutation research},
volume = {669},
number = {1-2},
pages = {131-138},
doi = {10.1016/j.mrfmmm.2009.06.003},
pmid = {19540247},
issn = {0027-5107},
mesh = {Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Bystander Effect ; Colorectal Neoplasms/drug therapy/*genetics/radiotherapy ; Combined Modality Therapy ; Female ; Fluorouracil/therapeutic use ; *Genomic Instability ; Humans ; Leucovorin/therapeutic use ; Male ; Membrane Potential, Mitochondrial ; Mitochondrial Diseases/*metabolism ; Organoplatinum Compounds/therapeutic use ; Oxidative Stress ; Prognosis ; Radiotherapy Dosage ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Telomere/*genetics/metabolism ; Tissue Culture Techniques ; Tissue Extracts ; Treatment Outcome ; },
abstract = {The bridge breakage fusion cycle is a chromosomal instability mechanism responsible for genomic changes. Radiation bystander effects induce genomic instability; however, the mechanism driving this instability is unknown. We examined if radiation and chemotherapy bystander effects induce early genomic instability events such as telomere shortening and bridge formation using a human colon cancer explant model. We assessed telomere lengths, bridge formations, mitochondrial membrane potential and levels of reactive oxygen species in bystander cells exposed to medium from irradiated and chemotherapy-treated explant tissues. Bystander cells exposed to media from 2Gy, 5Gy, FOLFOX treated tumor and matching normal tissue showed a significant reduction in telomere lengths (all p values <0.018) and an increase in bridge formations (all p values <0.017) compared to bystander cells treated with media from unirradiated tissue (0Gy) at 24h. There was no significant difference between 2Gy and 5Gy treatments, or between effects elicited by tumor versus matched normal tissue. Bystander cells exposed to media from 2Gy irradiated tumor tissue showed significant depolarisation of the mitochondrial membrane potential (p=0.012) and an increase in reactive oxygen species levels. We also used bystander cells overexpressing a mitochondrial antioxidant manganese superoxide dismutase (MnSOD) to examine if this antioxidant could rescue the mitochondrial changes and subsequently influence nuclear instability events. In MnSOD cells, ROS levels were reduced (p=0.02) and mitochondrial membrane potential increased (p=0.04). These events were coupled with a decrease in percentage of cells with anaphase bridges and a decrease in the number of cells undergoing telomere length shortening (p values 0.01 and 0.028 respectively). We demonstrate that radiation and chemotherapy bystander responses induce early genomic instability coupled with defects in mitochondrial function. Restoring mitochondrial function through overexpression of MnSOD significantly rescues nuclear instability events; anaphase bridges and telomere length shortening.},
}
@article {pmid19535548,
year = {2009},
author = {Zheng, YL and Loffredo, CA and Shields, PG and Selim, SM},
title = {Chromosome 9 arm-specific telomere length and breast cancer risk.},
journal = {Carcinogenesis},
volume = {30},
number = {8},
pages = {1380-1386},
pmid = {19535548},
issn = {1460-2180},
support = {P30 CA51008/CA/NCI NIH HHS/United States ; },
mesh = {Breast Neoplasms/blood/*genetics/pathology ; Case-Control Studies ; Chromosomes, Human, Pair 9/*genetics ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Lymphocytes ; Middle Aged ; Neoplasm Staging ; Odds Ratio ; Prognosis ; Risk Factors ; Telomere/*genetics ; },
abstract = {BACKGROUND: Telomere dysfunction is involved in the development of breast cancer and very short telomeres are frequent genetic alterations in breast tumors. However, the influence of telomere lengths of specific chromosomal arms on the breast cancer risk is unknown.<br><br>METHODS: We conducted a case-control study of breast cancer to examine the associations of the telomere length on chromosome 9 short arms (9p) and long arms (9q) with risk of breast cancer. Chromosome 9 arm-specific telomere lengths were measured by quantitative fluorescent in situ hybridization using cultured blood lymphocytes.<br><br>RESULTS: Telomere length on chromosome 9p was significantly shorter in breast cancer patients than in control subjects (P < 0.001). Using the 50th percentile value in controls as a cut point, women who have short 9p telomeres had an increased risk of breast cancer [adjusted odds ratio (OR) = 2.6; 95% confidence interval (CI) = 1.5-4.3]. When the 9p telomere length was divided into quartiles, a significant inverse dose-response relationship between 9p telomere length and breast cancer risk was observed (P(trend) < 0.001), with a quartile ORs of 3.0 (95% CI = 1.2-7.5), 3.9 (95% CI = 1.6-9.5) and 6.6 (95% CI = 2.8-15.9) for third, second and first quartile, respectively, when compared with women in the fourth quartile.<br><br>CONCLUSIONS: Short telomere length on chromosome 9p is strongly associated with the risk of breast cancer. If confirmed by future studies, chromosome 9p telomere length has the potential to be incorporated into the current prediction models to significantly enhance breast cancer risk prediction.},
}
@article {pmid19532124,
year = {2009},
author = {Qian, W and Wang, J and Jin, NN and Fu, XH and Lin, YC and Lin, JJ and Zhou, JQ},
title = {Ten1p promotes the telomeric DNA-binding activity of Cdc13p: implication for its function in telomere length regulation.},
journal = {Cell research},
volume = {19},
number = {7},
pages = {849-863},
doi = {10.1038/cr.2009.67},
pmid = {19532124},
issn = {1748-7838},
mesh = {Amino Acid Sequence ; Animals ; Cell Cycle Proteins/metabolism ; Cell Line ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; DNA, Single-Stranded/metabolism ; Immunoprecipitation ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Protein Binding ; Recombinant Proteins/isolation &amp; purification/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {In Saccharomyces cerevisiae, the essential gene CDC13 encodes a telomeric single-stranded DNA-binding protein that interacts with Stn1p and Ten1p genetically and physically, and is required for telomere end protection and telomere length control. The molecular mechanism by which Ten1 participates in telomere length regulation and chromosome end protection remains elusive. In this work, we observed a weak interaction of Cdc13p and Ten1p in a gel-filtration analysis using purified recombinant Cdc13p and Ten1p. Ten1p itself exhibits a weak DNA-binding activity, but enhances the telomeric TG(1-3) DNA-binding ability of Cdc13p. Cdc13p is co-immunoprecipitated with Ten1p. In the mutant ten1-55 or ten1-66 cells, the impaired interaction between Ten1p and Cdc13p results in much longer telomeres, as well as a decreased association of Cdc13p with telomeric DNA. Consistently, the Ten1-55 and Ten1-66 mutant proteins fail to stimulate the telomeric DNA-binding activity of Cdc13p in vitro. These results suggest that Ten1p enhances the telomeric DNA-binding activity of Cdc13p to negatively regulate telomere length.},
}
@article {pmid19531742,
year = {2009},
author = {Baker, AM and Fu, Q and Hayward, W and Lindsay, SM and Fletcher, TM},
title = {The Myb/SANT domain of the telomere-binding protein TRF2 alters chromatin structure.},
journal = {Nucleic acids research},
volume = {37},
number = {15},
pages = {5019-5031},
pmid = {19531742},
issn = {1362-4962},
support = {31-GM75427-01/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; DNA/metabolism ; Humans ; Micrococcal Nuclease ; Microscopy, Atomic Force ; Nucleosomes/*chemistry/metabolism/ultrastructure ; Oligonucleotides/analysis ; Protein Structure, Tertiary ; Telomere/*chemistry ; Telomeric Repeat Binding Protein 2/chemistry/*metabolism ; },
abstract = {Eukaryotic DNA is packaged into chromatin, which regulates genome activities such as telomere maintenance. This study focuses on the interactions of a myb/SANT DNA-binding domain from the telomere-binding protein, TRF2, with reconstituted telomeric nucleosomal array fibers. Biophysical characteristics of the factor-bound nucleosomal arrays were determined by analytical agarose gel electrophoresis (AAGE) and single molecules were visualized by atomic force microscopy (AFM). The TRF2 DNA-binding domain (TRF2 DBD) neutralized more negative charge on the surface of nucleosomal arrays than histone-free DNA. Binding of TRF2 DBD at lower concentrations increased the radius and conformational flexibility, suggesting a distortion of the fiber structure. Additional loading of TRF2 DBD onto the nucleosomal arrays reduced the flexibility and strongly blocked access of micrococcal nuclease as contour lengths shortened, consistent with formation of a unique, more compact higher-order structure. Mirroring the structural results, TRF2 DBD stimulated a strand invasion-like reaction, associated with telomeric t-loops, at lower concentrations while inhibiting the reaction at higher concentrations. Full-length TRF2 was even more effective at stimulating this reaction. The TRF2 DBD had less effect on histone-free DNA structure and did not stimulate the t-loop reaction with this substrate, highlighting the influence of chromatin structure on the activities of DNA-binding proteins.},
}
@article {pmid19528237,
year = {2009},
author = {Caslini, C and Connelly, JA and Serna, A and Broccoli, D and Hess, JL},
title = {MLL associates with telomeres and regulates telomeric repeat-containing RNA transcription.},
journal = {Molecular and cellular biology},
volume = {29},
number = {16},
pages = {4519-4526},
pmid = {19528237},
issn = {1098-5549},
support = {R01 CA092251/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cell Line ; Cellular Senescence/physiology ; Centromere/metabolism ; Gene Knockdown Techniques ; Heterochromatin/metabolism ; Histone-Lysine N-Methyltransferase ; Histones/metabolism ; Humans ; Myeloid-Lymphoid Leukemia Protein/genetics/*metabolism ; RNA/genetics/*metabolism ; RNA, Small Interfering/genetics/metabolism ; *Repetitive Sequences, Nucleic Acid ; Shelterin Complex ; *Telomere/genetics/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; *Transcription, Genetic ; Tumor Suppressor Protein p53/genetics/metabolism ; },
abstract = {Mammalian telomeres consist of TTAGGG repeats organized in nucleosomes and associated with a six-protein complex known as shelterin, which preserves telomere structure and protects chromosome ends from the cellular DNA damage response. Recent studies have found that telomeres are transcribed into telomeric UUAGGG repeat-containing RNA (TERRA) starting from subtelomeric regions. TERRA binding at telomeres appears to be involved in cis-based mechanisms of telomeric chromatin organization and maintenance. A number of histone methyltransferases (HMTs) are known to influence telomeric chromatin status; however, the regulatory mechanisms of telomere transcription are poorly understood. Here, we show that the histone 3/lysine 4 (H3/K4) HMT and the transcriptional regulator MLL associate with telomeres and contribute to their H3/K4 methylation and transcription in a telomere length-dependent manner. In human diploid fibroblasts, RNA interference-mediated MLL depletion affects telomere chromatin modification and transcription and induces the telomere damage response. Telomere uncapping through either TRF2 shelterin protein knockdown or exposure to telomere G-strand DNA oligonucleotides significantly increases the transcription of TERRA, an effect mediated by the functional cooperation between MLL and the tumor suppressor p53. In total, our findings identify a previously unrecognized role of MLL in modifying telomeric chromatin and provide evidence for the functional interaction between MLL, p53, and the shelterin complex in the regulation of telomeric transcription and stability.},
}
@article {pmid19525972,
year = {2009},
author = {DeZwaan, DC and Toogun, OA and Echtenkamp, FJ and Freeman, BC},
title = {The Hsp82 molecular chaperone promotes a switch between unextendable and extendable telomere states.},
journal = {Nature structural &amp; molecular biology},
volume = {16},
number = {7},
pages = {711-716},
pmid = {19525972},
issn = {1545-9985},
support = {R01 DK074270/DK/NIDDK NIH HHS/United States ; R01 DK074270-03/DK/NIDDK NIH HHS/United States ; T32 HL007121/HL/NHLBI NIH HHS/United States ; DK074270/DK/NIDDK NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics/metabolism ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; DNA, Fungal/*chemistry/metabolism ; Enzyme Activation ; HSP90 Heat-Shock Proteins/genetics/*metabolism ; *Nucleic Acid Conformation ; *Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/metabolism ; Telomere/*chemistry/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Distinct protein assemblies are nucleated at telomeric DNA to both guard the ends from damage and lengthen the DNA after replication. In yeast, Cdc13 recruits either Stn1-Ten1 to form a protective cap or the telomerase holoenzyme to extend the DNA. We have established an in vitro yeast telomere system in which Stn1-Ten1-unextendable or telomerase-extendable states can be observed. Both assemblies are Cdc13 dependent, as the Cdc13 C-terminal region supports Stn1-Ten1 interactions and the N-terminal region contains a telomerase-activation function. Notably, the yeast Hsp90 chaperone Hsp82 mediates the switch between the telomere capping and extending structures by modulating the DNA binding activity of Cdc13. Taken together, our data show that the Hsp82 chaperone facilitates telomere DNA maintenance by promoting transitions between two operative complexes and by reducing the potential for binding events that would otherwise block the assembly of downstream structures.},
}
@article {pmid19523870,
year = {2009},
author = {Qi, Y and Li, L and Li, B},
title = {Label-free detection of specific DNA sequence-telomere using unmodified gold nanoparticles as colorimetric probes.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {74},
number = {1},
pages = {127-131},
doi = {10.1016/j.saa.2009.05.023},
pmid = {19523870},
issn = {1873-3557},
mesh = {Base Sequence ; Biosensing Techniques/methods ; Colorimetry/methods ; DNA/*analysis ; Efficiency ; Gold/chemistry/*pharmacology ; Metal Nanoparticles/chemistry ; Models, Biological ; Nucleic Acid Hybridization/drug effects ; Sensitivity and Specificity ; Spectrophotometry, Ultraviolet ; Staining and Labeling/*methods ; Telomere/*chemistry ; },
abstract = {A simple and sensitive label-free colorimetric detection of telomere DNA has been developed. It was based on the color change of gold nanoparticles (AuNPs) due to DNA hybridization. UV-vis spectra and transmission electron microscopy (TEM) were used to investigate the change of AuNPs. Under the optimized conditions, the linear range for determination of telomere DNA was 5.7 x 10(-13) to 4.5 x 10(-6)mol/L. The detection limit (3 sigma) of this method has decreased to pico-molar level.},
}
@article {pmid19523475,
year = {2009},
author = {Mardanov, AV and Ravin, NV},
title = {Conversion of linear DNA with hairpin telomeres into a circular molecule in the course of phage N15 lytic replication.},
journal = {Journal of molecular biology},
volume = {391},
number = {2},
pages = {261-268},
doi = {10.1016/j.jmb.2009.06.021},
pmid = {19523475},
issn = {1089-8638},
mesh = {Bacteriolysis ; Coliphages/enzymology/genetics/*physiology ; DNA Replication ; DNA, Circular/*biosynthesis/chemistry ; DNA, Viral/*biosynthesis/chemistry ; Enzyme Precursors/genetics/metabolism ; Mutation ; Nucleic Acid Conformation ; Telomerase/genetics/metabolism ; Telomere/chemistry/genetics/*physiology ; Viral Proteins/genetics/metabolism ; *Virus Replication ; },
abstract = {The prophage of temperate coliphage N15 is not integrated into the bacterial chromosome but exists as a linear plasmid molecule with covalently closed ends. Upon infection of an Escherichia coli cell, the phage DNA circularises via cohesive ends. A phage-encoded enzyme, protelomerase, then cuts at another site, telRL, and forms hairpin ends (telomeres) of linear plasmid prophage. Bidirectional replication of a linear plasmid produces a molecule with duplicated telomeres that is subsequently resolved into unit-length plasmids by protelomerase. Here, we analysed the structures of N15 DNA in the course of phage lytic development and found that, upon circularisation of infecting phage DNA, the circular molecule is not used to initiate lambda-like lytic replication but is converted into a linear plasmid. Replication of N15 DNA then follows the plasmid mode, and only at late steps did the circular unit-length molecules that could start lambda-like late replication and DNA encapsidation appear. Consistently, we found that protelomerase is required not only for plasmid replication but also for phage N15 lytic development. We found that conversion of linear plasmid with hairpin telomeres into a circular molecule with unresolved telomeres in the course of lytic development depends on N15 DNA replication, suggesting that the circular monomer is generated not directly from a linear plasmid in reverse "telomere fusion" reaction but results from resolution of a circular dimer intermediate of plasmid replication into two circular molecules with joined telRL telomeres. Mutation H415A in protelomerase results in accumulation of monomeric circular molecules in the course of replication of linear plasmid. The switch to circular plasmid formation in the course of lytic replication of N15 may result from depletion of protelomerase or modification of its activity by some phage-encoded factor at late steps of lytic growth.},
}
@article {pmid19521025,
year = {2009},
author = {Okamoto, K and Shinkai, Y},
title = {TRFH domain is critical for TRF1-mediated telomere stabilization.},
journal = {Cell structure and function},
volume = {34},
number = {2},
pages = {71-76},
doi = {10.1247/csf.09007},
pmid = {19521025},
issn = {1347-3700},
mesh = {Animals ; Chickens ; Chromosomal Instability ; DNA Damage ; Dimerization ; Embryonic Stem Cells/cytology/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; Phenotype ; Point Mutation ; Protein Structure, Tertiary ; Recombinant Fusion Proteins/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 1/chemistry/*metabolism ; },
abstract = {The telomeres are nucleoprotein complexes essential for maintaining the genomic integrity of linear chromosomes. Six telomere localizing proteins form a complex named "shelterin/telosome" to cooperatively regulate telomere length and protect chromosomal ends from DNA damage and repair responses. Mouse embryonic stem (ES) cells lacking TRF1, a shelterin component, exhibit a high-incidence of broken or lost telomere FISH signals, supporting a critical role for TRF1 in telomere maintenance. We demonstrate that these abnormal telomere structures are not caused by the inability of TRF1-deficient cells to recruit TIN2 but are due to a specific role for TRF1 at telomeres. Furthermore, we provide evidence that the mTRF1 TRF homology (TRFH) domain is crucial for this abnormal telomere FISH phenotype. These novel findings suggest that the TRFH domain is crucial not only for dimerization of TRF1 and TIN2-telomere recruitment, but also telomere stabilization.},
}
@article {pmid19520832,
year = {2009},
author = {Gao, G and Bi, X and Chen, J and Srikanta, D and Rong, YS},
title = {Mre11-Rad50-Nbs complex is required to cap telomeres during Drosophila embryogenesis.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {106},
number = {26},
pages = {10728-10733},
pmid = {19520832},
issn = {1091-6490},
support = {//Intramural NIH HHS/United States ; },
mesh = {Animals ; Carrier Proteins/*genetics/metabolism ; Chromosome Segregation/genetics ; Crosses, Genetic ; Drosophila Proteins/*genetics/metabolism ; Drosophila melanogaster/embryology/*genetics/metabolism ; Embryo, Nonmammalian/embryology/metabolism ; Endodeoxyribonucleases/*genetics/metabolism ; Exodeoxyribonucleases/*genetics/metabolism ; Female ; Immunoblotting ; Immunohistochemistry ; Male ; Mitosis/genetics ; Mutation ; Telomere/*genetics/metabolism ; Time Factors ; },
abstract = {Using Drosophila as a model system, we identified here a stringent requirement for Mre11-Rad50-Nbs (MRN) function in telomere protection during early embryonic development. Animals homozygous for hypomorphic mutations in either mre11 or nbs develop normally with minimal telomere dysfunction. However, they produce inviable embryos that succumb to failure of mitosis caused by covalent fusion of telomeric DNA. Interestingly, the molecular defect is not the absence of MRN interaction or of Mre11 nuclease activities, but the depletion of the maternal pool of Nbs protein in these embryos. Because of Nbs depletion, Mre11 and Rad50 (MR) are excluded from chromatin. This maternal effect lethality in Drosophila is similar to that seen in mice carrying hypomorphic mrn mutations found in human patients, suggesting a common defect in telomere maintenance because of the loss of MRN integrity.},
}
@article {pmid19520803,
year = {2009},
author = {Salomons, HM and Mulder, GA and van de Zande, L and Haussmann, MF and Linskens, MH and Verhulst, S},
title = {Telomere shortening and survival in free-living corvids.},
journal = {Proceedings. Biological sciences},
volume = {276},
number = {1670},
pages = {3157-3165},
pmid = {19520803},
issn = {0962-8452},
mesh = {Animals ; Crows/genetics/*physiology ; Longevity/genetics ; Oxidative Stress/genetics ; Telomere/*metabolism ; Time Factors ; },
abstract = {Evidence accumulates that telomere shortening reflects lifestyle and predicts remaining lifespan, but little is known of telomere dynamics and their relation to survival under natural conditions. We present longitudinal telomere data in free-living jackdaws (Corvus monedula) and test hypotheses on telomere shortening and survival. Telomeres in erythrocytes were measured using pulsed-field gel electrophoresis. Telomere shortening rates within individuals were twice as high as the population level slope, demonstrating that individuals with short telomeres are less likely to survive. Further analysis showed that shortening rate in particular predicted survival, because telomere shortening was much accelerated during a bird's last year in the colony. Telomere shortening was also faster early in life, even after growth was completed. It was previously shown that the lengths of the shortest telomeres best predict cellular senescence, suggesting that shorter telomeres should be better protected. We test the latter hypothesis and show that, within individuals, long telomeres shorten faster than short telomeres in adults and nestlings, a result not previously shown in vivo. Moreover, survival selection in adults was most conspicuous on relatively long telomeres. In conclusion, our longitudinal data indicate that the shortening rate of long telomeres may be a measure of 'life stress' and hence holds promise as a biomarker of remaining lifespan.},
}
@article {pmid19518131,
year = {2009},
author = {Croy, JE and Altschuler, SE and Grimm, NE and Wuttke, DS},
title = {Nonadditivity in the recognition of single-stranded DNA by the schizosaccharomyces pombe protection of telomeres 1 DNA-binding domain, Pot1-DBD.},
journal = {Biochemistry},
volume = {48},
number = {29},
pages = {6864-6875},
pmid = {19518131},
issn = {1520-4995},
support = {R01 GM059414-08/GM/NIGMS NIH HHS/United States ; GM-071257/GM/NIGMS NIH HHS/United States ; P41 GM068928/GM/NIGMS NIH HHS/United States ; T32GM065103/GM/NIGMS NIH HHS/United States ; R01 GM059414/GM/NIGMS NIH HHS/United States ; GM-059414/GM/NIGMS NIH HHS/United States ; GM68928/GM/NIGMS NIH HHS/United States ; T32GM-008732/GM/NIGMS NIH HHS/United States ; T32 GM008732-08/GM/NIGMS NIH HHS/United States ; T32 GM065103/GM/NIGMS NIH HHS/United States ; T32 GM008732/GM/NIGMS NIH HHS/United States ; F32 GM071257/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA, Single-Stranded/*metabolism ; Electrophoretic Mobility Shift Assay ; Models, Molecular ; Mutagenesis ; Nuclear Magnetic Resonance, Biomolecular ; Schizosaccharomyces/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/chemistry/genetics/isolation &amp; purification/*metabolism ; *Telomere ; },
abstract = {The Schizosaccharomyces pombe protection of telomeres 1 (SpPot1) protein recognizes the 3' single-stranded ends of telomeres and provides essential protective and regulatory functions. The ssDNA-binding activity of SpPot1 is conferred by its ssDNA-binding domain, Pot1-DBD (residues 1-389), which can be further separated into two distinct domains, Pot1pN (residues 1-187) and Pot1pC (residues 188-389). Here we show that Pot1pC, like Pot1pN, can function independently of Pot1-DBD and binds specifically to a minimal nonameric oligonucleotide, d(GGTTACGGT), with a K(D) of 400 +/- 70 nM (specifically recognized nucleotides in bold). NMR chemical shift perturbation analysis indicates that the overall structures of the isolated Pot1pN and Pot1pC domains remain intact in Pot1-DBD. Furthermore, alanine scanning reveals modest differences in the ssDNA-binding contacts provided by isolated Pot1pN and within Pot1-DBD. Although the global character of both Pot1pN and Pot1pC is maintained in Pot1-DBD, chemical shift perturbation analysis highlights localized structural differences within the G1/G2 and T3/T4 binding pockets of Pot1pN in Pot1-DBD, which correlate with its distinct ssDNA-binding activity. Furthermore, we find evidence for a putative interdomain interface on Pot1pN that mediates interactions with Pot1pC that ultimately result in the altered ssDNA-binding activity of Pot1-DBD. Together, these data provide insight into the mechanisms underlying the activity and regulation of SpPot1 at the telomere.},
}
@article {pmid19506581,
year = {2009},
author = {Martin, OC and DeSevo, CG and Guo, BZ and Koshland, DE and Dunham, MJ and Zheng, Y},
title = {Telomere behavior in a hybrid yeast.},
journal = {Cell research},
volume = {19},
number = {7},
pages = {910-912},
doi = {10.1038/cr.2009.65},
pmid = {19506581},
issn = {1748-7838},
support = {P50 GM071508/GM/NIGMS NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; },
mesh = {DNA, Single-Stranded/metabolism ; Gene Expression ; Saccharomyces/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; },
}
@article {pmid19505961,
year = {2009},
author = {Longo, DL},
title = {Telomere dynamics in aging: much ado about nothing?.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {64},
number = {9},
pages = {963-964},
doi = {10.1093/gerona/glp071},
pmid = {19505961},
issn = {1758-535X},
mesh = {Aged ; Aging/blood/*genetics ; Blood Cell Count ; Humans ; *Telomere ; },
}
@article {pmid19493248,
year = {2009},
author = {Mirabello, L and Huang, WY and Wong, JY and Chatterjee, N and Reding, D and Crawford, ED and De Vivo, I and Hayes, RB and Savage, SA},
title = {The association between leukocyte telomere length and cigarette smoking, dietary and physical variables, and risk of prostate cancer.},
journal = {Aging cell},
volume = {8},
number = {4},
pages = {405-413},
pmid = {19493248},
issn = {1474-9726},
support = {R01 CA082838/CA/NCI NIH HHS/United States ; R01 CA082838-09/CA/NCI NIH HHS/United States ; CA82838/CA/NCI NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; },
mesh = {Aged ; Case-Control Studies ; *Diet ; Humans ; *Leukocytes ; *Life Style ; Male ; Middle Aged ; Prostatic Neoplasms/chemically induced/*epidemiology/genetics ; Risk Factors ; Smoking/*adverse effects ; *Telomere ; },
abstract = {Telomeres consist of nucleotide repeats and a protein complex at chromosome ends that are essential to maintaining chromosomal integrity. Several studies have suggested that subjects with shorter telomeres are at increased risk of bladder and lung cancer. In comparison to normal tissues, telomeres are shorter in high-grade intraepithelial neoplasia and prostate cancer. We examined prostate cancer risk associated with relative telomere length as determined by quantitative PCR on prediagnostic buffy coat DNA isolated from 612 advanced prostate cancer cases and 1049 age-matched, cancer-free controls from the PLCO Cancer Screening Trial. Telomere length was analyzed as both a continuous and a categorical variable with adjustment for potential confounders. Statistically significant inverse correlations between telomere length, age and smoking status were observed in cases and controls. Telomere length was not associated with prostate cancer risk (at the median, OR = 0.85, 95% CI: 0.67, 1.08); associations were similar when telomere length was evaluated as a continuous variable or by quartiles. The relationships between telomere length and inflammation-related factors, diet, exercise, body mass index, and other lifestyle variables were explored since many of these have previously been associated with shorter telomeres. Healthy lifestyle factors (i.e., lower BMI, more exercise, tobacco abstinence, diets high in fruit and vegetables) tended to be associated with greater telomere length. This study found no statistically significant association between leukocyte telomere length and advanced prostate cancer risk. However, correlations of telomere length with healthy lifestyles were noted, suggesting the role of these factors in telomere biology maintenance and potentially impacting overall health status.},
}
@article {pmid19489057,
year = {2009},
author = {Pavesi, E and Avondo, F and Aspesi, A and Quarello, P and Rocci, A and Vimercati, C and Pigullo, S and Dufour, C and Ramenghi, U and Dianzani, I},
title = {Analysis of telomeres in peripheral blood cells from patients with bone marrow failure.},
journal = {Pediatric blood &amp; cancer},
volume = {53},
number = {3},
pages = {411-416},
doi = {10.1002/pbc.22107},
pmid = {19489057},
issn = {1545-5017},
support = {GGP07242/TI_/Telethon/Italy ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Anemia, Aplastic/blood/*genetics ; Anemia, Diamond-Blackfan/blood/*genetics ; Cell Cycle Proteins/genetics ; Child ; Child, Preschool ; Dyskeratosis Congenita/*genetics ; Fanconi Anemia/blood/*genetics ; Humans ; Infant ; Middle Aged ; Nuclear Proteins/genetics ; Polymerase Chain Reaction ; *Telomere ; },
abstract = {BACKGROUND: The determination of telomere length is useful for the characterization of dyskeratosis congenita (DC) and of aplastic anemias (AA) as well as hematological malignancies. Short telomeres result from a specific defect of telomere maintenance in DC and likely from higher cellular turnover in AA and hematological malignancies. Data are not conclusive for Diamond-Blackfan anemia (DBA), a pure erythroid aplasia due to defects of ribosomal proteins. Our aim was to evaluate the utility of a qPCR method for telomere length assessment to evaluate the diagnostic contribution of telomere measurement in bone marrow failure syndromes (BMFS).<br><br>PROCEDURE: Telomere length was evaluated by qPCR in peripheral blood cells from 95 normal individuals and 62 patients with BMFS, including 45 patients with DBA.<br><br>RESULTS: Results obtained with qPCR are comparable with other quantitative methods, such as flow-FISH and Southern blotting. Our data show that only one DBA patient and a minority of other BMFS patients have very short telomeres, defined as less than the 1st percentile of controls.<br><br>CONCLUSIONS: The qPCR method for telomere length evaluation is an easy alternative to other methods and may thus be valuable in a clinical hematological laboratory setting. Telomere maintenance does not seem to be involved in the pathogenesis of DBA unlike in other BMFSs.},
}
@article {pmid19484154,
year = {2009},
author = {Wong, LS and Windt, WA and Roks, AJ and van Dokkum, RP and Schoemaker, RG and de Zeeuw, D and Henning, RH},
title = {Renal failure induces telomere shortening in the rat heart.},
journal = {Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation},
volume = {17},
number = {5},
pages = {190-194},
pmid = {19484154},
issn = {1568-5888},
abstract = {BACKGROUND: Renal failure aggravates pathological cardiac remodelling induced by myocardial infarction (MI). Cardiac remodelling is associated with telomere shortening, a marker for biological ageing. We investigated whether mild and severe renal failure shorten cardiac telomeres and excessively shorten telomeres after MI.<br><br>METHODS: Rats were subjected to sham, unilateral (UNX) or 5/6th nephrectomy (5/6NX) to induce none, mild or severe renal failure. MI was induced by left coronary artery ligation. Renal function parameters and blood pressure were measured. DNA was isolated from non-infarcted cardiac tissue. Telomere length was assessed by quantitative polymerase chain reaction (PCR).<br><br>RESULTS: Proteinuria was unchanged in UNX and MI compared with control, but strongly increased in 5/6NX, UNX+MI and 5/6NX+MI. Serum creatinine levels were increased fourfold in 5/6NX and tenfold in 5/6NX+MI. 5/6NX and groups with both renal failure and MI showed an approximate 20% reduction of telomere length, similar to the MI group. No excess telomere shortening was observed in hearts from rats with renal ablation after MI.<br><br>CONCLUSION: Severe renal failure, but not mild renal failure, leads to shortening of cardiac telomeres to a similar extent as found after MI. Renal failure did not induce excessive telomere shortening after MI. (Neth Heart J 2009;17:190-4.).},
}
@article {pmid19482563,
year = {2009},
author = {Denchi, EL},
title = {Give me a break: how telomeres suppress the DNA damage response.},
journal = {DNA repair},
volume = {8},
number = {9},
pages = {1118-1126},
doi = {10.1016/j.dnarep.2009.04.013},
pmid = {19482563},
issn = {1568-7856},
mesh = {Animals ; *DNA Damage ; Eukaryotic Cells/metabolism ; Humans ; Neoplasms/metabolism ; Signal Transduction ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Linear organization of the genome requires mechanisms to protect and replicate chromosome ends. To this end eukaryotic cells evolved telomeres, specialized nucleoproteic complexes, and telomerase, the enzyme that maintains the telomeric DNA. Telomeres allow cells to distinguish chromosome ends from sites of DNA damage. In mammalian cells this is accomplished by a protein complex, termed shelterin, that binds to telomeric DNA and is able to shield chromosome ends from the DNA damage machinery. In recent years, we have seen major advances in our understanding of how this protein complex works due to the generation of mouse models carrying mutations of individual shelterin components. This review will focus on our current understanding of how the shelterin complex is able to suppress the DNA damage response pathways, and on the cellular and organismal outcomes of telomere dysfunction.},
}
@article {pmid19477422,
year = {2009},
author = {Batista, LF and Artandi, SE},
title = {Telomere uncapping, chromosomes, and carcinomas.},
journal = {Cancer cell},
volume = {15},
number = {6},
pages = {455-457},
doi = {10.1016/j.ccr.2009.05.006},
pmid = {19477422},
issn = {1878-3686},
mesh = {Animals ; Carcinoma/*metabolism/pathology ; Cell Transformation, Neoplastic/genetics/*metabolism/pathology ; Chromosomal Instability/genetics/physiology ; Lymphoma/metabolism/pathology ; Mice ; Mice, Transgenic ; Phenotype ; Sarcoma/metabolism/pathology ; Skin Neoplasms/*metabolism/pathology ; Telomere/genetics/*physiology ; Tumor Suppressor Protein p53/genetics/*physiology ; },
abstract = {Data from mouse models and from human cancers have supported the idea that telomere shortening leads to chromosomal instability and epithelial carcinogenesis. In this issue of Cancer Cell, Else et al. demonstrate that telomere uncapping-altering a protein that protects chromosome ends without shortening telomeres-also results in epithelial cancers.},
}
@article {pmid19473118,
year = {2009},
author = {Soler, D and Pampalona, J and Tusell, L and Genescà, A},
title = {Radiation sensitivity increases with proliferation-associated telomere dysfunction in nontransformed human epithelial cells.},
journal = {Aging cell},
volume = {8},
number = {4},
pages = {414-425},
doi = {10.1111/j.1474-9726.2009.00488.x},
pmid = {19473118},
issn = {1474-9726},
mesh = {Cell Line ; Cell Proliferation/*radiation effects ; Cellular Senescence ; DNA Damage ; Epithelial Cells/cytology/metabolism/*radiation effects ; Genome, Human/radiation effects ; Humans ; *Radiation Tolerance ; Telomere/*radiation effects ; },
abstract = {Epidemiological studies have demonstrated age differences among human adults in susceptibility to radiation, with cancer cases attributable to radiation being more frequent for older individuals at time of exposure. In addition to the notion that susceptibility increases because of progressive decline in DNA monitoring and immunosurveillance, telomere function is now emerging as a new and important factor in modulating cellular and organism sensitivity to ionizing radiation. The link between telomeres and radiosensitivity is well-documented in humans, but the causal events remain elusive. In this paper, it is shown that irradiated human epithelial cells with short dysfunctional telomeres derived from normal mammary gland display elevated DNA damage. An approach identifying the specific chromosomes with critically shortened telomeres in each donor has allowed us to conclude that short dysfunctional telomeres in human epithelial cells join radiation-induced DNA broken ends, thus interfering with their efficient repair. These findings argue against telomeres participating as sensors or transducers of DNA damage, as previously suggested. Rather, our current findings give support to the idea that dysfunctional telomeres, by acting as an additional joining option, reduce the repair fidelity of DNA broken-ends induced by radiation throughout the genome. In the mammary gland, age-dependent telomere attrition due to epithelial turnover, together with the accretion of checkpoint deficiencies, might render the accumulation of short dysfunctional telomeres. This implies that the risks associated with mammography screening could be higher than previously assumed. Our results have the possibility of imprinting a temporal dimension onto radiation sensitivity, namely, that shortened telomeres in aged cells may more easily compromise normal tissue function in the elderly.},
}
@article {pmid19468068,
year = {2009},
author = {Jiang, WQ and Zhong, ZH and Nguyen, A and Henson, JD and Toouli, CD and Braithwaite, AW and Reddel, RR},
title = {Induction of alternative lengthening of telomeres-associated PML bodies by p53/p21 requires HP1 proteins.},
journal = {The Journal of cell biology},
volume = {185},
number = {5},
pages = {797-810},
pmid = {19468068},
issn = {1540-8140},
mesh = {Adaptor Proteins, Signal Transducing ; Antigens, Viral, Tumor/metabolism ; Cell Line ; Cellular Senescence/genetics/physiology ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/metabolism/*physiology ; Cyclin-Dependent Kinase 2/analysis/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism/physiology ; Humans ; Nuclear Proteins/analysis/metabolism ; RNA Interference ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/analysis ; Telomeric Repeat Binding Protein 2/analysis ; Tumor Suppressor Protein p53/metabolism/*physiology ; Up-Regulation ; },
abstract = {Alternative lengthening of telomeres (ALT) is a recombination-mediated process that maintains telomeres in telomerase-negative cancer cells. In asynchronously dividing ALT-positive cell populations, a small fraction of the cells have ALT-associated promyelocytic leukemia nuclear bodies (APBs), which contain (TTAGGG)n DNA and telomere-binding proteins. We found that restoring p53 function in ALT cells caused p21 up-regulation, growth arrest/senescence, and a large increase in cells containing APBs. Knockdown of p21 significantly reduced p53-mediated induction of APBs. Moreover, we found that heterochromatin protein 1 (HP1) is present in APBs, and knockdown of HP1alpha and/or HP1gamma prevented p53-mediated APB induction, which suggests that HP1-mediated chromatin compaction is required for APB formation. Therefore, although the presence of APBs in a cell line or tumor is an excellent qualitative marker for ALT, the association of APBs with growth arrest/senescence and with "closed" telomeric chromatin, which is likely to repress recombination, suggests there is no simple correlation between ALT activity level and the number of APBs or APB-positive cells.},
}
@article {pmid19468018,
year = {2009},
author = {Batty, GD and Wang, Y and Brouilette, SW and Shiels, P and Packard, C and Moore, J and Samani, NJ and Ford, I},
title = {Socioeconomic status and telomere length: the West of Scotland Coronary Prevention Study.},
journal = {Journal of epidemiology and community health},
volume = {63},
number = {10},
pages = {839-841},
doi = {10.1136/jech.2009.088427},
pmid = {19468018},
issn = {1470-2738},
support = {MC_U130059821/MRC_/Medical Research Council/United Kingdom ; /BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Aging/*genetics ; Cardiovascular Diseases/epidemiology/*genetics ; Chronic Disease ; Cross-Sectional Studies ; Employment/*statistics &amp; numerical data ; Humans ; Male ; Middle Aged ; Neoplasms/epidemiology/*genetics ; Risk Factors ; Scotland/epidemiology ; Social Class ; Telomere/*genetics ; },
abstract = {BACKGROUND: It has been hypothesised that socioeconomically deprived people age more rapidly than their more advantaged counterparts and this is biologically manifest in shorter telomeres. However, in the very few studies conducted, substantial uncertainty exists regarding this relationship.<br><br>METHODS: In the present investigation, 1542 men in the West of Scotland Coronary Prevention Study responded to a series of enquiries about their socioeconomic position (educational attainment, employment status, area-based deprivation), had their physical stature measured (a proxy for early life social circumstances) and provided a blood specimen from which leucocyte DNA was extracted and telomere length derived.<br><br>RESULTS: There was no strong evidence that any of these four indices of socioeconomic position was robustly related to telomere length. The only exception was employment status: men who reported being out of work had significantly shorter telomeres than those who were employed (p = 0.007).<br><br>CONCLUSION: In this cross-sectional study-the largest to date to examine the relationship-we found little evidence of an association between socioeconomic status and telomere length.},
}
@article {pmid19465904,
year = {2009},
author = {Lee, YH and Oh, BK and Yoo, JE and Yoon, SM and Choi, J and Kim, KS and Park, YN},
title = {Chromosomal instability, telomere shortening, and inactivation of p21(WAF1/CIP1) in dysplastic nodules of hepatitis B virus-associated multistep hepatocarcinogenesis.},
journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},
volume = {22},
number = {8},
pages = {1121-1131},
doi = {10.1038/modpathol.2009.76},
pmid = {19465904},
issn = {1530-0285},
mesh = {Adult ; Blotting, Southern ; Carcinoma, Hepatocellular/*genetics/pathology/virology ; Cell Transformation, Neoplastic/genetics/metabolism/pathology ; Chromosomal Instability ; Cyclin-Dependent Kinase Inhibitor p21/genetics/*metabolism ; Female ; Gene Expression ; Gene Expression Profiling ; Gene Silencing ; Hepatitis B, Chronic/complications/*genetics/pathology ; Humans ; Immunohistochemistry ; Liver Neoplasms/*genetics/pathology/virology ; Male ; Micronuclei, Chromosome-Defective ; Middle Aged ; Precancerous Conditions/*genetics/pathology/virology ; Telomere/*pathology ; },
abstract = {Systemic analysis for chromosomal instability and inactivation of cell cycle checkpoints are scarce during hepatocarcinogenesis. We studied 24 patients with chronic B viral cirrhosis including 30 cirrhotic regenerative nodules, 35 low-grade dysplastic nodules, 15 high-grade dysplastic nodules, 7 dysplastic nodules with hepatocellular carcinoma foci, and 18 hepatocellular carcinomas. Eight normal livers were studied as the control group. Telomere length and micronuclei were detected by Southern blot and Feulgen-fast green dyeing technique, respectively, and p21(WAF1/CIP1) expression was studied by immunohistochemistry. Micronuclei >1 per 3000 hepatocytes were found in 17% of low-grade dysplastic nodules, 87% of high-grade dysplastic nodules, and 100% of high-grade dysplastic nodules with hepatocellular carcinoma foci and hepatocellular carcinomas in contrast to those of all normal livers, and 90% of cirrhosis showed no micronuclei. The micronuclei index showed a gradual increase during hepatocarcinogenesis and there was a significant increase between cirrhosis and low-grade dysplastic nodules, low-grade dysplastic nodules and high-grade dysplastic nodules, and high-grade dysplastic nodules and hepatocellular carcinomas. Telomere length showed a gradual shortening during hepatocarcinogenesis and a significant reduction was found in high-grade dysplastic nodules (P=0.024) and hepatocellular carcinomas (P=0.031) compared with normal and cirrhotic livers. The micronuclei index was correlated with telomere shortening (P=0.016). The p21(WAF1/CIP1) labeling index was significantly higher in cirrhosis than in normal livers (P=0.024) and markedly decreased in low-grade dysplastic nodules, high-grade dysplastic nodules, and hepatocellular carcinomas compared with cirrhosis (P<0.05). The p21(WAF1/CIP1) labeling index was associated with telomere length (P<0.001) but not micronuclei index. This study shows that telomere shortening, chromosomal instability, and inactivation of p21(WAF1/CIP1) checkpoint function occur in low-grade dysplastic nodules as well as in high-grade dysplastic nodules, and their cooperation is considered to be critical for malignant transformation during hepatitis B virus associated-multistep hepatocarcinogenesis.},
}
@article {pmid19464579,
year = {2009},
author = {Ferrario, D and Collotta, A and Carfi, M and Bowe, G and Vahter, M and Hartung, T and Gribaldo, L},
title = {Arsenic induces telomerase expression and maintains telomere length in human cord blood cells.},
journal = {Toxicology},
volume = {260},
number = {1-3},
pages = {132-141},
doi = {10.1016/j.tox.2009.03.019},
pmid = {19464579},
issn = {1879-3185},
mesh = {Apoptosis/drug effects ; Arsenites/*toxicity ; Blotting, Western ; Buthionine Sulfoximine/pharmacology ; Cell Survival/drug effects ; Cyclic N-Oxides/pharmacology ; Enzyme Induction/drug effects ; Enzyme Inhibitors/pharmacology ; Female ; Fetal Blood/*drug effects/enzymology ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Humans ; Male ; Proto-Oncogene Proteins c-myc/biosynthesis/genetics ; RNA, Messenger/biosynthesis/genetics ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Sex Factors ; Sodium Compounds/*toxicity ; Stem Cells/drug effects/enzymology ; Telomerase/*biosynthesis/genetics ; Telomere/*drug effects/metabolism ; ras Proteins/biosynthesis/genetics ; },
abstract = {Inorganic arsenic (iAs) is a human carcinogen, well known as a clastogenic compound. To evaluate the molecular mechanism of arsenite (iAs(III)) toxicity, we investigated the effects on cell growth and apoptosis, telomere length, telomerase expression, as well as the formation of reactive oxygen species (ROS) in male and female human cord blood cells in vitro. Incubation with iAs(III) at the concentration of 0.0001 microM increased telomerase mRNA and protein expression maintained both telomere length and cellular growth, and induced mRNA over-expression of the two oncogenes ras and myc. Our results suggest that female cord blood cells are more sensitive than male ones to iAs(III) induced telomerase stimulation at low concentrations, possibly related to the increased expression of ras and myc oncogenes. On the contrary, at the concentration of 1 microM, iAs(III) decreased telomerase expression and telomere length, and induced apoptosis, necrosis and production of reactive oxygen species. Buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, markedly increased the percentage of apoptotic cells, suggesting that GSH is fundamental for detoxification of iAs(III) in cord blood cells. The reactive oxygen species (ROS) scavenger, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), protected cord blood cells from iAs(III) toxicity, and prevented telomere shortening and telomerase down-modulation. It can be concluded that telomerase expression and telomere length are associated with iAs(III) induced cell death, via production of reactive oxygen species, as well as with iAs(III) induced effects on cell differentiation processes and rate of cell growth.},
}
@article {pmid19464008,
year = {2009},
author = {Olivieri, F and Lorenzi, M and Antonicelli, R and Testa, R and Sirolla, C and Cardelli, M and Mariotti, S and Marchegiani, F and Marra, M and Spazzafumo, L and Bonfigli, AR and Procopio, A},
title = {Leukocyte telomere shortening in elderly Type2DM patients with previous myocardial infarction.},
journal = {Atherosclerosis},
volume = {206},
number = {2},
pages = {588-593},
doi = {10.1016/j.atherosclerosis.2009.03.034},
pmid = {19464008},
issn = {1879-1484},
mesh = {Aged ; Blood Glucose/metabolism ; Diabetes Mellitus, Type 2/*genetics ; Female ; Glycated Hemoglobin/metabolism ; Humans ; Leukocytes/metabolism ; Male ; Middle Aged ; Myocardial Infarction/*genetics ; Telomere/*metabolism ; Waist-Hip Ratio ; },
abstract = {OBJECTIVE: We performed a cross-sectional study to examine the differences in leukocyte telomere length among three groups of subjects: patients with type 2 diabetes mellitus without history of previous myocardial infarction (Type2DM), patients with type 2 diabetes mellitus with evidence of previous myocardial infarction (Type2DM+MI), and healthy control subjects (CTR). The main objective of the present study is to investigate differences in telomere length between the studied groups of subjects, with the aim to clarify if telomere length could be a reliable marker associated with MI in Type2DM patients. Secondary end point is the identification of associations between leukocyte telomere length and selected variables related to glycemic control, pro-inflammatory status and lipidic profile.<br><br>RESEARCH DESIGN AND METHODS: A total of 272 elderly subjects, 103 Type2DM (mean age 70+/-4 years, 59% males), 65 Type2DM+MI (mean age 68+/-7 years, 68% males), and 104 CTR (mean age 69+/-7 years, 50% males) were studied. Telomere length, defined as T/S (Telomere-Single copy gene ratio), was determined in leukocytes by quantitative real-time polymerase chain reaction (real-time PCR)-based assay. Moreover, we assessed: (1) high sensitive C reactive protein (hsCRP), fibrinogen and plasminogen-activator inibitor-1 (PAI-1) as inflammatory markers; (2) fasting glucose, insulin, glycated haemoglobin (HbA1C) and waist-to-hip ratio as markers of glycemic control; (3) total-cholesterol, HDL-cholesterol and triglycerides as markers of lipidic profile, in all sample population. The use of statins and sulfonylurea, as well as the presence of some relevant diabetes complications (nephropathy and retinopathy) were also assessed.<br><br>CONCLUSION: Type2DM+MI elderly patients have leukocyte telomere lengths shorter than those of Type2DM (without MI) and healthy CTR. Moreover, glucose, HbA1C and waist-to-hip ratio, variables related to glycemic control, showed a significant inverse correlation with leukocyte telomeres length.},
}
@article {pmid19463156,
year = {2009},
author = {Pollicita, M and Muscoli, C and Sgura, A and Biasin, A and Granato, T and Masuelli, L and Mollace, V and Tanzarella, C and Del Duca, C and Rodinò, P and Perno, CF and Aquaro, S},
title = {Apoptosis and telomeres shortening related to HIV-1 induced oxidative stress in an astrocytoma cell line.},
journal = {BMC neuroscience},
volume = {10},
number = {},
pages = {51},
pmid = {19463156},
issn = {1471-2202},
mesh = {Acetylcysteine/pharmacology ; Analysis of Variance ; Antiviral Agents/pharmacology ; Apoptosis/drug effects/*physiology ; Astrocytoma/*pathology/ultrastructure ; Cell Line, Tumor ; Enzyme-Linked Immunosorbent Assay ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; HIV-1/*metabolism ; Humans ; Microscopy, Electron/methods ; Oxidative Stress/drug effects/*physiology ; Telomere/drug effects/*pathology ; Time Factors ; },
abstract = {BACKGROUND: Oxidative stress plays a key role in the neuropathogenesis of Human Immunodeficiency Virus-1 (HIV-1) infection causing apoptosis of astroglia cells and neurons. Recent data have shown that oxidative stress is also responsible for the acceleration of human fibroblast telomere shortening in vitro. In the present study we analyzed the potential relations occurring between free radicals formation and telomere length during HIV-1 mediated astroglial death.<br><br>RESULTS: To this end, U373 human astrocytoma cells have been directly exposed to X4-using HIV-1IIIB strain, for 1, 3 or 5 days and treated (where requested) with N-acetylcysteine (NAC), a cysteine donor involved in the synthesis of glutathione (GSH, a cellular antioxidant) and apoptosis has been evaluated by FACS analysis. Quantitative-FISH (Q-FISH) has been employed for studying the telomere length while intracellular reduced/oxidized glutathione (GSH/GSSG) ratio has been determined by High-Performance Liquid Chromatography (HPLC). Incubation of U373 with HIV-1IIIB led to significant induction of cellular apoptosis that was reduced in the presence of 1 mM NAC. Moreover, NAC improved the GSH/GSSG, a sensitive indicator of oxidative stress, that significantly decreased after HIV-1IIIB exposure in U373. Analysis of telomere length in HIV-1 exposed U373 showed a statistically significant telomere shortening, that was completely reverted in NAC-treated U373.<br><br>CONCLUSION: Our results support the role of HIV-1-mediated oxidative stress in astrocytic death and the importance of antioxidant compounds in preventing these cellular damages. Moreover, these data indicate that the telomere structure, target for oxidative damage, could be the key sensor of cell apoptosis induced by oxidative stress after HIV infection.},
}
@article {pmid19461895,
year = {2009},
author = {Lamm, N and Ordan, E and Shponkin, R and Richler, C and Aker, M and Tzfati, Y},
title = {Diminished telomeric 3' overhangs are associated with telomere dysfunction in Hoyeraal-Hreidarsson syndrome.},
journal = {PloS one},
volume = {4},
number = {5},
pages = {e5666},
pmid = {19461895},
issn = {1932-6203},
mesh = {Adult ; Blood Cells/metabolism ; Cell Proliferation ; Cells, Cultured ; Child ; Child, Preschool ; Dyskeratosis Congenita/genetics/pathology/*physiopathology ; Enzyme Activation ; Female ; Fibroblasts/enzymology/pathology ; Humans ; Male ; Mutation/genetics ; Pedigree ; RNA/metabolism ; Siblings ; Skin/enzymology/pathology ; Syndrome ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Eukaryotic chromosomes end with telomeres, which in most organisms are composed of tandem DNA repeats associated with telomeric proteins. These DNA repeats are synthesized by the enzyme telomerase, whose activity in most human tissues is tightly regulated, leading to gradual telomere shortening with cell divisions. Shortening beyond a critical length causes telomere uncapping, manifested by the activation of a DNA damage response (DDR) and consequently cell cycle arrest. Thus, telomere length limits the number of cell divisions and provides a tumor-suppressing mechanism. However, not only telomere shortening, but also damaged telomere structure, can cause telomere uncapping. Dyskeratosis Congenita (DC) and its severe form Hoyeraal-Hreidarsson Syndrome (HHS) are genetic disorders mainly characterized by telomerase deficiency, accelerated telomere shortening, impaired cell proliferation, bone marrow failure, and immunodeficiency.<br><br>We studied the telomere phenotypes in a family affected with HHS, in which the genes implicated in other cases of DC and HHS have been excluded, and telomerase expression and activity appears to be normal. Telomeres in blood leukocytes derived from the patients were severely short, but in primary fibroblasts they were normal in length. Nevertheless, a significant fraction of telomeres in these fibroblasts activated DDR, an indication of their uncapped state. In addition, the telomeric 3' overhangs are diminished in blood cells and fibroblasts derived from the patients, consistent with a defect in telomere structure common to both cell types.<br><br>CONCLUSIONS/SIGNIFICANCE: Altogether, these results suggest that the primary defect in these patients lies in the telomere structure, rather than length. We postulate that this defect hinders the access of telomerase to telomeres, thus causing accelerated telomere shortening in blood cells that rely on telomerase to replenish their telomeres. In addition, it activates the DDR and impairs cell proliferation, even in cells with normal telomere length such as fibroblasts. This work demonstrates a telomere length-independent pathway that contributes to a telomere dysfunction disease.},
}
@article {pmid19458273,
year = {2009},
author = {Borie, R and Crestani, B and Bichat, H},
title = {Prevalence of telomere shortening in familial and sporadic pulmonary fibrosis is increased in men.},
journal = {American journal of respiratory and critical care medicine},
volume = {179},
number = {11},
pages = {1073},
doi = {10.1164/ajrccm.179.11.1073},
pmid = {19458273},
issn = {1535-4970},
mesh = {Androgens/*physiology ; Estrogens/physiology ; Female ; Genetic Predisposition to Disease/genetics ; Humans ; Male ; Pulmonary Fibrosis/*genetics ; Sex Distribution ; Telomerase/*genetics ; },
}
@article {pmid19458030,
year = {2009},
author = {Paul, L and Cattaneo, M and D'Angelo, A and Sampietro, F and Fermo, I and Razzari, C and Fontana, G and Eugene, N and Jacques, PF and Selhub, J},
title = {Telomere length in peripheral blood mononuclear cells is associated with folate status in men.},
journal = {The Journal of nutrition},
volume = {139},
number = {7},
pages = {1273-1278},
doi = {10.3945/jn.109.104984},
pmid = {19458030},
issn = {1541-6100},
mesh = {Cellular Senescence ; DNA/genetics ; Folic Acid/blood/*metabolism ; Genotype ; Homocysteine/blood ; Humans ; Leukocytes, Mononuclear/*cytology ; Male ; Methylenetetrahydrofolate Reductase (NADPH2)/genetics ; Polymerase Chain Reaction ; *Polymorphism, Single Nucleotide ; RNA/genetics ; Telomere/*ultrastructure ; Vitamin B 12/blood ; beta-Globins/genetics ; },
abstract = {Human chromosomes are capped by telomeres, which consist of tandem repeats of DNA and associated proteins. The length of the telomeres is reduced with increasing cell divisions except when the enzyme telomerase is active, as in stem cells and germ cells. Telomere dysfunction has been associated with development of age-related pathologies, including cancer, cardiovascular disease, Alzheimer's disease, and Parkinson's disease. DNA damage in the telomeric region causes attrition of telomeres. Because folate provides precursors for nucleotide synthesis and thus affects the integrity of DNA, including that of the telomeric region, folate status has the potential to influence telomere length. Telomere length is epigenetically regulated by DNA methylation, which in turn could be modulated by folate status. In this study, we determined whether folate status and the 677C > T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene are associated with the telomere length of peripheral blood mononuclear cells in healthy men. The results of our study showed that plasma concentration of folate was associated with telomere length of peripheral blood mononuclear cells in a nonlinear manner. When plasma folate concentration was above the median, there was a positive relationship between folate and telomere length. In contrast, there was an inverse relationship between folate and telomere length when plasma folate concentration was below the median. The MTHFR 677C > T polymorphism was weakly associated (P = 0.065) with increased telomere length at below-median folate status. We propose that folate status influences telomere length by affecting DNA integrity and the epigenetic regulation of telomere length through DNA methylation.},
}
@article {pmid19452298,
year = {2009},
author = {Amiel, A and Fejgin, MD and Goldberg-Bittman, L and Sharoni, R and Hadary, R and Kitay-Cohen, Y},
title = {Telomere aggregates in hepatitis C patients.},
journal = {Cancer investigation},
volume = {27},
number = {6},
pages = {650-654},
doi = {10.1080/07357900802350806},
pmid = {19452298},
issn = {1532-4192},
mesh = {Antiviral Agents/therapeutic use ; Cell Transformation, Viral/genetics ; Cells, Cultured ; Hepatitis C, Chronic/diagnosis/drug therapy/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes/*ultrastructure/virology ; Lymphoma, Non-Hodgkin/genetics ; Middle Aged ; Telomere/*ultrastructure ; Treatment Outcome ; },
abstract = {Telomeres of tumor nuclei tend to form aggregates (TA). The aim of this study was to estimate the TA formation in leukocytes of patients with chronic hepatitis C (HCV) which is considered to be premalignant disease, in patients of HCV who eradicated the virus. PNA Telomere kit (Dako) was used to evaluate the TA formation with the utilization of 2D fluorescence microscopy. A higher rate of TA was found in both HCV groups as compared to controls. Our results indicate that HCV patients have some of the components that create the cascade of events leading to malignancies.},
}
@article {pmid19446739,
year = {2009},
author = {Goldberg-Bittman, L and Amiel, A and Hadary, R and Fejgin, MD and Quitt, M and Kitay-Cohen, Y},
title = {Telomere capture in hepatitis C infection.},
journal = {Cancer genetics and cytogenetics},
volume = {191},
number = {2},
pages = {63-66},
doi = {10.1016/j.cancergencyto.2009.01.013},
pmid = {19446739},
issn = {1873-4456},
mesh = {Cell Culture Techniques ; Chromosomal Instability/*genetics ; Chromosomes, Human ; Hepatitis C/genetics/*pathology ; Hepatitis C, Chronic/genetics/pathology ; Humans ; In Situ Hybridization, Fluorescence ; Lymphocytes/cytology/pathology ; Lymphoma, Non-Hodgkin/genetics/*pathology ; Recombination, Genetic ; Reference Values ; Telomere/*genetics/*pathology ; Translocation, Genetic ; },
abstract = {Broken chromosomes can acquire new telomeres by "telomere capture" (TC), and it has become possible to investigate the terminus in cytogenetically visible telomere rearrangements. The TC phenomenon was observed in malignant conditions. We evaluated the TC rate in hepatitis C virus (HCV) patients compared to non-Hodgkin's lymphoma patients, as well as relative to a control group. For this purpose, we used two Cytocell probes, 15qter and 13qter. Higher TC rates were found in the three study groups relative to the control group. Our results showed that HCV patients have some of the components that can initiate the cascade of events leading to malignancies.},
}
@article {pmid19442255,
year = {2009},
author = {Royle, NJ and Méndez-Bermúdez, A and Gravani, A and Novo, C and Foxon, J and Williams, J and Cotton, V and Hidalgo, A},
title = {The role of recombination in telomere length maintenance.},
journal = {Biochemical Society transactions},
volume = {37},
number = {Pt 3},
pages = {589-595},
doi = {10.1042/BST0370589},
pmid = {19442255},
issn = {1470-8752},
support = {//Biotechnology and Biological Sciences Research Council/United Kingdom ; //Cancer Research UK/United Kingdom ; //Medical Research Council/United Kingdom ; },
mesh = {Acid Anhydride Hydrolases ; Cell Line ; Cellular Senescence/genetics ; *DNA Damage ; DNA Repair ; DNA Repair Enzymes/metabolism ; DNA-Binding Proteins/metabolism ; Humans ; MRE11 Homologue Protein ; Models, Biological ; *Recombination, Genetic ; Telomere/genetics/*metabolism ; },
abstract = {Human telomeres shorten during each cell division, predominantly because of incomplete DNA replication. This eventually results in short uncapped telomeres that elicit a DNA-damage response, leading to cellular senescence. However, evasion of senescence results in continued cell division and telomere erosion ultimately results in genome instability. In the long term, this genome instability is not sustainable, and cancer cells activate a TMM (telomere maintenance mechanism), either expression of telomerase or activation of the ALT (alternative lengthening of telomeres) pathway. Activation of the ALT mechanism results in deregulation of recombination-based activities at telomeres. Thus ALT+ cells show elevated T-SCE (telomere sister-chromatid exchange), misprocessing of t-loops that cap chromosomes and recombination-based processes between telomeres or between telomeres and ECTRs (extrachromosomal telomeric repeats). Some or all of these processes underlie the chaotic telomere length maintenance that allows cells in ALT+ tumours unlimited replicative capacity. ALT activation is also associated with destabilization of a minisatellite, MS32. The connection between the minisatellite instability and the deregulation of recombination-based activity at telomeres is not understood, but analysis of the minisatellite can be used as a marker for ALT. It is known that telomere length maintenance in ALT+ cells is dependent on the MRN [MRE11 (meiotic recombination 11)-Rad50-NBS1 (Nijmegen breakage syndrome 1)] complex, but knowledge of the role of other genes, including the Werner's (WRN) and Bloom's (BLM) syndrome DNA helicase genes, is still limited.},
}
@article {pmid19436937,
year = {2010},
author = {Tang, NL and Woo, J and Suen, EW and Liao, CD and Leung, JC and Leung, PC},
title = {The effect of telomere length, a marker of biological aging, on bone mineral density in elderly population.},
journal = {Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA},
volume = {21},
number = {1},
pages = {89-97},
pmid = {19436937},
issn = {1433-2965},
mesh = {Aged ; Aging/*genetics/physiology ; Bone Density/*genetics/physiology ; Female ; Femur Neck/physiopathology ; Follow-Up Studies ; Hip Joint/physiopathology ; Humans ; Leukocytes/ultrastructure ; Male ; Osteoporosis/*genetics/physiopathology ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Telomere/*ultrastructure ; },
abstract = {UNLABELLED: Telomere length (TL), as a reflection of aging and inflammatory processes, may be associated with bone mineral density (BMD). This study examines the association between TL and BMD cross-sectionally and the rate of bone loss over a 4-year period in 1,867 Chinese elderly community living subjects. After adjusting for confounding factors, no association was observed with BMD or bone loss. The decline in BMD with aging is not reflected by corresponding changes in telomere length.<br><br>INTRODUCTION: Bone mineral density (BMD) is influenced by the dynamics of aging, inflammatory, and bone remodeling processes. Telomere length (TL) is a reflection of the former two processes and may also be associated with bone loss.<br><br>METHODS: Hip BMD was measured in 1,867 Chinese elderly community living subjects and the relationship between leukocyte TL measured using quantitative real-time polymerase chain reaction, and bone loss after 4 years was examined.<br><br>RESULTS: Women had greater bone loss than men. In women, age of menopause, menarche, estrogen treatment/replacement therapy, and history of previous fracture were also among the significant covariates. However, in multivariate analyses, TL was not associated with BMD in either sex.<br><br>CONCLUSIONS: TL was not associated with either baseline BMD or bone loss over 4 years and accounted for less than 1.6% of the baseline BMD.},
}
@article {pmid19435952,
year = {2009},
author = {Mollica, L and Fleury, I and Belisle, C and Provost, S and Roy, DC and Busque, L},
title = {No association between telomere length and blood cell counts in elderly individuals.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {64},
number = {9},
pages = {965-967},
doi = {10.1093/gerona/glp065},
pmid = {19435952},
issn = {1758-535X},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*blood/*genetics ; *Blood Cell Count ; Female ; Humans ; Middle Aged ; *Telomere ; },
abstract = {BACKGROUND: Telomeres play a crucial role in maintaining the physical integrity of chromosomes. Telomere length (TL) is severely reduced in individuals with dyskeratosis congenita and a number of other bone marrow failure syndromes. The TL of healthy individuals is highly variable, but shortens with age. It is presently unclear if variations in TL observed in normal aging individuals affect significantly their hematopoietic reserve. Method We studied the correlation between leukocyte age-adjusted TL (aTL) and blood cell parameters (total leukocytes, neutrophils, monocytes, eosinophils, lymphocytes, hemoglobin, and platelets) in a large cohort (n=717) of women aged 38-100 years. Result We did not find any significant correlation between aTL and blood counts.<br><br>CONCLUSION: Our data suggest that the aTL of aging individuals is not significantly predictive of their hematopoietic reserve, which implies that TL measurement may not be clinically useful in the selection of hematopoietic stem cell transplantation donors.},
}
@article {pmid19435951,
year = {2009},
author = {Njajou, OT and Hsueh, WC and Blackburn, EH and Newman, AB and Wu, SH and Li, R and Simonsick, EM and Harris, TM and Cummings, SR and Cawthon, RM and , },
title = {Association between telomere length, specific causes of death, and years of healthy life in health, aging, and body composition, a population-based cohort study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {64},
number = {8},
pages = {860-864},
pmid = {19435951},
issn = {1758-535X},
support = {N01-AG-6-2101/AG/NIA NIH HHS/United States ; U19 AG023122/AG/NIA NIH HHS/United States ; N01-AG-6-2103/AG/NIA NIH HHS/United States ; K01 AG22782/AG/NIA NIH HHS/United States ; //Intramural NIH HHS/United States ; R01 AG023692/AG/NIA NIH HHS/United States ; N01-AG-6-2106/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; *Aging ; *Body Composition ; *Cause of Death ; Cohort Studies ; Female ; *Health Status ; Humans ; Male ; *Telomere ; },
abstract = {Although telomere length (TL) is known to play a critical role in cellular senescence, the relationship of TL to aging and longevity in humans is not well understood. In a large biracial population-based cohort, we tested the hypotheses that elderly persons with shorter TL in peripheral white blood cells have poorer survival, shorter life span, and fewer years of healthy life (YHL). Associations were evaluated using Cox proportional hazard models and linear regression analyses where appropriate. TL (in kilo base pairs) was not associated with overall survival (hazard ratio 1.0; 95% confidence interval 0.9-1.1) or death from any specific underlying cause including infectious diseases, cancer, or cardiac and cerebrovascular diseases. TL, however, was positively associated with more YHL (beta = 0.08 +/- 0.04, p = .03). Findings suggest that TL may not be a strong biomarker of survival in older individuals, but it may be an informative biomarker of healthy aging.},
}
@article {pmid19432888,
year = {2009},
author = {Liu, X and Bao, G and Huo, T and Wang, Z and He, X and Dong, G},
title = {Constitutive telomere length and gastric cancer risk: case-control analysis in Chinese Han population.},
journal = {Cancer science},
volume = {100},
number = {7},
pages = {1300-1305},
doi = {10.1111/j.1349-7006.2009.01169.x},
pmid = {19432888},
issn = {1349-7006},
mesh = {Adult ; Aged ; Aged, 80 and over ; Asian People/genetics ; Case-Control Studies ; China/epidemiology ; Female ; Humans ; Logistic Models ; Male ; Middle Aged ; Risk Factors ; Smoking/adverse effects ; Stomach Neoplasms/ethnology/*genetics ; Telomere/*chemistry ; },
abstract = {The shortening of telomeres may result in chromosome instability and thus promote tumorigenesis. Previous studies have demonstrated clear involvement of telomere shortening in the carcinogenesis of several malignancies. However, the association between constitutive telomere shortening and gastric cancer development has yet to be established. Therefore, in the present study, we measured average telomere length using quantitative real-time PCR in peripheral blood lymphocytes from a gastric cancer (GC) case-control study consisting of 396 cases and 378 controls. The results showed that GC patients had significantly shorter average telomere length than matched controls (mean +/- SD 0.89 +/- 0.19 vs 1.06 +/- 0.25, P < 0.001). We further categorized telomere length using the 50% value in the controls as a cut-off point and assessed the association between telomere length and GC risk using multivariate logistic regression analysis. We found that short telomere length was associated with a significantly increased GC risk (adjusted odds ratio = 2.14, 95% confidence interval = 1.52-2.93). Quartile stratification revealed a dose-response relationship between telomere shortening and GC risk (P for trend < 0.001). Stratified analysis showed that sex, age, and alcohol drinking, but not smoking and Helicobacter pylori infection, seem to have a modulating effect on the average telomere length in both cases and controls. We also found that telomere shortening and smoking had a significant joint effect on GC risk. Collectively, our findings provide the first evidence linking the short telomere length in peripheral blood lymphocytes to elevated GC risk, which warrants further investigation in other populations.},
}
@article {pmid19428457,
year = {2009},
author = {Decker, ML and Chavez, E and Vulto, I and Lansdorp, PM},
title = {Telomere length in Hutchinson-Gilford progeria syndrome.},
journal = {Mechanisms of ageing and development},
volume = {130},
number = {6},
pages = {377-383},
doi = {10.1016/j.mad.2009.03.001},
pmid = {19428457},
issn = {1872-6216},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Case-Control Studies ; Cell Line ; Child ; Child, Preschool ; Fibroblasts/*metabolism ; Granulocytes/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; Infant, Newborn ; Lamin Type A/*genetics ; Middle Aged ; *Mutation ; Progeria/*genetics ; T-Lymphocytes/metabolism ; Telomere/*metabolism ; Young Adult ; },
abstract = {Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disorder caused by mutations in the gene LMNA, which encodes the nuclear matrix protein lamin A. Previous research has shown that the average telomere length in fibroblasts from HGPS patients is shorter than in age-matched controls. How mutations in lamin A lead to shortened telomere lengths is not known nor is the contribution of individual chromosome ends to the low average length understood. To measure the telomere length of individual chromosomes, we used quantitative fluorescence in situ hybridization (Q-FISH). In agreement with previous studies, we found that the average telomere length in HPGS fibroblasts is greatly reduced; however, the telomere length at chromosome ends was variable. In contrast, the telomere length in hematopoietic cells which typically do not express lamin A, was within the normal range for three out of four HGPS patient samples. Our results suggest that mutant lamin A decreases telomere length via a direct effect and that expression of mutant LMNA is necessary for telomere loss in HGPS.},
}
@article {pmid19428446,
year = {2009},
author = {Hartmann, N and Reichwald, K and Lechel, A and Graf, M and Kirschner, J and Dorn, A and Terzibasi, E and Wellner, J and Platzer, M and Rudolph, KL and Cellerino, A and Englert, C},
title = {Telomeres shorten while Tert expression increases during ageing of the short-lived fish Nothobranchius furzeri.},
journal = {Mechanisms of ageing and development},
volume = {130},
number = {5},
pages = {290-296},
doi = {10.1016/j.mad.2009.01.003},
pmid = {19428446},
issn = {1872-6216},
mesh = {Animals ; Base Sequence ; Conserved Sequence ; Cyprinodontiformes/genetics/*physiology ; *Gene Expression Regulation, Enzymologic ; Longevity/*genetics ; Telomerase/*genetics ; Telomere/enzymology/*ultrastructure ; },
abstract = {Age research in vertebrates is often limited by the longevity of available models. The teleost fish Nothobranchius furzeri has an exceptionally short lifespan with 3.5 months for the laboratory strain GRZ and about 6 months for the wild-derived strain MZM-0403. Here we have investigated telomere length in muscle and skin tissue of young and old fish of both strains using different methods. We found age-dependent telomere shortening in the MZM-0403 strain with the longer lifespan, whereas the short-lived GRZ strain showed no significant telomere shortening with advanced age. Sequencing of the two main telomerase genes Tert and Terc revealed that both genes are highly conserved between the N. furzeri strains while there is little conservation to other fish species and humans. Both genes are ubiquitously expressed in N. furzeri and expression levels of Tert and Terc correlate with telomerase activity in a tissue-specific manner. Unexpectedly, the expression level of Tert is increased in aged muscle and skin tissue of MZM-0403 suggesting that telomeres shorten upon ageing despite increased Tert expression and hence high telomerase activity. We further conclude that the extremely short lifespan of the GRZ strain is not caused by diminished telomerase activity or accelerated telomere shortening.},
}
@article {pmid19424630,
year = {2009},
author = {Tang, T and Zhou, FX and Lei, H and Yu, HJ and Xie, CH and Zhou, YF and Liu, SQ},
title = {Increased expression of telomere-related proteins correlates with resistance to radiation in human laryngeal cancer cell lines.},
journal = {Oncology reports},
volume = {21},
number = {6},
pages = {1505-1509},
doi = {10.3892/or_00000381},
pmid = {19424630},
issn = {1021-335X},
mesh = {Blotting, Western ; Carcinoma, Squamous Cell/genetics/*metabolism/pathology ; Cell Cycle/radiation effects ; Cell Line, Tumor ; Cell Proliferation/radiation effects ; Cell Survival/radiation effects ; Dose-Response Relationship, Radiation ; Gene Expression Regulation, Neoplastic/radiation effects ; Humans ; Laryngeal Neoplasms/genetics/*metabolism/pathology ; *Radiation Tolerance ; Reverse Transcriptase Polymerase Chain Reaction ; Shelterin Complex ; Telomere-Binding Proteins/genetics/metabolism/*radiation effects ; Up-Regulation ; },
abstract = {Telomere-associated proteins function as survival factors in telomere maintenance, which are major contributors to radiosensitivity in human cancers. The aim of this study was to investigate the association of telomere-associated gene expression and radiation resistance in human larynx squamous carcinoma. The changes of telomere-associated gene expressions and bionomical characteristics that occur in two human larynx squamous carcinoma cell lines (Hep-2 and Hep-2R), with different radiosensitivities in vitro were explored in the present study. Based on previous research, elevated POT1 and TPP1 expressions were detected by reverse transcription-PCR and Western blotting in Hep-2R cell lines. Furthermore, Hep-2R cells showed increased recovery ratio accompanied by a reduction of cell arrested in G2/S phase, suggesting that the radioresistance of Hep-2R cells was due to a faster growth in which telomere length had recently been demonstrated to be a powerful prognostic marker. These results manifest that radioresistant Hep-2R cell lines showed certain changes in gene expression and bionomical profiles that are different from the profile changes of the more-sensitive Hep-2 cell lines, and that evaluation of telomere-associated genes may be a prognostic marker for response to radiotherapy in larynx squamous cell carcinoma (LSCC).},
}
@article {pmid19423724,
year = {2009},
author = {Antoniou, KM and Papadaki, HA and Soufla, G and Siafakas, NM},
title = {Short telomeres and treatment of pulmonary fibrosis: implications for early intervention.},
journal = {American journal of respiratory and critical care medicine},
volume = {179},
number = {10},
pages = {970},
doi = {10.1164/ajrccm.179.10.970},
pmid = {19423724},
issn = {1535-4970},
mesh = {Genetic Predisposition to Disease ; Humans ; Pulmonary Fibrosis/*genetics/therapy ; Telomere/*genetics ; },
}
@article {pmid19420923,
year = {2009},
author = {Gebre-Medhin, S and Broberg, K and Jonson, T and Gorunova, L and von Steyern, FV and Brosjö, O and Jin, Y and Gisselsson, D and Panagopoulos, I and Mandahl, N and Mertens, F},
title = {Telomeric associations correlate with telomere length reduction and clonal chromosome aberrations in giant cell tumor of bone.},
journal = {Cytogenetic and genome research},
volume = {124},
number = {2},
pages = {121-127},
doi = {10.1159/000207516},
pmid = {19420923},
issn = {1424-859X},
mesh = {Adolescent ; Adult ; *Chromosome Aberrations ; Chromosome Banding ; Clone Cells ; Female ; Gene Expression Regulation, Neoplastic ; Giant Cell Tumor of Bone/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Reverse Transcriptase Polymerase Chain Reaction ; Shelterin Complex ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; },
abstract = {Giant cell tumor of bone (GCTB) is characterized cytogenetically by frequent telomeric associations (tas). To explore the mechanisms behind the formation of tas in GCTB and to investigate their karyotypic consequences, the frequencies of tas and clonal aberrations other than tas in 20 GCTBs were compared to telomere length and status, as assessed by quantitative PCR, fluorescence in situ hybridization (FISH), and expression levels of four genes involved in telomere maintenance. Based on the G-banding results, the tumors were divided into two groups, one with a high frequency of tas and one with a low frequency. Clonal aberrations were found to be restricted to the group with a high level of tas, and the same group showed a significantly larger reduction in telomere length in tumor cells compared to peripheral blood cells. Furthermore, 65 out of 66 tas analyzed by FISH were negative for telomeric sequences. The expression levels of TERT, TERF1, TERF2, and POT1 did not correlate with telomere length or the frequency of tas. Thus, the present findings provide strong support for the notion that decreased telomere length is a prerequisite for tas in GCTBs and that the clonal changes occurring in GCTBs are derived from tas.},
}
@article {pmid19419704,
year = {2009},
author = {Kirwan, M and Dokal, I},
title = {Dyskeratosis congenita, stem cells and telomeres.},
journal = {Biochimica et biophysica acta},
volume = {1792},
number = {4},
pages = {371-379},
pmid = {19419704},
issn = {0006-3002},
support = {//Wellcome Trust/United Kingdom ; //Medical Research Council/United Kingdom ; },
mesh = {Anemia, Aplastic/genetics/metabolism/pathology ; Bone Marrow/metabolism/pathology ; Bone Marrow Diseases/genetics/metabolism/pathology ; Cell Cycle Proteins/genetics/metabolism ; Dyskeratosis Congenita/genetics/*metabolism/pathology ; Humans ; Idiopathic Pulmonary Fibrosis/genetics/metabolism/pathology ; Nuclear Proteins/genetics/metabolism ; Shelterin Complex ; Stem Cells/*metabolism/pathology ; Telomerase/genetics/*metabolism ; Telomere/*metabolism/pathology ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Dyskeratosis congenita (DC) is a multi-system disorder which in its classical form is characterised by abnormalities of the skin, nails and mucous membranes. In approximately 80% of cases, it is associated with bone marrow dysfunction. A variety of other abnormalities (including bone, brain, cancer, dental, eye, gastrointestinal, immunological and lung) have also been reported. Although first described almost a century ago it is the last 10 years, following the identification of the first DC gene (DKC1) in 1998, in which there has been rapid progress in its understanding. Six genes have been identified, defects in which cause different genetic subtypes (X-linked recessive, autosomal dominant, autosomal recessive) of DC. The products of these genes encode components that are critical for telomere maintenance; either because they are core constituents of telomerase (dyskerin, TERC, TERT, NOP10 and NHP2) or are part of the shelterin complex that protects the telomeric end (TIN2). These advances have also highlighted the connection between the more "cryptic/atypical" forms of the disease including aplastic anaemia and idiopathic pulmonary fibrosis. Equally, studies on this disease have demonstrated the critical importance of telomeres in human cells (including stem cells) and the severe consequences of their dysfunction. In this context DC and related diseases can now be regarded as disorders of "telomere and stem cell dysfunction".},
}
@article {pmid19419696,
year = {2009},
author = {Svenson, U and Roos, G},
title = {Telomere length as a biological marker in malignancy.},
journal = {Biochimica et biophysica acta},
volume = {1792},
number = {4},
pages = {317-323},
doi = {10.1016/j.bbadis.2009.01.017},
pmid = {19419696},
issn = {0006-3002},
mesh = {Animals ; Biomarkers, Tumor/*metabolism ; *Homeostasis ; Humans ; Neoplasms/diagnosis/*metabolism ; Prognosis ; Risk Factors ; Telomere/*metabolism ; },
abstract = {Telomere maintenance is important for tumor cell growth and survival. Telomere length (TL) is determined by the balance between positive and negative factors impacting telomere homeostasis. In the last decade, TL has emerged as a promising clinical marker for risk and prognosis prediction in patients with malignant disorders. Tumor TL, as well as TL in healthy tissues such as peripheral blood, may carry valuable information for future treatment strategies. Here we discuss the present status of TL as a biological marker in cancer patients.},
}
@article {pmid19419691,
year = {2009},
author = {Allen, ND and Baird, DM},
title = {Telomere length maintenance in stem cell populations.},
journal = {Biochimica et biophysica acta},
volume = {1792},
number = {4},
pages = {324-328},
doi = {10.1016/j.bbadis.2009.02.004},
pmid = {19419691},
issn = {0006-3002},
support = {G0300331/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Cell Division/*physiology ; Embryonic Stem Cells/cytology/*metabolism ; Genome, Human/*physiology ; Homeostasis/physiology ; Humans ; Telomere/*metabolism ; },
abstract = {The maintenance of telomere length is essential for upholding the integrity of the genome. There is good evidence to suggest that telomere length maintenance in stem cell populations is important to facilitate the cell division required for tissue homeostasis. This is balanced against the requirement in long lived species for proliferative life span barriers for tumour suppression; the gradual erosion of telomeres provides one such barrier. The dynamics of telomeres in stem cell populations may thus be crucial in the balance between tumour suppression and tissue homeostasis. Here we briefly discuss our current understanding of telomere dynamics in stem cell populations, and provide some data to indicate that telomeres in human embryonic stem cells may be more stable and less prone to large-scale stochastic telomeric deletion.},
}
@article {pmid19419690,
year = {2009},
author = {Krunic, D and Moshir, S and Greulich-Bode, KM and Figueroa, R and Cerezo, A and Stammer, H and Stark, HJ and Gray, SG and Nielsen, KV and Hartschuh, W and Boukamp, P},
title = {Tissue context-activated telomerase in human epidermis correlates with little age-dependent telomere loss.},
journal = {Biochimica et biophysica acta},
volume = {1792},
number = {4},
pages = {297-308},
doi = {10.1016/j.bbadis.2009.02.005},
pmid = {19419690},
issn = {0006-3002},
mesh = {Adult ; Aging/*metabolism ; Antibiotics, Antineoplastic/pharmacology ; *Cell Proliferation ; Cells, Cultured ; Depsipeptides/pharmacology ; Dermis/cytology/enzymology ; Enzyme Activation/physiology ; Epidermal Cells ; Epidermis/*enzymology ; Female ; Fibroblasts/cytology/metabolism ; Gene Expression Regulation, Enzymologic/drug effects/*physiology ; Histone Deacetylase Inhibitors ; Histone Deacetylases/metabolism ; Humans ; Infant ; Infant, Newborn ; Keratinocytes/cytology/*enzymology ; Male ; Melanocytes/cytology/enzymology ; Telomerase/*metabolism ; Telomere/*enzymology ; Time Factors ; },
abstract = {Telomerase- and telomere length regulation in normal human tissues is still poorly understood. We show here that telomerase is expressed in the epidermis in situ independent of age but was repressed upon the passaging of keratinocytes in monolayer culture. However, when keratinocytes were grown in organotypic cultures (OTCs), telomerase was re-established, indicating that telomerase activity is not merely proliferation-associated but is regulated in a tissue context-dependent manner in human keratinocytes. While not inducible by growth factors, treatment with the histone deacetylation inhibitor FK228 restored telomerase activity in keratinocytes grown in monolayer cultures. Accordingly, CHIP analyses demonstrated an acetylated, active hTERT promoter in the epidermis in situ and in the epidermis of OTCs but a deacetylated, silenced hTERT promoter with subsequent propagation in monolayer culture suggesting that histone acetylation is part of the regulatory program to guarantee hTERT expression/telomerase activity in the epidermis. In agreement with the loss of telomerase activity, telomeres shortened during continuous propagation in monolayer culture by an average of approximately 70 base pairs (bp) per population doubling (pd). However, telomere erosion varied strongly between different keratinocyte strains and even between individual cells within the same culture, thereby arguing against a defined rate of telomere loss per replication cycle. In the epidermis in situ, as determined from early-passage keratinocytes and tissue sections from different age donors, we calculated a telomere loss of only approximately 25 bp per year. Since we determined the same rate for the non-regenerating melanocytes and dermal fibroblasts, our data suggest that in human epidermis telomerase is a protective mechanism against excessive telomere loss during the life-long regeneration.},
}
@article {pmid19418995,
year = {2009},
author = {Lamb, KJ and Shiels, PG},
title = {Telomeres, ageing and oxidation.},
journal = {SEB experimental biology series},
volume = {62},
number = {},
pages = {117-137},
pmid = {19418995},
issn = {1946-4959},
mesh = {Aging/genetics/*physiology ; Animals ; Humans ; Models, Biological ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; },
}
@article {pmid19417100,
year = {2009},
author = {Gartenberg, MR},
title = {Life on the edge: telomeres and persistent DNA breaks converge at the nuclear periphery.},
journal = {Genes &amp; development},
volume = {23},
number = {9},
pages = {1027-1031},
pmid = {19417100},
issn = {1549-5477},
support = {R01 GM051402/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Nucleus/*physiology ; Chromosomal Instability ; *DNA Breaks, Double-Stranded ; DNA Replication ; Membrane Proteins/metabolism ; Nuclear Envelope/metabolism ; Saccharomyces cerevisiae/*genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Persistent DNA double-strand breaks and telomeres represent genomic hazards, as they can instigate inappropriate repair reactions. Two recent papers by Oza and colleagues (pp. 912-917) and Schober and colleagues (pp. 928-938) show that both types of DNA ends are sequestered from bulk DNA by Mps3, a SUN domain protein that spans the inner nuclear membrane. Anchorage maintains telomere integrity and steers double-strand breaks toward specialized repair pathways. This work defines the nuclear periphery as a subcompartment where dangerous DNA elements can be handled with care.},
}
@article {pmid19412578,
year = {2010},
author = {Tian, X and Chen, B and Liu, X},
title = {Telomere and telomerase as targets for cancer therapy.},
journal = {Applied biochemistry and biotechnology},
volume = {160},
number = {5},
pages = {1460-1472},
doi = {10.1007/s12010-009-8633-9},
pmid = {19412578},
issn = {1559-0291},
mesh = {Animals ; Humans ; Mutation/genetics ; Neoplasms/*enzymology/*therapy ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomere maintenance and telomerase reactivation is essential for the transformation of most human cancer cells. Telomere shortening to the threshold length, mutations of the telomere-associated proteins, and/or telomerase RNA lead to telomeric dysfunction and therefore genomic instability. Telomerase up-regulation in 85% of human cancer cells has become a hallmark of cancers, hence a promising target for anticancer therapy. In this review, we discuss the mechanism of cancer due to telomere dysfunction and the resulting biological effects, the control of telomerase activity, and the new developments in cancer therapies targeting telomere and telomerase.},
}
@article {pmid19412177,
year = {2009},
author = {Phalke, S and Nickel, O and Walluscheck, D and Hortig, F and Onorati, MC and Reuter, G},
title = {Retrotransposon silencing and telomere integrity in somatic cells of Drosophila depends on the cytosine-5 methyltransferase DNMT2.},
journal = {Nature genetics},
volume = {41},
number = {6},
pages = {696-702},
pmid = {19412177},
issn = {1546-1718},
mesh = {Animals ; Crosses, Genetic ; DNA (Cytosine-5-)-Methyltransferases/*genetics ; DNA Methylation ; DNA-Cytosine Methylases/genetics ; Drosophila/enzymology/*genetics ; Drosophila Proteins/*genetics ; Embryo, Nonmammalian/physiology ; Gene Knockout Techniques ; *Gene Silencing ; Histone-Lysine N-Methyltransferase/genetics ; In Situ Hybridization, Fluorescence ; Mutation ; Retroelements/*genetics ; Telomere/*genetics ; },
abstract = {Here we show that the cytosine-5 methyltransferase DNMT2 controls retrotransposon silencing in Drosophila somatic cells. In Drosophila, significant DNMT2-dependent DNA methylation occurs during early embryogenesis. Suppression of white gene silencing by Mt2 (Dnmt2) null mutations in variegated P[w(+)] element insertions identified functional targets of DNMT2. The enzyme controls DNA methylation at retrotransposons in early embryos and initiates histone H4K20 trimethylation catalyzed by the SUV4-20 methyltransferase. In somatic cells, loss of DNMT2 eliminates H4K20 trimethylation at retrotransposons and impairs maintenance of retrotransposon silencing. In Dnmt2 and Suv4-20 null genotypes, retrotransposons are strongly overexpressed in somatic but not germline cells, where retrotransposon silencing depends on an RNAi mechanism. DNMT2 also controls integrity of chromosome 2R and 3R telomeres. In Dnmt2 null strains, we found stable loss of the subtelomeric clusters of defective Invader4 elements. Together, these results demonstrate a previously unappreciated role of DNA methylation in retrotransposon silencing and telomere integrity in Drosophila.},
}
@article {pmid19411304,
year = {2009},
author = {Else, T},
title = {Telomeres and telomerase in adrenocortical tissue maintenance, carcinogenesis, and aging.},
journal = {Journal of molecular endocrinology},
volume = {43},
number = {4},
pages = {131-141},
doi = {10.1677/JME-08-0189},
pmid = {19411304},
issn = {1479-6813},
mesh = {Adrenal Cortex Neoplasms/enzymology/*genetics ; Adrenal Glands/enzymology/*metabolism/*pathology ; Animals ; Cellular Senescence/genetics/*physiology ; Humans ; Telomerase/genetics/metabolism/*physiology ; Telomere/genetics/*physiology ; },
abstract = {Telomere dysfunction and telomere maintenance mechanisms contribute to major steps of carcinogenesis. Dysfunctional telomeres lead to the generation of genomic aberrations, such as amplifications and deletions. Telomere maintenance mechanisms, such as telomerase activity and alternative telomere lengthening, provide the basis of malignant cell expansion independent of telomere shortening-induced apoptosis or senescence, ensuring tumor survival. Recent advances highlight the importance of these mechanisms in adrenocortical carcinogenesis. In this review, we will summarize the main models of telomere physiology and their impact on adrenocortical tissue maintenance, aging, and carcinogenesis.},
}
@article {pmid19408914,
year = {2009},
author = {Zhang, XF and Xiang, JF and Tian, MY and Yang, QF and Sun, HX and Yang, S and Tang, YL},
title = {Formation of an intramolecular G-quadruplex of human telomere induced by poly(L-lysine) under salt-deficient conditions.},
journal = {The journal of physical chemistry. B},
volume = {113},
number = {21},
pages = {7662-7667},
doi = {10.1021/jp811183a},
pmid = {19408914},
issn = {1520-6106},
mesh = {Circular Dichroism ; DNA, Single-Stranded/*chemistry ; Electrophoresis, Polyacrylamide Gel ; *G-Quadruplexes ; Humans ; Nucleic Acid Conformation ; Oligodeoxyribonucleotides/chemistry ; Polylysine/*chemistry ; Potassium/*chemistry ; Sodium/*chemistry ; Spectrometry, Mass, Electrospray Ionization ; Telomere/*chemistry ; },
abstract = {A single-stranded G-tract human telomere DNA sequence is able to fold into intramolecular G-quadruplex structures which may be important for a number of biological processes and disease-related mechanisms. Poly(L-lysine) (PLL) polymer is linear polypeptides with lysine as the repeat unit and has been employed as a gene carrier in achieving targeted delivery of DNA to cancer cells. To explore the influence of PLL on the conformation of Hum24 DNA, we have investigated the interaction of PLL with Hum24 by biophysical methods, mainly CD, ESI-MS, and polyacrylamide gel electrophoresis for the first time. The CD data have shown that PLL can induce single-stranded Hum24 to form an intramolecular parallel G-quadruplex structure, further confirmed by ESI-MS analysis and gel electrophoresis results. The formation of an intramolecular G-quadruplex is strongly dependent on the Hum24/PLL molar ratios and the length of both the polypeptides and oligonucleotide. Such phenomena may be interpreted by electrostatically attracting negative-charged Hum24 by positive-charged PLL which facilitates the close contact between the guanines and formation of hydrogen bonding, thus leading the final shape of a G-quadruplex structure.},
}
@article {pmid19405848,
year = {2009},
author = {Armanios, M},
title = {Syndromes of telomere shortening.},
journal = {Annual review of genomics and human genetics},
volume = {10},
number = {},
pages = {45-61},
pmid = {19405848},
issn = {1545-293X},
support = {K08 CA118416/CA/NCI NIH HHS/United States ; K08 CA118416-03/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Dyskeratosis Congenita/*genetics/physiopathology ; Genetic Predisposition to Disease ; Humans ; Pulmonary Fibrosis/*genetics/physiopathology ; Syndrome ; Telomerase/deficiency/genetics/metabolism ; Telomere/chemistry/*genetics/*metabolism ; },
abstract = {Telomeres and telomerase were initially discovered in pursuit of questions about how the ends of chromosomes are maintained. The implications of these discoveries to age-related disease have emerged in recent years with the recognition of a group of telomere-mediated syndromes. Telomere-mediated disease was initially identified in the context of dyskeratosis congenita, a rare syndrome of premature aging. More recently, mutations in telomerase components were identified in adults with idiopathic pulmonary fibrosis. These findings have revealed that the spectrum of telomere-mediated disease is broad and includes clinical presentations in both children and adults. We have previously proposed that these disorders be collectively considered as syndromes of telomere shortening. Here, the spectrum of these disorders and the unique telomere genetics that underlies them are reviewed. I also propose broader clinical criteria for defining telomere-mediated syndromes outside of dyskeratosis congenita, with the goal of facilitating their diagnosis and highlighting their pathophysiology.},
}
@article {pmid19401529,
year = {2009},
author = {Xing, J and Ajani, JA and Chen, M and Izzo, J and Lin, J and Chen, Z and Gu, J and Wu, X},
title = {Constitutive short telomere length of chromosome 17p and 12q but not 11q and 2p is associated with an increased risk for esophageal cancer.},
journal = {Cancer prevention research (Philadelphia, Pa.)},
volume = {2},
number = {5},
pages = {459-465},
pmid = {19401529},
issn = {1940-6215},
support = {CA 98897/CA/NCI NIH HHS/United States ; R01 CA111922-02/CA/NCI NIH HHS/United States ; R01 CA098897/CA/NCI NIH HHS/United States ; R01 CA111922/CA/NCI NIH HHS/United States ; R01 CA098897-05/CA/NCI NIH HHS/United States ; },
mesh = {Case-Control Studies ; Chromosomes, Human, Pair 11/*genetics ; Chromosomes, Human, Pair 12/*genetics ; Chromosomes, Human, Pair 17/*genetics ; Chromosomes, Human, Pair 2/*genetics ; Esophageal Neoplasms/*genetics ; Female ; Humans ; Male ; Middle Aged ; Reverse Transcriptase Polymerase Chain Reaction ; Risk Factors ; Telomere/*genetics ; },
abstract = {Shortened telomere length may cause chromosomal instability in Barrett's esophagus and thus promote tumorigenesis. However, whether short telomere length in all chromosomes or just some of them is associated with increased esophageal cancer (EC) risk is largely unknown. To address this question, we examined the overall and chromosome-specific telomere lengths of 17p, 12q, 2p, and 11q and assessed their associations with EC risk. In a case-control study with 94 EC cases and 94 matched controls, the overall telomere length and the chromosome-specific telomere lengths of 17p, 12q, 2p, and 11q in peripheral blood lymphocytes were determined by a real-time PCR and a modified single telomere length analysis assay, respectively. Multivariate logistic regression analysis was used to assess the association between telomere length and EC risk. Compared with controls, EC patients had significantly shorter overall telomere lengths (P = 0.004) and chromosome-specific telomere lengths of 17p (P = 0.003) and 12q (P = 0.006) but not of 11q (P = 0.632) and 2p (P = 0.972). Furthermore, the multivariate logistic regression analysis showed that the short overall telomere length and chromosome-specific telomere lengths of 17p and 12q were associated with a dose-dependent increase in EC risk. Our study provides the first epidemiologic evidence that short telomere length of 17p and 12q plays an important role in esophageal carcinogenesis, suggesting that short telomere length of specific chromosomes is associated with the etiology of different cancer types.},
}
@article {pmid19390840,
year = {2009},
author = {Hengstler, JG and Marchan, R and Bolt, HM},
title = {Mechanisms of telomere maintenance and attrition: linking cancer and ageing.},
journal = {Archives of toxicology},
volume = {83},
number = {5},
pages = {405-406},
doi = {10.1007/s00204-009-0428-9},
pmid = {19390840},
issn = {1432-0738},
mesh = {Aging/genetics/metabolism/*physiology ; Animals ; Cellular Senescence/genetics/physiology ; Humans ; Neoplasms/*genetics ; Telomere/genetics/metabolism/*physiology ; },
}
@article {pmid19390087,
year = {2009},
author = {Schober, H and Ferreira, H and Kalck, V and Gehlen, LR and Gasser, SM},
title = {Yeast telomerase and the SUN domain protein Mps3 anchor telomeres and repress subtelomeric recombination.},
journal = {Genes &amp; development},
volume = {23},
number = {8},
pages = {928-938},
pmid = {19390087},
issn = {1549-5477},
mesh = {Chromatin/metabolism ; DNA-Binding Proteins/metabolism ; Gene Deletion ; Gene Expression Regulation, Fungal ; Membrane Proteins/*metabolism ; Nuclear Envelope/metabolism ; Nuclear Pore/metabolism ; Nuclear Proteins ; Protein Binding ; Recombination, Genetic/genetics/*physiology ; S Phase/physiology ; Saccharomyces cerevisiae/enzymology/genetics/*physiology ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomerase/*metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {Telomeres form the ends of linear chromosomes and protect these ends from being recognized as DNA double-strand breaks. Telomeric sequences are maintained in most cells by telomerase, a reverse transcriptase that adds TG-rich repeats to chromosome ends. In budding yeast, telomeres are organized in clusters at the nuclear periphery by interactions that depend on components of silent chromatin and the telomerase-binding factor yeast Ku (yKu). In this study, we examined whether the subnuclear localization of telomeres affects end maintenance. A telomere anchoring pathway involving the catalytic yeast telomerase subunits Est2, Est1, and Tlc1 is shown to be necessary for the perinuclear anchoring activity of Yku80 during S phase. Additionally, we identify the conserved Sad1-UNC-84 (SUN) domain protein Mps3 as the principal membrane anchor for this pathway. Impaired interference with Mps3 anchoring through overexpression of the Mps3 N terminus in a tel1 deletion background led to a senescence phenotype and to deleterious levels of subtelomeric Y' recombination. This suggests that telomere binding to the nuclear envelope helps protect telomeric repeats from recombination. Our results provide an example of a specialized structure that requires proper spatiotemporal localization to fulfill its biological role, and identifies a novel pathway of telomere protection.},
}
@article {pmid19388798,
year = {2009},
author = {Valls Bautista, C and Piñol Felis, C and Reñé Espinet, JM and Buenestado García, J and Viñas Salas, J},
title = {Telomerase activity and telomere length in the colorectal polyp-carcinoma sequence.},
journal = {Revista espanola de enfermedades digestivas},
volume = {101},
number = {3},
pages = {179-186},
doi = {10.4321/s1130-01082009000300004},
pmid = {19388798},
issn = {1130-0108},
mesh = {Colonic Polyps/*enzymology/*genetics ; Colorectal Neoplasms/*enzymology/*genetics ; Disease Progression ; Pilot Projects ; Telomerase/*metabolism ; *Telomere ; },
abstract = {OBJECTIVE: The role of telomerase activity and telomere length in the adenoma-carcinoma sequence of colon carcinogenesis has not been well established. The objective of this study was to determine telomerase activity and telomere length patterns in patients with adenomatous polyps either associated or not with colorectal cancer, as well as the role of telomeric instability in the adenoma-carcinoma sequence.<br><br>PATIENTS AND METHODS: We included in the study 14 patients who underwent surgery for colorectal cancer and/or polyps. In 6 of these patients fresh samples of tumor tissue, polyps, and normal mucosa were obtained; in the 8 remaining cases, we collected only polyps and normal mucosa. We used the fluorescent-telomeric repeat amplification protocol assay (TRAP-F) to determine telomerase activity and telomere length using Southern-blot testing.<br><br>RESULTS: Telomerase activity was detected in 86% of polyps and 50% of associated normal mucosa. Mean telomerase activity in polyp tissue was 5.85; in the normal mucosa it was 0.58 TPG. Mean telomere length was 6.78 Kbp and 7.78, respectively. Polyps in patients without synchronous cancer had a telomerase activity that was significantly higher (9.4) than in those with cancer (1.1).<br><br>CONCLUSIONS: Telomerase activity increases in the colorectal adenoma-carcinoma sequence, concurrently with a decrease in telomere length. The presence of synchronous cancer modifies telomerase activity in polyps.},
}
@article {pmid19386739,
year = {2009},
author = {Aviv, A},
title = {Leukocyte telomere length: the telomere tale continues.},
journal = {The American journal of clinical nutrition},
volume = {89},
number = {6},
pages = {1721-1722},
pmid = {19386739},
issn = {1938-3207},
support = {AG021593/AG/NIA NIH HHS/United States ; AG20132/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*physiology ; Dietary Supplements ; Humans ; Iron/*pharmacology ; Leukocytes/*physiology ; Longevity ; Telomere/*drug effects ; Vitamins/*pharmacology ; },
}
@article {pmid19386622,
year = {2009},
author = {Ungar, L and Yosef, N and Sela, Y and Sharan, R and Ruppin, E and Kupiec, M},
title = {A genome-wide screen for essential yeast genes that affect telomere length maintenance.},
journal = {Nucleic acids research},
volume = {37},
number = {12},
pages = {3840-3849},
pmid = {19386622},
issn = {1362-4962},
mesh = {Actin-Related Protein 2-3 Complex/genetics ; Cell Nucleolus/metabolism ; DNA Replication ; DNA-Binding Proteins/genetics ; Epigenesis, Genetic ; Genes, Essential ; *Genes, Fungal ; Genome, Fungal ; *Mutation ; Nuclear Proteins/genetics ; Proteasome Endopeptidase Complex/genetics ; RNA Processing, Post-Transcriptional ; RNA Splicing ; RNA, Ribosomal/metabolism ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Small Ubiquitin-Related Modifier Proteins/genetics ; Telomere/*metabolism ; Transcription Factors/genetics ; Transcription, Genetic ; Ubiquitin/genetics ; },
abstract = {Telomeres are structures composed of repetitive DNA and proteins that protect the chromosomal ends in eukaryotic cells from fusion or degradation, thus contributing to genomic stability. Although telomere length varies between species, in all organisms studied telomere length appears to be controlled by a dynamic equilibrium between elongating mechanisms (mainly addition of repeats by the enzyme telomerase) and nucleases that shorten the telomeric sequences. Two previous studies have analyzed a collection of yeast deletion strains (deleted for nonessential genes) and found over 270 genes that affect telomere length (Telomere Length Maintenance or TLM genes). Here we complete the list of TLM by analyzing a collection of strains carrying hypomorphic alleles of most essential genes (DAmP collection). We identify 87 essential genes that affect telomere length in yeast. These genes interact with the nonessential TLM genes in a significant manner, and provide new insights on the mechanisms involved in telomere length maintenance. The newly identified genes span a variety of cellular processes, including protein degradation, pre-mRNA splicing and DNA replication.},
}
@article {pmid19383931,
year = {2009},
author = {Xue, J and Duncan, SR},
title = {Are telomere lengths of leukocytes from patients with pulmonary fibrosis really genetically determined?.},
journal = {American journal of respiratory and critical care medicine},
volume = {179},
number = {9},
pages = {852; author reply 852-853},
doi = {10.1164/ajrccm.179.9.852},
pmid = {19383931},
issn = {1535-4970},
mesh = {Genetic Predisposition to Disease ; Humans ; *Leukocytes ; Pulmonary Fibrosis/*genetics ; Telomere/*ultrastructure ; },
}
@article {pmid19381925,
year = {2009},
author = {Banerjee, PP and Jagadeesh, S},
title = {Non-radioactive assay methods for the assessment of telomerase activity and telomere length.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {523},
number = {},
pages = {383-394},
pmid = {19381925},
issn = {1064-3745},
support = {R01 DK060875/DK/NIDDK NIH HHS/United States ; },
mesh = {Base Sequence ; Biological Assay/*methods ; Cell Extracts ; Cell Line, Tumor ; Electrophoresis, Polyacrylamide Gel ; Humans ; Molecular Sequence Data ; Polymerase Chain Reaction ; Radioactivity ; Telomerase/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {The telomeric repeat amplification protocol (TRAP) assay is a highly sensitive PCR based assay and is an important tool for understanding the role of telomerase in cancer. This assay measures an enzymatic activity where the amount of target is dependent upon the activity of the enzyme. This protocol consists of two steps: first, telomeric repeats are added to the substrate by the enzyme and second, the extended products will be amplified by Taq-DNA polymerase. The amplified TRAP assay products will be separated on 10% native PAGE and detected by SYBR Green I dye.},
}
@article {pmid19380905,
year = {2009},
author = {Lebel, C and Rosonina, E and Sealey, DC and Pryde, F and Lydall, D and Maringele, L and Harrington, LA},
title = {Telomere maintenance and survival in saccharomyces cerevisiae in the absence of telomerase and RAD52.},
journal = {Genetics},
volume = {182},
number = {3},
pages = {671-684},
pmid = {19380905},
issn = {0016-6731},
support = {WT 084637/WT_/Wellcome Trust/United Kingdom ; WT 081164/WT_/Wellcome Trust/United Kingdom ; R01 AG02398/AG/NIA NIH HHS/United States ; 075294/WT_/Wellcome Trust/United Kingdom ; WT 075294/WT_/Wellcome Trust/United Kingdom ; G0800081/MRC_/Medical Research Council/United Kingdom ; HHMI 55005945/HHMI/Howard Hughes Medical Institute/United States ; G0800081-85694/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Blotting, Southern ; Cell Division/genetics ; DNA, Fungal/genetics/metabolism ; DNA-Directed DNA Polymerase/genetics/metabolism ; Diploidy ; Exodeoxyribonucleases/genetics/metabolism ; Gene Deletion ; Penetrance ; Phenotype ; Rad52 DNA Repair and Recombination Protein/*genetics/metabolism ; Saccharomyces cerevisiae/*genetics/growth &amp; development ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Signal Transduction/genetics ; Telomerase/*genetics/metabolism ; Telomere/enzymology/*genetics ; Time Factors ; },
abstract = {Telomeres are essential features of linear genomes that are crucial for chromosome stability. Telomeric DNA is usually replenished by telomerase. Deletion of genes encoding telomerase components leads to telomere attrition with each cycle of DNA replication, eventually causing cell senescence or death. In the Saccharomyces cerevisiae strain W303, telomerase-null populations bypass senescence and, unless EXO1 is also deleted, this survival is RAD52 dependent. Unexpectedly, we found that the S. cerevisiae strain S288C could survive the removal of RAD52 and telomerase at a low frequency without additional gene deletions. These RAD52-independent survivors were propagated stably and exhibited a telomere organization typical of recombination between telomeric DNA tracts, and in diploids behaved as a multigenic trait. The polymerase-delta subunit Pol32 was dispensable for the maintenance of RAD52-independent survivors. The incidence of this rare escape was not affected by deletion of other genes necessary for RAD52-dependent survival, but correlated with initial telomere length. If W303 strains lacking telomerase and RAD52 first underwent telomere elongation, rare colonies could then bypass senescence. We suggest that longer telomeres provide a more proficient substrate for a novel telomere maintenance mechanism that does not rely on telomerase, RAD52, or POL32.},
}
@article {pmid19375317,
year = {2009},
author = {Buscemi, G and Zannini, L and Fontanella, E and Lecis, D and Lisanti, S and Delia, D},
title = {The shelterin protein TRF2 inhibits Chk2 activity at telomeres in the absence of DNA damage.},
journal = {Current biology : CB},
volume = {19},
number = {10},
pages = {874-879},
doi = {10.1016/j.cub.2009.03.064},
pmid = {19375317},
issn = {1879-0445},
support = {GGP05226/TI_/Telethon/Italy ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/metabolism ; Cell Line ; Cellular Senescence ; Checkpoint Kinase 2 ; *DNA Damage ; DNA-Binding Proteins/genetics/metabolism ; Humans ; Neoplasms/metabolism ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Protein Structure, Tertiary ; Telomerase/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; Tumor Suppressor Proteins/genetics/metabolism ; },
abstract = {The shelterin complex [1] shapes and protects telomeric DNA from being processed as double strand breaks (DSBs) [2, 3]. Here we show that in human undamaged cells, a fraction of the kinase Chk2, a downstream target of ATM and mediator of checkpoint responses and senescence [4, 5], physically interacts with the shelterin subunit TRF2 and colocalizes with this complex at chromosome ends. This interaction, enhanced by TRF2 binding to telomeric DNA, inhibits the activation and senescence-induced function of Chk2 by a mechanism in which TRF2 binding to the N terminus of Chk2 surrounding Thr68 hinders the phosphorylation of this priming site. In response to radiation-induced DSBs, but not chromatin-remodelling agents, the telomeric Chk2-TRF2 binding dissociates in a Chk2 activity-dependent manner. Moreover, active Chk2 phosphorylates TRF2 and decreases its binding to telomeric DNA repeats, corroborating the evidences on the specific TRF2 relocalization in presence of DSBs [6]. Altogether, the capacity of TRF2 to locally repress Chk2 provides an additional level of control by which shelterin restrains the DNA damage response from an unwanted activation [6, 7] and may explain why TRF2 overexpression acts as a telomerase-independent oncogenic stimulus [8].},
}
@article {pmid19375218,
year = {2009},
author = {Lee, ME and Rha, SY and Jeung, HC and Chung, HC and Oh, BK},
title = {Subtelomeric DNA methylation and telomere length in human cancer cells.},
journal = {Cancer letters},
volume = {281},
number = {1},
pages = {82-91},
doi = {10.1016/j.canlet.2009.02.031},
pmid = {19375218},
issn = {1872-7980},
mesh = {Cell Line, Tumor/chemistry/ultrastructure ; Chromosomes, Human/chemistry/ultrastructure ; *DNA Methylation ; DNA, Neoplasm/chemistry/*genetics/ultrastructure ; Heterochromatin/chemistry/ultrastructure ; Humans ; Neoplasms/chemistry/*genetics/ultrastructure ; Polymerase Chain Reaction ; Sequence Analysis, DNA ; Sulfites/pharmacology ; Telomere/*ultrastructure ; },
abstract = {Subtelomeric epigenetic modifications are known to be associated with telomere length. We examined subtelomeric DNA methylation at seven sites for five chromosomes by methylation-specific PCR (MSP) and two sites for two chromosomes by bisulfite genomic sequencing (BGS) in 20 human cancer cell lines and subsequently analyzed their association with telomere length. Full-methylation (55/140) was more frequently found compared to un-methylation (35/140) (p=0.01). Subtelomeric-methylation patterns varied from region to region; full-methylation and un-methylation were dominant at one of 9q sites (20/20) and 9p (18/20), respectively. MSP and BGS data exhibited no apparent correlation between methylation status and telomere length. In addition, Hep3B subclones that possessed different telomere lengths exhibited no changes in methylation status according to telomeres. In summary, subtelomeres might form distinct chromatin structures from region to region and effect of subtelomeric DNA methylation on telomere regulation might be little.},
}
@article {pmid19372672,
year = {2009},
author = {Navajas-Pérez, R and Schwarzacher, T and Ruiz Rejón, M and Garrido-Ramos, MA},
title = {Characterization of RUSI, a telomere-associated satellite DNA, in the genus Rumex (Polygonaceae).},
journal = {Cytogenetic and genome research},
volume = {124},
number = {1},
pages = {81-89},
doi = {10.1159/000200091},
pmid = {19372672},
issn = {1424-859X},
mesh = {Base Pairing ; Base Sequence ; Chromosomes, Plant ; DNA, Plant/*genetics/isolation &amp; purification ; DNA, Satellite/*genetics ; Genome, Plant ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Phylogeny ; Plant Leaves/genetics ; Rumex/*classification/*genetics ; Seeds/genetics ; Sequence Alignment ; Sequence Analysis, DNA ; Species Specificity ; *Telomere ; },
abstract = {A satellite-DNA family (RUSI) has been isolated and characterized in Rumexinduratus Boiss and Reuter (Polygonaceae), an Iberian endemic polygamous sorrel. The RUSI repeats are 170 bp in length and approximately 68% AT-rich containing different variants of degenerate telomere motifs--(TT)(n)AN(GG)(n) -, a typical feature of subtelomeric DNA repeats adjacent to telomeres, which have been referred to as telomere-associated sequences or TASs. In fact, fluorescent in situhybridization showed that this satellite DNA is located in subtelomeric positions of most of the chromosomes of R. induratus, with some centromeric loci. PCR and Southern-blot hybridization assays for sequence conservation in the genus Rumex, indicated that the RUSI sequences are restricted to the genomes of R. induratus and R. scutatus, both species of the section Scutati, suggesting that they are recently evolved. Sequence variation within the two species is high (mean value of sequence differences between repeats of 15% for R. induratus and 7.5% for R. scutatus) and the degree of sequence differentiation between species is low with no species-specific variants, postulated to be due to slowed rates of spreading of sequence variants by molecular homogenizing mechanisms. Characteristics of RUSI sequences are discussed in the light of their chromosomal location and analyzed for their evolutionary and phylogenetic implications.},
}
@article {pmid19369944,
year = {2009},
author = {Meng, FL and Hu, Y and Shen, N and Tong, XJ and Wang, J and Ding, J and Zhou, JQ},
title = {Sua5p a single-stranded telomeric DNA-binding protein facilitates telomere replication.},
journal = {The EMBO journal},
volume = {28},
number = {10},
pages = {1466-1478},
pmid = {19369944},
issn = {1460-2075},
mesh = {*DNA Replication ; DNA, Fungal/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Gene Deletion ; Saccharomyces cerevisiae/*physiology ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {In budding yeast Saccharomyces cerevisiae, telomere length maintenance involves a complicated network as more than 280 telomere maintenance genes have been identified in the nonessential gene deletion mutant set. As a supplement, we identified additional 29 telomere maintenance genes, which were previously taken as essential genes. In this study, we report a novel function of Sua5p in telomere replication. Epistasis analysis and telomere sequencing show that sua5Delta cells display progressively shortened telomeres at early passages, and Sua5 functions downstream telomerase recruitment. Further, biochemical, structural and genetic studies show that Sua5p specifically binds single-stranded telomeric (ssTG) DNA in vitro through a distinct DNA-binding region on its surface, and the DNA-binding ability is essential for its telomere function. Thus, Sua5p represents a novel ssTG DNA-binding protein and positively regulates the telomere length in vivo.},
}
@article {pmid19363487,
year = {2009},
author = {Zeng, S and Xiang, T and Pandita, TK and Gonzalez-Suarez, I and Gonzalo, S and Harris, CC and Yang, Q},
title = {Telomere recombination requires the MUS81 endonuclease.},
journal = {Nature cell biology},
volume = {11},
number = {5},
pages = {616-623},
pmid = {19363487},
issn = {1476-4679},
support = {CA10445/CA/NCI NIH HHS/United States ; P01 CA104457-040002/CA/NCI NIH HHS/United States ; R01 NS034746-06S1/NS/NINDS NIH HHS/United States ; P01 CA104457-050002/CA/NCI NIH HHS/United States ; R01 NS034746/NS/NINDS NIH HHS/United States ; R01 CA123232-02/CA/NCI NIH HHS/United States ; CA123232/CA/NCI NIH HHS/United States ; R01 CA123232/CA/NCI NIH HHS/United States ; Z01 BC005795-13/ImNIH/Intramural NIH HHS/United States ; P01 CA104457/CA/NCI NIH HHS/United States ; R01 CA129537/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Biocatalysis ; Cell Cycle/physiology ; Cell Line, Tumor ; Cell Nucleolus/metabolism ; Cell Nucleus/metabolism ; Cell Proliferation ; Cell Survival/physiology ; Chromatin Immunoprecipitation ; DNA-Binding Proteins/*physiology ; Endodeoxyribonucleases/metabolism ; Endonucleases/*physiology ; G2 Phase/physiology ; Humans ; Mice ; Protein Binding/drug effects/physiology ; RNA Interference ; Recombination, Genetic/*physiology ; Sister Chromatid Exchange/physiology ; Telomerase/genetics ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism/pharmacology ; },
abstract = {Telomerase-negative cancer cells maintain their telomeres through the alternative lengthening of telomeres (ALT) pathway. Although a growing body of evidence demonstrates that the ALT mechanism is a post-replicative telomere recombination process, molecular details of this pathway are largely unknown. Here we demonstrate that MUS81, a DNA structure specific recombination endonuclease, has a key role in the maintenance of telomeres in human ALT cells. We find that MUS81 specifically localizes to ALT-associated promyelocytic leukaemia (PML) nuclear bodies (APBs) and associates with telomeric DNA in ALT cells, which is enriched during the G2 phase of the cell cycle. Depletion of MUS81 results in the reduction of ALT-specific telomere recombination and leads to proliferation arrest of ALT cells. In addition, the endonuclease activity of MUS81 is required for recombination-based ALT cell survival, and the interaction of MUS81 with the telomeric repeat-binding factor TRF2 regulates this enzymatic activity, thereby maintaining telomere recombination. Thus, our results suggest that MUS81 is involved in the maintenance of ALT cell survival at least in part by homologous recombination of telomeres.},
}
@article {pmid19363303,
year = {2009},
author = {Snyder, AR and Zhou, J and Deng, Z and Lieberman, PM},
title = {Therapeutic doses of hydroxyurea cause telomere dysfunction and reduce TRF2 binding to telomeres.},
journal = {Cancer biology &amp; therapy},
volume = {8},
number = {12},
pages = {1136-1145},
pmid = {19363303},
issn = {1555-8576},
support = {R01 CA093606/CA/NCI NIH HHS/United States ; R01 CA093606-10/CA/NCI NIH HHS/United States ; CA 093606/CA/NCI NIH HHS/United States ; },
mesh = {Antineoplastic Agents/*pharmacology ; Cell Culture Techniques ; Chromatin Immunoprecipitation ; HCT116 Cells ; HeLa Cells ; Humans ; Hydroxyurea/*pharmacology ; Neoplasms/*therapy ; Protein Processing, Post-Translational/drug effects ; Telomere/*drug effects/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Telomeric Repeat Binding Protein 2/*antagonists &amp; inhibitors/genetics/metabolism ; Transfection ; },
abstract = {Hydroxyurea (HU) is a chemotherapeutic agent commonly used for various malignancies and hematological disorders, including chronic myelogenous leukemia and sickle cell anemia. We show here that chronic, low-level treatment with HU induces a variety of defects in telomere replication and maintenance. HU treatment preferentially decreased the rate of telomere DNA synthesis and altered the cell cycle timing of telomere replication. HU reduced the expression levels of telomere repeat RNA (TERRA). In some cells, HU caused a rapid loss of telomere restriction fragment length. Chromatin immunoprecipitation (ChIP) assay indicated that telomere repeat binding factors TRF1 and TRF2 dissociate from telomere DNA after HU treatment. TRF2 protein purified from HU treated cells showed a modest reduction in DNA binding activity and a change in isoelectric point as measured by 2D gel electrophoresis. However, chronic low level HU treatment did not evoke a DNA replication checkpoint response, suggesting that the mechanism of action is distinct from the well-characterized S-phase checkpoint pathway. We conclude that therapeutic doses of HU preferentially effects telomere replication and maintenance, through a mechanism that may involve the direct modification of TRF2. These findings provide new insight into the potential mechanisms of action of HU at telomeres and in cancer chemotherapies.},
}
@article {pmid19360408,
year = {2009},
author = {Rehmeyer, CJ and Li, W and Kusaba, M and Farman, ML},
title = {The telomere-linked helicase (TLH) gene family in Magnaporthe oryzae: revised gene structure reveals a novel TLH-specific protein motif.},
journal = {Current genetics},
volume = {55},
number = {3},
pages = {253-262},
pmid = {19360408},
issn = {1432-0983},
mesh = {Amino Acid Motifs ; Amino Acid Sequence ; Base Sequence ; Chromosome Mapping ; Chromosomes, Fungal/genetics ; Conserved Sequence ; DNA Transposable Elements/genetics ; Fungal Proteins/*genetics/metabolism ; Gene Dosage ; Magnaporthe/enzymology/*genetics ; Molecular Sequence Data ; Mutagenesis, Insertional ; Mutation ; RecQ Helicases/*genetics/metabolism ; Selection, Genetic ; Sequence Alignment/methods ; Sequence Homology, Amino Acid ; Sequence Homology, Nucleic Acid ; Telomere/enzymology/*genetics ; },
abstract = {Telomere-linked RecQ helicase (TLH) genes have been identified in several fungi, where they occur as small gene families with each member copy residing within ~10 kb of a telomere. Here we describe the characterization of all 11 TLH gene copies in the reference strain of the fungus Magnaporthe oryzae. A consensus gene prediction revealed that the previously reported TLH1 gene is actually a mutated copy, and the full-length gene is almost two times longer. Only four full-length TLH genes were present in the strain that was analyzed, with the remaining copies containing premature stops caused by point mutations, indels, transposon insertions, and a telomere truncation. Interestingly, all of the TLH gene copies possessed numerous mutations indicative of the action of the repeat-induced point mutation process. However, there was evidence of purifying selection indicating maintenance of gene function. Alignment of full-length proteins from M. oryzae, Schizosaccharomyces pombe and M. anisopliae revealed the presence of a novel, highly conserved protein motif which suggests that the telomere-linked helicases have different functions and/or substrates to the RecQ helicases encoded by "internal" genes.},
}
@article {pmid19359441,
year = {2009},
author = {Cipriano, C and Tesei, S and Malavolta, M and Giacconi, R and Muti, E and Costarelli, L and Piacenza, F and Pierpaoli, S and Galeazzi, R and Blasco, M and Vera, E and Canela, A and Lattanzio, F and Mocchegiani, E},
title = {Accumulation of cells with short telomeres is associated with impaired zinc homeostasis and inflammation in old hypertensive participants.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {64},
number = {7},
pages = {745-751},
doi = {10.1093/gerona/glp048},
pmid = {19359441},
issn = {1758-535X},
mesh = {Aged ; Aged, 80 and over ; Aging/*metabolism ; Body Mass Index ; Cardiovascular Diseases/metabolism ; Case-Control Studies ; Cellular Senescence/genetics ; Down-Regulation ; Homeostasis ; Humans ; Hypertension/genetics/*metabolism/physiopathology ; Inflammation/genetics/*metabolism/physiopathology ; Metallothionein/metabolism ; Middle Aged ; Obesity/complications ; Risk Factors ; Smoking/adverse effects ; Surveys and Questionnaires ; Telomere/*metabolism ; Zinc/*metabolism ; },
abstract = {Critical shortening of telomeres, likely associated with a considerable increase of senescent cells, can be observed in PBMC of individuals aged 80 and older. We investigated the relationship between critical telomere shortening and zinc status in healthy or hypertensive participants with or without cardiovascular disease in old and very old participants. Telomere shortening and accumulation of cells with short telomeres (percent of cells with short telomeres) in advancing age was evident in patients and healthy controls, but exacerbated in those patients aged 80 and older. Moreover, in very old patients, the accumulation of % CST may impair intracellular zinc homeostasis and metallothioneins expression, which itself is linked to an increased number of inflammatory agents, thereby suggesting the existence of a possible causal relationship between % CST and zinc homeostasis. The determination of % CST could be a more reliable means than the simple measure of telomere length as fundamental parameter in ageing to determine whether individuals are still able to respond to stress.},
}
@article {pmid19359409,
year = {2009},
author = {Hills, M and Lücke, K and Chavez, EA and Eaves, CJ and Lansdorp, PM},
title = {Probing the mitotic history and developmental stage of hematopoietic cells using single telomere length analysis (STELA).},
journal = {Blood},
volume = {113},
number = {23},
pages = {5765-5775},
pmid = {19359409},
issn = {1528-0020},
support = {R01 AI029524/AI/NIAID NIH HHS/United States ; R21 AI029524/AI/NIAID NIH HHS/United States ; AI29524/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Blood Cells/*cytology/*metabolism ; *Cell Differentiation ; Cell Line ; *Cell Lineage ; Fetal Blood ; Hematopoietic Stem Cell Transplantation ; Humans ; Mice ; *Mitosis ; Spodoptera ; Telomere/*metabolism ; },
abstract = {In most human somatic cells, telomeres shorten as a function of DNA replication. Telomere length is therefore an indirect measure of the replicative history of cells. We measured the telomere lengths at XpYp chromosomes in purified human hematopoietic populations enriched for stem cells (Lin(-)CD34(+)CD38(-)Rho(-)) and successively more mature cells. The average telomere length showed expected length changes, pointing to the utility of this method for classifying novel differentiation markers. Interestingly, the frequency of abruptly shortened telomeres increased in terminally differentiated adult populations, suggesting that damage to telomeric DNA occurs or is not repaired upon hematopoietic differentiation. When Lin(-)CD34(+)CD38(-)Rho(-) cord blood cells were transplanted into immunodeficient mice, the telomeres of the most primitive regenerated human hematopoietic cells lost approximately 3 kb, indicative of more than 30 cell divisions. Further losses in differentiating cells were similar to those observed in pretransplantation cell populations. These results indicate extensive self-renewal divisions of human hematopoietic stem cells are the primary cause of telomere erosion upon transplantation rather than added cell divisions in downstream progenitors.},
}
@article {pmid19359360,
year = {2009},
author = {Tseng, SF and Shen, ZJ and Tsai, HJ and Lin, YH and Teng, SC},
title = {Rapid Cdc13 turnover and telomere length homeostasis are controlled by Cdk1-mediated phosphorylation of Cdc13.},
journal = {Nucleic acids research},
volume = {37},
number = {11},
pages = {3602-3611},
pmid = {19359360},
issn = {1362-4962},
mesh = {CDC2 Protein Kinase/*metabolism ; Cell Cycle/*genetics ; Homeostasis ; Mutation ; Phosphorylation ; Protein Stability ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/enzymology/genetics/metabolism ; Saccharomyces cerevisiae Proteins/chemistry/genetics/*metabolism ; Telomere/chemistry/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {Budding yeast telomerase is mainly activated by Tel1/Mec1 (yeast ATM/ATR) on Cdc13 from late S to G2 phase of the cell cycle. Here, we demonstrated that the telomerase-recruitment domain of Cdc13 is also phosphorylated by Cdk1 at the same cell cycle stage as the Tel1/Mec1-dependent regulation. Phosphor-specific gel analysis demonstrated that Cdk1 phosphorylates residues 308 and 336 of Cdc13. The residue T308 of Cdc13 is critical for efficient Mec1-mediated S306 phosphorylation in vitro. Phenotypic analysis in vivo revealed that the mutations in the Cdc13 S/TP motifs phosphorylated by Cdk1 caused cell cycle delay and telomere shortening and these phenotypes could be partially restored by the replacement with a negative charge residue. In the absence of Ku or Tel1, Cdk1-mediated phosphorylation of Cdc13 showed no effect on telomere length maintenance. Moreover, this Cdk1-mediated phosphorylation was required to promote the regular turnover of Cdc13. Together these results demonstrate that Cdk1 phosphorylates the telomerase recruitment domain of Cdc13, thereby preserves optimal function and expression level of Cdc13 for precise telomere replication and cell cycle progression.},
}
@article {pmid19359265,
year = {2009},
author = {Mangino, M and Richards, JB and Soranzo, N and Zhai, G and Aviv, A and Valdes, AM and Samani, NJ and Deloukas, P and Spector, TD},
title = {A genome-wide association study identifies a novel locus on chromosome 18q12.2 influencing white cell telomere length.},
journal = {Journal of medical genetics},
volume = {46},
number = {7},
pages = {451-454},
pmid = {19359265},
issn = {1468-6244},
support = {/WT_/Wellcome Trust/United Kingdom ; 077011/WT_/Wellcome Trust/United Kingdom ; },
mesh = {*Chromosomes, Human, Pair 18 ; Cohort Studies ; Data Interpretation, Statistical ; Female ; Genome, Human ; Genome-Wide Association Study/*methods ; Humans ; Leukocytes/metabolism/*ultrastructure ; Male ; Polymorphism, Single Nucleotide ; Reproducibility of Results ; Sex Factors ; Telomere/chemistry/*genetics/metabolism ; *Twins ; },
abstract = {BACKGROUND: Telomere length is a predictor for a number of common age related diseases and is a heritable trait.<br><br>METHODS AND RESULTS: To identify new loci associated with mean leukocyte telomere length we conducted a genome wide association study of 314,075 single nucleotide polymorphisms (SNPs) and validated the results in a second cohort (n for both cohorts combined = 2790). We identified two novel associated variants (rs2162440, p = 2.6 x 10(-6); and rs7235755, p = 5.5 x 10(-6)) on chromosome 18q12.2 in the same region as the VPS34/PIKC3C gene, which has been directly implicated in the pathway controlling telomere length variation in yeast.<br><br>CONCLUSION: These results provide new insights into the pathways regulating telomere homeostasis in humans.},
}
@article {pmid19359039,
year = {2009},
author = {Davy, P and Nagata, M and Bullard, P and Fogelson, NS and Allsopp, R},
title = {Fetal growth restriction is associated with accelerated telomere shortening and increased expression of cell senescence markers in the placenta.},
journal = {Placenta},
volume = {30},
number = {6},
pages = {539-542},
pmid = {19359039},
issn = {1532-3102},
support = {P20 RR011091/RR/NCRR NIH HHS/United States ; P20 RR011091-14/RR/NCRR NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; *Biomarkers/metabolism ; Case-Control Studies ; Cellular Senescence/*genetics ; Chromosomal Instability/physiology ; Female ; Fetal Growth Retardation/*genetics/metabolism ; Humans ; Infant, Newborn ; Middle Aged ; Pregnancy ; Telomere/metabolism/*physiology ; Up-Regulation/genetics ; Young Adult ; },
abstract = {A hallmark of fetal growth restriction (FGR) is restricted placental development and insufficient nutrient supply to the fetus. It has previously been shown that activity levels of telomerase, the enzyme responsible for completing replication of telomeric DNA during cell division, is suppressed in FGR placenta samples as compared to control placenta samples from donors of the same gestational age. Here we examine whether telomere length maintenance is also compromised in FGR placenta samples. Southern analysis of telomere length for placenta and cord blood samples from 32 FGR and 36 control donors, ranging in gestational age from 37 to 40 weeks, revealed significantly shorter telomeres (P<or=0.001) in FGR placenta samples, but not cord blood samples. Furthermore, analysis of telomerase extracts, RNA and DNA placental samples from donors with and without idiopathic FGR confirmed a direct association between suppression of telomerase activity and reduced telomere length in FGR placenta. In addition, expression levels of markers of telomere-induced senescence, p21, p16 and EF-1 alpha, were significantly elevated in FGR placenta samples (P<or=0.01). These observations support a direct affect of reduced telomerase activity levels on the placental pathology associated with FGR.},
}
@article {pmid19352407,
year = {2009},
author = {Price, CM},
title = {Antics at the telomere: uncoupled polymerases solve the end replication problem.},
journal = {The EMBO journal},
volume = {28},
number = {7},
pages = {795-796},
pmid = {19352407},
issn = {1460-2075},
support = {R01 GM073169/GM/NIGMS NIH HHS/United States ; GM041803/GM/NIGMS NIH HHS/United States ; R01 GM088728/GM/NIGMS NIH HHS/United States ; GM073169/GM/NIGMS NIH HHS/United States ; R01 GM041803/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Polymerase I/metabolism ; DNA Replication/*physiology ; DNA-Directed DNA Polymerase/*metabolism ; Models, Biological ; Schizosaccharomyces/enzymology/metabolism ; Telomere/*metabolism ; },
}
@article {pmid19352406,
year = {2009},
author = {Lustig, AJ},
title = {Separating the effects of telomere size from the mechanism of telomere elongation.},
journal = {The EMBO journal},
volume = {28},
number = {7},
pages = {793-794},
pmid = {19352406},
issn = {1460-2075},
support = {R56 GM069943/GM/NIGMS NIH HHS/United States ; },
mesh = {Models, Biological ; Recombination, Genetic ; Telomerase/metabolism ; Telomere/*metabolism ; },
}
@article {pmid19349587,
year = {2009},
author = {Kaplan, RC and Fitzpatrick, AL and Pollak, MN and Gardner, JP and Jenny, NS and McGinn, AP and Kuller, LH and Strickler, HD and Kimura, M and Psaty, BM and Aviv, A},
title = {Insulin-like growth factors and leukocyte telomere length: the cardiovascular health study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {64},
number = {11},
pages = {1103-1106},
pmid = {19349587},
issn = {1758-535X},
support = {HHSN268201200036C/HL/NHLBI NIH HHS/United States ; R01 AG031890/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aging/*immunology ; Cross-Sectional Studies ; Female ; Humans ; Insulin-Like Growth Factor Binding Protein 1/blood ; Insulin-Like Growth Factor Binding Protein 3 ; Insulin-Like Growth Factor Binding Proteins/blood ; Insulin-Like Growth Factor I/analysis/*physiology ; Leukocytes/*metabolism ; Linear Models ; Male ; Sex Characteristics ; *Telomere ; },
abstract = {The insulin-like growth factor (IGF) axis may affect immune cell replicative potential and telomere dynamics. Among 551 adults 65 years and older, leukocyte telomere length (LTL), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-binding proteins 1 and 3 (IGFBP-1, IGFBP-3) were measured. Multivariate linear regression was used to model the association of LTL with IGF-1 and IGFBPs, while controlling for confounding and increasing precision by adjusting for covariates. We observed a significant association between higher IGF-1 and longer LTL after adjustment for age, sex, race, smoking status, body mass index, hypertension, diabetes, and serum lipids. The results suggested an increase of .08 kb in LTL for each standard deviation increase of IGF-1 (p = .04). IGFBP-1 and IGFBP-3 were not significantly associated with LTL. High IGF-1 may be an independent predictor of longer LTL, consistent with prior evidence suggesting a role for IGF-1 in mechanisms relating to telomere maintenance.},
}
@article {pmid19340005,
year = {2009},
author = {Rossi, D and Lobetti Bodoni, C and Genuardi, E and Monitillo, L and Drandi, D and Cerri, M and Deambrogi, C and Ricca, I and Rocci, A and Ferrero, S and Bernocco, E and Capello, D and De Paoli, L and Bergui, L and Boi, M and Omedè, P and Massaia, M and Tarella, C and Passera, R and Boccadoro, M and Gaidano, G and Ladetto, M},
title = {Telomere length is an independent predictor of survival, treatment requirement and Richter's syndrome transformation in chronic lymphocytic leukemia.},
journal = {Leukemia},
volume = {23},
number = {6},
pages = {1062-1072},
doi = {10.1038/leu.2008.399},
pmid = {19340005},
issn = {1476-5551},
mesh = {Artificial Intelligence ; Biomarkers ; Cell Transformation, Neoplastic ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/complications/*diagnosis/mortality ; *Predictive Value of Tests ; Prognosis ; Survival Analysis ; Telomere/*pathology ; },
abstract = {Telomere length (TL) has been associated with outcome in chronic lymphocytic leukemia (CLL). The aim of this extensive analysis carried out on 401 CLL patients was to assess TL conclusively as a prognostic biomarker. Our study included two cohorts used as learning (191 patients) and blinded validation series (210 patients). A TL cutoff of 5000 bp was chosen by receiver operating characteristic (ROC) analysis and Youden's index in the learning series. In this series, TL< or =5000 bp was independently associated to a worse outcome for both overall survival (OS; 105.5 vs 281 months, P<0.001) and treatment-free survival (TFS; 24.6 vs 73 months, P<0.001). In the blinded validation series, TL< or =5000 bp was confirmed as an independent outcome predictor for OS (79.8 vs not reached, P<0.001) and TFS (15.2 vs 130.8 months, P<0.001). Moreover, TL< or =5000 bp independently predicted the risk of Richter's syndrome (5-year risk: 18.9 vs 6.4%, P=0.016). Within CLL subsets defined by biological predictors, TL consistently identified patient subgroups harboring unfavorable prognosis. These results demonstrate that TL is a powerful independent predictor of multiple outcomes in CLL, and contributes to refine the prognostic assessment of this disease when utilized in combination with other prognostic markers. We thus believe that this prognostic biomarker has the potential for a more widespread use in CLL.},
}
@article {pmid19339578,
year = {2009},
author = {Matsuo, T and Shay, JW and Wright, WE and Hiyama, E and Shimose, S and Kubo, T and Sugita, T and Yasunaga, Y and Ochi, M},
title = {Telomere-maintenance mechanisms in soft-tissue malignant fibrous histiocytomas.},
journal = {The Journal of bone and joint surgery. American volume},
volume = {91},
number = {4},
pages = {928-937},
doi = {10.2106/JBJS.G.01390},
pmid = {19339578},
issn = {1535-1386},
mesh = {Aged ; Female ; Histiocytoma, Malignant Fibrous/*genetics/metabolism/pathology ; Humans ; Male ; Middle Aged ; Prognosis ; RNA, Messenger/analysis ; Reverse Transcriptase Polymerase Chain Reaction ; Soft Tissue Neoplasms/*genetics/metabolism/pathology ; Telomerase/genetics/*metabolism ; Telomere/*genetics/ultrastructure ; },
abstract = {BACKGROUND: Sarcomas are distinct from carcinomas in that a substantial portion of them use the alternative lengthening of telomeres (ALT) mechanism to maintain their telomeres. The present study clarifies the prevalence of the ALT mechanism and examines the prognostic importance of telomere factors in soft-tissue malignant fibrous histiocytomas.<br><br>METHODS: We investigated a series of forty-three soft-tissue malignant fibrous histiocytoma samples from forty-three patients with regard to telomere length, telomerase activity, and human telomerase reverse transcriptase (hTERT) mRNA expression. Tumor samples were obtained from surgical specimens and were stored at -80 degrees C until use. Univariate analysis of the tumor samples from patients for whom data were available on age, sex, histological grade, tumor size, surgical margin, recurrence, and telomere factors was performed with use of the log-rank test. Multivariate analysis with only significant variables was then performed.<br><br>RESULTS: Telomerase activity was detectable in 79.1% of the tumor samples, hTERT expression was demonstrated in 90.7% of the tumor samples, and evidence of engagement of the ALT mechanism of telomere length maintenance was observed in 32.6% of the tumor samples. Among the variables tested, ALT-positive status emerged as the only independent prognostic factor for death of the patient (hazard ratio, 0.275; 95% confidence interval, 0.104 to 0.724; p=0.0089). There were no significant differences in survival rates between patients with ALT-positive, telomerase-positive tumors and those with ALT-positive, telomerase-negative tumors (p=0.301) or between patients with ALT-positive tumors that showed above-average telomerase activity and those with ALT-positive tumors that showed below-average telomerase activity (p=0.900). Therefore, telomerase activity does not affect the prognosis in patients with ALT-positive malignant fibrous histiocytoma. High telomerase expression is associated with a poor prognosis in patients with ALT-negative malignant fibrous histiocytoma (p=0.0027).<br><br>CONCLUSIONS: More detailed analysis will be needed to identify the most valuable prognostic factor in patients with malignant fibrous histiocytoma, and a more thorough understanding of telomere biology may give an indication of telomere-targeting therapy in the future.},
}
@article {pmid19338455,
year = {2009},
author = {Sanders, JL and Cauley, JA and Boudreau, RM and Zmuda, JM and Strotmeyer, ES and Opresko, PL and Hsueh, WC and Cawthon, RM and Li, R and Harris, TB and Kritchevsky, SB and Newman, AB and , },
title = {Leukocyte Telomere Length Is Not Associated With BMD, Osteoporosis, or Fracture in Older Adults: Results From the Health, Aging and Body Composition Study.},
journal = {Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research},
volume = {24},
number = {9},
pages = {1531-1536},
pmid = {19338455},
issn = {1523-4681},
support = {P30 AG024827/AG/NIA NIH HHS/United States ; N01-AG-6-2101/AG/NIA NIH HHS/United States ; U19 AG023122/AG/NIA NIH HHS/United States ; N01-AG-6-2103/AG/NIA NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; N01-AG-6-2106/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aging/*pathology ; *Body Composition ; *Bone Density ; Female ; Fractures, Bone/*genetics ; Humans ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Osteoporosis/*genetics ; Polymerase Chain Reaction ; Surveys and Questionnaires ; *Telomere ; },
abstract = {Short leukocyte telomere length (TL), low BMD, and osteoporosis have been associated with increased inflammation. Previous reports suggest an association between TL, BMD, and osteoporosis in women. We sought to verify these associations and to determine whether TL is related to fracture in a cohort of older men and women. Participants included 2750 community-dwelling older persons from the longitudinal Health, Aging, and Body Composition Study (Health ABC) in who average leukocyte TL was measured at baseline using qPCR. We used unconditional logistic regression to determine the association of TL with prevalent fracture, Cox proportional hazards regression for the association with 7-yr incident fracture, and mixed linear models for the association with BMD, change in BMD, and the number of incident fractures. TL was negatively correlated with age, weight, fasting insulin, and fasting glucose in men and women, and additionally, with C-reactive protein and IL-6 in men. TL was not associated with BMD; change in BMD over 1, 3, or 5 yr; osteoporosis; baseline fracture; or 7-yr incident fracture, before or after adjustment for age, race, smoking, and health characteristics. TL is not associated with BMD, osteoporosis, or fracture in older men or women in this sample.},
}
@article {pmid19337721,
year = {2009},
author = {Liew, LP and Norbury, CJ},
title = {Telomere maintenance: all's well that ends well.},
journal = {Archives of toxicology},
volume = {83},
number = {5},
pages = {407-416},
doi = {10.1007/s00204-009-0423-1},
pmid = {19337721},
issn = {1432-0738},
support = {A7791/CRUK_/Cancer Research UK/United Kingdom ; BB/F013531/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; *DNA Damage ; *DNA Replication ; Humans ; Models, Biological ; *Recombination, Genetic ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {The nucleoprotein structures termed telomeres serve to prevent the mis-identification of eukaryotic chromosome ends as sites of DNA damage, but are also among the genomic regions that pose the most problems during DNA replication. Here, we summarize some of the apparent difficulties encountered by the DNA replication machinery when it approaches the chromosome ends. Eukaryotic cells have evolved diverse mechanisms to overcome these problems, underlining the importance of telomere maintenance for a number of aspects of chromosome function. Of particular interest in this respect are the ways in which telomere-binding proteins and components of the DNA damage response machinery may facilitate replication fork progression through telomeres.},
}
@article {pmid19329760,
year = {2009},
author = {Vizlin-Hodzic, D and Ryme, J and Simonsson, S and Simonsson, T},
title = {Developmental studies of Xenopus shelterin complexes: the message to reset telomere length is already present in the egg.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {23},
number = {8},
pages = {2587-2594},
doi = {10.1096/fj.09-129619},
pmid = {19329760},
issn = {1530-6860},
mesh = {Animals ; Base Sequence ; DNA/genetics/metabolism ; DNA Primers/genetics ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Humans ; Models, Biological ; Molecular Sequence Data ; Ovum/metabolism ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Xenopus/genetics/*growth &amp; development/*metabolism ; Xenopus Proteins/chemistry/genetics/*metabolism ; Xenopus laevis/genetics/growth &amp; development/metabolism ; },
abstract = {The 6-protein complex shelterin protects the telomeres of human chromosomes. The recent discovery that telomeres are important for epigenetic gene regulation and vertebrate embryonic development calls for the establishment of model organisms to study shelterin and telomere function under normal developmental conditions. Here, we report the sequences of the shelterin-encoding genes in Xenopus laevis and its close relation Xenopus tropicalis. In vitro expression and biochemical characterization of the Xenopus shelterin proteins TRF1, TRF2, POT1, TIN2, RAP1, TPP1, and the shelterin accessory factor PINX1 indicate that all main functions of their human orthologs are conserved in Xenopus. The XlTRF1 and XtTRF1 proteins bind double-stranded telomeric DNA sequence specifically and interact with XlTIN2 and XtTIN2, respectively. Similarly, the XlTRF2 and XtTRF2 proteins bind double-stranded telomeric DNA and interact with XlRAP1 and XtRAP1, respectively, whereas the XlPOT1 and XtPOT1 proteins bind single-stranded telomeric DNA. Real-time PCR further reveals the gene expression profiles for telomerase and the shelterin genes during embryogenesis. Notably, the composition of shelterin and the formation of its subcomplexes appear to be temporally regulated during embryonic development. Moreover, unexpectedly high telomerase and shelterin gene expression during early embryogenesis may reflect a telomere length-resetting mechanism, similar to that reported for induced pluripotent stem cells and for animals cloned through somatic nuclear transfer.},
}
@article {pmid19325938,
year = {2009},
author = {Hartong, DT and McGee, TL and Sandberg, MA and Berson, EL and Asselbergs, FW and van der Harst, P and De Vivo, I and Dryja, TP},
title = {Search for a correlation between telomere length and severity of retinitis pigmentosa due to the dominant rhodopsin Pro23His mutation.},
journal = {Molecular vision},
volume = {15},
number = {},
pages = {592-597},
pmid = {19325938},
issn = {1090-0535},
support = {EY08683/EY/NEI NIH HHS/United States ; R01 EY000169/EY/NEI NIH HHS/United States ; R01 CA082838/CA/NCI NIH HHS/United States ; R01 EY008683/EY/NEI NIH HHS/United States ; CA132190/CA/NCI NIH HHS/United States ; R03 CA132190/CA/NCI NIH HHS/United States ; R37 EY000169/EY/NEI NIH HHS/United States ; CA082838/CA/NCI NIH HHS/United States ; EY00169/EY/NEI NIH HHS/United States ; },
mesh = {Adult ; Apoptosis/genetics ; Electroretinography ; Female ; Genes, Dominant ; Humans ; Male ; Middle Aged ; *Mutation, Missense ; Photoreceptor Cells, Vertebrate/physiology ; *Retinitis Pigmentosa/genetics/physiopathology ; Rhodopsin/*genetics ; *Telomere ; },
abstract = {PURPOSE: Great variation exists in the age of onset of symptoms and the severity of disease at a given age in patients with retinitis pigmentosa (RP). The final pathway for this disease may involve apoptotic photoreceptor cell death. Telomere length is associated with biologic aging, senescence, and apoptosis. We evaluated whether the length of telomeres in leukocytes correlated with the severity of RP in patients with the Pro23His rhodopsin mutation who have shown marked heterogeneity in disease severity.<br><br>METHODS: We evaluated 122 patients with the Pro23His rhodopsin mutation. The patients' retinal function was stratified according to their 30-Hz cone electroretinogram (ERG). The length of telomeres in leukocytes was measured by the quantitative real time polymerase chain reaction (qRT-PCR) method in the 15 patients with the highest age-adjusted 30-Hz ERG amplitudes and in the 15 patients with the lowest amplitudes.<br><br>RESULTS: Mean leukocyte telomere length was similar in the 15 patients with the highest cone ERG amplitudes (median: 0.40 units; interquartile range 0.36-0.56) and the 15 patients with the lowest cone amplitudes (median: 0.41 units; inter quartile range 0.34 -0.64; p=0.95).<br><br>CONCLUSIONS: We found no evidence for an association between telomere length and the severity of RP as monitored by the cone ERG in patients with the Pro23His rhodopsin mutation.},
}
@article {pmid19324831,
year = {2009},
author = {Bize, P and Criscuolo, F and Metcalfe, NB and Nasir, L and Monaghan, P},
title = {Telomere dynamics rather than age predict life expectancy in the wild.},
journal = {Proceedings. Biological sciences},
volume = {276},
number = {1662},
pages = {1679-1683},
pmid = {19324831},
issn = {0962-8452},
mesh = {Aging/*genetics ; Animals ; Birds/genetics/*physiology ; Female ; Genetic Variation ; Longevity/*genetics ; Male ; Telomere/*physiology ; },
abstract = {Despite accumulating evidence from in vitro studies that cellular senescence is linked to telomere dynamics, how this relates to whole-organism senescence and longevity is poorly understood and controversial. Using data on telomere length in red blood cells and long-term survival from wild Alpine swifts of a range of ages, we report that the telomere length and the rate of telomere loss are predictive of life expectancy, and that slow erosion of relatively long telomeres is associated with the highest survival probabilities. Importantly, because telomere dynamics, rather than chronological age, predict life expectancy, our study provides good evidence for a mechanistic link between telomere erosion and reduced organism longevity under natural conditions, chronological age itself possibly not becoming a significant predictor until very old ages beyond those in our sample.},
}
@article {pmid19321665,
year = {2009},
author = {Cooley, C and Baird, KM and Faure, V and Wenner, T and Stewart, JL and Modino, S and Slijepcevic, P and Farr, CJ and Morrison, CG},
title = {Trf1 is not required for proliferation or functional telomere maintenance in chicken DT40 cells.},
journal = {Molecular biology of the cell},
volume = {20},
number = {10},
pages = {2563-2571},
pmid = {19321665},
issn = {1939-4586},
support = {//Medical Research Council/United Kingdom ; },
mesh = {Animals ; Cell Line ; Cell Proliferation/radiation effects ; Chickens ; Gene Targeting ; In Situ Hybridization, Fluorescence ; Phenotype ; RNA Splicing/radiation effects ; Radiation, Ionizing ; Telomerase/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/deficiency/*metabolism ; Transfection ; },
abstract = {The telomere end-protection complex prevents the ends of linear eukaryotic chromosomes from degradation or inappropriate DNA repair. The homodimeric double-stranded DNA-binding protein, Trf1, is a component of this complex and is essential for mouse embryonic development. To define the requirement for Trf1 in somatic cells, we deleted Trf1 in chicken DT40 cells by gene targeting. Trf1-deficient cells proliferated as rapidly as control cells and showed telomeric localization of Trf2, Rap1, and Pot1. Telomeric G-strand overhang lengths were increased in late-passage Trf1-deficient cells, although telomere lengths were unaffected by Trf1 deficiency, as determined by denaturing Southern and quantitative FISH analysis. Although we observed some clonal variation in terminal telomere fragment lengths, this did not correlate with cellular Trf1 levels. Trf1 was not required for telomere seeding, indicating that de novo telomere formation can proceed without Trf1. The Pin2 isoform and a novel exon 4, 5-deleted isoform localized to telomeres in Trf1-deficient cells. Trf1-deficient cells were sensitive to DNA damage induced by ionizing radiation. Our data demonstrate that chicken DT40 B cells do not require Trf1 for functional telomere structure and suggest that Trf1 may have additional, nontelomeric roles involved in maintaining genome stability.},
}
@article {pmid19318563,
year = {2009},
author = {Svenson, U and Ljungberg, B and Roos, G},
title = {Telomere length in peripheral blood predicts survival in clear cell renal cell carcinoma.},
journal = {Cancer research},
volume = {69},
number = {7},
pages = {2896-2901},
doi = {10.1158/0008-5472.CAN-08-3513},
pmid = {19318563},
issn = {1538-7445},
mesh = {Adenocarcinoma, Clear Cell/blood/*genetics/pathology ; Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Kidney/ultrastructure ; Kidney Neoplasms/blood/*genetics/pathology ; Male ; Middle Aged ; Neoplasm Staging ; Survival Rate ; Telomere/*metabolism ; },
abstract = {Telomeres are repetitive structures located at chromosome ends. Previous studies have indicated that blood cell telomeres may serve as a biomarker for cancer risk. In addition, we recently reported that blood telomere length predicted survival in patients with breast cancer. In the present study, we examined whether blood telomere length may act as a predictor for survival in newly diagnosed patients with clear cell renal cell carcinoma. Furthermore, we analyzed telomere length in tumor samples and corresponding kidney cortex. Relative telomere length (RTL) was measured on extracted DNA using real-time PCR. Interestingly, and in line with our previous findings in breast cancer, patients with the longest blood telomeres (fourth quartile) had a significantly worse prognosis compared with patients with shorter blood RTL (P=0.005). A highly significant association was found between long blood telomeres and a poor outcome in patients with nonmetastatic disease (P<0.001), whereas patients with distant metastases had a poor survival regardless of blood RTL (P=0.432). No correlations were found between blood RTL and various clinical variables, such as erythrocyte sedimentation rate, hemoglobin, and thrombocyte count. Multivariate Cox regression analysis verified long blood RTL as an independent negative prognostic marker. In contrast, telomere length in kidney cortex and tumor tissue did not predict survival. In conclusion, our results indicate that blood RTL may predict kidney cancer survival, with implications for future treatment strategies.},
}
@article {pmid19302371,
year = {2009},
author = {Diez Roux, AV and Ranjit, N and Jenny, NS and Shea, S and Cushman, M and Fitzpatrick, A and Seeman, T},
title = {Race/ethnicity and telomere length in the Multi-Ethnic Study of Atherosclerosis.},
journal = {Aging cell},
volume = {8},
number = {3},
pages = {251-257},
pmid = {19302371},
issn = {1474-9726},
support = {R01 HL076831-04/HL/NHLBI NIH HHS/United States ; N01-HC-95162/HC/NHLBI NIH HHS/United States ; R01 HL76831/HL/NHLBI NIH HHS/United States ; N01-HC-95165/HC/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; N01-HC-95160/HC/NHLBI NIH HHS/United States ; N01-HC-95161/HC/NHLBI NIH HHS/United States ; N01-HC-95163/HC/NHLBI NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; N01-HC-95159/HC/NHLBI NIH HHS/United States ; R01 HL076831/HL/NHLBI NIH HHS/United States ; N01-HC-95169/HC/NHLBI NIH HHS/United States ; N01-HC-95164/HC/NHLBI NIH HHS/United States ; N01HC95165/HL/NHLBI NIH HHS/United States ; },
mesh = {Aging/*genetics ; Atherosclerosis/ethnology/genetics ; Black People/*genetics ; Female ; Hispanic or Latino/*genetics ; Humans ; Male ; Middle Aged ; Oxidative Stress/genetics ; Racial Groups/genetics ; Telomere/*metabolism ; White People/*genetics ; },
abstract = {Telomere length has emerged as a marker of exposure to oxidative stress and aging. Race/ethnic differences in telomere length have been infrequently investigated. Leukocyte telomere length (LTL) was assessed 981 white, black and Hispanic men and women aged 45-84 years participating in the Multi-Ethnic Study of Atherosclerosis. Direct measurement and questionnaire were used to assess covariates. Linear regression was used to estimate associations of LTL with race/ethnicity and age after adjustment for sex, income, education, smoking, physical activity, diet and body mass index. On average blacks and Hispanics had shorter telomeres than whites [adjusted mean differences (standard error) in T/S ratio compared to whites: -0.041 (0.018) for blacks and -0.044 (0.018) for Hispanics]. Blacks and Hispanics showed greater differences in telomere length associated with age than whites (adjusted mean differences in T/S ratio per 1 year increase in age -0.0018, -0.0047 and -0.0055 in whites, blacks and Hispanics respectively). Differences in age associations were more pronounced and only statistically significant in women. Race/ethnic differences in LTL may reflect the cumulative burden of differential exposure to oxidative stress (and its predictors) over the lifecourse.},
}
@article {pmid19301654,
year = {2009},
author = {Folini, M and Pennati, M and Zaffaroni, N},
title = {RNA interference-mediated validation of genes involved in telomere maintenance and evasion of apoptosis as cancer therapeutic targets.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {487},
number = {},
pages = {303-330},
doi = {10.1007/978-1-60327-547-7_15},
pmid = {19301654},
issn = {1064-3745},
mesh = {Apoptosis/*physiology ; Humans ; Neoplasms/genetics/*therapy ; *RNA Interference ; RNA, Small Interfering/*therapeutic use ; Telomere/*physiology ; },
abstract = {The discovery of new cancer-related therapeutic targets is mainly based on the identification of genes involved in pathways selectively exploited in cancer cells, including those leading to unlimited replicative potential, evasion of apoptosis, angiogenesis, tissue invasion and metastatic spread. Potentially, a gene--or a gene product--is recognized as a cancer target whether its modulation in experimental models can specifically modify or revert the cancer phenotype. As soon as RNA interference (RNAi)--a natural gene silencing mechanism--was demonstrated in mammalian cells, it rapidly became an essential means for gene knockdown in preclinical models, making it possible to define the role of several human genes and to identify those specifically involved in the onset and progression of cancer. Owing to its powerful gene-silencing properties, RNAi has been proposed as a useful tool to validate new therapeutic targets and to develop innovative anticancer therapies. This chapter summarizes the findings from recent studies relying on the use of RNAi-based approaches to functionally validate therapeutic targets related to two tumor hallmarks: the unlimited replicative potential (i.e., activation of telomere maintenance mechanisms) and evasion of apoptosis (i.e., up-regulation of anti-apoptotic factors).},
}
@article {pmid19295915,
year = {2009},
author = {Flores, I and Blasco, MA},
title = {A p53-dependent response limits epidermal stem cell functionality and organismal size in mice with short telomeres.},
journal = {PloS one},
volume = {4},
number = {3},
pages = {e4934},
pmid = {19295915},
issn = {1932-6203},
mesh = {Animals ; Cell Proliferation ; Cellular Senescence ; Epidermal Cells ; Epidermis/*physiology ; Hair Follicle/cytology/physiology ; Kidney/cytology/metabolism ; Mice ; Mice, Knockout ; Phenotype ; Stem Cells/cytology/*physiology ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; Wound Healing ; },
abstract = {Telomere maintenance is essential to ensure proper size and function of organs with a high turnover. In particular, a dwarf phenotype as well as phenotypes associated to premature loss of tissue regeneration, including the skin (hair loss, hair graying, decreased wound healing), are found in mice deficient for telomerase, the enzyme responsible for maintaining telomere length. Coincidental with the appearance of these phenotypes, p53 is found activated in several tissues from these mice, where is thought to trigger cellular senescence and/or apoptotic responses. Here, we show that p53 abrogation rescues both the small size phenotype and restitutes the functionality of epidermal stem cells (ESC) of telomerase-deficient mice with dysfunctional telomeres. In particular, p53 ablation restores hair growth, skin renewal and wound healing responses upon mitogenic induction, as well as rescues ESCmobilization defects in vivo and defective ESC clonogenic activity in vitro. This recovery of ESC functions is accompanied by a downregulation of senescence markers and an increased proliferation in the skin and kidney of telomerase-deficient mice with critically short telomeres without changes in apoptosis rates. Together, these findings indicate the existence of a p53-dependent senescence response acting on stem/progenitor cells with dysfunctional telomeres that is actively limiting their contribution to tissue regeneration, thereby impinging on tissue fitness.},
}
@article {pmid19293310,
year = {2009},
author = {De Vivo, I and Prescott, J and Wong, JY and Kraft, P and Hankinson, SE and Hunter, DJ},
title = {A prospective study of relative telomere length and postmenopausal breast cancer risk.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {18},
number = {4},
pages = {1152-1156},
pmid = {19293310},
issn = {1055-9965},
support = {CA082838/CA/NCI NIH HHS/United States ; CA065725/CA/NCI NIH HHS/United States ; R01 CA049449-19/CA/NCI NIH HHS/United States ; R01 CA065725-05/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; CA49449/CA/NCI NIH HHS/United States ; R01 CA065725/CA/NCI NIH HHS/United States ; R01 CA082838/CA/NCI NIH HHS/United States ; T32 CA09001/CA/NCI NIH HHS/United States ; P01 CA087969-09/CA/NCI NIH HHS/United States ; CA132190/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; U01 CA049449/CA/NCI NIH HHS/United States ; R01 CA082838-09/CA/NCI NIH HHS/United States ; CA87969/CA/NCI NIH HHS/United States ; R03 CA132190-02/CA/NCI NIH HHS/United States ; T32 CA009001-33/CA/NCI NIH HHS/United States ; R03 CA132190/CA/NCI NIH HHS/United States ; T32 CA009001/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; Breast Neoplasms/blood/*genetics ; Case-Control Studies ; DNA, Neoplasm/analysis/genetics ; Estradiol/blood ; Estrone/blood ; Female ; Humans ; Middle Aged ; Polymerase Chain Reaction ; *Postmenopause ; Prognosis ; Prospective Studies ; Risk Factors ; Telomere/*genetics ; },
abstract = {During breast cancer progression, a substantial increase in chromosomal aberrations is observed in the transition from ductal hyperplasia to carcinoma in situ. Telomeres are essential structures to chromosomal integrity. Consequently, telomere dysfunction, which leads to genomic instability, is hypothesized to play a causal role in the progression of breast cancer. However, the few epidemiologic studies that have assessed the relationship between telomere length and breast cancer risk have been inconsistent. We used quantitative real-time PCR to measure relative telomere length in genomic DNA extracted from peripheral blood leukocytes and examined its association with postmenopausal breast cancer risk in 1,122 invasive breast cancer cases and 1,147 matched controls free of diagnosed cancer nested within the prospective Nurses' Health Study. Our data show that relative telomere length was not associated with a significant elevation in postmenopausal breast cancer risk [below versus above median; odds ratio, 1.23; 95% confidence interval, 0.94-1.60; P(trend) = 0.20]. Estrone and estradiol hormone levels were significantly inversely associated with relative telomere length (P = 0.02). Other established breast cancer risk factors such as family history of breast cancer and history of benign breast disease were not associated with relative telomere length in separate linear regression models each adjusted for age and disease status (P > or = 0.07). Our results provide little support for an important role of telomere length, as measured in peripheral blood leukocytes, as a biomarker of breast cancer risk.},
}
@article {pmid19287395,
year = {2009},
author = {Kim, H and Lee, OH and Xin, H and Chen, LY and Qin, J and Chae, HK and Lin, SY and Safari, A and Liu, D and Songyang, Z},
title = {TRF2 functions as a protein hub and regulates telomere maintenance by recognizing specific peptide motifs.},
journal = {Nature structural &amp; molecular biology},
volume = {16},
number = {4},
pages = {372-379},
pmid = {19287395},
issn = {1545-9985},
mesh = {*Cell Cycle ; Cell Cycle Proteins ; Cell Line ; Cytoskeletal Proteins ; DNA-Binding Proteins/metabolism ; Humans ; Mutagenesis, Site-Directed ; Nerve Tissue Proteins/metabolism ; Nuclear Proteins/metabolism ; Protein Binding ; *Protein Interaction Domains and Motifs ; *Protein Interaction Mapping ; RNA-Binding Proteins/metabolism ; *Telomere ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; },
abstract = {In mammalian cells, the telomeric repeat binding factor (TRF) homology (TRFH) domain-containing telomeric proteins TRF1 and TRF2 associate with a collection of molecules necessary for telomere maintenance and cell-cycle progression. However, the specificity and the mechanisms by which TRF2 communicates with different signaling pathways remain largely unknown. Using oriented peptide libraries, we demonstrate that the TRFH domain of human TRF2 recognizes [Y/F]XL peptides with the consensus motif YYHKYRLSPL. Disrupting the interactions between the TRF2 TRFH domain and its targets resulted in telomeric DNA-damage responses. Furthermore, our genome-wide target analysis revealed phosphatase nuclear targeting subunit (PNUTS) and microcephalin 1 (MCPH1) as previously unreported telomere-associated proteins that directly interact with TRF2 via the [Y/F]XL motif. PNUTS and MCPH1 can regulate telomere length and the telomeric DNA-damage response, respectively. Our findings indicate that an array of TRF2 molecules functions as a protein hub and regulates telomeres by recruiting different signaling molecules via a linear sequence code.},
}
@article {pmid19285940,
year = {2009},
author = {Rog, O and Miller, KM and Ferreira, MG and Cooper, JP},
title = {Sumoylation of RecQ helicase controls the fate of dysfunctional telomeres.},
journal = {Molecular cell},
volume = {33},
number = {5},
pages = {559-569},
doi = {10.1016/j.molcel.2009.01.027},
pmid = {19285940},
issn = {1097-4164},
support = {//Cancer Research UK/United Kingdom ; },
mesh = {Alleles ; Cold Temperature ; DNA Helicases/genetics/*metabolism ; DNA Replication ; *Gene Expression Regulation, Fungal/radiation effects ; Genomic Instability ; Genotype ; Mutation ; Phenotype ; *Protein Processing, Post-Translational ; RecQ Helicases/genetics/*metabolism ; Recombination, Genetic ; Replication Origin ; Schizosaccharomyces/*enzymology/genetics/growth &amp; development ; Schizosaccharomyces pombe Proteins/genetics/*metabolism/radiation effects ; Small Ubiquitin-Related Modifier Proteins/*metabolism ; Stress, Physiological/genetics ; Telomere/*metabolism ; Telomere-Binding Proteins/deficiency/genetics ; Time Factors ; },
abstract = {Genome stability depends upon the RecQ helicases, which are conserved from bacteria to man, but little is known about how their myriad activities are regulated. Fission yeast lacking the telomere protein Taz1 (mammalian TRF1/TRF2 ortholog) lose many hallmarks of telomeres, including accurate replication and local protection from DNA repair reactions. Here we show that the RecQ homolog, Rqh1, is sumoylated. Surprisingly, Rqh1 acts on taz1Delta telomeres in a deleterious way, promoting telomere breakage and entanglement. Mutation of Rqh1 sumoylation sites rescues taz1Delta cells from these hazards without dramatically affecting nontelomeric Rqh1 functions. The prominence of Rqh1 in the etiology of several different telomere defects supports the idea that they originate from a common underlying lesion--aberrant processing of the stalled telomeric replication forks that accumulate in the absence of Taz1. Our work underscores the principle that RecQ helicases are "double-edged swords" whose activity, while necessary for maintaining genome-wide stability, must be vigilantly controlled.},
}
@article {pmid19285750,
year = {2009},
author = {Hosgood, HD and Cawthon, R and He, X and Chanock, S and Lan, Q},
title = {Genetic variation in telomere maintenance genes, telomere length, and lung cancer susceptibility.},
journal = {Lung cancer (Amsterdam, Netherlands)},
volume = {66},
number = {2},
pages = {157-161},
pmid = {19285750},
issn = {1872-8332},
support = {N01CO12400/CA/NCI NIH HHS/United States ; Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; N01-CO-12400/CO/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; China/epidemiology ; Female ; Genetic Predisposition to Disease/*genetics ; *Genetic Variation ; Humans ; Lung Neoplasms/epidemiology/*genetics ; Male ; Middle Aged ; Risk Factors ; Telomere/*genetics ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Telomeres are responsible for the protection of the chromosome ends and shortened telomere length has been associated with risk of multiple cancers. Genetic variation in telomere-related genes may alter cancer risk associated with telomere length. Using lung cancer cases (n=120) and population-based controls (n=110) from Xuanwei, China, we analyzed telomere length separately and in conjunction with single nucleotide polymorphisms in the telomere maintenance genes POT1, TERT, and TERF2, which we have previously reported were associated with risk of lung cancer in this study. POT1 rs10244817, TERT rs2075786, and TERF2 rs251796 were significantly associated with lung cancer (p(trend)< or =0.05). The shortest tertile of telomere length was not significantly associated with risk of lung cancer (OR=1.58; 95% CI=0.79-3.18) when compared to the longest tertile of telomere length. When stratified by genotype, there was a suggestion of a dose-response relationship between tertiles of telomere length and risk of lung cancer among the POT1 rs10244817 common variant carriers (OR (95% CI)=1.33 (0.47-3.75), 3.30 (1.14-9.56), respectively) but not among variant genotype carriers (p(interaction)=0.05). Our findings provide evidence that telomere length and genetic variation in telomere maintenance genes may be associated with risk of lung cancer susceptibility and warrant replication in larger studies.},
}
@article {pmid19279086,
year = {2009},
author = {Fernandez-Egea, E and Bernardo, M and Heaphy, CM and Griffith, JK and Parellada, E and Esmatjes, E and Conget, I and Nguyen, L and George, V and Stöppler, H and Kirkpatrick, B},
title = {Telomere length and pulse pressure in newly diagnosed, antipsychotic-naive patients with nonaffective psychosis.},
journal = {Schizophrenia bulletin},
volume = {35},
number = {2},
pages = {437-442},
pmid = {19279086},
issn = {0586-7614},
support = {R01 DK069265/DK/NIDDK NIH HHS/United States ; R01DK069265/DK/NIDDK NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aging/physiology ; Antipsychotic Agents/adverse effects/therapeutic use ; Blood Pressure/genetics/*physiology ; Diabetes Mellitus/blood/metabolism ; Diastole/genetics/physiology ; Female ; Glucose Tolerance Test ; Humans ; Hydrocortisone/blood ; Leukocytes/metabolism ; Male ; Middle Aged ; Psychiatric Status Rating Scales ; Psychotic Disorders/blood/diagnosis/genetics ; Schizophrenia/*diagnosis/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {INTRODUCTION: Recent studies suggest that in addition to factors such as treatment side effects, suicide, and poor health habits, people with schizophrenia may have an increased risk of diabetes prior to antipsychotic treatment. Diabetes is associated with an increased pulse pressure (PP) and a shortened telomere. We tested the hypothesis that prior to antipsychotic treatment, schizophrenia and related disorders are associated with a shortened telomere, as well as an increased PP.<br><br>METHODS: Telomere content (which is highly correlated with telomere length) and PP were measured in newly diagnosed, antipsychotic-naive patients with schizophrenia and related disorders on first clinical contact and in matched control subjects. Both groups were also administered an oral glucose tolerance test.<br><br>RESULTS: Compared with control subjects, the patients with psychosis had decreased telomere content and an increased PP. As previously reported, they also had increased glucose concentrations at 2 hours. These differences could not be attributed to differences in age, ethnicity, smoking, gender, body mass index, neighborhood of residence, socioeconomic status, aerobic conditioning, or an increased cortisol concentration in the psychotic subjects.<br><br>DISCUSSION: These results suggest that prior to antipsychotic use, nonaffective psychosis is associated with reduced telomere content and increased PP, indices that have been linked to an increased risk of diabetes and hypertension.},
}
@article {pmid19279081,
year = {2009},
author = {Xu, Q and Parks, CG and DeRoo, LA and Cawthon, RM and Sandler, DP and Chen, H},
title = {Multivitamin use and telomere length in women.},
journal = {The American journal of clinical nutrition},
volume = {89},
number = {6},
pages = {1857-1863},
pmid = {19279081},
issn = {1938-3207},
support = {//Intramural NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging/physiology ; Ascorbic Acid/*pharmacology ; Cross-Sectional Studies ; Dietary Supplements ; Female ; Humans ; Least-Squares Analysis ; Leukocytes ; Middle Aged ; Surveys and Questionnaires ; Telomere/*drug effects ; Vitamin E/*pharmacology ; Vitamins/administration &amp; dosage/*pharmacology ; },
abstract = {BACKGROUND: Telomere length may be a marker of biological aging. Multivitamin supplements represent a major source of micronutrients, which may affect telomere length by modulating oxidative stress and chronic inflammation.<br><br>OBJECTIVE: The objective was to examine whether multivitamin use is associated with longer telomeres in women.<br><br>DESIGN: We performed a cross-sectional analysis of data from 586 early participants (age 35-74 y) in the Sister Study. Multivitamin use and nutrient intakes were assessed with a 146-item food-frequency questionnaire, and relative telomere length of leukocyte DNA was measured by quantitative polymerase chain reaction.<br><br>RESULTS: After age and other potential confounders were adjusted for, multivitamin use was associated with longer telomeres. Compared with nonusers, the relative telomere length of leukocyte DNA was on average 5.1% longer among daily multivitamin users (P for trend = 0.002). In the analysis of micronutrients, higher intakes of vitamins C and E from foods were each associated with longer telomeres, even after adjustment for multivitamin use. Furthermore, intakes of both nutrients were associated with telomere length among women who did not take multivitamins.<br><br>CONCLUSION: This study provides the first epidemiologic evidence that multivitamin use is associated with longer telomere length among women.},
}
@article {pmid19276071,
year = {2009},
author = {Wu, TJ and Chiang, YH and Lin, YC and Tsai, CR and Yu, TY and Sung, MT and Lee, YH and Lin, JJ},
title = {Sequential loading of Saccharomyces cerevisiae Ku and Cdc13p to telomeres.},
journal = {The Journal of biological chemistry},
volume = {284},
number = {19},
pages = {12801-12808},
pmid = {19276071},
issn = {0021-9258},
mesh = {Chromatin Immunoprecipitation ; DNA/genetics/*metabolism ; DNA Damage ; DNA Footprinting ; DNA Repair ; DNA, Fungal/genetics/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Deoxyribonuclease I/metabolism ; Electrophoretic Mobility Shift Assay ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Ku is a heterodimeric protein involved in nonhomologous end-joining of the DNA double-stranded break repair pathway. It binds to the double-stranded DNA ends and then activates a series of repair enzymes that join the broken DNA. In addition to its function in DNA repair, the yeast Saccharomyces cerevisiae Ku (Yku) is also a component of telomere protein-DNA complexes that affect telomere function. The yeast telomeres are composed of duplex C(1-3)(A/T)G(1-3) telomeric DNA repeats plus single-stranded TG(1-3) telomeric DNA tails. Here we show that Yku is capable of binding to a tailed-duplex DNA formed by telomeric DNA that mimics the structure of telomeres. Addition of Cdc13p, a single-stranded telomeric DNA-binding protein, to the Yku-DNA complex enables the formation of a ternary complex with Cdc13p binding to the single-stranded tail of the DNA substrate. Because pre-loading of Cdc13p to the single-stranded telomeric tail inhibits the binding of Yku, the results suggested that loading of Yku and Cdc13p to telomeres is sequential. Through generating a double-stranded break near telomeric DNA sequences, we found that Ku protein appears to bind to the de novo synthesized telomeres earlier than that of Cdc13p in vivo. Thus, our results indicated that Yku interacts directly with telomeres and that sequential loading of Yku followed by Cdc13p to telomeres is required for both proteins to form a ternary complex on telomeres. Our results also offer a mechanism that the binding of Cdc13p to telomeres might prevent Yku from initiating DNA double-stranded break repair pathway on telomeres.},
}
@article {pmid19273484,
year = {2009},
author = {Kim, S and Parks, CG and DeRoo, LA and Chen, H and Taylor, JA and Cawthon, RM and Sandler, DP},
title = {Obesity and weight gain in adulthood and telomere length.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {18},
number = {3},
pages = {816-820},
pmid = {19273484},
issn = {1055-9965},
support = {Z99 ES999999/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Aged ; Anthropometry ; Body Mass Index ; Breast Neoplasms/epidemiology/*genetics ; Female ; Humans ; Linear Models ; Middle Aged ; Obesity/epidemiology/*genetics ; Prospective Studies ; Puerto Rico ; Risk Factors ; *Telomere ; United States/epidemiology ; Weight Gain/*genetics ; },
abstract = {Obesity and weight gain in adulthood are associated with an increased risk of several cancers. Telomeres play a critical role in maintaining genomic integrity and may be involved in carcinogenesis. Using data from 647 women ages 35 to 74 years in the United States and Puerto Rico (2003-2004), we examined the association between current and past anthropometric characteristics and telomere length in blood. In a multivariate linear regression model, higher current body mass index (BMI) and hip circumference were inversely associated with telomere length. Higher BMI in the 30s was associated with shorter telomere length among women ages>or=40 years (Ptrend<0.01). Weight gain since the age 30s (Ptrend=0.07) and weight cycling (Ptrend=0.04) were also inversely associated with telomere length. When current BMI and BMI at ages 30 to 39 years were considered together, the most marked decrease in telomere length was found for women who had overweight or obese BMI at both time points (mean telomere repeat copy number to single-copy gene copy number ratio=1.26; 95% confidence interval, 1.21-1.30) compared with women who had normal BMI at both times (mean telomere repeat copy number to single-copy gene copy number ratio=1.33; 95% confidence interval, 1.30-1.36). These findings support the hypothesis that obesity may accelerate aging, and highlight the importance of maintaining a desirable weight in adulthood.},
}
@article {pmid19271707,
year = {2009},
author = {Lim, KW and Amrane, S and Bouaziz, S and Xu, W and Mu, Y and Patel, DJ and Luu, KN and Phan, AT},
title = {Structure of the human telomere in K+ solution: a stable basket-type G-quadruplex with only two G-tetrad layers.},
journal = {Journal of the American Chemical Society},
volume = {131},
number = {12},
pages = {4301-4309},
pmid = {19271707},
issn = {1520-5126},
support = {R01 GM034504/GM/NIGMS NIH HHS/United States ; R01 GM034504-22/GM/NIGMS NIH HHS/United States ; GM34504/GM/NIGMS NIH HHS/United States ; },
mesh = {Circular Dichroism ; DNA/chemistry ; *G-Quadruplexes ; Guanine/chemistry ; Humans ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Molecular Conformation ; Nucleic Acid Conformation ; Potassium/*chemistry ; Spectrophotometry, Ultraviolet ; Telomere/*chemistry ; Temperature ; },
abstract = {Previously, it has been reported that human telomeric DNA sequences could adopt in different experimental conditions four different intramolecular G-quadruplexes each involving three G-tetrad layers, namely, Na(+) solution antiparallel-stranded basket form, K(+) crystal parallel-stranded propeller form, K(+) solution (3 + 1) Form 1, and K(+) solution (3 + 1) Form 2. Here we present a new intramolecular G-quadruplex adopted by a four-repeat human telomeric sequence in K(+) solution (Form 3). This structure is a basket-type G-quadruplex with only two G-tetrad layers: loops are successively edgewise, diagonal, and edgewise; glycosidic conformations of guanines are syn x syn x anti x anti around each tetrad. Each strand of the core has both a parallel and an antiparallel adjacent strands; there are one narrow, one wide, and two medium grooves. Despite the presence of only two G-tetrads in the core, this structure is more stable than the three-G-tetrad intramolecular G-quadruplexes previously observed for human telomeric sequences in K(+) solution. Detailed structural elucidation of Form 3 revealed extensive base pairing and stacking in the loops capping both ends of the G-tetrad core, which might explain the high stability of the structure. This novel structure highlights the conformational heterogeneity of human telomeric DNA. It establishes a new folding principle for G-quadruplexes and suggests new loop sequences and structures for targeting in human telomeric DNA.},
}
@article {pmid19261979,
year = {2008},
author = {Kaszubowska, L},
title = {Telomere shortening and ageing of the immune system.},
journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society},
volume = {59 Suppl 9},
number = {},
pages = {169-186},
pmid = {19261979},
issn = {1899-1505},
mesh = {Age Factors ; Aged ; Aged, 80 and over ; Aging/*immunology ; Animals ; Antigens/immunology ; B-Lymphocytes/metabolism ; Humans ; Immune System/*metabolism ; Oxidative Stress/immunology ; T-Lymphocytes/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are protein-DNA complexes localized at the ends of linear chromosomes constituted by short, tandem G-rich hexanucleotide repeats and associated proteins. Their length shortens with each cell division and correlates inversely with age. It can be modified by genetic and epigenetic factors, sex hormones, reactive oxygen species and inflammatory reactions. A critical minimum length of telomeres triggers a cell cycle arrest or senescence of the cell. The immune system is highly sensitive to shortening of telomeres as its competence depends strictly on cell renewal and clonal expansion of T- and B-cell populations. Cells of the immune system are unique among normal somatic cells as they can up-regulate telomerase, the telomere extending enzyme, and limit telomere attrition in the process of cell proliferation undergoing in activated cells. Telomere length is highly variable among humans. Lineage-specific telomere shortening with different kinetics of telomere attrition was observed in CD4+, CD8+ T lymphocytes, B lymphocytes, granulocytes, monocytes and NK cell population. Immunosenescence is characterized by a special remodeling of the immune system induced by antigen exposure and oxidative stress. In ageing immune system adaptive immunity deteriorates because of a progressive decline of naive T and B cells and decrease of absolute numbers of T and B lymphocytes. The innate compartment of the immune system is relatively well preserved although some age-dependent alterations can be also observed. Nonagenarians or centenarians represent phenomenon of successful ageing of the immune system as most of their immune parameters are well preserved.},
}
@article {pmid19270525,
year = {2009},
author = {Cenci, G},
title = {Drosophila cell cycle under arrest: uncapped telomeres plead guilty.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {8},
number = {7},
pages = {990-995},
doi = {10.4161/cc.8.7.7960},
pmid = {19270525},
issn = {1551-4005},
mesh = {Animals ; *Cell Cycle ; Cell Cycle Proteins/genetics/*physiology ; Chromosomal Proteins, Non-Histone/genetics/*physiology ; DNA Damage/genetics/physiology ; Drosophila/cytology/genetics/*physiology ; Drosophila Proteins/genetics/*physiology ; Genes, cdc ; Spindle Apparatus/genetics/physiology ; Telomere/genetics/*physiology ; },
abstract = {Telomeres are specialized structures that protect chromosome ends from degradation and fusion events. In most organisms, telomeres consist of short, repetitive G-rich sequences added to chromosome ends by a reverse transcriptase with an internal RNA template, called telomerase. Specific DNA-binding protein complexes associate with telomeric sequences preventing chromosome ends from being recognized as DNA double strand breaks (DSBs). Telomeres that lose their cap activate the DNA damage response (DDR) likewise DSBs and, if inappropriately repaired, generate telomeric fusions, which eventually lead to genome instability. In Drosophila there is not telomerase, and telomere length is maintained by transposition of three specialized retroelements. However, fly telomeres are protected by multi protein complexes like their yeast and vertebrate counterparts; these complexes bind chromosome ends in a sequence-independent fashion and are required to prevent checkpoint activation and end-to-end fusion. Uncapped Drosophila telomeres elicit a DDR just as dysfunctional human telomeres. Most interestingly, uncapped Drosophila telomeres also activate the spindle assembly checkpoint (SAC) by recruiting the SAC kinase BubR1. BubR1 accumulations at chromosome ends trigger the SAC that inhibits the metaphase-to-anaphase transition. These findings, reviewed here, highlight an intriguing and unsuspected connection between telomeres and cell cycle regulation, providing a clue to understand human telomere function.},
}
@article {pmid19268672,
year = {2009},
author = {Kapoor, V and Hakim, FT and Rehman, N and Gress, RE and Telford, WG},
title = {Quantum dots thermal stability improves simultaneous phenotype-specific telomere length measurement by FISH-flow cytometry.},
journal = {Journal of immunological methods},
volume = {344},
number = {1},
pages = {6-14},
pmid = {19268672},
issn = {1872-7905},
support = {Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Flow Cytometry/*methods ; Fluorescent Dyes/*chemistry ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Monocytes/immunology ; *Quantum Dots ; T-Lymphocyte Subsets/immunology ; Telomere/*chemistry ; },
abstract = {Telomere length analysis has been greatly simplified by the quantitative flow cytometry technique FISH-flow. In this method, a fluorescein-labeled synthetic oligonucleotide complementary to the telomere terminal repeat sequence is hybridized to the telomere sequence and the resulting fluorescence measured by flow cytometry. This technique has supplanted the traditional laborious Southern blot telomere length measurement techniques in many laboratories, and allows single cell analysis of telomere length in high-throughput sample formats. Nevertheless, the harsh conditions required for telomere probe annealing (82 degrees C) has made it difficult to successfully combine this technique with simultaneous immunolabeling. Most traditional organic fluorescent probes (i.e. fluorescein, phycoerythrin, etc.) have limited thermal stability and do not survive the high temperature annealing process, despite efforts to covalently crosslink the antigen-antibody-fluorophore complex. This loss of probe fluorescence has made it difficult to measure FISH-flow in complex lymphocyte populations, and has generally forced investigators to use fluorescent-activated cell sorting to pre-separate their populations, a laborious technique that requires prohibitively large numbers of cells. In this study, we have substituted quantum dots (nanoparticles) for traditional fluorophores in FISH-flow. Quantum dots were demonstrated to possess much greater thermal stability than traditional low molecular weight and phycobiliprotein fluorophores. Quantum dot antibody conjugates directed against monocyte and T cell antigens were found to retain most of their fluorescence following the high temperature annealing step, allowing simultaneous fluorescent immunophenotyping and telomere length measurement. Since quantum dots have very narrow emission bandwidths, we were able to analyze multiple quantum dot antibody conjugates (Qdot 605, 655 and 705) simultaneously with FISH-flow measurement to assess the age-associated decline in telomere length in both human monocytes and T cell subsets. With quantum dot immunolabeling, the mean decrease rate in telomere length for CD4+ cells was calculated at 41.8 bp/year, very close to previously reported values using traditional flow-FISH and Southern blotting. This modification to the traditional flow-FISH technique should therefore allow simultaneous fluorescent immunophenotyping and telomere length measurement, permitting complex cell subset-specific analysis in small numbers of cells without the requirement for prior cell sorting.},
}
@article {pmid19265708,
year = {2009},
author = {Yoo, JE and Oh, BK and Park, YN},
title = {Human PinX1 mediates TRF1 accumulation in nucleolus and enhances TRF1 binding to telomeres.},
journal = {Journal of molecular biology},
volume = {388},
number = {5},
pages = {928-940},
doi = {10.1016/j.jmb.2009.02.051},
pmid = {19265708},
issn = {1089-8638},
mesh = {Animals ; Cell Cycle/physiology ; Cell Cycle Proteins ; Cell Nucleolus/*metabolism ; Cell Nucleus/metabolism ; HeLa Cells ; Humans ; Mice ; Protein Binding ; Protein Structure, Tertiary ; Recombinant Fusion Proteins/genetics/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/chemistry/genetics/*metabolism ; Tumor Suppressor Proteins/chemistry/genetics/*metabolism ; },
abstract = {Human PinX1 (hPinX1) is known to interact with telomere repeat binding factor 1 (TRF1) and telomerase. Here, we report that hPinX1 regulates the nucleolar accumulation and telomeric association of TRF1. In HeLa, HA-hPinX1 was co-localized with fibrillarin, a nucleolar protein, in 51% of the transfected cells and was present in the nucleoplasm of the remaining 48%. Mutant analysis showed that the C-terminal region was important for nucleolar localization, while the N-terminus exhibited an inhibitory effect on nucleolar localization. Unlike HA- and Myc-hPinX1, GFP-hPinX1 resided predominantly in the nucleolus. Nuclear hPinX1 bound to telomeres and other repeat sequences as well but, despite its interaction with TRF1, nucleolar hPinX1 did not bind to telomeres. Nucleolar hPinX1 forced endogenous TRF1 accumulation in the nucleolus. Furthermore, TRF1 binding to telomeres was upregulated in cells over-expressing hPinX1. In an ALT cell line, WI-38 VA-13, TRF1 did not co-localize with hPinX1 in the nucleoli. In summary, hPinX1 likely interacts with TRF1 in both the nucleolus and the nucleoplasm, and excess hPinX1 results in increased telomere binding of TRF1. The PinX1 function of mediating TRF1 nucleolar accumulation is absent from ALT cells, suggesting that it might be telomerase-dependent.},
}
@article {pmid19264872,
year = {2009},
author = {Peng, SW and Zhu, LY and Chen, M and Zhang, M and Li, DZ and Fu, YC and Chen, SR and Wei, CJ},
title = {Heterogeneity in mitotic activity and telomere length implies an important role of young islets in the maintenance of islet mass in the adult pancreas.},
journal = {Endocrinology},
volume = {150},
number = {7},
pages = {3058-3066},
pmid = {19264872},
issn = {1945-7170},
mesh = {Aging ; Animals ; Biomarkers/*analysis ; Islets of Langerhans/*cytology ; Ki-67 Antigen/biosynthesis ; Male ; Mice ; Mice, Inbred BALB C ; Mitosis ; Pancreas/cytology/*metabolism ; Telomere/*metabolism ; },
abstract = {Understanding the mechanisms of beta-cell dynamics in postnatal animals is central to cure diabetes. A major obstacle in evaluating the status of pancreatic cells is the lack of surface markers. Here we performed quantitative measurements of two internal markers to follow the developmental history of islets. One marker, cell-cycle activity, was established by measuring expression of Ki67 and the incorporation of 5-bromodeoxyuridine. The other marker, the aging process, was delineated by the determination of telomere length. Moreover, islet neogenesis, possibly from ductal precursors, was monitored by pancreatic duct labeling with an enhanced green fluorescence protein (EGFP) transgene. We found that islets from younger animals, on average, expressed higher Ki67 transcripts, displayed elevated 5-bromodeoxyuridine incorporation, and had longer telomeres. However, significant heterogeneity of these parameters was observed among islets from the same mouse. In contrast, the levels of proinsulin-1 transcripts in islets of different ages did not change significantly. Moreover, mitotic activities correlated significantly with telomere lengths of individual islets. Lastly, after 5.5 d pancreatic duct labeling, a few EGFP-positive islets could be identified in neonatal but not from adult pancreases. Compared with unlabeled control islets, EGFP-positive islets had higher mitotic activities and longer telomeres. The results suggest that islets are born at different time points during the embryonic and neonatal stages and imply that young islets might play an important role in the maintenance of islet mass in the adult pancreas.},
}
@article {pmid19264125,
year = {2009},
author = {Proctor, A and Brownhill, SC and Burchill, SA},
title = {The promise of telomere length, telomerase activity and its regulation in the translocation-dependent cancer ESFT; clinical challenges and utility.},
journal = {Biochimica et biophysica acta},
volume = {1792},
number = {4},
pages = {260-274},
doi = {10.1016/j.bbadis.2009.02.011},
pmid = {19264125},
issn = {0006-3002},
mesh = {Animals ; Cell Proliferation ; Cell Survival ; Cellular Senescence ; *Gene Expression Regulation, Enzymologic ; *Gene Expression Regulation, Neoplastic ; Humans ; Neoplasm Proteins/*biosynthesis ; Sarcoma, Ewing/drug therapy/*enzymology/mortality ; Telomerase/*biosynthesis ; Telomere/*metabolism ; *Translocation, Genetic ; },
abstract = {The Ewing's sarcoma family of tumours (ESFT) are diagnosed by EWS-ETS gene translocations. The resulting fusion proteins play a role in both the initiation and maintenance of these solid aggressive malignant tumours, suppressing cellular senescence and increasing cell proliferation and survival. EWS-ETS fusion proteins have altered transcriptional activity, inducing expression of a number of different target genes including telomerase. Up-regulation of hTERT is most likely responsible for the high levels of telomerase activity in primary ESFT, although telomerase activity and expression of hTERT are not predictive of outcome. However levels of telomerase activity in peripheral blood may be useful to monitor response to some therapeutics. Despite high levels of telomerase activity, telomeres in ESFT are frequently shorter than those of matched normal cells. Uncertainty about the role that telomerase and regulators of its activity play in the maintenance of telomere length in normal and cancer cells, and lack of studies examining the relationship between telomerase activity, regulators of its activity and their clinical significance in patient samples have limited their introduction into clinical practice. Studies in clinical samples using standardised assays are critical to establish how telomerase and regulators of its activity might best be exploited for patient benefit.},
}
@article {pmid19259387,
year = {2009},
author = {Stout, GJ and Blasco, MA},
title = {Genetic dissection of the mechanisms underlying telomere-associated diseases: impact of the TRF2 telomeric protein on mouse epidermal stem cells.},
journal = {Disease models &amp; mechanisms},
volume = {2},
number = {3-4},
pages = {139-156},
pmid = {19259387},
issn = {1754-8411},
mesh = {Animals ; Cell Proliferation ; DNA-Binding Proteins/genetics ; *Epidermal Cells ; Genes, p53 ; In Situ Hybridization, Fluorescence ; Keratinocytes/cytology ; Male ; Mice ; Microscopy, Confocal ; Models, Genetic ; Skin/pathology ; Stem Cells/*cytology/*metabolism ; Telomere/*ultrastructure ; Telomeric Repeat Binding Protein 2/*genetics/*physiology ; },
abstract = {TRF2 is a telomere-binding protein involved in the protection of chromosome ends. Interestingly, TRF2 is overexpressed in a number of human cancers. Mice with increased TRF2 expression (K5TRF2 mice) display a severe skin phenotype including an increase in skin cancer and premature skin degeneration, which includes increased skin hyperpigmentation and skin dryness; these pathologies are concomitant with dramatic telomere shortening and increased chromosomal instability. Here, we show that K5TRF2 mice have a severe epidermal stem cell (ESC) dysfunction, which is reversed by abrogation of p53 in the absence of rescue of telomere length. Importantly, p53 deletion also rescues severe skin hyperpigmentation in these mice through regulation of alpha-melanocyte-stimulating hormone (alpha-MSH). In addition, skin carcinogenesis is accelerated in K5TRF2/p53(-/-)mice owing to attenuated p21 induction, which enables cell proliferation to resume. Altogether, these results reveal the existence of a DNA damage-dependent checkpoint that acts on ESCs with critically short telomeres and restricts skin proliferation, thereby increasing protection against skin cancer; however, the checkpoint also leads to premature skin aging phenotypes. Finally, the results described here are relevant to our understanding of the pathobiology of those human diseases that are characterized by the presence of critically short telomeres (hereafter referred to as 'telopathies'), such as dyskeratosis congenita which causes severe skin phenotypes including skin hyperpigmentation and skin cancer.},
}
@article {pmid19256795,
year = {2008},
author = {Itzkovitz, S and Shlush, LI and Gluck, D and Skorecki, K},
title = {Population mixture model for nonlinear telomere dynamics.},
journal = {Physical review. E, Statistical, nonlinear, and soft matter physics},
volume = {78},
number = {6 Pt 1},
pages = {060902},
doi = {10.1103/PhysRevE.78.060902},
pmid = {19256795},
issn = {1539-3755},
mesh = {Animals ; Biophysical Phenomena ; Cell Death/genetics/physiology ; Cell Division/genetics/physiology ; Cellular Senescence/genetics/physiology ; Models, Biological ; Nonlinear Dynamics ; Telomere/chemistry/genetics/*physiology ; },
abstract = {Telomeres are DNA repeats protecting chromosomal ends which shorten with each cell division, eventually leading to cessation of cell growth. We present a population mixture model that predicts an exponential decrease in telomere length with time. We analytically solve the dynamics of the telomere length distribution. The model provides an excellent fit to available telomere data and accounts for the previously unexplained observation of telomere elongation following stress and bone marrow transplantation, thereby providing insight into the nature of the telomere clock.},
}
@article {pmid19255364,
year = {2009},
author = {Yang, Z and Huang, X and Jiang, H and Zhang, Y and Liu, H and Qin, C and Eisner, GM and Jose, PA and Rudolph, L and Ju, Z},
title = {Short telomeres and prognosis of hypertension in a chinese population.},
journal = {Hypertension (Dallas, Tex. : 1979)},
volume = {53},
number = {4},
pages = {639-645},
pmid = {19255364},
issn = {1524-4563},
support = {R01 HL092196/HL/NHLBI NIH HHS/United States ; R01 HL092196-01A1/HL/NHLBI NIH HHS/United States ; HL074940/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging ; Asian People/*statistics &amp; numerical data ; Coronary Artery Disease/ethnology/genetics ; Female ; Follow-Up Studies ; Humans ; Hypertension/*ethnology/*genetics ; Leukocytes/immunology/pathology ; Male ; Middle Aged ; Polymerase Chain Reaction ; Predictive Value of Tests ; Prognosis ; Risk Factors ; Telomere/*genetics/immunology/*pathology ; },
abstract = {Aging is a major risk factor for hypertension and cardiovascular disease. Accumulating evidence suggests that telomere length is a marker for biological aging of the cardiovascular system. Telomere length is determined by genetic and environmental factors. Studies in different racial populations are required to determine the prognostic value of telomere length in hypertension and cardiovascular diseases. The main objective of this study was to investigate the association between leukocyte telomere length and the risk and prognosis of hypertension in a Chinese population. The relative telomere length of leukocytes was determined by a quantitative PCR-based method in 767 subjects: 379 healthy controls and 388 hypertensive patients, ages 30 to 80 years. The median telomere length ratio, 0.57 (interquartile range: 0.48 to 0.72), was shorter in hypertensive than in healthy normotensive subjects (0.67; interquartile range: 0.53 to 0.93; P<0.001). After 5 years of follow-up, subjects with shorter telomeres were at a higher risk of developing coronary artery disease than individuals with longer telomeres (odds ratio: 3.315; 95% CI: 1.662 to 6.609; P<0.001). Multivariate analysis showed that short telomere length and hypertension were independent risk factors for developing coronary artery disease. Our data suggest that mean leukocyte telomere length is a potential predictor of coronary artery disease and support the hypothesis that differences in biological aging can contribute to the risk and variability of developing hypertension and cardiovascular diseases.},
}
@article {pmid19255359,
year = {2009},
author = {Aviv, A},
title = {Leukocyte telomere length, hypertension, and atherosclerosis: are there potential mechanistic explanations?.},
journal = {Hypertension (Dallas, Tex. : 1979)},
volume = {53},
number = {4},
pages = {590-591},
doi = {10.1161/HYPERTENSIONAHA.109.128926},
pmid = {19255359},
issn = {1524-4563},
support = {AG021593/AG/NIA NIH HHS/United States ; AG20132/AG/NIA NIH HHS/United States ; },
mesh = {Atherosclerosis/*genetics/metabolism ; Cellular Senescence/physiology ; Humans ; Hypertension/*genetics/metabolism ; Leukocytes/metabolism/pathology ; Oxidative Stress/physiology ; Telomere/*genetics/immunology/*pathology ; },
}
@article {pmid19254719,
year = {2009},
author = {Tomaska, L and Nosek, J},
title = {Telomere heterogeneity: taking advantage of stochastic events.},
journal = {FEBS letters},
volume = {583},
number = {7},
pages = {1067-1071},
pmid = {19254719},
issn = {1873-3468},
support = {R03 TW005654/TW/FIC NIH HHS/United States ; R03 TW005654-06/TW/FIC NIH HHS/United States ; 2-R03-TW005654-04A1/TW/FIC NIH HHS/United States ; 55005622/HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {DNA/*metabolism ; *Evolution, Molecular ; Gene Expression Regulation/*physiology ; Telomere/*physiology ; },
abstract = {Various means employed to solve problems associated with the ends (telomeres) of linear DNA chromosomes exhibit one common feature: generation of both intra- and intercellular heterogeneity of telomeres at the level of their structural and functional states. We argue that this heterogeneity is not a simple by-product of molecular pathways mediating telomere maintenance. Instead, we propose that these mechanisms were selected because they generate heterogeneity. Similarly as noise in gene expression, stochastic events at telomeres may have an adaptive value allowing cells to sustain viable and flexible populations, with implications for fields ranging from evolutionary biology to molecular medicine.},
}
@article {pmid19250901,
year = {2009},
author = {Lue, NF},
title = {Closing the feedback loop: how cells "count" telomere-bound proteins.},
journal = {Molecular cell},
volume = {33},
number = {4},
pages = {413-414},
doi = {10.1016/j.molcel.2009.02.001},
pmid = {19250901},
issn = {1097-4164},
mesh = {DNA, Fungal/metabolism ; Fungal Proteins/metabolism ; Models, Biological ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomere length homeostasis is thought to occur via a "protein-counting" mechanism whereby high numbers of telomere-bound proteins inhibit telomerase activity. In a recent issue of Molecular Cell, Hirano et al. (2009) delineate the molecular interactions that underlie the budding yeast protein-counting machinery.},
}
@article {pmid19248826,
year = {2009},
author = {Hoffmann, J and Erben, Y and Zeiher, AM and Dimmeler, S and Spyridopoulos, I},
title = {Telomere length-heterogeneity among myeloid cells is a predictor for chronological ageing.},
journal = {Experimental gerontology},
volume = {44},
number = {5},
pages = {363-366},
doi = {10.1016/j.exger.2009.02.006},
pmid = {19248826},
issn = {1873-6815},
mesh = {Adult ; Aging/*metabolism ; Biomarkers/metabolism ; Female ; Humans ; Male ; Myeloid Cells/*metabolism ; Predictive Value of Tests ; Regression Analysis ; Telomere/*metabolism ; },
abstract = {We have previously shown that mean telomere length (TL) of granulocytes reflects TL of myeloid bone marrow cells extremely well. Here we analysed the distribution of TL from peripheral blood granulocytes and lymphocytes in 61 female and 68 age-matched male healthy volunteers. We show that the age-dependent decline in TL occurs more rapid in peripheral blood lymphocytes (53 bp/year) than in granulocytes (39 bp/year; p<0.001), while women having longer telomeres than men. We also observed the best correlation for age and telomere length to be present in lymphocytes. The coefficient variation (CV) of TL distribution in granulocytes and monocytes was significantly higher in older compared to younger individuals, indicating an increase in telomere length heterogeneity of myeloid cells and their bone marrow residing precursors during ageing. In a multivariate statistical model, CV and lymphocyte TL were able to explain 50% of chronological ageing.},
}
@article {pmid19245831,
year = {2009},
author = {Chavez, A and Tsou, AM and Johnson, FB},
title = {Telomeres do the (un)twist: helicase actions at chromosome termini.},
journal = {Biochimica et biophysica acta},
volume = {1792},
number = {4},
pages = {329-340},
pmid = {19245831},
issn = {0006-3002},
support = {P01-AG031862/AG/NIA NIH HHS/United States ; T32 AG000255-11A1/AG/NIA NIH HHS/United States ; P01 AG031862-01/AG/NIA NIH HHS/United States ; P01 AG031862/AG/NIA NIH HHS/United States ; R01-AG021521/AG/NIA NIH HHS/United States ; R01 AG021521-05/AG/NIA NIH HHS/United States ; R01 AG021521/AG/NIA NIH HHS/United States ; T32 AG000255/AG/NIA NIH HHS/United States ; T32-AG000255/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*metabolism/pathology ; Animals ; DNA Helicases/*metabolism ; *DNA Replication ; *Genomic Instability ; Humans ; Neoplasms/*enzymology/pathology ; Recombination, Genetic ; Telomerase/metabolism ; Telomere/*metabolism/pathology ; },
abstract = {Telomeres play critical roles in protecting genome stability, and their dysfunction contributes to cancer and age-related degenerative diseases. The precise architecture of telomeres, including their single-stranded 3' overhangs, bound proteins, and ability to form unusual secondary structures such as t-loops, is central to their function and thus requires careful processing by diverse factors. Furthermore, telomeres provide unique challenges to the DNA replication and recombination machinery, and are particularly suited for extension by the telomerase reverse transcriptase. Helicases use the energy from NTP hydrolysis to track along DNA and disrupt base pairing. Here we review current findings concerning how helicases modulate several aspects of telomere form and function.},
}
@article {pmid19244120,
year = {2009},
author = {Williams, ES and Klingler, R and Ponnaiya, B and Hardt, T and Schrock, E and Lees-Miller, SP and Meek, K and Ullrich, RL and Bailey, SM},
title = {Telomere dysfunction and DNA-PKcs deficiency: characterization and consequence.},
journal = {Cancer research},
volume = {69},
number = {5},
pages = {2100-2107},
pmid = {19244120},
issn = {1538-7445},
support = {R01 CA043322/CA/NCI NIH HHS/United States ; T32 CA009236/CA/NCI NIH HHS/United States ; CA-09236-30/CA/NCI NIH HHS/United States ; T32 CA009236-30/CA/NCI NIH HHS/United States ; R01 CA043322-20/CA/NCI NIH HHS/United States ; R01 AI048758/AI/NIAID NIH HHS/United States ; CA-043322-20/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; DNA Breaks, Double-Stranded ; DNA Ligase ATP ; DNA Ligases/physiology ; DNA-Activated Protein Kinase/*deficiency ; DNA-Binding Proteins/*deficiency ; Female ; Genomic Instability ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Nuclear Proteins/*deficiency ; Phosphorylation ; Telomere/*physiology ; },
abstract = {The mechanisms by which cells accurately distinguish between DNA double-strand break (DSB) ends and telomeric DNA ends remain poorly defined. Recent investigations have revealed intriguing interactions between DNA repair and telomeres. We were the first to report a requirement for the nonhomologous end-joining (NHEJ) protein DNA-dependent protein kinase (DNA-PK) in the effective end-capping of mammalian telomeres. Here, we report our continued characterization of uncapped (as opposed to shortened) dysfunctional telomeres in cells deficient for the catalytic subunit of DNA-PK (DNA-PKcs) and shed light on their consequence. We present evidence in support of our model that uncapped telomeres in this repair-deficient background are inappropriately detected and processed as DSBs and thus participate not only in spontaneous telomere-telomere fusion but, importantly, also in ionizing radiation-induced telomere-DSB fusion events. We show that phosphorylation of DNA-PKcs itself (Thr-2609 cluster) is a critical event for proper telomere end-processing and that ligase IV (NHEJ) is required for uncapped telomere fusion. We also find uncapped telomeres in cells from the BALB/c mouse, which harbors two single-nucleotide polymorphisms that result in reduced DNA-PKcs abundance and activity, most markedly in mammary tissue, and are both radiosensitive and susceptible to radiogenic mammary cancer. Our results suggest mechanistic links between uncapped/dysfunctional telomeres in DNA-PKcs-deficient backgrounds, radiation-induced instability, and breast cancer. These studies provide the first direct evidence of genetic susceptibility and environmental insult interactions leading to a unique and ongoing form of genomic instability capable of driving carcinogenesis.},
}
@article {pmid19240120,
year = {2009},
author = {Komonyi, O and Schauer, T and Papai, G and Deak, P and Boros, IM},
title = {A product of the bicistronic Drosophila melanogaster gene CG31241, which also encodes a trimethylguanosine synthase, plays a role in telomere protection.},
journal = {Journal of cell science},
volume = {122},
number = {Pt 6},
pages = {769-774},
doi = {10.1242/jcs.035097},
pmid = {19240120},
issn = {0021-9533},
mesh = {Alleles ; Animals ; Chromosomal Proteins, Non-Histone/*genetics ; Chromosomes/metabolism ; Drosophila Proteins/*genetics ; Drosophila melanogaster/cytology/*enzymology/*genetics ; Genes, Insect/*genetics ; Methyltransferases/*genetics ; Neurons/cytology/enzymology ; Open Reading Frames/genetics ; Protein Binding ; Telomere/*metabolism ; },
abstract = {Although telomere formation occurs through a different mechanism in Drosophila compared with other organisms, telomere associations result from mutations in homologous genes, indicating the involvement of similar pathways in chromosome end protection. We report here that mutations of the Drosophila melanogaster gene CG31241 lead to high frequency chromosome end fusions. CG31241 is a bicistronic gene that encodes trimethylguanosine synthase (TGS1), which forms the m3G caps of noncoding small RNAs, and a novel protein, DTL. We show that although TGS1 has no role in telomere protection, DTL is localized at specific sites, including the ends of polytene chromosomes, and its loss results in telomere associations. Mutations of ATM- and Rad3-related (ATR) kinase suppress telomere fusions in the absence of DTL. Thus, genetic interactions place DTL in an ATR-related pathway in telomere protection. In contrast to ATR kinase, mutations of ATM (ataxia telangiectasia mutated) kinase, which acts in a partially overlapping pathway of telomere protection, do not suppress formation of telomere associations in the absence of DTL. Thus, uncovering the role of DTL will help to dissect the evolutionary conserved pathway(s) controlling ATM-ATR-related telomere protection.},
}
@article {pmid19237394,
year = {2009},
author = {Méndez-Lago, M and Wild, J and Whitehead, SL and Tracey, A and de Pablos, B and Rogers, J and Szybalski, W and Villasante, A},
title = {Novel sequencing strategy for repetitive DNA in a Drosophila BAC clone reveals that the centromeric region of the Y chromosome evolved from a telomere.},
journal = {Nucleic acids research},
volume = {37},
number = {7},
pages = {2264-2273},
pmid = {19237394},
issn = {1362-4962},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Centromere/*chemistry ; Chromosomes, Artificial, Bacterial ; Cloning, Molecular ; DNA/chemistry ; DNA Transposable Elements ; Drosophila melanogaster/*genetics ; *Evolution, Molecular ; Repetitive Sequences, Nucleic Acid ; Sequence Analysis, DNA/*methods ; Telomere/*chemistry ; Y Chromosome/*chemistry ; },
abstract = {The centromeric and telomeric heterochromatin of eukaryotic chromosomes is mainly composed of middle-repetitive elements, such as transposable elements and tandemly repeated DNA sequences. Because of this repetitive nature, Whole Genome Shotgun Projects have failed in sequencing these regions. We describe a novel kind of transposon-based approach for sequencing highly repetitive DNA sequences in BAC clones. The key to this strategy relies on physical mapping the precise position of the transposon insertion, which enables the correct assembly of the repeated DNA. We have applied this strategy to a clone from the centromeric region of the Y chromosome of Drosophila melanogaster. The analysis of the complete sequence of this clone has allowed us to prove that this centromeric region evolved from a telomere, possibly after a pericentric inversion of an ancestral telocentric chromosome. Our results confirm that the use of transposon-mediated sequencing, including positional mapping information, improves current finishing strategies. The strategy we describe could be a universal approach to resolving the heterochromatic regions of eukaryotic genomes.},
}
@article {pmid19234557,
year = {2009},
author = {Li, J and Yang, F and Zhu, J and He, S and Li, L},
title = {Characterization of a tandemly repeated subtelomeric sequence with inverted telomere repeats in maize.},
journal = {Genome},
volume = {52},
number = {3},
pages = {286-293},
doi = {10.1139/G09-005},
pmid = {19234557},
issn = {0831-2796},
mesh = {Base Sequence ; Blotting, Southern ; Chromosome Mapping ; Chromosomes, Plant ; DNA Primers ; DNA, Plant/*genetics ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Polymerase Chain Reaction ; Tandem Repeat Sequences/*genetics ; Telomere/*genetics ; Zea mays/*genetics ; },
abstract = {In this study, two complementary telomere primers were applied to a single-primer PCR. A clear amplification band was obtained with one primer, while a smear pattern was seen with the other primer. Sequence analysis of the isolated clones from this specific amplification band revealed that a 412 bp clone designated as MTAS1 shared high homology with a reported subtelomeric sequence (382 bp) from maize (Zea mays L.), which indicated that this clone was possibly present at subtelomeric regions. The clone MTAS1 displayed a novel structural feature flanked by the forward and inverted telomere repeats. Southern hybridization revealed a ladder of hybridization bands, suggesting that MTAS1 was a tandemly repeated sequence. Fluorescence in situ hybridization results showed that the strong MTAS1 signals were present at the ends of short arms of several long chromosomes, confirming that MTAS1 was a subtelomeric sequence and the high brightness of signals further indicated this cloned sequence was a highly and tandemly repetitive sequence in maize. Fluorescence in situ hybridization with telomeric DNA and MTAS1 as probes on metaphase chromosomes and extended genomic DNA fibers showed that hybridization signals of this clone located adjacent to or overlapped with signals of telomere tandem repeats distributed heterogeneously in subtelomeric regions of several chromosomes and even exhibited differences in two subtelomeres of a single chromosome.},
}
@article {pmid19230891,
year = {2009},
author = {Chen, W and Gardner, JP and Kimura, M and Brimacombe, M and Cao, X and Srinivasan, SR and Berenson, GS and Aviv, A},
title = {Leukocyte telomere length is associated with HDL cholesterol levels: The Bogalusa heart study.},
journal = {Atherosclerosis},
volume = {205},
number = {2},
pages = {620-625},
doi = {10.1016/j.atherosclerosis.2009.01.021},
pmid = {19230891},
issn = {1879-1484},
mesh = {Adult ; Black or African American ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/metabolism ; Atherosclerosis/*blood ; Black People ; Cholesterol, HDL/*blood/metabolism ; Female ; Humans ; Inflammation ; Leukocytes/*cytology ; Male ; Oxidative Stress ; Risk ; Sex Factors ; Telomere/*ultrastructure ; White People ; },
abstract = {OBJECTIVE: This study examined the relationships of high-density lipoprotein cholesterol (HDL-C) with LTL and the rate of its shortening.<br><br>BACKGROUND: Diminished levels of HDL-C are associated with an increased risk for atherosclerosis. Shortened leukocyte telomere length (LTL) also entails an increased atherosclerotic risk.<br><br>METHODS: We studied 472 Whites and 190 African Americans (AfAs) enrolled in the Bogalusa Heart Study. Subjects were examined serially 3-13 times for HDL-C over an average period of 27.8 years from childhood through young adulthood. LTL was measured twice during adulthood at a mean age of 31.5 years (baseline exam) and 37.8 years (follow-up exam). HDL-C trajectories with age were constructed and the area under the curve (AUC) was used as a measure of cumulative HDL-C levels.<br><br>RESULTS: Multivariate regression analyses showed that LTL was positively associated with HDL-C in childhood (regression coefficient (bp per mg/dL) beta=3.1, p=0.024), adulthood (beta=4.4, p=0.058) and AUC from childhood to adulthood (beta=12.2, p=0.0004) in the combined sample of AfAs and Whites. The association between LTL and HDL-C AUC was stronger in females (beta=18.5, p<0.001) than in males (beta=2.9, p=0.590) (difference in slopes p=0.037). A slower rate of LTL shortening per year was associated with higher HDL-C AUC in the total sample (p=0.033), adjusting for baseline LTL.<br><br>CONCLUSIONS: As HDL-C exerts anti-oxidant and anti-inflammatory effects and LTL registers the accruing burden of oxidative stress and inflammation, the association between HDL-C and LTL might be explained by the lifelong status of oxidative stress and inflammation.},
}
@article {pmid19229535,
year = {2009},
author = {Mangerini, R and Lanino, E and Terranova, P and Faraci, M and Pistillo, MP and Gaetani, GF and Ferraris, AM},
title = {Telomere length of donors influences granulocyte recovery in children after hematopoietic stem cell transplantation.},
journal = {Annals of hematology},
volume = {88},
number = {10},
pages = {1029-1031},
doi = {10.1007/s00277-009-0712-z},
pmid = {19229535},
issn = {1432-0584},
mesh = {Adolescent ; Child ; Child, Preschool ; Female ; Granulocytes/*physiology ; *Hematopoietic Stem Cell Transplantation ; Humans ; Male ; Predictive Value of Tests ; Regeneration ; Telomere/*ultrastructure ; },
}
@article {pmid19229133,
year = {2009},
author = {Kaminker, PG and Kim, SH and Desprez, PY and Campisi, J},
title = {A novel form of the telomere-associated protein TIN2 localizes to the nuclear matrix.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {8},
number = {6},
pages = {931-939},
pmid = {19229133},
issn = {1551-4005},
support = {P01 AG017242-100003/AG/NIA NIH HHS/United States ; R37 AG009909-17/AG/NIA NIH HHS/United States ; R37 AG009909-16/AG/NIA NIH HHS/United States ; AG09909/AG/NIA NIH HHS/United States ; AG017242/AG/NIA NIH HHS/United States ; R37 AG009909/AG/NIA NIH HHS/United States ; P01 AG017242-080003/AG/NIA NIH HHS/United States ; R37 AG009909-19/AG/NIA NIH HHS/United States ; P01 AG017242-090003/AG/NIA NIH HHS/United States ; R37 AG009909-18/AG/NIA NIH HHS/United States ; P01 AG017242/AG/NIA NIH HHS/United States ; P01 AG017242-070003/AG/NIA NIH HHS/United States ; P01 AG017242-060003/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Cell Line, Tumor ; Humans ; Mice ; Nuclear Matrix/*metabolism/ultrastructure ; Protein Isoforms/metabolism ; RNA Interference ; Shelterin Complex ; Telomere/*metabolism/ultrastructure ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Telomeres are specialized heterochromatin at the ends of linear chromosomes. Telomeres are crucial for maintaining genome stability and play important roles in cellular senescence and tumor biology. Six core proteins-TRF1, TRF2, TIN2, POT1, TPP1 and Rap1 (termed the telosome or shelterin complex)-regulate telomere structure and function. One of these proteins, TIN2, regulates telomere length and structure indirectly by interacting with TRF1, TRF2 and TPP1, but no direct function has been attributed to TIN2. Here we present evidence for a TIN2 isoform (TIN2L) that differs from the originally described TIN2 isoform (TIN2S) in two ways: TIN2L contains an additional 97 amino acids, and TIN2L associates strongly with the nuclear matrix. Stringent salt and detergent conditions failed to extract TIN2L from the nuclear matrix, despite removing other telomere components, including TIN2S. In human mammary epithelial cells, each isoform showed a distinct nuclear distribution both as a function of cell cycle position and telomere length. Our results suggest a dual role for TIN2 in mediating the function of the shelterin complex and tethering telomeres to the nuclear matrix.},
}
@article {pmid19228779,
year = {2009},
author = {Effros, RB},
title = {Kleemeier Award Lecture 2008--the canary in the coal mine: telomeres and human healthspan.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {64},
number = {5},
pages = {511-515},
pmid = {19228779},
issn = {1758-535X},
support = {AI 060362/AI/NIAID NIH HHS/United States ; P30 AI028697/AI/NIAID NIH HHS/United States ; AI 028697/AI/NIAID NIH HHS/United States ; AG 023720/AG/NIA NIH HHS/United States ; R01 AG023720/AG/NIA NIH HHS/United States ; R01 AI060362/AI/NIAID NIH HHS/United States ; },
mesh = {Aging/*physiology ; Cell Division/*physiology ; Humans ; T-Lymphocytes/*physiology ; *Telomere ; },
abstract = {Telomeres, the repeated series of DNA sequences that cap the ends of linear chromosomes, become shorter during cell division and oxidative stress. Shortened telomeres have been documented in a wide variety of pathologies associated with aging and are also predictive of early mortality in the very old. However, telomere shortening--like the canary in the coal mine--is not the cause of the deleterious effects, but rather, the harbinger of increased health risk. Using immune responses to infection as a model system to further analyze the link between telomeres and age-related disease, we have demonstrated that the end-stage T cell with shortened telomeres is reduced in antiviral immune function and secretes large amounts of so-called proinflammatory factors. Our research has documented that maintaining high levels of the telomere-extending enzyme, telomerase, by either genetic manipulation or exposure of T cells to chemical telomerase activators, not only retards telomere loss but also restores a more youthful functional profile to the T cells. These observations suggest possible novel telomerase-based therapeutic approaches to enhancing healthspan in the elderly population.},
}
@article {pmid19226514,
year = {2009},
author = {Mori, Y and Meltzer, SJ},
title = {Honey, I shrunk the telomere: UC speeds aging.},
journal = {Inflammatory bowel diseases},
volume = {15},
number = {9},
pages = {1432-1433},
doi = {10.1002/ibd.20887},
pmid = {19226514},
issn = {1536-4844},
}
@article {pmid19225650,
year = {2009},
author = {Yang, Q and Xiang, J and Yang, S and Zhou, Q and Li, Q and Tang, Y and Xu, G},
title = {Verification of specific G-quadruplex structure by using a novel cyanine dye supramolecular assembly: I. recognizing mixed G-quadruplex in human telomeres.},
journal = {Chemical communications (Cambridge, England)},
volume = {},
number = {9},
pages = {1103-1105},
doi = {10.1039/b820101c},
pmid = {19225650},
issn = {1359-7345},
mesh = {Base Sequence ; Carbocyanines/*chemistry ; Circular Dichroism ; DNA/*chemistry ; *G-Quadruplexes ; Humans ; Molecular Conformation ; Telomere/*chemistry ; },
abstract = {A novel cyanine dye supramolecular assembly was designed to recognize mixed G-quadruplex in human telomeres.},
}
@article {pmid19223460,
year = {2009},
author = {Zou, Y and Misri, S and Shay, JW and Pandita, TK and Wright, WE},
title = {Altered states of telomere deprotection and the two-stage mechanism of replicative aging.},
journal = {Molecular and cellular biology},
volume = {29},
number = {9},
pages = {2390-2397},
pmid = {19223460},
issn = {1098-5549},
support = {R01 AG007992/AG/NIA NIH HHS/United States ; AG 07992/AG/NIA NIH HHS/United States ; CA 10445/CA/NCI NIH HHS/United States ; R01 CA123232/CA/NCI NIH HHS/United States ; CA 123232/CA/NCI NIH HHS/United States ; },
mesh = {Apoptosis/genetics ; Cell Cycle/genetics ; Cellular Senescence/*genetics ; Chromosome Aberrations ; DNA Damage ; DNA Repair ; *DNA Replication ; Humans ; Telomere/*metabolism ; },
abstract = {The molecular distinctions between mortality stages 1 (M1; senescence) and 2 (M2; crisis) of human replicative aging are ill defined. We demonstrate a qualitative difference between telomeric end associations at M1 and the end fusions that produce dicentric chromosomes and breakage-fusion cycles. Knockdown of ligase IV sufficient to completely inhibit radiation-induced dicentric chromosome formation had no effect on the frequency of telomere associations (TAs), establishing that TAs are not covalent conventional nonhomologous end-joining (NHEJ) products. TAs preceded and were more numerous than dicentric chromosomes. Cells initially tolerated dicentric chromosomes without dying, but eventually, a combination of too many TAs and dicentrics/complex chromosomal rearrangements resulted in apoptosis. We propose a working model in which end associations represent abortive DNA repair intermediates when the number of telomeric repeats is too small to completely inhibit DNA damage signaling but is sufficient to prevent the final covalent ligation step of NHEJ and induces the M1 checkpoint arrest in normal human cells. Rather than being all-or-none, telomere deprotection would thus proceed first through TAs before additional shortening leads to dicentric chromosomes. M2/crisis involves both qualitative changes (a shift from TAs to TAs plus dicentric chromosomes) and quantitative changes (an increase in the number of dysfunctional telomeres).},
}
@article {pmid19221928,
year = {2009},
author = {Shiraishi, H and Mikami, T and Aida, J and Nakamura, K and Izumiyama-Shimomura, N and Arai, T and Watanabe, M and Okayasu, I and Takubo, K},
title = {Telomere shortening in Barrett's mucosa and esophageal adenocarcinoma and its association with loss of heterozygosity.},
journal = {Scandinavian journal of gastroenterology},
volume = {44},
number = {5},
pages = {538-544},
doi = {10.1080/00365520902718705},
pmid = {19221928},
issn = {1502-7708},
mesh = {Adenocarcinoma/*genetics/pathology ; Analysis of Variance ; Barrett Esophagus/*genetics/pathology ; Esophageal Neoplasms/*genetics/pathology ; Female ; Gastric Mucosa/pathology ; Genetic Markers ; Humans ; In Situ Hybridization, Fluorescence ; *Loss of Heterozygosity ; Male ; *Microsatellite Instability ; Mucous Membrane/pathology ; Neoplasm Staging ; Precancerous Conditions/genetics/pathology ; Probability ; Sampling Studies ; Sensitivity and Specificity ; Statistics, Nonparametric ; Telomere/genetics/*metabolism/pathology ; Tissue Culture Techniques ; },
abstract = {OBJECTIVE: Telomere shortening is thought to be associated with genetic instability. The purpose of this study was to measure telomere length in a series of Barrett's adenocarcinomas (BAs), focusing on the telomere/centromere fluorescent intensity ratio (TCR) with tissue quantitative fluorescent in situ hybridization (Q-FISH).<br><br>MATERIAL AND METHODS: A total of 11 cases of BA were evaluated for upper esophagus (UE), lower esophagus (LE), Barrett's mucosa (BM), BA, and gastric cardiac mucosa (GC). Q-FISH was performed using two kinds of peptide nucleic acid probe, specific for telomeres and centromeres. The sections were analyzed with a CCD camera and original software (Tissue Telo) for measuring TCR. In addition, Laser Capture Microdissection and GeneScan were implemented for evaluation of genetic instability.<br><br>RESULTS: The TCR values in BM and, to a lesser extent, BA were significantly lower than those in the other tissues, particularly in heterozygosity (LOH)-positive cases. However, no significant difference was evident between microsatellite instability (MSI)-positive and -negative groups.<br><br>CONCLUSIONS: In our study of BA series, telomere length appeared to change with the degree of histological atypia, with decreases linked to LOH.},
}
@article {pmid19221198,
year = {2009},
author = {Hsiao, SJ and Smith, S},
title = {Sister telomeres rendered dysfunctional by persistent cohesion are fused by NHEJ.},
journal = {The Journal of cell biology},
volume = {184},
number = {4},
pages = {515-526},
pmid = {19221198},
issn = {1540-8140},
support = {R01 CA095099/CA/NCI NIH HHS/United States ; R01 CA116352/CA/NCI NIH HHS/United States ; R01 CA95099/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; *Cell Cycle ; Cell Line ; DNA Damage ; DNA Ligase ATP ; DNA Ligases/metabolism ; DNA Replication ; Humans ; Tankyrases/metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres protect chromosome ends from being viewed as double-strand breaks and from eliciting a DNA damage response. Deprotection of chromosome ends occurs when telomeres become critically short because of replicative attrition or inhibition of TRF2. In this study, we report a novel form of deprotection that occurs exclusively after DNA replication in S/G2 phase of the cell cycle. In cells deficient in the telomeric poly(adenosine diphosphate ribose) polymerase tankyrase 1, sister telomere resolution is blocked. Unexpectedly, cohered sister telomeres become deprotected and are inappropriately fused. In contrast to telomeres rendered dysfunctional by TRF2, which engage in chromatid fusions predominantly between chromatids from different chromosomes (Bailey, S.M., M.N. Cornforth, A. Kurimasa, D.J. Chen, and E.H. Goodwin. 2001. Science. 293:2462-2465; Smogorzewska, A., J. Karlseder, H. Holtgreve-Grez, A. Jauch, and T. de Lange. 2002. Curr. Biol. 12:1635-1644), telomeres rendered dysfunctional by tankyrase 1 engage in chromatid fusions almost exclusively between sister chromatids. We show that cohered sister telomeres are fused by DNA ligase IV-mediated nonhomologous end joining. These results demonstrate that the timely removal of sister telomere cohesion is essential for the formation of a protective structure at chromosome ends after DNA replication in S/G2 phase of the cell cycle.},
}
@article {pmid19217888,
year = {2009},
author = {Zee, RY and Michaud, SE and Germer, S and Ridker, PM},
title = {Association of shorter mean telomere length with risk of incident myocardial infarction: a prospective, nested case-control approach.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {403},
number = {1-2},
pages = {139-141},
pmid = {19217888},
issn = {1873-3492},
support = {R01 HL058755-02/HL/NHLBI NIH HHS/United States ; R01 HL063293-03/HL/NHLBI NIH HHS/United States ; R01 HL063293-01/HL/NHLBI NIH HHS/United States ; R01 HL063293-02/HL/NHLBI NIH HHS/United States ; R01 HL058755-03/HL/NHLBI NIH HHS/United States ; R01 HL063293-04/HL/NHLBI NIH HHS/United States ; HL-58755/HL/NHLBI NIH HHS/United States ; HL-63293/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Case-Control Studies ; *Disease Susceptibility ; Follow-Up Studies ; Humans ; Logistic Models ; Male ; Middle Aged ; Myocardial Infarction/*genetics ; Polymerase Chain Reaction ; Prospective Studies ; Randomized Controlled Trials as Topic ; Telomere/*genetics ; },
abstract = {BACKGROUND: Recent data have implicated telomere length shortening as a potential risk predictor for cardiovascular disease. However, to date, prospective epidemiological data are scarce.<br><br>METHODS: Using leukocyte DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we examined the relationship of mean telomere repeat copy number to single gene copy number (T/S ratio), using a re-modified quantitative polymerase chain reaction protocol, among 337 white males who subsequently developed an incident myocardial infarction (MI), and among an equal number of age- and smoking-matched white males who remained free of reported vascular disease during follow-up (controls).<br><br>RESULTS: The mean follow-up time since randomization was 3.85 y. The T/S ratio was inversely correlated with age in the controls (R=-0.114; p=0.036). The log(e)-transformed T/S ratios were significantly smaller in the MI cases (3.41+/-0.63) than the MI controls (3.52+/-0.78) (p=0.01). In a multi-variable adjusted analysis, decreased T/S ratio was significantly associated with risk of MI (odds ratio=1.621; 95%CI=1.140-2.304; p=0.007).<br><br>CONCLUSIONS: The present investigation has shown an association of telomere length shortening with increased risk of incident myocardial infarction, further suggesting the importance of telomere biology in atherogenesis.},
}
@article {pmid19216021,
year = {2009},
author = {Sidorov, I and Kimura, M and Yashin, A and Aviv, A},
title = {Leukocyte telomere dynamics and human hematopoietic stem cell kinetics during somatic growth.},
journal = {Experimental hematology},
volume = {37},
number = {4},
pages = {514-524},
doi = {10.1016/j.exphem.2008.11.009},
pmid = {19216021},
issn = {1873-2399},
support = {AG008761/AG/NIA NIH HHS/United States ; AG020132/AG/NIA NIH HHS/United States ; AG16592/AG/NIA NIH HHS/United States ; },
mesh = {Adolescent ; *Body Weight ; Child ; Child, Preschool ; Computer Simulation ; Female ; Hematopoietic Stem Cells/*physiology ; Humans ; Infant ; Infant, Newborn ; Kinetics ; Leukocytes/*physiology ; Male ; *Models, Biological ; Telomere/*metabolism ; Young Adult ; },
abstract = {OBJECTIVE: A central question in stem cell research is knowing the frequency of human hematopoietic stem cells (HSC) replication in vivo.<br><br>MATERIALS AND METHODS: We have constructed a model that characterizes HSC kinetics and the relative sizes of the hematopoietic progenitor cell (HPC) and HSC pools from birth onward. The model capitalizes on leukocyte telomere length (LTL) data and body weight-gain charts from birth to the age of 20 years. The core premise of the model is that during human growth, LTL dynamics (birth LTL and age-dependent LTL shortening afterward) chronicle the expansions of the HSC and HPC pools.<br><br>RESULTS: The model estimates that by the end of the first year of life, HSC have replicated approximately 17 times and they replicate approximately 2.5 times/year between the ages of 3 and 13 years. Subsequently, HSC replication slows considerably. In adults HSC replicate at a rate of approximately 0.6 times/year. In addition, the model predicts that newborns with small birth weight would have shorter LTL as adults and that women would have longer LTL than men.<br><br>CONCLUSION: Our findings will be useful in bone marrow transplantations and might explain a body of clinical observations related to LTL distribution in the general population.},
}
@article {pmid19214769,
year = {2009},
author = {Britt-Compton, B and Wyllie, F and Rowson, J and Capper, R and E Jones, R and M Baird, D},
title = {Telomere dynamics during replicative senescence are not directly modulated by conditions of oxidative stress in IMR90 fibroblast cells.},
journal = {Biogerontology},
volume = {10},
number = {6},
pages = {683-693},
doi = {10.1007/s10522-009-9216-4},
pmid = {19214769},
issn = {1573-6768},
support = {//Cancer Research UK/United Kingdom ; },
mesh = {Antioxidants/pharmacology ; Cell Hypoxia ; Cell Line ; *Cell Proliferation/drug effects ; *Cellular Senescence/drug effects ; Fibroblasts/drug effects/*metabolism ; Humans ; Kinetics ; *Oxidative Stress/drug effects ; Oxygen/*metabolism ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Transfection ; },
abstract = {The replicative lifespan of many cell types is determined by the length of telomeres in the initiating cell population. In 20% oxygen, IMR90 cells have a shorter replicative lifespan compared to that achieved in conditions that lower the levels of oxidative stress. We sought to address the role of telomere dynamics in determining the replicative lifespan of IMR90 cells. We analysed clonal populations cultured in parallel in 3 and 20% oxygen. We observed that, at senescence, telomere length was shorter in 3% oxygen and this was proportional to the lifespan extension. We observed no detectable difference in the rate of telomere erosion in the two culture conditions, however as the cells approached senescence the growth rate of the cultures slowed with a commensurate increase in the rate of telomere erosion. We conclude that, in 20% oxygen senescence of IMR90 is telomere-independent, but telomere-dependent in 3% oxygen.},
}
@article {pmid19214310,
year = {2009},
author = {Huang, J and Li, G and Wu, Z and Song, Z and Zhou, Y and Shuai, L and Weng, X and Zhou, X and Yang, G},
title = {Bisbenzimidazole to benzobisimidazole: from binding B-form duplex DNA to recognizing different modes of telomere G-quadruplex.},
journal = {Chemical communications (Cambridge, England)},
volume = {},
number = {8},
pages = {902-904},
doi = {10.1039/b819789j},
pmid = {19214310},
issn = {1359-7345},
mesh = {Benzimidazoles/*chemistry ; Circular Dichroism ; DNA/chemistry/*metabolism ; G-Quadruplexes ; Imidazoles/*chemistry/metabolism ; Molecular Structure ; Telomere/*chemistry ; },
abstract = {A bisbenzimidazole was discovered to bind helix DNA, while related benzobisimidazole derivatives were found to bind and induce different G-quadruplex isomers.},
}
@article {pmid19214207,
year = {2009},
author = {Nordfjäll, K and Svenson, U and Norrback, KF and Adolfsson, R and Lenner, P and Roos, G},
title = {The individual blood cell telomere attrition rate is telomere length dependent.},
journal = {PLoS genetics},
volume = {5},
number = {2},
pages = {e1000375},
pmid = {19214207},
issn = {1553-7404},
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Blood Cells/*chemistry/metabolism ; Child ; Child, Preschool ; Cohort Studies ; Female ; Humans ; Infant ; Male ; Telomere/*chemistry/genetics/metabolism ; Young Adult ; },
abstract = {Age-associated telomere shortening is a well documented feature of peripheral blood cells in human population studies, but it is not known to what extent these data can be transferred to the individual level. Telomere length (TL) in two blood samples taken at approximately 10 years interval from 959 individuals was investigated using real-time PCR. TL was also measured in 13 families from a multigenerational cohort. As expected, we found an age-related decline in TL over time (r = -0.164, P<0.001, n = 959). However, approximately one-third of the individuals exhibited a stable or increased TL over a decade. The individual telomere attrition rate was inversely correlated with initial TL at a highly significant level (r = -0.752, P<0.001), indicating that the attrition rate was most pronounced in individuals with long telomeres at baseline. In accordance, the age-associated telomere attrition rate was more prominent in families with members displaying longer telomeres at a young age (r = -0.691, P<0.001). Abnormal blood TL has been reported at diagnosis of various malignancies, but in the present study there was no association between individual telomere attrition rate or prediagnostic TL and later tumor development. The collected data strongly suggest a TL maintenance mechanism acting in vivo, providing protection of short telomeres as previously demonstrated in vitro. Our findings might challenge the hypothesis that individual TL can predict possible life span or later tumor development.},
}
@article {pmid19214203,
year = {2009},
author = {Vannier, JB and Depeiges, A and White, C and Gallego, ME},
title = {ERCC1/XPF protects short telomeres from homologous recombination in Arabidopsis thaliana.},
journal = {PLoS genetics},
volume = {5},
number = {2},
pages = {e1000380},
pmid = {19214203},
issn = {1553-7404},
mesh = {Arabidopsis/chemistry/*genetics/*metabolism ; Arabidopsis Proteins/genetics/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Endodeoxyribonucleases/genetics/*metabolism ; Endonucleases/genetics/*metabolism ; Genomic Instability ; Mutation ; *Recombination, Genetic ; Telomerase/genetics/metabolism ; Telomere/*chemistry/genetics/metabolism ; },
abstract = {Many repair and recombination proteins play essential roles in telomere function and chromosome stability, notwithstanding the role of telomeres in "hiding" chromosome ends from DNA repair and recombination. Among these are XPF and ERCC1, which form a structure-specific endonuclease known for its essential role in nucleotide excision repair and is the subject of considerable interest in studies of recombination. In contrast to observations in mammalian cells, we observe no enhancement of chromosomal instability in Arabidopsis plants mutated for either XPF (AtRAD1) or ERCC1 (AtERCC1) orthologs, which develop normally and show wild-type telomere length. However, in the absence of telomerase, mutation of either of these two genes induces a significantly earlier onset of chromosomal instability. This early appearance of telomere instability is not due to a general acceleration of telomeric repeat loss, but is associated with the presence of dicentric chromosome bridges and cytologically visible extrachromosomal DNA fragments in mitotic anaphase. Such extrachromosomal fragments are not observed in later-generation single-telomerase mutant plants presenting similar frequencies of anaphase bridges. Extensive FISH analyses show that these DNAs are broken chromosomes and correspond to two specific chromosome arms. Analysis of the Arabidopsis genome sequence identified two extensive blocks of degenerate telomeric repeats, which lie at the bases of these two arms. Our data thus indicate a protective role of ERCC1/XPF against 3' G-strand overhang invasion of interstitial telomeric repeats. The fact that the Atercc1 (and Atrad1) mutants dramatically potentiate levels of chromosome instability in Attert mutants, and the absence of such events in the presence of telomerase, have important implications for models of the roles of recombination at telomeres and is a striking illustration of the impact of genome structure on the outcomes of equivalent recombination processes in different organisms.},
}
@article {pmid19214192,
year = {2009},
author = {Moser, BA and Subramanian, L and Chang, YT and Noguchi, C and Noguchi, E and Nakamura, TM},
title = {Differential arrival of leading and lagging strand DNA polymerases at fission yeast telomeres.},
journal = {The EMBO journal},
volume = {28},
number = {7},
pages = {810-820},
pmid = {19214192},
issn = {1460-2075},
support = {GM078253/GM/NIGMS NIH HHS/United States ; GM077604/GM/NIGMS NIH HHS/United States ; R01 GM078253/GM/NIGMS NIH HHS/United States ; R01 GM077604/GM/NIGMS NIH HHS/United States ; R01 GM077604-01A2/GM/NIGMS NIH HHS/United States ; R01 GM078253-03/GM/NIGMS NIH HHS/United States ; R01 GM077604-02/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle ; Cell Cycle Proteins/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; DNA Polymerase I/metabolism ; DNA Repair ; DNA Replication ; DNA, Fungal/metabolism ; DNA-Directed DNA Polymerase/*metabolism ; Schizosaccharomyces/*enzymology/metabolism ; Schizosaccharomyces pombe Proteins/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {To maintain genomic integrity, telomeres must undergo switches from a protected state to an accessible state that allows telomerase recruitment. To better understand how telomere accessibility is regulated in fission yeast, we analysed cell cycle-dependent recruitment of telomere-specific proteins (telomerase Trt1, Taz1, Rap1, Pot1 and Stn1), DNA replication proteins (DNA polymerases, MCM, RPA), checkpoint protein Rad26 and DNA repair protein Nbs1 to telomeres. Quantitative chromatin immunoprecipitation studies revealed that MCM, Nbs1 and Stn1 could be recruited to telomeres in the absence of telomere replication in S-phase. In contrast, Trt1, Pot1, RPA and Rad26 failed to efficiently associate with telomeres unless telomeres are actively replicated. Unexpectedly, the leading strand DNA polymerase epsilon (Polepsilon) arrived at telomeres earlier than the lagging strand DNA polymerases alpha (Polalpha) and delta (Poldelta). Recruitment of RPA and Rad26 to telomeres matched arrival of DNA Polepsilon, whereas S-phase specific recruitment of Trt1, Pot1 and Stn1 matched arrival of DNA Polalpha. Thus, the conversion of telomere states involves an unanticipated intermediate step where lagging strand synthesis is delayed until telomerase is recruited.},
}
@article {pmid19214183,
year = {2009},
author = {Pickett, HA and Cesare, AJ and Johnston, RL and Neumann, AA and Reddel, RR},
title = {Control of telomere length by a trimming mechanism that involves generation of t-circles.},
journal = {The EMBO journal},
volume = {28},
number = {7},
pages = {799-809},
pmid = {19214183},
issn = {1460-2075},
mesh = {Cell Line, Tumor ; DNA, Circular/metabolism ; HeLa Cells ; Humans ; Leukemia, Promyelocytic, Acute/metabolism ; Telomerase/metabolism ; Telomere/*chemistry/*metabolism ; },
abstract = {Telomere lengths are maintained in many cancer cells by the ribonucleoprotein enzyme telomerase but can be further elongated by increasing telomerase activity through the overexpression of telomerase components. We report here that increased telomerase activity results in increased telomere length that eventually reaches a plateau, accompanied by the generation of telomere length heterogeneity and the accumulation of extrachromosomal telomeric repeat DNA, principally in the form of telomeric circles (t-circles). Telomeric DNA was observed in promyelocytic leukemia bodies, but no intertelomeric copying or telomere exchange events were identified, and there was no increase in telomere dysfunction-induced foci. These data indicate that human cells possess a mechanism to negatively regulate telomere length by trimming telomeric DNA from the chromosome ends, most likely by t-loop resolution to form t-circles. Additionally, these results indicate that some phenotypic characteristics attributed to alternative lengthening of telomeres (ALT) result from increased mean telomere length, rather than from the ALT mechanism itself.},
}
@article {pmid19211845,
year = {2009},
author = {Jegou, T and Chung, I and Heuvelman, G and Wachsmuth, M and Görisch, SM and Greulich-Bode, KM and Boukamp, P and Lichter, P and Rippe, K},
title = {Dynamics of telomeres and promyelocytic leukemia nuclear bodies in a telomerase-negative human cell line.},
journal = {Molecular biology of the cell},
volume = {20},
number = {7},
pages = {2070-2082},
pmid = {19211845},
issn = {1939-4586},
mesh = {Cell Line, Tumor ; Clone Cells ; Humans ; In Situ Hybridization, Fluorescence ; Interphase ; Intranuclear Inclusion Bodies/*metabolism ; Leukemia, Promyelocytic, Acute/*metabolism/*pathology ; Models, Biological ; Operator Regions, Genetic/genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Telomerase/*deficiency ; Telomere/*metabolism ; Time Factors ; },
abstract = {Telomerase-negative tumor cells maintain their telomeres via an alternative lengthening of telomeres (ALT) mechanism. This process involves the association of telomeres with promyelocytic leukemia nuclear bodies (PML-NBs). Here, the mobility of both telomeres and PML-NBs as well as their interactions were studied in human U2OS osteosarcoma cells, in which the ALT pathway is active. A U2OS cell line was constructed that had lac operator repeats stably integrated adjacent to the telomeres of chromosomes 6q, 11p, and 12q. By fluorescence microscopy of autofluorescent LacI repressor bound to the lacO arrays the telomere mobility during interphase was traced and correlated with the telomere repeat length. A confined diffusion model was derived that describes telomere dynamics in the nucleus on the time scale from seconds to hours. Two telomere groups were identified that differed with respect to the nuclear space accessible to them. Furthermore, translocations of PML-NBs relative to telomeres and their complexes with telomeres were evaluated. Based on these studies, a model is proposed in which the shortening of telomeres results in an increased mobility that could facilitate the formation of complexes between telomeres and PML-NBs.},
}
@article {pmid19210188,
year = {2009},
author = {Segal, NL},
title = {Twins reared apart: a forgotten case/twin research reviews: X-inactivation and female co-twin discordance for hemophilia; transplantation for breast reconstruction; chimerism and telomere attrition in dizygotic twins; divergent life histories in twins reared apart/current concerns: high ACT-scoring twins; dating a twin; when gender identities diverge/the Holland twins.},
journal = {Twin research and human genetics : the official journal of the International Society for Twin Studies},
volume = {12},
number = {1},
pages = {123-126},
doi = {10.1375/twin.12.1.123},
pmid = {19210188},
issn = {1832-4274},
mesh = {*Hemophilia A ; History, 20th Century ; Humans ; *Organ Transplantation ; Sex Characteristics ; *Telomere ; *Transplantation Chimera ; Twin Studies as Topic/history ; *Twins, Dizygotic ; },
abstract = {A forgotten story of monozygotic twins reared apart is described. The pair, born in 1941 in Fribourg, Switzerland, were separated due to switch-baby incident in the hospital. This caused one twin to be raised as a singleton by an unrelated family, and the other twin to be raised as a 'dizygotic' twin with an unrelated child. This is followed by reviews of recent twin research and case studies of X-inactivation and hemophilia, breast reconstruction, chimerism and life histories. The final section of the article includes human interest pieces on academic twins, dating twins, transsexual twins and athletic twins.},
}
@article {pmid19202142,
year = {2009},
author = {Hanna, CW and Bretherick, KL and Gair, JL and Fluker, MR and Stephenson, MD and Robinson, WP},
title = {Telomere length and reproductive aging.},
journal = {Human reproduction (Oxford, England)},
volume = {24},
number = {5},
pages = {1206-1211},
pmid = {19202142},
issn = {1460-2350},
mesh = {Abortion, Habitual/*genetics ; Adult ; Age Factors ; Aging, Premature/*genetics ; Cellular Senescence/*genetics ; Female ; Fertility/*genetics ; Humans ; Linear Models ; Maternal Age ; Polymerase Chain Reaction ; Primary Ovarian Insufficiency/*genetics ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Rate of reproductive aging may be related to rate of biological aging. Thus, indicators of aging, such as short telomere length, may be more frequent in women with a history suggestive of premature reproductive senescence.<br><br>METHODS: Telomere-specific quantitative PCR was used to assess telomere length in two groups of women with evidence of reproductive aging: (i) patients with idiopathic premature ovarian failure (POF, N = 34) and (ii) women with a history of recurrent miscarriage (RM, N = 95); and two control groups: (1) women from the general population (C1, N = 108) and (2) women who had a healthy pregnancy after 37 years of age (C2, N = 46).<br><br>RESULTS: The RM group had shorter age-adjusted mean telomere length than controls (8.46 versus 8.92 kb in C1 and 9.11 kb in C2, P = 0.0004 and P = 0.02 for C1 and C2, respectively), although short telomeres were not confined to subsets of this group known to have experienced single or multiple trisomic pregnancies. Although sample size is limited, mean telomere length in the POF group was significantly longer than that in C1 (9.58 versus 8.92 kb, P = 0.01).<br><br>CONCLUSIONS: Women experiencing RM may have shorter telomeres as a consequence of a more rapid rate of aging, or as a reflection of an increased level of cellular stress. Longer telomere length in the POF group may be explained by abnormal hormone exposure, slow cell division rates or autoimmunity in these women. Despite small sample sizes, these results suggest that different manifestations of reproductive aging are likely influenced by distinct physiological factors.},
}
@article {pmid19200803,
year = {2009},
author = {Marion, RM and Strati, K and Li, H and Tejera, A and Schoeftner, S and Ortega, S and Serrano, M and Blasco, MA},
title = {Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells.},
journal = {Cell stem cell},
volume = {4},
number = {2},
pages = {141-154},
doi = {10.1016/j.stem.2008.12.010},
pmid = {19200803},
issn = {1875-9777},
mesh = {Aging/physiology ; Animals ; Cells, Cultured ; Cellular Reprogramming ; Embryonic Stem Cells/cytology/*physiology ; Enzyme Activation ; Fibroblasts/cytology/physiology ; Humans ; Kruppel-Like Factor 4 ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Pluripotent Stem Cells/cytology/*physiology ; Proto-Oncogene Proteins c-myc/genetics/metabolism ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; Transplantation Chimera ; },
abstract = {Telomere shortening is associated with organismal aging. iPS cells have been recently derived from old patients; however, it is not known whether telomere chromatin acquires the same characteristics as in ES cells. We show here that telomeres are elongated in iPS cells compared to the parental differentiated cells both when using four (Oct3/4, Sox2, Klf4, cMyc) or three (Oct3/4, Sox2, Klf4) reprogramming factors and both from young and aged individuals. We demonstrate genetically that, during reprogramming, telomere elongation is usually mediated by telomerase and that iPS telomeres acquire the epigenetic marks of ES cells, including a low density of trimethylated histones H3K9 and H4K20 and increased abundance of telomere transcripts. Finally, reprogramming efficiency of cells derived from increasing generations of telomerase-deficient mice shows a dramatic decrease in iPS cell efficiency, a defect that is restored by telomerase reintroduction. Together, these results highlight the importance of telomere biology for iPS cell generation and functionality.},
}
@article {pmid19198626,
year = {2009},
author = {Gong, Y and Sun, Y and McNutt, MA and Sun, Q and Hou, L and Liu, H and Shen, Q and Ling, Y and Chi, Y and Zhang, B},
title = {Localization of TEIF in the centrosome and its functional association with centrosome amplification in DNA damage, telomere dysfunction and human cancers.},
journal = {Oncogene},
volume = {28},
number = {12},
pages = {1549-1560},
doi = {10.1038/onc.2008.503},
pmid = {19198626},
issn = {1476-5594},
mesh = {Adaptor Proteins, Vesicular Transport ; Cell Line, Tumor ; Centrosome/*chemistry/*physiology ; *DNA Damage ; DNA-Binding Proteins ; Humans ; Neoplasms/*genetics ; Protein Transport ; Sarcoma/genetics ; Shelterin Complex ; Telomere/*physiology ; Telomere-Binding Proteins/physiology ; Transcription Factors/*analysis/physiology ; },
abstract = {Centrosome amplification and telomere shortening, which are commonly detected in human cancers, have been implicated in the induction of chromosome instability in tumorigenesis. The functions of these two structures are closely related to DNA damage repair machinery, and some factors that operate in the maintenance of telomeres also take part in the regulation of centrosome status, suggesting they are functionally linked. We report that TEIF (telomerase transcriptional elements-interacting factor), a transactivator of the hTERT (human telomerase reverse transcriptase subunit) gene, is distributed in the centrosome throughout the cell cycle, but its transport into the centrosome is increased under some conditions, and its distribution is dependent on its C-terminal domain. Experimental modulation of TEIF expression through overexpression, polypeptide expression or depletion affected centrosome status and increased abnormalities of cell mitosis. Localization of TEIF to the centrosome was also stimulated by treatment with genotoxic agents and experimental telomere dysfunction, accompanying centrosome amplification. Moreover, we demonstrated that the expression level of TEIF is not only closely correlated with centrosome amplification in soft tissue sarcomas but it is also significantly related to tumor histologic grade. Our data confirmed TEIF functions as a centrosome regulator. Its participation in DNA damage response, including telomere dysfunction and tumorigenesis, indicates TEIF is likely to be a factor involved in linking centrosome amplification and telomere dysfunction in cancer development.},
}
@article {pmid19194115,
year = {2009},
author = {Achille, M and Boukheris, H and Caillou, B and Talbot, M and de Vathaire, F and Sabatier, L and Desmaze, C and Schlumberger, M and Soria, JC},
title = {Expression of cell cycle biomarkers and telomere length in papillary thyroid carcinoma: a comparative study between radiation-associated and spontaneous cancers.},
journal = {American journal of clinical oncology},
volume = {32},
number = {1},
pages = {1-8},
doi = {10.1097/COC.0b013e3181783336},
pmid = {19194115},
issn = {1537-453X},
mesh = {Adenocarcinoma, Follicular/metabolism/pathology ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Papillary/*metabolism/pathology ; Case-Control Studies ; Cell Cycle Proteins/*metabolism ; Child ; Child, Preschool ; Female ; Humans ; Immunoenzyme Techniques ; In Situ Hybridization, Fluorescence ; Infant ; Male ; Middle Aged ; Neoplasms, Radiation-Induced/*metabolism/pathology ; Prognosis ; Telomere/*metabolism ; Thyroid Neoplasms/*metabolism/pathology ; Tissue Array Analysis ; Young Adult ; },
abstract = {OBJECTIVE: Radiation exposure during childhood is the only well-established risk factor for papillary thyroid carcinoma (PTC). To better define the biologic profile of radiation-induced and sporadic PTC, we compared in these two groups of PTC the expression of cell cycle regulatory proteins and telomere length.<br><br>METHODS: Cell cycle markers (cyclin A, B1, D1, E, and Ki67) were evaluated on 100 PTC specimens (26 radiation-induced and 74 sporadic PTCs). The expression of cell cycle regulators was studied using immunohistochemistry; telomere length heterogeneity was studied using in situ hybridization in a subset of 16 formalin-fixed samples (8 radiation-induced and 8 sporadic PTCs).<br><br>RESULTS: At multivariate analysis, only cytoplasmic cyclin E staining was overexpressed in sporadic cases (P = 0.006). The other cell cycle markers and telomere length did not differ significantly between sporadic PTC and radiation-induced PTC.<br><br>CONCLUSIONS: These markers cannot be used to differentiate radiation-induced from sporadic PTCs.},
}
@article {pmid19193721,
year = {2009},
author = {Cassar, L and Nicholls, C and Pinto, AR and Li, H and Liu, JP},
title = {Bone morphogenetic protein-7 induces telomerase inhibition, telomere shortening, breast cancer cell senescence, and death via Smad3.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {23},
number = {6},
pages = {1880-1892},
doi = {10.1096/fj.08-119529},
pmid = {19193721},
issn = {1530-6860},
mesh = {Activin Receptors, Type II/genetics/metabolism ; Bone Morphogenetic Protein 7/genetics/metabolism ; Bone Morphogenetic Protein Receptors, Type II/genetics/metabolism ; Breast Neoplasms/genetics/*metabolism ; Cell Death/*physiology ; Cell Line, Tumor ; Cellular Senescence/*physiology ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Protein Serine-Threonine Kinases/genetics/metabolism ; RNA Interference ; Receptor, Transforming Growth Factor-beta Type II ; Receptors, Transforming Growth Factor beta/genetics/metabolism ; Recombinant Fusion Proteins/genetics/metabolism ; Signal Transduction/physiology ; Smad3 Protein/genetics/*metabolism ; Telomerase/*antagonists &amp; inhibitors/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {Human telomerase reverse transcriptase (hTERT) is central to maintain telomeres for continuous cell proliferation, but it remains unknown how extracellular cues regulate telomerase maintenance of telomeres. Here we report that the cytokine bone morphogenetic protein-7 (BMP7) induces Smad3 phosphorylation, nuclear translocation, and hTERT gene repression. BMP7 induces Smad3-dependent telomerase inhibition in a time- and concentration-dependent manner in breast cancer cells. Chronic exposure of breast cancer cells to BMP7 results in short telomeres, cell senescence, and apoptosis. Mutation of BMPRII receptor, but not TGFbetaRII, ACTRIIA, or ACTRIIB, blocked BMP7-induced repression of the hTERT gene promoter activity, leading to increased telomerase activity, lengthened telomeres, and continued cell proliferation. Expression of hTERT inhibits BMP7-induced breast cancer cell senescence and apoptosis. Thus, our data suggest that BMP7 induces breast cancer cell aging and death by a mechanism involving inhibition of telomerase activity and telomere maintenance via BMPRII receptor- and Smad3-mediated repression of the hTERT gene.},
}
@article {pmid19190333,
year = {2009},
author = {Zheng, YL and Hu, N and Sun, Q and Wang, C and Taylor, PR},
title = {Telomere attrition in cancer cells and telomere length in tumor stroma cells predict chromosome instability in esophageal squamous cell carcinoma: a genome-wide analysis.},
journal = {Cancer research},
volume = {69},
number = {4},
pages = {1604-1614},
pmid = {19190333},
issn = {1538-7445},
support = {P30 CA051008/CA/NCI NIH HHS/United States ; 2P30CA051008-13/CA/NCI NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; },
mesh = {Carcinoma, Squamous Cell/epidemiology/*genetics/pathology/surgery ; China ; Chromosomal Instability/*genetics ; *Chromosomes, Human, Pair 13 ; *Chromosomes, Human, Pair 15 ; Esophageal Neoplasms/epidemiology/*genetics/pathology/surgery ; *Genome, Human ; Humans ; Life Style ; *Loss of Heterozygosity ; Oligonucleotide Array Sequence Analysis ; Polymorphism, Single Nucleotide/genetics ; Predictive Value of Tests ; Stromal Cells/pathology ; Telomere/*genetics/ultrastructure ; },
abstract = {Previous studies showed that chromosomal instability was common in esophageal squamous cell carcinoma (ESCC); however, the mechanisms underlying this instability are unknown. Individuals with deficiencies in telomere maintenance are susceptible to enhanced telomere loss during cell proliferation; such deficiencies could result in telomere dysfunction and genomic instability. We investigated the association between genome-wide chromosomal changes in cancer cells and telomere length/attrition in cancer/stroma cells in 47 ESCC patients. Genome-wide detection of loss of heterozygosity was performed using the Affymetrix GeneChip single nucleotide polymorphism arrays. Telomere length was assessed separately for cancer cells, carcinoma-associated fibroblasts (CAF), infiltrative lymphocytes, and adjacent normal epithelial cells by quantitative fluorescent in situ hybridization using paraffin-embedded sections. Telomere length differed significantly among cell types, such that length in infiltrative lymphocytes > CAFs > cancer cells. Shortened telomeres were observed in cancer cells in 44 of 47 (94%) of the tumors examined. Telomere length in CAFs was significantly associated with chromosomal instability on 4q and 13q and lymphocyte telomere length was significantly associated with instability on chromosomal arms 15q. Although telomere length in cancer cells was not associated with chromosome arm instability, telomere attrition in cancer cells, defined as the telomere length in CAFs minus the telomere length in cancer cells, was significantly associated with chromosomal instability on 13q and 15q. This study provides evidence that telomere shortening is a common genetic alteration in ESCC and that chromosome arm instability is related to both telomere attrition in cancer cells and telomere length in tumor stroma cells.},
}
@article {pmid19190150,
year = {2009},
author = {Parks, CG and Miller, DB and McCanlies, EC and Cawthon, RM and Andrew, ME and DeRoo, LA and Sandler, DP},
title = {Telomere length, current perceived stress, and urinary stress hormones in women.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {18},
number = {2},
pages = {551-560},
pmid = {19190150},
issn = {1055-9965},
support = {Z99 ES999999/ImNIH/Intramural NIH HHS/United States ; Z01 ES04400509/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Aged ; Catecholamines/*urine ; Cross-Sectional Studies ; Female ; Humans ; Hydrocortisone/*urine ; Linear Models ; Middle Aged ; Prospective Studies ; Risk Factors ; Stress, Psychological/*complications ; Telomere/*ultrastructure ; },
abstract = {Telomeres are repetitive DNA sequences that cap and protect the ends of chromosomes; critically short telomeres may lead to cellular senescence or carcinogenic transformation. Previous findings suggest a link between psychosocial stress, shorter telomeres, and chronic disease risk. This cross-sectional study examined relative telomere length in relation to perceived stress and urinary stress hormones in a sample of participants (n = 647) in the National Institute of Environmental Health Sciences Sister Study, a cohort of women ages 35 to 74 years who have a sister with breast cancer. Average leukocyte telomere length was determined by quantitative PCR. Current stress was assessed using the Perceived Stress Scale and creatinine-adjusted neuroendocrine hormones in first morning urines. Linear regression models estimated differences in telomere length base pairs (bp) associated with stress measures adjusted for age, race, smoking, and obesity. Women with higher perceived stress had somewhat shorter telomeres [adjusted difference of -129bp for being at or above moderate stress levels; 95% confidence interval (CI), -292 to 33], but telomere length did not decrease monotonically with higher stress levels. Shorter telomeres were independently associated with increasing age (-27bp/year), obesity, and current smoking. Significant stress-related differences in telomere length were seen in women ages 55 years and older (-289bp; 95% CI, -519 to -59), those with recent major losses (-420bp; 95% CI, -814 to -27), and those with above-average urinary catecholamines (e.g., epinephrine: -484bp; 95% CI, -709 to -259). Although current perceived stress was only modestly associated with shorter telomeres in this broad sample of women, our findings suggest the effect of stress on telomere length may vary depending on neuroendocrine responsiveness, external stressors, and age.},
}
@article {pmid19188710,
year = {2008},
author = {Akimcheva, S and Zellinger, B and Riha, K},
title = {Genome stability in Arabidopsis cells exhibiting alternative lengthening of telomeres.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {388-395},
doi = {10.1159/000167827},
pmid = {19188710},
issn = {1424-859X},
mesh = {Anaphase/genetics ; Arabidopsis/cytology/enzymology/*genetics/growth &amp; development ; Arabidopsis Proteins/genetics/metabolism ; *Chromosome Aberrations ; Chromosomes, Plant/genetics ; DNA, Plant/genetics ; Gene Rearrangement ; *Genomic Instability ; Genotype ; Mitosis ; Ploidies ; Telomerase/deficiency/genetics/metabolism ; Telomere/*genetics/ultrastructure ; },
abstract = {Indefinite proliferation of eukaryotic cells depends on telomerase that counteracts the depletion of DNA from chromosome termini due to the end replication problem. The requirement for telomerase can, under certain conditions, be circumvented by employing homologous recombination-based mechanisms for telomere maintenance. Whereas yeast and mammalian cells lacking telomerase appear to readily adopt alternative telomere lengthening (ALT), in Arabidopsis ALT is inhibited by the Ku heterodimer. Although we failed to establish ALT cell lines from Ku-proficient lines, ALT can be efficiently induced in cells derived from mutants deficient for telomerase reverse transcriptase (TERT) and Ku70. In this study, we describe the growth performance, genome stability and long-term maintenance of telomeric DNA in Arabidopsis ku70 tert ALTcultures. ALT activation increases karyotype stability in the majority of tert ku70 cell lines, which contrasts with ongoing chromosomal rearrangements detected in survival tert cultures that lack any detectable telomeric sequences. Curiously, ku70 tert ALT lines and tert survivor cultures proliferate at a similar rate, although the latter display remarkable chromosomal abnormalities, including giant circular and linear megachromosomes that seem to arise by fusions of multiple chromosomes. This observation underlies the extraordinary tolerance of plant cells to telomere dysfunction.},
}
@article {pmid19188709,
year = {2008},
author = {Peska, V and Sýkorová, E and Fajkus, J},
title = {Two faces of Solanaceae telomeres: a comparison between Nicotiana and Cestrum telomeres and telomere-binding proteins.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {380-387},
doi = {10.1159/000167826},
pmid = {19188709},
issn = {1424-859X},
mesh = {Amino Acid Sequence ; Cestrum/enzymology/*genetics ; Conserved Sequence ; Electrophoresis, Polyacrylamide Gel ; Electrophoretic Mobility Shift Assay/methods ; Gene Amplification ; Molecular Sequence Data ; Plant Proteins/genetics/isolation &amp; purification/metabolism ; Sequence Alignment ; Sequence Homology, Amino Acid ; Solanaceae/enzymology/*genetics ; Telomerase/*genetics/*metabolism ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics/isolation &amp; purification/*metabolism ; Nicotiana/enzymology/*genetics ; },
abstract = {While most Solanaceae genera (e.g.Solanum, Nicotiana) possess Arabidopsis-type telomeres of (TTTAGGG)n maintained by telomerase, the genera Cestrum, Vestia and Sessea (Cestrum group) lack these telomeres. Here we show that in the Cestrum-group the activity of telomerase has been lost. Nevertheless, proteins binding the single-stranded G-rich strand of the Arabidopsis-type and related human-type (TTAGGG)n telomeric sequences are present in nuclear extracts of both Nicotiana and Cestrum species. These proteins may have a role in telomere function or other cellular activities. In addition to characterizing DNA binding specificity and molecular weights of these proteins, we searched in both N. tabacum (tobacco) and C. parqui for the presence of POT1-like proteins, involved in telomere capping and telomerase regulation. Analysis of POT1-like proteins available on public databases and cloned by us from C. parqui, revealed the N-terminal OB folds typical for this protein family and a novel, plant-specific conserved C-terminal OB-fold domain (CTOB). We propose that CTOB is involved in protein-protein interactions.},
}
@article {pmid19188708,
year = {2008},
author = {Siroky, J},
title = {Cytogenetics for the study of telomere function in plants.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {374-379},
doi = {10.1159/000167825},
pmid = {19188708},
issn = {1424-859X},
mesh = {Arabidopsis/*genetics/metabolism ; Arabidopsis Proteins/genetics/metabolism ; Chromosomes, Plant/genetics ; Cytogenetic Analysis/methods ; DNA Repair ; DNA, Plant/genetics ; Plant Cells ; *Plant Physiological Phenomena ; Plants/*genetics ; Telomerase/genetics/metabolism ; Telomere/*genetics/physiology/*ultrastructure ; },
abstract = {The ends of linear chromosomes of the vast majority of eukaryotic species possess specialized nucleo-protein structures called telomeres. Regardless of many exceptions, the structure and function of telomeres share high degrees of similarity between various eukaryotes. The underlying DNA structure of telomeres determines the particular setup of telomere chromatin and protein complexes as are telomere-associated proteins and a number of repair and cell cycle checkpoint agents. The structure of telomeres is highly dynamic during the cell's growth, replication, differentiation, senescence, or neoplastic transformation. Although the bulk of our knowledge about telomere function comes from molecular and biochemical studies in model organisms such as yeast and mouse, we want to show--with special emphasis on plants--in this short review that classical methods of plant cytogenetics can significantly complement the above experimental approaches and help in our understanding of telomere functions.},
}
@article {pmid19188707,
year = {2008},
author = {Ciapponi, L and Cenci, G},
title = {Telomere capping and cellular checkpoints: clues from fruit flies.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {365-373},
doi = {10.1159/000167824},
pmid = {19188707},
issn = {1424-859X},
mesh = {Animals ; Cell Cycle/genetics ; DNA Damage ; Drosophila/*genetics ; Drosophila Proteins/genetics ; Female ; Male ; Metaphase ; Plants/genetics ; Telomerase/genetics ; Telomere/*genetics ; Xenopus/genetics ; },
abstract = {In most organisms, telomeres consist of repetitive G-rich sequences that are elongated by a specific reverse transcriptase, telomerase. A large number of proteins are recruited by these terminal repeats, forming specialized structures that regulate telomerase activity and protect telomeres from degradation and recombination. Drosophila lacks telomerase and telomere length is maintained by transposition of three specialized retrotransposons. In addition, unlike yeast and mammals, Drosophila telomeres are epigenetically determined, sequence-independent structures. However, several proteins required for Drosophila telomere behavior are evolutionarily conserved. These include the Mre11-Rad50-Nbs (MRN) complex and the Ataxia Telangiectasia Mutated (ATM) kinase, which are required to prevent telomeric fusions. In addition, recent studies have provided evidence that Drosophila uncapped telomeres elicit a DNA damage response (DDR) just as dysfunctional yeast and human telomeres. Uncapped Drosophila telomeres also activate the spindle assembly checkpoint (SAC) by recruiting the SAC kinase BubR1. Telomere-induced DDR and SAC both require the wild type function of the MRN complex. In addition, while DDR is mediated by ATR kinase, SAC activation requires both the ATM and ATR activities. These results indicate that the DNA repair systems play multiple roles at Drosophila telomeres, highlighting the importance of this model organism for investigations on the relationships between DNA repair and telomere maintenance.},
}
@article {pmid19188706,
year = {2008},
author = {Capkova Frydrychova, R and Biessmann, H and Mason, JM},
title = {Regulation of telomere length in Drosophila.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {356-364},
pmid = {19188706},
issn = {1424-859X},
support = {R01 GM056729/GM/NIGMS NIH HHS/United States ; Z01 ES021054/ImNIH/Intramural NIH HHS/United States ; Z01 ES021054-14/ImNIH/Intramural NIH HHS/United States ; GM-56729/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromosome Mapping ; Chromosomes/genetics/ultrastructure ; DNA/genetics ; Drosophila/*genetics ; Drosophila Proteins/genetics ; Histones/genetics ; Integrases/genetics ; Methylation ; RNA/genetics ; RNA Interference ; Retroelements/*genetics ; Telomere/*genetics/*ultrastructure ; },
abstract = {Telomeres in all organisms must perform the same vital functions to ensure cell viability: to act as a protective chromosome cap that distinguishes natural chromosome ends from DNA double strand breaks, and to balance the loss of DNA from the chromosome end due to incomplete DNA replication. Most eukaryotes rely on a specialized reverse transcriptase, telomerase, to generate short repeats at the chromosome end to maintain chromosome length. Drosophila, however, uses retrotransposons that target telomeres. Transposition of these elements may be controlled by small RNAs and spreading of silent chromatin from the telomere associated sequence, both of which limit the retrotransposon expression level. Proteins binding to the retrotransposon array, such as HP1 and PROD, may also modulate transcription. It is not clear however, that simply increasing transcript levels of the telomeric retrotransposons is sufficient to increase transposition. The chromosome cap may control the ability of the telomere-specific elements to attach to chromosome ends. As in other organisms, chromosomes can be elongated by gene conversion. Although the mechanism is not known, HP1, a component of the cap, and the Ku proteins are key components in this pathway.},
}
@article {pmid19188705,
year = {2008},
author = {Banerjee, B and Peiris, DN and Koo, SH and Chui, P and Lee, EJ and Hande, MP},
title = {Genomic imbalances in key ion channel genes and telomere shortening in sudden cardiac death victims.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {350-355},
doi = {10.1159/000167822},
pmid = {19188705},
issn = {1424-859X},
mesh = {Adolescent ; Adult ; *Allelic Imbalance ; Child ; Chromosomes, Human/genetics ; Comparative Genomic Hybridization ; Death, Sudden, Cardiac/*pathology ; Female ; Heart Arrest/*genetics ; Humans ; Ion Channels/*genetics ; Male ; Polymerase Chain Reaction ; RNA/genetics/isolation &amp; purification ; Sequence Deletion ; Telomere/*genetics/ultrastructure ; Young Adult ; },
abstract = {Sudden cardiac death (SCD) can be caused by a number of reasons. Previous works have identified the genetic causes, such as alterations in the DNA sequence, for many of these diseases. We hypothesize that some patients may show genomic imbalances and changes in the gene copy number leading to genetic instability. To clarify this, we analysed DNA samples from SCD victims using comparative genomic hybridization (CGH), a molecular cytogenetic technique that permits the genome-wide screening of chromosomal imbalances, and telomere length measurement. DNA derived from peripheral blood and heart tissue of 14 SCD cases and six apparently healthy control individuals were subjected to CGH analysis. Telomere length measurements were done by the Southern blotting method. Eight out of 14 SCD cases exhibited changes in DNA/gene copy number. CGH analysis showed variation in the gene copy number of some of the genes associated with potassium (KCNAB1, KCNH2, and KCNA4) and calcium (RyR2, ATP2A2) ions which are involved in maintaining the ionic balance of the heart. Alterations in TERC and TERT genes were also detected in SCD victims. In nine SCD victims shorter telomeres were detected. This might have resulted from excessive cellular proliferation and/or oxidative stress in these individuals. Copy number changes observed and telomere shortening detected in SCD cases would possibly explain at least some of the causes of SCD at early ages in humans. Identification of biomarkers of SCD is of great importance and thus the present study will facilitate the identification of some of the biomarkers.},
}
@article {pmid19188704,
year = {2008},
author = {Salin, H and Ricoul, M and Morat, L and Sabatier, L},
title = {Increased genomic alteration complexity and telomere shortening in B-CLL cells resistant to radiation-induced apoptosis.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {343-349},
pmid = {19188704},
issn = {1424-859X},
mesh = {Apoptosis/radiation effects ; B-Lymphocytes/pathology ; *Chromosome Aberrations ; Chromosomes, Human, Pair 13/genetics/radiation effects ; Genomic Instability ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia, Lymphocytic, Chronic, B-Cell/enzymology/*genetics/pathology ; Metaphase ; Sequence Deletion/radiation effects ; Telomerase/metabolism ; Telomere/*genetics/ultrastructure ; },
abstract = {B-cell chronic lymphocytic leukemia (B-CLL) results in an accumulation of mature CD5(+)/CD23(+) B cells due to an uncharacterized defect in apoptotic cell death. B-CLL is not characterized by a unique recurrent genomic alteration but rather by genomic instability giving rise frequently to several chromosomal aberrations. Besides we reported that approximately 15% of B-CLL patients present malignant B-cells resistant to irradiation-induced apoptosis, contrary to approximately 85% of patients and normal human lymphocytes. Telomere length shortening is observed in radioresistant B-CLL cells. Using fluorescence in situ hybridization (FISH) and multicolour FISH, we tested whether specific chromosomal aberrations might be associated with the radioresistance of a subset of B-CLL cells and whether they are correlated with telomere shortening. In a cohort of 30 B-CLL patients, all of the radioresistant B-CLL cell samples exhibited homozygous or heterozygous deletion of 13q14.3 in contrast to 52% of the radiosensitive samples. In addition to the 13q14.3 deletion, ten out of the 11 radioresistant B-cell samples had another clonal genomic alteration such as trisomy 12, deletion 17p13.1, mutation of the p53 gene or translocations in contrast to only three out of 19 radiosensitive samples. Telomere fusions and non-reciprocal translocations, hallmarks of telomere dysfunction, are not increased in radioresistant B-CLL cells. These findings suggest (i) that the 13q14.3 deletion accompanied by another chromosomal aberration is associated with radioresistance of B-CLL cells and (ii) that telomere shortening is not causative of increased clonal chromosomal aberrations in radioresistant B-CLL cells.},
}
@article {pmid19188703,
year = {2008},
author = {Cabuy, E and Newton, C and Slijepcevic, P},
title = {BRCA1 knock-down causes telomere dysfunction in mammary epithelial cells.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {336-342},
doi = {10.1159/000167820},
pmid = {19188703},
issn = {1424-859X},
support = {RRX97//Department of Health/United Kingdom ; },
mesh = {BRCA1 Protein/deficiency/*genetics/metabolism ; Breast Neoplasms/*genetics ; Cell Culture Techniques ; Cell Line ; DNA Damage ; DNA Primers ; Epithelial Cells/*physiology ; Female ; Gene Amplification ; Humans ; Immunohistochemistry ; Mammary Glands, Human/cytology/*physiology ; RNA Interference ; RNA, Small Interfering/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*genetics ; Transfection ; },
abstract = {A breast cancer predisposing gene, BRCA1, is a major suppressor of chromosomal instability and its dysfunction affects multiple pathways involved in DNA damage response. There is increasing evidence that the mechanisms involved in maintenance of telomeres, specialized structures at chromosome ends, are linked with DNA damage response. We therefore investigated whether BRCA1 dysfunction affects telomere maintenance. To achieve this we knocked-down BRCA1 in two mammary epithelial cell lines using RNA interference. Subsequent analysis by immunofluorescence, RT-PCR and Western blotting revealed that a short interfering RNA oligonucleotide used was able to knock-down BRCA1 efficiently. This knock-down did not have any effect on telomerase enzyme activity and telomere length. However, BRCA1 knock-down correlated with the increase in chromatin bridges in anaphase cells which usually reflect telomere dysfunction. Therefore, this study suggests that BRCA1 knockdown in mammary epithelial cells causes telomere dysfunction.},
}
@article {pmid19188701,
year = {2008},
author = {Tusell, L and Soler, D and Agostini, M and Pampalona, J and Genescà, A},
title = {The number of dysfunctional telomeres in a cell: one amplifies; more than one translocate.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {315-325},
doi = {10.1159/000167818},
pmid = {19188701},
issn = {1424-859X},
mesh = {Cell Cycle/genetics/physiology ; Cell Transformation, Neoplastic/*genetics ; Chromatids/genetics ; Chromatin/genetics/physiology ; Chromosomal Instability/*genetics ; Chromosome Aberrations ; Chromosome Deletion ; Chromosomes, Human/genetics ; DNA Damage ; Gene Amplification ; Gene Fusion ; Genes, Plant/genetics ; Humans ; Neoplasms/*genetics ; Plants/genetics ; Telomere/*genetics/metabolism ; Translocation, Genetic ; },
abstract = {Chromosomal instability is increasingly appreciated as a key component of tumorigenesis in humans. A combination of abnormal telomere shortening and cell-cycle checkpoint deficiency has been proposed as the initial lesions causing destabilizing chromatin bridges in proliferative cells. We examined the participation of the different types of end-to-end fusions in generating instable karyotypes in non-transformed human breast epithelial cells. We concluded that short dysfunctional telomeres represent an initiating substrate for post-replicative rejoining of sister chromatids and are likely to make an important contribution to the formation of chromosomal rearrangements and the amplification of chromosome arm segments in breast epithelial cells. We propose that there is a chronological order in the participation of the different types of end-to-end fusions in the generation of chromosomal instability. Thus, intrachromosomal post-replicative joining would proceed mainly in the early stages after overcoming growth arrest, when telomere dysfunction is limited and affects only one chromosome end in a cell. The absence of a second substrate for end joining will conduct the cell with the uncapped chromosome to replicate its DNA and fuse the uncapped sister chromatids after replication. Later, since telomeres shorten progressively with each DNA replication round, the uncapping will affect many more chromosome ends, and fusions between the uncapped ends from different chromosomes will be produced. While the fusion of sister chromatids will produce chromosome segment amplification and terminal deletions in the daughter cells, interchromosomal fusion will produce unbalanced rearrangements other than chromosome segment amplifications.},
}
@article {pmid19188699,
year = {2008},
author = {Misri, S and Pandita, S and Kumar, R and Pandita, TK},
title = {Telomeres, histone code, and DNA damage response.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {297-307},
pmid = {19188699},
issn = {1424-859X},
support = {P01 CA104457-020002/CA/NCI NIH HHS/United States ; CA10445/CA/NCI NIH HHS/United States ; P01 CA104457-01A10002/CA/NCI NIH HHS/United States ; R01 CA123232/CA/NCI NIH HHS/United States ; P01 CA104457-030002/CA/NCI NIH HHS/United States ; P01 CA104457-050002/CA/NCI NIH HHS/United States ; R01 CA123232-02/CA/NCI NIH HHS/United States ; CA123232/CA/NCI NIH HHS/United States ; R01 CA123232-01A1/CA/NCI NIH HHS/United States ; P01 CA104457-040002/CA/NCI NIH HHS/United States ; P01 CA104457/CA/NCI NIH HHS/United States ; R01 CA129537/CA/NCI NIH HHS/United States ; },
mesh = {Acetylation ; Ataxia Telangiectasia/genetics ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle/genetics ; Cell Cycle Proteins/genetics ; Chromatin/genetics/ultrastructure ; *DNA Damage ; DNA-Binding Proteins/genetics ; Genomic Instability/genetics ; Histones/*genetics/metabolism ; Humans ; Methylation ; Phosphorylation ; Protein Serine-Threonine Kinases/genetics ; Radiation, Ionizing ; Telomere/*genetics/radiation effects/ultrastructure ; Tumor Suppressor Proteins/genetics ; Ubiquitin/genetics ; },
abstract = {Genomic stability is maintained by telomeres, the end terminal structures that protect chromosomes from fusion or degradation. Shortening or loss of telomeric repeats or altered telomere chromatin structure is correlated with telomere dysfunction such as chromosome end-to-end associations that could lead to genomic instability and gene amplification. The structure at the end of telomeres is such that its DNA differs from DNA double strand breaks (DSBs) to avoid nonhomologous end-joining (NHEJ), which is accomplished by forming a unique higher order nucleoprotein structure. Telomeres are attached to the nuclear matrix and have a unique chromatin structure. Whether this special structure is maintained by specific chromatin changes is yet to be thoroughly investigated. Chromatin modifications implicated in transcriptional regulation are thought to be the result of a code on the histone proteins (histone code). This code, involving phosphorylation, acetylation, methylation, ubiquitylation, and sumoylation of histones, is believed to regulate chromatin accessibility either by disrupting chromatin contacts or by recruiting non-histone proteins to chromatin. The histone code in which distinct histone tail-protein interactions promote engagement may be the deciding factor for choosing specific DSB repair pathways. Recent evidence suggests that such mechanisms are involved in DNA damage detection and repair. Altered telomere chromatin structure has been linked to defective DNA damage response (DDR), and eukaryotic cells have evolved DDR mechanisms utilizing proficient DNA repair and cell cycle checkpoints in order to maintain genomic stability. Recent studies suggest that chromatin modifying factors play a critical role in the maintenance of genomic stability. This review will summarize the role of DNA damage repair proteins specifically ataxia-telangiectasia mutated (ATM) and its effectors and the telomere complex in maintaining genome stability.},
}
@article {pmid19188698,
year = {2008},
author = {Bouffler, SD and Finnon, P and Blasco, MA and Ainsbury, E},
title = {A possible role for telomerase RNA and telomere length in global mitotic recombination.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {292-296},
doi = {10.1159/000167815},
pmid = {19188698},
issn = {1424-859X},
mesh = {Analysis of Variance ; Animals ; Cell Cycle ; Gene Expression Regulation, Enzymologic ; Gene Frequency ; Genotype ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitosis/*genetics ; Poly(ADP-ribose) Polymerases/deficiency/genetics ; RNA/*genetics ; *Recombination, Genetic ; Sister Chromatid Exchange/*genetics ; Spleen/cytology/enzymology ; Telomerase/deficiency/*genetics ; Telomere/*genetics/ultrastructure ; },
abstract = {Telomeres are specialised structures at the ends of mammalian chromosomes with many unique properties. Recombinational events at telomeres are more frequent than in the remainder of the genome by several orders of magnitude. This study examined the influence of telomerase status and telomere length on genome-wide recombination assessed by genomic sister chromatid exchange (G-SCE). Telomerase deficiency per se appears to increase G-SCE frequencies in splenocytes but as telomeres shorten through subsequent generations of mTerc(-/-) mice this increase is progressively lost. Telomerase status and telomere length also influences the induction of G-SCE by UV light. Even when mitotic recombination is affected by PARP deficiency, mTerc and telomere length interact to further affect G-SCE frequencies. Taken together the data presented here demonstrate that telomerase status and telomere length can affect recombination frequencies genome-wide.},
}
@article {pmid19188697,
year = {2008},
author = {Royle, NJ and Foxon, J and Jeyapalan, JN and Mendez-Bermudez, A and Novo, CL and Williams, J and Cotton, VE},
title = {Telomere length maintenance--an ALTernative mechanism.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {281-291},
doi = {10.1159/000167814},
pmid = {19188697},
issn = {1424-859X},
support = {//Medical Research Council/United Kingdom ; },
mesh = {Alternative Splicing ; Cell Line ; DNA/genetics ; DNA, Fungal/genetics ; DNA, Neoplasm/genetics ; Genomic Instability ; Humans ; Mutation ; Neoplasms/enzymology/*genetics ; Oligonucleotide Array Sequence Analysis ; Phenotype ; Recombination, Genetic ; Saccharomyces cerevisiae/enzymology ; Sarcoma/enzymology/genetics ; Telomerase/*genetics/*metabolism ; Telomere/genetics/ultrastructure ; },
abstract = {The Alternative Lengthening of Telomeres (ALT) mechanism is utilised by approximately 10% of human tumours and a higher proportion of some types of sarcomas. ALT+ cell lines and tumours show heterogeneous telomere length, extra-chromosomal circular and linear telomeric DNA, ALT associated promyelocytic bodies (APBs), a high frequency of post-replication exchanges in telomeres (designated as telomere-sister chromatid exchanges, T-SCE) and high instability at a GC-rich minisatellite, MS32 (D1S8). It is clear that there is a link between the minisatellite instability and the mechanism that underpins ALT, however currently the nature of this relationship is uncertain. Single molecule analysis of telomeric DNA from ALT+ cell lines and tumours has revealed complex telomere mutations that have not been seen in cell lines or tumours that express telomerase. These complex telomere mutations cannot be explained by T-SCE but must arise by another inter-molecular process. The break-induced replication (BIR) model that may explain the observed high frequency of T-SCE and the presence of complex telomere mutations is reviewed.},
}
@article {pmid19188693,
year = {2008},
author = {Stern, JL and Bryan, TM},
title = {Telomerase recruitment to telomeres.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {243-254},
doi = {10.1159/000167810},
pmid = {19188693},
issn = {1424-859X},
support = {R01 GM099705/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle ; DNA/genetics ; DNA Damage ; DNA, Fungal/genetics ; Fungal Proteins/genetics/metabolism ; Gene Expression Regulation ; Humans ; Models, Genetic ; Telomerase/genetics/*metabolism ; Telomere/*enzymology ; Telomere-Binding Proteins/genetics/metabolism ; Yeasts/physiology ; },
abstract = {The ability of most cancer cells to grow indefinitely relies on the presence of functional telomerase to maintain telomeres, thus circumventing normal cellular senescence. A key feature of telomerase functionality is the localization of the enzyme complex to telomeres, a process which is highly regulated. A number of recent studies have reported data with significant implications for our understanding of telomerase recruitment to telomeres. A picture is emerging that this process is governed by a number of factors including telomeric binding proteins, structural features of the enzyme complex, cell cycle regulated processes such as DNA replication, and components of the DNA damage response pathway. In this review we summarize recent findings relating to this fundamental process in eukaryotes.},
}
@article {pmid19188692,
year = {2008},
author = {Ramírez, MJ and Surrallés, J},
title = {Laser confocal microscopy analysis of human interphase nuclei by three-dimensional FISH reveals dynamic perinucleolar clustering of telomeres.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {237-242},
doi = {10.1159/000167809},
pmid = {19188692},
issn = {1424-859X},
mesh = {Animals ; Cell Nucleolus/*physiology/ultrastructure ; Cell Nucleus/*ultrastructure ; Chromosomes, Human, Pair 18/ultrastructure ; Fibroblasts/cytology/physiology ; Histones/deficiency/genetics ; Humans ; In Situ Hybridization, Fluorescence ; Interphase ; Lymphocytes/cytology/physiology ; Mice ; Mice, Knockout ; Microscopy, Confocal/methods ; Telomere/genetics/*ultrastructure ; },
abstract = {Nuclear functions are strongly dependent on the three-dimensional organization of the interphase nucleus. Given the importance of telomeres in the behaviour and stability of chromosomes, we have investigated the architecture of the human nucleus from the telomere perspective by 3D-FISH and laser confocal microscopy. We observed a randomly scattered telomere distribution in all confocal sections of the interphase nuclear volume with various levels of telomere clustering in different cell types. This distribution is independent of H2AX presence or phosphorylation status. We also observed that telomeres usually cluster at the periphery of the nucleolus following its cell cycle dependent dynamic formation but are never present in the interior of the nucleolus. These perinucleolar telomeric clusters contain the telomeres of the short arms of acrocentric chromosomes, explaining the p-arm association of acrocentric chromosomes frequently found in metaphase. Thus, chromosome positioning in metaphase spreads is tightly connected to the three-dimensional architecture of the interphase nucleus.},
}
@article {pmid19188691,
year = {2008},
author = {Arnoult, N and Shin-Ya, K and Londoño-Vallejo, JA},
title = {Studying telomere replication by Q-CO-FISH: the effect of telomestatin, a potent G-quadruplex ligand.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {229-236},
doi = {10.1159/000167808},
pmid = {19188691},
issn = {1424-859X},
mesh = {Animals ; Cell Cycle ; Cell Division ; Cell Line ; DNA/genetics ; DNA Replication ; Fibroblasts/cytology/physiology ; In Situ Hybridization, Fluorescence ; Metaphase/physiology ; Mice ; Nucleic Acid Hybridization ; Oxazoles/*pharmacology ; Telomerase/drug effects/metabolism ; Telomere/*genetics ; },
abstract = {Telomere replication is a critical process for preserving genome integrity. The telomere replication fork proceeds unidirectionally from the last subtelomeric origin towards the end of the chromosome, replicating the 5'-3' G-rich strand by lagging mechanisms and the complementary C-rich strand by leading mechanisms. It has been proposed that the G-rich nature of telomeres may favor the formation of secondary structures such as G-quadruplexes during replication and that specific mechanisms must prevent this to allow the fork to progress unimpeded. The potential of G-quadruplex formation by telomeric sequences has been clearly demonstrated in vitro but it is not known whether these structures form in vivo. We tested the effect of a potent and specific G-quadruplex ligand, telomestatin (TMS), on telomere replication using a novel quantitative approach applied to CO-FISH. We show that TMS, although it penetrates and persists within cells, does not affect telomere replication after short or long-term treatments of mouse embryonic fibroblasts. It does however affect the hybridization efficiency of FISH telomeric probes that recognize the G-rich strand. Our work illustrates the use of a novel technique to measure telomere replication efficiency and suggests that G-quadruplex ligands do not affect telomere replication in a non tumoral context.},
}
@article {pmid19188689,
year = {2008},
author = {Yang, Q},
title = {Cellular senescence, telomere recombination and maintenance.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {211-218},
doi = {10.1159/000167806},
pmid = {19188689},
issn = {1424-859X},
mesh = {Cell Division ; Cellular Senescence/*genetics ; DNA/genetics ; DNA Damage ; DNA, Neoplasm/genetics ; Fibroblasts/*cytology/physiology ; Humans ; Neoplasms/pathology ; *Recombination, Genetic ; Telomerase/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; },
abstract = {Cellular senescence can be activated by various types of stressful stimuli, including telomere shortening, oncogenic or tumor suppressor signals, and DNA damage. Progressive telomere shortening in successive cell divisions induces senescence due to the loss of terminal sequences during DNA replication. Maintenance of the telomere sequences at human chromosome ends is essential for immortalized cells to escape from the normal limitations of the proliferation capacity. In this article, the molecular and functional details of telomere maintenance and cellular senescence are reviewed, including the signals that trigger senescence, telomere capping, and the telomere length maintenance mechanisms.},
}
@article {pmid19188688,
year = {2008},
author = {Gonzalez-Suarez, I and Gonzalo, S},
title = {Crosstalk between chromatin structure, nuclear compartmentalization, and telomere biology.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {202-210},
doi = {10.1159/000167805},
pmid = {19188688},
issn = {1424-859X},
mesh = {Aging/genetics/physiology ; Animals ; Cell Nucleus/genetics/*physiology ; Chromatin/genetics/*physiology ; DNA/genetics ; DNA Repair ; Humans ; Mammals/genetics ; Phenotype ; Proteins/genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Signal Transduction/physiology ; Telomere/genetics/*physiology ; },
abstract = {Telomeres are heterochromatic structures essential for the maintenance of genomic stability and the proliferative potential of human somatic cells. A minimal length of telomeric DNA repeats and proper binding of specialized proteins are required for the maintenance of telomere structure and function. Activation of telomere length maintenance mechanisms is considered a hallmark of cancer, while attrition of telomeres is a known contributor to the phenotypes associated with the aging process. However, the molecular mechanisms responsible for telomere homeostasis are not completely understood. Compelling data indicates that the epigenetic status of telomeric and subtelomeric chromatin also plays a role in the regulation of telomere biology. In addition, genomic regions are not randomly distributed within the nucleus, but rather compartmentalized into spatial and temporal domains whose functional implications for the cell are only beginning to be unraveled. Recent studies indicate that alterations in some of the mechanisms responsible for nuclear organization associate with defects in chromatin structure. These observations suggest a link between these two processes, raising the question of whether nuclear compartmentalization of telomeres might also impact on telomere biology.},
}
@article {pmid19188686,
year = {2008},
author = {Slijepcevic, P},
title = {Telomeres and telomerase. Preface.},
journal = {Cytogenetic and genome research},
volume = {122},
number = {3-4},
pages = {193},
doi = {10.1159/000167803},
pmid = {19188686},
issn = {1424-859X},
mesh = {Animals ; Conserved Sequence ; DNA/genetics ; Drosophila/genetics ; Drosophila melanogaster/genetics ; Retroelements/genetics ; Telomerase/chemistry/*genetics ; Telomere/chemistry/*genetics ; },
}
@article {pmid19181850,
year = {2009},
author = {Raffa, GD and Siriaco, G and Cugusi, S and Ciapponi, L and Cenci, G and Wojcik, E and Gatti, M},
title = {The Drosophila modigliani (moi) gene encodes a HOAP-interacting protein required for telomere protection.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {106},
number = {7},
pages = {2271-2276},
pmid = {19181850},
issn = {1091-6490},
support = {GGP07200/TI_/Telethon/Italy ; },
mesh = {Alleles ; Animals ; Chromosomal Proteins, Non-Histone/*genetics/*metabolism ; DNA/metabolism ; Drosophila/*genetics ; Drosophila Proteins/*genetics/*metabolism ; Green Fluorescent Proteins/metabolism ; Humans ; Introns ; Models, Biological ; Mutation ; Open Reading Frames ; RNA, Messenger/metabolism ; Shelterin Complex ; Telomere/*ultrastructure ; Telomere-Binding Proteins/genetics ; },
abstract = {Several proteins have been identified that protect Drosophila telomeres from fusion events. They include UbcD1, HP1, HOAP, the components of the Mre11-Rad50-Nbs (MRN) complex, the ATM kinase, and the putative transcription factor Woc. Of these proteins, only HOAP has been shown to localize specifically at telomeres. Here we show that the modigliani gene encodes a protein (Moi) that is enriched only at telomeres, colocalizes and physically interacts with HOAP, and is required to prevent telomeric fusions. Moi is encoded by the bicistronic CG31241 locus. This locus produces a single transcript that contains 2 ORFs that specify different essential functions. One of these ORFs encodes the 20-kDa Moi protein. The other encodes a 60-kDa protein homologous to RNA methyltransferases that is not required for telomere protection (Drosophila Tat-like). Moi and HOAP share several properties with the components of shelterin, the protein complex that protects human telomeres. HOAP and Moi are not evolutionarily conserved unlike the other proteins implicated in Drosophila telomere protection. Similarly, none of the shelterin subunits is conserved in Drosophila, while most human nonshelterin proteins have Drosophila homologues. This suggests that the HOAP-Moi complex, we name "terminin," plays a specific role in the DNA sequence-independent assembly of Drosophila telomeres. We speculate that this complex is functionally analogous to shelterin, which binds chromosome ends in a sequence-dependent manner.},
}
@article {pmid19180191,
year = {2009},
author = {Morrish, TA and Greider, CW},
title = {Short telomeres initiate telomere recombination in primary and tumor cells.},
journal = {PLoS genetics},
volume = {5},
number = {1},
pages = {e1000357},
pmid = {19180191},
issn = {1553-7404},
support = {P01 CA016519/CA/NCI NIH HHS/United States ; P01 CA16519/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; Fibroblasts/chemistry/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Lymphoma/*chemistry/*genetics/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; *Recombination, Genetic ; Telomerase/genetics/metabolism ; Telomere/*chemistry/*genetics/metabolism ; Tumor Cells, Cultured ; },
abstract = {Human tumors that lack telomerase maintain telomeres by alternative lengthening mechanisms. Tumors can also form in telomerase-deficient mice; however, the genetic mechanism responsible for tumor growth without telomerase is unknown. In yeast, several different recombination pathways maintain telomeres in the absence of telomerase-some result in telomere maintenance with minimal effects on telomere length. To examine non-telomerase mechanisms for telomere maintenance in mammalian cells, we used primary cells and lymphomas from telomerase-deficient mice (mTR-/- and Emumyc+mTR-/-) and CAST/EiJ mouse embryonic fibroblast cells. These cells were analyzed using pq-ratio analysis, telomere length distribution outliers, CO-FISH, Q-FISH, and multicolor FISH to detect subtelomeric recombination. Telomere length was maintained during long-term growth in vivo and in vitro. Long telomeres, characteristic of human ALT cells, were not observed in either late passage or mTR-/- tumor cells; instead, we observed only minimal changes in telomere length. Telomere length variation and subtelomeric recombination were frequent in cells with short telomeres, indicating that length maintenance is due to telomeric recombination. We also detected telomere length changes in primary mTR-/- cells that had short telomeres. Using mouse mTR+/- and human hTERT+/- primary cells with short telomeres, we found frequent length changes indicative of recombination. We conclude that telomere maintenance by non-telomerase mechanisms, including recombination, occurs in primary cells and is initiated by short telomeres, even in the presence of telomerase. Most intriguing, our data indicate that some non-telomerase telomere maintenance mechanisms occur without a significant increase in telomere length.},
}
@article {pmid19179643,
year = {2009},
author = {Taddei, A and Van Houwe, G and Nagai, S and Erb, I and van Nimwegen, E and Gasser, SM},
title = {The functional importance of telomere clustering: global changes in gene expression result from SIR factor dispersion.},
journal = {Genome research},
volume = {19},
number = {4},
pages = {611-625},
pmid = {19179643},
issn = {1088-9051},
mesh = {Cell Membrane/metabolism ; Cell Nucleus/metabolism ; Computational Biology ; DNA-Binding Proteins/genetics/metabolism ; Endoribonucleases/genetics/metabolism ; *Gene Expression Regulation, Fungal ; *Gene Silencing ; Oligonucleotide Array Sequence Analysis ; Promoter Regions, Genetic ; Regulatory Elements, Transcriptional/*genetics ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/*genetics/metabolism ; Telomere/*physiology ; Transcription Factors/genetics/metabolism ; },
abstract = {Budding yeast telomeres and cryptic mating-type loci are enriched at the nuclear envelope, forming foci that sequester silent information regulators (SIR factors), much as heterochromatic chromocenters in higher eukaryotes sequester HP1. Here we examine the impact of such subcompartments for regulating transcription genome-wide. We show that the efficiency of subtelomeric reporter gene repression depends not only on the strength of SIR factor recruitment by cis-acting elements, but also on the accumulation of SIRs in such perinuclear foci. To monitor the effects of disrupting this subnuclear compartment, we performed microarray analyses under conditions that eliminate telomere anchoring, while preserving SIR complex integrity. We found 60 genes reproducibly misregulated. Among those with increased expression, 22% were within 20 kb of a telomere, confirming that the nuclear envelope (NE) association of telomeres helps repress natural subtelomeric genes. In contrast, loci that were down-regulated were distributed over all chromosomes. Half of this ectopic repression was SIR complex dependent. We conclude that released SIR factors can promiscuously repress transcription at nontelomeric genes despite the presence of "anti-silencing" mechanisms. Bioinformatic analysis revealed that promoters bearing the PAC (RNA Polymerase A and C promoters) or Abf1 binding consenses are consistently down-regulated by mislocalization of SIR factors. Thus, the normal telomeric sequestration of SIRs both favors subtelomeric repression and prevents promiscuous effects at a distinct subset of promoters. This demonstrates that patterns of gene expression can be regulated by changing the spatial distribution of repetitive DNA sequences that bind repressive factors.},
}
@article {pmid19179534,
year = {2009},
author = {Venteicher, AS and Abreu, EB and Meng, Z and McCann, KE and Terns, RM and Veenstra, TD and Terns, MP and Artandi, SE},
title = {A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis.},
journal = {Science (New York, N.Y.)},
volume = {323},
number = {5914},
pages = {644-648},
pmid = {19179534},
issn = {1095-9203},
support = {T32 GM007365/GM/NIGMS NIH HHS/United States ; R01 CA111691-04/CA/NCI NIH HHS/United States ; R01 CA125453-03/CA/NCI NIH HHS/United States ; R01 CA104676/CA/NCI NIH HHS/United States ; R01 CA111691/CA/NCI NIH HHS/United States ; GM07365/GM/NIGMS NIH HHS/United States ; CA104676/CA/NCI NIH HHS/United States ; R01 CA125453/CA/NCI NIH HHS/United States ; N01CO12400/CA/NCI NIH HHS/United States ; N01-CO-12400/CO/NCI NIH HHS/United States ; CA125453/CA/NCI NIH HHS/United States ; CA111691/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Coiled Bodies/*metabolism ; HeLa Cells ; Humans ; Immunoprecipitation ; Molecular Chaperones ; Molecular Sequence Data ; Nuclear Proteins/metabolism ; RNA/metabolism ; RNA Interference ; Telomerase/chemistry/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomerase is a ribonucleoprotein (RNP) complex that synthesizes telomere repeats in tissue progenitor cells and cancer cells. Active human telomerase consists of at least three principal subunits, including the telomerase reverse transcriptase, the telomerase RNA (TERC), and dyskerin. Here, we identify a holoenzyme subunit, TCAB1 (telomerase Cajal body protein 1), that is notably enriched in Cajal bodies, nuclear sites of RNP processing that are important for telomerase function. TCAB1 associates with active telomerase enzyme, established telomerase components, and small Cajal body RNAs that are involved in modifying splicing RNAs. Depletion of TCAB1 by using RNA interference prevents TERC from associating with Cajal bodies, disrupts telomerase-telomere association, and abrogates telomere synthesis by telomerase. Thus, TCAB1 controls telomerase trafficking and is required for telomere synthesis in human cancer cells.},
}
@article {pmid19179485,
year = {2009},
author = {Savale, L and Chaouat, A and Bastuji-Garin, S and Marcos, E and Boyer, L and Maitre, B and Sarni, M and Housset, B and Weitzenblum, E and Matrat, M and Le Corvoisier, P and Rideau, D and Boczkowski, J and Dubois-Randé, JL and Chouaid, C and Adnot, S},
title = {Shortened telomeres in circulating leukocytes of patients with chronic obstructive pulmonary disease.},
journal = {American journal of respiratory and critical care medicine},
volume = {179},
number = {7},
pages = {566-571},
pmid = {19179485},
issn = {1535-4970},
mesh = {Aged ; Aging/blood/genetics ; Case-Control Studies ; Female ; Humans ; *Leukocytes ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/*blood/*genetics ; Smoking ; *Telomere ; },
abstract = {RATIONALE: Telomere length is considered a marker for biological aging. Chronic obstructive pulmonary disease (COPD) may be associated with premature aging.<br><br>OBJECTIVES: To test the hypothesis that patients with COPD experience accelerated telomere shortening and that inflammation is linked to this process.<br><br>METHODS: We measured telomere length, using a quantitative polymerase chain reaction-based method, and plasma levels of various cytokines in 136 patients with COPD, 113 age- and sex-matched smokers, and 42 nonsmokers with normal lung function.<br><br>MEASUREMENTS AND MAIN RESULTS: Median (range) telomere length ratio was significantly lower in patients with COPD (0.57 [0.23-1.18]) than in control smokers (0.79 [0.34-1.58]) or nonsmokers (0.85 [0.38-1.55]) (P < 0.001). The difference remained highly significant when using logistic regression analysis adjusted for age, sex, and tobacco exposure. Both females and males with COPD had shorter telomere length than same-sex control subjects. Telomere length was related to age in patients and control subjects but was shorter in patients than in control subjects in all age groups. No relationship was found between telomere length and tobacco exposure in patients or control subjects, with no difference between control smokers and nonsmokers. In patients with COPD, telomere length was related to PaO2 (P < 0.001) and PaCO2 (P < 0.001) but not to lung function parameters or the BODE Index. Patients with COPD also had elevated plasma levels of various cytokines, interleukin-6 correlating negatively with telomere length (P < 0.001).<br><br>CONCLUSIONS: Given that in vivo telomere length reflects cellular turnover and exposure to oxidative and inflammatory damage, our data support accelerated aging in COPD.},
}
@article {pmid19176257,
year = {2010},
author = {Behjati, M and Hashemi, M and Salehi, M and Kelishadi, R},
title = {Can leukocyte telomere length (LTL) be considered as an index in application of neural network in the atherosclerosis risk stratification?.},
journal = {International journal of cardiology},
volume = {144},
number = {1},
pages = {136-137},
doi = {10.1016/j.ijcard.2008.12.120},
pmid = {19176257},
issn = {1874-1754},
mesh = {Atherosclerosis/epidemiology/*genetics ; Humans ; Incidence ; Leukocytes/*metabolism ; *Nerve Net ; Risk Assessment/*methods ; Telomere/*genetics ; },
}
@article {pmid19172739,
year = {2008},
author = {Puglisi, A and Bianchi, A and Lemmens, L and Damay, P and Shore, D},
title = {Distinct roles for yeast Stn1 in telomere capping and telomerase inhibition.},
journal = {The EMBO journal},
volume = {27},
number = {17},
pages = {2328-2339},
pmid = {19172739},
issn = {0261-4189},
mesh = {Cell Cycle Proteins/chemistry/genetics/*metabolism ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; Genes, Fungal ; Mutation ; Protein Binding ; Protein Structure, Tertiary ; Recombinant Fusion Proteins/chemistry/genetics/metabolism ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/genetics/*metabolism ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {The budding yeast Cdc13, Stn1 and Ten1 (CST) proteins are proposed to function as an RPA-like complex at telomeres that protects ('caps') chromosome ends and regulates their elongation by telomerase. We show that Stn1 has a critical function in both processes through the deployment of two separable domains. The N terminus of Stn1 interacts with Ten1 and carries out its essential capping function. The C terminus of Stn1 binds both Cdc13 and Pol12, and we present genetic data indicating that the Stn1-Cdc13 interaction is required to limit continuous telomerase action. Stn1 telomere association, similar to that of Cdc13, peaks during S phase. Significantly, the magnitude of Stn1 telomere binding is independent of telomere TG tract length, suggesting that the negative effect of Stn1 on telomerase action might be regulated by a modification of CST activity or structure in cis at individual telomeres. Genetic analysis suggests that the Tell kinase exerts an effect in parallel with the Stn1 C terminus to counteract its inhibition of telomerase. These data provide new insights into the coordination of telomere capping and telomerase regulation.},
}
@article {pmid19171895,
year = {2009},
author = {Gasparyan, HJ and Xu, L and Petreaca, RC and Rex, AE and Small, VY and Bhogal, NS and Julius, JA and Warsi, TH and Bachant, J and Aparicio, OM and Nugent, CI},
title = {Yeast telomere capping protein Stn1 overrides DNA replication control through the S phase checkpoint.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {106},
number = {7},
pages = {2206-2211},
pmid = {19171895},
issn = {1091-6490},
support = {R01 GM066190/GM/NIGMS NIH HHS/United States ; R01-GM66190/GM/NIGMS NIH HHS/United States ; R01 CA096972/CA/NCI NIH HHS/United States ; R01-CA96972/CA/NCI NIH HHS/United States ; R01-CA65494/CA/NCI NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/*metabolism ; Checkpoint Kinase 2 ; DNA Polymerase I/metabolism ; *DNA Replication ; Hydroxyurea/pharmacology ; Methyl Methanesulfonate/pharmacology ; Models, Biological ; Protein Binding ; Protein Serine-Threonine Kinases/metabolism ; Protein Structure, Tertiary ; S Phase ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Spindle Apparatus ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; Temperature ; },
abstract = {Telomere integrity is maintained through end-protection proteins that block nuclease degradation and prevent telomeres from being recognized as DNA breaks. Although less well understood, end protection proteins may also play a role in facilitating telomere replication. Here, we show that overproduction (OP) of the yeast telomere capping protein Stn1 makes cells highly sensitive to the replication inhibitors hydroxyurea (HU) and methyl-methane sulfonate (MMS). Unexpectedly, this sensitivity corresponds with Stn1 OP blocking most, if not all, aspects of the S phase checkpoint. The checkpoint kinase Rad53 is phosphorylated with normal timing in Stn1 OP cells, indicating Stn1 does not interfere with signaling steps involved in activating the checkpoint. Part of the role of Stn1 in telomere integrity is mediated through the Pol12 subunit of DNA polymerase alpha (Pol alpha). We show that overproduced Stn1 generally associates with chromosomes in HU treated and untreated cells, and, remarkably, Stn1 chromosome binding and OP checkpoint defects are rescued in pol12 mutants. We propose Stn1 normally promotes Pol alpha activity at telomeres but can be recruited through Pol12 to nontelomeric sites when overproduced. During replication stress, the mislocalized Stn1 may inappropriately promote Pol alpha in a manner that interferes with Rad53 effector mechanisms controlling replication fork integrity.},
}
@article {pmid19170885,
year = {2009},
author = {Kobryn, K and Briffotaux, J and Karpov, V},
title = {Holliday junction formation by the Borrelia burgdorferi telomere resolvase, ResT: implications for the origin of genome linearity.},
journal = {Molecular microbiology},
volume = {71},
number = {5},
pages = {1117-1130},
doi = {10.1111/j.1365-2958.2008.06584.x},
pmid = {19170885},
issn = {1365-2958},
mesh = {Bacterial Proteins/genetics/*metabolism ; Borrelia burgdorferi/*enzymology/genetics ; DNA, Bacterial/genetics ; DNA, Cruciform/*metabolism ; Endodeoxyribonucleases/genetics/*metabolism ; *Genome, Bacterial ; Recombinases/metabolism ; Substrate Specificity ; Telomere/metabolism ; },
abstract = {Spirochetes of the genus Borrelia include the causative agents of Lyme disease and relapsing fever. They possess unusual, highly segmented genomes composed mostly of linear replicons with covalently closed hairpin telomeres. The telomeres are formed from inverted repeat replicated telomere junctions (rTels) by the telomere resolvase, ResT. ResT uses a reaction mechanism with similarities to that employed by the type IB topoisomerases and tyrosine recombinases. Here, we report that the relationship of ResT to the tyrosine recombinases extends to the ability to synapse-replicated telomeres and to catalyse the formation of a Holliday junction. We also report that ResT can use asymmetrized substrates that mimic the properties of a recombination site for a tyrosine recombinase, to form Holliday junctions. We propose a model for how this explains the origin of genome linearity in the genus Borrelia.},
}
@article {pmid19168993,
year = {2008},
author = {Hatase, H and Sudo, R and Watanabe, KK and Kasugai, T and Saito, T and Okamoto, H and Uchida, I and Tsukamoto, K},
title = {Shorter telomere length with age in the loggerhead turtle: a new hope for live sea turtle age estimation.},
journal = {Genes &amp; genetic systems},
volume = {83},
number = {5},
pages = {423-426},
doi = {10.1266/ggs.83.423},
pmid = {19168993},
issn = {1341-7568},
mesh = {Age Factors ; Animals ; Polymerase Chain Reaction ; Telomere/*chemistry/metabolism ; Turtles/*genetics/physiology ; },
abstract = {We verified whether telomere length shortens with age in the loggerhead sea turtle (Caretta caretta) by measuring telomere lengths (relative telomere to single copy gene [T/S] ratios) in whole blood and epidermis from 20 captive individuals with a real-time PCR method. There was no significant correlation between age and relative T/S ratios in blood. Although the correlation between age and relative T/S ratios in epidermis was not significant, older turtles had smaller relative T/S ratios in epidermis. It was thus demonstrated that telomere length in epidermis could be a useful age estimator for sea turtles. Relative age information obtained with this simple, rapid, non-invasive technique may help to advance our understanding of the ecology of endangered sea turtles. This is the first publication on age-related changes in telomere length among chelonians.},
}
@article {pmid19167568,
year = {2009},
author = {Woo, J and Tang, N and Suen, E and Leung, J and Wong, M},
title = {Green space, psychological restoration, and telomere length.},
journal = {Lancet (London, England)},
volume = {373},
number = {9660},
pages = {299-300},
doi = {10.1016/S0140-6736(09)60094-5},
pmid = {19167568},
issn = {1474-547X},
mesh = {Aged ; Confounding Factors, Epidemiologic ; *Environment ; *Health Status ; Hong Kong ; Humans ; Logistic Models ; Male ; *Stress, Psychological ; Telomere/*classification ; },
}
@article {pmid19164295,
year = {2009},
author = {Her, YR and Chung, IK},
title = {Ubiquitin Ligase RLIM Modulates Telomere Length Homeostasis through a Proteolysis of TRF1.},
journal = {The Journal of biological chemistry},
volume = {284},
number = {13},
pages = {8557-8566},
pmid = {19164295},
issn = {0021-9258},
mesh = {Cell Line ; F-Box Proteins/genetics/metabolism ; Homeostasis/*physiology ; Humans ; Proteasome Endopeptidase Complex/genetics/metabolism ; Repressor Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/*metabolism ; Ubiquitin/genetics/metabolism ; Ubiquitin-Protein Ligases/genetics/*metabolism ; },
abstract = {The telomeric protein TRF1 negatively regulates telomere length by inhibiting telomerase access at the telomere termini, suggesting that the protein level of TRF1 at telomeres is tightly regulated. Regulation of TRF1 protein abundance is essential for proper telomere function and occurs primarily through post-translational modifications of TRF1. Here we describe RLIM, a RING H2 zinc finger protein with intrinsic ubiquitin ligase activity, as a TRF1-interacting protein. RLIM increases TRF1 turnover by targeting it for degradation by the proteasome in a ubiquitin-dependent manner, independently of Fbx4, which is known to interact with and negatively regulate TRF1. Whereas overexpression of RLIM decreases the level of TRF1 protein, depletion of endogenous RLIM expression by small hairpin RNA increases the level of TRF1 and leads to telomere shortening, thereby impairing cell growth. These results demonstrate that RLIM is involved in the negative regulation of TRF1 function through physical interaction and ubiquitin-mediated proteolysis. Hence, RLIM represents a new pathway for telomere maintenance by modulating the level of TRF1 at telomeres.},
}
@article {pmid19160102,
year = {2009},
author = {Chen, YC and Teng, SC and Wu, KJ},
title = {Phosphorylation of telomeric repeat binding factor 1 (TRF1) by Akt causes telomere shortening.},
journal = {Cancer investigation},
volume = {27},
number = {1},
pages = {24-28},
doi = {10.1080/07357900802027081},
pmid = {19160102},
issn = {1532-4192},
mesh = {Blotting, Western ; Carcinoma, Hepatocellular/metabolism/pathology ; Genomic Instability ; Humans ; Immunoprecipitation ; Liver Neoplasms/metabolism/pathology ; Mutagenesis, Site-Directed ; Organic Anion Transporters/genetics/metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/genetics/*metabolism ; Telomere/*physiology ; Telomeric Repeat Binding Protein 1/genetics/*metabolism ; Tumor Cells, Cultured ; },
abstract = {Telomeric repeat binding factor 1 (TRF1) belongs to the shelterin complex, which modulates the telomere structures. Akt/protein kinase B activation caused genomic instability and contributes to tumorigenesis, although the molecular mechanism remained little known. Here, we show the direct interaction between Akt and TRF1. In vitro kinase assays showed the phosphorylation of a putative Akt phosphorylation site (Threonine 273) in wild type TRF1, but not the mutant TRF1 (T273A), by Akt. Overexpression of Akt decreased telomere length in a HTC cell line. These results indicate that Akt plays an important role in telomere length regulation, contributing to genomic instability and tumorigenesis.},
}
@article {pmid19154407,
year = {2009},
author = {Omori, Y and Nakayama, F and Li, D and Kanemitsu, K and Semba, S and Ito, A and Yokozaki, H},
title = {Alternative lengthening of telomeres frequently occurs in mismatch repair system-deficient gastric carcinoma.},
journal = {Cancer science},
volume = {100},
number = {3},
pages = {413-418},
doi = {10.1111/j.1349-7006.2008.01063.x},
pmid = {19154407},
issn = {1349-7006},
mesh = {Adenocarcinoma/*genetics/metabolism ; *DNA Mismatch Repair ; Humans ; Image Processing, Computer-Assisted ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; *Microsatellite Instability ; Stomach Neoplasms/*genetics/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Maintenance of telomeric ends by the telomerase ribonucleoprotein complex or the telomerase-independent alternative lengthening of telomeres is necessary for the immortalization of human cells. The significance of alternative lengthening of telomeres has been suggested in DNA mismatch repair system-deficient cells; however, much remains unknown in human malignancies. In this study, we investigated the telomere maintenance mechanism in gastric carcinoma. In formalin-fixed and paraffin-embedded sections of the high frequency of microsatellite instability (MSI-H) and non-MSI-H gastric carcinomas, there was no difference in telomere length monitored by telomere intensity ratio using telomere-fluorescent in situ hybridization. Immunoreactivity of hTERT, the catalytic subunit of telomerase, was detected in 48% of MSI-H gastric carcinomas. The frequency was significantly lower than that in non-MSI-H gastric carcinomas (86%, P = 0.02). Conversely, the number of the alternative lengthening of telomeres-associated promyelocytic leukemia bodies (APBs) detected by combined promyelocytic leukemia immunofluorescence and telomere-fluorescent in situ hybridization was statistically higher (57%) in the MSI-H gastric carcinomas compared to that in non-MSI-H gastric carcinomas (19%, P = 0.026). The cases with hTERT(+)APBs(-) were more frequent in non-MSI-H gastric carcinomas (76%) than in MSI-H gastric carcinomas (24%), and the cases with hTERT(-)APBs(+) were more frequent in MSI-H gastric carcinomas (33%) than in non-MSI-H gastric carcinomas (10%). These results suggest that alternative lengthening of telomeres-mediated telomere maintenance plays an important role for microsatellite instability-mediated stomach carcinogenesis, as well as the telomerase ribonucleoprotein complex, although the incidence of MSI-H is low. Defects of the mismatch repair system may lead to homeologous recombination of telomeric ends for the telomerase-independent telomere maintenance in gastric carcinomas.},
}
@article {pmid19152740,
year = {2009},
author = {Keefe, DL and Liu, L},
title = {Telomeres and reproductive aging.},
journal = {Reproduction, fertility, and development},
volume = {21},
number = {1},
pages = {10-14},
doi = {10.1071/rd08229},
pmid = {19152740},
issn = {1031-3613},
mesh = {Aging/*physiology ; *DNA Damage ; DNA Replication/*physiology ; Female ; Humans ; Meiosis/*physiology ; Reproduction/*physiology ; Telomere/*physiology ; },
abstract = {Infertility, miscarriage and aneuploid offspring increase with age in women, and meiotic dysfunction underlies reproductive aging. How aging disrupts meiotic function in women remains unclear, but as women increasingly delay having children, solving this problem becomes an urgent priority. Telomeres consist of a (TTAGGG)(n) repeated sequence and associated proteins at chromosome ends, mediate aging in mitotic cells and may also mediate aging during meiosis. Telomeres shorten both during DNA replication and from the response to oxidative DNA damage. Oocytes do not divide in adult mammals, but their precursors do replicate during fetal oogenesis; eggs ovulated from older females have traversed more mitotic cell cycles before entering meiosis during fetal oogenesis than eggs ovulated from younger females. Telomeres also would be expected to shorten from inefficient DNA repair of oxidative damage, because the interval between fetal oogenesis and ovulation is exceptionally prolonged in women. We have tested the hypothesis that telomere shortening disrupts meiosis by shortening telomeres experimentally in mice, which normally do not exhibit age-related meiotic dysfunction. Interestingly, mouse telomeres are much longer than human telomeres, but genetic or pharmacological shortening of mouse telomeres recapitulates in mice the human reproductive aging phenotype as the mouse telomeres reach the length of telomeres from older women. These observations led us to propose a telomere theory of reproductive aging. Moreover, chronological oxidative stress increases with reproductive aging, leading to DNA damage preferentially at (TTAGGG)(n) repeats. Finally, if telomeres shorten with aging, how do they reset across generations? Telomerase could not play a significant role in telomere elongation during early development, because this enzyme is not active until the blastocyst stage, well after the stage when telomere elongation takes place. Rather, telomeres lengthen during the early cell cycles of development by a novel mechanism involving recombination and sister chromatid exchange. Telomere dysfunction resulting from oxidative stress, a DNA damage response or aberrant telomere recombination may contribute to reproductive aging-associated meiotic defects, miscarriage and infertility.},
}
@article {pmid19152316,
year = {2009},
author = {Ko, S and Yu, EY and Shin, J and Yoo, HH and Tanaka, T and Kim, WT and Cho, HS and Lee, W and Chung, IK},
title = {Solution structure of the DNA binding domain of rice telomere binding protein RTBP1.},
journal = {Biochemistry},
volume = {48},
number = {5},
pages = {827-838},
doi = {10.1021/bi801270g},
pmid = {19152316},
issn = {1520-4995},
mesh = {Amino Acid Sequence ; Binding Sites/genetics ; Crystallography, X-Ray ; DNA, Plant/*chemistry/genetics/*metabolism ; Humans ; Molecular Sequence Data ; *Oryza/chemistry/genetics ; Plant Proteins/*chemistry/genetics/*metabolism ; Protein Structure, Tertiary ; Solutions ; Telomere/chemistry/genetics/metabolism ; Telomere-Binding Proteins/*chemistry/genetics/*metabolism ; },
abstract = {RTBP1 is a rice telomeric protein that binds to the duplex array of TTTAGGG repeats at chromosome ends. The DNA binding domain of RTBP1 contains a Myb-type DNA binding motif and a highly conserved C-terminal Myb extension that is unique to plant telomeric proteins. Using an electrophoretic mobility shift assay, we identified the C-terminal 110-amino acid region (RTBP1(506-615)) as the minimal telomeric DNA binding domain, suggesting that the Myb extension is required for binding plant telomeric DNA. Like other telomeric proteins such as human TRF1 and yeast Rap1, RTBP1 induced a DNA bending in the telomeric repeat sequence, suggesting that RTBP1 may play a role in establishing and/or maintaining an active telomere configuration in vivo. To elucidate the DNA binding mode of RTBP1, we determined the three-dimensional structure of RTBP1(506-615) in solution by NMR spectroscopy. The overall structure of RTBP1(506-615) is composed of four alpha-helices and stabilized by three hydrophobic patches. The second and third helices in RTBP1 form a helix-turn-helix motif that interacts directly with DNA. The fourth helix located in the Myb extension is essential for binding to telomeric DNA via stabilization of the overall structure of the RTBP1 DNA binding domain. When DNA bound to RTBP1(506-615), large chemical shift perturbations were induced in the N-terminal arm, helix 3, and the loop between helices 3 and 4. These results suggest that helix 3 functions as a sequence-specific recognition helix while the N-terminal arm stabilizes the DNA binding.},
}
@article {pmid19145831,
year = {2008},
author = {Osipov, NV},
title = {[Telomere elongation and prolongation of lifespan in rats by unblocking of telomere caps].},
journal = {Likars'ka sprava},
volume = {},
number = {3-4},
pages = {110-112},
pmid = {19145831},
issn = {1019-5297},
mesh = {Animals ; Cells, Cultured ; Enzyme Activation ; Hair/growth &amp; development ; Humans ; Hypoxia/physiopathology ; Longevity/*genetics/physiology ; Lymphocytes/enzymology/metabolism/*ultrastructure ; Maze Learning/physiology ; Memory/physiology ; Rats ; Rats, Wistar ; Spatial Behavior/physiology ; Telomerase/metabolism ; Telomere/enzymology/metabolism/*ultrastructure ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomeres are the ends of chromosomes and are non-coding DNA "end-capped" with structures containing DNA-quadruplexes and proteins. Telomeres become shorter after each cell division, which is one of the mechanisms of gradual ageing. Telomerase is the reverse transcriptase responsible for the extension of telomere length. It is well known that activation of telomerase in the most types of organism's cells is not enough for telomere length stabilization. The reason may be in the telomere "caps", which cover telomere ends from telomerase action. This experiment shows that telomeres were elongated by the combination of hypoxia activated telomerase and a newly developed pharmacological method removing the telomere cap when this combined method was applied to the human lymphocyte culture and the Wistar rats. Rats from the control group died at the age 1 year 7 month - 1 year 8 month, which is typical for the Wistar rats from our sub-line. Rats from the experimental group died at the age 2 year 4 month. The result Morris's labyrinth water test showed the better spatial memory function of rats passed the telomere stabilization therapy. The results of these experiments show the significant role of telomere stabilization therapy in prolongation of lifespan.},
}
@article {pmid19142887,
year = {2009},
author = {De Boeck, G and Forsyth, RG and Praet, M and Hogendoorn, PC},
title = {Telomere-associated proteins: cross-talk between telomere maintenance and telomere-lengthening mechanisms.},
journal = {The Journal of pathology},
volume = {217},
number = {3},
pages = {327-344},
doi = {10.1002/path.2500},
pmid = {19142887},
issn = {1096-9896},
mesh = {Apoptosis ; Cell Cycle Proteins/metabolism ; Cellular Senescence/physiology ; DNA Repair ; DNA Repair Enzymes/*metabolism ; Humans ; Neoplasms/metabolism/ultrastructure ; Telomerase/metabolism ; Telomere/*metabolism/ultrastructure ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomeres, the ends of eukaryotic chromosomes, have been the subject of intense investigation over the last decade. As telomere dysfunction has been associated with ageing and developing cancer, understanding the exact mechanisms regulating telomere structure and function is essential for the prevention and treatment of human cancers and age-related diseases. The mechanisms by which cells maintain telomere lengthening involve either telomerase or the alternative lengthening of the telomere pathway, although specific mechanisms of the latter and the relationship between the two are as yet unknown. Many cellular factors directly (TRF1/TRF2) and indirectly (shelterin-complex, PinX, Apollo and tankyrase) interact with telomeres, and their interplay influences telomere structure and function. One challenge comes from the observation that many DNA damage response proteins are stably associated with telomeres and contribute to several other aspects of telomere function. This review focuses on the different components involved in telomere maintenance and their role in telomere length homeostasis. Special attention is paid to understanding how these telomere-associated factors, and mainly those involved in double-strand break repair, perform their activities at the telomere ends.},
}
@article {pmid19137021,
year = {2009},
author = {Saharia, A and Stewart, SA},
title = {FEN1 contributes to telomere stability in ALT-positive tumor cells.},
journal = {Oncogene},
volume = {28},
number = {8},
pages = {1162-1167},
doi = {10.1038/onc.2008.458},
pmid = {19137021},
issn = {1476-5594},
mesh = {Blotting, Western ; Bone Neoplasms/genetics/metabolism/pathology ; Flap Endonucleases/*physiology ; Genomic Instability ; Humans ; In Situ Hybridization, Fluorescence ; Osteosarcoma/genetics/metabolism/pathology ; RNA, Small Interfering/pharmacology ; Telomerase/metabolism ; Telomere/*genetics/metabolism ; Tumor Cells, Cultured ; },
abstract = {Abrogation of telomere stability through loss-of-function mutations in telomere binding proteins contributes to genomic instability and cancer progression. Recently, Flap endonuclease 1 (FEN1) was shown to contribute to telomere stability in human cells that had not yet activated a telomere maintenance mechanism, suggesting that abrogation of FEN1 function influences the transformation process by compromising telomere stability and driving genomic instability. Here, we analyse the telomeres in human cancer cells following FEN1 depletion. We show that FEN1 is required for telomere stability in cells that rely on the alternative lengthening of telomere (ALT) mechanism. Indeed, FEN1 depletion resulted in telomere dysfunction, characterized by formation of telomere dysfunction-induced foci (TIFs) and end-to-end fusions in ALT-positive cells. In contrast, no telomere phenotype was observed in telomerase-positive cells on FEN1 depletion, suggesting that ongoing telomerase activity protected telomeres. In consonance with this, we found that expression of the catalytic component of telomerase (hTERT) but not an inactive allele rescued telomere dysfunction on FEN1 depletion in ALT cells. Our data suggest that mutations that arise in FEN1 affect telomere stability and genome fidelity by promoting telomere fusions and anaphase-bridge-breakage cycles, which further drive genome instability and thereby contribute to the transformation process.},
}
@article {pmid19135888,
year = {2009},
author = {Li, S and Makovets, S and Matsuguchi, T and Blethrow, JD and Shokat, KM and Blackburn, EH},
title = {Cdk1-dependent phosphorylation of Cdc13 coordinates telomere elongation during cell-cycle progression.},
journal = {Cell},
volume = {136},
number = {1},
pages = {50-61},
pmid = {19135888},
issn = {1097-4172},
support = {R01 GM026259/GM/NIGMS NIH HHS/United States ; R01 GM026259-31/GM/NIGMS NIH HHS/United States ; },
mesh = {CDC28 Protein Kinase, S cerevisiae/*metabolism ; *Cell Cycle ; Phosphorylation ; Saccharomyces cerevisiae/*cytology/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Elongation of telomeres by telomerase replenishes the loss of terminal telomeric DNA repeats during each cell cycle. In budding yeast, Cdc13 plays an essential role in telomere length homeostasis, partly through its interactions with both the telomerase complex and the competing Stn1-Ten1 complex. Previous studies in yeast have shown that telomere elongation by telomerase is cell cycle dependent, but the mechanism underlying this dependence is unclear. In S. cerevisiae, a single cyclin-dependent kinase Cdk1 (Cdc28) coordinates the serial events required for the cell division cycle, but no Cdk1 substrate has been identified among telomerase and telomere-associated factors. Here we show that Cdk1-dependent phosphorylation of Cdc13 is essential for efficient recruitment of the yeast telomerase complex to telomeres by favoring the interaction of Cdc13 with Est1 rather than the competing Stn1-Ten1 complex. These results provide a direct mechanistic link between coordination of telomere elongation and cell-cycle progression in vivo.},
}
@article {pmid19132685,
year = {2009},
author = {Zimmermann, S and Biniossek, ML and Pantic, M and Pfeifer, D and Veelken, H and Martens, UM},
title = {Proteomic profiling of tumor cells after induction of telomere dysfunction.},
journal = {Proteomics},
volume = {9},
number = {3},
pages = {521-534},
doi = {10.1002/pmic.200800471},
pmid = {19132685},
issn = {1615-9861},
mesh = {Blotting, Southern ; Cell Line, Tumor ; Chromatography, High Pressure Liquid ; DNA-Binding Proteins/genetics ; Gene Expression Regulation, Neoplastic/genetics ; Histones/genetics/metabolism ; Humans ; Immunoblotting ; Immunoprecipitation ; Mass Spectrometry ; Proteome/*analysis ; Retroviridae/genetics ; Telomerase/genetics/metabolism ; Telomere/*genetics/pathology ; },
abstract = {Cell division in the absence of telomerase causes progressive telomere shortening which ultimately leads to telomere dysfunction and initiation of genome instability. In order to identify factors related to loss of telomere function, the effects of telomerase inhibition on the proteome of five tumor cell lines were followed by SELDI-TOF-MS. Five differentially expressed protein peaks (p<0.01) were found in a total of 60 clones of five cell lines representing four tissues (lung, breast, prostate, and colon) in which telomerase was inhibited by retroviral overexpression of a dominant negative (DN) mutant of human telomerase reverse transcriptase (hTERT). Among these, a 11.3 kDa peak diminished in DN-hTERT clones was identified as histone H4 by nanoflow-HPLC-MS/MS. Immunoblot analysis not only confirmed the decline of histone H4, but also of other core histone proteins including histone H3. Furthermore, upregulation of several cytokeratins was found to be associated with telomere attrition. In conclusion, loss of telomere function is associated with alterations in the proteome which may represent novel biomarkers for the detection of replicative senescence.},
}
@article {pmid19129235,
year = {2009},
author = {Fan, Q and Zhang, F and Barrett, B and Ren, K and Andreassen, PR},
title = {A role for monoubiquitinated FANCD2 at telomeres in ALT cells.},
journal = {Nucleic acids research},
volume = {37},
number = {6},
pages = {1740-1754},
pmid = {19129235},
issn = {1362-4962},
support = {R01 HL085587/HL/NHLBI NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/physiology ; Cell Line ; Cell Line, Transformed ; Fanconi Anemia Complementation Group A Protein/antagonists &amp; inhibitors/physiology ; Fanconi Anemia Complementation Group D2 Protein/analysis/antagonists &amp; inhibitors/*metabolism ; Fanconi Anemia Complementation Group L Protein/physiology ; HeLa Cells ; Humans ; Protein Serine-Threonine Kinases/physiology ; Sister Chromatid Exchange ; Telomere/chemistry/*metabolism ; Telomeric Repeat Binding Protein 1/analysis ; *Ubiquitination ; },
abstract = {Both Fanconi anemia (FA) and telomere dysfunction are associated with chromosome instability and an increased risk of cancer. Because of these similarities, we have investigated whether there is a relationship between the FA protein, FANCD2 and telomeres. We find that FANCD2 nuclear foci colocalize with telomeres and PML bodies in immortalized telomerase-negative cells. These cells maintain telomeres by alternative lengthening of telomeres (ALT). In contrast, FANCD2 does not colocalize with telomeres or PML bodies in cells which express telomerase. Using a siRNA approach we find that FANCA and FANCL, which are components of the FA nuclear core complex, regulate FANCD2 monoubiquitination and the telomeric localization of FANCD2 in ALT cells. Transient depletion of FANCD2, or FANCA, results in a dramatic loss of detectable telomeres in ALT cells but not in telomerase-expressing cells. Furthermore, telomere loss following depletion of these proteins in ALT cells is associated with decreased homologous recombination between telomeres (T-SCE). Thus, the FA pathway has a novel function in ALT telomere maintenance related to DNA repair. ALT telomere maintenance is therefore one mechanism by which monoubiquitinated FANCD2 may promote genetic stability.},
}
@article {pmid19129229,
year = {2009},
author = {Cawthon, RM},
title = {Telomere length measurement by a novel monochrome multiplex quantitative PCR method.},
journal = {Nucleic acids research},
volume = {37},
number = {3},
pages = {e21},
pmid = {19129229},
issn = {1362-4962},
support = {5R21AG030034/AG/NIA NIH HHS/United States ; },
mesh = {Albumins/genetics ; DNA Primers ; Gene Dosage ; Humans ; Polymerase Chain Reaction/*methods/standards ; Reference Standards ; Reproducibility of Results ; Tandem Repeat Sequences ; Telomere/*chemistry ; Temperature ; beta-Globins/genetics ; },
abstract = {The current quantitative polymerase chain reaction (QPCR) assay of telomere length measures telomere (T) signals in experimental DNA samples in one set of reaction wells, and single copy gene (S) signals in separate wells, in comparison to a reference DNA, to yield relative T/S ratios that are proportional to average telomere length. Multiplexing this assay is desirable, because variation in the amount of DNA pipetted would no longer contribute to variation in T/S, since T and S would be collected within each reaction, from the same input DNA. Multiplexing also increases throughput and lowers costs, since half as many reactions are needed. Here, we present the first multiplexed QPCR method for telomere length measurement. Remarkably, a single fluorescent DNA-intercalating dye is sufficient in this system, because T signals can be collected in early cycles, before S signals rise above baseline, and S signals can be collected at a temperature that fully melts the telomere product, sending its signal to baseline. The correlation of T/S ratios with Terminal Restriction Fragment (TRF) lengths measured by Southern blot was stronger with this monochrome multiplex QPCR method (R(2) = 0.844) than with our original singleplex method (R(2) = 0.677). Multiplex T/S results from independent runs on different days were highly reproducible (R(2) = 0.91).},
}
@article {pmid19126595,
year = {2009},
author = {Tarry-Adkins, JL and Chen, JH and Smith, NS and Jones, RH and Cherif, H and Ozanne, SE},
title = {Poor maternal nutrition followed by accelerated postnatal growth leads to telomere shortening and increased markers of cell senescence in rat islets.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {23},
number = {5},
pages = {1521-1528},
doi = {10.1096/fj.08-122796},
pmid = {19126595},
issn = {1530-6860},
support = {G0600717/MRC_/Medical Research Council/United Kingdom ; /BHF_/British Heart Foundation/United Kingdom ; BB/E00797X/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/D007909/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/E002161/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Cellular Senescence/*physiology ; DNA Repair/physiology ; Female ; Gene Expression Profiling ; Islets of Langerhans/*cytology ; *Maternal Nutritional Physiological Phenomena ; Pregnancy ; Protein Deficiency/*complications ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; Telomere/*metabolism ; },
abstract = {Low birth weight (LBW) followed by accelerated postnatal growth is associated with increased risk of developing age-associated diseases such as type 2 diabetes. Gestational protein restriction in rats causes LBW, beta-cell dysfunction, and reduced longevity. These effects may be mediated by accelerated cellular aging. This study tested the hypothesis that LBW followed by rapid postnatal catch-up growth leads to islet telomere shortening through alterations in antioxidant defense capacity, stress/senescence marker proteins, and DNA repair mechanisms at the gene expression level. We used our rat model of gestational protein restriction (recuperated offspring) and control offspring. Southern blotting revealed shorter (P<0.001) islet telomeres in recuperated animals compared to controls. This was associated with increased expression of peroxiredoxin 1 (P<0.05), peroxiredoxin 3 (P<0.01), and heme oxygenase-1 (HO-1) (P<0.05), which are up-regulated under stress conditions. MnSOD expression was significantly (P<0.05) decreased in recuperated offspring, suggesting partial impairment of mitochondrial antioxidant defenses. Markers of cellular senescence p21 and p16 were also increased (P<0.01 and P<0.05, respectively) in the recuperated group. We conclude that maternal diet influences expression of markers of cellular stress and telomere length in pancreatic islets. This may provide a mechanistic link between early nutrition and growth and type 2 diabetes.},
}
@article {pmid19124806,
year = {2009},
author = {Chakraborty, S and Sun, CL and Francisco, L and Sabado, M and Li, L and Chang, KL and Forman, S and Bhatia, S and Bhatia, R},
title = {Accelerated telomere shortening precedes development of therapy-related myelodysplasia or acute myelogenous leukemia after autologous transplantation for lymphoma.},
journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology},
volume = {27},
number = {5},
pages = {791-798},
pmid = {19124806},
issn = {1527-7755},
support = {M01 RR000043/RR/NCRR NIH HHS/United States ; P50 CA107399/CA/NCI NIH HHS/United States ; 5M01 RR00043/RR/NCRR NIH HHS/United States ; P50CA107399/CA/NCI NIH HHS/United States ; },
mesh = {Blotting, Southern ; Cohort Studies ; Female ; Flow Cytometry ; Hematopoietic Stem Cell Transplantation/*adverse effects ; Hodgkin Disease/therapy ; Humans ; Leukemia, Myeloid, Acute/*etiology/*genetics ; Longitudinal Studies ; Lymphoma/*therapy ; Lymphoma, Non-Hodgkin/therapy ; Male ; Middle Aged ; Myelodysplastic Syndromes/*etiology/*genetics ; Prospective Studies ; Telomere/*physiology ; Transplantation, Autologous ; },
abstract = {PURPOSE: Therapy-related myelodysplasia or acute myelogenous leukemia (t-MDS/AML) is a lethal complication of autologous hematopoietic stem-cell transplantation (aHCT) for Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). Here, we investigated the hypothesis that accelerated telomere shortening after aHCT could contribute to the development of t-MDS/AML.<br><br>PATIENTS AND METHODS: A prospective longitudinal cohort was constructed to investigate the sequence of cellular and molecular abnormalities leading to development of t-MDS/AML after aHCT for HL/NHL. This cohort formed the sampling frame for a nested case-control study to compare changes in telomere length in serial blood samples from patients who developed t-MDS/AML with matched controls who did not develop t-MDS/AML.<br><br>RESULTS: An initial increase in telomere length at day 100 after aHCT was followed by an accelerated telomere shortening in t-MDS/AML patients when compared with controls. These telomere alterations preceded the onset of t-MDS and were independent of other known risk factors associated with development of t-MDS/AML on multivariate analysis. Additionally, we observed reduced generation of committed progenitors in patients who developed t-MDS/AML, indicating that these telomere alterations were associated with reduced regenerative capacity of hematopoietic stem cells.<br><br>CONCLUSION: The development of t-MDS/AML after aHCT is associated with and preceded by markedly altered telomere dynamics in hematopoietic cells. Accelerated telomere loss in patients developing t-MDS/AML may reflect increased clonal proliferation and/or altered telomere regulation in premalignant cells. Genetic instability associated with shortened telomeres may contribute to leukemic transformation in t-MDS/AML.},
}
@article {pmid19124610,
year = {2009},
author = {Muñoz, P and Blanco, R and de Carcer, G and Schoeftner, S and Benetti, R and Flores, JM and Malumbres, M and Blasco, MA},
title = {TRF1 controls telomere length and mitotic fidelity in epithelial homeostasis.},
journal = {Molecular and cellular biology},
volume = {29},
number = {6},
pages = {1608-1625},
pmid = {19124610},
issn = {1098-5549},
mesh = {Animals ; Cell Cycle Proteins/metabolism ; Cells, Cultured ; DNA Damage/*physiology ; DNA-Binding Proteins/metabolism ; Endonucleases/metabolism ; Epidermal Cells ; Epidermis/*physiology ; Epithelium/physiology ; Homeostasis ; Keratinocytes/cytology/*physiology ; Mad2 Proteins ; Mice ; Mice, Mutant Strains ; Mice, Transgenic ; Mitosis/physiology ; Protein Serine-Threonine Kinases/metabolism ; Spindle Apparatus/physiology ; Telomere/*physiology ; Telomeric Repeat Binding Protein 1/genetics/*physiology ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {TRF1 is a component of the shelterin complex at mammalian telomeres; however, a role for TRF1 in telomere biology in the context of the organism is unclear. In this study, we generated mice with transgenic TRF1 expression targeted to epithelial tissues (K5TRF1 mice). K5TRF1 mice have shorter telomeres in the epidermis than wild-type controls do, and these are rescued in the absence of the XPF nuclease, indicating that TRF1 acts as a negative regulator of telomere length by controlling XPF activity at telomeres, similar to what was previously described for TRF2-overexpressing mice (K5TRF2 mice). K5TRF1 cells also show increased end-to-end chromosomal fusions, multitelomeric signals, and increased telomere recombination, indicating an impact of TRF1 on telomere integrity, again similar to the case in K5TRF2 cells. Intriguingly, K5TRF1 cells, but not K5TRF2 cells, show increased mitotic spindle aberrations. TRF1 colocalizes with the spindle assembly checkpoint proteins BubR1 and Mad2 at mouse telomeres, indicating a link between telomeres and the mitotic spindle. Together, these results demonstrate that TRF1, like TRF2, negatively regulates telomere length in vivo by controlling the action of the XPF nuclease at telomeres; in addition, TRF1 has a unique role in the mitotic spindle checkpoint.},
}
@article {pmid19124249,
year = {2009},
author = {Kashiwazaki, G and Bando, T and Shinohara, K and Minoshima, M and Nishijima, S and Sugiyama, H},
title = {Cooperative alkylation of double-strand human telomere repeat sequences by PI polyamides with 11-base-pair recognition based on a heterotrimeric design.},
journal = {Bioorganic &amp; medicinal chemistry},
volume = {17},
number = {3},
pages = {1393-1397},
doi = {10.1016/j.bmc.2008.12.019},
pmid = {19124249},
issn = {1464-3391},
mesh = {Alkylating Agents/*chemistry ; Alkylation ; Base Pairing ; Base Sequence ; Cell Line ; DNA/chemistry ; Distamycins/chemistry ; Humans ; Imidazoles/chemistry ; Jurkat Cells ; Nylons/*chemistry ; Pyrroles/chemistry ; Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; },
abstract = {We designed and synthesized alkylating conjugates 5-7 and their partner N-methylpyrrole-N-methylimidazole (PI) polyamides 8, 9. The DNA alkylating activities of conjugates 5-7 were evaluated by high-resolution denaturing polyacrylamide gel electrophoresis with a 219 base pair (bp) DNA fragment containing the human telomere repeat sequence. Conjugate 5 efficiently alkylated the sequence, 5'-GGTTAGGGTTA-3', in the presence of partner PI polyamide 8 or distamycin A (Dist). In contrast, the heterodimer system of 5 with 9 showed very weak alkylating activity. Accordingly, this heterotrimeric system of 5 with two short partners is an expedient way to attain improved precision and extension of the recognition of DNA sequences.},
}
@article {pmid19122193,
year = {2009},
author = {Tourand, Y and Deneke, J and Moriarty, TJ and Chaconas, G},
title = {Characterization and in vitro reaction properties of 19 unique hairpin telomeres from the linear plasmids of the lyme disease spirochete.},
journal = {The Journal of biological chemistry},
volume = {284},
number = {11},
pages = {7264-7272},
pmid = {19122193},
issn = {0021-9258},
support = {78190/CAPMC/CIHR/Canada ; },
mesh = {Bacterial Proteins/genetics/metabolism ; Base Sequence ; Borrelia burgdorferi/genetics/*metabolism ; Cell-Free System/metabolism ; DNA Replication/*physiology ; DNA, Bacterial/genetics/*metabolism ; Endodeoxyribonucleases/genetics/metabolism ; Genome, Bacterial/physiology ; *Lyme Disease ; Molecular Sequence Data ; Plasmids/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {The genome of the Lyme disease pathogen Borrelia burgdorferi contains about a dozen linear DNA molecules that carry covalently closed hairpin telomeres as a specialized mechanism for dealing with the end-replication problem. The hairpin telomeres are generated from replicative intermediates through a two-step transesterification promoted by the telomere resolvase ResT. Although the genome of B. burgdorferi has been sequenced, the sequence of most telomeres has remained unknown because of difficulties in recovering and completely sequencing the covalently closed hairpin ends. In this study we report a new approach for the direct sequencing Borrelia telomeres and report the sequence, characterization, and in vitro reaction properties of 19 unique telomeres. Surprisingly, a variation of greater than 160-fold in the initial reaction rates of in vitro ResT-mediated telomere resolution was observed between the most active and least active telomeres. Moreover, three of the hairpin telomeres were completely inactive in vitro, but their in vivo functionality was demonstrated. Our results provide important new information on the structure and function of the B. burgdorferi telomeres and suggest the possibility that factors besides the telomere resolvase ResT may influence the reaction in vivo and rescue those telomeres that are not functional in vitro with ResT alone.},
}
@article {pmid19117989,
year = {2009},
author = {Zhang, B and Bai, YX and Ma, HH and Feng, F and Jin, R and Wang, ZL and Lin, J and Sun, SP and Yang, P and Wang, XX and Huang, PT and Huang, CF and Peng, Y and Chen, YC and Kung, HF and Huang, JJ},
title = {Silencing PinX1 compromises telomere length maintenance as well as tumorigenicity in telomerase-positive human cancer cells.},
journal = {Cancer research},
volume = {69},
number = {1},
pages = {75-83},
doi = {10.1158/0008-5472.CAN-08-1393},
pmid = {19117989},
issn = {1538-7445},
mesh = {Animals ; Apoptosis/drug effects/genetics ; Cell Cycle Proteins ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics/*metabolism ; DNA Damage ; Etoposide/pharmacology ; Gene Silencing ; Humans ; Mice ; Mice, Inbred BALB C ; RNA, Small Interfering/genetics ; Shelterin Complex ; Telomerase/biosynthesis/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/metabolism ; Transfection ; Tumor Suppressor Proteins/biosynthesis/*deficiency/genetics ; },
abstract = {The nucleolar protein PinX1 has been proposed to be a putative tumor suppressor due to its binding to and inhibition of the catalytic activity of telomerase, an enzyme that is highly expressed in most human cancers in which it counteracts telomere shortening-induced senescence to confer cancer cell immortalization. However, the role of PinX1 in telomere regulation, as well as in cancer, is still poorly understood. In this study, we showed that the PinX1 protein is constitutively expressed in various human cells regardless of their telomerase activity and malignant status. Most interestingly, we found that silencing PinX1 expression by a potent short hairpin RNA construct led to a robust telomere length shortening and growth inhibition in telomerase-positive but not in telomerase-negative human cancer cells. We further showed that silencing PinX1 significantly reduced the endogenous association of telomerase with the Pot1-containing telomeric protein complex, and therefore, could account for the phenotypic telomere shortening in the affected telomerase-positive cancer cells. Our results thus reveal a novel positive role for PinX1 in telomerase/telomere regulations and suggest that the constitutive expression of PinX1 attributes to telomere maintenance by telomerase and tumorigenicity in cancer cells.},
}
@article {pmid20195384,
year = {2008},
author = {Epel, ES and Merkin, SS and Cawthon, R and Blackburn, EH and Adler, NE and Pletcher, MJ and Seeman, TE},
title = {The rate of leukocyte telomere shortening predicts mortality from cardiovascular disease in elderly men.},
journal = {Aging},
volume = {1},
number = {1},
pages = {81-88},
pmid = {20195384},
issn = {1945-4589},
support = {5P30AG017265-099002/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aging/metabolism ; Alcohol Drinking ; Body Mass Index ; Cardiovascular Diseases/diagnosis/*mortality ; Female ; Humans ; Leukocytes/*metabolism ; Longitudinal Studies ; Male ; Mortality ; Prognosis ; Proportional Hazards Models ; Risk ; Sex Characteristics ; Telomere/chemistry/*metabolism ; },
abstract = {Telomere length (TL) has been proposed as a marker of mitotic cell age and as a general index of human organismic aging. Short absolute leukocyte telomere length has been linked to cardiovascular-related morbidity and mortality. Our aim was to test whether the rate of change in leukocyte TL is related to mortality in a healthy elderly cohort. We examined a subsample of 236 randomly selected Caucasian participants from the MacArthur Health Aging Study (aged 70 to 79 years). DNA samples from baseline and 2.5 years later were assayed for mean TL of leukocytes. Percent change in TL was calculated as a measure of TL change (TLC). Associations between TL and TLC with 12-year overall and cardiovascular mortality were assessed. Over the 2.5 year period, 46% of the study participants showed maintenance of mean bulk TL, whereas 30% showed telomere shortening, and, unexpectedly, 24% showed telomere lengthening. For women, short baseline TL was related to greater mortality from cardiovascular disease (OR = 2.3; 95% CI: 1.0 - 5.3). For men, TLC (specifically shortening), but not baseline TL, was related to greater cardiovascular mortality, OR = 3.0 (95% CI: 1.1 - 8.2). This is the first demonstration that rate of telomere length change (TLC) predicts mortality and thus may be a useful prognostic factor for longevity.},
}
@article {pmid19114509,
year = {2009},
author = {Pérez, G and Pangilinan, J and Pisabarro, AG and Ramírez, L},
title = {Telomere organization in the ligninolytic basidiomycete Pleurotus ostreatus.},
journal = {Applied and environmental microbiology},
volume = {75},
number = {5},
pages = {1427-1436},
pmid = {19114509},
issn = {1098-5336},
mesh = {Alcohol Dehydrogenase/genetics ; Chromosome Mapping ; DNA, Fungal/chemistry/genetics ; Fungal Proteins/genetics ; Laccase/genetics ; Molecular Sequence Data ; Pleurotus/*genetics ; Polymorphism, Genetic ; Repetitive Sequences, Nucleic Acid ; Sequence Analysis, DNA ; Telomere/*genetics ; },
abstract = {Telomeres are structural and functional chromosome regions that are essential for the cell cycle to proceed normally. They are, however, difficult to map genetically and to identify in genome-wide sequence programs because of their structure and repetitive nature. We studied the telomeric and subtelomeric organization in the basidiomycete Pleurotus ostreatus using a combination of molecular and bioinformatics tools that permitted us to determine 19 out of the 22 telomeres expected in this fungus. The telomeric repeating unit in P. ostreatus is TTAGGG, and the numbers of repetitions of this unit range between 25 and 150. The mapping of the telomere restriction fragments to linkage groups 6 and 7 revealed polymorphisms compatible with those observed by pulsed field gel electrophoresis separation of the corresponding chromosomes. The subtelomeric regions in Pleurotus contain genes similar to those described in other eukaryotic systems. The presence of a cluster of laccase genes in chromosome 6 and a bipartite structure containing a Het-related protein and an alcohol dehydrogenase are especially relevant; this bipartite structure is characteristic of the Pezizomycotina fungi Neurospora crassa and Aspergillus terreus. As far as we know, this is the first report describing the presence of such structures in basidiomycetes and the location of a laccase gene cluster in the subtelomeric region, where, among others, species-specific genes allowing the organism to adapt rapidly to the environment usually map.},
}
@article {pmid19114299,
year = {2009},
author = {Cookson, JC and Laughton, CA},
title = {The levels of telomere-binding proteins in human tumours and therapeutic implications.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {45},
number = {4},
pages = {536-550},
doi = {10.1016/j.ejca.2008.11.014},
pmid = {19114299},
issn = {1879-0852},
mesh = {Biomarkers, Tumor/metabolism ; Humans ; Neoplasm Proteins/*metabolism ; Neoplasms/drug therapy/genetics/*metabolism ; Telomerase/metabolism ; Telomere/ultrastructure ; Telomere-Binding Proteins/*metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Tumours require telomeric integrity to maintain viability, conferred by adequate length of telomeric DNA replenished by telomerase, and binding of telomere-binding proteins (TBPs), thus telomeres have received attention as an anticancer target. Levels of TBPs in tumour tissue may have implications for drug development if they render some cancers relatively more sensitive or resistant to telomere targeted agents. This review gives an overview of the studies examining the levels of TBPs in tumours and discusses possible reasons for differences in the findings, given the interplay between various factors determining telomere stability. Whether cancers with lower levels of TBPs will be more susceptible to therapies targeting telomere maintenance will require clinical trials of these novel therapies.},
}
@article {pmid19111922,
year = {2009},
author = {O'Donovan, A and Lin, J and Tillie, J and Dhabhar, FS and Wolkowitz, OM and Blackburn, EH and Epel, ES},
title = {Pessimism correlates with leukocyte telomere shortness and elevated interleukin-6 in post-menopausal women.},
journal = {Brain, behavior, and immunity},
volume = {23},
number = {4},
pages = {446-449},
pmid = {19111922},
issn = {1090-2139},
support = {K08 MH064110-01A1/MH/NIMH NIH HHS/United States ; K08 MH064110-02/MH/NIMH NIH HHS/United States ; K08 MH064110-05/MH/NIMH NIH HHS/United States ; K08 MH064110-03/MH/NIMH NIH HHS/United States ; K08 MH064110-04/MH/NIMH NIH HHS/United States ; K08 MH064110/MH/NIMH NIH HHS/United States ; },
mesh = {Affect ; Aged ; Aged, 80 and over ; Aging/blood/genetics/immunology ; Attitude ; Caregivers ; Enzyme-Linked Immunosorbent Assay ; Female ; Health Behavior ; Humans ; Interleukin-6/*blood ; Leukocytes/immunology/metabolism ; Middle Aged ; Patient Selection ; Personality/*genetics ; Personality Inventory ; Regression Analysis ; Reverse Transcriptase Polymerase Chain Reaction ; Stress, Psychological/blood/*genetics/*immunology ; Surveys and Questionnaires ; Telomere/*genetics ; },
abstract = {The combination of less positive and more negative expectations for the future (i.e., lower optimism and higher pessimism) increases risk for disease and early mortality. We tested the possibility that expectancies might influence health outcomes by altering the rate of biological aging, specifically of the immune system (immunosenescence). However, no studies to date have examined associations between optimism or pessimism and indicators of immunosenescence such as leukocyte telomere length (TL) and interleukin-6 (IL-6) levels. We investigated whether dispositional tendencies towards optimism and pessimism were associated with TL and IL-6 in a sample of 36 healthy post-menopausal women. Multiple regression analyses where optimism and pessimism were entered simultaneously, and chronological age and caregiver status were controlled, indicated that pessimism was independently associated with shorter TL (beta=-.68, p=.001) and higher IL-6 concentrations (beta=.50, p=.02). In contrast, optimism was not independently associated with either measure of immunosenescence. These findings suggest that dispositional pessimism may increase IL-6 and accelerate rate of telomere shortening. Mechanistic causal relationships between these parameters need to be investigated.},
}
@article {pmid19102728,
year = {2009},
author = {Hofr, C and Sultesová, P and Zimmermann, M and Mozgová, I and Procházková Schrumpfová, P and Wimmerová, M and Fajkus, J},
title = {Single-Myb-histone proteins from Arabidopsis thaliana: a quantitative study of telomere-binding specificity and kinetics.},
journal = {The Biochemical journal},
volume = {419},
number = {1},
pages = {221-8, 2 p following 228},
doi = {10.1042/BJ20082195},
pmid = {19102728},
issn = {1470-8728},
mesh = {Arabidopsis/genetics/*metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Electrophoretic Mobility Shift Assay ; Fluorescence Polarization ; Histones/genetics/*metabolism ; Kinetics ; Models, Biological ; Protein Binding/genetics ; Surface Plasmon Resonance ; Telomere/genetics/*metabolism ; },
abstract = {Proteins that bind telomeric DNA modulate the structure of chromosome ends and control telomere function and maintenance. It has been shown that AtTRB (Arabidopsis thaliana telomere-repeat-binding factor) proteins from the SMH (single-Myb-histone) family selectively bind double-stranded telomeric DNA and interact with the telomeric protein AtPOT1b (A. thaliana protection of telomeres 1b), which is involved in telomere capping. In the present study, we performed the first quantitative DNA-binding study of this plant-specific family of proteins. Interactions of full-length proteins AtTRB1 and AtTRB3 with telomeric DNA were analysed by electrophoretic mobility-shift assay, fluorescence anisotropy and surface plasmon resonance to reveal their binding stoichiometry and kinetics. Kinetic analyses at different salt conditions enabled us to estimate the electrostatic component of binding and explain different affinities of the two proteins to telomeric DNA. On the basis of available data, a putative model explaining the binding stoichiometry and the protein arrangement on telomeric DNA is presented.},
}
@article {pmid19097172,
year = {2009},
author = {De Vos, WH and Hoebe, RA and Joss, GH and Haffmans, W and Baatout, S and Van Oostveldt, P and Manders, EM},
title = {Controlled light exposure microscopy reveals dynamic telomere microterritories throughout the cell cycle.},
journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology},
volume = {75},
number = {5},
pages = {428-439},
doi = {10.1002/cyto.a.20699},
pmid = {19097172},
issn = {1552-4930},
mesh = {Cell Cycle/*physiology ; Cell Line ; Cell Line, Tumor ; Cell Nucleus/physiology ; HeLa Cells ; Humans ; Microscopy, Fluorescence ; Recombinant Fusion Proteins/physiology ; Telomere/*physiology ; Telomeric Repeat Binding Protein 1/*physiology ; Telomeric Repeat Binding Protein 2/*physiology ; Transfection ; },
abstract = {Telomeres are complex end structures that confer functional integrity and positional stability to human chromosomes. Despite their critical importance, there is no clear view on telomere organization in cycling human cells and their dynamic behavior throughout the cell cycle. We investigated spatiotemporal organization of telomeres in living human ECV-304 cells stably expressing telomere binding proteins TRF1 and TRF2 fused to mCitrine using four dimensional microscopy. We thereby made use of controlled light exposure microscopy (CLEM), a novel technology that strongly reduces photodamage by limiting excitation in parts of the image where full exposure is not needed. We found that telomeres share small territories where they dynamically associate. These territories are preferentially positioned at the interface of chromatin domains. TRF1 and TRF2 are abundantly present in these territories but not firmly bound. At the onset of mitosis, the bulk of TRF protein dissociates from telomere regions, territories disintegrate and individual telomeres become faintly visible. The combination of stable cell lines, CLEM and cytometry proved essential in providing novel insights in compartment-based nuclear organization and may serve as a model approach for investigating telomere-driven genome-instability and studying long-term nuclear dynamics.},
}
@article {pmid19095716,
year = {2009},
author = {Muntoni, A and Neumann, AA and Hills, M and Reddel, RR},
title = {Telomere elongation involves intra-molecular DNA replication in cells utilizing alternative lengthening of telomeres.},
journal = {Human molecular genetics},
volume = {18},
number = {6},
pages = {1017-1027},
pmid = {19095716},
issn = {1460-2083},
mesh = {Base Sequence ; Clone Cells ; *DNA Replication ; Gene Duplication ; Humans ; In Situ Hybridization, Fluorescence ; Plasmids/genetics ; Polymerase Chain Reaction ; Reproducibility of Results ; Telomere/genetics/*metabolism ; Transfection ; },
abstract = {Alternative lengthening of telomeres (ALT) is a telomere length maintenance mechanism based on recombination, where telomeres use other telomeric DNA as a template for DNA synthesis. About 10% of all human tumors depend on ALT for their continued growth, and understanding its molecular details is critically important for the development of cancer treatments that target this mechanism. We have previously shown that telomeres of ALT-positive human cells can become lengthened via inter-telomeric copying, i.e. by copying the telomere of another chromosome. The possibility that such telomeres could elongate by using other sources of telomeric DNA as copy templates has not been investigated previously. In this study, we have determined whether a telomere can become lengthened by copying its own sequences, without the need for using another telomere as a copy template. To test this, we transduced an ALT cell line with a telomere-targeting construct and obtained clones with a single tagged telomere. We showed that the telomere tag can be amplified without the involvement of other telomeres, indicating that telomere elongation can also occur by intra-telomeric DNA copying. This is the first direct evidence that the ALT mechanism involves more than one method of telomere elongation.},
}
@article {pmid19091442,
year = {2009},
author = {Raynaud, CM and Mercier, O and Commo, F and Dartevelle, P and Gomez-Roca, C and de Montpreville, V and Sabatier, L and Soria, JC},
title = {Telomere length, telomeric proteins and DNA damage repair proteins are differentially expressed between primary lung tumors and their adrenal metastases.},
journal = {Lung cancer (Amsterdam, Netherlands)},
volume = {65},
number = {2},
pages = {144-149},
doi = {10.1016/j.lungcan.2008.10.030},
pmid = {19091442},
issn = {1872-8332},
mesh = {Adrenal Gland Neoplasms/genetics/*metabolism/secondary ; Adult ; Aged ; Biomarkers, Tumor/*analysis ; Carcinoma, Non-Small-Cell Lung/genetics/secondary ; Cluster Analysis ; DNA Repair/*physiology ; DNA Repair Enzymes/*metabolism ; Female ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Lung Neoplasms/genetics/*metabolism/pathology ; Male ; Middle Aged ; Neoplasm Staging ; Telomere/genetics/*metabolism ; },
abstract = {INTRODUCTION: The development of molecular targeted therapies as anti-cancer strategies raises important questions regarding the biological and molecular behavior of the metastatic sites as compared to their corresponding primary tumors. We analysed telomere related markers (telomere length and telomeric proteins) and DNA damage repair (DDR) markers in a cohort of patients with surgically resected primary lung NSCLC and adrenal metastasis. These markers were selected for two reasons: (i) small molecule inhibitors of 'druggable' DDR components as well as telomere-interacting agents are already being developed for clinical use; and (ii) limited data is available comparing the expression of these biomarkers between primary tumors and their metastases.<br><br>MATERIAL AND METHODS: We studied a single series of 21 patients who had undergone surgery of both their primary lung tumor and its related adrenal gland metastasis in a single Institution. DDR and telomeric proteins were analysed by immunohistochemistry and telomere length was assessed by fluorescent in situ hybridization in 17 paired samples.<br><br>RESULTS: DDR activation was observed in primary tumors and their corresponding metastasis. However, higher levels of p-Chk2 were observed in metastasis than in primary tumors (p=0.0113). This was not observed for p-ATM and gamma-H2AX. Telomere length was independent from primary or metastatic status (p=0.29). There was no correlation between primary and metastatic sites, although approximately 65% of metastases had shorter telomeres than their corresponding primary tumors. In the same way, telomeric protein expression was independent from primary/metastatic localization. Cluster analysis of each specimen according to its protein's expression levels and telomere length showed that matched primary tumors/adrenal metastasis were mostly separated into different clusters. Overall, our findings suggest that the levels of biomarkers analysed differ substantially between primary lung tumors and corresponding metastases.<br><br>CONCLUSION: There are clear molecular discrepancies at the telomeric and DDR level between primary tumors and their corresponding metastases. Our results may have important implications for the development of molecular targeted therapies aiming at DNA damage repair and telomeric components. Our findings suggest that primary tumors and their relevant metastases may respond differently to such approaches.},
}
@article {pmid19090788,
year = {2009},
author = {Satoh, M and Minami, Y and Takahashi, Y and Tabuchi, T and Itoh, T and Nakamura, M},
title = {Effect of intensive lipid-lowering therapy on telomere erosion in endothelial progenitor cells obtained from patients with coronary artery disease.},
journal = {Clinical science (London, England : 1979)},
volume = {116},
number = {11},
pages = {827-835},
doi = {10.1042/CS20080404},
pmid = {19090788},
issn = {1470-8736},
mesh = {Anticholesteremic Agents/*therapeutic use ; Atorvastatin ; Cell Count ; Cells, Cultured ; Cholesterol/blood ; Coronary Artery Disease/*drug therapy/pathology ; Endothelial Cells/pathology ; Female ; Heptanoic Acids/*therapeutic use ; Humans ; Male ; Middle Aged ; Pravastatin/*therapeutic use ; Prospective Studies ; Pyrroles/*therapeutic use ; Single-Blind Method ; Stem Cells/*pathology ; Telomere/*drug effects/pathology ; },
abstract = {Telomere erosion of EPCs (endothelial progenitor cells) may be a key factor in endothelial cell senescence and is highly dependent on cellular oxidative damage. The aim of the present study was to investigate whether LLT (lipid-lowering therapy) with statins could attenuate EPC telomere erosion in patients with CAD (coronary artery disease). The study included 100 patients with stable CAD and 25 subjects without CAD as controls. CAD patients were randomized to 12 months of intensive LLT with atorvastatin or moderate LLT with pravastatin. EPCs were obtained from peripheral blood at baseline and after 12 months of statin therapy. Telomere length in EPCs was measured by FISH (fluorescence in situ hybridization) and oxidative DNA damage by flow cytometry of oxidized DNA bases. EPC telomere length was shorter in the CAD group than in the controls, and oxidative DNA damage to EPCs was higher in the CAD group compared with controls. After 12 months of therapy, changes in lipid profiles were greater in the intensive LLT group than in the moderate LLT group. Intensive LLT markedly increased EPC number and decreased oxidative DNA damage in EPCs (both P<0.05), with no change in telomere length. In contrast, moderate LLT did not change EPC counts or oxidative DNA damage, but showed telomere shortening (P<0.05). There was a weak negative correlation between changes in EPC number and LDL (low-density lipoprotein)-cholesterol levels after intensive LLT, whereas there was no correlation between them after moderate LLT. With in vitro culturing of EPCs subjected to oxidative stress, atorvastatin led to the prevention of EPC telomere shortening compared with pravastatin. In conclusion, the present study has demonstrated that intensive LLT may prevent EPC telomere erosion in patients with CAD, possibly contributing to the beneficial effects of intensive LLT in this disorder.},
}
@article {pmid19089916,
year = {2009},
author = {Shen, J and Gammon, MD and Terry, MB and Wang, Q and Bradshaw, P and Teitelbaum, SL and Neugut, AI and Santella, RM},
title = {Telomere length, oxidative damage, antioxidants and breast cancer risk.},
journal = {International journal of cancer},
volume = {124},
number = {7},
pages = {1637-1643},
pmid = {19089916},
issn = {1097-0215},
support = {P30 ES010126/ES/NIEHS NIH HHS/United States ; R03 CA125768-02/CA/NCI NIH HHS/United States ; P30ES09089/ES/NIEHS NIH HHS/United States ; U01CA/ES66572/CA/NCI NIH HHS/United States ; R03CA125768/CA/NCI NIH HHS/United States ; P30ES10126/ES/NIEHS NIH HHS/United States ; R03 CA125768/CA/NCI NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; },
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Antioxidants/*pharmacology ; Biomarkers, Tumor/analysis ; Breast Neoplasms/*genetics/*metabolism ; Case-Control Studies ; Deoxyguanosine/analogs &amp; derivatives/urine ; Female ; Humans ; Isoprostanes/urine ; Oxidative Stress/*physiology ; Polymerase Chain Reaction ; Premenopause ; Risk Factors ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres play a critical role in maintaining the integrity and stability of the genome, and are susceptible to oxidative damage after telomere shortening to a critical length. In the present study, we explored the role of white blood cell DNA telomere length on breast cancer risk, and examined whether urinary 15-F(2)-isoprostanes (15-F(2t)-IsoP) and 8-oxo-7,8-dihydrodeoxyguanosine (8-oxodG) or dietary antioxidant intake modified the relationship between telomere length and breast cancer risk. A population-based case-control study-the Long Island Breast Cancer Study Project-was conducted among 1,067 cases and 1,110 controls. Telomere length was assessed by quantitative PCR. Overall, the mean levels of telomere length (T/S ratio), 15-F(2t)-IsoP and 8-oxodG were not significantly different between cases and controls. Among premenopausal women only, carrying shorter telomeres (Q3 and Q4), as compared with the longest (Q1), was associated with significantly increased breast cancer risk. Age-adjusted OR and 95% CI were 1.71 (1.10-2.67) and 1.61 (1.05-2.45). The 5-F(2t)-IsoP and 8-oxodG biomarkers did not modify the telomere-breast cancer association. A moderate increase in breast cancer risk was observed among women with the shortest telomeres (Q4) and lower dietary and supplemental intake of beta-carotene, vitamin C or E intake [OR (95% CI) = 1.48 (1.08-2.03), 1.39 (1.01-1.92) and 1.57 (1.14-2.18), respectively], although the trend test exhibited statistical significance only within the lower vitamin E intake subgroup (p(trend) = 0.01). These results provided the strongest evidence to date that breast cancer risk may be affected by telomere length among premenopausal women or women with low dietary intake of antioxidants or antioxidant supplements.},
}
@article {pmid19077045,
year = {2009},
author = {Chebel, A and Bauwens, S and Gerland, LM and Belleville, A and Urbanowicz, I and de Climens, AR and Tourneur, Y and Chien, WW and Catallo, R and Salles, G and Gilson, E and Ffrench, M},
title = {Telomere uncapping during in vitro T-lymphocyte senescence.},
journal = {Aging cell},
volume = {8},
number = {1},
pages = {52-64},
doi = {10.1111/j.1474-9726.2008.00448.x},
pmid = {19077045},
issn = {1474-9726},
mesh = {Aged ; Animals ; Cell Cycle/physiology ; Cell Division/physiology ; Cells, Cultured ; Cellular Senescence/genetics/immunology/physiology ; Cyclin-Dependent Kinase Inhibitor p16/biosynthesis/genetics ; Cyclin-Dependent Kinase Inhibitor p21/biosynthesis/genetics ; Down-Regulation ; Histones/blood ; Humans ; Immunophenotyping ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Lymphocyte Activation ; Mice ; Reverse Transcriptase Polymerase Chain Reaction ; Shelterin Complex ; T-Lymphocytes/cytology/immunology/metabolism/*ultrastructure ; Telomerase/genetics/metabolism ; Telomere/metabolism/*ultrastructure ; Telomere-Binding Proteins/biosynthesis/genetics ; Tumor Suppressor p53-Binding Protein 1 ; },
abstract = {Normal lymphocytes represent examples of somatic cells that are able to induce telomerase activity when stimulated. As previously reported, we showed that, during lymphocyte long-term culture and repeated stimulations, the appearance of senescent cells is associated with telomere shortening and a progressive drop in telomerase activity. We further showed that this shortening preferentially occured at long telomeres and was interrupted at each stimulation by a transitory increase in telomere length. In agreement with the fact that telomere uncapping triggers lymphocyte senescence, we observed an increase in gamma-H2AX and 53BP1 foci as well as in the percentage of cells exhibiting DNA damage foci in telomeres. Such a DNA damage response may be related to the continuous increase of p16(ink4a) upon cell stimulation and cell aging. Remarkably, at each stimulation, the expression of shelterin genes, such as hTRF1, hTANK1, hTIN2, hPOT1 and hRAP1, was decreased. We propose that telomere dysfunction during lymphocyte senescence caused by iterative stimulations does not only result from an excessive telomere shortening, but also from a decrease in shelterin content. These observations may be relevant for T-cell biology and aging.},
}
@article {pmid19068479,
year = {2009},
author = {Sampathi, S and Bhusari, A and Shen, B and Chai, W},
title = {Human flap endonuclease I is in complex with telomerase and is required for telomerase-mediated telomere maintenance.},
journal = {The Journal of biological chemistry},
volume = {284},
number = {6},
pages = {3682-3690},
pmid = {19068479},
issn = {0021-9258},
support = {R15 CA132090/CA/NCI NIH HHS/United States ; R15 CA132090-01/CA/NCI NIH HHS/United States ; R15CA132090/CA/NCI NIH HHS/United States ; R01CA073764/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; DNA Repair/physiology ; DNA Replication/physiology ; Flap Endonucleases/genetics/*metabolism ; HeLa Cells ; Humans ; Mice ; Multienzyme Complexes/genetics/*metabolism ; Recombination, Genetic/physiology ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Studies from budding yeast and ciliates have suggested that telomerase extension of telomeres requires the conventional DNA replication machinery, yet little is known about how DNA replication proteins regulate telomerase action in higher eukaryotic cells. Here we investigate the role of one of the DNA replication factors, flap endonuclease I (FEN1), in regulating telomerase activity in mammalian cells. FEN1 is a nuclease that plays an important role in DNA replication, repair, and recombination. We show that FEN1 is in complex with telomerase in vivo via telomeric DNA. We further demonstrate that FEN1 deficiency in mouse embryonic fibroblasts leads to an increase in telomere end-to-end fusions. In cancer cells, FEN1 deficiency induces gradual shortening of telomeres but does not alter the single-stranded G-overhangs. This is, to our knowledge, the first evidence that FEN1 and telomerase physically co-exist as a complex and that FEN1 can regulate telomerase activity at telomeres in mammalian cells.},
}
@article {pmid19061286,
year = {2008},
author = {Hansson, M and Zendehrokh, N and Ohyashiki, J and Ohyashiki, K and Westman, UB and Roos, G and Dejmek, A},
title = {Telomerase activity in effusions: a comparison between telomere repeat amplification protocol in situ and conventional telomere repeat amplification protocol assay.},
journal = {Archives of pathology &amp; laboratory medicine},
volume = {132},
number = {12},
pages = {1896-1902},
doi = {10.5858/132.12.1896},
pmid = {19061286},
issn = {1543-2165},
mesh = {Ascitic Fluid/*enzymology/pathology ; Enzyme-Linked Immunosorbent Assay/*methods ; Humans ; Mesothelioma/diagnosis/enzymology/pathology ; Nucleic Acid Amplification Techniques/*methods ; Pericardial Effusion/diagnosis/*enzymology/pathology ; Peritoneal Neoplasms/diagnosis/enzymology/pathology ; Pleural Effusion, Malignant/diagnosis/*enzymology/pathology ; Pleural Neoplasms/diagnosis/enzymology/pathology ; Retrospective Studies ; Sensitivity and Specificity ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {CONTEXT: We previously found telomere repeat amplification protocol (TRAP) in situ helpful in the diagnosis of malignancy in effusions, whereas varying sensitivities and specificities for malignancy were reported by investigators using extract-based TRAP.<br><br>OBJECTIVE: To compare the 2 methods and to elucidate the discrepancies between them.<br><br>DESIGN: Twenty-three effusions were analyzed. Telomerase activity of whole cell lysate was measured with a Telo TAGGG telomerase polymerase chain reaction ELISA PLUS kit with modifications to exclude polymerase chain reaction inhibitors. TRAP in situ was performed on cytospins. An estimate of total TRAP activity in the specimen was made based on the amount of positive cells, their fluorescence intensity, and the proportion of different cell types in the specimen. The estimate was compared with the level of telomerase activity in cell lysate-based TRAP.<br><br>RESULTS: TRAP in situ: Thirteen of 14 malignant cases and 2 of 2 equivocal cases showed moderate/strong reactivity. Five of 7 benign effusions were negative; in 2 of 7, mesothelial cells showed weak reactivity. Cell lysate-based TRAP assay: In 4 cases no internal standard was detected, indicating the presence of polymerase chain reaction inhibitors. The relative telomerase activities were 33.1 to 72.7 with a considerable overlap between malignant (48 +/- 9, mean +/- SD) and benign (43 +/- 9) cases.<br><br>CONCLUSIONS: The TRAP in situ results correlated to final diagnoses, whereas the cell lysate-based TRAP assay did not differentiate between malignant and benign cases. The varying proportions of positive cells and the variation in fluorescence intensity in the TRAP in situ slides explained some of the discrepancies. The problems encountered with TRAP performed on cell lysates are partly overcome using TRAP in situ.},
}
@article {pmid19060891,
year = {2009},
author = {Lee, TH and Tun-Kyi, A and Shi, R and Lim, J and Soohoo, C and Finn, G and Balastik, M and Pastorino, L and Wulf, G and Zhou, XZ and Lu, KP},
title = {Essential role of Pin1 in the regulation of TRF1 stability and telomere maintenance.},
journal = {Nature cell biology},
volume = {11},
number = {1},
pages = {97-105},
pmid = {19060891},
issn = {1476-4679},
support = {R01 GM058556/GM/NIGMS NIH HHS/United States ; R01 AG017870/AG/NIA NIH HHS/United States ; R01 CA122434/CA/NCI NIH HHS/United States ; R01 AG017870-07/AG/NIA NIH HHS/United States ; R01GM058556/GM/NIGMS NIH HHS/United States ; AG017870/AG/NIA NIH HHS/United States ; R01 CA122434-03/CA/NCI NIH HHS/United States ; R01 GM058556-10/GM/NIGMS NIH HHS/United States ; R01CA122434/CA/NCI NIH HHS/United States ; },
mesh = {*Aging/genetics/metabolism ; Animals ; Cell Line ; Cell Line, Tumor ; *Cellular Senescence/genetics ; Chromosomal Instability/genetics ; Humans ; Mice ; Mice, Knockout ; NIMA-Interacting Peptidylprolyl Isomerase ; Peptidylprolyl Isomerase/genetics/metabolism/*physiology ; Protein Binding/genetics ; Signal Transduction/genetics ; Telomerase/deficiency/genetics ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 1/genetics/*metabolism ; },
abstract = {Telomeres are essential for maintaining cellular proliferative capacity and their loss has been implicated in ageing. A key regulator in telomere maintenance is the telomeric protein TRF1, which was also identified as Pin2 in a screen for Pin1. Pin1 is a unique prolyl isomerase that regulates protein conformation and function after phosphorylation. However, little is known about the role of Pin1 in telomere regulation or the modulation of TRF1 by upstream signals. Here we identify TRF1 as a major conserved substrate for Pin1 during telomere maintenance and ageing. Pin1 inhibition renders TRF1 resistant to protein degradation, enhances TRF1 binding to telomeres, and leads to gradual telomere loss in human cells and in mice. Pin1-deficient mice also show widespread premature ageing phenotypes within just one generation, similar to those in telomerase-deficient mice after 4-5 consecutive generations. Thus, Pin1 is an essential regulator of TRF1 stability, telomere maintenance and ageing.},
}
@article {pmid19060421,
year = {2009},
author = {Higuchi, Y and Maeda, T and Guan, JZ and Oyama, J and Sugano, M and Makino, N},
title = {Diagonal earlobe crease are associated with shorter telomere in male Japanese patients with metabolic syndrome.},
journal = {Circulation journal : official journal of the Japanese Circulation Society},
volume = {73},
number = {2},
pages = {274-279},
doi = {10.1253/circj.cj-08-0267},
pmid = {19060421},
issn = {1346-9843},
mesh = {Aged ; Aging, Premature/genetics ; Atherosclerosis/epidemiology/genetics ; Biomarkers ; Case-Control Studies ; DNA Fragmentation ; Ear, External/*anatomy &amp; histology ; Genetic Predisposition to Disease/genetics ; Humans ; Japan ; Male ; Metabolic Syndrome/*ethnology/*genetics ; Middle Aged ; Pilot Projects ; Risk Factors ; Telomere/*genetics ; },
abstract = {BACKGROUND: Diagonal earlobe crease (ELC) have been proposed as a marker of generalized atherosclerosis, so in the present study it was investigated whether individuals with ELC have a shortened telomere, which correlates with an accelerated cell turnover and premature aging, leading to atherosclerosis.<br><br>METHODS AND RESULTS: The mean terminal restriction fragment (TRF) was determined by Southern blot hybridization in the peripheral blood cells of 34 male Japanese patients with metabolic syndrome (MetS) who were under 70 years of age with (n=17) and without (n=17) bilateral ELC, and assessed the relationship of ELC to atherosclerotic cardiovascular disease (AVD). The results showed that the TRF was shorter in the MetS patients with ELC in comparison to age- and risk-factor-matched MetS patients without ELC (7.6+/-1.1 kbp vs 8.6+/-1.2 kbp; P<0.05). ELC were present in 13 patients in the AVD group (n=18), but only 4 patients in the non-AVD group (n=16) had ELC (72.2% and 25% respectively; P<0.05).<br><br>CONCLUSIONS: These findings suggest that ELC is a useful dermatological indicator of an accelerated aging process, as suggested by excessive telomere loss, and might be a useful indirect marker of high-risk patients.},
}
@article {pmid19060156,
year = {2009},
author = {Lin, YR and Hahn, MY and Roe, JH and Huang, TW and Tsai, HH and Lin, YF and Su, TS and Chan, YJ and Chen, CW},
title = {Streptomyces telomeres contain a promoter.},
journal = {Journal of bacteriology},
volume = {191},
number = {3},
pages = {773-781},
pmid = {19060156},
issn = {1098-5530},
mesh = {Cell Line ; DNA-Directed RNA Polymerases/metabolism ; Electrophoretic Mobility Shift Assay ; Humans ; Models, Genetic ; Polymerase Chain Reaction ; Promoter Regions, Genetic/*genetics ; Protein Binding ; Streptomyces/*genetics ; Telomere/*genetics ; },
abstract = {Bidirectional replication of the linear chromosomes and plasmids of Streptomyces spp. results in single-strand overhangs at their 3' ends, which contain extensive complex palindromic sequences. The overhangs are believed to be patched by DNA synthesis primed by a terminal protein that remains covalently bound to the 5' ends of the telomeres. We discovered that in vitro a conserved 167-bp telomere DNA binds strongly to RNA polymerase holoenzyme and exhibits promoter activities stronger than those of an rRNA operon. In vivo, the telomere DNA exhibited promoter activity in both orientations on a circular plasmid in Streptomyces. The telomere promoter is also active on a linear plasmid during exponential growth. Such promoter activity in a telomere has not hitherto been observed in eukaryotic or prokaryotic replicons. Streptomyces telomere promoters may be involved in priming the terminal Okazaki fragment (during replication) replicative transfer (during conjugation), or expression of downstream genes (including a conserved ttrA helicase-like gene involved in conjugal transfer). Interestingly, the Streptomyces telomeres also function as a promoter in Escherichia coli and as a transcription enhancer in yeast.},
}
@article {pmid19056887,
year = {2008},
author = {Ebrahimi, H and Donaldson, AD},
title = {Release of yeast telomeres from the nuclear periphery is triggered by replication and maintained by suppression of Ku-mediated anchoring.},
journal = {Genes &amp; development},
volume = {22},
number = {23},
pages = {3363-3374},
pmid = {19056887},
issn = {0890-9369},
support = {G0600774/MRC_/Medical Research Council/United Kingdom ; 082377/Z/07/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Cell Nucleus ; Cyclins/metabolism ; *DNA Replication ; DNA-Binding Proteins/*physiology ; Nuclear Envelope/*ultrastructure ; S Phase ; Saccharomyces cerevisiae ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/*physiology ; Telomere/*physiology ; },
abstract = {The perinuclear localization of Saccharomyces cerevisiae telomeres provides a useful model for studying mechanisms that control chromosome positioning. Telomeres tend to be localized at the nuclear periphery during early interphase, but following S phase they delocalize and remain randomly positioned within the nucleus. We investigated whether DNA replication causes telomere delocalization from the nuclear periphery. Using live-cell fluorescence microscopy, we show that delaying DNA replication causes a corresponding delay in the dislodgment of telomeres from the nuclear envelope, demonstrating that replication of individual telomeres causes their delocalization. Telomere delocalization is not simply the result of recruitment to a replication factory in the nuclear interior, since we found that telomeric DNA replication can occur either at the nuclear periphery or in the nuclear interior. The telomere-binding complex Ku is one of the factors that localizes telomeres to the nuclear envelope. Using a gene locus tethering assay, we show that Ku-mediated peripheral positioning is switched off after DNA replication. Based on these findings, we propose that DNA replication causes telomere delocalization by triggering stable repression of the Ku-mediated anchoring pathway. In addition to maintaining genetic information, DNA replication may therefore regulate subnuclear organization of chromatin.},
}
@article {pmid19056834,
year = {2009},
author = {Aviv, A and Chen, W and Gardner, JP and Kimura, M and Brimacombe, M and Cao, X and Srinivasan, SR and Berenson, GS},
title = {Leukocyte telomere dynamics: longitudinal findings among young adults in the Bogalusa Heart Study.},
journal = {American journal of epidemiology},
volume = {169},
number = {3},
pages = {323-329},
pmid = {19056834},
issn = {1476-6256},
support = {R01 AG016592/AG/NIA NIH HHS/United States ; R01 AG020132/AG/NIA NIH HHS/United States ; R01 AG16592/AG/NIA NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aging/*genetics ; Blotting, Southern ; Body Mass Index ; Cardiovascular Diseases/genetics ; Child ; Child, Preschool ; Disease Progression ; Female ; Humans ; Leukocytes/*chemistry ; Longitudinal Studies ; Louisiana ; Male ; Middle Aged ; Telomere/*chemistry/*classification/genetics ; Young Adult ; },
abstract = {Leukocyte telomere length (LTL) is ostensibly a biomarker of human aging. Cross-sectional analyses have found that LTL is relatively short in a host of aging-related diseases. These studies have also provided indirect estimates of age-dependent LTL shortening. In this paper, the authors report findings of the first comprehensive longitudinal study of 450 whites and 185 African Americans in Louisiana (aged 31.4 and 37.4 years at baseline (1995-1996) and follow-up (2001-2006) examinations, respectively) participating in the Bogalusa Heart Study. Rate of change in LTL was highly variable among individuals, with some displaying a paradoxical gain in LTL during the follow-up period. The most striking observation was that age-dependent LTL shortening was proportional to LTL at baseline examination. At both baseline and follow-up examinations, African Americans had longer LTLs than whites, and smokers had shorter LTLs than nonsmokers. The longer LTL in African Americans than in whites explained in part the faster rate of LTL shortening observed among African Americans. These findings underscore the complexity of leukocyte telomere dynamics in vivo and suggest that determinants in addition to the "end-replication problem" contribute to telomere shortening in vivo.},
}
@article {pmid19056671,
year = {2008},
author = {Raz, V and Vermolen, BJ and Garini, Y and Onderwater, JJ and Mommaas-Kienhuis, MA and Koster, AJ and Young, IT and Tanke, H and Dirks, RW},
title = {The nuclear lamina promotes telomere aggregation and centromere peripheral localization during senescence of human mesenchymal stem cells.},
journal = {Journal of cell science},
volume = {121},
number = {Pt 24},
pages = {4018-4028},
doi = {10.1242/jcs.034876},
pmid = {19056671},
issn = {0021-9533},
mesh = {Cell Nucleus/physiology/ultrastructure ; Cells, Cultured ; *Cellular Senescence ; Centromere/*physiology/ultrastructure ; Histones/metabolism ; Humans ; Mesenchymal Stem Cells/*physiology/ultrastructure ; Microscopy, Electron, Transmission ; Nuclear Lamina/*physiology/ultrastructure ; Telomerase/metabolism ; Telomere/*physiology/ultrastructure ; beta-Galactosidase/metabolism ; },
abstract = {Ex vivo, human mesenchymal stem cells (hMSCs) undergo spontaneous cellular senescence after a limited number of cell divisions. Intranuclear structures of the nuclear lamina were formed in senescent hMSCs, which are identified by the presence of Hayflick-senescence-associated factors. Notably, spatial changes in lamina shape were observed before the Hayflick senescence-associated factors, suggesting that the lamina morphology can be used as an early marker to identify senescent cells. Here, we applied quantitative image-processing tools to study the changes in nuclear architecture during cell senescence. We found that centromeres and telomeres colocalised with lamina intranuclear structures, which resulted in a preferred peripheral distribution in senescent cells. In addition, telomere aggregates were progressively formed during cell senescence. Once formed, telomere aggregates showed colocalization with gamma-H2AX but not with TERT, suggesting that telomere aggregates are sites of DNA damage. We also show that telomere aggregation is associated with lamina intranuclear structures, and increased telomere binding to lamina proteins is found in cells expressing lamina mutants that lead to increases in lamina intranuclear structures. Moreover, three-dimensional image processing revealed spatial overlap between telomere aggregates and lamina intranuclear structures. Altogether, our data suggest a mechanical link between changes in lamina spatial organization and the formation of telomere aggregates during senescence of hMSCs, which can possibly contribute to changes in nuclear activity during cell senescence.},
}
@article {pmid19055473,
year = {2009},
author = {Kushner, EJ and Van Guilder, GP and Maceneaney, OJ and Cech, JN and Stauffer, BL and DeSouza, CA},
title = {Aging and endothelial progenitor cell telomere length in healthy men.},
journal = {Clinical chemistry and laboratory medicine},
volume = {47},
number = {1},
pages = {47-50},
pmid = {19055473},
issn = {1434-6621},
support = {RR00051/RR/NCRR NIH HHS/United States ; R01 HL077450-04/HL/NHLBI NIH HHS/United States ; HL076434/HL/NHLBI NIH HHS/United States ; R01 HL077450-01/HL/NHLBI NIH HHS/United States ; M01 RR000051/RR/NCRR NIH HHS/United States ; HL077450/HL/NHLBI NIH HHS/United States ; R01 HL076434/HL/NHLBI NIH HHS/United States ; R01 HL077450/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Aged ; Aging/*physiology ; Endothelial Cells/*physiology ; Humans ; Male ; Middle Aged ; Stem Cells/*physiology ; Telomere/*chemistry ; Young Adult ; },
abstract = {BACKGROUND: Telomere length declines with age in mature endothelial cells and is thought to contribute to endothelial dysfunction and atherogenesis. Bone marrow-derived circulating endothelial progenitor cells (EPCs) are critical to vascular health as they contribute to both reendothelialization and neovascularization. We tested the hypothesis that EPC telomere length decreases with age in healthy adult humans.<br><br>METHODS: Peripheral blood samples were collected from 40 healthy, non-obese, sedentary men: 12 young (age 21-34 years), 12 middle-aged (43-55 years) and 16 older (57-68 years). Putative EPCs were isolated from peripheral blood mononuclear cells and telomere length was determined using genomic DNA preparation and Southern hybridization techniques.<br><br>RESULTS: EPC telomere length (base pairs) was approximately 20% (p=0.01) lower in the older (8492+523 bp) compared to the middle-aged (10,565+572 bp) and young (10,205+501 bp) men. Of note, there was no difference in EPC telomere length between the middle-aged and young men.<br><br>CONCLUSIONS: These results demonstrate that EPC telomere length declines with age in healthy, sedentary men. Interestingly, telomere length was well preserved in the middle-aged compared to young men, suggesting that EPC telomere shortening occurs after the age of 55 years.},
}
@article {pmid19050887,
year = {2009},
author = {Marcondes, AM and Bair, S and Rabinovitch, PS and Gooley, T and Deeg, HJ and Risques, R},
title = {No telomere shortening in marrow stroma from patients with MDS.},
journal = {Annals of hematology},
volume = {88},
number = {7},
pages = {623-628},
pmid = {19050887},
issn = {1432-0584},
support = {HL36444/HL/NHLBI NIH HHS/United States ; P30 AG013280-14/AG/NIA NIH HHS/United States ; P01 AG001751/AG/NIA NIH HHS/United States ; HL082941/HL/NHLBI NIH HHS/United States ; R01 HL082941-04/HL/NHLBI NIH HHS/United States ; P01 HL036444-28/HL/NHLBI NIH HHS/United States ; P01 HL036444/HL/NHLBI NIH HHS/United States ; P30 AG013280/AG/NIA NIH HHS/United States ; R01 HL082941/HL/NHLBI NIH HHS/United States ; AG13280/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Bone Marrow/pathology ; Case-Control Studies ; Cells, Cultured ; Female ; Hematopoietic Stem Cells ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Myelodysplastic Syndromes/*pathology ; Polymerase Chain Reaction ; Stromal Cells/*pathology ; Telomere/*metabolism/ultrastructure ; },
abstract = {Telomere shortening with age may lead to genomic instability and an increased risk of cancer. Given the role of the microenvironment in the pathophysiology of the myelodysplastic syndrome (MDS), primarily a disease of older age, we determined telomere length in primary cultured marrow stroma cells using quantitative fluorescent in situ hybridization (qFISH) and quantitative polymerase chain reaction (qPCR). qFISH showed comparable rates of decrease in telomere length with age in MDS patients and age-matched healthy controls. Telomere length assessment by qPCR showed similar results. These findings suggest a lack of significant differences between MDS patients and healthy controls in terms of telomere stability in marrow stroma in contrast to that observed in hematopoietic cells. In conclusion, this demonstrates that, although MDS stroma cells and hematopoietic cells share the same microenvironment, the stromal cells do not share the processes that contribute to accelerated telomere attrition, suggesting that stromal cell proliferative potential is not limiting in MDS.},
}
@article {pmid19049455,
year = {2008},
author = {Petraccone, L and Trent, JO and Chaires, JB},
title = {The tail of the telomere.},
journal = {Journal of the American Chemical Society},
volume = {130},
number = {49},
pages = {16530-16532},
pmid = {19049455},
issn = {0002-7863},
support = {R01 GM077422-02/GM/NIGMS NIH HHS/United States ; GM077422/GM/NIGMS NIH HHS/United States ; R01 CA035635-22/CA/NCI NIH HHS/United States ; R01 CA035635/CA/NCI NIH HHS/United States ; CA35635/CA/NCI NIH HHS/United States ; R01 GM077422/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; DNA/chemistry/genetics ; *Models, Molecular ; Molecular Sequence Data ; Nucleic Acid Conformation ; Reproducibility of Results ; Telomere/*chemistry/genetics ; },
abstract = {The structure of a higher-order G-quadruplex structure for human telomeric DNA is presented. The structure was determined by a novel integrated approach in which molecular dynamics simulations were used to produce a stable structure, from which specific experimentally accessible properties were predicted. These properties were tested by sedimentation velocity and steady-state fluorescence measurements. The structure that emerges is a dimeric structure with two quadruplex units, each with a different structure. The interface between the quadruplex units is stabilized by specific stacking interactions of loop nucleotides. The interface is a unique structure and a unique target for drug design.},
}
@article {pmid19047370,
year = {2009},
author = {Grandin, N and Charbonneau, M},
title = {Telomerase- and Rad52-independent immortalization of budding yeast by an inherited-long-telomere pathway of telomeric repeat amplification.},
journal = {Molecular and cellular biology},
volume = {29},
number = {4},
pages = {965-985},
pmid = {19047370},
issn = {1098-5549},
mesh = {Cell Proliferation ; Kinetics ; Microbial Viability ; Rad52 DNA Repair and Recombination Protein/metabolism ; Recombination, Genetic/genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Saccharomycetales/*cytology/*enzymology ; Telomerase/metabolism ; Telomere/*genetics/*metabolism ; Time Factors ; },
abstract = {In the absence of telomerase, telomeres erode, provoking accumulation of DNA damage and death by senescence. Rare survivors arise, however, due to Rad52-based amplification of telomeric sequences by homologous recombination. The present study reveals that in budding yeast cells, postsenescence survival relying on amplification of the TG(1-3) telomeric repeats can take place in the absence of Rad52 when overelongated telomeres are present during senescence (hence its designation ILT, for inherited-long-telomere, pathway). By growth competition, the Rad52-independent pathway was almost as efficient as the Rad51- and Rad52-dependent pathway that predominates in telomerase-negative cells. The ILT pathway could also be triggered by increased telomerase accessibility before telomerase removal, combined with loss of telomere protection, indicating that prior accumulation of recombination proteins was not required. The ILT pathway was dependent on Rad50 and Mre11 but not on the Rad51 recombinase and Rad59, thus making it distinct from both the type II (budding yeast ALT [alternative lengthening of telomeres]) and type I pathways amplifying the TG(1-3) repeats and subtelomeric sequences, respectively. The ILT pathway also required the Rad1 endonuclease and Elg1, a replication factor C (RFC)-like complex subunit, but not Rad24 or Ctf18 (two subunits of two other RFC-like complexes), the Dnl4 ligase, Yku70, or Nej1. Possible mechanisms for this Rad52-independent pathway of telomeric repeat amplification are discussed. The effects of inherited long telomeres on Rad52-dependent recombination are also reported.},
}
@article {pmid19047341,
year = {2009},
author = {Wong, LS and Oeseburg, H and de Boer, RA and van Gilst, WH and van Veldhuisen, DJ and van der Harst, P},
title = {Telomere biology in cardiovascular disease: the TERC-/- mouse as a model for heart failure and ageing.},
journal = {Cardiovascular research},
volume = {81},
number = {2},
pages = {244-252},
doi = {10.1093/cvr/cvn337},
pmid = {19047341},
issn = {1755-3245},
mesh = {*Aging ; Animals ; Atherosclerosis/etiology ; Cardiovascular Diseases/*etiology ; Disease Models, Animal ; Heart Failure/*etiology ; Hypertension/etiology ; Mice ; Regeneration ; Signal Transduction ; Stem Cells/physiology ; Telomerase/chemistry/*physiology ; Telomere/*physiology ; },
abstract = {Atherosclerosis and heart failure are major causes of morbidity and mortality in Western countries. Recent studies are suggesting involvement of telomere biology in the development and progression of age-associated conditions, including hypertension, atherosclerosis, and heart failure. Whether any of these reported associations are based on causal relationships remains to be elucidated. The construction of telomerase-deficient (telomerase RNA component, TERC(-/-)) mice might provide a potential instrumental model to study the involvement of telomere biology in cardiovascular disease. Here, we review the current available information from all studies performed in TERC(-/-) mice providing information on the cardiovascular phenotypic characteristics. Although this mouse model has proven its value in the understanding of the role of telomere biology in cancer, stem cell, and basic telomere research, only few studies were specifically designed to answer cardiovascular-related questions. The TERC(-/-) mice provide exciting opportunities to expand our knowledge of telomere biology in cardiovascular disease and the potential identification of novel targets of treatment.},
}
@article {pmid19047177,
year = {2008},
author = {Spardy, N and Duensing, A and Hoskins, EE and Wells, SI and Duensing, S},
title = {HPV-16 E7 reveals a link between DNA replication stress, fanconi anemia D2 protein, and alternative lengthening of telomere-associated promyelocytic leukemia bodies.},
journal = {Cancer research},
volume = {68},
number = {23},
pages = {9954-9963},
pmid = {19047177},
issn = {1538-7445},
support = {R01 CA112598/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Cell Nucleus/metabolism ; DNA Replication ; DNA, Neoplasm/biosynthesis/genetics ; DNA, Single-Stranded/genetics/metabolism ; Fanconi Anemia Complementation Group D2 Protein/biosynthesis/metabolism ; HeLa Cells ; Humans ; Intranuclear Inclusion Bodies/genetics/*metabolism/virology ; Keratinocytes/pathology/virology ; Leukemia, Promyelocytic, Acute/genetics/*metabolism/virology ; Oncogene Proteins, Viral/*biosynthesis ; Papillomavirus E7 Proteins ; RNA, Small Interfering/genetics ; Telomere/*genetics/metabolism ; Transfection ; },
abstract = {Expression of the high-risk human papillomavirus (HPV-16) E7 oncoprotein extends the life span of primary human keratinocytes and partially restores telomere length in the absence of telomerase. The molecular basis of this activity is incompletely understood. Here, we show that HPV-16 E7 induces an increased formation of alternative lengthening of telomeres (ALT)-associated promyelocytic leukemia bodies (APBs) in early passage primary human keratinocytes as well as HPV-negative tumor cells. This activity was found to require sequences of HPV-16 E7 involved in degradation of the retinoblastoma tumor suppressor protein as well as regions in the COOH terminus. HPV-16 E7-induced APBs contained ssDNA and several proteins that are involved in the response to DNA replication stress, most notably the Fanconi anemia D2 protein (FANCD2) as well as BRCA2 and MUS81. In line with these results, we found that FANCD2-containing APBs form in an ATR-dependent manner in HPV-16 E7-expressing cells. To directly show a role of FANCD2 in ALT, we provide evidence that knockdown of FANCD2 rapidly causes telomere dysfunction in cells that rely on ALT to maintain telomeres. Taken together, our results suggest a novel link between replication stress and recombination-based telomere maintenance that may play a role in HPV-16 E7-mediated extension of host cell life span and immortalization.},
}
@article {pmid19041960,
year = {2009},
author = {Buysse, K and Antonacci, F and Callewaert, B and Loeys, B and Fränkel, U and Siu, V and Mortier, G and Speleman, F and Menten, B},
title = {Unusual 8p inverted duplication deletion with telomere capture from 8q.},
journal = {European journal of medical genetics},
volume = {52},
number = {1},
pages = {31-36},
doi = {10.1016/j.ejmg.2008.10.007},
pmid = {19041960},
issn = {1878-0849},
mesh = {*Chromosome Aberrations ; Chromosome Deletion ; Chromosome Inversion ; *Chromosomes, Human, Pair 8 ; Cytogenetic Analysis ; Gene Duplication ; Humans ; Infant ; Telomere ; },
abstract = {Inverted 8p duplication deletions are recurrent chromosomal rearrangements that are mediated through non-allelic homologous recombination (NAHR) between olfactory receptor (OR) gene clusters at 8p23.1. These rearrangements result in a proximal inverted duplication of various extent, a single copy region between the OR gene clusters and a terminal 8p deletion. The terminal deletions are stabilized by direct addition of telomeric repeats, so called telomere healing. Here, we report a patient with an unusual inverted duplication deletion of 8p. Stabilization of the broken chromosome end was achieved by telomere capture instead of telomere healing, resulting in an additional duplication of 8q24.13-->qter on the short arm of chromosome 8. Moreover, the inverted duplication was only 3.4 Mb in size (restricted to band 8p22) and thus cytogenetically undetectable. To the best of our knowledge this is the smallest inverted duplication reported hitherto. We describe the molecular characterization by FISH and array CGH of this unusual inv dup del (8p) and a previously reported patient with a similar 8q duplication and review the literature on cases associated with telomere capture.},
}
@article {pmid19039323,
year = {2009},
author = {Knecht, H and Sawan, B and Lichtensztejn, D and Lemieux, B and Wellinger, RJ and Mai, S},
title = {The 3D nuclear organization of telomeres marks the transition from Hodgkin to Reed-Sternberg cells.},
journal = {Leukemia},
volume = {23},
number = {3},
pages = {565-573},
doi = {10.1038/leu.2008.314},
pmid = {19039323},
issn = {1476-5551},
mesh = {B-Lymphocytes/*ultrastructure ; Cell Division ; Cell Line, Tumor/ultrastructure ; Cell Size ; *Chromosome Positioning ; Chromosome Segregation ; DNA Breaks, Double-Stranded ; DNA, Neoplasm/analysis ; Hodgkin Disease/*pathology ; Humans ; Imaging, Three-Dimensional ; Lymph Nodes/*pathology ; Multiprotein Complexes ; Neoplasm Proteins/analysis ; Reed-Sternberg Cells/*ultrastructure ; Shelterin Complex ; Spindle Apparatus/ultrastructure ; Telomere/*ultrastructure ; Telomere-Binding Proteins/analysis ; },
abstract = {To get an insight into the transition from mononuclear Hodgkin cells (H cells) to diagnostic multinuclear Reed-Sternberg cells (RS cells), we performed an analysis of the three-dimensional (3D) structure of the telomeres in the nuclei of the Hodgkin cell lines HDLM-2, L-428, L-1236 and lymph node biopsies of patients with Hodgkin's disease. Cellular localization of key proteins of the telomere-localized shelterin complex, the mitotic spindle and double-stranded DNA breaks was also analyzed. RS cells show significantly shorter and significantly fewer telomeres in relation to the total nuclear volume when compared with H cells; in particular, telomere-poor 'ghost' nuclei are often adjacent to one or two nuclei displaying huge telomeric aggregates. Shelterin proteins are mainly cytoplasmic in both H and RS cells, whereas double-stranded DNA breaks accumulate in the nuclei of RS cells. In RS cells, multipolar spindles prevent proper chromosome segregation. In conclusion, a process of nuclear disorganization seems to initiate in H cells and further progresses when the cells turn into RS cells and become end-stage tumor cells, unable to divide further because of telomere loss, shortening and aggregate formation, extensive DNA damage and aberrant mitotic spindles that may no longer sustain chromosome segregation. Our findings allow a mechanistic 3D understanding of the transition of H to RS cells.},
}
@article {pmid19036115,
year = {2009},
author = {Kirwan, M and Beswick, R and Vulliamy, T and Nathwani, AC and Walne, AJ and Casimir, C and Dokal, I},
title = {Exogenous TERC alone can enhance proliferative potential, telomerase activity and telomere length in lymphocytes from dyskeratosis congenita patients.},
journal = {British journal of haematology},
volume = {144},
number = {5},
pages = {771-781},
doi = {10.1111/j.1365-2141.2008.07516.x},
pmid = {19036115},
issn = {1365-2141},
support = {G0400534/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; },
mesh = {Adult ; B-Lymphocytes/enzymology/pathology ; Cell Line ; Cell Proliferation ; Cells, Cultured ; Dyskeratosis Congenita/immunology/pathology/*therapy ; Enzyme Activation ; Female ; Gene Expression ; Genetic Therapy/*methods ; Genetic Vectors/administration &amp; dosage ; Humans ; Lentivirus/genetics ; Male ; RNA/*administration &amp; dosage/genetics ; T-Lymphocytes/enzymology/pathology ; Telomerase/*administration &amp; dosage/genetics/metabolism ; Telomere/ultrastructure ; Transduction, Genetic/methods ; Young Adult ; },
abstract = {Dyskeratosis congenita (DC) is an inherited multi-system disorder characterised by muco-cutaneous abnormalities, bone marrow failure and a predisposition to malignancy. Bone marrow failure is the principal cause of mortality and is thought to be the result of premature cell death in the haematopoietic compartment because DC cells age prematurely and tend to have short telomeres. DC is genetically heterogeneous and patients have mutations in genes that encode components of the telomerase complex (DKC1, TERC, TERT, NOP10 and NHP2), and telomere shelterin complex (TINF2), both important in telomere maintenance. Here, we transduced primary T lymphocytes and B lymphocyte lines established from patients with TERC and DKC1 mutations with wild type TERC-bearing lentiviral vectors. We found that transduction with exogenous TERC alone was capable of increasing telomerase activity in mutant T lymphocytes and B lymphocyte lines and improved the survival and thus overall growth of B-lymphocyte lines over a prolonged period, regardless of their disease mutation. Telomeres in TERC-treated lines were longer than in the untreated cultures. This is the first study of its kind in DC lymphocytes and the first to demonstrate that transduction with TERC alone can improve cell survival and telomere length without the need for exogenous TERT.},
}
@article {pmid19035186,
year = {2008},
author = {Zhong, YC and Luo, PL and Jin, GE and Yang, HL and Han, SF and Ge, RL},
title = {[The dynamic changing profiles of peripheral white blood cell telomere length in populations of different ages living at different altitude areas].},
journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]},
volume = {42},
number = {7},
pages = {502-505},
pmid = {19035186},
issn = {0253-9624},
mesh = {Adult ; Age Factors ; Aged ; Altitude ; Blood Cells ; DNA/*genetics ; Female ; Humans ; *Leukocytes ; Male ; Malondialdehyde ; Middle Aged ; Repetitive Sequences, Nucleic Acid ; Superoxide Dismutase ; Telomere/*genetics ; },
abstract = {OBJECTIVE: To investigate the relationship between the length of telomere DNA and age at different altitude areas.<br><br>METHODS: All 172 peripheral blood samples were randomly selected from healthy individuals of different ages from 25 to 65 years old. High altitude group (47 males, 48 females) living at an altitude of 4380 m (HA group), sea level group (39 males, 38 females) living at an altitude of 43 m (SL group). The terminal restriction fragment (TRF) length of telomere DNA was measured by Southern blotting analysis. The plasma levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were assayed.<br><br>RESULTS: Average TRF lengths of males and females in HA groups were 10.45 +/- 1.35 and 10.50 +/- 1.45. Average TRF lengths of males and females in SL groups were 11.29 +/- 1.10 and 11.31 +/- 1.13. A negative correlation was shown between the average TRF length and age of males in two groups (P < 0.01). This was also the case for females. ANOVA test was used to analyze the difference between TRF length and gender at different ages (P < 0.001). It was shown that there was significant difference in TRF length between the male (25 years old and 55 years old) and female (25 years old and 55 years old) in two groups at different ages (P < 0.05). The plasma levels of SOD and MDA were significant different between HA groups and SL groups (25-44 years old groups/45-65 years old groups) (P < 0.05).<br><br>CONCLUSION: Obviously shortening of telomere was observed by increasing of ages in high altitude groups. There was a negative correlation between the length of telomere DNA and ages. Telomere shortening became more obviously in high altitude group than in sea level group in keeping with the age increases.},
}
@article {pmid19034420,
year = {2009},
author = {Cross, JA and Brennan, C and Gray, T and Temple, RC and Dozio, N and Hughes, JC and Levell, NJ and Murphy, H and Fowler, D and Hughes, DA and Sampson, MJ},
title = {Absence of telomere shortening and oxidative DNA damage in the young adult offspring of women with pre-gestational type 1 diabetes.},
journal = {Diabetologia},
volume = {52},
number = {2},
pages = {226-234},
pmid = {19034420},
issn = {1432-0428},
support = {//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Adolescent ; Biopsy ; *DNA Damage ; Diabetes Mellitus, Type 1/*genetics ; Female ; Fibroblasts/cytology/physiology ; Humans ; Mothers ; Patient Selection ; Pregnancy ; Skin Physiological Phenomena ; Telomere/*genetics ; Young Adult ; },
abstract = {AIMS/HYPOTHESIS: The offspring of mothers with pre-gestational type 1 diabetes (PGDM) may be at increased risk of glucose intolerance and cardiovascular disease in childhood. The underlying causes of these observations, and whether they persist into adulthood, are unknown. The aim of the present study was to test the hypothesis that fetal chromosomal telomere oxidative DNA damage resulting from maternal PGDM programmes the offspring towards a senescent phenotype that is detectable in young adulthood.<br><br>METHODS: We studied 21 young adult offspring (age 16-23 years) with a maternal history of PGDM and 23 age- and weight-matched controls with no maternal history of diabetes. All participants underwent anthropometric assessments, a standard 75 g OGTT, measurement of peripheral blood mononuclear cell and skin fibroblast telomere length, fibroblast senescence, cell DNA damage (by determination of 8-oxoguanine levels using flow cytometry), plasma lipoprotein profiles (determined by nuclear magnetic resonance) and plasma levels of soluble adhesion molecules and inflammatory markers.<br><br>RESULTS: The groups did not differ significantly with respect to anthropometric measures, glucose tolerance, fasting and 2 h plasma insulin levels during OGTT, estimated peripheral insulin resistance, peripheral blood mononuclear cell or fibroblast telomere length, DNA damage or senescence in vitro, plasma NMR lipoprotein profiles or levels of high-sensitivity C-reactive protein. Plasma concentrations of soluble intercellular adhesion molecule 1 (sICAM-1; p < 0.05) and IL-6 (p = 0.08) were higher in the PGDM offspring.<br><br>CONCLUSIONS/INTERPRETATION: Young adult offspring of mothers with PGDM do not differ in terms of glucose tolerance, DNA damage or telomere length from controls of the same weight and BMI. This does not preclude such abnormalities at an earlier age, but there is no evidence of telomere damage as a pre-programming mechanism in the young adults enrolled in this study.},
}
@article {pmid19031724,
year = {2008},
author = {Ning, XY and Fang, DC},
title = {[Telomeres and Shelterin complex: an update].},
journal = {Zhonghua bing li xue za zhi = Chinese journal of pathology},
volume = {37},
number = {6},
pages = {410-412},
pmid = {19031724},
issn = {0529-5807},
mesh = {Humans ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
}
@article {pmid19029249,
year = {2009},
author = {Bechard, LH and Butuner, BD and Peterson, GJ and McRae, W and Topcu, Z and McEachern, MJ},
title = {Mutant telomeric repeats in yeast can disrupt the negative regulation of recombination-mediated telomere maintenance and create an alternative lengthening of telomeres-like phenotype.},
journal = {Molecular and cellular biology},
volume = {29},
number = {3},
pages = {626-639},
pmid = {19029249},
issn = {1098-5549},
support = {R01 GM061645/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; DNA, Fungal/metabolism ; Gene Deletion ; Humans ; Kluyveromyces/*genetics ; Microbial Viability ; Molecular Sequence Data ; Mutation/*genetics ; Phenotype ; Recombination, Genetic/*genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; Telomerase/metabolism ; Telomere/*genetics ; },
abstract = {Some human cancers maintain telomeres using alternative lengthening of telomeres (ALT), a process thought to be due to recombination. In Kluyveromyces lactis mutants lacking telomerase, recombinational telomere elongation (RTE) is induced at short telomeres but is suppressed once telomeres are moderately elongated by RTE. Recent work has shown that certain telomere capping defects can trigger a different type of RTE that results in much more extensive telomere elongation that is reminiscent of human ALT cells. In this study, we generated telomeres composed of either of two types of mutant telomeric repeats, Acc and SnaB, that each alter the binding site for the telomeric protein Rap1. We show here that arrays of both types of mutant repeats present basally on a telomere were defective in negatively regulating telomere length in the presence of telomerase. Similarly, when each type of mutant repeat was spread to all chromosome ends in cells lacking telomerase, they led to the formation of telomeres produced by RTE that were much longer than those seen in cells with only wild-type telomeric repeats. The Acc repeats produced the more severe defect in both types of telomere maintenance, consistent with their more severe Rap1 binding defect. Curiously, although telomerase deletion mutants with telomeres composed of Acc repeats invariably showed extreme telomere elongation, they often also initially showed persistent very short telomeres with few or no Acc repeats. We suggest that these result from futile cycles of recombinational elongation and truncation of the Acc repeats from the telomeres. The presence of extensive 3' overhangs at mutant telomeres suggests that Rap1 may normally be involved in controlling 5' end degradation.},
}
@article {pmid19028761,
year = {2009},
author = {Mukherjee, M and Brouilette, S and Stevens, S and Shetty, KR and Samani, NJ},
title = {Association of shorter telomeres with coronary artery disease in Indian subjects.},
journal = {Heart (British Cardiac Society)},
volume = {95},
number = {8},
pages = {669-673},
doi = {10.1136/hrt.2008.150250},
pmid = {19028761},
issn = {1468-201X},
support = {//British Heart Foundation/United Kingdom ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Asian People/genetics ; Case-Control Studies ; Coronary Artery Disease/ethnology/*genetics ; Genetic Predisposition to Disease ; Humans ; India/epidemiology ; Leukocytes/ultrastructure ; Middle Aged ; Polymerase Chain Reaction ; Telomere/*ultrastructure ; },
abstract = {OBJECTIVE: Studies in white people have shown that telomere length, a marker of biological ageing, is shorter in individuals with coronary artery disease (CAD). South Asian Indians have a high prevalence of CAD, especially premature CAD. We examined the association of telomere length with CAD in Indian subjects.<br><br>DESIGN: Case-control study.<br><br>SETTING: Mumbai, India.<br><br>SUBJECTS: 238 consecutive patients (aged 29-82 years), admitted to Cumballa Hill Hospital for coronary investigations or treatment and 238 control subjects (aged 30-87 years) from the same area without any clinical evidence of CAD.<br><br>METHODS: Mean leucocyte telomere length was measured using a polymerase chain reaction (PCR)-based assay and expressed as a ratio (T/S ratio) of the telomere signal to that of a control single copy gene.<br><br>RESULTS: T/S ratio was significantly lower in CAD cases compared with controls (cases 1.21 (95% CI 1.16 to 1.26); controls 1.33 (1.28 to 1.38); p = 0.0003), equivalent to approximately 166 base pairs. The difference remained significant after adjustment for other clinical characteristics (p = 0.002). There were trends towards longer telomeres in vegetarian subjects compared with subjects on a mixed diet (vegetarians 1.31 (1.25 to 1.38); mixed 1.25 (1.18 to 1.33); p = 0.088) and shorter telomeres in subjects with a positive family history (FH) for CAD (+ve FH 1.25 (1.18 to 1.32); -ve FH 1.31 (1.24 to 1.38); p = 0.094).<br><br>CONCLUSION: Subjects of Indian ethnicity with CAD have shorter telomeres than subjects without such a history. The finding provides further evidence that telomere biology is altered in subjects with CAD.},
}
@article {pmid19026778,
year = {2008},
author = {Luke, B and Panza, A and Redon, S and Iglesias, N and Li, Z and Lingner, J},
title = {The Rat1p 5' to 3' exonuclease degrades telomeric repeat-containing RNA and promotes telomere elongation in Saccharomyces cerevisiae.},
journal = {Molecular cell},
volume = {32},
number = {4},
pages = {465-477},
doi = {10.1016/j.molcel.2008.10.019},
pmid = {19026778},
issn = {1097-4164},
mesh = {Exonucleases/genetics/*metabolism ; Exoribonucleases/genetics/*metabolism ; Models, Biological ; RNA/*genetics/metabolism ; RNA, Fungal/genetics ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/*metabolism ; },
abstract = {Vertebrate telomeres are transcribed into telomeric repeat-containing RNA (TERRA) that associates with telomeres and may be important for telomere function. Here, we demonstrate that telomeres are also transcribed in Saccharomyces cerevisiae by RNA polymerase II (RNAPII). Yeast TERRA is polyadenylated and stabilized by Pap1p and regulated by the 5' to 3' exonuclease, Rat1p. rat1-1 mutant cells accumulate TERRA and harbor short telomeres because of defects in telomerase-mediated telomere elongation. Overexpression of RNaseH overcomes telomere elongation defects in rat1-1 cells, indicating that RNA/DNA hybrids inhibit telomerase function at chromosome ends in these mutants. Thus, telomeric transcription combined with Rat1p-dependent TERRA degradation is important for regulating telomerase in yeast. Telomere transcription is conserved in different kingdoms of the eukaryotic domain.},
}
@article {pmid19023402,
year = {2008},
author = {Yang, Y and Sterling, J and Storici, F and Resnick, MA and Gordenin, DA},
title = {Hypermutability of damaged single-strand DNA formed at double-strand breaks and uncapped telomeres in yeast Saccharomyces cerevisiae.},
journal = {PLoS genetics},
volume = {4},
number = {11},
pages = {e1000264},
pmid = {19023402},
issn = {1553-7404},
support = {Z01 ES065073/ImNIH/Intramural NIH HHS/United States ; 1 Z01ES065073/ES/NIEHS NIH HHS/United States ; },
mesh = {*DNA Breaks, Double-Stranded/radiation effects ; DNA Repair ; DNA, Fungal/genetics ; DNA, Single-Stranded/*chemistry ; Genome, Fungal ; Models, Genetic ; Mutagenesis ; *Mutation ; Saccharomyces cerevisiae/*genetics/metabolism ; Telomere/*metabolism ; Ultraviolet Rays/adverse effects ; },
abstract = {The major DNA repair pathways operate on damage in double-strand DNA because they use the intact strand as a template after damage removal. Therefore, lesions in transient single-strand stretches of chromosomal DNA are expected to be especially threatening to genome stability. To test this hypothesis, we designed systems in budding yeast that could generate many kilobases of persistent single-strand DNA next to double-strand breaks or uncapped telomeres. The systems allowed controlled restoration to the double-strand state after applying DNA damage. We found that lesions induced by UV-light and methyl methanesulfonate can be tolerated in long single-strand regions and are hypermutagenic. The hypermutability required PCNA monoubiquitination and was largely attributable to translesion synthesis by the error-prone DNA polymerase zeta. In support of multiple lesions in single-strand DNA being a source of hypermutability, analysis of the UV-induced mutants revealed strong strand-specific bias and unexpectedly high frequency of alleles with widely separated multiple mutations scattered over several kilobases. Hypermutability and multiple mutations associated with lesions in transient stretches of long single-strand DNA may be a source of carcinogenesis and provide selective advantage in adaptive evolution.},
}
@article {pmid19015539,
year = {2009},
author = {Carneiro, M and Ferrand, N and Nachman, MW},
title = {Recombination and speciation: loci near centromeres are more differentiated than loci near telomeres between subspecies of the European rabbit (Oryctolagus cuniculus).},
journal = {Genetics},
volume = {181},
number = {2},
pages = {593-606},
pmid = {19015539},
issn = {0016-6731},
mesh = {Animals ; Animals, Wild/genetics ; Biological Evolution ; Centromere/genetics ; Gene Flow ; Genetic Speciation ; Genetics, Population ; Haplotypes ; Linkage Disequilibrium ; Models, Genetic ; Polymorphism, Genetic ; Portugal ; Rabbits/*classification/*genetics ; Recombination, Genetic ; Spain ; Telomere/genetics ; },
abstract = {Recent empirical and theoretical studies suggest that regions of restricted recombination play an important role in the formation of new species. To test this idea, we studied nucleotide variation in two parapatric subspecies of the European rabbit (Oryctolagus cuniculus). We surveyed five loci near centromeres, where recombination is expected to be suppressed, and five loci near telomeres, where recombination is expected to be higher. We analyzed this multilocus data set using a divergence-with-gene flow framework and we report three main findings. First, we estimated that these subspecies diverged approximately 1.8 MYA and maintained large effective population sizes (O. c. algirus N(e) approximately 1,600,000 and O. c. cuniculus N(e) approximately 780,000). Second, we rejected a strict allopatric model of divergence without gene flow; instead, high rates of gene flow were inferred in both directions. Third, we found different patterns between loci near centromeres and loci near telomeres. Loci near centromeres exhibited higher levels of linkage disequilibrium than loci near telomeres. In addition, while all loci near telomeres showed little differentiation between subspecies, three of five loci near centromeres showed strong differentiation. These results support a view of speciation in which regions of low recombination can facilitate species divergence in the presence of gene flow.},
}
@article {pmid19014413,
year = {2008},
author = {Wang, X and Kam, Z and Carlton, PM and Xu, L and Sedat, JW and Blackburn, EH},
title = {Rapid telomere motions in live human cells analyzed by highly time-resolved microscopy.},
journal = {Epigenetics &amp; chromatin},
volume = {1},
number = {1},
pages = {4},
pmid = {19014413},
issn = {1756-8935},
support = {R01 CA096840/CA/NCI NIH HHS/United States ; R01 GM025101/GM/NIGMS NIH HHS/United States ; },
abstract = {BACKGROUND: Telomeres cap chromosome ends and protect the genome. We studied individual telomeres in live human cancer cells. In capturing telomere motions using quantitative imaging to acquire complete high-resolution three-dimensional datasets every second for 200 seconds, telomere dynamics were systematically analyzed.<br><br>RESULTS: The motility of individual telomeres within the same cancer cell nucleus was widely heterogeneous. One class of internal heterochromatic regions of chromosomes analyzed moved more uniformly and showed less motion and heterogeneity than telomeres. The single telomere analyses in cancer cells revealed that shorter telomeres showed more motion, and the more rapid telomere motions were energy dependent. Experimentally increasing bulk telomere length dampened telomere motion. In contrast, telomere uncapping, but not a DNA damaging agent, methyl methanesulfonate, significantly increased telomere motion.<br><br>CONCLUSION: New methods for seconds-scale, four-dimensional, live cell microscopic imaging and data analysis, allowing systematic tracking of individual telomeres in live cells, have defined a previously undescribed form of telomere behavior in human cells, in which the degree of telomere motion was dependent upon telomere length and functionality.},
}
@article {pmid19010887,
year = {2008},
author = {Cassar, L and Li, H and Pinto, AR and Nicholls, C and Bayne, S and Liu, JP},
title = {Bone morphogenetic protein-7 inhibits telomerase activity, telomere maintenance, and cervical tumor growth.},
journal = {Cancer research},
volume = {68},
number = {22},
pages = {9157-9166},
doi = {10.1158/0008-5472.CAN-08-1323},
pmid = {19010887},
issn = {1538-7445},
mesh = {Animals ; Apoptosis/drug effects ; Bone Morphogenetic Protein 7/*pharmacology ; Dose-Response Relationship, Drug ; Female ; HeLa Cells ; Humans ; Mice ; Mice, Inbred BALB C ; Neoplasm Transplantation ; Telomerase/*antagonists &amp; inhibitors/genetics ; Telomere/*drug effects ; Transplantation, Heterologous ; Uterine Cervical Neoplasms/*drug therapy/genetics/pathology ; },
abstract = {Telomere maintenance is critical in tumor cell immortalization. Here, we report that the cytokine bone morphogenetic protein-7 (BMP7) inhibits telomerase activity that is required for telomere maintenance in cervical cancer cells. Application of human recombinant BMP7 triggers a repression of the human telomerase reverse transcriptase (hTERT) gene, shortening of telomeres, and hTERT repression-dependent cervical cancer cell death. Continuous treatment of mouse xenograft tumors with BMP7, or silencing the hTERT gene, results in sustained inhibition of telomerase activity, shortening of telomeres, and tumor growth arrest. Overexpression of hTERT lengthens telomeres and blocks BMP7-induced tumor growth arrest. Thus, BMP7 negatively regulates telomere maintenance, inducing cervical tumor growth arrest by a mechanism of inducing hTERT gene repression.},
}
@article {pmid19007917,
year = {2009},
author = {di Domenico, EG and Auriche, C and Viscardi, V and Longhese, MP and Gilson, E and Ascenzioni, F},
title = {The Mec1p and Tel1p checkpoint kinases allow humanized yeast to tolerate chronic telomere dysfunctions by suppressing telomere fusions.},
journal = {DNA repair},
volume = {8},
number = {2},
pages = {209-218},
doi = {10.1016/j.dnarep.2008.10.005},
pmid = {19007917},
issn = {1568-7864},
mesh = {Base Sequence ; Chromosomes, Fungal/metabolism ; DNA Damage ; DNA-Binding Proteins ; Genomic Instability ; Humans ; Intracellular Signaling Peptides and Proteins/*metabolism ; Microbial Viability ; Protein Serine-Threonine Kinases/*metabolism ; Saccharomyces cerevisiae/cytology/*enzymology ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomere/*enzymology/*pathology ; },
abstract = {In this work we report that budding yeasts carrying human-type telomeric repeats at their chromosome termini show a chronic activation of the Rad53-dependent DNA damage checkpoint pathway and a G2/M cell cycle delay. Furthermore, in the absence of either TEL1/ATM or MEC1/ATR genes, which encodes phosphatidylinositol 3-kinase-related kinases (PIKKs), we detected telomere fusions, whose appearance correlates with a reduced cell viability and a high rate of genome instability. Based on sequence analysis, telomere fusions occurred primarily between ultrashort telomeres. Microcolony formation assays argue against the possibility that fusion-containing cells are eliminated by PIKK-dependent signalling. These findings reveal that humanized telomeres in yeast cells are sensed as a chronically damaged DNA but do not greatly impair cell viability as long as the cells have a functional DNA damage checkpoint.},
}
@article {pmid19005480,
year = {2009},
author = {Bernard, L and Belisle, C and Mollica, L and Provost, S and Roy, DC and Gilliland, DG and Levine, RL and Busque, L},
title = {Telomere length is severely and similarly reduced in JAK2V617F-positive and -negative myeloproliferative neoplasms.},
journal = {Leukemia},
volume = {23},
number = {2},
pages = {287-291},
pmid = {19005480},
issn = {1476-5551},
support = {K08 HL082677/HL/NHLBI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Case-Control Studies ; Cell Proliferation ; Disease Progression ; Genomic Instability ; Genotype ; Humans ; Janus Kinase 2/*genetics ; *Mutation, Missense ; Myeloproliferative Disorders/*genetics/*pathology ; Polymerase Chain Reaction ; Telomere/*pathology ; },
abstract = {Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by chronic proliferation of hematopoietic progenitors. We studied the telomere length (TL) of 335 MPN patients and 93 gender- and age-matched controls using a quantitative PCR method (relative TL calculated as the ratio of the amount of telomere DNA vs single-copy DNA: T/S ratio). TL was markedly reduced in MPN patients compared with controls (T/S 0.561 vs 0.990, P<0.001). In JAK2V617F MPN patients, TL correlated inversely with allelic burden (P<0.001). Patients homozygous for the mutation (allelic burden 90-100%) had the shortest TL, even when compared with patients with lower allele burdens consistent with a dominant heterozygous population (allelic burden 55-65%) (T/S 0.367 vs 0.497, P=0.037). This suggests that the high degree of proliferation of the MPN clone reduces TL and suggests the possibility that TL shortening may be indicative of progressive genomic instability during MPN progression. The TL of JAK2V617F-negative MPN patients was similar to JAK2V617F-positive counterparts (T/S 0.527 vs 0.507, P=0.603), suggesting that the yet-to-be-discovered causative mutation(s) impact the mutated stem cell similarly to JAK2V617F, and that TL measurement may prove useful in the diagnostic workup of JAK2V617F-negative MPN.},
}
@article {pmid19003960,
year = {2009},
author = {Longe, HO and Romesser, PB and Rankin, AM and Faller, DV and Eller, MS and Gilchrest, BA and Denis, GV},
title = {Telomere homolog oligonucleotides induce apoptosis in malignant but not in normal lymphoid cells: mechanism and therapeutic potential.},
journal = {International journal of cancer},
volume = {124},
number = {2},
pages = {473-482},
pmid = {19003960},
issn = {1097-0215},
support = {T32HL007501/HL/NHLBI NIH HHS/United States ; R03 CA128006/CA/NCI NIH HHS/United States ; R03 CA102889/CA/NCI NIH HHS/United States ; R03 CA102889-02/CA/NCI NIH HHS/United States ; R03 CA128006-01/CA/NCI NIH HHS/United States ; T32 HL007501-20/HL/NHLBI NIH HHS/United States ; CA84193/CA/NCI NIH HHS/United States ; T32 HL007501/HL/NHLBI NIH HHS/United States ; T32 HL007501-21/HL/NHLBI NIH HHS/United States ; CA75107/CA/NCI NIH HHS/United States ; R03 CA128006-02/CA/NCI NIH HHS/United States ; CA102889/CA/NCI NIH HHS/United States ; R01 CA084193/CA/NCI NIH HHS/United States ; R29 CA075107/CA/NCI NIH HHS/United States ; R03 CA102889-01A1/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; *Apoptosis ; Caspase 3/metabolism ; Cell Line, Tumor ; Female ; Humans ; Lymphocytes/*metabolism/pathology ; Lymphoma/*metabolism/pathology ; Maximum Tolerated Dose ; Mice ; Oligonucleotides/*chemistry ; Phosphorylation ; Telomere/*ultrastructure ; },
abstract = {Human B- or T-cell lymphoma lines and primary murine lymphomas were treated with DNA oligonucleotides homologous to the telomere (TTAGGG repeat; "T-oligo"), either alone or in combination with standard, widely-used anticancer chemotherapeutic agents. T-oligo induces cell cycle arrest and apoptosis in cultured human or murine B or T-lymphoma cell lines and primary tumor cells, but exerts no detectable toxicity on normal human or murine primary lymphocytes. Exposure to T-oligo is hypothesized to mimic exposure of the 3' telomere repeat sequence, activating the ataxia telangiectasia mutated kinase, which phosphorylates downstream effectors such as p53, but effects are not dependent solely on functional p53. T-oligo causes early S-phase arrest and cooperates well with G(2)- or M-phase-specific anticancer agents; when combined at 1/10th of the conventional dose, vincristine and T-oligo produce greater-than-additive killing of human or murine lymphoma cells (78% of cells undergoing apoptosis after 6 hr vs. 5% of control cells). In mice, 1/10th of the conventional dose of a standard combination of cyclophosphamide, adriamycin, vincristine and prednisone is twice as effective when used in combination with low dose T-oligo. Thus, T-oligo sensitizes tumors to traditional anticancer agents and represents a potentially important new addition to the therapeutic arsenal for aggressive lymphomas.},
}
@article {pmid19003238,
year = {2004},
author = {Broccoli, D},
title = {Function, replication and structure of the mammalian telomere.},
journal = {Cytotechnology},
volume = {45},
number = {1-2},
pages = {3-12},
pmid = {19003238},
issn = {0920-9069},
abstract = {Telomeres are specialized structures at the ends of linear chromosomes that were originally defined functionally based on observations first by Muller (1938) and subsequently by McClintock (1941) that naturally occurring chromosome ends do not behave as double-stranded DNA breaks, in spite of the fact that they are the physical end of a linear, duplex DNA molecule. Double-stranded DNA breaks are highly unstable entities, being susceptible to nucleolytic attack and giving rise to chromosome rearrangements through end-to-end fusions and recombination events. In contrast, telomeres confer stability upon chromosome termini, as evidenced by the fact that chromosomes are extraordinarily stable through multiple cell divisions and even across evolutionary time. This protective function of telomeres is due to the formation of a nucleoprotein complex that sequesters the end of the DNA molecule, rendering it inaccessible to nucleases and recombinases as well as preventing the telomere from activating the DNA damage checkpoint pathways. The capacity of a functional end-protective complex to form is dependent upon maintenance of sufficient telomeric DNA. We have learned a great deal about telomere structure and how this specialized nucleoprotein complex confers stability on chromosome ends since the original observations that defined telomeres were made. This review summarizes our current understanding of mammalian telomere replication, structure and function.},
}
@article {pmid19003141,
year = {1999},
author = {Mizuarai, S and Nishijima, K and Iijima, S},
title = {Amplification of competitive telomere sequence in living animal cells induces chromatin instability.},
journal = {Cytotechnology},
volume = {31},
number = {1-2},
pages = {195-203},
pmid = {19003141},
issn = {0920-9069},
abstract = {We have reported the establishment of new episomal-type expression vector the copy number of which can be readily regulated by a temperature shift. In this study, we attempt to apply this vector for the functional analysis of the noncoding regions of DNA. A plasmid containing a 0.45 kb-telomere repeat sequence was constructed and transfected into simian CV-1 cells, leading to successful establishment of cell lines in which episomal telomere sequence could be amplified by temperature shift. When the episomal telomere sequence was amplified, the cells stopped proliferating at the G(2)/M phase of the cell cycle and exhibited a large size with flattened morphology and several small nucleus-like particles. These cells expressed Cdk inhibitor p21 and beta-galactosidase, which are expressed in some senescent cells. Microscopic analysis revealed frequent end-to-end attachments of chromosomes, which resulted in a variety of aberrant chromosome configurations. None of these characteristics was observed in nontransfected and control plasmid-transfected CV-1 cells at any cultivation temperature. These results indicate the usefulness of our vector system in analyzing telomeric DNA.},
}
@article {pmid18997415,
year = {2008},
author = {Suzuki, H and Marushima, K and Ohnishi, Y and Horinouchi, S},
title = {A novel pair of terminal protein and telomere-associated protein for replication of the linear chromosome of Streptomyces griseus IFO13350.},
journal = {Bioscience, biotechnology, and biochemistry},
volume = {72},
number = {11},
pages = {2973-2980},
doi = {10.1271/bbb.80454},
pmid = {18997415},
issn = {1347-6947},
mesh = {Amino Acid Sequence ; Bacterial Proteins/chemistry/*metabolism ; Base Sequence ; Chromosomes, Bacterial/*genetics ; *DNA Replication ; DNA, Single-Stranded/metabolism ; Molecular Sequence Data ; Operon ; Streptomyces griseus/*genetics/*metabolism ; Substrate Specificity ; Telomere/*metabolism ; },
abstract = {The linear chromosome of Streptomyces griseus IFO13350 contains not only atypical telomere sequences but also probable pseudogenes for two typical telomeric proteins. Two identical operons (SGR98t-SGR97t near one telomere and SGR7041t-SGR7042t near the other telomere) in the terminal inverted repeat sequence were predicted to encode a novel pair of telomeric proteins. SGR97t, a 185-amino-acid protein showing only 18% amino acid sequence identity to typical terminal proteins of Streptomyces, was found to be attached to the chromosomal ends, as determined by immunological analysis. On the other hand, electrophoretic mobility shift assays showed that SGR98t, an 837-amino-acid protein having a DnaB-like helicase C-terminal domain, was capable of binding specifically to the single-stranded terminal DNA corresponding to the 3' overhang of the replication intermediate. These results indicate that SGR97t (and SGR7042t) and SGR98t (and SGR7041t) were the functional telomeric proteins in the replication of the linear chromosome of S. griseus IFO13350.},
}
@article {pmid18996878,
year = {2008},
author = {Nettleton, JA and Diez-Roux, A and Jenny, NS and Fitzpatrick, AL and Jacobs, DR},
title = {Dietary patterns, food groups, and telomere length in the Multi-Ethnic Study of Atherosclerosis (MESA).},
journal = {The American journal of clinical nutrition},
volume = {88},
number = {5},
pages = {1405-1412},
pmid = {18996878},
issn = {1938-3207},
support = {N01-HC-95162/HC/NHLBI NIH HHS/United States ; M01 RR000645/RR/NCRR NIH HHS/United States ; M01-RR00645/RR/NCRR NIH HHS/United States ; N01-HC-95163/HC/NHLBI NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; N01-HC-95159/HC/NHLBI NIH HHS/United States ; N01-HC-95165/HC/NHLBI NIH HHS/United States ; N01-HC-95169/HC/NHLBI NIH HHS/United States ; N01-HC-95164/HC/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; N01-HC-95160/HC/NHLBI NIH HHS/United States ; N01-HC-95161/HC/NHLBI NIH HHS/United States ; N01 HC095163/HC/NHLBI NIH HHS/United States ; N01HC95166/HL/NHLBI NIH HHS/United States ; N01-HC-95166/HC/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*physiology ; Atherosclerosis/*epidemiology/*ethnology ; Biomarkers/blood ; Black People ; Cross-Sectional Studies ; *Diet ; Ethnicity ; Feeding Behavior ; Female ; Humans ; Inflammation/metabolism ; Male ; Meat Products/*adverse effects ; Middle Aged ; Racial Groups ; Risk Factors ; Telomere/*physiology ; White People ; },
abstract = {BACKGROUND: Telomere length reflects biological aging and may be influenced by environmental factors, including those that affect inflammatory processes.<br><br>OBJECTIVE: With data from 840 white, black, and Hispanic adults from the Multi-Ethnic Study of Atherosclerosis, we studied cross-sectional associations between telomere length and dietary patterns and foods and beverages that were associated with markers of inflammation.<br><br>DESIGN: Leukocyte telomere length was measured by quantitative polymerase chain reaction. Length was calculated as the amount of telomeric DNA (T) divided by the amount of a single-copy control DNA (S) (T/S ratio). Intake of whole grains, fruit and vegetables, low-fat dairy, nuts or seeds, nonfried fish, coffee, refined grains, fried foods, red meat, processed meat, and sugar-sweetened soda were computed with responses to a 120-item food-frequency questionnaire completed at baseline. Scores on 2 previously defined empirical dietary patterns were also computed for each participant.<br><br>RESULTS: After adjustment for age, other demographics, lifestyle factors, and intakes of other foods or beverages, only processed meat intake was associated with telomere length. For every 1 serving/d greater intake of processed meat, the T/S ratio was 0.07 smaller (beta +/- SE: -0.07 +/- 0.03, P = 0.006). Categorical analysis showed that participants consuming >or=1 serving of processed meat each week had 0.017 smaller T/S ratios than did nonconsumers. Other foods or beverages and the 2 dietary patterns were not associated with telomere length.<br><br>CONCLUSIONS: Processed meat intake showed an expected inverse association with telomere length, but other diet features did not show their expected associations.},
}
@article {pmid18992639,
year = {2008},
author = {Kitay-Cohen, Y and Goldberg-Bittman, L and Hadary, R and Fejgin, MD and Amiel, A},
title = {Telomere length in Hepatitis C.},
journal = {Cancer genetics and cytogenetics},
volume = {187},
number = {1},
pages = {34-38},
doi = {10.1016/j.cancergencyto.2008.08.006},
pmid = {18992639},
issn = {1873-4456},
mesh = {Alanine Transaminase/blood ; Antiviral Agents/therapeutic use ; Aspartate Aminotransferases/blood ; DNA/blood/genetics ; Female ; Hepatitis C, Chronic/drug therapy/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Lymphocytes/pathology ; Male ; Middle Aged ; Reference Values ; Telomere/*genetics ; },
abstract = {Telomeres are nucleoprotein structures located at the termini of chromosomes that protect the chromosomes from fusion and degradation. Hepatocyte cell-cycle turnover may be a primary mechanism of telomere shortening in hepatitis C virus (HCV) infection, inducing fibrosis and cellular senescence. HCV infection has been recognized as potential cause of B-cell lymphoma and hepatocellular carcinoma. The present study sought to assess relative telomere length in leukocytes from patients with chronic HCV infection, patients after eradication of HCV infection (in remission), and healthy controls. A novel method of manual evaluation was applied. Leukocytes derived from 22 patients with chronic HCV infection and age- and sex-matched patients in remission and healthy control subjects were subjected to a fluorescence-in-situ protocol (DAKO) to determine telomere fluorescence intensity and number. The relative, manual, analysis of telomere length was validated against findings on applied spectral imaging (ASI) in a random sample of study and control subjects. Leukocytes from patients with chronic HCV infection had shorter telomeres than leukocytes from patients in remission and healthy controls. On statistical analysis, more cells with low signal intensity on telomere FISH had shorter telomeres whereas more cells with high signal intensity had longer telomeres. The findings were corroborated by the ASI telomere software. Telomere shortening in leukocytes from patients with active HCV infection is probably due to the lower overall telomere level rather than higher cell cycle turnover. Manual evaluation is an accurate and valid method of assessing relative telomere length between patients with chronic HCV infection and healthy subjects.},
}
@article {pmid18989747,
year = {2009},
author = {Holmes, DK and Bellantuono, I and Walkinshaw, SA and Alfirevic, Z and Johnston, TA and Subhedar, NV and Chittick, R and Swindell, R and Wynn, RF},
title = {Telomere length dynamics differ in foetal and early post-natal human leukocytes in a longitudinal study.},
journal = {Biogerontology},
volume = {10},
number = {3},
pages = {279-284},
doi = {10.1007/s10522-008-9194-y},
pmid = {18989747},
issn = {1389-5729},
mesh = {Age Factors ; Cell Proliferation ; Cells, Cultured ; *Cellular Senescence ; Colony-Forming Units Assay ; Fetal Blood/cytology ; Fetal Stem Cells/*metabolism ; Gestational Age ; Hematopoietic Stem Cells/*metabolism ; Humans ; Infant, Newborn ; Infant, Premature ; Leukocytes/*metabolism ; Longitudinal Studies ; Telomere/*metabolism ; },
abstract = {Haemopoietic stem cells (HSC) undergo a process of self renewal to constantly maintain blood cell turnover. However, it has become apparent that adult HSC lose their self-renewal ability with age. Telomere shortening in peripheral blood leukocytes has been seen to occur with age and it has been associated with loss of HSC proliferative capacity and cellular ageing. In contrast foetal HSC are known to have greater proliferative capacity than post-natal stem cells. However it is unknown whether they undergo a similar process of telomere shortening. In this study we show a more accentuated rate of telomere loss in leukocytes from pre term infants compared to human foetuses of comparable age followed longitudinally for 8-12 weeks in a longitudinal study. Our results point to a difference in HSC behaviour between foetal and early postnatal life which is independent of age but may be influenced by events at birth itself.},
}
@article {pmid18986375,
year = {2009},
author = {Martinez, P and Siegl-Cachedenier, I and Flores, JM and Blasco, MA},
title = {MSH2 deficiency abolishes the anticancer and pro-aging activity of short telomeres.},
journal = {Aging cell},
volume = {8},
number = {1},
pages = {2-17},
doi = {10.1111/j.1474-9726.2008.00441.x},
pmid = {18986375},
issn = {1474-9726},
mesh = {Aging/*genetics ; Animals ; Cell Cycle/genetics ; Chromosomal Instability ; Cyclin-Dependent Kinase Inhibitor p21/biosynthesis/genetics ; Humans ; Intestine, Small/pathology ; Life Expectancy ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Models, Animal ; MutS Homolog 2 Protein/*deficiency ; Neoplasms, Experimental/genetics/metabolism ; Recombination, Genetic ; Telomerase/deficiency ; Telomere/*physiology ; Tumor Suppressor Protein p53/biosynthesis/genetics ; },
abstract = {Mutations in the mismatch repair (MMR) pathway occur in human colorectal cancers with microsatellite instability. Mounting evidence suggests that cell-cycle arrest in response to a number of cellular stresses, including telomere shortening, is a potent anticancer barrier. The telomerase-deficient mouse model illustrates the anticancer effect of cell-cycle arrest provoked by short telomeres. Here, we describe a role for the MMR protein, MSH2, in signaling cell-cycle arrest in a p21/p53-dependent manner in response to short telomeres in the context of telomerasedeficient mice. In particular, progressively shorter telomeres at successive generations of MSH2(-/-) Terc(-/--) mice did not suppress cancer in these mice, indicating that MSH2 deficiency abolishes the tumor suppressor activity of short telomeres. Interestingly, MSH2 deficiency prevented degenerative pathologies in the gastrointestinal tract of MSH2(-/-) Terc(-/-) mice concomitant with a rescue of proliferative defects. The abolishment of the anticancer and pro-aging effects of short telomeres provoked by MSH2 abrogation was independent of changes in telomere length. These results highlight a role for MSH2 in the organismal response to dysfunctional telomeres, which in turn may be important in the pathobiology of human cancers bearing mutations in the MMR pathway.},
}
@article {pmid18984569,
year = {2009},
author = {Robertson, HM},
title = {Simple telomeres in a simple animal: absence of subtelomeric repeat regions in the placozoan Trichoplax adhaerens.},
journal = {Genetics},
volume = {181},
number = {1},
pages = {323-325},
pmid = {18984569},
issn = {0016-6731},
mesh = {Animals ; Base Sequence ; Genome/genetics ; Models, Genetic ; Molecular Sequence Data ; Placozoa/*genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; Telomere/*genetics ; },
abstract = {Simple telomeres were identified in the genome assembly of the basal placozoan animal Trichoplax adhaerens. They have 1-2 kb of TTAGGG telomeric repeats, which are preceded by a subtelomeric region of 1.5-13 kb. Unlike subtelomeric regions in most animals examined, these subtelomeric regions are unique to each telomere.},
}
@article {pmid18981308,
year = {2008},
author = {Huzen, J and van Veldhuisen, DJ and van der Harst, P},
title = {Letter by Huzen et al regarding article, "Association of leukocyte telomere length with circulating biomarkers of the renin-angiotensin-aldosterone system: the Framingham Heart Study".},
journal = {Circulation},
volume = {118},
number = {19},
pages = {e688; author reply e689},
doi = {10.1161/CIRCULATIONAHA.108.775510},
pmid = {18981308},
issn = {1524-4539},
mesh = {Biomarkers/blood ; Humans ; Hypertension/*metabolism ; Leukocytes/*metabolism ; Renin-Angiotensin System/*physiology ; Telomere/*metabolism ; },
}
@article {pmid18977241,
year = {2008},
author = {Starr, JM and Shiels, PG and Harris, SE and Pattie, A and Pearce, MS and Relton, CL and Deary, IJ},
title = {Oxidative stress, telomere length and biomarkers of physical aging in a cohort aged 79 years from the 1932 Scottish Mental Survey.},
journal = {Mechanisms of ageing and development},
volume = {129},
number = {12},
pages = {745-751},
doi = {10.1016/j.mad.2008.09.020},
pmid = {18977241},
issn = {0047-6374},
support = {S18386/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; ETM/55/CSO_/Chief Scientist Office/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; CZB/4/505/CSO_/Chief Scientist Office/United Kingdom ; },
mesh = {Aged ; Aging/*genetics/*physiology ; Cohort Studies ; Female ; Hand Strength/physiology ; Humans ; Male ; Oxidative Stress/*genetics ; Polymorphism, Single Nucleotide ; Respiratory Physiological Phenomena ; Scotland ; Telomere/*genetics ; },
abstract = {Telomere shortening is a biomarker of cellular senescence and is associated with a wide range of age-related disease. Oxidative stress is also associated with physiological aging and several age-related diseases. Non-human studies suggest that variants in oxidative stress genes may contribute to both telomere shortening and biological aging. We sought to test whether oxidative stress-related gene polymorphisms contribute to variance in both telomere length and physical biomarkers of aging in humans. Telomere lengths were calculated for 190 (82 men, 108 women) participants aged 79 years and associations with 384 SNPs, from 141 oxidative stress genes, identified 9 significant SNPS, of which those from 5 genes (GSTZ1, MSRA, NDUFA3, NDUFA8, VIM) had robust associations with physical aging biomarkers, respiratory function or grip strength. Replication of associations in a sample of 318 (120 males, 198 females) participants aged 50 years confirmed significant associations for two of the five SNPs (MSRA rs4841322, p=0.008; NDUFA8 rs6822, p=0.048) on telomere length. These data indicate that oxidative stress genes may be involved in pathways that lead to both telomere shortening and physiological aging in humans. Oxidative stress may explain, at least in part, associations between telomere shortening and physiological aging.},
}
@article {pmid18975896,
year = {2008},
author = {Rodriguez, R and Müller, S and Yeoman, JA and Trentesaux, C and Riou, JF and Balasubramanian, S},
title = {A novel small molecule that alters shelterin integrity and triggers a DNA-damage response at telomeres.},
journal = {Journal of the American Chemical Society},
volume = {130},
number = {47},
pages = {15758-15759},
pmid = {18975896},
issn = {1520-5126},
support = {A5709/CRUK_/Cancer Research UK/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Cell Line, Tumor ; DNA Damage/*genetics ; Humans ; Molecular Structure ; Shelterin Complex ; Telomere/*chemistry/genetics/*metabolism ; Telomere-Binding Proteins/antagonists &amp; inhibitors/*chemistry/*metabolism ; },
abstract = {We describe a novel synthetic small molecule which shows an unprecedented stabilization of the human telomeric G-quadruplex with high selectivity relative to double-stranded DNA. We report that this compound can be used in vitro to inhibit telomerase activity and to uncap human POT1 (protection of telomeres 1) from the telomeric G-overhang. We also show that the small molecule G-quadruplex binder induces a partial alteration of shelterin through POT1 uncapping from telomeres in human HT1080 cancer cells and the presence of gammaH2AX foci colocalized at telomeres.},
}
@article {pmid18955647,
year = {2008},
author = {Woo, J and Tang, N and Leung, J},
title = {No association between physical activity and telomere length in an elderly Chinese population 65 years and older.},
journal = {Archives of internal medicine},
volume = {168},
number = {19},
pages = {2163-2164},
doi = {10.1001/archinte.168.19.2163},
pmid = {18955647},
issn = {1538-3679},
mesh = {Aged ; Aging/*physiology ; Asian People ; Exercise/*physiology ; Female ; Humans ; Male ; Telomere/*physiology ; },
}
@article {pmid18952756,
year = {2009},
author = {Lee, J and Reddy, R and Barsky, L and Scholes, J and Chen, H and Shi, W and Driscoll, B},
title = {Lung alveolar integrity is compromised by telomere shortening in telomerase-null mice.},
journal = {American journal of physiology. Lung cellular and molecular physiology},
volume = {296},
number = {1},
pages = {L57-70},
pmid = {18952756},
issn = {1040-0605},
support = {2R01-HL-65352-7/HL/NHLBI NIH HHS/United States ; },
mesh = {Actins/metabolism ; Animals ; Biomarkers/metabolism ; Collagen/metabolism ; DNA Damage ; Elastin/metabolism ; Female ; In Situ Nick-End Labeling ; Intercellular Signaling Peptides and Proteins ; JNK Mitogen-Activated Protein Kinases/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Oxidative Stress/physiology ; Peptides/metabolism ; Pulmonary Alveoli/metabolism/*pathology ; Pulmonary Surfactant-Associated Protein C ; RNA/*genetics/metabolism ; Respiratory Mucosa/metabolism/pathology ; Signal Transduction/physiology ; Telomerase/*genetics/metabolism ; Telomere/*genetics/*pathology ; },
abstract = {Shortened telomeres are a normal consequence of cell division. However, telomere shortening past a critical point results in cellular senescence and death. To determine the effect of telomere shortening on lung, four generations of B6.Cg-Terc(tm1Rdp) mice, null for the terc component of telomerase, the holoenzyme that maintains telomeres, were bred and analyzed. Generational inbreeding of terc-/- mice caused sequential shortening of telomeres. Lung histology from the generation with the shortest telomeres (terc-/- F4) showed alveolar wall thinning and increased alveolar size. Morphometric analysis confirmed a significant increase in mean linear intercept (MLI). terc-/- F4 lung showed normal elastin deposition but had significantly decreased collagen content. Both airway and alveolar epithelial type 1 cells (AEC1) appeared normal by immunohistochemistry, and the percentage of alveolar epithelial type 2 cells (AEC2) per total cell number was similar to wild type. However, because of a decrease in distal lung cellularity, the absolute number of AEC2 in terc-/- F4 lung was significantly reduced. In contrast to wild type, terc-/- F4 distal lung epithelium from normoxia-maintained mice exhibited DNA damage by terminal deoxynucleotidyltransferase (TdT)-mediated dUTP nick end labeling (TUNEL) and 8-oxoguanine immunohistochemistry. Western blotting of freshly isolated AEC2 lysates for stress signaling kinases confirmed that the stress-activated protein kinase (SAPK)/c-Jun NH(2)-terminal kinase (JNK) stress response pathway is stimulated in telomerase-null AEC2 even under normoxic conditions. Expression of downstream apoptotic/stress markers, including caspase-3, caspase-6, Bax, and HSP-25, was also observed in telomerase-null, but not wild-type, AEC2. TUNEL analysis of freshly isolated normoxic AEC2 showed that DNA strand breaks, essentially absent in wild-type cells, increased with each successive terc-/- generation and correlated strongly with telomere length (R(2) = 0.9631). Thus lung alveolar integrity, particularly in the distal epithelial compartment, depends on proper telomere maintenance.},
}
@article {pmid18951173,
year = {2008},
author = {Fajkus, J and Dvorácková, M and Sýkorová, E},
title = {Analysis of telomeres and telomerase.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {463},
number = {},
pages = {267-296},
doi = {10.1007/978-1-59745-406-3_17},
pmid = {18951173},
issn = {1940-6029},
mesh = {Cell Cycle ; Cellular Senescence ; Chromosomes/*ultrastructure ; DNA Repair ; DNA Restriction Enzymes/metabolism ; Endodeoxyribonucleases/*metabolism ; *Genetic Techniques ; Humans ; In Situ Hybridization, Fluorescence ; Molecular Weight ; Phenotype ; Polymerase Chain Reaction ; Sepharose/chemistry ; Telomerase/*metabolism ; Telomere/*ultrastructure ; },
abstract = {The terminal chromatin structures at the ends of eukaryotic chromosomes, the telomeres, are a focus of intensive research due to their importance for the maintenance of chromosome integrity. Their shortening due to incomplete replication functions as a molecular clock counting the number of cell divisions, and ultimately results in cell-cycle arrest and cellular senescence. Telomere shortening can be compensated by the nucleoprotein enzyme complex called telomerase, which is able to extend shortened telomeres. In humans, only embryonic and germ cells show telomerase activity that is sufficient for telomere length stability and cellular immortality. Unfortunately, telomerase is activated in cancer cells, which, thus, achieve unlimited growth and a malignant phenotype. Even if there were no any other links of telomere biology to other essential processes in the cell nucleus such as DNA repair, chromosome positioning, and nuclear architecture in mitosis and meiosis, the close connection of telomere biology to aging and cancer makes telomeres and techniques for their analysis important enough from the point of view of us, mortal and disease-prone people. In this chapter, we describe the most common types of analyses used in telomere biology: screening for typical and variant telomeric sequences, determination of telomere lengths, and measurement of telomerase activity.},
}
@article {pmid18949040,
year = {2008},
author = {Chan, A and Boulé, JB and Zakian, VA},
title = {Two pathways recruit telomerase to Saccharomyces cerevisiae telomeres.},
journal = {PLoS genetics},
volume = {4},
number = {10},
pages = {e1000236},
pmid = {18949040},
issn = {1553-7404},
support = {R01 GM043265/GM/NIGMS NIH HHS/United States ; GM43265/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle ; Protein Binding ; RNA/genetics/metabolism ; RNA, Fungal/genetics/metabolism ; Saccharomyces cerevisiae/cytology/*enzymology/genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/*enzymology/genetics ; },
abstract = {The catalytic subunit of yeast telomerase, Est2p, is a telomere associated throughout most of the cell cycle, while the Est1p subunit binds only in late S/G2 phase, the time of telomerase action. Est2p binding in G1/early S phase requires a specific interaction between telomerase RNA (TLC1) and Ku80p. Here, we show that in four telomerase-deficient strains (cdc13-2, est1A, tlc1-SD, and tlc1-BD), Est2p telomere binding was normal in G1/early S phase but reduced to about 40-50% of wild type levels in late S/G2 phase. Est1p telomere association was low in all four strains. Wild type levels of Est2p telomere binding in late S/G2 phase was Est1p-dependent and required that Est1p be both telomere-bound and associated with a stem-bulge region in TLC1 RNA. In three telomerase-deficient strains in which Est1p is not Est2p-associated (tlc1-SD, tlc1-BD, and est2A), Est1p was present at normal levels but its telomere binding was very low. When the G1/early S phase and the late S/G2 phase telomerase recruitment pathways were both disrupted, neither Est2p nor Est1p was telomere-associated. We conclude that reduced levels of Est2p and low Est1p telomere binding in late S/G2 phase correlated with an est phenotype, while a WT level of Est2p binding in G1 was not sufficient to maintain telomeres. In addition, even though Cdc13p and Est1p interact by two hybrid, biochemical and genetic criteria, this interaction did not occur unless Est1p was Est2p-associated, suggesting that Est1p comes to the telomere only as part of the holoenzyme. Finally, the G1 and late S/G2 phase pathways for telomerase recruitment are distinct and are likely the only ones that bring telomerase to telomeres in wild-type cells.},
}
@article {pmid18949037,
year = {2008},
author = {Qi, H and Chen, Y and Fu, X and Lin, CP and Zheng, XF and Liu, LF},
title = {TOR regulates cell death induced by telomere dysfunction in budding yeast.},
journal = {PloS one},
volume = {3},
number = {10},
pages = {e3520},
pmid = {18949037},
issn = {1932-6203},
support = {R01 CA039662/CA/NCI NIH HHS/United States ; R01 CA102463/CA/NCI NIH HHS/United States ; CA102463/CA/NCI NIH HHS/United States ; CA39662/CA/NCI NIH HHS/United States ; },
mesh = {Antioxidants/pharmacology ; Cell Death/drug effects/genetics ; DNA Damage/*genetics/physiology ; G1 Phase/drug effects/genetics ; Membrane Potential, Mitochondrial/drug effects ; Organisms, Genetically Modified ; Protein Binding/drug effects ; Protein Serine-Threonine Kinases/antagonists &amp; inhibitors/genetics/*physiology ; Reactive Oxygen Species/metabolism ; Saccharomyces cerevisiae Proteins/antagonists &amp; inhibitors/genetics/metabolism/*physiology ; Saccharomycetales/genetics/metabolism/*physiology ; Signal Transduction/genetics ; Sirolimus/pharmacology ; Telomerase/genetics/physiology ; Telomere/drug effects/genetics/metabolism/*physiology ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomere dysfunction is known to induce growth arrest (senescence) and cell death. However, the regulation of the senescence-death process is poorly understood. Here using a yeast dysfunctional telomere model cdc13-1, which carries a temperature sensitive-mutant telomere binding protein Cdc13p, we demonstrate that inhibition of TOR (Target of Rapamycin), a central regulator of nutrient pathways for cell growth, prevents cell death, but not growth arrest, induced by inactivation of Cdc13-1p. This function of TOR is novel and separable from its G1 inhibition function, and not associated with alterations in the telomere length, the amount of G-tails, and the telomere position effect (TPE) in cdc13-1 cells. Furthermore, antioxidants were also shown to prevent cell death initiated by inactivation of cdc13-1. Moreover, inhibition of TOR was also shown to prevent cell death induced by inactivation of telomerase in an est1 mutant. Interestingly, rapamycin did not prevent cell death induced by DNA damaging agents such as etoposide and UV. In the aggregate, our results suggest that the TOR signaling pathway is specifically involved in the regulation of cell death initiated by telomere dysfunction.},
}
@article {pmid18948753,
year = {2008},
author = {Small, VY and Chuang, C and Nugent, CI},
title = {Rad24 truncation, coupled with altered telomere structure, promotes cdc13-1 suppression in S. cerevisiae.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {7},
number = {21},
pages = {3428-3439},
doi = {10.4161/cc.7.21.6983},
pmid = {18948753},
issn = {1551-4005},
support = {R01-CA96972/CA/NCI NIH HHS/United States ; },
mesh = {Alleles ; Cell Cycle Proteins/chemistry/*metabolism ; Cell Proliferation ; Crosses, Genetic ; DNA, Single-Stranded/metabolism ; Genes, Suppressor ; Intracellular Signaling Peptides and Proteins/chemistry/*metabolism ; Mutation/*genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Saccharomyces cerevisiae/cytology/*genetics ; Saccharomyces cerevisiae Proteins/*genetics ; *Suppression, Genetic ; Telomere/*chemistry ; Telomere-Binding Proteins/*genetics ; Temperature ; },
abstract = {Distinguishing telomeres from DNA double strand breaks is critical for genome stability. In S. cerevisiae, the Cdc13 single-strand telomere binding protein is critical for protecting chromosome ends. The C-rich telomere strand is lost at high temperatures in cdc13-1 strains, leading to activation of the DNA damage checkpoint and cell inviability. Through a screen performed to identify activities involved in telomere C-strand loss, we identified two new rad24 alleles. Rad24 is an alternate Rfc1 subunit, functioning to load the 9-1-1 checkpoint clamp. In each rad24 allele, a transposon inserted within the RAD24 coding region leads to expression of different carboxyl-terminal portions of Rad24, deleting or truncating the amino-terminus. We show that an intact Rad24 amino-terminus is necessary for its checkpoint function. Interestingly, the initial cdc13-1 rad24-2 strains grew at 36 degrees C, but the extent of suppression associated with rad24-2 weakened in serial backcrosses, and cdc13-1 segregants from these crosses showed a modest increase in temperature resistance. Moreover, while a RAD24 plasmid suppressed the checkpoint defect in the initial cdc13-1 rad24-2 strain, the temperature resistance was only partially suppressed. These data suggest that the TG(1-3) amplification observed in this strain contributes to the suppression phenotype. By recreating the rad24-2 allele in a strain with normal telomeres, we find that, relative to the rad24-delta allele, rad24-2 increases the frequency of obtaining cdc13-1 cells capable of growth at high temperatures. Our hypothesis is that the Rad24-2 truncation protein affects telomere structure or recombination in a manner distinct from rad24-delta.},
}
@article {pmid18948709,
year = {2009},
author = {Alsheimer, M},
title = {The dance floor of meiosis: evolutionary conservation of nuclear envelope attachment and dynamics of meiotic telomeres.},
journal = {Genome dynamics},
volume = {5},
number = {},
pages = {81-93},
doi = {10.1159/000166621},
pmid = {18948709},
issn = {1660-9263},
mesh = {Animals ; *Biological Evolution ; Humans ; *Meiosis ; Meiotic Prophase I ; Nuclear Envelope/*metabolism ; Telomere/*metabolism/ultrastructure ; },
abstract = {Segregation of the homologous chromosomes is the most important feature of meiosis as it ensures the faithful haploidization of the genome. It essentially depends on an accurate prearrangement of chromosomes that culminates in a precise and unambiguous pairing of the homologs, which in turn is a prere - quisite for their correct segregation. Pairing with the right partner is accompanied by, moreover it implicitly requires characteristic chromosomal movements that, remarkably, appear to be driven by the chromosomal ends. In prophase I, telomeres firmly attach to the nuclear envelope and move to congregate in a small cluster, thus trailing homologs into close vicinity, a condition that was suggested to promote homolog recognition and alignment. The evolutionarily highly conserved phenomenon of the telomere driven meiotic chromosome rearrangement is yet known for a long time, but the molecular mechanisms responsible for telomere attachment and their directed movements have remained largely unknown. However, in the recent years significant progress has been made in this issue, which has provided some novel clues about the molecular requirements and function of the characteristic meiotic telomere dynamics.},
}
@article {pmid18945604,
year = {2009},
author = {Houben, JM and Mercken, EM and Ketelslegers, HB and Bast, A and Wouters, EF and Hageman, GJ and Schols, AM},
title = {Telomere shortening in chronic obstructive pulmonary disease.},
journal = {Respiratory medicine},
volume = {103},
number = {2},
pages = {230-236},
doi = {10.1016/j.rmed.2008.09.003},
pmid = {18945604},
issn = {1532-3064},
mesh = {Body Composition/physiology ; Catalase/*metabolism ; Female ; Genotype ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Oxidative Stress/*genetics/physiology ; Polymerase Chain Reaction ; Pulmonary Disease, Chronic Obstructive/*genetics/physiopathology ; Respiratory Function Tests ; Smoking/metabolism ; Superoxide Dismutase/*metabolism ; *Telomere ; },
abstract = {Chronic oxidative stress and systemic inflammation contribute to the pathology of several chronic diseases, one among which is chronic obstructive pulmonary disease (COPD). In addition, increased oxidative stress and inflammation have been observed to be negatively associated with telomere length (TL). Our aim was to investigate the TL in COPD patients in relation to pulmonary and extrapulmonary disease severity. Furthermore, based on experimental evidence suggesting the effects of oxidative stress on telomere shortening, we studied the association of TL with the antioxidant enzyme superoxide dismutase (SOD). One hundred and two COPD patients with moderate to severe COPD were studied and compared with 19 healthy age-matched controls. Patients were characterized by elevated levels of inflammatory markers (CRP, sTNF-receptors) and lower SOD-activity than the controls (p<0.001), irrespective of the SOD genotype. TL was negatively associated with age (p<0.01) and was significantly shorter in COPD patients than controls (p<0.05). Within the patient group age-adjusted TL variability could not be explained by lung function and smoking history but a modest association was found with the percentage of fat mass (p<0.05). These data provide evidence for a relationship between a disturbed oxidant/antioxidant balance and telomere shortening and indicate that preservation of fat mass may be protective in delaying telomere shortening in COPD patients.},
}
@article {pmid18936784,
year = {2008},
author = {Bayne, S and Jones, ME and Li, H and Pinto, AR and Simpson, ER and Liu, JP},
title = {Estrogen deficiency leads to telomerase inhibition, telomere shortening and reduced cell proliferation in the adrenal gland of mice.},
journal = {Cell research},
volume = {18},
number = {11},
pages = {1141-1150},
doi = {10.1038/cr.2008.291},
pmid = {18936784},
issn = {1748-7838},
mesh = {Adrenal Cortex/metabolism ; Adrenal Glands/growth &amp; development/metabolism ; Animals ; *Cell Proliferation ; Cellular Senescence/genetics ; Estrogens/administration &amp; dosage/*deficiency/*metabolism ; Female ; Gene Expression ; Mice ; Mice, Transgenic ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Estrogen deficiency mediates aging, but the underlying mechanism remains to be fully determined. We report here that estrogen deficiency caused by targeted disruption of aromatase in mice results in significant inhibition of telomerase activity in the adrenal gland in vivo. Gene expression analysis showed that, in the absence of estrogen, telomerase reverse transcriptase (TERT) gene expression is reduced in association with compromised cell proliferation in the adrenal gland cortex and adrenal atrophy. Stem cells positive in c-kit are identified to populate in the parenchyma of adrenal cortex. Analysis of telomeres revealed that estrogen deficiency results in significantly shorter telomeres in the adrenal cortex than that in wild-type (WT) control mice. To further establish the causal effects of estrogen, we conducted an estrogen replacement therapy in these estrogen-deficient animals. Administration of estrogen for 3 weeks restores TERT gene expression, telomerase activity and cell proliferation in estrogen-deficient mice. Thus, our data show for the first time that estrogen deficiency causes inhibitions of TERT gene expression, telomerase activity, telomere maintenance, and cell proliferation in the adrenal gland of mice in vivo, suggesting that telomerase inhibition and telomere shortening may mediate cell proliferation arrest in the adrenal gland, thus contributing to estrogen deficiency-induced aging under physiological conditions.},
}
@article {pmid18931659,
year = {2008},
author = {Dimitrova, N and Chen, YC and Spector, DL and de Lange, T},
title = {53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility.},
journal = {Nature},
volume = {456},
number = {7221},
pages = {524-528},
pmid = {18931659},
issn = {1476-4687},
support = {EY18244/EY/NEI NIH HHS/United States ; OD000379/OD/NIH HHS/United States ; R01 GM049046/GM/NIGMS NIH HHS/United States ; DP1 OD000379-04/OD/NIH HHS/United States ; GM42694/GM/NIGMS NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; DP1 OD000379/OD/NIH HHS/United States ; PN2 EY018244/EY/NEI NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; GM049046/GM/NIGMS NIH HHS/United States ; R01 GM042694/GM/NIGMS NIH HHS/United States ; R37 GM049046-16/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; Chromatin/genetics/*metabolism ; Chromosomal Proteins, Non-Histone ; DNA Breaks, Double-Stranded ; *DNA Damage ; *DNA Repair ; DNA-Binding Proteins ; Humans ; Intracellular Signaling Peptides and Proteins/deficiency/genetics/*metabolism ; Mice ; Movement ; Protein Binding ; Sequence Homology ; Signal Transduction ; Telomere/*genetics/*metabolism ; Telomeric Repeat Binding Protein 2/deficiency/genetics/metabolism ; Tumor Suppressor p53-Binding Protein 1 ; },
abstract = {Double-strand breaks activate the ataxia telangiectasia mutated (ATM) kinase, which promotes the accumulation of DNA damage factors in the chromatin surrounding the break. The functional significance of the resulting DNA damage foci is poorly understood. Here we show that 53BP1 (also known as TRP53BP1), a component of DNA damage foci, changes the dynamic behaviour of chromatin to promote DNA repair. We used conditional deletion of the shelterin component TRF2 (also known as TERF2) from mouse cells (TRF2(fl/-)) to deprotect telomeres, which, like double-strand breaks, activate the ATM kinase, accumulate 53BP1 and are processed by non-homologous end joining (NHEJ). Deletion of TRF2 from 53BP1-deficient cells established that NHEJ of dysfunctional telomeres is strongly dependent on the binding of 53BP1 to damaged chromosome ends. To address the mechanism by which 53BP1 promotes NHEJ, we used time-lapse microscopy to measure telomere dynamics before and after their deprotection. Imaging showed that deprotected telomeres are more mobile and sample larger territories within the nucleus. This change in chromatin dynamics was dependent on 53BP1 and ATM but did not require a functional NHEJ pathway. We propose that the binding of 53BP1 near DNA breaks changes the dynamic behaviour of the local chromatin, thereby facilitating NHEJ repair reactions that involve distant sites, including joining of dysfunctional telomeres and AID (also known as AICDA)-induced breaks in immunoglobulin class-switch recombination.},
}
@article {pmid18931339,
year = {2009},
author = {Du, HY and Pumbo, E and Ivanovich, J and An, P and Maziarz, RT and Reiss, UM and Chirnomas, D and Shimamura, A and Vlachos, A and Lipton, JM and Goyal, RK and Goldman, F and Wilson, DB and Mason, PJ and Bessler, M},
title = {TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements.},
journal = {Blood},
volume = {113},
number = {2},
pages = {309-316},
pmid = {18931339},
issn = {1528-0020},
support = {CA105312/CA/NCI NIH HHS/United States ; CA106995/CA/NCI NIH HHS/United States ; R01 CA106995/CA/NCI NIH HHS/United States ; P30 CA091842/CA/NCI NIH HHS/United States ; R01 CA105312/CA/NCI NIH HHS/United States ; CA91842/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Bone Marrow Diseases/*genetics/metabolism/pathology ; Child ; Child, Preschool ; Dyskeratosis Congenita/*genetics/metabolism/pathology ; Female ; Humans ; Infant ; Male ; Middle Aged ; *Mutation ; RNA/*genetics/metabolism ; Telomerase/*genetics/metabolism ; Telomere/*genetics/metabolism/pathology ; Young Adult ; },
abstract = {Dyskeratosis congenita (DC) is a rare inherited form of bone marrow failure (BMF) caused by mutations in telomere maintaining genes including TERC and TERT. Here we studied the prevalence of TERC and TERT gene mutations and of telomere shortening in an unselected population of patients with BMF at our medical center and in a selected group of patients referred from outside institutions. Less than 5% of patients with BMF had pathogenic mutations in TERC or TERT. In patients with BMF, pathogenic TERC or TERT gene mutations were invariably associated with marked telomere shortening (<< 1st percentile) in peripheral blood mononuclear cells (PBMCs). In asymptomatic family members, however, telomere length was not a reliable predictor for the presence or absence of a TERC or TERT gene mutation. Telomere shortening was not pathognomonic of DC, as approximately 30% of patients with BMF due to other causes had PBMC telomere lengths at the 1st percentile or lower. We conclude that in the setting of BMF, measurement of telomere length is a sensitive but nonspecific screening method for DC. In the absence of BMF, telomere length measurements should be interpreted with caution.},
}
@article {pmid18923417,
year = {2008},
author = {Pebernard, S and Schaffer, L and Campbell, D and Head, SR and Boddy, MN},
title = {Localization of Smc5/6 to centromeres and telomeres requires heterochromatin and SUMO, respectively.},
journal = {The EMBO journal},
volume = {27},
number = {22},
pages = {3011-3023},
pmid = {18923417},
issn = {1460-2075},
support = {R01 GM068608-07/GM/NIGMS NIH HHS/United States ; R01 GM068608-08/GM/NIGMS NIH HHS/United States ; R01 GM068608/GM/NIGMS NIH HHS/United States ; GM0680608/GM/NIGMS NIH HHS/United States ; R01 GM068608-06/GM/NIGMS NIH HHS/United States ; },
mesh = {Carrier Proteins/genetics/metabolism ; Cell Cycle Proteins/genetics/*metabolism ; Cell Nucleus/metabolism/ultrastructure ; Centromere/*metabolism ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; DNA Replication ; DNA, Fungal/chemistry/metabolism ; Heterochromatin/*metabolism ; Hydroxyurea/metabolism ; Methyl Methanesulfonate/metabolism ; Mutagens/metabolism ; Nucleic Acid Synthesis Inhibitors/metabolism ; Schizosaccharomyces/cytology/genetics/metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Small Ubiquitin-Related Modifier Proteins/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {The Smc5/6 holocomplex executes key functions in genome maintenance that include ensuring the faithful segregation of chromosomes at mitosis and facilitating critical DNA repair pathways. Smc5/6 is essential for viability and therefore, dissecting its chromosome segregation and DNA repair roles has been challenging. We have identified distinct epigenetic and post-translational modifications that delineate roles for fission yeast Smc5/6 in centromere function, versus replication fork-associated DNA repair. We monitored Smc5/6 subnuclear and genomic localization in response to different replicative stresses, using fluorescence microscopy and chromatin immunoprecipitation (ChIP)-on-chip methods. Following hydroxyurea treatment, and during an unperturbed S phase, Smc5/6 is transiently enriched at the heterochromatic outer repeats of centromeres in an H3-K9 methylation-dependent manner. In contrast, methyl methanesulphonate treatment induces the accumulation of Smc5/6 at subtelomeres, in an Nse2 SUMO ligase-dependent, but H3-K9 methylation-independent manner. Finally, we determine that Smc5/6 loads at all genomic tDNAs, a phenomenon that requires intact consensus TFIIIC-binding sites in the tDNAs.},
}
@article {pmid18923062,
year = {2008},
author = {Kiefer, A and Lin, J and Blackburn, E and Epel, E},
title = {Dietary restraint and telomere length in pre- and postmenopausal women.},
journal = {Psychosomatic medicine},
volume = {70},
number = {8},
pages = {845-849},
pmid = {18923062},
issn = {1534-7796},
support = {T32 MH019391/MH/NIMH NIH HHS/United States ; T32MH019391/MH/NIMH NIH HHS/United States ; K08 MH064110-01A1/MH/NIMH NIH HHS/United States ; K08 MH064110/MH/NIMH NIH HHS/United States ; T32 MH019391-08/MH/NIMH NIH HHS/United States ; K08 MH64110 TO 01A1/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging/*genetics ; Body Mass Index ; *Diet, Reducing ; Female ; Humans ; Hydrocortisone/blood ; Leukocytes/metabolism ; Middle Aged ; Obesity/diet therapy/genetics ; Overweight/diet therapy/genetics ; Postmenopause/*genetics ; Premenopause/*genetics ; Reference Values ; Risk Factors ; Smoking/adverse effects ; Stress, Physiological/genetics ; Stress, Psychological/complications/genetics ; Telomere/*genetics/pathology ; Weight Gain/genetics ; Young Adult ; },
abstract = {BACKGROUND: Leukocyte telomere shortening can serve as a biomarker of aging, as telomere length (TL) can decline with age and shortening is positively associated with morbidity and mortality. It is therefore important to identify psychological and behavioral factors linked to accelerated telomere shortening. Stress and poorer metabolic health (greater adiposity, insulin resistance, and cortisol) correlate with shorter telomeres. Self-reported dietary restraint (DR), defined as chronic preoccupation with weight and attempts at restricting food intake, is linked to greater perceived stress, cortisol, and weight gain, when assessed in community studies (versus in weight loss programs).<br><br>OBJECTIVE: To test for an association between DR and TL in healthy women across a range of ages.<br><br>METHODS: We examined whether DR is linked to TL in two samples, one of premenopausal women (aged 20-50 years;N = 36) and one of postmenopausal women (aged 53-69 years; N = 20).<br><br>RESULTS: In both samples, higher levels of DR were associated with shorter leukocyte TL, independent of body mass index, smoking, and age.<br><br>CONCLUSIONS: Chronic DR, as assessed by self-report (i.e. not caloric restriction), may be a risk factor for premature telomere shortening. Potential mechanisms are discussed.},
}
@article {pmid18922974,
year = {2008},
author = {Possemato, R and Timmons, JC and Bauerlein, EL and Wada, N and Baldwin, A and Masutomi, K and Hahn, WC},
title = {Suppression of hPOT1 in diploid human cells results in an hTERT-dependent alteration of telomere length dynamics.},
journal = {Molecular cancer research : MCR},
volume = {6},
number = {10},
pages = {1582-1593},
pmid = {18922974},
issn = {1541-7786},
support = {R01 AG023145/AG/NIA NIH HHS/United States ; R01 AG023145-05/AG/NIA NIH HHS/United States ; R01 AG23145/AG/NIA NIH HHS/United States ; },
mesh = {Cell Proliferation ; Cells, Cultured ; Cellular Senescence ; *Diploidy ; Fibroblasts/cytology/*enzymology ; Gene Expression Regulation ; Humans ; Male ; RNA, Messenger/genetics/metabolism ; S Phase ; Shelterin Complex ; *Suppression, Genetic ; Telomerase/antagonists &amp; inhibitors/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Time Factors ; },
abstract = {POT1 is a 3' telomeric single-stranded overhang binding protein that has been implicated in chromosome end protection, the regulation of telomerase function, and defining the 5' chromosome terminus. In human cancer cells that exhibit constitutive hTERT activity, hPOT1 exerts control over telomere length. Primary human fibroblasts express low levels of catalytically active hTERT in an S-phase-restricted manner that fails to counteract telomere attrition with cell division. Here, we show that diploid human fibroblasts in which hPOT1 expression has been suppressed harbor telomeres that are longer than control cells. This difference in telomere length delays the onset of replicative senescence and is dependent on S-phase-restricted hTERT expression. These findings are consistent with the view that hPOT1 promotes a nonextendable telomere state resistant to extension by S-phase-restricted telomerase. Manipulating this function of hPOT1 may thus hasten the cytotoxic effects of telomerase inhibition.},
}
@article {pmid18853771,
year = {2008},
author = {Proskuryakov, KA and Melnikova, LS},
title = {Functional separation of genetic factors telomere elongation (Tel) and enhancer of terminal gene conversion (E(tc)) involved in telomere elongation in Drosophila melanogaster.},
journal = {Doklady. Biochemistry and biophysics},
volume = {421},
number = {},
pages = {199-203},
pmid = {18853771},
issn = {1607-6729},
mesh = {Animals ; Chromosomes/genetics ; Crosses, Genetic ; DNA Repair ; Drosophila melanogaster/*genetics ; Enhancer Elements, Genetic/*genetics ; Female ; *Gene Conversion ; Male ; Phenotype ; Telomere/*genetics ; Transcription, Genetic ; },
}
@article {pmid18852018,
year = {2009},
author = {Tomasko, M and Vorlícková, M and Sagi, J},
title = {Substitution of adenine for guanine in the quadruplex-forming human telomere DNA sequence G(3)(T(2)AG(3))(3).},
journal = {Biochimie},
volume = {91},
number = {2},
pages = {171-179},
doi = {10.1016/j.biochi.2008.07.012},
pmid = {18852018},
issn = {1638-6183},
mesh = {Adenine/*chemistry ; Base Sequence ; Circular Dichroism ; DNA/*chemistry ; *G-Quadruplexes ; Guanine/*chemistry ; Humans ; Nucleic Acid Conformation ; Telomere/*chemistry ; },
abstract = {We have studied the formation and structural properties of quadruplexes of the human telomeric DNA sequence G(3)(T(2)AG(3))(3) and related sequences in which each guanine base was replaced by an adenine base. None of these single base substitutions hindered the formation of antiparallel quadruplexes, as shown by circular dichroism, gel electrophoresis, and UV thermal stability measurements in NaCl solutions. Effect of substitution did differ, however, depending on the position of the substituted base. The A-for-G substitution in the middle quartet of the antiparallel basket scaffold led to the most distorted and least stable structures and these sequences preferred to form bimolecular quadruplexes. Unlike G(3)(T(2)AG(3))(3), no structural transitions were observed for the A-containing analogs of G(3)(T(2)AG(3))(3) when sodium ions were replaced by potassium ions. The basic quadruplex topology remained the same for all sequences studied in both salts. As in vivo misincorporation of A for a G in the telomeric sequence is possible and potassium is a physiological salt, these findings may have biological relevance.},
}
@article {pmid18847490,
year = {2008},
author = {Kejariwal, D and Stepien, KM and Smith, T and Kennedy, H and Hughes, DA and Sampson, MJ},
title = {Lack of association of colonic epithelium telomere length and oxidative DNA damage in Type 2 diabetes under good metabolic control.},
journal = {BMC endocrine disorders},
volume = {8},
number = {},
pages = {12},
pmid = {18847490},
issn = {1472-6823},
abstract = {BACKGROUND: Telomeres are DNA repeat sequences necessary for DNA replication which shorten at cell division at a rate directly related to levels of oxidative stress. Critical telomere shortening predisposes to cell senescence and to epithelial malignancies. Type 2 diabetes is characterised by increased oxidative DNA damage, telomere attrition, and an increased risk of colonic malignancy. We hypothesised that the colonic mucosa in Type 2 diabetes would be characterised by increased DNA damage and telomere shortening.<br><br>METHODS: We examined telomere length (by flow fluorescent in situ hybridization) and oxidative DNA damage (flow cytometry of 8 - oxoguanosine) in the colonic mucosal cells of subjects with type 2 diabetes (n = 10; mean age 62.2 years, mean HbA1c 6.9%) and 22 matched control subjects. No colonic pathology was apparent in these subjects at routine gastrointestinal investigations.<br><br>RESULTS: Mean colonic epithelial telomere length in the diabetes group was not significantly different from controls (10.6 [3.6] vs. 12.1 [3.4] Molecular Equivalent of Soluble Fluorochrome Units [MESF]; P = 0.5). Levels of oxidative DNA damage were similar in both T2DM and control groups (2.6 [0.6] vs. 2.5 [0.6] Mean Fluorescent Intensity [MFI]; P = 0.7). There was no significant relationship between oxidative DNA damage and telomere length in either group (both p > 0.1).<br><br>CONCLUSION: Colonic epithelium in Type 2 diabetes does not differ significantly from control colonic epithelium in oxidative DNA damage or telomere length. There is no evidence in this study for increased oxidative DNA damage or significant telomere attrition in colonic mucosa as a carcinogenic mechanism.},
}
@article {pmid18845848,
year = {2008},
author = {Addinall, SG and Downey, M and Yu, M and Zubko, MK and Dewar, J and Leake, A and Hallinan, J and Shaw, O and James, K and Wilkinson, DJ and Wipat, A and Durocher, D and Lydall, D},
title = {A genomewide suppressor and enhancer analysis of cdc13-1 reveals varied cellular processes influencing telomere capping in Saccharomyces cerevisiae.},
journal = {Genetics},
volume = {180},
number = {4},
pages = {2251-2266},
pmid = {18845848},
issn = {0016-6731},
support = {075294//Wellcome Trust/United Kingdom ; BB/C008200/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {DNA Repair ; DNA, Fungal ; Gene Deletion ; Genes, Suppressor ; *Genome, Fungal ; *Mutation ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {In Saccharomyces cerevisiae, Cdc13 binds telomeric DNA to recruit telomerase and to "cap" chromosome ends. In temperature-sensitive cdc13-1 mutants telomeric DNA is degraded and cell-cycle progression is inhibited. To identify novel proteins and pathways that cap telomeres, or that respond to uncapped telomeres, we combined cdc13-1 with the yeast gene deletion collection and used high-throughput spot-test assays to measure growth. We identified 369 gene deletions, in eight different phenotypic classes, that reproducibly demonstrated subtle genetic interactions with the cdc13-1 mutation. As expected, we identified DNA damage checkpoint, nonsense-mediated decay and telomerase components in our screen. However, we also identified genes affecting casein kinase II activity, cell polarity, mRNA degradation, mitochondrial function, phosphate transport, iron transport, protein degradation, and other functions. We also identified a number of genes of previously unknown function that we term RTC, for restriction of telomere capping, or MTC, for maintenance of telomere capping. It seems likely that many of the newly identified pathways/processes that affect growth of budding yeast cdc13-1 mutants will play evolutionarily conserved roles at telomeres. The high-throughput spot-testing approach that we describe is generally applicable and could aid in understanding other aspects of eukaryotic cell biology.},
}
@article {pmid18845846,
year = {2008},
author = {Titen, SW and Golic, KG},
title = {Telomere loss provokes multiple pathways to apoptosis and produces genomic instability in Drosophila melanogaster.},
journal = {Genetics},
volume = {180},
number = {4},
pages = {1821-1832},
pmid = {18845846},
issn = {0016-6731},
support = {R01 GM065604/GM/NIGMS NIH HHS/United States ; T32 GM007464/GM/NIGMS NIH HHS/United States ; R01 GM65604/GM/NIGMS NIH HHS/United States ; T32-GM007464/GM/NIGMS NIH HHS/United States ; },
mesh = {Aneuploidy ; Animals ; Apoptosis/*genetics ; Cell Death ; Chromosomes/genetics ; Drosophila melanogaster/*genetics/*metabolism ; *Genomic Instability ; Mitosis ; Models, Biological ; Models, Genetic ; Telomere/*metabolism ; },
abstract = {Telomere loss was produced during development of Drosophila melanogaster by breakage of an induced dicentric chromosome. The most prominent outcome of this event is cell death through Chk2 and Chk1 controlled p53-dependent apoptotic pathways. A third p53-independent apoptotic pathway is additionally utilized when telomere loss is accompanied by the generation of significant aneuploidy. In spite of these three lines of defense against the proliferation of cells with damaged genomes a small fraction of cells that have lost a telomere escape apoptosis and divide repeatedly. Evasion of apoptosis is accompanied by the accumulation of karyotypic abnormalites that often typify cancer cells, including end-to-end chromosome fusions, anaphase bridges, aneuploidy, and polyploidy. There was clear evidence of bridge-breakage-fusion cycles, and surprisingly, chromosome segments without centromeres could persist and accumulate to high-copy number. Cells manifesting these signs of genomic instability were much more frequent when the apoptotic mechanisms were crippled. We conclude that loss of a single telomere is sufficient to generate at least two phenotypes of early cancer cells: genomic instability that involves multiple chromosomes and aneuploidy. This aneuploidy may facilitate the continued escape of such cells from the normal checkpoint mechanisms.},
}
@article {pmid18845840,
year = {2008},
author = {Rong, YS},
title = {Loss of the histone variant H2A.Z restores capping to checkpoint-defective telomeres in Drosophila.},
journal = {Genetics},
volume = {180},
number = {4},
pages = {1869-1875},
pmid = {18845840},
issn = {0016-6731},
support = {//Intramural NIH HHS/United States ; },
mesh = {Animals ; Drosophila/*genetics/metabolism ; Genes, cdc ; Histones/*genetics/metabolism ; Mutation ; Telomere/*genetics/metabolism ; },
abstract = {The conserved histone variant H2A.Z fulfills many functions by being an integral part of the nucleosomes placed at specific regions of the genome. Telomeres cap natural ends of chromosomes to prevent their recognition as double-strand breaks. At yeast telomeres, H2A.Z prevents the spreading of silent chromatin into proximal euchromatin. A role for H2A.Z in capping, however, has not been reported in any organism. Here, I uncover such a role for Drosophila H2A.Z. Loss of H2A.Z, through mutations in either its gene or the domino gene for the Swr1 chromatin-remodeling protein, suppressed the fusion of telomeres that lacked the protection of checkpoint proteins: ATM, ATR, and the Mre11-Rad50-NBS complex. Loss of H2A.Z partially restores the loading of the HOAP capping protein, possibly accounting for the partial restoration in capping. I propose that, in the absence of H2A.Z, checkpoint-defective telomeres adopt alternative structures, which are permissive for the loading of the capping machinery at Drosophila telomeres.},
}
@article {pmid18840804,
year = {2008},
author = {Aviv, A},
title = {The epidemiology of human telomeres: faults and promises.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {63},
number = {9},
pages = {979-983},
doi = {10.1093/gerona/63.9.979},
pmid = {18840804},
issn = {1079-5006},
support = {AG020132/AG/NIA NIH HHS/United States ; AG16592/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*genetics ; Animals ; Blotting, Southern ; Epidemiologic Measurements ; Humans ; Leukocytes/metabolism ; Longevity/*genetics ; Polymerase Chain Reaction ; Telomere/*genetics/ultrastructure ; },
abstract = {There are neglected but growing problems in the epidemiological field of telomere biology. The focus of the field has been on leukocyte telomere dynamics, which ostensibly register the accruing burden of oxidative stress and inflammation. Important as they are, studies that have examined associations between leukocyte telomere length and indices of aging and diseases of aging also include many that are compromised by poor epidemiological and laboratory methodology. The shortcomings of these studies muddle findings, undermine conclusions, and compromise the ability of the field to attain its goals, which include a better understanding of human aging. Specific steps are delineated to resolve these problems. They include a call for an impartial evaluation of the two major methods (Southern blots and quantitative polymerase chain reaction) currently in use to measure telomere parameters and a proposal for a working model to test the potential connections of leukocyte telomere dynamics with human aging and longevity.},
}
@article {pmid18836091,
year = {2008},
author = {Rosas-Hernández, LL and Juárez-Reyes, A and Arroyo-Helguera, OE and De Las Peñas, A and Pan, SJ and Cormack, BP and Castaño, I},
title = {yKu70/yKu80 and Rif1 regulate silencing differentially at telomeres in Candida glabrata.},
journal = {Eukaryotic cell},
volume = {7},
number = {12},
pages = {2168-2178},
pmid = {18836091},
issn = {1535-9786},
support = {R01 AI046223/AI/NIAID NIH HHS/United States ; },
mesh = {Candida glabrata/*genetics/metabolism ; Cell Adhesion Molecules/genetics/metabolism ; Fungal Proteins/genetics/*metabolism ; *Gene Expression Regulation, Fungal ; *Gene Silencing ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Candida glabrata, a common opportunistic fungal pathogen, adheres efficiently to mammalian epithelial cells in culture. This interaction in vitro depends mainly on the adhesin Epa1, one of a large family of cell wall proteins. Most of the EPA genes are located in subtelomeric regions, where they are transcriptionally repressed by silencing. In order to better characterize the transcriptional regulation of the EPA family, we have assessed the importance of C. glabrata orthologues of known regulators of subtelomeric silencing in Saccharomyces cerevisiae. To this end, we used a series of strains containing insertions of the reporter URA3 gene within different intergenic regions throughout four telomeres of C. glabrata. Using these reporter strains, we have assessed the roles of SIR2, SIR3, SIR4, HDF1 (yKu70), HDF2 (yKu80), and RIF1 in mediating silencing at four C. glabrata telomeres. We found that, whereas the SIR proteins are absolutely required for silencing of the reporter genes and the native subtelomeric EPA genes, the Rif1 and the Ku proteins regulate silencing at only a subset of the analyzed telomeres. We also mapped a cis element adjacent to the EPA3 locus that can silence a reporter gene when placed at a distance of 31 kb from the telomere. Our data show that silencing of the C. glabrata telomeres varies from telomere to telomere. In addition, recruitment of silencing proteins to the subtelomeres is likely, for certain telomeres, to depend both on the telomeric repeats and on particular discrete silencing elements.},
}
@article {pmid18835851,
year = {2008},
author = {Beneke, S and Cohausz, O and Malanga, M and Boukamp, P and Althaus, F and Bürkle, A},
title = {Rapid regulation of telomere length is mediated by poly(ADP-ribose) polymerase-1.},
journal = {Nucleic acids research},
volume = {36},
number = {19},
pages = {6309-6317},
pmid = {18835851},
issn = {1362-4962},
mesh = {Animals ; Benzamides/pharmacology ; Cell Line ; Cricetinae ; Enzyme Inhibitors/pharmacology ; Humans ; Kinetics ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/genetics/*physiology ; RNA Interference ; Telomere/chemistry/drug effects/*metabolism ; },
abstract = {Shelterin/telosome is a multi-protein complex at mammalian telomeres, anchored to the double-stranded region by the telomeric-repeat binding factors-1 and -2. In vitro modification of these proteins by poly(ADP-ribosyl)ation through poly(ADP-ribose) polymerases-5 (tankyrases) and -1/-2, respectively, impairs binding. Thereafter, at least telomeric-repeat binding factor-1 is degraded by the proteasome. We show that pharmacological inhibition of poly(ADP-ribose) polymerase activity in cells from two different species leads to rapid decrease in median telomere length and stabilization at a lower setting. Specific knockdown of poly(ADP-ribose) polymerase-1 by RNA interference had the same effect. The length of the single-stranded telomeric overhang as well as telomerase activity were not affected. Release of inhibition led to a fast re-gain in telomere length to control levels in cells expressing active telomerase. We conclude that poly(ADP-ribose) polymerase-1 activity and probably its interplay with telomeric-repeat binding factor-2 is an important determinant in telomere regulation. Our findings reinforce the link between poly(ADP-ribosyl)ation and aging/longevity and also impact on the use of poly(ADP-ribose) polymerase inhibitors in tumor therapy.},
}
@article {pmid18829574,
year = {2008},
author = {Gagos, S and Chiourea, M and Christodoulidou, A and Apostolou, E and Raftopoulou, C and Deustch, S and Jefford, CE and Irminger-Finger, I and Shay, JW and Antonarakis, SE},
title = {Pericentromeric instability and spontaneous emergence of human neoacrocentric and minute chromosomes in the alternative pathway of telomere lengthening.},
journal = {Cancer research},
volume = {68},
number = {19},
pages = {8146-8155},
doi = {10.1158/0008-5472.CAN-08-0945},
pmid = {18829574},
issn = {1538-7445},
mesh = {Cell Proliferation ; *Centromere/genetics/ultrastructure ; Chromosomal Instability/*physiology ; *Chromosome Aberrations ; Chromosome Breakage ; Cytogenetic Analysis ; HCT116 Cells ; HT29 Cells ; HeLa Cells ; Humans ; Signal Transduction/*genetics/physiology ; Telomerase/physiology ; Telomere/*physiology ; Tumor Cells, Cultured ; },
abstract = {In the alternative pathway of telomere lengthening (ALT), neoplastic cell growth is prolonged by telomere recombination. We show that ALT is unexpectedly characterized by high rates of ongoing pericentromeric chromosomal instability. Combined with telomeric recombination, ALT pericentromeric instability generates neoacrocentric chromosomes. In the present studies, we describe a subgroup of ALT neoacrocentric minute chromosomes, composed of DNA entities two to five times smaller in size than human chromosome 21. The frequencies of ALT minute chromosomes were increased by gamma-irradiation and suppressed by telomerase. Continuous growth after telomerase inhibition/depletion was followed by increased rates of telomeric sister chromatid recombination and the emergence of minute chromosomes. We show that ALT minute chromosomes were derived from true centromeric fissions and/or chromosomal breakage/fusion/bridge cycles. They exhibit a two-chromatid structure, carry genomic DNA, centromeric and telomeric repeats, and display regular mitotic functionality. These observations are important in understanding the global genomic instability that characterizes most human advanced malignancies.},
}
@article {pmid18828915,
year = {2008},
author = {Greenall, A and Lei, G and Swan, DC and James, K and Wang, L and Peters, H and Wipat, A and Wilkinson, DJ and Lydall, D},
title = {A genome wide analysis of the response to uncapped telomeres in budding yeast reveals a novel role for the NAD+ biosynthetic gene BNA2 in chromosome end protection.},
journal = {Genome biology},
volume = {9},
number = {10},
pages = {R146},
pmid = {18828915},
issn = {1474-760X},
support = {075294//Wellcome Trust/United Kingdom ; BB/C008200/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Cell Cycle Proteins/genetics/metabolism ; Chromosomes, Fungal/*genetics ; Fungal Proteins/*genetics/metabolism ; *Genome, Fungal ; NAD/*biosynthesis ; Saccharomycetales/*genetics ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {BACKGROUND: Telomeres prevent the ends of eukaryotic chromosomes from being recognized as damaged DNA and protect against cancer and ageing. When telomere structure is perturbed, a co-ordinated series of events promote arrest of the cell cycle so that cells carrying damaged telomeres do not divide. In order to better understand the eukaryotic response to telomere damage, budding yeast strains harboring a temperature sensitive allele of an essential telomere capping gene (cdc13-1) were subjected to a transcriptomic study.<br><br>RESULTS: The genome-wide response to uncapped telomeres in yeast cdc13-1 strains, which have telomere capping defects at temperatures above approximately 27 degrees C, was determined. Telomere uncapping in cdc13-1 strains is associated with the differential expression of over 600 transcripts. Transcripts affecting responses to DNA damage and diverse environmental stresses were statistically over-represented. BNA2, required for the biosynthesis of NAD+, is highly and significantly up-regulated upon telomere uncapping in cdc13-1 strains. We find that deletion of BNA2 and NPT1, which is also involved in NAD+ synthesis, suppresses the temperature sensitivity of cdc13-1 strains, indicating that NAD+ metabolism may be linked to telomere end protection.<br><br>CONCLUSIONS: Our data support the hypothesis that the response to telomere uncapping is related to, but distinct from, the response to non-telomeric double-strand breaks. The induction of environmental stress responses may be a conserved feature of the eukaryotic response to telomere damage. BNA2, which is involved in NAD+ synthesis, plays previously unidentified roles in the cellular response to telomere uncapping.},
}
@article {pmid18827602,
year = {2008},
author = {Fernandez-Garcia, I and Ortiz-de-Solorzano, C and Montuenga, LM},
title = {Telomeres and telomerase in lung cancer.},
journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer},
volume = {3},
number = {10},
pages = {1085-1088},
doi = {10.1097/JTO.0b013e3181886713},
pmid = {18827602},
issn = {1556-1380},
mesh = {Animals ; Humans ; Neoplasms/*metabolism/pathology/therapy ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {Protected telomeres ensure normal chromosomal segregation during mitosis but at the same time can endow genetically abnormal cancer cells with immortality. Telomerase has a pivotal role in telomere protection, both in normal and cancer cells. Understanding the functional interplay between telomere shortening and telomerase expression in cancer cells is of critical importance to elucidating the precise mechanisms by which these cells are able to bypass telomere crisis and become immortal.},
}
@article {pmid18820651,
year = {2008},
author = {Nordfjäll, K and Eliasson, M and Stegmayr, B and Melander, O and Nilsson, P and Roos, G},
title = {Telomere length is associated with obesity parameters but with a gender difference.},
journal = {Obesity (Silver Spring, Md.)},
volume = {16},
number = {12},
pages = {2682-2689},
doi = {10.1038/oby.2008.413},
pmid = {18820651},
issn = {1930-7381},
mesh = {Adult ; Body Mass Index ; Body Weight ; Cardiovascular Diseases/*genetics ; Cholesterol/blood ; Cohort Studies ; Female ; Glucose Tolerance Test ; Humans ; Insulin/blood ; Male ; Middle Aged ; Obesity/*genetics ; Sex Factors ; Sweden ; *Telomere ; Triglycerides/blood ; Waist Circumference ; },
abstract = {Cardiovascular disease (CVD) and obesity have been coupled to short telomere length in peripheral blood. The biological background to this observation is not obvious from the literature. In this study we have analyzed a large set of known risk factors for CVD in relation to telomere length in blood cells on a merged cohort of 989 individuals recruited in the Malmö Diet and Cancer Cohort (MDCC) and the Northern Sweden MONICA project. We found a significant or borderline association between obesity parameters and telomere length in women after age and center adjustments (BMI: r = -0.106, P = 0.021, weight: r = -0.087, P = 0.060, waist circumference: r = -0.099, P = 0.032, hip circumference: r = -0.128, P = 0.005). In men, a positive borderline correlation to high-density lipoprotein (HDL) (r = 0.111, P = 0.053) and a negative correlation to 2-h post-oral glucose-tolerance test (OGTT) was observed (r = -0.202, P = 0.045). In neither group any association was found between telomere length and cholesterol, serum triglycerides, serum low-density lipoprotein, plasma insulin, blood pressure, pulse pressure, or smoking habits. Our data indicate that telomere length is associated with an "obesity-phenotype" but only in women.},
}
@article {pmid18820466,
year = {2008},
author = {Pardue, ML and DeBaryshe, PG},
title = {Drosophila telomeres: A variation on the telomerase theme.},
journal = {Fly},
volume = {2},
number = {3},
pages = {101-110},
doi = {10.4161/fly.6393},
pmid = {18820466},
issn = {1933-6942},
support = {50315//PHS HHS/United States ; },
mesh = {3' Untranslated Regions/physiology ; Animals ; Chromatin/chemistry/ultrastructure ; Drosophila/cytology/*genetics/ultrastructure ; Drosophila Proteins/genetics/physiology ; *Evolution, Molecular ; Genome, Insect ; Models, Genetic ; Phylogeny ; Retroelements/physiology ; Species Specificity ; Telomerase/genetics/physiology ; Telomere/chemistry/*physiology/ultrastructure ; },
abstract = {In Drosophila, the role of telomerase is carried out by three specialized retrotransposable elements, HeT-A, TART and TAHRE. Telomeres contain long tandem head-to-tail arrays of these elements. Within each array, the three elements occur in random, but polarized, order. Some are truncated at the 5' end, giving the telomere an enriched content of the large 3' untranslated regions, which distinguish these telomeric elements from other retrotransposons. Thus, Drosophila telomeres resemble other telomeres because they are long arrays of repeated sequences, albeit more irregular arrays than those produced by telomerase. The telomeric retrotransposons are reverse-transcribed directly onto the end of the chromosome, extending the end by successive transpositions. Their transposition uses exactly the same method by which telomerase extends chromosome ends--copying an RNA template. In addition to these similarities in structure and maintenance, Drosophila telomeres have strong functional similarities to other telomeres and, as variants, provide an important model for understanding general principles of telomere function and evolution.},
}
@article {pmid18818742,
year = {2008},
author = {Kosaka, H and Shinohara, M and Shinohara, A},
title = {Csm4-dependent telomere movement on nuclear envelope promotes meiotic recombination.},
journal = {PLoS genetics},
volume = {4},
number = {9},
pages = {e1000196},
pmid = {18818742},
issn = {1553-7404},
mesh = {Cell Cycle Proteins/genetics/metabolism ; Chromosome Pairing ; *Meiosis ; Membrane Proteins/genetics/*metabolism ; Nuclear Envelope/genetics/*metabolism ; Nuclear Proteins ; *Recombination, Genetic ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/*genetics/metabolism ; },
abstract = {During meiotic prophase, chromosomes display rapid movement, and their telomeres attach to the nuclear envelope and cluster to form a "chromosomal bouquet." Little is known about the roles of the chromosome movement and telomere clustering in this phase. In budding yeast, telomere clustering is promoted by a meiosis-specific, telomere-binding protein, Ndj1. Here, we show that a meiosis-specific protein, Csm4, which forms a complex with Ndj1, facilitates bouquet formation. In the absence of Csm4, Ndj1-bound telomeres tether to nuclear envelopes but do not cluster, suggesting that telomere clustering in the meiotic prophase consists of at least two distinct steps: Ndj1-dependent tethering to the nuclear envelope and Csm4-dependent clustering/movement. Similar to Ndj1, Csm4 is required for several distinct steps during meiotic recombination. Our results suggest that Csm4 promotes efficient second-end capture of a double-strand break following a homology search, as well as resolution of the double-Holliday junction during crossover formation. We propose that chromosome movement and associated telomere dynamics at the nuclear envelope promotes the completion of key biochemical steps during meiotic recombination.},
}
@article {pmid18818741,
year = {2008},
author = {Wanat, JJ and Kim, KP and Koszul, R and Zanders, S and Weiner, B and Kleckner, N and Alani, E},
title = {Csm4, in collaboration with Ndj1, mediates telomere-led chromosome dynamics and recombination during yeast meiosis.},
journal = {PLoS genetics},
volume = {4},
number = {9},
pages = {e1000188},
pmid = {18818741},
issn = {1553-7404},
support = {R01 GM044794/GM/NIGMS NIH HHS/United States ; R01 GM053085/GM/NIGMS NIH HHS/United States ; GM44794/GM/NIGMS NIH HHS/United States ; GM53085/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics/*metabolism ; Chromosome Segregation ; Chromosomes, Fungal/*genetics ; Crosses, Genetic ; *Meiosis ; Membrane Proteins/genetics/*metabolism ; Nuclear Envelope/genetics/metabolism ; *Recombination, Genetic ; Saccharomyces cerevisiae/cytology/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Shelterin Complex ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Transcription Factors/genetics/metabolism ; },
abstract = {Chromosome movements are a general feature of mid-prophase of meiosis. In budding yeast, meiotic chromosomes exhibit dynamic movements, led by nuclear envelope (NE)-associated telomeres, throughout the zygotene and pachytene stages. Zygotene motion underlies the global tendency for colocalization of NE-associated chromosome ends in a "bouquet." In this study, we identify Csm4 as a new molecular participant in these processes and show that, unlike the two previously identified components, Ndj1 and Mps3, Csm4 is not required for meiosis-specific telomere/NE association. Instead, it acts to couple telomere/NE ensembles to a force generation mechanism. Mutants lacking Csm4 and/or Ndj1 display the following closely related phenotypes: (i) elevated crossover (CO) frequencies and decreased CO interference without abrogation of normal pathways; (ii) delayed progression of recombination, and recombination-coupled chromosome morphogenesis, with resulting delays in the MI division; and (iii) nondisjunction of homologs at the MI division for some reason other than absence of (the obligatory) CO(s). The recombination effects are discussed in the context of a model where the underlying defect is chromosome movement, the absence of which results in persistence of inappropriate chromosome relationships that, in turn, results in the observed mutant phenotypes.},
}
@article {pmid18817864,
year = {2008},
author = {Nalapareddy, K and Jiang, H and Guachalla Gutierrez, LM and Rudolph, KL},
title = {Determining the influence of telomere dysfunction and DNA damage on stem and progenitor cell aging: what markers can we use?.},
journal = {Experimental gerontology},
volume = {43},
number = {11},
pages = {998-1004},
doi = {10.1016/j.exger.2008.09.002},
pmid = {18817864},
issn = {1873-6815},
mesh = {Adult Stem Cells/*cytology/enzymology ; Animals ; Antimicrobial Cationic Peptides/analysis ; Biomarkers/analysis ; Cathelicidins ; Cellular Senescence/*physiology ; Chitinases/analysis ; DNA Damage ; Humans ; Mice ; Mice, Knockout ; Models, Animal ; Peptide Elongation Factor 1/analysis ; Stathmin/analysis ; Stem Cells/*cytology/enzymology ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {The decline in organ maintenance and function is one of the major problems limiting quality of life during aging. The accumulation of telomere dysfunction and DNA damage appears to be one of the underlying causes. Uncapping of chromosome ends in response to critical telomere shortening limits the proliferative capacity of human cells by activation of DNA damage checkpoints inducing senescence or apoptosis. Telomere shortening occurs in the vast majority of human tissues during aging and in chronic diseases that increase the rate of cell turnover. There is emerging evidence that telomere shortening can limit the maintenance and function of adult stem cells -- a cell type of utmost importance for organ maintenance and regeneration. In mouse models, telomere dysfunction leads to a depletion of adult stem cell compartments suggesting that stem cells are very sensitive to DNA damage. Both the rarity of stem and progenitor cells in adult organs and their removal in response to damage make it difficult to assess the impact of telomere dysfunction and DNA damage on stem and progenitor cell aging. Such approaches require the development of sensitive biomarkers recognizing low levels of telomere dysfunction and DNA damage in stem and progenitor cells. Here, we review experimental data on the prevalence of telomere dysfunction and DNA damage during aging and its possible impact on stem and progenitor cell aging.},
}
@article {pmid18817431,
year = {2008},
author = {Pomerantz, AK and Moerner, WE and Kool, ET},
title = {Visualization of long human telomere mimics by single-molecule fluorescence imaging.},
journal = {The journal of physical chemistry. B},
volume = {112},
number = {42},
pages = {13184-13187},
pmid = {18817431},
issn = {1520-6106},
support = {GM003638/GM/NIGMS NIH HHS/United States ; R01 GM069763/GM/NIGMS NIH HHS/United States ; P20 HG003638/HG/NHGRI NIH HHS/United States ; P20 HG003638-04/HG/NHGRI NIH HHS/United States ; GM069763/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Biomimetic Materials/*analysis/chemical synthesis/*chemistry ; DNA, Single-Stranded/chemical synthesis/*chemistry/genetics ; *Fluorescence ; Humans ; Telomere/*chemistry ; },
abstract = {Study of long single-stranded telomeric DNA is important for a variety of basic science and biotechnological applications, yet few methods exist for synthesis and visualization of single copies of this DNA in solution at biologically relevant length scales necessary for assessment of heterogeneity in its structure and behavior. We have synthesized kilobase-long single-stranded human telomere mimics in situ by rolling circle replication (RCR) on a microscope coverslip surface and visualized individual strands by staining with SYBR Gold. Under buffer flow, differential extensibility and varying morphology of these long telomere-mimicking DNA sequences were observed at the single-molecule level in real time. Using this procedure, we detected striking differences in the extensibility of individual RCR products based on the human G-rich telomeric sequence in the presence and absence of short, complementary single-stranded oligonucleotides. We also apply this new mode of single-stranded DNA characterization to probe the interaction of kilobase-length telomere mimics with the small-molecule G-quadruplex-binding agent TMPyP4.},
}
@article {pmid18816191,
year = {2008},
author = {van Baarle, D and Nanlohy, NM and Otto, S and Plunkett, FJ and Fletcher, JM and Akbar, AN},
title = {Progressive telomere shortening of Epstein-Barr virus-specific memory T cells during HIV infection: contributor to exhaustion?.},
journal = {The Journal of infectious diseases},
volume = {198},
number = {9},
pages = {1353-1357},
doi = {10.1086/592170},
pmid = {18816191},
issn = {0022-1899},
mesh = {Adolescent ; Adult ; Aged ; Antigens, Viral ; Child ; Child, Preschool ; Female ; HIV Infections/*immunology ; Herpesvirus 4, Human/*immunology ; Humans ; Immunologic Memory/*immunology ; Infant ; Infant, Newborn ; Male ; Middle Aged ; T-Lymphocytes/*cytology/*immunology ; Telomere/*physiology ; Viral Load ; Young Adult ; },
abstract = {Individuals infected with human immunodeficiency virus (HIV) have low numbers of functional Epstein-Barr virus (EBV)-specific CD8+ T cells in the face of a high EBV load, suggesting that these cells have become exhausted. We investigated whether the observed chronic EBV loads during HIV infection could cause exhaustion of EBV-specific T cells by using flow-FISH (flow cytometry in combination with fluorescence in situ hybridization) to analyze the telomere length of EBV-specific CD8+ T cells. Enhanced telomere shortening of EBV-specific T cells was observed during HIV infection, compared with the decline in telomere length observed in the CD8+ T cells of healthy subjects. Thus, chronic exposure to high antigen levels may lead to the progressive shortening of telomeres of antigen-specific T cells, which may impair viral control.},
}
@article {pmid18815070,
year = {2008},
author = {Wong, LS and de Boer, RA and Samani, NJ and van Veldhuisen, DJ and van der Harst, P},
title = {Telomere biology in heart failure.},
journal = {European journal of heart failure},
volume = {10},
number = {11},
pages = {1049-1056},
doi = {10.1016/j.ejheart.2008.08.007},
pmid = {18815070},
issn = {1388-9842},
support = {//British Heart Foundation/United Kingdom ; },
mesh = {Heart Failure/*genetics/metabolism ; Humans ; Risk Factors ; Telomerase/metabolism ; Telomere/*physiology ; },
abstract = {The incidence and prevalence of cardiovascular disease increases progressively with advancing age. Cardiovascular disease is a major cause of morbidity and mortality in Western Countries. In the near future, as the population ages, it is expected that the population prevalence of cardiovascular disease will increase dramatically, imposing a major social and economical burden on society. Not only is age closely related to the development and progression of cardiovascular disease, but genetic and environmental factors also play an important role. Recently, a chromosomal mechanism, telomere shortening, has been considered a driving force by which genetic and environmental factors jointly affect biological aging, and possibly the risk for developing age-associated diseases. Telomeres are the extreme ends of chromosomes and shorten progressively during every cell cycle and therefore can be considered an indicator of biological age. In heart failure, telomere length is severely reduced. In the current review, we will discuss the emerging role of telomere biology in the pathophysiology of heart failure.},
}
@article {pmid18813361,
year = {2008},
author = {Josse, T and Maurel-Zaffran, C and de Vanssay, A and Teysset, L and Todeschini, AL and Delmarre, V and Chaminade, N and Anxolabéhère, D and Ronsseray, S},
title = {Telomeric trans-silencing in Drosophila melanogaster: tissue specificity, development and functional interactions between non-homologous telomeres.},
journal = {PloS one},
volume = {3},
number = {9},
pages = {e3249},
pmid = {18813361},
issn = {1932-6203},
mesh = {Animals ; Chromosome Mapping ; Crosses, Genetic ; DNA Transposable Elements ; Drosophila melanogaster/*genetics ; Epigenesis, Genetic ; Gene Expression Regulation ; *Gene Silencing ; Models, Biological ; Models, Genetic ; Phenotype ; RNA Interference ; Telomere/*ultrastructure ; Temperature ; Transgenes ; },
abstract = {BACKGROUND: The study of P element repression in Drosophila melanogaster led to the discovery of the telomeric Trans-Silencing Effect (TSE), a homology-dependent repression mechanism by which a P-transgene inserted in subtelomeric heterochromatin (Telomeric Associated Sequences, "TAS") has the capacity to repress in trans, in the female germline, a homologous P-lacZ transgene located in euchromatin. TSE can show variegation in ovaries, displays a maternal effect as well as an epigenetic transmission through meiosis and involves heterochromatin and RNA silencing pathways.<br><br>PRINCIPAL FINDINGS: Here, we analyze phenotypic and genetic properties of TSE. We report that TSE does not occur in the soma at the adult stage, but appears restricted to the female germline. It is detectable during development at the third instar larvae where it presents the same tissue specificity and maternal effect as in adults. Transgenes located in TAS at the telomeres of the main chromosomes can be silencers which in each case show the maternal effect. Silencers located at non-homologous telomeres functionally interact since they stimulate each other via the maternally-transmitted component. All germinally-expressed euchromatic transgenes tested, located on all major chromosomes, were found to be repressed by a telomeric silencer: thus we detected no TSE escaper. The presence of the euchromatic target transgene is not necessary to establish the maternal inheritance of TSE, responsible for its epigenetic behavior. A single telomeric silencer locus can simultaneously repress two P-lacZ targets located on different chromosomal arms.<br><br>CONCLUSIONS AND SIGNIFICANCE: Therefore TSE appears to be a widespread phenomenon which can involve different telomeres and work across the genome. It can explain the P cytotype establishment by telomeric P elements in natural Drosophila populations.},
}
@article {pmid18812185,
year = {2008},
author = {Wu, Y and Mitchell, TR and Zhu, XD},
title = {Human XPF controls TRF2 and telomere length maintenance through distinctive mechanisms.},
journal = {Mechanisms of ageing and development},
volume = {129},
number = {10},
pages = {602-610},
doi = {10.1016/j.mad.2008.08.004},
pmid = {18812185},
issn = {0047-6374},
mesh = {Alleles ; Animals ; Cellular Senescence ; Chromatin Immunoprecipitation ; DNA-Binding Proteins/*metabolism ; Endonucleases/*metabolism ; *Gene Expression Regulation ; Humans ; Immunoprecipitation ; Mice ; Models, Biological ; *Recombination, Genetic ; Telomere/ultrastructure ; Telomeric Repeat Binding Protein 2/*metabolism ; beta-Galactosidase/metabolism ; },
abstract = {XPF-ERCC1, a structure-specific endonuclease, is involved in nucleotide excision repair, crosslink repair and homologous recombination. XPF-ERCC1 is also found to interact with TRF2, a duplex telomeric DNA binding protein. We have previously shown that XPF-ERCC1 is required for TRF2-promoted telomere shortening. However, whether XPF-ERCC1 by itself has a role in telomere length maintenance has not been determined. Here we report that overexpression of XPF induces telomere shortening in XPF-proficient cells whereas XPF complementation suppresses telomere lengthening in XPF-deficient cells. These results suggest that XPF-ERCC1 can function as a negative mediator of telomere length maintenance. In addition, we find that introduction of wild type XPF into XPF-deficient cells leads to over 40% reduction in TRF2 association with telomeric DNA, indicating that XPF-ERCC1 negatively regulates TRF2 binding to telomeric DNA. Furthermore, we show that XPF carrying mutations in the conserved nuclease domain fails to control TRF2 association with telomeric DNA but it is competent for modulating telomere length maintenance. These results imply that XPF-ERCC1 controls TRF2 and telomere length maintenance through two distinctive mechanisms, with the former requiring its nuclease activity. Our results further imply that TRF2 association with telomeres may be deregulated in cells derived from XPF patients.},
}
@article {pmid18809425,
year = {2008},
author = {Woo, J and Tang, NL and Suen, E and Leung, JC and Leung, PC},
title = {Telomeres and frailty.},
journal = {Mechanisms of ageing and development},
volume = {129},
number = {11},
pages = {642-648},
doi = {10.1016/j.mad.2008.08.003},
pmid = {18809425},
issn = {0047-6374},
mesh = {Age Factors ; Aged ; Aging/*genetics ; Biomarkers/metabolism ; Cohort Studies ; Cross-Sectional Studies ; Female ; *Frail Elderly ; Genotype ; Health Surveys ; Humans ; Male ; Mortality ; Phenotype ; Sex Factors ; Telomere/*metabolism ; Time Factors ; },
abstract = {Associations between telomere length and various chronic diseases associated with ageing have led to the suggestion that telomere length may be an ageing biomarker. At the clinical level, the suggestion of using measurements of frailty as a measure of biological ageing has also been suggested. This study examines the hypothesis that telomere shortening may form the biological basis for frailty, using data obtained from a health survey of 2000 men and women aged 65 years and over, living in the community, and followed up for 4 years to determine survival. Frailty was measured using the frailty index, a summation of deficits covering physical, psychological, and functional domains. Telomere length was measured in 976 men and 1030 women, using real-time quantitative polymerase chain reaction. Women were more frail than men but had longer telomere length. In men only, there was a negative association between telomere length and age and a positive association between frailty index and mortality after adjusting for age. There was no correlation between telomere length and frailty index in either sex. While telomere length may be a biomarker of cellular senescence, this relationship may not be extrapolated to the functional level represented by the frailty phenotype.},
}
@article {pmid18799986,
year = {2008},
author = {Ludlow, AT and Zimmerman, JB and Witkowski, S and Hearn, JW and Hatfield, BD and Roth, SM},
title = {Relationship between physical activity level, telomere length, and telomerase activity.},
journal = {Medicine and science in sports and exercise},
volume = {40},
number = {10},
pages = {1764-1771},
pmid = {18799986},
issn = {1530-0315},
support = {L30 AG024705-02/AG/NIA NIH HHS/United States ; AG022791/AG/NIA NIH HHS/United States ; K01 AG022791/AG/NIA NIH HHS/United States ; L30 AG024705/AG/NIA NIH HHS/United States ; AG025505/AG/NIA NIH HHS/United States ; R21 AG025505/AG/NIA NIH HHS/United States ; L30 AG024705-03/AG/NIA NIH HHS/United States ; R21 AG025505-02/AG/NIA NIH HHS/United States ; K01 AG022791-05/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Base Sequence ; DNA Primers ; *Exercise ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Reverse Transcriptase Polymerase Chain Reaction ; Stress, Psychological ; Telomerase/genetics/*metabolism ; *Telomere ; },
abstract = {PURPOSE: The purpose of this study was to examine the relationship of exercise energy expenditure (EEE) with both telomere length and telomerase activity in addition to accounting for hTERT C-1327T promoter genotype.<br><br>METHODS: Sixty-nine (n = 34 males; n = 35 females) participants 50-70 yr were assessed for weekly EEE level using the Yale Physical Activity Survey. Lifetime consistency of EEE was also determined. Subjects were recruited across a large range of EEE levels and separated into quartiles: 0-990, 991-2340, 2341-3540, and >3541 kcal x wk(-1). Relative telomere length and telomerase activity were measured in peripheral blood mononuclear cells (PBMC).<br><br>RESULTS: The second EEE quartile exhibited significantly longer telomere lengths [1.12 +/- 0.03 relative units (RU)] than both the first and fourth EEE quartiles (0.94 +/- 0.03 and 0.96 +/- 0.03 RU, respectively; P < 0.05) but was not different from the third quartile. Telomerase activity was not different among the EEE quartiles. An association was observed between telomerase enzyme activity and hTERT genotype with the TT genotype (1.0 x 10(-2) +/- 4.0 x 10(-3) attomoles (amol) per 10,000 cells; n = 19) having significantly greater telomerase enzyme activity than both the CT (1.3 x 10(-3) +/- 3.2 x 10(-3); n = 30) and CC groups (5.0 x 10(-4) +/- 3.9 x 10(-3); n = 20; P = 0.01).<br><br>CONCLUSION: These results indicate that moderate physical activity levels may provide a protective effect on PBMC telomere length compared with both low and high EEE levels.},
}
@article {pmid18798066,
year = {2008},
author = {Horn, T},
title = {Comments on quantitative real-time PCR for measurement of telomere length.},
journal = {Cancer investigation},
volume = {26},
number = {9},
pages = {867},
doi = {10.1080/07357900802027099},
pmid = {18798066},
issn = {1532-4192},
mesh = {Carcinoma, Hepatocellular/*genetics ; Gene Dosage ; Humans ; Liver Neoplasms/*genetics ; Polymerase Chain Reaction/*methods ; Reproducibility of Results ; Telomere/*chemistry/ultrastructure ; Time Factors ; },
}
@article {pmid18797459,
year = {2008},
author = {Tabori, U and Wong, V and Ma, J and Shago, M and Alon, N and Rutka, J and Bouffet, E and Bartels, U and Malkin, D and Hawkins, C},
title = {Telomere maintenance and dysfunction predict recurrence in paediatric ependymoma.},
journal = {British journal of cancer},
volume = {99},
number = {7},
pages = {1129-1135},
pmid = {18797459},
issn = {1532-1827},
mesh = {Central Nervous System Neoplasms/genetics/*pathology/therapy ; Child ; Cohort Studies ; Ependymoma/genetics/*pathology/therapy ; Humans ; Immunohistochemistry ; Prognosis ; Recurrence ; *Telomere ; },
abstract = {We have recently described the enzymatic subunit of telomerase (hTERT) as an important prognostic marker for paediatric ependymoma. Because of the lack of good, representative pre-clinical models for ependymoma, we took advantage of our large cohort of ependymoma patients, some with multiple recurrences, to investigate telomere biology in these tumours. Our cohort consisted of 133 ependymomas from 83 paediatric patients and included 31 patients with recurrences. Clinical outcome was measured as overall survival, progression-free survival and response to therapy. In all 133 tumours, hTERT expression correlated with proliferative markers, including MIB-1 index (P<0.0001) and mitotic index (P=0.005), as well as overall tumour grade (P=0.001), but not with other markers of anaplasia. There was no correlation between telomere length and hTERT expression or survival. Surprisingly, prior radiation or chemotherapy neither induced sustained DNA damage nor affected telomere maintenance in recurrent tumours. There was an inverse correlation between hTERT expression and telomere dysfunction as measured by gamma H2AX expression (P=0.016). Combining gamma H2AX and hTERT expressions could segregate tumours into three different survival groups (log rank, P<0.0001) such that those patients whose tumours expressed hTERT and showed no evidence of DNA damage had the worst outcome. This study emphasises the importance of telomere biology as a prognostic tool and telomerase inhibition as a therapeutic target for paediatric ependymoma. Furthermore, we have demonstrated that analysing tumours as they progress in vivo is a viable approach to studying tumour biology in humans.},
}
@article {pmid18795148,
year = {2008},
author = {Grodstein, F and van Oijen, M and Irizarry, MC and Rosas, HD and Hyman, BT and Growdon, JH and De Vivo, I},
title = {Shorter telomeres may mark early risk of dementia: preliminary analysis of 62 participants from the nurses' health study.},
journal = {PloS one},
volume = {3},
number = {2},
pages = {e1590},
pmid = {18795148},
issn = {1932-6203},
support = {P01 CA087969/CA/NCI NIH HHS/United States ; AG15424/AG/NIA NIH HHS/United States ; CA87969/CA/NCI NIH HHS/United States ; P50 AG005134/AG/NIA NIH HHS/United States ; R01 AG015424/AG/NIA NIH HHS/United States ; AG05134/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Cognition Disorders ; Dementia/*diagnosis ; Female ; Hippocampus ; Humans ; Leukocytes/ultrastructure ; Logistic Models ; Organ Size ; Pilot Projects ; *Predictive Value of Tests ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Dementia takes decades to develop, and effective prevention will likely require early intervention. Thus, it is critical to identify biomarkers of preclinical disease, allowing targeting of high-risk subjects for preventive efforts. Since telomeres shorten with age and oxidative stress, both of which are important contributors to the onset of dementia, telomere length might be a valuable biomarker.<br><br>Among 62 participants of the Nurses' Health Study, we conducted neurologic evaluations, including patient and caregiver interviews, physical exam, neurologic exam, and neuropsychologic testing. We also conducted magnetic resonance imaging (MRI) in a sample of 29 of these women. In these preliminary data, after adjustment for numerous health and lifestyle factors, we found that truncated telomeres in peripheral blood leukocytes segregate with preclinical dementia states, including mild cognitive impairment (MCI); the odds of MCI were 12-fold higher (odds ratio = 12.00, 95% confidence interval 1.24-116.5) for those with shorter telomere length compared to longer telomere length. In addition, decreasing telomere length was strongly related to decreasing hippocampal volume (p = 0.038).<br><br>CONCLUSIONS: These preliminary data suggest that telomere length may be a possible early marker of dementia risk, and merits further study in large, prospective investigations.},
}
@article {pmid18790082,
year = {2009},
author = {Au, DW and Mok, HO and Elmore, LW and Holt, SE},
title = {Japanese medaka: a new vertebrate model for studying telomere and telomerase biology.},
journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP},
volume = {149},
number = {2},
pages = {161-167},
doi = {10.1016/j.cbpc.2008.08.005},
pmid = {18790082},
issn = {1532-0456},
support = {P30ES03828-18/ES/NIEHS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Female ; Male ; *Models, Biological ; Molecular Sequence Data ; Oryzias/genetics/growth &amp; development/*metabolism ; Phylogeny ; RNA, Messenger/metabolism ; Sequence Homology, Amino Acid ; Spleen/enzymology ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; Testis/enzymology ; Vertebrates/genetics/*metabolism ; },
abstract = {A good understanding of telomeres and telomerase biology is crucial for unraveling mechanisms related to aging and cancer. However, in vivo vertebrate studies of telomere biogenesis and telomerase function have been limited by the development of appropriate animal model systems. The present study aims to demonstrate evolutionary conservation of telomerase in vertebrate species, supporting the potential application of fish as vertebrate model for studying telomeres and telomerase function. Comparison of genomic and protein information among vertebrate TERTs (TElomerase Reverse Transcriptase), the Japanese medaka Oryzias latipes shares the highest similarity to that of the human than the other small size fish species studied (including pufferfish and zebrafish). The ubiquitous expression of TERT mRNA, the high constitutive level of telomerase activity, and the humanized telomere lengths further substantiate that Japanese medaka is an ideal vertebrate model for the study of telomere and telomerase-related mechanisms in vivo. Moreover, medaka exhibits fast, invariable growth and is able to provide a variety of useful developmental and reproductive endpoints for lifelong and multi-generational experiments. Our earlier and present findings support the use of medaka for studying organismal aging, tissue regeneration and carcinogenesis.},
}
@article {pmid18787699,
year = {2008},
author = {McDonagh, A and Fedorova, ND and Crabtree, J and Yu, Y and Kim, S and Chen, D and Loss, O and Cairns, T and Goldman, G and Armstrong-James, D and Haynes, K and Haas, H and Schrettl, M and May, G and Nierman, WC and Bignell, E},
title = {Sub-telomere directed gene expression during initiation of invasive aspergillosis.},
journal = {PLoS pathogens},
volume = {4},
number = {9},
pages = {e1000154},
pmid = {18787699},
issn = {1553-7374},
support = {G0501164/MRC_/Medical Research Council/United Kingdom ; AI051144/AI/NIAID NIH HHS/United States ; G0501397/MRC_/Medical Research Council/United Kingdom ; R01 AI051144/AI/NIAID NIH HHS/United States ; P 18606/FWF_/Austrian Science Fund FWF/Austria ; /WT_/Wellcome Trust/United Kingdom ; N01AI30041/AI/NIAID NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; AI052236/AI/NIAID NIH HHS/United States ; CA16672/CA/NCI NIH HHS/United States ; U01AI48830/AI/NIAID NIH HHS/United States ; BBS/B/10331/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; R21 AI052236/AI/NIAID NIH HHS/United States ; },
mesh = {Adaptation, Physiological/*genetics ; Animals ; *Aspergillosis ; Aspergillus fumigatus/*genetics/pathogenicity ; Gene Expression Profiling ; Gene Expression Regulation, Viral/*physiology ; Genes, Viral/physiology ; Mice ; Telomere ; Virulence/genetics ; },
abstract = {Aspergillus fumigatus is a common mould whose spores are a component of the normal airborne flora. Immune dysfunction permits developmental growth of inhaled spores in the human lung causing aspergillosis, a significant threat to human health in the form of allergic, and life-threatening invasive infections. The success of A. fumigatus as a pathogen is unique among close phylogenetic relatives and is poorly characterised at the molecular level. Recent genome sequencing of several Aspergillus species provides an exceptional opportunity to analyse fungal virulence attributes within a genomic and evolutionary context. To identify genes preferentially expressed during adaptation to the mammalian host niche, we generated multiple gene expression profiles from minute samplings of A. fumigatus germlings during initiation of murine infection. They reveal a highly co-ordinated A. fumigatus gene expression programme, governing metabolic and physiological adaptation, which allows the organism to prosper within the mammalian niche. As functions of phylogenetic conservation and genetic locus, 28% and 30%, respectively, of the A. fumigatus subtelomeric and lineage-specific gene repertoires are induced relative to laboratory culture, and physically clustered genes including loci directing pseurotin, gliotoxin and siderophore biosyntheses are a prominent feature. Locationally biased A. fumigatus gene expression is not prompted by in vitro iron limitation, acid, alkaline, anaerobic or oxidative stress. However, subtelomeric gene expression is favoured following ex vivo neutrophil exposure and in comparative analyses of richly and poorly nourished laboratory cultured germlings. We found remarkable concordance between the A. fumigatus host-adaptation transcriptome and those resulting from in vitro iron depletion, alkaline shift, nitrogen starvation and loss of the methyltransferase LaeA. This first transcriptional snapshot of a fungal genome during initiation of mammalian infection provides the global perspective required to direct much-needed diagnostic and therapeutic strategies and reveals genome organisation and subtelomeric diversity as potential driving forces in the evolution of pathogenicity in the genus Aspergillus.},
}
@article {pmid18780750,
year = {2008},
author = {Lowden, MR and Meier, B and Lee, TW and Hall, J and Ahmed, S},
title = {End joining at Caenorhabditis elegans telomeres.},
journal = {Genetics},
volume = {180},
number = {2},
pages = {741-754},
pmid = {18780750},
issn = {0016-6731},
support = {R56 GM066228/GM/NIGMS NIH HHS/United States ; F31 GM072150/GM/NIGMS NIH HHS/United States ; GM-066228-02S1/GM/NIGMS NIH HHS/United States ; GM-066228/GM/NIGMS NIH HHS/United States ; R01 GM066228/GM/NIGMS NIH HHS/United States ; GM-072150/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Caenorhabditis elegans/*genetics/metabolism ; Chromosomes/metabolism ; DNA Ligases/metabolism ; DNA Repair ; Models, Genetic ; Mutation ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {Critically shortened telomeres can be subjected to DNA repair events that generate end-to-end chromosome fusions. The resulting dicentric chromosomes can enter breakage-fusion-bridge cycles, thereby impeding elucidation of the structures of the initial fusion events and a mechanistic understanding of their genesis. Current models for the molecular basis of fusion of critically shortened, uncapped telomeres rely on PCR assays that typically capture fusion breakpoints created by direct ligation of chromosome ends. Here we use independent approaches that rely on distinctive features of Caenorhabditis elegans to study the frequency of direct end-to-end chromosome fusion in telomerase mutants: (1) holocentric chromosomes that allow for genetic isolation of stable end-to-end fusions and (2) unique subtelomeric sequences that allow for thorough PCR analysis of samples of genomic DNA harboring multiple end-to-end fusions. Surprisingly, only a minority of end-to-end fusion events resulted from direct end joining with no additional genome rearrangements. We also demonstrate that deficiency for the C. elegans Ku DNA repair heterodimer does not affect telomere length or cause synthetic effects in the absence of telomerase.},
}
@article {pmid18778766,
year = {2008},
author = {Tsolou, A and Passos, JF and Nelson, G and Arai, Y and Zglinicki, Tv},
title = {ssDNA fragments induce cell senescence by telomere uncapping.},
journal = {Experimental gerontology},
volume = {43},
number = {10},
pages = {892-899},
doi = {10.1016/j.exger.2008.08.043},
pmid = {18778766},
issn = {1873-6815},
support = {//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Cell Cycle/genetics ; Cells, Cultured ; Cellular Senescence/genetics/*physiology ; DNA Damage/genetics/*physiology ; DNA Repair/genetics ; DNA, Single-Stranded/genetics ; Fibroblasts/*metabolism ; Fluorescent Antibody Technique ; Genomic Instability ; Humans ; Oligonucleotides/genetics/*metabolism ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*physiology ; },
abstract = {Telomere uncapping is known to induce senescence by activating a DNA damage response (DDR). However, it is still unclear what structural features of uncapped telomeres activate DDR. One hypothesis is that the exposure of the telomeric single-stranded G-rich 3' overhang triggers a DNA damage response and is, thus, equivalent to telomere uncapping. To mimic this, we compared the effects of two short single-stranded oligonucleotides, (TTAGGG)(2) and (CCCTAA)(2). G-rich oligonucleotides induced DNA damage foci containing gammaH2AX and senescence-like arrest, whilst C-rich oligonucleotides had no effect. Oligonucleotides did not co-localize with gammaEta2AlphaX foci, instead the induced DNA damage foci were preferentially localized at telomeres. BrdU incorporation assays showed that the effect of G oligonucleotides on gammaH2AX foci formation was cell cycle-dependent; entry of cells into S phase was necessary for subsequent DNA damage foci formation. Together, our results show that short G-rich single-stranded oligonucleotides induce telomere uncapping in a cell cycle-dependent manner, probably by titrating essential factors like Pot1 away from telomeres.},
}
@article {pmid18776307,
year = {2008},
author = {Xu, Y and Kimura, T and Komiyama, M},
title = {Human telomere RNA and DNA form an intermolecular G-quadruplex.},
journal = {Nucleic acids symposium series (2004)},
volume = {},
number = {52},
pages = {169-170},
doi = {10.1093/nass/nrn086},
pmid = {18776307},
issn = {1746-8272},
mesh = {Circular Dichroism ; DNA/*chemistry ; *G-Quadruplexes ; Models, Molecular ; RNA/*chemistry ; Telomere/*chemistry ; },
abstract = {For a long time, telomeres have been considered to be transcriptionally silent. Recently, Azzalin et al. demonstrated that telomeres are transcribed into telomeric repeat-containing RNA (TERRA) in mammalian cells. The telomere RNA was found to localize at the telomere DNA. These findings raise a possibility of that telomere RNA may be involved in an intermolecular G-quadruplex with the telomere DNA. In the current studies, we found that human telomere RNA and telomere DNA sequence can form hybrid-type parallel G-quadruplex structure. These results provide valuable information to allow understanding of the roles of human telomeric RNA in chromosome ends regulation and protection.},
}
@article {pmid18772468,
year = {2008},
author = {Terry, DF and Nolan, VG and Andersen, SL and Perls, TT and Cawthon, R},
title = {Association of longer telomeres with better health in centenarians.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {63},
number = {8},
pages = {809-812},
pmid = {18772468},
issn = {1079-5006},
support = {K24 AG025727-02/AG/NIA NIH HHS/United States ; U19 AG023122/AG/NIA NIH HHS/United States ; K24 AG025727/AG/NIA NIH HHS/United States ; K23 AG026754/AG/NIA NIH HHS/United States ; K23 AG 026754/AG/NIA NIH HHS/United States ; K24 AG 025727/AG/NIA NIH HHS/United States ; U19 AG 23122/AG/NIA NIH HHS/United States ; },
mesh = {Activities of Daily Living ; Aged, 80 and over/*physiology ; Female ; *Health Status ; Humans ; Longevity/*physiology ; Male ; *Telomere/ultrastructure ; },
abstract = {Prior animal model studies have demonstrated an association between telomere length and longevity. Our study examines telomere length in centenarians in good health versus poor health. Using DNA from blood lymphocytes, telomere length was measured by quantitative polymerase chain reaction in 38 sex- and age-matched centenarians (ages 97-108). "Healthy" centenarians (n = 19) with physical function in the independent range and the absence of hypertension, congestive heart failure, myocardial infarction, peripheral vascular disease, dementia, cancer, stroke, chronic obstructive pulmonary disease, and diabetes were compared to centenarians with physical function limitations and > or =2 of the above conditions (n = 19). Healthy centenarians had significantly longer telomeres than did unhealthy centenarians (p =.0475). Our study demonstrated that investigations of the association between telomere length and exceptional longevity must take into account the health status of the individuals. This raises the possibility that perhaps it is not exceptional longevity but one's function and health that may be associated with telomere length.},
}
@article {pmid18771173,
year = {2008},
author = {Zakharenko, LP and Perepelkina, MP and Mai, S},
title = {[Three-dimensional organization of telomeres in the Drosophila melanogaster salivary glands nuclei].},
journal = {Tsitologiia},
volume = {50},
number = {7},
pages = {585-589},
pmid = {18771173},
issn = {0041-3771},
mesh = {Animals ; Cell Nucleus/*ultrastructure ; Drosophila melanogaster/*ultrastructure ; Female ; In Situ Hybridization, Fluorescence/methods ; Male ; Microscopy, Confocal ; Salivary Glands/*ultrastructure ; Telomere/*ultrastructure ; X Chromosome/ultrastructure ; },
abstract = {The 3D-FISH was employed to investigate the telomere topology in polytene nuclei of salivary glands of Drosophila melanogaster. The majorities of telomeres in polytene nuclei of salivary glands in Drosophila strain y(2-717) are localized in the nuclear central area and have no contacts with nuclear membrane. In females of this strain, ectopic contacts between telomeres occur at 25 % higher frequency than in males. HeT-A DNA in y(2-717alk3-2) strain, which is a derivative of y(2-717) carrying an inversion between 1D and 13C bands, is found in region 13 of X chromosome. The frequency of ectopic contacts of telomeres in y(2-717alk3-2) males is 10 % higher than that in y(2-717) strain. The number of ectopic contacts can be significantly different in independent experiments, possibly indicating the role of random factors in the contact formation.},
}
@article {pmid18770817,
year = {2005},
author = {O'Sullivan, JN and Finley, JC and Risques, RA and Shen, WT and Gollahon, KA and Rabinovitch, PS},
title = {Quantitative fluorescence in situ hybridization (QFISH) of telomere lengths in tissue and cells.},
journal = {Current protocols in cytometry},
volume = {Chapter 12},
number = {},
pages = {Unit 12.6},
doi = {10.1002/0471142956.cy1206s33},
pmid = {18770817},
issn = {1934-9300},
mesh = {Animals ; Cells/cytology/ultrastructure ; Chromosomes/physiology/ultrastructure ; Formaldehyde ; Image Processing, Computer-Assisted ; In Situ Hybridization/*methods ; Spectrometry, Fluorescence/methods ; Telomere/*ultrastructure ; },
abstract = {Telomeres are repetitive DNA sequences at the end of each chromosome that provide stability and prevent end-to-end chromosome fusions. In order to understand mechanisms responsible for telomere shortening, it is necessary to develop methods for accurate telomere length measurement that can be applied to archival and fresh tissue and cells. This unit describes in situ-based quantitative fluorescence in situ hybridization (QFISH) protocols using a fluorescence-conjugated telomere probe (peptide nucleic acid, PNA) that stains telomeres proportionally to their length. These protocols can be used on formalin-fixed paraffin-embedded tissue, lightly fixed tissue, cells isolated from tissue, cultured cells, and agar-embedded cells. The basic protocol for QFISH staining is modified to achieve excellent QFISH staining for a variety of cell preparations. Image-analysis techniques to quantitate average telomere lengths from tissues and isolated stained cells are also described.},
}
@article {pmid18770803,
year = {2004},
author = {Schmid, I and Jamieson, BD},
title = {Assessment of telomere length, phenotype, and DNA content.},
journal = {Current protocols in cytometry},
volume = {Chapter 7},
number = {},
pages = {Unit 7.26},
pmid = {18770803},
issn = {1934-9300},
support = {P30 AI028697/AI/NIAID NIH HHS/United States ; P30 CA016042/CA/NCI NIH HHS/United States ; CA-16042/CA/NCI NIH HHS/United States ; AI-28697/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; DNA/*analysis ; Flow Cytometry/*methods ; Humans ; In Situ Hybridization, Fluorescence ; Phenotype ; Ploidies ; Resting Phase, Cell Cycle ; Telomere/*chemistry/ultrastructure ; },
abstract = {Telomere sequences at the end of chromosomes control somatic cell division; therefore, telomere length in a given cell population provides information about its replication potential. This unit describes a method for flow cytometric measurement of telomere length in subpopulations using fluorescence in situ hybridization of fluorescently-labeled probes (Flow-FISH) without prior cell separation. After cells are stained for surface immunofluorescence, antigen-antibody complexes are covalently cross-linked onto cell membranes before FISH with a telomere-specific probe. Cells with long telomeres are included as internal standards. Addition of a DNA dye permits exclusion of proliferating cells during data analysis. DNA ploidy measurements of cells of interest and internal standard are performed on separate aliquots in parallel to Flow-FISH. Telomere fluorescence of G(0/1) cells of subpopulations and internal standards obtained from Flow-FISH are normalized for DNA ploidy and telomere length in subsets of interest is expressed as a fraction of the internal standard telomere length.},
}
@article {pmid18769471,
year = {2008},
author = {Benetti, R and Gonzalo, S and Jaco, I and Muñoz, P and Gonzalez, S and Schoeftner, S and Murchison, E and Andl, T and Chen, T and Klatt, P and Li, E and Serrano, M and Millar, S and Hannon, G and Blasco, MA},
title = {A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases.},
journal = {Nature structural &amp; molecular biology},
volume = {15},
number = {9},
pages = {998},
doi = {10.1038/nsmb0908-998b},
pmid = {18769471},
issn = {1545-9985},
}
@article {pmid18765247,
year = {2008},
author = {Halaschek-Wiener, J and Vulto, I and Fornika, D and Collins, J and Connors, JM and Le, ND and Lansdorp, PM and Brooks-Wilson, A},
title = {Reduced telomere length variation in healthy oldest old.},
journal = {Mechanisms of ageing and development},
volume = {129},
number = {11},
pages = {638-641},
doi = {10.1016/j.mad.2008.07.004},
pmid = {18765247},
issn = {0047-6374},
mesh = {Adolescent ; Adult ; Age Distribution ; Age Factors ; Aged, 80 and over ; Aging/*genetics ; B-Lymphocytes/metabolism ; Case-Control Studies ; Child ; Child, Preschool ; Female ; Flow Cytometry ; Granulocytes/metabolism ; Humans ; Immunologic Memory ; In Situ Hybridization, Fluorescence ; Infant ; Leukocyte Common Antigens/analysis ; Leukocytes/immunology/*metabolism ; Male ; Middle Aged ; T-Lymphocytes/metabolism ; Telomere/*metabolism ; Young Adult ; },
abstract = {Telomeres protect against DNA degradation at the ends of linear chromosomes. The number of telomere repeats is reduced over time in human aging. Using flow FISH we have assessed telomere length in 134 exceptionally healthy seniors aged 85 or older who have never been diagnosed with cancer, cardiovascular disease, major pulmonary disease, diabetes or Alzheimer disease (the 'Super-seniors') and 47 randomly-ascertained mid-life individuals aged 40-50 years. We compared their telomere lengths to a reference interval based on 400 individuals aged 1-100 years and show that Super-seniors do not have exceptionally long telomeres for their age. Consistent with the known trend of telomere shortening over time; however, they have shorter telomeres than the younger control group. Furthermore, we show that variability in telomere length was lower in the Super-seniors than in the mid-life controls or the reference data. Reduced telomere length variation was observed for lymphocytes, CD45RA-positive T-cells and memory T-cells. These results suggest that individuals, some types of their somatic cells, or both, may be selected for an optimal rather than extreme telomere length. Selection of individuals and/or cells that have an optimal telomere repeat length could contribute to disease resistance and promote healthy aging.},
}
@article {pmid18762811,
year = {2008},
author = {Vera, E and Canela, A and Fraga, MF and Esteller, M and Blasco, MA},
title = {Epigenetic regulation of telomeres in human cancer.},
journal = {Oncogene},
volume = {27},
number = {54},
pages = {6817-6833},
doi = {10.1038/onc.2008.289},
pmid = {18762811},
issn = {1476-5594},
mesh = {Acetylation ; Cell Line, Tumor ; DNA Methylation/genetics ; DNA, Neoplasm/genetics ; Epigenesis, Genetic/*genetics ; Gene Amplification ; *Gene Expression Regulation, Neoplastic ; Genome, Human ; Histones/genetics ; Humans ; Neoplasms/*genetics ; Recombination, Genetic ; Repetitive Sequences, Nucleic Acid/genetics ; Telomerase/genetics/metabolism ; Telomere/chemistry/*genetics/ultrastructure ; },
abstract = {Hypomethylation of repeated elements in the genome is a common feature of human cancer, however, the direct consequences of this epigenetic defect for cancer biology are still largely unknown. Telomeres are specialized chromatin structures at the ends of eukaryotic chromosomes formed by tandem repeats of G-rich sequences and associated proteins, which have an essential role in chromosome end protection and genomic stability. Telomeric DNA repeats cannot be methylated, however, the adjacent subtelomeric DNA is heavily methylated in humans. Here, we show that the methylation status of subtelomeric DNA repeats negatively correlates with telomere length and telomere recombination in a large panel of human cancer cell lines. These findings suggest that tumor telomere length and integrity can be influenced by epigenetic factors. Finally, we show that treatment of human cancer cell lines with demethylating drugs results in hypomethylation of subtelomeric repeats and increased telomere recombination, which in turn may facilitate telomere elongation. All together, these findings suggest that tumor telomere length and integrity can be influenced by the epigenetic status of cancer cells.},
}
@article {pmid18762552,
year = {2008},
author = {Wilson, WR and Herbert, KE and Mistry, Y and Stevens, SE and Patel, HR and Hastings, RA and Thompson, MM and Williams, B},
title = {Blood leucocyte telomere DNA content predicts vascular telomere DNA content in humans with and without vascular disease.},
journal = {European heart journal},
volume = {29},
number = {21},
pages = {2689-2694},
doi = {10.1093/eurheartj/ehn386},
pmid = {18762552},
issn = {1522-9645},
support = {PG/2001110//British Heart Foundation/United Kingdom ; },
mesh = {Aged ; Aorta, Abdominal/*chemistry/pathology ; *Aortic Aneurysm, Abdominal/pathology ; Biopsy ; Cellular Senescence/physiology ; DNA/*analysis ; Female ; Humans ; Leukocytes/*chemistry/pathology ; Male ; Middle Aged ; Polymerase Chain Reaction ; Telomere/*genetics ; },
abstract = {AIMS: Previous studies have suggested that reduced telomere length in circulating leucocytes in humans is associated with premature vascular disease and by implication, accelerated vascular ageing. Importantly, a link between telomere length in circulating leucocytes and the blood vessel wall has never been established. We, thus, investigated the relationship between vascular wall and circulating leucocyte telomere length in humans with and without overt vascular disease.<br><br>METHODS AND RESULTS: Aortic biopsies and paired blood leucocytes were obtained from 20 patients with asymptomatic abdominal aortic aneurysms (AAAs), undergoing elective open repair, and 12 morphologically normal aortas from a group of cadaveric organ donors of similar mean age. Telomere content was compared by quantitative PCR and expressed as telomere:genomic DNA ratio. The telomere:genomic DNA content was significantly reduced in wall biopsies of AAA vs. normal aorta, and this difference remained after adjusting for age and gender. There were strong correlations between leucocyte and vascular telomere content when the AAA and control groups were analysed either separately or grouped irrespective of the presence of vascular disease (r = 0.62, P < 0.001).<br><br>CONCLUSION: The findings demonstrate that leucocyte DNA content is predictive of vascular telomere content and is an accurate surrogate for human vascular age.},
}
@article {pmid18761675,
year = {2008},
author = {Tatsumi, Y and Ezura, K and Yoshida, K and Yugawa, T and Narisawa-Saito, M and Kiyono, T and Ohta, S and Obuse, C and Fujita, M},
title = {Involvement of human ORC and TRF2 in pre-replication complex assembly at telomeres.},
journal = {Genes to cells : devoted to molecular &amp; cellular mechanisms},
volume = {13},
number = {10},
pages = {1045-1059},
doi = {10.1111/j.1365-2443.2008.01224.x},
pmid = {18761675},
issn = {1365-2443},
mesh = {Cell Cycle/physiology ; Cell Line, Transformed ; Cell Nucleus/metabolism ; Chromatin Immunoprecipitation ; *DNA Replication ; Fibroblasts/metabolism ; HeLa Cells/metabolism ; Humans ; Origin Recognition Complex/*metabolism ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {The origin recognition complex (ORC) binds to replication origins to regulate the cell cycle-dependent assembly of pre-replication complexes (pre-RCs). We have found a novel link between pre-RC assembly regulation and telomere homeostasis in human cells. Biochemical analyses showed that human ORC binds to TRF2, a telomere sequence-binding protein that protects telomeres and functions in telomere length homeostasis, via the ORC1 subunit. Immunostaining further revealed that ORC and TRF2 partially co-localize in nuclei, whereas chromatin immunoprecipitation analyses confirmed that pre-RCs are assembled at telomeres in a cell cycle-dependent manner. Over-expression of TRF2 stimulated ORC and MCM binding to chromatin and RNAi-directed TRF2 silencing resulted in reduced ORC binding and pre-RC assembly at telomeres. As expected from previous reports, TRF2 silencing induced telomere elongation. Interestingly, ORC1 silencing by RNAi weakened the TRF2 binding as well as the pre-RC assembly at telomeres, suggesting that ORC and TRF2 interact with each other to achieve stable binding. Furthermore, ORC1 silencing also resulted in modest telomere elongation. These data suggest that ORC might be involved in telomere homeostasis in human cells.},
}
@article {pmid18759763,
year = {2008},
author = {Röth, A and de Beer, D and Nückel, H and Sellmann, L and Dührsen, U and Dürig, J and Baerlocher, GM},
title = {Significantly shorter telomeres in T-cells of patients with ZAP-70+/CD38+ chronic lymphocytic leukaemia.},
journal = {British journal of haematology},
volume = {143},
number = {3},
pages = {383-386},
doi = {10.1111/j.1365-2141.2008.07363.x},
pmid = {18759763},
issn = {1365-2141},
mesh = {ADP-ribosyl Cyclase 1/blood ; Adult ; Aged ; Aged, 80 and over ; Antigens, Neoplasm/blood ; Cell Proliferation ; Female ; Humans ; Immunologic Memory ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics/*immunology ; Male ; Membrane Glycoproteins/blood ; Middle Aged ; Retrospective Studies ; T-Lymphocytes/*ultrastructure ; Telomere/*pathology ; ZAP-70 Protein-Tyrosine Kinase/blood ; },
abstract = {In contrast to other B-cell neoplasias, chronic lymphocytic leukaemia (CLL) is characterized by increased non-leukaemic T-cells. In order to assess their replicative history, telomere length was analyzed in subsets of leucocytes from CLL patients. Naive and memory T-cells from ZAP-70(+)/CD38(+) patients exhibited significantly shorter average telomere lengths than ZAP-70(-)/CD38(-) patients. Compared to the age-related percentiles of telomere length values from healthy individuals practically all values of the naive and memory T-cells from the ZAP-70(+)/CD38(+) CLL patients fell below the 50th percentile. This indicated an extensive expansion and a role for T-cells in ZAP-70(+)/CD38(+) CLL patients.},
}
@article {pmid18759744,
year = {2008},
author = {Rhodin Edsö, J and Tati, R and Cohn, M},
title = {Highly sequence-specific binding is retained within the DNA-binding domain of the Saccharomyces castellii Cdc13 telomere-binding protein.},
journal = {FEMS yeast research},
volume = {8},
number = {8},
pages = {1289-1302},
doi = {10.1111/j.1567-1364.2008.00431.x},
pmid = {18759744},
issn = {1567-1356},
mesh = {Base Sequence/*genetics ; Binding Sites ; Cyclin B/*chemistry/genetics/metabolism ; DNA, Fungal/chemistry/genetics/metabolism ; DNA, Single-Stranded/*metabolism ; Fungal Proteins/chemistry/genetics/metabolism ; Gene Expression Regulation, Fungal ; Molecular Sequence Data ; Saccharomyces/classification/genetics/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*chemistry/genetics/metabolism ; },
abstract = {The essential protein Cdc13p binds the single-stranded telomeric 3' overhangs in Saccharomyces cerevisiae and takes part in the regulation of telomere length. The DNA-binding domain (DBD) of Cdc13p is structurally established by an oligonucleotide/oligosaccharide-binding (OB)-fold domain. The sequence homolog in Saccharomyces castellii (scasCDC13) was characterized previously, and the full-length protein was found to bind telomeric DNA specifically. Here, the DBD of scasCdc13p was defined to the central part (402-658) of the protein. The region necessary for forming the scasCdc13p-DBD is larger than the minimal DBD of S. cerevisiae Cdc13p. Deletion of this extended DBD region from the full-length protein completely abolished the DNA binding, indicating the importance of the extended region for the correct formation of a binding-competent DBD. The scasCdc13p-DBD bound the same 8-mer minimal binding site as the full-length protein, but an extension of the target site in the 3' end increased the stability of the DNA-protein complex. Significantly, scasCdc13p-DBD showed a retained high sequence specific binding, where the four nucleotides of most importance for the sequence specificity are highly conserved in eukaryotic telomeric repeats. Thus, the unique single-stranded DNA-binding properties of the full-length protein are entirely retained within the isolated scasCdc13p-DBD.},
}
@article {pmid18753630,
year = {2008},
author = {Alder, JK and Chen, JJ and Lancaster, L and Danoff, S and Su, SC and Cogan, JD and Vulto, I and Xie, M and Qi, X and Tuder, RM and Phillips, JA and Lansdorp, PM and Loyd, JE and Armanios, MY},
title = {Short telomeres are a risk factor for idiopathic pulmonary fibrosis.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {105},
number = {35},
pages = {13051-13056},
pmid = {18753630},
issn = {1091-6490},
support = {K08 118416//PHS HHS/United States ; T32 60441//PHS HHS/United States ; },
mesh = {Biomarkers/metabolism ; Case-Control Studies ; Epithelium/pathology ; Family ; Fibrosis/complications/diagnostic imaging/pathology ; Germ-Line Mutation ; Heterozygote ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes, Mononuclear/metabolism ; Pulmonary Alveoli/pathology ; Pulmonary Fibrosis/complications/diagnostic imaging/*genetics/pathology ; RNA/genetics ; Risk Factors ; Telomerase/genetics ; Telomere/*metabolism ; Tomography, X-Ray Computed ; },
abstract = {Idiopathic interstitial pneumonias (IIPs) have a progressive and often fatal course, and their enigmatic etiology has complicated approaches to effective therapies. Idiopathic pulmonary fibrosis (IPF) is the most common of IIPs and shares with IIPs an increased incidence with age and unexplained scarring in the lung. Short telomeres limit tissue renewal capacity in the lung and germ-line mutations in telomerase components, hTERT and hTR, underlie inheritance in a subset of families with IPF. To examine the hypothesis that short telomeres contribute to disease risk in sporadic IIPs, we recruited patients who have no family history and examined telomere length in leukocytes and in alveolar cells. To screen for mutations, we sequenced hTERT and hTR. We also reviewed the cases for features of a telomere syndrome. IIP patients had shorter leukocyte telomeres than age-matched controls (P < 0.0001). In a subset (10%), IIP patients had telomere lengths below the first percentile for their age. Similar to familial cases with mutations, IPF patients had short telomeres in alveolar epithelial cells (P < 0.0001). Although telomerase mutations were rare, detected in 1 of 100 patients, we identified a cluster of individuals (3%) with IPF and cryptogenic liver cirrhosis, another feature of a telomere syndrome. Short telomeres are thus a signature in IIPs and likely play a role in their age-related onset. The clustering of cryptogenic liver cirrhosis with IPF suggests that the telomere shortening we identify has consequences and can contribute to what appears clinically as idiopathic progressive organ failure in the lung and the liver.},
}
@article {pmid18727506,
year = {2005},
author = {Greenberg, RA and Rudolph, KL},
title = {Telomere structural dynamics in genome integrity control and carcinogenesis.},
journal = {Advances in experimental medicine and biology},
volume = {570},
number = {},
pages = {311-341},
doi = {10.1007/1-4020-3764-3_11},
pmid = {18727506},
issn = {0065-2598},
mesh = {Aging/genetics/metabolism ; Animals ; Cell Transformation, Neoplastic/*genetics ; Chromosomal Instability ; DNA Damage ; Genome ; *Genomic Instability ; Humans ; Neoplasms/genetics/metabolism ; Telomere/*chemistry/*metabolism ; },
}
@article {pmid18726253,
year = {1998},
author = {Gong, X and Hong, D and Chen, S and Shen, L and Li, P and Yan, C},
title = {Isolation and characterization of five rice telomere-associated sequences.},
journal = {Science in China. Series C, Life sciences},
volume = {41},
number = {4},
pages = {372-380},
doi = {10.1007/BF02882736},
pmid = {18726253},
issn = {1006-9305},
abstract = {Acoording to the telomere-repeated sequences of rice, two primers: (TTTAGGG11)(3) and (CCC-TAA.A)(3)CCC were used to amplify rice telomere-assciated sequences (TASs). Fox PCR template preparation. total DNA was digested with restrictive endonuclease and then ligated. Using the ligates or total DNA sa template, eight fragments were obtained with the single primer by the PCR reaction. To confirm that the sequences are derived from telomeric DNA, we conducted Bal31 digestion analysis. Of the eight fragments, seven were susceptible to Bal31 treatment, suggesting that they were TASs. These DNA fragments were further demonstrated u, be rice sub-telomeric sequences by RFLP mapping Five sequences have been mapped to the distal ends on rice chromme 5,6,7 and 9, and two other sequences have been mapped at interstitial sites, suggesting that (TTTAGGG)(n). also exist in the middle of rice chromosomes-All eight fragments were sequenced and characterized.},
}
@article {pmid18726217,
year = {1998},
author = {Gong, X and Chen, S and Gong, J and Liu, F},
title = {Isolation and mapping of bacterial artificial chromosome (BAC) clone containing telomere-associated sequence.},
journal = {Science in China. Series C, Life sciences},
volume = {41},
number = {6},
pages = {617-622},
doi = {10.1007/BF02882903},
pmid = {18726217},
issn = {1006-9305},
abstract = {Using single primer (TTTAGGG)(3) or (CCCTAAA)(3)CCC corresponding to rice telomeric repeat sequences, two fragments were amplified from rice genomic DNA and named Tas1 and Tas2. These two fragments did not show polymorphism between the mapping parents. Tasl was found to hybridize to rice telomeric regions by in situ hybridization (FISH). Then a rice bacterial artificial chromosome (BAC) library was constructed and Tasl was used to screen it. One positive clone was identified. A single copy sequence of this BAC clone was mapped at the end of the 6th chromosome of rice.},
}
@article {pmid18724055,
year = {2006},
author = {Ju, Z and Rudolph, KL},
title = {Telomeres and telomerase in stem cells during aging and disease.},
journal = {Genome dynamics},
volume = {1},
number = {},
pages = {84-103},
doi = {10.1159/000092502},
pmid = {18724055},
issn = {1660-9263},
mesh = {*Aging/genetics ; Animals ; Cellular Senescence/genetics ; Disease Models, Animal ; Disease Progression ; Genetic Diseases, Inborn/*genetics ; Genetic Techniques ; Humans ; Mice ; Models, Biological ; Neoplasms/genetics ; Stem Cells/*cytology ; Telomerase/*genetics/metabolism/*physiology ; Telomere/*ultrastructure ; },
abstract = {Cell cycle checkpoints induced by telomere dysfunction represent one of the major in vivo tumor suppressor mechanisms preventing cancer but at the same time provoking age dependent decline in self-renewal and regeneration of tissues and organs. On the other hand, telomere shortening contributes to the initiation of cancer by inducing chromosomal instability. Telomere function and telomerase activity are mainly associated with actively proliferating cells. Since stem cells are continuously proliferating throughout lifetime, it is of great interest to explore the role of telomeres and telomerase in stem cells. Although most stem cell compartments express telomerase, the level of telomerase activity is not sufficient to maintain telomere length of stem cells during aging. Stem cells appear to have tighter DNAdamage checkpoint control in comparison to somatic cells, which may reflect the need to protect this long lasting cell compartment against malignant transformation. These enhanced checkpoint responses may have a detrimental impact on stem cell function, by causing increased sensitivity towards senescence or apoptosis induced by telomere shortening. This review summarizes our knowledge on telomere dynamics and its functional impact on stem cells during aging and transformation.},
}
@article {pmid18723888,
year = {2008},
author = {Frydrychova, RC and Mason, JM and Archer, TK},
title = {HP1 is distributed within distinct chromatin domains at Drosophila telomeres.},
journal = {Genetics},
volume = {180},
number = {1},
pages = {121-131},
pmid = {18723888},
issn = {0016-6731},
support = {//Intramural NIH HHS/United States ; },
mesh = {Animals ; Chromatin/*chemistry/genetics ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/*genetics ; Chromosomes/ultrastructure ; Drosophila Proteins/*genetics ; Drosophila melanogaster/*genetics ; Gene Silencing ; Micrococcal Nuclease/genetics ; Models, Genetic ; Mutation ; Nucleosomes/ultrastructure ; Protein Binding ; Protein Structure, Tertiary ; Telomere/*ultrastructure ; Transcription, Genetic ; Transgenes ; },
abstract = {Telomeric regions in Drosophila are composed of three subdomains. A chromosome cap distinguishes the chromosome end from a DNA double-strand break; an array of retrotransposons, HeT-A, TART, and TAHRE (HTT), maintains telomere length by targeted transposition to chromosome ends; and telomere-associated sequence (TAS), which consists of a mosaic of complex repeated sequences, has been identified as a source of gene silencing. Heterochromatin protein 1 (HP1) and HP1-ORC-associated protein (HOAP) are major protein components of the telomere cap in Drosophila and are required for telomere stability. Besides the chromosome cap, HP1 is also localized along the HTT array and in TAS. Mutants for Su(var)205, the gene encoding HP1, have decreased the HP1 level in the HTT array and increased transcription of individual HeT-A elements. This suggests that HP1 levels directly affect HeT-A activity along the HTT array, although they have little or no effect on transcription of a white reporter gene in the HTT. Chromatin immunoprecipitation to identify other heterochromatic proteins indicates that TAS and the HTT array may be distinct from either heterochromatin or euchromatin.},
}
@article {pmid18722365,
year = {2008},
author = {Derradji, H and Bekaert, S and De Meyer, T and Jacquet, P and Abou-El-Ardat, K and Ghardi, M and Arlette, M and Baatout, S},
title = {Ionizing radiation-induced gene modulations, cytokine content changes and telomere shortening in mouse fetuses exhibiting forelimb defects.},
journal = {Developmental biology},
volume = {322},
number = {2},
pages = {302-313},
doi = {10.1016/j.ydbio.2008.07.032},
pmid = {18722365},
issn = {1095-564X},
mesh = {Abnormalities, Radiation-Induced/etiology/*metabolism/pathology ; Amniotic Fluid/metabolism ; Animals ; Apoptosis ; Cytokines/*metabolism ; DNA Damage ; Female ; Fetus/abnormalities/*metabolism ; Forelimb/abnormalities/*metabolism ; Limb Buds/cytology/radiation effects ; MAP Kinase Signaling System/radiation effects ; Male ; Maternal Exposure/*adverse effects ; Mice ; Mice, Inbred C57BL ; Telomere/metabolism/*ultrastructure ; Tumor Suppressor Protein p53 ; },
abstract = {Several lines of evidence have linked limb teratogenesis to radiation-induced apoptosis and to the p53 status in murine fetuses. In previous reports, we studied the occurrence of various malformations after intrauterine irradiation and showed that these malformations were modulated by p53-deficiency as well as by the developmental stage at which embryos were irradiated. In this new study, we focused onto one particular phenotype namely forelimb defects to further unravel the cellular and molecular mechanisms underlying this malformation. We measured various parameters expected to be directly or indirectly influenced by irradiation damage. The mouse fetuses were irradiated at day 12 p.c. (post conception) and examined for forelimb defects on gestational days 15, 16, 17 and 19 of development. The release of inflammatory cytokines was determined in the amniotic fluid on day 16 p.c. and the mean telomere lengths assessed at days 12, 13 and 19 p.c. Differential gene expression within the forelimb bud tissues was determined using Real Time quantitative PCR (RTqPCR) 24 h following irradiation. Apoptosis was investigated in the normal and malformed fetuses using the TUNEL assay and RTqPCR. First, we found that irradiated fetuses with forelimb defects displayed excessive apoptosis in the predigital regions. Besides, overexpression of the pro-apoptotic Bax gene indicates a mitochondrial-mediated cell death. Secondly, our results showed overexpression of MKK3 and MKK7 (members of the stress-activated MAP kinase family) within the malformed fetuses. The latter could be involved in radiation-induced apoptosis through activation of the p38 and JNK pathways. Thirdly, we found that irradiated fetuses exhibiting forelimb defects showed a marked telomere shortening. Interestingly, telomere shortening was observed as the malformations became apparent. Fourthly, we measured cytokine levels in the amniotic fluid and detected a considerable inflammatory reaction among the irradiated fetuses as evidenced by the increase in pro-inflammatory cytokine levels. Altogether, our data suggest that transcriptional modulations of apoptotic, inflammation, stress, and DNA damage players are early events in radiation-induced forelimb defects. These changes resulted in harsh developmental conditions as indicated by a marked increase in cytokine levels in the amniotic fluid and telomere shortening, two features concomitant with the onset of the forelimb defect phenotype in our study.},
}
@article {pmid18722173,
year = {2008},
author = {Wang, X and Baumann, P},
title = {Chromosome fusions following telomere loss are mediated by single-strand annealing.},
journal = {Molecular cell},
volume = {31},
number = {4},
pages = {463-473},
doi = {10.1016/j.molcel.2008.05.028},
pmid = {18722173},
issn = {1097-4164},
mesh = {Blotting, Southern ; Chromosomes, Fungal/*metabolism ; DNA, Fungal/*metabolism ; Deoxyribonuclease EcoRI/metabolism ; Gene Deletion ; Microbial Viability ; Recombination, Genetic ; Schizosaccharomyces/cytology ; Schizosaccharomyces pombe Proteins/metabolism ; Sequence Homology, Nucleic Acid ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {Progressive telomere shortening eventually results in chromosome fusions and genome instability as the cell's ability to distinguish chromosome ends from DNA double-strand breaks is compromised. In fission yeast, such events frequently produce stable survivors with all circular chromosomes. To shed light on the repair pathways that mediate chromosome end fusions and generate circular chromosomes, we have examined a diverse array of DNA repair factors. We show that telomere attrition-induced chromosome fusions are dependent on the fission yeast homologs of Rad52, the ERCC1/XPF endonuclease, the single-stranded DNA-binding protein RPA, and the Srs2 and Werner/Bloom helicases, but not Ku and ligase 4. Consistent with a recombinational mechanism of single-strand annealing, cloned junctions map to four of five homology regions in subtelomeric DNA. A comparison with telomere uncapping caused by the absence of the double-stranded telomere-binding protein Taz1 demonstrates that the circumstances and cause of telomere dysfunction profoundly affect which DNA repair pathway is engaged.},
}
@article {pmid18720522,
year = {2008},
author = {Poonepalli, A and Banerjee, B and Ramnarayanan, K and Palanisamy, N and Putti, TC and Hande, MP},
title = {Telomere-mediated genomic instability and the clinico-pathological parameters in breast cancer.},
journal = {Genes, chromosomes &amp; cancer},
volume = {47},
number = {12},
pages = {1098-1109},
doi = {10.1002/gcc.20608},
pmid = {18720522},
issn = {1098-2264},
mesh = {Breast Neoplasms/enzymology/*genetics/pathology ; Female ; Genomic Instability/*genetics ; Humans ; RNA, Messenger/metabolism ; Shelterin Complex ; Tankyrases/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; },
abstract = {A study was undertaken to correlate telomere dysfunction and genomic instability with the histopathological grades and the estrogen and progesterone receptor status in breast cancer. Sixty-one archived breast tissues (38 cancer tissues and 23 paired normal tissues) were used in the study. The breast tumor tissues showed significantly shorter telomeres (7.7 kb) compared with the paired adjacent tissues (9.0 kb) by Southern blot analysis. Moreover, telomere shortening was more significant in Grade III tumors than in the Grade II tumors (P = 0.05). Quantitative fluorescence in situ hybridization on paraffin tissue sections revealed a similar trend in telomere shortening. Telomere attrition was associated with telomere dysfunction as revealed by the presence of significantly higher anaphase bridges in tumor cells which was tumor grade dependent. Furthermore, estrogen receptive negative tumors displayed higher anaphase and internuclear bridges. Selected samples from each grade showed greater genomic imbalances in the higher grades than the lower grade tumors as detected by array-comparative genomic hybridization. Telomerase activity was found to be higher in the higher grades (Grade II and III) compared with the lower grade (Grade I). The average mRNA expression of TRF1 and POT1 was lower in the tumor tissues than in the normal tissues. Tankyrase 1 mRNA expression showed a grade-dependent increase in tumor tissues and its expression was also high in estrogen and progesterone negative tumors. The data support the notion that telomere dysfunction might be of value as a marker of aggressiveness of the tumors in breast cancer patients.},
}
@article {pmid18718693,
year = {2010},
author = {Valdes, AM and Deary, IJ and Gardner, J and Kimura, M and Lu, X and Spector, TD and Aviv, A and Cherkas, LF},
title = {Leukocyte telomere length is associated with cognitive performance in healthy women.},
journal = {Neurobiology of aging},
volume = {31},
number = {6},
pages = {986-992},
pmid = {18718693},
issn = {1558-1497},
support = {R01 AG020132/AG/NIA NIH HHS/United States ; AG020132/AG/NIA NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; G0700704/MRC_/Medical Research Council/United Kingdom ; R01 AG020132-03/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 AG030678/AG/NIA NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; R01 AG030678-01A2/AG/NIA NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Association Learning/physiology ; Cognition/*physiology ; Cohort Studies ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/*physiology ; Memory/physiology ; Middle Aged ; Neuropsychological Tests ; Space Perception/physiology ; *Statistics as Topic ; Telomere/*physiology ; Young Adult ; },
abstract = {BACKGROUND: Age-related cognitive decline begins in mid-life and continues with advancing age. Leukocyte telomere length (LTL) shortens with age, and inflammation and oxidative stress enhance this process. Shorter LTL is associated with dementia.<br><br>METHODS: The relationship between cognitive function and LTL was investigated in a cross-sectional study of 382 women (mean age 50.6 years, range 19-78), not diagnosed with any form of dementia or cognitive impairment, from the TwinsUK cohort using six tests from the Cambridge neuropsychological test automated battery (CANTAB).<br><br>RESULTS: After adjusting for age and estimated prior intellectual ability, we observed significant correlations of LTL with episodic memory and associated learning (PAL, p=0.032), recognition memory for non-verbal patterns (DMS, p=0.007), and working memory capacity (SSP, p=0.003). In pairs of twins discordant for LTL the twin with longer telomeres also had significantly better DMS (p<0.05) and SSP (p<0.013) scores than their co-twin with shorter telomeres. The correlations between these two scores and LTL was significant both in women over the median mean age and in those below the median age, and remained significant after statistical adjustment for potential confounders.<br><br>CONCLUSIONS: Leukocyte telomere length correlates with a subset of measures of cognitive performance, suggesting that it might be a biomarker of cognitive aging in women before the onset of dementia.},
}
@article {pmid18710952,
year = {2008},
author = {Ruis, BL and Fattah, KR and Hendrickson, EA},
title = {The catalytic subunit of DNA-dependent protein kinase regulates proliferation, telomere length, and genomic stability in human somatic cells.},
journal = {Molecular and cellular biology},
volume = {28},
number = {20},
pages = {6182-6195},
pmid = {18710952},
issn = {1098-5549},
support = {P30 CA077598/CA/NCI NIH HHS/United States ; R01 GM069576/GM/NIGMS NIH HHS/United States ; P30 CA077598-09/CA/NCI NIH HHS/United States ; GM069576/GM/NIGMS NIH HHS/United States ; HL079559/HL/NHLBI NIH HHS/United States ; R01 HL079559/HL/NHLBI NIH HHS/United States ; },
mesh = {Biomarkers/metabolism ; *Catalytic Domain ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; DNA Damage ; DNA-Activated Protein Kinase/deficiency/*metabolism ; Etoposide/pharmacology ; Gene Targeting ; *Genomic Instability/drug effects ; HCT116 Cells ; Heterozygote ; Homozygote ; Humans ; Telomere/*metabolism ; },
abstract = {The DNA-dependent protein kinase (DNA-PK) complex is a serine/threonine protein kinase comprised of a 469-kDa catalytic subunit (DNA-PK(cs)) and the DNA binding regulatory heterodimeric (Ku70/Ku86) complex Ku. DNA-PK functions in the nonhomologous end-joining pathway for the repair of DNA double-stranded breaks (DSBs) introduced by either exogenous DNA damage or endogenous processes, such as lymphoid V(D)J recombination. Not surprisingly, mutations in Ku70, Ku86, or DNA-PK(cs) result in animals that are sensitive to agents that cause DSBs and that are also immune deficient. While these phenotypes have been validated in several model systems, an extension of them to humans has been missing due to the lack of patients with mutations in any one of the three DNA-PK subunits. The worldwide lack of patients suggests that during mammalian evolution this complex has become uniquely essential in primates. This hypothesis was substantiated by the demonstration that functional inactivation of either Ku70 or Ku86 in human somatic cell lines is lethal. Here we report on the functional inactivation of DNA-PK(cs) in human somatic cells. Surprisingly, DNA-PK(cs) does not appear to be essential, although the cell line lacking this gene has profound proliferation and genomic stability deficits not observed for other mammalian systems.},
}
@article {pmid18710936,
year = {2008},
author = {Errington, TM and Fu, D and Wong, JM and Collins, K},
title = {Disease-associated human telomerase RNA variants show loss of function for telomere synthesis without dominant-negative interference.},
journal = {Molecular and cellular biology},
volume = {28},
number = {20},
pages = {6510-6520},
pmid = {18710936},
issn = {1098-5549},
support = {R01 HL079585/HL/NHLBI NIH HHS/United States ; R56 HL079585/HL/NHLBI NIH HHS/United States ; HL079585/HL/NHLBI NIH HHS/United States ; },
mesh = {Anemia, Aplastic/*genetics ; Base Sequence ; Cell Line ; Cells, Cultured ; Chromatography, Affinity ; Dyskeratosis Congenita/*genetics ; *Genes, Dominant ; Humans ; Molecular Sequence Data ; Mutation/*genetics ; Nucleic Acid Conformation ; Protein Structure, Quaternary ; RNA/chemistry/*genetics ; Ribonucleoproteins/isolation &amp; purification/metabolism ; Telomerase/chemistry/*genetics ; Telomere/*metabolism ; Templates, Genetic ; },
abstract = {Telomerase adds simple-sequence repeats to chromosome ends to offset the terminal sequence loss inherent in each cycle of genome replication. Inherited mutations in genes encoding subunits of the human telomerase holoenzyme give rise to disease phenotypes including hematopoietic failure and pulmonary fibrosis. Disease-associated variants of the human telomerase RNA are expressed in heterozygous combination with wild-type telomerase RNA. Here, we exploit a sensitized human primary cell assay system to investigate the biological function of disease-linked telomerase RNA variants and their impact on the function of coexpressed wild-type telomerase RNA. We find that telomerase RNA variants discovered in patients with dyskeratosis congenita or aplastic anemia show loss of function without any indication of dominant-negative impact on telomere maintenance by the coexpressed wild-type RNA. To reconcile this result with contradictory findings from reconstitution assays in vitro, we demonstrate that the lack of dominant-negative impact on telomere maintenance correlates with physiological assembly of active human telomerase holoenzyme ribonucleoproteins harboring monomers rather than higher-order multimers of telomerase RNA and telomerase reverse transcriptase. These findings support loss of function of telomerase RNA as a general mechanism of human disease.},
}
@article {pmid18700033,
year = {2008},
author = {Young, R and Taylor, JE and Kurioka, A and Becker, M and Louis, EJ and Rudenko, G},
title = {Isolation and analysis of the genetic diversity of repertoires of VSG expression site containing telomeres from Trypanosoma brucei gambiense, T. b. brucei and T. equiperdum.},
journal = {BMC genomics},
volume = {9},
number = {},
pages = {385},
pmid = {18700033},
issn = {1471-2164},
support = {/WT_/Wellcome Trust/United Kingdom ; 095161/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Cloning, Molecular ; DNA, Protozoan/genetics ; Evolution, Molecular ; Gene Expression ; Gene Library ; Genes, Protozoan ; Genetic Variation ; Molecular Sequence Data ; Phylogeny ; Recombination, Genetic ; Sequence Homology, Amino Acid ; Sequence Homology, Nucleic Acid ; Species Specificity ; Telomere/genetics ; Trypanosoma/*genetics ; Trypanosoma brucei brucei/*genetics ; Trypanosoma brucei gambiense/*genetics ; Variant Surface Glycoproteins, Trypanosoma/*genetics ; },
abstract = {BACKGROUND: African trypanosomes (including Trypanosoma brucei) are unicellular parasites which multiply in the mammalian bloodstream. T. brucei has about twenty telomeric bloodstream form Variant Surface Glycoprotein (VSG) expression sites (BESs), of which one is expressed at a time in a mutually exclusive fashion. BESs are polycistronic transcription units, containing a variety of families of expression site associated genes (ESAGs) in addition to the telomeric VSG. These polymorphic ESAG families are thought to play a role in parasite-host adaptation, and it has been proposed that ESAG diversity might be related to host range. Analysis of the genetic diversity of these telomeric gene families has been confounded by the underrepresentation of telomeric sequences in standard libraries. We have previously developed a method to selectively isolate sets of trypanosome BES containing telomeres using Transformation associated recombination (TAR) cloning in yeast.<br><br>RESULTS: Here we describe the isolation of repertoires of BES containing telomeres from three trypanosome subspecies: Trypanosoma brucei gambiense DAL 972 (causative agent of West-African trypanosomiasis), T. b. brucei EATRO 2340 (a nonhuman infective strain) and T. equiperdum STIB 818 (which causes a sexually transmitted disease in equines). We have sequenced and analysed the genetic diversity at four BES loci (BES promoter region, ESAG6, ESAG5 and ESAG2) from these three trypanosome BES repertoires.<br><br>CONCLUSION: With the exception of ESAG2, the BES sequence repertoires derived from T. b. gambiense are both less diverse than and nearly reciprocally monophyletic relative to those from T. b. brucei and T. equiperdum. Furthermore, although we find evidence for adaptive evolution in all three ESAG repertoires in T. b. brucei and T. equiperdum, only ESAG2 appears to be under diversifying selection in T. b. gambiense. This low level of variation in the T. b. gambiense BES sequence repertoires is consistent both with the relatively narrow host range of this subspecies and its apparent long-term clonality. However, our data does not show a clear correlation between size of trypanosome host range and either number of BESs or extent of ESAG genetic diversity.},
}
@article {pmid18695223,
year = {2008},
author = {Jiang, H and Schiffer, E and Song, Z and Wang, J and Zürbig, P and Thedieck, K and Moes, S and Bantel, H and Saal, N and Jantos, J and Brecht, M and Jenö, P and Hall, MN and Hager, K and Manns, MP and Hecker, H and Ganser, A and Döhner, K and Bartke, A and Meissner, C and Mischak, H and Ju, Z and Rudolph, KL},
title = {Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {105},
number = {32},
pages = {11299-11304},
pmid = {18695223},
issn = {1091-6490},
mesh = {Aging/*metabolism/pathology/radiation effects ; Animals ; Antimicrobial Cationic Peptides/*biosynthesis ; Apoptosis/radiation effects ; Biomarkers/metabolism ; Bone Marrow Cells/metabolism/pathology ; Cathelicidins ; Cellular Senescence/radiation effects ; Chitinases/*biosynthesis ; *DNA Damage/radiation effects ; Female ; Fibroblasts/metabolism/pathology ; Fibrosis/*metabolism/pathology ; Gamma Rays/adverse effects ; Humans ; Male ; Mice ; Mice, Knockout ; Myelodysplastic Syndromes/*metabolism/pathology ; Peptide Elongation Factor 1/*biosynthesis ; Stathmin/*biosynthesis ; Telomerase/genetics/metabolism ; Telomere/*metabolism/pathology ; Up-Regulation/radiation effects ; },
abstract = {Telomere dysfunction limits the proliferative capacity of human cells by activation of DNA damage responses, inducing senescence or apoptosis. In humans, telomere shortening occurs in the vast majority of tissues during aging, and telomere shortening is accelerated in chronic diseases that increase the rate of cell turnover. Yet, the functional role of telomere dysfunction and DNA damage in human aging and diseases remains under debate. Here, we identified marker proteins (i.e., CRAMP, stathmin, EF-1alpha, and chitinase) that are secreted from telomere-dysfunctional bone-marrow cells of late generation telomerase knockout mice (G4mTerc(-/-)). The expression levels of these proteins increase in blood and in various tissues of aging G4mTerc(-/-) mice but not in aging mice with long telomere reserves. Orthologs of these proteins are up-regulated in late-passage presenescent human fibroblasts and in early passage human cells in response to gamma-irradiation. The study shows that the expression level of these marker proteins increases in the blood plasma of aging humans and shows a further increase in geriatric patients with aging-associated diseases. Moreover, there was a significant increase in the expression of the biomarkers in the blood plasma of patients with chronic diseases that are associated with increased rates of cell turnover and telomere shortening, such as cirrhosis and myelodysplastic syndromes (MDS). Analysis of blinded test samples validated the effectiveness of the biomarkers to discriminate between young and old, and between disease groups (MDS, cirrhosis) and healthy controls. These results support the concept that telomere dysfunction and DNA damage are interconnected pathways that are activated during human aging and disease.},
}
@article {pmid18694931,
year = {2008},
author = {Ponnusamy, S and Alderson, NL and Hama, H and Bielawski, J and Jiang, JC and Bhandari, R and Snyder, SH and Jazwinski, SM and Ogretmen, B},
title = {Regulation of telomere length by fatty acid elongase 3 in yeast. Involvement of inositol phosphate metabolism and Ku70/80 function.},
journal = {The Journal of biological chemistry},
volume = {283},
number = {41},
pages = {27514-27524},
pmid = {18694931},
issn = {0021-9258},
support = {AG006168/AG/NIA NIH HHS/United States ; CA88932/CA/NCI NIH HHS/United States ; DE016572/DE/NIDCR NIH HHS/United States ; },
mesh = {Acetyltransferases/genetics/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Fatty Acids/*biosynthesis/genetics ; Gene Deletion ; Inositol Phosphates/genetics/metabolism ; Phosphotransferases (Alcohol Group Acceptor)/genetics/metabolism ; Phosphotransferases (Phosphate Group Acceptor)/genetics/metabolism ; Saccharomyces cerevisiae/*enzymology/genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {In this study, we investigated the roles of very long-chain fatty acid (VLCFA) synthesis by fatty acid elongase 3 (ELO3) in the regulation of telomere length and life span in the yeast Saccharomyces cerevisiae. Loss of VLCFA synthesis via deletion of ELO3 reduced telomere length, and reconstitution of the expression of wild type ELO3, and not by its mutant with decreased catalytic activity, rescued telomere attrition. Further experiments revealed that alterations of phytoceramide seem to be dispensable for telomere shortening in response to loss of ELO3. Interestingly, telomere shortening in elo3Delta cells was almost completely prevented by deletion of IPK2 or KCS1, which are involved in the generation of inositol phosphates (IP4, IP5, and inositol pyrophosphates). Deletion of IPK1, which generates IP6, however, did not affect regulation of telomere length. Further data also suggested that elo3Delta cells exhibit accelerated chronologic aging, and reduced replicative life span compared with wild type cells, and deletion of KCS1 helped recover these biological defects. Importantly, to determine downstream mechanisms, epistasis experiments were performed, and data indicated that ELO3 and YKU70/80 share a common pathway for the regulation of telomere length. More specifically, chromatin immunoprecipitation assays revealed that the telomere binding and protective function of YKu80p in vivo was reduced in elo3Delta cells, whereas its non-homologues end-joining function was not altered. Deletion of KCS1 in elo3Delta cells recovered the telomere binding and protective function of Ku, consistent with the role of KCS1 mutation in the rescue of telomere length attrition. Thus, these findings provide initial evidence of a possible link between Elo3-dependent VLCFA synthesis, and IP metabolism by KCS1 and IPK2 in the regulation of telomeres, which play important physiological roles in the control of senescence and aging, via a mechanism involving alterations of the telomere-binding/protection function of Ku.},
}
@article {pmid18680434,
year = {2008},
author = {Palm, W and de Lange, T},
title = {How shelterin protects mammalian telomeres.},
journal = {Annual review of genetics},
volume = {42},
number = {},
pages = {301-334},
doi = {10.1146/annurev.genet.41.110306.130350},
pmid = {18680434},
issn = {0066-4197},
support = {AG016642/AG/NIA NIH HHS/United States ; CA076027/CA/NCI NIH HHS/United States ; GM049046/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA/genetics ; DNA Damage ; DNA Repair ; Eukaryotic Cells ; Humans ; Models, Biological ; Models, Molecular ; Multiprotein Complexes ; Repressor Proteins/chemistry/genetics/metabolism ; Shelterin Complex ; Signal Transduction ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {The genomes of prokaryotes and eukaryotic organelles are usually circular as are most plasmids and viral genomes. In contrast, the nuclear genomes of eukaryotes are organized on linear chromosomes, which require mechanisms to protect and replicate DNA ends. Eukaryotes navigate these problems with the advent of telomeres, protective nucleoprotein complexes at the ends of linear chromosomes, and telomerase, the enzyme that maintains the DNA in these structures. Mammalian telomeres contain a specific protein complex, shelterin, that functions to protect chromosome ends from all aspects of the DNA damage response and regulates telomere maintenance by telomerase. Recent experiments, discussed here, have revealed how shelterin represses the ATM and ATR kinase signaling pathways and hides chromosome ends from nonhomologous end joining and homology-directed repair.},
}
@article {pmid18677381,
year = {2008},
author = {Chi, YK and Shen, Q and Wang, JC and Zheng, XZ and Hou, L and Zhang, B},
title = {[Correlation of telomere length and the expression of its regulating proteins in mesenchymal sarcomas].},
journal = {Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences},
volume = {40},
number = {4},
pages = {363-368},
pmid = {18677381},
issn = {1671-167X},
mesh = {Adult ; Bone Neoplasms/*genetics/metabolism ; Chondrosarcoma/genetics/metabolism ; Female ; Humans ; In Situ Hybridization, Fluorescence/methods ; Liposarcoma/genetics/metabolism ; Male ; Middle Aged ; Osteosarcoma/*genetics/metabolism ; Proto-Oncogene Proteins c-myc/genetics/metabolism ; Rhabdomyosarcoma/genetics/metabolism ; Shelterin Complex ; Telomerase/genetics/metabolism ; Telomere/*ultrastructure ; Telomere-Binding Proteins/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; },
abstract = {OBJECTIVE: To explore the significance in the change of telomere length in mesenchymal sarcomas, through analyzing telomere length and expression of its associated proteins, including TRF1, POT1, hTERT, P53 and c-myc.<br><br>METHODS: The telomere length in 20 cases of osteosarcomas, 25 of chondrosarcomas, 19 of rhabdomyosarcomas, 26 of liposarcomas was measured by telomere fluorescence in situ hybridization (Telo-FISH), and the expression of TRF1, POT1, hTERT, p53 or c-myc was analyzed by immunohistochemistry, respectively.<br><br>RESULTS: The telomere length in osteosarcomas was significantly shorter than that of either chondrosarcomas or liposarcomas (P<0.05). Similarly, the telomere length of rhabdomyosarcoma was shorter than that of chondrosarcoma (P<0.05). Meanwhile, telomere shortening was positively correlated with down expression of telomere binding proteins TRF1 and POT1 (P<0.05), but trends were detected more frequently in positive expression of hTERT (P<0.05) and in nuclear accumulation of P53 or expression of c-myc. With advancing in histological grading, telomere length was shortened markedly in chondrosarcomas, especially in liposarcomas (P<0.05).<br><br>CONCLUSION: The shortening of telomere could prevail in mesenchymal sarcoma and reflect the malignant potential. Telomere attrition usually correlated with down expression of POT1, TRF1 and with increased levels of hTERT, P53 and c-myc.},
}
@article {pmid18676772,
year = {2008},
author = {Shammas, MA and Qazi, A and Batchu, RB and Bertheau, RC and Wong, JY and Rao, MY and Prasad, M and Chanda, D and Ponnazhagan, S and Anderson, KC and Steffes, CP and Munshi, NC and De Vivo, I and Beer, DG and Gryaznov, S and Weaver, DW and Goyal, RK},
title = {Telomere maintenance in laser capture microdissection-purified Barrett's adenocarcinoma cells and effect of telomerase inhibition in vivo.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {14},
number = {15},
pages = {4971-4980},
pmid = {18676772},
issn = {1078-0432},
support = {R01 CA071606/CA/NCI NIH HHS/United States ; P01-78378//PHS HHS/United States ; R01 CA125711/CA/NCI NIH HHS/United States ; NIH-P50-100007//PHS HHS/United States ; P01 CA078378/CA/NCI NIH HHS/United States ; P01 CA078378-06A10006/CA/NCI NIH HHS/United States ; P50-100007//PHS HHS/United States ; R01 CA154365/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma/metabolism/*ultrastructure ; Animals ; Apoptosis ; Barrett Esophagus/metabolism/*ultrastructure ; Cell Line, Tumor ; Cellular Senescence ; Epithelial Cells/ultrastructure ; Female ; Humans ; Lasers ; Mice ; Mice, SCID ; Microdissection ; Neoplasm Transplantation ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/*ultrastructure ; },
abstract = {PURPOSE: The aims of this study were to investigate telomere function in normal and Barrett's esophageal adenocarcinoma (BEAC) cells purified by laser capture microdissection and to evaluate the effect of telomerase inhibition in cancer cells in vitro and in vivo.<br><br>EXPERIMENTAL DESIGN: Epithelial cells were purified from surgically resected esophagi. Telomerase activity was measured by modified telomeric repeat amplification protocol and telomere length was determined by real-time PCR assay. To evaluate the effect of telomerase inhibition, adenocarcinoma cell lines were continuously treated with a specific telomerase inhibitor (GRN163L) and live cell number was determined weekly. Apoptosis was evaluated by Annexin labeling and senescence by beta-galactosidase staining. For in vivo studies, severe combined immunodeficient mice were s.c. inoculated with adenocarcinoma cells and following appearance of palpable tumors, injected i.p. with saline or GRN163L.<br><br>RESULTS: Telomerase activity was significantly elevated whereas telomeres were shorter in BEAC cells relative to normal esophageal epithelial cells. The treatment of adenocarcinoma cells with telomerase inhibitor, GRN163L, led to loss of telomerase activity, reduction in telomere length, and growth arrest through induction of both the senescence and apoptosis. GRN163L-induced cell death could also be expedited by addition of the chemotherapeutic agents doxorubicin and ritonavir. Finally, the treatment with GRN163L led to a significant reduction in tumor volume in a subcutaneous tumor model.<br><br>CONCLUSIONS: We show that telomerase activity is significantly elevated whereas telomeres are shorter in BEAC and suppression of telomerase inhibits proliferation of adenocarcinoma cells both in vitro and in vivo.},
}
@article {pmid18672169,
year = {2008},
author = {Werner, C and Hanhoun, M and Widmann, T and Kazakov, A and Semenov, A and Pöss, J and Bauersachs, J and Thum, T and Pfreundschuh, M and Müller, P and Haendeler, J and Böhm, M and Laufs, U},
title = {Effects of physical exercise on myocardial telomere-regulating proteins, survival pathways, and apoptosis.},
journal = {Journal of the American College of Cardiology},
volume = {52},
number = {6},
pages = {470-482},
doi = {10.1016/j.jacc.2008.04.034},
pmid = {18672169},
issn = {1558-3597},
mesh = {Animals ; Apoptosis/*physiology ; Apoptosis Regulatory Proteins/*genetics ; Cell Survival ; Cellular Senescence/*physiology ; Male ; Mice ; Mice, Inbred C57BL ; Motor Activity/physiology ; Myocardium/*metabolism ; Nitric Oxide Synthase Type III/deficiency ; Running/*physiology ; Telomere/*genetics ; Time Factors ; },
abstract = {OBJECTIVES: The purpose of this study was to study the underlying molecular mechanisms of the protective cardiac effects of physical exercise.<br><br>BACKGROUND: Telomere-regulating proteins affect cellular senescence, survival, and regeneration.<br><br>METHODS: C57/Bl6 wild-type, endothelial nitric oxide synthase (eNOS)-deficient and telomerase reverse transcriptase (TERT)-deficient mice were randomized to voluntary running or no running wheel conditions (n = 8 to 12 per group).<br><br>RESULTS: Short-term running (21 days) up-regulated cardiac telomerase activity to >2-fold of sedentary controls, increased protein expression of TERT and telomere repeat binding factor (TRF) 2, and reduced expression of the proapoptotic mediators cell-cycle-checkpoint kinase 2 (Chk2), p53, and p16. Myocardial and leukocyte telomere length did not differ between 3-week- and 6-month-old sedentary or running mice, but telomerase activity, TRF2 and TERT expression were persistently increased after 6 months and the expression of Chk2, p53, and p16 remained down-regulated. The exercise-induced changes were absent in both TERT(-/-) and eNOS(-/-) mice. Running increased cardiac expression of insulin-like growth factor (IGF)-1. Treatment with IGF-1 up-regulated myocardial telomerase activity >14-fold and increased the expression of phosphorylated Akt protein kinase and phosphorylated eNOS. To test the physiologic relevance of these exercise-mediated prosurvival pathways, apoptotic cardiomyopathy was induced by treatment with doxorubicin. Up-regulation of telomere-stabilizing proteins by physical exercise in mice reduced doxorubicin-induced p53 expression and potently prevented cardiomyocyte apoptosis in wild-type, but not in TERT(-/-) mice.<br><br>CONCLUSIONS: Long- and short-term voluntary physical exercise up-regulates cardiac telomere-stabilizing proteins and thereby induces antisenescent and protective effects, for example, to prevent doxorubicin-induced cardiomyopathy. These beneficial cardiac effects are mediated by TERT, eNOS, and IGF-1.},
}
@article {pmid18669893,
year = {2008},
author = {Walne, AJ and Vulliamy, T and Beswick, R and Kirwan, M and Dokal, I},
title = {TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes.},
journal = {Blood},
volume = {112},
number = {9},
pages = {3594-3600},
pmid = {18669893},
issn = {1528-0020},
support = {//Medical Research Council/United Kingdom ; //Wellcome Trust/United Kingdom ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Amino Acid Sequence ; Amino Acid Substitution ; Base Sequence ; Bone Marrow Diseases/*genetics/metabolism ; Child ; Child, Preschool ; Cohort Studies ; DNA Primers/genetics ; Dyskeratosis Congenita/*genetics/metabolism ; Female ; Heterozygote ; Humans ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Molecular Sequence Data ; *Mutation ; RNA/metabolism ; Sequence Homology, Amino Acid ; Syndrome ; Telomerase/metabolism ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {Dyskeratosis congenita (DC) is a multisystem bone marrow failure syndrome characterized by a triad of mucocutaneous abnormalities and a predisposition to cancer. The genetic basis of DC remains unknown in more than 60% of patients. Mutations have been identified in components of the telomerase complex (dyskerin, TERC, TERT, NOP10, and NHP2), and recently in one component of the shelterin complex TIN2 (gene TINF2). To establish the role of TINF2 mutations, we screened DNA from 175 uncharacterised patients with DC as well as 244 patients with other bone marrow failure disorders. Heterozygous coding mutations were found in 33 of 175 previously uncharacterized DC index patients and 3 of 244 other patients. A total of 21 of the mutations affected amino acid 282, changing arginine to histidine (n = 14) or cysteine (n = 7). A total of 32 of 33 patients with DC with TINF2 mutations have severe disease, with most developing aplastic anaemia by the age of 10 years. Telomere lengths in patients with TINF2 mutations were the shortest compared with other DC subtypes, but TERC levels were normal. In this large series, TINF2 mutations account for approximately 11% of all DC, but they do not play a significant role in patients with related disorders. This study emphasises the role of defective telomere maintenance on human disease.},
}
@article {pmid18668136,
year = {2009},
author = {Han, J and Qureshi, AA and Prescott, J and Guo, Q and Ye, L and Hunter, DJ and De Vivo, I},
title = {A prospective study of telomere length and the risk of skin cancer.},
journal = {The Journal of investigative dermatology},
volume = {129},
number = {2},
pages = {415-421},
pmid = {18668136},
issn = {1523-1747},
support = {R03 CA133914/CA/NCI NIH HHS/United States ; R03 CA133914-01/CA/NCI NIH HHS/United States ; R03 CA132175/CA/NCI NIH HHS/United States ; CA133914/CA/NCI NIH HHS/United States ; R03 CA132175-02/CA/NCI NIH HHS/United States ; T32 CA09001/CA/NCI NIH HHS/United States ; CA132175/CA/NCI NIH HHS/United States ; T32 CA009001/CA/NCI NIH HHS/United States ; T32 CA009001-30/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Carcinoma, Basal Cell/epidemiology/genetics ; Carcinoma, Squamous Cell/epidemiology/genetics ; Case-Control Studies ; Female ; Genetic Predisposition to Disease/epidemiology ; Humans ; Incidence ; Melanoma/*epidemiology/*genetics ; Middle Aged ; Prospective Studies ; Reverse Transcriptase Polymerase Chain Reaction ; Risk Factors ; Skin Neoplasms/*epidemiology/*genetics ; Telomere/*genetics ; },
abstract = {Telomere length is important in tumorigenesis. Using quantitative real-time PCR, we prospectively measured relative telomere length in a nested case-control study within the Nurses' Health Study: 218 melanoma cases, 285 squamous-cell carcinoma (SCC) cases, 300 basal-cell carcinoma (BCC) cases, and 870 controls. We observed that shorter telomeres were associated with a decreased number of moles (P=0.002) and a decreased risk of melanoma. Women in the second and first quartiles, those with the shortest telomere length, had an odds ratio (OR) for melanoma of 0.54 (95% confidence interval (CI), 0.29-1.01) and 0.59 (95% CI, 0.31-1.13), respectively, compared with those in the fourth quartile (P, trend=0.09). There was no clear trend between telomere length and SCC risk. In contrast, we found that shorter telomere length was associated with an increased risk of BCC. Compared with those in the fourth quartile, women in the first quartile had an OR of 1.85 (95% CI, 0.94-3.62) (P, trend=0.09). The opposing associations observed should be interpreted with caution, and further research is needed to confirm these possible associations.},
}
@article {pmid18665909,
year = {2008},
author = {De Meyer, T and De Buyzere, ML and Langlois, M and Rietzschel, ER and Cassiman, P and De Bacquer, D and Van Oostveldt, P and De Backer, GG and Gillebert, TC and Van Criekinge, W and Bekaert, S and , },
title = {Lower red blood cell counts in middle-aged subjects with shorter peripheral blood leukocyte telomere length.},
journal = {Aging cell},
volume = {7},
number = {5},
pages = {700-705},
doi = {10.1111/j.1474-9726.2008.00419.x},
pmid = {18665909},
issn = {1474-9726},
mesh = {Adult ; Aging/genetics ; Erythrocyte Count ; Erythrocytes/*cytology ; Female ; Humans ; Leukocytes/*metabolism ; Longitudinal Studies ; Male ; Middle Aged ; Random Allocation ; Telomere/*genetics/*metabolism ; },
abstract = {Although telomere biology was revealed to play an important role in several hematopoietic disorders, its impact on the age-dependent dynamics of regular hematopoiesis is poorly understood. In vitro results suggest that particularly the erythropoietic capacity might be limited by critically short telomere length (TL). However, it remains unclear whether TL also affects erythropoiesis in healthy individuals in vivo. Therefore, we analyzed the associations between relevant hematopoietic parameters and peripheral blood leukocyte TL in the apparently healthy Asklepios study population, aged approximately 35-55 years (N > 2500). Our data indicate a clear positive, age and paternal age at birth adjusted, correlation between TL and red blood cell count, both in men (p < 0.001) and women (p = 0.011). This association was particularly significant in the older segment of the population (> 45 years old, both sexes: p = 0.003) and in younger men (p = 0.013), but not in younger women (p = 0.521). Further adjustment for known determinants in a general linear model revealed that peripheral blood leukocyte TL is most probably an independent predictor of red blood cell count (p < 0.001), suggesting that critical telomere shortening might also limit erythropoiesis in vivo. While negligible in a middle-aged population, the clinical consequences might be important in the elderly (e.g. in anemia of chronic disease). Further studies are required to confirm the impact of our results.},
}
@article {pmid18664542,
year = {2008},
author = {Capezzone, M and Cantara, S and Marchisotta, S and Filetti, S and De Santi, MM and Rossi, B and Ronga, G and Durante, C and Pacini, F},
title = {Short telomeres, telomerase reverse transcriptase gene amplification, and increased telomerase activity in the blood of familial papillary thyroid cancer patients.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {93},
number = {10},
pages = {3950-3957},
doi = {10.1210/jc.2008-0372},
pmid = {18664542},
issn = {0021-972X},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Papillary/*blood/enzymology/*genetics/metabolism ; Child ; Female ; *Gene Amplification/physiology ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; RNA, Messenger/metabolism ; Telomerase/*blood/*genetics/metabolism ; Telomere/chemistry/*physiology ; Thyroid Neoplasms/*blood/enzymology/*genetics/metabolism ; },
abstract = {BACKGROUND: Differentiated papillary thyroid cancer is mostly sporadic, but the recurrence of the familial form has been reported. Short or dysfunctional telomeres have been associated with familial benign diseases and familial breast cancer.<br><br>OBJECTIVE: The aim of our work was to study the telomere-telomerase complex in the peripheral blood of patients with familial papillary thyroid cancer (FPTC), including the measurement of relative telomere length (RTL), telomerase reverse transcriptase (hTERT) gene amplification, hTERT mRNA expression, telomerase protein activity, and search of hTERT or telomerase RNA component gene mutations.<br><br>PATIENTS: Cumulating a series of patients seen at the University of Siena and a series at the University of Rome, the experiments were conducted in 47 FPTC patients, 75 sporadic papillary thyroid cancer (PTC) patients, 20 patients with nodular goiter, 19 healthy subjects, and 20 unaffected siblings of FPTC patients.<br><br>RESULTS: RTL, measured by quantitative PCR, was significantly (P < 0.0001) shorter in the blood of FPTC patients, compared with sporadic PTCs, healthy subjects, nodular goiter subjects, and unaffected siblings. Also by fluorescence in situ hybridization analysis, the results confirmed shorter telomere lengths in FPTC patients (P = 0.01). hTERT gene amplification was significantly (P < 0.0001) higher in FPTC patients, compared with the other groups, and in particular, it was significantly (P = 0.03) greater in offspring with respect to parents. hTERT mRNA expression, as well as telomerase activity, was significantly higher (P = 0.0003 and P < 0.0001, respectively) in FPTC patients, compared with sporadic PTCs. RTL, measured in cancer tissues, was shorter (P < 0.0001) in FPTC patients, compared with sporadic PTCs. No mutations of the telomerase RNA component and hTERT genes were found.<br><br>CONCLUSION: Our study demonstrates that patients with FPTC display an imbalance of the telomere-telomerase complex in the peripheral blood, characterized by short telomeres, hTERT gene amplification, and expression. These features may be implicated in the inherited predisposition to develop FPTC.},
}
@article {pmid18663749,
year = {2008},
author = {Ohali, A and Avigad, S and Naumov, I and Goshen, Y and Ash, S and Yaniv, I},
title = {Different telomere maintenance mechanisms in alveolar and embryonal rhabdomyosarcoma.},
journal = {Genes, chromosomes &amp; cancer},
volume = {47},
number = {11},
pages = {965-970},
doi = {10.1002/gcc.20600},
pmid = {18663749},
issn = {1098-2264},
mesh = {Blotting, Southern ; Cell Line, Tumor ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Karyotyping ; Male ; Rhabdomyosarcoma, Alveolar/enzymology/*genetics/pathology ; Rhabdomyosarcoma, Embryonal/enzymology/*genetics/pathology ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {The activation of a telomere maintenance mechanism (TMM) is crucial for the immortalization of tumor cells. Most human cancers apply telomerase-dependent TMM but some use a mechanism called alternative lengthening of telomeres (ALT). The latter was suggested to be mainly characterizing sarcomas with nonspecific complex karyotypes, whereas telomerase activation is typical of sarcomas generated by specific translocations. In this study, we investigated the TMM and its association with survival in rhabdomyosarcoma (RMS), which is characterized by two major subtypes: one that is harboring a specific translocation (alveolar) and one that has a nonspecific karyotype (embryonal). Telomerase activity (TA), using telomerase repeat amplification protocol (TRAP) assay, and telomere length (TRF), using Southern blotting, were analyzed in tumor samples from 31 patients (16 embryonal and 15 alveolar). Alveolar RMS tumors exhibited no ALT phenotype and the majority presented TA. Some embryonal tumors exhibited an ALT or "ALT-like" phenotype which lacked TA, whereas others expressed telomerase-dependent TMM, and neither TA nor ALT correlated with outcome. The average TRF length of the embryonal tumors was significantly higher than that of the alveolar tumors (10.8 vs. 7.2 kb, P = 0.003). Interestingly, some tumors of both subtypes presented no TMM. These observations suggest that alveolar RMS predominantly use telomerase-dependent TMM, whereas in embryonal tumors both telomerase and ALT may play a role. These findings have important implications for understanding the role of TMM in the development of RMS tumors, and for future designing adapted treatment strategies.},
}
@article {pmid18662931,
year = {2008},
author = {MacIntyre, A and Brouilette, SW and Lamb, K and Radhakrishnan, K and McGlynn, L and Chee, MM and Parkinson, EK and Freeman, D and Madhok, R and Shiels, PG},
title = {Association of increased telomere lengths in limited scleroderma, with a lack of age-related telomere erosion.},
journal = {Annals of the rheumatic diseases},
volume = {67},
number = {12},
pages = {1780-1782},
doi = {10.1136/ard.2007.086652},
pmid = {18662931},
issn = {1468-2060},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/genetics ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Blotting, Southern ; Female ; Humans ; Middle Aged ; Retrospective Studies ; Scleroderma, Limited/drug therapy/*genetics ; Telomere/*pathology ; Young Adult ; },
abstract = {OBJECTIVES: Telomere erosion, a feature of biological ageing, is implicated in a wide range of diseases. Its impact on autoimmune diseases remains unclear although autoantibodies against many telomere nucleoprotein components are prevalent in these diseases. We aimed to assess if telomere biology was abnormal in a cohort of patients with limited cutaneous systemic sclerosis (lcSSc).<br><br>METHODS: Telomere lengths in peripheral blood leucocytes (PBL) were determined using Southern blotting methods in a cohort of lcSSc subjects (n=43; age range 37-80 years) and a control population (n=107; age range 21-65 years).<br><br>RESULTS: Telomere lengths in lcSSc subjects were longer than controls (p<0.001), did not show age-related telomere erosion and differed significantly from age-matched controls only after 50 years of age (p<0.001).<br><br>CONCLUSIONS: This is the first report of maintenance of telomere lengths in an autoimmune disease state. These data indicate aberrant telomere biology and irregular biological ageing from the fifth decade of life. These findings provide insight into compromised DNA damage repair in lcSSc. Whether these observations indicate a causal or consequential relationship requires further investigation. This in turn, may provide potential novel targets for therapeutic intervention.},
}
@article {pmid18660531,
year = {2008},
author = {Maxwell, PH and Curcio, MJ},
title = {Incorporation of Y'-Ty1 cDNA destabilizes telomeres in Saccharomyces cerevisiae telomerase-negative mutants.},
journal = {Genetics},
volume = {179},
number = {4},
pages = {2313-2317},
pmid = {18660531},
issn = {0016-6731},
support = {R01 GM052072/GM/NIGMS NIH HHS/United States ; R29 GM052072/GM/NIGMS NIH HHS/United States ; GM52072/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA, Complementary/genetics/*metabolism ; DNA, Fungal/genetics/metabolism ; Gene Rearrangement ; Models, Genetic ; Mutation ; Retroelements/*genetics ; Saccharomyces cerevisiae/enzymology/*genetics/metabolism ; Telomerase/*genetics ; Telomere/*metabolism ; },
abstract = {Ty1 retrotransposons in Saccharomyces cerevisiae are activated by telomere erosion. Ty1-dependent reverse transcription of mRNA from subtelomeric Y' repeats generates chimeric Y'-Ty1 cDNA. Here, we show that Y'-Ty1 cDNA is incorporated at eroding telomeres in the absence of telomerase. Telomeric incorporation of Y'-Ty1 cDNA promotes genome rearrangements.},
}
@article {pmid18656239,
year = {2008},
author = {Kurabayashi, R and Takubo, K and Aida, J and Honma, N and Poon, SS and Kammori, M and Izumiyama-Shimomura, N and Nakamura, K and Tsuji, E and Matsuura, M and Ogawa, T and Kaminishi, M},
title = {Luminal and cancer cells in the breast show more rapid telomere shortening than myoepithelial cells and fibroblasts.},
journal = {Human pathology},
volume = {39},
number = {11},
pages = {1647-1655},
doi = {10.1016/j.humpath.2008.04.005},
pmid = {18656239},
issn = {1532-8392},
mesh = {Adult ; Aged ; Aged, 80 and over ; Breast/*pathology/ultrastructure ; Breast Neoplasms/*pathology ; Epithelial Cells/pathology/ultrastructure ; Female ; Fibroblasts/pathology/ultrastructure ; Humans ; In Situ Hybridization, Fluorescence ; Middle Aged ; Telomere/*pathology/ultrastructure ; },
abstract = {Critically shortened, dysfunctional telomeres may play a role in the genetic instabilities commonly found in cancer. We analyzed 30 surgical specimens of invasive breast carcinoma from women aged 34 to 91 years and estimated telomere lengths as telomere-to-centromere ratio values in the 5 different cell types comprising breast tissue in order to clarify telomere length variations within and between individuals using our tissue quantitative fluorescence in situ hybridization method. We obtained 3 novel findings. (1) In corresponding normal tissues, telomere length decreased in the order myoepithelial cells > normal-appearing fibroblasts > luminal epithelial cells, and telomere lengths were characteristic in these 3 cell types within each individual. (2) As expected, cancer cells had significantly shorter telomeres than myoepithelial cells (P < .0001) and normal-appearing fibroblasts (P = .0161), but there was no significant difference in telomere length between luminal cells and cancer cells (P = .6270). (3) Fibroblasts adjacent to cancer had longer telomeres than normal-appearing fibroblasts distant from cancer (P < .0001). This study, which represents the first reported assessment of telomere length variations in the 5 cell types comprising breast tissue within and between individuals, revealed that normal luminal epithelial cells and cancer cells had the shortest telomeres. Our new findings indicate that telomeres of background luminal cells are as short as those of cancer cells. Tissue quantitative fluorescence in situ hybridization, applicable to analysis of individual cells in tissue sections, is considered to be a powerful technique with considerable promise for studies in oncology.},
}
@article {pmid18647789,
year = {2008},
author = {Nordfjäll, K and Eliasson, M and Stegmayr, B and Lundin, S and Roos, G and Nilsson, PM},
title = {Increased abdominal obesity, adverse psychosocial factors and shorter telomere length in subjects reporting early ageing; the MONICA Northern Sweden Study.},
journal = {Scandinavian journal of public health},
volume = {36},
number = {7},
pages = {744-752},
doi = {10.1177/1403494808090634},
pmid = {18647789},
issn = {1403-4948},
mesh = {*Aging/physiology/psychology ; Body Mass Index ; Cellular Senescence/physiology ; Cross-Sectional Studies ; Female ; Humans ; Life Expectancy ; Life Style ; Male ; Metabolic Syndrome/prevention &amp; control ; *Obesity/prevention &amp; control ; Risk Factors ; Self Concept ; Smoking/adverse effects ; Socioeconomic Factors ; Surveys and Questionnaires ; Sweden/epidemiology ; *Telomere/physiology ; Waist-Hip Ratio ; },
abstract = {BACKGROUND: The rate of biological ageing is individual and represents the steady decrease in physiological and mental functions. Adverse social factors have been shown to influence this process. Self-perceived early ageing (SEA) might be a useful indicator of early biological ageing and increased mortality risk. The aim of this population-based study was to identify markers of SEA, including telomere length.<br><br>METHODS: We studied 1502 subjects (744 men, 758 women) from Northern Sweden. These subjects underwent a physical examination, blood sampling (including telomere length) and completed a self-administered questionnaire about their subjective age, social situation, lifestyle, and self-rated health (SRH). Age- and SRH-adjusted statistical analyses were made comparing SEA subjects with same-sex controls.<br><br>RESULTS: In all, 7.9% of men and 12.1% of women reported SEA. These subjects had significantly (p<0.0001) wider waist circumference and higher body mass index than controls. SEA men showed higher fasting glucose and SEA women showed higher total cholesterol levels than controls (p=0.020 and p=0.015, respectively). In addition, SEA women more often reported infrequent physical exercise (p=0.006), mental problems (p=0.064) and worse SRH (p=0.001) than controls. In a random sub-sample, telomere length was significantly shorter in SEA subjects (n=139) than controls (n=301; p=0.02), but not after full adjustment for BMI.<br><br>CONCLUSIONS: Self-perceived early ageing is not uncommon and is associated with abdominal obesity, poor self-rated health, lower education, and shorter telomere length. This could link adverse social factors with features of the metabolic syndrome as well as with early biological ageing, of importance for targeting preventive programmes.},
}
@article {pmid18641004,
year = {2008},
author = {Raynaud, CM and Jang, SJ and Nuciforo, P and Lantuejoul, S and Brambilla, E and Mounier, N and Olaussen, KA and André, F and Morat, L and Sabatier, L and Soria, JC},
title = {Telomere shortening is correlated with the DNA damage response and telomeric protein down-regulation in colorectal preneoplastic lesions.},
journal = {Annals of oncology : official journal of the European Society for Medical Oncology},
volume = {19},
number = {11},
pages = {1875-1881},
doi = {10.1093/annonc/mdn405},
pmid = {18641004},
issn = {1569-8041},
mesh = {Antibodies, Neoplasm/analysis ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/biosynthesis ; Checkpoint Kinase 2 ; Colorectal Neoplasms/*genetics/metabolism/pathology ; *DNA Damage ; DNA-Binding Proteins/biosynthesis ; Down-Regulation ; HT29 Cells ; Histones/biosynthesis ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Paraffin Embedding ; Precancerous Conditions/*genetics/metabolism/pathology ; Protein Serine-Threonine Kinases/biosynthesis ; Telomere/*metabolism/*pathology ; Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 1/biosynthesis ; Telomeric Repeat Binding Protein 2/biosynthesis ; Tumor Suppressor Proteins/biosynthesis ; },
abstract = {BACKGROUND: A relation between telomere attrition in early carcinogenesis and activation of DNA damage response (DDR) has been proposed. We explored telomere length and its link with DDR in colorectal multistep carcinogenesis.<br><br>PATIENTS AND METHODS: We studied normal mucosa, low-grade dysplasia (LGD) and high-grade dysplasia (HGD) and invasive carcinoma (IC) in matched human colon specimens by evaluating p-ataxia telangiectasia mutated (ATM), p-checkpoint kinase 2 (Chk2), c-H2AX, TRF1 and TRF2 expressions by immunohistochemistry. FISH was used to assess telomere length.<br><br>RESULTS: Telomeres shortened significantly from normal (N) to LGD and HGD (P < 0.0001; P = 0.012), then increased in length in IC (P = 0.006). TRF1 and TRF2 expressions were diminished from N to LGD and HGD (P = 0.004, P < 0.0001, ns) and were reexpressed at the invasive stage (P = 0.053 and P = 0.046). Phosphorylated ATM, Chk2 and H2AX appeared already in LGD (respectively, P = 0.001, P = 0.002 and P = 0.02). Their expression decreased from HGD to IC (respectively, P = 0.03, P = 0.02 and P = 0.37). These activating phosphorylations were inversely correlated with telomere length and TRF1/2 expression.<br><br>CONCLUSION: In a model of colon multistep carcinogenesis, our data indicate that telomeric length and protein expression levels are inversely correlated with the activation of the DDR pathway.},
}
@article {pmid18640258,
year = {2009},
author = {Song, Z and Ju, Z and Rudolph, KL},
title = {Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status.},
journal = {Experimental gerontology},
volume = {44},
number = {1-2},
pages = {75-82},
doi = {10.1016/j.exger.2008.06.009},
pmid = {18640258},
issn = {1873-6815},
mesh = {Animals ; Cellular Senescence/genetics/*physiology ; DNA Damage ; Humans ; Mice ; Mice, Inbred Strains ; Mice, Knockout ; Models, Animal ; Stem Cells/*cytology/ultrastructure ; Tandem Repeat Sequences ; Telomerase/genetics/metabolism ; Telomere/*ultrastructure ; },
abstract = {The function of adult stem cells declines during aging and chronic diseases. An understanding of the molecular mechanisms underlying these processes will help to identify targets for future therapies in order to improve regenerative reserve and organ maintenance. Telomere shortening represents a cell intrinsic mechanism inducing DNA damage in aging cells. Current studies in telomerase knockout mice have shown that telomere dysfunction induces cell intrinsic checkpoints and environmental alteration that limit stem cell function. While these phenotypes differ from wild-type mice with long telomere reserves, they appear to be relevant for human aging, which is associated with an accumulation of telomere dysfunction and DNA damage.},
}
@article {pmid18635962,
year = {2008},
author = {Villasante, A and de Pablos, B and Méndez-Lago, M and Abad, JP},
title = {Telomere maintenance in Drosophila: rapid transposon evolution at chromosome ends.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {7},
number = {14},
pages = {2134-2138},
doi = {10.4161/cc.7.14.6275},
pmid = {18635962},
issn = {1551-4005},
mesh = {Animals ; Drosophila/*metabolism ; *Evolution, Molecular ; Retroelements/*genetics ; Telomere/*genetics/*metabolism ; },
abstract = {The maintenance of terminal sequences is an important role of the telomere, since it prevents the loss of internal regions that encode essential genes. In most eukaryotes, this is accomplished by the telomerase. However, telomere length can also be maintained by other mechanisms, such as homologous recombination and transposition of telomeric retrotransposons to the chromosome ends. A remarkable situation is the case of Drosophila, where telomerase was lost, and thus telomeres managed to be maintained by occasional retrotransposition of telomeric elements to the receding ends. In the recent analysis of 12 Drosophila genomes, the multiplicity of autonomous and non-autonomous telomere-specific retrotransposons has revealed extensive and rapid evolution of telomeric DNA. The phylogenetic relationship among these telomeric retrotransposons is congruent with the species phylogeny, suggesting that they have been vertically transmitted from a common ancestor. In this review, we also suggest that the formation of a non-canonical DNA structure at Drosophila telomeres could be the way to protect the ends.},
}
@article {pmid18635888,
year = {2008},
author = {Cronkhite, JT and Xing, C and Raghu, G and Chin, KM and Torres, F and Rosenblatt, RL and Garcia, CK},
title = {Telomere shortening in familial and sporadic pulmonary fibrosis.},
journal = {American journal of respiratory and critical care medicine},
volume = {178},
number = {7},
pages = {729-737},
pmid = {18635888},
issn = {1535-4970},
support = {K23-RR020632/RR/NCRR NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Case-Control Studies ; Female ; Genetic Predisposition to Disease/*genetics ; Humans ; Male ; Middle Aged ; Mutation, Missense ; Pedigree ; Pulmonary Fibrosis/*genetics ; RNA/genetics ; Regeneration/*genetics ; Telomerase/*genetics ; Telomere/*pathology ; },
abstract = {RATIONALE: Heterozygous mutations in the coding regions of the telomerase genes, TERT and TERC, have been found in familial and sporadic cases of idiopathic interstitial pneumonia. All affected patients with mutations have short telomeres.<br><br>OBJECTIVES: To test whether telomere shortening is a frequent mechanism underlying pulmonary fibrosis, we have characterized telomere lengths in subjects with familial or sporadic disease who do not have coding mutations in TERT or TERC.<br><br>METHODS: Using a modified Southern blot assay, the telomerase restriction fragment length method, and a quantitative polymerase chain reaction assay we have measured telomere lengths of genomic DNA isolated from circulating leukocytes from normal control subjects and subjects with pulmonary fibrosis.<br><br>MEASUREMENTS AND MAIN RESULTS: All affected patients with telomerase mutations, including case subjects heterozygous for newly reported mutations in TERT, have short telomere lengths. A significantly higher proportion of probands with familial pulmonary fibrosis (24%) and sporadic case subjects (23%) in which no coding mutation in TERT or TERC was found had telomere lengths less than the 10th percentile when compared with control subjects (P = 2.6 x 10(-8)). Pulmonary fibrosis affectation status was significantly associated with telomerase restriction fragment lengths, even after controlling for age, sex, and ethnicity (P = 6.1 x 10(-11)). Overall, 25% of sporadic cases and 37% of familial cases of pulmonary fibrosis had telomere lengths less than the 10th percentile.<br><br>CONCLUSIONS: A significant fraction of individuals with pulmonary fibrosis have short telomere lengths that cannot be explained by coding mutations in telomerase. Telomere shortening of circulating leukocytes may be a marker for an increased predisposition toward the development of this age-associated disease.},
}
@article {pmid18635289,
year = {2010},
author = {Jenkins, EC and Ye, L and Gu, H and Ni, SA and Velinov, M and Pang, D and Krinsky-McHale, SJ and Zigman, WB and Schupf, N and Silverman, WP},
title = {Shorter telomeres may indicate dementia status in older individuals with Down syndrome.},
journal = {Neurobiology of aging},
volume = {31},
number = {5},
pages = {765-771},
pmid = {18635289},
issn = {1558-1497},
support = {P01 HD035897/HD/NICHD NIH HHS/United States ; U54 HD079123/HD/NICHD NIH HHS/United States ; R01 HD037425-05/HD/NICHD NIH HHS/United States ; R01 AG014673-09/AG/NIA NIH HHS/United States ; P01-HD35897/HD/NICHD NIH HHS/United States ; R01-HD37425/HD/NICHD NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; R01 AG014673/AG/NIA NIH HHS/United States ; R01 HD037425/HD/NICHD NIH HHS/United States ; P01 HD035897-21/HD/NICHD NIH HHS/United States ; R01-AG014673/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Apolipoproteins E/genetics ; Chromosomes, Human, Pair 21 ; Dementia/complications/*genetics ; Down Syndrome/complications/*genetics ; Female ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Neuropsychological Tests ; T-Lymphocytes ; Telomere/*genetics ; },
abstract = {We have recently reported reduced telomere length in T lymphocytes of individuals with Down syndrome (DS) and dementia due to Alzheimer's disease (AD). We have now replicated and extended that study by finding that people with DS and mild cognitive impairment (MCI-DS) also have shorter telomeres than people with DS without MCI-DS. Additional new findings demonstrated that light intensity measurements from chromosome 21 alone, or in concert with chromosomes 1, 2, and 16, exhibited shorter telomeres in adults with DS and with either dementia or MCI-DS compared to aging per se. Chromosome 21 measurements appeared to be especially promising for use as a biomarker because there was no overlap in the distribution of light intensity measurement scores between demented or MCI-DS and non-demented participants. Given that early clinical symptoms of AD can be very difficult to recognize in this population of adults due to their pre-existing cognitive impairments, a valid biomarker would be of great value. Early detection is especially important because it would allow treatments to begin before significant damage to the central nervous system has occurred. Our findings suggest that it may be feasible to use telomere shortening as a biomarker for accurately inferring dementia status.},
}
@article {pmid18628664,
year = {2008},
author = {Löf-Ohlin, ZM and Hagnelius, NO and Nilsson, TK},
title = {Relative telomere length in patients with late-onset Alzheimer's dementia or vascular dementia.},
journal = {Neuroreport},
volume = {19},
number = {12},
pages = {1199-1202},
doi = {10.1097/WNR.0b013e3283089220},
pmid = {18628664},
issn = {1473-558X},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Alzheimer Disease/*genetics ; Base Sequence ; Child ; Child, Preschool ; Dementia, Vascular/*genetics ; Female ; Humans ; Male ; Polymerase Chain Reaction/methods ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres generally shorten with age. An accelerated shortening of the telomeres has been linked to several age-related disorders. We hypothesized that the relative length of telomeres could discriminate between patients with late-onset Alzheimer's disease (AD) and vascular dementia (VaD). A quantitative real-time PCR method was used to calculate the relative telomere length in 76 age-matched and sex-matched, newly diagnosed late-onset AD or VaD patients recruited from our Memory Unit. No significant difference was found in the relative telomere length between AD and VaD cases neither in men (P=0.315) nor women (P=0.12). Thus, we could not confirm that the length of telomeres would predict which form of dementia, late-onset AD or VaD that develops.},
}
@article {pmid18628474,
year = {2008},
author = {Phatak, P and Dai, F and Butler, M and Nandakumar, MP and Gutierrez, PL and Edelman, MJ and Hendriks, H and Burger, AM},
title = {KML001 cytotoxic activity is associated with its binding to telomeric sequences and telomere erosion in prostate cancer cells.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {14},
number = {14},
pages = {4593-4602},
doi = {10.1158/1078-0432.CCR-07-4572},
pmid = {18628474},
issn = {1078-0432},
mesh = {Antineoplastic Agents/*pharmacology ; Arsenites/*pharmacology ; Blotting, Western ; Breast Neoplasms/drug therapy/genetics ; Cell Line, Tumor ; DNA Damage/*drug effects ; Female ; Fluorescent Antibody Technique ; Humans ; Immunoprecipitation ; In Situ Hybridization ; Lung Neoplasms/drug therapy/genetics ; Male ; Prostatic Neoplasms/*drug therapy/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Sodium Compounds/*pharmacology ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Telomerase/drug effects ; Telomere/*drug effects ; },
abstract = {PURPOSE: KML001 (sodium metaarsenite) is an orally bioavailable arsenic compound that has entered phase I/II clinical trials in prostate cancer. In this study, we elucidated the mode of action of KML001 and investigated its effects on telomerase and telomeres.<br><br>EXPERIMENTAL DESIGN: We compared telomere length to KML001 cytotoxic activity in a panel of human solid tumor cell lines. Duration of exposure and concentrations of KML001 that affect telomerase and telomeres were evaluated in relation to established mechanisms of arsenite action such as reactive oxygen species-related DNA damage induction. Binding of KML001 to telomeres was assessed by matrix-assisted laser desorption/ionization mass spectrometry.<br><br>RESULTS: We established a significant inverse correlation (r(2) = 0.9) between telomere length and cytotoxicity. KML001 exhibited activity in tumor cells with short telomeres at concentrations that can be achieved in serum of patients. We found that telomerase is not directly inhibited by KML001. Instead, KML001 specifically binds to telomeric sequences at a ratio of one molecule per three TTAGGG repeats leading to translocation of the telomerase catalytic subunit into the cytoplasm. In prostate cancer cells with short telomeres, KML001 caused telomere-associated DNA damage signaling as shown by gamma-H2AX induction and chromatin immunoprecipitation assays as well as a rapid telomere erosion shown by metaphase fluorescence in situ hybridization. These effects were not seen in a lung cancer cell line with long telomeres. Importantly, arsenification of telomeres preceded DNA lesions caused by reactive oxygen species production.<br><br>CONCLUSIONS: Sodium metaarsenite is a telomere targeting agent and should be explored for the treatment of tumors with short telomeres.},
}
@article {pmid18627461,
year = {2008},
author = {Meyer, DH and Bailis, AM},
title = {Mating type influences chromosome loss and replicative senescence in telomerase-deficient budding yeast by Dnl4-dependent telomere fusion.},
journal = {Molecular microbiology},
volume = {69},
number = {5},
pages = {1246-1254},
pmid = {18627461},
issn = {1365-2958},
support = {R01 GM057484/GM/NIGMS NIH HHS/United States ; R01 GM057484-09/GM/NIGMS NIH HHS/United States ; GM057484/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosome Deletion ; Chromosomes, Fungal/genetics/metabolism ; DNA Ligase ATP ; DNA Ligases/genetics/*metabolism ; Gene Expression Regulation, Fungal ; Mating Factor ; Microbial Viability ; Peptides/genetics/*metabolism ; Recombination, Genetic ; Saccharomyces cerevisiae/*cytology/enzymology/*genetics/metabolism ; Telomerase/genetics/*metabolism ; Telomere/*genetics/metabolism ; },
abstract = {As we age, the majority of our cells gradually lose the capacity to divide because of replicative senescence that results from the inability to replicate the ends of chromosomes. The timing of senescence is dependent on the length of telomeric DNA, which elicits a checkpoint signal when critically short. Critically short telomeres also become vulnerable to deleterious rearrangements, end-degradation and telomere-telomere fusions. Here we report a novel role of non-homologous end-joining (NHEJ), a pathway of double-strand break repair in influencing both the kinetics of replicative senescence and the rate of chromosome loss in telomerase-deficient Saccharomyces cerevisiae. In telomerase-deficient cells, the absence of NHEJ delays replicative senescence, decreases loss of viability during senescence, and suppresses senescence-associated chromosome loss and telomere-telomere fusion. Differences in mating-type gene expression in haploid and diploid cells affect NHEJ function, resulting in distinct kinetics of replicative senescence. These results suggest that the differences in the kinetics of replicative senescence in haploid and diploid telomerase-deficient yeast are determined by changes in NHEJ-dependent telomere fusion, perhaps through the initiation of the breakage-fusion-bridge cycle.},
}
@article {pmid18626023,
year = {2008},
author = {Gu, BW and Bessler, M and Mason, PJ},
title = {A pathogenic dyskerin mutation impairs proliferation and activates a DNA damage response independent of telomere length in mice.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {105},
number = {29},
pages = {10173-10178},
pmid = {18626023},
issn = {1091-6490},
support = {R01 CA106995/CA/NCI NIH HHS/United States ; R01CA106995/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle Proteins/*genetics/metabolism ; Cell Proliferation ; DNA Damage/genetics ; Dyskeratosis Congenita/*genetics/metabolism/pathology ; Embryonic Stem Cells/cytology/metabolism ; Etoposide/toxicity ; Female ; Genes, p53 ; Heterozygote ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; *Mutation ; Nuclear Proteins/*genetics/metabolism ; RNA Processing, Post-Transcriptional ; Telomere/*genetics ; },
abstract = {Telomeres are nucleoprotein structures that cap the ends of chromosomes, protecting them from exonucleases and distinguishing them from double-stranded breaks. Their integrity is maintained by telomerase, an enzyme consisting of a reverse transcriptase, TERT and an RNA template, TERC, and other components, including the pseudouridine synthase, dyskerin, the product of the DKC1 gene. When telomeres become critically short, a p53-dependent pathway causing cell cycle arrest is induced that can lead to senescence, apoptosis, or, rarely to genomic instability and transformation. The same pathway is induced in response to DNA damage. DKC1 mutations in the disease dyskeratosis congenita are thought to act via this mechanism, causing growth defects in proliferative tissues through telomere shortening. Here, we show that pathogenic mutations in mouse Dkc1 cause a growth disadvantage and an enhanced DNA damage response in the context of telomeres of normal length. We show by genetic experiments that the growth disadvantage, detected by disparities in X-inactivation patterns in female heterozygotes, depends on telomerase. Hemizygous male mutant cells showed a strikingly enhanced DNA damage response via the ATM/p53 pathway after treatment with etoposide with a significant number of DNA damage foci colocalizing with telomeres in cytological preparations. We conclude that dyskerin mutations cause slow growth independently of telomere shortening and that this slow growth is the result of the induction of DNA damage. Thus, dyskerin interacts with telomerase and affects telomere maintenance independently of telomere length.},
}
@article {pmid18625723,
year = {2008},
author = {Seidel, JJ and Anderson, CM and Blackburn, EH},
title = {A novel Tel1/ATM N-terminal motif, TAN, is essential for telomere length maintenance and a DNA damage response.},
journal = {Molecular and cellular biology},
volume = {28},
number = {18},
pages = {5736-5746},
pmid = {18625723},
issn = {1098-5549},
support = {R01 GM026259/GM/NIGMS NIH HHS/United States ; R37 GM026259/GM/NIGMS NIH HHS/United States ; GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {*Amino Acid Sequence ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/*metabolism ; Cell Nucleus/metabolism ; *DNA Damage ; DNA Repair ; DNA Repair Enzymes/genetics/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Humans ; *Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Molecular Sequence Data ; Protein Serine-Threonine Kinases/genetics/*metabolism ; *Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Sequence Alignment ; Sequence Homology, Amino Acid ; Telomere/genetics/*metabolism ; Tumor Suppressor Proteins/genetics/*metabolism ; },
abstract = {Tel1/ATM, a conserved phosphatidylinositol 3-kinase-related kinase (PIKK), acts in the response to DNA damage and regulates telomere maintenance. PIKK family members share an extended N-terminal region of low sequence homology. Sequence alignment of the N terminus of Tel1/ATM orthologs revealed a conserved, novel motif we term TAN (for Tel1/ATM N-terminal motif). Point mutations in conserved residues of the TAN motif resulted in telomere shortening, and its deletion caused the same short telomere phenotype as complete deletion of Tel1 did. Overexpressing Tel1 TAN mutants did not rescue telomere shortening. The TAN motif was also essential for the function of Tel1 in the response to DNA damage, as TAN-deleted Tel1 was indistinguishable from the complete lack of Tel1 in causing reduced viability and signaling through Rad53 upon DNA damage. Strikingly, TAN deletion reduced recruitment of Tel1 to a double-strand DNA break. Together, these results define a conserved sequence motif within an otherwise poorly defined region of the Tel1/ATM kinase family proteins that is essential for normal Tel1 function in Saccharomyces cerevisiae.},
}
@article {pmid18625717,
year = {2008},
author = {Wu, P and de Lange, T},
title = {No overt nucleosome eviction at deprotected telomeres.},
journal = {Molecular and cellular biology},
volume = {28},
number = {18},
pages = {5724-5735},
pmid = {18625717},
issn = {1098-5549},
support = {T32 GM007739/GM/NIGMS NIH HHS/United States ; GM07739/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Antigens, Nuclear/genetics/metabolism ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/metabolism ; Cell Line ; Chromatin/chemistry/metabolism ; *DNA Damage ; DNA Ligase ATP ; DNA Ligases/genetics/metabolism ; DNA Repair ; DNA-Binding Proteins/genetics/*metabolism ; Humans ; Ku Autoantigen ; Mice ; Mice, Knockout ; Micrococcal Nuclease/metabolism ; Nucleosomes/*metabolism ; Protein Serine-Threonine Kinases/genetics/metabolism ; Shelterin Complex ; Signal Transduction/physiology ; Telomere/*metabolism ; Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; Tumor Suppressor Proteins/genetics/metabolism ; },
abstract = {Dysfunctional telomeres elicit the canonical DNA damage response, which includes the activation of the ATM or ATR kinase signaling pathways and end processing by nonhomologous end joining (NHEJ) or homologous recombination (HR). The cellular response to DNA double-strand breaks has been proposed to involve chromatin remodeling and nucleosome eviction, but whether dysfunctional telomeres undergo chromatin reorganization is not known. Here, we report on the nucleosomal organization of telomeres that have become deprotected through the deletion of the shelterin components TRF2 or POT1. We found no evidence of changes in the nucleosomal organization of the telomeric chromatin or nucleosome eviction near the telomere terminus. An unaltered chromatin structure was observed at telomeres lacking TRF2, which activate the ATM kinase and are a substrate for NHEJ. Similarly, telomeres lacking POT1a and POT1b, which activate the ATR kinase, showed no overt nucleosome eviction. Finally, telomeres lacking TRF2 and Ku70, which are processed by HR, appeared to maintain their original nucleosomal organization. We conclude that ATM signaling, ATR signaling, NHEJ, and HR at deprotected telomeres can take place in the absence of overt nucleosome eviction.},
}
@article {pmid18625707,
year = {2008},
author = {Wu, ZQ and Yang, X and Weber, G and Liu, X},
title = {Plk1 phosphorylation of TRF1 is essential for its binding to telomeres.},
journal = {The Journal of biological chemistry},
volume = {283},
number = {37},
pages = {25503-25513},
pmid = {18625707},
issn = {0021-9258},
support = {K01 CA114401/CA/NCI NIH HHS/United States ; K01 CA 114401/CA/NCI NIH HHS/United States ; },
mesh = {Apoptosis ; Cell Cycle ; Cell Cycle Proteins/*metabolism ; DNA/chemistry ; HeLa Cells ; Humans ; Mitosis ; Models, Biological ; Phosphorylation ; Plasmids/metabolism ; Protein Binding ; Protein Serine-Threonine Kinases/*metabolism ; Proto-Oncogene Proteins/*metabolism ; RNA Interference ; Telomere/*chemistry/*ultrastructure ; Telomeric Repeat Binding Protein 1/*metabolism ; Transfection ; Polo-Like Kinase 1 ; },
abstract = {In a search for Polo-like kinase 1 (Plk1) interaction proteins, we have identified TRF1 (telomeric repeat binding factor 1) as a potential Plk1 target. In this communication we report further characterization of the interaction. We show that Plk1 associates with TRF1, and Plk1 phosphorylates TRF1 at Ser-435 in vivo. Moreover, Cdk1, serving as a priming kinase, phosphorylates TRF1 to generate a docking site for Plk1 toward TRF1. In the presence of nocodazole, ectopic expression of wild type TRF1 but not TRF1 with alanine mutation in the Plk1 phosphorylation site induces apoptosis in cells containing short telomeres but not in cells containing long telomeres. Unexpectedly, down-regulation of TRF1 by RNA interference affects cell proliferation and results in obvious apoptosis in cells with short telomeres but not in cells with long telomeres. Importantly, we observe that telomeric DNA binding ability of TRF1 is cell cycle-regulated and reaches a peak during mitosis. Upon phosphorylation by Plk1 in vivo and in vitro, the ability of TRF1 to bind telomeric DNA is dramatically increased. These results demonstrate that Plk1 interacts with and phosphorylates TRF1 and suggest that Plk1-mediated phosphorylation is involved in both TRF1 overexpression-induced apoptosis and its telomeric DNA binding ability.},
}
@article {pmid18619486,
year = {2008},
author = {Katepalli, MP and Adams, AA and Lear, TL and Horohov, DW},
title = {The effect of age and telomere length on immune function in the horse.},
journal = {Developmental and comparative immunology},
volume = {32},
number = {12},
pages = {1409-1415},
doi = {10.1016/j.dci.2008.06.007},
pmid = {18619486},
issn = {0145-305X},
mesh = {Age Factors ; Aging/*genetics/*immunology/pathology ; Animals ; Cellular Senescence/genetics/immunology ; Horses/*genetics/*immunology ; Inflammation/genetics/immunology/pathology ; Leukocytes, Mononuclear/immunology/metabolism/pathology ; Telomere/*genetics/immunology/pathology ; },
abstract = {Telomeres, specialized structures present at the ends of linear eukaryotic chromosomes, function to maintain chromosome stability and integrity. Telomeres shorten with each cell division eventually leading to replicative senescence, a process thought to be associated with age-related decline in immune function. We hypothesized that shortened PBMC telomere length is a factor contributing to immunosenescence of the aged horse. Telomere length was assessed in 19 horses ranging in age from 1 to 25 years. Mitogen-induced 3H-thymidine incorporation, total serum IgG, and pro-inflammatory cytokine expression was also determined for each horse. Relative telomere length (RTL) was highly correlated with overall age. RTL was positively correlated with 3H-thymidine incorporation and total IgG. Expression of pro-inflammatory cytokines was negatively correlated with RTL. These measures were also correlated with age, as expected. However, RTL was not correlated with immunosenescence and inflammaging in the oldest horse.},
}
@article {pmid18617059,
year = {2008},
author = {Goldberg-Bittman, L and Kitay-Cohen, Y and Quitt, M and Hadary, R and Fejgin, MD and Yukla, M and Amiel, A},
title = {Telomere aggregates in non-Hodgkin lymphoma patients at different disease stages.},
journal = {Cancer genetics and cytogenetics},
volume = {184},
number = {2},
pages = {105-108},
doi = {10.1016/j.cancergencyto.2008.04.006},
pmid = {18617059},
issn = {1873-4456},
mesh = {Aged ; Case-Control Studies ; Cells, Cultured ; Chromosome Aberrations ; Humans ; Lymphocytes/metabolism/pathology ; Lymphoma, Non-Hodgkin/*genetics/metabolism/*pathology ; Middle Aged ; Neoplasm Staging ; Telomere/*metabolism ; },
abstract = {Telomeres of tumor nuclei tend to form aggregates (TA). The same phenomenon was also observed in premalignant states. The aim of this study was to estimate TA formation in leukocytes of patients with non-Hodgkin lymphoma (NHL) at different disease stages (diagnosis, treatment, relapse, and remission). The peptide nucleic acid Telomere Kit was used to evaluate TA formation, using two-dimensional fluorescence microscopy. A higher rate of TA was found in all the NHL stages (including remission) than in the control group. Significantly higher TA formation was also observed in the relapse group, compared to the diagnosis group. It may be possible that patients with higher TA numbers are prone to relapse. From our previous results involving replication pattern, random aneuploidy rate, and (recently) TA formation, it can be concluded that the patients in remission are at higher risk of developing relapse than the normal population throughout their life span. The genetic instability parameters remain in the cells of these patients, who must continue to be monitored throughout their life.},
}
@article {pmid18616638,
year = {2008},
author = {Brüderlein, S and Müller, K and Melzner, J and Högel, J and Wiegand, P and Möller, P},
title = {Different rates of telomere attrition in peripheral lymphocytes in a pair of dizygotic twins with hematopoietic chimerism.},
journal = {Aging cell},
volume = {7},
number = {5},
pages = {663-666},
doi = {10.1111/j.1474-9726.2008.00413.x},
pmid = {18616638},
issn = {1474-9726},
mesh = {Adult ; Chimera/*blood/*genetics ; *Chimerism ; Chromosomes, Human, X/genetics ; Chromosomes, Human, Y/genetics ; Female ; Hematopoiesis/genetics ; Humans ; Lymphocyte Subsets/*metabolism/pathology ; Male ; Sex Characteristics ; Telomere/*genetics/metabolism ; Twins, Dizygotic/*blood/*genetics ; },
abstract = {Hematopoietic chimerism in dizygotic twins is due to placental vascular anastomoses and arises when hematopoietic stem cells from one twin home to the bone marrow of the other. We report a case of hematopoietic chimerism in a pair of 27-year-old dizygotic twins who each had a mixture of 46,XX and 46,XY blood lymphocytes, both with 98% male (XY) lymphocytes and 2% female (XX) lymphocytes. Analysis of telomere length by T/C FISH revealed that the female twin generally had longer telomeres than the male twin. Moreover, in the male sibling, the telomeres within the female lymphocytes were shortened to 87% of their original length, while the telomeres within the male lymphocytes were 33% longer in the female sibling. Thus, telomere length attrition in peripheral lymphocytes is determined mainly by the environment of the cell and less by intracellular factors.},
}
@article {pmid18606076,
year = {2008},
author = {Londono-Vallejo, JA},
title = {[Cancer as a microevolutionary process affecting telomere structure and dynamics: the contribution of telomeres to cancer].},
journal = {Ai zheng = Aizheng = Chinese journal of cancer},
volume = {27},
number = {7},
pages = {775-783},
pmid = {18606076},
mesh = {Aging ; Cell Proliferation ; Evolution, Molecular ; Genomic Instability ; Humans ; Mutation ; Neoplasms/*etiology/genetics ; Phenotype ; *Telomere ; },
abstract = {Telomeres play fundamental roles in genome stability, nuclear architecture and chromosome pairing during meiosis. They shorten at every cell division and may be re-elongated or not depending on the presence of the dedicated enzyme, telomerase. Since in most human somatic cells telomerase is not expressed, shortening of telomeres during development and aging is the rule. Short telomeres being, under physiological conditions, incompatible with extended cell proliferation, telomere length defines the proliferation potential of a cell and operates as a mechanism to prevent uncontrolled cell growth. Conversely, in cells in which proliferation checkpoints have been abolished, shortening of telomeres causes chromosomes to fuse and to initiate cycles of breakage-fusion-bridge thus becoming a strong driving force for genome instability. In vitro, transformed cells with highly unstable genomes because of severe telomere shortening accumulate deleterious genetic changes and die (crisis). At the same time, random genetic or epigenetic changes may allow cells to acquire a telomere maintenance mechanism (as well as other tumor phenotypes) and to become immortal. Although telomere shortening and other types of telomere dysfunction probably contribute to the genome instability detected in early tumors in vivo, the direct contributions of dysfunctional telomeres to the acquisition of tumor phenotypes in humans remain largely unspecified.},
}
@article {pmid18602523,
year = {2008},
author = {van der Harst, P and Wong, LS and de Boer, RA and Brouilette, SW and van der Steege, G and Voors, AA and Hall, AS and Samani, NJ and Wikstrand, J and van Gilst, WH and van Veldhuisen, DJ and , },
title = {Possible association between telomere length and renal dysfunction in patients with chronic heart failure.},
journal = {The American journal of cardiology},
volume = {102},
number = {2},
pages = {207-210},
doi = {10.1016/j.amjcard.2008.03.040},
pmid = {18602523},
issn = {0002-9149},
mesh = {Adult ; Aged ; Aged, 80 and over ; Chronic Disease ; Female ; Glomerular Filtration Rate ; Heart Failure/*complications/physiopathology ; Humans ; Kidney Diseases/*etiology/genetics/physiopathology ; *Leukocytes ; Male ; Middle Aged ; Pilot Projects ; Risk Factors ; Stroke Volume ; *Telomere/pathology ; },
abstract = {Renal function impairment relates to poor outcome in patients with chronic heart failure (HF). Differences in biological aging could affect the susceptibility to develop renal dysfunction in chronic HF. In the present study, we explored the association of leukocyte telomere length with renal function in patients with chronic HF. We studied 610 patients with HF, aged 40 to 80 years, NYHA class II-IV, with left ventricular ejection fraction of 0.40 or less. Glomerular filtration rate was estimated by the Modification of Diet in Renal Diseases (MDRD) formula, and telomere length of leukocytes was determined by a validated quantitative polymerase chain reaction-based method. Age-and gender-adjusted telomere length ratio decreased steadily with decreasing quartile of the MDRD formula (mean 0.80, 95% confidence interval [CI] 0.73 to 0.88; mean 0.74, 95% CI 0.68 to 0.81; 0.70 mean, 95% CI 0.63 to 0.76; mean 0.67, 95% CI 0.61 to 0.73; p <0.01). Telomere length of leukocytes correlated positively with the MDRD formula (correlation coefficient 0.141; p <0.001). These findings remained significant after adjustment for baseline differences and sensitivity analysis based on propensity score one-to-one matching. In conclusion, shorter leukocyte telomere length is associated with decreased renal function as estimated by the MDRD formula in patients with HF. Further studies will be needed to determine whether shorter leukocyte telomere length is the cause or consequence in this population and whether it plays a role in the prognosis of renal dysfunction in HF.},
}
@article {pmid18599611,
year = {2008},
author = {Akbay, EA and Contreras, CM and Perera, SA and Sullivan, JP and Broaddus, RR and Schorge, JO and Ashfaq, R and Saboorian, H and Wong, KK and Castrillon, DH},
title = {Differential roles of telomere attrition in type I and II endometrial carcinogenesis.},
journal = {The American journal of pathology},
volume = {173},
number = {2},
pages = {536-544},
pmid = {18599611},
issn = {1525-2191},
mesh = {Aged ; Aneuploidy ; Animals ; *Cell Transformation, Neoplastic ; Endometrial Neoplasms/*pathology ; Endometrium/*pathology ; Female ; Humans ; In Situ Hybridization/methods ; Mice ; Telomere/*physiology ; },
abstract = {Endometrial cancer has been generally categorized into two broad groups of tumors, type I (TI) and type II (TII), with distinct epidemiological/clinical features and genetic alterations. Because telomere attrition appears to trigger genomic instability in certain cancers, we explored the role of telomere dysfunction in endometrial cancer by analyzing telomeres and other markers of telomere status in both tumor types. We describe a new method, telomere chromogenic in situ hybridization, which permitted us to detect cells with short telomeres relative to control (stromal) cells within the same tissue section. Using this method, we found that both types of tumor cells had short telomeres. However, only TII tumors were significantly associated with critical telomere shortening in adjacent, morphologically normal epithelium, suggesting that telomere shortening contributes to the initiation of TII but not TI tumors. To explore this hypothesis, we analyzed mice with critically short telomeres and documented distinctive endometrial lesions that histologically resembled the in situ precursor of TII serous carcinomas; these lesions have not been observed previously in TI mouse models of endometrial cancer. Based on this and previous studies, we propose a model in which telomere attrition contributes to the initiation of TII and progression of TI endometrial cancers.},
}
@article {pmid18599157,
year = {2010},
author = {Zekry, D and Herrmann, FR and Irminger-Finger, I and Ortolan, L and Genet, C and Vitale, AM and Michel, JP and Gold, G and Krause, KH},
title = {Telomere length is not predictive of dementia or MCI conversion in the oldest old.},
journal = {Neurobiology of aging},
volume = {31},
number = {4},
pages = {719-720},
doi = {10.1016/j.neurobiolaging.2008.05.016},
pmid = {18599157},
issn = {1558-1497},
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/genetics ; Cellular Senescence/genetics ; Cognition Disorders/*genetics ; Cohort Studies ; DNA Mutational Analysis ; Dementia/*genetics ; Dementia, Vascular/genetics ; Disease Progression ; Female ; Frontotemporal Dementia/genetics ; Genetic Markers/*genetics ; Genetic Predisposition to Disease/*genetics ; Genetic Testing ; Genotype ; Humans ; Longitudinal Studies ; Male ; Prognosis ; Risk Factors ; Telomere/*genetics ; },
abstract = {The contribution of telomere shortening to the onset of certain age-related diseases, such as dementia, and its role as a predictor of cognitive impairment remain unclear. We tested these hypotheses by analyzing telomere length in 449 inpatients in a large cohort of the oldest old (mean age 85 years) followed up yearly. No significant difference in telomere length was observed between cognitively normal patients (205), demented patients (195; 82 mixed dementia, 77 Alzheimer's disease and 21 vascular dementia) and patients (49) with mild cognitive impairment (MCI). Similarly, no significant differences in telomere length were found between patients with different etiologies or severities of dementia. Telomere length and change in cognitive status (from normal to MCI or dementia, or from MCI to dementia) were not associated after two years of follow-up. This longitudinal study in very old patients provided no evidence to suggest that telomere length could be used to distinguish between demented and non demented patients, regardless of the type of dementia, or to predict dementia or MCI conversion.},
}
@article {pmid18597819,
year = {2008},
author = {Hatakeyama, H and Nakamura, K and Izumiyama-Shimomura, N and Ishii, A and Tsuchida, S and Takubo, K and Ishikawa, N},
title = {The teleost Oryzias latipes shows telomere shortening with age despite considerable telomerase activity throughout life.},
journal = {Mechanisms of ageing and development},
volume = {129},
number = {9},
pages = {550-557},
doi = {10.1016/j.mad.2008.05.006},
pmid = {18597819},
issn = {0047-6374},
mesh = {Aging/*genetics/metabolism ; Animals ; Enzyme Activation/physiology ; Female ; Longevity/genetics ; Male ; Oryzias/*genetics/growth &amp; development/*metabolism ; Telomerase/*metabolism/physiology ; Telomere/*genetics/metabolism ; },
abstract = {Previous studies of telomeres and telomerase have focused mostly on mammals, and data for other vertebrates are limited. We analyzed both telomere length (terminal restriction fragment length) and telomerase activity in a small freshwater teleost fish, the medaka (Oryzias latipes), and found that the telomeres shorten during ageing despite the fact that a considerable amount of telomerase activity is ubiquitously detectable throughout the life of the fish. Since the telomere attrition rate during development was greater than that in adulthood, telomere length is inversely correlated with the increase in body length. The difference in telomere length among medaka individuals was similar to that in humans, and the individual specific differences were evident even at the earliest embryonic stage. Telomerase activity was ubiquitously detectable not only in the body of the embryo but also in the systemic organs of mature individuals throughout their entire life span. These data suggest that telomere attrition during ageing in medaka, which is similar to that in humans, may be a major factor determining their mortality, and that telomere maintenance through strong telomerase activity may be required for the characteristic lifelong continuous growth of this fish.},
}
@article {pmid18593991,
year = {2008},
author = {Villa, R and Daidone, MG and Motta, R and Venturini, L and De Marco, C and Vannelli, A and Kusamura, S and Baratti, D and Deraco, M and Costa, A and Reddel, RR and Zaffaroni, N},
title = {Multiple mechanisms of telomere maintenance exist and differentially affect clinical outcome in diffuse malignant peritoneal mesothelioma.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {14},
number = {13},
pages = {4134-4140},
doi = {10.1158/1078-0432.CCR-08-0099},
pmid = {18593991},
issn = {1078-0432},
mesh = {Adult ; Aged ; Alternative Splicing ; Female ; Humans ; Male ; Mesothelioma/*genetics/*pathology/therapy ; Middle Aged ; Models, Biological ; Pleural Neoplasms/*genetics/*pathology/therapy ; Prognosis ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/metabolism ; Telomere/*ultrastructure ; Treatment Outcome ; },
abstract = {PURPOSE: This study aims to investigate the prevalence of the two known telomere maintenance mechanisms, telomerase activity (TA) and alternative lengthening of telomeres (ALT), and to assess their prognostic relevance in diffuse malignant peritoneal mesothelioma (DMPM).<br><br>EXPERIMENTAL DESIGN: In 44 DMPM specimens obtained from 38 patients, TA was determined using the telomeric repeat amplification protocol and ALT was detected by assaying ALT-associated promyelocytic leukemia nuclear bodies. The prognostic significance of telomere maintenance mechanisms was analyzed by Cox regression in the overall series and in a subset of 29 patients who underwent a uniform treatment regimen consisting of cytoreductive surgery and hyperthermic i.p. chemotherapy.<br><br>RESULTS: Telomere maintenance mechanisms were detectable in 86.4% of DMPM: ALT or TA alone was found in 18.2% or 63.6% of lesions, respectively, whereas two cases (4.6%) were ALT+/TA+. TA and ALT proved to be inversely associated (P = 0.002). In the overall series, TA was prognostic for 4-year relapse (TA+ versus TA-, hazard ratio, 3.30; 95% confidence interval, 1.23-8.86; P = 0.018) and cancer-related death (TA+ versus TA-, hazard ratio, 3.56; 95% confidence interval, 1.03-12.51; P = 0.045), whereas ALT failed to significantly affect clinical outcome. These results held true also in the subset of patients submitted to uniform treatment with cytoreductive surgery and hyperthermic i.p. chemotherapy.<br><br>CONCLUSIONS: Our results indicate that both known telomere maintenance mechanisms, TA and ALT, are present in DMPM and differentially affect patient prognosis.},
}
@article {pmid18593705,
year = {2008},
author = {Freibaum, BD and Counter, CM},
title = {The protein hSnm1B is stabilized when bound to the telomere-binding protein TRF2.},
journal = {The Journal of biological chemistry},
volume = {283},
number = {35},
pages = {23671-23676},
pmid = {18593705},
issn = {0021-9258},
support = {CA 082481/CA/NCI NIH HHS/United States ; },
mesh = {Cell Death/genetics ; DNA Repair Enzymes/genetics/*metabolism ; Exodeoxyribonucleases/genetics/*metabolism ; HeLa Cells ; Humans ; Nuclear Proteins/genetics/*metabolism ; Proteasome Endopeptidase Complex/genetics/metabolism ; Protein Binding/genetics ; Telomere/*enzymology/genetics ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; Ubiquitin/genetics/metabolism ; },
abstract = {hSnm1B is member of the SNM family of exonucleases involved in DNA processing and is known to be localized to telomeres via binding to the telomere-binding protein TRF2. Here we demonstrate that the C terminus of hSnm1B facilitates the concentration of hSnm1B on telomeres by promoting ubiquitin-mediated degradation of hSnm1B that is not localized to telomeres, as well as by blocking protein degradation and fostering localization to telomeres via binding of TRF2. Finally, a mutant of hSnm1B stabilized independently of exogenous TRF2-induced cell death. Taken together, we speculate that sequestering hSnm1B at telomeres by a combination of stabilizing the protein when bound to telomeres and degrading it when not bound to telomeres may be a means to prevent potentially lethal effects of unregulated hSnm1B activity.},
}
@article {pmid18592039,
year = {2008},
author = {Yu, WY and Chang, HW and Lin, CH and Cho, CL},
title = {Short telomeres in patients with chronic schizophrenia who show a poor response to treatment.},
journal = {Journal of psychiatry &amp; neuroscience : JPN},
volume = {33},
number = {3},
pages = {244-247},
pmid = {18592039},
issn = {1488-2434},
mesh = {Adult ; Blotting, Southern ; Chronic Disease ; *Drug Resistance ; Female ; Humans ; Male ; Middle Aged ; Schizophrenia/*drug therapy/*metabolism ; Telomere/*metabolism ; },
abstract = {OBJECTIVE: Telomere shortening has been observed in many human diseases, including atherosclerosis, cancer, aging syndromes, Alzheimer disease and vascular dementia. The present study aimed to investigate the mean telomere lengths of patients with schizophrenia.<br><br>METHODS: We analyzed the lengths of telomeric DNA, comparing 2 groups of patients with schizophrenia (34 good responders and 34 poor responders). A control group of 76 healthy volunteers was also included. Blood samples were obtained, and telomere length was measured by Southern blot analysis on the mean length of terminal restriction fragment (TRF).<br><br>RESULTS: Compared with the control group, a significant amount of telomere shortening was found in peripheral blood leukocytes from patients with schizophrenia who experienced poor response to antipsychotics (p < 0.001).<br><br>CONCLUSION: Shortened telomere length in chronic schizophrenia may be a trait marker caused by oxidative stress, and the ensuing cellular dysfunction may be a factor contributing to the progressive deterioration in treatment-resistant schizophrenia.},
}
@article {pmid18590810,
year = {2008},
author = {Aida, J and Izumiyama-Shimomura, N and Nakamura, K and Ishikawa, N and Poon, SS and Kammori, M and Sawabe, M and Arai, T and Matsuura, M and Fujiwara, M and Kishimoto, H and Takubo, K},
title = {Basal cells have longest telomeres measured by tissue Q-FISH method in lingual epithelium.},
journal = {Experimental gerontology},
volume = {43},
number = {9},
pages = {833-839},
doi = {10.1016/j.exger.2008.06.001},
pmid = {18590810},
issn = {1873-6815},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/genetics ; Biomarkers/metabolism ; Child ; Child, Preschool ; Epithelial Cells/metabolism/ultrastructure ; Female ; Humans ; In Situ Hybridization, Fluorescence/methods ; Infant ; Infant, Newborn ; Keratin-19/metabolism ; Male ; Membrane Proteins/metabolism ; Middle Aged ; Mouth Mucosa/metabolism/*ultrastructure ; Proliferating Cell Nuclear Antigen/metabolism ; Stem Cells/metabolism/ultrastructure ; Telomere/metabolism/*ultrastructure ; Tongue/metabolism/*ultrastructure ; Young Adult ; },
abstract = {We investigated the telomere lengths of individual cell types in lingual mucosa using an improved tissue quantitative fluorescence in situ hybridization (Q-FISH) method. Our tissue Q-FISH method compensates for partially cut nuclei in a tissue section by using the telomere:centromere ratio (TCR). We normalized our TCR measurements (NTCR) using a section from a block of cultured cells placed on the same slide, thus improving the accuracy and reproducibility of the results. Normal lingual mucosa was obtained from 21 autopsied individuals. Immunohistochemistry showed positivity mainly for p27, p63, and CK19 in basal cells, and for Ki-67 in parabasal cells. Q-FISH revealed that NTCR was significantly highest in basal cells and lowest in prickle cells, and also that telomere length regressed at a certain rate in each cell type, firstly. Significant correlations of NTCR among the three epithelial cell types were demonstrated. The present findings appear to support the theory that stem cells exist in the basal layer of the lingual epithelium. The reduction of telomere length with age and in each cell layer is consistent with the telomere biology theory of cell proliferation and differentiation in oral mucosa.},
}
@article {pmid18590060,
year = {2008},
author = {Huzen, J and van Veldhuisen, DJ and van Gilst, WH and van der Harst, P},
title = {[Telomeres and biological ageing in cardiovascular disease].},
journal = {Nederlands tijdschrift voor geneeskunde},
volume = {152},
number = {22},
pages = {1265-1270},
pmid = {18590060},
issn = {0028-2162},
mesh = {Age of Onset ; Aging/*genetics/*physiology ; Cardiovascular Diseases/*epidemiology/genetics/pathology ; Humans ; Risk Factors ; *Telomere/genetics ; },
abstract = {The striking variability in the age of onset of and the manifestation/ absence of manifestation of cardiovascular diseases is inadequately explained by conventional risk factors, but may be explained by variation in biological age. Telomere length is possibly a reliable marker of biological age, shorter telomeres reflecting more advanced age. The initial telomere length ofa person is mainly determined by genetic factors. Moreover, the telomere length shortens with each cell division, and exposition to harmful environmental factors also results in shorter telomeres. Leukocytes of patients with atherosclerosis and heart failure display remarkably shorter telomeres compared to leukocytes of healthy subjects of similar age. Conventional cardiovascular risk factors are also associated with telomere length. If telomeres are indeed causally involved in the pathogenesis of cardiovascular disease, this might provide new avenues for future preventive and therapeutic strategies.},
}
@article {pmid18589416,
year = {2008},
author = {Minty, F and Thurlow, JK and Harrison, PR and Parkinson, EK},
title = {Telomere dysfunction in human keratinocytes elicits senescence and a novel transcription profile.},
journal = {Experimental cell research},
volume = {314},
number = {13},
pages = {2434-2447},
doi = {10.1016/j.yexcr.2008.05.007},
pmid = {18589416},
issn = {1090-2422},
support = {//Cancer Research UK/United Kingdom ; },
mesh = {3T3 Cells ; Animals ; Cell Proliferation ; Cells, Cultured ; Cellular Senescence/*genetics ; Clone Cells ; DNA Damage/genetics ; Gene Expression Profiling ; Humans ; Infant, Newborn ; Keratinocytes/*metabolism/pathology ; Mice ; Oligonucleotide Array Sequence Analysis ; Telomere/pathology/*physiology ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; *Transcription, Genetic ; Transgenes ; },
abstract = {The uncapping of telomeres has been shown to precipitate senescence in normal human fibroblasts and apoptosis in lymphocytes and p53-competent cancer cell lines. However, the effects of telomere uncapping on normal epithelial cells have not previously been examined. We have used the well characterised telomere repeat binding factor 2 (TRF2) dominant-negative mutant, TRF2(DeltaBDeltaM), to deplete Normal Human Epidermal Keratinocytes (NHEK) telomeres of TRF2. We observed only a two fold increase in both phosphorylation of p53 at serine 15 and 53BP1 DNA damage foci and no detectable increase in p21(WAF). Despite the weak DNA damage response, the keratinocytes growth arrest, demonstrate reduced colony formation and senescence. The small, abortive senescent colonies did not incorporate Brd-U within 48 h and expressed senescence-associated beta galactosidase (SA-beta-gal). Transcriptional profiling of TRF2-depleted keratinocytes showed a reproducible up-regulation of several genes. These included histones, genes associated with DNA damage and keratinocyte terminal differentiation. Several of the same genes were also shown to be up-regulated when keratinocytes undergo natural telomere-mediated senescence and down-regulated by ectopic telomerase expression. This study has thus revealed highly sensitive and specific candidate indicators of telomere dysfunction that may find use in identifying telomere-mediated keratinocyte senescence in ageing, cancer and other diseases.},
}
@article {pmid18587156,
year = {2008},
author = {Okamoto, K and Iwano, T and Tachibana, M and Shinkai, Y},
title = {Distinct roles of TRF1 in the regulation of telomere structure and lengthening.},
journal = {The Journal of biological chemistry},
volume = {283},
number = {35},
pages = {23981-23988},
pmid = {18587156},
issn = {0021-9258},
mesh = {Animals ; Cell Line ; Chickens ; Chromosomal Instability/genetics ; Chromosomes, Mammalian/genetics/*metabolism ; DNA Damage/genetics ; Mice ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/*metabolism ; },
abstract = {The telomere is a functional chromatin structure that consists of G-rich repetitive sequences and various associated proteins. Telomeres protect chromosomal ends from degradation, provide escape from the DNA damage response, and regulate telomere lengthening by telomerase. Multiple proteins that localize at telomeres form a complex called shelterin/telosome. One component, TRF1, is a double-stranded telomeric DNA binding protein. Inactivation of TRF1 disrupts telomeric localization of other shelterin components and induces chromosomal instability. Here, we examined how the telomeric localization of shelterin components is crucial for TRF1-mediated telomere-associated functions. We found that many of the mTRF1 deficient phenotypes, including chromosomal instability, growth defects, and dysfunctional telomere damage response, were suppressed by the telomere localization of shelterin components in the absence of functional mTRF1. However, abnormal telomere signals and telomere elongation phenotypes were either not rescued or only partially rescued, respectively. These data suggest that TRF1 regulates telomere length and function by at least two mechanisms; in one TRF1 acts through the recruiting/tethering of other shelterin components to telomeres, and in the other TRF1 seems to play a more direct role.},
}
@article {pmid18585352,
year = {2008},
author = {Conrad, MN and Lee, CY and Chao, G and Shinohara, M and Kosaka, H and Shinohara, A and Conchello, JA and Dresser, ME},
title = {Rapid telomere movement in meiotic prophase is promoted by NDJ1, MPS3, and CSM4 and is modulated by recombination.},
journal = {Cell},
volume = {133},
number = {7},
pages = {1175-1187},
doi = {10.1016/j.cell.2008.04.047},
pmid = {18585352},
issn = {1097-4172},
mesh = {Biological Transport ; Cell Cycle Proteins/genetics/*metabolism ; Chromosome Pairing ; Chromosome Segregation ; Chromosomes, Fungal/*metabolism ; Crossing Over, Genetic ; *Meiosis ; Membrane Proteins/genetics/*metabolism ; Mutation ; Nuclear Proteins ; Recombination, Genetic ; Saccharomyces cerevisiae/*cytology/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Synaptonemal Complex ; Telomere/*metabolism ; },
abstract = {Haploidization of the genome in meiosis requires that chromosomes be sorted exclusively into pairs stabilized by synaptonemal complexes (SCs) and crossovers. This sorting and pairing is accompanied by active chromosome positioning in meiotic prophase in which telomeres cluster near the spindle pole to form the bouquet before dispersing around the nuclear envelope. We now describe telomere-led rapid prophase movements (RPMs) that frequently exceed 1 microm/s and persist throughout meiotic prophase. Bouquet formation and RPMs depend on NDJ1, MPS3, and a new member of this pathway, CSM4, which encodes a meiosis-specific nuclear envelope protein required specifically for telomere mobility. RPMs initiate independently of recombination but differ quantitatively in mutants that fail to complete recombination, suggesting that RPMs respond to recombination status. Together with recombination defects described for ndj1, our observations suggest that RPMs and SCs balance the disruption and stabilization of recombinational interactions, respectively, to regulate crossing over.},
}
@article {pmid18574498,
year = {2008},
author = {Cong, Y and Shay, JW},
title = {Actions of human telomerase beyond telomeres.},
journal = {Cell research},
volume = {18},
number = {7},
pages = {725-732},
doi = {10.1038/cr.2008.74},
pmid = {18574498},
issn = {1748-7838},
mesh = {Animals ; Apoptosis ; Cellular Senescence ; DNA Repair ; Gene Expression Regulation ; Humans ; RNA/metabolism ; Stem Cells/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomerase has fundamental roles in bypassing cellular aging and in cancer progression by maintaining telomere homeostasis and integrity. However, recent studies have led some investigators to suggest novel biochemical properties of telomerase in several essential cell signaling pathways without apparent involvement of its well established function in telomere maintenance. These observations may further enhance our understanding of the molecular actions of telomerase in aging and cancer. This review will provide an update on the extracurricular activities of telomerase in apoptosis, DNA repair, stem cell function, and in the regulation of gene expression.},
}
@article {pmid18571319,
year = {2008},
author = {Jenkins, EC and Ye, L and Gu, H and Ni, SA and Duncan, CJ and Velinov, M and Pang, D and Krinsky-McHale, SJ and Zigman, WB and Schupf, N and Silverman, WP},
title = {Increased "absence" of telomeres may indicate Alzheimer's disease/dementia status in older individuals with Down syndrome.},
journal = {Neuroscience letters},
volume = {440},
number = {3},
pages = {340-343},
pmid = {18571319},
issn = {0304-3940},
support = {P01 HD035897/HD/NICHD NIH HHS/United States ; U54 HD079123/HD/NICHD NIH HHS/United States ; R01-HD37425/HD/NICHD NIH HHS/United States ; P01 HD035897-21/HD/NICHD NIH HHS/United States ; P01 HD035897-20/HD/NICHD NIH HHS/United States ; P01-HD35897/HD/NICHD NIH HHS/United States ; R01 AG014673/AG/NIA NIH HHS/United States ; R01 HD037425/HD/NICHD NIH HHS/United States ; P01 HD035897-19/HD/NICHD NIH HHS/United States ; R01-AG 14673/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Alzheimer Disease/etiology/*genetics ; Case-Control Studies ; *Chromosome Aberrations ; Cognition Disorders/etiology/genetics ; Dementia/etiology/*genetics ; Down Syndrome/complications/*genetics ; Female ; Fluorescein-5-isothiocyanate ; Genetic Predisposition to Disease/genetics ; Humans ; Male ; Middle Aged ; Telomere/*genetics ; },
abstract = {We have reported previously that telomeres (ends of chromosomes consisting of highly conserved TTAGGG repeats) were shorter in metaphase and interphase preparations in T lymphocytes from short-term whole blood cultures of women with Down syndrome (DS) and dementia compared to age-matched women with DS but without dementia [E.C. Jenkins, M.T. Velinov, L. Ye, H. Gu, S. Li, E.C. Jenkins Jr., S.S. Brooks, D. Pang, D.A. Devenny, W.B. Zigman, N. Schupf, W.P. Silverman, Telomere shortening in T lymphocytes of older individuals with Down syndrome and dementia, Neurobiol. Aging 27 (2006) 41-45]. Our previous study was carried out by measuring changes in fluorescence intensity [using an FITC-labeled peptide nucleic acid (PNA) probe (Applied Biosystems; DAKO) and Applied Imaging software], and we now report on a substantially simpler metric, counts of signals at the ends of chromosomes. Nine adults with DS and dementia plus four who are exhibiting declines in cognition analogous to mild cognitive impairment in the general population (MCI-DS) were compared to their pair-matched peers with DS but without dementia or MCI-DS. Results indicated that the number of chromosome ends that failed to exhibit fluorescent signal from the PNA telomere probe was higher for people with dementia or mild cognitive impairment (MCI-DS). Thus, a simple count of chromosome ends for the "presence/absence" of fluorescence may provide a valid biomarker of dementia status. If this is the case, then after additional research for validation to assure high specificity and sensitivity, the test may be used to identify and ultimately guide treatment for people at increased risk for developing mild cognitive impairment and/or dementia.},
}
@article {pmid18567608,
year = {2008},
author = {Ghaffari, SH and Shayan-Asl, N and Jamialahmadi, AH and Alimoghaddam, K and Ghavamzadeh, A},
title = {Telomerase activity and telomere length in patients with acute promyelocytic leukemia: indicative of proliferative activity, disease progression, and overall survival.},
journal = {Annals of oncology : official journal of the European Society for Medical Oncology},
volume = {19},
number = {11},
pages = {1927-1934},
doi = {10.1093/annonc/mdn394},
pmid = {18567608},
issn = {1569-8041},
mesh = {Adolescent ; Adult ; Antineoplastic Agents/therapeutic use ; Arsenic Trioxide ; Arsenicals/therapeutic use ; Cell Growth Processes/drug effects/physiology ; Disease Progression ; Enzyme Activation/drug effects ; Female ; Humans ; Leukemia, Promyelocytic, Acute/drug therapy/*enzymology/*genetics ; Male ; Middle Aged ; Oncogene Proteins, Fusion/biosynthesis ; Oxides/therapeutic use ; Survival Rate ; Telomerase/*blood ; Telomere/drug effects/*metabolism ; },
abstract = {BACKGROUND: The progressive shortening of telomeres and the activation of telomerase have been considered to be one of the key mechanisms in cellular immortalization and tumor progression.<br><br>PATIENTS AND METHODS: About 300 sequential samples were collected from 40 patients during the course of acute promyelocytic leukemia (APL) disease. Telomerase activity (TA) and terminal restriction fragment (TRF) length were assessed by TRAP and Southern blot analyses, respectively. PML-retinoic acid receptor alpha (RARa)/glucose-6-phosphate dehydrogenase transcripts were quantified by real-time PCR.<br><br>RESULTS: About 90% of the patients had a significant reduction in telomere length (TL) relative to the control (median 3.5 versus 11.37 kbp; P < 0.001). A significant positive correlation between TL and PML-RARa expression was found (P = 0.001). Telomerase was activated in all patients; however, TA level was significantly higher in the group of relapsed patients than patient with newly diagnosed. The group of patients with shortened TRF and elevated TA had a significantly poorer overall survival.<br><br>CONCLUSIONS: The shortened TL and elevated TA in APL patients are mainly indicative of extensive proliferative activity and they correlate with disease progression and relapse; thus, they may serve as prognostic factors for a subset of APL patients with more aggressive disease and poor outcome, those who may not respond favorably to arsenic therapy.},
}
@article {pmid18562689,
year = {2008},
author = {Tomlinson, RL and Abreu, EB and Ziegler, T and Ly, H and Counter, CM and Terns, RM and Terns, MP},
title = {Telomerase reverse transcriptase is required for the localization of telomerase RNA to cajal bodies and telomeres in human cancer cells.},
journal = {Molecular biology of the cell},
volume = {19},
number = {9},
pages = {3793-3800},
pmid = {18562689},
issn = {1939-4586},
support = {T32 GM007103/GM/NIGMS NIH HHS/United States ; R01 CA104676/CA/NCI NIH HHS/United States ; GM07103/GM/NIGMS NIH HHS/United States ; R01 CA082481/CA/NCI NIH HHS/United States ; CA082481/CA/NCI NIH HHS/United States ; },
mesh = {Antigens, Polyomavirus Transforming/metabolism ; Bromodeoxyuridine/pharmacology ; Cell Line, Tumor ; Coiled Bodies/*metabolism ; *Gene Expression Regulation, Neoplastic ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Microscopy, Fluorescence ; RNA/*metabolism ; RNA, Long Noncoding ; *RNA, Untranslated ; S Phase ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomere maintenance by telomerase is critical for the unlimited division potential of most human cancer cells. The two essential components of human telomerase, telomerase RNA (hTR) and telomerase reverse transcriptase (hTERT), are recruited from distinct subnuclear sites to telomeres during S phase. Throughout the remainder of the cell cycle hTR is found primarily in Cajal bodies. The localization of hTR to Cajal bodies and telomeres is specific to cancer cells where telomerase is active and is not observed in primary cells. Here we show that the trafficking of hTR to both telomeres and Cajal bodies depends on hTERT. RNA interference-mediated depletion of hTERT in cancer cells leads to loss of hTR from both Cajal bodies and telomeres without affecting hTR levels. In addition, expression of hTERT in telomerase-negative cells (including primary and ALT cancer cell lines) induces hTR to localize to both sites. Factors that did not stimulate hTR localization in our experiments include increased hTR RNA levels and Cajal body numbers, and expression of SV40 large T antigen and oncogenic Ras. Our findings suggest that the trafficking of telomerase to Cajal bodies and telomeres in cancer cells correlates with and depends on the assembly of the enzyme.},
}
@article {pmid18558631,
year = {2008},
author = {Yehezkel, S and Segev, Y and Viegas-Péquignot, E and Skorecki, K and Selig, S},
title = {Hypomethylation of subtelomeric regions in ICF syndrome is associated with abnormally short telomeres and enhanced transcription from telomeric regions.},
journal = {Human molecular genetics},
volume = {17},
number = {18},
pages = {2776-2789},
doi = {10.1093/hmg/ddn177},
pmid = {18558631},
issn = {1460-2083},
mesh = {Cells, Cultured ; Chromosome Aberrations ; DNA (Cytosine-5-)-Methyltransferases/genetics/*metabolism ; *DNA Methylation ; Face/*abnormalities/physiopathology ; Female ; Humans ; Immunologic Deficiency Syndromes/genetics/*metabolism ; Male ; Telomere/chemistry/genetics/*metabolism ; *Transcription, Genetic ; DNA Methyltransferase 3B ; },
abstract = {Telomeres and adjacent subtelomeric regions are packaged as heterochromatin in many organisms. The heterochromatic features include DNA methylation, histones H3-Lys9 (Lysine 9) and H4-Lys20 (Lysine 20) methylation and heterochromatin protein1 alpha binding. Subtelomeric DNA is hypomethylated in human sperm and ova, and these regions are subjected to de novo methylation during development. In mice this activity is carried out by DNA methyltransferase 3b (Dnmt3b). Mutations in DNMT3B in humans lead to the autosomal-recessive ICF (immunodeficiency, centromeric region instability, facial anomalies) syndrome. Here we show that, in addition to several satellite and non-satellite repeats, the subtelomeric regions in lymphoblastoid and fibroblast cells of ICF patients are also hypomethylated to similar levels as in sperm. Furthermore, the telomeres are abnormally short in both the telomerase-positive and -negative cells, and many chromosome ends lack detectable telomere fluorescence in situ hybridization signals from either one or both sister-chromatids. In contrast to Dnmt3a/b(-/-) mouse embryonic stem cells, increased telomere sister-chromatid exchange was not observed in ICF cells. Hypomethylation of subtelomeric regions was associated in the ICF cells with advanced telomere replication timing and elevated levels of transcripts emanating from telomeric regions, known as TERRA (telomeric-repeat-containing RNA) or TelRNA. The current findings provide a mechanistic explanation for the abnormal telomeric phenotype observed in ICF syndrome and highlights the link between TERRA/TelRNA and structural telomeric integrity.},
}
@article {pmid18555689,
year = {2008},
author = {Okamoto, K and Sannohe, Y and Mashimo, T and Sugiyama, H and Terazima, M},
title = {G-quadruplex structures of human telomere DNA examined by single molecule FRET and BrG-substitution.},
journal = {Bioorganic &amp; medicinal chemistry},
volume = {16},
number = {14},
pages = {6873-6879},
doi = {10.1016/j.bmc.2008.05.053},
pmid = {18555689},
issn = {1464-3391},
mesh = {Bromine ; DNA/*chemistry ; Fluorescence Resonance Energy Transfer ; *G-Quadruplexes ; Guanine ; Humans ; Models, Molecular ; Nucleic Acid Conformation ; Telomere/*chemistry ; },
abstract = {The human telomere is known to form the G-quadruplex structure to inhibit the activity of telomerase. Its detailed structure has been of great interest. Recently, two kinds of the parallel-antiparallel hybrid structures have been specified in K(+) solution. However, the G-quadruplex structure is generally thought to be in equilibrium among different structures. Here, we describe the single-pair fluorescence resonance energy transfer (sp-FRET) experiments on telomere samples with bromoguanine (BrG)-substitutions, which control the G-quadruplex structures, at different positions and one without any substitution. The observed FRET distributions were decomposed into five components and the relative population of these components depended on the BrG-substitution positions. In order to consistently explain the variety of conformations, we proposed a novel structural model, the so-called triple-strand-core model. On the basis of this model, the components of the FRET distributions were attributed to the mixed-chair hybrid structures, which were reported recently, and chair-type antiparallel structures, which can be predicted from this model. The FRET efficiencies of these structures were explained in terms of partially broken structures due to steric hindrance and inappropriate capping. This basic model also consistently explains experimental results reported previously. Furthermore, using this model, the folding pathway of the hybrid structures and T-loop formation can be predicted.},
}
@article {pmid18550783,
year = {2008},
author = {Hockemeyer, D and Palm, W and Wang, RC and Couto, SS and de Lange, T},
title = {Engineered telomere degradation models dyskeratosis congenita.},
journal = {Genes &amp; development},
volume = {22},
number = {13},
pages = {1773-1785},
pmid = {18550783},
issn = {0890-9369},
support = {K08 CA164047/CA/NCI NIH HHS/United States ; R01 CA076027/CA/NCI NIH HHS/United States ; CA076027/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Bone Marrow/abnormalities/metabolism ; DNA-Binding Proteins/genetics/physiology ; Disease Models, Animal ; *Dyskeratosis Congenita/genetics/pathology ; Longevity ; Mice ; Phenotype ; Skin Pigmentation ; Telomerase/genetics/*metabolism ; Telomere/*ultrastructure ; },
abstract = {Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by cutaneous symptoms, including hyperpigmentation and nail dystrophy. Some forms of DC are caused by mutations in telomerase, the enzyme that counteracts telomere shortening, suggesting a telomere-based disease mechanism. However, mice with extensively shortened telomeres due to telomerase deficiency do not develop the characteristics of DC, raising questions about the etiology of DC and/or mouse models for human telomere dysfunction. Here we describe mice engineered to undergo telomere degradation due to the absence of the shelterin component POT1b. When combined with reduced telomerase activity, POT1b deficiency elicits several characteristics of DC, including hyperpigmentation and fatal bone marrow failure at 4-5 mo of age. These results provide experimental support for the notion that DC is caused by telomere dysfunction, and demonstrate that key aspects of a human telomere-based disease can be modeled in the mouse.},
}
@article {pmid18544700,
year = {2008},
author = {Jahrsdörfer, B and Weiner, GJ},
title = {Short telomeres in B-CLL: the chicken or the egg?.},
journal = {Blood},
volume = {111},
number = {12},
pages = {5756; author reply 5756-7},
doi = {10.1182/blood-2008-03-146027},
pmid = {18544700},
issn = {1528-0020},
mesh = {Cell Transformation, Neoplastic/*genetics ; *Chromosome Aberrations ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics ; Telomere/*genetics ; },
}
@article {pmid18536059,
year = {2008},
author = {Sasaki, M and Ikeda, H and Yamaguchi, J and Nakada, S and Nakanuma, Y},
title = {Telomere shortening in the damaged small bile ducts in primary biliary cirrhosis reflects ongoing cellular senescence.},
journal = {Hepatology (Baltimore, Md.)},
volume = {48},
number = {1},
pages = {186-195},
doi = {10.1002/hep.22348},
pmid = {18536059},
issn = {1527-3350},
mesh = {Bile Ducts, Intrahepatic/metabolism/pathology/*ultrastructure ; *Cellular Senescence ; Chronic Disease ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; DNA Damage ; Epithelial Cells/metabolism/pathology/ultrastructure ; Hepatitis, Viral, Human/genetics/pathology ; Histones/genetics ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Liver Cirrhosis, Biliary/genetics/pathology/*physiopathology ; Telomere/*ultrastructure ; },
abstract = {UNLABELLED: Telomere shortening is a trigger of cellular senescence. Biliary epithelial cells in damaged small bile ducts in primary biliary cirrhosis (PBC) show senescent features such as the expression of senescence-associated beta-galactosidase and the increased expression of p16(INK4a) and p21(WAF1/Cip1). We investigated whether the telomere shortening is involved in the pathogenesis of biliary cellular senescence in PBC. We analyzed the telomere length of biliary epithelial cells using quantitative fluorescence in situ hybridization in livers taken from the patients with PBC (n = 13) and control livers (n = 13). We also assessed immunohistochemically the prevalence of DNA damage and the expression of p16(INK4a) and p21(WAF1/Cip1). The study showed a significant decrease in telomere length in biliary epithelial cells in the damaged small bile ducts and bile ductules in PBC compared with normal-looking bile ducts and bile ductules in PBC, chronic viral hepatitis, and normal livers (P < 0.01). gammaH2AX-DNA-damage-foci were detected in biliary epithelial cells in damaged small bile ducts and bile ductules in PBC but were absent in biliary epithelial cells in chronic viral hepatitis and normal livers. The expression of p16(INK4a) and p21(WAF1/Cip1) was increased corresponding to telomere shortening and gammaH2AX-DNA-damage-foci in the damaged small bile ducts in PBC.<br><br>CONCLUSION: Telomere shortening and an accumulation of DNA damage coincide with increased expression of p16(INK4a) and p21(WAF1/Cip1) in the damaged bile ducts, characterize biliary cellular senescence, and may play a role in the following progressive bile duct loss in PBC.},
}
@article {pmid18535916,
year = {2008},
author = {Pouilly, N and Delourme, R and Alix, K and Jenczewski, E},
title = {Repetitive sequence-derived markers tag centromeres and telomeres and provide insights into chromosome evolution in Brassica napus.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {16},
number = {5},
pages = {683-700},
pmid = {18535916},
issn = {0967-3849},
mesh = {Biological Evolution ; Biomarkers/*analysis ; Brassica napus/*genetics ; Centromere/*ultrastructure ; Chromosome Mapping ; *Chromosomes, Plant ; DNA Primers ; Genetic Linkage ; Polymorphism, Genetic ; *Repetitive Sequences, Nucleic Acid ; Retroelements ; Telomere/*ultrastructure ; },
abstract = {Centromeres and telomeres are obvious markers on chromosomes but their location on genetic maps is difficult to determine, which hampers many basic and applied research programmes. In this study, we used the characteristic distribution of five Brassica repeated sequences to generate physically anchored molecular markers tentatively tagging Brassica centromeres (84 markers) and telomeres (31 markers). These markers were mapped to the existing oilseed rape genetic map. Clusters of centromere-related loci were observed on 14 linkage groups; in addition to previous reports, we could thus provide information about the most likely position of centromeres on 17 of the 19 B. napus linkage groups. The location of centromeres on linkage groups usually matches their position on chromosomes and coincides with sites of evolutionary breakage between chromosomes. Most telomere sequence-derived markers mapped interstitially or in the proximity of centromeres; this result echoes previous reports on many eukaryote genomes and may reflect different forms of chromosome evolution. Seven telomere sequence-derived markers were located at the outermost positions of seven linkage groups and therefore probably tagged telomeres.},
}
@article {pmid18535244,
year = {2008},
author = {Miyoshi, T and Kanoh, J and Saito, M and Ishikawa, F},
title = {Fission yeast Pot1-Tpp1 protects telomeres and regulates telomere length.},
journal = {Science (New York, N.Y.)},
volume = {320},
number = {5881},
pages = {1341-1344},
doi = {10.1126/science.1154819},
pmid = {18535244},
issn = {1095-9203},
mesh = {Amino Acid Sequence ; Carrier Proteins/chemistry/genetics/*metabolism ; Chromatin Immunoprecipitation ; DNA, Fungal/metabolism ; DNA-Binding Proteins ; Immunoprecipitation ; Molecular Sequence Data ; Mutation ; Protein Binding ; Protein Structure, Tertiary ; Schizosaccharomyces/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/chemistry/genetics/*metabolism ; Shelterin Complex ; Telomerase/metabolism ; Telomere/metabolism/*physiology/ultrastructure ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; Two-Hybrid System Techniques ; },
abstract = {Telomeres are specialized chromatin structures that protect chromosomal ends. Protection of telomeres 1 (Pot1) binds to the telomeric G-rich overhang, thereby protecting telomeres and regulating telomerase. Mammalian POT1 and TPP1 interact and constitute part of the six-protein shelterin complex. Here we report that Tpz1, the TPP1 homolog in fission yeast, forms a complex with Pot1. Tpz1 binds to Ccq1 and the previously undiscovered protein Poz1 (Pot1-associated in Schizosaccharomyces pombe), which protect telomeres redundantly and regulate telomerase in positive and negative manners, respectively. Thus, the Pot1-Tpz1 complex accomplishes its functions by recruiting effector molecules Ccq1 and Poz1. Moreover, Poz1 bridges Pot1-Tpz1 and Taz1-Rap1, thereby connecting the single-stranded and double-stranded telomeric DNA regions. Such molecular architectures are similar to those of mammalian shelterin, indicating that the overall DNA-protein architecture is conserved across evolution.},
}
@article {pmid18534183,
year = {2008},
author = {Reed, J and Gunaratnam, M and Beltran, M and Reszka, AP and Vilar, R and Neidle, S},
title = {TRAP-LIG, a modified telomere repeat amplification protocol assay to quantitate telomerase inhibition by small molecules.},
journal = {Analytical biochemistry},
volume = {380},
number = {1},
pages = {99-105},
doi = {10.1016/j.ab.2008.05.013},
pmid = {18534183},
issn = {1096-0309},
support = {//Cancer Research UK/United Kingdom ; //Medical Research Council/United Kingdom ; },
mesh = {Animals ; Cattle ; Cell Line, Tumor ; DNA-Directed DNA Polymerase/metabolism ; Enzyme Inhibitors/*pharmacology ; G-Quadruplexes ; Humans ; Ligands ; Nucleic Acid Amplification Techniques/*methods ; Reproducibility of Results ; Telomerase/*antagonists &amp; inhibitors/*metabolism ; Telomere/*metabolism ; },
abstract = {The telomerase enzyme is implicated in a large proportion of human cancers. Its major function is to maintain the length of telomeric DNA by synthesizing telomeric DNA repeats, and its enzymatic activity is assayed by means of the telomere repeat amplification protocol (TRAP) assay. We show here that this assay is unable to reliably determine the ability of small molecules to inhibit the enzyme because they interfere with the PCR step of the assay, resulting in a major overestimation of their activity. We report a modified TRAP assay that incorporates the addition of an intermediate step, enabling ligand to be removed from the final PCR process using a commercially available oligonucleotide purification kit, so that more reliable estimates of telomerase inhibition can be made.},
}
@article {pmid18528768,
year = {2008},
author = {Rezende-Teixeira, P and Siviero, F and Brandão, AS and Santelli, RV and Machado-Santelli, GM},
title = {Molecular characterization of a retrotransposon in the Rhynchosciara americana genome and its association with telomere.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {16},
number = {5},
pages = {729-742},
pmid = {18528768},
issn = {0967-3849},
mesh = {Animals ; Diptera/*genetics/growth &amp; development ; Gene Silencing ; In Situ Hybridization ; Long Interspersed Nucleotide Elements/*genetics ; Models, Genetic ; Phylogeny ; Reverse Transcriptase Polymerase Chain Reaction ; Salivary Glands ; Sequence Analysis, DNA ; Telomere/*physiology ; },
abstract = {Non-LTR retrotransposons, also known as long interspersed nuclear elements (LINEs), are transposable elements that encode a reverse transcriptase and insert into genomic locations via RNA intermediates. The sequence analysis of a cDNA library constructed from mRNA of the salivary glands of R. americana showed the presence of putative class I elements. The cDNA clone with homology to a reverse transcriptase was the starting point for the present study. Genomic phage was isolated and sequenced and the molecular structure of the element was characterized as being a non-LTR retrotransposable element. Southern blot analysis indicated that this transposable element is represented by repeat sequences in the genome of R. americana. Chromosome tips were consistently positive when this element was used as probe in in-situ hybridization. Real-time RT-PCR showed that this retrotransposon is transcribed at different periods of larval development. Most interesting, the silencing of this retrotransposon in R. americana by RNA interference resulted in reduced transcript levels and in accelerated larval development.},
}
@article {pmid18519588,
year = {2008},
author = {Barrientos, KS and Kendellen, MF and Freibaum, BD and Armbruster, BN and Etheridge, KT and Counter, CM},
title = {Distinct functions of POT1 at telomeres.},
journal = {Molecular and cellular biology},
volume = {28},
number = {17},
pages = {5251-5264},
pmid = {18519588},
issn = {1098-5549},
support = {R01 CA082481/CA/NCI NIH HHS/United States ; CA082481/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line ; DNA Damage ; DNA, Single-Stranded/genetics/metabolism ; Humans ; Models, Biological ; Mutant Proteins/metabolism ; Mutation/genetics ; Protein Binding ; Protein Transport ; Replication Protein A/metabolism ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/*metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {The mammalian protein POT1 binds to telomeric single-stranded DNA (ssDNA), protecting chromosome ends from being detected as sites of DNA damage. POT1 is composed of an N-terminal ssDNA-binding domain and a C-terminal protein interaction domain. With regard to the latter, POT1 heterodimerizes with the protein TPP1 to foster binding to telomeric ssDNA in vitro and binds the telomeric double-stranded-DNA-binding protein TRF2. We sought to determine which of these functions-ssDNA, TPP1, or TRF2 binding-was required to protect chromosome ends from being detected as DNA damage. Using separation-of-function POT1 mutants deficient in one of these three activities, we found that binding to TRF2 is dispensable for protecting telomeres but fosters robust loading of POT1 onto telomeric chromatin. Furthermore, we found that the telomeric ssDNA-binding activity and binding to TPP1 are required in cis for POT1 to protect telomeres. Mechanistically, binding of POT1 to telomeric ssDNA and association with TPP1 inhibit the localization of RPA, which can function as a DNA damage sensor, to telomeres.},
}
@article {pmid18519043,
year = {2008},
author = {Risques, RA and Lai, LA and Brentnall, TA and Li, L and Feng, Z and Gallaher, J and Mandelson, MT and Potter, JD and Bronner, MP and Rabinovitch, PS},
title = {Ulcerative colitis is a disease of accelerated colon aging: evidence from telomere attrition and DNA damage.},
journal = {Gastroenterology},
volume = {135},
number = {2},
pages = {410-418},
pmid = {18519043},
issn = {1528-0012},
support = {P30 AG13280/AG/NIA NIH HHS/United States ; P30 AG013280-13S1/AG/NIA NIH HHS/United States ; P20 CA103728/CA/NCI NIH HHS/United States ; P01 AG001751/AG/NIA NIH HHS/United States ; P30 AG013280/AG/NIA NIH HHS/United States ; P20 CA103728-01/CA/NCI NIH HHS/United States ; R01 CA068124-13/CA/NCI NIH HHS/United States ; R01 CA068124/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Distribution ; Age Factors ; Aged ; Aging/*genetics/metabolism/pathology ; Child ; Child, Preschool ; Colitis, Ulcerative/complications/*genetics/metabolism/pathology ; Colon/*metabolism/pathology ; Colorectal Neoplasms/*genetics/metabolism/pathology ; Cross-Sectional Studies ; *DNA Damage ; Female ; Fluorescent Antibody Technique ; Histones/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Intestinal Mucosa/metabolism ; Leukocytes/metabolism ; Male ; Middle Aged ; Phosphorylation ; Polymerase Chain Reaction ; Stromal Cells/metabolism ; Telomere/*metabolism ; Up-Regulation ; },
abstract = {BACKGROUND &amp; AIMS: Telomere shortening is implicated in cancer and aging and might link these 2 biologic events. We explored this hypothesis in ulcerative colitis (UC), a chronic inflammatory disease that predisposes to colorectal cancer and in which shorter telomeres have been associated with chromosomal instability and tumor progression.<br><br>METHODS: Telomere length was measured by quantitative polymerase chain reaction in colonocytes and leukocytes of 2 different sets of UC patients and compared with normal controls across a wide range of ages. For a subset of patients, telomere length was measured in epithelium and stroma of right and left colon biopsy specimens. A third set of biopsy specimens was analyzed for phosphorylation of histone H2AX (gammaH2AX), a DNA damage signal, by immunofluorescence and for telomere length by quantitative fluorescence in situ hybridization. Relationships between telomere length, gammaH2AX intensity, age, disease duration, and age of disease onset were explored.<br><br>RESULTS: Colonocyte telomeres shorten with age almost twice as rapidly in UC patients as in normal controls. This extensive shortening occurs within approximately 8 years of disease duration. Leukocyte telomeres are slightly shorter in UC patients than in controls, but telomeres of colon stromal cells are unaffected. gammaH2AX intensity is higher in colonocytes of UC patients than in controls and is not dependent on age or telomere length.<br><br>CONCLUSIONS: Colonocytes of UC patients show premature shortening of telomeres, which might explain the increased and earlier risk of cancer in this disease. Shorter leukocyte telomeres and increased gammaH2AX in colonocytes might reflect oxidative damage secondary to inflammation.},
}
@article {pmid18514000,
year = {2008},
author = {Sánchez-Alonso, P and Guzman, P},
title = {Predicted elements of telomere organization and function in Ustilago maydis.},
journal = {Fungal genetics and biology : FG &amp; B},
volume = {45 Suppl 1},
number = {},
pages = {S54-62},
doi = {10.1016/j.fgb.2008.04.009},
pmid = {18514000},
issn = {1096-0937},
mesh = {Chromosomes, Fungal/*genetics ; Fungal Proteins/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; Ustilago/*genetics/metabolism ; },
abstract = {Telomeres are specialized caps of nucleoprotein complexes located at the chromosome termini. They consist of short DNA repeats and of an assortment of associated proteins whose function is currently under intense investigation in model systems. These specialized structures protect the linear ends of eukaryotic chromosomes against DNA repair and degradation activities, and serve as the substrate for telomerase, the ribonucleoprotein complex that synthesises the telomere repeats. The pivotal role of the telomeres in the maintenance of cell viability in several model eukaryotes, including humans, greatly promoted research in telomere biology. Studies on telomere structure and function in fungi other than model systems are limited to providing information on the telomeric repeat sequences. Here, we have summarized the current knowledge on the organization of chromosome ends and on the proteins participating in telomere function in model systems including recent information obtained for filamentous fungi. We also describe Ustilago maydis genes that are potential homologs of proteins known from other systems to participate in telomere biology.},
}
@article {pmid18511749,
year = {2008},
author = {Guan, JZ and Maeda, T and Sugano, M and Oyama, J and Higuchi, Y and Suzuki, T and Makino, N},
title = {A percentage analysis of the telomere length in Parkinson's disease patients.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {63},
number = {5},
pages = {467-473},
doi = {10.1093/gerona/63.5.467},
pmid = {18511749},
issn = {1079-5006},
mesh = {Aged ; Humans ; Male ; Middle Aged ; Parkinson Disease/*genetics ; Telomere/*ultrastructure ; },
abstract = {Telomeres are the repeated sequences at the chromosome ends which undergo shortening with cell division. The telomere shortening of the peripheral leukocytes is also facilitated by enhanced oxidative stress in various kinds of disease including ischemic heart disease, diabetes mellitus, apoplexy, and Alzheimer's disease. Telomere shortening in Parkinson's disease (PD) has not yet been reported. The pathogenesis for PD is also regarded to be associated with oxidative stress. We investigated 28 Japanese male PD patients ages 47-69. Although we could not find a statistical difference in the mean telomere length of peripheral leukocytes between the PD patients and the control participants, we found the mean telomere lengths to be shorter than 5 kb in only the PD patients and a significant PD-associated decrease in the telomeres with a length ranging from 23.1 to 9.4 kb in the patients in their 50s and 60s. These observations suggest that telomere shortening is accelerated in PD patients in comparison to the normal population.},
}
@article {pmid18506590,
year = {2008},
author = {Paeschke, K and Juranek, S and Rhodes, D and Lipps, HJ},
title = {Cell cycle-dependent regulation of telomere tethering in the nucleus.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {16},
number = {5},
pages = {721-728},
pmid = {18506590},
issn = {0967-3849},
support = {MC_U105184333/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; *Cell Cycle ; Cell Nucleus/*genetics ; Ciliophora/*genetics ; DNA-Binding Proteins/*physiology ; Gene Expression Regulation ; Intranuclear Space ; Macronucleus/genetics ; Models, Genetic ; Nuclear Proteins/genetics ; Phosphorylation ; S Phase ; Telomere/*genetics ; },
abstract = {It is well established that telomeres are tethered in the eukaryotic nucleus, but a detailed analysis of the regulation of telomere attachment throughout the cell cycle is still lacking. We show here that the telomeres in the macronucleus of the ciliate Stylonychia lemnae are bound to a sub-nuclear structure by an interaction of the telomere end-binding protein TEBPalpha with three SNS proteins that are integral parts of this structure. In the course of replication, the interaction of TEBPalpha with the SNS proteins is resolved and this process is regulated by cell cycle-specific phosphorylation of the SNS proteins. Our data can be incorporated into a mechanistic model for the regulation of telomere conformation and localization throughout the cell cycle.},
}
@article {pmid18505885,
year = {2008},
author = {Kern, AD and Begun, DJ},
title = {Recurrent deletion and gene presence/absence polymorphism: telomere dynamics dominate evolution at the tip of 3L in Drosophila melanogaster and D. simulans.},
journal = {Genetics},
volume = {179},
number = {2},
pages = {1021-1027},
pmid = {18505885},
issn = {0016-6731},
support = {R01 GM071926/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; GM-071926/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Biological Evolution ; Chromosomes/genetics ; DNA Transposable Elements/genetics ; Drosophila/classification/*genetics ; Drosophila Proteins/genetics ; Drosophila melanogaster/*genetics ; Gene Deletion ; Gene Products, gag/genetics ; *Genes, Insect ; Genetic Variation ; Genetics, Population ; Linkage Disequilibrium ; Polymorphism, Genetic ; Polymorphism, Single Nucleotide ; Species Specificity ; Telomere/*genetics ; },
abstract = {Although Drosophila melanogaster has been the subject of intensive analysis of polymorphism and divergence, little is known about the distribution of variation at the most distal regions of chromosomes arms. Here we report a survey of genetic variation on the tip of 3L in D. melanogaster and D. simulans. Levels of single nucleotide polymorphism in the most distal euchromatic sequence are approximately one order of magnitude less than that typically observed in genomic regions of normal crossing over, consistent with what might be expected under models of linked selection in regions of low crossing over. However, despite this reduced level of nucleotide variation, we found abundant deletion polymorphism. These deletions create at least three gene presence/absence polymorphisms within D. melanogaster: the putative G-protein coupled receptor mthl-8 (which is the most distal known or predicted gene on 3L) and the unannotated mRNAs AY060886 and BT006009. Strikingly, D. simulans is also segregating deletions that cause mthl8 presence/absence polymorphism. Breakpoint sequencing and tests of correlations with segregating SNPs in D. melanogaster suggest that each deletion is unique. Cloned breakpoint sequences revealed the presence of Het-A elements just distal to unique, canonical euchromatic sequences. This pattern suggests a model in which repeated telomeric deficiencies cause deletions of euchromatic sequence followed by subsequent "healing" by retrotranposition of Het-A elements. These data reveal the dominance of telomeric dynamics on the evolution of closely linked sequences in Drosophila.},
}
@article {pmid18501800,
year = {2008},
author = {Carrero, JJ and Shiels, PG and Stenvinkel, P},
title = {Telomere biology alterations as a mortality risk factor in CKD.},
journal = {American journal of kidney diseases : the official journal of the National Kidney Foundation},
volume = {51},
number = {6},
pages = {1076-1077},
doi = {10.1053/j.ajkd.2008.02.367},
pmid = {18501800},
issn = {1523-6838},
mesh = {Chronic Disease ; Humans ; Kidney Diseases/*mortality ; Risk Factors ; Telomere/*physiology/ultrastructure ; },
}
@article {pmid18500246,
year = {2008},
author = {Deng, Y and Chan, SS and Chang, S},
title = {Telomere dysfunction and tumour suppression: the senescence connection.},
journal = {Nature reviews. Cancer},
volume = {8},
number = {6},
pages = {450-458},
pmid = {18500246},
issn = {1474-1768},
support = {R01 AG028888/AG/NIA NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; 1K01CA124461/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Apoptosis ; *Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p21/physiology ; DNA Damage ; Humans ; Neoplasms/genetics/pathology/*prevention &amp; control ; Retinoblastoma Protein/physiology ; Telomerase/physiology ; *Telomere ; Tumor Suppressor Protein p53/physiology ; },
abstract = {Long-lived organisms such as humans have evolved several intrinsic tumour suppressor mechanisms to combat the slew of oncogenic somatic mutations that constantly arise in proliferating stem-cell compartments. One of these anticancer barriers is the telomere, a specialized nucleoprotein complex that caps the ends of eukaryotic chromosome. Impaired telomere function activates the canonical DNA damage response pathway that engages p53 to initiate apoptosis or replicative senescence. Here, we discuss how p53-dependent senescence induced by dysfunctional telomeres may be as potent as apoptosis in suppressing tumorigenesis in vivo.},
}
@article {pmid18497972,
year = {2008},
author = {Zongaro, S and Verri, A and Giulotto, E and Mondello, C},
title = {Telomere length and radiosensitivity in human fibroblast clones immortalized by ectopic telomerase expression.},
journal = {Oncology reports},
volume = {19},
number = {6},
pages = {1605-1609},
pmid = {18497972},
issn = {1021-335X},
mesh = {Cells, Cultured ; Chromosome Aberrations ; Cobalt Radioisotopes ; Dose-Response Relationship, Radiation ; Fibroblasts/enzymology/*pathology/*radiation effects ; *Gamma Rays ; Humans ; *Radiation Tolerance ; Telomerase/genetics/*metabolism ; Telomere/*physiology/radiation effects ; },
abstract = {Telomeres, the ends of eukaryotic chromosomes, have a variable length among individuals and cell types. While studies in telomerase-deficient mice and cells showed an inverse correlation between telomere length and radiosensitivity, it is less clear whether this remains true in telomerase-proficient cells. To gain insight into this topic, we studied radiosensitivity in three telomerase immortalized fibroblast clones derived from the same cell line and characterized by different telomere length. In two clones, cen3tel4 and cen3tel5, the mean terminal restriction fragment length was approximately 13 and 10 kb, respectively and in the third clone, cen3pci16, it was approximately 4 kb, which is lower than in senescent fibroblasts. To test radiosensitivity, we determined survival to gamma-rays and the induction of chromosomal aberrations after irradiation. Neither the LD50, the gamma-ray dose that reduces survival to 50%, nor the frequency of aberrations detected in the three cell lines showed an inverse correlation with telomere length. In particular, the cen3pci16 cells, which have very short telomeres, did not show a higher sensitivity to irradiation or a greater frequency of chromosomal abnormalities compared to the other two cell lines. Our results suggest that, in the presence of telomerase activity, short telomeres are stabilized and do not cause an increase in radiosensitivity.},
}
@article {pmid18493662,
year = {2008},
author = {Moorhouse, AD and Haider, S and Gunaratnam, M and Munnur, D and Neidle, S and Moses, JE},
title = {Targeting telomerase and telomeres: a click chemistry approach towards highly selective G-quadruplex ligands.},
journal = {Molecular bioSystems},
volume = {4},
number = {6},
pages = {629-642},
doi = {10.1039/b801822g},
pmid = {18493662},
issn = {1742-2051},
mesh = {Benzene Derivatives/chemical synthesis/chemistry/*pharmacology ; Binding Sites ; Computer Simulation ; DNA/*chemistry/*metabolism ; G-Quadruplexes/*drug effects ; Ligands ; Models, Chemical ; Models, Molecular ; Molecular Structure ; Stereoisomerism ; Structure-Activity Relationship ; Substrate Specificity ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/chemistry/*metabolism ; Triazoles/chemical synthesis/chemistry/*pharmacology ; },
abstract = {Maintenance of telomeres--specialized complexes that protect the ends of chromosomes, is undertaken by the enzyme complex telomerase, which is a key factor that is activated in more than 80% of cancer cells, but is absent in most normal cells. Targeting telomere maintenance mechanisms could potentially halt tumour growth across a broad spectrum of cancer types, with little cytotoxic effect outside cancer cells. Here, we describe in detail a new class of G-quadruplex binding ligands synthesized using a click chemistry approach. These ligands comprise a 1,3-di(1,2,3-triazol-4-yl)benzene pharmacophore, and display high levels of selectivity for interaction with G-quadruplex DNA vs. duplex DNA. The ability of these ligands to inhibit the enzymatic activity of telomerase correlates with their ability to stabilize quadruplex DNA, and with estimates of affinity calculated by molecular modeling.},
}
@article {pmid18492102,
year = {2008},
author = {Vega, F and Cho-Vega, JH and Lennon, PA and Luthra, MG and Bailey, J and Breeden, M and Jones, D and Medeiros, LJ and Luthra, R},
title = {Splenic marginal zone lymphomas are characterized by loss of interstitial regions of chromosome 7q, 7q31.32 and 7q36.2 that include the protection of telomere 1 (POT1) and sonic hedgehog (SHH) genes.},
journal = {British journal of haematology},
volume = {142},
number = {2},
pages = {216-226},
doi = {10.1111/j.1365-2141.2008.07176.x},
pmid = {18492102},
issn = {1365-2141},
mesh = {Aged ; Chromosomes, Human, Pair 7/*genetics ; Comparative Genomic Hybridization/methods ; DNA Mutational Analysis ; DNA, Neoplasm/genetics/isolation &amp; purification ; Female ; Hedgehog Proteins/genetics/physiology ; Humans ; In Situ Hybridization, Fluorescence ; Lymphatic Diseases/*genetics/physiopathology ; Lymphoma, B-Cell, Marginal Zone/*genetics/physiopathology ; Male ; Middle Aged ; Nucleic Acid Hybridization/methods ; Oligonucleotide Array Sequence Analysis/methods ; Reverse Transcriptase Polymerase Chain Reaction ; Shelterin Complex ; Splenic Neoplasms/*genetics/physiopathology ; Telomere/genetics ; Telomere-Binding Proteins/genetics/physiology ; },
abstract = {To further characterize the genotypic features of splenic (S) and nodal (N) marginal zone lymphomas (MZL) we compared eight SMZL and five NMZL by array-based comparative genomic hybridization (aCGH). Arbitrarily, aberrations were divided into major imbalances, defined as gains or losses involving five or more contiguous genetic loci, and minor imbalances, defined as those involving four or fewer loci. SMZL, but not NMZL, demonstrated major imbalances. These included deletions involving various lengths of 7q (three cases), and 14q23q24 (one case) and gains of 9p13p21 (one case), 13q21q33 (one case) and 16p13.1 (one case). Common minor imbalances in SMZL were: loss of sonic hedgehog gene (SHH) at 7q36.2 (four cases), loss of protection of telomere 1 gene (POT1) at 7q31.32 (three cases), and gain of glioma associated oncogene 1 (GLI1) at 12q13.2 (three cases). Common minor alterations in NMZL were: loss of the fas-associated via death domain gene (FADD) at 11q13.2 (three cases) and gain of GLI1 (five cases). In conclusion, SMZL, but not NMZL, demonstrates large genomic imbalances and frequent loss of the 7q31.32 and 7q36.2 regions involving POT1 and SHH, respectively. In NMZL, loss of FADD and gain of GLI1 are frequent events.},
}
@article {pmid18491413,
year = {2008},
author = {Vondrusková, J and Kypr, J and Kejnovská, I and Fialová, M and Vorlícková, M},
title = {Guanine quadruplex formation by RNA/DNA hybrid analogs of Oxytricha telomere G(4)T(4)G(4) fragment.},
journal = {Biopolymers},
volume = {89},
number = {10},
pages = {797-806},
doi = {10.1002/bip.21015},
pmid = {18491413},
issn = {0006-3525},
mesh = {Animals ; Cations/chemistry ; Circular Dichroism ; DNA/*chemistry ; *G-Quadruplexes ; Guanine/chemistry ; Oxytricha/*chemistry/*genetics ; Potassium/chemistry ; RNA/*chemistry ; Sodium/chemistry ; Solutions ; Telomere/*chemistry ; Thymine/chemistry ; },
abstract = {Using circular dichroism spectroscopy, gel electrophoresis, and ultraviolet absorption spectroscopy, we have studied quadruplex folding of RNA/DNA analogs of the Oxytricha telomere fragment, G(4)T(4)G(4), which forms the well-known basket-type, antiparallel quadruplex. We have substituted riboguanines (g) for deoxyriboguanines (G) in the positions G1, G9, G4, and G12; these positions form the terminal tetrads of the G(4)T(4)G(4) quadruplex and adopt syn, syn, anti, and anti glycosidic geometries, respectively. We show that substitution of a single sugar was able to change the quadruplex topology. With the exception of G(4)T(4)G(3)g, which adopted an antiparallel structure, all the RNA/DNA hybrid analogs formed parallel, bimolecular quadruplexes in concentrated solution at low salt. In dilute solutions (approximately 0.1 mM nucleoside), the RNA/DNA hybrids substituted at positions 4 or 12 adopted antiparallel quadruplexes, which were especially stable in Na(+) solutions. The hybrids substituted at positions 1 and 9 preferably formed parallel quadruplexes, which were more stable than the nonmodified G(4)T(4)G(4) quadruplex in K(+) solutions. Substitutions near the 3'end of the molecule affected folding more than substitutions near the 5'end. The ability to control quadruplex folding will allow further studies of biophysical and biological properties of the various folding topologies.},
}
@article {pmid18491040,
year = {2008},
author = {Strub, GM and Depcrynski, A and Elmore, LW and Holt, SE},
title = {Recovery from stress is a function of age and telomere length.},
journal = {Cell stress &amp; chaperones},
volume = {13},
number = {4},
pages = {475-482},
pmid = {18491040},
issn = {1355-8145},
mesh = {Cells, Cultured ; *Cellular Senescence/drug effects ; Fibroblasts/cytology/drug effects/enzymology ; Humans ; Metals, Heavy/toxicity ; Molecular Chaperones/metabolism ; *Stress, Physiological/drug effects ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {Cells are constantly exposed to a wide variety of stimuli and must be able to mount appropriate physiological responses in order to maintain proper form and function. Cells from every organism have evolved highly conserved mechanisms to cope with environmental changes, including the widely studied heat shock response (HSR), which is induced by a variety of cellular stresses such as heavy metal ion exposure. It has long been known that as organisms and individual cells age, their ability to appropriately cope with environmental stress is attenuated. Here, we examine the ability of two heavy metal ions (ZnCl(2), SnCl(2)) to induce the HSR in human fibroblasts by assessing the expression of heat shock proteins (Hsp90, Hsp70, and p23) and the ability of the cells to recover over time. We demonstrate that the induction and recovery of chaperone levels is attenuated with age and that cells immortalized with the human telomerase reverse transcriptase component of the telomerase enzyme do not attenuate their HSR as their replicative age increases. Our data suggest that the recovery of normal human cells from an HSR is related in part to age and the cell's overall telomere length.},
}
@article {pmid18490858,
year = {2008},
author = {Kurome, M and Hisatomi, H and Matsumoto, S and Tomii, R and Ueno, S and Hiruma, K and Saito, H and Nakamura, K and Okumura, K and Matsumoto, M and Kaji, Y and Endo, F and Nagashima, H},
title = {Production efficiency and telomere length of the cloned pigs following serial somatic cell nuclear transfer.},
journal = {The Journal of reproduction and development},
volume = {54},
number = {4},
pages = {254-258},
doi = {10.1262/jrd.20038},
pmid = {18490858},
issn = {0916-8818},
mesh = {Aging/genetics ; Animals ; *Cloning, Organism ; Efficiency ; Embryo Culture Techniques ; Embryo, Mammalian ; Female ; *Nuclear Transfer Techniques/adverse effects ; *Swine/embryology/genetics ; Telomere/*chemistry/physiology ; },
abstract = {The aim of the present study was to examine the production efficiency of cloned pigs by serial somatic cell nuclear transfer (SCNT) and to ascertain any changes in the telomere lengths of multiple generations of pigs. Using fetal fibroblasts as the starting nuclear donor cells, porcine salivary gland progenitor cells were collected from the resultant first-generation cloned pigs to successively produce second- and third-generation clones, with no significant differences in production efficiency, which ranged from 1.4% (2/140) to 3.3% (13/391) among the 3 generations. The average telomere lengths (terminal restriction fragment values) for the first, second and third generation clones were 16.3, 18.1 and 20.5 kb, respectively, and were comparable to those in age-matched controls. These findings suggest that third-generation cloned pigs can be produced by serial somatic cell cloning without compromising production efficiency and that the telomere lengths of cloned pigs from the first to third generations are normal.},
}
@article {pmid18488043,
year = {2008},
author = {Paeschke, K and Juranek, S and Simonsson, T and Hempel, A and Rhodes, D and Lipps, HJ},
title = {Telomerase recruitment by the telomere end binding protein-beta facilitates G-quadruplex DNA unfolding in ciliates.},
journal = {Nature structural &amp; molecular biology},
volume = {15},
number = {6},
pages = {598-604},
doi = {10.1038/nsmb.1422},
pmid = {18488043},
issn = {1545-9985},
support = {MC_U105184333/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; Cell Cycle ; *Ciliophora ; *G-Quadruplexes ; Nucleic Acid Conformation ; Phosphorylation ; Protein Transport ; Telomerase/*metabolism ; Telomere ; Telomere-Binding Proteins/*metabolism ; },
abstract = {The telomeric G-overhangs of the ciliate Stylonychia lemnae fold into a G-quadruplex DNA structure in vivo. Telomeric G-quadruplex formation requires the presence of two telomere end binding proteins, TEBPalpha and TEBPbeta, and is regulated in a cell-cycle dependent manner. Unfolding of this structure in S phase is dependent on the phosphorylation of TEBPbeta. Here we show that TEBPbeta phosphorylation is necessary but not sufficient for a G-quadruplex unfolding rate compatible with telomere synthesis. The telomerase seems to be actively involved in telomeric G-quadruplex DNA structure unfolding in vivo. Significantly, the telomerase is recruited to telomeres by phosphorylated TEBPbeta, and hence telomerase recruitment is cell-cycle regulated through phosphorylation. These observations allow us to propose a model for the regulation of G-quadruplex unfolding and telomere synthesis during the cell cycle.},
}
@article {pmid18487243,
year = {2008},
author = {Mangino, M and Brouilette, S and Braund, P and Tirmizi, N and Vasa-Nicotera, M and Thompson, JR and Samani, NJ},
title = {A regulatory SNP of the BICD1 gene contributes to telomere length variation in humans.},
journal = {Human molecular genetics},
volume = {17},
number = {16},
pages = {2518-2523},
doi = {10.1093/hmg/ddn152},
pmid = {18487243},
issn = {1460-2083},
support = {//British Heart Foundation/United Kingdom ; },
mesh = {Adaptor Proteins, Signal Transducing/genetics/*metabolism ; Aged ; Chromosome Mapping ; Chromosomes, Human, Pair 12/genetics ; Cytoskeletal Proteins/genetics/*metabolism ; Female ; Gene Expression ; Genome, Human ; Humans ; Linkage Disequilibrium ; Male ; Microsatellite Repeats ; Middle Aged ; *Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Siblings ; Telomere/*chemistry/genetics/metabolism ; },
abstract = {Telomeres are repetitive sequences of variable length at the ends of chromosomes involved in maintaining their integrity. Telomere dysfunction is associated with increased risk of cancer and other age-related diseases. Telomere length is an important determinant of telomere function and has a strong genetic basis. We previously carried out a genome-wide linkage analysis of mean leukocyte telomere length, and identified a 12 cm quantitative-trait locus affecting telomere length on human chromosome 12. In the present study we confirmed linkage to this locus in an extended sample (380 families, 520 sib-pairs, maximum LOD score 4.3). Fine-mapping identified a 51 kb region of association within intron 1 of the Bicaudal-D homolog 1 (BICD1, MIM 602204) gene. The strongest association (P = 1.9 x 10(-5)) was with SNP rs2630578 where the minor allele C (frequency 0.21) was associated with telomeres that were shorter by 604 (+/-204) base pairs, equivalent to approximately 15-20 years of age-related attrition in telomere length. Subjects carrying the C allele for rs2630778 had 44% lower BICD1 mRNA levels in their leukocytes compared with GG homozygotes (P = 0.004). BICD1 is involved in Golgi-to-endoplasmic reticulum vacuolar transport. Previous studies have implicated vacuolar genes in telomere length homeostasis in yeast. Our study indicates that BICD1 plays a similar role in humans.},
}
@article {pmid18483243,
year = {2008},
author = {Svenson, U and Nordfjäll, K and Stegmayr, B and Manjer, J and Nilsson, P and Tavelin, B and Henriksson, R and Lenner, P and Roos, G},
title = {Breast cancer survival is associated with telomere length in peripheral blood cells.},
journal = {Cancer research},
volume = {68},
number = {10},
pages = {3618-3623},
doi = {10.1158/0008-5472.CAN-07-6497},
pmid = {18483243},
issn = {1538-7445},
mesh = {Age Factors ; Aged ; Biomarkers, Tumor/*metabolism ; Breast Neoplasms/*blood/*mortality ; Chromosomal Instability ; Female ; Humans ; Middle Aged ; Odds Ratio ; Prognosis ; Proportional Hazards Models ; Reverse Transcriptase Polymerase Chain Reaction ; Risk ; Telomere/*ultrastructure ; Treatment Outcome ; },
abstract = {Telomeres are essential for maintaining chromosomal stability. Previous studies have indicated that individuals with shorter blood telomeres may be at higher risk of developing various types of cancer, such as in lung, bladder, and kidney. We have analyzed relative telomere length (RTL) of peripheral blood cells in relation to breast cancer incidence and prognosis. The study included 265 newly diagnosed breast cancer patients and 446 female controls. RTL was measured by real-time PCR, and our results show that the patient group displayed significantly longer telomeres compared with controls (P < 0.001). Age-adjusted odds ratios (OR) for breast cancer risk increased with increasing telomere length, with a maximal OR of 5.17 [95% confidence interval (95% CI), 3.09-8.64] for the quartile with the longest telomeres. Furthermore, RTL carried prognostic information for patients with advanced disease. Node positive (N+) patients with short telomeres (</=median) showed an increased survival compared with N+ patients with long telomeres (P = 0.001). For patients with ages <50 years with tumors >16 mm (median tumor diameter), short telomeres were associated with a significantly better outcome than longer telomeres (P = 0.006). Cox regression analysis showed that long RTL was a significant independent negative prognostic factor (hazards ratio, 2.92; 95% CI, 1.33-6.39; P = 0.007). Our results indicate that blood RTL may serve as a prognostic indicator in breast cancer patients with advanced disease.},
}
@article {pmid18482746,
year = {2008},
author = {Perrem, K and Lynch, A and Al Nooh, F and Leader, M and Elaine Kay, },
title = {The different telomere lengths in basal and squamous cell carcinomas also differ between the nontransplant and renal transplant population.},
journal = {Human pathology},
volume = {39},
number = {7},
pages = {1034-1041},
doi = {10.1016/j.humpath.2007.11.008},
pmid = {18482746},
issn = {1532-8392},
mesh = {Adult ; Aged ; Aged, 80 and over ; Carcinoma, Basal Cell/genetics/immunology/*pathology ; Carcinoma, Squamous Cell/genetics/immunology/*pathology ; Cell Line, Tumor ; Female ; Humans ; Immunocompromised Host ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; *Kidney Transplantation ; Male ; Middle Aged ; Skin Neoplasms/genetics/immunology/*pathology ; Telomere/genetics/*pathology ; },
abstract = {Renal transplant recipients incur markedly higher rates of nonmelanoma skin cancer, including both basal and squamous cell carcinoma, by unknown mechanisms that are thought to be activated by long-term immunosuppression. These tumors typically arise in sun-exposed areas of the skin and are biologically more aggressive in renal transplant recipients compared with nontransplant patients. Interestingly also, the incidence of squamous cell carcinoma is generally 2- to 3-fold higher than that of basal cell carcinoma in renal transplant recipients, which is a reversal of the trend in the nontransplant population. We have shown in a previous report that the increased incidence of squamous cell carcinoma in renal transplant patients is characterized by increased telomere lengths when compared with the same tumors in the nontransplant population. This suggests a possible role of telomere lengthening via telomerase in the etiology of these lesions. In our current study, we performed a similar analysis of a cohort of 35 basal cell carcinoma samples from both the renal transplant and nontransplant patient groups. We find that, in contrast to the situation in squamous cell carcinoma, the telomeres of the basal cell carcinomas in renal transplant recipients are in fact shorter than their counterparts in the nontransplant population, but also that these lengths are considerably longer in both cases than their squamous cell counterparts. This is the first report to comprehensively show that the telomere lengths significantly differ between basal and squamous cell carcinomas. This may underlie not only the incidence of these tumors in solid organ transplant recipients, but may also reflect their differing biology that remains poorly understood. These data also suggest that future treatment strategies for nonmelanoma skin cancers that are based upon telomerase inhibition, including those arising in transplant patients, may require different approaches for these two different skin lesions.},
}
@article {pmid18481314,
year = {2008},
author = {Sgura, A and De Amicis, A and Stronati, L and Cinelli, S and Pacchierotti, F and Tanzarella, C},
title = {Chromosome aberrations and telomere length modulation in bone marrow and spleen cells of melphalan-treated p53+/- mice.},
journal = {Environmental and molecular mutagenesis},
volume = {49},
number = {6},
pages = {467-475},
doi = {10.1002/em.20405},
pmid = {18481314},
issn = {1098-2280},
mesh = {Animals ; Antineoplastic Agents, Alkylating/toxicity ; Bone Marrow Cells/cytology/*drug effects/metabolism ; Cells, Cultured ; Chromosome Aberrations/*chemically induced ; Chromosome Painting ; Female ; Genotype ; In Situ Hybridization, Fluorescence/methods ; Melphalan/*toxicity ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Spleen/cytology/*drug effects/metabolism ; Telomere/*drug effects/genetics ; Tumor Suppressor Protein p53/genetics/*physiology ; },
abstract = {The p53 gene regulates cell cycle and apoptotic pathways after induction of DNA damage. Telomeres, capping chromosome ends, are involved in maintaining chromosome stability; alterations of their length have been related to increased levels of chromosomal aberrations. To study a possible interaction between chromosome aberrations, telomere dysfunction, and p53, we investigated via painting analysis the induction and persistence of chromosome aberrations in bone marrow and spleen cells of p53+/- (and wild type) mice exposed for 4, 13, or 26 weeks to 2 mg/kg melphalan (MLP), a chemotherapeutic agent with carcinogenic potential. In addition, telomere length was evaluated in bone marrow cells by quantitative fluorescence in situ hybridization (Q-FISH). Chromosome aberrations were significantly increased in both tissues after MLP treatment. The p53 genotype did not influence the response of spleen cells, whereas a slight but significant increase of the aberration frequency was measured in the bone marrow of p53+/- mice exposed to MLP for 13 weeks with respect to the level detected in the matched wild-type group. The main finding of our still preliminary results on telomere length modulation was again a difference between the two genotypes. In bone marrow cells of wild-type mice, MLP treatment was associated with telomere shortening, while in p53+/- mice telomere elongation was the prevalent response to MLP exposure. In agreement with previous literature data, our in vivo study suggests that even the lack of a single functional copy of the p53 gene might have an impact on the quantity and quality of chromosome alterations induced in cycling cells by a clastogenic exposure.},
}
@article {pmid18479720,
year = {2008},
author = {Mozgová, I and Schrumpfová, PP and Hofr, C and Fajkus, J},
title = {Functional characterization of domains in AtTRB1, a putative telomere-binding protein in Arabidopsis thaliana.},
journal = {Phytochemistry},
volume = {69},
number = {9},
pages = {1814-1819},
doi = {10.1016/j.phytochem.2008.04.001},
pmid = {18479720},
issn = {0031-9422},
mesh = {Arabidopsis/genetics/*metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Cloning, Molecular ; DNA, Plant/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Electrophoresis, Polyacrylamide Gel ; Histones/metabolism ; Humans ; Oncogene Proteins v-myb/metabolism ; Protein Binding ; Telomere/*metabolism ; },
abstract = {Telomeres are nucleoprotein structures ensuring the stability of eukaryotic chromosome ends. Two protein families, TRFL (TFL-Like) and SMH (Single-Myb-Histone), containing a specific telobox motif in their Myb domain, have been identified as potential candidates involved in a functional nucleoprotein structure analogous to human "shelterin" at plant telomeres. We analyze the DNA-protein interaction of the full-length and truncated variants of AtTRB1, a SMH-family member with a typical structure: N-terminal Myb domain, central H1/5 domain and C-terminal coiled-coil. We show that preferential interaction of AtTRB1 with double-stranded telomeric DNA is mediated by the Myb domain, while the H1/5 domain is involved in non-specific DNA-protein interaction and in the multimerization of AtTRB1.},
}
@article {pmid18478592,
year = {2008},
author = {Jenkins, EC and Tassone, F and Ye, L and Gu, H and Xi, M and Velinov, M and Brown, WT and Hagerman, RJ and Hagerman, PJ},
title = {Reduced telomere length in older men with premutation alleles of the fragile X mental retardation 1 gene.},
journal = {American journal of medical genetics. Part A},
volume = {146A},
number = {12},
pages = {1543-1546},
pmid = {18478592},
issn = {1552-4833},
support = {P30 HD002274/HD/NICHD NIH HHS/United States ; R01 NS044299/NS/NINDS NIH HHS/United States ; R01 HD036071/HD/NICHD NIH HHS/United States ; RL1 AG032119-01/AG/NIA NIH HHS/United States ; HD02274/HD/NICHD NIH HHS/United States ; UL1 RR024922/RR/NCRR NIH HHS/United States ; RL1 AG032119/AG/NIA NIH HHS/United States ; NS044299/NS/NINDS NIH HHS/United States ; HD 036071/HD/NICHD NIH HHS/United States ; },
mesh = {Aged ; Alleles ; Ataxia/*diagnosis/genetics ; Dementia/*diagnosis/genetics ; Fragile X Mental Retardation Protein/*genetics ; Genetic Markers ; Humans ; Male ; Middle Aged ; Mutation ; Syndrome ; T-Lymphocytes/ultrastructure ; Telomere/*genetics/*ultrastructure ; Tremor/*diagnosis/genetics ; },
abstract = {Reduced telomere length has recently been reported in T lymphocytes of individuals with trisomy 21 Down syndrome (DS) and dementia. Shorter telomeres also have been documented in dyskeratosis congenita, cell senescence, Alzheimer disease, and neoplastic transformation. These observations suggest that similar shortening may occur in people with fragile X-associated tremor/ataxia syndrome (FXTAS), which frequently is accompanied by dementia. To test this hypothesis, telomere length has been quantified in T lymphocytes from older male carriers of premutation FMR1 alleles, with or without FXTAS, and FXTAS with dementia. Shorter telomeres (relative to age-matched controls) were observed in 5/5 individuals with FXTAS and dementia, in 2/2 individuals with FXTAS without dementia, and in 3/3 individuals with the fragile X premutation only (P values ranged from <0.001 to <0.05; Student's t-test), indicating that telomere shortening is associated with the premutation expansion of the FMR1 gene. The current study design allowed simultaneous comparisons among control, premutation, FXTAS, and FXTAS with dementia samples, and showed nearly equal degrees of shortening relative to controls among the three premutation sample groups. Thus, telomere shortening may serve as a biomarker for cellular dysregulation that may precede the development of the symptoms of FXTAS.},
}
@article {pmid18478110,
year = {2008},
author = {Ilmonen, P and Kotrschal, A and Penn, DJ},
title = {Telomere attrition due to infection.},
journal = {PloS one},
volume = {3},
number = {5},
pages = {e2143},
pmid = {18478110},
issn = {1932-6203},
mesh = {Animals ; Base Sequence ; DNA Primers ; Humans ; Mice ; Polymerase Chain Reaction ; Salmonella Infections/*genetics/microbiology ; Salmonella enterica/isolation &amp; purification ; *Telomere ; },
abstract = {BACKGROUND: Telomeres--the terminal caps of chromosomes--become shorter as individuals age, and there is much interest in determining what causes telomere attrition since this process may play a role in biological aging. The leading hypothesis is that telomere attrition is due to inflammation, exposure to infectious agents, and other types of oxidative stress, which damage telomeres and impair their repair mechanisms. Several lines of evidence support this hypothesis, including observational findings that people exposed to infectious diseases have shorter telomeres. Experimental tests are still needed, however, to distinguish whether infectious diseases actually cause telomere attrition or whether telomere attrition increases susceptibility to infection. Experiments are also needed to determine whether telomere erosion reduces longevity.<br><br>We experimentally tested whether repeated exposure to an infectious agent, Salmonella enterica, causes telomere attrition in wild-derived house mice (Mus musculus musculus). We repeatedly infected mice with a genetically diverse cocktail of five different S. enterica strains over seven months, and compared changes in telomere length with sham-infected sibling controls. We measured changes in telomere length of white blood cells (WBC) after five infections using a real-time PCR method. Our results show that repeated Salmonella infections cause telomere attrition in WBCs, and particularly for males, which appeared less disease resistant than females. Interestingly, we also found that individuals having long WBC telomeres at early age were relatively disease resistant during later life. Finally, we found evidence that more rapid telomere attrition increases mortality risk, although this trend was not significant.<br><br>CONCLUSIONS/SIGNIFICANCE: Our results indicate that infectious diseases can cause telomere attrition, and support the idea that telomere length could provide a molecular biomarker for assessing exposure and ability to cope with infectious diseases.},
}
@article {pmid18477473,
year = {2008},
author = {Byun, MY and Hong, JP and Kim, WT},
title = {Identification and characterization of three telomere repeat-binding factors in rice.},
journal = {Biochemical and biophysical research communications},
volume = {372},
number = {1},
pages = {85-90},
doi = {10.1016/j.bbrc.2008.04.181},
pmid = {18477473},
issn = {1090-2104},
mesh = {Amino Acid Sequence ; Dimerization ; Electrophoretic Mobility Shift Assay ; Molecular Sequence Data ; Oryza/genetics/*metabolism ; Plant Proteins/chemistry/genetics/*metabolism ; Protein Structure, Tertiary ; Telomere/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; Two-Hybrid System Techniques ; },
abstract = {Telomeres consist of nucleoprotein complexes that protect chromosome end structures. Here, we describe three OsTRBF genes, encoding telomere repeat-binding factors of the single Myb histone family in rice. The predicted proteins contain a Myb DNA-binding motif and a linker histone H1/H5 domain in the N-terminal and central regions, respectively. The OsTRBF transcripts were constitutively detected in rice plants grown under greenhouse conditions. Gel retardation assays showed that these OsTRBF proteins bind specifically to the plant double-stranded telomeric sequence, TTTAGGG, with markedly different binding affinities as judged by their respective dissociation constants. Yeast two-hybrid and in vitro pull-down assays indicated that both OsTRBF1 and OsTRBF2 interact with one another to form homo- and hetero-complexes, while OsTRBF3 appeared to act as a monomer. Our results suggest that OsTRBFs play combinatory roles in the function and structure of telomeres in rice.},
}
@article {pmid18477050,
year = {2008},
author = {Uziel, O and Reshef, H and Ravid, A and Fabian, I and Halperin, D and Ram, R and Bakhanashvili, M and Nordenberg, J and Lahav, M},
title = {Oxidative stress causes telomere damage in Fanconi anaemia cells - a possible predisposition for malignant transformation.},
journal = {British journal of haematology},
volume = {142},
number = {1},
pages = {82-93},
doi = {10.1111/j.1365-2141.2008.07137.x},
pmid = {18477050},
issn = {1365-2141},
mesh = {Anaphase/drug effects ; Antioxidants/pharmacology ; Cell Line ; Cell Transformation, Neoplastic/*drug effects ; Fanconi Anemia/*pathology ; Humans ; Hydrogen Peroxide/pharmacology ; Oligonucleotides/pharmacology ; Oxidants/pharmacology ; Oxidative Stress/*physiology ; Telomerase/antagonists &amp; inhibitors ; Telomere/drug effects/*pathology ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Fanconi anaemia (FA) is an autosomal recessive and X-linked disease characterized by severe genetic instability and increased incidence of cancer. One explanation for this instability may be the cellular hypersensitivity to oxidative stress leading to chromosomal breaks. This study explored the possible oxidative damage to telomeres of FA lymphocyte cell line, HSC536/N, and its possible effect on telomere function. We postulated that combination of oxidative damage with overexpression of telomerase may provide a possible model for malignant transformation in FA. The cells were grown in the presence of telomerase inhibitor and exposed for 1 month to H(2)O(2) combined with various antioxidants. This exposure caused shortening of telomere length and damage to the telomere single stranded overhang, which was prevented by several oxidants. This shortening was associated with development of severe telomere dysfunction. Control cells did not exhibit this sensitivity to H(2)O(2). Telomere dysfunction did not evoke damage response in FA cells, in contrast to normal P53 upregulation in control cells. Reconstitution of telomerase activity protected FA telomeres from further oxidative damage. These results suggest a scenario in which oxidative stress causes telomere shortening and ensuing telomere dysfunction may form the basis for malignant transformation in FA cells. Upregulation of telomerase activity in sporadic FA cells may perpetuate that process, thus explaining the malignant character of FA cells in vivo.},
}
@article {pmid18476834,
year = {2008},
author = {O'Callaghan, N and Dhillon, V and Thomas, P and Fenech, M},
title = {A quantitative real-time PCR method for absolute telomere length.},
journal = {BioTechniques},
volume = {44},
number = {6},
pages = {807-809},
doi = {10.2144/000112761},
pmid = {18476834},
issn = {0736-6205},
mesh = {Reverse Transcriptase Polymerase Chain Reaction/*methods ; Sensitivity and Specificity ; Specimen Handling/*methods ; Telomere/*genetics/*ultrastructure ; },
abstract = {Telomere shortening is an important risk factor for cancer and accelerated aging. Here we describe the development of a simple and reproducible method to measure absolute telomere length. Based on Cawthon's quantitative real-time PCR (qRT-PCR) assay, our method uses an oligomer standard that can be used to generate absolute telomere length values rather than relative quantification. We demonstrate a strong correlation between this improved method and the "gold standard" of telomere length measurement-terminal restriction fragment analysis (TRF) by Southern hybridization. The capability to generate absolute telomere length values should allow a more direct comparison of results between experiments within and between laboratories.},
}
@article {pmid18469136,
year = {2008},
author = {Kirk, KE and Christ, C and McGuire, JM and Paul, AG and Vahedi, M and Stuart, KR and Cole, ES},
title = {Abnormal micronuclear telomeres lead to an unusual cell cycle checkpoint and defects in Tetrahymena oral morphogenesis.},
journal = {Eukaryotic cell},
volume = {7},
number = {10},
pages = {1712-1723},
pmid = {18469136},
issn = {1535-9786},
mesh = {Animals ; *Cell Cycle ; Micronucleus, Germline/genetics/*metabolism ; Morphogenesis ; Mouth/*growth &amp; development/metabolism ; Telomere/genetics/*metabolism ; Tetrahymena/cytology/genetics/*growth &amp; development/metabolism ; },
abstract = {Telomere mutants have been well studied with respect to telomerase and the role of telomere binding proteins, but they have not been used to explore how a downstream morphogenic event is related to the mutated telomeric DNA. We report that alterations at the telomeres can have profound consequences on organellar morphogenesis. Specifically, a telomerase RNA mutation termed ter1-43AA results in the loss of germ line micronuclear telomeres in the binucleate protozoan Tetrahymena thermophila. These cells also display a micronuclear mitotic arrest, characterized by an extreme delay in anaphase with an elongated, condensed chromatin and a mitotic spindle apparatus. This anaphase defect suggests telomere fusions and consequently a spindle rather than a DNA damage checkpoint. Most surprisingly, these mutants exhibit unique, dramatic defects in the formation of the cell's oral apparatus. We suggest that micronuclear telomere loss leads to a "dynamic pause" in the program of cortical development, which may reveal an unusual cell cycle checkpoint.},
}
@article {pmid18467646,
year = {2008},
author = {Farzaneh-Far, R and Cawthon, RM and Na, B and Browner, WS and Schiller, NB and Whooley, MA},
title = {Prognostic value of leukocyte telomere length in patients with stable coronary artery disease: data from the Heart and Soul Study.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {28},
number = {7},
pages = {1379-1384},
pmid = {18467646},
issn = {1524-4636},
support = {R01 HL079235/HL/NHLBI NIH HHS/United States ; R01 HL079235-01A1/HL/NHLBI NIH HHS/United States ; },
mesh = {Aged ; C-Reactive Protein/metabolism ; Cardiovascular Diseases/*genetics/immunology/mortality ; Coronary Artery Disease/diagnostic imaging/*genetics/mortality/pathology ; Female ; Follow-Up Studies ; Heart Failure/*genetics/immunology/mortality ; Hospitalization ; Humans ; Kaplan-Meier Estimate ; Leukocytes/*pathology ; Male ; Middle Aged ; Prognosis ; Prospective Studies ; Risk Assessment ; San Francisco/epidemiology ; Telomere/*ultrastructure ; Time Factors ; Ultrasonography ; },
abstract = {BACKGROUND: Telomere shortening has been proposed as a marker of biological aging. Whether leukocyte telomere length is associated with mortality among patients with stable coronary artery disease (CAD) is unknown.<br><br>METHODS AND RESULTS: We measured leukocyte telomere length in 780 patients with stable CAD in a prospective cohort study. Participants were categorized by quartiles of telomere length. Hazard Ratios (HRs) and 95% confidence intervals were calculated for all-cause mortality, heart failure (HF) hospitalization, and cardiovascular (CV) events. After 4.4 years of follow-up there were 166 deaths. Compared with participants in the highest telomere length quartile, those in the lowest quartile were at increased risk of death (age-adjusted HR 1.8; 95% CI 1.2 to 2.9). After multivariate adjustment for clinical (HR 2.1; CI 1.3 to 3.3), inflammatory (HR 2.0; CI 1.2 to 3.2), and echocardiographic (HR 1.9; CI 1.0 to 3.5) risk factors, patients in the lowest quartile of telomere length remained at significantly increased risk of death compared to those in the highest quartile. Patients in the lowest quartile of telomere length were also at significantly increased risk of HF hospitalization (HR 2.6; CI 1.1 to 6.0) but not CV events (HR 1.7; CI 0.9 to 3.5).<br><br>CONCLUSIONS: Reduced leukocyte telomere length is associated with all-cause mortality in patients with stable CAD. The prognostic value of short telomeres in predicting death is not completely captured by existing clinical, inflammatory, and echocardiographic markers of risk.},
}
@article {pmid18466090,
year = {2008},
author = {Riethman, H},
title = {Human telomere structure and biology.},
journal = {Annual review of genomics and human genetics},
volume = {9},
number = {},
pages = {1-19},
doi = {10.1146/annurev.genom.8.021506.172017},
pmid = {18466090},
issn = {1527-8204},
support = {HG00567/HG/NHGRI NIH HHS/United States ; HG2933/HG/NHGRI NIH HHS/United States ; },
mesh = {Base Sequence ; DNA/genetics ; Epigenesis, Genetic ; Gene Dosage ; Gene Duplication ; Humans ; Models, Genetic ; RNA/genetics ; Telomere/*chemistry/*genetics ; Transcription, Genetic ; },
abstract = {Human telomeric DNA is complex and highly variable. Subterminal sequences are associated with cis-acting determinants of allele-specific (TTAGGG)n tract length regulation and may modulate susceptibility of (TTAGGG)n tracts to rapid deletion events. More extensive subtelomeric DNA tracts are filled with segmental duplications and segments that vary in copy number, leading to highly variable subtelomeric allele structures in the human population. RNA transcripts encoded in telomere regions include multicopy protein-encoding gene families and a variety of noncoding RNAs. One recently described family of (UUAGGG)n-containing subterminal RNAs appears to be critical for telomere integrity; these RNAs associate with telomeric chromatin and are regulated by RNA surveillance factors including human homologs of the yeast Est1p protein. An increasingly detailed and complete picture of telomeric DNA sequence organization and structural variation is essential for understanding and tracking allele-specific subterminal and subtelomeric features critical for human biology.},
}
@article {pmid18462275,
year = {2008},
author = {Kaufman, JS and Cooper, RS},
title = {Telomeres and race: what can we learn about human biology from health differentials?.},
journal = {Aging cell},
volume = {7},
number = {4},
pages = {448-450},
doi = {10.1111/j.1474-9726.2008.00396.x},
pmid = {18462275},
issn = {1474-9726},
mesh = {*Biology ; Health ; Humans ; *Racial Groups ; Telomere/*metabolism ; },
abstract = {The advent of molecular technology that can be applied across large population samples has added--rather than reduced--complexity in the analysis of the intertwined effects of social history and heritable factors on health outcomes. The report by Hunt et al. in this issue of Aging Cell provides an example of the promises and dilemmas associated with this increased complexity.},
}
@article {pmid18462274,
year = {2008},
author = {Hunt, SC and Chen, W and Gardner, JP and Kimura, M and Srinivasan, SR and Eckfeldt, JH and Berenson, GS and Aviv, A},
title = {Leukocyte telomeres are longer in African Americans than in whites: the National Heart, Lung, and Blood Institute Family Heart Study and the Bogalusa Heart Study.},
journal = {Aging cell},
volume = {7},
number = {4},
pages = {451-458},
pmid = {18462274},
issn = {1474-9726},
support = {U01 HL 678939/HL/NHLBI NIH HHS/United States ; U01 HL 67902/HL/NHLBI NIH HHS/United States ; AG16592/AG/NIA NIH HHS/United States ; R01 AG020132/AG/NIA NIH HHS/United States ; U01 HL067901/HL/NHLBI NIH HHS/United States ; R01 AG016592/AG/NIA NIH HHS/United States ; U01 HL067900/HL/NHLBI NIH HHS/United States ; U01 HL067898/HL/NHLBI NIH HHS/United States ; U01 HL067894-04/HL/NHLBI NIH HHS/United States ; U01 HL067895/HL/NHLBI NIH HHS/United States ; U01 HL038844-15/HL/NHLBI NIH HHS/United States ; U01 HL067902/HL/NHLBI NIH HHS/United States ; U01 HL 67901/HL/NHLBI NIH HHS/United States ; HL38844/HL/NHLBI NIH HHS/United States ; U01 HL067897/HL/NHLBI NIH HHS/United States ; U01 HL 67900/HL/NHLBI NIH HHS/United States ; U01 HL067893/HL/NHLBI NIH HHS/United States ; U01 HL 67894/HL/NHLBI NIH HHS/United States ; U01 HL067896/HL/NHLBI NIH HHS/United States ; R01 AG016592-10/AG/NIA NIH HHS/United States ; AG020132/AG/NIA NIH HHS/United States ; U01 HL067895-04/HL/NHLBI NIH HHS/United States ; U01 HL067894/HL/NHLBI NIH HHS/United States ; U01 HL 67899/HL/NHLBI NIH HHS/United States ; U01 HL067896-04/HL/NHLBI NIH HHS/United States ; U01 HL067897-04/HL/NHLBI NIH HHS/United States ; U01 HL067899/HL/NHLBI NIH HHS/United States ; U01 HL067893-04/HL/NHLBI NIH HHS/United States ; U01 HL 67898/HL/NHLBI NIH HHS/United States ; R01 AG020132-04/AG/NIA NIH HHS/United States ; U01 HL 67896/HL/NHLBI NIH HHS/United States ; U01 HL 67893/HL/NHLBI NIH HHS/United States ; U01 HL 67895/HL/NHLBI NIH HHS/United States ; U01 HL 67897/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; *Black or African American ; Aged ; Aged, 80 and over ; Aging ; Body Mass Index ; Cohort Studies ; Deoxyribonucleases, Type II Site-Specific/metabolism ; Female ; Heart/*physiology ; Humans ; Leukocytes/*physiology ; Male ; Middle Aged ; *National Heart, Lung, and Blood Institute (U.S.) ; Sex Characteristics ; Telomere/*physiology ; United States ; *White People ; },
abstract = {Leukocyte telomere length (LTL) is ostensibly a bio-indicator of human aging. Here we report that African Americans have longer LTL than whites. We studied cross-sectionally 2453 individuals from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study (age = 30-93 years) and the Bogalusa Heart Study (age = 19-37 years), comprising 1742 whites and 711 African Americans. We measured LTL by Southern blots of the terminal restriction fragments length. In 234 participants, telomere repeats were also measured by quantitative polymerase chain reaction (qPCR). Adjusted for age and body mass index (BMI), the respective leukocyte telomere lengths (mean +/- SEM) were considerably longer in African Americans than in whites both in the Family Heart Study (7.004 +/- 0.033 kb vs. 6.735 +/- 0.024 kb, p < 0.0001) and the Bogalusa Heart Study (7.923 +/- 0.063 kb vs. 7.296 +/- 0.039 kb, p < 0.0001). We confirmed the racial effect on LTL by qPCR (3.038 +/- 0.565 T/S units for African Americans vs. 2.714 +/- 0.487 T/S units for whites, p < 0.001). Cross-sectionally, sex- and BMI-adjusted LTL became shorter with age (range 19-93 years) at a steeper slope in African Americans than in whites (0.029 kb year(-1) vs. 0.020 kb year(-1), respectively, p = 0.0001). We suggest that racial difference in LTL arises from a host of interacting biological factors, including replication rates of hematopoietic stem cells.},
}
@article {pmid18456668,
year = {2008},
author = {Hapangama, DK and Turner, MA and Drury, JA and Quenby, S and Saretzki, G and Martin-Ruiz, C and Von Zglinicki, T},
title = {Endometriosis is associated with aberrant endometrial expression of telomerase and increased telomere length.},
journal = {Human reproduction (Oxford, England)},
volume = {23},
number = {7},
pages = {1511-1519},
doi = {10.1093/humrep/den172},
pmid = {18456668},
issn = {1460-2350},
mesh = {Adolescent ; Adult ; Endometriosis/*physiopathology ; Endometrium/metabolism ; Estrogen Receptor beta/biosynthesis ; Female ; Gene Expression/physiology ; Humans ; Immunohistochemistry ; Middle Aged ; Pilot Projects ; Prospective Studies ; Telomerase/*biosynthesis ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: In order to test our hypothesis that endometriosis is associated with abnormal expression of telomerase and telomere lengthening in endometrium, we assessed endometrial expression of the human telomerase enzyme and telomere length (TL).<br><br>METHODS: This prospective pilot study, included 29 women with symptomatic, surgically diagnosed endometriosis (Group 1) and 27 healthy, fertile, symptom-free women without endometriosis (Group 2, confirmed by laparoscopy). Seventeen women in Group 1 and 15 women in Group 2 had endometrial biopsies taken on Day 21 +/- 2 of the cycle. A further 12 women in each group were biopsied on Day 26 +/- 2. Telomerase and estrogen receptor beta (ERbeta) expression was evaluated by immunohistochemistry. Mean TL was determined by quantitative PCR.<br><br>RESULTS: The endometria of fertile healthy women showed either weak or no telomerase immunoreactivity throughout the luteal phase. Immunostaining for telomerase was significantly increased during the implantation window and the premenstrual endometria of women with endometriosis (P < 0.0001). This was associated with a loss of stromal and vascular ERbeta immunostaining (P < 0.05). The mean TL were significantly longer in endometria of women with endometriosis during the implantation window (P = 0.005), indicating the biological relevance of our novel finding of telomerase in benign endometrium. There was positive correlation of the circulating estradiol with peripheral blood TL in women.<br><br>CONCLUSIONS: We speculate that aberrant endometrial expression of telomerase mediates alterations in cell fate that enhance proliferation, contributing to the pathogenesis of endometriosis.},
}
@article {pmid18452563,
year = {2008},
author = {Jang, JS and Choi, YY and Lee, WK and Choi, JE and Cha, SI and Kim, YJ and Kim, CH and Kam, S and Jung, TH and Park, JY},
title = {Telomere length and the risk of lung cancer.},
journal = {Cancer science},
volume = {99},
number = {7},
pages = {1385-1389},
doi = {10.1111/j.1349-7006.2008.00831.x},
pmid = {18452563},
issn = {1349-7006},
mesh = {Aged ; Carcinoma, Small Cell/genetics ; Case-Control Studies ; Chromosomal Instability ; Female ; Humans ; Logistic Models ; Lung Neoplasms/etiology/*genetics ; Male ; Middle Aged ; Polymerase Chain Reaction ; Smoking/adverse effects ; *Telomere ; },
abstract = {Telomeres play a key role in the maintenance of chromosome integrity and stability. There is growing evidence that short telomeres induce chromosome instability and thereby promote the development of cancer. We investigated the association of telomere length and the risk of lung cancer. Relative telomere length in peripheral blood lymphocytes was measured by quantitative polymerase chain reaction in 243 lung cancer patients and 243 healthy controls that were frequency-matched for age, sex and smoking status. Telomere length was significantly shorter in lung cancer patients than in controls (mean +/- standard deviation: 1.59 +/- 0.75 versus 2.16 +/- 1.10, P < 0.0001). When the subjects were categorized into quartiles based on telomere length, the risk of lung cancer was found to increase as telomere length shortened (P(trend) < 0.0001). In addition, when the median of telomere length was used as the cutoff between long and short telomeres, individuals with short telomeres were at a significantly higher risk of lung cancer than those with long telomeres (adjusted odds ratio = 3.15, 95% confidence interval = 2.12-4.67, P < 0.0001). When the cases were categorized by tumor histology, the effect of short telomere length on the risk of lung cancer was more pronounced in patients with small cell carcinoma than in those with squamous cell carcinoma and adenocarcinoma (P = 0.001, test for homogeneity). These findings suggest that shortening of the telomeres may be a risk factor for lung cancer, and therefore, the presence of shortened telomeres may be used as a marker for susceptibility to lung cancer.},
}
@article {pmid18451109,
year = {2008},
author = {Konishi, A and de Lange, T},
title = {Cell cycle control of telomere protection and NHEJ revealed by a ts mutation in the DNA-binding domain of TRF2.},
journal = {Genes &amp; development},
volume = {22},
number = {9},
pages = {1221-1230},
pmid = {18451109},
issn = {0890-9369},
support = {OD000379/OD/NIH HHS/United States ; R01 GM049046/GM/NIGMS NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; DP1 OD000379/OD/NIH HHS/United States ; GM049046/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; Amino Acid Sequence ; Animals ; Cell Cycle/*genetics/physiology ; Cells, Cultured ; Chromatin Immunoprecipitation ; Electrophoresis, Gel, Pulsed-Field ; Embryonic Stem Cells/cytology/metabolism ; Fibroblasts/cytology/metabolism ; G1 Phase/genetics/physiology ; G2 Phase/genetics/physiology ; Immunoblotting ; In Situ Hybridization, Fluorescence ; Mice ; Molecular Sequence Data ; *Mutation ; Protein Binding ; Protein Structure, Tertiary ; Recombination, Genetic/*genetics ; Resting Phase, Cell Cycle/genetics/physiology ; S Phase/genetics/physiology ; Sequence Homology, Amino Acid ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/chemistry/*genetics/metabolism ; Temperature ; },
abstract = {TRF2 is a component of shelterin, the telomere-specific protein complex that prevents DNA damage signaling and inappropriate repair at the natural ends of mammalian chromosomes. We describe a temperature-sensitive (ts) mutation in the Myb/SANT DNA-binding domain of TRF2 that allows controlled and reversible telomere deprotection. At 32 degrees C, TRF2ts was functional and rescued the lethality of TRF2 deletion from conditional TRF2(F/-) mouse embryonic fibroblasts (MEFs). When shifted to the nonpermissive temperature (37 degrees C), TRF2ts cells showed extensive telomere damage resulting in activation of the ATM kinase and nonhomologous end-joining (NHEJ) of chromosome ends. The inactivation of TRF2ts at 37 degrees C was rapid and reversible, permitting induction of short periods (3-6 h) of telomere dysfunction in the G0, G1, and S/G2 phases of the cell cycle. The results indicate that both the induction of telomere dysfunction and the re-establishment of the protected state can take place throughout interphase. In contrast, the processing of dysfunctional telomeres by NHEJ occurred primarily in G1, being repressed in S/G2 in a cyclin-dependent kinase (CDK)-dependent manner.},
}
@article {pmid18451106,
year = {2008},
author = {Marcand, S and Pardo, B and Gratias, A and Cahun, S and Callebaut, I},
title = {Multiple pathways inhibit NHEJ at telomeres.},
journal = {Genes &amp; development},
volume = {22},
number = {9},
pages = {1153-1158},
pmid = {18451106},
issn = {0890-9369},
mesh = {Amino Acid Sequence ; Carrier Proteins/genetics ; *DNA Repair ; Models, Genetic ; Molecular Sequence Data ; Recombination, Genetic/*genetics ; Saccharomyces cerevisiae Proteins/genetics ; Sequence Homology, Amino Acid ; Shelterin Complex ; *Signal Transduction ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; Transcription Factors/genetics ; },
abstract = {The nonhomologous end-joining (NHEJ) repair pathway is inhibited at telomeres, preventing chromosome fusion. In budding yeast Saccharomyces cerevisiae, the Rap1 protein directly binds the telomere sequences and is required for NHEJ inhibition. Here we show that the Rap1 C-terminal domain establishes two parallel inhibitory pathways through the proteins Rif2 and Sir4. In addition, the central domain of Rap1 inhibits NHEJ independently of Rif2 and Sir4. Thus, Rap1 establishes several independent pathways to prevent telomere fusions. We discuss a possible mechanism that would explain Rif2 multifunctionality at telomeres and the recent evolutionary origin of Rif2 from an origin recognition complex (ORC) subunit.},
}
@article {pmid18448098,
year = {2008},
author = {Cosme-Blanco, W and Chang, S},
title = {Dual roles of telomere dysfunction in initiation and suppression of tumorigenesis.},
journal = {Experimental cell research},
volume = {314},
number = {9},
pages = {1973-1979},
pmid = {18448098},
issn = {1090-2422},
support = {R01 AG028888/AG/NIA NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; DNA Damage ; Humans ; Neoplasms/*metabolism ; Precancerous Conditions/*metabolism ; Telomerase/metabolism ; Telomere/*pathology ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Human carcinomas arise through the acquisition of genetic changes that endow precursor cancer cells with a critical threshold of cancer-relevant genetic lesions. This complex genomic alterations confer upon precursor cancer cells the ability to grow indefinitely and to metastasize to distant sites. One important mechanism underlying a cell's tumorigenic potential is the status of its telomere. Telomeres are G-rich simple repeat sequences that serve to prevent chromosomal ends from being recognized as DNA double-strand breaks (DSBs). Dysfunctional telomeres resemble DSBs, leading to the formation of dicentric chromosomes that fuel high degrees of genomic instability. In the setting of an intact p53 pathway, this instability promotes cellular senescence, a potent tumor suppressor mechanism. However, rare cells that stochastically lose p53 function emerge from this sea of genomic instability and progress towards cancer. In this review, we describe the use of mouse models to probe the impact of dysfunctional telomeres on tumor initiation and suppression.},
}
@article {pmid18443218,
year = {2008},
author = {Kim, SH and Davalos, AR and Heo, SJ and Rodier, F and Zou, Y and Beausejour, C and Kaminker, P and Yannone, SM and Campisi, J},
title = {Telomere dysfunction and cell survival: roles for distinct TIN2-containing complexes.},
journal = {The Journal of cell biology},
volume = {181},
number = {3},
pages = {447-460},
pmid = {18443218},
issn = {1540-8140},
support = {R01 AG011658/AG/NIA NIH HHS/United States ; AG011658-12/AG/NIA NIH HHS/United States ; CA107798A/CA/NCI NIH HHS/United States ; AG024399-02/AG/NIA NIH HHS/United States ; R01 AG024399/AG/NIA NIH HHS/United States ; R03 CA107798/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; Cell Survival/*physiology ; Cellular Senescence/physiology ; Chromosome Aberrations ; Humans ; Macromolecular Substances/*metabolism ; Mice ; Mutation ; Shelterin Complex ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; },
abstract = {Telomeres are maintained by three DNA-binding proteins (telomeric repeat binding factor 1 [TRF1], TRF2, and protector of telomeres 1 [POT1]) and several associated factors. One factor, TRF1-interacting protein 2 (TIN2), binds TRF1 and TRF2 directly and POT1 indirectly. Along with two other proteins, TPP1 and hRap1, these form a soluble complex that may be the core telomere maintenance complex. It is not clear whether subcomplexes also exist in vivo. We provide evidence for two TIN2 subcomplexes with distinct functions in human cells. We isolated these two TIN2 subcomplexes from nuclear lysates of unperturbed cells and cells expressing TIN2 mutants TIN2-13 and TIN2-15C, which cannot bind TRF2 or TRF1, respectively. In cells with wild-type p53 function, TIN2-15C was more potent than TIN2-13 in causing telomere uncapping and eventual growth arrest. In cells lacking p53 function, TIN2-15C was more potent than TIN2-13 in causing telomere dysfunction and cell death. Our findings suggest that distinct TIN2 complexes exist and that TIN2-15C-sensitive subcomplexes are particularly important for cell survival in the absence of functional p53.},
}
@article {pmid18438462,
year = {2008},
author = {Jacobus, JA and Flor, S and Klingelhutz, A and Robertson, LW and Ludewig, G},
title = {2-(4'-CHLOROPHENYL)-1,4-BENZOQUINONE INCREASES THE FREQUENCY OF MICRONUCLEI AND SHORTENS TELOMERES.},
journal = {Environmental toxicology and pharmacology},
volume = {25},
number = {2},
pages = {267-272},
pmid = {18438462},
issn = {1872-7077},
support = {P42 ES013661-029003/ES/NIEHS NIH HHS/United States ; P42 ES013661-01A19003/ES/NIEHS NIH HHS/United States ; P42 ES013661-01A10001/ES/NIEHS NIH HHS/United States ; P42 ES013661/ES/NIEHS NIH HHS/United States ; P42 ES013661-020001/ES/NIEHS NIH HHS/United States ; },
abstract = {The toxicity of polychlorinated biphenyls (PCBs) has been attributed widely to receptor-mediated effects, buttressed by the popularity of the Toxic Equivalency Factor. We propose that a crucial toxic mechanism of lower-chlorinated PCBs is their enzymatic biotransformation to electrophiles, including quinoid metabolites, that bind intracellular sulfhydryl groups, such as those found in microtubulin and enzymes like telomerase. To test this hypothesis, we have examined micronuclei induction, cell cycle, and telomere shortening in cells in culture. Our findings show a large increase in micronuclei frequency and cell cycle perturbation in V79 cells, and a marked decrease in telomere length in HaCaT cells exposed to 2-(4'-chlorophenyl)-1,4-benzoquinone (PCB3pQ).},
}
@article {pmid18432920,
year = {2004},
author = {Hathcock, KS and Hodes, RJ and Weng, NP},
title = {Analysis of telomere length and telomerase activity.},
journal = {Current protocols in immunology},
volume = {Chapter 10},
number = {},
pages = {10.30.1-10.30.27},
doi = {10.1002/0471142735.im1030s62},
pmid = {18432920},
issn = {1934-368X},
support = {Z01 AG000756-10/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Animals ; Cell Division/*physiology ; Cell Survival/physiology ; *Clinical Laboratory Techniques ; Humans ; Mice ; Microsatellite Repeats/*genetics ; Telomerase/*metabolism ; Telomere/*enzymology/*genetics ; },
abstract = {Telomeres are specialized DNA-protein structures present at the ends of all linear chromosomes and are characterized by (TTAGGG)(n) hexanucleotide repeats and associated proteins. Telomere length has been implicated in cell survival and replicative capacity of dividing somatic cells. In the absence of an active compensatory mechanism, telomere lengths shorten as a consequence of proliferation, both in vitro and in vivo. However, this loss of telomeric repeats can be compensated and telomere length maintained by the enzyme telomerase, which is capable of adding (TTAGGG) repeat sequences to the ends of telomeres. This unit describes methods that are used for the measurement of telomere length and telomerase activity in human and murine cells.},
}
@article {pmid18430074,
year = {2008},
author = {Zannolli, R and Mohn, A and Buoni, S and Pietrobelli, A and Messina, M and Chiarelli, F and Miracco, C},
title = {Telomere length and obesity.},
journal = {Acta paediatrica (Oslo, Norway : 1992)},
volume = {97},
number = {7},
pages = {952-954},
doi = {10.1111/j.1651-2227.2008.00783.x},
pmid = {18430074},
issn = {0803-5253},
mesh = {Adolescent ; Adult ; Aged ; Body Mass Index ; Child ; Child, Preschool ; Humans ; Middle Aged ; Obesity/*genetics ; Telomere/genetics/*pathology ; },
abstract = {AIM: To assess the telomere length in apparently healthy obese and normal-weight subjects.<br><br>METHODS: Seventy-six Caucasian subjects were chosen including 53 children (age 8.2+/-3.5 years) and 23 adults (age 40.5+/-8.4 years). Among these, 22 (12 children and 10 adults) were obese with a body mass index (BMI, kg/m2)>2 SD above the norm. Bioelectrical impedance analysis (BIA), measured with a multiple frequency analyzer, was used to estimate body composition. DNA extraction from white blood cells was used to estimate the telomere length by detection of terminal restriction fragments (TRF).<br><br>RESULTS: No difference was found between the TRF lengths of obese and normal children. Obese adults had shorter TRF lengths than adults who were not obese (mean TRF length difference, -884.5; 95% confidence intervals -1727 to -41.8; t=2.183; df=17; p<0.041).<br><br>CONCLUSIONS: Obese adults have shorter telomeres than their normal-weight counterparts, while this phenomenon is not present in childhood.},
}
@article {pmid18428312,
year = {2001},
author = {Lese, CM and Ledbetter, DH},
title = {Molecular cytogenetic analysis of telomere rearrangements.},
journal = {Current protocols in human genetics},
volume = {Chapter 8},
number = {},
pages = {Unit 8.11},
doi = {10.1002/0471142905.hg0811s24},
pmid = {18428312},
issn = {1934-8258},
mesh = {*Chromosome Aberrations ; Chromosome Disorders/diagnosis/genetics ; Chromosomes, Human/genetics ; Cytogenetic Analysis/*methods ; Female ; Genetics, Medical ; Humans ; In Situ Hybridization, Fluorescence/methods ; Male ; Molecular Probe Techniques ; Telomere/*genetics ; Translocation, Genetic ; },
abstract = {Genomic imbalances involving the telomeric regions of human chromosomes, which contain the highest gene concentration in the genome, are proposed to have severe phenotypic consequences. For this reason, it is important to identify telomere rearrangements and assess their contribution to human pathology. This unit describes the structure and function of human telomeres and outlines several FISH-based methodologies that can be employed to study these unique regions of human chromosomes.},
}
@article {pmid18425352,
year = {2008},
author = {Fujii, K and Sasahira, T and Moriwaka, Y and Oue, N and Yasui, W and Kuniyasu, H},
title = {Protection of telomeres 1 protein levels are associated with telomere length in gastric cancer.},
journal = {International journal of molecular medicine},
volume = {21},
number = {5},
pages = {599-604},
pmid = {18425352},
issn = {1107-3756},
mesh = {Aged ; Animals ; Cell Line, Tumor ; Female ; Gastric Mucosa/cytology/metabolism ; Humans ; Male ; Middle Aged ; Neoplasm Invasiveness ; Shelterin Complex ; Stomach Neoplasms/*genetics/metabolism/pathology ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Protection of telomeres 1 (Pot1) is a telomere-associated protein, which binds to the single-stranded DNA extensions of telomeres and regulates telomere length. Pot1 production was examined and compared with telomere length in gastric cancer. Pot1 production and telomere lengths were assessed in 5 human gastric cancer cell lines by immunoblotting and Southern blotting, respectively. Pot1 intracellular localization was examined with protein fractionation. Pot1 index and telomere volume were examined in human gastric mucosa and cancer by immunohistochemistry and in situ hybridization. Pot1 protein levels, which were lower than those in the lymphocytes of healthy persons, were significantly correlated with telomere length in gastric cancer cells (P=0.0167). Pot1 protein was mainly detected in the nuclear fraction and increased by G2/M blocking with nocodazole in MKN28 cells. Pot1 indexes were correlated with telomere volumes in gastric cancers (P<0.0001). Pot1 index was decreased in gastric epithelia distant from cancer (84+/-14%), in peritumoral epithelia (72+/-24%), and in stage I-II (39+/-14%) and stage III-IV (23+/-14%) gastric cancers (P<0.0001). Pot1 index was lower in stage III-IV than in stage I-II gastric cancers (P<0.05). Pot1-low cases showed advanced cancer invasion (P<0.05). Thus, Pot1 production was closely associated with telomere length in gastric mucosa and cancers. Pot1 might be a good in situ marker for the examination of cell-specific telomere length.},
}
@article {pmid18422278,
year = {2008},
author = {Chen, XH and Tong, Y and Xu, WL and Jin, J and Qian, WB},
title = {[Expression of telomere binding factor 2 (TRF2) on leukemia cell lines and primary leukemia cells].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {37},
number = {2},
pages = {170-175},
doi = {10.3785/j.issn.1008-9292.2008.02.012},
pmid = {18422278},
issn = {1008-9292},
mesh = {Adolescent ; Adult ; Female ; HL-60 Cells ; Humans ; Jurkat Cells ; K562 Cells ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, T-Cell/*metabolism/pathology ; Male ; Middle Aged ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Telomeric Repeat Binding Protein 2/*metabolism ; Young Adult ; },
abstract = {OBJECTIVE: To detect the expression levels of telomere binding factor 2 (TRF2) on leukemia cell lines and primary leukemia cells.<br><br>METHODS: The expression of TRF2 mRNA was detected with quantitative real-time RT-PCR in leukemia cell lines and primary leukemia cells. The Western blot analysis was used for the detection of TRF2 protein expression.<br><br>RESULT: TRF2 was overexpressed in T-cell leukemia cell lines but not in myelogenous leukemia cell lines. Significant higher expression levels of TRF2 were observed in primary leukemia cells from patients with M0 and M1 subtypes of acute myelogenous leukemia (AML) compared with normal control and other subtypes of AML.<br><br>CONCLUSION: Increased TRF2 expression levels are found in T-cell leukemia cell lines and AML patients with poor prognosis, which suggests that TRF2 expression might be related to the prognosis of leukemia.},
}
@article {pmid18421006,
year = {2008},
author = {van der Harst, P and van Veldhuisen, DJ and Samani, NJ},
title = {Expanding the concept of telomere dysfunction in cardiovascular disease.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {28},
number = {5},
pages = {807-808},
doi = {10.1161/ATVBAHA.108.164434},
pmid = {18421006},
issn = {1524-4636},
mesh = {Bone Marrow Cells/pathology/physiology ; Cardiovascular Diseases/*etiology/*physiopathology ; Granulocytes/pathology/physiology ; Humans ; Lymphocytes/pathology/physiology ; Telomere/*physiology ; },
}
@article {pmid18418389,
year = {2008},
author = {Temime-Smaali, N and Guittat, L and Wenner, T and Bayart, E and Douarre, C and Gomez, D and Giraud-Panis, MJ and Londono-Vallejo, A and Gilson, E and Amor-Guéret, M and Riou, JF},
title = {Topoisomerase IIIalpha is required for normal proliferation and telomere stability in alternative lengthening of telomeres.},
journal = {The EMBO journal},
volume = {27},
number = {10},
pages = {1513-1524},
pmid = {18418389},
issn = {1460-2075},
mesh = {Adenosine Triphosphatases/analysis/metabolism ; Anaphase ; Cell Line ; Cell Proliferation/drug effects ; Chromatin Immunoprecipitation ; *Chromosomal Instability/genetics ; DNA Helicases/analysis/metabolism ; DNA Topoisomerases, Type I/analysis/genetics/*metabolism ; Humans ; Neoplasm Proteins/analysis/metabolism ; Nuclear Proteins/analysis/metabolism ; Promyelocytic Leukemia Protein ; Protein Subunits/analysis/metabolism ; RNA, Small Interfering/genetics/pharmacology ; RecQ Helicases ; Shelterin Complex ; Telomere/*metabolism/*ultrastructure ; Telomere-Binding Proteins/analysis/metabolism ; Telomeric Repeat Binding Protein 2/analysis/metabolism ; Transcription Factors/analysis/metabolism ; Tumor Suppressor Proteins/analysis/metabolism ; },
abstract = {Topoisomerase (Topo) IIIalpha associates with BLM helicase, which is proposed to be important in the alternative lengthening of telomeres (ALT) pathway that allows telomere recombination in the absence of telomerase. Here, we show that human Topo IIIalpha colocalizes with telomeric proteins at ALT-associated promyelocytic bodies from ALT cells. In these cells, Topo IIIalpha immunoprecipitated with telomere binding protein (TRF) 2 and BLM and was shown to be associated with telomeric DNA by chromatin immunoprecipitation, suggesting that these proteins form a complex at telomere sequences. Topo IIIalpha depletion by small interfering RNA reduced ALT cell survival, but did not affect telomerase-positive cell lines. Moreover, repression of Topo IIIalpha expression in ALT cells reduced the levels of TRF2 and BLM proteins, provoked a strong increase in the formation of anaphase bridges, induced the degradation of the G-overhang signal, and resulted in the appearance of DNA damage at telomeres. In contrast, telomere maintenance and TRF2 levels were unaffected in telomerase-positive cells. We conclude that Topo IIIalpha is an important telomere-associated factor, essential for telomere maintenance and chromosome stability in ALT cells, and speculate on its potential mechanistic function.},
}
@article {pmid18418382,
year = {2008},
author = {Lazzaro, F and Sapountzi, V and Granata, M and Pellicioli, A and Vaze, M and Haber, JE and Plevani, P and Lydall, D and Muzi-Falconi, M},
title = {Histone methyltransferase Dot1 and Rad9 inhibit single-stranded DNA accumulation at DSBs and uncapped telomeres.},
journal = {The EMBO journal},
volume = {27},
number = {10},
pages = {1502-1512},
pmid = {18418382},
issn = {1460-2075},
support = {GM61766/GM/NIGMS NIH HHS/United States ; R01 GM020056-33/GM/NIGMS NIH HHS/United States ; GM20056/GM/NIGMS NIH HHS/United States ; R01 GM061766-06/GM/NIGMS NIH HHS/United States ; R01 GM061766-07/GM/NIGMS NIH HHS/United States ; R01 GM020056/GM/NIGMS NIH HHS/United States ; 075294/WT_/Wellcome Trust/United Kingdom ; C23629/A7951/CRUK_/Cancer Research UK/United Kingdom ; R01 GM061766/GM/NIGMS NIH HHS/United States ; GGP030406/TI_/Telethon/Italy ; /WT_/Wellcome Trust/United Kingdom ; R37 GM020056/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics/*metabolism ; *DNA Breaks, Double-Stranded ; DNA, Single-Stranded/*antagonists &amp; inhibitors ; Enzyme Activation ; Gene Deletion ; Histone-Lysine N-Methyltransferase ; Histones/metabolism ; Intracellular Signaling Peptides and Proteins ; Methylation ; Nuclear Proteins/genetics/*metabolism ; Protein Serine-Threonine Kinases ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Cells respond to DNA double-strand breaks (DSBs) and uncapped telomeres by recruiting checkpoint and repair factors to the site of lesions. Single-stranded DNA (ssDNA) is an important intermediate in the repair of DSBs and is produced also at uncapped telomeres. Here, we provide evidence that binding of the checkpoint protein Rad9, through its Tudor domain, to methylated histone H3-K79 inhibits resection at DSBs and uncapped telomeres. Loss of DOT1 or mutations in RAD9 influence a Rad50-dependent nuclease, leading to more rapid accumulation of ssDNA, and faster activation of the critical checkpoint kinase, Mec1. Moreover, deletion of RAD9 or DOT1 partially bypasses the requirement for CDK1 in DSB resection. Interestingly, Dot1 contributes to checkpoint activation in response to low levels of telomere uncapping but is not essential with high levels of uncapping. We suggest that both Rad9 and histone H3 methylation allow transmission of the damage signal to checkpoint kinases, and keep resection of damaged DNA under control influencing, both positively and negatively, checkpoint cascades and contributing to a tightly controlled response to DNA damage.},
}
@article {pmid18418035,
year = {2008},
author = {Azzalin, CM and Lingner, J},
title = {Telomeres: the silence is broken.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {7},
number = {9},
pages = {1161-1165},
doi = {10.4161/cc.7.9.5836},
pmid = {18418035},
issn = {1551-4005},
mesh = {Animals ; Cellular Senescence/*genetics ; Chromosomal Instability/*genetics ; Epigenesis, Genetic/*genetics ; Gene Expression Regulation/genetics ; Heterochromatin/genetics ; Humans ; RNA/*genetics/metabolism ; RNA Interference/physiology ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {The ends of linear eukaryotic chromosomes, telomeres, distinguish natural chromosome ends from DNA double stranded breaks and thus promote genome stability. Telomeres comprise a repetitive DNA skeleton, which is wrapped in specific protein complexes. Recent data indicate that an additional building block of telomeres is RNA and that the longstanding idea that telomeres are silent genomic regions needs to be overturned. Mammalian telomeres are indeed transcribed into RNA molecules, which remain associated with telomeric chromatin, suggesting RNA-mediated mechanisms in organizing telomere architecture.},
}
@article {pmid18414821,
year = {2008},
author = {Salpea, KD and Nicaud, V and Tiret, L and Talmud, PJ and Humphries, SE and , },
title = {The association of telomere length with paternal history of premature myocardial infarction in the European Atherosclerosis Research Study II.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {86},
number = {7},
pages = {815-824},
pmid = {18414821},
issn = {0946-2716},
support = {FS/06/053//British Heart Foundation/United Kingdom ; },
mesh = {Adult ; Atherosclerosis/ethnology/genetics ; Case-Control Studies ; Cohort Studies ; Family Health ; Humans ; Male ; Myocardial Infarction/ethnology/*genetics ; Telomere/*chemistry ; White People/genetics ; },
abstract = {Inter-individual variability in telomere length is highly heritable and has been correlated with risk of coronary heart disease (CHD). Our aim was to determine the association of mean leukocyte telomere length with paternal history of premature myocardial infarction (MI). Mean leukocyte telomere length was measured with real-time polymerase chain reactions in 369 male students (18-28 years) with a paternal history of MI before the age of 55, recruited from 14 European universities, serving as cases and 396 age-matched controls with no paternal history of CHD. Overall, cases had borderline significantly shorter mean length (approximately 550 bp), adjusted for age and geographical region, than controls (p = 0.05). A significant difference in telomere length across the geographical regions of Europe was observed (p < 0.0001), with shorter mean length in the Baltic and South and the longest in the Middle. The case-control difference (approximately 2.24 kb) in mean length was highly significant only in the Baltic region (p < 0.0001). There is suggestive evidence that, in young men, the biological expression of a paternal history of premature MI is at least in part mediated through inherited short telomeres. The association with paternal history of MI is strongly seen only in the Baltic compared to the rest of Europe, but this is not explained by shorter telomere length in this region.},
}
@article {pmid18414026,
year = {2008},
author = {Snyder, AR},
title = {Silent no more: expression of RNA from telomeres may regulate telomere length.},
journal = {Cancer biology &amp; therapy},
volume = {7},
number = {5},
pages = {619-621},
doi = {10.4161/cbt.7.5.6033},
pmid = {18414026},
issn = {1555-8576},
mesh = {Animals ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Cell Proliferation ; Epigenesis, Genetic ; Gene Expression ; Gene Expression Regulation, Neoplastic ; Heterochromatin/metabolism ; Humans ; Mice ; Mice, Transgenic ; RNA/*genetics/metabolism ; RNA Interference ; Telomere/*ultrastructure ; Transcription, Genetic ; },
}
@article {pmid18412988,
year = {2008},
author = {Bull, C and Fenech, M},
title = {Genome-health nutrigenomics and nutrigenetics: nutritional requirements or 'nutriomes' for chromosomal stability and telomere maintenance at the individual level.},
journal = {The Proceedings of the Nutrition Society},
volume = {67},
number = {2},
pages = {146-156},
doi = {10.1017/S0029665108006988},
pmid = {18412988},
issn = {0029-6651},
mesh = {Chromosomal Instability/*physiology ; DNA Damage/*physiology ; DNA Methylation ; Gene Expression ; Genetic Markers ; Genomics ; Humans ; Micronutrients/*deficiency ; *Nutrigenomics ; Nutritional Physiological Phenomena/*physiology ; *Nutritional Requirements ; Oxidative Stress ; },
abstract = {It is becoming increasingly evident that (a) risk for developmental and degenerative disease increases with more DNA damage, which in turn is dependent on nutritional status, and (b) the optimal concentration of micronutrients for prevention of genome damage is also dependent on genetic polymorphisms that alter the function of genes involved directly or indirectly in the uptake and metabolism of micronutrients required for DNA repair and DNA replication. The development of dietary patterns, functional foods and supplements that are designed to improve genome-health maintenance in individuals with specific genetic backgrounds may provide an important contribution to an optimum health strategy based on the diagnosis and individualised nutritional prevention of genome damage, i.e. genome health clinics. The present review summarises some of the recent knowledge relating to micronutrients that are associated with chromosomal stability and provides some initial insights into the likely nutritional factors that may be expected to have an impact on the maintenance of telomeres. It is evident that developing effective strategies for defining nutrient doses and combinations or 'nutriomes' for genome-health maintenance at the individual level is essential for further progress in this research field.},
}
@article {pmid18411302,
year = {2008},
author = {Mozdy, AD and Podell, ER and Cech, TR},
title = {Multiple yeast genes, including Paf1 complex genes, affect telomere length via telomerase RNA abundance.},
journal = {Molecular and cellular biology},
volume = {28},
number = {12},
pages = {4152-4161},
pmid = {18411302},
issn = {1098-5549},
support = {//Howard Hughes Medical Institute/United States ; },
mesh = {Gene Deletion ; *Gene Expression Regulation, Fungal ; Models, Biological ; Nuclear Proteins/*genetics/*physiology ; Phenotype ; Plasmids/metabolism ; Promoter Regions, Genetic ; RNA, Fungal/*chemistry/physiology ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/*genetics/*physiology ; Telomerase/*metabolism ; Telomere/*ultrastructure ; Transcription, Genetic ; },
abstract = {Twofold reductions in telomerase RNA levels cause telomere shortening in both humans and the yeast Saccharomyces cerevisiae. To test whether multiple genes that affect telomere length act by modulating telomerase RNA abundance, we used real-time reverse transcription-PCR to screen S. cerevisiae deletion strains reported to maintain shorter or longer telomeres to determine the levels of their telomerase RNA (TLC1) abundance. Of 290 strains screened, 5 had increased TLC1 levels; 4 of these maintained longer telomeres. Twenty strains had decreased TLC1 levels; 18 of these are known to maintain shorter telomeres. Four strains with decreased TLC1 RNA levels contained deletions of subunits of Paf1C (polymerase II-associated factor complex). While Paf1C had been implicated in the transcription of both polyadenylated and nonpolyadenylated RNAs, Paf1C had not been associated previously with the noncoding telomerase RNA. In Paf1C mutant strains, TLC1 overexpression partially rescues telomere length and cell growth defects, suggesting that telomerase RNA is a critical direct or indirect Paf1C target. Other factors newly identified as affecting TLC1 RNA levels include cyclin-dependent kinase, the mediator complex, protein phosphatase 2A, and ribosomal proteins L13B and S16A. This report establishes that a subset of telomere length genes act by modulating telomerase RNA abundance.},
}
@article {pmid18407488,
year = {2008},
author = {Rog, O and Cooper, JP},
title = {Telomeres in drag: Dressing as DNA damage to engage telomerase.},
journal = {Current opinion in genetics &amp; development},
volume = {18},
number = {2},
pages = {212-220},
doi = {10.1016/j.gde.2008.01.011},
pmid = {18407488},
issn = {0959-437X},
support = {//Cancer Research UK/United Kingdom ; },
mesh = {Animals ; DNA Damage/*genetics ; DNA Replication/genetics ; Humans ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {The telomere field concentrates both on mechanisms of telomere synthesis and the mechanisms by which telomeres protect chromosome termini from fusion and degradation. Recent studies show that the DNA damage response (DDR) machinery, formerly thought to be the culprit in deleterious telomeric fusion and degradation reactions, plays an active role not only in telomere protection but also in regulating telomere synthesis. Conversely, semi-conservative DNA replication, responsible for the bulk of telomere synthesis, now appears to be a pivotal event on the road to telomere de-protection. These advances prompt the notion that the two guises of telomere function are intricately entangled. Indeed, telomeres appear to expose themselves to the DDR upon passage of the replication fork, in turn attracting telomerase.},
}
@article {pmid18406479,
year = {2009},
author = {Bunout, D and Backhouse, C and Leiva, L and Barrera, G and Sierralta, W and de la Maza, MP and Hirsch, S},
title = {Relationship between protein and mitochondrial DNA oxidative injury and telomere length and muscle loss in healthy elderly subjects.},
journal = {Archives of gerontology and geriatrics},
volume = {48},
number = {3},
pages = {335-339},
doi = {10.1016/j.archger.2008.02.016},
pmid = {18406479},
issn = {1872-6976},
mesh = {Absorptiometry, Photon ; Adult ; Aged ; Aldehydes/metabolism ; Biopsy ; Body Composition/physiology ; Case-Control Studies ; *DNA Damage ; DNA, Mitochondrial/*metabolism ; Humans ; Muscle, Skeletal/*metabolism ; Polymerase Chain Reaction ; Risk Factors ; Statistics, Nonparametric ; Telomere/*metabolism ; },
abstract = {A blood sample and muscle biopsies were obtained from 54 elderly subjects. Twenty-seven subjects aged 77+/-3 years, had experienced a change in fat free mass (FFM) of +194+/-282g/year (lean body mass maintainers) and 27 subjects aged 78+/-3 years, had a change in FFM of -487+/-209g/year (lean body mass losers). Muscle biopsies were also obtained from 10 healthy subjects aged 34+/-4 years. In muscle, the ratio of mitochondrial DNA (mtDNA) to nuclear DNA (nDNA) and telomere length were assessed and deposition of 4-hydroxy-2-nonenal adducts (4HNE) was visualized by electron microscopy. In FFM maintainers, losers and young controls, the ratio of mtDNA to nDNA was 2.1 (95% confidence intervals (CI), 0.1-31.7), 1.5 (95% CI, 0.2-15.7) and 18.6 (95% CI, 2.8-46.2), respectively. 4HNE deposition was 5.9 (95% CI, 1.5-28), 4.9 (95% CI, 0.9-13) and 3.4 (95% CI, 1.1-4.6) gold particles/microm(2), respectively. Telomere length, expressed as T/S ratio, was 0.06 (95% CI, 0.01-0.16), 0.06 (95% CI, 0.03-0.27) and 0.34 (95% CI, 0.1-1.34), respectively (p<0.02 or less for all comparisons between elderly and young subjects).},
}
@article {pmid18405638,
year = {2008},
author = {Hoareau-Aveilla, C and Henry, Y and Leblanc, T},
title = {[Dyskeratosis congenita, a disease caused by defective telomere maintenance].},
journal = {Medecine sciences : M/S},
volume = {24},
number = {4},
pages = {390-398},
doi = {10.1051/medsci/2008244390},
pmid = {18405638},
issn = {0767-0974},
mesh = {Dyskeratosis Congenita/diagnosis/*genetics/physiopathology ; Humans ; Models, Genetic ; Phenotype ; Pseudouridine/metabolism ; RNA/genetics ; Telomerase/genetics/metabolism ; Telomere/*genetics ; Uridine/metabolism ; },
abstract = {Dyskeratosis congenita (DC), also called Zinsser-Cole-Engman syndrome, is a rare, often fatal, inherited disease described for the first time at the dermatological level by Zinsser in 1906. It is a very polymorphous disease at the clinical level, with several modes of inheritance. Several clinical symptoms of the disease can appear after a latency period. These features render DC particularly difficult to diagnose. Mutations of several genes can cause DC, four of them having been identified so far. However, for a majority of patients, the affected gene has not been found. Remarkably, all identified genes (DKC1, hTERC, hTERT, and NOP10) encode components of telomerase, all required for telomere length maintenance. DC is thus a unique clinical model for the study of the roles of telomerase and telomeres. Moreover, proteins encoded by the DKC1 and NOP10 genes are also components of so-called box H/ACA RNPs required for ribosome synthesis and pre-mRNA processing. Alterations of these processes could contribute to the symptoms of DC patients carrying mutations in DKC1 or NOP10.},
}
@article {pmid18405637,
year = {2008},
author = {Londoño-Vallejo, A and Lenain, C and Gilson, E},
title = {[Targeting telomeres to enforce cancer cells to senesce].},
journal = {Medecine sciences : M/S},
volume = {24},
number = {4},
pages = {383-389},
doi = {10.1051/medsci/2008244383},
pmid = {18405637},
issn = {0767-0974},
mesh = {Cellular Senescence ; Homeostasis ; Humans ; Models, Biological ; Neoplasms/genetics/pathology/*physiopathology/prevention &amp; control ; Telomere/genetics/*physiology ; },
abstract = {The telomeres protect the end of chromosomes from being recognized and processed as an accidental double stranded break. In human somatic cells, telomeres shorten progressively with every round of DNA replication, leading to dysfunctional telomeres that trigger cellular senescence or apoptosis depending on the cell type. This telomere erosion appears to play a role in cell renewal, ageing and cancer. Two recent studies demonstrated in mouse that eroded telomeres in cancer cells blocked for apoptosis limit cancer formation by triggering senescence. These results suggest that provoking senescence may provide a way to cure cancer and point to new therapeutical strategies targeting specific telomeric functions. Nevertheless, an important question remains unanswered: does replicative senescence limit tumor formation in human?},
}
@article {pmid18400657,
year = {2007},
author = {El-Zein, R and Albrecht, T and Knutson, E and Legator, MS and Abdel-Rahman, SZ},
title = {Reduction in telomere length in individuals exposed in utero to glycol ether.},
journal = {Archives of environmental &amp; occupational health},
volume = {62},
number = {3},
pages = {161-163},
doi = {10.3200/AEOH.62.3.161-163},
pmid = {18400657},
issn = {1933-8244},
mesh = {Adolescent ; Adult ; Child ; *Chromosome Aberrations ; Congenital Abnormalities/etiology/genetics ; Ethylene Glycols/*toxicity ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Intellectual Disability/chemically induced/genetics ; Male ; Maternal Exposure/*adverse effects ; Occupational Exposure/*adverse effects ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Telomere/*drug effects ; },
abstract = {Little is known about the mechanism by which ethylene glycol monomethyl ether (EGME) produces genotoxic effects in humans. The authors found that individuals exposed in utero to EGME showed characteristic dysmorphic features, unexplained mental retardation, and persistent cytogenetic damage. They hypothesized that these individuals had a higher level of terminal chromosome arrangements, accounting for the genomic instability detected. Results indicate that in utero-exposed individuals have significantly reduced telomeres relative to non-in utero-exposed participants. The M +/- SEM pixel intensity in the in utero-exposed participants was 43.6 +/- 7.6 compared with 74.1 +/- 1.9 in the non-in utero-exposed. Findings suggest that exposure to EGME in utero could result in terminal chromosome rearrangements and shortening of telomere length, leading to the observed dysmorphic features and idiopathic mental retardation.},
}
@article {pmid18394896,
year = {2008},
author = {Saharia, A and Guittat, L and Crocker, S and Lim, A and Steffen, M and Kulkarni, S and Stewart, SA},
title = {Flap endonuclease 1 contributes to telomere stability.},
journal = {Current biology : CB},
volume = {18},
number = {7},
pages = {496-500},
pmid = {18394896},
issn = {0960-9822},
support = {R21 AG025320-01/AG/NIA NIH HHS/United States ; R21 AG025320-02/AG/NIA NIH HHS/United States ; F32 CA093033/CA/NCI NIH HHS/United States ; P41 RR000954/RR/NCRR NIH HHS/United States ; P41-RR00954/RR/NCRR NIH HHS/United States ; },
mesh = {DNA Replication/*physiology ; Flap Endonucleases/*metabolism ; Humans ; Telomere/*metabolism ; },
abstract = {Telomere stability plays an important role in the preservation of genomic stability and is maintained through the coordinated actions of telomere-specific proteins and DNA repair and replication proteins [1, 2]. Flap endonuclease 1 (FEN1) is a protein that plays a role in lagging-strand DNA replication, base excision repair, homologous recombination, and reinitiation of stalled replication forks [3, 4]. Here, we demonstrate that FEN1 depletion leads to telomere dysfunction characterized by the presence of gammaH2AX and sister telomere loss. Expression of catalytically active telomerase, the reverse transcriptase that adds telomeric repeats to chromosome ends, was sufficient to rescue telomere dysfunction upon FEN1 depletion. Strikingly, FEN1 depletion exclusively abrogates telomeres replicated by lagging-strand DNA replication. Genetic rescue experiments utilizing FEN1 mutant proteins that retained the ability to localize to telomeric repeats revealed that FEN1's nuclease activity and ability to interact with the Werner protein (WRN) and telomere-binding protein (TRF2) were required for FEN1 activity at the telomere. Given FEN1's role in lagging-strand DNA replication and reinitiation of stalled replication forks, we propose that FEN1 contributes to telomere stability by ensuring efficient telomere replication.},
}
@article {pmid18391173,
year = {2008},
author = {Aubert, G and Lansdorp, PM},
title = {Telomeres and aging.},
journal = {Physiological reviews},
volume = {88},
number = {2},
pages = {557-579},
doi = {10.1152/physrev.00026.2007},
pmid = {18391173},
issn = {0031-9333},
support = {AI-29524/AI/NIAID NIH HHS/United States ; },
mesh = {Aging/*physiology ; Humans ; Telomerase/*metabolism ; *Telomere/metabolism ; },
abstract = {Telomeres play a central role in cell fate and aging by adjusting the cellular response to stress and growth stimulation on the basis of previous cell divisions and DNA damage. At least a few hundred nucleotides of telomere repeats must "cap" each chromosome end to avoid activation of DNA repair pathways. Repair of critically short or "uncapped" telomeres by telomerase or recombination is limited in most somatic cells and apoptosis or cellular senescence is triggered when too many "uncapped" telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germline which typically express high levels of telomerase. In somatic cells, telomere length is very heterogeneous but typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal and malignant cells, a process facilitated by the genome instability and aneuploidy triggered by dysfunctional telomeres. The crucial role of telomeres in cell turnover and aging is highlighted by patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Short telomeres in such patients are implicated in a variety of disorders including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and cancer. Here the role of telomeres and telomerase in human aging and aging-associated diseases is reviewed.},
}
@article {pmid18390681,
year = {2008},
author = {Zhang, R and Zeng, A and Fang, P and Qin, Z},
title = {Characterization of replication and conjugation of Streptomyces circular plasmids pFP1 and pFP11 and their ability to propagate in linear mode with artificially attached telomeres.},
journal = {Applied and environmental microbiology},
volume = {74},
number = {11},
pages = {3368-3376},
pmid = {18390681},
issn = {1098-5336},
mesh = {Bacterial Proteins/genetics ; Base Sequence ; *Conjugation, Genetic ; DNA Helicases/genetics ; *DNA Replication ; DNA, Bacterial/chemistry/genetics/metabolism ; DNA, Circular/genetics/metabolism ; Gene Order ; Molecular Sequence Data ; *Plasmids ; Recombination, Genetic ; Sequence Analysis, DNA ; Streptomyces/*genetics ; *Telomere ; Trans-Activators/genetics ; },
abstract = {Many Streptomyces species harbor circular plasmids (8 to 31 kb) as well as linear plasmids (12 to 1,700 kb). We report the characterization of two newly detected circular plasmids, pFP11 (35,139 bp) and pFP1 (39,360 bp). As on linear plasmids, their replication loci comprise repA genes and adjacent iterons, to which RepA proteins bind specifically in vitro. Plasmids containing the minimal iterons plus the repA locus of pFP11 were inherited extremely unstably; par and additional loci were required for stable inheritance. Surprisingly, plasmids containing replication loci from pFP11 or Streptomyces circular plasmid SCP2 but not from pFP1, SLP1, or pIJ101 propagated in a stable linear mode when the telomeres of a linear plasmid were attached. These results indicate bidirectional replication for pFP11 and SCP2. Both pFP11 and pFP1 contain, for plasmid transfer, a major functional traB gene (encoding a DNA translocase typical for Streptomyces plasmids) as well as, surprisingly, a putative traA gene (encoding a DNA nickase, characteristic of single-stranded DNA transfer of gram-negative plasmids), but this did not appear to be functional, at least in isolation.},
}
@article {pmid18388332,
year = {2008},
author = {O'Donnell, CJ and Demissie, S and Kimura, M and Levy, D and Gardner, JP and White, C and D'Agostino, RB and Wolf, PA and Polak, J and Cupples, LA and Aviv, A},
title = {Leukocyte telomere length and carotid artery intimal medial thickness: the Framingham Heart Study.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {28},
number = {6},
pages = {1165-1171},
pmid = {18388332},
issn = {1524-4636},
support = {N01-HC-25195/HC/NHLBI NIH HHS/United States ; N01 HC025195/HC/NHLBI NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; R01 AG021593-01/AG/NIA NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; Z99 HL999999/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Carotid Arteries/*pathology ; Carotid Artery Diseases/*genetics/*pathology ; Cohort Studies ; Cross-Sectional Studies ; Female ; Genetic Predisposition to Disease ; Humans ; Leukocytes/*pathology ; Linear Models ; Male ; Middle Aged ; Obesity/complications/pathology ; Risk Factors ; Sex Characteristics ; Smoking/adverse effects/pathology ; Telomere/*pathology ; Tunica Intima/*pathology ; Tunica Media/*pathology ; },
abstract = {BACKGROUND AND PURPOSE: Leukocyte telomere length (LTL) is relatively short in individuals who have evidence of cardiovascular disease. The purpose of this study was to examine the link between LTL and the predisposition to atherosclerosis, as determined by carotid artery intimal medial thickness (IMT) in participants of the Framingham Offspring Study.<br><br>METHODS AND RESULTS: LTL was assayed by the mean length of the terminal restriction fragments and carotid artery IMT by B-mode ultrasonography in 1062 individuals (496 men, 566 women) aged 33 to 86 years. In the whole sample, there was a significant association of age-and sex-adjusted LTL with internal carotid artery IMT (ICA-IMT) (r = -0.07, P = 0.02). In sex-stratified analysis, this association remained significant for men (r = -0.11, P = 0.02) but not for women (r = -0.04, P = 0.36). After further adjustment for cigarette smoking and BMI, a borderline significant association persisted in men (P = 0.06). In secondary analysis, the age-adjusted LTL was significantly (and negatively) associated with ICA-IMT (r = -0.28, p = 0.0006) in obese (BMI > 30 kg/m(2)) men but not in nonobese (BMI < or = 30 kg/m(2)) men. In addition, age-adjusted LTL was significantly shorter in men (6.89+/-0.02 kb) than women (7.01+/-0.02 kb; P < 0.0009) and in current cigarette smokers (6.87+/-0.05 kb) than never smokers (6.99+/-0.03 kb; P = 0.0006). Although there was no significant association of LTL with common carotid artery-IMT or with carotid artery stenosis, there was a significant inverse association of LTL with common carotid artery IMT in obese men.<br><br>CONCLUSIONS: In obese men, shortened LTL is a powerful marker of increased carotid IMT. Given the public health impact of atherosclerosis and in particular the current epidemic of obesity, the associations noted in obese men warrant further confirmation.},
}
@article {pmid18387366,
year = {2008},
author = {Schrumpfová, PP and Kuchar, M and Palecek, J and Fajkus, J},
title = {Mapping of interaction domains of putative telomere-binding proteins AtTRB1 and AtPOT1b from Arabidopsis thaliana.},
journal = {FEBS letters},
volume = {582},
number = {10},
pages = {1400-1406},
doi = {10.1016/j.febslet.2008.03.034},
pmid = {18387366},
issn = {0014-5793},
mesh = {Amino Acid Sequence ; Arabidopsis Proteins/genetics/*metabolism ; Cloning, Molecular ; Dimerization ; Humans ; Molecular Sequence Data ; *Protein Interaction Domains and Motifs ; Telomere-Binding Proteins/genetics/*metabolism ; Two-Hybrid System Techniques ; },
abstract = {We previously searched for interactions between plant telomere-binding proteins and found that AtTRB1, from the single-myb-histone (Smh) family, interacts with the Arabidopsis POT1-like-protein, AtPOT1b, involved in telomere capping. Here we identify domains responsible for that interaction. We also map domains in AtTRB1 responsible for interactions with other Smh-family-members. Our results show that the N-terminal OB-fold-domain of AtPOT1b mediates the interaction with AtTRB1. This domain is characteristic for POT1- proteins and is involved with binding the G-rich-strand of telomeric DNA. AtPOT1b also interacts with AtTRB2 and AtTRB3. The central histone-globular-domain of AtTRB1 is involved with binding to AtTRB2 and 3, as well as to AtPOT1b. AtTRB1-heterodimers with other Smh-family-members are more stable than AtTRB1-homodimers. Our results reveal interaction networks of plant telomeres.},
}
@article {pmid18386193,
year = {2008},
author = {Iwasaki, T and Robertson, N and Tsigani, T and Finnon, P and Scott, D and Levine, E and Badie, C and Bouffler, S},
title = {Lymphocyte telomere length correlates with in vitro radiosensitivity in breast cancer cases but is not predictive of acute normal tissue reactions to radiotherapy.},
journal = {International journal of radiation biology},
volume = {84},
number = {4},
pages = {277-284},
doi = {10.1080/09553000801953326},
pmid = {18386193},
issn = {0955-3002},
mesh = {Breast Neoplasms/*genetics/*pathology ; Dose-Response Relationship, Radiation ; Humans ; Lymphocytes/*radiation effects ; Radiation Dosage ; Radiation Injuries/*genetics/*pathology ; Radiation Tolerance/*genetics ; Telomere/*genetics/*ultrastructure ; Tumor Cells, Cultured ; },
abstract = {PURPOSE: To examine the hypothesis that lymphocyte telomere length may be predictive of both breast cancer susceptibility and severity of acute reactions to radiotherapy.<br><br>MATERIALS AND METHODS: Peripheral blood lymphocyte cultures from breast cancer patients (with normal or severe skin reactions to radiotherapy) and normal individuals were assessed for in vitro radiosensitivity as measured by apoptosis, cell cycle delay and cytotoxicity. Telomere lengths were determined by a flow cytometric fluorescence in situ hybridization assay (FLOW-FISH).<br><br>RESULTS: Female breast cancer cases (n = 24) had reduced lymphocyte telomere lengths by comparison with healthy controls (n = 20, p < 0.04). However, the average age of healthy controls was less (45.4) than cases (53). When the control group was modified to give a better age match (51.5, n = 13) the reduced telomere length in cases was not significantly different from controls. Lymphocytes from breast cancer cases also showed reduced cell cycle delay (p < 0.001) and increased apoptosis (p < 0.01) following irradiation in vitro at 3 and 5 Gy respectively, compared to healthy controls. Statistical significance was maintained with the improved age matching of groups. Comparison of lymphocytes from breast cancer patients with normal (n = 11) and severe (n = 13) skin reactions to radiotherapy failed to identify differences in telomere length or cellular radiosensitivity in this limited sample.<br><br>CONCLUSIONS: This study adds to the evidence suggesting a correlation between altered cellular radiosensitivity and breast cancer. However, in the cases investigated, telomere length does not appear to be predictive of acute skin reactions to radiotherapy.},
}
@article {pmid18378481,
year = {2008},
author = {Hewakapuge, S and van Oorschot, RA and Lewandowski, P and Baindur-Hudson, S},
title = {Investigation of telomere lengths measurement by quantitative real-time PCR to predict age.},
journal = {Legal medicine (Tokyo, Japan)},
volume = {10},
number = {5},
pages = {236-242},
doi = {10.1016/j.legalmed.2008.01.007},
pmid = {18378481},
issn = {1873-4162},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Child ; Child, Preschool ; Female ; Forensic Genetics ; Humans ; Infant ; Male ; Middle Aged ; Polymerase Chain Reaction ; Racial Groups/genetics ; Regression Analysis ; Sex Factors ; Telomere/*genetics/*ultrastructure ; Young Adult ; },
abstract = {Currently DNA profiling methods only compare a suspect's DNA with DNA left at the crime scene. When there is no suspect, it would be useful for the police to be able to predict what the person of interest looks like by analysing the DNA left behind in a crime scene. Determination of the age of the suspect is an important factor in creating an identikit. Human somatic cells gradually lose telomeric repeats with age. This study investigated if one could use a correlation between telomere length and age, to predict the age of an individual from their DNA. Telomere length, in buccal cells, of 167 individuals aged between 1 and 96 years old was measured using real-time quantitative PCR. Telomere length decreased with age (r=-0.185, P<0.05) and the age of an individual could be roughly determined by the following formula: (age=relative telomere length -1.5/-0.005). The regression (R(2)) value between telomere length and age was approximately 0.04, which is too low to be use for forensics. The causes for the presence of large variation in telomere lengths in the population were further investigated. The age prediction accuracies were low even after dividing samples into non-related Caucasians, males and females (5%, 9% and 1%, respectively). Mean telomere lengths of eight age groups representing each decade of life showed non-linear decrease in telomere length with age. There were variations in telomere lengths even among similarly aged individuals aged 26 years old (n=10) and age 54 years old (n=9). Therefore, telomere length measurement by real-time quantitative PCR cannot be used to predict age of a person, due to the presence of large inter-individual variations in telomere lengths.},
}
@article {pmid18369817,
year = {2007},
author = {El Daly, H and Martens, UM},
title = {Telomerase inhibition and telomere targeting in hematopoietic cancer cell lines with small non-nucleosidic synthetic compounds (BIBR1532).},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {405},
number = {},
pages = {47-60},
doi = {10.1007/978-1-60327-070-0_6},
pmid = {18369817},
issn = {1064-3745},
mesh = {Aminobenzoates/*pharmacology ; Blotting, Western ; Cell Line, Tumor ; Hematopoiesis/*drug effects ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes, Mononuclear/drug effects/pathology ; Molecular Biology/*methods ; Naphthalenes/*pharmacology ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Telomere maintenance has been shown to be essential for unlimited growth potential of human cells and is regarded as one hallmark of cancer. Telomere repeats at the ends of eukaryotic chromosomes are synthesized by the enzyme telomerase, which is active in most cancers and to some extend also in normal somatic cells. Therefore, targeting the telomerase/telomere complex offers great potential for the development of novel anticancer therapeutics. An example of such a strategy is the small molecule BIBR1532 that is a selective, non-nucleosidic inhibitor of the catalytic component hTERT. Treatment of cancer cells with this compound leads to progressive telomere shortening, consecutive telomere dysfunction, and finally growth arrest after a lag period that is largely dependent on initial telomere length. We have additionally shown that using this class of telomerase inhibitor at higher concentrations exerts a direct cytotoxic effect on malignant cells of the hematopoietic system but not on normal stem cells, which appears to derive from direct damage to the structure of individual telomeres.},
}
@article {pmid18369758,
year = {2008},
author = {Mattson, MP and Zhang, P and Cheng, A},
title = {Telomere neurobiology.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {438},
number = {},
pages = {185-196},
doi = {10.1007/978-1-59745-133-8_15},
pmid = {18369758},
issn = {1064-3745},
mesh = {Animals ; Gene Expression Regulation ; Immunoblotting ; Mice ; *Neurobiology ; Protein Transport ; RNA, Messenger/genetics/metabolism ; Rats ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {The ends of chromosomes consist of a hexanucleotide DNA repeat sequence and specialized DNA-binding and telomere-associated proteins. An enzyme activity called telomerase maintains telomere length by using an RNA template (TR) and a reverse transcriptase (TERT) to add the hexanucleotide sequence to the free chromosome end. The structure of telomeres is maintained and modified by telomere repeat-binding factors (TRF1 and TRF2) and proteins known for their role in DNA damage responses, including poly(ADP-ribose) polymerase-1, Werner, and ATM. Telomerase activity can be quantified using a telomere repeat amplification protocol (TRAP) assay, and levels of TERT and telomere-associated proteins are evaluated by immunoblot and immunocytochemical methods. Levels of TERT and telomere-associated proteins can be overexpressed or knocked down using viral vector-based methods. Using the kinds of approaches described here, evidence has been obtained suggesting that telomeres play important roles in regulating neural stem cell proliferation, neuronal differentiation, senescence of glial cells, and apoptosis and DNA damage responses of neural cells.},
}
@article {pmid18367475,
year = {2008},
author = {Ko, S and Jun, SH and Bae, H and Byun, JS and Han, W and Park, H and Yang, SW and Park, SY and Jeon, YH and Cheong, C and Kim, WT and Lee, W and Cho, HS},
title = {Structure of the DNA-binding domain of NgTRF1 reveals unique features of plant telomere-binding proteins.},
journal = {Nucleic acids research},
volume = {36},
number = {8},
pages = {2739-2755},
pmid = {18367475},
issn = {1362-4962},
mesh = {Arabidopsis Proteins/chemistry ; Binding Sites ; Crystallography, X-Ray ; DNA, Plant/*chemistry/metabolism ; Humans ; *Models, Molecular ; Mutagenesis, Site-Directed ; Nuclear Magnetic Resonance, Biomolecular ; Plant Proteins/*chemistry/genetics/metabolism ; Protein Structure, Tertiary ; Structural Homology, Protein ; Telomere/*chemistry/metabolism ; Telomeric Repeat Binding Protein 1/*chemistry/genetics/metabolism ; Nicotiana/genetics ; },
abstract = {Telomeres are protein-DNA elements that are located at the ends of linear eukaryotic chromosomes. In concert with various telomere-binding proteins, they play an essential role in genome stability. We determined the structure of the DNA-binding domain of NgTRF1, a double-stranded telomere-binding protein of tobacco, using multidimensional NMR spectroscopy and X-ray crystallography. The DNA-binding domain of NgTRF1 contained the Myb-like domain and C-terminal Myb-extension that is characteristic of plant double-stranded telomere-binding proteins. It encompassed amino acids 561-681 (NgTRF1(561-681)), and was composed of 4 alpha-helices. We also determined the structure of NgTRF1(561-681) bound to plant telomeric DNA. We identified several amino acid residues that interacted directly with DNA, and confirmed their role in the binding of NgTRF1 to telomere using site-directed mutagenesis. Based on a structural comparison of the DNA-binding domains of NgTRF1 and human TRF1 (hTRF1), NgTRF1 has both common and unique DNA-binding properties. Interaction of Myb-like domain with telomeric sequences is almost identical in NgTRF1(561-681) with the DNA-binding domain of hTRF1. The interaction of Arg-638 with the telomeric DNA, which is unique in NgTRF1(561-681), may provide the structural explanation for the specificity of NgTRF1 to the plant telomere sequences, (TTTAGGG)(n).},
}
@article {pmid18364569,
year = {2008},
author = {Sprung, CN and Davey, DS and Withana, NP and Distel, LV and McKay, MJ},
title = {Telomere length in lymphoblast cell lines derived from clinically radiosensitive cancer patients.},
journal = {Cancer biology &amp; therapy},
volume = {7},
number = {5},
pages = {638-644},
doi = {10.4161/cbt.7.5.5762},
pmid = {18364569},
issn = {1555-8576},
mesh = {Ataxia Telangiectasia/*genetics/*radiotherapy ; Cell Line, Tumor ; Cohort Studies ; DNA/analysis ; DNA Restriction Enzymes/metabolism ; Flow Cytometry/methods ; Humans ; In Situ Hybridization, Fluorescence ; Lymphocytes/*metabolism ; Neoplasms/*genetics/*radiotherapy ; Nijmegen Breakage Syndrome/*genetics/*radiotherapy ; Telomere/*ultrastructure ; },
abstract = {Approximately 1-5 percent of cancer patients suffer from significant side effects in normal tissue after radiotherapy (RT). Although RT is an effective cancer therapy, treatment dose intensities are restricted to minimize the incidence of such normal tissue reactions. Therefore, most patients receive lower dose intensities than can be tolerated in normal tissue. A primary aim for radiation oncology is to identify radiosensitive (RS) individuals prior to treatment. Such predictive ability should result in an improvement in tumor control rates and/or a reduction in the incidence of RT side effects. Recent evidence suggests a link between RS and telomere length. A positive correlation between cellular RS and telomere length in a cohort of breast cancer patients has been reported. Furthermore,individuals with cancer-prone recessive RS syndromes, such as ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome(NBS), have shortened telomeres. To determine whether the association between telomere length and RS could be used as a predictive assay to prospectively identify RS cancer patients, we utilized a bank of lymphoblastoid cell lines (LCLs) derived from 33 RS patients, along with 18 LCL samples from RT patients who did not have severe reactions, to assess the link between RS and telomere length. We found a subset of RS patient LCLs had abnormally long telomere lengths, so these data suggest that RS could potentially be predicted for a subset of RS patients based on telomere length in LCLs, and contribute to therapy individualization.},
}
@article {pmid18355038,
year = {2008},
author = {Croy, JE and Fast, JL and Grimm, NE and Wuttke, DS},
title = {Deciphering the mechanism of thermodynamic accommodation of telomeric oligonucleotide sequences by the Schizosaccharomyces pombe protection of telomeres 1 (Pot1pN) protein.},
journal = {Biochemistry},
volume = {47},
number = {15},
pages = {4345-4358},
pmid = {18355038},
issn = {0006-2960},
support = {GM-071257/GM/NIGMS NIH HHS/United States ; R01 GM059414/GM/NIGMS NIH HHS/United States ; GM-059414/GM/NIGMS NIH HHS/United States ; T32 GM008732-08/GM/NIGMS NIH HHS/United States ; T32 GM008732/GM/NIGMS NIH HHS/United States ; F32 GM071257/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Carbohydrates/chemistry ; DNA, Single-Stranded/*chemistry ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Nucleic Acid Conformation ; Oligonucleotides/chemistry ; Protein Binding ; Protein Structure, Tertiary ; Protons ; Schizosaccharomyces pombe Proteins/*chemistry ; Shelterin Complex ; Telomere/*chemistry ; Telomere-Binding Proteins/*chemistry ; *Thermodynamics ; },
abstract = {Linear chromosomes terminate in specialized nucleoprotein structures called telomeres, which are required for genomic stability and cellular proliferation. Telomeres end in an unusual 3' single-strand overhang that requires a special capping mechanism to prevent inappropriate recognition by the DNA damage machinery. In Schizosaccharomyces pombe, this protective function is mediated by the Pot1 protein, which binds specifically and with high affinity to telomeric ssDNA. We have characterized the thermodynamics and accommodation of both cognate and noncognate telomeric single-stranded DNA (ssDNA) sequences by Pot1pN, an autonomous ssDNA-binding domain (residues 1-187) found in full-length S. pombe Pot1. Direct calorimetric measurements of cognate telomeric ssDNA binding to Pot1pN show favorable enthalpy, unfavorable entropy, and a negative heat-capacity change. Thermodynamic analysis of the binding of noncognate telomeric ssDNA to Pot1pN resulted in unexpected changes in free energy, enthalpy, and entropy. Chemical-shift perturbation and structural analysis of these bound noncognate sequences show that these thermodynamic changes result from the structural rearrangement of both Pot1pN and the bound oligonucleotide. These data suggest that the ssDNA-binding interface is highly dynamic and, in addition to the conformation observed in the crystal structure of the Pot1pN/d(GGTTAC) complex, capable of adopting alternative thermodynamically equivalent conformations.},
}
@article {pmid18348304,
year = {2008},
author = {Gertler, R and Doll, D and Maak, M and Feith, M and Rosenberg, R},
title = {Telomere length and telomerase subunits as diagnostic and prognostic biomarkers in Barrett carcinoma.},
journal = {Cancer},
volume = {112},
number = {10},
pages = {2173-2180},
doi = {10.1002/cncr.23419},
pmid = {18348304},
issn = {0008-543X},
mesh = {Adenocarcinoma/*diagnosis/genetics/metabolism ; Adult ; Aged ; Aged, 80 and over ; Barrett Esophagus/*diagnosis/genetics/metabolism ; Biomarkers, Tumor/genetics/*metabolism ; Blotting, Southern ; Case-Control Studies ; Female ; Follow-Up Studies ; Humans ; Intestinal Mucosa/metabolism/pathology ; Male ; Middle Aged ; Prognosis ; RNA/*genetics ; RNA, Messenger/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*genetics/metabolism ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Maintenance of telomeres has been identified as an essential regulator of proliferative capacity and genomic integrity in malignant tumors. The authors evaluated telomere length and telomerase subunits, hTR and hTERT, as prognostic markers in patients with Barrett carcinoma.<br><br>METHODS: Telomere length was measured by Southern blot analysis and hTR expression and hTERT expression by real-time polymerase chain reaction in both cancer tissue and adjacent noncancerous Barrett mucosa in resection specimens from 46 patients with Barrett carcinoma (International Union Against Cancer [UICC] stages I-III). The median follow-up time of the surviving patients was 79 months.<br><br>RESULTS: Cancer tissue expressed more hTERT-mRNA than noncancerous mucosa (P < .05). Telomere lengths in cancer tissue and in noncancerous mucosa increased with higher pT category (P = .08 and P = .05, respectively). Twenty-one patients who died of tumor recurrence showed significantly longer telomeres in cancer tissue compared with 25 patients without tumor-related deaths (P < .05). Telomere length in both cancer tissue and in noncancerous mucosa and the telomere-length ratio cancer:noncancerous tissue were correlated with overall survival. In multivariate analysis, the telomere-length ratio proved to be an independent prognostic parameter (P < .02; relative risk of death 3.4; confidence interval, 1.3-8.9). Ten patients with telomere-length ratios >1.17 had a significantly poorer overall survival compared with 36 patients with telomere-length ratios <or=1.17 with 5-year survival rates of 0% and 60%, respectively (P < .02).<br><br>CONCLUSIONS: Telomere length and telomerase subunits were identified as diagnostic and prognostic biomarkers for Barrett carcinoma. Genetic alterations found in adjacent noncancerous mucosa suggested a "field effect" in Barrett carcinoma.},
}
@article {pmid18347373,
year = {2008},
author = {Brouilette, SW and Whittaker, A and Stevens, SE and van der Harst, P and Goodall, AH and Samani, NJ},
title = {Telomere length is shorter in healthy offspring of subjects with coronary artery disease: support for the telomere hypothesis.},
journal = {Heart (British Cardiac Society)},
volume = {94},
number = {4},
pages = {422-425},
doi = {10.1136/hrt.2007.139675},
pmid = {18347373},
issn = {1468-201X},
support = {//British Heart Foundation/United Kingdom ; },
mesh = {Adult ; Case-Control Studies ; Coronary Artery Disease/*genetics ; Female ; Genetic Predisposition to Disease ; Humans ; Male ; Polymorphism, Restriction Fragment Length ; Telomere/genetics/*ultrastructure ; },
abstract = {BACKGROUND: Telomeres are shorter in subjects with coronary artery disease (CAD) and may indicate premature biological ageing. However, whether shorter telomeres are a primary abnormality or secondary to the disease is unclear.<br><br>OBJECTIVE: To investigate whether shorter telomeres are a primary abnormality or secondary to CAD, telomere lengths in healthy young adults with contrasting familial risk of CAD were compared.<br><br>DESIGN: Case-control study.<br><br>METHODS: Mean telomere restriction fragment (TRF) length in DNA from circulating leucocytes was determined by Southern blotting in 45 healthy offspring of subjects with premature CAD (case offspring) and 59 offspring from families without such a history (control offspring). Correlation in mean TRF length was also assessed in 67 offspring-parent pairs.<br><br>RESULTS: On average, a decrease of 27.5 (10.7) bp in mean TRF per year of age was found. The unadjusted mean TRF length was 6.34 kb (95% CI 6.13 to 6.55) for case offspring and 6.75 kb (95% CI 6.57 to 6.94) for offspring of controls (p = 0.004). The adjusted difference in mean TRF between case and control offspring was 472 bp (95% CI 253 to 691, p<0.001), equivalent to about 17 years of age-related attrition in telomere length. Furthermore, there was a significant positive correlation in mean TRF length between offspring and their parents (r = 0.37, p = 0.002).<br><br>CONCLUSION: These findings suggest that inheritance of shorter telomeres is associated with increased familial risk of CAD. They support the hypothesis that telomere length is a primary abnormality involved in the pathogenesis of CAD.},
}
@article {pmid18347021,
year = {2008},
author = {Kim, MK and Kang, MR and Nam, HW and Bae, YS and Kim, YS and Chung, IK},
title = {Regulation of telomeric repeat binding factor 1 binding to telomeres by casein kinase 2-mediated phosphorylation.},
journal = {The Journal of biological chemistry},
volume = {283},
number = {20},
pages = {14144-14152},
doi = {10.1074/jbc.M710065200},
pmid = {18347021},
issn = {0021-9258},
mesh = {Casein Kinase II/*metabolism ; Cell Line, Tumor ; Enzyme Inhibitors/pharmacology ; Glutathione Transferase/metabolism ; Homeostasis ; Humans ; Models, Biological ; Phosphorylation ; Protein Binding ; Spectrometry, Mass, Electrospray Ionization ; Telomere/ultrastructure ; Telomeric Repeat Binding Protein 1/*metabolism ; Threonine/chemistry ; Two-Hybrid System Techniques ; Ubiquitin/chemistry ; },
abstract = {Telomere maintenance is essential for continued cell proliferation and chromosome stability. Telomeres are maintained by telomerase and a collection of associated proteins. The telomeric protein telomeric repeat binding factor 1 (TRF1) negatively regulates telomere length by inhibiting access of telomerase at telomere termini. Here we report that TRF1 interacts with the beta subunit of casein kinase 2 (CK2) and serves as a substrate for CK2. CK2-mediated phosphorylation is required for the efficient telomere binding of TRF1 in vitro and in vivo. Inhibition of CK2 by the CK2 inhibitor 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole decreased the ability of TRF1 to bind telomeric DNA. The resulting telomere-unbound form of TRF1 was then ubiquitinated and degraded by the proteasome. Partial knockdown of CK2 by small interfering RNA resulted in removal of TRF1 from telomeres and subsequent degradation of TRF1. Mapping of the CK2 target site identified threonine 122 as a substrate in TRF1. A threonine to alanine change at this position led to a diminished DNA binding due to reduced dimerization of TRF1. In addition, phosphorylation of threonine 122 seemed critical for TRF1-mediated telomere length control. Our findings suggest that CK2-mediated phosphorylation of TRF1 plays an important role in modulating telomere length homeostasis by determining the levels of TRF1 at telomeres.},
}
@article {pmid18339310,
year = {2008},
author = {Zhao, YM and Li, JY and Lan, JP and Lai, XY and Luo, Y and Sun, J and Yu, J and Zhu, YY and Zeng, FF and Zhou, Q and Huang, H},
title = {Cell cycle dependent telomere regulation by telomerase in human bone marrow mesenchymal stem cells.},
journal = {Biochemical and biophysical research communications},
volume = {369},
number = {4},
pages = {1114-1119},
doi = {10.1016/j.bbrc.2008.03.011},
pmid = {18339310},
issn = {1090-2104},
mesh = {Bone Marrow Cells/cytology/*enzymology ; *Cell Cycle ; Cell Differentiation ; Cells, Cultured ; Humans ; Mesenchymal Stem Cells/cytology/*enzymology ; Phenotype ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Human bone marrow mesenchymal stem cells (hMSCs) are a promising source for clinical stem cell transplantation. However, telomere regulation mechanisms, as one of the possible major mechanisms by which hMSCs sustain their stem cell characteristics, remain unknown. We isolated hMSCs by plastic adhesion and characterized these cells by morphology, immune phenotype and differentiation capacity. Telomerase was found negative in hMSCs, but slightly up-regulated in hMSC-derived adipocytes by the Telomeric Repeat Amplification Protocol (TRAP) assay. Moreover, hMSCs lack the alternative lengthening of telomeres (ALT) mechanism, because the hallmarks of ALT, such as very long and heterogeneous telomeres, extra-chromosome telomere repeat DNA (ECTR), and ALT-associated promyelocytic leukemia bodies (APBs), were not evident. However, when hMSCs were arrested in S phase with a combination of serum deprivation and aphidicolin, previously undetectable telomerase activity became predominantly positive. Meanwhile, the expression level of hTERT protein and mRNA increased, paralleled with the appearance of a large cohort of synchronized hMSCs at S phase. These findings provide a profile of telomere regulation by cell cycle dependent expression of telomerase in hMSCs and may lead to a better understanding of the stem cell nature of these cells.},
}
@article {pmid18335232,
year = {2008},
author = {Bhattacharyya, MK and Matthews, KM and Lustig, AJ},
title = {Mre11 nuclease and C-terminal tail-mediated DDR functions are required for initiating yeast telomere healing.},
journal = {Chromosoma},
volume = {117},
number = {4},
pages = {357-366},
pmid = {18335232},
issn = {0009-5915},
support = {R01 GM069943/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Repair/genetics/*physiology ; Endodeoxyribonucleases/*metabolism ; Exodeoxyribonucleases/*metabolism ; Mutation/genetics ; Plasmids/genetics ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomere/genetics/*physiology ; Two-Hybrid System Techniques ; Yeasts ; },
abstract = {Mre11 is a central factor in creating an optimal substrate for telomerase loading and elongation. We have used a G2/M synchronized telomere-healing assay as a tool to separate different functions of Mre11 that are not apparent in null alleles. An analysis of healing efficiencies of several mre11 alleles revealed that both nuclease and C-terminal mutations led to a loss of healing. Interestingly, trans-complementation of the 49 amino acid C-terminal deletion (DeltaC49) and the D16A mutant, deficient in nuclease activity and partially defective in MRX complex formation, restores healing. DeltaC49 provokes Rad53 phosphorylation after treatment with the radiomimetic agent MMS exclusively through the Tel1 pathway, suggesting that a Tel1-mediated function is initiated through the C-terminal tail.},
}
@article {pmid18334557,
year = {2008},
author = {Ahmed, S and Passos, JF and Birket, MJ and Beckmann, T and Brings, S and Peters, H and Birch-Machin, MA and von Zglinicki, T and Saretzki, G},
title = {Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress.},
journal = {Journal of cell science},
volume = {121},
number = {Pt 7},
pages = {1046-1053},
doi = {10.1242/jcs.019372},
pmid = {18334557},
issn = {0021-9533},
support = {//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Cells, Cultured ; DNA, Mitochondrial/metabolism ; Fibroblasts/cytology/drug effects/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Mitochondria/metabolism/*physiology ; Oxidative Stress/*physiology ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomerase is a ribonucleoprotein that counteracts telomere shortening and can immortalise human cells. There is also evidence for a telomere-independent survival function of telomerase. However, its mechanism is not understood. We show here that TERT, the catalytic subunit of human telomerase, protects human fibroblasts against oxidative stress. While TERT maintains telomere length under standard conditions, telomeres under increased stress shorten as fast as in cells without active telomerase. This is because TERT is reversibly excluded from the nucleus under stress in a dose- and time-dependent manner. Extranuclear telomerase colocalises with mitochondria. In TERT-overexpressing cells, mtDNA is protected, mitochondrial membrane potential is increased and mitochondrial superoxide production and cell peroxide levels are decreased, all indicating improved mitochondrial function and diminished retrograde response. We propose protection of mitochondria under mild stress as a novel function of TERT.},
}
@article {pmid18331649,
year = {2008},
author = {Daniel, A and St Heaps, L and Sylvester, D and Diaz, S and Peters, G},
title = {Two mosaic terminal inverted duplications arising post-zygotically: Evidence for possible formation of neo-telomeres.},
journal = {Cell &amp; chromosome},
volume = {7},
number = {},
pages = {1},
pmid = {18331649},
issn = {1475-9268},
abstract = {OBJECTIVE: To elucidate the structure of terminal inverted duplications and to investigate potential mechanisms of formation in two cases where there was mosaicism with cells of apparently normal karyotype.<br><br>RESULTS: A karyotype [46,XY,inv dup(4)(p16.3p15.1)/46,XY] performed on blood lymphocytes from a patient referred for developmental delay (case 1) demonstrated a normal karyotype in 60% of cells with a terminal inverted duplication 4p in the remainder. In case 2, referred for multiple fetal anomalies on an ultrasound scan, 33% of amniocyte colonies were karyotypically normal, with a terminal inv dup 10p in the remainder [46,XX,inv dup(10)(p15.3p11)/46,XX]. Duplicated FISH signals for GATA3 and NEBL loci (in case 2), and for the Wolf-Hirschhorn locus (case 1) confirmed the inverted structure of both duplications. In the GTL banded normal cells from both cases, there was a cryptic deletion detected by FISH of one copy of the subtelomere 4p (case 1, probe GS-36P21), and subtelomere 10p (case 2, probe GS-306F7). At pter on both inv dup chromosomes there was no FISH signal present for the specific subtelomere probe. However, a positive pantelomeric probe signal was detected at 4 pter and 10 pter in both the cryptically-deleted chromosomes and the inv dup chromosomes in the respective cell lines of both cases.<br><br>CONCLUSION: An inv dup structure was evident for both cases on GTL bands, and confirmed by the various FISH studies. The presence of telomere (TTAGGG repeat) sequences at pter on the inv dup chromosomes (where more proximal chromosome specific subtelomeric probes were negative) was indicated by the pantelomeric probe signals in both cases. We conclude the most likely mechanism of origin in both cases was by sub-telomeric breakage in the zygote at pter, and delayed repair/rearrangement until after one or more subsequent mitotic divisions. In these divisions, at least one breakage-fusion-bridge cycle occurred, to produce inverted duplications. It is proposed then that two differently "repaired" daughter cells proliferated in parallel. In one daughter cell line (with an overtly normal karyotype) there was deletion of the subtelomere and presumed repair through capping by a neo-telomere (i.e. "healing", as initially proposed by McClintock). This occurred in both cases presented. In the other daughter cell of each case, it is proposed that chromosome stabilization was achieved (after replication) by sister chromatid reunion to form a dicentric, which broke at a subsequent anaphase, to form an inverted duplication (with loss of the reciprocal product, and the other daughter cell line). One inv dup was repaired without an interstitial specific subtelomere (case 1) and one was repaired with a duplicated specific interstitial subtelomere (case 2). After repair TTAGGG repeats were detected by FISH at each respective new pter.},
}
@article {pmid18329362,
year = {2008},
author = {Raices, M and Verdun, RE and Compton, SA and Haggblom, CI and Griffith, JD and Dillin, A and Karlseder, J},
title = {C. elegans telomeres contain G-strand and C-strand overhangs that are bound by distinct proteins.},
journal = {Cell},
volume = {132},
number = {5},
pages = {745-757},
doi = {10.1016/j.cell.2007.12.039},
pmid = {18329362},
issn = {1097-4172},
support = {AG025837/AG/NIA NIH HHS/United States ; ES13773/ES/NIEHS NIH HHS/United States ; GM06525/GM/NIGMS NIH HHS/United States ; GM31819/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Animals, Genetically Modified ; Caenorhabditis elegans/*genetics/metabolism ; Cell Line ; DNA, Helminth/metabolism ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Embryo, Nonmammalian/metabolism ; Humans ; Structural Homology, Protein ; Telomere/chemistry/*metabolism/ultrastructure ; },
abstract = {Single-strand extensions of the G strand of telomeres are known to be critical for chromosome-end protection and length regulation. Here, we report that in C. elegans, chromosome termini possess 3' G-strand overhangs as well as 5' C-strand overhangs. C tails are as abundant as G tails and are generated by a well-regulated process. These two classes of overhangs are bound by two single-stranded DNA binding proteins, CeOB1 and CeOB2, which exhibit specificity for G-rich or C-rich telomeric DNA. Strains of worms deleted for CeOB1 have elongated telomeres as well as extended G tails, whereas CeOB2 deficiency leads to telomere-length heterogeneity. Both CeOB1 and CeOB2 contain OB (oligo-saccharide/oligo-nucleotide binding) folds, which exhibit structural similarity to the second and first OB folds of the mammalian telomere binding protein hPOT1, respectively. Our results suggest that C. elegans telomere homeostasis relies on a novel mechanism that involves 5' and 3' single-stranded termini.},
}
@article {pmid18326318,
year = {2008},
author = {Yamaguchi, H},
title = {[Abnormality of telomere maintenance linked to bone marrow failures].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {66},
number = {3},
pages = {483-489},
pmid = {18326318},
issn = {0047-1852},
mesh = {Animals ; Bone Marrow Diseases/*etiology ; Cell Cycle Proteins/genetics ; Cell Proliferation ; Hematopoietic Stem Cells/cytology ; Humans ; Mutation ; Nuclear Proteins/genetics ; Proteins/genetics ; RNA/genetics ; Telomerase/genetics ; Telomere/*genetics/*pathology ; },
abstract = {Telomeres are structural elements that seal and protect the ends of linear chromosomes from illegitimate recombination, end-to-end fusion, or being recognized as damaged DNA. These repeats are gradually lost with cellular replication and aging. Telomere attrition eventually leads to critically short telomeres, inducing cellular proliferative senescence and/or apoptosis possibly due to genomic instability. It is thought that telomeres are shortened as a result of pathogenic mutations in telomerase gene components which are DKC1, telomerase RNA component (TERC), and telomerase reverse transcriptase (TERT), and in SBDS gene that lead to an impairment in the proliferative capacity of hematopoietic stem cells in patients with inherited and acquired bone marrow failures.},
}
@article {pmid18319724,
year = {2008},
author = {Shachar, R and Ungar, L and Kupiec, M and Ruppin, E and Sharan, R},
title = {A systems-level approach to mapping the telomere length maintenance gene circuitry.},
journal = {Molecular systems biology},
volume = {4},
number = {},
pages = {172},
pmid = {18319724},
issn = {1744-4292},
mesh = {Gene Expression Regulation, Fungal ; Genome ; Genome, Fungal ; *Models, Genetic ; Models, Statistical ; Mutation ; Phenotype ; Probability ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/physiology ; Systems Biology ; Telomere/*ultrastructure ; Telomere-Binding Proteins/metabolism ; },
abstract = {The ends of eukaryotic chromosomes are protected by telomeres, nucleoprotein structures that are essential for chromosomal stability and integrity. Understanding how telomere length is controlled has significant medical implications, especially in the fields of aging and cancer. Two recent systematic genome-wide surveys measuring the telomere length of deleted mutants in the yeast Saccharomyces cerevisiae have identified hundreds of telomere length maintenance (TLM) genes, which span a large array of functional categories and different localizations within the cell. This study presents a novel general method that integrates large-scale screening mutant data with protein-protein interaction information to rigorously chart the cellular subnetwork underlying the function investigated. Applying this method to the yeast telomere length control data, we identify pathways that connect the TLM proteins to the telomere-processing machinery, and predict new TLM genes and their effect on telomere length. We experimentally validate some of these predictions, demonstrating that our method is remarkably accurate. Our results both uncover the complex cellular network underlying TLM and validate a new method for inferring such networks.},
}
@article {pmid18313869,
year = {2008},
author = {Taetz, S and Mürdter, TE and Zapp, J and Boettcher, S and Baldes, C and Kleideiter, E and Piotrowska, K and Schaefer, UF and Klotz, U and Lehr, CM},
title = {Decomposition of the telomere-targeting agent BRACO19 in physiological media results in products with decreased inhibitory potential.},
journal = {International journal of pharmaceutics},
volume = {357},
number = {1-2},
pages = {6-14},
doi = {10.1016/j.ijpharm.2008.01.026},
pmid = {18313869},
issn = {0378-5173},
mesh = {Acridines/*chemistry/*pharmacology ; Buffers ; Cells, Cultured ; Chromatography, High Pressure Liquid ; Drug Stability ; Gene Amplification ; Half-Life ; Hydrogen-Ion Concentration ; Hydrolysis ; Magnetic Resonance Spectroscopy ; Mass Spectrometry ; Solubility ; Solvents ; Spectrophotometry, Ultraviolet ; Telomere/*drug effects ; Temperature ; },
abstract = {The stability of the acridine-based telomere-targeting agent BRACO19, a G-quadruplex stabilizing substance, was tested at different pH, temperature and in different dissolution media. Analysis was performed by HPLC. Decomposition products were examined by LC/MS and NMR. The TRAP assay was used to determine the inhibitory potential of the decomposition products on telomerase activity. The results show that the stability of BRACO19 strongly depends on pH and temperature. Decomposition was fastest at physiological pH and temperature while the type of dissolution medium had no major influence on stability. The most probable mechanism for this decomposition seems to be a hydrolysis of the amide bonds in position 3 and 6 of the acridine ring and/or a deamination of the phenyl ring. The decomposition products showed a reduced inhibitory potential compared to the parent compound BRACO19. The results demonstrate that the preparation of dosage forms and their storage conditions will have an important influence on the stability--and hence biological efficacy--of BRACO19 and related substances.},
}
@article {pmid18311780,
year = {2008},
author = {Jeyapalan, JN and Mendez-Bermudez, A and Zaffaroni, N and Dubrova, YE and Royle, NJ},
title = {Evidence for alternative lengthening of telomeres in liposarcomas in the absence of ALT-associated PML bodies.},
journal = {International journal of cancer},
volume = {122},
number = {11},
pages = {2414-2421},
doi = {10.1002/ijc.23412},
pmid = {18311780},
issn = {1097-0215},
support = {G0500336/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Cell Line, Tumor ; Enzyme Activation ; Humans ; Liposarcoma/enzymology/genetics/*ultrastructure ; *Microsatellite Instability ; Minisatellite Repeats ; *Mutation ; *Neoplasm Proteins ; *Nuclear Proteins ; Polymerase Chain Reaction ; Promyelocytic Leukemia Protein ; Recombinant Proteins ; Recombination, Genetic ; Sequence Analysis, DNA ; Telomerase/genetics/*metabolism ; Telomere/*genetics/*ultrastructure ; Telomere-Binding Proteins/metabolism ; *Transcription Factors ; *Tumor Suppressor Proteins ; },
abstract = {Immortalized and cancer cells maintain their telomeres by activation of a telomere maintenance mechanism (TMM). In approximately 85% of cancers telomerase is activated (TA) but in some tumours, in particular sarcomas, an alternative lengthening of telomeres (ALT) pathway is used. Liposarcomas are the most common soft-tissue sarcoma in adults and they activate ALT or telomerase with equal frequency, however no TMM has been identified in approximately 50% of liposarcomas. In our study, we have shown that instability at the minisatellite MS32, usually associated with ALT activation, aids the identification of liposarcomas that have recombination-like activity at telomeres in absence of ALT associated PML-bodies (APBs). Furthermore, using single molecule telomere analysis, we have detected complex telomere mutations directly in ALT positive liposarcomas and interestingly in some liposarcomas with an unknown TMM but high MS32 instability. We have shown by sequence analysis that some of these complex telomere mutations must arise by an inter-molecular recombination-like process rather than by deletion caused by t-loop excision or by unequal telomere-sister-chromatid-exchange (T-SCE), which is known to be elevated in ALT cell lines. Preliminary evidence also suggests that inter-molecular recombination events may be processed differently in liposarcomas with APBs compared to those without. In conclusion, we have shown for the first time, that some telomerase negative liposarcomas without APBs have other features associated with ALT, indicating that the incidence of ALT in these tumours has previously been under-estimated. This has major implications for the use of cancer treatments targeted at TMMs.},
}
@article {pmid18311151,
year = {2008},
author = {Benetti, R and Gonzalo, S and Jaco, I and Muñoz, P and Gonzalez, S and Schoeftner, S and Murchison, E and Andl, T and Chen, T and Klatt, P and Li, E and Serrano, M and Millar, S and Hannon, G and Blasco, MA},
title = {A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases.},
journal = {Nature structural &amp; molecular biology},
volume = {15},
number = {3},
pages = {268-279},
pmid = {18311151},
issn = {1545-9985},
support = {P01 CA013106/CA/NCI NIH HHS/United States ; P01 CA013106-36/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/metabolism ; DEAD-box RNA Helicases/metabolism ; DNA (Cytosine-5-)-Methyltransferase 1 ; DNA (Cytosine-5-)-Methyltransferases/*metabolism ; *DNA Methylation ; Endoribonucleases/metabolism ; Histones/metabolism ; Mice ; MicroRNAs/*metabolism ; Models, Biological ; *Recombination, Genetic ; Retinoblastoma-Like Protein p130/*metabolism ; Ribonuclease III ; Telomerase/metabolism ; Telomere/*genetics ; DNA Methyltransferase 3B ; },
abstract = {Dicer initiates RNA interference by generating small RNAs involved in various silencing pathways. Dicer participates in centromeric silencing, but its role in the epigenetic regulation of other chromatin domains has not been explored. Here we show that Dicer1 deficiency in Mus musculus leads to decreased DNA methylation, concomitant with increased telomere recombination and telomere elongation. These DNA-methylation defects correlate with decreased expression of Dnmt1, Dnmt3a and Dnmt3b DNA methyltransferases (Dnmts), and methylation levels can be recovered by their overexpression. We identify the retinoblastoma-like 2 protein (Rbl2) as responsible for decreased Dnmt expression in Dicer1-null cells, suggesting the existence of Dicer-dependent small RNAs that target Rbl2. We identify the miR-290 cluster as being downregulated in Dicer1-deficient cells and show that it silences Rbl2, thereby controlling Dnmt expression. These results identify a pathway by which miR-290 directly regulates Rbl2-dependent Dnmt expression, indirectly affecting telomere-length homeostasis.},
}
@article {pmid18296269,
year = {2008},
author = {Wnuk, M and Bugno, M and Slota, E},
title = {Application of primed in situ DNA synthesis (PRINS) with telomere human commercial kit in molecular cytogenetics of Equus caballus and Sus scrofa scrofa.},
journal = {Folia histochemica et cytobiologica},
volume = {46},
number = {1},
pages = {85-88},
doi = {10.2478/v10042-008-0012-9},
pmid = {18296269},
issn = {1897-5631},
mesh = {Animals ; Chromosomes, Mammalian/metabolism ; Cytogenetic Analysis/*methods ; Horses/*genetics ; Humans ; Metaphase ; Primed In Situ Labeling/*methods ; *Reagent Kits, Diagnostic ; Sus scrofa/*genetics ; Telomere/*metabolism ; },
abstract = {Recently, molecular techniques have become an indispensable tools for cytogenetic research. Especially, development of in situ techniques made possible detection at the chromosomal level, genes as well as repetitive sequences like telomeres or the DNA component of telomeres. One of these methods is primed in situ DNA synthesis (PRINS) using an oligonucleotide primer complementary to the specific DNA sequence. In this report we described application of PRINS technique with telomere human commercial kit to telomere sequences identification. This commercial kit may be use to visualization of interstitial telomeric signal in pig genome. PRINS is attractive complement to FISH for detection of DNA repetitive sequences and displays lower level of non-specific hybridization than conventional FISH.},
}
@article {pmid18295822,
year = {2008},
author = {Shin, YA and Lee, JH and Song, W and Jun, TW},
title = {Exercise training improves the antioxidant enzyme activity with no changes of telomere length.},
journal = {Mechanisms of ageing and development},
volume = {129},
number = {5},
pages = {254-260},
doi = {10.1016/j.mad.2008.01.001},
pmid = {18295822},
issn = {0047-6374},
mesh = {Anthropometry ; Antioxidants/*metabolism ; Body Mass Index ; Erythrocytes/enzymology ; Exercise/*physiology ; Female ; Glutathione Peroxidase/*blood ; Humans ; Malondialdehyde/blood ; Middle Aged ; Obesity ; Oxidative Stress ; Physical Education and Training ; Superoxide Dismutase/*blood ; *Telomere ; Time Factors ; },
abstract = {The purpose of this study was to determine the changes of both oxidant and antioxidant levels with exercise training in obese middle-aged women. The association between telomere length and oxidative stress with exercise was also examined. Sixteen obese middle-aged women participated in this study. The subjects were randomly divided into exercise group (EX) and control group (CON). EX performed aerobic exercise training for 6 months. DNA was extracted from leukocytes in peripheral blood and their telomere lengths were measured by real time PCR analysis. Long-term exercise training decreased body weight and BMI, and increased VO2 max. Resting levels of erythrocyte glutathione peroxidase activity were higher in EX compared to CON. Superoxide dismutase (SOD) activities were higher after the acute exercise test at mid-intensity in post-exercise training than in the pre-exercise training conditions. The telomere length did not change significantly after the acute exercise test in the pre-exercise training condition in spite of the increased level of malondialdehyde (MDA) as a marker of oxidative stress. In conclusion, antioxidant enzyme activities were increased following long-term exercise training; however, the lengths of telomere in leukocytes were not influenced by both mid-intensity and high intensity of exercise stress.},
}
@article {pmid18294777,
year = {2008},
author = {Stindl, R},
title = {Defining the steps that lead to cancer: replicative telomere erosion, aneuploidy and an epigenetic maturation arrest of tissue stem cells.},
journal = {Medical hypotheses},
volume = {71},
number = {1},
pages = {126-140},
doi = {10.1016/j.mehy.2008.01.010},
pmid = {18294777},
issn = {0306-9877},
mesh = {Adult Stem Cells/pathology ; Aging/genetics/pathology ; Aneuploidy ; Cell Differentiation ; Drug Resistance, Neoplasm/genetics ; Epigenesis, Genetic ; Female ; Genes, Tumor Suppressor ; Humans ; Male ; Models, Biological ; Models, Genetic ; Mutation ; Neoplasms/*etiology/*genetics/pathology ; Neoplastic Stem Cells/pathology ; Oncogenes ; Telomere/genetics ; },
abstract = {Recently, an influential sequencing study found that more than 1700 genes had non-silent mutations in either a breast or colorectal cancer, out of just 11 breast and 11 colorectal tumor samples. This is not surprising given the fact that genomic instability is the hallmark of cancer cells. The plethora of genomic alterations found in every carcinoma does not obey the 'law of genotype-phenotype correlation', since the same histological subtype of cancer harbors different gene mutations and chromosomal aberrations in every patient. In an attempt to make sense out of the observed genetic and chromosomal chaos in cancer, I propose a cascade model. According to this model, tissue regeneration depends on the proliferation and serial activation of stem cells. Replicative telomere erosion limits the proliferative life span of adult stem cells and results in the Hayflick limit (M1). However, local tissue exhaustion or old age might promote the activation of M1-deficient tissue stem cells. Extended proliferation of these cells leads to telomere-driven chromosomal instability and aneuploidy (abnormal balance of chromosomes and/or chromosome material). Several of the aforementioned steps have been already described in the literature. However, in contrast to common theories, it is proposed here that the genomic damage blocks the epigenetic differentiation switch. As a result of aneuploidy, differentiation-specific genes cannot be activated by modification of methylation patterns. Consequently, the phenotype of cancer tissue is largely determined by the epigenetic maturation arrest of tissue stem cells, which in addition enables a fraction of cancer cells to proliferate, invade and metastasize, as normal adult stem cells do. The new model combines genetic and epigenetic alterations of cancer cells in one causative cascade and offers an explanation for why identical histologic cancer types harbor a confusing variety of chromosomal and gene aberrations. The Viennese Cascade, as presented here, may end the debate on if and how 'tumor-unspecific' aneuploidy leads to cancer.},
}
@article {pmid18283121,
year = {2008},
author = {Flores, I and Canela, A and Vera, E and Tejera, A and Cotsarelis, G and Blasco, MA},
title = {The longest telomeres: a general signature of adult stem cell compartments.},
journal = {Genes &amp; development},
volume = {22},
number = {5},
pages = {654-667},
pmid = {18283121},
issn = {0890-9369},
mesh = {Adult Stem Cells/*metabolism/*ultrastructure ; Animals ; Brain/cytology ; Cellular Senescence/*genetics ; Cornea/cytology ; Hair Follicle/cytology ; Intestine, Small/cytology ; Male ; Mice ; Mice, Inbred C57BL ; Skin/cytology ; Telomere/*metabolism/*ultrastructure ; Testis/cytology ; },
abstract = {Identification of adult stem cells and their location (niches) is of great relevance for regenerative medicine. However, stem cell niches are still poorly defined in most adult tissues. Here, we show that the longest telomeres are a general feature of adult stem cell compartments. Using confocal telomere quantitative fluorescence in situ hybridization (telomapping), we find gradients of telomere length within tissues, with the longest telomeres mapping to the known stem cell compartments. In mouse hair follicles, we show that cells with the longest telomeres map to the known stem cell compartments, colocalize with stem cell markers, and behave as stem cells upon treatment with mitogenic stimuli. Using K15-EGFP reporter mice, which mark hair follicle stem cells, we show that GFP-positive cells have the longest telomeres. The stem cell compartments in small intestine, testis, cornea, and brain of the mouse are also enriched in cells with the longest telomeres. This constitutes the description of a novel general property of adult stem cell compartments. Finally, we make the novel finding that telomeres shorten with age in different mouse stem cell compartments, which parallels a decline in stem cell functionality, suggesting that telomere loss may contribute to stem cell dysfunction with age.},
}
@article {pmid18283039,
year = {2008},
author = {Perera, SA and Maser, RS and Xia, H and McNamara, K and Protopopov, A and Chen, L and Hezel, AF and Kim, CF and Bronson, RT and Castrillon, DH and Chin, L and Bardeesy, N and Depinho, RA and Wong, KK},
title = {Telomere dysfunction promotes genome instability and metastatic potential in a K-ras p53 mouse model of lung cancer.},
journal = {Carcinogenesis},
volume = {29},
number = {4},
pages = {747-753},
doi = {10.1093/carcin/bgn050},
pmid = {18283039},
issn = {1460-2180},
support = {K26 RR024196/RR/NCRR NIH HHS/United States ; K26 RR024196-02/RR/NCRR NIH HHS/United States ; AG027757/AG/NIA NIH HHS/United States ; CA122794/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Disease Models, Animal ; *Genes, ras ; *Genomic Instability ; Lung Neoplasms/*genetics/*pathology ; Mice ; Mice, Transgenic ; Mutation ; Neoplasm Metastasis ; Telomere/*genetics ; Tumor Suppressor Protein p53/*genetics ; },
abstract = {Current mouse models of lung cancer recapitulate signature genetic lesions and some phenotypic features of human lung cancer. However, because mice have long telomeres, models to date do not recapitulate the aspects of lung carcinogenesis-telomere attrition and the genomic instability that ensues-believed to serve as key mechanisms driving lung tumor initiation and progression. To explore the contributions of telomere dysfunction to lung cancer progression, we combined a telomerase catalytic subunit (mTerc) mutation with the well-characterized K-rasG12D mouse lung cancer model. K-ras(G12D) mTerc(-/-) mice with telomere dysfunction but intact p53 exhibited increased lung epithelial apoptosis, delayed tumor formation and increased life span relative to K-ras(G12D) mTerc(+/-) mice with intact telomere function. This demonstrates that by itself, telomere dysfunction acts in a tumor-suppressive mechanism. Introduction of a heterozygous p53 mutation exerted a marked histopathological, biological and genomic impact. K-ras(G12D) mTerc(-/-) p53(+/-) mice developed aggressive tumors with more chromosomal instabilities and high metastatic potential, leading to decreased overall survival. Thus, we have generated a murine model that more faithfully recapitulates key aspects of the human disease. Furthermore, these findings clearly demonstrate (in an in vivo model system) the dual nature of telomere shortening as both a tumor-suppressive and tumor-promoting mechanism in lung cancer, dependent on p53 status.},
}
@article {pmid18282113,
year = {2008},
author = {Kimura, M and Cherkas, LF and Kato, BS and Demissie, S and Hjelmborg, JB and Brimacombe, M and Cupples, A and Hunkin, JL and Gardner, JP and Lu, X and Cao, X and Sastrasinh, M and Province, MA and Hunt, SC and Christensen, K and Levy, D and Spector, TD and Aviv, A},
title = {Offspring's leukocyte telomere length, paternal age, and telomere elongation in sperm.},
journal = {PLoS genetics},
volume = {4},
number = {2},
pages = {e37},
pmid = {18282113},
issn = {1553-7404},
support = {U01 HL67899/HL/NHLBI NIH HHS/United States ; U01 HL56564/HL/NHLBI NIH HHS/United States ; U01 HL67897/HL/NHLBI NIH HHS/United States ; U01 HL067893/HL/NHLBI NIH HHS/United States ; R01 AG020132/AG/NIA NIH HHS/United States ; U01 HL067901/HL/NHLBI NIH HHS/United States ; U01 HL067900/HL/NHLBI NIH HHS/United States ; U01 HL067898/HL/NHLBI NIH HHS/United States ; U01 HL67900/HL/NHLBI NIH HHS/United States ; U01 HL067894/HL/NHLBI NIH HHS/United States ; U01 HL67895/HL/NHLBI NIH HHS/United States ; U01 HL067895/HL/NHLBI NIH HHS/United States ; U01 HL067899/HL/NHLBI NIH HHS/United States ; U01 HL56567/HL/NHLBI NIH HHS/United States ; U01 HL067902/HL/NHLBI NIH HHS/United States ; R01-AG021593/AG/NIA NIH HHS/United States ; U01 HL56565/HL/NHLBI NIH HHS/United States ; U01 HL067897/HL/NHLBI NIH HHS/United States ; U01 HL056567/HL/NHLBI NIH HHS/United States ; U01 HL67896/HL/NHLBI NIH HHS/United States ; U01 HL067896/HL/NHLBI NIH HHS/United States ; U01 HL56566/HL/NHLBI NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; U01 HL56569/HL/NHLBI NIH HHS/United States ; 074951/WT_/Wellcome Trust/United Kingdom ; P01-AG0876/AG/NIA NIH HHS/United States ; N0HC25195/HC/NHLBI NIH HHS/United States ; U01 HL56568/HL/NHLBI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; U01 HL67898/HL/NHLBI NIH HHS/United States ; U01 HL56563/HL/NHLBI NIH HHS/United States ; U01 HL67902/HL/NHLBI NIH HHS/United States ; R01-AG020132/AG/NIA NIH HHS/United States ; U01 HL 67893/HL/NHLBI NIH HHS/United States ; U01 HL67894/HL/NHLBI NIH HHS/United States ; U01 HL67901/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/genetics/pathology ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Infant, Newborn ; Leukocytes/*ultrastructure ; Male ; Maternal Age ; Middle Aged ; *Paternal Age ; Pregnancy ; Regression Analysis ; Spermatozoa/*ultrastructure ; Telomere/*genetics/*ultrastructure ; },
abstract = {Leukocyte telomere length (LTL) is a complex genetic trait. It shortens with age and is associated with a host of aging-related disorders. Recent studies have observed that offspring of older fathers have longer LTLs. We explored the relation between paternal age and offspring's LTLs in 4 different cohorts. Moreover, we examined the potential cause of the paternal age on offspring's LTL by delineating telomere parameters in sperm donors. We measured LTL by Southern blots in Caucasian men and women (n=3365), aged 18-94 years, from the Offspring of the Framingham Heart Study (Framingham Offspring), the NHLBI Family Heart Study (NHLBI-Heart), the Longitudinal Study of Aging Danish Twins (Danish Twins), and the UK Adult Twin Registry (UK Twins). Using Southern blots, Q-FISH, and flow-FISH, we also measured telomere parameters in sperm from 46 young (<30 years) and older (>50 years) donors. Paternal age had an independent effect, expressed by a longer LTL in males of the Framingham Offspring and Danish Twins, males and females of the NHLBI-Heart, and females of UK Twins. For every additional year of paternal age, LTL in offspring increased at a magnitude ranging from half to more than twice of the annual attrition in LTL with age. Moreover, sperm telomere length analyses were compatible with the emergence in older men of a subset of sperm with elongated telomeres. Paternal age exerts a considerable effect on the offspring's LTL, a phenomenon which might relate to telomere elongation in sperm from older men. The implications of this effect deserve detailed study.},
}
@article {pmid18280685,
year = {2008},
author = {Rahman, R and Forsyth, NR and Cui, W},
title = {Telomeric 3'-overhang length is associated with the size of telomeres.},
journal = {Experimental gerontology},
volume = {43},
number = {4},
pages = {258-265},
doi = {10.1016/j.exger.2008.01.005},
pmid = {18280685},
issn = {0531-5565},
support = {//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Cell Division ; Cellular Senescence/genetics ; Fibroblasts/cytology/*metabolism ; Sheep ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres are specialized DNA/protein complexes that cap eukaryotic chromosome ends as T-loop structures and maintain genomic integrity. Vertebrate telomeric DNA consists of tandem double-strand repeats which terminate in a 3' single-strand G-rich overhang. The telomeric 3'-overhang is important for the formation of the T-loop. In mammalian mortal somatic cells, telomeres shorten with each successive division and contribute to the onset of replicative senescence. The exact molecular mechanism underlying replicative senescence remains unclear: whether telomere shortening is the only trigger or loss of telomeric 3'-overhang plays a causal role. To further address this issue, we investigated telomeric 3'-overhang and telomere changes during cell proliferation toward replicative senescence. We demonstrate here that telomeric 3'-overhang, similar to telomeres, exhibits progressive attrition with each cell division in primary sheep fibroblasts and that telomeric 3'-overhang size does not determine the rate of telomere shortening. Furthermore, the sizes of telomeric 3'-overhangs are associated with telomere lengths. Our results suggest that alteration of the 3'-overhang and the telomere during cellular proliferation are associated. Together they may contribute to maintain chromosomal stability and to regulate replicative senescence.},
}
@article {pmid18280483,
year = {2008},
author = {Richards, JB and Valdes, AM and Gardner, JP and Kato, BS and Siva, A and Kimura, M and Lu, X and Brown, MJ and Aviv, A and Spector, TD},
title = {Homocysteine levels and leukocyte telomere length.},
journal = {Atherosclerosis},
volume = {200},
number = {2},
pages = {271-277},
doi = {10.1016/j.atherosclerosis.2007.12.035},
pmid = {18280483},
issn = {1879-1484},
support = {AG020132/AG/NIA NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Cardiovascular Diseases/blood ; Cohort Studies ; Female ; Homocysteine/*blood ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Models, Biological ; Obesity/genetics ; Oxidative Stress ; Sex Factors ; Smoking ; Telomere/*ultrastructure ; },
abstract = {OBJECTIVE: Elevated plasma homocysteine is a risk factor for vascular diseases, possibly due to homocysteine-mediated increase in oxidative stress and inflammation. As leukocyte telomere length (LTL) registers the cumulative oxidative stress and inflammation, we examined the relationship between homocysteine and LTL.<br><br>METHODS: LTL was measured using the Southern blot method. The relationship between LTL and homocysteine levels was considered for confounding with the following covariates: age, sex, smoking, obesity, physical activity, menopause, hormone replacement therapy use and creatinine clearance.<br><br>RESULTS: 1,319 healthy subjects were recruited from a population-based cohort. LTL was negatively correlated with plasma homocysteine levels, after adjustment for smoking, obesity, physical activity, menopause, hormone replacement therapy use and creatinine clearance. The difference in multiply-adjusted LTL between the highest and lowest tertile of homocysteine levels was 111 base pairs (p=0.004), corresponding to 6.0 years of telomeric aging. This relationship was further accentuated by decreased concentrations of serum folate and increased levels of C-reactive protein.<br><br>CONCLUSIONS: Increased homocysteine levels are associated with shortened LTL, further supporting the tenet that LTL is an index of cardiovascular risk.},
}
@article {pmid18278785,
year = {2008},
author = {Forsyth, RG and De Boeck, G and Bekaert, S and De Meyer, T and Taminiau, AH and Uyttendaele, D and Roels, H and Praet, MM and Hogendoorn, PC},
title = {Telomere biology in giant cell tumour of bone.},
journal = {The Journal of pathology},
volume = {214},
number = {5},
pages = {555-563},
doi = {10.1002/path.2301},
pmid = {18278785},
issn = {0022-3417},
mesh = {Adolescent ; Adult ; Bone Neoplasms/*genetics/metabolism/pathology ; Female ; Giant Cell Tumors/*genetics/metabolism/pathology ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Microscopy, Confocal ; Middle Aged ; Neoplasm Proteins/metabolism ; Nuclear Proteins/metabolism ; Osteoclasts/metabolism/pathology ; Phosphoproteins/metabolism ; Promyelocytic Leukemia Protein ; RNA-Binding Proteins/metabolism ; Telomerase/metabolism ; Telomere/*genetics/ultrastructure ; Transcription Factors/metabolism ; Tumor Suppressor Proteins/metabolism ; Nucleolin ; },
abstract = {Giant cell tumour of bone (GCTB) is a benign bone tumour known for the unpredictable clinical behaviour of recurrences and, in rare instances, distant metastases. It consists of uniformly distributed osteoclastic giant cells in a background of mononuclear rounded and spindle-shaped cells. Cytogenetically, telomeric associations are the most common chromosomal aberrations, which, however, are normally almost exclusively found in high-grade malignancies. GCTB has often been regarded as a polyclonal tumour, but more recently a recurrent specific aberration was reported, which suggests a possible role for disturbed telomere maintenance. Here we further investigate telomere maintenance in GCTB using 19 samples from 19 patients. A combination of immunofluorescence and FISH was performed, applying antibodies directed against promyelocytic leukaemia body-related antigen and hTERT and using telomere peptide nucleic acid probes. The TRAP assay and telomere restriction fragment length analysis were performed for functional detection of telomerase activity and alternative telomere lengthening. Both osteoclastic giant cells and mononuclear cells showed positivity for hTERT and promyelocytic leukaemia body-related antigen. In most mononuclear cells, co-expression was present. The TRAP assay demonstrated heterogeneous telomerase activity, while telomere restriction fragment length analysis showed non-heterogeneous telomere lengths, indicating the absence of alternative telomere lengthening. Confocal microscopy showed stereometric co-localization of nucleolin with promyelocytic leukaemia body-related antigen in association with telomeres in the spindle-shaped cells. hTERT was more diffusely distributed throughout the nucleus. Our results show that GCTB demonstrates remarkable telomere maintenance of activated telomerase and inactivated alternative telomere lengthening in the presence of normal mean telomere restriction fragment lengths. These findings strongly suggest that these aggregates, while activating telomerase, are part of a structural telomere protective-capping mechanism rather than of a telomere-lengthening mechanism. Telomere maintenance could be considered an important key factor in the pathogenesis of GCTB.},
}
@article {pmid18276909,
year = {2008},
author = {Spyridopoulos, I and Erben, Y and Brummendorf, TH and Haendeler, J and Dietz, K and Seeger, F and Kissel, CK and Martin, H and Hoffmann, J and Assmus, B and Zeiher, AM and Dimmeler, S},
title = {Telomere gap between granulocytes and lymphocytes is a determinant for hematopoetic progenitor cell impairment in patients with previous myocardial infarction.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {28},
number = {5},
pages = {968-974},
doi = {10.1161/ATVBAHA.107.160846},
pmid = {18276909},
issn = {1524-4636},
mesh = {Adult ; Aged ; Atherosclerosis/pathology/physiopathology ; Biomarkers/blood ; Bone Marrow/pathology/physiopathology ; Case-Control Studies ; Coronary Artery Disease/pathology/physiopathology ; Female ; Granulocytes/*pathology/physiology ; Hematopoietic Stem Cells/*pathology/physiology ; Humans ; Lymphocytes/*pathology/physiology ; Male ; Middle Aged ; Myocardial Infarction/blood/*pathology/physiopathology ; Predictive Value of Tests ; Regression Analysis ; Telomere/*pathology/physiology ; },
abstract = {OBJECTIVE: We have previously demonstrated that ischemic cardiomyopathy is associated with selective impairment of progenitor cell function in the bone marrow and in the peripheral blood, which may contribute to an unfavorable left ventricular remodeling process.<br><br>METHODS AND RESULTS: With this study, we intended to identify the influence of telomere length on bone marrow functionality in 50 patients with coronary artery disease (CAD) and previous myocardial infarction. Mean telomere length (mTL) was measured simultaneously in peripheral blood leukocytes and mononuclear bone marrow cells (BMC), using the flow-FISH method. Telomere erosion already occurred at the bone marrow level, whereby age (39 bp/yr, P=0.025) and the number of affected vessels (434 bp/vessel, P=0.029) were the only independent predictors. Lymphocytes demonstrated significant TL shortening between BMCs and peripheral blood in CAD patients (-1011+/-897 bp) as opposed to an increase in a young control group (+235+/-459 bp, P<0.001). SDF- and VEGF-specific migration of BMCs correlated with mTL of lymphocytes (r=0.42, P<0.001) and was significantly reduced in CAD patients. Finally, the telomere length difference between granulocytes and lymphocytes was the most determinant for telomere-associated bone marrow impairment (P<0.001).<br><br>CONCLUSIONS: In patients with CAD, telomere shortening of BMCs is dependent on both age and the extent of CAD and correlates with bone marrow cell functionality.},
}
@article {pmid18273059,
year = {2008},
author = {Gallardo, F and Olivier, C and Dandjinou, AT and Wellinger, RJ and Chartrand, P},
title = {TLC1 RNA nucleo-cytoplasmic trafficking links telomerase biogenesis to its recruitment to telomeres.},
journal = {The EMBO journal},
volume = {27},
number = {5},
pages = {748-757},
pmid = {18273059},
issn = {1460-2075},
mesh = {In Situ Hybridization, Fluorescence ; Karyopherins/metabolism ; RNA Transport ; RNA, Fungal/*metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism ; Telomerase/*metabolism ; Telomere/metabolism ; Yeasts ; Exportin 1 Protein ; },
abstract = {The yeast telomerase holoenzyme, which adds telomeric repeats at the chromosome ends, is composed of the TLC1 RNA and the associated proteins Est1, Est2 and Est3. To study the biogenesis of telomerase in endogenous conditions, we performed fluorescent in situ hybridization on the native TLC1 RNA. We found that the telomerase RNA colocalizes with telomeres in G1- to S-phase cells. Strains lacking any one of the Est proteins accumulate TLC1 RNA in their cytoplasm, indicating that a critical stage of telomerase biogenesis could take place outside of the nucleus. We were able to demonstrate that endogenous TLC1 RNA shuttles between the nucleus and the cytoplasm, in association with the Crm1p exportin and the nuclear importins Mtr10p-Kap122p. Furthermore, nuclear retention of the TLC1 RNA is impaired in the absence of yKu70p, Tel1p or the MRX complex, which recruit telomerase to telomeres. Altogether, our results reveal that the nucleo-cytoplasmic trafficking of the TLC1 RNA is an important step in telomere homeostasis, and link telomerase biogenesis to its recruitment to telomeres.},
}
@article {pmid18272174,
year = {2008},
author = {Lotito, L and Russo, A and Chillemi, G and Bueno, S and Cavalieri, D and Capranico, G},
title = {Global transcription regulation by DNA topoisomerase I in exponentially growing Saccharomyces cerevisiae cells: activation of telomere-proximal genes by TOP1 deletion.},
journal = {Journal of molecular biology},
volume = {377},
number = {2},
pages = {311-322},
doi = {10.1016/j.jmb.2008.01.037},
pmid = {18272174},
issn = {1089-8638},
mesh = {Acetylation ; Catalysis ; Chromosomes, Fungal/genetics ; DNA Topoisomerases, Type I/deficiency/genetics/*metabolism ; DNA, Fungal/metabolism ; Down-Regulation ; Enzyme Activation ; *Gene Deletion ; *Gene Expression Regulation, Fungal ; Glucose/metabolism ; Histones/metabolism ; Mutation/genetics ; Saccharomyces cerevisiae/*enzymology/*genetics/growth &amp; development ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Telomere/*genetics ; Transcription, Genetic/*genetics ; },
abstract = {To establish the cellular functions of DNA topoisomerase I-B (Top1p) at a global level, we have determined the expression profiles and histone modification patterns affected by TOP1 gene deletion (DeltaTOP1) in Saccharomyces cerevisiae. In exponentially growing cells, DeltaTOP1 specifically increases transcription of telomere-proximal genes and decreases glucose utilization and energy production pathways. Immunoprecipitation data demonstrate that Top1p can bind to and is catalytically active at telomeric DNA repeats, and that both DeltaTOP1 and an inactive Y727F Top1p mutant increase H4 histone acetylation at telomere-proximal regions. Interestingly, while the Y727F mutation has no influence on enzyme recruitment to chromatin sites, it has a marked effect on H4 K16 acetylation at subtelomeric regions. The Top1p mutation also increases H3 histone K4 dimethylation, which has been associated with gene transcription, at 3' termini of subtelomeric genes. No major effect of DeltaTOP1 or mutation was detected on Sir3p recruitment; however, DeltaTOP1 has an effect on transcript levels of genes known to regulate telomeric silencing. Thus, the findings indicate that Top1p activity can favor both a repressed chromatin organization and a reduced gene expression level at telomere-proximal regions in yeast. As telomere-proximal regions are known to be enriched for stress-activated genes, our findings show that Top1p can optimize transcript levels for cell growth in exponentially growing cells under a synthetic medium with glucose.},
}
@article {pmid18271393,
year = {2007},
author = {Morán, Y and Valderrama, E and Camargo, ME and Rivero, MB and Chiurillo, MA},
title = {[Chemiluminescent measurement of telomere DNA content in archival biopsies of colon adenocarcinoma].},
journal = {Investigacion clinica},
volume = {48},
number = {4},
pages = {485-493},
pmid = {18271393},
issn = {0535-5133},
mesh = {Adenocarcinoma/*chemistry/genetics ; Aged ; Aged, 80 and over ; Bacterial Proteins ; Biological Specimen Banks ; Biopsy ; Biotinylation ; Colonic Neoplasms/*chemistry/genetics ; DNA Fragmentation ; DNA, Neoplasm/*analysis ; Electrophoresis, Agar Gel ; Female ; Horseradish Peroxidase ; Humans ; Luminescent Measurements/*methods ; Male ; Middle Aged ; Nucleic Acid Hybridization/*methods ; Reproducibility of Results ; Sensitivity and Specificity ; Telomere/*chemistry ; Tissue Fixation/methods ; },
abstract = {Telomeres are nucleoprotein complexes that protect the ends of eucaryotic chromosomes from degradation and recombination. In humans, telomeres measure 10-12 kbp in normal somatic cells, but they scarcely reach 1-2 kbp in tumor cells of rapid growth, due to the incomplete replication of these structures in each mitotic division. Telomeres shorten with age, which can be associated to genomic instability and to an increment of the risk of suffering from cancer. The standard method to measure the telomere length is the analysis of telomeric restriction fragments by Southern blot. However, a precise determination is not possible when the DNA is broken into small fragments or if it is scarce. In this work, a slot blot assay was adapted to quantify the relative content, instead of the length, of telomeric DNA from paraffin-embedded archival specimens of colon adenocarcinoma. The telomeric DNA content could be reproducibly measured with hardly 75 ng of highly degraded genomic DNA by chemiluminescent detection for hybridization.},
}
@article {pmid18270372,
year = {2008},
author = {Kimura, M and Hjelmborg, JV and Gardner, JP and Bathum, L and Brimacombe, M and Lu, X and Christiansen, L and Vaupel, JW and Aviv, A and Christensen, K},
title = {Telomere length and mortality: a study of leukocytes in elderly Danish twins.},
journal = {American journal of epidemiology},
volume = {167},
number = {7},
pages = {799-806},
pmid = {18270372},
issn = {1476-6256},
support = {AG16592/AG/NIA NIH HHS/United States ; R01 AG020132/AG/NIA NIH HHS/United States ; AG020132/AG/NIA NIH HHS/United States ; R01 AG016592/AG/NIA NIH HHS/United States ; P01-AG08761/AG/NIA NIH HHS/United States ; P01 AG008761/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*physiology ; Denmark/epidemiology ; Female ; Humans ; *Leukocytes ; Longitudinal Studies ; Male ; Mortality/*trends ; Predictive Value of Tests ; Proportional Hazards Models ; Telomere/*ultrastructure ; },
abstract = {Leukocyte telomere length, representing the mean length of all telomeres in leukocytes, is ostensibly a bioindicator of human aging. The authors hypothesized that shorter telomeres might forecast imminent mortality in elderly people better than leukocyte telomere length. They performed mortality analysis in 548 same-sex Danish twins (274 pairs) aged 73-94 years, of whom 204 pairs experienced the death of one or both co-twins during 9-10 years of follow-up (1997-2007). From the terminal restriction fragment length (TRFL) distribution, the authors obtained the mean TRFL (mTRFL) and the mean values of the shorter 50% (mTRFL(50)) and shortest 25% (mTRFL(25)) of TRFLs in the distribution and computed the mode of TRFL (MTRFL). They analyzed the proportions of twin pairs in which the co-twin with the shorter telomeres died first. The proportions derived from the intrapair comparisons indicated that the shorter telomeres predicted the death of the first co-twin better than the mTRFL did (mTRFL: 0.56, 95% confidence interval (CI): 0.49, 0.63; mTRFL(50): 0.59, 95% CI: 0.52, 0.66; mTRFL(25): 0.59, 95% CI: 0.52, 0.66; MTRFL: 0.60, 95% CI: 0.53, 0.67). The telomere-mortality association was stronger in years 3-4 than in the rest of the follow-up period, and it grew stronger with increasing intrapair difference in all telomere parameters. Leukocyte telomere dynamics might help explain the boundaries of the human life span.},
}
@article {pmid18268147,
year = {2008},
author = {Vasan, RS and Demissie, S and Kimura, M and Cupples, LA and Rifai, N and White, C and Wang, TJ and Gardner, JP and Cao, X and Benjamin, EJ and Levy, D and Aviv, A},
title = {Association of leukocyte telomere length with circulating biomarkers of the renin-angiotensin-aldosterone system: the Framingham Heart Study.},
journal = {Circulation},
volume = {117},
number = {9},
pages = {1138-1144},
pmid = {18268147},
issn = {1524-4539},
support = {N01-HC 25195/HC/NHLBI NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; K24 HL004334/HL/NHLBI NIH HHS/United States ; R01 HL067288/HL/NHLBI NIH HHS/United States ; R01HL67288/HL/NHLBI NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; 2K24 HL 4334/HL/NHLBI NIH HHS/United States ; R01 AG028321/AG/NIA NIH HHS/United States ; R01 AG021593-01/AG/NIA NIH HHS/United States ; AG028321/AG/NIA NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Biomarkers/blood ; *Clinical Trials as Topic ; Cross-Sectional Studies ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Renin-Angiotensin System/*physiology ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) chronicles the cumulative burden of oxidative stress and inflammation over a life course. Activation of the renin-angiotensin-aldosterone system is associated with increased oxidative stress and inflammation. Therefore, LTL may be related to circulating biomarkers of the renin-angiotensin-aldosterone system.<br><br>METHODS AND RESULTS: We evaluated the cross-sectional relations of LTL (dependent variable) to circulating renin and aldosterone concentrations and the renin-to-aldosterone ratio (all logarithmically transformed; independent variables) in 1203 Framingham Study participants (mean age, 59 years; 51% women). We used multivariable linear regression and adjusted for age, blood pressure, hypertension treatment, smoking, diabetes mellitus, body mass index, hormone replacement therapy, serum creatinine, and the urine sodium-to-creatinine ratio. Overall, multivariable-adjusted LTL was inversely related to renin (beta coefficient per unit increase, -0.038; P=0.036), directly related to aldosterone (beta=0.099; P=0.002), and inversely related to the renin-to-aldosterone ratio (beta=-0.049; P=0.003). Relations of LTL to biomarkers were stronger in those with hypertension, although a formal test of interaction was not statistically significant (P=0.20). Individuals with hypertension displayed significant associations of LTL with renin (beta=-0.060; P=0.005), aldosterone (beta=0.134; P=0.002), and renin-to-aldosterone ratio (beta=-0.072; P<0.001). Participants with hypertension who were in the top tertile of the renin-to-aldosterone ratio had LTL that was 182 base pairs shorter relative to those in the lowest tertile.<br><br>CONCLUSIONS: In our community-based sample, LTL was shorter in individuals with a higher renin-to-aldosterone ratio, especially in participants with hypertension. Additional investigations are warranted to confirm our observations.},
}
@article {pmid18263784,
year = {2008},
author = {Lansdorp, PM},
title = {Telomeres, stem cells, and hematology.},
journal = {Blood},
volume = {111},
number = {4},
pages = {1759-1766},
pmid = {18263784},
issn = {0006-4971},
support = {R01 AI029524/AI/NIAID NIH HHS/United States ; R21 AI029524/AI/NIAID NIH HHS/United States ; AI29524/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Blood Cells/cytology/*physiology ; Chromosomes, Human ; Hematopoietic Stem Cells/cytology/*physiology ; Humans ; Mitosis ; Stem Cells/cytology/*physiology ; Telomerase/metabolism ; Telomere/*physiology ; },
abstract = {Telomeres are highly dynamic structures that adjust the cellular response to stress and growth stimulation based on previous cell divisions. This critical function is accomplished by progressive telomere shortening and DNA damage responses activated by chromosome ends without sufficient telomere repeats. Repair of critically short telomeres by telomerase or recombination is limited in most somatic cells, and apoptosis or cellular senescence is triggered when too many uncapped telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germ line that typically express high levels of telomerase. In somatic cells, the telomere length typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal cells in which malignant progression is facilitated by genome instability resulting from uncapped telomeres. The critical role of telomeres in cell proliferation and aging is illustrated in patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Here, the role of telomeres and telomerase in human biology is reviewed from a personal historical perspective.},
}
@article {pmid18263609,
year = {2008},
author = {Pennarun, G and Granotier, C and Hoffschir, F and Mandine, E and Biard, D and Gauthier, LR and Boussin, FD},
title = {Role of ATM in the telomere response to the G-quadruplex ligand 360A.},
journal = {Nucleic acids research},
volume = {36},
number = {5},
pages = {1741-1754},
pmid = {18263609},
issn = {1362-4962},
mesh = {Apoptosis ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle ; Cell Cycle Proteins/antagonists &amp; inhibitors/*physiology ; Chromosome Aberrations ; DNA Damage ; *DNA Repair ; DNA-Binding Proteins/antagonists &amp; inhibitors/*physiology ; G-Quadruplexes/*drug effects ; HeLa Cells ; Humans ; Ligands ; Protein Serine-Threonine Kinases/antagonists &amp; inhibitors/*physiology ; Pyridines/*toxicity ; Quinolines/*toxicity ; Signal Transduction ; Sister Chromatid Exchange/drug effects ; Telomere/*chemistry/drug effects ; Tumor Suppressor Proteins/antagonists &amp; inhibitors/*physiology ; },
abstract = {Telomeres are known to prevent chromosome ends from being recognized as DNA double-strand breaks. Conversely, many DNA damage response proteins, including ATM, are thought to participate to telomere maintenance. However, the precise roles of ATM at telomeres remain unclear due to its multiple functions in cell checkpoints and apoptosis. To gain more insights into the role of ATM in telomere maintenance, we determined the effects of the G-quadruplex ligand 360A in various cell lines lacking functional ATM. We showed, by using Fluorescence in situ hybridization (FISH) and Chromosome Orientation-FISH using telomere PNA probes, that 360A induced specific telomere aberrations occurring during or after replication, mainly consisting in sister telomere fusions and also recombinations that involved preferentially the lagging strand telomeres. We demonstrate that ATM reduced telomere instability independently of apoptosis induction. Our results suggest thus that ATM has a direct role in preventing inappropriate DNA repair at telomeres, which could be related to its possible participation to the formation of protected structures at telomeres.},
}
@article {pmid18261910,
year = {2008},
author = {Ho, CY and Murnane, JP and Yeung, AK and Ng, HK and Lo, AW},
title = {Telomeres acquire distinct heterochromatin characteristics during siRNA-induced RNA interference in mouse cells.},
journal = {Current biology : CB},
volume = {18},
number = {3},
pages = {183-187},
doi = {10.1016/j.cub.2007.12.059},
pmid = {18261910},
issn = {0960-9822},
mesh = {Animals ; Cell Line ; Fibroblasts/*metabolism ; Heterochromatin/genetics/*metabolism ; Mice ; *RNA Interference ; RNA, Small Interfering/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres are protective structures present at the ends of linear chromosomes and consist of simple repeating-DNA sequences and specialized proteins [1, 2]. Integrity of the telomeres is important in maintaining genome stability[1-6]. RNA interference(RNAi) involves short double-stranded RNA (21-23 nucleotides long), termed short interference RNA(siRNA), resulting in the downregulation of genes with cognate sequences [7-9]. During transient siRNA-induced RNAi in mouse fibroblast cultures, we found significant reversible changes related to the telomeres. Telomeres acquired distinct heterochromatin features. There were increased bindings of Argonaute-1 (AGO1), telomeric repeat-binding factor 1(TERF1), and heterochromatin protein 1beta (HP1beta) on the telomeres. Histone H3 (lysine 9) was hypermethylated at the telomeres. The chromosome ends also were associated with an unidentified RNA. During RNAi, expression of a transgene inserted adjacent to the telomere was downregulated. In addition, the concentration of a group of heterogeneous high-molecular-weight RNA containing telomeric repeat sequences was increased, and this RNA formed a small number of transient, discrete nuclear foci. Our findings suggest that telomeres participate actively in the siRNA-induced RNAi process. These responses of telomeres to the RNAi process might partially account for the off-target effects of RNAi.},
}
@article {pmid18256459,
year = {2008},
author = {Takemura, M and Sugimura, K and Okumura, K and Limsirichaikul, S and Suzuki, M and Yamada, Y and Yoshida, S},
title = {Hyper-phosphorylated retinoblastoma protein suppresses telomere elongation.},
journal = {Bioscience, biotechnology, and biochemistry},
volume = {72},
number = {2},
pages = {630-635},
doi = {10.1271/bbb.70715},
pmid = {18256459},
issn = {1347-6947},
mesh = {HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Phosphorylation ; Retinoblastoma Protein/*metabolism ; *Telomere ; },
abstract = {Immortalized cell lines maintain telomeres by the expression of telomerase or by a mechanism designated alternative lengthening of telomeres (ALT). Although DNA polymerase alpha (pol-alpha) is reported to be required for telomere maintenance, the critical role of pol-alpha in telomere maintenance has not been firmly determined. We examined the role of retinoblastoma protein (pRb) and pol-alpha in the regulation of telomere length, using telomere-fiber FISH. Telomere length varied dependent on the intracellular abundance of pol-alpha or pRb in HeLa cells. A proportion of hyper-phosphorylated pRb (ppRb) molecules localized to sites of telomeric DNA replication in HeLa cells. Pol-alpha might thus contribute to telomere maintenance, and might be regulated by ppRb.},
}
@article {pmid18252230,
year = {2008},
author = {Savage, SA and Giri, N and Baerlocher, GM and Orr, N and Lansdorp, PM and Alter, BP},
title = {TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita.},
journal = {American journal of human genetics},
volume = {82},
number = {2},
pages = {501-509},
pmid = {18252230},
issn = {1537-6605},
support = {R01 AI029524/AI/NIAID NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; AI29524/AI/NIAID NIH HHS/United States ; R21 AI029524/AI/NIAID NIH HHS/United States ; N02CP11019/CP/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Base Sequence ; Child ; Child, Preschool ; Chromosome Mapping ; Chromosomes, Human, Pair 14/*genetics ; Dyskeratosis Congenita/*genetics ; Humans ; Molecular Sequence Data ; Mutation/genetics ; Pedigree ; Sequence Analysis, DNA ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {Patients with dyskeratosis congenita (DC), a heterogeneous inherited bone marrow failure syndrome, have abnormalities in telomere biology, including very short telomeres and germline mutations in DKC1, TERC, TERT, or NOP10, but approximately 60% of DC patients lack an identifiable mutation. With the very short telomere phenotype and a highly penetrant, rare disease model, a linkage scan was performed on a family with autosomal-dominant DC and no mutations in DKCI, TERC, or TERT. Evidence favoring linkage was found at 2p24 and 14q11.2, and this led to the identification of TINF2 (14q11.2) mutations, K280E, in the proband and her five affected relatives and TINF2 R282H in three additional unrelated DC probands, including one with Revesz syndrome; a fifth DC proband had a R282S mutation. TINF2 mutations were not present in unaffected relatives, DC probands with mutations in DKC1, TERC, or TERT or 298 control subjects. We demonstrate that a fifth gene, TINF2, is mutated in classical DC and, for the first time, in Revesz syndrome. This represents the first shelterin complex mutation linked to human disease and confirms the role of very short telomeres as a diagnostic test for DC.},
}
@article {pmid18249196,
year = {2008},
author = {Cattan, V and Mercier, N and Gardner, JP and Regnault, V and Labat, C and Mäki-Jouppila, J and Nzietchueng, R and Benetos, A and Kimura, M and Aviv, A and Lacolley, P},
title = {Chronic oxidative stress induces a tissue-specific reduction in telomere length in CAST/Ei mice.},
journal = {Free radical biology &amp; medicine},
volume = {44},
number = {8},
pages = {1592-1598},
doi = {10.1016/j.freeradbiomed.2008.01.007},
pmid = {18249196},
issn = {0891-5849},
mesh = {Animals ; Blood Pressure/drug effects ; Buthionine Sulfoximine/pharmacology ; Glutathione/*metabolism ; Male ; Mice ; Organ Specificity ; *Oxidative Stress ; Protein Carbonylation ; Telomerase/metabolism ; Telomere/drug effects/*ultrastructure ; Testis/metabolism ; },
abstract = {We examine whether increased oxidative stress in vivo promotes telomere shortening in CAST/Ei mice. We explored the effects of L-buthionine sulfoximine treatment (BSO) on telomere length. BSO shortened telomere length in white fat, brown fat, skin, tail, and testis in concert with diminished tissue glutathione content, increased tissue carbonyl content, and increased plasma advanced oxidized protein products. Telomerase activity was mainly detected in testis but no reduction of telomerase activity was observed in response to BSO. In conclusion, BSO-mediated increase in systemic oxidative stress shortens telomeres in several tissues of the mouse. The variable effect of BSO treatment on telomere length in different tissue may result from their different adaptive antioxidative capacity.},
}
@article {pmid18248213,
year = {2005},
author = {McChesney, PA and Elmore, LW and Holt, SE},
title = {Vertebrate marine species as model systems for studying telomeres and telomerase.},
journal = {Zebrafish},
volume = {1},
number = {4},
pages = {349-355},
doi = {10.1089/zeb.2005.1.349},
pmid = {18248213},
issn = {1557-8542},
abstract = {Due to the limitations of in vitro human tissue culture systems, it has long been recognized that in vivo model organisms are critically necessary for studying important biological processes related to human disease. Telomere shortening and dysfunction have been shown as a contributing factor in aging using tissue culture systems and after 6 generations in inbred strains of mice. Currently, there are no models and little or no data defining the role of telomeres and telomerase in toxicological response, metal-induced carcinogenesis, or aging in marine animals. One of our primary objectives has been to determine if fish have similar utility to mouse models of aging and cancer, at least related to telomere biogenesis and telomerase function. We have found that the vast majority of tissues from marine species have functional telomerase activity, and that several of these vertebrates, although telomerase-expressing, have telomere lengths that resemble those found in human cells and tissues. Thus, because aquatic species have "normal" telomere sizes, marine animals may be more biologically relevant and cost-effective models for studying stem cells, aging, and cancer than inbred strains of rodents.},
}
@article {pmid18247546,
year = {2008},
author = {Cheng, MK and Modi, C and Cookson, JC and Hutchinson, I and Heald, RA and McCarroll, AJ and Missailidis, S and Tanious, F and Wilson, WD and Mergny, JL and Laughton, CA and Stevens, MF},
title = {Antitumor polycyclic acridines. 20. Search for DNA quadruplex binding selectivity in a series of 8,13-dimethylquino[4,3,2-kl]acridinium salts: telomere-targeted agents.},
journal = {Journal of medicinal chemistry},
volume = {51},
number = {4},
pages = {963-975},
doi = {10.1021/jm070587t},
pmid = {18247546},
issn = {0022-2623},
support = {//Cancer Research UK/United Kingdom ; },
mesh = {Acridines/*chemical synthesis/chemistry/pharmacology ; Antineoplastic Agents/*chemical synthesis/chemistry/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA/chemistry ; Drug Screening Assays, Antitumor ; Fluorescence Resonance Energy Transfer ; *G-Quadruplexes ; Heterocyclic Compounds, 4 or More Rings/*chemical synthesis/chemistry/pharmacology ; Humans ; Quaternary Ammonium Compounds/*chemical synthesis/chemistry/pharmacology ; Structure-Activity Relationship ; Surface Plasmon Resonance ; Telomerase/antagonists &amp; inhibitors ; Telomere/*metabolism ; },
abstract = {The growth-inhibitory activities of an extensive series of quaternized quino[4,3,2- kl]acridinium salts against tumor cell lines in vitro have been measured and their biological properties interpreted in the light of differential binding to different DNA isoforms. Selectivity for quadruplex DNA binding and stabilization by compounds were explored through an array of methods: UV absorption and fluorescence emission spectroscopy, surface plasmon resonance, and competition dialysis. Quadruplex DNA interaction was further characterized through FRET and DNA polymerase arrest assays. Telomerase inhibition, inferred from the TRAP assay, is attributed to quadruplex stabilization, supported by the strong correlation (R(2) = 0.81) across the series between quadruplex DNA binding affinity and TRAP inhibition potency. Growth inhibition potency in the NCI60 human tumor cell line panel is more marked in compounds with greater DNA duplex binding affinity (R(2) = 0.82). Quantification of relative quadruplex and duplex binding affinity constants puts some of these ligands among the most selective quadruplex DNA interactive agents reported to date.},
}
@article {pmid18246067,
year = {2008},
author = {Musarò, M and Ciapponi, L and Fasulo, B and Gatti, M and Cenci, G},
title = {Unprotected Drosophila melanogaster telomeres activate the spindle assembly checkpoint.},
journal = {Nature genetics},
volume = {40},
number = {3},
pages = {362-366},
doi = {10.1038/ng.2007.64},
pmid = {18246067},
issn = {1546-1718},
support = {GGP07200/TI_/Telethon/Italy ; },
mesh = {Animals ; Animals, Genetically Modified ; Cdc20 Proteins ; Cell Cycle/genetics/physiology ; Cell Cycle Proteins/genetics/metabolism ; Checkpoint Kinase 1 ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; Cytoskeletal Proteins/metabolism ; DNA Damage/genetics/physiology ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster/*genetics ; Endodeoxyribonucleases/genetics ; Exodeoxyribonucleases/genetics ; Genes, cdc ; Microtubule-Associated Proteins/genetics ; Models, Biological ; Protein Binding ; Protein Kinases/genetics ; Protein Serine-Threonine Kinases/genetics ; Spindle Apparatus/genetics/metabolism/*physiology ; Telomere/*metabolism/*physiology ; },
abstract = {In both yeast and mammals, uncapped telomeres activate the DNA damage response (DDR) and undergo end-to-end fusion. Previous work has shown that the Drosophila HOAP protein, encoded by the caravaggio (cav) gene, is required to prevent telomeric fusions. Here we show that HOAP-depleted telomeres activate both the DDR and the spindle assembly checkpoint (SAC). The cell cycle arrest elicited by the DDR was alleviated by mutations in mei-41 (encoding ATR), mus304 (ATRIP), grp (Chk1) and rad50 but not by mutations in tefu (ATM). The SAC was partially overridden by mutations in zw10 (also known as mit(1)15) and bubR1, and also by mutations in mei-41, mus304, rad50, grp and tefu. As expected from SAC activation, the SAC proteins Zw10, Zwilch, BubR1 and Cenp-meta (Cenp-E) accumulated at the kinetochores of cav mutant cells. Notably, BubR1 also accumulated at cav mutant telomeres in a mei-41-, mus304-, rad50-, grp- and tefu-dependent manner. Our results collectively suggest that recruitment of BubR1 by dysfunctional telomeres inhibits Cdc20-APC function, preventing the metaphase-to-anaphase transition.},
}
@article {pmid18245359,
year = {2008},
author = {Smith, S and Banerjee, S and Rilo, R and Myung, K},
title = {Dynamic regulation of single-stranded telomeres in Saccharomyces cerevisiae.},
journal = {Genetics},
volume = {178},
number = {2},
pages = {693-701},
pmid = {18245359},
issn = {0016-6731},
support = {//Intramural NIH HHS/United States ; },
mesh = {Chromosomes, Fungal/*genetics ; DNA Helicases/genetics ; DNA Primers ; DNA, Fungal/*genetics ; DNA, Single-Stranded/*genetics ; DNA-Binding Proteins/genetics ; *Gene Expression Regulation, Fungal ; Genotype ; Polymerase Chain Reaction ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/genetics ; Telomere/*genetics/ultrastructure ; },
abstract = {The temperature-sensitive phenotypes of yku70Delta and yku80Delta have provided a useful tool for understanding telomere homeostasis. Mutating the helicase domain of the telomerase inhibitor Pif1 resulted in the inactivation of cell cycle checkpoints and the subsequent rescue of temperature sensitivity of the yku70Delta strain. The inactivation of Pif1 in yku70Delta increased overall telomere length. However, the long G-rich, single-stranded overhangs at the telomeres, which are the major cause of temperature sensitivity, were slightly increased. Interestingly, the rescue of temperature sensitivity in strains having both pif1-m2 and yku70Delta mutations depended on the homologous recombination pathway. Furthermore, the BLM/WRN helicase yeast homolog Sgs1 exacerbated the temperature sensitivity of the yku70Delta strain. Therefore, the yKu70-80 heterodimer and telomerase maintain telomere size, and the helicase activity of Pif1 likely also helps to balance the overall size of telomeres and G-rich, single-stranded overhangs in wild-type cells by regulating telomere protein homeostasis. However, the absence of yKu70 may provide other proteins such as those involved in homologous recombination, Sgs1, or Pif1 additional access to G-rich, single-stranded DNA and may determine telomere size, cell cycle checkpoint activation, and, ultimately, temperature sensitivity.},
}
@article {pmid18243729,
year = {2008},
author = {Raynaud, CM and Sabatier, L and Philipot, O and Olaussen, KA and Soria, JC},
title = {Telomere length, telomeric proteins and genomic instability during the multistep carcinogenic process.},
journal = {Critical reviews in oncology/hematology},
volume = {66},
number = {2},
pages = {99-117},
doi = {10.1016/j.critrevonc.2007.11.006},
pmid = {18243729},
issn = {1040-8428},
mesh = {Animals ; Cell Transformation, Neoplastic/*genetics/metabolism ; DNA Repair ; *Gene Expression Regulation, Neoplastic ; *Genomic Instability ; Genomics/methods ; Heterochromatin/metabolism ; Humans ; Neoplasms/enzymology/*genetics/metabolism ; Shelterin Complex ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomeres form specialized structures at the ends of eukaryotic chromosomes, preventing them from being wrongly recognized as DNA damage. The human telomere DNA sequence is a tandem repetition of the sequence TTAGGG. In normal cells, the DNA replication machinery is unable to completely duplicate the telomeric DNA; thus, telomeres are shortened after every cell division. Having reached a critical length, telomeres may be recognized as double strand break DNA lesions, and cells eventually enter senescence. Carcinogenesis is a multistep process involving multiple mutations and chromosomal aberrations. One of the most prevalent aberrations in pre-cancerous lesions is telomere shortening and telomerase activation. We discuss the role and homeostasis of telomeres in normal cells and their implication in the early steps of carcinogenesis. We also discuss various techniques used, and their limitations, in the study of telomeres and genome instability and their role in carcinogenesis and related genomic modifications.},
}
@article {pmid18242664,
year = {2008},
author = {Thomas, P and O' Callaghan, NJ and Fenech, M},
title = {Telomere length in white blood cells, buccal cells and brain tissue and its variation with ageing and Alzheimer's disease.},
journal = {Mechanisms of ageing and development},
volume = {129},
number = {4},
pages = {183-190},
doi = {10.1016/j.mad.2007.12.004},
pmid = {18242664},
issn = {0047-6374},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Alzheimer Disease/*genetics ; DNA/metabolism ; Female ; Hippocampus/*metabolism ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Mouth/*cytology/*metabolism ; Sensitivity and Specificity ; Telomere/genetics/*metabolism ; },
abstract = {Changes in telomere length have been associated with ageing and with certain age-related degenerative diseases. We report results using a quantitative RTm-PCR method to measure absolute telomere length (in kb per diploid genome) and show the age-related changes in white blood cells and buccal cell telomere length (in kb per diploid genome) in normal healthy individuals and Alzheimer's patients. We observed a significantly lower telomere length in white blood cells (P < 0.0001) and buccal cells (P < 0.01) in Alzheimer's patients relative to healthy age-matched controls (31.4% and 32.3%, respectively). However, there was a significantly greater telomere length in hippocampus cells of Alzheimer's brains (P = 0.01) compared to control samples (49.0%). We also observed that telomere length in buccal cells was 52.2-74.2% shorter than that observed in white blood cells (P < 0.0001). The odd's ratio of being diagnosed with Alzheimer's disease (AD) was 10.8 (95% CI 1.19-97.85) if white blood cell telomere length was less than 115 kb per diploid genome with a specificity of 46% and sensitivity of 92.9%. The odds ratio for AD diagnosis was 4.6 (95% CI 1.22-17.16) if buccal cell telomere length was less than 40 kb per diploid genome with a sensitivity of 72.7% and a specificity of 63.1%. These results suggest important differences in telomere maintenance in Alzheimer's cases compared to healthy controls depending on sampled tissue. These results need to be replicated in larger studies and in cohorts of other neurodegenerative disorders to determine specificity of changes to Alzheimer's patients.},
}
@article {pmid18239859,
year = {2008},
author = {Růcková, E and Friml, J and Procházková Schrumpfová, P and Fajkus, J},
title = {Role of alternative telomere lengthening unmasked in telomerase knock-out mutant plants.},
journal = {Plant molecular biology},
volume = {66},
number = {6},
pages = {637-646},
pmid = {18239859},
issn = {0167-4412},
mesh = {Arabidopsis/enzymology/*genetics/growth &amp; development ; Cell Division/genetics/physiology ; Chromosomes, Plant/genetics ; *Mutation ; Seeds/enzymology/genetics/growth &amp; development ; Telomerase/*genetics/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres in many eukaryotes are maintained by telomerase in whose absence telomere shortening occurs. However, telomerase-deficient Arabidopsis thaliana mutants (Attert (-/-)) show extremely low rates of telomere shortening per plant generation (250-500 bp), which does not correspond to the expected outcome of replicative telomere shortening resulting from ca. 1,000 meristem cell divisions per seed-to-seed generation. To investigate the influence of the number of cell divisions per seed-to-seed generation, Attert (-/-) mutant plants were propagated from seeds coming either from the lower-most or the upper-most siliques (L- and U-plants) and the length of their telomeres were followed over several generations. The rate of telomere shortening was faster in U-plants, than in L-plants, as would be expected from their higher number of cell divisions per generation. However, this trend was observed only in telomeres whose initial length is relatively high and the differences decreased with progressive general telomere shortening over generations. But in generation 4, the L-plants frequently show a net telomere elongation, while the U-plants fail to do so. We propose that this is due to the activation of alternative telomere lengthening (ALT), a process which is activated in early embryonic development in both U- and L-plants, but is overridden in U-plants due to their higher number of cell divisions per generation. These data demonstrate what so far has only been speculated, that in the absence of telomerase, the number of cell divisions within one generation influences the control of telomere lengths. These results also reveal a fast and efficient activation of ALT mechanism(s) in response to the loss of telomerase activity and imply that ALT is probably involved also in normal plant development.},
}
@article {pmid18239083,
year = {2008},
author = {Calado, RT and Young, NS},
title = {Telomere maintenance and human bone marrow failure.},
journal = {Blood},
volume = {111},
number = {9},
pages = {4446-4455},
pmid = {18239083},
issn = {1528-0020},
support = {//Intramural NIH HHS/United States ; },
mesh = {Bone Marrow Diseases/*etiology ; Humans ; Multiprotein Complexes ; Mutation ; Telomerase/genetics ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics ; },
abstract = {Acquired and congenital aplastic anemias recently have been linked molecularly and pathophysiologically by abnormal telomere maintenance. Telomeres are repeated nucleotide sequences that cap the ends of chromosomes and protect them from damage. Telomeres are eroded with cell division, but in hematopoietic stem cells, maintenance of their length is mediated by telomerase. Accelerated telomere shortening is virtually universal in dyskeratosis congenita, caused by mutations in genes encoding components of telomerase or telomere-binding protein (TERT, TERC, DKC1, NOP10, or TINF2). About one-third of patients with acquired aplastic anemia also have short telomeres, which in some cases associate with TERT or TERC mutations. These mutations cause low telomerase activity, accelerated telomere shortening, and diminished proliferative capacity of hematopoietic progenitors. As in other genetic diseases, additional environmental, genetic, and epigenetic modifiers must contribute to telomere erosion and ultimately to disease phenotype. Short telomeres also may cause genomic instability and malignant progression in these marrow failure syndromes. Identification of short telomeres has potential clinical implications: it may be useful in dyskeratosis congenita diagnosis, in suggesting mutations in patients with acquired aplastic anemia, and for selection of suitable hematopoietic stem cell family donors for transplantation in telomerase-deficient patients.},
}
@article {pmid18236464,
year = {2008},
author = {Ponsot, E and Lexell, J and Kadi, F},
title = {Skeletal muscle telomere length is not impaired in healthy physically active old women and men.},
journal = {Muscle &amp; nerve},
volume = {37},
number = {4},
pages = {467-472},
doi = {10.1002/mus.20964},
pmid = {18236464},
issn = {0148-639X},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*physiology ; Biopsy ; Female ; Humans ; Male ; Motor Activity/*physiology ; Muscle, Skeletal/cytology/*physiology ; Postural Balance/physiology ; Satellite Cells, Skeletal Muscle/cytology ; Telomere/*physiology ; Walking/physiology ; },
abstract = {We have previously shown that the number of satellite cells is lower in old than young men and women. The aim of this study was to further explore the effects of aging on the regenerative potential of skeletal muscle in 16 young and 26 old men and women with comparable physical activity level (young, 25 +/- 4 years; old, 75 +/- 4 years). Mean and minimum telomere lengths were determined using Southern blot analyses on biopsies obtained from the tibialis anterior muscle. There were no significant age or gender effects on mean and minimal telomeric lengths, suggesting that the replicative potential in the remaining satellite cells in the tibialis anterior muscle is not impaired with increasing age and the existence of in vivo regulatory mechanisms allowing the maintenance of telomere length. These results imply that moderate physical activity regularly performed by old subjects is not associated with accelerated telomere loss.},
}
@article {pmid18230683,
year = {2008},
author = {Tarry-Adkins, JL and Martin-Gronert, MS and Chen, JH and Cripps, RL and Ozanne, SE},
title = {Maternal diet influences DNA damage, aortic telomere length, oxidative stress, and antioxidant defense capacity in rats.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {22},
number = {6},
pages = {2037-2044},
doi = {10.1096/fj.07-099523},
pmid = {18230683},
issn = {1530-6860},
support = {BB/D007909/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/E002161/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/E00797X/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; /BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Age Factors ; Animals ; *Antioxidants ; Aorta/ultrastructure ; *DNA Damage ; *Diet ; Female ; Models, Animal ; Mothers ; *Oxidative Stress ; Rats ; Telomere/*ultrastructure ; },
abstract = {Low birth weight is associated with increased cardiovascular disease (CVD) in humans. Detrimental effects of low birth weight are amplified by rapid catch-up growth. Conversely, slow growth during lactation reduces CVD risk. Gestational protein restriction causes low birth weight, vascular dysfunction, and accelerated aging in rats. Atherosclerotic aortic tissue has shortened telomeres, and oxidative stress accelerates telomere shortening through generation of DNA single-strand breaks (ssbs). This study tested the hypothesis that maternal diet influences aortic telomere length through changes in DNA ssbs, antioxidant capacity, and oxidative stress. We used our models of gestational protein restriction followed by rapid catch-up growth (the recuperated group) and protein restriction during lactation (the postnatal low-protein [PLP] group). Southern blotting revealed fewer aortic DNA ssbs and subsequently fewer short telomeres (P<0.05) in the PLP group. This result was associated with reduced (P<0.01) 8-hydroxy-2-deoxyguanosine, a marker of oxidative stress. PLP animals expressed increased (P<0.01) manganese superoxide-dismutase, copper-zinc superoxide-dismutase, catalase, and glutathione-reductase. Age-dependent changes in antioxidant defense enzymes indicated more protection to oxidative stress in the PLP animals; conversely, recuperated animals demonstrated age-associated impairment of antioxidant defenses. We conclude that maternal diet has a major influence on aortic telomere length. This finding may provide a mechanistic link between early growth patterns and CVD.},
}
@article {pmid18228424,
year = {2003},
author = {Herbert, BS and Shay, JW and Wright, WE},
title = {Analysis of telomeres and telomerase.},
journal = {Current protocols in cell biology},
volume = {Chapter 18},
number = {},
pages = {Unit 18.6},
doi = {10.1002/0471143030.cb1806s20},
pmid = {18228424},
issn = {1934-2616},
mesh = {Base Sequence ; Blotting, Southern/*methods ; Cell Line, Tumor ; DNA Primers/metabolism ; Electrophoresis, Agar Gel ; Humans ; Molecular Sequence Data ; Molecular Weight ; Polymerase Chain Reaction/*methods ; Polymorphism, Restriction Fragment Length ; Protein Kinases/metabolism ; Telomerase/*metabolism ; Telomere/enzymology/*genetics/*metabolism ; },
abstract = {This unit describes techniques to analyze telomeric length and telomerase activity in human cells. Telomere length can be determined by a modification of Southern blotting in which the analysis of chromosome terminal restriction fragments (TRFs) provides the average lengths of all telomeres in a cell population. Telomerase activity can be measured in vitro by a sensitive and efficient polymerase chain reaction (PCR)-based detection method, also known as telomeric repeat amplification protocol (TRAP). These assays can be used to study the in vitro cellular effects of aging and cancer treatments on telomere biology and telomerase activity.},
}
@article {pmid18227361,
year = {2008},
author = {Cherkas, LF and Hunkin, JL and Kato, BS and Richards, JB and Gardner, JP and Surdulescu, GL and Kimura, M and Lu, X and Spector, TD and Aviv, A},
title = {The association between physical activity in leisure time and leukocyte telomere length.},
journal = {Archives of internal medicine},
volume = {168},
number = {2},
pages = {154-158},
doi = {10.1001/archinternmed.2007.39},
pmid = {18227361},
issn = {0003-9926},
support = {074951//Wellcome Trust/United Kingdom ; AG020132/AG/NIA NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; HL070137/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*physiology ; Female ; Humans ; Leisure Activities ; Leukocytes/*physiology ; Male ; Middle Aged ; *Motor Activity ; Polymorphism, Restriction Fragment Length ; Risk Factors ; Smoking ; Social Class ; Surveys and Questionnaires ; Telomere/*physiology ; White People ; },
abstract = {BACKGROUND: Physical inactivity is an important risk factor for many aging-related diseases. Leukocyte telomere dynamics (telomere length and age-dependent attrition rate) are ostensibly a biological indicator of human aging. We therefore tested the hypothesis that physical activity level in leisure time (over the past 12 months) is associated with leukocyte telomere length (LTL) in normal healthy volunteers.<br><br>METHODS: We studied 2401 white twin volunteers, comprising 2152 women and 249 men, with questionnaires on physical activity level, smoking status, and socioeconomic status. Leukocyte telomere length was derived from the mean terminal restriction fragment length and adjusted for age and other potential confounders.<br><br>RESULTS: Leukocyte telomere length was positively associated with increasing physical activity level in leisure time (P< .001); this association remained significant after adjustment for age, sex, body mass index, smoking, socioeconomic status, and physical activity at work. The LTLs of the most active subjects were 200 nucleotides longer than those of the least active subjects (7.1 and 6.9 kilobases, respectively; P= .006). This finding was confirmed in a small group of twin pairs discordant for physical activity level (on average, the LTL of more active twins was 88 nucleotides longer than that of less active twins; P= .03).<br><br>CONCLUSIONS: A sedentary lifestyle (in addition to smoking, high body mass index, and low socioeconomic status) has an effect on LTL and may accelerate the aging process. This provides a powerful message that could be used by clinicians to promote the potentially antiaging effect of regular exercise.},
}
@article {pmid18226592,
year = {2008},
author = {Bonaglia, MC and Giorda, R and Beri, S and Peters, GB and Kirk, EP and Hung, D and Ciccone, R and Gottardi, G and Zuffardi, O},
title = {Concurrent transposition of distal 6p and 20q to the 22q telomere: a recurrent benign chromosomal variant.},
journal = {European journal of medical genetics},
volume = {51},
number = {2},
pages = {148-155},
doi = {10.1016/j.ejmg.2007.11.005},
pmid = {18226592},
issn = {1769-7212},
mesh = {Angelman Syndrome/diagnosis/*genetics ; Chromosomes, Human, Pair 15/genetics ; Chromosomes, Human, Pair 20/*genetics ; Chromosomes, Human, Pair 22/*genetics ; Chromosomes, Human, Pair 6/*genetics ; *Genetic Variation ; Humans ; Infant ; Male ; Nucleic Acid Hybridization ; Oligonucleotide Array Sequence Analysis ; Polymorphism, Genetic ; Telomere/*genetics ; },
abstract = {We report the second instance of a complex unbalanced rearrangement consisting of distal trisomy 6p and 20q due to the concurrent transposition of distal 6p and 20q to the 22q telomere, previously described as a benign familial chromosomal variant. In the previous case, the nonpathogenicity of the rearrangement was based on the absence of genotypic differences between the affected proband and his normal father, and on the absence of imprinted genes in the unbalanced region. We now describe the same variant in an unrelated affected subject, in whom testing confirmed the diagnosis of Angelman syndrome, and in his healthy father. Molecular investigations confirmed that the two families have an identical subtelomeric rearrangement. However, genotyping of the flanking sequences on 22q showed a completely different pattern in the two families, demonstrating that they are indeed unrelated. Array-CGH analysis with a resolution of approximately 20 kb (Kit 244A, Agilent) defined a deletion size of 5.9 Mb on 15q11.2. No other imbalances were visible at subtelomeric regions. Further Array-CGH analysis using DNA of the proband (as test) and his mother (as reference) did not detect any duplication at the 6p and 20q subtelomeric regions. The proband and his father appear to have a copy number of the transposed regions equal to that of individuals with a normal repartition of the subtelomeric regions. This is not suggestive of a trisomy but rather of CNV regions. This type of rearrangement could define a new class of polymorphic variants, i.e. positional variants, as observed for pericentromeric heterochromatin.},
}
@article {pmid18224632,
year = {2008},
author = {Hagihara, M and Goto, Y and Nakatani, K},
title = {Ligand-stabilized hairpin structures interfere with elongation of human telomere.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {9},
number = {4},
pages = {510-513},
doi = {10.1002/cbic.200700667},
pmid = {18224632},
issn = {1439-7633},
mesh = {Humans ; Ligands ; *Nucleic Acid Conformation ; Telomere/*chemistry/genetics/*metabolism ; },
}
@article {pmid18221737,
year = {2008},
author = {Muramatsu, Y and Tahara, H and Ono, T and Tsuruo, T and Seimiya, H},
title = {Telomere elongation by a mutant tankyrase 1 without TRF1 poly(ADP-ribosyl)ation.},
journal = {Experimental cell research},
volume = {314},
number = {5},
pages = {1115-1124},
doi = {10.1016/j.yexcr.2007.12.005},
pmid = {18221737},
issn = {0014-4827},
mesh = {Binding Sites ; HeLa Cells ; Humans ; Mutant Proteins ; Poly Adenosine Diphosphate Ribose/*metabolism ; Shelterin Complex ; Tankyrases/*genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; Transfection ; },
abstract = {Telomeres are the capping structures of the eukaryotic chromosome ends. Tankyrase 1 is a poly(ADP-ribose) polymerase that elongates telomeres in a telomerase-dependent manner. This function of tankyrase 1 is mediated by down-regulation of TRF1, a negative regulator of telomere access to telomerase. Namely, tankyrase 1 poly(ADP-ribosyl)ates (PARsylates) TRF1, which in turn dissociates TRF1 from telomeres. The resulting telomeres become better substrates for telomerase-mediated DNA extension. Tankyrase 1 has five independent TRF1 binding sites, ARC (ANK repeat cluster) I to V. Among them, the most C-terminal ARC V is required for TRF1 PARsylation and its release from telomeres. By contrast, functional significance of other four ARCs remains elusive. In this study, we generated a mutant tankyrase 1 that had inactive ARC IV and lacked ARC V but elongated telomeres without TRF1 PARsylation. Consistent with the failure in PARsylation, this mutant only marginally released TRF1 from telomeres. Still, it decreased telomere binding of POT1, a downstream effector of TRF1-mediated telomere length control, and elongated the telomeric 3'-overhang as the wild-type tankyrase 1 did. Thus even without TRF1 PARsylation, this mutant tankyrase 1 seemed to loosen the closed structure of the telomeric heterochromatin. These findings suggest a new role for multiple ARCs in telomere extension by tankyrase 1.},
}
@article {pmid18215415,
year = {2008},
author = {Liu, Y and Bohr, VA and Lansdorp, P},
title = {Telomere, telomerase and aging.},
journal = {Mechanisms of ageing and development},
volume = {129},
number = {1-2},
pages = {1-2},
doi = {10.1016/j.mad.2007.12.001},
pmid = {18215415},
issn = {0047-6374},
mesh = {Aging/*genetics ; Cellular Senescence ; Humans ; Telomerase/*metabolism ; Telomere/*metabolism ; },
}
@article {pmid18215414,
year = {2008},
author = {Cesare, AJ and Reddel, RR},
title = {Telomere uncapping and alternative lengthening of telomeres.},
journal = {Mechanisms of ageing and development},
volume = {129},
number = {1-2},
pages = {99-108},
doi = {10.1016/j.mad.2007.11.006},
pmid = {18215414},
issn = {0047-6374},
mesh = {Animals ; Humans ; Models, Genetic ; Recombination, Genetic ; Telomere/chemistry/*metabolism ; },
abstract = {A substantial number of human tumors utilize a telomerase-independent telomere length maintenance mechanism referred to as alternative lengthening of telomeres (ALT). Although it is known that ALT is a telomere-specific, loss of function phenotype, which involves lengthening of telomeres by homologous recombination-mediated replication of telomeric DNA, many of the details of these processes require elucidation. Here we discuss the current literature on ALT and telomere capping, specifically focusing on how alterations in telomere capping functions may permit activation of ALT and explain the phenotypic characteristics of cells in which this occurs.},
}
@article {pmid18212065,
year = {2008},
author = {Li, B and Jog, SP and Reddy, S and Comai, L},
title = {WRN controls formation of extrachromosomal telomeric circles and is required for TRF2DeltaB-mediated telomere shortening.},
journal = {Molecular and cellular biology},
volume = {28},
number = {6},
pages = {1892-1904},
pmid = {18212065},
issn = {1098-5549},
support = {C06 CA062528/CA/NCI NIH HHS/United States ; R01 AG023873/AG/NIA NIH HHS/United States ; C06 RR10600-01/RR/NCRR NIH HHS/United States ; C06 RR014514-01/RR/NCRR NIH HHS/United States ; C06 RR014514/RR/NCRR NIH HHS/United States ; C06 CA62528/CA/NCI NIH HHS/United States ; },
mesh = {Cells, Cultured/cytology/enzymology ; Cellular Senescence/physiology ; DNA Damage ; DNA, Circular/*metabolism ; Exodeoxyribonucleases/deficiency/genetics/*physiology ; Fibroblasts/cytology/enzymology ; Gene Silencing ; Humans ; Nuclear Proteins/deficiency/genetics/*physiology ; Protein Interaction Mapping ; Protein Structure, Tertiary ; RecQ Helicases/deficiency/genetics/*physiology ; Recombinant Fusion Proteins/physiology ; Sequence Deletion ; Structure-Activity Relationship ; Telomere/metabolism/*ultrastructure ; Telomeric Repeat Binding Protein 2/deficiency/genetics/*physiology ; Transduction, Genetic ; Werner Syndrome/*enzymology/genetics ; Werner Syndrome Helicase ; },
abstract = {Telomere dysfunction has been proposed to contribute to the pathogenesis of Werner syndrome (WS), a premature-aging disorder. The WS protein WRN binds TRF2, a telomere-specific factor that protects chromosome ends. TRF2 possesses an amino-terminal domain that plays an essential role in preventing telomere shortening, as expression of TRF2(DeltaB), which lacks this domain, leads to the formation of telomeric circles, telomere shortening, and cell senescence. Our data show that the TRF2(DeltaB)-induced telomeric-loop homologous-recombination pathway requires WRN helicase. In addition, we show that WRN represses the formation of spontaneous telomeric circles, as demonstrated by the increased levels of telomeric circles observed in telomerase-positive WS fibroblasts. The mechanism of circle formation in WS cells does not involve XRCC3 function. Circle formation in WS cells is reduced by reconstitution with wild-type WRN but not mutant forms lacking either exonuclease or helicase activity, demonstrating that both enzymatic activities of WRN are required to suppress telomeric-circle formation in normal cells expressing telomerase reverse transcriptase. Thus, WRN has a key protective function at telomeres which influences telomere topology and inhibits accelerated attrition of telomeres.},
}
@article {pmid18212041,
year = {2008},
author = {Ji, H and Adkins, CJ and Cartwright, BR and Friedman, KL},
title = {Yeast Est2p affects telomere length by influencing association of Rap1p with telomeric chromatin.},
journal = {Molecular and cellular biology},
volume = {28},
number = {7},
pages = {2380-2390},
pmid = {18212041},
issn = {1098-5549},
support = {52003905//Howard Hughes Medical Institute/United States ; },
mesh = {Carrier Proteins/physiology ; Chromatin/*metabolism ; Chromosomes, Fungal/*metabolism/ultrastructure ; DNA Helicases/deficiency/physiology ; DNA, Fungal/metabolism ; DNA-Binding Proteins/deficiency/physiology ; Gene Silencing ; Mutation, Missense ; Protein Binding ; RNA/physiology ; Recombinant Fusion Proteins/physiology ; Repressor Proteins/physiology ; Saccharomyces cerevisiae/cytology/*genetics ; Saccharomyces cerevisiae Proteins/*physiology ; Shelterin Complex ; Telomerase/*physiology ; Telomere/metabolism/*ultrastructure ; Telomere-Binding Proteins/deficiency/*physiology ; Transcription Factors/*physiology ; },
abstract = {In Saccharomyces cerevisiae, the sequence-specific binding of the negative regulator Rap1p provides a mechanism to measure telomere length: as the telomere length increases, the binding of additional Rap1p inhibits telomerase activity in cis. We provide evidence that the association of Rap1p with telomeric DNA in vivo occurs in part by sequence-independent mechanisms. Specific mutations in EST2 (est2-LT) reduce the association of Rap1p with telomeric DNA in vivo. As a result, telomeres are abnormally long yet bind an amount of Rap1p equivalent to that observed at wild-type telomeres. This behavior contrasts with that of a second mutation in EST2 (est2-up34) that increases bound Rap1p as expected for a strain with long telomeres. Telomere sequences are subtly altered in est2-LT strains, but similar changes in est2-up34 telomeres suggest that sequence abnormalities are a consequence, not a cause, of overelongation. Indeed, est2-LT telomeres bind Rap1p indistinguishably from the wild type in vitro. Taken together, these results suggest that Est2p can directly or indirectly influence the binding of Rap1p to telomeric DNA, implicating telomerase in roles both upstream and downstream of Rap1p in telomere length homeostasis.},
}
@article {pmid18212040,
year = {2008},
author = {Kannan, K and Nelson, AD and Shippen, DE},
title = {Dyskerin is a component of the Arabidopsis telomerase RNP required for telomere maintenance.},
journal = {Molecular and cellular biology},
volume = {28},
number = {7},
pages = {2332-2341},
pmid = {18212040},
issn = {1098-5549},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; GM065383/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Amino Acid Substitution ; Arabidopsis Proteins/genetics/metabolism/*physiology ; Cells, Cultured/metabolism/ultrastructure ; Chromosomes, Plant/metabolism/*ultrastructure ; DNA-Binding Proteins/deficiency/genetics ; Humans ; Hydro-Lyases/genetics/*physiology ; Molecular Sequence Data ; Mutation, Missense ; Nuclear Proteins/*metabolism ; Plants, Genetically Modified ; Point Mutation ; Protein Interaction Mapping ; RNA Processing, Post-Transcriptional ; RNA, Plant/metabolism ; RNA-Binding Proteins/genetics/*physiology ; Recombinant Fusion Proteins/metabolism ; Sequence Alignment ; Sequence Homology, Amino Acid ; Shelterin Complex ; Telomerase/*metabolism ; Telomere/metabolism/*ultrastructure ; Telomere-Binding Proteins/*metabolism ; Uridine/metabolism ; },
abstract = {Dyskerin binds the H/ACA box of human telomerase RNA and is a core telomerase subunit required for RNP biogenesis and enzyme function in vivo. Missense mutations in dyskerin result in dyskeratosis congenita, a complex syndrome characterized by bone marrow failure, telomerase enzyme deficiency, and progressive telomere shortening. Here we demonstrate that dyskerin also contributes to telomere maintenance in Arabidopsis thaliana. We report that both AtNAP57, the Arabidopsis dyskerin homolog, and AtTERT, the telomerase catalytic subunit, accumulate in the plant nucleolus, and AtNAP57 associates with active telomerase RNP particles in an RNA-dependent manner. Furthermore, AtNAP57 interacts in vitro with AtPOT1a, a novel component of Arabidopsis telomerase. Although a null mutation in AtNAP57 is lethal, AtNAP57, like AtTERT, is not haploinsufficient for telomere maintenance in Arabidopsis. However, introduction of an AtNAP57 allele containing a T66A mutation decreased telomerase activity in vitro, disrupted telomere length regulation on individual chromosome ends in vivo, and established a new, shorter telomere length set point. These results imply that T66A NAP57 behaves as a dominant-negative inhibitor of telomerase. We conclude that dyskerin is a conserved component of the telomerase RNP complex in higher eukaryotes that is required for maximal enzyme activity in vivo.},
}
@article {pmid18202693,
year = {2008},
author = {Kao, HT and Cawthon, RM and Delisi, LE and Bertisch, HC and Ji, F and Gordon, D and Li, P and Benedict, MM and Greenberg, WM and Porton, B},
title = {Rapid telomere erosion in schizophrenia.},
journal = {Molecular psychiatry},
volume = {13},
number = {2},
pages = {118-119},
doi = {10.1038/sj.mp.4002105},
pmid = {18202693},
issn = {1359-4184},
support = {R01 MH044292/MH/NIMH NIH HHS/United States ; R01 MH070898/MH/NIMH NIH HHS/United States ; R01 NS047209/NS/NINDS NIH HHS/United States ; R21 MH071720/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Analysis of Variance ; Case-Control Studies ; Cohort Studies ; Family Health ; Female ; Humans ; Male ; Middle Aged ; Schizophrenia/*genetics/*physiopathology ; Telomere/genetics/*metabolism ; },
}
@article {pmid18202371,
year = {2008},
author = {Makovets, S and Williams, TL and Blackburn, EH},
title = {The telotype defines the telomere state in Saccharomyces cerevisiae and is inherited as a dominant non-Mendelian characteristic in cells lacking telomerase.},
journal = {Genetics},
volume = {178},
number = {1},
pages = {245-257},
pmid = {18202371},
issn = {0016-6731},
support = {R01 GM026259/GM/NIGMS NIH HHS/United States ; R37 GM026259/GM/NIGMS NIH HHS/United States ; GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Crosses, Genetic ; DNA, Mitochondrial/genetics ; Epigenesis, Genetic ; Gene Silencing ; *Genes, Dominant ; Genes, Mating Type, Fungal ; Inheritance Patterns/*genetics ; Microbial Viability ; Models, Genetic ; Mutation/genetics ; Prions/metabolism ; Saccharomyces cerevisiae/*cytology/*enzymology/genetics ; Telomerase/*deficiency ; Telomere/*metabolism ; Time Factors ; },
abstract = {Telomeres are an unusual component of the genome because they do not encode genes, but their structure and cellular maintenance machinery (which we define as "telotype") are essential for chromosome stability. Cells can switch between different phenotypic states. One such example is when they switch from maintenance mediated by telomerase (TERT telotype) to one of the two alternative mechanisms of telomere preservation (ALT I and ALT II telotype). The nature of this switch is largely unknown. Reintroduction of telomerase into ALT II, but not ALT I, yeast led to the loss of their ability to survive a second round of telomerase withdrawal. Mating-based genetic analysis of ALT I and II revealed that both types of telomerase-independent telomere maintenance are inherited as a non-Mendelian trait dominant over senescence (SEN telotype). Additionally, inheritance of ALT I and ALT II did not depend on either the mitochondrial genome or a prion-based mechanism. Type I, but not type II, survivor cells exhibited impaired gene silencing, potentially connecting the switch to the ALT telotype epigenetic changes. These data provide evidence that nonprion epigenetic-like mechanisms confer flexibility on cells as a population to adjust to the life-threatening situation of telomerase loss, allowing cells to switch from TERT to ALT telotypes that can sustain viable populations.},
}
@article {pmid18199471,
year = {2008},
author = {Weng, NP},
title = {Telomere and adaptive immunity.},
journal = {Mechanisms of ageing and development},
volume = {129},
number = {1-2},
pages = {60-66},
pmid = {18199471},
issn = {0047-6374},
support = {Z01 AG000756-10//Intramural NIH HHS/United States ; },
mesh = {B-Lymphocytes/cytology/enzymology/*immunology ; Cell Differentiation ; *Cellular Senescence ; Dyskeratosis Congenita/genetics ; Humans ; Immunity, Cellular ; Oxidative Stress ; T-Lymphocytes/cytology/enzymology/*immunology ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {The adaptive immune response relies on the ability of lymphocytes to undergo periodic massive expansion. It is an enigma how lymphocytes are able to undergo this seemingly unlimited number of cell divisions. Telomeres and telomerase play a critical role in regulation of the replicative lifespan of cells, providing a potential mechanism which lymphocytes may employ. Here I will review the recent progress of the role of telomeres and telomerase in lymphocyte differentiation, function, and aging.},
}
@article {pmid18198332,
year = {2008},
author = {Longhese, MP},
title = {DNA damage response at functional and dysfunctional telomeres.},
journal = {Genes &amp; development},
volume = {22},
number = {2},
pages = {125-140},
pmid = {18198332},
issn = {0890-9369},
mesh = {Animals ; DNA Breaks, Double-Stranded ; *DNA Damage ; DNA Repair ; DNA, Single-Stranded ; Eukaryotic Cells ; Models, Genetic ; Recombination, Genetic ; Telomere/*physiology ; },
abstract = {The ends of eukaryotic chromosomes have long been defined as structures that must avoid being detected as DNA breaks. They are protected from checkpoints, homologous recombination, end-to-end fusions, or other events that normally promote repair of intrachromosomal DNA breaks. This differentiation is thought to be the consequence of a unique organization of chromosomal ends into specialized nucleoprotein complexes called telomeres. However, it is becoming increasingly clear that proteins governing the DNA damage response are intimately involved in the regulation of telomeres, which undergo processing and structural changes that elicit a transient DNA damage response. This suggests that functional telomeres can be recognized as DNA breaks during a temporally limited window, indicating that the difference between a break and a telomere is less defined than previously assumed.},
}
@article {pmid18198226,
year = {2008},
author = {Else, T and Giordano, TJ and Hammer, GD},
title = {Evaluation of telomere length maintenance mechanisms in adrenocortical carcinoma.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {93},
number = {4},
pages = {1442-1449},
doi = {10.1210/jc.2007-1840},
pmid = {18198226},
issn = {0021-972X},
mesh = {Adrenal Cortex Neoplasms/*genetics ; Adult ; Aged ; Child ; Child, Preschool ; Female ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Telomerase/metabolism ; *Telomere ; },
abstract = {CONTEXT: Adrenocortical cancer (ACC) is a rare disease with an often fatal outcome. The clinical and pathological diagnosis of a malignant vs. benign adrenocortical tumor is sometimes challenging. Telomere maintenance mechanisms (TMMs) are critical for the persistence of the malignant phenotype, but little is known about these mechanisms or their diagnostic value in adrenocortical lesions.<br><br>OBJECTIVE: Tissue samples of diagnostically known adrenocortical neoplasms were evaluated for parameters of known TMMs, telomerase activity (TA), and alternative telomere lengthening (ALT).<br><br>DESIGN: The study analyzed retrospectively collected frozen adrenocortical tissue samples from the University of Michigan Health System.<br><br>PATIENT SAMPLES: Samples included 24 ACCs, 11 adrenocortical adenomas (ACAs), and three normal adrenal tissues.<br><br>MAIN OUTCOME MEASURES: Telomerase activity (telomerase activity protocol assay), alternative telomere lengthening (telomere restriction fragment analysis, telomere associated promyelocyte leukemia bodies) were measured.<br><br>RESULTS: A total of 22 of 24 ACCs (92%) could be definitively assigned to a TMM. The TMM classification was: 19 of 24 TA (79%), two of which displayed very long telomeres, one of 24 ALT (4%) and two of 24 (8%) TA and ALT. Results of two of 24 (8%) were inconclusive (one negative for TA and positive in one ALT assay, one negative in all assays). None of the normal adrenal tissues (none of three) or ACA (none of 11) samples had signs of an active TMM.<br><br>CONCLUSIONS: TA is the main TMM in the majority of ACCs, but subsets of ACCs additionally or exclusively exhibit signs of ALT. Determination of telomere maintenance mechanisms in diagnostically challenging adrenocortical tumors might be of additional diagnostic value in the pathological diagnosis of malignant vs. benign lesions.},
}
@article {pmid18197499,
year = {2008},
author = {Yi, BQ and Zhao, B and Wang, ZJ},
title = {[Expression of hRad21 and clinicopathological analysis in gastrointestinal malignant tumors maintained their telomeres by a mechanism of alternative lengthening of telomeres].},
journal = {Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery},
volume = {11},
number = {1},
pages = {67-71},
pmid = {18197499},
issn = {1671-0274},
mesh = {Cell Cycle Proteins ; DNA-Binding Proteins ; Female ; Gastrointestinal Neoplasms/*metabolism/*pathology ; Humans ; Male ; Neoplasm Invasiveness ; Nuclear Proteins/*metabolism ; Phosphoproteins/*metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {OBJECTIVE: To investigate the proportion between tumors which maintain their telomeres by a mechanism of alternative lengthening of telomeres(ALT) and telomerase-dependent tumors in gastrointestinal malignant tumors, the expression difference of hRad21 between the two groups and the clinicopathological characteristics of ALT tumors were also explored.<br><br>METHODS: One hundred and four cases of gastrointestinal malignant tumors were divided into 2 groups: ALT group and telomerase group by detecting telomerase activity using TRAP method. Expression difference of hRad21 was investigated between the two groups. All the patients were followed up and clinicopathological data of these patients were analyzed.<br><br>RESULTS: Of 104 cases, there were 12 cases in ALT group and 94 cases in telomerase group. Expression of hRad21 in ALT group was higher than that in telomerase group. Tumors in ALT group had a thinner invasion depth (lower T stage) as compared to telomerase group (P=0.021). Other indexes, such as age, gender, tumor size, tumor grade, location of tumor, CEA and CA199, were not significantly different between the two groups. Results of follow-up showed that the survival rate of ALT group was 100% while that of telomerase group was 56% at 30 months postoperatively.<br><br>CONCLUSIONS: There are tumors which maintain their telomeres by ALT in gastrointestinal malignant tumors, accounting for 10%-12% of the total tumors. As compared to telomerase group, ALT group presents higher expression of hRad21, thinner tumor invasion depth, and higher survival rate.},
}
@article {pmid18193446,
year = {2008},
author = {Rong, YS},
title = {Telomere capping in Drosophila: dealing with chromosome ends that most resemble DNA breaks.},
journal = {Chromosoma},
volume = {117},
number = {3},
pages = {235-242},
pmid = {18193446},
issn = {0009-5915},
support = {//Intramural NIH HHS/United States ; },
mesh = {Animals ; Chromosomes/*metabolism ; *DNA Breaks ; Drosophila Proteins/metabolism ; Drosophila melanogaster/*genetics ; Evolution, Molecular ; Telomere/*metabolism ; },
abstract = {Telomere caps prevent chromosome ends from being recognized as DNA double-strand breaks (DSBs). Unlike most organisms studied, the telomere-capping function of Drosophila does not require a specific sequence. Without this sequence component, Drosophila telomeres most resemble DNA breaks and, thus, represent a simpler system for the study of telomere capping. I review recent progress in Drosophila telomere studies, and challenge the notion that Drosophila may not be a relevant model for the study of telomere maintenance.},
}
@article {pmid18185984,
year = {2007},
author = {Else, T and Theisen, BK and Wu, Y and Hutz, JE and Keegan, CE and Hammer, GD and Ferguson, DO},
title = {Tpp1/Acd maintains genomic stability through a complex role in telomere protection.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {15},
number = {8},
pages = {1001-1013},
pmid = {18185984},
issn = {0967-3849},
support = {K08 HD042487/HD/NICHD NIH HHS/United States ; DK62027/DK/NIDDK NIH HHS/United States ; DK65313/DK/NIDDK NIH HHS/United States ; K08-HD42487/HD/NICHD NIH HHS/United States ; },
mesh = {Adrenal Cortex Diseases/*genetics/pathology ; Anaphase ; Animals ; Cells, Cultured ; Chromosomes/genetics ; Fibroblasts ; *Genomic Instability ; Humans ; Immunoenzyme Techniques ; In Situ Hybridization, Fluorescence ; Karyotyping ; Mice ; Mice, Inbred C57BL ; RNA, Messenger/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Shelterin Complex ; Spectral Karyotyping ; Telomere/*physiology ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {Telomeres serve to protect the ends of chromosomes, and failure to maintain telomeres can lead to dramatic genomic instability. Human TPP1 was identified as a protein which interacts with components of a telomere cap complex, but does not directly bind to telomeric DNA. While biochemical interactions indicate a function in telomere biology, much remains to be learned regarding the roles of TPP1 in vivo. We previously reported the positional cloning of the gene responsible for the adrenocortical dysplasia (acd) mouse phenotype, which revealed a mutation in the mouse homologue encoding TPP1. We find that cells from homozygous acd mice harbor chromosomes fused at telomere sequences, demonstrating a role in telomere protection in vivo. Surprisingly, our studies also reveal fusions and radial structures lacking internal telomere sequences, which are not anticipated from a simple deficiency in telomere protection. Employing spectral karyotyping and telomere FISH in a combined approach, we have uncovered a striking pattern; fusions with telomeric sequences involve nonhomologous chromosomes while those lacking telomeric sequences involve homologues. Together, these studies show that Tpp1/Acd plays a vital role in telomere protection, but likely has additional functions yet to be defined.},
}
@article {pmid18182620,
year = {2008},
author = {Bellon, M and Nicot, C},
title = {Regulation of telomerase and telomeres: human tumor viruses take control.},
journal = {Journal of the National Cancer Institute},
volume = {100},
number = {2},
pages = {98-108},
doi = {10.1093/jnci/djm269},
pmid = {18182620},
issn = {1460-2105},
support = {R01 CA106258/CA/NCI NIH HHS/United States ; R01 CA115398/CA/NCI NIH HHS/United States ; },
mesh = {Cell Division ; Cell Proliferation ; Cell Transformation, Neoplastic ; Cellular Senescence ; DNA Viruses ; Deltaretrovirus ; *Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Hepacivirus ; Hepatitis B virus ; Herpesvirus 4, Human ; Herpesvirus 8, Human ; Humans ; Neoplasms/enzymology/*virology ; Oncogene Proteins/metabolism ; Papillomaviridae ; RNA Viruses ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism/*virology ; *Transcription, Genetic ; Tumor Virus Infections/complications/*enzymology/virology ; Viral Proteins/metabolism ; },
abstract = {Human tumor viruses are responsible for one-fifth of all cancers worldwide. These viruses have evolved multiple strategies to evade immune defenses and to persist in the host by establishing a latent infection. Proliferation is necessary for pretumor cells to accumulate genetic alterations and to acquire a transformed phenotype. However, each cell division is associated with a progressive shortening of the telomeres, which can suppress tumor development by initiating senescence and irreversible cell cycle arrest. Therefore, the ability of virus-infected cells to circumvent the senescence program is essential for the long-term survival and proliferation of infected cells and the likelihood of transformation. We review the multiple strategies used by human DNA and RNA tumor viruses to subvert telomerase functions during cellular transformation and carcinogenesis. Epstein-Barr virus, Kaposi sarcoma-associated herpesvirus, human papillomavirus, hepatitis B virus, hepatitis C virus, and human T-cell leukemia virus-1 each can increase transcription of the telomerase reverse transcriptase. Several viruses appear to mediate cis-activation or enhance epigenetic activation of telomerase transcription. Epstein-Barr virus and human papillomavirus have each developed posttranscriptional mechanisms to regulate the telomerase protein. Finally, some tumor virus proteins can also negatively regulate telomerase transcription or activity. It is likely that, as future studies further expose the strategies used by viruses to deregulate telomerase activity and control of telomere length, novel mechanisms will emerge and underscore the importance of increased telomerase activity in sustaining virus-infected cells and its potential in therapeutic targeting.},
}
@article {pmid18178559,
year = {2008},
author = {Etheridge, KT and Compton, SA and Barrientos, KS and Ozgur, S and Griffith, JD and Counter, CM},
title = {Tethering telomeric double- and single-stranded DNA-binding proteins inhibits telomere elongation.},
journal = {The Journal of biological chemistry},
volume = {283},
number = {11},
pages = {6935-6941},
doi = {10.1074/jbc.M708711200},
pmid = {18178559},
issn = {0021-9258},
support = {CA82481/CA/NCI NIH HHS/United States ; ES13773/ES/NIEHS NIH HHS/United States ; GM31819/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line ; DNA/*chemistry ; DNA, Single-Stranded/*chemistry ; DNA-Binding Proteins/*chemistry ; *Gene Expression Regulation ; Humans ; Microscopy, Fluorescence ; Models, Biological ; Nuclear Proteins/chemistry/*physiology ; Nucleic Acid Conformation ; Protein Binding ; Shelterin Complex ; Telomerase/metabolism ; Telomere/ultrastructure ; Telomere-Binding Proteins/chemistry/*physiology ; Telomeric Repeat Binding Protein 1/chemistry/*physiology ; Telomeric Repeat Binding Protein 2/chemistry/*physiology ; Tripeptidyl-Peptidase 1 ; },
abstract = {Mammalian telomeres are composed of G-rich repetitive double-stranded (ds) DNA with a 3' single-stranded (ss) overhang and associated proteins that together maintain chromosome end stability. Complete replication of telomeric DNA requires de novo elongation of the ssDNA by the enzyme telomerase, with telomeric proteins playing a key role in regulating telomerase-mediated telomere replication. In regards to the protein component of mammalian telomeres, TRF1 and TRF2 bind to the dsDNA of telomeres, whereas POT1 binds to the ssDNA portion. These three proteins are linked through either direct interactions or by the proteins TIN2 and TPP1. To determine the biological consequence of connecting telomeric dsDNA to ssDNA through a multiprotein assembly, we compared the effect of expressing TRF1 and POT1 in trans versus in cis in the form of a fusion of these two proteins, on telomere length in telomerase-positive cells. When expressed in trans these two proteins induced extensive telomere elongation. Fusing TRF1 to POT1 abrogated this effect, inducing mild telomere shortening, and generated looped DNA structures, as assessed by electron microscopy, consistent with the protein forming a complex with dsDNA and ssDNA. We speculate that such a protein bridge between dsDNA and ssDNA may inhibit telomerase access, promoting telomere shortening.},
}
@article {pmid18162125,
year = {2008},
author = {Bechan, GI and Meeker, AK and De Marzo, AM and Racke, F and Jaffe, R and Sugar, E and Arceci, RJ},
title = {Telomere length shortening in Langerhans cell histiocytosis.},
journal = {British journal of haematology},
volume = {140},
number = {4},
pages = {420-428},
doi = {10.1111/j.1365-2141.2007.06904.x},
pmid = {18162125},
issn = {1365-2141},
mesh = {Antigens, CD1/analysis ; Histiocytosis, Langerhans-Cell/*genetics/pathology ; Humans ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Langerhans Cells/*ultrastructure ; Lymph Nodes/ultrastructure ; Precancerous Conditions/genetics/pathology ; Skin/ultrastructure ; Telomere/*ultrastructure ; },
abstract = {Langerhans cell histiocytosis (LCH) is a clonal, proliferative disorder of phenotypically immature CD1a(+) Langerhans cells (LC). The aetiology of LCH is unknown and data supporting an immune dysregulatory disorder as well as a clonal neoplasm have been reported. Telomere shortening has been associated with cancers and premalignant lesions as well as promoting chromosomal instability. To determine whether LCH LC have altered telomere lengths, we used dual detection of CD1a expression by immunofluorescence and telomere length by fluorescence in situ hybridization of LCH LC and lymphocytes in local, multisystem and systemic LCH and compared these with telomere lengths of LC and lymphocytes in reactive lymph nodes. LCH LC showed significantly shorter telomere lengths than LC from reactive lymph nodes or unaffected skin. Lymphocyte telomere lengths showed similar profiles among the different samples. These data show a significant telomere shortening in LCH LC in all stages of disease involvement compared with LC from reactive lymph nodes, suggesting that LCH may share mechanisms of telomere shortening and survival with clonal preneoplastic disorders and cancer, although an initiating infectious or immune event is still possible.},
}
@article {pmid18160795,
year = {2007},
author = {Galvão Bezerra dos Santos, K and Becker, HC and Ecke, W and Bellin, U},
title = {Molecular characterisation and chromosomal localisation of a telomere-like repetitive DNA sequence highly enriched in the C genome of Brassica.},
journal = {Cytogenetic and genome research},
volume = {119},
number = {1-2},
pages = {147-153},
doi = {10.1159/000109632},
pmid = {18160795},
issn = {1424-859X},
mesh = {Base Composition ; Base Sequence ; Brassica/*genetics ; Chromosomes, Plant/*genetics ; DNA, Plant/*genetics ; Diploidy ; Genome, Plant/*genetics ; Metaphase/genetics ; Molecular Sequence Data ; Telomere/*genetics ; },
abstract = {The aim of this work was to find C genome specific repetitive DNA sequences able to differentiate the homeologous A (B. rapa) and C (B. oleracea) genomes of Brassica, in order to assist in the physical identification of B. napus chromosomes. A repetitive sequence (pBo1.6) highly enriched in the C genome of Brassica was cloned from B. oleracea and its chromosomal organisation was investigated through fluorescent in situ hybridisation (FISH) in B. oleracea (2n = 18, CC), B. rapa (2n = 20, AA) and B. napus (2n = 38, AACC) genomes. The sequence was 203 bp long with a GC content of 48.3%. It showed up to 89% sequence identity with telomere-like DNA from many plant species. This repeat was clearly underrepresented in the A genome and the in situ hybridisation showed its B. oleracea specificity at the chromosomal level. Sequence pBo1.6 was localised at interstitial and/or telomeric/subtelomeric regions of all chromosomes from B. oleracea, whereas in B. rapa no signal was detected in most of the cells. In B. napus 18 to 24 chromosomes hybridised with pBo1.6. The discovery of a sequence highly enriched in the C genome of Brassica opens the opportunity for detailed studies regarding the subsequent evolution of DNA sequences in polyploid genomes. Moreover, pBo1.6 may be useful for the determination of the chromosomal location of transgenic DNA in genetically modified oilseed rape.},
}
@article {pmid18160783,
year = {2007},
author = {Skrobot Vidacek, N and Cukusić, A and Ferenac Kis, M and Ivanković, M and Jevtov, I and Mrsić, S and Rubelj, I},
title = {Telomere dynamics and genome stability in the human pancreatic tumor cell line MIAPaCa-2.},
journal = {Cytogenetic and genome research},
volume = {119},
number = {1-2},
pages = {60-67},
doi = {10.1159/000109620},
pmid = {18160783},
issn = {1424-859X},
mesh = {Apoptosis ; Cell Line, Tumor ; Chromosomes, Human, X/genetics ; Genome, Human/genetics ; Genomic Instability/*genetics ; Humans ; Karyotyping ; Pancreatic Neoplasms/*genetics/pathology ; Telomere/*genetics ; },
abstract = {Telomeres are specialized structures found at the ends of eukaryotic chromosomes serving as guardians of genome stability. In normal cells telomeres shorten with each cell division, but immortal cells undergoing multiple divisions constantly have to maintain telomere lengths above a critical level. This is accomplished either through expression of telomerase or the alternative recombination pathway (ALT). In the present study, we analyzed telomere dynamics of the telomerase positive human pancreatic tumor cell line MIAPaCa-2. The cells demonstrated genomic instability with a high frequency of chromosomal aberrations resulting in differences between individual karyotypes within the same cell population. The telomeres were short when compared with normal human fibroblasts, and about 39% of the chromosome ends did not have detectable telomere repeats as demonstrated by PNA-FISH. In many cases telomere signals were missing even when sister chromatids were strongly labeled. In addition, we used an internal PNA probe specific for the X chromosome, present in a single copy in these cells, in order to follow telomere dynamics on individual chromatids. High heterogeneity in telomere signals among individual X chromosomes as well as between their sister chromatids suggested sudden and stochastic loss or gain of telomere repeats. Such constant genomic instability often results in apoptosis and death of a fraction of cells present in the culture at all times. We discuss possible molecular mechanisms that may explain this observed telomere heterogeneity and possible adaptive repair mechanisms by which these cells maintain their chromosomes in order to survive such extreme and permanent genomic instability.},
}
@article {pmid18160711,
year = {2008},
author = {Subramanian, L and Moser, BA and Nakamura, TM},
title = {Recombination-based telomere maintenance is dependent on Tel1-MRN and Rap1 and inhibited by telomerase, Taz1, and Ku in fission yeast.},
journal = {Molecular and cellular biology},
volume = {28},
number = {5},
pages = {1443-1455},
pmid = {18160711},
issn = {1098-5549},
support = {GM28039/GM/NIGMS NIH HHS/United States ; R01 GM078253-02/GM/NIGMS NIH HHS/United States ; GM078253/GM/NIGMS NIH HHS/United States ; R01 GM028039/GM/NIGMS NIH HHS/United States ; R01 GM078253/GM/NIGMS NIH HHS/United States ; },
mesh = {Antigens, Nuclear/genetics ; DNA-Binding Proteins/*antagonists &amp; inhibitors/genetics ; Ku Autoantigen ; Plasmids ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Recombination, Genetic ; Schizosaccharomyces/genetics/*physiology ; Schizosaccharomyces pombe Proteins/*antagonists &amp; inhibitors/genetics/*metabolism ; Shelterin Complex ; Telomerase/*antagonists &amp; inhibitors/genetics ; Telomere/genetics/*physiology ; Telomere-Binding Proteins/*antagonists &amp; inhibitors/genetics/*metabolism ; },
abstract = {Fission yeast cells survive loss of the telomerase catalytic subunit Trt1 (TERT) through recombination-based telomere maintenance or through chromosome circularization. Although trt1Delta survivors with linear chromosomes can be obtained, they often spontaneously circularize their chromosomes. Therefore, it was difficult to establish genetic requirements for telomerase-independent telomere maintenance. In contrast, when the telomere-binding protein Taz1 is also deleted, taz1Delta trt1Delta cells are able to stably maintain telomeres. Thus, taz1Delta trt1Delta cells can serve as a valuable tool in understanding the regulation of telomerase-independent telomere maintenance. In this study, we show that the checkpoint kinase Tel1 (ATM) and the DNA repair complex Rad32-Rad50-Nbs1 (MRN) are required for telomere maintenance in taz1Delta trt1Delta cells. Surprisingly, Rap1 is also essential for telomere maintenance in taz1Delta trt1Delta cells, even though recruitment of Rap1 to telomeres depends on Taz1. Expression of catalytically inactive Trt1 can efficiently inhibit recombination-based telomere maintenance, but the inhibition requires both Est1 and Ku70. While Est1 is essential for recruitment of Trt1 to telomeres, Ku70 is dispensable. Thus, we conclude that Taz1, TERT-Est1, and Ku70-Ku80 prevent telomere recombination, whereas MRN-Tel1 and Rap1 promote recombination-based telomere maintenance. Evolutionarily conserved proteins in higher eukaryotic cells might similarly contribute to telomere recombination.},
}
@article {pmid18160098,
year = {2008},
author = {Savage, SA and Alter, BP},
title = {The role of telomere biology in bone marrow failure and other disorders.},
journal = {Mechanisms of ageing and development},
volume = {129},
number = {1-2},
pages = {35-47},
pmid = {18160098},
issn = {0047-6374},
support = {Z99 CA999999//Intramural NIH HHS/United States ; },
mesh = {Anemia, Aplastic/*genetics ; Dyskeratosis Congenita/genetics ; Hematologic Diseases/genetics ; Humans ; Inheritance Patterns ; Mutation ; Syndrome ; Telomere/chemistry/*metabolism ; },
abstract = {Telomeres, consisting of nucleotide repeats and a protein complex at chromosome ends, are essential in maintaining chromosomal integrity. Dyskeratosis congenita (DC) is the inherited bone marrow failure syndrome (IBMFS) that epitomizes the effects of abnormal telomere biology. Patients with DC have extremely short telomere lengths (<1st percentile) and many have mutations in telomere biology genes. Interpretation of telomere length in other IBMFSs is less straightforward. Abnormal telomere shortening has been reported in patients with apparently acquired hematologic disorders, including aplastic anemia, myeolodysplasia, paroxysmal nocturnal hemoglobinuria, and leukemia. In these disorders, the shortest-lived cells have the shortest telomeres, suggestive of increased hematopoietic stress. Telomeres are also markers of replicative and/or oxidative stress in other complex disease pathways, such as inflammation, stress, and carcinogenesis. The spectrum of related disorders caused by mutations in telomere biology genes extends beyond classical DC to include marrow failure that does not respond to immunosuppression, idiopathic pulmonary fibrosis, and possibly other syndromes. We suggest that such patients be categorized as having an inherited disorder of telomere biology. Longitudinal studies of patients with very short telomeres but without classical DC are necessary to further understand the long-term sequelae, such as malignancy, osteonecrosis/osteoporosis, and pulmonary and liver disease.},
}
@article {pmid18159961,
year = {2008},
author = {Bailey, SM},
title = {Telomeres and double-strand breaks - all's well that "ends" well. ..},
journal = {Radiation research},
volume = {169},
number = {1},
pages = {1-7},
doi = {10.1667/RR1197.1},
pmid = {18159961},
issn = {0033-7587},
mesh = {Animals ; *Awards and Prizes ; *DNA Breaks, Double-Stranded/radiation effects ; Humans ; Telomere/*genetics/*metabolism/radiation effects ; },
abstract = {Bailey, S. Telomeres and Double-Strand Breaks - All's Well that "Ends" Well. ... Radiat. Res. 169, 1-7 (2008). Sometimes one's life (including one's science) makes a lot more sense when viewed from the perspective of time, reflected back on over a number of years. That has indeed been the case for me. Strangely enough, the story begins with chromosomes and "ends" with telomeres, both at Colorado State University. And, just as with chromosomes, a lot happened in between. Telomeres were first identified based on their function-they protected the physical ends of chromosomes from interaction with broken DNA ends created by ionizing radiation. While I was at Los Alamos National Laboratory, the sequence of human telomeres was discovered, making probes available that allowed us to re-examine and provide direct support of these early observations; thus began my fascination with telomeres. Chromosome orientation in situ hybridization (CO-FISH) also came onto the scene while I was in Los Alamos. This strand-specific modification of standard FISH, especially when combined with telomeric sequence probes, has proven to be a powerful approach that provides information not available by any other means. Applications have included pericentric inversion detection, distinction between leading- and lagging-strand telomeres, and identification of telomere-double-strand break (DSB) fusions. We also provided the first direct evidence that DSB repair proteins (DNA-PK in particular) are required for mammalian telomeric end capping, and we have been characterizing telomere dysfunction in NHEJ and HR repair-deficient backgrounds ever since. Cells must correctly distinguish between DNA ends represented by telomeres and DNA ends produced by DSBs if all is to end well. Just as these studies have provided new insight into the complex, often surprising, interactions at DNA ends, they also provoke new questions. Whereas it is now well established that DSB repair proteins associate with telomeres, most recently we've been asking whether the reverse scenario holds: Do telomere proteins interact with DSBs? We find that DSBs induced by ionizing radiations are not sufficient to recruit the essential telomere protein TRF2 as an early damage response, so perhaps this interplay is a one-way street. The rest of the story waits to unfold.},
}
@article {pmid18158557,
year = {2008},
author = {Oh, BK and Kim, H and Park, YN and Yoo, JE and Choi, J and Kim, KS and Lee, JJ and Park, C},
title = {High telomerase activity and long telomeres in advanced hepatocellular carcinomas with poor prognosis.},
journal = {Laboratory investigation; a journal of technical methods and pathology},
volume = {88},
number = {2},
pages = {144-152},
doi = {10.1038/labinvest.3700710},
pmid = {18158557},
issn = {1530-0307},
mesh = {Adult ; Aged ; Carcinoma, Hepatocellular/*enzymology/metabolism/pathology ; Cell Differentiation/physiology ; Female ; Humans ; Keratin-19/metabolism ; Liver Neoplasms/*enzymology/metabolism/pathology ; Male ; Middle Aged ; Mitosis/*physiology ; Prognosis ; RNA, Messenger/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomerase reactivation and telomere maintenance are crucial in carcinogenesis and tumor progression. In this study, the relationships between telomere parameters, chromosomal instability and clinicopathological features were evaluated in hepatocellular carcinomas (HCCs). Telomere length (TL), telomerase activity (TA) and human telomerase reverse transcriptase (hTERT) mRNA levels were measured in 49 hepatitis B virus (HBV)-related HCCs and corresponding non-tumorous tissues. The results were compared with clinicopathological data, including differentiation, multipolar mitosis (MM), anaphase bridge, immunohistochemical stain results for cytokeratin 19 (CK19) and patient outcome. TL of HCCs ranged from 4.7 to 13.1 kb, and 44.4% of HCCs showed telomere lengthening. hTERT mRNA levels and TA were closely related (P=0.008), and were significantly higher in HCCs than non-tumorous tissues. TL was significantly higher in HCCs with strong TA (P=0.048), high hTERT mRNA levels (P=0.001) and poor differentiation (P=0.041). Frequent MM was associated with poor differentiation (P=0.007) and advanced stage (P<0.001). TA was positively correlated with MM, anaphase bridges and advanced stage (P=0.019, P=0.017 and P=0.029). Thirteen (28.3%) HCCs were CK19+ and demonstrated longer telomeres than CK19- HCCs (P=0.046). Overall survival was poor in HCCs with MM >0.4 per field (P=0.016), high TA (P=0.009) and high TL ratio (HCC/non-HCC) >0.8 (P=0.044). Our results show that long telomeres, high TA and high mitotic instability are poor prognostic markers for HBV-related HCCs and their close association suggests that telomere maintenance may be important for the progression of HCCs with high chromosomal instability to more aggressive ones.},
}
@article {pmid18157120,
year = {2008},
author = {Schoeftner, S and Blasco, MA},
title = {Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II.},
journal = {Nature cell biology},
volume = {10},
number = {2},
pages = {228-236},
doi = {10.1038/ncb1685},
pmid = {18157120},
issn = {1476-4679},
mesh = {Animals ; Cells, Cultured ; Gene Expression Regulation, Developmental ; Heterochromatin/genetics/metabolism ; In Situ Hybridization, Fluorescence ; Mice ; Protein Binding ; RNA/metabolism/*physiology ; RNA Polymerase II/*physiology ; Telomerase/physiology ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; Transcription, Genetic ; },
abstract = {Mammalian telomeres consist of non-coding TTAGGG repeats that are bound by the multi-protein complex 'shelterin', thus protecting chromosome ends from DNA repair mechanisms and degradation. Mammalian telomeric chromatin is enriched for the constitutive heterochromatin marks H3K9me3, H4K20me3 and HP1 (refs 2, 3, 4, 5, 6, 7). Similar to pericentric heterochromatin, telomeric heterochromatin is thought to be fundamental for the maintenance of chromosomal integrity. Here, we report that telomeric repeats are transcribed by DNA-dependent RNA polymerase II, which, in turn, interacts with the TRF1 shelterin protein. Telomeric RNAs (TelRNAs) contain UUAGGG repeats, are polyadenylated and are transcribed from the telomeric C-rich strand. Transcription of mammalian telomeres is regulated by several mechanisms, including developmental status, telomere length, cellular stress, tumour stage and chromatin structure. Using RNA-flourescent in situ hybridization (FISH), we show that TelRNAs are novel structural components of telomeric chromatin. Importantly, we provide evidence that TelRNAs block the activity of telomerase in vitro, suggesting that TelRNAs may regulate telomerase activity at chromosome ends. Our results indicate that TelRNAs are novel components of mammalian telomeres, which are anticipated to be fundamental for understanding telomere biology and telomere-related diseases, such as cancer and ageing.},
}
@article {pmid18155157,
year = {2008},
author = {Zhong, YH and Liao, ZK and Zhou, FX and Xie, CH and Xiao, CY and Pan, DF and Luo, ZG and Liu, SQ and Zhou, YF},
title = {Telomere length inversely correlates with radiosensitivity in human carcinoma cells with the same tissue background.},
journal = {Biochemical and biophysical research communications},
volume = {367},
number = {1},
pages = {84-89},
doi = {10.1016/j.bbrc.2007.12.078},
pmid = {18155157},
issn = {1090-2104},
mesh = {Blotting, Southern ; *Breast Neoplasms/pathology/therapy ; Cell Line, Tumor/cytology/pathology/radiation effects ; Cell Survival/physiology/radiation effects ; Colony-Forming Units Assay ; Dose-Response Relationship, Radiation ; *Gamma Rays ; Humans ; *Laryngeal Neoplasms/pathology/therapy ; *Liver Neoplasms/pathology/therapy ; Telomere/physiology/*radiation effects ; },
abstract = {A relationship between telomeres and radiosensitivity has been established by several studies based on non-mammalian model systems, mouse models, and few human genetic diseases. However, the relationship has not been proven in human carcinoma cells, which have more clinical significance than these other models. The present study aims to determine whether telomere length is related to radiosensitivity in human carcinoma cells, and to examine the influence of tissue or genetic background. Two HEp-2 larynx squamous carcinoma cell lines, eight hepatocellular carcinoma cell lines, and five breast cancer cell lines were used. Telomere length was determined by terminal restriction fragment (TRF) Southern blot analysis and cell survival was measured by a colony-forming assay. Our results indicated that there was a significant negative correlation of telomere length and radiosensitivity in the same tissue-derived cell lines, with or without the same genetic background. Thus, telomere length may be used as a promising tool to predict the radiosensitivity of human carcinomas.},
}
@article {pmid18154680,
year = {2007},
author = {Mickle, KL and Oliva, A and Huberman, JA and Leatherwood, J},
title = {Checkpoint effects and telomere amplification during DNA re-replication in fission yeast.},
journal = {BMC molecular biology},
volume = {8},
number = {},
pages = {119},
pmid = {18154680},
issn = {1471-2199},
support = {R01 GM070566/GM/NIGMS NIH HHS/United States ; GM-070566/GM/NIGMS NIH HHS/United States ; P40RR01632004/RR/NCRR NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics/metabolism ; Checkpoint Kinase 2 ; DNA Replication/*physiology ; Genome, Fungal/*physiology ; Heterochromatin/genetics/metabolism ; Protein Kinases/genetics/metabolism ; Protein Serine-Threonine Kinases/genetics/metabolism ; Replication Origin/*physiology ; S Phase/*physiology ; Schizosaccharomyces/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {BACKGROUND: Although much is known about molecular mechanisms that prevent re-initiation of DNA replication on newly replicated DNA during a single cell cycle, knowledge is sparse regarding the regions that are most susceptible to re-replication when those mechanisms are bypassed and regarding the extents to which checkpoint pathways modulate re-replication. We used microarrays to learn more about these issues in wild-type and checkpoint-mutant cells of the fission yeast, Schizosaccharomyces pombe.<br><br>RESULTS: We found that over-expressing a non-phosphorylatable form of the replication-initiation protein, Cdc18 (known as Cdc6 in other eukaryotes), drove re-replication of DNA sequences genome-wide, rather than forcing high level amplification of just a few sequences. Moderate variations in extents of re-replication generated regions spanning hundreds of kilobases that were amplified (or not) approximately 2-fold more (or less) than average. However, these regions showed little correlation with replication origins used during S phase. The extents and locations of amplified regions in cells deleted for the checkpoint genes encoding Rad3 (ortholog of human ATR and budding yeast Mec1) and Cds1 (ortholog of human Chk2 and budding yeast Rad53) were similar to those in wild-type cells. Relatively minor but distinct effects, including increased re-replication of heterochromatic regions, were found specifically in cells lacking Rad3. These might be due to Cds1-independent roles for Rad3 in regulating re-replication and/or due to the fact that cells lacking Rad3 continued to divide during re-replication, unlike wild-type cells or cells lacking Cds1. In both wild-type and checkpoint-mutant cells, regions near telomeres were particularly susceptible to re-replication. Highly re-replicated telomere-proximal regions (50-100 kb) were, in each case, followed by some of the least re-replicated DNA in the genome.<br><br>CONCLUSION: The origins used, and the extent of replication fork progression, during re-replication are largely independent of the replication and DNA-damage checkpoint pathways mediated by Cds1 and Rad3. The fission yeast pattern of telomere-proximal amplification adjacent to a region of under-replication has also been seen in the distantly-related budding yeast, which suggests that subtelomeric sequences may be a promising place to look for DNA re-replication in other organisms.},
}
@article {pmid18096749,
year = {2008},
author = {Schober, H and Kalck, V and Vega-Palas, MA and Van Houwe, G and Sage, D and Unser, M and Gartenberg, MR and Gasser, SM},
title = {Controlled exchange of chromosomal arms reveals principles driving telomere interactions in yeast.},
journal = {Genome research},
volume = {18},
number = {2},
pages = {261-271},
pmid = {18096749},
issn = {1088-9051},
support = {R01 GM051402/GM/NIGMS NIH HHS/United States ; },
mesh = {Blotting, Southern ; Chromosomes, Fungal/*genetics ; Crossing Over, Genetic/*genetics ; Electrophoresis, Agar Gel ; Gene Expression Regulation, Fungal/*genetics ; Microscopy, Fluorescence ; Saccharomyces cerevisiae/*genetics ; Telomere/genetics/*metabolism ; },
abstract = {The 32 telomeres in the budding yeast genome cluster in three to seven perinuclear foci. Although individual telomeres and telomeric foci are in constant motion, preferential juxtaposition of some telomeres has been scored. To examine the principles that guide such long-range interactions, we differentially tagged pairs of chromosome ends and developed an automated three-dimensional measuring tool that determines distances between two telomeres. In yeast, all chromosomal ends terminate in TG(1-3) and middle repetitive elements, yet subgroups of telomeres also share extensive homology in subtelomeric coding domains. We find that up to 21 kb of >90% sequence identity does not promote telomere pairing in interphase cells. To test whether unique sequence elements, arm length, or chromosome territories influence juxtaposition, we reciprocally swapped terminal domains or entire chromosomal arms from one chromosome to another. We find that the distal 10 kb of Tel6R promotes interaction with Tel6L, yet only when the two telomeres are present on the same chromosome. By manipulating the length and sequence composition of the right arm of chr 5, we confirm that contact between telomeres on opposite chromatid arms of equal length is favored. These results can be explained by the polarized Rabl arrangement of yeast centromeres and telomeres, which promote to telomere pairing by allowing contact between chromosome arms of equal length in anaphase.},
}
@article {pmid18091019,
year = {2008},
author = {Kadi, F and Ponsot, E and Piehl-Aulin, K and Mackey, A and Kjaer, M and Oskarsson, E and Holm, L},
title = {The effects of regular strength training on telomere length in human skeletal muscle.},
journal = {Medicine and science in sports and exercise},
volume = {40},
number = {1},
pages = {82-87},
doi = {10.1249/mss.0b013e3181596695},
pmid = {18091019},
issn = {0195-9131},
mesh = {Adult ; Case-Control Studies ; Humans ; Male ; Muscle Contraction/*physiology ; Muscle Strength/*physiology ; Muscle, Skeletal/*physiology ; Satellite Cells, Skeletal Muscle ; *Telomerase ; *Telomere ; *Telomeric Repeat Binding Protein 1 ; Weight Lifting/*physiology ; Weight-Bearing ; },
abstract = {PURPOSE: The length of DNA telomeres is an important parameter of the proliferative potential of tissues. A recent study has reported abnormally short telomeres in skeletal muscle of athletes with exercise-associated fatigue. This important report raises the question of whether long-term practice of sports might have deleterious effects on muscle telomeres. Therefore, we aimed to compare telomere length of a group of power lifters (PL; N = 7) who trained for 8 +/- 3 yr against that of a group of healthy, active subjects (C; N = 7) with no history of strength training.<br><br>METHODS: Muscle biopsies were taken from the vastus lateralis, and the mean and minimum telomeric restriction fragments (TRF) (telomere length) were determined, using the Southern blot protocol previously used for the analysis of skeletal muscle.<br><br>RESULTS: There was no abnormal shortening of telomeres in PL. On the contrary, the mean (P = 0.07) and the minimum (P = 0.09) TRF lengths in PL tended to be higher than in C. In PL, the minimum TRF length was inversely correlated to the individual records in squat (r = -0.86; P = 0.01) and deadlift (r = -0.88; P = 0.01).<br><br>CONCLUSION: These results show for the first time that long-term training is not associated with an abnormal shortening of skeletal muscle telomere length. Although the minimum telomere length in PL remains within normal physiological ranges, a heavier load put on the muscles means a shorter minimum TRF length in skeletal muscle.},
}
@article {pmid18089797,
year = {2007},
author = {Yang, Q and Zhang, R and Horikawa, I and Fujita, K and Afshar, Y and Kokko, A and Laiho, P and Aaltonen, LA and Harris, CC},
title = {Functional diversity of human protection of telomeres 1 isoforms in telomere protection and cellular senescence.},
journal = {Cancer research},
volume = {67},
number = {24},
pages = {11677-11686},
doi = {10.1158/0008-5472.CAN-07-1390},
pmid = {18089797},
issn = {1538-7445},
support = {//Intramural NIH HHS/United States ; },
mesh = {Alternative Splicing ; Cell Line ; Cell Line, Tumor ; Cellular Senescence/genetics/*physiology ; Fibroblasts/physiology ; Foreskin/cytology/physiology ; Gene Expression Regulation ; *Genetic Variation ; Humans ; Male ; RNA, Catalytic/genetics ; Shelterin Complex ; Telomere/genetics/*physiology ; Telomere-Binding Proteins/genetics/physiology ; },
abstract = {Protection of telomeres 1 (POT1) proteins in various organisms bind telomeres and regulate their structure and function. In contrast to mice carrying two distinct POT1 genes encoding two POT1 proteins (POT1a and POT1b), humans have the single POT1 gene. In addition to full-length POT1 protein (variant v1), the human POT1 gene encodes four other variants due to alternative RNA splicing (variants v2, v3, v4, and v5), whose functions are poorly understood. The functional analyses of the NH(2)-terminally and COOH-terminally truncated POT1 variants in this study showed that neither the single-stranded telomere-binding ability of the NH(2)-terminal oligonucleotide-binding (OB) folds nor the telomerase-dependent telomere elongation activity mediated by the COOH-terminal TPP1-interacting domain was telomere protective by itself. Importantly, a COOH-terminally truncated variant (v5), which consists of the NH(2)-terminal OB folds and the central region of unknown function, was found to protect telomeres and prevent cellular senescence as efficiently as v1. Our data revealed mechanistic and functional differences between v1 and v5: (a) v1, but not v5, functions through the maintenance of telomeric 3' overhangs; (b) p53 is indispensable to v5 knockdown-induced senescence; and (c) v5 functions at only a fraction of telomeres to prevent DNA damage signaling. Furthermore, v5 was preferentially expressed in mismatch repair (MMR)-deficient cells and tumor tissues, suggesting its role in chromosome stability associated with MMR deficiency. This study highlights a human-specific complexity in telomere protection and damage signaling conferred by functionally distinct isoforms from the single POT1 gene.},
}
@article {pmid18086770,
year = {2007},
author = {Risques, RA and Vaughan, TL and Li, X and Odze, RD and Blount, PL and Ayub, K and Gallaher, JL and Reid, BJ and Rabinovitch, PS},
title = {Leukocyte telomere length predicts cancer risk in Barrett's esophagus.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {16},
number = {12},
pages = {2649-2655},
doi = {10.1158/1055-9965.EPI-07-0624},
pmid = {18086770},
issn = {1055-9965},
support = {P01 CA91955/CA/NCI NIH HHS/United States ; P20CA103728/CA/NCI NIH HHS/United States ; P30AG13280/AG/NIA NIH HHS/United States ; },
mesh = {Adenocarcinoma/*pathology ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects ; Barrett Esophagus/*pathology ; Biomarkers, Tumor/*analysis ; Esophageal Neoplasms/*pathology ; Humans ; Leukocytes/*physiology ; Polymerase Chain Reaction ; Precancerous Conditions/pathology ; Risk Factors ; Smoking/adverse effects ; Telomere/*metabolism ; Waist-Hip Ratio ; },
abstract = {PURPOSE: Leukocyte telomere length has gained attention as a marker of oxidative damage and age-related diseases, including cancer. We hypothesize that leukocyte telomere length might be able to predict future risk of cancer and examined this in a cohort of patients with Barrett's esophagus, who are at increased risk of esophageal adenocarcinoma and thus were enrolled in a long-term cancer surveillance program.<br><br>PATIENTS AND METHODS: In this prospective study, telomere length was measured by quantitative PCR in baseline blood samples in a cohort of 300 patients with Barrett's esophagus followed for a mean of 5.8 years. Leukocyte telomere length hazard ratios (HR) for risk of esophageal adenocarcinoma were calculated using multivariate Cox models.<br><br>RESULTS: Shorter telomeres were associated with increased esophageal adenocarcinoma risk (age-adjusted HR between top and bottom quartiles of telomere length, 3.45; 95% confidence interval, 1.35-8.78; P = 0.009). This association was still significant when individually or simultaneously adjusted for age, gender, nonsteroidal anti-inflammatory drug (NSAID) use, cigarette smoking, and waist-to-hip ratio (HR, 4.18; 95% confidence interval, 1.60-10.94; P = 0.004). The relationship between telomere length and cancer risk was particularly strong among NSAID nonusers, ever smokers, and patients with low waist-to-hip ratio.<br><br>CONCLUSION: Leukocyte telomere length predicts risk of esophageal adenocarcinoma in patients with Barrett's esophagus independently of smoking, obesity, and NSAID use. These results show the ability of leukocyte telomere length to predict the risk of future cancer and suggest that it might also have predictive value in other cancers arising in a setting of chronic inflammation.},
}
@article {pmid18085522,
year = {2008},
author = {Venturini, L and Erdas, R and Costa, A and Gronchi, A and Pilotti, S and Zaffaroni, N and Daidone, M},
title = {ALT-associated promyelocytic leukaemia body (APB) detection as a reproducible tool to assess alternative lengthening of telomere stability in liposarcomas.},
journal = {The Journal of pathology},
volume = {214},
number = {4},
pages = {410-414},
doi = {10.1002/path.2288},
pmid = {18085522},
issn = {0022-3417},
mesh = {Adult ; Cryopreservation ; Disease Progression ; Formaldehyde ; Humans ; In Situ Hybridization, Fluorescence/methods ; Liposarcoma/*ultrastructure ; Paraffin Embedding ; Phenotype ; Reproducibility of Results ; Telomere/*ultrastructure ; },
abstract = {Most cancers maintain telomeres by activating telomerase, but a significant minority, mainly of mesenchymal origin, utilize an alternative lengthening of telomeres (ALT) mechanism. We previously showed the presence of ALT, as detected by ALT-associated promyelocytic leukaemia bodies (APBs) by combined promyelocytic leukaemia immunofluorescence and telomere fluorescence-in situ hybridization, in approximately 25% of frozen specimens obtained from adult patient liposarcomas and proved that ALT negatively affects patient prognosis. In the present study, we assessed the reproducibility of APB detection on frozen versus formalin-fixed, paraffin-embedded specimens from the same liposarcoma specimens and investigated the eventual stability of ALT in 103 different lesions from 40 adult patients followed during their disease. Irrespective of liposarcoma subtype, we (1) confirmed the presence of ALT in 21.4% of tumours; (2) demonstrated the reliability of ALT-associated promyelocytic leukaemia body detection in formalin-fixed, paraffin-embedded sections (with qualitative concordance between matched frozen and formalin-fixed, paraffin-embedded samples in 29/30 specimens, and high quantitative agreement, as indicated by a Spearman correlation coefficient of 0.85); and (3) suggested the stability of ALT status during disease evolution, since the ALT mechanism was never acquired in the 29 patients with initially ALT-negative lesions and lost over time in only two of 11 patients with initially ALT-positive liposarcomas. In conclusion, these results confirm the possibility of investigating the ALT mechanism in archival specimens to obtain biologically relevant information on liposarcoma progression, even when the primary lesion is not available.},
}
@article {pmid18082603,
year = {2007},
author = {Fu, D and Collins, K},
title = {Purification of human telomerase complexes identifies factors involved in telomerase biogenesis and telomere length regulation.},
journal = {Molecular cell},
volume = {28},
number = {5},
pages = {773-785},
pmid = {18082603},
issn = {1097-2765},
support = {R01 HL079585/HL/NHLBI NIH HHS/United States ; R01 HL079585-03/HL/NHLBI NIH HHS/United States ; R56 HL079585/HL/NHLBI NIH HHS/United States ; HL079585/HL/NHLBI NIH HHS/United States ; },
mesh = {Acetyltransferases/genetics/metabolism ; Cells, Cultured ; Chromatography, Affinity ; GTP-Binding Proteins/genetics/metabolism ; Heterogeneous-Nuclear Ribonucleoprotein Group C/genetics/metabolism ; Heterogeneous-Nuclear Ribonucleoprotein U/genetics/metabolism ; Holoenzymes/genetics/isolation &amp; purification/*metabolism ; Humans ; N-Terminal Acetyltransferase E ; N-Terminal Acetyltransferases ; Nuclear Proteins/genetics/metabolism ; Protein Binding ; RNA ; RNA, Long Noncoding ; RNA, Untranslated/genetics/*metabolism ; Ribonucleoproteins, Small Nuclear/genetics/metabolism ; Telomerase/genetics/*isolation &amp; purification/*metabolism ; Telomere/*genetics/metabolism ; },
abstract = {The identities and roles of proteins associated with human telomerase remain poorly defined. To gain insight, we undertook an affinity purification of endogenously assembled human telomerase complexes. We show that specific subsets of H/ACA, Sm, and hnRNP proteins associate with active and inactive telomerase RNPs, while two NTPase proteins associate preferentially with active enzyme. All three core H/ACA-motif binding proteins are telomerase holoenzyme components essential for RNP accumulation. On the other hand, telomerase RNPs lacking interaction with Sm proteins or hnRNP C remain fully functional for telomere elongation. Curiously, overexpression of either associated hnRNP protein (hnRNP C and hnRNP U) or either NTPase protein (NAT10 and GNL3L) induced telomere shortening. Our findings suggest that endogenous human telomerase complexes are more heterogeneous than those of single-celled eukaryotes, have predominantly shared rather than telomerase-specific proteins, and make numerous regulatory interactions.},
}
@article {pmid18081200,
year = {2008},
author = {Ponsot, E and Kadi, F},
title = {Signal modelization for improved precision of assessment of minimum and mean telomere lengths.},
journal = {Electrophoresis},
volume = {29},
number = {2},
pages = {542-544},
doi = {10.1002/elps.200700290},
pmid = {18081200},
issn = {0173-0835},
mesh = {Blotting, Southern/methods ; Electronic Data Processing ; Muscle, Skeletal/chemistry ; Telomere/*chemistry ; },
abstract = {Telomere length is an important measure of cell and tissue regenerative capacities. The mean telomere length is classically used as global indicator of a tissue telomere length. In skeletal muscle, which is made of postmitotic myonuclei and satellite cells (muscle stem cells), minimum telomere length is also used to assess the telomere length of satellite cells and newly incorporated myonuclei. At present, the estimation of the method reproducibility during the assessment of mean and minimum telomere length using Southern blot analysis has never been documented. The aim of this report is to describe a signal modelization for improved precision of assessment of minimum and mean telomere lengths and to document the method reproducibility. Telomeres are assessed using a Southern technique where the gel is directly hybridized with the specific probe without the membrane-transferring step in order to prevent telomeric low signal loss. We found that the improved signal analysis for determination of telomere length is associated with coefficients of variation ranging from 1.37 to 4.29% for the mean telomeric restriction fragment (TRF) length and from 2.04 to 4.95% for the minimum TRF length. Improved method reproducibility would allow saving time and biological material as duplicate and triplicate measurement of the same sample is no longer required.},
}
@article {pmid18081009,
year = {2008},
author = {Mason, JM and Frydrychova, RC and Biessmann, H},
title = {Drosophila telomeres: an exception providing new insights.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {30},
number = {1},
pages = {25-37},
pmid = {18081009},
issn = {0265-9247},
support = {R01 GM056729/GM/NIGMS NIH HHS/United States ; Z01 ES101764-04/ImNIH/Intramural NIH HHS/United States ; GM-56729/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromosomes/metabolism ; DNA-Binding Proteins/metabolism ; Drosophila/*genetics ; Evolution, Molecular ; Gene Silencing ; Models, Biological ; Mutagenesis, Insertional ; Oligonucleotide Array Sequence Analysis ; Polycomb-Group Proteins ; Repetitive Sequences, Nucleic Acid/genetics ; Repressor Proteins/physiology ; Retroelements/genetics/physiology ; Telomere/metabolism/*physiology ; },
abstract = {Drosophila telomeres comprise DNA sequences that differ dramatically from those of other eukaryotes. Telomere functions, however, are similar to those found in telomerase-based telomeres, even though the underlying mechanisms may differ. Drosophila telomeres use arrays of retrotransposons to maintain chromosome length, while nearly all other eukaryotes rely on telomerase-generated short repeats. Regardless of the DNA sequence, several end-binding proteins are evolutionarily conserved. Away from the end, the Drosophila telomeric and subtelomeric DNA sequences are complexed with unique combinations of proteins that also modulate chromatin structure elsewhere in the genome. Maintaining and regulating the transcriptional activity of the telomeric retrotransposons in Drosophila requires specific chromatin structures and, while telomeric silencing spreads from the terminal repeats in yeast, the source of telomeric silencing in Drosophila is the subterminal arrays. However, the subterminal arrays in both species may be involved in telomere-telomere associations and/or communication.},
}
@article {pmid18077981,
year = {2007},
author = {Zendehrokh, N and Rehnberg, J and Dejmek, A},
title = {Comparison of NCL-hTERT antibody reactivity and telomere repeat amplification protocol in situ in effusions.},
journal = {Acta cytologica},
volume = {51},
number = {6},
pages = {886-892},
doi = {10.1159/000325865},
pmid = {18077981},
issn = {0001-5547},
mesh = {Ascitic Fluid/*enzymology/pathology ; Biomarkers, Tumor/metabolism ; Cell Nucleus/enzymology/genetics ; DNA, Neoplasm/analysis ; Female ; Humans ; Immunohistochemistry/*methods ; Neoplasms, Mesothelial/diagnosis/enzymology ; Phosphoproteins/immunology/metabolism ; Pleural Effusion/*enzymology/pathology ; Polymerase Chain Reaction/*methods ; RNA-Binding Proteins/immunology/metabolism ; Repetitive Sequences, Nucleic Acid/genetics ; Reproducibility of Results ; Sensitivity and Specificity ; Telomerase/genetics/immunology/*metabolism ; Telomere/*enzymology/genetics ; Nucleolin ; },
abstract = {OBJECTIVE: To compare the performances of 2 methods, telomerase repeat amplification protocol (TRAP) in situ and antibodies to the hTERT protein, in assessing telomerase activity.<br><br>STUDY DESIGN: TRAP in situ and immunohistochemistry with a commercial antibody (NCL-hTERT) was performed on 54 body cavity effusions. The results were compared and correlated to diagnosis.<br><br>RESULTS: Thirty-four effusions from patients with verified malignant disease contained cytologically malignant cells. Both methods were positive in 33 of the cases, whereas only hTERT was positive in 1 case. Twenty effusions, all containing mesothelial cells, came from patients with benign conditions. In 2 fluids atypical, hyperplastic mesothelial cells were both TRAP in situ and hTERT positive. All remaining 18 fluids were TRAP in situ negative, whereas 12 of 18 were hTERT positive. Thus the results of TRAP in situ and hTERT immunohistochemistry disagreed in 1 of 34 (3%) malignant and 12 of 20 (60%) benign cases.<br><br>CONCLUSION: The sensitivities for malignancy were similar for TRAP in situ and hTERT immunohistochemistry. The specificity of the applied hTERT antibody was significantly lower, due to hTERT reactivity in mesothelial cells.},
}
@article {pmid18077937,
year = {2007},
author = {Omura, Y and Chen, Y and Lu, DP and Shimotsura, Y and Ohki, M and Duvvi, H},
title = {Anatomical relationship between traditional acupuncture point ST 36 and Omura's ST 36 (True ST 36) with their therapeutic effects: 1) inhibition of cancer cell division by markedly lowering cancer cell telomere while increasing normal cell telomere, 2) improving circulatory disturbances, with reduction of abnormal increase in high triglyceride, L-homocystein, CRP, or cardiac troponin I &amp; T in blood by the stimulation of Omura's ST 36--Part 1.},
journal = {Acupuncture &amp; electro-therapeutics research},
volume = {32},
number = {1-2},
pages = {31-70},
doi = {10.3727/036012907815844174},
pmid = {18077937},
issn = {0360-1293},
mesh = {Acupuncture ; *Acupuncture Points ; Blood Cell Count ; Blood Glucose/metabolism ; C-Reactive Protein/metabolism ; Cardiovascular Diseases/blood/*therapy ; Cell Division/physiology ; Electroacupuncture ; Gastric Fundus/physiology ; Homocysteine/blood ; Humans ; Hypertriglyceridemia/blood/therapy ; Lasers ; Lipids/blood ; Myocardium/metabolism ; Neoplasms/*pathology ; Telomere/*pathology/ultrastructure ; Troponin I/blood ; Uric Acid/blood ; },
abstract = {Using Bi-Digital O-Ring Test Resonance Phenomena between 2 identical substances, Omura, Y. succeeded in making the image of the outline of internal organs without use of standard imaging devices since 1982. When he imaged the outline of the stomach on the abdominal wall, a number of the lines came out from upper and lower parts of stomach wall. When the lines were followed, they were very close to the well-known stomach meridians. Subsequently, he found a method of localizing meridians and their corresponding acupuncture points as well as shapes and diameters accurately. At the anatomical location of ST 36 described in traditional textbooks, Omura, Y. found there is no acupuncture point. However, in the close vicinity, there is an acupuncture point which he named as true ST 36 in the mid 1980s, but it is generally known as Omura's ST 36. When the effects of the acupuncture on these 2 locations were compared, Omura's ST 36 (true ST 36) produced very significant well-known acupuncture beneficial effects including improved circulation and blood chemistry, while in the traditional ST 36, the effects were small. In this article, the anatomical relationship between these two acupuncture points, with a short distance of 0.6 approximately 1.5 cm between the centers of these locations, was described. In early 2000, Omura, Y. found Press Needle Stimulation of Omura's ST 36, using "Press-Release" procedure repeated 200 times, 4 times a day to cancer patients reduced high cancer cell telomere of 600-1500ng and high Oncogen C-fos Ab2 and Integrin alpha5beta1 of 100-700ng BDORT units to close to lyg (= 10(-24) g) BDORT units. In addition there was a significant reduction of Asbestos and Hg from cancer cells, while markedly reduced normal cell telomere of lyg was increased to optimally high amounts of 500-530ng BDORTunits. Thus, cancer cells can no longer divide and cancer activity is inhibited. The authors have successfully applied this method for a variety of cancers as well as for cardio-vascular diseases with hypertriglyceridemia, hyperglycemia, high L-homocystein, and CRP, high cardiac Troponim I &amp; T, and some hypertension. These beneficial effects were accompanied by euphoria, &amp; relaxation with increased alpha waves in EEG. Thus Omura's ST 36 stimulation is a safe, effective and highly desirable supplemental treatment. In addition to manual stimulation, similar beneficial effects can be induced by finger tip stmulation (without any needle) or with electroacupuncture stimulation, (+) Qi Gong energy stored paper and (+) solar energy stored paper which often resulted in significant clinical improvement.},
}
@article {pmid18077792,
year = {2008},
author = {Poncet, D and Belleville, A and t'kint de Roodenbeke, C and Roborel de Climens, A and Ben Simon, E and Merle-Beral, H and Callet-Bauchu, E and Salles, G and Sabatier, L and Delic, J and Gilson, E},
title = {Changes in the expression of telomere maintenance genes suggest global telomere dysfunction in B-chronic lymphocytic leukemia.},
journal = {Blood},
volume = {111},
number = {4},
pages = {2388-2391},
doi = {10.1182/blood-2007-09-111245},
pmid = {18077792},
issn = {0006-4971},
mesh = {Antigens, CD19/blood ; Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/enzymology/*genetics/pathology ; Mutation ; Shelterin Complex ; Telomerase/*genetics ; Telomere/*genetics/ultrastructure ; Telomere-Binding Proteins ; },
abstract = {In this study, we explored the telomeric changes that occur in B-chronic lymphocytic leukemia (B-CLL), in which telomere length has recently been demonstrated to be a powerful prognostic marker. We carried out a transcriptomic analysis of telomerase components (hTERT and DYSKERIN), shelterin proteins (TRF1, TRF2, hRAP1, TIN2, POT1, and TPP1), and a set of multifunctional proteins involved in telomere maintenance (hEST1A, MRE11, RAD50, Ku80, and RPA1) in peripheral B cells from 42 B-CLL patients and 20 healthy donors. We found that, in B-CLL cells, the expressions of hTERT, DYSKERIN, TRF1, hRAP1, POT1, hEST1A, MRE11, RAD50, and KU80 were more than 2-fold reduced (P < .001), contrasting with the higher expression of TPP1 and RPA1 (P < .001). This differential expression pattern suggests that both telomerase down-regulation and changes in telomeric proteins composition are involved in the pathogenesis of B-CLL.},
}
@article {pmid18077053,
year = {2008},
author = {Frías, C and García-Aranda, C and De Juan, C and Morán, A and Ortega, P and Gómez, A and Hernando, F and López-Asenjo, JA and Torres, AJ and Benito, M and Iniesta, P},
title = {Telomere shortening is associated with poor prognosis and telomerase activity correlates with DNA repair impairment in non-small cell lung cancer.},
journal = {Lung cancer (Amsterdam, Netherlands)},
volume = {60},
number = {3},
pages = {416-425},
doi = {10.1016/j.lungcan.2007.11.001},
pmid = {18077053},
issn = {0169-5002},
mesh = {Adaptor Proteins, Signal Transducing/genetics ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Non-Small-Cell Lung/diagnosis/enzymology/*genetics ; Cell Cycle Proteins/genetics ; *DNA Repair ; DNA Repair Enzymes/genetics ; DNA-Binding Proteins ; Endonucleases ; Female ; Humans ; Lung Neoplasms/diagnosis/enzymology/*genetics ; Male ; Middle Aged ; MutL Protein Homolog 1 ; N-Glycosyl Hydrolases/genetics ; Nuclear Proteins/genetics ; Phosphoproteins/genetics ; Poly(ADP-ribose) Polymerases/genetics ; Prognosis ; Telomerase/*genetics ; Telomere/*enzymology/genetics ; Telomeric Repeat Binding Protein 2/genetics ; Transcription Factor TFIIH ; Transcription Factors, TFII/genetics ; },
abstract = {BACKGROUND AND PURPOSE: Telomere function and DNA damage response pathways are frequently inactivated in cancer. Moreover, some telomere-binding proteins have been implicated in DNA repair. The purpose of this work consists of evaluating the prognostic impact of telomere dysfunction and its relationship with DNA repair systems in non-small cell lung cancer (NSCLC).<br><br>PATIENTS AND METHODS: We analysed 83 NSCLCs and their corresponding control samples obtained from patients submitted to surgery. Telomere function was evaluated by determining telomerase activity and telomere length. DNA repair expression assays were established by using cDNA arrays containing 96 DNA-repair genes and by Real Time Quantitative PCR.<br><br>RESULTS: Our data indicated that telomere attrition was significantly associated with poor clinical outcome of patients (P=0.02), being this parameter a significant prognostic factor independent of tumour stage (P=0.012; relative risk=1.887; 95% CI: 1.147-3.102). DNA-repair gene expression studies showed down regulation of DCLRE1C and GTF2H1 and a clear FLJ10858 up regulation in tumour tissues, as compared to controls. In addition, a number of genes related to DNA-repair were significantly down regulated in tumours that reactivated telomerase (DCLRE1C, GTF2H1, PARP-3, MLH1, and TRF2).<br><br>CONCLUSIONS: Telomere shortening emerged as a poor clinical evolution parameter in NSCLC. Moreover, results from this work suggest a relationship between the loss of several DNA repair genes and telomerase activity, which may be of relevance in the pathogenesis of non-small lung cancer.},
}
@article {pmid18075778,
year = {2007},
author = {Straatman, KR and Louis, EJ},
title = {Localization of telomeres and telomere-associated proteins in telomerase-negative Saccharomyces cerevisiae.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {15},
number = {8},
pages = {1033-1050},
pmid = {18075778},
issn = {0967-3849},
support = {P41 RR011823/RR/NCRR NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; P41 RR11823/RR/NCRR NIH HHS/United States ; },
mesh = {Cellular Senescence ; Histone Deacetylases/genetics/metabolism ; Saccharomyces cerevisiae/enzymology/*genetics/growth &amp; development ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Shelterin Complex ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Sirtuin 2 ; Sirtuins/genetics/metabolism ; Telomerase/*metabolism ; Telomere/*genetics ; Telomere-Binding Proteins/genetics/*metabolism ; Transcription Factors/genetics/metabolism ; },
abstract = {Cells lacking telomerase cannot maintain their telomeres and undergo a telomere erosion phase leading to senescence and crisis in which most cells become nonviable. On rare occasions survivors emerge from these cultures that maintain their telomeres in alternative ways. The movement of five marked telomeres in Saccharomyces cerevisiae was followed in wild-type cells and through erosion, senescence/crisis and eventual survival in telomerase-negative (est2::HYG) yeast cells. It was found that during erosion, movements of telomeres in est2::HYG cells were indistinguishable from wild-type telomere movements. At senescence/crisis, however, most cells were in G(2) arrest and the nucleus and telomeres traversed back and forth across the bud neck, presumably until cell death. Type I survivors, using subtelomeric Y' amplification for telomere maintenance, continued to show this aberrant telomere movement. However, Type II survivors, maintaining telomeres by a sudden elongation of the telomere repeats, became indistinguishable from wild-type cells, consistent with growth properties of the two types of survivors. When telomere-associated proteins Sir2p, Sir3p and Rap1p were tagged, the same general trend was seen-Type I survivors retained the senescence/crisis state of protein localization, while Type II survivors were restored to wild type.},
}
@article {pmid18073447,
year = {2007},
author = {Mondoux, MA and Zakian, VA},
title = {Subtelomeric elements influence but do not determine silencing levels at Saccharomyces cerevisiae telomeres.},
journal = {Genetics},
volume = {177},
number = {4},
pages = {2541-2546},
pmid = {18073447},
issn = {0016-6731},
mesh = {Base Sequence ; Chromosomes, Fungal ; *Gene Silencing ; Saccharomyces cerevisiae/*genetics ; *Telomere ; },
abstract = {In Saccharomyces cerevisiae, genes placed near telomeres are transcriptionally repressed (telomere position effect, TPE). Although telomeric DNA sequence is the same at all chromosome ends, the subtelomeric elements (STEs) and level of TPE vary from telomere to telomere. We tested whether STEs determine TPE levels. STEs contributed to TPE, as deleting the X element from the VI-R telomere modestly decreased silencing at this telomere. However, STEs were not the major determinant of TPE levels, as inserting the VI-R X element at the truncated VII-L telomere did not increase TPE. These data suggest that the TPE levels of individual telomeres are dependent on some aspect of chromosome context.},
}
@article {pmid18073421,
year = {2007},
author = {Mondoux, MA and Scaife, JG and Zakian, VA},
title = {Differential nuclear localization does not determine the silencing status of Saccharomyces cerevisiae telomeres.},
journal = {Genetics},
volume = {177},
number = {4},
pages = {2019-2029},
pmid = {18073421},
issn = {0016-6731},
mesh = {Cell Nucleus ; DNA-Binding Proteins/physiology ; *Gene Expression Regulation, Fungal ; Nuclear Proteins ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/physiology ; Shelterin Complex ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/physiology ; Telomere/*chemistry ; Telomere-Binding Proteins/physiology ; Transcription Factors/physiology ; },
abstract = {In Saccharomyces cerevisiae, genes near telomeres are transcriptionally repressed, a phenomenon termed telomere position effect (TPE). Yeast telomeres cluster near the nuclear periphery, as do foci of proteins essential for TPE: Rap1p, Sir2-4p, and yKu70p/yKu80p. However, it is not clear if localization of telomeres to the periphery actually contributes to TPE. We examined the localization patterns of two telomeres with different levels of TPE: truncated VII-L and native VI-R. For both telomeres, localization to the nuclear periphery or to the silencing foci was neither necessary nor sufficient for TPE. Moreover, there was no correlation between TPE levels and the extent of localization. Tethering the truncated VII-L telomere to the nuclear periphery resulted in a modest increase in TPE. However, tethering did not bypass the roles of yKu70p, Sir4p, or Esc1p in TPE. Using mutations in RIF genes that bypass the role of Ku in TPE, a correlation between the level of silencing and the number of Rap1p foci present in the nucleus was observed, suggesting that Sir protein levels at telomeres determine both the level of TPE and the number of foci.},
}
@article {pmid18071200,
year = {2008},
author = {Haussmann, MF and Mauck, RA},
title = {Telomeres and longevity: testing an evolutionary hypothesis.},
journal = {Molecular biology and evolution},
volume = {25},
number = {1},
pages = {220-228},
doi = {10.1093/molbev/msm244},
pmid = {18071200},
issn = {1537-1719},
mesh = {Animals ; Birds/*genetics ; Cellular Senescence/*genetics ; Female ; *Genetic Variation ; Longevity/*genetics ; Male ; Telomere/*genetics ; },
abstract = {Identifying mechanisms that underlie variation in adult survivorship provide insight into the evolution of life history strategies and phenotypic variation in longevity. There is accumulating evidence that shortening telomeres, the protective caps at the ends of chromosomes, play an important role in individual variation in longevity. Given that telomeres generally shorten with age, it was surprising to find that in a population of a long-lived seabird, Leach's storm petrel, telomeres appear to lengthen with age. This unique finding suggested that the longest lived individuals are able to elongate telomeres, an interpretation we call the "elongation hypothesis." Alternatively, the "selection hypothesis" states that the longest lived individuals start with the longest telomeres and variation in telomere length decreases with age due to the selective disappearance of individuals with short telomeres. In the same population in which evidence supporting both hypotheses was uncovered, we tested mutually exclusive predictions from the elongation and selection hypotheses by measuring telomere length with the telomere restriction fragment assay in hatchling and old, adult storm petrels. As previously found, adult birds had longer telomeres on average compared with hatchlings. We also found that 3 hatchlings had mean telomere lengths exceeding that of the most extreme old bird, old birds on average had longer initial telomere lengths than hatchlings, and the variance in mean telomere length was significantly greater for hatchlings than for old birds, all predicted by the selection hypothesis. Perhaps more surprisingly, the oldest adults also show little or no accumulation of short telomeres over time, a pattern unknown in other species. Long telomeres are thought to provide a buffer against cellular senescence and be generally indicative of genome stability and overall cell health. In storm petrels, because the progressive accumulation of short telomeres appears negligible, variation in telomere length at birth may be linked to individual variation in longevity.},
}
@article {pmid18070000,
year = {2008},
author = {Carrero, JJ and Stenvinkel, P and Fellström, B and Qureshi, AR and Lamb, K and Heimbürger, O and Bárány, P and Radhakrishnan, K and Lindholm, B and Soveri, I and Nordfors, L and Shiels, PG},
title = {Telomere attrition is associated with inflammation, low fetuin-A levels and high mortality in prevalent haemodialysis patients.},
journal = {Journal of internal medicine},
volume = {263},
number = {3},
pages = {302-312},
doi = {10.1111/j.1365-2796.2007.01890.x},
pmid = {18070000},
issn = {1365-2796},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*physiology ; Blood Proteins/*metabolism ; Cross-Sectional Studies ; Female ; Humans ; Inflammation Mediators/blood ; Kidney Failure, Chronic/*blood/*genetics/mortality ; Male ; Middle Aged ; Oxidative Stress/physiology ; *Renal Dialysis ; Retrospective Studies ; Telomere/*genetics ; alpha-2-HS-Glycoprotein ; },
abstract = {INTRODUCTION: Chronic kidney disease (CKD) predisposes to a 10- to 20-fold increased cardiovascular risk. Patients undergo accelerated atherogenesis and vascular ageing. We investigated whether telomere attrition, a marker of cell senescence, contributes to this increased mortality risk.<br><br>METHODS: This is a cross-sectional study in prevalent haemodialysis patients [n = 175; 98 Males; median (range) age: 66 (23-86) years]. Biochemical markers of oxidative stress and inflammatory status were measured in relation to the patient's leucocyte telomere length. Overall mortality was assessed after a median of 31 (range 2-42) months.<br><br>RESULTS: Telomere length was shorter in CKD men, despite women being older (average +/- SD 6.41 +/- 1.23 vs. 6.96 +/- 1.48 kb, P = 0.002). Telomere length was associated with age (rho = -0.18, P = 0.01), fetuin-A (rho = 0.26, P = 0.0004), high-sensitivity C-reactive protein (rho = -0.21, P = 0.005) and IL-6 (rho = -0.17, P = 0.02). In a multivariate logistic regression (pseudo r(2) = 0.14), telomere length was associated with age >65 years (odds ratio: 2.11; 95% CI: 1.10, 4.06), sex (2.01; 1.05, 3.86), fetuin-A (1.85; 0.97, 3.50) and white blood cell count (2.04; 1.02, 4.09). Receiver operating characteristic curves identified a telomere length < 6.28 kb as a fair predictor of mortality. Finally, reduced telomere length was associated with increased mortality, independently of age, gender and inflammation (likelihood ratio 41.6, P < 0.0001), but dependently on fetuin-A levels.<br><br>CONCLUSION: Age and male gender seem to be important contributors to reduced telomere length in CKD patients, possibly via persistent inflammation. Reduced telomere length also contributes to the mortality risk of these patients through pathways that could involve circulating levels of fetuin-A.},
}
@article {pmid18067921,
year = {2008},
author = {Denisenko, O and Bomsztyk, K},
title = {Epistatic interaction between the K-homology domain protein HEK2 and SIR1 at HMR and telomeres in yeast.},
journal = {Journal of molecular biology},
volume = {375},
number = {4},
pages = {1178-1187},
pmid = {18067921},
issn = {1089-8638},
support = {R01 GM045134/GM/NIGMS NIH HHS/United States ; R01 GM045134-16/GM/NIGMS NIH HHS/United States ; R37 DK045978/DK/NIDDK NIH HHS/United States ; R37 DK045978-14/DK/NIDDK NIH HHS/United States ; },
mesh = {Chromatin/metabolism ; Chromatin Immunoprecipitation ; *Epistasis, Genetic ; Ethidium/metabolism ; Gene Expression Regulation, Fungal ; Gene Silencing ; Genes, Fungal ; Genes, Mating Type, Fungal ; Mutation ; Plasmids ; Protein Structure, Tertiary ; Ribonucleoproteins/*chemistry/genetics ; Saccharomyces cerevisiae/*genetics/growth &amp; development ; Saccharomyces cerevisiae Proteins/*chemistry/genetics ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/*chemistry/genetics ; Telomere/*genetics ; },
abstract = {In budding yeast, telomeres, the ribosomal DNA array, and HM loci are transcriptionally silenced by chromatin complexes containing Sir proteins. Hek2, a protein containing three evolutionary conserved RNA-binding K-homology domains, was identified as a suppressor of telomeric silencing [telomeric position effect (TPE)]. To explore the mechanisms of Hek2p action in gene silencing, we examined its relationship with Sir proteins. This search revealed an epistatic interaction between HEK2 and SIR1 at telomeres. Both single mutations, sir1Delta and hek2Delta, enhanced TPE, whereas the effect of double mutation, sir1Delta hek2Delta, did not exceed that of the single mutations. The results of chromatin immunoprecipitation analysis demonstrate that the TPE enhancement observed in these mutants is associated with increased binding of Sir2 protein to telomeres. At the HMR locus, hek2Delta rescues the silencing defect caused by sir1Delta mutation and reverses the loss of Sir2p and Sir3p. These data suggest that the epistatic interaction of HEK2 and SIR1 reflects competition between telomeres and HMR for Sir2/3 factors where HEK2 acts to suppress silencing. Because chromatin immunoprecipitation analysis reveals the presence of Hek2p at a subtelomeric region and HMR, its silencing effects at these loci are likely direct. These observations suggest that HEK2 regulates the composition of Sir complexes at HMR and telomeres.},
}
@article {pmid18067891,
year = {2008},
author = {Marie-Egyptienne, DT and Brault, ME and Zhu, S and Autexier, C},
title = {Telomerase inhibition in a mouse cell line with long telomeres leads to rapid telomerase reactivation.},
journal = {Experimental cell research},
volume = {314},
number = {3},
pages = {668-675},
doi = {10.1016/j.yexcr.2007.10.020},
pmid = {18067891},
issn = {0014-4827},
mesh = {Amino Acid Motifs/genetics ; Amino Acid Substitution/genetics ; Animals ; Cell Cycle/genetics ; Cell Division/*genetics ; Cell Line, Tumor ; Cell Transformation, Neoplastic/*genetics/metabolism ; Cellular Senescence/*genetics ; Clone Cells/metabolism ; Enzyme Activation/genetics ; Gene Expression Regulation/genetics ; Mice ; Mutation/genetics ; Species Specificity ; Telomerase/antagonists &amp; inhibitors/biosynthesis/*metabolism ; Telomere/*genetics ; },
abstract = {The indefinite growth of cancer cells requires telomere maintenance, which, in the majority of mammalian cancers is mediated via the enzyme telomerase. The core components of telomerase are a catalytic reverse transcriptase (hTERT in human, mTERT in mouse) and an RNA (TR) that contains the template for the replenishment of telomeres. Fundamental differences in human and mouse telomerase and telomere biology should be considered when using mouse models for the study of human cancers. The responses to telomerase inhibition by the expression of a catalytically-inactive dominant-negative mutant of hTERT (hTERT-DN) vary in human cells with different telomere lengths. Only one similar study has been performed in a mouse cell line with short telomeres (RenCa, 7 kb). Thus, we asked whether the responses to telomerase inhibition are also telomere-length dependent in mouse cells by analyzing long-term stable expression of mTERT-DN in the CB17 cell line (telomere length, 11 kb). A brief initial telomerase inhibition was insufficient to mediate telomere shortening and led to extremely rapid telomerase reactivation due to an increase in the level of expression of the endogenous mTERT. Thus, mouse cells, in contrast to human cells may not tolerate telomerase inhibition by introduction of mTERT-DN, independently of telomere length.},
}
@article {pmid18066078,
year = {2008},
author = {Churikov, D and Price, CM},
title = {Pot1 and cell cycle progression cooperate in telomere length regulation.},
journal = {Nature structural &amp; molecular biology},
volume = {15},
number = {1},
pages = {79-84},
pmid = {18066078},
issn = {1545-9985},
support = {R01 GM041803/GM/NIGMS NIH HHS/United States ; R01 GM041803-17/GM/NIGMS NIH HHS/United States ; GM041803/GM/NIGMS NIH HHS/United States ; },
mesh = {Androstadienes/pharmacology ; Ataxia Telangiectasia Mutated Proteins ; Caffeine/pharmacology ; Carbazoles/pharmacology ; Cell Cycle/drug effects/*physiology ; Cell Cycle Proteins/genetics/metabolism ; Cell Line ; DNA-Binding Proteins/deficiency/genetics/metabolism ; Enzyme Inhibitors/pharmacology ; Flow Cytometry ; G2 Phase ; Humans ; Indoles/pharmacology ; Kinetics ; Protein Serine-Threonine Kinases/deficiency/genetics/metabolism ; S Phase ; Shelterin Complex ; Tamoxifen/pharmacology ; Telomere/chemistry/*physiology ; Telomere-Binding Proteins/deficiency/genetics/*physiology ; Tumor Suppressor Proteins/deficiency/genetics/metabolism ; Wortmannin ; },
abstract = {Removal of the vertebrate telomere protein Pot1 results in a DNA damage response and cell cycle arrest. Here we show that loss of chicken Pot1 causes Chk1 activation, and inhibition of Chk1 signaling prevents the cell cycle arrest. However, arrest still occurs after disruption of ATM, which encodes another DNA damage response protein. These results indicate that Pot1 is required to prevent a telomere checkpoint mediated by another such protein, ATR, that is most likely triggered by the G-overhang. We also show that removal of Pot1 causes exceptionally rapid telomere growth upon arrest in late S/G2 of the cell cycle. However, release of the arrest slows both telomere growth and G-overhang elongation. Thus, Pot1 seems to regulate telomere length and G-overhang processing both through direct interaction with the telomere and by preventing a late S/G2 delay in the cell cycle. Our results reveal that cell cycle progression is an important component of telomere length regulation.},
}
@article {pmid18064678,
year = {2007},
author = {Wu, X and Sandhu, S and Ding, H},
title = {Establishment of conditional knockout alleles for the gene encoding the regulator of telomere length (RTEL).},
journal = {Genesis (New York, N.Y. : 2000)},
volume = {45},
number = {12},
pages = {788-792},
doi = {10.1002/dvg.20359},
pmid = {18064678},
issn = {1526-968X},
mesh = {*Alleles ; Animals ; DNA Helicases/*genetics/physiology ; *Gene Targeting ; Integrases/genetics ; Mice ; Mice, Knockout ; },
abstract = {Regulator of telomere length (RTEL) is a DNA helicase-like protein that has recently been demonstrated to be required for the maintenance of telomere length and genomic stability. Rtel null mice are embryonic lethal with the defects in the nervous system, the heart, the vasculature, and extra-embryonic tissues. Rtel could also be important for the postnatal development as its expression is strongly induced in the proliferating adult cells. To further characterize the role of RTEL in adult tissue function and homeostasis, we have generated the floxed (loxP-flanked) alleles allowing to inactivate RTEL through Cre-mediated recombination in a cell- or tissue-specific manner and also to circumvent the embryonic lethality of the Rtel null allele. Mice heterozygous or homozygous for these alleles are viable and fertile. Crossing the floxed Rtel allele with a ubiquitous Cre transgenic line resulted in embryonic defects identical to those previously described for the Rtel null embryos. These conditional alleles will therefore be the important genetic tools for dissecting the spatial and temporal roles of RTEL in the regulation of telomere length and genomic stability during postnatal development and tumorigenesis.},
}
@article {pmid18063368,
year = {2008},
author = {Zhang, X and Bruice, TC},
title = {Complexation of single strand telomere and telomerase RNA template polyanions by deoxyribonucleic guanidine (DNG) polycations: plausible anticancer agents.},
journal = {Bioorganic &amp; medicinal chemistry letters},
volume = {18},
number = {2},
pages = {665-669},
doi = {10.1016/j.bmcl.2007.11.061},
pmid = {18063368},
issn = {1464-3405},
support = {5R37DK9174-43/DK/NIDDK NIH HHS/United States ; },
mesh = {Antineoplastic Agents/*pharmacology ; Base Sequence ; Guanidine/*chemistry ; Nucleic Acid Conformation ; *Polyamines ; Polyelectrolytes ; *Polymers ; RNA/*chemistry ; Telomerase/*genetics ; *Telomere ; *Templates, Genetic ; },
abstract = {Cancerous cell immortality is due to relatively high concentrations of telomerase enzyme which maintains telomere sequence during cell division. Deoxyribonucleic guanidine (DNG) is a positively charged DNA analog in which guanidine replaces the phosphordiester linkage of DNA. Mixed sequences of DNG and DNA oligonucleotides are referred to as chimera. Complexation of DNG and chimeric polycations with the complementary negatively charged non-coding telomere single strand d(5'-TTAGGG-3')(n) and the 11-base telomeric RNA template (5'-CUAACCCUAAC-3') in the active site of telomerase has been studied. Calculated by ensemble sampling simulations in GBMV solvent model, we found that binding of complementary DNG hexamer with telomere is favored over that of DNA-telomere by approximately 10(6)-fold and binding of chimera hexamer is favored by approximately 10(4)-fold. Binding of complementary DNG with telomeric RNA is favored by 43 kcal/mol over telomere substrate binding with telomeric RNA.},
}
@article {pmid18063293,
year = {2008},
author = {Portugal, RD and Land, MG and Svaiter, BF},
title = {A computational model for telomere-dependent cell-replicative aging.},
journal = {Bio Systems},
volume = {91},
number = {1},
pages = {262-267},
doi = {10.1016/j.biosystems.2007.10.003},
pmid = {18063293},
issn = {0303-2647},
mesh = {Cell Proliferation ; Cellular Senescence/*genetics ; *Computer Simulation ; Humans ; *Models, Biological ; Telomere/*genetics/metabolism ; },
abstract = {Telomere shortening provides a molecular basis for the Hayflick limit. Recent data suggest that telomere shortening also influence mitotic rate. We propose a stochastic growth model of this phenomena, assuming that cell division in each time interval is a random process which probability decreases linearly with telomere shortening. Computer simulations of the proposed stochastic telomere-regulated model provides good approximation of the qualitative growth of cultured human mesenchymal stem cells.},
}
@article {pmid18063009,
year = {2008},
author = {Slijepcevic, P},
title = {DNA damage response, telomere maintenance and ageing in light of the integrative model.},
journal = {Mechanisms of ageing and development},
volume = {129},
number = {1-2},
pages = {11-16},
doi = {10.1016/j.mad.2007.10.012},
pmid = {18063009},
issn = {0047-6374},
mesh = {Aging/*genetics ; Aging, Premature/genetics ; Animals ; *DNA Damage ; DNA Repair ; Humans ; Mice ; Models, Animal ; *Models, Genetic ; Telomere/chemistry/*metabolism ; },
abstract = {The complexity of the ageing process is reflected in the fact that numerous models have been proposed to explain why and how organisms age and yet they address the problem only to a limited extent. A logical solution is to integrate individual models together into a wider theoretical framework now known as the "network" theory of ageing. The "network" approach overcomes reduction nature of individual models and allows for interactions between individual contributing mechanisms. This review focuses on some aspects of the "network" approach, namely interactions between two individual mechanisms that contribute to ageing: DNA damage response and telomere maintenance. The key framework for considering these interactions is the previously proposed integrative model, which predicts that telomere maintenance is an integral part of DNA damage response machinery. The integrative model predicts the dual phenotype, namely dysfunctional DNA damage response and dysfunctional telomere maintenance, when one of these mechanisms is the cause of ageing. In line with this prediction between 87 and 90% of mouse and human models of premature ageing show this dual phenotype. It is concluded that the integrative model is consistent with the "network" theory of ageing.},
}
@article {pmid18060788,
year = {2007},
author = {Blitzblau, HG and Bell, GW and Rodriguez, J and Bell, SP and Hochwagen, A},
title = {Mapping of meiotic single-stranded DNA reveals double-stranded-break hotspots near centromeres and telomeres.},
journal = {Current biology : CB},
volume = {17},
number = {23},
pages = {2003-2012},
doi = {10.1016/j.cub.2007.10.066},
pmid = {18060788},
issn = {0960-9822},
mesh = {Centromere/*genetics ; *Chromosome Mapping ; Chromosomes, Fungal/genetics ; *DNA Breaks, Double-Stranded ; DNA Repair ; DNA, Single-Stranded/analysis/*genetics ; Meiosis ; Oligonucleotide Array Sequence Analysis/methods ; Saccharomycetales/*genetics ; Telomere/*genetics ; },
abstract = {BACKGROUND: Every chromosome requires at least one crossover to be faithfully segregated during meiosis. At least two levels of regulation govern crossover distribution: where the initiating DNA double-strand breaks (DSBs) occur and whether those DSBs are repaired as crossovers.<br><br>RESULTS: We mapped meiotic DSBs in budding yeast by identifying sites of DSB-associated single-stranded DNA (ssDNA) accumulation. These analyses revealed substantial DSB activity in pericentrometric regions, in which crossover formation is largely absent. Our data suggest that centromeric suppression of recombination occurs at the level of break repair rather than DSB formation. Additionally, we found an enrichment of DSBs within a approximately 100 kb region near the ends of all chromosomes. Introduction of new telomeres was sufficient for inducing large ectopic regions of increased DSB formation, thereby revealing a remarkable long-range effect of telomeres on DSB formation. The concentration of DSBs close to chromosome ends increases the relative DSB density on small chromosomes, providing an interference-independent mechanism that ensures that all chromosomes receive at least one crossover per homolog pair.<br><br>CONCLUSIONS: Together, our results indicate that selective DSB repair accounts for crossover suppression near centromeres and suggest a simple telomere-guided mechanism that ensures sufficient DSB activity on all chromosomes.},
}
@article {pmid18058538,
year = {2007},
author = {Liu, X and Inomata, M and Ogawara, T and Saneyoshi, M and Yamaguchi, T},
title = {Telomere shortening in human HL60 cells by treatment with 3'-azido-2',3'-dideoxynucleosides and telomerase inhibition by their 5'-triphosphates.},
journal = {Nucleosides, nucleotides &amp; nucleic acids},
volume = {26},
number = {8-9},
pages = {1067-1071},
doi = {10.1080/15257770701515468},
pmid = {18058538},
issn = {1525-7770},
mesh = {Dideoxyadenosine/analogs &amp; derivatives/chemistry/pharmacology ; Dideoxynucleosides/chemistry/*pharmacology ; Dideoxynucleotides/chemistry/*pharmacology ; Drug Design ; Enzyme Inhibitors/chemistry/pharmacology ; HL-60 Cells ; Humans ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects ; },
abstract = {Telomerase is thought to play an important role in the mechanism of tumor cell immortalization by maintenance of telomere length. To obtain information on the susceptibility of telomerase to nucleoside analogues, the effects of base-modified 3'-azido-2',3'-dideoxynucleoside triphosphates on the enzyme were investigated. It is suggested that the 2-amino group of the nucleotide purine nucleus is important for the inhibitory activity. Telomere shortening caused by long-term treatment with these nucleosides is also described.},
}
@article {pmid18058461,
year = {2007},
author = {Zhang, Y and Shen, J and Ming-Whei, and Lee, YP and Santella, RM},
title = {Telomere length in hepatocellular carcinoma and paired adjacent non-tumor tissues by quantitative PCR.},
journal = {Cancer investigation},
volume = {25},
number = {8},
pages = {668-677},
doi = {10.1080/07357900701561024},
pmid = {18058461},
issn = {1532-4192},
support = {R01ES05116/ES/NIEHS NIH HHS/United States ; R01 ES005116/ES/NIEHS NIH HHS/United States ; P30CA01396/CA/NCI NIH HHS/United States ; P30ES09089/ES/NIEHS NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; Aged ; Carcinoma, Hepatocellular/*genetics ; Female ; Genes, p53 ; Humans ; Liver Neoplasms/*genetics ; Male ; Middle Aged ; Mutation ; Polymerase Chain Reaction/*methods ; Telomere ; },
abstract = {Telomere shortening limits the proliferative capacity of human cells, restrains the regenerative capacity of organ systems during chronic diseases and aging and also induces chromosomal instability as well as initiation of cancer. Previous studies demonstrated that telomeres are often significantly shorter in tumor tissue, including hepatocellular carcinoma (HCC), compared to the surrounding tissue, but telomere length in HCC tissues was not correlated with several clinical parameters, such as age, sex, HBV or HCV infections and tumor size. In the present study, the telomere length ratio of 36 paired HCC, and their adjacent non-tumor tissues was measured by quantitative PCR (Q-PCR). The mean telomere lengths (SD) for HCC and adjacent non-tumor tissues were 0.26 (0.10) and 0.47 (0.20) respectively (t = 6.22, P < 0.0001). There was a large difference in the distribution of subjects based on telomere length in tumor and adjacent non-tumor tissues. The number of tumors with telomere length shorter than 0.50 was much higher than that of adjacent non-tumor tissues; more than 90% of the tissues with telomere length > or = 0.50 were adjacent non-tumor tissues. The correlations between telomere length and aflatoxin B1- and polycyclic aromatic hydrocarbon-DNA adducts level, p53 mutations and p16 hypermethylation status were also tested, but no significant associations were found. The relationship between telomere length shortening, chemical carcinogen exposure, and genetic and epigenetic changes in hepatocarcinogenesis needs further investigation.},
}
@article {pmid18056180,
year = {2007},
author = {Heaphy, CM and Baumgartner, KB and Bisoffi, M and Baumgartner, RN and Griffith, JK},
title = {Telomere DNA content predicts breast cancer-free survival interval.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {13},
number = {23},
pages = {7037-7043},
doi = {10.1158/1078-0432.CCR-07-0432},
pmid = {18056180},
issn = {1078-0432},
support = {T34 GM008751/GM/NIGMS NIH HHS/United States ; N0-1-CN-65034/CN/NCI NIH HHS/United States ; PC-05016-20/PC/NCI NIH HHS/United States ; RR0164880/RR/NCRR NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/genetics ; Breast Neoplasms/diagnosis/*genetics ; DNA, Neoplasm/*genetics ; Disease-Free Survival ; Female ; Humans ; Kaplan-Meier Estimate ; Middle Aged ; Prospective Studies ; Risk Factors ; Telomere/*genetics ; },
abstract = {BACKGROUND: Telomeres are nucleoprotein complexes that protect chromosome ends from degradation and recombination. Critically shortened telomeres generate genomic instability. It has been postulated that the extent of telomere DNA loss is related to the degree of genomic instability within a tumor and therefore may presage clinical outcome. The objective of this investigation was to evaluate the hypothesis that telomere DNA content (TC) in breast tumor tissues predicts breast cancer-free survival interval.<br><br>MATERIALS AND METHODS: Slot blot titration assay was used to quantitate TC in 530 archival breast tumor tissues in a population-based cohort. The relationships between TC, 12 risk factors for breast cancer adverse events (i.e., death due to breast cancer, breast cancer recurrence, or development of a new primary breast tumor), and breast cancer-free survival interval were evaluated by Fisher's exact test, log-rank analysis, and univariate and multivariate Cox proportional hazards models.<br><br>RESULTS: TC was independent of each of the 12 risk factors. Ethnicity, tumor-node-metastasis stage, estrogen receptor, progesterone receptor, and p53 status, chemotherapy sequence, adjuvant therapy, and TC each conferred significant relative hazards. The best overall multivariate Cox proportional hazards model included TC, p53 status, tumor-node-metastasis stage, and estrogen receptor status as independent predictors of breast cancer-free survival interval (P < 0.00005). Low TC (< or =200% of standard), relative to the high-TC group (>200% of standard), conferred an adjusted relative hazard of 2.88 (95% confidence interval, 1.16-7.15; P = 0.022) for breast cancer-related adverse events.<br><br>CONCLUSIONS: TC in breast cancer tissue is an independent predictor in this group of breast cancer-free survival interval.},
}
@article {pmid18054991,
year = {2008},
author = {Kappei, D and Londoño-Vallejo, JA},
title = {Telomere length inheritance and aging.},
journal = {Mechanisms of ageing and development},
volume = {129},
number = {1-2},
pages = {17-26},
doi = {10.1016/j.mad.2007.10.009},
pmid = {18054991},
issn = {0047-6374},
mesh = {Aging/*genetics ; Animals ; Caenorhabditis elegans/genetics ; Dyskeratosis Congenita/genetics ; Humans ; Longevity/genetics ; Mice ; Models, Animal ; Quantitative Trait, Heritable ; Saccharomyces cerevisiae/genetics ; Telomere/chemistry/*metabolism ; Werner Syndrome/genetics ; },
abstract = {Telomere shortening accompanies human aging, and premature aging syndromes are often associated with short telomeres. These two observations are central to the hypothesis that telomere length directly influences longevity. If true, genetically determined mechanisms of telomere length homeostasis should significantly contribute to variations of longevity in the human population. On the other hand, telomere shortening is also observed in the course of many aging-associated disorders but determining whether it is a cause or a consequence is not an easy task. Here, we review the most relevant experimental and descriptive data relating telomere length, as a quantitative trait, to aging and longevity.},
}
@article {pmid18054990,
year = {2008},
author = {Gilley, D and Herbert, BS and Huda, N and Tanaka, H and Reed, T},
title = {Factors impacting human telomere homeostasis and age-related disease.},
journal = {Mechanisms of ageing and development},
volume = {129},
number = {1-2},
pages = {27-34},
doi = {10.1016/j.mad.2007.10.010},
pmid = {18054990},
issn = {0047-6374},
support = {AG18736/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*genetics ; Cellular Senescence/genetics ; Environment ; Genomic Instability ; Homeostasis ; Humans ; Neoplasms/enzymology/*genetics ; Telomerase/metabolism ; Telomere/*metabolism ; Twin Studies as Topic ; },
abstract = {Loss of telomere length homeostasis has been linked to age-related disease especially cancer. In this review, we discuss two major causes of telomere dysfunction that potentially lead to tumorigenesis: replicative aging and environmental assaults. Aging has long been recognized as a source for telomere dysfunction through increasing numbers of cell divisions in the absence of sufficient telomerase activity. However, environmental assaults that cause telomere dysfunction are only beginning to be identified and recognized. Environmental stressors that influence telomere length may be physical or induced by psychological situations like stress. Knowledge of all factors, including genetic and environmental forces, that moderate telomere length will be critical for understanding basic mechanisms of human telomere maintenance during development and aging as well as for disease prevention and treatment strategies.},
}
@article {pmid18054793,
year = {2008},
author = {Opresko, PL},
title = {Telomere ResQue and preservation--roles for the Werner syndrome protein and other RecQ helicases.},
journal = {Mechanisms of ageing and development},
volume = {129},
number = {1-2},
pages = {79-90},
doi = {10.1016/j.mad.2007.10.007},
pmid = {18054793},
issn = {0047-6374},
support = {ES015052-01/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; DNA Replication ; Exodeoxyribonucleases ; Humans ; Mice ; RecQ Helicases/genetics/*physiology ; Telomere/chemistry/*metabolism ; Werner Syndrome/*enzymology/genetics ; Werner Syndrome Helicase ; },
abstract = {Werner syndrome is an autosomal recessive disorder resulting from loss of function of the RecQ helicase, WRN protein. WS patients prematurely develop numerous clinical symptoms and diseases associated with aging early in life and are predisposed to cancer. WRN protein and many other RecQ helicases in general, seem to function during DNA replication in the processing of stalled replication forks. Genetic, cellular and biochemical evidence support roles for WRN in proper replication and repair of telomeric DNA, and indicate that telomere dysfunction contributes to the WS disease pathology.},
}
@article {pmid18052745,
year = {2007},
author = {Cadile, CD and Kitchell, BE and Newman, RG and Biller, BJ and Hetler, ER},
title = {Telomere length in normal and neoplastic canine tissues.},
journal = {American journal of veterinary research},
volume = {68},
number = {12},
pages = {1386-1391},
doi = {10.2460/ajvr.68.12.1386},
pmid = {18052745},
issn = {0002-9645},
mesh = {Animals ; Dog Diseases/*metabolism ; Dogs ; Neoplasms/metabolism/*veterinary ; Telomerase/metabolism ; Telomere/*genetics ; },
abstract = {OBJECTIVE: To determine the mean telomere restriction fragment (TRF) length in normal and neoplastic canine tissues.<br><br>SAMPLE POPULATION: 57 solid-tissue tumor specimens collected from client-owned dogs, 40 samples of normal tissue collected from 12 clinically normal dogs, and blood samples collected from 4 healthy blood donor dogs.<br><br>PROCEDURES: Tumor specimens were collected from client-owned dogs during diagnostic or therapeutic procedures at the University of Illinois Veterinary Medical Teaching Hospital, whereas 40 normal tissue samples were collected from 12 control dogs. Telomere restriction fragment length was determined by use of an assay kit. A histologic diagnosis was provided for each tumor by personnel at the Veterinary Diagnostic Laboratory at the University of Illinois.<br><br>RESULTS: Mean of the mean TRF length for 44 normal samples was 19.0 kilobases (kb; range, 15.4 to 21.4 kb), and the mean of the mean TRF length for 57 malignant tumors was 19.0 kb (range, 12.9 to 23.5 kb). Although the mean of the mean TRF length for tumors and normal tissues was identical, tumor samples had more variability in TRF length.<br><br>Telomerase, which represents the main mechanism by which cancer cells achieve immortality, is an attractive therapeutic target. The ability to measure telomere length is crucial to monitoring the efficacy of telomerase inhibition. In contrast to many other mammalian species, the length of canine telomeres and the rate of telomeric DNA loss are similar to those reported in humans, making dogs a compelling choice for use in the study of human anti-telomerase strategies.},
}
@article {pmid18046431,
year = {2008},
author = {Lung, FW and Ku, CS and Kao, WT},
title = {Telomere length may be associated with hypertension.},
journal = {Journal of human hypertension},
volume = {22},
number = {3},
pages = {230-232},
doi = {10.1038/sj.jhh.1002314},
pmid = {18046431},
issn = {0950-9240},
mesh = {Aged ; Case-Control Studies ; China ; Female ; Humans ; Hypertension/*blood ; Linear Models ; Male ; Middle Aged ; Pilot Projects ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*ultrastructure ; },
}
@article {pmid18045969,
year = {2008},
author = {Roos, G and Kröber, A and Grabowski, P and Kienle, D and Bühler, A and Döhner, H and Rosenquist, R and Stilgenbauer, S},
title = {Short telomeres are associated with genetic complexity, high-risk genomic aberrations, and short survival in chronic lymphocytic leukemia.},
journal = {Blood},
volume = {111},
number = {4},
pages = {2246-2252},
doi = {10.1182/blood-2007-05-092759},
pmid = {18045969},
issn = {0006-4971},
mesh = {Adult ; Antigens, CD/analysis ; B-Lymphocytes/immunology/pathology ; Base Sequence ; *Chromosome Aberrations ; DNA Mutational Analysis ; Humans ; Immunoglobulin Variable Region/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/mortality ; Polymerase Chain Reaction ; Survival Analysis ; Survivors ; Telomere/*genetics/*ultrastructure ; },
abstract = {Telomere length is associated with mutation status of the immunoglobulin heavy chain variable (IGHV) gene and clinical course in B-cell chronic lymphocytic leukemia (B-CLL). In a B-CLL cohort of 152 patients, we analyzed telomere length, genomic aberrations, IGHV mutation status, CD38 and ZAP-70 expression to study the prognostic impact and associations among these factors. An inverse correlation existed between telomere length and IGHV homology (P < .001), CD38 (P < .001), and ZAP-70 expression (P = .01). Patients with telomere lengths below median (ie, "short telomeres") and above median (ie, "long telomeres") had similar incidences of genomic aberrations (74% vs 68%), 13q- (57% vs 49%), and +12q (5% vs 12%). In contrast, 13q- as a single aberration was more frequent in patients with long telomeres (51% vs 21%; P = .006), whereas 11q- (27% vs 9%; P = .014), 17p- (17% vs 0%; P < .001), and 2 or more genomic aberrations (39% vs 8%; P < .001) were more frequent in patients with short telomeres. Compared with patients with long telomeres, treatment-free survival (TFS) and overall survival (OS) was significantly shorter (P < .001 and P = .015, respectively) in the group with short telomeres, and telomere length was an independent prognostic indicator for TFS. These observations have biological and prognostic implications in B-CLL.},
}
@article {pmid18044760,
year = {2008},
author = {Wang, H and Chen, H and Gao, X and McGrath, M and Deer, D and De Vivo, I and Schwarzschild, MA and Ascherio, A},
title = {Telomere length and risk of Parkinson's disease.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {23},
number = {2},
pages = {302-305},
pmid = {18044760},
issn = {1531-8257},
support = {R01 NS048517/NS/NINDS NIH HHS/United States ; R01 NS048517-01A2/NS/NINDS NIH HHS/United States ; Z01 ES101986-02/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adult ; Aged ; Case-Control Studies ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Parkinson Disease/*genetics/*pathology ; Retrospective Studies ; Risk Factors ; Telomere/*pathology/*ultrastructure ; },
abstract = {We investigated whether telomere length was associated with the risk of Parkinson's disease (PD) in a case-control study (96 cases and 172 age-matched controls) nested within the Health Professionals Follow-up Study. Relative ratio of telomere repeat copy number to single-gene copy number in peripheral blood leukocytes was determined by quantitative real time PCR. Men with shorter telomeres had a lower PD risk (multivariate adjusted relative risk for the lowest vs. the highest quartile 0.33; 95% confidence interval: 0.12-0.90). Our results suggest that, contrary to telomere attrition observed in several aging-related diseases, shorter telomeres are not associated with an increased risk of PD.},
}
@article {pmid18042589,
year = {2007},
author = {Beier, F and Balabanov, S and Amberger, CC and Hartmann, U and Manger, K and Dietz, K and Kötter, I and Brummendorf, TH},
title = {Telomere length analysis in monocytes and lymphocytes from patients with systemic lupus erythematosus using multi-color flow-FISH.},
journal = {Lupus},
volume = {16},
number = {12},
pages = {955-962},
doi = {10.1177/0961203307084299},
pmid = {18042589},
issn = {0961-2033},
mesh = {Adult ; Case-Control Studies ; Humans ; In Situ Hybridization, Fluorescence ; Lupus Erythematosus, Systemic/*genetics ; *Lymphocytes ; Middle Aged ; *Monocytes ; Telomere/*genetics ; },
abstract = {In order to analyse telomere length in subsets of human peripheral blood lymphocytes and monocytes, we modified a recently developed multicolor flow- fluorescent in situ hybridization (FISH) methodology that combines flow-FISH and antibody staining for cell surface antigens. We analysed telomere length of peripheral blood mononuclear cells in a group of 22 patients with systemic lupus erythematosus (SLE) and 20 age-matched healthy donors. We found that neither CD4+, CD8+, CD19+ cells nor CD14+ monocytes have significantly shorter telomeres compared with their healthy counterparts. On the basis of these findings, we then used monocyte telomere length as internal reference in order to control for intra-individual variability in telomere length. By using this approach, we could demonstrate significant telomere shortening in all three lymphocyte subsets (in all cases P < 0.05) compared with monocytes. However, these differences did not vary significantly between SLE patients and controls. In summary, telomere lengths in subpopulations of hematopoietic cells can be monitored in patients with SLE using multicolor flow-FISH. While confirming data by other groups on telomere length in lymphocyte subpopulations, our data argue against an increased proliferation rate of peripheral blood monocytes reflected by accelerated telomere shortening in patients with SLE.},
}
@article {pmid18039933,
year = {2007},
author = {Bupp, JM and Martin, AE and Stensrud, ES and Jaspersen, SL},
title = {Telomere anchoring at the nuclear periphery requires the budding yeast Sad1-UNC-84 domain protein Mps3.},
journal = {The Journal of cell biology},
volume = {179},
number = {5},
pages = {845-854},
pmid = {18039933},
issn = {1540-8140},
mesh = {Cell Cycle Proteins/*chemistry ; Cell Nucleus/*metabolism ; Checkpoint Kinase 2 ; Chromosomes, Fungal/metabolism ; Gene Silencing ; Membrane Proteins/chemistry/*metabolism ; Mutation/genetics ; Nuclear Proteins ; Protein Binding ; Protein Serine-Threonine Kinases/*chemistry ; Protein Structure, Tertiary ; Recombinant Fusion Proteins/metabolism ; S Phase ; Saccharomyces cerevisiae Proteins/*chemistry/metabolism ; Saccharomycetales/*cytology/*metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/metabolism ; Telomere/*metabolism ; },
abstract = {Positioning of telomeres at the nuclear periphery can have dramatic effects on gene expression by establishment of heritable, transcriptionally repressive subdomains. However, little is known about the integral membrane proteins that mediate telomere tethering at the nuclear envelope. Here, we find a previously unrecognized function for the Saccharomyces cerevisiae Sad1-UNC-84 domain protein Mps3 in regulating telomere positioning in mitotic cells. Our data demonstrate that the nucleoplasmic N-terminal acidic domain of Mps3 is not essential for viability. However, this acidic domain is necessary and sufficient for telomere tethering during S phase and the silencing of reporter constructs integrated at telomeres. We show that this is caused by the role of the Mps3 acidic domain in binding and localization of the silent information regulator protein Sir4 to the nuclear periphery. Thus, Mps3 functions as an integral membrane anchor for telomeres and is a novel nuclear receptor for the Sir4 pathway of telomere tethering and gene inactivation.},
}
@article {pmid18029682,
year = {2007},
author = {Liu, X and Liu, J and Ogawara, T and Kurashina, Y and Yashi, R and Saneyoshi, M and Yamaguchi, T},
title = {Influence of nucleoside analogue treatment on telomere length and TRF2 amount in human HL60 cells.},
journal = {Nucleic acids symposium series (2004)},
volume = {},
number = {51},
pages = {253-254},
doi = {10.1093/nass/nrm127},
pmid = {18029682},
issn = {1746-8272},
mesh = {Dideoxynucleosides/chemistry/*pharmacology ; HL-60 Cells ; Humans ; Nuclear Proteins/*metabolism ; Telomere/*drug effects/metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {Long-term treatment with 3'-azido-2',3'-dideoxy-guanosine (AZddG) results in reproducible telomere shortening in cultured human HL60 cells. TRF2 protein has been implicated in the protection of chromosome ends. It binds to double-strand repeats and may have an indirect role in protecting the G-rich overhang by recruiting other telomere-binding proteins to the G-tail or by mediating the formation of the telomeric t-loop. Western blot analysis demonstrated no change or a slight increase, of the TRF2 protein level in HL60 cells with AZddG-induced telomere shortening. The effects of nucleoside analogues on TRF2 suggest that it is not telomere length per se, but rather the presence or absence of a protective telomere state, which determines whether senescence ensues.},
}
@article {pmid18029655,
year = {2007},
author = {Xu, Y and Hirohata, Y and Komiyama, M},
title = {Sequence-specific cleavage of human telomere DNA by G-quadruplex formation.},
journal = {Nucleic acids symposium series (2004)},
volume = {},
number = {51},
pages = {199-200},
doi = {10.1093/nass/nrm100},
pmid = {18029655},
issn = {1746-8272},
mesh = {Base Sequence ; Edetic Acid/chemistry ; *G-Quadruplexes ; Humans ; Oligonucleotide Probes/*chemistry ; Telomere/*chemistry ; },
abstract = {In the current study, we reported that oligonucleotide with EDTA-Fe at 5' end causes a sequence specific break in human telomeric DNA strand by G-quadruplex formation.},
}
@article {pmid18029594,
year = {2007},
author = {Ohyama, T and Furukawa, A and Miyoshi, T and Takada, Y and Ohgara, S and Hiratsuka, K and Imai, T and Okano, H and Nakagama, H and Nagata, T and Katahira, M},
title = {Interactions with RNA/DNA of proteins involved in the regulation of transcription, translation and telomere elongation.},
journal = {Nucleic acids symposium series (2004)},
volume = {},
number = {51},
pages = {77-78},
doi = {10.1093/nass/nrm039},
pmid = {18029594},
issn = {1746-8272},
mesh = {DNA/chemistry ; DNA-Binding Proteins/*chemistry ; Gene Expression Regulation ; Heterogeneous Nuclear Ribonucleoprotein A1 ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/*chemistry ; Nuclear Magnetic Resonance, Biomolecular ; Protein Biosynthesis ; Protein Structure, Tertiary ; RNA/chemistry ; RNA-Binding Proteins/*chemistry ; Telomere/chemistry ; Transcription Factors/*chemistry ; Transcription, Genetic ; },
abstract = {Interactions with DNA and RNA of three different proteins involved in the regulation of (1) transcription, (2) translation, and (3) telomere elongation were examined by NMR. In the first case, the combination of structural determination, dynamical analysis on the basis of relaxation data and identification of interactive surface for wild and phosphorylation-mimicking mutant proteins has given the insight on the increase of DNA-binding affinity through phosphorylation of the protein. In the second case, the arrangement of two tandem domains interacting with RNA has been determined with residual dipolar couplings and paramagnetic relaxation enhancement, which has given the idea on how the two tandem domains recognize the target RNA. In the third case, simultaneous binding of the other two tandem domains to both DNA and RNA has been analyzed with chemical shift perturbation analysis. The result has suggested that the protein composed of two tandem domains can recruit telomerase to telomere DNA.},
}
@article {pmid18029083,
year = {2008},
author = {Serakinci, N and Graakjaer, J and Kolvraa, S},
title = {Telomere stability and telomerase in mesenchymal stem cells.},
journal = {Biochimie},
volume = {90},
number = {1},
pages = {33-40},
doi = {10.1016/j.biochi.2007.09.005},
pmid = {18029083},
issn = {0300-9084},
mesh = {Adult Stem Cells/enzymology/metabolism/ultrastructure ; Cell Division ; Cellular Senescence/physiology ; Epigenesis, Genetic ; Humans ; Mesenchymal Stem Cells/enzymology/*physiology/ultrastructure ; Telomerase/genetics/*metabolism ; Telomere/genetics/*physiology ; },
abstract = {Telomeres are repetitive genetic material that cap and thereby protect the ends of chromosomes. Each time a cell divides, telomeres get shorter. Telomere length is mainly maintained by telomerase. This enzyme is present in high concentrations in the embryonic stem cells and in fast growing embryonic cells, and declines with age. It is still unclear to what extent there is telomerase in adult stem cells, but since these are the founder cells of cells of all the tissues in the body, understanding the telomere dynamics and expression of telomerase in adult stem cells is very important. In the present communication we focus on telomere expression and telomere length in stem cells, with a special focus on mesenchymal stem cells. We consider different mechanisms by which stem cells can maintain telomeres and also focus on the dynamics of telomere length in mesenchymal stem cells, both the overall telomere length and the telomere length of individual chromosomes.},
}
@article {pmid18029082,
year = {2008},
author = {Ju, Z and Lenhard Rudolph, K},
title = {Telomere dysfunction and stem cell ageing.},
journal = {Biochimie},
volume = {90},
number = {1},
pages = {24-32},
doi = {10.1016/j.biochi.2007.09.006},
pmid = {18029082},
issn = {0300-9084},
mesh = {Adult Stem Cells/enzymology/*physiology ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/metabolism ; Cellular Senescence/*physiology ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; *DNA Damage ; DNA-Binding Proteins/metabolism ; Protein Serine-Threonine Kinases/metabolism ; Telomerase/metabolism ; Telomere/*physiology ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins/metabolism ; },
abstract = {Ageing is characterized by a decline in organ maintenance and repair. Adult stem cells contribute to tissue repair and organ maintenance. Thus it is conceivable that ageing is partly due to a decline of stem cell function. At molecular level, ageing is associated with an accumulation of damage affecting DNA, proteins, membranes, and organelles, as well as the formation of insoluble protein aggregates. Telomere shortening represents a cell intrinsic mechanism, which contributes to the accumulation of DNA damage during cellular ageing. Telomere dysfunction in response to critical telomere shortening induces DNA damage checkpoints that lead to cell cycle arrest and/or cell death. Checkpoint responses induced by telomere dysfunction have mostly been studied in somatic cells but there are emerging data on cell intrinsic checkpoints that impair the maintenance and function of adult stem cell in response to telomere dysfunction. Moreover, telomere dysfunction induces alterations in the stem cell environment that limit the function of adult stem cells. In this review we summarize our current knowledge on the role of telomere dysfunction in adult stem cell ageing.},
}
@article {pmid18028256,
year = {2008},
author = {Pignolo, RJ and Suda, RK and McMillan, EA and Shen, J and Lee, SH and Choi, Y and Wright, AC and Johnson, FB},
title = {Defects in telomere maintenance molecules impair osteoblast differentiation and promote osteoporosis.},
journal = {Aging cell},
volume = {7},
number = {1},
pages = {23-31},
pmid = {18028256},
issn = {1474-9726},
support = {R01 AG028873/AG/NIA NIH HHS/United States ; R01 AG028873-01A1/AG/NIA NIH HHS/United States ; },
mesh = {Aging ; Animals ; Bone Marrow Cells ; *Cell Differentiation ; Cells, Cultured ; Cellular Senescence ; Mesenchymal Stem Cells ; Mice ; Mice, Knockout ; Osteoblasts/*cytology ; Osteogenesis ; Osteoporosis/*genetics/physiopathology ; RecQ Helicases/genetics ; Telomerase/genetics ; Telomere/*metabolism ; Werner Syndrome Helicase ; },
abstract = {Osteoporosis and the associated risk of fracture are major clinical challenges in the elderly. Telomeres shorten with age in most human tissues, including bone, and because telomere shortening is a cause of cellular replicative senescence or apoptosis in cultured cells, including mesenchymal stem cells (MSCs) and osteoblasts, it is hypothesized that telomere shortening contributes to the aging of bone. Osteoporosis is common in the Werner (Wrn) and dyskeratosis congenita premature aging syndromes, which are characterized by telomere dysfunction. One of the targets of the Wrn helicase is telomeric DNA, but the long telomeres and abundant telomerase in mice minimize the need for Wrn at telomeres, and thus Wrn knockout mice are relatively healthy. In a model of accelerated aging that combines the Wrn mutation with the shortened telomeres of telomerase (Terc) knockout mice, synthetic defects in proliferative tissues result. Here, we demonstrate that deficiencies in Wrn-/- Terc-/- mutant mice cause a low bone mass phenotype, and that age-related osteoporosis is the result of impaired osteoblast differentiation in the context of intact osteoclast differentiation. Further, MSCs from single and Wrn-/- Terc-/- double mutant mice have a reduced in vitro lifespan and display impaired osteogenic potential concomitant with characteristics of premature senescence. These data provide evidence that replicative aging of osteoblast precursors is an important mechanism of senile osteoporosis.},
}
@article {pmid18025071,
year = {2008},
author = {Zhang, YW and Zhang, ZX and Miao, ZH and Ding, J},
title = {The telomeric protein TRF2 is critical for the protection of A549 cells from both telomere erosion and DNA double-strand breaks driven by salvicine.},
journal = {Molecular pharmacology},
volume = {73},
number = {3},
pages = {824-832},
doi = {10.1124/mol.107.039081},
pmid = {18025071},
issn = {1521-0111},
mesh = {Ataxia Telangiectasia Mutated Proteins ; Carcinoma/pathology ; Cell Cycle Proteins/analysis/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Comet Assay ; DNA Breaks, Double-Stranded/*drug effects ; DNA-Binding Proteins/metabolism ; Humans ; Lung Neoplasms/pathology ; Naphthoquinones/*poisoning ; Nuclear Proteins/genetics/*metabolism ; Protein Serine-Threonine Kinases/analysis/metabolism ; RNA, Small Interfering/metabolism ; Statistics as Topic ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; Transfection ; Tumor Suppressor Proteins/metabolism ; },
abstract = {Telomere repeat binding factor 2 (TRF2) has been increasingly recognized to be involved in DNA damage response and telomere maintenance. Our previous report found that salvicine (SAL), a novel topoisomerase II poison, elicited DNA double-strand breaks and telomere erosion in separate experimental systems. However, it remains to be clarified whether they share a common response to these two events and in particular whether TRF2 is involved in this process. In this study, we found that SAL concurrently induced DNA double-strand breaks, telomeric DNA damage, and telomere erosion in lung carcinoma A549 cells. It was unexpected to find that SAL led to disruption of TRF2, independently of either its transcription or proteasome-mediated degradation. By overexpressing the full-length trf2 gene and transfecting TRF2 small interfering RNAs, we showed that TRF2 protein protected both telomeric and genomic DNA from the SAL-elicited events. It is noteworthy that although both the Ataxia-telangiectasia-mutated (ATM) and the ATM- and Rad3-related (ATR) kinases responded to the SAL-induced DNA damages, only ATR was essential for the telomere erosion. The study also showed that the activated ATR augmented the SAL-triggered TRF2 disruption, whereas TRF2 reduction in turn enhanced ATR function. All of these findings suggest the emerging significance of TRF2 protecting both telomeric DNA and genomic DNA on the one hand and reveal the mutual modulation between ATR and TRF2 in sensing DNA damage signaling during cancer development on the other hand.},
}
@article {pmid18021748,
year = {2008},
author = {Houben, JM and Moonen, HJ and van Schooten, FJ and Hageman, GJ},
title = {Telomere length assessment: biomarker of chronic oxidative stress?.},
journal = {Free radical biology &amp; medicine},
volume = {44},
number = {3},
pages = {235-246},
doi = {10.1016/j.freeradbiomed.2007.10.001},
pmid = {18021748},
issn = {0891-5849},
mesh = {Animals ; Biomarkers/chemistry/metabolism ; Humans ; Inflammation/*etiology/genetics ; *Oxidative Stress ; Poly(ADP-ribose) Polymerases/metabolism ; Telomere/*chemistry/genetics/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomeres are nucleoprotein structures, located at the ends of chromosomes and are subject to shortening at each cycle of cell division. They prevent chromosomal ends from being recognized as double strand breaks and protect them from end to end fusion and degradation. Telomeres consist of stretches of repetitive DNA with a high G-C content and are reported to be highly sensitive to damage induced by oxidative stress. The resulting DNA strand breaks can be formed either directly or as an intermediate step during the repair of oxidative bases. In contrast to the majority of genomic DNA, there is evidence that telomeric DNA is deficient in the repair of single strand breaks. Since chronic oxidative stress plays a major role in the pathophysiology of several chronic inflammatory diseases, it is hypothesized that telomere length is reducing at a faster rate during oxidative stress. Therefore, assessment of telomere length might be a useful biomarker of disease progression. In this review several features of telomere length regulation, their relation with oxidative stress, and the potential application of measurement of telomere length as biomarker of chronic oxidative stress, will be discussed.},
}
@article {pmid18021178,
year = {2007},
author = {Folini, M and Bandiera, R and Millo, E and Gandellini, P and Sozzi, G and Gasparini, P and Longoni, N and Binda, M and Daidone, MG and Berg, K and Zaffaroni, N},
title = {Photochemically enhanced delivery of a cell-penetrating peptide nucleic acid conjugate targeting human telomerase reverse transcriptase: effects on telomere status and proliferative potential of human prostate cancer cells.},
journal = {Cell proliferation},
volume = {40},
number = {6},
pages = {905-920},
pmid = {18021178},
issn = {1365-2184},
mesh = {Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; *Drug Delivery Systems ; Endocytosis/drug effects ; Gene Products, tat/metabolism ; Humans ; Male ; Metaphase/drug effects ; Peptide Nucleic Acids/metabolism/*pharmacology ; Photochemistry/*methods ; Prostatic Neoplasms/*pathology ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects/genetics ; },
abstract = {OBJECTIVES: Peptide nucleic acids (PNAs) are DNA mimics that have been demonstrated to be efficient antisense/antigene tools in cell-free systems. However, their potential as in vivo regulators of gene expression has been hampered by their poor uptake by living cells, and strategies need to be developed for their intracellular delivery. This study has aimed to demonstrate the possibility (i) of efficiently delivering a PNA, which targets mRNA of the catalytic component of human telomerase reverse transcriptase (hTERT), into DU145 prostate cancer cells through a combined approach based on conjugation of the PNA to Tat internalizing peptide (hTERT-PNA-Tat) and subsequent photochemical internalization, and (ii) to interfere with telomerase function.<br><br>MATERIALS AND METHODS: Treated cells were analysed for telomerase activity, hTERT expression, growth rate, ability to undergo apoptosis and telomere status.<br><br>RESULTS: After exposure to light, DU145 cells treated with hTERT-PNA-Tat and the photosensitiser TPPS2a showed dose-dependent inhibition of telomerase activity, which was accompanied by marked reduction of hTERT protein expression. A dose-dependent decline in DU145 cell population growth and induction of caspase-dependent apoptosis were also observed from 48 h after treatment. Such an antiproliferative effect was associated with the presence of telomeric dysfunction, as revealed by cytogenetic analysis, in the absence of telomere shrinkage, and with induction of DNA damage response as suggested by the increased expression of gamma-H2AX.<br><br>CONCLUSIONS: Our results (i) indicate photochemical internalization as an efficient approach for intracellular delivery of chimaeric PNAs, and (ii) corroborate earlier evidence suggesting pro-survival and anti-apoptotic roles of hTERT, which are independent of its ability to maintain telomere length.},
}
@article {pmid18020621,
year = {2007},
author = {Parkinson, EK and Minty, F},
title = {Anticancer therapy targeting telomeres and telomerase : current status.},
journal = {BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy},
volume = {21},
number = {6},
pages = {375-385},
doi = {10.2165/00063030-200721060-00005},
pmid = {18020621},
issn = {1173-8804},
mesh = {Animals ; Antineoplastic Agents/pharmacology/*therapeutic use ; Disease Models, Animal ; Enzyme Inhibitors/pharmacology/*therapeutic use ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Neoplasms/*drug therapy ; RNA/antagonists &amp; inhibitors/genetics/metabolism ; Telomerase/*antagonists &amp; inhibitors/genetics/metabolism ; Telomere/*drug effects/genetics ; },
abstract = {Normal human somatic cells undergo telomeric attrition causing replicative senescence. Most immortal cancer cells cope with this by upregulating the active form of telomerase. Long-term inhibition of telomerase results in telomeric attrition and highly specific killing of cancer cells, in which the maintenance of telomere length is reliant on telomerase activity. Unfortunately, telomere erosion requires many cell divisions, possibly opening the way for acquired drug resistance. Recent attempts to solve this problem include the development of drugs that are more potent catalytic inhibitors, deny telomerase access to the telomere in situ, or affect telomere structure; some of these drugs have entered clinical trials. Combinations of these approaches may ultimately produce the best clinical results. This article reviews the latest results in both basic and applied telomere research that indicate the most promising avenues for future anticancer drug development in this area.},
}
@article {pmid18006759,
year = {2007},
author = {Stewénius, Y and Jin, Y and Øra, I and de Kraker, J and Bras, J and Frigyesi, A and Alumets, J and Sandstedt, B and Meeker, AK and Gisselsson, D},
title = {Defective chromosome segregation and telomere dysfunction in aggressive Wilms' tumors.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {13},
number = {22 Pt 1},
pages = {6593-6602},
doi = {10.1158/1078-0432.CCR-07-1081},
pmid = {18006759},
issn = {1078-0432},
mesh = {Adolescent ; Child ; Child, Preschool ; *Chromosome Segregation ; Female ; Humans ; Infant ; Kidney Neoplasms/mortality/*pathology ; Male ; Mitosis ; Prognosis ; Telomere/*ultrastructure ; Wilms Tumor/mortality/*pathology ; },
abstract = {PURPOSE: In many childhood neoplasms, prognostic subgroups have been defined based on specific chromosome changes. In Wilms' tumor (WT), such subclassification has been hampered by the diverse and relatively unspecific pattern of chromosomal imbalances present in these tumors. Unspecific patterns of cytogenetic imbalances in tumors are often caused by mitotic segregation errors due to short dysfunctional telomeres. As an alternative to cytogenetic classification, we therefore have evaluated whether the rate of telomere-dependent chromosomal instability could influence the clinical course in WT patients.<br><br>EXPERIMENTAL DESIGN: Telomere function and mitotic segregation errors were assessed in 12 cultured tumors and in tumor tissue sections from 41 WT patients.<br><br>RESULTS: Abnormal telomere shortening was found in cultured cells and in tissue sections from highly aggressive tumors. In vitro, dysfunctional telomeres were associated to specific cell division abnormalities, including anaphase bridges and multipolar mitoses. Assessment of mitotic figures in tissue sections revealed that anaphase bridges and multipolar mitoses were predominantly, but not exclusively, present in high-risk tumors and were predictors of poor event-free and overall survival.<br><br>CONCLUSIONS: Telomere-dependent mitotic instability is present in a subgroup of WT, predominantly consisting of high-risk tumors.},
}
@article {pmid18006387,
year = {2008},
author = {Blagoev, KB and Goodwin, EH},
title = {Telomere exchange and asymmetric segregation of chromosomes can account for the unlimited proliferative potential of ALT cell populations.},
journal = {DNA repair},
volume = {7},
number = {2},
pages = {199-204},
doi = {10.1016/j.dnarep.2007.09.012},
pmid = {18006387},
issn = {1568-7864},
mesh = {*Cell Proliferation ; Chromosome Segregation/genetics/*physiology ; Computer Simulation ; Humans ; *Models, Genetic ; Sister Chromatid Exchange/genetics/*physiology ; Telomere/genetics/*physiology ; },
abstract = {Telomerase-negative cancer cells show increased telomere sister chromatid exchange (T-SCE) rates, a phenomenon that has been associated with an alternative lengthening of telomeres (ALT) mechanism for maintaining telomeres in this subset of cancers. Here we examine whether or not T-SCE can maintain telomeres in human cells using a combinatorial model capable of describing how telomere lengths evolve over time. Our results show that random T-SCE is unlikely to be the mechanism of telomere maintenance of ALT human cells, but that increased T-SCE rates combined with a recently proposed novel mechanism of non-random segregation of chromosomes with long telomeres preferentially into the same daughter cell during cell division can stabilize chromosome ends in ALT cancers. At the end we discuss a possible experiment that can validate the findings of this study.},
}
@article {pmid18006317,
year = {2007},
author = {Deng, Z and Dheekollu, J and Broccoli, D and Dutta, A and Lieberman, PM},
title = {The origin recognition complex localizes to telomere repeats and prevents telomere-circle formation.},
journal = {Current biology : CB},
volume = {17},
number = {22},
pages = {1989-1995},
doi = {10.1016/j.cub.2007.10.054},
pmid = {18006317},
issn = {0960-9822},
support = {CA093606/CA/NCI NIH HHS/United States ; },
mesh = {*Chromosome Aberrations ; HCT116 Cells ; Humans ; Origin Recognition Complex/genetics/*metabolism ; Repetitive Sequences, Nucleic Acid/*physiology ; Telomere/*genetics/metabolism ; },
abstract = {Chromosome ends are maintained by telomere-repeat-binding factors (TRFs) that coordinate DNA end protection with telomere replication. The origin recognition complex (ORC) coordinates bidirectional DNA replication at most chromosomal sites, but it is also known to function in transcriptional silencing, heterochromatin formation, and sister-chromatid cohesion. We now show that ORC localizes to telomere repeats and contributes to telomere maintenance. We found that ORC subunits can be affinity purified with telomere-repeat DNA along with other components of the known "shelterin" complex. ORC subunits colocalized with telomere-repeat foci and coimmunoprecipitated with TRF2 but not TRF2 lacking its amino-terminal basic domain (TRF2DeltaB). ORC2 depletion or hypomorphic cell lines caused a loss of telomere-repeat signal intensity and the appearance of dysfunctional telomeres, including telomere-signal-free ends and telomere-repeat-containing double minutes. Two-dimensional agarose gel electrophoresis revealed that ORC2 depletion increased telomere circle formation, comparable to the overexpression of TRF2DeltaB. A similar increase in telomere circle formation was induced by hydroxyurea treatment, providing evidence that replication stress produces telomere circles. These findings suggest that ORC recruitment by TRF2 contributes to telomere integrity by facilitating efficient telomere DNA replication and preventing the generation of telomere-repeat-containing circles.},
}
@article {pmid18006207,
year = {2008},
author = {Ayouaz, A and Raynaud, C and Heride, C and Revaud, D and Sabatier, L},
title = {Telomeres: hallmarks of radiosensitivity.},
journal = {Biochimie},
volume = {90},
number = {1},
pages = {60-72},
doi = {10.1016/j.biochi.2007.09.011},
pmid = {18006207},
issn = {0300-9084},
mesh = {Animals ; Cell Transformation, Neoplastic ; *DNA Damage ; *DNA Repair ; Humans ; Oxidative Stress ; Radiation Tolerance ; Recombination, Genetic ; Telomerase/*metabolism ; Telomere/enzymology/*physiology/*radiation effects ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomeres are the very ends of the chromosomes. They can be seen as natural double-strand breaks (DSB), specialized structures which prevent DSB repair and activation of DNA damage checkpoints. In somatic cells, attrition of telomeres occurs after each cell division until replicative senescence. In the absence of telomerase, telomeres shorten due to incomplete replication of the lagging strand at the very end of chromosome termini. Moreover, oxidative stress and accumulating reactive oxygen species (ROS) lead to an increased telomere shortening due to a less efficient repair of SSB in telomeres. The specialized structures at telomeres include proteins involved in both telomere maintenance and DNA repair. However when a telomere is damaged and has to be repaired, those proteins might fail to perform an accurate repair of the damage. This is the starting point of this article in which we first summarize the well-established relationships between DNA repair processes and maintenance of functional telomeres. We then examine how damaged telomeres would be processed, and show that irradiation alters telomere maintenance leading to possibly dramatic consequences. Our point is to suggest that those consequences are not restricted to the short term effects such as increased radiation-induced cell death. On the contrary, we postulate that the major impact of the loss of telomere integrity might occur in the long term, during multistep carcinogenesis. Its major role would be to act as an amplificator event unmasking in one single step recessive radiation-induced mutations among thousands of genes and providing cellular proliferative advantage. Moreover, the chromosomal instability generated by damaged telomeres will favour each step of the transformation from normal to fully transformed cells.},
}
@article {pmid18000505,
year = {2007},
author = {Barwell, J and Pangon, L and Georgiou, A and Docherty, Z and Kesterton, I and Ball, J and Camplejohn, R and Berg, J and Aviv, A and Gardner, J and Kato, BS and Carter, N and Paximadas, D and Spector, TD and Hodgson, S},
title = {Is telomere length in peripheral blood lymphocytes correlated with cancer susceptibility or radiosensitivity?.},
journal = {British journal of cancer},
volume = {97},
number = {12},
pages = {1696-1700},
pmid = {18000505},
issn = {0007-0920},
mesh = {Adult ; Aged ; Aged, 80 and over ; Apoptosis/radiation effects ; Breast Neoplasms/*genetics/*radiotherapy ; Chromosomes, Human/radiation effects ; Female ; *Genetic Predisposition to Disease ; Humans ; Lymphocytes/ultrastructure ; Middle Aged ; *Radiation Tolerance ; Telomere/*ultrastructure ; },
abstract = {Mean terminal restriction fragment (TRF) lengths in white blood cells (WBCs) have been previously found to be associated with breast cancer. To assess whether this marker could be used as a test for breast cancer susceptibility in women, TRF length was measured in 72 treated female breast cancer patients and 1696 unaffected female controls between the ages of 45 and 77 from the Twin Research Unit at St Thomas' Hospital, as well as 140 newly diagnosed breast cancer cases and 108 mammographically screened unaffected controls from Guy's Hospital. Mean TRF was also tested for correlation with chromosome radiosensitivity and apoptotic response in the Guy's Hospital patients. After adjusting for age, smoking and body mass index, there was no significant difference in TRF lengths between the treated breast cancer patients and unaffected controls (P=0.71). A positive correlation between age-adjusted apoptotic response and mean TRF in newly diagnosed untreated breast cancer patients (P=0.008) was identified but no significant difference in TRF lengths between breast cancer patients and unaffected controls was detected (P=0.53). This suggests that TRF lengths in WBC, is not a marker of breast cancer susceptibility and does not vary significantly between affected women before and after treatment.},
}
@article {pmid18000380,
year = {2007},
author = {Calcagnile, O and Gisselsson, D},
title = {Telomere dysfunction and telomerase activation in cancer--a pathological paradox?.},
journal = {Cytogenetic and genome research},
volume = {118},
number = {2-4},
pages = {270-276},
doi = {10.1159/000108310},
pmid = {18000380},
issn = {1424-859X},
mesh = {Enzyme Activation ; Genomic Instability ; Humans ; Neoplasms/enzymology/*genetics/pathology ; Telomerase/*metabolism ; Telomere/*physiology ; },
abstract = {Telomerase is expressed in more than 90% of human cancers. Telomere maintenance by this enzyme is believed to safeguard genomic integrity in neoplastic cells. Nevertheless, many telomerase-expressing tumours exhibit chromosomal instability triggered by short, dysfunctional telomeres, implying that active telomerase is not sufficient for preserving a functional telosomic nucleoprotein complex in cancer cells. We here examine three possible solutions to this ostensible paradox. First, prior to telomerase activation, telomere erosion may have evolved to a level where telomeric repeat sequences are too short to provide a functional substrate for telomerase enzyme activity. Second, mechanisms other than the continuous telomere erosion counteracted by telomerase may contribute to rapid shortening of telomere repeats. Third, dysfunction of telomere-regulating proteins may result in direct telomere uncapping. Moreover, telomerase may contribute to tumour development also through mechanisms unrelated to telomere length maintenance. Taken together, the available data on the role of telomerase in cancer strongly support that inhibition of this enzyme is a feasible strategy for cancer therapy.},
}
@article {pmid18000138,
year = {2007},
author = {Guan, JZ and Maeda, T and Sugano, M and Oyama, J and Higuchi, Y and Suzuki, T and Makino, N},
title = {An analysis of telomere length in sarcoidosis.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {62},
number = {11},
pages = {1199-1203},
doi = {10.1093/gerona/62.11.1199},
pmid = {18000138},
issn = {1079-5006},
mesh = {Adult ; Age Factors ; Analysis of Variance ; Case-Control Studies ; DNA/analysis ; Female ; Humans ; Male ; Middle Aged ; Sarcoidosis/*genetics ; Sex Factors ; Statistics, Nonparametric ; Telomere/*genetics ; },
abstract = {We investigated telomere (terminal restriction fragment [TRF]) length in 111 patients with sarcoidosis regarding both the mean TRF length and the telomere length distribution. A significant decrease was observed in the mean TRF length in sarcoidosis patients in comparison to the age-matched controls, whereas a decreased telomere length was only associated with age in men. The mean TRF shortening seemed to be accelerated in men in their 30s and 50s and in women in their 40s and 50s. We also found a significant decrease with age of telomeres with lengths of 9.4-6.6 kb in men and women in their 20s and an increase of telomeres with lengths of 4.4-2.3 kb in men and women in their 20s and in men in their 50s in sarcoidosis patients versus in the controls who were in their 20s and 50s. These findings suggest the occurrence of age-advanced changes in telomere length in patients with sarcoidosis, regardless of the patient age at the onset of sarcoidosis.},
}
@article {pmid17996538,
year = {2007},
author = {Huang, CZ and Liao, QG and Gan, LH and Guo, FL and Li, YF},
title = {Telomere DNA conformation change induced aggregation of gold nanoparticles as detected by plasmon resonance light scattering technique.},
journal = {Analytica chimica acta},
volume = {604},
number = {2},
pages = {165-169},
doi = {10.1016/j.aca.2007.10.016},
pmid = {17996538},
issn = {1873-4324},
mesh = {Base Sequence ; DNA/*chemistry ; DNA Probes ; Gold/*chemistry ; Light ; *Metal Nanoparticles ; *Nucleic Acid Conformation ; Scattering, Radiation ; Spectrometry, Fluorescence ; Surface Plasmon Resonance/*methods ; *Telomere ; },
abstract = {It has been reported that adsorption of uncoiled DNA (u-DNA) on the surface of gold nanoparticles (Au-NPs) can prevent the nanoparticle suspensions from aggregation even if in salt medium. Herein we report that quadruplex DNA (q-DNA), which is formed from uncoiled telomere DNA, via intramolecular hydrogen bonds in the presence of potassium ion, cannot keep Au-NPs stable, and the q-DNA/Au-NPs coexisting suspensions display aggregation tendency, giving plasmon resonance light scattering (PRLS) signals of Au-NPs. Mechanism investigations through a single point energy calculation on u- and q-structures of telomere DNA showed that q-DNA, compared with u-DNA, has a much higher surface negative charge density, symmetrical charge distribution and well self-structural stabilization, could not be adsorbed on the surface of Au-NPs.},
}
@article {pmid17991883,
year = {2008},
author = {Herbert, KE and Mistry, Y and Hastings, R and Poolman, T and Niklason, L and Williams, B},
title = {Angiotensin II-mediated oxidative DNA damage accelerates cellular senescence in cultured human vascular smooth muscle cells via telomere-dependent and independent pathways.},
journal = {Circulation research},
volume = {102},
number = {2},
pages = {201-208},
pmid = {17991883},
issn = {1524-4571},
support = {R01 HL083895/HL/NHLBI NIH HHS/United States ; R01 HL083895-03/HL/NHLBI NIH HHS/United States ; },
mesh = {Angiotensin II/*physiology ; Cells, Cultured ; *Cellular Senescence ; *DNA Damage ; Humans ; Muscle, Smooth, Vascular/*cytology ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Telomere/*physiology ; },
abstract = {Angiotensin II (Ang II) induces reactive oxygen species (ROS) production by human vascular smooth muscle cells (hVSMCs). ROS have been implicated in the development of both acute stress-induced premature senescence (SIPS) and chronic replicative senescence. Global oxidative DNA damage triggers SIPS and telomere DNA damage accelerates replicative senescence, both mediated via p53. This study tests the hypothesis that DNA is an important target for Ang II-induced ROS leading to senescence via telomere-dependent and independent pathways. DNA damage was quantified using the Comet assay, telomere DNA length by Southern blotting and hVSMC senescence by senescence-associated beta-galactosidase staining. Exposure to Ang II increased DNA damage in hVSMCs within 4 hours. Inhibition by an AT1 receptor antagonist (losartan metabolite: E3174) or catalase, confirmed that Ang II-induced DNA damage was AT1 receptor-mediated, via the induction of ROS. Acute exposure to Ang II resulted in SIPS within 24 hours that was prevented by coincubation with E3174 or catalase. SIPS was associated with increased p53 expression but was not dependent on telomere attrition because overexpression of human telomerase did not prevent Ang II-induced SIPS. Exposure to Ang II over several population doublings accelerated the rate of telomere attrition (by >2-fold) and induced premature replicative senescence of hVSMCs--an effect that was also attenuated by E3174 or catalase. These data demonstrate that Ang II-induced ROS-mediated DNA damage results in accelerated biological aging of hVSMCs via 2 mechanisms: (1) Acute SIPS, which is telomere independent, and (2) accelerated replicative senescence which is associated with accelerated telomere attrition.},
}
@article {pmid17991655,
year = {2007},
author = {Richards, JB and Valdes, AM and Gardner, JP and Paximadas, D and Kimura, M and Nessa, A and Lu, X and Surdulescu, GL and Swaminathan, R and Spector, TD and Aviv, A},
title = {Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women.},
journal = {The American journal of clinical nutrition},
volume = {86},
number = {5},
pages = {1420-1425},
pmid = {17991655},
issn = {0002-9165},
support = {R01 AG020132/AG/NIA NIH HHS/United States ; AG020132/AG/NIA NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 AG020132-01A2/AG/NIA NIH HHS/United States ; R01 AG021593-01/AG/NIA NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/blood/*pathology ; C-Reactive Protein/analysis ; Female ; Humans ; Leukocytes/*ultrastructure ; Middle Aged ; *Telomere ; Vitamin D/*blood ; },
abstract = {BACKGROUND: Vitamin D is a potent inhibitor of the proinflammatory response and thereby diminishes turnover of leukocytes. Leukocyte telomere length (LTL) is a predictor of aging-related disease and decreases with each cell cycle and increased inflammation.<br><br>OBJECTIVE: The objective of the study was to examine whether vitamin D concentrations would attenuate the rate of telomere attrition in leukocytes, such that higher vitamin D concentrations would be associated with longer LTL.<br><br>DESIGN: Serum vitamin D concentrations were measured in 2160 women aged 18-79 y (mean age: 49.4) from a large population-based cohort of twins. LTL was measured by using the Southern blot method.<br><br>RESULTS: Age was negatively correlated with LTL (r = -0.40, P < 0.0001). Serum vitamin D concentrations were positively associated with LTL (r = 0.07, P = 0.0010), and this relation persisted after adjustment for age (r = 0.09, P < 0.0001) and other covariates (age, season of vitamin D measurement, menopausal status, use of hormone replacement therapy, and physical activity; P for trend across tertiles = 0.003). The difference in LTL between the highest and lowest tertiles of vitamin D was 107 base pairs (P = 0.0009), which is equivalent to 5.0 y of telomeric aging. This difference was further accentuated by increased concentrations of C-reactive protein, which is a measure of systemic inflammation.<br><br>CONCLUSION: Our findings suggest that higher vitamin D concentrations, which are easily modifiable through nutritional supplementation, are associated with longer LTL, which underscores the potentially beneficial effects of this hormone on aging and age-related diseases.},
}
@article {pmid17991312,
year = {2007},
author = {Lu, HD and Huang, T and Shen, WZ and Zhen, Y and Kong, QZ},
title = {[Effect of tankyrase antisense oligonucleotide combined human telomerase reverse transcriptase antisense oligonucleotide on telomere dynamics in human lung adenocarcinoma A549 cells].},
journal = {Ai zheng = Aizheng = Chinese journal of cancer},
volume = {26},
number = {11},
pages = {1164-1169},
pmid = {17991312},
mesh = {Adenocarcinoma/enzymology/pathology ; Cell Line, Tumor ; Cellular Senescence/drug effects ; Humans ; Lung Neoplasms/enzymology/*pathology ; Oligonucleotides, Antisense/*pharmacology ; RNA, Messenger/metabolism ; Tankyrases/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/*pathology ; Transfection ; },
abstract = {BACKGROUND &amp; OBJECTIVE: Tankyrase (TANKS) regulates telomerase-mediated telomere elongation and plays an important role in cellular senescence and immortalization. This study was to determine the effect of tankyrase antisense oligonucleotide (asTANKS) combined human telomerase reverse transcriptase antisense oligonucleotide (ashTERT) on telomere dynamics in human lung adenocarcinoma A549 cells.<br><br>METHODS: A549 cells were transfected with ashTERT, asTANKS, ashTERT combined asTANKS, and human telomerase reverse transcriptase sense oligonucleotide (shTERT), tankyrase sense oligonucleotide (sTANKS), or blank vector as control. The expression of hTERT mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR). Telomerase activity was detected by enzyme-linked immunosorbent assay-PCR (ELISA-PCR). Tankyrase activity was detected by Western blot. Telomere length was analyzed by quantitative fluorescence in situ hybridization (Q-FISH). Cell proliferation was measured by population doubling test.<br><br>RESULTS: The mRNA level and telomerase activity of hTERT in A549 cells were strongly suppressed by ashTERT, but not by asTANKS; while tankyrase activity was significantly inhibited by asTANKS, not by ashTERT. Telomere length was significantly shorter in the cells treated with ashTERT combined asTANKS than in the cells treated with either ashTERT or asTANKS [(3.55+/-0.08) kb vs. (7.59+/-0.07) kb and (7.33+/-0.09) kb, t = 37.33, t = 32.50, P < 0.001]. The generational activity of the A549 cells continuously treated with ashTERT combined asTANKS was significantly weaker than those treated with either ashTERT or asTANKS [(24.53+/-0.40) population double times (PD) vs. (56.92+/-0.46) PD and (53.33+/-0.57) PD, t = 53.38, t = 43.39, P < 0.001].<br><br>CONCLUSIONS: The combination of ashTERT and asTANKS can enhance the efficacy of telomere shortening and hasten early tumor cellular crisis. Tankyrase might be a potential target of telomere-based molecular cancer therapy.},
}
@article {pmid17989233,
year = {2007},
author = {Vespa, L and Warrington, RT and Mokros, P and Siroky, J and Shippen, DE},
title = {ATM regulates the length of individual telomere tracts in Arabidopsis.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {104},
number = {46},
pages = {18145-18150},
pmid = {17989233},
issn = {1091-6490},
mesh = {Arabidopsis/*genetics ; Arabidopsis Proteins/*physiology ; Ataxia Telangiectasia Mutated Proteins ; Base Sequence ; Chromosomes, Artificial, Bacterial ; Chromosomes, Plant ; DNA Primers ; In Situ Hybridization, Fluorescence ; Mutation ; *Telomere ; },
abstract = {Telomeres have the paradoxical ability of protecting linear chromosome ends from DNA damage sensors by using these same proteins as essential components of their maintenance machinery. We have previously shown that the absence of ataxia telangiectasia mutated (ATM), a central regulator of the DNA damage response, accelerates the onset of genome instability in telomerase-deficient Arabidopsis, without increasing the rate of bulk telomere shortening. Here, we examine individual telomere tracts through successive plant generations using both fluorescence situ in hybridization (FISH) and primer extension telomere repeat amplification (PETRA). Unexpectedly, we found that the onset of profound developmental defects and abundant end-to-end chromosome fusions in fifth generation (G(5)) atm tert mutants required the presence of only one critically shortened telomere. Parent progeny analysis revealed that the short telomere arose as a consequence of an unusually large telomere rapid deletion (TRD) event. The most dramatic TRD was detected in atm tert mutants that had undergone meiosis. Notably, in contrast to TRD, alternative lengthening of telomeres (ALT) was suppressed in the absence of ATM. Finally, we show that size differences between telomeres on homologous chromosome ends are greater for atm tert than tert plants. Altogether, these findings suggest a dual role for ATM in regulating telomere size by promoting elongation of short telomeres and by preventing the accumulation of cells that harbor large telomere deletions.},
}
@article {pmid17989053,
year = {2007},
author = {Lan, TY and Liu, B and Dong, FP and Chen, RY and Li, XL and Chen, CB},
title = {[Multicolor FISH analysis of rDNA and telomere on spin-ach].},
journal = {Yi chuan = Hereditas},
volume = {29},
number = {11},
pages = {1405-1408},
doi = {10.1360/yc-007-1405},
pmid = {17989053},
issn = {0253-9772},
mesh = {Chromosomes, Plant ; DNA, Plant/analysis ; DNA, Ribosomal/*analysis ; In Situ Hybridization, Fluorescence/methods ; *Karyotyping ; RNA, Ribosomal/analysis/genetics ; RNA, Ribosomal, 5S/analysis/genetics ; Spinacia oleracea/*genetics ; Telomere/chemistry/*genetics ; },
abstract = {In this study, multicolor FISH analysis on metaphase chromosomes of spinach with biotin-labeled 25S rDNA, DIG-labeled telomere sequences and biotin-labeled and DIG-labeled 5S rDNA was performed. There were six 25S rDNA loci, which were located on the satellites of the third, the fifth and the sixth chromosomes, four 5S rDNA loci, which were located on the long arms of the third and the fifth chromosomes. The telomere loci were located on the end of the sixth chromosome and also on both the end and centromeric regions of other chromosomes. This study is an important complement to both traditional karyotype analysis and FISH karyotype analysis in spinach.},
}
@article {pmid17986462,
year = {2007},
author = {Passos, JF and Saretzki, G and von Zglinicki, T},
title = {DNA damage in telomeres and mitochondria during cellular senescence: is there a connection?.},
journal = {Nucleic acids research},
volume = {35},
number = {22},
pages = {7505-7513},
pmid = {17986462},
issn = {1362-4962},
support = {G0601333/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Cellular Senescence/*genetics ; *DNA Damage ; DNA, Mitochondrial/chemistry ; Humans ; Mitochondria/*metabolism ; Mutation ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {Cellular senescence is the ultimate and irreversible loss of replicative capacity occurring in primary somatic cell culture. It is triggered as a stereotypic response to unrepaired nuclear DNA damage or to uncapped telomeres. In addition to a direct role of nuclear DNA double-strand breaks as inducer of a DNA damage response, two more subtle types of DNA damage induced by physiological levels of reactive oxygen species (ROS) can have a significant impact on cellular senescence: Firstly, it has been established that telomere shortening, which is the major contributor to telomere uncapping, is stress dependent and largely caused by a telomere-specific DNA single-strand break repair inefficiency. Secondly, mitochondrial DNA (mtDNA) damage is closely interrelated with mitochondrial ROS production, and this might also play a causal role for cellular senescence. Improvement of mitochondrial function results in less telomeric damage and slower telomere shortening, while telomere-dependent growth arrest is associated with increased mitochondrial dysfunction. Moreover, telomerase, the enzyme complex that is known to re-elongate shortened telomeres, also appears to have functions independent of telomeres that protect against oxidative stress. Together, these data suggest a self-amplifying cycle between mitochondrial and telomeric DNA damage during cellular senescence.},
}
@article {pmid17983621,
year = {2008},
author = {Satoh, M and Ishikawa, Y and Takahashi, Y and Itoh, T and Minami, Y and Nakamura, M},
title = {Association between oxidative DNA damage and telomere shortening in circulating endothelial progenitor cells obtained from metabolic syndrome patients with coronary artery disease.},
journal = {Atherosclerosis},
volume = {198},
number = {2},
pages = {347-353},
doi = {10.1016/j.atherosclerosis.2007.09.040},
pmid = {17983621},
issn = {1879-1484},
mesh = {Aged ; Cell Count ; Cellular Senescence ; Coronary Artery Disease/*etiology ; DNA Damage ; Endothelial Cells/drug effects/*metabolism ; Female ; Humans ; Male ; Metabolic Syndrome/*blood/*complications ; Middle Aged ; *Oxidative Stress ; Peroxides/pharmacology ; Stem Cells/drug effects/*metabolism ; Telomerase/analysis ; Telomere/*metabolism ; },
abstract = {Metabolic syndrome (MS) induces an increase in oxidative stress and may be an important contributory factor for coronary artery disease (CAD). Telomere shortening of endothelial progenitor cells (EPCs) may be the key factor in endothelial cell senescence. The rate of telomere shortening is highly dependent on cellular oxidative damage. This study analyzed the relationship between telomere shortening and oxidative DNA damage in EPCs obtained from CAD patients with MS and without MS. We analyzed circulating EPCs in peripheral blood obtained from 57 patients with CAD (acute myocardial infarction [AMI], n=26; stable angina pectoris [AP], n=31) and 21 age-matched healthy subjects (control). Telomere length and telomerase activity were significantly lower in CAD patients than in controls, and were lower in AMI patients than in AP patients. Oxidative DNA damage was higher in CAD patients compared with controls, and oxidative DNA damage in AMI patients was also higher than in AP patients. There was a negative correlation between telomere length and oxidative DNA damage. Telomere length and telomerase activity were lower in CAD patients with MS than in those without MS. Oxidative DNA damage in CAD patients with MS was higher than in those without MS. In our in vitro study, oxidative treatments induced telomere shortening and decrease in telomerase activity of EPCs. These results suggest that EPC telomere shortening via increased oxidative DNA damage may play an important role in the pathogenesis of CAD. In addition, MS may be related to increased oxidative DNA damage and EPC telomere shortening.},
}
@article {pmid17983604,
year = {2008},
author = {Ségal-Bendirdjian, E and Gilson, E},
title = {Telomeres and telomerase: from basic research to clinical applications.},
journal = {Biochimie},
volume = {90},
number = {1},
pages = {1-4},
doi = {10.1016/j.biochi.2007.10.003},
pmid = {17983604},
issn = {0300-9084},
mesh = {Animals ; Cellular Senescence ; Chromatin/physiology ; Humans ; Telomerase/genetics/*metabolism ; Telomere/genetics/*physiology ; },
}
@article {pmid17982685,
year = {2007},
author = {Kammori, M and Poon, SS and Nakamura, K and Izumiyama, N and Ishikawa, N and Kobayashi, M and Naomoto, Y and Takubo, K},
title = {Squamous cell carcinomas of the esophagus arise from a telomere-shortened epithelial field.},
journal = {International journal of molecular medicine},
volume = {20},
number = {6},
pages = {793-799},
pmid = {17982685},
issn = {1107-3756},
mesh = {Carcinoma, Squamous Cell/*genetics/pathology ; *Chromosomal Instability ; Chromosome Aberrations ; Esophageal Neoplasms/*genetics/pathology ; Esophagus/cytology/*pathology ; Humans ; In Situ Hybridization, Fluorescence ; *Telomere/metabolism/ultrastructure ; Tumor Cells, Cultured ; },
abstract = {Critically shortened telomeres make chromosomes susceptible to the instability and widespread cytogenetic alterations that characterize most human cancers. We hypothesized that the very rapid cell proliferation observed in esophageal squamous cell carcinomas might accelerate telomere shortening and chromosomal instability associated with carcinogenesis. We used a number of telomere measurement techniques including quantitative fluorescence in situ hybridization (Q-FISH) to compare chromosomal aberrations and telomere lengths of individual chromosomes in esophageal squamous cell carcinomas (ESCCs) and nearby non-neoplastic esophageal epithelium (NNEE) cells. Our results showed that the mean telomere length in ESCC cells was significantly less than that in adjacent NNEE cells, and that telomeres in all NNEE cells were significantly shorter than those in normal esophageal epithelium (reported previously). In addition, there was no evidence linking telomere shortening of a particular chromosome to field cancerization in ESCC. However, a mechanistic link between telomere shortening and chromosomal instability was supported by a higher frequency of anaphase/telophase bridges and an increase in the frequency of aneuploidy. This study furthers our understanding of the mechanism by which telomere shortening and chromosomal instability lead to carcinogenesis and field cancerization in the esophagus.},
}
@article {pmid17982646,
year = {2007},
author = {Maes, L and Van Neste, L and Van Damme, K and Kalala, JP and De Ridder, L and Bekaert, S and Cornelissen, M},
title = {Relation between telomerase activity, hTERT and telomere length for intracranial tumours.},
journal = {Oncology reports},
volume = {18},
number = {6},
pages = {1571-1576},
doi = {10.3892/or.18.6.1571},
pmid = {17982646},
issn = {1021-335X},
mesh = {Astrocytoma/enzymology/genetics/pathology ; Biopsy ; Brain Neoplasms/enzymology/genetics/*pathology ; Glioblastoma/enzymology/genetics/pathology ; Humans ; Meningeal Neoplasms/enzymology/genetics/*pathology ; Meningioma/enzymology/genetics/*pathology ; Telomerase/*metabolism ; Telomere/*pathology/ultrastructure ; },
abstract = {Human linear chromosomes are capped by specialized DNA-protein structures called telomeres. The present study analysed the telomerase activity, hTERT protein and telomere length in meningiomas and gliomas in relation to their WHO grading. Fifty-three freshly dissected tumour biopsies were analysed for telomerase activity, hTERT protein expression and telomere length. Telomerase activity was examined in 41 of the 53 biopsies. Telomerase activity was detected in 3 of 35 (8.6%) screened meningiomas (1 benign, 1 atypical and 1 malignant meningioma). For hTERT expression, 56.4% of meningiomas were positive with a mean labelling index (hTERT LI) of 31.3% (SD=26.5) for the hTERT positive meningiomas. The mean telomere length for meningiomas was 6.983 kb (SD=1.969). For gliomas, no active telomerase was detected in 2 low-grade astrocytomas, whereas three of the four screened glioblastomas were positive for telomerase activity. The only hTERT protein positive astrocytoma had a mean labelling index of 9.0%. On the other hand, the hTERT LI for glioblastomas was 53.6% (SD=28.0). The two low-grade astrocytomas had a telomere length of 14.310 and 9.236 kb. The anaplastic astrocytoma had a telomere length of 4.903 kb and the glioblastomas 5.767 kb (SD=2.042). The normal meningeal and neuronal tissue is negative for telomerase activity and hTERT. The length was +/-10.000 kb. These results indicate that telomere shortening may be a critical step in pathogenesis of atypical and malignant meningiomas and gliomas. Critical telomere shortening in vitro was shown to activate telomerase.},
}
@article {pmid17982445,
year = {2007},
author = {Liu, L and Bailey, SM and Okuka, M and Muñoz, P and Li, C and Zhou, L and Wu, C and Czerwiec, E and Sandler, L and Seyfang, A and Blasco, MA and Keefe, DL},
title = {Telomere lengthening early in development.},
journal = {Nature cell biology},
volume = {9},
number = {12},
pages = {1436-1441},
doi = {10.1038/ncb1664},
pmid = {17982445},
issn = {1465-7392},
mesh = {ATP-Binding Cassette Transporters/metabolism ; Acid Anhydride Hydrolases ; Animals ; Blastocyst/physiology ; DNA-Binding Proteins ; Embryo, Mammalian/*physiology ; Female ; Male ; Mice ; Oocytes/physiology ; Parthenogenesis ; Sister Chromatid Exchange ; Telomerase/physiology ; Telomere/*physiology ; Telomeric Repeat Binding Protein 1/metabolism ; },
abstract = {Stem cells and cancer cells maintain telomere length mostly through telomerase. Telomerase activity is high in male germ line and stem cells, but is low or absent in mature oocytes and cleavage stage embryos, and then high again in blastocysts. How early embryos reset telomere length remains poorly understood. Here, we show that oocytes actually have shorter telomeres than somatic cells, but their telomeres lengthen remarkably during early cleavage development. Moreover, parthenogenetically activated oocytes also lengthen their telomeres, thus the capacity to elongate telomeres must reside within oocytes themselves. Notably, telomeres also elongate in the early cleavage embryos of telomerase-null mice, demonstrating that telomerase is unlikely to be responsible for the abrupt lengthening of telomeres in these cells. Coincident with telomere lengthening, extensive telomere sister-chromatid exchange (T-SCE) and colocalization of the DNA recombination proteins Rad50 and TRF1 were observed in early cleavage embryos. Both T-SCE and DNA recombination proteins decrease in blastocyst stage embryos, whereas telomerase activity increases and telomeres elongate only slowly. We suggest that telomeres lengthen during the early cleavage cycles following fertilization through a recombination-based mechanism, and that from the blastocyst stage onwards, telomerase only maintains the telomere length established by this alternative mechanism.},
}
@article {pmid17981770,
year = {2008},
author = {Minamino, T and Komuro, I},
title = {Role of telomeres in vascular senescence.},
journal = {Frontiers in bioscience : a journal and virtual library},
volume = {13},
number = {},
pages = {2971-2979},
doi = {10.2741/2902},
pmid = {17981770},
issn = {1093-9946},
mesh = {Aging ; Animals ; *Cellular Senescence ; Endothelium, Vascular/cytology/metabolism ; Humans ; Models, Biological ; Muscle, Smooth, Vascular/metabolism ; Nitric Oxide/metabolism ; Signal Transduction ; Stem Cells/metabolism ; Telomerase/metabolism ; Telomere/metabolism/*physiology/*ultrastructure ; },
abstract = {Telomeres are DNA regions composed of TTAGGG repeats that are located at the ends of chromosomes. Specific proteins associate with the telomeres and form non-nucleosomal DNA-protein complexes that serve as protective caps for the chromosome ends. There is accumulating evidence that progressive telomere shortening is closely related to cardiovascular disease. For example, vascular cell senescence has been reported to occur in human atherosclerotic lesions and this change is associated with telomere shortening. Impairment of telomere integrity causes vascular dysfunction, which is prevented by the activation of telomerase. Mice with short telomeres develop hypertension and exhibit impaired neovascularization. Short telomeres have also been reported in the leukocytes of patients with cardiovascular disease or various cardiovascular risk factors. Although it remains unclear whether short telomeres directly cause cardiovascular disease, manipulation of telomere function is potentially an attractive strategy for the treatment of vascular senescence.},
}
@article {pmid17981769,
year = {2008},
author = {De Meyer, T and Rietzschel, ER and De Buyzere, ML and Van Criekinge, W and Bekaert, S},
title = {Studying telomeres in a longitudinal population based study.},
journal = {Frontiers in bioscience : a journal and virtual library},
volume = {13},
number = {},
pages = {2960-2970},
doi = {10.2741/2901},
pmid = {17981769},
issn = {1093-9946},
mesh = {Aging ; Biomarkers ; Cardiovascular Diseases/*genetics/metabolism ; Cellular Senescence ; Chromosome Mapping ; Chromosomes/ultrastructure ; Female ; Genetics, Population ; Humans ; Male ; Mitosis ; Models, Biological ; Oxidative Stress ; Phenotype ; Telomere/*ultrastructure ; },
abstract = {Telomeres, the termini of linear chromosomes, consist of large but variable numbers of DNA oligomer repeats embedded in a nucleoprotein complex. In humans, telomere length (TL) is largely genetically determined but also featured by an age dependent attrition. TL has therefore been put forward as a marker for biological aging and was also reported to be associated with aging diseases such as cardiovascular disease. However it remains unclear whether the biomarker value in a particular disease depends on shorter TL at birth or rather if it's a mere reflection of an accelerated telomere attrition during lifetime, or else, if it is a combination of both. While the importance of telomere attrition is supported by cross-sectional evidence associating shorter telomeres with oxidative stress and inflammation, longitudinal studies are required to accurately assess telomere attrition and its presumed link with accelerated aging. In this review we present different models for the biomarker value of TL and discuss the theoretical and methodological considerations of studying TL in a longitudinal population study with a special emphasis on cardiovascular disease.},
}
@article {pmid17981693,
year = {2008},
author = {Cheung, AL and Deng, W},
title = {Telomere dysfunction, genome instability and cancer.},
journal = {Frontiers in bioscience : a journal and virtual library},
volume = {13},
number = {},
pages = {2075-2090},
doi = {10.2741/2825},
pmid = {17981693},
issn = {1093-9946},
mesh = {Animals ; Apoptosis ; Cell Cycle ; Chromosomal Instability ; Chromosomes/ultrastructure ; DNA Damage ; *Genome ; Genomic Instability ; Humans ; Neoplasms/*genetics/metabolism ; Telomerase/metabolism ; Telomere/*ultrastructure ; },
abstract = {Telomeres are highly specialized structures at the ends of chromosomes that are made up of tandem 5'-TTAGGG-3' repeats and a number of telomere associated proteins. By forming loop structures, the very end of a telomere is concealed and distinguished from a DNA break, thus protecting chromosomes from end-to-end fusions, misrepair and degradation. Telomere length is maintained by an enzyme called telomerase which is very weak or undetectable in most normal human somatic cells. In telomerase-negative cells, telomeric DNA is progressively lost with cell divisions until the cells undergo replicative senescence, which serves as an intrinsic mechanism to prevent normal somatic cells from replicating indefinitely. In checkpoint defective cells, telomere dysfunction resulting from excessive telomere attrition or disruption of telomere structure may initiate chromosomal instability through end-to-end fusion of unprotected chromosomes. Through propagation of breakage-fusion-bridge (BFB) cycles, genetic aberrations characteristic of cancers, including aneuploidy, loss of heterozygosity, gene amplification and gene loss can be generated. In vitro, cells with extensive chromosomal instability succumb to crisis which is characterized by wide-spread cell death. It has been reported that cells surviving crisis either have activated telomerase, or use an alternative telomere lengthening (ALT) mechanism to stabilize the existing telomeres and alleviate chromosome instability. The immortalized post-crisis cells have the potential to acquire additional genetic alterations for malignant transformation. In this review, we summarize our knowledge on the association between telomere dysfunction, genomic instability and cancer development.},
}
@article {pmid17981417,
year = {2008},
author = {Baird, DM},
title = {Telomeres II.},
journal = {Experimental gerontology},
volume = {43},
number = {1},
pages = {15-19},
doi = {10.1016/j.exger.2007.10.002},
pmid = {17981417},
issn = {0531-5565},
mesh = {Aged ; Animals ; Cellular Senescence/*physiology ; Chromosomal Instability ; Female ; Humans ; Longevity/*physiology ; Meiosis ; Mice ; Models, Animal ; Pregnancy ; Reproduction ; Telomere/*ultrastructure ; },
abstract = {The extent and potential significance of telomere erosion, as a function of age in human tissues, is becoming increasingly apparent. In this, the second yearly review on telomeres and ageing, I review a small selection of papers published between July 2006 and June 2007. This includes experimental evidence from mouse models concerning the mechanism by which telomere dysfunction could compromise tissue homeostasis, more evidence for telomere loss as a function of age, associations of telomere length with age-related disease and some new information concerning the inheritance of telomere length.},
}
@article {pmid17980263,
year = {2007},
author = {Oeseburg, H and Westenbrink, BD and de Boer, RA and van Gilst, WH and van Veldhuisen, DJ and van der Harst, P},
title = {Can critically short telomeres cause functional exhaustion of progenitor cells in postinfarction heart failure?.},
journal = {Journal of the American College of Cardiology},
volume = {50},
number = {19},
pages = {1911-2; author reply 1912-3},
doi = {10.1016/j.jacc.2007.07.055},
pmid = {17980263},
issn = {1558-3597},
mesh = {Cardiomyopathy, Dilated/physiopathology ; Cellular Senescence/*physiology ; Heart Failure/*physiopathology ; Humans ; Myocardial Infarction/*physiopathology ; Myocardial Ischemia/*physiopathology ; Myocytes, Cardiac/physiology ; Risk Factors ; Stem Cells/*physiology ; Telomere/*physiology ; },
}
@article {pmid17979498,
year = {2008},
author = {Forsyth, NR and McWhir, J},
title = {Human embryonic stem cell telomere length impacts directly on clonal progenitor isolation frequency.},
journal = {Rejuvenation research},
volume = {11},
number = {1},
pages = {5-17},
doi = {10.1089/rej.2007.0567},
pmid = {17979498},
issn = {1549-1684},
mesh = {Adipogenesis/physiology ; Cell Aggregation/physiology ; Cell Differentiation/drug effects ; Cell Proliferation/drug effects ; Cell Separation ; Cell Survival ; Cells, Cultured ; Cellular Senescence/genetics/physiology ; Chondrogenesis/physiology ; Clone Cells ; Embryonic Stem Cells/drug effects/*physiology ; Humans ; Mesenchymal Stem Cells/physiology ; Models, Biological ; Osteogenesis/physiology ; Oxygen/pharmacology ; Telomerase/genetics ; Telomere/metabolism/*physiology ; },
abstract = {The pluripotentiality of human embryonic stem cells is expected to yield an abundance of clinically useful cell types. Using physiologic oxygen culture systems, we show that it is possible to isolate highly proliferative clonal progenitor cells from partially differentiated human embryonic stem cells. These progenitors have similar, though not identical, immunophenotypes with a resemblance to bone marrow-derived adherent stem cells. Through telomere length analysis of multiple early senescing clones, we were able to show that the starting telomere length of a human embryonic stem cell line impacts on the proliferative potential of clonally isolated partially differentiated mortal progeny. Proliferative clones undergo growth arrest with telomere lengths consistent with telomere-driven replicative senescence. To bypass this phenomenon, we transduced progenitor cells with ectopic hTERT (the limiting catalytic component of telomerase). This enabled telomerase immortalization without affecting differentiation potential or immunophenotype. In summary we describe the derivation of clonal progenitor cells from human embryonic stem cells and the relevance of parental cell telomere length to the frequency of highly proliferative clone isolation.},
}
@article {pmid17972362,
year = {2007},
author = {Ledford, H},
title = {Minimum telomere length defined for healthy cells.},
journal = {Nature},
volume = {449},
number = {7162},
pages = {515},
doi = {10.1038/449515a},
pmid = {17972362},
issn = {1476-4687},
mesh = {Cellular Senescence ; Chromosome Aberrations ; *Health ; Humans ; Telomere/*genetics/metabolism/*pathology ; },
}
@article {pmid17969326,
year = {2007},
author = {Ueno, M},
title = {[Roles of DNA replication and recombination factors in telomere maintenance].},
journal = {Seikagaku. The Journal of Japanese Biochemical Society},
volume = {79},
number = {9},
pages = {868-871},
pmid = {17969326},
issn = {0037-1017},
mesh = {Animals ; *DNA Replication ; Exodeoxyribonucleases ; Humans ; Mutation ; RecQ Helicases/physiology ; *Recombination, Genetic ; Replication Protein A/*physiology ; Schizosaccharomyces pombe Proteins/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/genetics/physiology ; Werner Syndrome Helicase ; },
}
@article {pmid17967889,
year = {2008},
author = {Cesare, AJ and Groff-Vindman, C and Compton, SA and McEachern, MJ and Griffith, JD},
title = {Telomere loops and homologous recombination-dependent telomeric circles in a Kluyveromyces lactis telomere mutant strain.},
journal = {Molecular and cellular biology},
volume = {28},
number = {1},
pages = {20-29},
pmid = {17967889},
issn = {1098-5549},
support = {F32 GM077900/GM/NIGMS NIH HHS/United States ; R01 ES013773/ES/NIEHS NIH HHS/United States ; 5T32GMOO 10330//PHS HHS/United States ; R01 GM031819/GM/NIGMS NIH HHS/United States ; GM61645/GM/NIGMS NIH HHS/United States ; ES 013773/ES/NIEHS NIH HHS/United States ; GM31819/GM/NIGMS NIH HHS/United States ; R01 GM061645/GM/NIGMS NIH HHS/United States ; GM077900-01/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Chromatography, Gel ; DNA, Fungal/genetics ; Gene Deletion ; Gene Expression Regulation, Fungal ; Kluyveromyces/classification/*genetics/metabolism/*ultrastructure ; Microscopy, Electron ; Molecular Weight ; Mutation/genetics ; Phenotype ; Rad52 DNA Repair and Recombination Protein/genetics/metabolism ; Recombination, Genetic/*genetics ; TATA Box Binding Protein-Like Proteins/genetics/metabolism ; Telomere/*genetics/*ultrastructure ; },
abstract = {The Kluyveromyces lactis ter1-16T strain contains mutant telomeres that are poorly bound by Rap1, resulting in a telomere-uncapping phenotype and significant elongation of the telomeric DNA. The elongated telomeres of ter1-16T allowed the isolation and examination of native yeast telomeric DNA by electron microscopy. In the telomeric DNA isolated from ter1-16T, looped molecules were observed with the physical characteristics of telomere loops (t-loops) previously described in mammalian and plant cells. ter1-16T cells were also found to contain free circular telomeric DNA molecules (t-circles) ranging up to the size of an entire telomere. When the ter1-16T uncapping phenotype was repressed by overexpression of RAP1 or recombination was inhibited by deletion of rad52, the isolated telomeric DNA contained significantly fewer t-loops and t-circles. These results suggest that disruption of Rap1 results in elevated recombination at telomeres, leading to increased strand invasion of the 3' overhang within t-loop junctions and resolution of the t-loop junctions into free t-circles.},
}
@article {pmid17965232,
year = {2007},
author = {Rajaraman, S and Choi, J and Cheung, P and Beaudry, V and Moore, H and Artandi, SE},
title = {Telomere uncapping in progenitor cells with critical telomere shortening is coupled to S-phase progression in vivo.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {104},
number = {45},
pages = {17747-17752},
pmid = {17965232},
issn = {0027-8424},
support = {P30 DK056339/DK/NIDDK NIH HHS/United States ; R01 CA111691/CA/NCI NIH HHS/United States ; P30 DK56339/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Apoptosis ; Bromodeoxyuridine ; Crosses, Genetic ; DNA Damage ; G2 Phase ; In Situ Nick-End Labeling ; Intestinal Mucosa/cytology/physiology ; Mice ; Mice, Knockout ; Models, Genetic ; S Phase/*physiology ; Stem Cells/cytology/*physiology ; Telomerase/deficiency/genetics ; Telomere/*ultrastructure ; Tumor Suppressor Protein p53/genetics/physiology ; },
abstract = {Telomeres protect chromosome ends and serve as a substrate for telomerase, a reverse transcriptase that adds DNA repeats to the telomere terminus. In the absence of telomerase, telomeres progressively shorten, ultimately leading to telomere uncapping, a structural change at the telomere that activates DNA damage responses and leads to ligation of chromosome ends. Telomere uncapping has been implicated in aging and cancer, yet the precise mechanism of uncapping and its relationship to cell cycle remain to be defined. Here, we show that telomeres uncap in an S-phase-dependent manner in gastrointestinal progenitors of TERT(-/-) mice. We develop an in vivo assay that allows a quantitative kinetic assessment of telomere dysfunction-induced apoptosis and its relationship to cell cycle. By exploiting the mathematical relationship between rates of generation and clearance of apoptotic cells, we show that 86.2 +/- 8.8% of apoptotic gastrointestinal cells undergo programmed cell death either late in S-phase or in G2. Apoptosis is primarily triggered via a signaling cascade from newly uncapped telomeres to the tumor suppressor p53, rather than by chromosome fusion-bridge breakage, because mitotic blockade did not alter the rate of newly generated apoptotic bodies. These data support a model in which rapidly dividing progenitor cells within a tissue with short telomeres are vulnerable to telomere uncapping during or shortly after telomere replication.},
}
@article {pmid17964269,
year = {2007},
author = {Xu, L and Blackburn, EH},
title = {Human cancer cells harbor T-stumps, a distinct class of extremely short telomeres.},
journal = {Molecular cell},
volume = {28},
number = {2},
pages = {315-327},
pmid = {17964269},
issn = {1097-2765},
support = {R01 CA096840-04/CA/NCI NIH HHS/United States ; R01 CA096840-03/CA/NCI NIH HHS/United States ; R01 CA096840/CA/NCI NIH HHS/United States ; R01 CA096840-05/CA/NCI NIH HHS/United States ; CA96840/CA/NCI NIH HHS/United States ; R01 CA096840-01/CA/NCI NIH HHS/United States ; R01 CA096840-02/CA/NCI NIH HHS/United States ; },
mesh = {Apoptosis/genetics ; Ataxia Telangiectasia Mutated Proteins ; Base Sequence ; Cell Cycle Proteins/genetics/metabolism ; *Cell Proliferation ; Cloning, Molecular ; DNA-Binding Proteins/genetics/metabolism ; Fibroblasts/enzymology/metabolism/pathology ; *Gene Expression Regulation, Neoplastic ; HeLa Cells ; Humans ; Molecular Sequence Data ; Neoplasms/enzymology/genetics/*metabolism/pathology ; Nuclear Proteins/metabolism ; Phosphorylation ; Polymerase Chain Reaction/methods ; Protein Serine-Threonine Kinases/genetics/metabolism ; Reproducibility of Results ; Retinoblastoma Protein/metabolism ; TATA Box Binding Protein-Like Proteins/metabolism ; Telomerase/genetics/*metabolism ; Telomere/*metabolism/ultrastructure ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2 ; Transduction, Genetic ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins/genetics/metabolism ; },
abstract = {Using a modified single telomere length analysis protocol (STELA) to clone and examine the sequence composition of individual human XpYp telomeres, we discovered a distinct class of extremely short telomeres in human cancer cells with active telomerase. We name them "t-stumps," to distinguish them from the well-regulated longer bulk telomeres. T-stumps contained arrangements of telomeric repeat variants and a minimal run of seven canonical telomeric TTAGGG repeats, but all could bind at least one TRF1 or TRF2 in vitro. The abundance of t-stumps was unaffected by ATM alteration but could be changed by manipulating telomerase catalytic subunit (hTERT) levels in cancer cells. We propose that in the setting of active telomerase and compromised checkpoints characteristic of human cancer cells, t-stumps define the minimal telomeric unit that can still be protected by a TRF1/TRF2-capping complex and, further, that hTERT (or telomerase) may have a role in protecting t-stumps.},
}
@article {pmid17962804,
year = {2007},
author = {Canudas, S and Houghtaling, BR and Kim, JY and Dynek, JN and Chang, WG and Smith, S},
title = {Protein requirements for sister telomere association in human cells.},
journal = {The EMBO journal},
volume = {26},
number = {23},
pages = {4867-4878},
pmid = {17962804},
issn = {1460-2075},
support = {T32 CA009161/CA/NCI NIH HHS/United States ; R01 CA95099/CA/NCI NIH HHS/United States ; CA09161/CA/NCI NIH HHS/United States ; R01 CA116352/CA/NCI NIH HHS/United States ; T32 GM007238/GM/NIGMS NIH HHS/United States ; R01 CA095099/CA/NCI NIH HHS/United States ; GM07238/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/metabolism ; Centrifugation, Density Gradient ; Chromosomal Proteins, Non-Histone/metabolism ; Gene Expression Regulation, Neoplastic ; HeLa Cells ; Humans ; Immunoprecipitation ; In Situ Hybridization, Fluorescence ; Mitosis ; Models, Biological ; Nuclear Proteins/metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; Protein Binding ; Tankyrases/genetics/metabolism ; Telomere/*ultrastructure ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; Cohesins ; },
abstract = {Previous studies in human cells indicate that sister telomeres have distinct requirements for their separation at mitosis. In cells depleted for tankyrase 1, a telomeric poly(ADP-ribose) polymerase, sister chromatid arms and centromeres separate normally, but telomeres remain associated and cells arrest in mitosis. Here, we use biochemical and genetic approaches to identify proteins that might mediate the persistent association at sister telomeres. We use immunoprecipitation analysis to show that the telomeric proteins, TRF1 (an acceptor of PARsylation by tankyrase 1) and TIN2 (a TRF1 binding partner) each bind to the SA1 ortholog of the cohesin Scc3 subunit. Sucrose gradient sedimentation shows that TRF1 cosediments with the SA1-cohesin complex. Depletion of the SA1 cohesin subunit or the telomeric proteins (TRF1 and TIN2) restores the normal resolution of sister telomeres in mitosis in tankyrase 1-depleted cells. Moreover, depletion of TRF1 and TIN2 or SA1 abrogates the requirement for tankyrase 1 in mitotic progression. Our studies indicate that sister telomere association in human cells is mediated by a novel association between a cohesin subunit and components of telomeric chromatin.},
}
@article {pmid17960465,
year = {2008},
author = {Hashimoto, Y and Murakami, Y and Uemura, K and Hayashidani, Y and Sudo, T and Ohge, H and Fukuda, E and Shimamoto, F and Sueda, T and Hiyama, E},
title = {Telomere shortening and telomerase expression during multistage carcinogenesis of intraductal papillary mucinous neoplasms of the pancreas.},
journal = {Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract},
volume = {12},
number = {1},
pages = {17-28; discussion 28-9},
pmid = {17960465},
issn = {1091-255X},
mesh = {Adenocarcinoma, Mucinous/enzymology/genetics/*pathology ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Pancreatic Ductal/enzymology/genetics/*pathology ; Carcinoma, Papillary/enzymology/genetics/*pathology ; DNA, Neoplasm/*genetics ; Disease Progression ; Enzyme Activation ; Female ; *Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Pancreatic Neoplasms/enzymology/genetics/*pathology ; Prognosis ; Retrospective Studies ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/biosynthesis/*genetics ; Telomere/genetics ; Tumor Cells, Cultured ; },
abstract = {Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has been increasingly identified as a precursor to infiltrating ductal adenocarcinoma. Telomerase activation in response to telomere crisis followed by telomere shortening is thought to be a crucial event in the development of most human cancers. The aim of this study was to determine when this event occurs in the context of histologically defined IPMN progression. We analyzed telomerase expression in 68 IPMN samples and assessed telomere length by quantitative fluorescence in situ hybridization in samples taken from 17 sequential IPMN patients that included 37 individual loci. Samples from pancreatic ductal adenocarcinomas (PDACs, n=15) and chronic pancreatitis patients (n=10) were also examined. Telomeres were significantly shortened in 36 (97.3%) of 37 IPMN loci, with average telomere length decreasing with IPMN progression. Notably, even adenoma IPMNs demonstrated a 50% reduction of telomere length in 7 of 14 foci examined. Marked telomere shortening was observed from the in situ IPMN carcinoma stage (P<0.001; vs borderline IPMNs) through the invasive stage, although telomerase had been activated, indicating that telomeres had shortened to a critical length by this histological grade. Up-regulated human telomerase reverse transcriptase expression was detectable and increased gradually with cancer development and was primarily observed at the borderline IPMN stage and then in more advanced histopathologies. Progressive telomere shortening predominantly occurs during early IPMNs carcinogenesis before telomerase activation and progression from borderline to carcinoma in situ IPMNs is the critical stage of IPMNs carcinogenesis at which telomere dysfunction occurs.},
}
@article {pmid17960423,
year = {2008},
author = {Zimmermann, S and Martens, UM},
title = {Telomeres, senescence, and hematopoietic stem cells.},
journal = {Cell and tissue research},
volume = {331},
number = {1},
pages = {79-90},
doi = {10.1007/s00441-007-0469-4},
pmid = {17960423},
issn = {1432-0878},
mesh = {Animals ; Cell Proliferation ; *Cellular Senescence ; Hematopoietic Stem Cells/*cytology/enzymology/*metabolism ; Humans ; Mesenchymal Stem Cells/cytology/enzymology ; Telomerase/antagonists &amp; inhibitors/metabolism ; Telomere/*metabolism ; },
abstract = {The replicative lifespan of normal somatic cells is restricted by the erosion of telomeres, which are protective caps at the ends of linear chromosomes. The loss of telomeres induces antiproliferative signals that eventually lead to cellular senescence. The enzyme complex telomerase can maintain telomeres, but its expression is confined to highly proliferative cells such as stem cells and tumor cells. The immense regenerative capacity of the hematopoietic system is provided by a distinct type of adult stem cell: hematopoietic stem cells (HSCs). Although blood cells have to be produced continuously throughout life, the HSC pool seems not to be spared by aging processes. Indeed, limited expression of telomerase is not sufficient to prevent telomere shortening in these cells, which is thought ultimately to limit their proliferative capacity. In this review, we discuss the relevance of telomere maintenance for the hematopoietic stem cell compartment and consider potential functions of telomerase in this context. We also present possible clinical applications of telomere manipulation in HSCs and new insights affecting the aging of the hematopoietic stem cell pool and replicative exhaustion.},
}
@article {pmid17959650,
year = {2007},
author = {Grudic, A and Jul-Larsen, A and Haring, SJ and Wold, MS and Lønning, PE and Bjerkvig, R and Bøe, SO},
title = {Replication protein A prevents accumulation of single-stranded telomeric DNA in cells that use alternative lengthening of telomeres.},
journal = {Nucleic acids research},
volume = {35},
number = {21},
pages = {7267-7278},
pmid = {17959650},
issn = {1362-4962},
support = {R01 GM044721/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle ; Cell Line, Transformed ; Cell Line, Tumor ; DNA, Single-Stranded/*metabolism ; Humans ; Neoplasms/*genetics ; RNA Interference ; Replication Protein A/antagonists &amp; inhibitors/*physiology ; Telomere/chemistry/*metabolism ; },
abstract = {The activation of a telomere maintenance mechanism is required for cancer development in humans. While most tumors achieve this by expressing the enzyme telomerase, a fraction (5-15%) employs a recombination-based mechanism termed alternative lengthening of telomeres (ALT). Here we show that loss of the single-stranded DNA-binding protein replication protein A (RPA) in human ALT cells, but not in telomerase-positive cells, causes increased exposure of single-stranded G-rich telomeric DNA, cell cycle arrest in G2/M phase, accumulation of single-stranded telomeric DNA within ALT-associated PML bodies (APBs), and formation of telomeric aggregates at the ends of metaphase chromosomes. This study demonstrates differences between ALT cells and telomerase-positive cells in the requirement for RPA in telomere processing and implicates the ALT mechanism in tumor cells as a possible therapeutic target.},
}
@article {pmid17958006,
year = {2007},
author = {Nilsson, PM and Fyhrquist, F},
title = {[Short telomere length a marker of premature vascular aging].},
journal = {Lakartidningen},
volume = {104},
number = {39},
pages = {2801-2805},
pmid = {17958006},
issn = {0023-7205},
mesh = {*Aging/genetics/pathology/physiology ; Arteries/pathology/physiopathology ; Atherosclerosis/genetics/*pathology ; Biomarkers/analysis ; Cardiovascular Diseases/etiology/pathology/prevention &amp; control ; *Cellular Senescence/genetics/physiology ; Endothelium, Vascular/pathology/physiology ; Humans ; Muscle, Smooth, Vascular/pathology/physiology ; Risk Factors ; *Telomere/genetics/physiology/ultrastructure ; },
}
@article {pmid17954610,
year = {2007},
author = {Siegl-Cachedenier, I and Flores, I and Klatt, P and Blasco, MA},
title = {Telomerase reverses epidermal hair follicle stem cell defects and loss of long-term survival associated with critically short telomeres.},
journal = {The Journal of cell biology},
volume = {179},
number = {2},
pages = {277-290},
pmid = {17954610},
issn = {0021-9525},
mesh = {Animals ; Body Size ; Cell Proliferation ; Cell Survival ; Chromosomal Instability ; Hair Follicle/cytology/*enzymology/*pathology ; Hematopoietic Stem Cell Mobilization ; In Vitro Techniques ; Keratinocytes/cytology/enzymology ; Longevity ; Mice ; Neoplasms/pathology ; Phenotype ; RNA/genetics/*metabolism ; Siblings ; Spleen/cytology ; Stem Cells/cytology/*enzymology/*pathology ; Telomerase/deficiency/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Organ homeostasis and organismal survival are related to the ability of stem cells to sustain tissue regeneration. As a consequence of accelerated telomerase shortening, telomerase-deficient mice show defective tissue regeneration and premature death. This suggests a direct impact of telomere length and telomerase activity on stem cell biology. We recently found that short telomeres impair the ability of epidermal stem cells to mobilize out of the hair follicle (HF) niche, resulting in impaired skin and hair growth and in the suppression of epidermal stem cell proliferative capacity in vitro. Here, we demonstrate that telomerase reintroduction in mice with critically short telomeres is sufficient to correct epidermal HF stem cell defects. Additionally, telomerase reintroduction into these mice results in a normal life span by preventing degenerative pathologies in the absence of increased tumorigenesis.},
}
@article {pmid17954006,
year = {2008},
author = {Auriche, C and Di Domenico, EG and Ascenzioni, F},
title = {Budding yeast with human telomeres: a puzzling structure.},
journal = {Biochimie},
volume = {90},
number = {1},
pages = {108-115},
doi = {10.1016/j.biochi.2007.09.009},
pmid = {17954006},
issn = {0300-9084},
mesh = {Chromatin/*physiology ; Epigenesis, Genetic ; Homeostasis ; Humans ; Saccharomyces cerevisiae/*physiology ; Telomerase/metabolism ; Telomere/*physiology/ultrastructure ; Telomere-Binding Proteins/*physiology ; },
abstract = {Telomeres share some common features among eukaryotes, with few exceptions such as the fruit fly Drosophila that uses transposons as telomeres, they consist of G-rich repetitive DNA that is elongated by telomerase and/or alternative pathways depending on recombination. Telomere structure comprises both cis-acting satellite DNA (telomeric DNA) and proteins that interact directly and/or indirectly with the underlying DNA. Telomeric DNAs are surprisingly conserved among the vertebrates and very similar in most eukaryotes, but present some differences in yeast such as Saccharomyces cerevisiae. The telomeric proteins are more variable although the basic mechanisms which control telomere lengthening and capping are very similar, in fact orthologues of the yeast telomeric proteins, which have been studied first, have been identified in other organisms. Here we describe the structure of human telomeres in budding yeast as compared to canonical yeast and mammalian telomeres taking into consideration the more recent findings highlighting the mechanisms that are responsible for chromosome end protection and lengthening, and the role of chromatin organization in telomere function. This yeast represents a model for the study of mammalian telomeres that could be reconstituted step-by-step in all their components, moreover it could be useful for the assembly of mammalian artificial chromosome.},
}
@article {pmid17952625,
year = {2008},
author = {Betts, DH and Perrault, SD and King, WA},
title = {Low oxygen delays fibroblast senescence despite shorter telomeres.},
journal = {Biogerontology},
volume = {9},
number = {1},
pages = {19-31},
doi = {10.1007/s10522-007-9113-7},
pmid = {17952625},
issn = {1389-5729},
mesh = {Animals ; Cattle ; Cells, Cultured ; Cellular Senescence/*genetics ; Fibroblasts/cytology ; Oxygen/*metabolism ; *Telomere ; },
abstract = {It has been widely accepted that telomere shortening acts as a cell division counting mechanism that beyond a set critical length signals cells to enter replicative senescence. In this study, we demonstrate that by simply lowering the oxygen content of the cell culture environment 10-fold (20-2%) extends the replicative lifespan of fetal bovine fibroblasts at least five-times (30-150 days). Although, low oxygen fibroblasts display a slightly slower rate (P > 0.05) of telomere attrition than their high oxygen counterparts (171 bp versus 182 bp/PD), late passage fibroblasts (>50 PD) that have extended their replicative capacity under low oxygen conditions exhibited significantly (P < 0.05) shorter telomere lengths (11,135 +/- 467 bp) compared to senescent cells (25-34 PD) cultured under high oxygen conditions (14,827 +/- 1173 bp). There was a significant increase (P < 0.05) in chromosomal abnormalities with continual cell division under both high and low oxygen environments, however, fibroblasts displayed a significant reduction (P < 0.001) in chromosomal abnormalities at low oxygen tensions compared to those under 20% oxygen. These apparent protective effects on telomere shortening, delayed senescence and reduced chromosomal aberrations may be attributed to the up-regulation of telomerase activity observed for fibroblasts cultured under low oxygen. These results are consistent with the idea that a critically short telomere length may not be the sole trigger of replicative senescence, but may be regulated by the integrity of telomere structure itself and/or the amount of oxidative DNA damage in the cell.},
}
@article {pmid17949890,
year = {2008},
author = {Widmann, T and Kneer, H and König, J and Herrmann, M and Pfreundschuh, M},
title = {Sustained telomere erosion due to increased stem cell turnover during triple autologous hematopoietic stem cell transplantation.},
journal = {Experimental hematology},
volume = {36},
number = {1},
pages = {104-110},
doi = {10.1016/j.exphem.2007.08.028},
pmid = {17949890},
issn = {0301-472X},
mesh = {Antibodies, Monoclonal/administration &amp; dosage ; Antibodies, Monoclonal, Murine-Derived ; Antineoplastic Combined Chemotherapy Protocols/administration &amp; dosage/therapeutic use ; Cell Division ; Cellular Senescence ; Clinical Trials, Phase III as Topic ; Combined Modality Therapy ; Cyclophosphamide/administration &amp; dosage ; Doxorubicin/administration &amp; dosage ; Drug Administration Schedule ; Etoposide/administration &amp; dosage ; Female ; Granulocyte Colony-Stimulating Factor/administration &amp; dosage ; Granulocytes/drug effects/*ultrastructure ; Hematopoietic Stem Cells/cytology/*drug effects ; Humans ; Lymphocytes/drug effects/*ultrastructure ; Lymphoma, Non-Hodgkin/drug therapy/pathology/radiotherapy/surgery ; Male ; Middle Aged ; Myeloablative Agonists/adverse effects/pharmacology ; Myelopoiesis/*drug effects/radiation effects ; Peripheral Blood Stem Cell Transplantation/adverse effects/*methods ; Prednisolone/administration &amp; dosage ; Prospective Studies ; Rituximab ; Telomere/*ultrastructure ; Transplantation Conditioning/adverse effects ; Transplantation, Autologous ; Vincristine/administration &amp; dosage ; },
abstract = {Telomeres cap chromosomal ends and are shortened throughout a lifetime. Additional telomere erosion has been documented during conventional chemotherapy or hematopoietic stem cell transplantation. Previous studies of stem cell transplantation reported variable amounts of telomere shortening with inconsistent results regarding the persistence of telomere shortening. Here we have prospectively studied telomere length and proliferation kinetics of hematopoietic cells in aggressive non-Hodgkin lymphoma patients who underwent a four-course high-dose chemotherapy protocol combined with triple autologous stem cell transplantation. We observed sustained telomere shortening in hematopoietic cells after triple stem cell transplantation with prolonged stem cell replication during the first year after stem cell transplantation.},
}
@article {pmid17948054,
year = {2007},
author = {Guo, X and Deng, Y and Lin, Y and Cosme-Blanco, W and Chan, S and He, H and Yuan, G and Brown, EJ and Chang, S},
title = {Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis.},
journal = {The EMBO journal},
volume = {26},
number = {22},
pages = {4709-4719},
pmid = {17948054},
issn = {1460-2075},
support = {K01 CA124461/CA/NCI NIH HHS/United States ; R01 AG028888/AG/NIA NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; 1K01CA124461/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*metabolism ; Cells, Cultured ; *DNA Damage ; DNA-Binding Proteins/*metabolism ; Embryo, Mammalian/cytology ; Fibroblasts/metabolism ; Mice ; Neoplasms/genetics/metabolism ; Protein Serine-Threonine Kinases/*metabolism ; RNA, Messenger/metabolism ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/deficiency/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; Tumor Suppressor Proteins/*metabolism ; },
abstract = {The POT1 (protection of telomeres) protein binds the single-stranded G-rich overhang and is essential for both telomere end protection and telomere length regulation. Telomeric binding of POT1 is enhanced by its interaction with TPP1. In this study, we demonstrate that mouse Tpp1 confers telomere end protection by recruiting Pot1a and Pot1b to telomeres. Knockdown of Tpp1 elicits a p53-dependent growth arrest and an ATM-dependent DNA damage response at telomeres. In contrast to depletion of Trf2, which activates ATM, removal of Pot1a and Pot1b from telomeres initiates an ATR-dependent DNA damage response (DDR). Finally, we show that telomere dysfunction as a result of Tpp1 depletion promotes chromosomal instability and tumorigenesis in the absence of an ATM-dependent DDR. Our results uncover a novel ATR-dependent DDR at telomeres that is normally shielded by POT1 binding to the single-stranded G-overhang. In addition, our results suggest that loss of ATM can cooperate with dysfunctional telomeres to promote cellular transformation and tumor formation in vivo.},
}
@article {pmid17947491,
year = {2007},
author = {Morton, MJ and Zhang, S and Lopez-Beltran, A and MacLennan, GT and Eble, JN and Montironi, R and Sung, MT and Tan, PH and Zheng, S and Zhou, H and Cheng, L},
title = {Telomere shortening and chromosomal abnormalities in intestinal metaplasia of the urinary bladder.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {13},
number = {20},
pages = {6232-6236},
doi = {10.1158/1078-0432.CCR-07-0121},
pmid = {17947491},
issn = {1078-0432},
mesh = {Adenocarcinoma/etiology/genetics ; *Chromosome Aberrations ; Chromosomes/ultrastructure ; Cystitis/complications ; Cytogenetics ; Humans ; Immunohistochemistry/methods ; In Situ Hybridization, Fluorescence ; Intestines/*pathology ; Metaplasia/genetics/*pathology ; Precancerous Conditions/genetics ; Telomere/*ultrastructure ; Urinary Bladder Neoplasms/*genetics/*pathology ; },
abstract = {PURPOSE: Although intestinal metaplasia is often found in association with adenocarcinoma of the urinary bladder, it is unclear whether intestinal metaplasia of the bladder is a premalignant lesion. Telomere shortening has recently been implicated in epithelial carcinogenesis. We used quantitative fluorescent in situ hybridization (FISH) to measure telomere length and UroVysion FISH to detect cytogenetic abnormalities in urinary bladder specimens with intestinal metaplasia.<br><br>EXPERIMENTAL DESIGN: Paraffin-embedded tissue blocks from 34 patients with intestinal metaplasia of the urinary bladder were evaluated. Twelve of the 34 patients had coexistent cystitis glandularis, and telomere length was measured in these lesions for comparison. Tissue sections were prepared and hybridized with a telomere-specific peptide nucleic acid probe. Quantitative FISH on interphase nuclei was used to assess telomere signal intensity. Additional sections were hybridized with centromeric probes for chromosomes 3, 7, and 17 and a locus-specific probe 9p21. Multicolor FISH was used to analyze for cytogenic abnormalities in the interphase nuclei of intestinal metaplasia.<br><br>RESULTS: In all 34 cases, reduced average telomere signal intensity was observed in the nuclei of intestinal metaplasia cells compared with adjacent control nuclei to produce a mean relative intensity of 48.5% (P < 0.0001). When cystitis glandularis was present, significant differences in the telomere-specific signal intensity existed between cystitis glandularis and normal cells (P = 0.0005) and between cystitis glandularis and intestinal metaplasia cells (P = 0.0015). Three of the 34 cases showed chromosomal gains in the UroVysion FISH assay.<br><br>CONCLUSIONS: Our findings indicate that intestinal metaplasia in the urinary bladder is associated with significant telomere shortening relative to telomere length in adjacent normal urothelial cells. These lesions also occasionally showed cytogenetic abnormalities associated with telomere shortening. Our findings support the hypothesis that intestinal metaplasia of the urinary bladder is a precursor lesion to and could be a marker in the development of adenocarcinoma of the urinary bladder.},
}
@article {pmid17947422,
year = {2007},
author = {Petreaca, RC and Chiu, HC and Nugent, CI},
title = {The role of Stn1p in Saccharomyces cerevisiae telomere capping can be separated from its interaction with Cdc13p.},
journal = {Genetics},
volume = {177},
number = {3},
pages = {1459-1474},
pmid = {17947422},
issn = {0016-6731},
support = {R01 CA096972/CA/NCI NIH HHS/United States ; R01-CA96972/CA/NCI NIH HHS/United States ; },
mesh = {Alleles ; Binding Sites/genetics ; Cell Cycle Proteins/chemistry/*genetics/*metabolism ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; DNA Damage ; DNA, Fungal/genetics/metabolism ; Genes, Fungal ; Genetic Complementation Test ; Mutation ; Protein Binding ; Protein Structure, Tertiary ; Recombination, Genetic ; Saccharomyces cerevisiae/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*genetics/*metabolism ; Telomerase/genetics/metabolism ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/chemistry/*genetics/*metabolism ; },
abstract = {The function of telomeres is twofold: to facilitate complete chromosome replication and to protect chromosome ends against fusions and illegitimate recombination. In the budding yeast Saccharomyces cerevisiae, interactions among Cdc13p, Stn1p, and Ten1p are thought to be critical for promoting these processes. We have identified distinct Stn1p domains that mediate interaction with either Ten1p or Cdc13p, allowing analysis of whether the interaction between Cdc13p and Stn1p is indeed essential for telomere capping or length regulation. Consistent with the model that the Stn1p essential function is to promote telomere end protection through Cdc13p, stn1 alleles that truncate the C-terminal 123 residues fail to interact with Cdc13p and do not support viability when expressed at endogenous levels. Remarkably, more extensive deletions that remove an additional 185 C-terminal residues from Stn1p now allow cell growth at endogenous expression levels. The viability of these stn1-t alleles improves with increasing expression level, indicating that increased stn1-t dosage can compensate for the loss of Cdc13p-Stn1p interaction. However, telomere length is misregulated at all expression levels. Thus, an amino-terminal region of Stn1p is sufficient for its essential function, while a central region of Stn1p either negatively regulates the STN1 essential function or destabilizes the mutant Stn1 protein.},
}
@article {pmid17943234,
year = {2007},
author = {Jiang, H and Ju, Z and Rudolph, KL},
title = {Telomere shortening and ageing.},
journal = {Zeitschrift fur Gerontologie und Geriatrie},
volume = {40},
number = {5},
pages = {314-324},
pmid = {17943234},
issn = {0948-6704},
mesh = {Aging/*genetics/*pathology ; Cell Division/genetics ; Cellular Senescence/genetics ; Chronic Disease ; Genetic Predisposition to Disease/*genetics ; Humans ; *Models, Genetic ; Neoplasms/*genetics/pathology ; Telomere/*genetics/*ultrastructure ; },
abstract = {Telomeres form the ends of human chromosomes. Telomeres shorten with each round of cell division and this mechanism limits proliferation of human cells to a finite number of cell divisions by inducing replicative senescence, differentiation, or apoptosis. Telomere shortening can act as a tumor suppressor. However, as a downside, there is growing evidence indicating that telomere shortening also limits stem cell function, regeneration, and organ maintenance during ageing. Moreover, telomere shortening during ageing and disease is associated with increasing cancer risk. In this review we summarize our current knowledge on the role of telomere shortening in human ageing, chronic diseases, and cancer.},
}
@article {pmid17942424,
year = {2007},
author = {Liu, X and Takahashi, H and Harada, Y and Ogawara, T and Ogimura, Y and Mizushina, Y and Saneyoshi, M and Yamaguchi, T},
title = {3'-Azido-2',3'-dideoxynucleoside 5'-triphosphates inhibit telomerase activity in vitro, and the corresponding nucleosides cause telomere shortening in human HL60 cells.},
journal = {Nucleic acids research},
volume = {35},
number = {21},
pages = {7140-7149},
pmid = {17942424},
issn = {1362-4962},
mesh = {Antineoplastic Agents/chemistry/*pharmacology ; Cell Proliferation/drug effects ; DNA/chemistry/metabolism ; Dideoxyadenosine/analogs &amp; derivatives/chemistry/pharmacology ; Dideoxynucleosides/chemistry/*pharmacology ; Dideoxynucleotides/chemistry/*pharmacology ; Enzyme Inhibitors/chemistry/pharmacology ; HL-60 Cells ; HeLa Cells ; Humans ; Telomerase/*antagonists &amp; inhibitors ; Telomere/chemistry/*metabolism ; Zidovudine/chemistry/pharmacology ; },
abstract = {Telomerase adds telomeric DNA repeats to the ends of linear chromosomal DNA. 3'-Azido-3'-deoxythymidine 5'-triphosphate (AZTTP) is a known telomerase inhibitor. To obtain more selective and potent inhibitors that can be employed as tools for studying telomerase, we investigated the telomerase-inhibitory effects of purine nucleosides bearing a 3'-down azido group: 3'-azido-2',3'-dideoxyguanosine (AZddG) 5'-triphosphate (AZddGTP), 3'-azido-2',3'-dideoxy-6-thioguanosine (AZddSG) 5'-triphosphate (AZddSGTP), 3'-azido-2',3'-dideoxyadenosine (AZddA) 5'-triphosphate (AZddATP) and 3'-azido-2',3'-dideoxy-2-aminoadenosine (AZddAA) 5'-triphosphate (AZddAATP). Of these, AZddGTP showed the most potent inhibitory activity against HeLa cell telomerase. AZddGTP was significantly incorporated into the 3'-terminus of DNA by partially purified telomerase. However, AZddGTP did not exhibit significant inhibitory activity against DNA polymerases alpha and delta, suggesting that AZddGTP is a selective inhibitor of telomerase. We also investigated whether long-term treatment with these nucleosides could alter telomere length and growth rates of human HL60 cells in culture. Southern hybridization analysis of genomic DNA prepared from cells cultured in the presence of AZddG and AZddAA revealed reproducible telomere shortening.},
}
@article {pmid17935854,
year = {2008},
author = {Nittis, T and Guittat, L and Stewart, SA},
title = {Alternative lengthening of telomeres (ALT) and chromatin: is there a connection?.},
journal = {Biochimie},
volume = {90},
number = {1},
pages = {5-12},
doi = {10.1016/j.biochi.2007.08.009},
pmid = {17935854},
issn = {0300-9084},
mesh = {Animals ; Chromatin/chemistry/*physiology ; Epigenesis, Genetic ; Histones/metabolism ; Humans ; Methylation ; Neoplasms/enzymology ; Recombination, Genetic ; Sister Chromatid Exchange ; Telomerase/*metabolism ; Telomere/chemistry/*physiology ; },
abstract = {The acquisition of cellular immortality is a critical step in the tumorigenic process that requires stabilization of the telomeres, nucleoprotein structures at the termini of chromosomes. While the majority of human tumors stabilize their telomeres through activation of telomerase (hTERT), a significant portion (10-15%) utilize a poorly understood alternative mechanism of telomere maintenance referred to as ALT (Alternative Lengthening of Telomeres). Strikingly, the ALT mechanism is more prevalent in tumors arising from tissues of mesenchymal origin than in those of epithelial origin. This observation suggests that cell type specific mechanisms favor the activation of the ALT mechanism versus telomerase in human tumorigenesis. In addition, the presence of an alternative mechanism of telomere maintenance raises the possibility that telomerase-positive tumors undergoing anti-telomerase therapies might escape by activating the ALT pathway. For these reasons, delineating the ALT mechanism is critical for our understanding of the tumorigenic process and the development of ALT-specific anti-neoplastic therapies. Recent studies have demonstrated that epigenetic modifications at telomeres have a profound effect on telomere length, and may also be linked to the ALT mechanism. In this review we focus on these recent advances and their implications in telomere maintenance.},
}
@article {pmid17933469,
year = {2007},
author = {Bollmann, FM},
title = {Targeting ALT: the role of alternative lengthening of telomeres in pathogenesis and prevention of cancer.},
journal = {Cancer treatment reviews},
volume = {33},
number = {8},
pages = {704-709},
doi = {10.1016/j.ctrv.2007.08.006},
pmid = {17933469},
issn = {0305-7372},
mesh = {Animals ; Humans ; Neoplasms/*genetics/*physiopathology/*prevention &amp; control ; Telomerase ; Telomere/*physiology ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomere shortening in the course of cell divisions plays an important role in both suppression and pathogenesis of cancer. Telomere maintenance mechanisms such as telomerase and alternative lengthening of telomeres (ALT) are essential for long-term tumor growth. Consequently, interdiction of telomere lengthening has been proposed as an anti-cancer treatment but requires insight in the genes and pathways involved. In this article, the molecular and functional details of ALT are reviewed, and proposed next steps towards a therapy aimed at preventing ALT in human cancers are described.},
}
@article {pmid17932567,
year = {2007},
author = {Salvati, E and Leonetti, C and Rizzo, A and Scarsella, M and Mottolese, M and Galati, R and Sperduti, I and Stevens, MF and D'Incalci, M and Blasco, M and Chiorino, G and Bauwens, S and Horard, B and Gilson, E and Stoppacciaro, A and Zupi, G and Biroccio, A},
title = {Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect.},
journal = {The Journal of clinical investigation},
volume = {117},
number = {11},
pages = {3236-3247},
pmid = {17932567},
issn = {0021-9738},
mesh = {Acridines/*metabolism ; Animals ; Antineoplastic Agents/*metabolism ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/metabolism ; Cell Line, Tumor ; DNA/chemistry/genetics/metabolism ; *DNA Damage ; DNA Repair ; *G-Quadruplexes ; Histones/genetics/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Mice ; Neoplasm Transplantation ; Nuclear Proteins/genetics/metabolism ; Protein Serine-Threonine Kinases/genetics/metabolism ; Shelterin Complex ; Telomere/genetics/metabolism/*pathology ; Telomere-Binding Proteins/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Transplantation, Heterologous ; Tumor Suppressor p53-Binding Protein 1 ; },
abstract = {Functional telomeres are required for the replicability of cancer cells. The G-rich strand of telomeric DNA can fold into a 4-stranded structure known as the G-quadruplex (G4), whose stabilization alters telomere function limiting cancer cell growth. Therefore, the G4 ligand RHPS4 may possess antitumor activity. Here, we show that RHPS4 triggers a rapid and potent DNA damage response at telomeres in human transformed fibroblasts and melanoma cells, characterized by the formation of several telomeric foci containing phosphorylated DNA damage response factors gamma-H2AX, RAD17, and 53BP1. This was dependent on DNA repair enzyme ATR, correlated with delocalization of the protective telomeric DNA-binding protein POT1, and was antagonized by overexpression of POT1 or TRF2. In mice, RHPS4 exerted its antitumor effect on xenografts of human tumor cells of different histotype by telomere injury and tumor cell apoptosis. Tumor inhibition was accompanied by a strong DNA damage response, and tumors overexpressing POT1 or TRF2 were resistant to RHPS4 treatment. These data provide evidence that RHPS4 is a telomere damage inducer and that telomere disruption selectively triggered in malignant cells results in a high therapeutic index in mice. They also define a functional link between telomere damage and antitumor activity and reveal the key role of telomere-protective factors TRF2 and POT1 in response to this anti-telomere strategy.},
}
@article {pmid17925004,
year = {2007},
author = {Bakaysa, SL and Mucci, LA and Slagboom, PE and Boomsma, DI and McClearn, GE and Johansson, B and Pedersen, NL},
title = {Telomere length predicts survival independent of genetic influences.},
journal = {Aging cell},
volume = {6},
number = {6},
pages = {769-774},
doi = {10.1111/j.1474-9726.2007.00340.x},
pmid = {17925004},
issn = {1474-9726},
support = {AG04563/AG/NIA NIH HHS/United States ; AG08861/AG/NIA NIH HHS/United States ; AG10175/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Cohort Studies ; Female ; Follow-Up Studies ; Genetic Markers ; Humans ; Longevity/*genetics ; Male ; Middle Aged ; Survival Analysis ; Sweden ; Telomere/*genetics ; },
abstract = {Telomeres prevent the loss of coding genetic material during chromosomal replication. Previous research suggests that shorter telomere length may be associated with lower survival. Because genetic factors are important for individual differences in both telomere length and mortality, this association could reflect genetic or environmental pleiotropy rather than a direct biological effect of telomeres. We demonstrate through within-pair analyses of Swedish twins that telomere length at advanced age is a biomarker that predicts survival beyond the impact of early familial environment and genetic factors in common with telomere length and mortality. Twins with the shortest telomeres had a three times greater risk of death during the follow-up period than their co-twins with the longest telomere measurements [hazard ratio (RR) = 2.8, 95% confidence interval 1.1-7.3, P = 0.03].},
}
@article {pmid17921808,
year = {2007},
author = {Fuster, JJ and Díez, J and Andrés, V},
title = {Telomere dysfunction in hypertension.},
journal = {Journal of hypertension},
volume = {25},
number = {11},
pages = {2185-2192},
doi = {10.1097/HJH.0b013e3282ef6196},
pmid = {17921808},
issn = {0263-6352},
mesh = {Aging/physiology ; Aspartic Acid Endopeptidases/genetics ; Blood Pressure ; Endothelin-Converting Enzymes ; Humans ; Hypertension/complications/etiology/*genetics ; Leukocytes/metabolism ; Metalloendopeptidases/genetics ; Muscle, Smooth, Vascular/pathology ; Nuclear Proteins/physiology ; Oxidative Stress ; TATA Box Binding Protein-Like Proteins/physiology ; Telomerase/physiology ; *Telomere ; Telomeric Repeat Binding Protein 2 ; },
abstract = {Aging is a major risk factor for hypertension and associated cardiovascular disease. In most proliferative tissues, aging is characterized by shortening of the DNA component of telomeres, the specialized genetic segments that cap the end of eukaryotic chromosomes and protect them from end-to-end fusions. By inducing genomic instability, replicative senescence and apoptosis, telomere shortening is thought to contribute to organismal aging and to the development of age-related diseases. Here, we review animal and human studies that have investigated the possible links between telomere ablation and the pathogenesis of hypertension and related target organ damage. Although evidence is mounting that alterations in telomerase activity and telomere shortening may play a role in the pathogenesis of hypertension, additional studies are required to understand the molecular mechanisms by which telomere dysfunction and hypertension are functionally connected. As our knowledge on this emerging field grows, the challenge will be to ascertain whether all this information might translate into clinical applications.},
}
@article {pmid17917674,
year = {2007},
author = {Arnerić, M and Lingner, J},
title = {Tel1 kinase and subtelomere-bound Tbf1 mediate preferential elongation of short telomeres by telomerase in yeast.},
journal = {EMBO reports},
volume = {8},
number = {11},
pages = {1080-1085},
pmid = {17917674},
issn = {1469-221X},
mesh = {DNA-Binding Proteins/genetics/*metabolism ; Intracellular Signaling Peptides and Proteins/genetics/*metabolism ; Protein Serine-Threonine Kinases/genetics/*metabolism ; *Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; Transcription Factors ; },
abstract = {Telomerase enables telomere length homeostasis, exhibiting increasing preference for telomeres as their lengths decline. This regulation involves telomere repeat-bound Rap1, which provides a length-dependent negative feedback mechanism, and the Tel1 and Mec1 kinases, which are positive regulators of telomere length. By analysing telomere elongation of wild-type chromosome ends at single-molecule resolution, we show that in tel1Delta cells the overall frequency of elongation decreases considerably, explaining their short telomere phenotype. At an artificial telomere lacking a subtelomeric region, telomere elongation no longer increases with telomere shortening in tel1Delta cells. By contrast, a natural telomere, containing subtelomeric sequence, retains a preference for the elongation of short telomeres. Tethering of the subtelomere binding protein Tbf1 to the artificial telomere in tel1Delta cells restored preferential telomerase action at short telomeres; thus, Tbf1 might function in parallel to Tel1, which has a crucial role in a TG-repeat-controlled pathway for the activation of telomerase at short telomeres.},
}
@article {pmid17913750,
year = {2007},
author = {Patel, DJ and Phan, AT and Kuryavyi, V},
title = {Human telomere, oncogenic promoter and 5'-UTR G-quadruplexes: diverse higher order DNA and RNA targets for cancer therapeutics.},
journal = {Nucleic acids research},
volume = {35},
number = {22},
pages = {7429-7455},
pmid = {17913750},
issn = {1362-4962},
support = {R01 GM034504/GM/NIGMS NIH HHS/United States ; GM034504-22/GM/NIGMS NIH HHS/United States ; },
mesh = {5' Untranslated Regions/*chemistry ; DNA/chemistry/drug effects ; DNA Repeat Expansion ; *G-Quadruplexes/drug effects ; Humans ; Neoplasms/*drug therapy ; *Oncogenes ; *Promoter Regions, Genetic ; RNA/chemistry/drug effects ; Telomere/*chemistry ; },
abstract = {Guanine-rich DNA sequences can form G-quadruplexes stabilized by stacked G-G-G-G tetrads in monovalent cation-containing solution. The length and number of individual G-tracts and the length and sequence context of linker residues define the diverse topologies adopted by G-quadruplexes. The review highlights recent solution NMR-based G-quadruplex structures formed by the four-repeat human telomere in K(+) solution and the guanine-rich strands of c-myc, c-kit and variant bcl-2 oncogenic promoters, as well as a bimolecular G-quadruplex that targets HIV-1 integrase. Such structure determinations have helped to identify unanticipated scaffolds such as interlocked G-quadruplexes, as well as novel topologies represented by double-chain-reversal and V-shaped loops, triads, mixed tetrads, adenine-mediated pentads and hexads and snap-back G-tetrad alignments. The review also highlights the recent identification of guanine-rich sequences positioned adjacent to translation start sites in 5'-untranslated regions (5'-UTRs) of RNA oncogenic sequences. The activity of the enzyme telomerase, which maintains telomere length, can be negatively regulated through G-quadruplex formation at telomeric ends. The review evaluates progress related to ongoing efforts to identify small molecule drugs that bind and stabilize distinct G-quadruplex scaffolds associated with telomeric and oncogenic sequences, and outlines progress towards identifying recognition principles based on several X-ray-based structures of ligand-G-quadruplex complexes.},
}
@article {pmid17910953,
year = {2008},
author = {Dreesen, O and Cross, GA},
title = {Telomere length in Trypanosoma brucei.},
journal = {Experimental parasitology},
volume = {118},
number = {1},
pages = {103-110},
pmid = {17910953},
issn = {0014-4894},
support = {R01 AI050614-04/AI/NIAID NIH HHS/United States ; AI50614/AI/NIAID NIH HHS/United States ; R01 AI021729/AI/NIAID NIH HHS/United States ; R01 AI021729-23/AI/NIAID NIH HHS/United States ; AI21729/AI/NIAID NIH HHS/United States ; R01 AI050614/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Antigenic Variation/genetics ; Chromosomes/chemistry ; DNA, Protozoan/*chemistry/metabolism ; Electrophoresis, Gel, Two-Dimensional ; Female ; Male ; Mice ; Mice, Inbred ICR ; Polymorphism, Restriction Fragment Length ; Rats ; Rats, Sprague-Dawley ; Restriction Mapping ; Swine ; Telomerase/metabolism ; Trypanosoma brucei brucei/*genetics/immunology ; Variant Surface Glycoproteins, Trypanosoma/genetics/immunology ; },
abstract = {Trypanosoma brucei thwarts the host immune response by replacing its variant surface glycoprotein (VSG). The actively transcribed VSG is located in one of approximately 20 telomeric expression sites (ES). Antigenic variation can occur by transcriptional switching, reciprocal translocations, or duplicative gene conversion events among ES or with the large repertoire of telomeric and non-telomeric VSG. In recently isolated strains, duplicative gene conversion occurs at a high frequency and predominates, but the switching frequency decreases dramatically upon laboratory-adaptation. Uniquely, T. brucei telomeres grow--apparently indefinitely--at a steady rate of 6-12 base pairs (bp) per population doubling (PD), but the telomere adjacent to an active ES undergoes frequent truncations. Using two-dimensional gel electrophoresis, we demonstrate that all of the chromosome classes of fast-switching and minimally propagated T. brucei have shorter telomeres than extensively propagated Lister 427 clones, suggesting a link between laboratory adaptation, telomere growth, and VSG switching rates.},
}
@article {pmid17910073,
year = {2007},
author = {Ledbetter, DH and Martin, CL},
title = {Cryptic telomere imbalance: a 15-year update.},
journal = {American journal of medical genetics. Part C, Seminars in medical genetics},
volume = {145C},
number = {4},
pages = {327-334},
doi = {10.1002/ajmg.c.30149},
pmid = {17910073},
issn = {1552-4876},
support = {R01 MH074090/MH/NIMH NIH HHS/United States ; },
mesh = {Evolution, Molecular ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Nucleic Acid Hybridization/*methods ; Oligonucleotide Array Sequence Analysis/*methods ; Telomere/*genetics ; Time Factors ; },
abstract = {It has been 15 years since we proposed that assays of telomere integrity might reveal cryptic translocations and deletions as a significant cause of mental retardation (MR) in patients with normal G-banded karyotypes. Development of unique genomic probes adjacent to the subtelomeric repeats of each chromosome arm allowed multiplex FISH analyses that confirmed such cryptic telomeric imbalances in 3-6% of all unexplained MR. Although such "telomere FISH" analysis quickly became standard of care, limitations of this technology platform included a lack of information on the size and gene content of the deleted/duplicated segments and the failure to detect interstitial deletions not involving the most distal unique clone. The development of "molecular ruler" clone sets for every human telomere provided the foundation for accurate determination of size and gene content of each imbalance, as well as the detection of interstitial deletions within these regions. Array comparative genomic hybridization (aCGH) has emerged as a powerful technology to assess single copy changes (monosomy or trisomy) at targeted loci such as telomeres or across the whole genome. This technology now replaces multiplex FISH for the assessment of telomere integrity in unexplained MR and has the advantage of efficiently determining the size and gene content of the imbalance, as well as detecting interstitial deletions near telomeres or anywhere else in the genome covered by the array design. The application of aCGH in several studies of unexplained MR has confirmed that telomere imbalances are overrepresented compared to "average" chromosomal regions, although this is likely due to random chromosome breakage rather than specific molecular mechanisms associated with the genomic architecture of human telomeres. Telomere imbalances are significantly larger than initially envisioned (approximately 40% are >5 Mb in size), and indicate the analytic sensitivity of the G-banded karyotype is much lower than previously thought. Finally, experience with smaller benign variants compared to larger pathogenic imbalances at telomeres serves as a model for approaching whole-genome aCGH in a clinical setting.},
}
@article {pmid17909028,
year = {2007},
author = {Johnson, JE and Gettings, EJ and Schwalm, J and Pei, J and Testa, JR and Litwin, S and von Mehren, M and Broccoli, D},
title = {Whole-genome profiling in liposarcomas reveals genetic alterations common to specific telomere maintenance mechanisms.},
journal = {Cancer research},
volume = {67},
number = {19},
pages = {9221-9228},
doi = {10.1158/0008-5472.CAN-07-1133},
pmid = {17909028},
issn = {0008-5472},
support = {CA098087-03/CA/NCI NIH HHS/United States ; CA117675-01/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Female ; Gene Amplification ; Gene Expression Profiling ; Genome, Human ; Genomic Instability ; Humans ; Liposarcoma/*genetics ; Loss of Heterozygosity ; Male ; Middle Aged ; Telomere/*genetics ; },
abstract = {Telomere attrition ultimately leads to the activation of protective cellular responses, such as apoptosis or senescence. Impairment of such mechanisms can allow continued proliferation despite the presence of dysfunctional telomeres. Under such conditions, high levels of genome instability are often engendered. Data from both mouse and human model systems indicate that a period of genome instability might facilitate tumorigenesis. Here, we use a liposarcoma model system to assay telomere maintenance mechanism (TMM)-specific genetic alterations. A multiassay approach was used to assess the TMMs active in tumors. Genomic DNA from these samples was then analyzed by high-resolution DNA mapping array to identify genetic alterations. Our data reveal a higher level of genome instability in alternative lengthening of telomere (ALT)-positive tumors compared with telomerase-positive tumors, whereas tumors lacking both mechanisms have relatively low levels of genome instability. The bulk of the genetic changes are amplifications, regardless of the mode of telomere maintenance used. We also identified genetic changes specific to the ALT mechanism (e.g., deletion of chromosome 1q32.2-q44) as well as changes that are underrepresented among ALT-positive tumors, such as amplification of chromosome 12q14.3-q21.2. Taken together, these studies provide insight into the molecular pathways involved in the regulation of ALT and reveal several loci that might be exploited either as prognostic markers or targets of chemotherapeutic intervention.},
}
@article {pmid17909019,
year = {2007},
author = {Bernardo, ME and Zaffaroni, N and Novara, F and Cometa, AM and Avanzini, MA and Moretta, A and Montagna, D and Maccario, R and Villa, R and Daidone, MG and Zuffardi, O and Locatelli, F},
title = {Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms.},
journal = {Cancer research},
volume = {67},
number = {19},
pages = {9142-9149},
doi = {10.1158/0008-5472.CAN-06-4690},
pmid = {17909019},
issn = {0008-5472},
mesh = {Bone Marrow Cells/*pathology/physiology/ultrastructure ; Cell Transformation, Neoplastic/genetics/*pathology/ultrastructure ; Cells, Cultured ; Cellular Senescence/physiology ; Genes, p53 ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Mesenchymal Stem Cells/*pathology/physiology/ultrastructure ; Nucleic Acid Hybridization ; RNA, Messenger/biosynthesis/genetics ; Telomerase/biosynthesis/genetics ; Telomere/*genetics/metabolism ; Time Factors ; },
abstract = {Significant improvement in the understanding of mesenchymal stem cell (MSC) biology has opened the way to their clinical use. However, concerns regarding the possibility that MSCs undergo malignant transformation have been raised. We investigated the susceptibility to transformation of human bone marrow (BM)-derived MSCs at different in vitro culture time points. MSCs were isolated from BM of 10 healthy donors and propagated in vitro until reaching either senescence or passage (P) 25. MSCs in the senescence phase were closely monitored for 8 to 12 weeks before interrupting the cultures. The genetic characterization of MSCs was investigated through array-comparative genomic hybridization (array-CGH), conventional karyotyping, and subtelomeric fluorescent in situ hybridization analysis both before and after prolonged culture. MSCs were tested for the expression of telomerase activity, human telomerase reverse transcriptase (hTERT) transcripts, and alternative lengthening of telomere (ALT) mechanism at different passages. A huge variability in terms of proliferative capacity and MSCs life span was noted between donors. In eight of 10 donors, MSCs displayed a progressive decrease in proliferative capacity until reaching senescence. In the remaining two MSC samples, the cultures were interrupted at P25 to pursue data analysis. Array-CGH and cytogenetic analyses showed that MSCs expanded in vitro did not show chromosomal abnormalities. Telomerase activity and hTERT transcripts were not expressed in any of the examined cultures and telomeres shortened during the culture period. ALT was not evidenced in the MSCs tested. BM-derived MSCs can be safely expanded in vitro and are not susceptible to malignant transformation, thus rendering these cells suitable for cell therapy approaches.},
}
@article {pmid17908968,
year = {2007},
author = {Avigad, S and Naumov, I and Ohali, A and Jeison, M and Berco, GH and Mardoukh, J and Stark, B and Ash, S and Cohen, IJ and Meller, I and Kollender, Y and Issakov, J and Yaniv, I},
title = {Short telomeres: a novel potential predictor of relapse in Ewing sarcoma.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {13},
number = {19},
pages = {5777-5783},
doi = {10.1158/1078-0432.CCR-07-0308},
pmid = {17908968},
issn = {1078-0432},
mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; Chromosomal Instability ; Chromosomes/ultrastructure ; Female ; Humans ; Infant ; Male ; Multivariate Analysis ; Nucleic Acid Hybridization ; Prognosis ; Recurrence ; Risk ; Risk Factors ; Sarcoma, Ewing/diagnosis/*genetics/*pathology ; Telomere/*ultrastructure ; Treatment Outcome ; },
abstract = {PURPOSE: Despite advances in therapy, >50% of patients with Ewing sarcoma will relapse. The current prognostic factors are not optimal for risk prediction. Studies have shown that telomere length could predict outcome in different malignancies. Our aim was to evaluate whether telomere length could be a better prognostic factor in Ewing sarcoma and correlate the results with clinical variables, outcome, and chromosomal instability.<br><br>EXPERIMENTAL DESIGN: Telomere length was determined in the primary tumor and peripheral blood of 32 patients with Ewing sarcoma. Chromosomal instability was evaluated by combining classical cytogenetics, comparative genomic hybridization and random aneuploidy. Telomere length was correlated to clinical variables, chromosomal instability, and outcome.<br><br>RESULTS: In 75% of the tumors, changes in telomere length, when compared with the corresponding peripheral blood lymphocytes, were noted. The majority of changes consisted of a reduction in telomere length. Patients harboring shorter telomeres had a significantly adverse outcome (P = 0.015). Chromosomal instability was identified in 65% of tumors, significantly correlating with short telomeres (P = 0.0094). Using multivariate analysis, telomere length remained the only significant prognostic variable (P = 0.034). Patients with short telomeres had a 5.3-fold risk of relapse as compared to those with unchanged or longer telomeres.<br><br>CONCLUSION: We have shown that tumors with telomere length reduction result in genomic instability. In addition, telomere length reduction was the only significant predictor of outcome. We suggest that reduction of telomere length in tumor cells at diagnosis could serve as a prognostic marker in Ewing sarcoma.},
}
@article {pmid17908935,
year = {2007},
author = {Capper, R and Britt-Compton, B and Tankimanova, M and Rowson, J and Letsolo, B and Man, S and Haughton, M and Baird, DM},
title = {The nature of telomere fusion and a definition of the critical telomere length in human cells.},
journal = {Genes &amp; development},
volume = {21},
number = {19},
pages = {2495-2508},
pmid = {17908935},
issn = {0890-9369},
mesh = {Base Sequence ; Cell Line, Tumor ; Cellular Senescence/*genetics ; Chromosomal Instability/*genetics ; Humans ; Molecular Sequence Data ; Mutagenesis, Insertional ; Sequence Deletion ; Tandem Repeat Sequences ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/genetics ; },
abstract = {The loss of telomere function can result in telomeric fusion events that lead to the types of genomic rearrangements, such as nonreciprocal translocations, that typify early-stage carcinogenesis. By using single-molecule approaches to characterize fusion events, we provide a functional definition of fusogenic telomeres in human cells. We show that approximately half of the fusion events contained no canonical telomere repeats at the fusion point; of those that did, the longest was 12.8 repeats. Furthermore, in addition to end-replication losses, human telomeres are subjected to large-scale deletion events that occur in the presence or absence of telomerase. Here we show that these telomeres are fusogenic, and thus despite the majority of telomeres being maintained at a stable length in normal human cells, a subset of stochastically shortened telomeres can potentially cause chromosomal instability. Telomere fusion was accompanied by the deletion of one or both telomeres extending several kilobases into the telomere-adjacent DNA, and microhomology was observed at the fusion points. This contrasted with telomere fusion that was observed following the experimental disruption of TRF2. The distinct error-prone mutational profile of fusion between critically shortened telomeres in human cells was reminiscent of Ku-independent microhomology-mediated end-joining.},
}
@article {pmid17908934,
year = {2007},
author = {Chang, M and Arneric, M and Lingner, J},
title = {Telomerase repeat addition processivity is increased at critically short telomeres in a Tel1-dependent manner in Saccharomyces cerevisiae.},
journal = {Genes &amp; development},
volume = {21},
number = {19},
pages = {2485-2494},
pmid = {17908934},
issn = {0890-9369},
mesh = {Base Sequence ; Intracellular Signaling Peptides and Proteins/genetics/*metabolism ; Molecular Sequence Data ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Saccharomyces cerevisiae/*enzymology/genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; *Tandem Repeat Sequences ; Telomerase/*metabolism ; Telomere/*metabolism ; Templates, Genetic ; },
abstract = {Telomerase is the ribonucleoprotein enzyme that elongates telomeres to counteract telomere shortening. The core enzyme consists of a reverse transcriptase protein subunit and an RNA subunit. The RNA subunit contains a short region that is used as a template by the reverse transcriptase to add short, tandem, G-rich repeats to the 3' ends of telomeres. By coexpressing two RNA subunits that differ in the telomeric repeat sequence specified and examining the telomere extensions after one cell cycle, we determined that Saccharomyces cerevisiae telomerase can dissociate and reassociate from a given telomere during one cell cycle. We also confirmed that telomerase is nonprocessive in terms of telomeric repeat addition. However, repeat addition processivity is significantly increased at extremely short telomeres, a process that is dependent on the ATM-ortholog Tel1. We propose that this enhancement of telomerase processivity at short telomeres serves to rapidly elongate critically short telomeres.},
}
@article {pmid17905509,
year = {2008},
author = {de La Roche Saint-André, C},
title = {Alternative ends: telomeres and meiosis.},
journal = {Biochimie},
volume = {90},
number = {1},
pages = {181-189},
doi = {10.1016/j.biochi.2007.08.010},
pmid = {17905509},
issn = {0300-9084},
mesh = {Animals ; Humans ; Meiosis/*physiology ; Recombination, Genetic/*physiology ; Telomere/*physiology ; },
abstract = {Meiosis is a specialized type of cell division that halves the diploid number of chromosomes, yielding four haploid nuclei. Dramatic changes in chromosomal organization occur within the nucleus at the beginning of meiosis which are followed by the separation of homologous chromosomes at the first meiotic division. This is the case for telomeres that display a meiotic-specific behavior with gathering in a limited sector of the nuclear periphery. This leads to a characteristic polarized chromosomal configuration, called the "bouquet" arrangement. The widespread phenomenon of bouquet formation among eukaryotes has led to the hypothesis that it is functionally linked to the process of interactions between homologous chromosomes that are a unique feature of meiosis and are essential for proper chromosome segregation. Various studies in different model organisms have questioned the role of the telomere bouquet in chromosome pairing and recombination, and very recently in meiotic spindle formation, and have provided some clues about the molecular mechanisms that carry out this specific clustering of telomeres.},
}
@article {pmid17904525,
year = {2007},
author = {Hayashi, N and Kobayashi, M and Shimizu, H and Yamamoto, K and Murakami, S and Nishimoto, T},
title = {Mutations in Ran system affected telomere silencing in Saccharomyces cerevisiae.},
journal = {Biochemical and biophysical research communications},
volume = {363},
number = {3},
pages = {788-794},
doi = {10.1016/j.bbrc.2007.09.054},
pmid = {17904525},
issn = {0006-291X},
mesh = {Cell Cycle Proteins/genetics/metabolism ; Chromatin Immunoprecipitation ; GTPase-Activating Proteins/*genetics/metabolism ; Gene Expression Regulation, Fungal ; *Mutation ; Nuclear Proteins/genetics/metabolism ; Phosphorylation ; Protein Binding ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Telomere/*genetics ; },
abstract = {The Ran GTPase system regulates the direction and timing of several cellular events, such as nuclear-cytosolic transport, centrosome formation, and nuclear envelope assembly in telophase. To gain insight into the Ran system's involvement in chromatin formation, we investigated gene silencing at the telomere in several mutants of the budding yeast Saccharomyces cerevisiae, which had defects in genes involved in the Ran system. A mutation of the RanGAP gene, rna1-1, caused reduced silencing at the telomere, and partial disruption of the nuclear Ran binding factor, yrb2-delta2, increased this silencing. The reduced telomere silencing in rna1-1 cells was suppressed by a high dosage of the SIR3 gene or the SIT4 gene. Furthermore, hyperphosphorylated Sir3 protein accumulated in the rna1-1 mutant. These results suggest that RanGAP is required for the heterochromatin structure at the telomere in budding yeast.},
}
@article {pmid17899406,
year = {2007},
author = {Zhdanova, NS and Minina, JM and Karamisheva, TV and Draskovic, I and Rubtsov, NB and Londoño-Vallejo, JA},
title = {The very long telomeres in Sorex granarius (Soricidae, Eulipothyphla) contain ribosomal DNA.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {15},
number = {7},
pages = {881-890},
pmid = {17899406},
issn = {0967-3849},
mesh = {Animals ; *Biological Evolution ; Chromosomes, Mammalian/*genetics ; DNA, Ribosomal/analysis/*genetics ; In Situ Hybridization, Fluorescence ; RNA, Ribosomal, 18S/genetics ; Shrews/*genetics ; Telomere/*genetics ; },
abstract = {Two closely related shrew species, Sorex granarius and Sorex araneus, in which Robertsonian rearrangements have played a primary role in karyotype evolution, present very distinct telomere length patterns. S. granarius displays hyperlong telomeres specifically associated with the short arms of acrocentrics, whereas telomere lengths in S. araneus are rather short and homogenous. Using a combined approach of chromosome and fibre FISH, modified Q-FISH, 3D-FISH, Ag-NOR staining and TRF analysis, we carried out a comparative analysis of telomeric repeats and rDNA distribution on chromosome ends of Sorex granarius. Our results show that rDNA sequences forming active nuclear organizing regions are interspersed with the long telomere tracts of all short arms of acrocentrics. These observations suggest that the major rearrangements that gave rise to today's karyotype in S. granarius were accompanied by a profound reorganization of chromosome ends, which comprised extensive amplification of telomeric and rDNA repeats on the short arms of acrocentrics and finally contributed to the stabilization of telomeres. This is the first time that such telomeric structures have been observed in any mammalian species.},
}
@article {pmid17898784,
year = {2007},
author = {Röth, A and Dürig, J and Himmelreich, H and Bug, S and Siebert, R and Dührsen, U and Lansdorp, PM and Baerlocher, GM},
title = {Short telomeres and high telomerase activity in T-cell prolymphocytic leukemia.},
journal = {Leukemia},
volume = {21},
number = {12},
pages = {2456-2462},
doi = {10.1038/sj.leu.2404968},
pmid = {17898784},
issn = {1476-5551},
mesh = {Aged ; Aged, 80 and over ; Aminobenzoates/pharmacology ; B-Lymphocytes/ultrastructure ; Female ; Humans ; Leukemia, Prolymphocytic, T-Cell/enzymology/*genetics/pathology ; Male ; Middle Aged ; Naphthalenes/pharmacology ; Neoplasm Proteins/*analysis/antagonists &amp; inhibitors ; T-Lymphocytes/ultrastructure ; Telomerase/*analysis/antagonists &amp; inhibitors ; Telomere/*ultrastructure ; },
abstract = {To test the role of telomere biology in T-cell prolymphocytic leukemia (T-PLL), a rare aggressive disease characterized by the expansion of a T-cell clone derived from immuno-competent post-thymic T-lymphocytes, we analyzed telomere length and telomerase activity in subsets of peripheral blood leukocytes from 11 newly diagnosed or relapsed patients with sporadic T-PLL. Telomere length values of the leukemic T cells (mean+/-s.d.: 1.53+/-0.65 kb) were all below the 1st percentile of telomere length values observed in T cells from healthy age-matched controls whereas telomere length of normal T- and B cells fell between the 1st and 99th percentile of the normal distribution. Leukemic T cells exhibited high levels of telomerase and were sensitive to the telomerase inhibitor BIBR1532 at doses that showed no effect on normal, unstimulated T cells. Targeting the short telomeres and telomerase activity in T-PLL seems an attractive strategy for the future treatment of this devastating disease.},
}
@article {pmid17898116,
year = {2007},
author = {Kimura, M and Barbieri, M and Gardner, JP and Skurnick, J and Cao, X and van Riel, N and Rizzo, MR and Paoliso, G and Aviv, A},
title = {Leukocytes of exceptionally old persons display ultra-short telomeres.},
journal = {American journal of physiology. Regulatory, integrative and comparative physiology},
volume = {293},
number = {6},
pages = {R2210-7},
doi = {10.1152/ajpregu.00615.2007},
pmid = {17898116},
issn = {0363-6119},
support = {AG-020132/AG/NIA NIH HHS/United States ; AG-021593/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Cells, Cultured ; Female ; Humans ; Leukocytes/*physiology ; Longevity/*genetics ; Male ; Middle Aged ; Telomere/*physiology/*ultrastructure ; },
abstract = {With a view to understanding the association between leukocyte telomere length and the human lifespan, we performed genome-wide telomere length analyses by the terminal restriction fragment length (TRFL) and single molecule telomere length analysis (STELA) of the X and Y chromosomes in leukocytes of exceptionally old (aged 90-104 yr) and younger (aged 23-74 yr) individuals. We found that the mean TRFL of 82 exceptionally old individuals was within a range projected by age-dependent TRFL attrition of 99 younger individuals. However, compared with the younger individuals, exceptionally old persons exhibited peaking of the TRFL distribution with overrepresentation of ultra-short telomeres. These findings were confirmed by the STELA. Women had longer mean TRFL than men (6.10 vs. 5.86 kb), and exceptionally old women exhibited fewer ultra-short telomeres than exceptionally old men. Our results have implications for gerontological studies of the limitation of lifespan in humans.},
}
@article {pmid17898088,
year = {2008},
author = {Gabet, AS and Accardi, R and Bellopede, A and Popp, S and Boukamp, P and Sylla, BS and Londoño-Vallejo, JA and Tommasino, M},
title = {Impairment of the telomere/telomerase system and genomic instability are associated with keratinocyte immortalization induced by the skin human papillomavirus type 38.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {22},
number = {2},
pages = {622-632},
doi = {10.1096/fj.07-8389com},
pmid = {17898088},
issn = {1530-6860},
mesh = {Anaphase ; Cell Survival ; Cells, Cultured ; Chromosomes, Human/genetics ; Female ; Genomic Instability/*genetics ; Humans ; Keratinocytes/cytology/*metabolism ; Meiosis ; Oncogene Proteins, Viral/metabolism ; Papillomaviridae/*physiology ; Polyploidy ; RNA, Messenger/genetics ; Skin Diseases/genetics/*metabolism/pathology ; Telomerase/*metabolism ; Telomere/*genetics/*metabolism ; Up-Regulation ; },
abstract = {The skin human papillomavirus (HPV) types belonging to the genus beta of the HPV phylogenetic tree appear to be associated with nonmelanoma skin cancer. We previously showed that the beta HPV type 38 E6 and E7 oncoproteins are able to inactivate the tumor suppressors p53 and retinoblastoma. Here, both viral proteins were expressed in primary human skin keratinocytes in order to study their effects on the telomere/telomerase system. We show that immortalization of skin keratinocytes induced by HPV38 E6/E7 is associated with hTERT gene overexpression. This event is, in part, explained by the accumulation of the p53-related protein, DeltaNp73. Despite elevated levels of hTERT mRNA, the telomerase activity detected in HPV38 E6/E7 keratinocytes was lower than that observed in HPV16 E6/E7 keratinocytes. The low telomerase activation in highly proliferative HPV38 E6/E7 keratinocytes resulted in the presence of extremely short and unstable telomeres. In addition, we observed anaphase bridges, mitotic multipolarity, and dramatic genomic aberrations. Interestingly, the ectopic expression of hTERT prevents both telomere erosion and genomic instability. Thus, we showed that in HPV38 E6/E7 keratinocytes characterized by unscheduled proliferation, suboptimal activation of telomerase and subsequent extensive telomere shortening result in genomic instability facilitating cellular immortalization.},
}
@article {pmid17897968,
year = {2007},
author = {Heacock, ML and Idol, RA and Friesner, JD and Britt, AB and Shippen, DE},
title = {Telomere dynamics and fusion of critically shortened telomeres in plants lacking DNA ligase IV.},
journal = {Nucleic acids research},
volume = {35},
number = {19},
pages = {6490-6500},
pmid = {17897968},
issn = {1362-4962},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; T32 ES007059/ES/NIEHS NIH HHS/United States ; 5-32-ES07059/ES/NIEHS NIH HHS/United States ; GM065383/GM/NIGMS NIH HHS/United States ; },
mesh = {Arabidopsis/enzymology/*genetics ; Arabidopsis Proteins/genetics ; Chromosomes, Plant/chemistry ; DNA Ligase ATP ; DNA Ligases/genetics/*physiology ; DNA-Binding Proteins/genetics ; Mutation ; Phenotype ; Sequence Analysis, DNA ; Telomere/*chemistry/metabolism ; },
abstract = {In the absence of the telomerase, telomeres undergo progressive shortening and are ultimately recruited into end-to-end chromosome fusions via the non-homologous end joining (NHEJ) double-strand break repair pathway. Previously, we showed that fusion of critically shortened telomeres in Arabidopsis proceeds with approximately the same efficiency in the presence or absence of KU70, a key component of NHEJ. Here we report that DNA ligase IV (LIG4) is also not essential for telomere joining. We observed only a modest decrease (3-fold) in the frequency of chromosome fusions in triple tert ku70 lig4 mutants versus tert ku70 or tert. Sequence analysis revealed that, relative to tert ku70, chromosome fusion junctions in tert ku70 lig4 mutants contained less microhomology and less telomeric DNA. These findings argue that the KU-LIG4 independent end-joining pathway is less efficient and mechanistically distinct from KU-independent NHEJ. Strikingly, in all the genetic backgrounds we tested, chromosome fusions are initiated when the shortest telomere in the population reaches approximately 1 kb, implying that this size represents a critical threshold that heralds a detrimental structural transition. These data reveal the transitory nature of telomere stability, and the robust and flexible nature of DNA repair mechanisms elicited by telomere dysfunction.},
}
@article {pmid17895279,
year = {2007},
author = {Phan, AT and Kuryavyi, V and Luu, KN and Patel, DJ},
title = {Structure of two intramolecular G-quadruplexes formed by natural human telomere sequences in K+ solution.},
journal = {Nucleic acids research},
volume = {35},
number = {19},
pages = {6517-6525},
pmid = {17895279},
issn = {1362-4962},
support = {P41 GM066354/GM/NIGMS NIH HHS/United States ; R01 GM034504/GM/NIGMS NIH HHS/United States ; GM34504/GM/NIGMS NIH HHS/United States ; GM66354/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Cations ; DNA/chemistry ; *G-Quadruplexes ; Humans ; *Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Potassium/chemistry ; Repetitive Sequences, Nucleic Acid ; Solutions ; Telomere/*chemistry ; },
abstract = {Intramolecular G-quadruplexes formed by human telomere sequences are attractive anticancer targets. Recently, four-repeat human telomere sequences have been shown to form two different intramolecular (3 + 1) G-quadruplexes in K(+) solution (Form 1 and Form 2). Here we report on the solution structures of both Form 1 and Form 2 adopted by natural human telomere sequences. Both structures contain the (3 + 1) G-tetrad core with one double-chain-reversal and two edgewise loops, but differ in the successive order of loop arrangements within the G-quadruplex scaffold. Our results provide the structural details at the two ends of the G-tetrad core in the context of natural sequences and information on different loop conformations. This structural information might be important for our understanding of telomere G-quadruplex structures and for anticancer drug design targeted to such scaffolds.},
}
@article {pmid17889664,
year = {2007},
author = {Aihara, H and Huang, WM and Ellenberger, T},
title = {An interlocked dimer of the protelomerase TelK distorts DNA structure for the formation of hairpin telomeres.},
journal = {Molecular cell},
volume = {27},
number = {6},
pages = {901-913},
pmid = {17889664},
issn = {1097-2765},
support = {R01 GM059902/GM/NIGMS NIH HHS/United States ; R01 GM059902-09/GM/NIGMS NIH HHS/United States ; GM59902/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Bacteriophages/enzymology ; Binding Sites ; DNA/*chemistry/*metabolism ; DNA Replication ; Dimerization ; Enzyme Precursors/chemistry/*metabolism ; Models, Molecular ; Molecular Sequence Data ; *Nucleic Acid Conformation ; Protein Binding ; Static Electricity ; Substrate Specificity ; Telomerase/*chemistry/*metabolism ; Telomere/*chemistry/metabolism ; Viral Proteins/chemistry/metabolism ; X-Ray Diffraction ; },
abstract = {The termini of linear chromosomes are protected by specialized DNA structures known as telomeres that also facilitate the complete replication of DNA ends. The simplest type of telomere is a covalently closed DNA hairpin structure found in linear chromosomes of prokaryotes and viruses. Bidirectional replication of a chromosome with hairpin telomeres produces a catenated circular dimer that is subsequently resolved into unit-length chromosomes by a dedicated DNA cleavage-rejoining enzyme known as a hairpin telomere resolvase (protelomerase). Here we report a crystal structure of the protelomerase TelK from Klebsiella oxytoca phage varphiKO2, in complex with the palindromic target DNA. The structure shows the TelK dimer destabilizes base pairing interactions to promote the refolding of cleaved DNA ends into two hairpin ends. We propose that the hairpinning reaction is made effectively irreversible by a unique protein-induced distortion of the DNA substrate that prevents religation of the cleaved DNA substrate.},
}
@article {pmid17889662,
year = {2007},
author = {Cristofari, G and Adolf, E and Reichenbach, P and Sikora, K and Terns, RM and Terns, MP and Lingner, J},
title = {Human telomerase RNA accumulation in Cajal bodies facilitates telomerase recruitment to telomeres and telomere elongation.},
journal = {Molecular cell},
volume = {27},
number = {6},
pages = {882-889},
doi = {10.1016/j.molcel.2007.07.020},
pmid = {17889662},
issn = {1097-2765},
support = {R01 CA104676/CA/NCI NIH HHS/United States ; },
mesh = {Cell Extracts ; Coiled Bodies/*genetics/metabolism ; Enzyme Activation ; HeLa Cells ; Humans ; Mutation/genetics ; Nucleic Acid Conformation ; Protein Transport ; RNA/chemistry/*metabolism ; Telomerase/chemistry/*metabolism ; Telomere/enzymology/*metabolism ; },
abstract = {Telomerase is required for telomere maintenance and is responsible for the immortal phenotype of cancer cells. How telomerase is assembled and reaches telomeres in the context of nuclear architecture is not understood. Recently, the telomerase RNA subunit (hTR) was shown to accumulate in Cajal bodies (CBs), subnuclear structures implicated in ribonucleoprotein maturation. However, the functional relevance of this localization for telomerase was unknown. hTR localization to CBs requires a short sequence motif called the CAB box. Here, we reconstitute telomerase in human cells and determine the effects of CAB box mutations on telomere biology. We demonstrate that mutant hTR, which fails to accumulate in CBs, is fully capable of forming catalytically active telomerase in vivo but is strongly impaired in telomere extension. The functional deficiency is accompanied by a decreased association of telomerase with telomeres. Collectively, these data identify subnuclear localization as an important regulatory mechanism for telomere length homeostasis in human cells.},
}
@article {pmid17888604,
year = {2007},
author = {Richter, T and Proctor, C},
title = {The role of intracellular peroxide levels on the development and maintenance of telomere-dependent senescence.},
journal = {Experimental gerontology},
volume = {42},
number = {11},
pages = {1043-1052},
doi = {10.1016/j.exger.2007.08.004},
pmid = {17888604},
issn = {0531-5565},
mesh = {Cellular Senescence/*physiology ; DNA Damage ; DNA Repair ; Feedback, Physiological ; Fibroblasts/metabolism/ultrastructure ; Humans ; Models, Biological ; Oxidative Stress ; Peroxides/*metabolism ; Reactive Oxygen Species/metabolism ; Stochastic Processes ; Telomere/*physiology/ultrastructure ; },
abstract = {The fact that reactive oxygen species (ROS) influences telomere-shortening and with it the onset of senescence in cells is well known, but a detailed model describing this correlation has not been proposed so far. Based on experimental data, that span a wide range of intracellular peroxide levels we formulate here a deterministic equation and a stochastic model that describe this connection, taking into account biological functions such as DNA damage and repair. Through simulations of population development under oxidative stress and dynamics of telomere length distributions, we show that a subset of uncapped telomeres is required for cell cycle arrest. Our model also supports a possible mechanism by which the generation of ROS as a consequence of telomere dysfunction leads to a positive feedback that accelerates telomere erosion. In this model, telomere-state and ROS would mutually influence each other.},
}
@article {pmid17885666,
year = {2007},
author = {Gilson, E and Géli, V},
title = {How telomeres are replicated.},
journal = {Nature reviews. Molecular cell biology},
volume = {8},
number = {10},
pages = {825-838},
doi = {10.1038/nrm2259},
pmid = {17885666},
issn = {1471-0080},
mesh = {Animals ; DNA Replication Timing/genetics ; Humans ; Saccharomyces cerevisiae/cytology/enzymology/genetics ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {The replication of the ends of linear chromosomes, or telomeres, poses unique problems, which must be solved to maintain genome integrity and to allow cell division to occur. Here, we describe and compare the timing and specific mechanisms that are required to initiate, control and coordinate synthesis of the leading and lagging strands at telomeres in yeasts, ciliates and mammals. Overall, it emerges that telomere replication relies on a strong synergy between the conventional replication machinery, telomere protection systems, DNA-damage-response pathways and chromosomal organization.},
}
@article {pmid17881651,
year = {2007},
author = {De Meyer, T and Rietzschel, ER and De Buyzere, ML and De Bacquer, D and Van Criekinge, W and De Backer, GG and Gillebert, TC and Van Oostveldt, P and Bekaert, S and , },
title = {Paternal age at birth is an important determinant of offspring telomere length.},
journal = {Human molecular genetics},
volume = {16},
number = {24},
pages = {3097-3102},
doi = {10.1093/hmg/ddm271},
pmid = {17881651},
issn = {0964-6906},
mesh = {Adult ; Age Factors ; Aging/genetics ; Cross-Sectional Studies ; Female ; Humans ; *Infant, Newborn ; Longitudinal Studies ; Male ; Maternal Age ; Middle Aged ; *Paternal Age ; Telomere/*ultrastructure ; },
abstract = {Although evidence supports the function of telomere length (TL) as a marker for biological aging, no major determinants of TL are known besides inheritance, age and gender. Here we validate and, more importantly, assess the impact of paternal age at birth as a determinant for the offspring's peripheral blood leukocyte TL within the Asklepios study population. Telomere restriction fragment length and paternal age information were available for 2433 volunteers (1176 men and 1257 women) aged approximately 35-55 years old. Paternal age at birth was positively associated with offspring TL (offspring age and gender adjusted, P < 10 (-14)). The increase in TL was estimated at 17 base pairs for each supplemental year at birth and was not statistically different between male and female offspring. The effect size of paternal age outweighed the classical TL determinant gender by a factor of 2, demonstrating the large impact. Maternal age at birth was not independently associated with offspring TL. The peculiar interaction between paternal age at birth and inheritance might explain a large part of the genetic component of TL variance on a population level. This finding also provides further proof for the theory that TL is not completely reset in the zygote. Furthermore, as paternal age is subject to demographic evolution, its association with TL might have a substantial impact on the results and comparability of TL within and between epidemiological studies. In conclusion, paternal age is an important determinant for TL, with substantial consequences for future studies.},
}
@article {pmid17878747,
year = {2006},
author = {Kammori, M and Izumiyama, N and Nakamura, K and Kurabayashi, R and Kashio, M and Aida, J and Poon, SS and Kaminishi, M},
title = {Telomere metabolism and diagnostic demonstration of telomere measurement in the human esophagus for distinguishing benign from malignant tissue by tissue quantitative fluorescence in situ hybridization.},
journal = {Oncology},
volume = {71},
number = {5-6},
pages = {430-436},
doi = {10.1159/000108612},
pmid = {17878747},
issn = {1423-0232},
mesh = {Aged ; Anaphase/genetics ; Biomarkers, Tumor/biosynthesis ; Carcinoma, Squamous Cell/*diagnosis/genetics/metabolism ; Centromere/pathology ; Chromosomal Instability/genetics ; Esophageal Neoplasms/*diagnosis/genetics/metabolism ; Esophagus/metabolism/*pathology ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Male ; Middle Aged ; Stem Cells/pathology ; Telomere/*genetics/metabolism/pathology ; },
abstract = {OBJECTIVE: We have developed a novel method for evaluating telomere length in four different cell types in non-cancerous and cancerous mucosal tissue from 15 cases of squamous cell carcinoma of the esophagus using tissue quantitative fluorescence in situ hybridization (Q-FISH). We hypothesized that the very rapid cell proliferation observed in esophageal squamous cell carcinomas might accelerate the telomere shortening and chromosomal instability associated with carcinogenesis.<br><br>METHODS: Tissue Q-FISH and the telomere to centromere intensity ratio (TCR) were used to compare telomere shortening in tissue sections taken from esophageal squamous cell carcinomas and adjacent non-cancerous esophageal tissues.<br><br>RESULTS: The peak percentage of TCR was <1 for esophageal squamous carcinoma cells and >1 for the non-cancerous esophageal cell types. Basal layer cells had the longest telomeres in comparison with prickle, cancer, and stromal cells, and strongly expressed hTERT, cytokeratin 14 and CD49f, but not MIB-1.<br><br>CONCLUSION: These results suggest the presence of stem cells in the basal layer of the esophagus. Esophageal squamous cell carcinomas also display anaphase bridges, evidencing chromosomal instability. In conclusion, our TCR method can be used to distinguish between benign and malignant tissue in esophageal lesions. In order to apply this approach clinically to individual cases, further studies are in progress.},
}
@article {pmid17876526,
year = {2007},
author = {Bailey, SM and Cornforth, MN},
title = {Telomeres and DNA double-strand breaks: ever the twain shall meet?.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {64},
number = {22},
pages = {2956-2964},
doi = {10.1007/s00018-007-7242-4},
pmid = {17876526},
issn = {1420-682X},
mesh = {Animals ; Cytogenetics/history ; *DNA Breaks, Double-Stranded/radiation effects ; DNA Repair ; History, 20th Century ; History, 21st Century ; Models, Biological ; Recombination, Genetic ; Telomere/*genetics/*metabolism/radiation effects ; },
abstract = {Telomeres were first recognized as a bona fide constituent of the chromosome based on their inability to rejoin with broken chromosome ends produced by radiation. Today, we recognize two essential and interrelated properties of telomeres. They circumvent the so-called end-replication problem faced by genomes composed of linear chromosomes, which erode from their termini with each successive cell division. Equally vital is the end-capping function that telomeres provide, which is necessary to deter chromosome ends from illicit recombination. This latter property is critical in facilitating the distinction between the naturally occurring DNA double-strand breaks (DSBs) found at chromosome ends (i.e., telomeres) and DSBs produced by exogenous agents. Here we discuss, in a brief historical narrative, key discoveries that led investigators to appreciate the unique properties of telomeres in protecting chromosome ends, and the consequences of telomere dysfunction, particularly as related to recombination involving radiation-induced DSBs.},
}
@article {pmid17876321,
year = {2007},
author = {Blasco, MA},
title = {Telomere length, stem cells and aging.},
journal = {Nature chemical biology},
volume = {3},
number = {10},
pages = {640-649},
doi = {10.1038/nchembio.2007.38},
pmid = {17876321},
issn = {1552-4450},
mesh = {Aging/genetics/*physiology ; Animals ; Cell Proliferation ; Humans ; Models, Biological ; Stem Cells/cytology/pathology/*physiology ; Telomere/genetics/*physiology ; },
abstract = {Telomere shortening occurs concomitant with organismal aging, and it is accelerated in the context of human diseases associated with mutations in telomerase, such as some cases of dyskeratosis congenita, idiopathic pulmonary fibrosis and aplastic anemia. People with these diseases, as well as Terc-deficient mice, show decreased lifespan coincidental with a premature loss of tissue renewal, which suggests that telomerase is rate-limiting for tissue homeostasis and organismal survival. These findings have gained special relevance as they suggest that telomerase activity and telomere length can directly affect the ability of stem cells to regenerate tissues. If this is true, stem cell dysfunction provoked by telomere shortening may be one of the mechanisms responsible for organismal aging in both humans and mice. Here, we will review the current evidence linking telomere shortening to aging and stem cell dysfunction.},
}
@article {pmid17875000,
year = {2007},
author = {Du, HY and Idol, R and Robledo, S and Ivanovich, J and An, P and Londono-Vallejo, A and Wilson, DB and Mason, PJ and Bessler, M},
title = {Telomerase reverse transcriptase haploinsufficiency and telomere length in individuals with 5p- syndrome.},
journal = {Aging cell},
volume = {6},
number = {5},
pages = {689-697},
pmid = {17875000},
issn = {1474-9718},
support = {P30 CA091842/CA/NCI NIH HHS/United States ; R01 CA105312/CA/NCI NIH HHS/United States ; R01 CA106995/CA/NCI NIH HHS/United States ; P30 CA91842/CA/NCI NIH HHS/United States ; },
mesh = {Blood Cell Count ; Cri-du-Chat Syndrome/blood/*genetics/physiopathology ; Dyskeratosis Congenita/genetics/physiopathology ; Female ; *Gene Deletion ; Gene Dosage ; Hematopoietic Stem Cells ; Humans ; Male ; RNA/genetics ; Telomerase/*genetics ; Telomere/genetics/*physiology/ultrastructure ; },
abstract = {Telomerase, which maintains the ends of chromosomes, consists of two core components, the telomerase reverse transcriptase (TERT) and the telomerase RNA (TERC). Haploinsufficiency for TERC or TERT leads to progressive telomere shortening and autosomal dominant dyskeratosis congenita (DC). The clinical manifestations of autosomal dominant DC are thought to occur when telomeres become critically short, but the rate of telomere shortening in this condition is unknown. Here, we investigated the consequences of de novo TERT gene deletions in a large cohort of individuals with 5p- syndrome. The study group included 41 individuals in which the chromosome deletion resulted in loss of one copy of the TERT gene at 5p15.33. Telomere length in peripheral blood cells from these individuals, although within the normal range, was on average shorter than in normal controls. The shortening was more significant in older individuals suggesting an accelerated age-dependent shortening. In contrast, individuals with autosomal dominant DC due to an inherited TERC gene deletion had very short telomeres, and the telomeres were equally short regardless of the age. Although some individuals with 5p- syndrome showed clinical features that were reminiscent of autosomal dominant DC, these features did not correlate with telomere length, suggesting that these were not caused by critically short telomeres. We conclude that a TERT gene deletion leads to slightly shorter telomeres within one generation. However, our results suggest that several generations of TERT haploinsufficiency are needed to produce the very short telomeres seen in patients with DC.},
}
@article {pmid17874998,
year = {2007},
author = {Bekaert, S and De Meyer, T and Rietzschel, ER and De Buyzere, ML and De Bacquer, D and Langlois, M and Segers, P and Cooman, L and Van Damme, P and Cassiman, P and Van Criekinge, W and Verdonck, P and De Backer, GG and Gillebert, TC and Van Oostveldt, P and , },
title = {Telomere length and cardiovascular risk factors in a middle-aged population free of overt cardiovascular disease.},
journal = {Aging cell},
volume = {6},
number = {5},
pages = {639-647},
doi = {10.1111/j.1474-9726.2007.00321.x},
pmid = {17874998},
issn = {1474-9718},
mesh = {Adult ; Aging ; Biomarkers/analysis ; Blood Pressure ; Cardiovascular Diseases/*etiology ; Cholesterol/analysis ; Cohort Studies ; Cross-Sectional Studies ; Female ; Humans ; Inflammation Mediators/analysis ; Life Style ; Male ; Middle Aged ; Oxidative Stress ; Risk Factors ; Sex Characteristics ; Telomere/*physiology/ultrastructure ; },
abstract = {Evidence assembled over the last decade shows that average telomere length (TL) acts as a biomarker for biological aging and cardiovascular disease (CVD) in particular. Although essential for a more profound understanding of the underlying mechanisms, little reference information is available on TL. We therefore sought to provide baseline TL information and assess the association of prevalent CVD risk factors with TL in subjects free of overt CVD within a small age range. We measured mean telomere restriction fragment length of peripheral blood leukocytes in a large, representative Asklepios study cohort of 2509 community-dwelling, Caucasian female and male volunteers aged approximately 35-55 years and free of overt CVD. We found a manifest age-dependent telomere attrition, at a significantly faster rate in men as compared to women. No significant associations were established with classical CVD risk factors such as cholesterol status and blood pressure, yet shorter TL was associated with increased levels of several inflammation and oxidative stress markers. Importantly, shorter telomere length was associated with an increasingly unhealthy lifestyle, particularly in men. All findings were age and gender adjusted where appropriate. With these cross-sectional results we show that TL of peripheral blood leukocytes primarily reflects the burden of increased oxidative stress and inflammation, whether or not determined by an increasingly unhealthy lifestyle, while the association with classical CVD risk factors is limited. This further clarifies the added value of TL as a biomarker for biological aging and might improve our understanding of how TL is associated with CVD.},
}
@article {pmid17873644,
year = {2007},
author = {Martin, CL and Nawaz, Z and Baldwin, EL and Wallace, EJ and Justice, AN and Ledbetter, DH},
title = {The evolution of molecular ruler analysis for characterizing telomere imbalances: from fluorescence in situ hybridization to array comparative genomic hybridization.},
journal = {Genetics in medicine : official journal of the American College of Medical Genetics},
volume = {9},
number = {9},
pages = {566-573},
doi = {10.1097/gim.0b013e318149e1fc},
pmid = {17873644},
issn = {1530-0366},
support = {R01 MH074090/MH/NIMH NIH HHS/United States ; },
mesh = {*Evolution, Molecular ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Nucleic Acid Hybridization/*methods ; Oligonucleotide Array Sequence Analysis/*methods ; Telomere/*genetics ; },
abstract = {Submicroscopic telomere imbalances are a significant cause of mental retardation with or without other phenotypic abnormalities. We previously developed a set of unique telomere clones that identify imbalances in 3% to 5% of children with unexplained mental retardation and a normal karyotype. This targeted screening approach, however, does not provide information about the size or gene content of the imbalance. To enable such comprehensive characterization, a "molecular ruler" clone panel, extending up to 5 Mb proximal to the first telomere clone for each chromosome arm, was developed. This panel of clones was successfully used to delineate the size of unbalanced telomere aberrations in a fluorescence in situ hybridization assay. However, the fluorescence in situ hybridization analysis was quite labor-intensive, and for many cases, the imbalance extended beyond our 5-Mb coverage. Therefore, to develop a more efficient and comprehensive method for characterizing telomere imbalances, we developed a custom oligonucleotide microarray consisting of high-density coverage of all telomere regions as well as a whole-genome backbone. Overall, 44 pathogenic imbalances studied by fluorescence in situ hybridization or oligonucleotide array showed a size range of 400 kb to 13.5 Mb. In four of these, the array detected additional interstitial imbalances adjacent to the telomere imbalance, demonstrating the usefulness of added probe coverage. In 10 cases with benign imbalances inherited from a normal parent, the size ranged from 170 kb to 1.6 Mb. These results demonstrate that array comparative genomic hybridization will aid in more efficient and precise characterization of telomere imbalances leading to the development of gene dosage maps at human telomere regions for genotype/phenotype correlations.},
}
@article {pmid17870066,
year = {2008},
author = {Huang, S and Risques, RA and Martin, GM and Rabinovitch, PS and Oshima, J},
title = {Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A.},
journal = {Experimental cell research},
volume = {314},
number = {1},
pages = {82-91},
pmid = {17870066},
issn = {0014-4827},
support = {R24 CA078088-10/CA/NCI NIH HHS/United States ; R24 CA078088/CA/NCI NIH HHS/United States ; AG13280/AG/NIA NIH HHS/United States ; CA78088/CA/NCI NIH HHS/United States ; HD44782/HD/NICHD NIH HHS/United States ; P30 AG013280/AG/NIA NIH HHS/United States ; R21 HD044782/HD/NICHD NIH HHS/United States ; },
mesh = {Cell Division/genetics ; Cell Line, Transformed ; Cell Proliferation ; Cellular Senescence/*genetics ; DNA Replication/*genetics ; Fibroblasts/cytology/*metabolism ; Gene Dosage/genetics ; Humans ; Lamin Type A/biosynthesis/*genetics ; Mutation/genetics ; Phenotype ; Progeria/*genetics ; Telomere/*genetics ; Transfection ; },
abstract = {LMNA mutations are responsible for a variety of genetic disorders, including muscular dystrophy, lipodystrophy, and certain progeroid syndromes, notably Hutchinson-Gilford Progeria. Although a number of clinical features of these disorders are suggestive of accelerated aging, it is not known whether cells derived from these patients exhibit cellular phenotypes associated with accelerated aging. We examined a series of isogenic skin fibroblast lines transfected with LMNA constructs bearing known pathogenic point mutations or deletion mutations found in progeroid syndromes. Fibroblasts overexpressing mutant lamin A exhibited accelerated rates of loss of telomeres and shortened replicative lifespans, in addition to abnormal nuclear morphology. To our surprise, these abnormalities were also observed in lines overexpressing wild-type lamin A. Copy number variants are common in human populations; those involving LMNA, whether arising meiotically or mitotically, might lead to progeroid phenotypes. In an initial pilot study of 23 progeroid cases without detectable WRN or LMNA mutations, however, no cases of altered LMNA copy number were detected. Nevertheless, our findings raise a hypothesis that changes in lamina organization may cause accelerated telomere attrition, with different kinetics for overexpession of wild-type and mutant lamin A, which leads to rapid replicative senescence and progroid phenotypes.},
}
@article {pmid17869047,
year = {2007},
author = {Richter, T and von Zglinicki, T},
title = {A continuous correlation between oxidative stress and telomere shortening in fibroblasts.},
journal = {Experimental gerontology},
volume = {42},
number = {11},
pages = {1039-1042},
doi = {10.1016/j.exger.2007.08.005},
pmid = {17869047},
issn = {0531-5565},
mesh = {Animals ; Cells, Cultured ; Cellular Senescence/*physiology ; Cyclic N-Oxides/pharmacology ; Fibroblasts/*metabolism/*ultrastructure ; Free Radical Scavengers/pharmacology ; Humans ; Intracellular Fluid/chemistry ; Microscopy, Fluorescence ; Oxidative Stress ; Oxygen/pharmacology ; Peroxides/analysis ; Sheep ; Telomere/*ultrastructure ; },
abstract = {Telomere shortening in cells with low intrinsic telomerase activity like fibroblasts is governed by various mechanisms including the so-called end-replication problem, end processing and oxidative DNA damage. To assess the impact of oxidative stress on telomere shortening rates, we compared telomere shortening rates measured in fibroblasts from two different donor species (human and sheep) under both pro- and antioxidative culture regimes. Over an almost 50-fold change in peroxide indicator dye fluorescence intensity, we found a continuous, exponential correlation between cellular oxidative stress levels and telomere shortening rates, which was independent of donor species and cell strain. This correlation suggests stress-mediated telomere DNA damage as an important determinant of telomere shortening.},
}
@article {pmid17854971,
year = {2008},
author = {Cairney, CJ and Keith, WN},
title = {Telomerase redefined: integrated regulation of hTR and hTERT for telomere maintenance and telomerase activity.},
journal = {Biochimie},
volume = {90},
number = {1},
pages = {13-23},
doi = {10.1016/j.biochi.2007.07.025},
pmid = {17854971},
issn = {0300-9084},
mesh = {Animals ; Chromatin Assembly and Disassembly ; Gene Expression ; Gene Expression Regulation ; Humans ; Neoplasms/enzymology/metabolism ; RNA/chemistry/genetics/*metabolism ; Signal Transduction ; Telomerase/chemistry/genetics/*metabolism ; Telomere/*physiology ; },
abstract = {Telomerase activity is dependent on the expression of 2 main core component genes, hTERT, which encodes the catalytic component and hTR (also called TERC), which encodes the RNA component. The correlation between telomerase activity and carcinogenesis has made this molecule of great interest in cancer research, however in order to fully understand the regulation of telomerase the mechanisms controlling both telomerase genes need to be studied. Some of these mechanisms of regulation have begun to emerge, however many more remain to be deciphered. For many years hTERT has been regarded as the limiting component of telomerase and much of the research in this field has focussed on its regulation, however it was clear from an early stage that hTR expression was also tightly regulated in normal cells and disease. More recently evidence from biochemistry, promoter studies and mouse models has been steadily increasing for a role for hTR as a limiting and essential component for telomerase activity and telomere maintenance. Perhaps the time has come to redefine our view of telomerase regulation. Knowledge of the mechanisms controlling both telomerase genes in normal systems and cancer may aid our understanding of the role of telomerase in carcinogenesis or highlight potential areas for therapeutic intervention. Here we review the essential requirement of hTR for telomere maintenance and telomerase activity in normal tissues and disease and focus on recent advances in our understanding of hTR regulation in relation to hTERT.},
}
@article {pmid17854970,
year = {2008},
author = {Baird, DM},
title = {Telomere dynamics in human cells.},
journal = {Biochimie},
volume = {90},
number = {1},
pages = {116-121},
doi = {10.1016/j.biochi.2007.08.003},
pmid = {17854970},
issn = {0300-9084},
mesh = {Alleles ; Cell Proliferation ; Cells, Cultured ; Chromosomes, Human/ultrastructure ; DNA Replication ; Humans ; Recombination, Genetic ; Telomere/genetics/*physiology/ultrastructure ; Telomere-Binding Proteins/metabolism ; },
abstract = {Human telomeres are intrinsically dynamic structures, with multiple biological processes operating to generate substantial length heterogeneity. Processes that operate specifically at the terminus, that include the end-replication problem coupled with C-strand resection, result in gradual telomere erosion with ongoing cell division. Rates of telomere erosion can be modulated by cell culture conditions and pleiotropic effects. Other processes, that are not consistent with the end replication problem, generate sporadic large-scale changes in telomere length. These events are detected in normal human cells and tissues; the severely truncated telomeres that result are potentially fusogenic and may lead to the types of genetic rearrangements that typify early-stage neoplasia. The processes that underlie sporadic telomeric deletion are unclear, but may include intra-allelic recombination within the T-loop structure, unequal sister chromatid exchange and replication fork stalling. The relative contributions of these processes in the generation of the heterogeneous telomere length profiles observed in human cells are discussed.},
}
@article {pmid17849448,
year = {2008},
author = {Newman, JP and Banerjee, B and Fang, W and Poonepalli, A and Balakrishnan, L and Low, GK and Bhattacharjee, RN and Akira, S and Jayapal, M and Melendez, AJ and Baskar, R and Lee, HW and Hande, MP},
title = {Short dysfunctional telomeres impair the repair of arsenite-induced oxidative damage in mouse cells.},
journal = {Journal of cellular physiology},
volume = {214},
number = {3},
pages = {796-809},
doi = {10.1002/jcp.21276},
pmid = {17849448},
issn = {1097-4652},
support = {G0700794/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; Arsenites/*toxicity ; Cell Death/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Chromosomal Instability/drug effects ; Chromosomes, Mammalian/metabolism ; Comet Assay ; *DNA Damage ; DNA Repair/*drug effects ; Embryo, Mammalian/cytology/drug effects ; Fibroblasts/cytology/*drug effects ; Gene Expression Profiling ; In Situ Hybridization, Fluorescence ; Mice ; Microarray Analysis ; Micronuclei, Chromosome-Defective ; Oxidative Stress/*drug effects ; RNA/metabolism ; Telomerase/metabolism ; Telomere/*pathology ; },
abstract = {Telomeres and telomerase appear to participate in the repair of broken DNA ends produced by oxidative damage. Arsenite is an environmental contaminant and a potent human carcinogen, which induces oxidative stress on cells via the generation of reactive oxygen species affecting cell viability and chromosome stability. It promotes telomere attrition and reduces cell survival by apoptosis. In this study, we used mouse embryonic fibroblasts (MEFs) from mice lacking telomerase RNA component (mTERC(-/-) mice) with long (early passage or EP) and short (late passage or LP) telomeres to investigate the extent of oxidative damage by comparing the differences in DNA damage, chromosome instability, and cell survival at 24 and 48 h of exposure to sodium arsenite (As3+; NaAsO2). There was significantly high level of DNA damage in mTERC(-/-) cells with short telomeres as determined by alkaline comet assay. Consistent with elevated DNA damage, increased micronuclei (MN) induction reflecting gross genomic instability was also observed. Fluorescence in situ hybridization (FISH) analysis revealed that increasing doses of arsenite augmented the chromosome aberrations, which contributes to genomic instability leading to possibly apoptotic cell death and cell cycle arrest. Microarray analysis has revealed that As3+ treatment altered the expression of 456 genes of which 20% of them have known functions in cell cycle and DNA damage signaling and response, cell growth, and/or maintenance. Results from our studies imply that short dysfunctional telomeres impair the repair of oxidative damage caused by arsenite. The results will have implications in risk estimation as well as cancer chemotherapy.},
}
@article {pmid17848914,
year = {2007},
author = {Savage, SA and Chanock, SJ and Lissowska, J and Brinton, LA and Richesson, D and Peplonska, B and Bardin-Mikolajczak, A and Zatonski, W and Szeszenia-Dabrowska, N and Garcia-Closas, M},
title = {Genetic variation in five genes important in telomere biology and risk for breast cancer.},
journal = {British journal of cancer},
volume = {97},
number = {6},
pages = {832-836},
pmid = {17848914},
issn = {0007-0920},
support = {//Intramural NIH HHS/United States ; },
mesh = {Adult ; Aged ; Breast Neoplasms/*genetics ; Carrier Proteins/genetics ; Case-Control Studies ; DNA, Neoplasm ; Female ; *Genetic Variation ; Genotype ; Humans ; Middle Aged ; Nuclear Proteins/genetics ; Odds Ratio ; Poland ; *Polymorphism, Single Nucleotide ; RNA-Binding Proteins ; Risk Assessment ; Risk Factors ; Shelterin Complex ; TATA Box Binding Protein-Like Proteins/genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; Telomeric Repeat Binding Protein 2 ; },
abstract = {Telomeres, consisting of TTAGGG nucleotide repeats and a protein complex at chromosome ends, are critical for maintaining chromosomal stability. Genomic instability, following telomere crisis, may contribute to breast cancer pathogenesis. Many genes critical in telomere biology have limited nucleotide diversity, thus, single nucleotide polymorphisms (SNPs) in this pathway could contribute to breast cancer risk. In a population-based study of 1995 breast cancer cases and 2296 controls from Poland, 24 SNPs representing common variation in POT1, TEP1, TERF1, TERF2 and TERT were genotyped. We did not identify any significant associations between individual SNPs or haplotypes and breast cancer risk; however, data suggested that three correlated SNPs in TERT (-1381C>T, -244C>T, and Ex2-659G>A) may be associated with reduced risk of breast cancer among individuals with a family history of breast cancer (odds ratios 0.73, 0.66, and 0.57, 95% confidence intervals 0.53-1.00, 0.46-0.95 and 0.39-0.84, respectively). In conclusion, our data do not support substantial overall associations between SNPs in telomere pathway genes and breast cancer risk. Intriguing associations with variants in TERT among women with a family history of breast cancer warrant follow-up in independent studies.},
}
@article {pmid17846168,
year = {2007},
author = {Benetti, R and Gonzalo, S and Jaco, I and Schotta, G and Klatt, P and Jenuwein, T and Blasco, MA},
title = {Suv4-20h deficiency results in telomere elongation and derepression of telomere recombination.},
journal = {The Journal of cell biology},
volume = {178},
number = {6},
pages = {925-936},
pmid = {17846168},
issn = {0021-9525},
mesh = {Animals ; Chromosomes, Mammalian/genetics/metabolism ; *DNA Methylation ; Embryonic Stem Cells/metabolism ; Embryonic Structures/cytology ; Epigenesis, Genetic ; Fibroblasts/metabolism ; Histone-Lysine N-Methyltransferase/genetics/*metabolism ; Histones/genetics/metabolism ; In Vitro Techniques ; Methylation ; Mice ; *Recombination, Genetic ; Telomere/genetics/*metabolism ; },
abstract = {Mammalian telomeres have heterochromatic features, including trimethylated histone H3 at lysine 9 (H3K9me3) and trimethylated histone H4 at lysine 20 (H4K20me3). In addition, subtelomeric DNA is hypermethylated. The enzymatic activities responsible for these modifications at telomeres are beginning to be characterized. In particular, H4K20me3 at telomeres could be catalyzed by the novel Suv4-20h1 and Suv4-20h2 histone methyltransferases (HMTases). In this study, we demonstrate that the Suv4-20h enzymes are responsible for this histone modification at telomeres. Cells deficient for Suv4-20h2 or for both Suv4-20h1 and Suv4-20h2 show decreased levels of H4K20me3 at telomeres and subtelomeres in the absence of changes in H3K9me3. These epigenetic alterations are accompanied by telomere elongation, indicating a role for Suv4-20h HMTases in telomere length control. Finally, cells lacking either the Suv4-20h or Suv39h HMTases show increased frequencies of telomere recombination in the absence of changes in subtelomeric DNA methylation. These results demonstrate the importance of chromatin architecture in the maintenance of telomere length homeostasis and reveal a novel role for histone lysine methylation in controlling telomere recombination.},
}
@article {pmid17828613,
year = {2007},
author = {Murata, K and Hanzawa, K and Kasai, F and Takeuchi, M and Echigoya, T and Yasumoto, S},
title = {Robertsonian translocation as a result of telomere shortening during replicative senescence and immortalization of bovine oviduct epithelial cells.},
journal = {In vitro cellular &amp; developmental biology. Animal},
volume = {43},
number = {7},
pages = {235-244},
pmid = {17828613},
issn = {1071-2690},
mesh = {Animals ; Cattle ; Cell Line, Transformed ; Cell Shape ; Cells, Cultured ; *Cellular Senescence ; Epithelial Cells/cytology/*physiology ; Fallopian Tubes/*cytology ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Telomere/*metabolism ; *Translocation, Genetic ; },
abstract = {We investigated chromosome (Chr) aberrations in the process of replicative senescence and immortalization of cultured bovine oviduct epithelial cells (BOEC) before and after transfecting vectors SV40 large T or human telomerase reverse transcriptase (hTERT). We found that a gradual increase in the number of metacentric chromosomes occurred during replicative senescence but not immortalization of BOEC. The accumulation of metacentric chromosomes was concomitant with decreases in the number of acrocentric autosomes, strongly suggesting that Robertsonian (Rb) translocation frequently occurred in cultured BOEC. The process was also correlated with an accumulation of extremely shortened telomeres (<4 kb). The maximum number of metacentric chromosomes reached a plateau (8.75 +/- 0.53) in the senescent BOEC (approximately 48 population doublings), and the value was stably maintained in all immortalized lines. These results suggest that not all autosomes may be involved in Rb translocation. Fluorescence in situ hybridization analysis using probes specific for Chr1, Chr29, telomeres, and x-chromosomes of bovine confirmed the presence of t(1;29) with other unidentified fused chromosomes. There was no evidence for duplication of sex chromosomes. Because no detectable fluorescence in situ hybridization signals at the centromere for telomeres were indicative of no direct integration of telomere sequences in the Rb translocated chromosomes, these results raise a possibility that Rb translocation between certain autosomes of bovine cells is partly but critically dependent upon a physical state of telomere attrition. The cells and cell lines established in this study could provide a promising system for further studies on the mechanisms of chromosomal translocation because of centromeric fusion in bovine cells.},
}
@article {pmid17825467,
year = {2008},
author = {Hsiao, SJ and Smith, S},
title = {Tankyrase function at telomeres, spindle poles, and beyond.},
journal = {Biochimie},
volume = {90},
number = {1},
pages = {83-92},
doi = {10.1016/j.biochi.2007.07.012},
pmid = {17825467},
issn = {0300-9084},
support = {R01 CA095099/CA/NCI NIH HHS/United States ; GM07238/GM/NIGMS NIH HHS/United States ; R01 CA116352/CA/NCI NIH HHS/United States ; R01 CA95099/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Evolution, Molecular ; Humans ; Molecular Sequence Data ; Neoplasms/metabolism ; Phylogeny ; Sequence Alignment ; Shelterin Complex ; Spindle Apparatus/*metabolism ; Tankyrases/chemistry/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomeres have special needs; they require distinct mechanisms for their protection, replication, and separation at mitosis. A dedicated six-subunit protein complex termed shelterin attends to these needs. But shelterin cannot do it alone and often relies on recruits from other cellular locales. One such recruit is tankyrase 1, a poly(ADP-ribose) polymerase that is brought to telomeres by the shelterin DNA binding subunit TRF1, where it functions in telomere length regulation and sister chromatid separation. An understanding of how tankyrase 1 functions at telomeres has been confounded by its complexity; it localizes to multiple subcellular sites, it has many diverse binding partners, and it has a closely related homolog (tankyrase 2) with which it may functionally overlap. This review summarizes our current knowledge of tankyrases focusing on their localization, binding partners, and function.},
}
@article {pmid17822826,
year = {2008},
author = {De Cian, A and Lacroix, L and Douarre, C and Temime-Smaali, N and Trentesaux, C and Riou, JF and Mergny, JL},
title = {Targeting telomeres and telomerase.},
journal = {Biochimie},
volume = {90},
number = {1},
pages = {131-155},
doi = {10.1016/j.biochi.2007.07.011},
pmid = {17822826},
issn = {0300-9084},
mesh = {Antineoplastic Agents/metabolism/pharmacology/therapeutic use ; DNA Damage/drug effects ; Enzyme Inhibitors/chemistry/*metabolism/pharmacology/therapeutic use ; G-Quadruplexes ; Humans ; Ligands ; Neoplasms/drug therapy/enzymology/metabolism ; Shelterin Complex ; Telomerase/*antagonists &amp; inhibitors/*metabolism ; Telomere/drug effects/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomeres and telomerase represent, at least in theory, an extremely attractive target for cancer therapy. The objective of this review is to present the latest view on the mechanism(s) of action of telomerase inhibitors, with an emphasis on a specific class of telomere ligands called G-quadruplex ligands, and to discuss their potential use in oncology.},
}
@article {pmid17803948,
year = {2007},
author = {Hector, RE and Shtofman, RL and Ray, A and Chen, BR and Nyun, T and Berkner, KL and Runge, KW},
title = {Tel1p preferentially associates with short telomeres to stimulate their elongation.},
journal = {Molecular cell},
volume = {27},
number = {5},
pages = {851-858},
doi = {10.1016/j.molcel.2007.08.007},
pmid = {17803948},
issn = {1097-2765},
support = {R01 GM050752/GM/NIGMS NIH HHS/United States ; AG19660/AG/NIA NIH HHS/United States ; F32 AG022743/AG/NIA NIH HHS/United States ; T32 HD007104/HD/NICHD NIH HHS/United States ; },
mesh = {Cellular Senescence ; Endodeoxyribonucleases/metabolism ; Exodeoxyribonucleases/metabolism ; Intracellular Signaling Peptides and Proteins/analysis/*metabolism ; Models, Genetic ; Protein Serine-Threonine Kinases/analysis/*metabolism ; Recombination, Genetic ; Saccharomyces cerevisiae Proteins/analysis/*metabolism ; Telomere/*metabolism/ultrastructure ; },
abstract = {In many organisms, telomeric DNA consists of long tracts of short repeats. Shorter tracts are preferentially lengthened by telomerase, suggesting a conserved mechanism that recognizes and elongates short telomeres. Tel1p, an ATM family checkpoint kinase, plays an important role in telomere elongation, as cells lacking Tel1p have short telomeres and show reduced recruitment of telomerase components to telomeres. We show that Tel1p association increased as telomeres shortened in vivo in the presence or absence of telomerase and that Tel1p preferentially associated with the shortest telomeres. Tel1p association was independent of Tel1p kinase activity and enhanced by Mre11p. Tel1p overexpression simultaneously stimulated telomerase-mediated elongation and Tel1p association with all telomeres. Thus, Tel1p preferentially associates with the shortest telomeres and stimulates their elongation by telomerase.},
}
@article {pmid17803909,
year = {2007},
author = {Schaetzlein, S and Kodandaramireddy, NR and Ju, Z and Lechel, A and Stepczynska, A and Lilli, DR and Clark, AB and Rudolph, C and Kuhnel, F and Wei, K and Schlegelberger, B and Schirmacher, P and Kunkel, TA and Greenberg, RA and Edelmann, W and Rudolph, KL},
title = {Exonuclease-1 deletion impairs DNA damage signaling and prolongs lifespan of telomere-dysfunctional mice.},
journal = {Cell},
volume = {130},
number = {5},
pages = {863-877},
pmid = {17803909},
issn = {0092-8674},
support = {Z99 ES999999//Intramural NIH HHS/United States ; R01CA093484/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Apoptosis ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/metabolism ; Cell Proliferation ; Chromosomal Instability ; *DNA Damage ; DNA, Single-Stranded/metabolism ; Exodeoxyribonucleases/deficiency/genetics/*metabolism ; Gamma Rays ; *Gene Deletion ; Gene Fusion ; Genotype ; Intestinal Mucosa/drug effects/enzymology/*metabolism/pathology/radiation effects ; *Longevity/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mutagens/pharmacology ; Phenotype ; Protein Serine-Threonine Kinases/metabolism ; RNA/genetics/*metabolism ; Replication Protein A/metabolism ; *Signal Transduction/drug effects/genetics/radiation effects ; Telomerase/deficiency/genetics/*metabolism ; Telomere/*metabolism ; Thioguanine/pharmacology ; },
abstract = {Exonuclease-1 (EXO1) mediates checkpoint induction in response to telomere dysfunction in yeast, but it is unknown whether EXO1 has similar functions in mammalian cells. Here we show that deletion of the nuclease domain of Exo1 reduces accumulation of DNA damage and DNA damage signal induction in telomere-dysfunctional mice. Exo1 deletion improved organ maintenance and lifespan of telomere-dysfunctional mice but did not increase chromosomal instability or cancer formation. Deletion of Exo1 also ameliorated the induction of DNA damage checkpoints in response to gamma-irradiation and conferred cellular resistance to 6-thioguanine-induced DNA damage. Exo1 deletion impaired upstream induction of DNA damage responses by reducing ssDNA formation and the recruitment of Replication Protein A (RPA) and ATR at DNA breaks. Together, these studies provide evidence that EXO1 contributes to DNA damage signal induction in mammalian cells, and deletion of Exo1 can prolong survival in the context of telomere dysfunction.},
}
@article {pmid17785865,
year = {2007},
author = {Damjanovic, AK and Yang, Y and Glaser, R and Kiecolt-Glaser, JK and Nguyen, H and Laskowski, B and Zou, Y and Beversdorf, DQ and Weng, NP},
title = {Accelerated telomere erosion is associated with a declining immune function of caregivers of Alzheimer's disease patients.},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {179},
number = {6},
pages = {4249-4254},
pmid = {17785865},
issn = {0022-1767},
support = {M01-RR-0034/RR/NCRR NIH HHS/United States ; CA16058/CA/NCI NIH HHS/United States ; Z01 AG000756-10//Intramural NIH HHS/United States ; M01 RR000034/RR/NCRR NIH HHS/United States ; AG025732/AG/NIA NIH HHS/United States ; R21 AG025732/AG/NIA NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Alzheimer Disease/*genetics/*immunology/pathology ; *Caregivers ; Cells, Cultured ; Female ; Humans ; Leukocytes, Mononuclear/enzymology/immunology/pathology ; Lymphocyte Activation/genetics/immunology ; Male ; *Nuclear Family ; Siblings ; Stress, Psychological/genetics/immunology/pathology ; T-Lymphocytes/metabolism/pathology ; Telomerase/biosynthesis ; Telomere/genetics/immunology/*pathology ; Up-Regulation/*immunology ; },
abstract = {Caregivers of Alzheimer's disease patients endure chronic stress associated with a decline of immune function. To assess the psychological and immunological changes of caregivers, we compared depressive symptoms, PBMC composition, in vitro activation-induced proliferation and cytokine production, and telomere length and telomerase activity of 82 individuals (41 caregivers and 41 age- and gender-matched controls). We found depressive symptoms were significantly higher in caregivers than in controls (p < 0.001). Correspondingly, caregivers had significantly lower T cell proliferation but higher production of immune-regulatory cytokines (TNF-alpha and IL-10) than controls in response to stimulation in vitro. We examined the impact of these changes on cellular replicative lifespan and found that caregivers had significantly shorter telomere lengths in PBMC than controls (6.2 and 6.4 kb, respectively, p < 0.05) with similar shortening in isolated T cells and monocytes and that this telomere attrition in caregivers was not due to an increase of shorter telomere possessing T cell subsets in PBMC. Finally, we showed that basal telomerase activity in PBMC and T cells was significantly higher in caregivers than in controls (p < 0.0001), pointing to an unsuccessful attempt of cells to compensate the excessive loss of telomeres in caregivers. These findings demonstrate that chronic stress is associated with altered T cell function and accelerated immune cell aging as suggested by excessive telomere loss.},
}
@article {pmid17785545,
year = {2007},
author = {Kelland, L},
title = {Targeting the limitless replicative potential of cancer: the telomerase/telomere pathway.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {13},
number = {17},
pages = {4960-4963},
doi = {10.1158/1078-0432.CCR-07-0422},
pmid = {17785545},
issn = {1078-0432},
mesh = {Animals ; Humans ; Neoplasms/*drug therapy/enzymology/etiology/genetics ; Telomerase/*antagonists &amp; inhibitors/physiology ; *Telomere ; },
abstract = {The maintenance of telomeric DNA underlies the ability of tumors to possess unlimited replicative potential, one of the hallmarks of cancer. Telomere length and structure are maintained by the reverse transcriptase telomerase and a multiprotein telomere complex termed shelterin. Telomerase activity is elevated in the vast majority of tumors, and telomeres are critically shortened in tumors versus normal tissues, thus providing a compelling rationale to target the telomerase/telomere pathway for broad-spectrum cancer therapy. This strategy is supported by a variety of genetic-based target validation studies. Both telomerase inhibitors and telomere interactive molecules have shown stand-alone antitumor activity at nontoxic doses against a variety of human tumor xenografts in mice. These translational advances have resulted in the first antitelomerase agent, the oligonucleotide-based GRN163L targeting the telomerase RNA template, entering clinical evaluation. Additional translational approaches, such as targeting telomeres using G-quadruplex ligands, should result in antitelomere agents, such as RHPS4, entering the clinic in the near future. These prototype trials will be extremely informative in determining the role of the telomerase/telomere pathway in clinical oncology and, moreover, whether drugs targeting the unlimited replicative potential of cancer will find a place in cancer chemotherapy.},
}
@article {pmid17785530,
year = {2007},
author = {Siegl-Cachedenier, I and Muñoz, P and Flores, JM and Klatt, P and Blasco, MA},
title = {Deficient mismatch repair improves organismal fitness and survival of mice with dysfunctional telomeres.},
journal = {Genes &amp; development},
volume = {21},
number = {17},
pages = {2234-2247},
pmid = {17785530},
issn = {0890-9369},
mesh = {Adenosine Triphosphatases/*genetics ; Animals ; Apoptosis ; Cell Proliferation ; Cells, Cultured ; *DNA Mismatch Repair ; DNA Repair Enzymes/*genetics ; DNA-Binding Proteins/*genetics ; *Life Expectancy ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microsatellite Instability ; Mismatch Repair Endonuclease PMS2 ; Neoplasms, Experimental/genetics ; Proto-Oncogene Proteins p21(ras)/physiology ; Recombination, Genetic ; Telomerase/*deficiency/genetics ; Telomere/*physiology ; },
abstract = {Mismatch repair (MMR) has important roles in meiotic and mitotic recombination, DNA damage signaling, and various aspects of DNA metabolism including class-switch recombination, somatic hypermutation, and triplet-repeat expansion. Defects in MMR are responsible for human cancers characterized by microsatellite instability. Intriguingly, MMR deficiency has been shown to rescue survival and proliferation of telomerase-deficient yeast strains. A putative role for MMR at mammalian telomeres that could have an impact on cancer and aging is, however, unknown. Here, we studied the role of MMR in response to dysfunctional telomeres by generating mice doubly deficient for telomerase and the PMS2 MMR gene (Terc-/-/PMS2-/- mice). PMS2 deficiency prolonged the mean lifespan and median survival of telomerase-deficient mice concomitant with rescue of degenerative pathologies. This rescue of survival was independent of changes in telomere length, in sister telomere recombination, and in microsatellite instability. Importantly, PMS2 deficiency rescued cell proliferation defects but not apoptotic defects in vivo, concomitant with a decreased p21 induction in response to short telomeres. The proliferative advantage conferred to telomerase-deficient cells by the ablation of PMS2 did not produce increased tumors. Indeed, Terc-/-/PMS2-/- mice showed reduced tumors compared with PMS2-/- mice, in agreement with a tumor suppressor role for short telomeres in the context of MMR deficiencies. These results highlight an unprecedented role for MMR in mediating the cellular response to dysfunctional telomeres in vivo by attenuating p21 induction.},
}
@article {pmid17767195,
year = {2007},
author = {Deng, Y and Chang, S},
title = {Role of telomeres and telomerase in genomic instability, senescence and cancer.},
journal = {Laboratory investigation; a journal of technical methods and pathology},
volume = {87},
number = {11},
pages = {1071-1076},
doi = {10.1038/labinvest.3700673},
pmid = {17767195},
issn = {1530-0307},
support = {R01 AG028888/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Cell Transformation, Neoplastic/metabolism/*pathology ; Cellular Senescence/*physiology ; *Genomic Instability ; Humans ; Neoplasms/pathology ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {Telomeres are ribonucleoprotein structures that protect the end of linear chromosomes from recognition as DNA double-stranded breaks and activation of a DNA damage response. Telomere-associated proteins also regulate telomerase, the protein responsible for maintaining telomere length. Loss of telomere function results from either alteration in the capping function at telomeres, or from progressive loss of telomeric repeats necessary to maintain proper telomeric structure. Dysfunctional telomeres activate p53 to initiate cellular senescence or apoptosis to suppress tumorigenesis. However, in the absence of p53, telomere dysfunction is an important mechanism to generate chromosomal instability commonly found in human carcinomas. Telomerase is expressed in the majority of human cancers, making it an attractive therapeutic target. Emerging anti-telomerase therapies that are currently in clinical trials might prove useful against some forms of human cancers.},
}
@article {pmid17766184,
year = {2007},
author = {Davison, GM},
title = {Telomeres and telomerase in leukaemia and lymphoma.},
journal = {Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis},
volume = {37},
number = {1},
pages = {43-47},
doi = {10.1016/j.transci.2007.04.006},
pmid = {17766184},
issn = {1473-0502},
mesh = {Cell Death/genetics ; Cell Division/genetics ; Cell Transformation, Neoplastic/genetics/*metabolism ; *Chromosomal Instability/genetics ; Humans ; Leukemia/*enzymology/genetics/therapy ; Lymphoma/*enzymology/genetics/therapy ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres are DNA structures which serve to stabilize chromosomes. In human cells telomeres progressively shorten with each cell division leading to eventual chromosome instability and cell death. Telomerase is a DNA polymerase which is required for the maintenance of telomeres. Therefore, telomeres and telomerase play a role in the regulation of the life span of the cell. Human cells express low levels of telomerase, however when telomere length reaches a critical level abnormal activation of telomerase can lead to immortalization and uncontrolled proliferation. This process has been associated with the development of many leukaemias and lymphomas. Understanding these processes in normal and malignant cells could lead to therapies which target the telomere/telomerase complex.},
}
@article {pmid17765874,
year = {2007},
author = {Kim, H and Chen, J},
title = {c-Myc interacts with TRF1/PIN2 and regulates telomere length.},
journal = {Biochemical and biophysical research communications},
volume = {362},
number = {4},
pages = {842-847},
pmid = {17765874},
issn = {0006-291X},
support = {R01 CA092312/CA/NCI NIH HHS/United States ; R01 CA092312-08/CA/NCI NIH HHS/United States ; },
mesh = {DNA-Binding Proteins/*metabolism ; Humans ; Protein Binding ; Protein Interaction Mapping ; Telomere/*genetics/*ultrastructure ; Telomeric Repeat Binding Protein 1/*metabolism ; Transcription Factors/*metabolism ; },
abstract = {Telomere, the end of linear chromosome, is protected by DNA-protein complexes. These complexes cap the linear chromosome and play an important role in the maintenance of genomic stability. TRF1/PIN2, a double-stranded DNA-binding protein is known to regulate telomere length by not only protecting telomere but also blocking the access of telomerase to telomere in cis. To better understand the mechanism through which TRF1/PIN2 regulates telomere length, we performed the yeast two-hybrid screening and identified the transcriptional activator c-Myc as a TRF1/PIN2-binding protein. The c-Myc-TRF1/PIN2 interaction was observed both in vitro and in vivo. This interaction is mediated by the basic helix-loop-helix (bHLH) domain of c-Myc. Importantly, overexpression of this TRF1/PIN2-interacting domain of c-Myc leads to telomere elongation in vivo. Together, these results suggest that c-Myc may be involved in the regulation of telomere length through its direct binding with TRF1/PIN2.},
}
@article {pmid17764968,
year = {2007},
author = {Rotková, G and Sýkorová, E and Fajkus, J},
title = {Characterization of nucleoprotein complexes in plants with human-type telomere motifs.},
journal = {Plant physiology and biochemistry : PPB},
volume = {45},
number = {9},
pages = {716-721},
doi = {10.1016/j.plaphy.2007.07.009},
pmid = {17764968},
issn = {0981-9428},
mesh = {Base Sequence ; DNA, Plant/genetics ; Humans ; Liliaceae/*genetics ; Nucleoproteins/*genetics ; Plant Proteins ; Plants ; Protein Denaturation ; *Telomere ; },
abstract = {A conserved feature of telomeres is the 3'-overhang of their G-rich strand. These G-overhangs function as substrates for telomerase-mediated strand extension, and are critical for end-protection of telomeres. These functions and their regulations are mediated by specific G-overhang binding proteins. In species of the plant order Asparagales, telomere motifs have diverged from a type typical of the plant Arabidopsis thaliana (TTTAGGG)(n) to a type typical of human (TTAGGG)(n). Presumably, this change in motif had an impact on the structure of the telomere and/or the binding of telomeric proteins, including the G-overhang binding proteins. Therefore, we analyse here nucleoprotein complexes formed by protein extracts from plants possessing human-type telomeres (Muscari armeniacum and Scilla peruviana). Proteins were characterized that bind to the G-rich strand of both telomere motifs, or to the ancestral Arabidopsis-type motif alone, but none bound to double-stranded or C-rich complementary strand telomere motifs. We demonstrate the size, sequence-specificity and thermostability of these DNA-binding proteins. We also analysed the formation of complexes from renatured protein fractions after SDS-PAGE (sodium-dodecyl-sulphate polyacrylamide-gel-electrophoresis). We discuss the evolutionary consequences of protein binding flexibility, to act on both ancestral and present telomeric sequences. Of particular interest is that the ancestral repeat, which is thought not to form the telomere, binds the proteins most strongly. These data are discussed in line with other known plant telomere-binding proteins and with the complex nature of the telomere in Asparagales carrying a human-type motif.},
}
@article {pmid17764802,
year = {2008},
author = {Grandin, N and Charbonneau, M},
title = {Protection against chromosome degradation at the telomeres.},
journal = {Biochimie},
volume = {90},
number = {1},
pages = {41-59},
doi = {10.1016/j.biochi.2007.07.008},
pmid = {17764802},
issn = {0300-9084},
mesh = {Animals ; Cell Cycle ; Chromosomes/enzymology/*physiology ; DNA Damage ; Humans ; Recombination, Genetic ; Retroelements/physiology ; Telomerase/*metabolism ; Telomere/*physiology ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomeres, the ends of linear chromosomes, contain repeated TG-rich sequences which, in dividing cells, must be constantly replenished in order to avoid chromosome erosion and, hence, genomic instability. Moreover, unprotected telomeres are prone to end-to-end fusions. Telomerase, a specialized reverse transcriptase with a built-in RNA template, or, in the absence of telomerase, alternative pathways of telomere maintenance are required for continuous cell proliferation in actively dividing cells as well as in cancerous cells emerging in deregulated somatic tissues. The challenge is to keep these free DNA ends masked from the nucleolytic attacks that will readily operate on any DNA double-strand break in the cell, while also allowing the recruitment of telomerase at intervals. Specialized telomeric proteins, as well as DNA repair and checkpoint proteins with a dual role in telomere maintenance and DNA damage signaling/repair, protect the telomere ends from degradation and some of them also function in telomerase recruitment or other aspects of telomere length homeostasis. Phosphorylation of some telomeric proteins by checkpoint protein kinases appears to represent a mode of regulation of telomeric mechanisms. Finally, recent studies have allowed starting to understand the coupling between progression of the replication forks through telomeric regions and the subsequent telomere replication by telomerase, as well as retroaction of telomerase in cis on the firing of nearby replication origins.},
}
@article {pmid17728038,
year = {2008},
author = {Londoño-Vallejo, JA},
title = {Telomere instability and cancer.},
journal = {Biochimie},
volume = {90},
number = {1},
pages = {73-82},
doi = {10.1016/j.biochi.2007.07.009},
pmid = {17728038},
issn = {0300-9084},
mesh = {Aging ; Animals ; Cell Proliferation ; Cell Transformation, Neoplastic ; *Chromosomal Instability ; Epigenesis, Genetic ; *Genomic Instability ; Humans ; Mutation ; Neoplasms/*etiology/genetics ; Telomerase/*metabolism ; Telomere/enzymology/genetics/*physiology ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomeres are required to preserve genome integrity, chromosome stability, nuclear architecture and chromosome pairing during meiosis. Given that telomerase activity is limiting or absent in most somatic tissues, shortening of telomeres during development and aging is the rule. In vitro, telomere length operates as a mechanism to prevent uncontrolled cell growth and therefore defines the proliferation potential of a cell. In vitro, in somatic cells that have lost proliferation control, shortening of telomeres becomes the main source of genome instability leading to genetic or epigenetic changes that may allow cells to become immortal and to acquire tumor phenotypes. In vivo, mice models have indisputably shown both the protective and the promoting role of very short telomeres in cancer development. In humans, although telomere shortening and other types of telomere dysfunction probably contribute to the genome instability often detected in tumors, the specific contributions of such instability to the development of cancer remain largely undetermined.},
}
@article {pmid17726612,
year = {2007},
author = {Deng, W and Tsao, SW and Guan, XY and Cheung, AL},
title = {Microtubule breakage is not a major mechanism for resolving end-to-end chromosome fusions generated by telomere dysfunction during the early process of immortalization.},
journal = {Chromosoma},
volume = {116},
number = {6},
pages = {557-568},
pmid = {17726612},
issn = {0009-5915},
mesh = {Cell Line, Transformed ; Cell Transformation, Viral/genetics ; Chromosomal Instability/*genetics ; *Chromosome Aberrations ; Chromosomes, Human/*genetics ; Humans ; Microtubules/*genetics/pathology ; Models, Genetic ; Telomere/*genetics/pathology ; },
abstract = {Telomeres, the terminal chromosomal structure crucial for maintaining genomic integrity, shorten with deoxyribonucleic acid replications in most human somatic cells. Chromosomes carrying critically short telomeres tend to form end-to-end fusions, which are subject to breakage during cell division. However, it remains obscure how such telomere-mediated fusions are resolved during the process of immortalization, which is an early and indispensable step toward cancer. It has been hypothesized that the breakage could occur at either the microtubule or chromatid, causing numerical or structural chromosome instability, respectively. In this paper, we show that although the distributions of chromosomal segment losses or gains involved in structural aberrations were significantly correlated with the profiles of critically short telomeres in human epithelial cells undergoing immortalization, no such association was detected for whole-chromosome losses or gains in either metaphase or interphase cells. By distinguishing between homologues, we further showed that the specific homologues with critically short telomeres and frequent end-to-end fusions were not preferentially involved in respective whole-chromosome losses or gains. Our data therefore demonstrate that microtubule breakage is not a major mechanism for resolving chromosomal end-to-end fusions in human cells undergoing immortalization. An important implication of this finding is that microtubule-kinetochore attachment is stronger than the chromosome structure.},
}
@article {pmid17726375,
year = {2007},
author = {Gilson, E and Londoño-Vallejo, A},
title = {Telomere length profiles in humans: all ends are not equal.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {6},
number = {20},
pages = {2486-2494},
doi = {10.4161/cc.6.20.4798},
pmid = {17726375},
issn = {1551-4005},
mesh = {Animals ; Humans ; Models, Genetic ; Telomerase/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Telomere length is an important parameter of telomere function since it determines number of aspects controlling chromosome stability and cell division. Since telomeres shorten with age in humans and premature aging syndromes are often associated with the presence of short telomeres, it has been proposed that telomere length is also an important parameter for organismal aging. How mean telomere lengths are determined in humans remains puzzling, but it is clear that genetic and epigenetic factors appear to be of great importance. Experimental evidence obtained from many different organisms has provided the basis for a widely accepted counting mechanism based on a negative feedback loop for telomerase activity at the level of individual telomeres. In addition, recent studies in both normal and pathological contexts point to the existence of chromosome-specific mechanisms of telomere length regulation determining a telomere length profile, which is inherited and maintained throughout life. In this review, we recapitulate the available data, propose a synthetic view of telomere length control mechanisms in humans and suggest new approaches to test current hypotheses.},
}
@article {pmid17725691,
year = {2007},
author = {Huda, N and Tanaka, H and Herbert, BS and Reed, T and Gilley, D},
title = {Shared environmental factors associated with telomere length maintenance in elderly male twins.},
journal = {Aging cell},
volume = {6},
number = {5},
pages = {709-713},
doi = {10.1111/j.1474-9726.2007.00330.x},
pmid = {17725691},
issn = {1474-9718},
support = {AG18736/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; *Aging ; Cardiovascular Diseases/physiopathology ; Cohort Studies ; Diseases in Twins/physiopathology ; Environment ; Humans ; Hypertension/physiopathology ; Male ; Telomere/*physiology/ultrastructure ; Twins, Dizygotic/genetics/*physiology ; Twins, Monozygotic/genetics/*physiology ; },
abstract = {During aging, chromosome ends, or telomeres, gradually erode or shorten with each somatic cell division. Loss of telomere length homeostasis has been linked to age-related disease. Remarkably, specific environmental assaults, both physical and psychological, have been shown to correlate with shortened telomeres. However, the extent that genetic and/or environmental factors may influence telomere length during later stages of lifespan is not known. Telomere length was measured in 686 male US World War II and Korean War veteran monozygotic (MZ) and dizygotic (DZ) twins (including 181 MZ and 125 DZ complete pairs) with a mean age of 77.5 years (range 73-85 years). During the entire process of telomere length measurement, participant age and twin status were completely blinded. White blood cell mean telomere length shortened in this elderly population by 71 base pairs per year (P < 0.0001). We observed no evidence of heritable effects in this elderly population on telomere length maintenance, but rather find that telomere length was largely associated with shared environmental factors (P < 0.0001). Additionally, we found that individuals with hypertension and cardiovascular disease had significantly shorter telomeres (P = 0.0025 and 0.002, respectively). Our results emphasize that shared environmental factors can have a primary impact on telomere length maintenance in elderly humans.},
}
@article {pmid17724078,
year = {2007},
author = {Cullen, JK and Hussey, SP and Walker, C and Prudden, J and Wee, BY and Davé, A and Findlay, JS and Savory, AP and Humphrey, TC},
title = {Break-induced loss of heterozygosity in fission yeast: dual roles for homologous recombination in promoting translocations and preventing de novo telomere addition.},
journal = {Molecular and cellular biology},
volume = {27},
number = {21},
pages = {7745-7757},
pmid = {17724078},
issn = {0270-7306},
support = {G0700730/MRC_/Medical Research Council/United Kingdom ; MC_U142784382/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Alleles ; Base Sequence ; Chromosomes, Fungal/metabolism ; Crossing Over, Genetic ; *DNA Breaks, Double-Stranded ; DNA Repair ; Genetic Markers ; Loss of Heterozygosity/*genetics ; Models, Genetic ; Molecular Sequence Data ; Multiprotein Complexes/metabolism ; Mutation/genetics ; Phylogeny ; Rad51 Recombinase/metabolism ; *Recombination, Genetic ; Schizosaccharomyces/cytology/*genetics ; Schizosaccharomyces pombe Proteins/metabolism ; Telomere/*metabolism ; *Translocation, Genetic ; },
abstract = {Loss of heterozygosity (LOH), a causal event in tumorigenesis, frequently encompasses multiple genetic loci and whole chromosome arms. However, the mechanisms leading to such extensive LOH are poorly understood. We investigated the mechanisms of DNA double-strand break (DSB)-induced extensive LOH by screening for auxotrophic marker loss approximately 25 kb distal to an HO endonuclease break site within a nonessential minichromosome in Schizosaccharomyces pombe. Extensive break-induced LOH was infrequent, resulting from large translocations through both allelic crossovers and break-induced replication. These events required the homologous recombination (HR) genes rad32(+), rad50(+), nbs1(+), rhp51(+), rad22(+), rhp55(+), rhp54(+), and mus81(+). Surprisingly, LOH was still observed in HR mutants, which resulted predominantly from de novo telomere addition at the break site. De novo telomere addition was most frequently observed in rad22Delta and rhp55Delta backgrounds, which disrupt HR following end resection. Further, levels of de novo telomere addition, while increased in ku70Delta rhp55Delta strains, were reduced in exo1Delta rhp55Delta and an rhp55Delta strain overexpressing rhp51. These findings support a model in which HR prevents de novo telomere addition at DSBs by competing for resected ends. Together, these results suggest that the mechanisms of break-induced LOH may be predicted from the functional status of the HR machinery.},
}
@article {pmid17715303,
year = {2007},
author = {Martín, V and Du, LL and Rozenzhak, S and Russell, P},
title = {Protection of telomeres by a conserved Stn1-Ten1 complex.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {104},
number = {35},
pages = {14038-14043},
pmid = {17715303},
issn = {0027-8424},
support = {R01 CA077325/CA/NCI NIH HHS/United States ; R01 GM059447/GM/NIGMS NIH HHS/United States ; CA77325/CA/NCI NIH HHS/United States ; GM59447/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes, Fungal/genetics ; Conserved Sequence ; DNA Replication/genetics ; DNA, Fungal/genetics ; Haploidy ; Schizosaccharomyces/*genetics ; Schizosaccharomyces pombe Proteins/*genetics ; Shelterin Complex ; Telomere/*genetics ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Telomeres are specialized chromatin structures that protect chromosome ends. Critical among telomere proteins are those that bind the telomeric single-strand DNA (ssDNA) overhangs. These proteins are thought to differ among eukaryotes. Three interacting proteins (Cdc13, Stn1, and Ten1) associate with the telomeric overhang in budding yeast, a single protein known as Pot1 (protection of telomeres-1) performs this function in fission yeast, and a two-subunit complex consisting of POT1 and TPP1 associates with telomeric ssDNA in humans. Cdc13 and Pot1 have related oligonucleotide/oligosaccharide-binding fold (OB-fold) domains that bind the telomeric ssDNA overhang. Here we show that Schizosaccharomyces pombe has Stn1- and Ten1-like proteins that are essential for chromosome end protection. Stn1 orthologs exist in all species that have Pot1, whereas Ten1-like proteins can be found in all fungi. Fission yeast Stn1 and Ten1 localize at telomeres in a manner that correlates with the length of the ssDNA overhang, suggesting that they specifically associate with the telomeric ssDNA. Unlike in budding yeast, in which Cdc13, Stn1, and Ten1 all interact, fission yeast Stn1 and Ten1 associate with each other, but not with Pot1. Our findings suggest that two separate protein complexes are required for chromosome end protection in fission yeast. Structural profiling studies detect OB-fold domains in Stn1 and Ten1 orthologs, indicating that protection of telomeres by multiple proteins with OB-fold domains is conserved in eukaryotic evolution.},
}
@article {pmid17714958,
year = {2007},
author = {Walen, KH},
title = {Origin of diplochromosomal polyploidy in near-senescent fibroblast cultures: heterochromatin, telomeres and chromosomal instability (CIN).},
journal = {Cell biology international},
volume = {31},
number = {12},
pages = {1447-1455},
doi = {10.1016/j.cellbi.2007.06.015},
pmid = {17714958},
issn = {1065-6995},
mesh = {Biomarkers, Tumor/genetics/metabolism ; Cell Cycle ; Cell Line/metabolism/ultrastructure ; Cellular Senescence/*genetics ; Centromere/genetics/metabolism/ultrastructure ; Chromosomal Instability/*genetics ; Chromosome Segregation ; Chromosomes, Human/genetics/ultrastructure ; Diploidy ; Female ; Fibroblasts/physiology/*ultrastructure ; Heterochromatin/genetics/*ultrastructure ; Humans ; *Polyploidy ; Telomere/genetics/*ultrastructure ; Translocation, Genetic/genetics ; },
abstract = {The near-senescence associated phenomena of increases in cells with chromosomal damage (CIN) and in endopolyploid mitotic cells were analyzed for possible inter-relationships by cytogenetics. Gross chromosomal abnormalities in all phases of mitosis were analyzed in situ. Hetrochromatization of telomeres, centromeres and interstitial chromatin regions (i.e., chromocenters/SAHF) were shown to be specific occurrences in the near-senescent phase. Stickiness between such chromatin regions caused breakage/fragmentation by anaphase-pulls on clumped chromosomes. Gluey heterochromatin is therefore, seen as a cause of CIN in near-senescence. Detrimental effects on chromosomes from heterochromatin have been observed for decades, and can be explained from chromatin remodeling in epigenetics. A consequence of genomic damage was re-replication to polyploidy of arrest-escaped cells with G2/M-DNA content. This second synthetic period produced diplochromosomal cells that cycled by bi-polar division into genome reduced cells. This sequence from h-chromatization to CIN and further to cycling endopolyploidy is believed to be a basic mechanism for the production of genetic variability in neoplasia.},
}
@article {pmid17709220,
year = {2007},
author = {Uziel, O and Singer, JA and Danicek, V and Sahar, G and Berkov, E and Luchansky, M and Fraser, A and Ram, R and Lahav, M},
title = {Telomere dynamics in arteries and mononuclear cells of diabetic patients: effect of diabetes and of glycemic control.},
journal = {Experimental gerontology},
volume = {42},
number = {10},
pages = {971-978},
doi = {10.1016/j.exger.2007.07.005},
pmid = {17709220},
issn = {0531-5565},
mesh = {Adult ; Aged ; Aged, 80 and over ; Blood Glucose/*metabolism ; Cellular Senescence/genetics ; Coronary Artery Bypass ; Diabetes Mellitus/blood/*genetics ; Diabetes Mellitus, Type 1/blood/genetics ; Diabetes Mellitus, Type 2/blood/genetics ; Female ; Humans ; Leukocytes, Mononuclear/*ultrastructure ; Male ; Mammary Arteries/ultrastructure ; Middle Aged ; Telomere/*ultrastructure ; },
abstract = {Telomeres serve as a mitotic clock and biological marker of senescence. Diabetes mellitus (DM) is associated with damage to target organs and premature aging. We assessed the effect of glycemic control on telomere dynamics in arterial cells of 58 patients undergoing coronary artery bypass and in mononuclear blood cells of other diabetic (32 type I and 47 type II) patients comparing well controlled to uncontrolled patients. All were compared to age-dependent curve of healthy controls. Telomeres were significantly shorter in the arteries of diabetic versus non-diabetic patients (p=0.049) and in mononuclear cells of both type I and type II diabetes. In all study groups good glycemic control attenuated shortening of the telomeres. In arterial cells good glycemic control attenuated, but not abolished, the telomere shortening. In type II DM the mononuclear telomere attrition was completely prevented by adequate glycemic control. Telomere shortening in mononuclear cells of type I diabetic patients was attenuated but not prevented by good glycemic control. Results of this study suggest that diabetes is associated with premature cellular senescence which can be prevented by good glycemic control in type II DM and reduced in type I DM.},
}
@article {pmid17708685,
year = {2007},
author = {Tallen, G and Soliman, MA and Riabowol, K},
title = {The cancer-aging interface and the significance of telomere dynamics in cancer therapy.},
journal = {Rejuvenation research},
volume = {10},
number = {3},
pages = {387-395},
doi = {10.1089/rej.2007.0598},
pmid = {17708685},
issn = {1549-1684},
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; *Aging ; Child ; Child, Preschool ; Humans ; Immune System ; Infant ; Infant, Newborn ; Life Expectancy ; *Longevity ; Middle Aged ; Neoplasms/*pathology/*therapy ; Telomere/*ultrastructure ; },
abstract = {The efficacy of most cancer treatments depends markedly on the high replication rate of cancer cells, a characteristic frequently observed in neoplasms with higher grades of malignancy. Yet, the same characteristic is present in many normal regenerative tissues of the body, which makes them susceptible to the cytotoxic effects of chemotherapeutics and accounts for many of the toxic side effects of these drugs. In response to cell killing by chemotherapeutics, normal regenerative tissues replicate at a faster rate to regenerate, resulting in accelerated telomere attrition and leaving different cell populations with telomeres shorter than they would normally have in the absence of treatment. This accelerated erosion has implications regarding the recurrence of cancers at secondary sites because reduced replicative ability may compromise effective subsequent immune responses. In this review we discuss recent reports describing the effect of chemotherapeutics on telomere loss, how this may impact healthy tissues in an age-dependent manner, and describe in brief emerging cancer treatments that may avoid this telomere erosion effect.},
}
@article {pmid17707063,
year = {2007},
author = {Shao, L and Wood, CG and Zhang, D and Tannir, NM and Matin, S and Dinney, CP and Wu, X},
title = {Telomere dysfunction in peripheral lymphocytes as a potential predisposition factor for renal cancer.},
journal = {The Journal of urology},
volume = {178},
number = {4 Pt 1},
pages = {1492-1496},
doi = {10.1016/j.juro.2007.05.112},
pmid = {17707063},
issn = {0022-5347},
support = {CA98897/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Aged ; CD4-Positive T-Lymphocytes/pathology ; CD8-Positive T-Lymphocytes/pathology ; Carcinoma, Renal Cell/*genetics/pathology/surgery ; Cell Line ; Female ; Genetic Predisposition to Disease/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Kidney Neoplasms/*genetics/pathology/surgery ; Laser Scanning Cytometry ; Lymphocytes/*pathology ; Male ; Middle Aged ; Neoplasm Staging ; Reference Values ; Risk ; Telomere/*diagnostic imaging ; Ultrasonography ; },
abstract = {PURPOSE: Genetic integrity is maintained in part by the architecture of telomeres. We previously developed a laser scanning cytometry based quantitative fluorescence in situ hybridization assay to assess telomere length in peripheral blood lymphocytes. In this study we modified the assay by incorporating 9 control cell lines to normalize telomere length.<br><br>MATERIALS AND METHODS: We applied this assay to 65 patients with renal cell carcinoma, and 65 age, sex and ethnicity matched controls. For each subject we measured telomere length in CD4+ T cells, CD8+ T cells and overall peripheral blood lymphocytes.<br><br>RESULTS: For cases vs controls mean normalized telomere length +/- SD was 0.84 +/- 0.15 vs 0.95 +/- 0.18 for CD4+ T cells, 0.80 +/- 0.21 vs 0.95 +/- 0.22 for CD8+ T cells and 0.88 +/- 0.25 vs 0.99 +/- 0.22 for overall peripheral blood lymphocytes (each p <0.05). After adjustment for patient age, sex, ethnicity and smoking status, and using 75% of telomere length in controls as a cutoff point, short telomere length in CD4+ T cells was associated with a significantly increased risk of renal cell carcinoma (OR 3.08, 95% CI 1.14-8.34). Compared to individuals within the highest quartile of telomere length the OR for those within the 3rd, 2nd and 1st quartiles was 1.81 (95% CI 0.54-6.08), 2.15 (95% CI 0.67-6.91) and 5.41 (95% CI 1.78-16.4), respectively (p for trend <0.01). Similar trends were observed in CD8+ T cells and overall peripheral blood lymphocytes. In controls there was no significant difference among the telomere lengths of CD4+ T cells, CD8+ T cells and overall PBLs.<br><br>CONCLUSIONS: Our data argue against the possibility that telomere length difference between cancer cases and controls may be due to the variations of lymphocyte subpopulation or clonal expansion. Our data strongly support the hypothesis that telomere shortening in peripheral blood lymphocytes is a genetic predisposing factor for cancer.},
}
@article {pmid17705236,
year = {2007},
author = {Gerard-Blanluet, M and Pipiras, E and Levaillant, JM and Joye, N and Koubi, V and Kanafani, S and Vergnaud, A and Verloes, A and Gonzales, M and Jeny, R and Benzacken, B},
title = {Prenatal detection of Pierre Robin sequence with deletion Xp and additional trisomy 14q by telomere screening.},
journal = {Prenatal diagnosis},
volume = {27},
number = {11},
pages = {1062-1063},
doi = {10.1002/pd.1818},
pmid = {17705236},
issn = {0197-3851},
mesh = {Abortion, Eugenic ; Adult ; *Chromosome Deletion ; *Chromosomes, Human, Pair 14 ; *Chromosomes, Human, X ; Facial Asymmetry/congenital/diagnosis/genetics ; Female ; Genetic Testing ; Humans ; Pierre Robin Syndrome/*diagnosis/genetics ; Pregnancy ; Prenatal Diagnosis ; Telomere/*genetics ; Trisomy/*diagnosis/genetics ; },
}
@article {pmid17704807,
year = {2008},
author = {Datta, A and Nicot, C},
title = {Telomere attrition induces a DNA double-strand break damage signal that reactivates p53 transcription in HTLV-I leukemic cells.},
journal = {Oncogene},
volume = {27},
number = {8},
pages = {1135-1141},
doi = {10.1038/sj.onc.1210718},
pmid = {17704807},
issn = {1476-5594},
support = {R01 CA106258/CA/NCI NIH HHS/United States ; R01CA106258/CA/NCI NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/physiology ; Cell Line, Transformed ; Cell Line, Tumor ; Cellular Senescence/genetics ; *DNA Breaks, Double-Stranded ; DNA Damage/genetics ; DNA-Binding Proteins/physiology ; Gene Expression Regulation, Neoplastic/physiology ; *Human T-lymphotropic virus 1 ; Humans ; Jurkat Cells ; Leukemia-Lymphoma, Adult T-Cell/genetics/pathology/*virology ; Nuclear Proteins/physiology ; Protein Serine-Threonine Kinases/physiology ; Proto-Oncogene Proteins/physiology ; Signal Transduction/*genetics ; Telomere/*pathology ; Tumor Suppressor Protein p53/biosynthesis/*genetics ; Tumor Suppressor Proteins/physiology ; },
abstract = {Persistent inhibition of telomerase induces a severe telomere shortening in human T-cell leukemia virus type-1-infected cells which signals a DNA double-strand break damage response, formation of telomere dysfunction-induced foci and activates the ATM pathway. In turn, activation of ATM and its downstream effectors led to an increased phosphorylation and acetylation on specific residues of p53 known to be involved in transcriptional activation. Disruption of Mdm2-p53 complexes coupled with increased proteasomal degradation of MDMX further enhanced reactivation of p53 transcription, ultimately leading to senescence of tumor cells. Induction of senescence in these T-cells was associated with an increased expression of p21, p16 and activation of GSK3beta. Our results support the cancer-aging model and demonstrate that the halt of aging in cancer cells can be reversed through reactivation of p53.},
}
@article {pmid17697745,
year = {2007},
author = {Baerlocher, GM and Sloand, EM and Young, NS and Lansdorp, PM},
title = {Telomere length in paroxysmal nocturnal hemoglobinuria correlates with clone size.},
journal = {Experimental hematology},
volume = {35},
number = {12},
pages = {1777-1781},
doi = {10.1016/j.exphem.2007.06.010},
pmid = {17697745},
issn = {0301-472X},
support = {AI29524/AI/NIAID NIH HHS/United States ; },
mesh = {Flow Cytometry ; Hemoglobinuria, Paroxysmal/*genetics ; Humans ; *Telomere ; },
abstract = {OBJECTIVE: To study if telomere length can be used as a surrogate marker for the mitotic history in normal and affected hematopoietic cells from patients with paroxysmal nocturnal hemoglobinuria (PNH).<br><br>METHODS: The telomere length was measured by automated multicolor flow fluorescence in situ hybridization in glycosyl-phosphatidyl-inositol anchored protein (GPI)-negative and GPI-positive peripheral blood leukocytes. Eleven patients were studied, two with predominantly hemolytic PNH and nine with PNH associated with marrow failure.<br><br>RESULTS: Telomere length in GPI-negative cells was significantly shorter than in GPI-positive cells of the same patient (p < 0.01, n = 11). The difference in telomere length (telomere length in GPI-positive minus telomere length in GPI-negative cells) correlated with the percentage of GPI-negative white blood cells.<br><br>CONCLUSION: Our results support the hypothesis that telomere length is correlated to the replicative history of GPI-positive and GPI-negative cells and warrant further studies of telomere length in relation to disease progression in PNH.},
}
@article {pmid17694070,
year = {2007},
author = {Wu, Y and Xiao, S and Zhu, XD},
title = {MRE11-RAD50-NBS1 and ATM function as co-mediators of TRF1 in telomere length control.},
journal = {Nature structural &amp; molecular biology},
volume = {14},
number = {9},
pages = {832-840},
doi = {10.1038/nsmb1286},
pmid = {17694070},
issn = {1545-9993},
mesh = {Acid Anhydride Hydrolases ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*physiology ; Cell Line ; DNA Repair Enzymes/*physiology ; DNA-Binding Proteins/*physiology ; Humans ; MRE11 Homologue Protein ; Nuclear Proteins/*physiology ; Phosphorylation ; Protein Binding ; Protein Serine-Threonine Kinases/*physiology ; *Telomere ; Telomeric Repeat Binding Protein 1/*physiology ; Tumor Suppressor Proteins/*physiology ; },
abstract = {Human telomeres are associated with ATM and the protein complex consisting of MRE11, RAD50 and NBS1 (MRN), which are central to maintaining genomic stability. Here we show that when targeted to telomeres, wild-type RAD50 downregulates telomeric association of TRF1, a negative regulator of telomere maintenance. TRF1 binding to telomeres is upregulated in cells deficient in NBS1 or under ATM inhibition. The TRF1 association with telomeres induced by ATM inhibition is abrogated in cells lacking MRE11 or NBS1, suggesting that MRN and ATM function in the same pathway controlling TRF1 binding to telomeres. The ability of TRF1 to interact with telomeric DNA in vitro is impaired by ATM-mediated phosphorylation. We propose that MRN is required for TRF1 phosphorylation by ATM and that such phosphorylation results in the release of TRF1 from telomeres, promoting telomerase access to the ends of telomeres.},
}
@article {pmid17693401,
year = {2007},
author = {Zhong, ZH and Jiang, WQ and Cesare, AJ and Neumann, AA and Wadhwa, R and Reddel, RR},
title = {Disruption of telomere maintenance by depletion of the MRE11/RAD50/NBS1 complex in cells that use alternative lengthening of telomeres.},
journal = {The Journal of biological chemistry},
volume = {282},
number = {40},
pages = {29314-29322},
doi = {10.1074/jbc.M701413200},
pmid = {17693401},
issn = {0021-9258},
mesh = {Acid Anhydride Hydrolases ; Cell Cycle Proteins/*metabolism ; Cell Line, Tumor ; DNA Repair ; DNA Repair Enzymes/*metabolism ; DNA-Binding Proteins/*metabolism ; Humans ; In Situ Hybridization, Fluorescence ; MRE11 Homologue Protein ; Nuclear Proteins/*metabolism ; RNA/metabolism ; RNA, Small Interfering/metabolism ; Telomere/metabolism/*ultrastructure ; Telomere-Binding Proteins/metabolism ; Transfection ; },
abstract = {Immortalized human cells are able to maintain their telomeres by telomerase or by a recombination-mediated DNA replication mechanism known as alternative lengthening of telomeres (ALT). We showed previously that overexpression of Sp100 protein can suppress ALT and that this was associated with sequestration of the MRE11/RAD50/NBS1 (MRN) recombination protein complex by Sp100. In the present study, we determined whether MRN proteins are required for ALT activity. ALT cells were depleted of MRN proteins by small hairpin RNA-mediated knockdown, which was maintained for up to 100 population doublings. Knockdown of NBS1 had no effect on the level of RAD50 or MRE11, but knockdown of RAD50 also depleted cells of NBS1, and knockdown of MRE11 depleted cells of all three MRN proteins. Depletion of NBS1, with or without depletion of other members of the complex, resulted in inhibition of ALT-mediated telomere maintenance, as evidenced by decreased numbers of ALT-associated promyelocytic leukemia bodies and decreased telomere length. In some clones there was an initial period of rapid shortening followed by stabilization of telomere length, whereas in others there was continuous shortening at a rate within the reported range for normal human somatic cells lacking a telomere maintenance mechanism. In contrast, depletion of NBS1 in telomerase-positive cells did not result in telomere shortening. A recent study showed that NBS1 was required for the formation of extrachromosomal telomeric circles (Compton, S. A., Choi, J. H., Cesare, A. J., Ozgur, S., and Griffith, J. D. (2007) Cancer Res. 67, 1513-1519), also a marker for ALT. We conclude that the MRN complex, and especially NBS1, is required for the ALT mechanism.},
}
@article {pmid17687332,
year = {2007},
author = {Denchi, EL and de Lange, T},
title = {Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1.},
journal = {Nature},
volume = {448},
number = {7157},
pages = {1068-1071},
doi = {10.1038/nature06065},
pmid = {17687332},
issn = {1476-4687},
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/*metabolism ; *DNA Damage ; *DNA Repair ; DNA-Binding Proteins/antagonists &amp; inhibitors/deficiency/genetics/*metabolism ; Embryo, Mammalian/cytology ; Fibroblasts ; Gene Deletion ; Mice ; Models, Genetic ; Protein Serine-Threonine Kinases/deficiency/genetics/*metabolism ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 2/deficiency/genetics/*metabolism ; Tumor Suppressor Proteins/deficiency/genetics/*metabolism ; },
abstract = {When telomeres are rendered dysfunctional through replicative attrition of the telomeric DNA or by inhibition of shelterin, cells show the hallmarks of ataxia telangiectasia mutated (ATM) kinase signalling. In addition, dysfunctional telomeres might induce an ATM-independent pathway, such as ataxia telangiectasia and Rad3-related (ATR) kinase signalling, as indicated by the phosphorylation of the ATR target CHK1 in senescent cells and the response of ATM-deficient cells to telomere dysfunction. However, because telomere attrition is accompanied by secondary DNA damage, it has remained unclear whether there is an ATM-independent pathway for the detection of damaged telomeres. Here we show that damaged mammalian telomeres can activate both ATM and ATR and address the mechanism by which the shelterin complex represses these two important DNA damage signalling pathways. We analysed the telomere damage response on depletion of either or both of the shelterin proteins telomeric repeat binding factor 2 (TRF2) and protection of telomeres 1 (POT1) from cells lacking ATM and/or ATR kinase signalling. The data indicate that TRF2 and POT1 act independently to repress these two DNA damage response pathways. TRF2 represses ATM, whereas POT1 prevents activation of ATR. Unexpectedly, we found that either ATM or ATR signalling is required for efficient non-homologous end-joining of dysfunctional telomeres. The results reveal how mammalian telomeres use multiple mechanisms to avoid DNA damage surveillance and provide an explanation for the induction of replicative senescence and genome instability by shortened telomeres.},
}
@article {pmid17681636,
year = {2007},
author = {Hsu, CP and Ko, JL and Shai, SE and Lee, LW},
title = {Modulation of telomere shelterin by TRF1 [corrected] and TRF2 interacts with telomerase to maintain the telomere length in non-small cell lung cancer.},
journal = {Lung cancer (Amsterdam, Netherlands)},
volume = {58},
number = {3},
pages = {310-316},
doi = {10.1016/j.lungcan.2007.06.019},
pmid = {17681636},
issn = {0169-5002},
mesh = {Aged ; Aged, 80 and over ; Antigens, CD/*metabolism ; Carcinoma, Non-Small-Cell Lung/genetics/*metabolism ; Enzyme Activation ; Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms/genetics/*metabolism ; Male ; Middle Aged ; Protein Binding ; Receptors, Transferrin/*metabolism ; Shelterin Complex ; Telomerase/*metabolism ; Telomere/*genetics ; Telomere-Binding Proteins/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {Our previous report demonstrated good correlations between the expressions of h-TERT and its associated genes, such as c-Myc, TRF1 and TRF2. To observe the interaction between telomerase activity and expression of its associated genes in regulation of the telomere restriction fragment length (TRFL) in non-small cell lung cancer (NSCLC), 79 NSCLC specimens were examined. Telomerase activity, h-TERT, TRF1 and TRF2 genes expression were observed in 60.8, 66.7, 74.7, and 83.5% of the tumour tissues, respectively. The TRFL were shorter in both tumour tissues and telomerase positive tissues, as compared to their counterparts. The t/n-TRFLR (tumour-to-normal TRFL ratio) was also lower in telomerase positive tissues. When telomerase was negative, the t/n-TRFLR was lower in both TRF1 positive and TFR2 positive. However, when telomerase was positive, the t/n-TRFLR was only lower in the TFR2 positive group. When t/n-TRFLR level was equal to or less than 75%, the majority of the specimens became TRF1 and TRF2 positive. To explain these findings, our hypothesis is that when the TRF length becomes shorter during tumour progression, the tumour cells can sustain a better tolerance to shorter telomere with the help of both TRF1 and TRF2, but without immediate activation of the telomerase. However, when the TRF length reaches a critical level, changing the telomere shelterin by persistent expression of the TRF2, which in combination with telomerase activation reverses the telomere shortening.},
}
@article {pmid17679950,
year = {2007},
author = {Konomi, K and Joyce, NC},
title = {Age and topographical comparison of telomere lengths in human corneal endothelial cells.},
journal = {Molecular vision},
volume = {13},
number = {},
pages = {1251-1258},
pmid = {17679950},
issn = {1090-0535},
support = {R01 EY05767/EY/NEI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aging/*physiology ; Cell Separation ; Child ; Endothelial Cells/cytology/*metabolism ; Endothelium, Corneal/*cytology/*metabolism ; Fluorescein-5-isothiocyanate/metabolism ; Humans ; Peptide Nucleic Acids/metabolism ; Telomere/*metabolism ; },
abstract = {PURPOSE: Human corneal endothelium exhibits both age-related and topographical differences in relative proliferative capacity and in senescence characteristics. The purpose of these studies was to compare telomere lengths in human corneal endothelial cells (HCEC) from the central and peripheral areas of corneas from young and older donors to determine whether these changes may be due to replicative senescence or to stress-induced premature senescence.<br><br>METHODS: Pairs of corneas from five young (<30 years old) and six older donors (>65 years old) were separated into central and peripheral areas using a 9.5 mm diameter trephine to remove scleral tissue and a 6.0 mm diameter trephine to mark the central-peripheral boundary. One of the pair of corneas was cut into quarters and stained with a peptide nucleic acid (PNA)/fluorescein isothiocyanate (PNA/FITC) probe that specifically binds to telomere repeats. HCEC from the central (0-6.0 mm) and peripheral areas (6.0-9.5 mm) were isolated from the second cornea, mounted on slides by Cytospin, and stained with the PNA/FITC probe. Fluorescence confocal microscopy was used to obtain digital images. The average FITC intensity of nuclei was compared between the central and peripheral areas within and between the two age groups. Ccl185 and 1301 cells were analyzed as controls. Student's unpaired t-test was used to determine the statistical significance of the data.<br><br>RESULTS: Average FITC intensity from the central endothelium was 205.8+/-4.2 (younger) and 194.2+/-10.5 (older) and from the peripheral endothelium was 208.1+/-9.3 (younger) and 195.9+/-10.8 (older). Average intensity of single cells isolated from central endothelium was 113.9+/-31.1 (younger) and 107.9+/-26.1 (older) and from the periphery was 109.9+/-12.0 (younger) and 106.9+/-32.4 (older). Average FITC intensity of Ccl185 cells and 1301 cells was 50.5+/-5.0 and 206.9+/-19.4, respectively. Comparison of the results indicates no statistically significant difference between the central and peripheral areas within each group or between the young and older age group.<br><br>CONCLUSIONS: Results indicate that the age-related and topographical reduction in relative proliferative capacity and senescence characteristics observed in HCEC are not due to replicative senescence caused by critically short telomeres but implicate stress-induced premature senescence as a cause of these clinically important changes.},
}
@article {pmid17678615,
year = {2007},
author = {Lira, CB and de Siqueira Neto, JL and Khater, L and Cagliari, TC and Peroni, LA and dos Reis, JR and Ramos, CH and Cano, MI},
title = {LaTBP1: a Leishmania amazonensis DNA-binding protein that associates in vivo with telomeres and GT-rich DNA using a Myb-like domain.},
journal = {Archives of biochemistry and biophysics},
volume = {465},
number = {2},
pages = {399-409},
doi = {10.1016/j.abb.2007.06.020},
pmid = {17678615},
issn = {0003-9861},
mesh = {Amino Acid Sequence ; Animals ; Binding Sites ; DNA/*chemistry ; DNA-Binding Proteins/*chemistry ; Leishmania/*metabolism ; Molecular Sequence Data ; Oncogene Proteins v-myb/*chemistry ; Protein Binding ; Protein Structure, Tertiary ; Telomere/*chemistry ; },
abstract = {Different species of Leishmania can cause a variety of medically important diseases, whose control and treatment are still health problems. Telomere binding proteins (TBPs) have potential as targets for anti-parasitic chemotherapy because of their importance for genome stability and cell viability. Here, we describe LaTBP1 a protein that has a Myb-like DNA-binding domain, a feature shared by most double-stranded telomeric proteins. Binding assays using full-length and truncated LaTBP1 combined with spectroscopy analysis were used to map the boundaries of the Myb-like domain near to the protein only tryptophan residue. The Myb-like domain of LaTBP1 contains a conserved hydrophobic cavity implicated in DNA-binding activity. A hypothetical model helped to visualize that it shares structural homology with domains of other Myb-containing proteins. Competition assays and chromatin immunoprecipitation confirmed the specificity of LaTBP1 for telomeric and GT-rich DNAs, suggesting that LaTBP1 is a new TBP.},
}
@article {pmid17675845,
year = {2007},
author = {Delany, ME and Gessaro, TM and Rodrigue, KL and Daniels, LM},
title = {Chromosomal mapping of chicken mega-telomere arrays to GGA9, 16, 28 and W using a cytogenomic approach.},
journal = {Cytogenetic and genome research},
volume = {117},
number = {1-4},
pages = {54-63},
doi = {10.1159/000103165},
pmid = {17675845},
issn = {1424-859X},
mesh = {Animals ; Cell Lineage ; Cells, Cultured ; Chickens/*genetics ; Cytogenetic Analysis ; *Genomics ; In Situ Hybridization ; *Physical Chromosome Mapping ; Telomere/*genetics ; },
abstract = {Four mega-telomere loci were mapped to chicken chromosomes 9, 16, 28, and the W sex chromosome by dual-color fluorescence in situ hybridization using a telomeric sequence probe and BAC clones previously assigned to chicken chromosomes. The in-common features of the mega-telomere chromosomes are that microchromosomes are involved rather than macrochromosomes; in three cases (9, 16, 28) acrocentrics are involved with the mega-telomeres mapping to the p arms. Three of the four chromosomes (9, 16, W) encode tandem repeats which in two cases (9 and 16) involve the ribosomal DNA arrays (the 5S and 18S-5.8S-28S gene repeats, respectively). All involved chromosomes have a typical-sized telomere on the opposite terminus. Intra- and interindividual variation for mega-telomere distribution are discussed in terms of karyotype abnormalities and the potential for mitotic instability of some telomeres. The diversity and distribution of telomere array quantity in the chicken genome should be useful in contributing to research related to telomere length regulation - how and by what mechanism genomes and individual chromosomes establish and maintain distinct sets of telomere array sizes, as well as for future studies related to stability of the chicken genome affecting development, growth, cellular lifespan and disease. An additional impact of this study includes the listing of BAC clones (26 autosomal and six W BACs tested) that were cytogenetically verified; this set of BACs provide a useful tool for future cytogenetic analyses of the microchromosomes.},
}
@article {pmid17675446,
year = {2007},
author = {Fingerman, IM and Li, HC and Briggs, SD},
title = {A charge-based interaction between histone H4 and Dot1 is required for H3K79 methylation and telomere silencing: identification of a new trans-histone pathway.},
journal = {Genes &amp; development},
volume = {21},
number = {16},
pages = {2018-2029},
pmid = {17675446},
issn = {0890-9369},
support = {T32 CA009634/CA/NCI NIH HHS/United States ; R01 GM074183/GM/NIGMS NIH HHS/United States ; CA09634/CA/NCI NIH HHS/United States ; GM74183/GM/NIGMS NIH HHS/United States ; R01 GM074183-03/GM/NIGMS NIH HHS/United States ; R01 GM074183-02/GM/NIGMS NIH HHS/United States ; R01 GM074183-04/GM/NIGMS NIH HHS/United States ; R01 GM074183-01A1/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acids, Basic/chemistry ; Animals ; Binding Sites/genetics ; Cell Line ; Chickens ; Electrochemistry ; *Gene Silencing ; Histone-Lysine N-Methyltransferase ; Histones/chemistry/genetics/*metabolism ; Humans ; In Vitro Techniques ; Methylation ; Methyltransferases/*metabolism ; Models, Biological ; Nuclear Proteins/metabolism ; Recombinant Fusion Proteins/chemistry/genetics/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Substrate Specificity ; Telomere/*genetics/*metabolism ; },
abstract = {Saccharomyces cerevisiae cells lacking Dot1 exhibit a complete loss of H3K79 methylation and defects in heterochromatin-mediated silencing. To further understand the mechanism of Dot1-mediated methylation, the substrate requirement of Dot1 was determined. This analysis found that Dot1 requires histone H4 for in vitro methyltransferase activity and the histone H4 tail for Dot1-mediated methylation in yeast. Mutational analyses demonstrated that the basic patch residues (R(17)H(18)R(19)) of the histone H4 N-terminal tail are required for Dot1 methyltransferase activity in vitro as well as Dot1-mediated histone H3K79 methylation in vivo. In vitro binding assays show that Dot1 can interact with the H4 N-terminal tail via the basic patch residues. Furthermore, an acidic patch at the C terminus of Dot1 is required for histone H4 tail binding in vitro, histone H3K79 di- and trimethylation in vivo, and proper telomere silencing. Our data suggest a novel trans-histone regulatory pathway whereby charged residues of one histone are required for the modification of another histone. These findings not only provide key insights into the mechanism of Dot1 histone methylation but also illustrate how chromatin-modifying enzymes engage their nucleosomal substrates in vivo.},
}
@article {pmid17674153,
year = {2007},
author = {Siderakis, M and Tarsounas, M},
title = {Telomere regulation and function during meiosis.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {15},
number = {5},
pages = {667-679},
pmid = {17674153},
issn = {0967-3849},
support = {A6444/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Animals ; Female ; Humans ; Male ; Meiosis/*genetics/physiology ; Mice ; Models, Genetic ; Oogenesis/genetics/physiology ; Spermatogenesis/genetics/physiology ; Telomerase/deficiency/genetics ; Telomere/*genetics ; },
abstract = {Telomeres are essential for genomic stability and their dysfunction has been implicated in cancer and ageing. The most prominent function of the telomeres is to protect chromosome ends against degradation and fusion, which, in turn, requires maintenance of telomere DNA to a critical length that allows assembly of end-capping structures. During early meiosis, telomeres play the distinctive function of anchoring chromosomes to the inner nuclear membrane. Subsequently, as a consequence of the nuclear membrane polarization, telomeres cluster together into a bouquet configuration, which facilitates pairing and recombination of the homologous chromosomes. Here we review how the two fundamental aspects of telomere maintenance, elongation and protection, contribute to the essential functions performed by telomeres during meiosis.},
}
@article {pmid17671506,
year = {2007},
author = {Lydeard, JR and Jain, S and Yamaguchi, M and Haber, JE},
title = {Break-induced replication and telomerase-independent telomere maintenance require Pol32.},
journal = {Nature},
volume = {448},
number = {7155},
pages = {820-823},
doi = {10.1038/nature06047},
pmid = {17671506},
issn = {1476-4687},
support = {R01 GM020056-32/GM/NIGMS NIH HHS/United States ; R01 GM076020-02/GM/NIGMS NIH HHS/United States ; R01 GM076020/GM/NIGMS NIH HHS/United States ; R01 GM076020-01A1/GM/NIGMS NIH HHS/United States ; R01 GM020056-33/GM/NIGMS NIH HHS/United States ; R01 GM076020-03/GM/NIGMS NIH HHS/United States ; R01 GM020056/GM/NIGMS NIH HHS/United States ; T32 GM007122/GM/NIGMS NIH HHS/United States ; },
mesh = {*DNA Breaks, Double-Stranded ; DNA Polymerase I/metabolism ; DNA Polymerase II/metabolism ; DNA Polymerase III/metabolism ; DNA Primase/metabolism ; DNA Repair ; *DNA Replication ; DNA-Directed DNA Polymerase/*chemistry/*metabolism ; Deoxyribonucleases, Type II Site-Specific/metabolism ; Gene Conversion ; Kinetics ; Multienzyme Complexes/chemistry/metabolism ; Protein Subunits/chemistry/metabolism ; Saccharomyces cerevisiae/cytology/*enzymology/*genetics ; Saccharomyces cerevisiae Proteins/*chemistry/*metabolism ; Telomerase/metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {Break-induced replication (BIR) is an efficient homologous recombination process to initiate DNA replication when only one end of a chromosome double-strand break shares homology with a template. BIR is thought to re-establish replication at stalled and broken replication forks and to act at eroding telomeres in cells that lack telomerase in pathways known as 'alternative lengthening of telomeres' (reviewed in refs 2, 6). Here we show that, in haploid budding yeast, Rad51-dependent BIR induced by HO endonuclease requires the lagging strand DNA Polalpha-primase complex as well as Poldelta to initiate new DNA synthesis. Polepsilon is not required for the initial primer extension step of BIR but is required to complete 30 kb of new DNA synthesis. Initiation of BIR also requires the nonessential DNA Poldelta subunit Pol32 primarily through its interaction with another Poldelta subunit, Pol31. HO-induced gene conversion, in which both ends of a double-strand break engage in homologous recombination, does not require Pol32. Pol32 is also required for the recovery of both Rad51-dependent and Rad51-independent survivors in yeast strains lacking telomerase. These results strongly suggest that both types of telomere maintenance pathways occur by recombination-dependent DNA replication. Thus Pol32, dispensable for replication and for gene conversion, is uniquely required for BIR; this finding provides an opening into understanding how DNA replication re-start mechanisms operate in eukaryotes. We also note that Pol32 homologues have been identified both in fission yeast and in metazoans where telomerase-independent survivors with alternative telomere maintenance have also been identified.},
}
@article {pmid17671422,
year = {2007},
author = {Garbe, JC and Holst, CR and Bassett, E and Tlsty, T and Stampfer, MR},
title = {Inactivation of p53 function in cultured human mammary epithelial cells turns the telomere-length dependent senescence barrier from agonescence into crisis.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {6},
number = {15},
pages = {1927-1936},
doi = {10.4161/cc.6.15.4519},
pmid = {17671422},
issn = {1551-4005},
mesh = {Cell Death ; Cell Line ; Cell Proliferation ; Cell Shape ; Cellular Senescence/*physiology ; DNA Damage/genetics ; Epithelial Cells/*cytology/*metabolism ; Humans ; Mammary Glands, Human/*cytology ; Telomere/*genetics ; Tumor Suppressor Protein p53/genetics/*metabolism ; },
abstract = {Cultured human mammary epithelial cells (HMEC) encounter two distinct barriers to indefinite growth. The first barrier, originally termed selection, can be overcome through loss of expression of the cyclin-dependent kinase inhibitor p16(INK4A). The resultant p16-, p53+ post-selection HMEC encounter a second barrier, termed agonescence, associated with critically shortened telomeres and widespread chromosomal aberrations. Although some cell death is present at agonescence, the majority of the population retains long-term viability. We now show that abrogation of p53 function in post-selection HMEC inactivates cell cycle checkpoints and changes the mostly viable agonescence barrier into a crisis-like barrier with massive cell death. In contrast, inactivation of p53 does not affect the ability of HMEC to overcome the first barrier. These data indicate that agonescence and crisis represent two different forms of a telomere-length dependent proliferation barrier. Altogether, our data suggest a modified model of HMEC senescence barriers. We propose that the first barrier is Rb-mediated and largely or completely independent of telomere length. This barrier is now being termed stasis, for stress-associated senescence. The second barrier (agonescence or crisis) results from ongoing telomere erosion leading to critically short telomeres and telomere dysfunction.},
}
@article {pmid17666463,
year = {2007},
author = {Tentolouris, N and Nzietchueng, R and Cattan, V and Poitevin, G and Lacolley, P and Papazafiropoulou, A and Perrea, D and Katsilambros, N and Benetos, A},
title = {White blood cells telomere length is shorter in males with type 2 diabetes and microalbuminuria.},
journal = {Diabetes care},
volume = {30},
number = {11},
pages = {2909-2915},
doi = {10.2337/dc07-0633},
pmid = {17666463},
issn = {1935-5548},
mesh = {Aged ; Albuminuria/genetics/*physiopathology ; Cellular Senescence ; Diabetes Mellitus, Type 2/genetics/*physiopathology ; Diabetic Angiopathies/genetics/physiopathology ; Diabetic Nephropathies/genetics/physiopathology ; Humans ; Leukocytes/*pathology/physiology ; Male ; Middle Aged ; Multivariate Analysis ; Regression Analysis ; Telomere/*ultrastructure ; },
abstract = {OBJECTIVE: To examine differences in telomere (terminal restriction fragment [TRF]) length and pulse wave velocity (PWV)--an index of arterial stiffness--in patients with type 2 diabetes with and without microalbuminuria (MA).<br><br>RESEARCH DESIGN AND METHODS: A total of 84 men with type 2 diabetes, 40 with MA and 44 without MA (aged 63.5 +/- 9.0 vs. 61.2 +/- 9.8 years), were studied. TRF length was determined in white blood cells. MA was defined as albumin excretion rate (AER) in the range of 30-300 mg/24 h in at least two of three 24-h urine collections. PWV was assessed using applanation tonometry. Markers of oxidative stress were also measured.<br><br>RESULTS: TRF length was shorter in patients with MA than in those without MA (6.64 +/- 0.74 vs. 7.23 +/- 1.01 kb, respectively, P = 0.004). PWV was significantly higher in the patients with MA. Multivariate linear regression analysis in the total sample demonstrated an independent association between TRF length and age (P = 0.02), MA status (P = 0.04) or AER (P = 0.002), and plasma nitrotyrosine levels (P = 0.02). AER was associated significantly with PWV (P < 0.01).<br><br>CONCLUSIONS: Subjects with type 2 diabetes and MA have shorter TRF length and increased arterial stiffness than those without MA. Additionally, TRF length is associated with age, AER, and nitrosative stress. As shorter TRF length indicates older biological age, the increased arterial stiffness in patients with type 2 diabetes who have MA may be due to the more pronounced "aging " of these subjects.},
}
@article {pmid17656141,
year = {2007},
author = {Sabourin, M and Tuzon, CT and Zakian, VA},
title = {Telomerase and Tel1p preferentially associate with short telomeres in S. cerevisiae.},
journal = {Molecular cell},
volume = {27},
number = {4},
pages = {550-561},
pmid = {17656141},
issn = {1097-2765},
support = {GM43265/GM/NIGMS NIH HHS/United States ; R01 GM043265/GM/NIGMS NIH HHS/United States ; F32 GM068218/GM/NIGMS NIH HHS/United States ; F32 GM068218-03/GM/NIGMS NIH HHS/United States ; GM068218/GM/NIGMS NIH HHS/United States ; R01 GM043265-18/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes, Fungal/genetics/*metabolism ; DNA, Circular/metabolism ; Intracellular Signaling Peptides and Proteins/*metabolism ; Multiprotein Complexes/metabolism ; Protein Binding ; Protein Serine-Threonine Kinases/*metabolism ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; Telomerase/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {In diverse organisms, telomerase preferentially elongates short telomeres. We generated a single short telomere in otherwise wild-type (WT) S. cerevisiae cells. The binding of the positive regulators Ku and Cdc13p was similar at short and WT-length telomeres. The negative regulators Rif1p and Rif2p were present at the short telomere, although Rif2p levels were reduced. Two telomerase holoenzyme components, Est1p and Est2p, were preferentially enriched at short telomeres in late S/G2 phase, the time of telomerase action. Tel1p, the yeast ATM-like checkpoint kinase, was highly enriched at short telomeres from early S through G2 phase and even into the next cell cycle. Nonetheless, induction of a single short telomere did not elicit a cell-cycle arrest. Tel1p binding was dependent on Xrs2p and required for preferential binding of telomerase to short telomeres. These data suggest that Tel1p targets telomerase to the DNA ends most in need of extension.},
}
@article {pmid17652140,
year = {2007},
author = {Fasching, CL and Neumann, AA and Muntoni, A and Yeager, TR and Reddel, RR},
title = {DNA damage induces alternative lengthening of telomeres (ALT) associated promyelocytic leukemia bodies that preferentially associate with linear telomeric DNA.},
journal = {Cancer research},
volume = {67},
number = {15},
pages = {7072-7077},
doi = {10.1158/0008-5472.CAN-07-1556},
pmid = {17652140},
issn = {0008-5472},
mesh = {Cell Cycle Proteins/metabolism ; Cell Nucleus Structures/genetics/*metabolism ; Chromosomes, Human ; DNA Damage/*drug effects ; DNA Repair ; Electrophoresis, Gel, Two-Dimensional ; Humans ; Hydrogen Peroxide/pharmacology ; Intranuclear Inclusion Bodies/genetics/*metabolism/ultrastructure ; Methylnitronitrosoguanidine/pharmacology ; Telomere/*metabolism ; },
abstract = {The linear chromosomes of vertebrates terminate in telomeres that consist of a tandemly repeated hexameric sequence, 5'TTAGGG3'. Telomeres form a protective loop structure (t-loop), which is thought to prevent them from being recognized as a double-strand break. Approximately 10% of human tumors prevent shortening of their telomeres by using a recombination-mediated alternative lengthening of telomeres (ALT) mechanism. ALT-positive human cells contain extrachromosomal telomere repeat (ECTR) DNA that may either be circular or linear. It has been proposed that ECTR may be generated by recombination events involving the t-loop. A proportion of the cells within ALT-positive cell populations contain promyelocytic leukemia (PML) nuclear bodies that contain telomeric DNA and telomere-binding proteins that are called ALT-associated PML bodies (APB). Although the presence of APBs is very useful for determining whether tumors and cell lines use the ALT mechanism, the function of APBs is unknown. It has previously been shown that telomeric DNA is particularly susceptible to damage by hydrogen peroxide and N-methyl-N'-nitro-N-nitrosoguanidine. We report here that these DNA-damaging agents induce both linear and circular ECTR DNA in ALT cells and increase the proportion of cells that contain APBs. We partially purified APBs and showed that the telomeric repeat DNA they contain is predominantly linear. We propose that a function of APBs is to sequester linear telomeric DNA.},
}
@article {pmid17650438,
year = {2007},
author = {Bessler, M and Du, HY and Gu, B and Mason, PJ},
title = {Dysfunctional telomeres and dyskeratosis congenita.},
journal = {Haematologica},
volume = {92},
number = {8},
pages = {1009-1012},
doi = {10.3324/haematol.11221},
pmid = {17650438},
issn = {1592-8721},
support = {R01 CA105312/CA/NCI NIH HHS/United States ; R01 CA106995/CA/NCI NIH HHS/United States ; },
mesh = {Anticipation, Genetic ; Cell Cycle Proteins/genetics/physiology ; Dyskeratosis Congenita/*genetics ; Female ; Genes, Dominant ; Genetic Heterogeneity ; Humans ; Male ; Mutation ; Nuclear Proteins/genetics/physiology ; Phenotype ; RNA/genetics ; Telomerase/genetics/metabolism ; Telomere/*physiology/ultrastructure ; },
}
@article {pmid17643074,
year = {2007},
author = {Jiao, Y and Zhang, W and Liu, J and Ni, W and Xu, W and Jin, J and Qian, W},
title = {Telomere attrition and chromosome instability via downregulation of TRF2 contributes to arsenic trioxide-induced apoptosis of human T-Cell leukemia cell line molt-4 cells.},
journal = {Cancer biology &amp; therapy},
volume = {6},
number = {8},
pages = {1186-1192},
doi = {10.4161/cbt.6.8.4381},
pmid = {17643074},
issn = {1555-8576},
mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Caspases/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; *Chromosomal Instability ; Humans ; Leukemia-Lymphoma, Adult T-Cell/genetics/*metabolism ; Oxides/*pharmacology ; Telomerase/antagonists &amp; inhibitors/genetics/metabolism ; Telomere/*drug effects ; Telomeric Repeat Binding Protein 2/*antagonists &amp; inhibitors/metabolism ; },
abstract = {Overexpression of human telomere repeat binding factor 2 (TRF2), which may play an important role in the fate of cancer cells, has been observed in adult T-cell leukemia. Previous reports have shown that the inhibition of TRF2 results in the apoptosis of cancer cells. In this study, we demonstrated that arsenic trioxide (As2O3) induced in vitro growth inhibition and/or apoptosis of human T-cell leukemia cell line Molt-4 in a caspase-independent manner. Telomerase activity was not inhibited, although the level of the reverse transcriptase subunit of the human telomerase gene (hTERT) mRNA expression was down regulated during the early times and then recovered to the level found in untreated controls about 48 hours after treatment with As2O3. Furthermore, a remarkable telomere shortening related to exposure of As2O3 was observed in 50 population doubling. Inc ontrast, the alteration of telomere length did not occur after exposure to higher concentration of As2O3 (10 microM) for 24 hours and 48 hours, respectively, suggesting that the shortening of telomeres induced by As2O3 is dependent of a series of cell division cycles. Chromosomal analysis showed that As2O3 exposure caused chromosomal end-to-end fusion in human T-cell leukemia cells while downregulation of TRF2 was observed. Finally, the inhibition of TRF2 protein expression and the sensitivity to As2O3 in a panel of leukemia cell lines were checked. The data revealed that inhibition of TRF2 rendered leukemia cells more susceptible to As2O3. In conclusion, the downregulation of TRF2 by As2O3 contribute to chromosomal end-to-end fusion, and apoptosis in leukemia cells, suggesting that TRF2 could be an attractive target for new therapies of leukemia.},
}
@article {pmid17639079,
year = {2007},
author = {Bianchi, A and Shore, D},
title = {Increased association of telomerase with short telomeres in yeast.},
journal = {Genes &amp; development},
volume = {21},
number = {14},
pages = {1726-1730},
pmid = {17639079},
issn = {0890-9369},
mesh = {Base Sequence ; DNA Primers/genetics ; DNA, Fungal/genetics/metabolism ; Genes, Fungal ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Microsatellite Repeats ; Models, Biological ; Protein Serine-Threonine Kinases/genetics/metabolism ; Saccharomyces cerevisiae/*enzymology/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomerase/genetics/*metabolism ; Telomere/*enzymology/genetics/metabolism ; },
abstract = {Telomere function is mediated by the assembly of a protein complex on an array of telomeric DNA (TG) repeats synthesized by the telomerase enzyme. Telomerase action at chromosome ends is finely tuned by the telomeric complex so that a constant average number of repeats is maintained. This is achieved through a negative feedback process that is sensitive to TG tract length, but whose underlying mechanism is unknown. We show that short telomeres, which are preferential substrates for telomerase, display increased association with the enzyme in the S phase of the cell cycle, when telomerase acts. In addition, we provide support for a molecular mechanism by which this key step of telomerase recruitment is regulated by TG tract length.},
}
@article {pmid17636027,
year = {2007},
author = {Pike, BL and Heierhorst, J},
title = {Mdt1 facilitates efficient repair of blocked DNA double-strand breaks and recombinational maintenance of telomeres.},
journal = {Molecular and cellular biology},
volume = {27},
number = {18},
pages = {6532-6545},
pmid = {17636027},
issn = {0270-7306},
mesh = {Antibiotics, Antineoplastic/toxicity ; Antigens, Nuclear/genetics/physiology ; Antineoplastic Agents, Phytogenic/toxicity ; Bleomycin/toxicity ; Camptothecin/toxicity ; *DNA Damage ; DNA Repair/genetics/*physiology ; DNA, Fungal/drug effects/genetics/metabolism ; DNA-Binding Proteins/genetics/physiology ; Epistasis, Genetic ; Ku Autoantigen ; Rad52 DNA Repair and Recombination Protein/genetics/*metabolism ; *Recombination, Genetic ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism/*physiology ; Telomere/genetics/*metabolism ; },
abstract = {DNA recombination plays critical roles in DNA repair and alternative telomere maintenance. Here we show that absence of the SQ/TQ cluster domain-containing protein Mdt1 (Ybl051c) renders Saccharomyces cerevisiae particularly hypersensitive to bleomycin, a drug that causes 3'-phospho-glycolate-blocked DNA double-strand breaks (DSBs). mdt1Delta also hypersensitizes partially recombination-defective cells to camptothecin-induced 3'-phospho-tyrosyl protein-blocked DSBs. Remarkably, whereas mdt1Delta cells are unable to restore broken chromosomes after bleomycin treatment, they efficiently repair "clean" endonuclease-generated DSBs. Epistasis analyses indicate that MDT1 acts in the repair of bleomycin-induced DSBs by regulating the efficiency of the homologous recombination pathway as well as telomere-related functions of the KU complex. Moreover, mdt1Delta leads to severe synthetic growth defects with a deletion of the recombination facilitator and telomere-positioning factor gene CTF18 already in the absence of exogenous DNA damage. Importantly, mdt1Delta causes a dramatic shift from the usually prevalent type II to the less-efficient type I pathway of recombinational telomere maintenance in the absence of telomerase in liquid senescence assays. As telomeres resemble protein-blocked DSBs, the results indicate that Mdt1 acts in a novel blocked-end-specific recombination pathway that is required for the efficiency of both drug-induced DSB repair and telomerase-independent telomere maintenance.},
}
@article {pmid17635515,
year = {2007},
author = {Matulić, M and Sopta, M and Rubelj, I},
title = {Telomere dynamics: the means to an end.},
journal = {Cell proliferation},
volume = {40},
number = {4},
pages = {462-474},
pmid = {17635515},
issn = {0960-7722},
mesh = {Animals ; Cell Cycle ; DNA Damage ; Telomere/chemistry/metabolism/*physiology ; Telomere-Binding Proteins/physiology ; },
abstract = {Telomeres are among the most important structures in eukaryotic cells. Creating the physical ends of linear chromosomes, they play a crucial role in maintaining genome stability, control of cell division, cell growth and senescence. In vertebrates, telomeres consist of G-rich repetitive DNA sequences (TTAGGG)n and specific proteins, creating a specialized structure called the telosome that through mutual interactions with many other factors in the cell give rise to dynamic regulation of chromosome maintenance. In this review, we survey the structural and mechanistic aspects of telomere length regulation and how these processes lead to alterations in normal and immortal cell growth.},
}
@article {pmid17634573,
year = {2007},
author = {Canela, A and Klatt, P and Blasco, MA},
title = {Telomere length analysis.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {371},
number = {},
pages = {45-72},
doi = {10.1007/978-1-59745-361-5_5},
pmid = {17634573},
issn = {1064-3745},
mesh = {Aging/*metabolism/pathology ; Biomarkers/analysis/metabolism ; Blotting, Southern ; Cell Survival ; Humans ; *Regeneration ; Telomere/*metabolism ; },
abstract = {Most somatic cells of long-lived species undergo telomere shortening throughout life. Critically short telomeres trigger loss of cell viability in tissues, which has been related to alteration of tissue function and loss of regenerative capabilities in aging and aging-related diseases. Hence, telomere length is an important biomarker for aging and can be used in the prognosis of aging diseases. These facts highlight the importance of developing methods for telomere length determination that can be employed to evaluate telomere length during the human aging process. Telomere length quantification methods have improved greatly in accuracy and sensitivity since the development of the conventional telomeric Southern blot. Here, we describe the different methodologies recently developed for telomere length quantification, as well as their potential applications for human aging studies.},
}
@article {pmid17632522,
year = {2007},
author = {Hockemeyer, D and Palm, W and Else, T and Daniels, JP and Takai, KK and Ye, JZ and Keegan, CE and de Lange, T and Hammer, GD},
title = {Telomere protection by mammalian Pot1 requires interaction with Tpp1.},
journal = {Nature structural &amp; molecular biology},
volume = {14},
number = {8},
pages = {754-761},
doi = {10.1038/nsmb1270},
pmid = {17632522},
issn = {1545-9993},
support = {AG016642/AG/NIA NIH HHS/United States ; DK62027/DK/NIDDK NIH HHS/United States ; DK65313/DK/NIDDK NIH HHS/United States ; GM49046/GM/NIGMS NIH HHS/United States ; K08-HD42487/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; DNA-Binding Proteins/genetics/metabolism/*physiology ; Humans ; Mice ; Nuclear Proteins/antagonists &amp; inhibitors/physiology ; RNA Interference ; Shelterin Complex ; TATA Box Binding Protein-Like Proteins/antagonists &amp; inhibitors/physiology ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism/*physiology ; Telomeric Repeat Binding Protein 2 ; },
abstract = {The shelterin complex at mammalian telomeres contains the single-stranded DNA-binding protein Pot1, which regulates telomere length and protects chromosome ends. Pot1 binds Tpp1, the shelterin component that connects Pot1 to the duplex telomeric DNA-binding proteins Trf1 and Trf2. Control of telomere length requires that Pot1 binds Tpp1 as well as the single-stranded telomeric DNA, but it is not known whether the protective function of Pot1 depends on Tpp1. Alternatively, Pot1 might function similarly to the Pot1-like proteins of budding and fission yeast, which have no known Tpp1-like connection to the duplex telomeric DNA. Using mutant mouse cells with diminished Tpp1 levels, RNA interference directed to mouse Tpp1 and Pot1, and complementation of mouse Pot1 knockout cells with human and mouse Pot1 variants, we show here that Tpp1 is required for the protective function of mammalian Pot1 proteins.},
}
@article {pmid17632059,
year = {2007},
author = {Tomita, K and Cooper, JP},
title = {The telomere bouquet controls the meiotic spindle.},
journal = {Cell},
volume = {130},
number = {1},
pages = {113-126},
doi = {10.1016/j.cell.2007.05.024},
pmid = {17632059},
issn = {0092-8674},
mesh = {Chromosome Segregation/physiology ; Cytoskeleton/*physiology ; Meiosis/*physiology ; Microtubule-Organizing Center/*physiology ; Nuclear Envelope/*metabolism ; Recombinant Fusion Proteins/genetics/metabolism ; *Recombination, Genetic ; Schizosaccharomyces/cytology/*genetics/metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Bouquet formation, in which telomeres gather to a small region of the nuclear membrane in early meiosis, has been observed in diverse eukaryotes, but the function of the bouquet has remained a mystery. Here, we demonstrate that the telomere bouquet plays a crucial role in controlling the behavior of the fission yeast microtubule-organizing center (known as the spindle pole body or SPB) and the meiotic spindle. Using mutations that specifically disrupt the bouquet, we analyze chromosome, SPB, and spindle dynamics throughout meiosis. If the bouquet fails to form, the SPB becomes fragmented at meiosis I, leading to monopolar, multiple, and mislocalized spindles. Correct SPB and spindle behavior require not only the SPB recruitment of telomere proteins but also that the proteins are properly bound to telomeric DNA. This discovery illuminates an unanticipated level of communication between chromosomes and the spindle apparatus that may be widely conserved among eukaryotes.},
}
@article {pmid17631279,
year = {2007},
author = {Gunaratnam, M and Greciano, O and Martins, C and Reszka, AP and Schultes, CM and Morjani, H and Riou, JF and Neidle, S},
title = {Mechanism of acridine-based telomerase inhibition and telomere shortening.},
journal = {Biochemical pharmacology},
volume = {74},
number = {5},
pages = {679-689},
doi = {10.1016/j.bcp.2007.06.011},
pmid = {17631279},
issn = {1873-2968},
support = {//Cancer Research UK/United Kingdom ; },
mesh = {Acridines/chemistry/*pharmacology ; Antineoplastic Agents/chemistry/*pharmacology ; Cell Line ; Dose-Response Relationship, Drug ; Humans ; Molecular Structure ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*metabolism ; },
abstract = {The trisubstituted acridine compound BRACO-19 has been developed as a ligand for stabilising G-quadruplex structures. It is shown here that BRACO-19 produces short- and long-term growth arrest in cancer cell lines, and is significantly less potent in a normal cell line. BRACO-19 reduces telomerase activity and long-term telomere length attrition is observed. It is also shown that BRACO-19 binds to telomeric single-stranded overhang DNA, consistent with quadruplex formation, and the single-stranded protein hPOT1 has been shown to be displaced from the overhang in vitro and in cellular experiments. It is concluded that the cellular activity of BRACO-19 can be ascribed both to the uncapping of 3' telomere ends and to telomere shortening that may preferentially affect cells with short telomeres.},
}
@article {pmid17630723,
year = {2007},
author = {Yang, DY and Chang, TC and Sheu, SY},
title = {Interaction between human telomere and a carbazole derivative: a molecular dynamics simulation of a quadruplex stabilizer and telomerase inhibitor.},
journal = {The journal of physical chemistry. A},
volume = {111},
number = {38},
pages = {9224-9232},
doi = {10.1021/jp071963o},
pmid = {17630723},
issn = {1089-5639},
mesh = {Carbazoles/*chemistry/pharmacology ; Computer Simulation ; G-Quadruplexes ; Humans ; Models, Molecular ; Molecular Structure ; Pyridinium Compounds/*chemistry/pharmacology ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*chemistry ; },
abstract = {The mechanism of inhibition of telomerase by drugs is a key factor in an understanding of guanine-quadruplex complex stabilization during human cancer. This study describes a simulated annealing docking and molecular dynamics simulation to investigate a synthesized potent inhibitor, 3,6-bis(1-methyl-4-vinylpyridinium iodine) carbazole (BMVC), which stabilizes the quadruplex structure of the human telomeric DNA sequence d[AG3(T(2)AG(3))3] and inhibits telomerase activity. The compound was predicted to selectively interact with the quadruplex structure. During our simulation, the binding affinities were calculated and used to predict the best drug-binding sites as well as enhanced selectivity compared with other compounds. Our studies suggest that the simulation results quite coincide with the experimental results. In addition, molecular modeling shows that a 2:1 binding model involving the external binding of BMVC to both ends of the G-quartet of d[AG(3)(T(2)AG)3))3] is the most stable binding mode and this agrees with the absorbance titration results that show two binding sites. Of particular interest is that one pyridinium ring and carbazole moiety of the BMVC can stack well at the end of G-quartet. This implies that BMVC is a good human quadruplex stabilizer and also a good telomerase inhibitor.},
}
@article {pmid17629495,
year = {2007},
author = {Li, X and Lan, J and Zhu, Y and Yu, J and Dou, Z and Huang, H},
title = {Expression, purification, and characterization of Tara, a novel telomere repeat-binding factor 1 (TRF1)-binding protein.},
journal = {Protein expression and purification},
volume = {55},
number = {1},
pages = {84-92},
doi = {10.1016/j.pep.2007.05.004},
pmid = {17629495},
issn = {1046-5928},
mesh = {Amino Acid Sequence ; Antibodies/immunology ; Escherichia coli/genetics ; Genetic Vectors/genetics ; Humans ; Mass Spectrometry ; Microfilament Proteins/*biosynthesis/*chemistry/genetics ; Molecular Sequence Data ; Recombinant Proteins/*biosynthesis/chemistry/*isolation &amp; purification ; Telomeric Repeat Binding Protein 1/chemistry/metabolism ; },
abstract = {Tara was originally identified as a binding protein of guanine nucleotide exchange factor Trio. Although Tara may be involved in many fundamental cellular processes, ranging from actin remodeling, directed cell movement, to cell cycle regulation, aging, and cancer, the exact molecular mechanisms are poorly understood. We expressed recombinant Tara in Escherichia coli and purified the protein to approximately 99% purity using affinity chromatography and gel-filtration chromatography. The identity of the purified protein was confirmed by mass spectrometry. Non-denaturing polyacrylamide gel electrophoresis and gel-filtration chromatography showed that Tara forms multimer in vitro. The purified Tara was used to generate polyclonal antibody, which could specifically recognize both the recombinant and endogenous Tara. Using the pull-down assay, we showed that the purified Tara interacted with TRF1, suggesting that the purified protein is functional and biologically active. The availability of purified Tara and anti-Tara antibody provides critical reagents for elucidating Tara's cellular function and its molecular mechanism.},
}
@article {pmid17627276,
year = {2007},
author = {Surovtseva, YV and Shakirov, EV and Vespa, L and Osbun, N and Song, X and Shippen, DE},
title = {Arabidopsis POT1 associates with the telomerase RNP and is required for telomere maintenance.},
journal = {The EMBO journal},
volume = {26},
number = {15},
pages = {3653-3661},
pmid = {17627276},
issn = {0261-4189},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; GM65383/GM/NIGMS NIH HHS/United States ; },
mesh = {Arabidopsis/*metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Base Sequence ; DNA Primers ; Genomic Instability ; Mutation ; Reverse Transcriptase Polymerase Chain Reaction ; Ribonucleoproteins/*metabolism ; Shelterin Complex ; *Telomere ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {POT1 is a single-copy gene in yeast and humans that encodes a single-strand telomere binding protein required for chromosome end protection and telomere length regulation. In contrast, Arabidopsis harbors multiple, divergent POT-like genes that bear signature N-terminal OB-fold motifs, but otherwise share limited sequence similarity. Here, we report that plants null for AtPOT1 show no telomere deprotection phenotype, but rather exhibit progressive loss of telomeric DNA. Genetic analysis indicates that AtPOT1 acts in the same pathway as telomerase. In vitro levels of telomerase activity in pot1 mutants are significantly reduced and are more variable than wild-type. Consistent with this observation, AtPOT1 physically associates with active telomerase particles. Although low levels of AtPOT1 can be detected at telomeres in unsynchronized cells and in cells arrested in G2, AtPOT1 binding is significantly enhanced during S-phase, when telomerase is thought to act at telomeres. Our findings indicate that AtPOT1 is a novel accessory factor for telomerase required for positive telomere length regulation, and they underscore the coordinate and extraordinarily rapid evolution of telomere proteins and the telomerase enzyme.},
}
@article {pmid17627017,
year = {2007},
author = {Bataille, V and Kato, BS and Falchi, M and Gardner, J and Kimura, M and Lens, M and Perks, U and Valdes, AM and Bennett, DC and Aviv, A and Spector, TD},
title = {Nevus size and number are associated with telomere length and represent potential markers of a decreased senescence in vivo.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {16},
number = {7},
pages = {1499-1502},
doi = {10.1158/1055-9965.EPI-07-0152},
pmid = {17627017},
issn = {1055-9965},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Adolescent ; Adult ; Aged ; Aging ; Biomarkers/*metabolism ; Disease Progression ; Female ; Humans ; Middle Aged ; Nevus, Pigmented/*pathology ; Prognosis ; Risk Factors ; Telomere/*physiology ; White People ; },
abstract = {Nevus counts represent one of the strongest risk factors for melanoma. They appear in childhood and adolescence and involute from middle age onwards. Recent evidence has shown that nevus cells undergo oncogene-induced senescence involving the p16/retinoblastoma pathway. However, telomere length also influences senescence in proliferative somatic cells and varies between individuals. This study explores whether telomere length measured in white cells is associated with nevus count and size in 1,897 Caucasian women ages 18 to 79 years. Total body nevus counts were positively correlated with white cell telomere length (mean, 7.09 kbp; range, 5.09-9.37) after adjustment for age (P = 0.0001). Age-adjusted telomere length was also associated with nevus count for nevi above 5 mm in diameter (P = 0.04). Subjects in the top category for nevus count had an average age-adjusted telomere length 150 bp longer than those in the lowest category. The positive correlation between white cell telomere length and nevi number and size may reflect an increased replicative potential (reduced senescence) in individuals with longer telomeres, which may not be melanocyte specific. Understanding mechanisms influencing the induction and involution of nevi will not only help in understanding the pathophysiology of melanoma but should also shed light on the complex relationship between aging and cancer.},
}
@article {pmid17624691,
year = {2007},
author = {Oh, BK and Yoon, SM and Lee, CH and Park, YN},
title = {Rat homolog of PinX1 is a nucleolar protein involved in the regulation of telomere length.},
journal = {Gene},
volume = {400},
number = {1-2},
pages = {35-43},
doi = {10.1016/j.gene.2007.05.015},
pmid = {17624691},
issn = {0378-1119},
mesh = {Animals ; Cell Cycle Proteins ; Cell Nucleolus/metabolism ; Cells, Cultured ; Cellular Senescence ; Humans ; Mice ; Molecular Sequence Data ; NIH 3T3 Cells ; Nuclear Proteins/*genetics/metabolism ; Rats ; Sequence Homology, Amino Acid ; Telomere/*ultrastructure ; Transfection ; Tumor Suppressor Proteins/*genetics/metabolism ; },
abstract = {Human PinX1 involves in regulation of telomere length. Here, we describe the function of a rat homolog of PinX1. Rat PinX1 (rPinX1) was cloned from WB-F344, a rat hepatic stem-like epithelial cell. It encodes a protein of 331 amino acids with 70% homology to human PinX1 and 91% homology to mouse. Northern analysis revealed that rPinX1 is expressed in both somatic and germ tissues, most abundantly in heart, liver and testis. Co-localization with a nucleolar protein, fibrillarin, showed that rPinX1 resides in the nucleolus. Analysis of truncated mutants revealed that an internal K,E/D region seems to be important for nucleolar localization. A stable cell line expressing rPinX1 was established in NIH3T3, a mouse-transformed embryonic fibroblast cell line, and stable cells were subcultured for more than 150 population doublings. The growth of stable rPinX1 cells slowed down at late passages, and a fraction of these cells exhibited increased size and stained positively for senescence-associated beta-galactosidase. Overexpression of rPinX1 in NIH3T3 cells resulted in gradual telomere shortening over successive passages. However, the telomeric 3' overhang was not altered by PinX1 expression. This study demonstrates that a rat homolog of human PinX1 is a nucleolar protein, and that overexpression of rPinX1 induces cellular senescence and telomere shortening, but has no effect on 3' overhang length. The function of PinX1 in regulating telomere length is conserved in rodents, and this study may provide insight into the mechanism by which a nucleolar protein can regulate telomere length.},
}
@article {pmid17624411,
year = {2007},
author = {Zhang, F and Kato, BS and Gardner, JP and Kimura, M and Spector, TD and Ahmadi, KR},
title = {Lack of association between leukocyte telomere length and genetic variants in two ageing-related candidate genes.},
journal = {Mechanisms of ageing and development},
volume = {128},
number = {7-8},
pages = {415-422},
doi = {10.1016/j.mad.2007.05.007},
pmid = {17624411},
issn = {0047-6374},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Adolescent ; Adult ; Aged ; Aging/*genetics ; Female ; *Genetic Variation ; Glucuronidase/*genetics ; Haplotypes ; Humans ; Klotho Proteins ; Leukocytes/physiology ; Middle Aged ; Polymorphism, Single Nucleotide ; Telomere/*physiology ; Transforming Growth Factor beta1/*genetics ; Twins, Dizygotic ; White People/genetics ; },
abstract = {BACKGROUND: Leukocyte telomere length, a putative marker of ageing, is a highly variable and heritable complex trait. In order to determine the possible underlying genetic variants for leukocyte telomere length variation, we conducted an association study of leukocyte telomere length and two candidate genes for ageing-related traits, TGFB1 and KLOTHO, in a female Caucasian dizygotic twin population.<br><br>METHODS AND MATERIALS: Terminal restriction fragment (TRF) length, an index of telomere length, was measured using Southern Blotting. Six and four single nucleotide polymorphisms (SNP) were genotyped in TGFB1 and KLOTHO gene, respectively, and tested for association. When there is strong LD between SNPs (r(2) > 0.5), haplotypic association was investigated using haplotype trend regression approach.<br><br>RESULTS: All SNPs were in Hardy-Weinberg equilibrium (p > 0.05). No significant association was detected for individual SNPs (p > 0.101), or two-locus haplotypes (p = 0.7497) with TRF variation.<br><br>CONCLUSION: We failed to find any significant association between leukocyte telomere length and 10 SNPs in two ageing-related candidate genes, TGFB1 and KLOTHO. This result suggests that while we could not exclude minor effects, none of 10 SNPs in these two candidate genes showed significant association with the variation of leukocyte telomere length in our cohort. But as it is unclear whether telomere length dynamics is the cause or the effect of the ageing process, it is still possible the genes are associated with ageing via alternate mechanisms.},
}
@article {pmid17623782,
year = {2007},
author = {Njajou, OT and Cawthon, RM and Damcott, CM and Wu, SH and Ott, S and Garant, MJ and Blackburn, EH and Mitchell, BD and Shuldiner, AR and Hsueh, WC},
title = {Telomere length is paternally inherited and is associated with parental lifespan.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {104},
number = {29},
pages = {12135-12139},
pmid = {17623782},
issn = {0027-8424},
support = {R01 AR046838/AR/NIAMS NIH HHS/United States ; M01 RR 02719/RR/NCRR NIH HHS/United States ; M01 RR002719/RR/NCRR NIH HHS/United States ; K01 AG022782/AG/NIA NIH HHS/United States ; M01 RR 16500/RR/NCRR NIH HHS/United States ; R01 AR46838/AR/NIAMS NIH HHS/United States ; M01 RR016500/RR/NCRR NIH HHS/United States ; T32 AG000219/AG/NIA NIH HHS/United States ; R01 AG023692/AG/NIA NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Inheritance Patterns/*genetics ; Longevity/*genetics ; Male ; Middle Aged ; Telomere/*metabolism ; },
abstract = {Telomere length (TL) is emerging as a biomarker for aging and survival. To evaluate factors influencing this trait, we measured TL in a large homogeneous population, estimated the heritability (h(2)), and tested for parental effects on TL variation. Our sample included 356 men and 551 women, aged 18-92 years, from large Amish families. Mean TL in leukocytes was measured by quantitative PCR (mean: 6,198 +/- 1,696 bp). The h(2) of TL was 0.44 +/- 0.06 (P < 0.001), after adjusting for age, sex, and TL assay batch. As expected, TL was negatively correlated with age (r = -0.40; P < 0.001). There was no significant difference in TL between men and women, consistent with our previous findings that Amish men lived as long as Amish women. There was a stronger and positive correlation and association between TL in the offspring and paternal TL (r = 0.46, P < 0.001; beta = 0.22, P = 0.006) than offspring and maternal TL (r = 0.18, P = 0.04; beta = -0.02, P = 0.4). Furthermore, we observed a positive correlation and association between daughter's TL and paternal lifespan (r = 0.20, P < 0.001; beta = 0.21, P = 0.04), but not between daughter's TL and maternal lifespan (r = -0.01, beta = 0.04; both P = not significant). Our data, which are based on one of the largest family studies of human TL, support a link between TL and aging and lifespan and suggest a strong genetic influence, possibly via an imprinting mechanism, on TL regulation.},
}
@article {pmid17620088,
year = {2007},
author = {Shariftabrizi, A and Eller, MS},
title = {Telomere homolog oligonucleotides and the skin: current status and future perspectives.},
journal = {Experimental dermatology},
volume = {16},
number = {8},
pages = {627-633},
doi = {10.1111/j.1600-0625.2007.00580.x},
pmid = {17620088},
issn = {0906-6705},
mesh = {Animals ; *DNA Damage ; Humans ; Oligonucleotides/genetics/*pharmacology ; Skin Aging ; Skin Neoplasms/*prevention &amp; control ; *Skin Physiological Phenomena ; Telomere/*physiology ; },
}
@article {pmid17618841,
year = {2007},
author = {Tsolou, A and Lydall, D},
title = {Mrc1 protects uncapped budding yeast telomeres from exonuclease EXO1.},
journal = {DNA repair},
volume = {6},
number = {11},
pages = {1607-1617},
pmid = {17618841},
issn = {1568-7864},
support = {075294//Wellcome Trust/United Kingdom ; 054371//Wellcome Trust/United Kingdom ; },
mesh = {Cell Cycle ; Cell Cycle Proteins/genetics/*metabolism ; Cyclin B/genetics/metabolism ; DNA, Single-Stranded/metabolism ; Exodeoxyribonucleases/*metabolism ; Fungal Proteins/genetics/*metabolism ; Mutation ; Saccharomycetales/*enzymology/metabolism ; Telomere/*metabolism ; },
abstract = {Mrc1 (Mediator of Replication Checkpoint 1) is a component of the DNA replication fork machinery and is necessary for checkpoint activation after replication stress. In this study, we addressed the role of Mrc1 at uncapped telomeres. Our experiments show that Mrc1 contributes to the vitality of both cdc13-1 and yku70Delta telomere capping mutants. Cells with telomere capping defects containing MRC1 or mrc1(AQ), a checkpoint defective allele, exhibit similar growth, suggesting growth defects of cdc13-1 mrc1Delta are not due to checkpoint defects. This is in accordance with Mrc1-independent Rad53 activation after telomere uncapping. Poor growth of cdc13-1 mutants in the absence of Mrc1 is a result of enhanced single stranded DNA accumulation at uncapped telomeres. Consistent with this, deletion of EXO1, encoding a nuclease that contributes to single stranded DNA accumulation after telomere uncapping, improves growth of cdc13-1 mrc1Delta strains and decreases ssDNA production. Our observations show that Mrc1, a core component of the replication fork, plays an important role in telomere capping, protecting from nucleases and checkpoint pathways.},
}
@article {pmid17617873,
year = {2007},
author = {Glanz, C and Rebetz, J and Stewénius, Y and Persson, A and Englund, E and Mandahl, N and Mertens, F and Salford, LG and Widegren, B and Fan, X and Gisselsson, D},
title = {Genetic intratumour heterogeneity in high-grade brain tumours is associated with telomere-dependent mitotic instability.},
journal = {Neuropathology and applied neurobiology},
volume = {33},
number = {4},
pages = {440-454},
doi = {10.1111/j.1365-2990.2007.00832.x},
pmid = {17617873},
issn = {0305-1846},
mesh = {Adult ; Aged ; Animals ; Brain Neoplasms/*genetics/*pathology/ultrastructure ; Cells, Cultured ; Child ; Child, Preschool ; Chromatids/genetics ; Chromosome Segregation/physiology ; Female ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Middle Aged ; Neoplasm Transplantation ; Phenotype ; Sister Chromatid Exchange/genetics ; Spindle Apparatus/*pathology/ultrastructure ; Telomerase/antagonists &amp; inhibitors/metabolism ; Telomere/*pathology/ultrastructure ; Transplantation, Heterologous ; },
abstract = {Glioblastoma multiforme (GBM) and other high-grade brain tumours are typically characterized by complex chromosome abnormalities and extensive intratumour cytogenetic heterogeneity. The mechanisms behind this diversity have been little explored. In this study, we analysed the pattern of chromosome segregation at mitosis in 20 brain tumours. We found an abnormal segregation of chromatids at mitosis through anaphase bridging (10-25% of anaphase cells) in all 10 GBMs. Anaphase bridging was also found in two medulloblastomas (7-15%), one anaplastic astrocytoma (17%) and one oligodendroglioma (6%). These tumours showed a relatively high degree of cytogenetic complexity and heterogeneity. In contrast, cell division abnormalities were not found in low-grade brain tumours with less complex karyotypes, including two pilocytic astrocytomas and two ependymomas. Further analysis of two GBMs by fluorescence in situ hybridization with telomeric repeat probes revealed excessive shortening of TTAGGG repeats, indicating dysfunctional protection of chromosome ends. In xenografts established from these GBMs, there was a gradual reduction in cytogenetic heterogeneity through successive passages as the proportion of abnormally short telomeres was reduced and the frequency of anaphase bridges decreased from >25% to 0. However, bridging could be reintroduced in late-passage xenograft cells by pharmacological induction of telomere shortening, using a small-molecule telomerase inhibitor. Telomere-dependent abnormal segregation of chromosomes at mitosis is thus a common phenomenon in high-grade brain tumours and may be one important factor behind cytogenetic intratumour diversity in GBM.},
}
@article {pmid17617801,
year = {2007},
author = {Lund, TC and Grange, RW and Lowe, DA},
title = {Telomere shortening in diaphragm and tibialis anterior muscles of aged mdx mice.},
journal = {Muscle &amp; nerve},
volume = {36},
number = {3},
pages = {387-390},
doi = {10.1002/mus.20824},
pmid = {17617801},
issn = {0148-639X},
support = {R03 AG025861/AG/NIA NIH HHS/United States ; R03 AG025861-02/AG/NIA NIH HHS/United States ; K01 AG020990-05/AG/NIA NIH HHS/United States ; AR049881/AR/NIAMS NIH HHS/United States ; K01 AG020990/AG/NIA NIH HHS/United States ; },
mesh = {Age Factors ; Animals ; Cellular Senescence/*genetics ; Diaphragm/*metabolism ; Mice ; Mice, Inbred mdx ; Muscle, Skeletal/*metabolism ; Muscular Dystrophy, Duchenne/*genetics ; Satellite Cells, Skeletal Muscle/chemistry/metabolism ; Telomere/chemistry/*metabolism ; Tibia ; },
abstract = {The progression of Duchenne muscular dystrophy (DMD) is, in part, due to satellite cell senescence driven by high replicative pressure as these muscle stem cells repeatedly divide and fuse to damaged muscle fibers. We hypothesize that telomere shortening in satellite cells underlies their senescence. To test this hypothesis, we evaluated the diaphragm and a leg muscle from dystrophic mice of various ages for telomere dynamics. We found 30% telomere shortening in tibialis anterior muscles from 600-day-old mdx mice relative to age-matched wildtype mice. We also found a more severe shortening of telomere length in diaphragm muscles of old mdx mice. In those muscles, telomeres were shortened by approximately 15% and 40% in 100- and 600-day-old mdx mice, respectively. These findings indicate that satellite cells undergo telomere erosion, which may contribute to the inability of these cells to perpetually repair DMD muscle.},
}
@article {pmid17617738,
year = {2007},
author = {Yokoyama, T and Kondo, Y and Kondo, S},
title = {Roles of mTOR and STAT3 in autophagy induced by telomere 3' overhang-specific DNA oligonucleotides.},
journal = {Autophagy},
volume = {3},
number = {5},
pages = {496-498},
doi = {10.4161/auto.4602},
pmid = {17617738},
issn = {1554-8627},
support = {CA088936/CA/NCI NIH HHS/United States ; CA108558/CA/NCI NIH HHS/United States ; CA16672/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Autophagy/drug effects/genetics/*physiology ; Cell Line, Tumor ; Glioma/drug therapy/genetics/pathology/physiopathology ; Humans ; Mice ; Models, Biological ; Oligodeoxyribonucleotides/genetics/*pharmacology ; Protein Kinases/*physiology ; STAT3 Transcription Factor/antagonists &amp; inhibitors/*physiology ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases ; Tyrphostins/pharmacology ; },
abstract = {Telomere 3' overhang-specific DNA oligonucleotides (T-oligos) induce cancer cell death, presumably by mimicking telomere loop disruption and are, therefore, considered a promising new therapeutic strategy. We previously demonstrated that T-oligos inhibit the proliferation of malignant glioma cells in vitro and in vivo by inducing non-apoptotic autophagy. Using a reverse-phase protein microarray analysis and Western blotting, we revealed that T-oligos inhibit the mammalian target of rapamycin (mTOR) and the signal transducer and activator of transcription 3 (STAT3). Moreover, rapamycin (mTOR inhibitor) and AG490 (STAT3 inhibitor) sensitize malignant glioma cells to T-oligos by augmenting autophagy. Although mTOR is well known as a negative regulator of autophagy, the relationship between STAT3 and autophagy has never been demonstrated, to our knowledge. These findings suggest that, by exhibiting a novel mechanism of inducing autophagy through inhibition of mTOR and STAT3, T-oligos are a promising therapeutic agent for treating malignant gliomas. Here, we discuss evidence for T-oligos' effects on cell signaling pathways that may explain their ability to stimulate autophagy by inhibiting STAT3 as well as mTOR.},
}
@article {pmid17616810,
year = {2008},
author = {Salhab, M and Jiang, WG and Newbold, RF and Mokbel, K},
title = {The expression of gene transcripts of telomere-associated genes in human breast cancer: correlation with clinico-pathological parameters and clinical outcome.},
journal = {Breast cancer research and treatment},
volume = {109},
number = {1},
pages = {35-46},
doi = {10.1007/s10549-007-9622-8},
pmid = {17616810},
issn = {0167-6806},
support = {//Cancer Research UK/United Kingdom ; },
mesh = {Breast Neoplasms/*genetics/*metabolism/mortality ; Cell Transformation, Neoplastic ; DNA Primers/chemistry ; DNA, Complementary/metabolism ; Disease Progression ; *Gene Expression Regulation, Neoplastic ; Humans ; Neoplasm Metastasis ; Prognosis ; RNA/*genetics ; RNA, Messenger/metabolism ; RNA, Neoplasm/metabolism ; Telomerase/*genetics ; Telomere/*ultrastructure ; Time Factors ; Treatment Outcome ; },
abstract = {BACKGROUND: Telomerase is a ribonucleoprotein enzyme that synthesises telomeres in human germ cells, embryogenesis and in cancer, maintaining chromosomal length, stability and cellular immortality. The hTERT gene is the rate-limiting determinant of telomerase reactivation during immortalization and malignant transformation. Telomeric DNA-binding proteins have been attracting increasing interest due to their essential role in the regulation of telomeric DNA length and in protecting against chromosomal end-to-end fusion. These proteins include hTR, TRF1, TRF2, TANK1, TANK2, POT1, TIN2, EST1, and TEP. This study represents the first comprehensive investigation of the mRNA expression of key telomere-related genes in human breast cancer.<br><br>METHODS: One hundred and twenty seven tumour tissues and 33 normal tissues were analyzed. Levels of transcription of hTERT, hTR, TRF1, TRF2, TANK1, TANK2, POT1, TIN2, EST1, and TEP1 were determined using real-time quantitative PCR. The mRNA expression of these genes was normalized against CK19 and was then analyzed against the pathological parameters and clinical outcome over a 10 year follow up period.<br><br>RESULTS: The mRNA expressions of hTERT, hTR, TANK1, EST1, and TEP1 were higher in tumour samples compared with normal breast tissue. This reached statistical significance for EST1 when comparing good prognosis tumours with normal breast tissue (means=11013 vs 1160, P=0.05). Both hTERT and TEP1 levels significantly predicted overall survival (P=0.012 and 0.005 respectively) and disease-free survival (P=0.0011 and 0.01 respectively). The mRNA levels of TANK2 and POT1 were lower in malignant tissues compared with non-malignant breast tissues and this difference reached statistical significance when comparing the levels in normal tissues with those in advanced tumours (P=0.0008 and P=0.038 respectively). Their levels fell further with increasing tumour's stage and were higher in tumours from patients who remained disease free compared with those who developed local recurrence or distant metastasis or died from breast cancer.TRF2 showed a trend similar to that of TANK2 and POT1. Furthermore, there was a highly significant correlation between TANK1 expression and that of hTERT, hTR, TRF1, TRF2 and EST1, (r=0.533, 0.586, 0.608, 0.644 and 0.551 respectively, P<0.001).<br><br>CONCLUSIONS: Genes encoding telomere-associated proteins display different patterns of mRNA expression in human breast cancer, and in normal breast tissue, suggesting different and sometimes opposing roles in mammary carcinogenesis. hTERT, hTR, TANK1, EST1 and TEP1 seem to be up-regulated, with hTERT and TEP1 correlating with clinical outcome. Conversely, TANK2 and POT1 transcription levels demonstrate a compelling trend to be lower in malignant tissues and lower still in those patients who develop recurrent disease suggesting that TANK2 and POT1 may act as tumour suppressor genes possibly by negatively regulating telomerase activity.},
}
@article {pmid17614765,
year = {2007},
author = {Tiwari, A},
title = {Statins and telomere length: risk assessment and management for coronary heart disease.},
journal = {Expert opinion on therapeutic targets},
volume = {11},
number = {7},
pages = {979-982},
doi = {10.1517/14728222.11.7.979},
pmid = {17614765},
issn = {1744-7631},
abstract = {Cornoary heart disease (CHD) is identified as one of the diseases characterised by biological ageing as one of the important risk factors in several epidemiological studies. Premature biological ageing is distinct from chronological ageing and may predispose the individual to myocardial infarction, atherosclerosis and CHD in particular. The mean telomere length serves as a marker for the biological age at the cellular level, with shorter telomeres defining the increased biological age. Telomere length, therefore, correlates with the risk of CHD and atherosclerosis. Statins serve as the drugs of obvious choice based on their well established efficacy and safety profiles for the treatment of CHD and associated atherosclerosis. A present clinical study states that the treatment with a statin is associated with a reduction in the number of clinical events but only in individuals with increased risk based on their telomere length. This suggests a positive relationship of telomere length with the risk of CHD and, therefore, would help clinicians to categorise the patient populations based on their leucocyte telomere length for treatment with statins.},
}
@article {pmid17613124,
year = {2007},
author = {Sprung, CN and Davey, DS and Goh, SK and Radford, IR and McKay, MJ},
title = {Uncoupling of telomere length and radiosensitivity in mouse lymphoma cell lines of similar genetic background.},
journal = {International journal of radiation biology},
volume = {83},
number = {8},
pages = {515-521},
doi = {10.1080/09553000701452270},
pmid = {17613124},
issn = {0955-3002},
mesh = {Animals ; Base Sequence ; Cell Division/genetics/physiology/radiation effects ; Cell Line, Tumor/pathology/*radiation effects ; Cells, Cultured ; In Situ Hybridization, Fluorescence ; Leukemia L5178/genetics/*pathology ; Mice ; Phenotype ; Polymorphism, Restriction Fragment Length ; Radiation, Ionizing ; Telomere/physiology/*radiation effects ; },
abstract = {PURPOSE: To investigate the link between radiosensitivity and telomere length in murine lymphoid cell line stocks that have similar genetic backgrounds but different radiosensitivities.<br><br>MATERIALS AND METHODS: We used two stocks from both the parental L5,178Y-R cell line and the repair-deficient radiosensitive subline, L5,178Y-S, to assess telomere length. We used terminal restriction fragment analysis and flow-fluorescence in situ hybridization (FISH) telomere length assessment to determine telomere lengths in the related radiosensitive and non-radiosensitive cell lines. Each cell line was further tested for retention of its original radiation response phenotype using cell growth assays after treatment with ionizing radiation.<br><br>RESULTS: One stock of L5,178Y-R cells had long telomeres, whereas the other stock had short telomeres. Likewise, one stock of L5,178Y-S cells had long telomeres, whereas the other stock had short telomeres. Telomere lengths in these cell lines were relatively stable for over 80 divisions in culture. Each cell line was confirmed to have retained its original radiosensitivity phenotype.<br><br>CONCLUSION: We conclude that radiosensitivity is independent of telomere length in these genetically similar cell lines.},
}
@article {pmid17612498,
year = {2007},
author = {Zellinger, B and Akimcheva, S and Puizina, J and Schirato, M and Riha, K},
title = {Ku suppresses formation of telomeric circles and alternative telomere lengthening in Arabidopsis.},
journal = {Molecular cell},
volume = {27},
number = {1},
pages = {163-169},
doi = {10.1016/j.molcel.2007.05.025},
pmid = {17612498},
issn = {1097-2765},
mesh = {Arabidopsis/*metabolism ; Arabidopsis Proteins/*metabolism ; Chromosomes, Plant/genetics ; DNA Helicases/*metabolism ; DNA, Circular/*metabolism ; DNA-Binding Proteins/*metabolism ; Electrophoresis, Gel, Two-Dimensional ; Mutation/genetics ; Telomere/*metabolism ; },
abstract = {Telomeres in mammals and plants are protected by the terminal t loop structure, the formation of which parallels the first steps of intrachromatid homologous recombination (HR). Under some circumstances, cells can also utilize an HR-based mechanism (alternative lengthening of telomeres [ALT]) as a back-up pathway for telomere maintenance. We have found that the Ku70/80 heterodimer, a central nonhomologous end-joining DNA repair factor, inhibits engagement of ALT in Arabidopsis telomerase-negative cells. To further assess HR activities at telomeres, we have developed a sensitive assay for detecting extrachromosomal telomeric circles (t circles) that may arise from t loop resolution and aberrant HR. We show that Ku70/80 specifically inhibits circle formation at telomeres, but not at centromeric and rDNA repeats. Ku inactivation results in increased formation of t circles that represent approximately 4% of total telomeric DNA. However, telomeres in ku mutants are fully functional, indicating that telomerase efficiently heals ongoing terminal deletions arising from excision of the t circles.},
}
@article {pmid17611693,
year = {2007},
author = {Zhao, P and Wang, C and Fu, Z and You, Y and Cheng, Y and Lu, X and Lu, A and Liu, N and Pu, P and Kang, C and Salford, LG and Fan, X},
title = {Lentiviral vector mediated siRNA knock-down of hTERT results in diminished capacity in invasiveness and in vivo growth of human glioma cells in a telomere length-independent manner.},
journal = {International journal of oncology},
volume = {31},
number = {2},
pages = {361-368},
pmid = {17611693},
issn = {1019-6439},
mesh = {Animals ; Antineoplastic Agents/pharmacology ; Base Sequence ; Brain Neoplasms/*drug therapy/pathology ; Cell Line, Tumor ; Glioma/*drug therapy/pathology ; Humans ; Lentivirus/*genetics/metabolism ; Mice ; Mice, Inbred BALB C ; Molecular Sequence Data ; Neoplasm Invasiveness ; Neoplasm Transplantation ; RNA, Small Interfering/metabolism ; Telomerase/*genetics/*metabolism ; Telomere/*ultrastructure ; },
abstract = {Glioma cells are characterized by their invasiveness and resistance against conventional therapeutics. Telomerase activity has been suggested to be an important target for glioma treatment. Here we assessed the anticancer effects and its potential mechanisms of lentiviral vector mediated siRNA knock-down of the human telomerase reverse transcriptase (hTERT) in U87MG human glioblastoma cells. Stable expression of anti-hTERT siRNA reduced the hTERT expression and TRAP assay telomerase activity to barely detectable levels. Injection of lentiviral vectors encoding anti-hTERT siRNA significantly inhibited the growth of pre-established macroscopic xenograft tumors, which was in contrast to the finding that no obvious effects on cell growth, cell cycle progression and telomere length were observed in anti-hTERT siRNA expressing U87MG cells during short-term in vitro cultures. The in vivo glioma growth inhibition effect was already evident in the period coincided with no detectable telomere length changes, suggesting that hTERT inhibition may hinder glioma cell growth in a telomere length-independent manner. Importantly, transwell migration assay showed profound inhibitory effect on the invasive capacity of U87MG cells following short-term anti-hTERT siRNA expression. Thus, efficient knock-down of hTERT can inhibit glioma cell proliferation and migration prior to its effect on telomere length.},
}
@article {pmid17610516,
year = {2007},
author = {Farman, ML},
title = {Telomeres in the rice blast fungus Magnaporthe oryzae: the world of the end as we know it.},
journal = {FEMS microbiology letters},
volume = {273},
number = {2},
pages = {125-132},
doi = {10.1111/j.1574-6968.2007.00812.x},
pmid = {17610516},
issn = {0378-1097},
support = {5P20RR016481-03/RR/NCRR NIH HHS/United States ; },
mesh = {Chromosomal Instability ; Chromosomes, Fungal ; DNA Helicases/genetics ; Gene Rearrangement ; Genes, Fungal ; Magnaporthe/*genetics/isolation &amp; purification/pathogenicity ; Oryza/microbiology ; Retroelements/physiology ; Sequence Analysis, DNA ; Telomere/chemistry/*physiology ; },
abstract = {The subtelomeres of many microbial eukaryotes are highly enriched in genes with roles in niche adaptation. Host and cultivar specificity genes in the rice blast fungus Magnaporthe oryzae also tend to be located near telomeres. In addition, the M. oryzae telomeres are highly variable chromosome regions. These observations suggested that plant pathogenic fungi might also use subtelomere regions for the amplification of genes with adaptive significance. Targeted sequencing of the M. oryzae telomeres provided an opportunity to test this hypothesis, and has yielded valuable insights into the organization and dynamics of these important chromosome regions.},
}
@article {pmid19662189,
year = {2007},
author = {Sainger, RN and Telang, SD and Shukla, SN and Patel, PS},
title = {Clinical significance of telomere length and associated proteins in oral cancer.},
journal = {Biomarker insights},
volume = {2},
number = {},
pages = {9-19},
pmid = {19662189},
issn = {1177-2719},
abstract = {PURPOSE: Telomere shortening is an important event during carcinogenesis. Although studies suggest role of multiple proteins in telomere length regulation, there is dearth of reports in oral cancer which is a leading malignancy in Asian countries especially in India. Thus the present study was carried out to study these mechanisms and explore the pathways involved in telomere-telomerase regulation and identify possible prognostic markers to understand the biology of oral tumors for better treatment approaches.<br><br>METHODS: Telomere length was determined by Southern Hybridisation method, telomeric repeat binding factor (TRF) 1 and 2 expression was detected by Western blot method and telomerase activation by telomeric repeat amplification protocol. Statistical analysis was done using SPSS (Version 10) software.<br><br>RESULTS: Significant shortening of telomeres was seen in the tumor tissues as compared to normal tissues. Poor prognosis was observed in the patients with higher telomere length in malignant tissue, higher tumor to normal telomere length ratio (T/N TRF LR). Expression of TRF-2 but not TRF-1 protein was significantly higher in the malignant tissues. We also observed telomerase activation in 75 malignant tissues.<br><br>CONCLUSIONS: Our results reveal significant clinical usefulness of telomere length, T/N TRF LR and telomerase activation in the prognosis of oral cancer patients. TRF-2 overexpression in malignant tissues appears to play an important role in telomere length shortening in oral cancer.},
}
@article {pmid19595878,
year = {2006},
author = {Franco, S and Blasco, MA and Siedlak, SL and Harris, PL and Moreira, PI and Perry, G and Smith, MA},
title = {Telomeres and telomerase in Alzheimer's disease: epiphenomena or a new focus for therapeutic strategy?.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {2},
number = {3},
pages = {164-168},
doi = {10.1016/j.jalz.2006.03.001},
pmid = {19595878},
issn = {1552-5279},
abstract = {New approaches to the elucidation of Alzheimer disease, even those with solid data, are often ignored or dismissed as epiphenomenal when they differ from the mainstream or theoretical expectations. Here we present a new piece to the puzzle, decreases in telomere length, and telomerase expression in neuronal populations known to be vulnerable to degeneration and death in Alzheimer's disease. We can present the answers to the question "what," but the "why," "when," and "how" are not so easily answered. The goal of this report is to prompt discussion and more intensive study of this finding toward a new focus of therapeutic strategy.},
}
@article {pmid17708963,
year = {1997},
author = {Lusing, AJ},
title = {The identification of telomerase subunits: catalysing telomere research.},
journal = {Trends in cell biology},
volume = {7},
number = {8},
pages = {299-302},
doi = {10.1016/S0962-8924(97)01110-0},
pmid = {17708963},
issn = {0962-8924},
abstract = {Telomerase is the ribonucleoprotein complex responsible for the addition of simple sequences onto the physical ends, or telomeres, of most eukaryotic chromosomes. The activity of this complex is essential for the maintenance of genome integrity. Recent studies have begun to dissect the mechanism of telomerase action through the identification of a reverse-transcriptase-like activity as a catalytic subunit. At the same time, the regulation of telomere length appears to be a complex and possibly species-specific process, involving factors that are likely to interact with both the telomere and telomerase.},
}
@article {pmid17821645,
year = {1995},
author = {Spencer, F},
title = {The telomere.},
journal = {Science (New York, N.Y.)},
volume = {269},
number = {5231},
pages = {1743-1744},
doi = {10.1126/science.269.5231.1743-a},
pmid = {17821645},
issn = {0036-8075},
}
@article {pmid17609387,
year = {2007},
author = {Hsu, M and McEachern, MJ and Dandjinou, AT and Tzfati, Y and Orr, E and Blackburn, EH and Lue, NF},
title = {Telomerase core components protect Candida telomeres from aberrant overhang accumulation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {104},
number = {28},
pages = {11682-11687},
pmid = {17609387},
issn = {0027-8424},
support = {GM069507/GM/NIGMS NIH HHS/United States ; GM 26259/GM/NIGMS NIH HHS/United States ; DE11356/DE/NIDCR NIH HHS/United States ; R01 GM069507/GM/NIGMS NIH HHS/United States ; R01 GM026259/GM/NIGMS NIH HHS/United States ; R37 GM026259/GM/NIGMS NIH HHS/United States ; },
mesh = {Candida/*enzymology/genetics ; DNA, Fungal/*metabolism ; RNA/*physiology ; Telomerase/genetics/*physiology ; Telomere/genetics/*metabolism ; },
abstract = {Telomerase is a cellular reverse transcriptase that extends one strand (the G-strand) of the telomere terminal repeats. Aside from this role in telomere length maintenance, telomerase has been proposed to serve a protective function at chromosome ends, although this is not well understood mechanistically. Earlier analysis suggests that, in the pathogenic yeast Candida albicans, the catalytic reverse transcriptase subunit of telomerase (TERT/EST2) can protect telomeres against nucleolytic degradation. In this report we demonstrate that the RNA component (TER1) has a similar function; in addition to complete loss of telomerase activity and progressive telomere attrition, the ter1-DeltaDelta strains manifested a dramatic increase in the amount of G-strand overhangs, consistent with aberrant degradation of the complementary C-strand. We also demonstrate that a catalytically incompetent EST2 protein can suppress such overhang accumulation in the est2-DeltaDelta mutant to the same extent as the wild-type protein. Altogether, our data support the notion that the Candida telomerase core components mediate a protective function through a mechanism that is independent of its catalytic activity.},
}
@article {pmid17604920,
year = {2007},
author = {Castella, M and Puerto, S and Creus, A and Marcos, R and Surralles, J},
title = {Telomere length modulates human radiation sensitivity in vitro.},
journal = {Toxicology letters},
volume = {172},
number = {1-2},
pages = {29-36},
doi = {10.1016/j.toxlet.2007.05.012},
pmid = {17604920},
issn = {0378-4274},
mesh = {Adult ; Cells, Cultured ; Chromosomal Instability/*radiation effects ; Chromosomes, Human/*radiation effects ; Humans ; Lymphocytes/*drug effects ; Micronucleus Tests ; Radiation Tolerance/*genetics ; Reference Values ; *Telomere ; },
abstract = {The molecular basis of the interindividual differences of normal individuals to ionizing radiation is poorly understood. Several studies in telomerase KO mice with short telomeres have uncovered an inverse relationship between telomere length and radiation sensitivity. The present work aims to determine if chromosome radiosensitivity is correlated with telomere length in healthy individuals. With this purpose, individual radiosensitivity was determined by the micronucleus assay in peripheral blood lymphocytes from two groups of individuals of the same age but with highly heterogeneous telomere length, selected from a population of 181 individuals where we previously measured telomere length. Our study demonstrates that telomere length modulates chromosome in vitro radiosensitivity in healthy individuals as the group with short telomeres presented higher frequencies of ionizing radiation-induced micronuclei when compared to the long telomeres group. This result supports the conclusion that individual telomere length acts as biomarker of individual chromosome instability upon exposure to ionizing radiation.},
}
@article {pmid17594061,
year = {2007},
author = {Guan, JZ and Maeda, T and Sugano, M and Oyama, J and Higuchi, Y and Makino, N},
title = {Change in the telomere length distribution with age in the Japanese population.},
journal = {Molecular and cellular biochemistry},
volume = {304},
number = {1-2},
pages = {353-360},
pmid = {17594061},
issn = {0300-8177},
mesh = {Adult ; Age Factors ; Aged ; Aging/*genetics ; Cellular Senescence/genetics ; Female ; Humans ; Japan ; Male ; Middle Aged ; Polymorphism, Restriction Fragment Length ; Population ; Telomere/*metabolism/physiology ; },
abstract = {Telomeres play a role in cellular aging and they may also contribute to the genetic basis of human aging and longevity. A gradual loss of the telomeric repeat sequences has been reported in adult tissue specimens. This study determined the percentage of telomere restriction fragment in various molecular-sized regions in addition to measuring the average telomere length. Mean telomere restriction fragment (TRF) length was determined by Southern blot analysis using a longer telomeric repeat probe with higher sensitivity. A significant decrease in longer telomere fragments and a quick increase in the shortest fragments were observed, especially in male subjects. There was a tendency that the age-adjusted telomere length was longer in females than that observed in males, while males lose the telomeric sequence faster than females. These data indicated that the percentage of longer telomeres fragments decreased, while the shortest fragments increased quickly with age. In addition, the longest telomere fragments decreased and the short fragments increased with a relatively stable frequency with age. There was also a significant difference in the longest telomere fragment percentage between males and female in their 40s and 50s, whereas no difference was observed in the mean TRF length. Interestingly, the changing rate of the longest and the shortest range group of TRF percentage associated with aging seemed quite different between before and after 50-year old with a gender-related contrast. This contrast implies a drastic change around the age of 50 of unknown factors that affect telomere attrition.},
}
@article {pmid17590086,
year = {2007},
author = {Vega, LR and Phillips, JA and Thornton, BR and Benanti, JA and Onigbanjo, MT and Toczyski, DP and Zakian, VA},
title = {Sensitivity of yeast strains with long G-tails to levels of telomere-bound telomerase.},
journal = {PLoS genetics},
volume = {3},
number = {6},
pages = {e105},
pmid = {17590086},
issn = {1553-7404},
support = {R01 GM043265/GM/NIGMS NIH HHS/United States ; 5T32 CA009528/CA/NCI NIH HHS/United States ; R01 GM070539/GM/NIGMS NIH HHS/United States ; R37 GM026938/GM/NIGMS NIH HHS/United States ; R01 GM43265/GM/NIGMS NIH HHS/United States ; T32 CA009528/CA/NCI NIH HHS/United States ; },
mesh = {Anaphase-Promoting Complex-Cyclosome ; DNA Helicases/biosynthesis/genetics ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/biosynthesis/genetics ; Telomerase/*physiology ; Telomere/*metabolism ; Ubiquitin-Protein Ligase Complexes/deficiency/genetics ; },
abstract = {The Saccharomyces cerevisiae Pif1p helicase is a negative regulator of telomere length that acts by removing telomerase from chromosome ends. The catalytic subunit of yeast telomerase, Est2p, is telomere associated throughout most of the cell cycle, with peaks of association in both G1 phase (when telomerase is not active) and late S/G2 phase (when telomerase is active). The G1 association of Est2p requires a specific interaction between Ku and telomerase RNA. In mutants lacking this interaction, telomeres were longer in the absence of Pif1p than in the presence of wild-type PIF1, indicating that endogenous Pif1p inhibits the active S/G2 form of telomerase. Pif1p abundance was cell cycle regulated, low in G1 and early S phase and peaking late in the cell cycle. Low Pif1p abundance in G1 phase was anaphase-promoting complex dependent. Thus, endogenous Pif1p is unlikely to act on G1 bound Est2p. Overexpression of Pif1p from a non-cell cycle-regulated promoter dramatically reduced viability in five strains with impaired end protection (cdc13-1, yku80Delta, yku70Delta, yku80-1, and yku80-4), all of which have longer single-strand G-tails than wild-type cells. This reduced viability was suppressed by deleting the EXO1 gene, which encodes a nuclease that acts at compromised telomeres, suggesting that the removal of telomerase by Pif1p exposed telomeres to further C-strand degradation. Consistent with this interpretation, depletion of Pif1p, which increases the amount of telomere-bound telomerase, suppressed the temperature sensitivity of yku70Delta and cdc13-1 cells. Furthermore, eliminating the pathway that recruits Est2p to telomeres in G1 phase in a cdc13-1 strain also reduced viability. These data suggest that wild-type levels of telomere-bound telomerase are critical for the viability of strains whose telomeres are already susceptible to degradation.},
}
@article {pmid17589526,
year = {2007},
author = {Potts, PR and Yu, H},
title = {The SMC5/6 complex maintains telomere length in ALT cancer cells through SUMOylation of telomere-binding proteins.},
journal = {Nature structural &amp; molecular biology},
volume = {14},
number = {7},
pages = {581-590},
doi = {10.1038/nsmb1259},
pmid = {17589526},
issn = {1545-9993},
mesh = {Cell Cycle Proteins/analysis/antagonists &amp; inhibitors/*metabolism ; Cell Line, Tumor ; Chromosomal Proteins, Non-Histone ; Humans ; Ligases/metabolism ; Neoplasms/*genetics ; Protein Processing, Post-Translational ; Recombination, Genetic ; Small Ubiquitin-Related Modifier Proteins/metabolism ; Telomere/chemistry/*genetics ; Telomeric Repeat Binding Protein 1/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {Most cancer cells activate telomerase to elongate telomeres and achieve unlimited replicative potential. Some cancer cells cannot activate telomerase and use telomere homologous recombination (HR) to elongate telomeres, a mechanism termed alternative lengthening of telomeres (ALT). A hallmark of ALT cells is the recruitment of telomeres to PML bodies (termed APBs). Here, we show that the SMC5/6 complex localizes to APBs in ALT cells and is required for targeting telomeres to APBs. The MMS21 SUMO ligase of the SMC5/6 complex SUMOylates multiple telomere-binding proteins, including TRF1 and TRF2. Inhibition of TRF1 or TRF2 SUMOylation prevents APB formation. Depletion of SMC5/6 subunits by RNA interference inhibits telomere HR, causing telomere shortening and senescence in ALT cells. Thus, the SMC5/6 complex facilitates telomere HR and elongation in ALT cells by promoting APB formation through SUMOylation of telomere-binding proteins.},
}
@article {pmid17588641,
year = {2007},
author = {Aida, J and Izumiyama-Shimomura, N and Nakamura, K and Ishii, A and Ishikawa, N and Honma, N and Kurabayashi, R and Kammori, M and Poon, SS and Arai, T and Takubo, K},
title = {Telomere length variations in 6 mucosal cell types of gastric tissue observed using a novel quantitative fluorescence in situ hybridization method.},
journal = {Human pathology},
volume = {38},
number = {8},
pages = {1192-1200},
doi = {10.1016/j.humpath.2006.11.023},
pmid = {17588641},
issn = {0046-8177},
mesh = {Adenocarcinoma/genetics/*metabolism/pathology ; Aged ; Aged, 80 and over ; Cell Proliferation ; Centromere/genetics/metabolism ; Female ; Gastric Mucosa/*metabolism/pathology ; Helicobacter Infections/genetics/metabolism/pathology ; Humans ; Immunoenzyme Techniques ; *In Situ Hybridization, Fluorescence ; Ki-67 Antigen/metabolism ; Male ; Oligonucleotide Probes/analysis/genetics ; Peptide Nucleic Acids/analysis/genetics ; Stomach Neoplasms/genetics/*metabolism/pathology ; Telomere/genetics/*metabolism ; },
abstract = {We developed a novel method for evaluating telomere length in 6 cell types of noncancerous and cancerous mucosal tissues from 11 cases of gastric neoplasm using the quantitative fluorescence in situ hybridization method with telomere and centromere peptide nucleic acid probes. Our telomere length estimates were determined from the background-corrected telomere intensity divided by the background-corrected centromere intensity (telomere-to-centromere ratio). Our results indicated that telomere lengths in each of the cases studied were reduced in turn from fibroblasts to fundic gland cells, to glandular neck cells, and then to surface foveolar cells. However, the telomere lengths of intestinalized cells located among fundic glands were not always shorter than those of the other cell types, as reported previously by others. Helicobacter pylori infection was suggested to induce the telomere shortening seen in the fundic glands. Although the mean telomere lengths varied among the 8 gastric cancer cases, correlation of the telomere lengths with the Ki-67 labeling index was established after normalization with the fibroblast measurements. We conclude that our telomere-to-centromere ratio method can reliably estimate the telomere lengths of the 6 cell types in the gastric mucosa and clarifies the relationship between proliferative activity and the telomere length of cancer cells.},
}
@article {pmid17587609,
year = {2007},
author = {Gupta, N and Taneja, R and Pandey, A and Mukesh, M and Singh, H and Gupta, SC},
title = {Replicative senescence, telomere shortening and cell proliferation rate in Gaddi goat's skin fibroblast cell line.},
journal = {Cell biology international},
volume = {31},
number = {10},
pages = {1257-1264},
doi = {10.1016/j.cellbi.2007.05.004},
pmid = {17587609},
issn = {1065-6995},
mesh = {Animals ; Cell Nucleus/metabolism ; *Cell Proliferation ; Cells, Cultured ; *Cellular Senescence ; Fibroblasts/*cytology ; Goats ; Karyotyping ; Skin/*cytology/metabolism ; Telomere/*physiology ; },
abstract = {We assessed aging in continuous donor skin fibroblast cell line GGM5 up to the 25th passage by in vitro replicative senescence, telomere dynamics and chromosomal abnormalities. Cell proliferation rate increased from 0.84+/-0.26 (primary cells) to 1.20+/-0.17 (13-15 passage group) per day and reduced to 0.65+/-0.14 in 22-25 passages. Cell proliferation rate was reduced by 45.7% after 87.62 CPDs. Cell viability reduced from 100% to 97.4% up to the 25th passages. Frequency of beta gal(+) cells increased in successive passages and days in culture. The correlation coefficient between frequency of beta gal(+) cells and growth rate was -0.50 to -0.61. Loss of mean TRF length was 13.8 nucleotides (passage 15) to 95.4 nucleotides per cell division in later passages. All cells showed Robertsonian translocation in 22-25 passaged cells. The SCNT pre-implantation embryos production was highest (22.5%) in donor cells used from 10-15 passages as compared to early (<or=5) and late (22-25 passages). Our findings supports that cell proliferation rates, beta gal staining, mean TRF loss and karyological profile are useful marker for evaluation of competent nuclear donor.},
}
@article {pmid17586654,
year = {2007},
author = {Hong, JP and Byun, MY and Koo, DH and An, K and Bang, JW and Chung, IK and An, G and Kim, WT},
title = {Suppression of RICE TELOMERE BINDING PROTEIN 1 results in severe and gradual developmental defects accompanied by genome instability in rice.},
journal = {The Plant cell},
volume = {19},
number = {6},
pages = {1770-1781},
pmid = {17586654},
issn = {1040-4651},
mesh = {Cytogenetic Analysis ; DNA, Bacterial ; Flowers/growth &amp; development ; Genome, Plant ; *Genomic Instability ; Mutagenesis, Insertional ; Mutant Proteins/isolation &amp; purification/metabolism ; Oryza/*genetics/*growth &amp; development ; Phenotype ; Plant Proteins/*metabolism ; Plants, Genetically Modified ; Pollen/cytology ; *Suppression, Genetic ; Telomere/metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Although several potential telomere binding proteins have been identified in higher plants, their in vivo functions are still unknown at the plant level. Both knockout and antisense mutants of RICE TELOMERE BINDING PROTEIN1 (RTBP1) exhibited markedly longer telomeres relative to those of the wild type, indicating that the amount of functional RTBP1 is inversely correlated with telomere length. rtbp1 plants displayed progressive and severe developmental abnormalities in both germination and postgermination growth of vegetative organs over four generations (G1 to G4). Reproductive organ formation, including panicles, stamens, and spikelets, was also gradually and severely impaired in G1 to G4 mutants. Up to 11.4, 17.2, and 26.7% of anaphases in G2, G3, and G4 mutant pollen mother cells, respectively, exhibited one or more chromosomal fusions, and this progressively increasing aberrant morphology was correlated with an increased frequency of anaphase bridges containing telomeric repeat DNA. Furthermore, 35S:anti-RTBP1 plants expressing lower levels of RTBP1 mRNA exhibited developmental phenotypes intermediate between the wild type and mutants in all aspects examined, including telomere length, vegetative and reproductive growth, and degree of genomic anomaly. These results suggest that RTBP1 plays dual roles in rice (Oryza sativa), as both a negative regulator of telomere length and one of positive and functional components for proper architecture of telomeres.},
}
@article {pmid17586599,
year = {2007},
author = {Brassart, B and Gomez, D and De Cian, A and Paterski, R and Montagnac, A and Qui, KH and Temime-Smaali, N and Trentesaux, C and Mergny, JL and Gueritte, F and Riou, JF},
title = {A new steroid derivative stabilizes g-quadruplexes and induces telomere uncapping in human tumor cells.},
journal = {Molecular pharmacology},
volume = {72},
number = {3},
pages = {631-640},
doi = {10.1124/mol.107.036574},
pmid = {17586599},
issn = {0026-895X},
mesh = {Apocynaceae/chemistry ; Cell Line, Tumor ; DNA/metabolism ; DNA Damage ; Dose-Response Relationship, Drug ; Humans ; Ligands ; Molecular Structure ; Oligonucleotides/chemical synthesis/chemistry/metabolism ; Plant Leaves/chemistry ; Pregnanes/chemistry/isolation &amp; purification/metabolism/pharmacology ; Quinolinium Compounds/*chemistry/pharmacology ; Shelterin Complex ; Steroids/chemistry/isolation &amp; purification/*metabolism/pharmacology ; Telomerase/antagonists &amp; inhibitors ; Telomere/chemistry/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Human telomeric DNA consists of tandem repeats of the sequence d(TTAGGG) with a 3' single-stranded extension (the G-overhang). The stabilization of G-quadruplexes in the human telomeric sequence by small-molecule ligands inhibits the activity of telomerase and results in telomere uncapping, leading to senescence or apoptosis of tumor cells. Therefore, the search for new and selective G-quadruplex ligands is of considerable interest because a selective ligand might provide a telomere-targeted therapeutic approach to treatment of cancer. We have screened a bank of derivatives from natural and synthetic origin using a temperature fluorescence assay and have identified two related compounds that induce G-quadruplex stabilization: malouetine and steroid FG. These steroid derivatives have nonplanar and nonaromatic structures, different from currently known G-quadruplex ligands. Malouetine is a natural product isolated from the leaves of Malouetia bequaaertiana E. Woodson and is known for its curarizing and DNA-binding properties. Steroid FG, a funtumine derivative substituted with a guanylhydrazone moiety, interacted selectively with the telomeric G-quadruplex in vitro. This derivative induced senescence and telomere shortening of HT1080 tumor cells at submicromolar concentrations, corresponding to the phenotypic inactivation of telomerase activity. In addition, steroid FG induced a rapid degradation of the telomeric G-overhang and the formation of anaphase bridges, characteristics of telomere uncapping. Finally, the expression of protection of telomere 1 (POT1) induced resistance to the growth effect of steroid FG. These results indicate that these steroid ligands represent a new class of telomere-targeted agents with potential as antitumor drugs.},
}
@article {pmid17581575,
year = {2007},
author = {Verdun, RE and Karlseder, J},
title = {Replication and protection of telomeres.},
journal = {Nature},
volume = {447},
number = {7147},
pages = {924-931},
doi = {10.1038/nature05976},
pmid = {17581575},
issn = {1476-4687},
mesh = {Animals ; Cellular Senescence/genetics ; DNA Damage ; DNA Repair ; *DNA Replication ; Humans ; Neoplasms/genetics/pathology ; Telomere/*genetics/*metabolism ; },
abstract = {During the evolution of linear genomes, it became essential to protect the natural chromosome ends to prevent triggering of the DNA-damage repair machinery and enzymatic attack. Telomeres - tightly regulated complexes consisting of repetitive G-rich DNA and specialized proteins - accomplish this task. Telomeres not only conceal linear chromosome ends from detection and inappropriate repair but also provide a buffer to counteract replication-associated shortening. Lessons from many model organisms have taught us about the complications of maintaining these specialized structures. Here, we discuss how telomeres interact and cooperate with the DNA replication and DNA-damage repair machineries.},
}
@article {pmid17580124,
year = {2007},
author = {Lira, CB and Giardini, MA and Neto, JL and Conte, FF and Cano, MI},
title = {Telomere biology of trypanosomatids: beginning to answer some questions.},
journal = {Trends in parasitology},
volume = {23},
number = {8},
pages = {357-362},
doi = {10.1016/j.pt.2007.06.005},
pmid = {17580124},
issn = {1471-4922},
mesh = {Animals ; DNA, Protozoan/*chemistry/*genetics ; *Evolution, Molecular ; Species Specificity ; *Telomere ; Trypanosoma brucei brucei/chemistry/genetics ; Trypanosomatina/*chemistry/*genetics ; },
abstract = {Studies of telomere structure and maintenance in trypanosomatids have provided insights into the evolutionary origin and conservation of some telomeric components shared by trypanosomes and vertebrates. For example, trypanosomatid telomeres are maintained by telomerase and consist of the canonical TTAGGG repeats, which in Trypanosoma brucei can form telomeric loops (t-loops). However, the telomeric chromatin of trypanosomatids is composed of organism-specific proteins and other proteins that share little sequence similarity with their vertebrate counterparts. Because telomere maintenance mechanisms are essential for genome stability, we propose that the particular features shown by the trypanosome telomeric chromatin hold the key for the design of antiparasitic drugs.},
}
@article {pmid17567834,
year = {2007},
author = {Trkova, M and Prochazkova, K and Krutilkova, V and Sumerauer, D and Sedlacek, Z},
title = {Telomere length in peripheral blood cells of germline TP53 mutation carriers is shorter than that of normal individuals of corresponding age.},
journal = {Cancer},
volume = {110},
number = {3},
pages = {694-702},
doi = {10.1002/cncr.22834},
pmid = {17567834},
issn = {0008-543X},
mesh = {Adult ; Age of Onset ; Child ; Female ; Genetic Carrier Screening ; Genetic Predisposition to Disease ; Germ-Line Mutation/*genetics ; Humans ; Li-Fraumeni Syndrome/blood/*genetics ; Male ; Neoplasms/blood/*genetics ; RNA, Messenger/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*physiology ; Tumor Suppressor Protein p53/*genetics ; },
abstract = {BACKGROUND: A decrease in the age at cancer onset and increase in cancer incidence in successive generations in Li-Fraumeni syndrome (LFS) families with germline TP53 mutations have been previously described. In the current study a possible relation was analyzed between telomere length and cancer onset in TP53 mutation carriers.<br><br>METHODS: Telomere length was measured using real-time quantitative polymerase chain reaction (PCR) in 20 carriers of germline TP53 mutations and in 83 unrelated healthy individuals. According to the age at blood sampling, patients and controls were divided into 2 age groups, children and adults. Telomere length was correlated to TP53 mutation status and telomere shortening in patients to the age at cancer onset. A t-test and linear regression were used to analyze the data.<br><br>RESULTS: Compared with healthy controls, telomere length was significantly shorter both in the child (P = .001) and adult (P = .034) germline T53 mutation carriers. Although a statistically significant correlation between telomere shortening and the age at cancer onset was not observed, there was a trend of shorter telomeres in mutation carriers affected in childhood compared with those affected later in life. Neither cancer therapy nor sex differences were likely to affect the results.<br><br>CONCLUSIONS: The findings suggest a possible link between the carriership of a germline TP53 mutation, telomere length, predisposition to early-onset cancer, and anticipation in LFS.},
}
@article {pmid17565916,
year = {2007},
author = {Aydos, SE and Tükün, A},
title = {Does telomere length affect blood pressure?.},
journal = {Advances in therapy},
volume = {24},
number = {2},
pages = {269-272},
doi = {10.1007/BF02849894},
pmid = {17565916},
issn = {0741-238X},
mesh = {Blood Pressure/*genetics ; Body Mass Index ; Female ; Humans ; Leukocytes ; Middle Aged ; Statistics, Nonparametric ; *Telomere ; },
abstract = {Telomeres--tandem repeats at the ends of mammalian chromosomes--serve as clocks that pace cellular aging in vitro and in vivo and they may be a major determinant of human aging, not only at the cellular level but also at the organ and perhaps systemic levels. In industrialized nations, pulse pressure rises with age, and this might serve as a phenotype of biologic aging of the vasculature. In this study, investigators explored the relationship between telomere length in white blood cells and systolic/diastolic and pulse pressures. Telomere lengths of 37 female volunteers who were 50 years of age were measured with the fiber fluorescence in situ hybridization technique. With the use of Spearman's correlation coefficient, no relationship was found between pulse pressure, systolic blood pressure, diastolic blood pressure, body mass index, and telomere length. The results suggest that telomere length is not an indicator of blood pressure dynamics.},
}
@article {pmid17565702,
year = {2007},
author = {Graakjaer, J and Christensen, R and Kolvraa, S and Serakinci, N},
title = {Mesenchymal stem cells with high telomerase expression do not actively restore their chromosome arm specific telomere length pattern after exposure to ionizing radiation.},
journal = {BMC molecular biology},
volume = {8},
number = {},
pages = {49},
pmid = {17565702},
issn = {1471-2199},
mesh = {Cell Line, Transformed ; Chromosomes, Human/genetics/metabolism/*radiation effects ; Humans ; Mesenchymal Stem Cells/*enzymology/metabolism/*radiation effects ; RNA Probes/metabolism ; Radiation, Ionizing ; Telomerase/*metabolism ; Telomere/genetics/metabolism/*radiation effects ; Transduction, Genetic ; },
abstract = {BACKGROUND: Previous studies have demonstrated that telomeres in somatic cells are not randomly distributed at the end of the chromosomes. We hypothesize that these chromosome arm specific differences in telomere length (the telomere length pattern) may be actively maintained. In this study we investigate the existence and maintenance of the telomere length pattern in stem cells. For this aim we studied telomere length in primary human mesenchymal stem cells (hMSC) and their telomerase-immortalised counterpart (hMSC-telo1) during extended proliferation as well as after irradiation. Telomere lengths were measured using Fluorescence In Situ Hybridization (Q-FISH).<br><br>RESULTS: A telomere length pattern was found to exist in primary hMSC's as well as in hMSC-telo1. This pattern is similar to what was previously found in lymphocytes and fibroblasts. The cells were then exposed to a high dose of ionizing radiation. Irradiation caused profound changes in chromosome specific telomere lengths, effectively destroying the telomere length pattern. Following long term culturing after irradiation, a telomere length pattern was found to re-emerge. However, the new telomere length pattern did not resemble the telomere length pattern observed before irradiation.<br><br>CONCLUSION: Our findings indicate that a telomere length pattern does exist in mesenchymal stem cells and that the pattern is not actively re-established after destruction by irradiation.},
}
@article {pmid17562870,
year = {2007},
author = {Chen, LY and Liu, D and Songyang, Z},
title = {Telomere maintenance through spatial control of telomeric proteins.},
journal = {Molecular and cellular biology},
volume = {27},
number = {16},
pages = {5898-5909},
pmid = {17562870},
issn = {0270-7306},
mesh = {Active Transport, Cell Nucleus ; Amino Acid Sequence ; Animals ; Cell Nucleus/metabolism ; Humans ; Mice ; Models, Biological ; Molecular Sequence Data ; Nuclear Export Signals ; Protein Binding ; Protein Structure, Tertiary ; Protein Transport ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {The six human telomeric proteins TRF1, TRF2, RAP1, TIN2, POT1, and TPP1 can form a complex called the telosome/shelterin, which is required for telomere protection and length control. TPP1 has been shown to regulate both POT1 telomere localization and telosome assembly through its binding to TIN2. It remains to be determined where such interactions take place and whether cellular compartmentalization of telomeric proteins is important for telomere maintenance. We systematically investigated here the cellular localization and interactions of human telomeric proteins. Interestingly, we found TIN2, TPP1, and POT1 to localize and interact with each other in both the cytoplasm and the nucleus. Unexpectedly, TPP1 contains a functional nuclear export signal that directly controls the amount of TPP1 and POT1 in the nucleus. Furthermore, binding of TIN2 to TPP1 promotes the nuclear localization of TPP1 and POT1. We also found that disrupting TPP1 nuclear export could result in telomeric DNA damage response and telomere length disregulation. Our findings highlight how the coordinated interactions between TIN2, TPP1, and POT1 in the cytoplasm regulate the assembly and function of the telosome in the nucleus and indicate for the first time the importance of nuclear export and spatial control of telomeric proteins in telomere maintenance.},
}
@article {pmid17562861,
year = {2007},
author = {Yu, EY and Steinberg-Neifach, O and Dandjinou, AT and Kang, F and Morrison, AJ and Shen, X and Lue, NF},
title = {Regulation of telomere structure and functions by subunits of the INO80 chromatin remodeling complex.},
journal = {Molecular and cellular biology},
volume = {27},
number = {16},
pages = {5639-5649},
pmid = {17562861},
issn = {0270-7306},
support = {R01 GM062631/GM/NIGMS NIH HHS/United States ; K22 CA100017/CA/NCI NIH HHS/United States ; GM62631/GM/NIGMS NIH HHS/United States ; P30 ES007784/ES/NIEHS NIH HHS/United States ; ES07784/ES/NIEHS NIH HHS/United States ; },
mesh = {*Chromatin Assembly and Disassembly ; Microfilament Proteins/metabolism ; Mutation/genetics ; Protein Binding ; Protein Structure, Tertiary ; Protein Subunits/metabolism ; Protein Transport ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; Telomerase/chemistry/metabolism ; Telomere/*metabolism ; },
abstract = {ATP-dependent chromatin remodeling complexes have been implicated in the regulation of transcription, replication, and more recently DNA double-strand break repair. Here we report that the Ies3p subunit of the Saccharomyces cerevisiae INO80 chromatin remodeling complex interacts with a conserved tetratricopeptide repeat domain of the telomerase protein Est1p. Deletion of IES3 and some other subunits of the complex induced telomere elongation and altered telomere position effect. In telomerase-negative mutants, loss of Ies3p delayed the emergence of recombinational survivors and stimulated the formation of extrachromosomal telomeric circles in survivors. Deletion of IES3 also resulted in heightened levels of telomere-telomere fusions in telomerase-deficient strains. In addition, a delay in survivor formation was observed in an Arp8p-deficient mutant. Because Arp8p is required for the chromatin remodeling activity of the INO80 complex, the complex may promote recombinational telomere maintenance by altering chromatin structure. Consistent with this notion, we observed preferential localization of multiple subunits of the INO80 complex to telomeres. Our results reveal novel functions for a subunit of the telomerase complex and the INO80 chromatin remodeling complex.},
}
@article {pmid17561506,
year = {2007},
author = {Donigian, JR and de Lange, T},
title = {The role of the poly(ADP-ribose) polymerase tankyrase1 in telomere length control by the TRF1 component of the shelterin complex.},
journal = {The Journal of biological chemistry},
volume = {282},
number = {31},
pages = {22662-22667},
doi = {10.1074/jbc.M702620200},
pmid = {17561506},
issn = {0021-9258},
support = {CA076027/CA/NCI NIH HHS/United States ; T32 CA0096673/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Cell Line ; Fluorescent Antibody Technique, Indirect ; Gene Expression Regulation, Enzymologic ; Humans ; Mice ; Molecular Sequence Data ; Poly(ADP-ribose) Polymerases/*metabolism ; Protein Binding ; Shelterin Complex ; Tankyrases/biosynthesis/*physiology ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; },
abstract = {Tankyrase1 is a multifunctional poly(ADP-ribose) polymerase that can localize to telomeres through its interaction with the shelterin component TRF1. Tankyrase1 poly(ADP-ribosyl)ates TRF1 in vitro, and its nuclear overexpression leads to loss of TRF1 and telomere elongation, suggesting that tankyrase1 is a positive regulator of telomere length. In agreement with this proposal, we show that tankyrase1 RNA interference results in telomere shortening proportional to the level of knockdown. Furthermore, we show that a tankyrase1-resistant form of TRF1 enforced normal telomere length control, indicating that tankyrase1 is not required downstream of TRF1 in this pathway. Thus, in human cells, tankyrase1 appears to act upstream of TRF1, promoting telomere elongation through the removal of TRF1. This pathway appears absent from mouse cells. We show that murine TRF1, which lacks the canonical tankyrase1-binding site, is not a substrate for tankyrase1 poly(ADP-ribosyl)sylation in vitro. Furthermore, overexpression of tankyrase1 in mouse nuclei did not remove TRF1 from telomeres and had no detectable effect on other components of mouse shelterin. We propose that the tankyrase1-controlled telomere extension is a human-specific elaboration that allows additional control over telomere length in telomerase positive cells.},
}
@article {pmid17557836,
year = {2007},
author = {Villasante, A and Abad, JP and Méndez-Lago, M},
title = {Centromeres were derived from telomeres during the evolution of the eukaryotic chromosome.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {104},
number = {25},
pages = {10542-10547},
pmid = {17557836},
issn = {0027-8424},
mesh = {*Biological Evolution ; Centromere/*genetics ; Chromosomes/*genetics ; Eukaryotic Cells/*cytology ; Models, Genetic ; Telomere/*genetics ; },
abstract = {The centromere is the DNA region of the eukaryotic chromosome that determines kinetochore formation and sister chromatid cohesion. Centromeres interact with spindle microtubules to ensure the segregation of chromatids during mitosis and of homologous chromosomes in meiosis. The origin of centromeres, therefore, is inseparable from the evolution of cytoskeletal components that distribute chromosomes to offspring cells. Although the origin of the nucleus has been debated, no explanation for the evolutionary appearance of centromeres is available. We propose an evolutionary scenario: The centromeres originated from telomeres. The breakage of the ancestral circular genophore activated the transposition of retroelements at DNA ends that allowed the formation of telomeres by a recombination-dependent replication mechanism. Afterward, the modification of the tubulin-based cytoskeleton that allowed specific subtelomeric repeats to be recognized as new cargo gave rise to the first centromere. This switch from actin-based genophore partition to a tubulin-based mechanism generated a transition period during which both types of cytoskeleton contributed to fidelity of chromosome segregation. During the transition, pseudodicentric chromosomes increased the tendency toward chromosomal breakage and instability. This instability generated multiple telocentric chromosomes that eventually evolved into metacentric or holocentric chromosomes.},
}
@article {pmid17550308,
year = {2007},
author = {Lee, JY and Kozak, M and Martin, JD and Pennock, E and Johnson, FB},
title = {Evidence that a RecQ helicase slows senescence by resolving recombining telomeres.},
journal = {PLoS biology},
volume = {5},
number = {6},
pages = {e160},
pmid = {17550308},
issn = {1545-7885},
support = {F32 AG022769/AG/NIA NIH HHS/United States ; R01 AG021521/AG/NIA NIH HHS/United States ; 5R01AG021521/AG/NIA NIH HHS/United States ; F32AG22769/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*metabolism ; Electrophoresis, Gel, Two-Dimensional ; Mutation ; RecQ Helicases/*metabolism ; Recombination, Genetic ; Saccharomyces cerevisiae/enzymology/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Sequence Analysis, DNA ; Telomere/*metabolism ; },
abstract = {RecQ helicases, including Saccharomyces cerevisiae Sgs1p and the human Werner syndrome protein, are important for telomere maintenance in cells lacking telomerase activity. How maintenance is accomplished is only partly understood, although there is evidence that RecQ helicases function in telomere replication and recombination. Here we use two-dimensional gel electrophoresis (2DGE) and telomere sequence analysis to explore why cells lacking telomerase and Sgs1p (tlc1 sgs1 mutants) senesce more rapidly than tlc1 mutants with functional Sgs1p. We find that apparent X-shaped structures accumulate at telomeres in senescing tlc1 sgs1 mutants in a RAD52- and RAD53-dependent fashion. The X-structures are neither Holliday junctions nor convergent replication forks, but instead may be recombination intermediates related to hemicatenanes. Direct sequencing of examples of telomere I-L in senescing cells reveals a reduced recombination frequency in tlc1 sgs1 compared with tlc1 mutants, indicating that Sgs1p is needed for tlc1 mutants to complete telomere recombination. The reduction in recombinants is most prominent at longer telomeres, consistent with a requirement for Sgs1p to generate viable progeny following telomere recombination. We therefore suggest that Sgs1p may be required for efficient resolution of telomere recombination intermediates, and that resolution failure contributes to the premature senescence of tlc1 sgs1 mutants.},
}
@article {pmid17545803,
year = {2007},
author = {Johnson, JE and Broccoli, D},
title = {Telomere maintenance in sarcomas.},
journal = {Current opinion in oncology},
volume = {19},
number = {4},
pages = {377-382},
doi = {10.1097/CCO.0b013e3281214423},
pmid = {17545803},
issn = {1040-8746},
support = {CA098087-03/CA/NCI NIH HHS/United States ; CA117675-01/CA/NCI NIH HHS/United States ; },
mesh = {Chondrosarcoma, Mesenchymal ; Chromosomal Instability ; Disease Progression ; Humans ; Sarcoma/mortality/*pathology ; Survival ; *Telomerase ; *Telomere ; },
abstract = {PURPOSE OF REVIEW: To examine the activation of telomere maintenance in a variety of sarcoma subtypes, and to review the consequences of telomere maintenance with respect to genome stability and tumor progression.<br><br>RECENT FINDINGS: A hallmark of tumor cells is replicative immortality, which can be achieved, in part, by the activation of a telomere maintenance mechanism. A significant proportion of tumors show activation of telomerase, a specialized enzyme that adds telomeric repeats to pre-existing telomeres. Recent work has demonstrated, however, that a telomerase-independent mechanism called ALT (alternative lengthening of telomeres) is activated as frequently as telomerase in a variety of tumor types, particularly those of mesenchymal origin. Accordingly, panels of mesenchymal tumors have been interrogated for telomere maintenance mechanism, as well as characteristics such as tumor grade and patient survival.<br><br>SUMMARY: These studies indicate a strong positive correlation between the activation of a telomere maintenance mechanism and tumor progression in sarcomas. In addition, the activation of either ALT or telomerase is correlated with poorer patient prognosis as compared with a lack of telomere maintenance. Ongoing studies aimed at elucidating the roles of ALT and telomerase in tumorigenesis should ultimately allow for the development of strategies to improve treatment of these malignancies.},
}
@article {pmid17545637,
year = {2007},
author = {Shen, J and Terry, MB and Gurvich, I and Liao, Y and Senie, RT and Santella, RM},
title = {Short telomere length and breast cancer risk: a study in sister sets.},
journal = {Cancer research},
volume = {67},
number = {11},
pages = {5538-5544},
doi = {10.1158/0008-5472.CAN-06-3490},
pmid = {17545637},
issn = {0008-5472},
support = {P30 ES009089/ES/NIEHS NIH HHS/United States ; P30 CA13696/CA/NCI NIH HHS/United States ; P30 ES09089/ES/NIEHS NIH HHS/United States ; U01 CA69398/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Breast Neoplasms/*genetics ; Case-Control Studies ; Female ; Genetic Predisposition to Disease ; Humans ; Middle Aged ; Siblings ; Telomere/*genetics ; },
abstract = {Telomeres consist of a tandem repeats of the sequence TTAGGG at the ends of chromosomes and play a key role in the maintenance of chromosomal stability. Previous studies indicated that short telomeres are associated with increased risk for human bladder, head and neck, lung, and renal cell cancer. We investigated the association between white blood cell telomere length and breast cancer risk among 268 family sets (287 breast cancer cases and 350 sister controls). Telomere length was assessed by quantitative PCR. The mean telomere length was shorter in cases (mean, 0.70; range, 0.03-1.95) than in unaffected control sisters (mean, 0.74; range, 0.03-2.29), but no significant difference was observed (P = 0.11). When subjects were categorized according to the median telomere length in controls (0.70), affected sisters had shorter telomeres compared with unaffected sisters after adjusting for age at blood donation and smoking status [odds ratio (OR), 1.3; 95% confidence interval (95% CI), 0.9-1.8], but the association was not statistically significant. The association by quartile of telomere length (Q4 shortest versus Q1 longest) also supported an increase in risk from shorter telomere length, although the association was not statistically significant (OR, 1.6; 95% CI, 0.9-2.7). This association was more pronounced among premenopausal women (OR, 2.1; 95% CI, 0.8-5.5) than postmenopausal women (OR, 1.3; 95% CI, 0.5-3.6 for Q4 versus Q1). If these associations are replicated in larger studies, they provide modest epidemiologic evidence that shortened telomere length may be associated with breast cancer risk.},
}
@article {pmid17543860,
year = {2007},
author = {Ding, X and Xu, R and Yu, J and Xu, T and Zhuang, Y and Han, M},
title = {SUN1 is required for telomere attachment to nuclear envelope and gametogenesis in mice.},
journal = {Developmental cell},
volume = {12},
number = {6},
pages = {863-872},
doi = {10.1016/j.devcel.2007.03.018},
pmid = {17543860},
issn = {1534-5807},
mesh = {Animals ; Cell Nucleus/metabolism ; *Chromosome Pairing ; Chromosomes, Mammalian/metabolism ; Female ; *Gametogenesis ; In Situ Hybridization, Fluorescence ; Male ; *Meiosis ; Meiotic Prophase I/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microtubule-Associated Proteins/genetics/*physiology ; Nuclear Envelope/*metabolism ; Oogenesis/physiology ; Protein Transport ; Recombination, Genetic ; Telomere/*metabolism ; },
abstract = {Prior to the pairing and recombination between homologous chromosomes during meiosis, telomeres attach to the nuclear envelope and form a transient cluster. However, the protein factors mediating meiotic telomere attachment to the nuclear envelope and the requirement of this attachment for homolog pairing and synapsis have not been determined in animals. Here we show that the inner nuclear membrane protein SUN1 specifically associates with telomeres between the leptotene and diplotene stages during meiotic prophase I. Disruption of Sun1 in mice prevents telomere attachment to the nuclear envelope, efficient homolog pairing, and synapsis formation in meiosis. Massive apoptotic events are induced in the mutant gonads, leading to the abolishment of both spermatogenesis and oogenesis. This study provides genetic evidence that SUN1-telomere interaction is essential for telomere dynamic movement and is required for efficient homologous chromosome pairing/synapsis during mammalian gametogenesis.},
}
@article {pmid17539606,
year = {2007},
author = {Qi, J and Shafer, RH},
title = {Human telomere quadruplex: refolding and selection of individual conformers via RNA/DNA chimeric editing.},
journal = {Biochemistry},
volume = {46},
number = {25},
pages = {7599-7606},
doi = {10.1021/bi602392u},
pmid = {17539606},
issn = {0006-2960},
support = {GM067607/GM/NIGMS NIH HHS/United States ; },
mesh = {Circular Dichroism ; DNA/*chemistry ; Electrophoresis, Polyacrylamide Gel ; G-Quadruplexes ; Humans ; Models, Chemical ; Nuclear Magnetic Resonance, Biomolecular ; *Nucleic Acid Conformation ; Potassium/chemistry ; Protons ; RNA/*chemistry ; *RNA Editing ; Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; Ultracentrifugation ; },
abstract = {The conformation of the guanine quadruplex formed by the human telomere (HT) repeat in solutions containing physiological concentrations of K+ ions has been a topic of intensive investigation during the past several years. Of particular interest are the directionality of the overall folding pattern, i.e., parallel, antiparallel, or a combination of these two modes, and the alternation, if any, of the glycosidic bond conformation between syn and anti. An additional issue involves resolving mixtures of conformations when more than one species is present. We approach these questions using selective substitution of riboguanosine, rG, for deoxyriboguanosine, dG. Using a combination of circular dichroism, gel electrophoresis, equilibrium ultracentrifugation, and imino proton NMR, we are able to show that these modifications can yield sequences which fold into parallel or antiparallel conformations consisting of one or two strands. We also demonstrate that chimeric editing of the HT sequence permits isolating one of two conformational isomers existing in solution in the presence of KCl. The ability to engineer and control quadruplex folding motifs illustrated here with HT may prove useful more generally for a variety of quadruplex-forming sequences.},
}
@article {pmid17538011,
year = {2007},
author = {Viscardi, V and Bonetti, D and Cartagena-Lirola, H and Lucchini, G and Longhese, MP},
title = {MRX-dependent DNA damage response to short telomeres.},
journal = {Molecular biology of the cell},
volume = {18},
number = {8},
pages = {3047-3058},
pmid = {17538011},
issn = {1059-1524},
mesh = {*DNA Damage ; Models, Biological ; Multiprotein Complexes/*metabolism ; Protein Transport ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomere structure allows cells to distinguish the natural chromosome ends from double-strand breaks (DSBs). However, DNA damage response proteins are intimately involved in telomere metabolism, suggesting that functional telomeres may be recognized as DNA damage during a time window. Here we show by two different systems that short telomeres are recognized as DSBs during the time of their replication, because they induce a transient MRX-dependent DNA damage checkpoint response during their prolonged elongation. The MRX complex, which is recruited at telomeres under these conditions, dissociates from telomeres concomitantly with checkpoint switch off when telomeres reach a new equilibrium length. We also show that MRX recruitment to telomeres is sufficient to activate the checkpoint independently of telomere elongation. We propose that MRX can signal checkpoint activation by binding to short telomeres only when they become competent for elongation. Because full-length telomeres are refractory to MRX binding and the shortest telomeres are elongated of only a few base pairs per generation, this limitation may prevent unscheduled checkpoint activation during an unperturbed S phase.},
}
@article {pmid17533048,
year = {2007},
author = {Widmann, TA and Herrmann, M and Taha, N and König, J and Pfreundschuh, M},
title = {Short telomeres in aggressive non-Hodgkin's lymphoma as a risk factor in lymphomagenesis.},
journal = {Experimental hematology},
volume = {35},
number = {6},
pages = {939-946},
doi = {10.1016/j.exphem.2007.03.009},
pmid = {17533048},
issn = {0301-472X},
mesh = {Adult ; B-Lymphocytes/metabolism/pathology ; Cell Transformation, Neoplastic/genetics/*metabolism ; Chromosomes, Human/genetics/*metabolism ; Female ; Granulocytes/metabolism/pathology ; Humans ; Lymphoma, Non-Hodgkin/genetics/*metabolism/pathology ; Male ; Oxidative Stress/genetics ; Risk Factors ; T-Lymphocytes/metabolism/pathology ; Telomere/genetics/*metabolism ; },
abstract = {OBJECTIVE: Telomeres cap chromosomal ends and help to maintain chromosomal integrity. Telomere shortening may result in chromosomal instability and, ultimately, malignant transformation of cells. It has not been systematically studied whether patients with malignancy have shortened telomeres in their normal, nontransformed cells, which might point to a preexisting disposition for chromosomal instability.<br><br>METHODS: We designed an (age-) matched pair analysis that compared telomere length in nonmalignant peripheral leukocytes from previously untreated patients who recently developed an aggressive non-Hodgkin's lymphoma, with leukocytes from healthy individuals.<br><br>RESULTS: Telomere lengths in B and T lymphocytes as well as granulocytes from the patients' group were significantly shorter than those from age-matched healthy controls. We were able to rule out increased proliferation, telomerase defects, or increased oxidative stress in patients as confounding factors of shortened telomeres.<br><br>CONCLUSION: Short telomeres in nontransformed leukocytes may constitute a risk factor for lymphomagenesis.},
}
@article {pmid17531805,
year = {2007},
author = {Price, CM},
title = {wRAPing up the end to prevent telomere fusions.},
journal = {Molecular cell},
volume = {26},
number = {4},
pages = {463-464},
doi = {10.1016/j.molcel.2007.05.005},
pmid = {17531805},
issn = {1097-2765},
support = {R01 GM041803/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; DNA/*chemistry ; *DNA Repair ; DNA Replication ; Humans ; Models, Biological ; Nuclear Proteins/chemistry/*metabolism ; TATA Box Binding Protein-Like Proteins/chemistry/*metabolism ; Telomere/chemistry/*metabolism ; Telomere-Binding Proteins/chemistry/metabolism ; Telomeric Repeat Binding Protein 2 ; rap1 GTP-Binding Proteins/chemistry/*metabolism ; },
}
@article {pmid17530490,
year = {2007},
author = {Tabori, U and Dome, JS},
title = {Telomere biology of pediatric cancer.},
journal = {Cancer investigation},
volume = {25},
number = {3},
pages = {197-208},
doi = {10.1080/07357900701208683},
pmid = {17530490},
issn = {0735-7907},
mesh = {Antineoplastic Agents/pharmacology/therapeutic use ; Cell Proliferation ; Child ; Enzyme Inhibitors/pharmacology/therapeutic use ; *Gene Expression Regulation, Neoplastic ; Humans ; Neoplasms/drug therapy/enzymology/genetics/*metabolism/pathology ; Recombination, Genetic ; Telomerase/antagonists &amp; inhibitors/*metabolism ; Telomere/*metabolism ; },
abstract = {One of the hallmarks of cancer is limitless proliferative capacity, which is tightly associated with the ability to maintain telomeres. Over the last decade, the telomere biology of pediatric cancers has begun to be elucidated. Most pediatric leukemias and embryonal solid tumors activate the enzyme telomerase, a specialized reverse transcriptase that adds nucleotide repeats to telomeres. In general, high levels of tumor telomerase expression are associated with unfavorable outcome, although results vary according to tumor type. Some pediatric tumors, including osteosarcoma and glioblastoma multiforme, lack telomerase activity and maintain telomeres via a recombination-based mechanism called ALT (alternative lengthening of telomeres). Telomerase is a highly attractive therapeutic target for pediatric cancer because the enzyme plays a key role in conferring cellular immortality, is present in most tumors, and is relatively specific for cancer cells. Telomerase inhibitors have been evaluated in preclinical models of adult cancers, but few studies have been conducted on pediatric cancers. Further research is required to define how telomere biology can be used to clinical advantage in malignancies of childhood.},
}
@article {pmid17523598,
year = {2007},
author = {Kaushik, M and Bansal, A and Saxena, S and Kukreti, S},
title = {Possibility of an antiparallel (tetramer) quadruplex exhibited by the double repeat of the human telomere.},
journal = {Biochemistry},
volume = {46},
number = {24},
pages = {7119-7131},
doi = {10.1021/bi0621009},
pmid = {17523598},
issn = {0006-2960},
mesh = {Base Sequence ; Biophysical Phenomena ; Biophysics ; Chromatography, Gel ; Circular Dichroism ; DNA/*chemistry/*genetics ; Humans ; In Vitro Techniques ; Magnesium/chemistry ; Models, Molecular ; Nucleic Acid Conformation ; Nucleic Acid Denaturation ; Potassium/chemistry ; Repetitive Sequences, Nucleic Acid ; Sodium/chemistry ; Telomere/*chemistry/*genetics ; },
abstract = {Under physiological concentrations of Na+ and K+, human telomeric DNA can self-associate into G-quadruplexes. On the basis of circular dichroism, gel electrophoresis, gel filtration, and UV-melting experiments, we report here that the double repeat of human telomere (d-TTAGGGTTAGGG; HUM2) forms parallel as well as antiparallel quadruplexes in the presence of K+, whereas Na+ facilitates only the antiparallel form. Here, the gel techniques and CD studies have proved to be complementary in detecting the molecularity and pattern of strand orientation. By correlating the gel and CD experiments, the antiparallel G-quadruplex was identified as a tetrameric species, whereas the parallel G-quadruplex was found to be dimeric. Both structural species were separated through gel filtration, which when run on native polyacrylamide gel electrphoresis (PAGE), confirmed their molecularity. UV-melting profiles also confirm the presence of two biphasic and one monophasic structural species in the presence of K+ and Na+, respectively. Though our observation is consistent with the recent NMR report (Phan, A. T., and Patel, D. J. (2003) J. Am. Chem. Soc. 125, 15021-15027), it seems to differ in terms of the molecularity of the antiparallel quadruplex. A model is proposed for an antiparallel tetrameric quadruplex, showing the possibility of Watson-Crick hydrogen bonds between intervening bases on antiparallel strands. This article expands the known structural motifs of DNA quadruplexes. To the best of our knowledge, four-stranded antiparallel quadruplexes have not been characterized to date. On the basis of the model, we hypothesize a possible mechanism for telomere-telomere association involving their G-overhangs, during certain stages of the cell cycle. The knowledge of peculiar geometries of the G-quadruplexes may also have implications for its specific recognition by ligands.},
}
@article {pmid17512764,
year = {2007},
author = {Mayr, B and Korb, H and Oppeneiger, T and Demetz, F and Egger, J},
title = {Highly characteristic and individual specific telomere length patterns in cattle.},
journal = {Veterinary journal (London, England : 1997)},
volume = {174},
number = {3},
pages = {677-680},
doi = {10.1016/j.tvjl.2006.11.017},
pmid = {17512764},
issn = {1090-0233},
mesh = {Animals ; Cattle/*genetics ; Fluorescein-5-isothiocyanate ; Fluorescent Dyes ; Indoles ; Male ; Primed In Situ Labeling/veterinary ; Propidium ; Telomere/genetics/*metabolism ; },
abstract = {A combined primed in situ labelling (PRINS)/4',6-diamino-2-phenylindole (DAPI)/propidium iodide (PI)-fluorescence-banding method was used to characterise telomeres, identify their specific chromosomes and visualise neighbouring heterochromatin in 25 artificial insemination (AI) bulls. A highly heterogeneous telomere length pattern was found in cattle. Each bull possessed his own characteristic, specific telomere length pattern.},
}
@article {pmid17510654,
year = {2007},
author = {Karlseder, J and Cooper, JP},
title = {Of wombats and whales: telomere tales in Madrid. Conference on telomeres and telomerase.},
journal = {EMBO reports},
volume = {8},
number = {6},
pages = {542-546},
pmid = {17510654},
issn = {1469-221X},
mesh = {Aging/pathology ; Animals ; Biological Evolution ; Humans ; Marsupialia/genetics ; Neoplasms/pathology/therapy ; Spain ; Telomerase/*metabolism ; Telomere/*metabolism ; Whales/genetics ; },
}
@article {pmid17510216,
year = {2007},
author = {Drummond, MW and Balabanov, S and Holyoake, TL and Brummendorf, TH},
title = {Concise review: Telomere biology in normal and leukemic hematopoietic stem cells.},
journal = {Stem cells (Dayton, Ohio)},
volume = {25},
number = {8},
pages = {1853-1861},
doi = {10.1634/stemcells.2007-0057},
pmid = {17510216},
issn = {1066-5099},
mesh = {Acute Disease ; Animals ; Cell Proliferation ; DNA Replication/physiology ; DNA, Neoplasm/physiology ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/enzymology/*pathology/*physiology ; Humans ; Leukemia/enzymology/genetics/*pathology/physiopathology ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology/genetics/physiopathology ; Leukemia, Myeloid/enzymology/genetics/physiopathology ; Mice ; Mice, Knockout ; Models, Biological ; Neural Tube Defects/enzymology/genetics/physiopathology ; Telomerase/genetics/metabolism/physiology ; Telomere/metabolism/*physiology ; },
abstract = {The measurement of telomere length can give an insight into the replicative history of the cells in question. Much of the observed telomere loss occurs at the stem and progenitor cell level, even though these populations express the enzyme telomerase. Telomerase-transfected hematopoietic stem cells (HSC), although able to maintain telomere length, are still limited in terms of ability to undergo sequential transplantation, and other factors require to be addressed to achieve optimal levels of stem cell expansion. Unchecked telomere loss by HSC, meanwhile, would appear to play a significant role in the pathogenesis of bone marrow failure, as observed in the condition dyskeratosis congenita. This heterogeneous inherited condition appears to exhibit telomerase dysfunction as a common final pathogenic mechanism. Although less well-established for acquired marrow failure syndromes, mutations in key telomerase components have been described. The identification of the leukemic stem cell (LSC), along with the desire to target this population with anti-leukemia therapy, demands that telomerase biology be fully understood in this cell compartment. Future studies using primary selected LSC-rich samples are required. A better understanding of telomerase regulation in this population may allow effective targeting of the telomerase enzyme complex using small molecule inhibitors or additional novel approaches. Disclosure of potential conflicts of interest is found at the end of this article.},
}
@article {pmid17496367,
year = {2007},
author = {Balasubramanyam, M and Adaikalakoteswari, A and Monickaraj, SF and Mohan, V},
title = {Telomere shortening &amp; metabolic/vascular diseases.},
journal = {The Indian journal of medical research},
volume = {125},
number = {3},
pages = {441-450},
pmid = {17496367},
issn = {0971-5916},
mesh = {Animals ; Coronary Disease/pathology ; Diabetes Mellitus/genetics/pathology ; Disease Models, Animal ; Humans ; Metabolic Diseases/genetics/*pathology ; Telomere/genetics/*pathology ; Vascular Diseases/genetics/*pathology ; },
abstract = {Telomeres are specialized DNA-protein structures located at the ends of eukaryotic chromosomes whose length is progressively reduced in most somatic cells during ageing. Over the past decade, emerging evidence has shown that the telomeres are essential regulators of cellular life span and chromosome integrity in a dynamic fashion. By inducing genomic instability, replicative senescence and apoptosis, shortening of telomeres is thought to contribute to organismal ageing. While the aetiology of cardiovascular diseases and diabetes represent a complex interaction between various risk factors overlaid on different genetic backgrounds, the conventional risk factors often did not explain the inter-individual variability related to predisposition of disease states. This underscores the need for biological indicators of ageing in evaluating the aetiology of several age-related disorders, and recent studies indicate that telomere length could qualify as an ideal marker of biological ageing. Short telomeres have been detected in senescent endothelial cells and vascular smooth muscle cells from human atherosclerotic plaque as well as in myocardial tissue from patients with end-stage heart failure and cardiac hypertrophy. In addition, telomere shortening has been demonstrated in WBCs from patients with coronary heart disease, premature myocardial infarction, hypertension and diabetes mellitus. In this review, we discuss the telomere hypothesis of ageing as well as human studies that address the role of telomeres in cardiovascular, diabetes and other cardio-metabolic pathologies.},
}
@article {pmid17495544,
year = {2007},
author = {Vodenicharov, MD and Wellinger, RJ},
title = {The cell division cycle puts up with unprotected telomeres: cell cycle regulated telomere uncapping as a means to achieve telomere homeostasis.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {6},
number = {10},
pages = {1161-1167},
doi = {10.4161/cc.6.10.4224},
pmid = {17495544},
issn = {1551-4005},
mesh = {CDC2 Protein Kinase/*metabolism ; Cell Division/*physiology ; DNA Breaks, Double-Stranded ; DNA Repair/*physiology ; Telomerase/metabolism ; Telomere/genetics/*physiology ; Yeasts ; },
abstract = {Telomeres have unique properties that distinguish natural chromosomal ends from accidental DNA double-strand interruptions arising elsewhere in the genome. However, the slightest perturbation in their unique organization may obliterate this distinction, channelling chromosomal ends into unwarranted repair events, eventually causing genome instability. Recent results revealed that the processing of both dysfunctional telomeres and accidental DNA double strand breaks (DSB) by DNA repair activities is tightly regulated in a cell cycle-dependent manner by the S phase-promoting cell cycle kinase CDK1 (Clb-Cdc28p). Surprisingly, the cell cycle determinants and the timing of processing at unprotected telomeres closely match the requirements of other transactions that occur at telomeres. In particular, the replenishment of telomeric repeats by telomerase is tightly linked to cell cycle progression and occurs in the same interval. Furthermore, cell survival in the absence of essential telomeric proteins being dependent on telomere-telomere recombination mechanisms may require a similar regulation. Thus, a temporally limited state of telomere dysfunction leading to chromosome end processing may represent a well-governed cell cycle event that constitutes an integral part of the assembly of a new functional telomere.},
}
@article {pmid17491589,
year = {2007},
author = {Meier, A and Fiegler, H and Muñoz, P and Ellis, P and Rigler, D and Langford, C and Blasco, MA and Carter, N and Jackson, SP},
title = {Spreading of mammalian DNA-damage response factors studied by ChIP-chip at damaged telomeres.},
journal = {The EMBO journal},
volume = {26},
number = {11},
pages = {2707-2718},
pmid = {17491589},
issn = {0261-4189},
support = {A5290/CRUK_/Cancer Research UK/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; },
mesh = {Adaptor Proteins, Signal Transducing ; Cell Cycle Proteins ; Cell Line ; Cellular Senescence/physiology ; Chromatin Immunoprecipitation ; *DNA Damage ; DNA-Binding Proteins/metabolism ; Histones/*metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Microscopy, Fluorescence ; Nuclear Proteins/metabolism ; Phosphorylation ; Signal Transduction/genetics/*physiology ; Telomerase/metabolism ; Telomere/genetics/*physiology ; Trans-Activators/metabolism ; Tumor Suppressor p53-Binding Protein 1 ; },
abstract = {Phosphorylated histone H2AX (gammaH2AX) is generated in nucleosomes flanking sites of DNA double-strand breaks, triggering the recruitment of DNA-damage response proteins such as MDC1 and 53BP1. Here, we study shortened telomeres in senescent human cells. We show that most telomeres trigger gammaH2AX formation, which spreads up to 570 kb into the subtelomeric regions. Furthermore, we reveal that the spreading patterns of 53BP1 and MDC1 are very similar to that of gammaH2AX, consistent with a structural link between these factors. Moreover, different subsets of telomeres signal in different cell lines, with those that signal tending to equate to the shortest telomeres of the corresponding cell line, thus linking telomere attrition with DNA-damage signalling. Notably, we find that, in some cases, gammaH2AX spreading is modulated in a manner suggesting that H2AX distribution or its ability to be phosphorylated is not uniform along the chromosome. Finally, we observe weak gammaH2AX signals at telomeres of proliferating cells, but not in hTERT immortalised cells, suggesting that low telomerase activity leads to telomere uncapping and senescence in proliferating primary cells.},
}
@article {pmid17486088,
year = {2007},
author = {Ju, Z and Jiang, H and Jaworski, M and Rathinam, C and Gompf, A and Klein, C and Trumpp, A and Rudolph, KL},
title = {Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment.},
journal = {Nature medicine},
volume = {13},
number = {6},
pages = {742-747},
doi = {10.1038/nm1578},
pmid = {17486088},
issn = {1078-8956},
mesh = {Animals ; Apoptosis/genetics ; B-Lymphocytes/pathology ; Cell Proliferation ; Cells, Cultured ; Cellular Senescence/genetics ; *Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/*pathology ; Homeostasis/*genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myeloid Cells/pathology ; RNA/genetics ; Telomerase/deficiency/genetics ; Telomere/genetics/*physiology ; Up-Regulation/genetics ; },
abstract = {Cell-intrinsic checkpoints limit the proliferative capacity of primary cells in response to telomere dysfunction. It is not known, however, whether telomere dysfunction contributes to cell-extrinsic alterations that impair stem cell function and organ homeostasis. Here we show that telomere dysfunction provokes defects of the hematopoietic environment that impair B lymphopoiesis but increase myeloid proliferation in aging telomerase knockout (Terc(-/-)) mice. Moreover, the dysfunctional environment limited the engraftment of transplanted wild-type hematopoietic stem cells (HSCs). Dysfunction of the hematopoietic environment was age dependent and correlated with progressive telomere shortening in bone marrow stromal cells. Telomere dysfunction impaired mesenchymal progenitor cell function, reduced the capacity of bone marrow stromal cells to maintain functional HSCs, and increased the expression of various cytokines, including granulocyte colony-stimulating factor (G-CSF), in the plasma of aging mice. Administration of G-CSF to wild-type mice mimicked some of the defects seen in aging Terc(-/-) mice, including impairment of B lymphopoiesis and HSC engraftment. Conversely, inhibition of G-CSF improved HSC engraftment in aged Terc(-/-) mice. Taken together, these results show that telomere dysfunction induces alterations of the environment that can have implications for organismal aging and cell transplantation therapies.},
}
@article {pmid17485399,
year = {2007},
author = {Moon, IK and Jarstfer, MB},
title = {The human telomere and its relationship to human disease, therapy, and tissue engineering.},
journal = {Frontiers in bioscience : a journal and virtual library},
volume = {12},
number = {},
pages = {4595-4620},
doi = {10.2741/2412},
pmid = {17485399},
issn = {1093-9946},
mesh = {Aging/genetics ; DNA Replication ; *Genetic Predisposition to Disease ; Humans ; Neoplasms/genetics ; *Telomere ; *Therapeutics ; *Tissue Engineering ; },
abstract = {The chromosomes of eukaryotes end in a specialized complex of proteins and repetitive DNA called the telomere. Telomeres form a protective cap that prevents chromosome fusions, protects chromosome ends from degradation, and assists in positioning chromosomes in the nucleus. In the absence of replenishing mechanisms, telomeric DNA is lost during each cell cycle owing to incomplete replication, oxidative damage, and nucleolytic degradation. The ribonucleoprotein complex telomerase offsets this loss of telomeric DNA, but its activity is absent in most differentiated human cells. Thus, the aging process results in ever shortening lengths of telomeric DNA. Related to this is the requirement for a mechanism of telomeric DNA maintenance in tumors, leading to telomerase expression in >85% of all cancers cells. The integral roles of telomere biology in these pathophysiological states have substantially motivated its investigation. Here, the literature on the human telomere will be reviewed with an emphasis on the relationship to human health.},
}
@article {pmid17483479,
year = {2007},
author = {Gladyshev, EA and Arkhipova, IR},
title = {Telomere-associated endonuclease-deficient Penelope-like retroelements in diverse eukaryotes.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {104},
number = {22},
pages = {9352-9357},
pmid = {17483479},
issn = {0027-8424},
mesh = {Animals ; Base Sequence ; Endonucleases/*deficiency/genetics/metabolism ; Eukaryotic Cells/enzymology/*metabolism ; Molecular Sequence Data ; Phylogeny ; Retroelements/*genetics ; Telomere/*enzymology/*genetics ; },
abstract = {The evolutionary origin of telomerases, enzymes that maintain the ends of linear chromosomes in most eukaryotes, is a subject of debate. Penelope-like elements (PLEs) are a recently described class of eukaryotic retroelements characterized by a GIY-YIG endonuclease domain and by a reverse transcriptase domain with similarity to telomerases and group II introns. Here we report that a subset of PLEs found in bdelloid rotifers, basidiomycete fungi, stramenopiles, and plants, representing four different eukaryotic kingdoms, lack the endonuclease domain and are located at telomeres. The 5' truncated ends of these elements are telomere-oriented and typically capped by species-specific telomeric repeats. Most of them also carry several shorter stretches of telomeric repeats at or near their 3' ends, which could facilitate utilization of the telomeric G-rich 3' overhangs to prime reverse transcription. Many of these telomere-associated PLEs occupy a basal phylogenetic position close to the point of divergence from the telomerase-PLE common ancestor and may descend from the missing link between early eukaryotic retroelements and present-day telomerases.},
}
@article {pmid17482128,
year = {2007},
author = {Sedivy, JM},
title = {Telomeres limit cancer growth by inducing senescence: long-sought in vivo evidence obtained.},
journal = {Cancer cell},
volume = {11},
number = {5},
pages = {389-391},
doi = {10.1016/j.ccr.2007.04.014},
pmid = {17482128},
issn = {1535-6108},
mesh = {Animals ; Cellular Senescence/*genetics ; Humans ; Neoplasms/genetics/*pathology ; *Telomere ; },
abstract = {Cellular senescence triggered by telomere dysfunction has long been hypothesized to constitute a tumor suppression mechanism. The evidence has come primarily from in vitro cell culture studies, and more indirectly from analysis of tumor specimens. Two recent studies, published in the current issue of Cancer Cell and online at EMBO Reports, provide direct mechanistic evidence in cleverly manipulated mouse cancer models. This work shows that telomere-induced senescence is as effective as apoptosis in reducing cancer incidence and is mediated by the tumor suppressor p53.},
}
@article {pmid17481586,
year = {2007},
author = {Nordfjäll, K and Osterman, P and Melander, O and Nilsson, P and Roos, G},
title = {hTERT (-1327)T/C polymorphism is not associated with age-related telomere attrition in peripheral blood.},
journal = {Biochemical and biophysical research communications},
volume = {358},
number = {1},
pages = {215-218},
doi = {10.1016/j.bbrc.2007.04.099},
pmid = {17481586},
issn = {0006-291X},
mesh = {Aged ; Aging/*genetics ; Female ; Genomic Instability ; Genotype ; Humans ; Male ; Middle Aged ; Myocardial Infarction/blood/*genetics ; *Polymorphism, Genetic ; Sweden ; Telomerase/blood/*genetics ; Telomere/*genetics/ultrastructure ; },
abstract = {Regulation of the telomerase catalytic subunit, hTERT, is a complex process accomplished on many levels. Transcription of the hTERT gene has been widely studied but less is known about the implication of genetic variations. Recently, a functional T to C transition polymorphism was indicated 1327 bp upstream the hTERT transcription starting site. The (-1327)C/C genotype was associated with shorter telomere length compared to the alternative genotypes in healthy individuals and in coronary artery disease patients. We tested this observation and analysed telomere length and the (-1327)T/C polymorphism in 226 myocardial infarction patients and 444 controls from southern Sweden. No significant difference in telomere length was found among the genotypes after age adjustments in the control group (p=0.794) or in the MI group (p=0.339). Moreover, no increased age-related attrition was observed for the (-1327)C/C genotype as previously indicated, rather a telomere elongation in the control group (p=0.021) not seen in the MI group (p=0.249).},
}
@article {pmid17475542,
year = {2008},
author = {McCaul, JA and Gordon, KE and Minty, F and Fleming, J and Parkinson, EK},
title = {Telomere dysfunction is related to the intrinsic radio-resistance of human oral cancer cells.},
journal = {Oral oncology},
volume = {44},
number = {3},
pages = {261-269},
doi = {10.1016/j.oraloncology.2007.02.010},
pmid = {17475542},
issn = {1368-8375},
mesh = {Anaphase ; Carcinoma, Squamous Cell/enzymology/*pathology/radiotherapy ; Cell Line, Tumor ; Cell Survival ; Cellular Senescence ; Gamma Rays ; Humans ; Mouth Neoplasms/enzymology/*pathology/radiotherapy ; *Radiation Tolerance ; Regression Analysis ; Statistics, Nonparametric ; Telomerase/metabolism ; Telomere/*ultrastructure ; Treatment Failure ; },
abstract = {Evidence from telomerase-deficient mice strongly suggests that dysfunctional short telomeres affect cellular radio-sensitivity but this idea has yet to be extensively tested in relevant human cancer types such as oral squamous cell carcinomas (OSCCs), which are frequently treated by radiotherapy. The OSCC line BICR7 has low levels of telomerase activity, short telomeres and high levels of telomere dysfunction (judged by a high level of anaphase bridges); whereas the BICR6 line has high levels of telomerase and is more radio-resistant. Ectopic expression of the human TElomerase Reverse Transcriptase (hTERT) reduced telomere dysfunction and increased radio-resistance in BICR7 cells, but not BICR6. Furthermore, the radio-resistance of GM847 cells, which use telomerase-independent mechanisms of telomere maintenance, and of telomerase-negative normal human fibroblasts with long telomeres are similarly unaffected by ectopic expression of telomerase. We tested whether telomere function, as measured by the Anaphase Bridge Index (ABI), was found to be a useful predictor of radio-resistance in a panel of OSCC lines. Using inverse regression analysis, we found a strong inverse relationship between the ABI and radio-resistance (P<0.001), as measured by the Surviving Fraction at 4Gy (SF4). These results suggest that telomerase inhibitors could sensitise a subset of oral SCCs with short telomeres to radiotherapy and for the first time demonstrate that the tumour ABI may assist the selection of cancers that would be suitable for such sensitisation therapy.},
}
@article {pmid17472436,
year = {2007},
author = {Passos, JF and Saretzki, G and Ahmed, S and Nelson, G and Richter, T and Peters, H and Wappler, I and Birket, MJ and Harold, G and Schaeuble, K and Birch-Machin, MA and Kirkwood, TB and von Zglinicki, T},
title = {Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence.},
journal = {PLoS biology},
volume = {5},
number = {5},
pages = {e110},
pmid = {17472436},
issn = {1545-7885},
support = {BB/C008200/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Age Factors ; Calcium/metabolism ; Cell Line ; Cellular Senescence/*physiology ; Fibroblasts ; Flow Cytometry ; Humans ; In Situ Hybridization, Fluorescence ; Microscopy, Electron, Transmission ; Mitochondria/metabolism/*physiology/ultrastructure ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/*metabolism ; Stochastic Processes ; Telomere/*physiology ; },
abstract = {Aging is an inherently stochastic process, and its hallmark is heterogeneity between organisms, cell types, and clonal populations, even in identical environments. The replicative lifespan of primary human cells is telomere dependent; however, its heterogeneity is not understood. We show that mitochondrial superoxide production increases with replicative age in human fibroblasts despite an adaptive UCP-2-dependent mitochondrial uncoupling. This mitochondrial dysfunction is accompanied by compromised [Ca(2+)]i homeostasis and other indicators of a retrograde response in senescent cells. Replicative senescence of human fibroblasts is delayed by mild mitochondrial uncoupling. Uncoupling reduces mitochondrial superoxide generation, slows down telomere shortening, and delays formation of telomeric gamma-H2A.X foci. This indicates mitochondrial production of reactive oxygen species (ROS) as one of the causes of replicative senescence. By sorting early senescent (SES) cells from young proliferating fibroblast cultures, we show that SES cells have higher ROS levels, dysfunctional mitochondria, shorter telomeres, and telomeric gamma-H2A.X foci. We propose that mitochondrial ROS is a major determinant of telomere-dependent senescence at the single-cell level that is responsible for cell-to-cell variation in replicative lifespan.},
}
@article {pmid17471948,
year = {2006},
author = {Nakamura, M and Nishiyama, A and Ishikawa, F},
title = {[Replicative stress in telomeres].},
journal = {Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme},
volume = {51},
number = {14 Suppl},
pages = {2245-2249},
pmid = {17471948},
issn = {0039-9450},
mesh = {Animals ; Cell Cycle/genetics ; DNA Replication/*genetics ; Telomere/*genetics ; },
}
@article {pmid17470550,
year = {2007},
author = {Frydrychova, RC and Biessmann, H and Konev, AY and Golubovsky, MD and Johnson, J and Archer, TK and Mason, JM},
title = {Transcriptional activity of the telomeric retrotransposon HeT-A in Drosophila melanogaster is stimulated as a consequence of subterminal deficiencies at homologous and nonhomologous telomeres.},
journal = {Molecular and cellular biology},
volume = {27},
number = {13},
pages = {4991-5001},
pmid = {17470550},
issn = {0270-7306},
support = {R01 GM056729/GM/NIGMS NIH HHS/United States ; GM56729/GM/NIGMS NIH HHS/United States ; //Intramural NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Drosophila melanogaster/*genetics ; Gene Expression Regulation ; Molecular Sequence Data ; Promoter Regions, Genetic/genetics ; RNA, Messenger/genetics ; Retroelements/*genetics ; Sequence Homology ; Telomere/*genetics ; *Transcription, Genetic ; Transgenes ; },
abstract = {Drosophila melanogaster telomeres have two DNA domains: a terminal array of retrotransposons and a subterminal repetitive telomere-associated sequence (TAS), a source of telomere position effect (TPE). We reported previously that deletion of the 2L TAS array leads to dominant suppression of TPE by stimulating in trans expression of a telomeric transgene. Here, we compared the transcript activities of a w transgene inserted between the retrotransposon and TAS arrays at the 2L telomere in genotypes with different lengths of the 2L TAS. In contrast to individuals bearing a wild-type 2L homologue, flies with a TAS deficiency showed a significant increase in the level of telomeric w transcript during development, especially in pupae. Moreover, we identified a read-through w transcript initiated from a retrotransposon promoter in the terminal array. Read-through transcript levels also significantly increased with the presence of a 2L TAS deficiency in trans, indicating a stimulating force of the TAS deficiency on retrotransposon promoter activity. The read-through transcript contributes to total w transcript, although most w transcript originates at the w promoter. While silencing of transgenes in nonhomologous telomeres is suppressed by 2L TAS deficiencies, suggesting a global effect, the overall level of HeT-A transcripts is not increased under similar conditions.},
}
@article {pmid17468339,
year = {2007},
author = {Alter, BP and Baerlocher, GM and Savage, SA and Chanock, SJ and Weksler, BB and Willner, JP and Peters, JA and Giri, N and Lansdorp, PM},
title = {Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita.},
journal = {Blood},
volume = {110},
number = {5},
pages = {1439-1447},
pmid = {17468339},
issn = {0006-4971},
support = {R01 AI029524/AI/NIAID NIH HHS/United States ; //Intramural NIH HHS/United States ; AI29524/AI/NIAID NIH HHS/United States ; R21 AI029524/AI/NIAID NIH HHS/United States ; N02CP11019/CP/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antigens, CD ; Bone Marrow Diseases/*diagnosis/genetics/pathology/therapy ; Cell Cycle Proteins/genetics ; Child ; Child, Preschool ; Diagnosis, Differential ; Dyskeratosis Congenita/*diagnosis/genetics/pathology/therapy ; *Flow Cytometry ; Humans ; *In Situ Hybridization, Fluorescence ; Infant ; Infant, Newborn ; *Leukocytes/pathology ; Male ; Middle Aged ; Nuclear Proteins/genetics ; RNA/genetics ; Telomerase/genetics ; *Telomere/genetics/pathology ; },
abstract = {Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome in which the known susceptibility genes (DKC1, TERC, and TERT) belong to the telomere maintenance pathway; patients with DC have very short telomeres. We used multicolor flow fluorescence in situ hybridization analysis of median telomere length in total blood leukocytes, granulocytes, lymphocytes, and several lymphocyte subsets to confirm the diagnosis of DC, distinguish patients with DC from unaffected family members, identify clinically silent DC carriers, and discriminate between patients with DC and those with other bone marrow failure disorders. We defined "very short" telomeres as below the first percentile measured among 400 healthy control subjects over the entire age range. Diagnostic sensitivity and specificity of very short telomeres for DC were more than 90% for total lymphocytes, CD45RA+/CD20- naive T cells, and CD20+ B cells. Granulocyte and total leukocyte assays were not specific; CD45RA- memory T cells and CD57+ NK/NKT were not sensitive. We observed very short telomeres in a clinically normal family member who subsequently developed DC. We propose adding leukocyte subset flow fluorescence in situ hybridization telomere length measurement to the evaluation of patients and families suspected to have DC, because the correct diagnosis will substantially affect patient management.},
}
@article {pmid17462009,
year = {2007},
author = {Tourand, Y and Lee, L and Chaconas, G},
title = {Telomere resolution by Borrelia burgdorferi ResT through the collaborative efforts of tethered DNA binding domains.},
journal = {Molecular microbiology},
volume = {64},
number = {3},
pages = {580-590},
doi = {10.1111/j.1365-2958.2007.05691.x},
pmid = {17462009},
issn = {0950-382X},
mesh = {Bacterial Proteins/chemistry/genetics/*metabolism ; Base Sequence ; Binding Sites/genetics ; Borrelia burgdorferi/enzymology/genetics/*metabolism ; Chymotrypsin/metabolism ; DNA Replication/genetics ; DNA, Bacterial/genetics/metabolism ; Deoxyribonuclease I/metabolism ; Endodeoxyribonucleases/chemistry/genetics/*metabolism ; Genome, Bacterial ; Models, Genetic ; Protein Binding ; Recombinases/genetics/metabolism ; Telomere/enzymology/*metabolism ; },
abstract = {Borrelia burgdorferi, a causative agent of Lyme disease, has a highly unusual segmented genome composed of both circular molecules and linear DNA replicons terminated by covalently closed hairpin ends or telomeres. Replication intermediates of the linear molecules are processed into hairpin telomeres via the activity of ResT, a telomere resolvase. We report here the results of limited proteolysis and mass spectroscopy to identify two main structural domains in ResT, separated by a chymotrypsin cleavage site between residues 163 and 164 of the 449 amino acid protein. The two domains have been overexpressed and purified. DNA electrophoretic mobility shift assays revealed that the C-terminal domain (ResT(164-449)) displays sequence-specific DNA binding to the box 3,4,5 region of the telomere, while the N-terminal domain (ResT(1-163)) exhibits sequence-independent DNA binding activity. Further analysis by DNase I footprinting supports a model for telomere resolution in which the hairpin binding module of the N-terminal domain is delivered to the box 1,2 region of the telomere through its tethering to ResT(164-449). Conversely, ResT(1-164) may play an important regulatory role by modulating both sequence-specific DNA binding activity and catalysis by the C-terminal domain.},
}
@article {pmid17460770,
year = {2007},
author = {Rashid-Kolvear, F and Pintilie, M and Done, SJ},
title = {Telomere length on chromosome 17q shortens more than global telomere length in the development of breast cancer.},
journal = {Neoplasia (New York, N.Y.)},
volume = {9},
number = {4},
pages = {265-270},
pmid = {17460770},
issn = {1476-5586},
mesh = {Breast Neoplasms/etiology/*genetics/pathology ; Carcinoma, Ductal, Breast/etiology/*genetics/pathology ; Carcinoma, Intraductal, Noninfiltrating/etiology/*genetics/pathology ; Chromosomal Instability/genetics ; Chromosomes, Human, Pair 17/*genetics ; Female ; Humans ; Telomere/*genetics ; },
abstract = {It is known that total telomere length is shorter in invasive breast cancer than in normal breast tissue but the status of individual telomere lengths has not been studied. Part of the difficulty is that usually telomere length in interphase cells is measured on all chromosomes together. In this study we compared normal breast epithelium, duct carcinoma in situ (DCIS), and invasive duct carcinoma (IDC) from 18 patients. Telomere length was specifically measured on chromosome 17q and was found to be shorter in DCIS and IDC than in normal breast epithelial cells, with more heterogeneity in telomere length in DCIS associated with IDC than in DCIS alone. More importantly, we found that the shortening of telomere on chromosome 17q is greater than the average shortening of all telomeres. This finding indicates that telomere shortening is not simply the result of the end replication problem; otherwise, all telomeres should be subjected to the same rate of telomere shortening. It seems there are mechanisms that preferentially erode some telomeres more than others or preferentially protect some chromosome ends. Our results suggest that the increased level of telomere shortening on 17q may be involved in chromosome instability and the progression of DCIS.},
}
@article {pmid17455196,
year = {2007},
author = {Alexander, B and Coppola, G and Perrault, SD and Peura, TT and Betts, DH and King, WA},
title = {Telomere length status of somatic cell sheep clones and their offspring.},
journal = {Molecular reproduction and development},
volume = {74},
number = {12},
pages = {1525-1537},
doi = {10.1002/mrd.20735},
pmid = {17455196},
issn = {1040-452X},
mesh = {Age Factors ; Animals ; Cells, Cultured ; Chromosomes/*ultrastructure ; Clone Cells/metabolism ; DNA/analysis/ultrastructure ; Fibroblasts/metabolism/ultrastructure ; Genome/genetics ; Nucleic Acid Hybridization ; Sheep, Domestic/*genetics ; Skin/cytology ; Telomere/*ultrastructure ; },
abstract = {This study was carried out to determine the telomere length status of sheep clones and their offspring, and to examine telomere dynamics and chromosomal abnormalities in culture propagated donor cells. Skin samples were collected from somatic cell nuclear transfer-derived sheep clones, and three of their progeny generated by natural mating. Samples were collected from control animals (n = 35), spanning in age from 1 month to 36 months of age. Genomic DNA was extracted from cell/tissue samples and their telomere lengths were assessed by terminal restriction fragment (TRF) analysis. Results revealed: that (a) sheep clones derived from cultured somatic cells have shortened telomere lengths compared to age-matched controls; (b) the offspring derived from natural mating between clones had normal telomere lengths compared to their age-matched counterparts; and donor cell cultures beyond 20 population doublings had significantly (P < 0.05) shortened telomeres and exhibited a higher numerical and structural chromosomal abnormalities.},
}
@article {pmid17452729,
year = {2007},
author = {Gardner, JP and Kimura, M and Chai, W and Durrani, JF and Tchakmakjian, L and Cao, X and Lu, X and Li, G and Peppas, AP and Skurnick, J and Wright, WE and Shay, JW and Aviv, A},
title = {Telomere dynamics in macaques and humans.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {62},
number = {4},
pages = {367-374},
doi = {10.1093/gerona/62.4.367},
pmid = {17452729},
issn = {1079-5006},
support = {R21 AG041375/AG/NIA NIH HHS/United States ; R15 CA132090/CA/NCI NIH HHS/United States ; F32 GM067522/GM/NIGMS NIH HHS/United States ; CA75907/CA/NCI NIH HHS/United States ; AG020132/AG/NIA NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; R15 GM099008/GM/NIGMS NIH HHS/United States ; },
mesh = {Aged ; Aging/physiology ; Animals ; Female ; Humans ; Macaca fascicularis/*genetics/metabolism ; Male ; Middle Aged ; Polymorphism, Restriction Fragment Length ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/metabolism ; Telomere/*physiology ; Tissue Distribution ; },
abstract = {In humans, telomere length in proliferating tissues shortens with age--a process accelerated with age-related diseases. Thus, telomere length and attrition with age in the nonhuman primate may serve as a useful paradigm for understanding telomere biology in humans. We examined telomere parameters in tissues of young and old Macaca fascicularis and compared them with several tissues from humans. Macaque telomeres were variable in length and exhibited partial synchrony (equivalence) within animals. They were longer than humans, partially because of longer subtelomeric segments. As skeletal muscle telomere length was unchanged with age, we used it as an internal reference to offset interanimal variation in telomere length. We identified age-dependent telomere attrition in lung, pancreas, skin, and thyroid. Similar to humans, telomerase activity was detected in spleen, thymus, digestive tract, and gonads. We conclude that factors that modify telomere attrition and aging in humans may also operate in the macaque.},
}
@article {pmid17452644,
year = {2007},
author = {Schmitt, J and Benavente, R and Hodzic, D and Höög, C and Stewart, CL and Alsheimer, M},
title = {Transmembrane protein Sun2 is involved in tethering mammalian meiotic telomeres to the nuclear envelope.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {104},
number = {18},
pages = {7426-7431},
pmid = {17452644},
issn = {0027-8424},
mesh = {Animals ; Chromosomes, Mammalian/metabolism ; Laminin/metabolism ; Male ; *Meiosis ; Membrane Proteins/*metabolism ; Mice ; Microscopy, Immunoelectron ; Nuclear Envelope/*metabolism ; Protein Binding ; Rats ; Spermatocytes/cytology/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Dynamic repositioning of telomeres is a unique feature of meiotic prophase I that is highly conserved among eukaryotes. At least in fission yeast it was shown to be required for proper alignment and recombination of homologous chromosomes. On entry into meiosis telomeres attach to the nuclear envelope and transiently cluster at a limited area to form a chromosomal bouquet. Telomere clustering is thought to promote chromosome recognition and stable pairing of the homologs. However, the molecular basis of telomere attachment and movement is largely unknown. Here we report that mammalian SUN-domain protein Sun2 specifically localizes to the nuclear envelope attachment sites of meiotic telomeres. Sun2-telomere association is maintained throughout the dynamic movement of telomeres. This association does not require the assembly of chromosomal axial elements or the presence of A-type lamins. Detailed EM analysis revealed that Sun2 is part of a membrane-spanning fibrillar complex that interconnects attached telomeres with cytoplasmic structures. Together with recent findings in fission yeast, our study indicates that the molecular mechanisms required for tethering meiotic telomeres and their dynamic movements during bouquet formation are conserved among eukaryotes.},
}
@article {pmid17449721,
year = {2007},
author = {Aoki, H and Iwado, E and Eller, MS and Kondo, Y and Fujiwara, K and Li, GZ and Hess, KR and Siwak, DR and Sawaya, R and Mills, GB and Gilchrest, BA and Kondo, S},
title = {Telomere 3' overhang-specific DNA oligonucleotides induce autophagy in malignant glioma cells.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {21},
number = {11},
pages = {2918-2930},
doi = {10.1096/fj.06-6941com},
pmid = {17449721},
issn = {1530-6860},
support = {CA-088936/CA/NCI NIH HHS/United States ; CA-108558/CA/NCI NIH HHS/United States ; CA16672/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Apoptosis ; Astrocytes/metabolism ; *Autophagy ; Blotting, Western ; Brain Neoplasms/genetics/pathology/*therapy ; Cell Survival ; Cells, Cultured ; DNA/*pharmacology ; Female ; Flow Cytometry ; Glioma/genetics/pathology/*therapy ; Humans ; Membrane Potential, Mitochondrial ; Mice ; Mice, Nude ; Microtubule-Associated Proteins ; Mitochondria/metabolism ; Oligonucleotides/*pharmacology ; Protein Array Analysis ; Protein Kinases/metabolism ; STAT3 Transcription Factor/metabolism ; Sirolimus/pharmacology ; Survival Rate ; TOR Serine-Threonine Kinases ; Telomerase/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Telomere 3' overhang-specific DNA oligonucleotides (T-oligos) induce cell death in cancer cells, presumably by mimicking telomere loop disruption. Therefore, T-oligos are considered an exciting new therapeutic strategy. The purpose of this study was to elucidate how T-oligos exert antitumor effects on human malignant glioma cells in vitro and in vivo. We demonstrated that T-oligos inhibited the proliferation of malignant glioma cells through induction of nonapoptotic cell death and mitochondria hyperpolarization, whereas normal astrocytes were resistant to T-oligos. Tumor cells treated with T-oligos developed features compatible with autophagy, with development of autophagic vacuoles and conversion of an autophagy-related protein, microtubule-associated protein 1 light chain 3 from type I (cytoplasmic form) to type II (membrane form of autophagic vacuoles). A reverse-phase protein microarray analysis and Western blotting revealed that treatment with T-oligos inhibited the mammalian target of the rapamycin (mTOR) and the signal transducer and activator of transcription 3 (STAT3). Moreover, pretreatment with T-oligos significantly prolonged the survival time of mice inoculated intracranially with malignant glioma cells compared with that of untreated mice and those treated with control oligonucleotides (P=0.0065 and P=0.043, respectively). These results indicate that T-oligos stimulate the induction of nonapoptotic autophagic also known as type II programmed cell death and are thus promising in the treatment of malignant glioma.},
}
@article {pmid17448460,
year = {2007},
author = {Grafi, G and Ben-Meir, H and Avivi, Y and Moshe, M and Dahan, Y and Zemach, A},
title = {Histone methylation controls telomerase-independent telomere lengthening in cells undergoing dedifferentiation.},
journal = {Developmental biology},
volume = {306},
number = {2},
pages = {838-846},
doi = {10.1016/j.ydbio.2007.03.023},
pmid = {17448460},
issn = {0012-1606},
mesh = {Arabidopsis/*genetics/*physiology ; Arabidopsis Proteins/genetics/physiology ; Cell Cycle ; Cell Differentiation ; Chromatin/metabolism ; Chromatin Immunoprecipitation ; DNA Methylation ; *Gene Expression Regulation, Plant ; Histones/*chemistry/metabolism ; Mutation ; Oligonucleotide Array Sequence Analysis ; Plant Physiological Phenomena ; Protoplasts/metabolism ; Telomere/*ultrastructure ; Ubiquitin/metabolism ; },
abstract = {Cellular dedifferentiation underlies topical issues in biology such as regeneration and nuclear cloning and has common features in plants and animals. In plants, this process characterizes the transition of differentiated leaf cells to protoplasts (plant cells devoid of cell walls) and is accompanied by global chromatin reorganization associated with reprogramming of gene expression. A screen for mutants defective in proliferation and callus formation identified kyp-2-a mutant in the KRYPTONITE (KYP)/SUVH4 gene encoding a histone H3 lysine 9 (H3K9) methyltransferase. Analysis of telomere length revealed stochastic telomerase-independent lengthening of telomeres in wild type but not in kyp-2 protoplasts. In kyp-2 mutant, telomeric repeats were no longer associated with dimethylated H3K9. The Arabidopsis telomerase reverse transcriptase (tert) mutant displayed accelerated proliferation despite its short telomeres, though it also showed accelerated cell death. Microarray analysis uncovered several components of the ubiquitin proteolytic system, which are downregulated in kyp-2 compared to wild-type protoplasts. Thus, our results suggest that histone methylation activity is required for the establishment/maintenance of the dedifferentiated state and/or reentry into the cell cycle, at least partly, through activation of genes whose products are involved in the ubiquitin proteolytic pathway. In addition, our results illuminate the complexity of cellular dedifferentiation, particularly the occurrence of DNA recombination that can lead to genome instability.},
}
@article {pmid17447124,
year = {2007},
author = {Wuebbles, R and Jones, PL},
title = {Engineered telomeres in transgenic Xenopus laevis.},
journal = {Transgenic research},
volume = {16},
number = {3},
pages = {377-384},
pmid = {17447124},
issn = {0962-8819},
mesh = {Animals ; Animals, Genetically Modified/genetics/*growth &amp; development ; DNA/analysis ; *Epigenesis, Genetic ; Genetic Engineering ; In Situ Hybridization, Fluorescence ; Models, Animal ; Telomere/chemistry/genetics/*physiology ; Xenopus laevis/genetics/*growth &amp; development ; },
abstract = {The expanding roles of telomeres in epigenetic gene regulation, nuclear organization, and human disease have necessitated the establishment of model organisms in which to study telomere function under normal developmental conditions. We present an efficient system for generating numerous vertebrate animals containing engineered telomeres using a Xenopus laevis transgenesis technique. Our results indicate Xenopus zygotes efficiently recognize telomeric repeats at chromosome break points and form telomeric complexes thus generating a new telomere. The resulting transgenic animals progress through normal development and successfully metamorphose into froglets despite the chromosome breakage. Overall, this presents an efficient mechanism for generating engineered telomeres in a vertebrate system and provides an opportunity to investigate epigenetic aspects of telomere function during normal vertebrate development.},
}
@article {pmid17442269,
year = {2007},
author = {Tam, AT and Pike, BL and Hammet, A and Heierhorst, J},
title = {Telomere-related functions of yeast KU in the repair of bleomycin-induced DNA damage.},
journal = {Biochemical and biophysical research communications},
volume = {357},
number = {3},
pages = {800-803},
doi = {10.1016/j.bbrc.2007.04.011},
pmid = {17442269},
issn = {0006-291X},
mesh = {Antibiotics, Antineoplastic/toxicity ; Antigens, Nuclear/genetics/*physiology ; Bleomycin/*toxicity ; *DNA Damage ; DNA Ligase ATP ; DNA Ligases/genetics/physiology ; DNA Repair/genetics/*physiology ; DNA, Fungal/drug effects/genetics/metabolism ; DNA-Binding Proteins/genetics/*physiology ; Ku Autoantigen ; Microbial Viability/drug effects/genetics ; Mutation ; Rad52 DNA Repair and Recombination Protein/genetics/physiology ; Recombination, Genetic ; Saccharomyces cerevisiae/drug effects/genetics/growth &amp; development ; Saccharomyces cerevisiae Proteins/genetics/physiology ; Telomere/genetics/*metabolism ; },
abstract = {Bleomycins are small glycopeptide cancer chemotherapeutics that give rise to 3'-modified DNA double-strand breaks (DSBs). In Saccharomyces cerevisiae, DSBs are predominantly repaired by RAD52-dependent homologous recombination (HR) with some support by Yku70/Yku80 (KU)-dependent pathways. The main DSB repair function of KU is believed to be as part of the non-homologous end-joining (NHEJ) pathway, but KU also functions in a "chromosome healing" pathway that seals DSBs by de novo telomere addition. We report here that rad52Deltayku70Delta double mutants are considerably more bleomycin hypersensitive than rad52Deltalig4Delta cells that lack the NHEJ-specific DNA ligase 4. Moreover, the telomere-specific KU mutation yku80-135i also dramatically increases rad52Delta bleomycin hypersensitivity, almost to the level of rad52Deltayku80Delta. The results indicate that telomere-specific functions of KU play a more prominent role in the repair of bleomycin-induced damage than its NHEJ functions, which could have important clinical implications for bleomycin-based combination chemotherapies.},
}
@article {pmid17439933,
year = {2007},
author = {Wu, CH and Hsieh, SC and Li, KJ and Lu, MC and Yu, CL},
title = {Premature telomere shortening in polymorphonuclear neutrophils from patients with systemic lupus erythematosus is related to the lupus disease activity.},
journal = {Lupus},
volume = {16},
number = {4},
pages = {265-272},
doi = {10.1177/0961203307077155},
pmid = {17439933},
issn = {0961-2033},
mesh = {Adolescent ; Adult ; Aged ; Case-Control Studies ; Female ; Humans ; Leukocytes, Mononuclear/*pathology ; Lupus Erythematosus, Systemic/*blood/complications ; Male ; Neutrophils/*pathology ; Severity of Illness Index ; Sickness Impact Profile ; Telomerase/*analysis/blood ; Telomere/*pathology ; },
abstract = {We investigated whether premature telomeric loss occurred in peripheral polymorphonuclear neutrophils (PMN) as well as mononuclear cells (MNC) from patients with systemic lupus erythematosus (SLE). We measured the telomere length of MNC and PMN in 60 SLE patients and 26 sex-, race- and age-matched healthy volunteers by Southern blotting with chemiluminescence method. The possible predisposing factors associated with telomere change were also analysed. We found the telomere length of MNC and PMN shortened with age in different degrees in both SLE and control groups. Compared to the control group, the telomere length was shortened in both SLE-MNC (6.08 kb in SLE versus 6.71 kb in control, P = 0.0008) and PMN (6.24 kb in SLE versus 6.75 kb in control, P = 0.0025). The average reduction in telomere length in SLE patients was equivalent to a premature senescence of 16.5 years in MNC and 13.4 years in PMN. In addition, the accelerated telomere shortening was more prominent in SLE patients younger than 45 years old. SLE disease activity (SLEDAI) contributed remarkably to the accelerated telomere erosion, at least in PMN. Moreover, the telomere length of MNC was significantly shorter than PMN in the same SLE patients with leukopenia and lymphopenia. These data suggested that MNC and PMN from patients with SLE displayed premature and accelerated telomere shortening that SLE is an independent factor for it.},
}
@article {pmid17433785,
year = {2007},
author = {Feldser, DM and Greider, CW},
title = {Short telomeres limit tumor progression in vivo by inducing senescence.},
journal = {Cancer cell},
volume = {11},
number = {5},
pages = {461-469},
pmid = {17433785},
issn = {1535-6108},
support = {P01 CA013106/CA/NCI NIH HHS/United States ; P01 CA016519/CA/NCI NIH HHS/United States ; P01 CA 16519/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Burkitt Lymphoma/*genetics/pathology ; Cellular Senescence/*genetics ; Disease Progression ; Genes, myc ; Genes, p53 ; Mice ; Mice, Transgenic ; *Telomere ; },
abstract = {Telomere maintenance is critical for cancer progression. To examine mechanisms of tumor suppression induced by short telomeres, we crossed mice deficient for the RNA component of telomerase, mTR(-/-), with Emu-myc transgenic mice, an established model of Burkitt's lymphoma. Short telomeres suppressed tumor formation in Emu-myc transgenic animals. Expression of Bcl2 blocked apoptosis in tumor cells, but surprisingly, mice with short telomeres were still resistant to tumor formation. Staining for markers of cellular senescence showed that pretumor cells induced senescence in response to short telomeres. Loss of p53 abrogated the short telomere response. This study provides in vivo evidence for the existence of a p53-mediated senescence mechanism in response to short telomeres that suppresses tumorigenesis.},
}
@article {pmid17433324,
year = {2007},
author = {Lechel, A and Holstege, H and Begus, Y and Schienke, A and Kamino, K and Lehmann, U and Kubicka, S and Schirmacher, P and Jonkers, J and Rudolph, KL},
title = {Telomerase deletion limits progression of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease.},
journal = {Gastroenterology},
volume = {132},
number = {4},
pages = {1465-1475},
doi = {10.1053/j.gastro.2007.01.045},
pmid = {17433324},
issn = {0016-5085},
mesh = {Aneuploidy ; Animals ; Apoptosis ; Carcinoma, Hepatocellular/*genetics/metabolism/pathology ; Cell Cycle/genetics ; DNA, Neoplasm/*genetics ; Disease Progression ; Exons ; *Gene Deletion ; Gene Expression Regulation, Neoplastic ; Genes, p53/*genetics ; Humans ; Immunohistochemistry ; In Situ Hybridization ; Liver Diseases/*genetics/metabolism/pathology ; Liver Neoplasms, Experimental/*genetics/metabolism/pathology ; Mice ; Mice, Knockout ; Nucleic Acid Amplification Techniques ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*genetics ; Telomere/genetics ; },
abstract = {BACKGROUND &amp; AIMS: During early stages of carcinogenesis most human epithelial cancers including hepatocellular carcinoma (HCC) have been observed to transit through a "crisis" stage characterized by telomere shortening, loss of p53 checkpoint function, and a sharp increase in aneuploidy. The function of telomerase during in vivo hepatocarcinogenesis has not been studied in this genetic context.<br><br>METHODS: Here we generated a mouse model in which HCC was induced by chronic organ damage (HBs-AG transgene) in the presence of telomere shortening and p53 deletion. Tumor development was analyzed in late-generation telomerase knockout mice (mTERC(-/-)) and littermates, genetically rescued for telomerase gene expression (mTERC(+/-)).<br><br>RESULTS: The formation of HCCs was strongly suppressed in mTERC(-/-) mice compared to mTERC(+/-) siblings correlating with reduced rates of tumor cell proliferation and elevated rates of tumor cell apoptosis. Although the prevalence of short telomeres was similar in chronically damaged liver of both cohorts, mTERC(-/-) HCC developed increased levels of DNA damage and aneuploidy compared to mTERC(+/-) HCC.<br><br>CONCLUSIONS: This study provides direct evidence that telomerase is a critical component for in vivo progression of p53 mutant HCC with short telomeres in the chronically damaged liver. In this molecular context, telomerase limits the accumulation of telomere dysfunction, the evolution of excessive aneuploidy, and the activation of p53-independent checkpoints suppressing hepatocarcinogenesis.},
}
@article {pmid17429195,
year = {2007},
author = {Yoon, SY and Sung, HJ and Park, KH and Choi, IK and Kim, SJ and Oh, SC and Seo, JH and Choi, CW and Kim, BS and Shin, SW and Kim, YH and Kim, JS},
title = {Telomere length shortening of peripheral blood mononuclear cells in solid-cancer patients undergoing standard-dose chemotherapy might be correlated with good treatment response and neutropenia severity.},
journal = {Acta haematologica},
volume = {118},
number = {1},
pages = {30-37},
doi = {10.1159/000101558},
pmid = {17429195},
issn = {1421-9662},
mesh = {Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/*administration &amp; dosage/adverse effects ; Biomarkers, Tumor/blood ; Cohort Studies ; Comorbidity ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Female ; Follow-Up Studies ; Humans ; Leukocytes, Mononuclear/drug effects/*metabolism ; Male ; Neoplasms/blood/*drug therapy/*enzymology/mortality ; Neutropenia/chemically induced/*epidemiology ; Probability ; Prospective Studies ; Risk Factors ; Sensitivity and Specificity ; Survival Analysis ; Telomerase/*metabolism ; Telomere/*drug effects ; Treatment Outcome ; },
abstract = {This study evaluated the telomere length changes (DeltaTL) of peripheral blood mononuclear cells before and after repetitive standard-dose nonmyeloablative chemotherapy and the association of DeltaTL with treatment response and myelosuppression severity. TL was measured with Southern blot analysis in 32 solid-cancer patients without bone marrow metastasis. The mean TL before chemotherapy (t0 TL) and after the 2nd (t1 TL), 4th (t2 TL) and 6th cycle (t3 TL) was 8.49, 8.33, 8.08 and 8.10 kb, respectively. TL became significantly decreased after 4 (p = 0.005) and 6 (p = 0.026) cycles of chemotherapy. The mean value of DeltaTL before and after completion of chemotherapy (t0 TL - t3 TL) was 0.46 kb. DeltaTL has a significant correlation with good treatment response (r = 0.448, p = 0.005) and the frequency of severe neutropenia (r = 0.417, p < 0.05). Consequently, TL of peripheral blood mononuclear cells was decreased by the repetitive nonmyeloablative standard-dose chemotherapy in solid-cancer patients without bone marrow metastasis, and DeltaTL was associated with good treatment response and neutropenia severity.},
}
@article {pmid17429064,
year = {2007},
author = {Kibe, T and Ono, Y and Sato, K and Ueno, M},
title = {Fission yeast Taz1 and RPA are synergistically required to prevent rapid telomere loss.},
journal = {Molecular biology of the cell},
volume = {18},
number = {6},
pages = {2378-2387},
pmid = {17429064},
issn = {1059-1524},
mesh = {Cell Cycle ; DNA Helicases/genetics/metabolism ; Humans ; Mutation ; Phenotype ; Protein Binding ; Replication Protein A/genetics/*metabolism ; Schizosaccharomyces/cytology/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Shelterin Complex ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {The telomere complex must allow nucleases and helicases to process chromosome ends to make them substrates for telomerase, while preventing these same activities from disrupting chromosome end-protection. Replication protein A (RPA) binds to single-stranded DNA and is required for DNA replication, recombination, repair, and telomere maintenance. In fission yeast, the telomere binding protein Taz1 protects telomeres and negatively regulates telomerase. Here, we show that taz1-d rad11-D223Y double mutants lose their telomeric DNA, indicating that RPA (Rad11) and Taz1 are synergistically required to prevent telomere loss. Telomere loss in the taz1-d rad11-D223Y double mutants was suppressed by additional mutation of the helicase domain in a RecQ helicase (Rqh1), or by overexpression of Pot1, a single-strand telomere binding protein that is essential for protection of chromosome ends. From our results, we propose that in the absence of Taz1 and functional RPA, Pot1 cannot function properly and the helicase activity of Rqh1 promotes telomere loss. Our results suggest that controlling the activity of Rqh1 at telomeres is critical for the prevention of genomic instability.},
}
@article {pmid17428253,
year = {2007},
author = {Tresnasari, K and Takakuwa, T and Ham, MF and Rahadiani, N and Nakajima, H and Aozasa, K},
title = {Telomere dysfunction and inactivation of the p16(INK4a)/Rb pathway in pyothorax-associated lymphoma.},
journal = {Cancer science},
volume = {98},
number = {7},
pages = {978-984},
doi = {10.1111/j.1349-7006.2007.00482.x},
pmid = {17428253},
issn = {1347-9032},
mesh = {Cell Line, Tumor ; Cyclin-Dependent Kinase Inhibitor p16/antagonists &amp; inhibitors/*genetics ; DNA, Neoplasm/genetics/isolation &amp; purification ; Humans ; Lymphoma/*genetics/pathology ; Polymorphism, Restriction Fragment Length ; RNA, Neoplasm/genetics/isolation &amp; purification ; Retinoblastoma Protein/antagonists &amp; inhibitors/*genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*genetics ; Telomere/*genetics ; Thoracic Neoplasms/*genetics/pathology ; },
abstract = {Previous studies have indicated that genome instability is involved in the lymphomagenesis of pyothorax-associated lymphoma (PAL), which develops in patients with a long-standing history of pyothorax. One of the well-known causes of genome instability is telomere dysfunction. In the present study, the condition of telomeres was analyzed in the cell lines and clinical samples from PAL. Telomere length (TL) in PAL cell lines was extremely short (<4.5 kbp). TL in tumor samples was broad in range, and shorter than that in the peripheral blood leukocytes from the matched patients. Three of five PAL cell lines showed frequent loss of telomere signals (telomere erosion); however, telomerase activity in PAL cell lines was similar to that in Burkitt lymphoma cell lines. Rb expression was detected in three PAL cell lines and four of 15 clinical samples, respectively. Rb protein expressed in three PAL cell lines was heavily phosphorylated, indicating that function of Rb protein was suppressed. p16(INK4a) expression was not detected in either cell lines or clinical samples. The promoter region in p16(INK4a) was heavily methylated in all cell lines as well as the clinical samples. Inactivation of the p16(INK4a)/Rb pathway may allow continuous cell division and critical telomere shortening, which induce genome instability, finally leading to malignant transformation. Taken together, telomere dysfunction and inactivation of the p16(INK4a)/Rb pathway might play a role for PAL development.},
}
@article {pmid17427414,
year = {2007},
author = {Boubriak, I and Pouschuk, V and Grodzinsky, A and Osborne, DJ},
title = {Telomeres and seed banks.},
journal = {TSitologiia i genetika},
volume = {41},
number = {1},
pages = {23-29},
pmid = {17427414},
issn = {0564-3783},
mesh = {Blotting, Southern ; DNA, Plant/*genetics ; Electrophoresis, Agar Gel ; Germination/*physiology ; Preservation, Biological ; Secale/genetics/*growth &amp; development ; Seeds/genetics/*growth &amp; development ; Telomere/*genetics ; Time Factors ; },
abstract = {We have found that a progressive loss of telomeric sequences occurs from high molecular weight DNA with an increasing appearance at low molecular weight as the periods of storage in the dry state were extended in time to provide seed germination loss from 98 to 0%. Telomere distribution would appear to follow the general pattern of DNA random fragmentation that occurs in the embryos of seeds stored in the dry state, but there are also indications of an overall telomere loss from DNA as a consequence of storage. There is a need for a convenient "equality marker" for the seeds that can be monitored over time. Reviewing the implications of our results very carefully we believe that there is considerable potential in the use of telomere sequences to mark embryo ageing of seeds held in Seed Banks.},
}
@article {pmid17418962,
year = {2007},
author = {M'kacher, R and Bennaceur-Griscelli, A and Girinsky, T and Koscielny, S and Delhommeau, F and Dossou, J and Violot, D and Leclercq, E and Courtier, MH and Béron-Gaillard, N and Assaf, E and Ribrag, V and Bourhis, J and Feneux, D and Bernheim, A and Parmentier, C and Carde, P},
title = {Telomere shortening and associated chromosomal instability in peripheral blood lymphocytes of patients with Hodgkin's lymphoma prior to any treatment are predictive of second cancers.},
journal = {International journal of radiation oncology, biology, physics},
volume = {68},
number = {2},
pages = {465-471},
doi = {10.1016/j.ijrobp.2007.01.050},
pmid = {17418962},
issn = {0360-3016},
mesh = {Adult ; Aged ; Breast Neoplasms/genetics ; Carcinoma, Basal Cell/genetics ; Chromosomal Instability/*genetics ; Cohort Studies ; DNA Repair ; Female ; Follow-Up Studies ; Hodgkin Disease/drug therapy/*genetics/radiotherapy ; Humans ; *Lymphocytes/pathology/radiation effects ; Male ; Middle Aged ; Neoplasms, Second Primary/*etiology/genetics ; Prospective Studies ; Radiation Tolerance ; Skin Neoplasms/genetics ; Survivors ; Telomere/*pathology ; },
abstract = {PURPOSE: To investigate a potential link between telomere length, chromosomal instability, and the advent of a second cancer (SC) in patients with Hodgkin's lymphoma (HL), who are known to be at risk for SCs. This study was premised on the finding that telomere dysfunction and DNA repair pathways were related to many pathologic conditions.<br><br>METHODS AND MATERIALS: Three cohorts of patients with HL were studied: 73 who were prospectively followed >5 years after diagnosis (prospective HL cohort), 28 who developed a SC (SC HL cohort), and 18 long-term survivors with no evidence of disease or complication since their initial treatment (NED HL cohort). Telomere length was analyzed by a telomeric restriction fragment assay in peripheral blood lymphocytes. Thirty healthy donors and 70 patients with a newly diagnosed solid tumor were the control population.<br><br>RESULTS: Compared with controls, patients from the prospective HL cohort, before any treatment, showed age-independent shorter telomeres (mean, 8.3 vs. 11.7 kb in healthy donors; <6 kb in 18% in HL patients), increased spontaneous chromosomal abnormalities, and increased in vitro radiation sensitivity (p < 10(-4) each). After treatment, telomere shortening was associated with cytogenetic profiles characterized by the persistence of complex chromosomal rearrangement and clonal aberrations. Moreover, the two cases of SC in the prospective HL patients had short telomeres and CCR initially. In addition, the SC HL cohort was characterized by markedly short telomeres (6.6 vs. 9.7 kb in the NED HL cohort), the presence of complex chromosome rearrangements, and increased in vitro radiation sensitivity.<br><br>CONCLUSIONS: An intimate relationship between pre-treatment telomere shortening, chromosomal instability, radiation sensitivity and occurrence of SC was found in HL patients.},
}
@article {pmid17416776,
year = {2007},
author = {McGrath, M and Wong, JY and Michaud, D and Hunter, DJ and De Vivo, I},
title = {Telomere length, cigarette smoking, and bladder cancer risk in men and women.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {16},
number = {4},
pages = {815-819},
doi = {10.1158/1055-9965.EPI-06-0961},
pmid = {17416776},
issn = {1055-9965},
support = {CA55075/CA/NCI NIH HHS/United States ; CA87969/CA/NCI NIH HHS/United States ; K12 HD051959-01/HD/NICHD NIH HHS/United States ; T32 CA 09001-28/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Polymerase Chain Reaction ; Prospective Studies ; Risk Factors ; Smoking/*adverse effects ; Statistics, Nonparametric ; Telomere/*ultrastructure ; Urinary Bladder Neoplasms/*genetics ; },
abstract = {Truncated telomeres are among the defining characteristics of most carcinomas. Given the role of telomeres in tumorigenesis, we reasoned that constitutionally short telomeres might be associated with an increased risk of bladder cancer. Using quantitative real-time PCR, we measured relative telomere length in bladder cancer cases and healthy controls and evaluated the association between telomere length, cigarette smoking, and bladder cancer risk in a case-control study nested within the Health Professionals Follow-up Study and a case-control study nested within the Nurses' Health Study. Telomeres were significantly shorter in bladder cancer cases (n = 184) than in controls (n = 192). The mean relative telomere length in cases was 0.23 (SD, 0.16) versus 0.27 (SD, 0.15) in controls (P = 0.001). The adjusted odds ratio for bladder cancer was 1.88 (95% confidence interval, 1.05, 3.36) for individuals in the quartile with the shortest telomeres as compared with individuals in the quartile with the longest telomeres (P(trend) = 0.006). We observed a statistically significant difference in telomere length among men and women (P < 0.001); however, the interaction between gender, telomere length, and bladder cancer risk was not significant. We also observed a significant difference in telomere length across categories of pack-years of smoking (P = 0.01). These findings suggest that truncated telomeres are associated with an increased risk of bladder cancer.},
}
@article {pmid17409236,
year = {2007},
author = {Cheng, A and Shin-ya, K and Wan, R and Tang, SC and Miura, T and Tang, H and Khatri, R and Gleichman, M and Ouyang, X and Liu, D and Park, HR and Chiang, JY and Mattson, MP},
title = {Telomere protection mechanisms change during neurogenesis and neuronal maturation: newly generated neurons are hypersensitive to telomere and DNA damage.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {27},
number = {14},
pages = {3722-3733},
pmid = {17409236},
issn = {1529-2401},
support = {//Intramural NIH HHS/United States ; },
mesh = {Animals ; *Cell Differentiation/physiology ; Cell Line ; Cells, Cultured ; Cerebral Cortex/cytology/metabolism ; DNA Damage/*physiology ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neurons/*cytology/*metabolism ; Pregnancy ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres are DNA-protein complexes at the ends of eukaryotic chromosomes that play an important role in maintaining the integrity of the genome. In proliferative stem cells and cancer cells, telomere length is maintained by telomerase, and telomere structure and functions are regulated by telomere-associated proteins. We find that telomerase levels are high in embryonic cortical neural progenitor cells (NPCs) and low in newly generated neurons (NGNs) and mature neurons (MNs). In contrast, telomere repeat-binding factor 2 (TRF2) expression is undetectable in early brain development in vivo and in cultured NPCs and is expressed at progressively higher levels as NPCs cease proliferation and differentiate into postmitotic neurons. The telomere-disrupting agent telomestatin induces a DNA damage response and apoptosis in NGNs (which have low levels of TRF2 and telomerase), whereas NPCs (which have high levels of telomerase) and MNs (which have high levels of TRF2) are resistant to telomere damage. Overexpression of TRF2 in NGNs protects them against death induced by telomestatin and other DNA-damaging agents. Knockdown of TRF2 expression in MNs and knock-out of telomerase reverse transcriptase in NPCs increased their sensitivity to telomere- and DNA-damaging agents but did not affect the vulnerability of NGNs. These findings suggest that TRF2 and telomerase function as distinct telomere protection mechanisms during the processes of neurogenesis and neuronal maturation and that hypersensitivity of NGNs to telomere damage results from relative deficiencies of both telomerase and TRF2.},
}
@article {pmid17407150,
year = {2007},
author = {Tanaka, Y and Moritoh, Y and Miwa, N},
title = {Age-dependent telomere-shortening is repressed by phosphorylated alpha-tocopherol together with cellular longevity and intracellular oxidative-stress reduction in human brain microvascular endotheliocytes.},
journal = {Journal of cellular biochemistry},
volume = {102},
number = {3},
pages = {689-703},
doi = {10.1002/jcb.21322},
pmid = {17407150},
issn = {0730-2312},
mesh = {Aging ; Cell Size ; Cell Survival ; Cells, Cultured ; Cellular Senescence ; Endothelial Cells/*cytology ; Humans ; Hydrogen Peroxide/chemistry ; Lipids/chemistry ; Microcirculation ; Models, Biological ; *Oxidative Stress ; Phosphorylation ; Telomerase ; Telomere/*ultrastructure ; Vitamin E/metabolism ; alpha-Tocopherol/*metabolism ; },
abstract = {Cellular life-span of neonatal human brain microvascular endotheliocytes (HBME) was estimated by population doubling levels (PDLs) for serial subcultivations until spontaneous proliferation stoppage, and was 2.4-fold longer for continuous administration with the 6-O-phosphorylated derivative (TocP) of alpha-tocopherol (Toc), being bio-available owing to its water-solubility, or TocP plus 2-O-phosphorylated ascorbate (Asc2P), and 1.3-fold longer with Asc2P, at a dose of 150 microM, than for the non-administered control. Enlarged cell diameters indicative of cellular aging were repressed for TocP-administered cells as analyzed with a channelizer. Age-dependent shortening of telomeric DNA length (291 bp/PDL) was slowed markedly for TocP (165 bp/PDL) or TocP plus Asc2P, but slightly for Asc2P. Telomerase activity as assessed by the PCR-based TRAP method was detectable slightly at younger ages but no longer at middle ages for the non-administered cells, but, for TocP-administered cells, was intensely detected at younger ages and appreciably until middle ages. Intracellular TocP amounts were not changed age-dependently in contrast to a marked decrease in Toc which accrued from TocP esterolysis. This may be partly attributed to age-dependent changes in the lipid peroxidation product acrolein (ACR), which was abundant at older ages in non-administered cells, but scarcely in TocP-administered cells. Furthermore, intracellular reactive oxygen species (ROS) such as H(2)O(2) and hydroperoxides as detected using the redox indicator CDCFH-DA was less abundant in TocP-administered cells than in non-administered cells. Thus the telomeric-DNA retention, concurrently with retained telomerase activity, was shown to be correlated with cellular longevity, and may be supported by diminished oxidative stress, in hydrophobic microenvironment, which can be achieved by TocP rather than AscP.},
}
@article {pmid17406480,
year = {2006},
author = {Baerlocher, GM and Vulto, I and de Jong, G and Lansdorp, PM},
title = {Flow cytometry and FISH to measure the average length of telomeres (flow FISH).},
journal = {Nature protocols},
volume = {1},
number = {5},
pages = {2365-2376},
doi = {10.1038/nprot.2006.263},
pmid = {17406480},
issn = {1750-2799},
mesh = {Aged, 80 and over ; Blood Cells/chemistry ; Flow Cytometry/*methods ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Telomere/*chemistry ; },
abstract = {Telomeres have emerged as crucial cellular elements in aging and various diseases including cancer. To measure the average length of telomere repeats in cells, we describe our protocols that use fluorescent in situ hybridization (FISH) with labeled peptide nucleic acid (PNA) probes specific for telomere repeats in combination with fluorescence measurements by flow cytometry (flow FISH). Flow FISH analysis can be performed using commercially available flow cytometers, and has the unique advantage over other methods for measuring telomere length of providing multi-parameter information on the length of telomere repeats in thousands of individual cells. The accuracy and reproducibility of the measurements is augmented by the automation of most pipetting (aspiration and dispensing) steps, and by including an internal standard (control cells) with a known telomere length in every tube. The basic protocol for the analysis of nucleated blood cells from 22 different individuals takes about 12 h spread over 2-3 days.},
}
@article {pmid17406367,
year = {2007},
author = {Phatak, P and Cookson, JC and Dai, F and Smith, V and Gartenhaus, RB and Stevens, MF and Burger, AM},
title = {Telomere uncapping by the G-quadruplex ligand RHPS4 inhibits clonogenic tumour cell growth in vitro and in vivo consistent with a cancer stem cell targeting mechanism.},
journal = {British journal of cancer},
volume = {96},
number = {8},
pages = {1223-1233},
pmid = {17406367},
issn = {0007-0920},
mesh = {Acridines/*pharmacology ; Animals ; Antineoplastic Agents/*pharmacology ; Cell Proliferation/drug effects ; Drug Synergism ; Enzyme Inhibitors/*pharmacology ; Female ; Humans ; Mice ; Neoplastic Stem Cells/*drug effects ; Paclitaxel/pharmacology ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects ; },
abstract = {The pentacyclic acridinium methosulfate salt RHPS4 induces the 3'single-stranded guanine-rich telomeric overhang to fold into a G-quadruplex structure. Stabilisation of the latter is incompatible with an attachment of telomerase to the telomere and thus G-quadruplex ligands can effectively inhibit both the catalytic and capping functions of telomerase. In this study, we examined mechanisms underlying telomere uncapping by RHPS4 in uterus carcinoma cells (UXF1138L) with short telomeres and compared the susceptibility of bulk and clonogenic cancer cells to the G-quadruplex ligand. We show that treatment of UXF1138L cells with RHPS4 leads to the displacement of the telomerase catalytic subunit (hTERT) from the nucleus, induction of telomere-initiated DNA-damage signalling and chromosome fusions. We further report that RHPS4 is more potent against cancer cells that grow as colonies in soft agar than cells growing as monolayers. Human cord blood and HEK293T embryonic kidney cell colony forming units, however, were more resistant to RHPS4. RHPS4-treated UXF1138L xenografts had a decreased clonogenicity, showed loss of nuclear hTERT expression and an induction of mitotic abnormalities compared with controls. Although single-agent RHPS4 had limited in vivo efficacy, a combination of RHPS4 with the mitotic spindle poison Taxol caused tumour remissions and further enhancement of telomere dysfunction.},
}
@article {pmid17404276,
year = {2007},
author = {Romagnani, C and Juelke, K and Falco, M and Morandi, B and D'Agostino, A and Costa, R and Ratto, G and Forte, G and Carrega, P and Lui, G and Conte, R and Strowig, T and Moretta, A and Münz, C and Thiel, A and Moretta, L and Ferlazzo, G},
title = {CD56brightCD16- killer Ig-like receptor- NK cells display longer telomeres and acquire features of CD56dim NK cells upon activation.},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {178},
number = {8},
pages = {4947-4955},
doi = {10.4049/jimmunol.178.8.4947},
pmid = {17404276},
issn = {0022-1767},
support = {R01CA108609/CA/NCI NIH HHS/United States ; },
mesh = {CD56 Antigen/*analysis ; Cells, Cultured ; Humans ; Hyperplasia ; Interleukin-12/pharmacology ; Interleukin-15/pharmacology ; Interleukin-2/pharmacology ; Killer Cells, Natural/*immunology ; Lymph Nodes/immunology/pathology ; *Lymphocyte Activation ; Receptors, IgG/*analysis ; Receptors, Immunologic/*analysis ; Receptors, KIR ; Self Tolerance ; *Telomere ; },
abstract = {Human NK cells can be divided into CD56(dim)CD16(+) killer Ig-like receptors (KIR)(+/-) and CD56(bright)CD16(-) KIR(-) subsets that have been characterized extensively regarding their different functions, phenotype, and tissue localization. Nonetheless, the developmental relationship between these two NK cell subsets remains controversial. We report that, upon cytokine activation, peripheral blood (PB)-CD56(bright) NK cells mainly gain the signature of CD56(dim) NK cells. Remarkably, KIR can be induced not only on CD56(bright), but also on CD56(dim) KIR(-) NK cells, and their expression correlates with lower proliferative response. In addition, we demonstrate for the first time that PB-CD56(dim) display shorter telomeres than PB- and lymph node (LN)-derived CD56(bright) NK cells. Along this line, although human NK cells collected from nonreactive LN display almost no KIR and CD16 expression, NK cells derived from highly reactive LN, efferent lymph, and PB express significant amounts of KIR and CD16, implying that CD56(bright) NK cells could acquire these molecules in the LN during inflammation and then circulate through the efferent lymph into PB as KIR(+)CD16(+) NK cells. Altogether, our results suggest that CD56(bright)CD16(-) KIR(-) and CD56(dim)CD16(+)KIR(+/-) NK cells correspond to sequential steps of differentiation and support the hypothesis that secondary lymphoid organs can be sites of NK cell final maturation and self-tolerance acquisition during immune reaction.},
}
@article {pmid17403625,
year = {2007},
author = {Sampedro Camarena, F and Cano Serral, G and Sampedro Santaló, F},
title = {Telomerase and telomere dynamics in ageing and cancer: current status and future directions.},
journal = {Clinical &amp; translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico},
volume = {9},
number = {3},
pages = {145-154},
doi = {10.1007/s12094-007-0028-1},
pmid = {17403625},
issn = {1699-048X},
mesh = {Aging/*genetics ; Amino Acid Sequence ; Antineoplastic Agents/pharmacology/therapeutic use ; Biomarkers, Tumor ; Cellular Senescence ; Chromosomes, Human/ultrastructure ; Drug Design ; Forecasting ; Humans ; Molecular Sequence Data ; Neoplasm Proteins/analysis/antagonists &amp; inhibitors/*physiology ; Neoplasms/diagnosis/drug therapy/*enzymology/genetics/ultrastructure ; Organoplatinum Compounds/pharmacology/therapeutic use ; Telomerase/analysis/antagonists &amp; inhibitors/*physiology ; Telomere/*physiology/ultrastructure ; },
abstract = {This review will focus on the clinical utilities of telomerase for human cancer diagnosis and prognosis. Much attention has been focused on control of telomerase activity in early and late stage tumours. Telomerase stabilisation may be required for cells to escape replicative senescence and to proliferate indefinitely. Because of a very strong association between telomerase and malignancy, both clinicians and pathologists expect this molecule to be a useful diagnostic and prognostic marker and a new therapeutic target. These data have greatly inspired the development of various strategies to target telomere and telomerase for cancer therapy. Finally, evidence is now emerging that G-quadruplex ligands produce rapid senescence and selective cell death. A summary of recent experimental works with new small molecules as potential inhibitors of telomerase is presented.},
}
@article {pmid17398127,
year = {2008},
author = {Nasir, L},
title = {Telomeres and telomerase: Biological and clinical importance in dogs.},
journal = {Veterinary journal (London, England : 1997)},
volume = {175},
number = {2},
pages = {155-163},
doi = {10.1016/j.tvjl.2007.01.024},
pmid = {17398127},
issn = {1090-0233},
mesh = {Animals ; Cell Division/physiology ; Dog Diseases/*enzymology ; Dogs ; Neoplasms/drug therapy/enzymology/*veterinary ; Telomerase/antagonists &amp; inhibitors/*metabolism ; Telomere/*metabolism ; },
abstract = {In recent years in human oncology the enzyme telomerase has emerged as an ideal target for cancer therapy. This has led to the assessment of telomerase in cancers in companion animals, mainly dogs and these studies confirm that in dogs, like humans, telomere maintenance by telomerase is the primary mechanism by which cancer cells overcome their mortality and extend their lifespan. This review aims to provide an introduction to the biology of telomeres and telomerase and to discuss some of the telomere/telomerase directed therapeutic methodologies currently under development which may be of benefit to the canine cancer patient.},
}
@article {pmid17397675,
year = {2007},
author = {van der Harst, P and van der Steege, G and de Boer, RA and Voors, AA and Hall, AS and Mulder, MJ and van Gilst, WH and van Veldhuisen, DJ and , },
title = {Telomere length of circulating leukocytes is decreased in patients with chronic heart failure.},
journal = {Journal of the American College of Cardiology},
volume = {49},
number = {13},
pages = {1459-1464},
doi = {10.1016/j.jacc.2007.01.027},
pmid = {17397675},
issn = {1558-3597},
mesh = {Aged ; Atherosclerosis ; Case-Control Studies ; Female ; Heart Failure/etiology/*genetics ; Humans ; *Leukocytes ; Male ; Prospective Studies ; Severity of Illness Index ; Telomere/*ultrastructure ; },
abstract = {OBJECTIVES: This study sought to test the hypothesis that patients with chronic heart failure (CHF) have shorter telomeres compared with age-balanced and gender-balanced healthy individuals.<br><br>BACKGROUND: Telomere length is considered to be a marker of biological aging. Chronic heart failure might be viewed as a condition associated with accelerated biological aging.<br><br>METHODS: The telomere length ratio of leukocytes was determined prospectively by a quantitative polymerase chain reaction-based method in a case-control setting involving 803 participants: 183 healthy individuals and 620 CHF patients, ages 40 to 80 years, New York Heart Association functional class II to IV, and left ventricular ejection fraction of 0.40 or less.<br><br>RESULTS: The median telomere length ratio was 0.64 (interquartile range [IQR] 0.47 to 0.88) in CHF patients compared with 1.05 (IQR 0.86 to 1.29) in control patients (p < 0.001). The telomere length ratio in CHF patients related to severity of disease (median value [IQR] of patients with New York Heart Association class II, III, or IV function was 0.67 [0.48 to 0.92], 0.63 [0.46 to 0.86], and 0.55 [0.46 to 0.75], respectively; p for trend <0.05). In addition, telomeres were shorter in patients with an ischemic compared with a nonischemic etiology of CHF. Patients with none, 1 (coronary, cerebral, or peripheral vascular disease), 2 (any combination of the previous), or 3 atherosclerotic manifestations had a median (IQR) telomere length of 0.72 (0.51 to 1.01), 0.65 (0.48 to 0.87), 0.48 (0.39 to 0.72), and 0.43 (0.27 to 0.67), respectively (p for trend <0.001).<br><br>CONCLUSIONS: Telomere length is shorter in patients with CHF compared with age-balanced and gender-balanced control patients, and related to the severity of disease. In addition, telomere length was incrementally shorter according to the presence and extent of atherosclerotic disease manifestations.},
}
@article {pmid17396137,
year = {2007},
author = {Cosme-Blanco, W and Shen, MF and Lazar, AJ and Pathak, S and Lozano, G and Multani, AS and Chang, S},
title = {Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence.},
journal = {EMBO reports},
volume = {8},
number = {5},
pages = {497-503},
pmid = {17396137},
issn = {1469-221X},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; CA016672/CA/NCI NIH HHS/United States ; P01 CA34936-20/CA/NCI NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; P01 CA034936/CA/NCI NIH HHS/United States ; },
mesh = {9,10-Dimethyl-1,2-benzanthracene ; Animals ; Apoptosis ; *Cellular Senescence ; Embryo, Mammalian/cytology ; Fibroblasts/cytology ; Mice ; Papilloma/chemically induced ; Skin Neoplasms/chemically induced ; Telomere/*physiology ; Tumor Suppressor Protein p53/*physiology ; },
abstract = {Dysfunctional telomeres induce p53-dependent cellular senescence and apoptosis, but it is not known which function is more important for tumour suppression in vivo. We used the p53 (R172P) knock-in mouse, which is unable to induce apoptosis but retains intact cell-cycle arrest and cellular senescence pathways, to show that spontaneous tumorigenesis is potently repressed in Terc -/- p53 (R172P) mice. Tumour suppression is accompanied by global induction of p53, p21 and the senescence marker senescence-associated-beta-galactosidase. By contrast, cellular senescence was unable to suppress chemically induced skin carcinomas. These results indicate that suppression of spontaneous tumorigenesis by dysfunctional telomeres requires the activation of the p53-dependent cellular senescence pathway.},
}
@article {pmid17395902,
year = {2007},
author = {Souza, RF and Lunsford, T and Ramirez, RD and Zhang, X and Lee, EL and Shen, Y and Owen, C and Shay, JW and Morales, C and Spechler, SJ},
title = {GERD is associated with shortened telomeres in the squamous epithelium of the distal esophagus.},
journal = {American journal of physiology. Gastrointestinal and liver physiology},
volume = {293},
number = {1},
pages = {G19-24},
doi = {10.1152/ajpgi.00055.2007},
pmid = {17395902},
issn = {0193-1857},
support = {DK 63621/DK/NIDDK NIH HHS/United States ; },
mesh = {Adult ; Aged ; Barrett Esophagus/*genetics ; Esophagus/enzymology/*ultrastructure ; Female ; Gastric Fundus/enzymology ; Gastroesophageal Reflux/*genetics ; Humans ; Male ; Middle Aged ; Mucous Membrane/physiology ; Telomerase/metabolism ; Telomere/*ultrastructure ; },
abstract = {Telomeres are repetitive DNA sequences located at the ends of chromosomes. Telomeres are shortened by repeated cell divisions and by oxidative DNA damage, and cells with critically shortened telomeres cannot divide. We hypothesized that chronic gastroesophageal reflux disease (GERD)-induced injury of the esophageal squamous epithelium results in progressive telomeric shortening that eventually might interfere with mucosal healing. To address our hypothesis, we compared telomere length and telomerase activity in biopsy specimens of esophageal squamous epithelium from GERD patients and control patients. Endoscopic biopsies were taken from the esophageal squamous epithelium of 38 patients with GERD [10 long-segment Barrett's esophagus (LSBE), 15 short-segment (SSBE), 13 GERD without Barrett's esophagus] and 16 control patients without GERD. Telomere length was assessed using the terminal restriction fragment assay, and telomerase activity was studied by the PCR-based telomeric repeat amplification protocol assay. Patients with GERD had significantly shorter telomeres in the distal esophagus than controls [8.3 +/- 0.5 vs. 10.9 +/- 1.5 (SE) Kbp, P = 0.043]. Among the patients with GERD, telomere length in the distal esophagus did not differ significantly in those with and without Barrett's esophagus (LSBE 7.9 +/- 0.8, SSBE 8.6 +/- 0.9, GERD without BE 8.7 +/- 1.0 Kbp). No significant differences in telomerase activity in the distal esophagus were noted between patients with GERD and controls (4.0 +/- 0.39 vs. 5.2 +/- 0.53 RIUs). Telomeres in the squamous epithelium of the distal esophagus of patients who have GERD, with and without Barrett's esophagus, are significantly shorter than those of patients without GERD despite similar levels of telomerase activity.},
}
@article {pmid17395558,
year = {2007},
author = {Berardinelli, F and di Masi, A and Salvatore, M and Banerjee, S and Myung, K and De Villartay, JP and Revy, P and Plebani, A and Soresina, A and Taruscio, D and Tanzarella, C and Antoccia, A},
title = {A case report of a patient with microcephaly, facial dysmorphism, chromosomal radiosensitivity and telomere length alterations closely resembling "Nijmegen breakage syndrome" phenotype.},
journal = {European journal of medical genetics},
volume = {50},
number = {3},
pages = {176-187},
doi = {10.1016/j.ejmg.2007.01.006},
pmid = {17395558},
issn = {1769-7212},
support = {//Intramural NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics ; Chromosomes, Human/radiation effects ; Craniofacial Abnormalities/*genetics ; DNA Repair/genetics ; Female ; Humans ; Male ; Microcephaly/*genetics ; Nijmegen Breakage Syndrome/diagnosis/*genetics ; Nuclear Proteins/genetics ; Phenotype ; Radiation Tolerance/*genetics ; Telomere/*genetics/ultrastructure ; },
abstract = {Genetic heterogeneity in Nijmegen breakage syndrome (NBS) is highlighted by patients showing clinical and cellular features of NBS but with no mutations in NBS1 and normal levels of nibrin. NBS is an autosomal recessive disorder, whose clinical cellular signs include growth and developmental defects, dysmorphic facies, immunodeficiency, cancer predisposition, chromosomal instability and radiosensitivity. NBS is caused by mutations in the NBS1 gene, whose product is part of the MRE11/RAD50/NBS1 complex involved in the DNA double-strand break (DSB) response pathway. Since the identification of the NBS1 gene, patients with NBS clinical signs, particularly severe congenital microcephaly, are screened for mutations in the NBS1 gene. Further analyses include X-ray-induced chromosome aberrations, telomere analysis, kinetics of DSBs repair, levels of a panel of proteins involved in the maintenance of genetic stability, radiation-induced phosphorylation of various substrates and cell cycle analysis. We describe a patient with a NBS clinical phenotype, chromosomal sensitivity to X-rays but without mutations in the whole NBS1 or in the Cernunnos gene. Enhanced response to irradiation was mediated neither by DSBs rejoining defects nor by the NBS/AT-dependent DNA-damage response pathway. Notably, we found that primary fibroblasts from this patient displayed telomere length alterations. Cross-talk between pathways controlling response to DSBs and those involved in maintaining telomeres has been shown in the present patient. Dissecting the cellular phenotype of radiosensitive NBS-like patients represents a useful tool for the research of new genes involved in the cellular response to DSBs.},
}
@article {pmid17395247,
year = {2007},
author = {Richter, T and Saretzki, G and Nelson, G and Melcher, M and Olijslagers, S and von Zglinicki, T},
title = {TRF2 overexpression diminishes repair of telomeric single-strand breaks and accelerates telomere shortening in human fibroblasts.},
journal = {Mechanisms of ageing and development},
volume = {128},
number = {4},
pages = {340-345},
doi = {10.1016/j.mad.2007.02.003},
pmid = {17395247},
issn = {0047-6374},
mesh = {Cell Line ; *DNA Breaks, Single-Stranded ; DNA Repair/*genetics ; Fibroblasts/*metabolism ; Humans ; Nuclear Proteins/*biosynthesis/*genetics/physiology ; TATA Box Binding Protein-Like Proteins/*biosynthesis/*genetics/physiology ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 2 ; },
abstract = {Repair of single strand breaks in telomeric DNA is less efficient than in other genomic regions. This leads to an increased vulnerability of telomeric DNA towards damage induced by reactive oxygen species (ROS) and to accelerated telomere shortening under oxidative stress. The causes for the diminished repair efficacy in telomeres are unknown. We show here that overexpression of the telomere-binding protein TRF2 further reduces telomeric, but not genomic, single strand break repair. This suggests the possibility of strand break repair in telomeres being sterically hindered by the three-dimensional structure of the telomere DNA-protein complex and explains the effect of TRF2 on telomere shortening rates in telomerase-negative cells.},
}
@article {pmid17395154,
year = {2007},
author = {Yu, LR and Chan, KC and Tahara, H and Lucas, DA and Chatterjee, K and Issaq, HJ and Veenstra, TD},
title = {Quantitative proteomic analysis of human breast epithelial cells with differential telomere length.},
journal = {Biochemical and biophysical research communications},
volume = {356},
number = {4},
pages = {942-947},
pmid = {17395154},
issn = {0006-291X},
support = {N01 CO12400/CO/NCI/CA/NCI NIH HHS/United States ; N01CO12400/CA/NCI NIH HHS/United States ; N01-CO-12400/CO/NCI NIH HHS/United States ; },
mesh = {Breast/*metabolism/ultrastructure ; Cell Line ; DNA Repair/*physiology ; Epithelial Cells/*metabolism/ultrastructure ; Humans ; Proteome/*metabolism ; Telomere/*physiology/ultrastructure ; },
abstract = {Telomeres play important functional roles in cell proliferation, cell cycle regulation, and genetic stability, in which telomere length is critical. In this study, quantitative proteome comparisons for the human breast epithelial cells with short and long telomeres (184-hTERTL vs. 184-hTERTS and 90P-hTERTL vs. 90P-hTERTS), resulting from transfection of the human telomerase reverse transcriptase (hTERT) gene, were performed using cleavable isotope-coded affinity tags. More than 2000 proteins were quantified in each comparative experiment, with approximately 77% of the proteins identified in both analyses. In the cells with long telomeres, significant and consistent alterations were observed in metabolism (amino acid, nucleotide, and lipid metabolism), genetic information transmission (transcription and translation regulation, spliceosome and ribosome complexes), and cell signaling. Interestingly, the DNA excision repair pathway is enhanced, while integrin and its ligands are downregulated in the cells with long telomeres. These results may provide valuable information related to telomere functions.},
}
@article {pmid17393506,
year = {2007},
author = {Plentz, RR and Park, YN and Lechel, A and Kim, H and Nellessen, F and Langkopf, BH and Wilkens, L and Destro, A and Fiamengo, B and Manns, MP and Roncalli, M and Rudolph, KL},
title = {Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis.},
journal = {Hepatology (Baltimore, Md.)},
volume = {45},
number = {4},
pages = {968-976},
doi = {10.1002/hep.21552},
pmid = {17393506},
issn = {0270-9139},
mesh = {Adult ; Aged ; Carcinoma, Hepatocellular/*metabolism/pathology ; Cell Cycle/physiology ; Cell Transformation, Neoplastic/metabolism ; Cyclin-Dependent Kinase Inhibitor p16/*metabolism ; Cyclin-Dependent Kinase Inhibitor p21/*metabolism ; Female ; Humans ; Liver Neoplasms/*metabolism/pathology ; Male ; Middle Aged ; Precancerous Conditions/*metabolism/pathology ; Telomere/*metabolism ; },
abstract = {UNLABELLED: Telomere shortening and inactivation of cell cycle checkpoints characterize carcinogenesis. Whether these molecular features coincide at specific stages of human hepatocarcinogenesis is unknown. The preneoplasia-carcinoma sequence of human HCC is not well defined. Small cell changes (SCC) and large cell changes (LCC) are potential precursor lesions. We analyzed hepatocellular telomere length, the prevalence of DNA damage, and the expression of p21 and p16 in biopsy specimens of patients with chronic liver disease (n = 27) that showed different precursor lesions and/or HCC: liver cirrhosis (n = 25), LCC (n = 26), SCC (n = 13), and HCC (n = 13). The study shows a decrease in telomere length in nondysplastic cirrhotic liver compared with normal liver and a further significant shortening of telomeres in LCC, SCC, and HCC. HCC had the shortest telomeres, followed by SCC and LCC. Hepatocytes showed an increased p21 labeling index (p21-LI) at the cirrhosis stage, which remained elevated in most LCC. In contrast, most SCC and HCC showed a strongly reduced p21-LI. Similarly, p16 was strongly expressed in LCC but reduced in SCC and not detectable in HCC. gammaH2AX-DNA-damage-foci were not detected in LCC but were present in SCC and more frequently in HCC. These data indicate that LCC and SCC represent clonal expansions of hepatocytes with shortened telomeres.<br><br>CONCLUSION: The inactivation of cell cycle checkpoints coincides with further telomere shortening and an accumulation of DNA damage in SCC and HCC, suggesting that SCC represent more advanced precursor lesions compared with LCC.},
}
@article {pmid17389648,
year = {2007},
author = {Herrmann, G and Kais, S and Hoffbauer, J and Shah-Hosseini, K and Brüggenolte, N and Schober, H and Fäsi, M and Schär, P},
title = {Conserved interactions of the splicing factor Ntr1/Spp382 with proteins involved in DNA double-strand break repair and telomere metabolism.},
journal = {Nucleic acids research},
volume = {35},
number = {7},
pages = {2321-2332},
pmid = {17389648},
issn = {1362-4962},
mesh = {Cell Cycle Proteins ; *DNA Breaks, Double-Stranded ; *DNA Repair ; DNA-Binding Proteins/metabolism ; HeLa Cells ; Humans ; Nuclear Proteins/analysis/metabolism ; RNA Splicing Factors ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism/physiology ; Sequence Homology, Amino Acid ; Telomere/*metabolism ; Telomere-Binding Proteins/analysis ; Tumor Suppressor Proteins/metabolism ; Two-Hybrid System Techniques ; },
abstract = {The ligation of DNA double-strand breaks in the process of non-homologous end-joining (NHEJ) is accomplished by a heterodimeric enzyme complex consisting of DNA ligase IV and an associated non-catalytic factor. This DNA ligase also accounts for the fatal joining of unprotected telomere ends. Hence, its activity must be tightly controlled. Here, we describe interactions of the DNA ligase IV-associated proteins Lif1p and XRCC4 of yeast and human with the putatively orthologous G-patch proteins Ntr1p/Spp382p and NTR1/TFIP11 that have recently been implicated in mRNA splicing. These conserved interactions occupy the DNA ligase IV-binding sites of Lif1p and XRCC4, thus preventing the formation of an active enzyme complex. Consistently, an excess of Ntr1p in yeast reduces NHEJ efficiency in a plasmid ligation assay as well as in a chromosomal double-strand break repair (DSBR) assay. Both yeast and human NTR1 also interact with PinX1, another G-patch protein that has dual functions in the regulation of telomerase activity and telomere stability, and in RNA processing. Like PinX1, NTR1 localizes to telomeres and associates with nucleoli in yeast and human cells, suggesting a function in localized control of DSBR.},
}
@article {pmid17385051,
year = {2007},
author = {Traut, W and Szczepanowski, M and Vítková, M and Opitz, C and Marec, F and Zrzavý, J},
title = {The telomere repeat motif of basal Metazoa.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {15},
number = {3},
pages = {371-382},
pmid = {17385051},
issn = {0967-3849},
mesh = {Amino Acid Motifs ; Animals ; Cnidaria ; *Conserved Sequence ; Ctenophora ; Invertebrates/*genetics ; *Microsatellite Repeats ; *Phylogeny ; Porifera ; Telomerase ; Telomere/*chemistry/genetics ; },
abstract = {In most eukaryotes the telomeres consist of short DNA tandem repeats and associated proteins. Telomeric repeats are added to the chromosome ends by telomerase, a specialized reverse transcriptase. We examined telomerase activity and telomere repeat sequences in representatives of basal metazoan groups. Our results show that the 'vertebrate' telomere motif (TTAGGG)(n) is present in all basal metazoan groups, i.e. sponges, Cnidaria, Ctenophora, and Placozoa, and also in the unicellular metazoan sister group, the Choanozoa. Thus it can be considered the ancestral telomere repeat motif of Metazoa. It has been conserved from the metazoan radiation in most animal phylogenetic lineages, and replaced by other motifs-according to our present knowledge-only in two major lineages, Arthropoda and Nematoda.},
}
@article {pmid17383025,
year = {2007},
author = {Zellinger, B and Riha, K},
title = {Composition of plant telomeres.},
journal = {Biochimica et biophysica acta},
volume = {1769},
number = {5-6},
pages = {399-409},
doi = {10.1016/j.bbaexp.2007.02.001},
pmid = {17383025},
issn = {0006-3002},
mesh = {Animals ; DNA, Plant/genetics/metabolism ; Drosophila/genetics/metabolism ; Models, Biological ; Models, Molecular ; Phylogeny ; Plant Proteins/chemistry/genetics/metabolism ; Plants/*genetics/*metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Telomere/chemistry/*genetics/*metabolism ; },
abstract = {Telomeres are essential elements of eukaryotic chromosomes that differentiate native chromosome ends from deleterious DNA double-strand breaks (DSBs). This is achieved by assembling chromosome termini in elaborate high-order nucleoprotein structures that in most organisms encompass telomeric DNA, specific telomere-associated proteins as well as general chromatin and DNA repair factors. Although the individual components of telomeric chromatin are evolutionary highly conserved, cross species comparisons have revealed a remarkable flexibility in their utilization at telomeres. This review outlines the strategies used for chromosome end protection and maintenance in mammals, yeast and flies and discusses current progress in deciphering telomere structure in plants.},
}
@article {pmid17382879,
year = {2007},
author = {Bianchi, A and Shore, D},
title = {Early replication of short telomeres in budding yeast.},
journal = {Cell},
volume = {128},
number = {6},
pages = {1051-1062},
doi = {10.1016/j.cell.2007.01.041},
pmid = {17382879},
issn = {0092-8674},
mesh = {Chromosomes, Fungal/genetics ; *DNA Replication ; DNA, Fungal/metabolism ; Replication Origin ; S Phase ; Saccharomyces cerevisiae/*cytology/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {The maintenance of an appropriate number of telomere repeats by telomerase is essential for proper chromosome protection. The action of telomerase at the telomere terminus is regulated by opposing activities that either recruit/activate the enzyme at shorter telomeres or inhibit it at longer ones, thus achieving a stable average telomere length. To elucidate the mechanistic details of telomerase regulation we engineered specific chromosome ends in yeast so that a single telomere could be suddenly shortened and, as a consequence of its reduced length, elongated by telomerase. We show that shortened telomeres replicate early in S phase, unlike normal-length telomeres, due to the early firing of origins of DNA replication in subtelomeric regions. Early telomere replication correlates with increased telomere length and telomerase activity. These data reveal an epigenetic effect of telomere length on the activity of nearby replication origins and an unanticipated link between telomere replication timing and telomerase action.},
}
@article {pmid17381549,
year = {2007},
author = {Westin, ER and Chavez, E and Lee, KM and Gourronc, FA and Riley, S and Lansdorp, PM and Goldman, FD and Klingelhutz, AJ},
title = {Telomere restoration and extension of proliferative lifespan in dyskeratosis congenita fibroblasts.},
journal = {Aging cell},
volume = {6},
number = {3},
pages = {383-394},
pmid = {17381549},
issn = {1474-9718},
support = {P20 CA103672/CA/NCI NIH HHS/United States ; R01 AG027388-01A2/AG/NIA NIH HHS/United States ; R01 AI029524/AI/NIAID NIH HHS/United States ; R01 AG018265/AG/NIA NIH HHS/United States ; R01 AG018265-05/AG/NIA NIH HHS/United States ; R01 AG027388/AG/NIA NIH HHS/United States ; AI29524/AI/NIAID NIH HHS/United States ; R21 AI029524/AI/NIAID NIH HHS/United States ; T32 GM008629/GM/NIGMS NIH HHS/United States ; },
mesh = {Aging ; Cell Proliferation ; Cells, Cultured ; Cellular Senescence ; Dyskeratosis Congenita/*genetics/*metabolism/pathology ; Fibroblasts/*metabolism ; Genes, Dominant ; Genetic Therapy/methods ; Humans ; Models, Biological ; Mutation ; RNA/metabolism ; Telomerase/metabolism ; Telomere/metabolism/*ultrastructure ; Time Factors ; },
abstract = {Dyskeratosis congenita (DC), an inherited bone marrow failure syndrome, is caused by defects in telomerase. Somatic cells from DC patients have shortened telomeres and clinical symptoms are most pronounced in organs with a high cell turnover, including those involved in hematopoiesis and skin function. We previously identified an autosomal dominant (AD) form of DC that is caused by mutations in the telomerase RNA component (TER). In this study, we evaluated whether retroviral expression of TER and/or telomerase reverse transcriptase (TERT), the catalytic component of telomerase, could extend telomere length and rescue AD DC cells from a phenotype characteristic of early senescence. Exogenous TER expression, without TERT, could not activate telomerase in AD DC skin fibroblasts. Transduction of TERT alone, however, provided AD DC cells with sufficient telomerase activity to extend average telomere length and proliferative capacity. Interestingly, we found that expression of TER and TERT together resulted in extension of lifespan and higher levels of telomerase and longer telomeres than expression of TERT alone in both AD DC and normal cells. Our results provide evidence that AD DC cells can be rescued from defects in telomere maintenance and proliferation, and that coexpression of TERT and TER together provides a more efficient means to elongate telomeres than expression of TERT alone. Similar strategies may be useful for ameliorating the detrimental effects of telomere shortening in AD DC and other diseases associated with telomerase or telomere defects.},
}
@article {pmid17381301,
year = {2006},
author = {Greider, CW},
title = {Telomerase RNA levels limit the telomere length equilibrium.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {71},
number = {},
pages = {225-229},
doi = {10.1101/sqb.2006.71.063},
pmid = {17381301},
issn = {0091-7451},
support = {R01AG027406/AG/NIA NIH HHS/United States ; R01AG39383/AG/NIA NIH HHS/United States ; },
mesh = {Anemia, Aplastic/enzymology/genetics ; Animals ; Cell Division ; Dyskeratosis Congenita/enzymology/genetics ; Female ; Heterozygote ; Humans ; Male ; Mice ; Mice, Knockout ; RNA/genetics/*metabolism ; Telomerase/deficiency/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Small functional RNAs play essential roles in many biological processes. Regulating the level of these small RNAs can be as important as maintaining their function in cells. The telomerase RNA is maintained in cells at a steady-state level where small changes in concentration can have a profound impact on function. Cells that have half the level of the telomerase RNA cannot maintain telomeres through many cell divisions. People who are heterozygous for telomerase RNA mutations have the diseases dyskeratosis congenita and aplastic anemia, caused by short telomeres that result in loss of tissue renewal capacity. Mice heterozygous for telomerase RNA show haploinsufficiency in telomere length maintenance and also show loss of tissue renewal capacity. It is remarkable that small changes in the level of this functional RNA can have such profound effects in cells. This tight regulation highlights the importance of controlling the action of telomerase in cells.},
}
@article {pmid17379077,
year = {2007},
author = {Rocci, A and Ricca, I and Dellacasa, C and Longoni, P and Compagno, M and Francese, R and Lobetti Bodoni, C and Manzini, P and Caracciolo, D and Boccadoro, M and Ferrero, D and Ladetto, M and Carlo-Stella, C and Tarella, C},
title = {Long-term lymphoma survivors following high-dose chemotherapy and autograft: evidence of permanent telomere shortening in myeloid cells, associated with marked reduction of bone marrow hematopoietic stem cell reservoir.},
journal = {Experimental hematology},
volume = {35},
number = {4},
pages = {673-681},
doi = {10.1016/j.exphem.2006.12.006},
pmid = {17379077},
issn = {0301-472X},
mesh = {Adolescent ; Adult ; Aged ; Antineoplastic Agents/administration &amp; dosage/*therapeutic use ; *Bone Marrow Transplantation ; Dose-Response Relationship, Drug ; Female ; Hematopoietic Stem Cells/*cytology ; Humans ; Lymphoma/drug therapy/genetics/surgery/*therapy ; Male ; Middle Aged ; *Survivors ; *Telomere ; },
abstract = {OBJECTIVE: To investigate telomere length (TL) and hematopoietic progenitors in long-term survivors after high-dose chemotherapy and peripheral blood stem cell (PBSC) autograft.<br><br>METHODS: Peripheral blood (PB) and bone marrow (BM) samples were obtained from 31 subjects in continuous complete remission from a high-risk lymphoma, at a median of 5.8 years (range: 1-11 years) since autograft. Most of them were grafted with large PBSC quantities (median CD34(+ve) cells/kg: 7 x 10(6)). TL was determined by Southern blot analysis, BM progenitors by in vitro long-term culture-initiating cells (LTC-IC) and colony assays.<br><br>RESULTS: TL of PB granulocytes was significantly shortened in autografted subjects compared with age-matched healthy subjects; a similar finding was observed in BM. The median TL reduction in granulocytes from autografted subjects compared with age-matched controls (Delta(TelShortening)) was then assessed according to time interval since autograft. Three subject subgroups were identified-at 1 to <3 years, 3 to <6 years, and 6 to 11 years since autograft-and their telomere loss was the same, with Delta(TelShortening) of 1132, 1379, and 1214 bp in the three subgroups, respectively. The longitudinal assessment of TL in five representative patients followed for up to 40 months since autograft confirmed that telomere shortening occurring during exposure to chemotherapy as well as postautograft is persistent at long term. BM LTC-IC and multipotent and committed progenitors were assessed in subjects at >3 years after autograft and found to be markedly reduced compared with normal controls.<br><br>CONCLUSION: High-dose chemotherapy and PBSC autograft may result in myelopoietic cell abnormalities that appear to be irreversible.},
}
@article {pmid17377065,
year = {2007},
author = {Hirano, Y and Sugimoto, K},
title = {Cdc13 telomere capping decreases Mec1 association but does not affect Tel1 association with DNA ends.},
journal = {Molecular biology of the cell},
volume = {18},
number = {6},
pages = {2026-2036},
pmid = {17377065},
issn = {1059-1524},
support = {R01 GM073876/GM/NIGMS NIH HHS/United States ; GM073876/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle/physiology ; DNA, Fungal/genetics/*metabolism ; DNA, Single-Stranded/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Endodeoxyribonucleases/genetics/metabolism ; Exodeoxyribonucleases/genetics/metabolism ; Genes, cdc ; Intracellular Signaling Peptides and Proteins/genetics/*metabolism ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Replication Protein A ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Signal Transduction/physiology ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Transcription Factors/genetics/metabolism ; },
abstract = {Chromosome ends, known as telomeres, have to be distinguished from DNA breaks that activate DNA damage checkpoint. Two large protein kinases, ataxia-teleangiectasia mutated (ATM) and ATM-Rad3-related (ATR), control not only checkpoint activation but also telomere length. In budding yeast, Mec1 and Tel1 correspond to ATR and ATM, respectively. Here, we show that Cdc13-dependent telomere capping attenuates Mec1 association with DNA ends. The telomeric TG repeat sequence inhibits DNA degradation and decreases Mec1 accumulation at the DNA end. The TG-mediated degradation block requires binding of multiple Cdc13 proteins. The Mre11-Rad50-Xrs2 complex and Exo1 contribute to DNA degradation at DNA ends. Although the TG sequence impedes Exo1 association with DNA ends, it allows Mre11 association. Moreover, the TG sequence does not affect Tel1 association with the DNA end. Our results suggest that the Cdc13 telomere cap coordinates Mec1 and Tel1 accumulation rather than simply covering the DNA ends at telomeres.},
}
@article {pmid17369361,
year = {2007},
author = {Canela, A and Vera, E and Klatt, P and Blasco, MA},
title = {High-throughput telomere length quantification by FISH and its application to human population studies.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {104},
number = {13},
pages = {5300-5305},
pmid = {17369361},
issn = {0027-8424},
mesh = {Age Factors ; Aged ; Aged, 80 and over ; Animals ; Female ; *Genetics, Population ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Male ; Mice ; Middle Aged ; Neoplasms/*genetics ; Sex Factors ; Telomere/*ultrastructure ; },
abstract = {A major limitation of studies of the relevance of telomere length to cancer and age-related diseases in human populations and to the development of telomere-based therapies has been the lack of suitable high-throughput (HT) assays to measure telomere length. We have developed an automated HT quantitative telomere FISH platform, HT quantitative FISH (Q-FISH), which allows the quantification of telomere length as well as percentage of short telomeres in large human sample sets. We show here that this technique provides the accuracy and sensitivity to uncover associations between telomere length and human disease.},
}
@article {pmid17367390,
year = {2007},
author = {Huang, CH and Tsai, HH and Tsay, YG and Chien, YN and Wang, SL and Cheng, MY and Ke, CH and Chen, CW},
title = {The telomere system of the Streptomyces linear plasmid SCP1 represents a novel class.},
journal = {Molecular microbiology},
volume = {63},
number = {6},
pages = {1710-1718},
doi = {10.1111/j.1365-2958.2007.05616.x},
pmid = {17367390},
issn = {0950-382X},
mesh = {DNA, Bacterial/analysis ; Genes, Bacterial ; Plasmids/*genetics ; Streptomyces/*genetics ; Telomere/*genetics ; Telomere-Binding Proteins/*biosynthesis/metabolism ; Two-Hybrid System Techniques ; },
abstract = {Linear plasmids and chromosomes of Streptomyces carry terminal proteins (TPs) covalently attached to the 5' ends of the DNA. Most known telomeres are conserved in primary sequence and in the potential secondary structures formed during replication. The TP that caps these telomeres is also highly conserved and its coding gene, tpg, is present in all Streptomyces chromosomes and some linear plasmids. Linear plasmid SCP1 contains atypical telomere sequences and no tpg homologue, and can replicate in the absence of tpg, suggesting that it carries a novel TP gene. To isolate the TP on the SCP1 telomeres, we constructed a multicopy mini-SCP1 plasmid. The TP capping the plasmid was isolated and subjected to tryptic digestion and mass spectrometric analysis, and the results indicated that the TP was encoded by an open reading frame (ORF), SCP1.127 (tpc), on SCP1. Of the two ORFs upstream of tpc, SCP1.125 (tac) but not SCP1.126 was essential for replication of mini-SCP1. The Tac-Tpc system of SCP1 represents a convergently evolved novel telomere-capping system of Streptomyces linear replicons.},
}
@article {pmid17367333,
year = {2007},
author = {Borghans, JA and de Boer, RJ},
title = {Quantification of T-cell dynamics: from telomeres to DNA labeling.},
journal = {Immunological reviews},
volume = {216},
number = {},
pages = {35-47},
doi = {10.1111/j.1600-065X.2007.00497.x},
pmid = {17367333},
issn = {0105-2896},
mesh = {Cell Proliferation ; DNA/*analysis ; Humans ; Isotope Labeling ; *Models, Immunological ; T-Lymphocytes/cytology/*immunology ; Telomere/*chemistry/*metabolism ; Thymus Gland/cytology/immunology ; },
abstract = {Immunology has traditionally been a qualitative science describing the cellular and molecular components of the immune system and their functions. Only quite recently have new experimental techniques paved the way for a more quantitative approach of immunology. Lymphocyte telomere lengths have been measured to get insights into the proliferation rate of different lymphocyte subsets, T-cell receptor excision circles have been used to quantify the daily output of new T cells from the thymus, and bromodeoxyuridine and stable isotope labeling have been applied to measure proliferation and death rates of naive and memory lymphocytes. A common problem of the above techniques is the translation of the resulting data into relevant parameters, such as the typical division and death rate of the different lymphocyte populations. Theoretical immunology has contributed significantly to the interpretation of such quantitative experimental data, thereby resolving diverse controversies and, most importantly, has suggested novel experiments, allowing for more conclusive and quantitative interpretations. In this article, we review a variety of different models that have been used to interpret data on lymphocyte kinetics in healthy human subjects and discuss their contributions and limitations.},
}
@article {pmid17363977,
year = {2007},
author = {Blasco, MA},
title = {The epigenetic regulation of mammalian telomeres.},
journal = {Nature reviews. Genetics},
volume = {8},
number = {4},
pages = {299-309},
doi = {10.1038/nrg2047},
pmid = {17363977},
issn = {1471-0056},
mesh = {Aging/genetics ; Animals ; *Epigenesis, Genetic ; Histones/genetics/metabolism ; Humans ; Mice ; Models, Genetic ; Saccharomyces cerevisiae/genetics/metabolism ; Telomerase/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Increasing evidence indicates that chromatin modifications are important regulators of mammalian telomeres. Telomeres provide well studied paradigms of heterochromatin formation in yeast and flies, and recent studies have shown that mammalian telomeres and subtelomeric regions are also enriched in epigenetic marks that are characteristic of heterochromatin. Furthermore, the abrogation of master epigenetic regulators, such as histone methyltransferases and DNA methyltransferases, correlates with loss of telomere-length control, and telomere shortening to a critical length affects the epigenetic status of telomeres and subtelomeres. These links between epigenetic status and telomere-length regulation provide important new avenues for understanding processes such as cancer development and ageing, which are characterized by telomere-length defects.},
}
@article {pmid17360541,
year = {2007},
author = {Beliveau, A and Bassett, E and Lo, AT and Garbe, J and Rubio, MA and Bissell, MJ and Campisi, J and Yaswen, P},
title = {p53-dependent integration of telomere and growth factor deprivation signals.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {104},
number = {11},
pages = {4431-4436},
pmid = {17360541},
issn = {0027-8424},
support = {R37 AG009909/AG/NIA NIH HHS/United States ; R56 AG009909/AG/NIA NIH HHS/United States ; AG 09909/AG/NIA NIH HHS/United States ; },
mesh = {Cell Proliferation ; Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; DNA Damage ; Epidermal Growth Factor/metabolism ; Histones/chemistry/*metabolism ; Humans ; Insulin/metabolism ; Intercellular Signaling Peptides and Proteins/*metabolism ; Mammary Glands, Human/cytology ; Phosphorylation ; *Signal Transduction ; Telomere/*ultrastructure ; Tumor Suppressor Protein p53/*metabolism ; },
abstract = {Ectopically expressed hTERT enables p16(INK4A)(-) human mammary epithelial cells to proliferate in the absence of growth factors, a finding that has led to the hypothesis that hTERT has growth regulatory properties independent of its role in telomere maintenance. We now show that telomerase can alter the growth properties of cells indirectly through its role in telomere maintenance, without altering growth stimulatory pathways. We find that telomere dysfunction, indicated by 53BP1/phosphorylated histone H2AX foci at chromosome ends, is present in robustly proliferating human mammary epithelial cells long before senescence. These foci correlate with increased levels of active p53. Ectopic expression of hTERT reduces the number of foci and the level of active p53, thereby decreasing sensitivity to growth factor depletion, which independently activates p53. The continuous presence of hTERT is not necessary for this effect, indicating that telomere maintenance, rather than the presence of the enzyme itself, is responsible for the increased ability to proliferate in the absence of growth factors. Our findings provide a previously unrecognized mechanistic explanation for the observation that ectopically expressed hTERT conveys growth advantages to cells, without having to postulate nontelomeric functions for the enzyme.},
}
@article {pmid17353922,
year = {2007},
author = {Hiyama, E and Hiyama, K},
title = {Telomere and telomerase in stem cells.},
journal = {British journal of cancer},
volume = {96},
number = {7},
pages = {1020-1024},
pmid = {17353922},
issn = {0007-0920},
mesh = {Cell Lineage ; Embryonic Stem Cells/*physiology ; Hematologic Diseases/genetics/metabolism ; Humans ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres, guanine-rich tandem DNA repeats of the chromosomal end, provide chromosomal stability, and cellular replication causes their loss. In somatic cells, the activity of telomerase, a reverse transcriptase that can elongate telomeric repeats, is usually diminished after birth so that the telomere length is gradually shortened with cell divisions, and triggers cellular senescence. In embryonic stem cells, telomerase is activated and maintains telomere length and cellular immortality; however, the level of telomerase activity is low or absent in the majority of stem cells regardless of their proliferative capacity. Thus, even in stem cells, except for embryonal stem cells and cancer stem cells, telomere shortening occurs during replicative ageing, possibly at a slower rate than that in normal somatic cells. Recently, the importance of telomere maintenance in human stem cells has been highlighted by studies on dyskeratosis congenital, which is a genetic disorder in the human telomerase component. The regulation of telomere length and telomerase activity is a complex and dynamic process that is tightly linked to cell cycle regulation in human stem cells. Here we review the role of telomeres and telomerase in the function and capacity of the human stem cells.},
}
@article {pmid17353134,
year = {2007},
author = {Dolnik, AV and Pochukalina, GN and Parfenov, VN and Karpushev, AV and Podgornaya, OI and Voronin, AP},
title = {Dynamics of satellite binding protein CENP-B and telomere binding protein TRF2/MTBP in the nuclei of mouse spermatogenic line.},
journal = {Cell biology international},
volume = {31},
number = {4},
pages = {316-329},
doi = {10.1016/j.cellbi.2007.01.017},
pmid = {17353134},
issn = {1065-6995},
mesh = {Animals ; Carrier Proteins/*metabolism ; Cell Nucleus/*metabolism ; Centromere Protein B/*metabolism ; Male ; Mice ; Mice, Inbred C3H ; Microscopy, Fluorescence ; Microscopy, Immunoelectron ; Spermatogenesis ; Spermatozoa/*metabolism/ultrastructure ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {The location of centromeric protein CENP-B and telomeric protein TRF2/MTBP in the mouse spermatogenic line has been studied using indirect immunofluorescent and immunoelectron microscopy. CENP-B localized to the heterochromatic parts of the nuclei at meiotic stages. A clearly distinct chromocenter forms in the nucleus at stages 3-4 of spermatid maturation; CENP-B localizes in it and in the area adjacent to the future acrosome. CENP-B localization in the subacrosomal area and in the chromocenters' periphery demonstrates that centromeres are organized in two groups in mouse spermatozoa, unlike human centromeres. TRF2/MTBP concentrates around the forming chromocenter at spermiogenesis early stages. The TRF2/MTBP main signal migrates into the area of acrosomal membrane at the course of spermatozoon maturation. TRF2/MTBP never localizes inside the synaptonemal complex but can be found in the areas where the synaptonemal complex attaches to the nuclear envelope. At the pachytene and diplotene stages when chromosomes separate from the nuclear envelope, some amount of the protein remains bound to the nuclear membrane while the other part reveals itself in chromosomes. TRF2/MTBP accumulates in the future acrosome from the very beginning of its formation. In the mature spermatozoon TRF2/MTBP decorates the acrosomal membrane as well as spreads in condensed chromatin.},
}
@article {pmid17352261,
year = {2007},
author = {Matsuo, T and Hiyama, E and Sugita, T and Shimose, S and Kubo, T and Mochizuki, Y and Adachi, N and Ochi, M},
title = {Telomere length and telomerase activity in extra-abdominal desmoid tumors.},
journal = {Anticancer research},
volume = {27},
number = {1A},
pages = {411-415},
pmid = {17352261},
issn = {0250-7005},
mesh = {Adolescent ; Adult ; Aged ; Female ; Fibromatosis, Aggressive/*enzymology/*genetics/pathology ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Neoplasm Recurrence, Local/enzymology/genetics/pathology ; Proliferating Cell Nuclear Antigen/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {The telomere biology of extra-abdominal desmoids was investigated. In 12 specimens, telomere length was assessed by Southern-blot analysis and telomerase activity was measured using a PCR-based TRAP assay. There was a significant correlation between telomere length and tumor size, with telomeres being shorter with increasing tumor size (p = 0.049), and between telomere length and PCNA-positive cell rate, with telomere shortening with increased positive cell rate (p = 0.017). There was a significant correlation between telomerase activity and age at surgery, with increased activity with younger age (p = 0.015). Telomere length increased with recurrence, but telomerase activity decreased, and rate of PCNA-positive cells became lower, whenever the tumors were recurrent. Decreasing telomere length correlated with tumor size, probably due to increased duration of proliferation in the tumor, and tumor aggressiveness. Recurrent case results may be due to a lower rate of cell division and the presence of telomerase activity.},
}
@article {pmid17347788,
year = {2007},
author = {Valdes, AM and Richards, JB and Gardner, JP and Swaminathan, R and Kimura, M and Xiaobin, L and Aviv, A and Spector, TD},
title = {Telomere length in leukocytes correlates with bone mineral density and is shorter in women with osteoporosis.},
journal = {Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA},
volume = {18},
number = {9},
pages = {1203-1210},
pmid = {17347788},
issn = {0937-941X},
support = {AG020132/AG/NIA NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; //Wellcome Trust/United Kingdom ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Bone Density/*genetics ; Cellular Senescence/genetics ; Female ; Genetic Markers ; Humans ; Leukocytes/physiology/*ultrastructure ; Middle Aged ; Osteoporosis/*genetics/pathology ; Telomere/genetics/*pathology ; },
abstract = {UNLABELLED: Telomere length decreases with age and is associated with osteoblast senescence. In 2,150 unselected women, leukocyte telomere length was significantly correlated with bone mineral density. Clinical osteoporosis was associated with shorter telomeres, suggesting that telomere length can be used as a marker of bone aging.<br><br>INTRODUCTION: The length of telomeres in proliferative cells diminishes with age. Telomere shortening and telomerase activity have been linked to in vitro osteoblast senescence and to increased secretion of pro-inflammatory cytokines. We explored whether bone mineral density correlates with telomere length in leukocytes.<br><br>MATERIALS AND METHODS: The relationship between leukocyte telomere length, bone mineral density (BMD) and osteoporosis (as defined by the World Health Organization) was examined in a cohort of 2,150 women from a population-based twin cohort aged 18-79.<br><br>RESULTS: After adjusting for age, body mass index, menopausal status, smoking, hormone replacement therapy status, telomere length was positively correlated with BMD of the spine (p < 0.005), forearm (p < 0.013), but not the femoral neck (p < 0.06). Longer telomeres were associated with reduced the risk of clinical OP at two or more sites (odds ratio = 0.594 95% CI 0.42-0.84 p < 0.003) and in women over the age of 50, clinical osteoporosis was associated with 117 bp shorter telomere length (p < 0.02) equivalent to 5.2 years of telomeric aging.<br><br>CONCLUSIONS: Shortened leukocyte telomere length is independently associated with a decrease in BMD and the presence of osteoporosis in women. Our data provide evidence that leukocyte telomere length could be a marker of biological aging of bone.},
}
@article {pmid17346255,
year = {2007},
author = {Jemielity, S and Kimura, M and Parker, KM and Parker, JD and Cao, X and Aviv, A and Keller, L},
title = {Short telomeres in short-lived males: what are the molecular and evolutionary causes?.},
journal = {Aging cell},
volume = {6},
number = {2},
pages = {225-233},
pmid = {17346255},
issn = {1474-9718},
support = {R01 AG020132/AG/NIA NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; AG020132/AG/NIA NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; },
mesh = {Aging ; Animals ; Ants/*genetics/physiology ; *Evolution, Molecular ; Female ; *Longevity ; Male ; Telomerase/metabolism ; Telomere/*chemistry/genetics ; },
abstract = {Telomere length regulation is an important aspect of cell maintenance in eukaryotes, since shortened telomeres can lead to a number of defects, including impaired cell division. Although telomere length is correlated with lifespan in some bird species, its possible role in aging and lifespan determination is still poorly understood. Here we investigate telomere dynamics (changes in telomere length and attrition rate) and telomerase activity in the ant Lasius niger, a species in which different groups of individuals have evolved extraordinarily different lifespans. We found that somatic tissues of the short-lived males had dramatically shorter telomeres than those of the much longer-lived queens and workers. These differences were established early during larval development, most likely through faster telomere shortening in males compared with females. Workers did not, however, have shorter telomeres than the longer-lived queens. We discuss various molecular mechanisms that are likely to cause the observed sex-specific telomere dynamics in ants, including cell division, oxidative stress and telomerase activity. In addition, we discuss the evolutionary causes of such patterns in ants and in other species.},
}
@article {pmid17344914,
year = {2007},
author = {Schuller, CE and Jankowski, K and Mackenzie, KL},
title = {Telomere length of cord blood-derived CD34(+) progenitors predicts erythroid proliferative potential.},
journal = {Leukemia},
volume = {21},
number = {5},
pages = {983-991},
doi = {10.1038/sj.leu.2404631},
pmid = {17344914},
issn = {0887-6924},
mesh = {Antigens, CD34/*analysis ; Cell Lineage ; Cell Proliferation ; Erythroid Precursor Cells/*cytology ; Fetal Blood/*cytology ; Humans ; Interleukin-6/pharmacology ; Telomerase/metabolism ; *Telomere ; },
abstract = {Excessive telomere shortening has been demonstrated in inherited and acquired blood disorders, including aplastic anemia and myelodysplastic syndromes. It is possible that replicative exhaustion, owing to critical telomere shortening in hematopoietic progenitor cells (HPCs), contributes to the development of cytopenias in these disorders. However to date, a direct link between the telomere length (TL) of human HPCs and their proliferative potential has not been demonstrated. In the present investigation, the TL and level of telomerase enzyme activity (TA) detected in cord blood (CB)-derived HPCs was found to predict erythroid expansion (P<0.01 and P=0.01 respectively). These results were corroborated by a correlation between proliferation of erythroid cells and telomere loss (P=0.01). In contrast, no correlations were found between initial TL, telomere loss or TA and the expansion of other myeloid lineage-committed cells. There was also no correlation between TL or TA and the number of clonogenic progenitors, including primitive progenitors derived from long-term culture. Our investigations revealed upregulation of telomerase to tumor cell levels in CD34- cells undergoing erythroid differentiation. Together, these results provide new insight into the regulation of TL and TA during myeloid cell expansion and demonstrate that TL is an important determinant of CB-derived erythroid cell proliferation.},
}
@article {pmid17344853,
year = {2007},
author = {Morrish, TA and Garcia-Perez, JL and Stamato, TD and Taccioli, GE and Sekiguchi, J and Moran, JV},
title = {Endonuclease-independent LINE-1 retrotransposition at mammalian telomeres.},
journal = {Nature},
volume = {446},
number = {7132},
pages = {208-212},
doi = {10.1038/nature05560},
pmid = {17344853},
issn = {1476-4687},
mesh = {Animals ; Base Sequence ; Cell Line ; Chromosomal Instability/genetics ; Cricetinae ; Cricetulus ; Endonucleases/deficiency/genetics/metabolism ; Humans ; Long Interspersed Nucleotide Elements/*genetics ; Mutagenesis, Insertional/*genetics ; Polymerase Chain Reaction/methods ; Retroelements/*genetics ; Telomere/*genetics ; },
abstract = {Long interspersed element-1 (LINE-1 or L1) elements are abundant, non-long-terminal-repeat (non-LTR) retrotransposons that comprise approximately 17% of human DNA. The average human genome contains approximately 80-100 retrotransposition-competent L1s (ref. 2), and they mobilize by a process that uses both the L1 endonuclease and reverse transcriptase, termed target-site primed reverse transcription. We have previously reported an efficient, endonuclease-independent L1 retrotransposition pathway (EN(i)) in certain Chinese hamster ovary (CHO) cell lines that are defective in the non-homologous end-joining (NHEJ) pathway of DNA double-strand-break repair. Here we have characterized EN(i) retrotransposition events generated in V3 CHO cells, which are deficient in DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity and have both dysfunctional telomeres and an NHEJ defect. Notably, approximately 30% of EN(i) retrotransposition events insert in an orientation-specific manner adjacent to a perfect telomere repeat (5'-TTAGGG-3'). Similar insertions were not detected among EN(i) retrotransposition events generated in controls or in XR-1 CHO cells deficient for XRCC4, an NHEJ factor that is required for DNA ligation but has no known function in telomere maintenance. Furthermore, transient expression of a dominant-negative allele of human TRF2 (also called TERF2) in XRCC4-deficient XR-1 cells, which disrupts telomere capping, enables telomere-associated EN(i) retrotransposition events. These data indicate that L1s containing a disabled endonuclease can use dysfunctional telomeres as an integration substrate. The findings highlight similarities between the mechanism of EN(i) retrotransposition and the action of telomerase, because both processes can use a 3' OH for priming reverse transcription at either internal DNA lesions or chromosome ends. Thus, we propose that EN(i) retrotransposition is an ancestral mechanism of RNA-mediated DNA repair associated with non-LTR retrotransposons that may have been used before the acquisition of an endonuclease domain.},
}
@article {pmid17344711,
year = {1998},
author = {Iqbal, MA},
title = {Chromosome telomeres: The aging clock.},
journal = {Annals of Saudi medicine},
volume = {18},
number = {6},
pages = {495-496},
doi = {10.5144/0256-4947.1998.495},
pmid = {17344711},
issn = {0256-4947},
}
@article {pmid17340111,
year = {2007},
author = {Cysewski, P and Czeleń, P},
title = {Theoretical analysis of the effects of guanine oxidative damage on the properties of B-DNA telomere fragments.},
journal = {Journal of molecular modeling},
volume = {13},
number = {6-7},
pages = {739-750},
pmid = {17340111},
issn = {0948-5023},
mesh = {Base Pairing ; Base Sequence ; Computer Simulation ; DNA/*chemistry ; *DNA Damage ; Guanine/*chemistry ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Oxidation-Reduction ; *Oxidative Stress ; Protein Binding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Static Electricity ; Telomere/*chemistry ; Water/chemistry ; },
abstract = {The molecular dynamics as well as ab initio MP2/6-31G(d = 0.25) single point calculations were performed for native and oxidized B-DNA telomeric fragments. The structural, dynamic, energetic and electrostatic properties along with frontier orbitals distribution were described for the central triad consisting of three guanine molecules in its canonical or oxidized forms. Although the average structural parameters characterizing all of the studied telomere fragments are close each to other, the significant consequence on angular and displacement flexibilities are observed. Namely, the increase of mutual displacement of two successive base pairs along either axis and increase of the rotation of two bases of opposite strand are main dynamic consequences of presence of 8-oxo-guanine in the central triad of telomeric B-DNA. Besides, the significant increase of stacking energies in case of 8-oxo-guanine were found. Furthermore, the guanine pattern visible from the major groove may be described as donor-acceptor-acceptor formed by H8-N7-O6 atoms, respectively. To the contrary the presence of 8-oxo-guanine changes the electrostatic properties of the major groove into acceptor-donor-acceptor coming from O8-H7-O6 atoms. This results in significant alteration of ESP characteristics. Finally, the molecular orbital properties are also significantly affected by oxidation of telomeric B-DNA fragments. All these factors contribute to decrease of binding of telomere proteins.},
}
@article {pmid17339221,
year = {2007},
author = {Boerckel, J and Walker, D and Ahmed, S},
title = {The Caenorhabditis elegans Rad17 homolog HPR-17 is required for telomere replication.},
journal = {Genetics},
volume = {176},
number = {1},
pages = {703-709},
pmid = {17339221},
issn = {0016-6731},
support = {R01 GM066228/GM/NIGMS NIH HHS/United States ; R56 GM066228/GM/NIGMS NIH HHS/United States ; GM066228/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Apoptosis/radiation effects ; Caenorhabditis elegans/*genetics/radiation effects ; Caenorhabditis elegans Proteins/*metabolism ; Cell Cycle/radiation effects ; Cell Cycle Proteins/*metabolism ; DNA Damage ; *DNA Replication/radiation effects ; Mutation/genetics ; Nuclear Proteins/*metabolism ; Radiation, Ionizing ; Repetitive Sequences, Nucleic Acid/genetics ; *Sequence Homology, Amino Acid ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {Subunits of the Rad9/Rad1/Hus1 (9-1-1) proliferating cell nuclear antigen (PNCA)-like sliding clamp are required for DNA damage responses and telomerase-mediated telomere replication in the nematode Caenorhabditis elegans. PCNA sliding clamps are loaded onto DNA by a replication factor C (RFC) clamp loader. The C. elegans Rad17 RFC clamp loader homolog, hpr-17, functions in the same pathway as the 9-1-1 complex with regard to both the DNA damage response and telomerase-mediated telomere elongation. Thus, hpr-17 defines an RFC-like complex that facilitates telomerase activity in vivo in C. elegans.},
}
@article {pmid17338827,
year = {2007},
author = {Du, Z and Zhao, D and Zhao, Y and Wang, S and Gao, Y and Li, N},
title = {Identification and characterization of bovine regulator of telomere length elongation helicase gene (RTEL): molecular cloning, expression distribution, splice variants and DNA methylation profile.},
journal = {BMC molecular biology},
volume = {8},
number = {},
pages = {18},
pmid = {17338827},
issn = {1471-2199},
mesh = {*Alternative Splicing ; Amino Acid Sequence ; Animals ; Base Sequence ; Cattle ; Chromosome Mapping ; Cloning, Molecular ; DNA Helicases/*genetics/*metabolism ; *DNA Methylation ; Female ; Isoenzymes/genetics/metabolism ; Male ; Molecular Sequence Data ; Tissue Distribution ; },
abstract = {BACKGROUND: The genetic basis of telomere length heterogeneity among mammalian species is still not well understood. Recently, a gene named regulator of telomere length elongation helicase (RTEL) was identified and predicted to be an essential participant in species-specific telomere length regulation in two murine species. To obtain broader insights into its structure and biological functions and to ascertain whether RTEL is also a candidate gene in the regulation of telomere length diversity in other mammalian species, data from other mammals may be helpful.<br><br>RESULTS: Here we report the cDNA cloning, genomic structure, chromosomal location, alternative splicing pattern, expression distribution and DNA methylation profile of the bovine homolog of RTEL. The longest transcript of bovine RTEL is 4440 nt, encompassing 24.8 kb of genomic sequence that was mapped to chromosome 13q2.2. It encodes a conserved helicase-like protein containing seven characterized helicase motifs in the first 750 aa and a PIP box in the C-terminus. Four splice variants were identified within the transcripts in both the coding and 5'-untranslated regions; Western blot revealed that the most abundant splice variant SV-1 was translated to a truncated isoform of RTEL. The different 5'UTRs imply alternative transcription start sites in the promoter; Bovine RTEL was transcribed at the blastocyst stage, and expression levels were highest in adult testis, liver and ovary. DNA methylation analysis of tissues that differed significantly in expression level indicated that relatively low DNA methylation is associated with higher expression.<br><br>CONCLUSION: In this study, we have identified and characterized a bovine RTEL homolog and obtained basic information about it, including gene structure, expression distribution, splice variants and profile of DNA methylation around two putative transcription start sites. These data may be helpful for further comparative and functional analysis of RTEL in mammals.},
}
@article {pmid17333339,
year = {2008},
author = {Banerjee, B and Sharma, S and Hegde, S and Hande, MP},
title = {Analysis of telomere damage by fluorescence in situ hybridisation on micronuclei in lymphocytes of breast carcinoma patients after radiotherapy.},
journal = {Breast cancer research and treatment},
volume = {107},
number = {1},
pages = {25-31},
doi = {10.1007/s10549-007-9530-y},
pmid = {17333339},
issn = {1573-7217},
mesh = {Biomarkers, Tumor ; Breast Neoplasms/*metabolism/radiotherapy/*ultrastructure ; Carcinoma/*metabolism/radiotherapy/*ultrastructure ; Cell Line, Tumor ; Cell Proliferation ; Cytochrome P-450 Enzyme System/metabolism ; Dose-Response Relationship, Drug ; Estrogen Receptor Modulators/metabolism ; Humans ; In Situ Hybridization, Fluorescence/*methods ; *Micronuclei, Chromosome-Defective ; *Polymorphism, Genetic ; Protein Serine-Threonine Kinases/metabolism ; Receptor, Transforming Growth Factor-beta Type II ; Receptors, Transforming Growth Factor beta/metabolism ; Telomere/*ultrastructure ; Transforming Growth Factor beta2/metabolism ; },
abstract = {Radiotherapy has become an indispensable tool in the effective management of most of the cancers. There have been efforts earlier to study the differential radio-sensitivity patterns in patients undergoing radiation treatment to correlate with treatment induced complications such as tissue injury, cell death, and chromosomal aberration frequencies etc. The present study is an attempt to correlate the radiation-induced damage in the peripheral blood lymphocytes (PBLs) of breast cancer patients with the frequency of telomere mediated chromosomal damage. Blood samples from 55 patients with (Gr-II and Gr-III) CA-breast were obtained pre- and post-radiotherapy. The patients were treated with external beam radiotherapy of 50.4 Gy over a period of 6 weeks. Chromosome damage was measured by analysing micronucleus (MN) frequency in PBLs. The MN-frequency of the irradiated patients increased significantly compared to the patients being self-controls. The micronuclei were hybridized with telomere probes to study the extent of telomere damage. The fluorescence signals of the telomere regions in the first generation of the binucleated cells were significantly higher in the post-radiotherapy patients. There was also significant correlation observed in the patients with higher-grade tumours. Inter-individual variability was observed in the radiation-induced MN frequency in lymphocytes of patients after six weeks of radiotherapy. There was a significant correlation between functionally intact telomeres and the cellular response to ionising radiation. Our findings suggest that fluorescence in situ hybridisation on micronuclei could be effectively used as routine clinical application to determine the individual sensitivity to ionising radiation with respect to telomere damage.},
}
@article {pmid17332702,
year = {2007},
author = {Kurosaka, D},
title = {[Abnormalities in lymphocyte telomerase activity and telomere length in systemic lupus erythematosus].},
journal = {Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology},
volume = {30},
number = {1},
pages = {29-36},
doi = {10.2177/jsci.30.29},
pmid = {17332702},
issn = {0911-4300},
mesh = {Humans ; Lupus Erythematosus, Systemic/*immunology ; Lymphocytes/*enzymology ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {T-cell telomerase activity was high in the active and inactive stages of systemic lupus erythematosus (SLE). In contrast, B-cell telomerase activity was very high only in the active stage. Compared with normal subjects, SLE patients had a shorter T-cell telomere, but their B-cell telomere length did not differ from that of normal subjects. These findings suggest that T cells are always activated, and that the manifestation of the disease requires the activation of not only T but also B cells. B-cell inhibition alone may be sufficient to suppress the clinical symptoms of SLE, but we consider that the essential treatment of SLE should target T cells as well. In recent years, various biologicals have begun to be used for the treatment of SLE. It is interesting how the use of such biologicals in the future will change T- and B-cell telomerase activity. In formulating a therapeutic strategy using biologicals for SLE, the measurement of telomerase activity in T and B cells seems useful for the preparation of target cells, selection of therapeutic drugs, and evaluation of therapeutic responses.},
}
@article {pmid17331356,
year = {2006},
author = {Hu, XW and Huang, HZ and Xie, Q},
title = {[Effects of apoptosis of Tca8113 cells induced by adriamycin on telomerase and telomere repeat binding factor proteins].},
journal = {Zhonghua kou qiang yi xue za zhi = Zhonghua kouqiang yixue zazhi = Chinese journal of stomatology},
volume = {41},
number = {11},
pages = {654-655},
pmid = {17331356},
issn = {1002-0098},
mesh = {Apoptosis/*drug effects ; Carcinoma, Squamous Cell/*metabolism/pathology ; Cell Line, Tumor ; Doxorubicin/*pharmacology ; Humans ; Telomerase/*metabolism ; Telomere-Binding Proteins/*metabolism ; Tongue Neoplasms/*metabolism/pathology ; },
abstract = {OBJECTIVE: To investigate the role of telomerase and telomere repeat binding factors (TRF) in apoptosis.<br><br>METHODS: The proliferative activity of Tca8113 cells was assessed by methyl thiazolyl tetrazolium (MTT) assay. After Tca8113 cells were treated with adriamycin at 5 mg/L, apoptotic morphology was observed under microscope with Giemsa staining and apoptosis examined by flow cytometry; analysis of telomerase activity was performed by TRAP-enzyme-linked immunosorbent assay; expression and expression level of TRF proteins were detected with immunohistochemical staining and immunofluorescence label assay, respectively.<br><br>RESULTS: After Tca8113 cells were treated with adriamycin at 5 mg/L for 5 days and 7 days, the cells apoptosis was found. Telomerase activity dropped in time-dependent manner. Expression of TRF proteins appeared in nucleus of the cells. No statistical difference in expression levels of TRF was observed between the treated and untreated cells.<br><br>CONCLUSIONS: Tca8113 cells apoptosis induced by adriamycin decreased telomerase activity, but did not influence the expression level of TRF proteins.},
}
@article {pmid17325746,
year = {2007},
author = {Joshua, AM and Vukovic, B and Braude, I and Hussein, S and Zielenska, M and Srigley, J and Evans, A and Squire, JA},
title = {Telomere attrition in isolated high-grade prostatic intraepithelial neoplasia and surrounding stroma is predictive of prostate cancer.},
journal = {Neoplasia (New York, N.Y.)},
volume = {9},
number = {1},
pages = {81-89},
pmid = {17325746},
issn = {1476-5586},
mesh = {Aged ; Aged, 80 and over ; *Chromosomal Instability ; DNA Damage ; Fluorescence ; Humans ; Male ; Middle Aged ; Prostatic Intraepithelial Neoplasia/*genetics/*pathology ; Prostatic Neoplasms/*genetics/*pathology ; Regression Analysis ; *Telomere ; },
abstract = {The causes of early genomic events underlying the development of prostate cancer (CaP) remain unclear. The onset of chromosomal instability is likely to facilitate the formation of crucial genomic aberrations both in the precursor lesion high-grade prostatic intraepithelial neoplasia (HPIN) and in CaP. Instability generated by telomere attrition is one potential mechanism that could initiate chromosomal rearrangements. In this study, normalized telomere length variation was examined in a cohort of 68 men without CaP who had HPIN only on prostatic biopsies. Multiple significant associations between telomere attrition and eventual diagnosis of CaP in the HPIN and in the surrounding stroma were found. Kaplan-Meier analysis of telomere length demonstrated a significantly increased risk for the development of cancer with short telomeres in the surrounding stroma [P = .035; hazard ratio (HR) = 2.12; 95% confidence interval (95% CI) = 0.231-0.956], and a trend for HPIN itself (P = .126; HR = 1.72; 95% CI = 0.287-1.168). Cox regression analysis also demonstrated significance between the time from the original biopsy to the diagnosis of cancer and telomere length in HPIN and in the surrounding stroma. These analyses showed significance, both alone and in combination with baseline prostate-specific antigen, and lend support to the hypothesis that telomere attrition in prostatic preneoplasia may be fundamental to the generation of chromosomal instability and to the emergence of CaP.},
}
@article {pmid17323081,
year = {2007},
author = {Grandin, N and Charbonneau, M},
title = {Mrc1, a non-essential DNA replication protein, is required for telomere end protection following loss of capping by Cdc13, Yku or telomerase.},
journal = {Molecular genetics and genomics : MGG},
volume = {277},
number = {6},
pages = {685-699},
pmid = {17323081},
issn = {1617-4615},
mesh = {Cell Cycle Proteins/*metabolism ; DNA Replication ; DNA-Binding Proteins/*metabolism ; Gene Deletion ; Mutation ; Nuclear Proteins/metabolism ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Proteins involved in telomere end protection have previously been identified. In Saccharomyces cerevisiae, Cdc13, Yku and telomerase, mainly, prevent telomere uncapping, thus providing telomere stability and avoiding degradation and death by senescence. Here, we report that in the absence of Mrc1, a component of the replication forks, telomeres of cdc13 or yku70 mutants exhibited increased degradation, while telomerase-negative cells displayed accelerated senescence. Moreover, deletion of MRC1 increased the single-strandedness of the telomeres in cdc13-1 and yku70Delta mutant strains. An mrc1 deletion strain also exhibited slight but stable telomere shortening compared to a wild-type strain. Loss of Mrc1's checkpoint function alone did not provoke synthetic growth defects in combination with the cdc13-1 mutation. Combinations between the cdc13-1 mutation and deletion of either TOF1 or PSY2, coding for proteins physically interacting with Mrc1, also resulted in a synthetic growth defect. Thus, the present data suggest that non-essential components of the DNA replication machinery, such as Mrc1 and Tof1, may have a role in telomere stability in addition to their role in fork progression.},
}
@article {pmid17318223,
year = {2007},
author = {Wang, X and Liu, L and Montagna, C and Ried, T and Deng, CX},
title = {Haploinsufficiency of Parp1 accelerates Brca1-associated centrosome amplification, telomere shortening, genetic instability, apoptosis, and embryonic lethality.},
journal = {Cell death and differentiation},
volume = {14},
number = {5},
pages = {924-931},
doi = {10.1038/sj.cdd.4402105},
pmid = {17318223},
issn = {1350-9047},
support = {//Intramural NIH HHS/United States ; },
mesh = {Alleles ; Animals ; Antigens, Nuclear/metabolism ; *Apoptosis ; BRCA1 Protein/genetics/*metabolism ; Centrosome/*metabolism ; Crosses, Genetic ; DNA-Binding Proteins/metabolism ; Embryo Loss/*genetics/pathology ; Female ; Fibroblasts/metabolism ; *Genomic Instability ; Genotype ; Haploidy ; Karyotyping ; Ku Autoantigen ; Male ; Mice ; Mice, Mutant Strains ; Mutation/genetics ; Neural Tube Defects/pathology ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases/*deficiency/genetics ; Telomere/genetics/*metabolism ; },
abstract = {The breast tumor associated gene-1 (BRCA1) and poly(ADP-ribose) polymerase-1 (PARP1) are both involved in DNA-damage response and DNA-damage repair. Recent investigations have suggested that inhibition of PARP1 represents a promising chemopreventive/therapeutic approach for specifically treating BRCA1- and BRCA2-associated breast cancer. However, studies in mouse models reveal that Parp1-null mutation results in genetic instability and mammary tumor formation, casting significant doubt on the safety of PARP1 inhibition as a therapy for the breast cancer. To study the genetic interactions between Brca1 and Parp1, we interbred mice carrying a heterozygous deletion of full-length Brca1 (Brca1(+/Delta11)) with Parp1-null mice. We show that Brca1(Delta11/Delta11);Parp1(-/-) embryos die before embryonic (E) day 6.5, whereas Brca1(Delta11/Delta11) embryos die after E12.5, indicating that absence of Parp1 dramatically accelerates lethality caused by Brca1 deficiency. Surprisingly, haploinsufficiency of Parp1 in Brca1(Delta11/Delta11) embryos induces a severe chromosome aberrations, centrosome amplification, and telomere dysfunction, leading to apoptosis and accelerated embryonic lethality. Notably, telomere shortening in Brca1(Delta11/Delta11);Parp1(+/-) MEFs was correlated with decreased expression of Ku70, which plays an important role in telomere maintenance. Thus, haploid loss of Parp1 is sufficient to induce lethality of Brca1-deficient cells, suggesting that partial inhibition of PARP1 may represent a practical chemopreventive/therapeutic approach for BRCA1-associated breast cancer.},
}
@article {pmid17317176,
year = {2007},
author = {Franceschin, M and Pascucci, E and Alvino, A and D'Ambrosio, D and Bianco, A and Ortaggi, G and Savino, M},
title = {New highly hydrosoluble and not self-aggregated perylene derivatives with three and four polar side-chains as G-quadruplex telomere targeting agents and telomerase inhibitors.},
journal = {Bioorganic &amp; medicinal chemistry letters},
volume = {17},
number = {9},
pages = {2515-2522},
doi = {10.1016/j.bmcl.2007.02.021},
pmid = {17317176},
issn = {0960-894X},
mesh = {Chemistry, Pharmaceutical/methods ; DNA/chemistry ; Dose-Response Relationship, Drug ; Drug Design ; Enzyme Inhibitors/*chemical synthesis/chemistry/*pharmacology ; Humans ; Models, Chemical ; Molecular Conformation ; Nucleic Acid Conformation ; Perylene/analogs &amp; derivatives/*chemistry ; Solubility ; Spectrophotometry, Ultraviolet ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*chemistry ; },
abstract = {Four new perylene derivatives with three and four basic side-chains are reported here as G-quadruplex interactive compounds. The new perylene derivatives are readily soluble in water and not self-aggregated, in contrast to what happens with the previously reported two side-chain perylene derivatives. All four compounds are able to induce the G-quadruplex and to inhibit 50% of telomerase activity at about 5 microM concentration, showing a similar efficiency with respect to each other. Molecular modelling studies are presented to try to explain these findings.},
}
@article {pmid17315016,
year = {2007},
author = {Kuchinskaya, E and Nordgren, A and Heyman, M and Schoumans, J and Corcoran, M and Staaf, J and Borg, A and Söderhäll, S and Grandér, D and Nordenskjöld, M and Blennow, E},
title = {Tiling-resolution array-CGH reveals the pattern of DNA copy number alterations in acute lymphoblastic leukemia with 21q amplification: the result of telomere dysfunction and breakage/fusion/breakage cycles?.},
journal = {Leukemia},
volume = {21},
number = {6},
pages = {1327-1330},
doi = {10.1038/sj.leu.2404628},
pmid = {17315016},
issn = {0887-6924},
mesh = {Adolescent ; Child ; Chromosome Breakage ; *Chromosomes, Human, Pair 21 ; Cytogenetic Analysis ; *Gene Amplification ; *Gene Dosage ; Humans ; Nucleic Acid Hybridization ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics ; Telomere/pathology ; },
}
@article {pmid17314245,
year = {2007},
author = {Multani, AS and Chang, S},
title = {WRN at telomeres: implications for aging and cancer.},
journal = {Journal of cell science},
volume = {120},
number = {Pt 5},
pages = {713-721},
doi = {10.1242/jcs.03397},
pmid = {17314245},
issn = {0021-9533},
support = {R01 AG028888/AG/NIA NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; },
mesh = {Aging/physiology ; Animals ; Exodeoxyribonucleases ; Humans ; Models, Biological ; *Mutation ; Neoplasms/genetics/pathology/physiopathology ; RecQ Helicases/*genetics ; Telomere/genetics/*metabolism ; Werner Syndrome/genetics/pathology/physiopathology ; Werner Syndrome Helicase ; },
abstract = {Werner Syndrome (WS) is a premature aging syndrome characterized by early onset of age-related pathologies and cancer. Since WS is due to a single gene defect, it has attracted much interest from researchers seeking to understand pathways that contribute to cancer and aging at cellular and molecular levels. The protein mutated in WS, WRN, appears to play a major role in genome stability, particularly during DNA replication and telomere metabolism. Much of the pathophysiology associated with WS, including the rapid onset of cellular senescence, early cancer onset and premature aging, can be attributed to a defect in telomere maintenance. Recent genetic evidence from the mTerc(-/-) Wrn(-/-) mouse demonstrates that mice with critically shortened telomeres display aging phenotypes reminiscent of human WS, further reinforcing the notion that telomere dysfunction is required for the manifestation of aging pathophysiologies in the setting of WRN deficiency.},
}
@article {pmid17310277,
year = {2007},
author = {Zimmermann, S and Martens, UM},
title = {Telomeres and telomerase as targets for cancer therapy.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {64},
number = {7-8},
pages = {906-921},
doi = {10.1007/s00018-007-6481-8},
pmid = {17310277},
issn = {1420-682X},
mesh = {Animals ; Enzyme Inhibitors/pharmacology/therapeutic use ; Genetic Therapy ; Humans ; Immunotherapy ; Neoplasms/*therapy ; Oncolytic Virotherapy ; RNA, Messenger/genetics/metabolism ; Telomerase/*antagonists &amp; inhibitors/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are protective structures located at the ends of all eukaryotic chromosomes. Telomere shortening upon cell division restricts the proliferative capacity of most normal human cells due to the lack of telomerase, an enzyme synthesizing telomeric DNA de novo. Since most tumor cells are reliant on the activity of telomerase to maintain the stability of predominantly short individual telomeres, inhibition of this enzyme presents an attractive approach for a mechanism-based anticancer therapy. Here, we review advances and obstacles in targeting telomerase and telomeres and discuss potential applications of such approaches for the clinic.},
}
@article {pmid17308890,
year = {2007},
author = {Corredor, E and Naranjo, T},
title = {Effect of colchicine and telocentric chromosome conformation on centromere and telomere dynamics at meiotic prophase I in wheat-rye additions.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {15},
number = {2},
pages = {231-245},
pmid = {17308890},
issn = {0967-3849},
mesh = {Centromere/drug effects/*physiology ; Chromosome Pairing ; Chromosome Segregation/drug effects ; Chromosomes, Plant ; Colchicine/*pharmacology ; *Meiotic Prophase I ; Secale/*cytology/drug effects ; Telomere/drug effects/*physiology ; Triticum/*cytology/drug effects ; },
abstract = {Association of telomeres in a bouquet and clustering of centromere regions have been proposed to be involved in the search and recognition of homologous partners. We have analysed the role of these structures in meiotic chromosome pairing in wheat-rye addition lines by applying colchicine for disturbing presynaptic telomere movements and by modifying the centromere position from submetacentric to telocentric for studying centromere effects. Rye chromosomes, wheat and rye centromeres, and telomeres were identified by fluorescence in-situ hybridization. Presynaptic association of centromeres in pairs or in more complex structures involved mainly non-homologous chromosomes as deduced from the behaviour of rye centromeres. While centromere association was not affected by colchicine, colchicine inhibited bouquet formation, which caused failure of homologous synapsis. Homologous centromeres of rye telocentrics associated earlier than those of rye submetacentric chromosomes, indicating that migration of the telocentrics' centromeres to the telomere pole during bouquet formation facilitated their association. Homologous chromosomes associated in premeiotic interphase can recognize each other and initiate synapsis at zygotene. However, telomere convergence is needed for bringing together the majority of homologous pairs that normally occupy separate territories in premeiotic nuclei.},
}
@article {pmid17308089,
year = {2007},
author = {Compton, SA and Choi, JH and Cesare, AJ and Ozgür, S and Griffith, JD},
title = {Xrcc3 and Nbs1 are required for the production of extrachromosomal telomeric circles in human alternative lengthening of telomere cells.},
journal = {Cancer research},
volume = {67},
number = {4},
pages = {1513-1519},
doi = {10.1158/0008-5472.CAN-06-3672},
pmid = {17308089},
issn = {0008-5472},
support = {1F32 GM 077900-01/GM/NIGMS NIH HHS/United States ; ES 013773/ES/NIEHS NIH HHS/United States ; GM 31819/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics/*metabolism ; Cell Growth Processes/physiology ; Cell Line ; DNA-Binding Proteins/genetics/*metabolism ; Humans ; Nuclear Proteins/genetics/*metabolism ; Phenotype ; RNA, Small Interfering/genetics ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {The maintenance of telomere length is essential for the indefinite proliferation of cancer cells. This is most often achieved by the activation of telomerase; however, a substantial number of cancers lack detectable telomerase activity and are classified as using an alternative lengthening of telomeres (ALT) pathway. We showed recently that ALT cells have a high level of extrachromosomal telomeric circles (t circles) that may be a specific marker of the ALT phenotype. The mechanism underlying t circle production and the requirement of t circles in ALT remain unclear. Understanding the specific requirements of ALT is key to developing diagnostic tools and therapies that target this pathway and is critical for the treatment of cancers in which ALT is prevalent, including cancers of neuroepithelial and mesenchymal origin. In this study, we used short hairpin RNAs directed at either Xrcc3 or Nbs1, two proteins involved in the homologous recombination pathway, to determine the role of these proteins in t circle production and the requirement of t circles in maintaining the ALT pathway. We show that Xrcc3 and Nbs1 are indeed required for the production of t circles in human ALT. However, these cells continue to proliferate in the absence of t circles, suggesting that they are not required for the survival of ALT cells.},
}
@article {pmid17308077,
year = {2007},
author = {Tabori, U and Nanda, S and Druker, H and Lees, J and Malkin, D},
title = {Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome.},
journal = {Cancer research},
volume = {67},
number = {4},
pages = {1415-1418},
doi = {10.1158/0008-5472.CAN-06-3682},
pmid = {17308077},
issn = {0008-5472},
mesh = {Adolescent ; Adult ; Age Factors ; Child ; Child, Preschool ; Female ; Genes, p53 ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Humans ; Infant ; Li-Fraumeni Syndrome/blood/*genetics ; Lymphocytes/ultrastructure ; Male ; Middle Aged ; Neoplasms/blood/*genetics ; Pedigree ; Polymorphism, Single Nucleotide ; Telomere/*physiology ; },
abstract = {Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome frequently associated with germ line TP53 mutations. Unpredictable and disparate age of cancer onset is a major challenge in the management of LFS. Genetic modifiers, including the MDM2-SNP309 polymorphism, and genetic anticipation have been suggested as plausible explanations for young age of tumor onset, but the molecular mechanisms for these observations are unknown. We speculated that telomere attrition will increase genomic instability and cause earlier tumor onset in successive generations. We analyzed mean telomere length and MDM2-SNP309 polymorphism status in individuals from multiple LFS families and controls. A total of 45 peripheral blood lymphocyte samples were analyzed from 9 LFS families and 15 controls. High rate of MDM2-SNP309 was found in TP53 carriers (P = 0.0003). In children, telomere length was shorter in carriers affected with cancer than in nonaffected carriers and wild-type controls (P < 0.0001). The same pattern was seen in adults (P = 0.002). Within each family, telomere length was shorter in children with cancer than in their nonaffected siblings and their noncarrier parents. Telomere attrition between children and adults was faster in carriers than in controls. Our results support the role of MDM2-SNP309 as a genetic modifier in LFS. The novel finding of accelerated telomere attrition in LFS suggests that telomere length could explain earlier age of onset in successive generations of the same family with identical TP53/MDM2-SNP309 genotypes. Furthermore, telomere shortening could predict genetic anticipation observed in LFS and may serve as the first rational biological marker for clinical monitoring of these patients.},
}
@article {pmid17303822,
year = {2007},
author = {Ouyang, Q and Baerlocher, G and Vulto, I and Lansdorp, PM},
title = {Telomere length in human natural killer cell subsets.},
journal = {Annals of the New York Academy of Sciences},
volume = {1106},
number = {},
pages = {240-252},
doi = {10.1196/annals.1392.001},
pmid = {17303822},
issn = {0077-8923},
support = {AI29524/AI/NIAID NIH HHS/United States ; },
mesh = {Adult ; Aged ; Antigens, Surface/biosynthesis ; CD56 Antigen/biosynthesis ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Killer Cells, Natural/*cytology/metabolism ; Lectins, C-Type/biosynthesis ; Leukocytes, Mononuclear/cytology ; Male ; Middle Aged ; NK Cell Lectin-Like Receptor Subfamily B ; NK Cell Lectin-Like Receptor Subfamily C ; NK Cell Lectin-Like Receptor Subfamily D/biosynthesis ; NK Cell Lectin-Like Receptor Subfamily K ; Receptors, IgG/biosynthesis ; Receptors, Immunologic/metabolism ; Receptors, Natural Killer Cell ; Telomere/*ultrastructure ; },
abstract = {Natural killer (NK) cells are cytotoxic cells that play a critical role in the innate immune response against infections and tumors. In the elderly, the cytotoxic function of NK cells is often compromised. Telomeres progressively shorten with each cell division and with age in most somatic cells eventually leading to chromosomal instability and cellular senescence. We studied the telomere length in NK cell subsets isolated from peripheral blood using "flow FISH," a method in which the hybridization of telomere probe in cells of interest is measured relative to internal controls in the same tube. We found that the average telomere length in human NK cells decreased with age as was previously found for human T lymphocytes. Separation of adult NK cells based on CD56 and CD16 expression revealed that the telomere length was significantly shorter in CD56(dim)CD16(+) (mature) NK cells compared to CD56(bright)CD16(-) (immature) NK cells from the same donor. Furthermore, sorting of NK cells based on expression of activation markers, such as NKG2D and LFA-1, revealed that NK cells expressing these markers have significantly shorter telomeres. Telomere fluorescence was very heterogeneous in NK cells expressing CD94, killer inhibitory receptor (KIR), NKG2A, or CD161. Our observations indicate that telomeric DNA in NK cells is lost with cell division and with age similar to what has been observed for most other hematopoietic cells. Telomere attrition in NK cells is a plausible cause for diminished NK cell function in the elderly.},
}
@article {pmid17301820,
year = {2007},
author = {Ricca, I and Rocci, A and Drandi, D and Francese, R and Compagno, M and Lobetti Bodoni, C and De Marco, F and Astolfi, M and Monitillo, L and Vallet, S and Calvi, R and Ficara, F and Omedè, P and Rosato, R and Gallamini, A and Marinone, C and Bergui, L and Boccadoro, M and Tarella, C and Ladetto, M},
title = {Telomere length identifies two different prognostic subgroups among VH-unmutated B-cell chronic lymphocytic leukemia patients.},
journal = {Leukemia},
volume = {21},
number = {4},
pages = {697-705},
doi = {10.1038/sj.leu.2404544},
pmid = {17301820},
issn = {0887-6924},
mesh = {Adult ; Aged ; Aged, 80 and over ; Allelic Imbalance ; Burkitt Lymphoma/*genetics/immunology/mortality ; Disease-Free Survival ; Humans ; Immunoglobulin Variable Region ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/immunology/mortality ; Middle Aged ; Neoplasm Staging ; Prognosis ; Survival Analysis ; Telomere/*ultrastructure ; },
abstract = {Some evidences suggest that telomere restriction fragment length (TRF-L) is an effective indicator of histopathogenesis in B-cell tumors. As histopathogenesis is relevant for B-cell chronic lymphocytic leukemia (B-CLL) prognosis, TRF-L was assessed by Southern blot in 201 patients and compared to variable immunoglobulin heave chain gene mutational status (VH-MS) and to other known prognostic features. Overall survival (OS), time to first treatment (TTFT) and progression-free survival (PFS) were evaluated. Our results indicate the following: (1) TRF-L is heterogeneous among B-CLL patients (median 6014 bp, range 1465-16 762); (2) TRF-L correlates to VH-MS (r(2)=0.1994, P<0.0001) with VH-mutated patients showing long and VH-unmutated short telomeres; however, 41% of VH-unmutated and 5% of VH-mutated patients did not show this correlation and were thus defined as 'discordant'; (3) TRF-L effectively predicts outcome in terms of TTFT, PFS and OS; (4) VH-unmutated discordant patients have a better clinical outcome than VH-unmutated concordant patients (OS P<0.01, PFS P<0.05) and similar to that of VH-mutated patients (OS, PFS P=NS). Compared to VH-unmutated concordant patients, VH-unmutated discordant patients showed no peculiarity in their immunoglobulin rearrangement nor in their flow cytometry or fluorescence in situ hybridization profile. In conclusion, TRF-L can be helpful to refine prognostication of B-CLL patients, particularly those with a VH-unmutated immunoglobulin sequence.},
}
@article {pmid17297868,
year = {2007},
author = {Hiraoka, Y},
title = {[Telomere bouquet of meiotic chromosomes].},
journal = {Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme},
volume = {52},
number = {2},
pages = {145-150},
pmid = {17297868},
issn = {0039-9450},
mesh = {Animals ; Cell Movement/genetics/physiology ; Cell Nucleus ; Chromosomes, Fungal/*genetics ; Extracellular Signal-Regulated MAP Kinases/physiology ; Meiosis/*genetics ; *Multigene Family ; Schizosaccharomyces/*cytology/*genetics ; Schizosaccharomyces pombe Proteins/genetics/physiology ; Shelterin Complex ; Telomere/*genetics ; Telomere-Binding Proteins/genetics/physiology ; },
}
@article {pmid17297460,
year = {2007},
author = {Jiang, WQ and Zhong, ZH and Henson, JD and Reddel, RR},
title = {Identification of candidate alternative lengthening of telomeres genes by methionine restriction and RNA interference.},
journal = {Oncogene},
volume = {26},
number = {32},
pages = {4635-4647},
doi = {10.1038/sj.onc.1210260},
pmid = {17297460},
issn = {0950-9232},
mesh = {Acid Anhydride Hydrolases ; Antigens, Nuclear/genetics/physiology ; Autoantigens/genetics/physiology ; Cell Cycle Proteins/antagonists &amp; inhibitors/genetics/physiology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Repair Enzymes/antagonists &amp; inhibitors/genetics/physiology ; DNA-Binding Proteins/antagonists &amp; inhibitors/genetics/physiology ; G1 Phase ; *Genetic Techniques ; Humans ; Intracellular Signaling Peptides and Proteins/antagonists &amp; inhibitors/genetics/physiology ; MRE11 Homologue Protein ; Methionine/deficiency ; Neoplasm Proteins/antagonists &amp; inhibitors/genetics/physiology ; Nuclear Proteins/antagonists &amp; inhibitors/genetics/physiology ; Promyelocytic Leukemia Protein ; RNA Interference ; RNA, Small Interfering/pharmacology ; Resting Phase, Cell Cycle ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/antagonists &amp; inhibitors/genetics/physiology ; Telomeric Repeat Binding Protein 1/antagonists &amp; inhibitors/genetics/physiology ; Telomeric Repeat Binding Protein 2/antagonists &amp; inhibitors/genetics/physiology ; Transcription Factors/antagonists &amp; inhibitors/genetics/physiology ; Tumor Suppressor Proteins/antagonists &amp; inhibitors/genetics/physiology ; Tumor Suppressor p53-Binding Protein 1 ; },
abstract = {Telomerase-negative cancer cells can maintain their telomeres by a recombination-mediated alternative lengthening of telomeres (ALT) process. We reported previously that sequestration of MRE11/RAD50/NBS1 complexes represses ALT-mediated telomere length maintenance, and suppresses formation of ALT-associated promyelocytic leukemia (PML) bodies (APBs). APBs are PML bodies containing telomeric DNA and telomere-binding proteins, and are observed only in a small fraction of cells within asynchronously dividing ALT-positive cell populations. Here, we report that methionine restriction caused a reversible arrest in G0/G1 phase of the cell cycle and reversible induction of APB formation in most cells within an ALT-positive population. We combined methionine restriction with RNA interference to test whether the following proteins are required for APB formation: PML body-associated proteins, PML and Sp100; telomere-associated proteins, TRF1, TRF2, TIN2 and RAP1; and DNA repair proteins, MRE11, RAD50, NBS1 and 53BP1. APB formation was not decreased by depletion of Sp100 (as reported previously) or of 53BP1, although 53BP1 partially colocalizes with APBs. Depletion of the other proteins suppressed APB formation. Because of the close linkage between ALT-mediated telomere maintenance and ability to form APBs, the eight proteins identified by this screen as being required for APB formation are also likely to be required for the ALT mechanism.},
}
@article {pmid17295869,
year = {2007},
author = {Sekoguchi, S and Nakajima, T and Moriguchi, M and Jo, M and Nishikawa, T and Katagishi, T and Kimura, H and Minami, M and Itoh, Y and Kagawa, K and Tani, Y and Okanoue, T},
title = {Role of cell-cycle turnover and oxidative stress in telomere shortening and cellular senescence in patients with chronic hepatitis C.},
journal = {Journal of gastroenterology and hepatology},
volume = {22},
number = {2},
pages = {182-190},
doi = {10.1111/j.1440-1746.2006.04454.x},
pmid = {17295869},
issn = {0815-9319},
mesh = {Adult ; Aged ; Aged, 80 and over ; *Cell Cycle ; *Cellular Senescence ; Female ; Hepatitis C, Chronic/*metabolism/*pathology ; Hepatocytes/*cytology/*metabolism ; Humans ; Male ; Middle Aged ; *Oxidative Stress ; Telomere/*metabolism ; },
abstract = {BACKGROUND: In addition to the telomere shortening that occurs with cell division, oxidative stress can damage or shorten telomeres and induce a condition termed premature senescence, possibly before telomeres become critically short. We investigated the effects of cell-cycle turnover and oxidative stress on cellular senescence in hepatitis C virus (HCV)-related chronic liver injury.<br><br>METHOD: Using quantitative fluorescence in situ hybridization, the telomere lengths of hepatocytes in biopsy specimens from HCV-positive patients were estimated. We assessed clinicopathological parameters that reflect cell-cycle turnover, including Ki-67 positive index, serum alanine aminotransferase (ALT) level and degree of fibrosis, and also oxidative stress-related parameters, such as 8-hydroxy-2'-deoxyguanosine (8-OHdG) expression. Nuclear size and DNA content of hepatocytes were measured as morphological features of senescence.<br><br>RESULTS: Telomere shortening correlated with the degree of cell turnover, hepatic fibrosis and morphological features of aging cells. Furthermore, the rate of telomere shortening per year was positively correlated with fibrosis progression. In cases of no or mild fibrosis, telomere lengths of positive patients were generally shorter than those of 8-OHdG-negative patients, and this trend achieved statistical significance in advanced-stage fibrosis. HCV carriers with persistently normal serum ALT level (PNAL) showed significantly longer telomeres than patients with active hepatitis and mild fibrosis. There was no significant difference in telomere lengths between HCV carriers with PNAL and normal controls.<br><br>CONCLUSIONS: Cell-cycle turnover is the primary mechanism of telomere shortening, and can induce fibrosis progression and cellular senescence. However, oxidative stress can be an accelerator of senescence, especially in advanced-stage fibrosis.},
}
@article {pmid17293872,
year = {2007},
author = {Gao, H and Cervantes, RB and Mandell, EK and Otero, JH and Lundblad, V},
title = {RPA-like proteins mediate yeast telomere function.},
journal = {Nature structural &amp; molecular biology},
volume = {14},
number = {3},
pages = {208-214},
doi = {10.1038/nsmb1205},
pmid = {17293872},
issn = {1545-9993},
support = {GM55867/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Base Sequence ; Cell Cycle Proteins/chemistry/*metabolism ; Chromosomal Proteins, Non-Histone/chemistry/*metabolism ; DNA, Fungal/metabolism ; Molecular Sequence Data ; Protein Binding ; Protein Folding ; Protein Structure, Tertiary ; Replication Protein A/chemistry/*metabolism ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; Substrate Specificity ; Telomere/*metabolism ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {Cdc13, Stn1 and Ten1 are essential yeast proteins that both protect chromosome termini from unregulated resection and regulate telomere length. Cdc13, which localizes to telomeres through high-affinity binding to telomeric single-stranded DNA, has been extensively characterized, whereas the contribution(s) of the Cdc13-associated Stn1 and Ten1 proteins to telomere function have remained unclear. We show here that Stn1 and Ten1 are DNA-binding proteins with specificity for telomeric DNA substrates. Furthermore, Stn1 and Ten1 show similarities to Rpa2 and Rpa3, subunits of the heterotrimeric replication protein A (RPA) complex, which is the major single-stranded DNA-binding activity in eukaryotic cells. We propose that Cdc13, Stn1 and Ten1 function as a telomere-specific RPA-like complex. Identification of an RPA-like complex that is targeted to a specific region of the genome suggests that multiple RPA-like complexes have evolved, each making individual contributions to genomic stability.},
}
@article {pmid17291819,
year = {2007},
author = {Lamb, JC and Yu, W and Han, F and Birchler, JA},
title = {Plant chromosomes from end to end: telomeres, heterochromatin and centromeres.},
journal = {Current opinion in plant biology},
volume = {10},
number = {2},
pages = {116-122},
doi = {10.1016/j.pbi.2007.01.008},
pmid = {17291819},
issn = {1369-5266},
mesh = {Centromere/*genetics ; Chromosomes, Plant/*genetics ; Heterochromatin/*genetics ; Repetitive Sequences, Nucleic Acid ; Telomere/*genetics ; },
abstract = {Recent evidence indicates that heterochromatin in plants is composed of heterogeneous sequences, which are usually composed of transposable elements or tandem repeat arrays. These arrays are associated with chromatin modifications that produce a closed configuration that limits transcription. Centromere sequences in plants are usually composed of tandem repeat arrays that are homogenized across the genome. Analysis of such arrays in closely related taxa suggests a rapid turnover of the repeat unit that is typical of a particular species. In addition, two lines of evidence for an epigenetic component of centromere specification have been reported, namely an example of a neocentromere formed over sequences without the typical repeat array and examples of centromere inactivation. Although the telomere repeat unit is quite prevalent in the plant kingdom, unusual repeats have been found in some families. Recently, it was demonstrated that the introduction of telomere sequences into plants cells causes truncation of the chromosomes, and that this technique can be used to produce artificial chromosome platforms.},
}
@article {pmid17289918,
year = {2007},
author = {Negrini, S and Ribaud, V and Bianchi, A and Shore, D},
title = {DNA breaks are masked by multiple Rap1 binding in yeast: implications for telomere capping and telomerase regulation.},
journal = {Genes &amp; development},
volume = {21},
number = {3},
pages = {292-302},
pmid = {17289918},
issn = {0890-9369},
mesh = {Chromatin Immunoprecipitation ; Cyclin B/metabolism ; *DNA Breaks, Double-Stranded ; DNA-Binding Proteins/metabolism ; Dinucleotide Repeats ; Endodeoxyribonucleases/metabolism ; Exodeoxyribonucleases/metabolism ; Organisms, Genetically Modified ; Protein Binding ; Protein Structure, Tertiary ; Saccharomyces/genetics ; Saccharomyces cerevisiae Proteins/*metabolism ; Shelterin Complex ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; Transcription Factors/*metabolism ; },
abstract = {Eukaryotic cells distinguish their chromosome ends from accidental DNA double-strand breaks by packaging them in a protective structure referred to as the telomere "cap." Here we investigate the nature of the telomere cap by examining events at DNA breaks generated adjacent to either natural telomeric sequences (TG repeats) or arrays of Rap1-binding sites that vary in length. Although DNA breaks adjacent to either short or long telomeric sequences are efficiently converted into stable telomeres, they elicit very different initial responses. Short telomeric sequences (80 base pair [bp]) are avidly bound by Mre11, as well as the telomere capping protein Cdc13 and telomerase enzyme, consistent with their rapid telomerase-dependent elongation. Surprisingly, little or no Mre11 binding is detected at long telomere tracts (250 bp), and this is correlated with reduced Cdc13 and telomerase binding. Consistent with these observations, ends with long telomere tracts undergo strongly reduced exonucleolytic resection and display limited binding by both Rpa1 and Mec1, suggesting that they fail to elicit a checkpoint response. Rap1 binding is required for end concealment at long tracts, but Rif proteins, yKu, and Cdc13 are not. These results shed light on the nature of the telomere cap and mechanisms that regulate telomerase access at chromosome ends.},
}
@article {pmid17286609,
year = {2007},
author = {Walsh, SH and Grabowski, P and Berglund, M and Thunberg, U and Thorsélius, M and Tobin, G and Aleskog, A and Karlsson, K and Sundström, C and Laurell, A and Enblad, G and Rosenquist, R and Roos, G},
title = {Telomere length and correlation with histopathogenesis in B-cell leukemias/lymphomas.},
journal = {European journal of haematology},
volume = {78},
number = {4},
pages = {283-289},
doi = {10.1111/j.1600-0609.2007.00817.x},
pmid = {17286609},
issn = {0902-4441},
mesh = {DNA Mutational Analysis ; Germinal Center/*pathology ; Humans ; Immunoglobulins/*genetics ; Leukemia, B-Cell/diagnosis/*genetics ; Lymphoma, B-Cell/diagnosis/*genetics ; *Mutation ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Sensitivity and Specificity ; Telomere/*genetics ; },
abstract = {Telomere length was recently reported to correlate with cellular origin of B-cell malignancies in relation to the germinal center (GC). In this report, we measured telomere length by quantitative-PCR in 223 B-cell lymphomas/leukemias and correlated results with immunoglobulin (Ig) mutation status and immunostainings for GC/non-GC subtypes of diffuse large B-cell lymphoma (DLBCL). Shortest telomeres were found in Ig-unmutated chronic lymphocytic leukemia (CLL) [median telomere to single copy gene value (T/S) 0.33], differing significantly to Ig-mutated CLL (0.63). Contrary to this, mantle cell lymphomas (MCLs) exhibited similar telomere lengths regardless of Ig mutation status (0.47). Telomere length differed significantly between GC-like (0.73) and non-GC-like DLBCLs (0.43), and follicular lymphomas (FLs) had shorter telomeres (0.53) than GC-DLBCL. Hairy cell leukemias, which display Ig gene intraclonal heterogeneity, had longer telomeres (0.62) than FLs and non-GC-DLBCL, but shorter than GC-DLBCL. We conclude that although DLBCL and CLL subsets can be clearly distinguished, telomere length reflects many parameters and may not simply correlate with GC-related origin.},
}
@article {pmid17284601,
year = {2007},
author = {Crabbe, L and Jauch, A and Naeger, CM and Holtgreve-Grez, H and Karlseder, J},
title = {Telomere dysfunction as a cause of genomic instability in Werner syndrome.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {104},
number = {7},
pages = {2205-2210},
pmid = {17284601},
issn = {0027-8424},
support = {R01 AG025837/AG/NIA NIH HHS/United States ; R01 069525//PHS HHS/United States ; },
mesh = {Chromosome Aberrations ; DNA Replication ; Exodeoxyribonucleases ; Fibroblasts/metabolism/pathology ; *Genomic Instability ; Humans ; Metaphase ; RecQ Helicases/deficiency ; Telomerase/metabolism ; *Telomere ; Werner Syndrome/etiology/*genetics/pathology ; Werner Syndrome Helicase ; },
abstract = {Werner syndrome (WS) is a rare human premature aging disease caused by mutations in the gene encoding the RecQ helicase WRN. In addition to the aging features, this disorder is marked by genomic instability, associated with an elevated incidence of cancer. Several lines of evidence suggest that telomere dysfunction is associated with the aging phenotype of the syndrome; however, the origin of the genomic instability observed in WS cells and the reason for the high incidence of cancer in WS have not been established. We previously proposed that WRN helicase activity was necessary to prevent dramatic telomere loss during DNA replication. Here we demonstrate that replication-associated telomere loss is responsible for the chromosome fusions found in WS fibroblasts. Moreover, using metaphase analysis we show that telomere elongation by telomerase can significantly reduce the appearance of new chromosomal aberrations in cells lacking WRN, similar to complementation of WS cells with WRN. Our results suggest that the genome instability in WS cells depends directly on telomere dysfunction, linking chromosome end maintenance to chromosomal aberrations in this disease.},
}
@article {pmid17276687,
year = {2007},
author = {Martins, C and Gunaratnam, M and Stuart, J and Makwana, V and Greciano, O and Reszka, AP and Kelland, LR and Neidle, S},
title = {Structure-based design of benzylamino-acridine compounds as G-quadruplex DNA telomere targeting agents.},
journal = {Bioorganic &amp; medicinal chemistry letters},
volume = {17},
number = {8},
pages = {2293-2298},
doi = {10.1016/j.bmcl.2007.01.056},
pmid = {17276687},
issn = {0960-894X},
mesh = {Acridines/*chemical synthesis/pharmacology ; Antineoplastic Agents/chemical synthesis/pharmacology ; Benzylamines/*chemical synthesis/pharmacology ; DNA/*drug effects ; Drug Delivery Systems ; Drug Design ; Enzyme Inhibitors/chemical synthesis/pharmacology ; G-Quadruplexes ; Guanosine ; Humans ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects ; },
abstract = {The design, synthesis, biophysical and biochemical evaluation is presented of a new series of benzylamino-substituted acridines as G-quadruplex binding telomerase inhibitors. Replacement of the previously reported anilino substituents by benzylamino groups results in enhanced quadruplex interaction, and for one compound, superior telomerase inhibitory activity.},
}
@article {pmid17274602,
year = {2007},
author = {Parkinson, GN and Ghosh, R and Neidle, S},
title = {Structural basis for binding of porphyrin to human telomeres.},
journal = {Biochemistry},
volume = {46},
number = {9},
pages = {2390-2397},
doi = {10.1021/bi062244n},
pmid = {17274602},
issn = {0006-2960},
mesh = {Crystallography, X-Ray ; Humans ; Hydrogen Bonding ; Models, Molecular ; Molecular Structure ; Porphyrins/chemistry/*metabolism ; *Telomere ; },
abstract = {Maintenance of telomere integrity is a hallmark of human cancer, and the single-stranded 3' ends of telomeric DNA are targets for small-molecule anticancer therapies. We report here the crystal structure of a bimolecular human telomeric quadruplex, of the sequence d(TAGGGTTAGGG), in a complex with the quadruplex-binding ligand 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP4) to a resolution of 2.09 A. The DNA quadruplex topology is parallel-stranded with external double-chain-reversal propeller loops, consistent with previous structural determinations. The porphyrin molecules bind by stacking onto the TTA nucleotides, either as part of the external loop structure or at the 5' region of the stacked quadruplex. This involves stacked on hydrogen-bonded base pairs, formed from those nucleotides not involved in the formation of G-tetrads, and there are thus no direct ligand interactions with G-tetrads. This is in accord with the relative nonselectivity by TMPyP4 for quadruplex DNAs compared to duplex DNA. Porphyrin binding is achieved by remodeling of loops compared to the ligand-free structures. Implications for the design of quadruplex-binding ligands are discussed, together with a model for the formation of anaphase bridges, which are observed following cellular treatment with TMPyP4.},
}
@article {pmid17272298,
year = {2007},
author = {Hwang, MG and Cho, MH},
title = {Arabidopsis thaliana telomeric DNA-binding protein 1 is required for telomere length homeostasis and its Myb-extension domain stabilizes plant telomeric DNA binding.},
journal = {Nucleic acids research},
volume = {35},
number = {4},
pages = {1333-1342},
pmid = {17272298},
issn = {1362-4962},
mesh = {Amino Acid Sequence ; Arabidopsis/*genetics ; Arabidopsis Proteins/*chemistry/genetics/*physiology ; DNA, Plant/metabolism ; DNA-Binding Proteins/*chemistry/genetics/*physiology ; Homeostasis ; Molecular Sequence Data ; Mutation ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-myb/chemistry ; Telomere/chemistry/*metabolism ; },
abstract = {Telomeres are specific protein-DNA complexes that protect the ends of eukaryotic chromosomes from fusion and degradation and are maintained by a specialized mechanism exerted by telomerase and telomere-binding proteins (TBPs), which are evolutionarily conserved. AtTBP1 is an Arabidopsis thaliana protein that binds plant telomeric DNA in vitro. Here, we demonstrated that lack of AtTBP1 results in a deregulation of telomere length control, with mutant telomeres expanding steadily by the fourth generation. DNA-binding studies with mutant AtTBP1 proteins showed that the Myb-extension domain of AtTBP1 is required for binding to plant telomeric DNA. Our results suggest that AtTBP1 is involved in the telomere length mechanism in A. thaliana and that the Myb-extension domain of AtTBP1 may stabilize plant telomeric DNA binding.},
}
@article {pmid17270395,
year = {2007},
author = {Hills, M and Jeyapalan, JN and Foxon, JL and Royle, NJ},
title = {Mutation mechanisms that underlie turnover of a human telomere-adjacent segmental duplication containing an unstable minisatellite.},
journal = {Genomics},
volume = {89},
number = {4},
pages = {480-489},
doi = {10.1016/j.ygeno.2006.12.011},
pmid = {17270395},
issn = {0888-7543},
support = {G0500336/MRC_/Medical Research Council/United Kingdom ; G9806740/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Chromosomes, Human/genetics/*metabolism ; Crossing Over, Genetic ; *Gene Duplication ; Humans ; Kinetics ; Linkage Disequilibrium ; *Minisatellite Repeats ; *Mutation ; Polymorphism, Single Nucleotide ; Telomere/*metabolism ; },
abstract = {Subterminal regions, juxtaposed to telomeres on human chromosomes, contain a high density of segmental duplications, but relatively little is known about the evolutionary processes that underlie sequence turnover in these regions. We have characterized a segmental duplication adjacent to the Xp/Yp telomere, each copy containing a hypervariable array of the DXYS14 minisatellite. Both DXYS14 repeat arrays mutate at a high rate (0.3 and 0.2% per gamete) but linkage disequilibrium analysis across 27 SNPs and a direct crossover assay show that recombination during meiosis is suppressed. Therefore instability at DXYS14a and b is dominated by intra-allelic processes or possibly conversion limited to the repeat arrays. Furthermore some chromosomes (14%) carry only one copy of the duplicon, including one DXYS14 repeat array that is also highly mutable (1.2% per gamete). To explain these and other observations, we propose there is another low-rate mutation process that causes copy number change in part or all of the duplicon.},
}
@article {pmid17268175,
year = {2007},
author = {Yan, J and Bouchard, EF and Samassekou, O and Chen, BZ},
title = {Identification of a human chromosome-specific interstitial telomere-like sequence (ITS) at 22q11.2 using double-strand PRINS.},
journal = {Cytogenetic and genome research},
volume = {116},
number = {1-2},
pages = {29-37},
doi = {10.1159/000097415},
pmid = {17268175},
issn = {1424-859X},
mesh = {Adolescent ; Adult ; Base Sequence ; *Chromosomes, Human, Pair 22 ; *Cytogenetic Analysis ; DNA Repair ; Databases, Genetic ; Humans ; In Situ Hybridization, Fluorescence ; Lymphocytes/metabolism ; Male ; Middle Aged ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; Telomere/*ultrastructure ; },
abstract = {Interstitial telomeric sequences (ITSs), telomere-like repeats at intrachromosomal sites, are common in mammals and consist of tandem repeats of the canonical telomeric repeat, TTAGGG, or a repeat similar to this. We report that the ITS in human chromosome region 22q11.2 is, in the sequenced genome database, 101 tandem repeats of the sequence TTAGGGAGG. Using the primed in situ labeling (PRINS) technique and primers against the canonical telomeric repeat (TTAGGG), we illuminated telomeric sites for all chromosomes and an ITS locus at 22q11.2. Using the TTAGGGAGG sequence, we designed PRINS primers that efficiently and specifically illuminate the 22q11.2 ITS locus without illuminating telomeric and other ITS loci. The 22q11.2 locus has more repeat units than other ITSs loci enabling an unprecedented high detection frequency for this interstitial telomere locus. The 22q11.2 is associated with hot spots for disease-related chromosome breaks for multiple disorders, such as DiGeorge syndrome and chronic myeloid leukemia. We describe our findings that the ITS at 22q11.2 is in the same area of, and proximal to the common rearrangement region of multiple disorders. We suggest that the ITS might be involved in DNA repair processes in this area to protect the chromosome from more serious damage.},
}
@article {pmid17267157,
year = {2007},
author = {Starr, JM and McGurn, B and Harris, SE and Whalley, LJ and Deary, IJ and Shiels, PG},
title = {Association between telomere length and heart disease in a narrow age cohort of older people.},
journal = {Experimental gerontology},
volume = {42},
number = {6},
pages = {571-573},
doi = {10.1016/j.exger.2006.12.002},
pmid = {17267157},
issn = {0531-5565},
mesh = {Aged ; Aged, 80 and over ; Aging/genetics/*pathology ; Cohort Studies ; DNA/genetics/isolation &amp; purification ; Electrocardiography ; Female ; Heart Diseases/genetics/*pathology ; Humans ; Male ; Myocardial Ischemia/genetics/pathology ; Risk Factors ; Telomere/genetics/*pathology ; },
abstract = {Telomere shortening is a feature of cellular ageing common to a range of human tissues. Shorter telomeres are associated with an increased likelihood of mortality, including death from heart disease. We examined the association between telomere length and heart disease (present in 33%) in a well-characterised, narrow age cohort of older people (n=190, all born in 1921), and tested for any concomitant effects of medication use. Mean telomere length was significantly shorter in participants who reported heart disease (p=.001). Participants with ischemic changes on ECG had shorter telomere lengths (6.67 versus 7.65 kb, p=.021) after adjusting for other ECG abnormalities. This finding adds to the growing body of evidence for an association between telomere shortening and ischemic heart disease. Telomere shortening in peripheral blood leukocytes is a promising index of ischemic heart disease risk in older people and deserves further investigation as a potential mechanism.},
}
@article {pmid17264051,
year = {2007},
author = {Kotrschal, A and Ilmonen, P and Penn, DJ},
title = {Stress impacts telomere dynamics.},
journal = {Biology letters},
volume = {3},
number = {2},
pages = {128-130},
pmid = {17264051},
issn = {1744-9561},
mesh = {Animals ; Crowding/*physiopathology ; Female ; Male ; Mice/genetics/*physiology ; Reproduction/physiology ; Sex Factors ; Stress, Physiological/*genetics ; Telomere/genetics/*physiology ; },
abstract = {Telomeres are DNA-protein complexes at the ends of chromosomes that control genomic integrity but appear to become shorter with age and stress. To test whether stress causes telomere attrition, we exposed the offspring of wild-caught house mice (Mus musculus) to stressful conditions and examined the changes in telomere length over six months. We found that females exposed to males and reproductive stress (either with or without crowding) had significantly shorter telomeres than controls, and males exposed to crowding stress had shorter telomeres than males that were not crowded. Our results indicate that stress alters telomere dynamics, causing attrition and hindering restoration, and these effects are sex dependent. Telomeres may thus provide a biomarker for assessing an individual's cumulative exposure or ability to cope with stressful conditions.},
}
@article {pmid17251198,
year = {2007},
author = {Glover, L and Alsford, S and Beattie, C and Horn, D},
title = {Deletion of a trypanosome telomere leads to loss of silencing and progressive loss of terminal DNA in the absence of cell cycle arrest.},
journal = {Nucleic acids research},
volume = {35},
number = {3},
pages = {872-880},
pmid = {17251198},
issn = {1362-4962},
support = {/WT_/Wellcome Trust/United Kingdom ; 069909/WT_/Wellcome Trust/United Kingdom ; 052323/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Cell Cycle ; Chromosome Deletion ; DNA Repair ; DNA, Protozoan/*metabolism ; Deoxyribonucleases, Type II Site-Specific/metabolism ; Gene Deletion ; *Gene Silencing ; Saccharomyces cerevisiae Proteins ; Sirtuins/metabolism ; Telomerase/genetics ; Telomere/chemistry/metabolism/*physiology ; Trypanosoma brucei brucei/*genetics/metabolism ; Variant Surface Glycoproteins, Trypanosoma/genetics/metabolism ; },
abstract = {Eukaryotic chromosomes are capped with telomeres which allow complete chromosome replication and prevent the ends from being recognized by the repair machinery. The African trypanosome, Trypanosoma brucei, is a protozoan parasite where antigenic variation requires reversible silencing of a repository of telomere-adjacent variant surface glycoprotein (VSG) genes. We have investigated the role of the telomere adjacent to a repressed VSG. In cells lacking telomerase, the rate of telomere-repeat loss appeared to be inversely proportional to telomere length. We therefore constructed strains in which a single telomere could be immediately removed by conditional I-SceI meganuclease cleavage. Following telomere deletion, cells maintain and segregate the damaged chromosome without repairing it. These cells continue to proliferate at the normal rate but progressively lose terminal DNA at the broken end. Although sirtuin-dependent repression is lost along with the telomere, VSG-silencing is preserved. The results provide direct evidence for telomere-dependent repression but suggest a telomere-independent mode of VSG-silencing. They also indicate the absence of a telomere-loss checkpoint in T. brucei.},
}
@article {pmid17245108,
year = {2007},
author = {Antoniacci, LM and Kenna, MA and Skibbens, RV},
title = {The nuclear envelope and spindle pole body-associated Mps3 protein bind telomere regulators and function in telomere clustering.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {6},
number = {1},
pages = {75-79},
doi = {10.4161/cc.6.1.3647},
pmid = {17245108},
issn = {1551-4005},
mesh = {Membrane Proteins/genetics/*metabolism/physiology ; Nuclear Envelope/genetics/*metabolism/physiology ; Nuclear Proteins ; Protein Binding/genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism/physiology ; Spindle Apparatus/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism/physiology ; },
abstract = {It has long been posited that the nuclear envelope is a key regulator of both the spatial organization of chromatin and gene transcription. Mps3p is an integral nuclear envelope membrane protein with a single trans-membrane domain that is essential for spindle pole body duplication. More recently, Mps3p was shown to associate with the cohesion establishment factor Ctf7p and found to be critical for cohesion establishment. Here, we provide new evidence that the nuclear envelope, via Mps3p, plays a pivotal role in telomere foci formation. Results from in vitro pull-downs and in vivo coprecipitations also show that Mps3p associates with the telomerase-assembly component Est1p. Moreover, pair-wise combinations of mps3, est1 or ctf7 alleles all produce conditional lethality. Findings that Mps3p and the nuclear envelope recruit/sequester soluble chromatin metabolism factors such as Ctf7p and Est1p describe, at the molecular level, a new mechanism of nuclear envelope-dependent chromatin regulation.},
}
@article {pmid17237781,
year = {2007},
author = {Benetti, R and García-Cao, M and Blasco, MA},
title = {Telomere length regulates the epigenetic status of mammalian telomeres and subtelomeres.},
journal = {Nature genetics},
volume = {39},
number = {2},
pages = {243-250},
doi = {10.1038/ng1952},
pmid = {17237781},
issn = {1061-4036},
mesh = {Acylation ; Animals ; Cells, Cultured ; Chromatin Immunoprecipitation ; Chromosomal Proteins, Non-Histone/metabolism ; *DNA Methylation ; Epigenesis, Genetic ; Fibroblasts ; Heterochromatin/metabolism ; Histones/metabolism ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Knockout ; Polymorphism, Restriction Fragment Length ; Telomerase/genetics/*physiology ; Telomere/metabolism/*ultrastructure ; Telomere-Binding Proteins/metabolism ; },
abstract = {Mammalian telomeres have epigenetic marks of constitutive heterochromatin. Here, we study the impact of telomere length on the maintenance of heterochromatin domains at telomeres. Telomerase-deficient Terc(-/-) mice with short telomeres show decreased trimethylation of histone 3 at Lys9 (H3K9) and histone 4 at Lys20 (H4K20) in telomeric and subtelomeric chromatin as well as decreased CBX3 binding accompanied by increased H3 and H4 acetylation at these regions. Subtelomeric DNA methylation is also decreased in conjunction with telomere shortening in Terc(-/-) mice. In contrast, telomere repeat factors 1 and 2 show normal binding to telomeres independent of telomere length. These results indicate that loss of telomeric repeats leads to a change in the architecture of telomeric and subtelomeric chromatin consisting of loss of heterochromatic features leading to a more 'open' chromatin state. These observations highlight the importance of telomere repeats in the establishment of constitutive heterochromatin at mammalian telomeres and subtelomeres and point to histone modifications as important in counting telomere repeats.},
}
@article {pmid17237768,
year = {2007},
author = {Wang, F and Podell, ER and Zaug, AJ and Yang, Y and Baciu, P and Cech, TR and Lei, M},
title = {The POT1-TPP1 telomere complex is a telomerase processivity factor.},
journal = {Nature},
volume = {445},
number = {7127},
pages = {506-510},
doi = {10.1038/nature05454},
pmid = {17237768},
issn = {1476-4687},
mesh = {Crystallography, X-Ray ; DNA, Single-Stranded/chemistry/genetics/metabolism ; Humans ; Multiprotein Complexes/chemistry/metabolism ; Nucleic Acid Conformation ; Protein Binding ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Shelterin Complex ; Structural Homology, Protein ; Telomerase/antagonists &amp; inhibitors/*chemistry/*metabolism ; Telomere-Binding Proteins/*chemistry/*metabolism ; },
abstract = {Telomeres were originally defined as chromosome caps that prevent the natural ends of linear chromosomes from undergoing deleterious degradation and fusion events. POT1 (protection of telomeres) protein binds the single-stranded G-rich DNA overhangs at human chromosome ends and suppresses unwanted DNA repair activities. TPP1 is a previously identified binding partner of POT1 that has been proposed to form part of a six-protein shelterin complex at telomeres. Here, the crystal structure of a domain of human TPP1 reveals an oligonucleotide/oligosaccharide-binding fold that is structurally similar to the beta-subunit of the telomere end-binding protein of a ciliated protozoan, suggesting that TPP1 is the missing beta-subunit of human POT1 protein. Telomeric DNA end-binding proteins have generally been found to inhibit rather than stimulate the action of the chromosome end-replicating enzyme, telomerase. In contrast, we find that TPP1 and POT1 form a complex with telomeric DNA that increases the activity and processivity of the human telomerase core enzyme. We propose that POT1-TPP1 switches from inhibiting telomerase access to the telomere, as a component of shelterin, to serving as a processivity factor for telomerase during telomere extension.},
}
@article {pmid17237517,
year = {2007},
author = {Carter, SD and Iyer, S and Xu, J and McEachern, MJ and Aström, SU},
title = {The role of nonhomologous end-joining components in telomere metabolism in Kluyveromyces lactis.},
journal = {Genetics},
volume = {175},
number = {3},
pages = {1035-1045},
pmid = {17237517},
issn = {0016-6731},
support = {R01 GM061645/GM/NIGMS NIH HHS/United States ; GM61645-01/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Ligases/metabolism ; Fungal Proteins/*metabolism ; Kluyveromyces/genetics/*metabolism ; Nucleic Acid Hybridization ; Oligonucleotides/genetics ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {The relationship between telomeres and nonhomologous end-joining (NHEJ) is paradoxical, as NHEJ proteins are part of the telomere cap, which serves to differentiate telomeres from DNA double-strand breaks. We explored these contradictory functions for NHEJ proteins by investigating their role in Kluyveromyces lactis telomere metabolism. The ter1-4LBsr allele of the TER1 gene resulted in the introduction of sequence altered telomeric repeats and subsequent telomere-telomere fusions (T-TFs). In this background, Lig4 and Ku80 were necessary for T-TFs to form. Nej1, essential for NHEJ at internal positions, was not. Hence, T-TF formation was mediated by an unusual NHEJ mechanism. Rad50 and mre11 strains exhibited stable short telomeres, suggesting that Rad50 and Mre11 were required for telomerase recruitment. Introduction of the ter1-4LBsr allele into these strains failed to result in telomere elongation as normally observed with the ter1-4LBsr allele. Thus, the role of Rad50 and Mre11 in the formation of T-TFs was unclear. Furthermore, rad50 and mre11 mutants had highly increased subtelomeric recombination rates, while ku80 and lig4 mutants displayed moderate increases. Ku80 mutant strains also contained extended single-stranded 3' telomeric overhangs. We concluded that NHEJ proteins have multiple roles at telomeres, mediating fusions of mutant telomeres and ensuring end protection of normal telomeres.},
}
@article {pmid17229321,
year = {2007},
author = {Francia, S and Weiss, RS and d'Adda di Fagagna, F},
title = {Need telomere maintenance? Call 911.},
journal = {Cell division},
volume = {2},
number = {},
pages = {3},
pmid = {17229321},
issn = {1747-1028},
support = {R01 CA108773/CA/NCI NIH HHS/United States ; },
abstract = {"Natura non facit saltum" (nature makes no leap) the Latins used to say, meaning that nature does not like discontinuities. Cells make no exception and indeed any discontinuity in the DNA double helix is promptly detected, triggering an alteration of cell proliferation and an attempt to repair. Yet, linear chromosomes bear DNA ends that are compatible with normal cell proliferation and they escape, under normal conditions, any repair. How telomeres, the chromosomes tips, achieve that is not fully understood. We recently observed that the Rad9/Hus1/Rad1 (911) complex, previously known for its functions in DNA metabolism and DNA damage responses, is constitutively associated with telomeres and plays an important role in their maintenance. Here, we summarize the available data and discuss the potential mechanisms of 911 action at telomeres.},
}
@article {pmid17223635,
year = {2006},
author = {Sgura, A and Antoccia, A and Berardinelli, F and Cherubini, R and Gerardi, S and Zilio, C and Tanzarella, C},
title = {Telomere length in mammalian cells exposed to low- and high-LET radiations.},
journal = {Radiation protection dosimetry},
volume = {122},
number = {1-4},
pages = {176-179},
doi = {10.1093/rpd/ncl478},
pmid = {17223635},
issn = {0144-8420},
mesh = {Animals ; Cells, Cultured ; DNA/*genetics/*radiation effects ; *DNA Damage ; Dose-Response Relationship, Radiation ; Fibroblasts/cytology/*physiology/*radiation effects ; Humans ; Linear Energy Transfer/physiology/radiation effects ; Mice ; Radiation Dosage ; Radiation, Ionizing ; Telomere/*genetics/*radiation effects/ultrastructure ; },
abstract = {Telomeres are specialised nucleoprotein complexes that serve as protective caps of linear eukaryotic chromosomes. The loss of the ends of the chromosomes due to these un-rejoined double strand breaks (DSBs) may not be lethal to the cell, but may instead result in the loss of functional telomeres, chromosome fusions and initiation of breakage/fusion/bridge cycle-induced chromosome instability. The telomeres also participate in the process of DNA repair, as evidenced by 'de novo' synthesis of telomere repeats at DSBs and by the capacity of telomeres to binding the essential components of the DNA repair machinery. Based on the observation that high-LET radiations efficiently induce chromosome aberrations, it was tested whether protons were able to affect telomere structure. Human primary fibroblasts (HFFF2) and mouse embryonic fibroblasts (MEFs) were irradiated with 4 Gy of 3 MeV protons at the radiobiology facility of the INFN-LNL. Experiments with X rays were also carried out. Cells were fixed after either 24 h or 15 d from treatment. A difference in average telomere length, measured by quantitative fluorescence in situ hybridisation (Q-FISH), between X rays and protons treatment was observed. X rays are able to modify telomere length in HFFF2 harvested at a later time. On the other hand, 3 MeV low-energy protons induced, both in HFFF2 and in MEFs, a significant increase in telomere length at short as well as at long harvesting time periods from treatment. These results seem to indicate that lesions characterised by different complexity, as those expected after low-energy protons and those induced by damage similar to that induced by sparsely ionising radiation, are able to modulate telomere elongation at different time periods.},
}
@article {pmid17223473,
year = {2007},
author = {Brouilette, SW and Moore, JS and McMahon, AD and Thompson, JR and Ford, I and Shepherd, J and Packard, CJ and Samani, NJ and , },
title = {Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study.},
journal = {Lancet (London, England)},
volume = {369},
number = {9556},
pages = {107-114},
doi = {10.1016/S0140-6736(07)60071-3},
pmid = {17223473},
issn = {1474-547X},
mesh = {Aging/physiology ; Blood Pressure/drug effects ; Case-Control Studies ; Cholesterol/blood ; Coronary Disease/*etiology/prevention &amp; control ; Follow-Up Studies ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use ; Male ; Middle Aged ; Polymerase Chain Reaction ; Pravastatin/*therapeutic use ; Risk Factors ; Scotland ; Telomere/*drug effects/genetics/physiology ; },
abstract = {BACKGROUND: Inter-individual differences in biological ageing could affect susceptibility to coronary heart disease. Our aim was to determine whether mean leucocyte telomere length is a predictor of the development of coronary heart disease.<br><br>METHODS: We compared telomere lengths at recruitment in 484 individuals in the West of Scotland Primary Prevention Study (WOSCOPS) who went on to develop coronary heart disease events with those from 1058 matched controls who remained event free. We also investigated whether there was any association between telomere length and observed clinical benefit of statin treatment in WOSCOPS.<br><br>FINDINGS: Mean telomere length decreased with age by 9% per decade (95% CI 3.6-14.1; p=0.001) in controls; much the same trend was seen in cases (-5.9% per decade, -3.1 to 14.1; p=0.1902). Individuals in the middle and the lowest tertiles of telomere length were more at risk of developing a coronary heart disease event than were individuals in the highest tertile (odds ratio [OR] for coronary heart disease: 1.51, 95% CI 1.15-1.98; p=0.0029 in the middle tertile; 1.44, 1.10-1.90, p=0.0090 in the lowest). In placebo-treated patients, the risk of coronary heart disease was almost double in those in the lower two tertiles of telomere length compared with those in the highest tertile (1.93, 1.33-2.80, p=0.0005 in the middle tertile; 1.94, 1.33-2.84, p=0.0006 in the lowest). By contrast, in patients treated with pravastatin, the increased risk with shorter telomeres was substantially attenuated (1.12, 0.75-1.69, p=0.5755 in the middle tertile; 1.02, 0.68-1.52, p=0.9380 in the lowest).<br><br>INTERPRETATION: Mean leucocyte telomere length is a predictor of future coronary heart disease events in middle-aged, high-risk men and could identify individuals who would benefit most from statin treatment. Our findings lend support to the hypothesis that differences in biological ageing might contribute to the risk--and variability in age of onset--of coronary heart disease.},
}
@article {pmid17223451,
year = {2007},
author = {Spyridopoulos, I and Dimmeler, S},
title = {Can telomere length predict cardiovascular risk?.},
journal = {Lancet (London, England)},
volume = {369},
number = {9556},
pages = {81-82},
doi = {10.1016/S0140-6736(07)60042-7},
pmid = {17223451},
issn = {1474-547X},
mesh = {Anticholesteremic Agents/*therapeutic use ; Coronary Disease/etiology/*prevention &amp; control ; Humans ; Male ; Pravastatin/*therapeutic use ; Prognosis ; Randomized Controlled Trials as Topic ; Risk Factors ; Telomere/*drug effects/physiology ; Telomere-Binding Proteins/blood/drug effects ; },
}
@article {pmid17222848,
year = {2007},
author = {Adaikalakoteswari, A and Balasubramanyam, M and Ravikumar, R and Deepa, R and Mohan, V},
title = {Association of telomere shortening with impaired glucose tolerance and diabetic macroangiopathy.},
journal = {Atherosclerosis},
volume = {195},
number = {1},
pages = {83-89},
doi = {10.1016/j.atherosclerosis.2006.12.003},
pmid = {17222848},
issn = {1879-1484},
mesh = {Adult ; Aged ; Atherosclerosis/metabolism/pathology ; Diabetes Mellitus, Type 2/*pathology ; Female ; Glucose/*metabolism ; Glucose Tolerance Test ; Humans ; Lipid Peroxidation ; Male ; Middle Aged ; Oxidative Stress ; Telomere/*ultrastructure ; Tunica Intima/pathology ; Tunica Media/pathology ; Vascular Diseases/*pathology ; },
abstract = {OBJECTIVE: Shortening of telomere length has been reported in several conditions including Type 2 diabetes and atherosclerosis. The aims of this study were (1) to assess whether telomere shortening occurs at the stage of pre-diabetes, i.e., impaired glucose tolerance (IGT) and (2) whether telomere shortening was greater in Type 2 diabetic subjects with atherosclerotic plaques.<br><br>METHODS: Subjects with impaired glucose tolerance (IGT) (n=30), non-diabetic control subjects (n=30), Type 2 diabetic patients without (n=30) and with atherosclerotic plaques (n=30) were selected from the Chennai Urban Rural Epidemiology Study (CURES), an ongoing epidemiological population-based study. Southern-blot analysis was used to determine mean terminal restriction fragment (TRF) length, a measure of average telomere size, in leukocyte DNA. Levels of thiobarbituric acid reactive substances (TBARS), protein carbonyl content (PCO) and high sensitive C-reactive protein (hs-CRP) were measured by standard methodologies. Carotid intima-media thickness (IMT) was assessed by high resolution B-mode ultrasonography.<br><br>RESULTS: The mean (+/-S.E.) TRF lengths were significantly lower in IGT subjects (6.97+/-0.3 kb; p=0.002) and lower still in Type 2 diabetic subjects without plaques (6.21+/-0.2; p=0.0001) and lowest in Type 2 diabetic subjects with atherosclerotic plaques (5.39+/-0.2; p=0.0001) when compared to control subjects (8.7+/-0.5). In IGT subjects, TRF length was positively correlated to HDL cholesterol and negatively correlated to glycated hemoglobin (HbA1c), TBARS, PCO, HOMA-IR and IMT. In multiple linear regression analysis, presence of diabetes, HDL cholesterol and increased TBARS levels appear as significant determinants of telomere shortening.<br><br>CONCLUSION: Telomere shortening is seen even at the stage of IGT. Among subjects with Type 2 diabetes, those with atherosclerotic plaques had greater shortening of telomere length compared to those without plaques.},
}
@article {pmid17219026,
year = {2007},
author = {Keefe, DL},
title = {Telomeres and meiosis in health and disease.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {64},
number = {2},
pages = {115-116},
doi = {10.1007/s00018-006-6462-3},
pmid = {17219026},
issn = {1420-682X},
mesh = {*Chromosome Disorders ; Humans ; Meiosis/*genetics ; Telomere/*genetics ; },
}
@article {pmid17219025,
year = {2007},
author = {Scherthan, H},
title = {Telomere attachment and clustering during meiosis.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {64},
number = {2},
pages = {117-124},
doi = {10.1007/s00018-006-6463-2},
pmid = {17219025},
issn = {1420-682X},
mesh = {Actins/metabolism ; Cell Cycle Proteins/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosome Segregation/genetics/*physiology ; Heterochromatin/metabolism ; Meiosis/*genetics ; *Models, Biological ; Nuclear Envelope/*metabolism ; Nuclear Proteins/metabolism ; Spindle Apparatus/metabolism ; Telomere/*genetics/*metabolism ; Cohesins ; },
abstract = {Telomeres are important segments of chromosomes that protect chromosome ends from nucleolytic degradation and fusion. At meiosis telomeres display an unprecedented behavior which involves their attachment and motility along the nuclear envelope. The movements become restricted to a limited nuclear sector during the so-called bouquet stage, which is widely conserved among species. Recent observations suggest that telomere clustering involves actin and/or microtubules, and is altered in the presence of impaired recombinogenic and chromosome related functions. This review aims to provide an overview of what is currently known about meiotic telomere attachment, dynamics and regulation in synaptic meiosis.},
}
@article {pmid17219024,
year = {2007},
author = {Joseph, I and Lustig, AJ},
title = {Telomeres in meiotic recombination: the yeast side story.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {64},
number = {2},
pages = {125-130},
doi = {10.1007/s00018-006-6464-1},
pmid = {17219024},
issn = {1420-682X},
support = {R01 GM069943/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics ; Heterochromatin/genetics ; Meiosis/*genetics ; Mutation/genetics ; Recombination, Genetic/*genetics ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/genetics ; Schizosaccharomyces/*genetics ; Species Specificity ; Telomere/*genetics/metabolism ; },
abstract = {The aim of this review is threefold. First, we want to report on recent observations on the role of telomeres in the alignment of homolog and non-homologues in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe and the relationship of early telomere clustering to later recombination events. Second, we compare the similarities and differences between synaptic and asynaptic yeasts. Third, we report on the increasing evidence of the effect of meiosis on telomeric sequences that suggest an induction of a specific form of recombination processes termed telomere rapid deletion.},
}
@article {pmid17219023,
year = {2007},
author = {Pandita, TK and Hunt, CR and Sharma, GG and Yang, Q},
title = {Regulation of telomere movement by telomere chromatin structure.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {64},
number = {2},
pages = {131-138},
doi = {10.1007/s00018-006-6465-0},
pmid = {17219023},
issn = {1420-682X},
support = {CA10445/CA/NCI NIH HHS/United States ; NS34746/NS/NINDS NIH HHS/United States ; },
mesh = {Chromatin/*genetics ; Chromosome Segregation/*physiology ; Meiosis/*genetics ; *Models, Molecular ; Nuclear Matrix/*metabolism ; Telomere/*genetics/*physiology ; },
abstract = {Beyond their role in replication and chromosome end capping, telomeres are also thought to function in meiotic chromosome pairing, meiotic and mitotic chromosome segregation as well as in nuclear organization. Observations in both somatic and meiotic cells suggest that the positioning of telomeres within the nucleus is highly specific and believed to be dependent mainly on telomere interactions with the nuclear envelope either directly or through chromatin interacting proteins. Although little is known about the mechanism of telomere clustering, some studies show that it is an active process. Recent data have suggested a regulatory role for telomere chromatin structure in telomere movement. This review will summarize recent studies on telomere interactions with the nuclear matrix, telomere chromatin structure and factors that modify telomere chromatin structure as related to regulation of telomere movement.},
}
@article {pmid17219022,
year = {2007},
author = {Keefe, DL and Liu, L and Marquard, K},
title = {Telomeres and aging-related meiotic dysfunction in women.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {64},
number = {2},
pages = {139-143},
doi = {10.1007/s00018-006-6466-z},
pmid = {17219022},
issn = {1420-682X},
mesh = {Animals ; Cellular Senescence/*genetics/physiology ; Female ; Humans ; Meiosis/*physiology ; Mice ; Nondisjunction, Genetic/*genetics ; Reproduction/*genetics/physiology ; Spindle Apparatus/physiology ; Telomere/genetics/*physiology ; },
abstract = {Meiotic dysfunction increasingly afflicts women as they age, resulting in infertility, miscarriage and handicapped offspring. How aging disrupts meiotic function in women remains unclear, but as women increasingly delay childbearing, this issue becomes urgent. Telomeres, which mediate aging in mitotic cells, may also mediate aging during meiosis. Telomeres shorten during DNA replication. In mammals, oocytes remain quiescent, but their precursors replicated during fetal oogenesis. Moreover, eggs ovulated from older women entered meiosis later during fetal oogenesis than eggs ovulated when younger, and therefore underwent more replications. Telomeres also shorten from reactive oxygen, which triggers a DNA repair response, so the prolonged interval between fetal oogenesis and ovulation in some women would further shorten telomeres. Mice normally do not exhibit age-related meiotic dysfunction (interestingly, their telomeres are manyfold longer than telomeres in women), but genetic or pharmacologic shortening of mouse telomeres recapitulates the reproductive aging phenotype of women. This has led to a telomere theory of age-related meiotic dysfunction in women, and underlined the importance to human health of a mechanistic understanding of telomeres and meiosis.},
}
@article {pmid17217467,
year = {2007},
author = {Yoo, HH and Kwon, C and Lee, MM and Chung, IK},
title = {Single-stranded DNA binding factor AtWHY1 modulates telomere length homeostasis in Arabidopsis.},
journal = {The Plant journal : for cell and molecular biology},
volume = {49},
number = {3},
pages = {442-451},
doi = {10.1111/j.1365-313X.2006.02974.x},
pmid = {17217467},
issn = {0960-7412},
mesh = {Amino Acid Sequence ; Arabidopsis/genetics/*metabolism ; Arabidopsis Proteins/chemistry/genetics/*metabolism ; Binding Sites ; Chromosomes, Plant/metabolism ; DNA, Bacterial ; DNA, Single-Stranded/*metabolism ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Gene Expression ; Homeostasis/physiology ; Molecular Sequence Data ; Mutagenesis, Insertional ; Plants, Genetically Modified/metabolism ; Sequence Homology, Amino Acid ; Solanum tuberosum/chemistry ; Telomerase/antagonists &amp; inhibitors/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Telomere homeostasis, a process that is essential for the maintenance of chromosome integrity, is regulated by telomerase and a collection of associated proteins. By mass spectrometry we have identified a new telomeric protein encoded by the AtWHY1 (Arabidopsis thaliana Whirly 1) gene in Arabidopsis. AtWHY1 specifically binds the single-stranded plant telomeric DNA sequences, but not double-stranded telomeric DNA. To gain insights into the function of AtWHY1 in telomere biogenesis, we have identified two Arabidopsis lines harboring T-DNA insertions in AtWHY1. These lines exhibit neither growth nor developmental defects. However, AtWHY1-deficient plants show a steady increase in the length of telomere tracts over generations. This telomere elongation is correlated with a significant increase in telomerase activity. On the contrary, transgenic plants expressing AtWHY1 show a decreased telomerase activity and shortened telomeres. The evidence presented here indicates that AtWHY1 is a new family of telomere end-binding proteins that plays a role in regulating telomere-length homeostasis in Arabidopsis.},
}
@article {pmid17215319,
year = {2007},
author = {Collerton, J and Martin-Ruiz, C and Kenny, A and Barrass, K and von Zglinicki, T and Kirkwood, T and Keavney, B and , },
title = {Telomere length is associated with left ventricular function in the oldest old: the Newcastle 85+ study.},
journal = {European heart journal},
volume = {28},
number = {2},
pages = {172-176},
doi = {10.1093/eurheartj/ehl437},
pmid = {17215319},
issn = {0195-668X},
support = {G0500997/MRC_/Medical Research Council/United Kingdom ; G0601333/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aged, 80 and over ; Biomarkers ; Electrocardiography ; Female ; Heart Failure/*pathology ; Humans ; Male ; Stroke Volume/physiology ; Telomere/*pathology ; Ventricular Dysfunction, Left/*pathology ; },
abstract = {AIMS: Heart failure is a condition increasingly prevalent at older ages; however, mechanisms by which the ageing process affects cardiac function are largely unknown. Telomere length is a biomarker of ageing that has been suggested to be associated with a variety of diseases of late onset, but its relationship with cardiac function has not previously been studied. We measured telomere length in peripheral blood mononuclear cells and carried out echocardiography in a group of 85-year old subjects recruited from the community as part of the Newcastle 85+ Study.<br><br>METHODS AND RESULTS: Eighty-nine subjects were recruited through local family practitioners. They were visited in their homes for clinical assessment and echocardiography, which was performed using a handheld device. Telomere length was measured by a real-time PCR method. High sensitivity C-reactive protein was measured using ELISA. Echocardiographic M-mode ejection fraction (EF) was strongly associated with telomere length (P=0.006) in subjects without evidence of previous MI. Sex and telomere length were significant predictors of EF while current smoking, blood pressure, plasma high sensitivity C-reactive protein, and use of cardiovascular medications were not. One standard deviation longer telomeres were associated with a 5% higher EF. Telomere length accounted for 12% of the observed variability in EF.<br><br>CONCLUSION: These data show influences of the ageing process on myocardial function in the oldest old, apparently independent of other specific disease processes. This may be of importance in the aetiology of heart failure in this age group.},
}
@article {pmid17210516,
year = {2007},
author = {Kawai, T and Hiroi, S and Nakanishi, K and Meeker, AK},
title = {Telomere length and telomerase expression in atypical adenomatous hyperplasia and small bronchioloalveolar carcinoma of the lung.},
journal = {American journal of clinical pathology},
volume = {127},
number = {2},
pages = {254-262},
doi = {10.1309/91PY0RBD9W8Y5GNX},
pmid = {17210516},
issn = {0002-9173},
mesh = {Adenocarcinoma/*metabolism ; Adenocarcinoma, Bronchiolo-Alveolar/*metabolism ; Humans ; Hyperplasia ; In Situ Hybridization, Fluorescence ; Lung Neoplasms/*metabolism ; Telomerase/*biosynthesis ; Telomere/*physiology ; },
abstract = {Telomeres are located at the ends of every human chromosome and are subject to shortening at each cycle of cell division in cell senescence and early carcinogenesis. We examined the expression of telomeric DNA in 21 atypical adenomatous hyperplasias (AAHs) and 40 bronchioloalveolar carcinomas (BACs) measuring 2 cm or less in greatest diameter using fluorescent in situ hybridization and the expression of human telomerase reverse transcriptase (hTERT) messenger RNA (mRNA) in 35 AAHs and 37 BACs. The mean numbers of telomeric signals per nucleus were 5.0 in AAH and 7.4 in BAC, each significantly less than for normal cells (14.7; P < .0001), but the mean number of telomeric signals for AAH and BAC was not statistically different (P = .22). In "benign" lung samples, the pattern of expression of hTERT mRNA was barely detected in the nonciliated cells of the bronchioles and alveolar type II cells. Positive expression of hTERT mRNA was recognized in 66% of AAHs and 97% of BACs. Our results demonstrate telomere shortening, indicating its presence in the earliest phase of pulmonary carcinogenesis. Telomere length and telomerase may be involved in carcinogenesis in the lung.},
}
@article {pmid17209013,
year = {2007},
author = {Xhemalce, B and Riising, EM and Baumann, P and Dejean, A and Arcangioli, B and Seeler, JS},
title = {Role of SUMO in the dynamics of telomere maintenance in fission yeast.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {104},
number = {3},
pages = {893-898},
pmid = {17209013},
issn = {0027-8424},
mesh = {DNA, Recombinant/genetics ; Mutation/genetics ; Protein Binding ; Schizosaccharomyces/*genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/metabolism ; Small Ubiquitin-Related Modifier Proteins/*metabolism ; Telomere/*genetics/*metabolism ; Ubiquitin-Protein Ligases/metabolism ; },
abstract = {The sheltering of chromosome ends from illegitimate DNA repair reactions and telomere length homeostasis are critical for preserving genomic integrity. Growing evidence implicates covalent protein modification by SUMO (small ubiquitin-like modifier) (sumoylation) in the regulation of numerous DNA transactions, including DNA repair and transcription, as well as heterochromatin formation and maintenance. We have recently shown that fission yeast Pli1p is a SUMO E3 ligase and that pli1 mutants, which are impaired for global sumoylation, are viable, but exhibit de-regulated homologous recombination and marked defects in chromosome segregation and centromeric silencing, as well as a consistent increase in telomere length. In this work, we explore the mechanisms underlying sumoylation-dependent telomere maintenance. We show that Pli1p, but not the related Nse2p, is the principal SUMO E3 ligase enzyme involved. Using both a pli1 mutation and a physiological "knockdown" of sumoylation, achieved by inducible expression of a dominant negative form of the conjugating enzyme Ubc9p, we further show that telomere lengthening induced by lack of sumoylation is not due to unscheduled telomere-telomere recombination. Instead, sumoylation increases telomerase activity, therefore suggesting that this modification controls the activity of a positive or negative regulator of telomerase.},
}
@article {pmid17207936,
year = {2007},
author = {Zhang, P and Dilley, C and Mattson, MP},
title = {DNA damage responses in neural cells: Focus on the telomere.},
journal = {Neuroscience},
volume = {145},
number = {4},
pages = {1439-1448},
pmid = {17207936},
issn = {0306-4522},
support = {Z01 AG000313-05/AG/NIA NIH HHS/United States ; Z01 AG000314-05/AG/NIA NIH HHS/United States ; //Intramural NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics ; Cellular Senescence/*genetics ; DNA Damage/*genetics ; DNA Repair-Deficiency Disorders/genetics/metabolism/physiopathology ; DNA-Binding Proteins/genetics ; Humans ; Nervous System/cytology/*metabolism ; Neurodegenerative Diseases/*genetics/metabolism/physiopathology ; Neurons/*metabolism ; Nuclear Proteins/genetics ; Protein Serine-Threonine Kinases/genetics ; TATA Box Binding Protein-Like Proteins/genetics ; Telomere/*genetics ; Telomeric Repeat Binding Protein 2 ; Tumor Suppressor Proteins/genetics ; },
abstract = {Postmitotic neurons must survive for the entire life of the organism and be able to respond adaptively to adverse conditions of oxidative and genotoxic stress. Unrepaired DNA damage can trigger apoptosis of neurons which is typically mediated by the ataxia telangiectasia mutated (ATM)-p53 pathway. As in all mammalian cells, telomeres in neurons consist of TTAGGG DNA repeats and several associated proteins that form a nucleoprotein complex that prevents chromosome ends from being recognized as double strand breaks. Proteins that stabilize telomeres include TRF1 and TRF2, and proteins known to play important roles in DNA damage responses and DNA repair including ATM, Werner and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). We have been performing studies of developing and adult neurons aimed at understanding the effects of global and telomere-directed DNA damage responses in neuronal plasticity and survival in the contexts of aging and neurodegenerative disorders. Deficits in specific DNA repair proteins, including DNA-PKcs and uracil DNA glycosylase (UDG), render neurons vulnerable to adverse conditions of relevance to the pathogenesis of neurodegenerative disorders such as Alzheimer's disease and stroke. Similarly, early postmitotic neurons with reduced telomerase activity exhibit accentuated responses to DNA damage and are prone to apoptosis demonstrating a pivotal role for telomere maintenance in both mitotic cells and postmitotic neurons. Our recent findings suggest key roles for TRF2 in regulating the differentiation and survival of neurons. TRF2 affects cell survival and differentiation by modulating DNA damage pathways, and gene expression. A better understanding of the molecular mechanisms by which neurons respond to global and telomere-specific DNA damage may reveal novel strategies for prevention and treatment of neurodegenerative disorders. Indeed, work in this and other laboratories has shown that dietary folic acid can protect neurons against Alzheimer's disease by keeping homocysteine levels low and thereby minimizing the misincorporation of uracil into DNA in neurons.},
}
@article {pmid17204170,
year = {2006},
author = {Wang, Y and Fang, MY},
title = {Effect of ginseng saponin, arsenic trioxide, beta-elemene combined with CTX on telomere-telomerase system in K562 cell line.},
journal = {Zhongguo shi yan xue ye xue za zhi},
volume = {14},
number = {6},
pages = {1089-1095},
pmid = {17204170},
issn = {1009-2137},
mesh = {Arsenic Trioxide ; Arsenicals/*pharmacology ; Cyclophosphamide/*pharmacology ; Drug Synergism ; Humans ; K562 Cells ; Oxides/*pharmacology ; *Panax/chemistry ; Saponins/*pharmacology ; Sesquiterpenes/*pharmacology ; Telomerase/*drug effects/metabolism ; Telomere/drug effects ; },
abstract = {This study was aimed to investigate the modulating effects on telomere length and telomerase activity in K562 cells treated by arsenic trioxide, ginseng saponin, beta-elemene alone or in combination with cyclophosphamide (CTX) and to explore the possible mechanism and new therapy for acute leukemia. Human erythroleukemic cell line K562 was co-cultured with the above-mentioned drugs. Cells were collected after 24, 48 and 72 hours for further detection. Telomere length and telomerase activity were detected by Southern-blot and PCR-ELISA respectively. The effects of these drugs were observed at different concentrations and exposure time. The results showed that (1) ginseng saponin, arsenic trioxide, beta-elemene, or CTX could completely inhibit the telomerase activity of K562 cells at proper concentrations and exposure time. The inhibiting effects were enhanced when the three former drugs were used with CTX. Telomerase activity decreased proportionally with the concentrations and length of time. (2) viability of K562 cells was decreased after being co-cultured with arsenic trioxide, ginseng saponin, beta-elemene and CTX. The level of inhibition depends on the concentration and exposure time. (3) telomere length of K562 cells was 5.36 +/- 0.18 kb. After being co-cultured with those drugs for 72 hours, telomere length was 5.90 kb -6.50 kb, significantly longer than that of control (5.18 - 5.35 kb). It is concluded that arsenic trioxide, ginseng saponin, and beta-elemene can inhibit the growth and telomerase activity of K562 cells. The inhibiting effects were enhanced when they were used in combination with CTX. The depression of telomerase activity may be one of the mechanisms of anti-tumor effect. Less dosage and shorter course can be expected when arsenic trioxide, ginseng saponin, and beta-elemene are used in combination with CTX. When telomerase activity was depressed, the telomere length prolonged a little, indicating K562 cell line may extend telomeres by some alternative way other than telomerase activation.},
}
@article {pmid17200948,
year = {2007},
author = {Shay, JW and Wright, WE},
title = {Hallmarks of telomeres in ageing research.},
journal = {The Journal of pathology},
volume = {211},
number = {2},
pages = {114-123},
doi = {10.1002/path.2090},
pmid = {17200948},
issn = {0022-3417},
support = {P50 CA070907/CA/NCI NIH HHS/United States ; P50 CA75907/CA/NCI NIH HHS/United States ; },
mesh = {Aging/*genetics ; Animals ; Cell Transformation, Neoplastic/genetics ; Cellular Senescence/genetics ; DNA Damage/genetics ; DNA, Neoplasm/genetics ; Humans ; Neoplasms/diagnosis/genetics/therapy ; Precancerous Conditions/genetics ; Telomerase/antagonists &amp; inhibitors/metabolism/therapeutic use ; Telomere/*genetics ; },
abstract = {Telomeres are repetitive DNA sequences at the ends of linear chromosomes. Telomerase, a cellular reverse transcriptase, helps maintain telomere length in human stem cells, reproductive cells and cancer cells by adding TTAGGG repeats onto the telomeres. However, most normal human cells do not express telomerase and thus each time a cell divides some telomeric sequences are lost. When telomeres in a subset of cells become short (unprotected), cells enter an irreversible growth arrest state called replicative senescence. Cells in senescence produce a different constellation of proteins compared to normal quiescent cells. This may lead to a change in the homeostatic environment in a tissue-specific manner. In most instances cells become senescent before they can become cancerous; thus, the initial growth arrest induced by short telomeres may be thought of as a potent anti-cancer protection mechanism. When cells can be adequately cultured until they reach telomere-based replicative senescence, introduction of the telomerase catalytic protein component (hTERT) into telomerase-silent cells is sufficient to restore telomerase activity and extend cellular lifespan. Cells with introduced telomerase are not cancer cells, since they have not accumulated the other changes needed to become cancerous. This indicates that telomerase-induced telomere length manipulations may have utility for tissue engineering and for dissecting the molecular mechanisms underlying genetic diseases, including cancer.},
}
@article {pmid17199130,
year = {2007},
author = {Ferreira, MG},
title = {Telomeres on the Cdk roller-coaster ride.},
journal = {Nature cell biology},
volume = {9},
number = {1},
pages = {22-23},
doi = {10.1038/ncb0107-22},
pmid = {17199130},
issn = {1465-7392},
mesh = {Animals ; CDC2 Protein Kinase/*genetics ; Chromosomes/genetics/*metabolism ; *DNA Replication ; Enzyme Activation ; Models, Genetic ; Telomere/genetics/*metabolism ; },
}
@article {pmid17198091,
year = {2007},
author = {Shen, X and Zhou, J and Hathcock, KS and Robbins, P and Powell, DJ and Rosenberg, SA and Hodes, RJ},
title = {Persistence of tumor infiltrating lymphocytes in adoptive immunotherapy correlates with telomere length.},
journal = {Journal of immunotherapy (Hagerstown, Md. : 1997)},
volume = {30},
number = {1},
pages = {123-129},
pmid = {17198091},
issn = {1524-9557},
support = {Z01 SC003811-32//Intramural NIH HHS/United States ; },
mesh = {Humans ; Immunotherapy, Adoptive/*methods ; Lymphocyte Activation ; Lymphocytes, Tumor-Infiltrating/enzymology/*immunology ; Neoplasms/*immunology/*therapy ; Telomerase/metabolism ; Telomere/*immunology ; },
abstract = {Transfer of autologous tumor-specific tumor infiltrating lymphocytes (TILs) in adoptive immunotherapy can mediate the regression of tumor in patients with metastatic melanoma. In this procedure, TILs from resected tumors are expanded in vitro, then administered to patients and further stimulated to proliferate in vivo by the administration of high dose IL-2. After in vitro expansion, TILs are often dominated by a few specific clonotypes, and recently it was reported that the persistence in vivo of one or more of these clonotypes correlated with positive therapeutic response. We and others have previously shown that repeated in vitro stimulation and clonal expansion of normal human T lymphocytes results in progressive decrease in telomerase activity and shortening of telomeres, ultimately resulting in replicative senescence. In the studies reported here, we therefore compared telomerase activity and telomere length in persistent and nonpersistent TIL clonotypes before transfer in vivo, and found a correlation between telomere length and clonal persistence. We also observed that TILs proliferate extensively in vivo in the days after transfer, but fail to induce substantial telomerase activity, and undergo rapid decreases in telomere length within days after transfer. Thus, in vivo loss of telomeres by clonotypes that have the shortest telomeres at the time of administration may drive these clones to replicative senescence, whereas cells with longer telomeres are able to persist and mediate antitumor effects. These findings are relevant both to predicting effectiveness of adoptive immunotherapy and in deriving strategies for improving effectiveness by sustaining telomere length.},
}
@article {pmid17192782,
year = {2007},
author = {Bell, JF and Sharpless, NE},
title = {Telomeres, p21 and the cancer-aging hypothesis.},
journal = {Nature genetics},
volume = {39},
number = {1},
pages = {11-12},
doi = {10.1038/ng0107-11},
pmid = {17192782},
issn = {1061-4036},
mesh = {Aging/*genetics ; Animals ; Cyclin-Dependent Kinase Inhibitor p21/*physiology ; Humans ; Mice ; Models, Biological ; Neoplasms/*genetics ; Stem Cells/physiology ; Telomere/*physiology ; },
}
@article {pmid17189431,
year = {2007},
author = {Watson, JM and Shippen, DE},
title = {Telomere rapid deletion regulates telomere length in Arabidopsis thaliana.},
journal = {Molecular and cellular biology},
volume = {27},
number = {5},
pages = {1706-1715},
pmid = {17189431},
issn = {0270-7306},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; GM65383/GM/NIGMS NIH HHS/United States ; },
mesh = {Arabidopsis/*genetics/metabolism ; Chromosomes, Plant/genetics ; DNA, Plant/*analysis ; *Mutation ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomere length is maintained in species-specific equilibrium primarily through a competition between telomerase-mediated elongation and the loss of terminal DNA through the end-replication problem. Recombinational activities are also capable of both lengthening and shortening telomeres. Here we demonstrate that elongated telomeres in Arabidopsis Ku70 mutants reach a new length set point after three generations. Restoration of wild-type Ku70 in these mutants leads to discrete telomere-shortening events consistent with telomere rapid deletion (TRD). These findings imply that the longer telomere length set point is achieved through competition between overactive telomerase and TRD. Surprisingly, in the absence of telomerase, a subset of elongated telomeres was further lengthened, suggesting that in this background a mechanism of telomerase-independent lengthening of telomeres operates. Unexpectedly, we also found that plants possessing wild-type-length telomeres exhibit TRD when telomerase is inactivated. TRD is stochastic, and all chromosome ends appear to be equally susceptible. The frequency of TRD decreases as telomeres shorten; telomeres less than 2 kb in length are rarely subject to TRD. We conclude that TRD functions as a potent force to regulate telomere length in Arabidopsis.},
}
@article {pmid17188035,
year = {2006},
author = {Goudsouzian, LK and Tuzon, CT and Zakian, VA},
title = {S. cerevisiae Tel1p and Mre11p are required for normal levels of Est1p and Est2p telomere association.},
journal = {Molecular cell},
volume = {24},
number = {4},
pages = {603-610},
doi = {10.1016/j.molcel.2006.10.005},
pmid = {17188035},
issn = {1097-2765},
support = {GM43265/GM/NIGMS NIH HHS/United States ; T32 CA09528/CA/NCI NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Endodeoxyribonucleases/genetics/*physiology ; Exodeoxyribonucleases/genetics/*physiology ; Gene Deletion ; Intracellular Signaling Peptides and Proteins/genetics/*physiology ; Protein Serine-Threonine Kinases/genetics/*physiology ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/genetics/*metabolism/*physiology ; Telomerase/genetics/*metabolism ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {In diverse organisms, the Mre11 complex and phosphoinositide 3-kinase-related kinases (PIKKs), such as Tel1p and Mec1p from S. cerevisiae, are key mediators of DNA repair and DNA damage checkpoints that also function at telomeres. Here, we use chromatin immunoprecipitation (ChIP) to determine if Mre11p, Tel1p, or Mec1p affects telomere maintenance by promoting recruitment of telomerase subunits to S. cerevisiae telomeres. We find that recruitment of Est2p, the catalytic subunit of telomerase, and Est1p, a telomerase accessory protein, was severely reduced in mre11Delta and tel1Delta cells. In contrast, the levels of Est2p and Est1p binding in late S/G2 phase, the period in the cell cycle when yeast telomerase lengthens telomeres, were indistinguishable in wild-type (WT) and mec1Delta cells. These data argue that Mre11p and Tel1p affect telomere length by promoting telomerase recruitment to telomeres, whereas Mec1p has only a minor role in telomerase recruitment in a TEL1 cell.},
}
@article {pmid17188029,
year = {2006},
author = {Teixeira, MT and Gilson, E},
title = {When CDK1 rides the telomere cycle.},
journal = {Molecular cell},
volume = {24},
number = {4},
pages = {491-492},
doi = {10.1016/j.molcel.2006.10.033},
pmid = {17188029},
issn = {1097-2765},
mesh = {CDC2 Protein Kinase/*metabolism ; CDC28 Protein Kinase, S cerevisiae/*metabolism ; Cell Cycle/*physiology ; Cell Cycle Proteins/*metabolism ; Models, Biological ; Saccharomyces cerevisiae ; Telomere/*metabolism ; },
abstract = {Reconstitution of telomeric DNA at each cell division implies the coordination of DNA semiconservative replication with several processing events still poorly understood. Two reports published recently in Molecular Cell show that a cell-cycle cyclin-dependent kinase, Cdk1p, is required to create the cell-cycle-regulated overhang ().},
}
@article {pmid17182040,
year = {2007},
author = {Wolfrom, C and Martin, OC and Laurent, M and Deschatrette, J},
title = {Sinusoidal swinging dynamics of the telomere repair and cell growth activation functions of telomerase in rat liver cancer cells.},
journal = {FEBS letters},
volume = {581},
number = {1},
pages = {125-130},
doi = {10.1016/j.febslet.2006.12.007},
pmid = {17182040},
issn = {0014-5793},
mesh = {Animals ; *Biological Clocks ; Cell Line, Tumor ; Cell Proliferation ; Liver Neoplasms/genetics/*metabolism ; *Models, Biological ; Neoplasm Proteins/*metabolism ; Rats ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Time Factors ; },
abstract = {Telomerase is a multimolecular complex of reverse transcriptase, RNA template, and regulatory proteins. It has two known functions: catalysis of the addition of [TTAGGG] repeats to telomeric DNA and the activation of various genes controlling cell proliferation. The possible coordination of these two functions is a key issue in understanding the growth of cancer cells. We report long-term changes to this complex system, as shown by specific data analysis methods. We show that the dynamics of the two functions of telomerase are tightly linked, with a change in predominant function every 13-14 weeks. The conservative behavior of this dynamic system probably accounts for the persistent proliferation of cancer cells.},
}
@article {pmid17181645,
year = {2007},
author = {Boukamp, P and Mirancea, N},
title = {Telomeres rather than telomerase a key target for anti-cancer therapy?.},
journal = {Experimental dermatology},
volume = {16},
number = {1},
pages = {71-79},
doi = {10.1111/j.1600-0625.2006.00517.x},
pmid = {17181645},
issn = {0906-6705},
mesh = {Animals ; Antineoplastic Agents/pharmacology/*therapeutic use ; Cell Division/drug effects/physiology ; Humans ; Neoplasms/drug therapy/physiopathology ; Skin Neoplasms/drug therapy/physiopathology ; Telomerase/drug effects/*metabolism ; Telomere/drug effects/*physiology ; },
abstract = {It was in the 1930s that telomeres (from the Greek telos = end and meros = part) were first recognized as essential structures at the ends of the chromosomes and were shown to be important for chromosomal stability (Muller HJ: The remaking of chromosomes. The Collecting Net-Woods Hole 1938: 13: 181-198, McClintock B, The stability of broken ends of chromosomes in Zea mays. Genetics 1041: 26: 234-282). However, it was only in 1978 that the first telomeric sequence was identified -- in the protocoa Tetrahymena, a single cell organism that at a certain stage of development has many identical minichromosomes with twice as many telomeres (Blackburn EH and Gall JG. A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. J. Mol. Biol. 1978: 120: 33-53.). Today we know that telomeres form specialized, three-dimensional DNA-protein structures and fulfil important capping functions. Besides, telomeric DNA is essential as ''access DNA'' for those cells that are not able to counteract loss of DNA during replication because they do not express telomerase, the enzyme responsible for telomere length maintenance. Since telomerase is mostly found in tumor cells and inhibition correlates with telomere shortening and finally growth inhibition, telomerase and lately also the telomeres themselves have become attractive targets for anti-cancer therapy. This review aims to critically throw light on different therapeutical approaches and comes to the conclusion that telomeres may be the better targets for cancer therapeutics.},
}
@article {pmid17175117,
year = {2007},
author = {Gomez-Millan, J and Goldblatt, EM and Gryaznov, SM and Mendonca, MS and Herbert, BS},
title = {Specific telomere dysfunction induced by GRN163L increases radiation sensitivity in breast cancer cells.},
journal = {International journal of radiation oncology, biology, physics},
volume = {67},
number = {3},
pages = {897-905},
doi = {10.1016/j.ijrobp.2006.09.038},
pmid = {17175117},
issn = {0360-3016},
support = {R01 CA090885/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Breast Neoplasms/enzymology/pathology/*radiotherapy ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors/*therapeutic use ; Female ; Humans ; Mice ; Mice, Nude ; Oligonucleotides ; Oligopeptides/*therapeutic use ; *Radiation Tolerance ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects ; Tumor Cells, Cultured ; },
abstract = {PURPOSE: Telomerase is expressed in 80-90% of tumor cells, but is absent in most somatic cells. The absence of telomerase activity results in progressive telomere shortening, leading to cellular senescence or death through deoxyribonucleic acid (DNA) damage signals. In addition, a role for telomerase in DNA damage repair has also been suggested. A specific telomerase inhibitor, GRN163L that is complementary to the template region of the telomerase ribonucleic acid component (hTR). We hypothesized that exposure to GRN163L, either through immediate inhibition of telomerase activity or through eventual telomere shortening and dysfunction, may enhance radiation sensitivity. Our goal was to test whether the treatment with GRN163L enhances sensitivity to irradiation (IR) in MDA-MB-231 breast cancer cells.<br><br>METHODS AND MATERIALS: The MDA-MB-231 breast cancer cells were treated with or without GRN163L for 2-42 days. Inhibition of telomerase activity and shortening of telomeres were confirmed. Cells were then irradiated and clonogenic assays were performed to show cell survival differences. In vivo studies using MDA-MB-231 xenografts were performed to corroborate the in vitro results.<br><br>RESULTS: We show that cells with shortened telomeres due to GRN163L enhance the effect on IR reducing survival by an additional 30% (p < 0.01). These results are confirmed in vivo, with a significant decrease in tumor growth in mice exposed to GRN163L.<br><br>CONCLUSIONS: We found that GRN163L is a promising adjuvant treatment in combination with radiation therapy that may improve the therapeutic index by enhancing the radiation sensitivity. These studies prompt further investigation as to whether this combination can be applied to other cancers and the clinic.},
}
@article {pmid17172463,
year = {2007},
author = {Chabchoub, E and Rodríguez, L and Galán, E and Mansilla, E and Martínez-Fernandez, ML and Martínez-Frías, ML and Fryns, JP and Vermeesch, JR},
title = {Molecular characterisation of a mosaicism with a complex chromosome rearrangement: evidence for coincident chromosome healing by telomere capture and neo-telomere formation.},
journal = {Journal of medical genetics},
volume = {44},
number = {4},
pages = {250-256},
pmid = {17172463},
issn = {1468-6244},
mesh = {Abnormalities, Multiple/embryology/*genetics ; Adolescent ; Adult ; Chromatids/genetics/ultrastructure ; Chromosome Banding ; *Chromosome Breakage ; *Chromosome Deletion ; Chromosome Disorders/embryology/*genetics ; *Chromosome Inversion ; Chromosomes, Human, Pair 5/genetics/*ultrastructure ; Chromosomes, Human, Pair 9/genetics/*ultrastructure ; Female ; Gene Duplication ; Humans ; In Situ Hybridization, Fluorescence ; Infant, Newborn ; Intellectual Disability/embryology/*genetics ; Karyotyping ; Male ; Microsatellite Repeats ; *Mosaicism ; Nucleic Acid Hybridization ; Telomere/*physiology ; *Translocation, Genetic ; },
abstract = {BACKGROUND: Broken chromosomes must acquire new telomeric "caps" to be structurally stable. Chromosome healing can be mediated either by telomerase through neo-telomere synthesis or by telomere capture.<br><br>AIM: To unravel the mechanism(s) generating complex chromosomal mosaicisms and healing broken chromosomes.<br><br>METHODS: G banding, array comparative genomic hybridization (aCGH), fluorescence in-situ hybridisation (FISH) and short tandem repeat analysis (STR) was performed on a girl presenting with mental retardation, facial dysmorphism, urogenital malformations and limb anomalies carrying a complex chromosomal mosaicism.<br><br>RESULTS &amp; DISCUSSION: The karyotype showed a de novo chromosome rearrangement with two cell lines: one cell line with a deletion 9pter and one cell line carrying an inverted duplication 9p and a non-reciprocal translocation 5pter fragment. aCGH, FISH and STR analysis enabled the deduction of the most likely sequence of events generating this complex mosaic. During embryogenesis, a double-strand break occurred on the paternal chromosome 9. Following mitotic separation of both broken sister chromatids, one acquired a telomere vianeo-telomere formation, while the other generated a dicentric chromosome which underwent breakage during anaphase, giving rise to the del inv dup(9) that was subsequently healed by chromosome 5 telomere capture.<br><br>CONCLUSION: Broken chromosomes can coincidently be rescued by both telomere capture and neo-telomere synthesis.},
}
@article {pmid17169165,
year = {2007},
author = {Squina, FM and Pedrosa, AL and Nunes, VS and Cruz, AK and Tosi, LR},
title = {Shuttle mutagenesis and targeted disruption of a telomere-located essential gene of Leishmania.},
journal = {Parasitology},
volume = {134},
number = {Pt 4},
pages = {511-522},
doi = {10.1017/S0031182006001892},
pmid = {17169165},
issn = {0031-1820},
mesh = {Animals ; Cell Line ; Gene Expression Regulation ; Genes, Essential/genetics ; Leishmania major/*genetics ; Mutagenesis/*genetics ; Mutation/*genetics ; Protozoan Proteins/genetics/metabolism ; RNA Polymerase III/*genetics/metabolism ; Telomere/*genetics ; },
abstract = {Leishmania mutants have contributed greatly to extend our knowledge of this parasite's biology. Here we report the use of the mariner in vitro transposition system as a source of reagents for shuttle mutagenesis and targeted disruption of Leishmania genes. The locus-specific integration was achieved by the disruption of the subtelomeric gene encoding a DNA-directed RNA polymerase III subunit (RPC2). Further inactivation of RPC2 alleles required the complementation of the intact gene, which was transfected in an episomal context. However, attempts to generate a RPC2 chromosomal null mutant resulted in genomic rearrangements that maintained copies of the intact locus in the genome. The maintenance of the RPC2 chromosomal locus in complemented mutants was not mediated by an increase in the number of copies and did not involve chromosomal translocations, which are the typical characteristics of the genomic plasticity of this parasite. Unlike the endogenous locus, the selectable marker used to disrupt RPC2 did not display a tendency to remain in its chromosomal location but was targeted into supernumerary episomal molecules.},
}
@article {pmid17164914,
year = {2007},
author = {Hutchinson, I and Stevens, MF},
title = {Synthetic strategies to a telomere-targeted pentacyclic heteroaromatic salt.},
journal = {Organic &amp; biomolecular chemistry},
volume = {5},
number = {1},
pages = {114-120},
doi = {10.1039/b613580n},
pmid = {17164914},
issn = {1477-0520},
mesh = {Acridines/*chemical synthesis/chemistry/pharmacology ; Molecular Structure ; Telomerase/antagonists &amp; inhibitors ; Telomere/*drug effects ; },
abstract = {Three routes have been explored to synthesise the telomere-targeted agent 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate . Application of a 6-(2-azidophenyl)phenanthridine precursor gave an entry to the indazolo[2,3-f]phenanthridine ring system not the required quino[4,3,2-kl]acridine. A six step synthesis starting from 2,6-dibromo-4-methylbenzonitrile via a 1-arylacridin-9(10H)-one intermediate, or , gave the required in low overall yield (<10%). The most efficient route entailed the one-pot (five step) conversion of 1,2-dimethyl-6-fluoroquinolinium methosulfate to in 33% yield employing triethylamine as base and nitrobenzene as solvent.},
}
@article {pmid17160000,
year = {2007},
author = {Dreesen, O and Li, B and Cross, GA},
title = {Telomere structure and function in trypanosomes: a proposal.},
journal = {Nature reviews. Microbiology},
volume = {5},
number = {1},
pages = {70-75},
doi = {10.1038/nrmicro1577},
pmid = {17160000},
issn = {1740-1534},
mesh = {Animals ; Antigenic Variation/*genetics ; Antigens, Protozoan/genetics/immunology ; Chromosome Segregation ; Gene Expression Regulation ; Protozoan Proteins/chemistry/metabolism ; Telomere/chemistry/genetics/*physiology/ultrastructure ; Telomere-Binding Proteins/chemistry/metabolism ; Trypanosoma brucei brucei/*genetics/immunology/physiology ; Variant Surface Glycoproteins, Trypanosoma/genetics/immunology ; },
abstract = {Telomeres are specialized DNA-protein complexes that stabilize chromosome ends, protecting them from nucleolytic degradation and illegitimate recombination. Telomeres form a heterochromatic structure that can suppress the transcription of adjacent genes. These structures might have additional roles in Trypanosoma brucei, as the major surface antigens of this parasite are expressed during its infectious stages from subtelomeric loci. We propose that the telomere protein complexes of trypanosomes and vertebrates are conserved and offer the hypothesis that growth and breakage of telomeric repeats has an important role in regulating parasite antigenic variation in trypanosomes.},
}
@article {pmid17158924,
year = {2007},
author = {Jacob, NK and Lescasse, R and Linger, BR and Price, CM},
title = {Tetrahymena POT1a regulates telomere length and prevents activation of a cell cycle checkpoint.},
journal = {Molecular and cellular biology},
volume = {27},
number = {5},
pages = {1592-1601},
pmid = {17158924},
issn = {0270-7306},
support = {R01 GM041803/GM/NIGMS NIH HHS/United States ; T32 CA117846/CA/NCI NIH HHS/United States ; GM041803/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; Animals ; Caffeine/pharmacology ; Cell Cycle ; Cell Line ; Chromatin Immunoprecipitation ; Genes, Essential ; Genes, Protozoan ; Genes, cdc ; Protozoan Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; Tetrahymena/*genetics/growth &amp; development ; },
abstract = {The POT1/TEBP telomere proteins are a group of single-stranded DNA (ssDNA)-binding proteins that have long been assumed to protect the G overhang on the telomeric 3' strand. We have found that the Tetrahymena thermophila genome contains two POT1 gene homologs, POT1a and POT1b. The POT1a gene is essential, but POT1b is not. We have generated a conditional POT1a cell line and shown that POT1a depletion results in a monster cell phenotype and growth arrest. However, G-overhang structure is essentially unchanged, indicating that POT1a is not required for overhang protection. In contrast, POT1a is required for telomere length regulation. After POT1a depletion, most telomeres elongate by 400 to 500 bp, but some increase by up to 10 kb. This elongation occurs in the absence of further cell division. The growth arrest caused by POT1a depletion can be reversed by reexpression of POT1a or addition of caffeine. Thus, POT1a is required to prevent a cell cycle checkpoint that is most likely mediated by ATM or ATR (ATM and ATR are protein kinases of the PI-3 protein kinase-like family). Our findings indicate that the essential function of POT1a is to prevent a catastrophic DNA damage response. This response may be activated when nontelomeric ssDNA-binding proteins bind and protect the G overhang.},
}
@article {pmid17158742,
year = {2006},
author = {Dimitrova, N and de Lange, T},
title = {MDC1 accelerates nonhomologous end-joining of dysfunctional telomeres.},
journal = {Genes &amp; development},
volume = {20},
number = {23},
pages = {3238-3243},
pmid = {17158742},
issn = {0890-9369},
support = {AG16642/AG/NIA NIH HHS/United States ; R01 GM049046/GM/NIGMS NIH HHS/United States ; R56 AG016642/AG/NIA NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing ; Animals ; Base Sequence ; Cell Cycle ; Cell Cycle Proteins ; DNA Damage ; DNA Primers ; DNA Repair ; DNA-Binding Proteins/deficiency/genetics/physiology ; Humans ; In Situ Hybridization, Fluorescence ; Intracellular Signaling Peptides and Proteins/deficiency/genetics/*physiology ; Mice ; Nuclear Proteins/deficiency/genetics/*physiology ; Phosphorylation ; Signal Transduction/genetics ; TATA Box Binding Protein-Like Proteins/deficiency ; Telomere/*physiology ; Telomeric Repeat Binding Protein 2/deficiency ; Trans-Activators/deficiency/genetics/*physiology ; },
abstract = {Here we document the role of MDC1 (mediator of DNA damage checkpoint 1) in the detection and repair of human and mouse telomeres rendered dysfunctional through inhibition of TRF2. Consistent with its role in promoting DNA damage foci, MDC1 knockdown affected the formation of telomere dysfunction-induced foci (TIFs), diminishing the accumulation of phosphorylated ATM, 53BP1, Nbs1, and to a lesser extent, gamma-H2AX. In addition to this effect on TIFs, the rate of nonhomologous end-joining (NHEJ) of dysfunctional telomeres was significantly decreased when MDC1 itself or its recruitment to chromatin was inhibited. MDC1 appeared to promote a step in the NHEJ pathway after the removal of the 3' telomeric overhang. The acceleration of NHEJ was unlikely to be due to increased presence of 53BP1 and Mre11 in TIFs, since knockdown of neither factor affected telomere fusions. Furthermore, relevant cell cycle effectors (Chk2, p53, and p21) of the ATM kinase pathway were unaffected and there was no change in the rate of cell cycle progression. We propose that the binding of MDC1 to gamma-H2AX directly affects NHEJ in a manner that is independent of the ATM-dependent cell cycle arrest pathway.},
}
@article {pmid17156085,
year = {2007},
author = {Baerlocher, GM and Rice, K and Vulto, I and Lansdorp, PM},
title = {Longitudinal data on telomere length in leukocytes from newborn baboons support a marked drop in stem cell turnover around 1 year of age.},
journal = {Aging cell},
volume = {6},
number = {1},
pages = {121-123},
doi = {10.1111/j.1474-9726.2006.00254.x},
pmid = {17156085},
issn = {1474-9718},
support = {AI29524/AI/NIAID NIH HHS/United States ; },
mesh = {Aging/*physiology ; Animals ; Animals, Newborn ; Cell Division/physiology ; Cell Proliferation ; Cellular Senescence/*physiology ; Granulocytes/physiology ; Hematopoietic Stem Cells/*physiology ; Leukocytes/*physiology ; Longitudinal Studies ; Lymphocytes/physiology ; Papio/*physiology ; Telomere/*physiology ; },
abstract = {Stem cells of various tissues are typically defined as multipotent cells with 'self-renewal' properties. Despite the increasing interest in stem cells, surprisingly little is known about the number of times stem cells can or do divide over a lifetime. Based on telomere-length measurements of hematopoietic cells, we previously proposed that the self-renewal capacity of hematopoietic stem cells is limited by progressive telomere attrition and that such cells divide very rapidly during the first year of life. Recent studies of patients with aplastic anemia resulting from inherited mutations in telomerase genes support the notion that the replicative potential of hematopoietic stem cells is directly related to telomere length, which is indirectly related to telomerase levels. To revisit conclusions about stem cell turnover based on cross-sectional studies of telomere length, we performed a longitudinal study of telomere length in leukocytes from newborn baboons. All four individual animals studied showed a rapid decline in telomere length (approximately 2-3 kb) in granulocytes and lymphocytes in the first year after birth. After 50-70 weeks the telomere length appeared to stabilize in all cell types. These observations suggest that hematopoietic stem cells, after an initial phase of rapid expansion, switch at around 1 year of age to a different functional mode characterized by a markedly decreased turnover rate.},
}
@article {pmid17156082,
year = {2007},
author = {Adams, J and Martin-Ruiz, C and Pearce, MS and White, M and Parker, L and von Zglinicki, T},
title = {No association between socio-economic status and white blood cell telomere length.},
journal = {Aging cell},
volume = {6},
number = {1},
pages = {125-128},
doi = {10.1111/j.1474-9726.2006.00258.x},
pmid = {17156082},
issn = {1474-9718},
support = {G0601333/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aging/*genetics ; Aging, Premature/*genetics ; Causality ; Cellular Senescence/*genetics ; Child ; Child, Preschool ; Cohort Studies ; Humans ; Infant ; Infant, Newborn ; *Leukocytes ; Life Style ; Middle Aged ; *Population Dynamics ; Sex Factors ; *Social Class ; Telomere/*physiology ; },
abstract = {It has been hypothesized that more socio-economically deprived individuals age faster and, thus, have shorter telomeres than their more affluent counterparts. A weak association between white blood cell telomere length and socio-economic status in a large heterogeneous sample of females has recently been reported. In 318 individuals from a homogeneous birth cohort, we found no evidence of an association between any measure of socio-economic status and peripheral blood mononucleocyte telomere length at age 50 after control for lifestyle variables, gender and paternal age at birth. The results of this, and the previous study, suggest that there is little evidence of a strong or consistent correlation between white blood cell telomere length and markers of socio-economic status.},
}
@article {pmid17151233,
year = {2007},
author = {Meyer, DH and Bailis, AM},
title = {Telomere dysfunction drives increased mutation by error-prone polymerases Rev1 and zeta in Saccharomyces cerevisiae.},
journal = {Genetics},
volume = {175},
number = {3},
pages = {1533-1537},
pmid = {17151233},
issn = {0016-6731},
support = {R01 GM057484/GM/NIGMS NIH HHS/United States ; GM057484/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Transport Systems, Basic/*genetics ; Cell Division/*genetics ; Gene Rearrangement/genetics ; Mutagenesis ; Nucleotidyltransferases/*genetics ; Point Mutation/*genetics ; Saccharomyces cerevisiae/cytology/*genetics ; Saccharomyces cerevisiae Proteins/*genetics ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {Using a model system, we have shown that replicative senescence is accompanied by a 16-fold increase in base substitution and frameshift mutations near a chromosome end. The increase was dependent on error-prone polymerases required for the mutagenic response to DNA lesions that block the replication fork.},
}
@article {pmid17150944,
year = {2006},
author = {Inoue, M and Miyoshi, D and Sugimoto, N},
title = {Development of molecular logic gates using the structural switch of telomere DNAs.},
journal = {Nucleic acids symposium series (2004)},
volume = {},
number = {50},
pages = {315-316},
doi = {10.1093/nass/nrl157},
pmid = {17150944},
issn = {1746-8272},
mesh = {Cations, Monovalent/chemistry ; Circular Dichroism ; DNA/*chemistry ; Fluorescent Dyes ; G-Quadruplexes ; GC Rich Sequence ; Hydrogen-Ion Concentration ; Nucleic Acid Conformation ; Spectrometry, Fluorescence ; Telomere/*chemistry ; },
abstract = {Telomere DNAs consisting of double-stranded G-rich and C-rich sequences are particularly promising as scaffolds for molecular devices because they form high-ordered structures and have a highly polymorphic nature depending on surrounding factors. Based on the structural polymorphism of telomere DNAs, excellent molecular devices such as molecular motors and switches have been reported. Here we found that the dynamic structural conversion of telomere DNAs can be controlled by both monovalent cations (M(+)) and pH (H(+)). Based on this conversion, we propose a new concept of molecular logic gates in response to the surrounding conditions (M(+) and H(+)) with fluorescence intensity changes as the output signal.},
}
@article {pmid17150922,
year = {2006},
author = {Yamaguchi, T and Liu, X and Ogawara, T and Inomata, M and Saneyoshi, M},
title = {Telomerase inhibition by 3'-azido-2', 3'-dideoxynucleoside 5'-triphosphates and telomere shortening in human cultured cells by the corresponding nucleosides.},
journal = {Nucleic acids symposium series (2004)},
volume = {},
number = {50},
pages = {271-272},
doi = {10.1093/nass/nrl135},
pmid = {17150922},
issn = {1746-8272},
mesh = {Antineoplastic Agents/chemistry/*pharmacology ; Azides/chemistry/pharmacology ; Deoxyribonucleotides/chemistry/*pharmacology ; Dideoxynucleosides/chemistry/*pharmacology ; Enzyme Inhibitors/chemistry/pharmacology ; HL-60 Cells ; Humans ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects ; },
abstract = {Telomerase is believed to be a good target for the development of antitumor agents. In this study, 3'-azido-2',3'-dideoxy-2-aminoadenosine (AZddAA), 3'-azido-2',3'-dideoxyadenosine (AZddA), 9-(3-azido-2,3-dideoxy-beta-D-ribofuranosyl)-2-aminopurine (AZddAP), 3'-azido-2-chloro-2',3'-dideoxyadenosine (AZddClA) and their triphosphate derivatives were synthesized. Telomerase assay studies showed that the 2-amino group plays an important role in the inhibitory activity of these compounds. In addition, AZddAA was found to cause telomere shortening in of HL60 cells in culture.},
}
@article {pmid17150809,
year = {2006},
author = {Matsugami, A and Tsuchibayashi, H and Xu, Y and Noguchi, Y and Sugiyama, H and Katahira, M},
title = {The new models of the human telomere DNA in K+ solution revealed by NMR analysis assisted by the incorporation of 8-bromoguanines.},
journal = {Nucleic acids symposium series (2004)},
volume = {},
number = {50},
pages = {45-46},
doi = {10.1093/nass/nrl023},
pmid = {17150809},
issn = {1746-8272},
mesh = {DNA/*chemistry ; G-Quadruplexes ; Guanine/*analogs &amp; derivatives/chemistry ; Humans ; *Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Nucleic Acid Conformation ; Oligodeoxyribonucleotides/chemistry ; Potassium/*chemistry ; Solutions ; Telomere/*chemistry ; },
abstract = {The structure of human telomeric DNA has been controversial: the solution structure in the presence of Na(+) has been reported to be antiparallel basket-type quadruplex by NMR, while the crystal structure in the presence of K(+) has been reported to be parallel propeller-type quadruplex. The solution structure in the presence of K(+) has drawn intense interest, as the intracellular K(+) concentration is higher than that of Na(+), but the structure is still open to address. Recently Sugiyama et al. has suggested that the DNA exists as a mixture of mixed-parallel/antiparallel quadruplex and antiparallel chair-type quadruplex on the basis of the combination of a series of 8-bromoguanine mutations and CD analysis. Here, we have started NMR analysis of the DNAs with the mutations to evaluate the proposed model. So far, NMR analysis is qualitatively consistent with the proposal. The structure determination is in progress to evaluate the model at atomic resolution.},
}
@article {pmid17150747,
year = {2005},
author = {Yamaguchi, T and Kazama, K and Takashima, J and Ogawara, T and Iyono, S and Inomata, M and Saneyoshi, M},
title = {Influence of long-term treatment with cytosine arabinoside on telomere length in human HL60 cells.},
journal = {Nucleic acids symposium series (2004)},
volume = {},
number = {49},
pages = {289-290},
doi = {10.1093/nass/49.1.289},
pmid = {17150747},
issn = {1746-8272},
mesh = {Antimetabolites, Antineoplastic/administration &amp; dosage/*pharmacology ; Cell Proliferation/drug effects ; Cytarabine/administration &amp; dosage/*pharmacology ; Dideoxynucleosides/pharmacology ; HL-60 Cells ; Humans ; Telomere/chemistry/*metabolism ; },
abstract = {Immortal tumor cells employ a telomere length maintenance mechanism to escape the normal limits on proliferation. We investigated whether treatment with cytosine arabinoside (AraC), whose triphosphate derivative AraCTP might partially inhibit the synthesis of C-rich telomere strands, is effective for inducing telomere shortening in human HL60 cells. Long-term treatment with 0.01 microM AraC was found to cause significant telomere lengthening, but had no marked effects on cell population doubling rates or morphology.},
}
@article {pmid17150724,
year = {2005},
author = {Inoue, M and Miyoshi, D and Sugimoto, N},
title = {Structural switch of telomere DNA by pH and monovalent cation.},
journal = {Nucleic acids symposium series (2004)},
volume = {},
number = {49},
pages = {243-244},
doi = {10.1093/nass/49.1.243},
pmid = {17150724},
issn = {1746-8272},
mesh = {Cations, Monovalent/chemistry ; Circular Dichroism ; DNA/*chemistry ; G-Quadruplexes ; Hydrogen-Ion Concentration ; Nucleic Acid Conformation ; Telomere/*chemistry ; Thermodynamics ; },
abstract = {Because of the importance of telomere DNAs, the structures of these DNAs in vivo and in vitro are currently of great research interest in the medical, pharmaceutical, chemical, and industrial fields. In this study, we investigated the structure and thermodynamic properties of the telomere DNAs in the presence of monovalent cations, K+ or Na+. The results demonstrate that the duplex-quadruplex conversion of the 1:1 mixture of telomere G-rich and C-rich sequences can be induced depending on cation species and its concentration. Furthermore, slightly acidic condition stabilizes the i-motif and forces the mixture to dissociate. These results suggest that the structure and stability of telomere DNAs can be controlled by monovalent cation and pH.},
}
@article {pmid17150541,
year = {2004},
author = {Yamaguchi, T and Takahashi, H and Harada, Y and Yoshikawa, M and Iyono, S and Inomata, M and Maruyama, T and Saneyoshi, M},
title = {Telomere shortening in human HL60 cells by treatment with deoxyguanosine analogs.},
journal = {Nucleic acids symposium series (2004)},
volume = {},
number = {48},
pages = {187-188},
doi = {10.1093/nass/48.1.187},
pmid = {17150541},
issn = {1746-8272},
mesh = {Cell Division/drug effects ; Deoxyguanosine/analogs &amp; derivatives/chemistry/*pharmacology ; HL-60 Cells ; Humans ; Telomere/*metabolism ; },
abstract = {Telomerase is a cellular endogenous reverse transcriptase thought to play an important role in the maintenance of telomere length. We investigated the effects of 3'-azido-2',3'-dideoxyguanosine (AZddG) and carbocyclic oxetanocin G (C.OXT-G), of which the triphosphate derivatives AZddGTP and C.OXT-GTP show potent telomerase inhibition, on telomere length of human HL60 cells in culture. Although AZddG caused more significant telomere shortening than C.OXT-G, only a slight decrease of cell growth rate was observed.},
}
@article {pmid17148169,
year = {2005},
author = {Haussmann, MF and Winkler, DW and Vleck, CM},
title = {Longer telomeres associated with higher survival in birds.},
journal = {Biology letters},
volume = {1},
number = {2},
pages = {212-214},
pmid = {17148169},
issn = {1744-9561},
support = {R03 AG022207/AG/NIA NIH HHS/United States ; R03-AG022207/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Female ; Longevity/*physiology ; Swallows/*physiology ; Telomere/*physiology ; },
abstract = {Differences in individual quality and survival within species are a major focus in evolutionary ecology, but we know very little about the underlying physiological mechanisms that determine these differences. Telomere shortening associated with cellular senescence and ageing may be one such mechanism. To date, however, there is little evidence linking telomere length and survival. Here, we show that tree swallows (Tachycineta bicolor) with relatively short telomeres at the age of 1 year have lower survival than tree swallows of the same age with relatively long telomeres. The survival advantage in the long telomere group continues for at least three breeding seasons. It will be important to identify mechanisms that link telomere length with survival early in life.},
}
@article {pmid17146454,
year = {2006},
author = {Lundblad, V},
title = {Telomeres in the '80s: a few recollections.},
journal = {Nature structural &amp; molecular biology},
volume = {13},
number = {12},
pages = {1036-1038},
doi = {10.1038/nsmb1206-1036},
pmid = {17146454},
issn = {1545-9993},
mesh = {Animals ; Awards and Prizes ; Cell Proliferation ; Humans ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Elizabeth Blackburn, Carol Greider and Jack Szostak were recently recognized with the Lasker award for their work on telomerase and the role of this enzyme in cellular proliferation. Vicki Lundblad reflects on the excitement as these experiments were unfolding.},
}
@article {pmid17145779,
year = {2007},
author = {Maser, RS and Wong, KK and Sahin, E and Xia, H and Naylor, M and Hedberg, HM and Artandi, SE and DePinho, RA},
title = {DNA-dependent protein kinase catalytic subunit is not required for dysfunctional telomere fusion and checkpoint response in the telomerase-deficient mouse.},
journal = {Molecular and cellular biology},
volume = {27},
number = {6},
pages = {2253-2265},
pmid = {17145779},
issn = {0270-7306},
support = {U01CA84313/CA/NCI NIH HHS/United States ; U01 CA084313/CA/NCI NIH HHS/United States ; P01 CA095616/CA/NCI NIH HHS/United States ; P01CA95616/CA/NCI NIH HHS/United States ; R01 CA084628/CA/NCI NIH HHS/United States ; K08AG 2400401/AG/NIA NIH HHS/United States ; R01CA84628/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Bone Marrow Cells/metabolism ; Catalytic Domain ; *Cell Cycle ; Chromosomes/genetics ; DNA Ligase ATP ; DNA Ligases/genetics ; DNA-Activated Protein Kinase/genetics/*metabolism ; Genomic Instability/genetics ; Male ; Mice ; Mice, Knockout ; Mutation/genetics ; Protein Binding ; Telomerase/*deficiency/genetics/*metabolism ; Telomere/*metabolism ; Testis/cytology/metabolism ; },
abstract = {Telomeres are key structural elements for the protection and maintenance of linear chromosomes, and they function to prevent recognition of chromosomal ends as DNA double-stranded breaks. Loss of telomere capping function brought about by telomerase deficiency and gradual erosion of telomere ends or by experimental disruption of higher-order telomere structure culminates in the fusion of defective telomeres and/or the activation of DNA damage checkpoints. Previous work has implicated the nonhomologous end-joining (NHEJ) DNA repair pathway as a critical mediator of these biological processes. Here, employing the telomerase-deficient mouse model, we tested whether the NHEJ component DNA-dependent protein kinase catalytic subunit (DNA-PKcs) was required for fusion of eroded/dysfunctional telomere ends and the telomere checkpoint responses. In late-generation mTerc(-/-) DNA-PKcs(-/-) cells and tissues, chromosomal end-to-end fusions and anaphase bridges were readily evident. Notably, nullizygosity for DNA Ligase4 (Lig4)--an additional crucial NHEJ component--was also permissive for chromosome fusions in mTerc(-/-) cells, indicating that, in contrast to results seen with experimental disruption of telomere structure, telomere dysfunction in the context of gradual telomere erosion can engage additional DNA repair pathways. Furthermore, we found that DNA-PKcs deficiency does not reduce apoptosis, tissue atrophy, or p53 activation in late-generation mTerc(-/-) tissues but rather moderately exacerbates germ cell apoptosis and testicular degeneration. Thus, our studies indicate that the NHEJ components, DNA-PKcs and Lig4, are not required for fusion of critically shortened telomeric ends and that DNA-PKcs is not required for sensing and executing the telomere checkpoint response, findings consistent with the consensus view of the limited role of DNA-PKcs in DNA damage signaling in general.},
}
@article {pmid17143283,
year = {2007},
author = {Choudhury, AR and Ju, Z and Djojosubroto, MW and Schienke, A and Lechel, A and Schaetzlein, S and Jiang, H and Stepczynska, A and Wang, C and Buer, J and Lee, HW and von Zglinicki, T and Ganser, A and Schirmacher, P and Nakauchi, H and Rudolph, KL},
title = {Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation.},
journal = {Nature genetics},
volume = {39},
number = {1},
pages = {99-105},
doi = {10.1038/ng1937},
pmid = {17143283},
issn = {1061-4036},
mesh = {Animals ; Cells, Cultured ; Crosses, Genetic ; Cyclin-Dependent Kinase Inhibitor p21/*genetics ; Disease Progression ; *Gene Deletion ; Intestines/cytology ; Longevity/*genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neoplasms/*genetics/pathology ; Stem Cells/*physiology ; Telomerase/genetics ; Telomere/*physiology ; },
abstract = {Telomere shortening limits the proliferative lifespan of human cells by activation of DNA damage pathways, including upregulation of the cell cycle inhibitor p21 (encoded by Cdkn1a, also known as Cip1 and Waf1)) (refs. 1-5). Telomere shortening in response to mutation of the gene encoding telomerase is associated with impaired organ maintenance and shortened lifespan in humans and in mice. The in vivo function of p21 in the context of telomere dysfunction is unknown. Here we show that deletion of p21 prolongs the lifespan of telomerase-deficient mice with dysfunctional telomeres. p21 deletion improved hematolymphopoiesis and the maintenance of intestinal epithelia without rescuing telomere function. Moreover, deletion of p21 rescued proliferation of intestinal progenitor cells and improved the repopulation capacity and self-renewal of hematopoietic stem cells from mice with dysfunctional telomeres. In these mice, apoptotic responses remained intact, and p21 deletion did not accelerate chromosomal instability or cancer formation. This study provides experimental evidence that telomere dysfunction induces p21-dependent checkpoints in vivo that can limit longevity at the organismal level.},
}
@article {pmid17134737,
year = {2007},
author = {Perrem, K and Lynch, A and Conneely, M and Wahlberg, H and Murphy, G and Leader, M and Kay, E},
title = {The higher incidence of squamous cell carcinoma in renal transplant recipients is associated with increased telomere lengths.},
journal = {Human pathology},
volume = {38},
number = {2},
pages = {351-358},
doi = {10.1016/j.humpath.2006.08.019},
pmid = {17134737},
issn = {0046-8177},
mesh = {Base Sequence ; Bowen's Disease/enzymology/*etiology/genetics ; Carcinoma, Squamous Cell/enzymology/*etiology/genetics ; Cell Line ; HeLa Cells ; Humans ; Immunocompromised Host ; Immunohistochemistry ; In Situ Hybridization, Fluorescence/methods ; Kidney Transplantation/*adverse effects/statistics &amp; numerical data ; Skin Neoplasms/enzymology/*etiology/genetics ; Telomerase/biosynthesis ; Telomere/*genetics ; },
abstract = {The incidence and aggressiveness of nonmelanoma skin cancers, including basal cell carcinoma and squamous cell carcinoma (SCC), in immunocompromised renal transplant recipients (RTRs) is dramatically higher (up to 100-fold) compared with the normal population. SCC lesions are also predominant in RTRs, in contrast to the normal population where basal cell carcinoma is more common. The mechanisms underlying this phenomenon are unknown, but effective treatments for these skin tumors would have a significant impact upon morbidity in this group of patients. The fundamental role of telomeres and telomerase in the development of most human cancers, including melanoma, is well established, but very few reports have assessed their function during the onset of nonmelanoma skin cancer. To assess whether telomere maintenance plays any role in the increased incidence of SCC in renal transplant patients, we analyzed both the telomere lengths and telomerase expression levels in 44 SCCs and 22 Bowen's disease (BD) samples (carcinoma in situ) from RTRs and nontransplant patients. Our findings provide statistically significant evidence that the telomeres are consistently longer in both BD RTR and SCC RTR lesions compared with their nontransplant counterparts. We also show by immunohistochemistry that there is a trend toward higher telomerase levels in both the BD RTR and SCC RTR lesions, although this was not statistically significant. Our data thus suggest that telomere lengthening may possibly be an early event in the development of SCC in renal transplant patients and demonstrate that telomere maintenance mechanisms should be further evaluated with respect to developing a future therapeutic strategy for these cancers.},
}
@article {pmid17133364,
year = {2007},
author = {Ohashi, N and Yaar, M and Eller, MS and Truzzi, F and Gilchrest, BA},
title = {Features that determine telomere homolog oligonucleotide-induced therapeutic DNA damage-like responses in cancer cells.},
journal = {Journal of cellular physiology},
volume = {210},
number = {3},
pages = {582-595},
doi = {10.1002/jcp.20848},
pmid = {17133364},
issn = {0021-9541},
mesh = {Aging/drug effects ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Nucleus/pathology ; Cell Proliferation/drug effects ; Cell Transformation, Neoplastic/drug effects ; DNA Damage/*genetics ; DNA, Neoplasm/drug effects/genetics ; Histones/metabolism ; Humans ; Neoplasms/*drug therapy/genetics/pathology ; Oligonucleotides/chemistry/*genetics/*pharmacology ; Phosphorylation/drug effects ; S Phase/drug effects ; Telomere/*genetics ; },
abstract = {Cancer is the second leading cause of death in the USA, with metastatic disease proving a particular management challenge. Treatment modalities for patients with metastatic disease are limited, and survival beyond 5 years is uncommon. We have reported that an 11-base DNA oligonucleotide 100% homologous to the telomere 3' overhang can induce apoptosis, senescence and/or differentiation of several types of malignant cells in vitro and in vivo, while having minimal effect on normal cells. We now report that 22 oligonucleotides, 9-20 bases in length, with or without a 5' phosphate group and with varying homology (40-100%) to the 3' overhang, inhibit growth and induce apoptosis of human cell lines derived from breast cancers, pancreatic and ovarian carcinomas, and malignant melanoma, lines that lack p53 and/or p16 and harbor a variety of other abnormalities in key regulatory signaling pathways. Cytosine (C) content adversely affected oligonucleotide efficacy, decreasing their effect on cellular apoptosis by > or =80%. These data confirm and expand our earlier work suggesting that such telomere homolog oligonucleotides (T-oligos) target an innate anti-cancer defense system in human cells and may provide an effective treatment for cancers of multiple different cellular origins and genetic profile.},
}
@article {pmid17130244,
year = {2007},
author = {Snow, BE and Mateyak, M and Paderova, J and Wakeham, A and Iorio, C and Zakian, V and Squire, J and Harrington, L},
title = {Murine Pif1 interacts with telomerase and is dispensable for telomere function in vivo.},
journal = {Molecular and cellular biology},
volume = {27},
number = {3},
pages = {1017-1026},
pmid = {17130244},
issn = {0270-7306},
support = {R01 AG024398/AG/NIA NIH HHS/United States ; AG 024398/AG/NIA NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Cell Survival ; Chromosomal Instability ; Chromosomes, Mammalian/metabolism ; Cloning, Molecular ; DNA Helicases/chemistry/deficiency/genetics/*metabolism ; Embryonic Stem Cells/cytology/metabolism ; Gene Expression Profiling ; Gene Expression Regulation, Enzymologic ; Gene Targeting ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Protein Binding ; Protein Structure, Tertiary ; RNA, Messenger/genetics/metabolism ; Saccharomyces cerevisiae ; Sequence Alignment ; Spleen/cytology ; Telomerase/*metabolism ; Telomere/genetics/*metabolism ; Thymus Gland/cytology ; },
abstract = {Pif1 is a 5'-to-3' DNA helicase critical to DNA replication and telomere length maintenance in the budding yeast Saccharomyces cerevisiae. ScPif1 is a negative regulator of telomeric repeat synthesis by telomerase, and recombinant ScPif1 promotes the dissociation of the telomerase RNA template from telomeric DNA in vitro. In order to dissect the role of mPif1 in mammals, we cloned and disrupted the mPif1 gene. In wild-type animals, mPif1 expression was detected only in embryonic and hematopoietic lineages. mPif1(-/-) mice were viable at expected frequencies, displayed no visible abnormalities, and showed no reproducible alteration in telomere length in two different null backgrounds, even after several generations. Spectral karyotyping of mPif1(-/-) fibroblasts and splenocytes revealed no significant change in chromosomal rearrangements. Furthermore, induction of apoptosis or DNA damage revealed no differences in cell viability compared to what was found for wild-type fibroblasts and splenocytes. Despite a novel association of mPif1 with telomerase, mPif1 did not affect the elongation activity of telomerase in vitro. Thus, in contrast to what occurs with ScPif1, murine telomere homeostasis or genetic stability does not depend on mPif1, perhaps due to fundamental differences in the regulation of telomerase and/or telomere length between mice and yeast or due to genetic redundancy with other DNA helicases.},
}
@article {pmid17126422,
year = {2007},
author = {Genest, PA and Borst, P},
title = {Analysis of telomere length variation in Leishmania over time.},
journal = {Molecular and biochemical parasitology},
volume = {151},
number = {2},
pages = {213-215},
doi = {10.1016/j.molbiopara.2006.10.015},
pmid = {17126422},
issn = {0166-6851},
mesh = {Animals ; Antigens, Protozoan/genetics ; Leishmania/*genetics/immunology/metabolism ; Telomerase/metabolism ; Telomere/*ultrastructure ; Time Factors ; },
}
@article {pmid17124009,
year = {2007},
author = {Guillot, PV and Gotherstrom, C and Chan, J and Kurata, H and Fisk, NM},
title = {Human first-trimester fetal MSC express pluripotency markers and grow faster and have longer telomeres than adult MSC.},
journal = {Stem cells (Dayton, Ohio)},
volume = {25},
number = {3},
pages = {646-654},
doi = {10.1634/stemcells.2006-0208},
pmid = {17124009},
issn = {1066-5099},
support = {G0300340/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Cell Culture Techniques/methods ; Cell Division ; Female ; Humans ; Kinetics ; Mesenchymal Stem Cells/*cytology/*physiology ; Pluripotent Stem Cells/*cytology/*physiology ; Pregnancy ; Pregnancy Trimester, First ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*genetics ; Telomere/*physiology ; },
abstract = {The biological properties of stem cells are key to the success of cell therapy, for which MSC are promising candidates. Although most therapeutic applications to date have used adult bone marrow MSC, increasing evidence suggests that MSC from neonatal and mid-gestational fetal tissues are more plastic and grow faster. Fetal stem cells have been isolated earlier in development, from first-trimester blood and hemopoietic organs, raising the question of whether they are biologically closer to embryonic stem cells and thus have advantages over adult bone marrow MSC. In this study, we show that human first-trimester fetal blood, liver, and bone marrow MSC but not adult MSC express the pluripotency stem cell markers Oct-4, Nanog, Rex-1, SSEA-3, SSEA-4, Tra-1-60, and Tra-1-81. In addition, fetal MSC, irrespective of source, had longer telomeres (p < .001), had greater telomerase activity (p < .01), and expressed more human telomerase reverse transcriptase (p < .01). Fetal MSC were also more readily expandable and senesced later in culture than their adult counterparts (p < .01). Compared with adult MSC, first-trimester fetal tissues constitute a source of MSC with characteristics that appear advantageous for cell therapy.},
}
@article {pmid17122447,
year = {2006},
author = {Fuster, JJ and Andrés, V},
title = {Telomere biology and cardiovascular disease.},
journal = {Circulation research},
volume = {99},
number = {11},
pages = {1167-1180},
doi = {10.1161/01.RES.0000251281.00845.18},
pmid = {17122447},
issn = {1524-4571},
mesh = {Aging/physiology ; Animals ; Atherosclerosis/etiology/genetics ; Cardiovascular Diseases/*etiology/*genetics/pathology/physiopathology ; Heart/physiopathology ; Humans ; Myocytes, Cardiac/pathology ; Neovascularization, Pathologic/etiology/genetics ; Neovascularization, Physiologic/genetics/physiology ; Risk Factors ; Telomerase/metabolism ; Telomere/*physiology ; },
abstract = {Accumulation of cellular damage with advancing age leads to atherothrombosis and associated cardiovascular disease. Ageing is also characterized by shortening of the DNA component of telomeres, the specialized genetic segments located at the end of eukaryotic chromosomes that protect them from end-to-end fusions. By inducing genomic instability, replicative senescence and apoptosis, shortening of the telomeric DNA is thought to contribute to organismal ageing. In this Review, we discuss experimental and human studies that have linked telomeres and associated proteins to several factors which influence cardiovascular risk (eg, estrogens, oxidative stress, hypertension, diabetes, and psychological stress), as well as to neovascularization and the pathogenesis of atherosclerosis and heart disease. Two chief questions that remain unanswered are whether telomere shortening is cause or consequence of cardiovascular disease, and whether therapies targeting the telomere may find application in treating these disorders (eg, cell "telomerization" to engineer blood vessels of clinical value for bypass surgery, and to facilitate cell-based myocardial regeneration strategies). Given that most research to date has focused on the role of telomerase, it is also of up most importance to investigate whether alterations in additional telomere-associated proteins may contribute to the pathogenesis of cardiovascular disease.},
}
@article {pmid17120191,
year = {2006},
author = {Genescà, A and Martín, M and Latre, L and Soler, D and Pampalona, J and Tusell, L},
title = {Telomere dysfunction: a new player in radiation sensitivity.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {28},
number = {12},
pages = {1172-1180},
doi = {10.1002/bies.20501},
pmid = {17120191},
issn = {0265-9247},
mesh = {Humans ; Nucleic Acid Conformation ; Radiation Protection ; *Radiation Tolerance ; Telomere/chemistry/*metabolism/*radiation effects ; Telomere-Binding Proteins/metabolism ; },
abstract = {Human individuals often exhibit important differences in their sensitivity to ionising radiation. Extensive literature links radiation sensitivity with impaired DNA repair which is due to a lack of correct functioning in many proteins involved in DNA-repair pathways and/or in DNA-damage checkpoint responses. Given that ionising radiation is an important and widespread diagnostic and therapeutic tool, it is important to investigate further those factors and mechanisms that underlie individual radiosensitivity. Recently, evidence is accumulating that telomere function may well be involved in cellular and organism responses to ionising radiation, broadening still further the currently complex and challenging scenario.},
}
@article {pmid17114192,
year = {2007},
author = {Steer, SE and Williams, FM and Kato, B and Gardner, JP and Norman, PJ and Hall, MA and Kimura, M and Vaughan, R and Aviv, A and Spector, TD},
title = {Reduced telomere length in rheumatoid arthritis is independent of disease activity and duration.},
journal = {Annals of the rheumatic diseases},
volume = {66},
number = {4},
pages = {476-480},
pmid = {17114192},
issn = {0003-4967},
support = {R01 AG020132/AG/NIA NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; AG020132/AG/NIA NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; },
mesh = {Age Factors ; Aged ; Arthritis, Rheumatoid/*genetics ; Case-Control Studies ; Female ; Genetic Predisposition to Disease ; Genotype ; HLA-DR Antigens/genetics ; HLA-DRB1 Chains ; Humans ; Male ; Middle Aged ; Severity of Illness Index ; Sex Factors ; Telomere/*ultrastructure ; Time Factors ; },
abstract = {BACKGROUND: Rheumatoid arthritis (RA) is associated with reduced lifespan and shortened telomere length in lymphocytes, but the mechanism underlying this is unclear. Telomere loss in white blood cells (WBC) is accelerated by oxidative stress and inflammation in vitro. It was postulated that the accelerated WBC telomere shortening in RA occurs as a result of exposure to chronic inflammation.<br><br>OBJECTIVES: To measure telomere terminal restriction fragment (TRF) length in a large cohort of RA cases and healthy controls, to explore associations of TRF length with features of disease and with RA-associated HLA-DRB1 alleles.<br><br>METHODS: WBC and TRF length were measured by Southern blot in DNA from 176 hospital-based RA cases satisfying the 1987 American College of Rheumatology criteria and from 1151 controls. TRF length was compared between cases and controls, and the effects of disease duration, severity and HLA-DRB1 alleles encoding the shared epitope (SE) were assessed.<br><br>RESULTS: Age- and sex-adjusted TRF length was significantly shorter in RA cases compared with controls (p<0.001). There was no association between age- and sex-adjusted TRF length and disease duration, C reactive protein or Larsen score. The presence of one or more SE-encoding alleles was associated with reduced adjusted TRF length in RA cases (SE positive vs SE negative cases, p=0.038), but not in controls.<br><br>CONCLUSION: The reduced TRF length in a large group of patients with RA compared with controls has been shown. The reduction is apparently independent of disease duration and markers of disease severity, but is influenced by HLA-DRB1 genotype.},
}
@article {pmid17110331,
year = {2006},
author = {Verdun, RE and Karlseder, J},
title = {The DNA damage machinery and homologous recombination pathway act consecutively to protect human telomeres.},
journal = {Cell},
volume = {127},
number = {4},
pages = {709-720},
doi = {10.1016/j.cell.2006.09.034},
pmid = {17110331},
issn = {0092-8674},
support = {R01 GM06525/GM/NIGMS NIH HHS/United States ; },
mesh = {Bromodeoxyuridine ; Cells, Cultured ; DNA/biosynthesis ; *DNA Damage ; DNA Repair ; DNA Replication ; Fibroblasts/cytology/metabolism ; HeLa Cells ; Humans ; Models, Biological ; Nucleic Acid Conformation ; Protein Transport ; *Recombination, Genetic ; Telomerase/metabolism ; Telomere/chemistry/*metabolism ; },
abstract = {Telomeres protect chromosome ends from being detected as lesions and from triggering DNA damage checkpoints. Paradoxically, telomere function depends on checkpoint proteins such as ATM and ATR, but a molecular model explaining this seemingly contradictory relationship has been missing so far. Here we show that the DNA damage machinery acts on telomeres in at least two independent steps. First, the ATR-dependent machinery is recruited to telomeres before telomere replication is completed, likely in response to single-stranded DNA resulting from replication fork stalling. Second, after replication, telomeres attract ATM and the homologous recombination (HR) machinery. In vivo and in vitro results suggest that the HR machinery is required for formation of a telomere-specific structure at chromosome ends after replication. Our results suggest that telomere ends need to be recognized as DNA damage to complete end replication and to acquire a structure that is essential for function.},
}
@article {pmid17110277,
year = {2006},
author = {Green, NS and Mayeux, R},
title = {The long and short of it: telomeres and the brain.},
journal = {The Lancet. Neurology},
volume = {5},
number = {12},
pages = {999-1000},
doi = {10.1016/S1474-4422(06)70610-X},
pmid = {17110277},
issn = {1474-4422},
support = {P01 AG07232/AG/NIA NIH HHS/United States ; U01 AG023749/AG/NIA NIH HHS/United States ; },
mesh = {Awards and Prizes ; Biomedical Research ; Brain/*enzymology ; Telomerase/*metabolism ; Telomere/*physiology ; },
}
@article {pmid17109640,
year = {2006},
author = {Yanada, S and Ochi, M and Kojima, K and Sharman, P and Yasunaga, Y and Hiyama, E},
title = {Possibility of selection of chondrogenic progenitor cells by telomere length in FGF-2-expanded mesenchymal stromal cells.},
journal = {Cell proliferation},
volume = {39},
number = {6},
pages = {575-584},
pmid = {17109640},
issn = {0960-7722},
mesh = {Adolescent ; Adult ; Cell Differentiation ; Cell Division/drug effects ; Chondrocytes/*cytology ; Female ; Fibroblast Growth Factor 2/pharmacology ; *Genetic Markers ; Humans ; Male ; Mesenchymal Stem Cells/*cytology ; Middle Aged ; Stromal Cells/*cytology ; Telomerase/metabolism ; Telomere/drug effects/*genetics ; },
abstract = {Telomere length plays an important role in regulating the proliferative capacity of cells, and serves as a marker for cell cycle history and also for their remaining replicative potential. Mesenchymal stromal cells (MSC) are known to be a significant cell source for therapeutic intervention and tissue engineering. To investigate any possible limitations in the replicative potential and chondrogenic differentiation potential of fibroblast growth factor-2-expanded MSCs (FGF(+)MSC), these cells were differentiated at various population doublings (PDs), and telomere length and telomerase activity were measured before and after differentiation. FGF(+)MSC cultured at a relatively low density maintained proliferation capability past more than 80 PD and maintained chondrogenic differentiation potential up to at least 46 PD and long telomeres up to 105 PD, despite expressing low levels of telomerase activity. Interestingly, upon chondrogenic differentiation of these cells, telomeres showed a remarkable reduction in length. This shortening was more extensive when FGF(+)MSC of higher PD levels were differentiated. These findings suggest that telomere length may be a useful genetic marker for chondrogenic progenitor cells.},
}
@article {pmid17108359,
year = {2006},
author = {Tseng, SF and Lin, JJ and Teng, SC},
title = {The telomerase-recruitment domain of the telomere binding protein Cdc13 is regulated by Mec1p/Tel1p-dependent phosphorylation.},
journal = {Nucleic acids research},
volume = {34},
number = {21},
pages = {6327-6336},
pmid = {17108359},
issn = {1362-4962},
mesh = {DNA Polymerase I/metabolism ; Immunoprecipitation ; Intracellular Signaling Peptides and Proteins/*metabolism ; Mutation ; Phenotype ; Phosphorylation ; Protein Serine-Threonine Kinases/*metabolism ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/*enzymology/genetics ; Saccharomyces cerevisiae Proteins/chemistry/genetics/*metabolism ; Serine/metabolism ; Telomerase/*metabolism ; Telomere/chemistry ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {The DNA damage-responsive protein kinases ATM and ATR phosphorylate SQ/TQ motifs that lie in clusters in most of their in vivo targets. Budding yeast Cdc13p contains two clusters of SQ/TQ motifs, suggesting that it might be a target of Mec1p/Tel1p (yeast ATR/ATM). Here we demonstrated that the telomerase recruitment domain of Cdc13p is phosphorylated by Mec1p and Tel1p. Gel analysis showed that Cdc13p contains a Mec1/Tel1-dependent post-translational modification. Using an immunoprecipitate (IP)-kinase assay, we showed that Mec1p phosphorylates Cdc13p on serine 225, 249, 255 and 306, and Tel1p phosphorylates Cdc13p on serine 225, 249 and 255 in vitro. Phenotypic analysis in vivo revealed that the mutations in the Cdc13p SQ motifs phosphorylated by Mec1p and Tel1p caused multiple telomere and growth defects. In addition, normal telomere length and growth could be restored by expressing a Cdc13-Est1p hybrid protein. These results demonstrate the telomerase recruitment domain of Cdc13p as an important new telomere-specific target of Mec1p/Tel1p.},
}
@article {pmid17108106,
year = {2006},
author = {Wen, VW and Wu, K and Baksh, S and Hinshelwood, RA and Lock, RB and Clark, SJ and Moore, MA and Mackenzie, KL},
title = {Telomere-driven karyotypic complexity concurs with p16INK4a inactivation in TP53-competent immortal endothelial cells.},
journal = {Cancer research},
volume = {66},
number = {22},
pages = {10691-10700},
doi = {10.1158/0008-5472.CAN-06-0979},
pmid = {17108106},
issn = {0008-5472},
mesh = {Bone Marrow Cells/cytology ; Chromosome Deletion ; Chromosomes, Human, Pair 17/genetics ; Cyclin-Dependent Kinase Inhibitor p16/*genetics ; DNA Methylation ; Endothelial Cells/cytology/metabolism/*physiology ; Gene Silencing ; *Genes, p53 ; Humans ; Karyotyping ; Phosphorylation ; Retinoblastoma Protein/metabolism ; Telomerase/biosynthesis/genetics ; Telomere/*genetics ; Transduction, Genetic ; },
abstract = {Critically short telomeres promote chromosomal fusions, which in TP53-defective cells initiate the formation of cytogenetic aberrations that are typical of human cancer cells. Expression of the enzyme telomerase stabilizes normal and aberrant chromosomes by maintaining telomere length. However, previous investigations, including our own, have shown that overexpression of telomerase reverse transcriptase (hTERT) does not prevent net telomere shortening in human endothelial cells. In the present study, two mass cultures of hTERT-transduced bone marrow endothelial cells (BMhTERT) and 26 clones were employed to further investigate the immortalization process and consequences of telomere shortening. Eighty-five percent (22 of 26) of the clones and both mass cultures were immortalized. However, cytogenetic analyses revealed recurring cytogenetic aberrations in the mass cultures and 12 representative clones. Several of the recurring aberrations, including +5p, +11, -13, +19, and +20, and nonreciprocal translocations involving 17p and 2p were previously implicated in human carcinogenesis. One mass culture and a subset of clones (5 of 12) had complex karyotypes, characterized by cytogenetic heterogeneity and at least five chromosomal abnormalities. p16(INK4a) was silenced exclusively in the five clones and mass culture with complex karyotypes, whereas the p53/p21(cip1) pathway was defective in only one clone. Telomere dysfunction was implicated in the evolution of complex karyotypes by the presence of anaphase bridges, telomere associations, and dicentric chromosomes. These results show that complex karyotypes can evolve in TP53-competent cells and provide evidence that p16(INK4a) functions as a gatekeeper to prevent telomere-driven cytogenetic evolution. These investigations provide new insight to the role of p16(INK4a) as a tumor suppressor.},
}
@article {pmid17102608,
year = {2006},
author = {Babu, MM and Balaji, S and Iyer, LM and Aravind, L},
title = {Estimating the prevalence and regulatory potential of the telomere looping effect in yeast transcription regulation.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {5},
number = {20},
pages = {2354-2363},
doi = {10.4161/cc.5.20.3386},
pmid = {17102608},
issn = {1551-4005},
support = {MC_U105185859/MRC_/Medical Research Council/United Kingdom ; /ImNIH/Intramural NIH HHS/United States ; },
mesh = {Binding Sites ; Chromatin/metabolism/physiology ; Chromosome Mapping ; DNA/chemistry/metabolism ; *Gene Expression Regulation, Fungal ; Nucleic Acid Conformation ; Prevalence ; Saccharomyces cerevisiae/*genetics ; Telomere/chemistry/metabolism/*physiology ; Transcription Factors/metabolism ; *Transcription, Genetic ; },
abstract = {Telomeres have long been implicated in the regulation of gene expression. Some studies have reported that telomere looping effect (TLE) can juxtapose genes and regulatory sequences that are far apart and facilitate long-distance control of gene expression. In this work, we report a detailed investigation on the prevalence and regulatory potential of TLE on a genomic scale by assembling data on protein-DNA interactions from several large-scale ChIp-chip experiments in Saccharomyces cerevisiae. Analysis of the assembled data revealed that a statistically significant number of DNA segments that were inferred to be bound by ten or more transcription factors in these experiments physically mapped to the ends of several chromosomes (19 of 32 chromosome ends). For the 83 transcription factors that were inferred to interact with these DNA segments, we found a statistically significant skew in the distribution of their internal binding sites over the length of the entire chromosome, such that more than expected binding events occurred proximal to chromosomal ends than elsewhere. Taken together these observations suggest that the telomere looping effect is their most likely explanation and imply that a notable fraction of the internally bound yeast transcription factors potentially interact with looped back telomeres. Further, we also identified several components of the basal transcriptional machinery that are also frequently linked to these chromosome end segments, strengthening the proposal for a direct interaction between the chromosome ends and internally located transcriptional complexes. We observed that certain chromatin factors might participate in the TLE and potentially modulate gene expression by chromatin modifications such as histone deacetylation. Our findings provide the first computational evidence for a significant role of long-range regulatory interactions due to telomere looping. Based on these observations, we also propose that genome-wide chromatin immunoprecipitation data might be useful to systematically uncover long-range chromatin looping effects in gene expression.},
}
@article {pmid17095151,
year = {2007},
author = {Zhang, Y and Zhou, J and Cao, X and Zhang, Q and Lim, CU and Ullrich, RL and Bailey, SM and Liber, HL},
title = {Partial deficiency of DNA-PKcs increases ionizing radiation-induced mutagenesis and telomere instability in human cells.},
journal = {Cancer letters},
volume = {250},
number = {1},
pages = {63-73},
doi = {10.1016/j.canlet.2006.09.021},
pmid = {17095151},
issn = {0304-3835},
support = {CA49696/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line ; DNA-Activated Protein Kinase/*metabolism ; Genomic Instability ; Humans ; Lymphocytes/*enzymology/*radiation effects ; *Mutagenesis ; *Radiation, Ionizing ; Telomere/*physiology ; Transfection ; },
abstract = {The correct repair of DNA double-strand breaks (DSBs) is essential to maintaining the integrity of the genome. Misrepair of DSBs is detrimental to cells and organisms, leading to gene mutation, chromosomal aberration, and cancer development. Nonhomologous end-joining (NHEJ) is one of the principal rejoining processes in most higher eukaryotic cells. NHEJ is facilitated by DNA-dependent protein kinase (DNA-PK), which is composed of a catalytic subunit, DNA-PKcs, and the heterodimeric DNA binding regulatory complex Ku70/86. Null mutation of DNA-PKcs leads to immunodeficiency, chromosomal aberration, gene mutation, telomeric end-capping failure, and cancer predisposition in animals and cells. However, it is unknown whether partial deficiency of DNA-PKcs as might occur in a fraction of the population (e.g., heterozygotes), influences cellular function. Using small interfering RNA (siRNA) transfection, we established partial deficiency of DNA-PKcs in human cells, ranging from 4 to 85% of control levels. Our results reveal for the first time, that partial deficiency of DNA-PKcs leads to increased ionizing radiation (IR)-induced mutagenesis, cell killing, and telomere dysfunction. Radiation mutagenesis was increased inversely with DNA-PKcs protein level, with the most pronounced effect being observed in cells with protein levels below 50% of controls. A small but statistically significant increase in IR-induced cell killing was observed as DNA-PKcs levels decreased, over the entire range of protein levels. Frequencies of IR-induced telomere-DSB fusion was increased at levels of DNA-PKcs as low as approximately 50%, similar to what would be expected in heterozygous individuals. Taken together, our results suggest that even partial deficiency of DNA repair proteins may represent a considerable risk to genomic stability.},
}
@article {pmid17089138,
year = {2007},
author = {Walter, MF and Biessmann, MR and Benitez, C and Török, T and Mason, JM and Biessmann, H},
title = {Effects of telomere length in Drosophila melanogaster on life span, fecundity, and fertility.},
journal = {Chromosoma},
volume = {116},
number = {1},
pages = {41-51},
pmid = {17089138},
issn = {0009-5915},
support = {R01 GM056729/GM/NIGMS NIH HHS/United States ; Z01 ES021054-14//Intramural NIH HHS/United States ; GM-56729/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; Drosophila melanogaster/*physiology ; Female ; Fertility/*genetics ; Longevity/*genetics ; Male ; Mutation ; Ovary/growth &amp; development/pathology ; Retroelements/genetics ; Telomere/*genetics ; },
abstract = {Chromosome length in Drosophila is maintained by targeted transposition of three non-long terminal repeat retrotransposons, HeT-A, TART, and TAHRE, to the chromosome ends. The length and composition of these retrotransposon arrays can vary significantly between chromosome tips and between fly stocks, but the significance and consequences of these length differences are not understood. A dominant genetic factor, Tel, has been described, which causes a severalfold elongation of the retrotransposon arrays at all telomeres. We used this strain to assess possible affects of extended telomeres on the organism. While we found no effect on life span of the adults, we could demonstrate a correlation between long telomeres and reduced fertility and fecundity in individual females, which is also reflected in abnormal oocyte development.},
}
@article {pmid17085717,
year = {2006},
author = {Stark, A and Schultz, D},
title = {Units of analysis in accelerated telomere shortening in glycosylphosphatidylinositol (GPI)-negative compared with GPI-positive granulocytes from patients with paroxysmal nocturnal hemoglobinuria (PNH) detected by proaerolysin flow-FISH.},
journal = {Blood},
volume = {108},
number = {10},
pages = {3620; author reply 3620},
doi = {10.1182/blood-2006-05-023267},
pmid = {17085717},
issn = {0006-4971},
mesh = {Bacterial Toxins ; Case-Control Studies ; *Data Interpretation, Statistical ; Glycosylphosphatidylinositols ; Granulocytes/pathology ; Hemoglobinuria, Paroxysmal/genetics/pathology ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Pore Forming Cytotoxic Proteins ; Telomere/metabolism/*ultrastructure ; },
}
@article {pmid17085644,
year = {2006},
author = {Unryn, BM and Hao, D and Glück, S and Riabowol, KT},
title = {Acceleration of telomere loss by chemotherapy is greater in older patients with locally advanced head and neck cancer.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {12},
number = {21},
pages = {6345-6350},
doi = {10.1158/1078-0432.CCR-06-0486},
pmid = {17085644},
issn = {1078-0432},
mesh = {Adult ; Age Factors ; Aged ; Antineoplastic Agents/therapeutic use ; Cisplatin/therapeutic use ; Female ; Head and Neck Neoplasms/*pathology/*therapy ; Humans ; Male ; Middle Aged ; Neoplasm Staging ; Neoplasms, Squamous Cell/*pathology/*therapy ; Radiotherapy ; Sex Factors ; Telomere/drug effects/*pathology/radiation effects ; },
abstract = {PURPOSE: Chronic viral infection and combinations of chemotherapeutic drugs have been reported to accelerate telomere erosion. Here, we asked if chemoradiotherapy, using the single agent cisplatin, would accelerate telomere loss in head and neck cancer patients, and whether loss was linked to smoking status, age, gender, or stage of disease at diagnosis.<br><br>EXPERIMENTAL DESIGN: Blood samples were collected from 20 patients with squamous cell cancer of the head and neck before, during, and after chemoradiotherapy. Following DNA isolation from peripheral blood mononuclear cells, telomere length was measured by terminal restriction fragment analysis.<br><br>RESULTS: Chemoradiotherapy increased the rate of telomere erosion>100-fold. Telomere length before treatment in chemoradiotherapy patients was similar to age-matched controls. Although smokers began with significantly shorter telomeres, smoking status did not affect chemoradiotherapy-induced attrition, nor did gender or stage of disease. We also make the novel observation that a significantly greater telomere loss occurred in response to treatment in older patients, with those younger than 55 years losing an average of 400 bp of telomeric DNA compared with the 880 bp lost by those over 55 years.<br><br>CONCLUSIONS: The lack of telomere length difference before treatment suggests that shortened telomeres may not be a risk factor for development of head and neck cancer in the age range we examined. Chemoradiotherapy caused a severe telomere length reduction in all patients. The significant difference seen in the elderly (P=0.018) suggests that chemoradiotherapy may have more severe effects on the replicative capacity of blood cells in older patients.},
}
@article {pmid17085598,
year = {2006},
author = {Yu, W and Lamb, JC and Han, F and Birchler, JA},
title = {Telomere-mediated chromosomal truncation in maize.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {103},
number = {46},
pages = {17331-17336},
pmid = {17085598},
issn = {0027-8424},
mesh = {Chromosomes, Plant/*genetics ; Cytosol/metabolism ; *Gene Deletion ; Phenotype ; Plants, Genetically Modified ; Plasmids/genetics ; Rhizobium/genetics ; Telomere/*genetics ; Transformation, Genetic/genetics ; Zea mays/*genetics ; },
abstract = {Direct repeats of Arabidopsis telomeric sequence were constructed to test telomere-mediated chromosomal truncation in maize. Two constructs with 2.6 kb of telomeric sequence were used to transform maize immature embryos by Agrobacterium-mediated transformation. One hundred seventy-six transgenic lines were recovered in which 231 transgene loci were revealed by a FISH analysis. To analyze chromosomal truncations that result in transgenes located near chromosomal termini, Southern hybridization analyses were performed. A pattern of smear in truncated lines was seen as compared with discrete bands for internal integrations, because telomeres in different cells are elongated differently by telomerase. When multiple restriction enzymes were used to map the transgene positions, the size of the smears shifted in accordance with the locations of restriction sites on the construct. This result demonstrated that the transgene was present at the end of the chromosome immediately before the integrated telomere sequence. Direct evidence for chromosomal truncation came from the results of FISH karyotyping, which revealed broken chromosomes with transgene signals at the ends. These results demonstrate that telomere-mediated chromosomal truncation operates in plant species. This technology will be useful for chromosomal engineering in maize as well as other plant species.},
}
@article {pmid17084054,
year = {2006},
author = {Baird, DM},
title = {Telomeres.},
journal = {Experimental gerontology},
volume = {41},
number = {12},
pages = {1223-1227},
doi = {10.1016/j.exger.2006.09.009},
pmid = {17084054},
issn = {0531-5565},
mesh = {Aging/genetics/*physiology ; Bone Density/physiology ; Cellular Senescence/genetics/physiology ; Chromosomal Instability/genetics/physiology ; Genetic Markers/genetics ; Humans ; Leukocytes/physiology ; Mutation/genetics ; Restriction Mapping/methods ; Telomerase/genetics/physiology ; Telomere/genetics/*physiology ; },
abstract = {The role that telomere biology may play in the human ageing process is of a significant interest to many laboratories around the world. In this, the first of a series of yearly reviews on telomeres and ageing, I review a small selection of papers published between July 2005 and June 2006 that maybe of direct relevance to the gerontology research community.},
}
@article {pmid17082188,
year = {2006},
author = {Buczek, P and Horvath, MP},
title = {Structural reorganization and the cooperative binding of single-stranded telomere DNA in Sterkiella nova.},
journal = {The Journal of biological chemistry},
volume = {281},
number = {52},
pages = {40124-40134},
pmid = {17082188},
issn = {0021-9258},
support = {CA92584/CA/NCI NIH HHS/United States ; R01 GM067994-01/GM/NIGMS NIH HHS/United States ; R01 GM067994-03/GM/NIGMS NIH HHS/United States ; P01 CA092584/CA/NCI NIH HHS/United States ; R01 GM067994-02/GM/NIGMS NIH HHS/United States ; 5P30 CA42014/CA/NCI NIH HHS/United States ; R01 GM067994/GM/NIGMS NIH HHS/United States ; P30 CA042014/CA/NCI NIH HHS/United States ; R01 GM067994-04/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Binding Sites/genetics ; Calorimetry ; Crystallography, X-Ray ; DNA/*chemistry/metabolism ; DNA, Protozoan/*chemistry/metabolism ; DNA, Single-Stranded/*chemistry/metabolism ; G-Quadruplexes ; Histones/chemistry/genetics/metabolism ; Nucleic Acid Conformation ; *Oxytricha ; Protein Processing, Post-Translational/genetics ; Telomere/*chemistry/metabolism ; Telomere-Binding Proteins/chemistry/metabolism ; Thermodynamics ; },
abstract = {In Sterkiella nova, alpha and beta telomere proteins bind cooperatively with single-stranded DNA to form a ternary alpha.beta.DNA complex. Association of telomere protein subunits is DNA-dependent, and alpha-beta association enhances DNA affinity. To further understand the molecular basis for binding cooperativity, we characterized several possible stepwise assembly pathways using isothermal titration calorimetry. In one path, alpha and DNA first form a stable alpha.DNA complex followed by the addition of beta in a second step. Binding energy accumulates with nearly equal free energy of association for each of these steps. Heat capacity is nonetheless dramatically different, with DeltaCp = -305 +/- 3 cal mol(-1) K(-1) for alpha binding with DNA and DeltaCp = -2010 +/- 20 cal mol(-1) K(-1) for the addition of beta to complete the alpha.beta.DNA complex. By examining alternate routes including titration of single-stranded DNA with a preformed alpha.beta complex, a significant portion of binding energy and heat capacity could be assigned to structural reorganization involving protein-protein interactions and repositioning of the DNA. Structural reorganization probably affords a mechanism to regulate high affinity binding of telomere single-stranded DNA with important implications for telomere biology. Regulation of telomere complex dissociation is thought to involve post-translational modifications in the lysine-rich C-terminal portion of beta. We observed no difference in binding energetics or crystal structure when comparing complexes prepared with full-length beta or a C-terminally truncated form, supporting interesting parallels between the intrinsically disordered regions of histones and this portion of beta.},
}
@article {pmid17081156,
year = {2006},
author = {Lansdorp, PM},
title = {Stress, social rank and leukocyte telomere length.},
journal = {Aging cell},
volume = {5},
number = {6},
pages = {583-584},
doi = {10.1111/j.1474-9726.2006.00247.x},
pmid = {17081156},
issn = {1474-9718},
mesh = {Aging/*genetics ; Cell Cycle/genetics ; Cell Death/genetics ; Cellular Senescence/*genetics ; *Hierarchy, Social ; Humans ; Polymorphism, Genetic/genetics ; Social Class ; Stem Cells/cytology/physiology ; Stress, Psychological/*genetics ; Telomere/*genetics ; },
abstract = {Blood leukocytes are a heterogeneous mixture of cell types whose telomere lengths differ greatly, reflecting variation in stem cell turnover and recruitment, expansion and replacement of more mature cell types as well as variable telomere loss and telomere repair. These differences in cell and telomere length dynamics, together with the evidence that telomere length is influenced strongly by genetic polymorphisms, greatly complicate the interpretation of claims that socio-economic status modulates the rate of telomere attrition.},
}
@article {pmid17081154,
year = {2006},
author = {Hornsby, PJ},
title = {Short telomeres: cause or consequence of aging?.},
journal = {Aging cell},
volume = {5},
number = {6},
pages = {577-578},
doi = {10.1111/j.1474-9726.2006.00249.x},
pmid = {17081154},
issn = {1474-9718},
mesh = {Aging/*genetics/immunology ; Animals ; Cellular Senescence/*genetics/immunology ; Humans ; Immunity, Innate/*genetics/immunology ; Leukocytes/immunology ; Longevity/*genetics/immunology ; Psychoneuroimmunology/trends ; Social Class ; Stress, Psychological/*genetics/immunology ; Telomere/*genetics/immunology ; },
abstract = {Questions about mechanisms, about the direction of causality, and about cellular heterogeneity complicate interpretation of claims associating short telomeres with adverse health outcomes.},
}
@article {pmid17081153,
year = {2006},
author = {Kuh, D},
title = {A life course perspective on telomere length and social inequalities in aging.},
journal = {Aging cell},
volume = {5},
number = {6},
pages = {579-580},
doi = {10.1111/j.1474-9726.2006.00250.x},
pmid = {17081153},
issn = {1474-9718},
support = {MC_U120063239/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aging/*genetics ; Cellular Senescence/*genetics/immunology ; Hierarchy, Social ; Humans ; Leukocytes/cytology/metabolism ; Longevity/*genetics ; Psychoneuroimmunology ; Social Class ; Stress, Psychological/*genetics/immunology ; Telomere/*genetics ; },
abstract = {Longitudinal studies will be needed to test the idea that social class in adult life, or in childhood, influences the rate of change in telomere length in peripheral blood samples.},
}
@article {pmid17074584,
year = {2006},
author = {Haydeé Cottliar, AS and Noriega, MF and Narbaitz, M and Rodríguez, A and Slavutsky, IR},
title = {Association between telomere length and BCL2 gene rearrangements in low- and high-grade non-Hodgkin lymphomas.},
journal = {Cancer genetics and cytogenetics},
volume = {171},
number = {1},
pages = {1-8},
doi = {10.1016/j.cancergencyto.2006.05.016},
pmid = {17074584},
issn = {0165-4608},
mesh = {Adult ; Aged ; DNA, Neoplasm/genetics/metabolism ; Deoxyribonucleases, Type II Site-Specific/metabolism ; Electrophoresis, Agar Gel ; Female ; *Gene Rearrangement ; Humans ; Lymphoma, Non-Hodgkin/genetics/*pathology ; Male ; Middle Aged ; Proto-Oncogene Proteins c-bcl-2/*genetics ; Telomere/*genetics ; },
abstract = {Telomere length based on terminal restriction fragment (TRF) assay was evaluated in cells of bone marrow, lymph node, or both from 53 non-Hodgkin lymphoma (NHL) patients: 44 with follicular lymphoma (FL) and 9 with secondary diffuse large B-cell lymphoma (S-DLBCL) to FL. The TRF data were correlated with BCL2 gene rearrangement evaluated by nested and long-distance polymerase chain reaction approaches. Peripheral blood cells from 12 healthy donors were studied as controls. Both groups of NHL patients revealed significant telomere shortening compared with controls (8.50 +/- 0.50 kb; P < 0.001), with significantly shorter TRFs in S-DLBCL (3.49 +/- 0.26 kb) than in FL cases (4.09 +/- 0.12 kb; P = 0.047). Patients carrying BCL2 gene rearrangements showed longer telomere length (4.19 +/- 0.14 kb) than those without (3.51 +/- 0.14 kb; P = 0.05). Among patients with FL, telomere length was shortest in patients without t(14;18), intermediate when breakpoints occurred in the minor breakpoint cluster region (3.97 +/- 0.33 kb), and greater when breakpoints occurred in the major breakpoint region (MBR) (4.24 +/- 0.15 kb), with significant differences between MBR and BCL2-negative cases (P = 0.033). Our findings support the existence of alternative genetic pathways involved in the origin of these FL subsets. Even though the number of S-DLBCL cases was small, they showed the shortest telomere length, suggesting that this parameter reflects another genetic alteration involved in the progression from FL to a higher-grade lymphoma.},
}
@article {pmid17072335,
year = {2007},
author = {Wong, KK and Maser, RS and Sahin, E and Bailey, ST and Xia, H and Ji, H and McNamara, K and Naylor, M and Bronson, RT and Ghosh, S and Welsh, R and DePinho, RA},
title = {Diminished lifespan and acute stress-induced death in DNA-PKcs-deficient mice with limiting telomeres.},
journal = {Oncogene},
volume = {26},
number = {20},
pages = {2815-2821},
doi = {10.1038/sj.onc.1210099},
pmid = {17072335},
issn = {0950-9232},
support = {CA34461/CA/NCI NIH HHS/United States ; K08 AG2400401/AG/NIA NIH HHS/United States ; P01 CA95616/CA/NCI NIH HHS/United States ; R01 CA84628/CA/NCI NIH HHS/United States ; U01 CA84313/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Crosses, Genetic ; DNA-Activated Protein Kinase/*genetics ; DNA-Binding Proteins/*genetics ; Hepatitis, Animal/blood/genetics/immunology ; Interleukin-1beta/blood ; Interleukin-6/blood ; Liver/pathology ; Longevity/*genetics ; Mice ; Mice, Transgenic ; Murine hepatitis virus/immunology ; Nuclear Proteins/*genetics ; RNA/genetics ; Stress, Physiological/*genetics/*mortality/pathology ; Telomerase/genetics ; Telomere/*metabolism/physiology ; Tumor Necrosis Factor-alpha/blood ; },
abstract = {An adequate and appropriate response to physiological and pathophysiological stresses is critical for long-term homeostasis and viability of the aging organism. Previous work has pointed to the immune system, telomeres and DNA repair pathways as important and distinct determinants of a normal healthy lifespan. In this study, we explored the genetic interactions of telomeres and DNA-PKcs, a protein involved in non-homologous end-joining (NHEJ) and immune responses, in the context of a key aspect of aging and lifespan--the capacity to mount an acute and appropriate immune-mediated stress response. We observed that the combination of DNA-PKcs deficiency and telomere dysfunction resulted in a shortened lifespan that was reduced further following viral infection or experimental activation of the innate immune response. Analysis of the innate immune response in the DNA-PKcs-deficient mice with short dysfunctional telomeres revealed high basal serum levels of tumor necrosis factor alpha (TNFalpha) and hyper-active cytokine responses upon challenge with polyinosinic-polycytidylic acid (poly-IC). We further show that serum cytokine levels become elevated in telomere dysfunctional mice as a function of age. These results raise speculation that these genetic factors may contribute to misdirected immune responses of the aged under conditions of acute and chronic stress.},
}
@article {pmid17071826,
year = {2006},
author = {Dreesen, O and Cross, GA},
title = {Consequences of telomere shortening at an active VSG expression site in telomerase-deficient Trypanosoma brucei.},
journal = {Eukaryotic cell},
volume = {5},
number = {12},
pages = {2114-2119},
pmid = {17071826},
issn = {1535-9778},
support = {R01 AI021729/AI/NIAID NIH HHS/United States ; R01 AI050614/AI/NIAID NIH HHS/United States ; AI 21729/AI/NIAID NIH HHS/United States ; AI 50614/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Antigenic Variation ; Antigens, Protozoan/genetics ; Base Sequence ; DNA, Protozoan/genetics ; Gene Conversion ; Gene Expression ; Genes, Protozoan ; Models, Biological ; Telomerase/metabolism ; Telomere/*genetics ; Trypanosoma brucei brucei/enzymology/*genetics/*immunology ; Variant Surface Glycoproteins, Trypanosoma/*genetics/*immunology ; },
abstract = {Trypanosoma brucei evades the host immune response by sequential expression of a large family of variant surface glycoproteins (VSG) from one of approximately 20 subtelomeric expression sites (ES). VSG transcription is monoallelic, and little is known about the regulation of antigenic switching. To explore whether telomere length could affect antigenic switching, we created a telomerase-deficient cell line, in which telomeres shortened at a rate of 3 to 6 bp at each cell division. Upon reaching a critical length, short silent ES telomeres were stabilized by a telomerase-independent mechanism. The active ES telomere progressively shortened and frequently broke. Upon reaching a critical length, the short active ES telomere stabilized, but the transcribed VSG was gradually lost from the population and replaced by a new VSG through duplicative gene conversion. We propose a model in which subtelomeric-break-induced replication-mediated repair at a short ES telomere leads to duplicative gene conversion and expression of a new VSG.},
}
@article {pmid17070718,
year = {2006},
author = {Frank, CJ and Hyde, M and Greider, CW},
title = {Regulation of telomere elongation by the cyclin-dependent kinase CDK1.},
journal = {Molecular cell},
volume = {24},
number = {3},
pages = {423-432},
doi = {10.1016/j.molcel.2006.10.020},
pmid = {17070718},
issn = {1097-2765},
support = {GM43080/GM/NIGMS NIH HHS/United States ; },
mesh = {CDC2 Protein Kinase/*metabolism ; Carrier Proteins/metabolism ; DNA Breaks, Double-Stranded ; DNA Polymerase I/metabolism ; DNA, Single-Stranded/chemistry/metabolism ; Endodeoxyribonucleases/metabolism ; Exodeoxyribonucleases/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Nucleic Acid Conformation ; Protein Serine-Threonine Kinases/metabolism ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins ; },
abstract = {Telomere elongation is cell-cycle regulated and requires the coordinated activity of proteins involved in the DNA damage response. We used an assay that detects de novo telomere addition to examine the role of the cyclin-dependent kinase Cdk1 (Cdc28) in cell-cycle-specific telomere elongation. Inhibition of an ATP analog-sensitive allele of Cdk1 completely blocked the addition of telomere repeats. Mutations in Rif2 and DNA polymerase alpha that cause increased telomere elongation were unable to compensate for the loss of Cdk1 activity, suggesting Cdk1 activity is required for an early step in telomere addition. Mutations in DNA repair proteins that act with Cdk1 at double-strand breaks also prevented telomere elongation. Cdk1 activity was required for the generation of 3' single-strand overhangs at both native and de novo telomeres. We propose Cdk1 activity controls the timing of telomere elongation by regulating the single-strand overhang at chromosome ends.},
}
@article {pmid17065609,
year = {2006},
author = {Robertson, HM and Gordon, KH},
title = {Canonical TTAGG-repeat telomeres and telomerase in the honey bee, Apis mellifera.},
journal = {Genome research},
volume = {16},
number = {11},
pages = {1345-1351},
pmid = {17065609},
issn = {1088-9051},
support = {R01 AI056081/AI/NIAID NIH HHS/United States ; AI56081/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Bees/*enzymology/*genetics ; Bombyx/enzymology/genetics ; DNA/genetics ; Genes, Insect ; Microsatellite Repeats ; Phylogeny ; Species Specificity ; Telomerase/*genetics ; Telomere/*genetics ; Tribolium/enzymology/genetics ; },
abstract = {The draft assembly of the honey bee Apis mellifera genome sequence reveals that the 17 centromeric-distal telomeres are of a simple, shared, and canonical structure, with 3-4 kb of a unique subtelomeric sequence, followed by several kilobases of TTAGG or variant telomeric repeats. This simple subtelomeric structure differs from the centromeric-proximal telomeres on the short arms of the 15 acrocentric chromosomes, which are apparently composed primarily of the 176-bp AluI tandem repeat. This dichotomy between the distal and proximal telomeres may involve differential participation of the telomeres of the 15 acrocentric chromosomes in the Rabl configuration after mitosis and the chromosome bouquet in meiotic prophase I. As expected from the presence of canonical TTAGG telomeric repeats, we identified a candidate telomerase gene in the bee, as well as the silkmoth Bombyx mori and the flour beetle Tribolium castaneum.},
}
@article {pmid17060405,
year = {2007},
author = {Nishio, Y and Nakanishi, K and Ozeki, Y and Jiang, SX and Kameya, T and Hebisawa, A and Mukai, M and Travis, WD and Franks, TJ and Kawai, T},
title = {Telomere length, telomerase activity, and expressions of human telomerase mRNA component (hTERC) and human telomerase reverse transcriptase (hTERT) mRNA in pulmonary neuroendocrine tumors.},
journal = {Japanese journal of clinical oncology},
volume = {37},
number = {1},
pages = {16-22},
doi = {10.1093/jjco/hyl118},
pmid = {17060405},
issn = {1465-3621},
mesh = {Carcinoma, Neuroendocrine/*enzymology/*genetics/pathology ; Humans ; In Situ Hybridization ; Lung Neoplasms/*enzymology/*genetics/pathology ; RNA/*biosynthesis ; RNA, Messenger/biosynthesis ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/biosynthesis/*metabolism ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Telomeres are important for chromosome structure and function, protecting them against degradation. However, few studies have examined telomeres in pulmonary neuroendocrine (NE) tumors.<br><br>METHODS: We investigated deparaffinized sections obtained from 70 primary NE lung tumors [34 typical carcinoids (TCs), 10 atypical carcinoids (ACs), 16 large cell neuroendocrine carcinoma (LCNECs) and 10 small cell lung carcinomas (SCLCs)].<br><br>RESULTS: Positive expressions of human telomerase mRNA component (hTERC) and human telomerase reverse transcriptase (hTERT) mRNA were recognized, respectively, in 58% and 74% of TCs, and in 100% and 100% of ACs, LCNECs and SCLCs. Alteration of telomere length was greater in both LCNECs and SCLCs than in TCs. Telomerase activity was detected in LCNECs, but not in TCs. By the reverse-transcriptase polymerase chain reaction (RT-PCR), hTERC mRNA was detected in 100% of LCNECs and TCs examined, while hTERT mRNA was detected in 67% of LCNECs, but not at all in TCs.<br><br>CONCLUSIONS: These results suggest that alterations in telomere length, telomerase activity, and the expression of hTERT mRNA may (i) play roles in pathogenesis in pulmonary neuroendocrine tumors, and (ii) be a useful tool for differential diagnosis between TCs and LCNECs.},
}
@article {pmid17055587,
year = {2007},
author = {Bakalova, R and Zhelev, Z and Kubo, T and Mileva, M and Ohba, H},
title = {Dual-labeled telomere sensing probes for quantification of telomerase activity assay.},
journal = {Journal of biochemical and biophysical methods},
volume = {70},
number = {3},
pages = {503-506},
doi = {10.1016/j.jbbm.2006.09.002},
pmid = {17055587},
issn = {0165-022X},
mesh = {Base Sequence ; Carbocyanines ; DNA Probes/genetics ; Fluorescent Dyes ; *Molecular Probe Techniques ; Telomerase/*analysis ; Telomere/*enzymology/genetics ; },
abstract = {The present study describes an empirically discovered phenomenon that might be useful for development of a sensitive and rapid methodology for quantification of telomerase activity assay with simple data acquisition and possibility for calculation of telomerase product in absolute units. The method is based on the design and application of two single-stranded telomere sensing probes consisting of dual-labeled 16-mer oligonucleotides (fluorescent Cy3/Cy3-labeled and non-fluorescent IowaBlack/BHQ-labeled) that can simultaneously hybridize on the primary product of the telomerase reaction.},
}
@article {pmid17055345,
year = {2007},
author = {Wu, Y and Zacal, NJ and Rainbow, AJ and Zhu, XD},
title = {XPF with mutations in its conserved nuclease domain is defective in DNA repair but functions in TRF2-mediated telomere shortening.},
journal = {DNA repair},
volume = {6},
number = {2},
pages = {157-166},
doi = {10.1016/j.dnarep.2006.09.005},
pmid = {17055345},
issn = {1568-7864},
mesh = {Amino Acid Substitution ; Cell Line ; Conserved Sequence ; DNA Repair/*genetics/*physiology ; DNA-Binding Proteins/chemistry/*genetics/*metabolism ; Deoxyribonucleases/chemistry/genetics/metabolism ; Genetic Complementation Test ; Humans ; Mutagenesis, Site-Directed ; Mutation ; Protein Structure, Tertiary ; Recombinant Proteins/chemistry/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; Ultraviolet Rays ; },
abstract = {TRF2, a telomere-binding protein, is a crucial player in telomere length maintenance. Overexpression of TRF2 results in telomere shortening in both normal primary fibroblasts and telomerase-positive cancer cells. TRF2 is found to be associated with XPF-ERCC1, a structure-specific endonuclease involved in nucleotide excision repair, crosslink repair and DNA recombination. XPF-ERCC1 is implicated in TRF2-dependent telomere loss in mouse keratinocytes, however, whether XPF-ERCC1 and its nuclease activity are required for TRF2-mediated telomere shortening in human cells is unknown. Here we report that TRF2-induced telomere shortening is abrogated in human cells deficient in XPF, demonstrating that XPF-ERCC1 is required for TRF2-promoted telomere shortening. To further understand the role of XPF in TRF2-dependent telomere shortening, we generated constructs containing either wild type XPF or mutant XPF proteins carrying amino acid substitutions in its conserved nuclease domain. We show that wild type XPF can complement XPF-deficient cells for repair of UV-induced DNA damage whereas the nuclease-inactive XPF proteins fail to do so, indicating that the nuclease activity of XPF is essential for nucleotide excision repair. In contrast, both wild type XPF and nuclease-inactive XPF proteins, when expressed in XPF-deficient cells, are able to rescue TRF2-mediated telomere shortening. Thus, our results suggest that the function of XPF in TRF2-mediated telomere shortening is conserved between mouse and human. Furthermore, our findings reveal an unanticipated nuclease-independent function of XPF in TRF2-mediated telomere shortening.},
}
@article {pmid17053789,
year = {2006},
author = {He, H and Multani, AS and Cosme-Blanco, W and Tahara, H and Ma, J and Pathak, S and Deng, Y and Chang, S},
title = {POT1b protects telomeres from end-to-end chromosomal fusions and aberrant homologous recombination.},
journal = {The EMBO journal},
volume = {25},
number = {21},
pages = {5180-5190},
pmid = {17053789},
issn = {0261-4189},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; R01 CA129037/CA/NCI NIH HHS/United States ; CA016672/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Sequence/genetics ; Animals ; Cell Line ; Cellular Senescence/physiology ; *Chromosome Aberrations ; DNA-Binding Proteins/genetics/*metabolism ; Mice ; Mutation ; *Recombination, Genetic ; Sequence Deletion ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {POT1 (protection of telomere 1) is a highly conserved single-stranded telomeric binding protein that is essential for telomere end protection. Here, we report the cloning and characterization of a second member of the mouse POT family. POT1b binds telomeric DNA via conserved DNA binding oligonucleotide/oligosaccharide (OB) folds. Compared to POT1a, POT1b OB-folds possess less sequence specificity for telomeres. In contrast to POT1a, truncated POT1b possessing only the OB-folds can efficiently localize to telomeres in vivo. Overexpression of a mutant Pot1b allele that cannot bind telomeric DNA initiated a DNA damage response at telomeres that led to p53-dependent senescence. Furthermore, a reduction of the 3' G-rich overhang, increased chromosomal fusions and elevated homologous recombination (HR) were observed at telomeres. shRNA mediated depletion of endogenous Pot1b in Pot1a deficient cells resulted in increased chromosomal aberrations. Our results indicate that POT1b plays important protective functions at telomeres and that proper maintenance of chromosomal stability requires both POT proteins.},
}
@article {pmid17050546,
year = {2006},
author = {Gomez, D and Wenner, T and Brassart, B and Douarre, C and O'Donohue, MF and El Khoury, V and Shin-Ya, K and Morjani, H and Trentesaux, C and Riou, JF},
title = {Telomestatin-induced telomere uncapping is modulated by POT1 through G-overhang extension in HT1080 human tumor cells.},
journal = {The Journal of biological chemistry},
volume = {281},
number = {50},
pages = {38721-38729},
doi = {10.1074/jbc.M605828200},
pmid = {17050546},
issn = {0021-9258},
mesh = {Base Sequence ; Cell Line, Tumor ; Chromatin Immunoprecipitation ; DNA Damage ; DNA Primers ; Fluorescent Antibody Technique ; Green Fluorescent Proteins/genetics ; Humans ; Oxazoles/*pharmacology ; Shelterin Complex ; *Telomere ; Telomere-Binding Proteins/genetics/*physiology ; },
abstract = {Telomestatin is a potent G-quadruplex ligand that interacts with the 3' telomeric overhang, leading to its degradation, and induces a delayed senescence and apoptosis of cancer cells. POT1 and TRF2 were recently identified as specific telomere-binding proteins involved in telomere capping and t-loop maintenance and whose interaction with telomeres is modulated by telomestatin. We show here that the treatment of HT1080 human tumor cells by telomestatin induces a rapid decrease of the telomeric G-overhang and of the double-stranded telomeric repeats. Telomestatin treatment also provokes a strong decrease of POT1 and TRF2 from their telomere sites, suggesting that the ligand triggers the uncapping of the telomere ends. The effect of the ligand is associated with an increase of the gamma-H2AX foci, one part of them colocalizing at telomeres, thus indicating the occurrence of a DNA damage response at the telomere, but also the presence of additional DNA targets for telomestatin. Interestingly, the expression of GFP-POT1 in HT1080 cells increases both telomere and G-overhang length. As compared with HT1080 cells, HT1080GFP-POT1 cells presented a resistance to telomestatin treatment characterized by a protection to the telomestatin-induced growth inhibition and the G-overhang shortening. This protection is related to the initial G-overhang length rather than to its degradation rate and is overcome by increased telomestatin concentration. Altogether these results suggest that telomestatin induced a telomere dysfunction in which G-overhang length and POT1 level are important factors but also suggest the presence of additional DNA sites of action for the ligand.},
}
@article {pmid17049115,
year = {2006},
author = {Zhang, XF and Yang, RF and Wang, J and Zhao, L and Li, L and Shen, FM and Su, DF},
title = {Arterial baroreflex function does not influence telomere length in kidney of rats.},
journal = {Acta pharmacologica Sinica},
volume = {27},
number = {11},
pages = {1409-1416},
doi = {10.1111/j.1745-7254.2006.00422.x},
pmid = {17049115},
issn = {1671-4083},
mesh = {Animals ; Aorta/innervation ; Autonomic Denervation ; Baroreflex/*physiology ; Blood Pressure/physiology ; Carotid Sinus/innervation ; Female ; Heart Rate/physiology ; Hypertension/*physiopathology ; Kidney/*pathology ; Male ; Rats ; Rats, Inbred SHR ; Rats, Sprague-Dawley ; Telomere/*pathology ; },
abstract = {AIM: To investigate the relationship between arterial baroreflex (ABR) function and telomere length in kidney of rats.<br><br>METHODS: Stroke-prone spontaneously hypertensive rats (SHR-SP) and sinoaortic denervated rats (SAD) were used as models with depressed arterial baroreflex. In the first experiments, SHR-SP rats were examined at the age of 24 weeks for both sexes and 40 weeks for female rats. In the second experiments, SAD rats were studied 4 and 35 weeks after SAD operation. Blood pressure was continuously recorded for 4 h in a conscious state. After the determination of baroreflex sensitivity (BRS), the terminal restriction fragment (TRF) of rat kidney was analyzed using Southern blot.<br><br>RESULTS: The TRF length was found shorter in: a) male SHR-SP compared with age-matched female SHR-SP; b) female SHR-SP 40 weeks of age compared with 24 weeks of age; c) in rats 35 weeks after operation compared with rats 4 weeks post operation in both sham-operated and SAD rats.<br><br>CONCLUSION: In SHR-SP, the TRF length did not correlate with BRS. In addition, SAD did not affect TRF length at either 4 or 35 weeks post-surgery. It may be concluded that baroreflex function does not influence the terminal restriction fragment (TRF) length in rats.},
}
@article {pmid17046024,
year = {2007},
author = {Dyson, J and Sánchez, E and Villella-Bressan, R and Webb, GF},
title = {Stabilization of telomeres in nonlinear models of proliferating cell lines.},
journal = {Journal of theoretical biology},
volume = {244},
number = {3},
pages = {400-408},
doi = {10.1016/j.jtbi.2006.08.023},
pmid = {17046024},
issn = {0022-5193},
mesh = {Animals ; Cell Death ; Cell Line, Tumor/*ultrastructure ; Cell Proliferation ; Humans ; *Logistic Models ; Models, Biological ; Nonlinear Dynamics ; Telomere/*ultrastructure ; },
abstract = {We analyse an age-structured model of telomere loss in a proliferating cell population. The cell population is divided into telomere classes, which shorten each round of division. The model consists of a nonlinear system of partial differential equations for the telomere classes. We prove that if the highest telomere class is exempted from mortality, then all the classes stabilize to a nontrivial equilibrium dependent on the initial state of cells in the highest telomere class.},
}
@article {pmid17043079,
year = {2007},
author = {Fitzpatrick, AL and Kronmal, RA and Gardner, JP and Psaty, BM and Jenny, NS and Tracy, RP and Walston, J and Kimura, M and Aviv, A},
title = {Leukocyte telomere length and cardiovascular disease in the cardiovascular health study.},
journal = {American journal of epidemiology},
volume = {165},
number = {1},
pages = {14-21},
doi = {10.1093/aje/kwj346},
pmid = {17043079},
issn = {0002-9262},
support = {N01 HC-15103/HC/NHLBI NIH HHS/United States ; N01-HC-35129/HC/NHLBI NIH HHS/United States ; N01-HC-85079/HC/NHLBI NIH HHS/United States ; N01-HC-85086/HC/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Cardiovascular Diseases/*genetics/mortality/physiopathology ; DNA/analysis ; Female ; Humans ; Inflammation/*genetics ; *Leukocytes ; Male ; Myocardial Infarction/genetics/mortality ; Oxidative Stress ; Pilot Projects ; *Polymorphism, Restriction Fragment Length ; Risk ; Risk Assessment ; Risk Factors ; Telomere/*genetics ; },
abstract = {The telomere length of replicating somatic cells is inversely correlated with age and has been reported to be associated cross-sectionally with cardiovascular disease (CVD). Leukocyte telomere length, as expressed by mean terminal restriction fragment (TRF) length, was measured in 419 randomly selected participants from the Cardiovascular Health Study, comprising a community-dwelling cohort recruited in four US communities. The authors investigated associations between TRF length and selected measures of subclinical CVD/risk factors for CVD (data were collected at the 1992/1993 clinic visit) and incident CVD (ascertained through June 2002). In these participants (average age = 74.2 years (standard deviation, 5.2)), mean TRF length was 6.3 kilobase pairs (standard deviation, 0.62). Significant or borderline inverse associations were found between TRF length and diabetes, glucose, insulin, diastolic blood pressure, carotid intima-media thickness, and interleukin-6. Associations with body size and C-reactive protein were modified by gender and age, occurring only in men and in participants aged 73 years or younger. In younger (but not older) participants, each shortened kilobase pair of TRF corresponded with a threefold increased risk of myocardial infarction (hazard ratio = 3.08, 95% confidence interval: 1.22, 7.73) and stroke (hazard ratio = 3.22, 95% confidence interval: 1.29, 8.02). These results support the hypotheses that telomere attrition may be related to diseases of aging through mechanisms involving oxidative stress, inflammation, and progression to CVD.},
}
@article {pmid17038452,
year = {2006},
author = {Zhai, G and Aviv, A and Hunter, DJ and Hart, DJ and Gardner, JP and Kimura, M and Lu, X and Valdes, AM and Spector, TD},
title = {Reduction of leucocyte telomere length in radiographic hand osteoarthritis: a population-based study.},
journal = {Annals of the rheumatic diseases},
volume = {65},
number = {11},
pages = {1444-1448},
pmid = {17038452},
issn = {0003-4967},
support = {/WT_/Wellcome Trust/United Kingdom ; R01 AG020132/AG/NIA NIH HHS/United States ; AG020132/AG/NIA NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; 17489/ARC_/Arthritis Research UK/United Kingdom ; 17489/VAC_/Versus Arthritis/United Kingdom ; },
mesh = {Adult ; Aged ; Aging/genetics ; Diseases in Twins/*genetics ; Female ; Hand Joints/*diagnostic imaging ; Humans ; Leukocytes/*pathology ; Male ; Middle Aged ; Osteoarthritis/diagnostic imaging/*genetics ; Radiography ; Severity of Illness Index ; Telomere/*genetics ; },
abstract = {BACKGROUND: Although age is the strongest predictor of osteoarthritis, the exact mechanism underlying this disorder remains elusive.<br><br>OBJECTIVE: To examine the association between leucocyte telomere length (LTL), a bio-indicator of ageing, and radiographic hand osteoarthritis.<br><br>METHODS: An unselected, predominantly female sample from the TwinsUK Adult Twin Registry (Twin Research and Genetic Epidemiology Unit, St Thomas Hospital, London, UK) was studied. Radiographs of both hands were obtained with a standard posteroanterior view and assessed for radiographic osteoarthritis according to the Kellgren/Lawrence (K/L) score. Individual radiographic features including osteophytes and joint space narrowing (JSN) were also assessed on a four-point scale using a standard atlas. Hand osteoarthritis was defined radiographically as having >or=3 osteoarthritis-affected joints of both hands (K/L score>or=2). Severity of hand osteoarthritis was indicated semiquantitatively by total K/L scores, osteophytes, JSN scores and proportion of joints affected. Mean LTL was measured by the terminal restriction fragment length using the Southern blot.<br><br>RESULTS: A total of 1086 Caucasian subjects (mean (SD) age 55 (8.0) years) were studied. LTL was 6.95 (0.64) kb and was inversely correlated with age. After adjustment for age, sex, body mass index and smoking, LTL was significantly shorter by 178 bp in subjects with hand osteoarthritis (n = 160) than in those without (n = 926; p = 0.04). LTL was also significantly associated with semicontinuous measures of osteoarthritis (eg, total K/L score, JSN score, osteophyte score and proportion of joints affected) after adjustment (all p<or=0.02) in a dose-response fashion.<br><br>CONCLUSION: Shorter LTL equivalent to around 11 years of annual loss in normal people is associated with radiographic hand osteoarthritis and disease severity, suggesting potential shared mechanisms between osteoarthritis and ageing, and implicating oxidative stress and low-level chronic inflammation in both conditions.},
}
@article {pmid17034355,
year = {2006},
author = {Kajstura, J and Rota, M and Urbanek, K and Hosoda, T and Bearzi, C and Anversa, P and Bolli, R and Leri, A},
title = {The telomere-telomerase axis and the heart.},
journal = {Antioxidants &amp; redox signaling},
volume = {8},
number = {11-12},
pages = {2125-2141},
doi = {10.1089/ars.2006.8.2125},
pmid = {17034355},
issn = {1523-0864},
support = {AG-17042/AG/NIA NIH HHS/United States ; AG-23071/AG/NIA NIH HHS/United States ; AG-26107/AG/NIA NIH HHS/United States ; HL-38132/HL/NHLBI NIH HHS/United States ; HL-55757/HL/NHLBI NIH HHS/United States ; HL-65577/HL/NHLBI NIH HHS/United States ; HL-70897/HL/NHLBI NIH HHS/United States ; HL-75480/HL/NHLBI NIH HHS/United States ; HL-78825/HL/NHLBI NIH HHS/United States ; HL-81737/HL/NHLBI NIH HHS/United States ; HL65573/HL/NHLBI NIH HHS/United States ; HL68088/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Cardiovascular Diseases/etiology/*metabolism/prevention &amp; control ; Cellular Senescence/*physiology ; Homeostasis/physiology ; Humans ; Myocardium/enzymology/*metabolism ; Oxidative Stress/*physiology ; Reactive Oxygen Species/metabolism ; Telomerase/*metabolism ; Telomere/*physiology ; },
abstract = {The preservation of myocyte number and cardiac mass throughout life is dependent on the balance between cell death and cell division. Rapidly emerging evidence indicates that new myocytes can be formed through the activation and differentiation of resident cardiac progenitor cells. The critical issue is the identification of mechanisms that define the aging of cardiac progenitor cells and, ultimately, their inability to replace dying myocytes. The most reliable marker of cellular senescence is the modification of the telomere-telomerase axis, together with the expression of the cell cycle inhibitors p16INK4a and p53. Cellular senescence is characterized by biochemical events that occur within the cell. In this regard, one of the most relevant processes is represented by repeated oxidative stress that may evolve into the activation of the cell death program or result in the development of a senescent phenotype. Thus, the modulation of telomerase activity and the control of telomeric length, together with the attenuation of the formation of reactive oxygen species, may represent important therapeutic tools in regenerative medicine and in prevention of aging and diabetic cardiomyopathies.},
}
@article {pmid17031891,
year = {2006},
author = {Miyoshi, D and Inoue, M and Sugimoto, N},
title = {DNA logic gates based on structural polymorphism of telomere DNA molecules responding to chemical input signals.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {45},
number = {46},
pages = {7716-7719},
doi = {10.1002/anie.200602404},
pmid = {17031891},
issn = {1433-7851},
mesh = {Circular Dichroism ; Computers, Molecular ; DNA/*chemistry ; *Nucleic Acid Conformation ; *Polymorphism, Genetic ; Telomere/*chemistry ; },
}
@article {pmid17024208,
year = {2006},
author = {Blackburn, EH and Greider, CW and Szostak, JW},
title = {Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging.},
journal = {Nature medicine},
volume = {12},
number = {10},
pages = {1133-1138},
doi = {10.1038/nm1006-1133},
pmid = {17024208},
issn = {1078-8956},
mesh = {*Aging ; Animals ; Base Sequence ; DNA Fragmentation ; Fungal Proteins/metabolism ; Humans ; Models, Biological ; Molecular Sequence Data ; Neoplasms/enzymology/genetics/metabolism ; Publications ; Telomerase/metabolism/*physiology ; Telomere/metabolism/*ultrastructure ; Tetrahymena/*enzymology/genetics ; Zea mays/*enzymology/genetics ; },
}
@article {pmid17022371,
year = {2005},
author = {Czerlinski, G and Ypma, T},
title = {Mechanisms of telomerase binding to telomeres.},
journal = {Physiological chemistry and physics and medical NMR},
volume = {37},
number = {2},
pages = {89-108},
pmid = {17022371},
issn = {0748-6642},
mesh = {Kinetics ; *Models, Biological ; Protein Binding ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {There are essentially two alternative mechanisms for the binding of telomerase to telomeres, assuming that a protective component is initially bound to the telomerase binding region on the telomeres. Either the protective (or blocking) agent first dissociates and telomerase binds thereafter, or telomerase binds first and the protective agent then dissociates from the ternary complex. In the limit, this second possibility permits the ternary complex to become a transition complex (creating another possible mechanism). Numerical simulation of both rapid mixing and chemical relaxation is used to study these alternatives. We aim to determine how the mechanisms may be distinguished experimentally and identify an appropriate experimental design. We show that rapid mixing experiments are better than chemical relaxation experiments, since the latter are more affected by the statistics of single molecule kinetics. However, hidden fast steps can only be revealed by chemical relaxation. The detection of mechanistic changes hinges on linking fluorescence reporters to the reaction components, either directly (chemically) or indirectly (via an indicator reaction). Fluorescence is excited by two-photon absorption in a small reaction volume. Various detection strategies and design issues are examined, including limitations imposed by diffusion. Constant rather than stopped flow is shown to be preferable.},
}
@article {pmid17020976,
year = {2006},
author = {Lin, X and Gu, J and Lu, C and Spitz, MR and Wu, X},
title = {Expression of telomere-associated genes as prognostic markers for overall survival in patients with non-small cell lung cancer.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {12},
number = {19},
pages = {5720-5725},
doi = {10.1158/1078-0432.CCR-05-2809},
pmid = {17020976},
issn = {1078-0432},
support = {CA 111646/CA/NCI NIH HHS/United States ; CA 55769/CA/NCI NIH HHS/United States ; CA 70907/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Biomarkers, Tumor/genetics/metabolism ; Carcinoma, Non-Small-Cell Lung/*genetics/metabolism/mortality ; DNA, Neoplasm/*genetics/metabolism ; Female ; *Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms/*genetics/mortality ; Male ; Middle Aged ; Prognosis ; RNA, Messenger/genetics/metabolism ; Shelterin Complex ; Survival Rate ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/*genetics/metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; rap1 GTP-Binding Proteins/genetics/metabolism ; },
abstract = {PURPOSE: Human telomeres, which are composed of long, repetitive sequences of TTAGGG and a variety of proteins, function as a protective structure capping the ends of chromosomes. Telomere dysfunction plays important roles in cancer initiation and progression. TRF1, TRF2, POT1, and RAP1 are four major telomere proteins that regulate telomere stability and telomere length. We hypothesized that the expression of these genes would have significant predictive value for cancer development and prognosis.<br><br>EXPERIMENTAL DESIGN: We compared the mRNA expression level of TRF1, TRF2, POT1, and RAP1 between tumor and adjacent normal tissues from 148 patients with non-small cell lung cancer using real-time quantitative PCR. We then estimated the prognostic value of the mRNA expression of these genes in tumors.<br><br>RESULTS: The expression level of TRF1 was significantly lower in tumor tissues than in adjacent normal tissues (P < 0.0001); no significant difference was found for TRF2, POT1, and RAP1. The expression of RAP1 gene in tumors was highly predictive of overall survival. In the Cox proportional hazards model, patients with higher RAP1 expression were associated with a significantly better survival [hazard ratio (HR), 0.47; 95% confidence interval (95% CI), 0.24-0.91]. This improved survival was more prominent in men (HR, 0.45; 95% CI, 0.22-0.996) and in ever smokers (HR, 0.50; 95% CI, 0.24-1.02). Kaplan-Meier survival curves showed that patients with higher RAP1 expression had significantly longer median survival than patients with lower expression (median = 51.21 versus 15.34 months, P < 0.0009). The expressions of TRF2 in tumor tissues were significantly correlated with tumor grades (P = 0.0114).<br><br>CONCLUSIONS: RAP1 expression may be a useful biomarker of tumor progression and survival.},
}
@article {pmid17018298,
year = {2006},
author = {Vodenicharov, MD and Wellinger, RJ},
title = {DNA degradation at unprotected telomeres in yeast is regulated by the CDK1 (Cdc28/Clb) cell-cycle kinase.},
journal = {Molecular cell},
volume = {24},
number = {1},
pages = {127-137},
doi = {10.1016/j.molcel.2006.07.035},
pmid = {17018298},
issn = {1097-2765},
mesh = {CDC28 Protein Kinase, S cerevisiae/*physiology ; Cell Cycle ; Cell Cycle Proteins/genetics/physiology ; DNA/*metabolism ; *DNA Damage ; Genomic Instability ; Saccharomyces cerevisiae/*enzymology/genetics ; Saccharomyces cerevisiae Proteins/genetics/physiology ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/physiology ; },
abstract = {In the absence of functional telomeric cap protection, the ends of eukaryotic chromosomes are subject to DNA damage responses that lead to cell-cycle arrest and, eventually, genomic instability. However, the controlling activities responsible for the initiation of genome instability on unprotected telomeres remained unclear. Here we show that in budding yeast, unprotected telomeres undergo a tightly cell-cycle-regulated DNA degradation. Ablation of the function of essential capping proteins Cdc13p or Stn1p only caused telomere degradation in G2/M, but not in G1 of the cell cycle. Accordingly, G1-arrested cells with unprotected telomeres remained viable, while G2/M-arrested cells failed to recover. The data also show that completion of S phase and the activity of the S-Cdk1 kinase were required for telomere degradation. These results strongly suggest that after a loss of the telomere capping function, telomere-led genome instability is caused by tightly regulated cellular DNA repair attempts.},
}
@article {pmid17015833,
year = {2006},
author = {Eller, MS and Liao, X and Liu, S and Hanna, K and Bäckvall, H and Opresko, PL and Bohr, VA and Gilchrest, BA},
title = {A role for WRN in telomere-based DNA damage responses.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {103},
number = {41},
pages = {15073-15078},
pmid = {17015833},
issn = {0027-8424},
mesh = {Cells, Cultured ; Cellular Senescence/genetics ; *DNA Damage ; *DNA Repair ; Exodeoxyribonucleases ; Humans ; Infant, Newborn ; Oligodeoxyribonucleotides/pharmacology ; RecQ Helicases/genetics/*physiology ; Telomere/*genetics ; Werner Syndrome/*genetics/pathology ; Werner Syndrome Helicase ; },
abstract = {Telomeres cap the ends of eukaryotic chromosomes and prevent them from being recognized as DNA breaks. We have shown that certain DNA damage responses induced during senescence and, at times of telomere uncapping, also can be induced by treatment of cells with small DNA oligonucleotides homologous to the telomere 3' single-strand overhang (T-oligos), implicating this overhang in generation of these telomere-based damage responses. Here, we show that T-oligo-treated fibroblasts contain gammaH2AX foci and that these foci colocalize with telomeres. T-oligos with nuclease-resistant 3' ends are inactive, suggesting that a nuclease initiates T-oligo responses. We therefore examined WRN, a 3'-->5' exonuclease and helicase mutated in Werner syndrome, a disorder characterized by aberrant telomere maintenance, premature aging, chromosomal rearrangements, and predisposition to malignancy. Normal fibroblasts and U20S osteosarcoma cells rendered deficient in WRN showed reduced phosphorylation of p53 and histone H2AX in response to T-oligo treatment. Together, these data demonstrate a role for WRN in processing of telomeric DNA and subsequent activation of DNA damage responses. The T-oligo model helps define the role of WRN in telomere maintenance and initiation of DNA damage responses after telomere disruption.},
}
@article {pmid17015429,
year = {2006},
author = {Lazzerini Denchi, E and Celli, G and de Lange, T},
title = {Hepatocytes with extensive telomere deprotection and fusion remain viable and regenerate liver mass through endoreduplication.},
journal = {Genes &amp; development},
volume = {20},
number = {19},
pages = {2648-2653},
pmid = {17015429},
issn = {0890-9369},
support = {AG16642/AG/NIA NIH HHS/United States ; R01 GM049046/GM/NIGMS NIH HHS/United States ; R56 AG016642/AG/NIA NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Apoptosis/genetics/physiology ; Cell Proliferation ; Cellular Senescence/genetics/physiology ; DNA Damage ; Female ; Hepatocytes/cytology/*metabolism ; In Situ Hybridization, Fluorescence/methods ; Liver/pathology/physiopathology/surgery ; Liver Regeneration/*genetics/physiology ; Male ; Mice ; Mice, Knockout ; Mice, Transgenic ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/*genetics/metabolism/physiology ; Tumor Suppressor Protein p53/genetics/metabolism ; },
abstract = {We report that mouse liver cells are highly resistant to extensive telomere dysfunction. In proliferating cells, telomere dysfunction results in chromosome end fusions, a DNA damage signal, and apoptosis or senescence. To determine the consequences of telomere dysfunction in noncycling cells, we used conditional deletion of the telomeric protein TRF2 in hepatocytes. TRF2 loss resulted in telomeric accumulation of gamma-H2AX and frequent telomere fusions, indicating telomere deprotection. However, there was no induction of p53 or apoptosis, and liver function appeared unaffected. Furthermore, the loss of TRF2 did not compromise liver regeneration after partial hepatectomy. Remarkably, liver regeneration occurred without cell division involving endoreduplication and cell growth, thereby circumventing the chromosome segregation problems associated with telomere fusions. We conclude that nondividing hepatocytes can maintain and regenerate liver function despite substantial loss of telomere integrity.},
}
@article {pmid17015423,
year = {2006},
author = {Wong, JM and Collins, K},
title = {Telomerase RNA level limits telomere maintenance in X-linked dyskeratosis congenita.},
journal = {Genes &amp; development},
volume = {20},
number = {20},
pages = {2848-2858},
pmid = {17015423},
issn = {0890-9369},
support = {R01 HL079585/HL/NHLBI NIH HHS/United States ; R56 HL079585/HL/NHLBI NIH HHS/United States ; HL079585/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle Proteins/metabolism ; Cell Proliferation ; Chromosomes, Human, X/*ultrastructure ; Dyskeratosis Congenita/*genetics/*pathology ; Fibroblasts/metabolism ; Humans ; Kinetics ; Mice ; Nuclear Proteins/metabolism ; *RNA ; RNA, Ribosomal/chemistry/metabolism ; Ribosomes/metabolism ; Telomerase/*chemistry/metabolism ; Telomere/*ultrastructure ; },
abstract = {Dyskeratosis congenita (DC) patients suffer a progressive and ultimately fatal loss of hematopoietic renewal correlating with critically short telomeres. The predominant X-linked form of DC results from substitutions in dyskerin, a protein required both for ribosomal RNA (rRNA) pseudouridine modification and for cellular accumulation of telomerase RNA (TER). Accordingly, alternative models have posited that the exhaustion of cellular renewal in X-linked DC arises as a primary consequence of ribosome deficiency or telomerase deficiency. Here we test, for the first time, whether X-linked DC patient cells are compromised for telomerase function at telomeres. We show that telomerase activation in family-matched control cells allows telomere elongation and telomere length maintenance, while telomerase activation in X-linked DC patient cells fails to prevent telomere erosion with proliferation. Furthermore, we demonstrate by phenotypic rescue that telomere defects in X-linked DC patient cells arise solely from reduced accumulation of TER. We also show that X-linked DC patient cells averted from premature senescence support normal levels of rRNA pseudouridine modification and normal kinetics of rRNA precursor processing, in contrast with phenotypes reported for a proposed mouse model of the human disease. These findings support the significance of telomerase deficiency in the pathology of X-linked DC.},
}
@article {pmid17015293,
year = {2007},
author = {Proctor, CJ and Lydall, DA and Boys, RJ and Gillespie, CS and Shanley, DP and Wilkinson, DJ and Kirkwood, TB},
title = {Modelling the checkpoint response to telomere uncapping in budding yeast.},
journal = {Journal of the Royal Society, Interface},
volume = {4},
number = {12},
pages = {73-90},
pmid = {17015293},
issn = {1742-5689},
support = {/WT_/Wellcome Trust/United Kingdom ; 054371/WT_/Wellcome Trust/United Kingdom ; BB/C008200/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Cell Cycle/physiology ; Cell Cycle Proteins/*metabolism ; Computer Simulation ; DNA Damage/physiology ; DNA Repair/physiology ; Genes, cdc/*physiology ; Models, Biological ; Models, Statistical ; Saccharomyces cerevisiae/*cytology/*physiology ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*physiology ; },
abstract = {One of the DNA damage-response mechanisms in budding yeast is temporary cell-cycle arrest while DNA repair takes place. The DNA damage response requires the coordinated interaction between DNA repair and checkpoint pathways. Telomeres of budding yeast are capped by the Cdc13 complex. In the temperature-sensitive cdc13-1 strain, telomeres are unprotected over a specific temperature range leading to activation of the DNA damage response and subsequently cell-cycle arrest. Inactivation of cdc13-1 results in the generation of long regions of single-stranded DNA (ssDNA) and is affected by the activity of various checkpoint proteins and nucleases. This paper describes a mathematical model of how uncapped telomeres in budding yeast initiate the checkpoint pathway leading to cell-cycle arrest. The model was encoded in the Systems Biology Markup Language (SBML) and simulated using the stochastic simulation system Biology of Ageing e-Science Integration and Simulation (BASIS). Each simulation follows the time course of one mother cell keeping track of the number of cell divisions, the level of activity of each of the checkpoint proteins, the activity of nucleases and the amount of ssDNA generated. The model can be used to carry out a variety of in silico experiments in which different genes are knocked out and the results of simulation are compared to experimental data. Possible extensions to the model are also discussed.},
}
@article {pmid17005004,
year = {2006},
author = {Wallace, DL and Bérard, M and Soares, MV and Oldham, J and Cook, JE and Akbar, AN and Tough, DF and Beverley, PC},
title = {Prolonged exposure of naïve CD8+ T cells to interleukin-7 or interleukin-15 stimulates proliferation without differentiation or loss of telomere length.},
journal = {Immunology},
volume = {119},
number = {2},
pages = {243-253},
pmid = {17005004},
issn = {0019-2805},
mesh = {CD8-Positive T-Lymphocytes/*immunology ; Cell Differentiation/immunology ; Cell Proliferation ; Cells, Cultured ; Dose-Response Relationship, Immunologic ; Flow Cytometry/methods ; Humans ; Immunophenotyping ; Interleukin-15/*immunology ; Interleukin-7/*immunology ; Leukocyte Common Antigens/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Receptors, CCR7 ; Receptors, Chemokine/metabolism ; T-Lymphocyte Subsets/immunology ; Telomerase/metabolism ; Telomere/*immunology ; },
abstract = {Interleukin (IL)-7 and IL-15 are cytokines implicated in homeostatic control of the peripheral CD8 T-cell pool. We compared the effects of IL-7 and IL-15 on survival and proliferation of purified human CD8+ T-cell subsets. Low concentrations of either cytokine reduced the spontaneous apoptosis of all subsets, and enhancement of survival corresponded to the extent of Bcl-2 up-regulation. Surprisingly, although minimal proliferation of naïve CD8+ T cells was observed during the first week of culture with cytokines, a marked expansion of these cells occurred at later time points, particularly in response to IL-15. This occurred largely without phenotypic change or acquisition of effector function, indicating a dissociation of differentiation from proliferation. Notably, progression of naïve CD8+ T cells through several cell divisions resulted in up-regulation of telomerase and the maintenance of telomere length. These data show that IL-7 and IL-15 induce cell proliferation and rescue from apoptosis in a concentration, time and subset-dependent manner, and have implications for the homeostatic expansion of the naïve CD8+ T-cell pool.},
}
@article {pmid16999829,
year = {2006},
author = {Bankhead, T and Kobryn, K and Chaconas, G},
title = {Unexpected twist: harnessing the energy in positive supercoils to control telomere resolution.},
journal = {Molecular microbiology},
volume = {62},
number = {3},
pages = {895-905},
doi = {10.1111/j.1365-2958.2006.05423.x},
pmid = {16999829},
issn = {0950-382X},
mesh = {Bacterial Proteins/genetics/*metabolism ; Base Sequence ; DNA, Bacterial/*chemistry/metabolism ; Endodeoxyribonucleases/genetics/*metabolism ; Molecular Sequence Data ; Nucleic Acid Conformation ; Telomere/*chemistry/metabolism ; },
abstract = {Negative DNA supercoiling is an important conformational property of bacterial DNA that plays a significant role in a wide variety of DNA transactions. In contrast, positive DNA supercoiling is a by-product of cellular processes that involve helical unwinding or movement of DNA by a fixed translocase, and has generally been considered a necessary evil requiring removal. We now report the first evidence suggesting a physiological role for positive supercoiling; this occurs in telomere resolution in the related Lyme disease and relapsing fever Borrelia spirochetes. Telomere resolution is the process whereby covalently closed hairpin telomeres are generated from replicative intermediates by the telomere resolvase, ResT. We observe a 20-fold and greater stimulation of the reaction by positive supercoiling, which facilitates formation of a previously unobserved reaction intermediate. Our data suggest the possibility that the free energy of positive supercoiling, a resource with no previously described cellular function, may be harnessed and utilized as a regulator of post-replication events.},
}
@article {pmid16997848,
year = {2006},
author = {Aviv, A and Valdes, AM and Spector, TD},
title = {Human telomere biology: pitfalls of moving from the laboratory to epidemiology.},
journal = {International journal of epidemiology},
volume = {35},
number = {6},
pages = {1424-1429},
doi = {10.1093/ije/dyl169},
pmid = {16997848},
issn = {0300-5771},
support = {074951//Wellcome Trust/United Kingdom ; AG020132/AG/NIA NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; *Aging/genetics ; Bias ; Epidemiologic Research Design ; Humans ; *Leukocytes/classification/physiology ; Longitudinal Studies ; Molecular Epidemiology/*methods ; Sample Size ; Telomere/*genetics ; },
abstract = {Remarkable progress has been made during the last 2 decades in understanding telomere biology at the molecular and cellular levels. Clinical epidemiology research of human telomeres, in contrast, is a discipline just coming into its own. The most important observation in studying human telomere biology is that telomere length is highly variable among humans. Here we explain some of the reasons for this variability and propose several principles that should be considered in conducting epidemiological telomere research. Ignoring these principles could lead to misleading conclusions.},
}
@article {pmid16990794,
year = {2006},
author = {Vannier, JB and Depeiges, A and White, C and Gallego, ME},
title = {Two roles for Rad50 in telomere maintenance.},
journal = {The EMBO journal},
volume = {25},
number = {19},
pages = {4577-4585},
pmid = {16990794},
issn = {0261-4189},
mesh = {Anaphase/physiology ; Arabidopsis/*metabolism ; Arabidopsis Proteins/*metabolism ; Base Pairing/genetics ; Cell Nucleus/metabolism ; Chromosomes, Plant/metabolism ; DNA, Plant/metabolism ; Flowers/metabolism ; In Situ Hybridization, Fluorescence ; Indoles ; Models, Genetic ; Mutation/genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Reproducibility of Results ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {We describe two roles for the Rad50 protein in telomere maintenance and the protection of chromosome ends. Using fluorescence in situ hybridisation (FISH) and fibre-FISH analyses, we show that absence of AtRad50 protein leads to rapid shortening of a subpopulation of chromosome ends and subsequently chromosome-end fusions lacking telomeric repeats. In the absence of telomerase, mutation of atrad50 has a synergistic effect on the number of chromosome end fusions. Surprisingly, this 'deprotection' of the shortened telomeres does not result in increased exonucleolytic degradation, but in a higher proportion of anaphase bridges containing telomeric repeats in atrad50/tert plants, compared to tert mutant plants. Absence of AtRad50 thus facilitates the action of recombination on these shortened telomeres. We propose that this protective role of Rad50 protein on shortened telomeres results from its action in constraining recombination to sister chromatids and thus avoiding end-to-end interactions.},
}
@article {pmid16990382,
year = {2006},
author = {Artandi, SE},
title = {Telomeres, telomerase, and human disease.},
journal = {The New England journal of medicine},
volume = {355},
number = {12},
pages = {1195-1197},
doi = {10.1056/NEJMp068187},
pmid = {16990382},
issn = {1533-4406},
mesh = {Aging/genetics/physiology ; Cellular Senescence/genetics ; DNA-Binding Proteins/metabolism ; Dyskeratosis Congenita/genetics ; Humans ; Mutation ; Neoplasms/enzymology ; Telomerase/chemistry/genetics/metabolism/*physiology ; Telomere/chemistry/*physiology ; Up-Regulation ; },
}
@article {pmid16984147,
year = {2006},
author = {Casals, J and Debéthune, L and Alvarez, K and Risitano, A and Fox, KR and Grandas, A and Pedroso, E},
title = {Directing quadruplex-stabilizing drugs to the telomere: synthesis and properties of acridine-oligonucleotide conjugates.},
journal = {Bioconjugate chemistry},
volume = {17},
number = {5},
pages = {1351-1359},
doi = {10.1021/bc060194t},
pmid = {16984147},
issn = {1043-1802},
mesh = {Acridines/chemical synthesis/*chemistry/metabolism ; Humans ; Molecular Structure ; Oligonucleotides/chemical synthesis/*chemistry/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Conjugates containing quadruplex-stabilizing acridines linked to oligonucleotides that are complementary to the G-rich human telomere sequence were synthesized. Acylation of 3,6-diaminoacridine followed by two Michael reactions provided derivatives suitable for conjugation, which were coupled to resin-linked amine-modified oligonucleotides by activating the carboxyl group with pentafluorophenyl 4-nitrobenzenesulfonate. After deprotection with aqueous ammonia at room temperature, conjugates incorporating different acridines, linkers, and oligonucleotide sequences were obtained. These were tested for their ability to stabilize intramolecular DNA quadruplexes that are based on the human telomeric repeat sequence (GGGTTA)(n).},
}
@article {pmid16981080,
year = {2006},
author = {Plentz, RR and Rudolph, KL},
title = {[Telomere dysfunction and telomerase: implications for human pathophysiology during ageing and chronic diseases].},
journal = {Deutsche medizinische Wochenschrift (1946)},
volume = {131},
number = {38},
pages = {2087-2090},
doi = {10.1055/s-2006-951335},
pmid = {16981080},
issn = {0012-0472},
mesh = {Aging/*physiology ; *Chronic Disease ; Enzyme Activation ; Humans ; Neoplasms/enzymology/genetics ; Telomerase/*metabolism ; Telomere/genetics/*physiology ; },
}
@article {pmid16969091,
year = {2006},
author = {Lieberman, PM},
title = {Resistance from the flanks: a role for telomere repeat factor 2 in chemotherapeutic drug resistance.},
journal = {Cancer biology &amp; therapy},
volume = {5},
number = {8},
pages = {957-958},
doi = {10.4161/cbt.5.8.3284},
pmid = {16969091},
issn = {1538-4047},
mesh = {Antineoplastic Agents/*therapeutic use ; *Drug Resistance, Multiple ; *Drug Resistance, Neoplasm ; Humans ; Stomach Neoplasms/*drug therapy/enzymology ; Telomere/*physiology ; Telomeric Repeat Binding Protein 2/*physiology ; },
}
@article {pmid16967966,
year = {2006},
author = {Sasaki, S and Bando, T and Minoshima, M and Shimizu, T and Shinohara, K and Takaoka, T and Sugiyama, H},
title = {Sequence-specific alkylation of double-strand human telomere repeat sequence by pyrrole-imidazole polyamides with indole linkers.},
journal = {Journal of the American Chemical Society},
volume = {128},
number = {37},
pages = {12162-12168},
doi = {10.1021/ja0626584},
pmid = {16967966},
issn = {0002-7863},
mesh = {Alkylation ; Antineoplastic Agents/chemical synthesis/chemistry/pharmacology ; Base Sequence ; Cell Line, Tumor ; Electrophoresis, Polyacrylamide Gel ; Humans ; Indoles/chemical synthesis/*chemistry/*pharmacology ; Molecular Sequence Data ; Neoplasms/genetics/metabolism ; Pyrroles/chemical synthesis/*chemistry/*pharmacology ; Repetitive Sequences, Nucleic Acid ; Substrate Specificity ; Telomere/chemistry/genetics/*metabolism ; },
abstract = {We designed and synthesized pyrrole (Py)-imidazole (Im) hairpin polyamide 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI) conjugates 1 and 2, which target both strands of the double-stranded region of the human telomere repeat sequences, 5'-d(TTAGGG)(n)-3'/5'-d(CCCTAA)(n)-3'. High-resolution denaturing polyacrylamide gel electrophoresis demonstrated that conjugates 1 and 2 alkylated DNA at the 3' A of 5'-ACCCTA-3' and 5'-AGGGTTA-3', respectively. Cytotoxicities of conjugates 1 and 2 were evaluated using 39 human cancer cell lines; averages of log IC(50) values for conjugates 1 and 2 were -6.96 (110 nM) and -7.24 (57.5 nM), respectively. Conjugates 1 and 2 have potential as antitumor drugs capable of targeting telomere repeat sequence.},
}
@article {pmid16964373,
year = {2006},
author = {Ju, YJ and Park, JE and Juhn, KM and Jeong, J and Yun, M and Park, MJ and Park, GH and Choi, KY and Cho, MH and Wong, KK and Park, WB and Lee, KH},
title = {Chromosomal end fusion resulting from telomere erosion increases susceptibility to radiation via multinucleation: effect of p53.},
journal = {International journal of oncology},
volume = {29},
number = {4},
pages = {753-763},
pmid = {16964373},
issn = {1019-6439},
mesh = {Animals ; Cell Death ; Chromosomes/*genetics ; Genomic Instability ; Mice ; Mitosis ; *Radiation Tolerance/genetics ; *Recombination, Genetic ; Telomerase/*antagonists &amp; inhibitors/genetics/metabolism ; Telomere/genetics/*metabolism ; Tumor Suppressor Protein p53/antagonists &amp; inhibitors/genetics/metabolism ; },
abstract = {Loss of p53 tumor suppressor facilitates acquisition of telomerase activity. In fact, both p53 inactivation and telomerase activation are frequently found in human cancers. p53 inactivation, however, eliminates or attenuates the biological responses to telomerase inhibition and the eventual telomere erosion. We show that telomere erosion can increase the susceptibility to radiation, irrespective of p53 status. Both telomerase inhibition and critically shortened telomere with significant change of chromosomal end-to-end fusion were essential for the enhancement of radiosensitivity. The enhancement was correlated with greater formation of multinucleated cells. p53 inactivation did not eliminate the observed generation of chromosomal fusion and multinucleation, and the resulting increased susceptibility to radiation, as opposed to the previously proved role of p53 in mediating cellular responses to telomere dysfunction. The present findings suggest the importance of chromosomal end fusion in modulating radiosensitivity rather than p53 DNA damage signaling. Thus, the suggested anticancer radiotherapeutic strategy combined with telomerase inhibition could clinically be applicable to cancers, irrespective of p53 status.},
}
@article {pmid16963706,
year = {2006},
author = {George, JA and DeBaryshe, PG and Traverse, KL and Celniker, SE and Pardue, ML},
title = {Genomic organization of the Drosophila telomere retrotransposable elements.},
journal = {Genome research},
volume = {16},
number = {10},
pages = {1231-1240},
pmid = {16963706},
issn = {1088-9051},
support = {R01 GM050315/GM/NIGMS NIH HHS/United States ; R56 GM050315/GM/NIGMS NIH HHS/United States ; GM50315/GM/NIGMS NIH HHS/United States ; P50-HG00750/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Blotting, Southern ; Computational Biology ; Drosophila melanogaster/*genetics ; Genomics/*methods ; Heterochromatin/*genetics ; Retroelements/*genetics ; Telomere/*genetics ; },
abstract = {The emerging sequence of the heterochromatic portion of the Drosophila melanogaster genome, with the most recent update of euchromatic sequence, gives the first genome-wide view of the chromosomal distribution of the telomeric retrotransposons, HeT-A, TART, and Tahre. As expected, these elements are entirely excluded from euchromatin, although sequence fragments of HeT-A and TART 3 untranslated regions are found in nontelomeric heterochromatin on the Y chromosome. The proximal ends of HeT-A/TART arrays appear to be a transition zone because only here do other transposable elements mix in the array. The sharp distinction between the distribution of telomeric elements and that of other transposable elements suggests that chromatin structure is important in telomere element localization. Measurements reported here show (1) D. melanogaster telomeres are very long, in the size range reported for inbred mouse strains (averaging 46 kb per chromosome end in Drosophila stock 2057). As in organisms with telomerase, their length varies depending on genotype. There is also slight under-replication in polytene nuclei. (2) Surprisingly, the relationship between the number of HeT-A and TART elements is not stochastic but is strongly correlated across stocks, supporting the idea that the two elements are interdependent. Although currently assembled portions of the HeT-A/TART arrays are from the most-proximal part of long arrays, approximately 61% of the total HeT-A sequence in these regions consists of intact, potentially active elements with little evidence of sequence decay, making it likely that the content of the telomere arrays turns over more extensively than has been thought.},
}
@article {pmid16957187,
year = {2006},
author = {Zhang, R and Yang, Y and Fang, P and Jiang, C and Xu, L and Zhu, Y and Shen, M and Xia, H and Zhao, J and Chen, T and Qin, Z},
title = {Diversity of telomere palindromic sequences and replication genes among Streptomyces linear plasmids.},
journal = {Applied and environmental microbiology},
volume = {72},
number = {9},
pages = {5728-5733},
pmid = {16957187},
issn = {0099-2240},
mesh = {Amino Acid Sequence ; Bacterial Proteins/genetics ; Base Sequence ; Cloning, Molecular ; DNA Replication/genetics ; DNA, Bacterial/chemistry/genetics ; Genes, Bacterial ; Genetic Variation ; Molecular Sequence Data ; Nucleic Acid Conformation ; Plasmids/*genetics/isolation &amp; purification ; Sequence Homology, Amino Acid ; Sequence Homology, Nucleic Acid ; Streptomyces/*genetics/isolation &amp; purification ; Telomere/*genetics ; },
abstract = {Streptomyces sp. linear plasmids and linear chromosomes usually contain conserved terminal palindromic sequences bound by the conserved telomeric proteins Tap and Tp, encoded by the tap and tpg genes, respectively, as well as plasmid loci required for DNA replication in circular mode when the telomeres are deleted. These consist of iterons and an adjacent rep gene. By using PCR, we found that 8 of 17 newly detected linear plasmids in Streptomyces strains lack typical telomeric tap and tpg sequences. Instead, two novel telomeres in plasmids pRL1 and pRL2 from the eight strains and one conserved telomere in pFRL1 from the other strains were identified, while multiple short palindromes were also found in the plasmids. The complete nucleotide sequence of pRL2 revealed a gene encoding a protein containing two domains, resembling Tap of Streptomyces and a helicase of Thiobacillus, and an adjacent gene encoding a protein similar to Tpg of Streptomyces and a portion of the telomere terminal protein pTP of adenoviruses. No typical iterons-rep loci were found in the three plasmids. These results indicate an unexpected diversity of telomere palindromic sequences and replication genes among Streptomyces linear plasmids.},
}
@article {pmid16951210,
year = {2006},
author = {Costa, A and Daidone, MG and Daprai, L and Villa, R and Cantù, S and Pilotti, S and Mariani, L and Gronchi, A and Henson, JD and Reddel, RR and Zaffaroni, N},
title = {Telomere maintenance mechanisms in liposarcomas: association with histologic subtypes and disease progression.},
journal = {Cancer research},
volume = {66},
number = {17},
pages = {8918-8924},
doi = {10.1158/0008-5472.CAN-06-0273},
pmid = {16951210},
issn = {1538-7445},
mesh = {Adult ; Biomarkers ; Disease Progression ; Female ; Humans ; Liposarcoma/mortality/*pathology ; Male ; Middle Aged ; Retrospective Studies ; Survival Analysis ; Survivors ; Telomere/*metabolism ; },
abstract = {Human cancer cells maintain telomeres by telomerase activity (TA) or by alternative lengthening of telomeres (ALT). We proposed to define the prevalence of the two telomere maintenance mechanisms (TMM), to assess their association with histology, and to compare their prognostic relevance in a series of 93 patients with liposarcoma. ALT was detected by assaying ALT-associated promyelocytic leukemia nuclear bodies and TA was assayed using the telomeric repeat amplification protocol. ALT or TA was found in 25.9% or 26.6% of 139 tested liposarcoma lesions, respectively. Three lesions were ALT+/TA+ whereas approximately 50% of lesions did not show any known TMM. TMM phenotype was consistent during disease progression. ALT was prevalent in dedifferentiated and in grade 3 liposarcomas whereas TA prevailed in most round-cell myxoid and in grade 2 liposarcomas. ALT and TA incidence was similar in primary and recurrent lesions whereas metastases were more frequently TA+ than ALT+ (59% versus 18%; P = 0.04). TMM presence negatively affected patient prognosis (P = 0.001): increased mortality was associated with positivity for TA (P = 0.038) or ALT (P < 0.0001) compared with TMM absence. ALT proved to be a stronger prognostic discriminant of increased mortality than TA even when adjusted for tumor location, grade, and histology (hazard ratio for cause-specific death, 3.58 versus 1.15). Our results indicate that ALT can support fully malignant liposarcomas and is associated with unfavorable disease outcome.},
}
@article {pmid16941208,
year = {2006},
author = {Maillet, G and White, CI and Gallego, ME},
title = {Telomere-length regulation in inter-ecotype crosses of Arabidopsis.},
journal = {Plant molecular biology},
volume = {62},
number = {6},
pages = {859-866},
pmid = {16941208},
issn = {0167-4412},
mesh = {Arabidopsis/*genetics ; Chromosomes, Plant/genetics ; Crosses, Genetic ; DNA, Plant/genetics/metabolism ; Deoxyribonucleases, Type II Site-Specific/metabolism ; Genetic Variation ; Polymorphism, Genetic ; Species Specificity ; Telomere/*genetics ; },
abstract = {Telomeres, the nucleoprotein complexes at the ends of eukaryotic chromosomes, are maintained at a species-specific equilibrium length. Arabidopsis thaliana is a self-fertilizing plant and different geographical isolates or ecotypes show differing telomere-lengths. We have exploited this telomere-length polymorphism between Arabidopsis ecotypes to investigate the genetic regulation of telomere length by analysing telomere lengths in 16 different inter-ecotype crosses between plants with differing telomere sizes. With two exceptions, the inter-ecotype hybrid plants present a new telomere-length set point, intermediate between that of the two parents. A regulation mechanism thus shortens the longer and lengthens the shorter telomeres.},
}
@article {pmid16936037,
year = {2006},
author = {Tourand, Y and Bankhead, T and Wilson, SL and Putteet-Driver, AD and Barbour, AG and Byram, R and Rosa, PA and Chaconas, G},
title = {Differential telomere processing by Borrelia telomere resolvases in vitro but not in vivo.},
journal = {Journal of bacteriology},
volume = {188},
number = {21},
pages = {7378-7386},
pmid = {16936037},
issn = {0021-9193},
mesh = {Amino Acid Sequence ; Bacterial Proteins/chemistry/genetics/*metabolism ; Borrelia/*enzymology/genetics ; Cloning, Molecular ; DNA, Bacterial/chemistry/genetics/*metabolism ; Endodeoxyribonucleases/chemistry/genetics/*metabolism ; Gene Deletion ; Genetic Complementation Test ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; Telomere/*metabolism ; },
abstract = {Causative agents of Lyme disease and relapsing fever, including Borrelia burgdorferi and Borrelia hermsii, respectively, are unusual among bacteria in that they possess a segmented genome with linear DNA molecules terminated by hairpin ends, known as telomeres. During replication, these telomeres are processed by the essential telomere resolvase, ResT, in a unique biochemical reaction known as telomere resolution. In this study, we report the identification of the B. hermsii resT gene through cross-species hybridization. Sequence comparison of the B. hermsii protein with the B. burgdorferi orthologue revealed 67% identity, including all the regions currently known to be crucial for telomere resolution. In vitro studies, however, indicated that B. hermsii ResT was unable to process a replicated B. burgdorferi type 2 telomere substrate. In contrast, in vivo cross-species complementation in which the native resT gene of B. burgdorferi was replaced with B. hermsii resT had no discernible effect, even though B. burgdorferi strain B31 carries at least two type 2 telomere ends. The B. burgdorferi ResT protein was also able to process two telomere spacing mutants in vivo that were unresolvable in vitro. The unexpected differential telomere processing in vivo versus in vitro by the two telomere resolvases suggests the presence of one or more accessory factors in vivo that are normally involved in the reaction. Our current results are also expected to facilitate further studies into ResT structure and function, including possible interaction with other Borrelia proteins.},
}
@article {pmid16919874,
year = {2006},
author = {Harris, SE and Deary, IJ and MacIntyre, A and Lamb, KJ and Radhakrishnan, K and Starr, JM and Whalley, LJ and Shiels, PG},
title = {The association between telomere length, physical health, cognitive ageing, and mortality in non-demented older people.},
journal = {Neuroscience letters},
volume = {406},
number = {3},
pages = {260-264},
doi = {10.1016/j.neulet.2006.07.055},
pmid = {16919874},
issn = {0304-3940},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Aged ; Aging/*physiology ; Cognition/*physiology ; Cohort Studies ; Female ; *Geriatric Assessment ; Humans ; Male ; Motor Activity/*physiology ; Proportional Hazards Models ; Retrospective Studies ; Survival Analysis ; *Telomere ; },
abstract = {Telomeres are nucleo-protein complexes that protect the ends of chromosomes. The telomeric DNA component shortens each time a somatic cell replicates, eventually leading to cell senescence. Telomere length has been associated with morbidity and mortality rates from age-related diseases. We tested the hypotheses that mean peripheral blood leukocyte telomere length, at age 79 years, is associated with physical health at age 79, cognitive ability at age 79, lifetime cognitive change, smoking, alcohol consumption, social class in adulthood, and mortality in a cohort of people without dementia (the Lothian Birth Cohort 1921: LBC1921). There was a small, significant association between telomere length and verbal fluency (a test of executive function) before (r=-0.16, p=0.027) and after (r=-0.17, p=0.022) adjustment for mental ability at age 11. This might be a type 1 error. Otherwise, we find that telomere length in old age does not have a significant association with age-related physical and cognitive decline or mortality.},
}
@article {pmid16917952,
year = {2006},
author = {Ohali, A and Avigad, S and Ash, S and Goshen, Y and Luria, D and Feinmesser, M and Zaizov, R and Yaniv, I},
title = {Telomere length is a prognostic factor in neuroblastoma.},
journal = {Cancer},
volume = {107},
number = {6},
pages = {1391-1399},
doi = {10.1002/cncr.22132},
pmid = {16917952},
issn = {0008-543X},
mesh = {Blotting, Southern ; Child ; Child, Preschool ; DNA, Neoplasm/analysis/genetics ; Disease Progression ; Female ; Humans ; Infant ; Male ; Neuroblastoma/genetics/*pathology ; Prognosis ; Survival Analysis ; Telomere/*genetics ; },
abstract = {BACKGROUND: Maintenance of telomeres, in most instances by reactivation of telomerase, is obligatory for the indefinite proliferation of tumor cells. The objective of this study was to evaluate telomere length and telomerase activity (TA) as markers for progression and prognosis in neuroblastoma.<br><br>METHODS: Primary tumor samples from 51 patients were analyzed for telomere length and TA and were correlated with known prognostic parameters and outcome.<br><br>RESULTS: Telomere length had a highly significant correlation with prognosis (P = .007). Short telomeres were predictive of a favorable prognosis, whereas long or unchanged telomeres were predictive of a poor outcome. For the first time to their knowledge, the authors have shown that, within the high-risk group patients, telomere length could define a favorable subgroup that had a progression-free survival (PFS) rate of 86% compared with a PFS rate of 36% for patients with more adverse disease, which is the expected PFS rate for such patients (P = .04). In a multivariate analysis, telomere length was the most significant prognostic parameter (P = .032). TA was correlated significantly with outcome and with known prognostic factors. High TA and low TA were associated with adverse and favorable outcomes, respectively (P = .01).<br><br>CONCLUSION: The results of this investigation suggested that telomere length is a highly significant prognostic parameter of clinical relevance in patients with neuroblastoma. In high-risk patients, telomere length was the sole significant parameter that identified a group of patients who had a favorable prognosis. The authors suggest that telomere length should be included in the recommended diagnostic investigations for patients with neuroblastoma.},
}
@article {pmid16913878,
year = {2006},
author = {Demissie, S and Levy, D and Benjamin, EJ and Cupples, LA and Gardner, JP and Herbert, A and Kimura, M and Larson, MG and Meigs, JB and Keaney, JF and Aviv, A},
title = {Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study.},
journal = {Aging cell},
volume = {5},
number = {4},
pages = {325-330},
doi = {10.1111/j.1474-9726.2006.00224.x},
pmid = {16913878},
issn = {1474-9718},
support = {1R01 HL64753/HL/NHLBI NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; N01-HC 25195/HC/NHLBI NIH HHS/United States ; R01 HL076784/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Cohort Studies ; Humans ; Hypertension/*blood ; *Insulin Resistance ; Leukocytes/physiology/*ultrastructure ; Male ; Middle Aged ; *Oxidative Stress ; Telomere/*ultrastructure ; },
abstract = {Insulin resistance and oxidative stress are associated with accelerated telomere attrition in leukocytes. Both are also implicated in the biology of aging and in aging-related disorders, including hypertension. We explored the relations of leukocyte telomere length, expressed by terminal restriction fragment (TRF) length, with insulin resistance, oxidative stress and hypertension. We measured leukocyte TRF length in 327 Caucasian men with a mean age of 62.2 years (range 40-89 years) from the Offspring cohort of the Framingham Heart Study. TRF length was inversely correlated with age (r = -0.41, P < 0.0001) and age-adjusted TRF length was inversely correlated with the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (r =-0.16, P = 0.007) and urinary 8-epi-PGF(2alpha) (r = -0.16, P = 0.005) - an index of systemic oxidative stress. Compared with their normotensive peers, hypertensive subjects exhibited shorter age-adjusted TRF length (hypertensives = 5.93 +/- 0.042 kb, normotensives = 6.07 +/- 0.040 kb, P = 0.025). Collectively, these observations suggest that hypertension, increased insulin resistance and oxidative stress are associated with shorter leukocyte telomere length and that shorter leukocyte telomere length in hypertensives is largely due to insulin resistance.},
}
@article {pmid16912107,
year = {2006},
author = {Aviv, A},
title = {Telomeres and human somatic fitness.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {61},
number = {8},
pages = {871-873},
doi = {10.1093/gerona/61.8.871},
pmid = {16912107},
issn = {1079-5006},
support = {AG 020132/AG/NIA NIH HHS/United States ; AG 021593/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*physiology ; *Health Status ; Humans ; Leukocytes/*physiology ; Telomere/*physiology ; },
abstract = {Mean leukocyte telomere length may be an indicator of biological age, and as such it appears to provide information over and above chronological age of the risk for developing diseases of aging in humans. Here I propose that the mean leukocyte telomere length is an index of "somatic fitness," a concept that breaks down the artificial boundary between aging and diseases of aging. I also propose that, in exceptionally old humans, ultrashort leukocyte telomeres might be a determinant of life span.},
}
@article {pmid16909836,
year = {2006},
author = {Vorob'ev, NV and Biltueva, LS and Orlov, IuL and Grafodatskiĭ, AS and Kolchanov, NA},
title = {[Interstitial telomere repeats as markers of evolutionary changes in the mammalian karyotype: human chromosome 2].},
journal = {Biofizika},
volume = {51},
number = {4},
pages = {602-607},
pmid = {16909836},
issn = {0006-3029},
mesh = {Chromosomes, Human, Pair 2/*genetics ; *Evolution, Molecular ; Humans ; Repetitive Sequences, Nucleic Acid/*genetics ; *Sequence Analysis, DNA/methods ; *Software ; Telomere/*genetics ; },
abstract = {Telomer repeats represented by hexamer (TTAGGG)n at chromosome termini are required for correct function and chromosome stability. At the same time, interstitial telomer sequence (ITS) located far from the chromosome ends are known for several mammalian genomes, including the human genome. It is assumed that these repeats mark the points of fusion or other chromosome reconstructions of ancestors. Exact localization of all interstitial telomer sequences in the genome could greatly improve our understanding of the mechanism of karyotype evolution and species origin. We have developed a software for a search of interstitial telomer sequences in complete sequences of mammalian genomes. We have demonstrated the evolutionary significance of repeats by an example of human chromosome 2. The results and supplementary materials are available at the site of the Institute of Cytology and Genetics: http://www.bionet.nsc.ru/labs/theorylabmain/orlov/telomere/.},
}
@article {pmid16909412,
year = {2006},
author = {Maida, Y and Kyo, S and Forsyth, NR and Takakura, M and Sakaguchi, J and Mizumoto, Y and Hashimoto, M and Nakamura, M and Nakao, S and Inoue, M},
title = {Distinct telomere length regulation in premalignant cervical and endometrial lesions: implications for the roles of telomeres in uterine carcinogenesis.},
journal = {The Journal of pathology},
volume = {210},
number = {2},
pages = {214-223},
doi = {10.1002/path.2038},
pmid = {16909412},
issn = {0022-3417},
mesh = {Animals ; Cell Transformation, Neoplastic/genetics ; Chromosomal Instability ; Chromosomes, Human, Pair 17/genetics ; Disease Progression ; Endometrial Hyperplasia/genetics/pathology ; Endometrial Neoplasms/*genetics/pathology ; Female ; Humans ; Image Processing, Computer-Assisted/methods ; Immunoenzyme Techniques ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Inbred BALB C ; Precancerous Conditions/*genetics ; Telomere/*pathology ; Tumor Cells, Cultured ; Uterine Cervical Neoplasms/*genetics/pathology ; Uterine Cervical Dysplasia/*genetics/pathology ; },
abstract = {Mouse models show that progressive shortening of telomeres with ageing causes chromosomal instability, which can lead to the initiation of cancer. However, it is unclear what roles telomere shortening plays in human carcinogenesis. The present study has investigated the involvement of telomere dynamics in uterine carcinogenesis. Using telomere-FISH (telo-FISH) assays, telomere lengths in premalignant and malignant cervical and endometrial lesions were measured and compared with chromosomal arm loss or gain. Telo-FISH signals were visualized with Cy3-labelled telomere-specific probes and presented as telomere intensity (TI). Early-stage cervical intraepithelial neoplasias (CINs), especially CIN2, had significantly shorter telomeres than corresponding normal squamous epithelia (p = 0.019), together with increased rates of chromosomal arm loss/gain (p < 0.001). Cervical cancers had relatively short telomeres, but they also showed greater heterogeneity than other sampled tissues, including those with long telomeres. In contrast, there was no significant difference between the telomere length of normal endometrium and of endometrial hyperplasia and endometrial cancer. There was no significant difference in the rate of chromosomal arm loss/gain between normal endometrium and endometrial hyperplasia. These findings suggest that progressive shortening of telomeres occurs in CIN, in association with chromosomal instability, which may play critical roles in cervical carcinogenesis. In contrast, endometrial hyperplasias have relatively stable telomeres without widespread chromosome alteration, implying that endometrial carcinogenesis involves mechanisms distinct from those of cervical carcinogenesis, possibly including microsatellite instability.},
}
@article {pmid16899119,
year = {2006},
author = {Mastromonaco, GF and Perrault, SD and Betts, DH and King, WA},
title = {Role of chromosome stability and telomere length in the production of viable cell lines for somatic cell nuclear transfer.},
journal = {BMC developmental biology},
volume = {6},
number = {},
pages = {41},
pmid = {16899119},
issn = {1471-213X},
mesh = {Animals ; Biopsy ; Cattle ; Cell Culture Techniques/*methods ; Cell Division ; Cell Line ; Cell Survival ; Chromosomal Instability ; *Chromosome Aberrations ; Chromosome Mapping ; Ear ; Embryo, Mammalian ; Fibroblasts/cytology/*physiology ; Male ; Metaphase ; *Nuclear Transfer Techniques ; Skin/cytology ; Telomere/*genetics/ultrastructure ; },
abstract = {BACKGROUND: Somatic cell nuclear transfer (SCNT) provides an appealing alternative for the preservation of genetic material in non-domestic and endangered species. An important prerequisite for successful SCNT is the availability of good quality donor cells, as normal embryo development is dependent upon proper reprogramming of the donor genome so that embryonic genes can be appropriately expressed. The characteristics of donor cell lines and their ability to produce embryos by SCNT were evaluated by testing the effects of tissue sample collection (DART biopsy, PUNCH biopsy, post-mortem EAR sample) and culture initiation (explant, collagenase digestion) techniques.<br><br>RESULTS: Differences in initial sample size based on sample collection technique had an effect on the amount of time necessary for achieving primary confluence and the number of population doublings (PDL) produced. Thus, DART and PUNCH biopsies resulted in cultures with decreased lifespans (<30 PDL) accompanied by senescence-like morphology and decreased normal chromosome content (<40% normal cells at 20 PDL) compared to the long-lived (>50 PDL) and chromosomally stable (>70% normal cells at 20 PDL) cultures produced by post-mortem EAR samples. Chromosome stability was influenced by sample collection technique and was dependent upon the culture's initial telomere length and its rate of shortening over cell passages. Following SCNT, short-lived cultures resulted in significantly lower blastocyst development (< or = 0.9%) compared to highly proliferative cultures (11.8%). Chromosome stability and sample collection technique were significant factors in determining blastocyst development outcome.<br><br>CONCLUSION: These data demonstrate the influence of culture establishment techniques on cell culture characteristics, including the viability, longevity and normality of cells. The identification of a quantifiable marker associated with SCNT embryo developmental potential, chromosome stability, provides a means by which cell culture conditions can be monitored and improved.},
}
@article {pmid16897464,
year = {2007},
author = {Sinclair, CS and Richmond, RH and Ostrander, GK},
title = {Characterization of the telomere regions of scleractinian coral, Acropora surculosa.},
journal = {Genetica},
volume = {129},
number = {3},
pages = {227-233},
doi = {10.1007/s10709-006-0001-x},
pmid = {16897464},
issn = {0016-6707},
support = {S06 GM 44796-14/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Anthozoa/*genetics ; Blotting, Southern ; Conserved Sequence/genetics ; Endodeoxyribonucleases ; Guam ; Species Specificity ; Tandem Repeat Sequences/*genetics ; Telomere/*genetics ; },
abstract = {Terminal ends of vertebrate chromosomes are protected by tandem repeats of the sequence (TTAGGG). First thought to be vertebrate specific, (TTAGGG)(n) has recently been identified in several aquatic invertebrates including sea urchin (Strongylocentrotus purpuratus), bay scallop (Argopecten irradians), and wedgeshell clam (Donax trunculus). We analyzed genomic DNA from scleractinian corals, Acropora surculosa, Favia pallida, Leptoria phrygia, and Goniastrea retiformis to determine the telomere sequence. Southern blot analysis suggests the presence of the vertebrate telomere repeats in all four species. Treatment of A. surculosa sperm DNA with Bal31 exonuclease revealed progressive shortening of the DNA fragments positive for the (TTAGGG)(22) sequence, supporting location of the repeats at the chromosome ends. The presence of the vertebrate telomere repeats in corals is evidence that the (TTAGGG)(n) sequence is highly conserved among a divergent group of vertebrate and invertebrate species. Corals are members of the Lower Metazoans, the group of organisms that span the gap between the fungi and higher metazoans. Corals are the most basal organism reported to have the (TTAGGG)(n) sequence to date, which suggests that the vertebrate telomere sequence may be much older than previously thought and that corals may share a number of genes with their higher relatives.},
}
@article {pmid16896031,
year = {2006},
author = {Finley, JC and Reid, BJ and Odze, RD and Sanchez, CA and Galipeau, P and Li, X and Self, SG and Gollahon, KA and Blount, PL and Rabinovitch, PS},
title = {Chromosomal instability in Barrett's esophagus is related to telomere shortening.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {15},
number = {8},
pages = {1451-1457},
doi = {10.1158/1055-9965.EPI-05-0837},
pmid = {16896031},
issn = {1055-9965},
support = {P01CA91955/CA/NCI NIH HHS/United States ; P30AG13280/AG/NIA NIH HHS/United States ; T32CA09437/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma/genetics ; Aged ; Anaphase/genetics ; Barrett Esophagus/complications/*genetics ; *Chromosomal Instability ; Chromosomes, Human/genetics ; Esophageal Neoplasms/*genetics ; Esophagus/metabolism ; Flow Cytometry ; Gastroesophageal Reflux/genetics/pathology ; Humans ; In Situ Hybridization, Fluorescence/methods ; Metaplasia/genetics ; Middle Aged ; Telomere/genetics/*metabolism ; },
abstract = {Barrett's esophagus is a useful model for the study of carcinogenesis, as the metaplastic columnar epithelium that replaces squamous esophageal epithelium is at elevated risk for development of adenocarcinoma. We examined telomere length and chromosomal instability (CIN) in Barrett's esophagus biopsies using fluorescence in situ hybridization. To study CIN, we selected centromere and locus-specific arm probes to chromosomes 17/17p (p53), 11/11q (cyclin D1), and 9/9p (p16 INK4A), loci reported to be involved in early stages of Barrett's esophagus neoplasia. Telomere shortening was observed in Barrett's esophagus epithelium at all histologic grades, whereas CIN was highest in biopsies with dysplastic changes; there was, however, considerable heterogeneity between patients in each variable. Alterations on chromosome 17 were strongly correlated with telomere length (r = 0.55; P < 0.0001) and loss of the 17p arm signal was the most common event. CIN on chromosome 11 was also associated with telomere shortening (r =0.3; P = 0.05), although 11q arm gains were most common. On chromosome 9p, arm losses were the most common finding, but chromosome 9 CIN was not strongly correlated with telomere length. We conclude that CIN is related to telomere shortening in Barrett's esophagus but varies by chromosome. Whether instability is manifested as loss or gain seems to be influenced by the chromosomal loci involved. Because telomere shortening and CIN are early events in Barrett's esophagus neoplastic progression and are highly variable among patients, it will be important to determine whether they identify a subset of patients that is at risk for more rapid neoplastic evolution.},
}
@article {pmid16890531,
year = {2006},
author = {Francia, S and Weiss, RS and Hande, MP and Freire, R and d'Adda di Fagagna, F},
title = {Telomere and telomerase modulation by the mammalian Rad9/Rad1/Hus1 DNA-damage-checkpoint complex.},
journal = {Current biology : CB},
volume = {16},
number = {15},
pages = {1551-1558},
doi = {10.1016/j.cub.2006.06.066},
pmid = {16890531},
issn = {0960-9822},
support = {R01 CA108773/CA/NCI NIH HHS/United States ; R01 CA108773-01/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle Proteins/genetics/*metabolism ; Cells, Cultured ; Chromatin Immunoprecipitation ; *DNA Damage ; Flow Cytometry ; Genes, cdc/*physiology ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Knockout ; Microscopy, Fluorescence ; Multiprotein Complexes/*metabolism ; RNA, Small Interfering/genetics ; Telomerase/*metabolism ; Telomere/*physiology ; },
abstract = {Telomeres, the termini of linear chromosomes, are exceptional in that they are DNA ends that do not normally trigger a DNA-damage response (DDR) and are compatible with normal cellular proliferation. Mammalian telomeres are nevertheless a physiological substrate of the DDR apparatus, as shown by the fact that the inactivation of genes encoding certain DDR factors results in telomere dysfunction. However, how DDR factors are integrated with telomere physiology, including telomere length regulation by the specialized reverse transcriptase telomerase, is still largely unclear. Here we report that the mammalian Rad9/Rad1/Hus1 (911) checkpoint complex, which localizes to sites of genome damage and promotes DDR signaling, is an integral component of the telomere in human and mouse cells. By the use of quantitative telomere-length measurements, we demonstrate severe telomeric shortening in both Hus1-deficient mouse embryonic fibroblasts and thymocytes from conditional Hus1-knockout mice. We also show that 911 is found in association with catalytically competent telomerase in cell lysates and is a positive regulator of its DNA polymerase activity. These findings identify an unanticipated function for the 911 checkpoint complex at telomeres in mammals and provide a mechanistic link between the activity of DNA-damage-checkpoint proteins and the telomere-maintenance machinery.},
}
@article {pmid16890443,
year = {2006},
author = {Croy, JE and Wuttke, DS},
title = {Themes in ssDNA recognition by telomere-end protection proteins.},
journal = {Trends in biochemical sciences},
volume = {31},
number = {9},
pages = {516-525},
doi = {10.1016/j.tibs.2006.07.004},
pmid = {16890443},
issn = {0968-0004},
support = {R01 GM059414/GM/NIGMS NIH HHS/United States ; GM 071257/GM/NIGMS NIH HHS/United States ; GM 59414/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; DNA, Single-Stranded/*chemistry/metabolism ; DNA-Binding Proteins/*chemistry/metabolism ; Humans ; Models, Molecular ; Protein Conformation ; Telomere/*chemistry/metabolism ; },
abstract = {The ends of eukaryotic linear chromosomes are unique structures that require special management by the cell. If left unattended, the ends are inappropriately processed, leading to genomic instability and problems with proliferation. Telomeres are specialized nucleoprotein structures that restore chromosome stability by protecting and maintaining chromosome ends. Proper telomere function is facilitated, in part, by the telomere-end protection (TEP) family of proteins, which targets the 3' single-stranded (ss) overhang region of the telomere via a specialized ssDNA-binding domain (DBD). With the recent availability of the structures of these DBDs, the ssDNA-binding characteristics of TEP proteins can be compared and the common underlying mechanisms of ssDNA recognition identified, thus providing insights into telomere function.},
}
@article {pmid16888616,
year = {2006},
author = {Brümmendorf, TH and Balabanov, S},
title = {Telomere length dynamics in normal hematopoiesis and in disease states characterized by increased stem cell turnover.},
journal = {Leukemia},
volume = {20},
number = {10},
pages = {1706-1716},
doi = {10.1038/sj.leu.2404339},
pmid = {16888616},
issn = {0887-6924},
mesh = {Animals ; Cell Division ; *Cell Transformation, Neoplastic ; Hematopoiesis/*physiology ; Hematopoietic Stem Cells/pathology ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*pathology/physiopathology ; Myeloproliferative Disorders/*pathology/physiopathology ; Telomere/*pathology ; },
abstract = {Telomeres both reflect and limit the replicative lifespan of normal somatic cells. Immature sub-populations of human CD34+38- hematopoietic stem cell (HSC) can be identified in vitro based on their growth kinetics and telomere length. Fluorescence in situ hybridization and flow cytometry (flow-FISH) has been used to characterize telomere length dynamics as a surrogate marker for HSC turnover in vivo. Investigations in normal steady-state hematopoiesis provided the basis for follow-up studies in model scenarios characterized by increased HSC turnover. Disorders with underlying malignant transformation of HSC (e.g., chronic myeloid leukemia (CML)) can be discriminated from disease states with increased HSC turnover rates secondary to depletion of the stem cell compartment, for example, as in defined bone marrow failure syndromes. In some of these model scenarios, the degree of telomere shortening can be correlated with disease duration, disease stage and severity as well as with response to disease-modifying treatment strategies. Whether increased telomere shortening represents a causal link between HSC turnover, replicative senescence and/or the induction of genetic instability in acquired HSC disorders remains to be shown. However, data from congenital disorders, like dyskeratosis congenita (DKC), suggest that disturbed telomere maintenance may play a role for replicative exhaustion of the HSC pool in vivo.},
}
@article {pmid16886604,
year = {2006},
author = {Kashima, K and Nanashima, A and Yasutake, T and Sawai, T and Tsuji, T and Hidaka, S and Akama, F and Miyashita, K and Tagawa, Y and Nagayasu, T},
title = {Decrease of telomeres and increase of interstitial telomeric sites in chromosomes of short-term cultured gastric carcinoma cells detected by fluorescence in situ hybridization.},
journal = {Anticancer research},
volume = {26},
number = {4B},
pages = {2849-2855},
pmid = {16886604},
issn = {0250-7005},
mesh = {Adult ; Aged ; Chromosomes, Human, Pair 17/genetics ; DNA, Neoplasm/genetics ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Ploidies ; Stomach Neoplasms/*genetics/pathology ; Telomere/genetics/*metabolism ; },
abstract = {BACKGROUND: Deletion or shortening of chromosomal telomeres is associated with cellular aging and carcinogenesis. Telomeric sites are interstitially located in chromosomes. To clarify the frequency of telomerase abnormalities in cancer and their relationship with any characteristics of gastric carcinomas, telomeric aberrations in eleven cultured specimens of human gastric cancer were investigated by cytogenetic analysis.<br><br>MATERIALS AND METHODS: Chromosomal metaphase specimens, obtained by primary culture of cells from surgical specimens of eleven gastric cancer patients, were examined by fluorescent in situ hybridization (FISH) using all telomeric and chromosome 17 specific-telomeric DNA probes. The number of telomeric signals and interstitial telomeric signals (ITS) were counted. DNA ploidy was examined by flow cytometry.<br><br>RESULTS: The mean telomere signal per nucleus (MTS) observed in peripheral blood lymphocytes (PBLs) of normal volunteers (n=10) was 71.3+/-3.9%. The MTS in the carcinoma cells (46.9+/-2.6%) was significantly lower than in PBLs (p<0.01). Although ITS were not observed in PBLs, the mean rate of ITS was 41.2+/-22.0%, and the mean rate of ITS per chromosome was 2.1+/-2.1% in the cancer specimens. In DNA aneuploid carcinoma cells, the MTS was significantly lower, the mean rate of ITS tended to be higher (p=0.072), and the mean rate of ITS per chromosome was significantly higher (p<0.05), than in DNA diploid lymphocytes. Histologically, the mean rate of ITS per chromosome in carcinomas with venous infiltrations was significantly greater than in those without (p<0.05).<br><br>CONCLUSION: Deletion and interstitial translocation of telomeric loci of chromosomes were frequent alterations in gastric carcinoma cells and increased numbers of interstitial telomeric signals were associated with venous invasion.},
}
@article {pmid16886008,
year = {2006},
author = {Price, CM},
title = {Stirring the POT1: surprises in telomere protection.},
journal = {Nature structural &amp; molecular biology},
volume = {13},
number = {8},
pages = {673-674},
doi = {10.1038/nsmb0806-673},
pmid = {16886008},
issn = {1545-9993},
mesh = {Animals ; DNA-Binding Proteins/genetics/*metabolism ; Humans ; Mice ; Shelterin Complex ; *Telomere ; Telomere-Binding Proteins/metabolism ; },
}
@article {pmid16878997,
year = {2006},
author = {Fouché, N and Moon, IK and Keppler, BR and Griffith, JD and Jarstfer, MB},
title = {Electron microscopic visualization of telomerase from Euplotes aediculatus bound to a model telomere DNA.},
journal = {Biochemistry},
volume = {45},
number = {31},
pages = {9624-9631},
doi = {10.1021/bi060313s},
pmid = {16878997},
issn = {0006-2960},
support = {ES013773/ES/NIEHS NIH HHS/United States ; GM31819/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; DNA, Single-Stranded/chemistry/metabolism/ultrastructure ; Euplotes/chemistry/*enzymology/metabolism ; Telomerase/chemistry/metabolism/*ultrastructure ; Telomere/chemistry/*enzymology/metabolism ; },
abstract = {Binding of the telomerase ribonucleoprotein from the ciliate Euplotes aediculatus to telomeric DNA in vitro has been examined by electron microscopy (EM). Visualization of the structures that formed revealed a globular protein complex that localized to the DNA end containing the E. aediculatus telomere consensus 3'-single-strand T(4)G(4)T(4)G(4)T(4)G(2) overhang. Gel filtration confirmed that purified E. aediculatus telomerase is an active dimer in solution, and comparison of the size of the DNA-associated complex with apoferritin suggests that E. aediculatus telomerase binds to a single telomeric 3'-end as a dimer. Up to 43% of the telomerase-DNA complexes appeared by EM to involve tetramers or larger multimers of telomerase in association with two or more DNA ends. These data provide the first direct evidence that telomerase is a functional dimer and suggest that two telomerase ribonucleoprotein particles cooperate to elongate each Euplotes telomere in vivo.},
}
@article {pmid16878131,
year = {2006},
author = {Eugster, A and Lanzuolo, C and Bonneton, M and Luciano, P and Pollice, A and Pulitzer, JF and Stegberg, E and Berthiau, AS and Förstemann, K and Corda, Y and Lingner, J and Géli, V and Gilson, E},
title = {The finger subdomain of yeast telomerase cooperates with Pif1p to limit telomere elongation.},
journal = {Nature structural &amp; molecular biology},
volume = {13},
number = {8},
pages = {734-739},
doi = {10.1038/nsmb1126},
pmid = {16878131},
issn = {1545-9993},
mesh = {DNA Helicases/genetics/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Mutation ; Protein Structure, Tertiary ; RNA, Fungal/metabolism ; S Phase/physiology ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomere synthesis depends on telomerase, which contains an RNA subunit linked to a specialized reverse transcriptase subunit and several associated proteins. Here we report the characterization of four mutations in the yeast reverse transcriptase subunit Est2p that cause an overelongation of telomeres and an increase in the association of Est1p with telomeres during S phase. These 'up-mutations' are clustered in the finger subdomain of the reverse transcriptase. We show that the catalytic properties of the up-mutant telomerases are not improved in vitro. In vivo, the up-mutations neither bypass the activation step governed by Cdc13p nor do they uncouple telomerase from the Rap1p inhibition pathway. In the presence of the up-mutations, however, the ability of the Pif1p helicase to decrease telomere length and to inhibit the association of Est1p with telomeres is impaired. In addition, Pif1p associates in vivo with the telomerase RNA (TLC1) in a way that depends on the finger subdomain. We propose that, in addition to its catalytic role, the finger subdomain of Est2p facilitates the action of Pif1p at telomeres.},
}
@article {pmid16876792,
year = {2006},
author = {Francis, N and Gregg, T and Owen, R and Ebert, T and Bodnar, A},
title = {Lack of age-associated telomere shortening in long- and short-lived species of sea urchins.},
journal = {FEBS letters},
volume = {580},
number = {19},
pages = {4713-4717},
doi = {10.1016/j.febslet.2006.07.049},
pmid = {16876792},
issn = {0014-5793},
mesh = {Animals ; Sea Urchins/*genetics/growth &amp; development ; Species Specificity ; *Telomere ; },
abstract = {The red sea urchin, Strongylocentrotus franciscanus, can live in excess of 100 years while the sea urchin Lytechinus variegatus has an estimated lifespan of only 3-4 years. In an effort to understand the molecular mechanism underlying the difference in their longevity we characterized telomere biology in these species of sea urchins. Telomerase activity was found throughout early stages of development in L. variegatus and is maintained in adult tissues of L. variegatus and S. franciscanus. Terminal restriction fragment analysis indicated a lack of age-associated telomere shortening. These data suggest that long- and short-lived sea urchins do not utilize telomerase repression as a mechanism to suppress neoplastic transformation.},
}
@article {pmid16874667,
year = {2006},
author = {Weise, JM and Günes, C},
title = {Telomeres and telomerase. A survey about methods and recent advances in cancer diagnostic and therapy.},
journal = {Histology and histopathology},
volume = {21},
number = {11},
pages = {1249-1261},
doi = {10.14670/HH-21.1249},
pmid = {16874667},
issn = {1699-5848},
mesh = {Animals ; Base Sequence ; Cellular Senescence ; Genetic Therapy/methods ; Humans ; Immunotherapy/*methods ; Medical Oncology/*methods ; Mice ; Models, Biological ; Molecular Sequence Data ; Neoplasms/*diagnosis/metabolism/*therapy ; Prognosis ; Telomerase/genetics/*metabolism ; Telomere/*ultrastructure ; },
abstract = {Since the discovery that telomerase is repressed in most normal human somatic cells but strongly expressed in most human tumours, telomerase emerged as an attractive target for diagnostic, prognostic and therapeutic purposes to combat human cancer. In this review, a synopsis of methods detecting telomerase is presented evaluating their potential for diagnostic and prognostic use. Also, the most promising telomerase therapeutics are discussed in the light of recent advances in the field.},
}
@article {pmid16869754,
year = {2005},
author = {De Lange, T},
title = {Telomere-related genome instability in cancer.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {70},
number = {},
pages = {197-204},
doi = {10.1101/sqb.2005.70.032},
pmid = {16869754},
issn = {0091-7451},
support = {AG16642/AG/NIA NIH HHS/United States ; CA76027/CA/NCI NIH HHS/United States ; GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Aneuploidy ; Animals ; Chromosome Breakage ; Chromosome Inversion ; DNA Damage ; DNA Repair/genetics ; Gene Amplification ; Gene Deletion ; *Genomic Instability ; Humans ; Loss of Heterozygosity ; Mice ; Mice, Knockout ; Models, Genetic ; Mutation ; Neoplasms/*genetics ; Polyploidy ; Telomerase/deficiency/genetics ; Telomere/*metabolism ; Translocation, Genetic ; },
abstract = {Genome instability is a hallmark of most human cancers. Although a mutator phenotype is not required for tumorigenesis, it can foster mutations that promote tumor progression. Indeed, several inherited cancer-prone syndromes are due to mutations in DNA repair pathways. However, sporadic tumors are usually proficient in DNA repair, making it unlikely that unrepaired lesions are a major source of genome instability in sporadic cancers. A decade ago, I argued in another CSHL Press publication that a "collapse in telomere function can explain a significant portion of the genetic instability in tumors" (de Lange 1995). Since that time, the structure of mammalian telomeres has been analyzed, the consequences of telomere dysfunction have been determined, a mouse model for cancer-relevant aspects of telomere biology has been developed, and the nature and magnitude of cancer genome rearrangements have been revealed. In light of these developments, this is an opportune time to revisit the conjecture that telomere dysfunction contributes to genome instability in human cancer.},
}
@article {pmid16866556,
year = {2006},
author = {Luu, KN and Phan, AT and Kuryavyi, V and Lacroix, L and Patel, DJ},
title = {Structure of the human telomere in K+ solution: an intramolecular (3 + 1) G-quadruplex scaffold.},
journal = {Journal of the American Chemical Society},
volume = {128},
number = {30},
pages = {9963-9970},
pmid = {16866556},
issn = {0002-7863},
support = {GM34504/GM/NIGMS NIH HHS/United States ; R01 GM034504/GM/NIGMS NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; GM66354/GM/NIGMS NIH HHS/United States ; P41 GM066354/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA/*chemistry ; G-Quadruplexes ; Guanine/chemistry ; Humans ; Models, Molecular ; Nucleic Acid Conformation ; Potassium/*chemistry ; Solutions/chemistry ; Telomere/*chemistry ; },
abstract = {We present the intramolecular G-quadruplex structure of human telomeric DNA in physiologically relevant K(+) solution. This G-quadruplex, whose (3 + 1) topology differs from folds reported previously in Na(+) solution and in a K(+)-containing crystal, involves the following: one anti.syn.syn.syn and two syn.anti.anti.anti G-tetrads; one double-chain reversal and two edgewise loops; three G-tracts oriented in one direction and the fourth in the opposite direction. The topological characteristics of this (3 + 1) G-quadruplex scaffold should provide a unique platform for structure-based anticancer drug design targeted to human telomeric DNA.},
}
@article {pmid16862590,
year = {2006},
author = {Rando, TA},
title = {Prognostic value of telomere length: the long and short of it.},
journal = {Annals of neurology},
volume = {60},
number = {2},
pages = {155-157},
doi = {10.1002/ana.20927},
pmid = {16862590},
issn = {0364-5134},
support = {AG023806/AG/NIA NIH HHS/United States ; NS036409/NS/NINDS NIH HHS/United States ; OD000392/OD/NIH HHS/United States ; },
mesh = {Aging/physiology ; Humans ; Monocytes/ultrastructure ; Nervous System Diseases/pathology ; Predictive Value of Tests ; Telomere/*pathology/*ultrastructure ; },
}
@article {pmid16860732,
year = {2006},
author = {Szilard, RK and Durocher, D},
title = {Telomere protection: an act of God.},
journal = {Current biology : CB},
volume = {16},
number = {14},
pages = {R544-6},
doi = {10.1016/j.cub.2006.06.037},
pmid = {16860732},
issn = {0960-9822},
mesh = {DNA Repair ; DNA Repair Enzymes ; Exodeoxyribonucleases/genetics/metabolism/*physiology ; Gene Expression Regulation ; Humans ; Nuclear Proteins/genetics/metabolism/*physiology ; Protein Subunits/metabolism ; S Phase ; Shelterin Complex ; TATA Box Binding Protein-Like Proteins/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 2 ; },
abstract = {Telomeres are nucleoprotein structures that shelter the ends of linear chromosomes from being inappropriately recognized as DNA double-strand breaks. New work has revealed that Apollo, a nuclease previously implicated in DNA repair, also has a role in safeguarding telomeres during S phase.},
}
@article {pmid16860503,
year = {2006},
author = {Ishii, A and Nakamura, K and Kishimoto, H and Honma, N and Aida, J and Sawabe, M and Arai, T and Fujiwara, M and Takeuchi, F and Kato, M and Oshimura, M and Izumiyama, N and Takubo, K},
title = {Telomere shortening with aging in the human pancreas.},
journal = {Experimental gerontology},
volume = {41},
number = {9},
pages = {882-886},
doi = {10.1016/j.exger.2006.06.036},
pmid = {16860503},
issn = {0531-5565},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Child ; Child, Preschool ; DNA/analysis ; Female ; Humans ; Infant ; Longevity/genetics ; Male ; Middle Aged ; Pancreas/chemistry/cytology/*physiology ; Telomere/*genetics ; },
abstract = {We have conducted systematic studies to measure telomere length in human tissues of all types. Progressive telomere shortening with aging was studied in specimens of normal pancreas obtained at autopsy from 69 subjects aged 0 to 100 yr, and age-related shortening of telomere length at a rate of 36 base pairs (bp) per year was detected. Mean telomere length (+/-SD) was 13.9+/-1.4 kilobase pairs (kbp) in 16 neonates, as opposed to 8.4 kbp in 2 centenarians. Mean telomere length (+/-SD) in four age groups, 0-24, 25-49, 50-74, and 75-100 yr, was 13.5+/-1.5, 12.3+/-0.7, 11.3+/-2.5, and 10.7+/-1.8, respectively.},
}
@article {pmid16859480,
year = {2006},
author = {Kuznetsova, IS and Voronin, AP and Podgornaya, OI},
title = {Telomere and TRF2/MTBP localization in respect to satellite DNA during the cell cycle of mouse cell line L929.},
journal = {Rejuvenation research},
volume = {9},
number = {3},
pages = {391-401},
doi = {10.1089/rej.2006.9.391},
pmid = {16859480},
issn = {1549-1684},
mesh = {Animals ; Carrier Proteins/*genetics ; *Cell Cycle ; Centromere ; *DNA, Satellite ; Heterochromatin/genetics ; In Situ Hybridization, Fluorescence ; L Cells ; Mice ; Microscopy, Confocal ; Telomere/*genetics ; Telomeric Repeat Binding Protein 2/*genetics ; },
abstract = {The mouse Mus musculus chromosomes are all acrocentric; each centromere (CEN) is adjacent to a telomere. The aim of the current work is to find out if at least half of the mouse telomeres (Tel) always follow satellite DNA sequences and if membrane telomere binding protein TRF2/MTBP is always in association with the Tel during the cell cycle. FISH, immunoFISH and confocal microscopy were used. During the cell cycle, Tel undergo extensive movement and rearrangement. Most Tel tend to aggregate into large conglomerates in G0/G1. Aggregates colocalize with major satellite (MaSat) and minor satellite (MiSat) to a lesser extent. Tel aggregates are embedded into the MaSat granules at G0/G1. A number of single Tel signals underline the nuclear envelope. In prometaphase, during the metaphase plate formation, half of the Tel, together with CEN, are arranged in a circle and half of the long arms form four clusters. Most of the Tel hybridization signals are colocalized with TRF2/MTBP throughout all stages of the cell cycle, although it is possible to find some telomeres that are not covered with the protein. A prominent shift of TRF2/MTBP signals in respect to the Tel signals is visible in the prophase. The biochemical features of TRF2/MTBP make it possible for the protein to be responsible for Tel clustering.},
}
@article {pmid16858685,
year = {2006},
author = {Bisoffi, M and Heaphy, CM and Griffith, JK},
title = {Telomeres: prognostic markers for solid tumors.},
journal = {International journal of cancer},
volume = {119},
number = {10},
pages = {2255-2260},
doi = {10.1002/ijc.22120},
pmid = {16858685},
issn = {0020-7136},
mesh = {Animals ; *Biomarkers, Tumor ; Breast Neoplasms/genetics ; Colorectal Neoplasms/genetics ; DNA, Neoplasm/*analysis ; Female ; Genomic Instability ; Humans ; Lung Neoplasms/genetics ; Male ; Neoplasms/*genetics ; Predictive Value of Tests ; Prognosis ; Prostatic Neoplasms/genetics ; Risk Assessment ; Risk Factors ; Sequence Analysis, DNA ; *Telomere ; },
abstract = {Solid tumors continue to affect millions of people worldwide. Increasingly sophisticated diagnostic tools contribute to the high incidence rates for some tumor types, and treatment options continue to expand. However, the progression of solid tumors represents a challenge for the appropriate treatment of individual patients because of the relative inaccuracy of current prognostic markers, including the widely used Tumor-Nodes-Metastasis (TNM) staging system, to predict the course of disease. As a result, both over- and undertreatment are clinical realities in the management of patients diagnosed with solid tumors. Therefore, population-based screening programs that increase the overall cancer incidence rates are controversial, as they may do little to improve the patient's quality of life. Consequently, there is a strong need to develop novel and independent markers of prognosis. In this context, we review the use of telomeres as prognostic markers for solid tumors, including cancers from lung, breast, prostate, colon, brain and head and neck. Telomeric sequences, the repetitive DNA at the end of human chromosomes, are mediators of genomic stability and can undergo length alterations during tumor initiation and progression. In a number of studies reviewed here, these alterations, measured as telomere attrition and elongation, have been shown either to be associated with clinical markers of disease progression or to be independent markers of cancer prognosis. We conclude from these studies that careful assessment of telomere length or its proxies, such as telomere DNA content, will be part of novel risk assessment and prognostic modalities for patients with solid tumors.},
}
@article {pmid16856882,
year = {2006},
author = {Cherkas, LF and Aviv, A and Valdes, AM and Hunkin, JL and Gardner, JP and Surdulescu, GL and Kimura, M and Spector, TD},
title = {The effects of social status on biological aging as measured by white-blood-cell telomere length.},
journal = {Aging cell},
volume = {5},
number = {5},
pages = {361-365},
doi = {10.1111/j.1474-9726.2006.00222.x},
pmid = {16856882},
issn = {1474-9718},
support = {074951//Wellcome Trust/United Kingdom ; AG020132/AG/NIA NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; HL070137/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; *Aging ; Cohort Studies ; Female ; Humans ; *Leukocytes ; Linear Models ; Middle Aged ; Multivariate Analysis ; Polymorphism, Restriction Fragment Length ; Registries ; Risk Factors ; *Socioeconomic Factors ; Surveys and Questionnaires ; *Telomere ; Twins, Dizygotic ; Twins, Monozygotic ; White People ; },
abstract = {Low socio-economic status (SES) is associated with a shortened life expectancy, but its effect on aging is unknown. The rate of white-blood-cell (WBC) telomere attrition may be a biological indicator of human aging. We tested the hypothesis that SES is associated with telomere attrition independent of known risk factors influencing the aging process. We studied 1552 female twins. A venous blood sample was taken from each twin and isolated WBCs used for extraction of DNA. Terminal restriction fragment length (TRFL) was measured. Questionnaire data were collected on occupation, education, income, smoking, exercise, height and weight. Standard multiple linear regression and multivariate analyses of variance tested for associations between SES and TRFL, adjusting for covariates. A discordant twin analysis was conducted on a subset to verify findings. WBC telomere length was highly variable but significantly shorter in lower SES groups. The mean difference in TRFL between nonmanual and manual SES groups was 163.2 base pairs (bp) of which 22.9 bp (approximately 14%) was accounted for by body mass index, smoking and exercise. Comparison of TRFL in the 17 most discordant SES twin pairs confirmed this difference. Low SES, in addition to the harmful effects of smoking, obesity and lack of exercise, appears to have an impact on telomere length.},
}
@article {pmid16856866,
year = {2006},
author = {Britt-Compton, B and Baird, DM},
title = {Intra-allelic mutation at human telomeres.},
journal = {Biochemical Society transactions},
volume = {34},
number = {Pt 4},
pages = {581-582},
doi = {10.1042/BST0340581},
pmid = {16856866},
issn = {0300-5127},
mesh = {*Alleles ; Chromosomes, Human/genetics ; Humans ; Mutation/genetics ; Recombination, Genetic/genetics ; Telomere/*genetics ; },
abstract = {The maintenance of telomere length is important in upholding the integrity of the genome. However, it is clear from detailed observations of both telomere length and internal repeat structure that human telomeres are extremely dynamic structures and are subjected to multiple processes that create considerable heterogeneity. Genetic evidence suggests that meiotic recombination within telomeres is rare. However, there are various lines of evidence that implicate the involvement of intra-allelic processes in human telomere dynamics. In this paper, we briefly review some of this evidence and the putative mechanisms of intra-allelic telomeric mutation.},
}
@article {pmid16856857,
year = {2006},
author = {Scherthan, H},
title = {Factors directing telomere dynamics in synaptic meiosis.},
journal = {Biochemical Society transactions},
volume = {34},
number = {Pt 4},
pages = {550-553},
doi = {10.1042/BST0340550},
pmid = {16856857},
issn = {0300-5127},
mesh = {Actins/metabolism ; Animals ; Cytoskeleton/metabolism ; Meiosis ; Microtubules/metabolism ; Synapses/*genetics ; Telomere/*genetics ; },
abstract = {Meiosis creates haploid cells from diploid progenitors. Homologous chromosomes are moved, paired and segregated from each other in a specialized meiosis I division. A second division that lacks a preceding S-phase produces haploid cells. In prophase I, chromosomes attach with their telomeres to the nuclear envelope and undergo oscillating movements that become restricted to a limited nuclear sector during the widely conserved bouquet stage. Recent observations in budding yeast meiosis suggest that telomere clustering depends on actin, whereas exit from the bouquet stage requires meiotic cohesin. Telomere clustering may also be modulated by progression in recombination. These observations suggest that the unique meiotic nuclear topology and telomere dynamics are regulated at different levels.},
}
@article {pmid16855394,
year = {2006},
author = {Nishiyama, A and Ishikawa, F},
title = {Cell-cycle-dependent regulation of telomere binding proteins: roles of Polo-like kinase.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {5},
number = {13},
pages = {1403-1406},
doi = {10.4161/cc.5.13.2923},
pmid = {16855394},
issn = {1551-4005},
mesh = {Animals ; *Cell Cycle ; Chromatin/genetics/metabolism ; Humans ; Protein Binding ; Telomerase/metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {The telomere is a functional complex at chromosomal termini consisting of repetitive DNA and associated proteins, and protects the ends against degradation and fusion. Telomeric repeat binding factors TRF1 and TRF2 bind directly to double-stranded telomeric DNA. Although structurally related, TRF1 and TRF2 contribute to telomere maintenance in distinct ways: TRF1 negatively regulates telomerase-dependent telomere lengthening, whereas TRF2 plays an important role in protecting chromosomal ends. It is not known how the proteinaceous complex manages DNA metabolism such as DNA replication, which requires the recruitment of numerous trans-acting factors. We have found that Xenopus TRF1 (xTRF1) specifically associates with mitotic chromatin and dissociates from interphase replicating chromatin. In contrast, Xenopus TRF2 (xTRF2) binds to telomeric DNA throughout the cell cycle. Interestingly, telomerase activity is associated with the interphase chromatin, but not with the mitotic chromatin. These results support a model in which telomeres form a semi-open configuration that allows access of telomerase and replication machineries, yet protects the chromosomal ends in S phase. Interestingly, M phase specific telomere binding of xTRF1 requires Polo-like kinase, a key regulator of mitosis. We discuss the relevance of our studies and recent findings of other groups to indicate the possible role of Polo-like kinase in telomere regulation.},
}
@article {pmid16849533,
year = {2006},
author = {Gomez, D and O'Donohue, MF and Wenner, T and Douarre, C and Macadré, J and Koebel, P and Giraud-Panis, MJ and Kaplan, H and Kolkes, A and Shin-ya, K and Riou, JF},
title = {The G-quadruplex ligand telomestatin inhibits POT1 binding to telomeric sequences in vitro and induces GFP-POT1 dissociation from telomeres in human cells.},
journal = {Cancer research},
volume = {66},
number = {14},
pages = {6908-6912},
doi = {10.1158/0008-5472.CAN-06-1581},
pmid = {16849533},
issn = {0008-5472},
mesh = {Cell Line ; DNA/biosynthesis/drug effects/genetics/*metabolism ; G-Quadruplexes ; Green Fluorescent Proteins/genetics/metabolism ; Humans ; Kidney/cytology/drug effects/metabolism ; Nuclear Proteins/metabolism ; Oxazoles/*pharmacology ; Protein Binding ; Recombinant Fusion Proteins/genetics/metabolism ; Shelterin Complex ; TATA Box Binding Protein-Like Proteins/metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/*antagonists &amp; inhibitors/genetics/metabolism ; Telomeric Repeat Binding Protein 2 ; Transfection ; },
abstract = {Telomestatin is a potent G-quadruplex ligand that specifically interacts with the 3' telomeric overhang, leading to its degradation and that induces a delayed senescence and apoptosis of cancer cells. Protection of Telomere 1 (POT1) was recently identified as a specific single-stranded telomere-binding protein involved in telomere capping and T-loop maintenance. We showed here that a telomestatin treatment inhibits POT1 binding to the telomeric overhang in vitro. The treatment of human EcR293 cells by telomestatin induces a dramatic and rapid delocalization of POT1 from its normal telomere sites but does not affect the telomere localization of the double-stranded telomere-binding protein TRF2. Thus, we propose that G-quadruplex stabilization at telomeric G-overhang inactivates POT1 telomeric function, generating a telomere dysfunction in which chromosome ends are no longer properly protected.},
}
@article {pmid16845382,
year = {2006},
author = {Celli, GB and Denchi, EL and de Lange, T},
title = {Ku70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination.},
journal = {Nature cell biology},
volume = {8},
number = {8},
pages = {885-890},
doi = {10.1038/ncb1444},
pmid = {16845382},
issn = {1465-7392},
support = {GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Antigens, Nuclear/genetics/*physiology ; Checkpoint Kinase 2 ; Chromosomes, Mammalian/*genetics ; DNA Ligase ATP ; DNA Ligases/metabolism ; DNA Repair ; DNA-Binding Proteins/genetics/*physiology ; Immunoblotting ; Ku Autoantigen ; Mice ; Mice, Knockout ; Microscopy, Fluorescence ; Models, Biological ; Protein Serine-Threonine Kinases/metabolism ; Recombination, Genetic/genetics ; Signal Transduction/physiology ; Sister Chromatid Exchange/*genetics ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/physiology ; },
abstract = {Ku70-Ku80 heterodimers promote the non-homologous end-joining (NHEJ) of DNA breaks and, as shown here, the fusion of dysfunctional telomeres. Paradoxically, this heterodimer is also located at functional mammalian telomeres and interacts with components of shelterin, the protein complex that protects telomeres. To determine whether Ku contributes to telomere protection, we analysed Ku70(-/-) mouse cells. Telomeres of Ku70(-/-) cells had a normal DNA structure and did not activate a DNA damage signal. However, Ku70 repressed exchanges between sister telomeres - a form of homologous recombination implicated in the alternative lengthening of telomeres (ALT) pathway. Sister telomere exchanges occurred at approximately 15% of the chromosome ends when Ku70 and the telomeric protein TRF2 were absent. Combined deficiency of TRF2 and another NHEJ factor, DNA ligase IV, did not elicit this phenotype. Sister telomere exchanges were not elevated at telomeres with functional TRF2, indicating that TRF2 and Ku70 act in parallel to repress recombination. We conclude that mammalian chromosome ends are highly susceptible to homologous recombination, which can endanger cell viability if an unequal exchange generates a critically shortened telomere. Therefore, Ku- and TRF2-mediated repression of homologous recombination is an important aspect of telomere protection.},
}
@article {pmid16842820,
year = {2006},
author = {Croy, JE and Podell, ER and Wuttke, DS},
title = {A new model for Schizosaccharomyces pombe telomere recognition: the telomeric single-stranded DNA-binding activity of Pot11-389.},
journal = {Journal of molecular biology},
volume = {361},
number = {1},
pages = {80-93},
doi = {10.1016/j.jmb.2006.06.002},
pmid = {16842820},
issn = {0022-2836},
support = {R01 GM059414/GM/NIGMS NIH HHS/United States ; GM071257/GM/NIGMS NIH HHS/United States ; GM59414/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; DNA, Single-Stranded/genetics/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; *Models, Genetic ; Molecular Sequence Data ; Peptide Fragments/genetics/metabolism ; Protein Binding/genetics ; Protein Structure, Tertiary/genetics ; Schizosaccharomyces/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {The protection of telomeres 1 (Pot1) proteins specifically recognize the single-stranded 3' end of the telomere, an activity essential for sustained cellular viability and proliferation. The current model for the telomeric single-stranded DNA (ssDNA) binding activity of Schizosaccharomyces pombe Pot1 is based on a 20 kDa fragment, Pot1pN. Recent biochemical studies suggest that SpPot1 contains a larger ssDNA-binding domain and we have identified a novel ssDNA-binding domain similar in size to the human Pot1 domain. This domain, Pot1(1-389), binds extremely tightly to an oligonucleotide consisting of two conserved hexameric S. pombe telomere repeats, d(GGTTACGGTTAC), with an affinity approximately 4000-fold tighter than Pot1pN binds its cognate ssDNA. The Pot1(1-389)/ssDNA complex exhibits a half-life of 53 min, consistent with that estimated for full-length SpPot1 and significantly longer than that of Pot1pN. Single nucleotide substitutions reveal that, in contrast to Pot1pN, tandem trinucleotide repeats (GTT) within d(GGTTACGGTTAC) are specifically recognized by Pot1(1-389). Interestingly, certain single nucleotide substitutions that impacted Pot1pN binding exhibited no effect on binding affinity by Pot1(1-389). However, these substitutions reduced binding affinity when simultaneously substituted in each hexameric repeat. The non-additive nature of these substitutions suggests that certain nucleotides are coupled through the ability of the flexible ssDNA oligonucleotide to adopt alternate, thermodynamically equivalent conformations. The biochemical behavior of Pot1(1-389) is more similar to that of the full-length SpPot1 protein than to that of Pot1pN, making Pot1(1-389) a valuable domain for the future study of how full-length SpPot1 interacts with telomeric ssDNA.},
}
@article {pmid16839877,
year = {2006},
author = {Hockemeyer, D and Daniels, JP and Takai, H and de Lange, T},
title = {Recent expansion of the telomeric complex in rodents: Two distinct POT1 proteins protect mouse telomeres.},
journal = {Cell},
volume = {126},
number = {1},
pages = {63-77},
doi = {10.1016/j.cell.2006.04.044},
pmid = {16839877},
issn = {0092-8674},
support = {AG16642/AG/NIA NIH HHS/United States ; GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Division/genetics ; Cell Proliferation ; Cells, Cultured ; Cellular Senescence/*genetics ; DNA Damage/*genetics ; DNA Replication/genetics ; DNA, Single-Stranded/genetics ; DNA-Binding Proteins/*genetics ; Evolution, Molecular ; Genes, Lethal/genetics ; Genomic Instability/*genetics ; Humans ; Mice ; Mice, Knockout ; Protein Isoforms/genetics ; Repressor Proteins/genetics ; Shelterin Complex ; Signal Transduction/genetics ; Species Specificity ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; Telomeric Repeat Binding Protein 2/genetics ; },
abstract = {Human telomeres are protected by shelterin, a complex that includes the POT1 single-stranded DNA binding protein. We found that mouse telomeres contain two POT1 paralogs, POT1a and POT1b, and we used conditional deletion to determine their function. Double-knockout cells showed that POT1a/b are required to prevent a DNA damage signal at chromosome ends, endoreduplication, and senescence. In contrast, POT1a/b were largely dispensable for repression of telomere fusions. Single knockouts and complementation experiments revealed that POT1a and POT1b have distinct functions. POT1a, but not POT1b, was required to repress a DNA damage signal at telomeres. Conversely, POT1b, but not POT1a, had the ability to regulate the amount of single-stranded DNA at the telomere terminus. We conclude that mouse telomeres require two distinct POT1 proteins whereas human telomeres have one. Such divergence is unprecedented in mammalian chromosome biology and has implications for modeling human telomere biology in mice.},
}
@article {pmid16839876,
year = {2006},
author = {Wu, L and Multani, AS and He, H and Cosme-Blanco, W and Deng, Y and Deng, JM and Bachilo, O and Pathak, S and Tahara, H and Bailey, SM and Deng, Y and Behringer, RR and Chang, S},
title = {Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres.},
journal = {Cell},
volume = {126},
number = {1},
pages = {49-62},
doi = {10.1016/j.cell.2006.05.037},
pmid = {16839876},
issn = {0092-8674},
support = {R01 CA129037/CA/NCI NIH HHS/United States ; CA016672/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle Proteins/genetics ; Cells, Cultured ; Cellular Senescence/genetics ; Chromosome Aberrations ; DNA Damage/*genetics ; DNA Repair/genetics ; DNA-Binding Proteins/*genetics ; Gene Silencing/physiology ; Genes, cdc/*physiology ; Genomic Instability/*genetics ; Mice ; Mice, Knockout ; Nuclear Proteins/genetics ; Protein Isoforms/genetics ; Recombination, Genetic/*genetics ; Sequence Homology ; Shelterin Complex ; Sister Chromatid Exchange/genetics ; Telomere/*genetics ; Telomere-Binding Proteins ; },
abstract = {The terminal t-loop structure adopted by mammalian telomeres is thought to prevent telomeres from being recognized as double-stranded DNA breaks by sequestering the 3' single-stranded G-rich overhang from exposure to the DNA damage machinery. The POT1 (protection of telomeres) protein binds the single-stranded overhang and is required for both chromosomal end protection and telomere length regulation. The mouse genome contains two POT1 orthologs, Pot1a and Pot1b. Here we show that conditional deletion of Pot1a elicits a DNA damage response at telomeres, resulting in p53-dependent replicative senescence. Pot1a-deficient cells exhibit overall telomere length and 3' overhang elongation as well as aberrant homologous recombination (HR) at telomeres, manifested as increased telomere sister chromatid exchanges and formation of telomere circles. Telomeric HR following Pot1a loss requires NBS1. Pot1a deletion also results in chromosomal instability. Our results suggest that POT1a is crucial for the maintenance of both telomere integrity and overall genomic stability.},
}
@article {pmid16839874,
year = {2006},
author = {Baumann, P},
title = {Are mouse telomeres going to pot?.},
journal = {Cell},
volume = {126},
number = {1},
pages = {33-36},
doi = {10.1016/j.cell.2006.06.027},
pmid = {16839874},
issn = {0092-8674},
mesh = {Animals ; Cellular Senescence/genetics ; DNA/chemistry/*genetics ; DNA Damage/*genetics ; DNA Repair/*genetics ; DNA-Binding Proteins/*genetics ; Gene Expression Regulation/genetics ; Mice ; Shelterin Complex ; Signal Transduction/genetics ; Telomere/*genetics ; Telomere-Binding Proteins ; },
abstract = {Pot1 is a conserved single-stranded DNA binding protein with crucial functions in the protection of telomeres and maintenance of their length. In this issue of Cell, two papers (Hockemeyer et al., 2006; Wu et al., 2006) examine the roles of murine Pot1 homologs and describe intriguing new insights into how cells protect their chromosome ends from DNA-repair activities.},
}
@article {pmid16838844,
year = {2006},
author = {Yamaguchi, T and Saneyoshi, M and Takahashi, H and Hirokawa, S and Amano, R and Liu, X and Inomata, M and Maruyama, T},
title = {Synthetic nucleosides and nucleotides. 43. Inhibition of vertebrate telomerases by carbocyclic oxetanocin g (C.OXT-G) triphosphate analogues and influence of C.OXT-G treatment on telomere length in human HL60 cells.},
journal = {Nucleosides, nucleotides &amp; nucleic acids},
volume = {25},
number = {4-6},
pages = {539-551},
doi = {10.1080/15257770600684217},
pmid = {16838844},
issn = {1525-7770},
mesh = {Animals ; Guanine/*analogs &amp; derivatives/chemistry/pharmacology ; Guanosine Triphosphate/*chemistry ; HL-60 Cells ; Humans ; Molecular Structure ; Salmon/metabolism ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects/genetics/metabolism ; },
abstract = {Telomerase, responsible for telomere synthesis, is expressed in approximately 90% of human tumor cells but seldom in normal somatic cells. In this study, inhibition by carbocyclic oxetanocin G triphosphate (C. OXT-GTP) and its analogues was investigated in order to clarify the susceptibility of telomerase to various nucleotide analogues. C. OXT-GTP competitively inhibited telomerase activity with respect to dGTP However, C. OXT-GTP had a potent inhibitory effect on DNA polymerase alpha. It was examined whether the nucleoside (C. OXT-G) was able to alter telomere length in cultured human HL60 cells. Contrary to expectation, long-term treatment with 10 microM C. OXT-G was found to cause telomere lengthening.},
}
@article {pmid16834337,
year = {2006},
author = {Suzuki, T and McKenzie, M and Ott, E and Ilkun, O and Horvath, MP},
title = {DNA binding affinity and sequence permutation preference of the telomere protein from Euplotes crassus.},
journal = {Biochemistry},
volume = {45},
number = {28},
pages = {8628-8638},
pmid = {16834337},
issn = {0006-2960},
support = {R01 GM067994-01/GM/NIGMS NIH HHS/United States ; R01 GM067994-03/GM/NIGMS NIH HHS/United States ; R01 GM067994-02/GM/NIGMS NIH HHS/United States ; 5P30 CA42014/CA/NCI NIH HHS/United States ; R01 GM067994/GM/NIGMS NIH HHS/United States ; P30 CA042014/CA/NCI NIH HHS/United States ; R01 GM067994-04/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cloning, Molecular ; DNA, Single-Stranded/*chemistry/metabolism ; DNA-Binding Proteins/*chemistry/genetics/metabolism ; Escherichia coli/genetics ; Euplotes/*metabolism ; Phylogeny ; Protein Structure, Tertiary ; Protozoan Proteins/*chemistry/genetics/metabolism ; Telomere/chemistry/genetics/metabolism ; Telomere-Binding Proteins/*chemistry/genetics/metabolism ; },
abstract = {Telomere end binding proteins from diverse organisms use various forms of an ancient protein structure to recognize and bind with single-strand DNA found at the ends of telomeres. To further understand the biochemistry and evolution of these proteins, we have characterized the DNA binding properties of the telomere end binding protein from Euplotes crassus (EcTEBP). EcTEBP and its predicted amino-terminal DNA-binding domain, EcTEBP-N, were expressed in Escherichia coli and purified. Each protein formed stoichiometric (1:1) complexes with single-strand DNA oligos derived from the precisely defined d(TTTTGGGGTTTTGG) sequence found at DNA termini in Euplotes. Dissociation constants for DNA x EcTEBP and DNA x EcTEBP-N complexes were comparable: K(D-DNA) = 38 +/- 2 nM for the full-length protein and K(D-DNA) = 60 +/- 4 nM for the N-terminal domain, indicating that the N-terminal domain retains a high affinity for DNA even in the absence of potentially stabilizing moieties located in the C-terminal domain. Rate constants for DNA association and DNA dissociation corroborated a slightly improved DNA binding performance for the full-length protein (ka = 45 +/- 4 microM(-1) s(-1), kd = 0.10 +/- 0.02 s(-1)) relative to that of the N-terminal domain (ka = 18 +/- 1 microM(-1) s(-1), kd = 0.15 +/- 0.01 s(-1)). Equilibrium dissociation constants measured for sequence permutations of the telomere repeat spanned the range of 55-1400 nM, with EcTEBP and EcTEBP-N binding most tightly to d(TTGGGGTTTTGG), the sequence corresponding to that of mature DNA termini. Additionally, competition experiments showed that EcTEBP recognizes and binds the telomere-derived 14-nucleotide DNA in preference to shorter 5'-truncation variants. Compared with the results for multisubunit complexes assembled with telomere single-strand DNA from Oxytricha nova, our results highlight the relative simplicity of the E. crassus system where a telomere end binding protein has biochemical properties indicating one protein subunit caps the single-strand DNA.},
}
@article {pmid16828709,
year = {2006},
author = {Sklavounou, E and Hay, A and Ashraf, N and Lamb, K and Brown, E and Mac Intyre, A and George, WD and Hartley, RC and Shiels, PG},
title = {The use of telomere biology to identify and develop superior nitrone based anti-oxidants.},
journal = {Biochemical and biophysical research communications},
volume = {347},
number = {2},
pages = {420-427},
doi = {10.1016/j.bbrc.2006.06.087},
pmid = {16828709},
issn = {0006-291X},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Antioxidants/chemistry/*pharmacology ; Bromodeoxyuridine/metabolism ; Cells, Cultured ; Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Cyclin-Dependent Kinase Inhibitor p21/genetics ; DNA Helicases/genetics ; Dose-Response Relationship, Drug ; *Drug Design ; Fibroblasts/cytology/drug effects/metabolism ; Gene Expression/drug effects ; Humans ; Hydrogen Peroxide/pharmacology ; Infant, Newborn ; Ku Autoantigen ; Molecular Structure ; Nitrogen Oxides/*chemistry ; Oxidants/pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Structure-Activity Relationship ; Telomere/*drug effects/genetics/metabolism ; beta-Galactosidase/metabolism ; },
abstract = {We have employed a biological chemistry approach to dissect the mechanisms underpinning cellular responses to oxidant stress and to develop biologically relevant anti-oxidants. We have used telomere biology to define cellular stress responses and have observed telomere independent, p21- and p16-dependent stasis following oxidative insult in human fibroblasts. This was accompanied by a [corrected] reduction in XRCC5 expression and a reduction in [corrected] SIRT 1 expression. Using these markers in conjunction with senescence-associated beta-galactosidase expression, we have developed and screened novel nitrone based anti-oxidant compounds. We have identified functional compounds that are unsuitable for use in primary human cells. This has allowed subsequent identification of suitably structured compounds that act as superior biological anti-oxidants, which have potential for use in clinical interventions.},
}
@article {pmid16824017,
year = {2006},
author = {Stewart, SA and Weinberg, RA},
title = {Telomeres: cancer to human aging.},
journal = {Annual review of cell and developmental biology},
volume = {22},
number = {},
pages = {531-557},
doi = {10.1146/annurev.cellbio.22.010305.104518},
pmid = {16824017},
issn = {1081-0706},
mesh = {Aging/*physiology ; Animals ; Cellular Senescence ; Humans ; Neoplasms/genetics/*pathology ; Telomerase/metabolism ; Telomere/*metabolism/pathology ; Telomere-Binding Proteins/metabolism ; },
abstract = {The cell phenotypes of senescence and crisis operate to circumscribe the proliferative potential of mammalian cells, suggesting that both are capable of operating in vivo to suppress the formation of tumors. The key regulators of these phenotypes are the telomeres, which are located at the ends of chromosomes and operate to protect the chromosomes from end-to-end fusions. Telomere erosion below a certain length can trigger crisis. The relationship between senescence and telomere function is more complex, however: Cell-physiological stresses as well as dysfunction of the complex molecular structures at the ends of telomeric DNA can trigger senescence. Cells can escape senescence by inactivating the Rb and p53 tumor suppressor proteins and can surmount crisis by activating a telomere maintenance mechanism. The resulting cell immortalization is an essential component of the tumorigenic phenotype of human cancer cells. Here we discuss how telomeres are monitored and maintained and how loss of a functional telomere influences biological functions as diverse as aging and carcinogenesis.},
}
@article {pmid16823616,
year = {2006},
author = {Hu, J},
title = {Defining the sunflower (Helianthus annuus L.) linkage group ends with the Arabidopsis-type telomere sequence repeat-derived markers.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {14},
number = {5},
pages = {535-548},
pmid = {16823616},
issn = {0967-3849},
mesh = {Arabidopsis/*genetics ; Base Sequence ; Chromosome Mapping ; DNA, Plant ; Genetic Linkage/*genetics ; Helianthus/*genetics ; Molecular Sequence Data ; Polymorphism, Genetic ; Sequence Analysis, DNA ; Telomere ; *Telomere-Binding Proteins ; },
abstract = {The target region amplification polymorphism (TRAP) marker technique was employed to define sunflower (Helianthus annuus L.) linkage group ends. In combination with eight arbitrary primers, nine fixed primers containing the Arabidopsis-type telomere repeat sequences worked successfully in generating polymorphic markers in the mapping population of 92 F(7) recombinant inbred lines (RIL) derived from the cross RHA 280 x RHA 801. This population was used in the construction of the densest sunflower linkage map of 577 simple sequence repeat (SSR) markers. With 18 sets of PCR reactions, 226 polymorphic TRAP markers were amplified from the two parental lines and 92 RIL. The computer program, Mapmaker, placed 183 markers into the established 17 linkage groups of the SSR map. Although most of the added markers spread across the genome, 32 markers were mapped to the outermost positions of the linkage groups, defining 21 of the 34 linkage group ends of the sunflower linkage map. The telomeric origin of a few of these markers was confirmed by sequence analyses. These telomere-associated markers will provide an accurate assessment of the completeness of a linkage group and a better estimate of the actual genetic lengths. The potential application of the telomere mapping to sunflower improvement is discussed.},
}
@article {pmid16822606,
year = {2007},
author = {Kaushik, M and Suehl, N and Marky, LA},
title = {Calorimetric unfolding of the bimolecular and i-motif complexes of the human telomere complementary strand, d(C(3)TA(2))(4).},
journal = {Biophysical chemistry},
volume = {126},
number = {1-3},
pages = {154-164},
doi = {10.1016/j.bpc.2006.05.031},
pmid = {16822606},
issn = {0301-4622},
mesh = {Adenine/chemistry ; Base Sequence ; Calorimetry, Differential Scanning ; Cytosine/chemistry ; DNA, Complementary/*chemistry ; DNA, Single-Stranded/*chemistry ; Humans ; *Nucleic Acid Conformation ; Nucleic Acid Denaturation ; Protons ; Spectrophotometry, Ultraviolet ; Telomere/*chemistry ; *Thermodynamics ; Thymine/chemistry ; Transition Temperature ; Water/chemistry ; },
abstract = {A combination of spectroscopic and calorimetric techniques is used to determine the unfolding thermodynamics of the complexes formed by the complementary sequence of the human telomere, d(C(3)TA(2))(4), in the pH range of 4.2 to 6. Calorimetric melting curves show biphasic transitions; both transitions are shifted to higher temperatures as the pH is decreased, indicative of cytosine protonation, which favors the formation of C*C(+) base pairs. Furthermore, the transition temperature, T(M), of the lower transition depends on strand concentration, while the T(M) of the higher transition is independent of strand concentration, indicating the following sequential melting: bimolecular complex(s)-->intramolecular complex-->random coil. The thermodynamic profiles for the formation of each complex, bimolecular and i-motif reveals small favorable free energy terms resulting from favorable enthalpy-unfavorable entropy compensations, uptake of protons, marginal uptake of counterions (i-motif) and marginal release of water molecules (i-motif). Furthermore, an enthalpy of 3.2 kcal/mol (bimolecular complex) and 5.0 kcal/mol (i-motif) is estimated for a single C*C(+)/C*C(+) base-pair stack.},
}
@article {pmid16822175,
year = {2006},
author = {Riha, K and Heacock, ML and Shippen, DE},
title = {The role of the nonhomologous end-joining DNA double-strand break repair pathway in telomere biology.},
journal = {Annual review of genetics},
volume = {40},
number = {},
pages = {237-277},
doi = {10.1146/annurev.genet.39.110304.095755},
pmid = {16822175},
issn = {0066-4197},
mesh = {Animals ; *DNA Breaks, Double-Stranded ; *DNA Repair ; DNA-Binding Proteins/metabolism ; Genomic Instability ; Humans ; Models, Biological ; Telomere/*metabolism ; },
abstract = {Double-strand breaks are a cataclysmic threat to genome integrity. In higher eukaryotes the predominant recourse is the nonhomologous end-joining (NHEJ) double-strand break repair pathway. NHEJ is a versatile mechanism employing the Ku heterodimer, ligase IV/XRCC4 and a host of other proteins that juxtapose two free DNA ends for ligation. A critical function of telomeres is their ability to distinguish the ends of linear chromosomes from double-strand breaks, and avoid NHEJ. Telomeres accomplish this feat by forming a unique higher order nucleoprotein structure. Paradoxically, key components of NHEJ associate with normal telomeres and are required for proper length regulation and end protection. Here we review the biochemical mechanism of NHEJ in double-strand break repair, and in the response to dysfunctional telomeres. We discuss the ways in which NHEJ proteins contribute to telomere biology, and highlight how the NHEJ machinery and the telomere complex are evolving to maintain genome stability.},
}
@article {pmid16820926,
year = {2006},
author = {de Souza Nascimento, P and Alves, G and Fiedler, W},
title = {Telomerase inhibition by an siRNA directed against hTERT leads to telomere attrition in HT29 cells.},
journal = {Oncology reports},
volume = {16},
number = {2},
pages = {423-428},
pmid = {16820926},
issn = {1021-335X},
mesh = {Adenocarcinoma/*enzymology/genetics ; Colorectal Neoplasms/*enzymology/genetics ; DNA-Binding Proteins/*antagonists &amp; inhibitors/genetics ; Genomic Instability ; Humans ; Microsatellite Repeats ; RNA Interference ; RNA, Messenger/analysis/metabolism ; RNA, Small Interfering/genetics/*pharmacology ; Telomerase/*antagonists &amp; inhibitors/genetics ; Telomere/*metabolism ; Tumor Cells, Cultured ; },
abstract = {Human telomerase is a ribonucleoprotein complex composed of at least the reverse catalytic transcriptase hTERT and RNA component hTR. The enzyme stabilizes telomere length and thereby contributes to unlimited cell proliferation, i.e. immortality. Reactivation of telomerase activity during carcinogenesis is a common hallmark in most human tumor types. Consequently, telomerase is an attractive molecular target toward which to direct cancer therapeutic agents. RNA interference (RNAi) has been shown to be an effective method for inhibiting the expression of a given gene in human cells by targeting with short duplex RNA (short-interfering RNA or siRNA). Thus, we evaluated the ability of siRNAs to inhibit telomerase activity in the HT29 immortal human colorectal adenocarcinoma cell line as a model for colorectal carcinogenesis. By transient expression of a specific siRNA directed against hTERT, we reduced telomerase activity in the transfected cells. Moreover, telomere lengths were reduced in cells stably expressing this particular RNA sequence, cloned as an shRNA into an eukaryotic expression vector. The cell clone that displayed a telomerase-negative phenotype showed dramatically reduced telomere lengths and stopped proliferation. We observed that the vector was integrated into the cell genome and, despite telomere shortening, cells retained their MSI phenotype. We conclude that we have developed a potent telomerase inhibitor leading to cell death.},
}
@article {pmid16820888,
year = {2006},
author = {Fujiwara, M and Kamma, H and Wu, W and Yano, Y and Homma, S and Satoh, H},
title = {Alternative lengthening of telomeres in the human adrenocortical carcinoma cell line H295R.},
journal = {International journal of oncology},
volume = {29},
number = {2},
pages = {445-451},
pmid = {16820888},
issn = {1019-6439},
mesh = {Adrenal Cortex Neoplasms/pathology/*ultrastructure ; Carcinoma/pathology/*ultrastructure ; Cell Line, Tumor ; Cell Nucleus/metabolism ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Neoplasms/metabolism ; Oligonucleotides/chemistry ; Phenotype ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/metabolism ; Telomere/pathology/*ultrastructure ; },
abstract = {Telomere maintenance can occur in the absence of telomerase by a mechanism referred to as alternative lengthening of telomeres (ALT). ALT is considered to be rare in tumors of epithelial origin. The biological significance and molecular mechanism of ALT have not been well studied in human cancers. It has been reported that clinical samples of adrenocortical carcinoma show a low incidence of telomerase positivity. We characterized an adrenocortical carcinoma cell line, H295R, focusing on the telomere maintenance mechanism, and compared it with telomerase-positive 293 cells and HeLa cells. Telomerase activity could not be detected in H295R cells by the TRAP assay. Among the essential components of the telomerase holoenzyme, only hTERT expression was undetectable by RT-PCR, indicating that the lack of telomerase activity is due to suppression of hTERT. H295R cells had long and heterogeneous telomere DNA, and FISH revealed large nuclear bodies in a few interphase nuclei, which presumably represented ALT-associated PML bodies. These results suggest that H295R cells have the ALT phenotype. Several proteins that are possibly associated with the telomere maintenance mechanism were examined. TRF1 and TRF2 were expressed in H295R cells as well as in 293 cells and HeLa cells. The ratio of hnRNP B1 to A2 was higher in H295R cells than in 293 cells and HeLa cells. In conclusion, the H295R adrenocortical carcinoma cell line is negative for telomerase and maintains its telomeres by the ALT mechanism. We anticipate that H295R cells will be a good model for understanding the significance and mechanism of ALT in human cancers.},
}
@article {pmid16818615,
year = {2006},
author = {Chen, YJ and Hakin-Smith, V and Teo, M and Xinarianos, GE and Jellinek, DA and Carroll, T and McDowell, D and MacFarlane, MR and Boet, R and Baguley, BC and Braithwaite, AW and Reddel, RR and Royds, JA},
title = {Association of mutant TP53 with alternative lengthening of telomeres and favorable prognosis in glioma.},
journal = {Cancer research},
volume = {66},
number = {13},
pages = {6473-6476},
doi = {10.1158/0008-5472.CAN-06-0910},
pmid = {16818615},
issn = {0008-5472},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Astrocytoma/*genetics ; Female ; *Genes, p53 ; Genetic Predisposition to Disease ; Glioblastoma/*genetics ; Humans ; Male ; Middle Aged ; *Mutation ; Prognosis ; Telomere/*genetics ; },
abstract = {The molecular basis for alternative lengthening of telomeres (ALT), a prognostic marker for glioma patients, remains unknown. We examined TP53 status in relation to telomere maintenance mechanism (TMM) in 108 patients with glioblastoma multiforme and two patients with anaplastic astrocytoma from New Zealand and United Kingdom. Tumor samples were analyzed with respect to telomerase activity, telomere length, and ALT-associated promyelocytic leukemia nuclear bodies to determine their TMM. TP53 mutation was analyzed by direct sequencing of coding exons 2 to 11. We found an association between TP53 mutation and ALT mechanism and between wild-type TP53 and telomerase and absence of a known TMM (P < 0.0001). We suggest that TP53 deficiency plays a permissive role in the activation of ALT.},
}
@article {pmid16809764,
year = {2006},
author = {Lee, H and Sengupta, N and Villagra, A and Rezai-Zadeh, N and Seto, E},
title = {Histone deacetylase 8 safeguards the human ever-shorter telomeres 1B (hEST1B) protein from ubiquitin-mediated degradation.},
journal = {Molecular and cellular biology},
volume = {26},
number = {14},
pages = {5259-5269},
pmid = {16809764},
issn = {0270-7306},
support = {R01 CA109699/CA/NCI NIH HHS/United States ; R01 GM058486/GM/NIGMS NIH HHS/United States ; CA109699/CA/NCI NIH HHS/United States ; GM58486/GM/NIGMS NIH HHS/United States ; },
mesh = {Acetylation ; Base Sequence ; Cyclic AMP-Dependent Protein Kinases/metabolism ; DNA, Complementary/genetics ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Gene Silencing ; HSP70 Heat-Shock Proteins/chemistry/metabolism ; HSP90 Heat-Shock Proteins/chemistry/metabolism ; HeLa Cells ; Histone Deacetylases/chemistry/genetics/*metabolism ; Humans ; In Vitro Techniques ; Multiprotein Complexes ; Phosphorylation ; Protein Binding ; Recombinant Proteins/chemistry/genetics/metabolism ; Repressor Proteins/chemistry/genetics/*metabolism ; Telomerase/chemistry/genetics/*metabolism ; Two-Hybrid System Techniques ; Ubiquitin/*metabolism ; Ubiquitin-Protein Ligases/genetics/metabolism ; },
abstract = {Histone deacetylases (HDACs) are enzymes that regulate the functions of histones as well as nonhistones by catalyzing the removal of acetyl groups from lysine residues. HDACs regulate many biological processes, including the cell division cycle and tumorigenesis. Although recent studies have implicated HDAC8 in tumor cell proliferation, the molecular mechanisms linking HDAC8 to cell growth remain unknown. Here, we report that the human ortholog of the yeast ever-shorter telomeres 1B (EST1B) binds HDAC8. This interaction is regulated by protein kinase A-mediated HDAC8 phosphorylation and protects human EST1B (hEST1B) from ubiquitin-mediated degradation. Phosphorylated HDAC8 preferentially recruits Hsp70 to a complex that inhibits the CHIP (C-terminal heat shock protein interacting protein) E3 ligase-mediated degradation of hEST1B. Importantly, HDAC8 regulation of hEST1B protein stability modulates total telomerase enzymatic activity. Our findings reveal a novel mechanism by which HDAC8 contributes to tumorigenesis by regulating telomerase activity.},
}
@article {pmid16807921,
year = {2006},
author = {Honig, LS and Schupf, N and Lee, JH and Tang, MX and Mayeux, R},
title = {Shorter telomeres are associated with mortality in those with APOE epsilon4 and dementia.},
journal = {Annals of neurology},
volume = {60},
number = {2},
pages = {181-187},
doi = {10.1002/ana.20894},
pmid = {16807921},
issn = {0364-5134},
support = {P01AG07232/AG/NIA NIH HHS/United States ; P50AG08702/AG/NIA NIH HHS/United States ; RR00645/RR/NCRR NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Apolipoprotein E4 ; Apolipoproteins E/*genetics ; DNA/genetics ; Dementia/*genetics/*mortality/pathology ; Female ; Genotype ; Humans ; Leukocytes/pathology/ultrastructure ; Logistic Models ; Male ; New York City ; Risk ; Telomere/*pathology/*ultrastructure ; },
abstract = {OBJECTIVE: Reduced telomere length may be a marker of biological aging. We hypothesized that telomere length might thus relate to increased risk for dementia and mortality.<br><br>METHODS: This nested case-control study used stored leukocyte DNA from 257 individuals (mean age, 81.4 +/- 7.9 years; 64.6% female; 44.7% Hispanic, 33.5% non-Hispanic black, and 21.8% non-Hispanic white). Our assay used real-time polymerase chain reaction, with two separate reactions amplifying telomere sequence and reference single copy gene (ribosomal-protein-P0), providing a calculated telomere-to-single copy gene (T/S) ratio.<br><br>RESULTS: Mean telomere length was shorter among subjects dying during follow-up than in those surviving (0.453 +/- 0.211 vs 0.525 +/- 0.226 [+/- standard deviation]; p < 0.009). It was also shorter in those with Alzheimer's disease compared with control subjects (0.458 +/- 0.207 vs 0.516 +/- 0.229; p < 0.03). For participants with Alzheimer's disease, compared with those with the longest telomeres, the mortality odds ratio (OR) was 4.8 (95% confidence interval [CI], 1.7-13.8) in those with intermediate-length telomeres and 7.3 (95% CI, 2.4-22.0) in those with the shortest telomeres. The presence of an epsilon4 allele also increased the mortality OR, with an OR of 5.8 (95% CI, 1.3-26.4) for intermediate-length telomeres and an OR of 9.0 (95% CI, 1.9-41) for the shortest telomeres.<br><br>INTERPRETATION: Our findings suggest that leukocyte telomere length is related to both dementia and mortality and may be a marker of biological aging.},
}
@article {pmid16806460,
year = {2007},
author = {Allsopp, R and Shimoda, J and Easa, D and Ward, K},
title = {Long telomeres in the mature human placenta.},
journal = {Placenta},
volume = {28},
number = {4},
pages = {324-327},
doi = {10.1016/j.placenta.2006.04.003},
pmid = {16806460},
issn = {0143-4004},
support = {P20 RR11091/RR/NCRR NIH HHS/United States ; },
mesh = {Blotting, Northern ; Blotting, Southern ; Chorionic Villi/enzymology/*growth &amp; development ; DNA/analysis ; Fetal Blood/metabolism ; Gestational Age ; Humans ; Polymorphism, Restriction Fragment Length ; RNA/analysis ; Telomerase/blood/genetics ; Telomere/*physiology ; Time Factors ; },
abstract = {OBJECTIVE: To investigate whether telomere shortening may play a role in senescence of the placenta.<br><br>STUDY DESIGN: Villous tissue was collected from single, random sites of full-term placentas (39-41 weeks of gestation; n=10) as well as multiple, specific sites of the same placenta (39-41 weeks of gestation; n=5). For the latter group of placentas, samples were taken near the umbilical cord and at the periphery on both the maternal and fetal sides (a total of 4 samples per placenta). Cord blood samples were also obtained from all placental donors. Telomerase activity was assessed by the TRAP assay, and telomere length measured by Southern analysis of mean terminal restriction fragment (TRF) length.<br><br>RESULTS: We show for the first time that telomeres are longer (approximately 25% longer; P<0.001) in placenta tissue than in cord blood from the same donor.<br><br>CONCLUSION: Telomere shortening is unlikely to have a significant role in senescence or terminal maturation of the placenta.},
}
@article {pmid16804004,
year = {2006},
author = {Graakjaer, J and Londono-Vallejo, JA and Christensen, K and Kølvraa, S},
title = {The pattern of chromosome-specific variations in telomere length in humans shows signs of heritability and is maintained through life.},
journal = {Annals of the New York Academy of Sciences},
volume = {1067},
number = {},
pages = {311-316},
doi = {10.1196/annals.1354.042},
pmid = {16804004},
issn = {0077-8923},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*genetics/physiology ; Amnion/cytology ; Chromosomes, Human/*genetics ; Fibroblasts/physiology ; *Genetic Variation ; Humans ; In Situ Hybridization, Fluorescence ; Longevity/*genetics ; Lymphocytes/physiology ; Middle Aged ; Telomere/*genetics ; Twins, Dizygotic ; Twins, Monozygotic ; },
abstract = {This paper characterizes the distribution of telomere length on individual chromosome arms in humans. By fluorescent in situ hybridization (FISH), followed by computer-assisted analysis of digital images, it is shown that the distribution of telomere length on individual chromosome arms is not random, but that humans have a common telomere profile. This profile exists in lymphocytes, amniocytes and fibroblasts, and seems to be conserved during life. A closer look at the overall pattern of the profile shows that the length of the telomeres in general follows the total chromosome length. In addition to the common profile, it is found that each person has specific characteristics, which are also conserved throughout life. Studying both twins and families we have obtained indications that these individual characteristics are at least partly inherited. Altogether, our results suggest that the length of individual telomeres might occasionally play a role in the heritability of life span.},
}
@article {pmid16798109,
year = {2006},
author = {Slijepcevic, P},
title = {The role of DNA damage response proteins at telomeres--an "integrative" model.},
journal = {DNA repair},
volume = {5},
number = {11},
pages = {1299-1306},
doi = {10.1016/j.dnarep.2006.05.038},
pmid = {16798109},
issn = {1568-7864},
mesh = {Animals ; BRCA1 Protein/physiology ; Cell Cycle Proteins/physiology ; *DNA Damage ; DNA Repair/*physiology ; Humans ; Mice ; *Models, Genetic ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases/physiology ; Telomere/*metabolism/physiology ; },
abstract = {Telomeres are specialized structures at chromosome ends which play the key role in chromosomal end protection. There is increasing evidence that many DNA damage response proteins are involved in telomere maintenance. For example, cells defective in DNA double strand break repair proteins including Ku, DNA-PKcs, RAD51D and the MRN (MRE11/RAD51/NBS1) complex show loss of telomere capping function. Similarly, mouse and human cells defective in ataxia telangiectasia mutated (ATM) have defective telomeres. A total of 14 mammalian DNA damage response proteins have, so far, been implicated in telomere maintenance. Recent studies indicate that three more proteins, namely BRCA1, hRad9 and PARP1 are involved in telomere maintenance. The involvement of a wide range of DNA damage response proteins at telomeres raises an important question: do telomere maintenance mechanisms constitute an integral part of DNA damage response machinery? A model termed the "integrative" model is proposed here to argue in favour of telomere maintenance being an integral part of DNA damage response. The "integrative" model is supported by the observation that a telomeric protein, TRF2, is not confined to its local telomeric environment but it migrates to the sites of DNA breakage following exposure of cells to ionizing radiation. Furthermore, even if telomeres are maintained in a non-canonical way, as in the case of Drosophila, DNA damage response proteins are still involved in telomere maintenance suggesting integration of telomere maintenance mechanisms into the DNA damage response network.},
}
@article {pmid16794190,
year = {2006},
author = {Matthews, C and Gorenne, I and Scott, S and Figg, N and Kirkpatrick, P and Ritchie, A and Goddard, M and Bennett, M},
title = {Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress.},
journal = {Circulation research},
volume = {99},
number = {2},
pages = {156-164},
doi = {10.1161/01.RES.0000233315.38086.bc},
pmid = {16794190},
issn = {1524-4571},
mesh = {Atherosclerosis/*pathology ; Biomarkers/analysis ; *Cellular Senescence ; DNA Damage ; Humans ; Muscle, Smooth, Vascular/*pathology ; Myocytes, Smooth Muscle/*pathology ; Oxidants/pharmacology ; Oxidative Stress ; Telomerase/analysis ; Telomere/*physiology/ultrastructure ; },
abstract = {Although human atherosclerosis is associated with aging, direct evidence of cellular senescence and the mechanism of senescence in vascular smooth muscle cells (VSMCs) in atherosclerotic plaques is lacking. We examined normal vessels and plaques by histochemistry, Southern blotting, and fluorescence in situ hybridization for telomere signals. VSMCs in fibrous caps expressed markers of senescence (senescence-associated beta-galactosidase [SAbetaG] and the cyclin-dependent kinase inhibitors [cdkis] p16 and p21) not seen in normal vessels. In matched samples from the same individual, plaques demonstrated markedly shorter telomeres than normal vessels. Fibrous cap VSMCs exhibited markedly shorter telomeres compared with normal medial VSMCs. Telomere shortening was closely associated with increasing severity of atherosclerosis. In vitro, plaque VSMCs demonstrated morphological features of senescence, increased SAbetaG expression, reduced proliferation, and premature senescence. VSMC senescence was mediated by changes in cyclins D/E, p16, p21, and pRB, and plaque VSMCs could reenter the cell cycle by hyperphosphorylating pRB. Both plaque and normal VSMCs expressed low levels of telomerase. However, telomerase expression alone rescued plaque VSMC senescence despite short telomeres, normalizing the cdki/pRB changes. In vivo, plaque VSMCs exhibited oxidative DNA damage, suggesting that telomere damage may be induced by oxidant stress. Furthermore, oxidants induced premature senescence in vitro, with accelerated telomere shortening and reduced telomerase activity. We conclude that human atherosclerosis is characterized by senescence of VSMCs, accelerated by oxidative stress-induced DNA damage, inhibition of telomerase and marked telomere shortening. Prevention of cellular senescence may be a novel therapeutic target in atherosclerosis.},
}
@article {pmid16793407,
year = {2006},
author = {Zubko, MK and Maringele, L and Foster, SS and Lydall, D},
title = {Detecting repair intermediates in vivo: effects of DNA damage response genes on single-stranded DNA accumulation at uncapped telomeres in budding yeast.},
journal = {Methods in enzymology},
volume = {409},
number = {},
pages = {285-300},
doi = {10.1016/S0076-6879(05)09016-6},
pmid = {16793407},
issn = {0076-6879},
support = {075294//Wellcome Trust/United Kingdom ; 054371//Wellcome Trust/United Kingdom ; },
mesh = {Base Sequence ; DNA Damage/*genetics ; DNA Primers ; *DNA Repair ; DNA, Single-Stranded/*metabolism ; Saccharomyces cerevisiae/*genetics ; *Telomere ; },
abstract = {Single-stranded DNA (ssDNA) is an important intermediate in many DNA repair pathways. Here we describe protocols that permit the measurement of ssDNA that has arisen in the yeast genome in vivo, in response to telomere uncapping. Yeast strains defective in DNA damage response (DDR) genes can be used to infer the roles of the corresponding proteins in regulating ssDNA production and in responding to ssDNA. Using column based methods to purify yeast genomic DNA and quantitative amplification of single-stranded DNA (QAOS) it is possible to measure ssDNA at numerous single copy loci in the yeast genome. We describe how to measure ssDNA in synchronous cultures of cdc13-1 mutants, containing a temperature sensitive mutation in an essential telomere capping protein, and in asynchronous cultures of yku70Delta mutants also defective in telomere capping.},
}
@article {pmid16791617,
year = {2006},
author = {Sampson, MJ and Hughes, DA},
title = {Chromosomal telomere attrition as a mechanism for the increased risk of epithelial cancers and senescent phenotypes in type 2 diabetes.},
journal = {Diabetologia},
volume = {49},
number = {8},
pages = {1726-1731},
pmid = {16791617},
issn = {0012-186X},
mesh = {Carcinoma/epidemiology/*genetics ; Cell Division ; Cellular Senescence ; *Chromosomes, Human ; Diabetes Mellitus, Type 2/*genetics ; Diabetic Nephropathies/genetics ; Diabetic Retinopathy/genetics ; Humans ; Risk ; Telomere/*genetics/ultrastructure ; },
abstract = {Telomeres are the repeat DNA sequences at the end of chromosomes necessary for successful DNA replication and chromosomal integrity. Telomeres shorten at cell division at a rate determined by oxidative DNA damage, and cells are triggered into replicative senescence once telomeres shorten to a critical length. Telomere-related chromosomal maintenance also has a role in carcinogenesis. Type 2 diabetes is characterised by increased oxidative stress, increased oxidative DNA damage, senescent retinal and renal phenotypes, and an increased risk of epithelial malignancy. We suggest that increased oxidative DNA damage and telomere attrition in type 2 diabetes leads to: (1) carcinogenic telomere-dependent chromosomal non-reciprocal translocations, genomic instability, and the development of epithelial cancers; (2) senescent retinal and renal phenotypes (expressed as diabetic retinopathy and nephropathy); and (3) senescent vascular endothelial, monocyte-macrophage and vascular smooth muscle cells (expressed as endothelial dysfunction and accelerated atherogenesis). An adverse intrauterine environment leads to increased feto-placental oxidative stress and feto-placental oxidative DNA damage. We also suggest that intrauterine oxidative DNA damage and telomere shortening is another point at which increased oxidative stress could contribute to a pre-programmed increased risk of senescent phenotypes in adult offspring, characterised by type 2 diabetes and epithelial malignancy. These suggestions can be used to understand early glucose intolerance in the young children of type 1 diabetes pregnancies, poor cancer outcomes in type 2 diabetes, beta cell fatigue in type 2 diabetes and the absence of increased epithelial cancer risk in type 1 diabetes.},
}
@article {pmid16789902,
year = {2006},
author = {Deville, L and Hillion, J and Lanotte, M and Rousselot, P and Ségal-Bendirdjian, E},
title = {Diagnostics, prognostic and therapeutic exploitation of telomeres and telomerase in leukemias.},
journal = {Current pharmaceutical biotechnology},
volume = {7},
number = {3},
pages = {171-183},
doi = {10.2174/138920106777549768},
pmid = {16789902},
issn = {1389-2010},
mesh = {Humans ; *Leukemia/diagnosis/enzymology/genetics/therapy ; Prognosis ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are specialized structures at the end of human chromosomes. Telomere length decreases with each cell division, thus, reflecting the mitotic history of somatic cells. Telomerase, the ribonucleoprotein enzyme which maintains telomeres of eukaryotic chromosomes, is up-regulated in the vast majority of human neoplasia but not in normal somatic tissues. In contrast to other somatic cells, normal primitive human hematopoietic cells and some peripheral blood cells expressed low levels of telomerase activity. This activity is thought to play an important role in self-renewal of hematopoietic stem cells. In malignant disorders, telomere lengths are generally shortened and telomerase expression and activity enhanced with high differences in the levels. Although it is necessary to be cautious in interpreting these data, there are indications that telomere length and telomerase expression and activity can serve as a molecular marker of the clinical progression and prognosis of most leukemias. Approaches that directly target telomerase, telomeres or telomerase regulatory mechanisms have been developed. Some of these anti-telomerase strategies in combination with conventional drugs proved to be promising in some types of leukemias.},
}
@article {pmid16786598,
year = {2006},
author = {Bellon, M and Datta, A and Brown, M and Pouliquen, JF and Couppie, P and Kazanji, M and Nicot, C},
title = {Increased expression of telomere length regulating factors TRF1, TRF2 and TIN2 in patients with adult T-cell leukemia.},
journal = {International journal of cancer},
volume = {119},
number = {9},
pages = {2090-2097},
doi = {10.1002/ijc.22026},
pmid = {16786598},
issn = {0020-7136},
support = {R01 CA106258/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; DNA Primers ; HL-60 Cells ; Human T-lymphotropic virus 1 ; Humans ; Jurkat Cells ; Leukemia-Lymphoma, Adult T-Cell/*genetics/virology ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics ; Telomeric Repeat Binding Protein 1/*genetics ; Telomeric Repeat Binding Protein 2/*genetics ; },
abstract = {Here, we report that freshly isolated unstimulated adult T-cell leukemia (ATL) cells present high telomerase activity compared to asymptomatic carriers or normal donors. In spite of this high telomerase activity, ATL cells retained shorter telomeres compared to those of uninfected cells isolated from the same patients. Because the safeguarding of telomere length is critical to the unlimited proliferation of tumor cells, we investigated the underlying mechanism for short telomere maintenance in ATL cells. Transcriptional and posttranscriptional expression of telomere-binding proteins TRF1, TRF2, TIN2 and POT1, known to regulate telomere homeostasis and protection, were evaluated. We found that TRF1 and TRF2 are overexpressed in in vivo patient's samples from ATL but not asymptomatic carriers, while levels of POT1 expression did not specifically increase in ATL. To gain insights into the regulation of TRF genes in HTLV-I infected cells, we investigated the expression of TIN2, a regulator of these genes, and found an increase in TIN2 expression in ATL patients. Together our results underscore the importance of telomerase and telomere length regulating factors as novel markers for ATL disease progression and as potential therapeutic targets for the treatment of HTLV-I-associated malignancies.},
}
@article {pmid16784900,
year = {2006},
author = {Murnane, JP},
title = {Telomeres and chromosome instability.},
journal = {DNA repair},
volume = {5},
number = {9-10},
pages = {1082-1092},
doi = {10.1016/j.dnarep.2006.05.030},
pmid = {16784900},
issn = {1568-7864},
support = {R01 CA69044/CA/NCI NIH HHS/United States ; R01 ES008427/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; Biomarkers/analysis ; Cell Cycle ; *Chromosomal Instability ; *Chromosomes, Fungal ; Chromosomes, Mammalian ; Gene Amplification ; Humans ; Models, Genetic ; Neoplasms/*genetics ; Saccharomyces cerevisiae/*genetics ; Telomere/*genetics ; *Translocation, Genetic ; },
abstract = {Genomic instability has been proposed to play an important role in cancer by accelerating the accumulation of genetic changes responsible for cancer cell evolution. One mechanism for chromosome instability is through the loss of telomeres, which are DNA-protein complexes that protect the ends of chromosomes and prevent chromosome fusion. Telomere loss can occur as a result of exogenous DNA damage, or spontaneously in cancer cells that commonly have a high rate of telomere loss. Mouse embryonic stem cells and human tumor cell lines that contain a selectable marker gene located immediately adjacent to a telomere have been used to investigate the consequences of telomere loss. In both cell types, telomere loss is followed by either the addition of a new telomere on to the end of the broken chromosome, or sister chromatid fusion and prolonged breakage/fusion/bridge (B/F/B) cycles that result in DNA amplification and large terminal deletions. The regions amplified by B/F/B cycles can then be transferred to other chromosomes, either through the formation of double-minute chromosomes that reintegrate at other sites, or through end-to-end fusions between chromosomes. B/F/B cycles eventually end when a chromosome acquires a new telomere by one of several mechanisms, the most common of which is translocation, which can involve either nonreciprocal transfer or duplication of all or part of an arm of another chromosome. Telomere acquisition involving nonreciprocal translocations results in the loss of a telomere on the donor chromosome, which subsequently becomes unstable. In contrast, translocations involving duplications do not destabilize the donor chromosome, although they result in allelic imbalances. Thus, the loss of a single telomere can generate a wide variety of chromosome alterations commonly associated with human cancer, not only on the chromosome that originally lost its telomere, but other chromosomes as well. Factors promoting spontaneous telomere loss and the resulting B/F/B cycles are therefore likely to be important in generating the karyotypic changes associated with human cancer.},
}
@article {pmid16782900,
year = {2006},
author = {Matsumoto, T and Hamada, M and Osanai, M and Fujiwara, H},
title = {Essential domains for ribonucleoprotein complex formation required for retrotransposition of telomere-specific non-long terminal repeat retrotransposon SART1.},
journal = {Molecular and cellular biology},
volume = {26},
number = {13},
pages = {5168-5179},
pmid = {16782900},
issn = {0270-7306},
mesh = {Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Bombyx/genetics/metabolism ; Cells, Cultured ; Insect Proteins/genetics/*metabolism ; Molecular Sequence Data ; Mutation ; Open Reading Frames/genetics ; Protein Interaction Mapping ; Protein Structure, Tertiary ; RNA, Messenger/metabolism ; *Retroelements/genetics ; Ribonucleoproteins/*metabolism ; Telomere/*metabolism ; *Terminal Repeat Sequences ; },
abstract = {Non-long terminal repeat (LTR) retrotransposons are major components of the higher eukaryotic genome. Most of them have two open reading frames (ORFs): ORF2 encodes mainly the endonuclease and reverse transcriptase domains, but the functional features of ORF1 remain largely unknown. We used telomere-specific non-LTR retrotransposon SART1 in Bombyx mori and clarified essential roles of the ORF1 protein (ORF1p) in ribonucleoprotein (RNP) formation by novel approaches: in vitro reconstitution and in vivo/in vitro retrotransposition assays using the baculovirus expression system. Detailed mutation analyses showed that each of the three CCHC motifs at the ORF1 C terminus are essential for SART1 retrotransposition and are involved in packaging the SART1 mRNA specifically into RNP. We also demonstrated that amino acid residues 555 to 567 and 285 to 567 in the SART1 ORF1p are crucial for the ORF1p-ORF1p and ORF1p-ORF2p interactions, respectively. The loss of these domains abolishes protein-protein interaction, leading to SART1 retrotransposition deficiency. These data suggest that systematic formation of RNP composed of ORF1p, ORF2p, and mRNA is mainly mediated by ORF1p domains and is a common, essential step for many non-LTR retrotransposons encoding the two ORFs.},
}
@article {pmid16782879,
year = {2006},
author = {Dreesen, O and Cross, GA},
title = {Telomerase-independent stabilization of short telomeres in Trypanosoma brucei.},
journal = {Molecular and cellular biology},
volume = {26},
number = {13},
pages = {4911-4919},
pmid = {16782879},
issn = {0270-7306},
support = {R01 AI050614/AI/NIAID NIH HHS/United States ; AI 50614/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Chromosomes/metabolism ; DNA, Protozoan/*metabolism ; Repetitive Sequences, Nucleic Acid/genetics ; Sequence Deletion ; Telomerase/*genetics/metabolism ; Telomere/enzymology/*genetics/*metabolism ; Transcription, Genetic ; Trypanosoma brucei brucei/*enzymology/*genetics ; },
abstract = {In cancer cells and germ cells, shortening of chromosome ends is prevented by telomerase. Telomerase-deficient cells have a replicative life span, after which they enter senescence. Senescent cells can give rise to survivors that maintain chromosome ends through recombination-based amplification of telomeric or subtelomeric repeats. We found that in Trypanosoma brucei, critically short telomeres are stable in the absence of telomerase. Telomere stabilization ensured genomic integrity and could have implications for telomere maintenance in human telomerase-deficient cells. Cloning and sequencing revealed 7 to 27 TTAGGG repeats on stabilized telomeres and no changes in the subtelomeric region. Clones with short telomeres were used to study telomere elongation dynamics, which differed dramatically at transcriptionally active and silent telomeres, after restoration of telomerase. We propose that transcription makes the termini of short telomeres accessible for rapid elongation by telomerase and that telomere elongation in T. brucei is not regulated by a protein-counting mechanism. Many minichromosomes were lost after long-term culture in the absence of telomerase, which may reflect their different mitotic segregation properties.},
}
@article {pmid16769823,
year = {2006},
author = {Tang, X and Jin, Y and Cande, WZ},
title = {Bqt2p is essential for initiating telomere clustering upon pheromone sensing in fission yeast.},
journal = {The Journal of cell biology},
volume = {173},
number = {6},
pages = {845-851},
pmid = {16769823},
issn = {0021-9525},
support = {R01 GM067992/GM/NIGMS NIH HHS/United States ; R01-GM067992/GM/NIGMS NIH HHS/United States ; },
mesh = {Heterochromatin/metabolism ; Mutation ; Pheromones/*metabolism ; Prophase ; Schizosaccharomyces/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/metabolism/*physiology ; Shelterin Complex ; Spindle Apparatus/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*physiology ; },
abstract = {The telomere bouquet, i.e., telomere clustering on the nuclear envelope (NE) during meiotic prophase, is thought to promote homologous chromosome pairing. Using a visual screen, we identified bqt2/im295, a mutant that disrupts telomere clustering in fission yeast. Bqt2p is required for linking telomeres to the meiotic spindle pole body (SPB) but not for attachment of telomeres or the SPB to the NE. Bqt2p is expressed upon pheromone sensing and colocalizes thereafter to Sad1p, an SPB protein. This localization only depends on Bqt1p, not on other identified proteins required for telomere clustering. Upon pheromone sensing, generation of Sad1p foci next to telomeres depends on Bqt2p. However, depletion of Bqt2p from the SPB is dispensable for dissolving the telomere bouquet at the end of meiotic prophase. Therefore, telomere bouquet formation requires Bqt2p as a linking component and is finely regulated during meiotic progression.},
}
@article {pmid16767163,
year = {2006},
author = {Cerone, MA and Londoño-Vallejo, JA and Autexier, C},
title = {Mutated telomeres sensitize tumor cells to anticancer drugs independently of telomere shortening and mechanisms of telomere maintenance.},
journal = {Oncogene},
volume = {25},
number = {56},
pages = {7411-7420},
doi = {10.1038/sj.onc.1209727},
pmid = {16767163},
issn = {0950-9232},
mesh = {Antineoplastic Agents/*pharmacology ; Base Sequence ; Breast Neoplasms/enzymology/genetics/pathology ; Cell Cycle ; Cell Line, Tumor ; DNA Primers ; Fluorescent Antibody Technique ; Humans ; In Situ Hybridization, Fluorescence ; *Mutation ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*genetics ; },
abstract = {Telomerase is a ribonucleoprotein complex that maintains the stability of chromosome ends and regulates replicative potential. Telomerase is upregulated in over 85% of human tumors, but not in adjacent normal tissues and represents a promising target for anticancer therapy. Most telomerase-based therapies rely on the inhibition of telomerase activity and require extensive telomere shortening before inducing any antiproliferative effect. Disturbances of telomere structure rather than length may be more effective in inducing cell death. Telomerase RNA subunits (hTRs) with mutations in the template region reconstitute active holoenzymes that incorporate mutated telomeric sequences. Here, we analysed the feasibility of an anticancer approach based on the combination of telomere destabilization and conventional chemotherapeutic drugs. We show that a mutant template hTR dictates the synthesis of mutated telomeric repeats in telomerase-positive cancer cells, without significantly affecting their viability and proliferative ability. Nevertheless, the mutant hTR increased sensitivity to anticancer drugs in cells with different initial telomere lengths and mechanisms of telomere maintenance and without requiring overall telomere shortening. This report is the first to show that interfering with telomere structure maintenance in a telomerase-dependent manner may be used to increase the susceptibility of tumor cells to anticancer drugs and may lead to the development of a general therapy for the treatment of human cancers.},
}
@article {pmid16767084,
year = {2006},
author = {Zubko, MK and Lydall, D},
title = {Linear chromosome maintenance in the absence of essential telomere-capping proteins.},
journal = {Nature cell biology},
volume = {8},
number = {7},
pages = {734-740},
doi = {10.1038/ncb1428},
pmid = {16767084},
issn = {1465-7392},
support = {075294//Wellcome Trust/United Kingdom ; 054371//Wellcome Trust/United Kingdom ; },
mesh = {Cell Cycle Proteins/genetics/metabolism ; Cell Nucleus/*genetics/metabolism ; Chromosomes/*genetics ; DNA Damage/physiology ; DNA Repair/physiology ; Evolution, Molecular ; Mutation/genetics ; Recombination, Genetic/genetics ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {Telomeres were defined by their ability to cap chromosome ends. Proteins with high affinity for the structure at chromosome ends, binding the G-rich, 3' single-stranded overhang at telomeres include Pot1 in humans and fission yeast, TEBP in Oxytricha nova and Cdc13 in budding yeast. Cdc13 is considered essential for telomere capping because budding yeast that lack Cdc13 rapidly accumulate excessive single-stranded DNA (ssDNA) at telomeres, arrest cell division and die. Cdc13 has a separate, critical role in telomerase recruitment to telomeres. Here, we show that neither Cdc13 nor its partner Stn1 are necessary for telomere capping if nuclease activities that are active at uncapped telomeres are attenuated. Recombination-dependent and -independent mechanisms permit maintenance of chromosomes without Cdc13. Our results indicate that the structure of the eukaryotic telomere cap is remarkably flexible and that changes in the DNA damage response allow alternative strategies for telomere capping to evolve.},
}
@article {pmid16767083,
year = {2006},
author = {Larrivée, M and Wellinger, RJ},
title = {Telomerase- and capping-independent yeast survivors with alternate telomere states.},
journal = {Nature cell biology},
volume = {8},
number = {7},
pages = {741-747},
doi = {10.1038/ncb1429},
pmid = {16767083},
issn = {1465-7392},
mesh = {Cell Survival/genetics ; DNA Damage/genetics ; DNA Repair/genetics ; DNA, Circular/*genetics/metabolism ; DNA, Single-Stranded/genetics/metabolism ; Extrachromosomal Inheritance ; Gene Expression Regulation, Fungal/genetics ; Genomic Instability/genetics ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomerase/*genetics/metabolism ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {Maintaining telomeric DNA at chromosome ends is essential for genome stability. In virtually all organisms the telomerase enzyme provides this function; however, telomerase-independent mechanisms also exist. These latter mechanisms rely on recombination pathways to replenish telomeric DNA and extrachromosomal DNA may also be implicated. Here, we report that in Saccharomyces cerevisiae cells, extrachromosomal circular DNA occurs for both subtypes of telomerase-independent telomere-maintenance mechanisms. This DNA consists of circular molecules of full-length subtelomeric repeat elements in type I cells, and very heterogeneously sized circles of telomeric repeat DNA in type II cells that are at least partially single stranded. Surprisingly, both type I and type II cells can adapt to a loss of the normally essential telomere-capping protein Cdc13p by inducing an alternate and reversible state of chromosome ends. Chromosome capping, therefore, is not strictly dependent on canonical capping proteins, such as Cdc13p, but can be achieved by alternate mechanisms.},
}
@article {pmid16765654,
year = {2006},
author = {Foster, SS and Zubko, MK and Guillard, S and Lydall, D},
title = {MRX protects telomeric DNA at uncapped telomeres of budding yeast cdc13-1 mutants.},
journal = {DNA repair},
volume = {5},
number = {7},
pages = {840-851},
doi = {10.1016/j.dnarep.2006.04.005},
pmid = {16765654},
issn = {1568-7864},
support = {075294//Wellcome Trust/United Kingdom ; 054371//Wellcome Trust/United Kingdom ; },
mesh = {Base Sequence ; Cell Cycle ; DNA Repair ; DNA, Fungal/genetics/*metabolism ; DNA, Single-Stranded/genetics/metabolism ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Endodeoxyribonucleases/chemistry/genetics/*metabolism ; Exodeoxyribonucleases/chemistry/genetics/*metabolism ; Genes, Fungal ; Models, Biological ; Multiprotein Complexes ; Mutation ; Saccharomyces cerevisiae/cytology/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/*genetics/*metabolism ; },
abstract = {MRX, an evolutionally conserved DNA damage response complex composed of Mre11, Rad50 and Xrs2, is involved in DNA double strand break (DSB) repair, checkpoint activation and telomere maintenance. At DSBs, MRX plays a role in generating single stranded DNA (ssDNA) and signalling cell cycle arrest. Here we investigated whether MRX also contributes to generating ssDNA or signalling cell cycle arrest at uncapped telomeres. To investigate the role of MRX, we generated a conditionally degradable Rad50 protein and combined this with cdc13-1, a temperature sensitive mutation in the Cdc13 telomere capping protein. We show that Rad50 does not contribute to ssDNA generation or cell cycle arrest in response to cdcl3-1 uncapped telomeres. Instead, we find that Rad50 inhibits ssDNA accumulation and promotes cdc13-1 cell viability, consistent with a major role for MRX in telomere capping.},
}
@article {pmid16761726,
year = {2006},
author = {Betts, DH and Perrault, S and Harrington, L and King, WA},
title = {Quantitative analysis of telomerase activity and telomere length in domestic animal clones.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {325},
number = {},
pages = {149-180},
doi = {10.1385/1-59745-005-7:149},
pmid = {16761726},
issn = {1064-3745},
mesh = {Aging ; Animals ; Cell Line ; Cell Lineage ; Cellular Senescence ; Chromosomes/chemistry ; Cloning, Organism/*methods ; Humans ; In Situ Hybridization, Fluorescence ; Oocytes/metabolism ; Polymerase Chain Reaction ; Telomerase/*chemistry ; Telomere/chemistry/ultrastructure ; Zona Pellucida/chemistry ; },
abstract = {It has been speculated that incomplete epigenetic reprogramming of the somatic cell genome is the primary reason behind the developmental inefficiencies and postnatal abnormalities observed after nuclear transplantation in domestic animal clones. One chromosome structure that is altered in dividing somatic cells is telomere length-the terminal ends of linear chromosomes capped by repetitive sequences of G-rich noncoding DNA, (TTAGGG)", and specific binding proteins. Telomeres are critical structures that function in maintaining chromosome stability and ensure the full replication of coding DNA by acting as a buffer to terminal DNA attrition due to the end replication problem. Telomere shortening limits cellular proliferation through a DNA damage signal activating permanent cell cycle arrest at a critical telomere length or through structural telomere alterations that prevents effective chromosome capping. Telomere-mediated signaling of cellular senescence has been established for many somatic cell types in vitro, except for germ cells, cancer lines, and regenerative tissues in which telomere length is maintained primarily by the ribonucleoprotein telomerase, a reverse transcriptase that synthesizes TTAGGG repeats de novo onto the chromosome ends. Telomere length discrepancies have been reported in animal clones as being shorter, no different, and even longer than in age-matched control animals, but the etiology is not yet understood. Possible explanations include differences in donor cell type and the efficiency of telomerase reprogramming. This chapter summarizes the conventional protocols and recent advances in telomere length and telomerase activity measurement that will help elucidate the mechanism(s) behind telomere length deregulation in somatic cell clones and its role in chromosomal instability, cellular senescence, and organismal aging in vivo.},
}
@article {pmid16756487,
year = {2006},
author = {McEachern, MJ and Haber, JE},
title = {Break-induced replication and recombinational telomere elongation in yeast.},
journal = {Annual review of biochemistry},
volume = {75},
number = {},
pages = {111-135},
doi = {10.1146/annurev.biochem.74.082803.133234},
pmid = {16756487},
issn = {0066-4154},
mesh = {Cell Cycle/physiology ; Cellular Senescence ; *DNA Damage ; *DNA Replication ; DNA, Mitochondrial/genetics ; Genes, cdc ; Humans ; Rad51 Recombinase/metabolism ; *Recombination, Genetic ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {When a telomere becomes unprotected or if only one end of a chromosomal double-strand break succeeds in recombining with a template sequence, DNA can be repaired by a recombination-dependent DNA replication process termed break-induced replication (BIR). In budding yeasts, there are two BIR pathways, one dependent on the Rad51 recombinase protein and one Rad51 independent; these two repair processes lead to different types of survivors in cells lacking the telomerase enzyme that is required for normal telomere maintenance. Recombination at telomeres is triggered by either excessive telomere shortening or disruptions in the function of telomere-binding proteins. Telomere elongation by BIR appears to often occur through a "roll and spread" mechanism. In this process, a telomeric circle produced by recombination at a dysfunctional telomere acts as a template for a rolling circle BIR event to form an elongated telomere. Additional BIR events can then copy the elongated sequence to all other telomeres.},
}
@article {pmid16755657,
year = {2006},
author = {Kurosaka, D and Yasuda, J and Yoshida, K and Yoneda, A and Yasuda, C and Kingetsu, I and Toyokawa, Y and Yokoyama, T and Saito, S and Yamada, A},
title = {Abnormal telomerase activity and telomere length in T and B cells from patients with systemic lupus erythematosus.},
journal = {The Journal of rheumatology},
volume = {33},
number = {6},
pages = {1102-1107},
pmid = {16755657},
issn = {0315-162X},
mesh = {Adolescent ; Adult ; B-Lymphocytes/*enzymology ; Female ; Flow Cytometry ; Health Status ; Humans ; In Situ Hybridization, Fluorescence ; Lupus Erythematosus, Systemic/*blood/*genetics/physiopathology ; Male ; Middle Aged ; Severity of Illness Index ; T-Lymphocytes/*enzymology ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {OBJECTIVE: To evaluate the clinical significance of telomerase activity and telomere length in T and B lymphocytes from patients with systemic lupus erythematosus (SLE).<br><br>METHODS: CD3+ (T cell) and CD19+ (B cell) lymphocytes were isolated from the peripheral blood of SLE patients and healthy controls by means of magnetic bead-coupled antibodies. SLE patients were classified as active or inactive cases according to the SLE Disease Activity Index (SLEDAI). Telomere activity of lymphocytes was measured by telomeric-repeat amplification protocol. Telomere length was measured by flow cytometry-fluorescence in situ hybridization.<br><br>RESULTS: T cell telomerase activity was significantly higher in patients with both active and inactive SLE than in controls, but was lower than B cell telomerase activity in patients with active SLE, and was not correlated with SLEDAI results. B cell telomerase activity was only significantly higher than in controls in patients with active SLE, and was strongly correlated with SLEDAI. Four laboratory results, anti-dsDNA antibody titer, IgG level, C3 level, and CH50 level, were correlated with B cell telomerase activity. Telomere length in T cells was significantly shorter than in controls. In contrast, the telomere length in B cells did not differ significantly from controls.<br><br>CONCLUSION: In patients with SLE, many T cells divide continuously. Their telomerase activity was higher than that in control T cells, but not so high as to prevent telomere shortening. In contrast, B cells do not divide abnormally in the inactive phase of SLE, but divide rapidly in the active phase.},
}
@article {pmid16752076,
year = {2006},
author = {Fordyce, CA and Heaphy, CM and Bisoffi, M and Wyaco, JL and Joste, NE and Mangalik, A and Baumgartner, KB and Baumgartner, RN and Hunt, WC and Griffith, JK},
title = {Telomere content correlates with stage and prognosis in breast cancer.},
journal = {Breast cancer research and treatment},
volume = {99},
number = {2},
pages = {193-202},
doi = {10.1007/s10549-006-9204-1},
pmid = {16752076},
issn = {0167-6806},
support = {N01-CN-65034-29/CN/NCI NIH HHS/United States ; R25 GM60201/GM/NIGMS NIH HHS/United States ; T34 GM08751/GM/NIGMS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Breast Neoplasms/*genetics/pathology ; Carcinoma, Ductal, Breast/genetics/pathology ; Carcinoma, Lobular/genetics/pathology ; DNA, Neoplasm/*analysis ; Disease-Free Survival ; Female ; Humans ; Mastectomy ; Middle Aged ; Neoplasm Invasiveness/pathology ; Neoplasm Staging ; Prognosis ; Survival Rate ; Telomere/*genetics ; },
abstract = {PURPOSE: To evaluate the hypothesis that telomere DNA content (TC) in breast tumor tissue correlates with TNM staging and prognosis.<br><br>EXPERIMENTAL DESIGN: Slot blot assay was used to quantitate TC in 70 disease-free normal tissues from multiple organ sites, and two independent sets of breast tumors containing a total of 140 samples. Non-parametric Rank-Sums tests, logistic regression and Cox proportional hazards models were used to evaluate the relationships between TC and tumor size, nodal involvement, TNM stage, 5-year survival and disease-free interval.<br><br>RESULTS: TC in 95% of normal tissues was 75-143% of that in the placental DNA standard, whereas only 50% of tumors had TC values in this range. TC was associated with tumor size (p=0.02), nodal involvement (p<0.0001), TNM stage (p=0.004), 5-year overall survival (p=0.0001) and 5-year disease-free survival (p=0.0004). A multivariable Cox model was developed using age at diagnosis, TNM stage and TC as independent predictors of breast cancer-free survival. Relative to the high TC group (>123% of standard), low TC (<101% of standard) conferred an adjusted relative hazard of 4.43 (95% CI 1.4-13.6, p=0.009). Receiver operating characteristic curves using thresholds defined by the TC distribution in normal tissues predicted 5-year breast cancer-free survival with 50% sensitivity and 95% specificity, and predicted death due to breast cancer with 75% sensitivity and 70% specificity.<br><br>CONCLUSIONS: TC in breast cancer tissue is an independent predictor of clinical outcome and survival interval, and may discriminate by stage.},
}
@article {pmid16749892,
year = {2006},
author = {Songyang, Z and Liu, D},
title = {Inside the mammalian telomere interactome: regulation and regulatory activities of telomeres.},
journal = {Critical reviews in eukaryotic gene expression},
volume = {16},
number = {2},
pages = {103-118},
doi = {10.1615/critreveukargeneexpr.v16.i2.10},
pmid = {16749892},
issn = {1045-4403},
support = {CA84208/CA/NCI NIH HHS/United States ; GM068572/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromosomal Proteins, Non-Histone/metabolism ; Humans ; Multiprotein Complexes ; Proteomics ; Shelterin Complex ; Signal Transduction ; Systems Biology ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Work in model organisms, such as mouse, yeast, Tetrahymena, ciliates, and plants, has led to a deeper understanding of telomere biology. Telomeres together with telomere-binding proteins have evolved to protect chromosomal ends and maintain chromosomal length and integrity. Over the last two decades, biochemical, molecular, cellular, and genetic studies have greatly enhanced our knowledge of the unique function and structure of telomeres and telomere-associated factors. In this review, we focus on the important advances, in terms of our knowledge and the methods used, in understanding mammalian telomere regulation by telomeric proteins. Recently, the 6 telomeric proteins (TRF1, TRF2, POT1, TIN2, RAP1, and TPP1) were found to form a high-order complex. This complex and its associated partners provide the basis for constructing an interaction map of telomere regulators in mammalian cells, which we named the Telomere Interactome. The Telomere Interactome incorporates the various telomere signaling pathways and represents the molecular machinery that regulates mammalian telomeres. The establishment of the Telomere Interactome will also enable the integration of the intricate circuitries that regulate telomeres with other cellular interactomes in vertebrates.},
}
@article {pmid16741708,
year = {2006},
author = {Hug, N and Lingner, J},
title = {Telomere length homeostasis.},
journal = {Chromosoma},
volume = {115},
number = {6},
pages = {413-425},
pmid = {16741708},
issn = {0009-5915},
mesh = {Animals ; Cell Cycle/physiology ; Homeostasis/genetics ; Humans ; Models, Biological ; Saccharomyces cerevisiae/genetics/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism/physiology ; },
abstract = {The physical ends of chromosomes, known as telomeres, protect chromosome ends from nucleolytic degradation and DNA repair activities. Conventional DNA replication enzymes lack the ability to fully replicate telomere ends. In addition, nucleolytic activities contribute to telomere erosion. Short telomeres trigger DNA damage checkpoints, which mediate cellular senescence. Telomere length homeostasis requires telomerase, a cellular reverse transcriptase, which uses an internal RNA moiety as a template for the synthesis of telomere repeats. Telomerase elongates the 3' ends of chromosomes, whereas the complementary strand is filled in by conventional DNA polymerases. In humans, telomerase is ubiquitously expressed only during the first weeks of embryogenesis, and is subsequently downregulated in most cell types. Correct telomere length setting is crucial for long-term survival. The telomere length reserve must be sufficient to avoid premature cellular senescence and the acceleration of age-related disease. On the other side, telomere shortening suppresses tumor formation through limiting the replicative potential of cells. In recent years, novel insight into the regulation of telomerase at chromosome ends has increased our understanding on how telomere length homeostasis in telomerase-positive cells is achieved. Factors that recruit telomerase to telomeres in a cell cycle-dependent manner have been identified in Saccharomyces cerevisiae. In humans, telomerase assembles with telomeres during S phase of the cell cycle. Presumably through mediating formation of alternative telomere structures, telomere-binding proteins regulate telomerase activity in cis to favor preferential elongation of the shortest telomeres. Phosphoinositide 3-kinase related kinases are also required for telomerase activation at chromosome ends, at least in budding and fission yeast. In vivo analysis of telomere elongation kinetics shows that telomerase does not act on every telomere in each cell cycle but that it exhibits an increasing preference for telomeres as their lengths decline. This suggests a model in which telomeres switch between extendible and nonextendible states in a length-dependent manner. In this review we expand this model to incorporate the finding that telomerase levels also limit telomere length and we propose a second switch between a non-telomerase-associated "extendible" and a telomerase-associated "extending" state.},
}
@article {pmid16740715,
year = {2006},
author = {Goldkorn, A and Blackburn, EH},
title = {Assembly of mutant-template telomerase RNA into catalytically active telomerase ribonucleoprotein that can act on telomeres is required for apoptosis and cell cycle arrest in human cancer cells.},
journal = {Cancer research},
volume = {66},
number = {11},
pages = {5763-5771},
doi = {10.1158/0008-5472.CAN-05-3782},
pmid = {16740715},
issn = {0008-5472},
support = {CA96840/CA/NCI NIH HHS/United States ; T32 DK007636/DK/NIDDK NIH HHS/United States ; },
mesh = {Alleles ; Apoptosis/physiology ; Catalysis ; Cell Cycle/physiology ; Cell Growth Processes/physiology ; Cell Line, Tumor ; DNA Damage ; DNA-Binding Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Genetic Vectors/genetics ; Humans ; Melanoma/enzymology/genetics/*metabolism/therapy ; Mutation ; RNA/genetics/*metabolism ; RNA, Small Interfering/genetics ; Retroviridae/genetics ; Telomerase/antagonists &amp; inhibitors/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {The telomerase ribonucleoprotein is a promising target for cancer therapy, as it is highly active in many human malignancies. A novel telomerase targeting approach combines short interfering RNA (siRNA) knockdown of endogenous human telomerase RNA (hTer) with expression of a mutant-template hTer (MT-hTer). Such combination MT-hTer/siRNA constructs induce a rapid DNA damage response, telomere uncapping, and inhibition of cell proliferation in a variety of human cancer cell lines. We tested which functional aspects of the protein catalytic component of telomerase [human telomerase reverse transcriptase (hTERT)] are required for these effects using human LOX melanoma cells overexpressing various hTERTs of known properties. Within 3 days of MT-hTer/siRNA introduction, both growth inhibition and DNA damage responses were significantly higher in the setting of wild-type hTERT versus catalytically dead hTERT or mutant hTERT that is catalytically competent but unable to act on telomeres. These effects were not attenuated by siRNA-induced knockdown of the telomeric protein human Rap1 and were additive with knockdown of the telomere-binding protein TRF2. Hence, the effects of MT-hTer/siRNA require a telomerase that is both catalytically competent to polymerize DNA and able to act on telomeres in cells.},
}
@article {pmid16737810,
year = {2006},
author = {Hsu, CP and Hsu, NY and Lee, LW and Ko, JL},
title = {Ets2 binding site single nucleotide polymorphism at the hTERT gene promoter--effect on telomerase expression and telomere length maintenance in non-small cell lung cancer.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {42},
number = {10},
pages = {1466-1474},
doi = {10.1016/j.ejca.2006.02.014},
pmid = {16737810},
issn = {0959-8049},
mesh = {Aged ; Carcinoma, Non-Small-Cell Lung/enzymology/*genetics ; DNA-Binding Proteins/*genetics ; Female ; Humans ; Lung Neoplasms/enzymology/*genetics ; Male ; Polymorphism, Single Nucleotide ; Proto-Oncogene Protein c-ets-2/*genetics ; Proto-Oncogene Proteins c-myc/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/genetics/*metabolism ; Telomere/*pathology ; },
abstract = {The aim of this study was to elucidate the occurrence of DNA sequence changes in the promoter region of hTERT gene, and its effect on telomerase expression and telomere length maintenance in non-small cell lung cancer (NSCLC). Between January 2002 and December 2003, 66 NSCLC patients were studied. The expression of hTERT, telomerase activity (TA), and c-Myc were examined, and the terminal restriction fragment length (TRFL) was measured. A t/n-TRFLR was obtained by dividing the TRFL of the tumour tissue by TRFL of the paired normal tissue. PCR products were sequenced and compared with known hTERT gene promoter sequence for a length of 716 bp upstream of the transcription starting code. The changes of any known sequence and/or c-Myc expression with their impact on telomerase activity and TRFL maintenance were measured. Positive hTERT, TA and c-Myc expression was observed in 43 (65.2%), 39 (59.1%) and 59 (89.4%) of the tumour tissue samples, respectively. Except for one patient who had C/C (in normal tissue) homozygotes to T/C (in tumour tissue) heterozygotes point mutation, a novel single nucleotide polymorphism (SNP) -245 kb upstream (Ets2 binding site) of the hTERT gene was observed in all normal and tumour tissues, including C/C in 9, T/C in 35, and T/T in 22 of the tumour tissues. The TA of C/C homozygotes was lower than that of T/T homozygotes (P=0.0331), while the t/n-TRFLR of C/C homozygotes was higher than that of T/T homozygotes (P=0.0621). The latter was even more obvious when c-Myc were positive (P=0.0185). Our data shows that T/T homozygotes have a lower t/n-TRFLR, but a stronger TA expression, suggesting that the studied Ets2 binding site is a positive regulator of hTERT gene. SNP may interfere with Ets2 binding and lower TA expression in T/C heterozygotes and C/C homozygotes.},
}
@article {pmid16737559,
year = {2006},
author = {Casacuberta, E and Pardue, ML},
title = {RNA interference has a role in regulating Drosophila telomeres.},
journal = {Genome biology},
volume = {7},
number = {5},
pages = {220},
pmid = {16737559},
issn = {1474-760X},
support = {R01 GM050315/GM/NIGMS NIH HHS/United States ; R56 GM050315/GM/NIGMS NIH HHS/United States ; GM50315/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Drosophila Proteins/physiology ; Drosophila melanogaster/*genetics ; *RNA Interference ; *Retroelements ; Telomere/*chemistry/metabolism ; },
abstract = {Unlike many other organisms, Drosophila maintains its telomeres by the transposition of retrotransposons to chromosome ends. Recent work shows that proteins in the RNA interference pathway specifically regulate the expression of these retrotransposons and frequency of transposition in germline cells, but do not affect retrotransposon expression or telomere function in the soma.},
}
@article {pmid16735827,
year = {2006},
author = {Keefe, DL and Marquard, K and Liu, L},
title = {The telomere theory of reproductive senescence in women.},
journal = {Current opinion in obstetrics &amp; gynecology},
volume = {18},
number = {3},
pages = {280-285},
doi = {10.1097/01.gco.0000193019.05686.49},
pmid = {16735827},
issn = {1040-872X},
mesh = {Cellular Senescence/*genetics/physiology ; Female ; Fertilization in Vitro ; Humans ; Meiosis/*physiology ; Oocytes/*physiology ; Pregnancy ; Reproduction/*genetics/physiology ; Telomere/genetics/*physiology ; },
abstract = {PURPOSE OF REVIEW: A unifying theory of reproductive aging, based on telomere shortening, is proposed.<br><br>RECENT FINDINGS: Telomere shortening may mediate both 'hits' involved in reproductive aging, that is late exit from the fetal production line and long interval to ovulation in the adult.<br><br>SUMMARY: As women age egg dysfunction increases, with meiotic nondisjunction, embryonic arrest, apoptosis, and miscarriage. Egg dysfunction results from two 'hits' - reduced formation of chiasmata during fetal oogenesis, and accumulation of reactive oxygen damage during the prolonged interval until ovulation. Late exit from a production line during oogenesis presumably contributes to the first hit. The later insult also involves meiotic spindle abnormalities. Telomeres, repetitive sequences of DNA, cap chromosome ends and dissipate during divisions. Oocytes do not divide, but oogonia do, and telomerase, the enzyme responsible for maintaining telomere length, is inefficient, and remains inactive in oocytes and embryos until blastocyst stage. Reactive oxygen also shortens telomeres, so the prolonged interval between birth and ovulation would further shorten telomeres from chronic exposure to reactive oxygen. In support of this theory, experimental shortening of telomeres in mice produced a phenotype similar to reproductive aging in women, with abnormal chiasmata, spindles, cell cycles, apoptosis, and genomic instability, and telomere length in human eggs correlated with in-vitro fertilization outcome.},
}
@article {pmid16734822,
year = {2006},
author = {Pipes, BL and Tsang, T and Peng, SX and Fiederlein, R and Graham, M and Harris, DT},
title = {Telomere length changes after umbilical cord blood transplant.},
journal = {Transfusion},
volume = {46},
number = {6},
pages = {1038-1043},
doi = {10.1111/j.1537-2995.2006.00839.x},
pmid = {16734822},
issn = {0041-1132},
mesh = {Adult ; Cellular Senescence ; *Cord Blood Stem Cell Transplantation ; Hematologic Neoplasms/therapy ; Hematopoiesis ; Hematopoietic Stem Cells/physiology ; Humans ; Infant, Newborn ; Leukocytes, Mononuclear/ultrastructure ; Middle Aged ; Peripheral Blood Stem Cell Transplantation ; Telomere/*metabolism ; Transplantation, Homologous ; },
abstract = {BACKGROUND: The establishment of donor-derived hematopoiesis in the recipients of hematopoietic stem cell (HSC) transplants involves extensive proliferation and differentiation of HSCs. Data from long-term survivors of HSC transplants suggest that these transplanted HSCs may experience a debilitating replicative senescence. A significant posttransplant shortening of peripheral blood mononuclear cell (PBMNC) telomeres has been observed in both marrow transplant and peripheral blood progenitor cell transplant recipients. Similar studies have not been performed for umbilical cord blood (UCB) HSC transplants, which might be expected to exhibit increased posttransplant replicative potential due to their inherently greater telomere length.<br><br>STUDY DESIGN AND METHODS: Blood was obtained from donor-recipient pairs of allogeneic PBHSC transplant and UCB HSC transplant, both before transplant and at follow-up treatments (minimum 1 year after transplant) after engraftment. Telomere restriction fragment length (TRFL) analysis was performed on the blood samples. The mean TRFL and posttransplant changes in the mean TRFL were analyzed.<br><br>RESULTS: Measurements of telomere lengths in the PBMNCs of transplant patients revealed a significant net decrease in telomere length in all transplant recipients compared with their respective donors. Our results also revealed that the PBMNCs of umbilical cord stem cell transplant patients retain a significantly longer posttransplant telomere length.<br><br>CONCLUSION: The significantly longer telomeres observed in the allogeneic UCB HSC transplant recipients compared to the allogeneic PBHSC transplant recipients in our study may be indicative of a replicative advantage inherent in the use of UCB HSC for transplant.},
}
@article {pmid16730176,
year = {2006},
author = {van Overbeek, M and de Lange, T},
title = {Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S phase.},
journal = {Current biology : CB},
volume = {16},
number = {13},
pages = {1295-1302},
doi = {10.1016/j.cub.2006.05.022},
pmid = {16730176},
issn = {0960-9822},
support = {AG16642/AG/NIA NIH HHS/United States ; GM49046/GM/NIGMS NIH HHS/United States ; T32 CA009673/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line ; Chromosomes, Human/metabolism/ultrastructure ; DNA Damage ; DNA Repair Enzymes ; Deoxyribonucleases/*metabolism ; Exodeoxyribonucleases/analysis/genetics/*metabolism ; Humans ; Mass Spectrometry ; Nuclear Proteins/analysis/genetics/*metabolism ; RNA Interference ; S Phase/*physiology ; Shelterin Complex ; Telomere/*metabolism/ultrastructure ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {Human chromosome ends are protected by shelterin, an abundant six-subunit protein complex that binds specifically to the telomeric-repeat sequences, regulates telomere length, and ensures that chromosome ends do not elicit a DNA-damage response (reviewed in). Using mass spectrometry of proteins associated with the shelterin component Rap1, we identified an SMN1/PSO2 nuclease family member that is closely related to Artemis. We refer to this protein as Apollo and report that Apollo has the ability to localize to telomeres through an interaction with the shelterin component TRF2. Although its low abundance at telomeres indicates that Apollo is not a core component of shelterin, Apollo knockdown with RNAi resulted in senescence and the activation of a DNA-damage signal at telomeres as evidenced by telomere-dysfunction-induced foci (TIFs). The TIFs occurred primarily in S phase, suggesting that Apollo contributes to a processing step associated with the replication of chromosome ends. Furthermore, some of the metaphase chromosomes showed two telomeric signals at single-chromatid ends, suggesting an aberrant telomere structure. We propose that the Artemis-like nuclease Apollo is a shelterin accessory factor required for the protection of telomeres during or after their replication.},
}
@article {pmid16730175,
year = {2006},
author = {Lenain, C and Bauwens, S and Amiard, S and Brunori, M and Giraud-Panis, MJ and Gilson, E},
title = {The Apollo 5' exonuclease functions together with TRF2 to protect telomeres from DNA repair.},
journal = {Current biology : CB},
volume = {16},
number = {13},
pages = {1303-1310},
doi = {10.1016/j.cub.2006.05.021},
pmid = {16730175},
issn = {0960-9822},
mesh = {Animals ; COS Cells ; Chlorocebus aethiops ; DNA Repair/*physiology ; DNA Repair Enzymes ; Exodeoxyribonucleases/analysis/genetics/*physiology ; Glutathione Transferase/analysis ; Humans ; Nuclear Proteins/analysis/genetics/*physiology ; Recombinant Fusion Proteins/analysis ; Telomere/*metabolism/ultrastructure ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {A major issue in telomere research is to understand how the integrity of chromosome ends is preserved . The human telomeric protein TRF2 coordinates several pathways that prevent checkpoint activation and chromosome fusions. In this work, we identified hSNM1B, here named Apollo, as a novel TRF2-interacting factor. Interestingly, the N-terminal domain of Apollo is closely related to that of Artemis, a factor involved in V(D)J recombination and DNA repair. Both proteins belong to the beta-CASP metallo-beta-lactamase family of DNA caretaker proteins. Apollo appears preferentially localized at telomeres in a TRF2-dependent manner. Reduced levels of Apollo exacerbate the sensitivity of cells to TRF2 inhibition, resulting in severe growth defects and an increased number of telomere-induced DNA-damage foci and telomere fusions. Purified Apollo protein exhibits a 5'-to-3' DNA exonuclease activity. We conclude that Apollo is a novel component of the human telomeric complex and works together with TRF2 to protect chromosome termini from being recognized and processed as DNA damage. These findings unveil a previously undescribed telomere-protection mechanism involving a DNA 5'-to-3' exonuclease.},
}
@article {pmid16714448,
year = {2006},
author = {Steinberg-Neifach, O and Lue, NF},
title = {Modulation of telomere terminal structure by telomerase components in Candida albicans.},
journal = {Nucleic acids research},
volume = {34},
number = {9},
pages = {2710-2722},
pmid = {16714448},
issn = {1362-4962},
mesh = {Candida albicans/*enzymology/*genetics ; DNA, Fungal/analysis ; DNA-Binding Proteins/genetics/*physiology ; Fungal Proteins/genetics/*physiology ; Mutation ; Nucleic Acid Hybridization/methods ; Protein Subunits/genetics ; Telomerase/genetics/*physiology ; Telomere/*chemistry/metabolism ; },
abstract = {The telomerase ribonucleoprotein in Candida albicans is presumed to contain at least three Est proteins: CaEst1p, CaEst2p/TERT and CaEst3p. We constructed mutants missing each of the protein subunit of telomerase and analyzed overall telomere dynamics and single-stranded telomere overhangs over the course of many generations. The est1-DeltaDelta mutant manifested abrupt telomere loss and recovery, consistent with heightened recombination. Both the est2-DeltaDelta and est3-DeltaDelta mutant exhibited progressive telomere loss, followed by the gradual emergence of survivors with long telomeres. In no case was telomere loss accompanied by severe growth defects, suggesting that cells with short telomeres can continue to proliferate. Furthermore, the amount of G-strand terminal overhangs was greatly increased in the est2-DeltaDelta mutant, but not others. Our results suggest that in addition to their well-characterized function in telomere elongation, both CaEst1p and CaEst2p mediate some aspects of telomere protection in Candida, with the former suppressing excessive recombination, and the latter preventing excessive C-strand degradation.},
}
@article {pmid16710445,
year = {2006},
author = {Oikemus, SR and Queiroz-Machado, J and Lai, K and McGinnis, N and Sunkel, C and Brodsky, MH},
title = {Epigenetic telomere protection by Drosophila DNA damage response pathways.},
journal = {PLoS genetics},
volume = {2},
number = {5},
pages = {e71},
pmid = {16710445},
issn = {1553-7404},
mesh = {Alleles ; Animals ; Apoptosis ; Cell Cycle ; Chromosome Mapping ; Crosses, Genetic ; *DNA Damage ; DNA Repair ; Drosophila Proteins ; Drosophila melanogaster ; *Epigenesis, Genetic ; Gene Deletion ; Mitosis ; Telomere/*ultrastructure ; Time Factors ; },
abstract = {Analysis of terminal deletion chromosomes indicates that a sequence-independent mechanism regulates protection of Drosophila telomeres. Mutations in Drosophila DNA damage response genes such as atm/tefu, mre11, or rad50 disrupt telomere protection and localization of the telomere-associated proteins HP1 and HOAP, suggesting that recognition of chromosome ends contributes to telomere protection. However, the partial telomere protection phenotype of these mutations limits the ability to test if they act in the epigenetic telomere protection mechanism. We examined the roles of the Drosophila atm and atr-atrip DNA damage response pathways and the nbs homolog in DNA damage responses and telomere protection. As in other organisms, the atm and atr-atrip pathways act in parallel to promote telomere protection. Cells lacking both pathways exhibit severe defects in telomere protection and fail to localize the protection protein HOAP to telomeres. Drosophila nbs is required for both atm- and atr-dependent DNA damage responses and acts in these pathways during DNA repair. The telomere fusion phenotype of nbs is consistent with defects in each of these activities. Cells defective in both the atm and atr pathways were used to examine if DNA damage response pathways regulate telomere protection without affecting telomere specific sequences. In these cells, chromosome fusion sites retain telomere-specific sequences, demonstrating that loss of these sequences is not responsible for loss of protection. Furthermore, terminally deleted chromosomes also fuse in these cells, directly implicating DNA damage response pathways in the epigenetic protection of telomeres. We propose that recognition of chromosome ends and recruitment of HP1 and HOAP by DNA damage response proteins is essential for the epigenetic protection of Drosophila telomeres. Given the conserved roles of DNA damage response proteins in telomere function, related mechanisms may act at the telomeres of other organisms.},
}
@article {pmid16707619,
year = {2006},
author = {Hochreiter, AE and Xiao, H and Goldblatt, EM and Gryaznov, SM and Miller, KD and Badve, S and Sledge, GW and Herbert, BS},
title = {Telomerase template antagonist GRN163L disrupts telomere maintenance, tumor growth, and metastasis of breast cancer.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {12},
number = {10},
pages = {3184-3192},
doi = {10.1158/1078-0432.CCR-05-2760},
pmid = {16707619},
issn = {1078-0432},
mesh = {Adenocarcinoma/*drug therapy/genetics/pathology ; Animals ; Breast Neoplasms/*drug therapy/genetics/pathology ; Carcinoma, Ductal, Breast/*drug therapy/genetics/pathology ; Dose-Response Relationship, Drug ; Female ; Genes, BRCA1 ; Humans ; Lung Neoplasms/prevention &amp; control/secondary ; Mice ; Mice, Nude ; Oligonucleotides ; Oligopeptides/*pharmacology ; Receptor, ErbB-2/genetics ; Receptors, Estrogen/genetics ; Telomerase/*antagonists &amp; inhibitors ; Telomere/ultrastructure ; Transplantation, Heterologous ; Tumor Cells, Cultured ; },
abstract = {PURPOSE: Maintenance of telomeres by telomerase is critical for the continuing proliferation of most advanced cancer cells. Telomerase activity has been detected in the vast majority of cancer cells but not most normal cells, making the enzyme an attractive target for anticancer therapy. The aim of this study was to address the breast cancer translational potential of the novel telomerase inhibitor, GRN163L.<br><br>EXPERIMENTAL DESIGN: In the present study, we investigated the effects of GRN163L treatment on a panel of breast cancer cells representing different tumor subtypes with varying genetic backgrounds, including ER+, ER-, HER2+, BRCA1 mutant breast tumor cells as well as doxorubicin-resistant cancer cells. To investigate the in vivo effects of GRN163L, we employed a breast cancer xenograft and metastasis model that simulates a clinical situation in which a patient arrives with a primary tumor that may be then treated or surgically removed.<br><br>RESULTS: GRN163L effectively inhibited telomerase activity in a dose-dependent fashion in all breast cancer cell lines resulting in progressive telomere shortening. A mismatch control oligonucleotide showed no effect on telomerase activity and GRN163L did not significantly affect telomere shortening in normal human mammary epithelial cells or in endothelial cells. Breast cancer cells that exhibited telomerase inhibition also exhibited significant reduction in colony formation and tumorigenicity. Furthermore, GRN163L suppressed tumor growth and lung metastases (P = 0.017) of MDA-MB-231 cells in vivo after 4 weeks of treatment.<br><br>CONCLUSIONS: These results show in vivo effectiveness of GRN163L in breast cancer and support its promising clinical potential for breast cancer treatment.},
}
@article {pmid16701469,
year = {2006},
author = {Monaghan, P and Haussmann, MF},
title = {Do telomere dynamics link lifestyle and lifespan?.},
journal = {Trends in ecology &amp; evolution},
volume = {21},
number = {1},
pages = {47-53},
doi = {10.1016/j.tree.2005.11.007},
pmid = {16701469},
issn = {0169-5347},
mesh = {Aging/*physiology ; Animals ; Cell Division/physiology ; Humans ; *Life Expectancy ; *Life Style ; Mitosis ; Telomere/physiology/*ultrastructure ; },
abstract = {Identifying and understanding the processes that underlie the observed variation in lifespan within and among species remains one of the central areas of biological research. Questions directed at how, at what rate and why organisms grow old and die link disciplines such as evolutionary ecology to those of cell biology and gerontology. One process now thought to have a key role in ageing is the pattern of erosion of the protective ends of chromosomes, the telomeres. Here, we discuss what is currently known about the factors influencing telomere regulation, and how this relates to fundamental questions about the relationship between lifestyle and lifespan.},
}
@article {pmid16685698,
year = {2006},
author = {Martin-Ruiz, C and Dickinson, HO and Keys, B and Rowan, E and Kenny, RA and Von Zglinicki, T},
title = {Telomere length predicts poststroke mortality, dementia, and cognitive decline.},
journal = {Annals of neurology},
volume = {60},
number = {2},
pages = {174-180},
doi = {10.1002/ana.20869},
pmid = {16685698},
issn = {0364-5134},
support = {G0601333/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aged ; Aged, 80 and over ; *Cognition ; Cohort Studies ; Dementia/epidemiology/etiology ; Female ; Humans ; Male ; Monocytes/pathology/ultrastructure ; Neuropsychological Tests ; Odds Ratio ; Predictive Value of Tests ; Prognosis ; Risk ; Stroke/mortality/*pathology/*psychology ; Survival Analysis ; Telomere/*pathology/ultrastructure ; },
abstract = {OBJECTIVE: Long-term cognitive development is variable among stroke survivors, with a high proportion developing dementia. Early identification of those at risk is highly desirable to target interventions for secondary prevention. Telomere length in peripheral blood mononuclear cells was tested as prognostic risk marker.<br><br>METHODS: A cohort of 195 nondemented stroke survivors was followed prospectively from 3 months after stroke for 2 years for cognitive assessment and diagnosis of dementia and for 5 years for survival. Telomere lengths in peripheral blood mononuclear cells were measured at 3 months after stroke by in-gel hybridization. Hazard ratios for survival in relation to telomere length and odds ratios for dementia were estimated using multivariate techniques, and changes in Mini-Mental State Examination scores between baseline and 2 years were related to telomere length using multivariate linear regression.<br><br>RESULTS: Longer telomeres at baseline were associated with reduced risk for death (hazard ratio for linear trend per 1,000 bp = 0.52; 95% confidence interval, 0.28-0.98; p = 0.04, adjusted for age) and dementia (odds ratio for linear trend per 1,000 bp = 0.19; 95% confidence interval, 0.07-0.54; p = 0.002) and less reduction in Mini-Mental State Examination score (p = 0.04, adjusted for baseline score).<br><br>INTERPRETATION: Telomere length is a prognostic marker for poststroke cognitive decline, dementia, and death.},
}
@article {pmid16684995,
year = {2006},
author = {Kosa, P and Valach, M and Tomaska, L and Wolfe, KH and Nosek, J},
title = {Complete DNA sequences of the mitochondrial genomes of the pathogenic yeasts Candida orthopsilosis and Candida metapsilosis: insight into the evolution of linear DNA genomes from mitochondrial telomere mutants.},
journal = {Nucleic acids research},
volume = {34},
number = {8},
pages = {2472-2481},
pmid = {16684995},
issn = {1362-4962},
support = {R03 TW005654/TW/FIC NIH HHS/United States ; },
mesh = {Base Sequence ; Candida/classification/*genetics/metabolism ; Conserved Sequence ; DNA, Circular/chemistry ; DNA, Mitochondrial/*chemistry ; *Evolution, Molecular ; Gene Order ; *Genome, Fungal ; Mitochondria/*genetics ; Mutation ; Phylogeny ; RNA/metabolism ; RNA Processing, Post-Transcriptional ; RNA, Messenger/metabolism ; RNA, Mitochondrial ; RNA, Transfer/metabolism ; Telomere/*chemistry/genetics ; },
abstract = {We determined complete mitochondrial DNA sequences of the two yeast species, Candida orthopsilosis and Candida metapsilosis, and compared them with the linear mitochondrial genome of their close relative, C.parapsilosis. Mitochondria of all the three species harbor compact genomes encoding the same set of genes arranged in the identical order. Differences in the length of these genomes result mainly from the presence/absence of introns. Multiple alterations were identified also in the sequences of the ribosomal and transfer RNAs, and proteins. However, the most striking feature of C.orthopsilosis and C.metapsilosis is the existence of strains differing in the molecular form of the mitochondrial genome (circular-mapping versus linear). Their analysis opens a unique window for understanding the role of mitochondrial telomeres in the stability and evolution of molecular architecture of the genome. Our results indicate that the circular-mapping mitochondrial genome derived from the linear form by intramolecular end-to-end fusions. Moreover, we suggest that the linear mitochondrial genome evolved from a circular-mapping form present in a common ancestor of the three species and, at the same time, the emergence of mitochondrial telomeres enabled the formation of linear monomeric DNA forms. In addition, comparison of isogenic C.metapsilosis strains differing in the form of the organellar genome suggests a possibility that, under some circumstances, the linearity and/or the presence of telomeres provide a competitive advantage over a circular-mapping mitochondrial genome.},
}
@article {pmid16682448,
year = {2006},
author = {Bailey, SM and Murnane, JP},
title = {Telomeres, chromosome instability and cancer.},
journal = {Nucleic acids research},
volume = {34},
number = {8},
pages = {2408-2417},
pmid = {16682448},
issn = {1362-4962},
support = {R01 CA043322/CA/NCI NIH HHS/United States ; R01 CA69044/CA/NCI NIH HHS/United States ; R01 ES008427/ES/NIEHS NIH HHS/United States ; CA43322/CA/NCI NIH HHS/United States ; R01 CA069044/CA/NCI NIH HHS/United States ; },
mesh = {*Chromosomal Instability ; Humans ; Neoplasms/*genetics ; Repetitive Sequences, Nucleic Acid ; Telomere/chemistry/*physiology ; },
abstract = {Telomeres are composed of repetitive G-rich sequence and an abundance of associated proteins that together form a dynamic cap that protects chromosome ends and allows them to be distinguished from deleterious DSBs. Telomere-associated proteins also function to regulate telomerase, the ribonucleoprtotein responsible for addition of the species-specific terminal repeat sequence. Loss of telomere function is an important mechanism for the chromosome instability commonly found in cancer. Dysfunctional telomeres can result either from alterations in the telomere-associated proteins required for end-capping function, or from alterations that promote the gradual or sudden loss of sufficient repeat sequence necessary to maintain proper telomere structure. Regardless of the mechanism, loss of telomere function can result in sister chromatid fusion and prolonged breakage/fusion/bridge (B/F/B) cycles, leading to extensive DNA amplification and large terminal deletions. B/F/B cycles terminate primarily when the unstable chromosome acquires a new telomere, most often by translocation of the ends of other chromosomes, thereby providing a mechanism for transfer of instability from one chromosome to another. Thus, the loss of a single telomere can result in on-going instability, affect multiple chromosomes, and generate many of the types of rearrangements commonly associated with human cancer.},
}
@article {pmid16682351,
year = {2006},
author = {Antoniacci, LM and Skibbens, RV},
title = {Sister-chromatid telomere cohesion is nonredundant and resists both spindle forces and telomere motility.},
journal = {Current biology : CB},
volume = {16},
number = {9},
pages = {902-906},
doi = {10.1016/j.cub.2006.03.060},
pmid = {16682351},
issn = {0960-9822},
mesh = {Acetyltransferases/physiology ; Anaphase/physiology ; Cell Cycle Proteins/*physiology ; Chromatids/*physiology ; Chromosomal Proteins, Non-Histone/*physiology ; Nuclear Proteins/*physiology ; Phosphoproteins ; Saccharomyces/cytology/*physiology ; Saccharomyces cerevisiae Proteins/physiology ; Spindle Apparatus/physiology ; Telomere/*physiology ; Cohesins ; },
abstract = {It is well documented that inactivation of essential cohesion proteins results in precocious sister-chromatid separation. On average, however, only approximately 55% of cohesin-deficient budding yeast cells arrested prior to anaphase contain separated sister chromatids , suggesting that cohesin-independent factors also contribute to sister-chromatid pairing. Recently, redundant pairing mechanisms were found to occur at both rDNA and centromeres . Here, we tested whether redundant mechanisms also function to pair telomeres or whether cohesins provide sole pairing activity. Results from both mcd1 and ctf7 mutant cells show that nearly 100% of telomeres separate prior to anaphase, twice the cohesion defect reported for centromeres. Such complete loci separation reveals that cohesins are singularly responsible for maintaining telomere cohesion, in contrast to other loci. We also found that sister telomeres moved 141% farther apart than centromeres. Telomere separation occurred in the absence of spindle microtubules and an actin cytoskeleton and persisted in cells abrogated for Mps3p function-an integral nuclear envelope protein previously shown to function in cohesion . These findings are consistent with numerous studies that telomeres translocate along the nuclear periphery and provide new evidence that telomere dynamics can contribute to sister-chromatid separation, independent of centromere motility.},
}
@article {pmid16682210,
year = {2006},
author = {Xu, Y and Noguchi, Y and Sugiyama, H},
title = {The new models of the human telomere d[AGGG(TTAGGG)3] in K+ solution.},
journal = {Bioorganic &amp; medicinal chemistry},
volume = {14},
number = {16},
pages = {5584-5591},
doi = {10.1016/j.bmc.2006.04.033},
pmid = {16682210},
issn = {0968-0896},
mesh = {Base Sequence ; Circular Dichroism ; Crystallography, X-Ray ; DNA/*chemistry ; G-Quadruplexes ; Humans ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Nucleic Acid Conformation ; Potassium/*chemistry/pharmacology ; Sodium/chemistry/pharmacology ; Solutions/chemistry ; Telomere/*chemistry ; },
abstract = {The human telomeric sequence d[AGGG(TTAGGG)(3)] has been found to form different types of G-quadruplex structures. NMR revealed that in Na(+) solution this 22 nucleotide (nt) sequence exhibits an antiparallel structure, whereas crystallographic studies in the presence of K(+) showed a dramatically different parallel structure. The structure of this 22 nt sequence in the presence of K(+) has drawn intense interest as the intracellular K(+) concentration is greater than that of Na(+). However, the question of the type of structure for the 22 nt telomeric sequence in K(+) solution remains open. In this study, we substituted the Gs in the sequence with 8-bromoguanine and examined the resultant structures and thermal stabilities by circular dichroism (CD) spectroscopy. The results suggest that the 22 nt in K(+) solution exists as a mixture of mixed-parallel/antiparallel and chair-type G-quadruplex. To date, the exact structure of human telomeric G-quadruplex in K(+) solution is extremely controversial. The present study provides valuable information for understanding the discrepancies between the crystal and solution studies. We discuss the possible implications of the structure in understanding higher-order telomeric DNA structure and T-loop formation.},
}
@article {pmid16678852,
year = {2006},
author = {Buczek, P and Horvath, MP},
title = {Thermodynamic characterization of binding Oxytricha nova single strand telomere DNA with the alpha protein N-terminal domain.},
journal = {Journal of molecular biology},
volume = {359},
number = {5},
pages = {1217-1234},
pmid = {16678852},
issn = {0022-2836},
support = {GM067994/GM/NIGMS NIH HHS/United States ; R01 GM067994-01/GM/NIGMS NIH HHS/United States ; R01 GM067994-03/GM/NIGMS NIH HHS/United States ; R01 GM067994/GM/NIGMS NIH HHS/United States ; P30 CA042014/CA/NCI NIH HHS/United States ; R01 GM067994-04/GM/NIGMS NIH HHS/United States ; R01 GM067994-02/GM/NIGMS NIH HHS/United States ; 5P30 CA42014/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; DNA, Protozoan/chemistry/*metabolism ; DNA, Single-Stranded/chemistry/*metabolism ; Electrolytes/pharmacology ; Entropy ; Lithium Chloride/pharmacology ; Models, Molecular ; Mutation/genetics ; Nucleic Acid Conformation ; Oxytricha/*metabolism ; Protein Binding/drug effects ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/*chemistry/*metabolism ; Thermodynamics ; },
abstract = {The Oxytricha nova telemere binding protein alpha subunit binds single strand DNA and participates in a nucleoprotein complex that protects the very ends of chromosomes. To understand how the N-terminal, DNA binding domain of alpha interacts with DNA we measured the stoichiometry, enthalpy (DeltaH), entropy (DeltaS), and dissociation constant (K(D-DNA)) for binding telomere DNA fragments at different temperatures and salt concentrations using native gel electrophoresis and isothermal titration calorimetry (ITC). About 85% of the total free energy of binding corresponded with non-electrostatic interactions for all DNAs. Telomere DNA fragments d(T(2)G(4)), d(T(4)G(4)), d(G(3)T(4)G(4)), and d(G(4)T(4)G(4)) each formed monovalent protein complexes. In the case of d(T(4)G(4)T(4)G(4)), which has two tandemly repeated d(TTTTTGGGG) telomere motifs, two binding sites were observed. The high-affinity "A site" has a dissociation constant, K(D-DNA(A)) = 13(+/-4) nM, while the low-affinity "B site" is characterized by K(D-DNA(B)) = 5600(+/-600) nM at 25 degrees C. Nucleotide substitution variants verified that the A site corresponds principally with the 3'-terminal portion of d(T(4)G(4)T(4)G(4)). The relative contributions of entropy (DeltaS) and enthalpy (DeltaH) for binding reactions were DNA length-dependent as was heat capacity (DeltaCp). These trends with respect to DNA length likely reflect structural transitions in the DNA molecule that are coupled with DNA-protein association. Results presented here are important for understanding early intermediates and subsequent stages in the assembly of the full telomere nucleoprotein complex and how binding events can prepare the telomere DNA for extension by telomerase, a critical event in telomere biology.},
}
@article {pmid16677791,
year = {2006},
author = {Fehrer, C and Voglauer, R and Wieser, M and Pfister, G and Brunauer, R and Cioca, D and Grubeck-Loebenstein, B and Lepperdinger, G},
title = {Techniques in gerontology: cell lines as standards for telomere length and telomerase activity assessment.},
journal = {Experimental gerontology},
volume = {41},
number = {6},
pages = {648-651},
doi = {10.1016/j.exger.2006.03.016},
pmid = {16677791},
issn = {0531-5565},
mesh = {Cell Line ; Cell Line, Tumor ; Cellular Senescence/*physiology ; DNA/analysis ; Disease Progression ; Geriatrics/*methods ; Humans ; Polymerase Chain Reaction ; Reference Values ; Telomerase/*physiology ; Telomere/*ultrastructure ; },
abstract = {The length of telomeres is believed to critically influence cellular aging processes and disease development. In order to reliably monitor telomere length and the corresponding cellular telomerase activity by optimized procedures, either based on flow cytometry or quantitative PCR technique, we here propose three commonly used cell lines, HEK293, K562 and TCL1301 as standards. In this contribution, efficient methods to determine mean telomere length of eukaryotic chromosomal DNA and determination of the corresponding telomeras activity are outlined. In particular, wide-range standard curves for a precise assessment of telomere length of genomic DNA by quantitative PCR technique are presented, measures, which greatly simplify the evaluation of respective functional roles of telomeres when studying biological processes such as disease progression and aging.},
}
@article {pmid16651430,
year = {2006},
author = {Farazi, PA and Glickman, J and Horner, J and Depinho, RA},
title = {Cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression.},
journal = {Cancer research},
volume = {66},
number = {9},
pages = {4766-4773},
doi = {10.1158/0008-5472.CAN-05-4608},
pmid = {16651430},
issn = {0008-5472},
support = {U01 CA84313/CA/NCI NIH HHS/United States ; },
mesh = {Alleles ; Animals ; Carbon Tetrachloride/toxicity ; Carbon Tetrachloride Poisoning/genetics/pathology ; DNA-Binding Proteins/deficiency/genetics ; Disease Models, Animal ; Disease Progression ; *Genes, p53 ; Liver Neoplasms, Experimental/chemically induced/*genetics/*pathology ; Loss of Heterozygosity ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; *Mutation ; Telomerase/deficiency/genetics ; Telomere/*physiology ; Tumor Suppressor Protein p53/genetics ; },
abstract = {Hepatocellular carcinoma is among the most common and lethal cancers in humans. Hepatocellular carcinoma is commonly associated with physical or functional inactivation of the p53 tumor suppressor, high levels of chromosomal instability, and disease conditions causing chronic cycles of hepatocyte death and regeneration. Mounting evidence has implicated regeneration-induced telomere erosion as a potential mechanism fueling genome instability. In mouse models of hepatocellular carcinoma, telomere dysfunction has been shown to enhance initiation of hepatic neoplasias yet constrain full malignant progression of these neoplasms possibly due to activation of a p53-dependent checkpoint and/or intolerable levels of genomic instability. Here, in a hepatocellular carcinoma-prone model brought about through toxin-induced hepatocyte injury and regeneration, we sought to determine the cooperative interactions of germ line p53 mutation and telomere dysfunction [produced by telomerase reverse transcriptase (mTERT) gene knockout]. In the setting of intact telomeres, p53 mutation had no effect on hepatocarcinogenesis, whereas in the setting of telomere dysfunction, p53 mutation enabled advanced hepatocellular carcinoma disease. Notably, there was no evidence of deletion or mutation of the wild-type p53 allele in the late generation mTert(-/-)p53(+/-) mice, suggesting that reduced levels of p53 potently enable hepatocellular carcinoma progression in the setting of telomere dysfunction. Thus, this study supports a model that, in the face of chronic liver damage, attenuated p53 function and telomere-induced chromosomal instability play critical and cooperative roles in the progression of hepatocellular carcinoma.},
}
@article {pmid16649103,
year = {2006},
author = {Sýkorová, E and Leitch, AR and Fajkus, J},
title = {Asparagales telomerases which synthesize the human type of telomeres.},
journal = {Plant molecular biology},
volume = {60},
number = {5},
pages = {633-646},
pmid = {16649103},
issn = {0167-4412},
mesh = {Amino Acid Sequence ; Base Sequence ; Cloning, Molecular ; DNA, Complementary/chemistry/genetics ; DNA-Binding Proteins/genetics/metabolism ; Humans ; Magnoliopsida/enzymology/*genetics ; Molecular Sequence Data ; Phylogeny ; Sequence Alignment ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; Telomerase/*genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {The order of monocotyledonous plants Asparagales is attractive for studies of telomere evolution as it includes three phylogenetically distinct groups with telomeres composed of TTTAGGG (Arabidopsis-type), TTAGGG (human-type) and unknown alternative sequences, respectively. To analyze the molecular causes of these switches in telomere sequence (synthesis), genes coding for the catalytic telomerase subunit (TERT) of representative species in the first two groups have been cloned. Multiple alignments of the sequences, together with other TERT sequences in databases, suggested candidate amino acid substitutions grouped in the Asparagales TERT synthesizing the human-type repeat that could have contributed to the changed telomere sequence. Among these, mutations in the C motif are of special interest due to its functional importance in TERT. Furthermore, two different modes of initial elongation of the substrate primer were observed in Asparagales telomerases producing human-like repeats, which could be attributed to interactions between the telomerase RNA subunit (TR) and the substrate.},
}
@article {pmid16648465,
year = {2006},
author = {Wu, HY and Burgess, SM},
title = {Ndj1, a telomere-associated protein, promotes meiotic recombination in budding yeast.},
journal = {Molecular and cellular biology},
volume = {26},
number = {10},
pages = {3683-3694},
pmid = {16648465},
issn = {0270-7306},
support = {R01 GM075119/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics/*physiology ; Chromosomes, Fungal ; Cross-Linking Reagents/pharmacology ; DNA, Fungal ; Electrophoresis, Gel, Two-Dimensional ; Ficusin/pharmacology ; Fluorescent Dyes ; Indoles ; Kinetics ; *Meiosis ; Models, Genetic ; Mutation ; *Recombination, Genetic ; Saccharomyces cerevisiae/cytology/*genetics ; Saccharomyces cerevisiae Proteins/genetics/*physiology ; Spores, Fungal/drug effects ; *Telomere ; Telomere-Binding Proteins/genetics/*physiology ; },
abstract = {Dynamic telomere repositioning is a prominent feature of meiosis. Deletion of a telomere-associated protein, Ndj1, results in the failure of both attachment and clustering of telomeres at the nuclear envelope and delays several landmarks of meiosis I, such as pairing, synaptonemal complex formation, and timing of the meiosis I division. We explored the role of Ndj1 in meiotic recombination, which occurs through the formation and repair of programmed double-strand breaks. The ndj1delta mutation allows for the formation of the first detectable strand invasion intermediate (i.e., single-end invasion) with wild-type kinetics; however, it confers a delay in the formation of the double-Holliday junction intermediate and both crossover and noncrossover products. These results challenge the widely held notion that clustering of telomeres in meiosis promotes the ability of homologous chromosomes to find one another in budding Saccharomyces cerevisiae. We propose that an Ndj1-dependent function is critical for stabilizing analogous strand invasion intermediates that exist in two separate branches of the bifurcated pathway, leading to either noncrossover or crossover formation. These findings provide a link between telomere dynamics and a distinct mechanistic step of meiotic recombination that follows the homology search.},
}
@article {pmid16644207,
year = {2006},
author = {Ju, Z and Rudolph, KL},
title = {Telomeres and telomerase in cancer stem cells.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {42},
number = {9},
pages = {1197-1203},
doi = {10.1016/j.ejca.2006.01.040},
pmid = {16644207},
issn = {0959-8049},
mesh = {Cell Transformation, Neoplastic/*genetics/metabolism ; Humans ; Neoplasms/enzymology/*genetics ; Neoplastic Stem Cells/*enzymology ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {Alterations in telomere dynamics both suppress and facilitate malignant transformation by regulating genomic stability and cell lifespan. Checkpoints induced by telomere dysfunction play a major role in tumour suppression, whereas telomere shortening contributes to the initiation of cancer by inducing chromosomal instability. Since stem cells are exposed to various tumourigenic agents and stresses throughout their lifetime, the ageing stem cell is a major target of malignant transformation. This review summarises our knowledge of telomere length and telomerase activity in stem cells during ageing and carcinogenesis.},
}
@article {pmid16641934,
year = {2006},
author = {Finkel, T and Vijg, J and Shay, JW},
title = {Time, tumours and telomeres. Meeting on Cancer and Aging.},
journal = {EMBO reports},
volume = {7},
number = {5},
pages = {479-483},
pmid = {16641934},
issn = {1469-221X},
mesh = {Aging/genetics/*physiology ; Animals ; DNA Damage/genetics ; DNA Repair/genetics ; Humans ; Neoplasms/*genetics/metabolism/pathology/physiopathology ; Reactive Oxygen Species/metabolism ; Recombination, Genetic ; Telomere/genetics/*metabolism/physiology ; },
}
@article {pmid16634567,
year = {2006},
author = {Tahara, H and Ide, T},
title = {[Telomere and telomerase in age related diseases].},
journal = {Seikagaku. The Journal of Japanese Biochemical Society},
volume = {78},
number = {3},
pages = {230-241},
pmid = {16634567},
issn = {0037-1017},
mesh = {Aging/*genetics ; Animals ; Cell Division/genetics ; Cellular Senescence/*genetics ; DNA/genetics ; DNA-Binding Proteins/genetics/physiology ; Humans ; Progeria/genetics ; *Repetitive Sequences, Nucleic Acid ; Signal Transduction/genetics/physiology ; Telomerase/genetics/*physiology ; Telomere/genetics/*physiology ; Werner Syndrome/genetics ; },
}
@article {pmid16629820,
year = {2006},
author = {Pauliny, A and Wagner, RH and Augustin, J and Szép, T and Blomqvist, D},
title = {Age-independent telomere length predicts fitness in two bird species.},
journal = {Molecular ecology},
volume = {15},
number = {6},
pages = {1681-1687},
doi = {10.1111/j.1365-294X.2006.02862.x},
pmid = {16629820},
issn = {0962-1083},
mesh = {Age Factors ; Body Size ; Charadriiformes/anatomy &amp; histology/*genetics/growth &amp; development ; Longevity/*genetics ; Phylogeny ; Reproduction/*genetics ; Swallows/anatomy &amp; histology/*genetics/growth &amp; development ; Telomere/*chemistry ; },
abstract = {Telomeres are dynamic DNA-protein structures that form protective caps at the ends of eukaryotic chromosomes. Although initial telomere length is partly genetically determined, subsequent accelerated telomere shortening has been linked to elevated levels of oxidative stress. Recent studies show that short telomere length alone is insufficient to induce cellular senescence; advanced attrition of these repetitive DNA sequences does, however, reflect ageing processes. Furthermore, telomeres vary widely in length between individuals of the same age, suggesting that individuals differ in their exposure or response to telomere-shortening stress factors. Here, we show that residual telomere length predicts fitness components in two phylogenetically distant bird species: longevity in sand martins, Riparia riparia, and lifetime reproductive success in dunlins, Calidris alpina. Our results therefore imply that individuals with longer than expected telomeres for their age are of higher quality.},
}
@article {pmid16627805,
year = {2006},
author = {Kurz, DJ and Kloeckener-Gruissem, B and Akhmedov, A and Eberli, FR and Bühler, I and Berger, W and Bertel, O and Lüscher, TF},
title = {Degenerative aortic valve stenosis, but not coronary disease, is associated with shorter telomere length in the elderly.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {26},
number = {6},
pages = {e114-7},
doi = {10.1161/01.ATV.0000222961.24912.69},
pmid = {16627805},
issn = {1524-4636},
mesh = {Aged ; Aging/*genetics ; Aortic Valve Stenosis/blood/*genetics ; Case-Control Studies ; Cohort Studies ; Coronary Disease/blood/*genetics ; Female ; Humans ; Leukocytes ; Male ; Pilot Projects ; Polymorphism, Restriction Fragment Length ; Prospective Studies ; Telomere/*genetics ; },
abstract = {OBJECTIVE: The mechanisms responsible for the age-related increase in the incidence of calcific aortic valve stenosis (CAS) are unclear but may include telomere-driven cellular senescence. Because telomere length varies widely among individuals of the same age, we hypothesized that patients with shorter telomeres would be prone to develop CAS late in life.<br><br>METHODS AND RESULTS: Mean telomere length was measured in leukocytes from a cohort of 193 patients > or =70 years of age with and without CAS. Pilot experiments performed in 30 patients with CAS and controls pair-matched for age, sex, and presence or absence of coronary disease demonstrated significantly shorter telomeres in the CAS group both by Southern blot hybridization (5.75+/-0.55 kbp versus 6.27+/-0.7 kbp, P=0.0023) and by a quantitative polymerase chain reaction-based technique (relative telomere length 0.88+/-0.19 versus 1.0+/-0.19, P=0.01). This finding was then confirmed in the whole cohort (CAS n=64, controls n=129, relative telomere length=0.86+/-0.16 versus 0.94+/-0.12, P=0.0003). Both groups were comparable for potential confounding characteristics. Subgroup analysis according to the presence or absence of coronary disease demonstrated no association of this disorder with telomere length.<br><br>CONCLUSIONS: In the elderly, calcific aortic stenosis, but not coronary disease, is associated with shorter leukocyte telomere length.},
}
@article {pmid16623884,
year = {2006},
author = {Mizuno, H and Wu, J and Kanamori, H and Fujisawa, M and Namiki, N and Saji, S and Katagiri, S and Katayose, Y and Sasaki, T and Matsumoto, T},
title = {Sequencing and characterization of telomere and subtelomere regions on rice chromosomes 1S, 2S, 2L, 6L, 7S, 7L and 8S.},
journal = {The Plant journal : for cell and molecular biology},
volume = {46},
number = {2},
pages = {206-217},
doi = {10.1111/j.1365-313X.2006.02684.x},
pmid = {16623884},
issn = {0960-7412},
mesh = {Base Sequence ; *Chromosome Mapping ; *Chromosomes, Plant ; DNA, Plant/genetics ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Oryza/*genetics ; Repetitive Sequences, Nucleic Acid ; Telomere/*genetics/ultrastructure ; },
abstract = {Telomeres, which are important for chromosome maintenance, are composed of long, repetitive DNA sequences associated with a variety of telomere-binding proteins. We characterized the organization and structure of rice telomeres and adjacent subtelomere regions on the basis of cytogenetic and sequence analyses. The length of the rice telomeres ranged from 5.1 to 10.8 kb, as revealed by both fibre-fluorescent in situ hybridization and terminal restriction-fragment assay. Physical maps of the chromosomal ends were constructed from a fosmid library. This facilitated sequencing of the telomere regions of chromosomes 1S, 2S, 2L, 6L, 7S, 7L and 8S. The resulting sequences contained conserved TTTAGGG telomere repeats, which indicates that the physical maps partly covered the telomere regions of the respective chromosome arms. These repeats were organized in the order of 5'-TTTAGGG-3' from the chromosome-specific region, except in chromosome 7S, in which seven inverted copies also existed in tandem array. Analysis of the telomere-flanking regions revealed the occurrence of deletions, insertions, or chromosome-specific substitutions of single nucleotides within the repeat sequences at the junction between the telomere and subtelomere. The sequences of the 500-kb regions of the seven chromosome ends were analysed in detail. A total of 598 genes were predicted in the telomeric regions. In addition, repetitive sequences derived from various kinds of retrotransposon were identified. No significant evidence for segmental duplication could be detected within or among the subtelomere regions. These results indicate that the rice chromosome ends are heterogeneous in both sequence and characterization.},
}
@article {pmid16617690,
year = {2005},
author = {Omura, Y},
title = {Beneficial effects and side effects of DHEA: true anti-aging and age-promoting effects, as well as anti-cancer and cancer-promoting effects of DHEA evaluated from the effects on the normal and cancer cell telomeres and other parameters.},
journal = {Acupuncture &amp; electro-therapeutics research},
volume = {30},
number = {3-4},
pages = {219-261},
doi = {10.3727/036012905815901226},
pmid = {16617690},
issn = {0360-1293},
mesh = {Adjuvants, Immunologic/administration &amp; dosage/adverse effects ; Adult ; Aged ; Aged, 80 and over ; Aging/*drug effects ; Antineoplastic Agents/administration &amp; dosage/adverse effects ; Chromosome Aberrations ; Dehydroepiandrosterone/*administration &amp; dosage/*adverse effects ; Dose-Response Relationship, Drug ; Female ; Humans ; Male ; Middle Aged ; Neoplasms/*chemically induced/*drug therapy/genetics ; Telomere/*drug effects/*genetics ; Treatment Outcome ; },
abstract = {The author evaluated the effects of DHEA (Dehydroepiandrosterone) on the amount of telomeres of normal cells and cancer cells and found the following: Contrary to the literature, which often recommended 25-50 mg of DHEA daily for the average adult human being, the author found that, depending on the individual, the maximum increase of normal cell telomere was obtained by a single optimal dose of 1.25-12.5 mg. This was examined in 50 people, both males and females, between the ages of 20-80 years old. When one optimal dose was given to each individual, the average telomere amount in normal tissues, measured in Bi-Digital O-Ring Test units, often increased from anywhere between 25-300 ng to between 500-530 ng. Cancer cell telomere reduced from higher than 1100 ng to less than 1 yg (=10(-24) g) with equally significant normalization of abnormal cancer parameters (such as Integrin alpha5beta1, Oncogen C-fosAb2, Acetylcholine, etc.). Circulatory improvement and an increase in grasping force of up to 25% were also detected, along with the changing of a few white hairs to black hairs. The beneficial effects of one optimal dose of DHEA generally lasted between 1 to 4 months, though in some individuals it lasted for a much shorter period of time due to a number of negative factors such as excessive stress/work, excessive exposure to low temperatures and toxic substances, or use of common pain medicines. On the other hand, if a patient took an excessive dose of DHEA, the amount of normal cell telomere decreased, while there was an increase in cancer cell telomere. It was found that those who took an overdose of 25-50 mg daily for more than 3 months had a high incidence of cancer of the prostate gland, breast, colon, lung, and stomach. Also, when the average normal cell telomere levels were less than 110 ng, compared with a normal value of 120-130 ng, and when DHEA in different parts of the body was also extremely low (less than 1-2 ng), one could suspect the possible presence of a malignant tumor somewhere in the body. When normal cell telomere was less than 110 ng, most individuals felt very weary with marked tiredness in the eyes, and grasping force was often reduced.},
}
@article {pmid16615890,
year = {2006},
author = {Chikashige, Y and Tsutsumi, C and Yamane, M and Okamasa, K and Haraguchi, T and Hiraoka, Y},
title = {Meiotic proteins bqt1 and bqt2 tether telomeres to form the bouquet arrangement of chromosomes.},
journal = {Cell},
volume = {125},
number = {1},
pages = {59-69},
doi = {10.1016/j.cell.2006.01.048},
pmid = {16615890},
issn = {0092-8674},
mesh = {Cell Nucleus/metabolism ; *Chromosome Pairing ; Chromosomes, Fungal/*metabolism ; Equisetum/metabolism ; Genome, Fungal/genetics ; *Meiosis ; Models, Genetic ; Phenotype ; Prophase ; Schizosaccharomyces/cytology ; Schizosaccharomyces pombe Proteins/*metabolism ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {In many organisms, meiotic chromosomes are bundled at their telomeres to form a "bouquet" arrangement. The bouquet formation plays an important role in homologous chromosome pairing and therefore progression of meiosis. As meiotic telomere clustering occurs in response to mating pheromone signaling in fission yeast, we looked for factors essential for bouquet formation among genes induced under mating pheromone signaling. This genome-wide search identified two proteins, Bqt1 and Bqt2, that connect telomeres to the spindle-pole body (SPB; the centrosome equivalent in fungi). Neither Bqt1 nor Bqt2 alone functions as a connector, but together the two proteins form a bridge between Rap1 (a telomere protein) and Sad1 (an SPB protein). Significantly, when both Bqt1 and Bqt2 are ectopically expressed in mitotic cells, they also form a bridge between Rap1 and Sad1. Thus, a complex including Bqt1 and Bqt2 is essential for connecting telomeres to the SPB.},
}
@article {pmid16615797,
year = {2006},
author = {Chang, CC and Chu, JF and Kao, FJ and Chiu, YC and Lou, PJ and Chen, HC and Chang, TC},
title = {Verification of antiparallel G-quadruplex structure in human telomeres by using two-photon excitation fluorescence lifetime imaging microscopy of the 3,6-Bis(1-methyl-4-vinylpyridinium)carbazole diiodide molecule.},
journal = {Analytical chemistry},
volume = {78},
number = {8},
pages = {2810-2815},
doi = {10.1021/ac052218f},
pmid = {16615797},
issn = {0003-2700},
mesh = {Carbazoles/*chemistry ; Chromosomes, Human/genetics ; DNA/*chemistry ; Fluorescence ; G-Quadruplexes ; Humans ; Metaphase/genetics/physiology ; Pyridinium Compounds/*chemistry ; Spectrometry, Fluorescence/*methods ; Telomere/*chemistry/genetics/*ultrastructure ; },
abstract = {Different G-quadruplex structures for the human telomeric sequence d(T2AG3)4 in vitro have been documented in the presence of sodium and potassium. Verification of the G-quadruplex structures in human telomeres in vivo is the main issue in establishing the biological function of the G-quadruplex structures in telomeres as well as the development of anticancer agents. Here we have applied two-photon excitation fluorescence lifetime imaging microscopy to measure the fluorescence lifetime of the BMVC molecule upon interaction with various DNA structures. The distinction in lifetime measured with submicrometer spatial resolution in two-photon excitation fluorescence lifetime imaging microscopy provides a powerful approach not only to verify the existence of the antiparallel G-quadruplex structure in human telomeres but also to map its localizations in metaphase chromosomes.},
}
@article {pmid16611406,
year = {2006},
author = {Tabori, U and Vukovic, B and Zielenska, M and Hawkins, C and Braude, I and Rutka, J and Bouffet, E and Squire, J and Malkin, D},
title = {The role of telomere maintenance in the spontaneous growth arrest of pediatric low-grade gliomas.},
journal = {Neoplasia (New York, N.Y.)},
volume = {8},
number = {2},
pages = {136-142},
pmid = {16611406},
issn = {1476-5586},
mesh = {Astrocytoma/genetics/pathology ; Biopsy ; Brain Neoplasms/*pathology ; Cell Division ; Child ; DNA, Neoplasm/genetics/isolation &amp; purification ; Enzyme-Linked Immunosorbent Assay ; Ependymoma/genetics/pathology ; Glioma/*pathology ; Humans ; In Situ Hybridization, Fluorescence ; *Neoplasm Regression, Spontaneous ; Polymerase Chain Reaction ; Telomerase/genetics/metabolism ; Telomere/genetics/pathology/*physiology ; },
abstract = {Spontaneous tumor regression of pediatric low-grade gliomas (PLGG). We speculated that lack of telomere maintenance is responsible for this behavior. We first looked for evidence of telomerase activity and alternative lengthening of telomeres (ALT) in 56 PLGG. Telomerase activity was observed in 0 of 11 PLGG, in contrast to 10 of 13 high-grade pediatric brain tumors. There was no ALT in 45 of 45 samples. We then applied Q-FISH to eight patients whose indolent PLGG underwent two metachronous biopsies over a lag of several years. Telomere shortening was observed in the second biopsy in all tumors, but not in normal brain control (P < .0001), indicating that lack of telomere maintenance is associated with continuous telomere erosion. Based on these observations, we found that younger PLGG patients, who exhibit more aggressive and frequently recurrent tumors, had significantly longer telomeres than older ones (P = .00014). Tumors with a terminal restriction fragment length <7.5 did not recur, whereas the presence of longer telomeres (>8.0) conferred a high likelihood of late recurrences in PLGG. Our findings provide a plausible biologic mechanism to explain the tendency of PLGG to exhibit growth arrest and spontaneous regression. Telomere maintenance may therefore represent the first known biologic prognostic marker in PLGG.},
}
@article {pmid16608397,
year = {2006},
author = {Flanary, BE and Kletetschka, G},
title = {Analysis of telomere length and telomerase activity in tree species of various lifespans, and with age in the bristlecone pine Pinus longaeva.},
journal = {Rejuvenation research},
volume = {9},
number = {1},
pages = {61-63},
doi = {10.1089/rej.2006.9.61},
pmid = {16608397},
issn = {1549-1684},
mesh = {Aging ; Longevity/*genetics ; Pinus/metabolism ; Telomerase/*metabolism ; *Telomere ; Trees/*genetics ; },
abstract = {Normal somatic cells have a finite replicative capacity, and with each cell division telomeres progressively shorten, unless the telomerase enzyme is present. The bristlecone pine, Pinus longaeva, is the oldest known living eukaryotic organism, with the oldest on record turning 4770 years old in 2005. The results from our study of telomere length and telomerase activity in samples (needle, root, core) from P. longaeva with age, and in other tree species of various lifespans, support the hypothesis that both increased telomere length and telomerase activity may contribute to the increased lifespan and longevity evident in long-lived pine trees (i.e., 2000- to 5000-year lifespan) compared with medium-lived (400- to 500-year lifespan) and short-lived (100- to 200-year lifespan) pine trees, as well as in P. longaeva with age.},
}
@article {pmid16607537,
year = {2006},
author = {Díez, JL and Vilariño, VR and Medina, FJ and Morcillo, G},
title = {Nucleolar localization of a reverse transcriptase related to telomere maintenance in Chironomus (Diptera).},
journal = {Histochemistry and cell biology},
volume = {126},
number = {4},
pages = {445-452},
pmid = {16607537},
issn = {0948-6143},
mesh = {Animals ; Cell Nucleolus/*enzymology ; Chironomidae/*enzymology/genetics ; RNA-Directed DNA Polymerase/*analysis ; Telomere/*metabolism ; },
abstract = {A growing number of cellular processes originally thought not to involve the nucleolus now seem to be associated with this organelle. In recent years, a variety of RNAs and proteins with no apparent function in ribosome genesis have been discovered in this nuclear compartment. This paper reports the presence in the nucleolus of a reverse transcriptase (RT) previously found to be associated with telomeres in Chironomus. Immunofluorescence detection using a specific antibody against conserved domains shared by RTs showed a distinct pattern of staining in the giant nucleoli of polytenized cells. This nucleolar localization was confirmed in a number of larval tissues and embryonic cells of Chironomus thummi and C. pallidivitatus; its distribution showed a definite necklace pattern that did not completely colocalize with fibrillarin or nucleolin and appeared to be different to that of typical nucleolar components. There is evidence that both telomerase RT and RNA template subunits are present in the nucleoli of mammalian and yeast cells. However, chironomids do not have typical telomeres or telomerase. As in other Diptera, telomeres lack the short, simple repeats maintained by telomerase and instead have more complex sequences in the range of hundreds of nucleotides. It has been suggested that the RT associated with these telomeres might be involved in their maintenance, perhaps involving a mechanism similar to that of telomerase retrotranscription and retrotransposition in Drosophila. The present results indicate that the putative Chironomus telomere elongation machinery and telomerase share a nucleolar localization. This reinforces the idea that nucleoli are functionally linked to telomere maintenance irrespective of the differences in their molecular organization and therefore in the strategy adopted for their elongation.},
}
@article {pmid16606622,
year = {2006},
author = {Freibaum, BD and Counter, CM},
title = {hSnm1B is a novel telomere-associated protein.},
journal = {The Journal of biological chemistry},
volume = {281},
number = {22},
pages = {15033-15036},
doi = {10.1074/jbc.C600038200},
pmid = {16606622},
issn = {0021-9258},
support = {CA82481/CA/NCI NIH HHS/United States ; },
mesh = {Binding Sites ; Cell Line ; Chromatin Immunoprecipitation ; DNA Repair Enzymes ; DNA-Binding Proteins/*chemistry/genetics/*metabolism ; Exodeoxyribonucleases ; Fluorescent Antibody Technique ; Humans ; Nuclear Proteins/*chemistry/genetics/*metabolism ; Peptide Mapping ; Protein Binding ; Protein Structure, Tertiary ; Recombinant Proteins/chemistry/genetics/metabolism ; Sequence Deletion ; TATA Box Binding Protein-Like Proteins/chemistry/genetics/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2 ; },
abstract = {Artemis, a member of the beta-CASP family, has been implicated in the regulation of both telomere stability and length. Prompted by this, we examined whether the other two putative DNA-binding members of this family, hSnm1A and hSnm1B, may associate with telomeres. hSnm1A was found to not interact with the telomere. Conversely, hSnm1B was found to associate with telomeres in vivo by both immunofluorescence and chromatin immunoprecipitation. Furthermore, the C terminus of hSnm1B was shown to interact with the TRF homology domain of TRF2 indicating that hSnm1B is likely recruited to the telomere via interaction with the double-stranded telomere-binding protein TRF2.},
}
@article {pmid16603717,
year = {2006},
author = {Zhang, QS and Manche, L and Xu, RM and Krainer, AR},
title = {hnRNP A1 associates with telomere ends and stimulates telomerase activity.},
journal = {RNA (New York, N.Y.)},
volume = {12},
number = {6},
pages = {1116-1128},
pmid = {16603717},
issn = {1355-8382},
support = {P01 CA013106/CA/NCI NIH HHS/United States ; CA13106/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; Cells, Cultured ; Chromatin Immunoprecipitation ; DNA/chemistry/metabolism ; DNA, Single-Stranded/metabolism ; HeLa Cells ; Heterogeneous Nuclear Ribonucleoprotein A1 ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/*metabolism ; Humans ; Models, Biological ; Molecular Sequence Data ; Protein Binding ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomerase is a ribonucleoprotein enzyme complex that reverse-transcribes an integral RNA template to add short DNA repeats to the 3'-ends of telomeres. G-quadruplex structure in a DNA substrate can block its extension by telomerase. We have found that hnRNP A1--which was previously implicated in telomere length regulation--binds to both single-stranded and structured human telomeric repeats, and in the latter case, it disrupts their higher-order structure. Using an in vitro telomerase assay, we observed that depletion of hnRNP A/B proteins from 293 human embryonic kidney cell extracts dramatically reduced telomerase activity, which was fully recovered upon addition of purified recombinant hnRNP A1. This finding suggests that hnRNP A1 functions as an auxiliary, if not essential, factor of telomerase holoenzyme. We further show, using chromatin immunoprecipitation, that hnRNP A1 associates with human telomeres in vivo. We propose that hnRNP A1 stimulates telomere elongation through unwinding of a G-quadruplex or G-G hairpin structure formed at each translocation step.},
}
@article {pmid16600870,
year = {2006},
author = {Kong, LJ and Meloni, AR and Nevins, JR},
title = {The Rb-related p130 protein controls telomere lengthening through an interaction with a Rad50-interacting protein, RINT-1.},
journal = {Molecular cell},
volume = {22},
number = {1},
pages = {63-71},
doi = {10.1016/j.molcel.2006.02.016},
pmid = {16600870},
issn = {1097-2765},
mesh = {Cell Cycle Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Cells, Cultured ; DNA-Binding Proteins/metabolism ; Humans ; Immunoprecipitation ; RNA, Small Interfering/pharmacology ; Retinoblastoma-Like Protein p130/*physiology ; Saccharomyces cerevisiae/genetics/growth &amp; development ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; Two-Hybrid System Techniques ; },
abstract = {The oncogenic process often leads to a loss of normal telomere length control, usually as a result of activation of telomerase. Nevertheless, there are also telomerase-independent events that involve a Rad50-dependent recombination mechanism to maintain telomere length. Previous work has implicated the Rb family of proteins in the control of telomere length, and we now demonstrate that the p130 member of the Rb family is critical for telomere length control. p130 interacts specifically with the RINT-1 protein, previously identified as a Rad50-interacting protein. We further show that RINT-1 is essential for telomere length control. We propose that p130, forming a complex with Rad50 through RINT-1, blocks telomerase-independent telomere lengthening in normal cells. Given previous work implicating E2F in the control of telomerase gene expression, these results thus point to complementary roles for the Rb/E2F pathway in the control of telomere length.},
}
@article {pmid16598261,
year = {2006},
author = {Miller, KM and Rog, O and Cooper, JP},
title = {Semi-conservative DNA replication through telomeres requires Taz1.},
journal = {Nature},
volume = {440},
number = {7085},
pages = {824-828},
doi = {10.1038/nature04638},
pmid = {16598261},
issn = {1476-4687},
mesh = {*DNA Replication ; DNA-Binding Proteins/deficiency/genetics/metabolism ; Kinetics ; Schizosaccharomyces/*genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Shelterin Complex ; Telomerase/deficiency/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/deficiency/genetics/*metabolism ; Templates, Genetic ; },
abstract = {Telomere replication is achieved through the combined action of the conventional DNA replication machinery and the reverse transcriptase, telomerase. Telomere-binding proteins have crucial roles in controlling telomerase activity; however, little is known about their role in controlling semi-conservative replication, which synthesizes the bulk of telomeric DNA. Telomere repeats in the fission yeast Schizosaccharomyces pombe are bound by Taz1, a regulator of diverse telomere functions. It is generally assumed that telomere-binding proteins impede replication fork progression. Here we show that, on the contrary, Taz1 is crucial for efficient replication fork progression through the telomere. Using two-dimensional gel electrophoresis, we find that loss of Taz1 leads to stalled replication forks at telomeres and internally placed telomere sequences, regardless of whether the telomeric G-rich strand is replicated by leading- or lagging-strand synthesis. In contrast, the Taz1-interacting protein Rap1 is dispensable for efficient telomeric fork progression. Upon loss of telomerase, taz1Delta telomeres are lost precipitously, suggesting that maintenance of taz1Delta telomere repeats cannot be sustained through semi-conservative replication. As the human telomere proteins TRF1 and TRF2 are Taz1 orthologues, we predict that one or both of the human TRFs may orchestrate fork passage through human telomeres. Stalled forks at dysfunctional human telomeres are likely to accelerate the genomic instability that drives tumorigenesis.},
}
@article {pmid16585183,
year = {2006},
author = {Brachner, A and Sasgary, S and Pirker, C and Rodgarkia, C and Mikula, M and Mikulits, W and Bergmeister, H and Setinek, U and Wieser, M and Chin, SF and Caldas, C and Micksche, M and Cerni, C and Berger, W},
title = {Telomerase- and alternative telomere lengthening-independent telomere stabilization in a metastasis-derived human non-small cell lung cancer cell line: effect of ectopic hTERT.},
journal = {Cancer research},
volume = {66},
number = {7},
pages = {3584-3592},
doi = {10.1158/0008-5472.CAN-05-2839},
pmid = {16585183},
issn = {0008-5472},
mesh = {Animals ; Carcinoma, Non-Small-Cell Lung/*enzymology/*genetics/pathology ; Cell Growth Processes/genetics ; Cell Line, Tumor ; DNA-Binding Proteins/biosynthesis/genetics/pharmacology/*physiology ; HeLa Cells ; Humans ; Lung Neoplasms/*enzymology/*genetics/pathology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mice, SCID ; Telomerase/biosynthesis/deficiency/genetics/*metabolism/pharmacology/physiology ; Telomere ; Transfection ; },
abstract = {In the majority of human malignancies, maintenance of telomeres is achieved by reactivation of telomerase, whereas a smaller fraction uses an alternative telomere lengthening (ALT) mechanism. Here, we used 16 non-small cell lung cancer (NSCLC) cell lines to investigate telomere stabilization mechanisms and their effect on tumor aggressiveness. Three of 16 NSCLC cell lines (VL-9, SK-LU-1, and VL-7) lacked telomerase activity, correlating with significantly reduced tumorigenicity in vitro and in vivo. Of the three telomerase-negative cell lines, only SK-LU-1 displayed characteristics of an ALT mechanism (i.e., highly heterogeneous telomeres and ALT-associated promyelocytic leukemia bodies). VL-9 cells gained telomerase during in vitro propagation, indicating incomplete immortalization in vivo. In contrast, NSCLC metastasis-derived VL-7 cells remained telomerase and ALT negative up to high passage numbers and following transplantation in severe combined immunodeficient mice. Telomeres of VL-7 cells were homogeneously short, and chromosomal instability (CIN) was comparable with most telomerase-positive cell lines. This indicates the presence of an efficient telomere stabilization mechanism different from telomerase and ALT in VL-7 cells. To test the effect of ectopic telomerase reverse transcriptase (hTERT) in these unique ALT- and telomerase-negative tumor backgrounds, hTERT was transfected into VL-7 cells. The activation of telomerase led to an excessively rapid gain of telomeric sequences resulting in very long (approximately 14 kb), uniform telomeres. Additionally, hTERT expression induced a more aggressive growth behavior in vitro and in vivo without altering the level of CIN. These data provide further evidence for a direct oncogenic activity of hTERT not based on the inhibition of CIN.},
}
@article {pmid16582880,
year = {2006},
author = {García-Cao, I and García-Cao, M and Tomás-Loba, A and Martín-Caballero, J and Flores, JM and Klatt, P and Blasco, MA and Serrano, M},
title = {Increased p53 activity does not accelerate telomere-driven ageing.},
journal = {EMBO reports},
volume = {7},
number = {5},
pages = {546-552},
pmid = {16582880},
issn = {1469-221X},
mesh = {Aging/*genetics/metabolism ; Animals ; Gene Dosage/genetics ; Kinetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Telomerase/deficiency/genetics ; Telomere/enzymology/*genetics ; Tumor Suppressor Protein p53/*genetics/physiology ; Up-Regulation/genetics ; },
abstract = {There is a great interest in determining the impact of p53 on ageing and, for this, it is important to discriminate among the known causes of ageing. Telomere loss is a well-established source of age-associated damage, which by itself can recapitulate ageing in mouse models. Here, we have used a genetic approach to interrogate whether p53 contributes to the elimination of telomere-damaged cells and its impact on telomere-driven ageing. We have generated compound mice carrying three functional copies of the p53 gene (super-p53) in a telomerase-deficient background and we have measured the presence of chromosomal abnormalities and DNA damage in several tissues. We have found that the in vivo load of telomere-derived chromosomal damage is significantly decreased in super-p53/telomerase-null mice compared with normal-p53/telomerase-null mice. Interestingly, the presence of extra p53 activity neither accelerates nor delays telomere-driven ageing. From these observations, we conclude that p53 has an active role in eliminating telomere-damaged cells, and we exclude the possibility of an age-promoting effect of p53 on telomere-driven ageing.},
}
@article {pmid16581649,
year = {2006},
author = {Shin, JS and Hong, A and Solomon, MJ and Lee, CS},
title = {The role of telomeres and telomerase in the pathology of human cancer and aging.},
journal = {Pathology},
volume = {38},
number = {2},
pages = {103-113},
doi = {10.1080/00313020600580468},
pmid = {16581649},
issn = {0031-3025},
mesh = {Aging/*physiology ; DNA Repair/physiology ; DNA, Neoplasm/physiology ; Humans ; Neoplasms/*metabolism ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {Cellular senescence, the state of permanent growth arrest, is the inevitable fate of replicating normal somatic cells. Postulated to underlie this finite replicative span is the physiology of telomeres, which constitute the ends of chromosomes. The repetitive sequences of these DNA-protein complexes progressively shorten with each mitosis. When the critical length is bridged, telomeres trigger DNA repair and cell cycle checkpoint mechanisms that result in chromosomal fusions, cell cycle arrest, senescence and/or apoptosis. Should senescence be bypassed at such time, continued cell divisions in the face of dysfunctional telomeres and activated DNA repair machinery can result in the genomic instability favourable for oncogenesis. The longevity and malignant progression of the thus transformed cell requires coincident telomerase expression or other means to negate the constitutional telomeric loss. Practically then, telomeres and telomerase may represent plausible prognostic and screening cancer markers. Furthermore, if the argument is extended, with assumptions that telomeric attrition is indeed the basis of cellular senescence and that accumulation of the latter equates to aging at the organismal level, then telomeres may well explain the increased incidence of cancer with human aging.},
}
@article {pmid16581033,
year = {2006},
author = {Simon, NM and Smoller, JW and McNamara, KL and Maser, RS and Zalta, AK and Pollack, MH and Nierenberg, AA and Fava, M and Wong, KK},
title = {Telomere shortening and mood disorders: preliminary support for a chronic stress model of accelerated aging.},
journal = {Biological psychiatry},
volume = {60},
number = {5},
pages = {432-435},
doi = {10.1016/j.biopsych.2006.02.004},
pmid = {16581033},
issn = {0006-3223},
support = {K08-MH01770/MH/NIMH NIH HHS/United States ; K08AG2400401/AG/NIA NIH HHS/United States ; MH01831-01/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Aging/*genetics ; Anxiety/complications/genetics ; Bipolar Disorder/complications/genetics ; Case-Control Studies ; Cellular Senescence/genetics ; *Chromosome Breakage ; Chronic Disease ; Female ; Humans ; Male ; Matched-Pair Analysis ; Middle Aged ; Models, Genetic ; Mood Disorders/complications/*genetics ; Reference Values ; Statistics, Nonparametric ; Stress, Psychological/etiology/*genetics ; *Telomere ; },
abstract = {BACKGROUND: Little is known about the biological mechanisms underlying the excess medical morbidity and mortality associated with mood disorders. Substantial evidence supports abnormalities in stress-related biological systems in depression. Accelerated telomere shortening may reflect stress-related oxidative damage to cells and accelerated aging, and severe psychosocial stress has been linked to telomere shortening. We propose that chronic stress associated with mood disorders may contribute to excess vulnerability for diseases of aging such as cardiovascular disease and possibly some cancers through accelerated organismal aging.<br><br>METHODS: Telomere length was measured by Southern Analysis in 44 individuals with chronic mood disorders and 44 nonpsychiatrically ill age-matched control subjects.<br><br>RESULTS: Telomere length was significantly shorter in those with mood disorders, representing as much as 10 years of accelerated aging.<br><br>CONCLUSIONS: These results provide preliminary evidence that mood disorders are associated with accelerated aging and may suggest a novel mechanism for mood disorder-associated morbidity and mortality.},
}
@article {pmid16575002,
year = {2006},
author = {Tabori, U and Ma, J and Carter, M and Zielenska, M and Rutka, J and Bouffet, E and Bartels, U and Malkin, D and Hawkins, C},
title = {Human telomere reverse transcriptase expression predicts progression and survival in pediatric intracranial ependymoma.},
journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology},
volume = {24},
number = {10},
pages = {1522-1528},
doi = {10.1200/JCO.2005.04.2127},
pmid = {16575002},
issn = {1527-7755},
mesh = {Adolescent ; Age Factors ; Brain Neoplasms/*chemistry/mortality ; Child ; Child, Preschool ; DNA-Binding Proteins/*analysis ; Disease Progression ; Ependymoma/*chemistry/mortality ; Female ; Humans ; Infant ; Male ; Neoplasm Recurrence, Local ; Prognosis ; Risk Factors ; Telomerase/*analysis ; },
abstract = {PURPOSE: Pediatric intracranial ependymomas are a heterogeneous group of neoplasms with unpredictable clinical and biologic behavior. As part of ongoing studies to identify potential biologic and therapeutic markers, we analyzed the role of human telomere reverse transcriptase (hTERT; the catalytic subunit of telomerase) expression as a prognostic marker for this disease.<br><br>PATIENTS AND METHODS: Primary intracranial ependymomas that were resected at our institution between 1986 and 2004 were identified through the pathology and oncology databases. A tissue array was constructed from the patient samples and hTERT expression was evaluated by immunohistochemistry. Twenty-one samples were also analyzed for telomerase activity (telomerase repeat amplification protocol assay).<br><br>RESULTS: Eighty-seven tumors from 65 patients were analyzed. Five-year progression-free survival was 57% (SEM, 12%) and 21% (SEM, 8%) for hTERT-negative and hTERT-positive tumors, respectively (P = .002). Five-year overall survival was 84% (SEM, 7%) and 41% (SEM, 7%) for hTERT-negative and hTERT-positive tumors, respectively (P = .001). There was good correlation between telomerase activity and hTERT expression (kappa = 0.637). Multivariate analysis revealed hTERT expression to be the single most important predictor of survival of all known pathologic, clinical, and treatment factors (hazard ratio, 60.4; 95% CI, 6.4 to 561). All four patients with hTERT-negative tumors at relapse are still alive, with median follow-up of 11.2 years.<br><br>CONCLUSION: In this study, hTERT expression was the strongest predictor of outcome and was independent of other clinical and pathologic prognostic markers. It represents a simple and reliable biologic prognostic factor for intracranial ependymomas. These results should be confirmed in larger prospective trials.},
}
@article {pmid16568010,
year = {2006},
author = {Riou, JF and Morjani, H and Trentesaux, C},
title = {[Telomeres and telomerase, new targets for anticancer chemotherapy].},
journal = {Annales pharmaceutiques francaises},
volume = {64},
number = {2},
pages = {97-105},
doi = {10.1016/s0003-4509(06)75301-9},
pmid = {16568010},
issn = {0003-4509},
mesh = {Animals ; Antineoplastic Agents/pharmacology/*therapeutic use ; DNA, Neoplasm/drug effects/genetics ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors/pharmacology ; Humans ; Ligands ; Neoplasms/*drug therapy/enzymology/*pathology ; Telomerase/*antagonists &amp; inhibitors ; Telomere/drug effects/*ultrastructure ; },
abstract = {Telomeres are composed of single-strand DNA rich in guanine which can adopt particular structures such as T-loop or G-quadruples, a four-strand DAN structure formed by guanine repeats. Telomeric single-strand DNA is the substrate of telomerase, an enzyme necessary for telomeric replication which is suppressed in most cancer cells and which participates in tumor genesis. The formation of a telomeric G-quadruplex blocks telomerase activity and offers an original strategy for new anti-cancer agents. Using an original approach combining rational screening and synthesis, several series of compounds have been identified which specifically bind to the telomeric quadruplex. These derivatives, called "G-quadruplex DNA ligands", are able to block telomeric replication in cancer cells and provoke replicative senescence and/or apoptosis after a few cell cycles. Our team is working on characterizing the cellular and molecular mechanisms of action of these ligands. Using mutant cell models resistant to these ligands or expressing a protein cuff covering the telomere in tumor lines, we have demonstrated that the telomere is the principal intracellular target of action of these compounds and the implicit existence of the G-quadruplex structure. In collaboration with academic and industrial partners, optimization of these ligands to develop pharmacologically active products should enable in vivo validation of a new therapeutic concept.},
}
@article {pmid16565708,
year = {2006},
author = {Gonzalo, S and Jaco, I and Fraga, MF and Chen, T and Li, E and Esteller, M and Blasco, MA},
title = {DNA methyltransferases control telomere length and telomere recombination in mammalian cells.},
journal = {Nature cell biology},
volume = {8},
number = {4},
pages = {416-424},
doi = {10.1038/ncb1386},
pmid = {16565708},
issn = {1465-7392},
mesh = {Animals ; Cell Nucleus Structures/metabolism ; Chromatin Immunoprecipitation ; Coiled Bodies/genetics/metabolism ; CpG Islands ; DNA (Cytosine-5-)-Methyltransferase 1 ; DNA (Cytosine-5-)-Methyltransferases/genetics/*physiology ; DNA Methylation ; DNA Methyltransferase 3A ; Embryo, Mammalian/cytology/metabolism ; Heterochromatin/genetics/metabolism ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Knockout ; *Recombination, Genetic ; Sister Chromatid Exchange ; Stem Cells/metabolism ; Telomere/*genetics ; DNA Methyltransferase 3B ; },
abstract = {Here, we describe a role for mammalian DNA methyltransferases (DNMTs) in telomere length control. Mouse embryonic stem (ES) cells genetically deficient for DNMT1, or both DNMT3a and DNMT3b have dramatically elongated telomeres compared with wild-type controls. Mammalian telomere repeats (TTAGGG) lack the canonical CpG methylation site. However, we demonstrate that mouse subtelomeric regions are heavily methylated, and that this modification is decreased in DNMT-deficient cells. We show that other heterochromatic marks, such as histone 3 Lys 9 (H3K9) and histone 4 Lys 20 (H4K20) trimethylation, remain at both subtelomeric and telomeric regions in these cells. Lack of DNMTs also resulted in increased telomeric recombination as indicated by sister-chromatid exchanges involving telomeric sequences, and by the presence of 'alternative lengthening of telomeres' (ALT)-associated promyelocytic leukaemia (PML) bodies (APBs). This increased telomeric recombination may lead to telomere-length changes, although our results do not exclude a potential involvement of telomerase and telomere-binding proteins in the aberrant telomere elongation observed in DNMT-deficient cells. Together, these results demonstrate a previously unappreciated role for DNA methylation in maintaining telomere integrity.},
}
@article {pmid16564010,
year = {2006},
author = {Downey, M and Houlsworth, R and Maringele, L and Rollie, A and Brehme, M and Galicia, S and Guillard, S and Partington, M and Zubko, MK and Krogan, NJ and Emili, A and Greenblatt, JF and Harrington, L and Lydall, D and Durocher, D},
title = {A genome-wide screen identifies the evolutionarily conserved KEOPS complex as a telomere regulator.},
journal = {Cell},
volume = {124},
number = {6},
pages = {1155-1168},
doi = {10.1016/j.cell.2005.12.044},
pmid = {16564010},
issn = {0092-8674},
support = {075294//Wellcome Trust/United Kingdom ; 054371//Wellcome Trust/United Kingdom ; },
mesh = {*Evolution, Molecular ; *Gene Expression Regulation, Enzymologic ; *Genomic Library ; Multiprotein Complexes/chemistry/genetics/metabolism ; Mutation ; Protein Serine-Threonine Kinases/genetics/metabolism ; Saccharomyces cerevisiae/genetics/physiology ; Saccharomyces cerevisiae Proteins/genetics/metabolism/*physiology ; Telomerase/metabolism ; Telomere/*physiology ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Telomere capping is the essential function of telomeres. To identify new genes involved in telomere capping, we carried out a genome-wide screen in Saccharomyces cerevisiae for suppressors of cdc13-1, an allele of the telomere-capping protein Cdc13. We report the identification of five novel suppressors, including the previously uncharacterized gene YML036W, which we name CGI121. Cgi121 is part of a conserved protein complex -- the KEOPS complex -- containing the protein kinase Bud32, the putative peptidase Kae1, and the uncharacterized protein Gon7. Deletion of CGI121 suppresses cdc13-1 via the dramatic reduction in ssDNA levels that accumulate in cdc13-1 cgi121 mutants. Deletion of BUD32 or other KEOPS components leads to short telomeres and a failure to add telomeres de novo to DNA double-strand breaks. Our results therefore indicate that the KEOPS complex promotes both telomere uncapping and telomere elongation.},
}
@article {pmid16564005,
year = {2006},
author = {Bianchi, A and Shore, D},
title = {The KEOPS complex: a rosetta stone for telomere regulation?.},
journal = {Cell},
volume = {124},
number = {6},
pages = {1125-1128},
doi = {10.1016/j.cell.2006.03.008},
pmid = {16564005},
issn = {0092-8674},
mesh = {*Gene Expression Regulation, Enzymologic ; Macromolecular Substances/metabolism ; Telomerase/genetics/*physiology ; Telomere/*physiology ; },
abstract = {The detailed mechanisms underlying telomere capping and its relationship to telomerase activity are still unclear, although many proteins have been implicated in either or both processes. In this issue of Cell, the surprising identification of a new complex, called KEOPS, which promotes both telomere uncapping and elongation is presented.},
}
@article {pmid16557277,
year = {2006},
author = {Hansel, DE and Meeker, AK and Hicks, J and De Marzo, AM and Lillemoe, KD and Schulick, R and Hruban, RH and Maitra, A and Argani, P},
title = {Telomere length variation in biliary tract metaplasia, dysplasia, and carcinoma.},
journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},
volume = {19},
number = {6},
pages = {772-779},
doi = {10.1038/modpathol.3800591},
pmid = {16557277},
issn = {0893-3952},
mesh = {Biliary Tract Neoplasms/*genetics/pathology ; Carcinoma in Situ/*genetics/pathology ; DNA, Neoplasm/analysis ; Epithelium/pathology ; Gallbladder/pathology ; Humans ; In Situ Hybridization, Fluorescence ; Metaplasia/genetics/pathology ; Precancerous Conditions/*genetics/pathology ; Telomere/*pathology ; },
abstract = {Biliary tract carcinoma, including carcinoma of the gallbladder, intrahepatic bile ducts (cholangiocarcinoma), and extrahepatic bile ducts, affects 7500 people in the United States annually, and has an overall 32% 5-year survival rate for disease limited to the mucosa, and a dismal 10% 5-year survival for more advanced disease. The identification of factors involved in the pathogenesis and progression of biliary tract carcinoma is critical for devising effective methods of screening and treatment. Recent evidence suggests that reduction of the length of telomeres, which normally help maintain chromosomal stability, may promote the development and progression of a variety of carcinomas. Using a novel, recently validated telomere fluorescence in situ hybridization method, we examined telomere length in normal and inflamed gallbladder epithelium, metaplasia and dysplasia of the gallbladder, and biliary tract carcinoma to determine whether telomere shortening is associated with neoplastic progression in the biliary tract. Although normal and inflamed gallbladder epithelium demonstrated uniform normal telomere lengths, over half of all metaplastic lesions demonstrated shortened telomeres, supporting prior evidence that metaplastic lesions of the gallbladder are pre-neoplastic. Dysplastic epithelium and invasive carcinomas demonstrated almost universally abnormally short telomeres, indicating that telomere shortening occurs at an early, preinvasive stage of cancer development. In addition, invasive adenocarcinoma of the biliary tract frequently demonstrated intratumoral heterogeneity of telomere lengths. We conclude that telomere shortening is a consistent and early finding in the development of biliary tract carcinoma.},
}
@article {pmid16552446,
year = {2006},
author = {Gatbonton, T and Imbesi, M and Nelson, M and Akey, JM and Ruderfer, DM and Kruglyak, L and Simon, JA and Bedalov, A},
title = {Telomere length as a quantitative trait: genome-wide survey and genetic mapping of telomere length-control genes in yeast.},
journal = {PLoS genetics},
volume = {2},
number = {3},
pages = {e35},
pmid = {16552446},
issn = {1553-7404},
support = {R37 MH059520/MH/NIMH NIH HHS/United States ; P20 CA103728/CA/NCI NIH HHS/United States ; CA 103728/CA/NCI NIH HHS/United States ; HL04211/HL/NHLBI NIH HHS/United States ; R37 MH59520/MH/NIMH NIH HHS/United States ; CA 78746/CA/NCI NIH HHS/United States ; },
mesh = {Chromosome Mapping/*methods ; Chromosomes, Fungal ; Fungal Proteins/*genetics ; Gene Deletion ; *Genes, Fungal ; Genome, Fungal ; Polymorphism, Genetic ; Quantitative Trait Loci ; Saccharomyces cerevisiae/*genetics ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics ; Sister Chromatid Exchange ; Telomere/*ultrastructure ; },
abstract = {Telomere length-variation in deletion strains of Saccharomyces cerevisiae was used to identify genes and pathways that regulate telomere length. We found 72 genes that when deleted confer short telomeres, and 80 genes that confer long telomeres relative to those of wild-type yeast. Among identified genes, 88 have not been previously implicated in telomere length control. Genes that regulate telomere length span a variety of functions that can be broadly separated into telomerase-dependent and telomerase-independent pathways. We also found 39 genes that have an important role in telomere maintenance or cell proliferation in the absence of telomerase, including genes that participate in deoxyribonucleotide biosynthesis, sister chromatid cohesion, and vacuolar protein sorting. Given the large number of loci identified, we investigated telomere lengths in 13 wild yeast strains and found substantial natural variation in telomere length among the isolates. Furthermore, we crossed a wild isolate to a laboratory strain and analyzed telomere length in 122 progeny. Genome-wide linkage analysis among these segregants revealed two loci that account for 30%-35% of telomere length-variation between the strains. These findings support a general model of telomere length-variation in outbred populations that results from polymorphisms at a large number of loci. Furthermore, our results laid the foundation for studying genetic determinants of telomere length-variation and their roles in human disease.},
}
@article {pmid16547498,
year = {2006},
author = {Pantic, M and Zimmermann, S and El Daly, H and Opitz, OG and Popp, S and Boukamp, P and Martens, UM},
title = {Telomere dysfunction and loss of p53 cooperate in defective mitotic segregation of chromosomes in cancer cells.},
journal = {Oncogene},
volume = {25},
number = {32},
pages = {4413-4420},
doi = {10.1038/sj.onc.1209486},
pmid = {16547498},
issn = {0950-9232},
mesh = {Chromosome Segregation/*genetics ; HCT116 Cells ; Humans ; Mitosis/*genetics ; Neoplasms/*genetics/*pathology ; Telomere/*pathology ; Tumor Suppressor Protein p53/*deficiency/*genetics/physiology ; },
abstract = {Aneuploidy is a fundamental principle of many cancer cells and is mostly related to defects in mitotic segregation of chromosomes. Many solid tumors as well as some preneoplastic lesions have been shown to contain polyploid chromosome numbers. The exact mechanisms behind whole-genome duplications are not known but have been linked to compromised mitotic checkpoint genes. We now report that the telomere checkpoint plays a key role for polyploidy in colon cancer cells. Telomerase suppression by a dominant-negative mutant of hTERT and consecutive telomere dysfunction in wild-type HCT116 colon cancer cells resulted in only minor stable chromosomal alterations. However, higher ploidy levels with up to 350 chromosomes were found when the cell-cycle checkpoint proteins p53 or p21 were absent. These findings indicate that telomere dysfunction in the absence of cell-cycle control may explain the high frequency of alterations in chromosome numbers found in many solid tumors.},
}
@article {pmid16546998,
year = {2006},
author = {Tsai, HJ and Huang, WH and Li, TK and Tsai, YL and Wu, KJ and Tseng, SF and Teng, SC},
title = {Involvement of topoisomerase III in telomere-telomere recombination.},
journal = {The Journal of biological chemistry},
volume = {281},
number = {19},
pages = {13717-13723},
doi = {10.1074/jbc.M600649200},
pmid = {16546998},
issn = {0021-9258},
mesh = {Carrier Proteins/metabolism ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; DNA Topoisomerases, Type I/*metabolism ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation, Enzymologic ; Humans ; Mutation ; Protein Serine-Threonine Kinases/metabolism ; Repressor Proteins/metabolism ; Saccharomyces cerevisiae/cytology/enzymology/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomere maintenance is required for chromosome stability, and telomeres are typically replicated by the action of telomerase. In both mammalian tumor and yeast cells that lack telomerase, telomeres are maintained by an alternative (ALT) recombination mechanism. In yeast, Sgs1p and its associated type IA topoisomerase, Top3p, may work coordinately in removing Holliday junction intermediates from a crossover-producing recombination pathway. Previous studies have also indicated that Sgs1 helicase acts in a telomere recombination pathway. Here we show that topoisomerase III is involved in telomere-telomere recombination. The recovery of telomere recombination-dependent survivors in a telomerase-minus yeast strain was dependent on Top3p catalytic activity. Moreover, the RIF1 and RIF2 genes are required for the establishment of TOP3/SGS1-dependent telomere-telomere recombination. In human Saos-2 ALT cells, human topoisomerase IIIalpha (hTOP3alpha) also contributes to telomere recombination. Strikingly, the telomerase activity is clearly enhanced in surviving si-hTOP3alpha Saos-2 ALT cells. Altogether, the present results suggest a potential role for hTOP3alpha in dissociating telomeric structures in telomerase-deficient cells, providing therapeutic implications in human tumors.},
}
@article {pmid16546132,
year = {2006},
author = {Wen, WY and Tsai, HJ and Lin, CC and Tseng, SF and Wong, CW and Teng, SC},
title = {Telomere configuration influences the choice of telomere maintenance pathways.},
journal = {Biochemical and biophysical research communications},
volume = {343},
number = {2},
pages = {459-466},
doi = {10.1016/j.bbrc.2006.03.011},
pmid = {16546132},
issn = {0006-291X},
mesh = {Base Sequence ; DNA Replication/*genetics ; Molecular Sequence Data ; Recombination, Genetic/*genetics ; Saccharomycetales/*genetics ; Signal Transduction/*genetics ; Structure-Activity Relationship ; Telomere/*genetics ; },
abstract = {Telomere maintenance is required for chromosome stability, and telomeres are typically replicated by the action of telomerase. In yeast cells that lack telomerase, telomeres are maintained by alternative type I and type II recombination mechanisms. Previous studies identified several proteins to control the choice between two types of recombinations. Here, we demonstrate that configuration of telomeres also plays a role to determine the fate of telomere replication in progeny. When diploid yeasts from mating equip with a specific type of telomeric structure in their genomes, they prefer to maintain this type of telomere replication in their descendants. While inherited telomere structure is easier to be utilized in progeny at the beginning stage, the telomeres in type I diploids can gradually switch to the type II cells in liquid culture. Importantly, the TLC1/tlc1 yeast cells develop type II survivors suggesting that haploid insufficiency of telomerase RNA component, which is similar to a type of dyskeratosis congenital in human. Altogether, our results suggest that both protein factors and substrate availability contribute to the choice among telomere replication pathways in yeast.},
}
@article {pmid16537718,
year = {2006},
author = {O'Sullivan, J and Risques, RA and Mandelson, MT and Chen, L and Brentnall, TA and Bronner, MP and Macmillan, MP and Feng, Z and Siebert, JR and Potter, JD and Rabinovitch, PS},
title = {Telomere length in the colon declines with age: a relation to colorectal cancer?.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {15},
number = {3},
pages = {573-577},
doi = {10.1158/1055-9965.EPI-05-0542},
pmid = {16537718},
issn = {1055-9965},
support = {P01 CA74184/CA/NCI NIH HHS/United States ; P20 CA103728/CA/NCI NIH HHS/United States ; P30 AG13280/AG/NIA NIH HHS/United States ; R01 CA68124-10/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Aging/genetics ; Biomarkers, Tumor/analysis ; Cellular Senescence/*genetics ; Child ; Child, Preschool ; Colon/pathology ; Colonic Neoplasms/*genetics/*pathology ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; Intestinal Mucosa/pathology/physiology ; Male ; Middle Aged ; Predictive Value of Tests ; Reference Values ; Reverse Transcriptase Polymerase Chain Reaction ; Risk Assessment ; Sampling Studies ; Sensitivity and Specificity ; Telomere/genetics/*ultrastructure ; Tissue Culture Techniques ; },
abstract = {Telomeres shorten with age, which may be linked to genomic instability and an increased risk of cancer. To explore this association, we analyzed telomere length in normal colorectal tissue of individuals at different ages using quantitative-fluorescence in situ hybridization (Q-FISH) and quantitative-PCR (Q-PCR). Using Q-FISH, we also examined the histologically normal epithelium adjacent to, or distant from, colon adenomas and cancers, in addition to the neoplasms. Q-FISH and Q-PCR showed that telomere length was inversely associated with age until approximately ages 60 to 70; surprisingly, beyond this age, telomere length was positively associated with age. This association was found exclusively in epithelial, and not in stromal, cells. Peripheral blood lymphocytes showed an inverse association between telomere length and age, but without any apparent increase in telomere length in the oldest individuals. Telomere length in larger adenoma lesions (>2 cm) was significantly shorter than in normal adjacent (P = 0.004) or normal distant (P = 0.05) tissue from the same individuals. However, telomere length in histologically normal epithelium adjacent to cancers or in adenomas <2 cm was not statistically different from that of the normal distant mucosa or from normal controls, evidence that a telomere-shortening field effect was not present. We suggest that the positive association between telomere length and age in the oldest patients is a consequence of selective survival of elderly patients with long colonocyte telomeres.},
}
@article {pmid16537449,
year = {2006},
author = {Guney, I and Wu, S and Sedivy, JM},
title = {Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16(INK4a).},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {103},
number = {10},
pages = {3645-3650},
pmid = {16537449},
issn = {0027-8424},
support = {R01 GM41690/GM/NIGMS NIH HHS/United States ; R01 AG16694/AG/NIA NIH HHS/United States ; P20 RR015578/RR/NCRR NIH HHS/United States ; R01 AG016694/AG/NIA NIH HHS/United States ; P20 RR15578/RR/NCRR NIH HHS/United States ; R01 GM041690/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Cells, Cultured ; Cellular Senescence/genetics/*physiology ; Cyclin-Dependent Kinase Inhibitor p16/genetics/*metabolism ; DNA/genetics ; Genes, myc ; Humans ; Nuclear Proteins/genetics/*metabolism ; Polycomb Repressive Complex 1 ; Proto-Oncogene Proteins/genetics/*metabolism ; Proto-Oncogene Proteins c-myc/genetics/*metabolism ; RNA Interference ; RNA, Messenger/genetics/metabolism ; Repressor Proteins/genetics/*metabolism ; Signal Transduction ; Telomere/metabolism ; },
abstract = {Increased mitogenic signaling by positive effectors such as Ras or Myc can trigger senescence in normal cells, a response believed to function as a tumor-suppressive mechanism. We report here the existence of a checkpoint that monitors hypoproliferative signaling imbalances. Normal human fibroblasts with one copy of the c-myc gene inactivated by targeted homologous recombination switched with an increased frequency to a telomere-independent senescent state mediated by the cyclin-dependent kinase inhibitor p16(INK4a). p16(INK4a) expression was regulated by the Polycomb group repressor Bmi-1, which we show is a direct transcriptional target of c-Myc. The Myc-Bmi circuit provides a mechanism for the conversion of environmental inputs that converge on c-Myc into discrete cell-fate decisions coupled to cell-cycle recruitment. A mechanism for limiting the proliferation of damaged or otherwise physiologically compromised cells would be expected to have important consequences on the generation of replicatively senescent cells during organismal aging.},
}
@article {pmid16530337,
year = {2006},
author = {Hertzog, RG},
title = {Ancestral telomere shortening: a countdown that will increase mean life span?.},
journal = {Medical hypotheses},
volume = {67},
number = {1},
pages = {157-160},
doi = {10.1016/j.mehy.2006.01.034},
pmid = {16530337},
issn = {0306-9877},
mesh = {Aged ; Aged, 80 and over ; Animals ; Germ Cells/cytology ; Humans ; Longevity ; Mice ; Middle Aged ; Models, Biological ; Neoplasms/metabolism ; Stem Cells/cytology ; Telomere/chemistry/*ultrastructure ; Time Factors ; },
abstract = {Like cells, all mammals have a limited life span. Among cells there are a few exceptions (e.g., immortal cells), among mammals not, even if some of them live longer. Many in vitro and in vivo studies support the consensus that telomere length is strongly correlated with life span. At the somatic cellular level, long telomeres have been associated with longer life span. A different situation can be seen in immortal cells, such as cancer, germ and stem cells, where telomeres are maintained by telomerase, a specialized reverse transcriptase that is involved in synthesis of telomeres. Irrespective of telomere length, if telomerase is active, telomeres can be maintained at a sufficient length to ensure cell survival. To the contrary, telomeres shorten progressively with each cell division and when a critical telomere length (Hayflick limit) is reached, the cells undergo senescence and subsequently apoptosis. In mammals, those with the longest telomeres (e.g., mice) have the shortest life span. Furthermore, the shorter the mean telomere length, the longer the mean life span, as observed in humans (10-14 kpb) and bowhead-whales (undetermined telomere length), which have the longest mean life span among mammals. Over the past centuries, human average life span has increased. The hypothesis presented here suggests that this continual increase in the mean life span could be due to a decrease of mean telomere length over the last hundreds years. Actually, the life span is not directly influenced by length of telomeres, but rather by telomere length - dependent gene expression pattern. According to Greider, "rather than average telomere length, it is the shortest telomere length that makes the biggest difference to a cell". In the context of fast-growing global elderly population due to increase in life expectancy, it also seem to be an age related increase in cancer incidence. Nevertheless, extending healthy life span could depend on how good cells achieve, during the prenatal period and few years after birth, the equilibrium between telomere length and telomerase activity, as seen in germ cells. After all, I suggest that decrease in mean telomere length might result in, on the one hand, an increased life span and, on the other, a higher risk of tumorigenesis.},
}
@article {pmid16529544,
year = {2006},
author = {Pendino, F and Tarkanyi, I and Dudognon, C and Hillion, J and Lanotte, M and Aradi, J and Ségal-Bendirdjian, E},
title = {Telomeres and telomerase: Pharmacological targets for new anticancer strategies?.},
journal = {Current cancer drug targets},
volume = {6},
number = {2},
pages = {147-180},
doi = {10.2174/156800906776056482},
pmid = {16529544},
issn = {1568-0096},
mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Enzyme Inhibitors/*pharmacology ; Humans ; Neoplasms/*drug therapy/pathology ; Telomerase/*antagonists &amp; inhibitors ; Telomere/chemistry/*drug effects ; },
abstract = {Telomeres are located at the ends of eukaryotic chromosomes. Human telomerase, a cellular reverse transcriptase, is a ribonucleoprotein enzyme that catalyzes the synthesis and extension of telomeric DNA. It is composed of at least, a template RNA component (hTR; human Telomerase RNA) and a catalytic subunit, the telomerase reverse transcriptase (hTERT). The absence of telomerase is associated with telomere shortening and aging of somatic cells, while high telomerase activity is observed in over 85% of human cancer cells, strongly indicating its key role during tumorigenesis. Several details regarding telomere structure and telomerase regulation have already been elucidated, providing new targets for therapeutic exploitation. Further support for anti-telomerase approaches comes from recent studies indicating that telomerase is endowed of additional functions in the control of growth and survival of tumor cells that do not depend only on the ability of this enzyme to maintain telomere length. This observation suggests that inhibiting telomerase or its synthesis may have additional anti-proliferative and apoptosis inducing effect, independently of the reduction of telomere length during cell divisions. This article reviews the basic information about the biology of telomeres and telomerase and attempts to present various approaches that are currently under investigation to inhibit its expression and its activity. We summarize herein distinct anti-telomerase approaches like antisense strategies, reverse transcriptase inhibitors, and G-quadruplex interacting agents, and also review molecules targeting hTERT expression, such as retinoids and evaluate them for their therapeutic potential. "They conceive a certain theory, and everything has to fit into that theory. If one little fact will not fit it, they throw it aside. But it is always the facts that will not fit in that are significant". "Death on the Nile". Agatha Christie.},
}
@article {pmid16525505,
year = {2006},
author = {Hiraga, S and Robertson, ED and Donaldson, AD},
title = {The Ctf18 RFC-like complex positions yeast telomeres but does not specify their replication time.},
journal = {The EMBO journal},
volume = {25},
number = {7},
pages = {1505-1514},
pmid = {16525505},
issn = {0261-4189},
mesh = {Cell Nucleus/metabolism ; Chromatin/metabolism ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; *DNA Replication ; DNA-Binding Proteins/genetics/metabolism ; G1 Phase ; Replication Protein C/genetics/*metabolism ; S Phase ; Saccharomyces cerevisiae/genetics/*physiology ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Shelterin Complex ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Telomere/genetics/*physiology ; Telomere-Binding Proteins/genetics/metabolism ; Transcription Factors/genetics/metabolism ; },
abstract = {Chromosome ends in Saccharomyces cerevisiae are positioned in clusters at the nuclear rim. We report that Ctf18, Ctf8, and Dcc1, the subunits of a Replication Factor C (RFC)-like complex, are essential for the perinuclear positioning of telomeres. In both yeast and mammalian cells, peripheral nuclear positioning of chromatin during G1 phase correlates with late DNA replication. We find that the mislocalized telomeres of ctf18 cells still replicate late, showing that late DNA replication does not require peripheral positioning during G1. The Ku and Sir complexes have been shown to act through separate pathways to position telomeres, but in the absence of Ctf18 neither pathway can act fully to maintain telomere position. Surprisingly CTF18 is not required for Ku or Sir4-mediated peripheral tethering of a nontelomeric chromosome locus. Our results suggest that the Ctf18 RFC-like complex modifies telomeric chromatin to make it competent for normal localization to the nuclear periphery.},
}
@article {pmid16524700,
year = {2006},
author = {Sugimoto, M and Yamashita, R and Ueda, M},
title = {Telomere length of the skin in association with chronological aging and photoaging.},
journal = {Journal of dermatological science},
volume = {43},
number = {1},
pages = {43-47},
doi = {10.1016/j.jdermsci.2006.02.004},
pmid = {16524700},
issn = {0923-1811},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; DNA/genetics/metabolism ; Dermis/metabolism/radiation effects/ultrastructure ; Epidermis/metabolism/radiation effects/ultrastructure ; Humans ; Middle Aged ; Phenotype ; Skin Aging/*genetics/pathology ; Telomere/*genetics/ultrastructure ; },
abstract = {BACKGROUND: Telomere shortening has been implicated in cellular senescence, which may cause certain aging phenotypes.<br><br>OBJECTIVE: To reveal whether telomere shortening is associated with chronological aging and/or photoaging of the skin, we measured telomere length in the epidermis and in the dermis from sun-protected and from sun-exposed sites of the skin.<br><br>METHODS: Seventy-six specimens of epidermis from sun-protected sites and 24 specimens of epidermis from sun-exposed sites were analyzed. Sixty specimens of the dermis were also analyzed. In six cases, epidermal specimens from sun-protected and from sun-exposed sites of the same individual were analyzed.<br><br>RESULTS: Comparison of telomere lengths revealed that the epidermis has shorter telomeres than the dermis. Telomere length in the epidermis and in the dermis was reduced with age, and average telomere shortening rates in the epidermis and in the dermis were 9 and 11 bp/yr, respectively. Unexpectedly, telomere length was not significantly different between epidermis from sun-exposed sites and from sun-protected sites.<br><br>CONCLUSION: We could not show the evidence that telomere shortening is associated with photoaging of the skin.},
}
@article {pmid16521855,
year = {2006},
author = {Callicott, RJ and Womack, JE},
title = {Real-time PCR assay for measurement of mouse telomeres.},
journal = {Comparative medicine},
volume = {56},
number = {1},
pages = {17-22},
pmid = {16521855},
issn = {1532-0820},
mesh = {Animals ; Chromosome Mapping ; DNA Primers/genetics ; Mice ; Polymerase Chain Reaction/*methods ; Reproducibility of Results ; Species Specificity ; Telomere/*genetics/ultrastructure ; },
abstract = {Measurement of telomeres by polymerase chain reaction (PCR) amplification has been problematic due to the formation of dimers by the primers designed to hybridize to the telomere repeats. Recently, a set of primers that overcome this problem has been created and used to develop an assay to measure human telomeres by real-time quantitative PCR. We modified this assay to measure mouse telomeres. Results showed that the primers do indeed amplify mammalian telomere repeats without forming dimers. Results obtained from the real-time quantitative PCR assay of mouse DNA were similar to terminal restriction fragment analysis by pulsed-field gel electrophoresis followed by Southern hybridization. The assay performed with mouse DNA in a similar manner as it performs with human DNA. Preliminary linkage mapping suggests a gene influencing telomere length on the X chromosome. This assay will aid in the study of telomere function and importance in diseases associated with aging and cancer formation.},
}
@article {pmid16520276,
year = {2006},
author = {Meeker, AK},
title = {Telomeres and telomerase in prostatic intraepithelial neoplasia and prostate cancer biology.},
journal = {Urologic oncology},
volume = {24},
number = {2},
pages = {122-130},
doi = {10.1016/j.urolonc.2005.11.002},
pmid = {16520276},
issn = {1078-1439},
mesh = {Humans ; Male ; Prostatic Hyperplasia/*enzymology/*etiology ; Prostatic Neoplasms/*enzymology/*etiology ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {Telomeres are terminal, repeated deoxyribonucleic acid (DNA) sequences that stabilize and protect the ends of the chromosomes. Mounting evidence indicates that by initiating chromosomal instability, short dysfunctional telomeres may be involved in prostate carcinogenesis. Although the exact cause of the telomere shortening observed in prostate cancer remains a mystery, telomere loss is known to occur during cell division and oxidative DNA damage, 2 byproducts of chronic inflammation, which is a common histologic finding in the prostate. In addition to prostate cancer causation, telomeres may also play a role in disease progression, and there are indications that tumor telomere content may prove useful as a prognostic marker. Once established, prostate cancer cells almost invariably activate the telomeric DNA polymerase enzyme telomerase, the detection of which may prove useful for diagnostic purposes. Interestingly, telomerase activity is suppressed in prostate cancer cells after androgen withdrawal, raising the possibility that androgen ablative therapies may re-instigate telomere loss, and consequent genetic instability, in surviving cancer cells, thus contributing to the emergence of an androgen-independent, lethal phenotype. A more thorough understanding of telomere biology as it relates to prostate cancer should provide new opportunities for disease prevention, diagnosis, prognostication, and treatment.},
}
@article {pmid16518699,
year = {2005},
author = {Davis, T and Kipling, D},
title = {Telomeres and telomerase biology in vertebrates: progress towards a non-human model for replicative senescence and ageing.},
journal = {Biogerontology},
volume = {6},
number = {6},
pages = {371-385},
doi = {10.1007/s10522-005-4901-4},
pmid = {16518699},
issn = {1389-5729},
mesh = {Aging/*physiology ; Animals ; Cell Proliferation ; Cellular Senescence/*physiology ; Humans ; *Models, Biological ; Telomerase/*metabolism ; Telomere/*physiology ; Tumor Suppressor Protein p53/*metabolism ; Vertebrates ; },
abstract = {Studies on telomere and telomerase biology are fundamental to the understanding of human ageing and age-related diseases such as cancer. However, human studies of whole body ageing are hampered by the lack of suitable fully reflective animal model systems, the wild-type mouse model being unsuitable due to differences in telomere biology. Here we summarise recent data on the biology of telomeres, telomerase, and the tumour suppressor protein p53 in various animals, and examine their possible roles in replicative senescence, ageing, and tumourigenesis. The advantages and disadvantages of various animals as model systems for whole body ageing in humans are discussed.},
}
@article {pmid16510904,
year = {2006},
author = {Chkhotua, A and Abendroth, D and Schelzig, H},
title = {Renal ischemia/reperfusion and its influence on telomere length and expression of cell cycle regulatory genes.},
journal = {Georgian medical news},
volume = {},
number = {130},
pages = {22-26},
pmid = {16510904},
issn = {1512-0112},
mesh = {Animals ; Biopsy ; Cell Cycle Proteins/*genetics/metabolism ; Disease Models, Animal ; *Gene Expression ; Immunohistochemistry ; Kidney/*blood supply/metabolism ; Macaca ; Reperfusion Injury/*genetics/metabolism/pathology ; Swine ; Telomere/*ultrastructure ; },
abstract = {The aim of the study was to evaluate the influence of renal ischemia/reperfusion (I/R) on telomere (T) length and tissue expression of cyclin-dependent kinase inhibitor genes (CDKIG). An experimental model of ex-vivo hemoperfusion of the kidney was used as described earlier. Telomere length measurement and expression of p16((INK4a)), p21((WAF1/CIP1)) and p27((Kip1)) CDKIGs was studied immunohistochemically in kidney biopsy samples at baseline and different time points after the reperfusion. The mean T length decreased after reperfusion from 5.56+/-0.60 kbp to 5.46+/-0.36 kbp (p=NS). All 3 genes were up-regulated in kidney tissue however their activation was different in diverse renal cells according to the reperfusion time. Expression of p16 significantly increased in tubular cells at 180 min of reperfusion as compared with the baseline. Activation of the p27 in glomerular cells was significantly higher at 60, 120 and 180 min of reperfusion as compared with 0 and 15 min. The marker started increasing in tubular cells at 15 min and was elevated at every time point afterwards. p21 was significantly over-expressed in all renal cells after the reperfusion. The current study shows that renal I/R causes T shortening and over-expression of CDKIGs indicating on substantial DNA damage and/or accelerated tissue senescence. The tissue expression of CDKIGs is positively related with the reperfusion time.},
}
@article {pmid16507985,
year = {2006},
author = {Hsiao, SJ and Poitras, MF and Cook, BD and Liu, Y and Smith, S},
title = {Tankyrase 2 poly(ADP-ribose) polymerase domain-deleted mice exhibit growth defects but have normal telomere length and capping.},
journal = {Molecular and cellular biology},
volume = {26},
number = {6},
pages = {2044-2054},
pmid = {16507985},
issn = {0270-7306},
support = {R01 CA95099/CA/NCI NIH HHS/United States ; T32 GM007308/GM/NIGMS NIH HHS/United States ; T32 GM007238/GM/NIGMS NIH HHS/United States ; R01 CA095099/CA/NCI NIH HHS/United States ; GM07308/GM/NIGMS NIH HHS/United States ; GM07238/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Body Size/genetics ; Cells, Cultured ; Female ; Growth/*genetics ; Humans ; Male ; Mice ; Mice, Mutant Strains/growth &amp; development ; Poly(ADP-ribose) Polymerases/metabolism ; Protein Structure, Tertiary ; Reference Values ; Stem Cells/cytology/physiology ; Tankyrases/*genetics/*metabolism ; Telomere/*physiology ; },
abstract = {Regulation of telomere length maintenance and capping are a critical cell functions in both normal and tumor cells. Tankyrase 2 (Tnks2) is a poly(ADP-ribose) polymerase (PARP) that has been shown to modify itself and TRF1, a telomere-binding protein. We show here by overexpression studies that tankyrase 2, like its closely related homolog tankyrase 1, can function as a positive regulator of telomere length in human cells, dependent on its catalytic PARP activity. To study the role of Tnks2 in vivo, we generated mice with the Tnks2 PARP domain deleted. These mice are viable and fertile but display a growth retardation phenotype. Telomere analysis by quantitative fluorescence in situ hybridization (FISH), flow-FISH, and restriction fragment analysis showed no change in telomere length or telomere capping in these mice. To determine the requirement for Tnks2 in long-term maintenance of telomeres, we generated embryonic stem cells with the Tnks2 PARP domain deleted and observed no change, even upon prolonged growth, in telomere length or telomere capping. Together, these results suggest that Tnks2 has a role in normal growth and development but is not essential for telomere length maintenance or telomere capping in mice.},
}
@article {pmid16507984,
year = {2006},
author = {Chiang, YJ and Nguyen, ML and Gurunathan, S and Kaminker, P and Tessarollo, L and Campisi, J and Hodes, RJ},
title = {Generation and characterization of telomere length maintenance in tankyrase 2-deficient mice.},
journal = {Molecular and cellular biology},
volume = {26},
number = {6},
pages = {2037-2043},
pmid = {16507984},
issn = {0270-7306},
support = {//Intramural NIH HHS/United States ; },
mesh = {Animals ; Body Weight/genetics ; Female ; Male ; Mice ; Mice, Knockout ; Sex Factors ; Tankyrases/*genetics/*metabolism ; Telomere/*physiology ; },
abstract = {Telomere length and function are crucial factors that determine the capacity for cell proliferation and survival, mediate cellular senescence, and play a role in malignant transformation in eukaryotic systems. The telomere length of a specific mammalian species is maintained within a given range by the action of telomerase and telomere-associated proteins. TRF1 is a telomere-associated protein that inhibits telomere elongation by its binding to telomere repeats, preventing access to telomerase. Human TRF1 interacts with tankyrase 1 and tankyrase 2 proteins, two related members of the tankyrase family shown to have poly(ADP-ribose) polymerase activity. Human tankyrase 1 is reported to ADP-ribosylate TRF1 and to down-regulate the telomeric repeat binding activity of TRF1, resulting in telomerase-dependent telomere elongation. Human tankyrase 2 is proposed to have activity similar to that of tankyrase 1, although tankyrase 2 function has been less extensively characterized. In the present study, we have assessed the in vivo function of mouse tankyrase 2 by germ line gene inactivation and show that inactivation of tankyrase 2 does not result in detectable alteration in telomere length when monitored through multiple generations of breeding. This finding suggests that either mouse tankyrases 1 and 2 have redundant functions in telomere length maintenance or that mouse tankyrase 2 differs from human tankyrase 2 in its role in telomere length maintenance. Tankyrase 2 deficiency did result in a significant decrease in body weight sustained through at least the first year of life, most marked in male mice, suggesting that tankyrase 2 functions in potentially telomerase-independent pathways to affect overall development and/or metabolism.},
}
@article {pmid16507852,
year = {2006},
author = {Morlá, M and Busquets, X and Pons, J and Sauleda, J and MacNee, W and Agustí, AG},
title = {Telomere shortening in smokers with and without COPD.},
journal = {The European respiratory journal},
volume = {27},
number = {3},
pages = {525-528},
doi = {10.1183/09031936.06.00087005},
pmid = {16507852},
issn = {0903-1936},
mesh = {Adult ; Age Factors ; Aged ; Female ; Humans ; *Lymphocytes ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/blood/*genetics ; Smoking/blood/*genetics ; Telomere/*ultrastructure ; },
abstract = {Telomeres are complex DNA-protein structures located at the end of eukaryotic chromosomes. Telomere length shortens with age in all replicating somatic cells. It has been shown that tobacco smoking enhances telomere shortening in circulating lymphocytes. The present study investigated whether this effect was further amplified in smokers who develop chronic obstructive pulmonary disease. Telomere length was determined by fluorescence in situ hybridisation in circulating lymphocytes harvested from 26 never-smokers, 24 smokers with normal lung function and 26 smokers with moderate-to-severe airflow obstruction (forced expiratory flow in one second 48+/-4% predicted). In contrast to never-smokers, telomere length significantly decreased with age in smokers. There was also a dose-effect relationship between the cumulative long-life exposure to tobacco smoking (pack-yrs) and telomere length. The presence and/or severity of chronic airflow obstruction did not modify this relationship. The results of the current study confirm that smoking exposure enhances telomere shortening in circulating lymphocytes. It also demonstrates a dose-effect relationship between exposure to tobacco smoking and telomere length, but failed to show that this effect is amplified in smokers who develop chronic obstructive pulmonary disease.},
}
@article {pmid16503597,
year = {2006},
author = {Cao, Z and Huang, CC and Tan, W},
title = {Nuclease resistance of telomere-like oligonucleotides monitored in live cells by fluorescence anisotropy imaging.},
journal = {Analytical chemistry},
volume = {78},
number = {5},
pages = {1478-1484},
doi = {10.1021/ac0517601},
pmid = {16503597},
issn = {0003-2700},
mesh = {Breast Neoplasms/enzymology/genetics/*pathology ; Cell Line, Tumor ; DNA/metabolism ; DNA, Single-Stranded/metabolism ; Diagnostic Imaging/*methods ; Endonucleases/*metabolism ; Female ; Fluorescence Polarization/*methods ; G-Quadruplexes ; Humans ; Oligonucleotides/*metabolism ; Telomere/*chemistry/metabolism ; },
abstract = {Telomeres carry important biological functions such as the protection of chromosomes. In this paper, we have developed a fluorescence anisotropy imaging system for monitoring DNA digestion inside live cells. The nuclease-resistant capability of telomere-like ssDNAs in nuclei of human breast cancer cells is studied. We found that those oligonucleotides were clearly more stable than regular DNA sequences during the time course of the experiments. We conclude that the G-quadruplex structure of the telomere-like ssDNA makes it inherently more stable in intracellular environments than non-G-quadruplex structures. This will help us understand why the G-quadruplex forming telomere sequences were adopted by almost all eukaryotic cells to protect the ends of chromosomes. This is the first time such a phenomenon was observed in live cells. Our fluorescence anisotropy imaging provides an efficient way to directly monitor DNA digestion in any region of live cells in real time, providing insights into many important and related intracellular processes.},
}
@article {pmid16492566,
year = {2006},
author = {Nakai, R and Ishida, H and Asai, A and Ogawa, H and Yamamoto, Y and Kawasaki, H and Akinaga, S and Mizukami, T and Yamashita, Y},
title = {Telomerase inhibitors identified by a forward chemical genetics approach using a yeast strain with shortened telomere length.},
journal = {Chemistry &amp; biology},
volume = {13},
number = {2},
pages = {183-190},
doi = {10.1016/j.chembiol.2005.11.010},
pmid = {16492566},
issn = {1074-5521},
mesh = {Cell Cycle ; Cell Line, Tumor ; Cell-Free System ; Cellular Senescence ; Diterpenes/chemistry/pharmacology ; Enzyme Inhibitors/chemistry/*pharmacology ; Humans ; Saccharomyces cerevisiae/*genetics ; Telomerase/*antagonists &amp; inhibitors ; *Telomere ; beta-Galactosidase/metabolism ; },
abstract = {Telomerase has been proposed as a selective target for cancer chemotherapy. We established a forward chemical genetics approach using a yeast strain with shortened telomere length. Since this strain rapidly enters cell senescence in the absence of active telomerase, compounds that induce selective growth defects against telomere-shortened yeast could be candidates for drugs acting on telomeres and telomerase. We screened our microbial products library and identified three structurally unrelated antibiotics, chrolactomycin, UCS1025A, and radicicol, as active compounds. Detailed analysis showed that chrolactomycin inhibited human telomerase in a cell-free assay as well as in a cellular assay. Long-term culture of cancer cells with chrolactomycin revealed population-doubling-dependent antiproliferative activity accompanied by telomere shortening. These results suggest that chrolactomycin is a telomerase inhibitor, and that the yeast-based assay is useful for discovering the small molecules acting on human telomerase.},
}
@article {pmid16490380,
year = {2006},
author = {Bolzán, AD and Bianchi, MS},
title = {Telomeres, interstitial telomeric repeat sequences, and chromosomal aberrations.},
journal = {Mutation research},
volume = {612},
number = {3},
pages = {189-214},
doi = {10.1016/j.mrrev.2005.12.003},
pmid = {16490380},
issn = {0027-5107},
mesh = {Animals ; *Chromosome Aberrations ; In Situ Hybridization, Fluorescence ; Telomere/*genetics ; Terminal Repeat Sequences/*genetics ; },
abstract = {Telomeres are specialized nucleoproteic complexes localized at the physical ends of linear eukaryotic chromosomes that maintain their stability and integrity. The DNA component of telomeres is characterized by being a G-rich double stranded DNA composed by short fragments tandemly repeated with different sequences depending on the species considered. At the chromosome level, telomeres or, more properly, telomeric repeats--the DNA component of telomeres--can be detected either by using the fluorescence in situ hybridization (FISH) technique with a DNA or a peptide nucleic acid (PNA) (pan)telomeric probe, i.e., which identifies simultaneously all of the telomeres in a metaphase cell, or by the primed in situ labeling (PRINS) reaction using an oligonucleotide primer complementary to the telomeric DNA repeated sequence. Using these techniques, incomplete chromosome elements, acentric fragments, amplification and translocation of telomeric repeat sequences, telomeric associations and telomeric fusions can be identified. In addition, chromosome orientation (CO)-FISH allows to discriminate between the different types of telomeric fusions, namely telomere-telomere and telomere-DNA double strand break fusions and to detect recombination events at the telomere, i.e., telomeric sister-chromatid exchanges (T-SCE). In this review, we summarize our current knowledge of chromosomal aberrations involving telomeres and interstitial telomeric repeat sequences and their induction by physical and chemical mutagens. Since all of the studies on the induction of these types of aberrations were conducted in mammalian cells, the review will be focused on the chromosomal aberrations involving the TTAGGG sequence, i.e., the telomeric repeat sequence that "caps" the chromosomes of all vertebrate species.},
}
@article {pmid16487204,
year = {2006},
author = {Akkad, A and Hastings, R and Konje, JC and Bell, SC and Thurston, H and Williams, B},
title = {Telomere length in small-for-gestational-age babies.},
journal = {BJOG : an international journal of obstetrics and gynaecology},
volume = {113},
number = {3},
pages = {318-323},
doi = {10.1111/j.1471-0528.2005.00839.x},
pmid = {16487204},
issn = {1470-0328},
mesh = {Adult ; Blotting, Southern ; Case-Control Studies ; Chromosome Disorders/genetics/*pathology ; Cohort Studies ; Female ; Fetal Blood/chemistry ; Fetal Growth Retardation/blood/genetics/*pathology ; Gestational Age ; Humans ; Infant, Newborn ; Infant, Small for Gestational Age/blood/*physiology ; Male ; Parity ; Pregnancy ; Prospective Studies ; Telomere/*pathology ; },
abstract = {OBJECTIVE: Short telomeres are associated with adult cardiovascular disease. Our aim was to determine whether small-for-gestational-age (SGA) newborns have shortened telomeres compared with appropriately grown controls.<br><br>DESIGN: Prospective cohort study.<br><br>SETTING: Large tertiary referral unit in Trent, UK.<br><br>POPULATION: Seventy-two women who delivered at 35-42 weeks of gestation were recruited; 34 delivered SGA babies (less than or equal to the third birthweight centile) and 38 had appropriately grown babies (greater than the tenth centile).<br><br>METHODS: Maternal and cord blood samples were collected at delivery. A Southern blot of DNA from these samples was hybridised with a 32P-labelled telomeric probe and telomere length was measured.<br><br>MAIN OUTCOME MEASURES: Mean maternal and newborn telomere length.<br><br>RESULTS: Maternal and newborn telomere lengths were significantly correlated in both the SGA and the control groups (r2 = 0.25, P < 0.0001). Telomere lengths were similar in both maternal (control 8.41 +/- 0.9 kb versus SGA 8.29 +/- 1.0 kb, P = 0.57) and newborn (control 10.36 +/- 1.5 kb versus SGA 10.33 +/- 1.3 kb, P = 0.93) cohorts in the two groups.<br><br>CONCLUSIONS: Intrauterine events associated with impaired fetal growth do not appear to be associated with increased telomere shortening.},
}
@article {pmid16484772,
year = {2006},
author = {Mayer, S and Brüderlein, S and Perner, S and Waibel, I and Holdenried, A and Ciloglu, N and Hasel, C and Mattfeldt, T and Nielsen, KV and Möller, P},
title = {Sex-specific telomere length profiles and age-dependent erosion dynamics of individual chromosome arms in humans.},
journal = {Cytogenetic and genome research},
volume = {112},
number = {3-4},
pages = {194-201},
doi = {10.1159/000089870},
pmid = {16484772},
issn = {1424-859X},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Child, Preschool ; Chromosomes, Human/*ultrastructure ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; Lymphocytes/cytology/physiology ; Male ; Metaphase ; Middle Aged ; Reference Values ; Regression Analysis ; Sex Characteristics ; Telomere/*ultrastructure ; },
abstract = {During aging, telomeres are gradually shortened, eventually leading to cellular senescence. By T/C-FISH (telomere/centromere-FISH), we investigated human telomere length differences on single chromosome arms of 205 individuals in different age groups and sexes. For all chromosome arms, we found a linear correlation between telomere length and donor age. Generally, males had shorter telomeres and higher attrition rates. Every chromosome arm had its individual age-specific telomere length and erosion pattern, resulting in an unexpected heterogeneity in chromosome-specific regression lines. This differential erosion pattern, however, does not seem to be accidental, since we found a correlation between average telomere length of single chromosome arms in newborns and their annual attrition rate. Apart from the above-mentioned sex-specific discrepancies, chromosome arm-specific telomere lengths were strikingly similar in men and women. This implies a mechanism that arm specifically regulates the telomere length independent of gender, thus leading to interchromosomal telomere variations.},
}
@article {pmid16479005,
year = {2006},
author = {Pedram, M and Sprung, CN and Gao, Q and Lo, AW and Reynolds, GE and Murnane, JP},
title = {Telomere position effect and silencing of transgenes near telomeres in the mouse.},
journal = {Molecular and cellular biology},
volume = {26},
number = {5},
pages = {1865-1878},
pmid = {16479005},
issn = {0270-7306},
support = {R01 ES008427/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; DNA Methylation ; Gene Expression Regulation ; Gene Order ; *Gene Silencing ; Genetic Engineering/methods ; Hydroxamic Acids/pharmacology ; Mice ; Mice, Transgenic ; Promoter Regions, Genetic ; Stem Cells/physiology ; *Telomere/drug effects ; Transgenes/*genetics ; },
abstract = {Reversible transcriptional silencing of genes located near telomeres, termed the telomere position effect (TPE), is well characterized in Saccharomyces cerevisiae. TPE has also been observed in human tumor cell lines, but its function remains unknown. To investigate TPE in normal mammalian cells, we developed clones of mouse embryonic stem (ES) cells that contain single-copy marker genes integrated adjacent to different telomeres. Analysis of these telomeric transgenes demonstrated that they were expressed at very low levels compared to the same transgenes integrated at interstitial sites. Similar to the situation in yeast, but in contrast to studies with human tumor cell lines, TPE in mouse ES cells was not reversed with trichostatin A. Prolonged culturing without selection resulted in extensive DNA methylation and complete silencing of telomeric transgenes, which could be reversed by treatment with 5-azacytidine. Thus, complete silencing of the telomeric transgenes appears to involve a two-step process in which the initial repression is reinforced by DNA methylation. Extensive methylation of the telomeric transgenes was also observed in various tissues and embryonic fibroblasts isolated from transgenic mice. In contrast, telomeric transgenes were not silenced in ES cell lines isolated from 3-day-old preimplantation embryos, consistent with the hypothesis that TPE plays a role in the development of the embryo.},
}
@article {pmid16479004,
year = {2006},
author = {Pandita, RK and Sharma, GG and Laszlo, A and Hopkins, KM and Davey, S and Chakhparonian, M and Gupta, A and Wellinger, RJ and Zhang, J and Powell, SN and Roti Roti, JL and Lieberman, HB and Pandita, TK},
title = {Mammalian Rad9 plays a role in telomere stability, S- and G2-phase-specific cell survival, and homologous recombinational repair.},
journal = {Molecular and cellular biology},
volume = {26},
number = {5},
pages = {1850-1864},
pmid = {16479004},
issn = {0270-7306},
support = {CA89816/CA/NCI NIH HHS/United States ; CA10445/CA/NCI NIH HHS/United States ; NS34746/NS/NINDS NIH HHS/United States ; R01 GM052493/GM/NIGMS NIH HHS/United States ; R01 CA089816/CA/NCI NIH HHS/United States ; GM52493/GM/NIGMS NIH HHS/United States ; R01 NS034746/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle/*genetics/radiation effects ; Cell Cycle Proteins/genetics/*metabolism ; Cell Survival/genetics ; Checkpoint Kinase 2 ; Chromosome Aberrations ; DNA/genetics/metabolism/radiation effects ; DNA Damage/genetics ; DNA Repair/*genetics ; DNA-Binding Proteins/metabolism ; G2 Phase/genetics/radiation effects ; Histones/genetics/metabolism/radiation effects ; Humans ; Mammals ; Mutation ; Nuclear Proteins/metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases/metabolism ; Radiation, Ionizing ; *Recombination, Genetic ; S Phase/genetics/radiation effects ; Schizosaccharomyces pombe Proteins ; TATA Box Binding Protein-Like Proteins/metabolism ; Telomere/*genetics/radiation effects ; Telomeric Repeat Binding Protein 2 ; Tumor Suppressor Proteins/metabolism ; },
abstract = {The protein products of several rad checkpoint genes of Schizosaccharomyces pombe (rad1+, rad3+, rad9+, rad17+, rad26+, and hus1+) play crucial roles in sensing changes in DNA structure, and several function in the maintenance of telomeres. When the mammalian homologue of S. pombe Rad9 was inactivated, increases in chromosome end-to-end associations and frequency of telomere loss were observed. This telomere instability correlated with enhanced S- and G2-phase-specific cell killing, delayed kinetics of gamma-H2AX focus appearance and disappearance, and reduced chromosomal repair after ionizing radiation (IR) exposure, suggesting that Rad9 plays a role in cell cycle phase-specific DNA damage repair. Furthermore, mammalian Rad9 interacted with Rad51, and inactivation of mammalian Rad9 also resulted in decreased homologous recombinational (HR) repair, which occurs predominantly in the S and G2 phases of the cell cycle. Together, these findings provide evidence of roles for mammalian Rad9 in telomere stability and HR repair as a mechanism for promoting cell survival after IR exposure.},
}
@article {pmid16477260,
year = {2006},
author = {Bischoff, C and Petersen, HC and Graakjaer, J and Andersen-Ranberg, K and Vaupel, JW and Bohr, VA and Kølvraa, S and Christensen, K},
title = {No association between telomere length and survival among the elderly and oldest old.},
journal = {Epidemiology (Cambridge, Mass.)},
volume = {17},
number = {2},
pages = {190-194},
doi = {10.1097/01.ede.0000199436.55248.10},
pmid = {16477260},
issn = {1044-3983},
support = {P01-AG08761/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*physiology ; Denmark ; Female ; Humans ; Longitudinal Studies ; Male ; Proportional Hazards Models ; Registries ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: The consistent findings of a negative correlation between telomere length and replicative potential of cultured cells, as well as a decreasing telomere length in a number of different tissues in humans with age, have led to the suggestion that telomeres play a role in cellular aging in vivo and ultimately even in organismal aging. Furthermore, one small longitudinal study of elderly individuals has suggested that longer telomeres are associated with better survival.<br><br>METHODS: Telomere length was measured as mean terminal restriction fragment length on blood cells from 812 persons, age 73 to 101 years, who participated in population-based surveys in 1997-1998. Among the participants were 652 twins. The participants were followed up through the Danish Civil Registration system until January 2005, at which time 412 (51%) were dead.<br><br>RESULTS: Univariate Cox regression analyses revealed that longer telomeres were associated with better survival (hazard ratios = 0.89 [95% confidence interval = 0.76-1.04] per 1 kb in males and 0.79 [0.72-0.88] per 1 kb in females, respectively). However, including age in the analyses changed the estimates to 0.97 (0.83-1.14) and 0.93 (0.85-1.03), respectively. Intrapair comparison showed that among 175 twin pairs in which at least one died during follow up, it was the twin with the shorter telomere length who died first in 97 (55%) of the pairs (95% confidence interval = 48-63%). We could not confirm the recently reported negative correlation between telomere length and obesity or between telomere length and smoking.<br><br>CONCLUSION: This longitudinal study of the elderly and oldest old does not support the hypothesis that telomere length is a predictor for remaining lifespan once age is controlled for.},
}
@article {pmid16473311,
year = {2006},
author = {Palanduz, S and Serakinci, N and Cefle, K and Aktan, M and Tutkan, G and Ozturk, S and Bozkurt, G and Dincol, G and Pekcelen, Y and Koch, J},
title = {A different approach to telomere analysis with ddPRINS in chronic lymphocytic leukemia.},
journal = {European journal of medical genetics},
volume = {49},
number = {1},
pages = {63-69},
doi = {10.1016/j.ejmg.2005.01.023},
pmid = {16473311},
issn = {1769-7212},
mesh = {Aged ; Case-Control Studies ; Female ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics ; Male ; Middle Aged ; Nucleic Acid Hybridization ; Primed In Situ Labeling/*methods ; *Repetitive Sequences, Nucleic Acid ; Telomere/*genetics ; },
abstract = {Telomeric sequences, located at the very end of the chromosomes, compensate for the chromosomal shortening as it happens after each round of cell division. Telomeric sequences influence the progress of cellular senescence and cancer progression. It has been reported that telomeres are shortened in acute leukemias where the cell turnover is high. B-cell chronic lymphocytic leukemia (CLL) is a particularly interesting haematological malignancy in regard to telomere dynamics because most of the malignant cells in CLL are mitotically inactive. In this study, we analysed the telomere length in patients with B-cell CLL in a comparison with the control group by using ddPRINS technique. Twenty patients with CLL and four healthy donors as a control group were included. We found short telomeres and no detectable telomeric repeats at the sites of chromosome fusion. We hypothesise that the telomeric erosion in CLL may reflect the dominance of malignant cells with an abnormally long life span. These cells may have encountered many antigenic stimulants in the past and hence underwent multiple clonal expansions. Our findings imply that shortened telomeres in CLL may be reflecting the "history" of the disease and serve as an independent prognostic factor.},
}
@article {pmid16473138,
year = {2006},
author = {Zhang, L and Tamura, K and Shin-ya, K and Takahashi, H},
title = {The telomerase inhibitor telomestatin induces telomere shortening and cell death in Arabidopsis.},
journal = {Biochimica et biophysica acta},
volume = {1763},
number = {1},
pages = {39-44},
doi = {10.1016/j.bbamcr.2005.12.002},
pmid = {16473138},
issn = {0006-3002},
mesh = {Arabidopsis/*cytology/drug effects/*enzymology/genetics ; Cell Death/drug effects ; Cells, Cultured ; Oryza/enzymology ; Oxazoles/*pharmacology ; RNA, Messenger/genetics/metabolism ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/chemistry/genetics/*metabolism ; },
abstract = {The cellular response to telomere dysfunction in plants was investigated with the use of telomestatin, an inhibitor of human telomerase activity. Telomestatin bound to plant telomeric repeat sequence, and inhibited telomerase activity in suspension-cultured cells of Arabidopsis thaliana and Oryza sativa (rice) in a dose-dependent manner. The inhibitor did not affect transcript level of the TERT gene, which encodes the catalytic subunit of telomerase, in the plant cells. Inhibition of telomerase activity by telomestatin resulted in rapid shortening of telomeres and the induction of cell death by an apoptosis-like mechanism in Arabidopsis cells. These results suggest that telomerase contributes to the survival of proliferating plant cells by maintaining telomere length, and that telomere erosion triggers cell death.},
}
@article {pmid16470760,
year = {2006},
author = {Kan, ZY and Yao, Y and Wang, P and Li, XH and Hao, YH and Tan, Z},
title = {Molecular crowding induces telomere G-quadruplex formation under salt-deficient conditions and enhances its competition with duplex formation.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {45},
number = {10},
pages = {1629-1632},
doi = {10.1002/anie.200502960},
pmid = {16470760},
issn = {1433-7851},
mesh = {Base Sequence ; Circular Dichroism ; DNA/*chemistry/genetics ; G-Quadruplexes ; Nucleic Acid Conformation/drug effects ; Salts/*pharmacology ; Telomere/*chemistry/genetics ; Transition Temperature ; },
}
@article {pmid16469501,
year = {2006},
author = {Olaussen, KA and Dubrana, K and Domont, J and Spano, JP and Sabatier, L and Soria, JC},
title = {Telomeres and telomerase as targets for anticancer drug development.},
journal = {Critical reviews in oncology/hematology},
volume = {57},
number = {3},
pages = {191-214},
doi = {10.1016/j.critrevonc.2005.08.007},
pmid = {16469501},
issn = {1040-8428},
mesh = {Antineoplastic Agents/chemistry/metabolism/*therapeutic use ; Catalytic Domain/drug effects/genetics ; Drug Design ; Enzyme Inhibitors/chemistry/metabolism/*therapeutic use ; Female ; Genetic Therapy ; Humans ; Immunotherapy ; Male ; Neoplasms/*enzymology/genetics/*therapy ; Telomerase/*antagonists &amp; inhibitors/genetics/metabolism ; },
abstract = {In most human cancers, the telomere erosion problem has been bypassed through the activation of a telomere maintenance system (usually activation of telomerase). Therefore, telomere and telomerase are attractive targets for anti-cancer therapeutic interventions. Here, we review a large panel of strategies that have been explored to date, from small inhibitors of the catalytic sub-unit of telomerase to anti-telomerase immunotherapy and gene therapy. The many positive results that are reported from anti-telomere/telomerase assays suggest a prudent optimism for a possible clinical application in a close future. However, we discuss some of the main limits for these approaches of antitumour drug development and why significant work remains before a clinically useful drug can be proposed to patients.},
}
@article {pmid16468981,
year = {2006},
author = {Pennaneach, V and Putnam, CD and Kolodner, RD},
title = {Chromosome healing by de novo telomere addition in Saccharomyces cerevisiae.},
journal = {Molecular microbiology},
volume = {59},
number = {5},
pages = {1357-1368},
doi = {10.1111/j.1365-2958.2006.05026.x},
pmid = {16468981},
issn = {0950-382X},
support = {GM26017/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosome Breakage ; Chromosomes, Fungal/*genetics ; DNA Helicases/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Gene Expression Regulation, Fungal ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomerase/metabolism ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {The repair of spontaneous or induced DNA damage by homologous recombination (HR) in Saccharomyces cerevisiae will suppress chromosome rearrangements. Alternative chromosome healing pathways can result in chromosomal instability. One of these pathways is de novo telomere addition where the end of a broken chromosome is stabilized by telomerase-dependent addition of telomeres at non-telomeric sites. De novo telomere addition requires the recruitment of telomerase to chromosomal targets. Subsequently, annealing of the telomerase reverse transcriptase RNA-template (guide RNA) at short regions of homology is followed by extension of the nascent 3'-end of the broken chromosome to copy a short region of the telomerase guide RNA; multiple cycles of this process yield the new telomere. Proteins including Pif1 helicase, the single-stranded DNA-binding protein Cdc13 and the Ku heterocomplex are known to participate in native telomere functions and also regulate the de novo telomere addition reaction. Studies of the sequences added at de novo telomeres have lead to a detailed description of the annealing-extension-dissociation cycles that copy the telomerase guide RNA, which can explain the heterogeneity of telomeric repeats at de novo and native telomeres in S. cerevisiae.},
}
@article {pmid16467875,
year = {2006},
author = {Zhang, Y and Zhou, J and Lim, CU},
title = {The role of NBS1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control.},
journal = {Cell research},
volume = {16},
number = {1},
pages = {45-54},
doi = {10.1038/sj.cr.7310007},
pmid = {16467875},
issn = {1001-0602},
mesh = {Cell Cycle/*physiology ; Cell Cycle Proteins/*physiology ; *Chromosomal Instability ; DNA Damage ; *DNA Repair ; Genes, cdc ; Humans ; Models, Biological ; Nuclear Proteins/*physiology ; Phosphatidylinositol 3-Kinases/metabolism ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomere/genetics/*physiology ; },
abstract = {The genomes of eukaryotic cells are under continuous assault by environmental agents and endogenous metabolic byproducts. Damage induced in DNA usually leads to a cascade of cellular events, the DNA damage response. Failure of the DNA damage response can lead to development of malignancy by reducing the efficiency and fidelity of DNA repair. The NBS1 protein is a component of the MRE11/RAD50/NBS1 complex (MRN) that plays a critical role in the cellular response to DNA damage and the maintenance of chromosomal integrity. Mutations in the NBS1 gene are responsible for Nijmegen breakage syndrome (NBS), a hereditary disorder that imparts an increased predisposition to development of malignancy. The phenotypic characteristics of cells isolated from NBS patients point to a deficiency in the repair of DNA double strand breaks. Here, we review the current knowledge of the role of NBS1 in the DNA damage response. Emphasis is placed on the role of NBS1 in the DNA double strand repair, modulation of the DNA damage sensing and signaling, cell cycle checkpoint control and maintenance of telomere stability.},
}
@article {pmid16467854,
year = {2006},
author = {Berthiau, AS and Yankulov, K and Bah, A and Revardel, E and Luciano, P and Wellinger, RJ and Géli, V and Gilson, E},
title = {Subtelomeric proteins negatively regulate telomere elongation in budding yeast.},
journal = {The EMBO journal},
volume = {25},
number = {4},
pages = {846-856},
pmid = {16467854},
issn = {0261-4189},
mesh = {Chromatin/metabolism ; Chromosomes, Fungal/*metabolism ; DNA-Binding Proteins/*metabolism ; Fungal Proteins/*metabolism ; Humans ; Intracellular Signaling Peptides and Proteins ; Protein Serine-Threonine Kinases ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomere/*metabolism ; Transcription Factors ; },
abstract = {The Tbf1 and Reb1 proteins are present in yeast subtelomeric regions. We establish in this work that they inhibit telomerase-dependent lengthening of telomere. For example, tethering the N-terminal domain of Tbf1 and Reb1 in a subtelomeric region shortens that telomere proportionally to the number of domains bound. We further identified a 90 amino-acid long sequence within the N-terminal domain of Tbf1 that is necessary but not sufficient for its length regulation properties. The role of the subtelomeric factors in telomere length regulation is antagonized by TEL1 and does not correlate with a global telomere derepression. We show that the absence of TEL1 induces an alteration in the structure of telomeric chromatin, as defined biochemically by an increased susceptibility to nucleases and a greater heterogeneity of products. We propose that the absence of TEL1 modifies the organization of the telomeres, which allows Tbf1 and Reb1 to cis-inhibit telomerase. The involvement of subtelomeric factors in telomere length regulation provides a possible mechanism for the chromosome-specific length setting observed at yeast and human telomeres.},
}
@article {pmid16467853,
year = {2006},
author = {Hediger, F and Berthiau, AS and van Houwe, G and Gilson, E and Gasser, SM},
title = {Subtelomeric factors antagonize telomere anchoring and Tel1-independent telomere length regulation.},
journal = {The EMBO journal},
volume = {25},
number = {4},
pages = {857-867},
pmid = {16467853},
issn = {0261-4189},
mesh = {Chromosomes, Fungal/genetics/*metabolism ; DNA-Binding Proteins/genetics/metabolism ; Dinucleotide Repeats/physiology ; Fungal Proteins/genetics/*metabolism ; Herpes Simplex Virus Protein Vmw65/genetics/metabolism ; Intracellular Signaling Peptides and Proteins ; Nuclear Envelope/genetics/*metabolism ; Protein Serine-Threonine Kinases ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Yeast telomeres are anchored at the nuclear envelope (NE) through redundant pathways that require the telomere-binding factors yKu and Sir4. Significant variation is observed in the efficiency with which different telomeres are anchored, however, suggesting that other forces influence this interaction. Here, we show that subtelomeric elements and the insulator factors that bind them antagonize the association of telomeres with the NE. This is detectable when the redundancy in anchoring pathways is compromised. Remarkably, these same conditions lead to a reduction in steady-state telomere length in the absence of the ATM-kinase homologue Tel1. Both the delocalization of telomeres and reduction in telomere length can be induced by targeting of Tbf1 or Reb1, or the viral transactivator VP16, to a site 23 kb away from the TG repeat. This correlation suggests that telomere anchoring and a Tel1-independent pathway of telomere length regulation are linked, lending a functional significance to the association of yeast telomeres with the NE.},
}
@article {pmid16467146,
year = {2006},
author = {Feldser, D and Strong, MA and Greider, CW},
title = {Ataxia telangiectasia mutated (Atm) is not required for telomerase-mediated elongation of short telomeres.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {103},
number = {7},
pages = {2249-2251},
pmid = {16467146},
issn = {0027-8424},
support = {P01 CA016519/CA/NCI NIH HHS/United States ; P01 CA16519/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/*physiology ; DNA-Binding Proteins/genetics/*physiology ; Mice ; Mice, Mutant Strains ; Mutation ; Protein Serine-Threonine Kinases/genetics/*physiology ; Telomerase/*metabolism ; Telomere/*metabolism ; Tumor Suppressor Proteins/genetics/*physiology ; },
abstract = {Telomerase-mediated telomere addition counteracts telomere shortening due to incomplete DNA replication. Short telomeres are the preferred substrate for telomere addition by telomerase; however, the mechanism by which telomerase recognizes short telomeres is unclear. In yeast, the Ataxia telangiectasia mutated (Atm) homolog, Tel1, is necessary for normal telomere length regulation likely by altering telomere structure, allowing telomerase recruitment to short telomeres. To examine the role of Atm in establishing preference for elongation of short telomeres in mice, we examined telomerase-mediated elongation of short dysfunctional telomeres in the presence or absence of Atm. Here we show that Atm is dispensable for elongation of short telomeres by telomerase, suggesting that telomerase recruitment in mammalian cells and in yeast may be regulated differently.},
}
@article {pmid16457208,
year = {2006},
author = {Matsuura, A},
title = {[Mechanism of telomere replication and its relevance to the DNA double-strand break repair].},
journal = {Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme},
volume = {51},
number = {2},
pages = {162-168},
pmid = {16457208},
issn = {0039-9450},
mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/physiology ; Chromatin Immunoprecipitation ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes, Human/genetics/metabolism ; DNA/*genetics ; DNA Damage/*genetics ; DNA Repair/*genetics ; DNA Replication/*genetics ; DNA, Fungal/genetics ; DNA-Binding Proteins/physiology ; Humans ; Intracellular Signaling Peptides and Proteins ; Protein Serine-Threonine Kinases/physiology ; S Phase ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins ; Signal Transduction/genetics/physiology ; Telomerase/physiology ; Telomere/*genetics ; Tumor Suppressor Proteins/physiology ; },
}
@article {pmid16455497,
year = {2006},
author = {Chai, W and Du, Q and Shay, JW and Wright, WE},
title = {Human telomeres have different overhang sizes at leading versus lagging strands.},
journal = {Molecular cell},
volume = {21},
number = {3},
pages = {427-435},
doi = {10.1016/j.molcel.2005.12.004},
pmid = {16455497},
issn = {1097-2765},
support = {AG01228/AG/NIA NIH HHS/United States ; },
mesh = {Cell Line ; *DNA Replication ; Humans ; Telomerase/metabolism ; Telomere/*chemistry/metabolism ; },
abstract = {G-rich 3' telomeric overhangs are required both for forming the distinct telomere structures to protect chromosome ends and for extending telomeres by telomerase. However, little is known about the molecular mechanisms generating telomere overhangs in human cells. We show here that cultured normal human diploid cells have longer G overhangs at telomeres generated by lagging-strand synthesis than by leading-strand synthesis. We also demonstrate that telomerase expression results in elongated overhangs at the leading daughter telomeres. Thus, the overhangs at the leading and lagging daughter telomeres are generated differently in human cells, and telomerase may preferentially affect overhangs generated at the telomeres produced by leading-strand synthesis.},
}
@article {pmid16452506,
year = {2006},
author = {Savitsky, M and Kwon, D and Georgiev, P and Kalmykova, A and Gvozdev, V},
title = {Telomere elongation is under the control of the RNAi-based mechanism in the Drosophila germline.},
journal = {Genes &amp; development},
volume = {20},
number = {3},
pages = {345-354},
pmid = {16452506},
issn = {0890-9369},
mesh = {Adenosine Triphosphatases/genetics/metabolism ; Animals ; DNA Transposable Elements ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/*genetics/physiology ; Female ; Gene Silencing ; Heterozygote ; Homozygote ; Mutation ; Ovary/cytology/metabolism ; Peptide Initiation Factors/genetics/metabolism ; RNA Interference/*physiology ; Retroelements/genetics ; Telomere/genetics/*physiology ; },
abstract = {Telomeres in Drosophila are maintained by transposition of specialized telomeric retroelements HeT-A, TAHRE, and TART instead of the short DNA repeats generated by telomerase in other eukaryotes. Here we implicate the RNA interference machinery in the control of Drosophila telomere length in ovaries. The abundance of telomeric retroelement transcripts is up-regulated owing to mutations in the spn-E and aub genes, encoding a putative RNA helicase and protein of the Argonaute family, respectively, which are related to the RNA interference (RNAi) machinery. These mutations cause an increase in the frequency of telomeric element retrotransposition to a broken chromosome end. spn-E mutations eliminate HeT-A and TART short RNAs in ovaries, suggesting an RNAi-based mechanism in the control of telomere maintenance in the Drosophila germline. Enhanced frequency of TART, but not HeT-A, attachments in individuals carrying one dose of mutant spn-E or aub alleles suggests that TART is a primary target of the RNAi machinery. At the same time, we detected enhanced HeT-A attachments to broken chromosome ends in oocytes from homozygous spn-E mutants. Double-stranded RNA (dsRNA)-mediated control of telomeric retroelement transposition may occur at premeiotic stages, resulting in the maintenance of appropriate telomere length in gamete precursors.},
}
@article {pmid16450377,
year = {2006},
author = {Heaphy, CM and Bisoffi, M and Fordyce, CA and Haaland, CM and Hines, WC and Joste, NE and Griffith, JK},
title = {Telomere DNA content and allelic imbalance demonstrate field cancerization in histologically normal tissue adjacent to breast tumors.},
journal = {International journal of cancer},
volume = {119},
number = {1},
pages = {108-116},
doi = {10.1002/ijc.21815},
pmid = {16450377},
issn = {0020-7136},
support = {R25 GM60201/GM/NIGMS NIH HHS/United States ; T34 GM08751/GM/NIGMS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; *Allelic Imbalance ; Breast/*chemistry/pathology ; Breast Neoplasms/chemistry/*genetics/pathology ; Cell Transformation, Neoplastic/*genetics ; DNA, Neoplasm/*analysis ; Female ; Genomic Instability ; Humans ; Male ; Middle Aged ; Precancerous Conditions/*genetics ; Telomere/*genetics ; },
abstract = {Cancer arises from an accumulation of mutations that promote the selection of cells with progressively malignant phenotypes. Previous studies have shown that genomic instability, a hallmark of cancer cells, is a driving force in this process. In the present study, two markers of genomic instability, telomere DNA content and allelic imbalance, were examined in two independent cohorts of mammary carcinomas. Altered telomeres and unbalanced allelic loci were present in both tumors and surrounding histologically normal tissues at distances at least 1 cm from the visible tumor margins. Although the extent of these genetic changes decreases as a function of the distance from the visible tumor margin, unbalanced loci are conserved between the surrounding tissues and the tumors, implying cellular clonal evolution. Our results are in agreement with the concepts of "field cancerization" and "cancer field effect," concepts that were previously introduced to describe areas within tissues consisting of histologically normal, yet genetically aberrant, cells that represent fertile grounds for tumorigenesis. The finding that genomic instability occurs in fields of histologically normal tissues surrounding the tumor is of clinical importance, as it has implications for the definition of appropriate tumor margins and the assessment of recurrence risk factors in the context of breast-sparing surgery.},
}
@article {pmid16449656,
year = {2006},
author = {Compton, SA and Elmore, LW and Haydu, K and Jackson-Cook, CK and Holt, SE},
title = {Induction of nitric oxide synthase-dependent telomere shortening after functional inhibition of Hsp90 in human tumor cells.},
journal = {Molecular and cellular biology},
volume = {26},
number = {4},
pages = {1452-1462},
pmid = {16449656},
issn = {0270-7306},
support = {R01 ES012074/ES/NIEHS NIH HHS/United States ; R01 ES12074/ES/NIEHS NIH HHS/United States ; },
mesh = {Base Sequence ; Cell Line, Tumor ; Chromosome Aberrations ; DNA/genetics ; DNA Damage ; Dimethyl Sulfoxide/pharmacology ; Enzyme Inhibitors/pharmacology ; Free Radicals/metabolism ; HSP90 Heat-Shock Proteins/*antagonists &amp; inhibitors/genetics/metabolism ; Humans ; Lactones/pharmacology ; Macrolides ; Models, Biological ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide Synthase/antagonists &amp; inhibitors/*metabolism ; RNA, Small Interfering/genetics ; Telomere/drug effects/genetics/*metabolism ; },
abstract = {In most cancer cells, the lengths of telomeres, the functional DNA-protein complexes located at chromosome ends, are maintained by the ribonucleoprotein telomerase. Hsp90 facilitates the assembly of telomerase and remains associated with the functional complex, implying a direct involvement of Hsp90 in telomere length regulation. In an effort to elucidate the effects of Hsp90 inhibition on function and viability of human prostate cancer cells, both pharmacological (radicicol) and genetic (small interfering RNA) approaches were utilized to target Hsp90. Depletion of functional Hsp90 caused dramatic telomere shortening followed by apoptosis. Of particular significance, these cells exhibit a high level of nitric oxide synthase (NOS)-dependent free radical production, and simultaneous treatment of cells with the NOS inhibitor L-NAME resulted in telomere elongation and prevention of apoptosis. In addition, we observe significant DNA damage assessed by telomere dysfunction, although in the absence of a classical DNA damage response. Overall, our data suggest a novel mechanism whereby inhibition of Hsp90 disrupts free radical homeostasis and contributes directly to telomere erosion, further implicating Hsp90 as a potential therapeutic target for cancer cells.},
}
@article {pmid16443874,
year = {2006},
author = {Sampson, MJ and Winterbone, MS and Hughes, JC and Dozio, N and Hughes, DA},
title = {Monocyte telomere shortening and oxidative DNA damage in type 2 diabetes.},
journal = {Diabetes care},
volume = {29},
number = {2},
pages = {283-289},
doi = {10.2337/diacare.29.02.06.dc05-1715},
pmid = {16443874},
issn = {0149-5992},
mesh = {Case-Control Studies ; Cell Division ; DNA Damage/*physiology ; DNA Replication ; Diabetes Mellitus, Type 2/*genetics/therapy ; Glycated Hemoglobin ; Humans ; Hypoglycemic Agents/therapeutic use ; In Situ Hybridization, Fluorescence ; Insulin Resistance/genetics ; Male ; Middle Aged ; *Monocytes ; Oxidative Stress/*genetics ; *Telomere ; },
abstract = {OBJECTIVE: Telomeres are DNA sequences necessary for DNA replication, which shorten at cell division at a rate related to levels of oxidative stress. Once shortened to a critical length, cells are triggered into replicative senescence. Type 2 diabetes is associated with oxidative DNA damage, and we hypothesized that telomere shortening would characterize type 2 diabetes.<br><br>RESEARCH DESIGN AND METHODS: We studied 21 male type 2 diabetic subjects (mean age 61.2 years, mean HbA(1c) 7.9%) selected to limit confounding effects on telomere length and 29 matched control subjects. Telomere length was measured in peripheral venous monocyte and T-cells (na&#xef;ve and memory) by fluorescent in situ hybridization and oxidative DNA damage by flow cytometry of oxidized DNA bases. Peripheral insulin resistance (homeostasis model assessment) and high-sensitivity C-reactive protein (hsCRP) were measured.<br><br>RESULTS: Mean monocyte telomere length in the diabetic group was highly significantly lower than in control subjects (4.0 [1.1] vs. 5.5 [1.1]; P < 0.0001), without significant differences in lymphocyte telomere length. There was a trend toward increased oxidative DNA damage in all diabetes cell types examined and a significant inverse relationship between oxidative DNA damage and telomere length (r = -0.55; P = 0.018) in the diabetic group. Telomere length was unrelated to plasma CRP concentration or insulin resistance.<br><br>CONCLUSIONS: Monocyte telomere shortening in type 2 diabetes could be due to increased oxidative DNA damage to monocyte precursors during cell division. This data suggests that monocytes adhering to vascular endothelium and entering the vessel wall in type 2 diabetes are from a population with shorter telomeres and at increased risk of replicative senescence within vascular plaque.},
}
@article {pmid16440201,
year = {2006},
author = {Graakjaer, J and Der-Sarkissian, H and Schmitz, A and Bayer, J and Thomas, G and Kolvraa, S and Londoño-Vallejo, JA},
title = {Allele-specific relative telomere lengths are inherited.},
journal = {Human genetics},
volume = {119},
number = {3},
pages = {344-350},
pmid = {16440201},
issn = {0340-6717},
mesh = {*Alleles ; Analysis of Variance ; Child ; Chromosomal Instability ; Chromosome Segregation ; Chromosomes, Human/chemistry ; Family ; Genetic Markers ; Humans ; Inheritance Patterns ; Models, Biological ; Parents ; Peptide Nucleic Acids/analysis ; Recombination, Genetic ; Telomerase/metabolism ; Telomere/*genetics ; },
abstract = {Previous studies have indicated that single relative telomere lengths are defined in the zygote. In order to explore the possibility that single telomere lengths segregate in families, we compared relative telomere lengths obtained from allelic chromosome extremities transmitted from parent to child, representing a total of 31 independent meiotic events. We find a significant positive correlation of 0.65 (P=0.0004) between these telomere lengths, whereas the correlation between the non-transmitted parental homologue and the transmitted homologue in the child is not statistically significant (r=0.16; P=0.195). This study indicates that, even though there is a telomerase-mediated maintenance/elongation of telomeres in germ cells, allele-specific relative telomere lengths are preserved in the next generation.},
}
@article {pmid16437597,
year = {2005},
author = {Hsu, CP and Lee, LW and Shai, SE and Chen, CY},
title = {Clinical significance of telomerase and its associate genes expression in the maintenance of telomere length in squamous cell carcinoma of the esophagus.},
journal = {World journal of gastroenterology},
volume = {11},
number = {44},
pages = {6941-6947},
pmid = {16437597},
issn = {1007-9327},
mesh = {Adult ; Aged ; *Carcinoma, Squamous Cell/enzymology/genetics/pathology ; *Esophageal Neoplasms/enzymology/genetics/pathology ; Female ; *Gene Expression ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Retrospective Studies ; Survival Rate ; *Telomerase/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {AIM: To observe the interaction between the expression of telomerase activity (TA) and its associate genes in regulation of the terminal restriction fragment length (TRFL) in esophageal squamous cell carcinoma (SCC).<br><br>METHODS: Seventy-four specimens of esophageal SCC were examined. The TA was measured by telomeric repeat amplification protocol (TRAP) assay, and the associated genes [human telomerase-specific reverse transcriptase (hTERT), hTERC, TP1, c-Myc, TRF1, and TRF2] were detected using RT-PCR method. The TRFL was measured by Telomere Length Assay Kit and Southern blotting. The correlations between the expression of telomerase and its associated genes with the TRFL and survivals were examined.<br><br>RESULTS: Expressions of the TA, hTERT, hTERC, TP1, c-Myc, TRF1, and TRF2 genes were observed in 85.1%, 64.9%, 79.7%, 100.0%, 94.6%, 82.4%, and 91.9% of the tumor tissues, respectively. The TRFL of the tumor and normal esophageal tissues were 2.70+/-1.42 and 4.93+/-1.74 kb, respectively (P<0.0001). The TRFL of the telomerase positive and telomerase negative tumor tissues were 2.72+/-1.44 and 2.58+/-1.32 kb, respectively (P = 0.767). The TRFL ratios (TRFLR) of the telomerase positive and telomerase negative tumor tissues were 0.55+/-0.22 and 0.59+/-0.41, respectively (P = 0.742). The expression rates of h-TERT (P = 0.0002), hTERC (P<0.0001), and TRF1 (P = 0.002) in the tumor tissues are higher than those of the normal paired tissues. Though TA is markedly activated in tumor tissues (P<0.0001), its expression is not related to clinicopathological parameters including gender, tumor differentiation, and TNM stages. The cumulative 4-year survival rates of telomerase positive and telomerase negative cases were 35.86% and 31.2%, respectively (P = 0.8442). The cumulative 4-year survival rates of patients with their TRFLR <or=85% and >85% were 38.7% and 15.7%, respectively (P = 0.1307).<br><br>CONCLUSION: Though telomerase expression is not related to tumor stages and prognosis, our data support that the TA increased as the TRFL decreased, probably under the control of hTERT, hTERC, and TRF1. When telomerase expression was activated, only TRF2 overexpression persisted to stabilize T-loop formation. Furthermore, as the TRFLR decreased to 85%, a trend of better prognosis was observed. Cox model analysis indicates a higher t/n TRFLR and distant metastasis are independent poorer prognostic factors (P = 0.035 and P = 0.042, respectively).},
}
@article {pmid16436511,
year = {2006},
author = {Hovest, MG and Brüggenolte, N and Hosseini, KS and Krieg, T and Herrmann, G},
title = {Senescence of human fibroblasts after psoralen photoactivation is mediated by ATR kinase and persistent DNA damage foci at telomeres.},
journal = {Molecular biology of the cell},
volume = {17},
number = {4},
pages = {1758-1767},
pmid = {16436511},
issn = {1059-1524},
mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/antagonists &amp; inhibitors/genetics/*physiology ; Cellular Senescence/genetics/*physiology ; Cross-Linking Reagents/*toxicity ; DNA/drug effects/radiation effects ; *DNA Damage ; Fibroblasts/drug effects/enzymology/radiation effects ; Histones/analysis/metabolism ; Humans ; Methoxsalen/*toxicity ; Phosphorylation ; Protein Serine-Threonine Kinases/antagonists &amp; inhibitors/genetics/*physiology ; RNA, Small Interfering/genetics/pharmacology ; Telomere/*drug effects/genetics/radiation effects ; Ultraviolet Rays ; },
abstract = {Cellular senescence is a phenotype that is likely linked with aging. Recent concepts view different forms of senescence as permanently maintained DNA damage responses partially characterized by the presence of senescence-associated DNA damage foci at dysfunctional telomeres. Irradiation of primary human dermal fibroblasts with the photosensitizer 8-methoxypsoralen and ultraviolet A radiation (PUVA) induces senescence. In the present study, we demonstrate that senescence after PUVA depends on DNA interstrand cross-link (ICL) formation that activates ATR kinase. ATR is necessary for the manifestation and maintenance of the senescent phenotype, because depletion of ATR expression before PUVA prevents induction of senescence, and reduction of ATR expression in PUVA-senesced fibroblasts releases cells from growth arrest. We find an ATR-dependent phosphorylation of the histone H2AX (gamma-H2AX). After PUVA, ATR and gamma-H2AX colocalize in multiple nuclear foci. After several days, only few predominantly telomere-localized foci persist and telomeric DNA can be coimmunoprecipitated with ATR from PUVA-senesced fibroblasts. We thus identify ATR as a novel mediator of telomere-dependent senescence in response to ICL induced by photoactivated psoralens.},
}
@article {pmid16436506,
year = {2006},
author = {Gomez, M and Wu, J and Schreiber, V and Dunlap, J and Dantzer, F and Wang, Y and Liu, Y},
title = {PARP1 Is a TRF2-associated poly(ADP-ribose)polymerase and protects eroded telomeres.},
journal = {Molecular biology of the cell},
volume = {17},
number = {4},
pages = {1686-1696},
pmid = {16436506},
issn = {1059-1524},
mesh = {Animals ; Cells, Cultured ; Chromosomes/metabolism ; DNA/metabolism ; DNA Damage ; Dimerization ; Embryo, Mammalian/cytology ; Fibroblasts/drug effects/enzymology ; Genomic Instability ; Humans ; Mice ; Mice, Mutant Strains ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases/analysis/genetics/*metabolism ; Protein Interaction Mapping ; Telomere/chemistry/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {Poly(ADP-ribose)polymerase 1 (PARP1) is well characterized for its role in base excision repair (BER), where it is activated by and binds to DNA breaks and catalyzes the poly(ADP-ribosyl)ation of several substrates involved in DNA damage repair. Here we demonstrate that PARP1 associates with telomere repeat binding factor 2 (TRF2) and is capable of poly(ADP-ribosyl)ation of TRF2, which affects binding of TRF2 to telomeric DNA. Immunostaining of interphase cells or metaphase spreads shows that PARP1 is detected sporadically at normal telomeres, but it appears preferentially at eroded telomeres caused by telomerase deficiency or damaged telomeres induced by DNA-damaging reagents. Although PARP1 is dispensable in the capping of normal telomeres, Parp1 deficiency leads to an increase in chromosome end-to-end fusions or chromosome ends without detectable telomeric DNA in primary murine cells after induction of DNA damage. Our results suggest that upon DNA damage, PARP1 is recruited to damaged telomeres, where it can help protect telomeres against chromosome end-to-end fusions and genomic instability.},
}
@article {pmid16435298,
year = {2006},
author = {Calado, RT and Chen, J},
title = {Telomerase: not just for the elongation of telomeres.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {28},
number = {2},
pages = {109-112},
doi = {10.1002/bies.20365},
pmid = {16435298},
issn = {0265-9247},
mesh = {Animals ; Blood Cells/enzymology/metabolism/pathology ; Humans ; Neoplasms/enzymology/genetics/pathology ; Stem Cells/cytology/enzymology/physiology ; Telomerase/*metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {Telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT) function together to elongate telomeres and to protect chromosomal ends. Recent studies have discovered that overexpression of telomerase's TERT subunit promoted epidermal stem-cell mobilization, hair growth and stem-cell proliferation without changes in length of telomeres.1,2 This telomerase functional characteristic is TERC independent and is operated through a mechanism other than telomere elongation. These findings open new doors for future explorations to understand telomerase function and its interaction with other cell components in the regulation of cell senescence and tumorigenesis.},
}
@article {pmid16435294,
year = {2006},
author = {Nosek, J and Kosa, P and Tomaska, L},
title = {On the origin of telomeres: a glimpse at the pre-telomerase world.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {28},
number = {2},
pages = {182-190},
doi = {10.1002/bies.20355},
pmid = {16435294},
issn = {0265-9247},
support = {1-R03-TW05654-01/TW/FIC NIH HHS/United States ; },
mesh = {Animals ; Biological Evolution ; DNA, Mitochondrial/genetics ; Humans ; *Models, Biological ; Models, Genetic ; Mutation/genetics ; Phylogeny ; Telomerase/*metabolism ; Telomere/chemistry/*genetics/*metabolism ; },
abstract = {Chromosomes may be either circular or linear, the latter being prone to erosion caused by incomplete replication, degradation and inappropriate repair. Despite these problems, the linear form of DNA is frequently found in viruses, bacteria, eukaryotic nuclei and organelles. The high incidence of linear chromosomes and/or genomes evokes why and how they emerged in evolution. Here we suggest that the primordial terminal structures (telomeres) of linear chromosomes in eukaryotic nuclei were derived from selfish element(s), which caused the linearization of ancestral circular genome. The telomeres were then essential in solving the emerged problems. Molecular fossils of such elements were recently identified in phylogenetically distant genomes and were shown to generate terminal arrays of tandem repeats. These arrays might mediate the formation of higher order structures at chromosomal termini that stabilize the linear chromosomal form by fulfilling essential telomeric functions.},
}
@article {pmid16428246,
year = {2006},
author = {Azam, M and Lee, JY and Abraham, V and Chanoux, R and Schoenly, KA and Johnson, FB},
title = {Evidence that the S.cerevisiae Sgs1 protein facilitates recombinational repair of telomeres during senescence.},
journal = {Nucleic acids research},
volume = {34},
number = {2},
pages = {506-516},
pmid = {16428246},
issn = {1362-4962},
support = {F32 AG022769/AG/NIA NIH HHS/United States ; R01 AG021521/AG/NIA NIH HHS/United States ; 5R01AG021521/AG/NIA NIH HHS/United States ; F32AG22769/AG/NIA NIH HHS/United States ; },
mesh = {Cellular Senescence ; DNA Helicases/chemistry/genetics/*physiology ; *DNA Repair ; Mutation ; Protein Structure, Tertiary ; Rad52 DNA Repair and Recombination Protein/genetics ; RecQ Helicases ; *Recombination, Genetic ; S Phase ; Saccharomyces cerevisiae/*enzymology/*genetics ; Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism/*physiology ; Telomere/*metabolism ; },
abstract = {RecQ DNA helicases, including yeast Sgs1p and the human Werner and Bloom syndrome proteins, participate in telomere biology, but the underlying mechanisms are not fully understood. Here, we explore the protein sequences and genetic interactors of Sgs1p that function to slow the senescence of telomerase (tlc1) mutants. We find that the S-phase checkpoint function of Sgs1p is dispensable for preventing rapid senescence, but that Sgs1p sequences required for homologous recombination, including the helicase domain and topoisomerase III interaction domain, are essential. sgs1 and rad52 mutations are epistatic during senescence, indicating that Sgs1p participates in a RAD52-dependent recombinational pathway of telomere maintenance. Several mutations that are synthetically lethal with sgs1 mutation and which individually lead to genome instability, including mus81, srs2, rrm3, slx1 and top1, do not speed the senescence of tlc1 mutants, indicating that the rapid senescence of sgs1 tlc1 mutants is not caused by generic genome instability. However, mutations in SLX5 or SLX8, which encode proteins that function together in a complex that is required for viability in sgs1 mutants, do speed the senescence of tlc1 mutants. These observations further define roles for RecQ helicases and related proteins in telomere maintenance.},
}
@article {pmid16427234,
year = {2006},
author = {Goronzy, JJ and Fujii, H and Weyand, CM},
title = {Telomeres, immune aging and autoimmunity.},
journal = {Experimental gerontology},
volume = {41},
number = {3},
pages = {246-251},
doi = {10.1016/j.exger.2005.12.002},
pmid = {16427234},
issn = {0531-5565},
support = {R01AG15043/AG/NIA NIH HHS/United States ; R01AI57266/AI/NIAID NIH HHS/United States ; R01AR 42527/AR/NIAMS NIH HHS/United States ; R01AR41974/AR/NIAMS NIH HHS/United States ; },
mesh = {Aging/genetics/*immunology ; Animals ; Autoimmunity/genetics/*immunology ; B-Lymphocytes/immunology ; Cell Division/genetics/immunology ; DNA Damage/genetics/immunology ; Humans ; Mice ; Models, Genetic ; Neoplasms/genetics/immunology ; T-Lymphocytes/immunology ; Telomere/genetics/*immunology ; },
abstract = {Telomere length is important in constraining the replicative potential of cells; cellular systems that are dependent on cell replenishment for renewal or on cell proliferation for functionality are highly sensitive to telomeric erosion. Cell replication invariably leads to telomere loss, which, in some cellular systems, is partially compensated for by telomerase activity. In addition to this typical telomere loss, several mechanisms of sporadic telomere loss exist. Heterogeneity in age-dependent telomere loss can be a consequence of increased cellular turnover during a lifetime, accelerated telomeric DNA damage, or defects in telomere repair. The immune system is a prime example of a highly dynamic cellular system, for which telomere maintenance is pivotal. Immune competence is strictly dependent on rapid expansions of clonal T- and B-cell populations, and telomere loss may contribute to defective immune responses in the elderly. Equally interestingly, accelerated T-cell aging combined with telomeric shortening may predispose for autoimmune responses and thereby explain the increased susceptibility for chronic inflammatory diseases in the elderly.},
}
@article {pmid16424902,
year = {2006},
author = {Cristofari, G and Lingner, J},
title = {Telomere length homeostasis requires that telomerase levels are limiting.},
journal = {The EMBO journal},
volume = {25},
number = {3},
pages = {565-574},
pmid = {16424902},
issn = {0261-4189},
mesh = {Cell Line ; Cell Line, Tumor ; Chromatin/metabolism ; DNA-Binding Proteins/*biosynthesis/genetics ; Enzyme Activation ; Homeostasis ; Humans ; Nuclear Proteins/metabolism ; Ribonuclease P/biosynthesis/genetics ; TATA Box Binding Protein-Like Proteins/metabolism ; Telomerase/biosynthesis/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2 ; },
abstract = {Stabilization of telomere length in germline and highly proliferative human cells is required for long-term survival and for the immortal phenotype of cancer-derived cells. This is achieved through expression of telomerase reverse transcriptase (TERT), which synthesizes telomeric repeats through reverse transcription of its tightly associated RNA template (TR). The telomeric repeat binding factor TRF1 inhibits telomerase at telomeres in cis in a length-dependent manner to achieve telomere length homeostasis. Here we manipulate telomerase activity over a wide range in cancer and primary cells. Concomitant overexpression of TERT and TR was necessary and sufficient to substantially increase telomerase activity. Upon overexpression, more telomerase associated with telomeres and telomeres elongated at a constant rate (up to 0.8 kb/population doubling (PD)) in a length-independent manner. Thus, in less than 50 PDs, the length of telomeres increased 3-8-fold beyond physiological size, while telomere-bound TRF1 and TRF2 increased proportionally to telomere length. Thus, long telomeres do not permanently adopt a structural state that is non-extendible. A low cellular concentration of telomerase is critical to achieve preferential elongation of short telomeres and telomere length homeostasis.},
}
@article {pmid16424898,
year = {2006},
author = {Nishiyama, A and Muraki, K and Saito, M and Ohsumi, K and Kishimoto, T and Ishikawa, F},
title = {Cell-cycle-dependent Xenopus TRF1 recruitment to telomere chromatin regulated by Polo-like kinase.},
journal = {The EMBO journal},
volume = {25},
number = {3},
pages = {575-584},
pmid = {16424898},
issn = {0261-4189},
mesh = {Animals ; CDC2 Protein Kinase/metabolism ; *Cell Cycle ; Cell Cycle Proteins/*metabolism ; Chromatin/*metabolism ; In Vitro Techniques ; Mitosis ; Ovum/metabolism ; Phosphorylation ; Protein Binding ; Protein Serine-Threonine Kinases/*metabolism ; Protein Structure, Tertiary ; Proto-Oncogene Proteins/*metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; Xenopus Proteins/*metabolism ; Xenopus laevis ; Polo-Like Kinase 1 ; },
abstract = {Telomeres are regulated by a homeostatic mechanism that includes telomerase and telomeric repeat binding proteins, TRF1 and TRF2. Recently, it has been hypothesized that telomeres assume distinct configurations in a cell-cycle-dependent manner, although direct biochemical evidence is lacking. Here we demonstrated that Xenopus TRF1 (xTRF1) associates with telomere chromatin specifically in mitotic Xenopus egg extracts, and dissociates from it upon mitotic exit. Both the N-terminal TRF-homology (TRFH) domain and the linker region connecting the TRFH domain and the C-terminal Myb domain are required for this cell-cycle-dependent association of xTRF1 with chromatin. In contrast, Xenopus TRF2 (xTRF2) associates with chromatin throughout the cell cycle. We showed that Polo-like kinase (Plx1) phosphorylates xTRF1 in vitro. Moreover, the mitotic xTRF1-chromatin association was significantly impaired when Plx1 was immunodepleted from the extracts. Finally, high telomerase activities were detected in association with replicating interphase chromatin compared with mitotic chromatin. These results indicate that telomere chromatin is actively regulated by cell-cycle-dependent processes, and provide an insight for understanding how telomeres undergo DNA metabolisms during the cell cycle.},
}
@article {pmid16424294,
year = {2005},
author = {Benetos, A and Gardner, JP and Kimura, M and Labat, C and Nzietchueng, R and Dousset, B and Zannad, F and Lacolley, P and Aviv, A},
title = {Aldosterone and telomere length in white blood cells.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {60},
number = {12},
pages = {1593-1596},
doi = {10.1093/gerona/60.12.1593},
pmid = {16424294},
issn = {1079-5006},
support = {AG021593/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aldosterone/*blood ; Humans ; *Leukocytes ; Male ; Middle Aged ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Aldosterone accelerates cardiovascular aging by mechanisms that generate reactive oxygen species. Telomere length in white blood cells (WBCs) may be a bioindicator that registers the accruing burden of systemic oxidative stress. The aim of the present study was, therefore, to examine the relationship between plasma aldosterone and telomere length in WBCs.<br><br>METHODS: We studied 75 normotensive and never-treated mildly hypertensive men whose blood was drawn for the measurements of plasma aldosterone concentration and the terminal restriction fragment (TRF) length in WBCs.<br><br>RESULTS: The slope of the TRF-age relationship in the entire cohort showed a decrease in telomere length of 26 +/- 5 base pairs per year (r = -0.46, p <.001). Age-adjusted TRF length was the longest in the lowest aldosterone quartile (6.74 +/- 0.12 kb) and shortest in the highest aldosterone quartile (6.36 +/- 0.11 kb), with intermediate TRF lengths in the second and third aldosterone quartiles (analysis of variance [ANOVA] trend test, p =.025). In telomeric attrition equivalence, participants in the upper aldosterone quartile were 15 years older than their peers in the lowest quartile.<br><br>CONCLUSIONS: The inverse relationship between aldosterone and WBC telomere length suggests not only that aldosterone is pro-oxidant but that elevated concentrations of this hormone might be linked to a higher rate of telomere attrition and perhaps increased biological aging in humans.},
}
@article {pmid16421168,
year = {2006},
author = {Britt-Compton, B and Rowson, J and Locke, M and Mackenzie, I and Kipling, D and Baird, DM},
title = {Structural stability and chromosome-specific telomere length is governed by cis-acting determinants in humans.},
journal = {Human molecular genetics},
volume = {15},
number = {5},
pages = {725-733},
doi = {10.1093/hmg/ddi486},
pmid = {16421168},
issn = {0964-6906},
mesh = {Alleles ; Cell Line, Tumor ; Cells, Cultured ; Cellular Senescence ; Chromosomes, Human/*genetics ; Clone Cells ; DNA Primers ; Fibroblasts/cytology/metabolism ; Genetic Variation ; Genome, Human ; Humans ; Polymorphism, Genetic ; Telomerase/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Single telomere length analysis (STELA) of the XpYp telomere has revealed extensive allelic variation and ultra-short telomeres in senescent cells. Superimposed on end-replication losses are additional mutational events that result in large-scale changes in telomere length. In order to establish if the dynamics of the XpYp telomere are typical of human telomeres, here we describe an analysis using STELA of the telomeres of 2p, 11q, 12q, 17p and XpYp. The dynamics of telomere loss (erosion rates and stochastic length changes) was conserved among 2p, 11q, 12q and XpYp within the same cell strains and was dependent on the replicative kinetics of the cells in culture. However, of the telomeres analysed, the telomere of 17p was more stable with a striking paucity of large-scale length changes, and exhibited the shortest recorded allelic distribution (300 bp) in senescent cells and displayed a general, but not absolute, trend towards being the shortest telomere. Ectopic over-expression of hTERT homogenized both allelic and chromosome-specific telomeric distributions. However, telomerase-expressing cancer cells displayed both allelic variation and chromosome-specific telomere length, with 17p displaying the shortest allelic telomere length. Although other telomeres in the genome may share the properties of 17p, these data suggest that physiological levels of telomerase allow differential telomere length regulation and indicate the presence of cis-acting factors that govern both telomeric stability and chromosome-specific telomere length in the presence of telomerase.},
}
@article {pmid16420506,
year = {2006},
author = {Nakajima, T and Moriguchi, M and Katagishi, T and Sekoguchi, S and Nishikawa, T and Takashima, H and Kimura, H and Minami, M and Itoh, Y and Kagawa, K and Tani, Y and Okanoue, T},
title = {Premature telomere shortening and impaired regenerative response in hepatocytes of individuals with NAFLD.},
journal = {Liver international : official journal of the International Association for the Study of the Liver},
volume = {26},
number = {1},
pages = {23-31},
doi = {10.1111/j.1478-3231.2005.01178.x},
pmid = {16420506},
issn = {1478-3223},
mesh = {Adult ; Aged ; Biopsy, Needle ; Case-Control Studies ; Cells, Cultured ; *Chromosomal Instability ; Disease Progression ; Fatty Liver/*genetics/pathology ; Female ; Hepatocytes/*physiology ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Insulin Resistance ; Liver Cirrhosis/genetics/pathology ; Liver Regeneration/*genetics ; Male ; Microscopy, Fluorescence ; Middle Aged ; Probability ; Prognosis ; Reference Values ; Risk Factors ; Sensitivity and Specificity ; Statistics, Nonparametric ; Telomere/*genetics ; },
abstract = {AIMS: The risk factors associated with poor prognosis of nonalcoholic fatty liver disease (NAFLD) are not fully understood. Our aim was to assess the role of progressive hepatocellular telomere shortening in the clinical course of NAFLD.<br><br>METHODS: We measured average telomere lengths in liver tissue samples from 44 patients with NAFLD by quantitative fluorescence in situ hybridization using a telomere-specific probe. Patients in which telomeres measured at least 80% of the lengths of age-matched controls were categorized as group A. Those patients with telomeres measuring less than 80% of the control lengths formed group B.<br><br>RESULTS: Within group B, some samples showed a remarkable shortening of hepatocyte telomeres in younger patients, whereas some group A patients showed almost normal telomere lengths until their seventies. Among clinicopathological factors, body mass index (BMI), homeostasis model assessment insulin resistance (HOMA-IR), histological degree of steatosis and intensity of 8-hydroxy-2'-deoxyguanosine (8-OHdG) immunostaining were all significantly higher in group B than in group A. Ki-67 immunohistochemistry demonstrated that group B liver tissues were significantly less proliferative than those from group A, despite no significant difference in the necroinflammatory activities of group A and B samples. In group B patients, the ratios of Ki-67 positive index to alanine aminotransferase value were significantly lower than group A.<br><br>CONCLUSIONS: Greater insulin resistance can result in more severe hepatic steatosis among group B patients, leading to an overproduction of reactive oxygen species, which may accelerate telomere erosion. Furthermore the regenerative response of hepatocytes with prominent telomere shortening may be impaired, making these cells vulnerable to the effect of a 'second-hit' insult.},
}
@article {pmid16420044,
year = {2006},
author = {Moore, MJ and Schultes, CM and Cuesta, J and Cuenca, F and Gunaratnam, M and Tanious, FA and Wilson, WD and Neidle, S},
title = {Trisubstituted acridines as G-quadruplex telomere targeting agents. Effects of extensions of the 3,6- and 9-side chains on quadruplex binding, telomerase activity, and cell proliferation.},
journal = {Journal of medicinal chemistry},
volume = {49},
number = {2},
pages = {582-599},
doi = {10.1021/jm050555a},
pmid = {16420044},
issn = {0022-2623},
support = {GM61587/GM/NIGMS NIH HHS/United States ; },
mesh = {Acridines/*chemical synthesis/chemistry/pharmacology ; Antineoplastic Agents/*chemical synthesis/chemistry/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA/*metabolism ; Drug Screening Assays, Antitumor ; Fluorescence Resonance Energy Transfer ; G-Quadruplexes ; Humans ; Ligands ; Models, Molecular ; Quantitative Structure-Activity Relationship ; Quantum Theory ; Surface Plasmon Resonance ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/*drug effects/enzymology ; },
abstract = {The synthesis is reported of a group of 3,6,9-trisubstituted acridine compounds as telomeric quadruplex-stabilizing ligands with systematic variations at the 3-, 6-, and 9-positions. A new microwave-assisted methodology has been developed for trisubstituted acridine synthesis. Structure-activity relationships are reported using surface plasmon resonance and a fluorescence melting assay to examine quadruplex binding, together with a telomerase inhibition assay. These reveal relationships between G-quadruplex stabilization and telomerase inhibition and optimal 3,6- and 9-substituent side-chain lengths for maximal activity. Qualitative molecular modeling using molecular dynamics simulations has been undertaken on four quadruplex-DNA complexes. Long-term exposure of MCF7 cancer cells to a subset of the most active compounds, at doses lower than the IC(50) values, showed that one compound produced a marked decrease in population growth, accompanied by senescence, which is consistent with telomere targeting by this agent.},
}
@article {pmid16418532,
year = {2006},
author = {Therizols, P and Fairhead, C and Cabal, GG and Genovesio, A and Olivo-Marin, JC and Dujon, B and Fabre, E},
title = {Telomere tethering at the nuclear periphery is essential for efficient DNA double strand break repair in subtelomeric region.},
journal = {The Journal of cell biology},
volume = {172},
number = {2},
pages = {189-199},
pmid = {16418532},
issn = {0021-9525},
mesh = {Base Sequence ; Cell Nucleus/*metabolism ; Chromosomes, Fungal ; DNA/*metabolism ; DNA Damage ; *DNA Repair ; Gene Silencing ; Molecular Sequence Data ; Nuclear Pore/metabolism ; Nuclear Pore Complex Proteins/genetics/metabolism ; Nuclear Proteins/genetics/metabolism ; Saccharomyces cerevisiae/cytology/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {In the yeast Saccharomyces cerevisiae that lacks lamins, the nuclear pore complex (NPC) has been proposed to serve a role in chromatin organization. Here, using fluorescence microscopy in living cells, we show that nuclear pore proteins of the Nup84 core complex, Nup84p, Nup145Cp, Nup120p, and Nup133p, serve to anchor telomere XI-L at the nuclear periphery. The integrity of this complex is shown to be required for repression of a URA3 gene inserted in the subtelomeric region of this chromosome end. Furthermore, altering the integrity of this complex decreases the efficiency of repair of a DNA double-strand break (DSB) only when it is generated in the subtelomeric region, even though the repair machinery is functional. These effects are specific to the Nup84 complex. Our observations thus confirm and extend the role played by the NPC, through the Nup84 complex, in the functional organization of chromatin. They also indicate that anchoring of telomeres is essential for efficient repair of DSBs occurring therein and is important for preserving genome integrity.},
}
@article {pmid16418502,
year = {2006},
author = {Yang, CP and Chen, YB and Meng, FL and Zhou, JQ},
title = {Saccharomyces cerevisiae Est3p dimerizes in vitro and dimerization contributes to efficient telomere replication in vivo.},
journal = {Nucleic acids research},
volume = {34},
number = {2},
pages = {407-416},
pmid = {16418502},
issn = {1362-4962},
mesh = {DNA Replication ; Dimerization ; Mutation ; Protein Subunits/genetics/metabolism ; Recombinant Proteins/isolation &amp; purification/metabolism ; Saccharomyces cerevisiae/*enzymology/*genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {In Saccharomyces cerevisiae at least five genes, EST1, EST2, EST3, TLC1 and CDC13, are required for telomerase activity in vivo. The telomerase catalytic subunit Est2p and telomerase RNA subunit Tlc1 constitute the telomerase core enzyme. Est1p and Est3p are the other subunits of telomerase holoenzyme. In order to dissect the function of Est3p in telomere replication, we over-expressed and purified recombinant wild-type and mutant Est3 proteins. The wild-type protein, as well as the K71A, E104A and T115A mutants were able to dimerize in vitro, while the Est3p-D49A, -K68A or -D166A mutant showed reduced ability to dimerize. Mutations in Est3p that decreased dimerization also appeared to cause telomere shortening in vivo. Double point mutation of Est3p-D49A-K68A and single point mutation of Est3p-K68A showed similar telomere shortening, suggesting that the K68 residue might be more important for telomerase activity. The ectopic co-expression of K71A or T115A mutant with wild-type Est3p using centromere plasmids caused telomere shortening, while co-expression of the D49A, K68A, D86A or F103A mutants with wild-type Est3p had no effect on telomere length regulation. These data suggested that dimerization is important for Est3p function in vivo.},
}
@article {pmid16412982,
year = {2006},
author = {Matsubara, Y and Murata, M and Yoshida, T and Watanabe, K and Saito, I and Miyaki, K and Omae, K and Ikeda, Y},
title = {Telomere length of normal leukocytes is affected by a functional polymorphism of hTERT.},
journal = {Biochemical and biophysical research communications},
volume = {341},
number = {1},
pages = {128-131},
doi = {10.1016/j.bbrc.2005.12.163},
pmid = {16412982},
issn = {0006-291X},
mesh = {Base Sequence ; Cells, Cultured ; DNA-Binding Proteins/*genetics ; Endothelial Cells/*metabolism ; Genetic Variation/genetics ; Humans ; Leukocytes/*metabolism ; Molecular Sequence Data ; Polymorphism, Genetic ; Promoter Regions, Genetic/genetics ; Telomerase/*genetics ; Telomere/*genetics ; Transcription, Genetic/*genetics ; Transcriptional Activation/*genetics ; },
abstract = {Transcriptional regulation of human telomerase reverse transcriptase (hTERT), a catalytic subunit of telomerase, is essential for telomerase activity associated with telomere length. In this study, we investigated the effects of a (-1327)T/C polymorphism within the hTERT promoter region on the hTERT promoter activity and leukocyte telomere length in normal individuals. The promoter activity in the (-1327)T-sequence was significantly higher than that in the (-1327)C-sequence (p = 0.0004). For leukocyte telomere length, the (-1327)T-allele carriers had significantly longer than the (-1327)T-allele non-carriers (p = 0.0007). Also, there was no age-related shortening in leukocyte telomere length in the (-1327)T/T (p = 0.6633) and (-1327)T/C subjects (p = 0.1691), whereas there was clear age-related telomere shortening in the (-1327)C/C subjects (p = 0.0117). These findings suggest that the functional (-1327)T/C polymorphism of hTERT is associated with leukocyte telomere length in normal individuals.},
}
@article {pmid16412254,
year = {2006},
author = {Lobo, NF and Behura, SK and Aggarwal, R and Chen, MS and Collins, FH and Stuart, JJ},
title = {Genomic analysis of a 1 Mb region near the telomere of Hessian fly chromosome X2 and avirulence gene vH13.},
journal = {BMC genomics},
volume = {7},
number = {},
pages = {7},
pmid = {16412254},
issn = {1471-2164},
mesh = {Animals ; *Chromosome Mapping ; Diptera/*genetics/pathogenicity ; Female ; *Genome, Insect ; In Situ Hybridization, Fluorescence ; Male ; Plant Diseases/genetics/parasitology ; Telomere/*genetics ; Triticum/parasitology ; X Chromosome ; },
abstract = {BACKGROUND: To have an insight into the Mayetiola destructor (Hessian fly) genome, we performed an in silico comparative genomic analysis utilizing genetic mapping, genomic sequence and EST sequence data along with data available from public databases.<br><br>RESULTS: Chromosome walking and FISH were utilized to identify a contig of 50 BAC clones near the telomere of the short arm of Hessian fly chromosome X2 and near the avirulence gene vH13. These clones enabled us to correlate physical and genetic distance in this region of the Hessian fly genome. Sequence data from these BAC ends encompassing a 760 kb region, and a fully sequenced and assembled 42.6 kb BAC clone, was utilized to perform a comparative genomic study. In silico gene prediction combined with BLAST analyses was used to determine putative orthology to the sequenced dipteran genomes of the fruit fly, Drosophila melanogaster, and the malaria mosquito, Anopheles gambiae, and to infer evolutionary relationships.<br><br>CONCLUSION: This initial effort enables us to advance our understanding of the structure, composition and evolution of the genome of this important agricultural pest and is an invaluable tool for a whole genome sequencing effort.},
}
@article {pmid16407328,
year = {2006},
author = {Cheung, I and Schertzer, M and Rose, A and Lansdorp, PM},
title = {High incidence of rapid telomere loss in telomerase-deficient Caenorhabditis elegans.},
journal = {Nucleic acids research},
volume = {34},
number = {1},
pages = {96-103},
pmid = {16407328},
issn = {1362-4962},
mesh = {Animals ; Caenorhabditis elegans/*enzymology/*genetics ; DNA Repair ; DNA-Binding Proteins/genetics/*physiology ; Gene Deletion ; Kinetics ; Telomerase/genetics/*physiology ; Telomere/*metabolism ; },
abstract = {Telomerase is essential to maintain telomere length in most eukaryotes. Other functions for telomerase have been proposed but molecular mechanisms remain unclear. We studied Caenorhabditis elegans with a mutation in the trt-1 telomerase reverse transcriptase gene. Mutant animals showed a progressive decrease in brood size and typically failed to reproduce after five generations. Using PCR analysis to measure the length of individual telomere repeat tracks on the left arm of chromosome V we observed that trt-1 mutants lost approximately 125bp of telomeric DNA per generation. Chromosome fusions involving complex recombination reactions were observed in late generations. Strikingly, trt-1 mutant animals displayed a high frequency of telomeres with many fewer repeats than average. Such outlying short telomeres were not observed in mrt-2 mutants displaying progressive telomere loss very similar to trt-1 mutants. We speculate that, apart from maintaining the average telomere length, telomerase is required to prevent or repair sporadic telomere truncations that are unrelated to the typical 'end-replication' problems.},
}
@article {pmid16407326,
year = {2006},
author = {Hansen, KR and Ibarra, PT and Thon, G},
title = {Evolutionary-conserved telomere-linked helicase genes of fission yeast are repressed by silencing factors, RNAi components and the telomere-binding protein Taz1.},
journal = {Nucleic acids research},
volume = {34},
number = {1},
pages = {78-88},
pmid = {16407326},
issn = {1362-4962},
mesh = {Adenosine Triphosphatases/*genetics ; Base Sequence ; Centromere/chemistry ; Conserved Sequence ; DNA Helicases/*genetics ; Enzyme Inhibitors/pharmacology ; Evolution, Molecular ; Gene Expression Regulation, Enzymologic ; *Gene Expression Regulation, Fungal ; *Gene Silencing ; Heterochromatin/genetics ; Histone Deacetylase Inhibitors ; Hydroxamic Acids/pharmacology ; RNA Interference ; RecQ Helicases ; Repetitive Sequences, Nucleic Acid ; Schizosaccharomyces/enzymology/*genetics/metabolism ; Schizosaccharomyces pombe Proteins/*metabolism ; Sequence Homology, Nucleic Acid ; *Telomere ; Telomere-Binding Proteins/*metabolism ; Transcription Factors/metabolism ; },
abstract = {In Schizosaccharomyces pombe the RNAi machinery and proteins mediating heterochromatin formation regulate the transcription of non-coding centromeric repeats. These repeats share a high sequence similarity with telomere-linked helicase (tlh) genes, implying an ancestral relationship between the two types of elements and suggesting that transcription of the tlh genes might be regulated by the same factors as centromeric repeats. Indeed, we found that mutants lacking the histone methyltransferase Clr4, the Pcu4 cullin, Clr7 or Clr8, accumulate high levels of tlh forward and reverse transcripts. Mutations and conditions perturbing histone acetylation had similar effects further demonstrating that the tlh genes are normally repressed by heterochromatin. In contrast, mutations in the RNAi factors Dcr1, Ago1 or Rdp1 led only to a modest derepression of the tlh genes indicating an alternate pathway recruits heterochromatin components to telomeres. The telomere-binding protein Taz1 might be part of such a redundant pathway, tlh transcripts being present at low levels in Deltataz1 mutants and at higher levels in Deltataz1 Deltadcr1 double mutants. Surprisingly, the chromodomain protein Chp1, a component of the Ago1-containing RITS complex, contributes more to tlh repression than Ago1, indicating the repressive effects of Chp1 are partially independent of RITS. The tlh genes are found in the subtelomeric regions of several other fungi raising the intriguing possibility of conserved regulation and function.},
}
@article {pmid16406636,
year = {2006},
author = {Bhattacharyya, MK and Lustig, AJ},
title = {Telomere dynamics in genome stability.},
journal = {Trends in biochemical sciences},
volume = {31},
number = {2},
pages = {114-122},
doi = {10.1016/j.tibs.2005.12.001},
pmid = {16406636},
issn = {0968-0004},
support = {R01 GM069943/GM/NIGMS NIH HHS/United States ; R01 GM 069943-02/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Gene Deletion ; Humans ; Neoplasm Proteins/physiology ; Nuclear Proteins/physiology ; Promyelocytic Leukemia Protein ; Recombination, Genetic/physiology ; Saccharomyces cerevisiae/genetics/physiology ; Telomerase/deficiency ; Telomere/*physiology ; Transcription Factors/physiology ; Tumor Suppressor Proteins/physiology ; },
abstract = {The past several years have seen an increasing interest in telomere recombinational interactions that provide many functions in telomere capping, in telomere size homeostasis and in overcoming the catastrophic effects of telomerase deficiency. Several key recombination mechanisms have emerged from recent investigations. In the yeasts, these mechanisms include exchange between subtelomeric regions and telomere sequences, rapid telomere expansion and telomere deletion. These processes proceed by pathways that use both the cellular recombination machinery and novel mechanisms such as rolling circle replication. The insights gained from recent studies extend our understanding of similar processes in higher eukaryotes and suggest that the recombinational dynamics of telomeres have additional roles that contribute to genomic stability and instability.},
}
@article {pmid16400618,
year = {2006},
author = {Andrew, T and Aviv, A and Falchi, M and Surdulescu, GL and Gardner, JP and Lu, X and Kimura, M and Kato, BS and Valdes, AM and Spector, TD},
title = {Mapping genetic loci that determine leukocyte telomere length in a large sample of unselected female sibling pairs.},
journal = {American journal of human genetics},
volume = {78},
number = {3},
pages = {480-486},
pmid = {16400618},
issn = {0002-9297},
support = {R01 AG020132/AG/NIA NIH HHS/United States ; AG020132/AG/NIA NIH HHS/United States ; R01 AG021593/AG/NIA NIH HHS/United States ; AG021593/AG/NIA NIH HHS/United States ; 074951//Wellcome Trust/United Kingdom ; },
mesh = {Chromosome Mapping ; Chromosomes, Human/genetics ; Female ; Humans ; Leukocytes/metabolism ; *Polymorphism, Restriction Fragment Length ; *Quantitative Trait Loci ; *Quantitative Trait, Heritable ; Siblings ; Telomere/*genetics ; Twins, Dizygotic/*genetics ; },
abstract = {Telomeres play a central role in cellular senescence and cancer pathobiology and are associated with age-related diseases such as atherosclerosis and dementia. Telomere length varies between individuals of the same age, is influenced by DNA-damaging factors such as oxidative stress, and is heritable. We performed a quantitative-trait linkage analysis using an approximate 10-cM genomewide map for mean leukocyte terminal-restriction fragment (TRF) lengths measured by Southern blotting, in 2,050 unselected women aged 18-80 years, comprising 1,025 complete dizygotic twin pairs. Heritability of mean batch-adjusted TRF was 36% (95% confidence interval [CI] 18%-48%), with a large common environmental effect of 49% (95% CI 40%-58%). Significant linkage was observed on chromosome 14 (LOD 3.9) at 14q23.2, and suggestive linkage at 10q26.13 (LOD 2.4) and 3p26.1 (LOD 2.7). This is the first report of loci, mapped in a sample of healthy individuals, that influence mean telomere variation in humans.},
}
@article {pmid16400001,
year = {2006},
author = {Russo, V and Berardinelli, P and Martelli, A and Di Giacinto, O and Nardinocchi, D and Fantasia, D and Barboni, B},
title = {Expression of telomerase reverse transcriptase subunit (TERT) and telomere sizing in pig ovarian follicles.},
journal = {The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society},
volume = {54},
number = {4},
pages = {443-455},
doi = {10.1369/jhc.4A6603.2006},
pmid = {16400001},
issn = {0022-1554},
mesh = {Animals ; Cell Compartmentation ; DNA-Binding Proteins/*biosynthesis ; Female ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Oocytes/metabolism/ultrastructure ; Ovarian Follicle/*enzymology/ultrastructure ; Protein Subunits/metabolism ; Swine ; Telomerase/*biosynthesis ; Telomere/*ultrastructure ; },
abstract = {Telomerase is crucial for chromosome stability because it maintains telomere length. Little is known about telomerase in ovarian follicles, where an intense cell division is crucial to sustain estrous cycle and to drive oocyte development. The present research was performed to detect, by immunohistochemistry, the distribution of telomerase catalytic subunit (TERT) during folliculogenesis and to study the effect of TERT expression on telomeres. To this aim, telomere length has been measured on fluorescence in situ hybridization (FISH)-processed sections either in follicular or in germ cells. In primary and preantral follicles, TERT was observed in granulosa and in germ cells, with a typical nuclear location. During antral differentiation, only somatic cells close to the antrum (antral layer) and cumulus cells maintained TERT expression. The relative oocytes located TERT in the ooplasm independent from the process of meiotic maturation. FISH results indicate that a correlation exists between TERT expression and telomere size. In fact, progressively bigger telomeres were observed from preantral to antral follicles where longer structures were recorded in cells of the cumulus oophorus and of the antral layer than those of the basal one. Stable and elongated telomeres were detected in fully grown oocytes that lost the functional TERT distribution within the nucleus.},
}
@article {pmid16399890,
year = {2005},
author = {Olovnikov, A},
title = {Lunasensor, infradian rhythms, telomeres, and the chronomere program of aging.},
journal = {Annals of the New York Academy of Sciences},
volume = {1057},
number = {},
pages = {112-132},
doi = {10.1196/annals.1356.006},
pmid = {16399890},
issn = {0077-8923},
mesh = {Aging/*genetics/physiology ; Animals ; Biological Clocks/physiology ; Circadian Rhythm/*physiology ; DNA/metabolism ; Epigenesis, Genetic ; Female ; *Gravitation ; Growth Hormone/metabolism ; Humans ; Metabolic Syndrome/metabolism ; *Moon ; Phenotype ; Pineal Gland/cytology/metabolism ; Pituitary Gland, Anterior/metabolism ; Pregnancy ; Telomere/*metabolism ; },
abstract = {According to the redusome hypothesis, the aging of an organism is determined by the shortening of chronomeres (small perichromosomal linear DNA molecules). In this paper, a presumptive role for infradian hormonal rhythms is considered. Endogenous infradian rhythms are supposed to actively interact with those hormonal shifts which are governed by an exogenous infradian gravitational lunar rhythm. As a result of this interaction, the so-called T-rhythm is formed. Peaks of T-rhythms are used as the pacemaker signals to keep the life-long "clockwork" of the brain running. The "ticking" of this clock is realized by the periodically repeated shortening of chronomeres in postmitotic neuroendocrine cells, which occurs just at the maxima of T-rhythms. Shortening of telomeres in mitotic cells in vivo is a witness of the aging of the organism, but not the cause of aging. The primary cause of aging is shortening of chronomeres, the material carriers of a temporal program of development and aging. To recognize exogenous gravitational infradian rhythms, a special physiological system--the "lunasensor" system--evolved. It is assumed that it is a necessity to have a lunasensor as a particular variant of sensors of gravitation.},
}
@article {pmid16397223,
year = {2006},
author = {Muftuoglu, M and Wong, HK and Imam, SZ and Wilson, DM and Bohr, VA and Opresko, PL},
title = {Telomere repeat binding factor 2 interacts with base excision repair proteins and stimulates DNA synthesis by DNA polymerase beta.},
journal = {Cancer research},
volume = {66},
number = {1},
pages = {113-124},
doi = {10.1158/0008-5472.CAN-05-2742},
pmid = {16397223},
issn = {0008-5472},
mesh = {DNA Damage ; DNA Polymerase beta/*metabolism ; DNA Repair/*physiology ; DNA, Neoplasm/*biosynthesis ; Flap Endonucleases/metabolism ; HeLa Cells ; Humans ; Immunoprecipitation ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {The ends of linear chromosomes are capped and protected by protein-DNA complexes termed telomeres. Consequences of telomere dysfunction include genomic instability that can contribute to neoplastic transformation and progression. Telomere binding proteins interact with numerous proteins involved in DNA repair, underscoring the importance of regulating DNA repair pathways at telomeres. Telomeric DNA is particularly susceptible to oxidative damage, and such damage is repaired primarily via the base excision repair (BER) pathway. Using a screen for potential interactions between telomere repeat binding factor 2 (TRF2) and proteins involved in BER of oxidized bases in vitro, we found that TRF2 physically bound DNA polymerase beta (Pol beta) and flap endonuclease 1 (FEN-1). The interactions with endogenous proteins in human cell extracts were confirmed by coimmunoprecipitation experiments. The primary binding sites for both Pol beta and FEN-1 mapped to the TRF2 NH2-terminal and COOH-terminal domains. We further tested the ability of TRF2 to modulate BER protein partners individually on a variety of substrates in vitro. TRF2 stimulated Pol beta primer extension DNA synthesis on telomeric and nontelomeric primer/template substrates, resulting in up to a 75% increase in the proportion of longer products. TRF2 also stimulated Pol beta strand displacement DNA synthesis in reconstituted BER reactions and increased the percent of long-patch BER intermediates on both telomeric and nontelomeric substrates. Potential roles of TRF2 in cooperation with BER proteins for DNA repair pathways at telomeres, as well as other genomic regions, are discussed.},
}
@article {pmid16394794,
year = {2006},
author = {Getliffe, KM and Martin Ruiz, C and Passos, JF and von Zglinicki, T and Nwokolo, CU},
title = {Extended lifespan and long telomeres in rectal fibroblasts from late-onset ulcerative colitis patients.},
journal = {European journal of gastroenterology &amp; hepatology},
volume = {18},
number = {2},
pages = {133-141},
doi = {10.1097/00042737-200602000-00005},
pmid = {16394794},
issn = {0954-691X},
support = {G0601333/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Age of Onset ; Aged ; Cell Survival ; Cells, Cultured ; Colitis, Ulcerative/enzymology/*genetics/pathology ; DNA-Binding Proteins/biosynthesis/genetics ; Female ; Fibroblasts/enzymology/*pathology ; Humans ; Male ; Middle Aged ; Oxidative Stress ; Polymerase Chain Reaction/methods ; RNA/genetics ; RNA, Messenger/genetics ; Rectum/enzymology/*pathology ; Superoxide Dismutase/biosynthesis/genetics ; Telomerase/biosynthesis/genetics ; Telomere/*pathology ; },
abstract = {OBJECTIVES: Ulcerative colitis (UC) is characterized by damage to the intestinal epithelium and connective tissue. The causes of this damage could include changes in the ability of colonic fibroblasts to heal wounds and maintain epithelial cell proliferation. Telomeres shorten with each cell division and eventually signal senescence. The aim of this study is to investigate whether the impaired function of rectal fibroblasts in UC is due to accelerated telomere shortening, oxidative stress and premature senescence.<br><br>METHODS: We isolated rectal fibroblasts from eight UC patients and nine non-colitis controls, and recorded their in-vitro lifespans. Telomere lengths and superoxide dismutase mRNA expression were also measured by real-time polymerase chain reaction and peroxide levels were measured by flow cytometry.<br><br>RESULTS: The fibroblast lifespan decreased as patient age increased (R2=0.68, P=0.003) in control patients, but this relationship was absent in UC fibroblasts. We identified a group of patients who were diagnosed later in life than a second group (59 versus 35 years, P=0.002). Fibroblasts from these late-onset UC patients underwent significantly more population doublings before senescence than age-matched controls (25 versus 15, P=0.02). Slower in-vitro telomere shortening rates (32 versus 344, P=0.006) and trends towards longer telomeres at explant were also observed in late-onset UC fibroblasts. Peroxide levels correlated positively with telomere shortening rate (r=0.581, P=0.078).<br><br>CONCLUSIONS: Some UC-predisposed individuals may have more efficient antioxidant systems that protect the telomeres from oxidative damage. This may allow their rectal fibroblasts to live longer, function better and thus delay the onset of the disease until later life.},
}
@article {pmid16392962,
year = {2006},
author = {Durante, M and George, K and Cucinotta, FA},
title = {Chromosomes lacking telomeres are present in the progeny of human lymphocytes exposed to heavy ions.},
journal = {Radiation research},
volume = {165},
number = {1},
pages = {51-58},
doi = {10.1667/rr3477.1},
pmid = {16392962},
issn = {0033-7587},
mesh = {Cell Division/radiation effects ; Cells, Cultured ; Chromosome Aberrations/*radiation effects ; Chromosomes/*radiation effects/ultrastructure ; Dose-Response Relationship, Radiation ; Gamma Rays/adverse effects ; Heavy Ions/*adverse effects ; Humans ; In Situ Hybridization, Fluorescence ; Lymphocytes/*radiation effects ; Radiation Dosage ; Telomere/pathology/*radiation effects ; },
abstract = {High-charge and energy (HZE) nuclei represent one of the main health risks for human space exploration, yet little is known about the mechanisms responsible for the high biological effectiveness of these particles. We have used in situ hybridization probes for cross-species multicolor banding (RxFISH) in combination with telomere detection to compare yields of different types of chromosomal aberrations in the progeny of human peripheral blood lymphocytes exposed to either high-energy iron ions or gamma rays. Terminal deletions showed the greatest relative variation, with many more of these types of aberrations induced after exposure to accelerated iron ions (energy 1 GeV/nucleon) compared with the same dose of gamma rays. We found that truncated chromosomes without telomeres could be transmitted for at least three cell cycles after exposure and represented about 10% of all aberrations observed in the progeny of cells exposed to iron ions. On the other hand, the fraction of cells carrying stable, transmissible chromosomal aberrations was similar in the progeny of cells exposed to the same dose of densely or sparsely ionizing radiation. The results demonstrate that unrejoined chromosome breaks are an important component of aberration spectra produced by the exposure to HZE nuclei. This finding may well be related to the ability of such energetic particles to produce untoward late effects in irradiated organisms.},
}
@article {pmid16388518,
year = {2006},
author = {Garcia-Aranda, C and de Juan, C and Diaz-Lopez, A and Sanchez-Pernaute, A and Torres, AJ and Diaz-Rubio, E and Balibrea, JL and Benito, M and Iniesta, P},
title = {Correlations of telomere length, telomerase activity, and telomeric-repeat binding factor 1 expression in colorectal carcinoma.},
journal = {Cancer},
volume = {106},
number = {3},
pages = {541-551},
doi = {10.1002/cncr.21625},
pmid = {16388518},
issn = {0008-543X},
mesh = {Aged ; Carcinoma/*genetics/metabolism/pathology ; Colorectal Neoplasms/*genetics/metabolism/pathology ; Female ; Humans ; Male ; Middle Aged ; Prognosis ; Risk Factors ; Survival Analysis ; Telomerase/*metabolism ; Telomere/*ultrastructure ; Telomeric Repeat Binding Protein 1/*biosynthesis ; },
abstract = {BACKGROUND: Telomere maintenance has been proposed as an essential step for tumor cell immortalization. The objectives of the current study were to investigate the mechanisms implicated in telomere length in colorectal carcinoma (CRC) and to evaluate the prognostic impact of telomere status.<br><br>METHODS: Ninety-one colorectal carcinoma samples that were obtained from patients who underwent surgery were analyzed to investigate the factors related to telomere function. The authors studied telomerase activity, terminal restriction fragment (TRF) length, and telomeric-repeat binding factor (TRF1) expression and analyzed the prognostic implications of those factors.<br><br>RESULTS: Most tumors (81.3%) displayed telomerase activity. Overall, telomeres in CRC specimens were significantly shorter compared with telomeres in normal, adjacent specimens (P=0.02). Moreover, tumors that demonstrated shortened telomeres displayed higher TRF1 levels than tumors without telomere shortening. In relation to patient prognosis, a significantly poor clinical course was observed in the group of patients who had tumors with longer telomeres (P=0.02), and this finding emerged as an independent prognostic factor in a Cox proportional hazards model (P=0.04; relative risk, 6.48). Among patients with tumors classified as telomerase-positive, telomere length ratios (the ratio of tumor tissues to normal tissues)<or=0.66 or TRF1 over-expression conferred a favorable outcome (P=0.03 and P=0.05, respectively).<br><br>CONCLUSIONS: The majority of CRC specimens in the current study displayed telomerase reactivation. However, only those tumors that displayed telomere elongation conferred a poor prognosis. Conversely, colorectal tumors that over-expressed TRF1 demonstrated telomere shortening, and patients with those tumors had a better clinical course.},
}
@article {pmid16381006,
year = {2006},
author = {Jeyapalan, JC and Saretzki, G and Leake, A and Tilby, MJ and von Zglinicki, T},
title = {Tumour-cell apoptosis after cisplatin treatment is not telomere dependent.},
journal = {International journal of cancer},
volume = {118},
number = {11},
pages = {2727-2734},
doi = {10.1002/ijc.21675},
pmid = {16381006},
issn = {0020-7136},
mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Cisplatin/*pharmacology ; DNA Damage/*drug effects ; HeLa Cells ; Humans ; Neuroblastoma/pathology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Signal Transduction ; Telomere/*drug effects ; },
abstract = {Cisplatin is a major chemotherapeutic agent, especially for the treatment of neuroblastoma. Telomeres with their sequence (TTAGGG)n are probable targets for cisplatin intrastrand cross-linking, but the role of telomeres in mediating cisplatin cytotoxicity is not clear. After exposure to cisplatin as single dose or continuous treatment, we found no loss of telomeres in either SHSY5Y neuroblastoma cells (telomere length, approximately 4 kbp), HeLa 229 cells (telomere length, 20 kbp) or in the acute lymphoblastic T cell line 1301 (telomere length, approximately 80 kbp). There was no induction of telomeric single strand breaks, telomeric overhangs were not degraded and telomerase activity was down-regulated only after massive onset of apoptosis. In contrast, cisplatin induced a delayed formation of DNA strand breaks and induced DNA damage foci containing gamma-H2A.X at nontelomeric sites. Interstitial DNA damage appears to be more important than telomere loss or telomeric damage as inducer of the signal pathway towards apoptosis and/or growth arrest in cisplatin-treated tumour cells.},
}
@article {pmid16374507,
year = {2006},
author = {Chai, W and Sfeir, AJ and Hoshiyama, H and Shay, JW and Wright, WE},
title = {The involvement of the Mre11/Rad50/Nbs1 complex in the generation of G-overhangs at human telomeres.},
journal = {EMBO reports},
volume = {7},
number = {2},
pages = {225-230},
pmid = {16374507},
issn = {1469-221X},
support = {R01 AG001228/AG/NIA NIH HHS/United States ; AG01228/AG/NIA NIH HHS/United States ; },
mesh = {Acid Anhydride Hydrolases ; Base Sequence ; Cell Cycle Proteins/genetics/*metabolism ; *DNA Repair ; DNA Repair Enzymes/genetics/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; HeLa Cells ; Humans ; MRE11 Homologue Protein ; Nuclear Proteins/genetics/*metabolism ; Polymerase Chain Reaction ; RNA Interference ; RNA, Small Interfering/metabolism ; Telomere/chemistry/*metabolism ; },
abstract = {A central function of telomeres is to prevent chromosome ends from being recognized as DNA double-strand breaks (DSBs). Several proteins involved in processing DSBs associate with telomeres, but the roles of these factors at telomeres are largely unknown. To investigate whether the Mre11/Rad50/Nbs1 (MRN) complex is involved in the generation of proper 3' G-overhangs at human telomere ends, we used RNA interference to decrease expression of MRN and analysed their effects. Reduction of MRN resulted in a transient shortening of G-overhang length in telomerase-positive cells. The terminal nucleotides of both C- and G-rich strands remain unaltered in Mre11-diminished cells, indicating that MRN is not responsible for specifying the final end-processing event. The reduction in overhang length was not seen in telomerase-negative cells, but was observed after the expression of exogenous telomerase, which suggested that the MRN complex might be involved in the recruitment or action of telomerase.},
}
@article {pmid16373996,
year = {2006},
author = {Boxall, MC and Goodship, TH and Brown, AL and Ward, MC and von Zglinicki, T},
title = {Telomere shortening and haemodialysis.},
journal = {Blood purification},
volume = {24},
number = {2},
pages = {185-189},
doi = {10.1159/000090517},
pmid = {16373996},
issn = {0253-5068},
mesh = {Aldehydes/analysis ; C-Reactive Protein/analysis ; Female ; Humans ; Male ; Malondialdehyde/analysis ; Middle Aged ; Oxidative Stress/physiology ; Predictive Value of Tests ; Renal Dialysis/*adverse effects/*methods ; Telomere/*genetics/*pathology ; },
abstract = {BACKGROUND: Increased oxidative stress is a well described feature of haemodialysis (HD). This is secondary to an increase in the production of reactive oxygen species and impaired antioxidant mechanisms. Telomeres are the specialized ends of eukaryotic chromosomes and consist of tandemly repeated DNA sequences. Telomeres shorten with each cell division and it is well known that telomere length in peripheral blood mononuclear cells (PBMCs) decreases with age. Telomere shortening rate is increased by oxidative stress. In this study we have examined a possible relationship between oxidative stress and telomere shortening in haemodialysis.<br><br>METHODS: 20 control subjects, 20 non-diabetic and 18 diabetic HD patients were studied. Peripheral blood mononuclear cell telomere length, plasma malondialdehyde plus 4-hydroxyalkenal (MDA+4-HAE) concentration (a marker of oxidative stress) and C-reactive protein (CRP) concentration were measured.<br><br>RESULTS: MDA+4-HAE and CRP were significantly higher in the HD patients (CRP, controls 7.5 +/- 1.5, HD patients 16.4 +/- 3.1 mg/l, p < 0.05). There was no difference in mean telomere length between the HD patients and controls (control, 8,283 +/- 179 bp; non-diabetic HD, 7,966 +/- 160 bp; diabetic HD, 8,033 +/- 197 bp) but age adjusted residual telomere length was inversely associated with the length of time on dialysis (r = -0.35, p = 0.03).<br><br>CONCLUSION: These results suggest that length of time on dialysis is independently associated with increased telomere shortening in HD patients. We hypothesise that this reflects cumulative DNA exposure to oxidative stress.},
}
@article {pmid16364206,
year = {2005},
author = {Lin, KW and Yan, J},
title = {The telomere length dynamic and methods of its assessment.},
journal = {Journal of cellular and molecular medicine},
volume = {9},
number = {4},
pages = {977-989},
pmid = {16364206},
issn = {1582-1838},
mesh = {Aging ; Animals ; Blotting, Southern ; Cell Line, Tumor ; Flow Cytometry ; *Genetic Techniques ; Humans ; In Situ Hybridization, Fluorescence ; Models, Genetic ; Neoplasms/metabolism/pathology/*ultrastructure ; Nucleic Acid Hybridization ; Polymerase Chain Reaction ; Telomerase/metabolism ; Telomere/*ultrastructure ; },
abstract = {Human telomeres are composed of long repeating sequences of TTAGGG, associated with a variety of telomere-binding proteins. Its function as an end-protector of chromosomes prevents the chromosome from end-to-end fusion, recombination and degradation. Telomerase acts as reverse transcriptase in the elongation of telomeres, which prevent the loss of telomeres due to the end replication problems. However, telomerase activity is detected at low level in somatic cells and high level in embryonic stem cells and tumor cells. It confers immortality to embryonic stem cells and tumor cells. In most tumor cells, telomeres are extremely short and stable. Telomere length is an important indicator of the telomerase activity in tumor cells and it may be used in the prognosis of malignancy. Thus, the assessment of telomeres length is of great experimental and clinical significance. This review describes the role of telomere and telomerase in cancer pathogenesis and the dynamics of the telomeres length in different cell types. The various methods of measurement of telomeres length, i.e. southern blot, hybridization protection assay, fluorescence in situ hybridization, primed in situ, quantitative PCR and single telomere length analysis are discussed. The principle and comparative evaluation of these methods are reviewed. The detection of G-strand overhang by telomeric-oligonucleotide ligation assay, primer extension/nick translation assay and electron microscopy are briefly discussed.},
}
@article {pmid16363064,
year = {2005},
author = {Gilchrest, BA and Eller, MS},
title = {The tale of the telomere: implications for prevention and treatment of skin cancers.},
journal = {The journal of investigative dermatology. Symposium proceedings},
volume = {10},
number = {2},
pages = {124-130},
doi = {10.1111/j.1087-0024.2005.200406.x},
pmid = {16363064},
issn = {1087-0024},
support = {R01CA1C5156/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; DNA Damage ; Humans ; SOS Response, Genetics ; Skin Neoplasms/genetics/*prevention &amp; control/therapy ; Telomere/chemistry/*physiology ; },
abstract = {Work in many laboratories over the past decade has established a central role for the telomere in maintaining genomic integrity. Available data may be interpreted to indicate that telomere disruption, whether due to acute DNA damage or progressive telomere shortening, is the initial event that triggers multiple DNA damage responses. The specific initiating event is likely exposure of the otherwise concealed single-stranded 3' overhang, tandem repeats of TTAGGG, a signal that can be provided to cells in the absence of DNA damage by exogenously provided T-oligos. The ability of T-oligo treatment to trigger SOS-like responses and/or to cause selective apoptosis of already malignantly transformed cells may provide an important new means of cancer prevention and treatment.},
}
@article {pmid16362412,
year = {2006},
author = {Wolf, D and Rumpold, H and Koppelstätter, C and Gastl, GA and Steurer, M and Mayer, G and Gunsilius, E and Tilg, H and Wolf, AM},
title = {Telomere length of in vivo expanded CD4(+)CD25 (+) regulatory T-cells is preserved in cancer patients.},
journal = {Cancer immunology, immunotherapy : CII},
volume = {55},
number = {10},
pages = {1198-1208},
doi = {10.1007/s00262-005-0107-5},
pmid = {16362412},
issn = {0340-7004},
mesh = {Aged ; Blotting, Southern ; CD4 Antigens/*metabolism ; Cell Proliferation ; Cell Transformation, Neoplastic/genetics ; Enzyme Activation ; Flow Cytometry ; Humans ; In Situ Hybridization, Fluorescence ; Middle Aged ; Neoplasms/*immunology ; RNA, Messenger/analysis ; Receptors, Interleukin-2/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; T-Lymphocytes, Regulatory/*physiology ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {PURPOSE: CD4(+)CD25(+) regulatory T-cells (Treg) are increased in the peripheral blood of cancer patients. It remains unclear whether this is due to redistribution or active proliferation. The latter would require the upregulation of telomerase activity, whose regulation also remains unknown for Treg.<br><br>EXPERIMENTAL DESIGN: Treg and CD4(+)CD25(-) T-cells were isolated from peripheral blood of cancer patients (n=23) and healthy age-matched controls (n=17) and analyzed for their content of T-cell receptor excision circles (TREC) and for telomere length using flow-FISH, real-time PCR and Southern blotting. The in vitro regulation of telomerase of Treg was studied using PCR-ELISA in bulk cultures as well as in isolated proliferating and non-proliferating Treg.<br><br>RESULTS: Treg isolated from peripheral blood of cancer patients exhibit significantly decreased levels of TREC when compared to Treg from healthy controls. Despite their in vivo proliferation, telomere length is not further shortened in Treg from cancer patients. Accordingly, telomerase activity of Treg was readily inducible in vitro. Notably, sorting of in vitro proliferating Treg revealed a significant telomere shortening in Treg with high-proliferative capacity. The latter are characterized by shortened telomeres despite high telomerase activity.<br><br>CONCLUSIONS: Increased frequencies of Treg in peripheral blood of cancer patients are due to active proliferation rather than due to redistribution from other compartments (i.e., secondary lymphoid organs or bone marrow). In vivo expansion does not further shorten telomere length, probably due to induction of telomerase activity. In contrast, under conditions of strong in vitro stimulation telomerase induction seems to be insufficient to avoid progressive telomere shortening.},
}
@article {pmid16360040,
year = {2005},
author = {Hao, LY and Armanios, M and Strong, MA and Karim, B and Feldser, DM and Huso, D and Greider, CW},
title = {Short telomeres, even in the presence of telomerase, limit tissue renewal capacity.},
journal = {Cell},
volume = {123},
number = {6},
pages = {1121-1131},
doi = {10.1016/j.cell.2005.11.020},
pmid = {16360040},
issn = {0092-8674},
support = {P01 CA16519/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Anticipation, Genetic/genetics ; Blood Cell Count ; Bone Marrow Transplantation/mortality ; Crosses, Genetic ; Dyskeratosis Congenita/genetics ; Fluorouracil/pharmacology ; Genotype ; Haplotypes/genetics ; Hematopoietic System/drug effects/metabolism/pathology ; Heterozygote ; Intestinal Mucosa/metabolism/pathology ; Intestines/*pathology ; Longevity/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Mutant Strains ; Phenotype ; Seminiferous Tubules/metabolism/pathology ; Stem Cells/metabolism/pathology ; Survival Rate ; Telomerase/*genetics/metabolism ; Telomere/*genetics/metabolism ; Testis/metabolism/*pathology ; Time Factors ; },
abstract = {Autosomal-dominant dyskeratosis congenita is associated with heterozygous mutations in telomerase. To examine the dosage effect of telomerase, we generated a line of mTR+/- mice on the CAST/EiJ background, which has short telomeres. Interbreeding of heterozygotes resulted in progressive telomere shortening, indicating that limiting telomerase compromises telomere maintenance. In later-generation heterozygotes, we observed a decrease in tissue renewal capacity in the bone marrow, intestines, and testes that resembled defects seen in dyskeratosis congenita patients. The progressive worsening of disease with decreasing telomere length suggests that short telomeres, not telomerase level, cause stem cell failure. Further, wild-type mice derived from the late-generation heterozygous parents, termed wt*, also had short telomeres and displayed a germ cell defect, indicating that telomere length determines these phenotypes. We propose that short telomeres in mice that have normal telomerase levels can cause an occult form of genetic disease.},
}
@article {pmid16358816,
year = {2005},
author = {Boukamp, P and Popp, S and Krunic, D},
title = {Telomere-dependent chromosomal instability.},
journal = {The journal of investigative dermatology. Symposium proceedings},
volume = {10},
number = {2},
pages = {89-94},
doi = {10.1111/j.1087-0024.2005.200401.x},
pmid = {16358816},
issn = {1087-0024},
mesh = {Animals ; Cellular Senescence ; *Chromosomal Instability ; Genomic Instability ; Humans ; Telomerase/analysis ; *Telomere ; },
abstract = {Telomeres are specialized DNA-protein structures at the ends of the linear chromosomes. In mammalian cells, they are composed of multifold hexameric TTAGGG repeats and a number of associated proteins. The double-stranded telomeric DNA ends in a 3' single stranded overhang of 150 to 300 base pair (bp) which is believed to be required for a higher order structure (reviewed in (Blackburn, 2001)). One important model is that the telomeres form loop structures, the T-loops, and by invasion of the 3' overhang into the duplex region of the double stranded part protect the DNA against degradation and hinder the cellular machinery to recognize the ends as broken DNA, thus providing chromosomal integrity (Griffith et al, 1999). If telomeres become critically short they loose their capping function, become sticky, and are prone to illegitimate chromosome end-to-end fusions. The resulting dicentric chromosomes are highly unusable and because of bridge-fusion-breakage cycles they give rise to chromosomal translocations, deletions, and amplifications. Thus, critically short telomeres are thought to be responsible for the onset of genomic instability. In addition, we provide evidence that in a length-independent manner telomeres can confer to genomic instability by forming telomericaggregates which through chromosomal dys-locations contribute to chromosomal aberrations.},
}
@article {pmid16357844,
year = {2006},
author = {Patton, KT and Cheng, L and Papavero, V and Blum, MG and Yeldandi, AV and Adley, BP and Luan, C and Diaz, LK and Hui, P and Yang, XJ},
title = {Benign metastasizing leiomyoma: clonality, telomere length and clinicopathologic analysis.},
journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},
volume = {19},
number = {1},
pages = {130-140},
doi = {10.1038/modpathol.3800504},
pmid = {16357844},
issn = {0893-3952},
mesh = {Adult ; Clone Cells/chemistry/metabolism/pathology ; Female ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Leiomyoma/genetics/metabolism/*pathology ; Lung/diagnostic imaging/pathology ; Lung Neoplasms/genetics/metabolism/*secondary ; Receptors, Androgen/genetics ; Receptors, Estrogen/analysis ; Receptors, Progesterone/analysis ; Telomere/genetics ; Tomography, X-Ray Computed ; Trinucleotide Repeats/genetics ; Uterine Neoplasms/genetics/metabolism/*pathology ; X Chromosome Inactivation/genetics ; },
abstract = {Benign metastasizing leiomyoma is a rare condition affecting women with a history of uterine leiomyomata and is characterized by multiple histologically benign pulmonary smooth muscle tumors. Speculations on its pathogenesis include a benign uterine leiomyoma colonizing the lung, a metastatic low-grade uterine leiomyosarcoma, and primary pulmonary leiomyomatosis. To elucidate its pathogenesis, we analyzed the clinical, pathological and immunohistochemical features, clonality, and telomere length of multiple lung and uterine tumors in three patients with benign metastasizing leiomyoma. In all cases, pulmonary tumors had benign histology and immunohistochemical profiles (estrogen receptor positive, progesterone receptor positive, and very low proliferative index) identical to uterine leiomyoma. In eight tumors from three patients, clonality was assessed by analyzing the variable length of the polymorphic CAG repeat sequence within the human androgen receptor gene. In the two informative patients pulmonary and uterine tumors showed identical patterns of androgen receptor allelic inactivation, indicating that they were clonal. The telomere length measured by fluorescence in situ hybridization in pulmonary leiomyomas of all three patients were either long or very long and were identical to the uterine counterparts, indicating significant telomere shortening is not a crucial step for developing metastases. Our evidence supports the notion that benign metastasizing leiomyoma is clonally derived from benign-appearing uterine leiomyomas.},
}
@article {pmid16339888,
year = {2006},
author = {Rosa, A and Maddocks, JH and Neumann, FR and Gasser, SM and Stasiak, A},
title = {Measuring limits of telomere movement on nuclear envelope.},
journal = {Biophysical journal},
volume = {90},
number = {3},
pages = {L24-6},
pmid = {16339888},
issn = {0006-3495},
mesh = {Binding Sites ; Biophysics/*methods ; Cell Nucleus/metabolism ; Chromatin/chemistry/metabolism ; Galactose/chemistry ; Microscopy, Confocal ; Microscopy, Fluorescence ; Microscopy, Video ; Models, Statistical ; Nuclear Envelope/*chemistry ; Saccharomyces cerevisiae/metabolism ; Telomere/*ultrastructure ; Time Factors ; },
abstract = {The dynamic behavior of the decondensed chromatin can be monitored by real-time fluorescence confocal microscopy. It can be observed that different chromosomal sites enjoy different degrees of freedom during a certain period, exploring larger or smaller portions of nuclear volume. Here we measure the accessible surface for two chromosomal sites (yeast telomeres Tel3R and Tel6R) that both exhibit strong preferential association with the nuclear membrane in galactose-containing media, but differ significantly in gene activity. Telomere Tel6R, which harbors an inducible gene with high levels of transcription, explores a much larger surface than the telomere Tel3R, which is adjacent to inactive chromatin. Thus, our results distinguish two perinuclear movements characteristic of different transcriptional state, allowing for a better understanding of the correlation between activity of genes and chromatin dynamics.},
}
@article {pmid16339074,
year = {2006},
author = {Tomlinson, RL and Ziegler, TD and Supakorndej, T and Terns, RM and Terns, MP},
title = {Cell cycle-regulated trafficking of human telomerase to telomeres.},
journal = {Molecular biology of the cell},
volume = {17},
number = {2},
pages = {955-965},
pmid = {16339074},
issn = {1059-1524},
support = {T32 GM007103/GM/NIGMS NIH HHS/United States ; GM-07103/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle/*physiology ; Cell Nucleolus/enzymology/ultrastructure ; Coiled Bodies/chemistry/ultrastructure ; DNA-Binding Proteins/analysis/*metabolism ; HeLa Cells ; Humans ; Models, Biological ; Protein Transport ; RNA ; RNA, Long Noncoding ; RNA, Untranslated/analysis/*metabolism ; S Phase/physiology ; Telomerase/analysis/*metabolism ; Telomere/*metabolism/ultrastructure ; },
abstract = {Telomerase synthesizes telomeres at the ends of human chromosomes during S phase. The results presented here suggest that telomerase activity may be regulated by intranuclear trafficking of the key components of the enzyme in human cells. We examined the subcellular localization of endogenous human telomerase RNA (hTR) and telomerase reverse transcriptase (hTERT) in HeLa cervical carcinoma cells. Throughout most of the cell cycle, we found that the two essential components of telomerase accumulate at intranuclear sites separate from telomeres. However, during S phase, both hTR and hTERT are specifically recruited to subsets of telomeres. The localization of telomerase to telomeres is dynamic, peaking at mid-S phase. We also found complex associations of both hTR and hTERT with nucleoli and Cajal bodies during S phase, implicating both structures in the biogenesis and trafficking of telomerase. Our results mark the first observation of human telomerase at telomeres and provide a mechanism for the cell cycle-dependent regulation of telomere synthesis in human cells.},
}
@article {pmid16333825,
year = {2006},
author = {Kulikowski, LD and Christ, LA and Nogueira, SI and Brunoni, D and Schwartz, S and Melaragno, MI},
title = {Breakpoint mapping in a case of mosaicism with partial monosomy 9p23 --&gt; pter and partial trisomy 1q41 --&gt; qter suggests neo-telomere formation in stabilizing the deleted chromosome.},
journal = {American journal of medical genetics. Part A},
volume = {140},
number = {1},
pages = {82-87},
doi = {10.1002/ajmg.a.31045},
pmid = {16333825},
issn = {1552-4825},
mesh = {Child ; *Chromosome Aberrations ; Chromosome Banding ; Chromosome Breakage/genetics ; Chromosome Deletion ; Chromosomes, Human, Pair 1/*genetics ; Chromosomes, Human, Pair 9/*genetics ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Models, Genetic ; Monosomy ; *Mosaicism ; Telomere/*genetics ; Translocation, Genetic ; Trisomy ; },
abstract = {We report on a clinical and molecular cytogenetic study of a patient who presents a complex chromosomal rearrangement with two different cell lines. Using high-resolution GTG banding and fluorescence in situ hybridization (FISH) with several probes, including bacterial artificial chromosomes (BACs), the karyotype was defined as 46,XX,del(9)(p23)[54]/46,XX,der(9)t(1;9)(q41;p23)[46], indicating the presence of monosomy 9p23 in all cells and trisomy 1q41 in approximately 50% of the cells. The patient studied presents most of the manifestations of the 9p deletion and 1q duplication syndromes. The breakpoint was mapped at 9p23 with a loss of approximately 13.9-Mb of DNA. The duplicated segment consists of approximately 35 Mb from 1q41-qter region. We also suggest that a mechanism for telomere capture and interstitial telomeric sequences (ITs) is involved in a neo-telomere formation in one of the cell lines. This study highlights the importance of combining high-resolution chromosome and FISH with BACs in order to make genotype-phenotype correlations and to understand the mechanisms involved chromosomal aberrations.},
}
@article {pmid16332973,
year = {2006},
author = {Vulliamy, TJ and Marrone, A and Knight, SW and Walne, A and Mason, PJ and Dokal, I},
title = {Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation.},
journal = {Blood},
volume = {107},
number = {7},
pages = {2680-2685},
doi = {10.1182/blood-2005-07-2622},
pmid = {16332973},
issn = {0006-4971},
mesh = {Chromosomes, Human, X ; Dyskeratosis Congenita/*genetics ; Female ; Genes, Dominant ; *Genetic Variation ; Humans ; Male ; Models, Molecular ; *Mutation ; RNA/chemistry/*genetics ; Siblings ; Telomerase/chemistry/*genetics ; Telomere/*genetics/ultrastructure ; },
abstract = {The two genes mutated in the bone marrow failure syndrome dyskeratosis congenita (DC) both encode components of the telomerase complex responsible for maintaining the ends of chromosomes in stem cells and in the germ line. In reviewing the mutation profile that is found in DC, we describe 9 novel mutations in the DKC1 gene and 3 novel TERC mutations responsible for the X-linked and autosomal dominant forms of the disease, respectively, but find that two thirds of the families do not have mutations in either of these genes. In a significant subset of these uncharacterized families, the index case presents with severe disease previously defined as the Hoyeraal Hreidarsson (HH) syndrome. The diverse clinical phenotype seen in patients with X-linked DC is not explained by the different amino acid substitutions: Presentation of the recurrent A353V substitution ranges from classic DC to the severe HH variant. However, we do see that patients with HH have significantly shorter telomeres than those with a relatively mild presentation. In the new families described with TERC mutations, there is further evidence of disease anticipation associated with shorter telomeres in the younger generations. This study highlights the considerable genetic and phenotypic diversity of DC.},
}
@article {pmid16331816,
year = {2005},
author = {Lin, J and Xie, J and Qian, WB},
title = {[Telomerase activity and telomere length in CD4+,CD8+ and CD19+ lymphocytes from patients with systemic lupus erythematosus].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {34},
number = {6},
pages = {534-537},
doi = {10.3785/j.issn.1008-9292.2005.06.012},
pmid = {16331816},
issn = {1008-9292},
mesh = {Adolescent ; Adult ; Antigens, CD19/immunology ; CD4-Positive T-Lymphocytes/*enzymology ; CD8-Positive T-Lymphocytes/*enzymology ; Female ; Humans ; Lupus Erythematosus, Systemic/enzymology/*immunology ; Lymphocytes/enzymology ; Male ; Middle Aged ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {OBJECTIVE: To investigate the telomerase activity and the telomere length in CD4(+), CD8(+) and CD19(+) lymphocytes from patients with systemic lupus erythematosus (SLE).<br><br>METHODS: Telomerase activity of CD4(+), CD8(+) and CD19(+) cells from patients with SLE and normal controls was examined by telomeric repeats amplification protocol. Telomere length in those cells was measured by Southern blot method.<br><br>RESULT: CD4(+), CD8(+) and CD19(+) cells in patients with SLE showed high telomerase activity, but only telomerase activity of CD19(+) cells was significantly higher than that in controls. The length of telomere in CD4(+) and CD8(+) cells was significantly shorter than that in controls, but not in CD19(+) cells.<br><br>CONCLUSION: Higher telomerase activity in CD19(+) cells and shortened telomere length in CD4(+) and CD8(+) cells of patients with SLE may be associated with pathogenesis of SLE.},
}
@article {pmid16331258,
year = {2006},
author = {Campbell, MR and Wang, Y and Andrew, SE and Liu, Y},
title = {Msh2 deficiency leads to chromosomal abnormalities, centrosome amplification, and telomere capping defect.},
journal = {Oncogene},
volume = {25},
number = {17},
pages = {2531-2536},
doi = {10.1038/sj.onc.1209277},
pmid = {16331258},
issn = {0950-9232},
mesh = {Animals ; Centrosome ; *Chromosome Aberrations ; DNA Repair ; Embryo, Mammalian/cytology/*metabolism ; Fibroblasts/cytology/*metabolism ; *Gene Amplification ; Mice ; Mice, Knockout ; MutS Homolog 2 Protein/*deficiency ; Telomere/*physiology ; },
abstract = {Msh2 is a key mammalian DNA mismatch repair (MMR) gene and mutations or deficiencies in mammalian Msh2 gene result in microsatellite instability (MSI+) and the development of cancer. Here, we report that primary mouse embryonic fibroblasts (MEFs) deficient in the murine MMR gene Msh2 (Msh2(-/-)) showed a significant increase in chromosome aneuploidy, centrosome amplification, and defective mitotic spindle organization and unequal chromosome segregation. Although Msh2(-/-) mouse tissues or primary MEFs had no apparent change in telomerase activity, telomere length, or recombination at telomeres, Msh2(-/-) MEFs showed an increase in chromosome end-to-end fusions or chromosome ends without detectable telomeric DNA. These data suggest that MSH2 helps to maintain genomic stability through the regulation of the centrosome and normal telomere capping in vivo and that defects in MMR can contribute to oncogenesis through multiple pathways.},
}
@article {pmid16326384,
year = {2005},
author = {Weinert, T},
title = {Do telomeres ask checkpoint proteins: "gimme shelter-in"?.},
journal = {Developmental cell},
volume = {9},
number = {6},
pages = {725-726},
doi = {10.1016/j.devcel.2005.11.012},
pmid = {16326384},
issn = {1534-5807},
mesh = {DNA Damage/physiology ; DNA Repair/physiology ; Genes, cdc/*physiology ; Humans ; Telomerase/metabolism ; Telomere/*physiology ; },
abstract = {Telomeres are complicated structures designed to allow one thing and avoid another. They allow replication of chromosome ends, an issue mostly about telomerase, which we seem to understand (though details of its regulation are works in progress). Telomeres must also avoid being detected as DNA breaks. This is important for two reasons: DNA breaks activate checkpoints that cause arrest of cell division, and DNA breaks engage repair machinery. Clearly, normal telomeres neither activate cell cycle arrest nor allow themselves to be repaired; arrest blocks cell division, and repair fuses chromosomes.},
}
@article {pmid16319170,
year = {2006},
author = {Jády, BE and Richard, P and Bertrand, E and Kiss, T},
title = {Cell cycle-dependent recruitment of telomerase RNA and Cajal bodies to human telomeres.},
journal = {Molecular biology of the cell},
volume = {17},
number = {2},
pages = {944-954},
pmid = {16319170},
issn = {1059-1524},
mesh = {Cell Cycle/physiology ; Cell Nucleus/ultrastructure ; Coiled Bodies/*metabolism/ultrastructure ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; RNA ; RNA, Long Noncoding ; RNA, Untranslated/*analysis/metabolism ; Recombinant Fusion Proteins/analysis ; S Phase/physiology ; Telomerase/*analysis/metabolism ; Telomere/*metabolism/ultrastructure ; },
abstract = {Telomerase is a ribonucleoprotein enzyme that counteracts replicative telomere erosion by adding telomeric sequence repeats onto chromosome ends. Despite its well-established role in telomere synthesis, telomerase has not yet been detected at telomeres. The RNA component of human telomerase (hTR) resides in the nucleoplasmic Cajal bodies (CBs) of interphase cancer cells. Here, in situ hybridization demonstrates that in human HeLa and Hep2 S phase cells, besides accumulating in CBs, hTR specifically concentrates at a few telomeres that also accumulate the TRF1 and TRF2 telomere marker proteins. Surprisingly, telomeres accumulating hTR exhibit a great accessibility for in situ oligonucleotide hybridization without chromatin denaturation, suggesting that they represent a structurally distinct, minor subset of HeLa telomeres. Moreover, we demonstrate that more than 25% of telomeres accumulating hTR colocalize with CBs. Time-lapse fluorescence microscopy demonstrates that CBs moving in the nucleoplasm of S phase cells transiently associate for 10-40 min with telomeres. Our data raise the intriguing possibility that CBs may deliver hTR to telomeres and/or may function in other aspects of telomere maintenance.},
}
@article {pmid16314528,
year = {2005},
author = {Nakamura, M and Nabetani, A and Mizuno, T and Hanaoka, F and Ishikawa, F},
title = {Alterations of DNA and chromatin structures at telomeres and genetic instability in mouse cells defective in DNA polymerase alpha.},
journal = {Molecular and cellular biology},
volume = {25},
number = {24},
pages = {11073-11088},
pmid = {16314528},
issn = {0270-7306},
mesh = {Animals ; Cells, Cultured ; Chromatin/*chemistry/metabolism ; Chromosome Aberrations ; Chromosomes/metabolism ; DNA/chemistry/metabolism ; DNA Polymerase I/antagonists &amp; inhibitors/genetics/*metabolism ; DNA Replication/genetics ; DNA-Binding Proteins/metabolism ; Genomic Instability/*genetics ; Mice ; Point Mutation ; Shelterin Complex ; Telomerase/metabolism ; Telomere/*chemistry/metabolism ; Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 1/metabolism ; Temperature ; },
abstract = {Telomere length is controlled by a homeostatic mechanism that involves telomerase, telomere-associated proteins, and conventional replication machinery. Specifically, the coordinated actions of the lagging strand synthesis and telomerase have been argued. Although DNA polymerase alpha, an enzyme important for the lagging strand synthesis, has been indicated to function in telomere metabolism in yeasts and ciliates, it has not been characterized in higher eukaryotes. Here, we investigated the impact of compromised polymerase alpha activity on telomeres, using tsFT20 mouse mutant cells harboring a temperature-sensitive polymerase alpha mutant allele. When polymerase alpha was temperature-inducibly inactivated, we observed sequential events that included an initial extension of the G-tail followed by a marked increase in the overall telomere length occurring in telomerase-independent and -dependent manners, respectively. These alterations of telomeric DNA were accompanied by alterations of telomeric chromatin structures as revealed by quantitative chromatin immunoprecipitation and immunofluorescence analyses of TRF1 and POT1. Unexpectedly, polymerase alpha inhibition resulted in a significantly high incidence of Robertsonian chromosome fusions without noticeable increases in other types of chromosomal aberrations. These results indicate that although DNA polymerase alpha is essential for genome-wide DNA replication, hypomorphic activity leads to a rather specific spectrum of chromosomal abnormality.},
}
@article {pmid16312260,
year = {2005},
author = {Szeto, CC and Poon, PY and Lai, FM and Chow, KM and Szeto, CY and Li, PK},
title = {Chromosomal telomere shortening of kidney cells in IgA nephropathy by the measurement of DNA in urinary sediment.},
journal = {Clinical nephrology},
volume = {64},
number = {5},
pages = {337-342},
doi = {10.5414/cnp64337},
pmid = {16312260},
issn = {0301-0430},
mesh = {Adult ; DNA/*urine ; Female ; Glomerulonephritis, IGA/*genetics/*urine ; Humans ; Kidney/*cytology ; Telomere/*genetics ; },
abstract = {BACKGROUND: The histology and function of the kidney deteriorates with age and progressive renal failure, but the mechanisms involved in renal ageing are not known. In vitro studies suggest that telomere shortening is important in replicative senescence, and is accelerated by stress factors that increase replication. We investigated whether IgA nephropathy, a prototype chronic kidney disease, is associated with localized intrarenal cellular ageing.<br><br>METHODS: We studied the mean length of terminal restriction fragments (TRF), a measure of average telomere size, in the DNA of peripheral blood mononuclear cells and urinary sediment of 15 patients with IgA nephropathy.<br><br>RESULTS: The mean TRF lengths in peripheral blood is 7043.8 +/- 1 182.8 base pairs, and in urinary sediment is 6 749.7 +/- 636.5 base pairs. The mean TRF lengths of urinary DNA significantly correlate with the serum creatinine (r = -0.525, p = 0.044) and estimated glomerular filtration rate (GFR) (r = 0.651, p = 0.009). The mean TRF lengths of urinary DNA had an insignificant inverse correlation with patient age (r = -0.364, p = 0.2), and do not correlate with the degree of glomerulosclerosis (r = 0.004, p = 0.9) or tubulointerstitial scarring in renal biopsy (r =-0.032, p = 0.9). After 30 months of follow-up, the rate of decline of estimated GFR has an inverse correlation with the mean TRF lengths of urinary DNA (r = -0.699, p = 0.004). The TRF lengths of peripheral blood DNA do not correlate with any clinical or histological parameter or the rate of renal function decline.<br><br>CONCLUSIONS: Although this is a pilot study, our observation indicates that the TRF lengths of genomic DNA extracted from urinary sediment is related to the degree of renal impairment. However, a long telomere length of genomic DNA in urinary sediment is associated with a more rapid decline of renal function. Our findings might be relevant to the pathogenesis of progressive renal failure.},
}
@article {pmid16311518,
year = {2006},
author = {Glover, L and Horn, D},
title = {Repression of polymerase I-mediated gene expression at Trypanosoma brucei telomeres.},
journal = {EMBO reports},
volume = {7},
number = {1},
pages = {93-99},
pmid = {16311518},
issn = {1469-221X},
mesh = {Animals ; *Gene Expression Regulation ; Humans ; Protozoan Proteins/genetics/*metabolism ; RNA Polymerase I/*metabolism ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; Trypanosoma brucei brucei/*genetics/metabolism ; Variant Surface Glycoproteins, Trypanosoma/genetics/metabolism ; },
abstract = {The African trypanosome, Trypanosoma brucei, is a flagellated pathogenic protozoan that branched early from the eukaryotic lineage. Unusually, it uses RNA polymerase I (Pol I) for mono-telomeric expression of variant surface glycoprotein (VSG) genes in bloodstream-form cells. Many other subtelomeric VSG genes are reversibly repressed, but no repressive DNA sequence has been identified in any trypanosomatid. Here, we show that artificially seeded de novo telomeres repress Pol I-dependent gene expression in mammalian bloodstream and insect life-cycle stages of T. brucei. In a telomeric VSG expression site, repression spreads further along the chromosome and this effect is specific to the bloodstream stage. We also show that de novo telomere extension is telomerase dependent and that the rate of extension correlates with the expression level of the adjacent gene. Our results show constitutive telomeric repression in T. brucei and indicate that an enhanced, developmental stage-specific repression mechanism controls antigenic variation.},
}
@article {pmid16311252,
year = {2006},
author = {Baird, DM and Britt-Compton, B and Rowson, J and Amso, NN and Gregory, L and Kipling, D},
title = {Telomere instability in the male germline.},
journal = {Human molecular genetics},
volume = {15},
number = {1},
pages = {45-51},
doi = {10.1093/hmg/ddi424},
pmid = {16311252},
issn = {0964-6906},
mesh = {Age Factors ; DNA Primers ; *Genetic Variation ; Genomic Instability/*genetics ; Humans ; Male ; Polymerase Chain Reaction ; Polymorphism, Restriction Fragment Length ; Spermatozoa/*chemistry ; Telomere/*genetics ; },
abstract = {Telomeres play a key role in upholding the integrity of the genome, and telomerase expression in spermatogonial stem cells is responsible for the maintenance of telomere length in the human male germline. We have previously described extensive allelic variation in somatic cell telomere length that is set in the zygote, the ultimate source of which may be the germline. This implies that despite telomerase activity, substantial telomere length variation can be generated and tolerated in the germline; in order to investigate this further, we have examined the nature of telomere length variation in the human male germline. Here, we describe an analysis of both genome-wide telomere length and single molecule analysis of specific chromosome ends in human sperm. We observed individual specific differences in genome-wide telomere length. This variation may result from genetic differences within the components that determine the telomere length setting of each individual. Superimposed on the genome wide telomere length setting was a stochastic component of variation that generates germ-cells containing severely truncated telomeres. If not re-lengthened during early embryogenesis, such telomeres may limit the replicative capacity of cells derived from the zygote and have the potential to create fusagenic chromosomes, unbalanced translocations and terminal micro-deletions. These data may have implications for the genetic determination of ageing, genetic disease and fertility.},
}
@article {pmid16311000,
year = {2006},
author = {Wieser, M and Stadler, G and Böhm, E and Borth, N and Katinger, H and Grillari, J and Voglauer, R},
title = {Nuclear flow FISH: isolation of cell nuclei improves the determination of telomere lengths.},
journal = {Experimental gerontology},
volume = {41},
number = {2},
pages = {230-235},
doi = {10.1016/j.exger.2005.09.013},
pmid = {16311000},
issn = {0531-5565},
mesh = {Cell Nucleus/*ultrastructure ; *Cellular Senescence ; Flow Cytometry ; Humans ; *In Situ Hybridization, Fluorescence ; Kidney/ultrastructure ; Telomere/*ultrastructure ; },
abstract = {Understanding telomere biology is of utmost importance for aging and cancer research. An essential tool is the determination of telomere length, which traditionally is done by telomere restriction fragment analysis, a laborious and time consuming method. Therefore, large efforts have been made to establish alternative methods like flow FISH analysis. This method, combining fluorescence in situ hybridization with a telomere specific peptide nucleic acid probe and flow cytometry, measures single cells, is suitable for analysis of non-dividing cells, and can be performed within 24 h. However, when performing flow FISH analysis with normal human kidney epithelial cells, we observed strong variation of autofluorescence at different population doubling levels, especially at replicative senescence, which limits the suitability of this method for the analysis of normal human cells. Since molecules responsible for autofluorescence are predominantly accumulating in the cytoplasm, we decided to isolate the nuclei to perform flow FISH analysis. With this novel nuclear flow FISH (NFF) technique we were able to minimize autofluorescence and its variability, thereby improving the signal-to-noise ratio and consequently, allowing the determination of telomere length during in vitro aging with high accuracy. Moreover, NFF will find broader applications, whenever in situ hybridization signals have to be quantitated.},
}
@article {pmid16307919,
year = {2005},
author = {Verdun, RE and Crabbe, L and Haggblom, C and Karlseder, J},
title = {Functional human telomeres are recognized as DNA damage in G2 of the cell cycle.},
journal = {Molecular cell},
volume = {20},
number = {4},
pages = {551-561},
doi = {10.1016/j.molcel.2005.09.024},
pmid = {16307919},
issn = {1097-2765},
support = {R01 GM069525/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line ; DNA Damage/*physiology ; DNA Repair/physiology ; DNA-Binding Proteins/metabolism ; Fibroblasts/cytology/metabolism ; G2 Phase/*genetics/physiology ; Humans ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres have to be distinguished from DNA breaks that initiate a DNA damage response. Proteins involved in the DNA damage response have previously been found at telomeres in transformed cells; however, the importance of these factors for telomere function has not been understood. Here, we show that telomeres of telomerase-negative primary cells recruit Mre11, phosphorylated NBS1, and ATM in every G2 phase of the cell cycle. This recruitment correlates with a partial release of telomeric POT1; moreover, telomeres were found to be accessible to modifying enzymes at this time in the cell cycle, suggesting that they are unprotected. Degradation of the MRN complex, as well as inhibition of ATM, led to telomere dysfunction. Consequentially, we propose that a localized DNA damage response at telomeres after replication is essential for recruiting the processing machinery that promotes formation of a chromosome end protection complex.},
}
@article {pmid16303830,
year = {2006},
author = {Aviv, A and Valdes, A and Gardner, JP and Swaminathan, R and Kimura, M and Spector, TD},
title = {Menopause modifies the association of leukocyte telomere length with insulin resistance and inflammation.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {91},
number = {2},
pages = {635-640},
doi = {10.1210/jc.2005-1814},
pmid = {16303830},
issn = {0021-972X},
support = {AG 020132/AG/NIA NIH HHS/United States ; AG 021593/AG/NIA NIH HHS/United States ; HL 070137/HL/NHLBI NIH HHS/United States ; //Wellcome Trust/United Kingdom ; },
mesh = {Adolescent ; Adult ; Aged ; Blood Glucose/metabolism ; C-Reactive Protein/metabolism ; Cohort Studies ; Female ; Humans ; Insulin/blood ; Insulin Resistance/*physiology ; Leptin/blood ; Leukocytes/*physiology ; Menopause/*physiology ; Middle Aged ; Telomere/genetics/*physiology ; },
abstract = {CONTEXT: Leukocyte telomere length is inversely correlated with age, insulin resistance, serum leptin, and smoking.<br><br>OBJECTIVE: We explored whether menopausal status modifies the relations between leukocyte telomere length and insulin resistance. In addition, we examined the effect of menopause on the relation between leukocyte telomere length and C-reactive protein (CRP), an index of inflammation.<br><br>DESIGN: This was an observational cohort study.<br><br>SETTING: The study setting was community based.<br><br>PARTICIPANTS: A total of 1517 women aged 18-79 yr selected only for belonging to a twin pair and representative of the general population participated in the study.<br><br>MAIN OUTCOME MEASURE: Leukocyte telomere restriction fragment length (TRFL) was measured.<br><br>RESULTS: Insulin resistance (expressed in the homeostasis model assessment), leptin, and CRP were inversely correlated with leukocyte TRFL in premenopausal but not postmenopausal women. Insulin resistance, CRP, but not leptin independently accounted for variation in white blood cell TRFL in premenopausal women.<br><br>CONCLUSIONS: Menopausal status impacts leukocyte telomere length and its relation with insulin resistance and inflammation in women.},
}
@article {pmid16302000,
year = {2006},
author = {Tahara, H and Shin-Ya, K and Seimiya, H and Yamada, H and Tsuruo, T and Ide, T},
title = {G-Quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3' telomeric overhang in cancer cells.},
journal = {Oncogene},
volume = {25},
number = {13},
pages = {1955-1966},
doi = {10.1038/sj.onc.1209217},
pmid = {16302000},
issn = {0950-9232},
mesh = {Anaphase ; Breast Neoplasms/*pathology ; Cell Death ; Dose-Response Relationship, Drug ; Epithelial Cells ; Female ; Fibroblasts ; HeLa Cells ; Humans ; Nuclear Proteins/*metabolism ; Oxazoles/*pharmacology ; TATA Box Binding Protein-Like Proteins/*metabolism ; *Telomere/ultrastructure ; Telomeric Repeat Binding Protein 2 ; Tumor Cells, Cultured ; },
abstract = {Inhibition of telomerase activity by telomerase inhibitors induces a gradual loss of telomeres, and this in turn causes cancer cells to enter to a crisis stage. Here, we report the telomerase inhibitor telomestatin, which is known to stabilize G-quadruplex structures at 3' single-stranded telomeric overhangs (G-tails), rapidly dissociates TRF2 from telomeres in cancer cells within a week, when given at a concentration that does not cause normal cells to die. The G-tails were dramatically reduced upon short-term treatment with the drug in cancer cell lines, but not in normal fibroblasts and epithelial cells. In addition, telomestatin also induced anaphase bridge formation in cancer cell lines. These effects of telomestatin were similar to those of dominant negative TRF2, which also causes a prompt loss of the telomeric G-tails and induces an anaphase bridge. These results indicate that telomestatin exerts its anticancer effect not only through inhibiting telomere elongation, but also by rapidly disrupting the capping function at the very ends of telomeres. Unlike conventional telomerase inhibitors that require long-term treatments, the G-quadruplex stabilizer telomestatin induced prompt cell death, and it was selectively effective in cancer cells. This study also identifies the TRF2 protein as a therapeutic target for treating many types of cancer which have the TRF2 protein at caps of the telomere DNA of each chromosome.},
}
@article {pmid16300480,
year = {2005},
author = {Martin-Ruiz, CM and Gussekloo, J and van Heemst, D and von Zglinicki, T and Westendorp, RG},
title = {Telomere length in white blood cells is not associated with morbidity or mortality in the oldest old: a population-based study.},
journal = {Aging cell},
volume = {4},
number = {6},
pages = {287-290},
doi = {10.1111/j.1474-9726.2005.00171.x},
pmid = {16300480},
issn = {1474-9718},
mesh = {Aged, 80 and over ; Aging/*physiology ; Biomarkers ; Cross-Sectional Studies ; Female ; Follow-Up Studies ; Humans ; Male ; Monocytes/cytology ; Morbidity ; Mortality ; Survival Analysis ; Telomere/*ultrastructure ; },
abstract = {Cross-sectional studies have repeatedly suggested peripheral blood monocyte telomere length as a biomarker of aging. To test this suggestion in a large population-based follow-up study of the oldest old, we measured telomere length at baseline in 598 participants of the Leiden 85-plus Study (mean age at baseline 89.8 years). We also obtained second telomere measurements from 81 participants after an average time span of between 3.9 and 12.9 years. Telomere length at baseline was not predictive for mortality (P > 0.40 for all-cause, cardiovascular causes, cancer or infectious diseases, Cox regression for gender-adjusted tertiles of telomere length) or for the incidence of dementia (P = 0.78). Longitudinally, telomere length was highly unstable in a large fraction of participants. We conclude that blood monocyte telomere length is not a predictive indicator for age-related morbidity and mortality at ages over 85 years, possibly because of a high degree of telomere length instability in this group.},
}
@article {pmid16299424,
year = {2005},
author = {Tsuji, A and Ishiko, A and Ikeda, N},
title = {Telomere shortening and age estimation in forensic medicine.},
journal = {Gerontology},
volume = {51},
number = {6},
pages = {416},
doi = {10.1159/000088707},
pmid = {16299424},
issn = {0304-324X},
mesh = {Adult ; Aged ; Aging/genetics/*pathology ; DNA/analysis/genetics ; Forensic Pathology/methods ; Humans ; Middle Aged ; Telomere/genetics/*pathology ; },
}
@article {pmid16284252,
year = {2005},
author = {Goldman, F and Bouarich, R and Kulkarni, S and Freeman, S and Du, HY and Harrington, L and Mason, PJ and Londoño-Vallejo, A and Bessler, M},
title = {The effect of TERC haploinsufficiency on the inheritance of telomere length.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {102},
number = {47},
pages = {17119-17124},
pmid = {16284252},
issn = {0027-8424},
support = {P30 CA091842/CA/NCI NIH HHS/United States ; R01 CA105312/CA/NCI NIH HHS/United States ; R01 CA 105312/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/genetics ; Anticipation, Genetic/genetics ; Cells, Cultured ; Child ; Child, Preschool ; Dyskeratosis Congenita/*enzymology/*genetics/physiopathology ; Female ; Gene Deletion ; *Haploidy ; Heterozygote ; Humans ; Male ; Middle Aged ; Pedigree ; RNA/*genetics/physiology ; Telomerase/*genetics/physiology ; Telomere/*enzymology/*genetics ; },
abstract = {Telomeres protect chromosome ends from end-to-end fusion and degradation. Loss of telomere function causes cell-cycle arrest or cell death. Autosomal dominant dyskeratosis congenita (AD DC), a rare inherited bone marrow failure syndrome, is caused by mutations in TERC, the RNA component of telomerase. Here, we studied the telomere dynamics over three generations in a 32-member extended family with AD DC due to a TERC gene deletion. Our analysis shows that peripheral blood cells from family members haploinsufficient for TERC have very short telomeres. Telomeres are equally short in all individuals carrying the TERC gene deletion irrespective of their age. Chromosome-specific telomere analysis distinguishing the parental origin of telomeres showed that in gene deletion carriers, paternal and maternal telomeres are similarly short and similar in length to those of the affected parent. In children of affected parents who have normal TERC genes, parental telomeres are again similar in length, but two generations appear to be necessary to fully restore normal telomere length. These results are consistent with a model in which telomerase preferentially acts on the shortest telomeres. When TERC is limiting, this preference leads to the accelerated shortening of longer telomeres. The limited amount of active telomerase in TERC RNA haploinsufficiency may not be able to maintain the minimal length of the increasing number of short telomeres. Thus, the number of cells with excessively short telomeres and the degree of residual telomerase activity may determine the onset of disease in patients with AD DC.},
}
@article {pmid16283620,
year = {2006},
author = {French, JD and Dunn, J and Smart, CE and Manning, N and Brown, MA},
title = {Disruption of BRCA1 function results in telomere lengthening and increased anaphase bridge formation in immortalized cell lines.},
journal = {Genes, chromosomes &amp; cancer},
volume = {45},
number = {3},
pages = {277-289},
doi = {10.1002/gcc.20290},
pmid = {16283620},
issn = {1045-2257},
mesh = {Anaphase/genetics/*physiology ; Cell Line, Transformed ; Genes, BRCA1/*physiology ; Humans ; Mutation ; Neoplasm Proteins/metabolism ; Nuclear Proteins/metabolism ; Promyelocytic Leukemia Protein ; Protein Binding ; Telomerase/metabolism ; Telomere/genetics/*physiology ; Telomeric Repeat Binding Protein 1/genetics ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; Transcription Factors/metabolism ; Tumor Suppressor Proteins/metabolism ; },
abstract = {BRCA1 is a tumor suppressor that functions in controlling cell growth and maintaining genomic stability. BRCA1 has also been implicated in telomere maintenance through its ability to regulate the transcription of hTERT, the catalytic subunit of telomerase, resulting in telomere shortening, and to colocalize with the telomere-binding protein TRF1. The high incidence of nonreciprocal translocations in tumors arising from BRCA1 mutation carriers and Brca1-null mice also raises the possibility that BRCA1 plays a role in telomere protection. To date, however, the consequences for telomere status of disrupting BRCA1 have not been reported. To examine the role of BRCA1 in telomere regulation, we have expressed a dominant-negative mutant of BRCA1 (trBRCA1), known to disrupt multiple functions of BRCA1, in telomerase-positive mammary epithelial cells (SVCT) and telomerase-negative ALT cells (GM847). In SVCT cells, expression of trBRCA1 resulted in an increased incidence of anaphase bridges and in an increase in telomere length, but no change in telomerase activity. In GM847 cells, trBRCA1 also increased anaphase bridge formation but did not induce any change in telomere length. BRCA1 colocalized with TRF2 in telomerase-positive cells and with a small subset of ALT-associated PML bodies (APBs) in ALT cells. Together, these results raise the possibility that BRCA1 could play a role in telomere protection and suggest a potential mechanism for one of the phenotypes of BRCA1-deficient cells.},
}
@article {pmid16281260,
year = {2006},
author = {Swiggers, SJ and Kuijpers, MA and de Cort, MJ and Beverloo, HB and Zijlmans, JM},
title = {Critically short telomeres in acute myeloid leukemia with loss or gain of parts of chromosomes.},
journal = {Genes, chromosomes &amp; cancer},
volume = {45},
number = {3},
pages = {247-256},
doi = {10.1002/gcc.20286},
pmid = {16281260},
issn = {1045-2257},
mesh = {Acute Disease ; Adult ; Aged ; Bone Marrow/pathology ; *Cellular Senescence ; *Chromosome Aberrations ; Humans ; Leukemia, Myeloid/genetics/*pathology ; Middle Aged ; Nuclear Proteins/metabolism ; Shelterin Complex ; TATA Box Binding Protein-Like Proteins/metabolism ; Telomerase/metabolism ; Telomere/genetics/*physiology ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 2 ; Tumor Cells, Cultured ; },
abstract = {Telomeres, nucleoprotein complexes at chromosome ends, protect chromosomes against end-to-end fusion. Previous in vitro studies in human fibroblast models indicated that telomere dysfunction results in chromosome instability. Loss of telomere function can result either from critical shortening of telomeric DNA or from loss of distinct telomere-capping proteins. It is less clear whether telomere dysfunction has an important role in human cancer development in vivo. Acute myeloid leukemia (AML) is a good model to study mechanisms that generate chromosome instability in human cancer development because distinct groups of AML are characterized either by aberrations that theoretically could result from telomere dysfunction (terminal deletions, gains/losses of chromosome parts, nonreciprocal translocations), or aberrations that are unlikely to result from telomere dysfunction (e.g., reciprocal translocations or inversions). Here we demonstrate that AML with multiple chromosome aberrations that theoretically could result from telomere dysfunction is invariably characterized by critically short telomeres. Short telomeres in this group are not associated with low telomerase activity or decreased expression of essential telomeric capping proteins TRF2 and POT1. In contrast, telomerase activity levels are significantly higher in AML with short telomeres. Notably, short telomeres in the presence of high telomerase may relate to significantly higher expression of TRF1, a negative regulator of telomere length. Our observations suggest that, consistent with previous in vitro fibroblast models, age-related critical telomere shortening may have a role in generating chromosome instability in human AML development.},
}
@article {pmid16278652,
year = {2005},
author = {Tahara, H and Kusunoki, M and Yamanaka, Y and Matsumura, S and Ide, T},
title = {G-tail telomere HPA: simple measurement of human single-stranded telomeric overhangs.},
journal = {Nature methods},
volume = {2},
number = {11},
pages = {829-831},
doi = {10.1038/nmeth797},
pmid = {16278652},
issn = {1548-7091},
mesh = {Base Sequence ; Cell Line, Tumor ; DNA, Single-Stranded/*analysis/genetics ; Humans ; Nucleic Acid Hybridization/*methods ; Repetitive Sequences, Nucleic Acid/genetics ; Sensitivity and Specificity ; Telomere/chemistry/*genetics ; },
abstract = {Accurate measurement of telomeric 3'-overhang (G-tail) lengths is essential for investigation of the biological effects of telomere dysfunction. G-tail telomere hybridization protection assay (Gt-telomere HPA) has the advantages of being simple to perform, accurate and highly sensitive for G tails as short as 20 nucleotides. Furthermore, Gt-telomere HPA is specific and quantitative for human G tails, and can be used to assay cell lysates as well as genomic DNA.},
}
@article {pmid16278293,
year = {2005},
author = {Andreyeva, EN and Belyaeva, ES and Semeshin, VF and Pokholkova, GV and Zhimulev, IF},
title = {Three distinct chromatin domains in telomere ends of polytene chromosomes in Drosophila melanogaster Tel mutants.},
journal = {Journal of cell science},
volume = {118},
number = {Pt 23},
pages = {5465-5477},
doi = {10.1242/jcs.02654},
pmid = {16278293},
issn = {0021-9533},
mesh = {Animals ; Chromatin/*genetics ; Chromosome Banding ; Chromosome Mapping ; Chromosomes/*genetics/*ultrastructure ; Drosophila melanogaster/genetics ; Euchromatin/genetics ; Gene Amplification ; Heterochromatin/genetics ; Mutation ; Retroelements ; Telomere/*genetics/*ultrastructure ; },
abstract = {Drosophila melanogaster telomeric DNA is known to comprise two domains: the terminal tract of retrotransposons (HeT-A, TART and TAHRE) and telomere-associated sequences (TAS). Chromosome tips are capped by a protein complex, which is assembled on the chromosome ends independently of the underlying terminal DNA sequences. To investigate the properties of these domains in salivary gland polytene chromosomes, we made use of Tel mutants. Telomeres in this background are elongated owing to the amplification of a block of terminal retroelements. Supercompact heterochromatin is absent from the telomeres of polytene chromosomes: electron microscopy analysis identifies the telomeric cap and the tract of retroelements as a reticular material, having no discernible banding pattern, whereas TAS repeats appear as faint bands. According to the pattern of bound proteins, the cap, tract of retroelements and TAS constitute distinct and non-overlapping domains in telomeres. SUUR, HP2, SU(VAR)3-7 and H3Me3K27 localize to the cap region, as has been demonstrated for HP1. All these proteins are also found in pericentric heterochromatin. The tract of retroelements is associated with proteins characteristic for both heterochromatin (H3Me3K9) and euchromatin (H3Me3K4, JIL-1, Z4). The TAS region is enriched for H3Me3K27. PC and E(Z) are detected both in TAS and many intercalary heterochromatin regions. Telomeres complete replication earlier than heterochromatic regions. The frequency of telomeric associations in salivary gland polytene chromosomes does not depend on the SuUR gene dosage, rather it appears to be defined by the telomere length.},
}
@article {pmid16275645,
year = {2006},
author = {Lee, TH and Perrem, K and Harper, JW and Lu, KP and Zhou, XZ},
title = {The F-box protein FBX4 targets PIN2/TRF1 for ubiquitin-mediated degradation and regulates telomere maintenance.},
journal = {The Journal of biological chemistry},
volume = {281},
number = {2},
pages = {759-768},
doi = {10.1074/jbc.M509855200},
pmid = {16275645},
issn = {0021-9258},
support = {R01 AG011085/AG/NIA NIH HHS/United States ; R01AG11085/AG/NIA NIH HHS/United States ; R01GM56230/GM/NIGMS NIH HHS/United States ; R21CA022082/CA/NCI NIH HHS/United States ; },
mesh = {Adenosine Triphosphate/chemistry ; Cell Line ; Cell Line, Tumor ; DNA/chemistry/metabolism ; *Down-Regulation ; F-Box Proteins/*metabolism/*physiology ; Genetic Vectors ; Glutathione Transferase/metabolism ; HeLa Cells ; Humans ; Immunoblotting ; Immunoprecipitation ; Mitosis ; Protein Binding ; Protein Isoforms ; Protein Synthesis Inhibitors/pharmacology ; RNA Interference ; RNA, Messenger/metabolism ; Recombinant Proteins/chemistry ; Substrate Specificity ; Telomere/*ultrastructure ; Telomeric Repeat Binding Protein 1/*metabolism ; Time Factors ; Two-Hybrid System Techniques ; Ubiquitin/*chemistry/metabolism ; },
abstract = {Pin2/TRF1 was identified previously as both a protein (TRF1) that binds to telomeric DNA repeats and as a protein (Pin2) that associates with the kinase NIMA and suppresses its mitosis inducing activity. Pin2/TRF1 negatively regulates telomere length and also plays a critical role in cell cycle checkpoint control. Pin2/TRF1 is down-regulated in many human cancers and may be degraded by the ubiquitin-proteasome pathway, but components of the pathway involved in Pin2/TRF1 turnover have not been elucidated. By using the two-hybrid system, we recently identified Pin2/TRF1-interacting proteins, PinX1-4, and we demonstrated that PinX1 is a conserved telomerase inhibitor and a putative tumor suppressor. Here we report the characterization of PinX3. PinX3 was later found to be identical to Fbx4, a member of the F-box family of proteins, which function as substrate-specific adaptors of Cul1-based ubiquitin ligases. Fbx4 interacts with both Pin2 and TRF1 isoforms and promotes their ubiquitination in vitro and in vivo. Moreover, overexpression of Fbx4 reduces endogenous Pin2/TRF1 protein levels and causes progressive telomere elongation in human cells. In contrast, inhibition of Fbx4 by RNA interference stabilizes Pin2/TRF1 and promotes telomere shortening, thereby impairing cell growth. These results demonstrate that Fbx4 is a central regulator of Pin2/TRF1 protein abundance and that alterations in the stability of Pin2/TRF1 can have a dramatic impact on telomere length. Thus, Fbx4 may play a critical role in telomere maintenance.},
}
@article {pmid16273215,
year = {2005},
author = {Sebastian, S and Grammatica, L and Paradiso, A},
title = {Telomeres, telomerase and oral cancer (Review).},
journal = {International journal of oncology},
volume = {27},
number = {6},
pages = {1583-1596},
pmid = {16273215},
issn = {1019-6439},
mesh = {Humans ; Models, Biological ; Mouth Neoplasms/enzymology/genetics/*therapy ; Prognosis ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {Oral squamous cell carcinoma (oral cancer) and many squamous cell carcinomas of the head and neck arise as a consequence of multiple molecular events induced by the effects of various carcinogens related to tobacco use, environmental factors, and viruses in some instances (e.g., mucosal oncogenic human papillomaviruses), against a background of inheritable resistance or susceptibility. Consequent genetic damage affects many chromosomes and genes, and it is the accumulation of these changes that appears to lead to carcinoma. Telomere maintenance by telomerase or, in its absence, alternative lengthening of telomeres protect this acquired altered genetic information ensuring immortality without losing eukaryotic linear DNA; when this does not occur DNA is lost and end-replication problems arise. Telomerase is reactivated in 80-90% of cancers thus attracting the attention of pathologists and clinicians who have explored its use as a target for anticancer therapy and to develop better diagnostic and prognostic markers. In the last few years, valuable research from various laboratories has provided major insights into telomerase and telomeres leading to their use as diagnostic and prognostic markers in several types of cancer. Moreover, many strategies have emerged which inhibit this complex enzyme for anticancer therapy and are one step ahead of clinical trials. This review explains the basic biology and the clinical implications of telomerase-based diagnosis and prognosis, the prospects for its use in anticancer therapy, and the limitations it presents in the context of oral cancer.},
}
@article {pmid16272366,
year = {2005},
author = {Zhou, J and Shen, X and Huang, J and Hodes, RJ and Rosenberg, SA and Robbins, PF},
title = {Telomere length of transferred lymphocytes correlates with in vivo persistence and tumor regression in melanoma patients receiving cell transfer therapy.},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {175},
number = {10},
pages = {7046-7052},
pmid = {16272366},
issn = {0022-1767},
support = {Z01 SC003811-31/SC/NCI NIH HHS/United States ; //Intramural NIH HHS/United States ; },
mesh = {Base Sequence ; Biomarkers/metabolism ; Cell Proliferation ; DNA, Neoplasm/genetics ; Humans ; *Immunotherapy, Adoptive ; Lymphocytes, Tumor-Infiltrating/*metabolism/pathology ; Melanoma/genetics/immunology/metabolism/*therapy ; Phenotype ; Telomere/*genetics ; },
abstract = {Recent studies have indicated that adoptive immunotherapy with autologous antitumor tumor-infiltrating lymphocytes (TILs) following nonmyeloablative chemotherapy mediates tumor regression in approximately 50% of treated patients with metastatic melanoma, and that tumor regression is correlated with the degree of persistence of adoptively transferred T cells in peripheral blood. These findings, which suggested that the proliferative potential of transferred T cells may play a role in clinical responses, led to the current studies in which telomere length as well as phenotypic markers expressed on the administered TILs were examined. TILs that were associated with objective clinical responses following adoptive transfer possessed a mean telomere length of 6.3 kb, whereas TILs that were not associated with significant clinical responses were significantly shorter, averaging 4.9 kb (p < 0.01). Furthermore, individual TIL-derived T cell clonotypes that persisted in vivo following adoptive cell transfer possessed telomeres that were longer than telomeres of T cell clonotypes that failed to persist (6.2 vs 4.5 kb, respectively; p < 0.001). Expression of the costimulatory molecule CD28 also appeared to be associated with long telomeres and T cell persistence. These results, indicating that the telomere length of transferred lymphocytes correlated with in vivo T cell persistence following adoptive transfer, and coupled with the previous observation that T cell persistence was associated with clinical responses in this adoptive immunotherapy trial, suggest that telomere length and the proliferative potential of the transferred T cells may play a significant role in mediating response to adoptive immunotherapy.},
}
@article {pmid16271950,
year = {2005},
author = {Amiel, A and Goldzak, G and Gaber, E and Yosef, G and Fejgin, MD and Yukla, M and Lishner, M},
title = {Random aneuploidy and telomere capture in chronic lymphocytic leukemia and chronic myeloid leukemia patients.},
journal = {Cancer genetics and cytogenetics},
volume = {163},
number = {1},
pages = {12-16},
doi = {10.1016/j.cancergencyto.2005.04.007},
pmid = {16271950},
issn = {0165-4608},
mesh = {Aged ; Aged, 80 and over ; *Aneuploidy ; Bone Marrow Cells/pathology ; Chromosome Mapping ; Chromosomes, Human, Pair 15 ; *Chromosomes, Human, Pair 21 ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/pathology ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*genetics/pathology ; Middle Aged ; Telomere/*genetics ; Translocation, Genetic ; *Trisomy ; },
abstract = {Telomeric regions of the human genome are of particular interest, because rearrangements of these regions are difficult to identify by conventional chromosome banding technology. With the advent of molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH), it has been possible to investigate the terminus in cytogenetically visible terminal deletions and telomere rearrangements. We investigated telomere capture and aneuploidy rates in chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) patients, as well as in healthy control subsets. Using a FISH technique, we estimated the random aneuploidy and telomere capture of the 21q22, SNRPN, and 15qter loci. Higher aneuploidy rates were found in the leukocytes of CLL and CML patients, compared with the control group, for the 21q22 and SNRPN loci. There was no difference in the aneuploidy rate between the CML and CLL groups. Telomere capture was found in the two groups (CLL and CML), but not in the control group. We propose that the telomere capture phenomenon is much more common than has been reported in the literature; however, its prognostic significance is yet to be established.},
}
@article {pmid16264192,
year = {2005},
author = {Laud, PR and Multani, AS and Bailey, SM and Wu, L and Ma, J and Kingsley, C and Lebel, M and Pathak, S and DePinho, RA and Chang, S},
title = {Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway.},
journal = {Genes &amp; development},
volume = {19},
number = {21},
pages = {2560-2570},
pmid = {16264192},
issn = {0890-9369},
support = {R01 CA084628/CA/NCI NIH HHS/United States ; U01 CA084313/CA/NCI NIH HHS/United States ; R01CA84628/CA/NCI NIH HHS/United States ; U01CA84313/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; Cellular Senescence/*genetics ; Chromatids/genetics/*metabolism ; Chromosomal Instability/genetics ; DNA Helicases/*deficiency/genetics/metabolism ; Humans ; Mice ; Neoplasms/etiology/genetics/metabolism ; RecQ Helicases ; Recombination, Genetic/*genetics ; Telomere/*metabolism ; Werner Syndrome/complications/genetics/metabolism ; Werner Syndrome Helicase ; },
abstract = {Werner Syndrome (WS) is characterized by premature aging, genomic instability, and cancer. The combined impact of WRN helicase deficiency and limiting telomere reserves is central to disease pathogenesis. Here, we report that cells doubly deficient for telomerase and WRN helicase show chromosomal aberrations and elevated recombination rates between telomeres of sister chromatids. Somatic reconstitution of WRN function, but not a WRN helicase-deficient mutant, abolished telomere sister chromatid exchange (T-SCE), indicating that WRN normally represses T-SCEs. Elevated T-SCE was associated with greater immortalization potential and resultant tumors maintained telomeres via the alternative lengthening of telomere (ALT) pathway. We propose that the increased incidence of chromosomal instability and cancer in WS relates in part to aberrant recombinations between sister chromatids at telomeres, which facilitates the activation of ALT and engenders cancer-relevant chromosomal aberrations and tumor formation.},
}
@article {pmid16264188,
year = {2005},
author = {Baumgartner, BL and Lundblad, V},
title = {Telomere identity crisis.},
journal = {Genes &amp; development},
volume = {19},
number = {21},
pages = {2522-2525},
doi = {10.1101/gad.1373205},
pmid = {16264188},
issn = {0890-9369},
mesh = {Animals ; Cell Cycle/*physiology ; DNA Damage/physiology ; DNA Repair/*physiology ; Gene Rearrangement, T-Lymphocyte/*physiology ; Humans ; T-Lymphocytes/cytology/*physiology ; Telomerase/*metabolism ; Telomere/genetics/*metabolism ; },
}
@article {pmid16258279,
year = {2005},
author = {Sfeir, AJ and Shay, JW and Wright, WE},
title = {Fine-tuning the chromosome ends: the last base of human telomeres.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {4},
number = {11},
pages = {1467-1470},
doi = {10.4161/cc.4.11.2161},
pmid = {16258279},
issn = {1551-4005},
support = {AG01228/AG/NIA NIH HHS/United States ; },
mesh = {Base Sequence/*genetics ; Chromosomes, Human/*chemistry/genetics ; Cytosine/chemistry ; Guanine/chemistry ; Humans ; Telomere/*chemistry/genetics ; },
abstract = {Telomeres protect chromosomes from degradation and loss of vital sequence, block end-end fusion, and allow the cell to distinguish between broken ends and chromosome ends. Mammalian telomeres end in single-stranded (TTAGGG)-rich 3'-overhangs that are tucked back into the preceding double stranded region to form a T-loop. The end structure of mammalian telomeres has just started to be elucidated and through this extra views we highlight one aspect of that structure. We have recently identified the terminal nucleotides of both the C-rich and G-rich telomere strands in human cells and showed that approximately 80% of the C-rich strands terminate precisely in ATC-5', while the last base of the G-strand is less precise. This finding has important implications for the processing events that act on the telomere ends post-replication. While the mechanism behind this phenotype is yet to be unraveled, we discuss potential models that could explain the last base specificity.},
}
@article {pmid16258070,
year = {2005},
author = {Nordfjäll, K and Larefalk, A and Lindgren, P and Holmberg, D and Roos, G},
title = {Telomere length and heredity: Indications of paternal inheritance.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {102},
number = {45},
pages = {16374-16378},
pmid = {16258070},
issn = {0027-8424},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; DNA-Binding Proteins/genetics ; Female ; *Heredity ; Humans ; Male ; Middle Aged ; Sex Characteristics ; Telomerase/genetics ; *Telomere ; },
abstract = {Cellular telomere length is linked to replicative life span. Telomere repeats are lost in peripheral blood cells in vivo by age, and women show less telomere attrition than men. Previous reports have indicated that telomere length and chromosome-specific telomere-length patterns partly are inherited. The mode of heredity has not been clarified, but a link to the X chromosome was recently suggested. We analyzed peripheral mononuclear cells from 49 unrelated families for telomere length using a real-time PCR method. Short-term cultured Epstein-Barr virus-transformed lymphoblasts from the same individuals (n = 130) were analyzed for ability to maintain telomere length and possible gender-linked inheritance. A statistically significant association between telomere lengths comparing father-son (P = 0.011, n = 20) and father-daughter (P = 0.005, n = 22) pairs was found. However, no correlation was observed between mother-daughter (P = 0.463, n = 23) or mother-son (P = 0.577, n = 18). The father-offspring correlation was highly significant (P < 0.0001), in contrast to mother-offspring (P = 0.361). Epstein-Barr virus cultures demonstrated in most cases telomere preservation inversely related to initial mononuclear cell telomere length with short telomeres displaying the most pronounced elongation. Telomere length is inherited, and evidence for a father-to-offspring heritage of this trait was obtained, whereas in vitro telomere length maintenance was found to be dependent on the initial telomere length.},
}
@article {pmid16254243,
year = {2005},
author = {Trelles-Sticken, E and Bonfils, S and Sollier, J and Géli, V and Scherthan, H and de La Roche Saint-André, C},
title = {Set1- and Clb5-deficiencies disclose the differential regulation of centromere and telomere dynamics in Saccharomyces cerevisiae meiosis.},
journal = {Journal of cell science},
volume = {118},
number = {Pt 21},
pages = {4985-4994},
doi = {10.1242/jcs.02612},
pmid = {16254243},
issn = {0021-9533},
mesh = {Cell Cycle Proteins/genetics/metabolism ; Cell Nucleus/genetics ; Centromere/*metabolism ; Chromosome Pairing/genetics ; Cyclin B/deficiency/*genetics ; DNA-Binding Proteins/deficiency/*genetics ; Epistasis, Genetic ; Gene Silencing ; Histone Methyltransferases ; Histone-Lysine N-Methyltransferase/deficiency/genetics ; Intracellular Signaling Peptides and Proteins ; Meiosis/genetics ; Protein Methyltransferases ; Protein Serine-Threonine Kinases ; S Phase/genetics ; Saccharomyces cerevisiae/cytology/enzymology/genetics ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Transcription Factors/deficiency/*genetics/metabolism ; },
abstract = {The entry into meiosis is characterized by a lengthy premeiotic S phase and a reorganization of the nuclear architecture. Analysis of centromere and telomere dynamics in wild-type Saccharomyces cerevisiae meiosis suggests that resolution of vegetative centromere and telomere clusters are independent events differently connected to premeiotic S phase. Absence of the B-type cyclin Clb5 or the Set1 histone methyltransferase leads to a delay of premeiotic S phase by separate mechanisms. In clb5Delta cells, centromere cluster resolution appears normal, whereas dissolution of the vegetative telomere clusters is impaired and meiosis-specific clustering of telomeres, i.e. bouquet formation, is grossly delayed. In set1Delta cells, centromere and telomere redistribution are both impaired and bouquet nuclei are absent, despite proper location of the meiosis-specific telomere protein Ndj1. Thus, centromere and telomere redistribution at the onset of prophase I is differentially regulated, with centromere dispersion occurring independently of premeiotic S phase. The normal kinetics of dissolution of the vegetative telomere clusters in a set1Delta mec1-1 mutant suggests the presence of a checkpoint that limits the dispersion of telomeres in absence of Set1.},
}
@article {pmid16253503,
year = {2005},
author = {Binz, N and Shalaby, T and Rivera, P and Shin-ya, K and Grotzer, MA},
title = {Telomerase inhibition, telomere shortening, cell growth suppression and induction of apoptosis by telomestatin in childhood neuroblastoma cells.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {41},
number = {18},
pages = {2873-2881},
doi = {10.1016/j.ejca.2005.08.025},
pmid = {16253503},
issn = {0959-8049},
mesh = {Apoptosis/*drug effects ; Cell Division/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Child ; Enzyme Inhibitors/*pharmacology ; Humans ; Neuroblastoma/*enzymology/pathology ; Oxazoles/*pharmacology ; Proto-Oncogene Mas ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects ; },
abstract = {Neuroblastoma is a tumour derived from primitive cells of the sympathetic nervous system and is the most common extracranial solid tumour in childhood. Unfavourable tumours are characterised not only by structural changes, including 1p deletion and amplification of the MYCN proto-oncogene, but also by high telomerase activity. Telomeric G-rich single-stranded DNA can adopt in vitro an intramolecular quadruplex structure, which has been shown to inhibit telomerase activity. In this study, we examined telomestatin, a G-quadruplex interactive agent, for its ability to inhibit telomere maintenance of neuroblastoma cells. Telomere length was determined by the terminal restriction fragment method, telomerase activity was measured by a quantitative telomeric repeat amplification protocol, and the expression of human telomerase by quantitative real-time polymerase chain reaction (RT-PCR). Short-term treatment with telomestatin resulted in dose-dependent cytotoxicity and induction of apoptosis. Long-term treatment with telomestatin at non-cytotoxic, but still telomerase activity-inhibiting, concentrations resulted in telomere shortening, growth arrest and induction of apoptosis. These results suggest that the effect of telomestatin is dose-dependent and at least 2-fold. Prolonged low-dose treatment with telomestatin limits the cellular lifespan of NB cells through disruption of telomere maintenance.},
}
@article {pmid16249747,
year = {2005},
author = {Lahav, M and Uziel, O and Kestenbaum, M and Fraser, A and Shapiro, H and Radnay, J and Szyper-Kravitz, M and Avihai, S and Hardan, I and Shem-Tov, N and Nagler, A},
title = {Nonmyeloablative conditioning does not prevent telomere shortening after allogeneic stem cell transplantation.},
journal = {Transplantation},
volume = {80},
number = {7},
pages = {969-976},
doi = {10.1097/01.tp.0000173649.99261.df},
pmid = {16249747},
issn = {0041-1337},
mesh = {Adolescent ; Adult ; *Bone Marrow Transplantation ; Cellular Senescence ; DNA/analysis ; Female ; Graft vs Leukemia Effect ; Humans ; Leukocytes, Mononuclear/chemistry/metabolism ; Male ; Middle Aged ; Telomere/*metabolism ; Tissue Donors ; *Transplantation Conditioning ; Transplantation, Homologous ; },
abstract = {BACKGROUND: Stem cell transplantation (SCT) may be associated with premature aging of the hematopoietic stem cells. Telomere length reflects the proliferative history of a cell. In most studies published so far on telomere dynamics after myeloablative allogeneic SCT, recipients had shorter telomeres than their respective donors, thus reflecting "accelerated aging" of hematopoietic cells. We evaluated telomere dynamics in patients who underwent transplantation with nonmyeloablative protocols, assuming that the decreased intensity of chemotherapy might prevent telomere attrition.<br><br>METHODS: Telomere length was measured using FISH-FACS method. Telomeres of recipients were compared to their respective donors. Twenty-three consecutive patients after nonmyeloablative SCT were evaluated. A control group consisted of 10 donor-recipient pairs after conventional myeloablative transplantation.<br><br>RESULTS: There was significant telomere shortening in both recipients of nonmyeloablative and myeloablative conditioning (0.487+/-0.65 kb, P=0.003; 0.361+/-0.50 kb, P=0.047 respectively). The extent of telomere shortening in the two groups was not different (P=0.64). There was no correlation between the degree of shortening and parameters such as time interval from transplant, age of donor or recipient, and the number of infused cells.<br><br>CONCLUSIONS: This is the first study on telomere dynamics after nonmyeloablative conditioning SCT. The study demonstrates significant shortening of telomeres in recipients in spite of decreased intensity conditioning. Results of this study suggest that the main mechanism following transplantation is the proliferative stress imposed upon the stem cells and not direct damage by cytotoxic drugs. The different kinetics of restoration of hematopoiesis and the probable ongoing process of graft-versus-leukemia in the bone marrow do not prevent the attrition of telomeric ends of chromosomes.},
}
@article {pmid16243027,
year = {2005},
author = {Kanoh, J and Sadaie, M and Urano, T and Ishikawa, F},
title = {Telomere binding protein Taz1 establishes Swi6 heterochromatin independently of RNAi at telomeres.},
journal = {Current biology : CB},
volume = {15},
number = {20},
pages = {1808-1819},
doi = {10.1016/j.cub.2005.09.041},
pmid = {16243027},
issn = {0960-9822},
mesh = {Chromatin Immunoprecipitation ; Chromosomal Proteins, Non-Histone/*metabolism ; Cloning, Molecular ; Gene Deletion ; Heterochromatin/*metabolism ; In Situ Hybridization, Fluorescence ; RNA Interference ; RNA, Small Interfering/genetics/metabolism ; Schizosaccharomyces/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Signal Transduction/*genetics ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/*metabolism ; Terminal Repeat Sequences/genetics ; },
abstract = {BACKGROUND: The telomere is a specialized heterochromatin conserved among eukaryotes. However, it remains unknown how heterochromatin protein 1 (HP1) is recruited to telomeres and how telomere heterochromatin is formed. In fission yeast, the RNAi (RNA interference)-RITS (RNA-induced initiation of transcriptional silencing) pathway initiates heterochromatin formation at the centromeres and the silent mat locus by using common DNA sequences, the dg and dh repeats, as the templates for small interfering RNA (siRNA).<br><br>RESULTS: We found that telomeric repeats are sufficient for the establishment of Swi6 (a fission-yeast HP1 homolog) heterochromatin, and the establishment requires Taz1, a telomere binding protein of the TRF family. Additionally, Swi6 heterochromatin is established by a part of the subtelomere that contains sequences highly homologous to that of the dh repeat, and it is strikingly destabilized by the deletion of both Taz1 and RNAi-RITS. Transcripts from the telomeric dh-homologous region were specifically associated with RITS, and deletion of the telomeric dh-homologous region showed the phenotype similar to that of the rnai mutant in terms of the telomeric silencing, indicating that the RNAi-RITS pathway acts at the telomeric dh-homologous region to establish Swi6 heterochromatin. Furthermore, we found that Taz1 establishes Swi6 heterochromatin independently of the telomeric repeats and the RNAi-RITS pathway at the subtelomeres.<br><br>CONCLUSION: The telomere heterochromatin is regulated by at least two factors: One is Taz1, which is telomere specific, and the other is RNAi-RITS, which is commonly used at the constitutive heterochromatin regions.},
}
@article {pmid16238614,
year = {2005},
author = {Chaconas, G},
title = {Hairpin telomeres and genome plasticity in Borrelia: all mixed up in the end.},
journal = {Molecular microbiology},
volume = {58},
number = {3},
pages = {625-635},
doi = {10.1111/j.1365-2958.2005.04872.x},
pmid = {16238614},
issn = {0950-382X},
mesh = {Bacterial Proteins/metabolism ; Borrelia burgdorferi/*genetics/metabolism ; Chromosomes, Bacterial ; Endodeoxyribonucleases/metabolism ; Gene Rearrangement ; *Genome, Bacterial ; *Nucleic Acid Conformation ; Recombination, Genetic ; Replicon ; Telomere/*chemistry ; },
abstract = {Spirochetes of the genus Borrelia have a highly unusual genome structure composed of over 20 replicons. Most of these replicons are linear and terminated by covalently closed hairpin ends or telomeres. Moreover, the linear replicons are affected by extensive DNA rearrangements, including telomere exchanges, DNA duplications, and harbour a large number of pseudogenes. The mechanism for the unusual genome plasticity in the linear replicons has remained elusive. The enzymatic machinery (the telomere resolvase ResT) responsible for generating the hairpin ends from replicative intermediates has recently been shown to also perform a reverse reaction that fuses telomeres on unrelated replicons. Infrequent stabilization of such fusion events over evolutionary time provides the first proposed biochemical mechanism for the DNA rearrangements that are so prominent in the linear replicons of B. burgdorferi.},
}
@article {pmid16231738,
year = {2005},
author = {Li, ZY and Qin, R and Jin, WW and Xiong, ZY and Song, YC},
title = {FISH analysis of pachytene chromosome and DNA fiber of telomere sequence in rice (Oryza sativa L. indica).},
journal = {Yi chuan xue bao = Acta genetica Sinica},
volume = {32},
number = {8},
pages = {832-836},
pmid = {16231738},
issn = {0379-4172},
mesh = {Chromosomes, Plant/*genetics ; DNA, Plant/*genetics ; In Situ Hybridization, Fluorescence/methods ; Oryza/*genetics ; Pachytene Stage ; Plant Leaves/genetics ; Tandem Repeat Sequences ; Telomere/*genetics ; },
abstract = {Telomere sequences were analyzed by using pachytene chromosome and extended DNA fiber FISH in rice (Oryza, sativa ssp. indica cv. -Guangluai No.4). Pachytene FISH results showed that most of chromosome ends possess the telomere tandem repeats, but the signals on different chromosomes were not the same in intensity. Fiber FISH results indicated that the longest string of beads was 6.55 microm, while the shortest one was 1.82 microm long,which were equal to 16.44 and 4.56 kb correspondingly based on a stretching factor of 2.51 kb/microm. The average value of signal length was 3.62 +/- 1.32 microm, i.e. 9.09 +/- 3.31 kb. It could be estimated that the longest and the shortest as well as the average value were equal to 2,349,651 and 1298 +/- 473 of copy number respectively.},
}
@article {pmid16230714,
year = {2005},
author = {Yonai, M and Kaneyama, K and Miyashita, N and Kobayashi, S and Goto, Y and Bettpu, T and Nagai, T},
title = {Growth, reproduction, and lactation in somatic cell cloned cows with short telomeres.},
journal = {Journal of dairy science},
volume = {88},
number = {11},
pages = {4097-4110},
doi = {10.3168/jds.S0022-0302(05)73094-0},
pmid = {16230714},
issn = {1525-3198},
mesh = {Animals ; Cattle/*genetics/growth &amp; development/physiology ; *Cloning, Organism ; Embryo Transfer/veterinary ; Epithelial Cells/ultrastructure ; Fallopian Tubes/ultrastructure ; Female ; Fertilization ; Lactation/*genetics/physiology ; *Nuclear Transfer Techniques ; Parturition ; Pregnancy ; Reproduction/*genetics/physiology ; Sexual Maturation ; Telomere/genetics/*ultrastructure ; Weight Gain ; },
abstract = {We previously showed that telomere lengths of 10 somatic cell cloned cows were significantly shorter than normal. In this study, we investigated growth, reproduction, and lactation in these animals to determine if shortened telomeres have any effect on these characteristics. Six Holstein and 4 Jersey cloned cows, derived from oviduct cells, were reared under general group feeding. Body weights were recorded from birth to 48 mo of age. A number of reproductive characteristics were screened during the prepubertal, postpubertal, and postpartum periods. After parturition, milk yields were recorded daily and percentages of milk fat, proteins, and solids-not-fat were measured at monthly intervals. These data were used to estimate production of milk components over a 305-d period. Overall, the cloned heifers exceeded standard growth rates for each breed. The cows were inseminated at the first estrus after they reached 450 d of age, and delivered normal calves except for one stillbirth in the Holstein group. They were inseminated at postpartum estrus to provide second and third parturitions and, again, these pregnancies were normal. Gestational periods and birth weights of the calves were both within the normal range. The average total milk yield per cow in Holstein group clones was less than that of the original cow, whereas Jersey group clones showed a higher average milk yield than the original cow. In both groups of cloned cows, inter-individual variation in milk production was relatively large; however, the coefficient of variation was less than 10%. Our results suggest that the cloned cows have normal growth, reproductive, and lactation characteristics, and thus normal productivity, despite having reduced telomere lengths.},
}
@article {pmid16229875,
year = {2006},
author = {Herbig, U and Sedivy, JM},
title = {Regulation of growth arrest in senescence: telomere damage is not the end of the story.},
journal = {Mechanisms of ageing and development},
volume = {127},
number = {1},
pages = {16-24},
doi = {10.1016/j.mad.2005.09.002},
pmid = {16229875},
issn = {0047-6374},
mesh = {Animals ; Cell Proliferation ; Cellular Senescence/*physiology ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Humans ; Telomere/metabolism/*pathology ; Up-Regulation ; },
abstract = {After a limited number of divisions, most eukaryotic cells grown in culture will undergo a terminal growth arrest called cellular senescence. This growth arrest is thought to be a consequence of progressive telomere shortening that occurs due to incomplete DNA replication of the chromosome ends. In addition, cellular senescence can also be induced by a number of environmental stresses and signaling imbalances which are independent of telomere shortening. The cyclin dependent kinase inhibitors p21 and p16(INK4a) have been shown to execute and maintain the cell cycle arrest in senescence but the nature of the signals that cause upregulation of these inhibitors in senescent cells are only now starting to be discovered. Here we will review the current literature that leads us to propose a model how independent signals activate distinct signaling pathways to regulate p21 and p16(INK4a) levels in senescent cells.},
}
@article {pmid16228977,
year = {2005},
author = {Narath, R and Lörch, T and Greulich-Bode, KM and Boukamp, P and Ambros, PF},
title = {Automatic telomere length measurements in interphase nuclei by IQ-FISH.},
journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology},
volume = {68},
number = {2},
pages = {113-120},
doi = {10.1002/cyto.a.20190},
pmid = {16228977},
issn = {1552-4922},
mesh = {Adult ; Blotting, Southern ; Cell Line, Tumor ; Cell Nucleus/*ultrastructure ; Data Interpretation, Statistical ; Fluorescent Dyes ; Humans ; In Situ Hybridization, Fluorescence/*methods ; *Interphase ; Leukocytes, Mononuclear/cytology/ultrastructure ; Metaphase ; Microscopy, Fluorescence/*methods ; Neuroblastoma/ultrastructure ; Osteosarcoma/ultrastructure ; Telomere/*ultrastructure ; },
abstract = {To benefit from the fluorescence-based automatic microscope (FLAME), we have adapted a PNA FISH technique to automatically determine telomere length in interphase nuclei. The method relies on the simultaneous acquisition of pan-telomeric signals and reference probe signals. We compared the quantitative figures to those for existing methods, i.e. Southern blot analysis and quantitative FISH (Q-FISH). Quantitative-FISH on interphase nuclei (IQ-FISH) allows the exact quantification of telomere length in interphase nuclei. Thus, this enables us to obtain not only exact information on the telomere length, but also morphological and topological details. The automatic measurement of large cell numbers allows the measurement of statistically relevant cell populations.},
}
@article {pmid16228207,
year = {2005},
author = {Chakhparonian, M and Faucher, D and Wellinger, RJ},
title = {A mutation in yeast Tel1p that causes differential effects on the DNA damage checkpoint and telomere maintenance.},
journal = {Current genetics},
volume = {48},
number = {5},
pages = {310-322},
pmid = {16228207},
issn = {0172-8083},
mesh = {Cell Cycle/drug effects ; Cell Cycle Proteins/genetics/metabolism ; Checkpoint Kinase 2 ; Chromosome Mapping ; *DNA Damage ; Fungal Proteins/genetics/*metabolism ; Intracellular Signaling Peptides and Proteins ; Methyl Methanesulfonate/pharmacology ; Mutant Proteins/metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases/genetics/metabolism ; Saccharomyces cerevisiae/cytology/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/chemistry/*metabolism ; Temperature ; },
abstract = {ATM/ATR homologs are the central elements of genome surveillance mechanisms in many organisms, including yeasts, flies, and mammals. In Saccharomyces cerevisiae, most checkpoint responses depend on the ATR ortholog Mec1p. The yeast ATM ortholog, Tel1p, so far has been implicated in a specific DNA damage checkpoint during S-phase as well as in telomere homeostasis. In particular, yeast cells lacking only Tel1p harbor short but stable telomeres, while cells lacking both Tel1p and Mec1p are unable to maintain telomeric repeats and senesce. Here, we present the characterization of a new mutation in the TEL1-gene, called tel1-11, which was isolated by virtue of a synthetic lethal interaction at 37 degrees C with a previously described mec1-ts mutation. Interestingly, telomere and checkpoint functions are differentially affected by the mutant protein Tel1-11p. The Tel1p-dependent checkpoint response is undetectable in cells containing Tel1-11p and incubated at 37 degrees C, but basic telomere function is maintained. Further, when the same cells are incubated at 26 degrees C, Tel1-11p confers full proficiency for all telomere functions analyzed, whereas the function for DNA-damage checkpoint activation is clearly affected. The results thus strongly suggest that the different cellular pathways affected by Tel1p do not require the same level of Tel1p activity to be fully functional.},
}
@article {pmid16223874,
year = {2005},
author = {Tanaka, H and Mendonca, MS and Bradshaw, PS and Hoelz, DJ and Malkas, LH and Meyn, MS and Gilley, D},
title = {DNA damage-induced phosphorylation of the human telomere-associated protein TRF2.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {102},
number = {43},
pages = {15539-15544},
pmid = {16223874},
issn = {0027-8424},
support = {R01 CA090885/CA/NCI NIH HHS/United States ; R01 CA 090885-01A2/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/physiology ; *DNA Damage ; DNA Repair ; DNA-Binding Proteins/physiology ; Humans ; Metalloendopeptidases ; Molecular Sequence Data ; Nuclear Proteins/*metabolism ; Phosphorylation ; Protein Kinases/physiology ; Protein Serine-Threonine Kinases/physiology ; Signal Transduction ; TATA Box Binding Protein-Like Proteins/*metabolism ; Telomeric Repeat Binding Protein 2 ; Tumor Suppressor Proteins/physiology ; },
abstract = {Several protein kinases from diverse eukaryotes known to perform important roles in DNA repair have also been shown to play critical roles in telomere maintenance. Here, we report that the human telomere-associated protein TRF2 is rapidly phosphorylated in response to DNA damage. We find that the phosphorylated form of TRF2 is not bound to telomeric DNA, as is the ground form of TRF2, and is rapidly localized to damage sites. Our results suggest that the ataxia-telangiectasia-mutated (ATM) protein kinase signal-transduction pathway is primarily responsible for the DNA damage-induced phosphorylation of TRF2. Unlike DNA damage-induced phosphorylation of other ATM targets, the phosphorylated form of TRF2 is transient, being detected rapidly at DNA damage sites postirradiation, but largely dissipated by 2 hours. In addition, we report that the phosphorylated form of TRF2 is present at telomeres in cell types undergoing telomere-based crisis and a recombination-driven, telomerase-independent, alternative lengthening of telomeres (ALT) pathway, likely as a consequence of a telomere-based DNA damage response. Our results link the induction of TRF2 phosphorylation to the DNA damage-response system, providing an example of direct cross-talk via a signaling pathway between these two major cellular processes essential for genomic stability, telomere maintenance, and DNA repair.},
}
@article {pmid16221978,
year = {2005},
author = {Vorlícková, M and Chládková, J and Kejnovská, I and Fialová, M and Kypr, J},
title = {Guanine tetraplex topology of human telomere DNA is governed by the number of (TTAGGG) repeats.},
journal = {Nucleic acids research},
volume = {33},
number = {18},
pages = {5851-5860},
pmid = {16221978},
issn = {1362-4962},
mesh = {Circular Dichroism ; DNA/*chemistry ; Electrophoresis, Polyacrylamide Gel ; G-Quadruplexes ; Guanine/*chemistry ; Humans ; Nucleic Acid Conformation ; Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; Thermodynamics ; },
abstract = {Secondary structures of the G-rich strand of human telomere DNA fragments G3(TTAG3)n, n = 1-16, have been studied by means of circular dichroism spectroscopy and PAGE, in solutions of physiological potassium cation concentrations. It has been found that folding of these fragments into tetraplexes as well as tetraplex thermostabilities and enthalpy values depend on the number of TTAG3 repeats. The suggested topologies include, e.g. antiparallel and parallel bimolecular tetraplexes, an intramolecular antiparallel tetraplex, a tetraplex consisting of three parallel chains and one antiparallel chain, a poorly stable parallel intramolecular tetraplex, and both parallel and antiparallel tetramolecular tetraplexes. G3(TTAG3)3 folds into a single, stable and very compact intramolecular antiparallel tetraplex. With an increasing repeat number, the fragment tetraplexes surprisingly are ever less thermostable and their migration and enthalpy decrease indicate increasing irregularities or domain splitting in their arrangements. Reduced stability and different topology of lengthy telomeric tails could contribute to the stepwise telomere shortening process.},
}
@article {pmid16219549,
year = {2005},
author = {Widmann, TA and Willmann, B and Pfreundschuh, M and Beelen, DW},
title = {Influence of telomere length on short-term recovery after allogeneic stem cell transplantation.},
journal = {Experimental hematology},
volume = {33},
number = {10},
pages = {1257-1261},
doi = {10.1016/j.exphem.2005.05.019},
pmid = {16219549},
issn = {0301-472X},
mesh = {Adolescent ; Adult ; Aging/physiology ; Colony-Forming Units Assay/methods ; Female ; Granulocyte Precursor Cells/cytology/*physiology ; Hematopoiesis/*physiology ; Humans ; *Living Donors ; Male ; Middle Aged ; *Peripheral Blood Stem Cell Transplantation/methods ; Recovery of Function/*physiology ; Telomere/genetics/*metabolism ; Transplantation Conditioning/methods ; Transplantation, Homologous ; },
abstract = {OBJECTIVE: Telomeres shorten in somatic cells during aging and states of increased turnover, including hematopoietic stem cell transplantation. Fast hematopoietic recovery is critical for the patients' course after hematopoietic stem cell transplantation. It is unknown whether telomere length in hematopoietic stem cells (HSCs) predicts short-term hematopoietic recovery.<br><br>METHODS: We quantified telomere length by flow fluorescence in situ hybridization analysis in HSCs and granulocytes of healthy stem cell donors and monitored time to peripheral blood cell recovery in transplanted hosts. Furthermore, we measured in vitro repopulation potency of HSCs by assaying for colony-forming units granulocyte-macrophage (CFU-GM).<br><br>RESULTS: Telomere length in HSC shortens continuously in vivo and is comparable to telomere length in granulocytes from the same individual. Numbers of in vitro formed CFU-GM per HSC show an inverse relationship to age and telomere length. However, telomere length in HSCs was not correlated with short-term recovery after HSC transplantation.<br><br>CONCLUSION: These findings suggest that healthy stem cell donors have sufficient telomere length reserve to repopulate a myeloablatively treated host, despite continuous aging of HSCs in vivo and decreased repopulation ability of HSCs from older donors in vitro.},
}
@article {pmid16218837,
year = {1999},
author = {Shiels, PG and Kind, AJ and Campbell, KH and Wilmut, I and Waddington, D and Colman, A and Schnieke, AE},
title = {Analysis of telomere length in Dolly, a sheep derived by nuclear transfer.},
journal = {Cloning},
volume = {1},
number = {2},
pages = {119-125},
doi = {10.1089/15204559950020003},
pmid = {16218837},
issn = {1520-4553},
abstract = {We have used a (TTAGGG) oligonucleotide probe to demonstrate that ovine telomeres are composed of (TTAGGG) repeat arrays and to compare the terminal restriction fragment lengths of sheep derived by natural mating and nuclear transfer. Here we show that ovine somatic telomeres decrease in length with age, and that Dolly, derived by the transfer of 6-year-old adult somatic nucleus, exhibits diminished terminal restriction fragment lengths. The decrease is consistent with the age of the donor tissue and telomere erosion during in vitro culture. Nuclear transfer does not restore telomere lengths. Dolly otherwise appears physiologically and phenotypically normal for her breed and age. We further report on apparent telomere lengthening in sheep, occurring during the first year in naturally derived lambs.},
}
@article {pmid16213831,
year = {2005},
author = {Rodríguez, S and Goyanes, V and Segrelles, E and Blasco, M and Gosálvez, J and Fernández, JL},
title = {Critically short telomeres are associated with sperm DNA fragmentation.},
journal = {Fertility and sterility},
volume = {84},
number = {4},
pages = {843-845},
doi = {10.1016/j.fertnstert.2005.05.014},
pmid = {16213831},
issn = {1556-5653},
mesh = {Animals ; DNA Fragmentation/*genetics ; Genetic Techniques ; In Situ Hybridization, Fluorescence/methods ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Spermatozoa/pathology/*physiology ; Telomere/*genetics/pathology ; },
abstract = {The influence of critical telomeric attrition, a well-known trigger of apoptosis and cell arrest, on sperm DNA fragmentation was studied in late-generation knockout mice for Terc, the RNA component of telomerase, as a model of choice. Terc knockout mice had a sixfold mean increase in the percentage of sperm cells with fragmented DNA.},
}
@article {pmid16212832,
year = {2005},
author = {Bischoff, C and Graakjaer, J and Petersen, HC and Hjelmborg, Jv and Vaupel, JW and Bohr, V and Koelvraa, S and Christensen, K},
title = {The heritability of telomere length among the elderly and oldest-old.},
journal = {Twin research and human genetics : the official journal of the International Society for Twin Studies},
volume = {8},
number = {5},
pages = {433-439},
doi = {10.1375/183242705774310141},
pmid = {16212832},
issn = {1832-4274},
support = {P01-AG-08761/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Models, Theoretical ; Telomere/*ultrastructure ; },
abstract = {A tight link exists between telomere length and both population doublings of a cell culture and age of a given organism. The more population doublings of the cell culture or the higher the age of the organism, the shorter the telomeres. The proposed model for telomere shortening, called the end replication problem, explains why the telomere erodes at each cellular turnover. Telomere length is regulated by a number of associated proteins through a number of different signaling pathways. The determinants of telomere length were studied using whole blood samples from 287 twin pairs aged 73 to 95 years. Structural equation models revealed that a model including additive genetic effects and non-shared environment was the best fitting model and that telomere length was moderately heritable, with an estimate that was sensitive to the telomere length standardization procedure. Sex-specific analyses showed lower heritability in males, although not statistically significant, which is in line with our earlier finding of a sex difference in telomere dynamics among the elderly and oldest-old.},
}
@article {pmid16212831,
year = {2005},
author = {Bischoff, C and Graakjaer, J and Petersen, HC and Jeune, B and Bohr, VA and Koelvraa, S and Christensen, K},
title = {Telomere length among the elderly and oldest-old.},
journal = {Twin research and human genetics : the official journal of the International Society for Twin Studies},
volume = {8},
number = {5},
pages = {425-432},
doi = {10.1375/183242705774310079},
pmid = {16212831},
issn = {1832-4274},
support = {P01-AG08761/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/physiology ; Cohort Studies ; Cross-Sectional Studies ; Denmark ; Female ; Humans ; Longitudinal Studies ; Male ; Telomere/*ultrastructure ; },
abstract = {Human chromosomes terminate in a number of repeats of the sequence TTAGGG. At birth, each chromosome end is equipped with approximately 15 kb of telomere sequence, but this sequence is shortened during each cell division. In cell cultures telomere shortening is associated with senescence, a phenomenon that has also been observed in normal adult tissues, indicating that telomere loss is associated with organismal ageing. Previous work has established that the rate of telomere loss in humans is age dependent, and recent work shows a sex-specific difference in telomere length and shortening in individuals over the age span of 20 to 75 years. Here, terminal restriction fragment lengths on DNA purified from whole blood were measured to examine the mean telomere length in a cross-sectional cohort of 816 Danish individuals of age 73 to 101 years. In this age group, females show a linear correlation between telomere length and age, whereas the pattern tends to be nonlinear (quadratic in age) for males. This difference in telomere length dynamics between the 2 sexes may be caused by several different mechanisms, including differences in selection by mortality, differences in leukocyte population or different telomerase expression pattern.},
}
@article {pmid16211269,
year = {2005},
author = {Wick, U and Gebhart, E},
title = {The order of PNA-FISH-detected chromosomal telomere lengths in human T-cells is rather stable, even under the influence of strong mutagens.},
journal = {International journal of molecular medicine},
volume = {16},
number = {5},
pages = {951-957},
doi = {10.3892/ijmm.16.5.951},
pmid = {16211269},
issn = {1107-3756},
mesh = {Bleomycin/toxicity ; Cell Line, Tumor ; Chromosomes, Human/drug effects/genetics ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia-Lymphoma, Adult T-Cell ; Mitomycin/toxicity ; Mutagens/*toxicity ; Nucleic Acid Probes ; Nucleoproteins/metabolism ; Peptide Nucleic Acids/chemistry ; T-Lymphocytes/chemistry/drug effects ; Telomere/*drug effects/genetics ; },
abstract = {The nucleo-protein structure of an intact telomere protects each chromosome from being recognized as a break and subsequently being degraded. The DNA component of this structure, the telomeric repeats, undergo attrition with every cell division, as well as in response to endogenous events, like oxidative stress. Exposure to exogenous damage promotes this process and leads to growth arrest, apoptosis and eventually to malignant transformation. It was thought that the shortest chromosome ends in humans are the most susceptible ones to become dysfunctional telomeres, and have therefore an important role in cell death and cancer. Here, we show that a stable hierarchy exists in the form of a telomere length profile of the whole human karyotype. This rank order is conserved between different human cell types and individuals, is maintained throughout a lifetime, and seems to be genetically determined. As a particular feature, this telomere length profile differs only marginally when normal human cell cultures and malignant transformed cells are compared. The profile is moreover stable when these different human cells are exposed to mutagens such as bleomycin or mitomycin C. From these findings, the question arises if also the stably long telomeres have a basic biological function.},
}
@article {pmid16211259,
year = {2005},
author = {Sashida, G and Ohyashiki, JH and Kubota, N and Shoji, N and Ishii, Y and Tauchi, T and Kimura, Y and Shay, JW and Ohyashiki, K},
title = {Marked telomere fluctuation of leukocytes during graft-versus-host disease in allogeneic stem cell transplantation.},
journal = {International journal of molecular medicine},
volume = {16},
number = {5},
pages = {883-888},
pmid = {16211259},
issn = {1107-3756},
mesh = {Bone Marrow Transplantation/*immunology ; DNA/analysis/genetics ; Flow Cytometry ; Graft vs Host Disease/*genetics/*immunology ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes/*chemistry ; Stem Cell Transplantation ; Telomere/genetics/*metabolism ; Transplantation, Homologous/immunology ; },
abstract = {Immune dysfunction after allogeneic stem cell transplantation (SCT) is closely associated with cell turnover of lymphocytes and homeostasis of hematopoietic stem cells. Telomeres, repetitive sequences (TTAGGG)n on the end of linear chromosomes, reflect the mitotic history of stem cells. Using telomere fluorescence in situ hybridization (FISH) and flow cytometry (flow-FISH), we measured telomere length in lymphocytes and neutrophils at various intervals to analyze the relationship between telomere length change and clinical features in 5 patients who underwent allogeneic bone marrow transplantation. During the first year after allogeneic stem cell transplantation, a marked fluctuation of telomere length in peripheral blood leukocytes was observed in all recipients, and in 3 patients there was a reduction of telomere length during chronic graft-versus-host disease (GvHD) or during post-transplant lymphoproliferative disorder. The reduction of telomere length during GvHD was evident in lymphocytes and neutrophils, but telomere length in neutrophils tended to recover earlier than that observed in lymphocytes. The rapid reduction of telomere length in leukocytes during GvHD was too extensive to be explained by the end-replication problem, suggesting the presence of a telomerically unstable hematopoietic condition after transplant in vivo.},
}
@article {pmid16210918,
year = {2005},
author = {Shao, L and Li, QH and Wang, J and Tan, Z},
title = {Fragmentation and rapid shortening of telomere in HeLa cells in the early phase of hydroxyl radical-induced apoptosis.},
journal = {Cancer biology &amp; therapy},
volume = {4},
number = {3},
pages = {336-341},
doi = {10.4161/cbt.4.3.1643},
pmid = {16210918},
issn = {1538-4047},
mesh = {*Apoptosis ; Cell Cycle/drug effects ; DNA/analysis/drug effects ; DNA Damage ; *DNA Fragmentation ; HeLa Cells ; Humans ; Hydroxyl Radical/*toxicity ; Oligonucleotides/genetics/pharmacology ; Telomere/*drug effects/genetics/metabolism ; Transfection ; },
abstract = {In order to maintain genomic stability, cells recognize and respond to DNA damage by either cell cycle arrest or apoptosis. Telomeres are the special DNA sequences at chromosome termini that plays an important role in maintaining chromosomal stability. Telomeric DNA has been shown to be much more susceptible to damage than non-telomere sequences. Recent studies suggest that telomere disruption can trigger apoptosis in certain cell types, mimicking a major cellular response to DNA damage. In this work, we studied the DNA damage at the telomere region during hydroxyl radical-induced apoptosis in HeLa cells. It was found that HeLa cells experienced telomere strand fragmentation and rapid telomere shortening following treatment with H(2)O(2) well before caspase-3 activation and apoptosis. The percentage of cells undergoing apoptosis correlated with the extent of telomere strand fragmentation. Introducing telomere oligonucleotide into cells induced cell cycle arrest in S-phase and apoptosis. We speculate that telomere fragments released from chromosomes might serve as a triggering signal in DNA damage-induced apoptosis in the HeLa cells.},
}
@article {pmid16207588,
year = {2005},
author = {Walne, AJ and Marrone, A and Dokal, I},
title = {Dyskeratosis congenita: a disorder of defective telomere maintenance?.},
journal = {International journal of hematology},
volume = {82},
number = {3},
pages = {184-189},
pmid = {16207588},
issn = {0925-5710},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Cell Cycle Proteins/genetics/*metabolism ; Chromosomes, Human, X/genetics/metabolism ; Dyskeratosis Congenita/genetics/*metabolism/pathology ; Humans ; Nuclear Proteins/genetics/*metabolism ; RNA Processing, Post-Transcriptional/genetics ; RNA, Ribosomal/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Dyskeratosis congenita (DC) is a rare multisystem bone marrow failure syndrome that displays marked clinical and genetic heterogeneity. X-linked recessive, autosomal dominant and autosomal recessive forms of the disease are recognized. The gene that is mutated in the X-linked form of the disease is DKC1. The DKC1-encoded protein, dyskerin, is a component of small nucleolar ribonucleoprotein particles, which are important in ribosomal RNA processing, and of the telomerase complex. The autosomal dominant form of DC is due to mutations in the gene for the RNA component of telomerase (TERC). Because both dyskerin and TERC are components of the telomerase complex and all patients with DC have short telomeres, the principal pathology of DC appears to relate to telomerase dysfunction, although defects in ribosomal processing via dyskerin's involvement in pseudouridylation cannot be completely ruled out. The gene or genes involved in autosomal recessive DC remain elusive, although genes whose products are required for telomere maintenance remain strong candidates. The study of DC highlights the importance of telomerase in humans and how its deficiency results in multiple abnormalities, including premature aging, bone marrow failure, and cancer.},
}
@article {pmid16206324,
year = {2005},
author = {Zhao, Y and Zeng, ZX and Kan, ZY and Hao, YH and Tan, Z},
title = {The folding and unfolding kinetics of the i-motif structure formed by the C-rich strand of human telomere DNA.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {6},
number = {11},
pages = {1957-1960},
doi = {10.1002/cbic.200500175},
pmid = {16206324},
issn = {1439-4227},
mesh = {Base Pairing ; Biosensing Techniques ; Cytidine/*chemistry ; DNA/*chemistry ; Humans ; Hydrogen Bonding ; Hydrogen-Ion Concentration ; Kinetics ; *Nucleic Acid Conformation ; Telomere/*chemistry ; },
}
@article {pmid16205109,
year = {2005},
author = {Hao, ZM and Luo, JY and Cheng, J and Li, L and He, D and Wang, QY and Yang, GX},
title = {Intensive inhibition of hTERT expression by a ribozyme induces rapid apoptosis of cancer cells through a telomere length-independent pathway.},
journal = {Cancer biology &amp; therapy},
volume = {4},
number = {10},
pages = {1098-1103},
doi = {10.4161/cbt.4.10.2016},
pmid = {16205109},
issn = {1538-4047},
mesh = {Animals ; Apoptosis/*drug effects ; Carcinoma/pathology ; Cell Line, Tumor ; Colonic Neoplasms/enzymology/genetics/pathology ; DNA, Recombinant/genetics ; DNA-Binding Proteins/*antagonists &amp; inhibitors/genetics/*metabolism ; Humans ; Mice ; NIH 3T3 Cells ; RNA, Catalytic/metabolism/*pharmacology ; Retroviridae/genetics ; Stomach Neoplasms/enzymology/genetics/pathology ; Telomerase/*antagonists &amp; inhibitors/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Restoration of telomerase activity is essential for most of the malignancies. Telomerase reverse transcriptase (TERT) is the key component of telomerase. In this study, we designed a hammerhead ribozyme against human telomerase reverse transcriptase (hTERT) and observed its growth inhibition and pro-apoptosis effects on cancer cells. The efficiency of this ribozyme was verified in in vitro cleavage experiment. A recombinant retrovirus was constructed to transduce the ribozyme to telomerase positive colon carcinoma cell line SW480 and gastric carcinoma cell line SGC7901. We found that the ribozyme could strongly inhibit hTERT expression and telomerase activity, resulting in rapid apoptosis of cancer cells. Shortening of telomere and replicative senescence were not observed before cell death, indicating intensive inhibition of hTERT expression can induce apoptosis by some mechanism(s) except telomere shortening and replicative senescence. This study suggests that hTERT exerts a direct antiapoptotic function in cancer cells. Anti-hTERT ribozyme might be a potential means in the therapy of telomerase-positive malignancies.},
}
@article {pmid16203987,
year = {2005},
author = {Bi, X and Srikanta, D and Fanti, L and Pimpinelli, S and Badugu, R and Kellum, R and Rong, YS},
title = {Drosophila ATM and ATR checkpoint kinases control partially redundant pathways for telomere maintenance.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {102},
number = {42},
pages = {15167-15172},
pmid = {16203987},
issn = {0027-8424},
support = {R01 GM059765/GM/NIGMS NIH HHS/United States ; GM059765/GM/NIGMS NIH HHS/United States ; //Intramural NIH HHS/United States ; },
mesh = {Animals ; Animals, Genetically Modified ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/*metabolism ; DNA Damage ; DNA Repair Enzymes/genetics/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Drosophila Proteins/genetics/*metabolism ; *Drosophila melanogaster/enzymology/genetics ; Endodeoxyribonucleases/genetics/metabolism ; Female ; Gene Silencing ; Male ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Recombinant Fusion Proteins/genetics/metabolism ; Telomere/*metabolism ; Tumor Suppressor Proteins/genetics/*metabolism ; },
abstract = {In higher eukaryotes, the ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) checkpoint kinases play distinct, but partially overlapping, roles in DNA damage response. Yet their interrelated function has not been defined for telomere maintenance. We discover in Drosophila that the two proteins control partially redundant pathways for telomere protection: the loss of ATM leads to the fusion of some telomeres, whereas the loss of both ATM and ATR renders all telomeres susceptible to fusion. The ATM-controlled pathway includes the Mre11 and Nijmegen breakage syndrome complex but not the Chk2 kinase, whereas the ATR-regulated pathway includes its partner ATR-interacting protein but not the Chk1 kinase. This finding suggests that ATM and ATR regulate different molecular events at the telomeres compared with the sites of DNA damage. This compensatory relationship between ATM and ATR is remarkably similar to that observed in yeast despite the fact that the biochemistry of telomere elongation is completely different in the two model systems. We provide evidence suggesting that both the loading of telomere capping proteins and normal telomeric silencing requires ATM and ATR in Drosophila and propose that ATM and ATR protect telomere integrity by safeguarding chromatin architecture that favors the loading of telomere-elongating, capping, and silencing proteins.},
}
@article {pmid16203743,
year = {2005},
author = {Huang, G and Krig, S and Kowbel, D and Xu, H and Hyun, B and Volik, S and Feuerstein, B and Mills, GB and Stokoe, D and Yaswen, P and Collins, C},
title = {ZNF217 suppresses cell death associated with chemotherapy and telomere dysfunction.},
journal = {Human molecular genetics},
volume = {14},
number = {21},
pages = {3219-3225},
doi = {10.1093/hmg/ddi352},
pmid = {16203743},
issn = {0964-6906},
support = {CA85799/CA/NCI NIH HHS/United States ; NS42927/NS/NINDS NIH HHS/United States ; P01 CA099031/CA/NCI NIH HHS/United States ; P01 CA64602/CA/NCI NIH HHS/United States ; P50 CA83639/CA/NCI NIH HHS/United States ; P50 CA97527/CA/NCI NIH HHS/United States ; R21 CA87522-01/CA/NCI NIH HHS/United States ; },
mesh = {Apoptosis/*genetics ; Breast Neoplasms/*genetics ; Cell Line, Tumor ; Chromosomes, Human, Pair 20/*genetics ; DNA Damage ; DNA Primers ; Doxorubicin ; Drug Therapy ; Gene Silencing ; Humans ; Immunoblotting ; Neoplasm Proteins/genetics/*metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Telomere/genetics/*physiology ; Trans-Activators/genetics/*metabolism ; },
abstract = {Chromosome 20q13.2 is amplified in 20-30% of early-stage breast tumors and is associated with poor prognosis. Detailed mapping of the amplified region using molecular cytogenetics, positional cloning and genomic sequencing culminated in a detailed molecular description of the candidate oncogene ZNF217. ZNF217 proteins resemble Kruppel-like transcription factors, localize predominately to the nucleus and associate with proteins involved in transcriptional repression. The findings that ZNF217 can immortalize human mammary epithelial cells and that its amplification is associated with poor prognosis suggest that it may play roles in both early- and late-stage breast cancer. We present evidence that ZNF217 can attenuate apoptotic signals resulting from telomere dysfunction as well as from doxorubicin-induced DNA damage and that silencing ZNF217 with siRNA restores sensitivity to doxorubicin. Moreover, elevated ZNF217 leads to increased phosphorylation of Akt, whereas inhibition of the phosphatidylinositol 3 kinase pathway and Akt phosphorylation decreases ZNF217 protein levels and increases sensitivity to doxorubicin. These results suggest that ZNF217 may promote neoplastic transformation by increasing cell survival during telomeric crisis and may promote later stages of malignancy by increasing cell survival during chemotherapy.},
}
@article {pmid16199886,
year = {2005},
author = {Ji, H and Platts, MH and Dharamsi, LM and Friedman, KL},
title = {Regulation of telomere length by an N-terminal region of the yeast telomerase reverse transcriptase.},
journal = {Molecular and cellular biology},
volume = {25},
number = {20},
pages = {9103-9114},
pmid = {16199886},
issn = {0270-7306},
mesh = {Alleles ; Base Sequence ; Carrier Proteins/genetics/metabolism ; Catalytic Domain/genetics ; DNA, Fungal/genetics ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Fungal Proteins/genetics/metabolism ; Genes, Fungal ; Intracellular Signaling Peptides and Proteins ; Mutation ; Protein Serine-Threonine Kinases ; Repressor Proteins/genetics/metabolism ; Saccharomyces cerevisiae/*enzymology/*genetics ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomerase/chemistry/genetics/*metabolism ; Telomere/*enzymology/*genetics ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Telomerase is a reverse transcriptase that maintains chromosome integrity through synthesis of repetitive telomeric sequences on the ends of eukaryotic chromosomes. In the yeast Saccharomyces cerevisiae, telomere length homeostasis is achieved through negative regulation of telomerase access to the chromosome terminus by telomere-bound Rap1 protein and its binding partners, Rif1p and Rif2p, and positive regulation by factors such as Ku70/80, Tel1p, and Cdc13p. Here we report the identification of mutations within an N-terminal region (region I) of the yeast telomerase catalytic subunit (Est2p) that cause telomere lengthening without altering measurable catalytic properties of the enzyme in vitro. These telomerase mutations affect telomere length through a Ku-independent mechanism and do not alter chromosome end structure. While Tel1p is required for expression of the telomere-lengthening phenotype, Rif1p and Rif2p are not, suggesting that telomere overextension is independent of Rap1p. Taken together, these data suggest that specific amino acids within region I of the catalytic subunit of yeast telomerase play a previously unanticipated role in the response to Tel1p regulation at the telomere.},
}
@article {pmid16199868,
year = {2005},
author = {Gómez, EB and Espinosa, JM and Forsburg, SL},
title = {Schizosaccharomyces pombe mst2+ encodes a MYST family histone acetyltransferase that negatively regulates telomere silencing.},
journal = {Molecular and cellular biology},
volume = {25},
number = {20},
pages = {8887-8903},
pmid = {16199868},
issn = {0270-7306},
support = {R01 GM059321/GM/NIGMS NIH HHS/United States ; R01 GM059321-05A1/GM/NIGMS NIH HHS/United States ; R01 GM59321/GM/NIGMS NIH HHS/United States ; },
mesh = {Acetylation ; Base Sequence ; Cell Cycle ; Cell Nucleus/enzymology ; Chromatin/enzymology ; DNA, Fungal/genetics ; Gene Silencing ; Genes, Fungal ; Histones/chemistry/metabolism ; Meiosis/genetics ; Mutation ; Phylogeny ; Schizosaccharomyces/cytology/*enzymology/*genetics ; Telomere/genetics ; },
abstract = {Histone acetylation and deacetylation are associated with transcriptional activity and the formation of constitutively silent heterochromatin. Increasingly, histone acetylation is also implicated in other chromosome transactions, including replication and segregation. We have cloned the only Schizosaccharomyces pombe MYST family histone acetyltransferase genes, mst1(+) and mst2(+). Mst1p, but not Mst2p, is essential for viability. Both proteins are localized to the nucleus and bound to chromatin throughout the cell cycle. Deltamst2 genetically interacts with mutants that affect heterochromatin, cohesion, and telomere structure. Mst2p is a negative regulator of silencing at the telomere but does not affect silencing in the centromere or mating type region. We generated a census of proteins and histone modifications at wild-type telomeres. A histone acetylation gradient at the telomeres is lost in Deltamst2 cells without affecting the distribution of Taz1p, Swi6p, Rad21p, or Sir2p. We propose that the increased telomeric silencing is caused by histone hypoacetylation and/or an increase in the ratio of methylated to acetylated histones. Although telomere length is normal, meiosis is aberrant in Deltamst2 diploid homozygote mutants, suggesting that telomeric histone acetylation contributes to normal meiotic progression.},
}
@article {pmid16192571,
year = {2005},
author = {Marie-Egyptienne, DT and Cerone, MA and Londoño-Vallejo, JA and Autexier, C},
title = {A human-Tetrahymena pseudoknot chimeric telomerase RNA reconstitutes a nonprocessive enzyme in vitro that is defective in telomere elongation.},
journal = {Nucleic acids research},
volume = {33},
number = {17},
pages = {5446-5457},
pmid = {16192571},
issn = {1362-4962},
mesh = {Animals ; Cell Line ; DNA-Binding Proteins/metabolism ; Dimerization ; Humans ; Mutation ; Nucleic Acid Conformation ; Polymerase Chain Reaction ; RNA/*chemistry/genetics/*metabolism ; Telomerase/*chemistry/genetics/*metabolism ; Telomere/*metabolism ; Tetrahymena/enzymology/*genetics ; },
abstract = {The phylogenetically-derived secondary structures of telomerase RNAs (TR) from ciliates, yeasts and vertebrates are surprisingly conserved and contain a pseudoknot domain at a similar location downstream of the template. As the pseudoknot domains of Tetrahymena TR (tTR) and human TR (hTR) mediate certain similar functions, we hypothesized that they might be functionally interchangeable. We constructed a chimeric TR (htTR) by exchanging the hTR pseudoknot sequences for the tTR pseudoknot region. The chimeric RNA reconstituted human telomerase activity when coexpressed with hTERT in vitro, but exhibited defects in repeat addition processivity and levels of DNA synthesis compared to hTR. Activity was dependent on tTR sequences within the chimeric RNA. htTR interacted with hTERT in vitro and dimerized predominantly via a region of its hTR backbone, the J7b/8a loop. Introduction of htTR in telomerase-negative cells stably expressing hTERT did not reconstitute an active enzyme able to elongate telomeres. Thus, our results indicate that the chimeric RNA reconstituted a weakly active nonprocessive human telomerase enzyme in vitro that was defective in telomere elongation in vivo. This suggests that there may be species-specific requirements for pseudoknot functions.},
}
@article {pmid16189290,
year = {2006},
author = {Tarry-Adkins, JL and Ozanne, SE and Norden, A and Cherif, H and Hales, CN},
title = {Lower antioxidant capacity and elevated p53 and p21 may be a link between gender disparity in renal telomere shortening, albuminuria, and longevity.},
journal = {American journal of physiology. Renal physiology},
volume = {290},
number = {2},
pages = {F509-16},
doi = {10.1152/ajprenal.00215.2005},
pmid = {16189290},
issn = {1931-857X},
mesh = {Albuminuria/*metabolism ; Animals ; Calcium-Binding Proteins ; Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p21/*metabolism ; Female ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Kidney Cortex/enzymology/*metabolism ; Kidney Medulla/enzymology/*metabolism ; *Longevity ; Male ; Rats ; Rats, Wistar ; Sex Factors ; Sulfotransferases ; Superoxide Dismutase/metabolism ; Telomere/*physiology ; Tumor Suppressor Protein p53/*metabolism ; Glutathione Peroxidase GPX1 ; },
abstract = {It is well documented that females live longer than males and more renal damage occurs in males. However, the underlying mechanisms are not fully understood. The aim of this study was to define aging effects on albuminuria and kidney telomere length from male and female rats and to determine mechanisms, which may explain any observed differences. Cellular senescence is known to play a major role in nephropathology, and as such, a range of senescence markers were compared in male and female renal tissue. Oxidative stress has been shown to accelerate telomere shortening and elicit cellular growth arrest. Thus major antioxidants, MnSOD, glutathione peroxidase I, and glutathione reductase, were also evaluated. Urinary albumin excretion increased with age in both sexes, but the increase was greater in males than females. In the cortex and medulla of both male and female rats, age-related telomere shortening occurred, the effect being more pronounced in males than in females. The cortical region had more short telomeres than the medulla in both genders. p53 And p21 expression over time significantly increased in males, but not in females. MnSOD expression was elevated in female vs. male cortex. Gxp1 and glutathione reductase levels were increased in the older female cortex compared with males. Our findings indicate that a reduction in oxidative damage protection may be responsible for accelerated telomere shortening over time, resulting in increased cellular senescence, loss of renal function, and death in male rats.},
}
@article {pmid16187756,
year = {2005},
author = {Zhang, Q and Williams, ES and Askin, KF and Peng, Y and Bedford, JS and Liber, HL and Bailey, SM},
title = {Suppression of DNA-PK by RNAi has different quantitative effects on telomere dysfunction and mutagenesis in human lymphoblasts treated with gamma rays or HZE particles.},
journal = {Radiation research},
volume = {164},
number = {4 Pt 2},
pages = {497-504},
doi = {10.1667/rr3366.1},
pmid = {16187756},
issn = {0033-7587},
support = {CA49696/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line ; Cosmic Radiation/*adverse effects ; DNA-Activated Protein Kinase ; DNA-Binding Proteins/*antagonists &amp; inhibitors/physiology ; Gamma Rays/*adverse effects ; Humans ; *Mutagenesis ; Nuclear Proteins ; Protein Serine-Threonine Kinases/*antagonists &amp; inhibitors/physiology ; *RNA Interference ; Telomere/physiology/*radiation effects ; },
abstract = {Basic to virtually all relevant biological effects of ionizing radiation is the underlying damage produced in DNA and the subsequent cellular processing of such damage. The damage can be qualitatively different for different kinds of radiations, and the genetics of the biological systems exposed can greatly affect damage processing and ultimate outcome--the biological effect of concern. The accurate repair of DNA double-strand breaks (DSBs) is critical for the maintenance of genomic integrity and function. Incorrect repair of such lesions results in chromosomal rearrangements and mutations that can lead to cancer and heritable defects in the progeny of irradiated parents. We have focused on the consequent phenotypic effects of faulty repair by examining connections between cellular radiosensitivity phenotypes relevant for carcinogenesis after exposure to ionizing radiation, and deficiencies in various components of the non-homologous end-joining (NHEJ) system. Here we produced deficiencies of individual components of the DNA-dependent protein kinase (DNA-PK) holoenzyme (Ku86 and the catalytic subunit, DNA-PKcs), both singly and in combination, using RNA interference (RNAi) in human lymphoblastoid cell lines. Exposure of cells exhibiting reduced protein expression to either gamma rays or 1 GeV/nucleon iron particles demonstrated differential effects on telomere dysfunction and mutation frequency as well as differential effects between radiation qualities.},
}
@article {pmid16182339,
year = {2005},
author = {Koppelstaetter, C and Jennings, P and Hochegger, K and Perco, P and Ischia, R and Karkoszka, H and Mayer, G},
title = {Effect of tissue fixatives on telomere length determination by quantitative PCR.},
journal = {Mechanisms of ageing and development},
volume = {126},
number = {12},
pages = {1331-1333},
doi = {10.1016/j.mad.2005.08.003},
pmid = {16182339},
issn = {0047-6374},
mesh = {Cellular Senescence ; DNA Primers/chemistry ; Fixatives/*pharmacology ; Formaldehyde/pharmacology ; Humans ; Paraffin/pharmacology ; Polymerase Chain Reaction/*methods ; RNA/chemistry ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/drug effects/*ultrastructure ; Time Factors ; },
abstract = {Telomere length is a well established marker of cellular senescence and thus biological age. Quantitative PCR allows the determination even from very low amounts of tissue by using telomere specific and single copy gene primers. Comparing a directly processed tissue sample to a 4% formaldehyde fixed one showed a significantly reduced efficiency of PCR reactions (mainly in single copy gene experiments) in a storage time-dependent manner resulting in an artificial increase in reported relative telomere length. This effect was not seen when the tissue was stored in RNA later solution. In summary, telomere length determination from formaldehyde fixed material by quantitative PCR is not a reliable method. Unfortunately therefore, many easily accessible tissue samples from pathology laboratories are unsuitable for this technique.},
}
@article {pmid16177573,
year = {2005},
author = {Jacobs, JJ and de Lange, T},
title = {p16INK4a as a second effector of the telomere damage pathway.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {4},
number = {10},
pages = {1364-1368},
doi = {10.4161/cc.4.10.2104},
pmid = {16177573},
issn = {1551-4005},
support = {AG16642/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Cyclin-Dependent Kinase Inhibitor p16/*metabolism ; Humans ; Neoplasms/genetics/metabolism/pathology ; Telomere/*genetics/*metabolism/pathology ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Telomere damage resulting from telomere shortening can potentially suppress tumorigenesis by permanently arresting or eliminating incipient cancer cells. Dysfunctional telomeres activate the canonical DNA damage response pathway, resulting in a p53-mediated G(1)/S arrest and senescence or apoptosis. Experimental induction of telomere damage through inhibition of the telomeric protein TRF2 recapitulates aspects of telomere attrition, including a p53-mediated cell cycle arrest. Using this system, we have shown that telomere damage can also elicit a G(1)/S arrest through the RB-regulator p16INK4a, especially in cells lacking p53 function. Here we discuss the significance of p16INK4a as a second effector of the telomere damage response.},
}
@article {pmid16175576,
year = {2005},
author = {Flanary, BE and Streit, WJ},
title = {Effects of axotomy on telomere length, telomerase activity, and protein in activated microglia.},
journal = {Journal of neuroscience research},
volume = {82},
number = {2},
pages = {160-171},
doi = {10.1002/jnr.20636},
pmid = {16175576},
issn = {0360-4012},
support = {AG 023665/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Axotomy ; Cell Division/physiology ; Cell Proliferation ; Cell Survival/genetics ; Cellular Senescence/*genetics ; Disease Models, Animal ; Facial Nerve/cytology/enzymology ; Facial Nerve Injuries/*enzymology/genetics/physiopathology ; Female ; Gliosis/*enzymology/genetics ; Male ; Microglia/*enzymology ; Motor Neurons/cytology/enzymology ; Rats ; Rats, Sprague-Dawley ; Retrograde Degeneration/enzymology/genetics ; Rhombencephalon/cytology/enzymology ; Telomerase/*metabolism ; Telomere/*physiology ; Up-Regulation/genetics ; },
abstract = {The adult central nervous system (CNS) is generally thought of as a postmitotic organ. However, DNA labeling studies have shown that one major population of nonneuronal cells, called microglia, retain significant mitotic potential. Microglial cell division is prominent during acute CNS injury involving neuronal damage or death. Prior work from this laboratory has shown that purified microglia maintained in vitro with continual mitogenic stimulation exhibit telomere shortening before entering senescence. In the current study, we sought to investigate whether telomere shortening occurs in dividing microglia in vivo. For this purpose, we used a nerve injury model that is known to trigger localized microglial proliferation in a well-defined CNS region, the facial motor nucleus. Adult Sprague-Dawley rats underwent facial nerve axotomy, and facial motor nuclei were microdissected after 1, 4, 7, and 10 days. Whole tissue samples were subjected to measurements of telomere length, telomerase activity, and telomerase protein. Results revealed a tendency for all of these parameters to be increased in lesioned samples. In addition, microglial cells isolated directly from axotomized facial nuclei with fluorescence-activated cell sorting (FACS) showed increased telomerase activity relative to unoperated controls, suggesting that microglia are the primary cell type responsible for the increases observed in whole tissue samples. Overall, the results show that microglia activated by injury are capable of maintaining telomere length via telomerase during periods of high proliferation in vivo. We conclude that molecular mechanisms pertaining to telomere maintenance are active in the injured CNS.},
}
@article {pmid16172394,
year = {2005},
author = {Wang, JC and Warner, JK and Erdmann, N and Lansdorp, PM and Harrington, L and Dick, JE},
title = {Dissociation of telomerase activity and telomere length maintenance in primitive human hematopoietic cells.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {102},
number = {40},
pages = {14398-14403},
pmid = {16172394},
issn = {0027-8424},
mesh = {*Cell Proliferation ; Cloning, Molecular ; DNA, Complementary/genetics ; DNA-Binding Proteins/*metabolism ; Fetal Blood/cytology ; Flow Cytometry ; Fluorescein-5-isothiocyanate ; HeLa Cells ; Hematopoietic Stem Cells/*enzymology ; Humans ; Lentivirus ; Leukemia/*enzymology ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {Primitive human hematopoietic cells have low endogenous telomerase activity, yet telomeres are not maintained. In contrast, ectopic telomerase expression in fibroblasts and other cells leads to telomere length maintenance or elongation. It is unclear whether this disparity can be attributed to telomerase level or stems from fundamentally different telomere biology. Here, we show that telomerase overexpression does not prevent proliferation-associated telomere shortening in human hematopoietic cells, pointing to the existence of cell type-specific differences in telomere dynamics. Furthermore, we observed eventual stabilization of telomere length without detectable changes in telomerase activity during establishment of two leukemic cell lines from normal cord blood cells, indicating that additional cooperating events are required for telomere maintenance in immortalized human hematopoietic cells.},
}
@article {pmid16170623,
year = {2005},
author = {Rodrigue, KL and May, BP and Famula, TR and Delany, ME},
title = {Meiotic instability of chicken ultra-long telomeres and mapping of a 2.8 megabase array to the W-sex chromosome.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {13},
number = {6},
pages = {581-591},
pmid = {16170623},
issn = {0967-3849},
mesh = {Animals ; Chickens/*genetics ; Female ; In Situ Hybridization, Fluorescence ; Male ; Meiosis/*genetics ; *Sex Chromosomes ; *Telomere ; },
abstract = {The objective of this research was to study the meiotic stability of a subset of chicken telomere arrays, which are the largest reported for any vertebrate species. Inheritance of these ultra-long telomere arrays (200 kb to 3 mb) was studied in a highly homozygous inbred line, UCD 003 (F >or= 99.9). Analysis of array transmission in four families indicated unexpected heterogeneity and non-Mendelian segregation including high-frequency-generation of novel arrays. Additionally, the largest array detected (2.8 Mb) was female-specific and correlated to the most intense telomeric DNA signal on the W-sex chromosome by fluorescence in situ hybridization (FISH). These results are discussed in regard to the potential functions of the ultra-long telomere arrays in the chicken genome including generation of genetic variation through enhanced recombination, protection against erosion by providing a buffer for gene-dense regions, and sex-chromosome organization.},
}
@article {pmid16170347,
year = {2006},
author = {Zhou, JM and Zhu, XF and Lu, YJ and Deng, R and Huang, ZS and Mei, YP and Wang, Y and Huang, WL and Liu, ZC and Gu, LQ and Zeng, YX},
title = {Senescence and telomere shortening induced by novel potent G-quadruplex interactive agents, quindoline derivatives, in human cancer cell lines.},
journal = {Oncogene},
volume = {25},
number = {4},
pages = {503-511},
doi = {10.1038/sj.onc.1209067},
pmid = {16170347},
issn = {0950-9232},
mesh = {Alkaloids/*pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cellular Senescence/drug effects ; Cyclin-Dependent Kinase Inhibitor p16/analysis ; Cyclin-Dependent Kinase Inhibitor p21/analysis ; Cyclin-Dependent Kinase Inhibitor p27/analysis ; DNA ; G-Quadruplexes ; Guanine/*chemistry ; Humans ; Indoles/*pharmacology ; K562 Cells ; Neoplasms/*drug therapy/genetics ; Quinolines/*pharmacology ; Telomerase/antagonists &amp; inhibitors ; *Telomere ; },
abstract = {Agents stabilizing G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalysed by telomerase or telomerase-independent mechanism and could therefore act as antitumor agents. In this study, we found that quindoline derivatives interacted preferentially with intramolecular G-quadruplex structures and were novel potent telomerase inhibitors. Treatment with quindoline derivatives reproducibly inhibited telomerase activity in human leukemia K562 cells and colon cancer SW620 cells. N'-(10H-Indolo [3,2-b] quinolin-11-yl)-N, N-dimethyl-propane-1,3-diamine (SYUIQ-5), (one of quindoline derivatives), when added to K562 and SW620 cell culture at nonacute cytotoxic concentrations, increased time of population doublings of K562 and SW620 cells, induced a marked cessation in cell growth and cellular senescence phenotype after 35 and 18 days, respectively. Growth cessation was accompanied by a shortening of telomere length, and induction of p16, p21 and p27 protein expression. However, another compound SYUIQ-7 with greater IC(50) for telomerase had no obvious cellular effect in nonacute cytotoxic concentrations. These results indicate that quindoline derivatives as novel potent G-quadruplex interactive agents induce senescence and telomere shortening in cancer cells and therefore are promising agents for cancer treatment.},
}
@article {pmid16166375,
year = {2005},
author = {de Lange, T},
title = {Shelterin: the protein complex that shapes and safeguards human telomeres.},
journal = {Genes &amp; development},
volume = {19},
number = {18},
pages = {2100-2110},
doi = {10.1101/gad.1346005},
pmid = {16166375},
issn = {0890-9369},
support = {CA76027-8/CA/NCI NIH HHS/United States ; GM16642-7/GM/NIGMS NIH HHS/United States ; GM49046-12/GM/NIGMS NIH HHS/United States ; },
mesh = {Antigens, Surface ; Binding Sites ; Cell Adhesion Molecules ; Chromosomal Instability ; DNA Damage ; Humans ; Membrane Glycoproteins ; Models, Biological ; Multiprotein Complexes/chemistry/*metabolism ; Peptide Hydrolases ; Protein Binding ; Protein Structure, Tertiary ; Protein Subunits/chemistry ; Proteins/antagonists &amp; inhibitors/chemistry/*metabolism ; Shelterin Complex ; Tandem Repeat Sequences ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/chemistry/*metabolism ; Telomeric Repeat Binding Protein 1 ; Telomeric Repeat Binding Protein 2 ; rap1 GTP-Binding Proteins ; },
abstract = {Added by telomerase, arrays of TTAGGG repeats specify the ends of human chromosomes. A complex formed by six telomere-specific proteins associates with this sequence and protects chromosome ends. By analogy to other chromosomal protein complexes such as condensin and cohesin, I will refer to this complex as shelterin. Three shelterin subunits, TRF1, TRF2, and POT1 directly recognize TTAGGG repeats. They are interconnected by three additional shelterin proteins, TIN2, TPP1, and Rap1, forming a complex that allows cells to distinguish telomeres from sites of DNA damage. Without the protective activity of shelterin, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. How does shelterin avert these events? The current data argue that shelterin is not a static structural component of the telomere. Instead, shelterin is emerging as a protein complex with DNA remodeling activity that acts together with several associated DNA repair factors to change the structure of the telomeric DNA, thereby protecting chromosome ends. Six shelterin subunits: TRF1, TRF2, TIN2, Rap1, TPP1, and POT1.},
}
@article {pmid16165343,
year = {2006},
author = {Thibeault, SL and Glade, RS and Li, W},
title = {Comparison of telomere length of vocal folds with different tissues: a physiological measurement of vocal senescence.},
journal = {Journal of voice : official journal of the Voice Foundation},
volume = {20},
number = {2},
pages = {165-170},
doi = {10.1016/j.jvoice.2005.04.006},
pmid = {16165343},
issn = {0892-1997},
support = {R01 DC4336/DC/NIDCD NIH HHS/United States ; },
mesh = {Aged ; Aging/*physiology ; Analysis of Variance ; Aorta/ultrastructure ; Blood Cells/ultrastructure ; Bone Marrow Cells/ultrastructure ; DNA/chemistry ; Female ; Humans ; Linear Models ; Male ; Middle Aged ; Polymerase Chain Reaction ; Prospective Studies ; Skin/cytology ; Telomere/*chemistry/ultrastructure ; Vocal Cords/*cytology/*physiology ; },
abstract = {The objective of this article is to determine telomere length, a measure of biological age, in true vocal fold (TVF), false vocal fold (FVF), and five other tissue types, to ascertain whether there is tissue-specific telomere shortening. The study design is that of a prospective, basic science study. Tissue samples were obtained from the TVF, FVF, skin from the back of hand, skin from thigh, aorta, blood, and bone marrow from 12 patients ages 54 to 76 years. Genomic DNA was isolated from each sample, and telomere lengths were calculated with real-time polymerase chain reaction. In our small age group, age was not significantly associated with telomere length across tissue types, nor were there any linear correlations within tissue types and age. Controlling for age, significant differences were found between the following tissues: aorta and blood (P < 0.000), aorta and bone marrow (P = 0.033), aorta and FVF (P = 0.015), aorta and hand skin (P = 0.004), blood and thigh skin (P = 0.012), and blood and TVF (P = 0.048). A significant linear correlation between telomere length and tissue type without considering donor age was established between bone marrow and hand skin (P < 0.05, R2 = 0.766), thigh skin and hand skin (P < 0.01, R2 = 0.926), TVF and blood (P < 0.01, R2 = 0.836), and thigh skin and TVF (P < 0.05, R2 = 0.624). Our findings indicate that surrogate tissue for measurement of telomere length of TVF includes FVF, bone marrow, skin, and aorta. These findings have implications for understanding vocal fold aging at the cellular level.},
}
@article {pmid16163702,
year = {2005},
author = {Potter, AJ and Wener, MH},
title = {Flow cytometric analysis of fluorescence in situ hybridization with dye dilution and DNA staining (flow-FISH-DDD) to determine telomere length dynamics in proliferating cells.},
journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology},
volume = {68},
number = {1},
pages = {53-58},
doi = {10.1002/cyto.a.20181},
pmid = {16163702},
issn = {1552-4922},
support = {P30-DK035816/DK/NIDDK NIH HHS/United States ; },
mesh = {Carbocyanines/chemistry ; Cell Cycle/physiology ; *Cell Proliferation ; Cellular Senescence/genetics ; DNA/*analysis/chemistry/genetics ; Flow Cytometry/*methods ; Fluoresceins/chemistry ; Fluorescent Dyes/chemistry ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Indoles/chemistry ; Leukocytes, Mononuclear/cytology/drug effects/metabolism ; Peptide Nucleic Acids/chemistry ; Phytohemagglutinins/pharmacology ; Staining and Labeling/methods ; Succinimides/chemistry ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Telomeres shorten during DNA replication; extensive erosion of telomeres likely promotes replicative senescence and chromosomal instability. Telomere length in individual cells has been quantified by flow cytometric analysis of fluorescence in situ hybridization (flow-FISH). To determine the rate of telomere attrition (telomere erosion per cell division), we combined flow-FISH with dye dilution and DNA staining (flow-FISH-DDD) and measured telomere-specific fluorescence in proliferating cells identified by cell generation and cell cycle phase.<br><br>METHODS: Peripheral blood mononuclear cells (PBMC) were stained with the cell division tracking dye carboxyfluorescein diacetate succinimidyl ester (CFSE), stimulated with phytohemagglutinin (PHA), grown for 5-6 days, hybridized with a telomere sequence-specific peptide nucleic acid fluorescent probe (PNA-Cy5), counterstained with DAPI, and analyzed by flow cytometry. The cell cycle distribution and cell division generations were respectively identified by analysis of DAPI emission and deconvolution of CFSE emission, and Cy5 emission was used to determine telomere-specific fluorescence, an indicator of telomere length, in each cell.<br><br>RESULTS: In stimulated PBMC, in each cell cycle phase, the telomere-specific fluorescence diminished with increasing cell generation. The rate of decline of the telomere-specific fluorescence per cell generation did not significantly differ between cell cycle phases.<br><br>CONCLUSIONS: Application of flow-FISH-DDD to measure mean telomere length and the rate of telomere attrition in proliferating cells may find use in studies of ageing and disease, the effects of telomere-modifying agents, and variability between individuals.},
}
@article {pmid16163697,
year = {2005},
author = {Vermolen, BJ and Garini, Y and Mai, S and Mougey, V and Fest, T and Chuang, TC and Chuang, AY and Wark, L and Young, IT},
title = {Characterizing the three-dimensional organization of telomeres.},
journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology},
volume = {67},
number = {2},
pages = {144-150},
doi = {10.1002/cyto.a.20159},
pmid = {16163697},
issn = {1552-4922},
mesh = {Algorithms ; Animals ; B-Lymphocytes/cytology ; Bromodeoxyuridine ; Cell Cycle ; Cell Nucleus ; Image Processing, Computer-Assisted ; Imaging, Three-Dimensional/*methods ; In Situ Hybridization, Fluorescence/*methods ; Mice ; Microscopy ; Telomere/*chemistry/*metabolism ; },
abstract = {BACKGROUND: Quantitative analysis can be used in combination with fluorescence microscopy. Although the human eye is able to obtain good qualitative results, when analyzing the spatial organization of telomeres in interphase nuclei, there is a need for quantitative results based on image analysis.<br><br>METHODS: We developed a tool for analyzing three-dimensional images of telomeres stained by fluorescence in situ hybridization in interphase nuclei with DNA counterstained with 4',6-diamidino-2-phenylindole. After deconvolution of the image, we segmented individual telomeres. From the location of the telomeres we derived a distribution parameter rhoT, which indicated whether the telomeres were in a disk (rhoT >> 1) or not (rhoT approximately 1). We sorted mouse lymphocyte nuclei and measured rhoT. We also performed a bromodeoxyuridine synchronous cell sorting experiment on live cells and measured rhoT at several instances.<br><br>RESULTS: Measuring rhoT for nuclei in G0/G1, S, and G2 produced 1.4 +/- 0.1, 1.5 +/- 0.2, and 14 +/- 2, respectively, showing a significant difference between G2 and G0/G1 or S. For the bromodeoxyuridine synchronous cell sorting experiment, we found a cell cycle dependency of rhoT and a correlation between rhoT and an observer.<br><br>CONCLUSIONS: In this study we present a quantitative method to characterize the organization of telomeres using three-dimensional imaging, image processing, and image analysis.},
}
@article {pmid16151516,
year = {2005},
author = {Raices, M and Maruyama, H and Dillin, A and Karlseder, J},
title = {Uncoupling of longevity and telomere length in C. elegans.},
journal = {PLoS genetics},
volume = {1},
number = {3},
pages = {e30},
pmid = {16151516},
issn = {1553-7404},
support = {R01 AG024365/AG/NIA NIH HHS/United States ; R01 GM069525/GM/NIGMS NIH HHS/United States ; },
mesh = {Aging/physiology ; Animals ; Caenorhabditis elegans/cytology/*genetics/*growth &amp; development ; Caenorhabditis elegans Proteins/genetics ; DNA/genetics ; Forkhead Transcription Factors ; Longevity ; Mitosis ; Receptor, Insulin/genetics ; Telomere/genetics/*ultrastructure ; Transcription Factors/genetics ; },
abstract = {The nematode Caenorhabditis elegans, after completing its developmental stages and a brief reproductive period, spends the remainder of its adult life as an organism consisting exclusively of post-mitotic cells. Here we show that telomere length varies considerably in clonal populations of wild-type worms, and that these length differences are conserved over at least ten generations, suggesting a length regulation mechanism in cis. This observation is strengthened by the finding that the bulk telomere length in different worm strains varies considerably. Despite the close correlation of telomere length and clonal cellular senescence in mammalian cells, nematodes with long telomeres were neither long lived, nor did worm populations with comparably short telomeres exhibit a shorter life span. Conversely, long-lived daf-2 and short-lived daf-16 mutant animals can have either long or short telomeres. Telomere length of post-mitotic cells did not change during the aging process, and the response of animals to stress was found independent of telomere length. Collectively, our data indicate that telomere length and life span can be uncoupled in a post-mitotic setting, suggesting separate pathways for replication-dependent and -independent aging.},
}
@article {pmid16150933,
year = {2005},
author = {Cookson, JC and Dai, F and Smith, V and Heald, RA and Laughton, CA and Stevens, MF and Burger, AM},
title = {Pharmacodynamics of the G-quadruplex-stabilizing telomerase inhibitor 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) in vitro: activity in human tumor cells correlates with telomere length and can be enhanced, or antagonized, with cytotoxic agents.},
journal = {Molecular pharmacology},
volume = {68},
number = {6},
pages = {1551-1558},
doi = {10.1124/mol.105.013300},
pmid = {16150933},
issn = {0026-895X},
mesh = {Acridines/pharmacokinetics/*pharmacology ; Antineoplastic Agents/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA ; DNA-Binding Proteins/*antagonists &amp; inhibitors ; Drug Interactions ; Enzyme Inhibitors/pharmacology ; G-Quadruplexes ; Humans ; Pharmacokinetics ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*ultrastructure ; },
abstract = {Telomeric integrity is required to maintain the replicative ability of cancer cells and is a target for the G-quadruplex-stabilizing drug 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4). We report a senescent-like growth arrest in MCF-7 breast cancer cells, within 14 to 17 days, and a reduction in telomere length (from 5.2 kilobases (kb) to 4.7 and 4.3 kb after 17 days of treatment at 0.5 and 1 microM, respectively). These effects occurred at noncytotoxic drug concentrations (doses < 1 microM over a 14-day exposure) compatible with long-term drug dosing. The telomere length of cancer cells influences their sensitivity to growth inhibition by RHPS4: mutant (mt) human telomerase reverse transcriptase (hTERT)-expressing MCF-7 cells [short telomere restriction fragment (TRF) length, 1.9 kb; IC50, 0.2 microM] were 10 times more sensitive to RHPS4 compared with wild-type (wt) hTERT-expressing, vector-transfected control cells (longer TRF-length 5.2 kb; IC50 2 microM) in the 5 day SRB assay. This relationship was corroborated in a panel of 36 human tumor xenografts grown in vitro showing a positive correlation between telomere length and growth inhibitory potency of RHPS4 (15-day clonogenic assay, r = 0.75). These observations are consistent with loss of the protective capping status of telomeres mediated by RHPS4 G-quadruplex-stabilization, thus leading to greater susceptibility of cells with shorter telomeres. In combination studies, paclitaxel (Taxol), doxorubicin (Adriamycin), and the experimental therapeutic agent 17-(allylamino)-17-demethoxygeldanamycin, which inhibits the 90-kDa heat shock protein, conferred enhanced sensitivity in RHPS4 treated MCF-7 cells, whereas the DNA-interactive temozolomide and cisplatin antagonized the action of RHPS4. Our results support the combined use of certain classes of cytotoxic anticancer agents with RHPS4 to enhance potential clinical benefit.},
}
@article {pmid16143601,
year = {2005},
author = {Biessmann, H and Prasad, S and Semeshin, VF and Andreyeva, EN and Nguyen, Q and Walter, MF and Mason, JM},
title = {Two distinct domains in Drosophila melanogaster telomeres.},
journal = {Genetics},
volume = {171},
number = {4},
pages = {1767-1777},
pmid = {16143601},
issn = {0016-6731},
support = {Z01 ES021054-12/ES/NIEHS NIH HHS/United States ; R01 GM056729/GM/NIGMS NIH HHS/United States ; //Intramural NIH HHS/United States ; R01 GM056729-04/GM/NIGMS NIH HHS/United States ; GM 56729/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Blotting, Southern ; Chromosomes/*genetics/ultrastructure ; Computational Biology ; DNA Primers ; Drosophila melanogaster/*genetics ; Gene Components ; Genomic Library ; Heterochromatin/genetics ; In Situ Hybridization ; Microscopy, Electron ; Molecular Sequence Data ; Retroelements/genetics ; Sequence Analysis, DNA ; Telomere/*genetics ; Terminal Repeat Sequences/genetics ; Transgenes/genetics ; },
abstract = {Telomeres are generally considered heterochromatic. On the basis of DNA composition, the telomeric region of Drosophila melanogaster contains two distinct subdomains: a subtelomeric region of repetitive DNA, termed TAS, and a terminal array of retrotransposons, which perform the elongation function instead of telomerase. We have identified several P-element insertions into this retrotransposon array and compared expression levels of transgenes with similar integrations into TAS and euchromatic regions. In contrast to insertions in TAS, which are silenced, reporter genes in the terminal HeT-A, TAHRE, or TART retroelements did not exhibit repressed expression in comparison with the same transgene construct in euchromatin. These data, in combination with cytological studies, provide evidence that the subtelomeric TAS region exhibits features resembling heterochromatin, while the terminal retrotransposon array exhibits euchromatic characteristics.},
}
@article {pmid16142795,
year = {2005},
author = {Betts, DH and Perrault, SD and Petrik, J and Lin, L and Favetta, LA and Keefer, CL and King, WA},
title = {Telomere length analysis in goat clones and their offspring.},
journal = {Molecular reproduction and development},
volume = {72},
number = {4},
pages = {461-470},
doi = {10.1002/mrd.20371},
pmid = {16142795},
issn = {1040-452X},
mesh = {Aging/genetics/*metabolism ; Animals ; *Cloning, Organism/methods ; Female ; Goats ; Male ; *Sequence Analysis, DNA/methods ; Telomere/genetics/*metabolism ; },
abstract = {Incomplete epigenetic reprogramming of the donor genome is believed to be the cause behind the high rate of developmental mortality and post-natal anomalies observed in animal clones. It appears that overt phenotypic abnormalities are not transmitted to their progeny suggesting that epigenetic errors are corrected in the germline of clones. Here, we show variation in telomere lengths among Nigerian dwarf goat clones derived from different somatic cell types and that the offspring of two male clones have significantly shorter telomere lengths than age-matched noncloned animals. Telomere lengths were significantly shorter in skin biopsies of goat clones derived from adult granulosa cells compared to those measured for controls. Telomere lengths were highly variable in male goat clones reconstructed from fetal fibroblasts but their mean terminal repeat fragment (TRF) length was within normal range of normal goats. However, in the progeny of two male clones, mean TRF lengths were considerably shorter than age-matched controls for both skin and leukocyte samples. Evidence for possible inheritance of shortened telomeres was obtained by measuring telomere lengths in testicular biopsies obtained from the clones, which when compared with those from noncloned animals of a similar age were significantly shorter. The offspring exhibited telomere lengths intermediate to the TRF values obtained for their cloned fathers' and age-matched control testes. These results demonstrate that telomere length reprogramming in clones is dependent on the type of donor cell used and that the progeny of clones may inherit telomere length alterations acquired through the cloning procedure.},
}
@article {pmid16142245,
year = {2005},
author = {Paeschke, K and Simonsson, T and Postberg, J and Rhodes, D and Lipps, HJ},
title = {Telomere end-binding proteins control the formation of G-quadruplex DNA structures in vivo.},
journal = {Nature structural &amp; molecular biology},
volume = {12},
number = {10},
pages = {847-854},
doi = {10.1038/nsmb982},
pmid = {16142245},
issn = {1545-9993},
mesh = {Animals ; Cell Nucleus/genetics/metabolism ; Ciliophora/*genetics/metabolism ; DNA/*chemistry/*metabolism ; G-Quadruplexes ; Guanine/*chemistry ; Molecular Sequence Data ; Nucleic Acid Conformation ; Protozoan Proteins/genetics/*metabolism ; RNA Interference ; Telomere/chemistry/*metabolism ; Telomere-Binding Proteins/analysis/genetics/*metabolism ; },
abstract = {Telomere end-binding proteins (TEBPs) bind to the guanine-rich overhang (G-overhang) of telomeres. Although the DNA binding properties of TEBPs have been investigated in vitro, little is known about their functions in vivo. Here we use RNA interference to explore in vivo functions of two ciliate TEBPs, TEBPalpha and TEBPbeta. Silencing the expression of genes encoding both TEBPs shows that they cooperate to control the formation of an antiparallel guanine quadruplex (G-quadruplex) DNA structure at telomeres in vivo. This function seems to depend on the role of TEBPalpha in attaching telomeres in the nucleus and in recruiting TEBPbeta to these sites. In vitro DNA binding and footprinting studies confirm the in vivo observations and highlight the role of the C terminus of TEBPbeta in G-quadruplex formation. We have also found that G-quadruplex formation in vivo is regulated by the cell cycle-dependent phosphorylation of TEBPbeta.},
}
@article {pmid16142233,
year = {2005},
author = {Muñoz, P and Blanco, R and Flores, JM and Blasco, MA},
title = {XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer.},
journal = {Nature genetics},
volume = {37},
number = {10},
pages = {1063-1071},
doi = {10.1038/ng1633},
pmid = {16142233},
issn = {1061-4036},
mesh = {Aging, Premature/*genetics ; Animals ; Cattle ; Cross-Linking Reagents ; DNA Damage/genetics ; DNA-Binding Proteins/*metabolism ; Disease Models, Animal ; Humans ; Keratinocytes/drug effects/radiation effects ; Mice ; Mice, Mutant Strains ; RNA, Messenger/analysis/metabolism ; RNA, Neoplasm/chemistry ; Sequence Deletion ; Skin Neoplasms/chemistry/*genetics/metabolism ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/*genetics/metabolism ; Transcriptional Activation ; Ultraviolet Rays ; },
abstract = {TRF2 is a telomere-binding protein that has a role in telomere protection. We generated mice that overexpress TRF2 in the skin. These mice had a severe phenotype in the skin in response to light, consisting of premature skin deterioration, hyperpigmentation and increased skin cancer, which resembles the human syndrome xeroderma pigmentosum. Keratinocytes from these mice were hypersensitive to ultraviolet irradiation and DNA crosslinking agents. The skin cells of these mice had marked telomere shortening, loss of the telomeric G-strand overhang and increased chromosomal instability. Telomere loss in these mice was mediated by XPF, a structure-specific nuclease involved in ultraviolet-induced damage repair and mutated in individuals with xeroderma pigmentosum. These findings suggest that TRF2 provides a crucial link between telomere function and ultraviolet-induced damage repair, whose alteration underlies genomic instability, cancer and aging. Finally, we show that a number of human skin tumors have increased expression of TRF2, further highlighting a role for TRF2 in skin cancer.},
}
@article {pmid16140922,
year = {2005},
author = {Atkinson, SP and Hoare, SF and Glasspool, RM and Keith, WN},
title = {Lack of telomerase gene expression in alternative lengthening of telomere cells is associated with chromatin remodeling of the hTR and hTERT gene promoters.},
journal = {Cancer research},
volume = {65},
number = {17},
pages = {7585-7590},
doi = {10.1158/0008-5472.CAN-05-1715},
pmid = {16140922},
issn = {0008-5472},
mesh = {Acetylation ; Cell Line, Tumor ; Chromatin/*genetics/metabolism ; DNA Methylation ; DNA-Binding Proteins/*genetics ; Enzyme Activation ; Gene Expression ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Histones/metabolism ; Humans ; Lysine/metabolism ; Methylation ; Promoter Regions, Genetic ; Telomerase/biosynthesis/*genetics ; Telomere/genetics/*metabolism ; Transcription, Genetic ; },
abstract = {The presence of active telomere maintenance mechanisms in immortal cells allows the bypass of senescence by maintaining telomere length. In most immortal cell lines and tumors, telomere maintenance is attributable to telomerase reactivation. However, a number of immortal cell lines and tumors can achieve telomere maintenance in the absence of detectable telomerase activity by the alternative lengthening of telomere (ALT) mechanism. Epigenetic mechanisms have been implicated in the regulation of telomerase expression. We show that specific modifications within the chromatin environment of the hTR and hTERT promoters correlate with expression of hTR and hTERT in ALT, normal and telomerase-positive tumor cell lines. Lack of expression of hTR and hTERT in ALT cell lines is associated with histone H3 and H4 hypoacetylation and methylation of Lys9 histone H3. Conversely, hTR and hTERT expression in telomerase-positive cell lines is associated with hyperacetylation of H3 and H4 and methylation of Lys4 H3. Methylation of Lys20 H4 was not linked to gene expression but instead was specific to the hTR and hTERT promoters of ALT cells. This may provide an insight into the differences between ALT and telomerase-positive cells as well as a novel marker for the ALT phenotype. Treatment of normal and ALT cells with 5-azadeoxycytidine in combination with Trichostatin A caused chromatin remodeling of both promoters and reactivation of hTR and hTERT expression in ALT and normal cell lines. This data establishes a definite link between the chromatin environment of the telomerase gene promoters and transcriptional activity.},
}
@article {pmid16136653,
year = {2005},
author = {Blasco, MA},
title = {Telomeres and human disease: ageing, cancer and beyond.},
journal = {Nature reviews. Genetics},
volume = {6},
number = {8},
pages = {611-622},
doi = {10.1038/nrg1656},
pmid = {16136653},
issn = {1471-0056},
mesh = {Aging/*genetics ; Humans ; Neoplasms/chemistry/*genetics/metabolism ; *Telomere/chemistry/genetics/metabolism ; },
abstract = {Telomere length and telomerase activity are important factors in the pathobiology of human disease. Age-related diseases and premature ageing syndromes are characterized by short telomeres, which can compromise cell viability, whereas tumour cells can prevent telomere loss by aberrantly upregulating telomerase. Altered functioning of both telomerase and telomere-interacting proteins is present in some human premature ageing syndromes and in cancer, and recent findings indicate that alterations that affect telomeres at the level of chromatin structure might also have a role in human disease. These findings have inspired a number of potential therapeutic strategies that are based on telomerase and telomeres.},
}
@article {pmid16135798,
year = {2005},
author = {Iyer, S and Chadha, AD and McEachern, MJ},
title = {A mutation in the STN1 gene triggers an alternative lengthening of telomere-like runaway recombinational telomere elongation and rapid deletion in yeast.},
journal = {Molecular and cellular biology},
volume = {25},
number = {18},
pages = {8064-8073},
pmid = {16135798},
issn = {0270-7306},
support = {R01 GM061645/GM/NIGMS NIH HHS/United States ; GM 61645-01/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Genes, Fungal ; Kluyveromyces/enzymology/*genetics ; Molecular Sequence Data ; Mutation ; Rad52 DNA Repair and Recombination Protein ; *Recombination, Genetic ; Sequence Deletion/genetics ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*genetics ; },
abstract = {Some human cancer cells achieve immortalization by using a recombinational mechanism termed ALT (alternative lengthening of telomeres). A characteristic feature of ALT cells is the presence of extremely long and heterogeneous telomeres. The molecular mechanism triggering and maintaining this pathway is currently unknown. In Kluyveromyces lactis, we have identified a novel allele of the STN1 gene that produces a runaway ALT-like telomeric phenotype by recombination despite the presence of an active telomerase pathway. Additionally, stn1-M1 cells are synthetically lethal in combination with rad52 and display chronic growth and telomere capping defects including extensive 3' single-stranded telomere DNA and highly elevated subtelomere gene conversion. Strikingly, stn1-M1 cells undergo a very high rate of telomere rapid deletion (TRD) upon reintroduction of STN1. Our results suggest that the protein encoded by STN1, which protects the terminal 3' telomere DNA, can regulate both ALT and TRD.},
}
@article {pmid16132818,
year = {2005},
author = {Teixeira, MT and Gilson, E},
title = {Telomere maintenance, function and evolution: the yeast paradigm.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {13},
number = {5},
pages = {535-548},
pmid = {16132818},
issn = {0967-3849},
mesh = {Ascomycota/genetics/physiology ; Base Sequence ; *Evolution, Molecular ; Models, Genetic ; Phylogeny ; Saccharomyces cerevisiae ; Telomere/*genetics/physiology ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Telomeres are multifunctional genetic elements that cap chromosome ends, playing essential roles in genome stability, chromosome higher-order organization and proliferation control. The telomere field has largely benefited from the study of unicellular eukaryotic organisms such as yeasts. Easy cultivation in laboratory conditions and powerful genetics have placed mainly Saccharomyces cerevisiae, Kluveromyces lactis and Schizosaccharomyces pombe as crucial model organisms for telomere biology research. Studies in these species have made it possible to elucidate the basic mechanisms of telomere maintenance, function and evolution. Moreover, comparative genomic analyses show that telomeres have evolved rapidly among yeast species and functional plasticity emerges as one of the driving forces of this evolution. This provides a precious opportunity to further our understanding of telomere biology.},
}
@article {pmid16132817,
year = {2005},
author = {Horn, D and Barry, JD},
title = {The central roles of telomeres and subtelomeres in antigenic variation in African trypanosomes.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {13},
number = {5},
pages = {525-533},
pmid = {16132817},
issn = {0967-3849},
support = {AI043062/AI/NIAID NIH HHS/United States ; //Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Antigenic Variation/*genetics/physiology ; Base Sequence ; GC Rich Sequence/genetics/immunology ; Gene Silencing/immunology ; Molecular Sequence Data ; Telomere/*physiology ; Telomere-Binding Proteins/genetics/immunology/physiology ; Trypanosoma brucei brucei/*genetics/physiology ; Variant Surface Glycoproteins, Trypanosoma/*genetics/immunology ; },
abstract = {Telomeres and subtelomeres are important to the virulence of a number of pathogens, as they harbour large diverse gene families associated with the maintenance of infection. Evasion of immunity by African trypanosomes involves the differential expression of variant surface glycoproteins (VSGs), which are encoded by a family of >1500 genes and pseudogenes. This silent archive is located subtelomerically and is activated by gene conversion into specialized transcription units, which themselves are subject to silencing by allelic exclusion. Current research addresses the role of telomeres in the conversion and silencing mechanisms and in the diversification of the VSG archive.},
}
@article {pmid16132816,
year = {2005},
author = {Figueiredo, L and Scherf, A},
title = {Plasmodium telomeres and telomerase: the usual actors in an unusual scenario.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {13},
number = {5},
pages = {517-524},
pmid = {16132816},
issn = {0967-3849},
mesh = {Animals ; Catalytic Domain/genetics ; Cell Nucleus/enzymology ; DNA-Binding Proteins/chemistry/genetics/metabolism ; Gene Silencing/physiology ; Genes, Protozoan ; Models, Genetic ; Plasmodium/*genetics ; Telomerase/chemistry/genetics/metabolism/*physiology ; Telomere/genetics/metabolism/*physiology ; },
abstract = {In the last decade, telomeres of malaria parasites have been in the spotlight. A number of different host-parasite interactions involve genes that are regulated through processes unique to telomeres. In the highly proliferative human pathogen, Plasmodium falciparum, telomerase appears to not only promote telomere maintenance but also to repair broken chromosome ends. The characterization of the plasmodial gene that encodes the telomerase reverse transcriptase protein has revealed several unusual features. For example, the predicted protein is approximately three times larger than the yeast homologue, due to many insertions of stretches of basic amino acids. Other telomere-associated proteins have also been identified. One of them, the P. falciparum gene homologous to yeast Sir2, seems to be required for the establishment of a heterochromatin-like structure at the telomeres, which leads to the silencing of subtelomeric genes. It has been shown that PfSir2 associates with promoter regions of silenced genes involved in antigenic variation.},
}
@article {pmid16132814,
year = {2005},
author = {Harrington, L},
title = {Making the most of a little: dosage effects in eukaryotic telomere length maintenance.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {13},
number = {5},
pages = {493-504},
pmid = {16132814},
issn = {0967-3849},
mesh = {Animals ; *Gene Dosage ; Gene Frequency/genetics ; Humans ; Mammals ; Models, Genetic ; Neoplasms/genetics ; Telomerase/genetics/*physiology ; Telomere/genetics/metabolism/*physiology ; },
abstract = {Telomerase contains at least two essential components: the telomerase reverse transcriptase (TERT), and the telomerase RNA, which provides the template for the reverse transcription of new telomere DNA by TERT. Loss of telomerase enzymatic function leads to a progressive attrition of telomeric sequence over time, eventually resulting in the disappearance of detectable telomeric DNA and the emergence of chromosome end-to-end fusions, followed by growth arrest or cell death. Recently, the consequences of partial loss of telomerase function have revealed interesting dosage-dependent effects on telomere length and stability. In both mice and humans, hemizygosity for the telomerase RNA or TERT leads to an inability to maintain telomeres; in humans, this insufficiency can lead to diseases such as aplastic anaemia or dyskeratosis congenita. In the budding yeast S. cerevisiae, compound heterozygosity in different telomerase components also results in shortened telomeres. Thus, partial loss of telomerase function can result in a latent but measurable compromise in telomere length. These dosage-dependent effects illuminate a mechanism by which subtle heritable defects in genome integrity can eventually become pernicious.},
}
@article {pmid16132813,
year = {2005},
author = {Gallego, ME and White, CI},
title = {DNA repair and recombination functions in Arabidopsis telomere maintenance.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {13},
number = {5},
pages = {481-491},
pmid = {16132813},
issn = {0967-3849},
mesh = {Arabidopsis/genetics/metabolism/*physiology ; DNA Repair/genetics/*physiology ; DNA Repair Enzymes/genetics/metabolism/physiology ; DNA-Binding Proteins/genetics/metabolism/physiology ; Models, Genetic ; Recombination, Genetic/genetics/*physiology ; Telomerase/genetics/metabolism ; Telomere/genetics/*physiology ; Telomere-Binding Proteins/physiology ; },
abstract = {In this review, we discuss recent advances in the knowledge of plant telomere maintenance, focusing on the model plant Arabidopsis thaliana and, in particular, on the roles of proteins involved in DNA repair and recombination. The question of the interrelationships between DNA repair and recombination pathways and proteins with telomere function and maintenance is of increasing interest and has been the subject of a number of recent reviews (Cech 2004, d'Adda di Fagagna et al. 2004, Hande 2004, Harrington 2004, Maser and DePinho 2004). Understanding of telomere biology, DNA repair and recombination in plants has rapidly progressed over the last decade, substantially due to genetic approaches in Arabidopsis, and we feel that this is an appropriate time to review current knowledge in this field. A number of recent reviews have dealt more generally with the subject of plant telomere structure and evolution (Riha et al. 2001, McKnight et al. 2002, Riha and Shippen 2003b, McKnight and Shippen 2004, Fajkus et al. 2005) and we thus focus specifically on plant telomere biology in the context of DNA repair and recombination in Arabidopsis.},
}
@article {pmid16132812,
year = {2005},
author = {Fajkus, J and Sýkorová, E and Leitch, AR},
title = {Telomeres in evolution and evolution of telomeres.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {13},
number = {5},
pages = {469-479},
pmid = {16132812},
issn = {0967-3849},
mesh = {Chromosomes, Plant/genetics/metabolism ; *Evolution, Molecular ; *Genome, Plant ; Minisatellite Repeats ; Phylogeny ; Repetitive Sequences, Nucleic Acid ; Retroelements ; Telomere/*genetics/physiology ; Telomere-Binding Proteins/*physiology ; },
abstract = {This paper examines telomeres from an evolutionary perspective. In the monocot plant order Asparagales two evolutionary switch-points in telomere sequence are known. The first occurred when the Arabidopsis-type telomere was replaced by a telomere based on a repeat motif more typical of vertebrates. The replacement is associated with telomerase activity, but the telomerase has low fidelity and this may have implications for the binding of telomeric proteins. At the second evolutionary switch-point, the telomere and its mode of synthesis are replaced by an unknown mechanism. Elsewhere in plants (Sessia, Vestia, Cestrum) and in arthropods, the telomere "typical" of the group is lost. Probably many other groups with "unusual" telomeres will be found. We question whether telomerase is indeed the original end-maintenance system and point to other candidate processes involving t-loops, t-circles, rolling circle replication and recombination. Possible evolutionary outcomes arising from the loss of telomerase activity in alternative lengthening of telomere (ALT) systems are discussed. We propose that elongation of minisatellite repeats using recombination/replication processes initially substitutes for the loss of telomerase function. Then in more established ALT groups, subtelomeric satellite repeats may replace the telomeric minisatellite repeat whilst maintaining the recombination/replication mechanisms for telomere elongation. Thereafter a retrotransposition-based end-maintenance system may become established. The influence of changing sequence motifs on the properties of the telomere cap is discussed. The DNA and protein components of telomeres should be regarded--as with any other chromosome elements--as evolving and co-evolving over time and responding to changes in the genome and to environmental stresses. We describe how telomere dysfunction, resulting in end-to-end chromosome fusions, can have a profound effect on chromosome evolution and perhaps even speciation.},
}
@article {pmid16132811,
year = {2005},
author = {Fujiwara, H and Osanai, M and Matsumoto, T and Kojima, KK},
title = {Telomere-specific non-LTR retrotransposons and telomere maintenance in the silkworm, Bombyx mori.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {13},
number = {5},
pages = {455-467},
pmid = {16132811},
issn = {0967-3849},
mesh = {Animals ; Bombyx/*genetics/physiology ; Evolution, Molecular ; Models, Genetic ; Phylogeny ; Retroelements/*genetics ; Reverse Transcription/genetics ; Telomerase/metabolism ; Telomere/chemistry/genetics/*physiology ; Terminal Repeat Sequences/genetics/physiology ; },
abstract = {Most insects have telomeres that consist of pentanucleotide (TTAGG) telomeric repeats, which are synthesized by telomerase. However, all species in Diptera so far examined and several species in other orders of insect have lost the (TTAGG)n repeats, suggesting that some of them recruit telomerase-independent telomere maintenance. The silkworm, Bombyx mori, retains the TTAGG motifs in the chromosomal ends but expresses quite a low level of telomerase activity in all stages of various tissues. Just proximal to a 6-8-kb stretch of the TTAGG repeats in B. mori, more than 1000 copies of non-LTR retrotransposons, designated TRAS and SART families, occur among the telomeric repeats and accumulate. TRAS and SART are abundantly transcribed and actively retrotransposed into TTAGG telomeric repeats in a highly sequence-specific manner. They have three possible mechanisms to ensure specific integration into the telomeric repeats. This article focuses on the telomere structure and telomere-specific non-LTR retrotransposons in B. mori and discusses the mechanisms for telomere maintenance in this insect.},
}
@article {pmid16132810,
year = {2005},
author = {Pardue, ML and Rashkova, S and Casacuberta, E and DeBaryshe, PG and George, JA and Traverse, KL},
title = {Two retrotransposons maintain telomeres in Drosophila.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {13},
number = {5},
pages = {443-453},
pmid = {16132810},
issn = {0967-3849},
support = {R01 GM050315/GM/NIGMS NIH HHS/United States ; R56 GM050315/GM/NIGMS NIH HHS/United States ; GM50315/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Nucleus/genetics ; Chromosomes/genetics ; Drosophila/*genetics ; Drosophila Proteins/genetics/metabolism ; Evolution, Molecular ; Gene Products, gag/genetics/metabolism ; Green Fluorescent Proteins/genetics/metabolism ; Microscopy, Fluorescence ; Protein Structure, Tertiary/genetics ; Recombinant Fusion Proteins/genetics/metabolism ; Retroelements/*genetics/physiology ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres across the genus Drosophila are maintained, not by telomerase, but by two non-LTR retrotransposons, HeT-A and TART, that transpose specifically to chromosome ends. Successive transpositions result in long head-to-tail arrays of these elements. Thus Drosophila telomeres, like those produced by telomerase, consist of repeated sequences reverse transcribed from RNA templates. The Drosophila repeats, complete and 5'-truncated copies of HeT-A and TART, are more complex than telomerase repeats; nevertheless, these evolutionary variants have functional similarities to the more common telomeres. Like other telomeres, the Drosophila arrays are dynamic, fluctuating around an average length that can be changed by changes in the genetic background. Several proteins that interact with telomeres in other species have been found to have homologues that interact with Drosophila telomeres. Although they have hallmarks of non-LTR retrotransposons, HeT-A and TART appear to have a special relationship to Drosophila. Their Gag proteins are efficiently transported into diploid nuclei where HeT-A Gag recruits TART Gag to chromosome ends. Gags of other non-LTR elements remain predominantly in the cytoplasm. These studies provide intriguing evolutionary links between telomeres and retrotransposable elements.},
}
@article {pmid16132809,
year = {2005},
author = {Melnikova, L and Georgiev, P},
title = {Drosophila telomeres: the non-telomerase alternative.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {13},
number = {5},
pages = {431-441},
pmid = {16132809},
issn = {0967-3849},
mesh = {Animals ; Chromatin/genetics/metabolism ; Drosophila/*genetics/metabolism ; Evolution, Molecular ; Models, Genetic ; Retroelements/genetics/physiology ; Telomerase/genetics/*physiology ; Telomere/metabolism/*physiology ; },
abstract = {In most eukaryotes, telomeres are composed of simple repetitive sequences renewable by telomerase. By contrast, Drosophila telomeres comprise arrays of non-LTR retrotransposons HeT-A, TART, and TAHRE belonging to three different families. However, closer inspection reveals that the two quite different telomere systems share quite a few components and regulatory circuits. Here we present the current knowledge on Drosophila telomeres and discuss the possible mechanisms of telomere length control.},
}
@article {pmid16132531,
year = {2005},
author = {Ji, HJ and Rha, SY and Jeung, HC and Yang, SH and An, SW and Chung, HC},
title = {Cyclic induction of senescence with intermittent AZT treatment accelerates both apoptosis and telomere loss.},
journal = {Breast cancer research and treatment},
volume = {93},
number = {3},
pages = {227-236},
doi = {10.1007/s10549-005-5156-0},
pmid = {16132531},
issn = {0167-6806},
mesh = {Apoptosis/*drug effects ; Breast Neoplasms/*drug therapy ; Cellular Senescence/drug effects/genetics ; DNA-Binding Proteins/drug effects/metabolism ; Dose-Response Relationship, Drug ; Gene Expression/drug effects ; Humans ; Reverse Transcriptase Inhibitors/*pharmacology ; Telomerase/*drug effects/genetics/metabolism ; Telomere/*drug effects/metabolism/ultrastructure ; Transcription Factors/drug effects/metabolism ; Tumor Cells, Cultured ; Zidovudine/*pharmacology ; },
abstract = {BACKGROUND: 3'-azido-2',3'-dideoxythymidine (AZT) is phosphorylated intracellularly to 3'-azido-3'-deoxythymidine-5'-triphosphate (AZT-TP), which is incorporated into telomeric DNA, thereby blocking chain elongation. AZT is also known to inhibit reverse transcriptase, as well as other cellular enzymes including DNA polymerase gamma, thymidine kinase, and telomerase.<br><br>METHODS: We induced cancer cell senescence by treating MCF-7 cells with AZT in dosages of IC10 and IC20 for an extended period (about 120 population doublings (PD)). We then investigated the sequential changes in cellular growth, expression of telomerase subunits and transcription factors (c-Myc, Mad1), telomerase activity and telomere length.<br><br>RESULTS: Senescence, apoptosis, growth delay, inhibition of telomerase activity and shortening of telomere length were all observed in a dose- and time-dependent manner. After the onset of senescence, the apoptosis rate increased slowly during early PDs. In contrast to senescence, the apoptotic rate showed little change after AZT removal, while it increased suddenly and significantly in a dose-dependent manner upon the second introduction of AZT. Continuous shortening of the telomeric length was observed with AZT, and, upon re-exposure to AZT, shortening of the telomere occurred more rapidly than with first exposure. Of the telomerase subunits, telomerase reverse transcriptase (hTERT) and c-Myc were the first to show a reduction in activity after AZT treatment, followed by changes in hTER , Mad1 and hTEP-1.<br><br>CONCLUSION: Cyclic treatment with AZT initially suppressed hTERT and c-Myc, followed by suppression of hTER, Mad1 and hTEP-1. Furthermore, the treatment accelerated both telomere loss and apoptosis, even when administered at a senescence-inducing dosage level.},
}
@article {pmid16131840,
year = {2005},
author = {Wang, Y and Giannone, RJ and Liu, Y},
title = {Telomere sister chromatid exchange in telomerase deficient murine cells.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {4},
number = {10},
pages = {1320-1322},
doi = {10.4161/cc.4.10.2075},
pmid = {16131840},
issn = {1551-4005},
mesh = {Animals ; Humans ; Mice ; Mice, Knockout ; Sister Chromatid Exchange/*genetics ; Stem Cells/*metabolism ; Telomerase/*deficiency/genetics/*metabolism ; Telomere/*genetics ; },
abstract = {We have recently demonstrated that several types of genomic rearrangements (i.e., telomere sister chromatid exchange (T-SCE), genomic-SCE, or end-to-end fusions) were more often detected in long-term cultured murine telomerase deficient embryonic stem (ES) cells than in freshly prepared murine splenocytes, even through they possessed similar frequencies of critically short telomeres. The high rate of genomic rearrangements in telomerase deficient ES cells, when compared to murine splenocytes, may reflect the cultured cells' gained ability to protect chromosome ends with eroded telomeres allowing them to escape "end crisis". However, the possibility that ES cells were more permissive to genomic rearrangements than other cell types or that differences in the microenvironment or genetic background of the animals might consequentially determine the rate of T-SCEs or other genomic rearrangements at critically short telomeres could not be ruled out.},
}
@article {pmid16131355,
year = {2005},
author = {Wright, WE and Shay, JW},
title = {Telomere biology in aging and cancer.},
journal = {Journal of the American Geriatrics Society},
volume = {53},
number = {9 Suppl},
pages = {S292-4},
doi = {10.1111/j.1532-5415.2005.53492.x},
pmid = {16131355},
issn = {0002-8614},
mesh = {Aging/*genetics/physiology ; Animals ; Biology ; Cell Division/physiology ; Cell Survival/physiology ; Cellular Senescence/physiology ; Humans ; Longevity/genetics ; Neoplasms/*genetics ; Rejuvenation/physiology ; Telomerase/physiology ; Telomere/genetics/*physiology ; },
abstract = {It is thought that a limited investment by the body in many types of maintenance and repair causes aging. Cell turnover is one mechanism of replacing damaged cells, and cell division thus contributes to good repair, but the number of times cells can divide is limited to form a barrier against cancer. Precancerous cells must divide many times to accumulate all of the mutations needed to become malignant. Limiting the number of times they can divide helps prevent cancer. The mechanism for counting cell divisions lies in structures at the ends of the chromosomes called telomeres that shorten with every division, eventually causing cell aging. This shortening can be prevented and cells immortalized using the enzyme telomerase, which can elongate telomeres. Immortalizing all of the cells in the body might increase repair but would remove the barrier to malignancy and would probably cause premature death from cancer in many cases, although the ability to immortalize cells opens up enormous opportunities for using normal cells for therapeutic purposes in localized areas. Eventually, once better controls and treatments for cancer are available, cellular rejuvenation by manipulating telomeres may reduce some of the physiological declines that accompany aging. Such treatments should increase health span, but because replicative aging represents only one of many processes that may contribute to overall human aging, modest increases in life span are expected at best.},
}
@article {pmid16128746,
year = {2005},
author = {Painter, RG and Lanson, NA and Jin, Z and Park, F and Wang, G},
title = {Conditional expression of a suicide gene by the telomere reverse transcriptase promoter for potential post-therapeutic deletion of tumorigenesis.},
journal = {Cancer science},
volume = {96},
number = {9},
pages = {607-613},
doi = {10.1111/j.1349-7006.2005.00085.x},
pmid = {16128746},
issn = {1347-9032},
mesh = {Animals ; Antiviral Agents/pharmacology ; Carcinoma, Squamous Cell/pathology ; Cell Transformation, Neoplastic/*genetics ; DNA-Binding Proteins/*genetics ; Fibroblasts ; Fibrosarcoma/pathology ; Ganciclovir/pharmacology ; Gene Silencing ; *Gene Transfer Techniques ; *Genes, Transgenic, Suicide ; Genetic Therapy/*methods ; Genetic Vectors ; Head and Neck Neoplasms/pathology ; Humans ; Lentivirus/genetics ; Leukemia, T-Cell/pathology ; Mice ; Promoter Regions, Genetic ; Risk Factors ; Safety ; Simplexvirus/enzymology ; Telomerase/*genetics ; Thymidine Kinase/*biosynthesis ; Transduction, Genetic ; Tumor Cells, Cultured ; },
abstract = {Integration of a therapeutic gene into the host cell genome permits stable expression of the gene product in the target cells and its progeny. However, non-directional integration of any given gene can pose the risk of activating tumor genes or silencing tumor suppressor genes. Therefore, including a safety-control element into integrating vector systems is an important advance towards safer human gene therapy. Here, we report on a gene expression cassette that can be potentially exploited in integrating vector systems to eliminate post-therapeutic tumorigenesis. The Herpes simplex virus thymidine kinase (hsvTK) gene under the transcriptional control of the human telomere reverse transcriptase promoter (hTERTp) was incorporated into a self-inactivating HIV-based lentiviral vector. The hTERT promoter is silent in normal somatic cells and re-activated in tumor cells. Therefore, normal gene-corrected cells should not express hsvTK from the promoter. However, if some gene-corrected cells subsequently become tumorigenic and the hTERT promoter is re-activated, application of ganciclovir (GCV), a clinically used antiviral drug, will achieve selective deletion of the cancerous cells. Our experimental data indicated that the hTERTp-hsvTK cassette in the lentiviral vector was sufficient to differentiate between tumor cells and normal cells, thus eradicating tumor cells selectively in vitro and in vivo. These results proved the principle of using the element in integrating vectors for safer gene delivery.},
}
@article {pmid16127770,
year = {2005},
author = {Lee, DC and Im, JA and Kim, JH and Lee, HR and Shim, JY},
title = {Effect of long-term hormone therapy on telomere length in postmenopausal women.},
journal = {Yonsei medical journal},
volume = {46},
number = {4},
pages = {471-479},
pmid = {16127770},
issn = {0513-5796},
mesh = {Aged ; DNA Damage ; Estrogens/*administration &amp; dosage ; Female ; *Hormone Replacement Therapy ; Humans ; Middle Aged ; Postmenopause ; Progesterone/*administration &amp; dosage ; Telomere/*drug effects ; Time Factors ; },
abstract = {Telomeres undergo attrition with each cell division, and telomere length is associated with age-related diseases and mortality in the elderly. Estrogen can influence the attrition of telomeres by diverse mechanisms. This is a retrospective case control study that investigated the influence of long-term hormone therapy (HT) on telomere length in postmenopausal women. We recruited 130 postmenopausal women from 55 to 69 years of age for this study, and divided them into two groups. The first group included 65 women who had been on estrogen and progesterone therapy for more than five years (HT group). The other group was composed of 65 women matched in age to the HT group who had never had HT (non- HT group). The relative ratios of telomere length of study subjects to a reference DNA from a healthy young female were measured using quantitative PCR. Plasma levels of lipid profiles, total antioxidant status (TAS), C-reactive proteins (CRP), fasting glucose levels, and estradiol levels were measured. Age at menopause, vitamin use, and exercise, alcohol, and cigarette smoking histories were also assessed in a questionnaire. Mean duration (+/- SD) of HT was 8.4 +/- 2.3 years. Prevalence of vitamin use and regular exercise were higher in the HT group than in the non-HT group (p < 0.01). Relative telomere length ratios in the HT group were significantly greater than those in the non-HT group (p < 0.01). HT was significantly correlated with the relative telomere length ratio in multivariate analysis when potential confounding variables were controlled for (p < 0.05). In conclusion, telomere lengths were longer in postmenopausal women who had a history of long-term HT than in postmenopausal women without HT. Long-term HT in postmenopausal women may alleviate telomere attrition.},
}
@article {pmid16117665,
year = {2004},
author = {Gasser, SM and Hediger, F and Taddei, A and Neumann, FR and Gartenberg, MR},
title = {The function of telomere clustering in yeast: the circe effect.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {69},
number = {},
pages = {327-337},
doi = {10.1101/sqb.2004.69.327},
pmid = {16117665},
issn = {0091-7451},
support = {GM51402/GM/NIGMS NIH HHS/United States ; },
mesh = {*Gene Silencing ; Genetic Variation ; In Situ Hybridization, Fluorescence ; Microscopy, Fluorescence ; Models, Genetic ; Nuclear Envelope/genetics/metabolism ; Saccharomyces cerevisiae/*genetics/metabolism/*ultrastructure ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Telomere/*genetics/metabolism/*ultrastructure ; },
}
@article {pmid16116624,
year = {2005},
author = {Plentz, RR and Schlegelberger, B and Flemming, P and Gebel, M and Kreipe, H and Manns, MP and Rudolph, KL and Wilkens, L},
title = {Telomere shortening correlates with increasing aneuploidy of chromosome 8 in human hepatocellular carcinoma.},
journal = {Hepatology (Baltimore, Md.)},
volume = {42},
number = {3},
pages = {522-526},
doi = {10.1002/hep.20847},
pmid = {16116624},
issn = {0270-9139},
mesh = {Adult ; Aged ; *Aneuploidy ; Biopsy, Fine-Needle ; Carcinoma, Hepatocellular/*genetics/pathology ; *Chromosomes, Human, Pair 8 ; Female ; Genomic Instability ; Humans ; In Situ Hybridization, Fluorescence ; Liver/cytology ; Liver Neoplasms/*genetics/pathology ; Male ; Middle Aged ; Telomere/*genetics/*pathology ; },
abstract = {Chromosomal instability (CIN) leads to an increase in aneuploidy and chromosomal aberrations in human hepatocellular carcinoma (HCC). Telomere shortening appears as one mechanism fostering the development of CIN. Whether telomere shortening correlates to specific genetic changes that characterize a certain type of cancer has yet to be established. In our recent study, we combined on a cellular level the analysis of hepatocellular telomere fluorescent intensity (TFI) and copy number of chromosome 8-one of the hallmark chromosomal alterations in hepatocellular carcinoma (HCC). We investigated 15 cytological fine-needle biopsies of aneuploid HCC and 5 touch prints of cadaver livers without cancer. Hepatocyte-specific TFI and the measurement of centromere-specific probe for chromosome 8 were both performed by quantitative fluorescence in situ hybridization (qFISH) or FISH. Combined analysis of both methods (coFISH) allowed measurement of telomere length and chromosome 8 copy number on a single cell level. We observed that telomere shortening correlates significantly with increasing copy number of chromosome 8 in HCC on the cellular level. Above the level of 5 copies of chromosome 8 per nucleus, no further shortening of telomeres was found, indicating that telomeres had reached a critically short length at this stage of aneuploidy. In conclusion, our study gives direct evidence that telomere shortening is linked to a specific genetic alteration characteristic for human HCC.},
}
@article {pmid16116482,
year = {2005},
author = {Cerone, MA and Autexier, C and Londoño-Vallejo, JA and Bacchetti, S},
title = {A human cell line that maintains telomeres in the absence of telomerase and of key markers of ALT.},
journal = {Oncogene},
volume = {24},
number = {53},
pages = {7893-7901},
doi = {10.1038/sj.onc.1208934},
pmid = {16116482},
issn = {0950-9232},
mesh = {Biomarkers/analysis ; Cell Proliferation ; Humans ; Phenotype ; Telomerase/*metabolism ; Telomere/*ultrastructure ; Transfection ; *Tumor Cells, Cultured ; },
abstract = {In human somatic cells proliferation results in telomere shortening due to the end replication problem and the absence of adequate levels of telomerase activity. The progressive loss of telomeric DNA has been associated with replicative senescence. Maintenance of telomere structure and function is, therefore, an essential requisite for cells that proliferate indefinitely. Human cells that have acquired the immortal phenotype mostly rely on telomerase to compensate for telomere shortening with cell division. However, a certain percentage of immortalized cell lines and human tumors maintain their telomeres by Alternative Lengthening of Telomeres (ALT), a mechanism not fully understood but apparently based on homologous recombination. Here, we report the isolation of an immortal human cell line that is derived from an ALT cell line but maintains telomeres in the absence of key features of ALT and of telomerase. The properties of these cells suggest that the identification of ALT cells may not be reliably based on known ALT markers. This finding is of relevance for discriminating between the mortal and immortal phenotype among telomerase-negative cells in vitro and in vivo, particularly in regard to the development of pharmacological approaches for cancer treatment based on telomerase inhibition.},
}
@article {pmid16112303,
year = {2005},
author = {Valdes, AM and Andrew, T and Gardner, JP and Kimura, M and Oelsner, E and Cherkas, LF and Aviv, A and Spector, TD},
title = {Obesity, cigarette smoking, and telomere length in women.},
journal = {Lancet (London, England)},
volume = {366},
number = {9486},
pages = {662-664},
doi = {10.1016/S0140-6736(05)66630-5},
pmid = {16112303},
issn = {1474-547X},
support = {AG021593/AG/NIA NIH HHS/United States ; //Wellcome Trust/United Kingdom ; },
mesh = {Adolescent ; Adult ; Aged ; Aging/genetics ; Female ; Humans ; Middle Aged ; Obesity/*genetics ; Risk Factors ; Smoking/*genetics ; Telomere/*pathology ; },
abstract = {Obesity and smoking are important risk factors for many age-related diseases. Both are states of heightened oxidative stress, which increases the rate of telomere erosion per replication, and inflammation, which enhances white blood cell turnover. Together, these processes might accelerate telomere erosion with age. We therefore tested the hypothesis that increased body mass and smoking are associated with shortened telomere length in white blood cells. We investigated 1122 white women aged 18-76 years and found that telomere length decreased steadily with age at a mean rate of 27 bp per year. Telomeres of obese women were 240 bp shorter than those of lean women (p=0.026). A dose-dependent relation with smoking was recorded (p=0.017), and each pack-year smoked was equivalent to an additional 5 bp of telomere length lost (18%) compared with the rate in the overall cohort. Our results emphasise the pro-ageing effects of obesity and cigarette smoking.},
}
@article {pmid16110488,
year = {2005},
author = {Savage, SA and Stewart, BJ and Eckert, A and Kiley, M and Liao, JS and Chanock, SJ},
title = {Genetic variation, nucleotide diversity, and linkage disequilibrium in seven telomere stability genes suggest that these genes may be under constraint.},
journal = {Human mutation},
volume = {26},
number = {4},
pages = {343-350},
doi = {10.1002/humu.20226},
pmid = {16110488},
issn = {1098-1004},
support = {//Intramural NIH HHS/United States ; },
mesh = {Animals ; Conserved Sequence ; Ethnicity/genetics ; *Genetic Variation ; Haplotypes ; Heterozygote ; Humans ; Linkage Disequilibrium/*genetics ; Mice ; Pan troglodytes/genetics ; *Polymorphism, Single Nucleotide ; Pongo pygmaeus/genetics ; Regulatory Elements, Transcriptional ; Sequence Analysis, DNA ; Species Specificity ; Telomere/genetics/metabolism ; Telomere-Binding Proteins/*genetics/metabolism ; },
abstract = {To maintain chromosomal integrity and to protect the ends of chromosomes against recognition as damaged DNA, end-to-end fusion, or recombination, a coordinated set of genes is required to stabilize the telomere. We surveyed common genetic variation in seven genes that are vital to telomere stability (TERT, POT1, TNKS, TERF1, TINF2, TERF2, and TERF2IP) and validated single nucleotide polymorphisms (SNPs) in four different ethnic groups (n=118 total). Overall, our data show limited degrees of nucleotide diversity in comparison with data from other gene families. We observed that these genes are highly conserved in sequence between species, and that for nearly all of the coding SNPs the most common allele is ancestral (i.e., it is observed in primate sequences). Our findings support the hypothesis that genetic variation in a pathway that is critical for telomere stability may be under constraint. These data establish a foundation for further investigation of these genes in population-genetics, evolution, and disease-association studies.},
}
@article {pmid16110239,
year = {2005},
author = {Lahnert, P},
title = {An improved method for determining telomere length and its use in assessing age in blood and saliva.},
journal = {Gerontology},
volume = {51},
number = {5},
pages = {352-356},
doi = {10.1159/000086374},
pmid = {16110239},
issn = {0304-324X},
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aging/*physiology ; *Biomarkers ; Blotting, Southern/methods ; Forensic Medicine/*methods ; Genetic Markers ; Humans ; Middle Aged ; *Saliva ; Sensitivity and Specificity ; Telomere/*genetics ; },
abstract = {BACKGROUND: It is disputed whether telomeres shorten with age.<br><br>OBJECTIVE: The proposition of this study was to answer this question.<br><br>METHODS: The question was answered by a simple method consisting of a color reaction combined with long-term electrophoresis and weak voltage.<br><br>RESULTS: The telomeres shorten and the shortening is much higher than previously assumed.<br><br>CONCLUSION: The telomere theory of ageing and cancer is corroborated and for the first time it is possible to estimate age in blood or saliva.},
}
@article {pmid16108841,
year = {2005},
author = {Adaikalakoteswari, A and Balasubramanyam, M and Mohan, V},
title = {Telomere shortening occurs in Asian Indian Type 2 diabetic patients.},
journal = {Diabetic medicine : a journal of the British Diabetic Association},
volume = {22},
number = {9},
pages = {1151-1156},
doi = {10.1111/j.1464-5491.2005.01574.x},
pmid = {16108841},
issn = {0742-3071},
mesh = {Aging/genetics ; Cholesterol/blood ; Diabetes Mellitus, Type 2/epidemiology/*genetics ; Female ; Humans ; India/epidemiology ; Insulin Resistance/genetics ; Lipid Peroxidation/genetics ; Lipoproteins, HDL/blood ; Male ; Middle Aged ; Oxidative Stress/genetics ; Polymorphism, Restriction Fragment Length ; Population Surveillance/methods ; Sex Distribution ; Telomere/*genetics ; Thiobarbituric Acid Reactive Substances/analysis ; },
abstract = {AIM: Telomere shortening has been reported in several diseases including atherosclerosis and Type 1 diabetes. Asian Indians have an increased predilection for Type 2 diabetes and premature coronary artery disease. The aim of this study was to determine whether telomeric shortening occurs in Asian Indian Type 2 diabetic patients.<br><br>METHODS: Using Southern-blot analysis we determined mean terminal restriction fragment (TRF) length, a measure of average telomere size, in leucocyte DNA. Type 2 diabetic patients without any diabetes-related complications (n = 40) and age- and sex-matched control non-diabetic subjects (n = 40) were selected from the Chennai Urban Rural Epidemiology Study (CURES). Plasma level of malondialdehyde (MDA), a marker of lipid peroxidation, was measured by TBARS (thiobarbituric acid reactive substances) using a fluorescence method.<br><br>RESULTS: Mean (+/- SE) TRF lengths of the Type 2 diabetic patients (6.01 +/- 0.2 kb) were significantly shorter than those of the control subjects (9.11 +/- 0.6 kb) (P = 0.0001). Among the biochemical parameters, only levels of TBARS showed a negative correlation with shortened telomeres in the diabetic subjects (r = -0.36; P = 0.02). However, telomere lengths were negatively correlated with insulin resistance (HOMA-IR) (r = -0.4; P = 0.01) and age (r = -0.3; P = 0.058) and positively correlated with HDL levels (r = 0.4; P = 0.01) in the control subjects. Multiple linear regression (MLR) analysis revealed diabetes to be significantly (P < 0.0001) associated with shortening of TRF lengths.<br><br>CONCLUSIONS: Telomere shortening occurs in Asian Indian Type 2 diabetic patients.},
}
@article {pmid16107718,
year = {2005},
author = {Shakirov, EV and Surovtseva, YV and Osbun, N and Shippen, DE},
title = {The Arabidopsis Pot1 and Pot2 proteins function in telomere length homeostasis and chromosome end protection.},
journal = {Molecular and cellular biology},
volume = {25},
number = {17},
pages = {7725-7733},
pmid = {16107718},
issn = {0270-7306},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; GM65383/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Arabidopsis/chemistry/*genetics/growth &amp; development/*metabolism ; Arabidopsis Proteins/chemistry/genetics/*metabolism ; Chromosomes, Plant/genetics/*metabolism ; Cloning, Molecular ; Gene Expression Regulation, Plant ; *Homeostasis ; Humans ; Molecular Sequence Data ; Mutation/genetics ; Plants, Genetically Modified ; Sequence Alignment ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; Transgenes/genetics ; },
abstract = {Pot1 (protection of telomeres 1) is a single-stranded telomere binding protein that is essential for chromosome end protection and telomere length homeostasis. Arabidopsis encodes two Pot1-like proteins, dubbed AtPot1 and AtPot2. Here we show that telomeres in transgenic plants expressing a truncated AtPot1 allele lacking the N-terminal oligonucleotide/oligosaccharide binding fold (P1DeltaN) are 1 to 1.5 kb shorter than in the wild type, suggesting that AtPot1 contributes to the positive regulation of telomere length control. In contrast, telomere length is unperturbed in plants expressing the analogous region of AtPot2. A strikingly different phenotype is observed in plants overexpressing the AtPot2 N terminus (P2DeltaC) but not the corresponding region in AtPot1. Although bulk telomeres in P2DeltaC mutants are 1 to 2 kb shorter than in the wild type, these plants resemble late-generation telomerase-deficient mutants with severe growth defects, sterility, and massive genome instability, including bridged chromosomes and aneuploidy. The genome instability associated with P2DeltaC mutants implies that AtPot2 contributes to chromosome end protection. Thus, Arabidopsis has evolved two Pot genes that function differently in telomere biology. These findings provide unanticipated information about the evolution of single-stranded telomere binding proteins.},
}
@article {pmid16106044,
year = {2005},
author = {Li, J and Correia, JJ and Wang, L and Trent, JO and Chaires, JB},
title = {Not so crystal clear: the structure of the human telomere G-quadruplex in solution differs from that present in a crystal.},
journal = {Nucleic acids research},
volume = {33},
number = {14},
pages = {4649-4659},
pmid = {16106044},
issn = {1362-4962},
support = {R01 CA035635/CA/NCI NIH HHS/United States ; CA35635/CA/NCI NIH HHS/United States ; },
mesh = {2-Aminopurine/chemistry ; *Crystallography, X-Ray ; DNA/*chemistry ; Fluorescent Dyes/chemistry ; G-Quadruplexes ; Guanine/chemistry ; Humans ; *Models, Molecular ; *Nuclear Magnetic Resonance, Biomolecular ; Potassium/chemistry ; Sodium/chemistry ; Solutions ; Telomere/*chemistry ; Ultracentrifugation ; },
abstract = {The structure of human telomere DNA is of intense interest because of its role in the biology of both cancer and aging. The sequence [5'-AGGG(TTAGGG)3] has been used as a model for telomere DNA in both NMR and X-ray crystallographic studies, the results of which show dramatically different structures. In Na+ solution, NMR revealed an antiparallel G-quadruplex structure that featured both diagonal and lateral TTA loops. Crystallographic studies in the presence of K+ revealed a flattened, propeller-shaped structure featuring a parallel-stranded G-quadruplex with symmetrical external TTA loops. We report the results of biophysical experiments in solution and computational studies that are inconsistent with the reported crystal structure, indicating that a different structure exists in K+ solutions. Sedimentation coefficients were determined experimentally in both Na+ and K+ solutions and were compared with values calculated using bead models for the reported NMR and crystal structures. Although the solution NMR structure accurately predicted the observed S-value in Na+ solution, the crystal structure predicted an S-value that differed dramatically from that experimentally observed in K+ solution. The environments of loop adenines were probed by quantitative fluorescence studies using strategic and systematic single-substitutions of 2-aminopurine for adenine bases. Both fluorescence intensity and quenching experiments in K+ yielded results at odds with quantitative predictions from the reported crystal structure. Circular dichroism and fluorescence quenching studies in the presence of the crowding agent polyethylene glycol showed dramatic changes in the quadruplex structure in K+ solutions, but not in Na+ solutions, suggesting that the crystal environment may have selected for a particular conformational form. Molecular dynamics simulations were performed to yield model structures for the K+ quadruplex form that are consistent with our biophysical results and with previously reported chemical modification studies. These models suggest that the biologically relevant structure of the human telomere quadruplex in K+ solution is not the one determined in the published crystalline state.},
}
@article {pmid16105549,
year = {2005},
author = {Michailidis, G and Saretzki, G and Hall, J},
title = {Endogenous and ectopic expression of telomere regulating genes in chicken embryonic fibroblasts.},
journal = {Biochemical and biophysical research communications},
volume = {335},
number = {1},
pages = {240-246},
doi = {10.1016/j.bbrc.2005.07.058},
pmid = {16105549},
issn = {0006-291X},
mesh = {Animals ; Avian Proteins ; Cells, Cultured ; Chick Embryo ; Chickens/*genetics ; DNA-Binding Proteins/genetics ; Fibroblasts/*metabolism ; *Gene Expression ; Rad51 Recombinase ; Rad52 DNA Repair and Recombination Protein ; Telomerase/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/genetics ; Telomeric Repeat Binding Protein 2/genetics ; },
abstract = {In this study, we compared the endogenous expression of genes encoding telomere regulating proteins in cultured chicken embryonic fibroblasts (CEFs) and 10-day-old chicken embryos. CEFs maintained in vitro senesced and senescence was accompanied by reduced telomere length, telomerase activity, and expression of the chicken (c) TRF1 gene. There was no change in TRF2 gene expression although the major TRF2 transcript identified in 10-day-old chicken embryos encoded a truncated TRF2 protein (TRF2'), containing an N-terminal dimerisation domain but lacking a myb-related DNA binding domain and nuclear localisation signal. Senescence of the CEFs in vitro was associated with the loss of the TRF2' transcript, indicative of a novel function for the encoded protein. Senescence was also coupled with decreased expression of RAD51, but increased RAD52 expression. These data support that RAD51 independent recombination mechanisms do not function in vitro to maintain chicken telomeres. To attempt to rescue the CEFs from replicative senescence, we stably transfected passage 3 CEFs with the human telomerase reverse transcriptase (hTERT) catalytic subunit. While hTERT expression was detected in the stable transfectants neither telomerase activity nor the stabilisation of telomere length was observed, and the transfectant cells senesced at the same passage number as the untransfected cells. These data indicate that the human TERT is incompatible with the avian telomere maintenance apparatus and suggest the functioning of a species specific telomere system in the avian.},
}
@article {pmid16104591,
year = {2005},
author = {Takahira, M},
title = {[Biological significance of DNA quadruplex and its unfolding by protein in replication, recombination and telomere elongation].},
journal = {Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme},
volume = {50},
number = {10 Suppl},
pages = {1241-1246},
pmid = {16104591},
issn = {0039-9450},
mesh = {Animals ; DNA/chemistry/*genetics/*metabolism ; DNA Replication/genetics ; Heterogeneous Nuclear Ribonucleoprotein A1 ; Heterogeneous-Nuclear Ribonucleoprotein D/*physiology ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/*physiology ; Humans ; Molecular Chaperones/physiology ; Nucleic Acid Conformation ; Protein Binding ; Recombination, Genetic/*genetics ; Telomere/*genetics/*metabolism ; Trinucleotide Repeats/genetics ; },
}
@article {pmid16101148,
year = {2005},
author = {Pillich, RT and Scarsella, G and Galati, G and Izzo, L and Iacoangeli, A and Castelli, M and Risuleo, G},
title = {The diimide drug PIPER has a cytotoxic dose-dependent effect in vitro and inhibits telomere elongation in HELA cells.},
journal = {Anticancer research},
volume = {25},
number = {5},
pages = {3341-3346},
pmid = {16101148},
issn = {0250-7005},
mesh = {Dose-Response Relationship, Drug ; HeLa Cells ; Humans ; Perylene/*analogs &amp; derivatives/pharmacology ; Piperidines/*pharmacology ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects/metabolism ; },
abstract = {It is known that, in vitro, PIPER (N,N'-bis [2-(1-piperidino)ethyl]-3,4,9,10-tetracarboxylic diimide) induces the formation of the Hoogsteen quadruplex structure in telomere DNA, thus inhibiting the polymerisation of telomeric repeats. Since the action of PIPER in vivo has been scarcely investigated, this study was addressed to gain some insight into the effects of this drug on cultured HeLa cells. Vital staining with erythrosine, performed on cells exposed to different PIPER concentrations (from 1 to 50 microM), showed that the drug exerts a dose-dependent cytotoxic effect, clearly evident after a short-term (24 h) treatment. This early cytotoxic effect of PIPER on cultured HeLa cells was confirmed by a spectrophotometric/colorimetric method employing methylthiazoletetrazolium (Mossmann assay). Hematoxylin/eosin staining of cells treated with PIPER for 24 h showed a nuclear condensation and a cytoplasmic vacuolisation, very pronounced at higher drug concentrations. These pictures suggest that PIPER-induced cell death might be of the apoptotic type. Finally, the anti-telomerase activity of PIPER was monitored by TRAP assay, performed on HeLa cell nuclear extracts treated with increasing drug concentrations. It was found that some inhibition of telomerase is apparent even at low concentrations, while at the highest concentration the enzyme is completely inhibited. These results indicate that the cytotoxic power of PIPER is possibly related to its antitelomeric effect.},
}
@article {pmid16101139,
year = {2005},
author = {Chau, NP and Deschatrette, J and Wolfrom, C},
title = {Reversal of hepatoma cells resistance to anticancer drugs is correlated to cell proliferation kinetics, telomere length and telomerase activity.},
journal = {Anticancer research},
volume = {25},
number = {5},
pages = {3279-3285},
pmid = {16101139},
issn = {0250-7005},
mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Cell Growth Processes/physiology ; Cisplatin/*pharmacology ; Drug Resistance, Neoplasm ; Liver Neoplasms, Experimental/*drug therapy/enzymology/genetics/pathology ; Logistic Models ; Methotrexate/*pharmacology ; Predictive Value of Tests ; Rats ; Telomerase/*metabolism ; Telomere/*physiology ; },
abstract = {BACKGROUND: Clinical and experimental observations indicate that resistance to anticancer drugs may be spontaneously reversible over time.<br><br>MATERIALS AND METHODS: This work is a mathematical and statistical analysis of the relationship, during a 9-month experiment, between the resistance of repeatedly re-seeded hepatoma cells to methotrexate (MTX) or to cisplatin (cisP) and untreated cell proliferation, telomere length and telomerase activity.<br><br>RESULTS: All variables showed complex oscillations, as previously published. In this work, cell proliferation was modelized by the logistic model, and the proliferation rates (a-values) together with their variations (va-values) were calculated.<br><br>CONCLUSION: Significant correlations were discovered between cell resistance to treatments and a-values, va-values, telomere length and telomerase activities. These results open new insights into the handling of chemotherapy in the treatment of cancers.},
}
@article {pmid16097085,
year = {2005},
author = {Hartmann, N and Scherthan, H},
title = {Assignment of the telomere-repeat binding factor genes TERF1 and TERF2 to Chinese muntjac (2n = 46) chromosome bands 12q3 and 2q33 by in situ hybridization.},
journal = {Cytogenetic and genome research},
volume = {111},
number = {1},
pages = {96},
doi = {10.1159/000085680},
pmid = {16097085},
issn = {1424-859X},
mesh = {Animals ; Chromosome Mapping ; Chromosomes, Mammalian ; In Situ Hybridization ; Molecular Sequence Data ; Muntjacs/*genetics ; Telomeric Repeat Binding Protein 1/*genetics ; Telomeric Repeat Binding Protein 2/*genetics ; },
}
@article {pmid16097000,
year = {2005},
author = {Robinson, WP and Peñaherrera, MS and Gair, J and Hatakeyama, C and Ma, S},
title = {X-chromosome inactivation and telomere size in newborns resulting from intracytoplasmic sperm injection.},
journal = {American journal of medical genetics. Part A},
volume = {137A},
number = {3},
pages = {343-345},
doi = {10.1002/ajmg.a.30886},
pmid = {16097000},
issn = {1552-4825},
mesh = {Adolescent ; Adult ; Analysis of Variance ; Animals ; Base Sequence ; Cattle ; Child ; Child, Preschool ; Chromosomes, Human, X/*genetics ; DNA/genetics/metabolism ; Deoxyribonucleases, Type II Site-Specific/metabolism ; *Dosage Compensation, Genetic ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Sex Chromosome Aberrations/embryology/statistics &amp; numerical data ; Sex Chromosome Disorders/etiology/genetics ; Sperm Injections, Intracytoplasmic/adverse effects/*methods ; Telomere/*genetics ; },
}
@article {pmid16096640,
year = {2005},
author = {Pardo, B and Marcand, S},
title = {Rap1 prevents telomere fusions by nonhomologous end joining.},
journal = {The EMBO journal},
volume = {24},
number = {17},
pages = {3117-3127},
pmid = {16096640},
issn = {0261-4189},
mesh = {Cell Survival/physiology ; Chromosomes, Fungal/genetics ; DNA Ligase ATP ; DNA Ligases/metabolism ; DNA Repair ; DNA Restriction Enzymes/chemistry ; Endodeoxyribonucleases/metabolism ; Endonucleases ; Exodeoxyribonucleases/metabolism ; Fungal Proteins/metabolism ; Intracellular Signaling Peptides and Proteins ; Protein Serine-Threonine Kinases ; Recombination, Genetic ; Saccharomyces cerevisiae/genetics/*physiology ; Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism/*physiology ; Shelterin Complex ; Telomere/genetics/*physiology ; Telomere-Binding Proteins/chemistry/genetics/*physiology ; Transcription Factors/chemistry/genetics/*physiology ; },
abstract = {Telomeres protect chromosomes from end-to-end fusions. In yeast Saccharomyces cerevisiae, the protein Rap1 directly binds telomeric DNA. Here, we use a new conditional allele of RAP1 and show that Rap1 loss results in frequent fusions between telomeres. Analysis of the fusion point with restriction enzymes indicates that fusions occur between telomeres of near wild-type length. Telomere fusions are not observed in cells lacking factors required for nonhomologous end joining (NHEJ), including Lig4 (ligase IV), KU and the Mre11 complex. SAE2 and TEL1 do not affect the frequency of fusions. Together, these results show that Rap1 is essential to block NHEJ between telomeres. Since the presence of Rap1 at telomeres has been conserved through evolution, the establishment of NHEJ suppression by Rap1 could be universal.},
}
@article {pmid16096639,
year = {2005},
author = {Miller, KM and Ferreira, MG and Cooper, JP},
title = {Taz1, Rap1 and Rif1 act both interdependently and independently to maintain telomeres.},
journal = {The EMBO journal},
volume = {24},
number = {17},
pages = {3128-3135},
pmid = {16096639},
issn = {0261-4189},
mesh = {Cell Survival ; Chromosomes, Fungal/genetics ; Mutation ; Protein Binding ; Schizosaccharomyces/genetics/*physiology ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Telomere/genetics/*physiology ; Telomere-Binding Proteins/genetics/*metabolism ; Transcription Factors/genetics/*metabolism ; },
abstract = {Telomere protection and maintenance are accomplished through the coordinated actions of telomere-specific DNA binding proteins and their interacting partners. The fission yeast ortholog of human TRF1/2, Taz1, binds telomeric DNA and regulates numerous aspects of telomere function. Here, we ask which aspects of Taz1 function are mediated through its interacting proteins, Rap1 and Rif1. We demonstrate that rap1+ deletion phenocopies some, but not all, aspects of taz1Delta telomere dysfunction, while Rif1 exhibits a very different functional spectrum. Rap1 acts in a Taz1-dependent pathway to prevent chromosome end fusions and regulate telomeric 3' overhang formation, while Rif1 is dispensable for these functions. Telomerase inhibition by Taz1 is mediated by two separate pathways, one involving Rap1 and the other involving Rif1. In contrast, Taz1 is uniquely required to prevent chromosomal entanglements and missegregation at cold temperatures. Strikingly, while rap1+ deletion exacerbates the cold sensitivity of taz1Delta cells, rif1+ deletion restores full viability. Thus, Rap1 and Rif1 are each required for a subset of the functions of Taz1, but each acquires Taz1-independent functions in its absence. Furthermore, Taz1 can function independently of its known binding partners.},
}
@article {pmid16094451,
year = {2005},
author = {Biessmann, H and Prasad, S and Walter, MF and Mason, JM},
title = {Euchromatic and heterochromatic domains at Drosophila telomeres.},
journal = {Biochemistry and cell biology = Biochimie et biologie cellulaire},
volume = {83},
number = {4},
pages = {477-485},
doi = {10.1139/o05-053},
pmid = {16094451},
issn = {0829-8211},
support = {GM-56729/GM/NIGMS NIH HHS/United States ; TW-05653/TW/FIC NIH HHS/United States ; },
mesh = {Animals ; *DNA Transposable Elements ; Drosophila/*genetics ; Euchromatin/*genetics ; Heterochromatin/*genetics ; *Telomere ; },
abstract = {Noncoding repetitive sequences make up a large portion of eukaryotic genomes, but their function is not well understood. Large blocks of repetitive DNA-forming heterochromatin around the centromeres are required for this region to function properly, but are difficult to analyze. The smaller regions of heterochromatin at the telomeres provide an opportunity to study their DNA and protein composition. Drosophila telomere length is maintained through the targeted transposition of specific non-long terminal repeat retrotransposons to chromosome ends, where they form long tandem arrays. A subterminal telomere-associated sequence (TAS) lies immediately proximal to the terminal-retrotransposon array. Here, we review the experimental support for the heterochromatic features of Drosophila telomeres, and provide evidence that telomeric regions contain 2 distinct chromatin subdomains: TAS, which exhibits features that resemble beta heterochromatin; and the terminal array of retrotransposons, which appears euchromatic. This organization is significantly different from the telomeric organization of other eukaryotes, where the terminal telomerase-generated repeats are often folded in a t-loop structure and become part of the heterochromatin protein complex.},
}
@article {pmid16091631,
year = {2005},
author = {Dreesen, O and Li, B and Cross, GA},
title = {Telomere structure and shortening in telomerase-deficient Trypanosoma brucei.},
journal = {Nucleic acids research},
volume = {33},
number = {14},
pages = {4536-4543},
pmid = {16091631},
issn = {1362-4962},
mesh = {Amino Acid Sequence ; Animals ; Cell Line ; DNA, Protozoan/chemistry ; DNA-Binding Proteins ; Gene Deletion ; Gene Silencing ; Guanine/analysis ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Sequence Alignment ; Telomerase/chemistry/*genetics ; Telomere/*chemistry ; Trypanosoma brucei brucei/enzymology/*genetics ; },
abstract = {Telomerase consists of a reverse transcriptase (TERT) and an RNA that contains a template for telomere-repeat extension. Telomerase is required to prevent telomere erosion and its activity or lack thereof is important for tumorigenesis and ageing. Telomerase has been identified in numerous organisms but it has not been studied in kinetoplastid protozoa. Trypanosoma brucei, the causative agent of African sleeping sickness, evades the host immune response by frequently changing its variant surface glycoprotein (VSG). The single expressed VSG is transcribed from one of approximately 20 subtelomeric 'Expression Sites', but the role telomeres might play in regulating VSG transcription and switching is unknown. We identified and sequenced the T.brucei TERT gene. Deleting TERT resulted in progressive telomere shortening of 3-6 bp per generation. In other organisms, the rate of telomere shortening is proportional to the length of the terminal 3' single-strand overhang. In T.brucei, G-overhangs were undetectable (<30 nt) by in-gel hybridization. The rate of telomere shortening therefore, agrees with the predicted shortening due to the end replication problem, and is consistent with our observation that G-overhangs are short. Trypanosomes whose telomere length can be manipulated provide a new tool to investigate the role of telomeres in antigenic variation.},
}
@article {pmid16085552,
year = {2005},
author = {Ram, R and Uziel, O and Lahav, M},
title = {The importance of the telomere and telomerase system in hematological malignancies.},
journal = {Leukemia &amp; lymphoma},
volume = {46},
number = {8},
pages = {1121-1135},
doi = {10.1080/10428190500125853},
pmid = {16085552},
issn = {1042-8194},
mesh = {Antineoplastic Agents/pharmacology/therapeutic use ; Cell Division/physiology ; Chromosomes/metabolism ; DNA/metabolism ; Hematologic Neoplasms/drug therapy/genetics/*metabolism ; Humans ; Telomerase/drug effects/*metabolism ; Telomere/genetics/*physiology ; },
abstract = {Telomeres are specialized chromosomal end structures composed of repeat TTAGGG sequences in humans. They shorten with each cell division and thus serve as the "mitotic clock" of the cell. One of their main functions is the maintenance of chromosomal integrity and their excessive shortening is associated with DNA instability. Telomerase, a unique reverse transcriptase, is inactive in most somatic human cells and is up-regulated in most cancer cells. Recently, the biology of the telomere/telomerase system has attracted much attention because of its possible role in carcinogenesis and aging. In this article we review the biology of this system and its relevance to normal and malignant hematopoietic cells. The biological, diagnostic and prognostic value of telomere/telomerase biology is discussed, as well as its potential future applications in cancer therapeutics.},
}
@article {pmid16080560,
year = {2005},
author = {Bekaert, S and De Meyer, T and Van Oostveldt, P},
title = {Telomere attrition as ageing biomarker.},
journal = {Anticancer research},
volume = {25},
number = {4},
pages = {3011-3021},
pmid = {16080560},
issn = {0250-7005},
mesh = {Aging/genetics/metabolism/*physiology ; Animals ; Biomarkers/metabolism ; Cellular Senescence/genetics/physiology ; Humans ; Telomere/genetics/metabolism/*physiology ; },
abstract = {Telomeres, the tandem-repeated hexamers at the termini of mammalian chromosomes, form protective complexes in association with specific proteins that together with telomerase, a specialised telomere-synthesizing enzyme, regulate telomere length. Telomere shortening is associated with cellular senescence and is implicated in tumorigenesis and cancer. Hence, mean telomere length has emerged as a replicative clock within each population of cells and the tissues and organs they build up in vitro and, consequently, as a biomarker for biological ageing in vivo. Chronological ageing per se does not parallel biological ageing, yet accurate and reliable biomarkers are lacking to distinguish between them. The question remains as to whether telomere dynamics is a determinant or merely a predictor of human biological age over and above chronological ageing. Although several reports have suggested a link between telomere attrition and ageing phenotypes and disorders, both reference values and a complete set of determinants are missing. Within this review, current evidence and knowledge on telomere length and telomere erosion rates reported, are summarised.},
}
@article {pmid16079203,
year = {2005},
author = {Ferenac, M and Polancec, D and Huzak, M and Pereira-Smith, OM and Rubelj, I},
title = {Early-senescing human skin fibroblasts do not demonstrate accelerated telomere shortening.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {60},
number = {7},
pages = {820-829},
doi = {10.1093/gerona/60.7.820},
pmid = {16079203},
issn = {1079-5006},
mesh = {Antimetabolites/pharmacology ; Blotting, Southern ; Bromodeoxyuridine/pharmacology ; Cell Division/drug effects ; Cell Line ; Cell Separation ; Cells, Cultured ; Cellular Senescence/*physiology ; Child ; DNA/analysis ; Densitometry ; Female ; Fibroblasts/drug effects/*metabolism/ultrastructure ; Humans ; In Vitro Techniques ; Skin/*cytology ; Telomere/drug effects/genetics/*metabolism/ultrastructure ; },
abstract = {Most normal mammalian cell lines demonstrate limited growth capacity due to the gradual accumulation of senescent cells in the culture. Senescent cells appear initially at a low incidence, but with increasing frequency as the culture accumulates more divisions. Because it has been suggested that senescence is regulated by telomere shortening in human cells, we compared the telomere lengths of the subpopulation of senescent cells, present in presenescent cultures, with those of young cells. Senescent cells were separated from young cycling cells by either bromodeoxyuridine (BrdU) incorporation followed by Hoechst dye and light treatment or DiI staining followed by separation on a high-speed cell sorter. Our results demonstrate that telomeres of early-senescing cells are the same length, and must shorten at the same rate, as cycling sister cells in the culture. Therefore, senescent cells in young mass cultures occur as a result of a stochastic, nontelomere-dependent process that we have described: sudden senescence syndrome.},
}
@article {pmid16077956,
year = {2005},
author = {Wick, U and Gebhart, E},
title = {Studies on the action of mitomycin C and bleomycin on telomere lengths of human lymphocyte chromosomes.},
journal = {International journal of molecular medicine},
volume = {16},
number = {3},
pages = {463-469},
doi = {10.3892/ijmm.16.3.463},
pmid = {16077956},
issn = {1107-3756},
mesh = {Adult ; Antibiotics, Antineoplastic/pharmacology ; Bleomycin/*pharmacology ; Chromosome Aberrations/drug effects ; Dose-Response Relationship, Drug ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Lymphocytes/*drug effects/metabolism ; Male ; Mitomycin/*pharmacology ; Telomere/*genetics ; },
abstract = {In order to address the problem of the action of cytostatics on chromosome ends, telomere length was measured in human lymphocyte cultures exposed to mitomycin C (MMC) and bleomycin (BLM). Telomere-specific PNA probes were used for the quantitative estimation of the relative telomere length of each individual chromosome by fluorescence in situ hybridization. A high inter-cellular and inter-individual variability of relative telomere lengths was found throughout all experiments. Different responses could be observed with respect to the action of the examined mutagens: The total average fluorescence intensity of labeled telomere repeats was decreased under the action of MMC in two of the experiments, while two revealed no significant alteration. BLM caused no significant change of total average telomeric signal intensity in four, a clear decrease in one of the six experiments, and an increase in another. Although all chromosome ends contributed to the observed trends, single telomeres were affected in a very distinct way. The highest concentration of MMC (1 microg/ml) induced significant shortening of telomeres of the chromosome arms; 2q, 3p, 5q, 7p, 10q, 11p, 13q, 17p, 18p&amp;q, and 21q in two independent experiments. In one BLM experiment with 8 microg/ml, the most distinct decrease (p< or =0.005) of telomeric fluorescence was found at the ends of chromosome arms; 1q, 6p, 17p, 20p&amp;q, and 22q. The increase of telomeric signal intensity affected the telomeres of some individual chromosome arms more than others, e.g. 4q, 6p, 7p, 8p, 13p, and 18q. Although the telomere length of the individual chromosome arms varied widely, clear trends could be observed with respect to the rank which was occupied by telomeric length of the various chromosome arms. The telomeres of the 1p, 3p, 4q, 5p, 12q, and 13q chromosome arms throughout all experiments were among the longest; and those of 13p, 15p, 21p, and 22p were among the shortest telomeres of the karyotype. From these data, it can be concluded that MMC affects the telomeric repeat area of chromosomes more than BLM, which mostly had no significant effect on telomere length in the performed experiments.},
}
@article {pmid16075809,
year = {2005},
author = {Cottliar, AS and Noriega, MF and Narbaitz, M and Slavutsky, IR},
title = {[Molecular analysis of telomere length in follicular lymphomas. Its participation in tumor progression].},
journal = {Medicina},
volume = {65},
number = {2},
pages = {143-146},
pmid = {16075809},
issn = {0025-7680},
mesh = {Adult ; Aged ; Bone Marrow/pathology ; Female ; Ganglia/pathology ; Genes, bcl-2/genetics ; Humans ; Lymphoma, B-Cell/*genetics ; Lymphoma, Follicular/*genetics ; Lymphoma, Large B-Cell, Diffuse/*genetics ; Male ; Middle Aged ; Telomere/genetics/*physiology ; },
abstract = {Telomeres are essential for maintaining chromosomal integrity and stability. We studied here telomere length (TL) in bone marrow and/or lymph node from 36 patients: 29 with follicular lymphoma (FL) at diagnosis and 7 with diffuse large B cell lymphoma secondary to FL (S-DLBCL). TL was evaluated using terminal restriction fragments (TRF) assay. BCL-2 gene rearrangement was analyzed by nested and long distance PCR. Mean TRF values showed significant telomere shortening in FL (4.18 +/- 0.18 Kb) and S-DLBCL (3.31 +/- 0.25 Kb) respect to controls (8.50 +/- 0.50 Kb) (p<0.001). Differences between both histological subtypes (p=0.036) were also detected. Moreover, the samples positive for BCL-2 rearrangements showed longer TL (4.25 +/- 0.19 Kb) than the negative ones (3.39 +/- 0.30 Kb) (p=0.023). A trend to telomere shortening was observed when Major Breakpoint Region (MBR-JH), minor cluster region (mcr-JH) and BCL-2 negative patients were compared (4.35 +/- 0.21 Kb; 3.84 +/- 0.45 Kb and 3.39 +/- 0.30 Kb, respectively). Our results show a TL reduction in FL and S-DLBCL, with significant short TRFs in the last group, suggesting the participation of telomere shortening in tumor progression. Furthermore, the differences detected between BCL-2 positive and negative FL support the involvement of diverse pathogenic mechanisms.},
}
@article {pmid16061847,
year = {2005},
author = {Johnson, JE and Varkonyi, RJ and Schwalm, J and Cragle, R and Klein-Szanto, A and Patchefsky, A and Cukierman, E and von Mehren, M and Broccoli, D},
title = {Multiple mechanisms of telomere maintenance exist in liposarcomas.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {11},
number = {15},
pages = {5347-5355},
doi = {10.1158/1078-0432.CCR-05-0684},
pmid = {16061847},
issn = {1078-0432},
support = {CA006927/CA/NCI NIH HHS/United States ; CA098087-03/CA/NCI NIH HHS/United States ; CA109442-01/CA/NCI NIH HHS/United States ; T32 CA09035-29/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Blotting, Southern ; Cell Proliferation ; Female ; Fluorescent Antibody Technique, Indirect ; Genome ; Humans ; Image Processing, Computer-Assisted ; Liposarcoma/metabolism/*ultrastructure ; Male ; Middle Aged ; Mutation ; Nucleoproteins/metabolism ; Peritoneal Neoplasms/metabolism/ultrastructure ; RNA, Messenger/metabolism ; Recurrence ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/metabolism ; Telomere/*ultrastructure ; },
abstract = {PURPOSE: Telomeres are specialized nucleoprotein complexes that protect and confer stability upon chromosome ends. Loss of telomere function as a consequence of proliferation-associated sequence attrition results in genome instability, which may facilitate carcinogenesis by generating growth-promoting mutations. However, unlimited cellular proliferation requires the maintenance of telomeric DNA; thus, the majority of tumor cells maintain their telomeres either through the activity of telomerase or via a mechanism known as alternative lengthening of telomeres (ALT). Recent data suggest that constitutive telomere maintenance may not be required in all tumor types. Here we assess the role and requirement of telomere maintenance in liposarcoma.<br><br>EXPERIMENTAL DESIGN: Tumor samples were analyzed with respect to telomerase activity, telomere length, and the presence of ALT-specific subcellular structures, ALT-associated promyelocytic leukemia nuclear bodies. This multi-assay assessment improved the accuracy of categorization.<br><br>RESULTS: Our data reveal a significant incidence (24%) of ALT-positive liposarcomas, whereas telomerase is used at a similar frequency (27%). A large number of tumors (49%) do not show characteristics of telomerase or ALT. In addition, telomere length was always shorter in recurrent disease, regardless of the telomere maintenance mechanism.<br><br>CONCLUSIONS: These results suggest that approximately one half of liposarcomas either employ a novel constitutively active telomere maintenance mechanism or lack such a mechanism. Analysis of recurrent tumors suggests that liposarcomas can develop despite limiting or undetectable activity of a constitutively active telomere maintenance mechanism.},
}
@article {pmid16061476,
year = {2005},
author = {Drosopoulos, WC and Direnzo, R and Prasad, VR},
title = {Human telomerase RNA template sequence is a determinant of telomere repeat extension rate.},
journal = {The Journal of biological chemistry},
volume = {280},
number = {38},
pages = {32801-32810},
doi = {10.1074/jbc.M506319200},
pmid = {16061476},
issn = {0021-9258},
support = {K01-CACA87542/CA/NCI NIH HHS/United States ; R01-AI30861/AI/NIAID NIH HHS/United States ; },
mesh = {Base Sequence ; Binding, Competitive ; Cloning, Molecular ; DNA Primers/chemistry ; DNA, Complementary/metabolism ; Gene Library ; Humans ; Kinetics ; Molecular Sequence Data ; Mutagenesis ; Mutagenesis, Site-Directed ; Mutation ; Oligonucleotides/chemistry ; RNA/*chemistry ; Sequence Homology, Nucleic Acid ; Telomerase/*chemistry ; Telomere/*ultrastructure ; Transcription, Genetic ; },
abstract = {Human telomerase is a specialized reverse transcriptase that utilizes an integral RNA subunit to template the synthesis of telomeres. In the present study, we demonstrate that the human telomerase template sequence not only determines the composition, but also the rate of synthesis, of telomere repeats. Mutagenesis of the template sequence identified variants that reconstitute enzymes with repeat extension rates that were either faster or slower than wild type template. Changes in extension rate could not be attributed solely to altered heteroduplex melting, strongly suggesting that specific interactions between telomerase template, protein, and products contribute significantly in determining repeat extension rate. Furthermore, some substitutions that had no effect on extension rate led to striking increases in repeat processivity, indicating that processivity and extension rates can be regulated independently of each other. Our results suggest that telomerase RNA template sequence is a key determinant of the contribution of telomerase to telomere length regulation.},
}
@article {pmid16052508,
year = {2005},
author = {Soler, D and Genescà, A and Arnedo, G and Egozcue, J and Tusell, L},
title = {Telomere dysfunction drives chromosomal instability in human mammary epithelial cells.},
journal = {Genes, chromosomes &amp; cancer},
volume = {44},
number = {4},
pages = {339-350},
doi = {10.1002/gcc.20244},
pmid = {16052508},
issn = {1045-2257},
mesh = {Blotting, Western ; Cell Culture Techniques ; Cell Line ; *Chromosomal Instability ; Chromosome Painting ; Chromosomes, Human, Pair 1 ; DNA/genetics ; Epithelial Cells/*cytology ; Female ; Fluorescent Antibody Technique, Direct ; Fluorescent Dyes ; Humans ; In Situ Hybridization, Fluorescence ; Indoles ; Karyotyping ; Mammary Glands, Human/*cytology ; Metaphase ; Nucleic Acid Hybridization ; Telomerase/analysis ; Telomere/*metabolism ; },
abstract = {The development of genomic instability is an important step toward generating the multiple genetic changes required for cancer. Telomere dysfunction is one of the factors that contribute to tumorigenesis. Telomeres shorten with each cell division in the absence of telomerase. Human mammary epithelial cells (HMECs) obtained from normal human tissue demonstrate two growth phases. After an initial phase of active growth, HMECs exhibit a growth plateau termed selection. However, some cells can emerge from this growth plateau by spontaneously losing expression of the p16(INK4a) protein. These post-selection HMECs are capable of undergoing an additional 20-50 population doublings in culture. Continued proliferation of these post-selection HMECs leads to further telomere erosion, loss of the capping function, and the appearance of end-to-end chromosome fusions that can enter bridge-fusion-breakage (BFB) cycles, generating massive chromosomal instability before terminating in a population growth plateau termed agonescence. We have found that the chromosome arms carrying the shortest telomeres are those involved in telomere-telomere type rearrangements. In addition, we found that the risk of a particular chromosome being unstable differs between individuals. Most importantly, we identified sister chromatid fusion as a first event in generating genomic instability in HMECs. During post-selection HMEC growth, double strand breaks are generated by both fused chromosomes as well as individual chromosomes with fused chromatids entering BFB cycles. These broken chromosome extremities are able to join other broken ends or eroded telomeres, producing massive chromosomal instability at the later passages of the cell culture. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.},
}
@article {pmid16046031,
year = {2006},
author = {Jenkins, EC and Velinov, MT and Ye, L and Gu, H and Li, S and Jenkins, EC and Brooks, SS and Pang, D and Devenny, DA and Zigman, WB and Schupf, N and Silverman, WP},
title = {Telomere shortening in T lymphocytes of older individuals with Down syndrome and dementia.},
journal = {Neurobiology of aging},
volume = {27},
number = {7},
pages = {941-945},
doi = {10.1016/j.neurobiolaging.2005.05.021},
pmid = {16046031},
issn = {0197-4580},
support = {P01 HD35897/HD/NICHD NIH HHS/United States ; R01 AG 14673/AG/NIA NIH HHS/United States ; R01 HD37425/HD/NICHD NIH HHS/United States ; },
mesh = {*Chromosome Aberrations ; Dementia/*genetics ; Down Syndrome/*complications/*genetics ; Female ; Genetic Markers/genetics ; Genetic Predisposition to Disease/genetics ; Humans ; Interphase/genetics ; Metaphase/genetics ; Middle Aged ; Predictive Value of Tests ; Risk Factors ; T-Lymphocytes/pathology ; Telomere/*genetics/*pathology ; },
abstract = {Telomere shortening has been recently correlated with Alzheimer's disease status. Therefore, we hypothesized that a possible association might exist for adults with Down syndrome (DS). Using blind, quantitative telomere protein nucleic acid FISH analyses of metaphase and interphase preparations from 18 age-matched trisomy 21 female study participants with and without dementia, we have observed increased telomere shortening in adults with DS and dementia (p < .01). From this initial study, we conclude that telomere shortening is associated with dementia in this high-risk population and suggest that additional research may show that telomere shortening may be a biological marker of dementia status.},
}
@article {pmid16042688,
year = {2005},
author = {Ferraris, AM and Pujic, N and Mangerini, R and Rapezzi, D and Gallamini, A and Racchi, O and Casciaro, S and Gaetani, GF},
title = {Clonal granulocytes in polycythaemia vera and essential thrombocythaemia have shortened telomeres.},
journal = {British journal of haematology},
volume = {130},
number = {3},
pages = {391-393},
doi = {10.1111/j.1365-2141.2005.05618.x},
pmid = {16042688},
issn = {0007-1048},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Case-Control Studies ; Clone Cells ; Female ; Granulocytes/*ultrastructure ; Hematopoietic Stem Cells/ultrastructure ; Humans ; Image Processing, Computer-Assisted ; Leukocytes, Mononuclear/ultrastructure ; Middle Aged ; Polycythemia Vera/complications/*immunology ; Telomere/*ultrastructure ; Thrombocythemia, Essential/complications/*immunology ; },
abstract = {Summary The purpose of this study was to evaluate telomere length in peripheral blood granulocytes and mononuclear cells collected from 22 women with polycythaemia vera (PV) and essential thrombocythaemia (ET). PV and ET are chronic myeloproliferative diseases whose heterogeneity of stem cell origin and clonal development has been established through analysis of X-chromosome inactivation patterns. The results from clonality assay and determination of telomere length show that only clonal granulocytes have shortened telomeres.},
}
@article {pmid16037417,
year = {2005},
author = {Flores, I and Cayuela, ML and Blasco, MA},
title = {Effects of telomerase and telomere length on epidermal stem cell behavior.},
journal = {Science (New York, N.Y.)},
volume = {309},
number = {5738},
pages = {1253-1256},
doi = {10.1126/science.1115025},
pmid = {16037417},
issn = {1095-9203},
mesh = {Animals ; Cell Count ; Cell Differentiation ; Cell Movement ; Cell Proliferation ; Clone Cells ; *Epidermal Cells ; Hair Follicle/cytology ; Keratinocytes/*cytology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Multipotent Stem Cells/cytology/*physiology ; Telomerase/genetics/*metabolism ; Telomere/*physiology/ultrastructure ; Tetradecanoylphorbol Acetate/pharmacology ; Up-Regulation ; },
abstract = {A key process in organ homeostasis is the mobilization of stem cells out of their niches. We show through analysis of mouse models that telomere length, as well as the catalytic component of telomerase, Tert, are critical determinants in the mobilization of epidermal stem cells. Telomere shortening inhibited mobilization of stem cells out of their niche, impaired hair growth, and resulted in suppression of stem cell proliferative capacity in vitro. In contrast, Tert overexpression in the absence of changes in telomere length promoted stem cell mobilization, hair growth, and stem cell proliferation in vitro. The effects of telomeres and telomerase on stem cell biology anticipate their role in cancer and aging.},
}
@article {pmid16036647,
year = {2005},
author = {Steinberg, JR},
title = {Response to Fritz Allhoff, "Telomeres and the ethics of human cloning" (AJOB 4:2).},
journal = {The American journal of bioethics : AJOB},
volume = {5},
number = {1},
pages = {W27-8},
doi = {10.1080/15265160590931250},
pmid = {16036647},
issn = {1536-0075},
mesh = {*Aging ; Cloning, Organism/adverse effects/*ethics ; Ethical Analysis ; *Ethical Theory ; Ethics, Research ; Genetic Engineering/ethics ; Humans ; *Telomere ; },
}
@article {pmid16034678,
year = {2005},
author = {Flanary, BE and Kletetschka, G},
title = {Analysis of telomere length and telomerase activity in tree species of various life-spans, and with age in the bristlecone pine Pinus longaeva.},
journal = {Biogerontology},
volume = {6},
number = {2},
pages = {101-111},
doi = {10.1007/s10522-005-3484-4},
pmid = {16034678},
issn = {1389-5729},
mesh = {Aging/*physiology ; Enzyme Activation ; Longevity/physiology ; Pinus/*classification/*physiology ; Species Specificity ; Telomerase/*physiology ; Telomere/*physiology/*ultrastructure ; },
abstract = {Normal somatic cells have a finite replicative capacity. With each cell division, telomeres (the physical ends of linear chromosomes) progressively shorten until they reach a critical length, at which point the cells enter replicative senescence. Some cells maintain telomere length by the action of the telomerase enzyme. The bristlecone pine, Pinus longaeva, is the oldest known living eukaryotic organism, with the oldest on record turning 4770 years old in 2005. To determine what changes occur, if any, in telomere length and telomerase activity with age, and what roles, if any, telomere length and telomerase activity may play in contributing to the increased life-span and longevity of P. longaeva with age, as well as in other tree species of various life-spans, we undertook a detailed investigation of telomere length and telomerase activity in such trees. The results from this study support the hypothesis that both increased telomere length and telomerase activity may directly/indirectly contribute to the increased life-span and longevity evident in long-lived pine trees (2000-5000 year life-spans) compared to medium-lived (400-500 year life-span) and short-lived (100-200 year life-span) pine trees, as well as in P. longaeva with age.},
}
@article {pmid16027219,
year = {2005},
author = {Trelles-Sticken, E and Adelfalk, C and Loidl, J and Scherthan, H},
title = {Meiotic telomere clustering requires actin for its formation and cohesin for its resolution.},
journal = {The Journal of cell biology},
volume = {170},
number = {2},
pages = {213-223},
pmid = {16027219},
issn = {0021-9525},
mesh = {Actins/*physiology ; Cell Cycle Proteins/metabolism/*physiology ; Cell Nucleus/genetics/physiology ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes, Fungal/physiology ; Fungal Proteins/*physiology ; Green Fluorescent Proteins/genetics ; *Meiosis ; Microtubules/physiology ; Mutation ; Nuclear Envelope/physiology ; Nuclear Proteins/*physiology ; Phosphorylation ; Protein Kinases/metabolism ; Protein Serine-Threonine Kinases ; Saccharomyces cerevisiae/genetics/*physiology/ultrastructure ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Shelterin Complex ; Spindle Apparatus ; Telomere/genetics/*physiology ; Telomere-Binding Proteins/genetics/metabolism ; Transcription Factors/genetics/metabolism ; Cohesins ; },
abstract = {In diploid organisms, meiosis reduces the chromosome number by half during the formation of haploid gametes. During meiotic prophase, telomeres transiently cluster at a limited sector of the nuclear envelope (bouquet stage) near the spindle pole body (SPB). Cohesin is a multisubunit complex that contributes to chromosome segregation in meiosis I and II divisions. In yeast meiosis, deficiency for Rec8 cohesin subunit induces telomere clustering to persist, whereas telomere cluster-SPB colocalization is defective. These defects are rescued by expressing the mitotic cohesin Scc1 in rec8delta meiosis, whereas bouquet-stage exit is independent of Cdc5 pololike kinase. An analysis of living Saccharomyces cerevisiae meiocytes revealed highly mobile telomeres from leptotene up to pachytene, with telomeres experiencing an actin- but not microtubule-dependent constraint of mobility during the bouquet stage. Our results suggest that cohesin is required for exit from actin polymerization-dependent telomere clustering and for linking the SPB to the telomere cluster in synaptic meiosis.},
}
@article {pmid16012858,
year = {2005},
author = {Cenci, G and Ciapponi, L and Gatti, M},
title = {The mechanism of telomere protection: a comparison between Drosophila and humans.},
journal = {Chromosoma},
volume = {114},
number = {3},
pages = {135-145},
pmid = {16012858},
issn = {0009-5915},
mesh = {Animals ; Chromosomal Proteins, Non-Histone/metabolism ; Drosophila/*genetics/physiology ; Drosophila Proteins/metabolism/physiology ; Humans ; Models, Biological ; Telomere/*genetics/physiology/ultrastructure ; },
abstract = {Drosophila telomeres are maintained by transposition of specialized retrotransposons rather than by telomerase activity, and their stability is independent of the sequence of DNA termini. Recent studies have identified several proteins that protect Drosophila telomeres from fusion events. These proteins include the telomere capping factors HP1/ORC-associated protein (HOAP) and heterochromatin protein 1 (HP1), the Rad50 and Mre11 DNA repair proteins that are required for HOAP and HP1 localization at telomeres, and the ATM kinase. Another telomere-protecting factor identified in Drosophila is UbcD1, a polypeptide highly homologous to class I ubiquitin-conjugating E2 enzymes. In addition, it has been shown that HP1 and both components of the Drosophila Ku70/80 heterodimer act as negative regulators of telomere length. Except for HOAP, all these proteins are conserved in humans and are associated with human telomeres. Collectively, these results indicate that Drosophila is an excellent model system for the analysis of the mechanisms of telomere maintenance. In past and current studies, 15 Drosophila genes have been identified that prevent telomeric fusion, and it has been estimated that the Drosophila genome contains at least 40 genes required for telomere protection. We believe that the molecular characterization of these genes will lead to identification of many novel human genes with roles in telomere maintenance.},
}
@article {pmid16000404,
year = {2005},
author = {Wang, Y and Erdmann, N and Giannone, RJ and Wu, J and Gomez, M and Liu, Y},
title = {An increase in telomere sister chromatid exchange in murine embryonic stem cells possessing critically shortened telomeres.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {102},
number = {29},
pages = {10256-10260},
pmid = {16000404},
issn = {0027-8424},
support = {AG16629-03/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; DNA-Binding Proteins/*deficiency ; Embryo, Mammalian/*cytology ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Mutant Strains ; Sister Chromatid Exchange/genetics/*physiology ; Spleen/cytology ; Stem Cells/*cytology ; Telomerase/*deficiency ; Telomere/genetics/*physiology ; },
abstract = {Telomerase deficiency leads to a progressive loss of telomeric DNA that eventually triggers cell apoptosis in human primary cells during prolonged growth in culture. Rare survivors can maintain telomere length through either activation of telomerase or recombination-based telomere lengthening, and thus proliferate indefinitely. We have explored the possibility that telomeres may be maintained through telomere sister chromatid exchange (T-SCE) in murine telomere reverse transcriptase-deficient (mTert-/-) splenocytes and ES cells. Because telomerase deficiency leads to gradual loss of telomeric DNA in mTert-/- splenocytes and ES cells and eventually to chromosomes with telomere signal-free ends (SFEs), we examined these cell types for evidence of sister chromatid exchange at telomeres, and observed an increase in T-SCEs only in a subset of mTert-/- splenocytes or ES cells that possessed multiple SFEs. Furthermore, T-SCEs were more often detected in ES cells than in splenocytes that harbored a similar frequency of SFEs. In mTert heterozygous (mTert+/-) ES cells or splenocytes, which are known to exhibit a decrease in average telomere length but no SFEs, no increase in T-SCE was observed. In addition to T-SCE, other genomic rearrangements (i.e., SCE) were also significantly increased in mTert-/- ES cells possessing critically short telomeres, but not in splenocytes. Our results suggest that animals and cell culture differ in their ability to carry out genomic rearrangements as a means of maintaining telomere integrity when telomeres become critically shortened.},
}
@article {pmid15996118,
year = {2005},
author = {Meerdo, LN and Reed, WA and White, KL},
title = {Telomere-to-centromere ratio of bovine clones, embryos, gametes, fetal cells, and adult cells.},
journal = {Cloning and stem cells},
volume = {7},
number = {1},
pages = {62-73},
doi = {10.1089/clo.2005.7.62},
pmid = {15996118},
issn = {1536-2302},
mesh = {Animals ; Cattle ; Cell Nucleus/metabolism ; Centrosome/*ultrastructure ; Cloning, Organism/*methods ; Cryopreservation ; DNA/chemistry ; Female ; Fertilization ; Fertilization in Vitro ; Fibroblasts/metabolism ; Oocytes/cytology/metabolism ; Ovary/metabolism ; Sheep ; Telomere/*ultrastructure ; Tissue Distribution ; },
abstract = {In 1997, Dolly, the first animal cloned from an adult cell, was born. It was announced in 1999 that Dolly might be aging faster than normal because her telomeres were shorter than age-matched control sheep. Telomeres, a repeated DNA sequence located at the ends of linear chromosomes, allow for base pair loss during DNA replication. Telomere shortening acts as a "mitotic clock," leading to replicative senescence. By using whole cell lysate and slot-blot analysis, we determined the telomere-to-centromere ratio (T/C) for bovine gametes, embryos, fetal tissues (brain, heart, lung, kidney, uterus, ovary, and skin), adult donor cells, and cloned embryos. Our data indicates a consistency in T/C among the various fetal tissues. The T/C of sperm is significantly lower than in oocytes. The T/C decreases from the oocyte to the 2-8-cell stage embryo, increases dramatically at the morula stage, and decreases at the blastocyst stage. Our data shows no significant difference in T/C between cloned embryos and in vitro fertilized (IVF) embryos, but there is a significant difference between cloned embryos and adult donor cells. In conclusion, the enucleated bovine oocyte has the ability to reestablish the telomere length of adult somatic cell donor nuclei.},
}
@article {pmid15994926,
year = {2005},
author = {Zhang, Y and Lim, CU and Williams, ES and Zhou, J and Zhang, Q and Fox, MH and Bailey, SM and Liber, HL},
title = {NBS1 knockdown by small interfering RNA increases ionizing radiation mutagenesis and telomere association in human cells.},
journal = {Cancer research},
volume = {65},
number = {13},
pages = {5544-5553},
doi = {10.1158/0008-5472.CAN-04-4368},
pmid = {15994926},
issn = {0008-5472},
support = {CA49696/CA/NCI NIH HHS/United States ; },
mesh = {Apoptosis/radiation effects ; B-Lymphocytes/physiology/radiation effects ; Cell Cycle Proteins/*antagonists &amp; inhibitors/genetics ; Cell Line ; Checkpoint Kinase 2 ; Down-Regulation ; Gamma Rays ; Histones/genetics/metabolism ; Humans ; Mutagenesis/*radiation effects ; Nuclear Proteins/*antagonists &amp; inhibitors/genetics ; Phosphorylation/radiation effects ; Protein Serine-Threonine Kinases/metabolism/radiation effects ; RNA, Small Interfering/*genetics ; Telomere/genetics/metabolism/*radiation effects ; Transfection ; Tumor Suppressor Protein p53/metabolism/radiation effects ; },
abstract = {Hypomorphic mutations which lead to decreased function of the NBS1 gene are responsible for Nijmegen breakage syndrome, a rare autosomal recessive hereditary disorder that imparts an increased predisposition to development of malignancy. The NBS1 protein is a component of the MRE11/RAD50/NBS1 complex that plays a critical role in cellular responses to DNA damage and the maintenance of chromosomal integrity. Using small interfering RNA transfection, we have knocked down NBS1 protein levels and analyzed relevant phenotypes in two closely related human lymphoblastoid cell lines with different p53 status, namely wild-type TK6 and mutated WTK1. Both TK6 and WTK1 cells showed an increased level of ionizing radiation-induced mutation at the TK and HPRT loci, impaired phosphorylation of H2AX (gamma-H2AX), and impaired activation of the cell cycle checkpoint regulating kinase, Chk2. In TK6 cells, ionizing radiation-induced accumulation of p53/p21 and apoptosis were reduced. There was a differential response to ionizing radiation-induced cell killing between TK6 and WTK1 cells after NBS1 knockdown; TK6 cells were more resistant to killing, whereas WTK1 cells were more sensitive. NBS1 deficiency also resulted in a significant increase in telomere association that was independent of radiation exposure and p53 status. Our results provide the first experimental evidence that NBS1 deficiency in human cells leads to hypermutability and telomere associations, phenotypes that may contribute to the cancer predisposition seen among patients with this disease.},
}
@article {pmid15994923,
year = {2005},
author = {Lillard-Wetherell, K and Combs, KA and Groden, J},
title = {BLM helicase complements disrupted type II telomere lengthening in telomerase-negative sgs1 yeast.},
journal = {Cancer research},
volume = {65},
number = {13},
pages = {5520-5522},
doi = {10.1158/0008-5472.CAN-05-0632},
pmid = {15994923},
issn = {0008-5472},
support = {P30-ES06096/ES/NIEHS NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases/genetics/metabolism/*physiology ; DNA Helicases/deficiency/genetics/metabolism/*physiology ; Mutagenesis, Site-Directed ; RecQ Helicases ; Saccharomyces cerevisiae/*enzymology/genetics/ultrastructure ; Saccharomyces cerevisiae Proteins/genetics/metabolism/*physiology ; Telomerase/*deficiency ; Telomere/genetics/metabolism/*physiology ; },
abstract = {Recombination-mediated pathways for telomere lengthening may be utilized in the absence of telomerase activity. The RecQ-like helicases, BLM and Sgs1, are implicated in recombination-mediated telomere lengthening in human cells and budding yeast, respectively. Here, we show that BLM expression rescues disrupted telomere lengthening in telomerase-negative sgs1 yeast. BLM helicase activity is required for this complementation, indicating BLM and Sgs1 resolve the same telomeric structures. These data support a conserved function for BLM and Sgs1 in recombination-mediated telomere lengthening.},
}
@article {pmid15992610,
year = {2005},
author = {Plunkett, FJ and Franzese, O and Belaramani, LL and Fletcher, JM and Gilmour, KC and Sharifi, R and Khan, N and Hislop, AD and Cara, A and Salmon, M and Gaspar, HB and Rustin, MH and Webster, D and Akbar, AN},
title = {The impact of telomere erosion on memory CD8+ T cells in patients with X-linked lymphoproliferative syndrome.},
journal = {Mechanisms of ageing and development},
volume = {126},
number = {8},
pages = {855-865},
doi = {10.1016/j.mad.2005.03.006},
pmid = {15992610},
issn = {0047-6374},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; CD8-Positive T-Lymphocytes/*cytology ; Cell Differentiation ; Cell Line ; Cell Proliferation ; DNA-Binding Proteins/chemistry ; Epitopes/chemistry ; Flow Cytometry ; Genetic Vectors ; Green Fluorescent Proteins/metabolism ; Humans ; Immunologic Memory ; Lentivirus/genetics ; Longevity ; Lymphoma, B-Cell/immunology ; Lymphoproliferative Disorders/*genetics ; Mutation ; Phenotype ; Retroviridae/genetics ; T-Lymphocytes/chemistry/cytology/metabolism ; Telomerase/chemistry ; Telomere/chemistry/*ultrastructure ; Time Factors ; },
abstract = {Patients with X-linked lymphoproliferative syndrome (XLP) experience excessive T cell proliferation after primary Epstein-Barr virus (EBV) infection, due to mutations in the signalling lymphocyte activation molecule (SLAM) associated protein (SAP) molecule. We examined the impact of dysfunctional proliferative control on the extent of CD8+ T cell differentiation in XLP patients who recovered from primary EBV infection. Although these young patients have normal numbers of lytic and latent EBV-epitope-specific CD8+ T cells, they were extremely differentiated as defined by loss of CCR7 and CD27, low telomerase activity and very short telomeres. This was not a direct effect arising from the loss of SAP, but was due to excessive T cell stimulation due to this defect. Thus, transduction of XLP CD8+ T cells with the catalytic component of telomerase (hTERT), but not SAP, prevented telomere loss and considerably extended proliferative lifespan in vitro. These results indicate that excessive proliferation in CD8+ T cells in XLP patients may lead to end-stage differentiation and loss of functional EBV-specific CD8+ T cells through replicative senescence. This may contribute to the defective immunity found in XLP patients who survive acute EBV infection who develop EBV-related B cell lymphomas before the fourth decade of life.},
}
@article {pmid15991892,
year = {1997},
author = {Sharma, S and Raymond, E and Soda, H and Von Hoff, DD},
title = {Telomerase and telomere inhibitors in preclinical development.},
journal = {Expert opinion on investigational drugs},
volume = {6},
number = {9},
pages = {1179-1185},
doi = {10.1517/13543784.6.9.1179},
pmid = {15991892},
issn = {1744-7658},
abstract = {Telomerase is an enzyme required by actively dividing cells to maintain the ends of chromosomes (telomeres). It is present in germline tissue, stem cells and cancer cells, but is repressed in somatic cells. Efforts are underway to exploit this selective expression of telomerase in cancer therapeutics. This review describes the status of telomerase research, which although at present predominantly preclinical, has the potential to enter clinical research.},
}
@article {pmid15990362,
year = {2005},
author = {Bekaert, S and Derradji, H and De Meyer, T and Michaux, A and Buset, J and Neefs, M and Mergeay, M and Jacquet, P and Van Oostveldt, P and Baatout, S},
title = {Telomere shortening is associated with malformation in p53-deficient mice after irradiation during specific stages of development.},
journal = {DNA repair},
volume = {4},
number = {9},
pages = {1028-1037},
doi = {10.1016/j.dnarep.2005.05.010},
pmid = {15990362},
issn = {1568-7864},
mesh = {*Abnormalities, Radiation-Induced ; Animals ; Chromosomal Instability/*radiation effects ; DNA Damage ; Embryonic Development/genetics/*radiation effects ; Female ; Genes, p53 ; Genotype ; Humans ; Male ; Mice ; Mice, Inbred C57BL/genetics ; Mice, Knockout ; Pregnancy ; Telomere/genetics/*radiation effects ; Telomere-Binding Proteins/metabolism ; Tumor Suppressor Protein p53/*deficiency/metabolism ; },
abstract = {The natural ends of linear chromosomes, the telomeres, recruit specific proteins in the formation of protective caps that preserve the integrity of the genome. Unprotected chromosomes induce DNA damage checkpoint cascades and ultimately lead to senescence both in mouse and man in a p53 dependent manner and initial telomere length setting therefore determines the proliferative capacity of each cell. Yet, only little information is available on telomere biology during embryonic development. We have previously shown that the p53 gene plays a crucial role in the development of malformations (exencephaly, gastroschisis, polydactyly, cleft palate and dwarfism) in control and irradiated mouse embryos. Here, we investigated telomere biology and the outcome of radiation exposure in wild type (p53+/+) and p53-mutant (p53+/-- and--/--) C57BL mouse foetuses irradiated at three different developmental stages. We show that telomeres are significantly shorter in malformed foetuses as compared to normal counterparts. In addition, our results indicate that the observed telomere attrition is primarily associated with p53-deficiency but is also modulated by irradiation, more specifically during the gastrulation and organogenesis stages. In conclusion, we formulate a hypothesis in which telomere shortening is linked to the absence of p53 in mouse foetuses and that when, in the presence of shorter telomeres, these foetuses are irradiated, the chance for the occurrence of developmental defects increases substantially.},
}
@article {pmid15989978,
year = {2005},
author = {Viscardi, V and Clerici, M and Cartagena-Lirola, H and Longhese, MP},
title = {Telomeres and DNA damage checkpoints.},
journal = {Biochimie},
volume = {87},
number = {7},
pages = {613-624},
doi = {10.1016/j.biochi.2004.10.022},
pmid = {15989978},
issn = {0300-9084},
support = {E.1247/TI_/Telethon/Italy ; },
mesh = {*DNA Damage ; DNA Repair ; DNA Replication ; Genomic Instability ; Humans ; Telomerase/*metabolism ; Telomere/*chemistry/metabolism ; },
abstract = {In all eukaryotic organisms, interruptions in duplex DNA molecules elicit a DNA damage response, which includes activation of DNA repair machineries and surveillance mechanisms, known as DNA damage checkpoints. Telomeres and double-strand breaks (DSBs) share the common feature of being physical ends of chromosomes. However, unlike DSBs, telomeres do not activate the DNA damage checkpoints and are usually protected from end-to-end fusions and other processing events that normally promote repair of DNA breaks. This indicates that they are shielded from being recognized and processed as DSBs. On the other hand, chromosome ends resemble damaged DNA, as several factors required for DNA repair and checkpoint networks play important roles in telomere length maintenance. Due to the critical role of both DNA damage checkpoints and telomere homeostasis in maintaining genetic stability and in counteracting cancer development, the knowledge of their interconnections is essential for our understanding of these key cellular controls.},
}
@article {pmid15986178,
year = {2005},
author = {Mochida, A and Gotoh, E and Senpuku, H and Harada, S and Kitamura, R and Takahashi, T and Yanagi, K},
title = {Telomere size and telomerase activity in Epstein-Barr virus (EBV)-positive and EBV-negative Burkitt's lymphoma cell lines.},
journal = {Archives of virology},
volume = {150},
number = {10},
pages = {2139-2150},
doi = {10.1007/s00705-005-0557-2},
pmid = {15986178},
issn = {0304-8608},
mesh = {Base Sequence ; Burkitt Lymphoma/enzymology/*genetics/*virology ; Cell Line, Tumor ; DNA, Neoplasm/genetics ; Herpesvirus 4, Human/genetics/*isolation &amp; purification/pathogenicity ; Humans ; In Situ Hybridization, Fluorescence ; Mutation ; Telomerase/genetics/*metabolism ; Telomere/enzymology/*genetics/ultrastructure ; },
abstract = {The telomere repeat lengths of BL cell lines were quantified by measuring terminal restriction fragment (TRF). Epstein-Barr virus (EBV)-positive Namalwa, Raji, and EB-3 cell lines have long telomeres, i.e. TRFs 10-19 kbp, whereas the Daudi cell line, producing a transformation-defective EBV mutant, has TRFs approximately 2.2 kbp. EBV-negative BJAB and DG75 cell lines have short TRFs 3.9-5.4 kbp, shorter than the approximately 12 kbp TRFs in PBLs. Telomerase activities of these BL cell lines are similar. TRFs of non-BL lymphoma cell lines are 2.3-5.5 kbp. Fluorescent in situ hybridization (FISH) studies of these cell lines showed remarkable heterogeneity of telomere size in chromosomes in the same BL cell. These results suggest that EBV-positive and EBV-negative BL cell lines have experienced various telomere dynamics.},
}
@article {pmid15983382,
year = {2005},
author = {Louis, SF and Vermolen, BJ and Garini, Y and Young, IT and Guffei, A and Lichtensztejn, Z and Kuttler, F and Chuang, TC and Moshir, S and Mougey, V and Chuang, AY and Kerr, PD and Fest, T and Boukamp, P and Mai, S},
title = {c-Myc induces chromosomal rearrangements through telomere and chromosome remodeling in the interphase nucleus.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {102},
number = {27},
pages = {9613-9618},
pmid = {15983382},
issn = {0027-8424},
mesh = {Animals ; Apoptosis/physiology ; Cell Line, Tumor ; Cell Nucleus/physiology ; Chromosomal Instability/genetics/*physiology ; Chromosome Painting ; Chromosomes, Mammalian/genetics/*physiology ; *Gene Expression Regulation, Neoplastic ; Gene Rearrangement/*genetics ; Image Processing, Computer-Assisted ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Interphase/genetics/*physiology ; Karyotyping ; Mice ; Proto-Oncogene Proteins c-myc/*metabolism ; Telomere/*genetics ; },
abstract = {In previous work, we showed that telomeres of normal cells are organized within the 3D space of the interphase nucleus in a nonoverlapping and cell cycle-dependent manner. This order is distorted in tumor cell nuclei where telomeres are found in close association forming aggregates of various numbers and sizes. Here we show that c-Myc overexpression induces telomeric aggregations in the interphase nucleus. Directly proportional to the duration of c-Myc deregulation, we observe three or five cycles of telomeric aggregate formation in interphase nuclei. These cycles reflect the onset and propagation of breakage-bridge-fusion cycles that are initiated by end-to-end telomeric fusions of chromosomes. Subsequent to initial chromosomal breakages, new fusions follow and the breakage-bridge-fusion cycles continue. During this time, nonreciprocal translocations are generated. c-Myc-dependent remodeling of the organization of telomeres thus precedes the onset of genomic instability and subsequently leads to chromosomal rearrangements. Our findings reveal that c-Myc possesses the ability to structurally modify chromosomes through telomeric fusions, thereby reorganizing the genetic information.},
}
@article {pmid15979949,
year = {2005},
author = {Fisher, TS and Zakian, VA},
title = {Ku: a multifunctional protein involved in telomere maintenance.},
journal = {DNA repair},
volume = {4},
number = {11},
pages = {1215-1226},
doi = {10.1016/j.dnarep.2005.04.021},
pmid = {15979949},
issn = {1568-7864},
support = {GM43265/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Antigens, Nuclear/*physiology ; DNA Helicases/*physiology ; DNA-Activated Protein Kinase/*physiology ; DNA-Binding Proteins/*physiology ; Humans ; Ku Autoantigen ; Nuclear Proteins/*physiology ; Saccharomyces cerevisiae Proteins/*physiology ; Telomere/chemistry/*physiology ; },
abstract = {The DNA-binding protein Ku plays a critical role in a variety of cellular processes, including the repair of double-stranded DNA breaks and V(D)J recombination. Paradoxically, while Ku is required for double-stranded break repair by non-homologous end-joining, in many organisms, Ku is also associated with telomeres. Although telomeres are naturally occurring double-stranded DNA breaks, one of their first identified functions is to protect chromosomes from end-to-end fusions, a process that is promoted by non-homologous end-joining. While located at telomeres, Ku appears to play several important roles, including: (1) regulating telomere addition, (2) protecting telomeres from recombination and nucleolytic degradation, (3) promoting transcriptional silencing of telomere-proximal genes and (4) nuclear positioning of telomeres. Here, we review the role of Ku at telomeres in the model organism, Saccharomyces cerevisiae and compare and contrast it to the roles of Ku at telomeres in other organisms.},
}
@article {pmid15976439,
year = {2005},
author = {LeBel, C and Wellinger, RJ},
title = {Telomeres: what's new at your end?.},
journal = {Journal of cell science},
volume = {118},
number = {Pt 13},
pages = {2785-2788},
doi = {10.1242/jcs.02394},
pmid = {15976439},
issn = {0021-9533},
mesh = {Chromosomes/genetics ; DNA/chemistry/metabolism ; Eukaryotic Cells/metabolism ; Humans ; Models, Biological ; Saccharomyces cerevisiae/chemistry ; *Telomere/chemistry/genetics/physiology ; },
}
@article {pmid15975611,
year = {2005},
author = {Al-Wahiby, S and Wong, HP and Slijepcevic, P},
title = {Shortened telomeres in murine scid cells expressing mutant hRAD54 coincide with reduction in recombination at telomeres.},
journal = {Mutation research},
volume = {578},
number = {1-2},
pages = {134-142},
doi = {10.1016/j.mrfmmm.2005.04.008},
pmid = {15975611},
issn = {0027-5107},
mesh = {Alkylating Agents/pharmacology ; Animals ; Cell Line ; Chromosome Aberrations/drug effects ; DNA Helicases ; DNA-Activated Protein Kinase ; DNA-Binding Proteins ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Knockout ; Mice, SCID ; Mitomycin/pharmacology ; *Mutation ; Nuclear Proteins/*genetics/*metabolism ; *Recombination, Genetic ; Sister Chromatid Exchange/drug effects ; *Telomere ; },
abstract = {Murine severe combined immunodeficiency (scid) cells are characterized by defective Prkdc (DNA-PKcs), one of the key genes involved in the repair of DNA double-strand breaks. Interestingly, scid mice are not null mutants and their cells are likely to show low DNA-PKcs activity. Prkdc is also involved in telomere maintenance and in contrast to mice genetically engineered to lack Prkdc (i.e. null mutants), which show complete absence of DNA-PKcs activity, loss of telomere capping function and normal telomere length, cells from scid mice show not only loss of telomere capping function but also abnormally elongated telomeres. Here we demonstrate that telomere elongation observed in murine scid cells can be reversed by expressing mutant hRAD54, a protein involved in homologous recombination. In addition, we measured recombination rates at telomeres using chromosome orientation fluorescence in situ hybridization (CO-FISH) and found that these are elevated in scid cells in comparison with control cells, or significantly reduced in scid cells expressing mutant hRAD54. Similarly, recombination rates at telomeres are reduced in scid cells following introduction of functional Prkdc. Since expression of mutant hRAD54 and restoration of functional Prkdc in scid cells cause the same effects, i.e. telomere shortening and reduced recombination rates at telomeres, these results argue that telomere elongation in scid cells is a complex trait resulting from interactions between homologous recombination mechanisms and DNA-PKcs.},
}
@article {pmid15974880,
year = {2005},
author = {Stewart, SA},
title = {Telomere maintenance and tumorigenesis: an "ALT"ernative road.},
journal = {Current molecular medicine},
volume = {5},
number = {2},
pages = {253-257},
doi = {10.2174/1566524053586653},
pmid = {15974880},
issn = {1566-5240},
mesh = {Cell Transformation, Neoplastic/*genetics ; Humans ; Telomere/*metabolism ; },
abstract = {The acquisition of cellular immortality is a critical step in human tumorigenesis. While the vast majority of human tumors activate the catalytic component of telomerase (hTERT) to stabilize their telomeres and attain immortality, a significant portion (7-10%) utilize a poorly defined alternative form of telomere maintenance referred to as ALT. Interestingly, telomerase activation is often favored in tumors arising from the epithelial compartment whereas ALT occurs in a more significant portion of tumors that arise from tissues of mesenchymal origin. This observation raises the possibility that cell type specific mechanisms favor the activation of telomerase versus ALT in human tumorigenesis. Because cellular immortality is critical to tumorigenesis it may represent an important anti-neoplastic target. Indeed, several approaches have successfully eliminated telomerase activity in human tumor models and some of these approaches are now moving into clinical trials. While these results are encouraging, it is clear that these approaches will have no impact on cells that utilize the ALT mechanism for telomere maintenance. Furthermore, the existence of ALT raises the possibility that telomerase-positive tumors undergoing anti-telomerase therapies may escape by activating the ALT pathway. For these reasons a detailed understanding of the ALT pathway is critical to the future design of anti-neoplastic therapies.},
}
@article {pmid15974877,
year = {2005},
author = {Hahn, WC},
title = {Telomere and telomerase dynamics in human cells.},
journal = {Current molecular medicine},
volume = {5},
number = {2},
pages = {227-231},
doi = {10.2174/1566524053586572},
pmid = {15974877},
issn = {1566-5240},
support = {K01 CA94223/CA/NCI NIH HHS/United States ; R01 AG023145/AG/NIA NIH HHS/United States ; },
mesh = {*Cellular Senescence ; *Genomic Instability ; Humans ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Accumulating evidence now implicates telomeres and telomerase as critical regulators genomic stability and replicative lifespan in mammalian cells. Disruption of telomere maintenance and/or telomerase expression contributes to the etiology of some degenerative diseases and may participate in the process of aging. Although telomere dysfunction and aberrant telomerase expression clearly play important roles in cancer development, the contribution of telomere biology to cancer is complex and involves both positive and negative influences on tumor development. Indeed, recent work from several laboratories suggests additional roles for telomeres and telomerase in both normal and malignant physiology. Understanding the complexity of telomere biology will provide further insights into chromosome biology in both normal and malignant cells.},
}
@article {pmid15974876,
year = {2005},
author = {Opitz, OG},
title = {Telomeres, telomerase and malignant transformation.},
journal = {Current molecular medicine},
volume = {5},
number = {2},
pages = {219-226},
doi = {10.2174/1566524053586626},
pmid = {15974876},
issn = {1566-5240},
mesh = {Cell Transformation, Neoplastic/*genetics/*metabolism ; Humans ; Telomerase/*physiology ; Telomere/*metabolism ; },
abstract = {Human cancer arises in a stepwise process by the accumulation of genetic alterations in oncogenes, tumor suppressor genes and other genes involved in the regulation of cell growth and proliferation. Many genes, important for the pathogenesis of various cancers and the pathways through which they act, have been characterized over the past decades. Nevertheless, recent successes in experimental models of immortalization and malignant transformation of human cells indicate that the disruption of a limited number of cellular pathways is sufficient to induce a cancerous phenotype in a wide variety of normal cells. In this context, immortalization is an essential prerequisite for the formation of a tumor cell. Besides classical cancer related pathways as the pRB and p53 tumor suppressor pathway or the ras signaling pathway, the maintenance of telomeres plays an essential role in both of these processes. Alterations in telomere biology both suppress and facilitate malignant transformation by regulating genomic stability and cellular life span. This review will summarize recent advances in the understanding of the molecular mechanisms of malignant transformation in human cells and the role of telomere maintenance in these processes. This ultimately leads to the development of cellular models of human cancer that phenocopy the corresponding disease. Furthermore, in the future these models could provide an ideal basis for the testing of novel chemopreventive or therapeutic approaches in the treatment of different types of human cancer.},
}
@article {pmid15974875,
year = {2005},
author = {Greenberg, RA},
title = {Telomeres, crisis and cancer.},
journal = {Current molecular medicine},
volume = {5},
number = {2},
pages = {213-218},
doi = {10.2174/1566524053586590},
pmid = {15974875},
issn = {1566-5240},
mesh = {Animals ; *Genomic Instability ; Humans ; Neoplasms/*genetics ; Telomere/*chemistry/*metabolism ; },
abstract = {Eukaryotic chromosomes terminate in specialized nucleic acid-protein complexes known as telomeres. Disruption of telomere structure by erosion of telomeric DNA or loss of telomere binding protein function activates a signal transduction program that closely resembles the cellular responses generated upon DNA damage. Telomere dysfunction in turn induces a permanent proliferation arrest known as senescence. Senescence is postulated to perform a tumor suppressor function by limiting cellular proliferative capacity, thus imposing a barrier to cellular immortalization. Genetic or epigenetic silencing of components of the DNA damage pathway, allows cells to proliferate beyond senescence limits. However, these cells eventually reach a stage of extreme telomere dysfunction known as crisis that is characterized by cell death and the concomitant appearance of cytogenetic abnormalities. Telomeric crisis produces significant chromosomal instability, a hallmark of human cancer, and may thus be relevant to carcinogenesis by increasing the occurrence of genetic alterations that would favor neoplastic transformation. The following review examines the relationship of telomere function during crisis in accelerating chromosomal instability and cancer.},
}
@article {pmid15974873,
year = {2005},
author = {von Zglinicki, T and Martin-Ruiz, CM},
title = {Telomeres as biomarkers for ageing and age-related diseases.},
journal = {Current molecular medicine},
volume = {5},
number = {2},
pages = {197-203},
doi = {10.2174/1566524053586545},
pmid = {15974873},
issn = {1566-5240},
mesh = {*Aging/metabolism ; Biomarkers/metabolism ; *Cellular Senescence ; Humans ; Leukocytes/metabolism ; Prognosis ; Telomere/*metabolism ; },
abstract = {Telomeres in telomerase-negative cells shorten during DNA replication in vitro due to numerous causes including the inability of DNA polymerases to fully copy the lagging strand, DNA end processing and random damage, often caused by oxidative stress. Short telomeres activate replicative senescence, an irreversible cell cycle arrest. Thus, telomere length is an indicator of replicative history, of the probability of cell senescence, and of the cumulative history of oxidative stress. Telomeres in most human cells shorten during ageing in vivo as well, suggesting that telomere length could be a biomarker of ageing and age-related morbidity. There are two distinct possibilities: First, in a tissue-specific fashion, short telomeres might indicate senescence of (stem) cells, and this might contribute to age-related functional attenuation in this tissue. Second, short telomeres in one tissue might cause systemic effects or might simply indicate a history of high stress and damage in the individual and could thus act as risk markers for age-related disease residing in a completely different tissue. In recent years, data have been published to support both approaches, and we will review these. While they together paint a fairly promising picture, it needs to be pointed out that until now most of the evidence is correlative, that much of it comes from underpowered studies, and that causal evidence for essential pathways, for instance for the impact of cell senescence on tissue ageing in vivo, is still very weak.},
}
@article {pmid15974872,
year = {2005},
author = {Beeharry, N and Broccoli, D},
title = {Telomere dynamics in response to chemotherapy.},
journal = {Current molecular medicine},
volume = {5},
number = {2},
pages = {187-196},
doi = {10.2174/1566524053586554},
pmid = {15974872},
issn = {1566-5240},
support = {CA006927/CA/NCI NIH HHS/United States ; CA098087-01/CA/NCI NIH HHS/United States ; },
mesh = {Neoplasms/*drug therapy/genetics ; Telomere/*metabolism ; },
abstract = {The use of chemotherapy provides an essential arm in the treatment of a number of cancers. The biological feature common to all cancerous cells that sensitizes them to chemotherapeutic agents is their elevated division rate. Rapidly dividing cells, such as tumor cells, are more sensitive to chemotherapeutic agents that act to initiate pathways leading to cell death, a process enhanced in cells with compromised DNA damage responses. The toxicity accompanying chemotherapy is due to side-effects induced in normal regenerative tissues which also have relatively high replication rates, such as hair follicles, the hematopoietic system, the gastrointestinal system, the germline and skin cells. While the side-effects of chemotherapy may be tolerated by the patient, the long term impact of the cytotoxic effects of chemotherapy on healthy tissues is only now becoming apparent. Chemotherapy-induced cytotoxicity in regenerative tissues requires multiple cell divisions in order to reconstitute the affected tissues. At least in part as a consequence of these extra divisions, telomeres in individuals treated with chemotherapy are shorter than age-matched control individuals who have never been exposed to these drugs. Given the essential role of telomeres in regulating cellular aging and chromosomal stability, it is possible that the prematurely shortened telomeres that arise following chemotherapy may impact the long-term replicative potential of these tissues. This review is focused on how telomeres may be modulated, directly or indirectly, by anticancer drugs and the potential long-term consequences of accelerated telomere shortening in healthy tissue as a result of current cancer treatment protocols.},
}
@article {pmid15974871,
year = {2005},
author = {Zimmermann, S and Martens, UM},
title = {Telomere dynamics in hematopoietic stem cells.},
journal = {Current molecular medicine},
volume = {5},
number = {2},
pages = {179-185},
doi = {10.2174/1566524053586608},
pmid = {15974871},
issn = {1566-5240},
mesh = {Animals ; Hematopoietic Stem Cells/*enzymology ; Humans ; Mice ; Telomerase/*antagonists &amp; inhibitors/*metabolism ; Telomere/*metabolism ; },
abstract = {The hematopoietic system has an outstanding regenerative capacity which depends on a relatively small population of hematopoietic stem cells (HSC). In contrast to normal human cells, blood-forming stem cells, like most of their counterparts from other adult tissues, exhibit telomerase activity to a certain level. Nevertheless, this telomerase activity does not prevent telomere shortening in HSC, suggesting a restriction of their proliferative capacity. Here, we review recent studies on telomere dynamics in HSC of humans and mice. Furthermore, we discuss the impact of telomere manipulation in HSC for possible clinical applications and speculate on functions of telomerase beyond telomere lengthening.},
}
@article {pmid15974870,
year = {2005},
author = {Boukamp, P},
title = {Skin aging: a role for telomerase and telomere dynamics?.},
journal = {Current molecular medicine},
volume = {5},
number = {2},
pages = {171-177},
doi = {10.2174/1566524053586644},
pmid = {15974870},
issn = {1566-5240},
mesh = {Animals ; Cell Proliferation ; Down-Regulation ; Epidermal Cells ; Epidermis/*enzymology ; Hair Color/genetics/physiology ; Humans ; Mice ; Skin Aging/*genetics ; Telomerase/*metabolism ; Telomere/*physiology ; Wound Healing/genetics/physiology ; },
abstract = {Skin is a complex tissue composed of two very different compartments -- the continuously renewing epidermis made up mostly by keratinocytes and the underlying matrix-rich dermis with the resting fibroblasts as its major cellular components. Both compartments are tightly interconnected and a paracrine mutual interaction is essential for epidermal growth, differentiation, and tissue homeostasis. Skin aging is commonly viewed as wrinkle formation, hair greying, and impaired wound healing. Nevertheless, the epidermis as the outermost shield needs to remain intact in order to guarantee an inside-out and outside-in barrier function throughout life time of a human being. Furthermore, the epidermis is one of the few regenerative tissues that express telomerase, the ribonucleoprotein complex that can counteract telomere erosion, one of the presently mostly favoured potential mechanisms causing cellular aging. This raises the question whether in the epidermis telomerase is able to counteract telomere erosion and thereby to prevents a telomere-dependent aging process and consequently which part of the skin is responsible for the most obvious changes associated with skin aging.},
}
@article {pmid15974869,
year = {2005},
author = {Mason, PJ and Wilson, DB and Bessler, M},
title = {Dyskeratosis congenita -- a disease of dysfunctional telomere maintenance.},
journal = {Current molecular medicine},
volume = {5},
number = {2},
pages = {159-170},
doi = {10.2174/1566524053586581},
pmid = {15974869},
issn = {1566-5240},
support = {CA105312-01/CA/NCI NIH HHS/United States ; },
mesh = {Chromosomes, Human, X/*genetics ; Dyskeratosis Congenita/diagnosis/*genetics/therapy ; Genetic Predisposition to Disease ; Genetic Therapy ; Humans ; Mutation ; Neoplasms/genetics ; Telomerase/*genetics ; Telomere/*metabolism ; },
abstract = {Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome associated with abnormalities of the skin, fingernails, and tongue. Other clinical manifestations may include epiphora, lung fibrosis, liver cirrhosis, osteoporosis, and a predisposition to develop a variety of malignancies. The clinical picture often resembles that of a premature aging syndrome and tissues affected are those with a high cell turnover. DC has been linked to mutations in at least four distinct genes, three of which have been identified. The product of these genes, dyskerin, the telomerase RNA (TERC), and the catalytic unit of telomerase (TERT) are part of a ribonucleoprotein complex, the telomerase enzyme, that is essential for the elongation and maintenance of chromosome ends or telomeres. All patients with DC have excessively short telomeres, indicating that the underlying defect in these individuals is an inability to maintain the telomeres. The purpose of the current review is to highlight recent insights into the molecular pathogenesis of DC. We discuss the impact these findings have on our current understanding of telomere function and maintenance, and on the diagnosis, management, and treatment of patients with conditions caused by dysfunctional telomeres.},
}
@article {pmid15974867,
year = {2005},
author = {Hezel, AF and Bardeesy, N and Maser, RS},
title = {Telomere induced senescence: end game signaling.},
journal = {Current molecular medicine},
volume = {5},
number = {2},
pages = {145-152},
doi = {10.2174/1566524053586563},
pmid = {15974867},
issn = {1566-5240},
mesh = {Aging/*genetics ; Animals ; *Genomic Instability ; Humans ; Mice ; Signal Transduction ; Telomere/*chemistry/*metabolism ; },
abstract = {The telomere-based model of cell aging has proven to among been among the most enduring hypotheses in cell biology. This model, suggesting that the gradual loss of telomere sequences during the proliferation of cultured human somatic cells imposes a barrier on cellular replicative potential, has been strongly supported by recent genetic and biochemical studies. In addition, evidence implicating telomere dynamics in organismal ageing and cancer progression in vivo suggest that such a process is likely to have considerable physiological relevance in homeostasis and disease. What is the sensing mechanism for shortened telomeres and what is the molecular basis for the ensuing checkpoint response? Moreover, what is the outcome when such failsafe mechanisms are lost? Here we will review the signaling pathways that are induced by alterations in telomere length and integrity and illustrate how these processes provoke downstream effects on cell proliferation and survival. In addition, we discuss how the telomere-induced pathways intersect with the DNA damage response and document how the failure in either process results in unrestrained chromosomal instability.},
}
@article {pmid15974865,
year = {2005},
author = {Rudolph, KL},
title = {Telomeres and telomerase influence the course of human diseases, aging and carcinogenesis.},
journal = {Current molecular medicine},
volume = {5},
number = {2},
pages = {133-134},
doi = {10.2174/1566524053586617},
pmid = {15974865},
issn = {1566-5240},
mesh = {*Aging ; Genetic Predisposition to Disease ; Humans ; Neoplasms/enzymology/*genetics ; Telomerase/*physiology ; Telomere/*chemistry/physiology ; },
}
@article {pmid15973431,
year = {2005},
author = {Hockemeyer, D and Sfeir, AJ and Shay, JW and Wright, WE and de Lange, T},
title = {POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end.},
journal = {The EMBO journal},
volume = {24},
number = {14},
pages = {2667-2678},
pmid = {15973431},
issn = {0261-4189},
support = {AG01228/AG/NIA NIH HHS/United States ; AG16642/AG/NIA NIH HHS/United States ; R01 GM049046/GM/NIGMS NIH HHS/United States ; R01 AG001228/AG/NIA NIH HHS/United States ; R56 AG016642/AG/NIA NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Alternative Splicing ; Cell Proliferation ; Chromosomes, Human/chemistry/*metabolism ; DNA Damage/*physiology ; HeLa Cells ; Humans ; Protein Isoforms/chemistry/genetics/metabolism ; Shelterin Complex ; Telomere/chemistry/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {The hallmarks of telomere dysfunction in mammals are reduced telomeric 3' overhangs, telomere fusions, and cell cycle arrest due to a DNA damage response. Here, we report on the phenotypes of RNAi-mediated inhibition of POT1, the single-stranded telomeric DNA-binding protein. A 10-fold reduction in POT1 protein in tumor cells induced neither telomere fusions nor cell cycle arrest. However, the 3' overhang DNA was reduced and all telomeres elicited a transient DNA damage response in G1, indicating that extensive telomere damage can occur without cell cycle arrest or telomere fusions. RNAi to POT1 also revealed its role in generating the correct sequence at chromosome ends. The recessed 5' end of the telomere, which normally ends on the sequence ATC-5', was changed to a random position within the AATCCC repeat. Thus, POT1 determines the structure of the 3' and 5' ends of human chromosomes, and its inhibition generates a novel combination of telomere dysfunction phenotypes in which chromosome ends behave transiently as sites of DNA damage, yet remain protected from nonhomologous end-joining.},
}
@article {pmid15970505,
year = {2005},
author = {de Grey, AD},
title = {Whole-body interdiction of lengthening of telomeres: a proposal for cancer prevention.},
journal = {Frontiers in bioscience : a journal and virtual library},
volume = {10},
number = {},
pages = {2420-2429},
doi = {10.2741/1707},
pmid = {15970505},
issn = {1093-9946},
mesh = {Humans ; Neoplasms/diagnosis/enzymology/*genetics/pathology ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {The intrinsic genetic instability of cancer cells makes age-related cancers more difficult to postpone or treat than any other age-related diseases. Any treatment that a cancer can resist by activating or inactivating specific genes is unlikely to succeed over the long term, because pre-existing cancer cells with the necessary gene expression pattern will withstand the therapy and proliferate. "Whole-body Interdiction of Lengthening of Telomeres" (WILT) is a proposal to pre-empt this problem by deleting from as many of our cells as possible the genes needed for telomere elongation. Cancers lacking these genes can never reach a life-threatening stage by altering gene expression, only by acquiring new genes, which is far more unlikely. Continuously-renewing tissues can be maintained by periodic reseeding with telomere elongation-incompetent stem cells that have had their telomeres lengthened in vitro with exogenous telomerase. Here, I describe why WILT might prove to be an exceptionally powerful anti-cancer modality.},
}
@article {pmid15968270,
year = {2005},
author = {Celli, GB and de Lange, T},
title = {DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion.},
journal = {Nature cell biology},
volume = {7},
number = {7},
pages = {712-718},
doi = {10.1038/ncb1275},
pmid = {15968270},
issn = {1465-7392},
support = {GM49046-12/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*metabolism ; Cells, Cultured ; Checkpoint Kinase 2 ; Chromosomal Proteins, Non-Histone ; Crosses, Genetic ; DNA/genetics/*metabolism ; *DNA Damage ; DNA Ligase ATP ; DNA Ligases/genetics ; DNA-Binding Proteins/*metabolism ; Embryo, Mammalian/cytology ; Fibroblasts/cytology/metabolism ; Gene Deletion ; Histones/metabolism ; In Situ Hybridization, Fluorescence ; Intracellular Signaling Peptides and Proteins/metabolism ; Mice ; Mice, Knockout ; Mice, Transgenic ; Phosphoproteins/metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases/*metabolism ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/*genetics/metabolism ; Transfection ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Proteins/*metabolism ; Tumor Suppressor p53-Binding Protein 1 ; rap1 GTP-Binding Proteins/metabolism ; },
abstract = {Telomere attrition and other forms of telomere damage can activate the ATM kinase pathway. What generates the DNA damage signal at mammalian chromosome ends or at other double-strand breaks is not known. Telomere dysfunction is often accompanied by disappearance of the 3' telomeric overhang, raising the possibility that DNA degradation could generate the structure that signals. Here we address these issues by studying telomere structure after conditional deletion of mouse TRF2, the protective factor at telomeres. Upon removal of TRF2 from TRF2(F/-) p53-/- mouse embryo fibroblasts, a telomere damage response is observed at most chromosome ends. As expected, the telomeres lose the 3' overhang and are processed by the non-homologous end-joining pathway. Non-homologous end joining of telomeres was abrogated in DNA ligase IV-deficient (Lig4-/-) cells. Unexpectedly, the telomeres of TRF2-/- Lig4-/- p53-/- cells persisted in a free state without undergoing detectable DNA degradation. Notably, the telomeres retained their 3' overhangs, but they were recognized as sites of DNA damage, accumulating the DNA damage response factors 53BP1 and gamma-H2AX, and activating the ATM kinase. Thus, activation of the ATM kinase pathway at chromosome ends does not require overhang degradation or other overt DNA processing.},
}
@article {pmid15968105,
year = {2005},
author = {Wu, KD and Moore, MA},
title = {Determination of telomerase activity and telomere length.},
journal = {Methods in molecular medicine},
volume = {113},
number = {},
pages = {207-223},
doi = {10.1385/1-59259-916-8:207},
pmid = {15968105},
issn = {1543-1894},
mesh = {Base Sequence ; Biomarkers, Tumor/*analysis ; DNA Primers ; Drug Design ; Enzyme Inhibitors/therapeutic use ; Humans ; Multiple Myeloma/enzymology/genetics ; Polymerase Chain Reaction/methods ; Substrate Specificity ; Telomerase/*analysis/antagonists &amp; inhibitors/metabolism ; Telomere/*ultrastructure ; },
abstract = {Telomerase is an enzyme that has been attracting much attention in recent years because its activities are so central to the processes of malignant transformation. It is a reverse transcriptase enzyme that can synthesize telomeric DNA using its own RNA component as a template. Without telomerase, telomeres will shorten until, at a critical length, cells enter senescence and die. The low level or absence of telomerase activity in most nonneoplastic tissues and somatic cells, and its presence in almost all malignant tumors is thus of great interest for potential diagnostic, prognostic, and therapeutic applications in the management of human cancer. It has been documented that high telomerase activity and short telomere length correlate with poor prognosis in patients with multiple myeloma, and antitelomerase therapy has become a novel therapeutic approach for the disease. Thus, determination of telomerase activity and telomere length is essential in the study of cancer. In this chapter, we provide a standard telomeric repeat amplification protocol for telomerase activity assay and a Southern blot terminal restriction fragment protocol for telomere length assay. We also discuss comparison with related assay methods.},
}
@article {pmid15967485,
year = {2005},
author = {Bekaert, S and Van Pottelbergh, I and De Meyer, T and Zmierczak, H and Kaufman, JM and Van Oostveldt, P and Goemaere, S},
title = {Telomere length versus hormonal and bone mineral status in healthy elderly men.},
journal = {Mechanisms of ageing and development},
volume = {126},
number = {10},
pages = {1115-1122},
doi = {10.1016/j.mad.2005.04.007},
pmid = {15967485},
issn = {0047-6374},
mesh = {Aged ; Aged, 80 and over ; Aging/*blood/genetics ; Biomarkers/blood ; Bone Density ; Estradiol/*blood ; Humans ; Male ; Osteoporosis/*blood/genetics ; Phenotype ; Sex Hormone-Binding Globulin/analysis ; Telomere/genetics/*metabolism ; Testosterone/*blood ; },
abstract = {Telomeres, the termini of linear chromosomes, exert a key role in the process of cellular ageing. Progressive telomere shortening is implicated in senescence in vitro and ample evidence exists to support the hypothesis that telomere length is correlated with chronological age and ageing phenotypes in vivo. In this study, we assessed whether mean telomere length of peripheral blood leukocytes predicts age-associated bone loss and/or is related to sex steroid status in an elderly healthy male population (71-86 years). Out of this population, we selected 110 samples for telomere restriction fragment (TRF) length analysis. Fasting blood was analysed for testosterone, estradiol, sex hormone binding globulin and biochemical markers of bone turnover. Also, the bioavailable fractions of sex steroids were calculated. Bone mineral density was measured at baseline and longitudinal follow-up was available for 84 men. We found that mean TRF length was inversely correlated with age (r=-0.19; P=0.049). Although no correlations were found with sex steroids or BMD at baseline, age corrected mean TRF length was associated with longitudinal bone loss for different distal forearm sites (P<0.05). Further studies are required to confirm our results, yet in this study, the predictive value of telomere length for bone loss appears to be substantial, hence underscoring the role of telomere length as a biomarker of ageing phenotypes.},
}
@article {pmid15967465,
year = {2005},
author = {Buczek, P and Orr, RS and Pyper, SR and Shum, M and Kimmel, E and Ota, I and Gerum, SE and Horvath, MP},
title = {Binding linkage in a telomere DNA-protein complex at the ends of Oxytricha nova chromosomes.},
journal = {Journal of molecular biology},
volume = {350},
number = {5},
pages = {938-952},
pmid = {15967465},
issn = {0022-2836},
support = {R01 GM067994-01/GM/NIGMS NIH HHS/United States ; R01 GM067994-03/GM/NIGMS NIH HHS/United States ; R01 GM067994-02/GM/NIGMS NIH HHS/United States ; 5P30 CA42014/CA/NCI NIH HHS/United States ; R01 GM067994/GM/NIGMS NIH HHS/United States ; P30 CA042014/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Chromosomes/*metabolism ; DNA/metabolism ; Multiprotein Complexes ; Oxytricha/chemistry/*genetics ; Protein Binding ; Protein Subunits ; Protozoan Proteins ; Recombinant Fusion Proteins ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Alpha and beta protein subunits of the telomere end binding protein from Oxytricha nova (OnTEBP) combine with telomere single strand DNA to form a protective cap at the ends of chromosomes. We tested how protein-protein interactions seen in the co-crystal structure relate to DNA binding through use of fusion proteins engineered as different combinations of domains and subunits derived from OnTEBP. Joining alpha and beta resulted in a protein that bound single strand telomere DNA with high affinity (K(D-DNA)=1.4 nM). Another fusion protein, constructed without the C-terminal protein-protein interaction domain of alpha, bound DNA with 200-fold diminished affinity (K(D-DNA)=290 nM) even though the DNA-binding domains of alpha and beta were joined through a peptide linker. Adding back the alpha C-terminal domain as a separate protein restored high-affinity DNA binding. The binding behaviors of these fusion proteins and the native protein subunits are consistent with cooperative linkage between protein-association and DNA-binding equilibria. Linking DNA-protein stability to protein-protein contacts at a remote site may provide a trigger point for DNA-protein disassembly during telomere replication when the single strand telomere DNA must exchange between a very stable OnTEBP complex and telomerase.},
}
@article {pmid15966765,
year = {2005},
author = {Cabuy, E and Newton, C and Joksic, G and Woodbine, L and Koller, B and Jeggo, PA and Slijepcevic, P},
title = {Accelerated telomere shortening and telomere abnormalities in radiosensitive cell lines.},
journal = {Radiation research},
volume = {164},
number = {1},
pages = {53-62},
doi = {10.1667/rr3376},
pmid = {15966765},
issn = {0033-7587},
support = {CA82423/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; Cell Survival/*genetics/*radiation effects ; *Chromosome Aberrations ; Dose-Response Relationship, Radiation ; Fibroblasts/physiology/ultrastructure ; Humans ; Mice ; Radiation Dosage ; Radiation Tolerance/*genetics ; Stem Cells/physiology/ultrastructure ; Telomere/*genetics/ultrastructure ; },
abstract = {We examined telomere maintenance in cells of 11 primary fibroblast cell lines with differing genetic defects that confer sensitivity to ionizing radiation. These included cell lines derived from patients with ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi anemia, defective Artemis, DNA ligase I and DNA ligase IV, an immunodeficient patient with a defect in DNA double-strand break repair, and a patient diagnosed with xeroderma pigmentosum who, in addition, showed severe clinical sensitivity to ionizing radiation. Our results, based on Southern blot, flow-FISH and Q-FISH (quantitative FISH) measurements, revealed an accelerated rate of telomere shortening in most cell lines derived from the above patients compared to cell lines from normal individuals or a cell line isolated from a heterozygotic parent of one radiosensitive patient. This accelerated telomere shortening was accompanied by the formation of chromatin bridges in anaphase cells, indicative of the early loss of telomere capping function and in some cases low levels of chromosome abnormalities in metaphase cells. We also analyzed telomere maintenance in mouse embryonic stem cells deficient in Brca1, another defect that confers radiosensitivity. Similarly, these cells showed accelerated telomere shortening and mild telomere dysfunction in comparison to control cells. Our results suggest that mechanisms that confer sensitivity to ionizing radiation may be linked with mechanisms that cause telomere dysfunction.},
}
@article {pmid15965650,
year = {2005},
author = {Yang, TJ and Yu, Y and Chang, SB and de Jong, H and Oh, CS and Ahn, SN and Fang, E and Wing, RA},
title = {Toward closing rice telomere gaps: mapping and sequence characterization of rice subtelomere regions.},
journal = {TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik},
volume = {111},
number = {3},
pages = {467-478},
pmid = {15965650},
issn = {0040-5752},
mesh = {Base Sequence ; Cloning, Molecular ; DNA, Plant/analysis ; Genetic Vectors ; *Genome, Plant ; *Genomic Library ; Genomics ; Molecular Sequence Data ; Oryza/*genetics ; Polymerase Chain Reaction ; Sequence Homology, Nucleic Acid ; Telomere/*genetics ; },
abstract = {Despite the collective efforts of the international community to sequence the complete rice genome, telomeric regions of most chromosome arms remain uncharacterized. In this report we present sequence data from subtelomere regions obtained by analyzing telomeric clones from two 8.8 x genome equivalent 10-kb libraries derived from partial restriction digestion with HaeIII or Sau3AI (OSJNPb HaeIII and OSJNPc Sau3AI). Seven telomere clones were identified and contain 25-100 copies of the telomere repeat (CCCTAAA)(n) on one end and unique sequences on the opposite end. Polymorphic sequence-tagged site markers from five clones and one additional PCR product were genetically mapped on the ends of chromosome arms 2S, 5L, 10S, 10L, 7L, and 7S. We found distinct chromosome-specific telomere-associated tandem repeats (TATR) on chromosome 7 (TATR7) and on the short arm of chromosome 10 (TATR10s) that showed no significant homology to any International Rice Genome Sequencing Project (IRGSP) genomic sequence. The TATR7, a degenerate tandem repeat which is interrupted by transposable elements, appeared on both ends of chromosome 7. The TATR10s was found to contain an inverted array of three tandem repeats displaying an interesting secondary folding pattern that resembles a telomere loop (t-loop) and which may be involved in a protective function against chromosomal end degradation.},
}
@article {pmid15965466,
year = {2005},
author = {Qi, L and Strong, MA and Karim, BO and Huso, DL and Greider, CW},
title = {Telomere fusion to chromosome breaks reduces oncogenic translocations and tumour formation.},
journal = {Nature cell biology},
volume = {7},
number = {7},
pages = {706-711},
doi = {10.1038/ncb1276},
pmid = {15965466},
issn = {1465-7392},
support = {CA16519/CA/NCI NIH HHS/United States ; RR00171/RR/NCRR NIH HHS/United States ; RR07002/RR/NCRR NIH HHS/United States ; },
mesh = {Age Factors ; Animals ; Apoptosis/genetics ; Ataxia Telangiectasia Mutated Proteins ; B-Lymphocytes/chemistry/metabolism ; Body Weight/genetics ; Cell Cycle Proteins/genetics ; Cell Proliferation ; Chromosome Breakage/*genetics ; Crosses, Genetic ; DNA-Binding Proteins/genetics ; Female ; Gene Rearrangement, T-Lymphocyte/genetics ; Genes, T-Cell Receptor/genetics ; Genomic Instability/genetics ; Genotype ; In Situ Hybridization, Fluorescence ; Lymphoma, T-Cell/genetics/pathology ; Male ; Mice ; Mice, Knockout ; Mice, SCID ; Models, Genetic ; Neoplasm Transplantation ; Neoplasms, Experimental/*genetics/pathology ; Protein Serine-Threonine Kinases/genetics ; Spectral Karyotyping ; Survival Analysis ; Telomerase/genetics ; Telomere/genetics/*metabolism ; Translocation, Genetic/*genetics ; Tumor Suppressor Proteins/genetics ; },
abstract = {Telomeres protect chromosome ends from fusion, degradation and recombination. Loss of telomere function has opposite effects on tumorigenesis: apoptosis, which inhibits tumour growth, and genomic instability, which accelerates tumour formation. Here we describe a new mechanism by which short telomeres inhibit tumorigenesis through interference with oncogenic translocations. In mice that are null for both ataxia-telangiectasia-mutated (Atm) and telomerase RNA (mTR), the first generation (G1) Atm-/- mTR-/- mice have a lower rate of tumour formation than Atm-/- mTR+/+ mice. These Atm-/- mTR-/- G1 tumours show no increase in either apoptosis or overall genomic instability. Strikingly, the tumours show a high fraction of translocations containing telomere signals at the translocation junctions. Translocations of the T-cell receptors on chromosome 14, which initiate tumorigenesis, were interrupted by fusion with telomeres. Telomere repeats were also detected at the translocation junctions in pre-malignant thymocytes. We propose that telomere fusion to DNA double-strand breaks competes with the generation of oncogenic translocations and thus reduces tumour formation.},
}
@article {pmid15965256,
year = {2005},
author = {Keely, SP and Renauld, H and Wakefield, AE and Cushion, MT and Smulian, AG and Fosker, N and Fraser, A and Harris, D and Murphy, L and Price, C and Quail, MA and Seeger, K and Sharp, S and Tindal, CJ and Warren, T and Zuiderwijk, E and Barrell, BG and Stringer, JR and Hall, N},
title = {Gene arrays at Pneumocystis carinii telomeres.},
journal = {Genetics},
volume = {170},
number = {4},
pages = {1589-1600},
pmid = {15965256},
issn = {0016-6731},
support = {R01AI36701/AI/NIAID NIH HHS/United States ; R01 AI044651/AI/NIAID NIH HHS/United States ; TW01200-02/TW/FIC NIH HHS/United States ; R01AI44651/AI/NIAID NIH HHS/United States ; R01 AI036701/AI/NIAID NIH HHS/United States ; R03 TW001200/TW/FIC NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; },
mesh = {Amino Acid Sequence ; Antigens, Fungal ; Base Sequence ; Chromosome Mapping ; Chromosomes, Fungal ; Cloning, Molecular ; Cosmids ; DNA, Fungal ; Evolution, Molecular ; Gene Duplication ; Gene Expression Regulation, Fungal ; Gene Library ; *Genes, Fungal ; Genetic Linkage ; Genome, Fungal ; Open Reading Frames ; Pneumocystis carinii/*genetics ; RNA, Messenger/genetics ; Recombination, Genetic ; Repetitive Sequences, Nucleic Acid ; Selection, Genetic ; Sequence Analysis, DNA ; Sequence Homology, Nucleic Acid ; Telomere/*genetics ; },
abstract = {In the fungus Pneumocystis carinii, at least three gene families (PRT1, MSR, and MSG) have the potential to generate high-frequency antigenic variation, which is likely to be a strategy by which this parasitic fungus is able to prolong its survival in the rat lung. Members of these gene families are clustered at chromosome termini, a location that fosters recombination, which has been implicated in selective expression of MSG genes. To gain insight into the architecture, evolution, and regulation of these gene clusters, six telomeric segments of the genome were sequenced. Each of the segments began with one or more unique genes, after which were members of different gene families, arranged in a head-to-tail array. The three-gene repeat PRT1-MSR-MSG was common, suggesting that duplications of these repeats have contributed to expansion of all three families. However, members of a gene family in an array were no more similar to one another than to members in other arrays, indicating rapid divergence after duplication. The intergenic spacers were more conserved than the genes and contained sequence motifs also present in subtelomeres, which in other species have been implicated in gene expression and recombination. Long mononucleotide tracts were present in some MSR genes. These unstable sequences can be expected to suffer frequent frameshift mutations, providing P. carinii with another mechanism to generate antigen variation.},
}
@article {pmid15965161,
year = {2005},
author = {McKay, JD and Patterson, B and Craig, JE and Russell-Eggitt, IM and Wirth, MG and Burdon, KP and Hewitt, AW and Cohn, AC and Kerdraon, Y and Mackey, DA},
title = {The telomere of human chromosome 1p contains at least two independent autosomal dominant congenital cataract genes.},
journal = {The British journal of ophthalmology},
volume = {89},
number = {7},
pages = {831-834},
pmid = {15965161},
issn = {0007-1161},
mesh = {Aphakia, Postcataract/genetics ; Cataract/*congenital/genetics ; Chromosomes, Human, Pair 1/*genetics ; Female ; Genes, Dominant/*genetics ; Genetic Linkage/genetics ; Haplotypes ; Homeodomain Proteins/genetics ; Humans ; Lod Score ; Male ; Microsatellite Repeats/genetics ; PAX7 Transcription Factor ; Pedigree ; Phenotype ; Strabismus/genetics ; Telomere/*genetics ; },
abstract = {AIMS: Multiple genetic causes of congenital cataract have been identified, both as a component of syndromes and in families that present with isolated congenital cataract. Linkage analysis was used to map the genetic locus in a six generation Australian family presenting with total congenital cataract.<br><br>METHODS: Microsatellite markers located across all known autosomal dominant congenital cataract loci were genotyped in all recruited family members of the Tasmanian family. Both two point and multipoint linkage analysis were used to assess each locus under an autosomal dominant model.<br><br>RESULTS: Significant linkage was detected at the telomere of the p arm of chromosome 1, with a maximum two point LOD of 4.21 at marker D1S507, a maximum multipoint exact LOD of 5.44, and an estimated location score of 5.61 at marker D1S507. Haplotype analysis places the gene inside a critical region between D1S228 and D1S199, a distance of approximately 6 megabases. The candidate gene PAX7 residing within the critical interval was excluded by direct sequencing in affected individuals.<br><br>CONCLUSION: This is the third report of congenital cataract linkage to 1ptel. The critical region as defined by the shared haplotype in this family is clearly centromeric from the Volkmann cataract locus identified through study of a Danish family, indicating that two genes causing autosomal dominant congenital cataract map to the telomeric region of chromosome 1p.},
}
@article {pmid15964812,
year = {2005},
author = {Bunch, JT and Bae, NS and Leonardi, J and Baumann, P},
title = {Distinct requirements for Pot1 in limiting telomere length and maintaining chromosome stability.},
journal = {Molecular and cellular biology},
volume = {25},
number = {13},
pages = {5567-5578},
pmid = {15964812},
issn = {0270-7306},
mesh = {Amino Acid Sequence ; *Chromosomal Instability ; Chromosomes, Fungal ; Fungal Proteins/chemistry/genetics/*metabolism ; Molecular Sequence Data ; Mutation ; Protein Structure, Tertiary ; Sequence Homology, Amino Acid ; Telomerase/metabolism ; Telomere/chemistry/genetics/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {The fission yeast Pot1 (protection of telomeres) protein binds to the single-stranded extensions at the ends of telomeres, where its presence is critical for the maintenance of linear chromosomes. Homologs of Pot1 have been identified in a wide variety of eukaryotes, including plants, animals, and humans. We now show that Pot1 plays dual roles in telomere length regulation and chromosome end protection. Using a series of Pot1 truncation mutants, we have defined distinct areas of the protein required for chromosome stability and for limiting access to telomere ends by telomerase. We provide evidence that a large portion of Pot1, including the N-terminal DNA binding domain and amino acids close to the C terminus, is essential for its protective function. C-terminal Pot1 fragments were found to exert a dominant-negative effect by displacing endogenous Pot1 from telomeres. Reducing telomere-bound Pot1 in this manner resulted in dramatic lengthening of the telomere tract. Upon further reduction of Pot1 at telomeres, the opposite phenotype was observed: loss of telomeric DNA and chromosome end fusions. Our results demonstrate that cells must carefully regulate the amount of telomere-bound Pot1 to differentiate between allowing access to telomerase and catastrophic loss of telomeres.},
}
@article {pmid15963673,
year = {2005},
author = {Passos, JF and von Zglinicki, T},
title = {Mitochondria, telomeres and cell senescence.},
journal = {Experimental gerontology},
volume = {40},
number = {6},
pages = {466-472},
doi = {10.1016/j.exger.2005.04.006},
pmid = {15963673},
issn = {0531-5565},
mesh = {Cell Division/physiology ; Cell Nucleus/physiology ; Cellular Senescence/*physiology ; DNA/physiology ; DNA, Mitochondrial/physiology ; Fibroblasts/physiology ; Free Radicals/metabolism ; Humans ; Mitochondria/*physiology ; Models, Biological ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; Telomere/*physiology ; Uncoupling Agents/metabolism ; },
abstract = {The accumulation of oxidative damage is one of the most widely accepted causes of ageing. Mitochondrial dysfunction, in particular damage to the mitochondrial DNA has been hypothesised, more than thirty years ago, as responsible for increased production of reactive oxygen species (ROS) and, thus, as one possible causal factor for ageing. There is now a wealth of data that supports this hypothesis, which is mostly derived from models considering the ageing of post-mitotic or slowly dividing cells in vivo. One major cellular model of ageing, however, is replicative senescence, the irreversible loss of division potential of somatic cells after a more or less constant number of cell divisions. Not much data exists concerning the role of mitochondria in this model. Here, we review evidence supporting an involvement of mitochondria in replicative senescence and a possible link to telomere shortening.},
}
@article {pmid15963630,
year = {2005},
author = {Fernandez-Gomez, J and Escaf Barmadah, S and Gosalbez, D and Rodriguez-Faba, O and Jalon, A and Gonzalez, R and Garcia Miralles, T and Calas, A},
title = {Telomere length on bladder washing samples from patients with bladder cancer correlates with tumor characteristics flow cytometry method for quantitative fluorescence in situ hybridization (flow-FISH technique).},
journal = {European urology},
volume = {48},
number = {3},
pages = {432-437},
doi = {10.1016/j.eururo.2005.04.030},
pmid = {15963630},
issn = {0302-2838},
mesh = {Analysis of Variance ; Case-Control Studies ; Flow Cytometry ; Humans ; *In Situ Hybridization, Fluorescence ; Neoplasm Staging ; Statistics, Nonparametric ; Telomere/*pathology ; Urinary Bladder Neoplasms/*pathology ; },
abstract = {OBJECTIVE: The purpose of the present study was to evaluate the length of telomeres in patients with bladder cancer using a quantitative flow cytometry (flow-FISH) technique.<br><br>METHODS: Bladder washing samples from 51 patients with bladder cancer were obtained immediately before transurethral resection. The average length of telomere repeats was measured by flow-FISH, as previously reported. Results were expressed in molecular equivalents of soluble fluorochrome (MESF) units.<br><br>RESULTS: Bladder washing specimens provided adequate cell numbers for flow-FISH in 49 cases. The TEL means were 1014.71, 2343.36, 5567 and 18267.57 for Ta, T1, T2 and T3/4 tumors, respectively. Regarding grade it was obtained a mean MESF value of 1379.46, 3391.29 and 15925.11 for G1, G2 and G3, respectively. ANOVA demonstrated statistically significant differences in stage (p: 0.014) and tumor grades (p: 0.012). In relation to ploidy, we found a mean MESF value of 2701.37 and 16085.44 MESF units for diploid and aneuploid cells, respectively. Significant difference (p: 0.003) was observed between both groups.<br><br>CONCLUSION: To date, this is the first report wherein telomere length was measured using flow-FISH method in exfoliated cells in urine from patients with bladder cancer. Further investigations are required to demonstrate whether flow-FISH technique might be considered as a tumor marker of bladder cancer.},
}
@article {pmid15959677,
year = {2005},
author = {Arndt, PF and Hwa, T and Petrov, DA},
title = {Substantial regional variation in substitution rates in the human genome: importance of GC content, gene density, and telomere-specific effects.},
journal = {Journal of molecular evolution},
volume = {60},
number = {6},
pages = {748-763},
pmid = {15959677},
issn = {0022-2844},
mesh = {*Base Composition ; Chromosomes/ultrastructure ; *Evolution, Molecular ; Exons ; *GC Rich Sequence ; Genetic Variation ; *Genome ; *Genome, Human ; Humans ; Models, Statistical ; Models, Theoretical ; Mutation ; Short Interspersed Nucleotide Elements ; Telomere/*ultrastructure ; },
abstract = {This study presents the first global, 1-Mbp-level analysis of patterns of nucleotide substitutions along the human lineage. The study is based on the analysis of a large amount of repetitive elements deposited into the human genome since the mammalian radiation, yielding a number of results that would have been difficult to obtain using the more conventional comparative method of analysis. This analysis revealed substantial and consistent variability of rates of substitution, with the variability ranging up to twofold among different regions. The rates of substitutions of C or G nucleotides with A or T nucleotides vary much more sharply than the reverse rates, suggesting that much of that variation is due to differences in mutation rates rather than in the probabilities of fixation of C/G vs. A/T nucleotides across the genome. For all types of substitution we observe substantially more hotspots than coldspots, with hotspots showing substantial clustering over tens of Mbp's. Our analysis revealed that GC-content of surrounding sequences is the best predictor of the rates of substitution. The pattern of substitution appears very different near telomeres compared to the rest of the genome and cannot be explained by the genome-wide correlations of the substitution rates with GC content or exon density. The telomere pattern of substitution is consistent with natural selection or biased gene conversion acting to increase the GC-content of the sequences that are within 10-15 Mbp away from the telomere.},
}
@article {pmid15958582,
year = {2005},
author = {McHugh, MM and Gawron, LS and Matsui, S and Beerman, TA},
title = {The antitumor enediyne C-1027 alters cell cycle progression and induces chromosomal aberrations and telomere dysfunction.},
journal = {Cancer research},
volume = {65},
number = {12},
pages = {5344-5351},
doi = {10.1158/0008-5472.CAN-05-0015},
pmid = {15958582},
issn = {0008-5472},
support = {CA 106312/CA/NCI NIH HHS/United States ; CA 16056/CA/NCI NIH HHS/United States ; },
mesh = {Aminoglycosides/*pharmacology ; Antibiotics, Antineoplastic/*pharmacology ; Cell Cycle/*drug effects ; Chromosome Aberrations/*chemically induced ; Comet Assay ; Enediynes ; HCT116 Cells ; Humans ; Karyotyping ; Telomere/*drug effects/physiology ; },
abstract = {This study examined the extent of chromosome instability induced in cultured human colon carcinoma HCT116 cells by the antitumor radiomimetic enediyne antibiotic C-1027. Spectral karyotype analysis showed frequent intrachromosomal fusions and fragmentations 26 hours after addition of as little as 0.035 nmol/L C-1027. When the concentration was increased to 0.14 nmol/L C-1027, 92% of cells showed chromosomal aberrations compared with only 2.9% after treatment with an equivalent growth inhibitory dose of ionizing radiation (20 Gy). Thus, chromosome misrejoining was associated to a much greater extent with C-1027-induced than with ionizing radiation-induced cell growth inhibition. Despite these aberrations, a large fraction of C-1027-treated cells progressed into G1. Comet analysis showed that these extensive chromosomal anomalies were not due to increased induction or reduced repair of C-1027-induced compared with ionizing radiation-induced strand breaks. Fluorescence in situ hybridization analysis showed that misrejoining of telomere repeats (i.e., chromosomes joined end to end at their telomeres or fused together after complete loss of telomere sequences) was observed within 26 hours of C-1027 addition. The extreme cytotoxicity of C-1027 may reflect both induction and erroneous repair of DNA double-strand break in the whole genome and/or in subgenomic targets such as telomere sequences.},
}
@article {pmid15949576,
year = {2005},
author = {Savage, SA and Stewart, BJ and Liao, JS and Helman, LJ and Chanock, SJ},
title = {Telomere stability genes are not mutated in osteosarcoma cell lines.},
journal = {Cancer genetics and cytogenetics},
volume = {160},
number = {1},
pages = {79-81},
doi = {10.1016/j.cancergencyto.2004.12.004},
pmid = {15949576},
issn = {0165-4608},
mesh = {Bone Neoplasms/*genetics ; Cell Line, Tumor ; Humans ; *Mutation ; Osteosarcoma/*genetics ; Polymorphism, Single Nucleotide ; Telomerase/genetics ; *Telomere ; Telomeric Repeat Binding Protein 1/genetics ; Telomeric Repeat Binding Protein 2/genetics ; },
abstract = {Osteosarcoma (OS), the most common primary bone tumor in adolescents and young adults, is characterized by a high degree of chromosomal abnormalities. Because telomeres are important for maintaining chromosomal integrity, it is plausible that germ-line or somatic mutations in the genes responsible for stabilizing the telomere complex could contribute to OS. We performed bi-directional sequence analysis in five OS cell lines and targeted all exons and proximal promoter regions in eight genes important in telomere stability: telomerase, the RNA component of telomerase (TERC), telomeric repeat binding factor 1, telomeric repeat binding factor 2, TERF1 interacting nuclear factor 2, human Rap1, protection of telomeres 1 and tankyrase. In this pilot study, we did not identify either somatic mutations or novel germ-line mutations in the five cell lines studied. However, we did confirm common genetic polymorphisms; an analysis of heterozygous sites suggests that loss of heterozygosity in OS is not present across these eight genes.},
}
@article {pmid15946472,
year = {2005},
author = {Xiao, CY and Zhou, FX and Liu, SQ and Xie, CH and Dai, J and Zhou, YF},
title = {[Correlations of telomere length and telomerase activity to radiosensitivity of human laryngeal squamous carcinoma cells].},
journal = {Ai zheng = Aizheng = Chinese journal of cancer},
volume = {24},
number = {6},
pages = {653-656},
pmid = {15946472},
mesh = {*Carcinoma, Squamous Cell/enzymology/pathology ; Cell Line, Tumor ; Cell Survival/radiation effects ; Dose-Response Relationship, Radiation ; *Gamma Rays ; Humans ; *Laryngeal Neoplasms/enzymology/pathology ; Radiation Dosage ; Radiation Tolerance ; Telomerase/*metabolism ; Telomere/radiation effects/*ultrastructure ; },
abstract = {BACKGROUND &amp; OBJECTIVE: Many studies showed that telomere length and telomerase activity closely correlate with proliferation and malignant degree of tumor cells, and both of them might be involved in the repair of radiation-induced DNA damage. So it was speculated that telomere length and telomerase activity maybe correlate to radiosensitivity of carcinoma cells. This study was designed to investigate the correlations of telomere length and telomerase activity to radiosensitivity of human laryngeal squamous carcinoma cell line Hep-2.<br><br>METHODS: Hep-2 cells were irradiated with 0, 2, 4, 8, or 12 Gy of gamma-ray for 3 times. Survival cells were subcultured for 20 generations. Radiosensitivity index, survival fraction at 2 Gy (SF(2)), was measured by clone formation assay. Telomere length (mean length of telomere restriction fragments, TRF) was examined by Southern blot&#xfb; telomerase activity (TA) was detected by polymerase chain reaction-based telomeric repeat amplification protocol (PCR-TRAP) coupled with ELISA.<br><br>RESULTS: After different doses of irradiation, SF(2) of Hep-2 cells was 0.47-0.64; TRF was 3.76-9.43 kb; TA was 1.761-2.606. Each parameter had significant differences among the survival progenies (P<0.05). SF(2) was positively correlated with TRF (r=0.921, P<0.01), and negatively correlated with TA (r=-0.929, P<0.01); TRF was negatively correlated with TA (r=-0.944, P<0.01).<br><br>CONCLUSION: Radiosensitivity of Hep-2 cells negatively correlates with telomere length, and positively correlates with telomerase activity, which suggest that both telomere length and telomerase activity may be used to predict cellular radiosensitivity.},
}
@article {pmid15944464,
year = {2005},
author = {Aviv, A and Shay, J and Christensen, K and Wright, W},
title = {The longevity gender gap: are telomeres the explanation?.},
journal = {Science of aging knowledge environment : SAGE KE},
volume = {2005},
number = {23},
pages = {pe16},
doi = {10.1126/sageke.2005.23.pe16},
pmid = {15944464},
issn = {1539-6150},
mesh = {Aged ; Aging/*physiology ; Cardiovascular Diseases/genetics/physiopathology ; Cell Survival ; Chromosomes, Human, X/*ultrastructure ; Chromosomes, Human, Y/*ultrastructure ; Estrogens/physiology ; Female ; Humans ; *Longevity ; Male ; Middle Aged ; Oxidative Stress ; Sex Factors ; *Telomere ; },
abstract = {In this Perspective, we focus on the greater longevity of women as compared with men. We propose that, like aging itself, the longevity gender gap is exceedingly complex and argue that it may arise from sex-related hormonal differences and from somatic cell selection that favors cells more resistant to the ravages of time. We discuss the interplay of these factors with telomere biology and oxidative stress and suggest that an explanation for the longevity gender gap may arise from a better understanding of the differences in telomere dynamics between men and women.},
}
@article {pmid15942929,
year = {2005},
author = {Lahue, E and Heckathorn, J and Meyer, Z and Smith, J and Wolfe, C},
title = {The Saccharomyces cerevisiae Sub2 protein suppresses heterochromatic silencing at telomeres and subtelomeric genes.},
journal = {Yeast (Chichester, England)},
volume = {22},
number = {7},
pages = {537-551},
doi = {10.1002/yea.1231},
pmid = {15942929},
issn = {0749-503X},
support = {1 P20 RR16469/RR/NCRR NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases/*metabolism ; Chromatin Immunoprecipitation ; *Gene Expression Regulation, Fungal ; *Gene Silencing ; Heterochromatin/*genetics ; RNA Helicases/metabolism ; RNA, Fungal/metabolism ; RNA, Messenger/metabolism ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/*genetics ; Telomere/*genetics ; },
abstract = {We show that overexpression of Sub2p, a multifunctional Saccharomyces cerevisiae helicase family member that is involved in mRNA elongation and transport, also suppresses heterochromatic silencing at telomeres. Genetic assays show cells that overexpress SUB2 from a high copy plasmid exhibit increased survival rates when selecting for a telomere-silenced URA3 reporter. Two temperature-sensitive sub2 mutations that affect different helicase domains were also examined at the permissive temperature; these mutants also overcome silencing of the URA3 reporter. The degree to which silencing is suppressed correlates with SUB2 RNA and protein levels. Additionally, we find that Sub2p localizes to the telomeres, as determined by chromatin immunoprecipitation assays, suggesting that Sub2p has a direct effect at telomeres. Genome-wide analysis of transcripts was used to assess whether Sub2p overproduction affects only the silenced URA3 reporter gene, or whether other subtelomeric genes are also affected. Of the 70 RNA transcripts elevated in the Sub2p overexpressing cells, 28% are encoded by subtelomeric genes that are located within 5 Kbp of a core X or Y' repeat. The remainder of the transcripts clustered into several functional groups, including the iron homeostasis pathway, purine nucleotide metabolism, and miscellaneous transport genes, among others. These results suggest a targeted effect of Sub2p on transcription. Our results also confirm that Sub2p affects heterochromatic gene expression, similar to that observed with the Drosophila Hel25E homologue. The above observations imply that Sub2p affects chromatin structure in addition to, or in parallel with, its functions in transcription elongation, splicing and mRNA transport.},
}
@article {pmid15941854,
year = {2005},
author = {Bartolović, K and Balabanov, S and Berner, B and Bühring, HJ and Komor, M and Becker, S and Hoelzer, D and Kanz, L and Hofmann, WK and Brümmendorf, TH},
title = {Clonal heterogeneity in growth kinetics of CD34+CD38- human cord blood cells in vitro is correlated with gene expression pattern and telomere length.},
journal = {Stem cells (Dayton, Ohio)},
volume = {23},
number = {7},
pages = {946-957},
doi = {10.1634/stemcells.2004-0311},
pmid = {15941854},
issn = {1066-5099},
mesh = {ADP-ribosyl Cyclase/*biosynthesis ; ADP-ribosyl Cyclase 1 ; Antigens, CD/*biosynthesis ; Antigens, CD34/*biosynthesis ; Cell Proliferation ; Cell Separation/*methods ; Culture Media, Serum-Free/pharmacology ; Fetal Blood/*metabolism ; Flow Cytometry ; *Gene Expression Regulation ; Humans ; In Situ Hybridization, Fluorescence ; In Vitro Techniques ; Kinetics ; Light ; Membrane Glycoproteins ; Methylcellulose/pharmacology ; Oligonucleotide Array Sequence Analysis ; Retrospective Studies ; Scattering, Radiation ; Stem Cell Factor/metabolism ; Stem Cells/metabolism ; Telomere/*ultrastructure ; Time Factors ; },
abstract = {Human hematopoietic stem cells (HSCs) are characterized by an extensive proliferative capacity that decreases from fetal liver to cord blood (CB) to adult bone marrow. In previous studies, it was demonstrated that the proliferative capacity of individual CD34+CD38- HSC clones is correlated with their growth kinetics in vitro and that HSC turnover in vivo can be estimated by telomere-length measurements. The present study was aimed at the characterization of the clonal composition of CD34+CD38- human umbilical CB cells in terms of growth kinetics, telomere length, and gene expression profile. For this purpose, individual CD34+CD38- CB cells were sorted into 96-well plates containing serum-free medium supplemented with six growth factors. During expansion, cell numbers in each individual well were scored in 3-day intervals. Once sufficient cell numbers were achieved, telomere length was measured by flow fluorescence in situ hybridization (flow FISH). In a second set of experiments, gene expression and colony-forming capacity were analyzed in slowly growing clones as compared with fast-growing clones, using linear amplification and oligonucleotide microarrays (HG-U133A; Affymetrix). Individual CD34+CD38- cells from CB displayed an extensive functional heterogeneity in growth kinetics. Among highly proliferative clones, the most slowly growing clones were characterized by the longest telomeres. Furthermore, significant differences in gene expression were detected between slow- and fast-growing clones, whereas no significant difference in colony-forming capacity was observed. These data provide further evidence for a functional hierarchy in the human HSC compartment and suggest a link between telomere length and proliferation capacity of individual HSC clones.},
}
@article {pmid15933211,
year = {2005},
author = {Qi, J and Shafer, RH},
title = {Covalent ligation studies on the human telomere quadruplex.},
journal = {Nucleic acids research},
volume = {33},
number = {10},
pages = {3185-3192},
pmid = {15933211},
issn = {1362-4962},
support = {P41 RR001614/RR/NCRR NIH HHS/United States ; R01 GM067607/GM/NIGMS NIH HHS/United States ; GM067607/GM/NIGMS NIH HHS/United States ; RR01614/RR/NCRR NIH HHS/United States ; },
mesh = {Aptamers, Nucleotide ; Buffers ; Circular Dichroism ; DNA/*chemistry ; DNA, Circular/chemistry ; Diphosphates/chemistry ; G-Quadruplexes ; Guanine/*chemistry ; Humans ; Ions ; Metals/chemistry ; Nucleic Acid Conformation ; Oligodeoxyribonucleotides/chemistry ; Oligonucleotides/chemistry ; Phosphates/analysis ; Telomere/*chemistry ; },
abstract = {Recent X-ray crystallographic studies on the human telomere sequence d[AGGG(TTAGGG)3] revealed a unimolecular, parallel quadruplex structure in the presence of potassium ions, while earlier NMR results in the presence of sodium ions indicated a unimolecular, antiparallel quadruplex. In an effort to identify and isolate the parallel form in solution, we have successfully ligated into circular products the single-stranded human telomere and several modified human telomere sequences in potassium-containing solutions. Using these sequences with one or two terminal phosphates, we have made chemically ligated products via creation of an additional loop. Circular products have been identified by polyacrylamide gel electrophoresis, enzymatic digestion with exonuclease VII and electrospray mass spectrometry in negative ion mode. Optimum pH for the ligation reaction of the human telomere sequence ranges from 4.5 to 6.0. Several buffers were also examined, with MES yielding the greatest ligation efficiency. Human telomere sequences with two phosphate groups, one each at the 3' and 5' ends, were more efficient at ligation, via pyrophosphate bond formation, than the corresponding sequences with only one phosphate group, at the 5' end. Circular dichroism spectra showed that the ligation product was derived from an antiparallel, single-stranded guanine quadruplex rather than a parallel single-stranded guanine quadruplex structure.},
}
@article {pmid15932060,
year = {2005},
author = {Spink, K and Ho, JC and Tanaka, K and Watts, FZ and Chambers, A},
title = {The telomere-binding protein Taz1p as a target for modification by a SUMO-1 homologue in fission yeast.},
journal = {Biochemical genetics},
volume = {43},
number = {3-4},
pages = {103-117},
doi = {10.1007/s10528-005-1503-4},
pmid = {15932060},
issn = {0006-2928},
mesh = {Repressor Proteins/*metabolism ; Schizosaccharomyces/genetics/metabolism ; Schizosaccharomyces pombe Proteins/*metabolism ; Telomere-Binding Proteins/*metabolism ; Two-Hybrid System Techniques ; Ubiquitin-Activating Enzymes/*metabolism ; },
abstract = {In fission yeast (Schizosaccharomyces pombe) the homologue of the mammalian SUMO-1 ubiquitin-like modifier is encoded by the pmt3 gene. A two-hybrid screen using the telomere-binding protein Taz1p as bait identified Pmt3p as an interacting factor. In vitro experiments using purified components of the fission yeast Pmt3p modification system demonstrated that Taz1p could be modified directly by Pmt3p. The amino acid sequence of Taz1p contains a close match to the consensus modification site for SUMO-1, and a PEST sequence similar to those found in established SUMO-1 targets. Although previous experiments have identified an increase in telomere length as one consequence of the pmt3--genotype, we could not detect Pmt3p modification of Taz1p in protein extracts made from exponentially growing haploid cells or any effect of Pmt3p on the localization of GFP-Taz1p at discrete foci in the haploid cell nucleus.},
}
@article {pmid15931759,
year = {2005},
author = {Sun, HW and Gao, CR},
title = {[The application of telomere DNA in age estimation of forensic medicine].},
journal = {Fa yi xue za zhi},
volume = {21},
number = {2},
pages = {155-158},
pmid = {15931759},
issn = {1004-5619},
mesh = {Adolescent ; Adult ; Aging/*physiology ; Blotting, Southern/methods ; Cell Division/physiology ; DNA/*analysis ; Forensic Medicine/*methods ; Humans ; Polymorphism, Restriction Fragment Length ; Telomere/genetics/*physiology ; },
abstract = {Estimating tooth age and skeletal age are the two primary methods in age estimation of forensic medicine. But they are often impacted with geographical environment, nutrition, habitation and ethenologic differences, so the accuracy will be reduced, especially to the adult. With the study of telomere, it is certain that the length of the telomere DNA can reflect the cell division and represent the cell lifespan, and it has some pertinence to the age of the donor, so to measure the length of telomere DNA is a new and valuable method for age estimation in the forensic medicine.},
}
@article {pmid15923618,
year = {2005},
author = {Li, B and Espinal, A and Cross, GA},
title = {Trypanosome telomeres are protected by a homologue of mammalian TRF2.},
journal = {Molecular and cellular biology},
volume = {25},
number = {12},
pages = {5011-5021},
pmid = {15923618},
issn = {0270-7306},
support = {R01 AI050614/AI/NIAID NIH HHS/United States ; AI50614/AI/NIAID NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Cell Cycle/physiology ; Humans ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Protein Binding ; Protein Isoforms/genetics/*metabolism ; RNA Interference ; Recombinant Fusion Proteins/genetics/metabolism ; Sequence Alignment ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/*metabolism ; Trypanosoma/*genetics/metabolism ; },
abstract = {Putative TTAGGG repeat-binding factor (TRF) homologues in the genomes of Trypanosoma brucei, Trypanosoma cruzi, and Leishmania major were identified. They have significant sequence similarity to higher eukaryotic TRFs in their C-terminal DNA-binding myb domains but only weak similarity in their N-terminal domains. T. brucei TRF (tbTRF) is essential and was shown to bind to duplex TTAGGG repeats. The RNA interference-mediated knockdown of tbTRF arrested bloodstream cells at G(2)/M and procyclic cells partly at S phase. Functionally, tbTRF resembles mammalian TRF2 more than TRF1, as knockdown diminished telomere single-stranded G-overhang signals. This suggests that tbTRF, like vertebrate TRF2, is essential for telomere end protection, and this also supports the hypothesis that TRF rather than Rap1 is the more ancient DNA-binding component of the telomere protein complex. Identification of the first T. brucei telomere DNA-binding protein and characterization of its function provide a new route to explore the roles of telomeres in pathogenesis of this organism. This work also establishes T. brucei as an attractive model for telomere biology.},
}
@article {pmid15922726,
year = {2005},
author = {Quina, AS and Parreira, L},
title = {Telomere-surrounding regions are transcription-permissive 3D nuclear compartments in human cells.},
journal = {Experimental cell research},
volume = {307},
number = {1},
pages = {52-64},
doi = {10.1016/j.yexcr.2005.02.025},
pmid = {15922726},
issn = {0014-4827},
mesh = {Bromodeoxyuridine/metabolism ; Cell Nucleus/*genetics ; Cells, Cultured ; Centromere/genetics ; Humans ; *Imaging, Three-Dimensional ; Leukocytes, Mononuclear/*cytology/drug effects ; Microscopy, Confocal ; Phytohemagglutinins/pharmacology ; Resting Phase, Cell Cycle ; Telomere/*genetics ; *Transcription, Genetic ; },
abstract = {Positioning of genes relative to nuclear heterochromatic compartments is thought to help regulate their transcriptional activity. Given that human subtelomeric regions are rich in highly expressed genes, we asked whether human telomeres are related to transcription-permissive nuclear compartments. To address this question, we investigated in the nuclei of normal human lymphocytes the spatial relations of two constitutively expressed genes (ACTB and RARA) and three nuclear transcripts (ACTB, IL2RA and TCRB) to telomeres and centromeres, as a function of gene activity and transcription levels. We observed that genes and gene transcripts locate close to telomere clusters and away from chromocenters upon activation of transcription. These findings, together with the observation that SC35 domains, which are enriched in pre-mRNA processing factors, are in close proximity to telomeres, indicate that telomere-neighboring regions are permissive to gene expression in human cells. Therefore, the associations of telomeres observed in the interphase nucleus might contribute, as opposed to chromocenters, for the establishment of transcription-permissive 3D nuclear compartments.},
}
@article {pmid15922407,
year = {2005},
author = {Swanberg, SE and Delany, ME},
title = {Differential expression of genes associated with telomere length homeostasis and oncogenesis in an avian model.},
journal = {Mechanisms of ageing and development},
volume = {126},
number = {10},
pages = {1060-1070},
doi = {10.1016/j.mad.2005.03.022},
pmid = {15922407},
issn = {0047-6374},
mesh = {Animals ; Cell Line, Transformed ; Cellular Senescence/*physiology ; Chick Embryo ; Fibroblasts/cytology/*metabolism ; Gastrula/cytology/*physiology ; Pluripotent Stem Cells/cytology/*physiology ; RNA, Messenger/biosynthesis/genetics ; Telomere/*genetics/metabolism ; Up-Regulation/*physiology ; },
abstract = {Telomere-binding proteins, their interaction partners and transcription factors play a prominent role in telomere maintenance and telomerase activation. We examined mRNA expression levels of tankyrase 1 and 2, TRF1 and 2, c-myc, TERT and TR in Gallus domesticus, the domestic chicken, by quantitative real-time PCR, establishing expression profiles for three contrasting cell systems: the pluripotent gastrula, differentiated embryo fibroblasts and transformed DT40 cells. All seven genes were up-regulated in DT40 cells compared to telomerase-negative CEFs and a majority of the genes were also up-regulated in the gastrula relative to CEFs. Surprisingly, we found TERT and TR transcripts in CEFs, albeit at low levels. TRF1 was down-regulated in the six CEF cultures by the time of culture growth arrest. A marked increase in the TRF2:TRF1 ratio occurred at or near senescence in all of the CEF cultures studied, with the most elevated ratio found in a short-lived culture in which TRF1 mRNA levels decreased two-fold and TRF2 levels increased 21-fold. This culture also showed highly reduced, degraded telomeres by Southern blot analysis. These data suggest that genes involved in telomere maintenance and telomerase induction are expressed differentially in pluripotent, differentiated and transformed cell systems.},
}
@article {pmid15919587,
year = {2005},
author = {Baird, DM},
title = {New developments in telomere length analysis.},
journal = {Experimental gerontology},
volume = {40},
number = {5},
pages = {363-368},
doi = {10.1016/j.exger.2005.02.008},
pmid = {15919587},
issn = {0531-5565},
mesh = {Base Sequence ; DNA/genetics ; Humans ; In Situ Hybridization, Fluorescence/methods ; Polymerase Chain Reaction/methods ; Restriction Mapping/methods ; Telomere/*genetics ; },
abstract = {Telomeres provide an essential 'capping' function, which prevents the natural end of a chromosome from being recognised as a simple dsDNA break. The biology of human telomeres is inextricably linked with both cancer and ageing. As such there is considerable interest in determining the length of these essential and dynamic structures. Here I review, from the standpoint of ageing research in humans, the current situation with regards to technologies available to determine telomere length in human cells and tissues.},
}
@article {pmid15917226,
year = {2005},
author = {Kobryn, K and Burgin, AB and Chaconas, G},
title = {Uncoupling the chemical steps of telomere resolution by ResT.},
journal = {The Journal of biological chemistry},
volume = {280},
number = {29},
pages = {26788-26795},
doi = {10.1074/jbc.M504530200},
pmid = {15917226},
issn = {0021-9258},
mesh = {Bacterial Proteins/*genetics ; Binding Sites ; Borrelia burgdorferi/*enzymology ; DNA Replication ; Endodeoxyribonucleases/*genetics ; Nucleic Acid Conformation ; Recombinases/genetics ; Replicon ; Telomere/chemistry/*metabolism ; },
abstract = {ResT is the telomere resolvase of the spirochete Borrelia burgdorferi, the causative agent of Lyme disease. ResT is an essential cellular function that processes replication intermediates to produce linear replicons terminated by covalently closed hairpin telomeres. ResT generates these hairpin telomeres in a reaction with mechanistic similarities to those catalyzed by type IB topoisomerases and tyrosine recombinases. We report here, that like most of the tyrosine recombinases, ResT requires interprotomer communication, likely in an in-line synapse, to activate reaction chemistry. Unlike the tyrosine recombinases, however, we infer that the cleavage and strand transfer reactions on the two sides of the replicated telomere occur nearly simultaneously. Nonetheless, the chemical steps of the forward and reverse reactions performed by ResT can occur in a non-concerted fashion (i.e. events on the two sides of the replicated telomere can occur independently). We propose that uncoupling of reaction completion on the two sides of the substrate is facilitated by an early commitment to hairpin formation that is imposed by the precleavage action of the hairpin binding module of the ResT active site.},
}
@article {pmid15917199,
year = {2005},
author = {Marrone, A and Walne, A and Dokal, I},
title = {Dyskeratosis congenita: telomerase, telomeres and anticipation.},
journal = {Current opinion in genetics &amp; development},
volume = {15},
number = {3},
pages = {249-257},
doi = {10.1016/j.gde.2005.04.004},
pmid = {15917199},
issn = {0959-437X},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Anticipation, Genetic/*genetics ; Dyskeratosis Congenita/*enzymology/*genetics ; Humans ; Mutation/genetics ; Telomerase/*metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {Dyskeratosis congenita (DC) is a rare bone marrow failure syndrome that displays marked clinical and genetic heterogeneity. The identification of dyskeratosis congenita gene 1 (DKC1) mutations in X-linked recessive patients initially suggested that DC is a defective pseudouridylation disorder. The subsequent identification of mutations in the telomerase RNA component (TERC) of autosomal dominant DC patients together with the discovery that both TERC and the DKC1-encoded protein, dyskerin, are closely associated in the telomerase complex have suggested that the pathophysiology of DC predominantly relates to defective telomere maintenance. Recent discoveries have shown that autosomal dominant DC exhibits disease anticipation and that this is associated with progressive telomere shortening owing to the haplo-insufficiency of TERC.},
}
@article {pmid15911975,
year = {2005},
author = {Kiyozuka, Y},
title = {Correlation of telomerase activity and telomere length to chemosensitivity.},
journal = {Methods in molecular medicine},
volume = {111},
number = {},
pages = {97-108},
doi = {10.1385/1-59259-889-7:097},
pmid = {15911975},
issn = {1543-1894},
mesh = {Actins/metabolism ; Animals ; Antineoplastic Agents/*pharmacology ; Blotting, Southern ; Cell Line, Tumor ; *Drug Screening Assays, Antitumor ; Humans ; Mice ; Neoplasms/*drug therapy/*enzymology/pathology ; Oligonucleotides/chemistry ; Polymerase Chain Reaction ; RNA/chemistry ; Telomerase/*metabolism ; Telomere/*ultrastructure ; Time Factors ; Ultraviolet Rays ; },
abstract = {Telomerase, which is selectively expressed in germline or cancer cells, is a ribonucleoprotein polymerase that contains an integral RNA with a short template element that can compensate telomeric loss by synthesizing TTAGGG repeats at chromosome ends. Telomeres appear to be critical for the integrity of chromosomes, stabilizing them from exonucleolytic degradation, preventing chromosome-to-chromosome fusions, and determining the maximum replicative capacity of cells. During the past decade, the roles of telomere length and telomerase activity have been investigated extensively in a variety of benign and malignant tumors of human origin, and stronger telomerase activity has been observed in more advanced tumors. Generally, the acquisition of telomerase activity in cancer cells is rather universal, which suggests that telomerase inhibition as a novel and potentially selective target for therapeutic intervention. Although a telomerase-specific inhibitor has not been found yet, the possible effect of anticancer agents on telomerase inhibition or the alteration of telomere length has been proposed. Recent development of TRAP assay not only increased the sensitivity but also allowed fast and efficient detection of telomerase activity. Technical aspects of this assay using self-established internal standard and nonradioisotopic detection method are addressed in this report. In addition, an overview of how to determine the telomere length is described.},
}
@article {pmid15905643,
year = {2005},
author = {Al-Wahiby, S and Slijepcevic, P},
title = {Chromosomal aberrations involving telomeres in BRCA1 deficient human and mouse cell lines.},
journal = {Cytogenetic and genome research},
volume = {109},
number = {4},
pages = {491-496},
doi = {10.1159/000084208},
pmid = {15905643},
issn = {1424-859X},
mesh = {Animals ; BRCA1 Protein/*deficiency/genetics ; Bleomycin/pharmacology ; Breast Neoplasms/enzymology/genetics/metabolism ; Cell Line ; Cell Line, Tumor ; *Chromosome Aberrations ; Cytogenetic Analysis ; Embryo, Mammalian/cytology ; Epithelial Cells/chemistry/drug effects/enzymology/metabolism ; Humans ; In Situ Hybridization, Fluorescence/methods ; Lymphocytes/chemistry/drug effects/enzymology/metabolism ; Metaphase/genetics ; Mice ; Mutation/genetics ; Stem Cells/chemistry/metabolism ; Telomerase/metabolism ; Telomere/*genetics ; },
abstract = {Cells defective in BRCA1 show genomic instability as evidenced by increased radiosensitivity, the presence of chromosomal abnormalities and the loss of heterozygosity at many loci. Reported chromosomal abnormalities in BRCA1 deficient cells include dicentric chromosomes. Dicentric chromosomes, in some cases, may arise as a result of end-to-end chromosome fusions, which represent signatures of telomere dysfunction. In this study we examined BRCA1 deficient human and mouse cells for the presence of chromosomal aberrations indicative of telomere dysfunction. We identified a lymphoblastoid cell line, GM14090, established from a BRCA1 carrier that showed elevated levels of dicentric chromosomes. Molecular cytogenetic analysis revealed that these dicentric chromosomes result from end-to-end chromosome fusions. The frequency of end-to-end chromosome fusions did not change after exposure of GM14090 cells to bleomycin but we observed elevated levels of chromosomal abnormalities involving interactions between DNA double strand breaks and uncapped telomeres in this cell line. We observed similar chromosomal abnormalities involving telomeres in the breast cancer cell line, HCC1937, homozygous for BRCA1 mutation. Finally, we analyzed mouse embryonic stem cells lacking functional Brca1 and observed the presence of telomere dysfunction following exposure of these cells to bleomycin. Our results reveal cytogenetic evidence of telomere dysfunction in BRCA1 deficient cells.},
}
@article {pmid15905204,
year = {2005},
author = {Gu, J and Spitz, MR and Zhao, H and Lin, J and Grossman, HB and Dinney, CP and Wu, X},
title = {Roles of tumor suppressor and telomere maintenance genes in cancer and aging--an epidemiological study.},
journal = {Carcinogenesis},
volume = {26},
number = {10},
pages = {1741-1747},
doi = {10.1093/carcin/bgi126},
pmid = {15905204},
issn = {0143-3334},
support = {CA 74880/CA/NCI NIH HHS/United States ; CA 91846/CA/NCI NIH HHS/United States ; },
mesh = {Aged ; Aging/*physiology ; DNA-Binding Proteins/genetics ; *Genes, Tumor Suppressor ; Genes, p53 ; Humans ; Incidence ; Middle Aged ; RNA, Messenger/genetics ; Telomerase/genetics ; Telomere/*genetics ; Telomeric Repeat Binding Protein 2/genetics ; Urinary Bladder Neoplasms/epidemiology/*genetics ; },
abstract = {Advanced age is strikingly linked to increased incidence of cancer. To gain insight into the mechanism underlying the association between increased cancer incidence and aging in normal human physiological conditions, we used a case-control design and measured the mRNA expression levels of p53, ATM, hTERT and TRF2, the four major protectors of genomic integrity, in isolated peripheral blood lymphocytes from 202 confirmed bladder cancer (BC) patients and 199 healthy controls. Significant age effects on expression levels were observed. When we divided the study subjects into three age groups (<57, 57-65 and > or = 65), the expressions of p53, ATM and TRF2 significantly decreased with advancing age in cases (P for trend < or = 0.001, 0.01 and 0.01 for p53, ATM and TRF2, respectively). In controls, however, p53 expression significantly increased with advancing age (P for trend = 0.05). Among subjects > or = 65 years of age, the expressions of p53, ATM and TRF2 were significantly lower in cases than in controls (P = 0.003, 0.04 and 0.05 for p53, ATM and TRF2, respectively), suggesting that attenuated genomic maintenance mechanisms lead to increased cancer risk in older individuals. When we dichotomized our study population at the median age of study subjects (61 years old), low p53 expression was associated with a significantly increased BC risk in older people (OR = 2.27, 95% CI = 1.00-5.16). In addition, older subjects without detectable hTERT expression had a significantly reduced BC risk (OR = 0.41, 95% CI = 0.17-0.99). Our study provides the first epidemiologic evidence that the increased genomic instability resulting from the combination of telomere dysfunction, impaired ATM- and p53-mediated DNA damage, and/or telomere dysfunction response pathway contributes to increased cancer incidence in the elderly population.},
}
@article {pmid15904916,
year = {2005},
author = {Zhang, Y and Cao, EH and Qin, JF},
title = {Up-regulation of telomere-binding TRF1, TRF2 related to reactive oxygen species induced by As(2)O(3) in MGC-803 cells.},
journal = {European journal of pharmacology},
volume = {516},
number = {1},
pages = {1-9},
doi = {10.1016/j.ejphar.2005.04.022},
pmid = {15904916},
issn = {0014-2999},
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Blotting, Western ; Cell Cycle/drug effects ; Cell Division/drug effects ; Cell Line, Tumor ; Deoxyguanosine/analogs &amp; derivatives/biosynthesis ; Flow Cytometry ; G2 Phase/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Microscopy, Atomic Force ; Oxides/*pharmacology ; Protein Binding/drug effects ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/genetics/metabolism ; Telomeric Repeat Binding Protein 1/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/*genetics/metabolism ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation ; },
abstract = {In this work, our study focused on As(2)O(3) action in view point of telomere. Results showed that treatment of human gastric cancer MGC-803 cells with arsenic trioxide could cause up-regulation of telomeric repeat binding factor TRF1 and TRF2 mRNA and protein levels, and induced G2/M phase arrest and cell apoptosis. At the same time, telomere length shortening and telomerase inhibitory were not obvious. Flow cytometry measurements indicated that the increase of TRF1 and TRF2 proteins is related to oxidative stress by arsenic trioxide. Results also indicate that after arsenic trioxide treatment, p53 protein levels increased significantly and also could bind directly at the telomere t-loop junction. These findings demonstrate arsenic trioxide-induced cell cycle arrest and apoptosis might involve a novel pathway related to TRF1, TRF2 protein.},
}
@article {pmid15899847,
year = {2005},
author = {Groff-Vindman, C and Cesare, AJ and Natarajan, S and Griffith, JD and McEachern, MJ},
title = {Recombination at long mutant telomeres produces tiny single- and double-stranded telomeric circles.},
journal = {Molecular and cellular biology},
volume = {25},
number = {11},
pages = {4406-4412},
pmid = {15899847},
issn = {0270-7306},
support = {5T32GMOO/GM/NIGMS NIH HHS/United States ; CGM61645/GM/NIGMS NIH HHS/United States ; GM10330/GM/NIGMS NIH HHS/United States ; GM31819/GM/NIGMS NIH HHS/United States ; R01 GM031819/GM/NIGMS NIH HHS/United States ; R01 GM061645/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes, Fungal/metabolism ; DNA/metabolism/ultrastructure ; DNA Replication ; DNA, Circular/*metabolism/ultrastructure ; DNA, Fungal/*metabolism/ultrastructure ; Kluyveromyces/*genetics ; Mutation ; RNA/*genetics ; *Recombination, Genetic ; Telomerase/*genetics ; Telomere/genetics/*metabolism ; },
abstract = {Recombinational telomere elongation (RTE) known as alternate lengthening of telomeres is the mechanism of telomere maintenance in up to 5 to 10% of human cancers. The telomeres of yeast mutants lacking telomerase can also be maintained by recombination. Previously, we proposed the roll-and-spread model to explain this elongation in the yeast Kluveromyces lactis. This model suggests that a very small (approximately 100-bp) circular molecule of telomeric DNA is copied by a rolling circle event to generate a single long telomere. The sequence of this primary elongated telomere is then spread by recombination to all remaining telomeres. Here we show by two-dimensional gel analysis and electron microscopy that small circles of single- and double-stranded telomeric DNA are commonly made by recombination in a K. lactis mutant with long telomeres. These circles were found to be especially abundant between 100 and 400 bp (or nucleotides). Interestingly, the single-stranded circles consist of only the G-rich telomeric strand sequence. To our knowledge this is the first report of single-stranded telomeric circles as a product of telomere dysfunction. We propose that the small telomeric circles form through the resolution of an intratelomeric strand invasion which resembles a t-loop. Our data reported here demonstrate that K. lactis can, in at least some circumstances, make telomeric circles of the very small sizes predicted by the roll-and-spread model. The very small circles seen here are both predicted products of telomere rapid deletion, a process observed in both human and yeast cells, and predicted templates for roll-and-spread RTE.},
}
@article {pmid15893973,
year = {2005},
author = {Tanemura, K and Ogura, A and Cheong, C and Gotoh, H and Matsumoto, K and Sato, E and Hayashi, Y and Lee, HW and Kondo, T},
title = {Dynamic rearrangement of telomeres during spermatogenesis in mice.},
journal = {Developmental biology},
volume = {281},
number = {2},
pages = {196-207},
doi = {10.1016/j.ydbio.2005.02.025},
pmid = {15893973},
issn = {0012-1606},
mesh = {Animals ; Cell Nucleus/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Spermatogenesis/*physiology ; Telomerase/genetics/*metabolism ; Telomere/*physiology ; Testis/metabolism/ultrastructure ; },
abstract = {Chromosomal structure within the nucleus influences various biological processes such as transcription and replication. Telomeres are located at the end of eukaryotic chromosomes and they can be a decisive factor for correct chromosomal positioning. To gain new insight into telomere dynamics, we examined telomere length and positional changes during spermatogenesis using improved fluorescence in situ hybridization (FISH) and in situ telomeric repeat amplification protocols (TRAP) on histological sections. FISH revealed telomere length and chromosome position within nuclei change dynamically. Telomere extension occurred during spermiogenesis. In situ TRAP analysis verified elevated telomerase activity in elongating spermatids. Together, these data show that elongated spermatids have longer telomeres than precursor spermatogenic cells. This observation indicates that telomere elongation in haploid cells occurs after meiosis and in the absence of genomic replication. Analyses of testes from telomerase null mice further support the significance of telomere dynamics during spermatogenesis and the existence of an alternative telomere extension pathway.},
}
@article {pmid15888482,
year = {2005},
author = {Jeyapalan, JN and Varley, H and Foxon, JL and Pollock, RE and Jeffreys, AJ and Henson, JD and Reddel, RR and Royle, NJ},
title = {Activation of the ALT pathway for telomere maintenance can affect other sequences in the human genome.},
journal = {Human molecular genetics},
volume = {14},
number = {13},
pages = {1785-1794},
doi = {10.1093/hmg/ddi185},
pmid = {15888482},
issn = {0964-6906},
mesh = {Cell Line, Tumor ; *Genome, Human ; Humans ; *Minisatellite Repeats/genetics ; *Mutation ; Quantitative Trait Loci ; Recombination, Genetic/genetics ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Immortal human cells maintain telomere length by the expression of telomerase or through the alternative lengthening of telomeres (ALT). The ALT mechanism involves a recombination-like process that allows the rapid elongation of shortened telomeres. However, it is not known whether activation of the ALT pathway affects other sequences in the genome. To address this we have investigated, in ALT-expressing cell lines and tumours, the stability of tandem repeat sequences known to mutate via homologous recombination in the human germline. We have shown extraordinary somatic instability in the human minisatellite MS32 (D1S8) in ALT-expressing (ALT+) but not in normal or telomerase-expressing cell lines. The MS32 mutation frequency varied across 15 ALT+ cell lines and was on average 55-fold greater than in ALT- cell lines. The MS32 minisatellite was also highly unstable in three of eight ALT+ soft tissue sarcomas, indicating that somatic destabilization occurs in vivo. The MS32 mutation rates estimated for two ALT+ cell lines were similar to that seen in the germline. However, the internal structures of ALT and germline mutant alleles are very different, indicating differences in the underlying mutation mechanisms. Five other hypervariable minisatellites did not show elevated instability in ALT-expressing cell lines, indicating that minisatellite destabilization is not universal. The elevation of MS32 instability upon activation of the ALT pathway and telomere length maintenance suggests there is overlap between the underlying processes that may be tractable through analysis of the D1S8 locus.},
}
@article {pmid15888323,
year = {2005},
author = {Forsyth, NR and Elder, FF and Shay, JW and Wright, WE},
title = {Lagomorphs (rabbits, pikas and hares) do not use telomere-directed replicative aging in vitro.},
journal = {Mechanisms of ageing and development},
volume = {126},
number = {6-7},
pages = {685-691},
doi = {10.1016/j.mad.2005.01.003},
pmid = {15888323},
issn = {0047-6374},
support = {AG01228/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; Cellular Senescence/*physiology ; Hares/physiology ; Rabbits ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomere shortening is used for replicative aging in primates and ungulates but not rodents. We examined telomere biology in rabbits to expand the comparative biology of telomere-directed replicative senescence within mammals. The order Lagomorpha consists of two families; Leporidae and Ochotonidae. We examined telomere biology in species representing three leporid genera (European White Rabbit, Black-tailed Jack Rabbit, and Swamp Rabbit) and the monotypic ochotonid genus (North American Pika). Of the leporids one species was a laboratory strain and the others were wild caught. The leporids neither exhibited cellular senescence after sustained periods in culture nor displayed detectable telomerase activity. Continued culture was possible because of their extremely long telomeric arrays. Immunofluorescence showed robust telomere signals at chromosome ends and significant internal chromosomal staining in some instances. Pika was unique in displaying endogenous telomerase activity throughout time in culture. These results show that it is unlikely that lagomorphs use telomere shortening and replicative senescence as a tumor protective mechanism.},
}
@article {pmid15885185,
year = {2005},
author = {Kahn, A},
title = {[Telomeres, diseases and aging].},
journal = {Medecine sciences : M/S},
volume = {21},
number = {5},
pages = {451-452},
doi = {10.1051/medsci/2005215451},
pmid = {15885185},
issn = {0767-0974},
mesh = {Aging/*genetics ; Animals ; Genetic Diseases, Inborn/*genetics ; Humans ; Telomere/*genetics ; },
}
@article {pmid15882348,
year = {2005},
author = {Hathcock, KS and Jeffrey Chiang, Y and Hodes, RJ},
title = {In vivo regulation of telomerase activity and telomere length.},
journal = {Immunological reviews},
volume = {205},
number = {},
pages = {104-113},
doi = {10.1111/j.0105-2896.2005.00267.x},
pmid = {15882348},
issn = {0105-2896},
mesh = {Animals ; Cellular Senescence ; Humans ; Receptors, Antigen, T-Cell/genetics/immunology ; T-Lymphocytes/*immunology/*metabolism ; Telomerase/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres are specialized DNA-protein structures found at the ends of all linear chromosomes. In mammalian cells, they consist of hexanucleotide (TTAGGG) repeats and multiple associated proteins. Telomeres protect the ends of chromosomes and prevent their recognition as DNA breaks. Loss of functional telomere length below a critical threshold can activate programs leading to cell senescence or death. Telomere length represents a balance between the loss of terminal telomeric repeats, which occurs during cell division with incomplete DNA replication, and the addition of telomeric repeats by the unique RNA-dependent DNA polymerase telomerase. Although most somatic cells do not express telomerase, telomerase is induced in lymphocytes at critical stages of development and activation. Telomerase expression thus may prolong the replicative capacity of lymphocytes and thereby enhance their function in immune responses. We have used murine model systems to address two broadly defined questions about lymphocyte telomere biology: how is telomerase physiologically regulated in T cells responding to antigen challenge, and what is the effect of transcriptionally altered telomerase expression on telomere length and, consequently, on immune function?},
}
@article {pmid15878333,
year = {2005},
author = {Hartmann, N and Scherthan, H},
title = {Characterization of the telomere complex, TERF1 and TERF2 genes in muntjac species with fusion karyotypes.},
journal = {Experimental cell research},
volume = {306},
number = {1},
pages = {64-74},
doi = {10.1016/j.yexcr.2005.02.001},
pmid = {15878333},
issn = {0014-4827},
mesh = {Alternative Splicing/genetics ; Amino Acid Sequence ; Animals ; Chromosomes, Mammalian/genetics ; Cloning, Molecular ; DNA, Complementary/chemistry/genetics ; Gene Expression/genetics ; Humans ; Karyotyping ; Mice ; Molecular Sequence Data ; Muntjacs/*genetics/metabolism ; Nuclear Proteins/genetics/metabolism ; Protein Isoforms/genetics ; Sequence Alignment ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; Telomerase/genetics ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/*genetics/metabolism ; },
abstract = {The telomere binding proteins TRF1 and TRF2 maintain and protect chromosome ends and confer karyotypic stability. Chromosome evolution in the genus Muntiacus is characterized by numerous tandem (end-to-end) fusions. To study TRF1 and TRF2 telomere binding proteins in Muntiacus species, we isolated and characterized the TERF1 and -2 genes from Indian muntjac (Muntiacus muntjak vaginalis; 2n = 6 female) and from Chinese muntjac (Muntiacus reveesi; 2n = 46). Expression analysis revealed that both genes are ubiquitously expressed and sequence analysis identified several transcript variants of both TERF genes. Control experiments disclosed a novel testis-specific splice variant of TERF1 in human testes. Amino acid sequence comparisons demonstrate that Muntiacus TRF1 and in particular TRF2 are highly conserved between muntjac and human. In vivo TRF2-GFP and immuno-staining studies in muntjac cell lines revealed telomeric TRF2 localization, while deletion of the DNA binding domain abrogated this localization, suggesting muntjac TRF2 represents a functional telomere protein. Finally, expression analysis of a set of telomere-related genes revealed their presence in muntjac fibroblasts and testis tissue, which suggests the presence of a conserved telomere complex in muntjacs. However, a deviation from the common theme was noted for the TERT gene, encoding the catalytic subunit of telomerase; TERT expression could not be detected in Indian or Chinese muntjac cDNA or genomic DNA using a series of conserved primers, while TRAP assay revealed functional telomerase in Chinese muntjac testis tissues. This suggests muntjacs may harbor a diverged telomerase sequence.},
}
@article {pmid15870889,
year = {2005},
author = {Wick, U and Gebhart, E},
title = {Are telomeres a specific target for mutagenic attack by cytostatics in neoplastic cells?.},
journal = {International journal of oncology},
volume = {26},
number = {6},
pages = {1707-1713},
doi = {10.3892/ijo.26.6.1707},
pmid = {15870889},
issn = {1019-6439},
mesh = {Bleomycin/toxicity ; Cell Cycle ; Cell Line, Tumor ; DNA Damage ; Humans ; Mitomycin/toxicity ; Mutagens/*toxicity ; Telomerase/antagonists &amp; inhibitors/metabolism ; Telomere/*drug effects ; },
abstract = {Damage to telomeres induced by cytostatic therapy theoretically could generate telomere shortening and, subsequently, induce an additional genomic instability in neoplastic cells. Model experiments were carried out to examine this hypothesis. Cells of the T-ALL derived cell line CCRF-CEM were exposed to various different concentrations of Bleomycin (BLM) or Mitomycin C (MMC) for various times. Telomere lengths of metaphase chromosomes of the exposed cells were compared with those without this exposure (controls). In addition, telomerase activity was determined with a TRAP assay under the given conditions using the BLM experiments as a model. Although slight changes of total telomere length could be found in single experiments, the differences between exposed and non-exposed cells were not significant. Also, a considerable telomerase activity was shown which, however, did not substantially differ between exposed and non-exposed cells. From these data it may be concluded that, at least in the examined cell line, telomeres are not a preferential target for this kind of mutagenic attack.},
}
@article {pmid15868944,
year = {2005},
author = {Derradji, H and Bekaert, S and Van Oostveldt, P and Baatout, S},
title = {Comparison of different protocols for telomere length estimation by combination of quantitative fluorescence in situ hybridization (Q-FISH) and flow cytometry in human cancer cell lines.},
journal = {Anticancer research},
volume = {25},
number = {2A},
pages = {1039-1050},
pmid = {15868944},
issn = {0250-7005},
mesh = {Blotting, Southern ; Cell Cycle/physiology ; Cell Line, Tumor ; Fixatives ; Flow Cytometry ; Humans ; In Situ Hybridization, Fluorescence ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*genetics/pathology ; Multiple Myeloma/*genetics/pathology/ultrastructure ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: The end of eukaryotic chromosomes terminates with nucleoprotein structures called telomeres. They insure several functions including capping the end of the chromosomes, ensuring their stability and protecting them from end-to-end fusion and preventing the activation of the DNA damage checkpoints.<br><br>MATERIALS AND METHODS: A flow-FISH methodology, i.e. quantitative fluorescence in situ hybridization (Q-FISH) in combination with flow cytometry, has been developed in our laboratory in order to estimate telomere length in three human cancer cell lines: K-562 (chronic myelogenous leukaemia), IM-9 (multiple myeloma) and 1301 (T cell lymphoblastic leukaemia). Telomeres were visualised after hybridisation with FITC-labelled PNA (Peptide Nucleic Acid) probes. We evaluated the most critical steps of the flow-FISH protocol to ensure reproducibility. Different methodological set ups were compared. Three fixation procedures (ethanol 80%, methanol 80% and formaldehyde 4%) were tested besides different fixation times (15 min and 60 min) as well as hybridization times (2 h and overnight). For each of these protocols the following parameters were compared: forward scatter (related to the cell size), side scatter (related to the cell granularity), DNA (FL3 and FL4 fluorescence) and PNA content (FL1 fluorescence) using an EPICS XL flow cytometer.<br><br>RESULTS: Regarding the fixation procedures, methanol proved to be the best, followed by ethanol and formaldehyde, with respect to the efficiency to measure the different parameters cited above. Indeed, fixation using methanol gave the optimal PNA signal compared to using ethanol and formaldehyde in two of the studied cell lines (K-562 and 1301); the difference observed was highly significant in the 1301 cell line. The duration of fixation did not show significant interference in the reproducibility of the results for the three cell lines studied. An overnight hybridization appeared to be more effective when compared to the 2-h hybridization in the case of the K-562 cell line.<br><br>CONCLUSION: The most important steps of the flow-FISH technique, namely the fixative procedure, as well as the hybridization and the fixation times, were investigated. Considering the latter, suitable protocols were set up for routine and fast telomere length estimation in the cancer cell lines.},
}
@article {pmid15868185,
year = {2005},
author = {Aydos, SE and Elhan, AH and Tükün, A},
title = {Is telomere length one of the determinants of reproductive life span?.},
journal = {Archives of gynecology and obstetrics},
volume = {272},
number = {2},
pages = {113-116},
doi = {10.1007/s00404-004-0690-2},
pmid = {15868185},
issn = {0932-0067},
mesh = {DNA/genetics ; Female ; Fertility/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Menopause/*genetics ; Middle Aged ; Statistics, Nonparametric ; Telomere/genetics/*physiology ; },
abstract = {The mechanism of final cessation of the reproductive life span has not been solved yet. It is generally assumed that the most important factor is ovarian follicular reserve. In ovaries at intrauterine period, a major factor that determines the number of the primordial follicle is the mitotic ability as well as the number of primordial germ cells, which migrate to gonadal ridge. The telomere length is one factor that determines the number of mitosis of the cell. The differences between the telomere lengths of same aged healthy women reflect the difference of the telomeres of the primordial germ cells at the intrauterine period. Women with long telomeres supposedly have had their primordial germ cells at the beginning of life with long telomeres. So, these cells should have had more mitotic division and more follicle numbers in the ovaries than the short ones. The aim of this study was to analyse the relation of the reproductive life span and telomere length. The telomere lengths of 37 women volunteers aged 50 years were measured by fiber FISH technique. A positive correlation was found between reproductive life span and the telomere length.},
}
@article {pmid15867339,
year = {2005},
author = {Shay, JW},
title = {Meeting report: the role of telomeres and telomerase in cancer.},
journal = {Cancer research},
volume = {65},
number = {9},
pages = {3513-3517},
doi = {10.1158/0008-5472.CAN-05-0728},
pmid = {15867339},
issn = {0008-5472},
mesh = {Animals ; Humans ; Neoplasms/*enzymology/*genetics ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {The role of telomeres and telomerase in cancer is an area of much recent interest. This conference sponsored by the American Association of Cancer Research provided a timely opportunity to bring together basic and clinical scientists interested in the field of telomeres and telomerase cancer biology. The meeting included over 250 attendees with 150 oral and poster presentations focused on understanding telomere and telomerase biology for the development of cancer therapeutics. The meeting chairpersons were Dr. Jerry W. Shay, University of Texas Southwestern Medical Center, Dallas, TX; Dr. Elizabeth H. Blackburn, University of California San Francisco, CA; and Dr. Maria A. Blasco, Spanish National Cancer Center, Madrid, Spain. The meeting provided an update on the field, pointing to areas in which our knowledge is deficient, and explored how the most promising areas may be advanced into translational research. This conference brought together cell and molecular biologists with clinicians interested in fundamental cancer mechanisms as they relate to telomeres and telomerase. The symposium consisted of formal presentations by prominent scientists working in these areas and by participants selected from submitted abstracts. In addition, there were two poster sessions. Whereas there were many basic research advances presented, the focus of this overview will be the areas of clinical advances.},
}
@article {pmid15865944,
year = {2005},
author = {Artandi, SE and Attardi, LD},
title = {Pathways connecting telomeres and p53 in senescence, apoptosis, and cancer.},
journal = {Biochemical and biophysical research communications},
volume = {331},
number = {3},
pages = {881-890},
doi = {10.1016/j.bbrc.2005.03.211},
pmid = {15865944},
issn = {0006-291X},
mesh = {Aging/*physiology ; Animals ; Apoptosis/*physiology ; Chromosomal Instability/physiology ; DNA Damage/physiology ; G1 Phase ; Genes, p53 ; Humans ; Mice ; Neoplasms/*physiopathology ; Signal Transduction ; Telomerase/physiology ; Telomere/*physiology ; Tumor Suppressor Protein p53/*physiology ; },
abstract = {The ends of eukaryotic chromosomes are protected by specialized structures termed telomeres that serve in part to prevent the chromosome end from activating a DNA damage response. However, this important function for telomeres in chromosome end protection can be lost as telomeres shorten with cell division in culture or in self-renewing tissues with advancing age. Impaired telomere function leads to induction of a DNA damage response and activation of the tumor suppressor protein p53. p53 serves a critical role in enforcing both senescence and apoptotic responses to dysfunctional telomeres. Loss of p53 creates a permissive environment in which critically short telomeres are inappropriately joined to generate chromosomal end-to-end fusions. These fused chromosomes result in cycles of chromosome fusion-bridge-breakage, which can fuel cancer initiation, especially in epithelial tissues, by facilitating changes in gene copy number.},
}
@article {pmid15863512,
year = {2005},
author = {Chen, YB and Yang, CP and Li, RX and Zeng, R and Zhou, JQ},
title = {Def1p is involved in telomere maintenance in budding yeast.},
journal = {The Journal of biological chemistry},
volume = {280},
number = {26},
pages = {24784-24791},
doi = {10.1074/jbc.M413562200},
pmid = {15863512},
issn = {0021-9258},
mesh = {Cellular Senescence ; Chromatography, Affinity ; Chromatography, Gel ; Chromosomal Proteins, Non-Histone/chemistry/*physiology ; DNA Damage ; DNA Helicases/metabolism ; Electrophoresis, Polyacrylamide Gel ; Gene Deletion ; Glutathione Transferase/metabolism ; Immunoprecipitation ; Mitochondria/metabolism ; Mutation ; Phenotype ; Plasmids/metabolism ; Protein Binding ; Recombinant Fusion Proteins/chemistry ; Recombinant Proteins/chemistry ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/chemistry/*physiology ; Telomerase/metabolism ; Telomere/*ultrastructure ; },
abstract = {Saccharomyces Rrm3p, a member of Pif1 5'-3' DNA helicase subfamily, helps replication forks traverse protein-DNA complexes, including the telomere. Here we have identified an Rrm3p interaction protein known to be Def1p. In def1 mutants, telomeres were approximately 200-bp shorter than that in wild-type cells. DEF1 is also required for the stable maintenance of mitochondrial DNA, and the telomere shortening phenotype seen in def1 cells is not a secondary consequence of the mitochondrion defect. A combination of DEF1 null mutation with deletion of EST2 or EST3 resulted in an accelerated senescence phenotype, suggesting that Def1p is not involved in the telomerase recruitment pathway. In the absence of telomerase, cells escape senescence by either amplifying Y' regions or TG-telomeric repeats to generate type I or type II survivors, respectively. Only type I survivors were recovered from both def1Delta est2Delta and def1Delta est3Delta double mutant cells, further suggesting that the function of Def1p in telomere maintenance is specific. Our novel findings of the functions of Def1p in telomere and mitochondria suggested that Def1p plays multiple roles in yeast.},
}
@article {pmid15862745,
year = {2005},
author = {Kelland, LR},
title = {Overcoming the immortality of tumour cells by telomere and telomerase based cancer therapeutics--current status and future prospects.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {41},
number = {7},
pages = {971-979},
doi = {10.1016/j.ejca.2004.11.024},
pmid = {15862745},
issn = {0959-8049},
mesh = {Cell Division/*drug effects ; DNA-Binding Proteins ; Enzyme Inhibitors/therapeutic use ; Forecasting ; Humans ; Neoplasms/*drug therapy/enzymology/pathology ; RNA/*antagonists &amp; inhibitors ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects ; },
abstract = {A key property of malignant tumours is their immortality or limitless replicative potential. Cell replication is associated with the maintenance of telomeres and in the great majority of cases, through the reactivation of the reverse transcriptase telomerase. Targeting the telomere/telomerase machinery offers a novel and potentially broad-spectrum anticancer therapeutic strategy since telomerase is constitutively overexpressed in the vast majority of human cancers. Telomeres are also critically short in most tumours compared to normal tissues. Strategies that exploit these differences include the direct targeting of components of telomerase: the protein component hTERT or RNA component hTR. Examples of such agents include the small molecule hTERT inhibitor BIBR1532 and GRN163L, a thio-phosphoramidate oligonucleotide targeting the template region of hTR as a "template antagonist". Anti-tumour effects have been observed in both cell lines and, especially for GRN163L, in xenografted human tumours in mice. Effects, however, are largely dependent upon initial telomere length, which can result in a substantial lag before antitumour activity is observed in tumours possessing relatively long telomeres. An alternative approach is to target the telomere itself (Telomere Targeting Agents, TTAs). Several classes of small molecules have been described that induce the G-rich single-stranded overhang of telomeric DNA to fold into 4-stranded G-quadruplex structures. Such folding is incompatible with telomerase function and may induce rapid telomere uncapping. These molecules have shown potent telomerase inhibition in nanomolar concentrations in vitro and the rapid induction of senescence in cancer cells. The trisubstituted acridine based TTA, BRACO19, has demonstrated single agent activity against human tumour xenografts with anti-tumour effects apparent from only 7 days of treatment. In the near future, it is expected that lead examples from both the direct telomerase targeted agents (e.g., GRN163L) and from the distinct class of those targeting telomeres (e.g., AS1410 based on BRACO19) will enter Phase I clinical trial where clinical benefit from this class of novel drugs will be determined.},
}
@article {pmid15862744,
year = {2005},
author = {D'Incalci, M and Zupi, G},
title = {Are we close to the clinical development of novel drugs targeting telomeres and telomerase?.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {41},
number = {7},
pages = {970},
doi = {10.1016/j.ejca.2005.02.006},
pmid = {15862744},
issn = {0959-8049},
mesh = {Drug Design ; Humans ; Neoplasms/*drug therapy/enzymology ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects ; },
}
@article {pmid15861380,
year = {2005},
author = {Miyoshi, D and Karimata, H and Sugimoto, N},
title = {Drastic effect of a single base difference between human and tetrahymena telomere sequences on their structures under molecular crowding conditions.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {44},
number = {24},
pages = {3740-3744},
doi = {10.1002/anie.200462667},
pmid = {15861380},
issn = {1433-7851},
mesh = {Animals ; Base Pairing ; Circular Dichroism ; Humans ; *Nucleic Acid Conformation ; *Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; Tetrahymena/*chemistry ; },
}
@article {pmid15860505,
year = {2005},
author = {Franco, S and Canela, A and Klatt, P and Blasco, MA},
title = {Effectors of mammalian telomere dysfunction: a comparative transcriptome analysis using mouse models.},
journal = {Carcinogenesis},
volume = {26},
number = {9},
pages = {1613-1626},
doi = {10.1093/carcin/bgi107},
pmid = {15860505},
issn = {0143-3334},
mesh = {Animals ; Antigens, Nuclear/*genetics ; DNA-Binding Proteins/deficiency/*genetics ; Gene Expression Regulation ; Ku Autoantigen ; Mice ; Mice, Knockout ; Models, Animal ; Oligonucleotide Array Sequence Analysis ; Reference Values ; Telomerase/*deficiency/genetics/*metabolism ; Telomere/*genetics ; *Transcription, Genetic ; },
abstract = {Critical telomere shortening in the absence of telomerase in late generation Terc-/- mice (G3 Terc-/-) or loss of telomere capping due to abrogation of the DNA repair/telomere binding protein Ku86 (Ku86-/- mice) results in telomere dysfunction and organismal premature aging. Here, we report on genome-wide transcription in mouse G3 Terc-/-, Ku86-/- and G3 Terc-/-/Ku86-/- germ cells using high-density oligonucleotide microarrays. Although a few transcripts are modulated specifically in Ku86- or Terc-deficient cells, the observed transcriptional response is mainly inductive and qualitatively similar for all three genotypes, with highest transcriptional induction observed in double mutant G3 Terc-/-/Ku86-/- cells compared with either single mutant. Analysis of 92 known genes induced in G3 Terc-/-/Ku86-/- germ cells compared with wild-type cells shows predominance of genes involved in cell adhesion, cell-to-cell and cell-to-matrix communication, as well as increased metabolic turnover and augmented antioxidant responses. In addition, the data presented in this study support the view that telomere dysfunction induces a robust compensatory response to rescue impaired germ cell function through the induction of survival signals related to the PI3-kinase pathway, as well as by the coordinated upregulation of transcripts that are essential for mammalian spermatogenesis.},
}
@article {pmid15857955,
year = {2005},
author = {Moriarty, TJ and Ward, RJ and Taboski, MA and Autexier, C},
title = {An anchor site-type defect in human telomerase that disrupts telomere length maintenance and cellular immortalization.},
journal = {Molecular biology of the cell},
volume = {16},
number = {7},
pages = {3152-3161},
pmid = {15857955},
issn = {1059-1524},
support = {54638//Canadian Institutes of Health Research/Canada ; },
mesh = {Amino Acid Motifs ; Catalysis ; Catalytic Domain ; Cell Line ; DNA/chemistry ; DNA Primers/chemistry ; Dose-Response Relationship, Drug ; Humans ; Immunoblotting ; Mutation ; Phenotype ; Promoter Regions, Genetic ; Protein Structure, Tertiary ; Retroviridae/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/genetics/*metabolism ; Telomere/ultrastructure ; Time Factors ; },
abstract = {Telomerase-mediated telomeric DNA synthesis is important for eukaryotic cell immortality. Telomerase adds tracts of short telomeric repeats to DNA substrates using a unique repeat addition form of processivity. It has been proposed that repeat addition processivity is partly regulated by a telomerase reverse transcriptase (TERT)-dependent anchor site; however, anchor site-mediating residues have not been identified in any TERT. We report the characterization of an N-terminal human TERT (hTERT) RNA interaction domain 1 (RID1) mutation that caused telomerase activity defects consistent with disruption of a template-proximal anchor site, including reduced processivity on short telomeric primers and reduced activity on substrates with nontelomeric 5' sequences, but not on primers with nontelomeric G-rich 5' sequences. This mutation was located within a subregion of RID1 previously implicated in biological telomerase functions unrelated to catalytic activity (N-DAT domain). Other N-DAT and C-terminal DAT (C-DAT) mutants and a C-terminally tagged hTERT-HA variant were defective in elongating short telomeric primers, and catalytic phenotypes of DAT variants were partially or completely rescued by increasing concentrations of DNA primers. These observations imply that RID1 and the hTERT C terminus contribute to telomerase's affinity for its substrate, and that RID1 may form part of the human telomerase anchor site.},
}
@article {pmid15851602,
year = {2005},
author = {Gardner, JP and Li, S and Srinivasan, SR and Chen, W and Kimura, M and Lu, X and Berenson, GS and Aviv, A},
title = {Rise in insulin resistance is associated with escalated telomere attrition.},
journal = {Circulation},
volume = {111},
number = {17},
pages = {2171-2177},
doi = {10.1161/01.CIR.0000163550.70487.0B},
pmid = {15851602},
issn = {1524-4539},
support = {AG-16592/AG/NIA NIH HHS/United States ; HL-38844/HL/NHLBI NIH HHS/United States ; },
mesh = {Adiposity ; Adult ; Aging ; Black People ; Body Mass Index ; Female ; Homeostasis ; Humans ; *Insulin Resistance ; Leukocytes ; Longitudinal Studies ; Male ; Telomere/*metabolism/ultrastructure ; White People ; },
abstract = {BACKGROUND: Insulin resistance predisposes to cardiovascular disease and shortens human lifespan. We therefore tested the hypothesis that a rise in insulin resistance in concert with gain in body mass is associated with accelerated white blood cell telomere attrition.<br><br>METHODS AND RESULTS: We measured white blood cell telomere dynamics and age-related changes in insulin resistance and body mass index in young adults of the Bogalusa Heart Study. Over 10.1 to 12.8 years, the relative changes in telomere length were correlated with the homeostasis model assessment of insulin resistance (r=-0.531, P<0.001) and changes in the body mass index (r=-0.423, P<0.001).<br><br>CONCLUSIONS: These findings provide the first tangible nexus of telomere biology with insulin resistance and adiposity in humans.},
}
@article {pmid15850831,
year = {2005},
author = {Hartmann, U and Balabanov, S and Ziegler, P and Fellenberg, J and van der Kuip, H and Duyster, J and Lipp, HP and Bokemeyer, C and Kanz, L and Brümmendorf, TH},
title = {Telomere length and telomerase activity in the BCR-ABL-transformed murine Pro-B cell line BaF3 is unaffected by treatment with imatinib.},
journal = {Experimental hematology},
volume = {33},
number = {5},
pages = {542-549},
doi = {10.1016/j.exphem.2005.02.002},
pmid = {15850831},
issn = {0301-472X},
mesh = {Animals ; B-Lymphocytes/*drug effects/enzymology/metabolism ; Benzamides ; Cell Division/drug effects ; Cell Line, Transformed ; Culture Media ; Fluorescent Antibody Technique ; Fusion Proteins, bcr-abl/*physiology ; Imatinib Mesylate ; In Situ Hybridization, Fluorescence ; Interleukin-3/pharmacology ; Mice ; Piperazines/*pharmacology ; Pyrimidines/*pharmacology ; Telomerase/*metabolism ; *Telomere ; },
abstract = {OBJECTIVE: Imatinib mesylate is a novel tyrosine kinase inhibitor used for the treatment of Philadelphia chromosome positive (Ph+) leukemia and other malignancies. In previous studies, we found significant telomere shortening in Ph+ cells from patients with chronic myeloid leukemia (CML). Interestingly, imatinib treatment was found to lead to a normalization of previously shortened telomere length in CML patients. Based on recent reports demonstrating that c-ABL phosphorylates hTERT and thereby inhibits hTERT activity, a direct effect of imatinib on hTERT activity leading to telomere elongation in BCR-ABL-positive cells has been proposed by others. Such an effect could be of potential importance for telomere maintenance in Ph+ cells by facilitating clonal selection and progression of the disease to blast crisis.<br><br>METHODS: We investigated the impact of imatinib on telomere length and telomerase activity of the interleukin-3 (IL-3)-dependent murine pro-B cell line BaF3 and the BCR-ABL-positive, IL-3-independent transfectant BaF3p185 in vitro.<br><br>RESULTS: When BaF3 and BaF3p185 cells were treated with imatinib (the latter being rescued with IL-3), no effect on either telomerase activity or telomere length was observed. These findings can be explained by the cytoplasmatic localization of BCR-ABL found in BaF3p185 as compared to the nuclear localization of telomerase (and c-ABL).<br><br>CONCLUSION: As opposed to recent reports for c-ABL, we do not see evidence for a functional interaction between BCR-ABL and hTERT in this model system arguing against imatinib-mediated upregulation of hTERT as a crucial factor for clonal selection and disease progression of CML.},
}
@article {pmid15846215,
year = {2005},
author = {Keefe, DL and Franco, S and Liu, L and Trimarchi, J and Cao, B and Weitzen, S and Agarwal, S and Blasco, MA},
title = {Telomere length predicts embryo fragmentation after in vitro fertilization in women--toward a telomere theory of reproductive aging in women.},
journal = {American journal of obstetrics and gynecology},
volume = {192},
number = {4},
pages = {1256-60; discussion 1260-1},
doi = {10.1016/j.ajog.2005.01.036},
pmid = {15846215},
issn = {0002-9378},
mesh = {Adult ; Apoptosis/genetics ; Cellular Senescence/*genetics/physiology ; Cohort Studies ; DNA Fragmentation/genetics/*physiology ; Embryo Transfer ; Embryonic Structures ; Female ; Fertilization in Vitro ; Humans ; Linear Models ; Oocytes/*physiology ; Reproductive Medicine ; Sensitivity and Specificity ; Telomerase/genetics/metabolism ; Telomere/*genetics/physiology ; },
abstract = {OBJECTIVE: Telomeres are DNA repeats which cap and protect chromosome ends, facilitate homologue pairing and chiasmata formation during early meiosis, and shorten with cell division and exposure to reactive oxygen to mediate aging. Early germ cells contain telomerase, a reverse transcriptase which adds telomeres to 3-prime DNA ends, but telomerase activity declines in oocytes, fixing telomere length earlier during development. Experimentally induced telomere shortening in mice disrupts meiosis, impairs chiasmata formation, halts embryonic cell cycles, and promotes apoptosis in embryos, a phenotype which mimics reproductive senescence in women. Ethical constraints limit study of human embryos to nondestructive assays, such as morphologic evaluation under transmission optics, but cytoplasmic fragmentation is a reliable marker of apoptosis.<br><br>STUDY DESIGN: Study design consisted of observational study of effect of telomere length in human eggs on cytoplasmic fragmentation, and on other morphologic features of preimplantation embryos. To test the hypothesis that telomere shortening triggers apoptosis in human embryos, we evaluated telomere length as a predictor of cytoplasmic fragmentation in embryos from women undergoing in vitro fertilization.<br><br>RESULTS: Telomere length negatively predicted fragmentation in day 3 preimplantation embryos, after controlling for patient age and basal follicle stimulating hormone level. Telomere length did not predict other features of preimplantation embryo morphology.<br><br>CONCLUSION: The finding that telomere length in human eggs predicts cytoplasmic fragmentation in embryos provides evidence that telomere shortening induces apoptosis in human preimplantation embryos, consistent with a telomere theory of reproductive senescence in women.},
}
@article {pmid15846103,
year = {2005},
author = {Tarsounas, M and West, SC},
title = {Recombination at mammalian telomeres: an alternative mechanism for telomere protection and elongation.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {4},
number = {5},
pages = {672-674},
doi = {10.4161/cc.4.5.1689},
pmid = {15846103},
issn = {1551-4005},
support = {2002:445/BCN_/Breast Cancer Now/United Kingdom ; },
mesh = {Animals ; DNA/genetics ; DNA Repair ; DNA-Binding Proteins/physiology ; Genomic Instability ; Humans ; Nuclear Proteins/physiology ; Rad51 Recombinase/metabolism ; *Recombination, Genetic ; Sequence Homology, Nucleic Acid ; Telomere/*physiology ; Telomere-Binding Proteins/physiology ; },
abstract = {In human cells, homologous recombination (HR) provides an accurate mechanism for the repair of DNA double-strand breaks caused by replication fork breakdown or DNA damaging agents. HR also plays a role in the maintenance of eukaryotic telomeres; cells defective in the recombinational repair proteins RAD51D or RAD54 exhibit telomere shortening and end-to-end chromosome fusions. Here we discuss the way in which HR contributes to telomere protection and elongation in mammalian cells. Understanding the mechanisms by which HR promotes telomere maintenance has important implications for genomic stability and tumorigenesis.},
}
@article {pmid15843951,
year = {2005},
author = {Slijepcevic, P and Al-Wahiby, S},
title = {Telomere biology: integrating chromosomal end protection with DNA damage response.},
journal = {Chromosoma},
volume = {114},
number = {4},
pages = {275-285},
pmid = {15843951},
issn = {0009-5915},
mesh = {Animals ; Antigens, Nuclear/genetics ; Chromosomes/*genetics ; *DNA Damage ; DNA Repair/genetics ; DNA-Binding Proteins/genetics ; Humans ; Ku Autoantigen ; Mice ; Telomere/genetics/*physiology ; },
abstract = {Telomeres play the key protective role at chromosomes. Many studies indicate that loss of telomere function causes activation of DNA damage response. Here, we review evidence supporting interdependence between telomere maintenance and DNA damage response and present a model in which these two pathways are combined into a single mechanism for protecting chromosomal integrity. Proteins directly involved in telomere maintenance and DNA damage response include Ku, DNA-PKcs, RAD51D, PARP-2, WRN and RAD50/MRE11/NBS1 complex. Since most of these proteins participate in the repair of DNA double-strand breaks (DSBs), this was perceived by many authors as a paradox, given that telomeres function to conceal natural DNA ends from mechanisms that detect and repair DSBs. However, we argue here that the key function of one particular DSB protein, Ku, is to prevent or control access of telomerase, the enzyme that synthesises telomeric sequences, to both internal DSBs and natural chromosomal ends. This view is supported by observations that Ku has a high affinity for DNA ends; it acts as a negative regulator of telomerase and that telomerase itself can target internal DSBs. Ku then directs other DSB repair/telomere maintenance proteins to either repair DSBs at internal chromosomal sites or prevent uncontrolled elongation of telomeres by telomerase. This model eliminates the above paradox and provides a testable scenario in which the role of DSB repair proteins is to protect chromosomal integrity by balancing repair activities and telomere maintenance. In our model, a close association between telomeres and different DNA damage response factors is not an unexpected event, but rather a logical result of chromosomal integrity maintenance activities.},
}
@article {pmid15843932,
year = {2005},
author = {Hayashi, N and Nomura, T and Sakumoto, N and Mukai, Y and Kaneko, Y and Harashima, S and Murakami, S},
title = {The SIT4 gene, which encodes protein phosphatase 2A, is required for telomere function in Saccharomyces cerevisiae.},
journal = {Current genetics},
volume = {47},
number = {6},
pages = {359-367},
pmid = {15843932},
issn = {0172-8083},
mesh = {Cell Cycle ; Cell Division ; Gene Silencing ; Oxidative Stress ; Phosphoprotein Phosphatases/*metabolism/physiology ; Protein Phosphatase 2 ; Saccharomyces cerevisiae/*genetics/*physiology ; Saccharomyces cerevisiae Proteins ; Telomere/*physiology ; Time Factors ; },
abstract = {Life span and number of cell divisions in eukaryotes are limited. The accumulation of stress-associated damage due to ageing may cause irreversible cell cycle arrest, so-called "cellular senescence". Although many genes have been implicated in determining life span, regulatory systems that counteract age-related stress have not yet been clarified. We examined senescence during a stress of Saccharomyces cerevisiae strains carrying disruptions in protein phosphatase (PPase)-encoding genes in order to identify the system counteracting senescence. Among these strains, short telomeres were found in the sit4 disruptant that lacks one form of protein phosphatase 2A (PP2A). Silencing ability in the subtelomeric region was impaired and hyperphosphorylation of Sir3 was also observed in this mutant. The sit4 mutant was found to have altered nucleoli and a life span as short as an sgs1 mutant. These observations suggest that the PP2A pathway regulates life span in yeast.},
}
@article {pmid15842766,
year = {2005},
author = {Hsu, YH and Lin, JJ},
title = {Telomere and telomerase as targets for anti-cancer and regeneration therapies.},
journal = {Acta pharmacologica Sinica},
volume = {26},
number = {5},
pages = {513-518},
doi = {10.1111/j.1745-7254.2005.00098.x},
pmid = {15842766},
issn = {1671-4083},
mesh = {DNA-Binding Proteins/genetics/*metabolism ; Enzyme Inhibitors/*pharmacology ; Genetic Therapy ; Humans ; Neoplasms/*enzymology/therapy ; RNA, Messenger/metabolism ; Telomerase/antagonists &amp; inhibitors/genetics/*metabolism ; Telomere/pathology/*physiology ; },
abstract = {Telomerase is a ribonucleoprotein that directs the synthesis of telomeric sequence. It is detected in majority of malignant tumors, but not in most normal somatic cells. Because telomerase plays a critical role in cell immortality and tumor formation, it has been one of the targets for anti-cancer and regeneration drug development. In this review, we will discuss therapeutic approaches based mainly on small molecules that have been developed to inhibit telomerase activity, modulate telomerase expression, and telomerase directed gene therapy.},
}
@article {pmid15837730,
year = {2005},
author = {Zaffaroni, N and Villa, R and Pastorino, U and Cirincione, R and Incarbone, M and Alloisio, M and Curto, M and Pilotti, S and Daidone, MG},
title = {Lack of telomerase activity in lung carcinoids is dependent on human telomerase reverse transcriptase transcription and alternative splicing and is associated with long telomeres.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {11},
number = {8},
pages = {2832-2839},
doi = {10.1158/1078-0432.CCR-04-1293},
pmid = {15837730},
issn = {1078-0432},
mesh = {*Alternative Splicing ; Carcinoid Tumor/enzymology/genetics/*pathology ; DNA-Binding Proteins ; Humans ; Lung Neoplasms/enzymology/genetics/*pathology ; RNA, Messenger/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*genetics/metabolism ; Telomere/enzymology/*genetics ; Transcription, Genetic ; },
abstract = {PURPOSE: Preliminary evidence indicates that telomerase activity is significantly less expressed in typical carcinoids than in large cell neuroendocrine carcinomas or in small cell lung cancers. Knowledge of the mechanisms by which telomerase is differentially regulated in neuroendocrine lung tumors is important for a better understanding of the pathogenesis of these malignancies.<br><br>EXPERIMENTAL DESIGN: We investigated telomerase activity in 86 neuroendocrine lung tumors and correlated the enzyme activity with the expression of the enzyme subunits [human RNA component (hTR), human telomerase reverse transcriptase (hTERT), and alternatively spliced hTERT variants], with the telomere-associated protein human protection of telomere-1, and with the telomere length pattern.<br><br>RESULTS: A significantly (P = 0.0001) lower frequency of telomerase-positive cases was found in typical carcinoids (14%) than in large cell neuroendocrine carcinomas (87%) and small cell lung cancers (92%). hTR was constitutively expressed in all carcinoids. Telomerase-negative carcinoids were characterized by the absence of any hTERT transcript, only displayed the beta(-) alternatively spliced variant, or concomitantly expressed the alpha(+)beta(+) full-length message with different combinations of alternatively spliced variants. However, in these tumors, a more abundant level of alternatively spliced transcripts than that of the alpha(+)beta(+) full-length transcript was generally found. No significant difference was observed in human protection of telomere-1 expression between telomerase-negative and telomerase-positive carcinoids. Telomeres were significantly (P < 0.05) longer in telomerase-negative carcinoids than in telomerase-positive carcinoids (median value, 9.15 versus 4.47 kb). However, alternative lengthening of telomeres, as shown by associated promyelocytic leukemia bodies, was not observed in these tumors.<br><br>CONCLUSIONS: Our results indicate that telomerase is repressed in most lung carcinoids and that hTERT transcription and alternative splicing play a role in such a negative regulation. Moreover, the absence of any telomerase maintenance mechanism may contribute to the favorable prognosis of this malignancy.},
}
@article {pmid15837418,
year = {2005},
author = {Price, C and Jacob, NK},
title = {Engineering the end: DNA processing at human telomeres.},
journal = {Molecular cell},
volume = {18},
number = {2},
pages = {147-148},
doi = {10.1016/j.molcel.2005.03.024},
pmid = {15837418},
issn = {1097-2765},
mesh = {Animals ; Base Sequence ; Chromosomes, Human/*genetics/*metabolism ; Cytosine/chemistry/metabolism ; *DNA Replication ; DNA, Protozoan/chemistry ; Guanine/chemistry/metabolism ; Humans ; Polymerase Chain Reaction ; Telomere/chemistry/*metabolism ; Tetrahymena/genetics ; },
abstract = {A series of new techniques developed by Sfeir et al. (2005) have made it possible to analyze the sequence at the terminus of mammalian telomeres and have shown that the C strand is subject to a highly specific DNA processing step.},
}
@article {pmid15835310,
year = {2005},
author = {Matsuura, A},
title = {[Role of ATM-related proteins in the assembly of telomere replication proteins].},
journal = {Seikagaku. The Journal of Japanese Biochemical Society},
volume = {77},
number = {3},
pages = {233-240},
pmid = {15835310},
issn = {0037-1017},
mesh = {Aging/genetics ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle/genetics ; Cell Cycle Proteins/*physiology ; Chromatin Assembly and Disassembly/*genetics ; DNA/metabolism ; DNA-Binding Proteins/*physiology ; Evolution, Molecular ; Protein Serine-Threonine Kinases/*physiology ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/genetics ; Signal Transduction/genetics ; Telomerase/physiology ; Telomere/*genetics ; Tumor Suppressor Proteins/*physiology ; },
}
@article {pmid15833310,
year = {2005},
author = {Arkus, N},
title = {A mathematical model of cellular apoptosis and senescence through the dynamics of telomere loss.},
journal = {Journal of theoretical biology},
volume = {235},
number = {1},
pages = {13-32},
doi = {10.1016/j.jtbi.2004.12.016},
pmid = {15833310},
issn = {0022-5193},
mesh = {Animals ; Apoptosis ; Cell Death ; *Cell Physiological Phenomena ; Cell Proliferation ; Cells, Cultured ; Cellular Senescence ; Chromosomes ; Fibroblasts/cytology ; Humans ; Kidney/cytology/embryology ; *Models, Genetic ; Oxidative Stress ; Telomerase/*metabolism ; Telomere/*metabolism/*ultrastructure ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {The shortening of telomeric repeats as a cell replicates has long been implicated as a determinant of cell viability. However, recent studies have indicated that it is not telomere length, but rather whether telomeres have bound a telomere-related protein, which in mammals is TTAGGG repeat binding factor-2 (TRF2), that determines whether a cell undergoes apoptosis (programmed cell death), enters senescence (a quiescent, non-replicative state), or continues to proliferate. When bound to a telomere, TRF2 allows a cell to recognize the telomere as the point where a chromosome ends rather than a break in DNA. When telomeres are not bound by TRF2, the cell can either immediately trigger senescence or apoptosis via the DNA damage response pathway, or indirectly trigger it by attempting to repair the chromosome, which results in chromosomal end joining. We model the ability of telomeres to bind TRF2 as a function of telomere length and apply the resulting binding probability to a model of cellular replication that assumes a homogeneous cell population. The model fits data from cultured human fibroblasts and human embryonic kidney cells for two free parameters well. We extract values for the percent of telomere loss at which cell proliferation ceases. We show, in agreement with previous experiments, that overexpression of TRF2 allows a cell to delay the senescence setpoint. We explore the effect of oxidative stress, which increases the rate of telomere loss, on cell viability and show that cells in the presence of oxidative stress have reduced lifespans. We also show that the addition of telomerase, an enzyme that maintains telomere length, is sufficient to result in cell immortality. We conclude that the increasing inability of TRF2 to bind telomeres as they shorten is a quantitatively reasonable model for a cause of either cellular apoptosis or senescence.},
}
@article {pmid15833273,
year = {2005},
author = {Duan, J and Duan, J and Zhang, Z and Tong, T},
title = {Irreversible cellular senescence induced by prolonged exposure to H2O2 involves DNA-damage-and-repair genes and telomere shortening.},
journal = {The international journal of biochemistry &amp; cell biology},
volume = {37},
number = {7},
pages = {1407-1420},
doi = {10.1016/j.biocel.2005.01.010},
pmid = {15833273},
issn = {1357-2725},
mesh = {Cell Cycle Proteins/biosynthesis ; Cell Proliferation/drug effects ; Cells, Cultured ; Cellular Senescence/drug effects/*physiology ; Comet Assay ; Cyclin-Dependent Kinase Inhibitor p21 ; DNA Damage/*genetics ; DNA Repair/*genetics ; Diploidy ; Electrophoretic Mobility Shift Assay ; Fibroblasts/drug effects/physiology/ultrastructure ; Humans ; Hydrogen Peroxide/*pharmacology ; Intracellular Signaling Peptides and Proteins/metabolism ; Oxidative Stress ; Telomere/drug effects/*ultrastructure ; Time Factors ; Tumor Suppressor Protein p53/biosynthesis ; beta-Galactosidase/metabolism ; GADD45 Proteins ; },
abstract = {H2O2 has been the most commonly used inducer for stress-induced premature senescence (SIPS), which shares features of replicative senescence. However, there is still uncertainty whether SIPS and replicative senescence differ or utilize different pathways. 'Young' human diploid fibroblasts (HDFs), treated with prolonged low doses of hydrogen peroxide, led to irreversible cellular senescence. Cells exhibited senescent-morphological features, irreversible G1 cell cycle arrest and irreversible senescence-associated beta-galactosidase positivity. The appearance of these cellular senescence markers was accompanied by significant increases of p21, gadd45 expression and p53 binding activity, as well as a significant decline in DNA repair capability and accelerated telomere shortening. Our results suggest that multiple pathways might be involved in oxidative SIPS, including genes related to DNA-damage-and-repair and telomere shortening, and that SIPS shares the same mechanisms with replicative senescence in vivo. Our findings indicate that several aging theories can be merged together by a common mechanism of oxidative damage, and that the level of oxidative DNA-damage-and-repair capacity may be exploited as reliable markers of cell senescence.},
}
@article {pmid15824455,
year = {2005},
author = {Tani, A and Murata, M},
title = {Alternative splicing of Pot1 (Protection of telomere)-like genes in Arabidopsis thaliana.},
journal = {Genes &amp; genetic systems},
volume = {80},
number = {1},
pages = {41-48},
doi = {10.1266/ggs.80.41},
pmid = {15824455},
issn = {1341-7568},
mesh = {Alternative Splicing/*physiology ; Amino Acid Sequence ; Arabidopsis/genetics/*physiology ; Arabidopsis Proteins/*biosynthesis/genetics ; Molecular Sequence Data ; Plant Proteins/*biosynthesis/genetics ; Shelterin Complex ; Telomere/genetics/metabolism ; Telomere-Binding Proteins/*biosynthesis/genetics ; },
abstract = {The Pot1 (Protection of telomere 1) is a G-rich single-stranded telomeric DNA binding protein, identified first in Schizosaccharomyces pombe, and shown to play an important role in stabilizing chromosomes. Pot1-like proteins or their encoding genes have been identified from yeasts to mammals. Based on the N-terminal amino acid sequences of fission yeast and human Pot1, two Pot1-like proteins (AtPOT1-1 and AtPOT1-2) have been identified in Arabidopsis thaliana, but neither of them has been characterized yet. In this study, we amplified their full-length cDNAs by RT-PCR and found three different variants for AtPOT1-1 and two for AtPOT1-2 genes, suggesting that they are exposed to alternative splicing. Alternative splicing also occurs in human Pot1, and only one out of five splicing variants had tissue specificity. However, no tissue specificity was found for any variants of the AtPOT1-1 and AtPOT1-2 genes among buds, flowers, leaves, roots, stems, siliques and cultured cells. Northern blot hybridization indicated that AtPOT1-1 expresses more in meristematic tissues than in vegetative tissues. By western blot analysis, we found that the antibody made against the N-terminal amino acids of AtPOT1-1 recognized three different polypeptides, indicating that all three variants are being translated in Arabidopsis.},
}
@article {pmid15820190,
year = {2005},
author = {Edo, MD and Andrés, V},
title = {Aging, telomeres, and atherosclerosis.},
journal = {Cardiovascular research},
volume = {66},
number = {2},
pages = {213-221},
doi = {10.1016/j.cardiores.2004.09.007},
pmid = {15820190},
issn = {0008-6363},
mesh = {Aged ; Aging/*physiology ; Animals ; Arteriosclerosis/*genetics ; Cellular Senescence ; Diabetic Angiopathies/genetics ; Female ; Humans ; Hypertension/genetics ; Male ; Neovascularization, Pathologic/genetics ; Oxidative Stress ; Telomerase/genetics ; Telomere/*physiology/ultrastructure ; X Chromosome ; },
abstract = {Although the level and pace of population aging display high geographical variability, virtually all countries have been experiencing growth in their elderly population, particularly in developed nations. Because aging is a major risk factor for atherosclerosis and associated disease, it is of up most importance to unravel the molecular mechanisms involved in vascular aging. Telomeres are specialized DNA-protein structures located at the ends of eukaryotic chromosomes whose length is progressively reduced in most somatic cells during aging. It is accepted that telomere exhaustion contributes to organismal ageing at least by impairing cell proliferation and viability. An emerging question is whether telomere erosion contributes to atherosclerosis. Here we discuss recent advances on the molecular control of telomere length in vascular cells, as well as animal and human studies that address the role of telomeres in vascular pathobiology. Although the interrelationships between telomere length and cardiovascular disease appear obvious, a chief question that remains unanswered is whether telomere ablation is cause of vascular injury or a surrogate phenomenon.},
}
@article {pmid15817566,
year = {2005},
author = {Rujan, IN and Meleney, JC and Bolton, PH},
title = {Vertebrate telomere repeat DNAs favor external loop propeller quadruplex structures in the presence of high concentrations of potassium.},
journal = {Nucleic acids research},
volume = {33},
number = {6},
pages = {2022-2031},
pmid = {15817566},
issn = {1362-4962},
support = {GM06581/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Aptamers, Nucleotide ; Base Sequence ; Circular Dichroism ; DNA/*chemistry/drug effects ; Deoxyadenosines/chemistry ; G-Quadruplexes ; Nucleic Acid Conformation ; Oligonucleotides/chemistry ; Oxytricha/genetics ; Potassium/*pharmacology ; Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; Tetrahymena/genetics ; Vertebrates/*genetics ; },
abstract = {The circular dichroism, CD, spectra of the telomere repeats of vertebrates, d(TTAGGG), indicate that parallel type quadruplex structures or disordered single-stranded structures are formed in low salt. Anti-parallel quadruplex structures are favored in the presence of high concentrations, 140 mM, of sodium. External loop, also known as propeller, parallel type structures are favored in the presence of high concentrations, 100 mM, of potassium in the presence of either 5 or 140 mM sodium. The cation dependence of the CD spectra of the vertebrate telomere repeat DNAs is distinctly different from that of the telomere repeats of Tetrahymena and Oxytricha as well as that of the thrombin binding aptamer. These results indicate that the external loop structures may be present in vertebrate telomeres under the conditions of high potassium and low sodium concentration found in nuclei.},
}
@article {pmid15812355,
year = {2005},
author = {Arutyunyan, R and Rapp, A and Greulich, KO and Hovhannisyan, G and Haroutiunian, S and Gebhart, E},
title = {Fragility of telomeres after bleomycin and cisplatin combined treatment measured in human leukocytes with the Comet-FISH technique.},
journal = {Experimental oncology},
volume = {27},
number = {1},
pages = {38-42},
pmid = {15812355},
issn = {1812-9269},
mesh = {Adult ; Antineoplastic Agents/*pharmacology ; Bleomycin/*pharmacology ; Cisplatin/*pharmacology ; Comet Assay ; Cross-Linking Reagents/pharmacology ; DNA/*drug effects ; DNA Damage/physiology ; Dose-Response Relationship, Drug ; Female ; Humans ; In Situ Hybridization, Fluorescence ; In Vitro Techniques ; Leukocytes/*drug effects ; Telomere/*drug effects ; },
abstract = {UNLABELLED: THE AIM of the present study was the comparative investigation of action of widely applied anticancer preparations: cisplatin (cis-DDP) and bleomycin (BLM) on total DNA and telomeres damage in human blood cells.<br><br>METHODS: The "Comet-FISH technique" -- single cell gel electrophoresis ("comet assay") in combination with fluorescent in situ hybridization (FISH) was used for this purpose. This newly applied combined approach permits to detect on the same specimen the total DNA damage in individual cells and evaluate specific DNA sequences as well. Telomere -- specific -- PNA (peptide nucleic acid) probes were used for the localization of telomeres in the comet's head and their migration to the tail. THE RESULTS obtained indicate that in control variants, due to DNA metabolism and handling, approximately 7% of the DNA and 17% of the telomeres were found in the tail. In cells treated with BLM alone, telomeres leak out with equal probability as total DNA. In turn, the combination of cis-DDP with BLM reduces telomere migration more than the migration of total DNA due to cis-DDP crosslinking effect. Thus, preferentially telomeric action of the cis-DDP can be concluded.<br><br>CONCLUSION: The Comet-FISH approach permitted us to reveal the induction of DNA breaks with BLM and its modification due to platinum-crosslink formation, using telomeric PNA probes.},
}
@article {pmid15811960,
year = {2005},
author = {Beier, F and Balabanov, S and Buckley, T and Dietz, K and Hartmann, U and Rojewski, M and Kanz, L and Schrezenmeier, H and Brümmendorf, TH},
title = {Accelerated telomere shortening in glycosylphosphatidylinositol (GPI)-negative compared with GPI-positive granulocytes from patients with paroxysmal nocturnal hemoglobinuria (PNH) detected by proaerolysin flow-FISH.},
journal = {Blood},
volume = {106},
number = {2},
pages = {531-533},
doi = {10.1182/blood-2004-10-3996},
pmid = {15811960},
issn = {0006-4971},
mesh = {Adolescent ; Adult ; Aged ; Bacterial Toxins ; Case-Control Studies ; Glycosylphosphatidylinositols/*blood ; Granulocytes/*metabolism ; Hematopoietic Stem Cells/metabolism ; Hemoglobinuria, Paroxysmal/*blood/*genetics ; Humans ; In Situ Hybridization, Fluorescence/methods ; Middle Aged ; Pore Forming Cytotoxic Proteins ; Telomere/*genetics/metabolism ; },
abstract = {Telomere length has been linked to disease stage and degree of (pan-)cytopenia in patients with bone marrow failure syndromes. The aim of the current study was to analyze the impact of replicative stress on telomere length in residual glycosylphosphatidylinositol-positive (GPI+) versus GPI- hematopoiesis in patients with paroxysmal nocturnal hemoglobinuria (PNH). Peripheral blood granulocytes from 16 patients and 22 healthy individuals were analyzed. For this purpose, we developed proaerolysin flow-FISH, a novel methodology that combines proaerolysin staining (for GPI expression) with flow-FISH (for telomere length measurement). We found significantly shortened telomeres in GPI- granulocytes (mean +/- SE: 6.26 +/- 0.27 telomere fluorescence units [TFU]), both compared with their GPI+ counterparts (6.88 +/- 0.38 TFU; P = .03) as well as with age-matched healthy individuals (7.73 +/- 0.23 TFU; P < .001). Our findings are in support of a selective growth advantage model of PNH assuming that damage to the GPI+ hematopoietic stem-cell (HSC) compartment leads to compensatory hyperproliferation of residual GPI- HSCs.},
}
@article {pmid15811846,
year = {2005},
author = {Riou, JF and Gomez, D and Mergny, JL and Guittat, L and Paterski, R and Chenais, B and Morjani, H and Trentesaux, C},
title = {[Regulation of telomeres length: making the telomeres accessible?].},
journal = {Bulletin du cancer},
volume = {92},
number = {1},
pages = {13-22},
pmid = {15811846},
issn = {1769-6917},
mesh = {Cell Division ; DNA Helicases/physiology ; DNA Replication/*genetics ; Genomic Instability ; Humans ; Repetitive Sequences, Nucleic Acid ; Telomerase/*physiology ; Telomere/*genetics ; Telomeric Repeat Binding Protein 1/*physiology ; Telomeric Repeat Binding Protein 2/*physiology ; },
abstract = {Under a normal state, the extremities of chromosomes, telomeres, are protected against undesired fusion events. Alterations of the telomere structure are associated with genetic instability, while erosion of the telomeric repeats, occurring at each cell division, provides a mechanism controlling the long-term proliferation of somatic cells. Although the structure and composition of the human telomerase enzyme are now well characterized, the protein partners regulating the stability and conformation of its DNA substrate, the telomeric end, are much less known. A functional link has been recently evidenced between proteins that bind the double-stranded telomere repeats and those recruited at the 3' G-rich telomeric overhang. This review presents an update on these telomeric factors controlling telomere lengthening and discuss the actual models proposed for its regulation.},
}
@article {pmid15809713,
year = {2005},
author = {Pantic, M and Zimmermann, S and Waller, CF and Martens, UM},
title = {The level of telomere dysfunction determines the efficacy of telomerase-based therapeutics in a lung cancer cell line.},
journal = {International journal of oncology},
volume = {26},
number = {5},
pages = {1227-1232},
pmid = {15809713},
issn = {1019-6439},
mesh = {Carcinoma, Non-Small-Cell Lung/*genetics/*pathology/therapy ; Cell Survival ; DNA-Binding Proteins ; Humans ; In Situ Hybridization, Fluorescence ; Lung Neoplasms/*genetics/*pathology/therapy ; Telomerase/antagonists &amp; inhibitors/*metabolism ; Telomere/*physiology/*ultrastructure ; Tumor Cells, Cultured ; },
abstract = {Telomerase is the ribonucleoprotein enzyme that maintains telomeres of eukaryotic chromosomes. Activation of telomerase is a common feature of the majority of human cancers, and inhibition of this enzyme has been proposed as a novel target for cancer therapeutics. Here, we investigated the effects of telomerase inhibition in the non-small cell lung cancer cell line NCI-H460, using a genetic approach by ectopic expression of dominant-negative (DN)-hTERT. Five clones were selected in which telomerase activity was completely abolished. As a result, telomere erosion was observed leading to proliferation arrest after a lag period of 20-28 population doublings. Although overall telomere length was similar between the different clones as measured by quantitative fluorescence in situ hybridization (Q-FISH), striking differences were found in telomere length of individual chromosomes. In particular, lack of individual telomeres and formation of end-to-end fusions were variable. Interestingly, this level of individual telomere dysfunction was positively correlated with the remaining life span of the different clones in vitro. In addition, the amount of telomere dysfunction induced by DN-hTERT was twice as high compared to the small molecule telomerase inhibitor BIBR1532, which induced growth arrest after >100 population doublings. Thus, pharmacological strategies that aim at inhibition of telomerase in cancer cells should take into account that not only overall telomere shortening, but rapid induction of a high level telomere dysfunction appears to be the crucial surrogate parameter for the development of future telomerase-based therapeutics.},
}
@article {pmid15809428,
year = {2005},
author = {Stewénius, Y and Gorunova, L and Jonson, T and Larsson, N and Höglund, M and Mandahl, N and Mertens, F and Mitelman, F and Gisselsson, D},
title = {Structural and numerical chromosome changes in colon cancer develop through telomere-mediated anaphase bridges, not through mitotic multipolarity.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {102},
number = {15},
pages = {5541-5546},
pmid = {15809428},
issn = {0027-8424},
mesh = {*Anaphase ; Aneuploidy ; Cell Division ; Cell Line, Tumor ; Cell Survival ; Centromere/genetics/metabolism ; Chromatin/genetics/metabolism ; *Chromosome Aberrations ; Chromosome Breakage/genetics ; Chromosome Segregation ; Chromosomes, Human/genetics/*metabolism ; Colonic Neoplasms/*genetics/*pathology ; Humans ; Microsatellite Repeats/genetics ; *Mitosis ; Mutagenesis/genetics ; Polyploidy ; Telomere/genetics/*metabolism ; },
abstract = {Telomere dysfunction has been associated with chromosomal instability in colorectal carcinoma, but the consequences of telomere-dependent instability for chromosome integrity and clonal evolution have been little explored. We show here that abnormally short telomeres lead to a wide spectrum of mitotic disturbances in colorectal cancer cell lines, including anaphase bridging, whole-chromosome lagging, and mitotic multipolarity. These abnormalities were found in both the presence and absence of microsatellite instability. The mean telomere length varied extensively between cells from the same tumor, allowing the establishment of tumor cell subpopulations with highly different frequencies of mitotic disturbances. Anaphase bridging typically resulted in either inter-centromeric chromatin fragmentation or centromere detachment, leading to pericentromeric chromosome rearrangements and loss of whole chromosomes, respectively. There was a strong correlation between anaphase bridges and multipolar mitoses, and the induction of dicentric chromosomes by gamma irradiation and telomerase inhibition led to an elevated frequency of multipolar mitotic spindles, suggesting that multipolarity could result from polyploidization triggered by anaphase bridging. Chromatid segregation in multipolar mitoses was close to random, resulting in frequent nullisomies and nonviable daughter cells. In contrast, there was a high clonogenic survival among cells having gone through anaphase bridging in bipolar mitoses. Bridging of telomere-deficient chromosomes could thus be a major mutational mechanism in colorectal cancer, whereas mitotic multipolarity appears to be a secondary phenomenon that rarely, if ever, contributes to clonal evolution.},
}
@article {pmid15808515,
year = {2005},
author = {Sfeir, AJ and Chai, W and Shay, JW and Wright, WE},
title = {Telomere-end processing the terminal nucleotides of human chromosomes.},
journal = {Molecular cell},
volume = {18},
number = {1},
pages = {131-138},
doi = {10.1016/j.molcel.2005.02.035},
pmid = {15808515},
issn = {1097-2765},
support = {AG01228/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Chromosomes, Human/*genetics/*metabolism ; DNA Replication ; DNA-Directed DNA Polymerase/metabolism ; Euplotes/genetics ; Humans ; Telomerase/metabolism ; Telomere/*genetics/*metabolism ; Tetrahymena/genetics ; },
abstract = {Mammalian telomeres end in single-stranded, G-rich 3' overhangs resulting from both the "end-replication problem" (the inability of DNA polymerase to replicate the very end of the telomeres) and postreplication processing. Telomeric G-rich overhangs are precisely defined in ciliates; the length and the terminal nucleotides are fixed. Human telomeres have very long overhangs that are heterogeneous in size (35-600 nt), indicating that their processing must differ in some respects from model organisms. We developed telomere-end ligation protocols that allowed us to identify the terminal nucleotides of both the C-rich and the G-rich telomere strands. Up to approximately 80% of the C-rich strands terminate in CCAATC-5', suggesting that after replication a nuclease with high specificity or constrained action acts on the C strand. In contrast, the G-terminal nucleotide was less precise than Tetrahymena and Euplotes but still had a bias that changed as a function of telomerase expression.},
}
@article {pmid15806556,
year = {2005},
author = {Jeon, HY and Hyun, SH and Lee, GS and Kim, HS and Kim, S and Jeong, YW and Kang, SK and Lee, BC and Han, JY and Ahn, C and Hwang, WS},
title = {The analysis of telomere length and telomerase activity in cloned pigs and cows.},
journal = {Molecular reproduction and development},
volume = {71},
number = {3},
pages = {315-320},
doi = {10.1002/mrd.20279},
pmid = {15806556},
issn = {1040-452X},
mesh = {Animals ; Blastocyst/*metabolism ; Cattle ; *Cloning, Organism ; Gene Expression Regulation, Developmental/physiology ; Swine ; Telomerase/*metabolism ; Telomere/*metabolism ; Up-Regulation/physiology ; },
abstract = {Inefficiency in the production of cloned animals is most likely due to epigenetic reprogramming errors after somatic cell nuclear transfer (SCNT). In order to investigate whether nuclear reprogramming restores cellular age of donor cells after SCNT, we measured telomere length and telomerase activity in cloned pigs and cattle. In normal pigs and cattle, the mean telomere length was decreased with biological aging. In cloned or transgenic cloned piglets, the mean telomere length was elongated compared to nuclear donor fetal fibroblasts and age-matched normal piglets. In cloned cattle, no increases in mean telomere length were observed compared to nuclear donor adult fibroblasts. In terms of telomerase activity, significant activity was observed in nuclear donor cells and normal tissues from adult or new-born pigs and cattle, with relatively higher activity in the porcine tissues compared to the bovine tissues. Cloned calves and piglets showed the same level of telomerase activity as their respective donor cells. In addition, no difference in telomerase activity was observed between normal and transgenic cloned piglets. However, increased telomerase activity was observed in porcine SCNT blastocysts compared to nuclear donor cells and in vitro fertilization (IVF)-derived blastocysts, suggesting that the elongation of telomere lengths observed in cloned piglets could be due to the presence of higher telomerase activity in SCNT blastocysts. In conclusion, gathering from the comparative studies with cattle, we were able to demonstrate that telomere length in cloned piglets was rebuilt or elongated with the use of cultured donor fetal fibroblasts.},
}
@article {pmid15805468,
year = {2005},
author = {Kim, JH and Park, SM and Kang, MR and Oh, SY and Lee, TH and Muller, MT and Chung, IK},
title = {Ubiquitin ligase MKRN1 modulates telomere length homeostasis through a proteolysis of hTERT.},
journal = {Genes &amp; development},
volume = {19},
number = {7},
pages = {776-781},
pmid = {15805468},
issn = {0890-9369},
mesh = {Benzoquinones ; DNA-Binding Proteins ; HSP90 Heat-Shock Proteins/antagonists &amp; inhibitors ; Homeostasis/genetics/physiology ; Humans ; Lactams, Macrocyclic ; Nerve Tissue Proteins ; Proteasome Endopeptidase Complex/metabolism ; Quinones/pharmacology ; Ribonucleoproteins/genetics/*metabolism ; Telomerase/antagonists &amp; inhibitors/genetics/*metabolism ; Telomere/genetics/*metabolism ; Ubiquitin/metabolism ; },
abstract = {Telomere homeostasis is regulated by telomerase and a collection of associated proteins. Telomerase is, in turn, regulated by post-translational modifications of the rate-limiting catalytic subunit hTERT. Here we show that disruption of Hsp90 by geldanamycin promotes efficient ubiquitination and proteasome-mediated degradation of hTERT. Furthermore, we have used the yeast two-hybrid method to identify a novel RING finger gene (MKRN1) encoding an E3 ligase that mediates ubiquitination of hTERT. Overexpression of MKRN1 in telomerase-positive cells promotes the degradation of hTERT and decreases telomerase activity and subsequently telomere length. Our data suggest that MKRN1 plays an important role in modulating telomere length homeostasis through a dynamic balance involving hTERT protein stability.},
}
@article {pmid15805272,
year = {2005},
author = {Marciniak, RA and Cavazos, D and Montellano, R and Chen, Q and Guarente, L and Johnson, FB},
title = {A novel telomere structure in a human alternative lengthening of telomeres cell line.},
journal = {Cancer research},
volume = {65},
number = {7},
pages = {2730-2737},
doi = {10.1158/0008-5472.CAN-04-2888},
pmid = {15805272},
issn = {0008-5472},
support = {K08AG000775/AG/NIA NIH HHS/United States ; },
mesh = {Base Sequence ; Cell Line ; DNA/genetics/metabolism ; Fibroblasts/cytology ; HeLa Cells ; Humans ; Leukemia, Promyelocytic, Acute/genetics ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; Simian virus 40/*genetics ; Telomere/*genetics/metabolism ; Transcription, Genetic ; },
abstract = {Cancer cells require mechanisms to maintain telomeres. Most use telomerase, but 5% to 20% of tumors use alternative lengthening of telomeres (ALT), a telomerase-independent mechanism that seems to depend on recombination. ALT is characterized by amplification of telomere TTAGGG repeats to lengths beyond 50 kb, by elevated rates of telomere recombination, and by nuclear structures called ALT-associated promyelocytic leukemia bodies. In Saccharomyces cerevisiae, survivors of telomerase inactivation also use recombination to maintain telomeres. There are two types of survivors, which differ in telomere structure. The first possesses telomere repeats and the Y' subtelomeric element amplified together as a tandem array at chromosome termini (type I), and the other possesses amplification of telomeric repeats alone (type II), similar to previously described human ALT cells. Here, we describe the first human ALT cell line having "tandem array" telomeres with a structure similar to that of type I yeast survivors. The chromosome termini consist of a repeat unit containing approximately 2.5 kb of SV40 DNA and a variable amount of TTAGGG sequence repeated in tandem an average of 10 to 20 times. Similar to previously described ALT cells, they show evidence of telomere recombination, but unlike standard ALT cells, they lack ALT-associated promyelocytic leukemia bodies and their telomeres are transcribed. These findings have implications for the pathogenesis and diagnosis of cancer.},
}
@article {pmid15805271,
year = {2005},
author = {Fasching, CL and Bower, K and Reddel, RR},
title = {Telomerase-independent telomere length maintenance in the absence of alternative lengthening of telomeres-associated promyelocytic leukemia bodies.},
journal = {Cancer research},
volume = {65},
number = {7},
pages = {2722-2729},
doi = {10.1158/0008-5472.CAN-04-2881},
pmid = {15805271},
issn = {0008-5472},
mesh = {DNA, Viral/genetics ; Humans ; Leukemia, Promyelocytic, Acute/enzymology/*genetics/pathology ; Polymorphism, Restriction Fragment Length ; Simian virus 40/genetics ; Telomerase/*metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {Immortal tumor cells and cell lines employ a telomere maintenance mechanism that allows them to escape the normal limits on proliferative potential. In the absence of telomerase, telomere length may be maintained by an alternative lengthening of telomeres (ALT) mechanism. All human ALT cell lines described thus far have nuclear domains of unknown function, termed ALT-associated promyelocytic leukemia bodies (APB), containing promyelocytic leukemia protein, telomeric DNA and telomere binding proteins. Here we describe telomerase-negative human cells with telomeres that contain a substantial proportion of nontelomeric DNA sequences (like telomerase-null Saccharomyces cerevisiae survivor type I cells) and that are maintained in the absence of APBs. In other respects, they resemble typical ALT cell lines: the telomeres are highly heterogeneous in length (ranging from very short to very long) and undergo rapid changes in length. In addition, these cells are capable of copying a targeted DNA tag from one telomere into other telomeres. These data show that APBs are not always essential for ALT-mediated telomere maintenance.},
}
@article {pmid15798094,
year = {2005},
author = {Sabatier, L and Ricoul, M and Pottier, G and Murnane, JP},
title = {The loss of a single telomere can result in instability of multiple chromosomes in a human tumor cell line.},
journal = {Molecular cancer research : MCR},
volume = {3},
number = {3},
pages = {139-150},
doi = {10.1158/1541-7786.MCR-04-0194},
pmid = {15798094},
issn = {1541-7786},
support = {R01 CA69044/CA/NCI NIH HHS/United States ; },
mesh = {Alleles ; Cell Line, Tumor ; Chromosome Mapping ; Chromosomes/*ultrastructure ; DNA/metabolism ; *DNA Sequence, Unstable ; *Gene Duplication ; *Genome ; Humans ; Karyotyping ; Models, Biological ; Models, Genetic ; Plasmids/metabolism ; Telomere/*ultrastructure ; Translocation, Genetic ; },
abstract = {Spontaneous telomere loss has been proposed as an important mechanism for initiating the chromosome instability commonly found in cancer cells. We have previously shown that spontaneous telomere loss in a human cancer cell line initiates breakage/fusion/bridge (B/F/B) cycles that continue for many cell generations, resulting in DNA amplification and translocations on the chromosome that lost its telomere. We have now extended these studies to determine the effect of the loss of a single telomere on the stability of other chromosomes. Our study showed that telomere acquisition during B/F/B cycles occurred mainly through translocations involving either the nonreciprocal transfer or duplication of the arms of other chromosomes. Telomere acquisition also occurred through small duplications involving the subtelomeric region of the other end of the same chromosome. Although all of these mechanisms stabilized the chromosome that lost its telomere, they differed in their consequences for the stability of the genome as a whole. Telomere acquisition involving nonreciprocal translocations resulted in the loss of a telomere on the donor chromosome, which consequently underwent additional translocations, isochromosome formation, or complete loss. In contrast, telomere acquisition involving duplications stabilized the genome, although the large duplications created substantial allelic imbalances. Thus, the loss of a single telomere can generate a variety of chromosome alterations commonly associated with human cancer, not only on a chromosome that loses its telomere but also on other chromosomes. Factors promoting telomere loss are therefore likely to have an important role in generating the karyotype evolution associated with human cancer.},
}
@article {pmid15795509,
year = {2005},
author = {Nwosu, BU and Nilsson, O and Mitchum, RD and Coco, M and Barnes, KM and Baron, J},
title = {Lack of telomere shortening with age in mouse resting zone chondrocytes.},
journal = {Hormone research},
volume = {63},
number = {3},
pages = {125-128},
doi = {10.1159/000084687},
pmid = {15795509},
issn = {0301-0163},
mesh = {Aging/*physiology ; Animals ; Blotting, Southern ; Cell Division/physiology ; Chondrocytes/cytology/*physiology ; Growth Plate/cytology/*physiology ; Mice ; Telomere/*physiology ; },
abstract = {BACKGROUND AND AIM: Telomeres are hexameric repeat sequences that flank eukaryotic chromosomes. The telomere hypothesis of cellular aging proposes that replication of normal somatic cells leads to progressive telomere shortening which induces replicative senescence. Previous studies suggest that growth plate chondrocytes have a finite proliferative capacity in vivo. We therefore hypothesized that telomere shortening in resting zone chondrocytes leads to replicative senescence.<br><br>METHOD: To test this hypothesis we compared the telomere restriction fragment (TRF) length of Mus casteneus at 1, 4, 8, and 56 weeks of age.<br><br>RESULTS AND CONCLUSIONS: We found that TRF length did not diminish measurably with age, suggesting that telomere shortening in resting zone chondrocytes is not the mechanism that limits proliferation of growth plate chondrocytes in vivo.},
}
@article {pmid15795250,
year = {2005},
author = {Deng, Z and Atanasiu, C and Zhao, K and Marmorstein, R and Sbodio, JI and Chi, NW and Lieberman, PM},
title = {Inhibition of Epstein-Barr virus OriP function by tankyrase, a telomere-associated poly-ADP ribose polymerase that binds and modifies EBNA1.},
journal = {Journal of virology},
volume = {79},
number = {8},
pages = {4640-4650},
pmid = {15795250},
issn = {0022-538X},
support = {R01 CA093606/CA/NCI NIH HHS/United States ; CA93606/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Cell Line ; Consensus Sequence ; Epstein-Barr Virus Nuclear Antigens/*metabolism ; HeLa Cells ; Herpesvirus 4, Human/*genetics ; Humans ; Plasmids/metabolism ; Replication Origin/genetics ; Tankyrases/*metabolism ; Transfection ; Virus Replication ; },
abstract = {Tankyrase (TNKS) is a telomere-associated poly-ADP ribose polymerase (PARP) that has been implicated along with several telomere repeat binding factors in the regulation of Epstein-Barr virus origin of plasmid replication (OriP). We now show that TNKS1 can bind to the family of repeats (FR) and dyad symmetry regions of OriP by using a chromatin immunoprecipitation assay and DNA affinity purification. TNKS1 and TNKS2 bound to EBNA1 in coimmunoprecipitation experiments with transfected cell lysates and with purified recombinant proteins in vitro. Two RXXPDG-like TNKS-interacting motifs in the EBNA1 amino-terminal domain mediated binding with the ankyrin repeat domain of TNKS. Mutations of both motifs at EBNA1 G81 and G425 abrogated TNKS binding and enhanced EBNA1-dependent replication of OriP. Small hairpin RNA targeted knock-down of TNKS1 enhanced OriP-dependent DNA replication. Overexpression of TNKS1 or TNKS2 inhibited OriP-dependent DNA replication, while a PARP-inactive form of TNKS2 (M1045V) was compromised for this inhibition. We show that EBNA1 is subject to PAR modification in vivo and to TNKS1-mediated PAR modification in vitro. These results indicate that TNKS proteins can interact directly with the EBNA1 protein, associate with the FR region of OriP in vivo, and inhibit OriP replication in a PARP-dependent manner.},
}
@article {pmid15791450,
year = {2005},
author = {Shibata, F and Matsusaki, Y and Hizume, M},
title = {AT-rich sequences containing Arabidopsis-type telomere sequence and their chromosomal distribution in Pinus densiflora.},
journal = {TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik},
volume = {110},
number = {7},
pages = {1253-1258},
pmid = {15791450},
issn = {0040-5752},
mesh = {AT Rich Sequence/*genetics ; Arabidopsis/genetics ; Base Sequence ; Blotting, Southern ; Chromosomes, Plant/*genetics ; Cloning, Molecular ; Gene Library ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Pinus/*genetics ; Sequence Analysis, DNA ; Telomere/*genetics ; },
abstract = {Japanese red pine Pinus densiflora has 2 n=24 chromosomes and after FISH-detection of Arabidopsis-type (A-type) telomere sequences, many telomere signals were observed on these chromosomes at interstitial and proximal regions in addition to the chromosome ends. These interstitial and proximal signal sites were observed as DAPI-positive bands, suggesting that the interstitial and proximal telomere signal sites are composed of AT-rich highly repetitive sequences. Four DNA clones (PAL810, PAL1114, PAL1539, PAL1742) localized at the interstitial telomere signals were selected from AluI-digested genomic DNA library using colony blot hybridization probed with A-type telomere sequences and characterized using FISH and Southern blot hybridization. The AT-contents of these selected four clones were 60.8-76.3%, and repeat units of the telomere sequence and degenerated telomere sequences were found in their nucleotide sequences. Except for two sites of PAL1114, FISH signals of the four clones co-localized with interstitial and proximal A-type telomere sequence signals. FISH signals a showed similar distribution pattern, but the patterns of signal intensity were different among the four clones. PAL810, PAL1539 and PAL 1742 showed similar FISH signal patterns, and the differences were only with respect to the signal intensity of some signal sites. PAL1114 had unique signals that appeared on chromosomes 7 and 10. Based on results of the Southern blot hybridization these four sequences are not arranged tandemly. Our results suggest that the interstitial A-type telomere sequence signal sites were composed of a mixture of several AT-rich repetitive sequences and that these repetitive sequences contained A-type telomere sequences or degenerated A-type telomere sequence repeats.},
}
@article {pmid15781709,
year = {2005},
author = {Melnikova, L and Biessmann, H and Georgiev, P},
title = {The Ku protein complex is involved in length regulation of Drosophila telomeres.},
journal = {Genetics},
volume = {170},
number = {1},
pages = {221-235},
pmid = {15781709},
issn = {0016-6731},
support = {TW-05653/TW/FIC NIH HHS/United States ; },
mesh = {Animals ; Antigens, Nuclear/*genetics/physiology ; Crosses, Genetic ; DNA-Binding Proteins/*genetics/physiology ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/*genetics/metabolism ; Gene Conversion ; Gene Dosage ; Gene Products, gag/genetics/metabolism ; Heterozygote ; Ku Autoantigen ; RNA, Messenger ; Telomere/*genetics/metabolism ; Transcription, Genetic ; },
abstract = {Chromosome ends in Drosophila melanogaster can be elongated either by terminal attachment of the telomere-specific retrotransposons HeT-A and TART or by terminal gene conversion. Here we show that a decrease in Ku70 or Ku80 gene dosage causes a sharp increase in the frequency of HeT-A and TART attachments to a broken chromosome end and in terminal DNA elongation by gene conversion. Loss of Ku80 has more pronounced effects than loss of Ku70. However, lower Ku70 concentration reduces the stability of terminally deficient chromosomes. Our results suggest a role of the end-binding Ku complex in the accessibility and length regulation of Drosophila telomeres.},
}
@article {pmid15780935,
year = {2005},
author = {Kobryn, K and Chaconas, G},
title = {Fusion of hairpin telomeres by the B. burgdorferi telomere resolvase ResT implications for shaping a genome in flux.},
journal = {Molecular cell},
volume = {17},
number = {6},
pages = {783-791},
doi = {10.1016/j.molcel.2005.02.025},
pmid = {15780935},
issn = {1097-2765},
mesh = {Bacterial Proteins ; Borrelia burgdorferi/*enzymology/genetics ; *DNA Replication ; DNA, Bacterial/genetics/*metabolism ; Endodeoxyribonucleases/*metabolism ; *Genome, Bacterial ; Telomere/genetics/*metabolism ; },
abstract = {Spirochetes of the genus Borrelia include the causative agents of Lyme disease and relapsing fever. These bacteria have a highly segmented genome where most replicons are linear molecules terminated by covalently closed hairpin telomeres. Moreover, these genomes appear to be in a state of flux with extensive and ongoing DNA rearrangements by unknown mechanisms. The B. burgdorferi telomere resolvase ResT generates the hairpin telomeres from replication intermediates in a reaction with mechanistic similarities to that catalyzed by type IB topoisomerases and tyrosine recombinases. We report here the unexpected ability of ResT to catalyze the fusion of hairpin telomeres in a reversal of the telomere resolution reaction. We propose that stabilized ResT-mediated telomere fusions are an underlying force for maintaining the B. burgdorferi genome in a state of flux.},
}
@article {pmid15779064,
year = {2005},
author = {de Pauw, ES and Roelofs, H and Zwinderman, A and van Houwelingen, JC and Fibbe, WE and de Knijff, P and Pearson, PL and Tanke, HJ},
title = {Studying the biological and technical sources of variation in telomere length of individual chromosomes.},
journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology},
volume = {65},
number = {1},
pages = {35-39},
doi = {10.1002/cyto.a.20131},
pmid = {15779064},
issn = {1552-4922},
mesh = {Adult ; Aged ; Chromosomes, Human/*genetics ; Chromosomes, Human, X/genetics ; Chromosomes, Human, Y/genetics ; DNA Probes ; *Genetic Variation ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Male ; Middle Aged ; Telomere/chemistry/*genetics ; },
abstract = {BACKGROUND: Consistent average length differences between species and chromosome arm differences within species indicate that telomere length is genetically determined. This seems to contradict an observed large variation in lengths of the same human telomere between metaphases of the same individual. We examined the extent to which the variation in the telomeres of the human X and Y chromosomes is heritable, induced, or technical in origin.<br><br>METHODS: Metaphase chromosomes were stained by fluorescence in situ hybridization with a telomere repeat-specific probe, and fluorescence intensities of the X and Y chromosomes were measured. If telomere length variation is predominantly genetically determined and a 50% probability of meiotic recombination between the pseudo-autosomal regions of Yp and Xp in the father is taken into account, one expects an equal chance that the Yp telomere of a son is derived from his father's Xp or Yp telomere. This implies that the Yp/Yq telomere ratios in fathers and sons will be identical in the absence of paternal meiotic recombination and different when recombination occurs.<br><br>RESULTS: Among five father-son pairs, four showed similar Yp/Yq ratios (P > 0.05), whereas one pair exhibited a large difference in the Yp/Yq ratio that was attributable to a significantly longer Xp than Yp telomere in the father and a presumptive meiotic exchange between X and Y during paternal meiosis. Further, the Xq telomere exhibited a generally shorter telomere length than the others.<br><br>CONCLUSIONS: The high variation in telomere length appeared to be intracellular (between sister chromatids) and, hence, technical in nature. We found no measurable induced variation in the cells studied, implying that, if induced variation exists, it is small compared with the technical variation.},
}
@article {pmid15778359,
year = {2005},
author = {Li, Y and Zhi, W and Wareski, P and Weng, NP},
title = {IL-15 activates telomerase and minimizes telomere loss and may preserve the replicative life span of memory CD8+ T cells in vitro.},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {174},
number = {7},
pages = {4019-4024},
doi = {10.4049/jimmunol.174.7.4019},
pmid = {15778359},
issn = {0022-1767},
mesh = {CD8-Positive T-Lymphocytes/enzymology/*physiology ; Cellular Senescence/*immunology ; Enzyme Activation ; Humans ; *Immunologic Memory ; Interleukin-15/*physiology ; Janus Kinase 3 ; Phosphatidylinositol 3-Kinases/metabolism ; Protein-Tyrosine Kinases/metabolism ; Signal Transduction ; Telomerase/*metabolism ; Telomere/*metabolism/ultrastructure ; },
abstract = {The preservation of the replicative life span of memory CD8(+) T cells is vital for long-term immune protection. Although IL-15 plays a key role in the homeostasis of memory CD8(+) T cells, it is unknown whether IL-15 regulates the replicative life span of memory CD8(+) T cells. In this study, we report an analysis of telomerase expression and telomere length in human memory phenotype CD8(+) T cells maintained by IL-15 in vitro. We demonstrate that IL-15 is capable of activating telomerase in memory CD8(+) T cells via Jak3 and PI3K signaling pathways. Furthermore, IL-15 induces a sustained level of telomerase activity over long periods of time, and in turn minimizes telomere loss in memory CD8(+) T cells after substantial cell divisions. These findings suggest that IL-15 activates stable telomerase expression and compensates telomere loss in memory phenotype CD8(+) T cells, and that telomerase may play an important role in memory CD8(+) T cell homeostasis.},
}
@article {pmid15775986,
year = {2005},
author = {Blasco, MA},
title = {Mice with bad ends: mouse models for the study of telomeres and telomerase in cancer and aging.},
journal = {The EMBO journal},
volume = {24},
number = {6},
pages = {1095-1103},
pmid = {15775986},
issn = {0261-4189},
mesh = {Aging/*genetics/metabolism ; Animals ; Chromatin/genetics/metabolism ; Disease Models, Animal ; Epigenesis, Genetic ; Humans ; Mice/*genetics ; *Models, Animal ; Neoplasms/enzymology/*genetics ; Telomerase/genetics/*physiology ; Telomere/*metabolism ; },
abstract = {Telomeres are capping structures at the ends of eukaryotic chromosomes, which consist of repetitive DNA bound to an array of specialized proteins. Telomeres are part of the constitutive heterochromatin and are subjected to epigenetic modifications. The function of telomeres is to prevent chromosome ends from being detected as damaged DNA. Both the length of telomere repeats and the integrity of the telomere-binding proteins are important for telomere protection. Telomere length is regulated by telomerase, by the telomere-binding proteins, as well as by activities that modify the state of the chromatin. Various mouse models with altered levels of telomerase activity, or mutant for different telomere-binding proteins, have been recently generated. Here, I will discuss how these different mouse models have contributed to our understanding on the role of telomeres and telomerase in cancer and aging.},
}
@article {pmid15773752,
year = {2005},
author = {Taddei, A and Gartenberg, MR and Neumann, FR and Hediger, F and Gasser, SM},
title = {Multiple pathways tether telomeres and silent chromatin at the nuclear periphery: functional implications for sir-mediated repression.},
journal = {Novartis Foundation symposium},
volume = {264},
number = {},
pages = {140-56; discussion 156-65, 227-30},
pmid = {15773752},
issn = {1528-2511},
mesh = {Cell Nucleus/genetics/*metabolism ; Chromatin/genetics/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Saccharomyces cerevisiae/genetics ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/*metabolism ; Telomere/*physiology ; },
abstract = {The positioning of chromosomal domains within interphase nuclei is thought to contribute to establishment and maintenance of epigenetic control. Using GFP-tagged chromosomal domains, LexA-fusion targeting and live microscopy, we investigated mechanisms through which chromatin can be anchored to the nuclear envelope (NE). We find that a subdomain of the silencing information regulator Sir4 (Sir4(PAD)) and yKu80 are sufficient to tether a chromatin region to the nuclear periphery, independently of their silencing function. Sir4(PAD) interacts with Esc1 (Establishes Silent Chromatin 1), a large acidic protein, localized at the nuclear periphery in the absence of Sir4 and yKu. Sir4 also binds to the periphery through yKu80, whose perinuclear ligand is unidentified. Both pathways are involved in the localization of natural telomeres. To show that silent chromatin can also mediate anchorage, we uncoupled the HMR silent mating-type locus from the chromosome using inducible site-specific recombination. Real-time cytological techniques reveal the position and dynamics of the excised locus. We show that the silent HMR ring associates with the NE in a SIR-dependent manner, while derepressed excised rings move without detectable constraint throughout the nucleoplasm. Dual anchoring pathways thus cooperate to generate high concentrations of SIR proteins in perinuclear foci, which in turn promote repression.},
}
@article {pmid15771613,
year = {2005},
author = {Unryn, BM and Cook, LS and Riabowol, KT},
title = {Paternal age is positively linked to telomere length of children.},
journal = {Aging cell},
volume = {4},
number = {2},
pages = {97-101},
doi = {10.1111/j.1474-9728.2005.00144.x},
pmid = {15771613},
issn = {1474-9718},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/blood/*genetics ; Cross-Sectional Studies ; Female ; Humans ; Male ; Middle Aged ; Muscle Cells/ultrastructure ; *Paternal Age ; Quantitative Trait Loci ; Sex Factors ; Telomere/*genetics ; },
abstract = {Telomere length is linked to age-associated diseases, with shorter telomeres in blood associated with an increased probability of mortality from infection or heart disease. Little is known about how human telomere length is regulated despite convincing data from twins that telomere length is largely heritable, uniform in various tissues during development until birth and variable between individuals. As sperm cells show increasing telomere length with age, we investigated whether age of fathers at conception correlated with telomere length of their offspring. Telomere length in blood from 125 random subjects was shown to be positively associated with paternal age (+22 bp yr -1, 95% confidence interval 5.2-38.3, P = 0.010), and paternal age was calculated to affect telomere length by up to 20% of average telomere length per generation. Males lose telomeric sequence faster than females (31 bp yr -1, 17.6-43.8, P < 0.0001 vs. 14 bp yr -1, 3.5-24.8, P < 0.01) and the rate of telomere loss slows throughout the human lifespan. These data indicate that paternal age plays a role in the vertical transmission of telomere length and may contribute significantly to the variability of telomere length seen in the human population, particularly if effects are cumulative through generations.},
}
@article {pmid15769667,
year = {2005},
author = {Lai, SR and Phipps, SM and Liu, L and Andrews, LG and Tollefsbol, TO},
title = {Epigenetic control of telomerase and modes of telomere maintenance in aging and abnormal systems.},
journal = {Frontiers in bioscience : a journal and virtual library},
volume = {10},
number = {},
pages = {1779-1796},
doi = {10.2741/1661},
pmid = {15769667},
issn = {1093-9946},
mesh = {Aging/*physiology ; Cellular Senescence/*physiology ; Humans ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {Epigenetic control provides a mechanism for the reversible silencing of telomerase expression that occurs as a natural consequence of differentiation. Significant overlap between indirect telomerase regulation pathways and cell cycle checkpoint pathways exist, suggesting that these discrete genetic elements (namely, p21, p53, and hTERT) synergistically cooperate to inhibit tumorigenesis. Mutations in these pathways have been known to contribute to cancer formation. However, the incorporation of epigenetic regulatory mechanisms provides another line of defense against these negative occurrences. These proteins are also implicated in the process of senescence, caused in eukaryotic cell lines by telomere shortening. Although the debate continues, there is significant evidence to classify the process of cellular senescence as an in vitro model for human aging. In addition, the study of stem cells gives information about the down-regulation of hTERT in the aging process. Diseases such as Werner S syndrome, ATM (ataxia telangiectasia mutated kinase), DKC (dyskeratosis congenita), and atherosclerosis have been linked to aberrant telomerase expression and other aging-related tissue malfunctions could be related to the presence of senescent cells changing the cellular microenvironment. Therefore, restoring telomerase activity as a putative therapeutic strategy necessitates further study to elucidate the intricacies linking genetic and epigenetic modulations of hTERT.},
}
@article {pmid15767676,
year = {2005},
author = {Jiang, WQ and Zhong, ZH and Henson, JD and Neumann, AA and Chang, AC and Reddel, RR},
title = {Suppression of alternative lengthening of telomeres by Sp100-mediated sequestration of the MRE11/RAD50/NBS1 complex.},
journal = {Molecular and cellular biology},
volume = {25},
number = {7},
pages = {2708-2721},
pmid = {15767676},
issn = {0270-7306},
mesh = {Cell Line ; DNA-Binding Proteins/*metabolism ; Gene Expression Regulation ; Humans ; Mutation/genetics ; Nuclear Proteins/genetics/*metabolism ; Protein Binding ; RNA, Small Interfering ; Telomere/genetics/*metabolism ; Transgenes/genetics ; },
abstract = {Approximately 10% of cancers overall use alternative lengthening of telomeres (ALT) instead of telomerase to prevent telomere shortening, and ALT is especially common in astrocytomas and various types of sarcomas. The hallmarks of ALT in telomerase-negative cancer cells include a unique pattern of telomere length heterogeneity, rapid changes in individual telomere lengths, and the presence of ALT-associated promyelocytic leukemia bodies (APBs) containing telomeric DNA and proteins involved in telomere binding, DNA replication, and recombination. The ALT mechanism appears to involve recombination-mediated DNA replication, but the molecular details are largely unknown. In telomerase-null Saccharomyces cerevisiae, an analogous survivor mechanism is dependent on the RAD50 gene. We demonstrate here that overexpression of Sp100, a constituent of promyelocytic leukemia nuclear bodies, sequestered the MRE11, RAD50, and NBS1 recombination proteins away from APBs. This resulted in repression of the ALT mechanism, as evidenced by progressive telomere shortening at 121 bp per population doubling, a rate within the range found in telomerase-negative normal cells, suppression of rapid telomere length changes, and suppression of APB formation. Spontaneously generated C-terminally truncated Sp100 that did not sequester the MRE11, RAD50, and NBS1 proteins failed to inhibit ALT. These findings identify for the first time proteins that are required for the ALT mechanism.},
}
@article {pmid15764387,
year = {2004},
author = {Laughton, CA and Grindon, C and Girard, P and Nikjoo, H},
title = {The mysteries of telomere structure and recognition: could radioprobing help?.},
journal = {International journal of radiation biology},
volume = {80},
number = {11-12},
pages = {805-811},
doi = {10.1080/09553000400017739},
pmid = {15764387},
issn = {0955-3002},
mesh = {Animals ; Antineoplastic Agents/administration &amp; dosage ; Binding Sites ; Crystallography/*methods ; Drug Delivery Systems/methods ; *Drug Design ; Humans ; Models, Molecular ; Molecular Conformation ; *Molecular Probe Techniques ; Neoplasms/diagnostic imaging/drug therapy/metabolism ; *Radioisotopes ; Radionuclide Imaging ; Structure-Activity Relationship ; Telomere/*chemistry/drug effects/*metabolism/ultrastructure ; },
abstract = {PURPOSE: Telomeres are specialized DNA-protein complexes found at the ends of eukaryotic chromosomes. In normal somatic cells these become shorter with each cell division and appear to control their replicative lifespan. However almost all tumours show activation of the enzyme telomerase, a specialised reverse transcriptase/DNA polymerase, that can add new telomeric repeats to the ends of chromosomes and this appears to be a key factor in the cell immortalization process. Consequently there is much current interest in the potential for inhibitors of telomere extension in the treatment of cancer. Several groups have found that it is possible to produce inhibitory molecules that target the telomeric repeat (substrate) DNA rather than the telomerase enzyme itself. This is thought to work because it has been found that in vitro, these DNA sequences can fold up into a four-stranded (quadruplex) structure that the drugs recognise and stabilize, but which is not recognised by the enzyme. However, while medicinal chemists continue to base rational design programs on this hypothesis, there is currently very little evidence that these structures form in vivo, and that in vivo the drugs work by binding to them. To have incontrovertible evidence of where and how these telomerase inhibitors and DNA interact is therefore a pressing concern for a basic understanding of their mechanism of action and effective drug development.<br><br>MATERIALS AND METHODS: Radioprobing represents a valuable new approach to the study of DNA structures. Recently we have shown through computer simulations of radioprobing that the technique is a remarkably sensitive probe of quite fine details of DNA conformation. Here we report on our simulations of the binding of a radiolabelled telomerase inhibitor, related to a class of novel inhibitors under development at Nottingham, to a variety of possible structures for telomeric DNA.<br><br>RESULTS AND CONCLUSIONS: The predicted cleavage patterns prove to be very sensitive to the DNA structure, and the mode of binding of the drug. These results suggest that radioprobing experiments should be able to provide unambiguous evidence as to the 'true' nature of the telomere-drug complexes, and so aid the rational design programme.},
}
@article {pmid15760303,
year = {2005},
author = {Grandin, N and Bailly, A and Charbonneau, M},
title = {Activation of Mrc1, a mediator of the replication checkpoint, by telomere erosion.},
journal = {Biology of the cell},
volume = {97},
number = {10},
pages = {799-814},
doi = {10.1042/BC20040526},
pmid = {15760303},
issn = {0248-4900},
mesh = {Cell Cycle/physiology ; Cell Cycle Proteins/genetics/*metabolism ; DNA Replication/*physiology ; DNA, Fungal/*metabolism ; Enzyme Activation/physiology ; Genes, cdc/*physiology ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/deficiency/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {BACKGROUND INFORMATION: In budding yeast, the loss of either telomere sequences (in telomerase-negative cells) or telomere capping (in mutants of two telomere end-protection proteins, Cdc13 and Yku) lead, by distinct pathways, to telomeric senescence. After DNA damage, activation of Rad53, which together with Chk1 represents a protein kinase central to all checkpoint pathways, normally requires Rad9, a checkpoint adaptor.<br><br>RESULTS: We report that in telomerase-negative (tlc1Delta) cells, activation of Rad53, although diminished, could still take place in the absence of Rad9. In contrast, Rad9 was essential for Rad53 activation in cells that entered senescence in the presence of functional telomerase, namely in senescent cells bearing mutations in telomere end-protection proteins (cdc13-1 yku70Delta). In telomerase-negative cells deleted for RAD9, Mrc1, another checkpoint adaptor previously implicated in the DNA replication checkpoint, mediated Rad53 activation. Rad9 and Rad53, as well as other DNA damage checkpoint proteins (Mec1, Mec3, Chk1 and Dun1), were required for complete DNA-damage-induced cell-cycle arrest after loss of telomerase function. However, unexpectedly, given the formation of an active Rad53-Mrc1 complex in tlc1Delta rad9Delta cells, Mrc1 did not mediate the cell-cycle arrest elicited by telomerase loss. Finally, we report that Rad9, Mrc1, Dun1 and Chk1 are activated by phosphorylation after telomerase inactivation.<br><br>CONCLUSIONS: These results indicate that loss of telomere capping and loss of telomere sequences, both of which provoke telomeric senescence, are perceived as two distinct types of damages. In contrast with the Rad53-Rad9-mediated cell-cycle arrest that functions in a similar way in both types of telomeric senescence, activation of Rad53-Mrc1 might represent a specific response to telomerase inactivation and/or telomere shortening, the functional significance of which has yet to be uncovered.},
}
@article {pmid15756034,
year = {2005},
author = {Lantuejoul, S and Soria, JC and Morat, L and Lorimier, P and Moro-Sibilot, D and Sabatier, L and Brambilla, C and Brambilla, E},
title = {Telomere shortening and telomerase reverse transcriptase expression in preinvasive bronchial lesions.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {11},
number = {5},
pages = {2074-2082},
doi = {10.1158/1078-0432.CCR-04-1376},
pmid = {15756034},
issn = {1078-0432},
mesh = {Adult ; Aged ; Apoptosis ; Carcinoma/*genetics/*physiopathology ; Carcinoma, Non-Small-Cell Lung/*genetics/*physiopathology ; Cell Survival ; *Cell Transformation, Neoplastic ; DNA-Binding Proteins ; Female ; *Gene Expression Profiling ; Humans ; Immunohistochemistry ; In Situ Hybridization ; Lung Neoplasms/*genetics/*physiopathology ; Male ; Middle Aged ; Precancerous Conditions ; RNA, Messenger/biosynthesis ; Signal Transduction ; Telomerase/*biosynthesis/pharmacology ; Telomere/*ultrastructure ; },
abstract = {PURPOSE: Telomerase, a ribonucleoprotein complex whose activity is related to the expression of its catalytic subunit human telomerase reverse transcriptase (hTERT), restores telomere length in tumor cells and enables immortality after p53/Rb inactivation has been achieved. To determine the timing of hTERT derepression during bronchial carcinogenesis and its relationship with telomere shortening and the p53/Rb pathway alterations, we did an immunohistochemical and in situ hybridization study in preinvasive and invasive bronchial lesions.<br><br>EXPERIMENTAL DESIGN: hTERT, P53, P16, cyclin D1, Bax-to-Bcl2 ratio, and Ki67 immunostainings were done in 106 preneoplastic lesions and in paired lung carcinoma and normal bronchial mucosae. Concomitantly, hTERT mRNA levels and qualitative telomere shortening were assessed by in situ hybridization and fluorescence in situ hybridization, respectively, in a subset of preneoplastic and neoplastic lesions.<br><br>RESULTS: Telomerase was increasingly expressed from normal epithelium to squamous metaplasia, dysplasia, and carcinoma in situ, and decreased in invasive carcinoma (P < 0.0001), with a direct correlation between protein and mRNA levels of expression (P < 0.0001). hTERT expression was directly correlated with P53, Ki67, and Bcl2-to-Bax ratio, suggesting a coupling between telomerase reactivation, proliferation, and resistance to apoptosis. Telomere signals significantly decreased as early as squamous metaplasia and progressively increased over the spectrum of preneoplastic lesions.<br><br>CONCLUSIONS: Telomere shortening represents an early genetic abnormality in bronchial carcinogenesis, preceding telomerase expression and p53/Rb inactivation, which predominate in high-grade preinvasive lesions.},
}
@article {pmid15753647,
year = {2005},
author = {Cerone, MA and Ward, RJ and Londoño-Vallejo, JA and Autexier, C},
title = {Telomerase RNA mutated in autosomal dyskeratosis congenita reconstitutes a weakly active telomerase enzyme defective in telomere elongation.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {4},
number = {4},
pages = {585-589},
pmid = {15753647},
issn = {1551-4005},
mesh = {Cell Cycle Proteins/chemistry ; Cell Line, Tumor ; Chromosome Mapping ; Chromosomes/ultrastructure ; Dyskeratosis Congenita/*genetics ; Genes, Dominant ; Humans ; In Situ Hybridization, Fluorescence ; *Mutation ; Nuclear Proteins/chemistry ; RNA/chemistry/*genetics ; RNA, Ribosomal/chemistry ; Reverse Transcriptase Polymerase Chain Reaction ; Sequence Analysis, DNA ; Telomerase/*genetics/metabolism ; Telomere/*ultrastructure ; Transfection ; },
abstract = {Dyskeratosis congenita (DC) is a rare multi-system syndrome characterized by nail dystrophy, abnormal skin pigmentation and mucosal leukoplakia. The gene mutated in the X-linked form of human DC encodes for dyskerin, a nucleolar pseudourydilase that is involved in rRNA maturation. Dyskerin is also involved in telomerase function through its interaction with the telomerase RNA (hTR). Mutations in dyskerin result in low levels of hTR, decreased telomerase activity and telomere shortening. Autosomal dominant DC is characterized by mutations in hTR, supporting the hypothesis that the DC phenotype may be caused by impaired telomere maintenance. Several mutations have been identified in different regions of hTR in patients affected by autosomal dominant DC. Recent reports have shown that coexpression of wild-type hTR with hTR harboring mutations found in the pseudoknot domain does not affect telomerase activity in vitro. However, these studies did not assess the consequences of mutant hTR expression at the telomeres. Here we provide the first direct in vivo evidence that a mutant hTR carrying the GC to AG double substitution in the pseudoknot at nucleotides 107-108 found in patients affected by autosomal dominant DC does not behave as a dominant-negative for telomere maintenance. Rather it reconstitutes a weakly active telomerase enzyme, which is defective in telomere elongation.},
}
@article {pmid15753570,
year = {2005},
author = {de la Herrán, R and Cuñado, N and Navajas-Pérez, R and Santos, JL and Ruiz Rejón, C and Garrido-Ramos, MA and Ruiz Rejón, M},
title = {The controversial telomeres of lily plants.},
journal = {Cytogenetic and genome research},
volume = {109},
number = {1-3},
pages = {144-147},
doi = {10.1159/000082393},
pmid = {15753570},
issn = {1424-859X},
mesh = {Blotting, Southern ; Chromosomes, Plant/*genetics ; DNA, Plant/genetics ; In Situ Hybridization ; Lilium/classification/cytology/*genetics ; Meiosis ; Telomere/*genetics/ultrastructure ; },
abstract = {The molecular structure of the exceptional telomeres of six plant species belonging to the order Asparagales and two species of the order Liliales was analyzed using Southern blot and fluorescence in situ hybridization. Three different situations were found, namely: i) In the two Liliales species, Tulipa australis (Liliaceae) and Merendera montana (Colchicaceae), the chromosome ends display hybridization signals with oligonucleotides resembling telomere repeats of both plants (TTTAGGG)n and vertebrates (TTAGGG)n. ii) Asparagales species such as Phormium tenax (Hemerocallidaceae), Muscari comosum (Hyacinthaceae), Narcissus jonquilla (Amaryllidaceae) and Allium sativum (Alliaceae) lack both the plant telomere repeats and the vertebrate telomere repeats. iii) Two other Asparagales species, Aloe vera (Asphodelaceae) and an Iris hybrid (Iridaceae), display positive hybridization with the vertebrate telomere repeats but not with the plant telomere repeats. Southern blot hybridization revealed concurring results. On this basis, the composition of the telomere structure in this plant group is discussed.},
}
@article {pmid15749662,
year = {2005},
author = {Hartmann, U and Brümmendorf, TH and Balabanov, S and Thiede, C and Illme, T and Schaich, M},
title = {Telomere length and hTERT expression in patients with acute myeloid leukemia correlates with chromosomal abnormalities.},
journal = {Haematologica},
volume = {90},
number = {3},
pages = {307-316},
pmid = {15749662},
issn = {1592-8721},
mesh = {Acute Disease ; Adolescent ; Adult ; Aged ; Case-Control Studies ; *Chromosome Aberrations ; Gene Expression Regulation, Neoplastic ; Humans ; Leukemia, Myeloid/etiology/*genetics ; Middle Aged ; Telomerase/*genetics ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND AND OBJECTIVES: Acute myeloid leukemia (AML) is a malignant, genetically heterogenous disorder characterized by uncontrolled growth of immature myeloid cells. The aim of this study was to analyze whether telomere length and/or hTERT expression are correlated with clonal chromosomal aberrations in AML.<br><br>DESIGN AND METHODS: Telomere length in mononuclear cells derived from 137 previously untreated patients with >or= 80% blasts was analyzed by flow fluorescent in situ hybridization. Results were expressed in telomere fluorescence Units (1 TFU=1 kb). The expression of hTERT, including its different splice variants was studied by reverse transcription-polymerase chain reaction.<br><br>RESULTS: Age-adjusted telomere length in AML patients was significantly reduced as compared to in matched controls, consisting of peripheral blood granulocytes from healthy individuals (0-90 years) (median: -2.5 TFU; p<0.001). Patients with an aberrant karyotype had significantly shorter telomeres than patients with a normal karyotype (median -3.0 vs. -2.3 TFU; p=0.03). The shortest telomeres were found in patients with multiple aberrations (median -3.7 TFU; p=0.03). hTERT expression was found to be correlated with chromosomal abnormalities as well as with the detection of functional hTERT splicing variants.<br><br>These findings suggest an important role of intense telomere loss in the development of genetic instability during the pathogenesis of AML. It is assumed that critical telomere shortening in AML blasts could lead to telomerase activation and therefore prevent blasts from replicative senescence, one possible mechanism for clonal selection and disease progression. Therefore, telomere length might serve as a prognostic marker for AML patients. These findings would have to be confirmed in large, prospective studies.},
}
@article {pmid15749652,
year = {2005},
author = {Engelhardt, M and Wäsch, R},
title = {Telomere length and hTERT expression in patients with acute myeloid leukemia correlate with karyotypic instability.},
journal = {Haematologica},
volume = {90},
number = {3},
pages = {289B},
pmid = {15749652},
issn = {1592-8721},
mesh = {Acute Disease ; Chromosome Aberrations ; Humans ; Karyotyping ; Leukemia, Myeloid/etiology/*genetics ; Telomerase/*genetics ; Telomere/*ultrastructure ; },
}
@article {pmid15746160,
year = {2005},
author = {Broberg, K and Björk, J and Paulsson, K and Höglund, M and Albin, M},
title = {Constitutional short telomeres are strong genetic susceptibility markers for bladder cancer.},
journal = {Carcinogenesis},
volume = {26},
number = {7},
pages = {1263-1271},
doi = {10.1093/carcin/bgi063},
pmid = {15746160},
issn = {0143-3334},
mesh = {Adult ; Aged ; Aged, 80 and over ; Carcinogens/metabolism/toxicity ; Case-Control Studies ; DNA Damage ; DNA Repair ; Female ; *Genetic Markers ; *Genetic Predisposition to Disease ; Genotype ; Glutathione Transferase/genetics ; Humans ; Male ; Middle Aged ; Odds Ratio ; Polymerase Chain Reaction ; Risk Factors ; Smoking/adverse effects ; Telomere/*ultrastructure ; Urinary Bladder Neoplasms/*genetics ; },
abstract = {Lack of functional telomeres can cause chromosomal aberrations. This type of genetic instability may promote tumorigenesis. We have investigated the association between mean telomere length in buccal cells (assessed with quantitative real-time PCR) and bladder cancer risk in a case-control study. Patients with bladder cancer displayed significantly shorter telomeres than control subjects (P = 0.001). Median telomere length ratio was 0.95 (range 0.53-3.2) for cases and 1.1 (0.51-2.4) for controls. Moreover, the adjusted odds ratio (OR) for bladder cancer was significantly increased in the quartile with the shortest telomere length OR = 4.5 [95% confidence interval (CI) 1.7-12]. It is known that oxidative stress, alkylation or UV radiation increases shortening of telomeres. Therefore, we also analyzed whether environmental and genetic factors associated with DNA damage, i.e. smoking and polymorphisms in the genes involved in the metabolism of genotoxic carcinogens (EPHX1, GSTA1, GSTM1, GSTP1, GSTT1, NAT1, NAT2 and NQO1) or DNA repair (APE1, NBS1, XPC, XPD, XRCC1, XRCC3 and XRCC4), could modify the association between telomere length and cancer risk. A clear effect of smoking and telomere length could be observed. Current smokers with short telomeres had more than six times as higher risk as non-smokers/former smokers with long telomeres (OR = 6.3, 95% CI 1.7-23). Lack of the biotransformation gene GSTM1 and short telomeres were associated with OR = 6.5 (95% CI 2.4-18), whereas homozygous carriers of 312Asn in the DNA repair gene XPD, with short telomeres, displayed an OR of 17 (95% CI 1.9-150). However, no significant interaction for cancer risk could be proven for telomere length, smoking and susceptibility genotypes of metabolizing and DNA-repairing genes.},
}
@article {pmid15746080,
year = {2005},
author = {Grabowski, P and Hultdin, M and Karlsson, K and Tobin, G and Aleskog, A and Thunberg, U and Laurell, A and Sundström, C and Rosenquist, R and Roos, G},
title = {Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status.},
journal = {Blood},
volume = {105},
number = {12},
pages = {4807-4812},
doi = {10.1182/blood-2004-11-4394},
pmid = {15746080},
issn = {0006-4971},
mesh = {Adult ; Aged ; Aged, 80 and over ; Blotting, Southern ; Female ; *Genes, Immunoglobulin ; Humans ; Immunoglobulin Heavy Chains/*genetics ; Immunophenotyping ; In Situ Hybridization, Fluorescence ; Leukemia, Lymphocytic, Chronic, B-Cell/*diagnosis/*genetics ; Lymph Nodes/pathology ; Male ; Middle Aged ; Models, Statistical ; *Mutation ; Polymerase Chain Reaction ; Prognosis ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*ultrastructure ; Time Factors ; Treatment Outcome ; },
abstract = {B-cell chronic lymphocytic leukemia (CLL) consists of 2 prognostic entities where cases with mutated immunoglobulin V(H) genes have better outcome than unmutated cases. V(H)-mutated CLLs display longer telomeres compared with unmutated cases and telomere length has been indicated to predict outcome, although the prognostic value of telomere length has not been fully established in CLL. We analyzed telomere length, V(H) gene mutation status, and clinical parameters in a large series of CLL. Telomere length was assessed by quantitative polymerase chain reaction (PCR), giving a very good correlation to telomere length estimated by Southern blotting (P < .001). The prognostic information given by mutation status (n = 282) and telomere length (n = 246) was significant (P < .001, respectively). Telomere length was a prognostic factor for stage A (P = .021) and stage B/C (P = .018) patients, whereas mutation status predicted outcome only in stage A patients (P < .001). Furthermore, mutated CLLs were subdivided by telomere length into 2 groups with different prognoses (P = .003), a subdivision not seen for unmutated cases (P = .232). Interestingly, the V(H)-mutated group with short telomeres had an overall survival close to that of the unmutated cases. Thus, by combining V(H) mutation status and telomere length, an improved subclassification of CLL was achieved identifying previously unrecognized patient groups with different outcomes.},
}
@article {pmid15745634,
year = {2005},
author = {Schaetzlein, S and Rudolph, KL},
title = {Telomere length regulation during cloning, embryogenesis and ageing.},
journal = {Reproduction, fertility, and development},
volume = {17},
number = {1-2},
pages = {85-96},
doi = {10.1071/rd04112},
pmid = {15745634},
issn = {1031-3613},
mesh = {Aging/*genetics ; Animals ; Animals, Genetically Modified/genetics ; *Cloning, Organism ; Embryonic Development/*genetics ; Humans ; Telomerase/metabolism ; Telomere/*ultrastructure ; },
abstract = {Telomeres are nucleoprotein complexes at the end of eukaryotic chromosomes with an essential role in chromosome capping. Owing to the end-replication problem of DNA polymerase, telomeres shorten during each cell division. When telomeres become critically short, they loose their capping function, which in turn induces a DNA damage-like response. This mechanism inhibits cell proliferation at the senescence stage and there is evidence that it limits the regenerative capacity of tissues and organs during chronic diseases and ageing. The holoenzyme telomerase synthesises telomeric DNA de novo, but, in humans, it is active only during embryogenesis, in immature germ cells and in a subset of stem/progenitor cells during postnatal life. Telomere length can be maintained or increased by telomerase, a process that appears to be regulated by a variety of telomere-binding proteins that control telomerase recruitment and activity at the telomeres. During embryogenesis, telomerase is strongly activated at the morula/blastocyst transition. At this transition, telomeres are significantly elongated in murine and bovine embryos. Early embryonic telomere elongation is telomerase dependent and leads to a rejuvenation of telomeres in cloned bovine embryos. Understanding of the molecular mechanisms underlying this early embryonic telomere elongation programme is of great interest for medical research in the fields of regeneration, cell therapies and therapeutic cloning.},
}
@article {pmid15743814,
year = {2005},
author = {Chai, W and Shay, JW and Wright, WE},
title = {Human telomeres maintain their overhang length at senescence.},
journal = {Molecular and cellular biology},
volume = {25},
number = {6},
pages = {2158-2168},
pmid = {15743814},
issn = {0270-7306},
support = {R01 AG001228/AG/NIA NIH HHS/United States ; AG01228/AG/NIA NIH HHS/United States ; },
mesh = {Antigens, Polyomavirus Transforming/genetics/physiology ; Biological Assay ; Cells, Cultured ; Cellular Senescence/genetics/*physiology ; DNA/chemistry ; Fibroblasts/cytology ; Gene Silencing ; Heterogeneous Nuclear Ribonucleoprotein A1 ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B ; Humans ; Nucleic Acid Hybridization/genetics ; Oncogene Proteins, Viral/genetics/physiology ; Papillomavirus E7 Proteins ; Repressor Proteins/genetics/physiology ; Retinoblastoma Protein/metabolism/physiology ; Ribonucleoproteins/chemistry ; Telomere/*chemistry/genetics/*physiology ; Thymus Hormones/chemistry ; Tumor Suppressor Protein p53/metabolism/physiology ; },
abstract = {Normal human cells in culture enter replicative senescence after a finite number of population doublings. The exact molecular mechanisms triggering the growth arrest are poorly understood. A recent report on the disappearance of the G-rich 3' telomeric overhang in senescent cells led to the hypothesis that loss of the 3' G-rich overhang is the molecular signal that triggers senescence. Here, we describe a quantitative assay to measure the length of the G-rich 3' telomeric overhangs from cultured cells. Using both this assay and the conventional nondenaturing hybridization assay for measuring G-rich overhangs, we show that normal human fibroblasts can maintain their overhangs at senescence. Furthermore, cells do not lose their overhangs when they bypass senescence after the inactivation of p53 and Rb. We thus conclude that a global reduction in overhang length is not the molecular signal that triggers replicative senescence.},
}
@article {pmid15743674,
year = {2005},
author = {Gilley, D and Tanaka, H and Herbert, BS},
title = {Telomere dysfunction in aging and cancer.},
journal = {The international journal of biochemistry &amp; cell biology},
volume = {37},
number = {5},
pages = {1000-1013},
doi = {10.1016/j.biocel.2004.09.003},
pmid = {15743674},
issn = {1357-2725},
mesh = {Aging/*genetics ; Antineoplastic Agents/pharmacology ; Cellular Senescence/drug effects ; DNA Damage ; Genomic Instability/drug effects ; Humans ; Neoplasms/*genetics ; Telomere/chemistry/drug effects/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomeres are unique DNA-protein structures that contain noncoding TTAGGG repeats and telomere-associated proteins. These specialized structures are essential for maintaining genomic integrity. Alterations that lead to the disruption of telomere maintenance result in chromosome end-to-end fusions and/or ends being recognized as double-strand breaks. A large body of evidence suggests that the cell responds to dysfunctional telomeres by undergoing senescence, apoptosis, or genomic instability. In conjunction with other predisposing mechanisms, the genomic instability encountered in preimmortal cells due to dysfunctional or uncapped telomeres might lead to cancer. Furthermore, telomere dysfunction has been proposed to play critical roles in aging as well as cancer progression. Conversely, recent evidence has shown that targeting telomere maintenance mechanisms and inducing telomere dysfunction in cancer cells by inhibiting telomerase can lead to catastrophic events including rapid cell death and increased sensitivity to other cancer therapeutics. Thus, given the major role telomeres play during development, it is important to continue our understanding telomere structure, function and maintenance. Herein, we provide an overview of the emerging knowledge of telomere dysfunction and how it relates to possible links between aging and cancer.},
}
@article {pmid15743672,
year = {2005},
author = {Rodier, F and Kim, SH and Nijjar, T and Yaswen, P and Campisi, J},
title = {Cancer and aging: the importance of telomeres in genome maintenance.},
journal = {The international journal of biochemistry &amp; cell biology},
volume = {37},
number = {5},
pages = {977-990},
doi = {10.1016/j.biocel.2004.10.012},
pmid = {15743672},
issn = {1357-2725},
mesh = {*Aging ; Animals ; DNA-Binding Proteins/physiology ; *Genomic Instability ; Humans ; Neoplasms/*genetics ; Telomere/chemistry/*physiology ; },
abstract = {Telomeres are the specialized DNA-protein structures that cap the ends of linear chromosomes, thereby protecting them from degradation and fusion by cellular DNA repair processes. In vertebrate cells, telomeres consist of several kilobase pairs of DNA having the sequence TTAGGG, a few hundred base pairs of single-stranded DNA at the 3' end of the telomeric DNA tract, and a host of proteins that organize the telomeric double and single-stranded DNA into a protective structure. Functional telomeres are essential for maintaining the integrity and stability of genomes. When combined with loss of cell cycle checkpoint controls, telomere dysfunction can lead to genomic instability, a common cause and hallmark of cancer. Consequently, normal mammalian cells respond to dysfunctional telomeres by undergoing apoptosis (programmed cell death) or cellular senescence (permanent cell cycle arrest), two cellular tumor suppressor mechanisms. These tumor suppressor mechanisms are potent suppressors of cancer, but recent evidence suggests that they can antagonistically also contribute to aging phenotypes. Here, we review what is known about the structure and function of telomeres in mammalian cells, particularly human cells, and how telomere dysfunction may arise and contribute to cancer and aging phenotypes.},
}
@article {pmid15743486,
year = {2005},
author = {Yudoh, K and Nguyen, vT and Nakamura, H and Hongo-Masuko, K and Kato, T and Nishioka, K},
title = {Potential involvement of oxidative stress in cartilage senescence and development of osteoarthritis: oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function.},
journal = {Arthritis research &amp; therapy},
volume = {7},
number = {2},
pages = {R380-91},
pmid = {15743486},
issn = {1478-6362},
mesh = {Aged ; Antioxidants/pharmacology ; Ascorbic Acid/pharmacology ; Cartilage, Articular/metabolism/*pathology ; Cell Division/drug effects ; Cells, Cultured/metabolism ; Cellular Senescence/*physiology ; Chondrocytes/drug effects/physiology/*ultrastructure ; DNA Replication/drug effects ; Disease Progression ; Female ; Free Radicals ; *Genomic Instability ; Glycosaminoglycans/biosynthesis ; Humans ; Middle Aged ; Organ Culture Techniques ; Osteoarthritis, Knee/*etiology/metabolism/pathology/surgery ; Oxidative Stress/*physiology ; Reactive Oxygen Species/pharmacology ; Telomere/*ultrastructure ; Tyrosine/analogs &amp; derivatives/analysis ; },
abstract = {Oxidative stress leads to increased risk for osteoarthritis (OA) but the precise mechanism remains unclear. We undertook this study to clarify the impact of oxidative stress on the progression of OA from the viewpoint of oxygen free radical induced genomic instability, including telomere instability and resulting replicative senescence and dysfunction in human chondrocytes. Human chondrocytes and articular cartilage explants were isolated from knee joints of patients undergoing arthroplastic knee surgery for OA. Oxidative damage and antioxidative capacity in OA cartilage were investigated in donor-matched pairs of intact and degenerated regions of tissue isolated from the same cartilage explants. The results were histologically confirmed by immunohistochemistry for nitrotyrosine, which is considered to be a maker of oxidative damage. Under treatment with reactive oxygen species (ROS; 0.1 micromol/l H2O2) or an antioxidative agent (ascorbic acid: 100.0 micromol/l), cellular replicative potential, telomere instability and production of glycosaminoglycan (GAG) were assessed in cultured chondrocytes. In tissue cultures of articular cartilage explants, the presence of oxidative damage, chondrocyte telomere length and loss of GAG to the medium were analyzed in the presence or absence of ROS or ascorbic acid. Lower antioxidative capacity and stronger staining of nitrotyrosine were observed in the degenerating regions of OA cartilages as compared with the intact regions from same explants. Immunostaining for nitrotyrosine correlated with the severity of histological changes to OA cartilage, suggesting a correlation between oxidative damage and articular cartilage degeneration. During continuous culture of chondrocytes, telomere length, replicative capacity and GAG production were decreased by treatment with ROS. In contrast, treatment with an antioxidative agent resulted in a tendency to elongate telomere length and replicative lifespan in cultured chondrocytes. In tissue cultures of cartilage explants, nitrotyrosine staining, chondrocyte telomere length and GAG remaining in the cartilage tissue were lower in ROS-treated cartilages than in control groups, whereas the antioxidative agent treated group exhibited a tendency to maintain the chondrocyte telomere length and proteoglycan remaining in the cartilage explants, suggesting that oxidative stress induces chondrocyte telomere instability and catabolic changes in cartilage matrix structure and composition. Our findings clearly show that the presence of oxidative stress induces telomere genomic instability, replicative senescence and dysfunction of chondrocytes in OA cartilage, suggesting that oxidative stress, leading to chondrocyte senescence and cartilage ageing, might be responsible for the development of OA. New efforts to prevent the development and progression of OA may include strategies and interventions aimed at reducing oxidative damage in articular cartilage.},
}
@article {pmid15741234,
year = {2005},
author = {Kaminker, P and Plachot, C and Kim, SH and Chung, P and Crippen, D and Petersen, OW and Bissell, MJ and Campisi, J and Lelièvre, SA},
title = {Higher-order nuclear organization in growth arrest of human mammary epithelial cells: a novel role for telomere-associated protein TIN2.},
journal = {Journal of cell science},
volume = {118},
number = {Pt 6},
pages = {1321-1330},
pmid = {15741234},
issn = {0021-9533},
support = {R37 CA064786/CA/NCI NIH HHS/United States ; T32 AG000266/AG/NIA NIH HHS/United States ; AG09909/AG/NIA NIH HHS/United States ; R01 CA064786-05/CA/NCI NIH HHS/United States ; R37 AG009909/AG/NIA NIH HHS/United States ; R56 AG009909/AG/NIA NIH HHS/United States ; R01 CA064786/CA/NCI NIH HHS/United States ; AG00266/AG/NIA NIH HHS/United States ; CA64786/CA/NCI NIH HHS/United States ; R37 AG009909-10/AG/NIA NIH HHS/United States ; },
mesh = {Blotting, Western ; Breast/*cytology ; Bromodeoxyuridine/pharmacology ; Cell Culture Techniques/methods ; Cell Differentiation ; Cell Nucleus/*metabolism ; Cell Proliferation ; Cells, Cultured ; Deoxyribonuclease I/metabolism ; Deoxyribonucleases/metabolism ; Epithelial Cells/*cytology/metabolism ; Heterochromatin/chemistry ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Ki-67 Antigen/biosynthesis ; Microscopy, Fluorescence ; Phenotype ; Protein Structure, Tertiary ; Retroviridae/genetics ; Ribonuclease, Pancreatic/metabolism ; Ribonucleases/metabolism ; Telomere/metabolism/ultrastructure ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Nuclear organization, such as the formation of specific nuclear subdomains, is generally thought to be involved in the control of cellular phenotype; however, there are relatively few specific examples of how mammalian nuclei organize during radical changes in phenotype, such as those occurring during differentiation and growth arrest. Using human mammary epithelial cells in which growth arrest is essential for morphological differentiation, we show that the arrest of cell proliferation is accompanied by a reorganization of the telomere-associated protein, TIN2, into one to three large nuclear subdomains. The large TIN2 domains do not contain telomeres and occur concomitant with the continued presence of TIN2 at telomeres. The TIN2 domains were sensitive to DNase, but not RNase, occurred frequently, but not exclusively near nucleoli, and overlapped often with dense domains containing heterochromatin protein 1gamma. Expression of truncated forms of TIN2 simultaneously prevented the formation of TIN2 domains and relaxed the stringent morphogenesis-induced growth arrest in human mammary epithelial cells. Here we show that a novel extra-telomeric organization of TIN2 is associated with the control of cell proliferation and identify TIN2 as an important regulator of mammary epithelial differentiation.},
}
@article {pmid15741219,
year = {2005},
author = {Röth, A and Baerlocher, GM and Schertzer, M and Chavez, E and Dührsen, U and Lansdorp, PM},
title = {Telomere loss, senescence, and genetic instability in CD4+ T lymphocytes overexpressing hTERT.},
journal = {Blood},
volume = {106},
number = {1},
pages = {43-50},
pmid = {15741219},
issn = {0006-4971},
support = {AI29524/AI/NIAID NIH HHS/United States ; },
mesh = {Adult ; CD4-Positive T-Lymphocytes/*cytology/physiology ; Cell Division/immunology ; Cell Nucleus ; Cells, Cultured ; Cellular Senescence/*immunology ; DNA-Binding Proteins ; Gene Expression/immunology ; Gene Expression Profiling ; Green Fluorescent Proteins/genetics ; Humans ; Immunologic Memory/physiology ; Telomerase/*genetics/metabolism ; Telomere/*metabolism ; Transduction, Genetic ; },
abstract = {Little is known about the long-term consequences of overexpression of the human telomerase reverse transcriptase (hTERT) gene in T lymphocytes. To address this issue, we transduced polyclonal as well as clonally derived populations of naive and memory CD44 T cells from 2 healthy donors (aged 24 and 34 years) with retroviral vectors encoding green fluorescence protein (GFP) and hTERT (GFP-hTERT) or GFP alone. After transduction, cells were sorted on the basis of GFP expression and cultured in vitro until senescence. T cells transduced with hTERT exhibited high stable telomerase activity throughout the culture period. Relative to GFP controls, minor changes in overall gene expression were observed yet the proliferative lifespan of the hTERT-transduced populations was significantly increased and the rate of telomere loss was lower. Nevertheless, hTERT-transduced cells showed progressive telomere loss and had shorter telomeres at senescence than controls (2.3 +/- 0.3 kilobase [kb] versus 3.4 +/- 0.1 kb). Furthermore, a population of cells with 4N DNA consisting of binucleated cells with connected nuclei emerged in the hTERT-transduced cells prior to senescence. We conclude that overexpression of hTERT in CD4+ T cells provides a proliferative advantage independent of the average telomere length but does not prevent eventual genetic instability and replicative senescence.},
}
@article {pmid15737568,
year = {2005},
author = {Folini, M and Brambilla, C and Villa, R and Gandellini, P and Vignati, S and Paduano, F and Daidone, MG and Zaffaroni, N},
title = {Antisense oligonucleotide-mediated inhibition of hTERT, but not hTERC, induces rapid cell growth decline and apoptosis in the absence of telomere shortening in human prostate cancer cells.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {41},
number = {4},
pages = {624-634},
doi = {10.1016/j.ejca.2004.12.002},
pmid = {15737568},
issn = {0959-8049},
mesh = {Apoptosis ; Cell Division ; Cell Line, Tumor ; DNA-Binding Proteins ; Humans ; Male ; Oligonucleotides, Antisense/*pharmacology ; Prostatic Neoplasms/*genetics/pathology ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/*pathology ; },
abstract = {Recent evidence points to a novel function of human telomerase reverse transcriptase (hTERT) in promoting tumour cell survival, which might be independent of the telomere-elongating activity of the enzyme. To test this hypothesis, we evaluated comparatively the effects of telomerase inhibition, accomplished through antisense oligonucleotide-mediated interference with hTERT or human telomerase RNA component (hTERC), on the proliferative potential of DU145 human prostate cancer cells. Exposure of cells to a 2'-O-methyl-RNA phosphorothioate oligonucleotide targeting a splicing site within hTERT pre-mRNA induced almost complete inhibition of telomerase activity as a consequence of a marked reduction of the hTERT mRNA expression level, an early decline of DU145 cell growth and apoptotic cell death without any appreciable telomere shortening. Conversely, exposure of DU145 cells to a 2'-O-methyl-RNA phosphorothioate oligonucleotide targeting the template region of hTERC failed to interfere with cell proliferation in spite of the almost complete abrogation of telomerase activity. These results extend and corroborate earlier evidence in favour of an enzymatic activity-independent mechanism by which hTERT maintains tumour cell survival and proliferation.},
}
@article {pmid15735722,
year = {2005},
author = {Pennarun, G and Granotier, C and Gauthier, LR and Gomez, D and Hoffschir, F and Mandine, E and Riou, JF and Mergny, JL and Mailliet, P and Boussin, FD},
title = {Apoptosis related to telomere instability and cell cycle alterations in human glioma cells treated by new highly selective G-quadruplex ligands.},
journal = {Oncogene},
volume = {24},
number = {18},
pages = {2917-2928},
doi = {10.1038/sj.onc.1208468},
pmid = {15735722},
issn = {0950-9232},
mesh = {Apoptosis/*physiology ; Cell Cycle ; Cell Division/genetics/immunology ; Genomic Instability/*physiology ; Glioma/drug therapy ; Humans ; Ligands ; Pyridines/pharmacology ; Telomerase/antagonists &amp; inhibitors ; Telomere/*genetics/*metabolism ; },
abstract = {Telomerase represents a relevant target for cancer therapy. Molecules able to stabilize the G-quadruplex (G4), a structure adopted by the 3'-overhang of telomeres, are thought to inhibit telomerase by blocking its access to telomeres. We investigated the cellular effects of four new 2,6-pyridine-dicarboxamide derivatives displaying strong selectivity for G4 structures and strong inhibition of telomerase in in vitro assays. These compounds inhibited cell proliferation at very low concentrations and then induced a massive apoptosis within a few days in a dose-dependent manner in cultures of three telomerase-positive glioma cell lines, T98G, CB193 and U118-MG. They had also antiproliferative effects in SAOS-2, a cell line in which telomere maintenance involves an alternative lengthening of telomeres (ALT) mechanism. We show that apoptosis was preceded by multiple alterations of the cell cycle: activation of S-phase checkpoints, dramatic increase of metaphase duration and cytokinesis defects. These effects were not associated with telomere shortening, but they were directly related to telomere instability involving telomere end fusion and anaphase bridge formation. Pyridine-based G-quadruplex ligands are therefore promising agents for the treatment of various tumors including malignant gliomas.},
}
@article {pmid15735711,
year = {2005},
author = {Nijjar, T and Bassett, E and Garbe, J and Takenaka, Y and Stampfer, MR and Gilley, D and Yaswen, P},
title = {Accumulation and altered localization of telomere-associated protein TRF2 in immortally transformed and tumor-derived human breast cells.},
journal = {Oncogene},
volume = {24},
number = {20},
pages = {3369-3376},
doi = {10.1038/sj.onc.1208482},
pmid = {15735711},
issn = {0950-9232},
support = {CA-108480/CA/NCI NIH HHS/United States ; CA-24844/CA/NCI NIH HHS/United States ; },
mesh = {Breast/pathology ; Breast Neoplasms/*metabolism/*pathology ; Cell Line, Transformed ; Cell Line, Tumor ; Cell Proliferation ; Cellular Senescence ; DNA-Binding Proteins ; Disease Progression ; Genes, Dominant ; Humans ; Immunohistochemistry ; RNA, Messenger/metabolism ; Telomerase/metabolism ; Telomere/metabolism/ultrastructure ; Telomeric Repeat Binding Protein 2/*biosynthesis/metabolism ; Time Factors ; Tumor Suppressor Protein p53 ; Up-Regulation ; },
abstract = {We have used cultured human mammary epithelial cells (HMEC) and breast tumor-derived lines to gain information on defects that occur during breast cancer progression. HMEC immortalized by a variety of agents (the chemical carcinogen benzo(a)pyrene, oncogenes c-myc and ZNF217, and/or dominant negative p53 genetic suppressor element GSE22) displayed marked upregulation (10-15 fold) of the telomere-binding protein, TRF2. Upregulation of TRF2 protein was apparently due to differences in post-transcriptional regulation, as mRNA levels remained comparable in finite lifespan and immortal HMEC. TRF2 protein was not upregulated by the oncogenic agents alone in the absence of immortalization, nor by expression of exogenously introduced hTERT genes. We found TRF2 levels to be at least twofold higher than in control cells in 11/15 breast tumor cell lines, suggesting that elevated TRF2 levels are a frequent occurrence during the transformation of breast tumor cells in vivo. The dispersed distribution of TRF2 throughout the nuclei in some immortalized and tumor-derived cells indicated that not all the TRF2 was associated with telomeres in these cells. The process responsible for accumulation of TRF2 in immortalized HMEC and breast tumor-derived cell lines may promote tumorigenesis by contributing to the cells' ability to maintain an indefinite lifespan.},
}
@article {pmid15735707,
year = {2005},
author = {Schleiermacher, G and Bourdeaut, F and Combaret, V and Picrron, G and Raynal, V and Aurias, A and Ribeiro, A and Janoueix-Lerosey, I and Delattre, O},
title = {Stepwise occurrence of a complex unbalanced translocation in neuroblastoma leading to insertion of a telomere sequence and late chromosome 17q gain.},
journal = {Oncogene},
volume = {24},
number = {20},
pages = {3377-3384},
doi = {10.1038/sj.onc.1208486},
pmid = {15735707},
issn = {0950-9232},
mesh = {Base Sequence ; Blotting, Southern ; Chromosome Aberrations ; Chromosome Mapping ; Chromosomes, Human, Pair 1 ; *Chromosomes, Human, Pair 17 ; Chromosomes, Human, Pair 4 ; Cloning, Molecular ; Humans ; In Situ Hybridization, Fluorescence ; Models, Genetic ; Molecular Sequence Data ; Neuroblastoma/*genetics/metabolism ; Polymerase Chain Reaction ; Telomere/*ultrastructure ; *Translocation, Genetic ; },
abstract = {In neuroblastoma, the most frequent genetic alterations are unbalanced translocations involving chromosome 17. To gain insights into these rearrangements, we have characterized a previously identified der(1)t(1;17) of the CLB-Bar cell line. The 17q breakpoint was mapped by FISH. Subsequently, a rearranged fragment was identified by Southern analysis, cloned in a lambda vector and sequenced. The chromosome rearrangement is more complex than expected due to the presence of an interstitial 4p telomeric sequence between chromosome 1p and 17q. Three different genes, which may play a role in neuroblastoma development, are disrupted by the translocation breakpoints. Indeed, the 3'UTR of the PIP5K2B gene on chromosome 17q is directly fused to the (TTAGGG)n repeat of the chromosome 4p telomere, and the (1;4) fusion disrupts the MACF1 (microtubule-actin crosslinking factor 1) and POLN genes, respectively. Interestingly, the (1;4) fusion was present at diagnosis and at relapse, whereas the (4;17) fusion was detected at relapse only, leading to a secondary 17q gain confirmed by array CGH therefore indicating that 17q gain may not be a primary event in neuroblastoma. Finally, screening of a panel of neuroblastoma cell lines identified interstitial telomeric sequences in three other cases, suggesting that this may be a recurrent mechanism leading to unbalanced translocations in neuroblastoma.},
}
@article {pmid15735037,
year = {2005},
author = {Burger, AM and Dai, F and Schultes, CM and Reszka, AP and Moore, MJ and Double, JA and Neidle, S},
title = {The G-quadruplex-interactive molecule BRACO-19 inhibits tumor growth, consistent with telomere targeting and interference with telomerase function.},
journal = {Cancer research},
volume = {65},
number = {4},
pages = {1489-1496},
doi = {10.1158/0008-5472.CAN-04-2910},
pmid = {15735037},
issn = {0008-5472},
mesh = {Acridines/*pharmacology ; Animals ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; DNA/drug effects/genetics/*metabolism ; DNA, Single-Stranded/drug effects/genetics/metabolism ; DNA-Binding Proteins ; Female ; G-Quadruplexes ; Guanine/metabolism ; Humans ; Mice ; Mice, Nude ; Telomerase/*antagonists &amp; inhibitors/biosynthesis/metabolism ; Telomere/*drug effects/genetics/metabolism ; Ubiquitin/metabolism ; Uterine Neoplasms/*drug therapy/enzymology/genetics ; Xenograft Model Antitumor Assays ; },
abstract = {Interference with telomerase and telomere maintenance is emerging as an attractive target for anticancer therapies. Ligand-induced stabilization of G-quadruplex formation by the telomeric DNA single-stranded 3' overhang inhibits telomerase from catalyzing telomeric DNA synthesis and from capping telomeric ends. We report here the effects of a 3,6,9-trisubstituted acridine compound, BRACO-19, on telomerase function in vitro and in vivo. The biological activity of BRACO-19 was evaluated in the human uterus carcinoma cell line UXF1138L, which has very short telomeres (2.7 kb). In vitro, nuclear human telomerase reverse transcriptase (hTERT) expression was drastically decreased after 24 hours, induction of cellular senescence and complete cessation of growth was seen after 15 days, paralleled by telomere shortening of ca. 0.4 kb. In vivo, BRACO-19 was highly active as a single agent against early-stage (68 mm(3)) tumors in a s.c. growing xenograft model established from UXF1138L cells, if given chronically at 2 mg per kg per day i.p. BRACO-19 produced growth inhibition of 96% compared with controls accompanied by partial regressions (P < 0.018). Immunostaining of xenograft tissues showed that this response was paralleled by loss of nuclear hTERT protein expression and an increase in atypical mitoses indicative of telomere dysfunction. Cytoplasmic hTERT expression and its colocalization with ubiquitin was observed suggesting that hTERT is bound to ubiquitin and targeted for enhanced degradation upon BRACO-19 treatment. This is in accord with a model of induced displacement of telomerase from the telomere. The in vitro and in vivo data presented here is consistent with the G-quadruplex binding ligand BRACO-19 producing an anticancer effect by inhibiting the capping and catalytic functions of telomerase.},
}
@article {pmid15734733,
year = {2005},
author = {Enokizono, Y and Konishi, Y and Nagata, K and Ouhashi, K and Uesugi, S and Ishikawa, F and Katahira, M},
title = {Structure of hnRNP D complexed with single-stranded telomere DNA and unfolding of the quadruplex by heterogeneous nuclear ribonucleoprotein D.},
journal = {The Journal of biological chemistry},
volume = {280},
number = {19},
pages = {18862-18870},
doi = {10.1074/jbc.M411822200},
pmid = {15734733},
issn = {0021-9258},
mesh = {Circular Dichroism ; DNA/chemistry ; DNA Primers/chemistry ; DNA, Single-Stranded/*chemistry ; Heterogeneous-Nuclear Ribonucleoprotein D/*chemistry ; Humans ; Hydrogen Bonding ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Mutation ; Nucleic Acid Conformation ; Protein Binding ; Protein Conformation ; Protein Denaturation ; Protein Folding ; Protein Structure, Tertiary ; Telomerase/chemistry ; Telomere/ultrastructure ; Time Factors ; },
abstract = {Heterogeneous nuclear ribonucleoprotein D, also known as AUF1, has two DNA/RNA-binding domains, each of which can specifically bind to single-stranded d(TTAGGG)n, the human telomeric repeat. Here, the structure of the C-terminal-binding domain (BD2) complexed with single-stranded d(TTAGGG) determined by NMR is presented. The structure has revealed that each residue of the d(TAG) segment is recognized by BD2 in a base-specific manner. The interactions deduced from the structure have been confirmed by gel retardation experiments with mutant BD2 and DNA. It is known that single-stranded DNA with the telomeric repeat tends to form a quadruplex and that the quadruplex has an inhibitory effect on telomere elongation by telomerase. This time it is revealed that BD2 unfolds the quadruplex of such DNA upon binding. Moreover, the effect of BD2 on the elongation by telomerase was examined in vitro. These results suggest the possible involvement of heterogeneous nuclear ribonucleoprotein D in maintenance of the telomere 3'-overhang either through protection of a single-stranded DNA or destabilization of the potentially deleterious quadruplex structure for the elongation by telomerase.},
}
@article {pmid15727130,
year = {2005},
author = {Fajkus, J and Sýkorová, E and Leitch, AR},
title = {Techniques in plant telomere biology.},
journal = {BioTechniques},
volume = {38},
number = {2},
pages = {233-243},
doi = {10.2144/05382RV01},
pmid = {15727130},
issn = {0736-6205},
mesh = {Cell Nucleus/*physiology ; DNA, Plant/*physiology ; In Situ Hybridization, Fluorescence/methods ; Nucleic Acid Amplification Techniques/*methods ; Plants/*genetics ; Plants, Genetically Modified/physiology ; Sequence Analysis, DNA/methods ; Telomerase/*metabolism ; Telomere/*chemistry/*physiology ; },
abstract = {The role model systems have played in understanding telomere biology has been enormous, and understanding has rapidly transferred to human telomere research. Most work using model organisms to study telomerase and nontelomerase-based telomere-maintenance systems has centered on yeasts, ciliates, and insects. But it is now timely to put considerably more effort into plant models for a number of reasons: (i) the rice and Arabidopsis genome sequencing projects make data mining possible; (ii) extensive collections of insertion mutants of Arabidopsis thaliana enable phenotypic effects of protein gene knockouts to be analyzed, including for those genes involved in telomere structure, function (including, for example, in meiosis), and maintenance; and (iii) the variability of plant telomeres is considerable and ranges from the telomerase-mediated synthesis of the Arabidopsis-type (TTTAGGG) and vertebrate-type (TTAGGG) repeats to sequences synthesized by telomerase-independent mechanism(s) that are still to be discovered. Here we describe how the understanding of telomere biology has been advanced by methods used to isolate telomeric sequences and prove that the putative sequences isolated are indeed telomeric. We show how assays designed to prove the activity of telomerase [e.g., telomeric repeat amplification protocol (TRAP)] lead not only to an understanding of telomere structure and function, but also to the understanding of cell activity in development and in the cell cycle. We review how assays designed to reveal protein/protein and protein/nucleic acid interactions promote understanding of the structure and activities of plant telomeres. Together, the data are making significant contributions to telomere biology in general and could have medical implications.},
}
@article {pmid15726427,
year = {2005},
author = {García-Escarp, M and Martinez-Muñoz, V and Barquinero, J and Sales-Pardo, I and Domingo, JC and Marin, P and Petriz, J},
title = {A rare fraction of human hematopoietic stem cells with large telomeres.},
journal = {Cell and tissue research},
volume = {319},
number = {3},
pages = {405-412},
doi = {10.1007/s00441-004-1022-3},
pmid = {15726427},
issn = {0302-766X},
mesh = {Antigens, CD34/metabolism ; Cell Line ; *Cell Separation ; Clone Cells ; *Flow Cytometry ; Hematopoietic Stem Cells/metabolism/*ultrastructure ; Humans ; In Situ Hybridization, Fluorescence ; Microscopy, Confocal ; Telomere/physiology/*ultrastructure ; },
abstract = {The lack of specific markers for stem cells makes the physical identification of this compartment difficult. Hematopoietic stem cells differ in their repopulating and self-renewal potential. Our study shows that multiple classes of human hematopoietic CD34+ greatly differ in telomere length. Flow-cytometry-based fluorescent in situ hybridization and confocal microscopy of CD34+ cells has revealed remarkable telomere length heterogeneity, with a hybridization pattern consistent with different classes of human hematopoietic progenitor cells. These results also point to the existence of a significant clonal heterogeneity among primitive hematopoietic cells and provide the first evidence of a rare fraction of CD34+ cells with large telomeres in humans.},
}
@article {pmid15723042,
year = {2005},
author = {Lechel, A and Satyanarayana, A and Ju, Z and Plentz, RR and Schaetzlein, S and Rudolph, C and Wilkens, L and Wiemann, SU and Saretzki, G and Malek, NP and Manns, MP and Buer, J and Rudolph, KL},
title = {The cellular level of telomere dysfunction determines induction of senescence or apoptosis in vivo.},
journal = {EMBO reports},
volume = {6},
number = {3},
pages = {275-281},
pmid = {15723042},
issn = {1469-221X},
mesh = {Animals ; Apoptosis/*physiology ; Cellular Senescence/*physiology ; Female ; Liver/cytology/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mutation/genetics ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/antagonists &amp; inhibitors/genetics/metabolism ; Tumor Suppressor Protein p53/deficiency/genetics/metabolism ; },
abstract = {Telomere dysfunction induces two types of cellular response: cellular senescence and apoptosis. We analysed the extent to which the cellular level of telomere dysfunction and p53 gene status affect these cellular responses in mouse liver using the experimental system of TRF2 inhibition by a dominant-negative version of the protein (TRF2delta B delta M). We show that the level of telomere dysfunction correlates with the level of TRF2delta B delta M protein expression resulting in chromosomal fusions, aberrant mitotic figures and aneuploidy of liver cells. These alterations provoked p53-independent apoptosis, but a strictly p53-dependent senescence response in distinct populations of mouse liver cells depending on the cellular level of TRF2delta B delta M expression. Apoptosis was associated with higher expression of TRF2delta B delta M, whereas cellular senescence was associated with low levels of TRF2delta B delta M) expression. Our data provide experimental evidence that induction of senescence or apoptosis in vivo depends on the cellular level of telomere dysfunction and differentially on p53 gene function.},
}
@article {pmid15721261,
year = {2005},
author = {Emre, NC and Ingvarsdottir, K and Wyce, A and Wood, A and Krogan, NJ and Henry, KW and Li, K and Marmorstein, R and Greenblatt, JF and Shilatifard, A and Berger, SL},
title = {Maintenance of low histone ubiquitylation by Ubp10 correlates with telomere-proximal Sir2 association and gene silencing.},
journal = {Molecular cell},
volume = {17},
number = {4},
pages = {585-594},
doi = {10.1016/j.molcel.2005.01.007},
pmid = {15721261},
issn = {1097-2765},
mesh = {Acetylation ; Chromatin Immunoprecipitation ; DNA, Ribosomal ; Down-Regulation ; Gene Expression Regulation, Fungal/*physiology ; *Gene Silencing ; Histone Deacetylases/*physiology ; Histones/*metabolism ; Lysine/metabolism ; Methylation ; Nuclear Proteins/*physiology ; Proteasome Endopeptidase Complex ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/*physiology ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/*physiology ; Sirtuin 2 ; Sirtuins/*physiology ; Telomere/*physiology ; Transcription, Genetic ; Transcriptional Activation ; Ubiquitin/*metabolism ; Ubiquitin Thiolesterase ; },
abstract = {Low levels of histone covalent modifications are associated with gene silencing at telomeres and other regions in the yeast S. cerevisiae. Although the histone deacetylase Sir2 maintains low acetylation, mechanisms responsible for low H2B ubiquitylation and low H3 methylation are unknown. Here, we show that the ubiquitin protease Ubp10 targets H2B for deubiquitylation, helping to localize Sir2 to the telomere. Ubp10 exhibits reciprocal Sir2-dependent preferential localization proximal to telomeres, where Ubp10 serves to maintain low H2B Lys123 ubiquitylation in this region and, through previously characterized crosstalk, maintains low H3 Lys4 and Lys79 methylation in a slightly broader region. Ubp10 is also localized to the rDNA locus, a second silenced domain, where it similarly maintains low histone methylation. We compare Ubp10 to Ubp8, the SAGA-associated H2B deubiquitylase involved in gene activation, and show that telomeric and gene-silencing functions are specific to Ubp10. Our results suggest that these H2B-deubiquitylating enzymes have distinct genomic functions.},
}
@article {pmid15721260,
year = {2005},
author = {Takata, H and Tanaka, Y and Matsuura, A},
title = {Late S phase-specific recruitment of Mre11 complex triggers hierarchical assembly of telomere replication proteins in Saccharomyces cerevisiae.},
journal = {Molecular cell},
volume = {17},
number = {4},
pages = {573-583},
doi = {10.1016/j.molcel.2005.01.014},
pmid = {15721260},
issn = {1097-2765},
mesh = {Chromatin Immunoprecipitation ; DNA/genetics ; *DNA Repair ; *DNA Replication ; DNA-Binding Proteins/genetics/metabolism ; Endodeoxyribonucleases/*genetics/metabolism ; Exodeoxyribonucleases/*genetics/metabolism ; Intracellular Signaling Peptides and Proteins ; Phenotype ; Protein Serine-Threonine Kinases ; *S Phase ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {In Saccharomyces cerevisiae, telomere replication occurs in late S phase and is accompanied by dynamic remodeling of its protein components. Here, we show that MRX (Mre11-Rad50-Xrs2), an evolutionarily conserved protein complex involved in DNA double-strand break (DSB) repair, is recruited to the telomeres in late S phase. MRX is required for the late S phase-specific recruitment of ATR-like kinase Mec1 to the telomeres. Mec1, in turn, contributes to the assembly of the telomerase regulators Cdc13 and Est1 at the telomere ends. Our results provide a model for the hierarchical assembly of telomere-replication proteins in late S phase; this involves triggering by the loading of MRX onto the chromosome termini. The recruitment of DNA repair-related proteins to the telomeres at particular times in the cell cycle suggests that the normal terminus of a chromosome is recognized as a DSB during the course of replication.},
}
@article {pmid15716989,
year = {2005},
author = {Ricca, I and Compagno, M and Ladetto, M and Rocci, A and Dell'Aquila, M and Omedè, P and De Marco, F and D'Antico, S and Caracciolo, D and Ferrero, D and Carlo-Stella, C and Tarella, C},
title = {Marked telomere shortening in mobilized peripheral blood progenitor cells (PBPC) following two tightly spaced high-dose chemotherapy courses with G-CSF.},
journal = {Leukemia},
volume = {19},
number = {4},
pages = {644-651},
doi = {10.1038/sj.leu.2403652},
pmid = {15716989},
issn = {0887-6924},
mesh = {Adolescent ; Adult ; Antibiotics, Antineoplastic/administration &amp; dosage/adverse effects ; Antigens, CD34/metabolism ; Antimetabolites, Antineoplastic/administration &amp; dosage/adverse effects ; Antineoplastic Agents, Alkylating/administration &amp; dosage/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/administration &amp; dosage/*adverse effects ; Combined Modality Therapy ; Cyclophosphamide/administration &amp; dosage/adverse effects ; Cytarabine/administration &amp; dosage/adverse effects ; Doxorubicin/administration &amp; dosage/*adverse effects ; Female ; Granulocyte Colony-Stimulating Factor/administration &amp; dosage/*adverse effects ; Hematopoietic Stem Cell Mobilization ; *Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/metabolism/*pathology ; Humans ; Lymphoma, Non-Hodgkin/*drug therapy/*pathology ; Male ; Middle Aged ; Platelet Count ; Predictive Value of Tests ; Prednisone/administration &amp; dosage/*adverse effects ; Telomere ; Transplantation, Autologous ; Vincristine/administration &amp; dosage/*adverse effects ; },
abstract = {The purpose of the study was to compare telomere length (TL) in peripheral blood progenitor cells (PBPC) collected after two tightly spaced high-dose (hd) chemotherapy courses. We assessed 37 previously untreated lymphoma patients undergoing a hd-chemotherapy program with autografting. They sequentially received hd-cyclophosphamide (CY) and hd-Ara-C, both followed by PBPC harvesting. Both post-CY and post-Ara-C harvests were assessed for TL by Southern blot analysis. In 12 patients, the assay was also performed on purified CD34+ cells. All patients displayed high PBPC mobilization following both hd-CY and hd-Ara-C. In all but one patient, TL was shorter in PBPC collected after Ara-C compared to CY: 7226bp (range: 4135-9852) vs 8282 bp (range 4895-14860) (P < 0.0001). This result was confirmed on CD34+ cells. Platelet recovery in patients receiving post-Ara-C PBPC was significantly slower compared to those receiving post-CY PBPC. In conclusion, (i) administration of tightly spaced hd-chemotherapy courses induces marked telomere shortening on harvested PBPC; (ii) engraftment kinetics seem slower, with delayed platelet recovery, in patients autografted with PBPC suffering marked TL erosion; (iii) long-term follow-up is required to verify whether PBPC with shortened telomeres display defective engraftment stability and/or risk of secondary leukemia; (iv) TL evaluation is advisable whenever new mobilization procedures are developed.},
}
@article {pmid15716104,
year = {2005},
author = {Kabir, MA and Rustchenko, E},
title = {Determination of gaps by contig alignment with telomere-mediated chromosomal fragmentation in Candida albicans.},
journal = {Gene},
volume = {345},
number = {2},
pages = {279-287},
doi = {10.1016/j.gene.2004.11.029},
pmid = {15716104},
issn = {0378-1119},
support = {AI29433/AI/NIAID NIH HHS/United States ; },
mesh = {Candida albicans/*genetics ; Chromosomes, Fungal ; Contig Mapping/*methods ; DNA Fragmentation ; Molecular Sequence Data ; Plasmids ; Sequence Alignment ; *Telomere ; },
abstract = {We have adopted a method of telomere-mediated chromosome fragmentation in order to demonstrate the alignment of contigs and determination of gaps. We established the order and orientation of four contigs of Candida albicans chromosome 5 and determined the sizes of three gaps between these contigs. We confirmed this proposed alignment of contigs, as well as gap sizes, by sequencing one gap and analyzing three mega deletions of approximately 41 kbp, 58 kbp, and 77 kbp, which covered two other gaps. These gaps could be also conveniently sequenced, which is an important step in establishing a complete sequence. The combined length of contigs and gaps covered approximately 422 kbp, which is one third of chromosome 5. Telomere-mediated chromosome fragmentation, used here for the first time to align the contigs of C. albicans and determine the gaps, proved to be a reliable method. The method could be helpful in sequencing projects of other diploid organisms, in particular those in which centromeres have not been identified. In addition, our approach can be used to assign any contig to a chromosome, or to induce the loss of a specific chromosome.},
}
@article {pmid15716016,
year = {2005},
author = {Kim, D and Chiurillo, MA and El-Sayed, N and Jones, K and Santos, MR and Porcile, PE and Andersson, B and Myler, P and da Silveira, JF and Ramírez, JL},
title = {Telomere and subtelomere of Trypanosoma cruzi chromosomes are enriched in (pseudo)genes of retrotransposon hot spot and trans-sialidase-like gene families: the origins of T. cruzi telomeres.},
journal = {Gene},
volume = {346},
number = {},
pages = {153-161},
doi = {10.1016/j.gene.2004.10.014},
pmid = {15716016},
issn = {0378-1119},
support = {U01 AI045038/AI/NIAID NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; *Chromosomes ; Chromosomes, Artificial, Bacterial ; DNA, Protozoan/genetics ; *Genes, Protozoan ; Glycoproteins/chemistry/*genetics ; Molecular Sequence Data ; *Multigene Family ; Neuraminidase/chemistry/*genetics ; *Pseudogenes ; *Retroelements ; Sequence Homology, Amino Acid ; Sequence Homology, Nucleic Acid ; *Telomere ; Trypanosoma cruzi/*genetics ; },
abstract = {Here, we sequenced two large telomeric regions obtained from the pathogen protozoan Trypanosoma cruzi. These sequences, together with in silico assembled contigs, allowed us to establish the general features of telomeres and subtelomeres of this parasite. Our findings can be summarized as follows: We confirmed the presence of two types of telomeric ends; subtelomeric regions appeared to be enriched in (pseudo)genes of RHS (retrotransposon hot spot), TS (trans-sialidase)-like proteins, and putative surface protein DGF-1 (dispersed gene family-1). Sequence analysis of the ts-like genes located at the telomeres suggested that T. cruzi chromosomal ends could have been the site for generation of new gp85 variants, an important adhesin molecule involved in the invasion of mammalian cells by T. cruzi. Finally, a mechanism for generation of T. cruzi telomere by chromosome breakage and telomere healing is proposed.},
}
@article {pmid15713803,
year = {2005},
author = {Topcu, Z and Nickles, K and Davis, C and McEachern, MJ},
title = {Abrupt disruption of capping and a single source for recombinationally elongated telomeres in Kluyveromyces lactis.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {102},
number = {9},
pages = {3348-3353},
pmid = {15713803},
issn = {0027-8424},
support = {R01 GM061645/GM/NIGMS NIH HHS/United States ; GM61645-01/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; DNA Primers ; Kluyveromyces/*genetics ; *Recombination, Genetic ; *Telomere ; },
abstract = {Eukaryotic cells, including some human cancers, that lack telomerase can sometimes maintain telomeres by using recombination. It was recently proposed that recombinational telomere elongation (RTE) in a telomerase-deletion mutant of the yeast Kluyveromyces lactis occurs through a roll-and-spread mechanism as described in our previous work. According to this model, a tiny circle of telomeric DNA is copied by a rolling-circle mechanism to generate one long telomere, the sequence of which is then spread to all other telomeres by gene-conversion events. In support of this model, we demonstrate here that RTE in K. lactis occurs by amplification of a sequence originating from a single telomere. When a mutationally tagged telomere is of normal length, its sequence is spread to all other telomeres at a frequency (approximately 10%) consistent with random selection among the 12 telomeres in the cell. However, when the mutationally tagged telomere is considerably longer than other telomeres, cellular senescence is partially suppressed, and the sequence of the tagged telomere is spread to all other telomeres in >90% of cells. Strikingly, the transition between a state resistant to recombination and a state capable of initiating recombination is abrupt, typically occurring when telomeres are approximately 3-4 repeats long. Last, we show that mutant repeats that are defective at regulating telomerase are also defective at regulating telomere length during RTE.},
}
@article {pmid15702420,
year = {2004},
author = {Solov'eva, L and Svetlova, M and Bodinski, D and Zalensky, AO},
title = {Nature of telomere dimers and chromosome looping in human spermatozoa.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {12},
number = {8},
pages = {817-823},
pmid = {15702420},
issn = {0967-3849},
support = {R01 HD039830/HD/NICHD NIH HHS/United States ; R01 HD042748/HD/NICHD NIH HHS/United States ; HD-39830/HD/NICHD NIH HHS/United States ; R01 HD-42748/HD/NICHD NIH HHS/United States ; },
mesh = {Cell Nucleus/ultrastructure ; Chromosomes, Human/*ultrastructure ; Chromosomes, Human, 1-3/ultrastructure ; Chromosomes, Human, 16-18/ultrastructure ; Chromosomes, Human, 4-5/ultrastructure ; Dimerization ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Nucleic Acid Conformation ; Spermatozoa/*ultrastructure ; Telomere/*ultrastructure ; },
abstract = {Specific and well-organized chromosome architecture in human sperm cells is supported by the prominent interactions between centromeres and between telomeres. The telomere-telomere interactions result in telomere dimers that are positioned at the nuclear periphery. It is unknown whether composition of sperm telomere dimers is random or specific. We now report that telomere dimers result from specific interactions between the two ends of each chromosome. FISH using pairs of subtelomeric DNA probes that correspond to the small and long arms of seven human chromosomes demonstrates that subtelomeres of one chromosome are brought together. Statistical analysis confirmed that telomere associations could not result from the random proximity of DNA sequences. Therefore, chromosomes in human sperm nuclei adopt a looped conformation. This higher-order chromosome structure is most likely required for chromosome withdrawal/decondensation during the early fertilization events leading to zygote formation.},
}
@article {pmid15701877,
year = {2005},
author = {Schroecksnadel, K and Ueberall, F and Fuchs, D},
title = {Telomere length abnormalities and human cancer.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {11},
number = {2 Pt 1},
pages = {860},
pmid = {15701877},
issn = {1078-0432},
mesh = {Animals ; *Chromosome Aberrations ; Humans ; Neoplasms, Glandular and Epithelial/*metabolism ; Telomere/*metabolism ; },
}
@article {pmid15701795,
year = {2005},
author = {Lin, CY and Chang, HH and Wu, KJ and Tseng, SF and Lin, CC and Lin, CP and Teng, SC},
title = {Extrachromosomal telomeric circles contribute to Rad52-, Rad50-, and polymerase delta-mediated telomere-telomere recombination in Saccharomyces cerevisiae.},
journal = {Eukaryotic cell},
volume = {4},
number = {2},
pages = {327-336},
pmid = {15701795},
issn = {1535-9778},
support = {R01 GM026938/GM/NIGMS NIH HHS/United States ; R37 GM026938/GM/NIGMS NIH HHS/United States ; GM26938/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Polymerase III/*metabolism ; DNA, Fungal ; DNA-Binding Proteins/genetics/*metabolism ; Genetic Markers ; Genome, Fungal ; *Nucleic Acid Conformation ; Rad52 DNA Repair and Recombination Protein ; *Recombination, Genetic ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/metabolism ; *Telomere/genetics/metabolism ; },
abstract = {Telomere maintenance is required for chromosome stability, and telomeres are typically replicated by the telomerase reverse transcriptase. In both tumor and yeast cells that lack telomerase, telomeres are maintained by an alternative recombination mechanism. By using an in vivo inducible Cre-loxP system to generate and trace the fate of marked telomeric DNA-containing rings, the efficiency of telomere-telomere recombination can be determined quantitatively. We show that the telomeric loci are the primary sites at which a marked telomeric ring-containing DNA is observed among wild-type and surviving cells lacking telomerase. Marked telomeric DNAs can be transferred to telomeres and form tandem arrays through Rad52-, Rad50-, and polymerase delta-mediated recombination. Moreover, increases of extrachromosomal telomeric and Y' rings were observed in telomerase-deficient cells. These results imply that telomeres can use looped-out telomeric rings to promote telomere-telomere recombination in telomerase-deficient Saccharomyces cerevisiae.},
}
@article {pmid15698852,
year = {2005},
author = {Li, WG and Li, QH and Tan, Z},
title = {Epigallocatechin gallate induces telomere fragmentation in HeLa and 293 but not in MRC-5 cells.},
journal = {Life sciences},
volume = {76},
number = {15},
pages = {1735-1746},
doi = {10.1016/j.lfs.2004.09.024},
pmid = {15698852},
issn = {0024-3205},
mesh = {Anticarcinogenic Agents/*pharmacology ; Apoptosis/*drug effects ; Catechin/*analogs &amp; derivatives/*pharmacology ; Free Radical Scavengers/pharmacology ; HeLa Cells ; Humans ; Reactive Oxygen Species ; *Telomere ; },
abstract = {Telomeres are the tandem repetitive sequence at the end of chromosomes and its integrity is crucial for cell vitality. We studied the effect of (-)-epigallocatechin-3-gallate (EGCG), one of the major tea polyphenols, on telomeres in HeLa, 293 cells and MRC-5 fibroblasts. At concentrations of above 50 microM, EGCG was found to causes telomere fragmentation in HeLa cells as a result of single-strand breaks in a dose-dependent manner. Treatment of EGCG also caused telomere fragmentation in 293 cells but had little or only marginal effect on MRC-5 fibroblasts. The telomere fragments detected by electrophoresis showed a unique size distribution that seems to suggest that the strand breaks were not produced randomly, but with preference at some specific sites. We speculate that the differential effect of EGCG in inducing telomere fragmentation in HeLa and 293 verse MRC-5 cells might be relevant to the apoptosis-inducing effect of EGCG on cancerous cells but not on normal cells.},
}
@article {pmid15694306,
year = {2005},
author = {Joseph, I and Jia, D and Lustig, AJ},
title = {Ndj1p-dependent epigenetic resetting of telomere size in yeast meiosis.},
journal = {Current biology : CB},
volume = {15},
number = {3},
pages = {231-237},
doi = {10.1016/j.cub.2005.01.039},
pmid = {15694306},
issn = {0960-9822},
support = {R01 GM069943/GM/NIGMS NIH HHS/United States ; GM069943/GM/NIGMS NIH HHS/United States ; },
mesh = {*Base Sequence ; Blotting, Southern ; Cell Cycle Proteins/*physiology ; *Chromosomes, Fungal ; Epigenesis, Genetic/*physiology ; Meiosis/*physiology ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/*physiology ; Sequence Deletion/*genetics ; Telomere/*physiology ; Time Factors ; },
abstract = {Telomeres are essential for the protection of chromosomes against nucleases and recombinases and for the addition of G+T-rich simple sequence by the ribonucleoprotein reverse transcriptase telomerase . Telomere size instability and loss of telomerase activity in somatic cells is strongly associated with both oncogenesis and aging . Yet, an understanding of the mechanisms that maintain telomere size and structure during meiosis is still in its infancy . We have investigated the stability of single elongated telomeres during yeast meiosis. We find that elongated telomeres undergo high rates of precise deletion to wild-type telomere size via an intrachromatid pathway that shares properties with mitotic telomere rapid deletion (TRD). Loss of Ndj1p, a telomeric protein necessary for meiotic bouquet structure formation , confers a severe reduction in deletion rates. Return-to-growth (RTG) experiments suggest that deletion occurs at or near the period of meiotic recombination in NDJ1/NDJ1, but not in ndj1Delta/ndj1Delta diploids . We propose that Ndj1p facilitates deletion by promoting telomeric interactions during meiosis, resulting in an effective increase in the concentration of limiting factors for deletion.},
}
@article {pmid15690454,
year = {2005},
author = {Li, WG and Li, QH and Tan, Z},
title = {Detection of telomere damage as a result of strand breaks in telomeric and subtelomeric DNA.},
journal = {Electrophoresis},
volume = {26},
number = {3},
pages = {533-536},
doi = {10.1002/elps.200410123},
pmid = {15690454},
issn = {0173-0835},
mesh = {*DNA Damage ; DNA Fragmentation ; DNA Repair ; Electrophoresis, Agar Gel/*methods ; HeLa Cells ; Humans ; Hydrogen Peroxide/pharmacology ; Oligodeoxyribonucleotides/isolation &amp; purification ; Telomere/*drug effects ; },
abstract = {Telomeres are the tandem repetitive DNA sequences at both ends of a chromosome with a repeating unit of TTAGGG. The integrity of a telomere is crucial to chromosomal stability and cellular viability. Damages to telomere DNA disrupt telomere integrity and accelerate telomere shortening. We describe a method for the assessment of strand breaks in the telomere/subtelomere region in cultured cells. Cells were embedded in agarose plugs and subjected to lysis and alkaline treatment to relax the DNA double helix. The telomere fragments as the result of strand breaks in the telomere/subtelomere region were then separated from the genomic DNA by electrophoresis, blotted onto membranes, and detected by a probe specific to the telomere sequence. Because of the large content of the telomere in human cells and the fact that telomere DNA is much more prone to damage than the bulk genomic DNA, the analysis may serve as a good indication of general DNA damage as well.},
}
@article {pmid15686568,
year = {2005},
author = {Castaño, I and Pan, SJ and Zupancic, M and Hennequin, C and Dujon, B and Cormack, BP},
title = {Telomere length control and transcriptional regulation of subtelomeric adhesins in Candida glabrata.},
journal = {Molecular microbiology},
volume = {55},
number = {4},
pages = {1246-1258},
doi = {10.1111/j.1365-2958.2004.04465.x},
pmid = {15686568},
issn = {0950-382X},
support = {2PO1 DK49720/DK/NIDDK NIH HHS/United States ; R01 AI46223/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; CHO Cells ; Candida glabrata/*genetics ; Cell Line ; Cricetinae ; DNA Primers ; Fungal Proteins/*genetics ; Gene Expression Regulation, Fungal/*genetics ; Genotype ; Humans ; Kidney ; Lectins/*genetics ; Molecular Sequence Data ; Mutation ; Plasmids/genetics ; Telomere/*genetics/*ultrastructure ; Transfection ; },
abstract = {The pathogenic yeast Candida glabrata is able to bind in vitro to human epithelial cells. This interaction depends on expression of the adhesin Epa1p. The genome contains a number of EPA1 paralogues which localize to the subtelomeric regions of the C. glabrata. We have identified three hyperadherent mutants of C. glabrata. The first has an insertion adjacent to EPA7, an EPA1-related adhesin. The others disrupt the SIR3 and RIF1 genes of C. glabrata. We show that SIR3 and RIF1 are required for subtelomeric silencing in C. glabrata and that RIF1 regulates telomere length in C. glabrata. We show that the hyperadherent phenotype of the sir3Delta and rif1Delta deletion strains depends primarily on derepression of two novel members of the EPA gene family -EPA6 and EPA7. The sir3Delta and rif1Delta mutants show increased colonization of the kidney in a murine model of disseminated infection and this hypercolonization depends, at least in part, on derepression of EPA6 and EPA7. The analysis here is the first evidence that multiple EPA genes encode adhesins and demonstrates that transcription of at least two of these adhesins is regulated by subtelomeric silencing.},
}
@article {pmid15684046,
year = {2005},
author = {Shears, SB},
title = {Telomere maintenance by intracellular signals: new kid on the block?.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {102},
number = {6},
pages = {1811-1812},
pmid = {15684046},
issn = {0027-8424},
mesh = {Animals ; Inositol Phosphates/chemistry/*metabolism ; Molecular Structure ; Second Messenger Systems/*physiology ; Telomere/*metabolism ; },
}
@article {pmid15684028,
year = {2005},
author = {Bystricky, K and Laroche, T and van Houwe, G and Blaszczyk, M and Gasser, SM},
title = {Chromosome looping in yeast: telomere pairing and coordinated movement reflect anchoring efficiency and territorial organization.},
journal = {The Journal of cell biology},
volume = {168},
number = {3},
pages = {375-387},
pmid = {15684028},
issn = {0021-9525},
mesh = {Cell Nucleolus/physiology ; Cell Nucleus/physiology ; Chromosomes, Fungal/*physiology ; DNA-Binding Proteins/genetics ; Fluorescence Recovery After Photobleaching ; G1 Phase/physiology ; Gene Deletion ; Genotype ; Interphase/physiology ; Luminescent Proteins/genetics ; Microscopy, Fluorescence ; Recombinant Fusion Proteins/genetics ; Repressor Proteins/genetics ; Saccharomyces cerevisiae/genetics/*physiology ; Saccharomyces cerevisiae Proteins/genetics ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics ; Spindle Apparatus/physiology ; Telomere/*physiology ; },
abstract = {Long-range chromosome organization is known to influence nuclear function. Budding yeast centromeres cluster near the spindle pole body, whereas telomeres are grouped in five to eight perinuclear foci. Using live microscopy, we examine the relative positions of right and left telomeres of several yeast chromosomes. Integrated lac and tet operator arrays are visualized by their respective repressor fused to CFP and YFP in interphase yeast cells. The two ends of chromosomes 3 and 6 interact significantly but transiently, forming whole chromosome loops. For chromosomes 5 and 14, end-to-end interaction is less frequent, yet telomeres are closer to each other than to the centromere, suggesting that yeast chromosomes fold in a Rabl-like conformation. Disruption of telomere anchoring by deletions of YKU70 or SIR4 significantly compromises contact between two linked telomeres. These mutations do not, however, eliminate coordinated movement of telomere (Tel) 6R and Tel6L, which we propose stems from the territorial organization of yeast chromosomes.},
}
@article {pmid15681620,
year = {2005},
author = {Toussaint, M and Dionne, I and Wellinger, RJ},
title = {Limited TTP supply affects telomere length regulation in a telomerase-independent fashion.},
journal = {Nucleic acids research},
volume = {33},
number = {2},
pages = {704-713},
pmid = {15681620},
issn = {1362-4962},
mesh = {Cell Growth Processes ; Deoxyuracil Nucleotides/metabolism ; Mutation ; Nucleoside-Phosphate Kinase/genetics ; Nucleotides/metabolism ; Saccharomyces cerevisiae/enzymology/genetics/metabolism ; Telomerase/*metabolism ; Telomere/*chemistry/metabolism ; Thymidylate Synthase/genetics ; Thymine Nucleotides/biosynthesis/*metabolism ; },
abstract = {An adequate supply of nucleotides is essential for DNA replication and DNA repair. Moreover, inhibition of TTP synthesis can cause cell death by a poorly characterized mechanism called thymine-less death. In the yeast Saccharomyces cerevisiae, the genes encoding thymidylate synthetase (CDC21) and thymidylate kinase (CDC8) are both essential for de novo TTP synthesis. The effects of temperature-sensitive mutations in these genes have been characterized and, curiously, the phenotypes displayed by cells harboring them include shortened telomeric repeat tracts. This finding raised the possibility that the enzyme telomerase is very sensitive to TTP-pools. We tested this possibility in vivo by assessing telomerase-dependent extension in situations of lowered TTP supply. The results show that the above-mentioned short telomere phenotype is not a consequence of an inability of telomerase to elongate telomeres when TTP synthesis is impaired. Moreover, this telomere shortening was abolished in cells harboring a mutation in DNA polymerase alpha. Previously, this same mutation was shown to affect the coordination between conventional replication and telomerase-mediated extension. These results thus re-emphasize the importance of the interplay between conventional replication and telomerase-mediated addition of telomeric repeats in telomere replication.},
}
@article {pmid15680963,
year = {2005},
author = {Blackburn, EH},
title = {Telomeres and telomerase: their mechanisms of action and the effects of altering their functions.},
journal = {FEBS letters},
volume = {579},
number = {4},
pages = {859-862},
doi = {10.1016/j.febslet.2004.11.036},
pmid = {15680963},
issn = {0014-5793},
support = {CA96840/CA/NCI NIH HHS/United States ; GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Apoptosis ; Chromosome Aberrations ; DNA-Binding Proteins ; Humans ; Neoplasms/metabolism ; Telomerase/chemistry/metabolism/*physiology ; Telomere/genetics/*metabolism ; },
abstract = {The molecular features of telomeres and telomerase are conserved among most eukaryotes. How telomerase and telomeres function and how they interact to promote the chromosome-stabilizing properties of telomeres are discussed here.},
}
@article {pmid15679761,
year = {2005},
author = {Getliffe, KM and Al Dulaimi, D and Martin-Ruiz, C and Holder, RL and von Zglinicki, T and Morris, A and Nwokolo, CU},
title = {Lymphocyte telomere dynamics and telomerase activity in inflammatory bowel disease: effect of drugs and smoking.},
journal = {Alimentary pharmacology &amp; therapeutics},
volume = {21},
number = {2},
pages = {121-131},
doi = {10.1111/j.1365-2036.2005.02311.x},
pmid = {15679761},
issn = {0269-2813},
mesh = {Adult ; Aged ; Antimetabolites/pharmacology ; Azathioprine/pharmacology ; DNA-Binding Proteins/metabolism ; Female ; Humans ; Inflammatory Bowel Diseases/*enzymology ; Lymphocytes/*enzymology/pathology ; Male ; Middle Aged ; RNA, Messenger/metabolism ; Smoking/*metabolism ; Telomerase/drug effects/*metabolism ; Telomere/*metabolism ; },
abstract = {BACKGROUND: The chromosome instability observed in peripheral blood lymphocytes in ulcerative colitis could be a biomarker of cancer susceptibility.<br><br>AIM: To determine whether accelerated telomere shortening could explain chromosome instability and assess the effect of drugs and smoking on telomere dynamics in these cells.<br><br>METHODS: Peripheral blood lymphocytes were isolated from ulcerative colitis, Crohn's disease and non-inflammatory bowel disease control patients. Telomere lengths were measured by quantitative real-time polymerase chain reaction. After activation and cell separation, telomerase activity and human telomerase reverse transcriptase messenger ribonucleic acid were measured by telomerase repeat amplification protocol enzyme-linked immunosorbent serological assay and quantitative real-time polymerase chain reaction, respectively.<br><br>RESULTS: Age-related telomere loss in peripheral blood lymphocytes was similar in ulcerative colitis, Crohn's disease and control patients. Telomerase activity decreased with age in all groups and correlated positively with telomere length (r = 0.489, P = 0.006). Among Crohn's disease patients, azathioprine was associated with decreased telomerase activity (0.66 vs. 1.54, P = 0.026, P < 0.05) and smoking was associated with decreased human telomerase reverse transcriptase mRNA expression (10.5 vs. 33.3, P = 0.036, P < 0.05).<br><br>CONCLUSIONS: Telomere shortening is not accelerated and therefore cannot be the cause of the chromosome instability observed in ulcerative colitis peripheral blood lymphocytes. Azathioprine and cigarette smoking modify telomerase expression in these cells.},
}
@article {pmid15679112,
year = {2004},
author = {Ermler, S and Krunic, D and Knoch, TA and Moshir, S and Mai, S and Greulich-Bode, KM and Boukamp, P},
title = {Cell cycle-dependent 3D distribution of telomeres and telomere repeat-binding factor 2 (TRF2) in HaCaT and HaCaT-myc cells.},
journal = {European journal of cell biology},
volume = {83},
number = {11-12},
pages = {681-690},
doi = {10.1078/0171-9335-00430},
pmid = {15679112},
issn = {0171-9335},
mesh = {Cell Cycle/*physiology ; Cell Line, Transformed ; Cell Nucleus/chemistry/metabolism ; Chromosomes, Human/metabolism ; Genomic Instability/*physiology ; Humans ; Mitosis/physiology ; Proto-Oncogene Proteins c-myc/metabolism/physiology ; Telomere/chemistry/*metabolism ; Telomeric Repeat Binding Protein 2/analysis/*metabolism ; Up-Regulation ; },
abstract = {Telomeres are specialized structures at the ends of the chromosomes that, with the help of proteins--such as the telomere repeat-binding factor TRF2 -, form protective caps which are essential for chromosomal integrity. Investigating the structure and three-dimensional (3D) distribution of the telomeres and TRF2 in the nucleus, we now show that the telomeres of the immortal HaCaT keratinocytes are distributed in distinct non-overlapping territories within the inner third of the nuclear space in interphase cells, while they extend more widely during mitosis. TRF2 is present at the telomeres at all cell cycle phases. During mitosis additional TRF2 protein concentrates all around the chromosomes. This change in staining pattern correlates with a significant increase in TRF2 protein at the S/G2 transition as seen in Western blots of synchronized cells and is paralleled by a cell cycle-dependent regulation of TRF2 mRNA, arguing for a specific role of TRF2 during mitosis. The distinct territorial localization of telomeres is abrogated in a HaCaT variant that constitutively expresses c-Myc--a protein known to contribute to genomic instability. These cells are characterized by overlapping telomere territories, telomeric aggregates (TAs), that are accompanied by an overall irregular telomere distribution and a reduced level in TRF2 protein. These TAs which are readily detectable in interphase nuclei, are similarly present in mitotic cells, including cells in telophase. Thus, we propose that TAs, which subsequently also cluster their respective chromosomes, contribute to genomic instability by forcing an abnormal chromosome segregation during mitosis.},
}
@article {pmid15678140,
year = {2005},
author = {Wright, WE and Shay, JW},
title = {Telomere-binding factors and general DNA repair.},
journal = {Nature genetics},
volume = {37},
number = {2},
pages = {116-118},
doi = {10.1038/ng0205-116},
pmid = {15678140},
issn = {1061-4036},
mesh = {Animals ; *DNA Repair ; DNA-Binding Proteins/*physiology ; Fibroblasts ; Humans ; Models, Genetic ; Repetitive Sequences, Nucleic Acid ; Telomeric Repeat Binding Protein 2/*physiology ; },
}
@article {pmid15671549,
year = {2005},
author = {Henson, JD and Hannay, JA and McCarthy, SW and Royds, JA and Yeager, TR and Robinson, RA and Wharton, SB and Jellinek, DA and Arbuckle, SM and Yoo, J and Robinson, BG and Learoyd, DL and Stalley, PD and Bonar, SF and Yu, D and Pollock, RE and Reddel, RR},
title = {A robust assay for alternative lengthening of telomeres in tumors shows the significance of alternative lengthening of telomeres in sarcomas and astrocytomas.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {11},
number = {1},
pages = {217-225},
pmid = {15671549},
issn = {1078-0432},
mesh = {Adult ; Aged ; Apoptosis ; Astrocytoma/genetics/*metabolism ; Blotting, Southern/methods ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Cellular Senescence ; Child ; *Gene Expression Regulation, Neoplastic ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Leukemia, Promyelocytic, Acute/diagnosis/metabolism ; Microscopy, Fluorescence/*methods ; Middle Aged ; Osteosarcoma/diagnosis/metabolism ; Sarcoma/genetics/*metabolism ; Telomerase/metabolism ; Telomere/*ultrastructure ; Thyroid Neoplasms/metabolism ; Time Factors ; },
abstract = {Telomeres of tumor cells may be maintained by telomerase or by alternative lengthening of telomeres (ALT). The standard ALT assay requires Southern analysis of high molecular weight genomic DNA. We aimed to establish and validate an ALT assay suitable for archived paraffin-embedded tumors and to use it to examine the prevalence and clinical significance of ALT in various types of tumors that are often telomerase negative.<br><br>RESULTS: To assay for ALT, we detected ALT-associated promyelocytic leukemia (PML) bodies (APBs) by combined PML immunofluorescence and telomere fluorescence in situ hybridization. APBs are PML nuclear domains containing telomeric DNA and are a known hallmark of ALT in cell lines. The APB assay concurred with the standard ALT assay in 62 of 62 tumors and showed that 35% of 101 soft tissue sarcomas (STS), 47% of 58 osteosarcomas (especially younger patients), 34% of 50 astrocytomas, and 0% of 17 papillary thyroid carcinomas were ALT positive (ALT+). The prevalence of ALT varied greatly among different STS subtypes: malignant fibrous histiocytomas, 77%; leiomyosarcomas, 62%; liposarcomas, 33%; synovial sarcomas, 9%; and rhabdomyosarcomas, 6%. ALT correlated with survival in glioblastoma multiforme and occurred more often in lower-grade astrocytomas, but ALT+ and ALT- sarcomas were equally aggressive in terms of grade and clinical outcome.<br><br>CONCLUSION: The APB assay for ALT is suitable for paraffin-embedded tumors. It showed that a substantial proportion of STS, osteosarcomas, and astrocytomas, but not papillary thyroid carcinomas use ALT. APB positivity correlated strongly with survival of patients with astrocytomas.},
}
@article {pmid15670901,
year = {2005},
author = {Jin, YL and Yue, W and Shi, GX and Liu, Y and Zhao, FT and Zhu, LP},
title = {Inhibition of 6A8 alpha-mannosidase gene expression resulted in telomere length shortening in nasopharyngeal carcinoma cell CNE-2L2.},
journal = {Cancer letters},
volume = {218},
number = {2},
pages = {229-234},
doi = {10.1016/j.canlet.2004.04.020},
pmid = {15670901},
issn = {1872-7980},
mesh = {Cell Line, Tumor ; Concanavalin A/metabolism ; Glycosylation ; Humans ; Nasopharyngeal Neoplasms/*genetics/pathology ; Nuclear Proteins/genetics ; TATA Box Binding Protein-Like Proteins/genetics ; *Telomere ; Telomeric Repeat Binding Protein 1/genetics ; Telomeric Repeat Binding Protein 2 ; alpha-Mannosidase/*antagonists &amp; inhibitors/genetics ; },
abstract = {Telomere length shortening was observed in the nasopharyngeal carcinoma cell CNE-2L2 when 6A8 alpha-mannosidase expression was inhibited by antisense 6A8 DNA. Transduction with mock or an irrelevant DNA did not affect the telomere length in the carcinoma cells. Telomerase activity and mRNA transcription of TRF 1 and 2 were not changed in the cells treated with antisense 6A8. The Con A binding test showed an enhancement on the proteins isolated from the cells treated with antisense 6A8, but not on those from mock- or irrelevant DNA-treated cells. The data imply an association between glycosylation modification with telomere shortening in antisense 6A8-treated cells.},
}
@article {pmid15665079,
year = {2005},
author = {Saiardi, A and Resnick, AC and Snowman, AM and Wendland, B and Snyder, SH},
title = {Inositol pyrophosphates regulate cell death and telomere length through phosphoinositide 3-kinase-related protein kinases.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {102},
number = {6},
pages = {1911-1914},
pmid = {15665079},
issn = {0027-8424},
support = {DA00074/DA/NIDA NIH HHS/United States ; R37 MH018501/MH/NIMH NIH HHS/United States ; MH068830-02/MH/NIMH NIH HHS/United States ; MH18501/MH/NIMH NIH HHS/United States ; R01 MH018501/MH/NIMH NIH HHS/United States ; K05 DA000074/DA/NIDA NIH HHS/United States ; P50 MH068830/MH/NIMH NIH HHS/United States ; },
mesh = {Androstadienes/metabolism ; Caffeine/metabolism ; Cell Death/*physiology ; Fungal Proteins/genetics/*metabolism ; Inositol Phosphates/*metabolism ; Intracellular Signaling Peptides and Proteins ; Phosphatidylinositol 3-Kinases/*metabolism ; Protein Kinase Inhibitors/metabolism ; Protein Serine-Threonine Kinases ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/*metabolism ; Wortmannin ; },
abstract = {Inositol pyrophosphates physiologically regulate vesicular endocytosis, ribosomal disposition, and directly phosphorylate proteins. Here we demonstrate roles in cell death and regulation of telomere length. Lethal actions of wortmannin and caffeine are selectively abolished in yeast mutants that cannot synthesize inositol pyrophosphates. Wortmannin and caffeine appear to act through the phosphoinositide 3-kinase-related protein kinases Tel1 and Mec1, known regulators of telomere length. Inositol pyrophosphates physiologically antagonize the actions of these kinases, which is demonstrated by the fact that yeast mutants with reduced or elevated levels of inositol pyrophosphates, respectively, display longer and shorter telomeres.},
}
@article {pmid15659580,
year = {2005},
author = {Moran-Jones, K and Wayman, L and Kennedy, DD and Reddel, RR and Sara, S and Snee, MJ and Smith, R},
title = {hnRNP A2, a potential ssDNA/RNA molecular adapter at the telomere.},
journal = {Nucleic acids research},
volume = {33},
number = {2},
pages = {486-496},
pmid = {15659580},
issn = {1362-4962},
mesh = {Animals ; Binding Sites ; Cell Nucleus Structures/chemistry ; Consensus Sequence ; DNA Mutational Analysis ; DNA, Single-Stranded/chemistry/*metabolism ; Deoxyribonucleases/metabolism ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/chemistry/genetics/*metabolism ; Humans ; Neoplasm Proteins/analysis ; Nuclear Proteins/analysis ; Promyelocytic Leukemia Protein ; Protein Structure, Tertiary ; RNA/chemistry/*metabolism ; Rats ; Repetitive Sequences, Nucleic Acid ; Telomerase/chemistry/*metabolism ; Telomere/chemistry/*metabolism ; Telomeric Repeat Binding Protein 2/analysis ; Transcription Factors/analysis ; Tumor Suppressor Proteins ; },
abstract = {The heterogeneous nuclear ribonucleoprotein (hnRNP) A2 is a multi-tasking protein that acts in the cytoplasm and nucleus. We have explored the possibility that this protein is associated with telomeres and participates in their maintenance. Rat brain hnRNP A2 was shown to have two nucleic acid binding sites. In the presence of heparin one site binds single-stranded oligodeoxyribonucleotides irrespective of sequence but not the corresponding oligoribonucleotides. Both the hnRNP A2-binding cis-acting element for the cytoplasmic RNA trafficking element, A2RE, and the ssDNA telomere repeat match a consensus sequence for binding to a second sequence-specific site identified by mutational analysis. hnRNP A2 protected the telomeric repeat sequence, but not the complementary sequence, against DNase digestion: the glycine-rich domain was found to be necessary, but not sufficient, for protection. The N-terminal RRM (RNA recognition motif) and tandem RRMs of hnRNP A2 also bind the single-stranded, template-containing segment of telomerase RNA. hnRNP A2 colocalizes with telomeric chromatin in the subset of PML bodies that are a hallmark of ALT cells, reinforcing the evidence for hnRNPs having a role in telomere maintenance. Our results support a model in which hnRNP A2 acts as a molecular adapter between single-stranded telomeric repeats, or telomerase RNA, and another segment of ssDNA.},
}
@article {pmid15659210,
year = {2005},
author = {Ball, AJ and Levine, F},
title = {Telomere-independent cellular senescence in human fetal cardiomyocytes.},
journal = {Aging cell},
volume = {4},
number = {1},
pages = {21-30},
doi = {10.1111/j.1474-9728.2004.00137.x},
pmid = {15659210},
issn = {1474-9718},
mesh = {Cell Hypoxia/physiology ; Cell Proliferation ; Cells, Cultured ; Cellular Senescence/*physiology ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; DNA-Binding Proteins/genetics ; Fetus/cytology ; Gene Expression/genetics ; Humans ; Inhibitor of Differentiation Protein 1 ; Inhibitor of Differentiation Protein 2 ; Inhibitor of Differentiation Proteins ; Myocytes, Cardiac/cytology/metabolism/*physiology ; Neoplasm Proteins/genetics ; Nuclear Proteins/genetics ; Polycomb Repressive Complex 1 ; Proto-Oncogene Protein c-ets-1 ; Proto-Oncogene Protein c-ets-2 ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins c-ets ; Repressor Proteins/genetics ; Telomerase/genetics/metabolism ; Telomere/metabolism/*physiology ; Trans-Activators/genetics ; Transcription Factors/genetics ; beta-Galactosidase/metabolism ; },
abstract = {Fetal cardiomyocytes have been proposed as a potential source of cell-based therapy for heart failure. This study examined cellular senescence in cultured human fetal ventricular cardiomyocytes (HFCs). HFCs were isolated and identified by immunocytochemistry and RT-PCR. Cells were found to senesce after 20-25 population doublings, as determined by growth arrest, morphological changes and senescence-associated beta-galactosidase activity. Using the telomeric repeat amplification protocol assay, telomerase activity was undetectable in primary HFCs. Cells were transduced to express the human reverse transcriptase subunit (hTERT) of telomerase. This resulted in greatly increased telomerase activity, but no significant lifespan extension. Analysis of telomere length in primary HFCs revealed that the senescent phenotype was not accompanied by telomere shortening. Telomeres in hTERT-positive cells were elongated in comparison with primary cells, and elongation was retained in senescent cells. Levels of the tumor suppressor protein p16INK4A increased in all senescent cells whether telomerase-positive or -negative. Senescence was accompanied by a decline in transcript levels of the polycomb gene Bmi-1, Ets1 and Ets2 transcription factors, and Id1, Id2 and Id3 helix-loop-helix proteins, suggesting roles for these genes in maintenance of cardiomyocyte proliferative capacity. In addition to offering novel insights into the behavior of human fetal cardiomyocytes in culture, these findings have implications for the development of a cell-based therapy for cardiac injury using primary fetal heart tissue.},
}
@article {pmid15658653,
year = {2004},
author = {Hu, ZW and Shen, ZY and Huang, JH},
title = {[Experimental study on effect of epimedium flavonoids in protecting telomere length of senescence cells HU].},
journal = {Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine},
volume = {24},
number = {12},
pages = {1094-1097},
pmid = {15658653},
issn = {1003-5370},
mesh = {Animals ; Cells, Cultured ; Cellular Senescence/*genetics ; Cyclin-Dependent Kinase Inhibitor p16/biosynthesis/genetics ; Epimedium/*chemistry ; Fibroblasts/cytology ; Flavonoids/*pharmacology ; Male ; RNA, Messenger/biosynthesis/genetics ; Rats ; Rats, Sprague-Dawley ; Retinoblastoma Protein/metabolism ; Telomerase/biosynthesis ; Telomere/genetics/*metabolism ; Transduction, Genetic ; },
abstract = {OBJECTIVE: To investigate the mechanism of senescence delay of human diploid fibroblast (2BS) and protecting telomere length by epimedium flavonoids (EF).<br><br>METHODS: The drug sera of EF were used to treat the 2BS. The population doublings of 2BS cells were observed, the mRNA expression of p16 gene were determined by fluorescence real-time quantitative RT-PCR, the telomerase activation of 2BS cells were determined by TRAP-Hyb, the total retinoblastoma (Rb) and phosphorated Rb protein content were detected by ELISA, the telomere length of 2BS cells were determined by telomere restriction fragment (TRF) Southern blot assay.<br><br>RESULTS: EF could significantly extend the population doublings of 2BS cells, the expression of p16 mRNA was decreased and the content of phosphorated Rb protein were increased by EF. The telomere lengthening of 2BS cells were improved by EF, but the telomerase was not activated.<br><br>CONCLUSION: In senescence human fibroblasts 2BS cells, p16 gene mRNA expression increased, content of phosphorated Rb protein decreased and the telomere length of 2BS shortened, EF might delay the aging of cells through inhibiting the p16 gene expression, promoting the production of phosphorated Rb protein and to protect the length of telomere, but not activating the telomerase.},
}
@article {pmid15652747,
year = {2005},
author = {Seimiya, H and Muramatsu, Y and Ohishi, T and Tsuruo, T},
title = {Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics.},
journal = {Cancer cell},
volume = {7},
number = {1},
pages = {25-37},
doi = {10.1016/j.ccr.2004.11.021},
pmid = {15652747},
issn = {1535-6108},
mesh = {Apoptosis ; Benzamides/metabolism/pharmacology ; Catalytic Domain ; Cell Line, Tumor ; Cells, Cultured ; Enzyme Inhibitors/metabolism/pharmacology ; Humans ; In Situ Hybridization, Fluorescence ; Neoplasms/*drug therapy/metabolism ; Nuclear Localization Signals ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/metabolism ; Tankyrases/antagonists &amp; inhibitors/genetics/*metabolism ; Telomerase/antagonists &amp; inhibitors/genetics/*metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; },
abstract = {Telomere elongation by telomerase is repressed in cis by the telomeric protein TRF1. Tankyrase 1 poly(ADP-ribosyl)ates TRF1 and releases it from telomeres, allowing access of telomerase to telomeres. Here we demonstrate that tankyrase 1 inhibition in human cancer cells enhances telomere shortening by a telomerase inhibitor and hastens cell death. Conversely, either tankyrase 1 upregulation or telomere shortening, each of which decreased TRF1 loading on a chromosome end, attenuated the impact of telomerase inhibition. These results are consistent with the idea that telomeres having fewer TRF1s increase the efficiency of their elongation by telomerase. This study implies that both enzyme activity and accessibility to telomeres can be targets for telomerase inhibition.},
}
@article {pmid15643274,
year = {2005},
author = {Fordyce, CA and Heaphy, CM and Joste, NE and Smith, AY and Hunt, WC and Griffith, JK},
title = {Association between cancer-free survival and telomere DNA content in prostate tumors.},
journal = {The Journal of urology},
volume = {173},
number = {2},
pages = {610-614},
doi = {10.1097/01.ju.0000143195.49685.ce},
pmid = {15643274},
issn = {0022-5347},
support = {T34 GM008751/GM/NIGMS NIH HHS/United States ; R25 GM62021/GM/NIGMS NIH HHS/United States ; R33 CA 86136/CA/NCI NIH HHS/United States ; T32 GM08751/GM/NIGMS NIH HHS/United States ; },
mesh = {Aged ; DNA, Neoplasm/*analysis ; Disease-Free Survival ; Humans ; Male ; Middle Aged ; Prostatic Neoplasms/*chemistry/*mortality ; Telomere/*chemistry ; },
abstract = {PURPOSE: We evaluated the hypothesis that telomere DNA content (TC) in prostate tumor tissue is associated with time to prostate cancer recurrence.<br><br>MATERIALS AND METHODS: The cohort was comprised of 77 men who underwent prostatectomy between 1982 and 1995. Slot blot assay was used to measure TC in DNA extracted from paraffin embedded tumor and nearby, histologically normal prostate (NHN) tissues. Multivariate Cox proportional hazards analysis was done to relate TC, patient age at diagnosis, Gleason sum and pelvic node involvement to time of prostate cancer recurrence. Regression analysis was done to relate TC in paired tumor and NHN tissues. Nonparametric Kruskal-Wallis analysis was done to relate TC in tumor and NHN tissues with 72-month disease-free survival.<br><br>RESULTS: TC was a predictor of time to prostate cancer recurrence when controlling for age at diagnosis, Gleason sum and pelvic node involvement (RH = 5.02, 95% CI 1.40 to 17.96, p = 0.0132). TC in tumor tissue was associated with TC in NHN tissue (R = 0.601, p <0.0001). Median TC in tumor and NHN tissues from men in whom cancer recurred within 6 years was approximately half that in men who remained disease-free (p = 0.012 and 0.024, respectively).<br><br>CONCLUSIONS: Decreased TC in prostate tissues obtained by radical prostatectomy predicts prostate cancer recurrence independent of age at diagnosis, Gleason sum and pelvic node involvement. TC in tumor tissue is also associated with TC in NHN prostate tissue. Thus, mechanisms known to generate genomic instability are operative in fields of cells beyond the tumor margins prior to histological changes.},
}
@article {pmid15639833,
year = {2003},
author = {Wang, WX and Liu, XC and Zhu, TH},
title = {[Progress of telomere and telomerase in higher plant].},
journal = {Yi chuan = Hereditas},
volume = {25},
number = {1},
pages = {113-118},
pmid = {15639833},
issn = {0253-9772},
abstract = {Telomere is an important DNA-protein structure. It caps the ends of linear eukaryotic chromosomes. Telomeric DNA consists of tandemly repeated simple sequences. Telomere is synthesized with the action of telomerase, a ribonucleoprotein with reverse transcriptase activity. Telomere plays an important role in maintaining the stability of intact chromosome,genome and cell. This paper is a review of telomere, telomerase, telomere-binding protein and developmental control of telomere change, telomerase activity in higher plant.},
}
@article {pmid15639018,
year = {2005},
author = {Brunori, M and Gilson, E},
title = {[Telomere and cancer: what's more at the end?].},
journal = {Medecine sciences : M/S},
volume = {21},
number = {1},
pages = {37-42},
doi = {10.1051/medsci/200521137},
pmid = {15639018},
issn = {0767-0974},
mesh = {Chromosomes/genetics ; Humans ; Neoplasms/enzymology/*genetics ; Telomerase/genetics ; *Telomere ; },
abstract = {Telomeres are nucleoprotein complexes that cap the end of eukaryotic chromosomes. They are essential for the functions and the stability of the genomes. There is now compelling evidences that telomerase, the enzyme that adds telomeric DNA repeats to chromosome end, is an important player in oncogenesis. The absence of telomerase in somatic tissues is thought to promote genome instability at initial stages of oncogenesis, favoring the emergence of cancer-associated chromosomal abnormalities \; restablishment of telomerase activity is expected afterwards if long term cell cycling is to occur. In addition to telomerase, various factors control the structure and function of telomeres, suggesting that additional telomeric components play important roles during oncogenesis.},
}
@article {pmid15637058,
year = {2005},
author = {Trujillo, KM and Bunch, JT and Baumann, P},
title = {Extended DNA binding site in Pot1 broadens sequence specificity to allow recognition of heterogeneous fission yeast telomeres.},
journal = {The Journal of biological chemistry},
volume = {280},
number = {10},
pages = {9119-9128},
doi = {10.1074/jbc.M414511200},
pmid = {15637058},
issn = {0021-9258},
mesh = {Base Sequence ; Binding Sites ; Cloning, Molecular ; DNA, Fungal/*metabolism ; Escherichia coli/metabolism ; Schizosaccharomyces/*genetics/metabolism ; Schizosaccharomyces pombe Proteins/*metabolism ; Shelterin Complex ; Telomere/chemistry/*genetics/metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {The Pot1 (protection of telomeres) protein binds to single-stranded telomeric DNA and is essential for the protection of chromosome ends from degradation and end-to-end fusions. The Pot1 amino-terminal DNA binding domain, Pot1N, adopts an oligonucleotide/oligosaccharide binding fold and binds GGTTAC motifs cooperatively and with exceptionally high sequence specificity. We have now examined DNA binding to naturally occurring telomeric substrates based on the analysis of 100 cloned chromosome ends and in the context of the full-length Pot1 protein. Here, we describe several important differences between Pot1 and Pot1N with apparent consequences for chromosome end protection. Specifically, full-length Pot1.DNA complexes are more stable, and the minimal binding site for a Pot1 monomer is extended into two adjacent telomeric repeats. We provide evidence that Pot1 contains a second DNA binding motif that recognizes DNA with reduced sequence specificity compared with the domain present in Pot1N. The two DNA binding motifs cooperate, whereby the amino-terminal oligonucleotide/oligosaccharide binding fold determines the registry of binding, and the internal DNA binding motif stabilizes the complex and expands the protected region toward the 3' -end. Consistent with a role in chromosome end capping, Pot1 prevents access of telomerase to the 3'-end and protects against exonucleolytic degradation.},
}
@article {pmid15632080,
year = {2005},
author = {Kelleher, C and Kurth, I and Lingner, J},
title = {Human protection of telomeres 1 (POT1) is a negative regulator of telomerase activity in vitro.},
journal = {Molecular and cellular biology},
volume = {25},
number = {2},
pages = {808-818},
pmid = {15632080},
issn = {0270-7306},
mesh = {Animals ; Binding Sites ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/genetics/metabolism ; HeLa Cells ; Humans ; Protein Binding ; Protein Structure, Tertiary ; Shelterin Complex ; Telomerase/*antagonists &amp; inhibitors/genetics/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {The telomeric single-strand DNA binding protein protection of telomeres 1 (POT1) protects telomeres from rapid degradation in Schizosaccharomyces pombe and has been implicated in positive and negative telomere length regulation in humans. Human POT1 appears to interact with telomeres both through direct binding to the 3' overhanging G-strand DNA and through interaction with the TRF1 duplex telomere DNA binding complex. The influence of POT1 on telomerase activity has not been studied at the molecular level. We show here that POT1 negatively effects telomerase activity in vitro. We find that the DNA binding activity of POT1 is required for telomerase inhibition. Furthermore, POT1 is incapable of inhibiting telomeric repeat addition to substrate primers that are defective for POT1 binding, suggesting that in vivo, POT1 likely affects substrate access to telomerase.},
}
@article {pmid15632001,
year = {2005},
author = {Oh, BK and Kim, YJ and Park, C and Park, YN},
title = {Up-regulation of telomere-binding proteins, TRF1, TRF2, and TIN2 is related to telomere shortening during human multistep hepatocarcinogenesis.},
journal = {The American journal of pathology},
volume = {166},
number = {1},
pages = {73-80},
pmid = {15632001},
issn = {0002-9440},
mesh = {Carcinoma, Hepatocellular/*genetics/pathology ; DNA Primers ; DNA, Complementary/genetics ; *Gene Expression Regulation ; Humans ; Immunohistochemistry ; Liver Neoplasms/*genetics/pathology ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics ; Telomeric Repeat Binding Protein 1/*genetics ; Telomeric Repeat Binding Protein 2/*genetics ; },
abstract = {The telomeric repeat-binding factor 1 (TRF1), TRF2, and the TRF1-interacting nuclear protein 2 (TIN2) are involved in telomere maintenance. We describe the regulation of expression of these genes along with their relationship to telomere length in hepatocarcinogenesis. The transcriptional expression of these genes, TRF1 protein, and telomere length was examined in 9 normal livers, 14 chronic hepatitis, 24 liver cirrhosis, 5 large regenerative nodules, 14 low-grade dysplastic nodules (DNs), 7 high-grade DNs, 10 DNs with hepatocellular carcinoma (HCC) foci, and 31 HCCs. The expression of TRF1, TRF2, TIN2 mRNA, and TRF1 protein was gradually increased according to the progression of hepatocarcinogenesis with a marked increase in high-grade DNs and DNs with HCC foci and a further increase in HCCs. There was a gradual shortening of telomere during hepatocarcinogenesis with a significant reduction in length in DNs. Most nodular lesions (52 of 67) had shorter telomeres than their adjacent chronic hepatitis or liver cirrhosis, and the telomere lengths were inversely correlated with the mRNA level of these genes (P </= 0.001). This was more evident in DNs and DNs with HCC foci. In conclusion, TRF1, TRF2, and TIN2 might be involved in multistep hepatocarcinogenesis by playing crucial roles in telomere shortening.},
}
@article {pmid15621829,
year = {2005},
author = {Kubuki, Y and Suzuki, M and Sasaki, H and Toyama, T and Yamashita, K and Maeda, K and Ido, A and Matsuoka, H and Okayama, A and Nakanishi, T and Tsubouchi, H},
title = {Telomerase activity and telomere length as prognostic factors of adult T-cell leukemia.},
journal = {Leukemia &amp; lymphoma},
volume = {46},
number = {3},
pages = {393-399},
doi = {10.1080/10428190400018349},
pmid = {15621829},
issn = {1042-8194},
mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; HTLV-I Infections/blood/*enzymology/genetics ; Humans ; Leukemia-Lymphoma, Adult T-Cell/diagnosis/*enzymology/genetics ; Leukocytes, Mononuclear/chemistry/enzymology ; Male ; Middle Aged ; Prognosis ; Prospective Studies ; Restriction Mapping ; Serologic Tests ; Survival Analysis ; Telomerase/genetics/*metabolism ; Telomere/chemistry/genetics/*metabolism ; },
abstract = {For the oncogenesis of many malignancies, it is crucial to prevent the shortening of the telomeres by the action of telomerase. In this study, clinical data and disease outcomes were analyzed in conjunction with the telomerase activity (TA) and telomere length (TL) of peripheral blood mononuclear cells. The study was carried out in 22 patients with adult T-cell leukemia (ATL) (7 chronic and 15 acute types) and in 13 asymptomatic human T-lymphotropic virus type 1 (HTLV-1) carriers. The mean values of TA in acute and chronic type patients were 13.8 and 1.6 total product generated (TPG) units, respectively, as determined by telomeric repeat amplification assays. The mean TA values in HTLV-1 carriers and healthy volunteers were 1.8 and 0.7 TPG, respectively. The mean TA value in acute type patients was significantly higher than in the three other subject groups. The mean TL values in patients with acute and chronic types were 5.39 and 4.38 Kb, respectively, while the mean TL values in HTLV-1 carriers and healthy volunteers were 7.69 and 7.06 Kb, respectively. The mean TL values in all ATL patients and in non-ATL subjects were 5.2 and 7.3 Kb, respectively. The former value is significantly shorter than the latter (p < 0.01). Neither TA nor TL of ATL cells showed any significant association with the number of ATL cells, serum soluble interleukin-2 receptor, or serum lactate dehydrogenase in the peripheral blood of acute type patients. This suggests that the levels of TA and TL did not reflect the ATL tumor load. The median survival period of acute ATL patients with high TA and shortened TL was 0.47 years, however, which was significantly shorter than that of acute ATL patients with low TA and normal TL (4.21 years) (p < 0.002). These data suggest that high TA and shortened TL were associated with poorer prognosis, and that TA and TL may be novel markers for the prognosis of ATL patients.},
}
@article {pmid15620701,
year = {2005},
author = {Yeo, M and Rha, SY and Jeung, HC and Shen, XH and Yang, SH and An, SW and Roh, JK and Chung, HC},
title = {Different role of functional domains of hTR in DNA binding to telomere and telomerase reconstruction.},
journal = {FEBS letters},
volume = {579},
number = {1},
pages = {127-132},
doi = {10.1016/j.febslet.2004.11.058},
pmid = {15620701},
issn = {0014-5793},
mesh = {Binding Sites ; DNA/drug effects/metabolism ; Humans ; Immunoprecipitation ; Mutation/genetics ; Nucleic Acid Conformation ; Oligonucleotides, Antisense/genetics/pharmacology ; RNA ; RNA, Long Noncoding ; RNA, Untranslated/*chemistry/genetics/*metabolism ; Telomerase/*chemistry/genetics/*metabolism ; Telomere/*metabolism ; Templates, Genetic ; },
abstract = {Even if template sequence of hTR played an essential role in telomere binding, a 326 nucleotide fragment of hTR containing template, pseudoknot, and CR4-5 domains is critical for both binding with telomeric DNA and reconstitution of telomerase activity. A functional study with antisense oligonucleotides suggested that targeted disruption of the template region efficiently abrogated both telomeric DNA binding and telomerase activity, whereas disruption of the CR4-5 region induced only loss of telomerase activity. hTR interacts with telomeric DNA via structural region composed of the template, pseudoknot, and CR4-5 domains, however, each structural domain plays a distinct role in telomere binding and telomerase activity reconstitution.},
}
@article {pmid15620660,
year = {2004},
author = {Jacobs, JJ and de Lange, T},
title = {Significant role for p16INK4a in p53-independent telomere-directed senescence.},
journal = {Current biology : CB},
volume = {14},
number = {24},
pages = {2302-2308},
doi = {10.1016/j.cub.2004.12.025},
pmid = {15620660},
issn = {0960-9822},
support = {AG16642/AG/NIA NIH HHS/United States ; },
mesh = {Bromodeoxyuridine ; Cells, Cultured ; Cellular Senescence/*physiology ; Cyclin-Dependent Kinase Inhibitor p16/*physiology ; DNA Damage/physiology ; Fibroblasts/physiology ; Fluorescent Antibody Technique ; Humans ; Immunohistochemistry ; Telomere/*physiology ; Telomeric Repeat Binding Protein 2/metabolism ; Tumor Suppressor Protein p53/deficiency ; },
abstract = {Telomere attrition in primary human fibroblasts induces replicative senescence accompanied by activation of the p53 and p16(INK4a)/RB tumor suppressor pathways. Although the contribution of p53 and its target, p21, to telomere-driven senescence have been well established, the role of p16(INK4a) is controversial. Attempts to dissect the significance of p16(INK4a) in response to telomere shortening have been hampered by the concomitant induction of p16(INK4a) by cell culture conditions. To circumvent this problem, we studied the role of p16(INK4a) in the cellular response to acute telomere damage induced by a dominant negative allele of TRF2, TRF2(Delta B Delta M). This approach avoids the confounding aspects of culture stress because parallel cultures with and without telomere damage can be compared. Telomere damage generated with TRF2(Delta B Delta M) resulted in induction of p16(INK4a) in the majority of cells as detected by immunohistochemistry. Inhibition of p16(INK4a) with shRNA or overexpression of BMI1 had a significant effect on the telomere damage response in p53-deficient cells. While p53 deficiency alone only partially abrogated the telomere damage-induced cell cycle arrest, combined inhibition of p16(INK4a) and p53 led to nearly complete bypass of telomere-directed senescence. We conclude that p16(INK4a) contributes to the p53-independent response to telomere damage.},
}
@article {pmid15620654,
year = {2004},
author = {Veldman, T and Etheridge, KT and Counter, CM},
title = {Loss of hPot1 function leads to telomere instability and a cut-like phenotype.},
journal = {Current biology : CB},
volume = {14},
number = {24},
pages = {2264-2270},
doi = {10.1016/j.cub.2004.12.031},
pmid = {15620654},
issn = {0960-9822},
support = {CA82481/CA/NCI NIH HHS/United States ; },
mesh = {Apoptosis/physiology ; Chromosomal Instability/genetics/*physiology ; Chromosome Segregation/physiology ; DNA/*metabolism ; DNA Primers ; HeLa Cells ; Humans ; Immunoblotting ; Micronuclei, Chromosome-Defective ; *Phenotype ; Reverse Transcriptase Polymerase Chain Reaction ; Shelterin Complex ; Telomere/genetics/*physiology ; Telomere-Binding Proteins/metabolism/*physiology ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {The human telomere binding protein hPot1 binds to the most distal single-stranded extension of telomeric DNA in vitro, and probably in vivo, as well as associating with the double-stranded telomeric DNA binding proteins TRF1 and TRF2 through the bridging proteins PTOP (also known as PIP1 or TINT1) and TIN2. Disrupting either the DNA binding activity of hPot1 or its association with PTOP results in elongated telomeres, suggesting a role for hPot1 in telomere length regulation. However, mutations to POT1 and Cdc13p, the fission and budding yeast genes encoding the structural orthologs of this protein, leads to telomere instability and cell death. Thus, it is possible that the hPot1 protein may also serve to cap and protect telomeres in humans. Indeed, we now find that knocking down the expression of hPot1 in human cells causes apoptosis or senescence, as well as an increase in telomere associations and anaphase bridges, telltale signs of telomere instability. In addition, knockdown cells also displayed chromatin bridges between interphase cells, reminiscent of the cut phenotype that was first described in fission yeast and in which cytokinesis progresses despite a failure of chromatid separation. However, unlike the yeast cut phenotypes, we suggest that the cut-like phenotype observed in hPot1 knockdown cells is a consequence of the fusion of chromosome ends and that this fusion impedes proper chromosomal segregation. We conclude that hPot1 protects chromosome ends from illegitimate recombination, catastrophic chromosome instability, and abnormal chromosome segregation.},
}
@article {pmid15618136,
year = {2004},
author = {Aviv, A},
title = {Telomeres and human aging: facts and fibs.},
journal = {Science of aging knowledge environment : SAGE KE},
volume = {2004},
number = {51},
pages = {pe43},
doi = {10.1126/sageke.2004.51.pe43},
pmid = {15618136},
issn = {1539-6150},
support = {AG021593/AG/NIA NIH HHS/United States ; HL70137/HL/NHLBI NIH HHS/United States ; },
mesh = {Aging/*genetics ; Humans ; Telomere/*genetics ; },
abstract = {Can telomere dynamics, defined by telomere length and attrition rate, provide information about the biology of human aging above and beyond that provided by chronological age? Accruing data suggest that it can. White blood cells (WBCs) have been used as the primary model in attempts to decipher links between aging, aging-related disorders, and telomere dynamics in humans. The WBC model may be appropriate in clinical settings, provided that we fully appreciate its drawbacks and limitations. On the basis of WBC telomere data, it is evident that age-adjusted telomere length is highly variable, highly heritable, longer in women than men, and shorter in people who harbor a host of age-related disorders, whose common denominators may prove to be increased oxidative stress and inflammation. It appears that shorter age-adjusted WBC telomere length augurs a greater risk of morbidity and premature mortality in the elderly. However, it is unsettled whether human telomere dynamics is only a proxy for fundamental mechanisms that govern the course of aging or a key determinant in its progression.},
}
@article {pmid15616866,
year = {2004},
author = {Abad, JP and de Pablos, B and Agudo, M and Molina, I and Giovinazzo, G and Martín-Gallardo, A and Villasante, A},
title = {Genomic and cytological analysis of the Y chromosome of Drosophila melanogaster: telomere-derived sequences at internal regions.},
journal = {Chromosoma},
volume = {113},
number = {6},
pages = {295-304},
pmid = {15616866},
issn = {0009-5915},
mesh = {Animals ; Antibodies/immunology ; Base Sequence ; Cell Cycle Proteins ; Chromosomes, Artificial, Bacterial/genetics ; Chromosomes, Artificial, Yeast/genetics ; Contig Mapping ; DNA Transposable Elements ; Drosophila Proteins/genetics/metabolism/physiology ; Drosophila melanogaster/*genetics ; Gene Products, gag/genetics/metabolism/physiology ; Genomics ; Heterochromatin/*genetics ; In Situ Hybridization, Fluorescence ; Male ; Molecular Sequence Data ; Protein Kinases/analysis/immunology/metabolism ; Protein Serine-Threonine Kinases ; Telomere/*genetics ; Y Chromosome/chemistry/*genetics/metabolism ; },
abstract = {The genomic analysis of heterochromatin is essential for studying chromosome behavior as well as for understanding chromosome evolution. The Y chromosome of Drosophila melanogaster is entirely heterochromatic and the under-representation of this chromosome in genomic libraries together with the difficulty of assembling its sequence has made its study very difficult. Here, we present the construction of bacterial artificial chromosome (BAC) contigs from regions h14, h16 and the centromeric region h18. The analysis of these contigs shows that telomere-derived sequences are present at internal regions. In addition, immunostaining of prometaphase chromosomes with an antibody to the kinetochore-specific protein BubR1 has revealed the presence of this protein in some Y chromosome regions rich in telomere-related sequences. Collectively, our data provide further evidence for the hypothesis that the Drosophila Y chromosomes might have evolved from supernumerary chromosomes.},
}
@article {pmid15613284,
year = {2005},
author = {Gisselsson, D and Höglund, M},
title = {Connecting mitotic instability and chromosome aberrations in cancer--can telomeres bridge the gap?.},
journal = {Seminars in cancer biology},
volume = {15},
number = {1},
pages = {13-23},
doi = {10.1016/j.semcancer.2004.09.002},
pmid = {15613284},
issn = {1044-579X},
mesh = {*Chromosome Aberrations ; *Genomic Instability ; Humans ; Mitosis/*genetics ; Neoplasms/*genetics ; Telomere/*genetics ; },
abstract = {Gross mitotic disturbances are often found in malignant tumours, but not until recently have the molecular causes and the genomic consequences of these abnormalities started to become known. One potential source of mitotic instability is chromosomes with dysfunctional telomeres, giving rise to a high rate of chromatin bridges at anaphase. These bridges could lead either to structural chromosome rearrangements through chromatin fragmentation or to whole-chromosome losses through kinetochore-spindle detachment. Statistical meta-analyses have recently revealed that tumours with high rates of anaphase bridging, such as ovarian, head and neck, and pancreatic carcinomas, are characterised by multimodal distributions of genomic imbalances, consistent with a dramatically increased rate of chromosome rearrangements. In contrast, tumours without gross cell division disturbances are characterised by a monotonously decreasing distribution of genomic changes. This distribution follows a power-law, best described by a preferential attachment model in which the tolerance for chromosomal changes increases steadily with tumour growth. Even though many common cancers, such as breast, colorectal, and renal cell carcinomas adhere to this simple power-law dynamics, the underlying molecular mechanisms remain elusive.},
}
@article {pmid15611654,
year = {2005},
author = {Prime, G and Markie, D},
title = {The telomere repeat binding protein Trf1 interacts with the spindle checkpoint protein Mad1 and Nek2 mitotic kinase.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {4},
number = {1},
pages = {121-124},
doi = {10.4161/cc.4.1.1351},
pmid = {15611654},
issn = {1551-4005},
mesh = {Animals ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics/*metabolism ; Cell Cycle/genetics/physiology ; *Gene Expression Regulation ; Kinetochores/physiology ; Metaphase/genetics/physiology ; Mice ; Mitosis/genetics/physiology ; NIMA-Related Kinases ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Protein Structure, Tertiary ; Repressor Proteins/genetics/*metabolism ; Spindle Apparatus/genetics/physiology ; Telomere/genetics/physiology/ultrastructure ; Telomeric Repeat Binding Protein 1/genetics/*metabolism ; },
abstract = {The mitotic spindle checkpoint arrests cells in metaphase until all kinetochores are correctly attached to spindle fibres. In a search for new components of the spindle checkpoint, based on protein interaction, we have identified mouse Telomeric Repeat Binding Factor 1 (Trf1) as a protein that interacts directly with the spindle checkpoint protein Mad1 and the mitotic kinase Nek2. Trf1 has a role in the regulation of telomere length, but has also been implicated in cell cycle regulation. These interactions now provide a direct link between telomere length regulation and the control of mitotic progression.},
}
@article {pmid15608677,
year = {2005},
author = {Wiemann, SU and Satyanarayana, A and Buer, J and Kamino, K and Manns, MP and Rudolph, KL},
title = {Contrasting effects of telomere shortening on organ homeostasis, tumor suppression, and survival during chronic liver damage.},
journal = {Oncogene},
volume = {24},
number = {9},
pages = {1501-1509},
doi = {10.1038/sj.onc.1208308},
pmid = {15608677},
issn = {0950-9232},
mesh = {Animals ; Apoptosis ; Carbon Tetrachloride Poisoning ; Cell Division ; Cell Nucleus/pathology ; Cytoskeletal Proteins/analysis ; DNA-Binding Proteins ; Homeostasis ; Liver/*pathology ; Liver Neoplasms/pathology/*prevention &amp; control ; Mice ; Mice, Knockout ; Mice, Transgenic ; Telomerase/deficiency/genetics/*metabolism ; Trans-Activators/analysis ; beta Catenin ; },
abstract = {Telomere shortening limits the regenerative capacity of cells during aging and chronic disease but at the same time inhibits tumor progression, and it has yet to be determined which of these mechanisms is dominantly affecting organismal survival. Here we show that telomere shortening in telomerase knockout (mTERC-/-) mice in combination with chronic liver damage significantly reduced organismal survival even though telomere shortening strongly inhibited liver tumor formation. Decreased survival induced by telomere shortening correlated with an imbalance between liver cell proliferation and liver cell apoptosis. Specific changes in gene expression were associated with telomere shortening and chronic liver damage and these gene expression changes were partially reversed by adenovirus mediated telomerase gene delivery. This study gives experimental evidence that the negative impact of telomere shortening on organ homeostasis and organismal survival can surpass the beneficial effects of telomere shortening on suppression of tumor growth in the setting of chronic organ damage.},
}
@article {pmid15603450,
year = {2004},
author = {Baerlocher, GM and Lansdorp, PM},
title = {Telomere length measurements using fluorescence in situ hybridization and flow cytometry.},
journal = {Methods in cell biology},
volume = {75},
number = {},
pages = {719-750},
doi = {10.1016/s0091-679x(04)75031-1},
pmid = {15603450},
issn = {0091-679X},
support = {AI 29524/AI/NIAID NIH HHS/United States ; },
mesh = {Algorithms ; Animals ; Automation/instrumentation ; Blotting, Southern/methods ; Cattle ; Cell Separation/methods ; DNA/chemistry/genetics ; Flow Cytometry/*methods ; Fluorescent Dyes/chemistry ; Humans ; In Situ Hybridization, Fluorescence/instrumentation/*methods/statistics &amp; numerical data ; Nucleic Acid Denaturation ; Nucleic Acid Probes/genetics ; Papio ; Reference Standards ; Reproducibility of Results ; Staining and Labeling/methods ; Telomere/*genetics/metabolism ; },
}
@article {pmid15602000,
year = {2004},
author = {Janzen, CJ and Lander, F and Dreesen, O and Cross, GA},
title = {Telomere length regulation and transcriptional silencing in KU80-deficient Trypanosoma brucei.},
journal = {Nucleic acids research},
volume = {32},
number = {22},
pages = {6575-6584},
pmid = {15602000},
issn = {1362-4962},
support = {R01 AI050614/AI/NIAID NIH HHS/United States ; AI50614/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Antigens, Nuclear/analysis/genetics/*physiology ; Cell Line ; Chromatin/genetics ; DNA-Binding Proteins/analysis/genetics/*physiology ; Gene Deletion ; *Gene Silencing ; Ku Autoantigen ; Telomere/chemistry/*metabolism ; Transcription, Genetic ; Trypanosoma brucei brucei/*genetics/growth &amp; development/metabolism ; Variant Surface Glycoproteins, Trypanosoma/biosynthesis/genetics ; },
abstract = {KU is a heterodimer, consisting of approximately 70 and approximately 80 kDa subunits (KU70 and KU80, respectively), which is involved in a variety of nuclear functions. We generated tbKU80-deficient trypanosomes to explore the potential role of the tbKU complex in telomere maintenance and transcriptional regulation of variant surface glycoprotein (VSG) genes in Trypanosoma brucei. Using real-time PCR, we demonstrated that the expression of several different VSG genes remains tightly regulated in tbKU80-deficient bloodstream-form cell lines, suggesting that VSG transcription profiles do not change in these cells. Owing to developmental silencing of the VSG Expression Sites (ES), no VSG is transcribed in the insect procyclic stage. With a green fluorescent protein reporter system, we showed that tbKU80-deficient mutants are fully capable of ES silencing after differentiation into procyclic forms. Using T7 RNA polymerase to explore the transcriptional accessibility of ES chromatin in vivo, we demonstrated that tbKU80-deficient bloodstream-form cells were able to generate transcriptionally repressed ES chromatin after differentiation into procyclic cells. Finally, we demonstrated progressive telomere shortening in tbKU80-deficient mutants. The possible function of tbKU80 in telomere maintenance and regulation of telomerase is discussed.},
}
@article {pmid15593287,
year = {2005},
author = {Zeng, ZX and Zhao, Y and Hao, YH and Tan, Z},
title = {Tetraplex formation of surface-immobilized human telomere sequence probed by surface plasmon resonance using single-stranded DNA binding protein.},
journal = {Journal of molecular recognition : JMR},
volume = {18},
number = {3},
pages = {267-271},
doi = {10.1002/jmr.731},
pmid = {15593287},
issn = {0952-3499},
mesh = {DNA/*chemistry ; DNA, Single-Stranded/*chemistry ; DNA-Binding Proteins/*chemistry/metabolism ; Escherichia coli/chemistry/metabolism ; G-Quadruplexes ; Humans ; Kinetics ; Nucleic Acid Conformation ; Oligonucleotides/chemistry ; *Surface Plasmon Resonance ; Telomere/*chemistry ; },
abstract = {Many sequences in genomic DNA are able to form unique tetraplex structures. Such structures are involved in a variety of important cellular processes and are emerging as a new class of therapeutic targets for cancers and other diseases. Screening for molecules targeting the tetraplex structure has been explored using such sequences immobilized on solid surfaces. Immobilized nucleic acids, in certain situations, may better resemble the molecules under in vivo conditions. In this report, we studied the formation of tetraplex structure of both the G-rich and C-rich strands of surface-immobilized human telomere sequence by surface plasmon resonance using the single-stranded DNA binding protein from Escherichia coli as probe. We demonstrate how the formation of G-quadruplex and i-motif could be probed under various conditions by this sequence-universal method. Our results also show that immobilization destabilized the tetraplex structure.},
}
@article {pmid15591207,
year = {2004},
author = {Crabbe, L and Verdun, RE and Haggblom, CI and Karlseder, J},
title = {Defective telomere lagging strand synthesis in cells lacking WRN helicase activity.},
journal = {Science (New York, N.Y.)},
volume = {306},
number = {5703},
pages = {1951-1953},
doi = {10.1126/science.1103619},
pmid = {15591207},
issn = {1095-9203},
support = {GM069525/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; Anaphase ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins ; Cell Line ; Cells, Cultured ; Chromatids/metabolism ; Chromosomes, Human/physiology ; DNA Damage ; DNA Helicases/genetics/*metabolism ; DNA-Binding Proteins ; Exodeoxyribonucleases ; Genomic Instability ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Models, Genetic ; Mutation ; Protein Serine-Threonine Kinases/metabolism ; RecQ Helicases ; S Phase ; Telomerase/metabolism ; Telomere/*metabolism ; Tumor Suppressor Proteins ; Werner Syndrome/*genetics ; Werner Syndrome Helicase ; },
abstract = {Cells from Werner syndrome patients are characterized by slow growth rates, premature senescence, accelerated telomere shortening rates, and genome instability. The syndrome is caused by the loss of the RecQ helicase WRN, but the underlying molecular mechanism is unclear. Here we report that cells lacking WRN exhibit deletion of telomeres from single sister chromatids. Only telomeres replicated by lagging strand synthesis were affected, and prevention of loss of individual telomeres was dependent on the helicase activity of WRN. Telomere loss could be counteracted by telomerase activity. We propose that WRN is necessary for efficient replication of G-rich telomeric DNA, preventing telomere dysfunction and consequent genomic instability.},
}
@article {pmid15590829,
year = {2004},
author = {Banerjee, S and Myung, K},
title = {Increased genome instability and telomere length in the elg1-deficient Saccharomyces cerevisiae mutant are regulated by S-phase checkpoints.},
journal = {Eukaryotic cell},
volume = {3},
number = {6},
pages = {1557-1566},
pmid = {15590829},
issn = {1535-9778},
mesh = {Base Sequence ; Carrier Proteins/*genetics/*physiology ; DNA/metabolism ; DNA Damage ; DNA Helicases/genetics ; DNA Repair ; DNA Replication ; DNA-Binding Proteins/genetics ; Gene Deletion ; Genome, Fungal ; *Genomic Instability ; Methyl Methanesulfonate/pharmacology ; Molecular Sequence Data ; Mutagens ; Mutation ; Recombination, Genetic ; Repressor Proteins/genetics ; *S Phase ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Sequence Homology, Nucleic Acid ; Telomere/*ultrastructure ; Telomere-Binding Proteins/genetics ; Time Factors ; },
abstract = {Gross chromosomal rearrangements (GCRs) are frequently observed in cancer cells. Abnormalities in different DNA metabolism including DNA replication, cell cycle checkpoints, chromatin remodeling, telomere maintenance, and DNA recombination and repair cause GCRs in Saccharomyces cerevisiae. Recently, we used genome-wide screening to identify several genes the deletion of which increases GCRs in S. cerevisiae. Elg1, which was discovered during this screening, functions in DNA replication by participating in an alternative replication factor complex. Here we further characterize the GCR suppression mechanisms observed in the elg1Delta mutant strain in conjunction with the telomere maintenance role of Elg1. The elg1Delta mutation enhanced spontaneous DNA damage and resulted in GCR formation. However, DNA damage due to inactivation of Elg1 activates the intra-S checkpoints, which suppress further GCR formation. The intra-S checkpoints activated by the elg1Delta mutation also suppress GCR formation in strains defective in the DNA replication checkpoint. Lastly, the elg1Delta mutation increases telomere size independently of other previously known telomere maintenance proteins such as the telomerase inhibitor Pif1 or the telomere size regulator Rif1. The increase in telomere length caused by the elg1Delta mutation was suppressed by a defect in the DNA replication checkpoint, which suggests that DNA replication surveillance by Dpb11-Mec1/Tel1-Dun1 also has an important role in telomere length regulation.},
}
@article {pmid15589838,
year = {2004},
author = {Kuchar, M and Fajkus, J},
title = {Interactions of putative telomere-binding proteins in Arabidopsis thaliana: identification of functional TRF2 homolog in plants.},
journal = {FEBS letters},
volume = {578},
number = {3},
pages = {311-315},
doi = {10.1016/j.febslet.2004.11.021},
pmid = {15589838},
issn = {0014-5793},
mesh = {Amino Acid Sequence ; Arabidopsis/*metabolism ; Arabidopsis Proteins/chemistry/genetics/*metabolism ; Autoradiography ; Binding Sites ; Cloning, Molecular ; DNA, Plant/chemistry/genetics/metabolism ; Electrophoresis, Polyacrylamide Gel ; Methionine/chemistry ; Open Reading Frames ; Plant Proteins/chemistry/genetics/*metabolism ; Precipitin Tests ; Protein Processing, Post-Translational ; Protein Structure, Tertiary ; Sequence Deletion ; Sulfur Radioisotopes ; *Telomere ; Telomere-Binding Proteins/*metabolism ; Telomeric Repeat Binding Protein 2/chemistry/genetics/*metabolism ; Transcription, Genetic ; Two-Hybrid System Techniques ; },
abstract = {Telomere-binding proteins are required for forming the functional structure of chromosome ends and regulating telomerase action. Although a number of candidate proteins have been identified by homology searches to plant genome databases and tested for their affinity to telomeric DNA sequences in vitro, there are minimal data relevant to their telomeric function. To address this problem, we made a collection of cDNAs of putative telomere-binding proteins of Arabidopsis thaliana to analyse their protein-protein interactions with the yeast two-hybrid system. Our results show that one myb-like protein, AtTRP1, interacts specifically with AtKu70, the latter protein having a previously described role in plant telomere metabolism. In analogy to the interaction between human Ku70 and TRF2 proteins, our results suggest that AtTRP1 is a likely homolog of TRF2. The AtTRP1 domain responsible for AtKu70 interaction occurs between amino acid sequence positions 80 and 269. The protein AtTRB1, a member of the single myb histone (Smh) family, shows self-interaction and interactions to the Smh family proteins AtTRB2 and AtTRB3. Protein AtTRB1 also interacts with AtPot1, the Arabidopsis homolog of oligonucleotide-binding-fold-containing proteins which bind G-rich telomeric DNA. In humans, the TRF1-complex recruits hPot1 to telomeres by protein-protein interactions where it is involved in telomere length regulation. Possibly, AtTRB1 has a similar role in recruiting AtPot1.},
}
@article {pmid15588516,
year = {2004},
author = {Flanary, B},
title = {Regulation of murine telomere length via Rtel.},
journal = {Rejuvenation research},
volume = {7},
number = {3},
pages = {168-170},
doi = {10.1089/rej.2004.7.168},
pmid = {15588516},
issn = {1549-1684},
mesh = {Animals ; Cell Division ; Cellular Senescence/*genetics ; DNA Helicases/*genetics ; *Genes, Essential ; Genes, Regulator ; Mice ; Muridae/genetics ; Telomere/*physiology ; },
abstract = {Normal somatic cells have a finite replicative capacity. With each cell division, telomeres (the physical ends of linear chromosomes) progressively shorten until they reach a critical length, at which point the cells enter replicative senescence. Some cells can maintain telomere length by the action of the telomerase enzyme. A recent article described in detail the organization and function of Rtel, a murine gene encoding a DNA helicase-like protein. The Rtel protein was found to be essential for genomic stability and embryonic development and survival, and is proposed to be a dominant regulator of murine telomere length.},
}
@article {pmid15586405,
year = {2004},
author = {Shi, JM and Ding, W and Huang, H and Zhang, ZG and Tang, LD and Lin, MF},
title = {[Expression of telomere repeat binding factor 1 (TRF1) protein in kidney cancer].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {33},
number = {6},
pages = {496-9, 508},
doi = {10.3785/j.issn.1008-9292.2004.06.006},
pmid = {15586405},
issn = {1008-9292},
mesh = {Adenocarcinoma, Clear Cell/metabolism ; Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Kidney/*metabolism ; Kidney Neoplasms/*metabolism ; Male ; Middle Aged ; RNA, Messenger/biosynthesis/genetics ; Telomeric Repeat Binding Protein 1/*biosynthesis/genetics ; },
abstract = {OBJECTIVE: To investigate the expression levels of telomere repeat binding factor 1(TRF1) protein in normal kidney tissue and kidney cancer.<br><br>METHODS: Specimens of kidney cancer and pericancerous tissues were collected from 32 cases of renal carcinoma. A quantitative Western blotting technique was developed using TRF1 monoclonal antibody to determine the expression level of TRF1 protein in total protein extracts from tissue specimens.<br><br>RESULTS: The expression level of TRF1 protein was higher in normal kidney tissues (3.611 +/-1.922 microg/microl) than that of cancer tissues (2.428 +/-1.352 microg/microl) (t=5.776, P<0.01).<br><br>CONCLUSION: The expression level of TRF1 protein is significantly reduced in kidney cancer and the level is negatively correlated with malignant degree of the cancer.},
}
@article {pmid15586404,
year = {2004},
author = {Sun, J and Lai, XY and Zhu, YY and Lan, JP and Tang, LD and Li, JY and Yu, J and Tan, YM and Lin, MF and Huang, H},
title = {[Expression of human telomere repeat binding factor 1 (TRF1) in acute leukemia cells and its correlation with telomerase activities].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {33},
number = {6},
pages = {491-495},
doi = {10.3785/j.issn.1008-9292.2004.06.005},
pmid = {15586404},
issn = {1008-9292},
mesh = {Adolescent ; Adult ; Aged ; Female ; Humans ; Leukemia, Myeloid, Acute/enzymology/*metabolism ; Male ; Middle Aged ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology/*metabolism ; RNA, Messenger/biosynthesis/genetics ; Telomerase/*metabolism ; Telomeric Repeat Binding Protein 1/*biosynthesis/genetics ; },
abstract = {OBJECTIVE: To study the expression of human telomere repeat binding factor 1 (TRF1) to investigate the correlation of telomerase activity with acute leukemia.<br><br>METHODS: Leukemic cells were collected from 30 cases of acute leukemia. Realtime quantitative PCR with fluorescence probe hybridization was used to measure expression of TRF1 and hTERT mRNA in leukemic cells.<br><br>RESULTS: TRF1 mRNA expression was 0.0126 (0.0127-0.0546) in acute non-lymphocytic leukemia (ANLL), which was lower than that in normal mononuclear cells [0.0457 (0.00839-0.262), P<0.001], but its expression in acute lymphoblastic leukemia (ALL) cells [0.0745 (1.92 x 10(-6)-0.193)] had no significant difference compared with that in normal mononuclear cells. TRF1 expression in ANLL cells was significantly lower than that in ALL cells (P=0.001). The expressions of TRF1 mRNA in AL cells and normal mononuclear cells had no significant correlation with expression of hTERT mRNA (r=-0.173, P=0.207).<br><br>CONCLUSION: The expression of TRF1 is lower in ANLL cells, which indicates TRF1 may have some effect on telomerase activity by regulating telomere length in ANLL cells.},
}
@article {pmid15586401,
year = {2004},
author = {Lan, JP and La, XY and Zhu, YY and Sun, J and Li, JY and Yu, J and Tan, YM and Shi, JM and Lin, MF and Huang, H},
title = {[Localization of human telomere repeat binding factor 1 in telomerase-positive and-negative cells and its expression during cell cycle].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {33},
number = {6},
pages = {475-80, 495},
doi = {10.3785/j.issn.1008-9292.2004.06.002},
pmid = {15586401},
issn = {1008-9292},
mesh = {*Cell Cycle ; HeLa Cells ; Humans ; Leukemia, Promyelocytic, Acute/pathology ; Mutation ; Telomerase/*metabolism ; Telomere-Binding Proteins/biosynthesis/genetics/metabolism ; Telomeric Repeat Binding Protein 1/*biosynthesis/*genetics/metabolism ; Tumor Cells, Cultured ; },
abstract = {OBJECTIVE: To observe the distribution pattern of human telomere repeat binding factor 1(TRF1) in the telomerase-positive (HeLa) and telomerase-negative cells (WI38-2RA) and to investigate its expression level during the cell cycle.<br><br>METHODS: The full-length sequences of TRF1(TRF1FL) and its mutant with N and C terminus deletion (TRF1DeltaNC) were generated by PCR amplification, the resulting fragments were cloned into pEGFP-C2 mammalian expression vector. GFP-tagged proteins were verified by Western blotting with rabbit anti-TRF1 and mouse anti-GFP antibodies after cell transfection. Immunofluorescence staining were performed to detect the TRF1 localization in HeLa and WI38-2RA cells. Metaphase spreads from HeLa cells were also prepared to observe TRF1 localization in chromosomes. HeLa cells were arrested by thymidine and nocodazole at different cell stages. Cell cycles were analyzed by flow cytometry and TRF1 levels were evaluated by semi-quantitative Western blotting.<br><br>RESULTS: TRF1FL and TRF1PNC fragments were sized about 1.3 kb and 0.95 kb. GFP-tagged TRF1FL and TRF1DeltaNC proteins were 80 kD and 60 kD, respectively. In both HeLa and WI38-2RA cells, TRF1FL had a speckled distribution in the nuclei,however, TRF1FL did not coincide with promyelocytic leukemia (PML) nuclear body in HeLa cells while it exclusively did in WI38-2RA cells. Moreover, TRF1FL was exactly localized at the termini of metaphase spreads in HeLa cells. In contrast, TRF1PNC was diffusely distributed throughout the nuclei. Analysis by semi-quantitative Western blotting indicated that TRF1 levels increased with cell cycle progression, which reached the zenith at the M phase and went down to the nadir at G1/S point. The TRF1 level at M phase was about 3.9 times than that at G1/S point(t=12.92iP<0.01).<br><br>CONCLUSION: TRF1 has a different localization in telomerase-positive and telomerase-negative cells, which suggests TRF1 might exert different functions in these cells. TRF1 level is regulated with cell cycle.},
}
@article {pmid15586400,
year = {2004},
author = {Huang, H and Sun, J},
title = {[Research progress on telomere binding proteins].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {33},
number = {6},
pages = {469-473},
doi = {10.3785/j.issn.1008-9292.2004.06.001},
pmid = {15586400},
issn = {1008-9292},
mesh = {Apoptosis/physiology ; Cell Cycle/physiology ; Humans ; Neoplasms/etiology/metabolism ; Tankyrases/genetics/physiology ; Telomerase/metabolism/*physiology ; *Telomere/genetics/metabolism ; Telomere-Binding Proteins/genetics/*physiology ; Telomeric Repeat Binding Protein 1/genetics/physiology ; Telomeric Repeat Binding Protein 2/genetics/physiology ; },
}
@article {pmid15583028,
year = {2004},
author = {Xu, L and Blackburn, EH},
title = {Human Rif1 protein binds aberrant telomeres and aligns along anaphase midzone microtubules.},
journal = {The Journal of cell biology},
volume = {167},
number = {5},
pages = {819-830},
pmid = {15583028},
issn = {0021-9525},
support = {R01 CA096840/CA/NCI NIH HHS/United States ; CA096840/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Sequence/genetics ; Anaphase/genetics/*physiology ; Base Sequence/genetics ; Cell Compartmentation/genetics ; Cell Cycle/*genetics ; Cell Line, Tumor ; Cell Nucleus/genetics ; DNA Damage/genetics ; DNA, Complementary/analysis/genetics ; Humans ; Microtubules/genetics/*metabolism ; Molecular Sequence Data ; Protein Transport/genetics ; RNA/genetics/metabolism ; RNA Interference ; Saccharomyces cerevisiae/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/isolation &amp; purification/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Up-Regulation/genetics ; rap1 GTP-Binding Proteins/genetics/metabolism ; },
abstract = {We identified and characterized a human orthologue of Rif1 protein, which in budding yeast interacts in vivo with the major duplex telomeric DNA binding protein Rap1p and negatively regulates telomere length. Depletion of hRif1 by RNA interference in human cancer cells impaired cell growth but had no detectable effect on telomere length, although hRif1 overexpression in S. cerevisiae interfered with telomere length control, in a manner specifically dependent on the presence of yeast Rif1p. No localization of hRif1 on normal human telomeres, or interaction with the human telomeric proteins TRF1, TRF2, or hRap1, was detectable. However, hRif1 efficiently translocated to telomerically located DNA damage foci in response to the synthesis of aberrant telomeres directed by mutant-template telomerase RNA. The hRif1 level rose during late S/G2 but hRif1 was not visible on chromosomes in metaphase and anaphase; however, notably, specifically during early anaphase, hRif1 aligned along a subset of the midzone microtubules between the separating chromosomes. In telophase, hRif1 localized to chromosomes, and in interphase, it was intranuclear. These results define a novel subcellular localization behavior for hRif1 during the cell cycle.},
}
@article {pmid15577208,
year = {2004},
author = {Higaki, T and Watanabe, T and Tamatomi, I and Tahara, H and Sugimoto, M and Furuichi, Y and Ide, T},
title = {Terminal telomere repeats are actually short in telomerase-negative immortal human cells.},
journal = {Biological &amp; pharmaceutical bulletin},
volume = {27},
number = {12},
pages = {1932-1938},
doi = {10.1248/bpb.27.1932},
pmid = {15577208},
issn = {0918-6158},
mesh = {Cell Line ; Cell Line, Transformed ; Humans ; Telomerase/analysis/*genetics ; Telomere/chemistry/*genetics ; Terminal Repeat Sequences/*genetics ; },
abstract = {Telomerase-negative immortal human cells maintained telomere length by a mechanism called alternative lengthening of telomeres (ALT mechanism). These cells (ALT cells) have two prominent characteristics of long telomere repeats at each chromosome end revealed by Southern blotting (terminal restriction fragments: TRF) and the presence extrachromosomal telomere repeat (ECTR) DNA. We report here that the TRF length of ALT cells revealed by the conventional unidirectional (UD) current or pulse-field (PF) current electrophoresis appeared to be over estimated. The TRF length determined by the pulse inverse-field (PIF) current electrophoresis (2-9 kbp depending upon cell lines) was much smaller than that (ca. 23 kbp) by UD or PF current electrophoresis. These results were in consistent with very weak telomere staining in situ at chromosome ends in ALT cells. When a mixture of HinfI-digested genomic DNA of human diploid fibroblasts and synthetic telomere repeat DNA with similar size of ECTR DNA was electrophoresed using a UD current, the apparent TRF size shifted to larger molecular weight, while the size shift did not occur by PIF current electrophoresis. These results together with other data indicate that the unusually long TRF of ALT cells determined by using conventional electrophoresis is an artifact produced by a complex formed by short TRF and short ECTR DNA.},
}
@article {pmid15574587,
year = {2004},
author = {Zhang, H and Cohen, SN},
title = {Smurf2 up-regulation activates telomere-dependent senescence.},
journal = {Genes &amp; development},
volume = {18},
number = {24},
pages = {3028-3040},
pmid = {15574587},
issn = {0890-9369},
mesh = {Blotting, Northern ; Blotting, Western ; Cell Line ; Cellular Senescence/*physiology ; Fibroblasts/cytology ; Fluorescent Antibody Technique ; Genetic Vectors ; Humans ; Oligonucleotide Array Sequence Analysis ; Plasmids/genetics ; Retinoblastoma Protein/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*physiology ; Tumor Suppressor Protein p53/metabolism ; Ubiquitin-Protein Ligases/*metabolism ; Up-Regulation/*physiology ; },
abstract = {Progressive telomere shortening activates replicative senescence, which prevents somatic cells from being propagated indefinitely in culture. The limitation of proliferative capacity imposed by replicative senescence is thought to contribute to both organismal aging and the prevention of tumor development. Here we report that up-regulation of Smurf2, an E3 ubiquitin ligase previously implicated in TGF-beta signaling, is a specific consequence of telomere attrition in human fibroblasts and that such up-regulation is sufficient to produce the senescence phenotype. Adventitious production of the Smurf2 protein in early passage fibroblasts at the same physiological level observed during telomere-mediated senescence resulted in proliferative arrest in a viable state, morphological and biochemical alterations characteristic of senescence, acquisition of senescence-specific alterations in gene expression, and reversal of cellular immortalization by telomerase. We show that the senescence-inducing actions of Smurf2 occur in the absence of detectable DNA damage or stress response, that Smurf2's effects require a novel function distinct from its E3 activity, that Smurf2 recruits the Rb and p53 pathways for senescence induction, and that while p21 is elevated by Smurf2, Smurf2-mediated senescence is independent of p21. Smurf2 is the first gene found to be both up-regulated by telomere attrition and sufficient to induce senescence.},
}
@article {pmid15574496,
year = {2004},
author = {Epel, ES and Blackburn, EH and Lin, J and Dhabhar, FS and Adler, NE and Morrow, JD and Cawthon, RM},
title = {Accelerated telomere shortening in response to life stress.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {101},
number = {49},
pages = {17312-17315},
pmid = {15574496},
issn = {0027-8424},
support = {GM26259/GM/NIGMS NIH HHS/United States ; GM15431/GM/NIGMS NIH HHS/United States ; M01-RR01271/RR/NCRR NIH HHS/United States ; M01 RR001271/RR/NCRR NIH HHS/United States ; P01 CA077839/CA/NCI NIH HHS/United States ; P01 GM015431/GM/NIGMS NIH HHS/United States ; DK48851/DK/NIDDK NIH HHS/United States ; P50 GM015431/GM/NIGMS NIH HHS/United States ; RR00095/RR/NCRR NIH HHS/United States ; R01 AI048995/AI/NIAID NIH HHS/United States ; M01 RR000095/RR/NCRR NIH HHS/United States ; R01 GM026259/GM/NIGMS NIH HHS/United States ; AI48995/AI/NIAID NIH HHS/United States ; K08 MH064110/MH/NIMH NIH HHS/United States ; K08 MH64110-01A1/MH/NIMH NIH HHS/United States ; R37 GM026259/GM/NIGMS NIH HHS/United States ; CA77839/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Cellular Senescence ; Female ; Humans ; Leukocytes, Mononuclear/physiology ; Middle Aged ; Mothers ; Oxidative Stress ; Premenopause ; *Stress, Psychological ; Telomere/*metabolism/ultrastructure ; },
abstract = {Numerous studies demonstrate links between chronic stress and indices of poor health, including risk factors for cardiovascular disease and poorer immune function. Nevertheless, the exact mechanisms of how stress gets "under the skin" remain elusive. We investigated the hypothesis that stress impacts health by modulating the rate of cellular aging. Here we provide evidence that psychological stress--both perceived stress and chronicity of stress--is significantly associated with higher oxidative stress, lower telomerase activity, and shorter telomere length, which are known determinants of cell senescence and longevity, in peripheral blood mononuclear cells from healthy premenopausal women. Women with the highest levels of perceived stress have telomeres shorter on average by the equivalent of at least one decade of additional aging compared to low stress women. These findings have implications for understanding how, at the cellular level, stress may promote earlier onset of age-related diseases.},
}
@article {pmid15573694,
year = {2004},
author = {Brando, B and Longo, A and Beltrami, B and Passoni, D and Verna, R and Licastro, F and Corsi, MM},
title = {Determination of telomere length by flow-fluorescence in situ hybridization in Down's syndrome patients.},
journal = {International journal of tissue reactions},
volume = {26},
number = {1-2},
pages = {61-64},
pmid = {15573694},
issn = {0250-0868},
mesh = {Adolescent ; Adult ; Down Syndrome/blood/*genetics ; Flow Cytometry/*methods ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Middle Aged ; Telomere/*ultrastructure ; },
abstract = {A new method for measuring telomere length in a population of Down's syndrome patients aged 18-60 years old is presented. The method is based on flow cytometry and quantitative fluorescence in situ hybridization (flow-FISH) on whole cells. At least three methods for measuring the length of telomere repeats have been described: (i) Southern blot analysis, and quantitative FISH using either (ii) digital fluorescence microscopy (Q-FISH) or (iii) flow cytometry (flow-FISH). Both Southern blot analysis and Q-FISH have specific limitations and are time-consuming, whereas flow-FISH needed relatively few cells (1.5-2.5 x 106) and could be completed in 24-48 h. The method can be used to rapidly determine telomere length in subsets of nucleated blood cells from patients with age-related diseases such as Down's syndrome, Alzheimer's disease and Werner syndrome.},
}
@article {pmid15572688,
year = {2004},
author = {Levy, DL and Blackburn, EH},
title = {Counting of Rif1p and Rif2p on Saccharomyces cerevisiae telomeres regulates telomere length.},
journal = {Molecular and cellular biology},
volume = {24},
number = {24},
pages = {10857-10867},
pmid = {15572688},
issn = {0270-7306},
support = {R01 GM026259/GM/NIGMS NIH HHS/United States ; R37 GM026259/GM/NIGMS NIH HHS/United States ; GM 26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites ; Carrier Proteins/genetics/*metabolism ; DNA, Fungal/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Fungal Proteins/genetics/*metabolism ; Models, Biological ; Repressor Proteins/genetics/*metabolism ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/genetics/*metabolism ; Shelterin Complex ; *Telomere ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; Transcription Factors/chemistry/metabolism ; },
abstract = {Telomere length is negatively regulated by proteins of the telomeric DNA-protein complex. Rap1p in Saccharomyces cerevisiae binds the telomeric TG(1-3) repeat DNA, and the Rap1p C terminus interacts with Rif1p and Rif2p. We investigated how these three proteins negatively regulate telomere length. We show that direct tethering of each Rif protein to a telomere shortens that telomere proportionally to the number of tethered molecules, similar to previously reported counting of Rap1p. Surprisingly, Rif proteins could also regulate telomere length even when the Rap1p C terminus was absent, and tethered Rap1p counting was completely dependent on the Rif proteins. Thus, Rap1p counting is in fact Rif protein counting. In genetic settings that cause telomeres to be abnormally long, tethering even a single Rif2p molecule was sufficient for maximal effectiveness in preventing the telomere overelongation. We show that a heterologous protein oligomerization domain, the mammalian PDZ domain, when fused to Rap1p can confer telomere length control. We propose that a nucleation and spreading mechanism is involved in forming the higher-order telomere structure that regulates telomere length.},
}
@article {pmid15565356,
year = {2005},
author = {Chkhotua, AB and Schelzig, H and Wiegand, P and Grosse, S and Reis, S and Art, M and Abendroth, D},
title = {Influence of ischaemia/reperfusion and LFA-1 inhibition on telomere lengths and CDKI genes in ex vivo haemoperfusion of primate kidneys.},
journal = {Transplant international : official journal of the European Society for Organ Transplantation},
volume = {17},
number = {11},
pages = {692-698},
doi = {10.1007/s00147-004-0766-8},
pmid = {15565356},
issn = {0934-0874},
mesh = {Animals ; Antibodies, Monoclonal/immunology ; Cell Cycle Proteins/genetics/*metabolism ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclin-Dependent Kinase Inhibitor p27 ; Gene Expression ; *Hemoperfusion ; Humans ; Immunohistochemistry ; Kidney/*blood supply/metabolism ; Lymphocyte Function-Associated Antigen-1/immunology/*metabolism ; Macaca fascicularis ; Reperfusion Injury/*genetics/*pathology ; Telomere/*genetics ; Tumor Suppressor Proteins/genetics/metabolism ; },
abstract = {The telomere (T) length, p21(WAF1/CIP1) and p27(Kip1) cyclin-dependent kinase inhibitor (CDKI) genes are the markers of cell senescence and DNA damage. The aim of the study was to determine the influence of renal ischaemia/reperfusion (I/R) and anti-lymphocyte function-associated antigen-1 (LFA-1) monoclonal antibody (mAb) treatment on the value of the above-mentioned markers. Significantly higher levels of p21 and p27 were expressed by the glomeruli (P=0.001 and P=0.0001), tubules (P=0.0065 and P=0.0006), and interstitial cells (P=0.0017 and P=0.0022, respectively) of the xenoperfused kidneys. The mean T length of non-perfused renal specimens (5.56+/-0.60 kbp) was longer than that of the xenoperfused kidneys (5.46+/-0.36 kbp) [P= non-significant (NS)]. Addition of anti-LFA-1 mAb did not significantly influence the gene expression profile in the xenoperfused kidneys. The mean T length was longer in the kidneys with anti-LFA-1 mAb than in those without the medication (5.7+/-0.11 vs 5.13+/-0.31 kbp) (P=0.0661). Kidney I/R is associated with telomere shortening and an over-expression of p21 and p27 CDKIs, which indicates substantial DNA damage and/or accelerated tissue senescence. Although anti-LFA-1 mAb had some protective effect on the telomeres, it did not influence the gene expression profile in this study.},
}
@article {pmid15561716,
year = {2005},
author = {York, SJ and Armbruster, BN and Greenwell, P and Petes, TD and York, JD},
title = {Inositol diphosphate signaling regulates telomere length.},
journal = {The Journal of biological chemistry},
volume = {280},
number = {6},
pages = {4264-4269},
doi = {10.1074/jbc.M412070200},
pmid = {15561716},
issn = {0021-9258},
support = {GM-531576/GM/NIGMS NIH HHS/United States ; HL-55672/HL/NHLBI NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins ; Biological Transport ; Blotting, Southern ; Cell Cycle Proteins/metabolism ; DNA-Binding Proteins/metabolism ; Enzyme Activation ; Gene Expression Regulation ; Genetic Complementation Test ; Hydrolysis ; Inositol Phosphates/*metabolism ; Models, Biological ; Mutation ; Open Reading Frames ; Phosphorylation ; Phosphotransferases (Phosphate Group Acceptor) ; Plasmids/metabolism ; Protein Serine-Threonine Kinases/metabolism ; RNA, Messenger/metabolism ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/biosynthesis/*physiology ; *Signal Transduction ; Telomere/*ultrastructure ; Time Factors ; Tumor Suppressor Proteins/metabolism ; Type C Phospholipases/chemistry/metabolism ; },
abstract = {Activation of phospholipase C-dependent inositol polyphosphate signaling pathways generates distinct messengers derived from inositol 1,4,5-trisphosphate that control gene expression and mRNA export. Here we report the regulation of telomere length by production of a diphosphorylinositol tetrakisphosphate, PP-IP4, synthesized by the KCS1 gene product. Loss of PP-IP4 production results in lengthening of telomeres, whereas overproduction leads to their shortening. This effect requires the presence of Tel1, the yeast homologue of ATM, the protein mutated in the human disease ataxia telangiectasia. Our data provide in vivo evidence of a regulatory link between inositol polyphosphate signaling and the checkpoint kinase family and describe a third nuclear process modulated by phospholipase C activation.},
}
@article {pmid15557801,
year = {2004},
author = {Meeker, AK and Argani, P},
title = {Telomere shortening occurs early during breast tumorigenesis: a cause of chromosome destabilization underlying malignant transformation?.},
journal = {Journal of mammary gland biology and neoplasia},
volume = {9},
number = {3},
pages = {285-296},
pmid = {15557801},
issn = {1083-3021},
support = {CA58236/CA/NCI NIH HHS/United States ; CA88843/CA/NCI NIH HHS/United States ; T32DK07552/DK/NIDDK NIH HHS/United States ; },
mesh = {Breast Neoplasms/*genetics/*physiopathology ; Carcinoma, Intraductal, Noninfiltrating/*genetics/*physiopathology ; Cell Transformation, Neoplastic/*genetics ; *Chromosomal Instability ; DNA Damage ; Epithelial Cells ; Humans ; Telomerase/pharmacology ; Telomere/*ultrastructure ; },
abstract = {Chromosomal instability appears early during breast carcinogenesis and is considered a major driving force in malignant transformation. While current evidence suggests that centrosomal and mitotic checkpoint defects may, in large part, account for numerical chromosomal abnormalities, the mechanisms underlying structural chromosomal abnormalities remain largely unknown. Telomeres stabilize and protect chromosomal termini, but shorten due to cell division and oxidative damage. Moderate telomere shortening signals a tumor suppressive growth arrest in normal cells. Critically short telomeres, in the setting of abrogated DNA damage checkpoints, cause chromosomal instability due to end-to-end chromosomal fusions, subsequent breakage, and rearrangement, resulting in an increased cancer incidence in animal models. Recent results from high resolution in situ telomere length assessment in human breast tissues indicate that significant telomere shortening is prevalent in preinvasive breast lesions (DCIS), as well as focal areas of histologically normal epithelium from which breast carcinoma is thought to arise. Telomere shortening is therefore a strong candidate for the cause of structural chromosome defects that contribute to breast cancer development.},
}
@article {pmid15555545,
year = {2004},
author = {Nakajima, T and Katagishi, T and Moriguchi, M and Sekoguchi, S and Nishikawa, T and Takashima, H and Watanabe, T and Kimura, H and Minami, M and Itoh, Y and Kagawa, K and Okanoue, T},
title = {Tumor size-independence of telomere length indicates an aggressive feature of HCC.},
journal = {Biochemical and biophysical research communications},
volume = {325},
number = {4},
pages = {1131-1135},
doi = {10.1016/j.bbrc.2004.10.152},
pmid = {15555545},
issn = {0006-291X},
mesh = {Carcinoma, Hepatocellular/genetics/*pathology ; Cell Proliferation ; Female ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Liver Neoplasms/diagnosis/*pathology ; Male ; Middle Aged ; Neoplasm Staging/*methods ; Reproducibility of Results ; Sensitivity and Specificity ; Severity of Illness Index ; Telomere/*ultrastructure ; },
abstract = {Using quantitative fluorescence in situ hybridization (Q-FISH), the average telomere length of hepatoma cells was assessed by the average telomeric signal intensity of cancer cells relative to that of stromal cells. We demonstrated first the applicability of Q-FISH for tissue sections by comparing Q-FISH and Southern blotting results. Tumors less than 50mm in diameter and with a relative telomeric intensity of less than 0.6 were categorized as group A and the remainder as group B. In group A, the telomere length correlated negatively with tumor size, whereas in group B there was no correlation. Compared with the group A tumors, the group B tumors were of significantly more advanced stage, showed higher telomerase and proliferative activities, and exhibited less differentiated histology. Therefore, we considered that a lack of correlation between telomere length and tumor size, namely, size-independence of telomere length, is associated with unfavorable clinicopathological features of hepatocellular carcinomas.},
}
@article {pmid15551357,
year = {2005},
author = {Dixon, IM and Lopez, F and Estève, JP and Tejera, AM and Blasco, MA and Pratviel, G and Meunier, B},
title = {Porphyrin derivatives for telomere binding and telomerase inhibition.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {6},
number = {1},
pages = {123-132},
doi = {10.1002/cbic.200400113},
pmid = {15551357},
issn = {1439-4227},
mesh = {DNA/metabolism ; Enzyme Inhibitors/chemical synthesis/*chemistry/metabolism ; G-Quadruplexes ; Humans ; Manganese/chemistry/metabolism ; Metalloporphyrins/chemical synthesis/*chemistry/metabolism ; Nickel/chemistry/metabolism ; Nucleic Acid Amplification Techniques ; Surface Plasmon Resonance ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*metabolism ; },
abstract = {The capacity of G-quadruplex ligands to stabilize four-stranded DNA makes them able to inhibit telomerase, which is involved in tumour cell proliferation. A series of cationic metalloporphyrin derivatives was prepared by making variations on a meso-tetrakis(4-N-methyl-pyridiniumyl)porphyrin skeleton (TMPyP). The DNA binding properties of nickel(II) and manganese(III) porphyrins were studied by surface plasmon resonance, and the capacity of the nickel porphyrins to inhibit telomerase was tested in a TRAP assay. The nature of the metal influences the kinetics (the process is faster for Ni than for Mn) and the mode of interaction (stacking or external binding). The chemical alterations did not lead to increased telomerase inhibition. The best selectivity for G-quadruplex DNA was observed for Mn-TMPyP, which has a tenfold preference for quadruplex over duplex.},
}
@article {pmid15551135,
year = {2005},
author = {Rog, O and Smolikov, S and Krauskopf, A and Kupiec, M},
title = {The yeast VPS genes affect telomere length regulation.},
journal = {Current genetics},
volume = {47},
number = {1},
pages = {18-28},
pmid = {15551135},
issn = {0172-8083},
mesh = {Homeostasis ; Signal Transduction ; Telomerase/*pharmacology ; Telomere/*ultrastructure ; Vesicular Transport Proteins/*genetics/*pharmacology ; Yeasts/*genetics ; },
abstract = {Eukaryotic cells invest a large proportion of their genome in maintaining telomere length homeostasis. Among the 173 non-essential yeast genes found to affect telomere length, a large proportion is involved in vacuolar traffic. When mutated, these vacuolar protein-sorting (VPS) genes lead to telomeres shorter than those observed in the wild type. Using genetic analysis, we characterized the pathway by which VPS15, VPS34, VPS22, VPS23 and VPS28 affect the telomeres. Our results indicate that these VPS genes affect telomere length through a single pathway and that this effect requires the activity of telomerase and the Ku heterodimer, but not the activity of Tel1p or Rif2p. We present models to explain the link between vacuolar traffic and telomere length homeostasis.},
}
@article {pmid15549250,
year = {2004},
author = {Schieker, M and Gülkan, H and Austrup, B and Neth, P and Mutschler, W},
title = {[Telomerase activity and telomere length of human mesenchymal stem cells. Changes during osteogenic differentiation].},
journal = {Der Orthopade},
volume = {33},
number = {12},
pages = {1373-1377},
pmid = {15549250},
issn = {0085-4530},
mesh = {Cell Differentiation/*genetics ; Cell Division/*genetics ; Cell Separation/methods ; Gene Expression/physiology ; Humans ; Mesenchymal Stem Cells/*cytology ; Osteogenesis/*genetics ; Polymerase Chain Reaction ; Polymorphism, Restriction Fragment Length ; Telomerase/*genetics ; Telomere/*genetics ; Tissue Engineering/*methods ; },
abstract = {Human mesenchymal stem cells (hMSC) exhibit properties of self-renewal and differentiation. Assuming that telomerase activity is associated with self-renewal, it might be useful to identify and define hMSC on the basis of their telomerase status. However, telomerase activity in hMSC remains a controversial issue. Therefore, the aim of our study was to investigate telomerase activity in proliferating and highly proliferating hMSC and to measure telomerase activity and changes in telomere restriction fragment (TRF) length of confluent hMSC and of osteogenically differentiated hMSC. For tissue engineering applications scaffolds should be seeded with cells that have not lost their ability to self-replicate and differentiate during in vitro cell culture. Telomerase activity could be used to characterise and isolate these cells.},
}
@article {pmid15549144,
year = {2005},
author = {Kleideiter, E and Bangerter, U and Schwab, M and Boukamp, P and Koscielniak, E and Klotz, U and Greil, J},
title = {Telomeres and telomerase in paediatric patients with T-cell acute lymphoblastic leukaemia (T-ALL).},
journal = {Leukemia},
volume = {19},
number = {2},
pages = {296-298},
doi = {10.1038/sj.leu.2403596},
pmid = {15549144},
issn = {0887-6924},
mesh = {Adolescent ; Blast Crisis ; Bone Marrow/pathology ; Child ; Child, Preschool ; Female ; Humans ; Leukemia-Lymphoma, Adult T-Cell/*blood/enzymology ; Male ; Telomerase/*blood ; Telomere/*pathology ; },
}
@article {pmid15548595,
year = {2005},
author = {Tsukamoto, Y and Mitsuoka, C and Terasawa, M and Ogawa, H and Ogawa, T},
title = {Xrs2p regulates Mre11p translocation to the nucleus and plays a role in telomere elongation and meiotic recombination.},
journal = {Molecular biology of the cell},
volume = {16},
number = {2},
pages = {597-608},
pmid = {15548595},
issn = {1059-1524},
mesh = {Alleles ; Amino Acid Sequence ; Binding Sites ; Cell Nucleus/*metabolism ; Cytoplasm/metabolism ; DNA Repair ; Endodeoxyribonucleases/*metabolism ; Exodeoxyribonucleases/*metabolism ; Immunohistochemistry ; Meiosis ; Point Mutation ; Precipitin Tests ; Protein Binding ; Protein Structure, Tertiary ; *Recombination, Genetic ; Saccharomyces cerevisiae/genetics/growth &amp; development/metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; Telomere/*metabolism ; *Translocation, Genetic ; Two-Hybrid System Techniques ; },
abstract = {The Mre11-Rad50-Xrs2 (MRX) protein complex plays pivotal roles in meiotic recombination, repair of damaged DNA, telomere elongation, and cell cycle checkpoint control. Xrs2p is known to be essential for all the functions of the complex, but its role in the complex has not been clearly elucidated. A 32-amino acid region near the C terminus of Xrs2p was identified as an Mre11p-binding site. No more function of Xrs2p than translocation of Mre11p from the cytoplasm to the nucleus is necessary for response to DNA damage. However, domains in Xrs2p located both 49 amino acids upstream and 104 amino acids downstream of the Mre11p binding site are required for meiotic recombination and telomere elongation, respectively, in addition to the 32-amino acid region. These findings demonstrate that Xrs2p acts as a specificity factor that allows the MRX complex to function in meiotic recombination and in telomere elongation.},
}
@article {pmid15546916,
year = {2004},
author = {Dechat, T and Gajewski, A and Korbei, B and Gerlich, D and Daigle, N and Haraguchi, T and Furukawa, K and Ellenberg, J and Foisner, R},
title = {LAP2alpha and BAF transiently localize to telomeres and specific regions on chromatin during nuclear assembly.},
journal = {Journal of cell science},
volume = {117},
number = {Pt 25},
pages = {6117-6128},
doi = {10.1242/jcs.01529},
pmid = {15546916},
issn = {0021-9533},
mesh = {Animals ; Bacterial Proteins/metabolism ; Cell Line ; Cell Nucleus/*metabolism ; Chromatin/metabolism ; Chromosomes/diagnostic imaging/metabolism ; DNA/metabolism ; DNA-Binding Proteins/*biosynthesis/metabolism ; Electrophoresis, Polyacrylamide Gel ; HeLa Cells ; Histones/metabolism ; Humans ; Image Processing, Computer-Assisted ; Immunoblotting ; Immunoprecipitation ; Kidney/cytology ; Lamins/metabolism ; Luminescent Proteins/metabolism ; Membrane Proteins/*biosynthesis/metabolism ; Microscopy, Fluorescence ; Microtubules/ultrastructure ; Mitosis ; Models, Biological ; Nuclear Proteins/*biosynthesis/metabolism ; Protein Binding ; Rats ; Telomere/metabolism/*ultrastructure ; Ultrasonography ; },
abstract = {Lamina-associated polypeptide (LAP) 2alpha is a LEM (lamina-associated polypeptide emerin MAN1) family protein associated with nucleoplasmic A-type lamins and chromatin. Using live cell imaging and fluorescence microscopy we demonstrate that LAP2alpha was mostly cytoplasmic in metaphase and associated with telomeres in anaphase. Telomeric LAP2alpha clusters grew in size, formed 'core' structures on chromatin adjacent to the spindle in telophase, and translocated to the nucleoplasm in G1 phase. A subfraction of lamin C and emerin followed LAP2alpha to the core region early on, whereas LAP2beta, lamin B receptor and lamin B initially bound to more peripheral regions of chromatin, before they spread to core structures with different kinetics. Furthermore, the DNA-crosslinking protein barrier-to-autointegration factor (BAF) bound to LAP2alpha in vitro and in mitotic extracts, and subfractions of BAF relocalized to core structures with LAP2alpha. We propose that LAP2alpha and a subfraction of BAF form defined complexes in chromatin core regions and may be involved in chromatin reorganization during early stages of nuclear assembly.},
}
@article {pmid15546621,
year = {2004},
author = {Flory, MR and Carson, AR and Muller, EG and Aebersold, R},
title = {An SMC-domain protein in fission yeast links telomeres to the meiotic centrosome.},
journal = {Molecular cell},
volume = {16},
number = {4},
pages = {619-630},
doi = {10.1016/j.molcel.2004.10.027},
pmid = {15546621},
issn = {1097-2765},
support = {P41 RR11823/RR/NCRR NIH HHS/United States ; },
mesh = {Alleles ; Cell Nucleus/metabolism ; Centrosome/*metabolism ; Chromosomes, Fungal ; Fluorescence Resonance Energy Transfer ; Mass Spectrometry ; Meiosis ; Microscopy, Fluorescence ; Models, Biological ; Models, Molecular ; Oligonucleotide Array Sequence Analysis ; Open Reading Frames ; Peptide Mapping ; Plasmids ; Protein Structure, Tertiary ; RNA, Messenger/metabolism ; Schizosaccharomyces/cytology/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/*chemistry/genetics/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {Abnormal centrosomal structures similar to those occurring in human cancers are induced in fission yeast by overexpression of the pericentrin homolog Pcp1p. Analysis of abnormal Pcp1p-containing structures with quantitative mass spectrometry and isotope-coded affinity tags identified a coiled-coil, structural maintenance of chromosomes (SMC) domain protein. This protein, termed Ccq1p (coiled-coil protein quantitatively enriched), localizes with Taz1p to telomeres in normal vegetative cells. Fluorescence resonance energy transfer (FRET) measurements indicate that Ccq1p also interacts with centrosomal Pcp1p in mating pheromone-stimulated cells containing centrosomally clustered telomeres. We provide evidence that the Ccq1p-Pcp1p interaction, while essential for meiosis, is deleterious when forced to occur during vegetative growth. Cells lacking one ccq1 allele exhibit a loss-of-function phenotype including abnormally long cell length, chromosome segregation failure, telomeric shortening, and defective telomeric clustering during meiotic prophase. Our data indicate a mechanism underlying meiotic chromosomal bouquet formation and suggest a recruitment model for supernumerary centrosome toxicity.},
}
@article {pmid15546610,
year = {2004},
author = {Haber, JE},
title = {Telomeres thrown for a loop.},
journal = {Molecular cell},
volume = {16},
number = {4},
pages = {502-503},
doi = {10.1016/j.molcel.2004.11.006},
pmid = {15546610},
issn = {1097-2765},
mesh = {Cell Line, Transformed ; Chromatids/metabolism ; Chromosomes/metabolism ; *Crossing Over, Genetic ; DNA, Cruciform/metabolism ; In Situ Hybridization, Fluorescence ; Models, Biological ; Recombinases/metabolism ; *Recombination, Genetic ; Sequence Deletion ; Telomere/*chemistry ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {A remarkable paper from the de Lange lab (Wang et al., 2004) in a recent issue of Cell reveals that homologous recombination can result in the abrupt shortening of telomeres in a process that appears to involve reciprocal crossing over within the t-loop structure that protects chromosome ends.},
}
@article {pmid15539081,
year = {2004},
author = {Shepherd, BE and Guttorp, P and Lansdorp, PM and Abkowitz, JL},
title = {Estimating human hematopoietic stem cell kinetics using granulocyte telomere lengths.},
journal = {Experimental hematology},
volume = {32},
number = {11},
pages = {1040-1050},
doi = {10.1016/j.exphem.2004.07.023},
pmid = {15539081},
issn = {0301-472X},
support = {R01 HL46598/HL/NHLBI NIH HHS/United States ; },
mesh = {Age Factors ; Animals ; Cats ; Cell Cycle ; Granulocytes/*ultrastructure ; Hematopoietic Stem Cells/*cytology ; Humans ; Kinetics ; *Models, Theoretical ; Telomere/*ultrastructure ; },
abstract = {OBJECTIVE: To study in vivo behavior of hematopoietic stem cells (HSC).<br><br>MATERIALS AND METHODS: Behavior of HSC is difficult to study because one cannot observe and track cells within the marrow microenvironment. Therefore, information must be obtained from indirect means, such as competitive repopulation assays or surrogate studies, such as observations of telomere shortening in granulocytes. In this article, we use granulocyte telomere length data and a novel approach, stochastic simulation, to derive replication rates of HSC. The approach is first applied to cats and then to humans.<br><br>RESULTS: Human HSC replicate infrequently, on average once per 45 weeks (range: once per 23 to once per 67 weeks).<br><br>CONCLUSIONS: This rate is substantially slower than the average replication rates estimated for murine (once per 2.5 weeks) and feline (once per 8.3-10 weeks) HSC in vivo.},
}
@article {pmid15530855,
year = {2004},
author = {Li, GZ and Eller, MS and Hanna, K and Gilchrest, BA},
title = {Signaling pathway requirements for induction of senescence by telomere homolog oligonucleotides.},
journal = {Experimental cell research},
volume = {301},
number = {2},
pages = {189-200},
doi = {10.1016/j.yexcr.2004.08.019},
pmid = {15530855},
issn = {0014-4827},
mesh = {Base Sequence ; Cell Line ; Cellular Senescence/*drug effects ; DNA Damage ; Humans ; Oligonucleotides/*pharmacology ; Retinoblastoma Protein/metabolism/physiology ; Signal Transduction/drug effects/*physiology ; *Telomere/chemistry/metabolism ; Time Factors ; Tumor Suppressor Protein p53/metabolism/physiology ; },
abstract = {Cellular senescence is a major defense against cancer. In human fibroblasts, suppressing both the p53 and pRb pathways is necessary to bypass replicative senescence as well as senescence induced by ectopic expression of a dominant negative form of the telomere repeat binding factor 2, TRF2(DN). We recently reported that exposure to oligonucleotides homologous to the telomere 3' overhang (T-oligos) activates both the p53 and pRb pathways and leads to senescence in primary human fibroblasts. To further characterize T-oligo-induced senescence, we compared established isogenic fibroblast cell lines lacking functional p53 and/or pRb pathways to the normal parental line. Here, we report that, as in physiologic senescence, inactivation of both the p53 and pRb pathways is necessary to suppress T-oligo-induced senescence. Moreover, T-oligo rapidly induces senescence in a malignant fibroblast-derived cell line, demonstrating the potential of using T-oligo as a novel anticancer therapeutic. Our data support the hypothesis that exposure of the TTAGGG tandem repeat telomere 3' overhang sequence is the event that initiates signaling through DNA damage response pathways after experimental telomere disruption, serial passage, or acute genomic damage of normal cells.},
}
@article {pmid15528948,
year = {2004},
author = {Tchakmakjian, L and Gardner, JP and Wilson, PD and Kimura, M and Skurnick, J and Zielke, HR and Aviv, A},
title = {Age-dependent telomere attrition as a potential indicator of racial differences in renal growth patterns.},
journal = {Nephron. Experimental nephrology},
volume = {98},
number = {3},
pages = {e82-8},
doi = {10.1159/000080683},
pmid = {15528948},
issn = {1660-2129},
support = {DK 4083/DK/NIDDK NIH HHS/United States ; HL47906/HL/NHLBI NIH HHS/United States ; HL63351/HL/NHLBI NIH HHS/United States ; N01-HD8-3283/HD/NICHD NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; *Black or African American ; Aged ; Aging/*physiology ; Autopsy ; Cell Proliferation ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Infant, Newborn ; Kidney/*growth &amp; development ; Kidney Cortex/physiology ; Kidney Tubules, Proximal ; Male ; Middle Aged ; Sodium, Dietary/metabolism ; Telomere/*ultrastructure ; *White People ; },
abstract = {BACKGROUND: Racial differences in the predilection to salt sensitivity may arise from different renal growth patterns. To test this idea, we monitored age-dependent telomere attrition rate, reflecting largely the replicative history of somatic cells, in the outer renal cortex and the inner renal medulla of African Americans and Caucasians.<br><br>METHODS: Telomere length, determined by the mean length of the terminal restriction fragments (TRF), was measured in specimens from 58 African-American and 63 Caucasian males, ages 1 day to 71 years.<br><br>RESULTS: In the outer renal cortex, TRF length attrition rate was significantly slower in African Americans (-0.021 +/- 0.0064 kb/year) than in Caucasians (-0.060 +/- 0.0094 kb/year) (p = 0.0007). In both ethnic groups the TRF length attrition rate was slower in the inner medulla than in the outer renal cortex, but without significant racial differences.<br><br>CONCLUSIONS: The proximal tubule is the most abundant nephron structure in the outer renal cortex. Less proliferative growth of proximal tubular cells in kidneys from African Americans may be one factor explaining the slower age-dependent telomere attrition rate in the outer renal cortex of African Americans than in Caucasians.},
}
@article {pmid15528369,
year = {2004},
author = {Dagarag, M and Evazyan, T and Rao, N and Effros, RB},
title = {Genetic manipulation of telomerase in HIV-specific CD8+ T cells: enhanced antiviral functions accompany the increased proliferative potential and telomere length stabilization.},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {173},
number = {10},
pages = {6303-6311},
doi = {10.4049/jimmunol.173.10.6303},
pmid = {15528369},
issn = {0022-1767},
support = {AG 05920/AG/NIA NIH HHS/United States ; AI 47665/AI/NIAID NIH HHS/United States ; },
mesh = {Adjuvants, Immunologic/biosynthesis/genetics/metabolism/*physiology ; Antiviral Agents/biosynthesis/genetics/metabolism/*physiology ; CD28 Antigens/biosynthesis/physiology ; CD8-Positive T-Lymphocytes/cytology/*enzymology/*immunology/virology ; Cell Cycle/genetics/immunology ; Cell Proliferation ; Cells, Cultured ; Cellular Senescence/genetics/immunology ; Cytotoxicity, Immunologic/genetics ; DNA-Binding Proteins ; Epitopes, T-Lymphocyte/*immunology ; Growth Inhibitors/antagonists &amp; inhibitors/biosynthesis ; HIV-1/growth &amp; development/*immunology/physiology ; Humans ; Interferon-gamma/biosynthesis/physiology ; Telomerase/biosynthesis/genetics/metabolism/*physiology ; Telomere/enzymology/genetics/*metabolism ; Tumor Necrosis Factor-alpha/biosynthesis/physiology ; Up-Regulation/immunology ; Virus Replication/genetics/immunology ; },
abstract = {A large proportion of the CD8(+) T cell pool in persons chronically infected with HIV consists of cells that show features of replicative senescence, an end stage characterized by irreversible cell cycle arrest, multiple genetic and functional changes, and shortened telomeres. The objective of our research was to determine whether constitutive expression of the gene for the human telomerase (hTERT) can prevent senescence-induced impairments in human virus-specific CD8(+) T cells, particularly in the context of HIV-1 disease. Our results indicate that hTERT-expressing HIV-specific CD8(+) lymphocytes show both an enhanced and sustained capacity to inhibit HIV-1 replication in in vitro coculture experiments, as well as prolonged ability to produce IFN-gamma and TNF-alpha in response to stimulation with HIV-1-derived peptides, as compared with vector-transduced controls. Loss of CD28 expression, the signature change of replicative senescence in cell culture, was retarded in those CD8(+) T cell cultures that had high levels of CD28 at the time of hTERT transduction. These findings suggest that telomere shortening may be the primary driving force behind several aspects of CD8(+) T cell dysfunction associated with replicative senescence. We also demonstrate reduced accumulation of the p16(INK4a) and p21(WAF1) cell cycle inhibitors in hTERT-transduced lymphocytes, providing a possible mechanism by which stable hTERT expression is able to circumvent the senescence barrier in CD8(+) T cells. Given the key role of CD8(+) T cell function in controlling a variety of acute and latent viral infections, approaches to retard the functional decrements associated with replicative senescence may lead to novel types of immunotherapy.},
}
@article {pmid15528297,
year = {2004},
author = {Yang, SW and Kim, SK and Kim, WT},
title = {Perturbation of NgTRF1 expression induces apoptosis-like cell death in tobacco BY-2 cells and implicates NgTRF1 in the control of telomere length and stability.},
journal = {The Plant cell},
volume = {16},
number = {12},
pages = {3370-3385},
pmid = {15528297},
issn = {1040-4651},
mesh = {Apoptosis/*genetics ; Cell Line, Transformed/metabolism ; Cell Nucleus/genetics ; Cell Survival/genetics ; DNA Fragmentation/genetics ; Gene Expression Regulation, Plant/*genetics ; Plant Proteins/genetics/*metabolism ; Plants, Genetically Modified/genetics ; Telomerase/metabolism ; Telomere/*genetics ; Telomeric Repeat Binding Protein 1/genetics/*metabolism ; Nicotiana/genetics/*metabolism ; Transgenes/genetics ; },
abstract = {Telomeres are specialized nucleoprotein complexes that are essential for preserving chromosome integrity in eukaryotic cells. Several potential telomere binding proteins have recently been identified in higher plants, but nothing is known about their in vivo functions. We previously identified NgTRF1 as a double-stranded telomeric repeat binding factor in tobacco (Nicotiana tabacum) and here show that the binding of NgTRF1 to telomeric repeats inhibits telomerase-mediated telomere extension. To determine whether NgTRF1 is involved in telomere length regulation, we established transgenic tobacco BY-2 cell lines that overexpress or suppress NgTRF1. Pulsed-field gel electrophoresis showed that 35S::NgTRF1 cells exhibited significantly shortened telomeres (45 to 10 kb), whereas 35S::antisense-NgTRF1 cells contained longer telomeres (80 to 25 kb) compared with wild-type and 35S::GUS control cells (65 to 15 kb), indicating that telomere length inversely correlates with the amount of functional NgTRF1 in BY-2 cells. 35S::NgTRF1 cells with shorter telomeres displayed a progressive reduction in cell viability and stopped dividing after 25 to 40 successive rounds of 12-d batch subculture, in sharp contrast with control cells, which have an unlimited capacity for division. Internucleosomal DNA fragmentation, mitochondrial release of cytochrome c, and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling positive nuclei were detected in 35S::NgTRF1 cells during prolonged subculture, indicating that enhanced cell death was attributable to an apoptosis-like mechanism. 35S::antisense-NgTRF1 cells containing low levels of NgTRF1 also exhibited a progressive decrease in cell viability and apoptotic cell death, but less so than did 35S::NgTRF1 cells, suggesting that the level of NgTRF1 is critically associated with cell viability. Taken together, these data indicate that perturbation of NgTRF1 expression results in changes in telomere length and stability, which in turn causes apoptotic cell death in transgenic BY-2 cells. These results are discussed in light of the suggestion that NgTRF1 is involved in the mechanism by which telomere length and stability are maintained. We further suggest that the structural stability of telomeres, in addition to length maintenance, is essential for their function and for the immortality of BY-2 cells.},
}
@article {pmid15523603,
year = {2004},
author = {Cabuy, E and Newton, C and Roberts, T and Newbold, R and Slijepcevic, P},
title = {Identification of subpopulations of cells with differing telomere lengths in mouse and human cell lines by flow FISH.},
journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology},
volume = {62},
number = {2},
pages = {150-161},
doi = {10.1002/cyto.a.20096},
pmid = {15523603},
issn = {1552-4922},
mesh = {Animals ; Cell Line, Tumor ; Fibroblasts/*cytology ; Flow Cytometry ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/metabolism ; *Telomere ; },
abstract = {BACKGROUND: Telomeres are specialized nucleoprotein structures at chromosome ends that undergo dynamic changes after each cell cycle. Understanding the mechanisms of telomere dynamics is critically dependent on the ability to accurately measure telomere length in a cell population of interest. Techniques such as Southern blot, which measures average telomere length, and quantitative fluorescence in situ hybridization (Q-FISH), which can estimate telomere length in individual chromosomes, are limited in their capacity to determine the distribution of cells with differing telomere lengths in a given cell population.<br><br>METHODS: We employed flow-FISH to determine whether mouse and human cell lines exhibit subpopulations of cells with differing telomere lengths.<br><br>RESULTS: Our analysis showed that at least one of four analyzed mouse cell lines had two subpopulations of cells with differing telomere lengths. Differences in telomere length between subpopulations of cells were significant, and we term this phenomenon TELEFLUCS (TElomere LEngth FLUctuations in Cell Subpopulations). We also observed TELEFLUCS in 1 of 19 analyzed human nonalternative lengthening of telomere cell lines and in 1 of 2 analyzed human alternative lengthening of telomere cell lines. The existence of cell subpopulations with differing telomere lengths was confirmed by Q-FISH.<br><br>CONCLUSION: Our results underscore the importance of flow-FISH in telomere length analysis.},
}
@article {pmid15522895,
year = {2004},
author = {Lowell, JE and Cross, GA},
title = {A variant histone H3 is enriched at telomeres in Trypanosoma brucei.},
journal = {Journal of cell science},
volume = {117},
number = {Pt 24},
pages = {5937-5947},
doi = {10.1242/jcs.01515},
pmid = {15522895},
issn = {0021-9533},
support = {AI10380/AI/NIAID NIH HHS/United States ; AI21729/AI/NIAID NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Cell Cycle ; Cell Line ; Cell Nucleus/metabolism ; Cell Survival ; Chromatin Immunoprecipitation ; Chromosomes/ultrastructure ; Cloning, Molecular ; DNA/metabolism ; DNA Repair ; Fluorescent Antibody Technique, Indirect ; Gene Silencing ; Green Fluorescent Proteins/metabolism ; Histones/chemistry/genetics/*metabolism ; In Situ Hybridization ; In Situ Hybridization, Fluorescence ; Microscopy, Fluorescence ; Molecular Sequence Data ; Mutation ; Recombinant Fusion Proteins/metabolism ; Sequence Homology, Amino Acid ; Spindle Apparatus ; Telomere/*ultrastructure ; Trypanosoma brucei brucei ; },
abstract = {Variant histones play critical roles in transcriptional activation and repression, DNA repair and chromosome segregation. We have identified HTV, a single-copy gene in Trypanosoma brucei encoding a variant form of histone H3 (H3V). H3V is present at discrete nuclear foci that shift over the course of the cell cycle and associate with the mitotic spindle, a pattern of localization reminiscent of that described previously for both mini-chromosomes and telomeres. By combining fluorescence in situ hybridization with indirect immunofluorescence, we confirmed that the H3V foci overlap with a 177-bp repetitive sequence element found predominantly in mini-chromosomes, as well as with the TTAGGG repeats that compose telomeres. Chromatin immunoprecipitation studies, however, reveal that only the telomeric repeat DNA is substantially enriched with H3V. HTV is not essential for viability, mini-chromosome segregation, telomere maintenance or transcriptional silencing at the telomere-proximal expression sites from which bloodstream-form T. brucei controls antigenic variation. We propose that H3V represents a novel class of histone H3 variant, a finding that has evolutionary implications.},
}
@article {pmid15520935,
year = {2005},
author = {Vasa-Nicotera, M and Brouilette, S and Mangino, M and Thompson, JR and Braund, P and Clemitson, JR and Mason, A and Bodycote, CL and Raleigh, SM and Louis, E and Samani, NJ},
title = {Mapping of a major locus that determines telomere length in humans.},
journal = {American journal of human genetics},
volume = {76},
number = {1},
pages = {147-151},
pmid = {15520935},
issn = {0002-9297},
mesh = {Adolescent ; Adult ; Aged ; Chromosome Mapping/*methods ; Chromosomes, Human, Pair 12 ; Coronary Disease/genetics ; DEAD-box RNA Helicases ; DNA Helicases/*genetics ; Female ; Humans ; Leukocytes/ultrastructure ; Lod Score ; Male ; Microsatellite Repeats ; Middle Aged ; Quantitative Trait Loci ; Telomere/*diagnostic imaging ; Ultrasonography ; },
abstract = {Telomere length is a crucial factor for both normal chromosomal function and senescence. Mean telomere length in humans shows considerable interindividual variation and strong genetic determination. To see if a locus (or loci) affecting telomere length in humans could be mapped, we performed a quantitative-trait linkage analysis of mean leukocyte telomere-restriction-fragment (TRF) lengths, measured by Southern blotting, in 383 adult subjects comprising 258 sib pairs. Heritability of mean (+/-SE) TRF was 81.9%+/-11.8%. There was significant linkage (LOD score 3.20) of mean TRF length to a locus on chromosome 12, which explained 49% of the overall variability in mean TRF length. We present preliminary analysis of a strong candidate gene in the region, the DNA helicase DDX11. In conclusion, we report mapping of the first locus that determines mean telomere length in humans. Identification of the gene involved and elucidation of its mechanism of action could have important implications for our understanding of chromosomal assembly, telomere biology, and susceptibility to age-related diseases.},
}
@article {pmid15520642,
year = {2004},
author = {Wai, LK},
title = {Telomeres, telomerase, and tumorigenesis--a review.},
journal = {MedGenMed : Medscape general medicine},
volume = {6},
number = {3},
pages = {19},
pmid = {15520642},
issn = {1531-0132},
mesh = {Animals ; Humans ; Neoplasms/*enzymology/*genetics ; Telomerase/*metabolism ; *Telomere ; },
abstract = {Human telomeres function as a protective structure capping both ends of the chromosome. They are composed of long, repetitive sequences of TTAGGG, associated with a variety of telomere-binding proteins. Telomeres protect the chromosomes from end-to-end fusion, recombination, and degradation, all events that can lead to cell death. At cell replication, telomeres cannot be completely replicated. They are gradually shortened, and when the telomeres reach a critical threshold, cell replication is arrested in what is called "replicative senescence." Thus, telomeres act as an intrinsic "counting" mechanism of the cell's aging process. Telomerase is an enzymatic ribonucleoprotein complex that acts as a reverse transcriptase in the elongation of telomeres. Telomerase activity is almost absent in somatic cells, but it is detected in embryonic stem cells and in the vast majority of tumor cells. Tumor cells, in fact, may contain short and stable telomeres that confer immortality to the cancer cells, which are thus able to replicate indefinitely. The deregulation of telomeres thus plays an important role in the relationship between premature aging syndrome and cancer. This review describes the recent advances in the molecular characterization of telomeres, the regulation of telomerase},
}
@article {pmid15520461,
year = {2004},
author = {Hartig, JS and Kool, ET},
title = {Small circular DNAs for synthesis of the human telomere repeat: varied sizes, structures and telomere-encoding activities.},
journal = {Nucleic acids research},
volume = {32},
number = {19},
pages = {e152},
pmid = {15520461},
issn = {1362-4962},
support = {R01 GM069763/GM/NIGMS NIH HHS/United States ; GM069763/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA, Circular/biosynthesis/*chemistry/metabolism ; DNA-Directed DNA Polymerase/metabolism ; Humans ; Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry/metabolism ; },
abstract = {We describe the construction, structural properties and enzymatic substrate abilities of a series of circular DNA oligonucleotides that are entirely composed of the C-rich human telomere repeat, (CCCTAA)n. The nanometer-sized circles range in length from 36 to 60 nt, and act as templates for synthesis of human telomere repeats in vitro. The circles were constructed successfully by the application of a recently developed adenine-protection strategy, which allows for cyclization/ligation with T4 DNA ligase. Thermal denaturation studies showed that at pH 5.0, all five circles form folded structures with similar stability, while at pH 7.0 no melting transitions were seen. Circular dichroism spectra at the two pH conditions showed evidence for i-motif structures at the lower pH value. The series was tested as rolling circle templates for a number of DNA polymerases at pH = 7.3-8.5, using 18mer telomeric primers. Results showed that surprisingly small circles were active, although the optimum size varied from enzyme to enzyme. Telomeric repeats >>1000 nt in length could be synthesized in 1 h by the Klenow (exo-) DNA polymerase. The results establish a convenient way to make long human telomeric repeats for in vitro study of their folding and interactions, and establish optimum molecules for carrying this out.},
}
@article {pmid15520325,
year = {2004},
author = {Spyridopoulos, I and Haendeler, J and Urbich, C and Brummendorf, TH and Oh, H and Schneider, MD and Zeiher, AM and Dimmeler, S},
title = {Statins enhance migratory capacity by upregulation of the telomere repeat-binding factor TRF2 in endothelial progenitor cells.},
journal = {Circulation},
volume = {110},
number = {19},
pages = {3136-3142},
doi = {10.1161/01.CIR.0000142866.50300.EB},
pmid = {15520325},
issn = {1524-4539},
mesh = {Adenoviridae/genetics ; Amino Acid Sequence ; Atorvastatin ; Cell Movement/drug effects ; Cells, Cultured/cytology/drug effects/metabolism ; Cellular Senescence/drug effects ; Checkpoint Kinase 2 ; Endothelial Cells/*drug effects/metabolism ; Endothelium, Vascular/*drug effects/metabolism ; Enzyme Induction/drug effects ; Flow Cytometry ; Genetic Vectors/genetics/pharmacology ; Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology ; Hematopoietic Stem Cells/cytology/*drug effects/metabolism ; Heptanoic Acids/*pharmacology ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology ; In Situ Hybridization, Fluorescence ; Interleukin-4/pharmacology ; Lovastatin/*analogs &amp; derivatives/*pharmacology ; Macrophage Colony-Stimulating Factor/pharmacology ; Molecular Sequence Data ; Protein Serine-Threonine Kinases/biosynthesis/genetics ; Pyrroles/*pharmacology ; Recombinant Proteins/pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/metabolism ; Telomeric Repeat Binding Protein 2/*biosynthesis/genetics ; Vascular Endothelial Growth Factor A/pharmacology ; },
abstract = {BACKGROUND: Cultivation of endothelial progenitor cells (EPCs) leads to premature replicative senescence, limiting ex vivo expansion for potential clinical cell therapy. Recent studies have linked senescence to the dysfunction of telomeres, the "ends" of chromosomes, via the so-called mitotic clock or culture-induced stress. The purpose of this study was to elucidate a possible role of telomere biology in the functional augmentation of EPCs by statins.<br><br>METHODS AND RESULTS: Human EPCs were isolated from peripheral blood. Using flow cytometry after fluorescence in situ hybridization with a telomere-specific (C3TA2)3 peptide nucleic acid probe (Flow-FISH), we found mean telomere length in untreated EPCs from healthy subjects to range between 8.5+/-0.2 and 11.1+/-0.5 kb with no change over 6 days of culture, excluding telomere erosion as one cause for premature senescence. Although mean telomere length did not differ between statin-treated and untreated EPCs, atorvastatin (0.1 micromol/L) and mevastatin (1.0 micromol/L) both led to a more than 3-fold increase in the expression of the telomere capping protein TRF2 (telomere repeat-binding factor), as shown by immunoblotting, whereas quantitative reverse transcription-polymerase chain reaction demonstrated no increase in TRF2 mRNA. Telomere dysfunction of EPCs was also paralleled by a 4-fold increase in the DNA damage checkpoint-kinase 2 (Chk2). Conversely, statin cotreatment or overexpression of TRF2 completely suppressed Chk2 induction. Finally, overexpression of a dominant negative mutant of the TRF2 protein abrogated statin-induced enhancement of migratory activity down to baseline values.<br><br>CONCLUSIONS: Ex vivo culturing of EPCs leads to "uncapping" of telomeres, indicated by the loss of TRF2. Statin cotreatment of EPCs prevents impairment of their functional capacity by a TRF2-dependent, posttranscriptional mechanism. This is the first time a beneficial effect of statins on telomere biology has been described.},
}
@article {pmid15520294,
year = {2004},
author = {Becker, M and Aitcheson, N and Byles, E and Wickstead, B and Louis, E and Rudenko, G},
title = {Isolation of the repertoire of VSG expression site containing telomeres of Trypanosoma brucei 427 using transformation-associated recombination in yeast.},
journal = {Genome research},
volume = {14},
number = {11},
pages = {2319-2329},
pmid = {15520294},
issn = {1088-9051},
support = {095161//Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Antigenic Variation/genetics ; Cloning, Molecular ; Evolution, Molecular ; Gene Expression Regulation ; Genes, Protozoan/*genetics ; Molecular Sequence Data ; Phylogeny ; *Recombination, Genetic ; Saccharomyces cerevisiae/*genetics ; Sequence Analysis, DNA ; Telomere/*genetics ; Trypanosoma brucei brucei/*genetics/*pathogenicity ; Variant Surface Glycoproteins, Trypanosoma/*genetics ; Virulence/genetics ; },
abstract = {Trypanosoma brucei switches between variant surface glycoproteins (VSGs) allowing immune escape. The active VSG is in one of many telomeric bloodstream form VSG expression sites (BESs), also containing expression site-associated genes (ESAGs) involved in host adaptation. The role of BES sequence diversity in parasite virulence can best be understood through analysis of the full repertoire of BESs from a given T. brucei strain. However, few BESs have been cloned, as telomeres are highly underrepresented in standard libraries. We devised a strategy for isolating the repertoire of T. brucei 427 BES-containing telomeres in Saccaromyces cerevisiae by using transformation-associated recombination (TAR). We isolated 182 T. brucei 427 BES TAR clones, 167 of which could be subdivided into minimally 17 BES groups. This set gives us the first view of the breadth and diversity of BESs from one T. brucei strain. Most BESs ranged between 40 and 70 kb (average, 57 +/- 17 kb) and contained most identified ESAGs. Phylogenetic comparison of the cohort of BES promoter and ESAG6 sequences did not show similar trees, indicating rapid evolution most likely mediated by sequence exchange between BESs. This cloning strategy could be used for any T. brucei strain, facilitating research on the biodiversity of telomeric gene families and host-pathogen interactions.},
}
@article {pmid15508750,
year = {2004},
author = {de Arruda Cardoso Smith, M and Borsatto-Galera, B and Feller, RI and Gonçalves, A and Oyama, RS and Segato, R and Chen, E and Carvalheira, GM and Filho, AS and Burbano, RR and Payão, SL},
title = {Telomeres on chromosome 21 and aging in lymphocytes and gingival fibroblasts from individuals with Down syndrome.},
journal = {Journal of oral science},
volume = {46},
number = {3},
pages = {171-177},
doi = {10.2334/josnusd.46.171},
pmid = {15508750},
issn = {1343-4934},
mesh = {Adolescent ; Adult ; Cellular Senescence/*genetics ; Child ; Child, Preschool ; Chromosomes, Human, Pair 21/*genetics ; Down Syndrome/*genetics ; Fibroblasts/*diagnostic imaging ; Humans ; Linear Models ; Lymphocytes/*ultrastructure ; Middle Aged ; Statistics, Nonparametric ; Telomere/*genetics ; Ultrasonography ; },
abstract = {Progressive chromosome 21 loss in individuals with trisomy 21 or Down syndrome (DS) is supposedly related to their premature senescence. In addition, the telomere hypothesis of cellular aging involving telomere shortening in normal and accelerated aging in vivo and in vitro is well documented. This study investigated the integrity of two chromosome 21 regions (the 21q telomere and the 21q22.13-q22.2 region) and their relationship with aging by means of fluorescence in situ hybridization (FISH) in lymphocytes and gingival fibroblasts cells. The use of tissues from different germ layers allows detection of mosaicism. Chromosome variations in tissue from the neuroectoderm layer could explain the variable phenotype of DS. This approach is original in the literature. Lymphocyte and gingival fibroblast nuclei from 18 affected individuals aged 5-54 years were analyzed. Although not significant (P = 0.06), analysis from 11 tissue-matched individuals as well as the comparison between lymphocytes and fibroblasts from different subjects (P = 0.05) suggested that lymphocyte cells are more likely to miss 21q telomere signals. Hence, gingival fibroblasts are probably capable of more efficient cell repair, and the occurrence of mosaicism is more related to cell proliferation than to germ layer origin. Investigation of the 21q22.13-q22.2 region from six tissue-matched individuals and from different DS patients revealed no significant differences between the tissues.},
}
@article {pmid15508706,
year = {2004},
author = {Haruhiko, F},
title = {[Retrotransposition mechanisms and adaptive behavior of telomere specific LINE].},
journal = {Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme},
volume = {49},
number = {13},
pages = {2090-2096},
pmid = {15508706},
issn = {0039-9450},
mesh = {Animals ; Antigens, Neoplasm/genetics/physiology ; Drosophila Proteins/genetics/physiology ; Endonucleases/physiology ; Evolution, Molecular ; Humans ; *Long Interspersed Nucleotide Elements/genetics/physiology ; Reverse Transcription/genetics ; Ribonucleoproteins, Small Nuclear/genetics/physiology ; Telomere/*genetics/physiology ; Untranslated Regions/genetics/physiology ; },
}
@article {pmid15507522,
year = {2005},
author = {El-Daly, H and Kull, M and Zimmermann, S and Pantic, M and Waller, CF and Martens, UM},
title = {Selective cytotoxicity and telomere damage in leukemia cells using the telomerase inhibitor BIBR1532.},
journal = {Blood},
volume = {105},
number = {4},
pages = {1742-1749},
doi = {10.1182/blood-2003-12-4322},
pmid = {15507522},
issn = {0006-4971},
mesh = {Acute Disease ; Aminobenzoates/*toxicity ; Apoptosis/drug effects ; Cell Line, Transformed ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Diploidy ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/toxicity ; Fibroblasts/cytology/drug effects/enzymology ; Growth Inhibitors/toxicity ; Hematopoietic Stem Cells/cytology/drug effects/enzymology ; Humans ; Jurkat Cells ; Leukemia/*enzymology/*pathology ; Leukemia, Lymphocytic, Chronic, B-Cell/enzymology/pathology ; Leukemia, Myeloid/enzymology/pathology ; Naphthalenes/*toxicity ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects/enzymology/*pathology ; Time Factors ; },
abstract = {Telomerase represents an attractive target for a mechanism-based therapeutic approach because its activation has been associated with unlimited proliferation in most cancer cells. Recently, a nonnucleosidic small molecule inhibitor, BIBR1532 (2-[(E)-3-naphtalen-2-yl-but-2-enoylamino]-benzoic acid), has been identified that is highly selective for inhibition of telomerase, resulting in delayed growth arrest of tumor cells. Here we examined the effects of BIBR1532 in different leukemia cell lines as well as in primary cells from patients with acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) in short-term culture assays. We observed a dose-dependent direct cytotoxicity in concentrations ranging from 30 to 80 microM. Interestingly, cell death was not dependent on the catalytic activity of telomerase but was delayed in cells with very long telomeres. We observed time-dependent individual telomere erosion, which was associated with loss of telomeric repeat binding factor 2 (TRF2) and increased phosphorylation of p53. Importantly, the proliferative capacity of normal CD34(+) cells from cord blood and leukapheresis samples was not affected by treatment with BIBR1532. We conclude that using this class of telomerase inhibitor at higher concentrations exerts a direct cytotoxic effect on malignant cells of the hematopoietic system, which appears to derive from direct damage of the structure of individual telomeres and must be dissected from telomerase-suppressed overall telomere shortening.},
}
@article {pmid15507207,
year = {2004},
author = {Wang, RC and Smogorzewska, A and de Lange, T},
title = {Homologous recombination generates T-loop-sized deletions at human telomeres.},
journal = {Cell},
volume = {119},
number = {3},
pages = {355-368},
doi = {10.1016/j.cell.2004.10.011},
pmid = {15507207},
issn = {0092-8674},
support = {K08 CA164047/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle Proteins/metabolism ; Cellular Senescence/genetics/physiology ; DNA Replication/physiology ; DNA, Circular/metabolism ; DNA-Binding Proteins/metabolism ; Humans ; Mice ; Mutation ; Nuclear Proteins/metabolism ; Recombination, Genetic/*physiology ; Saccharomycetales/genetics/metabolism ; *Sequence Deletion ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; },
abstract = {The t-loop structure of mammalian telomeres is thought to repress nonhomologous end joining (NHEJ) at natural chromosome ends. Telomere NHEJ occurs upon loss of TRF2, a telomeric protein implicated in t-loop formation. Here we describe a mutant allele of TRF2, TRF2DeltaB, that suppressed NHEJ but induced catastrophic deletions of telomeric DNA. The deletion events were stochastic and occurred rapidly, generating dramatically shortened telomeres that were accompanied by a DNA damage response and induction of senescence. TRF2DeltaB-induced deletions depended on XRCC3, a protein implicated in Holliday junction resolution, and created t-loop-sized telomeric circles. These telomeric circles were also detected in unperturbed cells and suggested that t-loop deletion by homologous recombination (HR) might contribute to telomere attrition. Human ALT cells had abundant telomeric circles, pointing to frequent t-loop HR events that could promote rolling circle replication of telomeres in the absence of telomerase. These findings show that t-loop deletion by HR influences the integrity and dynamics of mammalian telomeres.},
}
@article {pmid15504910,
year = {2004},
author = {Tam, R and Smith, KP and Lawrence, JB},
title = {The 4q subtelomere harboring the FSHD locus is specifically anchored with peripheral heterochromatin unlike most human telomeres.},
journal = {The Journal of cell biology},
volume = {167},
number = {2},
pages = {269-279},
pmid = {15504910},
issn = {0021-9525},
support = {R01 GM068138/GM/NIGMS NIH HHS/United States ; GM 68138/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; Cell Line ; Cell Nucleus/metabolism ; Chromosomes, Human, Pair 17 ; Chromosomes, Human, Pair 4/*ultrastructure ; Fibroblasts/metabolism ; Heterochromatin/*chemistry/metabolism/ultrastructure ; Heterozygote ; Humans ; Image Processing, Computer-Assisted ; In Situ Hybridization ; Interphase ; Microfilament Proteins ; Muscles/cytology/metabolism ; Muscular Dystrophy, Facioscapulohumeral/*genetics ; Mutation ; Nuclear Proteins ; Protein Structure, Tertiary ; Proteins/*genetics ; RNA-Binding Proteins ; Telomere/metabolism/*ultrastructure ; },
abstract = {This paper investigates the nuclear localization of human telomeres and, specifically, the 4q35 subtelomere mutated in facioscapulohumeral dystrophy (FSHD). FSHD is a common muscular dystrophy that has been linked to contraction of D4Z4 tandem repeats, widely postulated to affect distant gene expression. Most human telomeres, such as 17q and 17p, avoid the nuclear periphery to reside within the internal, euchromatic compartment. In contrast, 4q35 localizes at the peripheral heterochromatin with 4p more internal, generating a reproducible chromosome orientation that we relate to gene expression profiles. Studies of hybrid and translocation cell lines indicate this localization is inherent to the distal tip of 4q. Investigation of heterozygous FSHD myoblasts demonstrated no significant displacement of the mutant allele from the nuclear periphery. However, consistent association of the pathogenic D4Z4 locus with the heterochromatic compartment supports a potential role in regulating the heterochromatic state and makes a telomere positioning effect more likely. Furthermore, D4Z4 repeats on other chromosomes also frequently organize with the heterochromatic compartment at the nuclear or nucleolar periphery, demonstrating a commonality among chromosomes harboring this subtelomere repeat family.},
}
@article {pmid15500951,
year = {2004},
author = {Gelmini, S and Poggesi, M and Distante, V and Bianchi, S and Simi, L and Luconi, M and Raggi, CC and Cataliotti, L and Pazzagli, M and Orlando, C},
title = {Tankyrase, a positive regulator of telomere elongation, is over expressed in human breast cancer.},
journal = {Cancer letters},
volume = {216},
number = {1},
pages = {81-87},
doi = {10.1016/j.canlet.2004.05.010},
pmid = {15500951},
issn = {0304-3835},
mesh = {Breast Neoplasms/*genetics/pathology ; DNA-Binding Proteins ; Female ; *Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Humans ; Membrane Proteins ; Receptors, Progesterone ; Reverse Transcriptase Polymerase Chain Reaction ; Tankyrases/*biosynthesis ; Telomerase/biosynthesis ; Tumor Cells, Cultured ; },
abstract = {Tankyrase promotes telomere elongation by interaction with the telomeric protein binding factor TRF1, a negative regulator of telomere extension. We measured tankyrase mRNA by real-time RT-PCR in 66 breast cancers and in paired normal tissues. Results were compared with hTERT mRNA expression. The levels of tankyrase in breast cancers were significantly higher in comparison to normal tissues (P<0.0001) and significantly related to the status of progesterone receptors. No relationship was found between tankyrase and hTERT mRNA expression in breast cancers. According to our results, tankyrase expression appeared up regulated in breast cancers.},
}
@article {pmid15499579,
year = {2004},
author = {Murnane, JP and Sabatier, L},
title = {Chromosome rearrangements resulting from telomere dysfunction and their role in cancer.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {26},
number = {11},
pages = {1164-1174},
doi = {10.1002/bies.20125},
pmid = {15499579},
issn = {0265-9247},
support = {R01 CA69044/CA/NCI NIH HHS/United States ; R01 ES008427/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle ; *Chromosomal Instability ; *Chromosome Aberrations ; Genetic Markers/genetics ; Humans ; Neoplasms/*genetics/pathology ; Telomere/*metabolism ; },
abstract = {Telomeres play a vital role in protecting the ends of chromosomes and preventing chromosome fusion. The failure of cancer cells to properly maintain telomeres can be an important source of the chromosome instability involved in cancer cell progression. Telomere loss results in sister chromatid fusion and prolonged breakage/fusion/bridge (B/F/B) cycles, leading to extensive DNA amplification and large deletions. These B/F/B cycles end primarily when the unstable chromosome acquires a new telomere by translocation of the ends of other chromosomes. Many of these translocations are nonreciprocal, resulting in the loss of the telomere from the donor chromosome, providing a mechanism for transfer of instability from one chromosome to another until a chromosome acquires a telomere by a mechanism other than nonreciprocal translocation. B/F/B cycles can also result in other forms of chromosome rearrangements, including double-minute chromosomes and large duplications. Thus, the loss of a single telomere can result in instability in multiple chromosomes, and generate many of the types of rearrangements commonly associated with human cancer.},
}
@article {pmid15498484,
year = {2004},
author = {Colgin, L and Reddel, R},
title = {Telomere biology: a new player in the end zone.},
journal = {Current biology : CB},
volume = {14},
number = {20},
pages = {R901-2},
doi = {10.1016/j.cub.2004.09.075},
pmid = {15498484},
issn = {0960-9822},
mesh = {*Models, Molecular ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/*genetics/*metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Yet another protein has been added to the crowd of players found at the ends of chromosomes. Known variously as PTOP, PIP1 or TINT1, this negative regulator of telomere length connects some of the key proteins already known to be present - TRF1, TIN2, POT1, and TRF2 - and adds even more complexity to telomere protein interactions.},
}
@article {pmid15492246,
year = {2004},
author = {Jaco, I and Muñoz, P and Blasco, MA},
title = {Role of human Ku86 in telomere length maintenance and telomere capping.},
journal = {Cancer research},
volume = {64},
number = {20},
pages = {7271-7278},
doi = {10.1158/0008-5472.CAN-04-1381},
pmid = {15492246},
issn = {0008-5472},
mesh = {Animals ; Antigens, Nuclear/genetics/*physiology ; Apoptosis/genetics ; Cell Division/genetics ; Cell Line, Tumor ; Chromatids/genetics ; DNA-Binding Proteins/genetics/*physiology ; HeLa Cells ; Humans ; Ku Autoantigen ; Mice ; RNA, Small Interfering/genetics ; Telomerase/metabolism ; Telomere/genetics/*physiology ; },
abstract = {The role of Ku86 at telomeres has been extensively studied in various organisms; however, a role for Ku86 at human telomeres was unknown because Ku86 deletion is lethal for human cells. Here, we used small interference RNA to decrease Ku86 protein levels in human cells. An approximately 50% reduction in the amount of Ku86 protein was achieved 72 hours after transfection with Ku86-specific small interference RNAs. This decrease in Ku86 levels resulted in a rapid loss of cell viability characterized by increased apoptosis and decreased mitotic index in the cell population. Importantly, Ku86 knockdown was concomitant with a significant loss of telomeric sequences and with increased chromosomal aberrations, including chromatid-type fusions involving telomeric sequences. These findings demonstrate a role for Ku86 in regulating telomere length and telomere capping in human cells, which, in turn, could impact on cancer and aging.},
}
@article {pmid15489894,
year = {2004},
author = {Deng, W and Tsao, SW and Guan, XY and Lucas, JN and Si, HX and Leung, CS and Mak, P and Wang, LD and Cheung, AL},
title = {Distinct profiles of critically short telomeres are a key determinant of different chromosome aberrations in immortalized human cells: whole-genome evidence from multiple cell lines.},
journal = {Oncogene},
volume = {23},
number = {56},
pages = {9090-9101},
doi = {10.1038/sj.onc.1208119},
pmid = {15489894},
issn = {0950-9232},
mesh = {Cell Line, Transformed ; *Chromosome Aberrations ; DNA Probes ; *Genome, Human ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; *Telomere ; },
abstract = {Chromosomal aberrations are common in cancers. However, the search for chromosomal aberrations leading to development of specific solid tumors has been severely hindered because the majority of solid tumors have complex chromosomal aberrations that differ within the same tumor types. A similar phenomenon exists in immortalized cell lines. The underlying mechanisms driving these diverse aberrations are largely unknown. Telomeres play crucial roles in protecting the integrity of eucaryotic chromosomes and maintaining genomic stability of human cells. Telomere lengths on individual chromosomes in normal human somatic cells are heterogeneous and undergo progressive shortening with aging process. In this study, for the first time, a molecular cytogenetic method using sequential telomere quantitative fluorescence in situ hybridization and spectral karyotyping on the same human metaphases was applied successfully to examine the dynamic profiles of individual telomere shortening and their relationship to chromosome aberrations in multiple human cell lines undergoing immortalization. Human ovarian surface epithelial cells and esophageal epithelial cells were immortalized by the expression of HPV16 E6 and E7, which drive cells to proliferate by inactivating p53 and Rb genes. In these cell lines, we consistently detected large-scale differences in telomere signal intensities not only among nonhomologous chromosome arms but also between some homologous chromosome arms. The cell lines derived from different donors had different profiles of critically short telomeres (lacking telomere signals). Strikingly, the different profiles of chromosomal structural aberrations in multiple immortalized cell lines were highly significantly associated with the distinct distributions of critically short telomeres in whole-genome. Since cellular immortalization is one of the hallmarks of cancer, our findings suggest that distinct profiles of critically short telomeres in different human individuals might play an essential role in determining the complex and individual-specific chromosomal structural aberrations in human solid tumors.},
}
@article {pmid15488760,
year = {2004},
author = {Argilla, D and Chin, K and Singh, M and Hodgson, JG and Bosenberg, M and de Solórzano, CO and Lockett, S and DePinho, RA and Gray, J and Hanahan, D},
title = {Absence of telomerase and shortened telomeres have minimal effects on skin and pancreatic carcinogenesis elicited by viral oncogenes.},
journal = {Cancer cell},
volume = {6},
number = {4},
pages = {373-385},
doi = {10.1016/j.ccr.2004.08.032},
pmid = {15488760},
issn = {1535-6108},
mesh = {Anaphase ; Animals ; Carcinoma, Squamous Cell/enzymology/genetics/pathology ; Cell Division ; Cell Transformation, Neoplastic ; Chromosomal Instability ; Chromosomes, Mammalian/genetics/metabolism ; Disease Progression ; Hybridization, Genetic ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Knockout ; Oncogene Proteins, Viral/*genetics ; Pancreatic Neoplasms/enzymology/*genetics/*pathology ; Phenotype ; Skin Neoplasms/enzymology/*genetics/*pathology ; Telomerase/*deficiency/genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {The telomere-stabilizing enzyme telomerase is induced in tumors and functionally associated with unlimited replicative potential. To further explore its necessity, transgenic mice expressing SV40 or HPV16 oncogenes, which elicit carcinomas in pancreas and skin, respectively, were rendered telomerase-deficient. Absence of telomerase had minimal impact on tumorigenesis, even in terc(-/-) generations (G5-7) exhibiting shortened telomeres and phenotypic abnormalities in multiple organs. Analyses of chromosomal aberrations were not indicative of telomere dysfunction or increased genomic instability in tumors. Quantitative image analysis of telomere repeat intensities comparing biopsies of skin hyperplasia, dysplasia, and carcinoma revealed that telomere numbers and relative lengths were maintained during progression, implicating a means for preserving telomere repeats and functionality in the absence of telomerase.},
}
@article {pmid15486186,
year = {2004},
author = {Incles, CM and Schultes, CM and Kempski, H and Koehler, H and Kelland, LR and Neidle, S},
title = {A G-quadruplex telomere targeting agent produces p16-associated senescence and chromosomal fusions in human prostate cancer cells.},
journal = {Molecular cancer therapeutics},
volume = {3},
number = {10},
pages = {1201-1206},
pmid = {15486186},
issn = {1535-7163},
mesh = {3T3 Cells ; Acridines/pharmacology ; Animals ; Blotting, Western ; Catalysis ; Cell Line, Tumor ; Cell Proliferation ; *Cellular Senescence ; Chromosomes/*ultrastructure ; Cyclin-Dependent Kinase Inhibitor p16/*genetics/metabolism ; *DNA ; G-Quadruplexes ; Humans ; Ligands ; Male ; Metaphase ; Mice ; Models, Chemical ; Nucleic Acid Conformation ; Prostatic Neoplasms/*genetics/metabolism ; Rhodamines/pharmacology ; Telomerase/metabolism ; Telomere/*ultrastructure ; Time Factors ; Up-Regulation ; },
abstract = {The trisubstituted acridine derivative BRACO-19 has been designed to interact with and stabilize the quadruplex DNA structures that can be formed by folding of the single-stranded repeats at the 3' end of human telomeres. We suggest that the BRACO-19 complex inhibits the catalytic function of telomerase in human cancer cells and also destabilizes the telomerase-telomere capping complex so that cells enter senescence. Here, we present evidence showing that the inhibition of cell growth caused by BRACO-19 in DU145 prostate cancer cells occurs more rapidly than would be expected solely by the inhibition of the catalytic function of telomerase, and that senescence is accompanied by an initial up-regulation of the cyclin-dependent kinase inhibitor p21, with subsequent increases in p16(INK4a) expression. We also show that treatment with BRACO-19 causes extensive end-to-end chromosomal fusions, consistent with telomere uncapping.},
}
@article {pmid15485911,
year = {2004},
author = {Zhang, H and Richardson, DO and Roberts, DN and Utley, R and Erdjument-Bromage, H and Tempst, P and Côté, J and Cairns, BR},
title = {The Yaf9 component of the SWR1 and NuA4 complexes is required for proper gene expression, histone H4 acetylation, and Htz1 replacement near telomeres.},
journal = {Molecular and cellular biology},
volume = {24},
number = {21},
pages = {9424-9436},
pmid = {15485911},
issn = {0270-7306},
support = {5-T32DK07115-29/DK/NIDDK NIH HHS/United States ; T32 DK007115/DK/NIDDK NIH HHS/United States ; R01 GM060415/GM/NIGMS NIH HHS/United States ; CA24014/CA/NCI NIH HHS/United States ; GM60415/GM/NIGMS NIH HHS/United States ; },
mesh = {Acetylation ; Acetyltransferases/chemistry/deficiency/genetics/*metabolism ; Adenosine Triphosphatases/chemistry/genetics/*metabolism ; Amino Acid Sequence ; Cell Division ; DNA Repair ; DNA, Fungal/metabolism ; *Gene Expression Regulation, Fungal ; Gene Silencing ; Genes, Essential/genetics ; Histone Acetyltransferases ; Histones/genetics/*metabolism ; Molecular Sequence Data ; Multiprotein Complexes ; Phenotype ; Protein Binding ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/cytology/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/genetics/*metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/deficiency/genetics ; Telomere/genetics/*metabolism ; Temperature ; },
abstract = {Yaf9, Taf14, and Sas5 comprise the YEATS domain family in Saccharomyces cerevisiae, which in humans includes proteins involved in acute leukemias. The YEATS domain family is essential, as a yaf9Delta taf14Delta sas5Delta triple mutant is nonviable. We verify that Yaf9 is a stable component of NuA4, an essential histone H4 acetyltransferase complex. Yaf9 is also associated with the SWR1 complex, which deposits the histone H2A variant Htz1. However, the functional contribution of Yaf9 to these complexes has not been determined. Strains lacking YAF9 are sensitive to DNA-damaging agents, cold, and caffeine, and the YEATS domain is required for full Yaf9 function. NuA4 lacking Yaf9 retains histone acetyltransferase activity in vitro, and Yaf9 does not markedly reduce bulk H4 acetylation levels, suggesting a role for Yaf9 in the targeting or regulation of NuA4. Interestingly, yaf9Delta strains display reduced transcription of genes near certain telomeres, and their repression is correlated with reduced H4 acetylation, reduced occupancy by Htz1, and increased occupancy by the silencing protein Sir3. Additionally, the spectra of phenotypes, genes, and telomeres affected in yaf9Delta and htz1Delta strains are significantly similar, further supporting a role for Yaf9 in Htz1 deposition. Taken together, these data indicate that Yaf9 may function in NuA4 and SWR1 complexes to help antagonize silencing near telomeres.},
}
@article {pmid15479079,
year = {2004},
author = {Zhao, Y and Kan, ZY and Zeng, ZX and Hao, YH and Chen, H and Tan, Z},
title = {Determining the folding and unfolding rate constants of nucleic acids by biosensor. Application to telomere G-quadruplex.},
journal = {Journal of the American Chemical Society},
volume = {126},
number = {41},
pages = {13255-13264},
doi = {10.1021/ja048398c},
pmid = {15479079},
issn = {0002-7863},
mesh = {Biosensing Techniques/*methods ; DNA/*chemistry ; G-Quadruplexes ; Guanine/*chemistry ; Humans ; Kinetics ; Mathematical Computing ; *Nucleic Acid Conformation ; Nucleic Acid Hybridization ; Oligonucleotides/chemistry ; Optics and Photonics ; Surface Plasmon Resonance/methods ; Telomere/*chemistry ; },
abstract = {Nucleic acid molecules may fold into secondary structures, and the formation of such structures is involved in many biological processes and technical applications. The folding and unfolding rate constants define the kinetics of conformation interconversion and the stability of these structures and is important in realizing their functions. We developed a method to determine these kinetic parameters using an optical biosensor based on surface plasmon resonance. The folding and unfolding of a nucleic acid is coupled with a hybridization reaction by immobilization of the target nucleic acid on a sensor chip surface and injection of a complementary probe nucleic acid over the sensor chip surface. By monitoring the time course of duplex formation, both the folding and unfolding rate constants for the target nucleic acid and the association and dissociation rate constants for the target-probe duplex can all be derived from the same measurement. We applied this method to determine the folding and unfolding rate constants of the G-quadruplex of human telomere sequence (TTAGGG)(4) and its association and dissociation rate constants with the complementary strand (CCCTAA)(4). The results show that both the folding and unfolding occur on the time scale of minutes at physiological concentration of K(+). We speculate that this property might be important for telomere elongation. A complete set of the kinetic parameters for both of the structures allows us to study the competition between the formation of the quadruplex and the duplex. Calculations indicate that the formation of both the quadruplex and the duplex is strand concentration-dependent, and the quadruplex can be efficiently formed at low strand concentration. This property may provide the basis for the formation of the quadruplex in vivo in the presence of a complementary strand.},
}
@article {pmid15476325,
year = {2004},
author = {Qian, WB and Meng, HT and Jin, J},
title = {[Quantitative detection of telomere binding factor 2 gene expression in non-Hodgkin lymphoma with a real-time reverse transcription-polymerase chain reaction assay].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {33},
number = {5},
pages = {416-420},
doi = {10.3785/j.issn.1008-9292.2004.05.010},
pmid = {15476325},
issn = {1008-9292},
mesh = {Adult ; Aged ; Burkitt Lymphoma/genetics/metabolism ; Female ; Humans ; Lymphoma, B-Cell/genetics/metabolism ; Lymphoma, Non-Hodgkin/genetics/*metabolism/pathology ; Male ; Middle Aged ; RNA, Neoplasm/analysis/biosynthesis/genetics ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Telomeric Repeat Binding Protein 2/analysis/*biosynthesis/genetics ; },
abstract = {OBJECTIVE: To detect the expression levels of telomere binding factor 2 (TRF2) mRNA in tumor tissue of non-Hodgkin lymphoma (NHL) patients using quantitative real-time RT-PCR.<br><br>METHODS: The target gene mRNA was amplified with RT-PCR, then was sequentially electrophoresed and purified as standards, and the standard curves of gene expression were established. The expression levels of TRF2 mRNA of lymphoid tissue from NHL and reactive lymphoadenopathy were detected with real-time RT-PCR.<br><br>RESULTS: The correlation coefficient was 0.996 between the amount of template cDNA and the intensity of fluorescence signal when gene expression standard curves were established. The correlation coefficient of template cDNA amount and grey density of bands derived from gel electrophoresis of real-time RT-PCR final products was 0.779 (P<0.05). Of all NHL patients, expression levels of TRF2 mRNA of follicular lymphoma, mantle cell lymphoma and diffuse large B cell lymphoma were(22.943 +/-9.424) amol, (23.181 +/-5.983) amol and (18.339 +/-7.910) amol, respectively, which had no significant difference compared with reactive lymphoadenopathy [(21.796 +/-4.800) amol, P>0.05]. The expression level of TRF2 mRNA of Burkitt lymphoma was (33.170 +/-12.841) amol, which was significantly higher than that of reactive lymphoadenopathy and other types of NHL (P<0.05).<br><br>CONCLUSION: Alcohol drinking isn't one of the risk factors of colorectal cancer among Jiashan County population.},
}
@article {pmid15474517,
year = {2004},
author = {Shao, L and Li, QH and Tan, Z},
title = {L-carnosine reduces telomere damage and shortening rate in cultured normal fibroblasts.},
journal = {Biochemical and biophysical research communications},
volume = {324},
number = {2},
pages = {931-936},
doi = {10.1016/j.bbrc.2004.09.136},
pmid = {15474517},
issn = {0006-291X},
mesh = {Aging ; Blotting, Southern ; Carnosine/metabolism/*physiology ; Cell Division ; Cell Line, Tumor ; Cell Proliferation ; Cells, Cultured ; DNA/chemistry/metabolism ; Diploidy ; Fibroblasts/*metabolism ; Flow Cytometry ; Humans ; Reactive Oxygen Species ; Sepharose/chemistry ; Telomere/*ultrastructure ; Time Factors ; beta-Galactosidase/metabolism ; },
abstract = {Telomere is the repetitive DNA sequence at the end of chromosomes, which shortens progressively with cell division and limits the replicative potential of normal human somatic cells. L-carnosine, a naturally occurring dipeptide, has been reported to delay the replicative senescence, and extend the lifespan of cultured human diploid fibroblasts. In this work, we studied the effect of carnosine on the telomeric DNA of cultured human fetal lung fibroblast cells. Cells continuously grown in 20 mM carnosine exhibited a slower telomere shortening rate and extended lifespan in population doublings. When kept in a long-term nonproliferating state, they accumulated much less damages in the telomeric DNA when cultured in the presence of carnosine. We suggest that the reduction in telomere shortening rate and damages in telomeric DNA made an important contribution to the life-extension effect of carnosine.},
}
@article {pmid15473314,
year = {2004},
author = {Wang, HM and Xia, YF and Wu, XY},
title = {[ATM and telomere instability].},
journal = {Yi chuan xue bao = Acta genetica Sinica},
volume = {31},
number = {2},
pages = {212-216},
pmid = {15473314},
issn = {0379-4172},
mesh = {Ataxia Telangiectasia/*genetics ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins ; Chromosomal Instability ; *DNA Damage ; DNA-Binding Proteins ; Humans ; Protein Serine-Threonine Kinases/*genetics/physiology ; Signal Transduction ; Telomerase/metabolism ; *Telomere ; Tumor Suppressor Proteins ; },
abstract = {Accumulation of DNA damage has been associated with the onset of senescence and the predisposition to cancer. The gene responsible for ataxia telangiectasia (A-T) is ATM (Ataxia-telangiectasia mutant), a master controller of cellular pathways and networks, orchestrating the response to a specific type of DNA damage, i.e., the double strand break. It has now been demonstrated that mutations in ATM lead to defective telomere maintenance in mammalian cells. This review will focus on its roles in telomere metabolism and how ATM and telomeres serve as controllers of cellular responses to DNA damage.},
}
@article {pmid15471900,
year = {2005},
author = {Shay, JW and Wright, WE},
title = {Senescence and immortalization: role of telomeres and telomerase.},
journal = {Carcinogenesis},
volume = {26},
number = {5},
pages = {867-874},
doi = {10.1093/carcin/bgh296},
pmid = {15471900},
issn = {0143-3334},
support = {AG07992/AG/NIA NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; },
mesh = {Aging/genetics/physiology ; *Cell Transformation, Neoplastic ; Cellular Senescence/*physiology ; DNA Damage/genetics/physiology ; Humans ; Neoplasms/enzymology/genetics/metabolism ; Telomerase/*physiology ; Telomere/genetics/*physiology ; },
abstract = {Telomere dynamics are a critical component of both aging and cancer. Telomeres progressively shorten in almost all dividing cells and most human cells do not express or maintain sufficient telomerase activity to fully maintain telomeres. There is accumulating evidence that when only a few telomeres are short, they form end-associations, leading to a DNA damage signal resulting in replicative senescence (a cellular growth arrest, also called the M1 stage). In the absence of cell-cycle checkpoint pathways (e.g. p53 and or p16/Rb), cells bypass M1 senescence and telomeres continue to shorten eventually resulting in crisis (also called the M2 stage). M2 is characterized by many 'uncapped' chromosome ends, end-fusions, chromosome breakage fusion-bridge cycles, mitotic catastrophe and a high fraction of apoptotic cells. In a rare M2 cell, telomerase (a cellular reverse transcriptase) can be reactivated or up-regulated, resulting in indefinite cell proliferation. This cellular immortalization is a potentially rate-limiting step in carcinogenesis that is important for the continuing evolution of most advanced cancers. In this perspective we will present our views on the evidence for telomere dysfunction in aging and in cancer progression. We will argue that telomere shortening in the absence of other alterations may be a potent tumor suppressor mechanism and we will discuss the evidence for and against the major molecular mechanisms proposed to initiate replicative senescence.},
}
@article {pmid15471873,
year = {2004},
author = {Deneke, J and Burgin, AB and Wilson, SL and Chaconas, G},
title = {Catalytic residues of the telomere resolvase ResT: a pattern similar to, but distinct from, tyrosine recombinases and type IB topoisomerases.},
journal = {The Journal of biological chemistry},
volume = {279},
number = {51},
pages = {53699-53706},
doi = {10.1074/jbc.M409001200},
pmid = {15471873},
issn = {0021-9258},
mesh = {Amino Acid Motifs ; Amino Acid Sequence ; Binding Sites ; Borrelia burgdorferi/enzymology ; Catalysis ; Catalytic Domain ; DNA/chemistry/metabolism ; DNA Topoisomerases, Type I/*chemistry ; Models, Chemical ; Molecular Sequence Data ; Mutagenesis ; Mutation ; Peptides/chemistry ; Plasmids/metabolism ; Protein Structure, Tertiary ; Recombinases/*chemistry ; Sequence Homology, Amino Acid ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Substrate Specificity ; Telomere/*chemistry ; Time Factors ; Trypsin/chemistry ; Tyrosine/chemistry/metabolism ; },
abstract = {ResT is a member of the telomere resolvases, a newly discovered class of DNA breakage and reunion enzymes. These enzymes are involved in the formation of co-valently closed hairpin DNA ends that are found in linear prokaryotic chromosomes and plasmids. The hairpins are generated by telomere resolution, where the replicated linear DNA ends are processed by DNA breakage followed by joining of DNA free ends to the complementary strand of the same molecule. Previous studies have shown that ResT catalyzes hairpin formation through a two-step transesterification similar to tyrosine recombinases and type IB topoisomerases. In the present study we have probed the reaction mechanism of ResT. The enzyme was found to efficiently utilize a substrate with a 5'-bridging phosphorothiolate at each cleavage site, similar to tyrosine recombinases/type IB topoisomerases. Using such a substrate to trap the covalent protein-DNA intermediate, coupled with affinity purification and mass spectroscopy, we report a new, non-radioactive approach to directly determine the position of the amino acid in the protein, which is linked to the DNA. We report that tyrosine 335 is the active site nucleophile in ResT, strengthening the link between ResT and tyrosine recombinases/type IB topoisomerases. However, a distinct pattern of catalytic residues with similarities, but distinct differences from the above enzymes was suggested. The differences include the apparent absence of a general acid catalyst, as well as the dispensability of the final histidine in the RKHRHY hexad. Finally, two signature motifs (GRR(2X)E(6X)F and LGH(4-6X)T(3X)Y) near the catalytic residues of aligned telomere resolvases are noted.},
}
@article {pmid15467458,
year = {2004},
author = {Gire, V},
title = {Dysfunctional telomeres at senescence signal cell cycle arrest via Chk2.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {3},
number = {10},
pages = {1217-1220},
doi = {10.4161/cc.3.10.1167},
pmid = {15467458},
issn = {1551-4005},
mesh = {*Cell Cycle ; *Cellular Senescence ; Checkpoint Kinase 2 ; DNA Damage ; Fibroblasts/pathology ; Humans ; Protein Serine-Threonine Kinases/*metabolism ; Telomere/*metabolism/*pathology ; },
abstract = {Loss of telomere integrity can have two outcomes with opposite predicted effects on tumorigenesis. On the one hand, shortened telomeres in normal cells may trigger cell cycle arrest, leading to tumor suppression. On the other hand, in a tumor cell in which neither the p53 nor pRb pathway is intact, shortened telomeres could initiate chromosome instability and promote tumorigenesis A major issue in telomere research is to understand how shortened dysfunctional telomeres can regulate the onset of cellular senescence. Recent studies have revealed that critically shortened or acutely uncapped telomeres share molecular features with damaged DNA. We have recently linked the phosphorylation and activation of one major DNA damage effector checkpoint kinase, Chk2, to telomere erosion in signalling cell cycle arrest in normal fibroblasts. Here, we discuss several hypotheses to explain the molecular events occurring at shortened telomeres that ultimately lead to cell cycle arrest or increased genomic instability.},
}
@article {pmid15467446,
year = {2004},
author = {Satyanarayana, A and Manns, MP and Rudolph, KL},
title = {Telomeres, telomerase and cancer: an endless search to target the ends.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {3},
number = {9},
pages = {1138-1150},
pmid = {15467446},
issn = {1551-4005},
mesh = {Animals ; Antineoplastic Agents/pharmacology ; Cell Division/drug effects/physiology ; Cell Proliferation/drug effects ; Cell Transformation, Neoplastic/genetics/*metabolism ; DNA-Binding Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Humans ; Neoplasms/drug therapy/genetics/*metabolism ; RNA/genetics/metabolism ; Telomerase/antagonists &amp; inhibitors/genetics/*metabolism ; Telomere/*physiology ; },
abstract = {Maintenance of functional telomeres, the highly complex nucleo-protein structures, at the end of linear eukaryotic chromosomes appears to be essential for growth and survival of the cells. The compelling correlation between telomerase reactivation and cellular immortalization led to the idea that inhibition of telomerase may provide a way for effective hindrance of cancer cell growth by interfering with telomere maintenance. In addition to targeting the components of telomerase enzyme directly to prevent telomere synthesis, several approaches including disruption of telomeres, interference with telomerase component assembly, translocation of the catalytic component of telomerase have also been under extensive investigation due to the advances in understanding the biology of telomeres and telomerase in recent years. This review will focus on the so far identified approaches to prevent cancer cell growth by targeting telomerase and telomeres with a brief introduction about structure and function of telomeres and telomerase.},
}
@article {pmid15467107,
year = {2004},
author = {Liu, Q and Wang, H and Hu, D and Ding, C and Xu, H and Tao, D},
title = {Effects of trace elements on the telomere lengths of hepatocytes L-02 and hepatoma cells SMMC-7721.},
journal = {Biological trace element research},
volume = {100},
number = {3},
pages = {215-227},
doi = {10.1385/BTER:100:3:215},
pmid = {15467107},
issn = {0163-4984},
mesh = {Apoptosis/drug effects ; Carcinoma, Hepatocellular/*drug therapy ; Cell Line ; Cell Line, Tumor ; Chromium/pharmacology ; Dose-Response Relationship, Drug ; Fluorescent Dyes ; Hepatocytes/*drug effects ; Humans ; In Situ Hybridization, Fluorescence/methods ; Iron/pharmacology ; Lead/pharmacology ; Liver Neoplasms/*drug therapy ; Sodium Selenite/pharmacology ; Telomere/*drug effects/*genetics ; Trace Elements/chemistry/*pharmacology ; Zinc/pharmacology ; },
abstract = {The effects of selenium, zinc, iron, chromium, and lead on telomere lengths of human cells have not been investigated. This article adopted flow cytometry and fluorescence in situ hybridization to investigate the impact of different elements on cellular apoptosis and telomere lengths of human hepatocytes L-02 and hepatoma cells SMMC-7721. Results showed that these trace elements under the following dosages did not have remarkable effect on cellular apoptosis. However, sodium selenite at doses of 0.5 and 2.5 micromol/L significantly extended the telomere length of hepatocytes L-02; 0.5 micromol/L lead acetate remarkably shortened the telomere length of L-02 cells; 80 micromol/L zinc sulfate, 20 micromol/L ferric chloride, and 200 micromol/L chromic chloride only had slight impact on the telomere length, respectively. Regarding hepatoma cells SMMC-7721, sodium seleite at 0.5 and 2.5 micromol/L had little impact on the telomere length; 80 micromol/L zinc sulfate significantly accelerated the loss of telomere length, whereas 20 micromol/L ferric chloride, 200 micromol/L chromic chloride, and 0.5 micromol/L lead acetate remarkably extended the telomere lengths, respectively. The results revealed differential effects of each trace element on the life-span of human hepatocytes and hepatoma cell lines, which suggested further research on somatic hepatocytes and hepatoma in vivo.},
}
@article {pmid15458635,
year = {2004},
author = {Theobald, DL and Wuttke, DS},
title = {Prediction of multiple tandem OB-fold domains in telomere end-binding proteins Pot1 and Cdc13.},
journal = {Structure (London, England : 1993)},
volume = {12},
number = {10},
pages = {1877-1879},
doi = {10.1016/j.str.2004.07.015},
pmid = {15458635},
issn = {0969-2126},
support = {R01 GM059414/GM/NIGMS NIH HHS/United States ; R01 GM059414-01/GM/NIGMS NIH HHS/United States ; },
mesh = {Algorithms ; Animals ; Cell Cycle Proteins/*chemistry ; Computational Biology/*methods ; Oxytricha/genetics ; Profilins ; Protein Structure, Tertiary ; Saccharomyces cerevisiae Proteins/*chemistry ; Sequence Analysis, Protein/*methods ; Telomere-Binding Proteins/*chemistry/genetics ; },
abstract = {The heterodimeric Oxytricha nova telomere end binding protein, the original telomere end binding protein characterized, contains four OB-fold domains used for recognition of single-stranded telomeric DNA. In contrast, only solitary OB-fold domains have been found in the telomere end binding proteins from yeast and higher eukaryotes. Using a sliding-window algorithm coupled with sequence profile-profile analysis, we provide support for the existence of multiple OB-fold domains in two other telomeric ssDNA binding proteins, vertebrate Pot1 and budding yeast Cdc13. This common usage of multiple, tandem OB-fold domains in telomeric end binding proteins extends the known evolutionary conservation of eukaryotic end-protection mechanisms.},
}
@article {pmid15458514,
year = {2004},
author = {Rigolin, GM and Porta, MD and Bugli, AM and Castagnari, B and Mauro, E and Bragotti, LZ and Ciccone, M and Cuneo, A and Castoldi, G},
title = {Flow cytometric detection of accelerated telomere shortening in myelodysplastic syndromes: correlations with aetiological and clinical-biological findings.},
journal = {European journal of haematology},
volume = {73},
number = {5},
pages = {351-358},
doi = {10.1111/j.1600-0609.2004.00305.x},
pmid = {15458514},
issn = {0902-4441},
mesh = {Aged ; Aged, 80 and over ; Anemia, Refractory/blood ; Anemia, Refractory, with Excess of Blasts/blood ; Antigens, CD34/analysis ; Apoptosis ; Chromosomes, Human, Pair 19 ; Chromosomes, Human, Pair 5 ; Chromosomes, Human, Pair 8 ; Chromosomes, Human, Y ; Female ; *Flow Cytometry/methods ; Gene Deletion ; Granulocytes/ultrastructure ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia, Myelomonocytic, Chronic/blood ; Male ; Middle Aged ; Monosomy ; Myelodysplastic Syndromes/*blood/etiology/genetics ; Pesticides/toxicity ; Prognosis ; Solvents/toxicity ; Survival Rate ; Telomere/*ultrastructure ; Trisomy ; },
abstract = {Using quantitative fluorescence in situ hybridisation and flow cytometry (flow-FISH), we investigated the biological and clinical relevance of telomere length in 55 patients affected by myelodysplastic syndromes (MDS) compared with 55 sex- and age-matched controls. We found that telomere fluorescence in MDS granulocytes, and CD34+ cells did not decline with age as in normal controls and that MDS granulocytes and CD34+ cells had significantly shorter telomeres than healthy controls. A significant higher incidence of cases with intermediate-unfavourable cytogenetics and International Prognostic Scoring System (IPSS) int-2/high-risk group was observed among patients with lower telomere fluorescence. We also found that apoptosis in CD34+ cells was significantly higher in IPSS int-1 low-risk patients when compared with IPSS int-2 high-risk cases and healthy controls and that CD34+ cell telomere fluorescence directly correlated with CD34+ cell apoptosis. Reduced telomere fluorescence was associated with a history of occupational exposure to toxic agents and with worse survival in univariate and multivariate analyses. Our results suggest that flow-cytometry assessment of telomere dynamics may represent a valuable tool in the biological and clinical-prognostic characterisation of MDS disorders.},
}
@article {pmid15454610,
year = {2004},
author = {Lue, NF and Jiang, S},
title = {Reverse transcriptase at bacterial telomeres.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {101},
number = {40},
pages = {14307-14308},
pmid = {15454610},
issn = {0027-8424},
mesh = {Bacteria/*enzymology ; Bacterial Proteins/metabolism ; DNA, Bacterial/biosynthesis ; DNA-Binding Proteins ; RNA, Bacterial/metabolism ; RNA-Directed DNA Polymerase/*metabolism ; Telomerase/metabolism ; Telomere/*enzymology ; },
}
@article {pmid15454530,
year = {2004},
author = {Zubko, MK and Guillard, S and Lydall, D},
title = {Exo1 and Rad24 differentially regulate generation of ssDNA at telomeres of Saccharomyces cerevisiae cdc13-1 mutants.},
journal = {Genetics},
volume = {168},
number = {1},
pages = {103-115},
pmid = {15454530},
issn = {0016-6731},
mesh = {Cell Cycle/genetics ; Cell Cycle Proteins/*genetics ; Colony Count, Microbial ; DNA Primers ; *DNA Repair ; DNA, Single-Stranded/*genetics ; Exodeoxyribonucleases/*genetics ; *Genes, cdc ; Intracellular Signaling Peptides and Proteins ; Models, Genetic ; Mutation/genetics ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; Temperature ; },
abstract = {Cell cycle arrest in response to DNA damage depends upon coordinated interactions between DNA repair and checkpoint pathways. Here we examine the role of DNA repair and checkpoint genes in responding to unprotected telomeres in budding yeast cdc13-1 mutants. We show that Exo1 is unique among the repair genes tested because like Rad9 and Rad24 checkpoint proteins, Exo1 inhibits the growth of cdc13-1 mutants at the semipermissive temperatures. In contrast Mre11, Rad50, Xrs2, and Rad27 contribute to the vitality of cdc13-1 strains grown at permissive temperatures, while Din7, Msh2, Nuc1, Rad2, Rad52, and Yen1 show no effect. Exo1 is not required for cell cycle arrest of cdc13-1 mutants at 36 degrees but is required to maintain arrest. Exo1 affects but is not essential for the production of ssDNA in subtelomeric Y' repeats of cdc13-1 mutants. However, Exo1 is critical for generating ssDNA in subtelomeric X repeats and internal single-copy sequences. Surprisingly, and in contrast to Rad24, Exo1 is not essential to generate ssDNA in X or single-copy sequences in cdc13-1 rad9Delta mutants. We conclude that Rad24 and Exo1 regulate nucleases with different properties at uncapped telomeres and propose a model to explain our findings.},
}
@article {pmid15454527,
year = {2004},
author = {Martins-Taylor, K and Dula, ML and Holmes, SG},
title = {Heterochromatin spreading at yeast telomeres occurs in M phase.},
journal = {Genetics},
volume = {168},
number = {1},
pages = {65-75},
pmid = {15454527},
issn = {0016-6731},
mesh = {Cell Division/*genetics ; DNA Primers ; Fungal Proteins/genetics ; *Gene Silencing ; Heterochromatin/*genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Saccharomycetales/*genetics ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Species Specificity ; Telomere/*genetics ; },
abstract = {Heterochromatin regulation of gene expression exhibits epigenetic inheritance, in which some feature of the structure is retained and can reseed formation in new cells. To understand the cell-cycle events that influence heterochromatin assembly and maintenance in budding yeast, we have conducted two types of experiments. First we have examined the kinetics of heterochromatin spreading at telomeres. We have constructed a strain in which the efficient silencing of a telomere-linked URA3 gene depends on the inducible expression of the Sir3 silencing factor. Prior studies determined that S-phase passage was required for the establishment of silencing at the HM loci in yeast. We find that establishment of silencing in our strain occurs at a point coincident with mitosis and does not require S-phase passage. In addition, we find that passage through mitosis is sufficient to establish silencing at the HML locus in a strain bearing a conditional allele of SIR3. Finally, we have also assessed the stability of yeast heterochromatin in the absence of the cis-acting elements required for its establishment. We show that silencing is stable through S phase in the absence of silencers and therefore possesses the ability to self-propagate through DNA replication. However, silencing is lost in the absence of silencers during progression through M phase. These experiments point to crucial events in mitosis influencing the assembly and persistence of heterochromatin.},
}
@article {pmid15453908,
year = {2004},
author = {Daniel, A and St Heaps, L},
title = {Chromosome loops arising from intrachromosomal tethering of telomeres occur at high frequency in G1 (non-cycling) mitotic cells: Implications for telomere capture.},
journal = {Cell &amp; chromosome},
volume = {3},
number = {1},
pages = {3},
pmid = {15453908},
issn = {1475-9268},
abstract = {BACKGROUND: To investigate potential mechanisms for telomere capture the spatial arrangement of telomeres and chromosomes was examined in G1 (non-cycling) mitotic cells with diploid or triploid genomes. This was examined firstly by directly labelling the respective short arm (p) and long arm subtelomeres (q) with different fluorophores and probing cell preparations using a number of subtelomere probe pairs, those for chromosomes 1, 3, 4, 5, 6, 7, 9, 10, 12, 17, 18, and 20. In addition some interstitial probes (CEN15, PML and SNRPN on chromosome 15) and whole chromosome paint probes (e.g. WCP12) were jointly hybridised to investigate the co-localization of interphase chromosome domains and tethered subtelomeres. Cells were prepared by omitting exposure to colcemid and hypotonic treatments. RESULTS: In these cells a specific interphase chromosome topology was detected. It was shown that the p and q telomeres of the each chromosome associate frequently (80% pairing) in an intrachromosomal manner, i.e. looped chromosomes with homologues usually widely spaced within the nucleus. This p-q tethering of the telomeres from the one chromosome was observed with large (chromosomes 3, 4, 5), medium sized (6, 7, 9, 10, 12), or small chromosomes (17, 18, 20). When triploid nuclei were probed there were three tetherings of p-q subtelomere signals representing the three widely separated looped chromosome homologues. The separate subtelomere pairings were shown to coincide with separate chromosome domains as defined by the WCP and interstitial probes. The 20% of apparently unpaired subtelomeric signals in diploid nuclei were partially documented to be pairings with the telomeres of other chromosomes. CONCLUSIONS: A topology for telomeres was detected where looped chromosome homologues were present at G1 interphase. These homologues were spatially arranged with respect to one-another independently of other chromosomes, i.e. there was no chromosome order on different sides of the cell nuclei and no segregation into haploid sets was detected. The normal function of this high frequency of intrachromosomal loops is unknown but a potential role is likely in the genesis of telomere captures whether of the intrachromosomal type or between non-homologues. This intrachromosomal tethering of telomeres cannot be related to telomeric or subtelomeric sequences since these are shared in varying degree with other chromosomes. In our view, these intrachromosomal telomeric tetherings with the resulting looped chromosomes arranged in a regular topology must be important to normal cell function since non-cycling cells in G1 are far from quiescent, are in fact metabolically active, and these cells represent the majority status since only a small proportion of cells are normally dividing.},
}
@article {pmid15451415,
year = {2004},
author = {Wu, G and Wong, A},
title = {Solid-state 23Na NMR determination of the number and coordination of sodium cations bound to Oxytricha nova telomere repeat d(G4T4G4).},
journal = {Biochemical and biophysical research communications},
volume = {323},
number = {4},
pages = {1139-1144},
doi = {10.1016/j.bbrc.2004.08.210},
pmid = {15451415},
issn = {0006-291X},
mesh = {Animals ; Binding Sites ; Cations ; Magnetic Resonance Spectroscopy/*methods ; Oligodeoxyribonucleotides/*chemistry ; Oxytricha/*genetics ; Sodium/*analysis/*chemistry ; Sodium Isotopes ; Telomere/*chemistry ; Trinucleotide Repeats ; },
abstract = {We report a solid-state (23)Na NMR study of the bound sodium cations in a G-quadruplex formed by Oxytricha nova telomere DNA repeat, d(G(4)T(4)G(4)) (Oxy-1.5). Using a 2D multiple-quantum magic-angle spinning (23)Na NMR method, we observed three sodium cations residing inside the quadruplex channel of the Na(+) form of Oxy-1.5. Each of these sodium cations is sandwiched between two G-quartets. We found no evidence for sodium cations in the T(4) loop region. For comparison, solid-state (15)N MAS NMR spectra were also obtained for the (15)NH(4)(+) form of Oxy-1.5. The insufficient resolution in the (15)N MAS NMR spectra did not permit determination of the number of NH(4)(+) ions inside the quadruplex channel. The solid-state (23)Na and (15)N NMR spectra for Oxy-1.5 were also compared with those obtained for guanosine 5'-monophosphate.},
}
@article {pmid15390185,
year = {2005},
author = {Gisselsson, D and Lv, M and Tsao, SW and Man, C and Jin, C and Höglund, M and Kwong, YL and Jin, Y},
title = {Telomere-mediated mitotic disturbances in immortalized ovarian epithelial cells reproduce chromosomal losses and breakpoints from ovarian carcinoma.},
journal = {Genes, chromosomes &amp; cancer},
volume = {42},
number = {1},
pages = {22-33},
doi = {10.1002/gcc.20094},
pmid = {15390185},
issn = {1045-2257},
mesh = {Cell Cycle/genetics/physiology ; Cell Line, Tumor ; Chromosome Aberrations ; *Chromosome Deletion ; Chromosomes, Human/genetics ; Epithelial Cells/*cytology ; Female ; Gene Expression Profiling ; Humans ; Karyotyping ; Mitosis/*physiology ; Ovarian Neoplasms/*genetics/pathology ; Telomere/*genetics/ultrastructure ; },
abstract = {Ovarian carcinomas (OCs) often exhibit highly complex cytogenetic changes. Abnormal chromosome segregation at mitosis is one potential mechanism for genomic rearrangements in tumors. In this study, OCs were demonstrated to have dysfunctional short telomeres, anaphase bridging, and multipolar mitoses with supernumerary centrosomes. When normal human ovarian surface epithelial (HOSE) cells were transfected with human papilloma virus 16 e6/e7 genes and subsequently driven into telomere crisis, the same set of mitotic disturbances occurred in a distinct sequence, initiated by telomere dysfunction, followed by anaphase bridging, and then supernumerary centrosomes and multipolar mitoses. The anaphase bridges resolved either by kinetochore-spindle detachment, corresponding to whole-chromosome losses in the HOSE karyotypes, or by extensive fragmentation of intercentromeric DNA sequences, corresponding to a high frequency of pericentromeric rearrangements. At later passages, the high degree of instability at telomere crisis was moderated by telomerase expression and centrosome coalescence, ultimately leading to a level of mitotic instability that was highly similar to that in OC cell lines and to complex karyotypes that were similar to those observed in high-grade OCs. This suggests that a significant proportion of the structural chromosome changes and genomic losses in OC are caused by a specific sequence of mitotic disturbances triggered by telomere crisis. That the model did not produce any of the whole-chromosome gains observed in OC indicates that these changes develop through a different mechanism.},
}
@article {pmid15389260,
year = {2005},
author = {Zendehrokh, N and Dejmek, A},
title = {Telomere repeat amplification protocol (TRAP) in situ reveals telomerase activity in three cell types in effusions: malignant cells, proliferative mesothelial cells, and lymphocytes.},
journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},
volume = {18},
number = {2},
pages = {189-196},
doi = {10.1038/modpathol.3800278},
pmid = {15389260},
issn = {0893-3952},
mesh = {Ascitic Fluid/enzymology/metabolism/pathology ; Cell Proliferation ; Cytodiagnosis/methods ; Epithelium/enzymology/metabolism/pathology ; Female ; Gene Amplification ; Humans ; Lymphocytes/enzymology/metabolism/pathology ; Pericardial Effusion/enzymology/genetics/pathology ; Pleural Effusion/enzymology/genetics/pathology ; Repetitive Sequences, Nucleic Acid/*genetics ; Reproducibility of Results ; Telomerase/*metabolism ; Telomere/enzymology/*genetics ; },
abstract = {Telomerase Repeat Amplification Protocol (TRAP) in situ was performed on cytospin preparations from 65 effusions from the serous cavities (45 pleural and 19 ascitic fluids and one pericardial fluid) submitted for routine diagnosis and the results were correlated to cytological morphology. Three types of cells with nuclear fluorescence were identified: malignant cells, hyperplastic mesothelial cell and lymphocytes. Of 38 cytologically malignant effusions, 12 showed strong reactivity in all malignant cells, three strong reactivity in part of the malignant population, whereas 12 showed moderate reactivity in the whole and five in part of the malignant population, respectively. In five malignant effusions weak reactivity was found in all (one case) and in scattered (four cases) malignant cells. Two effusions contained telomerase-negative malignant cells. Two pleural and two ascitic fluids contained proliferative mesothelial cells with weak or, in one case, moderate reactivity. Lymphocytes usually showed weak telomerase activity. Telomerase was expressed in almost all malignant tumours metastatic to serous cavities. Heterogeneity in tumour populations was demonstrated, which may have diagnostic implications, especially in cytology. Weak or moderate reactivity was found in lymphocytes and in some mesothelial proliferations and may explain the low specificity for malignancy sometimes obtained with the TRAP extract method. The weak reactivity found in lymphocytes may reduce the specificity when the extract method is used but causes no diagnostic problem with the TRAP in situ method.},
}
@article {pmid15387273,
year = {2004},
author = {Kammori, M and Takubo, K},
title = {[Recent advances of telomere research].},
journal = {Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics},
volume = {41},
number = {4},
pages = {365-368},
doi = {10.3143/geriatrics.41.365},
pmid = {15387273},
issn = {0300-9173},
mesh = {Humans ; Research ; *Telomere/metabolism ; },
}
@article {pmid15383534,
year = {2004},
author = {Liu, D and O'Connor, MS and Qin, J and Songyang, Z},
title = {Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins.},
journal = {The Journal of biological chemistry},
volume = {279},
number = {49},
pages = {51338-51342},
doi = {10.1074/jbc.M409293200},
pmid = {15383534},
issn = {0021-9258},
mesh = {Blotting, Western ; Cell Line ; Cell Nucleus/metabolism ; Electrophoresis, Polyacrylamide Gel ; Fluorescent Antibody Technique, Indirect ; Gene Deletion ; HeLa Cells ; Humans ; Immunoprecipitation ; Mass Spectrometry ; Microscopy, Fluorescence ; *Multiprotein Complexes ; Mutation ; Protein Binding ; Protein Structure, Tertiary ; Shelterin Complex ; Tankyrases/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/physiology ; Telomeric Repeat Binding Protein 1/physiology ; Telomeric Repeat Binding Protein 2/physiology ; rap1 GTP-Binding Proteins/physiology ; },
abstract = {In mammalian cells, telomere-binding proteins TRF1 and TRF2 play crucial roles in telomere biology. They interact with several other telomere regulators including TIN2, PTOP, POT1, and RAP1 to ensure proper maintenance of telomeres. TRF1 and TRF2 are believed to exert distinct functions. TRF1 forms a complex with TIN2, PTOP, and POT1 and regulates telomere length, whereas TRF2 mediates t-loop formation and end protection. However, whether cross-talk occurs between the TRF1 and TRF2 complexes and how the signals from these complexes are integrated for telomere maintenance remain to be elucidated. Through gel filtration and co-immunoprecipitation experiments, we found that TRF1 and TRF2 are in fact subunits of a telomere-associated high molecular weight complex (telosome) that also contains POT1, PTOP, RAP1, and TIN2. We demonstrated that the TRF1-interacting protein TIN2 binds TRF2 directly and in vivo, thereby bridging TRF2 to TRF1. Consistent with this multi-protein telosome model, stripping TRF1 off the telomeres by expressing tankyrase reduced telomere recruitment of not only TIN2 but also TRF2. These results help to unify previous observations and suggest that telomere maintenance depends on the multi-subunit telosome.},
}
@article {pmid15383525,
year = {2004},
author = {Tomaska, L and Willcox, S and Slezakova, J and Nosek, J and Griffith, JD},
title = {Taz1 binding to a fission yeast model telomere: formation of telomeric loops and higher order structures.},
journal = {The Journal of biological chemistry},
volume = {279},
number = {49},
pages = {50764-50772},
doi = {10.1074/jbc.M409790200},
pmid = {15383525},
issn = {0021-9258},
support = {CA19014/CA/NCI NIH HHS/United States ; GM31819/GM/NIGMS NIH HHS/United States ; TW05654-01/TW/FIC NIH HHS/United States ; },
mesh = {DNA/chemistry ; Electrophoresis, Polyacrylamide Gel ; Immunoblotting ; Mass Spectrometry ; Microscopy, Electron ; Oligonucleotides/chemistry ; Plasmids/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Recombinant Proteins/chemistry ; Schizosaccharomyces/*metabolism ; Schizosaccharomyces pombe Proteins/chemistry/*metabolism ; Telomere/metabolism/*ultrastructure ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {Similar to its human homologues TRF1 and TRF2, fission yeast Taz1 protein is a component of telomeric chromatin regulating proper telomere maintenance. As mammalian TRF1 and TRF2 proteins have been shown to directly bind telomeric DNA to form protein arrays and looped structures, termed t-loops, the ability of Taz1p to act on fission yeast telomeric DNA in similar ways was examined using purified protein and model DNA templates. When incubated with Taz1p, model telomeres containing 3' single-stranded telomeric overhangs formed t-loops at a frequency approaching 13%. Termini with blunt ends and non-telomeric overhangs were deficient in t-loop formation. In addition, we observed arrays of multiple Taz1p molecules bound to the telomeric regions, resembling the pattern of TRF1 binding. The presence of t-loops larger than the telomeric tract, a high frequency of end-bound DNAs and a donut shape of the Taz1p complex suggest that Taz1p binds the 3' overhang then extrudes a loop that grows in size as the donut slides along the duplex DNA. Based on these in vitro results we discuss possible general implications for fission yeast telomere dynamics.},
}
@article {pmid15380063,
year = {2004},
author = {Houghtaling, BR and Cuttonaro, L and Chang, W and Smith, S},
title = {A dynamic molecular link between the telomere length regulator TRF1 and the chromosome end protector TRF2.},
journal = {Current biology : CB},
volume = {14},
number = {18},
pages = {1621-1631},
doi = {10.1016/j.cub.2004.08.052},
pmid = {15380063},
issn = {0960-9822},
support = {R01 CA095099/CA/NCI NIH HHS/United States ; CA09161/CA/NCI NIH HHS/United States ; GM07238/GM/NIGMS NIH HHS/United States ; R01 CA95099/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; Blotting, Northern ; Cell Cycle/physiology ; Fluorescent Antibody Technique ; HeLa Cells ; Humans ; Immunoprecipitation ; Models, Biological ; Molecular Sequence Data ; Plasmids/genetics ; Sequence Analysis, DNA ; Shelterin Complex ; Telomere/*metabolism/physiology ; Telomere-Binding Proteins/*genetics/*metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; Two-Hybrid System Techniques ; },
abstract = {BACKGROUND: Human telomeres are coated by the telomere repeat binding proteins TRF1 and TRF2, which are believed to function independently to regulate telomere length and protect chromosome ends, respectively.<br><br>RESULTS: Here, we show that TRF1 and TRF2 are linked via TIN2, a previously identified TRF1-interacting protein, and its novel binding partner TINT1. TINT1 localized to telomeres via TIN2, where it functioned as a negative regulator of telomerase-mediated telomere elongation. TIN2 associated with TINT1, and TRF1 or TRF2 throughout the cell cycle, revealing a partially redundant unit in telomeric chromatin that may provide flexibility in telomere length control. Indeed, when TRF1 was removed from telomeres by overexpression of the positive telomere length regulator tankyrase 1, the TIN2/TINT1 complex remained on telomeres via an increased association with TRF2.<br><br>CONCLUSIONS: Our findings suggest a dynamic cross talk between TRF1 and TRF2 and provide a molecular mechanism for telomere length homeostasis by TRF2 in the absence of TRF1.},
}
@article {pmid15378602,
year = {2004},
author = {Yokoo, S and Furumoto, K and Hiyama, E and Miwa, N},
title = {Slow-down of age-dependent telomere shortening is executed in human skin keratinocytes by hormesis-like-effects of trace hydrogen peroxide or by anti-oxidative effects of pro-vitamin C in common concurrently with reduction of intracellular oxidative stress.},
journal = {Journal of cellular biochemistry},
volume = {93},
number = {3},
pages = {588-597},
doi = {10.1002/jcb.20208},
pmid = {15378602},
issn = {0730-2312},
mesh = {Ascorbic Acid/*analogs &amp; derivatives/pharmacology ; Cell Proliferation/*drug effects ; Cell Size/drug effects ; Cells, Cultured ; Cellular Senescence/drug effects/*physiology ; Flow Cytometry ; Humans ; Hydrogen Peroxide/pharmacology ; Keratinocytes/drug effects/*physiology ; Oxidative Stress/drug effects/*physiology ; Skin/cytology ; Telomerase/metabolism ; Telomere/drug effects/*physiology ; },
abstract = {The cellular life-span of cultivated human skin epidermis keratinocytes NHEK-F was shown to be extended up to 150% of population doubling levels (PDLs) by repetitive addition with two autooxidation-resistant derivatives of ascorbic acid (Asc), Asc-2-O-phosphate (Asc2P), and Asc-2-O-alpha-glucoside (Asc2G), respectively, but to be not extended with Asc itself. In contrast, hydrogen peroxide (H(2)O(2)) as dilute as 20 microM which was non-cytotoxic to the keratinocytes, or at 60 microM being marginally cytotoxic achieved the cellular longevity, unexpectedly, up to 160 and 120% of PDLs, respectively, being regarded as a hormesis-like stimulatory effect. The lifespan-extended cells that were administered with Asc2P, Asc2G, or 20 microM H(2)O(2) were prevented from senescence-induced symptoms such as PDL-dependent enlargement of a cell size of 14.7 microm finally up to 17.4 microm upon Hayflick's limit-called loss of proliferation ability as estimated with a channelizer, and retained young cell morphological aspects such as thick and compact shape and intense attachment to the culture substratum even upon advanced PDLs, whereas other non-extended cells looked like thin or fibrous shape and large size upon lower PDLs. The PDL-dependent shortening of telomeric DNA of 11.5 kb finally down to 9.12-8.10 kb upon Hayflick's limit was observed in common for each additive-given cells, but was decelerated in the following order: 20 microM H(2)O(2) > Asc2P = Asc2G > 60 microM H(2)O(2) > Asc = no additive, being in accord with the order of cell longevity. Intracellular reactive oxygen species (ROS) was diminished by Asc2P, Asc2G or 20 microM H(2)O(2), but not significantly by Asc or 60 microM H(2)O(2) as estimated by fluorometry using the redox indicator dye CDCFH. There was no appreciable difference among NHEK keratinocytes that were administered with or without diverse additives in terms of telomerase activity per cell, which was 1.40 x 10(4)-4.48 x 10(4) times lower for the keratinocytes than for HeLa cells which were examined as the typical tumor cells. Thus longevity of the keratinocytes was suggested to be achieved by slowdown of age-dependent shortening of telomeric DNA rather than by telomerase; telomeres may suffer from less DNA lesions due to the continuous and thorough repression of intracellular ROS, which was realized either by pro-vitamin C such as Asc2P or Asc2G that exerted an antioxidant ability more persistent than Asc itself or by 20 microM H(2)O(2) which diminished intracellular ROS assumedly through a hormesis-like effect.},
}
@article {pmid15368430,
year = {2004},
author = {Satyanarayana, A and Manns, MP and Rudolph, KL},
title = {Telomeres and telomerase: a dual role in hepatocarcinogenesis.},
journal = {Hepatology (Baltimore, Md.)},
volume = {40},
number = {2},
pages = {276-283},
doi = {10.1002/hep.20308},
pmid = {15368430},
issn = {0270-9139},
mesh = {Animals ; Carcinoma, Hepatocellular/*enzymology/*genetics ; DNA-Binding Proteins ; Disease Progression ; Enzyme Activation ; Humans ; Liver Neoplasms/*enzymology/*genetics ; Liver Neoplasms, Experimental/physiopathology ; Mice ; Mice, Knockout/genetics ; RNA/genetics ; Telomerase/deficiency/genetics/*metabolism ; *Telomere ; },
abstract = {Telomere shortening limits the proliferative capacity of primary human cells and restrains the regenerative capacity of organ systems during chronic diseases and aging. Telomere shortening apparently has a dual role in tumor development and progression. On the one hand, it induces chromosomal instability and the initiation of cancer; on the other hand, tumor progression requires stabilization of telomeres. The predominant mechanism of telomere stabilization in tumor cells is the activation of the telomere-synthesizing enzyme telomerase. The potential use of telomerase activators for the treatment of regenerative disorders will ultimately depend on their effects on tumorigenesis. This review focuses on the role of telomere shortening and telomerase in carcinogenesis with a special focus on hepatocellular carcinoma.},
}
@article {pmid15367665,
year = {2004},
author = {Du, X and Shen, J and Kugan, N and Furth, EE and Lombard, DB and Cheung, C and Pak, S and Luo, G and Pignolo, RJ and DePinho, RA and Guarente, L and Johnson, FB},
title = {Telomere shortening exposes functions for the mouse Werner and Bloom syndrome genes.},
journal = {Molecular and cellular biology},
volume = {24},
number = {19},
pages = {8437-8446},
pmid = {15367665},
issn = {0270-7306},
mesh = {Animals ; Bloom Syndrome/genetics/*metabolism ; Body Constitution/genetics/physiology ; Infertility/genetics/metabolism ; Intestine, Small/pathology ; Longevity/genetics/physiology ; Male ; Mice ; Mutation ; RNA/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Testis/pathology ; Werner Syndrome/genetics/*metabolism ; Wound Healing/genetics/physiology ; },
abstract = {The Werner and Bloom syndromes are caused by loss-of-function mutations in WRN and BLM, respectively, which encode the RecQ family DNA helicases WRN and BLM, respectively. Persons with Werner syndrome displays premature aging of the skin, vasculature, reproductive system, and bone, and those with Bloom syndrome display more limited features of aging, including premature menopause; both syndromes involve genome instability and increased cancer. The proteins participate in recombinational repair of stalled replication forks or DNA breaks, but the precise functions of the proteins that prevent rapid aging are unknown. Accumulating evidence points to telomeres as targets of WRN and BLM, but the importance in vivo of the proteins in telomere biology has not been tested. We show that Wrn and Blm mutations each accentuate pathology in later-generation mice lacking the telomerase RNA template Terc, including acceleration of phenotypes characteristic of latest-generation Terc mutants. Furthermore, pathology not observed in Terc mutants but similar to that observed in Werner syndrome and Bloom syndrome, such as bone loss, was observed. The pathology was accompanied by enhanced telomere dysfunction, including end-to-end chromosome fusions and greater loss of telomere repeat DNA compared with Terc mutants. These findings indicate that telomere dysfunction may contribute to the pathogenesis of Werner syndrome and Bloom syndrome.},
}
@article {pmid15365172,
year = {2004},
author = {Bankhead, T and Chaconas, G},
title = {Mixing active-site components: a recipe for the unique enzymatic activity of a telomere resolvase.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {101},
number = {38},
pages = {13768-13773},
pmid = {15365172},
issn = {0027-8424},
mesh = {Amino Acid Sequence ; Bacterial Proteins/chemistry/metabolism ; Base Sequence ; Binding Sites ; Borrelia burgdorferi/enzymology ; Endodeoxyribonucleases/*chemistry/*metabolism ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Oligodeoxyribonucleotides ; Protein Conformation ; Recombinant Proteins/chemistry/metabolism ; Telomere/metabolism ; },
abstract = {The ResT protein, a telomere resolvase from Borrelia burgdorferi, processes replication intermediates into linear replicons with hairpin ends by using a catalytic mechanism similar to that for tyrosine recombinases and type IB topoisomerases. We have identified in ResT a hairpin binding region typically found in cut-and-paste transposases. We show that substitution of residues within this region results in a decreased ability of these mutants to catalyze telomere resolution. However, the mutants are capable of resolving heteroduplex DNA substrates designed to allow spontaneous destabilization and prehairpin formation. These findings support the existence of a hairpin binding region in ResT, the only known occurrence outside a transposase. The combination of transposase-like and tyrosine-recombinase-like domains found in ResT indicates the use of a composite active site and helps explain the unique breakage-and-reunion reaction observed with this protein. Comparison of the ResT sequence with other known telomere resolvases suggests that a hairpin binding motif is a common feature in this class of enzyme; the sequence motif also appears in the RAG recombinases. Finally, our data support a mechanism of action whereby ResT induces prehairpin formation before the DNA cleavage step.},
}
@article {pmid15361381,
year = {2004},
author = {Salonen, EM and Miettinen, A and Walle, TK and Koskenmies, S and Kere, J and Julkunen, H},
title = {Anti-telomere antibodies in systemic lupus erythematosus (SLE): a comparison with five antinuclear antibody assays in 430 patients with SLE and other rheumatic diseases.},
journal = {Annals of the rheumatic diseases},
volume = {63},
number = {10},
pages = {1250-1254},
pmid = {15361381},
issn = {0003-4967},
mesh = {Adult ; Aged ; Aged, 80 and over ; Antibodies, Antinuclear/*blood ; Autoimmune Diseases/diagnosis/immunology ; Biomarkers/blood ; Diagnosis, Differential ; Enzyme-Linked Immunosorbent Assay/methods ; Female ; Humans ; Lupus Erythematosus, Systemic/*diagnosis/immunology ; Lupus Nephritis/diagnosis/immunology ; Male ; Middle Aged ; Predictive Value of Tests ; Rheumatic Diseases/diagnosis/immunology ; Sensitivity and Specificity ; Telomere/*immunology ; },
abstract = {OBJECTIVE: To investigate the prevalence and diagnostic significance of antibodies against telomeric DNA in systemic lupus erythematosus (SLE) and other autoimmune rheumatic diseases, and to make comparisons with five conventional anti-DNA or anti-nuclear antibody (ANA) assays.<br><br>METHODS: Antibodies to telomeres, which are highly repetitive sequences of DNA (TTAGGG/CCCTAA) at the end of eukaryotic chromosomes, were measured by an enzyme linked immunosorbent assay (ELISA) in 305 patients with SLE and 125 patients with other autoimmune rheumatic diseases (78 rheumatoid arthritis, 32 primary Sj&#xf6;gren's syndrome, eight mixed connective tissue disease, seven miscellaneous rheumatic diseases). Other assays used were two commercial ELISA assays for anti-dsDNA using calf thymus as antigen, Crithidialuciliae immunofluorescence, and radioimmunoassay (RIA) for anti-dsDNA and immunofluorescence using Hep-2 cells for ANA.<br><br>RESULTS: The prevalence of anti-telomere in SLE was 60%, v 5% in rheumatoid arthritis and 18% in other autoimmune rheumatic diseases. Specificity of anti-telomere for SLE was 91%; positive and negative predictive values were 95% and 46%, respectively. For anti-dsDNA by two ELISA assays using calf thymus as antigen, sensitivities were 69% and 29% and specificities 66% and 96%, respectively. Other anti-dsDNA assays had low sensitivities (RIA 43%, Crithidia immunofluorescence 13%). The association of anti-telomere with a history of nephritis in patients with SLE was stronger (p = 0.005) than by any other assay (p = 0.006-0.999). The correlations between the different assays were good (p<0.001 for all comparisons).<br><br>CONCLUSIONS: The new ELISA for anti-telomere antibodies using standardised human dsDNA as antigen is a sensitive and highly specific test for SLE.},
}
@article {pmid15359282,
year = {2004},
author = {Xhemalce, B and Seeler, JS and Thon, G and Dejean, A and Arcangioli, B},
title = {Role of the fission yeast SUMO E3 ligase Pli1p in centromere and telomere maintenance.},
journal = {The EMBO journal},
volume = {23},
number = {19},
pages = {3844-3853},
pmid = {15359282},
issn = {0261-4189},
mesh = {Amino Acid Sequence ; Centromere/*physiology ; Chromosomes, Fungal/metabolism ; Genes, Reporter/physiology ; Heterochromatin/*physiology ; Ligases ; Mitosis/drug effects ; Molecular Sequence Data ; Phenotype ; Point Mutation/genetics ; Recombination, Genetic ; Schizosaccharomyces/*physiology ; Schizosaccharomyces pombe Proteins/*physiology ; Sequence Deletion ; Sequence Homology, Amino Acid ; Small Ubiquitin-Related Modifier Proteins/*physiology ; Telomere/*physiology ; Ubiquitin-Protein Ligases/*physiology ; },
abstract = {Sumoylation represents a conserved mechanism of post-translational protein modification. We report that Pli1p, the unique fission yeast member of the SP-RING family, is a SUMO E3 ligase in vivo and in vitro. pli1Delta cells display no obvious mitotic growth defects, but are sensitive to the microtubule-destabilizing drug TBZ and exhibit enhanced minichromosome loss. The weakened centromeric function of pli1Delta cells may be related to the defective heterochromatin structure at the central core, as shown by the reduced silencing of an ura4 variegation reporter gene inserted at cnt and imr. Interestingly, pli1Delta cells also exhibit enhanced loss of the ura4 reporter at these loci, likely by gene conversion using homologous sequences as information donors. Moreover, pli1Delta cells exhibit consistent telomere length increase, possibly achieved by a similar process. Point mutations within the RING finger of Pli1p totally or partially reproduce the pli1 deletion phenotypes, thus correlating with their sumoylation activity. Altogether, these results strongly suggest that Pli1p, and by extension sumoylation, is involved in mechanisms that regulate recombination in particular heterochromatic repeated sequences.},
}
@article {pmid15355785,
year = {2004},
author = {Bekaert, S and Derradji, H and Baatout, S},
title = {Telomere biology in mammalian germ cells and during development.},
journal = {Developmental biology},
volume = {274},
number = {1},
pages = {15-30},
doi = {10.1016/j.ydbio.2004.06.023},
pmid = {15355785},
issn = {0012-1606},
mesh = {Aging/*physiology ; Animals ; DNA Repair ; Germ Cells/*physiology ; Humans ; Longevity ; Mammals/*embryology ; Meiosis/physiology ; Neural Tube Defects/etiology ; Reproduction/physiology ; Telomerase/metabolism ; Telomere/metabolism/*physiology ; Telomere-Binding Proteins/metabolism ; },
abstract = {The development of an organism is a strictly regulated program in which controlled gene expression guarantees the establishment of a specific phenotype. The chromosome termini or so-called telomeres preserve the integrity of the genome within developing cells. In the germline, during early development, and in highly proliferative organs, human telomeres are balanced between shortening processes with each cell division and elongation by telomerase, but once terminally differentiated or mature the equilibrium is shifted to gradual shortening by repression of the telomerase enzyme. Telomere length is to a large extent genetically determined and the neonatal telomere length equilibrium is, in fact, a matter of evolution. Gradual telomere shortening in normal human somatic cells during consecutive rounds of replication eventually leads to critically short telomeres that induce replicative senescence in vitro and probably in vivo. Hence, a molecular clock is set during development, which determines the replicative potential of cells during extrauterine life. Telomeres might be directly or indirectly implicated in longevity determination in vivo, and information on telomere length setting in utero and beyond should help elucidate presumed causal connections between early growth and aging disorders later in life. Only limited information exists concerning the mechanisms underlying overall telomere length regulation in the germline and during early development, especially in humans. The intent of this review is to focus on recent advances in our understanding of telomere biology in germline cells as well as during development (pre- and postimplantation periods) in an attempt to summarize our knowledge about telomere length determination and its importance for normal development in utero and the occurrence of the aging and abnormal phenotype later on.},
}
@article {pmid15353591,
year = {2004},
author = {Bao, K and Cohen, SN},
title = {Reverse transcriptase activity innate to DNA polymerase I and DNA topoisomerase I proteins of Streptomyces telomere complex.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {101},
number = {40},
pages = {14361-14366},
pmid = {15353591},
issn = {0027-8424},
support = {R01 AI008619/AI/NIAID NIH HHS/United States ; AI 08619/AI/NIAID NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Base Sequence ; DNA Polymerase I/genetics/*metabolism ; DNA Topoisomerases, Type I/genetics/*metabolism ; DNA, Bacterial/genetics ; Escherichia coli/enzymology/genetics ; Genes, Bacterial ; Molecular Sequence Data ; Mutagenesis ; RNA-Directed DNA Polymerase/genetics/*metabolism ; Sequence Homology, Amino Acid ; Streptomyces/*enzymology/genetics ; Telomere/*enzymology ; },
abstract = {Replication of Streptomyces linear chromosomes and plasmids proceeds bidirectionally from a central origin, leaving recessed 5' termini that are extended by a telomere binding complex. This complex contains both a telomere-protecting terminal protein (Tpg) and a telomere-associated protein that interacts with Tpg and the DNA ends of linear Streptomyces replicons. By using histidine-tagged telomere-associated protein (Tap) as a scaffold, we identified DNA polymerase (PolA) and topoisomerase I (TopA) proteins as other components of the Streptomyces telomere complex. Biochemical characterization of these proteins indicated that both PolA and TopA exhibit highly efficient reverse transcriptase (RT) activity in addition to their predicted functions. Although RT activity innate to other DNA-dependent DNA polymerases has been observed previously, its occurrence in a topoisomerase is unprecedented. Deletion mapping and sequence analysis showed that the RT activity of Streptomcyces TopA resides in a peptide region containing motifs that are absent from most bacterial topoisomerases but are highly conserved in a novel subfamily of eubacterial topoisomerases found largely in Actinobacteria. Within one of these motifs, and essential to the RT function of Streptomyces TopA, is an Asp-Asp doublet sequence required also for the RT activities of human immunodeficiency virus and eukaryotic cell telomerases.},
}
@article {pmid15349787,
year = {2004},
author = {Yan, J and Chen, BZ and Bouchard, EF and Drouin, R},
title = {The labeling efficiency of human telomeres is increased by double-strand PRINS.},
journal = {Chromosoma},
volume = {113},
number = {4},
pages = {204-209},
pmid = {15349787},
issn = {0009-5915},
mesh = {Adult ; DNA Primers/chemistry ; Humans ; Indicators and Reagents ; Microscopy, Fluorescence ; Primed In Situ Labeling/*methods ; Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry/ultrastructure ; Temperature ; },
abstract = {Telomeres are composed of tandem repeated sequences, TTAGGG, that can be detected either by fluorescence in situ hybridization (FISH), more efficiently by using a peptide nucleic acid (PNA) probe, or by the primed in situ (PRINS) technique. However, the efficiency of human telomere labeling using PRINS is somewhat lower than the efficiency using PNA-FISH. To solve this problem, we developed a double-strand PRINS technique, which uses two primers, (TTAGGG)(7) and (CCCTAA)(7), to label both forward and reverse telomeric DNA strands. A total of 120 lymphocyte metaphases obtained from three normal adults were scored to evaluate the labeling efficiency based upon the telomere signal frequency present in chromatid ends and chromosome arms. As a comparison, 30 metaphases from the same three individuals were evaluated using PNA-FISH. The average labeling efficiency of PRINS was increased to a level very close to that obtained with PNA-FISH. Therefore, we demonstrated that the low labeling efficiency of human telomeres with regular PRINS was likely caused by uneven annealing of primers at the relatively short human telomere sequences, resulting in some telomere sites with very weak or absent labeling. We suggest that the present double-strand labeling protocol is critical to maximize the labeling efficiency of the human telomere sequence when using the PRINS technique.},
}
@article {pmid15343372,
year = {2004},
author = {Akbar, AN and Beverley, PC and Salmon, M},
title = {Will telomere erosion lead to a loss of T-cell memory?.},
journal = {Nature reviews. Immunology},
volume = {4},
number = {9},
pages = {737-743},
doi = {10.1038/nri1440},
pmid = {15343372},
issn = {1474-1733},
mesh = {Adult ; Aged ; Animals ; Cellular Senescence/immunology ; Communicable Diseases/immunology ; Humans ; Immunologic Memory/genetics/*immunology ; Mice ; T-Lymphocytes/*immunology ; Telomere/*genetics/immunology ; },
abstract = {Evidence is accumulating that elderly individuals are more susceptible to infection with organisms to which they were previously immune. This indicates that there might be a limit to the persistence of immune memory. This fact is particularly disturbing because the average life expectancy of humans has almost doubled in the past 200 years and is still increasing. We discuss mechanisms that might constrain the persistence of memory T cells and consider whether humans will suffer from memory T-cell exhaustion as life expectancy increases.},
}
@article {pmid15342932,
year = {2004},
author = {Baxter, MA and Wynn, RF and Jowitt, SN and Wraith, JE and Fairbairn, LJ and Bellantuono, I},
title = {Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion.},
journal = {Stem cells (Dayton, Ohio)},
volume = {22},
number = {5},
pages = {675-682},
doi = {10.1634/stemcells.22-5-675},
pmid = {15342932},
issn = {1066-5099},
mesh = {Bone Marrow Cells/*metabolism ; Cell Culture Techniques/methods ; Cell Differentiation/genetics ; Cell Division/*genetics ; Cells, Cultured ; Cellular Senescence/*genetics ; Humans ; Kinetics ; Longevity/genetics ; Mesenchymal Stem Cell Transplantation/methods ; Mesenchymal Stem Cells/*metabolism ; Osteocytes/metabolism ; Osteogenesis/genetics ; Stromal Cells/metabolism ; Telomere/*genetics ; },
abstract = {Human marrow stromal cells (MSCs) can be isolated from bone marrow and differentiate into multiple tissues in vitro and in vivo. These properties make them promising tools in cell and gene therapy. The lack of a specific MSC marker and the low frequency of MSCs in bone marrow necessitate their isolation by in vitro expansion prior to clinical use. This may severely reduce MSC proliferative capacity to the point that the residual proliferative potential is insufficient to maintain long-term tissue regeneration upon reinfusion. In this study we determined the effect of in vitro expansion on the replicative capacity of MSCs by correlating their rate of telomere loss during in vitro expansion with their behavior in vivo. We report that even protocols that involve minimal expansion induce a rapid aging of MSCs, with losses equivalent to about half their total replicative lifespan.},
}
@article {pmid15342136,
year = {2004},
author = {Dabouras, V and Rothermel, A and Reininger-Mack, A and Wien, SL and Layer, PG and Robitzki, AA},
title = {Exogenous application of glucose induces aging in rat cerebral oligodendrocytes as revealed by alteration in telomere length.},
journal = {Neuroscience letters},
volume = {368},
number = {1},
pages = {68-72},
doi = {10.1016/j.neulet.2004.06.066},
pmid = {15342136},
issn = {0304-3940},
mesh = {Aging/*drug effects ; Animals ; Blotting, Western ; Cerebral Cortex/*cytology/drug effects/ultrastructure ; Culture Media ; DNA/genetics ; Enzyme-Linked Immunosorbent Assay ; Glucose/*pharmacology ; Immunohistochemistry ; Nerve Growth Factors/metabolism ; Netrin-1 ; Oligodendroglia/*drug effects/metabolism/ultrastructure ; Rats ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/drug effects/metabolism/*ultrastructure ; Tumor Suppressor Proteins ; ras Proteins/metabolism ; },
abstract = {To investigate aspects of aging on rat oligodendrocytes, cells of an oligodendrocyte cell line, so-called OLN-93, were cultured either in the presence or absence of glucose. Our data demonstrated that glucose-induced aging in vitro caused an elongation and thickening of cell processes and significantly increased the expression of netrin reflecting a more mature state of oligodendrocyte development. A possible age-inducing effect of glucose is also supported by the decrease of ras protein expression and shortening of telomeres in glucose-treated oligodendrocytes. The present study clearly shows that OLN-93 cells are an exciting and suitable model system for the investigation of age-inducing molecules and the analysis of signaling pathways involved in cerebral aging and degenerations.},
}
@article {pmid15341904,
year = {2004},
author = {Callén, E and Surrallés, J},
title = {Telomere dysfunction in genome instability syndromes.},
journal = {Mutation research},
volume = {567},
number = {1},
pages = {85-104},
doi = {10.1016/j.mrrev.2004.06.003},
pmid = {15341904},
issn = {0027-5107},
mesh = {Animals ; Ataxia Telangiectasia/*genetics ; DNA Damage ; DNA Repair ; *Genome ; Genomic Instability ; Humans ; *Mutation ; Syndrome ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {Telomeres are nucleoprotein complexes located at the end of eukaryotic chromosomes. They have essential roles in preventing terminal fusions, protecting chromosome ends from degradation, and in chromosome positioning in the nucleus. These terminal structures consist of a tandemly repeated DNA sequence (TTAGGG in vertebrates) that varies in length from 5 to 15 kb in humans. Several proteins are attached to this telomeric DNA, some of which are also involved in different DNA damage response pathways, including Ku80, Mre11, NBS and BLM, among others. Mutations in the genes encoding these proteins cause a number of rare genetic syndromes characterized by chromosome and/or genetic instability and cancer predisposition. Deletions or mutations in any of these genes may also cause a telomere defect resulting in accelerated telomere shortening, lack of end-capping function, and/or end-to-end chromosome fusions. This telomere phenotype is also known to promote chromosomal instability and carcinogenesis. Therefore, it is essential to understand the interplay between telomere biology and genome stability. This review is focused in the dual role of chromosome fragility proteins in telomere maintenance.},
}
@article {pmid15341022,
year = {2004},
author = {Londoño-Vallejo, JA},
title = {Telomere length heterogeneity and chromosome instability.},
journal = {Cancer letters},
volume = {212},
number = {2},
pages = {135-144},
doi = {10.1016/j.canlet.2004.05.008},
pmid = {15341022},
issn = {0304-3835},
mesh = {Alleles ; Blotting, Southern ; *Chromosome Aberrations ; Chromosomes/*ultrastructure ; Humans ; Karyotyping ; Polymorphism, Genetic ; Telomere/*ultrastructure ; },
abstract = {Chromosome aberrations are the hallmark of cancer cells. Although a few specific chromosome aberrations are frequently detected in some types of cancer, the majority of karyotypic abnormalities tend to differ between different histological types and between individuals with the same type of cancer. Recent work indicates that telomeres may be directly involved in shaping the karyotypes of tumor cells. In particular, the heterogeneity of telomere lengths within cells may have direct influence on the frequency with which chromosomes engage in telomeric fusions and in subsequent breakage-fusion-bridge cycles. Since telomere length distribution among chromosome arms is a polymorphic trait, difference in distributions between individuals may account, at least in part, for the karyotypic differences found among tumors of the same type. Conversely, if single telomere lengths happen to be inherited, the segregation of particularly short telomeres in families may increase the incidence of specific chromosome aberrations during tumor evolution, and perhaps contribute, along with other factors, to cancer pre-disposition.},
}
@article {pmid15338723,
year = {2002},
author = {Parwaresch, R and Krupp, G},
title = {Telomere biology and the molecular basis of aging.},
journal = {Arkhiv patologii},
volume = {64},
number = {3},
pages = {37-39},
pmid = {15338723},
issn = {0004-1955},
mesh = {*Aging/genetics/pathology/physiology ; Animals ; Cell Cycle/physiology ; Humans ; Mutation ; Neoplasms/enzymology ; *Telomere/enzymology ; },
abstract = {Process of aging is regulated on the level of organism, clones and cellular level. Genes regulating aging on the individual (organism) level are detected in unicellular fungi. Mutations of such genes may lead to life lengthening by 60%. A similar gene is found in mice. Aging at the clonal level takes place by means of telomere shortening--that of DNA regions close to chromosome endings. Telomere shortening results in the chromosomes instability, their breaks and mutations, this apparently being a mechanism responsible for the increase of cancer incidence at advanced age. Telomerase is an enzyme responsible for the stability of the telomere length, supporting proliferation and by this that of life. This explains the increase of telomerase activity practically in all cases of malignant tumors. Aging is regulated by molecular components of cell cycle on cellular level.},
}
@article {pmid15336914,
year = {2004},
author = {Leach, NT and Rehder, C and Jensen, K and Holt, S and Jackson-Cook, C},
title = {Human chromosomes with shorter telomeres and large heterochromatin regions have a higher frequency of acquired somatic cell aneuploidy.},
journal = {Mechanisms of ageing and development},
volume = {125},
number = {8},
pages = {563-573},
doi = {10.1016/j.mad.2004.06.006},
pmid = {15336914},
issn = {0047-6374},
support = {R01 ES012074/ES/NIEHS NIH HHS/United States ; R01 ES12074/ES/NIEHS NIH HHS/United States ; },
mesh = {Adult ; *Aneuploidy ; Chromosomes/*ultrastructure ; Chromosomes, Human, X/ultrastructure ; DNA/genetics ; Female ; Flow Cytometry ; Heterochromatin/*ultrastructure ; Humans ; Lymphocytes/ultrastructure ; Metaphase ; Middle Aged ; Mouth Mucosa/cytology/ultrastructure ; Peptide Nucleic Acids/chemistry ; Telomere/*ultrastructure ; },
abstract = {Both telomere shortening and increases in aneuploidy frequencies have been associated with aging. To test if these chromosomal attributes are correlated, chromosome-specific telomere lengths and aneuploidy frequencies were estimated and compared. Aneuploidy frequencies were determined for 10 autosomes (1, 3, 5, 8, 9, 10, 13, 16, 17, 21) and the X chromosome in lymphocytes, and for chromosomes 17 and X in buccal mucosa cells. Overall, chromosomal loss was seen more often than gain in lymphocytes, with the highest loss rates being observed for chromosomes X (3.03%), 17 (2.00%), and the autosomes having large blocks of heterochromatin (1 [1.93%]; 16 [1.53%]; and 9 [1.05%]). The frequencies of loss were significantly lower in the buccal mucosa cells compared to lymphocytes for chromosomes 17 (P = 0.006) and X (P = 0.003). However, the chromosome 17 trisomy frequencies did not vary between tissues. Using a semi-quantitative FISH assay to estimate chromosome-specific telomere length, a significant negative correlation (r = -0.379; P = 0.007) was seen for chromosomal aneuploidy and telomere length, with chromosomes having higher loss rates being noted to have shorter telomeres. Collectively, these studies show that acquired, spontaneous chromosomal loss is associated with multiple factors including the amount of heterochromatin, the chromosome's telomere length, and tissue-specific factors.},
}
@article {pmid15336455,
year = {2004},
author = {Lechel, A and Manns, MP and Rudolph, KL},
title = {Telomeres and telomerase: new targets for the treatment of liver cirrhosis and hepatocellular carcinoma.},
journal = {Journal of hepatology},
volume = {41},
number = {3},
pages = {491-497},
doi = {10.1016/j.jhep.2004.06.010},
pmid = {15336455},
issn = {0168-8278},
mesh = {Carcinoma, Hepatocellular/drug therapy/*enzymology/*genetics ; Chromosomal Instability ; DNA Replication Timing ; Enzyme Activation/drug effects ; Enzyme Inhibitors/therapeutic use ; Humans ; Liver Cirrhosis/drug therapy/*enzymology/*genetics ; Liver Neoplasms/drug therapy/*enzymology/*genetics ; Telomerase/antagonists &amp; inhibitors/*metabolism ; Telomere/*genetics ; },
}
@article {pmid15333580,
year = {2004},
author = {Puri, N and Eller, MS and Byers, HR and Dykstra, S and Kubera, J and Gilchrest, BA},
title = {Telomere-based DNA damage responses: a new approach to melanoma.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {18},
number = {12},
pages = {1373-1381},
doi = {10.1096/fj.04-1774com},
pmid = {15333580},
issn = {1530-6860},
support = {R03 AR050110-02/AR/NIAMS NIH HHS/United States ; },
mesh = {Animals ; Apoptosis/drug effects ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Damage/drug effects/*genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Melanoma/drug therapy/*genetics/*pathology ; Mice ; Mice, SCID ; Neoplasm Metastasis/drug therapy/pathology ; Oligodeoxyribonucleotides/administration &amp; dosage/genetics/*pharmacology/therapeutic use ; Telomere/*genetics ; },
abstract = {Melanoma is the most fatal skin cancer, often highly resistant to chemotherapy. Here we show that treatment with an 11-base DNA oligonucleotide homologous to the telomere 3' overhang sequence (T-oligo) induces apoptosis of several established human melanoma cell lines, including the aggressive MM-AN line, whereas normal human melanocytes exposed to the same or higher T-oligo concentrations show only transient cell cycle arrest, implying that malignant cells are more sensitive to T-oligo effects. When MM-AN cells were briefly exposed to T-oligo in culture and injected into the flank or tail vein of SCID mice, eventual tumor volume and number of metastases were reduced 85-95% compared with control mice. Similarly, T-oligos administered intralesionally or systemically selectively inhibited the growth of previously established MM-AN tumor nodules in the flank and peritoneal cavity by 85 to 90% without detectable toxicity. We previously showed that T-oligos act through ATM, p95/Nbs1, E2F1, p16INK4A, p53, and the p53 homologue p73 to modulate downstream effectors and now additionally demonstrate striking down-regulation of the inhibitor of apoptosis protein livin/ML-IAP. We suggest that T-oligo mimics a physiologic DNA damage signal that is frequently masked in malignant cells and thereby activates innate cancer prevention responses. T-oligos may provide a novel therapeutic approach to melanoma.},
}
@article {pmid15328403,
year = {2004},
author = {Putnam, CD and Pennaneach, V and Kolodner, RD},
title = {Chromosome healing through terminal deletions generated by de novo telomere additions in Saccharomyces cerevisiae.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {101},
number = {36},
pages = {13262-13267},
pmid = {15328403},
issn = {0027-8424},
support = {R01 GM026017/GM/NIGMS NIH HHS/United States ; R37 GM026017/GM/NIGMS NIH HHS/United States ; GM26017/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosome Aberrations ; *Chromosome Deletion ; Saccharomyces cerevisiae/*genetics ; Telomerase/physiology ; *Telomere ; },
abstract = {Broken chromosomes healed by de novo addition of a telomere are a major class of genome rearrangements seen in Saccharomyces cerevisiae and similar to rearrangements seen in human tumors. We have analyzed the sequences of 534 independent de novo telomere additions within a 12-kb region of chromosome V. The distribution of events mirrored that of four-base sequences consisting of the GG, GT, and TG dinucleotides, suggesting that de novo telomere additions occur at short regions of homology to the telomerase guide RNA. These chromosomal sequences restrict potential registrations of the added telomere sequence. The first 11 nucleotides of the addition sequences fell into common families that included 91% of the breakpoints. The observed registrations suggest that the 3' end of the TLC1 guide RNA is involved in annealing but not as a template for synthesis. Some families of added sequences can be accounted for by one cycle of annealing and extension, whereas others require a minimum of two. The same pattern emerges for sequences added onto the most common addition sequence, indicating that de novo telomeres are added and extended by the same process. Together, these data indicate that annealing is central to telomerase registration, which limits telomere heterogeneity and resolves the problem of synthesizing Rap1 binding sites by a nonprocessive telomerase with a low-complexity guide RNA sequence.},
}
@article {pmid15326479,
year = {2004},
author = {Dudognon, C and Pendino, F and Hillion, J and Saumet, A and Lanotte, M and Ségal-Bendirdjian, E},
title = {Death receptor signaling regulatory function for telomerase: hTERT abolishes TRAIL-induced apoptosis, independently of telomere maintenance.},
journal = {Oncogene},
volume = {23},
number = {45},
pages = {7469-7474},
doi = {10.1038/sj.onc.1208029},
pmid = {15326479},
issn = {0950-9232},
mesh = {Apoptosis/*physiology ; Apoptosis Regulatory Proteins ; DNA-Binding Proteins ; Green Fluorescent Proteins ; Humans ; Luminescent Proteins/metabolism ; Membrane Glycoproteins/*antagonists &amp; inhibitors/physiology ; Receptors, Tumor Necrosis Factor/metabolism/*physiology ; *Signal Transduction ; TNF-Related Apoptosis-Inducing Ligand ; Telomerase/*metabolism/*physiology ; *Telomere ; Tretinoin/pharmacology ; Tumor Necrosis Factor-alpha/*antagonists &amp; inhibitors/physiology ; },
abstract = {Human telomerase has been implicated in cell immortalization and cancer. Recent works suggest that telomerase confers additional function required for tumorigenesis that does not depend on its ability to maintain telomeres. This new action may influence tumor therapy outcomes by yet unraveled mechanisms. Here, we show that overexpression of the catalytic subunit of telomerase (hTERT) protects a maturation-resistant acute promyelocytic leukemia (APL) cell line from apoptosis induced by the tumor necrosis factor (TNF) or TNF-related apoptosis-inducing ligand (TRAIL) and not from apoptosis induced by chemotherapeutic drugs such as etoposide or cisplatin. Conversely, in these cells, TRAIL-induced cell death is magnified by all-trans retinoic acid (ATRA) treatment, independently of telomerase activity on telomeres. Of note, this response is subordinated neither to maturation nor to telomere shortening. This work underlines that retinoids and death receptor signaling cross-talks offer new perspectives for antitumor therapy.},
}
@article {pmid15326395,
year = {2004},
author = {Jeyapalan, J and Leake, A and Ahmed, S and Saretzki, G and Tilby, M and von Zglinicki, T},
title = {The role of telomeres in Etoposide induced tumor cell death.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {3},
number = {9},
pages = {1169-1176},
pmid = {15326395},
issn = {1551-4005},
mesh = {Adaptation, Physiological/drug effects/physiology ; Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/*drug effects/physiology ; Cell Line, Tumor ; DNA/drug effects/physiology ; DNA Damage/drug effects/physiology ; DNA Topoisomerases, Type II/metabolism ; Dose-Response Relationship, Drug ; Etoposide/*pharmacology ; Genes, cdc/drug effects/physiology ; Humans ; Neoplasms/*drug therapy/genetics/metabolism ; Telomerase/*drug effects/metabolism ; Telomere/*drug effects/metabolism ; Topoisomerase II Inhibitors ; },
abstract = {Etoposide, a topoisomerase II poison is used in the treatment of a number of solid tumors. Contradictory data exist on the role of the telomere/telomerase complex in etoposide induced apoptosis. Therefore we examined the effects of etoposide treatment in the neuroblastoma cell line SHSY5Y, with very short telomeres and the acute lymphoblastic T cell line 1301, which displays extremely long telomeres. Both short-term and continuous exposure to the drug were examined. Etoposide induced widespread DNA damage followed by DNA damage foci formation and ultimately growth arrest and apoptosis in a concentration-dependent manner. However, length of telomeres and of single stranded telomeric G rich overhangs did not change significantly under the treatments in any cell line. There was no significant induction of single-strand breaks in the G-rich strand of telomeres. Telomerase activity was transiently upregulated under low concentrations of etoposide, while high concentrations resulted in decreased telomerase activity only after onset of apoptosis. Telomerase overexpression protected against etoposide induced apoptosis in fibroblasts. The data suggest that telomeres are not major signal transducers towards growth arrest or apoptosis after etoposide treatment. However, upregulation of telomerase might be part of an attempted adaptative response, which protects cells by a mechanism that might be independent of telomere length maintenance.},
}
@article {pmid15322275,
year = {2004},
author = {Zou, Y and Gryaznov, SM and Shay, JW and Wright, WE and Cornforth, MN},
title = {Asynchronous replication timing of telomeres at opposite arms of mammalian chromosomes.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {101},
number = {35},
pages = {12928-12933},
pmid = {15322275},
issn = {0027-8424},
support = {R01 AG007992/AG/NIA NIH HHS/United States ; AG07992/AG/NIA NIH HHS/United States ; CA76260/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; DNA Replication/*physiology ; Female ; In Situ Hybridization, Fluorescence ; Muntjacs/genetics/physiology ; S Phase/physiology ; Telomere/*genetics/physiology ; },
abstract = {Telomeres are defining structural elements of all linear chromosomes, yet information concerning the timing of their replication in higher eukaryotes is surprisingly limited. We developed an approach that allowed a study of telomere replication patterns of specific mammalian chromosomes. In the Indian muntjac (Muntiacus muntjac), replication timing between respective telomeres of homologous chromosomes was highly coordinated, but no such synchrony was evident for p- and q-arm telomeres of the same chromosome. This finding contrasts with the coordinated timing of both ends of each chromosome in yeast. Also in contrast to yeast, where replication of all telomeres is confined to late S phase, we found specific telomeres in Indian muntjac chromosomes that replicated early in S and other telomeres that replicated later. Finally, replication timing of some but not all telomeres was influenced by telomere length. Knowledge of telomere replication timing represents a first step toward understanding the relationship between telomere replication and telomerase action. The approach, which we call replicative detargeting fluorescence in situ hybridization, is widely applicable to different species and genetic loci.},
}
@article {pmid15322096,
year = {2004},
author = {Hao, LY and Strong, MA and Greider, CW},
title = {Phosphorylation of H2AX at short telomeres in T cells and fibroblasts.},
journal = {The Journal of biological chemistry},
volume = {279},
number = {43},
pages = {45148-45154},
doi = {10.1074/jbc.M403924200},
pmid = {15322096},
issn = {0021-9258},
support = {P01 CA16519/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Annexin A5/pharmacology ; Apoptosis ; Bromodeoxyuridine/pharmacology ; Cell Division ; Cell Separation ; Chromosomes/ultrastructure ; Coloring Agents/pharmacology ; DNA/chemistry ; DNA Damage ; Fibroblasts/*metabolism ; Flow Cytometry ; Histones/genetics/*metabolism ; Immunoblotting ; Karyotyping ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microscopy, Fluorescence ; Mitogens/chemistry ; Mitosis ; Phosphorylation ; Signal Transduction ; T-Lymphocytes/*metabolism/pathology ; Telomere/*metabolism/ultrastructure ; Time Factors ; Transgenes ; },
abstract = {Eukaryotic cells undergo arrest and enter apoptosis in response to short telomeres. T cells from late generation mTR(-/-) mice that lack telomerase show increased apoptosis when stimulated to enter the cell cycle. The increased apoptosis was not inhibited by colcemid, indicating that the response did not result from breakage of dicentric chromosomes at mitosis. The damage response protein gamma-H2AX localized to telomeres in metaphases from T cells and fibroblasts from mTR(-/-) cells with short telomeres. These data suggest that the major mechanism for induction of apoptosis in late generation mTR(-/-) cells is independent of chromosome segregation and that loss of telomere function through progressive telomere shortening in the absence of telomerase leads to recognition of telomeres as DNA breaks.},
}
@article {pmid15319283,
year = {2004},
author = {Franco, S and van de Vrugt, HJ and Fernández, P and Aracil, M and Arwert, F and Blasco, MA},
title = {Telomere dynamics in Fancg-deficient mouse and human cells.},
journal = {Blood},
volume = {104},
number = {13},
pages = {3927-3935},
doi = {10.1182/blood-2003-10-3626},
pmid = {15319283},
issn = {0006-4971},
mesh = {Animals ; Base Sequence ; DNA Primers ; DNA Repair/genetics ; DNA-Binding Proteins/deficiency/*genetics ; Fanconi Anemia/genetics ; Fanconi Anemia Complementation Group G Protein ; Fibroblasts/physiology ; Hematopoietic Stem Cells/physiology ; Humans ; Mice ; Mice, Knockout ; Polymerase Chain Reaction ; RNA/genetics/metabolism ; Spleen/cytology/physiology ; Telomerase/deficiency/genetics/metabolism ; Telomere/*genetics ; },
abstract = {A number of DNA repair proteins also play roles in telomere metabolism. To investigate whether the accelerated telomere shortening reported in Fanconi anemia (FA) hematopoietic cells relates to a direct role of the FA pathway in telomere maintenance, we have analyzed telomere dynamics in Fancg-deficient mouse and human cells. We show here that both hematopoietic (stem and differentiated bone marrow cells, B and T lymphocytes) and nonhematopoietic (germ cells, mouse embryonic fibroblasts [MEFs]) Fancg(-/-) mouse cells display normal telomere length, normal telomerase activity, and normal chromosome end-capping, even in the presence of extensive clastogen-induced cytogenetic instability (mitomycin C [MMC], gamma-radiation). In addition, telomerase-deficient MEFs with humanlike telomere length and decreased Fancg expression (G5 Terc(-/-)/Fancg shRNA3 MEFs) display normal telomere maintenance. Finally, early-passage primary fibroblasts from patients with FA of complementation group G as well as primary human cells with reduced FANCG expression (FANCG shRNA IMR90 cells) show no signs of telomere dysfunction. Our observations indicate that accelerated telomere shortening in patients with FA is not due to a role of FANCG at telomeres but instead may be secondary to the disease. These findings suggest that telomerase-based therapies could be useful prophylactic agents in FA aplastic anemia by preserving their telomere reserve in the context of the disease.},
}
@article {pmid15318175,
year = {2004},
author = {Zhang, A and Wang, J and Zheng, B and Fang, X and Angström, T and Liu, C and Li, X and Erlandsson, F and Björkholm, M and Nordenskjörd, M and Gruber, A and Wallin, KL and Xu, D},
title = {Telomere attrition predominantly occurs in precursor lesions during in vivo carcinogenic process of the uterine cervix.},
journal = {Oncogene},
volume = {23},
number = {44},
pages = {7441-7447},
doi = {10.1038/sj.onc.1207527},
pmid = {15318175},
issn = {0950-9232},
mesh = {DNA Damage ; DNA-Binding Proteins ; Female ; Humans ; Neoplasm Invasiveness ; Precancerous Conditions/*genetics ; Telomerase/genetics ; Telomere/*genetics ; Uterine Cervical Neoplasms/*genetics/pathology ; Uterine Cervical Dysplasia/genetics ; },
abstract = {Although human papillomavirus (HPV) has been defined as the pathogen for cervical carcinomas, molecular events underlying the oncogenic process are unclear. As telomere dysfunction-mediated chromosomal instability and telomerase activation have been suggested as key events in carcinogenesis, we dissected the dynamic changes in telomere length, checkpoint response, and temporal profile of telomerase expression during the evolution from precursor lesions (cervical intraepithelial neoplasia, CINs) to invasive cancers of the uterine cervix in sequential samples from 16 patients. Telomeres were significantly shortened in all CIN samples and no further substantial attritions occurred in most cases with the acquisition of malignant phenotype. Very short telomeres were coupled with constitutive activation of the DNA damage response pathway (Chk2 phosphorylation) and increased cellular proliferation in those cervical specimens. Telomerase reverse transcriptase (hTERT) expression was preferably induced at advanced CINs or invasive cancers. The present finding demonstrates that excessive telomere shortening predominantly occurs in the early carcinogenesis of the uterine cervix largely prior to telomerase activation. Widespread over-erosion of telomeres or telomere dysfunction in very early stages of cervical tumorigenesis might fuel transformation processes by driving chromosomal instability.},
}
@article {pmid15316974,
year = {2004},
author = {Huang, B and Martin, CL and Sandlin, CJ and Wang, S and Ledbetter, DH},
title = {Mitotic and meiotic instability of a telomere association involving the Y chromosome.},
journal = {American journal of medical genetics. Part A},
volume = {129A},
number = {2},
pages = {120-123},
doi = {10.1002/ajmg.a.30146},
pmid = {15316974},
issn = {1552-4825},
mesh = {Adult ; Amniocentesis ; Cell Division/*genetics ; Chromosomal Instability/*genetics ; Chromosomes, Human, Y/*genetics ; Female ; Hispanic or Latino ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Male ; Microsatellite Repeats/genetics ; Pregnancy ; Telomere/*genetics ; Translocation, Genetic/*genetics ; },
abstract = {Constitutional telomere associations and jumping translocations (JTs) are rare events and usually occur post-zygotically. We report a telomere association involving the Y chromosome which "jumped" during meiosis. A 21-year-old woman was referred for amniocentesis due to non-immune hydrops seen in a previous pregnancy. Cytogenetic analysis of the amniocytes showed a 45,X,tas(Y;15)[4]/45,X[16] karyotype with the long arm of the Y chromosome attached to the end of the short arm of chromosome 15. Parental chromosome analyzes revealed a tas(Y;19)[63]/45,X[7] karyotype in the father with Yq attached to the end of the short arm of chromosome 19. A phenotypically normal male was born and blood chromosome analysis confirmed a 45,X,tas(Y;15)[39]/45,X[10]/46,XY[1] karyotype. Two other male children have 46,XY karyotypes, which further demonstrates the instability of the tas(Y;19) in meiosis. Fluorescence in situ hybridization (FISH) analysis with probes for theY-centromere, the Yqh region, the shared Xq/Yq telomere and SRY showed hybridization on the tas(Y;19) and tas(Y;15). A chromosome 19p specific subtelomeric probe showed hybridization to the tas(Y;19) in the father. In addition, a probe for the simple telomeric sequences TTAGGG showed positive hybridization to the junction of the associations. The presence of TTAGGG telomere repeats and unique telomere sequences indicate that the Y;15 and Y;19 associations occur with no detectable loss of any sequences. The interstitial telomere sequences at the junction of the telomere association may explain the mitotic and meiotic instability of the association.},
}
@article {pmid15316005,
year = {2004},
author = {Ye, JZ and Donigian, JR and van Overbeek, M and Loayza, D and Luo, Y and Krutchinsky, AN and Chait, BT and de Lange, T},
title = {TIN2 binds TRF1 and TRF2 simultaneously and stabilizes the TRF2 complex on telomeres.},
journal = {The Journal of biological chemistry},
volume = {279},
number = {45},
pages = {47264-47271},
doi = {10.1074/jbc.M409047200},
pmid = {15316005},
issn = {0021-9258},
support = {GM49069/GM/NIGMS NIH HHS/United States ; K08CA93604/CA/NCI NIH HHS/United States ; RR00862/RR/NCRR NIH HHS/United States ; },
mesh = {Antigens, Surface ; Blotting, Western ; Cell Adhesion Molecules/*chemistry/metabolism ; Cell Nucleus/metabolism ; Chromatography, Gel ; DNA Damage ; Electrophoresis, Polyacrylamide Gel ; Escherichia coli/metabolism ; Gene Deletion ; Glutathione Transferase/metabolism ; Green Fluorescent Proteins/metabolism ; HeLa Cells ; Humans ; Immunoprecipitation ; Mass Spectrometry ; Membrane Glycoproteins/*chemistry/metabolism ; Phenotype ; Protein Binding ; Protein Structure, Tertiary ; RNA Interference ; RNA, Small Interfering/metabolism ; Telomere/metabolism/*ultrastructure ; Telomeric Repeat Binding Protein 1/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; Two-Hybrid System Techniques ; beta-Galactosidase/metabolism ; },
abstract = {Human telomeres contain two related telomeric DNA-binding proteins, TRF1 and TRF2. The TRF1 complex contains the TRF1 interacting partner, TIN2, as well as PIP1 and POT1 and regulates telomere-length homeostasis. The TRF2 complex is primarily involved in telomere protection and contains the TRF2 interacting partner human (h)Rap1 as well as several factors involved in the DNA damage response. A prior report showed that conditional deletion of murine TRF1 reduced the presence of TRF2 on telomeres. Here we showed that TRF2 is also lost from human telomeres upon TRF1 depletion with small interfering RNA prompting a search for the connection between the TRF1 and TRF2 complexes. Using mass spectrometry and co-immunoprecipitation, we found that TRF1, TIN2, PIP1, and POT1 are associated with the TRF2-hRap1 complex. Gel filtration identified a TRF2 complex containing TIN2 and POT1 but not TRF1 indicating that TRF1 is not required for this interaction. Co-immunoprecipitation, Far-Western assays, and two-hybrid assays showed that TIN2, but not POT1 or PIP1, interacts directly with TRF2. Furthermore, TIN2 was found to bind TRF1 and TRF2 simultaneously, showing that TIN2 can link these telomeric proteins. This connection appeared to stabilize TRF2 on the telomeres as the treatment of cells with TIN2 small interfering RNA resulted in a decreased presence of TRF2 and hRap1 at chromosome ends. The TIN2-mediated cooperative binding of TRF1 and TRF2 to telomeres has important implications for the mechanism of telomere length regulation and protection.},
}
@article {pmid15315667,
year = {2004},
author = {Nakagawa, S and Gemmell, NJ and Burke, T},
title = {Measuring vertebrate telomeres: applications and limitations.},
journal = {Molecular ecology},
volume = {13},
number = {9},
pages = {2523-2533},
doi = {10.1111/j.1365-294X.2004.02291.x},
pmid = {15315667},
issn = {0962-1083},
mesh = {Aging/*genetics ; Animals ; *Biological Evolution ; Conservation of Natural Resources ; Genetic Techniques ; Species Specificity ; Telomere/*genetics ; Vertebrates/*genetics ; },
abstract = {Telomeres are short tandem repeated sequences of DNA found at the ends of eukaryotic chromosomes that function in stabilizing chromosomal end integrity. In vivo studies of somatic tissue of mammals and birds have shown a correlation between telomere length and organismal age within species, and correlations between telomere shortening rate and lifespan among species. This result presents the tantalizing possibility that telomere length could be used to provide much needed information on age, ageing and survival in natural populations where longitudinal studies are lacking. Here we review methods available for measuring telomere length and discuss the potential uses and limitations of telomeres as age and ageing estimators in the fields of vertebrate ecology, evolution and conservation.},
}
@article {pmid15312299,
year = {2004},
author = {de Magalhães, JP and Toussaint, O},
title = {Telomeres and telomerase: a modern fountain of youth?.},
journal = {Rejuvenation research},
volume = {7},
number = {2},
pages = {126-133},
doi = {10.1089/1549168041553044},
pmid = {15312299},
issn = {1549-1684},
mesh = {Aging/*physiology ; Animals ; Humans ; Rejuvenation/*physiology ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {Since ageing is a universal human feature, it is not surprising that, from the Babylonian epic of Gilgamesh to Ponce de Leon seeking the "Fountain of Youth," countless people have dreamed of finding a way to avoid ageing, to no avail. Yet the search continues. In this review, we present one of the latest candidates: the enzyme telomerase, capable of elongating the tips of chromosomes, the telomeres. Research into the causes of cellular ageing established the telomeres as the molecular clock that counts the number of times cells divide and triggers cellular senescence. Herein, we review arguments both in favor and against the use of telomerase as an anti-ageing therapy. The importance of the telomeres in cellular ageing, the low or non-existent levels of telomerase activity in human tissues, and the ability of telomerase to immortalize human cells suggest that telomerase can be used as an anti-ageing therapy. On the other hand, recent experiments in mice have raised doubts whether telomerase affects organismal ageing. Results from human cells expressing telomerase have also suggested telomerase may promote tumorigenesis. We conclude that, though telomerase may be used in regenerative medicine and to treat specific diseases, it is unlikely to become a source of anti-ageing therapies.},
}
@article {pmid15308640,
year = {2004},
author = {Taylor, LM and James, A and Schuller, CE and Brce, J and Lock, RB and Mackenzie, KL},
title = {Inactivation of p16INK4a, with retention of pRB and p53/p21cip1 function, in human MRC5 fibroblasts that overcome a telomere-independent crisis during immortalization.},
journal = {The Journal of biological chemistry},
volume = {279},
number = {42},
pages = {43634-43645},
doi = {10.1074/jbc.M402388200},
pmid = {15308640},
issn = {0021-9258},
mesh = {Cell Cycle Proteins/*metabolism ; Cell Death/physiology ; Cell Division ; Cell Line ; Cell Survival/physiology ; Cellular Senescence/physiology ; Clone Cells ; Cyclin-Dependent Kinase Inhibitor p21 ; DNA-Binding Proteins ; Fibroblasts/*cytology ; Humans ; Kinetics ; Lung ; Retinoblastoma Protein/*metabolism ; Telomerase/*metabolism ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Recent investigations, including our own, have shown that specific strains of fibroblasts expressing telomerase reverse transcriptase (hTERT) have an extended lifespan, but are not immortal. We previously demonstrated that hTERT-transduced MRC5 fetal lung fibroblasts (MRC5hTERTs) bypassed senescence but eventually succumbed to a second mortality barrier (crisis). In the present study, 67 MRC5hTERT clones were established by limiting dilution of a mass culture. Whereas 39/67 clones had an extended lifespan, all 39 extended lifespan clones underwent crisis. 11 of 39 clones escaped crisis and were immortalized. There was no apparent relationship between the fate of clones at crisis and the level of telomerase activity. Telomeres were hyperextended in the majority of the clones analyzed. There was no difference in telomere length of pre-crisis compared with post-crisis and immortal clones, indicating that hyperextended telomeres were conducive for immortalization and confirming that crisis was independent of telomere length. Immortalization of MRC5hTERT cells was associated with repression of the cyclin-dependent kinase inhibitor p16INK4a and up-regulation of pRB. However, the regulation of pRB phosphorylation and the response of the p53/p21cip1/waf1 pathway were normal in immortal cells subject to genotoxic stress. Overexpression of oncogenic ras failed to de-repress p16INK4a in immortal cells. Furthermore, expression of ras enforced senescent-like growth arrest in p16INK4a-positive, but not p16INK4a-negative MRC5hTERT cells. Immortal cells expressing ras formed small, infrequent colonies in soft agarose, but were non-tumorigenic. Overall, these results implicate the inactivation of p16INK4a as a critical event for overcoming telomere-independent crisis, immortalizing MRC5 fibroblasts and overcoming ras-induced premature senescence.},
}
@article {pmid15308436,
year = {2004},
author = {Ulaner, GA},
title = {Telomere maintenance in clinical medicine.},
journal = {The American journal of medicine},
volume = {117},
number = {4},
pages = {262-269},
doi = {10.1016/j.amjmed.2004.02.048},
pmid = {15308436},
issn = {0002-9343},
support = {DK07217/DK/NIDDK NIH HHS/United States ; },
mesh = {Biomarkers, Tumor/metabolism ; *Clinical Medicine ; Drug Therapy ; Humans ; Neoplasms/diagnosis/metabolism/therapy ; Prognosis ; Rejuvenation ; Telomerase/metabolism/therapeutic use ; Telomere/*physiology ; },
abstract = {Telomeres, the ends of linear chromosomes, shorten with each round of DNA replication. Loss of telomeric DNA can lead to senescence, a state in which cells no longer divide, and crisis, which triggers cell death. To prevent these phenomena, cancer and stem cells must maintain their telomeres, for example, by expressing telomerase, an enzyme that can extend telomeres. As our knowledge of telomere maintenance increases, opportunities arise for translating telomere biology into clinical medicine. Areas of current investigation include the development of diagnostic and prognostic markers for cancer; the development of chemotherapeutic agents based on telomerase inhibition, an immune response to telomerase, or telomerase-based gene therapy; and engineering rejuvenated tissues by restoring telomerase expression.},
}
@article {pmid15306302,
year = {2004},
author = {Hall, ME and Nasir, L and Daunt, F and Gault, EA and Croxall, JP and Wanless, S and Monaghan, P},
title = {Telomere loss in relation to age and early environment in long-lived birds.},
journal = {Proceedings. Biological sciences},
volume = {271},
number = {1548},
pages = {1571-1576},
pmid = {15306302},
issn = {0962-8452},
mesh = {Age Factors ; Aging/genetics/*physiology ; Animals ; Atlantic Islands ; Birds/genetics/*physiology ; Blotting, Southern ; *Environment ; Erythrocytes/physiology ; Longevity/physiology ; Principal Component Analysis ; Scotland ; Species Specificity ; Telomere/genetics/*physiology ; },
abstract = {Shortening of telomeres, specific nucleotide repeats that cap eukaryotic chromosomes, is thought to play an important role in cellular and organismal senescence. We examined telomere dynamics in two long-lived seabirds, the European shag and the wandering albatross. Telomere length in blood cells declines between the chick stage and adulthood in both species. However, among adults, telomere length is not related to age. This is consistent with reports of most telomere loss occurring early in life in other vertebrates. Thus, caution must be used in estimating annual rates of telomere loss, as these are probably not constant with age. We also measured changes within individuals in the wild, using repeat samples taken from individual shags as chicks and adults. We found high inter-individual variation in the magnitude of telomere loss, much of which was explained by circumstances during growth. Individuals laying down high tissue mass for their size showed greater telomere shortening. Independently of this, individuals born late in the season showed more telomere loss. Early conditions, possibly through their effects on oxidative stress, appear to play an important role in telomere attrition and thus potentially in the longevity of individuals.},
}
@article {pmid15306020,
year = {2004},
author = {Ciudad, T and Andaluz, E and Steinberg-Neifach, O and Lue, NF and Gow, NA and Calderone, RA and Larriba, G},
title = {Homologous recombination in Candida albicans: role of CaRad52p in DNA repair, integration of linear DNA fragments and telomere length.},
journal = {Molecular microbiology},
volume = {53},
number = {4},
pages = {1177-1194},
doi = {10.1111/j.1365-2958.2004.04197.x},
pmid = {15306020},
issn = {0950-382X},
support = {R01 AI51949-01A2/AI/NIAID NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Candida albicans/enzymology/*genetics ; DNA Damage ; *DNA Repair ; DNA, Fungal/*genetics ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Molecular Sequence Data ; Mutation ; Rad52 DNA Repair and Recombination Protein ; *Recombination, Genetic ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Chromosomal rearrangements are common in both clinical isolates and spontaneous mutants of Candida albicans. It appears that many of these rearrangements are caused by translocations around the major sequence repeat (MSR) that is present in all chromosomes except chromosome 3, suggesting that homologous recombination (HR) may play an important role in the survival of this organism. In order to gain information on these processes, we have cloned the homologue of RAD52, which in Saccharomyces cerevisiae is the only gene required for all HR events. CaRAD52 complemented poorly a rad52 mutant of S. cerevisiae. Two null Carad52Delta/Carad52Delta mutants were constructed by sequential deletion of both alleles and two reconstituted strains were obtained by reintegration of the gene. Characterization of these mutants indicated that HR plays an essential role in the repair of DNA lesions caused by both UV light and the radiomimetic compound methyl-methane-sulphonate (MMS), whereas the non-homologous end-joining pathway (NHEJ) is used only in the absence of Rad52p or after extensive DNA damage. Repair by HR is more efficient in exponentially growing than in stationary cells, probably because a larger number of cells are in late S or G2 phases of the cell cycle (and therefore, can use a sister chromatid as a substrate for recombinational repair), whereas stationary phase cells are mainly in G0 or G1, and only can be repaired using the chromosomal homologue. In addition, CaRad52p is absolutely required for the integration of linear DNA with long flanking homologous sequences. Finally, the absence of CaRad52p results in the lengthening of telomeres, even in the presence of an active telomerase, an observation not described in any other organism. This raises the possibility that both telomerase and homologous recombination may function simultaneously at C. albicans telomeres.},
}
@article {pmid15305069,
year = {2004},
author = {Rotková, G and Sklenicková, M and Dvorácková, M and Sýkorová, E and Leitch, AR and Fajkus, J},
title = {An evolutionary change in telomere sequence motif within the plant section Asparagales had significance for telomere nucleoprotein complexes.},
journal = {Cytogenetic and genome research},
volume = {107},
number = {1-2},
pages = {132-138},
doi = {10.1159/000079584},
pmid = {15305069},
issn = {1424-859X},
mesh = {Arabidopsis/genetics ; Base Composition/genetics ; Cell Extracts/chemistry/pharmacology ; Cell Nucleus/chemistry/genetics ; Chromatin/genetics ; Chromosomal Proteins, Non-Histone/genetics/pharmacology ; Chromosomes, Plant/genetics/metabolism ; DNA, Plant/genetics/metabolism ; *Evolution, Molecular ; Guanine/metabolism ; Humans ; Liliaceae/cytology/enzymology/genetics ; Magnoliopsida/*genetics ; Nucleoproteins/*genetics ; Plant Leaves/cytology ; Plant Proteins/genetics/metabolism/pharmacology ; Repetitive Sequences, Nucleic Acid/genetics ; Scilla/cytology/enzymology/genetics ; Telomerase/antagonists &amp; inhibitors ; Telomere/enzymology/*genetics/metabolism ; },
abstract = {In association with a phylogenetic tree of Asparagales, our previous results showed that a distinct clade included plant species where the ancestral, Arabidopsis-type of telomeric repeats (TTTAGGG)n had been partially, or fully, replaced by the human-type telomeric sequence (TTAGGG)n. Telomerases of these species synthesize human repeats with a high error rate in vitro. Here we further characterize the structure of telomeres in these plants by analyzing the overall arrangement of major and minor variants of telomeric repeats using fluorescence in situ hybridization on extended DNA strand(s). Whilst the telomeric array is predominantly composed of the human variant of the repeat, the ancestral, Arabidopsis-type of telomeric repeats was ubiquitously observed at one of the ends and/or at intercalary positions of extended telomeric DNAs. Another variant of the repeat typical of Tetrahymena was observed interspersed in about 20% of telomerics. Micrococcal nuclease digestions indicated that Asparagales plants with a human-type of telomere have telomeric DNA organised into nucleosomes. However, unexpectedly, the periodicity of the nucleosomes is not significantly shorter than bulk chromatin as is typical of telomeric chromatin. Using electrophoretic mobility shift assays we detected in Asparagales plants with a human type of telomere a 40-kDa protein that forms complexes with both Arabidopsis- and human-type G-rich telomeric strands. However, the protein shows a higher affinity to the ancestral Arabidopsis-type sequence. Two further proteins were found, a 25-kDa protein that binds specifically to the ancestral sequence and a 15-kDa protein that binds to the human-type telomeric repeat. We discuss how the organisation of the telomere repeats in Asparagales may have arisen and stabilised the new telomere at the point of mutation.},
}
@article {pmid15304549,
year = {2004},
author = {Leonetti, C and Amodei, S and D'Angelo, C and Rizzo, A and Benassi, B and Antonelli, A and Elli, R and Stevens, MF and D'Incalci, M and Zupi, G and Biroccio, A},
title = {Biological activity of the G-quadruplex ligand RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate) is associated with telomere capping alteration.},
journal = {Molecular pharmacology},
volume = {66},
number = {5},
pages = {1138-1146},
doi = {10.1124/mol.104.001537},
pmid = {15304549},
issn = {0026-895X},
mesh = {Acridines/*pharmacology ; *Apoptosis ; Cell Cycle/drug effects ; Cellular Senescence/*drug effects ; Humans ; Ligands ; Melanoma ; Telomere/*drug effects/physiology ; Tumor Cells, Cultured ; },
abstract = {This study had two goals: 1) to evaluate the biological effect of the novel pentacyclic acridine 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) on human melanoma lines possessing long telomeres, and 2) to elucidate the relationship between G-quadruplex-based telomerase inhibitor-induced cellular effects and telomere length/dysfunction. The cellular pharmacological effects of RHPS4 have been evaluated by treating melanoma lines with increasing concentrations of RHPS4. A dose-dependent inhibition of cell proliferation was observed in all the lines during short-term treatment. Flow cytometric analysis demonstrated that RHPS4 induced a dose-dependent accumulation of cells in the S-G(2)/M phase of cell cycle. The RHPS4-induced cell cycle alteration was irreversible even at low doses, and the cells died from apoptosis. At high RHPS4 concentration, apoptosis was accompanied by the induction of a senescence phenotype: large cell size, vacuolated cytoplasm, and beta-galactosidase activity. The short-term biological activity of RHPS4 was not caused by telomere shortening, but it was associated with telomere dysfunction, in terms of presence of telomeric fusions, polynucleated cells, and typical images of telophase bridge. In conclusion, our results demonstrate that the G-quadruplex ligand RHPS4 can function in a telomere length-independent manner through its ability to cause telomere-capping alteration.},
}
@article {pmid15304225,
year = {2004},
author = {Perrini, B and Piacentini, L and Fanti, L and Altieri, F and Chichiarelli, S and Berloco, M and Turano, C and Ferraro, A and Pimpinelli, S},
title = {HP1 controls telomere capping, telomere elongation, and telomere silencing by two different mechanisms in Drosophila.},
journal = {Molecular cell},
volume = {15},
number = {3},
pages = {467-476},
doi = {10.1016/j.molcel.2004.06.036},
pmid = {15304225},
issn = {1097-2765},
mesh = {Animals ; Chromosomal Proteins, Non-Histone/*metabolism ; DNA/metabolism ; Drosophila/*genetics/metabolism ; Drosophila Proteins/*metabolism ; Gene Silencing/*physiology ; Nuclear Proteins/metabolism ; Polycomb Repressive Complex 2 ; RNA Interference/physiology ; Repressor Proteins/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {HP1 is a conserved chromosomal protein, first discovered in Drosophila, which is predominantly associated with the heterochromatin of many organisms. Recently, it has been shown that HP1 is required for telomere capping, telomere elongation, and transcriptional repression of telomeric sequences. Several studies have suggested a model for heterochromatin formation and epigenetic gene silencing in different species that is based on interactions among histone methyltransferases (HMTases), histone H3 methylated at lysine 9 (H3-MeK9), and the HP1 chromodomain. This model has been extended to HP1 telomeric localization by data showing that H3-MeK9 is present at all of the telomeres. Here, we tested this model, and we found that the capping function of HP1 is due to its direct binding to telomeric DNA, while the silencing of telomeric sequences and telomere elongation is due to its interaction with H3-MeK9.},
}
@article {pmid15296775,
year = {2004},
author = {Purdy, A and Su, TT},
title = {Telomeres: not all breaks are equal.},
journal = {Current biology : CB},
volume = {14},
number = {15},
pages = {R613-4},
doi = {10.1016/j.cub.2004.07.042},
pmid = {15296775},
issn = {0960-9822},
mesh = {Acid Anhydride Hydrolases ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/metabolism ; *Chromosomal Instability ; DNA Damage/physiology ; *DNA Repair ; DNA Repair Enzymes/metabolism ; DNA-Binding Proteins/metabolism ; Protein Serine-Threonine Kinases/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; Tumor Suppressor Proteins ; },
abstract = {ATM, Rad50 and Mre11 have been shown to prevent telomere fusion in Drosophila, thereby extending the protective role of DNA damage checkpoint proteins to non-canonical telomeres formed without telomerase. How do these proteins help chromosomal termini escape fusion through 'repair' while promoting repair of induced DNA breaks?},
}
@article {pmid15296751,
year = {2004},
author = {Bi, X and Wei, SC and Rong, YS},
title = {Telomere protection without a telomerase; the role of ATM and Mre11 in Drosophila telomere maintenance.},
journal = {Current biology : CB},
volume = {14},
number = {15},
pages = {1348-1353},
doi = {10.1016/j.cub.2004.06.063},
pmid = {15296751},
issn = {0960-9822},
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Blotting, Southern ; Cell Cycle Proteins ; Chromosomal Instability/genetics ; DNA Ligase ATP ; DNA Ligases/metabolism ; DNA Primers ; DNA Repair/*genetics ; DNA-Binding Proteins ; Drosophila/*physiology ; Drosophila Proteins/metabolism/*physiology ; Endodeoxyribonucleases/metabolism/*physiology ; Epistasis, Genetic ; Protein Serine-Threonine Kinases/metabolism/*physiology ; Telomere/*physiology ; Tumor Suppressor Proteins ; },
abstract = {The conserved ATM checkpoint kinase and the Mre11 DNA repair complex play essential and overlapping roles in maintaining genomic integrity. We conducted genetic and cytological studies on Drosophila atm and mre11 knockout mutants and discovered a telomere defect that was more severe than in any of the non-Drosophila systems studied. In mutant mitotic cells, an average of 30% of the chromosome ends engaged in telomere fusions. These fusions led to the formation and sometimes breakage of dicentric chromosomes, thus starting a devastating breakage-fusion-bridge cycle. Some of the fusions depended on DNA ligase IV, which suggested that they occurred by a nonhomologous end-joining (NHEJ) mechanism. Epistasis analyses results suggest that ATM and Mre11 might also act in the same telomere maintenance pathway in metazoans. Since Drosophila telomeres are not added by a telomerase, our findings support an additional role for both ATM and Mre11 in telomere maintenance that is independent of telomerase regulation.},
}
@article {pmid15296750,
year = {2004},
author = {Silva, E and Tiong, S and Pedersen, M and Homola, E and Royou, A and Fasulo, B and Siriaco, G and Campbell, SD},
title = {ATM is required for telomere maintenance and chromosome stability during Drosophila development.},
journal = {Current biology : CB},
volume = {14},
number = {15},
pages = {1341-1347},
doi = {10.1016/j.cub.2004.06.056},
pmid = {15296750},
issn = {0960-9822},
support = {GM46409/GM/NIGMS NIH HHS/United States ; GM49883/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Apoptosis/physiology ; Ataxia Telangiectasia Mutated Proteins ; Body Patterning/*physiology ; Cell Cycle Proteins ; Chromosomal Instability/*physiology ; Crosses, Genetic ; *DNA Repair ; DNA-Binding Proteins ; Drosophila/*growth &amp; development/ultrastructure ; Eye/pathology ; Larva/growth &amp; development/ultrastructure ; Locomotion/physiology ; Microscopy, Electron ; Mutagenesis ; Mutation/genetics ; Neurons/metabolism ; Protein Serine-Threonine Kinases/genetics/*metabolism/physiology ; Recombination, Genetic/physiology ; Telomere/*physiology ; Temperature ; Transgenes/genetics ; Tumor Suppressor Proteins ; Wings, Animal/pathology ; },
abstract = {ATM is a large, multifunctional protein kinase that regulates responses required for surviving DNA damage: including DNA repair, apoptosis, and cell cycle checkpoints. Here, we show that Drosophila ATM function is essential for normal adult development. Extensive, inappropriate apoptosis occurs in proliferating atm mutant tissues, and in clonally derived atm mutant embryos, frequent mitotic defects were seen. At a cellular level, spontaneous telomere fusions and other chromosomal abnormalities are common in atm larval neuroblasts, suggesting a conserved and essential role for dATM in the maintenance of normal telomeres and chromosome stability. Evidence from other systems supports the idea that DNA double-strand break (DSB) repair functions of ATM kinases promote telomere maintenance by inhibition of illegitimate recombination or fusion events between the legitimate ends of chromosomes and spontaneous DSBs. Drosophila will be an excellent model system for investigating how these ATM-dependent chromosome structural maintenance functions are deployed during development. Because neurons appear to be particularly sensitive to loss of ATM in both flies and humans, this system should be particularly useful for identifying cell-specific factors that influence sensitivity to loss of dATM and are relevant for understanding the human disease, ataxia-telangiectasia.},
}
@article {pmid15292264,
year = {2004},
author = {Kim, SH and Beausejour, C and Davalos, AR and Kaminker, P and Heo, SJ and Campisi, J},
title = {TIN2 mediates functions of TRF2 at human telomeres.},
journal = {The Journal of biological chemistry},
volume = {279},
number = {42},
pages = {43799-43804},
doi = {10.1074/jbc.M408650200},
pmid = {15292264},
issn = {0021-9258},
mesh = {Cell Line ; Humans ; Protein Binding ; Recombinant Proteins/isolation &amp; purification/metabolism ; Telomerase/metabolism ; Telomere/*physiology ; Telomere-Binding Proteins/isolation &amp; purification/*metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {Telomeres are protective structures at chromosome ends and are crucial for genomic stability. Mammalian TRF1 and TRF2 bind the double-stranded telomeric repeat sequence and in turn are bound by TIN2, TANK1, TANK2, and hRAP1. TRF1 is a negative regulator of telomere length in telomerase-positive cells, whereas TRF2 is important for telomere capping. TIN2 was identified as a TRF1-interacting protein that mediates TRF1 function. We show here that TIN2 also interacts with TRF2 in vitro and in yeast and mammalian cells. TIN2 mutants defective in binding of TRF1 or TRF2 induce a DNA damage response and destabilize TRF1 and TRF2 at telomeres in human cells. Our findings suggest that the functions of TRF1 and TRF2 are linked by TIN2.},
}
@article {pmid15289453,
year = {2004},
author = {d'Adda di Fagagna, F and Teo, SH and Jackson, SP},
title = {Functional links between telomeres and proteins of the DNA-damage response.},
journal = {Genes &amp; development},
volume = {18},
number = {15},
pages = {1781-1799},
doi = {10.1101/gad.1214504},
pmid = {15289453},
issn = {0890-9369},
mesh = {Animals ; DNA/genetics/metabolism ; DNA Damage/*physiology ; DNA Repair/*physiology ; DNA-Binding Proteins/physiology ; Humans ; Nuclear Proteins/*physiology ; Telomere/*physiology ; },
abstract = {In response to DNA damage, cells engage a complex set of events that together comprise the DNA-damage response (DDR). These events bring about the repair of the damage and also slow down or halt cell cycle progression until the damage has been removed. In stark contrast, the ends of linear chromosomes, telomeres, are generally not perceived as DNA damage by the cell even though they terminate the DNA double-helix. Nevertheless, it has become clear over the past few years that many proteins involved in the DDR, particularly those involved in responding to DNA double-strand breaks, also play key roles in telomere maintenance. In this review, we discuss the current knowledge of both the telomere and the DDR, and then propose an integrated model for the events associated with the metabolism of DNA ends in these two distinct physiological contexts.},
}
@article {pmid15289012,
year = {2004},
author = {Sieglová, Z and Zilovcová, S and Cermák, J and Ríhová, H and Brezinová, D and Dvoráková, R and Marková, M and Maaloufová, J and Sajdová, J and Brezinová, J and Zemanová, Z and Michalová, K},
title = {Dynamics of telomere erosion and its association with genome instability in myelodysplastic syndromes (MDS) and acute myelogenous leukemia arising from MDS: a marker of disease prognosis?.},
journal = {Leukemia research},
volume = {28},
number = {10},
pages = {1013-1021},
doi = {10.1016/j.leukres.2003.11.020},
pmid = {15289012},
issn = {0145-2126},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/*genetics ; Child ; Chromosome Aberrations ; Disease Progression ; *Genomic Instability ; Humans ; Karyotyping ; Leukemia, Myeloid, Acute/*diagnosis/*genetics ; Middle Aged ; Myelodysplastic Syndromes/*diagnosis/*genetics ; Prognosis ; Risk Factors ; Telomere/*genetics ; },
abstract = {Telomere length was evaluated by terminal repeat fragment method (TRF) in 50 patients with myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) arising from MDS and in 21 patients with untreated primary AML to ascertain, whether telomere erosion was associated with progression of MDS towards overt leukemia. Heterogeneity of TRF among MDS FAB subgroups (P=0.004) originated from its shortening in increased number of patients during progression of the disease. Chromosomal aberrations were present in 32% MDS patients with more eroded telomeres (P=0.022), nevertheless a difference between mean TRF in the subgroups with normal and abnormal karyotype diminished during progression of MDS. A negative correlation between individual TRF and IPSS value (P=0.039) showed that telomere dynamics might serve as a useful prognostic factor for assessment of an individual MDS patient's risk and for decision of an optimal treatment strategy.},
}
@article {pmid15289009,
year = {2004},
author = {Engelhardt, M and Wäsch, R and Guo, Y},
title = {Telomeres and telomerase in normal and leukemic hematopoietic cells.},
journal = {Leukemia research},
volume = {28},
number = {10},
pages = {1001-1004},
doi = {10.1016/j.leukres.2004.01.015},
pmid = {15289009},
issn = {0145-2126},
mesh = {Hematopoietic Stem Cells/*metabolism ; Humans ; *Leukemia, Myeloid, Acute/genetics/metabolism ; *Myelodysplastic Syndromes/genetics/metabolism ; Neoplastic Stem Cells/*metabolism ; *Telomerase/genetics/metabolism ; *Telomere/genetics/metabolism ; },
abstract = {Telomere length and telomerase have an important role in normal and malignant hematopoiesis. Telomere erosion can lead to chromosome end fusion and thereby contribute to genomic instability during tumorigenesis. Thus, like complex chromosomal aberrations, telomere length may be a prognostic factor in hematopoietic malignancies. A paper by Sieglova et al. in this issue of Leukemia Research reports on the prognostic impact of telomere shortening in bone marrow (BM) and peripheral blood (PB) specimens of myelodysplastic syndrome (MDS) and MDS converted-AML patients (pts). Their results underline the importance to study telomere biology together with cytogenetics, genomic and proteomic profiling as prognostic factors, in order to improve risk-adapted therapy of MDS and AML pts.},
}
@article {pmid15287028,
year = {2004},
author = {Ulaner, GA and Hoffman, AR and Otero, J and Huang, HY and Zhao, Z and Mazumdar, M and Gorlick, R and Meyers, P and Healey, JH and Ladanyi, M},
title = {Divergent patterns of telomere maintenance mechanisms among human sarcomas: sharply contrasting prevalence of the alternative lengthening of telomeres mechanism in Ewing's sarcomas and osteosarcomas.},
journal = {Genes, chromosomes &amp; cancer},
volume = {41},
number = {2},
pages = {155-162},
doi = {10.1002/gcc.20074},
pmid = {15287028},
issn = {1045-2257},
support = {DK07217/DK/NIDDK NIH HHS/United States ; },
mesh = {Actins/genetics ; Adolescent ; Adult ; Base Sequence ; Bone Neoplasms/*genetics ; Cell Line, Tumor ; Child, Preschool ; DNA Primers ; Female ; Humans ; Infant ; Male ; Osteosarcoma/*genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Sarcoma/*genetics ; Sarcoma, Ewing/*genetics ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {Two types of telomere maintenance mechanisms (TMMs) have been described in human tumors: telomerase activation and alternative lengthening of telomeres (ALT). Although the vast majority of epithelial tumors rely on telomerase activation, many mesenchymal tumors rely on ALT for telomere maintenance, but within this tumor group, the TMMs used by translocation-associated sarcomas have not been systematically studied. We studied telomere lengths and telomerase expression and activity in 30 uncultured tumor samples and in 10 cell lines of Ewing's sarcoma, a prototypical translocation-associated sarcoma, and compared the data to an identical analysis of 60 osteosarcomas, the most common type of sarcoma lacking a specific translocation. Telomerase activity was demonstrated in 21 Ewing's sarcoma tumor samples (70%) and in 9 of 10 Ewing's sarcoma cell lines. Evidence of ALT, indicated by the presence of long and heterogeneous telomeres, was observed only in the cell line without telomerase activity and in none of the 30 Ewing's sarcoma tumor samples. The 9 Ewing's sarcoma patients whose tumors lacked detectable telomerase activity did not differ significantly from the remaining patients in age, stage, EWSR1-FLI1 fusion type, prevalence of TP53 point mutations, or overall survival. The low prevalence of ALT in Ewing's sarcoma contrasted sharply with our data on TMMs in 60 osteosarcomas, which showed ALT in 38 of 60 cases (P<0.0001). The present study, together with emerging published data on other sarcoma types, suggests that a predominance of telomerase activation in the absence of ALT may characterize sarcomas with specific chromosomal translocations (such as Ewing's sarcoma), whereas a high prevalence of ALT appears typical of sarcomas with nonspecific complex karyotypes (such as osteosarcoma).},
}
@article {pmid15284903,
year = {2004},
author = {Mondello, C and Scovassi, AI},
title = {Telomeres, telomerase, and apoptosis.},
journal = {Biochemistry and cell biology = Biochimie et biologie cellulaire},
volume = {82},
number = {4},
pages = {498-507},
doi = {10.1139/o04-048},
pmid = {15284903},
issn = {0829-8211},
mesh = {Animals ; *Apoptosis ; Chromatin/physiology ; DNA/chemistry ; DNA-Binding Proteins ; Humans ; Mice ; Mice, Knockout ; Models, Biological ; Neoplasms/pathology ; Nucleotides/chemistry ; Telomerase/genetics/*physiology ; Telomere/*ultrastructure ; },
abstract = {Telomeres are specialized high-order chromatin structures that cap the ends of eukaryotic chromosomes. In vertebrates, telomeric DNA is composed of repetitions of the TTAGGG hexanucleotide, is bound to a set of specific proteins, and is elongated by the reverse transcriptase enzyme telomerase. Telomerase activity is promptly detected in cells with an indefinite replicative potential, such as cancer cells, while is almost undetectable in normal cells, which are characterized by a limited life span. Mounting evidence indicates that the maintenance of telomere integrity and telomerase protect cells from apoptosis. Disruption of the telomere capping function and (or) telomerase inhibition elicit an apoptotic response in cancer cells, while restoration of telomerase activity in somatic cells confers resistance to apoptosis. The possible mechanisms linking telomeres, telomerase and apoptosis are discussed in this review, together with the impact of this field in anticancer research.},
}
@article {pmid15284068,
year = {2004},
author = {Op den Buijs, J and Musters, M and Verrips, T and Post, JA and Braam, B and van Riel, N},
title = {Mathematical modeling of vascular endothelial layer maintenance: the role of endothelial cell division, progenitor cell homing, and telomere shortening.},
journal = {American journal of physiology. Heart and circulatory physiology},
volume = {287},
number = {6},
pages = {H2651-8},
doi = {10.1152/ajpheart.00332.2004},
pmid = {15284068},
issn = {0363-6135},
mesh = {Arteriosclerosis/pathology/physiopathology ; Cell Division/physiology ; Cellular Senescence/physiology ; Endothelium, Vascular/cytology/*physiology ; Humans ; *Models, Cardiovascular ; Oxidative Stress/physiology ; Stem Cells/cytology/*physiology ; Telomere/*physiology ; },
abstract = {Maintenance of the endothelial cell (EC) layer of the vessel wall is essential for proper functioning of the vessel and prevention of vascular disorders. Replacement of damaged ECs could occur through division of surrounding ECs. Furthermore, EC progenitor cells (EPCs), derived from the bone marrow and circulating in the bloodstream, can differentiate into ECs. Therefore, these cells might also play a role in maintenance of the endothelial layer in the vascular system. The proliferative potential of both cell types is limited by shortening of telomeric DNA. Accelerated telomere shortening might lead to senescent vascular wall cells and eventually to the inability of the endothelium to maintain a continuous monolayer. The aim of this study was to describe the dynamics of EC damage and repair and telomere shortening by a mathematical model. In the model, ECs were integrated in a two-dimensional structure resembling the endothelium in a large artery. Telomere shortening was described as a stochastic process with oxidative damage as the main cause of attrition. Simulating the model illustrated that increased cellular turnover or elevated levels of oxidative stress could lead to critical telomere shortening and senescence at an age of 65 yr. The model predicted that under those conditions the EC layer could display defects, which could initiate severe vascular wall damage in reality. Furthermore, simulations showed that 5% progenitor cell homing/yr can significantly delay the EC layer defects. This stresses the potential importance of EPC number and function to the maintenance of vascular wall integrity during the human life span.},
}
@article {pmid15283592,
year = {2004},
author = {Chang, CC and Kuo, IC and Ling, IF and Chen, CT and Chen, HC and Lou, PJ and Lin, JJ and Chang, TC},
title = {Detection of quadruplex DNA structures in human telomeres by a fluorescent carbazole derivative.},
journal = {Analytical chemistry},
volume = {76},
number = {15},
pages = {4490-4494},
doi = {10.1021/ac049510s},
pmid = {15283592},
issn = {0003-2700},
mesh = {Binding Sites ; Carbazoles/chemistry ; Cell Line ; Cell Nucleus/ultrastructure ; DNA/*chemistry ; Fluorescent Dyes ; Humans ; Metaphase ; Microscopy, Confocal ; Pyridinium Compounds/chemistry ; Spectrometry, Fluorescence ; Telomere/*genetics/*ultrastructure ; },
abstract = {Single-stranded telomeric DNA tends to form a four-base-paired planar structure termed G-quadruplex. This structure was easily formed in vitro in the presence of monovalent cations. However, the existence of this structure in native human telomeres is unclear. Here we address this important question through the distinctive properties of 3,6-bis(1-methyl-4-vinylpyridinium)carbazole diiodide (BMVC) upon binding to various DNA structures. Although the fluorescence of BMVC increases significantly in the presence of DNA, BMVC has high sensitivity and binding preference to quadruplex d(T(2)AG(3))(4) over duplex DNA. In addition, the fluorescent emissions were characterized around 575 nm for quadruplex d(T(2)AG(3))(4) and 545 nm for most of duplex DNA. The 575-nm fluorescence emissions were detected in the mixtures of 2 nM BMVC with the chromosomal DNA that were extracted from human cells, suggesting the presence of quadruplex structure in human nucleus. Further analyzing the BMVC fluorescence at the ends of metaphase chromosomes and other regions of chromosomes, we detected the quadruplex-binding BMVC fluorescence at telomere-proximal regions. Together these results provide the first evidence for the presence of quadruplex structures in human telomeres.},
}
@article {pmid15283144,
year = {2004},
author = {Shin-ya, K},
title = {[Telomerase inhibitor, telomestatin, a specific mechanism to interact with telomere structure].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {62},
number = {7},
pages = {1277-1282},
pmid = {15283144},
issn = {0047-1852},
mesh = {Oxazoles/*pharmacology ; Telomerase/*antagonists &amp; inhibitors ; Telomere/chemistry/*drug effects ; },
abstract = {A novel telomerase inhibitor, telomestatin, isolated from Streptomyces anulatus is the most potent telomerase inhibitor so far. Telomestatin specifically inhibited telomerase without affecting reverse transcriptases and polymerases. In addition, telomestatin induced telomere shortening, but its ratio was extremely faster than that observed in physiological telomere shortening. These results suggested the existence of other mechanisms to inhibit telomerase. Telomeres consist of guanine rich sequences which compose a characteristic three-dimensional structure designated as G-quadruplex. Stabilization of G-quadruplex structure inhibited the catalysis of not only telomerase but also other DNA interacting molecules. Telomestatin potently stabilized G-quadruplex structure in a specific manner. G-quadruplex structure is also involved in a lot of oncogene promoters. Thus, telomestatin provide the novel therapeutic molecular target for cancer chemotherapy.},
}
@article {pmid15283143,
year = {2004},
author = {Ide, T},
title = {[Telomere and telomerase as targets for anti-cancer drugs].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {62},
number = {7},
pages = {1271-1276},
pmid = {15283143},
issn = {0047-1852},
mesh = {Animals ; Antineoplastic Agents/administration &amp; dosage ; Drug Delivery Systems/*methods ; Humans ; Neoplasms/*drug therapy ; Telomerase/*antagonists &amp; inhibitors/genetics ; Telomere/*drug effects ; },
abstract = {Telomerase is a hopeful molecular target of anti-cancer drugs because it is practically specific and essential for survival and growth of cancer cells. Cancer cells in vitro ceased proliferation after introduction of dominant-negative cDNA or RNAi of telomerase catalytic subunit (hTERT) or anti-sense RNA of template RNA subunit (hTR) of telomerase. Some reverse-transcriptase inhibitors, compounds that stabilize G-quartet structure of telomere DNA and other natural or synthetic compounds were reported to inhibit telomerase activity and proliferation of cancer cells in vitro. Vectors carrying cDNA that produces mutant hTR partly blocked proliferation of cancer cells probably through inhibition of sequence-specific binding of telomere proteins. Telomere binding proteins are possible targets of anti-cancer drugs that modify telomere structure and block recruitment of telomerase. Combination of inhibitors with different action mechanisms accelerated telomere shortening and reduced period of time required for cancer cell killing. Repressor of hTERT expression, menin, is a possible target in future.},
}
@article {pmid15282303,
year = {2004},
author = {Chiang, YJ and Hemann, MT and Hathcock, KS and Tessarollo, L and Feigenbaum, L and Hahn, WC and Hodes, RJ},
title = {Expression of telomerase RNA template, but not telomerase reverse transcriptase, is limiting for telomere length maintenance in vivo.},
journal = {Molecular and cellular biology},
volume = {24},
number = {16},
pages = {7024-7031},
pmid = {15282303},
issn = {0270-7306},
support = {K01 CA094223/CA/NCI NIH HHS/United States ; P01 CA016519/CA/NCI NIH HHS/United States ; CA16519/CA/NCI NIH HHS/United States ; K01 CA94223/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; DNA-Binding Proteins ; Gene Targeting ; Heterozygote ; Humans ; Mice ; RNA/*metabolism ; Telomerase/*genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomerase consists of two essential components, the telomerase RNA template (TR) and telomerase reverse transcriptase (TERT). The haplo-insufficiency of TR was recently shown to cause one form of human dyskeratosis congenita, an inherited disease marked by abnormal telomere shortening. Consistent with this finding, we recently reported that mice heterozygous for inactivation of mouse TR exhibit a similar haplo-insufficiency and are deficient in the ability to elongate telomeres in vivo. To further assess the genetic regulation of telomerase activity, we have compared the abilities of TR-deficient and TERT-deficient mice to maintain or elongate telomeres in interspecies crosses. Homozygous TERT knockout mice had no telomerase activity and failed to maintain telomere length. In contrast, TERT(+/-) heterozygotes had no detectable defect in telomere elongation compared to wild-type controls, whereas TR(+/-) heterozygotes were deficient in telomere elongation. Levels of TERT mRNA in heterozygous mice were one-third to one-half the levels expressed in wild-type mice, similar to the reductions in telomerase RNA observed in TR heterozygotes. These findings indicate that both TR and TERT are essential for telomere maintenance and elongation but that gene copy number and transcriptional regulation of TR, but not TERT, are limiting for telomerase activity under the in vivo conditions analyzed.},
}
@article {pmid15279784,
year = {2004},
author = {Maser, RS and DePinho, RA},
title = {Telomeres and the DNA damage response: why the fox is guarding the henhouse.},
journal = {DNA repair},
volume = {3},
number = {8-9},
pages = {979-988},
doi = {10.1016/j.dnarep.2004.05.009},
pmid = {15279784},
issn = {1568-7864},
mesh = {*DNA Damage ; DNA Repair ; Endodeoxyribonucleases/physiology ; Exodeoxyribonucleases/physiology ; Fungal Proteins/physiology ; Humans ; Intracellular Signaling Peptides and Proteins ; Models, Biological ; Models, Genetic ; Mutation ; Phenotype ; Protein Serine-Threonine Kinases ; *Recombination, Genetic ; Saccharomyces cerevisiae/*genetics/physiology ; Saccharomyces cerevisiae Proteins/physiology ; Telomere/*ultrastructure ; },
abstract = {DNA double strand breaks (DSBs) are repaired by an extensive network of proteins that recognize damaged DNA and catalyze its repair. By virtue of their similarity, the normal ends of linear chromosomes and internal DNA DSBs are both potential substrates for DSB repair enzymes. Thus, telomeres, specialized nucleo-protein complexes that cap chromosomal ends, serve a critical function to differentiate themselves from internal DNA strand breaks, and as a result prevent genomic instability that can result from their inappropriate involvement in repair reactions. Telomeres that become critically short due to failure of telomere maintenance mechanisms, or which become dysfunctional by loss of telomere binding proteins, elicit extensive checkpoint responses that in normal cells blocks proliferation. In this situation, the DNA DSB repair machinery plays a major role in responding to these "damaged" telomeres - creating chromosome fusions or capturing telomeres from other chromosomes in an effort to rid the cell of the perceived damage. However, a surprising aspect of telomere maintenance is that many of the same proteins that facilitate this repair of damaged telomeres are also necessary for their proper integrity. Here, we review recent work defining the roles for DSB repair machinery in telomere maintenance and in response to telomere dysfunction.},
}
@article {pmid15273408,
year = {2004},
author = {Baur, JA and Wright, WE and Shay, JW},
title = {Analysis of mammalian telomere position effect.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {287},
number = {},
pages = {121-136},
doi = {10.1385/1-59259-828-5:121},
pmid = {15273408},
issn = {1064-3745},
support = {AG07792/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Cloning, Molecular ; DNA/isolation &amp; purification ; Gene Silencing ; Genes, Reporter ; *Genetic Techniques ; Genetic Vectors ; HeLa Cells ; Humans ; Mammals/*genetics ; Telomere/*genetics ; Transgenes ; },
abstract = {Methods relating to the positioning of a transgene next to a newly formed telomere in human (HeLa) cells and the subsequent analysis of the resulting clones are described. These include vector design, analysis of integration sites by Southern blotting, pharmacological relief of silencing, and enhancement of silencing by telomere elongation. Several potential pitfalls of applying these techniques to other cell lines are discussed. In addition, detailed instructions are provided for several more general methods related to human telomeres including terminal restriction fragment analysis and purification of telomeres from digested genomic DNA. This chapter summarizes the techniques currently in use that relate to human telomere position effect.},
}
@article {pmid15269598,
year = {2004},
author = {Deschatrette, J and Ng, KH and Gouthière, L and Maigné, J and Guerroui, S and Wolfrom, C},
title = {Telomere dynamics determine episodes of anticancer drug resistance in rat hepatoma cells.},
journal = {Anti-cancer drugs},
volume = {15},
number = {7},
pages = {671-678},
doi = {10.1097/01.cad.0000136879.96680.bc},
pmid = {15269598},
issn = {0959-4973},
mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Cell Division/drug effects ; Cell Line, Tumor ; Cisplatin/*pharmacology ; Clone Cells ; DNA, Neoplasm/analysis ; Drug Resistance, Neoplasm/*drug effects ; Liver Neoplasms, Experimental/pathology/ultrastructure ; Methotrexate/*pharmacology ; Rats ; Telomere/*drug effects/ultrastructure ; },
abstract = {Clinical and experimental observations indicate that resistance to anticancer drugs may be spontaneously reversible over time, but the mechanisms of this reversal are unknown. The resistance of cultured hepatoma cells to methotrexate (MTX) and cisplatin was followed for 9 months. Cells were exposed to three treatments: MTX 200 nM for 24 h or 15 nM continuously and cisplatin 50 microM for 2 h. We investigated the relation between the temporal pattern of cell resistance and the previously reported fluctuations in cell proliferation rate, telomere length and telomerase activity. Spontaneous major peaks in resistance to each drug fell in time windows of 2-3 months (60-70 population doublings) and were at different times for each drug. The frequency of the fluctuations in drug resistance was the same as that of variations in cell growth rate, but amplitudes were unrelated. By contrast, resistance was directly related to telomere length dynamics in the same cells. MTX resistance occurred when telomeres shortened and cisplatin resistance when they were elongated. Furthermore, peaks of resistance to the continuous treatment with MTX were observed at 350-bp intervals of mean telomere length (9.06, 9.41, and 9.76 kbp) during the two 2-month phases of telomere shortening. Statistical analysis demonstrates the sinusoidal relationship between intermittent MTX resistance and telomere length. Possibly, erosion of telomeres encroaches on periodically spaced nucleosomal proteins, defining the onset of resistance phases. This evidence that resistance of tumoral cells to anticancer drugs may be intermittent and that onset of resistance is dictated by telomere length has major implications for clinical practice.},
}
@article {pmid15269166,
year = {2004},
author = {Ferrón, S and Mira, H and Franco, S and Cano-Jaimez, M and Bellmunt, E and Ramírez, C and Fariñas, I and Blasco, MA},
title = {Telomere shortening and chromosomal instability abrogates proliferation of adult but not embryonic neural stem cells.},
journal = {Development (Cambridge, England)},
volume = {131},
number = {16},
pages = {4059-4070},
doi = {10.1242/dev.01215},
pmid = {15269166},
issn = {0950-1991},
mesh = {Animals ; Brain/embryology ; Cell Division/physiology ; Cell Nucleus/physiology ; Chromosomal Instability/genetics/*physiology ; Female ; Ganglia, Sensory/embryology ; Mice ; Mice, Knockout ; Stem Cells/cytology/*physiology ; Telomerase/deficiency/genetics ; Telomere/genetics/*physiology ; Tumor Suppressor Protein p53/physiology ; },
abstract = {Chromosome integrity is essential for cell viability and, therefore, highly proliferative cell types require active telomere elongation mechanisms to grow indefinitely. Consistently, deletion of telomerase activity in a genetically modified mouse strain results in growth impairments in all highly proliferative cell populations analyzed so far. We show that telomere attrition dramatically impairs the in vitro proliferation of adult neural stem cells (NSCs) isolated from the subventricular zone (SVZ) of telomerase-deficient adult mice. Reduced proliferation of postnatal neurogenic progenitors was also observed in vivo, in the absence of exogenous mitogenic stimulation. Strikingly, severe telomere erosion resulting in chromosomal abnormalities and nuclear accumulation of p53 did not affect the in vitro proliferative potential of embryonic NSCs. These results suggest that intrinsic differences exist between embryonic and adult neural progenitor cells in their response to telomere shortening, and that some populations of tissue-specific stem cells can bypass DNA damage check points.},
}
@article {pmid15265989,
year = {2004},
author = {Yamamoto, TG and Chikashige, Y and Ozoe, F and Kawamukai, M and Hiraoka, Y},
title = {Activation of the pheromone-responsive MAP kinase drives haploid cells to undergo ectopic meiosis with normal telomere clustering and sister chromatid segregation in fission yeast.},
journal = {Journal of cell science},
volume = {117},
number = {Pt 17},
pages = {3875-3886},
doi = {10.1242/jcs.01248},
pmid = {15265989},
issn = {0021-9533},
mesh = {Binding Sites ; Chromatids/ultrastructure ; Culture Media ; DNA Primers/chemistry ; Diploidy ; Flow Cytometry ; Genotype ; Haploidy ; Humans ; In Situ Hybridization, Fluorescence ; *MAP Kinase Signaling System ; Meiosis ; Microscopy, Fluorescence ; Models, Biological ; Mutation ; Pheromones ; Phosphorylation ; Plasmids/metabolism ; Protein Kinases/metabolism ; Protein Serine-Threonine Kinases/metabolism ; Schizosaccharomyces ; Schizosaccharomyces pombe Proteins/metabolism ; Signal Transduction ; *Sister Chromatid Exchange ; Telomere/metabolism/*ultrastructure ; Temperature ; Time Factors ; },
abstract = {Meiosis is a process of importance for sexually reproducing eukaryotic organisms. In the fission yeast Schizosaccharomyces pombe, meiosis normally proceeds in a diploid zygote which is produced by conjugation of haploid cells of opposite mating types. We demonstrate that activation of the pheromone-responsive MAPK, Spk1, by the ectopic expression of a constitutively active form of Byr1 (MAPKK for Spk1) induced the cells to undergo meiosis while in the haploid state. Moreover, the induction of meiosis required Mei2 (a key positive regulator of meiosis), but did not require Mei3; Mei3 is normally required to inactivate the Pat1 kinase (a negative regulator of Mei2) thereby allowing Mei2 to drive meiosis. Therefore, expression of a constitutively active form of Byr1 activates Mei2 without the need of Mei3. In cells induced to undergo meiosis by activating the Spk1 MAPK signaling pathway, telomeres clustered at the spindle pole body (SPB) and centromeres detached normally from the SPB during meiotic prophase, and the cells showed the correct segregation of sister chromatids during meiotic divisions. In contrast, in meiosis induced by inactivation of Pat1, sister chromatids segregate precociously during the first meiotic division. Thus, these results suggest that activation of Spk1 drives meiosis in S. pombe.},
}
@article {pmid15265692,
year = {2004},
author = {Oh, BK and Lee, CH and Park, C and Park, YN},
title = {Telomerase regulation and progressive telomere shortening of rat hepatic stem-like epithelial cells during in vitro aging.},
journal = {Experimental cell research},
volume = {298},
number = {2},
pages = {445-454},
doi = {10.1016/j.yexcr.2004.04.032},
pmid = {15265692},
issn = {0014-4827},
mesh = {Animals ; Catalytic Domain/genetics ; Cell Differentiation/genetics ; Cell Division/genetics ; Cell Line ; Cell Transformation, Neoplastic/genetics/metabolism ; Cellular Senescence/*genetics ; DNA-Binding Proteins ; Epithelial Cells/cytology/*enzymology ; Gene Expression Regulation, Neoplastic/genetics ; Hepatocytes/cytology/*enzymology ; Liver/cytology/enzymology/growth &amp; development ; Liver Neoplasms/genetics/metabolism ; RNA/genetics/metabolism ; Rats ; Stem Cells/cytology/*enzymology ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; Up-Regulation/genetics ; },
abstract = {Rat hepatic stem-like epithelial cells, LE/2, LE/6, and WB-F344, share some phenotypic properties with oval cells, observed in the early stages of hepatocarcinogenesis. Here, we describe regulations of telomerase and telomere length during in vitro aging of LEs and WB-F344. These cells displayed no apparent aging phenotypes for over 140 passages. Telomerase activity and telomere length of these cells progressively decreased with the passages, and at the late passages, telomere shortening appeared to be reduced as telomerase activity increased. Regulation of TERT and TR, key components of telomerase, was similar to that of the telomerase activity. LEs possessed weak telomerase activity with a slow rate of proliferation compared to WB-F344, and were not tumorigenic, whereas WB-F344 was transformed in vitro from intermediate passage. In conclusion, LEs and WB-F344 have different biochemical properties, and telomerase activation and short telomeres are unlikely necessary for the transformation of WB-F344. TERT and TR seem to be the regulators of the telomerase activity. The relationship between telomere length and telomerase activity suggests that telomerase contributes to the regulation of telomere length in these cells. Our findings provide a better understanding of mechanisms in neoplastic transformation of rat hepatic stem-like epithelial cells.},
}
@article {pmid15258808,
year = {2004},
author = {Tek, AL and Jiang, J},
title = {The centromeric regions of potato chromosomes contain megabase-sized tandem arrays of telomere-similar sequence.},
journal = {Chromosoma},
volume = {113},
number = {2},
pages = {77-83},
pmid = {15258808},
issn = {0009-5915},
mesh = {Base Sequence ; Centromere/*genetics ; DNA Methylation ; DNA, Plant/*genetics ; Heterochromatin/*genetics ; Molecular Sequence Data ; Sequence Homology, Nucleic Acid ; Solanum/*genetics ; Telomere/*genetics ; },
abstract = {Telomere-similar sequences have been found in non-telomeric regions in various eukaryotic species. Centromeric regions often harbor such interstitial telomeric repeats (ITRs). We isolated a 2.8 kb ITR, pSbTC1, in a diploid potato species Solanum bulbocastanum. DNA sequences related to the pSbTC1 family are widely distributed in different Solanum species. The pSbTC1-related sequences are organized into tandem arrays and located mainly in the centromeric regions of potato chromosomes. Most notably, the pSbTC1-related sequences have undergone extensive amplification and a single array can span up to multiple megabases. These results suggest that the pSbTC1-related sequences are not simple relics of ancient events in karyotype evolution, such as chromosomal fusions. We also demonstrated that the pSbTC1-related sequences are heavily methylated and are associated with highly condensed centromeric heterochromatin.},
}
@article {pmid15258557,
year = {2004},
author = {Lincz, LF and Scorgie, FE and Sakoff, JA and Fagan, KA and Ackland, SP and Enno, A},
title = {Telomere length predicts neutrophil recovery in the absence of G-CSF after autologous peripheral blood stem cell transplantation.},
journal = {Bone marrow transplantation},
volume = {34},
number = {5},
pages = {439-445},
doi = {10.1038/sj.bmt.1704607},
pmid = {15258557},
issn = {0268-3369},
mesh = {Adolescent ; Adult ; Blood Component Removal ; Blood Platelets/cytology ; Female ; Granulocyte Colony-Stimulating Factor/*pharmacology ; Hematologic Neoplasms/immunology/*therapy ; Hematopoietic Stem Cell Transplantation/*adverse effects ; Humans ; In Vitro Techniques ; Male ; Middle Aged ; Neutrophils/*cytology ; Predictive Value of Tests ; Recovery of Function/immunology ; *Telomere ; },
abstract = {Haemopoietic regeneration after autologous peripheral blood progenitor cell (PBPC) transplantation can be delayed in some patients despite adequate infusion of CD34(+) cells. This suggests variability in the proliferation potential of the implanted cells, a capacity that may be predicted by their telomere length. To test this theory, telomere length was measured on stored apheresis samples from 36 patients aged 46.6+/-11.1 years, who had undergone successful autologous PBPC transplantation with a median of 5.6 x 10(6)/kg (1.3 x 10(6)-36.1 x 10(6)/kg) CD34(+) cells. The mean PBPC telomere length for the cohort was 9.4+/-2.3 kbp. For patients who did not receive G-CSF post transplantation (n=7), days to absolute neutrophil recovery (ANC), >/=0.1, 0.5 and 1.0 x 10(9) cells/l, were significantly inversely correlated with telomere length of the infused PBPC (r=-0.88, -0.81, -0.77, respectively; P<0.05,). However, no correlation was found for patients who received G-CSF from day 1 post transplantation (n=20). These data suggest that for transplantation with sufficient CD34(+) cells, neutrophil recovery is less efficient in patients receiving infusions of cells with short telomeres, but this deficiency can be corrected with adequate post transplantation administration of G-CSF. Bone Marrow Transplantation (2004) 34, 439-445. doi:10.1038/sj.bmt.1704607 Published online 19 July 2004},
}
@article {pmid15258263,
year = {2004},
author = {Shakirov, EV and Shippen, DE},
title = {Length regulation and dynamics of individual telomere tracts in wild-type Arabidopsis.},
journal = {The Plant cell},
volume = {16},
number = {8},
pages = {1959-1967},
pmid = {15258263},
issn = {1040-4651},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; GM65383/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Arabidopsis/*genetics/metabolism ; DNA, Plant/*analysis ; Ecosystem ; Evolution, Molecular ; Genetic Variation ; Humans ; Random Allocation ; Telomere/genetics/*metabolism ; },
abstract = {Although length of the telomeric DNA tract varies widely across evolution, a species-specific set point is established and maintained by unknown mechanisms. To investigate how telomere length is controlled in Arabidopsis thaliana, we analyzed bulk telomere length in 14 wild-type accessions. We found that telomere tracts in Arabidopsis are fairly uniformly distributed throughout a size range of 2 to 9 kb. Unexpectedly, telomeres in plants of the Wassilewskija ecotype displayed a bimodal size distribution, with some individuals harboring telomeres of 2 to 5 kb and others telomeres of 4 to 9 kb. F1 and F2 progeny of a cross between long and short telomere parents had intermediate telomeres, implying that telomere length in Arabidopsis is not controlled by a single genetic factor. We provide evidence that although global telomere length is strictly regulated within an ecotype-specific range, telomere tracts on individual chromosome ends do not occupy a predetermined length territory. We also demonstrate that individual telomere tracts on homologous chromosomes are coordinately regulated throughout development and that telomerase acts preferentially on the shortest telomeres. We propose that an optimal size for telomere tracts is established and maintained for each Arabidopsis ecotype.},
}
@article {pmid15256487,
year = {2004},
author = {Oikemus, SR and McGinnis, N and Queiroz-Machado, J and Tukachinsky, H and Takada, S and Sunkel, CE and Brodsky, MH},
title = {Drosophila atm/telomere fusion is required for telomeric localization of HP1 and telomere position effect.},
journal = {Genes &amp; development},
volume = {18},
number = {15},
pages = {1850-1861},
pmid = {15256487},
issn = {0890-9369},
mesh = {Animals ; Animals, Genetically Modified ; Apoptosis ; Ataxia Telangiectasia/pathology ; Ataxia Telangiectasia Mutated Proteins ; Base Sequence ; Cell Cycle ; Cell Cycle Proteins ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/*metabolism ; Chromosomes/genetics/*metabolism ; DNA Damage ; DNA-Binding Proteins ; Drosophila melanogaster/cytology/*genetics/metabolism ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Mutation ; Protein Serine-Threonine Kinases/genetics/*physiology ; Sequence Homology, Nucleic Acid ; Telomere/*physiology ; Terminal Repeat Sequences/*genetics ; Tumor Suppressor Protein p53/genetics/metabolism ; Tumor Suppressor Proteins ; },
abstract = {Terminal deletions of Drosophila chromosomes can be stably protected from end-to-end fusion despite the absence of all telomere-associated sequences. The sequence-independent protection of these telomeres suggests that recognition of chromosome ends might contribute to the epigenetic protection of telomeres. In mammals, Ataxia Telangiectasia Mutated (ATM) is activated by DNA damage and acts through an unknown, telomerase-independent mechanism to regulate telomere length and protection. We demonstrate that the Drosophila homolog of ATM is encoded by the telomere fusion (tefu) gene. In the absence of ATM, telomere fusions occur even though telomere-specific Het-A sequences are still present. High levels of spontaneous apoptosis are observed in ATM-deficient tissues, indicating that telomere dysfunction induces apoptosis in Drosophila. Suppression of this apoptosis by p53 mutations suggests that loss of ATM activates apoptosis through a DNA damage-response mechanism. Loss of ATM reduces the levels of heterochromatin protein 1 (HP1) at telomeres and suppresses telomere position effect. We propose that recognition of chromosome ends by ATM prevents telomere fusion and apoptosis by recruiting chromatin-modifying complexes to telomeres.},
}
@article {pmid15254230,
year = {2004},
author = {Chiang, YJ and Kim, SH and Tessarollo, L and Campisi, J and Hodes, RJ},
title = {Telomere-associated protein TIN2 is essential for early embryonic development through a telomerase-independent pathway.},
journal = {Molecular and cellular biology},
volume = {24},
number = {15},
pages = {6631-6634},
pmid = {15254230},
issn = {0270-7306},
mesh = {Animals ; Blastocyst/metabolism ; Blotting, Southern ; Cell Survival ; DNA/chemistry ; Gene Targeting ; Genetic Vectors ; Genotype ; Heterozygote ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Mice, Transgenic ; Models, Genetic ; Mutation ; Polymerase Chain Reaction ; Protein Binding ; Repetitive Sequences, Nucleic Acid ; Telomerase/*metabolism ; Telomere-Binding Proteins/metabolism/*physiology ; Telomeric Repeat Binding Protein 1/metabolism ; Time Factors ; },
abstract = {TIN2 is a negative regulator of telomere elongation that interacts with telomeric DNA repeat binding factor 1 (TRF1) and affects telomere length by a telomerase-dependent mechanism. Here we show that inactivation of the mouse TRF1-interacting protein 2 (TIN2) gene results in early embryonic lethality. We further observed that the embryonic lethality of TIN2 mutant mice was not affected by inactivation of the telomerase reverse transcriptase gene, indicating that embryonic lethality is not the result of telomerase-dependent changes in telomere length or function. Our findings suggest that TIN2 has a role independent of telomere length regulation that is essential for embryonic development and cell viability.},
}
@article {pmid15247331,
year = {2004},
author = {Cheung, I and Schertzer, M and Baross, A and Rose, AM and Lansdorp, PM and Baird, DM},
title = {Strain-specific telomere length revealed by single telomere length analysis in Caenorhabditis elegans.},
journal = {Nucleic acids research},
volume = {32},
number = {11},
pages = {3383-3391},
pmid = {15247331},
issn = {1362-4962},
mesh = {Animals ; Base Sequence ; Caenorhabditis elegans/*genetics ; Molecular Sequence Data ; Mutation ; Polymerase Chain Reaction/*methods ; Species Specificity ; Telomere/*ultrastructure ; },
abstract = {Terminal restriction fragment analysis is the only method currently available for measuring telomere length in Caenorhabditis elegans. Its limitations include low sensitivity and interference by the presence of interstitial telomeric sequences in the C.elegans genome. Here we report the adaptation of single telomere length analysis (STELA) to measure the length of telomeric repeats on the left arm of chromosome V in C.elegans. This highly sensitive PCR-based method allows telomere length measurement from as few as a single worm. The application of STELA to eight wild-type C.elegans strains revealed considerable strain-specific differences in telomere length. Within individual strains, short outlying telomeres were observed that were clearly distinct from the bulk telomere length distributions, suggesting that processes other than end-replication losses and telomerase-mediated lengthening may generate telomere length heterogeneity in C.elegans. The utility of this method was further demonstrated by the characterization of telomere shortening in mrt-2 mutants. We conclude that STELA appears to be a valuable tool for studying telomere biology in C.elegans.},
}
@article {pmid15247245,
year = {2004},
author = {Maita, N and Anzai, T and Aoyagi, H and Mizuno, H and Fujiwara, H},
title = {Crystal structure of the endonuclease domain encoded by the telomere-specific long interspersed nuclear element, TRAS1.},
journal = {The Journal of biological chemistry},
volume = {279},
number = {39},
pages = {41067-41076},
doi = {10.1074/jbc.M406556200},
pmid = {15247245},
issn = {0021-9258},
mesh = {Amino Acid Sequence ; Aspartic Acid/chemistry ; Base Sequence ; Catalytic Domain ; Crystallography, X-Ray/methods ; DNA/chemistry ; DNA Mutational Analysis ; Electrons ; Endonucleases/*chemistry ; Humans ; *Long Interspersed Nucleotide Elements ; Magnesium/chemistry ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; *Nucleic Acid Conformation ; Oligonucleotides/chemistry ; Plasmids/metabolism ; Protein Binding ; Protein Conformation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Sequence Homology, Amino Acid ; Telomere/chemistry/ultrastructure ; },
abstract = {The telomere-specific long interspersed nuclear element, TRAS1, encodes an endonuclease domain, TRAS1-EN, which specifically cleaves the telomeric repeat targets (TTAGG)n of insects and (TTAGGG)n of vertebrates. To elucidate the sequence-specific recognition properties of TRAS1-EN, we determined the crystal structure at 2.4-A resolution. TRAS1-EN has a four-layered alpha/beta sandwich structure; its topology is similar to apurinic/apyrimidinic endonucleases, but the beta-hairpin (beta10-beta11) at the edge of the DNA-binding surface makes an extra loop that distinguishes TRAS1-EN from cellular apurinic/apyrimidinic endonucleases. A protein-DNA complex model suggests that the beta10-beta11 hairpin fits into the minor groove, enabling interaction with the telomeric repeats. Mutational studies of TRAS1-EN also indicated that the Asp-130 and beta10-beta11 hairpin structure are involved in specific recognition of telomeric repeats.},
}
@article {pmid15247029,
year = {2004},
author = {Kawanishi, S and Oikawa, S},
title = {Mechanism of telomere shortening by oxidative stress.},
journal = {Annals of the New York Academy of Sciences},
volume = {1019},
number = {},
pages = {278-284},
doi = {10.1196/annals.1297.047},
pmid = {15247029},
issn = {0077-8923},
mesh = {8-Hydroxy-2'-Deoxyguanosine ; *Aging ; Copper/metabolism ; DNA/metabolism ; DNA Damage ; Deoxyguanosine/*analogs &amp; derivatives/pharmacology ; Fibroblasts/metabolism ; Free Radicals ; HL-60 Cells ; Humans ; Hydrogen Peroxide/pharmacology ; Oligonucleotides/chemistry ; *Oxidative Stress ; Oxygen/metabolism ; Riboflavin/pharmacology ; Telomere/*ultrastructure ; Ultraviolet Rays ; },
abstract = {We investigated whether oxidative stress, which contributes to aging, accelerates the telomere shortening in human cultured cells. The terminal restriction fragment (TRF) from WI-38 fibroblasts irradiated with UVA (365-nm light) decreased with increasing of the irradiation dose. Furthermore, UVA irradiation dose-dependently increased the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in both WI-38 fibroblasts and HL-60 cells. In order to clarify the mechanism of the acceleration of telomere shortening, we investigated site-specific DNA damage induced by UVA irradiation in the presence of endogenous photosensitizers using (32)P 5' end-labeled DNA fragments containing telomeric oligonucleotide (TTAGGG)(4). UVA irradiation with riboflavin induced 8-oxodG formation in the DNA fragments containing telomeric sequence, and Fpg protein treatment led to chain cleavages at the central guanine of 5'-GGG-3' in telomere sequence. Human 8-oxodG-DNA glycosylase introduces a chain break in a double-stranded oligonucleotide specifically at an 8-oxodG residue. The amount of 8-oxodG formation in DNA fragment containing telomere sequence [5'-CGC(TTAGGG)(7)CGC-3'] was approximately five times more than that in the DNA fragment containing nontelomere sequence [5'-CGC(TGTGAG)(7)CGC-3']. Furthermore, H(2)O(2) plus Cu(II) caused DNA damage, including 8-oxodG formation, specifically at the GGG sequence in the telomere sequence (5'-TTAGGG-3'). It is concluded that the formation of 8-oxodG at the GGG triplet in telomere sequence induced by oxidative stress could participate in acceleration of telomere shortening.},
}
@article {pmid15247026,
year = {2004},
author = {Baird, DM and Kipling, D},
title = {The extent and significance of telomere loss with age.},
journal = {Annals of the New York Academy of Sciences},
volume = {1019},
number = {},
pages = {265-268},
doi = {10.1196/annals.1297.044},
pmid = {15247026},
issn = {0077-8923},
mesh = {*Aging ; Humans ; In Situ Hybridization, Fluorescence ; Polymerase Chain Reaction ; Telomere/*pathology/ultrastructure ; },
abstract = {By imposing a limit on the proliferative life span of some human cell types, telomere loss and the subsequent onset of replicative senescence have been proposed to contribute to age-related disease. Although there is a large body of in vitro data to reveal the mechanisms by which telomere erosion triggers senescence, technical limitations have hampered our ability to understand the full extent of telomere erosion in vivo. Thus far, we have evidence of age-related telomere loss; however, the lack of resolution of existing technologies does not allow us to determine if telomere erosion is extensive enough to trigger replicative senescence in vivo. This coupled with the considerable interindividual heterogeneity, and the overlap in telomere lengths between young and elder individuals, render any correlation weak and the significance unclear. However, recent technical developments, including adaptations of quantitative telomere fluorescence, in situ hybridization (Q-FISH), and the PCR-based single telomere length analysis (STELA), have increased the resolution of telomere length analysis. These technologies promise to provide the evidence required to address the full extent and significance of telomere loss in the human aging process. Here, we review published data on the dynamics of telomere erosion with age in the human body.},
}
@article {pmid15247008,
year = {2004},
author = {de Grey, AD and Campbell, FC and Dokal, I and Fairbairn, LJ and Graham, GJ and Jahoda, CA and Porterg, AC},
title = {Total deletion of in vivo telomere elongation capacity: an ambitious but possibly ultimate cure for all age-related human cancers.},
journal = {Annals of the New York Academy of Sciences},
volume = {1019},
number = {},
pages = {147-170},
doi = {10.1196/annals.1297.026},
pmid = {15247008},
issn = {0077-8923},
mesh = {Animals ; Antineoplastic Agents/pharmacology ; Bone Marrow Cells/pathology ; Cellular Senescence ; DNA/ultrastructure ; Disease Progression ; Gene Deletion ; Humans ; Immune System ; Mice ; Mice, Knockout ; Models, Biological ; Mutation ; Neoplasm Metastasis ; Neoplasms/*drug therapy/*pathology ; Stem Cells/metabolism ; Telomerase/metabolism ; Telomere/*ultrastructure ; },
abstract = {Despite enormous effort, progress in reducing mortality from cancer remains modest. Can a true cancer "cure" ever be developed, given the vast versatility that tumors derive from their genomic instability? Here we consider the efficacy, feasibility, and safety of a therapy that, unlike any available or in development, could never be escaped by spontaneous changes of gene expression: the total elimination from the body of all genetic potential for telomere elongation, combined with stem cell therapies administered about once a decade to maintain proliferative tissues despite this handicap. We term this therapy WILT, for whole-body interdiction of lengthening of telomeres. We first argue that a whole-body gene-deletion approach, however bizarre it initially seems, is truly the only way to overcome the hypermutation that makes tumors so insidious. We then identify the key obstacles to developing such a therapy and conclude that, while some will probably be insurmountable for at least a decade, none is a clear-cut showstopper. Hence, given the absence of alternatives with comparable anticancer promise, we advocate working toward such a therapy.},
}
@article {pmid15245567,
year = {2004},
author = {Hastings, R and Qureshi, M and Verma, R and Lacy, PS and Williams, B},
title = {Telomere attrition and accumulation of senescent cells in cultured human endothelial cells.},
journal = {Cell proliferation},
volume = {37},
number = {4},
pages = {317-324},
pmid = {15245567},
issn = {0960-7722},
mesh = {Cell Line ; Cells, Cultured ; *Cellular Senescence ; DNA/metabolism ; Endothelium, Vascular/*ultrastructure ; Humans ; Telomere/*diagnostic imaging ; Ultrasonography ; Umbilical Veins/cytology ; },
abstract = {The human umbilical vein endothelial cell (HUVEC) is an important model of the human endothelium that is widely used in vascular research. HUVECs and the adult endothelium share many characteristics including progression into senescence as the cells age. Despite this, the shortening of telomeres and its relationship to the progression into senescence are poorly defined in HUVECs. In this study of several HUVEC lines we show notable consistency in their growth curves. There is a steady decline in the growth rate of HUVECs grown continually in culture and we estimate complete cessation of growth after approximately 70 population doublings. The HUVECs lose telomeric DNA at a consistent rate of 90 base pairs/population doubling and show a progressive accumulation of shortened telomeres (below 5 kilobases). This telomeric loss correlates with the accumulation of senescent HUVECs in culture as assessed by staining for beta-galactosidase activity at pH 6. Although the telomere length of a large population of cells is a relatively crude measure, we suggest that in HUVECs a mean telomere length (as measured by terminal restriction fragment length) of 5 kilobases is associated with entry into senescence. These data demonstrate the strong relationship between telomere attrition and cell senescence in HUVECs. They suggest that DNA damage and subsequent telomere attrition are likely to be key mechanisms driving the development of endothelial senescence in the pathogenesis of vascular disease.},
}
@article {pmid15242758,
year = {2004},
author = {Rubio, MA and Davalos, AR and Campisi, J},
title = {Telomere length mediates the effects of telomerase on the cellular response to genotoxic stress.},
journal = {Experimental cell research},
volume = {298},
number = {1},
pages = {17-27},
doi = {10.1016/j.yexcr.2004.04.004},
pmid = {15242758},
issn = {0014-4827},
support = {AG00266/AG/NIA NIH HHS/United States ; AG09909/AG/NIA NIH HHS/United States ; AG17242/AG/NIA NIH HHS/United States ; },
mesh = {Antineoplastic Agents/pharmacology/therapeutic use ; Bleomycin/pharmacology ; Catalytic Domain/genetics ; Cell Division/drug effects/genetics ; Cell Line ; Cellular Senescence/drug effects/genetics ; DNA Damage/drug effects/*genetics ; Drug Resistance, Neoplasm/*genetics ; Enzyme Inhibitors/pharmacology/therapeutic use ; Etoposide/pharmacology ; Fibroblasts/cytology/metabolism/radiation effects ; Gene Transfer Techniques ; Humans ; Hydrogen Peroxide/pharmacology ; Oxidative Stress/drug effects/genetics ; Telomerase/*genetics/*metabolism ; Telomere/*genetics ; },
abstract = {Telomerase inhibition may be a novel anti-cancer strategy that can be used in combination with conventional therapies, such as DNA damaging agents. There are conflicting reports as to whether and to what extent telomerase and telomere length influence the sensitivity of cells to genotoxins. To understand the relationship between telomere length, telomerase expression, and sensitivity to genotoxic stress, we expressed the catalytic subunit of telomerase, hTERT, in human fibroblasts having different telomere lengths. We show that telomerase confers resistance to ionizing radiation, bleomycin, hydrogen peroxide, and etoposide only in cells with short, presumably near-dysfunctional, telomeres. This resistance depended on the ability of telomerase to elongate the short telomeres, and telomerase did not protect cells with long telomeres. Interestingly, although long telomeres had no effect on sensitivity to etoposide and bleomycin, they exacerbated sensitivity to hydrogen peroxide, supporting the idea that, compared to other types of DNA damage, telomeres are particularly vulnerable to oxidative damage. Our findings identify a mechanism and conditions under which telomerase and telomeres affect the response of human cells to genotoxic agents and may have important implications for anti-cancer interventions.},
}
@article {pmid15239089,
year = {2004},
author = {Plentz, RR and Caselitz, M and Bleck, JS and Gebel, M and Flemming, P and Kubicka, S and Manns, MP and Rudolph, KL},
title = {Hepatocellular telomere shortening correlates with chromosomal instability and the development of human hepatoma.},
journal = {Hepatology (Baltimore, Md.)},
volume = {40},
number = {1},
pages = {80-86},
doi = {10.1002/hep.20271},
pmid = {15239089},
issn = {0270-9139},
mesh = {Adult ; Aged ; Aneuploidy ; Biopsy, Needle ; Carcinoma, Hepatocellular/etiology/*genetics/pathology ; Chromosomal Instability/*genetics ; Female ; Hepatocytes/*ultrastructure ; Humans ; In Situ Hybridization, Fluorescence ; Liver/pathology ; Liver Cirrhosis/complications ; Liver Neoplasms/etiology/*genetics/pathology ; Male ; Middle Aged ; Telomere/*ultrastructure ; },
abstract = {The telomere hypothesis of cancer initiation indicates that telomere shortening initiates cancer by induction of chromosomal instability. To test whether this hypothesis applies to human hepatocellular carcinoma (HCC), we analyzed the telomere length of hepatocytes in cytological smears of fine-needle biopsies of liver tumors from patients with cirrhosis (n = 39). The tumors consisted of 24 HCC and 15 regenerative nodules as diagnosed by combined histological and cytological diagnostics. In addition, we analyzed the telomere length of hepatocytes in HCC and surrounding noncancerous liver tissue within individual patients in another cohort of 10 patients with cirrhosis. Telomere length analysis of hepatocytes was correlated with tumor pathology and ploidy grade of the tumors, which was analyzed by cytophotometry. Telomeres were significantly shortened in hepatocytes of HCC compared to hepatocytes in regenerative nodules or surrounding noncancerous liver tissue. Hepatocyte telomere shortening in HCC was independent of the patient's age. There was no overlap in mean telomere lengths of individual samples when comparing HCC with regenerative nodules or noncancerous surrounding liver. Within the HCC group, telomeres were significantly shorter in hepatocytes of aneuploid tumors compared to diploid tumors. In conclusion, our data suggest that the telomere hypothesis of cancer initiation applies to human HCC and that cell type-specific telomere length analysis might indicate the risk of HCC development.},
}
@article {pmid15238429,
year = {2005},
author = {Knudson, M and Kulkarni, S and Ballas, ZK and Bessler, M and Goldman, F},
title = {Association of immune abnormalities with telomere shortening in autosomal-dominant dyskeratosis congenita.},
journal = {Blood},
volume = {105},
number = {2},
pages = {682-688},
doi = {10.1182/blood-2004-04-1673},
pmid = {15238429},
issn = {0006-4971},
support = {CA105312/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Antibody Formation ; Apoptosis/immunology ; Cell Division/immunology ; Cell Survival/immunology ; Child ; Child, Preschool ; Dyskeratosis Congenita/*genetics/immunology/*pathology ; Female ; Genes, Dominant ; Homeostasis/immunology ; Humans ; Immunity, Cellular ; Male ; Middle Aged ; Mitosis/immunology ; Pedigree ; T-Lymphocytes/cytology/physiology ; Telomere/*immunology/*pathology ; },
abstract = {Dyskeratosis congenita (DC) is an inherited bone marrow failure disorder characterized by abnormal skin pigmentation and nail dystrophy. We have recently described, in 10 members of a large 3-generation family, an autosomal-dominant form of DC (AD DC) that is due to a mutation in the gene-encoding human telomerase RNA (TERC), resulting in telomere shortening. In studying the immunologic consequences of TERC mutations, severe B lymphopenia and decreased immunoglobulin M (IgM) levels were noted. T cells were found to overexpress senescent markers, including CD57 and Fas receptor, and were moderately reduced in cell number. To determine whether these in vivo findings were related to cellular replicative defects, short-term cultures of AD DC lymphocytes were established to measure proliferation, mitoses, and apoptosis. AD DC lymphocytes displayed a markedly reduced proliferative capacity and increased basal apoptotic rate. Finally, telomere shortening was most prominent in third-generation subjects, and there appeared to be a correlation between telomere length and in vivo and in vitro immune findings. In summary, the observed lymphopenia and hypogammaglobulinemia in AD DC is likely a consequence of replicative failure and premature senescence of lymphocytes, supporting a role of telomerase activity in immune homeostasis.},
}
@article {pmid15237236,
year = {2004},
author = {Xin, Z and Broccoli, D},
title = {Manipulating mouse telomeres: models of tumorigenesis and aging.},
journal = {Cytogenetic and genome research},
volume = {105},
number = {2-4},
pages = {471-478},
doi = {10.1159/000078221},
pmid = {15237236},
issn = {1424-859X},
mesh = {Aging/*genetics ; Animals ; Antigens, Nuclear ; Cell Transformation, Neoplastic/*genetics ; Cyclin-Dependent Kinase Inhibitor p16/deficiency ; DNA-Activated Protein Kinase ; DNA-Binding Proteins/deficiency ; Disease Models, Animal ; Ku Autoantigen ; Mice ; Models, Animal ; Protein Serine-Threonine Kinases/deficiency ; RNA ; Telomerase/deficiency/genetics ; *Telomere ; Tumor Suppressor Protein p14ARF/deficiency ; Tumor Suppressor Protein p53/deficiency ; },
abstract = {Telomeres are capping structures at the ends of chromosomes, composed of a repetitive DNA sequence and associated proteins. Both a minimal length of telomeric repeats and telomere-associated binding proteins are necessary for proper telomere function. Functional telomeres are essential for maintaining the integrity and stability of eukaryotic genomes. The capping structure enables cells to distinguish chromosome ends from double strand breaks (DSBs) in the genome. Uncapped chromosome ends are at great risk for degradation, recombination, or chromosome fusion by cellular DNA repair systems. Dysfunctional telomeres have been proposed to contribute to tumorigenesis and some aging phenotypes. The analysis of mice deficient in telomerase activity and other telomere-associated proteins has allowed the roles of dysfunctional telomeres in tumorigenesis and aging to be directly tested. Here we will focus on the analysis of different mouse models disrupted for proteins that are important for telomere functions and discuss known and proposed consequences of telomere dysfunction in tumorigenesis and aging.},
}
@article {pmid15237235,
year = {2004},
author = {Wong, HP and Slijepcevic, P},
title = {Telomere length measurement in mouse chromosomes by a modified Q-FISH method.},
journal = {Cytogenetic and genome research},
volume = {105},
number = {2-4},
pages = {464-470},
doi = {10.1159/000078220},
pmid = {15237235},
issn = {1424-859X},
mesh = {Animals ; Cell Line, Tumor ; Chromosomes ; Demecolcine/pharmacology ; In Situ Hybridization, Fluorescence/*methods ; Mice ; Reference Standards ; *Telomere/drug effects ; },
abstract = {Telomeres are physical ends of mammalian chromosomes that dynamically change during the lifetime of a cell or organism. In order to understand mechanisms responsible for telomere dynamics, it is necessary to develop methods for accurate telomere length measurement. The most sensitive method for measuring telomere length in mouse chromosomes is quantitative fluorescence in situ hybridization (Q-FISH). The usual protocol for Q-FISH requires plasmids with variable numbers of telomeric repeats and fluorescence beads as calibration standards. Here, we describe a Q-FISH protocol in which two mouse lymphoma cell lines with well-defined telomere lengths are used as calibration standards. Using this protocol we demonstrate that reproducible results can be obtained in a set of four different mouse cell lines. This method can be adapted so that any pair of mammalian cell lines can serve as an internal calibration standard.},
}
@article {pmid15237205,
year = {2004},
author = {Tankimanova, M and Hultén, MA and Tease, C},
title = {The initiation of homologous chromosome synapsis in mouse fetal oocytes is not directly driven by centromere and telomere clustering in the bouquet.},
journal = {Cytogenetic and genome research},
volume = {105},
number = {2-4},
pages = {172-181},
doi = {10.1159/000078187},
pmid = {15237205},
issn = {1424-859X},
mesh = {Animals ; Centromere/*physiology ; Chromosome Pairing/*physiology ; Cryopreservation ; Female ; Fluorescent Antibody Technique ; In Situ Hybridization, Fluorescence ; Male ; Meiosis/*physiology ; Mice ; Mice, Inbred C3H ; Models, Genetic ; Oocytes/*cytology ; Sex Characteristics ; Telomere/*physiology ; },
abstract = {We investigated the behaviour of centromeres and distal telomeres during the initial phases of female meiosis in mice. In particular, we wished to determine whether clustering of centromeres and telomeres (bouquet formation) played the same crucial role in homologous chromosome pairing in female meiosis as it does in the male. We found that synapsis (intimate homologous chromosome pairing) is most frequently initiated in the interstitial regions of homologous chromosomes, apparently ahead of the distal regions. The proximal ends of the chromosomes appear to be disfavoured for synaptic initiation. Moreover, initiation of synapsis occurred in oocytes that showed little or no evidence of bouquet formation. A bouquet was present in a substantial proportion of cells at mid to late zygotene, and was still present in some pachytene oocytes. This pattern of bouquet formation and pairing initiation is in stark contrast to that previously described in the male mouse. We propose that although dynamic movements of centromeres and telomeres to form clusters may facilitate alignment of homologues or homologous chromosome segments during zygotene, in the female mouse positional control of synaptic initiation is dependent on some other mechanism.},
}
@article {pmid15235794,
year = {2004},
author = {Roig, I and Liebe, B and Egozcue, J and Cabero, L and Garcia, M and Scherthan, H},
title = {Female-specific features of recombinational double-stranded DNA repair in relation to synapsis and telomere dynamics in human oocytes.},
journal = {Chromosoma},
volume = {113},
number = {1},
pages = {22-33},
pmid = {15235794},
issn = {0009-5915},
mesh = {Adaptor Proteins, Signal Transducing ; Carrier Proteins ; Centromere/physiology ; Chromosome Pairing/*physiology ; DNA Repair/*physiology ; Female ; Fluorescent Antibody Technique ; Histones/metabolism ; Humans ; Karyotyping ; Meiotic Prophase I/physiology ; MutL Protein Homolog 1 ; Neoplasm Proteins/metabolism ; Nuclear Proteins ; Oocytes/*physiology ; Phosphorylation ; Synaptonemal Complex/physiology ; Telomere/*physiology ; },
abstract = {Chromosome segregation errors are a significant cause of aneuploidy among human neonates and often result from errors in female meiosis that occur during fetal life. For the latter reason, little is known about chromosome dynamics during female prophase I. Here, we analyzed chromosome reorganization, and centromere and telomere dynamics in meiosis in the human female by immunofluorescent staining of the SYCP3 and SYCP1 synaptonemal complex proteins and the course of recombinational DNA repair by IF of phospho-histone H2A.X (gamma-H2AX), RPA and MLH1 recombination proteins. We found that SYCP3, but not SYCP1, aggregates appear in the preleptotene nucleus and some persist up to pachytene. Telomere clustering (bouquet stage) in oocytes lasted from late-leptotene to early pachytene-significantly longer than in the male. Leptotene and zygotene oocytes and spermatocytes showed strong gamma-H2AX labeling, while gamma-H2AX patches, which colocalized with RPA, were present on SYCP1-tagged pachytene SCs. This was rarely seen in the male and may suggest that synapsis installs faster with respect to progression of recombinational double-strand break repair or that the latter is slower in the female. It is speculated that the presence of gamma-H2AX into pachytene highlights female-specific peculiarities of recombination, chromosome behavior and checkpoint control that may contribute to female susceptibility for aneuploidy.},
}
@article {pmid15235603,
year = {2004},
author = {Chang, S and Multani, AS and Cabrera, NG and Naylor, ML and Laud, P and Lombard, D and Pathak, S and Guarente, L and DePinho, RA},
title = {Essential role of limiting telomeres in the pathogenesis of Werner syndrome.},
journal = {Nature genetics},
volume = {36},
number = {8},
pages = {877-882},
doi = {10.1038/ng1389},
pmid = {15235603},
issn = {1061-4036},
support = {K08 AG001019/AG/NIA NIH HHS/United States ; K08 AG024873/AG/NIA NIH HHS/United States ; },
mesh = {Aging, Premature/genetics ; Animals ; Apoptosis/genetics ; Cells, Cultured ; Cellular Senescence ; Chromosomal Instability ; DNA Damage ; Diabetes Mellitus, Type 2/genetics ; Female ; Life Expectancy ; Mice ; Mice, Mutant Strains ; Neoplasms, Experimental/genetics ; Telomere/pathology/*physiology ; Werner Syndrome/*genetics ; Wound Healing/genetics ; },
abstract = {Mutational inactivation of the gene WRN causes Werner syndrome, an autosomal recessive disease characterized by premature aging, elevated genomic instability and increased cancer incidence. The capacity of enforced telomerase expression to rescue premature senescence of cultured cells from individuals with Werner syndrome and the lack of a disease phenotype in Wrn-deficient mice with long telomeres implicate telomere attrition in the pathogenesis of Werner syndrome. Here, we show that the varied and complex cellular phenotypes of Werner syndrome are precipitated by exhaustion of telomere reserves in mice. In late-generation mice null with respect to both Wrn and Terc (encoding the telomerase RNA component), telomere dysfunction elicits a classical Werner-like premature aging syndrome typified by premature death, hair graying, alopecia, osteoporosis, type II diabetes and cataracts. This mouse model also showed accelerated replicative senescence and accumulation of DNA-damage foci in cultured cells, as well as increased chromosomal instability and cancer, particularly nonepithelial malignancies typical of Werner syndrome. These genetic data indicate that the delayed manifestation of the complex pleiotropic of Wrn deficiency relates to telomere shortening.},
}
@article {pmid15234574,
year = {2004},
author = {Gil, ME and Coetzer, TL},
title = {Real-time quantitative RT-PCR for human telomere elongation reverse transcriptase in chronic myeloid leukemia.},
journal = {Leukemia research},
volume = {28},
number = {9},
pages = {969-972},
doi = {10.1016/j.leukres.2004.01.002},
pmid = {15234574},
issn = {0145-2126},
mesh = {DNA-Binding Proteins/standards ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*enzymology/genetics ; RNA, Neoplasm/*analysis ; Reverse Transcriptase Polymerase Chain Reaction/*methods/standards ; Telomerase/analysis/*genetics ; Ubiquitin C/standards ; },
abstract = {Telomeres cap chromosome ends and are pivotal for DNA stability. Deregulation of the telomere stabilising enzyme telomerase in malignancy has implications in diagnosis, prognosis and therapeutics of cancer. Quantification of the expression of the telomerase catalytic subunit, hTERT, using the LightCycler TeloTAGGG hTERT Quantification kit is not optimal for analysis of chronic myeloid leukemia (CML) samples. The internal control, porphobilinogen deaminase (PBGD) is amplified in a separate tube to hTERT and has an unstable genomic localisation of 11q23. Our laboratory thus developed a real-time reverse transcriptase polymerase chain reaction which co-amplifies hTERT and either mitochondrial single-stranded DNA binding protein 1 (ssBP1) or ubiquitin C (UBC).},
}
@article {pmid15231715,
year = {2004},
author = {Ye, JZ and Hockemeyer, D and Krutchinsky, AN and Loayza, D and Hooper, SM and Chait, BT and de Lange, T},
title = {POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex.},
journal = {Genes &amp; development},
volume = {18},
number = {14},
pages = {1649-1654},
pmid = {15231715},
issn = {0890-9369},
support = {P41 RR000862/RR/NCRR NIH HHS/United States ; K08 CA093604/CA/NCI NIH HHS/United States ; K08 CA93604/CA/NCI NIH HHS/United States ; T32 CA009673/CA/NCI NIH HHS/United States ; RR00862/RR/NCRR NIH HHS/United States ; T32 CA09673-26A1/CA/NCI NIH HHS/United States ; },
mesh = {Carrier Proteins/*metabolism ; Cloning, Molecular ; Fluorescent Antibody Technique ; HeLa Cells ; Humans ; *Intracellular Signaling Peptides and Proteins ; Mass Spectrometry ; RNA Interference ; Shelterin Complex ; Telomere/metabolism/*physiology ; Telomere-Binding Proteins/*metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; Two-Hybrid System Techniques ; },
abstract = {Human telomere length is controlled by a negative feedback loop based on the binding of TRF1 to double-stranded telomeric DNA. The TRF1 complex recruits POT1, a single-stranded telomeric DNA-binding protein necessary for cis-inhibition of telomerase. By mass spectrometry, we have identified a new telomeric protein, which we have named POT1-interacting protein 1 (PIP1). PIP1 bound both POT1 and the TRF1-interacting factor TIN2 and could tether POT1 to the TRF1 complex. Reduction of PIP1 or POT1 levels with shRNAs led to telomere elongation, indicating that PIP1 contributes to telomere length control through recruitment of POT1.},
}
@article {pmid15229185,
year = {2004},
author = {Lillard-Wetherell, K and Machwe, A and Langland, GT and Combs, KA and Behbehani, GK and Schonberg, SA and German, J and Turchi, JJ and Orren, DK and Groden, J},
title = {Association and regulation of the BLM helicase by the telomere proteins TRF1 and TRF2.},
journal = {Human molecular genetics},
volume = {13},
number = {17},
pages = {1919-1932},
doi = {10.1093/hmg/ddh193},
pmid = {15229185},
issn = {0964-6906},
support = {CA59268-06A1/CA/NCI NIH HHS/United States ; ES06096/ES/NIEHS NIH HHS/United States ; NS-008900/NS/NINDS NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases/*metabolism ; Base Sequence ; Bromodeoxyuridine ; Cell Cycle/genetics/physiology ; Cytogenetic Analysis ; DNA Helicases/*metabolism ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Humans ; Immunohistochemistry ; Immunoprecipitation ; In Situ Hybridization, Fluorescence ; *Models, Biological ; Molecular Sequence Data ; Oligonucleotides ; RecQ Helicases ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; Transfection ; Tumor Cells, Cultured ; Yeasts ; },
abstract = {In addition to increased DNA-strand exchange, a cytogenetic feature of cells lacking the RecQ-like BLM helicase is a tendency for telomeres to associate. We also report additional cellular and biochemical evidence for the role of BLM in telomere maintenance. BLM co-localizes and complexes with the telomere repeat protein TRF2 in cells that employ the recombination-mediated mechanism of telomere lengthening known as ALT (alternative lengthening of telomeres). BLM co-localizes with TRF2 in foci actively synthesizing DNA during late S and G2/M; co-localization increases in late S and G2/M when ALT is thought to occur. Additionally, TRF1 and TRF2 interact directly with BLM and regulate BLM unwinding activity in vitro. Whereas TRF2 stimulates BLM unwinding of telomeric and non-telomeric substrates, TRF1 inhibits BLM unwinding of telomeric substrates only. Finally, TRF2 stimulates BLM unwinding with equimolar concentrations of TRF1, but not when TRF1 is added in molar excess. These data suggest a function for BLM in recombination-mediated telomere lengthening and support a model for the coordinated regulation of BLM activity at telomeres by TRF1 and TRF2.},
}
@article {pmid15228657,
year = {2004},
author = {Wang, Y and Fang, MY and Jiang, F and Peng, HJ},
title = {[Effects of arsenic trioxide, ginseng saponin and beta-elemene on telomere-telomerase system in K562 cell line].},
journal = {Zhongguo shi yan xue ye xue za zhi},
volume = {12},
number = {3},
pages = {315-320},
pmid = {15228657},
issn = {1009-2137},
mesh = {Arsenic Trioxide ; Arsenicals/*pharmacology ; Cell Survival/drug effects ; Humans ; K562 Cells ; Oxides/*pharmacology ; *Panax ; Saponins/*pharmacology ; Sesquiterpenes/*pharmacology ; Telomerase/*metabolism ; Telomere/*drug effects ; },
abstract = {The aim was to explore the modulating and inhibiting effects of arsenic trioxide, ginseng saponin and beta-elemene on telomere length and telomerase activity in K562 cell line, and to study their anti-tumor mechanism and seek new method of therapy for acute leukemia. Human erythroleukemia cell line K562 was co-cultured with arsenic trioxide, ginseng saponin, beta-elemene separately, cells were collected after 24, 48 and 72 hours for further detecting. Telomere length and telomerase activity were detected by the methods of Southern-blot and PCR-ELISA respectively. The effects of these drugs on telomere length and telomerase activity were observed at different concentrations and length of time. The results showed that (1) telomerase activity of K562 cells decreased after co-cultured with arsenic trioxide, ginseng saponin and beta-elemene. The inhibiting effects depended on drug concentrations and length of time. When co-cultured at proper concentration and period of time, telomerase activity could be inhibited; (2) viability of K562 cells decreased after co-cultured with arsenic trioxide, ginseng saponin and beta-elemene, the inhibiting effect depends on drug concentrations and length of time; (3) after co-cultured with arsenic trioxide, ginseng saponin, and beta-elemene for 72 hours, telomere length of K562 cell line prolonged a little. It is concluded that (1) arsenic trioxide, ginseng saponin and beta-elemene can inhibit telomerase activity in K562 cell line, the suppression of telomerase activity may be one of the mechanisms of anti-tumor effect; (2) arsenic trioxide, ginseng saponin and beta-elemene can inhibit the growth of K562 cell line, the inhibiting effect depends on concentration and time; (3) when telomerase activity was suppressed, the telomere length prolonged a little, indicating that in K562 cell line may exist another mechanism to regulate telomere length, except telomerase activation.},
}
@article {pmid15223635,
year = {2004},
author = {Drummond, M and Lennard, A and Brûmmendorf, T and Holyoake, T},
title = {Telomere shortening correlates with prognostic score at diagnosis and proceeds rapidly during progression of chronic myeloid leukemia.},
journal = {Leukemia &amp; lymphoma},
volume = {45},
number = {9},
pages = {1775-1781},
doi = {10.1080/10428190410001693542},
pmid = {15223635},
issn = {1042-8194},
mesh = {Adult ; Aged ; Aged, 80 and over ; Benzamides ; Cells, Cultured ; Disease Progression ; Drug Resistance, Neoplasm ; Female ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*diagnosis/drug therapy/*genetics/pathology ; Male ; Middle Aged ; Neoplasm Staging ; Piperazines/therapeutic use ; Prognosis ; Pyrimidines/therapeutic use ; T-Lymphocytes/drug effects/metabolism/pathology ; Telomere/*metabolism ; Time Factors ; },
abstract = {Chronic myeloid leukemia (CML) is associated increased stem cell turnover. We have previously shown that short telomeres in chronic phase (CP) predict for early progression to blast phase (BP). Poor prognostic score patients may therefore exhibit increased telomere loss at diagnosis and/or a greater than normal rate of loss during the disease course. We prospectively studied newly diagnosed CML patients for degree of telomere loss; measured telomere length in CML patients at all stages of disease; and performed follow-up sampling according to cytogenetic response to imatinib mesylate. Using flow-FISH, telomere length in peripheral blood leucocytes (PBL) from 32 consecutive newly diagnosed patients was measured (with ex-vivo expanded T-cells as an internal BCR-ABL negative control), in addition to 65 samples from all CML stages and 7 paired CP/BP samples. Fifty-five normal individuals served as a control population. Patients who attained either a complete cytogenetic response (CCR, 0% Ph+, n = 10) or no CR (100% Ph+, n = 11) underwent follow-up measurement. All statistical tests were two sided. Telomeres in accelerated phase (AP) and BP patients were significantly shorter than in CP, and mean telomere shortening was significantly greater in high-risk score than low-risk patients (P < 0.05) at diagnosis. The rate of shortening during disease progression was 10-20 times the rate observed in normal granulocytes. BP samples had undergone at least 30-60 additional divisions from baseline Ph- telomere length. Our findings show that telomere shortening in CML is greatest in high-risk score patients at diagnosis, and occurs rapidly during disease progression.},
}
@article {pmid15222684,
year = {2004},
author = {Demerath, EW and Cameron, N and Gillman, MW and Towne, B and Siervogel, RM},
title = {Telomeres and telomerase in the fetal origins of cardiovascular disease: a review.},
journal = {Human biology},
volume = {76},
number = {1},
pages = {127-146},
pmid = {15222684},
issn = {0018-7143},
support = {HL68041/HL/NHLBI NIH HHS/United States ; DK64391/DK/NIDDK NIH HHS/United States ; R01 DK064391/DK/NIDDK NIH HHS/United States ; K24 HL068041/HL/NHLBI NIH HHS/United States ; R03 AG023251-01A1/AG/NIA NIH HHS/United States ; R01 HD012252/HD/NICHD NIH HHS/United States ; HD12252/HD/NICHD NIH HHS/United States ; DK68070/DK/NIDDK NIH HHS/United States ; R03 AG023251/AG/NIA NIH HHS/United States ; },
mesh = {Aging/genetics/pathology ; Cardiovascular Diseases/enzymology/*genetics/physiopathology ; Cellular Senescence/genetics ; Embryonic and Fetal Development/*genetics ; Female ; Growth/genetics ; Humans ; Pregnancy ; Selection, Genetic ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*pathology ; },
abstract = {Telomeres are noncoding functional DNA repeat sequences at the ends of chromosomes that decrease in length by a predictable amount at each cell division. When the telomeres become critically short, the cell is no longer able to replicate and enters cellular senescence. Recent work has shown that within individuals, telomere length tracks with cardiovascular health and aging and is also affected by growth variation, both prenatally and postnatally. Therefore telomere length can be a marker of both growth history (cell division) and tissue function (senescence). Relationships between early growth and later health have emerged as a research focus in the epidemiology of chronic diseases of aging, such as heart disease and diabetes. The "fetal origins" literature has demonstrated that hormonal and nutritional aspects of the intrauterine environment not only affect fetal growth but also can permanently alter the metabolic program of the individual. Smaller infants tend to have a higher risk of developing cardiovascular disease. Much less attention has been paid to possible genetic links between the processes of early growth and later disease. Our aim in this review is to summarize evidence for one such genetic mechanism, telomere attrition, that may underlie the fetal origins of cardiovascular disease and to discuss this mechanism in light of the evolution of senescence.},
}
@article {pmid15220541,
year = {2004},
author = {Gordon, KE and Parkinson, EK},
title = {Analysis of telomerase activity and telomere function in cancer.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {281},
number = {},
pages = {333-348},
doi = {10.1385/1-59259-811-0:333},
pmid = {15220541},
issn = {1064-3745},
mesh = {Chromosome Aberrations ; Humans ; Neoplasms/*enzymology ; Repetitive Sequences, Nucleic Acid/genetics ; Telomerase/*metabolism ; Telomere/*physiology ; },
abstract = {Telomeres are the structures at the ends of chromosomes, composed of repetitive sequences and associated proteins, which cap chromosome ends to maintain genomic stability. These structures are maintained by the enzyme complex telomerase in germ cells and some stem cells, but are absent in the majority of somatic cells. The consequence of this lack of telomerase in normal somatic cells is the shortening of the telomeric repeat, which results in a limited replicative life span. However, in cancer cells, which grow indefinitely, telomerase activity has been detected in a large number of different cancer cell types. This has lead to a great deal of interest in establishing techniques to measure telomerase activity, telomere length, and telomere function in both normal and cancer cells/tissue. Here we describe the TRAP (telomeric repeat amplification protocol) assay, a technique to measure telomerase activity in cells, TRF (terminal restriction fragment length) analysis to estimate telomere length, and both the anaphase bridge index and the frequency of dicentric chromosomes as indicators of telomere dysfunction.},
}
@article {pmid15213417,
year = {2003},
author = {Ning, Y},
title = {Telomeres and Senescence.},
journal = {Journal of the Association of Genetic Technologists},
volume = {29},
number = {3},
pages = {94-95},
pmid = {15213417},
issn = {1523-7834},
}
@article {pmid15213325,
year = {2004},
author = {Edmonds, D and Breitkreutz, BJ and Harrington, L},
title = {A genome-wide telomere screen in yeast: the long and short of it all.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {101},
number = {26},
pages = {9515-9516},
pmid = {15213325},
issn = {0027-8424},
mesh = {DNA, Fungal/genetics/metabolism ; Genes, Fungal/genetics ; *Genome, Fungal ; *Genomics ; Phenotype ; Saccharomyces cerevisiae/classification/*cytology/*genetics ; Sequence Deletion/*genetics ; Telomere/*metabolism ; },
}
@article {pmid15212946,
year = {2004},
author = {Swiggers, SJ and Nibbeling, HA and Zeilemaker, A and Kuijpers, MA and Mattern, KA and Zijlmans, JM},
title = {Telomerase activity level, but not hTERT mRNA and hTR level, regulates telomere length in telomerase-reconstituted primary fibroblasts.},
journal = {Experimental cell research},
volume = {297},
number = {2},
pages = {434-443},
doi = {10.1016/j.yexcr.2004.03.028},
pmid = {15212946},
issn = {0014-4827},
mesh = {Cells, Cultured ; Clone Cells ; DNA-Binding Proteins ; Fibroblasts/*enzymology ; Flow Cytometry ; *Gene Expression Regulation, Enzymologic ; Green Fluorescent Proteins ; Humans ; In Situ Hybridization, Fluorescence ; Luminescent Proteins ; Polymerase Chain Reaction ; RNA ; Retroviridae/genetics ; Skin/cytology ; Telomerase/*analysis ; Telomere/*metabolism ; },
abstract = {The critical factors in the regulation of telomere length are not yet clearly defined. Telomerase is a key player in telomere elongation, although previous studies have shown that telomeres are differentially elongated after telomerase reconstitution. Moreover, a clear relation between the level of telomerase activity and telomere length was not observed. To investigate which factors are critical in telomere length regulation, we generated 24 telomerase-reconstituted primary human fibroblast clones. In these clones, in vitro telomerase activity level is clearly related to telomere length. High levels of telomerase activity are associated with longer telomeres and better telomere maintenance over time. The correlation coefficient, however, indicates that the level of telomerase activity is not the only factor in the regulation of telomere length. Clearly, factors that are not measured in an in vitro telomerase activity assay are involved in telomere length regulation in vivo. To investigate which telomerase components are critical in regulating telomerase activity levels, we studied expression levels of hTERT mRNA and hTR. Expression is highly variable between individual clones, but not related to the level of telomerase activity or telomere length. Our results indicate that expression levels of hTERT mRNA and hTR do not regulate the activity level of the telomerase complex, suggesting posttranscriptional modification of hTERT or the presence of additional proteins that modulate telomerase enzyme activity.},
}
@article {pmid15211818,
year = {2004},
author = {Yang, X and Tao, M},
title = {[Progress on telomere and telomerase].},
journal = {Wei sheng yan jiu = Journal of hygiene research},
volume = {33},
number = {3},
pages = {369-371},
pmid = {15211818},
issn = {1000-8020},
mesh = {Animals ; Cell Cycle ; DNA-Binding Proteins ; Gene Expression Regulation, Enzymologic/*physiology ; Humans ; Neoplasms/enzymology ; Telomerase/genetics/*metabolism ; Telomere/*genetics/metabolism ; Transcription, Genetic ; },
abstract = {Telomere is a specific ribonucleoprotein complex composed of repeats of sequence TTAGGG, and located at the eukaryotic chromosometerminus. While it plays an important role in maintenance of telomere structural stability, telomerase is also involved in the regulation of telomerase activity. Telomerase activity is due to transcriptional repression of the catalytic subunit hTERT in most tissues prior to birth and is reactivated by upregulation of hTERT expression in over 90% of cancer cells. The mechanisms involved in telomerase regulation are still far from being fully established. Telomerase activity is subject to multiple levels of control and may be regulated by different factors in different cellular contexts. In this paper, some factors such as cell differentiation, molecular regulation, cell cycle and actuality of telomerase was reviewed.},
}
@article {pmid15210109,
year = {2004},
author = {Ding, H and Schertzer, M and Wu, X and Gertsenstein, M and Selig, S and Kammori, M and Pourvali, R and Poon, S and Vulto, I and Chavez, E and Tam, PP and Nagy, A and Lansdorp, PM},
title = {Regulation of murine telomere length by Rtel: an essential gene encoding a helicase-like protein.},
journal = {Cell},
volume = {117},
number = {7},
pages = {873-886},
doi = {10.1016/j.cell.2004.05.026},
pmid = {15210109},
issn = {0092-8674},
mesh = {Abnormalities, Multiple ; Alternative Splicing ; Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Cell Differentiation ; Chromosome Aberrations ; Chromosome Mapping ; Conserved Sequence ; Crosses, Genetic ; DNA Helicases/chemistry/*genetics ; Exons ; Gene Expression ; Gene Expression Regulation, Developmental ; *Genes, Essential ; Genes, Regulator ; Mice ; Mice, Knockout ; Mice, Mutant Strains ; Models, Biological ; Molecular Sequence Data ; Muridae/genetics ; Protein Structure, Tertiary ; Recombination, Genetic ; Sequence Homology, Amino Acid ; Stem Cells/cytology ; *Telomere ; Tissue Distribution ; },
abstract = {Little is known about the genes that regulate telomere length diversity between mammalian species. A candidate gene locus was previously mapped to a region on distal mouse Chr 2q. Within this region, we identified a gene similar to the dog-1 DNA helicase-like gene in C. elegans. We cloned this Regulator of telomere length (Rtel) gene and inactivated its expression in mice. Rtel(-/-) mice died between days 10 and 11.5 of gestation with defects in the nervous system, heart, vasculature, and extraembryonic tissues. Rtel(-/-) embryonic stem cells showed telomere loss and displayed many chromosome breaks and fusions upon differentiation in vitro. Crosses of Rtel(+/-) mice with Mus spretus showed that Rtel from the Mus musculus parent is required for telomere elongation of M. spretus chromosomes in F1 cells. We conclude that Rtel is an essential gene that regulates telomere length and prevents genetic instability.},
}
@article {pmid15208457,
year = {2004},
author = {Gil, ME and Coetzer, TL},
title = {Real-time quantitative PCR of telomere length.},
journal = {Molecular biotechnology},
volume = {27},
number = {2},
pages = {169-172},
pmid = {15208457},
issn = {1073-6085},
mesh = {Animals ; Biotechnology/*methods ; Humans ; Reverse Transcriptase Polymerase Chain Reaction/*instrumentation/*methods ; Telomere/*ultrastructure ; },
abstract = {Telomeres cap the ends of chromosomes and are essential for the protection of chromosomes, as well as restricting the replicative potential of a cell. These functions are achieved by the regulation of telomeric repeat length, making the measurement of telomere length a useful aid in the elucidation of the replicative history and potential of cells. Previously published techniques employed either hybridization or flow cytometry methods, which are technically demanding and time-consuming. In 2002, R. M. Cawthon published a real-time polymerase chain reaction (PCR)-based method for telomere length measurement using the Applied Biosystems Prism 7700 sequence detection system. The technique measures the factor by which the ratio of telomere repeat copy number to single-gene copy number differs between a sample and that of a reference deoxyribonucleic acid sample. In many laboratories worldwide, including ours, real-time PCR is carried out using the Roche LightCycler, as opposed to the AB Prism 7700 system. This benchmark details the modifications to Cawthon's method and describes the parameters and reagents required to measure telomere length using the Roche LightCycler.},
}
@article {pmid15207499,
year = {2004},
author = {Salmon, M and Akbar, AN},
title = {Telomere erosion: a new link between HLA DR4 and rheumatoid arthritis?.},
journal = {Trends in immunology},
volume = {25},
number = {7},
pages = {339-341},
doi = {10.1016/j.it.2004.05.002},
pmid = {15207499},
issn = {1471-4906},
mesh = {Arthritis, Rheumatoid/etiology/genetics/*immunology ; HLA-DR4 Antigen/genetics/*immunology ; Homeostasis/immunology ; Humans ; T-Lymphocytes/immunology/metabolism ; Telomere/*metabolism ; },
}
@article {pmid15205414,
year = {2004},
author = {Huang, WM and Robertson, M and Aron, J and Casjens, S},
title = {Telomere exchange between linear replicons of Borrelia burgdorferi.},
journal = {Journal of bacteriology},
volume = {186},
number = {13},
pages = {4134-4141},
pmid = {15205414},
issn = {0021-9193},
support = {R01 AI049003/AI/NIAID NIH HHS/United States ; AI49003/AI/NIAID NIH HHS/United States ; },
mesh = {Borrelia burgdorferi/*genetics ; Chromosomes, Bacterial ; Plasmids ; *Replicon ; *Telomere ; },
abstract = {Spirochetes in the genus Borrelia carry a linear chromosome and numerous linear plasmids that have covalently closed hairpin telomeres. The overall organization of the large chromosome of Borrelia burgdorferi appears to have been quite stable over recent evolutionary time; however, a large fraction of natural isolates carry differing lengths of DNA that extend the right end of the chromosome between about 7 and 20 kbp relative to the shortest chromosomes. We present evidence here that a rather recent nonhomologous recombination event in the B. burgdorferi strain Sh-2-82 lineage has replaced its right chromosomal telomere with a large portion of the linear plasmid lp21, which is present in the strain B31 lineage. At least two successive rounds of addition of linear plasmid genetic material to the chromosomal right end appear to have occurred at the Sh-2-82 right telomere, suggesting that this is an evolutionary mechanism by which plasmid genetic material can become part of the chromosome. The unusual nonhomologous nature of this rearrangement suggests that, barring horizontal transfer, it can be used as a unique genetic marker for this lineage of B. burgdorferi chromosomes.},
}
@article {pmid15199944,
year = {2004},
author = {McChesney, PA and Turner, KC and Jackson-Cook, C and Elmore, LW and Holt, SE},
title = {Telomerase resets the homeostatic telomere length and prevents telomere dysfunction in immortalized human cells.},
journal = {DNA and cell biology},
volume = {23},
number = {5},
pages = {293-300},
doi = {10.1089/104454904323090921},
pmid = {15199944},
issn = {1044-5498},
mesh = {Antigens, Polyomavirus Transforming/genetics ; Cell Line, Transformed ; DNA-Binding Proteins ; Fibroblasts ; Homeostasis ; Humans ; Telomerase/genetics/*metabolism ; Telomere/*physiology ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; },
}
@article {pmid15199150,
year = {2004},
author = {Razak, ZR and Varkonyi, RJ and Kulp-McEliece, M and Caslini, C and Testa, JR and Murphy, ME and Broccoli, D},
title = {p53 differentially inhibits cell growth depending on the mechanism of telomere maintenance.},
journal = {Molecular and cellular biology},
volume = {24},
number = {13},
pages = {5967-5977},
pmid = {15199150},
issn = {0270-7306},
support = {R01 CA045745/CA/NCI NIH HHS/United States ; R01 CA098087/CA/NCI NIH HHS/United States ; CA006927/CA/NCI NIH HHS/United States ; CA098087-01/CA/NCI NIH HHS/United States ; P30 CA006927/CA/NCI NIH HHS/United States ; CA-45745-14/CA/NCI NIH HHS/United States ; },
mesh = {Alleles ; Cell Division/*genetics ; Cell Line ; DNA Replication ; Humans ; Mutation/physiology ; Recombination, Genetic ; S Phase ; Telomere/*metabolism ; Transfection ; Tumor Suppressor Protein p53/genetics/metabolism/*physiology ; },
abstract = {Telomere stabilization is critical for tumorigenesis. A number of tumors and cell lines use a recombination-based mechanism, alternative lengthening of telomeres (ALT), to maintain telomere repeat arrays. Current data suggest that the mutation of p53 facilitates the activation of this pathway. In addition to its functions in response to DNA damage, p53 also acts to suppress recombination, independent of transactivation activity, raising the possibility that p53 might regulate the ALT mechanism via its role as a regulator of recombination. To test the role of p53 in ALT we utilized inducible alleles of human p53. We show that expression of transactivation-incompetent p53 inhibits DNA synthesis in ALT cell lines but does not affect telomerase-positive cell lines. The expression of temperature-sensitive p53 in clonal cell lines results in ALT-specific, transactivation-independent growth inhibition, due in part to the perturbation of S phase. Utilizing chromatin immunoprecipitation assays, we demonstrate that p53 is associated with the telomeric complex in ALT cells. Furthermore, the inhibition of DNA synthesis in ALT cells by p53 requires intact specific DNA binding and suppression of recombination functions. We propose that p53 causes transactivation-independent growth inhibition of ALT cells by perturbing telomeric recombination.},
}
@article {pmid15198981,
year = {2004},
author = {Larrivée, M and LeBel, C and Wellinger, RJ},
title = {The generation of proper constitutive G-tails on yeast telomeres is dependent on the MRX complex.},
journal = {Genes &amp; development},
volume = {18},
number = {12},
pages = {1391-1396},
pmid = {15198981},
issn = {0890-9369},
mesh = {Base Sequence ; Cell Cycle ; Chromosomes, Fungal ; Endodeoxyribonucleases/*physiology ; Exodeoxyribonucleases/*physiology ; Nucleic Acid Conformation ; Protein Binding ; S Phase ; Saccharomyces cerevisiae/cytology/*genetics ; Saccharomyces cerevisiae Proteins/*physiology ; Telomere/chemistry/*ultrastructure ; Telomere-Binding Proteins/physiology ; },
abstract = {The precise DNA arrangement at chromosomal ends and the proteins involved in its maintenance are of crucial importance for genome stability. For the yeast Saccharomyces cerevisiae, this constitutive DNA configuration has remained unknown. We demonstrate here that G-tails of 12-14 bases are present outside of S phase on normal yeast telomeres. Furthermore, the Mre11p protein is essential for the proper establishment of this constitutive end-structure. However, the timing of extended G-tails occurring during S phase is not affected in strains lacking Mre11p. Thus, G-tails are present on yeast chromosomes throughout the cell cycle and the MRX complex is required for their normal establishment.},
}
@article {pmid15198733,
year = {2004},
author = {Fern, L and Pallis, M and Ian Carter, G and Seedhouse, C and Russell, N and Byrne, J},
title = {Clonal haemopoiesis may occur after conventional chemotherapy and is associated with accelerated telomere shortening and defects in the NQO1 pathway; possible mechanisms leading to an increased risk of t-AML/MDS.},
journal = {British journal of haematology},
volume = {126},
number = {1},
pages = {63-71},
doi = {10.1111/j.1365-2141.2004.05006.x},
pmid = {15198733},
issn = {0007-1048},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Clone Cells ; Female ; Flow Cytometry ; *Hematopoiesis ; Hodgkin Disease/surgery ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia, Myeloid/*genetics ; Lymphoma, Non-Hodgkin/surgery ; Male ; Middle Aged ; Multiple Myeloma/surgery ; Myelodysplastic Syndromes/*genetics ; NAD(P)H Dehydrogenase (Quinone)/*genetics ; Polymorphism, Genetic ; Stem Cell Transplantation/*adverse effects ; Telomere/*ultrastructure ; },
abstract = {The molecular pathogenesis of therapy-related acute myeloid leukaemia/myelodysplastic syndrome (t-AML/MDS) remains uncertain. However, clonal haemopoiesis may develop following stem cell transplantation and precede the development of t-AML/MDS. Moreover, accelerated telomere shortening may be induced by replicative stress or oxidative damage, leading to genomic instability, and inactivating polymorphisms of the gene encoding NADPH-quinone oxidoreductase (NQO1) are more frequently observed in patients with t-AML. We studied clonal haemopoiesis, telomere length and NQO1 status in 146 patients receiving conventional chemotherapy for non-myeloid malignancies. Clonal haemopoiesis was demonstrated in eight of 98 (8%) patients. Telomere length was reduced in patients following chemotherapy (n = 52) compared with controls (n = 42) (P < 0.001), particularly in those with clonal haemopoiesis (P < 0.002). Whilst there was a trend towards telomere shortening in control subjects polymorphic for NQO1-187Ser (n = 12), chemotherapy-exposed patients polymorphic for the NQO1-187Ser allele (n = 29) had significantly shorter telomeres (P < 0.001). Furthermore, chemotherapy-treated patients with the NQO1-187Ser, polymorphism were more likely to develop clonal haemopoiesis than patients with wild type NQO1 (odds ratio = 7; 1.16-42.6). We conclude that a switch to clonal haemopoiesis may occur after conventional chemotherapy and lead to accelerated telomere shortening. Patients with the NQO1-187Ser polymorphism have an increased risk of developing both clonal haemopoiesis and telomere shortening, which may partly explain the predisposition to t-AML in NQO1-187Ser null individuals.},
}
@article {pmid15198478,
year = {2004},
author = {Nakashima, H and Ozono, R and Suyama, C and Sueda, T and Kambe, M and Oshima, T},
title = {Telomere attrition in white blood cell correlating with cardiovascular damage.},
journal = {Hypertension research : official journal of the Japanese Society of Hypertension},
volume = {27},
number = {5},
pages = {319-325},
doi = {10.1291/hypres.27.319},
pmid = {15198478},
issn = {0916-9636},
mesh = {Adult ; Aged ; Aging/genetics ; Blotting, Southern ; Brachial Artery/physiopathology ; Cardiovascular Diseases/*blood/*genetics/physiopathology ; Case-Control Studies ; Endothelium, Vascular/physiopathology ; Female ; Humans ; *Leukocytes ; Male ; Middle Aged ; Polymorphism, Restriction Fragment Length ; Reproducibility of Results ; Risk Factors ; *Telomere ; Vasodilation ; },
abstract = {Aging is a major risk factor for cardiovascular disease. Chronological aging does not always parallel biological aging, but there is no reliable biomarker for the latter. In the present study, we tested the hypothesis that telomere attrition in white blood cells is related to endothelial dysfunction and the extent of atherosclerosis, and thus may serve as a useful marker for biological aging. We evaluated telomere lengths in white blood cells by measuring the mean telomere restriction fragment length (mTRFL), as well as endothelial function by flow mediated dilatation (FMD) in the brachial artery, in patients with various degrees of cardiovascular damage and in normal subjects. Cardiovascular damage was assessed by a cardiovascular damage (CVD) score, with 1 point being given for the presence of each cardiovascular risk factor (hypertension, hyperlipidemia and diabetes) and for each event (angina, myocardial infarction, cerebrovascular event and peripheral vascular disease). Subset analysis of CVD score groups revealed that mTRFL and FMD decreased in the rank order of CVD score. Although mTRFL was inversely correlated with age, telomere index, defined as the ratio of TRFL to TRFL predicted by age, also decreased with increase in CVD score. These results indicate that telomere attrition in white blood cells is more closely associated with endothelial damage and atherosclerosis than is chronological aging, supporting the hypothesis that mTRFL in white blood cells is a useful marker for biological aging of the cardiovascular system.},
}
@article {pmid15197176,
year = {2004},
author = {Tuzon, CT and Borgstrom, B and Weilguny, D and Egel, R and Cooper, JP and Nielsen, O},
title = {The fission yeast heterochromatin protein Rik1 is required for telomere clustering during meiosis.},
journal = {The Journal of cell biology},
volume = {165},
number = {6},
pages = {759-765},
pmid = {15197176},
issn = {0021-9525},
mesh = {Chromosomal Proteins, Non-Histone/genetics/*physiology ; Cloning, Molecular ; Gene Deletion ; Heterochromatin/*physiology/*ultrastructure ; Meiosis/*physiology ; Schizosaccharomyces/*cytology/ultrastructure ; Schizosaccharomyces pombe Proteins/genetics/*physiology ; Telomere/*physiology/ultrastructure ; },
abstract = {Telomeres share the ability to silence nearby transcription with heterochromatin, but the requirement of heterochromatin proteins for most telomere functions is unknown. The fission yeast Rik1 protein is required for heterochromatin formation at centromeres and the mating-type locus, as it recruits the Clr4 histone methyltransferase, whose modification of histone H3 triggers binding by Swi6, a conserved protein involved in spreading of heterochromatin. Here, we demonstrate that Rik1 and Clr4, but not Swi6, are required along with the telomere protein Taz1 for crucial chromosome movements during meiosis. However, Rik1 is dispensable for the protective roles of telomeres in preventing chromosome end-fusion. Thus, a Swi6-independent heterochromatin function distinct from that at centromeres and the mating-type locus operates at telomeres during sexual differentiation.},
}
@article {pmid15195144,
year = {2004},
author = {Zhang, H and Herbert, BS and Pan, KH and Shay, JW and Cohen, SN},
title = {Disparate effects of telomere attrition on gene expression during replicative senescence of human mammary epithelial cells cultured under different conditions.},
journal = {Oncogene},
volume = {23},
number = {37},
pages = {6193-6198},
doi = {10.1038/sj.onc.1207834},
pmid = {15195144},
issn = {0950-9232},
support = {AG07992/AG/NIA NIH HHS/United States ; CA70907/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Cell Lineage ; Cellular Senescence/*genetics ; Epithelial Cells/cytology ; Female ; *Gene Expression Regulation ; Humans ; Mammary Glands, Animal/*cytology ; Oligonucleotide Array Sequence Analysis ; *Telomere ; },
abstract = {Telomere shortening in populations of human mammary epithelial cells (HMECs) that survive early replicative arrest (M0) by the inactivation of p16(INK4A) during cell culture on plastic dishes leads to a state of permanent replicative arrest termed senescence. While culture of HMECs on feeder layers abrogates M0 and p16(INK4A) inactivation, progressive telomere attrition in these cells also eventually results in permanent replicative arrest. Expression of telomerase prevents both senescence on plastic (S-P) and senescence on feeder layers (S-FL) in HMECs, as it does also in cultured primary human fibroblasts. We report here that the gene expression profiles of senescence in HMECs of the same lineage maintained under different culture conditions showed surprisingly little commonality. Moreover, neither of these senescence-associated profiles in HMECs resembles the profile for senescence in human fibroblasts. These results indicate that senescence-associated alterations in gene expression resulting from telomere attrition are affected by culture conditions as well as by cell origins, and argue that replicative senescence at the molecular level is a diverse rather than unique cellular process.},
}
@article {pmid15194652,
year = {2004},
author = {Sato, R and Maesawa, C and Fujisawa, K and Wada, K and Oikawa, K and Takikawa, Y and Suzuki, K and Oikawa, H and Ishikawa, K and Masuda, T},
title = {Prevention of critical telomere shortening by oestradiol in human normal hepatic cultured cells and carbon tetrachloride induced rat liver fibrosis.},
journal = {Gut},
volume = {53},
number = {7},
pages = {1001-1009},
pmid = {15194652},
issn = {0017-5749},
mesh = {Animals ; Carbon Tetrachloride ; Cell Line ; Cellular Senescence/*drug effects ; DNA-Binding Proteins ; Estradiol/*pharmacology ; Estrogen Receptor alpha ; Female ; Gene Expression Regulation/drug effects ; Hepatocytes/*drug effects/metabolism ; Humans ; Liver Cirrhosis, Experimental/chemically induced/genetics/*pathology ; Male ; RNA, Messenger/genetics ; Rats ; Rats, Inbred F344 ; Receptors, Estrogen/metabolism ; Telomerase/genetics/metabolism ; Telomere/*drug effects ; beta-Galactosidase/metabolism ; },
abstract = {BACKGROUND AND AIM: Significant telomere shortening of hepatocytes is associated with replicative senescence and a non-dividing state in chronic liver disease, resulting in end stage liver failure and/or development of hepatocellular carcinoma. To prevent critical telomere shortening in hepatocytes, we have focused on oestrogen dependent transactivation of the human telomerase reverse transcriptase (hTERT) gene as a form of telomerase therapy in chronic liver disease.<br><br>METHODS: We examined expression of hTERT mRNA and its protein, and telomerase activity (TA) in three human normal hepatic cell lines (Hc-cells, h-Nheps, and WRL-68) before and after treatment with 17beta-oestradiol. The effects of exogenous oestradiol administration were examined in a carbon tetrachloride (CCl(4)) induced model of liver fibrosis in rats.<br><br>RESULTS: Expression of hTERT mRNA and its protein was upregulated by oestradiol treatment. Telomere length decreased in Hc-cells and h-Nheps with accumulated passages whereas with long term oestradiol exposure it was greater than without oestradiol. The incidence of beta-galactosidase positive cells, indicating a state of senescence, decreased significantly in oestradiol treated cells in comparison with non-treated cells (p<0.05). TA in both male and female rats with CCl(4) induced liver fibrosis was significantly higher with oestradiol administration than without (p<0.05). Long term oestradiol administration markedly rescued the hepatic telomere from extensive shortening in both male and female rats.<br><br>CONCLUSION: These results suggest that oestradiol acts as a positive modulator of the hTERT gene in the liver. Oestrogen dependent transactivation of the hTERT gene is a new strategy for slowing the progression of chronic liver disease.},
}
@article {pmid15186685,
year = {2004},
author = {Allhoff, F},
title = {Telomeres and the ethics of human cloning.},
journal = {The American journal of bioethics : AJOB},
volume = {4},
number = {2},
pages = {W29-31},
doi = {10.1162/152651604323097961},
pmid = {15186685},
issn = {1536-0075},
mesh = {*Aging ; Cell Division/genetics ; Cloning, Organism/*ethics ; *Ethical Analysis ; *Ethical Theory ; Ethics, Research ; Genetic Engineering/ethics ; Humans ; *Telomere ; },
abstract = {In search of a potential problem with cloning, I investigate the phenomenon of telomere shortening which is caused by cell replication; clones created from somatic cells will have shortened telomeres and therefore reach a state of senescence more rapidly. While genetic intervention might fix this problem at some point in the future, I ask whether, absent technological advances, this biological phenomenon undermines the moral permissibility of cloning.},
}
@article {pmid15183754,
year = {2004},
author = {Velinov, M and Gu, H and Genovese, M and Duncan, C and Warburton, P and Brooks, SS and Jenkins, EC},
title = {Characterization of an analphoid, neocentromere-positive inv dup 8p marker chromosome using multiplex whole chromosome and sub-telomere FISH analyses.},
journal = {Annales de genetique},
volume = {47},
number = {2},
pages = {199-205},
doi = {10.1016/j.anngen.2004.02.005},
pmid = {15183754},
issn = {0003-3995},
mesh = {Adult ; Centromere/*genetics/metabolism ; Chromosome Banding ; Chromosome Disorders/*genetics ; Chromosomes, Human, Pair 8/*genetics ; Humans ; In Situ Hybridization, Fluorescence/methods ; Intellectual Disability/*genetics ; Kinetochores/metabolism ; Male ; Sexual Behavior ; },
abstract = {A 30-year-old male patient with mild mental retardation was found to have a small supernumerary marker chromosome (SMC) in 90% of his peripheral blood cells and in 100% of his fibroblast cells. Multiplex whole chromosome and sub-telomere FISH analyses were used to determine that this SMC is an inverted duplicated distal chromosome 8p fragment. Although it was negative for alpha-DNA sequences, this marker had a functional kinetochore (neocentromere) demonstrated by a positive signal with a CENP-C antibody. Apparently intact 8p telomeres at the marker's ends were demonstrated by using a telomere repeat FISH probe. The patient's phenotypically normal mother on G-banding analysis had a small marker chromosome in 8% of her peripheral blood cells in two cultures of the first specimen studied. The marker was not seen in any subsequent maternal peripheral blood or fibroblast specimens. Although it was impossible to further characterize the maternal SMC, it was suggested that the mother had the same marker as the one seen in the proband. Inverted duplicated chromosomal fragments are the most frequent type of analphoid markers. Stable inverted duplicated 8p marker chromosomes were previously reported in three other patients. They all apparently occurred de novo and were found to be positive for kinetochore-associated proteins. Evidence for the possible inheritance of an inverted-duplicated, analphoid SMC was not shown to-date. This study also demonstrates a practical, straightforward approach for analphoid marker characterization in clinical laboratory settings, using whole chromosome multiplex and subtelomere-specific FISH analyses. FISH probes for all sub-telomere chromosomal regions are commercially available and the large majority of analphoid marker chromosomes involve telomere regions.},
}
@article {pmid15181449,
year = {2004},
author = {Liu, D and Safari, A and O'Connor, MS and Chan, DW and Laegeler, A and Qin, J and Songyang, Z},
title = {PTOP interacts with POT1 and regulates its localization to telomeres.},
journal = {Nature cell biology},
volume = {6},
number = {7},
pages = {673-680},
doi = {10.1038/ncb1142},
pmid = {15181449},
issn = {1465-7392},
mesh = {Active Transport, Cell Nucleus/genetics ; Cellular Senescence/genetics ; DNA, Complementary/analysis/genetics ; DNA, Single-Stranded/genetics/metabolism ; Dimerization ; HeLa Cells ; Humans ; Molecular Sequence Data ; Mutation/genetics ; Protein Binding/genetics ; Protein Structure, Tertiary/genetics ; Protein Transport/genetics ; RNA Interference/physiology ; Sequence Homology, Amino Acid ; Sequence Homology, Nucleic Acid ; Shelterin Complex ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/genetics/isolation &amp; purification/*metabolism ; },
abstract = {Telomere maintenance has been implicated in cancer and ageing, and requires cooperation between a multitude of telomeric factors, including telomerase, TRF1, TRF2, RAP1, TIN2, Tankyrase, PINX1 and POT1 (refs 1-12). POT1 belongs to a family of oligonucleotide-binding (OB)-fold-containing proteins that include Oxytricha nova TEBP, Cdc13, and spPot1, which specifically recognize telomeric single-stranded DNA (ssDNA). In human cells, the loading of POT1 to telomeric ssDNA controls telomerase-mediated telomere elongation. Surprisingly, a human POT1 mutant lacking an OB fold is still recruited to telomeres. However, the exact mechanism by which this recruitment occurs remains unclear. Here we identify a novel telomere protein, PTOP, which interacts with both POT1 and TIN2. PTOP binds to the carboxyl terminus of POT1 and recruits it to telomeres. Inhibition of PTOP by RNA interference (RNAi) or disruption of the PTOP-POT1 interaction hindered the localization of POT1 to telomeres. Furthermore, expression of the respective interaction domains on PTOP and POT1 alone extended telomere length in human cells. Therefore, PTOP heterodimerizes with POT1 and regulates POT1 telomeric recruitment and telomere length.},
}
@article {pmid15181152,
year = {2004},
author = {Zou, Y and Sfeir, A and Gryaznov, SM and Shay, JW and Wright, WE},
title = {Does a sentinel or a subset of short telomeres determine replicative senescence?.},
journal = {Molecular biology of the cell},
volume = {15},
number = {8},
pages = {3709-3718},
pmid = {15181152},
issn = {1059-1524},
support = {R01 AG007992/AG/NIA NIH HHS/United States ; AG07992/AG/NIA NIH HHS/United States ; },
mesh = {Cellular Senescence/*genetics ; Chromosomes, Human/genetics ; DNA/analysis/metabolism ; DNA Damage/genetics ; DNA Replication/*genetics ; Fibroblasts/metabolism ; Histones/analysis/metabolism ; Humans ; In Situ Hybridization ; Telomere/chemistry/classification/*physiology ; },
abstract = {The proliferative life span of human cells is limited by telomere shortening, but the specific telomeres responsible for determining the onset of senescence have not been adequately determined. We here identify the shortest telomeres by the frequency of signal-free ends after in situ hybridization with telomeric probes and demonstrate that probes adjacent to the shortest ends colocalize with gammaH2AX-positive DNA damage foci in senescent cells. Normal BJ cells growth arrest at senescence before developing significant karyotypic abnormalities. We also identify all of the telomeres involved in end-associations in BJ fibroblasts whose cell-cycle arrest at the time of replicative senescence has been blocked and demonstrate that the 10% of the telomeres with the shortest ends are involved in >90% of all end-associations. The failure to find telomeric end-associations in near-senescent normal BJ metaphases, the presence of signal-free ends in 90% of near-senescent metaphases, and the colocalization of short telomeres with DNA damage foci in senescent interphase cells suggests that end-associations rather than damage signals from short telomeres per se may be the proximate cause of growth arrest. These results demonstrate that a specific group of chromosomes with the shortest telomeres rather than either all or only one or two sentinel telomeres is responsible for the induction of replicative senescence.},
}
@article {pmid15178133,
year = {2004},
author = {op den Buijs, J and van den Bosch, PP and Musters, MW and van Riel, NA},
title = {Mathematical modeling confirms the length-dependency of telomere shortening.},
journal = {Mechanisms of ageing and development},
volume = {125},
number = {6},
pages = {437-444},
doi = {10.1016/j.mad.2004.03.007},
pmid = {15178133},
issn = {0047-6374},
mesh = {Aging/*physiology ; Algorithms ; Animals ; Cell Line ; Computer Simulation ; Fibroblasts/physiology/ultrastructure ; Humans ; Models, Statistical ; Rats ; Telomere/*physiology/*ultrastructure ; },
abstract = {Telomeres, the ends of chromosomes, shorten with each cell division in human somatic cells, because of the end-replication problem, C-strand processing and oxidative damage. On the other hand, the reverse transcriptase telomerase can add back telomeric repeats at the telomere ends. It has been suggested that once telomeres have reached a critical length, cells cease proliferation, also known as senescence. Evidence is accumulating that telomere shortening and subsequent senescence might play a crucial role in life-threatening diseases. So far, mathematical models described telomere shortening as an autonomous process, where the loss per cell division does not depend on the telomere length itself. In this study, published measurements of telomere distributions in human fibroblasts and human endothelial cells were used to show that telomeres shorten in a length-dependent fashion. Thereafter, a mathematical model of telomere attrition was composed, in which a shortening factor and an autonomous loss were incorporated. It was assumed that the percentage of senescence was related to the percentage of telomeres below a critical length. The model was compared with published data of telomere length and senescence of human endothelial cells using the maximum likelihood method. This enabled the estimation of physiologically important parameters and confirmed the length-dependency of telomere shortening.},
}
@article {pmid15177038,
year = {2004},
author = {Bailey, SM and Brenneman, MA and Halbrook, J and Nickoloff, JA and Ullrich, RL and Goodwin, EH},
title = {The kinase activity of DNA-PK is required to protect mammalian telomeres.},
journal = {DNA repair},
volume = {3},
number = {3},
pages = {225-233},
doi = {10.1016/j.dnarep.2003.10.013},
pmid = {15177038},
issn = {1568-7864},
support = {CA43322/CA/NCI NIH HHS/United States ; CA77693/CA/NCI NIH HHS/United States ; },
mesh = {Acetophenones/*metabolism ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Culture Techniques ; Cell Cycle Proteins ; *DNA Damage ; DNA Repair/*genetics ; DNA-Activated Protein Kinase ; *DNA-Binding Proteins ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Morpholines/*metabolism ; Protein Serine-Threonine Kinases/antagonists &amp; inhibitors/*metabolism ; Telomere/*genetics ; Tumor Suppressor Proteins ; },
abstract = {The kinase activity of DNA-dependent protein kinase (DNA-PK) is required for efficient repair of DNA double-strand breaks (DSB) by non-homologous end joining (NHEJ). DNA-PK also participates in protection of mammalian telomeres, the natural ends of chromosomes. Here we investigate whether the kinase activity of DNA-PK is similarly required for effective telomere protection. DNA-PK proficient mouse cells were exposed to a highly specific inhibitor of DNA-PK phosphorylation designated IC86621. Chromosomal end-to-end fusions were induced in a concentration-dependent manner, demonstrating that the telomere end-protection role of DNA-PK requires its kinase activity. These fusions were uniformly chromatid-type, consistent with a role for DNA-PK in capping telomeres after DNA replication. Additionally, fusions involved exclusively telomeres produced via leading-strand DNA synthesis. Unexpectedly, the rate of telomeric fusions induced by IC86621 exceeded that which occurs spontaneously in DNA-dependent protein kinase catalytic subunit (DNA-PKcs) mutant cells by up to 110-fold. One explanation, that IC86621 might inhibit other, as yet unknown proteins, was ruled out when the drug failed to induce fusions in DNA-PKcs knock-out mouse cells. IC86621 did not induce fusions in Ku70 knock-out cells suggesting the drug requires the holoenzyme to be effective. ATM also is required for effective chromosome end protection. IC86621 increased fusions in ATM knock-out cells suggesting DNA-PK and ATM act in different telomere pathways. These results indicate that the kinase activity of DNA-PK is crucial to reestablishing a protective terminal structure, specifically on telomeres replicated by leading-strand DNA synthesis.},
}
@article {pmid15176976,
year = {2004},
author = {Chuang, TC and Moshir, S and Garini, Y and Chuang, AY and Young, IT and Vermolen, B and van den Doel, R and Mougey, V and Perrin, M and Braun, M and Kerr, PD and Fest, T and Boukamp, P and Mai, S},
title = {The three-dimensional organization of telomeres in the nucleus of mammalian cells.},
journal = {BMC biology},
volume = {2},
number = {},
pages = {12},
pmid = {15176976},
issn = {1741-7007},
mesh = {Animals ; B-Lymphocytes/*cytology ; Cell Cycle ; *Cell Nucleus ; Cell Separation ; Cells, Cultured ; Flow Cytometry ; Hepatocytes/*cytology ; Humans ; Image Processing, Computer-Assisted/methods ; Imaging, Three-Dimensional/*methods ; In Situ Hybridization ; Interphase ; Mice ; Mice, Inbred BALB C ; Telomere/*chemistry/metabolism ; },
abstract = {BACKGROUND: The observation of multiple genetic markers in situ by optical microscopy and their relevance to the study of three-dimensional (3D) chromosomal organization in the nucleus have been greatly developed in the last decade. These methods are important in cancer research because cancer is characterized by multiple alterations that affect the modulation of gene expression and the stability of the genome. It is, therefore, essential to analyze the 3D genome organization of the interphase nucleus in both normal and cancer cells.<br><br>RESULTS: We describe a novel approach to study the distribution of all telomeres inside the nucleus of mammalian cells throughout the cell cycle. It is based on 3D telomere fluorescence in situ hybridization followed by quantitative analysis that determines the telomeres' distribution in the nucleus throughout the cell cycle. This method enables us to determine, for the first time, that telomere organization is cell-cycle dependent, with assembly of telomeres into a telomeric disk in the G2 phase. In tumor cells, the 3D telomere organization is distorted and aggregates are formed.<br><br>CONCLUSIONS: The results emphasize a non-random and dynamic 3D nuclear telomeric organization and its importance to genomic stability. Based on our findings, it appears possible to examine telomeric aggregates suggestive of genomic instability in individual interphase nuclei and tissues without the need to examine metaphases. Such new avenues of monitoring genomic instability could potentially impact on cancer biology, genetics, diagnostic innovations and surveillance of treatment response in medicine.},
}
@article {pmid15175413,
year = {2004},
author = {Abad, JP and De Pablos, B and Osoegawa, K and De Jong, PJ and Martín-Gallardo, A and Villasante, A},
title = {TAHRE, a novel telomeric retrotransposon from Drosophila melanogaster, reveals the origin of Drosophila telomeres.},
journal = {Molecular biology and evolution},
volume = {21},
number = {9},
pages = {1620-1624},
doi = {10.1093/molbev/msh180},
pmid = {15175413},
issn = {0737-4038},
mesh = {Animals ; Base Sequence ; Chromosomes, Artificial, Bacterial/genetics ; Drosophila melanogaster/*genetics ; Evolution, Molecular ; Models, Genetic ; Molecular Sequence Data ; Phylogeny ; Retroelements/*genetics ; Telomere/*genetics ; },
abstract = {Drosophila telomeres do not have typical telomerase repeats. Instead, two families of non-LTR retrotransposons, HeT-A and TART, maintain telomere length by occasional transposition to the chromosome ends. Despite the work on Drosophila telomeres, its evolutionary origin remains controversial. Herein we describe a novel telomere-specific retroelement that we name TAHRE (Telomere-Associated and HeT-A-Related Element). The structure of the three telomere-specific elements indicates a common ancestor. These results suggest that preexisting transposable elements were recruited to perform the cellular function of telomere maintenance. A recruitment similar to that of a retrotransposal reverse transcriptase has been suggested as the common origin of telomerases.},
}
@article {pmid15172990,
year = {2004},
author = {Fotiadou, P and Henegariu, O and Sweasy, JB},
title = {DNA polymerase beta interacts with TRF2 and induces telomere dysfunction in a murine mammary cell line.},
journal = {Cancer research},
volume = {64},
number = {11},
pages = {3830-3837},
doi = {10.1158/0008-5472.CAN-04-0136},
pmid = {15172990},
issn = {0008-5472},
support = {CA16038/CA/NCI NIH HHS/United States ; ES10995/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; DNA Polymerase beta/biosynthesis/*metabolism ; HeLa Cells ; Humans ; Mammary Glands, Animal/*enzymology/*ultrastructure ; Mice ; Telomere/enzymology/*physiology ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {DNA polymerase beta (Polbeta) is a DNA repair protein that functions in base excision repair and meiosis. The enzyme has deoxyribose phosphate lyase and polymerase activity, but it is error prone because it bears no proofreading activity. Errors in DNA repair can lead to the accumulation of mutations and consequently to tumorigenesis. Polbeta expression has been found to be higher in tumors, and deregulation of its expression has been found to induce chromosomal instability, a hallmark of tumorigenesis, but the underlying mechanisms are unclear. In the present study, we have investigated whether ectopic expression of Polbeta influences the stability of chromosomes in a murine mammary cell line. The results demonstrate a telomere dysfunction phenotype: an increased rate of telomere loss and chromosome fusion, suggesting that ectopic expression of Polbeta leads to telomere dysfunction. In addition, Polbeta interacts with TRF2, a telomeric DNA binding protein. Colocalization of the two proteins occurs at nontelomeric sites and appears to be influenced by the change in the status of the telomeric complex.},
}
@article {pmid15172978,
year = {2004},
author = {Bakkenist, CJ and Drissi, R and Wu, J and Kastan, MB and Dome, JS},
title = {Disappearance of the telomere dysfunction-induced stress response in fully senescent cells.},
journal = {Cancer research},
volume = {64},
number = {11},
pages = {3748-3752},
doi = {10.1158/0008-5472.CAN-04-0453},
pmid = {15172978},
issn = {0008-5472},
support = {CA21765/CA/NCI NIH HHS/United States ; CA71387/CA/NCI NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins ; Cell Nucleus/metabolism ; Cells, Cultured ; Cellular Senescence/*physiology ; DNA-Binding Proteins ; Fibroblasts/cytology/ultrastructure ; HeLa Cells ; Histones/metabolism ; Humans ; Microscopy, Fluorescence ; Protein Serine-Threonine Kinases/physiology ; Signal Transduction/physiology ; Telomere/*physiology ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins ; },
abstract = {Replicative senescence is a natural barrier to cellular proliferation that is triggered by telomere erosion and dysfunction. Here, we demonstrate that ATM activation and H2AX-gamma nuclear focus formation are sensitive markers of telomere dysfunction in primary human fibroblasts. Whereas the activated form of ATM and H2AX-gamma foci were rarely observed in early-passage cells, they were readily detected in late-passage cells. The ectopic expression of telomerase in late-passage cells abrogated ATM activation and H2AX-gamma focus formation, suggesting that these stress responses were the consequence of telomere dysfunction. ATM activation was induced in quiescent fibroblasts by inhibition of TRF2 binding to telomeres, indicating that telomere uncapping is sufficient to initiate the telomere signaling response; breakage of chromosomes with telomeric associations is not required for this activation. Although ATM activation and H2AX-gamma foci were readily observed in late-passage cells, they disappeared once cells became fully senescent, indicating that constitutive signaling from dysfunctional telomeres is not required for the maintenance of senescence.},
}
@article {pmid15169917,
year = {2004},
author = {Mattern, KA and Swiggers, SJ and Nigg, AL and Löwenberg, B and Houtsmuller, AB and Zijlmans, JM},
title = {Dynamics of protein binding to telomeres in living cells: implications for telomere structure and function.},
journal = {Molecular and cellular biology},
volume = {24},
number = {12},
pages = {5587-5594},
pmid = {15169917},
issn = {0270-7306},
mesh = {Green Fluorescent Proteins ; HeLa Cells ; Humans ; Kinetics ; Luminescent Proteins/genetics/metabolism ; Protein Binding ; Recombinant Fusion Proteins/genetics/metabolism ; Shelterin Complex ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; },
abstract = {Telomeric proteins have an essential role in the regulation of the length of the telomeric DNA tract and in protection against end-to-end chromosome fusion. Telomere organization and how individual proteins are involved in different telomere functions in living cells is largely unknown. By using green fluorescent protein tagging and photobleaching, we investigated in vivo interactions of human telomeric DNA-binding proteins with telomeric DNA. Our results show that telomeric proteins interact with telomeres in a complex dynamic fashion: TRF2, which has a dual role in chromosome end protection and telomere length homeostasis, resides at telomeres in two distinct pools. One fraction (approximately 73%) has binding dynamics similar to TRF1 (residence time of approximately 44 s). Interestingly, the other fraction of TRF2 binds with similar dynamics as the putative end-protecting factor hPOT1 (residence time of approximately 11 min). Our data support a dynamic model of telomeres in which chromosome end-protection and telomere length homeostasis are governed by differential binding of telomeric proteins to telomeric DNA.},
}
@article {pmid15169907,
year = {2004},
author = {Satyanarayana, A and Greenberg, RA and Schaetzlein, S and Buer, J and Masutomi, K and Hahn, WC and Zimmermann, S and Martens, U and Manns, MP and Rudolph, KL},
title = {Mitogen stimulation cooperates with telomere shortening to activate DNA damage responses and senescence signaling.},
journal = {Molecular and cellular biology},
volume = {24},
number = {12},
pages = {5459-5474},
pmid = {15169907},
issn = {0270-7306},
mesh = {Animals ; Base Sequence ; Cell Cycle/drug effects ; Cell Division ; Cells, Cultured ; Cellular Senescence/genetics ; *DNA Damage ; DNA, Complementary/genetics ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitogens/*pharmacology ; Phenotype ; RNA/genetics ; Signal Transduction ; Telomerase/deficiency/genetics ; Telomere/*genetics ; },
abstract = {Replicative senescence is induced by critical telomere shortening and limits the proliferation of primary cells to a finite number of divisions. To characterize the activity status of the replicative senescence program in the context of cell cycle activity, we analyzed the senescence phenotypes and signaling pathways in quiescent and growth-stimulated primary human fibroblasts in vitro and liver cells in vivo. This study shows that replicative senescence signaling operates at a low level in cells with shortened telomeres but becomes fully activated when cells are stimulated to enter the cell cycle. This study also shows that the dysfunctional telomeres and nontelomeric DNA lesions in senescent cells do not elicit a DNA damage signal unless the cells are induced to enter the cell cycle by mitogen stimulation. The amplification of senescence signaling and DNA damage responses by mitogen stimulation in cells with shortened telomeres is mediated in part through the MEK/mitogen-activated protein kinase pathway. These findings have implications for the further understanding of replicative senescence and analysis of its role in vivo.},
}
@article {pmid15169872,
year = {2004},
author = {Jacob, NK and Stout, AR and Price, CM},
title = {Modulation of telomere length dynamics by the subtelomeric region of tetrahymena telomeres.},
journal = {Molecular biology of the cell},
volume = {15},
number = {8},
pages = {3719-3728},
pmid = {15169872},
issn = {1059-1524},
support = {R01 GM041803/GM/NIGMS NIH HHS/United States ; GM-41803/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromatin/*chemistry/metabolism ; DNA, Ribosomal/chemistry/genetics/metabolism ; Telomere/*chemistry/genetics/metabolism ; Tetrahymena/chemistry/*genetics/metabolism ; },
abstract = {Tetrahymena telomeres usually consist of approximately 250 base pairs of T(2)G(4) repeats, but they can grow to reach a new length set point of up to 900 base pairs when kept in log culture at 30 degrees C. We have examined the growth profile of individual macronuclear telomeres and have found that the rate and extent of telomere growth are affected by the subtelomeric region. When the sequence of the rDNA subtelomeric region was altered, we observed a decrease in telomere growth regardless of whether the GC content was increased or decreased. In both cases, the ordered structure of the subtelomeric chromatin was disrupted, but the effect on the telomeric complex was relatively minor. Examination of the telomeres from non-rDNA chromosomes showed that each telomere exhibited a unique and characteristic growth profile. The subtelomeric regions from individual chromosome ends did not share common sequence elements, and they each had a different chromatin structure. Thus, telomere growth is likely to be regulated by the organization of the subtelomeric chromatin rather than by a specific DNA element. Our findings suggest that at each telomere the telomeric complex and subtelomeric chromatin cooperate to form a unique higher order chromatin structure that controls telomere length.},
}
@article {pmid15167346,
year = {2004},
author = {Polychronopoulou, S and Koutroumba, P},
title = {Telomere length and telomerase activity: variations with advancing age and potential role in childhood malignancies.},
journal = {Journal of pediatric hematology/oncology},
volume = {26},
number = {6},
pages = {342-350},
doi = {10.1097/00043426-200406000-00003},
pmid = {15167346},
issn = {1077-4114},
mesh = {Cell Survival ; Child ; Humans ; Neoplasms/enzymology/genetics/pathology/*physiopathology ; Telomerase/*metabolism ; Telomere/*physiology ; },
abstract = {Telomeres, representing the chromosome nucleoprotein tails, shorten during each cell division due to the inability of conventional DNA polymerases to completely replicate the chromosome termini. When telomeres become critically short, cells are directed to exit from the cell division cycle (replicative senescence). Telomerase is a reverse transcriptase that synthesizes telomeric sequences, thereby prolonging the lifespan of cells. Telomere length and telomerase activity expression vary significantly in different normal somatic tissues and age groups. In many childhood malignancies (ie, acute leukemias and solid tumors), telomere length and telomerase activity of the malignant cell population may be correlated with the disease outcome and thus may be promising tools in evaluating prognosis and monitoring treatment progress. Finally, telomerase inhibition by using several strategies (ie, antisense oligonucleotides) represents a potentially valuable target for antitumor therapy in the near future.},
}
@article {pmid15164174,
year = {2004},
author = {Gao, W and Clancy, JA and Han, F and Jones, BL and Budde, A and Wesenberg, DM and Kleinhofs, A and Ullrich, SE and , },
title = {Fine mapping of a malting-quality QTL complex near the chromosome 4H S telomere in barley.},
journal = {TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik},
volume = {109},
number = {4},
pages = {750-760},
pmid = {15164174},
issn = {0040-5752},
mesh = {Breeding/methods ; *Chromosome Mapping ; Crosses, Genetic ; Hordeum/*genetics ; Phenotype ; *Quantitative Trait Loci ; },
abstract = {Malting quality has long been an active objective in barley (Hordeum vulgare L.) breeding programs.However, it is difficult for breeders to manipulate malting-quality traits because of inheritance complexity and difficulty in evaluation of these quantitative traits. Quantitative trait locus (QTL) mapping provides breeders a promising basis with which to manipulate quantitative trait genes. A malting-quality QTL complex, QTL2, was mapped previously to a 30-cM interval in the short-arm telomere region of barley chromosome 4H in a "Step-toe"/"Morex" doubled haploid population by the North American Barley Genome Project, using an interval mapping method with a relatively low-resolution genetic map. The QTL2 complex has moderate effects on several malting-quality traits, including malt extract percentage(ME), a-amylase activity (AA), diastatic power (DP), malt 13-glucan content (BG), and seed dormancy, which makes it a promising candidate gene source in malting barley-cultivar development. Fine mapping QTL2 is desirable for precisely studying barley malting-quality trait inheritance and for efficiently manipulating QTL2 in breeding. A reciprocal-substitution mapping method was employed to fine map QTL2. Molecular marker-assisted backcrossing was used to facilitate the generation of isolines. Fourteen different types of "Steptoe" isolines, including regenerated "Steptoe" and 13 different types of "Morex" isolines,including regenerated "Morex", were made within a 41.5-cM interval between MWG634 and BCD265B on chromosome 4H. Duplicates were identified for 12 "Steptoe" and 12 "Morex" isoline types. The isolines together with "Steptoe" and "Morex" were grown variously at three locations in 2 years for a total of five field environments.Four malting-quality traits were measured: ME, DP, AA,and BG. Few significant differences were found between duplicate isolines for these traits. A total of 15 putative QTLs were mapped; three for ME, four for DP, six for AA,and two for BG. Background genotype seemed to make a difference in expression/detection of QTLs. Of the 15 QTLs identified, ten were from the "Morex" and only five from the "Steptoe" background. By combining the results from different years, field environments, and genetic backgrounds and taking into account overlapping QTLsegments, six QTLs can be conservatively estimated: two each for ME and AA and one each for DP and BG with chromosome segments ranging from 0.7 cM to 27.9 cM. A segment of 15.8 cM from the telomere (MWG634-CDO669) includes all or a portion of all QTLs identified. Further study and marker-assisted breeding should focus on this 15.8-cM chromosome region.},
}
@article {pmid15163766,
year = {2004},
author = {Abad, JP and De Pablos, B and Osoegawa, K and De Jong, PJ and Martín-Gallardo, A and Villasante, A},
title = {Genomic analysis of Drosophila melanogaster telomeres: full-length copies of HeT-A and TART elements at telomeres.},
journal = {Molecular biology and evolution},
volume = {21},
number = {9},
pages = {1613-1619},
doi = {10.1093/molbev/msh174},
pmid = {15163766},
issn = {0737-4038},
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Chromosomes, Artificial, Bacterial/genetics ; Drosophila Proteins/*genetics ; Drosophila melanogaster/*genetics ; Evolution, Molecular ; Gene Products, gag/*genetics ; Genes, Insect ; Genome ; Heterochromatin/genetics ; Models, Genetic ; Molecular Sequence Data ; Retroelements/genetics ; Sequence Homology, Amino Acid ; Sequence Homology, Nucleic Acid ; Telomere/genetics ; },
abstract = {The repetitive nature of heterochromatin hampers its analysis in general genome-sequencing projects. Specific studies are needed to extend the sequence into telomeric and centromeric heterochromatin. Drosophila telomeres lack the telomerase-generated repeats that are characteristic of other eukaryotic chromosomes. Instead, they consist of tandem arrays of HeT-A and TART elements. Herein, we present the genomic organization of the telomeres in the isogenic strain (y; cn bw sp) that was used for the Drosophila melanogaster sequencing project. The data indicate that the canonical features of telomere organization are widely conserved in evolution. In addition, we have identified full-length elements, likely competent elements, for HeT-A and TART.},
}
@article {pmid15162157,
year = {2004},
author = {Gisselsson, D and Gorunova, L and Höglund, M and Mandahl, N and Elfving, P},
title = {Telomere shortening and mitotic dysfunction generate cytogenetic heterogeneity in a subgroup of renal cell carcinomas.},
journal = {British journal of cancer},
volume = {91},
number = {2},
pages = {327-332},
pmid = {15162157},
issn = {0007-0920},
mesh = {Adult ; Aged ; Aged, 80 and over ; Carcinoma, Renal Cell/*genetics/pathology ; Centrosome ; *Chromosome Aberrations ; Chromosome Banding ; Cytogenetic Analysis ; Female ; *Genetic Heterogeneity ; Humans ; In Situ Hybridization, Fluorescence ; Interphase ; Karyotyping ; Kidney Neoplasms/*genetics/pathology ; Male ; Middle Aged ; Mitosis/*physiology ; Telomere/*genetics ; },
abstract = {Most renal cell carcinomas (RCC) show only simple chromosomal changes. However, a more complex cytogenetic pattern has been found in a subgroup of aggressive RCC, indicating that further accumulation of chromosome changes could play a role in tumour progression. To explore the possible mechanisms behind cytogenetic evolution in RCC, a parallel assessment of chromosome mutations and mitotic segregation pattern in eight tumours was performed. In the majority of cases, no abnormalities in the cell division machinery were found and the rate of alterations in chromosome copy number, as measured by interphase FISH, was similar to that in non-neoplastic cells. This was reflected by relatively simple karyotypes, with little cytogenetic intratumour heterogeneity. In contrast, another group of tumours exhibited several cytogenetically related clones with additional structural chromosomal changes at two or more ploidy levels and a frequency of copy number alterations that was higher than in normal cells. In these cases, the telomere repeat sequences were abnormally short and chromosomal breakage-fusion-bridge events were observed at cell division, as well as multipolar configurations and supernumerary centrosomes. Abnormalities of the cell division machinery may thus contribute to the evolution of complex karyotypes and genetic intratumour heterogeneity in a subgroup of RCC.},
}
@article {pmid15162057,
year = {2004},
author = {Jin, G and Ikushima, T},
title = {Frequent occurrence of UVB-induced sister chromatid exchanges in telomere regions and its implication to telomere maintenance.},
journal = {Cytogenetic and genome research},
volume = {104},
number = {1-4},
pages = {310-314},
doi = {10.1159/000077508},
pmid = {15162057},
issn = {1424-859X},
mesh = {Animals ; BALB 3T3 Cells/radiation effects/ultrastructure ; CHO Cells/radiation effects/ultrastructure ; Cricetinae ; Cricetulus ; Cross-Linking Reagents/pharmacology ; Enzyme Induction/radiation effects ; Mice ; Mice, Inbred BALB C ; Mitomycin/pharmacology ; Sister Chromatid Exchange/drug effects/*radiation effects ; Telomerase/biosynthesis ; Telomere/*radiation effects/ultrastructure ; Ultraviolet Rays/*adverse effects ; },
abstract = {Sister chromatid exchanges (SCEs) are symmetrical exchanges between newly replicated chromatids and their sisters. While homologous recombination may be one of the principal mechanisms responsible for SCEs, the full details of their molecular basis and biological significance remain to be elucidated. Following exposure to ultraviolet light B (UVB), mitomycin C (MMC) and cisplatin, we analyzed the location of SCEs on metaphase chromosomes in Chinese hamster CHO cells. The frequency of SCEs increased over the spontaneous level in proportion to the agent's dose. UVB-induced SCEs occurred frequently in telomere regions, as cisplatin-induced SCEs did, differing from MMC-induced ones. The remarkable difference of intrachromosomal distribution among the three mutagens may be attributed to the specificity of induced DNA lesions and structures of different chromosome regions. Telomeric DNA at the end of chromosomes is composed of multiple copies of a repeated motif, 5'-TTAGGG-3' in mammalian cells. Telomeric repeats may be potential targets for UVB and cisplatin, which mainly form pyrimidine dimers and intrastrand d(GpG) cross-links, respectively, resulting in SCE formation. UVB irradiation shortened telomeres and augmented the telomerase activity. The possible implications of the frequent occurrence of SCEs in telomere regions are discussed in connection with the maintenance of telomere integrity.},
}
@article {pmid15162024,
year = {2004},
author = {Hande, MP},
title = {DNA repair factors and telomere-chromosome integrity in mammalian cells.},
journal = {Cytogenetic and genome research},
volume = {104},
number = {1-4},
pages = {116-122},
doi = {10.1159/000077475},
pmid = {15162024},
issn = {1424-859X},
mesh = {Aging/genetics ; Animals ; Antigens, Nuclear/physiology ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins ; Cell Transformation, Neoplastic/genetics ; Chromosomal Instability/genetics ; Chromosomes/*physiology/ultrastructure ; DNA Repair/*physiology ; DNA Repair Enzymes/deficiency/genetics/*physiology ; DNA-Activated Protein Kinase ; DNA-Binding Proteins/physiology ; Ku Autoantigen ; Mammals/*genetics ; Mice ; Mice, SCID ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases/physiology ; Protein Serine-Threonine Kinases/physiology ; Recombination, Genetic ; Stem Cells/cytology ; Telomere/*physiology ; Telomeric Repeat Binding Protein 1/physiology ; Tumor Suppressor Protein p53/physiology ; Tumor Suppressor Proteins ; },
abstract = {Loss of telomere equilibrium and associated chromosome-genomic instability might effectively promote tumour progression. Telomere function may have contrasting roles: inducing replicative senescence and promoting tumourigenesis and these roles may vary between cell types depending on the expression of the enzyme telomerase, the level of mutations induced, and efficiency/deficiency of related DNA repair pathways. We have identified an alternative telomere maintenance mechanism in mouse embryonic stem cells lacking telomerase RNA unit (mTER) with amplification of non-telomeric sequences adjacent to existing short stretches of telomere repeats. Our quest for identifying telomerase-independent or alternative mechanisms involved in telomere maintenance in mammalian cells has implicated the involvement of potential DNA repair factors in such pathways. We have reported earlier on the telomere equilibrium in scid mouse cells which suggested a potential role of DNA repair proteins in telomere maintenance in mammalian cells. Subsequently, studies by us and others have shown the association between the DNA repair factors and telomere function. Mice deficient in a DNA-break sensing molecule, PARP-1 (poly [ADP]-ribopolymerase), have increased levels of chromosomal instability associated with extensive telomere shortening. Ku80 null cells showed a telomere shortening associated with extensive chromosome end fusions, whereas Ku80+/- cells exhibited an intermediate level of telomere shortening. Inactivation of PARP-1 in p53-/- cells resulted in dysfunctional telomeres and severe chromosome instability leading to advanced onset and increased tumour incidence in mice. Interestingly, haploinsufficiency of PARP-1 in Ku80 null cells causes more severe telomere shortening and chromosome abnormalities compared to either PARP-1 or Ku80 single null cells and Ku80+/-PARP-/- mice develop spontaneous tumours. This overview will focus mainly on the role of DNA repair/recombination and DNA damage signalling molecules such as PARP-1, DNA-PKcs, Ku70/80, XRCC4 and ATM which we have been studying for the last few years. Because the maintenance of telomere function is crucial for genomic stability, our results will provide new insights into the mechanisms of chromosome instability and tumour formation.},
}
@article {pmid15162023,
year = {2004},
author = {Bailey, SM and Goodwin, EH},
title = {DNA and telomeres: beginnings and endings.},
journal = {Cytogenetic and genome research},
volume = {104},
number = {1-4},
pages = {109-115},
doi = {10.1159/000077474},
pmid = {15162023},
issn = {1424-859X},
support = {CA-43322/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Antigens, Nuclear/physiology ; Chromosome Breakage ; Chromosomes/ultrastructure ; Chromosomes, Human/genetics/ultrastructure ; DNA/*genetics ; DNA Repair ; DNA Repair Enzymes/physiology ; DNA Replication ; DNA-Activated Protein Kinase ; DNA-Binding Proteins/physiology ; Dog Diseases/genetics ; Dogs ; Humans ; Ku Autoantigen ; Mammals/genetics ; Mice ; Mice, Inbred BALB C ; Mice, SCID ; Nuclear Proteins ; Protein Serine-Threonine Kinases/deficiency/genetics/physiology ; Radiation Tolerance/genetics ; Severe Combined Immunodeficiency/genetics/veterinary ; Telomere/genetics/*physiology/ultrastructure ; },
abstract = {How a cell deals with its DNA ends is a question that returns us to the very beginnings of modern telomere biology. It is also a question we are still asking today because it is absolutely essential that a cell correctly distinguishes between natural chromosomal DNA ends and broken DNA ends, then processes each appropriately - preserving the one, rejoining the other. Effective end-capping of mammalian telomeres has a seemingly paradoxical requirement for proteins more commonly associated with DNA double strand break (DSB) repair. Ku70, Ku80, DNA-PKcs (the catalytic subunit of DNA-dependent protein kinase), Xrcc4 and Artemis all participate in DSB repair through nonhomologous end-joining (NHEJ). Somewhat surprisingly, mutations in any of these genes cause spontaneous chromosomal end-to-end fusions that maintain large blocks of telomeric sequence at the points of fusion, suggesting loss or failure of a critical terminal structure, rather than telomere shortening, is at fault. Nascent telomeres produced via leading-strand DNA synthesis are especially susceptible to these end-to-end fusions, suggesting a crucial difference in the postreplicative processing of telomeres that is linked to their mode of replication. Here we will examine the dual roles played by DNA repair proteins. Our review of this rapidly advancing field primarily will focus on mammalian cells, and cannot include even all of this. Despite these limitations, we hope the review will serve as a useful gateway to the literature, and will help to frame the major issues in this exciting and rapidly progressing field. Our apologies to those whose work we are unable to include.},
}
@article {pmid15161972,
year = {2004},
author = {Askree, SH and Yehuda, T and Smolikov, S and Gurevich, R and Hawk, J and Coker, C and Krauskopf, A and Kupiec, M and McEachern, MJ},
title = {A genome-wide screen for Saccharomyces cerevisiae deletion mutants that affect telomere length.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {101},
number = {23},
pages = {8658-8663},
pmid = {15161972},
issn = {0027-8424},
support = {R01 GM061645/GM/NIGMS NIH HHS/United States ; GM61645-01/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; DNA, Fungal/genetics ; Gene Deletion ; *Genome, Fungal ; *Mutation ; Phenotype ; Saccharomyces cerevisiae/*genetics ; Telomere/*genetics ; },
abstract = {Telomeres are nucleoprotein structures present at the ends of eukaryotic chromosomes that play a central role in guarding the integrity of the genome by protecting chromosome ends from degradation and fusion. Length regulation is central to telomere function. To broaden our knowledge about the mechanisms that control telomere length, we have carried out a systematic examination of approximately 4,800 haploid deletion mutants of Saccharomyces cerevisiae for telomere-length alterations. By using this screen, we have identified >150 candidate genes not previously known to affect telomere length. In two-thirds of the identified mutants, short telomeres were observed; whereas in one-third, telomeres were lengthened. The genes identified are very diverse in their functions, but certain categories, including DNA and RNA metabolism, chromatin modification, and vacuolar traffic, are overrepresented. Our results greatly enlarge the number of known genes that affect telomere metabolism and will provide insights into how telomere function is linked to many other cellular processes.},
}
@article {pmid15161685,
year = {2004},
author = {Meeker, AK and Hicks, JL and Iacobuzio-Donahue, CA and Montgomery, EA and Westra, WH and Chan, TY and Ronnett, BM and De Marzo, AM},
title = {Telomere length abnormalities occur early in the initiation of epithelial carcinogenesis.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {10},
number = {10},
pages = {3317-3326},
doi = {10.1158/1078-0432.CCR-0984-03},
pmid = {15161685},
issn = {1078-0432},
support = {K08CA78588/CA/NCI NIH HHS/United States ; P50CA58236/CA/NCI NIH HHS/United States ; R01DK07552/DK/NIDDK NIH HHS/United States ; },
mesh = {Adult ; Aged ; Animals ; Biomarkers, Tumor ; Breast Neoplasms/pathology ; Chromosome Aberrations ; Chromosomes/metabolism ; Colonic Neoplasms/metabolism ; Epithelial Cells/*metabolism ; Esophageal Neoplasms/metabolism ; Female ; Humans ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Mice, Knockout ; Middle Aged ; Mouth Neoplasms/metabolism ; Neoplasms/metabolism ; Neoplasms, Glandular and Epithelial/genetics/*ultrastructure ; Nucleic Acid Hybridization ; Prostatic Neoplasms/metabolism ; Telomere/*ultrastructure ; Urinary Bladder Neoplasms/metabolism ; Uterine Cervical Neoplasms/metabolism ; },
abstract = {PURPOSE: Telomeres help maintain chromosomal integrity. Dysfunctional telomeres can cause genetic instability in vitro and an increased cancer incidence in telomerase knock out mouse models. We recently reported that telomere shortening was a prevalent alteration in human prostate, pancreas, and breast cancer precursor lesions. In the present study, we address whether the previous findings are broadly applicable to human epithelial cancer precursors in general.<br><br>EXPERIMENTAL DESIGN: Surgical specimens of epithelial cancer precursor lesions from the urinary bladder, esophagus, large intestine, oral cavity, and uterine cervix were examined using a recently developed technique for direct in situ telomere length assessment in formalin-fixed human tissue specimens.<br><br>RESULTS: Widespread telomere length abnormalities were nearly universal (97.1% of cases) in the preinvasive stages of human epithelial carcinogenesis in all sites examined in this series, with telomere shortening the predominant abnormality (88.6% of cases).<br><br>CONCLUSIONS: Telomere length abnormalities appear to be one of the earliest and most prevalent genetic alterations acquired in the multistep process of malignant transformation. These findings support a model whereby telomere dysfunction induces chromosomal instability as an initiating event in many, perhaps most, human epithelial cancers. Together with previous findings from the prostate and pancreas, the percentage of intraepithelial neoplasia lesions showing telomere length abnormalities is 95.6%. The implications of these findings include the potential that telomere length assessment in situ may be a widely useful biomarker for monitoring disease prevention strategies and for improved early diagnosis.},
}
@article {pmid15159428,
year = {2004},
author = {Ocalewicz, K and Babiak, I and Dobosz, S and Nowaczyk, J and Goryczko, K},
title = {The stability of telomereless chromosome fragments in adult androgenetic rainbow trout.},
journal = {The Journal of experimental biology},
volume = {207},
number = {Pt 13},
pages = {2229-2236},
doi = {10.1242/jeb.01007},
pmid = {15159428},
issn = {0022-0949},
mesh = {Animals ; Centromere/genetics ; Chromosomal Instability/*genetics ; Chromosomes/*genetics ; DNA Fragmentation/*genetics ; *Gamma Rays ; Indoles ; Karyotyping ; Oncorhynchus mykiss/*genetics ; Parthenogenesis/genetics ; Staining and Labeling ; Telomere/genetics ; },
abstract = {The study provides new data on the stability of gamma radiation-induced chromosome fragments of a putative maternal nuclear genome in an androgenetic vertebrate, rainbow trout (Oncorhynchus mykiss Walbaum). The fragments were found in five of 16 examined individuals and they were mostly centromeric parts of metacentric or subtelocentric chromosomes. Chromosome fragments were identical in all cells of a given androgenetic individual, indicating that segregation of chromosome fragments is active from the early cell divisions. Most of the fragments were telomereless, i.e. they had no telomeric sequences on their ends. This shows that telomeres are not necessary for stability of chromosomal structures in a vertebrate genome. In one individual, the interstitial telomeric sites were found in chromosomes, which could be the effect of joining chromosome fragments.},
}
@article {pmid15153178,
year = {2004},
author = {Keys, B and Serra, V and Saretzki, G and Von Zglinicki, T},
title = {Telomere shortening in human fibroblasts is not dependent on the size of the telomeric-3'-overhang.},
journal = {Aging cell},
volume = {3},
number = {3},
pages = {103-109},
doi = {10.1111/j.1474-9728.2004.00094.x},
pmid = {15153178},
issn = {1474-9718},
mesh = {Electrophoresis, Gel, Pulsed-Field ; Fibroblasts/*metabolism ; Humans ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres shorten in human somatic cells with each round of DNA replication, and this shortening is thought to ultimately trigger replicative senescence. Telomere shortening is caused partly by the inability of semiconservative DNA replication to copy a linear strand of DNA to its very end. Post-replicative processing of telomeric ends, producing single-stranded G-rich 3' overhangs, has also been suggested to contribute to telomere shortening. This suggestion implies that a positive correlation should exist between the length of 3' overhangs and the rate of telomere shortening. We confirmed shortening of overhangs as human lung (MRC5) and foreskin (BJ) fibroblasts approach senescence by measuring overhang length using in-gel hybridization. However, a large study of fibroblast strains from 21 donors maintained under conditions which lead to two orders of magnitude of variation in telomere shortening rate failed to show any correlation between telomere overhang length and shortening rate, suggesting that overhang length is neither a cause nor a correlate of telomere shortening.},
}
@article {pmid15153177,
year = {2004},
author = {Graakjaer, J and Pascoe, L and Der-Sarkissian, H and Thomas, G and Kolvraa, S and Christensen, K and Londoño-Vallejo, JA},
title = {The relative lengths of individual telomeres are defined in the zygote and strictly maintained during life.},
journal = {Aging cell},
volume = {3},
number = {3},
pages = {97-102},
doi = {10.1111/j.1474-9728.2004.00093.x},
pmid = {15153177},
issn = {1474-9718},
mesh = {Age Factors ; Aged ; Aged, 80 and over ; Humans ; In Situ Hybridization ; Lymphocytes/metabolism ; Models, Biological ; Telomere/*metabolism ; Twin Studies as Topic ; Zygote/*metabolism ; },
abstract = {Previous studies have indicated that average telomere length is partly inherited (Slagboom et al., 1994; Rufer et al., 1999) and that there is an inherited telomere pattern in each cell (Graakjaer et al., 2003); (Londoño-Vallejo et al., 2001). In this study, we quantify the importance of the initially inherited telomere lengths within cells, in relation to other factors that influence telomere length during life. We have estimated the inheritance by measuring telomere length in monozygotic (MZ) twins using Q-FISH with a telomere specific peptide nucleic acid (PNA)-probe. Homologous chromosomes were identified using subtelomeric polymorphic markers. We found that identical homologous telomeres from two aged MZ twins show significantly less differences in relative telomere length than when comparing the two homologues within one individual. This result means that towards the end of life, individual telomeres retain the characteristic relative length they had at the outset of life and that any length alteration during the lifespan impacts equally on genetically identical homologues. As the result applies across independent individuals, we conclude that, at least in lymphocytes, epigenetic/environmental effects on relative telomere length are relatively minor during life.},
}
@article {pmid15150162,
year = {2004},
author = {Baird, DM and Davis, T and Rowson, J and Jones, CJ and Kipling, D},
title = {Normal telomere erosion rates at the single cell level in Werner syndrome fibroblast cells.},
journal = {Human molecular genetics},
volume = {13},
number = {14},
pages = {1515-1524},
doi = {10.1093/hmg/ddh159},
pmid = {15150162},
issn = {0964-6906},
mesh = {Cells, Cultured ; Cellular Senescence ; Fibroblasts/*metabolism/ultrastructure ; Humans ; Telomere/*genetics/metabolism ; Werner Syndrome/*genetics/metabolism ; },
abstract = {The aim of this study was to investigate whether the accelerated replicative senescence seen in Werner syndrome (WS) fibroblasts is due to accelerated telomere loss per cell division. Using single telomere length analysis (STELA) we show that the mean rate of telomere shortening in WS bulk cultures ranges between that of normal fibroblasts [99 bp/population doubling (PD)] and four times that of normal (355 bp/PD). The telomere erosion rate in the fastest eroding strain slows in the later stages of culture to that observed in normal fibroblasts, and appears to be correlated with a reduction in the heterogeneity of the telomere-length distributions. Telomere erosion rates in clones of WS cells are much reduced compared with bulk cultures, as are the variances of the telomere-length distributions. The overall lack of length heterogeneity and the normal erosion rates of the clonal populations are consistent with simple end-replication losses as the major contributor to telomere erosion in WS cells. We propose that telomere dynamics at the single cell level in WS fibroblasts are not significantly different from those in normal fibroblasts, and suggest that the accelerated replicative decline seen in WS fibroblasts does not result from accelerated telomere erosion.},
}
@article {pmid15149600,
year = {2004},
author = {Takata, H and Kanoh, Y and Gunge, N and Shirahige, K and Matsuura, A},
title = {Reciprocal association of the budding yeast ATM-related proteins Tel1 and Mec1 with telomeres in vivo.},
journal = {Molecular cell},
volume = {14},
number = {4},
pages = {515-522},
doi = {10.1016/s1097-2765(04)00262-x},
pmid = {15149600},
issn = {1097-2765},
mesh = {ATP-Binding Cassette Transporters/genetics/metabolism ; Cell Cycle/genetics ; DNA/genetics ; DNA Repair/*genetics ; Fungal Proteins/genetics/*metabolism ; Intracellular Signaling Peptides and Proteins ; Phosphatidylinositol 3-Kinases/genetics/metabolism ; Protein Serine-Threonine Kinases ; S Phase/genetics ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {The phosphoinositide (PI)-3-kinase-related kinase (PIKK) family proteins Tel1p and Mec1p have been implicated in the telomere integrity of Saccharomyces cerevisiae. However, the mechanism of PIKK-mediated telomere length control remains unclear. Here, we show that Tel1p and Mec1p are recruited to the telomeres at specific times in the cell cycle in a mutually exclusive manner. In particular, Mec1p interacts with the telomeres during late S phase and is associated preferentially with shortened telomeres. We propose a model in which telomere integrity is maintained by the reciprocal association of PIKKs, and Mec1p acts as a sensor for structural abnormalities in the telomeres. Our study suggests a mechanistic similarity between telomere length regulation and DNA double-strand break repair, both of which are achieved by the direct association of PIKKs.},
}
@article {pmid15149599,
year = {2004},
author = {Herbig, U and Jobling, WA and Chen, BP and Chen, DJ and Sedivy, JM},
title = {Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a).},
journal = {Molecular cell},
volume = {14},
number = {4},
pages = {501-513},
doi = {10.1016/s1097-2765(04)00256-4},
pmid = {15149599},
issn = {1097-2765},
support = {F32 CA099388/CA/NCI NIH HHS/United States ; P20 RR-15578/RR/NCRR NIH HHS/United States ; R01 AG16694/AG/NIA NIH HHS/United States ; R01 AG18949/AG/NIA NIH HHS/United States ; R01 CA50519/CA/NCI NIH HHS/United States ; T32 GM-07601/GM/NIGMS NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/metabolism ; Cell Death/genetics ; Cell Line ; Cellular Senescence/*genetics ; Cyclin-Dependent Kinase Inhibitor p16/genetics/metabolism ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins/genetics/*metabolism ; DNA Damage/genetics ; DNA-Binding Proteins ; G1 Phase/genetics ; G2 Phase/genetics ; Genes, cdc/physiology ; Humans ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Signal Transduction/*genetics ; Stress, Physiological/genetics/metabolism ; Telomere/*genetics ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; Tumor Suppressor Proteins ; Up-Regulation/genetics ; },
abstract = {Cellular senescence can be triggered by telomere shortening as well as a variety of stresses and signaling imbalances. We used multiparameter single-cell detection methods to investigate upstream signaling pathways and ensuing cell cycle checkpoint responses in human fibroblasts. Telomeric foci containing multiple DNA damage response factors were assembled in a subset of senescent cells and signaled through ATM to p53, upregulating p21 and causing G1 phase arrest. Inhibition of ATM expression or activity resulted in cell cycle reentry, indicating that stable arrest requires continuous signaling. ATR kinase appears to play a minor role in normal cells but in the absence of ATM elicited a delayed G2 phase arrest. These pathways do not affect expression of p16, which was upregulated in a telomere- and DNA damage-independent manner in a subset of cells. Distinct senescence programs can thus progress in parallel, resulting in mosaic cultures as well as individual cells responding to multiple signals.},
}
@article {pmid15149591,
year = {2004},
author = {Shay, JW and Wright, WE},
title = {Telomeres are double-strand DNA breaks hidden from DNA damage responses.},
journal = {Molecular cell},
volume = {14},
number = {4},
pages = {420-421},
doi = {10.1016/s1097-2765(04)00269-2},
pmid = {15149591},
issn = {1097-2765},
mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics ; DNA/*genetics ; DNA Damage/*genetics ; DNA-Binding Proteins ; Genes, cdc/*physiology ; Genome ; Humans ; Protein Serine-Threonine Kinases/genetics ; Signal Transduction/genetics ; Telomere/*genetics ; Tumor Suppressor Proteins ; },
abstract = {A network of ATM/ATR-mediated events regulates cell cycle checkpoints and genomic integrity and contributes to the processing of DNA double-strand breaks in both genomic DNA and at telomeres. In yeast and in human cells, investigators, including, and Herbig et al., published in this issue of Molecular Cell, are beginning to decipher the signaling pathways involved at the telomeres.},
}
@article {pmid15148368,
year = {2004},
author = {Schaetzlein, S and Lucas-Hahn, A and Lemme, E and Kues, WA and Dorsch, M and Manns, MP and Niemann, H and Rudolph, KL},
title = {Telomere length is reset during early mammalian embryogenesis.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {101},
number = {21},
pages = {8034-8038},
pmid = {15148368},
issn = {0027-8424},
mesh = {Animals ; Blastocyst/metabolism ; Cattle ; Embryonic and Fetal Development/*genetics ; Gene Deletion ; In Situ Hybridization, Fluorescence ; Mammals/genetics ; Mice ; Mice, Knockout ; Morula/metabolism ; RNA/genetics ; Telomerase/deficiency/genetics ; Telomere/*chemistry/*genetics ; Time Factors ; },
abstract = {The enzyme telomerase is active in germ cells and early embryonic development and is crucial for the maintenance of telomere length. Whereas the different length of telomeres in germ cells and somatic cells is well documented, information on telomere length regulation during embryogenesis is lacking. In this study, we demonstrate a telomere elongation program at the transition from morula to blastocyst in mice and cattle that establishes a specific telomere length set point during embryogenesis. We show that this process restores telomeres in cloned embryos derived from fibroblasts, regardless of the telomere length of donor nuclei, and that telomere elongation at this stage of embryogenesis is telomerase-dependent because it is abrogated in telomerase-deficient mice. These data demonstrate that early mammalian embryos have a telomerase-dependent genetic program that elongates telomeres to a defined length, possibly required to ensure sufficient telomere reserves for species integrity.},
}
@article {pmid15148341,
year = {2004},
author = {Reed, JR and Vukmanovic-Stejic, M and Fletcher, JM and Soares, MV and Cook, JE and Orteu, CH and Jackson, SE and Birch, KE and Foster, GR and Salmon, M and Beverley, PC and Rustin, MH and Akbar, AN},
title = {Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo.},
journal = {The Journal of experimental medicine},
volume = {199},
number = {10},
pages = {1433-1443},
pmid = {15148341},
issn = {0022-1007},
mesh = {BCG Vaccine/immunology ; CD4-Positive T-Lymphocytes/immunology ; Cells, Cultured ; Enzyme Inhibitors/pharmacology ; Humans ; Immunologic Memory/*immunology ; In Situ Hybridization, Fluorescence ; Lymphocyte Activation ; T-Lymphocytes/*immunology ; Telomerase/*drug effects/*immunology ; Telomere/*genetics ; },
abstract = {The extent of human memory T cell proliferation, differentiation, and telomere erosion that occurs after a single episode of immune challenge in vivo is unclear. To investigate this, we injected tuberculin purified protein derivative (PPD) into the skin of immune individuals and isolated responsive T cells from the site of antigenic challenge at different times. PPD-specific CD4+ T cells proliferated and differentiated extensively in the skin during this secondary response. Furthermore, significant telomere erosion occurred in specific T cells that respond in the skin, but not in those that are found in the blood from the same individuals. Tissue fluid obtained from the site of PPD challenge in the skin inhibited the induction of the enzyme telomerase in T cells in vitro. Antibody inhibition studies indicated that type I interferon (IFN), which was identified at high levels in the tissue fluid and by immunohistology, was responsible in part for the telomerase inhibition. Furthermore, the addition of IFN-alpha to PPD-stimulated CD4+ T cells directly inhibited telomerase activity in vitro. Therefore, these results suggest that the rate of telomere erosion in proliferating, antigen-specific CD4+ T cells may be accelerated by type I IFN during a secondary response in vivo.},
}
@article {pmid15143195,
year = {2004},
author = {Myung, K and Ghosh, G and Fattah, FJ and Li, G and Kim, H and Dutia, A and Pak, E and Smith, S and Hendrickson, EA},
title = {Regulation of telomere length and suppression of genomic instability in human somatic cells by Ku86.},
journal = {Molecular and cellular biology},
volume = {24},
number = {11},
pages = {5050-5059},
pmid = {15143195},
issn = {0270-7306},
mesh = {Antigens, Nuclear/*metabolism ; DNA-Binding Proteins/*metabolism ; Gene Expression Regulation/*physiology ; Genomic Instability/*physiology ; Heterozygote ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Ku Autoantigen ; Telomere/*metabolism ; },
abstract = {Ku86 plays a key role in nonhomologous end joining in organisms as evolutionarily disparate as bacteria and humans. In eukaryotic cells, Ku86 has also been implicated in the regulation of telomere length although the effect of Ku86 mutations varies considerably between species. Indeed, telomeres either shorten significantly, shorten slightly, remain unchanged, or lengthen significantly in budding yeast, fission yeast, chicken cells, or plants, respectively, that are null for Ku86 expression. Thus, it has been unclear which model system is most relevant for humans. We demonstrate here that the functional inactivation of even a single allele of Ku86 in human somatic cells results in profound telomere loss, which is accompanied by an increase in chromosomal fusions, translocations, and genomic instability. Together, these experiments demonstrate that Ku86, separate from its role in nonhomologous end joining, performs the additional function in human somatic cells of suppressing genomic instability through the regulation of telomere length.},
}
@article {pmid15143073,
year = {2004},
author = {Gertler, R and Rosenberg, R and Stricker, D and Friederichs, J and Hoos, A and Werner, M and Ulm, K and Holzmann, B and Nekarda, H and Siewert, JR},
title = {Telomere length and human telomerase reverse transcriptase expression as markers for progression and prognosis of colorectal carcinoma.},
journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology},
volume = {22},
number = {10},
pages = {1807-1814},
doi = {10.1200/JCO.2004.09.160},
pmid = {15143073},
issn = {0732-183X},
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/*biosynthesis/genetics ; Blotting, Southern ; Case-Control Studies ; Colorectal Neoplasms/*genetics/metabolism/*mortality/pathology/surgery ; DNA-Binding Proteins ; Female ; *Gene Expression Regulation, Neoplastic ; Germany ; Humans ; Male ; Middle Aged ; Neoplasm Staging ; Polymerase Chain Reaction ; Predictive Value of Tests ; Prognosis ; Proportional Hazards Models ; RNA, Messenger/analysis ; Survival Analysis ; Telomerase/*biosynthesis/genetics ; Telomere/*metabolism ; },
abstract = {PURPOSE: Maintenance of telomeres through reactivation of telomerase is a prerequisite for tumors to preserve their ability to proliferate. The purpose of this study was to evaluate telomere length and human telomerase reverse transcriptase (hTERT) expression as markers for progression and prognosis of colorectal carcinoma.<br><br>PATIENTS AND METHODS: Telomere length and hTERT expression were analyzed in matched cancer and adjacent noncancer mucosa samples from 57 patients with R0-resected colorectal carcinoma. The median follow-up time was 76 months.<br><br>RESULTS: Telomere length and hTERT expression correlated significantly in cancer tissues and adjacent mucosa samples (r = 0.52, P <.001; and r = 0.54, P <.001, respectively). Overall, cancer tissue had shorter telomeres than adjacent mucosa (P <.001). Only in noncancer tissue did telomere length decrease with age (r = 0.36; P <.01). Telomere length in cancer tissue was significantly correlated with tumor stage (P <.01), with longer telomeres in advanced tumors. Patients with ratios of telomere length in cancer to noncancer tissue greater than 0.90 had a significantly poorer overall survival compared with patients with smaller telomere length ratios (P <.002). In multivariate analysis, the telomere length ratio proved to be of independent prognostic value (P <.03).<br><br>CONCLUSION: Telomeres in colorectal carcinoma tissue were significantly shorter compared with adjacent normal mucosa as an indication for extensive cell proliferation. The correlation with tumor stage and patient survival suggest that hTERT-mediated telomere stabilization may be critical for progression and prognosis of colorectal carcinoma.},
}
@article {pmid15142431,
year = {2003},
author = {Flanary, BE and Streit, WJ},
title = {Telomeres shorten with age in rat cerebellum and cortex in vivo.},
journal = {Journal of anti-aging medicine},
volume = {6},
number = {4},
pages = {299-308},
doi = {10.1089/109454503323028894},
pmid = {15142431},
issn = {1094-5458},
mesh = {Aging/*physiology ; Animals ; Cerebellum/*physiology ; Cerebral Cortex/*physiology ; Rats ; Rats, Sprague-Dawley ; Telomere/*physiology ; },
abstract = {Normal somatic cells have a finite replicative capacity. With each cell division, telomeres, the ends of linear chromosomes, progressively shorten until they reach a critical length, at which point the cells enter replicative senescence. Some cells maintain their telomeres by the action of the telomerase enzyme. Glia, particularly microglia, are the only adult cell type in the central nervous system (CNS) that exhibit a significant mitotic potential, and are thus susceptible to telomere shortening. Previous research in our laboratory has found that telomeres shorten in rat microglia with increasing time in vitro. Our current hypothesis is that telomeres shorten in rat brain in vivo with increasing age. Tissue samples of cerebellum and cortex were obtained from Sprague-Dawley rats of various ages. Genomic DNA and total protein was isolated from each sample for telomere length measurement via Southern blot analysis (up to 5 months) and telomerase activity measurement via TRAP analysis (up to 6 months), respectively. Telomere shortening occurs in vivo in both rat cerebellum and cortex from day 21 to approximately 5 months of age. Cortex samples possessed shorter telomeres than did cerebellum samples. The longest telomeres undergo the most dramatic shortening, while the shortest telomeres exhibit only slight attrition. Telomerase activity slowly increases from day 21 to approximately 6 months of age, with the cerebellum exhibiting higher activity than cortex in all instances. These results indicate that telomere shortening occurs in rat brain in vivo with increasing age, and that the low levels of telomerase activity present may be preferentially recruited to maintain the shortest telomeres while allowing the longer ones to shorten more rapidly. Since microglia are thought to be the only mature cells of the postnatal CNS undergoing appreciable cell division, we propose that the telomere shortening occurring in the adult rat brain with age can be largely attributed to microglial cell division. Our findings provide an impetus to further investigate the pattern of telomere length and telomerase activity that emerges with further aging in the rat brain.},
}
@article {pmid15141167,
year = {2004},
author = {Heacock, M and Spangler, E and Riha, K and Puizina, J and Shippen, DE},
title = {Molecular analysis of telomere fusions in Arabidopsis: multiple pathways for chromosome end-joining.},
journal = {The EMBO journal},
volume = {23},
number = {11},
pages = {2304-2313},
pmid = {15141167},
issn = {0261-4189},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; GM65383/GM/NIGMS NIH HHS/United States ; },
mesh = {Arabidopsis/*genetics/growth &amp; development ; Arabidopsis Proteins/*genetics/metabolism ; Catalytic Domain ; *Chromosomes, Plant ; DNA Repair ; DNA-Binding Proteins/genetics/metabolism ; MRE11 Homologue Protein ; Mutation ; Telomerase/chemistry ; *Telomere ; },
abstract = {End-to-end fusion of critically shortened telomeres in higher eucaryotes is presumed to be mediated by nonhomologous end-joining (NHEJ). Here we describe two PCR-based methods to monitor telomere length and examine the fate of dysfunctional telomeres in Arabidopsis lacking the catalytic subunit of telomerase (TERT) and the DNA repair proteins Ku70 and Mre11. Primer extension telomere repeat amplification relies on the presence of an intact G-overhang, and thus measures functional telomere length. The minimum functional telomere length detected was 300-400 bp. PCR amplification and sequence analysis of chromosome fusion junctions revealed exonucleolytic digestion of dysfunctional ends prior to fusion. In ku70 tert mutants, there was a greater incidence of microhomology at the fusion junction than in tert mutants. In triple ku70 tert mre11 mutants, chromosome fusions were still detected, but microhomology at the junction was no longer favored. These data indicate that both Ku70 and Mre11 contribute to fusion of critically shortened telomeres in higher eucaryotes. Furthermore, Arabidopsis processes critically shortened telomeres as double-strand breaks, using a variety of end-joining pathways.},
}
@article {pmid15139326,
year = {2004},
author = {Labrune, P},
title = {[Telomere anomalies: focus].},
journal = {Archives de pediatrie : organe officiel de la Societe francaise de pediatrie},
volume = {11},
number = {4},
pages = {367},
pmid = {15139326},
issn = {0929-693X},
mesh = {*Chromosome Aberrations ; Humans ; Intellectual Disability/*genetics ; Phenotype ; *Telomere ; },
}
@article {pmid15138591,
year = {2004},
author = {Sumi, M and Tauchi, T and Sashida, G and Nakajima, A and Gotoh, A and Shin-Ya, K and Ohyashiki, JH and Ohyashiki, K},
title = {A G-quadruplex-interactive agent, telomestatin (SOT-095), induces telomere shortening with apoptosis and enhances chemosensitivity in acute myeloid leukemia.},
journal = {International journal of oncology},
volume = {24},
number = {6},
pages = {1481-1487},
pmid = {15138591},
issn = {1019-6439},
mesh = {Acute Disease ; Aged ; Antibiotics, Antineoplastic/pharmacology ; Antimetabolites, Antineoplastic/pharmacology ; Apoptosis/*drug effects ; Cytarabine/pharmacology ; DNA-Binding Proteins ; Daunorubicin/pharmacology ; *Drug Resistance, Neoplasm ; Female ; Humans ; Leukemia, Myeloid/*drug therapy/enzymology ; Male ; Middle Aged ; Oxazoles/*pharmacology ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*genetics/metabolism ; U937 Cells/drug effects/metabolism/pathology ; },
abstract = {Telomerase, the ribonucleoprotein enzyme maintaining the telomeres of eukaryotic chromosomes, is up-regulated in the vast majority of human neoplasias but not in normal somatic tissues. Therefore, the telomerase complex represents a promising universal therapeutic target in cancer. Telomeric G-rich single-stranded DNA can adopt in vitro an intramolecular quadruplex structure, which has been shown to inhibit telomerase activity. We examined G-quadruplex interactive agent, telomestatin (SOT-095), for its ability to inhibit the proliferation of human leukemia cells, including freshly obtained leukemia cells. Telomere length was determined by either the terminal restriction fragment method or flow-FISH, and apoptosis was assessed by flow cytometry. Moreover, chemosensitivity was examined in telomestatin-treated U937 cells before ultimate telomere shortening. Treatment with telomestatin reproducibly inhibited telomerase activity in U937 and NB4 cells followed by telomere shortening. Enhanced chemosensitivity toward daunorubicin and cytosine-arabinoside was observed in telomestatin-treated U937 cells, before ultimate telomere shortening. Telomere shortening associated with apoptosis by telomestatin was evident in some freshly obtained leukemia cells from acute myeloid leukemia patients, regardless of sub-types of AML and post-myelodysplasia AML. These results suggest that disruption of telomere maintenance by telomestatin limits the cellular lifespan of AML cells, as well. However, in a minority of AML patients apoptosis was not evident, thus indicating that resistant mechanism might exist in some freshly obtained AML cells. Therefore, further investigation of telomestatin as a therapeutic agent is warranted.},
}
@article {pmid15138570,
year = {2004},
author = {Terasaki, T and Kyo, S and Takakura, M and Maida, Y and Tsuchiya, H and Tomita, K and Inoue, M},
title = {Analysis of telomerase activity and telomere length in bone and soft tissue tumors.},
journal = {Oncology reports},
volume = {11},
number = {6},
pages = {1307-1311},
pmid = {15138570},
issn = {1021-335X},
mesh = {Bone Neoplasms/enzymology/*genetics/secondary ; DNA-Binding Proteins ; Humans ; Mesenchymoma/pathology ; Mesoderm/pathology ; Neoplasm Recurrence, Local/enzymology/*genetics/secondary ; Neoplasm Staging ; Osteosarcoma/enzymology/*genetics/secondary ; RNA, Messenger/genetics/metabolism ; Sarcoma/enzymology/*genetics/secondary ; Survival Rate ; Telomerase/genetics/*metabolism ; Telomere/*chemistry ; },
abstract = {Telomerase activation is prevalent in most epithelial tumors, and may be a critical step in cellular immortalization and carcinogenesis. However, telomerase activity in tumors of mesenchymal origin is not well understood. In the present study, we examined telomerase activity in clinical samples from osteosarcoma and soft tissue sarcoma and representative sarcoma cell lines (HOS, OST and Saos2), using the telomeric repeat amplification protocol (TRAP) assay. The cell lines HOS and OST were telomerase-positive, but Saos2 cells lacked telomerase activity and hTERT mRNA expression. Treatment of Saos2 cells with the demethylating agent 5-aza-2'-deoxy-cytidine, alone or together with the histone deacetylase inhibitor tricostatin A, did not induce hTERT mRNA expression. Twenty-six of the 83 sarcoma samples (31.3%) were telomerase-positive [bone sarcoma, 15 of 42 samples (35.7%); soft tissue sarcoma, 11 of 41 samples (26.8%)], whereas neither benign tumors nor normal bone tissue expressed telomerase activity. There was no significant correlation between histological type, tumor staging and telomerase activity. However, patients with telomerase-positive tumors had significantly shorter survival than those with telomerase-negative tumors. There was heterogeneity in telomere length (range, 6-18 kb) among the tumors examined, but there was no significant difference in length between telomerase-positive and -negative tumors. Thus, these mesenchymal tumors comprise heterologous groups, some positive and some negative for telomerase, with long and short telomeres, suggesting multiple carcinogenesis pathways. The present results indicate that telomerase activation is not prevalent in mesenchymal tumors and is not a critical determinant of telomere length, but it may be a prognostic indicator of mesenchymal tumors.},
}
@article {pmid15133513,
year = {2004},
author = {Ye, JZ and de Lange, T},
title = {TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex.},
journal = {Nature genetics},
volume = {36},
number = {6},
pages = {618-623},
doi = {10.1038/ng1360},
pmid = {15133513},
issn = {1061-4036},
mesh = {HeLa Cells ; Humans ; In Vitro Techniques ; Macromolecular Substances ; Poly(ADP-ribose) Polymerases/*metabolism ; RNA, Small Interfering/genetics ; Recombinant Proteins/chemistry/genetics/metabolism ; Tankyrases/chemistry/*metabolism ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/chemistry/*genetics/*metabolism ; Telomeric Repeat Binding Protein 1/chemistry/*metabolism ; Transfection ; },
abstract = {Telomere length in humans is partly controlled by a feedback mechanism in which telomere elongation by telomerase is limited by the accumulation of the TRF1 complex at chromosome ends. TRF1 itself can be inhibited by the poly(ADP-ribose) polymerase (PARP) activity of its interacting partner tankyrase 1, which abolishes its DNA binding activity in vitro and removes the TRF1 complex from telomeres in vivo. Here we report that the inhibition of TRF1 by tankyrase is in turn controlled by a second TRF1-interacting factor, TIN2 (ref. 6). Partial knockdown of TIN2 by small hairpin RNA in a telomerase-positive cell line resulted in telomere elongation, which is typical of reduced TRF1 function. Transient inhibition of TIN2 with small interfering RNA led to diminished telomeric TRF1 signals. This effect could be reversed with the PARP inhibitor 3-aminobenzamide and did not occur in cells overexpressing a PARP-dead mutant of tankyrase 1. TIN2 formed a ternary complex with TRF1 and tankyrase 1 and stabilized their interaction, an effect also observed with the PARP-dead mutant of tankyrase 1. In vitro, TIN2 protected TRF1 from poly(ADP-ribosyl)ation by tankyrase 1 without affecting tankyrase 1 automodification. These data identify TIN2 as a PARP modulator in the TRF1 complex and can explain how TIN2 contributes to the regulation of telomere length.},
}
@article {pmid15133512,
year = {2004},
author = {Pennaneach, V and Kolodner, RD},
title = {Recombination and the Tel1 and Mec1 checkpoints differentially effect genome rearrangements driven by telomere dysfunction in yeast.},
journal = {Nature genetics},
volume = {36},
number = {6},
pages = {612-617},
doi = {10.1038/ng1359},
pmid = {15133512},
issn = {1061-4036},
mesh = {Artificial Gene Fusion ; Base Sequence ; DNA, Fungal/genetics ; Fungal Proteins/*genetics ; *Gene Rearrangement ; *Genome, Fungal ; Humans ; Intracellular Signaling Peptides and Proteins ; Models, Genetic ; Molecular Sequence Data ; Mutation ; Protein Serine-Threonine Kinases ; Recombination, Genetic ; Saccharomyces cerevisiae/cytology/*genetics ; Saccharomyces cerevisiae Proteins/*genetics ; Sequence Homology, Nucleic Acid ; Telomere/*genetics ; Translocation, Genetic ; },
abstract = {In telomerase-deficient Saccharomyces cerevisiae, telomeres are maintained by recombination. Here we used a S. cerevisiae assay for characterizing gross chromosomal rearrangements (GCRs) to analyze genome instability in post-senescent telomerase-deficient cells. Telomerase-deficient tlc1 and est2 mutants did not have increased GCR rates, but their telomeres could be joined to other DNAs resulting in chromosome fusions. Inactivation of Tel1 or either the Rad51 or Rad59 recombination pathways in telomerase-deficient cells increased the GCR rate, even though telomeres were maintained. The GCRs were translocations and chromosome fusions formed by nonhomologous end joining. We observed chromosome fusions only in mutant strains expressing Rad51 and Rad55 or when Tel1 was inactivated. In contrast, inactivation of Mec1 resulted in more inversion translocations such as the isochromosomes seen in human tumors. These inversion translocations seemed to be formed by recombination after replication of broken chromosomes.},
}
@article {pmid15133297,
year = {2004},
author = {Ojima, M and Hamano, H and Suzuki, M and Suzuki, K and Kodama, S and Watanabe, M},
title = {Delayed induction of telomere instability in normal human fibroblast cells by ionizing radiation.},
journal = {Journal of radiation research},
volume = {45},
number = {1},
pages = {105-110},
doi = {10.1269/jrr.45.105},
pmid = {15133297},
issn = {0449-3060},
mesh = {Adaptation, Physiological/genetics/radiation effects ; Cell Line ; Cell Survival/radiation effects ; Chromosomal Instability/genetics/radiation effects ; Dose-Response Relationship, Radiation ; Fibroblasts/*pathology/*radiation effects ; Gene Expression Regulation/radiation effects ; Humans ; Radiation Dosage ; Radiation, Ionizing ; Telomere/*genetics/*radiation effects/ultrastructure ; },
abstract = {We examined the delayed induction of telomere instability in hTERT-immortalized normal human fibroblast (BJ1-hTERT) cells exposed to X-rays. BJ1-hTERT cells were irradiated with 2 Gy of X-rays, and chromosome aberrations were analyzed 24 hours after irradiation and in the surviving cells 14 days after X-ray exposure. We found that the X-ray-surviving cells showed an increased frequency of chromatid gaps and breaks and chromosome fragments compared to the control cells. Furthermore, centromere- and telomere-FISH revealed that the frequency of telomere loss and duplication significantly increased in surviving cells compared to the control level. Because no induction of telomere abnormality was observed in cells 24 hours after irradiation, X-irradiation might not affect telomeres directly, but it specifically induces delayed telomere instability in normal human fibroblast cells.},
}
@article {pmid15132993,
year = {2004},
author = {Grossi, S and Puglisi, A and Dmitriev, PV and Lopes, M and Shore, D},
title = {Pol12, the B subunit of DNA polymerase alpha, functions in both telomere capping and length regulation.},
journal = {Genes &amp; development},
volume = {18},
number = {9},
pages = {992-1006},
pmid = {15132993},
issn = {0890-9369},
mesh = {Cell Cycle Proteins/metabolism ; DNA Polymerase I/*chemistry/genetics/*metabolism ; DNA Primase/*chemistry/genetics/*metabolism ; Genes, Fungal ; Mutation ; Phenotype ; Protein Subunits ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/metabolism ; },
abstract = {The regulation of telomerase action, and its coordination with conventional DNA replication and chromosome end "capping," are still poorly understood. Here we describe a genetic screen in yeast for mutants with relaxed telomere length regulation, and the identification of Pol12, the B subunit of the DNA polymerase alpha (Pol1)-primase complex, as a new factor involved in this process. Unlike many POL1 and POL12 mutations, which also cause telomere elongation, the pol12-216 mutation described here does not lead to either reduced Pol1 function, increased telomeric single-stranded DNA, or a reduction in telomeric gene silencing. Instead, and again unlike mutations affecting POL1, pol12-216 is lethal in combination with a mutation in the telomere end-binding and capping protein Stn1. Significantly, Pol12 and Stn1 interact in both two-hybrid and biochemical assays, and their synthetic-lethal interaction appears to be caused, at least in part, by a loss of telomere capping. These data reveal a novel function for Pol12 and a new connection between DNA polymerase alpha and Stn1. We propose that Pol12, together with Stn1, plays a key role in linking telomerase action with the completion of lagging strand synthesis, and in a regulatory step required for telomere capping.},
}
@article {pmid15131795,
year = {2004},
author = {Shammas, MA and Koley, H and Beer, DG and Li, C and Goyal, RK and Munshi, NC},
title = {Growth arrest, apoptosis, and telomere shortening of Barrett's-associated adenocarcinoma cells by a telomerase inhibitor.},
journal = {Gastroenterology},
volume = {126},
number = {5},
pages = {1337-1346},
doi = {10.1053/j.gastro.2004.01.026},
pmid = {15131795},
issn = {0016-5085},
support = {DK 031092/DK/NIDDK NIH HHS/United States ; P01 78378//PHS HHS/United States ; P50 CA 10070/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma/etiology/pathology/*physiopathology ; Anthraquinones/*pharmacology ; *Apoptosis/drug effects ; Barrett Esophagus/*complications ; Cell Division/drug effects ; Cell Line, Tumor ; Enzyme Inhibitors/*pharmacology ; Esophageal Neoplasms/etiology/pathology/*physiopathology ; Gene Expression/drug effects ; Gene Expression Profiling ; Humans ; Piperidines/*pharmacology ; Stem Cells/pathology ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/drug effects/*genetics ; },
abstract = {BACKGROUND &amp; AIMS: Barrett's esophageal adenocarcinoma (BEAC) is a complication of gastroesophageal reflux disease, with no effective chemotherapy and poor prognosis. BEAC cells, like many other types of cancers, may reactivate telomerase to achieve unlimited proliferative potential, making telomerase a unique therapeutic target. The purpose of this study was to evaluate effects of telomerase inhibition on BEAC.<br><br>METHODS: We examined the effect of a selective G-quadruplex intercalating telomerase inhibitor, 2,6-bis[3-(N-Piperidino)propionamido]anthracene-9,10-dione (PPA), on telomerase activity, telomere length, colony size distribution, and proliferative potential in 2 BEAC cell lines, BIC-1 and SEG-1.<br><br>RESULTS: Telomerase activity was >10-fold and >600-fold elevated in the adenocarcinoma cells as compared with normal gastric/intestinal cells and normal diploid fibroblasts, respectively. Telomeres were short, being less than 4 kilobase pair in both tumor cell lines. Exposure to PPA effectively inhibited telomerase activity and shortened telomeres. PPA also arrested cell proliferation and reduced colony number and size after a lag period of about 10 cell generations, consistent with the attrition of telomeres. The growth arrest was not due to senescence but was due to apoptosis. Expression analysis of the cells following PPA treatment did not show significant change in the expression of genes involved in cell-cycle proliferation and apoptosis. Exposure to PPA had no effect on proliferative potential of normal intestinal cells.<br><br>CONCLUSIONS: We conclude that telomerase inhibition by PPA induces cell growth arrest in BEAC cells and demonstrate the potential of telomerase inhibitors in chemoprevention and treatment of Barrett's-associated esophageal adenocarcinoma.},
}
@article {pmid15131012,
year = {2004},
author = {Blasco, MA},
title = {Carcinogenesis Young Investigator Award. Telomere epigenetics: a higher-order control of telomere length in mammalian cells.},
journal = {Carcinogenesis},
volume = {25},
number = {7},
pages = {1083-1087},
doi = {10.1093/carcin/bgh185},
pmid = {15131012},
issn = {0143-3334},
mesh = {Animals ; Chromatin/*physiology ; Epigenesis, Genetic/*physiology ; Heterochromatin/physiology ; Histones/physiology ; Humans ; Nucleosomes/physiology ; Telomere/*genetics/physiology ; Telomere-Binding Proteins/physiology ; },
abstract = {Telomeres are capping structures at the ends of eukaryotic chromosomes composed of TTAGGG repeats bound to an array of specialized proteins. Telomeres, together with centromeres, have been classically considered heterochromatic regions. Constitutive heterochromatin domains typically consist of repetitive DNA and have a very low gene content. In addition, constitutive heterochromatin is characterized by a number of hallmark histone modifications, as well as DNA modifications. In the case of pericentric heterochromatin, several activities responsible for these epigenetic modifications have been recently identified and characterized. In contrast, very little is still known on the architecture of telomeric chromatin, as well as on the activities that may regulate its structure and function. Here, we will discuss recent findings suggesting that telomeric chromatin shares many features with pericentric chromatin, and that disruption of telomeric heterochromatin results in changes in telomere length.},
}
@article {pmid15130681,
year = {2004},
author = {Hastings, R and Li, NC and Lacy, PS and Patel, H and Herbert, KE and Stanley, AG and Williams, B},
title = {Rapid telomere attrition in cardiac tissue of the ageing Wistar rat.},
journal = {Experimental gerontology},
volume = {39},
number = {5},
pages = {855-857},
doi = {10.1016/j.exger.2004.02.003},
pmid = {15130681},
issn = {0531-5565},
mesh = {Aging/*physiology ; Animals ; Blotting, Southern/methods ; Brain/physiology ; DNA/analysis ; Heart/embryology/physiology ; Kidney/physiology ; Liver/physiology ; Lung/physiology ; Male ; *Myocardium ; Rats ; Rats, Wistar ; Telomere/*genetics ; },
abstract = {Many studies show an association between ageing and mean telomere length in DNA isolated from peripheral blood mononuclear cells, few studies have examined less accessible tissues. This study has two objectives: (i) to define the best method to prepare rodent DNA for telomere length measurement by Southern blotting and (ii) to determine whether there are differential rates of telomere attrition in different rodent tissues. We found that the use of agarose plugs for DNA isolation was essential for the accurate measurement of rodent telomere length. Tissue was collected from neonatal (3 days) or aged (18-24 months) male Wistar rats and terminal restriction fragment (TRF) length was measured by Southern blotting. Cardiac tissue from aged rats showed a 38% loss of TRF length compared with newborn animals (p<0.001, n=13), this contrasts with much smaller reductions in brain (1.6%), liver (14.2%), kidney (8.9%) and lung (9.7%). This study demonstrates that the methods of DNA preparation are critical for accurate measurement of telomeres in rodent tissues. Moreover, we show differential rates of telomere attrition in rat tissues, the heart being most susceptible to telomere loss. These observations could have important implications for the study of age-specific changes in tissue function.},
}
@article {pmid15129004,
year = {2004},
author = {Leslie, M},
title = {If telomeres thrive, you will survive. Augmenting chromosome caps extends worm life span.},
journal = {Science of aging knowledge environment : SAGE KE},
volume = {2004},
number = {18},
pages = {nf47},
doi = {10.1126/sageke.2004.18.nf47},
pmid = {15129004},
issn = {1539-6150},
mesh = {Aging/genetics ; Animals ; Cellular Senescence/*genetics/physiology ; Nematoda ; *Telomere ; },
}
@article {pmid15126641,
year = {2004},
author = {Kurz, DJ and Decary, S and Hong, Y and Trivier, E and Akhmedov, A and Erusalimsky, JD},
title = {Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells.},
journal = {Journal of cell science},
volume = {117},
number = {Pt 11},
pages = {2417-2426},
doi = {10.1242/jcs.01097},
pmid = {15126641},
issn = {0021-9533},
mesh = {Buthionine Sulfoximine/pharmacology/toxicity ; Cell Cycle/drug effects ; Cell Line ; *Cellular Senescence/drug effects ; Down-Regulation ; Endothelial Cells/*cytology/drug effects/*metabolism ; Enzyme Inhibitors/pharmacology/toxicity ; Glutamate-Cysteine Ligase/antagonists &amp; inhibitors ; Humans ; Oxidative Stress/drug effects/*physiology ; Reactive Oxygen Species/metabolism ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; tert-Butylhydroperoxide/pharmacology/toxicity ; },
abstract = {Replicative senescence and oxidative stress have been implicated in ageing, endothelial dysfunction and atherosclerosis. Replicative senescence is determined primarily by telomere integrity. In endothelial cells the glutathione redox-cycle plays a predominant role in the detoxification of peroxides. The aim of this study was to elucidate the role of the glutathione-dependent antioxidant system on the replicative capacity and telomere dynamics of cultured endothelial cells. Human umbilical vein endothelial cells were serially passaged while exposed to regular treatment with 0.1 microM tert-butyl hydroperoxide, a substrate of glutathione peroxidase, or 10 microM L-buthionine-[S,R]-sulphoximine, an inhibitor of glutathione synthesis. Both treatments induced intracellular oxidative stress but had no cytotoxic or cytostatic effects. Nonetheless, treated cultures entered senescence prematurely (30 versus 46 population doublings), as determined by senescence-associated beta-galactosidase staining and a sharp decrease in cell density at confluence. In cultures subjected to oxidative stress terminal restriction fragment (TRF) analysis demonstrated faster telomere shortening (110 versus 55 bp/population doubling) and the appearance of distinct, long TRFs after more than 15-20 population doublings. Fluorescence in situ hybridisation analysis of metaphase spreads confirmed the presence of increased telomere length heterogeneity, and ruled out telomeric end-to-end fusions as the source of the long TRFs. The latter was also confirmed by Bal31 digestion of genomic DNA. Similarly, upregulation of telomerase could not account for the appearance of long TRFs, as oxidative stress induced a rapid and sustained decrease in this activity. These findings demonstrate a key role for glutathione-dependent redox homeostasis in the preservation of telomere function in endothelial cells and suggest that loss of telomere integrity is a major trigger for the onset of premature senescence under mild chronic oxidative stress.},
}
@article {pmid15126387,
year = {2004},
author = {Bertuch, AA and Lundblad, V},
title = {EXO1 contributes to telomere maintenance in both telomerase-proficient and telomerase-deficient Saccharomyces cerevisiae.},
journal = {Genetics},
volume = {166},
number = {4},
pages = {1651-1659},
pmid = {15126387},
issn = {0016-6731},
support = {K08 HD001231/HD/NICHD NIH HHS/United States ; K08 HD01231/HD/NICHD NIH HHS/United States ; R01 AG16626/AG/NIA NIH HHS/United States ; },
mesh = {Cell Proliferation ; DNA-Binding Proteins/*metabolism ; Electrophoresis, Agar Gel ; Exodeoxyribonucleases/genetics/*metabolism ; Genotype ; Oligonucleotide Probes ; Plasmids/genetics ; Recombination, Genetic/genetics ; Saccharomyces cerevisiae/*metabolism/physiology ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Previous work in budding yeast has indicated that telomeres are protected, at least in part, from the action of Exo1, which degrades the C-rich strand of partially uncapped telomeres. To explore this further, we examined the consequences of Exo1-mediated activity in strains that lacked Ku, telomerase, or both. Loss of Exo1 partially rescued the telomere length defect in a yku80delta strain, demonstrating that exonuclease action can directly contribute to telomere shortening. The rapid loss of inviability displayed by a yku80delta est2delta strain was also partially alleviated by an exo1delta mutation, further supporting the proposal that Exo1 is one target of the activities that normally protect wild-type telomeres. Conversely, however, Exo1 activity was also capable of enhancing telomere function and consequently cell proliferation, by contributing to a telomerase-independent pathway for telomere maintenance. The recovery of recombination-dependent survivors that arose in a yku80delta est2delta strain was partially dependent on Exo1 activity. Furthermore, the types of recombination events that facilitate telomerase-independent survival were influenced by Exo1 activity, in both est2delta and yku80delta est2delta strains. These data demonstrate that Exo1 can make either positive or negative contributions to telomere function and cell viability, depending on whether telomerase or recombination is utilized to maintain telomere function.},
}
@article {pmid15124860,
year = {2004},
author = {Tucker, VC and Rye, AD and Harrison, J and King, L and Duddridge, M and Browning, MJ},
title = {Lymphocyte subpopulations from patients with primary antibody deficiency do not show increased telomere erosion.},
journal = {Immunobiology},
volume = {208},
number = {5},
pages = {455-462},
doi = {10.1078/0171-2985-00292},
pmid = {15124860},
issn = {0171-2985},
mesh = {Adult ; Age Factors ; Aged ; Cell Division/physiology ; Female ; Humans ; Immunologic Deficiency Syndromes/complications/*immunology/metabolism/microbiology ; Lymphocyte Subsets/immunology/*metabolism ; Male ; Middle Aged ; Telomere/*genetics/immunology/metabolism ; },
abstract = {Telomere erosion and residual replicative capacity can be used as markers of the replicative history of somatic cells. We have investigated telomere length, in vitro replicative capacity and rate of telomere erosion in T and B lymphocyte populations from patients with primary antibody deficiency requiring immunoglobulin replacement therapy. We found no significant differences in telomere lengths of B cells, or of CD4+, CD8+, CD45RA+ (naive) and CD45RO+ (memory) T cell populations between patients and age matched controls. Overall, telomere length correlated inversely with age, and was reduced in memory (CD45RO+) as compared with naive (CD45RA+) T cells. In vitro long-term (6 months) cell cultures showed no differences between patients and controls in the mitogen-stimulated replicative potential of T cell subpopulations (CD4+, CD8+, CD45RA+, CD45RO+), or in the rates of telomere erosion with cellular replication in these cell populations. The rate of telomere erosion per population doubling in CD45RA+ cells, however, was greater than in CD45RO+ cells in both patients and controls. These data suggest that premature immune exhaustion is unlikely to represent a long-term complication of primary antibody deficiency.},
}
@article {pmid15118675,
year = {2004},
author = {Shay, JW and Wright, WE},
title = {Telomeres in dyskeratosis congenita.},
journal = {Nature genetics},
volume = {36},
number = {5},
pages = {437-438},
doi = {10.1038/ng0504-437},
pmid = {15118675},
issn = {1061-4036},
mesh = {Dyskeratosis Congenita/diagnosis/*genetics ; Genes, Dominant ; Humans ; Mutation/*genetics ; RNA/*genetics ; Telomerase/*genetics ; Telomere/*genetics ; },
}
@article {pmid15116319,
year = {2004},
author = {Morita, M and Nakanishi, K and Kawai, T and Fujikawa, K},
title = {Telomere length, telomerase activity, and expression of human telomerase reverse transcriptase mRNA in growth plate of epiphyseal articular cartilage in femoral head during normal human development and in thanatophoric dysplasia.},
journal = {Human pathology},
volume = {35},
number = {4},
pages = {403-411},
doi = {10.1016/j.humpath.2003.08.022},
pmid = {15116319},
issn = {0046-8177},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Blotting, Southern ; Cartilage, Articular/*physiology ; Child ; Child, Preschool ; DNA-Binding Proteins ; Female ; Femur Head/physiology ; Fetus ; Growth Plate/*physiology ; Humans ; In Situ Hybridization ; Infant ; Infant, Newborn ; Middle Aged ; Polymerase Chain Reaction ; Pregnancy ; RNA, Messenger/analysis ; Telomerase/*biosynthesis/*metabolism ; Telomere/*physiology ; Thanatophoric Dysplasia/*enzymology ; },
abstract = {Telomeres are important in chromosome structure and function, protecting against their degradation. However, few studies have examined telomeres in growth plates within articular cartilage during normal development. We investigated frozen sections that were obtained from 57 reference autopsy cases (aged from 16 weeks of gestation to 91 years) and from 2 patients with thanatophoric dysplasia. In the reference cases, telomere length was significantly longer in growth plates obtained from the 10 cases that were aged from 16 weeks of gestation to 10 years than in those from 47 of the adult cases (aged 20 to 91 years). In fetal, neonatal, and child cases, telomerase activity was significantly higher in the hypertrophied zone (HZ) in growth plates than in the other 3 zones. The hTERT mRNA staining intensity (staining area) was stronger (larger) in HZ and the proliferating zone than in the calcified zone and resting zone. In thanatophoric dysplasia, telomere length and telomerase activity were short and low, respectively, compared with those of normal growth plates at an equivalent age, and expression of hTERT mRNA was negative or weakly positive in all 4 zones within growth plates. These results suggest that telomere length and telomerase activity have significant effects in the growth plates of articular cartilage, particularly at developmental ages from fetus to child. We speculate that short telomere length and low telomerase activity may be important for chondrocyte differentiation in rhizomeric shortening of the limbs in thanatophoric dysplasia.},
}
@article {pmid15114935,
year = {2003},
author = {Schelzig, H and Chkhotua, AB and Wiegand, P and Grosse, S and Reis, S and Art, M and Abendroth, D},
title = {Effect of ischemia/reperfusion on telomere length and CDKI genes expression in a concordant ex-vivo hemoperfusion model of primate kidneys.},
journal = {Annals of transplantation},
volume = {8},
number = {3},
pages = {17-21},
pmid = {15114935},
issn = {1425-9524},
mesh = {Animals ; CDC2 Protein Kinase/*genetics ; Gene Expression Regulation ; Hemoperfusion ; Ischemia ; Kidney/*blood supply/cytology/*physiology ; Kidney Glomerulus/cytology ; Macaca fascicularis ; Models, Animal ; Organ Preservation ; Reperfusion ; Telomere/*ultrastructure ; },
abstract = {OBJECTIVES: The telomere (T) length, p21(WAF1/CIP1) and p27(Kip1) cyclin dependent kinase inhibitor (CDKI) genes are considered the markers of cell senescence and DNA damage. The aim of the study was to evaluate the influence of renal ischemia/reperfusion (I/R) on the value of above-mentioned markers.<br><br>METHODS: 13 Macaque cynomolgus monkey kidneys were harvested and placed in Eurocollins solution. 9 kidneys were ex-vivo perfused with human blood and 4 kidneys were not perfused at all (control group). Tissue expression of p21(WAF1/CIP1) and p27(Kip1) was evaluated immunohistochemically and the T lengths were measured by southern blotting technique.<br><br>RESULTS: Significantly higher levels of p21 and p27 were expressed by the glomeruli (p = 0.001 and 0.0001), tubules (p = 0.0065 and 0.0006) and interstitial cells (p = 0.0017 and 0.0022, respectively) of the xenoperfused kidneys. The mean T length was higher in the control group (5.56 +/- 0.60 kbp) than in the study group kidneys (5.46 +/- 0.36 kbp) (P = NS).<br><br>CONCLUSION: Renal I/R is associated with telomere shortening and an over-expression of p21 and p27 genes indicating substantial DNA damage and/or accelerated tissue senescence.},
}
@article {pmid15113592,
year = {2004},
author = {Miyata, Y and Okada, K and Fujimoto, A and Hata, K and Kagami, H and Tomita, Y and Ueda, M},
title = {The effect of the long-term cultivation on telomere length and morphology of cultured epidermis.},
journal = {Journal of dermatological science},
volume = {34},
number = {3},
pages = {221-230},
doi = {10.1016/j.jdermsci.2004.02.004},
pmid = {15113592},
issn = {0923-1811},
mesh = {Cells, Cultured ; *Cellular Senescence ; Culture Media, Serum-Free ; *Epidermal Cells ; Humans ; Keratinocytes/*cytology/metabolism ; Skin Transplantation ; Telomerase/metabolism ; Telomere/*physiology ; Tissue Culture Techniques ; },
abstract = {BACKGROUND: Cultured epidermis has been successfully used in clinical treatment such as burns and pigmentary disorders. Although the generation of wide cultured epidermis for clinical use may require repeated passages, especially for allografts, the effects of long-term cultivation on its quality and cell viability are not well known.<br><br>OBJECTIVES: To investigate the changes in morphology, telomere length, and telomerase activity during the passages of cultured epidermis and keratinocytes up to the passage limit, and to examine the usefulness of telomere length as a performance criterion for cultured epidermis.<br><br>METHODS: The keratinocytes obtained from five patients were used to generate cultured epidermis. At the early passage and after cultivation up to the passage limit, morphology, telomere length and telomerase activity were investigated by using microscopes, southern blot analysis and telomeric repeat amplification protocol assay, respectively.<br><br>RESULTS: The cultured cells started to show morphological changes when each passage was close to its limit and the cell sheets assumed an irregular stratification with various sizes of cytoplasm and nuclei. At the passage limit, the telomere length had decreased approximately 80-85%, and the average telomerase activity had declined under serum-free culture conditions.<br><br>CONCLUSION: The results of this study showed the morphological change and telomere length reduction by long-term cultivation on cultured epidermis. Although the reduction in telomere length and telomerase activity may not be the major cause of the senescence, they could provide a useful information for the quality of the cultured epidermis.},
}
@article {pmid15111298,
year = {2004},
author = {Montgomery, E and Argani, P and Hicks, JL and DeMarzo, AM and Meeker, AK},
title = {Telomere lengths of translocation-associated and nontranslocation-associated sarcomas differ dramatically.},
journal = {The American journal of pathology},
volume = {164},
number = {5},
pages = {1523-1529},
pmid = {15111298},
issn = {0002-9440},
support = {P50 CA088843/CA/NCI NIH HHS/United States ; P50 CA058236/CA/NCI NIH HHS/United States ; T32DK07552/DK/NIDDK NIH HHS/United States ; CA58236/CA/NCI NIH HHS/United States ; CA88843/CA/NCI NIH HHS/United States ; T32 DK007552/DK/NIDDK NIH HHS/United States ; },
mesh = {Cell Nucleus ; Chromosome Aberrations ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Leiomyosarcoma/pathology ; Microscopy, Fluorescence ; Sarcoma/diagnosis/*genetics/*pathology ; Sarcoma, Synovial/pathology ; Telomerase/metabolism ; Telomere/*ultrastructure ; Translocation, Genetic ; },
abstract = {Sarcomas can be divided into those with specific translocations displaying monotonous cytomorphology, and those with complex karyotypes and marked cellular pleomorphism. Telomeres contain terminal DNA sequence repeats that maintain chromosomal stability. Telomeres shorten with cell division and may become dysfunctional leading to chromosomal instability. Using a fluorescence in situ hybridization/immunofluorescence method to assess telomere lengths in archival tissues we analyzed these two types of sarcomas using paraffin-embedded primary tumor specimens. Tissues from nine sarcomas with characteristic translocations (two synovial sarcomas, two alveolar rhabdomyosarcomas, two desmoplastic round cell tumors, and one each of infantile fibrosarcoma, myxoid liposarcoma, cellular congenital mesoblastic nephroma) and nine without (four malignant fibrous histiocytomas, two leiomyosarcomas, one pleomorphic rhabdomyosarcoma, one dedifferentiated chondrosarcoma, and one malignant peripheral nerve sheath tumor) were analyzed. In all (nine of nine) cases with specific translocations, which generally have few karyotypic abnormalities, telomere lengths were similar to or reduced compared to surrounding nonneoplastic tissues. In contrast, telomeres in cases lacking specific translocations, which generally contain complex karyotypes, were often found to be dramatically lengthened and heterogeneous. In addition to markedly elongated telomeres, seven of nine (78%) complex cases exhibited large brightly stained regions corresponding to a specific type of promyelocytic leukemia nuclear body found in immortalized cells that maintain telomeres in a telomerase-independent manner [alternative lengthening of telomeres (ALT) pathway]. This phenotype is unlike that of epithelial neoplasms that typically display complex karyotypes with abnormally short telomeres maintained by the enzyme telomerase. The discovery of heterogeneous telomere lengths and evidence of the ALT pathway in the majority of sarcomas with complex karyotypes supports the existence of a telomere maintenance pathway incapable of full karyotypic stabilization in pleomorphic sarcomas. These findings provide additional molecular-genetic evidence supporting the dichotomous grouping of sarcomas into those with characteristic signature translocations without extensive additional karyotypic abnormalities, and those without such signature translocations that typically display very complex karyotypes, and point to telomere dysfunction as a plausible contributor to the chromosomal aberrations found in complex sarcomas.},
}
@article {pmid15109494,
year = {2004},
author = {Tarsounas, M and Muñoz, P and Claas, A and Smiraldo, PG and Pittman, DL and Blasco, MA and West, SC},
title = {Telomere maintenance requires the RAD51D recombination/repair protein.},
journal = {Cell},
volume = {117},
number = {3},
pages = {337-347},
doi = {10.1016/s0092-8674(04)00337-x},
pmid = {15109494},
issn = {0092-8674},
support = {2002:445/BCN_/Breast Cancer Now/United Kingdom ; },
mesh = {Animals ; Antibodies, Monoclonal/metabolism ; Blotting, Western ; Cell Line, Transformed ; Cell Transformation, Neoplastic ; Chromatin/metabolism ; Chromosome Aberrations ; DNA Damage ; *DNA Repair ; DNA, Cruciform/metabolism/ultrastructure ; DNA-Binding Proteins/*metabolism/ultrastructure ; Fibroblasts/metabolism ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Mice, Knockout ; Precipitin Tests ; RNA, Small Interfering/metabolism ; Recombination, Genetic ; Spermatocytes/metabolism/ultrastructure ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {The five RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) are required in mammalian cells for normal levels of genetic recombination and resistance to DNA-damaging agents. We report here that RAD51D is also involved in telomere maintenance. Using immunofluorescence labeling, electron microscopy, and chromatin immunoprecipitation assays, RAD51D was shown to localize to the telomeres of both meiotic and somatic cells. Telomerase-positive Rad51d(-/-) Trp53(-/-) primary mouse embryonic fibroblasts (MEFs) exhibited telomeric DNA repeat shortening compared to Trp53(-/-) or wild-type MEFs. Moreover, elevated levels of chromosomal aberrations were detected, including telomeric end-to-end fusions, a signature of telomere dysfunction. Inhibition of RAD51D synthesis in telomerase-negative immortalized human cells by siRNA also resulted in telomere erosion and chromosome fusion. We conclude that RAD51D plays a dual cellular role in both the repair of DNA double-strand breaks and telomere protection against attrition and fusion.},
}
@article {pmid15109493,
year = {2004},
author = {Teixeira, MT and Arneric, M and Sperisen, P and Lingner, J},
title = {Telomere length homeostasis is achieved via a switch between telomerase- extendible and -nonextendible states.},
journal = {Cell},
volume = {117},
number = {3},
pages = {323-335},
doi = {10.1016/s0092-8674(04)00334-4},
pmid = {15109493},
issn = {0092-8674},
mesh = {Base Sequence ; Cell Cycle ; Chromosomes, Fungal/metabolism ; Crosses, Genetic ; DNA/analysis ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Fungal ; Genetic Variation ; *Homeostasis ; Kinetics ; Models, Biological ; Polymerase Chain Reaction ; Recombination, Genetic ; Saccharomyces cerevisiae/*enzymology/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Telomerase/deficiency/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomerase counteracts telomere erosion that stems from incomplete chromosome end replication and nucleolytic processing. A precise understanding of telomere length homeostasis has been hampered by the lack of assays that delineate the nonuniform telomere extension events of single chromosome molecules. Here, we measure telomere elongation at nucleotide resolution in Saccharomyces cerevisiae. The number of nucleotides added to a telomere in a single cell cycle varies between a few to more than 100 nucleotides and is independent of telomere length. Telomerase does not act on every telomere in each cell cycle, however. Instead, it exhibits an increasing preference for telomeres as their lengths decline. Deletion of the telomeric proteins Rif1 or Rif2 gives rise to longer telomeres by increasing the frequency of elongation events. Thus, by taking a molecular snapshot of a single round of telomere replication, we demonstrate that telomere length homeostasis is achieved via a switch between telomerase-extendible and -nonextendible states.},
}
@article {pmid15109487,
year = {2004},
author = {Loayza, D and de Lange, T},
title = {Telomerase regulation at the telomere: a binary switch.},
journal = {Cell},
volume = {117},
number = {3},
pages = {279-280},
doi = {10.1016/s0092-8674(04)00409-x},
pmid = {15109487},
issn = {0092-8674},
mesh = {Crosses, Genetic ; *Gene Expression Regulation, Enzymologic ; *Gene Expression Regulation, Fungal ; Genes, Fungal ; Genetic Variation ; Recombination, Genetic ; Saccharomyces cerevisiae/*enzymology/genetics ; Telomerase/deficiency/genetics/*metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Telomerase is known to preferentially elongate the shortest telomeres in a cell. Using an elegant yeast assay, Texeira et al. (2004 [this issue of Cell]) address what aspect of telomerase action is regulated by telomere length: the frequency or the extent of telomere elongation. They show that short telomeres are elongated more frequently than long telomeres, arguing that telomeres switch between two states, one that allows telomere extension and one that does not.},
}
@article {pmid15108801,
year = {2004},
author = {Harrington, L},
title = {Those dam-aged telomeres!.},
journal = {Current opinion in genetics &amp; development},
volume = {14},
number = {1},
pages = {22-28},
doi = {10.1016/j.gde.2003.12.007},
pmid = {15108801},
issn = {0959-437X},
mesh = {Apoptosis/physiology ; DNA Damage/*genetics ; DNA Repair/genetics/*physiology ; DNA-Binding Proteins/genetics/physiology ; Models, Biological ; Telomerase/*physiology ; Telomere/*genetics/physiology ; },
abstract = {Telomere integrity plays a crucial role in the capacity for continuous cell proliferation. In some circumstances, shortened telomeres contribute to cell arrest or death, but in others, shortened telomeres may actually enhance the incidence and spectrum of tumors. Resolution of this apparent paradox requires a more detailed understanding of a non-functional telomere. Recent evidence reveals that critically shortened or uncapped telomeres share molecular hallmarks of damaged DNA. It is likely that the cellular response to this DNA damage, influenced by the nature of the damage itself, affects the outcome of loss of telomere function.},
}
@article {pmid15105825,
year = {2004},
author = {Espejel, S and Martín, M and Klatt, P and Martín-Caballero, J and Flores, JM and Blasco, MA},
title = {Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice.},
journal = {EMBO reports},
volume = {5},
number = {5},
pages = {503-509},
pmid = {15105825},
issn = {1469-221X},
mesh = {Aging/*genetics/physiology ; Animals ; Body Weight ; Cell Cycle ; Chromosomes/metabolism/ultrastructure ; DNA Damage ; DNA Repair ; DNA-Activated Protein Kinase ; DNA-Binding Proteins/genetics/*metabolism ; Female ; Life Expectancy ; Lymphoma/genetics/*metabolism ; Male ; Meiosis ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nuclear Proteins ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Spine/abnormalities ; Telomere/*metabolism ; Testis/cytology ; },
abstract = {Non-homologous end joining (NHEJ) is the principal repair mechanism used by mammalian cells to cope with double-strand breaks (DSBs) that continually occur in the genome. One of the key components of the mammalian NHEJ machinery is the DNA-PK complex, formed by the Ku86/70 heterodimer and the DNA-PK catalytic subunit (DNA-PKcs). Here, we report on the detailed life-long follow-up of DNA-PKcs-defective mice. Apart from defining a role of DNA-PKcs in telomere length maintenance in the context of the ageing organism, we observed that DNA-PKcs-defective mice had a shorter life span and showed an earlier onset of ageing-related pathologies than the corresponding wild-type littermates. In addition, DNA-PKcs ablation was associated with a markedly higher incidence of T lymphomas and infections. In conclusion, these data link the dual role of DNA-PKcs in DNA repair and telomere length maintenance to organismal ageing and cancer.},
}
@article {pmid15100233,
year = {2004},
author = {O'Connor, MS and Safari, A and Liu, D and Qin, J and Songyang, Z},
title = {The human Rap1 protein complex and modulation of telomere length.},
journal = {The Journal of biological chemistry},
volume = {279},
number = {27},
pages = {28585-28591},
doi = {10.1074/jbc.M312913200},
pmid = {15100233},
issn = {0021-9258},
support = {CA 84208/CA/NCI NIH HHS/United States ; },
mesh = {Antigens, Nuclear/metabolism ; Blotting, Western ; Cell Line ; Cell Nucleus/metabolism ; DNA Repair ; DNA-Binding Proteins/metabolism ; Endodeoxyribonucleases/metabolism ; Exodeoxyribonucleases/metabolism ; Gene Deletion ; Genes, Dominant ; Genetic Vectors ; HeLa Cells ; Humans ; Ku Autoantigen ; Mass Spectrometry ; Microscopy, Fluorescence ; Mutation ; Poly(ADP-ribose) Polymerases/metabolism ; Precipitin Tests ; Protein Binding ; Protein Structure, Tertiary ; RNA/metabolism ; RNA Interference ; Retroviridae/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Telomere/*ultrastructure ; Time Factors ; rap1 GTP-Binding Proteins/*chemistry/metabolism ; },
abstract = {Proper maintenance of telomere length and structure is necessary for normal proliferation of mammalian cells. Mammalian telomere length is regulated by a number of proteins including human repressor activator protein (hRap1), a known association factor of TRF2. To further delineate hRap1 function and its associated proteins, we affinity-purified and identified the hRap1 protein complex through mass spectrometry analysis. In addition to TRF2, we found DNA repair proteins Rad50, Mre11, PARP1 (poly(ADP-ribose) polymerase), and Ku86/Ku70 to be in this telomeric complex. We demonstrated by deletional analysis that Rad-50/Mre-11 and Ku86 were recruited to hRap1 independent of TRF2. PARP1, however, most likely interacted with hRap1 through TRF2. Interestingly, knockdown of endogenous hRap1 expression by small hairpin interference RNA resulted in longer telomeres. In addition, overexpression of full-length and mutant hRap1 that lacked the BRCA1 C-terminal domain functioned as dominant negatives and extended telomeres. Deletion of a novel linker domain of hRap1 (residues 199-223), however, abolished the dominant negative effect of hRap1 overexpression. These results indicate that hRap1 negatively regulates telomere length in vivo and suggest that the linker region of hRap1 may modulate the recruitment of negative regulators of telomere length.},
}
@article {pmid15098033,
year = {2004},
author = {Vulliamy, T and Marrone, A and Szydlo, R and Walne, A and Mason, PJ and Dokal, I},
title = {Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC.},
journal = {Nature genetics},
volume = {36},
number = {5},
pages = {447-449},
doi = {10.1038/ng1346},
pmid = {15098033},
issn = {1061-4036},
mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; Dyskeratosis Congenita/diagnosis/*genetics ; Family ; Female ; Genes, Dominant ; Humans ; Male ; Middle Aged ; Mutation/*genetics ; Pedigree ; RNA/*genetics ; Sequence Deletion ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {Telomerase is a ribonucleoprotein complex that is required to synthesize DNA repeats at the ends of each chromosome. The RNA component of this reverse transcriptase is mutated in the bone marrow failure syndrome autosomal dominant dyskeratosis congenita. Here we show that disease anticipation is observed in families with this disease and that this is associated with progressive telomere shortening.},
}
@article {pmid15095283,
year = {2004},
author = {Kang, MK and Kameta, A and Shin, KH and Baluda, MA and Park, NH},
title = {Senescence occurs with hTERT repression and limited telomere shortening in human oral keratinocytes cultured with feeder cells.},
journal = {Journal of cellular physiology},
volume = {199},
number = {3},
pages = {364-370},
doi = {10.1002/jcp.10410},
pmid = {15095283},
issn = {0021-9541},
support = {DE14147/DE/NIDCR NIH HHS/United States ; DE14635/DE/NIDCR NIH HHS/United States ; },
mesh = {Blotting, Southern ; Blotting, Western ; Cells, Cultured ; Cellular Senescence/*physiology ; Coculture Techniques ; Culture Media/chemistry ; Cyclin-Dependent Kinase Inhibitor p16/biosynthesis ; DNA-Binding Proteins ; Flavin-Adenine Dinucleotide ; Humans ; Keratinocytes/*physiology ; Mouth/cytology ; Phenotype ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*biosynthesis/metabolism ; Telomere/*physiology ; },
abstract = {We investigated the phenotypic and molecular alterations in normal human oral keratinocytes (NHOK) during in vitro replication in two different culture conditions. The cells were cultured either in chemically defined Keratinocyte Growth Medium (KGM) without feeder layers or in serum-containing flavin-adenine dinucleotide (FAD) medium with feeder layers. Primary NHOK underwent 22 +/- 3 population doublings (PDs) in KGM and 42 +/- 4 PDs in FAD medium, reflecting 52% increase in replication capacity with feeder layers. In both culture conditions, exponentially replicating NHOK demonstrated telomerase activity and expression of human telomerase reverse transcriptase (hTERT) gene. Telomerase activity and hTERT expression were rapidly diminished in senescing NHOK, which exhibited small decrease of telomere length for the remaining limited cellular replications until the complete arrest of cell division. However, telomere length in senescent NHOK was 6.7 +/- 0.5 kilobase pairs (kbps), significantly longer than that (5.12 kbps) of senescent human fibroblasts. The onset of senescence was accompanied with marked induction of p16(INK4A), and this occurred in both culture systems using either KGM or FAD medium. These results indicate that replicative senescence of NHOK is associated with loss of telomerase activity followed by limited telomere shortening.},
}
@article {pmid15084742,
year = {2004},
author = {Liu, L and Franco, S and Spyropoulos, B and Moens, PB and Blasco, MA and Keefe, DL},
title = {Irregular telomeres impair meiotic synapsis and recombination in mice.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {101},
number = {17},
pages = {6496-6501},
pmid = {15084742},
issn = {0027-8424},
mesh = {Animals ; Chromosome Pairing/*genetics ; Female ; In Situ Hybridization, Fluorescence ; In Situ Nick-End Labeling ; Mice ; Microscopy, Fluorescence/methods ; Recombination, Genetic/*genetics ; *Telomere ; },
abstract = {Telomere shortening can lead to chromosome instability, replicative senescence, and apoptosis in both somatic and male germ cells. To study roles for mammalian telomeres in homologous pairing and recombination, we characterized effects of telomere shortening on spermatogenesis and oogenesis in late-generation telomerase-deficient mice. We show that shortened telomeres of late-generation telomerase-deficient mice impair meiotic synapsis and decrease recombination, in particular, in females. In response to telomere shortening, male germ cells mostly undergo apoptosis, whereas female germ cells preferentially arrest in early meiosis, suggesting sexually dimorphic surveillance mechanisms for telomere dysfunction during meiosis in mice. Further, meiocytes of late-generation telomerase-deficient females with shortened telomeres, bred with early-generation males harboring relatively long telomeres, exhibit severely impaired chromosome pairing and synapsis and reduced meiotic recombination. These findings imply that functional telomeres are important in mammalian meiotic synapsis and recombination.},
}
@article {pmid15083607,
year = {2003},
author = {Dettlaff-Pokora, A and Schlichtholz, B},
title = {[Alternative lengthening of telomeres].},
journal = {Postepy biochemii},
volume = {49},
number = {3},
pages = {147-156},
pmid = {15083607},
issn = {0032-5422},
mesh = {Animals ; Humans ; RNA ; Telomerase ; Telomere/enzymology/genetics/*metabolism ; },
}
@article {pmid15082104,
year = {2004},
author = {Manestar-Blazić, T},
title = {Hypothesis on transmission of longevity based on telomere length and state of integrity.},
journal = {Medical hypotheses},
volume = {62},
number = {5},
pages = {770-772},
doi = {10.1016/j.mehy.2003.12.017},
pmid = {15082104},
issn = {0306-9877},
mesh = {Aging/genetics ; Humans ; Longevity/*genetics ; *Models, Genetic ; *Quantitative Trait, Heritable ; Telomere/*genetics/*ultrastructure ; },
abstract = {Different studies have demonstrated that offspring longevity depends on parental longevity and parental age at conception. The present paper suggests, based on the telomere theory of aging, that the longevity of the offspring is proportional to the telomere length and inversely proportional to the telomere state of integrity in the sperm cell and oocyte at conception. These two characteristics of telomeres depend on the age of parents. Telomeres become longer in gametes during the course of life, but at the same time they accumulate mutations (reduced state of integrity) that cause a faster loss of repetitive sequences. Because of these two mechanisms with opposing effects, there could exist an ideal age of the parents for the transmission of maximal longevity. The different longevity of men and women could partly be the result of different telomere dynamics of the sex chromosomes. The hypothesis also explains the risk of some birth defects associated with parental age at birth (telomeres are taken as a cause of birth defects).},
}
@article {pmid15079066,
year = {2004},
author = {Erdmann, N and Liu, Y and Harrington, L},
title = {Distinct dosage requirements for the maintenance of long and short telomeres in mTert heterozygous mice.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {101},
number = {16},
pages = {6080-6085},
pmid = {15079066},
issn = {0027-8424},
support = {AG16629-04/AG/NIA NIH HHS/United States ; },
mesh = {Alleles ; Animals ; DNA-Binding Proteins ; Fertility/genetics ; *Gene Dosage ; Mice ; Mice, Inbred C57BL ; Neoplasms/enzymology/genetics ; Telomerase/*genetics ; *Telomere ; },
abstract = {Telomerase is a ribonucleoprotein containing an essential telomerase RNA template and telomerase reverse transcriptase (TERT) that maintains telomeres. The dosage requirements for mammalian TERT in telomere length homeostasis are not known, but are of importance in cellular senescence, stem cell renewal, and cancer. Here, we characterize telomere maintenance and function upon successive breeding of mice deficient in mTert. These studies reveal a unique dosage requirement for telomere length maintenance by TERT; despite haploinsufficiency for the maintenance of long telomeres, mTert+/- mice retain minimal telomere DNA at all chromosome ends and do not exhibit the infertility typical of telomerase-deficient strains. Unlike the long (>50 kbp) average telomere lengths of wild-type laboratory mice, mTert+/- animals mice possess short telomere lengths similar to humans and wild-derived mice. Unexpectedly, mTert+/- mice are ersatz carriers for genetic instability, because their mating led to accelerated genetic instability and infertility in null progeny. Thus, limiting TERT levels play a key role in the maintenance of genome integrity, with important ramifications for the maintenance of short telomeres in human cancer and aging.},
}
@article {pmid15077181,
year = {2004},
author = {Plug-DeMaggio, AW and Sundsvold, T and Wurscher, MA and Koop, JI and Klingelhutz, AJ and McDougall, JK},
title = {Telomere erosion and chromosomal instability in cells expressing the HPV oncogene 16E6.},
journal = {Oncogene},
volume = {23},
number = {20},
pages = {3561-3571},
doi = {10.1038/sj.onc.1207388},
pmid = {15077181},
issn = {0950-9232},
mesh = {Anaphase ; Chromosomal Instability/*physiology ; Chromosome Aberrations ; Humans ; Keratinocytes/cytology ; Micronuclei, Chromosome-Defective/genetics ; Oncogene Proteins, Viral/genetics/*metabolism ; *Repressor Proteins ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {Progression to advanced-stage cervical carcinomas is characterized by a recurrent pattern of chromosomal rearrangements. Structural chromosome rearrangements are generated through the fusion of broken chromosome ends. These chromosome breaks may be induced by mutagenic agents such as ionizing radiation, or chromosome ends may be exposed through extensive telomere shortening. The human papilloma virus oncogene 16E6 induces telomerase activity in human keratinocytes, a model system for cervical tumor formation. The present study explores the relationship between 16E6 expression, telomerase activity, and chromosomal instability. We show that the frequency of anaphase bridges is dependent on the level of telomerase activity in 16E6/E7-expressing clones, and is the result of telomere shortening. High frequencies of anaphase bridges, associated with low telomerase activity, correlate with increased chromosome instability. Anaphase bridge formation is also associated with the presence of micronuclei, which are shown to contain unstable chromosomes frequently involved in rearrangements. As anaphase bridges are observed in both high and low telomerase 16E6/E7 clones, but not in hTERT-expressing control clones, expression of 16E6 in these immortalized clones is not sufficient to stabilize shortened telomeres completely. We suggest a model in which HPV-induced tumorigenesis may be dependent on persistent bridge-breakage-fusion cycles that allow for continued genomic rearrangements.},
}
@article {pmid15075340,
year = {2004},
author = {Nabetani, A and Yokoyama, O and Ishikawa, F},
title = {Localization of hRad9, hHus1, hRad1, and hRad17 and caffeine-sensitive DNA replication at the alternative lengthening of telomeres-associated promyelocytic leukemia body.},
journal = {The Journal of biological chemistry},
volume = {279},
number = {24},
pages = {25849-25857},
doi = {10.1074/jbc.M312652200},
pmid = {15075340},
issn = {0021-9258},
mesh = {Bromodeoxyuridine/metabolism ; Caffeine/*pharmacology ; Cell Cycle Proteins/*analysis/physiology ; Cell Line ; DNA Replication/*drug effects ; DNA-Binding Proteins ; Exonucleases/*analysis ; Neoplasm Proteins/*analysis ; Nuclear Proteins/*analysis ; Protein Serine-Threonine Kinases/physiology ; *Telomere ; Transcription Factors/*analysis ; Tumor Suppressor Proteins ; },
abstract = {Telomere maintenance is essential for continued cell proliferation. Although most cells accomplish this by activating telomerase, a subset of immortalized tumors and cell lines do so in a telomerase-independent manner, a process called alternative lengthening of telomeres (ALT). DNA recombination has been shown to be involved in ALT, but the precise mechanisms remain unknown. A fraction of cells in a given ALT population contain a unique nuclear structure called APB (ALT-associated promyelocytic leukemia (PML) body), which is characterized by the presence of telomeric DNA in the PML body. Here we describe that hRad9, hHus1, and hRad1, which form a DNA clamp complex that is associated with DNA damage, as well as its clamp loader, hRad17, are constitutive components of APB. Phosphorylated histone H2AX (gamma-H2AX), a molecular marker of double-strand breaks (DSBs), also colocalizes with some APBs. The results suggest that telomeric DNAs at APBs are recognized as DSBs. PML staining and fluorescence in situ hybridization analyses of mitotic ALT cells revealed that telomeric DNAs present at APBs are of both extrachromosomal and native telomere origins. Furthermore, we demonstrated that DNA synthesis occurs at APBs and is significantly inhibited by caffeine, an inhibitor of phosphatidylinositol 3-kinase-related kinases. Taken together, we suggest that telomeric DNAs at APBs are recognized and processed as DSBs, leading to telomeric DNA synthesis and thereby contributing to telomere maintenance in ALT cells.},
}
@article {pmid15075267,
year = {2004},
author = {Underwood, DH and Carroll, C and McEachern, MJ},
title = {Genetic dissection of the Kluyveromyces lactis telomere and evidence for telomere capping defects in TER1 mutants with long telomeres.},
journal = {Eukaryotic cell},
volume = {3},
number = {2},
pages = {369-384},
pmid = {15075267},
issn = {1535-9778},
support = {R01 GM061645/GM/NIGMS NIH HHS/United States ; GM61645-01/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites ; DNA Mutational Analysis ; DNA Probes/genetics ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/physiology ; Fungal Proteins/metabolism ; Kluyveromyces/*genetics/physiology ; Point Mutation ; RNA/*genetics/metabolism ; Rad52 DNA Repair and Recombination Protein ; Recombination, Genetic ; Tandem Repeat Sequences/genetics ; Telomerase/*genetics/metabolism ; Telomere/chemistry/*genetics/*metabolism ; Telomere-Binding Proteins/metabolism ; Templates, Genetic ; Terminal Repeat Sequences ; },
abstract = {In the yeast Kluyveromyces lactis, the telomeres are composed of perfect 25-bp repeats copied from a 30-nucleotide RNA template defined by 5-nucleotide terminal repeats. A genetic dissection of the K. lactis telomere was performed by using mutant telomerase RNA (TER1) alleles to incorporate mutated telomeric repeats. This analysis has shown that each telomeric repeat contains several functional regions, some of which may physically overlap. Mutations in the terminal repeats of the template RNA typically lead to telomere shortening, as do mutations in the right side of the Rap1p binding site. Mutations in the left half of the Rap1p binding site, however, lead to the immediate formation of long telomeres. When mutated, the region immediately 3' of the Rap1p binding site on the TG-rich strand of the telomere leads to telomeres that are initially short but eventually undergo extreme telomere elongation. Mutations between this region and the 3' terminal repeat cause elevated recombination despite the presence of telomeres of nearly wild-type length. Mutants with highly elongated telomeres were further characterized and exhibit signs of telomere capping defects, including elevated levels of subtelomeric recombination and the formation of extrachromosomal and single-stranded telomeric DNA. Lengthening caused by some Rap1 binding site mutations can be suppressed by high-copy-number RAP1. Mutated telomeric repeats from a delayed elongation mutant are shown to be defective at regulating telomere length in cells with wild-type telomerase, indicating that the telomeric repeats are defective at telomere length regulation.},
}
@article {pmid15071557,
year = {2004},
author = {de Lange, T},
title = {T-loops and the origin of telomeres.},
journal = {Nature reviews. Molecular cell biology},
volume = {5},
number = {4},
pages = {323-329},
doi = {10.1038/nrm1359},
pmid = {15071557},
issn = {1471-0072},
mesh = {Animals ; DNA Replication ; Evolution, Molecular ; Humans ; Macromolecular Substances ; *Nucleic Acid Conformation ; Telomerase/metabolism ; Telomere/*metabolism ; },
}
@article {pmid15065663,
year = {2004},
author = {Chan, SR and Blackburn, EH},
title = {Telomeres and telomerase.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {359},
number = {1441},
pages = {109-121},
pmid = {15065663},
issn = {0962-8436},
support = {GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Damage/genetics ; *DNA Replication ; DNA-Binding Proteins/*metabolism ; Evolution, Molecular ; Gene Library ; *Models, Genetic ; Mutation/genetics ; RNA/metabolism ; Telomerase/*metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres are the protective DNA-protein complexes found at the ends of eukaryotic chromosomes. Telomeric DNA consists of tandem repeats of a simple, often G-rich, sequence specified by the action of telomerase, and complete replication of telomeric DNA requires telomerase. Telomerase is a specialized cellular ribonucleoprotein reverse transcriptase. By copying a short template sequence within its intrinsic RNA moiety, telomerase synthesizes the telomeric DNA strand running 5' to 3' towards the distal end of the chromosome, thus extending it. Fusion of a telomere, either with another telomere or with a broken DNA end, generally constitutes a catastrophic event for genomic stability. Telomerase acts to prevent such fusions. The molecular consequences of telomere failure, and the molecular contributors to telomere function, with an emphasis on telomerase, are discussed here.},
}
@article {pmid15064743,
year = {2004},
author = {Preto, A and Singhrao, SK and Haughton, MF and Kipling, D and Wynford-Thomas, D and Jones, CJ},
title = {Telomere erosion triggers growth arrest but not cell death in human cancer cells retaining wild-type p53: implications for antitelomerase therapy.},
journal = {Oncogene},
volume = {23},
number = {23},
pages = {4136-4145},
doi = {10.1038/sj.onc.1207564},
pmid = {15064743},
issn = {0950-9232},
mesh = {Apoptosis/physiology ; DNA-Binding Proteins ; Humans ; Telomerase/*metabolism ; Telomere/*metabolism ; Thyroid Neoplasms/genetics/*metabolism/therapy ; Tumor Suppressor Protein p53/*metabolism ; },
abstract = {Telomerase activity in tumours is often associated with p53 mutation. Many antitelomerase therapies take advantage of the inability of cells expressing mutant p53 to undergo replicative senescence, since this allows telomere erosion to continue until 'crisis', hence providing the desired cytotoxic effect. However, some tumour types, including breast, melanomas and thyroid, retain wild-type p53 function and the effectiveness of antitelomerase therapies in such tumour cells have not been adequately addressed. To explore this, we made use of two thyroid cancer cell lines K1 and K2, which retain wt p53. Telomere erosion induced by the expression of a dominant-negative (DN) hTERT resulted in delayed onset of growth arrest in K1 and K2 cells, reminiscent of replicative senescence, with low levels of BrdU labelling and apoptosis, associated with high p21(WAF1) and senescence-associated beta galactosidase expression. In contrast, abrogation of p53 function by the expression of HPV16 E6 in K1 and K2 cells either at the same time as DNhTERT or just prior to the onset of senescence allowed cells to continue growing until 'crisis'. Likewise, microinjection of a p53 neutralizing antibody into 'senescent' K1 DNhTERT cells permitted re-entry into the cell cycle. We conclude that thyroid tumour cells with wild-type p53 retain an intact p53-mediated growth arrest response to telomere erosion. This raises the intriguing question of why, therefore, p53 mutation is not selected for in such cancers, and also calls into question the therapeutic value of telomerase inhibitors in such cases.},
}
@article {pmid15064417,
year = {2004},
author = {Dynek, JN and Smith, S},
title = {Resolution of sister telomere association is required for progression through mitosis.},
journal = {Science (New York, N.Y.)},
volume = {304},
number = {5667},
pages = {97-100},
doi = {10.1126/science.1094754},
pmid = {15064417},
issn = {1095-9203},
support = {R01 CA095099/CA/NCI NIH HHS/United States ; GM07238-28/GM/NIGMS NIH HHS/United States ; R01 CA95099-01/CA/NCI NIH HHS/United States ; },
mesh = {*Anaphase ; Anaphase-Promoting Complex-Cyclosome ; Chromatids/*physiology ; Chromosome Segregation ; DNA Replication ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Metaphase ; *Mitosis ; Phenotype ; RNA, Small Interfering/metabolism ; Tankyrases/genetics/*metabolism ; Telomere/*physiology ; Transfection ; Ubiquitin-Protein Ligase Complexes/metabolism ; },
abstract = {Cohesins keep sister chromatids associated from the time of their replication in S phase until the onset of anaphase. In vertebrate cells, two distinct pathways dissociate cohesins, one acts on chromosome arms and the other on centromeres. Here, we describe a third pathway that acts on telomeres. Knockdown of tankyrase 1, a telomeric poly(ADP-ribose) polymerase caused mitotic arrest. Chromosomes aligned normally on the metaphase plate but were unable to segregate. Sister chromatids separated at centromeres and arms but remained associated at telomeres, apparently through proteinaceous bridges. Thus, telomeres may require a unique tankyrase 1-dependent mechanism for sister chromatid resolution before anaphase.},
}
@article {pmid15064409,
year = {2004},
author = {Azzalin, CM and Lingner, J},
title = {Cell biology. Telomere wedding ends in divorce.},
journal = {Science (New York, N.Y.)},
volume = {304},
number = {5667},
pages = {60-62},
doi = {10.1126/science.1096809},
pmid = {15064409},
issn = {1095-9203},
mesh = {*Anaphase ; Cell Cycle ; Chromatids/*physiology ; DNA Repair ; DNA Replication ; *Mitosis ; RNA, Small Interfering/metabolism ; Recombination, Genetic ; Tankyrases/genetics/*metabolism ; Telomere/*physiology ; Telomeric Repeat Binding Protein 1/metabolism ; },
}
@article {pmid15064365,
year = {2004},
author = {McKnight, TD and Shippen, DE},
title = {Plant telomere biology.},
journal = {The Plant cell},
volume = {16},
number = {4},
pages = {794-803},
pmid = {15064365},
issn = {1040-4651},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; GM65383/GM/NIGMS NIH HHS/United States ; },
mesh = {Apoptosis ; Botany/history ; DNA-Binding Proteins/history ; Genetics/history ; History, 20th Century ; Models, Biological ; Plant Proteins/history ; Plants/*genetics/metabolism ; Telomerase/history ; Telomere/*genetics/metabolism ; },
}
@article {pmid15061078,
year = {2004},
author = {Hirata, Y and Suzuki, C and Sakai, S},
title = {Characterization and gene cloning of telomere-binding protein from tobacco BY-2 cells.},
journal = {Plant physiology and biochemistry : PPB},
volume = {42},
number = {1},
pages = {7-14},
doi = {10.1016/j.plaphy.2003.10.002},
pmid = {15061078},
issn = {0981-9428},
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Cloning, Molecular ; Consensus Sequence ; DNA, Complementary/genetics ; Electrophoretic Mobility Shift Assay ; Molecular Sequence Data ; Nuclear Proteins/genetics/metabolism ; Oligonucleotide Probes/genetics/metabolism ; Plant Proteins/genetics/metabolism ; Protein Binding ; Recombinant Proteins/genetics/metabolism ; Repetitive Sequences, Nucleic Acid ; Salmon ; Sequence Alignment ; Telomere/chemistry/genetics/metabolism ; Telomere-Binding Proteins/*genetics/*metabolism ; Nicotiana/cytology/genetics/*metabolism ; },
abstract = {In this study, we performed gel mobility shift assays using tobacco BY-2 nuclei extracts to identify the plant telomere-binding proteins (TBP). Although no complexes were detected using C-strand as a probe, a single DNA-protein complex was detected using single-stranded 32P-(TTTAGGG)4 as a probe. In competition experiments, formation of the complex was inhibited only when an ssG-strand telomere repeat was used as a competitor. These results indicate that the observed band reflects a G-strand specific single-stranded telomere-binding protein (NtGTBP1). We purified the binding protein and subsequently used RT-PCR to isolate a gene encoding the protein. The sequence reveals that the protein (NtGTBP1) is a novel TBP from a higher plant, and a search for conserved domains showed that NtGTBP1 contains two RNA recognition motifs (RRMs).},
}
@article {pmid15060173,
year = {2004},
author = {Armbruster, BN and Linardic, CM and Veldman, T and Bansal, NP and Downie, DL and Counter, CM},
title = {Rescue of an hTERT mutant defective in telomere elongation by fusion with hPot1.},
journal = {Molecular and cellular biology},
volume = {24},
number = {8},
pages = {3552-3561},
pmid = {15060173},
issn = {0270-7306},
support = {K12 HD043494/HD/NICHD NIH HHS/United States ; R01 CA082481/CA/NCI NIH HHS/United States ; CA82481/CA/NCI NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Cell Line ; DNA/metabolism ; DNA-Binding Proteins ; Humans ; Molecular Sequence Data ; *Mutation ; Recombinant Fusion Proteins/genetics/metabolism ; Sequence Alignment ; Shelterin Complex ; Telomerase/*genetics/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {The protein hPot1 shares homology with telomere-binding proteins in lower eukaryotes and associates with single-stranded telomeric DNA in vitro as well as colocalizing with telomere-binding proteins in vivo. We now show that hPot1 is coimmunoprecipitated with telomeric DNA and that stable expression of this protein in telomerase-positive cells results in telomere elongation, supporting the idea that hPot1 is a bona fide mammalian telomere-binding protein. We previously found that mutations in the N-terminal DAT domain of the hTERT catalytic subunit of telomerase rendered the enzyme catalytically active but unable to elongate telomeres in vivo. This phenotype could be partially rescued by fusion with the double-stranded telomeric protein hTRF2. Given that hPot1 binds to single-stranded DNA in vitro (at the same site that hTERT binds to in vivo), we addressed whether fusion of hPot1 can rescue the DAT mutations more efficiently than that of hTRF2. We now report that a DAT mutant of hTERT is indeed efficiently rescued upon fusion to hPot1. However, this rescue depended on the ability of hPot1 to localize to telomeres rather than binding to DNA per se. These data support a model whereby the DAT domain of hTERT is implicated in telomere-telomerase associations.},
}
@article {pmid15059879,
year = {2004},
author = {Londoño-Vallejo, JA and Der-Sarkissian, H and Cazes, L and Bacchetti, S and Reddel, RR},
title = {Alternative lengthening of telomeres is characterized by high rates of telomeric exchange.},
journal = {Cancer research},
volume = {64},
number = {7},
pages = {2324-2327},
doi = {10.1158/0008-5472.can-03-4035},
pmid = {15059879},
issn = {0008-5472},
mesh = {Animals ; Cell Line, Tumor ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; NIH 3T3 Cells ; Neoplasms/*genetics ; Sister Chromatid Exchange ; Telomere/*genetics ; },
abstract = {Telomere maintenance activity is a hallmark of cancer. In some telomerase-negative tumors, telomeres become lengthened by alternative lengthening of telomeres (ALT), a recombination-mediated DNA replication process in which telomeres use other telomeric DNA as a copy template. Using chromosome orientation fluorescence in situ hybridization, we found that postreplicative exchange events involving a telomere and another TTAGGG-repeat tract occur at remarkably high frequencies in ALT cells (range 28-280/100 metaphases) and rarely or never in non-ALT cells, including cell lines with very long telomeres. Like the ALT phenotype itself, the telomeric exchanges were not suppressed when telomerase was activated in ALT cells. These exchanges are telomere specific because there was no correlation with sister chromatid exchange rates at interstitial locations, and they were not observed in non-ALT Bloom syndrome cells with very high sister chromatid exchange rates.},
}
@article {pmid15157529,
year = {1996},
author = {Zakian, VA},
title = {Telomere functions: lessons from yeast.},
journal = {Trends in cell biology},
volume = {6},
number = {1},
pages = {29-33},
doi = {10.1016/0962-8924(96)81035-x},
pmid = {15157529},
issn = {0962-8924},
abstract = {Telomeres are specialized DNA protein structures that form the ends of eukaryotic chromosomes. In yeast, loss of even a single telomere causes a prolonged, but transitory, cell-cycle arrest. During this arrest, many broken chromosomes acquire a new telomere by one of three pathways, although at the cost of a partial loss of heterozygosity. In addition, a substantial fraction of the chromosomes lacking a telomere is lost, which generates an aneuploid cell. In these cases, the broken chromosome is usually replicated and segregated for ten or more cell divisions in unstable form. Extrapolation from yeast suggests that the gradual loss of telomeric DNA that accompanies ageing in humans may initiate the kinds of chromosomal rearrangements and genetic changes that are associated with tumorigenesis.},
}
@article {pmid15335998,
year = {1992},
author = {Greider, CW},
title = {Telomere chromatin and gene expression.},
journal = {Current biology : CB},
volume = {2},
number = {2},
pages = {62-64},
doi = {10.1016/0960-9822(92)90190-l},
pmid = {15335998},
issn = {0960-9822},
}
@article {pmid17248303,
year = {1966},
author = {Sved, JA},
title = {Telomere attachment of chromosomes. Some genetical and cytological consequences.},
journal = {Genetics},
volume = {53},
number = {4},
pages = {747-756},
pmid = {17248303},
issn = {0016-6731},
}
@article {pmid15057965,
year = {2004},
author = {O'Sullivan, JN and Finley, JC and Risques, RA and Shen, WT and Gollahon, KA and Moskovitz, AH and Gryaznov, S and Harley, CB and Rabinovitch, PS},
title = {Telomere length assessment in tissue sections by quantitative FISH: image analysis algorithms.},
journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology},
volume = {58},
number = {2},
pages = {120-131},
doi = {10.1002/cyto.a.20006},
pmid = {15057965},
issn = {1552-4922},
mesh = {*Algorithms ; Barrett Esophagus/pathology ; Biopsy ; Cell Line ; Cellular Senescence ; Centromere/genetics/metabolism ; Colitis, Ulcerative/pathology ; Colon/pathology ; Fibroblasts ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Microscopy, Confocal ; Oligonucleotide Probes/analysis/genetics ; Peptide Nucleic Acids/analysis/genetics ; Telomere/genetics/*metabolism ; },
abstract = {BACKGROUND: Telomeres are tandem repeated DNA sequences at the ends of every chromosome, which cap, stabilize, and prevent chromosome fusions and instability. Telomere regulation is an important mechanism in cellular proliferation and senescence in normal diploid and neoplastic cells. Quantitative methods to assess telomere lengths are essential to understanding how telomere dynamics play a role in these processes.<br><br>METHODS: Telomere lengths have been conventionally measured using terminal restriction fragment (TRF), quantitative fluorescence in situ hybridization (QFISH), and flow FISH. In this study, we have applied QFISH to measure average telomere lengths in cultured cells and human tissues of the GI tract. Importantly, this method can be used to analyze telomere lengths in sections using confocal microscopy. We describe and compare three image analysis algorithms: a simple pixel histogram calculation of background corrected fluorescence, a telomere spot-finding method, and a background curve subtraction algorithm.<br><br>RESULTS: Using normal human diploid fibroblasts (NHDF) either dropped on slides or sectioned after agar embedding, similar telomere length shortening is evident with increasing population doubling levels (PDLs), using peptide nucleic acid (PNA) and an N3'-P5'-phosphoamidate (PA) oligonucleotide probe for all three methods. Validation of these in situ telomere quantification methods showed excellent agreement with the commonly used telomere repeat fragment-Southern blot method. Telomere length reductions can also be demonstrated in tissue sections from histologically normal mucosa from patients with chronic ulcerative colitis (with dysplasia or cancer elsewhere in the colon), in colon adenomas, and in mucosal biopsies from patients with Barrett's esophagus. Both on slides and in tissue sections, the telomere spot-finding method has the greatest variability, while intra- and inter-biopsy variability in telomere length assessment using the other methods is relatively low.<br><br>CONCLUSIONS: Accurate and reproducible telomere length measurements can be made in tissue sections using QFISH and confocal microscopy. The simplest methods proved the most reliable and make these methods readily accessible to many laboratories. The use of these methods will enhance the ability to measure telomere lengths in tissue samples and aid in the understanding of the role of telomere length in aging and disease.},
}
@article {pmid15054855,
year = {2004},
author = {Stindl, R},
title = {Is telomere erosion a mechanism of species extinction?.},
journal = {Journal of experimental zoology. Part B, Molecular and developmental evolution},
volume = {302},
number = {2},
pages = {111-120},
doi = {10.1002/jez.b.20006},
pmid = {15054855},
issn = {1552-5007},
mesh = {*Biodiversity ; *Biological Evolution ; Chromosomal Instability/*genetics ; Mitosis/*physiology ; *Models, Genetic ; Telomerase/physiology ; Telomere/genetics/*physiology ; },
abstract = {According to the fossil record, 99.9% of all species that have ever lived on Earth have disappeared. However, only about 4% died out during the five mass extinction events, whereas it seems that the majority of species vanished without any signs of significant earthbound or extraterrestrial physical threats. Clearly, biological extinction mechanisms are by far the most important, but they are subject to serious limitations concerning the worldwide disappearance of species. In view of that, species-inherent mechanisms, which could lead to the worldwide destabilization of a population, might be worth reconsideration. Telomeres, the protective caps of chromosome ends, and the enzyme telomerase have been well preserved in plants and animals during evolution. In the absence of telomerase activity, telomeric DNA has been shown to shorten every time a cell divides. The concept of a mitotic clock based on the gradual erosion of telomeres is now generally accepted and has been confirmed in numerous plants and animals. Chromosomal rearrangements are the hallmarks of two completely different biological phenomena, cancer and speciation. In premalignant cells, gradual telomere erosion beyond a critical threshold is a well-known inducer of chromosomal instability. The species clock hypothesis, as presented here, is based on the idea of a tiny loss of mean telomere length per generation. This mechanism would not rapidly endanger the survival of a particular species. Yet, after many thousands of generations, critically short telomeres could lead to the weakening and even the extinction of old species and would simultaneously create the unstable chromosomal environment that might result in the origination of new species.},
}
@article {pmid15052408,
year = {2004},
author = {Mathieu, N and Pirzio, L and Freulet-Marrière, MA and Desmaze, C and Sabatier, L},
title = {Telomeres and chromosomal instability.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {61},
number = {6},
pages = {641-656},
doi = {10.1007/s00018-003-3296-0},
pmid = {15052408},
issn = {1420-682X},
mesh = {Animals ; *Cellular Senescence ; *Chromosomal Instability ; Humans ; Neoplasms/enzymology/*genetics ; Repetitive Sequences, Nucleic Acid ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {Telomeres are distinctive structures, composed of a repetitive DNA sequence and associated proteins, which enable cells to distinguish chromosome ends from DNA double-strand breaks. Telomere alterations, caused by replication-mediated shortening, direct damage or defective telomere-associated proteins, usually generate chromosomal instability, which is observed in senescence and during the immortalization process. In cancer cells, this chromosome instability could be extended by their ability to 'repair' chromosomes and terminate in break-fusion-bridge cycles. Dysfunctional telomeres can be healed by activation of telomerase or by the 'alternative mechanism' of telomere lengthening. Activation of such telomere maintenance mechanisms may help to preserve the integrity of chromosomes even if they play a role in chromosomal instability. This review focuses on molecular processes involved in telomere maintenance and chromosomal instability associated with dysfunctional telomeres in mammalian cells.},
}
@article {pmid15051944,
year = {2003},
author = {Scherthan, H},
title = {Knockout mice provide novel insights into meiotic chromosome and telomere dynamics.},
journal = {Cytogenetic and genome research},
volume = {103},
number = {3-4},
pages = {235-244},
doi = {10.1159/000076809},
pmid = {15051944},
issn = {1424-859X},
mesh = {Animals ; Cell Cycle Proteins ; Chromatin/ultrastructure ; Chromosome Pairing ; Chromosomes, Mammalian/*ultrastructure ; DNA Repair ; DNA-Binding Proteins ; Histones/genetics/physiology ; Male ; Meiosis ; Mice ; Mice, Knockout ; Nuclear Envelope/ultrastructure ; Nuclear Proteins/genetics/physiology ; Repetitive Sequences, Nucleic Acid ; Spermatogenesis ; Spermatozoa/metabolism/*ultrastructure ; Telomere/chemistry/*ultrastructure ; },
abstract = {Meiosis is a succession of two specialized cell divisions that leads to the formation of gametes and thereby compensates for genome doubling at fertilization. During the extended prophase of the first meiotic division chromosomes assemble protein cores (axial elements) that attach their ends to the nuclear envelope. These ends transiently gather at a limited sector of the nuclear periphery (bouquet stage) at a time when meiotic recombination is initiated and when chromosomes initiate stable pairing (synapsis). This review discusses novel insights into the relation between recombinational DNA repair and meiotic telomere dynamics that have arrived from recent studies of transchromosomal mice and knockout mice. Analysis of mice deficient for A-type lamins, histone H2AX, Suv39h HMTases, and the AE protein SYCP3 suggests that entry into prophase I requires heterochromatin integrity and lamin A expression. Initiation of meiotic telomere clustering represents an early recombination-independent event in first meiotic prophase, while exit from the bouquet stage depends on signals that emanate from the progress of recombinational DNA repair as sensed by ATM kinase and relayed through histone H2AX.},
}
@article {pmid15051503,
year = {2004},
author = {Shammas, MA and Liu, X and Gavory, G and Raney, KD and Balasubramanian, S and Shmookler Reis, RJ},
title = {Targeting the single-strand G-rich overhang of telomeres with PNA inhibits cell growth and induces apoptosis of human immortal cells.},
journal = {Experimental cell research},
volume = {295},
number = {1},
pages = {204-214},
doi = {10.1016/j.yexcr.2004.01.003},
pmid = {15051503},
issn = {0014-4827},
support = {G09923/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Adenocarcinoma ; Apoptosis/*drug effects ; Cell Division/*drug effects ; Cell Line ; Cell Line, Transformed ; Cell Line, Tumor ; Electroporation ; Esophageal Neoplasms ; Humans ; Peptide Nucleic Acids/chemical synthesis/pharmacokinetics/*pharmacology ; Telomere/drug effects/*physiology/ultrastructure ; },
abstract = {Telomeres are believed to stabilize chromosomes through several mechanisms that are dependent upon specific DNA-DNA and protein-DNA interactions. Telomeres are maintained by the enzyme telomerase. Telomerase activity, which is below detectable level in almost all types of diploid cells, is re-activated in most immortal and cancer cells. For this study, we designed peptide nucleic acid (PNA) oligonucleotides targeted to the telomeric G-rich strand, and tested their efficacy to reverse the immortality of transformed human fibroblasts. Anti-telomere PNAs, transfected into human fibroblasts along with a selectable marker, resulted in a significant reduction in colony size and elicited cell death by apoptosis. This PNA inhibitor does not inhibit telomerase activity in vitro, suggesting a distinct cellular mechanism from known PNA inhibitors. A combination of this class of PNA inhibitor with a PNA that does block telomerase activity resulted in nearly complete inhibition of colony growth, induction of apoptosis, and an apparent reduction in telomere length. Each effect was greater than that evoked by either agent alone, indicating enhanced efficacy for therapeutic approaches that target multiple, distinct mechanism of telomere maintenance.},
}
@article {pmid15048084,
year = {2004},
author = {Pickett, HA and Baird, DM and Hoff-Olsen, P and Meling, GI and Rognum, TO and Shaw, J and West, KP and Royle, NJ},
title = {Telomere instability detected in sporadic colon cancers, some showing mutations in a mismatch repair gene.},
journal = {Oncogene},
volume = {23},
number = {19},
pages = {3434-3443},
doi = {10.1038/sj.onc.1207477},
pmid = {15048084},
issn = {0950-9232},
mesh = {*Base Pair Mismatch ; Colonic Neoplasms/*genetics ; DNA Repair/*genetics ; *Genomic Instability ; Genotype ; Humans ; *Microsatellite Repeats ; *Mutation ; Polymorphism, Single Nucleotide ; Receptors, Transforming Growth Factor beta/genetics ; *Telomere ; },
abstract = {Human telomeres are essential for genome stability and are composed of long simple tandem repeat arrays (STRs), comprising the consensus TTAGGG repeat interspersed, at the proximal end, with sequence-variant repeats. While the dynamics of telomere attrition through incomplete replication has been studied extensively, the effects on telomeres of error-prone DNA repair processes, known to affect other STRs, are poorly understood. We have compared the TTAGGG and sequence-variant interspersion patterns in the proximal 720 bp of telomeres in colon cancer and normal DNA samples. The frequency of telomere mutations was 5.8% per allele in a randomly collected panel of sporadic colon cancers, showing that telomere mutations occur in vivo. The mutation frequency rose to 18.6% per allele in sporadic tumours that exhibit instability at the polyA tract in the TGFbetaRII gene and to 35% per allele in tumours with somatic mutations in the hMSH2 gene. The majority of the characterized mutations resulted in the loss of one or a few repeats. If the mutation spectrum and frequency described here is reiterated in the rest of the array, there is the potential for extensive telomere destabilization especially in mismatch repair-defective cells. This may in turn lead to a greater requirement for telomere length maintenance earlier in tumourigenesis.},
}
@article {pmid15047858,
year = {2004},
author = {Bah, A and Bachand, F and Clair, E and Autexier, C and Wellinger, RJ},
title = {Humanized telomeres and an attempt to express a functional human telomerase in yeast.},
journal = {Nucleic acids research},
volume = {32},
number = {6},
pages = {1917-1927},
pmid = {15047858},
issn = {1362-4962},
mesh = {Cell Nucleus/enzymology ; Genetic Complementation Test ; Humans ; Saccharomyces cerevisiae/enzymology/*genetics ; Telomerase/analysis/genetics/*metabolism ; Telomere/chemistry/metabolism ; },
abstract = {The maintenance of telomeric repeat DNA depends on an evolutionarily conserved reverse trans criptase called telomerase. In vitro, only the catalytic subunit and a telomerase-associated RNA are required for the synthesis of species-specific repeat DNA. In an attempt to establish a heterologous system for the study of the human telomerase enzyme, we expressed the two core components and predicted regulatory subunits in the yeast Saccharomyces cerevisiae. We show that adequate substrates for human telomerase can be generated; the expressed enzyme was localized in the nucleus and it had the capacity to synthesize human-specific repeats in vitro. However, there was no evidence for human telomerase activity at yeast telomeres in vivo. Therefore functional replacement of the yeast telomerase by the human enzyme may require additional human-specific components. We also replaced the template region of the yeast telomerase RNA with one that dictates the synthesis of vertebrate repeats and performed a detailed molecular analysis of the composition of the telomeres upon outgrowth of such strains. The results suggest that vertebrate repeats on yeast telomeres are subject to a very high degree of repeat turnover and show that an innermost tract of 50 bp of yeast repeats are resistant to replacement.},
}
@article {pmid15044100,
year = {2004},
author = {Song, H and Li, Y and Chen, G and Xing, Z and Zhao, J and Yokoyama, KK and Li, T and Zhao, M},
title = {Human MCRS2, a cell-cycle-dependent protein, associates with LPTS/PinX1 and reduces the telomere length.},
journal = {Biochemical and biophysical research communications},
volume = {316},
number = {4},
pages = {1116-1123},
doi = {10.1016/j.bbrc.2004.02.166},
pmid = {15044100},
issn = {0006-291X},
mesh = {Base Sequence ; Brain/metabolism ; Carcinoma, Hepatocellular/genetics/metabolism ; Cell Cycle ; Cell Cycle Proteins/*genetics/*metabolism ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic/genetics ; Humans ; Liver/metabolism ; Molecular Sequence Data ; Nuclear Proteins ; Proteins/*genetics/*metabolism ; RNA-Binding Proteins ; Telomere/*genetics/*metabolism ; Tumor Suppressor Proteins/*genetics/*metabolism ; },
abstract = {Human LPTS/PinX1 is a telomerase-inhibitory protein, which binds to the telomere protein Pin2/TRF1 and the catalytic subunit hTERT of telomerase. To explore the proteins that might be involved in the telomerase pathway, we performed a yeast two-hybrid screening with LPTS/PinX1 as the bait. A novel gene, MCRS2, encoding for an isoform of MCRS1/p78 and MSP58 was isolated. The expression of MCRS2 protein is cell-cycle dependent, accumulating in the very early S phase. MCRS2 interacts with LPTS/PinX1 in vitro, in vivo and colocalizes with LPTS/PinX1 in cells. MCRS2 and its amino terminus inhibit telomerase activity in vitro and long-term overexpression of MCRS2 in SMMC-7721 cells results in a gradual and progressive shortening of telomeres. Our findings suggest that MCRS2 might be a linker between telomere maintenance and cell-cycle regulation.},
}
@article {pmid15042697,
year = {2004},
author = {Adams, IR and McLaren, A},
title = {Identification and characterisation of mRif1: a mouse telomere-associated protein highly expressed in germ cells and embryo-derived pluripotent stem cells.},
journal = {Developmental dynamics : an official publication of the American Association of Anatomists},
volume = {229},
number = {4},
pages = {733-744},
doi = {10.1002/dvdy.10471},
pmid = {15042697},
issn = {1058-8388},
mesh = {Amino Acid Sequence ; Animals ; Chromatin/chemistry ; Cloning, Molecular ; Culture Techniques ; DNA-Binding Proteins/genetics/metabolism ; Embryo, Mammalian/cytology ; Female ; Fluorescent Antibody Technique ; Gene Expression ; Germ Cells/*metabolism ; Male ; Mice/*embryology/genetics/metabolism ; Molecular Sequence Data ; Oocytes/metabolism ; Pluripotent Stem Cells/*metabolism ; Precipitin Tests ; Repressor Proteins/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Sequence Alignment ; Telomere-Binding Proteins/*genetics/*metabolism ; },
abstract = {We have identified a mouse ortholog of the yeast Rif1 family of telomere-associated proteins on the basis of its high expression in primordial germ cells and embryo-derived pluripotent stem cell lines. mRif1 is also highly expressed in totipotent and pluripotent cells during early mouse development, and in male and female germ cells in adult mice. mRif1 expression is induced during derivation of embryonic stem cells and is rapidly down-regulated upon differentiation of embryonic stem cells in vitro. Furthermore, we show that mRif1 physically interacts with the telomere-associated protein mTrf2 and can be cross-linked to telomeric repeat DNA in mouse embryonic stem cells. mRif1 may be involved in the maintenance of telomere length or pluripotency in the germline and during early mouse development.},
}
@article {pmid15036269,
year = {2004},
author = {Kosmadaki, MG and Gilchrest, BA},
title = {The role of telomeres in skin aging/photoaging.},
journal = {Micron (Oxford, England : 1993)},
volume = {35},
number = {3},
pages = {155-159},
doi = {10.1016/j.micron.2003.11.002},
pmid = {15036269},
issn = {0968-4328},
mesh = {Apoptosis ; Cell Division ; Cellular Senescence/physiology ; DNA/radiation effects ; DNA Damage ; Humans ; Oxidative Stress ; Skin/radiation effects/*ultrastructure ; Skin Aging/*pathology ; Sunlight/adverse effects ; Tandem Repeat Sequences ; Telomerase/physiology ; Telomere/*physiology/ultrastructure ; Telomeric Repeat Binding Protein 2/physiology ; },
abstract = {Recent work has substantially elucidated the mechanisms of skin aging and photoaging. In particular, a central role for telomere-based signaling can be inferred. Intrinsic aging is largely controlled by progressive telomere shortening, compounded by low grade oxidative damage to telomeres and other cellular constituents, the consequence of aerobic cellular metabolism. In sun exposed skin, UV irradiation also damages DNA and accelerates telomere shortening. Aging and photodamage appear to share a common final pathway that involves signaling through p53 following disruption of the telomere. These telomere-initiated responses, in combination with UV-induced damage to critical regulatory genes, lead to the familiar picture of "photoaging." These and other insights into the molecular basis for skin aging/photoaging may lead to enhanced management options.},
}
@article {pmid15034298,
year = {2004},
author = {Reaper, PM and di Fagagna, Fd and Jackson, SP},
title = {Activation of the DNA damage response by telomere attrition: a passage to cellular senescence.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {3},
number = {5},
pages = {543-546},
pmid = {15034298},
issn = {1538-4101},
mesh = {Cell Cycle/physiology ; Cell Cycle Proteins/metabolism ; Cell Line ; Cellular Senescence/*physiology ; *DNA Damage ; DNA Repair ; DNA-Binding Proteins ; Humans ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {Critical telomere shortening induces senescence in many normal human cell types grown in culture. Recent data have revealed that dysfunctional telomeres can resemble certain forms of DNA damage, and point to a role for DNA damage signaling in the establishment and maintenance of telomere-initiated senescence. Here, we review these new observations and highlight potential avenues of future research. We consider the identities of the key DNA damage response factors involved in senescence and discuss a model for the molecular events occurring in pre-senescent cells that ultimately lead to a permanent cell cycle arrest phenotype.},
}
@article {pmid15034232,
year = {2004},
author = {Polychronopoulou, S and Koutroumba, P},
title = {Telomere length variation and telomerase activity expression in patients with congenital and acquired aplastic anemia.},
journal = {Acta haematologica},
volume = {111},
number = {3},
pages = {125-131},
doi = {10.1159/000076519},
pmid = {15034232},
issn = {0001-5792},
mesh = {Anemia, Aplastic/congenital/etiology/*genetics ; Dyskeratosis Congenita/etiology/genetics ; Fanconi Anemia/etiology/genetics ; Humans ; Telomerase/metabolism/*physiology ; Telomere/metabolism/*physiology/ultrastructure ; },
abstract = {Telomeres represent the nucleoprotein tails of chromosomes that get shortened with each cell division. When the telomere length reaches a critical point, cell senescence and death occur. Telomerase is a reverse transcriptase that counteracts telomere loss by adding telomeric sequences. In patients with acquired aplastic anemia, the mean telomere length (TRF) of peripheral blood leukocytes is generally short when compared to normal controls, without it being clear whether a relationship between TRF and disease severity exists. Additionally, increased telomerase activity (TA) is found in the bone marrow mononuclear cell population (MNCs) of aplastic anemia patients, especially in the chronic form of the disease. Fanconi anemia (FA) patients generally demonstrate increased TA and short telomeres in peripheral blood MNCs, a fact attributed to the high turnover of hematopoietic progenitor cells in combination with direct breakages at telomeric sequences. Furthermore, a strong correlation has been shown between TRF and the severity of aplastic anemia, but not with FA evolution towards myelodysplastic syndrome or acute myeloblastic leukemia. In respect of dyskeratosis congenita (DC), a disease of either X-linked or autosomal dominant/recessive inheritance which is characterized by premature ageing of highly regenerative tissues, studies have been carried out in order to elucidate whether the X-linked DC is caused by a defect in ribosomal RNA processing and/or telomere maintenance. Finally, the direct genetic link established between DC pathogenesis and short telomeres may lead to the development of new therapeutic protocols for diseases characterized by short telomere length and subsequent genomic instability.},
}
@article {pmid15031270,
year = {2004},
author = {Serrano, AL and Andrés, V},
title = {Telomeres and cardiovascular disease: does size matter?.},
journal = {Circulation research},
volume = {94},
number = {5},
pages = {575-584},
doi = {10.1161/01.RES.0000122141.18795.9C},
pmid = {15031270},
issn = {1524-4571},
mesh = {Adolescent ; Adult ; Aging/genetics ; Animals ; Arteriosclerosis/genetics ; Cardiovascular Diseases/*genetics/therapy ; Collateral Circulation/physiology ; Diabetic Angiopathies/genetics ; Estrogens/physiology ; Female ; Genetic Therapy ; Heart Failure/genetics ; Humans ; Hypertension/genetics ; Ischemia/physiopathology ; Male ; Mice ; Mice, Transgenic ; Models, Biological ; Rats ; Telomerase/physiology ; Telomere/*physiology/ultrastructure ; },
abstract = {Telomeres-the specialized DNA-protein structures at the ends of eukaryotic chromosomes-are essential for maintaining genome stability and integrity and for extended proliferative life span in both cultured cells and in the whole organism. Telomerase and additional telomere-associated proteins are necessary for preserving telomeric DNA length. Age-dependent telomere shortening in most somatic cells, including vascular endothelial cells, smooth muscle cells, and cardiomyocytes, is thought to impair cellular function and viability of the aged organism. Telomere dysfunction is emerging as an important factor in the pathogenesis of hypertension, atherosclerosis, and heart failure. In this Review, we discuss present studies on telomeres and telomere-associated proteins in cardiovascular pathobiology and their implications for therapeutics.},
}
@article {pmid15026461,
year = {2004},
author = {Hede, K},
title = {For telomeres, longer is not always better.},
journal = {Journal of the National Cancer Institute},
volume = {96},
number = {6},
pages = {426-427},
doi = {10.1093/jnci/96.6.426},
pmid = {15026461},
issn = {1460-2105},
mesh = {Animals ; Cell Death ; DNA Damage ; DNA Repair ; *Genomic Instability ; Humans ; Immunity, Cellular ; *Telomerase/drug effects/genetics/metabolism ; *Telomere/genetics/metabolism ; Yeasts ; },
}
@article {pmid15025282,
year = {2003},
author = {Menon, MM and Simha, MR},
title = {Telomerase and telomere length in normal and malignant human endometrium as prognostic markers.},
journal = {Indian journal of pathology &amp; microbiology},
volume = {46},
number = {3},
pages = {394-398},
pmid = {15025282},
issn = {0377-4929},
mesh = {Biomarkers, Tumor ; Endometrial Neoplasms/*enzymology/*pathology ; Endometrium/enzymology/ultrastructure ; Female ; Humans ; Menstrual Cycle ; Prognosis ; Telomerase/*metabolism ; Telomere/*pathology ; },
abstract = {Telomerase activation and telomere length maintainence are thought to be essential for cellular immortality and oncogenesis. Normal human endometrium expresses significant telomerase activity in a menstrual phase dependent manner. In this report, we have evaluated telomerase activity and telomere length in post menopausal endometrial hyperplasias and endometrial cancers to study their usefulness as prognostic markers. Telomerase activity was measured by the TRAP assay (Boehringer Mannheim, Germany) and telomere restriction fragment (trf) by the telomere length assay kit (BD Pharmingen). Proliferation markers PCNA and Bcl2 were studied by immunohistochemistry. Senescence associated Ogal activity was studied simultaneously and correlated with the above markers. Strong telomerase activity was observed in the proliferative phase of the normal endometrium, endometrial cancers and post-menopausal endometrial hyperplasias compared to normal, secretory and resting phases of the endometrium. PCNA and Bcl2 showed high positivity in telomerase positive cases. Telomerase activity was inversely proportional to Ogal activity. Mean trf lengths became shortened as the normal tissues underwent neoplastic changes. Our study suggests that high telomerase activity and short telomere lengths could be useful prognostic markers in human endometrium.},
}
@article {pmid15025219,
year = {2004},
author = {Takahashi, K and Nishida, H and Takeda, H and Shin, K},
title = {Telomere length in leukocytes and cultured gingival fibroblasts from patients with aggressive periodontitis.},
journal = {Journal of periodontology},
volume = {75},
number = {1},
pages = {84-90},
doi = {10.1902/jop.2004.75.1.84},
pmid = {15025219},
issn = {0022-3492},
mesh = {Acute Disease ; Adult ; Blotting, Southern ; Case-Control Studies ; Cells, Cultured ; Cellular Senescence ; Female ; Fibroblasts/enzymology/pathology ; Gingiva/pathology ; Humans ; Leukocytes/pathology ; Male ; Periodontitis/blood/*genetics/*pathology/physiopathology ; Telomere/*pathology ; beta-Galactosidase/biosynthesis ; },
abstract = {BACKGROUND: The association of genetic risk factors with the pathogenesis of aggressive periodontitis (AgP) has been a focus of attention. Telomeres, which are nucleoprotein complexes at the ends of chromosomes, could be a genetic marker for Down's syndrome and Hutchinson-Gilford progeria, in which patients' premature aging is involved in the pathogenesis. It has been reported that these patients tend to experience severe periodontitis. Therefore, we investigated the telomere length of peripheral blood leukocytes (PBL) obtained from patients with AgP and that in the patients' gingival fibroblasts undergoing cellular aging in vitro.<br><br>METHODS: Twenty-one patients with AgP and 50 age-matched, periodontally healthy subjects (HS) participated in this study. Genomic DNA from PBL and from human gingival fibroblasts (HGF) was analyzed by Southern blotting for telomere length. The percentage of HGF positive for beta-galactosidase (beta-gal), a marker for cellular senescence, was also investigated.<br><br>RESULTS: There was no significant difference in the telomere length (P = 0.20, Student's t test) between the two groups, and wide interindividual variation was found (5.93 to 11.4 kbp, average 8.35 +/- 1.19 kbp). The telomere length from PBL negatively correlated with donor age, but no significant difference in telomere loss between the two groups was observed. With HGF undergoing aging in culture, the mean telomere length of these cells from six patients with AgP and seven HS decreased an average of -67.5 bp and -81.0 bp, respectively. No association was found in the telomere length between PBL and HGF from the same donors (r = 0.56, P = 0.20). A significant association was found between the telomere length and the percentages of beta-gal-positive HGF during cell passages (r = 0.70, P < 0.001).<br><br>CONCLUSIONS: These results indicate that patients with AgP do not have excessive telomere loss and thus do not support the notion of the occurrence of a generalized premature cellular aging in patients with AgP. Further studies are required to investigate the association between telomere length and beta-gal in HGF.},
}
@article {pmid15024344,
year = {2004},
author = {Elwood, N},
title = {Telomere biology of human hematopoietic stem cells.},
journal = {Cancer control : journal of the Moffitt Cancer Center},
volume = {11},
number = {2},
pages = {77-85},
doi = {10.1177/107327480401100214},
pmid = {15024344},
issn = {1526-2359},
mesh = {Biomarkers, Tumor/metabolism ; Hematologic Neoplasms/enzymology/genetics/therapy ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/*ultrastructure ; Humans ; Leukemia/diagnosis/enzymology ; Prognosis ; Telomerase/metabolism ; Telomere/*physiology ; },
abstract = {BACKGROUND: Telomeres are protein DNA structures present at the ends of chromosomes and are essential for genetic stability and cell replication. Telomerase is the enzyme complex that maintains telomere integrity. Hematopoietic stem cells express telomerase and contain long telomeres, which become shorter as cells differentiate and mature. The extent of telomere shortening and the level of telomerase activity often correlate with the presence and severity of some hematopoietic diseases.<br><br>METHODS: The fundamentals of telomeres and telomerase are reviewed, and the telomere biology of human hematopoietic cells is discussed.<br><br>RESULTS: Telomere length and telomerase activity are important in the self-renewal of hematopoietic stem cells. Changes within these compartments affect both normal hematopoietic cells and the generation of hematopoietic disease. Telomere length provides information pertaining to the proliferative history and potential of a hematopoietic cell.<br><br>CONCLUSIONS: The role of telomerase and telomeres within the hematopoietic compartment needs further clarification. Advances in our knowledge in this field may improve clinical outcomes for the treatment of hematologic disease.},
}
@article {pmid15020465,
year = {2004},
author = {Jia, X and Weinert, T and Lydall, D},
title = {Mec1 and Rad53 inhibit formation of single-stranded DNA at telomeres of Saccharomyces cerevisiae cdc13-1 mutants.},
journal = {Genetics},
volume = {166},
number = {2},
pages = {753-764},
pmid = {15020465},
issn = {0016-6731},
mesh = {Cell Cycle Proteins/*genetics/metabolism ; Checkpoint Kinase 1 ; Checkpoint Kinase 2 ; DNA/metabolism ; Exodeoxyribonucleases/genetics/metabolism ; Intracellular Signaling Peptides and Proteins ; Mutation ; Protein Kinases/genetics/metabolism ; Protein Serine-Threonine Kinases/*genetics/metabolism ; Saccharomyces cerevisiae/enzymology/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*genetics/metabolism ; Time Factors ; },
abstract = {Here we examine the roles of budding-yeast checkpoint proteins in regulating degradation of dsDNA to ssDNA at unprotected telomeres (in Cdc13 telomere-binding protein defective strains). We find that Rad17, Mec3, as well as Rad24, members of the putative checkpoint clamp loader (Rad24) and sliding clamp (Rad17, Mec3) complexes, are important for promoting degradation of dsDNA in and near telomere repeats. We find that Mec1, Rad53, as well as Rad9, have the opposite role: they inhibit degradation. Downstream checkpoint kinases Chk1 and Dun1 play no detectable role in either promoting degradation or inhibiting it. These data suggest, first, that the checkpoint sliding clamp regulates and/or recruits some nucleases for degradation, and, second, that Mec1 activates Rad9 to activate Rad53 to inhibit degradation. Further analysis shows that Rad9 inhibits ssDNA generation by both Mec1/Rad53-dependent and -independent pathways. Exo1 appears to be targeted by the Mec1/Rad53-dependent pathway. Finally, analysis of double mutants suggests a minor role for Mec1 in promoting Rad24-dependent degradation of dsDNA. Thus, checkpoint proteins orchestrate carefully ssDNA production at unprotected telomeres.},
}
@article {pmid15020053,
year = {2004},
author = {Taddei, A and Gasser, SM},
title = {Multiple pathways for telomere tethering: functional implications of subnuclear position for heterochromatin formation.},
journal = {Biochimica et biophysica acta},
volume = {1677},
number = {1-3},
pages = {120-128},
doi = {10.1016/j.bbaexp.2003.11.014},
pmid = {15020053},
issn = {0006-3002},
mesh = {Animals ; Basic Helix-Loop-Helix Transcription Factors ; Cell Nucleus Structures/*metabolism ; DNA-Binding Proteins/genetics/metabolism ; Heterochromatin/genetics/*metabolism/ultrastructure ; Interphase/genetics ; Molecular Biology/methods ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Schizosaccharomyces pombe Proteins/genetics/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Telomere/*physiology ; Transcription Factors/genetics/metabolism ; Transcription, Genetic ; },
abstract = {Technical advances in the imaging of GFP derivatives in living cells have improved our ability to determine the position and dynamics of specific chromatin loci. This approach, combined with genetics and functional assays, has shed new light on how nuclear compartments facilitate gene repression in yeast.},
}
@article {pmid15010310,
year = {2004},
author = {Bailey, SM and Cornforth, MN and Ullrich, RL and Goodwin, EH},
title = {Dysfunctional mammalian telomeres join with DNA double-strand breaks.},
journal = {DNA repair},
volume = {3},
number = {4},
pages = {349-357},
doi = {10.1016/j.dnarep.2003.11.007},
pmid = {15010310},
issn = {1568-7864},
support = {CA-43322/CA/NCI NIH HHS/United States ; CA-73929/CA/NCI NIH HHS/United States ; CA-76260/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; *DNA Damage ; DNA-Activated Protein Kinase ; DNA-Binding Proteins ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, SCID ; Nuclear Proteins ; *Telomere ; },
abstract = {In addition to joining broken DNA strands, several non-homologous end-joining (NHEJ) proteins have a second seemingly antithetical role in constructing functional telomeres, the nucleoprotein structures at the termini of linear eukaryotic chromosomes that prevent joining between natural chromosome ends. Although NHEJ deficiency impairs double-strand break (DSB) repair, it also promotes inappropriate chromosomal end fusions that are observed microscopically as dicentric chromosomes with telomeric DNA sequence at points of joining. Here, we test the proposition that unprotected telomeres can fuse not only to other dysfunctional telomeres, but also to ends created by DSBs. Severe combined immunodeficiency (scid) is caused by a mutation in the catalytic subunit of DNA-dependent protein kinase (DNA-PK), an enzyme required for both efficient DSB repair and telomeric end-capping. Cells derived from wild-type, Trp53-/-, scid, and Trp53-/-/scid mice were exposed to gamma radiation to induce DSBs, and chromosomal aberrations were analyzed using a novel cytogenetic technique that can detect joining of a telomere to a DSB end. Telomere-DSB fusions were observed in both cell lines having the scid mutation, but not in wild-type nor Trp53-/- cells. Over a range of 25-340 cGy, half of the visible exchange-type chromosomal aberrations in Trp53-/-/scid cells involved telomere-DSB fusions. Our results demonstrate that unprotected telomeres are not only sensed as, but also acted upon, by the DNA repair machinery as if they were DSB ends. By opening a new pathway for misrepair, telomere-DSB fusion decreases the overall fidelity of DSB repair. The high frequency of these events in scid cells indicates telomere dysfunction makes a strong, and previously unsuspected, contribution to the characteristic radiation sensitivity associated with DNA-PK deficiency.},
}
@article {pmid15007655,
year = {2004},
author = {Prieto, P and Santos, AP and Moore, G and Shaw, P},
title = {Chromosomes associate premeiotically and in xylem vessel cells via their telomeres and centromeres in diploid rice (Oryza sativa).},
journal = {Chromosoma},
volume = {112},
number = {6},
pages = {300-307},
pmid = {15007655},
issn = {0009-5915},
mesh = {Centromere/*genetics ; Chromosome Pairing/genetics ; Chromosomes, Plant/*genetics ; In Situ Hybridization, Fluorescence ; Meiosis/*genetics ; Oryza/*genetics ; Plant Roots/growth &amp; development ; *Polyploidy ; Telomere/*genetics ; },
abstract = {Studies of the meiosis of diploid plants such as Arabidopsis, maize and diploid progenitors of wheat have revealed no premeiotic association of chromosomes. Premeiotic and somatic association of chromosomes has only been previously observed in the anther tissues and xylem vessel cells of developing roots in polyploid plants such as hexaploid and tetraploid wheat, polyploid relatives of wheat and artificial polyploids made from the progenitor diploids of wheat. This suggested that this association was confined specifically to polyploids or was induced by polyploidy. However, we developed procedures for in situ hybridization on structurally well-preserved tissue sections of rice, and analysed two diploid rice species (Oryza sativa and O. punctata). Contrary to expectation, this has revealed that centromeres and telomeres also associate both in the xylem vessel cells of developing root and in undifferentiated anther cells in these diploids. However, in contrast to wheat and related polyploids, where the initial association in undifferentiated anthers is between either non-homologous or related chromosomes, and not homologous chromosomes, the initial association of rice chromosomes seems to be between homologues. Thus, in contrast to the diploid dicot model Arabidopsis, meiotic studies on the diploid model cereal, rice, will now need to take into account the effects of premeiotic chromosome association.},
}
@article {pmid15007108,
year = {2004},
author = {Ohki, R and Ishikawa, F},
title = {Telomere-bound TRF1 and TRF2 stall the replication fork at telomeric repeats.},
journal = {Nucleic acids research},
volume = {32},
number = {5},
pages = {1627-1637},
pmid = {15007108},
issn = {1362-4962},
mesh = {Cell Cycle ; *DNA Replication ; HeLa Cells ; Humans ; Repetitive Sequences, Nucleic Acid ; Telomere/chemistry/*genetics/metabolism ; Telomeric Repeat Binding Protein 1/metabolism/*physiology ; Telomeric Repeat Binding Protein 2/metabolism/*physiology ; },
abstract = {Vertebrate telomeres consist of tandem repeats of T2AG3 and associated proteins including the telomeric DNA-binding proteins, TRF1 and TRF2. It has been proposed that telomeres assume two interswitchable states, the open state that is accessible to various trans-acting factors and the closed state that excludes those factors. TRF1 and TRF2 are believed to promote the formation of the closed state. However, little is known about how those two states influence DNA replication. We analyzed the effects of TRF1 and TRF2 on telomeric replication both in vitro and in vivo. By exploiting the in vitro replication system of linear SV40 DNA, we found that telomeric repeats are a poor replication template. Moreover, the addition of recombinant TRF1 and TRF2 significantly stalled the replication fork progression at telomeric repeats. When TRF1 was overexpressed in HeLa cells, cells with 4N DNA content were accumulated. Furthermore, cytological analyses revealed that the replication focus overlapped with telomere signals at a significantly higher frequency in TRF1-overexpressing cells than in control cells. The results suggest that TRF1 and TRF2 exert inhibitory effects on replication fork progression.},
}
@article {pmid15004529,
year = {2004},
author = {Nguyen, B and Elmore, LW and Holt, SE},
title = {Telomere maintenance: at the crossroads of mismatch repair?.},
journal = {Cancer biology &amp; therapy},
volume = {3},
number = {3},
pages = {293-295},
doi = {10.4161/cbt.3.3.764},
pmid = {15004529},
issn = {1538-4047},
mesh = {Base Pair Mismatch/*genetics ; Cell Transformation, Neoplastic ; *DNA Damage ; *DNA Repair ; Humans ; Neoplasms/physiopathology ; Telomere/*metabolism ; },
}
@article {pmid15000677,
year = {2004},
author = {Kuimov, AN},
title = {Polypeptide components of telomere nucleoprotein complex.},
journal = {Biochemistry. Biokhimiia},
volume = {69},
number = {2},
pages = {117-129},
doi = {10.1023/b:biry.0000018941.81962.1c},
pmid = {15000677},
issn = {0006-2979},
mesh = {Animals ; DNA/*metabolism ; Fungal Proteins/genetics/*metabolism ; Humans ; Nuclear Proteins/genetics/*metabolism ; Nucleoproteins/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Yeasts/genetics/metabolism ; },
abstract = {Chromosome telomeres of humans and many model organisms contain a structure called a t-loop, which is maintained by TERF, TINF2, Pot1, and other proteins. Increase in TERF1 concentration prevents telomere elongation by telomerase. Decrease in TERF2 concentration (preventing t-loop formation) is accompanied by blockade of proliferation and appearance of other signs of cellular senescence in experiments. Natural regulation of TERF1 involves tankyrase, ATM protein kinase, and fluctuations of the protein level across a cell cycle. The telomere nucleoprotein complex also interacts with various polypeptide macromolecules (e.g., Sir2, PinX1, Rap1, Ku, Rad50/Mre11/Nbs1) responsible for heterochromatin formation, modulation of telomerase activity, DNA repair, and signaling to other cell compartments about telomere state. Study of structure and functioning of telomere nucleoprotein complex may contribute to elucidation of poorly understood mechanisms of aging and processes of tumor transformation of cells.},
}
@article {pmid14988160,
year = {2004},
author = {Ladetto, M and Compagno, M and Ricca, I and Pagano, M and Rocci, A and Astolfi, M and Drandi, D and di Celle, PF and Dell'Aquila, M and Mantoan, B and Vallet, S and Pagliano, G and De Marco, F and Francese, R and Santo, L and Cuttica, A and Marinone, C and Boccadoro, M and Tarella, C},
title = {Telomere length correlates with histopathogenesis according to the germinal center in mature B-cell lymphoproliferative disorders.},
journal = {Blood},
volume = {103},
number = {12},
pages = {4644-4649},
doi = {10.1182/blood-2003-12-4412},
pmid = {14988160},
issn = {0006-4971},
mesh = {B-Lymphocytes/*pathology ; Humans ; Leukemia/genetics/pathology ; Lymphoproliferative Disorders/genetics/*pathology ; Multiple Myeloma/genetics/pathology ; Restriction Mapping ; Telomere/pathology/*ultrastructure ; },
abstract = {In this study we investigated telomere restriction fragment (TRF) length in a panel of mature B-cell lymphoproliferative disorders (MBCLDs) and correlated this parameter with histology and histopathogenesis in relation to the germinal center (GC). We assessed 123 MBCLD samples containing 80% or more tumor cells. TRF length was evaluated by Southern blot analysis using a chemiluminescence-based assay. GC status was assessed through screening for stable and ongoing somatic mutations within the immunoglobulin heavy-chain genes. Median TRF length was 6170 bp (range, 1896-11 200 bp) and did not correlate with patient age or sex. TRF length was greater in diffuse large cell lymphoma, Burkitt lymphoma, and follicular lymphoma (medians: 7789 bp, 9471 bp, and 7383 bp, respectively) than in mantle cell lymphoma and chronic lymphocytic leukemia (medians: 3582 bp and 4346 bp, respectively). GC-derived MBCLDs had the longest telomeres, whereas those arising from GC-inexperienced cells had the shortest (P < 10(-9)). We conclude that (1) TRF length in MBCLD is highly heterogeneous; (2) GC-derived tumors have long telomeres, suggesting that minimal telomere erosion occurs during GC-derived lymphomagenesis; and (3) the short TRF lengths of GC-inexperienced MBCLDs indicates that these neoplasms are good candidates for treatment with telomerase inhibitors, a class of molecules currently the subject of extensive preclinical evaluation.},
}
@article {pmid14987795,
year = {2004},
author = {Fradiani, PA and Ascenzioni, F and Lavitrano, M and Donini, P},
title = {Telomeres and telomerase activity in pig tissues.},
journal = {Biochimie},
volume = {86},
number = {1},
pages = {7-12},
doi = {10.1016/j.biochi.2003.11.009},
pmid = {14987795},
issn = {0300-9084},
mesh = {Animals ; Base Sequence ; HeLa Cells ; Humans ; Male ; Mice ; Molecular Sequence Data ; Organ Specificity ; Spermatozoa/*metabolism ; Swine ; Telomerase/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {The current state of the art concerning telomeres and telomerase stems almost exclusively from the analysis of protozoa, yeast, and a small number of mammals. In the present study, we confirm that the pig telomeric sequence is indeed T(2)AG(3), as previously suggested. By making use of sequence analysis of pig telomeric DNA variant telomeric repeats in the medial region of the telomeres, interspersed with canonical T(2)AG(3) repeats, were identified. This telomere organization is similar to the one present in humans. Analysis of terminal restriction fragments showed that the majority of telomeres from different pig tissues are longer than in humans but shorter than in Mus musculus. Telomeres from spermatozoa were found to be longer, ranging in size between 13 and 44 kb. Most of the somatic pig tissues expressed significant levels of telomerase activity, a situation more similar to mouse and that contrasts with the one in humans and dog. Moreover, the analysis of sperm cells from different epididymal compartments of an adult animal showed that telomerase activity is absent in maturing spermatozoa, suggesting that sperm telomere elongation is restricted during spermatogenesis.},
}
@article {pmid14987434,
year = {2003},
author = {Voronin, AP and Lobov, IB and Gilson, E and Podgornaya, OI},
title = {A telomere-binding protein (TRF2/MTBP) from mouse nuclear matrix with motives of an intermediate filament-type rod domain.},
journal = {Journal of anti-aging medicine},
volume = {6},
number = {3},
pages = {205-218},
doi = {10.1089/109454503322733054},
pmid = {14987434},
issn = {1094-5458},
mesh = {Animals ; Blotting, Western ; Carrier Proteins/*metabolism ; Chromatography, Ion Exchange ; Intermediate Filament Proteins/metabolism ; Mice ; Nuclear Matrix-Associated Proteins/metabolism ; Telomere-Binding Proteins/metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {In previous work, we identified a telomeric DNA-binding protein (termed telomere-membrane binding protein, MTBP) in the envelope of the frog oocyte nucleus and raised antibodies against it. Here we present immunological evidence which suggests strongly that MTBP is identical with the vertebrate telomeric DNA-binding protein TRF2 (telomere-repeat factor 2). MTBP/TRF2 possesses motif which resembles rod domain characteristic of intermediate filament (IF) proteins as shown by immunological cross-reactivity with characteristic antibodies, as well as amino acid sequence homology. Anti-MTBP antibodies recognised a protein of the same M, as TRF2 in extracts of mouse nuclei and nuclear matrix as shown by ion-exchange chromatography, gel shift assays, and Western blots. This mouse MTBP analogue forms more stable complexes with the vertebrate telomeric DNA fragment (T(2)AG(3))(135) than with the corresponding fragment from Tetrahymena (T(2)G(4))(130). Proteins in each of these complexes are recognised by anti-MTBP antibody. In situ hybridization with the vertebrate telomeric DNA sequence (T(2)AG(3))(135) and immunofluorescence with anti-MTBP antibody had shown earlier that these are co-localised in the nucleus of mouse cells, and here MTBP is shown to be associated with the residual membrane of hepatocyte nuclei using Western blotting and immunofluorescence. Some immunofluorescence signal from MTBP is localized at chromosome extremities on metaphase plates from mouse cell culture, but the main signal is seen in patches scattered around the chromosomes which were identified as remnants of the nuclear envelope by double labelling with antibodies against lamin B. These observations suggest that MTBP/TRF2 is a good candidate for the attachment of telomeres to the nuclear envelope in somatic cells.},
}
@article {pmid14983937,
year = {2004},
author = {Angèle, S and Falconer, A and Foster, CS and Taniere, P and Eeles, RA and Hall, J},
title = {ATM protein overexpression in prostate tumors: possible role in telomere maintenance.},
journal = {American journal of clinical pathology},
volume = {121},
number = {2},
pages = {231-236},
doi = {10.1309/JTKG-GGKU-RFX3-XMGT},
pmid = {14983937},
issn = {0002-9173},
mesh = {Adenocarcinoma/genetics/*metabolism/secondary ; Aged ; Humans ; Immunoenzyme Techniques ; Male ; Middle Aged ; Pilot Projects ; Prostate/metabolism/pathology ; Prostatic Neoplasms/genetics/*metabolism/pathology ; *Telomere ; },
abstract = {It has been postulated that telomere dysfunction and telomerase activation have important roles in prostate tumorigenesis. Since the ataxia-telangiectasia mutated gene product (ATM protein) is involved in maintaining telomere length and integrity, we hypothesized that its expression might be altered in prostate tumors and, thus, examined its profile in 49 tumor samples. The majority (32/49) had ATM protein levels higher than those observed in normal tissues, with only 5 of 49 tissue samples showing reduced or absent ATM levels. Three of these were from the group of 6 young-onset or sibling-pair tumors. There was a trend toward higher ATM expression in tumors with a higher Gleason score (23/32 [72%] for grade 8-10 vs 9/17 [53%] for grades 5-7), although this difference was not statistically significant. These findings support our hypothesis that the presence of the ATM protein at the same or a higher level than that in normal prostate cells might have an important role in the maintenance of the shortened telomeres commonly found in prostate cancer cells.},
}
@article {pmid14982846,
year = {2004},
author = {Meeker, AK and Hicks, JL and Gabrielson, E and Strauss, WM and De Marzo, AM and Argani, P},
title = {Telomere shortening occurs in subsets of normal breast epithelium as well as in situ and invasive carcinoma.},
journal = {The American journal of pathology},
volume = {164},
number = {3},
pages = {925-935},
pmid = {14982846},
issn = {0002-9440},
support = {P50 CA088843/CA/NCI NIH HHS/United States ; P50 CA058236/CA/NCI NIH HHS/United States ; T32DK07552/DK/NIDDK NIH HHS/United States ; CA58236/CA/NCI NIH HHS/United States ; CA88843/CA/NCI NIH HHS/United States ; T32 DK007552/DK/NIDDK NIH HHS/United States ; },
mesh = {Biomarkers, Tumor ; Breast/metabolism/pathology ; Breast Neoplasms/metabolism/*pathology ; Carcinoma/metabolism/*pathology ; Carcinoma, Intraductal, Noninfiltrating/*pathology ; Cell Transformation, Neoplastic/pathology ; Centromere/metabolism/pathology ; Female ; Humans ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Male ; Mammary Glands, Human/metabolism/*pathology ; Telomere/metabolism/*pathology ; },
abstract = {In the setting of inactivated DNA damage-sensitive checkpoints, critically shortened telomeres promote chromosomal instability and the types of widespread cytogenetic alterations that characterize most human carcinomas. Using a direct telomere fluorescence in situ hybridization technique, we analyzed 114 invasive breast carcinomas, 29 carcinoma in situ lesions, 10 benign proliferative lesions, and different normal epithelial components of the male and female breast. We found marked telomere shortening in the majority (52.5%) of invasive carcinomas; smaller subsets of invasive carcinoma demonstrated moderate telomere shortening (17.5%) or normal telomere lengths (21%), while a small subgroup (5%) contained elongated telomeres. Strikingly, the majority (78%) of ductal carcinoma in situ demonstrated markedly or moderately shortened telomeres. Surprisingly, unlike all other normal epithelia studied to date, moderate telomere shortening was observed in benign secretory cells in approximately 50% of histologically-normal terminal duct lobular units (from which most breast cancer is thought to arise), while such shortening was not seen in myoepithelial cells or normal large lactiferous ducts of the female breast or male breast ducts (from which breast cancer infrequently arises). We postulate that such shortening is the result of hormonally driven, physiological proliferation, and may delineate a population of epithelial cells at risk for subsequent malignant transformation.},
}
@article {pmid14976379,
year = {2004},
author = {Kapoor, V and Telford, WG},
title = {Telomere length measurement by fluorescence in situ hybridization and flow cytometry.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {263},
number = {},
pages = {385-398},
doi = {10.1385/1-59259-773-4:385},
pmid = {14976379},
issn = {1064-3745},
mesh = {CD4 Antigens/biosynthesis ; CD4-Positive T-Lymphocytes/metabolism ; Calibration ; Cell Membrane/metabolism ; Cross-Linking Reagents/pharmacology ; Flow Cytometry/*methods ; Humans ; Immunologic Memory ; In Situ Hybridization, Fluorescence/*methods ; Jurkat Cells ; Peptide Nucleic Acids/chemistry ; Peptides/chemistry ; Phenotype ; T-Lymphocytes/metabolism ; Telomerase/metabolism ; Telomere/*ultrastructure ; },
abstract = {Telomere length is an important measure of cellular differentiation and progression to senescence. Flow cytometric assays for measuring telomere length have become an important adjunct to more laborious Southern blotting methods; telomere length can be estimated with considerable accuracy in small numbers of individual cells by flow cytometry, and can be measured in cell population subsets with simultaneous fluorescent immunophenotyping. In this chapter, we describe the standard flow cytometric assay for measuring telomere length, including the incorporation of fluorochrome-conjugated antibody immunolabeling for measurement in cell subsets.},
}
@article {pmid14975611,
year = {2004},
author = {Nawrot, TS and Staessen, JA and Gardner, JP and Aviv, A},
title = {Telomere length and possible link to X chromosome.},
journal = {Lancet (London, England)},
volume = {363},
number = {9408},
pages = {507-510},
doi = {10.1016/S0140-6736(04)15535-9},
pmid = {14975611},
issn = {1474-547X},
support = {AG021593/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aging/*genetics/physiology ; Base Composition ; Belgium ; Chromosomes, Human, X/*genetics/ultrastructure ; Cohort Studies ; Family ; Female ; Humans ; Leukocytes/physiology/ultrastructure ; Male ; Marriage ; Middle Aged ; Pedigree ; Restriction Mapping/methods ; Sampling Studies ; Tandem Repeat Sequences/genetics/physiology ; Telomere/*genetics/ultrastructure ; },
abstract = {BACKGROUND: Because telomeres are eroded during mitosis, telomere length indicates the replicative history of human somatic cells. Clinical markers of ageing--such as pulse pressure and survival--are associated with telomere length. On the basis of findings of studies in twins, telomere length seems to be familial, but little is known about its mode of inheritance. We aimed to investigate the inheritance of telomere length.<br><br>METHODS: We measured terminal restriction fragment (TRF) length in white-blood-cell DNA taken from individuals from the family-based cohort of the Flemish Study on Environment, Genes, and Health Outcomes.<br><br>FINDINGS: We recorded no correlation in sex and age adjusted TRF length between spouses (r=-0.05; p=0.70) nor between fathers and sons (r=-0.16; p=0.35). By contrast, we noted robust correlations in TRF length between fathers and daughters (r=0.60; p<0.0001); between mothers and sons (r=0.41; p=0.0017) and daughters (r=0.59; p<0.0001); and among siblings (r> or =0.61; p< or =0.0004).<br><br>INTERPRETATION: X-linked inheritance of TRF length is the most probable explanation for our findings. Pending confirmation, our observations suggest that the process of ageing might be an X-linked trait.},
}
@article {pmid14970723,
year = {2003},
author = {Swanberg, SE and Delany, ME},
title = {Dynamics of telomere erosion in transformed and non-transformed avian cells in vitro.},
journal = {Cytogenetic and genome research},
volume = {102},
number = {1-4},
pages = {318-325},
doi = {10.1159/000075769},
pmid = {14970723},
issn = {1424-859X},
mesh = {Animals ; B-Lymphocytes/chemistry/enzymology/metabolism/pathology ; Cell Line ; Cell Line, Transformed ; Cell Line, Tumor ; Chick Embryo ; Chickens/genetics ; Chromosomal Instability/genetics ; Fibroblasts/chemistry/enzymology/metabolism/pathology ; Hepatocytes/chemistry/enzymology/metabolism/pathology ; Humans ; Kidney/cytology/embryology/enzymology ; Macrophages/chemistry/enzymology/metabolism/pathology ; Quail/embryology/genetics ; T-Lymphocytes/chemistry/enzymology/metabolism/pathology ; Telomerase/metabolism ; Telomere/*genetics ; Turkeys/embryology/genetics ; },
abstract = {Although vertebrate telomeres are highly conserved, telomere dynamics and telomerase profiles vary among species. The objective of the present study was to examine telomerase activity and telomere length profiles of transformed and non-transformed avian cells in vitro. Non-transformed chicken embryo fibroblasts (CEFs) showed little or no telomerase activity from the earliest passages through senescence. Unexpectedly, a single culture of particularly long-lived senescent CEFs showed telomerase activity after over 250 days in culture. Transformed avian lines (six chicken, two quail and one turkey) and tumor samples (two chicken) exhibited telomerase activity. Telomere length profiles of non-transformed CEF cultures derived from individual embryos of an inbred line (UCD 003) exhibited cycles of shortening and lengthening with a substantial net loss of telomeric DNA by senescence. The telomere length profiles of several transformed cell lines resembled telomere length profiles of senescent CEFs in that they exhibited little of the typical smear of terminal restriction fragments (TRFs) suggesting that these transformed cells may possess a reduced amount of telomeric DNA. These results show that avian telomerase activity profiles are consistent with the telomerase activity profiles of human primary and transformed cells. Further, monitoring of telomere lengths of primary cells provides evidence for a dynamic series of changes over the lifespan of any specific cell culture ultimately resulting in net telomeric DNA loss by senescence.},
}
@article {pmid14970665,
year = {2004},
author = {Pandita, TK},
title = {Detecting the influence of cell cycle regulatory proteins on human telomeres.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {241},
number = {},
pages = {329-339},
doi = {10.1385/1-59259-646-0:329},
pmid = {14970665},
issn = {1064-3745},
mesh = {Biochemistry/*methods ; Blotting, Southern ; Cell Cycle Proteins/biosynthesis/*physiology ; Cell Line ; Cell Nucleus/metabolism ; G1 Phase ; G2 Phase ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Metaphase ; Telomerase/metabolism ; Telomere/*metabolism ; },
}
@article {pmid14970408,
year = {2004},
author = {Ascenzioni, F and Fradiani, PA and Donini, P},
title = {Telomere length analysis and in vitro telomerase assay.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {240},
number = {},
pages = {123-146},
doi = {10.1385/1-59259-434-4:123},
pmid = {14970408},
issn = {1064-3745},
mesh = {Base Sequence ; Blotting, Southern ; DNA Primers ; Electrophoresis, Agar Gel ; In Situ Hybridization, Fluorescence ; Nucleic Acid Hybridization ; Telomerase/*metabolism ; *Telomere ; },
}
@article {pmid14966288,
year = {2004},
author = {Wei, C and Price, CM},
title = {Cell cycle localization, dimerization, and binding domain architecture of the telomere protein cPot1.},
journal = {Molecular and cellular biology},
volume = {24},
number = {5},
pages = {2091-2102},
pmid = {14966288},
issn = {0270-7306},
support = {AG17212/AG/NIA NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Cell Cycle/*physiology ; Cells, Cultured ; Chickens ; Dimerization ; Humans ; Molecular Sequence Data ; Nucleic Acid Conformation ; Protein Binding ; *Protein Conformation ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Schizosaccharomyces pombe Proteins ; Sequence Alignment ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/*chemistry/*metabolism ; Two-Hybrid System Techniques ; },
abstract = {Pot1 is a single-stranded-DNA-binding protein that recognizes telomeric G-strand DNA. It is essential for telomere capping in Saccharomyces pombe and regulates telomere length in humans. Human Pot1 also interacts with proteins that bind the duplex region of the telomeric tract. Thus, like Cdc13 from S. cerevisiae, Pot 1 may have multiple roles at the telomere. We show here that endogenous chicken Pot1 (cPot1) is present at telomeres during periods of the cell cycle when t loops are thought to be present. Since cPot1 can bind internal loops and directly adjacent DNA-binding sites, it is likely to fully coat and protect both G-strand overhangs and the displaced G strand of a t loop. The minimum binding site of cPot1 is double that of the S. pombe DNA-binding domain. Although cPot can self associate, dimerization is not required for DNA binding and hence does not explain the binding-site duplication. Instead, the DNA-binding domain appears to be extended to contain a second binding motif in addition to the conserved oligonucleotide-oligosaccharide (OB) fold present in other G-strand-binding proteins. This second motif could be another OB fold. Although dimerization is inefficient in vitro, it may be regulated in vivo and could promote association with other telomere proteins and/or telomere compaction.},
}
@article {pmid14966275,
year = {2004},
author = {Seimiya, H and Muramatsu, Y and Smith, S and Tsuruo, T},
title = {Functional subdomain in the ankyrin domain of tankyrase 1 required for poly(ADP-ribosyl)ation of TRF1 and telomere elongation.},
journal = {Molecular and cellular biology},
volume = {24},
number = {5},
pages = {1944-1955},
pmid = {14966275},
issn = {0270-7306},
mesh = {Amino Acid Sequence ; Ankyrins/*metabolism ; Binding Sites ; HeLa Cells ; Humans ; Molecular Sequence Data ; Phylogeny ; Poly Adenosine Diphosphate Ribose/*metabolism ; Protein Structure, Tertiary ; Recombinant Fusion Proteins/genetics/metabolism ; Sequence Alignment ; Tankyrases/chemistry/classification/genetics/*metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/*metabolism ; },
abstract = {In human cells, telomere elongation by telomerase is repressed in cis by the telomeric protein TRF1. Tankyrase 1 binds TRF1 via its ankyrin domain and poly(ADP-ribosyl)ates it. Overexpression of tankyrase 1 in telomerase-positive cells releases TRF1 from telomeres, resulting in telomere elongation. The tankyrase 1 ankyrin domain is classified into five conserved subdomains, ARCs (ankyrin repeat clusters) I to V. Here, we investigated the biological significance of the ARCs. First, each ARC worked as an independent binding site for TRF1. Second, ARCs II to V recognized the N-terminal acidic domain of TRF1 whereas ARC I bound a discrete site between the homodimerization and the Myb-like domains of TRF1. Inactivation of TRF1 binding in the C-terminal ARC, ARC V, either by deletion or point mutation, significantly reduced the ability of tankyrase 1 to poly(ADP-ribosyl)ate TRF1, release TRF1 from telomeres, and elongate telomeres. In contrast, other ARCs, ARC II and/or IV, inactivated by point mutations still retained the biological function of tankyrase 1. On the other hand, ARC V per se was not sufficient for telomere elongation, suggesting a structural role for multiple ARCs. This work provides evidence that specific ARC-TRF1 interactions play roles in the essential catalytic function of tankyrase 1.},
}
@article {pmid14963037,
year = {2004},
author = {Martin-Ruiz, C and Saretzki, G and Petrie, J and Ladhoff, J and Jeyapalan, J and Wei, W and Sedivy, J and von Zglinicki, T},
title = {Stochastic variation in telomere shortening rate causes heterogeneity of human fibroblast replicative life span.},
journal = {The Journal of biological chemistry},
volume = {279},
number = {17},
pages = {17826-17833},
doi = {10.1074/jbc.M311980200},
pmid = {14963037},
issn = {0021-9258},
mesh = {Blotting, Southern ; Bromodeoxyuridine/pharmacology ; Cell Division ; Cell Line ; Cell Separation ; Cellular Senescence ; DNA Damage ; Enzyme-Linked Immunosorbent Assay ; Fibroblasts/metabolism/*physiology ; Flow Cytometry ; Genes, Reporter ; Humans ; Oxidative Stress ; Oxygen/metabolism ; Phenotype ; Stochastic Processes ; Telomerase/metabolism ; Telomere/*ultrastructure ; Time Factors ; beta-Galactosidase/metabolism ; },
abstract = {The replicative life span of human fibroblasts is heterogeneous, with a fraction of cells senescing at every population doubling. To find out whether this heterogeneity is due to premature senescence, i.e. driven by a nontelomeric mechanism, fibroblasts with a senescent phenotype were isolated from growing cultures and clones by flow cytometry. These senescent cells had shorter telomeres than their cycling counterparts at all population doubling levels and both in mass cultures and in individual subclones, indicating heterogeneity in the rate of telomere shortening. Ectopic expression of telomerase stabilized telomere length in the majority of cells and rescued them from early senescence, suggesting a causal role of telomere shortening. Under standard cell culture conditions, there was a minor fraction of cells that showed a senescent phenotype and short telomeres despite active telomerase. This fraction increased under chronic mild oxidative stress, which is known to accelerate telomere shortening. It is possible that even high telomerase activity cannot fully compensate for telomere shortening in all cells. The data show that heterogeneity of the human fibroblast replicative life span can be caused by significant stochastic cell-to-cell variation in telomere shortening.},
}
@article {pmid14769133,
year = {2004},
author = {Didiano, D and Shalaby, T and Lang, D and Grotzer, MA},
title = {Telomere maintenance in childhood primitive neuroectodermal brain tumors.},
journal = {Neuro-oncology},
volume = {6},
number = {1},
pages = {1-8},
pmid = {14769133},
issn = {1522-8517},
mesh = {Adolescent ; Adult ; Brain Neoplasms/*enzymology/pathology ; Catechin/*analogs &amp; derivatives/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects/physiology ; Child ; Child, Preschool ; DNA-Binding Proteins ; Dose-Response Relationship, Drug ; Female ; Fetus ; Humans ; Infant ; Male ; Middle Aged ; Neuroectodermal Tumors, Primitive/*enzymology/pathology ; Telomerase/antagonists &amp; inhibitors/biosynthesis/genetics ; Telomere/*enzymology ; },
abstract = {Primitive neuroectodermal tumors (PNETs), including medulloblastoma (PNET/MB) and supratentorial PNET (sPNET), are the most common malignant brain tumors of childhood. The stabilization of telomere lengths by telomerase activation is an important step in carcinogenesis and cell immortalization. Epigallocatechin gallate (EGCG), the major polyphenol in green tea, is a telomerase inhibitor with antiproliferative and anticarcinogenic effects against different types of cancer. In this study, we used real-time reverse transcriptase-polymerase chain reaction to measure the mRNA expression of the human telomerase reverse transcriptase (hTERT) in 50 primary PNET samples (43 PNET/MB, 7 sPNET), 14 normal human brain samples, and 6 human PNET cell lines. Compared to normal human cerebellum, 38/50 (76%) primary PNET samples had >or= 5-fold upregulated hTERT mRNA expression. We then examined PNET cell lines for telomerase activity using a quantitative telomeric repeat amplification protocol (TRAP), and for telomere length using terminal restriction fragment analysis. While a positive correlation between hTERT mRNA expression and telomerase activity was detected in PNET cell lines, no correlation was found between telomerase activity and telomere length. Treatment of PNET cell lines with EGCG resulted in a dose-dependent inhibition of telomerase activity at micromolar levels. Although EGCG displayed strong proliferation inhibitory effects against TRAP-positive PNET cell lines, it had no significant effect against TRAP-negative D425 cells. These results provide evidence for a possible role of telomerase in the pathogenesis of most PNETs and indicate that subsets of PNETs maintain telomere length by alternative mechanisms. Inhibition of telomerase function represents a novel experimental therapeutic strategy in childhood PNETs that warrants further investigation.},
}
@article {pmid14763510,
year = {2003},
author = {Wege, H and Chui, MS and Le, HT and Strom, SC and Zern, MA},
title = {In vitro expansion of human hepatocytes is restricted by telomere-dependent replicative aging.},
journal = {Cell transplantation},
volume = {12},
number = {8},
pages = {897-906},
doi = {10.3727/000000003771000138},
pmid = {14763510},
issn = {0963-6897},
mesh = {Albumins/metabolism ; Cell Division/*physiology ; Cells, Cultured ; Cellular Senescence/*physiology ; DNA Replication ; DNA-Binding Proteins ; Hepatocytes/cytology/*physiology ; Humans ; Keratins/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {Currently, different techniques to expand human hepatocytes in vitro are being investigated to generate enough cells for liver-directed cell therapies. However, based on observations in fibroblasts and other cell types, telomere attrition limits the proliferative capacity of normal somatic cells. Therefore, we explored whether telomere-dependent replicative aging restricts the in vitro proliferation of human hepatocytes. Subpopulations of cells isolated from a neonatal liver and characterized as hepatocyte derived by RT-PCR and flow cytometry started to proliferate 5-7 days after plating and were termed proliferating human hepatocytes (PHH). Following retroviral-mediated transduction of the catalytic telomerase subunit, telomerase reverse transcriptase (hTERT), telomerase activity increased from almost undetectable levels to levels as high as in HepG2 and other telomerase-positive cell lines. As expected, untransduced PHH progressively lost telomeric repeats and arrested after 30-35 cell divisions with telomeres of less than 5 kilo bases. In comparison, telomerase-reconstituted PHH maintained elongated telomeres and continued to proliferate as shown by colorimetric assays and cell counts. In this study, telomere stabilization extended the proliferative capacity of in vitro proliferating human neonatal hepatocytes. Therefore, telomere attrition needs to be addressed when developing techniques to expand human hepatocytes.},
}
@article {pmid14757838,
year = {2004},
author = {Ueno, M and Murase, T and Kibe, T and Ohashi, N and Tomita, K and Murakami, Y and Uritani, M and Ushimaru, T and Harata, M},
title = {Fission yeast Arp6 is required for telomere silencing, but functions independently of Swi6.},
journal = {Nucleic acids research},
volume = {32},
number = {2},
pages = {736-741},
pmid = {14757838},
issn = {1362-4962},
mesh = {Actins/genetics/*metabolism ; Active Transport, Cell Nucleus ; Cell Nucleus/metabolism ; Centromere/genetics/metabolism ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; Gene Deletion ; Gene Expression Regulation, Fungal ; *Gene Silencing ; Heterochromatin/genetics/metabolism ; Protein Binding ; RNA, Fungal/genetics/metabolism ; Schizosaccharomyces/*genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Transcription, Genetic/genetics ; },
abstract = {The actin-related proteins (Arps), which are subdivided into at least eight subfamilies, are conserved from yeast to humans. A member of the Arp6 subfamily in Drosophila, Arp4/Arp6, co-localizes with heterochromatin protein 1 (HP1) in pericentric heterochromatin. Fission yeast Schizosaccharomyces pombe possesses both an HP1 homolog and an Arp6 homolog. However, the function of S.pombe Arp6 has not been characterized yet. We found that deletion of arp6(+) impaired telomere silencing, but did not affect centromere silencing. Chromatin immunoprecipitation assays revealed that Arp6 bound to the telomere region. However, unlike Drosophila Arp4/Arp6, S.pombe Arp6 was distributed throughout nuclei. The binding of Arp6 to telomere DNA was not affected by deletion of swi6(+). Moreover, the binding of Swi6 to telomere ends was not affected by deletion of arp6(+). These results suggest that Arp6 and Swi6 function independently at telomere ends. We propose that the Arp6-mediated repression mechanism works side by side with Swi6-based telomere silencing in S.pombe.},
}
@article {pmid14756758,
year = {2004},
author = {Weiss-Schneeweiss, H and Riha, K and Jang, CG and Puizina, J and Scherthan, H and Schweizer, D},
title = {Chromosome termini of the monocot plant Othocallis siberica are maintained by telomerase, which specifically synthesises vertebrate-type telomere sequences.},
journal = {The Plant journal : for cell and molecular biology},
volume = {37},
number = {4},
pages = {484-493},
doi = {10.1046/j.1365-313x.2003.01974.x},
pmid = {14756758},
issn = {0960-7412},
mesh = {Base Sequence ; Brassica/genetics ; Chromosome Mapping/methods ; Chromosomes, Plant/*genetics ; Cytogenetic Analysis/methods ; DNA Fingerprinting/methods ; Endodeoxyribonucleases/metabolism ; In Situ Hybridization, Fluorescence ; Liliaceae/enzymology/*genetics ; Molecular Sequence Data ; Polymorphism, Restriction Fragment Length ; Repetitive Sequences, Nucleic Acid/*genetics ; Telomerase/*genetics/metabolism ; Telomere/enzymology/*genetics ; },
abstract = {Lack of Arabidopsis-type T3AG3 telomere sequences has recently been reported for the majority of investigated taxa of the monocot order Asparagales. In order to investigate this phenomenon in more detail, we conducted extensive cytogenetic and molecular analyses of the telomeres in Othocallis siberica, a member of this order. Terminal restriction fragment analysis together with Bal31 exonuclease assay showed that chromosome termini in O. siberica are formed by long stretches (more than 10 kbp) of vertebrate-type T2AG3 repeats. In addition, telomerase activity specifically synthesising (T2AG3)n sequence was detected in O. siberica protein extracts by telomerase repeat amplification protocol (TRAP). Fluorescence in situ hybridisation (FISH) revealed the presence of the vertebrate-type T2AG3 telomere sequences at all chromosome termini and at a few additional regions of O. siberica chromosomes, whereas Arabidopsis-type T3AG3 DNA and peptide nucleic acid (PNA) probes did not hybridise to chromosomes of Othocallis, except for polymorphic blocks in chromosomes 2 (interstitial) and 4 (terminal). These interstitial/terminal regions are apparently composed of large blocks of (T2AG3)n and (T3AG3)n DNA and represent a unique example of interspersion of two types of telomeric repeats within one genome. This may be a reflection of the recent evolutionary switch from Arabidopsis- to vertebrate-type telomeric repeats in this plant group.},
}
@article {pmid14751224,
year = {2004},
author = {Freulet-Marriere, MA and Potocki-Veronese, G and Deverre, JR and Sabatier, L},
title = {Rapid method for mean telomere length measurement directly from cell lysates.},
journal = {Biochemical and biophysical research communications},
volume = {314},
number = {4},
pages = {950-956},
doi = {10.1016/j.bbrc.2003.12.190},
pmid = {14751224},
issn = {0006-291X},
mesh = {Blotting, Southern ; Cell Line ; Humans ; Nucleic Acid Hybridization ; *Telomere ; },
abstract = {Telomere length is involved in cell survival, tumorigenesis, and early aging. We present here an innovative method to determine the mean telomere length without any DNA purification. Our strategy is to measure both the DNA concentration and the number of telomeric units (TTAGGG) directly from cell lysate produced by the combined action of NaOH (pH>13) and sonication directly on cell pellet. Telomere units are quantified using an enzyme hybridization assay on 96-well microtiter plates grafted with a captor sequence. A biotin-coupled-tracer oligonucleotide hybridizes with telomere fragments and the enzymatic reaction is performed with a streptavidin-acetylcholinesterase conjugate, using the colorimetric method of Ellman. OD measure is directly proportional to the number of telomere units in cell lysate. This scalable technique allows the determination of mean telomere length simultaneously in many samples. This assay will be highly efficient to screen new drugs involved in chemotherapy targeting telomerase or directly telomeres.},
}
@article {pmid14749296,
year = {2004},
author = {Jiang, L and Carter, DB and Xu, J and Yang, X and Prather, RS and Tian, XC},
title = {Telomere lengths in cloned transgenic pigs.},
journal = {Biology of reproduction},
volume = {70},
number = {6},
pages = {1589-1593},
doi = {10.1095/biolreprod.103.022616},
pmid = {14749296},
issn = {0006-3363},
support = {R01 RR13438/RR/NCRR NIH HHS/United States ; },
mesh = {Age Factors ; Animals ; Animals, Genetically Modified ; Animals, Newborn ; Cloning, Organism ; DNA/genetics ; Female ; Pregnancy ; Reproductive Techniques, Assisted ; Sus scrofa/*genetics ; Telomere/*genetics ; },
abstract = {Studies of cloned cattle and mice have resulted in controversies regarding the restoration of eroded telomere length of donor cells by the nuclear transfer process. Little is known about telomere lengths in pigs from either natural reproduction or nuclear transfer. In this study, we measured the telomere lengths in six major porcine organs from animals of different ages, and found that their lengths remained consistent throughout different tissues during fetal stages, and then shortened, in a tissue- specific manner, after birth. Telomeres of skin samples from six cloned transgenic pigs at 4 mo of age did not differ significantly from those of age-matched controls. Two cloned pigs that died shortly after birth had skin telomere lengths equivalent to those of late-stage fetuses.},
}
@article {pmid14745004,
year = {2004},
author = {Smolikov, S and Mazor, Y and Krauskopf, A},
title = {ELG1, a regulator of genome stability, has a role in telomere length regulation and in silencing.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {101},
number = {6},
pages = {1656-1661},
pmid = {14745004},
issn = {0027-8424},
mesh = {Base Sequence ; Carrier Proteins/genetics/*physiology ; DNA Primers ; *Gene Silencing ; Saccharomyces cerevisiae Proteins ; *Telomere ; },
abstract = {Telomeres, the natural ends of eukaryotic chromosomes, prevent the loss of chromosomal sequences and preclude their recognition as broken DNA. Telomere length is kept under strict boundaries by the action of various proteins, some with negative and others with positive effects on telomere length. Recently, data have been accumulating to support a role for DNA replication in the control of telomere length, although through a currently poorly understood mechanism. Elg1p, a replication factor C (RFC)-like protein of yeast, contributes to genome stability through a putative replication-associated function. Here, we show that Elg1p participates in negative control of telomere length and in telomeric silencing through a replication-mediated pathway. We show that the telomeric function of Elg1 is independent of recombination and completely dependent on an active telomerase. Additionally, this function depends on yKu and DNA polymerase. We discuss alternative models to explain how Elg1p affects telomere length.},
}
@article {pmid14744765,
year = {2004},
author = {Kondo, T and Oue, N and Yoshida, K and Mitani, Y and Naka, K and Nakayama, H and Yasui, W},
title = {Expression of POT1 is associated with tumor stage and telomere length in gastric carcinoma.},
journal = {Cancer research},
volume = {64},
number = {2},
pages = {523-529},
doi = {10.1158/0008-5472.can-03-1196},
pmid = {14744765},
issn = {0008-5472},
mesh = {3' Untranslated Regions/genetics ; Cell Line, Tumor ; DNA Primers ; Gene Expression Regulation, Neoplastic/*genetics ; Humans ; Neoplasm Staging ; Polymorphism, Restriction Fragment Length ; RNA, Messenger/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Shelterin Complex ; Stomach Neoplasms/*genetics ; Telomere/*genetics/*ultrastructure ; Telomere-Binding Proteins/*genetics ; },
abstract = {Pot1, a telomere end-binding protein in fission yeast and human, is proposed not only to cap telomeres but also to recruit telomerase to the ends of chromosomes. No study has been performed regarding Pot1 expression status in human cancers. Thus, we examined POT1 mRNA expression in 51 gastric cancer (GC) tissues and evaluated telomere length and 3' telomeric overhang signals in 20 of the 51 GC tissues. Quantitative reverse transcription-PCR analysis showed that POT1 expression levels in the tumor relative to those in nonneoplastic mucosa (T/N ratio) were significantly higher in stage III/IV tumors than in stage I/II tumors (P = 0.005). Down-regulation of POT1 (T/n < 0.5) was observed more frequently in stage I/II GC (52.4%, 11 of 21) than in stage III/IV GC (23.3%, 7 of 30; P = 0.033), whereas up-regulation of POT1 (T/n > 2.0) was observed more frequently in stage III/IV GC (33.3%, 10 of 30) than in stage I/II GC (9.5%, 2 of 21; P = 0.048). POT1 expression levels showed decreased in accordance with telomere shortening (r = 0.713, P = 0.002). In-gel hybridization analysis showed that 3' telomeric overhang signals decreased in accordance with decreases in POT1 expression levels (r = 0.696, P = 0.002) and telomere shortening (r = 0.570, P = 0.013). Reduced POT1 expression was observed in GC cell lines with telomeres shortened by treatment with azidothymidine. In addition, inhibition of Pot1 by antisense oligonucleotides led to telomere shortening as well as inhibition of telomerase activity in GC cells. Moreover, inhibition of Pot1 decreased 3' overhang signals and increased the frequency of anaphase bridge (P = 0.0005). These data suggest that Pot1 may play an important role in regulation of telomere length and that inhibition of Pot1 may induce telomere dysfunction. Moreover, changes in POT1 expression levels may be associated with stomach carcinogenesis and GC progression.},
}
@article {pmid14742705,
year = {2004},
author = {Lin, J and Smith, DL and Blackburn, EH},
title = {Mutant telomere sequences lead to impaired chromosome separation and a unique checkpoint response.},
journal = {Molecular biology of the cell},
volume = {15},
number = {4},
pages = {1623-1634},
pmid = {14742705},
issn = {1059-1524},
mesh = {Base Sequence ; Blotting, Southern ; Cell Division ; Chromosomes/ultrastructure ; Cloning, Molecular ; DNA Damage ; Fungal Proteins/*genetics/metabolism ; Gene Deletion ; Genotype ; Intracellular Signaling Peptides and Proteins ; Molecular Sequence Data ; Mutation ; Phenotype ; Plasmids/metabolism ; Protein Serine-Threonine Kinases ; RNA/chemistry ; Saccharomyces cerevisiae/*enzymology/genetics ; Saccharomyces cerevisiae Proteins ; Sister Chromatid Exchange ; Telomere/*ultrastructure ; Time Factors ; },
abstract = {Mutation of the template region in the RNA component of telomerase can cause incorporation of mutant DNA sequences at telomeres. We made all 63 mutant sequence combinations at template positions 474-476 of the yeast telomerase RNA, TLC1. Mutants contained faithfully incorporated template mutations, as well as misincorporated sequences in telomeres, a phenotype not previously reported for Saccharomyces cerevisiae telomerase template mutants. Although growth rates and telomere profiles varied widely among the tlc1 mutants, chromosome separation and segregation were always aberrant. The mutants showed defects in sister chromatid separation at centromeres as well as telomeres, suggesting activation of a cell cycle checkpoint. Deletion of the DNA damage response genes DDC1, MEC3, or DDC2/SML1 failed to restore chromosome separation in the tlc1 template mutants. These results suggest that mutant telomere sequences elicit a checkpoint that is genetically distinct from those activated by deletion of telomerase or DNA damage.},
}
@article {pmid14742666,
year = {2004},
author = {Hsu, CL and Chen, YS and Tsai, SY and Tu, PJ and Wang, MJ and Lin, JJ},
title = {Interaction of Saccharomyces Cdc13p with Pol1p, Imp4p, Sir4p and Zds2p is involved in telomere replication, telomere maintenance and cell growth control.},
journal = {Nucleic acids research},
volume = {32},
number = {2},
pages = {511-521},
pmid = {14742666},
issn = {1362-4962},
mesh = {Adaptor Proteins, Signal Transducing ; Cell Division ; DNA Polymerase I/*metabolism ; Genetic Complementation Test ; Protein Binding ; Ribosomal Proteins/*metabolism ; Saccharomyces cerevisiae/*cytology/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/genetics/*metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {Telomeres are the physical ends of eukaryotic chromosomes. They are important for maintaining the integrity of chromosomes and this function is mediated through a number of protein factors. In Saccharomyces cerevisiae, Cdc13p binds to telomeres and affects telomere maintenance, telomere position effects and cell cycle progression through G(2)/M phase. We identified four genes encoding Pol1p, Sir4p, Zds2p and Imp4p that interact with amino acids 1-252 of Cdc13p using a yeast two-hybrid screening system. Interactions of these four proteins with Cdc13p were through direct protein-protein interactions as judged by in vitro pull-down assays. Direct protein-protein interactions were also observed between Pol1p-Imp4p, Pol1p-Sir4p and Sir4p-Zds2p, whereas no interaction was detected between Imp4p-Sir4p and Zds2p-Imp4p, suggesting that protein interactions were specific in the complex. Pol1p was shown to interact with Cdc13p. Here we show that Zds2p and Imp4p also form a stable complex with Cdc13p in yeast cells, because Zds2p and Imp4p co-immunoprecipitate with Cdc13p, whereas Sir4p does not. The function of the N-terminal 1-252 region of Cdc13p was also analyzed. Expressing Cdc13(252-924)p, which lacks amino acids 1-252 of Cdc13p, causes defects in progressive cell growth and eventually arrested in the G(2)/M phase of the cell cycle. These growth defects were not caused by progressive shortening of telomeres because telomeres in these cells were long. Point mutants in the amino acids 1-252 region of Cdc13p that reduced the interaction between Cdc13p and its binding proteins resulted in varying level of defects in cell growth and telomeres. These results indicate that the interactions between Cdc13(1-252)p and its binding proteins are important for the function of Cdc13p in telomere regulation and cell growth. Together, our results provide evidence for the formation of a Cdc13p-mediated telosome complex through its N-terminal region that is involved in telomere maintenance, telomere length regulation and cell growth control.},
}
@article {pmid14734088,
year = {2003},
author = {Greenwood, MJ and Lansdorp, PM},
title = {Telomeres, telomerase, and hematopoietic stem cell biology.},
journal = {Archives of medical research},
volume = {34},
number = {6},
pages = {489-495},
doi = {10.1016/j.arcmed.2003.07.003},
pmid = {14734088},
issn = {0188-4409},
support = {AI29524/AI/NIAID NIH HHS/United States ; },
mesh = {Cell Lineage ; Hematologic Diseases/genetics/metabolism ; Hematopoiesis ; Hematopoietic Stem Cells/*physiology ; Humans ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are composed of the tandem DNA repeats and associated proteins that cap the end of linear chromosomes. They provide stability to the chromosome and protect against DNA loss associated with cellular replication. Telomeres are maintained by the reverse transcriptase, telomerase. The regulation of telomere length and telomerase activity is a complex and dynamic process that is tightly linked to cell cycle regulation. Hematopoietic stem cells have an impressive but finite proliferative potential and demonstrate telomeric shortening during replicative aging despite expression of low levels of telomerase. Recently, the important role of telomeres in human illness has been highlighted by studies of the rare genetic disorder dyskeratosis congenita. Here we review the role of telomeres and telomerase in the function and regulation of the hematopoietic stem cell compartment and their importance in hematologic disease.},
}
@article {pmid14732735,
year = {2004},
author = {Benetos, A and Gardner, JP and Zureik, M and Labat, C and Xiaobin, L and Adamopoulos, C and Temmar, M and Bean, KE and Thomas, F and Aviv, A},
title = {Short telomeres are associated with increased carotid atherosclerosis in hypertensive subjects.},
journal = {Hypertension (Dallas, Tex. : 1979)},
volume = {43},
number = {2},
pages = {182-185},
doi = {10.1161/01.HYP.0000113081.42868.f4},
pmid = {14732735},
issn = {1524-4563},
support = {HL-63351/HL/NHLBI NIH HHS/United States ; HL-7906/HL/NHLBI NIH HHS/United States ; },
mesh = {Carotid Artery Diseases/diagnostic imaging/*etiology/genetics ; Humans ; Hypertension/*complications ; Male ; Middle Aged ; Telomere/*chemistry ; Ultrasonography ; },
abstract = {Recent studies have shown that individuals with shorter telomeres present a higher prevalence of arterial lesions and higher risk of cardiovascular disease mortality. As a group, patients with high blood pressure are at an increased risk for cardiovascular diseases. However, some hypertensive patients are more prone than others to atherosclerotic lesions. The main objective of this study was to examine the relationship between telomere length, as expressed in white blood cells, and carotid artery atherosclerotic plaques in hypertensive males. Data from 163 treated hypertensive men who were volunteers for a free medical examination were analyzed. Extracranial carotid plaques were assessed with B-mode ultrasound. Telomere length was measured from DNA samples extracted from white blood cells. The results of this study show that telomere length was shorter in hypertensive men with carotid artery plaques versus hypertensive men without plaques (8.17+/-0.07 kb versus 8.46+/-0.07 kb; P<0.01). Multivariate analysis showed that in addition to age, telomere length was a significant predictor of the presence of carotid artery plaques. The findings from this study suggest that in the presence of chronic hypertension, which is a major risk factor for atherosclerotic lesions, shorter telomere length in white blood cells is associated with an increased predilection to carotid artery atherosclerosis.},
}
@article {pmid14731390,
year = {2004},
author = {Ferreira, MG and Miller, KM and Cooper, JP},
title = {Indecent exposure: when telomeres become uncapped.},
journal = {Molecular cell},
volume = {13},
number = {1},
pages = {7-18},
doi = {10.1016/s1097-2765(03)00531-8},
pmid = {14731390},
issn = {1097-2765},
mesh = {Animals ; Chromosome Aberrations ; DNA Damage ; Humans ; Models, Molecular ; Saccharomyces cerevisiae Proteins/metabolism ; Schizosaccharomyces pombe Proteins/metabolism ; Telomerase/metabolism ; Telomere/metabolism/*physiology ; },
abstract = {The protective "cap" that assembles at chromosome ends recruits and controls an intricate network of biochemical activities, each one critical for telomere structure and the maintenance of genomic stability. Recent studies have uncovered the components of telomere caps and have started to define the pathways that lead from telomere dysfunction to chromosomal catastrophe.},
}
@article {pmid14729022,
year = {2004},
author = {Stindl, R},
title = {Tying it all together: telomeres, sexual size dimorphism and the gender gap in life expectancy.},
journal = {Medical hypotheses},
volume = {62},
number = {1},
pages = {151-154},
doi = {10.1016/s0306-9877(03)00316-5},
pmid = {14729022},
issn = {0306-9877},
mesh = {Aging/physiology ; Body Constitution/*physiology ; Cellular Senescence/physiology ; Female ; Humans ; Life Expectancy/*trends ; Longevity/*physiology ; Male ; *Models, Biological ; Mortality/*trends ; Risk Factors ; Sex Distribution ; Sex Factors ; Survival Analysis ; Telomere/chemistry/*physiology/ultrastructure ; },
abstract = {The classic explanation that women outlive men solely due to hormonal and lifestyle differences, does not withstand a critical analysis. In developed countries, the average gap in life expectancy between the sexes is 7 years. It has widened over the last decades, despite the trend of women copying the 'unhealthy' lifestyle of men. Estrogen levels in postmenopausal women are virtually identical to estrogen levels in males and can hardly explain the discrepancy. Furthermore, testosterone got its bad reputation from one study on mentally retarded men, which has to be interpreted with caution. However, sexual size dimorphism with men being the larger sex in conjunction with the limited replication potential of human somatic cells might account for higher mortality rates in males, especially at old age. The hypothesis, as presented here, is based on the well-known concept of a cellular mitotic clock, which was discovered by Leonard Hayflick almost half a century ago. The underlying counting mechanism, namely the gradual erosion of chromosome ends (telomeres) due to the end replication problem of linear DNA molecules, was first described by Alexey Olovnikov in 1971 and with minor modifications has become a widely accepted paradigm. In a recent Lancet study, an inverse correlation between mean telomere length and mortality in people has been found. In this and two other studies, it was confirmed that males do have shorter telomeres than females at the same age. This is almost certainly a consequence of men being usually taller than women, although nobody has done an investigation yet. Clearly, a larger body requires more cell doublings, especially due to the ongoing regeneration of tissues over a lifetime. Accordingly, the replicative history of male cells might be longer than that of female cells, resulting in the exhaustion of the regeneration potential and the early onset of age-associated diseases predominantly in large-bodied males. Inherited telomere length variation between unrelated individuals might have obscured a clear correlation between body height and mortality, leading to conflicting results in some studies. Finally, I propose that the secular height increase over the last decades, of about 2.5 cm per generation in the western world, has to be blamed for the widening of the gender gap in life expectancy.},
}
@article {pmid14726417,
year = {2004},
author = {Ogami, M and Ikura, Y and Ohsawa, M and Matsuo, T and Kayo, S and Yoshimi, N and Hai, E and Shirai, N and Ehara, S and Komatsu, R and Naruko, T and Ueda, M},
title = {Telomere shortening in human coronary artery diseases.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {24},
number = {3},
pages = {546-550},
doi = {10.1161/01.ATV.0000117200.46938.e7},
pmid = {14726417},
issn = {1524-4636},
mesh = {Aged ; Cell Division ; Cells, Cultured/chemistry ; Cellular Senescence ; Coronary Artery Disease/*pathology ; Coronary Vessels/*pathology ; DNA/analysis ; Endothelial Cells/ultrastructure ; Endothelium, Vascular/*pathology ; Female ; Fibroblasts/chemistry ; Humans ; Male ; Middle Aged ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Increased cell turnover in response to injury is considered to be important in the development of atherosclerotic plaques. Telomere shortening has been shown to be associated with cell turnover. We assessed the telomere length of human coronary endothelial cells to clarify whether there is a relationship between telomere shortening and coronary artery disease (CAD).<br><br>METHODS AND RESULTS: Coronary endothelial cells were obtained from 11 patients with CAD who underwent autopsy and 22 patients without CAD who underwent autopsy by scraping off the luminal surface of coronary arteries. DNA extracted from the endothelial cells were blotted and hybridized with telomere-specific oligonucleotide ([TTAGGG]4). The hybridization signal intensity, which represented telomeric DNA content, was standardized with centromeric DNA content (T/C ratio) to estimate telomere length. The T/C ratios were significantly smaller (P<0.0001) in CAD patients than in age-matched non-CAD patients (CAD patients, 0.462+/-0.135; non-CAD patients, 1.002+/-0.212). In 6 individual CAD patients, the T/C ratio at the atherosclerotic lesion was significantly smaller (P<0.05) than that at the non-atherosclerotic portion.<br><br>CONCLUSIONS: These findings suggest that focal replicative senescence and telomere shortening of endothelial cells may play a critical role in coronary atherogenesis and CAD.},
}
@article {pmid14726371,
year = {2004},
author = {Gammaitoni, L and Weisel, KC and Gunetti, M and Wu, KD and Bruno, S and Pinelli, S and Bonati, A and Aglietta, M and Moore, MA and Piacibello, W},
title = {Elevated telomerase activity and minimal telomere loss in cord blood long-term cultures with extensive stem cell replication.},
journal = {Blood},
volume = {103},
number = {12},
pages = {4440-4448},
doi = {10.1182/blood-2003-09-3079},
pmid = {14726371},
issn = {0006-4971},
support = {HL 61401/HL/NHLBI NIH HHS/United States ; HL 66952/HL/NHLBI NIH HHS/United States ; P01 CA 59350/CA/NCI NIH HHS/United States ; U19 CA 67842/CA/NCI NIH HHS/United States ; },
mesh = {Adenoviridae/genetics ; Animals ; Antigens, CD/blood ; Antigens, CD34/blood ; Cell Division ; Fetal Blood/*cytology ; Genetic Vectors ; Hematopoietic Stem Cells/*cytology/*enzymology ; Humans ; Infant, Newborn ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Telomerase/*blood/deficiency/*metabolism ; Thrombopoietin/genetics ; Transfection ; },
abstract = {Telomerase activity, telomere length, stem/progenitor cell production, and function of CD34+ cells from cord blood (CB), bone marrow, and mobilized peripheral blood were evaluated in long-term cultures. CB cells were cultured either on OP-9 stromal cells transduced with an adenovector expressing thrombopoietin (TPO) or stimulated by a cytokine cocktail in the absence of stroma, with, in one method, CD34+ cells reisolated at monthly intervals for passage. Continuous expansion of stem cells as measured by in vitro cobblestone area and secondary colony-forming assays was noted for 18 to 20 weeks and by severe combined immunodeficiency (SCID)-repopulating cells (SRCs), capable of repopulating and serially passage in nonobese diabetic/SCID mice, for 16 weeks. Despite this extensive proliferation, telomere length initially increased and only at late stages of culture was evidence of telomere shortening noted. This telomere stabilization correlated with maintenance of high levels of telomerase activity in the CD34+ cell population for prolonged periods of culture. Cytokine-stimulated cultures of adult CD34+ cells showed CD34+ and SRC expansion (6-fold) for only 3 to 4 weeks with telomere shortening and low levels of telomerase. There is clearly a clinical value for a system that provides extensive stem cell expansion without concomitant telomere erosion.},
}
@article {pmid14722605,
year = {2004},
author = {Sharpless, NE and DePinho, RA},
title = {Telomeres, stem cells, senescence, and cancer.},
journal = {The Journal of clinical investigation},
volume = {113},
number = {2},
pages = {160-168},
pmid = {14722605},
issn = {0021-9738},
mesh = {Aging ; Animals ; *Apoptosis ; *Cellular Senescence ; Genes, Tumor Suppressor ; Humans ; Models, Biological ; Models, Genetic ; Mutation ; Neoplasms/*metabolism/*pathology ; Stem Cells/pathology ; Telomerase/metabolism ; Telomere/*ultrastructure ; },
abstract = {Mammalian aging occurs in part because of a decline in the restorative capacity of tissue stem cells. These self-renewing cells are rendered malignant by a small number of oncogenic mutations, and overlapping tumor suppressor mechanisms (e.g., p16(INK4a)-Rb, ARF-p53, and the telomere) have evolved to ward against this possibility. These beneficial antitumor pathways, however, appear also to limit the stem cell life span, thereby contributing to aging.},
}
@article {pmid14716292,
year = {2004},
author = {der-Sarkissian, H and Bacchetti, S and Cazes, L and Londoño-Vallejo, JA},
title = {The shortest telomeres drive karyotype evolution in transformed cells.},
journal = {Oncogene},
volume = {23},
number = {6},
pages = {1221-1228},
doi = {10.1038/sj.onc.1207152},
pmid = {14716292},
issn = {0950-9232},
mesh = {Cell Division ; Cell Line ; Cell Transformation, Neoplastic/*genetics ; *Chromosome Aberrations ; Clone Cells ; *Evolution, Molecular ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Neoplasms/*genetics ; Simian virus 40/genetics ; Telomere/*genetics ; },
abstract = {Maintenance of telomeres is essential for chromosome stability. In the absence of telomerase, telomeres shorten with cell division until they approach a stability threshold, at which point cells enter senescence. When senescence-signaling pathways are inactive, further telomere shortening leads to chromosome instability characterized by telomeric fusions and breakage-fusion-bridge (BFB) cycles. Since the distribution of telomere lengths among chromosome extremities is heterogeneous, we wondered about the impact of such variability on the stability of particular chromosome arms. We correlated the initial length of individual telomeres in telomerase-negative-transformed cells with the stability of the corresponding chromosome arms during the precrisis period. We show that arms carrying the shortest telomeres are the first to become unstable and this instability affects the chromosome homologues with shorter telomeres almost exclusively. The analysis of several postcrisis cell populations, which had stabilized their telomeres by re-expressing telomerase, showed that the karyotypic outcome is strongly influenced by the initial telomere length heterogeneity. The timing of telomerase re-expression also seems to play a role in limiting the extent of karyotypic changes, probably by reducing the frequency of telomeric fusions and hence BFB. Since the distribution of telomere lengths within somatic cells is proper to every individual, our results predict that the risk for a particular chromosome arm of becoming unstable early in tumorigenesis will differ between individuals and contribute directly to the heterogeneity of chromosome aberrations found in tumors.},
}
@article {pmid14712865,
year = {2003},
author = {Viera, A and Parra, MT and Page, J and Santos, JL and Rufas, JS and Suja, JA},
title = {Dynamic relocation of telomere complexes in mouse meiotic chromosomes.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {11},
number = {8},
pages = {797-807},
pmid = {14712865},
issn = {0967-3849},
mesh = {Animals ; Chromosomes, Mammalian/*physiology ; Colchicine/pharmacology ; Kinetochores/physiology ; Male ; *Meiosis ; Mice/*genetics ; Mice, Inbred C57BL ; Spermatocytes/cytology ; Synaptonemal Complex/physiology ; Telomere/*physiology ; },
abstract = {Telomeric DNA repeats as well as different specific proteins such as TRF1 and Rap1 associate in functional telomere complexes found at chromosome ends. Using spreading techniques, the presence of TRF1 and Rap1 has been reported at mammalian meiotic telomeres during prophase I. In the present study, we have analysed, by fluorescence in-situ hybridization and immunofluorescence, the appearance and location of telomere complexes during both male mouse meiotic divisions. Additionally, we have studied their relationship with different centromere/kinetochore proteins and the synaptonemal complex protein SCP3. Our results show that telomere complexes are not located at condensed meiotic chromosome tips. Therefore, a change in chromosome structure may occur from pachytene up to metaphase I involving the dynamic relocation of telomere complexes in condensed chromosomes. Moreover, we have found that proximal telomere complexes are relocated internally to kinetochores from metaphase I up to anaphase II. We discuss the functional significance of the location of telomere complexes into internal domains of condensed meiotic chromosomes.},
}
@article {pmid14709080,
year = {2004},
author = {Miyoshi, D and Matsumura, S and Nakano, S and Sugimoto, N},
title = {Duplex dissociation of telomere DNAs induced by molecular crowding.},
journal = {Journal of the American Chemical Society},
volume = {126},
number = {1},
pages = {165-169},
doi = {10.1021/ja036721q},
pmid = {14709080},
issn = {0002-7863},
mesh = {Calorimetry/methods ; Circular Dichroism ; DNA/*chemistry/genetics ; Models, Molecular ; Nucleic Acid Conformation ; Polymorphism, Genetic ; Telomere/*chemistry/genetics ; Thermodynamics ; },
abstract = {Because of the importance of telomere DNAs, the structures of these DNAs in vivo are currently of great research interest in the medical, pharmaceutical, chemical, and industrial fields. To understand the structure of biomolecules in vivo, their properties studied in vitro are extrapolated to the in vivo condition, while the condition in a living cell is inherently molecularly crowded and a nonideal solution contains various biomolecules. We investigated the effect of molecular crowding, which is one of the most important cellular environmental conditions, on the structure and stability of the telomere and G-rich and C-rich DNAs using circular dichroism (CD) spectra, CD melting curves, and isothermal titration calorimetry (ITC). The CD spectra and CD melting curves of G-rich DNA, C-rich DNA, and the 1:1 mixture of G-rich and C-rich DNAs showed that each G-rich DNA, C-rich DNA, and the 1:1 mixture form the antiparallel G-quadruplex, I-motif, and duplex, respectively, in the noncrowding condition as previously considered. On the contrary, the G-rich and C-rich DNAs individually form the parallel G-quadruplex and I-motif, respectively, in the molecular crowding condition, and the 1:1 mixture folds into the parallel G-quadruplex and I-motif but does not form a duplex. The ITC measurements indicated that the thermodynamic stability (DeltaG degrees (20)) of the duplex formation between the G-rich and C-rich DNAs in the noncrowding condition was -10.2 kcal mol(-)(1), while only a small heat change was observed in the ITC measurements in the molecular crowding condition. These ITC results also demonstrated that the molecular crowding condition prevents any duplex formation between G-rich and C-rich DNAs. These results indicate that a structural polymorphism of the telomere DNAs is induced by molecular crowding in vivo.},
}
@article {pmid14707289,
year = {2003},
author = {Bai, Y and Murnane, JP},
title = {Telomere instability in a human tumor cell line expressing NBS1 with mutations at sites phosphorylated by ATM.},
journal = {Molecular cancer research : MCR},
volume = {1},
number = {14},
pages = {1058-1069},
pmid = {14707289},
issn = {1541-7786},
mesh = {Ataxia Telangiectasia ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle ; Cell Cycle Proteins/*genetics/metabolism ; Cell Survival/radiation effects ; *Chromosomal Instability ; DNA/metabolism/radiation effects ; DNA-Binding Proteins ; Humans ; *Mutation ; Nuclear Proteins/*genetics/metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases/*metabolism ; Radiation, Ionizing ; Recombination, Genetic ; Telomerase/metabolism ; *Telomere ; Tumor Cells, Cultured ; Tumor Suppressor Proteins ; },
abstract = {Nijmegen breakage syndrome (NBS) is an autosomal genetic disease demonstrating a variety of phenotypic abnormalities, including premature aging, increased cancer incidence, chromosome instability, and sensitivity to ionizing radiation. The gene involved in NBS, NBS1, is part of the MRE11/RAD50/NBS1 (MRN) complex that also includes MRE11 and RAD50, which is involved in DNA repair and cell cycle regulation in response to DNA damage. The MRN complex is also involved in telomere maintenance, as demonstrated by the shortened telomeres in NBS primary human fibroblasts and the association of NBS1 with the telomere-binding protein TRF2. To learn more about how a deficiency in telomere maintenance might contribute to chromosome instability in NBS, we have investigated the stability of telomeres in two telomerase-positive human tumor cell clones, BNmt-On and BNmt-Off, expressing an inducible NBS1(S278A/S343A) gene containing mutations at serines 278 and 343 phosphorylated by ATM. The results demonstrate an increased rate of telomere loss in both clones following expression of NBS1(S278A/S343A). The absence of detectable changes in average telomere length suggests that NBS1-associated telomere loss results from stochastic events involving complete telomere loss or loss of telomere capping function. The recombination events associated with telomere loss were found to be similar to those shown previously to result in breakage/fusion/bridge cycles, suggesting that telomere loss can contribute to chromosome instability in NBS1-deficient cells. Telomere loss showed no correlation with radiosensitivity or radioresistant DNA synthesis, demonstrating that NBS1(S278A/S343A) promotes telomere loss through a separate pathway from these other phenotypes associated with NBS.},
}
@article {pmid14706647,
year = {2004},
author = {Urushibara, A and Kodama, S and Suzuki, K and Desa, MB and Suzuki, F and Tsutsui, T and Watanabe, M},
title = {Involvement of telomere dysfunction in the induction of genomic instability by radiation in scid mouse cells.},
journal = {Biochemical and biophysical research communications},
volume = {313},
number = {4},
pages = {1037-1043},
doi = {10.1016/j.bbrc.2003.12.039},
pmid = {14706647},
issn = {0006-291X},
mesh = {Animals ; Cell Line ; Chromosomal Instability/radiation effects ; Chromosome Aberrations ; DNA Damage ; DNA-Activated Protein Kinase ; *DNA-Binding Proteins ; Dose-Response Relationship, Radiation ; Genomic Instability/*radiation effects ; In Situ Hybridization, Fluorescence ; Mice ; Mice, SCID ; Protein Serine-Threonine Kinases/metabolism ; Radiation Tolerance/genetics ; Telomere/genetics/pathology/*radiation effects ; },
abstract = {To determine the effects of a defect in NHEJ on the induction of genomic instability by radiation, we investigated X-ray-induced delayed chromosomal aberrations such as dicentrics and fragments in scid mouse cells. We found that radiosensitive scid mouse cells are more susceptible than wild-type mouse cells to the induction of delayed chromosomal aberrations when the cells are exposed to an equivalent survival dose of X-rays. Telomere FISH analysis revealed that radiation enhances the induction of telomeric fusions where telomeric sequences remain at the fused position (tel+ end-fusions), suggesting that radiation induces telomere dysfunction. Moreover, formation of the tel+ end-fusions was found to be enhanced in scid mouse cells, suggesting that DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a role in telomeric stabilization. Thus, the present study suggests that a cause of genomic instability is telomere dysfunction induced by radiation and that a defect in DNA-PKcs enhances the telomeric destabilization.},
}
@article {pmid14704659,
year = {2004},
author = {Lewis, NL and Mullaney, M and Mangan, KF and Klumpp, T and Rogatko, A and Broccoli, D},
title = {Measurable immune dysfunction and telomere attrition in long-term allogeneic transplant recipients.},
journal = {Bone marrow transplantation},
volume = {33},
number = {1},
pages = {71-78},
doi = {10.1038/sj.bmt.1704300},
pmid = {14704659},
issn = {0268-3369},
support = {K12 CA01728/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Bone Marrow Transplantation/*standards ; Cell Differentiation/drug effects ; Cellular Senescence ; Cytokines/pharmacology ; Female ; Hematopoiesis ; Humans ; Immune System/cytology/*physiopathology ; Leukocytes, Mononuclear/immunology/physiology ; Lymphocyte Activation/drug effects ; Male ; Middle Aged ; Myeloid Cells/cytology ; Myeloid Progenitor Cells ; Myelopoiesis ; Peripheral Blood Stem Cell Transplantation/*standards ; Phytohemagglutinins/pharmacology ; Survivors ; Telomere/*immunology/ultrastructure ; Transplantation, Homologous ; },
abstract = {This study was conducted to determine if the accelerated telomere attrition that occurs as a consequence of allogeneic stem cell transplantation leads to measurable functional defects. Telomere lengths in mononuclear leukocytes obtained from 15 long-term allogeneic stem cell transplant recipients and their respective donors were determined by Southern hybridization and densitometric analysis. Functional assays evaluated the ability of these cells to proliferate in response to a mitogenic stimulus and to differentiate under appropriate cytokine stimulation. Lymphocyte proliferation in response to phytohemagglutinin was determined by measurement of (3)[H]thymidine uptake. The ability of circulating myeloid cells to differentiate was determined after incubation of peripheral blood mononuclear cells with IL-3 and GM-CSF. A total of 13 patients demonstrated telomeric loss, ranging from 0.1 to 3.7 kbp. Strikingly, lymphocytes from 14 of the 15 patients demonstrated a significant decrease in proliferation when compared to their respective donors (68%+/-22, P=0.001). All patients demonstrated at least a 50% decrease in the number of myeloid colony-forming units when compared to their respective donors (P<0.0001). A decreased ability of hematopoietic cells to proliferate and differentiate is phenotypically consistent with an aged immune system. This may correlate with diminished clinically relevant immune responses to infection or vaccination, as seen in the elderly.},
}
@article {pmid14702045,
year = {2004},
author = {García-Cao, M and O'Sullivan, R and Peters, AH and Jenuwein, T and Blasco, MA},
title = {Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases.},
journal = {Nature genetics},
volume = {36},
number = {1},
pages = {94-99},
doi = {10.1038/ng1278},
pmid = {14702045},
issn = {1061-4036},
mesh = {Animals ; Histone Methyltransferases ; *Histone-Lysine N-Methyltransferase ; Methylation ; Methyltransferases/*physiology ; Mice ; Mice, Mutant Strains ; Models, Genetic ; Protein Methyltransferases ; Repressor Proteins/*physiology ; Telomere/metabolism/*physiology ; },
abstract = {Telomeres are capping structures at the ends of eukaryotic chromosomes composed of TTAGGG repeats bound to an array of specialized proteins. Telomeres are heterochromatic regions. Yeast and flies with defects in activities that modify the state of chromatin also have abnormal telomere function, but the putative role of chromatin-modifying activities in regulating telomeres in mammals is unknown. Here we report on telomere length and function in mice null with respect to both the histone methyltransferases (HMTases) Suv39h1 and Suv39h2 (called SUV39DN mice). Suv39h1 and Suv39h2 govern methylation of histone H3 Lys9 (H3-Lys9) in heterochromatic regions. We show that primary cells derived from SUV39DN mice have abnormally long telomeres relative to wild-type controls. Using chromatin immunoprecipitation (ChIP) analysis, we found that telomeres were enriched in di- and trimethylated H3-Lys9 but that telomeres of SUV39DN cells had less dimethylated and trimethylated H3-Lys9 but more monomethylated H3-Lys9. Concomitant with the decrease in H3-Lys9 methylation, telomeres in SUV39DN cells had reduced binding of the chromobox proteins Cbx1, Cbx3 and Cbx5, homologs of Drosophila melanogaster heterochromatin protein 1 (HP1). These findings indicate substantial changes in the state of telomeric heterochromatin in SUV39DN cells, which are associated with abnormal telomere elongation. Taken together, the results indicate epigenetic regulation of telomere length in mammals by Suv39h1 and Suv39h2.},
}
@article {pmid14701754,
year = {2004},
author = {Enomoto, S and Glowczewski, L and Lew-Smith, J and Berman, JG},
title = {Telomere cap components influence the rate of senescence in telomerase-deficient yeast cells.},
journal = {Molecular and cellular biology},
volume = {24},
number = {2},
pages = {837-845},
pmid = {14701754},
issn = {0270-7306},
support = {F32 GM063352/GM/NIGMS NIH HHS/United States ; F32 GM 63352/GM/NIGMS NIH HHS/United States ; GM 38626/GM/NIGMS NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing ; Base Sequence ; Cell Cycle ; Cell Cycle Proteins/genetics/metabolism ; Cell Division ; Codon, Nonsense/genetics ; DNA, Fungal/genetics ; DNA-Binding Proteins/genetics/metabolism ; *Fungal Proteins ; Genes, Fungal ; Models, Biological ; Mutation ; Proteins/genetics/metabolism ; RNA Helicases/genetics/metabolism ; RNA, Fungal/genetics/metabolism ; RNA, Messenger/genetics/metabolism ; RNA-Binding Proteins/genetics/metabolism ; Rad52 DNA Repair and Recombination Protein ; Saccharomyces cerevisiae/*cytology/*enzymology/genetics ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomerase/chemistry/genetics/*metabolism ; Telomere/genetics/*metabolism/ultrastructure ; Telomere-Binding Proteins/genetics/metabolism ; Trans-Activators/genetics/metabolism ; },
abstract = {Cells lacking telomerase undergo senescence, a progressive reduction in cell division that involves a cell cycle delay and culminates in "crisis," a period when most cells become inviable. In telomerase-deficient Saccharomyces cerevisiae cells lacking components of the nonsense-mediated mRNA decay (NMD) pathway (Upf1,Upf2, or Upf3 proteins), senescence is delayed, with crisis occurring approximately 10 to 25 population doublings later than in Upf+ cells. Delayed senescence is seen in upfDelta cells lacking the telomerase holoenzyme components Est2p and TLC1 RNA, as well as in cells lacking the telomerase regulators Est1p and Est3p. The delay of senescence in upfDelta cells is not due to an increased rate of survivor formation. Rather, it is caused by alterations in the telomere cap, composed of Cdc13p, Stn1p, and Ten1p. In upfDelta mutants, STN1 and TEN1 levels are increased. Increasing the levels of Stn1p and Ten1p in Upf+ cells is sufficient to delay senescence. In addition, cdc13-2 mutants exhibit delayed senescence rates similar to those of upfDelta cells. Thus, changes in the telomere cap structure are sufficient to affect the rate of senescence in the absence of telomerase. Furthermore, the NMD pathway affects the rate of senescence in telomerase-deficient cells by altering the stoichiometry of telomere cap components.},
}
@article {pmid14690602,
year = {2003},
author = {Zhu, XD and Niedernhofer, L and Kuster, B and Mann, M and Hoeijmakers, JH and de Lange, T},
title = {ERCC1/XPF removes the 3' overhang from uncapped telomeres and represses formation of telomeric DNA-containing double minute chromosomes.},
journal = {Molecular cell},
volume = {12},
number = {6},
pages = {1489-1498},
doi = {10.1016/s1097-2765(03)00478-7},
pmid = {14690602},
issn = {1097-2765},
support = {AG16642/AG/NIA NIH HHS/United States ; AG17242/AG/NIA NIH HHS/United States ; GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cells, Cultured ; Chromosome Aberrations ; Chromosomes, Human/genetics/*metabolism ; DNA Repair ; DNA-Binding Proteins/genetics/*metabolism ; Endonucleases/genetics/*metabolism ; Fibroblasts/cytology/physiology ; Humans ; Mice ; Mice, Knockout ; Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Human telomeres are protected by TRF2. Inhibition of this telomeric protein results in partial loss of the telomeric 3' overhang and chromosome end fusions formed through nonhomologous end-joining (NHEJ). Here we report that ERCC1/XPF-deficient cells retained the telomeric overhang after TRF2 inhibition, identifying this nucleotide excision repair endonuclease as the culprit in overhang removal. Furthermore, these cells did not accumulate telomere fusions, suggesting that overhang processing is a prerequisite for NHEJ of telomeres. ERCC1/XPF was also identified as a component of the telomeric TRF2 complex. ERCC1/XPF-deficient mouse cells had a novel telomere phenotype, characterized by Telomeric DNA-containing Double Minute chromosomes (TDMs). We speculate that TDMs are formed through the recombination of telomeres with interstitial telomere-related sequences and that ERCC1/XPF functions to repress this process. Collectively, these data reveal an unanticipated involvement of the ERCC1/XPF NER endonuclease in the regulation of telomere integrity and establish that TRF2 prevents NHEJ at telomeres through protection of the telomeric overhang from ERCC1/XPF.},
}
@article {pmid14688476,
year = {2003},
author = {Hauguel, T and Bunz, F},
title = {Haploinsufficiency of hTERT leads to telomere dysfunction and radiosensitivity in human cancer cells.},
journal = {Cancer biology &amp; therapy},
volume = {2},
number = {6},
pages = {679-684},
pmid = {14688476},
issn = {1538-4047},
mesh = {Alleles ; Cell Division/genetics ; Cell Survival/genetics ; Cellular Senescence/genetics ; Chromosomes, Human, Pair 7 ; Clone Cells ; DNA Damage ; DNA-Binding Proteins ; Dose-Response Relationship, Radiation ; Enzyme Activation ; Gene Targeting ; HCT116 Cells ; Humans ; Immunohistochemistry ; Neoplasms/enzymology/*genetics/*pathology ; *Radiation Tolerance ; Radiation, Ionizing ; Recombination, Genetic ; Telomerase/*genetics/physiology ; Telomere/*physiology ; },
abstract = {One of the most consistent differences between cancer cells and normal somatic cells is the continuous expression of telomerase, an enzyme that is important for maintenance of chromosome ends, or telomeres. It is believed that telomerase expression allows cancer cells to maintain their telomeres after many cell divisions and thereby avoid replicative senescence. We have tested this hypothesis by targeting the gene encoding the catalytic subunit of the telomerase holoenzyme, hTERT, in a human cancer cell line. Heterozygous disruption of hTERT led to a reduction in telomerase activity, telomere shortening, activation of DNA damage signaling and the appearance of a subpopulation of cells that displayed features of senescence. Targeted cells were radiosensitive, as compared with parental controls that had two intact hTERT alleles, and expressed a classical marker of senescence after irradiation. These results suggest that telomerase inhibitors might be useful in the sensitization of cancer cells to DNA damaging agents.},
}
@article {pmid14688198,
year = {2004},
author = {Poch, E and Carbonell, P and Franco, S and Díez-Juan, A and Blasco, MA and Andrés, V},
title = {Short telomeres protect from diet-induced atherosclerosis in apolipoprotein E-null mice.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {18},
number = {2},
pages = {418-420},
doi = {10.1096/fj.03-0710fje},
pmid = {14688198},
issn = {1530-6860},
mesh = {Animals ; Apolipoproteins E/*deficiency/genetics ; Arteriosclerosis/*chemically induced/*genetics/metabolism/pathology ; Cell Division ; Cholesterol, Dietary/*pharmacology ; *Diet ; Female ; *Gene Deletion ; Leukocytes/cytology/enzymology/metabolism ; Male ; Mice ; Mice, Knockout ; RNA/genetics ; Sex Characteristics ; Telomerase/deficiency/genetics ; Telomere/*metabolism ; },
abstract = {By imposing a replicative defect in most somatic cells, gradual telomere attrition during aging is thought to progressively impair cellular function and viability and may contribute to age-related disease. Immune cells play important roles in all phases of atherosclerosis, a multifactorial disease that prevails within the elderly. Because shorter telomeres have been found in circulating blood leukocytes of human patients with advanced coronary atherosclerosis, it has been suggested that telomere shortening may predispose the organism to atheroma development. In this study, we assessed the impact of telomere attrition on atherogenesis induced by dietary cholesterol in apolipoprotein E (apoE)-deficient mice, a well-established model of experimental atherosclerosis that recapitulates important aspects of the human disease. Our study shows that late-generation mice doubly deficient in apoE and telomerase RNA experience telomere attrition and a substantial reduction of atherosclerosis compared with control mice with intact telomerase, in spite of sustained hypercholesterolemia in response to the atherogenic diet. Short telomeres impaired the proliferation of both lymphocytes and macrophages, an important step in atherosclerosis development. Therefore, telomere exhaustion resulting in replicative immunosenescence may serve as a mechanism for restricting atheroma progression.},
}
@article {pmid14687824,
year = {2003},
author = {Cottliar, A and Palumbo, M and La Motta, G and de Barrio, S and Crivelli, A and Viola, M and Gómez, JC and Slavutsky, I},
title = {Telomere length study in celiac disease.},
journal = {The American journal of gastroenterology},
volume = {98},
number = {12},
pages = {2727-2731},
doi = {10.1111/j.1572-0241.2003.08720.x},
pmid = {14687824},
issn = {0002-9270},
mesh = {Adult ; Aged ; Case-Control Studies ; Celiac Disease/genetics/*pathology ; Chromosome Aberrations ; Female ; Humans ; Intestine, Small/pathology ; Lymphocytes ; Male ; Middle Aged ; Telomere/genetics/*ultrastructure ; },
abstract = {OBJECTIVES: Telomeres are important structures that are critical for maintaining chromosomal integrity and cell surveillance. The aim of this study was to analyze telomere length in patients with celiac disease (CD), a multifactorial disorder with a strong genetic component that exhibits genomic instability and cancer predisposition, particularly T-cell lymphomas.<br><br>METHODS: Telomere length measured by telomere restriction fragments (TRF) was studied in small intestinal biopsy (SIB) samples and peripheral blood lymphocytes (PBL) from 20 untreated CD patients, distributed according to the clinical form as four asymptomatic, five monosymptomatic, and 11 polysymptomatic individuals. We also analyzed TRF from normal peripheral blood lymphocytes and normal biopsy samples as normal controls.<br><br>RESULTS: TRF evaluation showed a significant telomere shortening in SIB samples from CD patients (4.21 +/- 0.29 Kb) compared to PBL from the same individuals (9.17 +/- 0.35 Kb) (p < 0.0001), independently of clinical form. Mean TRF peak values from normal biopsy samples were significantly higher (8.33 +/- 0.38 Kb) than those observed in CD biopsy samples (p < 0.001). No differences between TRF values in CD-PBL and normal peripheral blood lymphocytes (8.89 +/- 0.37Kb) were found.<br><br>CONCLUSIONS: Our findings in patients with CD, a disorder in which the gluten-induced mucosal injury could accelerate telomere shortening, would increase the process of end-to-end fusions resulting in chromosomal changes, supports the hypothesis that genomic instability and telomere reduction may play a role in the cancer predisposition observed in these patients.},
}
@article {pmid14685090,
year = {2004},
author = {Meeker, AK and De Marzo, AM},
title = {Recent advances in telomere biology: implications for human cancer.},
journal = {Current opinion in oncology},
volume = {16},
number = {1},
pages = {32-38},
doi = {10.1097/00001622-200401000-00007},
pmid = {14685090},
issn = {1040-8746},
support = {K08CA787588/CA/NCI NIH HHS/United States ; P50CA58236/CA/NCI NIH HHS/United States ; R01DK07552/DK/NIDDK NIH HHS/United States ; },
mesh = {*Chromosomal Instability ; Humans ; Neoplasms/*genetics/*physiopathology/therapy ; Telomerase/pharmacology ; Telomere/*physiology ; },
abstract = {PURPOSE OF REVIEW: Research into the basic biology of telomeres continues to reveal details relevant to fundamental aspects of human cancer. The goal of this review is to highlight discoveries made within the last year, with emphasis on their relevance to cancer prevention, diagnosis, prognostics, and treatment.<br><br>RECENT FINDINGS: Increasing evidence indicates that dysfunctional telomeres likely play a causal role in the process of malignant transformation, in at least a fraction of human cancers, by initiating chromosomal instability. Telomeres form protective capping structures composed of telomeric DNA complexed with a multitude of associated proteins, the loss of which can have profound effects on telomeric stability. Critical telomeric shortening can lead to telomere "uncapping" and may occur at the earliest recognizable stages of malignant transformation in epithelial tissues. The widespread activation of the telomere synthesizing enzyme telomerase in human cancers not only confers unlimited replicative potential but also prevents intolerable levels of chromosomal instability. Several details regarding telomere structure and telomerase regulation have recently been elucidated, providing new targets for therapeutic exploitation. Various therapeutic strategies aimed at either telomerase or its telomeric substrate are showing promise and may synergize with established anti-cancer agents. Further support for anti-telomerase approaches comes from recent studies indicating that telomerase may possess additional functions, beyond telomere maintenance, that support the growth and survival of tumor cells.<br><br>SUMMARY: Substantial progress has been made in understanding the complex relationships that exist between telomeres and cancer. However, important issues, such as transient activation of telomerase in normal cells and the potential for tumor cell immortalization via telomerase independent means, remain to be clarified.},
}
@article {pmid14681297,
year = {2004},
author = {Okabe, J and Eguchi, A and Wadhwa, R and Rakwal, R and Tsukinoki, R and Hayakawa, T and Nakanishi, M},
title = {Limited capacity of the nuclear matrix to bind telomere repeat binding factor TRF1 may restrict the proliferation of mortal human fibroblasts.},
journal = {Human molecular genetics},
volume = {13},
number = {3},
pages = {285-293},
doi = {10.1093/hmg/ddh032},
pmid = {14681297},
issn = {0964-6906},
mesh = {Cell Division/physiology ; Fibroblasts/cytology/*metabolism ; Humans ; Nuclear Matrix/*metabolism ; Telomere/metabolism ; Telomeric Repeat Binding Protein 1/*metabolism ; Up-Regulation ; },
abstract = {The maintenance of telomere integrity is essential for prolonged cell proliferation, and failure in this mechanism is a most consistent manifestation of cellular senescence. In this study, we investigated the role of telomere repeat binding factor (TRF1) in the proliferation of human fibroblasts. TRF1 expression is upregulated in a large variety of immortal human cells and supports de novo telomere formation in a dose-dependent manner. These observations suggest that the suppression of TRF1 might limit telomere maintenance and thus the life span of mortal cells. However, primary fibroblasts ectopically overexpressing TRF1 were unable to avoid senescence. On the other hand, exogenously expressed TRF1 in primary fibroblasts neither supported de novo telomere formation nor bound to the nuclear matrix as tightly as observed in immortal cells that show upregulated TRF1 expression. We present evidence suggesting that mortal human cells lack specific ligand(s) that anchor TRF1 to the nuclear matrix and that this contributes to their limited lifespan.},
}
@article {pmid14680393,
year = {2004},
author = {Slijepcevic, P},
title = {Is there a link between telomere maintenance and radiosensitivity?.},
journal = {Radiation research},
volume = {161},
number = {1},
pages = {82-86},
doi = {10.1667/rr3093},
pmid = {14680393},
issn = {0033-7587},
mesh = {Animals ; Chromosome Aberrations ; Chromosomes/physiology/radiation effects ; Gene Expression Regulation/*genetics/*radiation effects ; Humans ; Mice ; *Phenotype ; Radiation Tolerance/*genetics/physiology ; Telomere/*genetics/physiology/*radiation effects ; },
abstract = {Several recent studies point to the possibility that telomere maintenance may constitute a potential genetic marker of radiosensitivity. For example, the human diseases ataxia telangiectasia and Nijmegen breakage syndrome, which are characterized by clinical radiosensitivity, show alterations in telomere maintenance. In addition, Fanconi's anemia patients, who are characterized by mild cellular radiosensitivity and in some cases marked clinical radiosensitivity, have altered telomere maintenance. Similarly, a correlation between telomere maintenance and cellular radiosensitivity was reported in a group of breast cancer patients. Another study demonstrated that radiosensitivity may be more pronounced in human fibroblasts with short telomeres than in their counterparts with long telomeres. Several mouse models including mice deficient in Ku, DNA-PKcs (Prkdc), Parp and Atm, all of which are radiosensitive in vivo, show clear telomere alterations. The link between telomere maintenance and radiosensitivity is also apparent in mice genetically engineered to have dysfunctional telomeres. Finally, studies using non-mammalian model systems such as C. elegans and yeast point to the link between radiosensitivity and telomere maintenance. These results warrant further investigation to identify the extent to which these two phenotypes, namely radiosensitivity and telomere maintenance, are linked.},
}
@article {pmid14680225,
year = {2003},
author = {Lu, J and Lau, C and Kai, M},
title = {Magnetic bead-based label-free chemiluminescence detection of telomeres.},
journal = {Chemical communications (Cambridge, England)},
volume = {},
number = {23},
pages = {2888-2889},
doi = {10.1039/b306895a},
pmid = {14680225},
issn = {1359-7345},
mesh = {Base Sequence ; Glyoxal/chemistry ; Guanine/chemistry ; Kinetics ; Luminescent Measurements ; *Magnetics ; Microspheres ; Molecular Structure ; Telomere/*chemistry/*metabolism ; },
abstract = {For the first time we report on the detection of telomeres by coupling of the label-free guanine CL detection route with an efficient magnetic isolation of the hybrid.},
}
@article {pmid14678974,
year = {2003},
author = {Qi, L and Strong, MA and Karim, BO and Armanios, M and Huso, DL and Greider, CW},
title = {Short telomeres and ataxia-telangiectasia mutated deficiency cooperatively increase telomere dysfunction and suppress tumorigenesis.},
journal = {Cancer research},
volume = {63},
number = {23},
pages = {8188-8196},
pmid = {14678974},
issn = {0008-5472},
support = {CA16519/CA/NCI NIH HHS/United States ; RR00171/RR/NCRR NIH HHS/United States ; RR07002/RR/NCRR NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins ; Cell Death/genetics ; Cell Transformation, Neoplastic ; Chromosomal Instability/genetics ; Crosses, Genetic ; DNA-Binding Proteins ; Female ; Lymphoma, T-Cell/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Protein Serine-Threonine Kinases/*deficiency/genetics ; T-Lymphocytes/physiology ; Telomerase/deficiency ; Telomere/genetics/*physiology ; Tumor Suppressor Proteins ; },
abstract = {To examine the role of ataxia-telangiectasia mutated (Atm) in telomere function, we generated Atm and telomerase null mice (Atm(-/-) mTR(-/-) iG6 mice). These mice exhibited increased germ cell death and chromosome fusions compared with either Atm(-/-) or mTR(-/-) iG6 mice. Furthermore, the Atm(-/-) mTR(--) iG6 mice had a delayed onset and reduced incidence of thymic lymphoma compared with Atm(-/-) mice. The tumors in the Atm(-/-) mTR(-/-) iG6 mice showed increased apoptosis and anaphase bridges. Finally, lymphomas from Atm(-/-) mTR(-/-) iG6 mice were derived from CD8 immature, single-positive T cells, whereas Atm(-/-) lymphomas were from CD4(+)CD8(+) double-positive T cells. We propose that Atm protects short telomeres and that Atm deficiency cooperates with short telomeres, leading to increased cell death, decreased tumorigenesis, and increased overall survival.},
}
@article {pmid14673642,
year = {2004},
author = {Sawa, Y and Yamaoka, Y and Kuroshima, S and Yoshida, S},
title = {Reduction of alkaline phosphatase activity in aged human osteogenic periodontal ligament fibroblasts exhibiting short telomeres.},
journal = {Cell and tissue research},
volume = {315},
number = {3},
pages = {331-337},
doi = {10.1007/s00441-003-0837-7},
pmid = {14673642},
issn = {0302-766X},
mesh = {Adult ; *Aging ; Alkaline Phosphatase/*metabolism ; Cells, Cultured ; Child ; DNA/analysis ; Fibroblasts/cytology/*enzymology ; Histocytochemistry ; Humans ; Middle Aged ; Osteocalcin/metabolism ; Osteopontin ; Periodontal Ligament/cytology/*enzymology ; Sialoglycoproteins/metabolism ; *Telomere/chemistry ; },
abstract = {The osteogenic cell type of human periodontal ligament fibroblasts (PDLF) undergoes senescence at finite population doubling numbers unrelated to donor ages. This study investigated telomere lengths of osteogenic PDLF from differently aged donors and alterations of the osteoblast-like properties in the aged PDLF with short telomeres. Telomere lengths of osteogenic PDLF were biased towards long or short among all 15- to 51-year-old individuals, and did not show a normal distribution by Pearson's test or a correlation to donor age by simple regression analysis. In osteogenic PDLF, senescence-associated beta-galactosidase was expressed in 78.5% of cells in the clones with short telomeres (mean 3.02 kbp), and in 9.4% of cells in the clones with long telomeres (mean 13.06 kbp). These results suggest that human periodontium comprises aged osteogenic PDLF without correlation to age. Osteogenic PDLF with long telomeres strongly expressed alkaline phosphatase (ALPase) activity whereas cells with short telomeres expressed ALPase activity to a weaker extent. Total activity of ALPase in the clones of osteogenic PDLF with long telomeres was significantly higher than that in the clones with short telomeres. The produced amounts of both osteopontin and osteocalcin in the clones of osteogenic PDLF with long telomeres were slightly but statistically significantly smaller than those in the clones with short telomeres. These findings suggest that aged osteogenic PDLF reduce the expression of ALPase activity but that there is not a critical alteration in bone-associated protein production. Aged osteogenic PDLF may impair the ability to induce ALPase-dependent calcification.},
}
@article {pmid14673504,
year = {2003},
author = {Liu, Q and Wang, H and Hu, DC and Ding, CJ and Xiao, H and Xu, HB and Shu, BH and Xu, SQ},
title = {[Effects of sodium selenite on telomerase activity and telomere length].},
journal = {Sheng wu hua xue yu sheng wu wu li xue bao Acta biochimica et biophysica Sinica},
volume = {35},
number = {12},
pages = {1117-1122},
pmid = {14673504},
issn = {0582-9879},
mesh = {Cell Line ; DNA-Binding Proteins ; Dose-Response Relationship, Drug ; Gene Expression Regulation, Enzymologic/drug effects ; Hepatocytes/drug effects/enzymology/metabolism ; RNA, Messenger/drug effects/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Sodium Selenite/*pharmacology ; Telomerase/*genetics/metabolism ; },
abstract = {To study the biological basis of selenium in resisting senescence through its effects on cellular telomerase activity and telomere length. In the experiments, the cell line of hepatocytes L-02 was divided into three groups supplemented with sodium selenite at final concentrations of 0, 0.5 and 2.5 micromol/L, respectively. Cellular telomerase activity was measured by telomeric repeat amplification protocol and enzymatic luminometric inorganic pyrophosphate detection assay. RT-PCR was used to semi-quantitatively detect human telomerase reverse transcriptase (hTERT) gene expression. The change of telomere length was assayed through flow cytometry and fluorescence in situ hybridization. Results showed that L-02 cells had low telomerase activity and hTERT gene expression level when cultured in the normal way. The cells grew well after 3-week-cultivation in the media supplemented with 0.5 or 2.5 micromol/L sodium selenite. Besides, sodium selenite significantly increased cellular telomerase activity and hTERT gene expression level. The telomere length of L-02 cells was also extended after 4-week-cultivation with sodium selenite. Thus, sodium selenite at nutritional doses could prolong the life span of hepatocytes L-02 through increasing telomerase activity and telomere length. This result provides a possible mechanism for explaining the anti-senescence function of selenium.},
}
@article {pmid14673157,
year = {2004},
author = {Iida, T and Araki, H},
title = {Noncompetitive counteractions of DNA polymerase epsilon and ISW2/yCHRAC for epigenetic inheritance of telomere position effect in Saccharomyces cerevisiae.},
journal = {Molecular and cellular biology},
volume = {24},
number = {1},
pages = {217-227},
pmid = {14673157},
issn = {0270-7306},
mesh = {Adenosine Triphosphatases/*metabolism ; Chromatin/metabolism ; DNA Polymerase II/*antagonists &amp; inhibitors ; DNA Replication/physiology ; Saccharomyces cerevisiae/enzymology/*genetics ; Telomere/*metabolism ; Transcription Factors/*metabolism ; },
abstract = {Relocation of euchromatic genes near the heterochromatin region often results in mosaic gene silencing. In Saccharomyces cerevisiae, cells with the genes inserted at telomeric heterochromatin-like regions show a phenotypic variegation known as the telomere-position effect, and the epigenetic states are stably passed on to following generations. Here we show that the epigenetic states of the telomere gene are not stably inherited in cells either bearing a mutation in a catalytic subunit (Pol2) of replicative DNA polymerase epsilon (Pol epsilon) or lacking one of the nonessential and histone fold motif-containing subunits of Pol epsilon, Dpb3 and Dpb4. We also report a novel and putative chromatin-remodeling complex, ISW2/yCHRAC, that contains Isw2, Itc1, Dpb3-like subunit (Dls1), and Dpb4. Using the single-cell method developed in this study, we demonstrate that without Pol epsilon and ISW2/yCHRAC, the epigenetic states of the telomere are frequently switched. Furthermore, we reveal that Pol epsilon and ISW2/yCHRAC function independently: Pol epsilon operates for the stable inheritance of a silent state, while ISW2/yCHRAC works for that of an expressed state. We therefore propose that inheritance of specific epigenetic states of a telomere requires at least two counteracting regulators.},
}
@article {pmid14673147,
year = {2004},
author = {Matsumoto, T and Takahashi, H and Fujiwara, H},
title = {Targeted nuclear import of open reading frame 1 protein is required for in vivo retrotransposition of a telomere-specific non-long terminal repeat retrotransposon, SART1.},
journal = {Molecular and cellular biology},
volume = {24},
number = {1},
pages = {105-122},
pmid = {14673147},
issn = {0270-7306},
mesh = {Amino Acid Sequence ; Animals ; Cell Nucleus/*metabolism ; Drosophila/genetics/metabolism ; Genes, Reporter ; Molecular Sequence Data ; Retroelements/*physiology ; Transcription, Genetic ; },
abstract = {Non-long terminal repeat (non-LTR) retrotransposons, most of which carry two open reading frames (ORFs), are abundant mobile elements that are distributed widely among eukaryotes. ORF2 encodes enzymatic domains, such as reverse transcriptase, that are conserved in all retroelements, but the functional roles of ORF1 in vivo are little understood. We show with green fluorescent protein-ORF1 fusion proteins that the ORF1 proteins of SART1, a telomeric repeat-specific non-LTR retrotransposon in Bombyx mori, are transported into the nucleus to produce a dotted localization pattern. Nuclear localization signals N1 (RRKR) and N2 (PSKRGRG) at the N terminus and a highly basic region in the center of SART1 ORF1 are involved in nuclear import and the dotted localization pattern in the nucleus, respectively. An in vivo retrotransposition assay clarified that at least three ORF1 domains, N1/N2, the central basic domain, and CCHC zinc fingers are required for SART1 retrotransposition. The nuclear import activity of SART1 ORF1 makes it clear that the ORF1 proteins of non-LTR retrotransposons work mainly in the nucleus, in contrast to the cytoplasmic action of Gag proteins of LTR elements. The functional domains found here in SART1 ORF1 will be useful for developing a more efficient and target-specific LINE-based gene delivery vector.},
}
@article {pmid14673098,
year = {2003},
author = {Scholes, DT and Kenny, AE and Gamache, ER and Mou, Z and Curcio, MJ},
title = {Activation of a LTR-retrotransposon by telomere erosion.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {100},
number = {26},
pages = {15736-15741},
pmid = {14673098},
issn = {0027-8424},
support = {R01 GM052072/GM/NIGMS NIH HHS/United States ; R29 GM052072/GM/NIGMS NIH HHS/United States ; GM52072/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Damage ; DNA Replication ; DNA, Fungal/*genetics ; Gene Expression Regulation, Fungal/*genetics ; Homozygote ; Models, Genetic ; Retroelements/*genetics ; Saccharomyces cerevisiae/*genetics/growth &amp; development ; Telomere/*genetics ; Terminal Repeat Sequences/*genetics ; },
abstract = {Retrotransposons can facilitate repair of broken chromosomes, and therefore an important question is whether the host can activate retrotransposons in response to chromosomal lesions. Here we show that Ty1 elements, which are LTR-retrotransposons in Saccharomyces cerevisiae, are mobilized when DNA lesions are created by the loss of telomere function. Inactivation of telomerase in yeast results in progressive shortening of telomeric DNA, eventually triggering a DNA-damage checkpoint that arrests cells in G2/M. A fraction of cells, termed survivors, recover from arrest by forming alternative telomere structures. When telomerase is inactivated, Ty1 retrotransposition increases substantially in parallel with telomere erosion and then partially declines when survivors emerge. Retrotransposition is stimulated at the level of Ty1 cDNA synthesis, causing cDNA levels to increase 20-fold or more before survivors form. This response is elicited through a signaling pathway that includes Rad24, Rad17, and Rad9, three components of the DNA-damage checkpoint. Our findings indicate that Ty1 retrotransposons are activated as part of the cellular response to telomere dysfunction.},
}
@article {pmid14672427,
year = {2003},
author = {McKevitt, TP and Nasir, L and Wallis, CV and Argyle, DJ},
title = {A cohort study of telomere and telomerase biology in cats.},
journal = {American journal of veterinary research},
volume = {64},
number = {12},
pages = {1496-1499},
doi = {10.2460/ajvr.2003.64.1496},
pmid = {14672427},
issn = {0002-9645},
mesh = {Age Factors ; Aging/*genetics ; Animals ; Autoradiography ; Cats/*genetics/*physiology ; Cohort Studies ; Polymorphism, Restriction Fragment Length ; Telomerase/*physiology ; Telomere/*genetics ; },
abstract = {OBJECTIVE: To investigate telomere lengths in tissues of domestic shorthair (DSH) cats of various ages, evaluate the relationship between telomere length and age of cats, and investigate telomerase activity in the somatic tissues of cats.<br><br>SAMPLE POPULATION: Tissues obtained from 2 DSH cats and blood samples obtained from 30 DSH cats.<br><br>PROCEDURE: DNA isolated from blood cells and somatic tissue samples was subjected to terminal restriction fragment (TRF) analysis to determine mean telomere repeat lengths. Protein samples were subjected to analysis by use of a telomeric repeat-amplification protocol to assess telomerase activity.<br><br>RESULTS: MeanTRF values of cats ranged from 4.7 to 26.3 kilobase pairs, and there was significant telomeric attrition with increasing age of cat. Telomerase activity was not found in a wide range of normal tissues obtained from 2 cats.<br><br>Analysis of these results clearly indicates that telomeres are shorter in older cats, compared with young cats; therefore, telomeres are implicated in the aging process. The analysis of telomerase activity in normal somatic tissues of cats reveals a pattern of expression similar to that found in human tissues.<br><br>IMPACT FOR HUMAN MEDICINE: Fundamental differences in the biological characteristics of telomeres and telomerase exist between humans and the other most widely studied species (ie, mice). The results reported here reveal similarities in telomere and telomerase biologic characteristics between DSH cats and humans. Hence, as well as developing our understanding of aging in cats, these data may be usefully extrapolated to aging in humans.},
}
@article {pmid14667196,
year = {2003},
author = {Cottliar, A and Pedrazzini, E and Corrado, C and Engelberger, MI and Narbaitz, M and Slavutsky, I},
title = {Telomere shortening in patients with plasma cell disorders.},
journal = {European journal of haematology},
volume = {71},
number = {5},
pages = {334-340},
doi = {10.1034/j.1600-0609.2003.00157.x},
pmid = {14667196},
issn = {0902-4441},
mesh = {Bone Marrow/pathology ; Chromosome Aberrations ; Disease Progression ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Male ; Multiple Myeloma/*genetics/pathology ; Paraproteinemias/*genetics/pathology ; Plasma Cells/pathology ; Telomere/*ultrastructure ; },
abstract = {OBJECTIVES: Telomeres are essential for maintaining chromosomal integrity; their shortening is associated with chromosome instability. The aim of this work was to study telomere length (TL) on bone marrow (BM) cells from patients with multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS).<br><br>METHODS: Thirty-one MM patients: 12 at diagnosis (D), 11 at relapse (R) and eight at remission (RE) and two cases with MGUS were studied. TL based on terminal restriction fragment (TRF) assay was evaluated. Cytogenetic and molecular cytogenetic analyses were performed. Telomeric associations (TAs) on BM metaphases were also studied.<br><br>RESULTS: TRF analysis in total MM patients showed a mean TRF peak value (5.20 +/- 0.35 kb) shorter than those observed in controls (8.5 +/- 0.5 kb) (P < 0.001). Moreover, TRF at D and R showed a significant telomere shortening (P < 0.001), with TL restored at RE. A strong correlation with the percentage of BM plasma cell infiltration (BMPCI) (rK = -0.540; P = 0.002) was found. Patients with abnormal karyotypes (AK) had significantly shorter TRFs than that observed in MM patients with normal karyotypes (P < 0.05). TRFs in MGUS patients did not differ with respect to controls. TA analysis showed an increased percentage in MM (19.46 +/- 1.98%) with respect to MGUS (6.12 +/- 1.87%) and normal BM cells (2.00 +/- 0.93%) (P < 0.001).<br><br>CONCLUSIONS: MM patients showed a significant reduction in TL (> 60% of BMPCI and AK), suggesting a probable association with clinical evolution. Moreover, our findings support the idea that telomere shortening usually leads to increased frequencies of TAs and chromosome instability.},
}
@article {pmid14663525,
year = {2003},
author = {Puizina, J and Weiss-Schneeweiss, H and Pedrosa-Harand, A and Kamenjarin, J and Trinajstic, I and Riha, K and Schweizer, D},
title = {Karyotype analysis in Hyacinthella dalmatica (Hyacinthaceae) reveals vertebrate-type telomere repeats at the chromosome ends.},
journal = {Genome},
volume = {46},
number = {6},
pages = {1070-1076},
doi = {10.1139/g03-078},
pmid = {14663525},
issn = {0831-2796},
mesh = {Animals ; Chromosome Banding ; Chromosomes, Plant/*genetics ; In Situ Hybridization, Fluorescence/methods ; Karyotyping ; Liliaceae/*genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; Telomere/*genetics ; Vertebrates/genetics ; },
abstract = {Chromosome analysis of three different populations of Hyacinthella dalmatica (Lallem.) Trinajstić, an endemic species of the coastal region of southeastern Europe, showed a unique chromosome number, 2n = 2x = 20, and bimodal karyotype with one large and nine smaller pairs of chromosomes. Staining with fluorochromes CMA3 (chromomycin A3) and DAPI (4,6-diamidino-2-phenylindole) revealed heterochromatic regions associated with NORs, centromeres, and several interstitial heterochromatic bands on the longest chromosome pair. Double-target FISH with two ribosomal DNA probes revealed one locus of 5S rRNA genes in the pericentromeric region of chromosome pair 3 and one locus of 18S-5.8S-26S rRNA genes on the short arm of chromosome pair 4 in all plants and populations analyzed. Southern hybridization analysis and FISH experiments demonstrated that the distal ends of H. dalmatica chromosomes contain the vertebrate telomere (5'-TTAGGG-3') repeat type rather than the Arabidopsis (5'-TTTAGGG-3') heptamer, and so suggest that this Asparagales species along with Aloe and Othocallis contains the vertebrate-type telomere repeat.},
}
@article {pmid14657602,
year = {2003},
author = {Kuniyasu, H and Kitadai, Y and Mieno, H and Yasui, W},
title = {Helicobactor pylori infection is closely associated with telomere reduction in gastric mucosa.},
journal = {Oncology},
volume = {65},
number = {3},
pages = {275-282},
doi = {10.1159/000074481},
pmid = {14657602},
issn = {0030-2414},
mesh = {Blotting, Southern ; Case-Control Studies ; DNA-Binding Proteins ; Gastric Mucosa/*metabolism/microbiology ; Helicobacter Infections/*metabolism ; *Helicobacter pylori ; Humans ; In Situ Hybridization, Fluorescence ; Intestine, Small/metabolism/pathology ; Metaplasia ; Stomach Neoplasms/*metabolism/microbiology ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; Tumor Cells, Cultured ; },
abstract = {OBJECTIVE: To investigate differential reduction in telomere DNA in tissue components of gastric mucosa with respect to Helicobactor pylori infection.<br><br>MATERIALS AND METHODS: The telomere content was examined by fluorescent in situ hybridization with the (TTAGGG)(4) probe. To compare the signal intensities from the probe (telomere volume) with telomere length, five gastric carcinoma cell lines were used. Telomere volumes were examined in 9 healthy persons, 124 non-cancer patients, and 86 gastric cancer patients.<br><br>RESULTS: Telomere volume showed a linear correlation with telomere length measured by Southern blotting in gastric carcinoma cells. In healthy persons without H. pylori infection, the telomere volumes of gastric epithelial tissues were 70-79% that of intramucosal lymphocytes (internal control). In 124 patients without gastric cancer, telomere volume of H.-PYLORI-infected mucosa was significantly less than that of H.-pylori-negative mucosa in both metaplastic and non- metaplastic tissues (p < 0.0001). In 86 gastric cancer patients, telomere volumes in intestinal metaplasia adjacent to cancer were 75% that of intestinal metaplasia of non-cancer patients (p = 0.0001). hTERT expression was detected in 6 cancer-associated and 2 cancer-negative intestinal metaplasia specimens, in which telomere volume was markedly reduced.<br><br>CONCLUSION: H. pylori infection is closely associated with telomere reduction in gastric epithelium.},
}
@article {pmid14657244,
year = {2004},
author = {Liebe, B and Alsheimer, M and Höög, C and Benavente, R and Scherthan, H},
title = {Telomere attachment, meiotic chromosome condensation, pairing, and bouquet stage duration are modified in spermatocytes lacking axial elements.},
journal = {Molecular biology of the cell},
volume = {15},
number = {2},
pages = {827-837},
pmid = {14657244},
issn = {1059-1524},
mesh = {Acetyl-CoA C-Acetyltransferase ; Animals ; Carrier Proteins ; Cell Cycle Proteins ; Centromere/metabolism ; Chromatids/metabolism ; Chromosome Pairing/*physiology ; Chromosomes, Mammalian/*metabolism ; In Situ Hybridization, Fluorescence ; Male ; Meiosis/genetics/*physiology ; Mice ; Microscopy, Immunoelectron ; Nuclear Envelope/metabolism ; Nuclear Proteins/metabolism ; Spermatocytes/*metabolism ; Telomere/*metabolism ; },
abstract = {During the extended prophase to the meiosis I division, chromosomes assemble axial elements (AE) along replicated sister chromatids whose ends attach to the inner nuclear membrane (NM) via a specialized conical thickening. Here, we show at the EM level that in Sycp3(-/-) spermatocyte chromosomes lack the AE and the conical end thickening, but still they attach their telomeres to the inner NM with an electron-dense plate that contains T(2)AG(3) repeats. Immunofluorescence detected telomere proteins, SCP2, and the meiosis-specific cohesin STAG3 at the Sycp3(-/-) telomere. Bouquet stage spermatocytes were approximately threefold enriched, and the number of telomere but not centromere signals was reduced to the haploid in advanced Sycp3(-/-) spermatocytes, which indicates a special mode of homolog pairing at the mammalian telomere. Fluorescence in situ hybridization with mouse chromosome 8- and 12-specific subsatellite probes uncovered reduced levels of regional homolog pairing, whereas painting of chromosomes 13 revealed partial or complete juxtapositioning of homologs; however, condensation of Sycp3(-/-) bivalents was defective. Electron microscopic analysis of AE-deficient spermatocytes revealed that transverse filaments formed short structures reminiscent of the synaptonemal complex central region, which likely mediate stable homolog pairing. It appears that the AE is required for chromosome condensation, rapid exit from the bouquet stage, and fine-tuning of homolog pairing.},
}
@article {pmid14657034,
year = {2003},
author = {Molenaar, C and Wiesmeijer, K and Verwoerd, NP and Khazen, S and Eils, R and Tanke, HJ and Dirks, RW},
title = {Visualizing telomere dynamics in living mammalian cells using PNA probes.},
journal = {The EMBO journal},
volume = {22},
number = {24},
pages = {6631-6641},
pmid = {14657034},
issn = {0261-4189},
mesh = {Base Sequence ; Bone Neoplasms ; Humans ; Kinetics ; Movement ; Nucleic Acid Hybridization ; Osteosarcoma ; Peptide Nucleic Acids/*chemistry ; Repetitive Sequences, Nucleic Acid ; Telomere/*physiology/*ultrastructure ; Tumor Cells, Cultured ; },
abstract = {Chromosome ends are protected from degradation by the presence of the highly repetitive hexanucleotide sequence of TTAGGG and associated proteins. These so-called telomeric complexes are suggested to play an important role in establishing a functional nuclear chromatin organization. Using peptide nucleic acid (PNA) probes, we studied the dynamic behavior of telomeric DNA repeats in living human osteosarcoma U2OS cells. A fluorescent cy3-labeled PNA probe was introduced in living cells by glass bead loading and was shown to specifically associate with telomeric DNA shortly afterwards. Telomere dynamics were imaged for several hours using digital fluorescence microscopy. While the majority of telomeres revealed constrained diffusive movement, individual telomeres in a human cell nucleus showed significant directional movements. Also, a subfraction of telomeres were shown to associate and dissociate, suggesting that in vivo telomere clusters are not stable but dynamic structures. Furthermore, telomeres were shown to associate with promyelocytic leukemia (PML) bodies in a dynamic manner.},
}
@article {pmid14656155,
year = {2003},
author = {D'Aiuto, L and de las Heras, JI and Ross, A and Shen, MH and Cooke, H},
title = {Generation of a telomere-based episomal vector.},
journal = {Biotechnology progress},
volume = {19},
number = {6},
pages = {1775-1780},
doi = {10.1021/bp0341500},
pmid = {14656155},
issn = {8756-7938},
mesh = {Cell Line, Tumor ; Chromosomes, Artificial, P1 Bacteriophage/*genetics/ultrastructure ; Cloning, Molecular/*methods ; Fibrosarcoma/*genetics/pathology ; *Gene Transfer Techniques ; Genetic Vectors/*genetics ; Humans ; Plasmids/*genetics/ultrastructure ; Telomere/*genetics/ultrastructure ; Transfection/*methods ; },
abstract = {We have developed a telomere-based episome by large-scale amplification in Escherichia coli cells. This episome consists of a PAC vector in which a 6 Kb sequence, containing an array of telomeric repeats spaced by a synthetic sequence, is tandemly repeated by large-scale multimerization in E. coli. After transfection in human HT1080 cells, the construct, called clone 106, was able to persist in episomal form or integrated into some endogenous chromosomes. Integrations occurred exclusively at the telomeres. Episomes were still present in HT1080 cells after more than 100 days in the absence of selection. Integrations of clone 106 into the telomeric regions were retained only under selective conditions, and when the selection was removed the construct was progressively eliminated from the chromosome. The long-term maintenance of clone 106 into human cells as an episome and its ability to integrate transiently into the telomeres of the host chromosomes suggest that this PAC-based episome is potentially a good candidate vector for gene therapy applications.},
}
@article {pmid14654689,
year = {2003},
author = {Ono, Y and Tomita, K and Matsuura, A and Nakagawa, T and Masukata, H and Uritani, M and Ushimaru, T and Ueno, M},
title = {A novel allele of fission yeast rad11 that causes defects in DNA repair and telomere length regulation.},
journal = {Nucleic acids research},
volume = {31},
number = {24},
pages = {7141-7149},
pmid = {14654689},
issn = {1362-4962},
mesh = {*Alleles ; DNA Damage/drug effects/genetics/radiation effects ; *DNA Repair/drug effects/genetics/radiation effects ; DNA-Binding Proteins/genetics/*metabolism ; Epistasis, Genetic ; Gamma Rays ; Genes, Fungal/genetics ; Hydroxyurea/pharmacology ; Methyl Methanesulfonate/pharmacology ; Mutation/genetics ; Protein Binding ; Radiation Tolerance ; Recombination, Genetic/drug effects/genetics/radiation effects ; Repetitive Sequences, Nucleic Acid/genetics ; Replication Protein A ; Schizosaccharomyces/drug effects/*genetics/*metabolism/radiation effects ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Telomere/drug effects/genetics/*metabolism/radiation effects ; Ultraviolet Rays ; },
abstract = {Replication protein A (RPA) is a heterotrimeric single-stranded DNA-binding protein involved in DNA replication, recombination and repair. In Saccharomyces cerevisiae, several mutants in the RFA1 gene encoding the large subunit of RPA have been isolated and one of the mutants with a missense allele, rfa1-D228Y, shows a synergistic reduction in telomere length when combined with a yku70 mutation. So far, only one mutant allele of the rad11(+) gene encoding the large subunit of RPA has been reported in Schizosaccharomyces pombe. To study the role of S.pombe RPA in DNA repair and possibly in telomere maintenance, we constructed a rad11-D223Y mutant, which corresponds to the S.cerevisiae rfa1-D228Y mutant. rad11-D223Y cells were methylmethane sulfonate, hydroxyurea, UV and gamma-ray sensitive, suggesting that rad11-D223Y cells have a defect in DNA repair activity. Unlike the S.cerevisiae rfa1-D228Y mutation, the rad11-D223Y mutation itself caused telomere shortening. Moreover, Rad11-Myc bound to telomere in a ChIP assay. These results strongly suggest that RPA is directly involved in telomere maintenance.},
}
@article {pmid14648548,
year = {2004},
author = {Flanary, BE and Streit, WJ},
title = {Progressive telomere shortening occurs in cultured rat microglia, but not astrocytes.},
journal = {Glia},
volume = {45},
number = {1},
pages = {75-88},
doi = {10.1002/glia.10301},
pmid = {14648548},
issn = {0894-1491},
mesh = {Animals ; Astrocytes/*cytology/drug effects/physiology ; Cell Division/drug effects/physiology ; Cells, Cultured ; Colony-Stimulating Factors/pharmacology ; Microglia/*cytology/drug effects/enzymology ; Rats ; Telomerase/metabolism ; *Telomere/drug effects/enzymology ; },
abstract = {Normal somatic cells have a finite replicative capacity. With each cell division, telomeres shorten progressively until they reach a critical length, at which point the cells enter replicative senescence. Some cells maintain their telomeres by the action of the telomerase enzyme. Glia, particularly microglia, are the only adult cell types in the central nervous system (CNS) that exhibit a significant mitotic potential, and are thus susceptible to telomere shortening. In this study, we show that telomere shortening accompanied by low to moderate telomerase activity, and ultimately senescence, occurs in rat microglia in vitro. When microglia are stimulated to divide with the mitogen granulocyte macrophage-colony stimulating factor (GM-CSF), longer telomeres are allowed to shorten, while shorter telomeres are lengthened. Telomerase activity is nearly 3-fold higher in GM-CSF-stimulated microglia initially, relative to unstimulated controls, and then declines to levels below those seen in controls before increasing again. Telomere attrition is also more rapid when microglia are grown in culture dishes of increasing size. Fluorescence in situ hybridization (FISH) analysis indicates that a nearly 3-fold variation in both inter- and intra-chromosomal telomere length exists in microglia. In contrast to microglia, cultured astrocytes exhibit a cyclical pattern of telomere lengthening and shortening over time, corresponding to a similar cycle of higher and lower telomerase activity. When astrocytes are passaged, mean telomere length increases initially from passage 1-2, remaining constant until passage 5, while the shortest telomeres are continually lengthened. In conclusion, the telomere shortening evident in microglia is accompanied by their progression to senescence by 32 days in vitro. In contrast, astrocytes, perhaps due to greater telomerase activity, have longer life spans and may be passaged repeatedly before entering senescence. Our findings provide an impetus to investigate the possibility that microglial telomere shortening may occur in vivo.},
}
@article {pmid14643186,
year = {2004},
author = {Sidorov, IA and Gee, D and Dimitrov, DS},
title = {A kinetic model of telomere shortening in infants and adults.},
journal = {Journal of theoretical biology},
volume = {226},
number = {2},
pages = {169-175},
doi = {10.1016/j.jtbi.2003.08.009},
pmid = {14643186},
issn = {0022-5193},
mesh = {Adult ; Aging/*physiology ; Cell Division/physiology ; Growth/physiology ; HIV Infections/immunology ; Humans ; Infant ; Leukocyte Count ; Leukocytes, Mononuclear/*ultrastructure ; Models, Biological ; Telomere/*ultrastructure ; },
abstract = {We have previously demonstrated that telomeres shorten more rapidly in peripheral mononuclear cells (PBMC) of infants than in adults (Zeichner et al., Blood 93 (1999) 2824). Here we describe a mathematical model that allows quantification of telomere dynamics both in infants and in adults. In this model the dependence of the telomere dynamics on age is accounted by assuming proportionality between the body growth, as approximated by the Gompertz equation, and the increase in the number of PBMCs. The model also assumes the existence of two subpopulations of PBMC with significantly different rates of division. This assumption is based on the results from a previous analysis of in vitro data for telomere dynamics in presence of telomerase inhibitors and our recent data obtained by measurements of BrdU incorporation in T lymphocytes in humans (Kovacs et al., J. Exp. Med. 194 (2001) 1731). The average telomere length of PBMC was calculated as the average length of these two subpopulations. The model fitted our experimental data well and allowed to derive a characteristic time of conversion of the rapidly proliferating cells to slowly proliferating cells on the order of 20 days. The half-life of the slowly proliferating cells was estimated to be about 6 months, which is in good agreement with data obtained by independent methodologies. Comparison of the one-population and two-subpopulations models demonstrated that one population model cannot explain the observed parameters of the terminal restriction fragment (TRF) dynamics while two-subpopulations model does. These results suggest that the rapid telomere shortening in infants is largely determined by the faster PBMC turnover compared to adults. This may have major implications for elucidation of the HIV pathogenesis in infants. One can speculate that the more rapid course of the HIV disease in infants is due to the existence of rapidly dividing cells, which are susceptible to HIV infection. In addition, these results could have implications for understanding of mechanisms of aging.},
}
@article {pmid14647922,
year = {2004},
author = {Parsch, D and Fellenberg, J and Brümmendorf, TH and Eschlbeck, AM and Richter, W},
title = {Telomere length and telomerase activity during expansion and differentiation of human mesenchymal stem cells and chondrocytes.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {82},
number = {1},
pages = {49-55},
pmid = {14647922},
issn = {0946-2716},
mesh = {Age Factors ; Aged ; Cell Differentiation/*physiology ; Chondrocytes/cytology/*physiology ; Collagen Type II/metabolism ; Female ; Humans ; Male ; Mesenchymal Stem Cells/cytology/*physiology ; Middle Aged ; Spheroids, Cellular/physiology ; Statistics as Topic ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Chondrocyte ex vivo expansion currently performed to replace damaged articular surfaces is associated with a loss of telomeric repeats similar to decades of aging in vivo. This might affect the incidence or time of onset of age-related disorders within transplanted cells or tissues. This study examined whether more immature progenitor cells, such as mesenchymal stem cells (MSC), which can be expanded and subsequently differentiated into chondrocytes is advantageous regarding telomere-length related limitations of expansion protocols. Primary chondrocytes and bone-marrow-derived MSC were isolated from 12 donors, expanded separately to 4 x 10(6) cells, and (re-)differentiated as three-dimensional chondrogenic spheroids. Cells were collected during expansion, after three-dimensional culturing and chondrogenic differentiation, and sequential analyses of telomere length and telomerase activity were performed. Surprisingly, telomeres of expanded MSC were significantly shorter than those from expanded chondrocytes from the same donor (11.4+/-2.5 vs. 13.4+/-2.2 kb) and tended to remain shorter after differentiation in chondrogenic spheroids (11.9+/-1.8 vs. 13.0+/- kb). While telomere lengths in native chondrocytes and MSC were not related to the age of the donor, significant negative correlations with age were observed in expanded (136 bp/year), three-dimensionally reconstituted (188 bp/year), and redifferentiated (229 bp/year) chondrocytes. Low levels of telomerase activity were found in MSC and chondrocytes during expansion and after (re-)differentiation to chondrogenic spheroids. In terms of replicative potential, as determined by telomere length, ex vivo expansion followed by chondrogenic differentiation of MSC did not provide a benefit compared to the expansion of adult chondrocytes. However, accelerated telomere shortening with age during expansion and redifferentiation argues for an "age phenotype" in chondrocytes as opposed to MSC and suggests an advantage for the use of MSC especially in older individuals and protocols requiring extensive expansion},
}
@article {pmid14634639,
year = {2003},
author = {Lustig, AJ},
title = {Clues to catastrophic telomere loss in mammals from yeast telomere rapid deletion.},
journal = {Nature reviews. Genetics},
volume = {4},
number = {11},
pages = {916-923},
doi = {10.1038/nrg1207},
pmid = {14634639},
issn = {1471-0056},
mesh = {Animals ; *Biological Evolution ; Mammals/*genetics ; Neoplasms/genetics ; *Sequence Deletion ; *Telomere ; Yeasts/*genetics ; },
abstract = {Catastrophic losses of telomeric sequences have recently been described during apoptosis, senescence and tumorigenesis in murine and human cells, in ataxia telangiectasia patients and in immortalized cells in which telomerase is inactive. A mechanism that underlies a single-step non-reciprocal telomere deletion called telomere rapid deletion in Saccharomyces cerevisiae might provide clues for future studies of catastrophic telomere loss in higher eukaryotes.},
}
@article {pmid14630995,
year = {2004},
author = {Sotillo-Piñeiro, E and Sierrasesúmaga, L and Patiñno-García, A},
title = {Telomerase activity and telomere length in primary and metastatic tumors from pediatric bone cancer patients.},
journal = {Pediatric research},
volume = {55},
number = {2},
pages = {231-235},
doi = {10.1203/01.PDR.0000102455.36737.3C},
pmid = {14630995},
issn = {0031-3998},
mesh = {Blotting, Southern ; Bone Neoplasms/*metabolism/*pathology ; Child ; Humans ; Osteosarcoma/*metabolism/*secondary ; Sarcoma, Ewing/metabolism/secondary ; Telomerase/*metabolism ; Telomere/genetics/metabolism ; },
abstract = {The presence of telomerase activity has been analyzed in almost all tumor types and tumor-derived cell lines. However, there are very few studies that focus on the presence of telomerase activity in bone tumors, and most of them report analysis on very few samples or bone-derived cell lines. The objective of this study was to analyze the telomere length and telomerase activity in primary tumors and metastatic lesions from pediatric osteosarcoma and Ewing's sarcoma patients. The presence of telomerase activity was analyzed by the telomeric repeat amplification protocol assay, and the telomere length was measured by Southern blot. Results were related to survival and clinical outcome. Telomerase activity was detected in 85% of the bone tumor metastases (100% Ewing's sarcomas and 75% osteosarcomas) but only in 12% of the primary tumors (11.1% osteosarcomas and 12.5% Ewing's sarcomas). Bone tumor tissues with telomerase activity had mean telomere lengths 3 kb shorter than those with no detectable telomerase activity (p = 0.041). The presence of telomerase activity was associated with survival (p = 0.009), and longer event-free survival periods were found in patients who lacked telomerase activity compared with those who had detectable telomerase activity levels in their tumor tissues (p = 0.037). The presence of longer telomeres in primary pediatric bone tumors than in metastases could be indicative of alternative mechanisms of lengthening of telomeres for their telomere maintenance rather than telomerase activity. Nevertheless, the activation of telomerase seems to be a crucial step in the malignant progression and acquisition of invasive capability of bone tumors.},
}
@article {pmid14630908,
year = {2004},
author = {Sundararaj, KP and Wood, RE and Ponnusamy, S and Salas, AM and Szulc, Z and Bielawska, A and Obeid, LM and Hannun, YA and Ogretmen, B},
title = {Rapid shortening of telomere length in response to ceramide involves the inhibition of telomere binding activity of nuclear glyceraldehyde-3-phosphate dehydrogenase.},
journal = {The Journal of biological chemistry},
volume = {279},
number = {7},
pages = {6152-6162},
doi = {10.1074/jbc.M310549200},
pmid = {14630908},
issn = {0021-9258},
support = {AG16583/AG/NIA NIH HHS/United States ; CA88932/CA/NCI NIH HHS/United States ; P01 CA097132/CA/NCI NIH HHS/United States ; },
mesh = {Blotting, Western ; Cell Cycle ; Cell Line, Tumor ; Cell Nucleus/*enzymology/metabolism ; Ceramides/*chemistry/metabolism ; Chromatin/metabolism ; Cytoplasm/metabolism ; Electrophoresis, Gel, Two-Dimensional ; Flow Cytometry ; Glyceraldehyde-3-Phosphate Dehydrogenase (NADP+)(Phosphorylating)/*chemistry ; Humans ; In Situ Hybridization, Fluorescence ; Microscopy, Fluorescence ; Peptides/chemistry ; Plasmids/metabolism ; Precipitin Tests ; Protein Binding ; Protein Isoforms ; RNA, Small Interfering/metabolism ; Silver Staining ; Telomerase/metabolism ; Telomere/chemistry/ultrastructure ; Time Factors ; Transfection ; Ultraviolet Rays ; },
abstract = {Ceramide has been demonstrated as one of the upstream regulators of telomerase activity. However, the role for ceramide in the control of telomere length remains unknown. It is shown here that treatment of the A549 human lung adenocarcinoma cells with C(6)-ceramide results in rapid shortening of telomere length. During the examination of ceramide-regulated telomere-binding proteins, nuclear glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was identified to associate with both single- and double-stranded telomeric DNA with high specificity in vitro. The association of nuclear GAPDH with telomeres in interphase nuclei was also demonstrated by co-fluorescence in situ hybridization and chromatin immunoprecipitation analysis. Further data demonstrated that the nuclear localization of GAPDH is regulated by ceramide in a cell cycle-dependent manner parallel with the inhibition of its telomere binding activity in response to ceramide. In addition, the results revealed that nuclear GAPDH is distinct from its cytoplasmic isoform and that telomere binding function of nuclear GAPDH is strikingly higher than the cytoplasmic isoform. More importantly, the functional role for nuclear GAPDH in the maintenance and/or protection of telomeric DNA was identified by partial inhibition of the expression of GAPDH using small interfering RNA, which resulted in rapid shortening of telomeres. In contrast, overexpression of nuclear GAPDH resulted in the protection of telomeric DNA in response to exogenous ceramide as well as in response to anticancer drugs, which have been shown to induce endogenous ceramide levels. Therefore, these results demonstrate a novel function for nuclear GAPDH in the maintenance and/or protection of telomeres and also show that mechanisms of the rapid degradation of telomeres in response to ceramide involve the inhibition of the telomere binding activity of nuclear GAPDH.},
}
@article {pmid14626563,
year = {2003},
author = {Sklenicková, M and Fajkus, J},
title = {[Telomere analysis in tumor cells using in situ techniques].},
journal = {Casopis lekaru ceskych},
volume = {142},
number = {8},
pages = {479-482},
pmid = {14626563},
issn = {0008-7335},
mesh = {DNA Probes ; DNA, Neoplasm/*genetics ; *Genetic Techniques ; Humans ; In Situ Hybridization, Fluorescence ; Primed In Situ Labeling ; Telomere/genetics/*pathology ; },
abstract = {Stable telomere maintenance is essential for the indefinite cellular proliferation of germline and tumour cells. In most cases, telomere synthesis is performed by nucleoprotein enzyme complex of telomerase, that results in stabilisation of telomeres shortened to < or = 7 kb. Rarely, telomeres may be maintained via alternative (recombination-based) mechanism, which produces telomeres of heterogenous lengths (3-50 kb). Analysis of telomeres by in situ techniques, such as fluorescent in situ hybridisation (FISH) on metaphase spreads or on extended DNA fibres (fiber-FISH) and Primed in situ labelling (PRINS), enables to distinguish between these two mechanisms and to analyse individual telomeres in the given type of cells.},
}
@article {pmid14625679,
year = {2003},
author = {Biessmann, H and Mason, JM},
title = {Telomerase-independent mechanisms of telomere elongation.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {60},
number = {11},
pages = {2325-2333},
pmid = {14625679},
issn = {1420-682X},
support = {GM-56729/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromosomes/physiology ; DNA Damage ; Drosophila melanogaster/genetics ; Recombination, Genetic ; Retroelements ; Tandem Repeat Sequences ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {The ends of linear chromosomes must be elongated in a DNA-replication-independent fashion. For chromosome end elongation the majority of eukaryotes use a specialized reverse transcriptase, telomerase, which adds a short, tandemly repeated DNA sequence motif to chromosome ends. Chromosome elongation can also be achieved, however, by mechanisms other than telomerase. Such elongation events have been detected under conditions where telomerase has been inactivated experimentally and in the few organisms that naturally lack telomerase. We will summarize current knowledge on these telomerase-independent elongation mechanisms in yeast and mammalian cells and will discuss in more detail the telomere elongation mechanism by retrotransposons in Drosophila melanogaster.},
}
@article {pmid14625678,
year = {2003},
author = {Bass, HW},
title = {Telomere dynamics unique to meiotic prophase: formation and significance of the bouquet.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {60},
number = {11},
pages = {2319-2324},
pmid = {14625678},
issn = {1420-682X},
mesh = {Animals ; DNA/metabolism ; Humans ; *Meiosis ; Nuclear Envelope/ultrastructure ; *Prophase ; Telomere/*physiology/ultrastructure ; },
abstract = {Telomeres carry out conserved and possibly ancient functions in meiosis. During the specialized prophase of meiosis I, meiotic prophase, telomeres cluster on the nuclear envelope and move the diploid genetic material around within the nucleus so that homologous chromosomes can align two by two and efficiently recombine with precision. This recombination is in turn required for proper segregation of the homologs into viable haploid daughter cells. The meiosis-specific telomere clustering on the nuclear envelope defines the bouquet stage, so named for its resemblance to the stems from a bouquet of cut flowers. Here, a comparative analysis of the literature on meiotic telomeres from a variety of different species illustrates that the bouquet is nearly universal among life cycles with sexual reproduction. The bouquet has been well documented for over 100 years, but our understanding of how it forms and how it functions has only recently begun to increase. Early and recent observations document the timing and provide clues about the functional significance of these striking telomere movements.},
}
@article {pmid14625677,
year = {2003},
author = {Perrod, S and Gasser, SM},
title = {Long-range silencing and position effects at telomeres and centromeres: parallels and differences.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {60},
number = {11},
pages = {2303-2318},
pmid = {14625677},
issn = {1420-682X},
mesh = {Animals ; Centromere/*physiology ; *Gene Silencing ; Heterochromatin/physiology ; Histone Deacetylases/physiology ; Humans ; Methylation ; RNA Interference ; Saccharomycetales/genetics ; Schizosaccharomyces/genetics ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/physiology ; Sirtuin 2 ; Sirtuins/physiology ; Telomere/*physiology ; },
abstract = {Most of the human genome is compacted into heterochromatin, a form that encompasses multiple forms of inactive chromatin structure. Transcriptional silencing mechanisms in budding and fission yeasts have provided genetically tractable models for understanding heritably repressed chromatin. These silent domains are typically found in regions of repetitive DNA, that is, either adjacent to centromeres or telomeres or within the tandemly repeated ribosomal DNA array. Here we address the mechanisms of centromeric, telomeric and locus-specific gene silencing, comparing simple and complex animals with yeast. Some aspects are universally shared, such as histone-tail modifications, while others are unique to either centromeres or telomeres. These may reflect roles for heterochromatin in other chromosomal functions, like kinetochore attachment and DNA ends protection.},
}
@article {pmid14625675,
year = {2003},
author = {Wei, C and Price, M},
title = {Protecting the terminus: t-loops and telomere end-binding proteins.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {60},
number = {11},
pages = {2283-2294},
pmid = {14625675},
issn = {1420-682X},
support = {AG17212/AG/NIA NIH HHS/United States ; GM41803/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cyclin B/chemistry/physiology ; DNA Replication ; Heterogeneous-Nuclear Ribonucleoproteins/physiology ; Humans ; *Telomere/chemistry/physiology ; Telomere-Binding Proteins/chemistry/*physiology ; },
abstract = {Telomeric DNA is composed of a region of duplex telomeric tract followed by a single-strand overhang on the 3' G-rich strand. The DNA is packaged by proteins that associate directly with the single- and double-strand regions of the telomeric tract and by their associated proteins. This review discusses the evidence that G-strand overhangs are present on both ends of eukaryotic chromosomes and the steps needed to generate these overhangs. The overhangs are protected by specialized G-overhang-binding protein and/or invasion by the overhang of the duplex region of the telomeric tract to form a structure called a 't-loop'. The G-overhang-binding proteins identified from different species are described, and their properties compared. The data supporting the existence of t-loops at native telomeres is discussed, and the conditions required to promote their in vitro formation are presented.},
}
@article {pmid14619037,
year = {2003},
author = {Viidik, A},
title = {[Short telomeres in disease--cause of effect? Telomerase dysfunction weakens the protective endings of the chromosomes].},
journal = {Lakartidningen},
volume = {100},
number = {42},
pages = {3286-3287},
pmid = {14619037},
issn = {0023-7205},
mesh = {Cell Division/genetics/physiology ; Chromosome Aberrations ; Genetic Predisposition to Disease ; Genetic Therapy ; Humans ; *Telomerase/genetics/physiology ; *Telomere/genetics/physiology ; },
}
@article {pmid14616071,
year = {2003},
author = {Pardue, ML and DeBaryshe, PG},
title = {Retrotransposons provide an evolutionarily robust non-telomerase mechanism to maintain telomeres.},
journal = {Annual review of genetics},
volume = {37},
number = {},
pages = {485-511},
doi = {10.1146/annurev.genet.38.072902.093115},
pmid = {14616071},
issn = {0066-4197},
support = {GM50315/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Biological Evolution ; Drosophila/genetics/physiology ; Drosophila Proteins/physiology ; Gene Products, gag/physiology ; Retroelements/*physiology ; Telomerase/physiology ; Telomere/*physiology ; },
abstract = {Telomere molecular biology is far more complex than originally thought. Understanding biological systems is aided by study of evolutionary variants, and Drosophila telomeres are remarkable variants. Drosophila lack telomerase and the arrays of simple repeats generated by telomerase in almost all other organisms; instead, Drosophila telomeres are long tandem arrays of two non-LTR retrotransposons, HeT-A and TART. These are the first transposable elements found to have a bona fide role in cell structure, revealing an unexpected link between telomeres and what is generally considered to be parasitic DNA. In addition to providing insight into the cellular functions performed by telomeres, analysis of HeT-A and TART is providing insight into the evolution of chromosomes, retrotransposons, and retroviruses. Recent studies show that retrotransposon telomeres constitute a robust system for maintaining chromosome ends. These telomeres are now known to predate the separation of extant Drosophila species, allowing ample time for elements and hosts to coevolve interesting mechanisms.},
}
@article {pmid14614800,
year = {2003},
author = {Dolnik, AV and Kuznetsova, IS and Voronin, AP and Podgornaya, OI},
title = {Telomere-binding TRF2/MTBP localization during mouse spermatogenesis and cell cycle of the mouse cells L929.},
journal = {Journal of anti-aging medicine},
volume = {6},
number = {2},
pages = {107-121},
doi = {10.1089/109454503769684784},
pmid = {14614800},
issn = {1094-5458},
mesh = {Animals ; Bromodeoxyuridine/metabolism ; Cell Cycle/physiology ; Flow Cytometry ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Male ; Meiosis/physiology ; Mice ; Nuclear Envelope/physiology ; Spermatocytes/metabolism ; Spermatogenesis/*physiology ; Telomere/*physiology ; Telomere-Binding Proteins/*physiology ; Telomeric Repeat Binding Protein 2/*metabolism ; },
abstract = {Observations of the organization and distribution of telomeres (Tel) in somatic tissues still remain controversial. The Tel topography revealed by modern microscopy shows them to be associated with the nuclear envelope (NE) in a wide variety of eukaryotic cells, although not at the Rabl orientation (peripheral position at one pole of the nucleus at prophase). We used two cell types that have different nuclear architectures. The cell line L929 shows lack of any rigid Tel architecture in the nucleus. In contrast, spermatozoa have a precise architecture established during spermiogenesis. We observed Tel and membrane Tel binding protein (MTBP/TRF2) position by immunoFISH in L929 cells and by immunofluorescence and immunogold electron microscopy, using antibodies against Membrane Tel Binding Protein (MTBP/TRF2), during different stages of spermiogenesis. At all stages of the L929 cell cycle, MTBP/TRF2 is co-localized with Tel. The only Tel order found in this cell type is similar to the Rabl-orientation, probably due to fast divisions. In the mouse pachytene spermatocytes, the membrane structures abut on the synaptonemal complex (SC) attachment sites contain MTBP/TRF2. In fully formed spermatozoa and during spermiogenesis, apart from the expected MTBP/TRF2 position at the nuclear periphery, MTBP/TRF2 unexpectedly localized at the acrosomal membrane that is adjacent to the nucleus. The difference in the MTBP/TRF2 distribution in the oocyte and spermatozoa leads to the suggestion that the MTBP/TRF2 location might reflect preparation for fertilization events. The Tel distribution is not static in cultured cells throughout the cell cycle or during spermatogenesis. When the Tel are attached to the NE, as during SC formation, MTBP/TRF2 is the member of the protein complex, which appears to be responsible for this attachment.},
}
@article {pmid14614149,
year = {2003},
author = {Casacuberta, E and Pardue, ML},
title = {HeT-A elements in Drosophila virilis: retrotransposon telomeres are conserved across the Drosophila genus.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {100},
number = {24},
pages = {14091-14096},
pmid = {14614149},
issn = {0027-8424},
support = {R01 GM050315/GM/NIGMS NIH HHS/United States ; R56 GM050315/GM/NIGMS NIH HHS/United States ; GM50315/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Conserved Sequence ; DNA/genetics ; Drosophila/*genetics ; Drosophila Proteins/*genetics ; Drosophila melanogaster/genetics ; Evolution, Molecular ; Gene Products, gag/*genetics ; Genes, Insect ; In Situ Hybridization ; Molecular Sequence Data ; Phylogeny ; Retroelements/*genetics ; Species Specificity ; Telomere/*genetics ; },
abstract = {Drosophila melanogaster telomeres are composed of two retrotransposons, HeT-A and TART. Drosophila virilis has recently been shown to have telomere-specific TART elements with many of the characteristics of their D. melanogaster homologues. We now report identification of the second telomere-specific retrotransposon, HeT-A, from D. virilis. These results show that HeT-A and TART have been maintaining telomeres in Drosophila for more than the 60 million years that separate D. melanogaster and D. virilis. All Drosophila species and stocks studied have both of these telomeric elements, suggesting that the elements collaborate, an assumption supported by evidence from D. melanogaster that their Gag proteins interact. Although the HeT-A sequence evolves at a high rate, the element retains the unusual structural features that characterize all HeT-A homologues. These features may be involved in the role of HeT-A at the telomere. The Gag protein from HeT-Avir is as much like TART Gag from other species as it is like HeT-A Gag, suggesting that these Gags are evolving under similar constraints, probably to maintain appropriate interactions with host telomeres and possibly to allow collaborative interactions like those seen in D. melanogaster. In addition, we have identified a chimeric element, Uvir, carrying a pol coding sequence only distantly related to sequences thus far found in any telomere arrays.},
}
@article {pmid14614008,
year = {2003},
author = {Igarashi, M and Suda, T and Hara, H and Takimoto, M and Nomoto, M and Takahashi, T and Okoshi, S and Kawai, H and Mita, Y and Waguri, N and Aoyagi, Y},
title = {Interferon can block telomere erosion and in rare cases result in hepatocellular carcinoma development with telomeric repeat binding factor 1 overexpression in chronic hepatitis C.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {9},
number = {14},
pages = {5264-5270},
pmid = {14614008},
issn = {1078-0432},
mesh = {Antineoplastic Agents/*therapeutic use ; Carcinoma, Hepatocellular/*etiology/metabolism/pathology ; Hepacivirus/isolation &amp; purification/pathogenicity ; Hepatitis C, Chronic/complications/*drug therapy ; Humans ; Immunoenzyme Techniques ; Interferon-alpha/*therapeutic use ; Liver ; Liver Neoplasms/*etiology/metabolism/pathology ; Repetitive Sequences, Nucleic Acid ; *Telomere ; Telomeric Repeat Binding Protein 1/*metabolism ; },
abstract = {PURPOSE: The purpose of this study was to evaluate whether IFN therapy for chronic hepatitis C could overcome telomere reduction in the liver, a possible risk factor for hepatocellular carcinoma (HCC) development.<br><br>EXPERIMENTAL DESIGN: Relative telomeric repeat content (RTC) in the liver was measured before and after IFN therapy in 21 chronic hepatitis C cases. Liver samples were obtained at average intervals of 12, 75, and 32 months in eight complete responders (CRs) and one biochemical responder (BR), four CRs in whom HCC developed after an eradication of hepatitis C virus, and eight nonresponders, respectively. Telomeric repeat binding factor 1 (TRF1) was immunostained in specimens from CRs and a BR.<br><br>RESULTS: Although the average RTC of 0.96 +/- 0.14 (mean +/- SD) significantly decreased to 0.85 +/- 0.12 after IFN therapy in nonresponders (P = 0.023), the value of 0.91 +/- 0.14 before IFN therapy in CRs and a BR increased significantly to 1.0 +/- 0.085 (P = 0.031). TRF1 expression was barely detectable and attenuated after IFN therapy, except in CRs developing HCC, in which frequent staining appeared, and the RTC evidently decreased from 0.97 +/- 0.11 to 0.63 +/- 0.0092 in corresponding noncancerous liver tissues.<br><br>CONCLUSIONS: It is strongly suggested that successful IFN therapy blocks telomere erosion, except in rare cases in which telomere reduction continues with overexpression of TRF1. Successive RTC evaluation in the liver may distinguish a risky case from a clinically cured one.},
}
@article {pmid14612969,
year = {2003},
author = {Januszkiewicz, D and Wysoki, J and Lewandowski, K and Pernak, M and Nowicka, K and Rembowska, J and Nowak, J},
title = {Lack of correlation between telomere length and telomerase activity and expression in leukemic cells.},
journal = {International journal of molecular medicine},
volume = {12},
number = {6},
pages = {935-938},
pmid = {14612969},
issn = {1107-3756},
mesh = {Chromosome Mapping ; Humans ; Leukemia/*enzymology/*genetics ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {The expression of three components of telomerase complex (hTR, hTERT, TP1) along with telomerase activity and telomere length in leukemic cells was investigated. Cells were isolated from peripheral blood and/or bone marrow of children with acute lymphoblastic (ALL) and non-lymphoblastic (ANLL) leukemia. Expression of three components of telomerase as well as telomerase activity was found in all leukemic cells. Chemiluminescent detection of terminal restriction fragments (TRF) from DNA isolated from ALL cells showed variable patterns expressing considerable heterogeneity of telomere length. The ALL cells appeared to have both long and short telomere lengths, in contrast to normal peripheral lymphocytes, which produced limited pattern of TRF. The ANLL cells produced predominantly short telomere pattern despite high telomerase activity and expression. It can be concluded that high telomerase activity and expression in leukemic cells is not always correlated with long telomeres (TRF pattern).},
}
@article {pmid14612923,
year = {2003},
author = {Miracco, C and De Santi, MM and Luzi, P and Lalinga, AV and Laurini, L and De Nisi, MC and Angeloni, G and Brogi, M and Cardone, C and Carducci, A and Arcuri, F and Tosi, P and Rubino, G and Pirtoli, L},
title = {In situ detection of telomeres by fluorescence in situ hybridization and telomerase activity in glioblastoma multiforme: correlation with p53 status, EGFR, c-myc, MIB1, and Topoisomerase IIalpha protein expression.},
journal = {International journal of oncology},
volume = {23},
number = {6},
pages = {1529-1535},
pmid = {14612923},
issn = {1019-6439},
mesh = {Acid Phosphatase/metabolism ; Adolescent ; Adult ; Antigens, Neoplasm ; Brain Neoplasms/enzymology ; Cell Division ; Child ; DNA Topoisomerases, Type II/metabolism ; DNA-Binding Proteins ; ErbB Receptors/metabolism ; Glioblastoma/*enzymology/metabolism/pathology ; Humans ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence/*methods ; Isoenzymes/metabolism ; Ki-67 Antigen/biosynthesis/metabolism ; Middle Aged ; Polymorphism, Single-Stranded Conformational ; Proto-Oncogene Proteins c-myc/metabolism ; Tartrate-Resistant Acid Phosphatase ; Telomerase/*metabolism ; Telomere/*ultrastructure ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Aberrations of genes/proteins regulating cell cycle and growth, increased proliferation and telomerase activity (TA) are documentable in glioblastoma multiforme. TA is more frequently detectable in secondary glioblastoma, which is also characterized by p53 mutation/overexpression. Discordant telomere (Te) length values have been reported in glioblastomas with and without TA. In 31 glioblastomas, in which pre-existing astrocytoma was not documented, we compared cases with and without TA for the expression of p53, EGFR, c-Myc, MIB-1 and Topoisomerase IIalpha; p53 mutations were also investigated by SSCP-PCR. Correlations were made with Te parameters [TePs: number (TeNo), length and area] as evaluated by image analysis in interphase nuclei of fluorescence in situ hybridization (FISH)-processed sections. We found no differences in the expression of the proteins evaluated and in TePs, except Te/nuclear area %, which was significantly lower in TA+ cases (p=0.02). TePs were, instead, inversely correlated with TA (p=0.0001). TA was positively correlated with MIB1 staining index in the TA+ cases (p=0.033), which also showed a positive correlation between TeNo and EGFR expression (p=0.042), and a trend towards a negative correlation between TeNo and p53 expression (p=0.05). Tumors overexpressing EGFR had a significantly shorter lifetime (p=0.0001). TeNo seems to be inversely correlated to tumor proliferation and lifetime in glioblastoma multiforme.},
}
@article {pmid14612493,
year = {2003},
author = {González-Suárez, E and Goytisolo, FA and Flores, JM and Blasco, MA},
title = {Telomere dysfunction results in enhanced organismal sensitivity to the alkylating agent N-methyl-N-nitrosourea.},
journal = {Cancer research},
volume = {63},
number = {21},
pages = {7047-7050},
pmid = {14612493},
issn = {0008-5472},
mesh = {Alkylating Agents/*toxicity ; Animals ; Female ; Male ; Methylnitrosourea/*toxicity ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neoplasms, Experimental/chemically induced/enzymology/genetics ; Telomerase/antagonists &amp; inhibitors/deficiency/genetics ; Telomere/*physiology ; },
abstract = {Here, we use telomerase-deficient mice, Terc(-/-), to study the impact of telomerase abrogation in response to treatment with the alkylating agent N-Methyl-N-Nitrosourea (MNU), a potent carcinogen in the mouse. Wild-type mice treated with MNU developed lymphomas and carcinomas. In contrast, similarly treated G5 Terc(-/-) mice with critically short telomeres did not develop tumors and died of acute toxicity to the small intestine. G2 Terc(-/-) mice, which have long telomeres, were less susceptible to MNU-induced tumors than wild-type mice, as well as less sensitive to MNU toxicity than G5 Terc(-/-) mice. The results indicate that short telomeres suppress tumor growth and that lack of telomerase retards tumor progression, even in the presence of long telomeres. Finally, G5 Terc(-/-) hypersensitivity to MNU supports the notion that short telomeres interfere with proper DNA damage repair.},
}
@article {pmid14612413,
year = {2003},
author = {Smolikov, S and Krauskopf, A},
title = {The Rap1p-telomere complex does not determine the replicative capacity of telomerase-deficient yeast.},
journal = {Molecular and cellular biology},
volume = {23},
number = {23},
pages = {8729-8739},
pmid = {14612413},
issn = {0270-7306},
mesh = {Cell Division ; DNA Replication ; DNA, Fungal/biosynthesis/genetics ; Kluyveromyces/cytology/genetics/metabolism ; Protein Binding ; Saccharomyces cerevisiae/cytology/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/genetics/*metabolism ; Shelterin Complex ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; Transcription Factors/chemistry/genetics/*metabolism ; },
abstract = {Telomeres are nucleoprotein structures that cap the ends of chromosomes and thereby protect their stability and integrity. In the presence of telomerase, the enzyme that synthesizes telomeric repeats, telomere length is controlled primarily by Rap1p, the budding yeast telomeric DNA binding protein which, through its C-terminal domain, nucleates a protein complex that limits telomere lengthening. In the absence of telomerase, telomeres shorten with every cell division, and eventually, cells enter replicative senescence. We have set out to identify the telomeric property that determines the replicative capacity of telomerase-deficient budding yeast. We show that in cells deficient for both telomerase and homologous recombination, replicative capacity is dependent on telomere length but not on the binding of Rap1p to the telomeric repeats. Strikingly, inhibition of Rap1p binding or truncation of the C-terminal tail of Rap1p in Kluyveromyces lactis and deletion of the Rap1p-recruited complex in Saccharomyces cerevisiae lead to a dramatic increase in replicative capacity. The study of the role of telomere binding proteins and telomere length on replicative capacity in yeast may have significant implications for our understanding of cellular senescence in higher organisms.},
}
@article {pmid14609199,
year = {2003},
author = {Fletcher, TM},
title = {Telomere higher-order structure and genomic instability.},
journal = {IUBMB life},
volume = {55},
number = {8},
pages = {443-449},
doi = {10.1080/15216540310001612228},
pmid = {14609199},
issn = {1521-6543},
mesh = {Animals ; Cell Death ; Cell Division ; Chromatin/*chemistry/genetics ; Chromosomes/ultrastructure ; DNA/ultrastructure ; DNA Damage ; *Genome ; Humans ; Models, Biological ; Models, Chemical ; Neoplasms/metabolism ; Potassium/chemistry ; Protein Structure, Tertiary ; Signal Transduction ; Sodium/chemistry ; Telomerase/metabolism/ultrastructure ; Telomere/*ultrastructure ; },
abstract = {Telomeres, nucleoprotein complexes at the end of eukaryotic chromosomes, have vital roles in chromosome integrity. Telomere chromatin structure is both intricate and dynamic allowing for a variety of responses to several stimuli. A critical determinant in telomere structure is the G-strand overhang. Facilitated by telomeric proteins, the G-strand overhang stabilizes telomere higher-order assemblies most likely by adopting unusual DNA structures. These structures influence activities that occur at the chromosome end. Dysfunctional telomeres induce signals resulting in cell growth arrest or death. To overcome telomere dysfunction, cancer cells activate the DNA polymerase, telomerase. The presence of telomerase at the telomere may establish a particular telomeric state. If the chromosome ends of cancer and normal cells exist in different states, cancer-specific telomere structures would offer a unique chemotherapeutic target.},
}
@article {pmid14608368,
year = {2003},
author = {d'Adda di Fagagna, F and Reaper, PM and Clay-Farrace, L and Fiegler, H and Carr, P and Von Zglinicki, T and Saretzki, G and Carter, NP and Jackson, SP},
title = {A DNA damage checkpoint response in telomere-initiated senescence.},
journal = {Nature},
volume = {426},
number = {6963},
pages = {194-198},
doi = {10.1038/nature02118},
pmid = {14608368},
issn = {1476-4687},
mesh = {Adaptor Proteins, Signal Transducing ; Carrier Proteins/metabolism ; *Cell Cycle ; Cell Cycle Proteins/metabolism ; *Cellular Senescence ; Checkpoint Kinase 1 ; Checkpoint Kinase 2 ; Chromatin/metabolism ; *DNA Damage ; DNA Repair ; DNA-Binding Proteins/metabolism ; Fibroblasts/cytology/metabolism ; Histones/metabolism ; Humans ; *Intracellular Signaling Peptides and Proteins ; Nuclear Proteins/metabolism ; *Phosphoproteins ; Phosphorylation ; Protein Binding ; Protein Kinases/metabolism ; *Protein Serine-Threonine Kinases ; S Phase ; Telomere/*metabolism/pathology ; Trans-Activators/metabolism ; Tumor Suppressor p53-Binding Protein 1 ; },
abstract = {Most human somatic cells can undergo only a limited number of population doublings in vitro. This exhaustion of proliferative potential, called senescence, can be triggered when telomeres--the ends of linear chromosomes-cannot fulfil their normal protective functions. Here we show that senescent human fibroblasts display molecular markers characteristic of cells bearing DNA double-strand breaks. These markers include nuclear foci of phosphorylated histone H2AX and their co-localization with DNA repair and DNA damage checkpoint factors such as 53BP1, MDC1 and NBS1. We also show that senescent cells contain activated forms of the DNA damage checkpoint kinases CHK1 and CHK2. Furthermore, by chromatin immunoprecipitation and whole-genome scanning approaches, we show that the chromosome ends of senescent cells directly contribute to the DNA damage response, and that uncapped telomeres directly associate with many, but not all, DNA damage response proteins. Finally, we show that inactivation of DNA damage checkpoint kinases in senescent cells can restore cell-cycle progression into S phase. Thus, we propose that telomere-initiated senescence reflects a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres.},
}
@article {pmid14596906,
year = {2003},
author = {Fuchs, U and Rehkamp, GF and Slany, R and Follo, M and Borkhardt, A},
title = {The formin-binding protein 17, FBP17, binds via a TNKS binding motif to tankyrase, a protein involved in telomere maintenance.},
journal = {FEBS letters},
volume = {554},
number = {1-2},
pages = {10-16},
doi = {10.1016/s0014-5793(03)01063-9},
pmid = {14596906},
issn = {0014-5793},
mesh = {Amino Acid Motifs ; Binding Sites ; Cell Line ; Cytoplasm/chemistry ; Humans ; Mutagenesis, Site-Directed ; Precipitin Tests ; Protein Binding ; Sequence Deletion ; Tankyrases/*metabolism/physiology ; Telomere/metabolism ; Two-Hybrid System Techniques ; },
abstract = {In acute myelogenous and lymphoid leukemias, rearrangements involving the MLL (mixed lineage leukemia) gene at chromosome 11q23 are frequent. The truncated MLL protein is fused in-frame to a series of partner proteins. We previously identified the formin-binding protein 17 (FBP17) as such an MLL fusion partner. In this study, we explored in vivo physiological interaction partners of FBP17 using a two-hybrid assay and found tankyrase (TNKS), an ADP-ribose polymerase protein involved in telomere maintenance and mitogen-activated protein kinase signaling. We demonstrate that FBP17 binds via a special TNKS-binding motif to tankyrase. The physiological relevance is indicated by co-immunoprecipitation of endogenous proteins in 293T cells.},
}
@article {pmid14595125,
year = {2003},
author = {Van Ziffle, JA and Baerlocher, GM and Lansdorp, PM},
title = {Telomere length in subpopulations of human hematopoietic cells.},
journal = {Stem cells (Dayton, Ohio)},
volume = {21},
number = {6},
pages = {654-660},
doi = {10.1634/stemcells.21-6-654},
pmid = {14595125},
issn = {1066-5099},
support = {AI29524/AI/NIAID NIH HHS/United States ; },
mesh = {ADP-ribosyl Cyclase/analysis ; ADP-ribosyl Cyclase 1 ; Adolescent ; Adult ; Antigens, CD/analysis ; Antigens, CD34/analysis ; Bone Marrow Cells/physiology/ultrastructure ; Female ; Flow Cytometry/methods ; Hematopoietic Stem Cells/*diagnostic imaging/physiology ; Humans ; In Situ Hybridization, Fluorescence/methods ; Male ; Membrane Glycoproteins ; Middle Aged ; Telomere/physiology/*ultrastructure ; Ultrasonography ; },
abstract = {In order to test the hypothesis that the telomere length in human hematopoietic cells correlates with their proliferative potential, we analyzed the telomere length in highly purified subpopulations of bone marrow cells. Cells were sorted on the basis of CD34 and CD38 cell surface markers, and two samples were additionally sorted on the basis of Hoechst 33342 dye efflux allowing isolation of side population (SP) cells. The telomere length in limiting numbers of sorted cells was analyzed using a newly developed fluorescence in situ hybridization (flow-FISH) method in which hybridization of telomere probe in cells of interest is measured relative to control cells in the same tube. In all seven bone marrow samples analyzed, the telomere length in CD34(+)CD38(-) cells was longer than in CD34(+)CD38(+) cells from the same donor (p < 0.02). Results with sorted SP cells were less clear: the telomere fluorescence in these cells was very heterogeneous, and a reproducible difference in telomere length relative to CD34(+)CD38(-) cells could not be observed. We conclude that the telomere length in subpopulations of hematopoietic cells does appear to be correlated with the known proliferative potential of such cells and that further characterization of cells on the basis of telomere length is warranted for enrichment of very rare precursors of hematopoietic and other tissues.},
}
@article {pmid14585993,
year = {2003},
author = {Sharma, GG and Hwang, KK and Pandita, RK and Gupta, A and Dhar, S and Parenteau, J and Agarwal, M and Worman, HJ and Wellinger, RJ and Pandita, TK},
title = {Human heterochromatin protein 1 isoforms HP1(Hsalpha) and HP1(Hsbeta) interfere with hTERT-telomere interactions and correlate with changes in cell growth and response to ionizing radiation.},
journal = {Molecular and cellular biology},
volume = {23},
number = {22},
pages = {8363-8376},
pmid = {14585993},
issn = {0270-7306},
support = {R01 NS034746/NS/NINDS NIH HHS/United States ; NS 34746/NS/NINDS NIH HHS/United States ; R01 CA 66974/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Carrier Proteins/genetics/*metabolism ; Cell Division ; Cell Line ; Cell Survival/radiation effects ; Cell Transformation, Neoplastic ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/*genetics/*metabolism ; DNA Repair ; DNA-Binding Proteins ; Green Fluorescent Proteins ; Heterochromatin/genetics/*metabolism ; Humans ; Luminescent Proteins/genetics/metabolism ; Mice ; Protein Isoforms/genetics/metabolism ; Radiation Tolerance ; Recombinant Fusion Proteins/genetics/metabolism ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; Transplantation, Heterologous ; },
abstract = {Telomeres are associated with the nuclear matrix and are thought to be heterochromatic. We show here that in human cells the overexpression of green fluorescent protein-tagged heterochromatin protein 1 (GFP-HP1) or nontagged HP1 isoforms HP1(Hsalpha) or HP1(Hsbeta), but not HP1(Hsgamma), results in decreased association of a catalytic unit of telomerase (hTERT) with telomeres. However, reduction of the G overhangs and overall telomere sizes was found in cells overexpressing any of these three proteins. Cells overexpressing HP1(Hsalpha) or HP1(Hsbeta) also display a higher frequency of chromosome end-to-end associations and spontaneous chromosomal damage than the parental cells. None of these effects were observed in cells expressing mutants of GFP-DeltaHP1(Hsalpha), GFP-DeltaHP1(Hsbeta), or GFP-DeltaHP1(Hsgamma) that had their chromodomains deleted. An increase in the cell population doubling time and higher sensitivity to cell killing by ionizing radiation (IR) treatment was also observed for cells overexpressing HP1(Hsalpha) or HP1(Hsbeta). In contrast, cells expressing mutant GFP-DeltaHP1(Hsalpha) or GFP-DeltaHP1(Hsbeta) showed a decrease in population doubling time and decreased sensitivity to IR compared to the parental cells. The effects on cell doubling times were paralleled by effects on tumorigenicity in mice: overexpression of HP1(Hsalpha) or HP1(Hsbeta) suppressed tumorigenicity, whereas expression of mutant HP1(Hsalpha) or HP1(Hsbeta) did not. Collectively, the results show that human cells are exquisitely sensitive to the amount of HP1(Hsalpha) or HP1(Hsbeta) present, as their overexpression influences telomere stability, population doubling time, radioresistance, and tumorigenicity in a mouse xenograft model. In addition, the isoform-specific effects on telomeres reinforce the notion that telomeres are in a heterochromatinized state.},
}
@article {pmid14584801,
year = {2003},
author = {Heald, RA and Stevens, MF},
title = {Antitumour polycyclic acridines. Palladium(0) mediated syntheses of quino[4,3,2-kl]acridines bearing peripheral substituents as potential telomere maintenance inhibitors.},
journal = {Organic &amp; biomolecular chemistry},
volume = {1},
number = {19},
pages = {3377-3389},
doi = {10.1039/b305177n},
pmid = {14584801},
issn = {1477-0520},
mesh = {Acridines/*chemical synthesis/chemistry/*pharmacology ; Alkenes/chemistry ; Antineoplastic Agents/*chemical synthesis/chemistry/*pharmacology ; Cell Line, Tumor ; Dioxanes/chemistry ; Humans ; Inhibitory Concentration 50 ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Molecular Conformation ; Molecular Structure ; Palladium/*chemistry ; Telomerase/antagonists &amp; inhibitors/metabolism ; Telomere/*drug effects/genetics/*metabolism ; },
abstract = {Pd(0) mediated couplings between substituted 2-(pivaloylamino)benzeneboronic acids and 3,6-disubstituted-10-methylacridones 13 bearing a bromo or trifluoromethylsulfonyloxy substituent in the 1-position yield intermediate 1-arylacridones 16 which can be can be cyclised to new 8-methylquino[4,3,2-kl]acridines 17 with phosphorus oxychloride or 6 M HCI in EtOH. Heck reactions between triflate-substituted substrates 17 and acrylic acid derivatives afforded quinoacridines with unsaturated side-chains in the 6-position. Alkylboranes, prepared by interaction of 9-borabicyclo[3,3,1]nonane (9-BBN) and allyl acetate or N-allyltrifluoroacetamide, participated in Suzuki-Miyaura reactions with chloro-substituted 8-methylquinoacridines to form derivatives bearing functionalised propyl groups in the 6- and 10-positions. Representative 8-methylquinoacridines were methylated with methyl iodide to yield telomerase-inhibitory 8,13-dimethylquinoacridinium iodides 24.},
}
@article {pmid14582532,
year = {2003},
author = {Blasco, MA},
title = {Mammalian telomeres and telomerase: why they matter for cancer and aging.},
journal = {European journal of cell biology},
volume = {82},
number = {9},
pages = {441-446},
doi = {10.1078/0171-9335-00335},
pmid = {14582532},
issn = {0171-9335},
mesh = {Aging/*metabolism ; Animals ; Cell Cycle Proteins/metabolism ; Cell Survival ; Chromosomes/metabolism ; DNA Damage ; DNA Helicases ; DNA-Binding Proteins ; Mice ; Mice, Knockout ; Neoplasms/*metabolism ; Nuclear Proteins/metabolism ; RNA/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Chromosome ends, or telomeres, are formed by a special chromatin structure that protects them from recombination and degradation, thus preventing end-to-end chromosome fusions and other chromosomal aberrations. The functionality of telomeres, and that of the cellular activity that synthesizes them, telomerase, has been shown to impact on both cancer and aging, as well as on the organismal sensitivity to ionizing radiation. This review focuses on the analysis of different mouse models for proteins that are important for telomere function, which have highlighted the importance of telomeres and telomerase for cancer and aging.},
}
@article {pmid14581536,
year = {2003},
author = {Deng, Z and Atanasiu, C and Burg, JS and Broccoli, D and Lieberman, PM},
title = {Telomere repeat binding factors TRF1, TRF2, and hRAP1 modulate replication of Epstein-Barr virus OriP.},
journal = {Journal of virology},
volume = {77},
number = {22},
pages = {11992-12001},
pmid = {14581536},
issn = {0022-538X},
support = {R01 CA093606/CA/NCI NIH HHS/United States ; CA93606/CA/NCI NIH HHS/United States ; },
mesh = {Cell Cycle ; DNA/metabolism ; *DNA Replication ; HeLa Cells ; Humans ; *Plasmids ; Shelterin Complex ; Telomere ; Telomere-Binding Proteins/*physiology ; Telomeric Repeat Binding Protein 1/*physiology ; Telomeric Repeat Binding Protein 2/*physiology ; *Virus Replication ; },
abstract = {Epstein-Barr virus OriP confers cell cycle-dependent DNA replication and stable maintenance on plasmids in EBNA1-positive cells. The dyad symmetry region of OriP contains four EBNA1 binding sites that are punctuated by 9-bp repeats referred to as nonamers. Previous work has shown that the nonamers bind to cellular factors associated with human telomeres and contribute to episomal maintenance of OriP. In this work, we show that substitution mutation of all three nonamer sites reduces both DNA replication and plasmid maintenance of OriP-containing plasmids by 2.5- to 5-fold. The nonamers were required for high-affinity binding of TRF1, TRF2, and hRap1 to the dyad symmetry element but were not essential for the binding of EBNA1 as determined by DNA affinity purification from nuclear extracts. Chromatin immunoprecipitation assays indicated that TRF1, TRF2, and hRap1 bound OriP in vivo. Cell cycle studies indicate that TRF2 binding to OriP peaks in G(1)/S while TRF1 binding peaks in G(2)/M. OriP replication was inhibited by transfection of full-length TRF1 but not by deletion mutants lacking the myb DNA binding domain. In contrast, OriP replication was not affected by transfection of full-length TRF2 or hRap1 but was potently inhibited by dominant-negative TRF2 or hRap1 amino-terminal truncation mutants. Knockdown experiments with short interfering RNAs (siRNAs) directed against TRF2 and hRap1 severely reduced OriP replication, while TRF1 siRNA had a modest stimulatory effect on OriP replication. These results indicate that TRF2 and hRap1 promote, while TRF1 antagonizes, OriP-dependent DNA replication and suggest that these telomeric factors contribute to the establishment of replication competence at OriP.},
}
@article {pmid14579147,
year = {2004},
author = {Ballif, BC and Wakui, K and Gajecka, M and Shaffer, LG},
title = {Translocation breakpoint mapping and sequence analysis in three monosomy 1p36 subjects with der(1)t(1;1)(p36;q44) suggest mechanisms for telomere capture in stabilizing de novo terminal rearrangements.},
journal = {Human genetics},
volume = {114},
number = {2},
pages = {198-206},
pmid = {14579147},
issn = {0340-6717},
support = {P01 HD 39420/HD/NICHD NIH HHS/United States ; },
mesh = {*Chromosome Aberrations ; Chromosome Banding ; Chromosome Disorders ; Chromosome Mapping ; Chromosomes, Human, Pair 1/*genetics ; Cytogenetic Analysis/methods ; DNA/genetics ; DNA Probes ; DNA Replication/genetics ; *Gene Deletion ; Gene Rearrangement ; Humans ; In Situ Hybridization, Fluorescence ; Monosomy/*genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Telomere/*genetics ; *Translocation, Genetic ; },
abstract = {Monosomy 1p36 results from a variety of chromosome rearrangements, including terminal deletions, interstitial deletions, derivative chromosomes, and complex rearrangements. Our previous molecular studies on a large cohort of monosomy 1p36 subjects suggest that a significant percentage of terminal deletions of 1p36 are stabilized by the acquisition of telomeric sequences from other chromosome ends, forming derivative chromosomes (i.e., "telomere capture"). However, the molecular mechanism(s) that results in and/or stabilizes terminal deletions of 1p36 by telomere capture is poorly understood. In this report, we have mapped the translocation breakpoints in three subjects with der(1)t(1;1)(p36;q44) chromosomes by fluorescence in situ hybridization (FISH). These results indicate that the breakpoint locations are variable in all three subjects, with no common 1p deletion or 1q translocation breakpoints. In addition, sequence analysis of the 1p and 1q breakpoint-containing clones did not identify homologous sequences or low-copy repeats in the breakpoint regions, suggesting that nonallelic homologous recombination did not play a role in mediating these rearrangements. Microsatellite marker analysis indicates that two of the three derivative chromosomes were formed by intra-chromosomal rearrangements. These data are consistent with a number of recent reports in other model organisms that suggest break-induced replication at the site of a double-strand break may act as a mechanism of telomere capture by generating nonreciprocal translocations from terminally deleted chromosomes. Alternative models are also discussed.},
}
@article {pmid14578175,
year = {2003},
author = {Perner, S and Brüderlein, S and Hasel, C and Waibel, I and Holdenried, A and Ciloglu, N and Chopurian, H and Nielsen, KV and Plesch, A and Högel, J and Möller, P},
title = {Quantifying telomere lengths of human individual chromosome arms by centromere-calibrated fluorescence in situ hybridization and digital imaging.},
journal = {The American journal of pathology},
volume = {163},
number = {5},
pages = {1751-1756},
pmid = {14578175},
issn = {0002-9440},
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Blotting, Southern ; Calibration ; Centromere ; Child ; Child, Preschool ; Female ; Humans ; Image Processing, Computer-Assisted/*methods ; In Situ Hybridization, Fluorescence/*methods ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Sex Factors ; Telomere/*ultrastructure ; },
abstract = {Telomere length analysis has aroused considerable interest in biology and oncology. However, most published data are pan-genomic Southern-blot-based estimates. We developed T/C-FISH (telomere/centromere-FISH), allowing precise measurement of individual telomeres at every single chromosome arm. Metaphase preparations are co-hybridized with peptide nucleic acid probes for telomeric sequences and the chromosome 2 centromere serving as internal reference. Metaphase images are captured and karyotyped using dedicated software. A software module determines the absolute integrated fluorescence intensities of the p- and q-telomeres of each chromosome and the reference signal. Normalized data are derived by calculating the ratio of absolute telomere and reference signal intensities, and descriptive statistics are calculated. T/C-FISH detects even small differences in telomere length. Using T/C-FISH we have discovered an epigenetic process occurring in the human male postzygote or early embryo: in umbilical cord blood lymphocytes, telomeres on male Xqs are around 1100 bp shorter than female Xqs.},
}
@article {pmid14577841,
year = {2003},
author = {Schawalder, J and Paric, E and Neff, NF},
title = {Telomere and ribosomal DNA repeats are chromosomal targets of the bloom syndrome DNA helicase.},
journal = {BMC cell biology},
volume = {4},
number = {},
pages = {15},
pmid = {14577841},
issn = {1471-2121},
mesh = {Adenosine Triphosphatases/*analysis/chemistry/metabolism ; Alleles ; Binding Sites ; Bloom Syndrome/*enzymology/etiology/genetics ; Cell Cycle ; Cell Line ; Cell Nucleolus/enzymology ; Cell Nucleus Structures/enzymology ; Chromosomes/*enzymology/ultrastructure ; DNA Helicases/*analysis/chemistry/metabolism ; DNA Repair ; DNA Replication ; DNA, Ribosomal/analysis/*chemistry ; Genetic Variation ; Humans ; Protein Structure, Tertiary ; RecQ Helicases ; Recombinant Fusion Proteins/analysis/isolation &amp; purification ; Recombination, Genetic ; Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry/enzymology ; },
abstract = {BACKGROUND: Bloom syndrome is one of the most cancer-predisposing disorders and is characterized by genomic instability and a high frequency of sister chromatid exchange. The disorder is caused by loss of function of a 3' to 5' RecQ DNA helicase, BLM. The exact role of BLM in maintaining genomic integrity is not known but the helicase has been found to associate with several DNA repair complexes and some DNA replication foci.<br><br>RESULTS: Chromatin immunoprecipitation of BLM complexes recovered telomere and ribosomal DNA repeats. The N-terminus of BLM, required for NB localization, is the same as the telomere association domain of BLM. The C-terminus is required for ribosomal DNA localization. BLM localizes primarily to the non-transcribed spacer region of the ribosomal DNA repeat where replication forks initiate. Bloom syndrome cells expressing the deletion alleles lacking the ribosomal DNA and telomere association domains have altered cell cycle populations with increased S or G2/M cells relative to normal.<br><br>CONCLUSION: These results identify telomere and ribosomal DNA repeated sequence elements as chromosomal targets for the BLM DNA helicase during the S/G2 phase of the cell cycle. BLM is localized in nuclear bodies when it associates with telomeric repeats in both telomerase positive and negative cells. The BLM DNA helicase participates in genomic stability at ribosomal DNA repeats and telomeres.},
}
@article {pmid14576282,
year = {2003},
author = {Marian, CO and Bordoli, SJ and Goltz, M and Santarella, RA and Jackson, LP and Danilevskaya, O and Beckstette, M and Meeley, R and Bass, HW},
title = {The maize Single myb histone 1 gene, Smh1, belongs to a novel gene family and encodes a protein that binds telomere DNA repeats in vitro.},
journal = {Plant physiology},
volume = {133},
number = {3},
pages = {1336-1350},
pmid = {14576282},
issn = {0032-0889},
mesh = {Amino Acid Sequence ; Arabidopsis/genetics ; Base Sequence ; Chromosome Mapping ; Cloning, Molecular ; DNA, Complementary/chemistry/genetics ; DNA, Plant/chemistry/genetics ; DNA-Binding Proteins/metabolism ; Genes, Duplicate ; Molecular Sequence Data ; Multigene Family/genetics ; Oligonucleotides/metabolism ; Phylogeny ; Plant Proteins/*genetics/metabolism ; Sequence Analysis, DNA ; Telomere-Binding Proteins/*genetics/metabolism ; Zea mays/chemistry/*genetics/metabolism ; },
abstract = {We screened maize (Zea mays) cDNAs for sequences similar to the single myb-like DNA-binding domain of known telomeric complex proteins. We identified, cloned, and sequenced five full-length cDNAs representing a novel gene family, and we describe the analysis of one of them, the gene Single myb histone 1 (Smh1). The Smh1 gene encodes a small, basic protein with a unique triple motif structure of (a) an N-terminal SANT/myb-like domain of the homeodomain-like superfamily of 3-helical-bundle-fold proteins, (b) a central region with homology to the conserved H1 globular domain found in the linker histones H1/H5, and (c) a coiled-coil domain near the C terminus. The Smh-type genes are plant specific and include a gene family in Arabidopsis and the PcMYB1 gene of parsley (Petroselinum crispum) but are distinct from those (AtTRP1, AtTBP1, and OsRTBP1) recently shown to encode in vitro telomere-repeat DNA-binding activity. The Smh1 gene is expressed in leaf tissue and maps to chromosome 8 (bin 8.05), with a duplicate locus on chromosome 3 (bin 3.09). A recombinant full-length SMH1, rSMH1, was found by band-shift assays to bind double-stranded oligonucleotide probes with at least two internal tandem copies of the maize telomere repeat, TTTAGGG. Point mutations in the telomere repeat residues reduced or abolished the binding, whereas rSMH1 bound nonspecifically to single-stranded DNA probes. The two DNA-binding motifs in SMH proteins may provide a link between sequence recognition and chromatin dynamics and may function at telomeres or other sites in the nucleus.},
}
@article {pmid14575650,
year = {2003},
author = {Golubev, A and Khrustalev, S and Butov, A},
title = {An in silico investigation into the causes of telomere length heterogeneity and its implications for the Hayflick limit.},
journal = {Journal of theoretical biology},
volume = {225},
number = {2},
pages = {153-170},
doi = {10.1016/s0022-5193(03)00229-7},
pmid = {14575650},
issn = {0022-5193},
mesh = {Animals ; Cell Death ; Cell Division ; *Cell Physiological Phenomena ; Cellular Senescence ; *Computer Simulation ; Humans ; Models, Biological ; Telomere/*ultrastructure ; },
abstract = {UNLABELLED: In telomerase-negative cell populations the mean telomere length (TL) decreases with increasing population doubling number (PD). A critically small TL is believed to stop cell proliferation at a cell-, age- and species-specific PD thus defining the Hayflick limit. However, positively skewed TL distributions are broad compared to differences between initial and final mean TL and strongly overlap at middle and late PD, which is inconsistent with a limiting role of TL. We used computer-assisted modelling to define what set of premises may account for the above. Our model incorporates the following concepts. DNA end replication problem: telomeres loose 1 shortening unit (SU) upon each cell division. Free radical-caused TL decrease: telomeres experience random events resulting in the loss of a random SU number within a remaining TL. Stochasticity of gene expression and cell differentiation: cells experience random events inducing mitoses or committing cells to proliferation arrest, the latter option requiring a specified number of mitoses to be passed. Cells whose TL reaches 1SU cannot divide. The proliferation kinetics of such virtual cells conforms to the transition probability model of cell cycle. When no committing events occur and at realistic SU estimates of the initial TL, maximal PD values far exceed the Hayflick limit observed in normal cells and are consistent with the crisis stage entered by transformed cells that have surpassed the Hayflick limit. At intermediate PD, symmetrical TL distributions are yielded. Upon introduction of committing events making the ratio of the rates of proliferating and committing events (P/C) range from 1.10 to 1.25, TL distributions at intermediate PD become positively skewed, and virtual cell clones show bimodal size distributions. At P/C as high as 1.25 the majority of virtual cells at maximal PD contain telomeres with TL>1SU. A 10% increase in P/C within the 1.10-1.25 range produces a two-fold increase in the maximal PD, which can reach values of up to 25 observed in rodent and some human cells. Increasing the number of committed mitoses from 0 to 10 can increases PD to about 50 observed in human fibroblasts. Introduction of the random TL breakage makes the shapes of TL distributions quite dissimilar from those observed in real cells.<br><br>CONCLUSIONS: Telomere length decrease is a correlate of cell proliferation that cannot alone account for the Hayflick limit, which primarily depends on parameters of cell population kinetics. Free radical damage influences the Hayflick limit not through TL but rather by affecting the ratio of the rates of events that commit cells to mitoses or to proliferation arrest.},
}
@article {pmid14573759,
year = {2003},
author = {Incles, CM and Schultes, CM and Kelland, LR and Neidle, S},
title = {Acquired cellular resistance to flavopiridol in a human colon carcinoma cell line involves up-regulation of the telomerase catalytic subunit and telomere elongation. Sensitivity of resistant cells to combination treatment with a telomerase inhibitor.},
journal = {Molecular pharmacology},
volume = {64},
number = {5},
pages = {1101-1108},
doi = {10.1124/mol.64.5.1101},
pmid = {14573759},
issn = {0026-895X},
mesh = {Acridines/pharmacology ; Antineoplastic Agents/*pharmacology ; Catalytic Domain ; Colonic Neoplasms/pathology ; Cyclin D1/biosynthesis ; Cyclin T ; Cyclin-Dependent Kinase 9/biosynthesis ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins/biosynthesis ; DNA-Binding Proteins ; Drug Combinations ; Drug Resistance, Neoplasm/*physiology ; Enzyme Inhibitors/*pharmacology ; Flavonoids/*pharmacology ; Humans ; Piperidines/*pharmacology ; Telomerase/antagonists &amp; inhibitors/biosynthesis/metabolism ; Telomere/metabolism ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/biosynthesis ; Up-Regulation/drug effects ; },
abstract = {Flavopiridol is a broad-spectrum inhibitor of cyclin-dependent kinases and of global transcription via the inhibition of positive transcription elongation factor b (P-TEFb). Although flavopiridol is currently undergoing phase II clinical trials, acquired cellular resistance to the compound during treatment is a potential problem, as it is with almost all current anticancer agents. A HCT116 human colon carcinoma cell line with an acquired 8-fold resistance to flavopiridol has been established. We report here that there are changes in these resistant cells in terms of telomere length and telomerase activity, whereas no change in the expression of the P-TEFb subunits CDK9, cyclin T1, cyclin T2a, or cyclin T2b was observed. The level of mRNA expression for the telomerase catalytic subunit hTERT was increased over 2-fold in the resistant cells, and mean telomere length was found to be 2 kb longer than the parental length, although telomerase activity was unchanged. The level of mRNA expression for the telomeric binding protein Pot1 was also increased. We also report that treatment of HCT116 cells with a combination of the G-quadruplex interacting telomerase inhibitor BRACO-19 and flavopiridol results in a 3-fold decrease in population doubling and prevents recovery from treatment with either compound alone. Treatment of flavopiridol-resistant cells with BRACO-19 alone also led to rapid inhibition of cell growth, which is not observed in the parental line. The finding that only the resistant line, with up-regulated telomerase, responds to this G-quadruplex inhibitor is consistent with the hypothesis that the mechanism of BRACO-19 down-regulation of cell growth directly involves the targeting of telomeres and telomerase.},
}
@article {pmid14568262,
year = {2003},
author = {Oh, BK and Jo Chae, K and Park, C and Kim, K and Jung Lee, W and Han, KH and Nyun Park, Y},
title = {Telomere shortening and telomerase reactivation in dysplastic nodules of human hepatocarcinogenesis.},
journal = {Journal of hepatology},
volume = {39},
number = {5},
pages = {786-792},
doi = {10.1016/s0168-8278(03)00395-7},
pmid = {14568262},
issn = {0168-8278},
mesh = {Adult ; Carcinoma, Hepatocellular/*etiology/pathology ; Case-Control Studies ; Chronic Disease ; Enzyme Activation ; Female ; Hepatitis/complications/enzymology/genetics ; Humans ; Liver Cirrhosis/complications/enzymology/genetics ; Liver Diseases/complications/*enzymology/*genetics/pathology ; Liver Neoplasms/*etiology/pathology ; Male ; Middle Aged ; Polymorphism, Restriction Fragment Length ; Precancerous Conditions/complications/*enzymology/*genetics/pathology ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {BACKGROUNDS/AIMS: The maintenance of telomere with telomerase reactivation, vital for carcinogenesis, was studied in human multistep hepatocarcinogenesis for the characterization of borderline lesions.<br><br>METHODS: The terminal restriction fragment length (TRFL) and telomerase activity (TA) were examined in 3 chronic hepatitis (CH), 10 cirrhosis, 7 large regenerative nodules (LRNs), 30 low grade dysplastic nodules (LGDNs), 6 high grade DNs (HGDNs), 3 DNs with hepatocellular carcinoma (HCC) foci, 11 HCCs, and 4 normal livers by Southern hybridization and TRAPeze Elisa telomerase detection.<br><br>RESULTS: The TRFL and TA showed significant differences between the LGDNs and HGDNs. Most LGDNs had similar levels of TRFL and TA to those of the CH, cirrhosis and LRNs, however, 17% of LGDNs revealed shortening of telomeres up to the levels of HGDNs and 7% of LGDNs showed high levels of TA. The levels of TRFL and TA in HGDNs showed no significant differences from those of DNs with HCC foci and HCCs.<br><br>CONCLUSIONS: The shortening of telomeres and reactivation of telomerase occur in the DNs during the early stages of hepatocarcinogenesis, with a significant change in the transition of LGDNs to HGDNs. The characteristics of HGDNs are considered to be closer to those of HCCs.},
}
@article {pmid14565979,
year = {2003},
author = {Li, B and de Lange, T},
title = {Rap1 affects the length and heterogeneity of human telomeres.},
journal = {Molecular biology of the cell},
volume = {14},
number = {12},
pages = {5060-5068},
pmid = {14565979},
issn = {1059-1524},
support = {K08 CA076026/CA/NCI NIH HHS/United States ; CA 76026/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Nucleus/*metabolism ; Cells, Cultured ; Cloning, Molecular ; DNA-Binding Proteins/metabolism ; Fluorescent Antibody Technique, Indirect ; HeLa Cells ; Humans ; Models, Molecular ; Mutation ; Protein Binding ; Protein Structure, Tertiary/physiology ; Repressor Proteins/metabolism ; Retroviridae ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/*metabolism ; Transcription Factors/genetics/*metabolism ; },
abstract = {Telomere length is controlled in part by cis-acting negative regulators that limit telomere extension by telomerase. In budding yeast, the major telomere length regulator scRap1 binds to telomeric DNA and acts to inhibit telomere elongation in cis. Because the human Rap1 ortholog hRap1 does not bind to telomeric DNA directly but is recruited to telomeres by TRF2, we examined its role in telomere length control. The data are consistent with hRap1 being a negative regulator of telomere length, indicating functional conservation. Deletion mapping confirmed that hRap1 is tethered to telomeres through interaction of its C terminus with TRF2. The telomere length phenotypes of hRap1 deletion mutants implicated both the BRCT and Myb domain as protein interaction domains involved in telomere length regulation. By contrast, scRap1 binds to telomeres with its Myb domains and uses its C terminus to recruit the telomere length regulators Rif1 and Rif2. Together, our data show that although the role of Rap1 at telomeres has been largely conserved, the domains of Rap1 have undergone extensive functional changes during eukaryotic evolution. Surprisingly, hRap1 alleles lacking the BRCT domain diminished the heterogeneity of human telomeres, indicating that hRap1 also plays a role in the regulation of telomere length distribution.},
}
@article {pmid14563172,
year = {2003},
author = {McGuire, JM and Gana, JA and Petcherskaia, M and Kirk, KE},
title = {Protein binding to expanded telomere repeats in Tetrahymena thermophila.},
journal = {The Journal of eukaryotic microbiology},
volume = {50},
number = {5},
pages = {341-348},
doi = {10.1111/j.1550-7408.2003.tb00146.x},
pmid = {14563172},
issn = {1066-5234},
mesh = {Animals ; DNA, Protozoan/physiology ; Electrophoretic Mobility Shift Assay ; Guanine/physiology ; Protein Binding/physiology ; Protozoan Proteins/metabolism/*physiology ; Repetitive Sequences, Nucleic Acid/physiology ; Telomere/metabolism/*physiology ; Telomere-Binding Proteins/metabolism/*physiology ; Tetrahymena thermophila/genetics/metabolism/*physiology ; Thymine/physiology ; },
abstract = {The ends of eukaryotic chromosomes are protected by DNA-protein structures called telomeres. Telomeric DNA is highly conserved, usually consisting of long tracts of a repeating G-rich sequence. Tetrahymena thermophila telomeric DNA consists of alternating blocks of GGGG and TT sequences (i.e. a G4T2 repeat sequence). We examined the relative importance of the guanine and thymine elements of the repeat sequence in promoting in vitro binding by T. thermophila proteins. We identified single- and, for the first time, double-stranded telomere binding activities from a crude T. thermophila protein extract and tested the binding of these activities to altered telomere repeat sequences. All deletions or substitutions made to the guanine element virtually abolished binding, indicating that four G's are essential for recognition by the binding activity. However, G's alone are not sufficient for efficient binding, as elimination of the thymine element dramatically reduced binding. By contrast, substantial expansion of the thymine element was well tolerated, even though one such change, G4T4, is lethal in vivo. We tested up to a four-fold expansion of the thymine element and found that highly efficient binding was still achieved. These results suggest a minimal recognition sequence for T. thermophila proteins, with the T element providing an important spacer between essential G elements.},
}
@article {pmid14561997,
year = {2003},
author = {Lee, JJ and Nam, CE and Kook, H and Maciejewski, JP and Kim, YK and Chung, IJ and Park, KS and Lee, IK and Hwang, TJ and Kim, HJ},
title = {Constitution and telomere dynamics of bone marrow stromal cells in patients undergoing allogeneic bone marrow transplantation.},
journal = {Bone marrow transplantation},
volume = {32},
number = {9},
pages = {947-952},
doi = {10.1038/sj.bmt.1704253},
pmid = {14561997},
issn = {0268-3369},
mesh = {Adolescent ; Adult ; Bone Marrow Cells ; *Bone Marrow Transplantation ; Case-Control Studies ; Cells, Cultured ; Child ; Female ; Genotype ; Hematologic Diseases/therapy ; Humans ; Male ; Mesenchymal Stem Cells/cytology ; Stromal Cells/*cytology ; Telomere/*metabolism ; *Transplantation Chimera ; Transplantation, Homologous ; },
abstract = {We evaluated the genotypic origin of mesenchymal stem cells (MSC) following sex-mismatched allogeneic bone marrow transplantation (BMT), and investigated the telomere dynamics in MSC in normal individuals and patients after BMT. The study population consisted of 11 patients with hematologic disorders who showed complete chimerism after BMT. Telomere length was measured in MSC using Southern blotting analysis in eight patients and 18 healthy subjects as a control group. Following culture, MSC were identified by the expression of SH2 and SH4, and lack of CD14, CD34, and CD45. All MSC showed the recipient genotype, based on the results of fluorescent in situ hybridization analysis using X-chromosome satellite probes or microsatellite DNA polymorphism analysis. The mean telomere length in MSC from normal controls was 7.2+/-0.53 kb (range, 6.12-7.78), and progressive telomere shortening was seen with age. There was no significant difference in MSC telomere length between the BMT group and age-matched controls. This study confirmed that the MSC isolated from the recipients of allogeneic BMT did not have the donor genotype, despite complete chimerism. Moreover, MSC were demonstrated to show progressive loss of telomere length with age, but the telomeres in MSC were not affected by BMT.},
}
@article {pmid14561302,
year = {2003},
author = {Sýkorová, E and Lim, KY and Kunická, Z and Chase, MW and Bennett, MD and Fajkus, J and Leitch, AR},
title = {Telomere variability in the monocotyledonous plant order Asparagales.},
journal = {Proceedings. Biological sciences},
volume = {270},
number = {1527},
pages = {1893-1904},
pmid = {14561302},
issn = {0962-8452},
mesh = {Autoradiography ; DNA Primers ; *Genetic Variation ; In Situ Hybridization, Fluorescence ; Liliaceae/*enzymology/*genetics ; *Phylogeny ; Sequence Analysis, DNA ; Telomerase/genetics/metabolism ; Telomere/*genetics ; },
abstract = {A group of monocotyledonous plants within the order Asparagales, forming a distinct clade in phylogenetic analyses, was reported previously to lack the 'typical' Arabidopsis-type telomere (TTTAGGG)(n). This stimulated us to determine what has replaced these sequences. Using slot-blot and fluorescent in situ hybridization (FISH) to species within this clade, our results indicate the following. 1. The typical Arabidopsis-type telomeric sequence has been partly or fully replaced by the human-type telomeric sequence (TTAGGG)(n). Species in Allium lack the human-type variant. 2. In most cases the human variant occurs along with a lower abundance of two or more variants of the minisatellite sequences (of seven types evaluated), usually these being the consensus telomeric sequence of Arabidopsis, Bombyx (TTAGG)(n) and Tetrahymena (TTGGGG)(n). FISH shows that the variants can occur mixed together at the telomere. 3. Telomerases generate products with a 6 base pair periodicity and when sequenced they reveal predominantly a reiterated human-type motif. These motifs probably form the 'true telomere' but the error rate of motif synthesis is higher compared with 'typical' plant telomerases. The data indicate that the Asparagales clade is unified by a mutation resulting in a switch from synthesis of Arabidopsis-like telomeres to a low-fidelity synthesis of human-like telomeres.},
}
@article {pmid14559908,
year = {2004},
author = {Iwano, T and Tachibana, M and Reth, M and Shinkai, Y},
title = {Importance of TRF1 for functional telomere structure.},
journal = {The Journal of biological chemistry},
volume = {279},
number = {2},
pages = {1442-1448},
doi = {10.1074/jbc.M309138200},
pmid = {14559908},
issn = {0021-9258},
mesh = {Animals ; Chromatin/metabolism ; Chromosome Aberrations ; DNA/metabolism ; Embryo, Mammalian/cytology ; Flow Cytometry ; Gene Deletion ; In Situ Hybridization, Fluorescence ; Mice ; Microscopy, Fluorescence ; Molecular Sequence Data ; Mutation ; Precipitin Tests ; Protein Binding ; Stem Cells/metabolism ; Telomere/*physiology/ultrastructure ; Telomeric Repeat Binding Protein 1/metabolism/*physiology ; Transgenes ; },
abstract = {Telomeres are comprised of telomeric DNA sequences and associated binding molecules. Their structure functions to protect the ends of linear chromosomes and ensure chromosomal stability. One of the mammalian telomere-binding factors, TRF1, localizes telomeres by binding to double-stranded telomeric DNA arrays. Because the overexpression of wild-type and dominant-negative TRF1 induces progressive telomere shortening and elongation in human cells, respectively, a proposed major role of TRF1 is that of a negative regulator of telomere length. Here we report another crucial function of TRF1 in telomeres. In conditional mouse TRF1 null mutant embryonic stem cells, TRF1 deletion induced growth defect and chromosomal instability. Although no clear telomere shortening or elongation was observed in short term cultured TRF1-deficient cells, abnormal telomere signals were observed, and TRF1-interacting telomere-binding factor, TIN2, lost telomeric association. Furthermore, another double-stranded telomeric DNA-binding factor, TRF2, also showed decreased telomeric association. Importantly, end-to-end fusions with detectable telomere signals at fusion points accumulated in TRF1-deficient cells. These results strongly suggest that TRF1 interacts with other telomere-binding molecules and integrates into the functional telomere structure.},
}
@article {pmid14559794,
year = {2003},
author = {Gomez, D and Aouali, N and Renaud, A and Douarre, C and Shin-Ya, K and Tazi, J and Martinez, S and Trentesaux, C and Morjani, H and Riou, JF},
title = {Resistance to senescence induction and telomere shortening by a G-quadruplex ligand inhibitor of telomerase.},
journal = {Cancer research},
volume = {63},
number = {19},
pages = {6149-6153},
pmid = {14559794},
issn = {0008-5472},
mesh = {Cell Line, Tumor ; Cellular Senescence/drug effects/physiology ; DNA/metabolism ; DNA-Binding Proteins ; Drug Resistance, Neoplasm ; Enzyme Inhibitors/*pharmacology ; G-Quadruplexes ; Humans ; Ligands ; Lung Neoplasms/*drug therapy/enzymology/pathology ; RNA, Messenger/biosynthesis/genetics ; Telomerase/*antagonists &amp; inhibitors/biosynthesis/genetics ; Telomere/*drug effects/physiology ; Triazines/*pharmacology ; },
abstract = {The molecular mechanisms induced by G-quadruplex ligands to trigger senescence in mammalian cells are still unknown, although the critical role of telomerase is highly suspected. JFA2 cells selected for resistance to senescence induced by the G-quadruplex ligand 12459 presented an overexpression of hTERT transcript that correlated to a functional increase in telomerase activity and telomere length. Consistently, treatment with 12459 failed to trigger senescence and telomere shortening in JFA2 cells. Resistant cells also presented cross-resistance for senescence induction to telomestatin, another G-quadruplex ligand from a different series, but not to other anticancer agents, indicating the selectivity of the resistance mechanism. We, thus, provide evidence that telomerase activity and telomere length are key cellular determinants of the resistance to G-quadruplex ligands.},
}
@article {pmid14535890,
year = {2003},
author = {Cesare, AJ and Quinney, N and Willcox, S and Subramanian, D and Griffith, JD},
title = {Telomere looping in P. sativum (common garden pea).},
journal = {The Plant journal : for cell and molecular biology},
volume = {36},
number = {2},
pages = {271-279},
doi = {10.1046/j.1365-313x.2003.01882.x},
pmid = {14535890},
issn = {0960-7412},
support = {GM31819/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; *Chromosomes, Plant ; DNA, Plant/chemistry/genetics ; Image Processing, Computer-Assisted ; Nucleic Acid Conformation ; Oligonucleotide Array Sequence Analysis ; Pisum sativum/*genetics ; Telomere/*chemistry/genetics/ultrastructure ; },
abstract = {Telomeres vary greatly in size among plants and, in most higher plants, consist of a long array of 5'-TTTAGGG-3'/3'-AAATCCC-5' (TTTAGGG) repeats. Recently, telomeric DNA in human, mouse, oxytricha, and trypanosome chromosomes have been found arranged into loops (t-loops), proposed to sequester the telomere from unwanted repair events and prevent activation of DNA damage checkpoints. We have asked whether t-loops exist in the higher order plant Pisum sativum (garden pea). DNA was isolated from the shoots and root tips of germinating seeds. Analysis of the telomeric restriction fragments showed that DNA hybridizing to a (TTTAGGG)n probe migrated as a smear centering around 25 kb, and direct sequencing verified the repeat to be (TTTAGGG)n. Total DNA in isolated nuclei was photo-cross-linked, and the telomeric restriction fragments were purified by gel filtration. Electron microscopic (EM) analysis revealed DNA molecules arranged as t-loops with a size distribution consistent with that seen by gel electrophoresis. Some molecules had loops as large as 75 kb. These results show that the arrangement of telomeric DNA into loops occurs in higher plants.},
}
@article {pmid14534687,
year = {2003},
author = {Sharma, GG and Hall, EJ and Dhar, S and Gupta, A and Rao, PH and Pandita, TK},
title = {Telomere stability correlates with longevity of human beings exposed to ionizing radiations.},
journal = {Oncology reports},
volume = {10},
number = {6},
pages = {1733-1736},
pmid = {14534687},
issn = {1021-335X},
support = {CA49062/CA/NCI NIH HHS/United States ; NS34746/NS/NINDS NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Cell Death ; Cell Division ; Chromosomes/radiation effects/ultrastructure ; DNA/radiation effects ; Female ; G2 Phase ; Genes, p53 ; Humans ; Karyotyping ; *Longevity ; Lymphocytes/ultrastructure ; Male ; Metaphase ; Middle Aged ; Mitosis ; Occupational Exposure ; Prostatic Neoplasms/metabolism ; *Radiation, Ionizing ; Retinoblastoma Protein/genetics/metabolism ; Spectroscopy, Fourier Transform Infrared ; Telomere/*radiation effects/*ultrastructure ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Normal somatic cells have a finite number of divisions, a limited capacity to proliferate. Human telomeres contain TTAGGG repeats which are considered a molecular clock marker. The gradual and progressive telomere shortening at each replicative cycle is associated, through the activation of pRB and p53 pathways and genomic instability, to the replicative senescence, a non-dividing state and widespread cell death. There is no information available about telomere status in individuals who live long and have been exposed to ionizing radiations (IR). To determine the telomere stability, we examined telomeres at metaphase, G2-type chromosome aberrations after IR treatment and karyotypic analysis of 15 individuals. Three individuals were above the age of 80 years and 1 among the 3 was estimated to have received more than 10 Gy of occupational exposure about 30 years back. The other 12 were cancer patients that had received more than 50 Gy of gamma-radiation for therapeutic purposes. No telomere instability or defective G2 chromosome repair was found in 3 individuals above the age of 80 years. Whereas, 3 out of 7 prostate and 1 out of 5 breast cancer patients showed higher G2-type chromosome damage as well as a high frequency of telomeric association (also known as chromosome end associations) along with frequent loss of telomeres. Present studies demonstrate that telomere stability along with normal G2 chromosome repair correlates with the longevity of human beings, whereas defective G2 chromosome repair and telomere instability correlate with the radiotherapy related late toxicity.},
}
@article {pmid14530986,
year = {2003},
author = {Sýkorová, E and Lim, KY and Fajkus, J and Leitch, AR},
title = {The signature of the Cestrum genome suggests an evolutionary response to the loss of (TTTAGGG)n telomeres.},
journal = {Chromosoma},
volume = {112},
number = {4},
pages = {164-172},
pmid = {14530986},
issn = {0009-5915},
mesh = {Base Sequence ; Blotting, Southern ; Cestrum/*genetics ; DNA Primers ; DNA Probes ; *Evolution, Molecular ; *Genome, Plant ; In Situ Hybridization, Fluorescence ; Minisatellite Repeats/*genetics ; Sequence Alignment ; Telomere/*genetics ; },
abstract = {The genus Cestrumin the Solanaceae family is unusual in lacking Arabidopsis-type telomeres (TTTAGGG)n, although short interstitial telomeric sequences (ITSs) occur scattered throughout the genome in both orientations. To isolate candidate telomeric sequences in Cestrum we assumed that some of the ITSs were residues of the original telomeres and that they may still be located in the vicinity of present-day telomeres. Three sequence types associated with ITSs were cloned and characterized; these were termed NA3G, BR23 and A/T-rich minisatellite. These high copy number sequences are dispersed across the genome and clustered at a number of chromosomal loci. Their association with ITSs, which can act as recombination hotspots, might indicate past recombination and chromosomal fusion events, processes that may have contributed to the large size of Cestrum chromosomes. The sequences are frequently arranged as NA3G-ITS-BR23 blocks embedded in an A/T-rich minisatellite array. The A/T-rich minisatellite is of particular interest because the consensus 5'-T(4-5)AGCAG-3' might be a derivative of "typical" eukaryotic telomeric sequence motifs. The sequence is abundant at the end of some chromosomes in C. parqui and is found not only in Cestrum but also in the closely related genera Sessea and Vestia, which also lack Arabidopsis-type telomeric sequences. However, the sequence is absent from the Solanaceae genera investigated that are outside the group, including the closely related genus Streptosolen, which all have the Arabidopsis-type telomere. The data indicate that the A/T rich minisatellite might have evolved in response to the loss of Arabidopsis-type telomeres.},
}
@article {pmid14530383,
year = {2003},
author = {Fernandez-Capetillo, O and Liebe, B and Scherthan, H and Nussenzweig, A},
title = {H2AX regulates meiotic telomere clustering.},
journal = {The Journal of cell biology},
volume = {163},
number = {1},
pages = {15-20},
pmid = {14530383},
issn = {0021-9525},
mesh = {Animals ; Histones/deficiency/*metabolism ; In Situ Hybridization, Fluorescence ; Meiosis/*physiology ; Mice ; Telomere/*physiology ; },
abstract = {The histone H2A variant H2AX is phosphorylated in response to DNA double-strand breaks originating from diverse origins, including dysfunctional telomeres. Here, we show that normal mitotic telomere maintenance does not require H2AX. Moreover, H2AX is dispensable for the chromosome fusions arising from either critically shortened or deprotected telomeres. However, H2AX has an essential role in controlling the proper topological distribution of telomeres during meiotic prophase I. Our results suggest that H2AX is a downstream effector of the ataxia telangiectasia-mutated kinase in controlling telomere movement during meiosis.},
}
@article {pmid14525974,
year = {2003},
author = {Gomez, D and Aouali, N and Londoño-Vallejo, A and Lacroix, L and Mégnin-Chanet, F and Lemarteleur, T and Douarre, C and Shin-ya, K and Mailliet, P and Trentesaux, C and Morjani, H and Mergny, JL and Riou, JF},
title = {Resistance to the short term antiproliferative activity of the G-quadruplex ligand 12459 is associated with telomerase overexpression and telomere capping alteration.},
journal = {The Journal of biological chemistry},
volume = {278},
number = {50},
pages = {50554-50562},
doi = {10.1074/jbc.M308440200},
pmid = {14525974},
issn = {0021-9258},
mesh = {Cell Division ; Cell Line, Tumor ; DNA/metabolism ; DNA, Complementary/metabolism ; DNA-Binding Proteins ; Dose-Response Relationship, Drug ; Dose-Response Relationship, Radiation ; Drug Resistance, Multiple ; Humans ; In Situ Hybridization, Fluorescence ; Inhibitory Concentration 50 ; Ligands ; Mutation ; Oligonucleotides/metabolism ; Phenotype ; Protein Binding ; Quinolinium Compounds/*chemistry/pharmacology ; RNA/metabolism ; Radiation, Ionizing ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*biosynthesis/metabolism ; Telomere/metabolism/*ultrastructure ; Transfection ; Triazines/*chemistry/pharmacology ; },
abstract = {Ligands that stabilize the telomeric G-rich single-stranded DNA overhang into G-quadruplex can be considered as potential antitumor agents that block telomere replication. Ligand 12459, a potent G-quadruplex ligand that belongs to the triazine series, has been previously shown to induce both telomere shortening and apoptosis in the human A549 cell line as a function of its concentration and time exposure. We show here that A549 clones obtained after mutagenesis and selected for resistance to the short term effect of ligand 12459 frequently displayed hTERT transcript overexpression (2-6-fold). Overexpression of hTERT was also characterized in two resistant clones (JFD10 and JFD18) as an increase in telomerase activity, leading to an increase in telomere length. An increased frequency of anaphase bridges was also detected in JFD10 and JFD18, suggesting an alteration of telomere capping functions. Transfection of either hTERT or DN-hTERT cDNAs into A549 cells did not confer resistance or hypersensitivity to the short term effect of ligand 12459, indicating that telomerase expression is not the main determinant of the antiproliferative effect of ligand 12459. In contrast, transfection of DN-hTERT cDNA into resistant JFD18 cells restored sensitivity to apoptotic concentrations of ligand 12459, suggesting that telomerase does participate in the resistance to this G-quadruplex ligand. This work provides evidence that telomerase activity is not the main target for the 12459 G-quadruplex ligand but that hTERT functions contribute to the resistance phenotype to this class of agents.},
}
@article {pmid14522942,
year = {2003},
author = {Bertuch, AA and Lundblad, V},
title = {Which end: dissecting Ku's function at telomeres and double-strand breaks.},
journal = {Genes &amp; development},
volume = {17},
number = {19},
pages = {2347-2350},
doi = {10.1101/gad.1146603},
pmid = {14522942},
issn = {0890-9369},
mesh = {Antigens, Nuclear/chemistry/*physiology ; DNA/*metabolism ; *DNA Helicases ; DNA Repair/physiology ; DNA-Binding Proteins/chemistry/*physiology ; Dimerization ; Humans ; Ku Autoantigen ; Mutation ; Protein Conformation ; Telomere/*physiology ; Yeasts/genetics ; },
}
@article {pmid14522904,
year = {2003},
author = {Velicescu, M and Yu, J and Herbert, BS and Shay, JW and Granada, E and Dubeau, L},
title = {Aneuploidy and telomere attrition are independent determinants of crisis in SV40-transformed epithelial cells.},
journal = {Cancer research},
volume = {63},
number = {18},
pages = {5813-5820},
pmid = {14522904},
issn = {0008-5472},
support = {CA 70907/CA/NCI NIH HHS/United States ; CA 79750/CA/NCI NIH HHS/United States ; CA14089/CA/NCI NIH HHS/United States ; CA51167/CA/NCI NIH HHS/United States ; },
mesh = {*Aneuploidy ; Antigens, Polyomavirus Transforming/biosynthesis ; Cell Line, Tumor ; Cell Transformation, Viral/*genetics ; Cystadenoma/*genetics/metabolism/pathology ; DNA-Binding Proteins ; Diploidy ; Enzyme Activation ; Epithelial Cells/pathology/physiology ; Female ; Humans ; Ovarian Neoplasms/*genetics/metabolism/pathology ; Simian virus 40 ; Telomerase/biosynthesis/metabolism ; Telomere/*genetics ; },
abstract = {Replicative immortality is achieved in vitro by overcoming two mortality checkpoints, M1 (senescence) and M2 (crisis). Cancer cells are thought to overcome M2 by activating telomerase, an enzyme believed to confer genomic stability in addition to maintaining telomeric sequences above a critical length. Here we show that a subset of cultured ovarian cystadenoma cells expressing SV40 large T-antigen, which allows bypassing of M1, develop a specific type of genomic instability, characterized by numerical (as opposed to structural) chromosomal alterations, that leads to non-telomere-based premature growth arrest/crisis. Cells recover from this type of growth arrest and stabilize their ploidy status without telomerase expression. In these cases, telomeres continue to shorten until a second, telomere-based growth arrest/crisis event is reached. Transfection of the catalytic subunit of telomerase does not immortalize cells harboring severe abnormalities in their DNA ploidy but results in immortalization of diploid cells. We conclude that changes in DNA ploidy constitute an important determinant of growth arrest that is independent of telomere attrition in a subset of SV40 large T-antigen-expressing cystadenoma cells. Reestablishment or emergence of ploidy stability, which is not always dependent on telomerase activation, is necessary for acquisition of the potential to achieve replicative immortality.},
}
@article {pmid14516782,
year = {2003},
author = {Ichiyoshi, H and Kiyozuka, Y and Kishimoto, Y and Fukuhara, S and Tsubura, A},
title = {Massive telomere loss and telomerase RNA expression in dexamethasone-induced apoptosis in mouse thymocytes.},
journal = {Experimental and molecular pathology},
volume = {75},
number = {2},
pages = {178-186},
doi = {10.1016/s0014-4800(03)00050-9},
pmid = {14516782},
issn = {0014-4800},
mesh = {Animals ; Apoptosis/*drug effects ; Body Weight ; Cells, Cultured ; DNA/drug effects ; DNA Primers/chemistry ; Dexamethasone/*pharmacology ; Female ; Flow Cytometry ; Glucocorticoids/*pharmacology ; Mice ; Mice, Inbred BALB C ; RNA/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*genetics ; Telomere/*metabolism ; Thymus Gland/*metabolism/pathology ; Time Factors ; },
abstract = {Apoptosis is a well-recognized process of cell death occurring under several physiological and pathological conditions and represents the principal mechanism involved in cell selection in the thymus. Glucocorticoids are well known to stimulate apoptosis in rat thymocytes. However, it is unclear whether the same changes occur after in vivo glucocorticoid treatment in mice. Chromosomal stability and cell viability require a proficient telomeric end-capping function. Cells with critical telomere shortening and telomerase dysfunction undergo increased apoptosis. In turn, the change in telomere function in cells undergoing apoptosis is not fully characterized. In order to investigate this, we studied the changes in thymocytes after dexamethasone administration in BALB/c mice. The loss of normal thymocytes coincided with the appearance of small dense cells with characteristic features of apoptosis including condensed chromatin, internucleosomal DNA cleavage, and a "hypodiploid" peak on flow cytometry, which suggested that dexamethasone-induced thymocyte apoptosis in BALB/c mice could be considered a well-defined experimental model for studying apoptotic processes. Dexamethasone-treated thymocytes exhibited rapid and dynamic loss of telomeric sequences and up-regulation of telomerase RNA as an early event in the apoptotic process. Telomerase activity was unchanged in this event. Thereafter, telomere gain associated with an increase in telomerase activity occurred in the regenerative process of the thymus. These results suggest a role of telomere loss and up-regulation of telomerase RNA as key apoptosis sensors.},
}
@article {pmid14512543,
year = {2003},
author = {Grubisha, O and Traktman, P},
title = {Genetic analysis of the vaccinia virus I6 telomere-binding protein uncovers a key role in genome encapsidation.},
journal = {Journal of virology},
volume = {77},
number = {20},
pages = {10929-10942},
pmid = {14512543},
issn = {0022-538X},
support = {R01 AI021758/AI/NIAID NIH HHS/United States ; R01 AI 21758/AI/NIAID NIH HHS/United States ; },
mesh = {Alleles ; Amino Acid Sequence ; DNA, Viral/analysis/biosynthesis ; *Genome, Viral ; Molecular Sequence Data ; Morphogenesis ; Phenotype ; Telomere-Binding Proteins/*genetics/physiology ; Vaccinia virus/*genetics/physiology ; Viral Core Proteins/metabolism ; Viral Proteins/*genetics/physiology ; *Virus Assembly ; },
abstract = {The linear, double-stranded DNA genome of vaccinia virus contains covalently closed hairpin termini. These hairpin termini comprise a terminal loop and an A+T-rich duplex stem that has 12 extrahelical bases. DeMasi et al. have shown previously that proteins present in infected cells and in virions form distinct complexes with the telomeric hairpins and that these interactions require the extrahelical bases. The vaccinia virus I6 protein was identified as the protein showing the greatest specificity and affinity for interaction with the viral hairpins (J. DeMasi, S. Du, D. Lennon, and P. Traktman, J. Virol. 75:10090-10105, 2001). To gain insight into the role of I6 in vivo, we generated eight recombinant viruses bearing altered alleles of I6 in which clusters of charged amino acids were changed to alanine residues. One allele (temperature-sensitive I6-12 [tsI6-12]) conferred a tight ts phenotype and was used to examine the stage(s) of the viral life cycle that was affected at the nonpermissive temperature. Gene expression, DNA replication, and genome resolution proceeded normally in this mutant. However, proteolytic processing of structural proteins, which accompanies virus maturation, was incomplete. Electron microscopic studies confirmed a severe block in morphogenesis in which immature, but no mature, virions were observed. Instead, aberrant spherical virions and large crystalloids were seen. When purified, these aberrant virions were found to have normal protein content but to be devoid of viral DNA. We propose that the binding of I6 to viral telomeres directs genome encapsidation into the virus particle.},
}
@article {pmid14511933,
year = {2003},
author = {Wong, JM and Collins, K},
title = {Telomere maintenance and disease.},
journal = {Lancet (London, England)},
volume = {362},
number = {9388},
pages = {983-988},
doi = {10.1016/S0140-6736(03)14369-3},
pmid = {14511933},
issn = {1474-547X},
mesh = {Animals ; B-Lymphocytes/physiology ; Bone Marrow Transplantation/immunology ; Cell Death/genetics ; Cell Division/genetics/physiology ; DNA Damage/genetics/immunology ; DNA Repair/genetics/immunology ; Enzyme Activation/physiology ; Genetic Therapy ; HIV Infections/genetics/physiopathology/therapy ; Hematologic Diseases/genetics/*physiopathology/therapy ; Humans ; Mice ; T-Lymphocytes/physiology ; Telomerase/genetics/physiology ; Telomere/genetics/*physiology ; },
abstract = {The proliferative capacity of human cells is regulated by telomerase, an enzyme uniquely specialised for telomeric DNA synthesis. The critical role of telomerase activation in tumour progression and tumour maintenance has been well established in studies of cancer and of oncogenic transformation in cell culture. New evidence suggests that telomerase activation has an important role in normal somatic cells, and that failure to activate sufficient telomerase also promotes disease. We review the evidence for premature telomere attrition in proliferative deficiencies of the human haemopoietic system, and discuss the potential use of telomerase activation in telomere-restorative gene therapy.},
}
@article {pmid14510465,
year = {2003},
author = {Enokizono, Y and Matsugami, A and Uesugi, S and Fukuda, H and Tsuchiya, N and Sugimura, T and Nagao, M and Nakagama, H and Katahira, M},
title = {Destruction of quadruplex by proteins, and its biological implications in replication and telomere maintenance.},
journal = {Nucleic acids research. Supplement (2001)},
volume = {},
number = {3},
pages = {231-232},
doi = {10.1093/nass/3.1.231},
pmid = {14510465},
mesh = {*DNA Replication ; Heterogeneous Nuclear Ribonucleoprotein A1 ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/*chemistry/metabolism ; *Nucleic Acid Conformation ; Protein Binding ; *Telomere ; },
abstract = {The minisatellite DNA Pc-1 consists of tandem repeats of d(GGCAG). We previously reported that a d(GGCAG)n strand folds into an intramolecular quadruplex under physiological conditions and that during replication the progression of DNA polymerase is blocked by the quadruplex in vitro. Therefore, the formation of the quadruplex was supposed to be responsible for the hypermutable features of Pc-1. Then, we have identified proteins that bind to Pc-1, one of which is hnRNP A1. Here, we have demonstrated that hnRNP A1 destroys the quadruplex of Pc-1 on binding and abrogates the arrest of DNA polymerase at the repeat. Thus, hnRNP A1 functions as if it is a chaperon to assist Pc-1 DNA to form the proper folding suitable for replication. We have also found that hnRNP A1 and a related protein, hnRNP D, destroy the quadruplex of telomere DNA, which suggests the involvement of these proteins in telomere maintenance as DNA chaperons.},
}
@article {pmid14510376,
year = {2003},
author = {Koga, M and Yamamuro, T and Tamai, K and Kanda, M and Shigeta, M and Suzuki, T and Saeki, T},
title = {Synthesis and properties of telomere-mimic carbocyclic 5'-nor 3'-deoxyoligonucleotide.},
journal = {Nucleic acids research. Supplement (2001)},
volume = {},
number = {3},
pages = {53-54},
doi = {10.1093/nass/3.1.53},
pmid = {14510376},
mesh = {Antineoplastic Agents/chemistry ; Circular Dichroism ; *Molecular Mimicry ; Nuclear Magnetic Resonance, Biomolecular ; Oligonucleotides/*chemistry ; Oligonucleotides, Antisense/chemistry ; *Telomere ; },
abstract = {Telomere-mimic carbocyclic 5'-nor 3'-deoxyoligonucleotide was synthesized. And it's selectivity to RNA was shown.},
}
@article {pmid14506137,
year = {2003},
author = {Shay, JW},
title = {Telomerase therapeutics: telomeres recognized as a DNA damage signal: commentary re: K. Kraemer et al., antisense-mediated hTERT inhibition specifically reduces the growth of human bladder cancer cells. Clin. Cancer Res., 9: 3794-3800, 2003.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {9},
number = {10 Pt 1},
pages = {3521-3525},
pmid = {14506137},
issn = {1078-0432},
support = {CA70907/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Line, Tumor ; Cell Survival ; Cell Transformation, Neoplastic ; DNA/*ultrastructure ; DNA Damage ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; Microscopy, Fluorescence ; Neoplasms/*pathology ; Telomerase/*physiology ; Telomere/*ultrastructure ; },
}
@article {pmid14504108,
year = {2004},
author = {Damle, RN and Batliwalla, FM and Ghiotto, F and Valetto, A and Albesiano, E and Sison, C and Allen, SL and Kolitz, J and Vinciguerra, VP and Kudalkar, P and Wasil, T and Rai, KR and Ferrarini, M and Gregersen, PK and Chiorazzi, N},
title = {Telomere length and telomerase activity delineate distinctive replicative features of the B-CLL subgroups defined by immunoglobulin V gene mutations.},
journal = {Blood},
volume = {103},
number = {2},
pages = {375-382},
doi = {10.1182/blood-2003-04-1345},
pmid = {14504108},
issn = {0006-4971},
support = {CA 81554/CA/NCI NIH HHS/United States ; CA 87956/CA/NCI NIH HHS/United States ; },
mesh = {Antigens, Differentiation, B-Lymphocyte ; B-Lymphocytes/enzymology/*immunology ; *Genes, Immunoglobulin ; Humans ; Immunoglobulin Variable Region/*genetics ; Kinetics ; Leukemia, Lymphocytic, Chronic, B-Cell/blood/enzymology/*genetics ; Leukocytes, Mononuclear/enzymology ; Lymphocyte Activation ; *Mutation ; Neutrophils/enzymology/immunology ; Telomerase/*metabolism ; Telomere/*enzymology/ultrastructure ; Time Factors ; },
abstract = {Patients with B-cell chronic lymphocytic leukemia (B-CLL) segregate into subgroups with very different survival times. Because clinical observations suggest that leukemic cells accumulate at different rates, we measured telomere length and telomerase activity in B-CLL cells to distinguish differences in cellular replication. Our data indicate that the telomeres of B-CLL cells are shorter than telomeres of B cells from healthy subjects, indicating that the leukemic cells have a prolonged proliferative history. Leukemic cells of the immunoglobulin V gene mutation subgroups differ in telomere length and telomerase activity. B lymphocytes from the subgroup with poor outcome and with limited IgV gene mutations have uniformly shorter telomeres and more telomerase activity than those from the subgroup with better outcome and with considerable mutations. Differences in telomere length appear to largely reflect the proliferative histories of precursors of the leukemic cells, although differences in cell division, masked by the action of telomerase, cannot be excluded. These results may provide insight into the stages of maturation and the activation pathways of the cells that give rise to B-CLL. In addition, they reinforce the concept that B-CLL is not simply an accumulative disease of slowly dividing B lymphocytes but possibly one of B cells with extensive proliferative histories.},
}
@article {pmid14501538,
year = {2003},
author = {Zhang, J and Kong, Q and Zhang, Z and Ge, P and Ba, D and He, W},
title = {Telomere dysfunction of lymphocytes in patients with Alzheimer disease.},
journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology},
volume = {16},
number = {3},
pages = {170-176},
doi = {10.1097/00146965-200309000-00004},
pmid = {14501538},
issn = {1543-3633},
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*blood/immunology ; Case-Control Studies ; Cell Division ; Dementia, Vascular/*blood/immunology ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Lymphocytes/*enzymology/pathology ; Male ; Middle Aged ; Polymerase Chain Reaction ; Telomerase/blood ; Telomere/*enzymology ; },
abstract = {OBJECTIVE: The objective of this study was to investigate the telomerase activity of phytohemagglutinin-activated lymphocytes from patients with Alzheimer disease.<br><br>BACKGROUND: There is impairment of immune function in patients with Alzheimer disease, and the perturbation of immune system is involved the pathogenesis of Alzheimer disease. However, the mechanism of the impairment is unclear so far.<br><br>METHODS: We analyzed telomerase activities of phytohemagglutinin-activated lymphocytes from 187 cases of patients with Alzheimer disease, 53 cases of patients with vascular dementia, and 80 cases of age-matched healthy controls, respectively. Telomerase activity was measured using the telomeric repeat amplification protocol-based telomerase polymerase chain reaction enzyme-linked immunosorbent assay. We also detected the proliferation activity of peripheral blood mononuclear cells from 10 cases of patients with Alzheimer disease or 10 cases of age-matched healthy controls by [3H] thymidine incorporation.<br><br>RESULTS: Telomerase activity of phytohemagglutinin-activated lymphocytes in Alzheimer disease patients was significantly elevated compared with healthy controls (P < 0.01) and vascular dementia patients (P < 0.01), respectively. There was significant statistical correlation between the telomerase activities of lymphocytes and the degree of dementia in Alzheimer disease patients. The proliferation activity of peripheral blood mononuclear cells to phytohemagglutinin was significantly decreased in Alzheimer disease patients compared with age-matched healthy controls (P < 0.01).<br><br>CONCLUSIONS: Our data suggest that there could be an accelerated telomere dysfunction in lymphocytes of Alzheimer disease patients, which induces the increase of telomerase activity and the decrease of proliferation activity of lymphocytes, and subsequently results in the impairment of immune function in Alzheimer disease patients.},
}
@article {pmid14499633,
year = {2003},
author = {Guilleret, I and Benhattar, J},
title = {Demethylation of the human telomerase catalytic subunit (hTERT) gene promoter reduced hTERT expression and telomerase activity and shortened telomeres.},
journal = {Experimental cell research},
volume = {289},
number = {2},
pages = {326-334},
doi = {10.1016/s0014-4827(03)00281-7},
pmid = {14499633},
issn = {0014-4827},
mesh = {Antimetabolites, Antineoplastic/pharmacology ; Azacitidine/*analogs &amp; derivatives/pharmacology ; Cell Division/drug effects/genetics ; Cellular Senescence/drug effects/genetics ; DNA Methylation/*drug effects ; DNA-Binding Proteins ; Decitabine ; Down-Regulation/drug effects/genetics ; Gene Expression Regulation, Neoplastic/drug effects/genetics ; Humans ; Neoplasms/*enzymology/genetics ; Promoter Regions, Genetic/drug effects/*genetics ; Proto-Oncogene Proteins c-myc/drug effects/genetics/metabolism ; RNA, Messenger/drug effects/metabolism ; Telomerase/drug effects/genetics/*metabolism ; Telomere/drug effects/genetics/*metabolism ; Transcription, Genetic/drug effects/genetics ; Tumor Cells, Cultured ; },
abstract = {Telomerase is the ribonucleoproteic complex involved in maintaining telomere size. It is expressed in germ and stem cells but not in normal somatic cells. In most tumors, telomerase is reactivated. In humans, telomerase activity is tightly regulated by expression of the hTERT gene. In a previous study, we found a direct correlation between methylation of the hTERT promoter and hTERT gene expression. In order to demonstrate this correlation, demethylation experiments were performed with the demethylating agent 5aza-2'-deoxycytidine (5azadC). Three telomerase-positive tumor cell lines (Lan-1, HeLa, and Co115), presenting a hypermethylated hTERT promoter, were treated with different doses and types of treatment for a long period. Analysis of methylation revealed a final hTERT promoter demethylation up to 95%. Quantification of hTERT mRNA showed that transcription was strongly repressed during drug exposure. In contrast, expression of c-Myc, an activator of hTERT promoter, was barely down-regulated or increased by the treatment. Using a TRAP assay, telomerase activity was semiquantified in all experiments. It strongly decreased or was suppressed after two to four passages. Finally, telomere length was measured by Southern blot. Their averages were not modified, but ranges concentrated around the mean. Thus, it is likely that hTERT promoter hypermethylation would be necessary for its expression.},
}
@article {pmid14499491,
year = {2003},
author = {Kang, MK and Kameta, A and Baluda, MA and Park, NH},
title = {Telomere shortening does not occur during postmaturational aging in situ in normal human oral fibroblasts.},
journal = {Mechanisms of ageing and development},
volume = {124},
number = {8-9},
pages = {873-876},
doi = {10.1016/s0047-6374(03)00145-3},
pmid = {14499491},
issn = {0047-6374},
support = {DE14147/DE/NIDCR NIH HHS/United States ; DE14635-01/DE/NIDCR NIH HHS/United States ; },
mesh = {Adult ; Aged ; Blotting, Southern ; Cell Division ; Cells, Cultured ; Cellular Senescence/physiology ; Electronic Data Processing ; Fibroblasts/cytology/*physiology ; Humans ; Middle Aged ; Mouth/*cytology ; Reference Values ; Telomere/*genetics ; },
abstract = {We investigated whether the telomere length, i.e. mean terminal restriction fragment (TRF) length, decreases during in situ aging in normal human oral fibroblasts (NHOF). For this purpose, NHOF cultures were established from 50 different donors and tested after 14 population doublings (PD) when the cells were replicating exponentially. Telomere-specific Southern blotting and digital quantitation showed that the mean (+/-standard error (S.E.)) TRF length of all tested cultures was 7.72+/-0.17 kbps. The plot of TRF mean length versus donor age showed high variability in individual length with an apparent average decline of -7.8 bp per year of age, which was not statistically significant (r=0.11; P>0.1). These data indicate that telomere shortening does not occur during donor aging in situ, and therefore, is not physiologically relevant for NHOF.},
}
@article {pmid12975323,
year = {2003},
author = {Stellwagen, AE and Haimberger, ZW and Veatch, JR and Gottschling, DE},
title = {Ku interacts with telomerase RNA to promote telomere addition at native and broken chromosome ends.},
journal = {Genes &amp; development},
volume = {17},
number = {19},
pages = {2384-2395},
pmid = {12975323},
issn = {0890-9369},
support = {F32 GM020104/GM/NIGMS NIH HHS/United States ; R01 GM043893/GM/NIGMS NIH HHS/United States ; F32 GM20104/GM/NIGMS NIH HHS/United States ; R01 GM43893/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; Antigens, Nuclear/genetics/*metabolism ; Base Sequence ; Chromosomes, Fungal/genetics ; DNA/genetics/metabolism ; *DNA Helicases ; *DNA Repair ; DNA-Binding Proteins/genetics/*metabolism ; Ku Autoantigen ; Molecular Sequence Data ; Mutation ; RNA, Fungal/chemistry/genetics/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/*genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Ku is a conserved DNA end-binding protein that plays various roles at different kinds of DNA ends. At telomeres, Ku is part of the structure that protects the chromosome end, whereas at broken DNA ends, Ku promotes DNA repair as part of the nonhomologous end-joining (NHEJ) pathway. Here, we present evidence of a new role for Ku that impacts both telomere-length maintenance and DNA repair in Saccharomyces cerevisiae. We show that Ku binds TLC1, the RNA component of telomerase. We also describe a novel separation-of-function allele of Ku that is specifically defective in TLC1 binding. In this mutant, telomeres are short and the kinetics of telomere addition are slow, but other Ku-dependent activities, such as chromosome end protection and NHEJ, are unaffected. At low frequency, yeast will use telomerase to heal DNA damage by capping the broken chromosome with telomeric DNA sequences. We show that when Ku's ability to bind TLC1 is disrupted, DNA repair via telomere healing is reduced 10- to 100-fold, and the spectrum of sequences that can acquire a telomere changes. Thus, the interaction between Ku and TLC1 RNA enables telomerase to act at both broken and normal chromosome ends.},
}
@article {pmid12972872,
year = {2003},
author = {Collins, M and Renault, V and Grobler, LA and St Clair Gibson, A and Lambert, MI and Wayne Derman, E and Butler-Browne, GS and Noakes, TD and Mouly, V},
title = {Athletes with exercise-associated fatigue have abnormally short muscle DNA telomeres.},
journal = {Medicine and science in sports and exercise},
volume = {35},
number = {9},
pages = {1524-1528},
doi = {10.1249/01.MSS.0000084522.14168.49},
pmid = {12972872},
issn = {0195-9131},
mesh = {Adult ; Biopsy ; DNA ; Exercise/*physiology ; Fatigue/*physiopathology ; Female ; Humans ; Male ; Middle Aged ; Muscle, Skeletal/injuries/pathology ; Physical Endurance ; Sports ; Syndrome ; *Telomere ; },
abstract = {INTRODUCTION/PURPOSE: Although the beneficial health effects of regular moderate exercise are well established, there is substantial evidence that the heavy training and racing carried out by endurance athletes can cause skeletal muscle damage. This damage is repaired by satellite cells that can undergo a finite number of cell divisions. In this study, we have compared a marker of skeletal muscle regeneration of athletes with exercise-associated chronic fatigue, a condition labeled the "fatigued athlete myopathic syndrome" (FAMS), with healthy asymptomatic age- and mileage-matched control endurance athletes.<br><br>METHODS: Muscle biopsies of the vastus lateralis were obtained from 13 patients diagnosed with FAMS and from 13 healthy control subjects. DNA was extracted from the muscle samples and their telomeric restriction fragment (TRF) or telomere lengths were measured by Southern blot analysis.<br><br>RESULTS: All 13 symptomatic athletes reported a progressive decline in athletic performance, decreased ability to tolerate high mileage training, and excessive muscular fatigue during exercise. The minimum value of TRF lengths (4.0 +/- 1.8 kb) measured on the DNA from vastus lateralis biopsies from these athletes were significantly shorter than those from 13 age- and mileage-matched control athletes (5.4 +/- 0.6 kb, P < 0.05). Three of the FAMS patients had extremely short telomeres (1.0 +/- 0.3 kb). The minimum TRF lengths of the remaining 10 symptomatic athletes (4.9 +/- 0.5 kb, P < 0.05) were also significantly shorter that those of the control athletes.<br><br>CONCLUSION: These findings suggest that skeletal muscle from symptomatic athletes with FAMS show extensive regeneration which most probably results from more frequent bouts of satellite cell proliferation in response to recurrent training- and racing-induced muscle injury.},
}
@article {pmid12972499,
year = {2003},
author = {Lydall, D},
title = {Hiding at the ends of yeast chromosomes: telomeres, nucleases and checkpoint pathways.},
journal = {Journal of cell science},
volume = {116},
number = {Pt 20},
pages = {4057-4065},
doi = {10.1242/jcs.00765},
pmid = {12972499},
issn = {0021-9533},
mesh = {Cell Cycle ; Cell Cycle Proteins/metabolism ; Chromosomes, Fungal/*metabolism ; DNA Damage/physiology ; DNA Repair/physiology ; DNA Replication/physiology ; Deoxyribonucleases/*metabolism ; Endodeoxyribonucleases/metabolism ; Enzyme Induction ; Exodeoxyribonucleases/metabolism ; Models, Molecular ; Saccharomyces cerevisiae Proteins/metabolism ; Saccharomycetales/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres stabilise DNA at the ends of chromosomes, preventing chromosome fusion and genetic instability. Telomeres differ from double strand breaks in that they activate neither DNA repair nor DNA damage checkpoint pathways. Paradoxically DNA repair and checkpoint genes play critical roles in telomere stability. Recent work has provided insights into the roles of DNA repair and DNA damage checkpoint pathways in the physiological maintenance of telomeres and in cellular responses when telomeres become uncapped. In budding yeast the Mre11p nuclease, along with other unidentified nucleases, plays critical roles in physiological telomere maintenance. However, when telomeres are uncapped, the 5'-to-3' exonuclease, Exo1p, plays a critical role in generating single-stranded DNA and activating checkpoint pathways. Intriguingly Exo1p does not play an important role in normal telomere maintenance. Although checkpoint pathways are not normally activated by telomeres, at least four different types of telomere defect activate checkpoint pathways. Interestingly, each of these telomere defects depends on a different subset of checkpoint proteins to induce cell cycle arrest. A model for how a spectrum of telomeric states might interact with telomerase and checkpoint pathways is proposed.},
}
@article {pmid12972463,
year = {2003},
author = {Paynter, N and Watkins, S},
title = {Telomere length: an independent risk factor for premature MI?.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {23},
number = {9},
pages = {1704; author reply 1704},
doi = {10.1161/01.ATV.0000087621.49739.48},
pmid = {12972463},
issn = {1524-4636},
mesh = {Genetic Predisposition to Disease/*genetics ; Humans ; Myocardial Infarction/*etiology/genetics ; Risk Factors ; Telomere/*genetics ; },
}
@article {pmid12972254,
year = {2003},
author = {Wahlin, J and Rosén, M and Cohn, M},
title = {DNA binding and telomere length regulation of yeast RAP1 homologues.},
journal = {Journal of molecular biology},
volume = {332},
number = {4},
pages = {821-833},
doi = {10.1016/s0022-2836(03)00850-7},
pmid = {12972254},
issn = {0022-2836},
mesh = {Animals ; Binding Sites ; DNA, Fungal/*metabolism ; Fungal Proteins/*metabolism ; Protein Binding ; Saccharomyces/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Shelterin Complex ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; Transcription Factors/*metabolism ; },
abstract = {The repressor activator protein 1 (RAP1) has many important functions in Saccharomyces cerevisiae. At the chromosome ends, it is a negative regulator of telomere length. Here, we show that Saccharomyces castellii/Saccharomyces dairensis telomeric sequences inserted into a S.cerevisiae telomere are counted as part of the telomere, consistent with the presence of high-affinity Rap1p binding sites within these sequences. We show that S.castellii Rap1p (scasRap1p) can regulate telomere length in a S.cerevisiae strain, albeit less stringently. Cloning of the S.dairensis RAP1 homologue (sdaiRAP1) revealed that it encodes the largest RAP1 protein identified to date. Despite its large size, binding analyses of the recombinant sdaiRap1p revealed that the protein binds with the same spacing and with similar affinity to yeast telomeric sequences, as the scer- and scasRAP1 proteins. According to the Rap1p counting model for telomere length regulation, a low density of Rap1p binding sites in a telomere would result in a longer telomere in S.cerevisiae. We have compared the lengths of two individual S.dairensis telomeres and find that their lengths are not regulated to give the same number of high-affinity binding sites. This may be due to other factors than Rap1p having influence on the telomere length regulation.},
}
@article {pmid12971724,
year = {2003},
author = {Weierich, C and Brero, A and Stein, S and von Hase, J and Cremer, C and Cremer, T and Solovei, I},
title = {Three-dimensional arrangements of centromeres and telomeres in nuclei of human and murine lymphocytes.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {11},
number = {5},
pages = {485-502},
pmid = {12971724},
issn = {0967-3849},
mesh = {Animals ; *Cell Nucleus ; Centromere/*genetics ; Humans ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Lymphocytes/*cytology ; Mice ; Microscopy, Confocal ; Telomere/*genetics ; },
abstract = {The location of centromeres and telomeres was studied in human and mouse lymphocyte nuclei (G0) employing 3D-FISH, confocal microscopy, and quantitative image analysis. In both human and murine lymphocytes, most centromeres were found in clusters at the nuclear periphery. The distribution of telomere clusters, however, differed: in mouse nuclei, most clusters were detected at the nuclear periphery, while, in human nuclei, most clusters were located in the nuclear interior. In human cell nuclei we further studied the nuclear location of individual centromeres and their respective chromosome territories (CTs) for chromosomes 1, 11, 12, 15, 17, 18, 20, and X. We found a peripheral location of both centromeres and CTs for 1, 11, 12, 18, X. A mostly interior nuclear location was observed for CTs 17 and 20 and the CTs of the NOR-bearing acrocentric 15 but the corresponding centromeres were still positioned in the nuclear periphery. Autosomal centromeres, as well as the centromere of the active X, were typically located at the periphery of the respective CTs. In contrast, in about half of the inactive X-CTs, the centromere was located in the territory interior. While the centromere of the active X often participated in the formation of centromere clusters, such a participation was never observed for the centromere of the inactive X.},
}
@article {pmid12969961,
year = {2004},
author = {Soares, MV and Plunkett, FJ and Verbeke, CS and Cook, JE and Faint, JM and Belaramani, LL and Fletcher, JM and Hammerschmitt, N and Rustin, M and Bergler, W and Beverley, PC and Salmon, M and Akbar, AN},
title = {Integration of apoptosis and telomere erosion in virus-specific CD8+ T cells from blood and tonsils during primary infection.},
journal = {Blood},
volume = {103},
number = {1},
pages = {162-167},
doi = {10.1182/blood-2003-06-1791},
pmid = {12969961},
issn = {0006-4971},
mesh = {Acute Disease ; Apoptosis ; CD28 Antigens/metabolism ; CD8-Positive T-Lymphocytes/enzymology/*immunology/*pathology ; Case-Control Studies ; Cell Differentiation ; Cell Division ; Cytokines/metabolism ; Herpesvirus 4, Human/immunology ; Humans ; Immunologic Memory ; Infectious Mononucleosis/enzymology/*immunology/*pathology ; Palatine Tonsil/immunology/pathology ; Telomerase/*metabolism ; },
abstract = {Human-virus-specific CD8+ T cells that are found during primary infection have been studied almost exclusively in the peripheral blood, and it is unclear whether these cells are regulated in the same way as those in secondary lymphoid tissue. We investigated, therefore, the control of apoptosis and telomere erosion of Epstein-Barr virus (EBV)-specific CD8+ T cells found in the blood and tonsils of the same patients during acute infectious mononucleosis (AIM). Although the clonal composition of CD8+ T cells as determined by heteroduplex analysis was similar in both compartments, there was greater CD28 expression in the tonsil population, indicating that they were less differentiated. EBV-specific CD8+ T cells in both tissue types were extremely susceptible to apoptosis related to low Bcl-2 expression and were dependent on exogenous cytokines such as interleukin-2 (IL-2), IL-15, and interferon-alpha/beta (IFN-alpha/beta) for survival. In both compartments, however, these cells maintained their telomere lengths through telomerase induction. Thus, apoptosis-prone EBV-specific CD8+ T cells found during acute infection have to be rescued from death to persist as a memory population. However, signals that induce telomerase ensure that the rescued cells retain their replicative capacity. Significantly, these processes operate identically in cells found in blood and secondary lymphoid tissue.},
}
@article {pmid12967660,
year = {2003},
author = {Mallory, JC and Bashkirov, VI and Trujillo, KM and Solinger, JA and Dominska, M and Sung, P and Heyer, WD and Petes, TD},
title = {Amino acid changes in Xrs2p, Dun1p, and Rfa2p that remove the preferred targets of the ATM family of protein kinases do not affect DNA repair or telomere length in Saccharomyces cerevisiae.},
journal = {DNA repair},
volume = {2},
number = {9},
pages = {1041-1064},
doi = {10.1016/s1568-7864(03)00115-0},
pmid = {12967660},
issn = {1568-7864},
mesh = {Amino Acids ; *Cell Cycle Proteins ; DNA Damage/genetics ; *DNA Repair ; DNA-Binding Proteins/*genetics/metabolism ; Endodeoxyribonucleases ; Exodeoxyribonucleases ; Intracellular Signaling Peptides and Proteins ; Mutation ; Phosphorylation ; Plasmids ; Precipitin Tests ; Protein Kinases/*genetics/metabolism ; Protein Serine-Threonine Kinases ; Replication Protein A ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Telomere/*genetics ; Transcription Factors/*genetics/metabolism ; Transformation, Genetic ; },
abstract = {In eukaryotes, mutations in a number of genes that affect DNA damage checkpoints or DNA replication also affect telomere length [Curr. Opin. Cell Biol. 13 (2001) 281]. Saccharomyces cerevisae strains with mutations in the TEL1 gene (encoding an ATM-like protein kinase) have very short telomeres, as do strains with mutations in XRS2, RAD50, or MRE11 (encoding members of a trimeric complex). Xrs2p and Mre11p are phosphorylated in a Tel1p-dependent manner in response to DNA damage [Genes Dev. 15 (2001) 2238; Mol. Cell 7 (2001) 1255]. We found that Xrs2p, but not Mre11p or Rad50p, is efficiently phosphorylated in vitro by immunopreciptated Tel1p. Strains with mutations eliminating all SQ and TQ motifs in Xrs2p (preferred targets of the ATM kinase family) had wild-type length telomeres and wild-type sensitivity to DNA damaging agents. We also showed that Rfa2p (a subunit of RPA) and the Dun1p checkpoint kinase, which are required for DNA damage repair and which are phosphorylated in response to DNA damage in vivo, are in vitro substrates of the Tel1p and Mec1p kinases. In addition, Dun1p substrates with no SQ or TQ motifs are phosphorylated by Mec1p in vitro very inefficiently, but retain most of their ability to be phosphorylated by Tel1p. We demonstrated that null alleles of DUN1 and certain mutant alleles of RFA2 result in short telomeres. As observed with Xrs2p, however, strains with mutations of DUN1 or RFA2 that eliminate SQ motifs have no effect on telomere length or DNA damage sensitivity.},
}
@article {pmid12965030,
year = {2003},
author = {Haussmann, MF and Winkler, DW and O'Reilly, KM and Huntington, CE and Nisbet, IC and Vleck, CM},
title = {Telomeres shorten more slowly in long-lived birds and mammals than in short-lived ones.},
journal = {Proceedings. Biological sciences},
volume = {270},
number = {1522},
pages = {1387-1392},
pmid = {12965030},
issn = {0962-8452},
mesh = {Aging/genetics/physiology ; Animals ; Birds/*genetics/*physiology ; Erythrocytes/cytology/metabolism ; Longevity/*genetics/*physiology ; Mammals/genetics/*physiology ; Species Specificity ; Telomere/genetics/*physiology ; },
abstract = {We know very little about physiological constraints on the evolution of life-history traits in general, and, in particular, about physiological and molecular adjustments that accompany the evolution of variation in lifespan. Identifying mechanisms that underlie adaptive variation in lifespan should provide insight into the evolution of trade-offs between lifespan and other life-history traits. Telomeres, the DNA caps at the ends of linear chromosomes, usually shorten as animals age, but whether telomere rate of change is associated with lifespan is unknown. We measured telomere length in erythrocytes from five bird species with markedly different lifespans. Species with shorter lifespans lost more telomeric repeats with age than species with longer lifespans. A similar correlation is seen in mammals. Furthermore, telomeres did not shorten with age in Leach's storm-petrels, an extremely long-lived bird, but actually lengthened. This novel finding suggests that regulation of telomere length is associated not only with cellular replicative lifespan, but also with organismal lifespan, and that very long-lived organisms have escaped entirely any telomeric constraint on cellular replicative lifespan.},
}
@article {pmid12963812,
year = {2003},
author = {Mieczkowski, PA and Mieczkowska, JO and Dominska, M and Petes, TD},
title = {Genetic regulation of telomere-telomere fusions in the yeast Saccharomyces cerevisae.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {100},
number = {19},
pages = {10854-10859},
pmid = {12963812},
issn = {0027-8424},
support = {R01 GM052319/GM/NIGMS NIH HHS/United States ; GM52319/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; DNA, Fungal ; Molecular Sequence Data ; Polymerase Chain Reaction ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; *Telomere ; },
abstract = {Yeast strains with mutations in both TEL1 and MEC1 have short telomeres and elevated rates of chromosome deletions. By using a PCR assay, we demonstrate that mec1 tel1 strains also have telomere-telomere fusions (T-TFs). T-TFs require Lig4p (a ligase required for nonhomologous end-joining DNA repair). The highest rates of T-TFs are found in strains with combination of mutations that affect telomere length and DNA damage checkpoints (mec1 tel1, mec3 tel1, mre11 mec1, and ddc1 tel1 strains). Examining many mutant genotypes, we find good agreement between the level of T-TFs and the rate of chromosomal deletions. In addition, if telomeres are elongated in a mec1 tel1 strain, we eliminate T-TFs and reduce the deletion rate. The correlation between the level of T-TFs and the rate of deletions argues that many of these deletions reflect a cycle of T-TF formation (resulting in dicentric chromosomes), followed by chromosome breakage.},
}
@article {pmid12956959,
year = {2003},
author = {Takai, H and Smogorzewska, A and de Lange, T},
title = {DNA damage foci at dysfunctional telomeres.},
journal = {Current biology : CB},
volume = {13},
number = {17},
pages = {1549-1556},
doi = {10.1016/s0960-9822(03)00542-6},
pmid = {12956959},
issn = {0960-9822},
support = {AG16643/AG/NIA NIH HHS/United States ; GM07739/GM/NIGMS NIH HHS/United States ; GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Carrier Proteins/metabolism ; DNA Damage/*genetics ; Endodeoxyribonucleases/metabolism ; Exodeoxyribonucleases/metabolism ; Fluorescent Antibody Technique ; HeLa Cells ; Humans ; Immunoblotting ; *Intracellular Signaling Peptides and Proteins ; Phosphoinositide-3 Kinase Inhibitors ; *Phosphoproteins ; Saccharomyces cerevisiae Proteins/metabolism ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/antagonists &amp; inhibitors/*metabolism ; Transfection ; Tumor Suppressor p53-Binding Protein 1 ; },
abstract = {We report cytologic and genetic data indicating that telomere dysfunction induces a DNA damage response in mammalian cells. Dysfunctional, uncapped telomeres, created through inhibition of TRF2, became associated with DNA damage response factors, such as 53BP1, gamma-H2AX, Rad17, ATM, and Mre11. We refer to the domain of telomere-associated DNA damage factors as a Telomere Dysfunction-Induced Focus (TIF). The accumulation of 53BP1 on uncapped telomeres was reduced in the presence of the PI3 kinase inhibitors caffeine and wortmannin, which affect ATM, ATR, and DNA-PK. By contrast, Mre11 TIFs were resistant to caffeine, consistent with previous findings on the Mre11 response to ionizing radiation. A-T cells had a diminished 53BP1 TIF response, indicating that the ATM kinase is a major transducer of this pathway. However, in the absence of ATM, TRF2 inhibition still induced TIFs and senescence, pointing to a second ATM-independent pathway. We conclude that the cellular response to telomere dysfunction is governed by proteins that also control the DNA damage response. TIFs represent a new tool for evaluating telomere status in normal and malignant cells suspected of harboring dysfunctional telomeres. Furthermore, induction of TIFs through TRF2 inhibition provides an opportunity to study the DNA damage response within the context of well-defined, physically marked lesions.},
}
@article {pmid12955560,
year = {2002},
author = {Kumakura, S and Yamamoto, A and Yagisawa, J and Uchida, M and Tsutsui, T},
title = {Telomere length and telomerase activity in the process of human fibroblast immortalization.},
journal = {Odontology},
volume = {90},
number = {1},
pages = {13-21},
doi = {10.1007/s102660200002},
pmid = {12955560},
issn = {1618-1247},
abstract = {To examine the telomere maintenance mechanism in the process of human fibroblast immortalization, we studied telomere length, telomerase activity, chromosome instability, and minisatellite alterations in human fibroblasts following the introduction of the human papillomavirus type 16 E6 gene or E7 gene, or both. One cell line immortalized by E6 alone maintained short telomeres, and its telomerase activity was positive. Fairly long and heterogeneous telomeres were maintained in all four E7-immortalized cell lines lacking telomerase activity. Of the three clones immortalized by both E6 and E7, two cell lines with telomerase activity maintained short telomeres, and the other cell line, which lacked telomerase activity, maintained long and heterogeneous telomeres. Although all immortal cell lines expressed mRNAs for human telomerase RNA component and telomerase-associated protein, expression of mRNA for human telomerase reverse transcriptase was detected only in the telomerase-positive cell lines. All immortal cell lines showed both chromosomal abnormalities, including structural and numerical changes, and minisatellite alterations detected by DNA fingerprinting. These findings indicate the existence of different telomere maintenance mechanisms in telomerase-positive and -negative fibroblast cell lines immortalized by E6, E7, or E6/ E7, and the possible involvement of chromosome instability and minisatellite alterations in the activation of the telomere maintenance mechanisms.},
}
@article {pmid12952934,
year = {2003},
author = {Voet, T and Liebe, B and Labaere, C and Marynen, P and Scherthan, H},
title = {Telomere-independent homologue pairing and checkpoint escape of accessory ring chromosomes in male mouse meiosis.},
journal = {The Journal of cell biology},
volume = {162},
number = {5},
pages = {795-807},
pmid = {12952934},
issn = {0021-9525},
mesh = {Animals ; Body Weight ; Calcium-Binding Proteins/metabolism ; *Carrier Proteins ; Cell Cycle Proteins/metabolism ; Centromere/metabolism ; Female ; Fibroblasts/physiology ; Fungal Proteins/metabolism ; Genes, cdc ; Humans ; In Situ Hybridization, Fluorescence ; Mad2 Proteins ; Male ; Meiosis/*physiology ; Mice ; Nuclear Proteins ; Organ Size ; Protein Kinases/metabolism ; Protein Serine-Threonine Kinases ; *Ring Chromosomes ; Spermatogenesis/physiology ; Spermatozoa/cytology/physiology ; Telomere/*metabolism ; },
abstract = {We analyzed transmission of a ring minichromosome (MC) through mouse spermatogenesis as a monosome and in the presence of a homologue. Mice, either monosomic or disomic for the MC, produced MC+ offspring. In the monosomic condition, most univalents underwent self-synapsis as indicated by STAG3, SCP3, and SCP1 deposition. Fluorescent in situ hybridization and three-dimensional fluorescence microscopy revealed that ring MCs did not participate in meiotic telomere clustering while MC homologues paired at the XY-body periphery. Self-synapsis of MC(s) and association with the XY-body likely allowed them to pass putative pachytene checkpoints. At metaphase I and II, MC kinetochores assembled MAD2 and BUBR1 spindle checkpoint proteins. Unaligned MCs triggered the spindle checkpoint leading to apoptosis of metaphase cells. Other MCs frequently associated with mouse pericentric heterochromatin, which may have allowed them to pass the spindle checkpoint. Our findings indicate a telomere-independent mechanism for pairing of mammalian MCs, illuminate escape routes to meiotic checkpoints, and give clues for genetic engineering of germ line-permissive chromosomal vectors.},
}
@article {pmid12952894,
year = {2003},
author = {Sadaie, M and Naito, T and Ishikawa, F},
title = {Stable inheritance of telomere chromatin structure and function in the absence of telomeric repeats.},
journal = {Genes &amp; development},
volume = {17},
number = {18},
pages = {2271-2282},
pmid = {12952894},
issn = {0890-9369},
mesh = {Chromatin/*genetics ; Chromosomal Proteins, Non-Histone/metabolism ; DNA-Binding Proteins ; Repetitive Sequences, Nucleic Acid ; Schizosaccharomyces/genetics/metabolism ; Schizosaccharomyces pombe Proteins/metabolism ; Telomerase/genetics/metabolism ; Telomere/*genetics ; Telomere-Binding Proteins/metabolism ; },
abstract = {It is generally believed that telomeric repeats are a necessary and sufficient cis-element for telomere function. Here we show that telomere structure and meiotic function are stably inherited in fission yeast circular chromosomes that have lost all telomeric repeats. We found that the telomeric repeat binding protein, Taz1, and the heterochromatin protein, Swi6, remain associated with subtelomeres in the absence of telomeric repeats. We also found that the fusion point of circular chromosomes that lack telomeric repeats associates with SPB (the yeast counterpart of the centrosome) in the premeiotic horsetail stage, similarly to wild-type telomeres. However, a taz1+ deletion/reintroduction experiment revealed that the maintenance of Taz1 binding and premeiotic function is achieved via different strategies. Taz1 is recruited to subtelomeres by an autonomous element present in subtelomeric DNA, thus in a genetic mechanism. In contrast, the premeiotic subtelomere-SPB association is maintained in an epigenetic manner. These results shed light on the previously unrecognized role played by the subtelomere and underscore the robust nature of the functional telomere complex that is maintained by both genetic and epigenetic mechanisms. Furthermore, we suggest that the establishment and the maintenance of the functional telomere complex are mechanistically distinguishable.},
}
@article {pmid12945717,
year = {2003},
author = {Kurosaka, D and Yasuda, J and Yoshida, K and Yokoyama, T and Ozawa, Y and Obayashi, Y and Kingetsu, I and Saito, S and Yamada, A},
title = {Telomerase activity and telomere length of peripheral blood mononuclear cells in SLE patients.},
journal = {Lupus},
volume = {12},
number = {8},
pages = {591-599},
doi = {10.1191/0961203303lu426oa},
pmid = {12945717},
issn = {0961-2033},
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Anti-Inflammatory Agents/administration &amp; dosage ; Biomarkers/blood ; Dose-Response Relationship, Drug ; Female ; Follow-Up Studies ; Hemoglobins/drug effects/metabolism ; Humans ; Leukocytes, Mononuclear/drug effects/*metabolism ; Lupus Erythematosus, Systemic/*blood/drug therapy/enzymology/etiology ; Male ; Middle Aged ; Prednisolone/administration &amp; dosage ; Remission, Spontaneous ; Sickness Impact Profile ; Statistics as Topic ; Statistics, Nonparametric ; Telomerase/drug effects/*metabolism ; Telomere/drug effects/*metabolism ; Treatment Outcome ; },
abstract = {We evaluated the clinical significance of the telomerase activity and telomere length of peripheral blood mononuclear cells (PBMC) in systemic lupus erythematosus (SLE). PBMC were isolated from 55 patients with SLE and the telomerase activity was measured by TRAP assay. The telomere length of PBMC was also measured in 30 of these subjects. As a control group, 45 healthy adults with no particular clinical history were studied. The results were compared with clinical data. In patients with active SLE, the telomerase activity of PBMC was significantly increased compared with the control group. In patients with inactive SLE, the PBMC telomerase activity was not different compared with the controls in their 20s, 30s and 40s, but it was significantly increased compared with the controls in their 50s. In SLE patients, the telomerase activity of PBMC was significantly correlated with modified SLEDAI. The telomere length of PBMC in younger SLE patients tended to be shorter than that in the controls, but no difference was observed in older patients. The correlation coefficient between the telomerase activity and telomere length of PBMC in SLE patients was not significant. Abnormalities in the telomerase activity and telomere length observed in SLE patients are considered to be important findings for evaluation of the pathology of SLE.},
}
@article {pmid12944481,
year = {2003},
author = {Ueno, M and Nakazaki, T and Akamatsu, Y and Watanabe, K and Tomita, K and Lindsay, HD and Shinagawa, H and Iwasaki, H},
title = {Molecular characterization of the Schizosaccharomyces pombe nbs1+ gene involved in DNA repair and telomere maintenance.},
journal = {Molecular and cellular biology},
volume = {23},
number = {18},
pages = {6553-6563},
pmid = {12944481},
issn = {0270-7306},
mesh = {Amino Acid Sequence ; Binding Sites ; Cell Cycle Proteins/genetics ; Cell Nucleus/physiology ; Chromosomal Proteins, Non-Histone/*genetics/*metabolism ; DNA Repair/*physiology ; DNA-Binding Proteins/genetics/metabolism ; Endodeoxyribonucleases/metabolism ; Exodeoxyribonucleases/metabolism ; Hydroxyurea/pharmacology ; Methyl Methanesulfonate/pharmacology ; Molecular Sequence Data ; Mutation ; Nuclear Proteins/genetics ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Schizosaccharomyces/drug effects/*genetics/radiation effects ; Schizosaccharomyces pombe Proteins/*genetics/*metabolism ; Sequence Homology, Amino Acid ; Telomere/*physiology ; Two-Hybrid System Techniques ; Ultraviolet Rays ; },
abstract = {The human MRN complex is a multisubunit nuclease that is composed of Mre11, Rad50, and Nbs1 and is involved in homologous recombination and DNA damage checkpoints. Mutations of the MRN genes cause genetic disorders such as Nijmegen breakage syndrome. Here we identified a Schizosaccharomyces pombe nbs1(+) homologue by screening for mutants with mutations that caused methyl methanesulfonate (MMS) sensitivity and were synthetically lethal with the rad2Delta mutation. Nbs1 physically interacts with the C-terminal half of Rad32, the Schizosaccharomyces pombe Mre11 homologue, in a yeast two-hybrid assay. nbs1 mutants showed sensitivities to gamma-rays, UV, MMS, and hydroxyurea and displayed telomere shortening similar to the characteristics of rad32 and rad50 mutants. nbs1, rad32, and rad50 mutant cells were elongated and exhibited abnormal nuclear morphology. These findings indicate that S. pombe Nbs1 forms a complex with Rad32-Rad50 and is required for homologous recombination repair, telomere length regulation, and the maintenance of chromatin structure. Amino acid sequence features and some characteristics of the DNA repair function suggest that the S. pombe Rad32-Rad50-Nbs1 complex has functional similarity to the corresponding MRN complexes of higher eukaryotes. Therefore, S. pombe Nbs1 will provide an additional model system for studying the molecular function of the MRN complex associated with genetic diseases.},
}
@article {pmid12944479,
year = {2003},
author = {Karlseder, J and Kachatrian, L and Takai, H and Mercer, K and Hingorani, S and Jacks, T and de Lange, T},
title = {Targeted deletion reveals an essential function for the telomere length regulator Trf1.},
journal = {Molecular and cellular biology},
volume = {23},
number = {18},
pages = {6533-6541},
pmid = {12944479},
issn = {0270-7306},
support = {R01 GM049046/GM/NIGMS NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; R01 CA076027/CA/NCI NIH HHS/United States ; CA 76027/CA/NCI NIH HHS/United States ; GM 49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Blastocyst/pathology ; Cell Division ; Cells, Cultured ; Female ; Fetal Death/genetics ; Gene Targeting ; Mice ; Mice, Mutant Strains ; Pregnancy ; Sequence Deletion ; Telomerase/deficiency/genetics ; Telomere/*physiology ; Telomeric Repeat Binding Protein 1/*genetics/*metabolism ; Tumor Suppressor Protein p53/genetics ; },
abstract = {The human telomeric DNA binding factor TRF1 (hTRF1) and its interacting proteins TIN2, tankyrase 1 and 2, and PINX1 have been implicated in the regulation of telomerase-dependent telomere length maintenance. Here we show that targeted deletion of exon 1 of the mouse gene encoding Trf1 causes early (day 5 to 6 postcoitus) embryonic lethality. The absence of telomerase did not alter the Terf1(ex1Delta/ex1Delta) lethality, indicating that the phenotype was not due to inappropriate telomere elongation by telomerase. Terf1(ex1Delta/ex1Delta) blastocysts had a severe growth defect of the inner cell mass that was accompanied by apoptosis. However, no evidence was found for telomere uncapping causing this cell death; chromosome spreads of Terf1(ex1Delta/ex1Delta) blastocysts did not reveal chromosome end-to-end fusions, and p53 deficiency only briefly delayed Terf1(ex1Delta/ex1Delta) lethality. These data suggest that murine Trf1 has an essential function that is independent of telomere length regulation.},
}
@article {pmid12941829,
year = {2003},
author = {Farazi, PA and Glickman, J and Jiang, S and Yu, A and Rudolph, KL and DePinho, RA},
title = {Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma.},
journal = {Cancer research},
volume = {63},
number = {16},
pages = {5021-5027},
pmid = {12941829},
issn = {0008-5472},
support = {5R01CA84628-11/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Carcinoma, Hepatocellular/*etiology/genetics/pathology ; Disease Progression ; Liver Neoplasms/*etiology/genetics/pathology ; Male ; Mice ; Proliferating Cell Nuclear Antigen/analysis ; Telomere/*physiology ; Tumor Suppressor Protein p53/physiology ; },
abstract = {Telomere maintenance and telomerase reactivation are near universal features of human hepatocellular carcinoma (HCC), yet the shorter telomeres and highly abnormal cytogenetic profiles of HCC suggest that telomere erosion and dysfunction may be operative during the formative stages of tumorigenesis. Previous studies have established that the cancer-enhancing or suppressing impact of telomere dysfunction is highly dependent on several parameters including cell type, tumor stage, and p53 status. Here, to understand better the pathogenetic role of telomere dysfunction in the initiation and progression in human HCC, we have used three mechanistically distinct liver cancer-prone model systems (urokinase plasminogen activator transgenic mice, carbon tetrachloride exposure, and diethylnistrosamine treatment) in the context of successive generations of telomerase-deficient mice null for the telomerase RNA component, mTERC. Across all of the HCC model systems, telomere dysfunction suppressed both the incidence and growth of HCC lesions, a trend that mirrored the level of intratumoral proliferative arrest and apoptosis. On the histological level, telomere dysfunction was associated with a significant increase in the number of early stage neoplastic lesions and a reciprocal decline in the occurrence of high-grade malignancies. These genetic data in the mouse indicate that telomere dysfunction exerts an opposing role in the initiation versus progression of HCC and provide a framework for understanding the intimate link among chronic liver disease, chromosomal instability, and increased HCC in humans.},
}
@article {pmid12941806,
year = {2003},
author = {Evans, RJ and Wyllie, FS and Wynford-Thomas, D and Kipling, D and Jones, CJ},
title = {A P53-dependent, telomere-independent proliferative life span barrier in human astrocytes consistent with the molecular genetics of glioma development.},
journal = {Cancer research},
volume = {63},
number = {16},
pages = {4854-4861},
pmid = {12941806},
issn = {0008-5472},
mesh = {Astrocytes/*physiology ; Cell Division ; Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p16/analysis ; DNA-Binding Proteins ; Glioma/*etiology/genetics ; Humans ; Oncogene Proteins, Viral/analysis ; *Repressor Proteins ; Telomerase/analysis ; *Telomere ; Tumor Suppressor Protein p53/*physiology ; },
abstract = {An in vitro model, based on normal (primary) human astrocytes (NHAs), was used to investigate the nature of the selection pressures for events that occur during the progression of astrocyte-derived tumors and, in particular, the potential role of proliferative life span barriers (PLBs). As with fibroblasts, NHAs senesced with elevated p21(WAF1) and senescence-associated beta-galactosidase activities. Unlike fibroblasts, replicative senescence (M1) occurred much earlier, after approximately 20 pd and was not bypassed by hTERT expression. Abrogation of p53 function, by expression of human papillomavirus type 16 E6, led to an extension of life span, implying that replicative senescence in NHAs was p53-dependent but telomere-independent. human papillomavirus type16 E6 expression promoted additional growth of up to 12 pd, until a second telomere-independent PLB (termed M(INT)) was imposed associated with elevated p16(INK4A) levels. A proportion of cells escaped from M(INT) lost p16(INK4A) expression and achieved approximately an additional 25 pd until a crisis-like third PLB (M2) was reached. Expression of hTERT in post-M(INT) cells allowed these cells to become immortal and bypass this third PLB. The in vitro PLBs appear, in order of occurrence, dependent upon p53, p16(INK4A), and telomere erosion, a situation that mirrors an equivalent order of mutational events during tumor progression in vivo. This study describes a model that provides a plausible explanation for the selective pressures driving mutational events in this tumor type and provides direct evidence of a p53-dependent, telomere-independent PLB.},
}
@article {pmid12941600,
year = {2003},
author = {Amrichová, J and Lukásová, E and Kozubek, S and Kozubek, M},
title = {Nuclear and territorial topography of chromosome telomeres in human lymphocytes.},
journal = {Experimental cell research},
volume = {289},
number = {1},
pages = {11-26},
doi = {10.1016/s0014-4827(03)00208-8},
pmid = {12941600},
issn = {0014-4827},
mesh = {Cell Compartmentation/genetics ; Cell Nucleus/*genetics/ultrastructure ; Cell Polarity/genetics ; Centromere/genetics ; Chromosomes/*genetics/ultrastructure ; Chromosomes, Human, Pair 13/genetics/ultrastructure ; Chromosomes, Human, Pair 19/genetics/ultrastructure ; Chromosomes, Human, Pair 3/genetics/ultrastructure ; Chromosomes, Human, Pair 8/genetics/ultrastructure ; Chromosomes, Human, Pair 9/genetics/ultrastructure ; Humans ; Interphase/genetics ; Lymphocytes/cytology/*physiology ; Telomere/*genetics/ultrastructure ; },
abstract = {Nuclear and territorial positioning of p- and q-telomeres and centromeres of chromosomes 3, 8, 9, 13, and 19 were studied by repeated fluorescence in situ hybridization, high-resolution cytometry, and three-dimensional image analysis in human blood lymphocytes before and after stimulation. Telomeres were found on the opposite side of the territories as compared with the centromeres for all chromosome territories investigated. Mutual distances between telomeres of submetacentric chromosomes were very short, usually shorter than centromere-to-telomere distances, which means that the chromosome territory is nonrandomly folded. Telomeres are, on average, much nearer to the center of the cell nucleus than centromeres; q-telomeres were found, on average, more centrally localized as compared with p-telomeres. Consequently, we directly showed that chromosome territories in the cell nucleus are (1) polar and (2) partially oriented in cell nuclei. The distributions of genetic elements relative to chromosome territories (territorial distributions) can be either narrower or broader than their nuclear distributions, which reflects the degree of adhesion of an element to the territory or to the nucleus. We found no tethering of heterologous telomeres of chromosomes 8, 9, and 19. In contrast, both pairs of homologous telomeres of chromosome 19 (but not in other chromosomes) are tethered (associated) very frequently.},
}
@article {pmid12938182,
year = {2003},
author = {Baerlocher, GM and Lansdorp, PM},
title = {Telomere length measurements in leukocyte subsets by automated multicolor flow-FISH.},
journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology},
volume = {55},
number = {1},
pages = {1-6},
doi = {10.1002/cyto.a.10064},
pmid = {12938182},
issn = {1552-4922},
support = {AI29524/AI/NIAID NIH HHS/United States ; },
mesh = {Antigens, CD20/biosynthesis ; Automation ; B-Lymphocytes/cytology ; CD57 Antigens/biosynthesis ; Granulocytes/cytology ; Humans ; Immunologic Memory ; In Situ Hybridization ; In Situ Hybridization, Fluorescence/*methods ; Killer Cells, Natural/cytology ; Leukocyte Common Antigens/biosynthesis ; Leukocytes/cytology/*ultrastructure ; Lymphocytes/metabolism ; T-Lymphocytes/cytology ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Telomeres are essential protein-DNA structures at the end of chromosomes which are implicated in genome stability and cell replication. The average length of telomere repeats can be measured by in situ hybridization and flow cytometry [flow-FISH]. Such telomere length values reflect telomere shortening (resulting from cell divisions, oxidative damage and other causes) and telomere elongation (mainly resulting from telomerase activity) of the chromosome-specific telomere length inherited in the gametes. Here we report improvements in flow-FISH methodology that enable measurements of telomere length in subsets of human nucleated blood cells.<br><br>METHODS AND RESULTS: In order to measure the telomere length in granulocytes, naive T cells, memory T cells, B cells and natural killer (NK)/NKT cells within a blood sample, we combined flow-FISH with antibody-staining (Multicolor flow-FISH). Most steps in the staining protocol were automated using a 96-well microdispenser device. The minimum detectable difference in telomere length and the reproducibility of the method are in the range of 0.2-0.5 kb and measurements can be made with as few as a thousand cells.<br><br>CONCLUSIONS: Automated multicolor flow-FISH will greatly facilitate studies of telomere length regulation in subsets of nucleated blood cells, especially when only few cells are available and when differences in telomere length are small.},
}
@article {pmid12937682,
year = {2003},
author = {Khavinson, VKh and Bondarev, IE and Butyugov, AA},
title = {Epithalon peptide induces telomerase activity and telomere elongation in human somatic cells.},
journal = {Bulletin of experimental biology and medicine},
volume = {135},
number = {6},
pages = {590-592},
doi = {10.1023/a:1025493705728},
pmid = {12937682},
issn = {0007-4888},
mesh = {Animals ; Fibroblasts/cytology/*physiology ; Flow Cytometry ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Oligopeptides/*pharmacology ; Protein Subunits/genetics/metabolism ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Addition of Epithalon peptide in telomerase-negative human fetal fibroblast culture induced expression of the catalytical subunit, enzymatic activity of telomerase, and telomere elongation, which can be due to reactivation of telomerase gene in somatic cells and indicates the possibility of prolonging life span of a cell population and of the whole organism.},
}
@article {pmid12930956,
year = {2003},
author = {Kibe, T and Tomita, K and Matsuura, A and Izawa, D and Kodaira, T and Ushimaru, T and Uritani, M and Ueno, M},
title = {Fission yeast Rhp51 is required for the maintenance of telomere structure in the absence of the Ku heterodimer.},
journal = {Nucleic acids research},
volume = {31},
number = {17},
pages = {5054-5063},
pmid = {12930956},
issn = {1362-4962},
mesh = {Antigens, Nuclear/chemistry/*genetics/metabolism ; *DNA Helicases ; DNA, Fungal/genetics/metabolism ; DNA-Binding Proteins/chemistry/*genetics/*metabolism ; Dimerization ; Fungal Proteins/genetics/metabolism ; G2 Phase ; Ku Autoantigen ; Meiosis/genetics ; Mutation ; Poly G/genetics/metabolism ; Protein Binding ; Rad51 Recombinase ; S Phase ; Schizosaccharomyces/genetics/physiology ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Spores, Fungal/genetics/growth &amp; development ; Telomere/*genetics/metabolism ; },
abstract = {The Schizosaccharomyces pombe Ku70-Ku80 heterodimer is required for telomere length regulation. Lack of pku70+ results in telomere shortening and striking rearrangements of telomere-associated sequences. We found that the rearrangements of telomere-associated sequences in pku80+ mutants are Rhp51 dependent, but not Rad50 dependent. Rhp51 bound to telomere ends when the Ku heterodimer was not present at telomere ends. We also found that the single-stranded G-rich tails increased in S phase in wild-type strains, while deletion of pku70+ increased the single-stranded overhang in both G2 and S phase. Based on these observations, we propose that Rhp51 binds to the G-rich overhang and promotes homologous pairing between two different telomere ends in the absence of Ku heterodimer. Moreover, pku80 rhp51 double mutants showed a significantly reduced telomere hybridization signal. Our results suggest that, although Ku heterodimer sequesters Rhp51 from telomere ends to inhibit homologous recombination activity, Rhp51 plays important roles for the maintenance of telomere ends in the absence of the Ku heterodimer.},
}
@article {pmid12930628,
year = {2003},
author = {Shiels, PG and Jardine, AG},
title = {Dolly, no longer the exception: telomeres and implications for transplantation.},
journal = {Cloning and stem cells},
volume = {5},
number = {2},
pages = {157-160},
doi = {10.1089/153623003322234768},
pmid = {12930628},
issn = {1536-2302},
mesh = {Animals ; Cattle ; Cell Survival ; *Cloning, Organism ; Mice ; *Nuclear Transfer Techniques ; *Sheep ; Telomere/*physiology/*ultrastructure ; },
}
@article {pmid12928346,
year = {2003},
author = {Wu, X and Amos, CI and Zhu, Y and Zhao, H and Grossman, BH and Shay, JW and Luo, S and Hong, WK and Spitz, MR},
title = {Telomere dysfunction: a potential cancer predisposition factor.},
journal = {Journal of the National Cancer Institute},
volume = {95},
number = {16},
pages = {1211-1218},
doi = {10.1093/jnci/djg011},
pmid = {12928346},
issn = {1460-2105},
support = {CA-55769/CA/NCI NIH HHS/United States ; CA-70907/CA/NCI NIH HHS/United States ; CA-85576/CA/NCI NIH HHS/United States ; CA-86390/CA/NCI NIH HHS/United States ; CA52051/CA/NCI NIH HHS/United States ; P50-CA-91846/CA/NCI NIH HHS/United States ; R01-CA-74880/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Blotting, Southern ; Carcinoma, Renal Cell/genetics ; Case-Control Studies ; DNA Damage ; DNA Repair ; DNA, Neoplasm ; Female ; Flow Cytometry ; Genetic Predisposition to Disease ; Head and Neck Neoplasms/genetics ; Humans ; In Situ Hybridization, Fluorescence ; Kidney Neoplasms/genetics ; Lung Neoplasms/genetics ; Lymphocytes/metabolism ; Male ; Middle Aged ; Neoplasms/etiology/*genetics/metabolism ; Odds Ratio ; Risk Assessment ; Risk Factors ; Smoking/adverse effects ; Telomere/genetics/*metabolism ; Urinary Bladder Neoplasms/genetics ; },
abstract = {BACKGROUND: Genetic instability associated with telomere dysfunction (i.e., short telomeres) is an early event in tumorigenesis. We investigated the association between telomere length and cancer risk in four ongoing case-control studies.<br><br>METHODS: All studies had equal numbers of case patients and matched control subjects (92 for head and neck cancer, 135 for bladder cancer, 54 for lung cancer, and 32 for renal cell carcinoma). Telomere length was measured in peripheral blood lymphocytes from study participants. Genetic instability was assessed with the comet assay. Patient and disease characteristics were collected and analyzed for associations with risk for these cancers. All statistical tests were two-sided.<br><br>RESULTS: Telomeres were statistically significantly shorter in patients with head and neck cancer (6.5 kilobases [kb]) than in control subjects (7.4 kb) (difference = 0.9 kb, 95% confidence interval [CI] = 0.5 to 1.2 kb; P<.001). Nine percent of patients with head and neck cancer were in the longest quartile of telomere length, whereas 59% were in the shortest quartile. Similar patterns were observed for lung, renal cell, and bladder cancer. When subjects were categorized into telomere length quartiles defined by the distribution in control subjects, the following inverse relationship between telomere length and cancer risk was observed: adjusted odds ratios [ORs] for decreasing quartiles = 0.84 (95% CI = 0.36 to 1.97), 1.77 (95% CI = 0.72 to 4.36), and 5.11 (95% CI = 1.90 to 13.77). In stratified analysis, we found a suggestive greater-than-additive interaction between smoking status and telomere length: for ever smokers with short telomeres, OR = 25.05 (95% CI = 6.91 to 90.73); for never smokers with short telomeres, OR = 6.18 (95% CI = 1.72 to 22.13); and for ever smokers with long telomeres, OR = 6.49 (95% CI = 1.54 to 27.38). Telomere length was statistically significantly and inversely associated with baseline and mutagen-induced genetic instability.<br><br>CONCLUSION: Short telomeres appear to be associated with increased risks for human bladder, head and neck, lung, and renal cell cancers.},
}
@article {pmid12928335,
year = {2003},
author = {Wong, KK and DePinho, RA},
title = {Walking the telomere plank into cancer.},
journal = {Journal of the National Cancer Institute},
volume = {95},
number = {16},
pages = {1184-1186},
doi = {10.1093/jnci/djg028},
pmid = {12928335},
issn = {1460-2105},
mesh = {Animals ; Biomarkers, Tumor/*genetics ; Cell Transformation, Neoplastic/genetics ; Genetic Markers/*genetics ; Genetic Predisposition to Disease ; Head and Neck Neoplasms/genetics ; Humans ; Kidney Neoplasms/genetics ; Lung Neoplasms/genetics ; Lymphocytes/metabolism ; Neoplasms/*genetics ; Precancerous Conditions/genetics ; Predictive Value of Tests ; Prognosis ; Risk Assessment ; Risk Factors ; Telomere/*genetics ; Urinary Bladder Neoplasms/genetics ; },
}
@article {pmid12925751,
year = {2003},
author = {Viscardi, V and Baroni, E and Romano, M and Lucchini, G and Longhese, MP},
title = {Sudden telomere lengthening triggers a Rad53-dependent checkpoint in Saccharomyces cerevisiae.},
journal = {Molecular biology of the cell},
volume = {14},
number = {8},
pages = {3126-3143},
pmid = {12925751},
issn = {1059-1524},
support = {E.1247/TI_/Telethon/Italy ; },
mesh = {Cell Cycle/genetics ; *Cell Cycle Proteins ; Checkpoint Kinase 2 ; DNA Damage/physiology ; Endonucleases ; Fungal Proteins/*metabolism ; Genes, cdc ; Intracellular Signaling Peptides and Proteins ; Mutation/genetics ; Protein Serine-Threonine Kinases/*metabolism ; Recombinant Fusion Proteins/metabolism ; Saccharomyces cerevisiae/cytology/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Telomerase/metabolism ; Telomere/enzymology/*genetics ; Telomere-Binding Proteins/metabolism ; },
abstract = {Telomeres are specialized functional complexes that ensure chromosome stability by protecting chromosome ends from fusions and degradation and avoiding chromosomal termini from being sensed as DNA breaks. Budding yeast Tel1 is required both for telomere metabolism and for a Rad53-dependent checkpoint responding to unprocessed double-strand breaks. We show that overexpression of a GAL1-TEL1 fusion causes transient telomere lengthening and activation of a Rad53-dependent G2/M checkpoint in cells whose telomeres are short due to the lack of either Tel1 or Yku70. Sudden telomere elongation and checkpoint-mediated cell cycle arrest are also triggered in wild-type cells by overproducing a protein fusion between the telomeric binding protein Cdc13 and the telomerase-associated protein Est1. Checkpoint activation by GAL1-TEL1 requires ongoing telomere elongation. In fact, it is turned off concomitantly with telomeres reaching a new stable length and is partially suppressed by deletion of the telomerase EST2 gene. Moreover, both telomere length rebalancing and checkpoint inactivation under galactose-induced conditions are accelerated by high levels of either the Sae2 protein, involved in double-strand breaks processing, or the negative telomere length regulator Rif2. These data suggest that sudden telomere lengthening elicits a checkpoint response that inhibits the G2/M transition.},
}
@article {pmid12921855,
year = {2003},
author = {Zhang, Y and Cao, EH and Liang, XQ and Qin, JF},
title = {Increasing sensitivity to arsenic trioxide-induced apoptosis by altered telomere state.},
journal = {European journal of pharmacology},
volume = {474},
number = {2-3},
pages = {141-147},
doi = {10.1016/s0014-2999(03)02013-2},
pmid = {12921855},
issn = {0014-2999},
mesh = {Apoptosis/*drug effects/physiology ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Cell Line ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Growth Inhibitors/pharmacology ; Humans ; Oxides/*pharmacology ; Telomerase/antagonists &amp; inhibitors/metabolism ; Telomere/*drug effects/physiology ; },
abstract = {In this work, we investigated the synergic effects between low-dose arsenic trioxide and diethyloxadicarbocyanine (DODC), a telomerase inhibitor, on cell apoptosis. Results revealed that low-dose arsenic could block cell cycle arrest at the G2/M phase and induce apoptosis, whereas DODC could block cell cycle arrest at the G0/G1 phase but not induce apoptosis. However, cells pretreated with DODC showed greater sensitivity to arsenic than untreated cells. The percentage of apoptosis produced by combination treatment with the two agents increased and that was similar to the effect of high-dose arsenic treatment alone. Further studies showed that DODC alone could induce hairpin G-quadruplex formation and inhibit telomerase activity in a dose-dependent manner. Compared with HT1080 cells, 293 cells were more sensitive to cell growth inhibition and apoptosis and were less sensitivity to telomerase activity. These results indicate that DODC can synergistically enhance the apoptosis induced by arsenic, suggesting the increased cell senescence in response to arsenic is induced by an altered telomere state rather than by a loss of telomerase. Thus clinical application of combination treatment with arsenic and telomerase inhibitor may have potential in cancer therapy.},
}
@article {pmid12920086,
year = {2003},
author = {Bonaglia, MC and Giorda, R and Cavallini, A and Pramparo, T and Rocchi, M and Borgatti, R and Zuffardi, O},
title = {Distal trisomy 6p and 20q owing to the concurrent transposition of distal 6p and 20q to the 22q telomere: a genomic polymorphism?.},
journal = {Journal of medical genetics},
volume = {40},
number = {8},
pages = {e94},
doi = {10.1136/jmg.40.8.e94},
pmid = {12920086},
issn = {1468-6244},
support = {GP0247Y01/TI_/Telethon/Italy ; },
mesh = {Child, Preschool ; Chromosomes, Human, Pair 20/*genetics ; Chromosomes, Human, Pair 22/*genetics ; Chromosomes, Human, Pair 6/*genetics ; Humans ; Male ; *Polymorphism, Genetic ; Telomere/*genetics ; Translocation, Genetic/*genetics ; Trisomy/diagnosis/*genetics ; },
}
@article {pmid12919960,
year = {2003},
author = {Zhang, TC and Schmitt, MT and Mumford, JL},
title = {Effects of arsenic on telomerase and telomeres in relation to cell proliferation and apoptosis in human keratinocytes and leukemia cells in vitro.},
journal = {Carcinogenesis},
volume = {24},
number = {11},
pages = {1811-1817},
doi = {10.1093/carcin/bgg141},
pmid = {12919960},
issn = {0143-3334},
mesh = {Apoptosis/*drug effects ; Arsenic/*pharmacology ; Cell Division/*drug effects ; Cell Line ; Cyclic N-Oxides/pharmacology ; Humans ; Keratinocytes/*drug effects/enzymology/ultrastructure ; Leukemia, Promyelocytic, Acute/enzymology/*pathology ; Spin Labels ; Telomerase/*drug effects ; Telomere/*drug effects ; },
abstract = {Telomeres are critical in maintaining chromosome and genomic stability. Arsenic, a human carcinogen as well as an anticancer agent, is known for its clastogenicity. To better understand molecular mechanisms of arsenic actions, we investigated arsenite effects on telomere and telomerase and determined cell growth and apoptosis in HL-60 and HaCaT cells in vitro. Low concentrations (0.1-1 microM in HaCaT and 0.1-0.5 microM in HL-60) of arsenite increased telomerase activity, maintained or elongated telomere length, and promoted cellular proliferation. High concentrations (>1-40 microM) of arsenite decreased telomerase activity, telomere length and induced apoptosis. Results from the studies comparing cell lines with and without telomerase activity suggested that telomerase was involved in arsenic-induced apoptosis. The spin trap agent, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) was effective in protecting the arsenite-induced telomere attrition and apoptosis, suggesting that reactive oxygen species may play an important role in the shortening of telomeres and apoptosis induced by arsenic. These findings suggest the carcinogenic effects of arsenic may be partly attributed to increase in telomerase activity leading to promotion of cell proliferation and its anticancer effects by exerting oxidative stress and leading to telomeric DNA attrition and apoptosis.},
}
@article {pmid12915884,
year = {2003},
author = {Klapper, W and Krams, M and Qian, W and Janssen, D and Parwaresch, R},
title = {Telomerase activity in B-cell non-Hodgkin lymphomas is regulated by hTERT transcription and correlated with telomere-binding protein expression but uncoupled from proliferation.},
journal = {British journal of cancer},
volume = {89},
number = {4},
pages = {713-719},
pmid = {12915884},
issn = {0007-0920},
mesh = {Biomarkers, Tumor/genetics/*metabolism ; Cell Division ; DNA Helicases/genetics/metabolism ; DNA Primers/chemistry ; DNA-Binding Proteins ; Gene Expression Regulation, Enzymologic ; Humans ; Lymphoma, B-Cell/*enzymology/genetics/pathology ; Neoplasm Proteins/genetics/*metabolism ; Proto-Oncogene Proteins c-myc/genetics/metabolism ; RNA/genetics/metabolism ; RNA, Messenger/metabolism ; RNA, Neoplasm/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; *Saccharomyces cerevisiae Proteins ; Tankyrases/genetics/metabolism ; Telomerase/*genetics/*metabolism ; Telomere/genetics/metabolism ; Telomeric Repeat Binding Protein 1/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/*genetics/metabolism ; },
abstract = {Telomere maintenance is a prerequisite for immortalisation, and in most malignant cells is carried out by telomerase, an enzyme that synthesis new telomeric repeats on the chromosome ends. In normal or reactive tissues with a high regenerative capacity, telomerase is regulated according to the telomere loss that occurs during proliferation. To evaluate the interaction of proliferation and telomerase activity in malignant lymphomas, we quantified telomerase expression in different non-Hodgkin lymphomas in comparison to normal or reactive lymph nodes. Surprisingly, the activity levels were the same in most of the lymphomas analysed as compared to reactive lymph nodes. Significantly higher activity was detected only in Burkitt's lymphoma. Telomerase activity correlated well with hTERT and c-myc expression, but was independent of proliferation. To evaluate interactions of telomere-binding protein expression on telomerase expression in non-Hodgkin lymphoma, the mRNA levels of TRF1, TRF2, tankyrase and hPif1 were assessed by real-time RT-PCR. We demonstrate here that the magnitude of telomerase upregulation does not necessarily reflect the requirement of telomere compensation caused by proliferation. Telomerase regulation in non-Hodgkin lymphomas is therefore uncoupled from proliferative stimuli found in reactive lymphoid tissue. We suggest that the upregulation of specific telomere-binding proteins like TRF2 may contribute to telomere maintenance in malignant lymphoma.},
}
@article {pmid12914150,
year = {2003},
author = {Viidik, A},
title = {[Telomeres are not a key to eternal life].},
journal = {Lakartidningen},
volume = {100},
number = {30-31},
pages = {2468},
pmid = {12914150},
issn = {0023-7205},
mesh = {Aging/*physiology ; Apoptosis/physiology ; Humans ; *Mortality ; Telomere/*physiology ; },
}
@article {pmid12912928,
year = {2003},
author = {Theobald, DL and Schultz, SC},
title = {Nucleotide shuffling and ssDNA recognition in Oxytricha nova telomere end-binding protein complexes.},
journal = {The EMBO journal},
volume = {22},
number = {16},
pages = {4314-4324},
pmid = {12912928},
issn = {0261-4189},
support = {R01 CA081109/CA/NCI NIH HHS/United States ; 1R01CA81109/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Binding Sites ; Crystallography, X-Ray ; DNA, Single-Stranded/*chemistry/genetics/*metabolism ; Dimerization ; Hydrogen Bonding ; Models, Molecular ; Nucleic Acid Conformation ; *Oxytricha/chemistry/genetics ; Protein Binding ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Repetitive Sequences, Nucleic Acid/genetics ; Structure-Activity Relationship ; Telomere/chemistry/genetics/*metabolism ; Thermodynamics ; },
abstract = {Sequence-specific protein recognition of single-stranded nucleic acids is critical for many fundamental cellular processes, such as DNA replication, DNA repair, transcription, translation, recombination, apoptosis and telomere maintenance. To explore the mechanisms of sequence-specific ssDNA recognition, we determined the crystal structures of 10 different non-cognate ssDNAs complexed with the Oxytricha nova telomere end-binding protein (OnTEBP) and evaluated their corresponding binding affinities (PDB ID codes 1PH1-1PH9 and 1PHJ). The thermodynamic and structural effects of these sequence perturbations could not have been predicted based solely upon the cognate structure. OnTEBP accommodates non-cognate nucleotides by both subtle adjustments and surprisingly large structural rearrangements in the ssDNA. In two complexes containing ssDNA intermediates that occur during telomere extension by telomerase, entire nucleotides are expelled from the complex. Concurrently, the sequence register of the ssDNA shifts to re-establish a more cognate-like pattern. This phenomenon, termed nucleotide shuffling, may be of general importance in protein recognition of single-stranded nucleic acids. This set of structural and thermodynamic data highlights a fundamental difference between protein recognition of ssDNA versus dsDNA.},
}
@article {pmid12912862,
year = {2003},
author = {Plentz, RR and Wiemann, SU and Flemming, P and Meier, PN and Kubicka, S and Kreipe, H and Manns, MP and Rudolph, KL},
title = {Telomere shortening of epithelial cells characterises the adenoma-carcinoma transition of human colorectal cancer.},
journal = {Gut},
volume = {52},
number = {9},
pages = {1304-1307},
pmid = {12912862},
issn = {0017-5749},
mesh = {Adenoma/genetics/*ultrastructure ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; Colorectal Neoplasms/genetics/*ultrastructure ; Connective Tissue/ultrastructure ; Epithelial Cells/ultrastructure ; Humans ; In Situ Hybridization, Fluorescence ; Telomere/genetics/*ultrastructure ; },
abstract = {BACKGROUND: and aims: Chromosomal instability is one of the most consistent markers of sporadic colorectal cancer in humans. There is growing evidence that telomere shortening is one of the mechanisms leading to chromosomal instability and cancer initiation.<br><br>METHODS: To test this hypothesis, the telomere length of colorectal epithelial cells and cells from connective tissue was determined at the adenoma-carcinoma transition at the cellular level by quantitative fluorescence in situ hybridisation.<br><br>RESULTS: Our study showed that the telomere fluorescence intensity of epithelial cells was significantly weaker at the earliest morphologically definable stage of carcinoma-high grade dysplasia with minimal invasive growth-compared with the surrounding adenoma. In contrast, cells from connective tissue had a similar telomere signal intensity at the carcinoma stage compared with the adenoma, and in turn cells from connective tissue had overall significantly stronger telomere fluorescence signals compared with epithelial cells.<br><br>CONCLUSIONS: These results demonstrate that short telomeres of epithelial cells characterise the adenoma-carcinoma transition during human colorectal carcinogenesis, suggesting that carcinomas arise from cells with critical short telomeres within the adenoma. Since the adenoma-carcinoma transition in colorectal cancer is characterised by an increase in chromosomal instability and anaphase bridges, our data support the hypothesis that short telomeres initiate colorectal cancer by induction of chromosomal instability.},
}
@article {pmid12910376,
year = {2003},
author = {Lee, JJ and Nam, CE and Cho, SH and Park, KS and Chung, IJ and Kim, HJ},
title = {Telomere length shortening in non-Hodgkin's lymphoma patients undergoing chemotherapy.},
journal = {Annals of hematology},
volume = {82},
number = {8},
pages = {492-495},
doi = {10.1007/s00277-003-0691-4},
pmid = {12910376},
issn = {0939-5555},
mesh = {Antineoplastic Combined Chemotherapy Protocols ; Antineoplastic Protocols ; Blotting, Southern ; Case-Control Studies ; Cyclophosphamide ; Doxorubicin ; Female ; Humans ; Lymphoma, Non-Hodgkin/*drug therapy/*genetics ; Male ; Monocytes ; Prednisolone ; Telomere/*genetics ; Time Factors ; Vincristine ; },
abstract = {We investigated telomere length changes in patients with non-Hodgkin's lymphoma (NHL) receiving conventional-dose chemotherapy. Using Southern blot analysis, telomere length was measured in peripheral blood mononuclear cells from five NHL patients at diagnosis, 15 NHL patients after chemotherapy, and 39 healthy controls. Compared with age-matched putative normal controls, telomeres were significantly shorter in NHL patients at diagnosis. Mean telomere length was shorter after chemotherapy than before chemotherapy and was shorter after chemotherapy than in age-matched putative healthy controls. There was no correlation between the extent of telomere shortening and time elapsed after chemotherapy. These findings suggest that in NHL patients hematopoietic stem cells lose telomere length during the recovery period from bone marrow suppression after conventional-dose chemotherapy.},
}
@article {pmid12903220,
year = {2002},
author = {Kanaori, K and Yoshida, S and Shoji, T and Tajima, K and Makino, K},
title = {Structural change of G-quartet by 5'-elongation of telomere DNA oligomer.},
journal = {Nucleic acids research. Supplement (2001)},
volume = {},
number = {2},
pages = {293-294},
doi = {10.1093/nass/2.1.293},
pmid = {12903220},
mesh = {Biopolymers/*chemistry ; Circular Dichroism ; DNA/*chemistry ; *Nucleic Acid Conformation ; *Telomere ; },
abstract = {Structural change of G-quartet formed by telomere G-rich DNA oligomers are investigated by NMR and CD spectroscopy. G-quartet structure changes depending on the length of 5'-terminal sequence.},
}
@article {pmid12902228,
year = {2003},
author = {Kim, SY and Sohn, JH and Bae, JH and Pyun, YR and Agaphonov, MO and Ter-Avanesyan, MD and Choi, ES},
title = {Efficient library construction by in vivo recombination with a telomere-originated autonomously replicating sequence of Hansenula polymorpha.},
journal = {Applied and environmental microbiology},
volume = {69},
number = {8},
pages = {4448-4454},
pmid = {12902228},
issn = {0099-2240},
mesh = {DNA Replication ; *Gene Library ; Pichia/*genetics ; *Recombination, Genetic ; *Telomere ; Transformation, Genetic ; },
abstract = {A high frequency of transformation and an equal gene dosage between transformants are generally required for activity-based selection of mutants from a library obtained by directed evolution. An efficient library construction method was developed by using in vivo recombination in Hansenula polymorpha. Various linear sets of vectors and insert fragments were transformed and analyzed to optimize the in vivo recombination system. A telomere-originated autonomously replicating sequence (ARS) of H. polymorpha, reported as a recombination hot spot, facilitates in vivo recombination between the linear transforming DNA and chromosomes. In vivo recombination of two linear DNA fragments containing the telomeric ARS drastically increases the transforming frequency, up to 10-fold, compared to the frequency of circular plasmids. Direct integration of the one-end-recombined linear fragment into chromosomes produced transformants with single-copy gene integration, resulting in the same expression level for the reporter protein between transformants. This newly developed in vivo recombination system of H. polymorpha provides a suitable library for activity-based selection of mutants after directed evolution.},
}
@article {pmid12902162,
year = {2003},
author = {Chakhparonian, M and Wellinger, RJ},
title = {Telomere maintenance and DNA replication: how closely are these two connected?.},
journal = {Trends in genetics : TIG},
volume = {19},
number = {8},
pages = {439-446},
doi = {10.1016/S0168-9525(03)00135-5},
pmid = {12902162},
issn = {0168-9525},
mesh = {Animals ; *DNA Replication ; Humans ; Mice ; Saccharomyces cerevisiae/genetics ; Telomere/*genetics/*metabolism ; },
abstract = {The maintenance of the DNA at chromosome ends, the telomeres, depends on conventional semiconservative replication and on the action of telomerase, a specialized reverse transcriptase. Current research strongly suggests a regulatory interplay between this conventional semiconservative replication and telomerase, thus ensuring that no sequences are lost at the very ends of the telomeres during replication. Here, we describe recent findings on the interactions between the conventional replication machinery and telomere replication, and we discuss how DNA-integrity checkpoints might impinge on both the processing of the telomeric DNA ends and the establishment of the DNA end structure required for end protection and genome stability.},
}
@article {pmid12899613,
year = {2003},
author = {Classen, S and Lyons, D and Cech, TR and Schultz, SC},
title = {Sequence-specific and 3'-end selective single-strand DNA binding by the Oxytricha nova telomere end binding protein alpha subunit.},
journal = {Biochemistry},
volume = {42},
number = {31},
pages = {9269-9277},
doi = {10.1021/bi0273718},
pmid = {12899613},
issn = {0006-2960},
support = {1R01CA81109/CA/NCI NIH HHS/United States ; GM28039/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; Crystallography, X-Ray ; DNA, Protozoan/genetics ; DNA, Single-Stranded/chemistry/genetics/*metabolism ; Dimerization ; Electrophoretic Mobility Shift Assay ; *Oxytricha/chemistry/genetics ; Protein Conformation ; Protein Subunits ; Protozoan Proteins/chemistry/genetics/*metabolism ; Substrate Specificity ; Telomere/*genetics ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; },
abstract = {Oxytricha nova telomere end binding protein (OnTEBP) specifically recognizes and caps single-strand (T(4)G(4))(2) telomeric DNA at the very 3'-ends of O. nova macronuclear chromosomes. The discovery of proteins homologous to the N-terminal domain of the OnTEBP alpha subunit in Euplotes crassus, Schizosaccharomyces pombe, and Homo sapiens suggests that related proteins are widely distributed in eukaryotes. Previously reported crystal structures of the ssDNA binding domain of the OnTEBP alpha subunit both uncomplexed and complexed with telomeric ssDNA have suggested specific mechanisms for sequence-specific and 3'-end selective recognition of the single-strand telomeric DNA. We now describe comparative binding studies of ssDNA recognition by the N-terminal domain of the OnTEBP alpha subunit. Addition of nucleotides to the 3'-end of the TTTTGGGG telomere repeat decreases the level of alpha binding by up to 7-fold, revealing a modest specificity for a 3'-terminus relative to an internal DNA binding site. Nucleotide substitutions at specific positions within the t(1)t(2)t(3)T(4)G(5)G(6)G(7)G(8) repeat show that base substitutions at some sites do not substantially decrease the binding affinity (<2-fold for lowercase letters), while substitutions at other sites dramatically reduce the binding affinity (>20-fold decrease for the uppercase bold letter). Comparison of the structural and binding data provides unique insights into the ways in which proteins recognize and bind single-stranded DNA.},
}
@article {pmid12898604,
year = {2003},
author = {Ferlicot, S and Youssef, N and Feneux, D and Delhommeau, F and Paradis, V and Bedossa, P},
title = {Measurement of telomere length on tissue sections using quantitative fluorescence in situ hybridization (Q-FISH).},
journal = {The Journal of pathology},
volume = {200},
number = {5},
pages = {661-666},
doi = {10.1002/path.1392},
pmid = {12898604},
issn = {0022-3417},
mesh = {Adult ; Aged ; Aging/genetics ; Blotting, Southern/methods ; Child ; Cryopreservation ; Humans ; Image Processing, Computer-Assisted/methods ; In Situ Hybridization, Fluorescence/*methods ; Kidney/ultrastructure ; Leukemia/genetics ; Middle Aged ; Reproducibility of Results ; Telomere/*ultrastructure ; Tumor Cells, Cultured ; },
abstract = {Loss of telomere repeat sequences occurs after each cell division and telomere shortening has been implicated in cellular senescence. The measurement of telomere length might therefore assess the lifespan of a cell. The aim of this study was to set up and validate a technique enabling the assessment of telomere length on tissue sections. Quantitative fluorescence in situ hybridization (Q-FISH) with telomeric probes was performed on smears and sections from cell preparations or human tissues. The mean fluorescence intensity of telomere spots (FI/spot) was automatically quantified by image analysis. Telomeric restriction fragment (TRF) length was assessed by Southern blotting. There was a positive significant correlation between telomere length, as assessed by Q-FISH, and TRF length determined by Southern blotting in corresponding samples (p < 0.01, r = 0.6 for tissue and p < 0.01, r = 0.79 for cells). FI/spot was higher on smears than on sections, but pairwise comparison showed a significant correlation both for cells and for tissues (r = 0.77, p < 0.001 for cells and p < or = 0.01, r = 0.64 for tissue). Finally, since telomere length is expected to shorten with age, FI/spot was assessed in liver samples according to the age of patients: a negative correlation was demonstrated (r = 0.76, p < 0.01). Inter-assay variation was 7% for Q-FISH performed on tissue sections and 12% on touch preparations. This study shows that Q-FISH can be performed with confidence on fixed frozen tissue sections in order to assess telomere length. It is an easy, accurate, and reproducible in situ method for assessing telomeres in the context of cell type and tissue architecture.},
}
@article {pmid12897131,
year = {2003},
author = {Jaco, I and Muñoz, P and Goytisolo, F and Wesoly, J and Bailey, S and Taccioli, G and Blasco, MA},
title = {Role of mammalian Rad54 in telomere length maintenance.},
journal = {Molecular and cellular biology},
volume = {23},
number = {16},
pages = {5572-5580},
pmid = {12897131},
issn = {0270-7306},
support = {R01 CA043322/CA/NCI NIH HHS/United States ; CA43322/CA/NCI NIH HHS/United States ; CA76409/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; Chromosome Aberrations ; DNA Helicases ; *DNA Repair ; DNA Repair Enzymes ; Genotype ; Heterozygote ; In Situ Hybridization, Fluorescence ; Mice ; *Recombination, Genetic ; Saccharomyces cerevisiae Proteins/metabolism/*physiology ; Telomerase/metabolism ; Telomere/*genetics ; },
abstract = {The homologous recombination (HR) DNA repair pathway participates in telomere length maintenance in yeast but its putative role at mammalian telomeres is unknown. Mammalian Rad54 is part of the HR machinery, and Rad54-deficient mice show a reduced HR capability. Here, we show that Rad54-deficient mice also show significantly shorter telomeres than wild-type controls, indicating that Rad54 activity plays an essential role in telomere length maintenance in mammals. Rad54 deficiency also resulted in an increased frequency of end-to-end chromosome fusions involving telomeres compared to the controls, suggesting a putative role of Rad54 in telomere capping. Finally, the study of mice doubly deficient for Rad54 and DNA-PKcs showed that telomere fusions due to DNA-PKcs deficiency were not rescued in the absence of Rad54, suggesting that they are not mediated by Rad54 activity.},
}
@article {pmid12894250,
year = {2003},
author = {Feldser, DM and Hackett, JA and Greider, CW},
title = {Telomere dysfunction and the initiation of genome instability.},
journal = {Nature reviews. Cancer},
volume = {3},
number = {8},
pages = {623-627},
doi = {10.1038/nrc1142},
pmid = {12894250},
issn = {1474-175X},
mesh = {Cellular Senescence ; Chromosome Aberrations ; Genome ; Humans ; Models, Genetic ; *Mutation ; Neoplasms/*genetics ; Telomere/*physiology ; },
abstract = {Tumour growth is an evolutionary process that is characterized by the selection of clonal populations of cells that acquire distinct genetic changes. Many cancer therapies aim to exploit the specific changes that occur in cancer cells, but understanding the underlying mechanisms of genomic instability that cause these mutations could lead to more effective therapies. If common mechanisms exist for initiating genomic instability in tumours, selection could explain the differences in specific gene mutations that accumulate in different tumour types. The cause of genomic instability in human tumours is unclear, although there is evidence to indicate that telomere dysfunction could make an important contribution.},
}
@article {pmid12890806,
year = {2003},
author = {Montanaro, L and Tazzari, PL and Derenzini, M},
title = {Enhanced telomere shortening in transformed lymphoblasts from patients with X linked dyskeratosis.},
journal = {Journal of clinical pathology},
volume = {56},
number = {8},
pages = {583-586},
pmid = {12890806},
issn = {0021-9746},
mesh = {Apoptosis ; Cell Division ; Cell Line ; Cell Line, Transformed ; Dyskeratosis Congenita/*genetics/*immunology ; Flow Cytometry ; Humans ; In Situ Hybridization, Fluorescence ; *Lymphocyte Activation ; Lymphocytes/*ultrastructure ; Telomere/*ultrastructure ; },
abstract = {AIM: Dyskeratosis congenita (DC) is characterised by the failure of those tissues that are rapidly dividing in the adult, particularly the skin, mucosae, and haemopoietic system. The X linked form of the disease is caused by mutations of the DKC1 gene, which encodes dyskerin, a protein that is necessary for the function of telomerase. Cultured DC lymphoblastoid cells are characterised by a reduced expansion of the cell population because of the progressive increase in apoptosis compared with the number of cell divisions. This report aimed to verify whether this is caused by a defect in telomerase function.<br><br>METHODS: Variations in telomere length over time were evaluated in two cultured lymphoblastoid cell lines derived from patients with X linked DC and control cells derived from a non-affected individual. In addition, the effect of inhibiting poly (ADP-ribose) polymerase (PARP), which is involved in the cellular response to excessive telomere shortening, was assessed. One DC cell line and the control cells were treated with the specific PARP inhibitor 1,5-dihydroxyquinoline (IQ).<br><br>RESULTS: In DC cells the increase in cell death was associated with progressive telomere shortening, and this was not seen in the control cells. Treatment with IQ delayed the increase of apoptosis in DC cells.<br><br>CONCLUSIONS: These observations indicate that the reduced expansion that characterises cultured cells obtained from patients with X linked DC is caused by premature telomere shortening.},
}
@article {pmid12888526,
year = {2003},
author = {Yamamoto, Y and Fujimoto, Y and Arai, R and Fujie, M and Usami, S and Yamada, T},
title = {Retrotransposon-mediated restoration of Chlorella telomeres: accumulation of Zepp retrotransposons at termini of newly formed minichromosomes.},
journal = {Nucleic acids research},
volume = {31},
number = {15},
pages = {4646-4653},
pmid = {12888526},
issn = {1362-4962},
mesh = {Base Sequence ; Chlorella/*genetics/radiation effects ; Chromosomes/radiation effects ; Molecular Sequence Data ; *Retroelements ; Sequence Analysis, DNA ; Telomere/*chemistry ; },
abstract = {To elucidate the contribution of LINE-like retrotransposon Zepp elements to the formation and maintenance of chromosomal telomeres, newly formed minichromosomes in irradiated Chlorella vulgaris cells were isolated and structurally characterized. A minichromosome (miniV4) of approximately 700 kb in size contained a Zepp cluster taking the place of the telomeric repeats on one terminus, whereas the other end of this chromosome consisted of canonical telomeric repeats. The Zepp copies in this cluster were in a tandem array with their poly(A) tails towards the centromere. Another minichromosome Y32 (approximately 400 kb in size) was shown to have several copies of Zepp elements on both termini. On the right arm terminus, two copies of Zepp were found in a tandem array with poly(A) tracts facing towards the chromosomal end. The poly(A) tail and the 3'-end of approximately 400 bp of the distal copy were replaced by the telomeric repeats. On the 5'-side of the proximal copy was another Zepp element in the reverse orientation. These newly formed telomeric structures are very similar to those previously found in the left arm of chromosome I and the terminus of an unidentified chromosome and support the model of Zepp-mediated restoration and maintenance of Chlorella telomeres.},
}
@article {pmid12887925,
year = {2003},
author = {Masutomi, K and Yu, EY and Khurts, S and Ben-Porath, I and Currier, JL and Metz, GB and Brooks, MW and Kaneko, S and Murakami, S and DeCaprio, JA and Weinberg, RA and Stewart, SA and Hahn, WC},
title = {Telomerase maintains telomere structure in normal human cells.},
journal = {Cell},
volume = {114},
number = {2},
pages = {241-253},
doi = {10.1016/s0092-8674(03)00550-6},
pmid = {12887925},
issn = {0092-8674},
support = {F32 CA93033/CA/NCI NIH HHS/United States ; K01 CA94223/CA/NCI NIH HHS/United States ; R01 CA78461/CA/NCI NIH HHS/United States ; },
mesh = {Antibodies, Monoclonal/metabolism ; Cell Nucleus/metabolism ; Cell Transformation, Viral/genetics ; DNA Replication ; Enzyme Activation ; Fibroblasts/cytology/enzymology/metabolism ; HeLa Cells ; Humans ; Kinetics ; Models, Biological ; Mutation ; Proliferating Cell Nuclear Antigen/metabolism ; RNA, Messenger/metabolism ; RNA, Small Interfering/metabolism ; Retroviridae/genetics ; Telomerase/genetics/immunology/*metabolism ; Telomere/genetics/*metabolism ; Tumor Cells, Cultured ; },
abstract = {In normal human cells, telomeres shorten with successive rounds of cell division, and immortalization correlates with stabilization of telomere length. These observations suggest that human cancer cells achieve immortalization in large part through the illegitimate activation of telomerase expression. Here, we demonstrate that the rate-limiting telomerase catalytic subunit hTERT is expressed in cycling primary presenescent human fibroblasts, previously believed to lack hTERT expression and telomerase activity. Disruption of telomerase activity in normal human cells slows cell proliferation, restricts cell lifespan, and alters the maintenance of the 3' single-stranded telomeric overhang without changing the rate of overall telomere shortening. Together, these observations support the view that telomerase and telomere structure are dynamically regulated in normal human cells and that telomere length alone is unlikely to trigger entry into replicative senescence.},
}
@article {pmid12885883,
year = {2003},
author = {Burnett, E and Tattersall, P},
title = {Reverse genetic system for the analysis of parvovirus telomeres reveals interactions between transcription factor binding sites in the hairpin stem.},
journal = {Journal of virology},
volume = {77},
number = {16},
pages = {8650-8660},
pmid = {12885883},
issn = {0022-538X},
support = {AI26109/AI/NIAID NIH HHS/United States ; CA29303/CA/NCI NIH HHS/United States ; T32 GM07499/GM/NIGMS NIH HHS/United States ; R37 AI026109/AI/NIAID NIH HHS/United States ; T32 GM007499/GM/NIGMS NIH HHS/United States ; R01 AI026109/AI/NIAID NIH HHS/United States ; R01 CA029303/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Binding Sites ; Cell Line ; DNA Replication ; DNA, Viral/chemistry/genetics/*metabolism ; Fluorescent Antibody Technique ; Mice ; Mutagenesis ; *Nucleic Acid Conformation ; Parvovirus/*genetics ; *Telomere ; Transcription Factors/*metabolism ; },
abstract = {The left-hand or 3'-terminal hairpin of minute virus of mice (MVM) contains sequence elements essential for both viral DNA replication at the left-hand origin (oriL) and for the modulation of the P4 promoter, from which the viral nonstructural gene cassette is transcribed. This hairpin sequence has proven difficult to manipulate in the context of the viral genome. Here we describe a system for generating mutant viruses using synthetic hairpin oligonucleotides and a truncated form of the infectious clone. This allows manipulation of the sequence of the left-hand hairpin and examination of the effects in the context of the viral life cycle. We have confirmed the requirement for a functional parvovirus initiation factor (PIF) binding site and determined that an optimized PIF binding site, with 6 bases between the half-sites, was actually detrimental to viral growth. The distal PIF half-site overlaps a cyclic AMP-responsive element (CRE), which was shown to play an important role in initiating infection, particularly in 324K simian virus 40-transformed human fibroblasts. Interestingly, reducing the spacing of the PIF half-sites, and thus the affinity of the binding site for PIF, increased viral fitness relative to wild type in 324K cells, but not in murine A9 cells. These results indicate that the relative importance of factor binding to the CRE and PIF sites during the establishment of an infection differs markedly between these two host cells and suggest that the suboptimal spacing of PIF half-sites found in wild-type virus represents a necessary reduction in the affinity of the PIF interaction in favor of CRE function.},
}
@article {pmid12884954,
year = {2003},
author = {Padmavathi, J and UmaDevi, K and Rao, CU and Reddy, NN},
title = {Telomere fingerprinting for assessing chromosome number, isolate typing and recombination in the entomopathogen Beauveria bassiana.},
journal = {Mycological research},
volume = {107},
number = {Pt 5},
pages = {572-580},
doi = {10.1017/s0953756203007573},
pmid = {12884954},
issn = {0953-7562},
mesh = {Animals ; Ascomycota/*classification/*genetics/isolation &amp; purification ; Chromosomes, Fungal/genetics ; DNA Fingerprinting/*methods ; DNA, Fungal/analysis ; Deoxyribonuclease EcoRI ; Insecta/*microbiology ; Mycological Typing Techniques ; Recombination, Genetic ; Telomere/*genetics ; },
abstract = {Beauveria bassiana is a popular biocontrol agent used as 'green' pesticide in crop insect pest management. Chromosome number has been variously reported as five, six, seven and eight in this species. The range of chromosome number and the minimum chromosome number in this economically important fungus were assessed through telomere fingerprint analysis of a sample of 17 isolates from different and similar hosts and distant and same geographic origin. Genomic DNA digested with EcoRI, which has no cutting site in the telomere repeat sequence arrays was probed with a radioisotope-labelled (5'-TTAGGG-3')s oligonucleotide. The probe-hybridised regions appeared as discrete bands--each representing a telomere. The number of bands in each lane was counted and halved to arrive at the chromosome number of that isolate. The chromosome number varied from 5 to 10 in the different isolates. The telomere probe hybridised bands were also scored for presence or absence in a 0-1 matrix and a dendrogram based on similarities between the isolates was constructed using the NTSYS-pc ver. 2.02i software. The isolates showed very little similarity; the overall similarity was 14%. Only two isolates which were of diverse host and geographic origin showed 100% similarity. Isolates from the same epizootic that showed 43% similarity in their telomere fingerprints had 96 % similarity in their RAPD (Random amplified polymorphic DNA) fingerprints with 10 primers. The genetic distances computed from any one DNA fingerprinting method thus do not reflect the true genetic similarities of the isolates. The frequency distribution pattern of the pair-wise similarities computed from telomere fingerprints hinted at the occurrence of recombination in this fungus. Telomere fingerprinting proved very useful in typing isolates since each of them was found to have a unique fingerprint. Isolates with the same chromosome number neither showed a distinct morphology or virulence character nor a close similarity in telomere or RAPD fingerprints to merit their subgrouping into a taxonomically relevant or practically useful unit.},
}
@article {pmid12882407,
year = {2003},
author = {Proctor, CJ and Kirkwood, TB},
title = {Modelling cellular senescence as a result of telomere state.},
journal = {Aging cell},
volume = {2},
number = {3},
pages = {151-157},
doi = {10.1046/j.1474-9728.2003.00050.x},
pmid = {12882407},
issn = {1474-9718},
support = {BEP17042/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Cell Division ; Cellular Senescence/*physiology ; Computer Simulation ; Kinetics ; Models, Biological ; Telomere/*physiology ; },
abstract = {Telomeres in mammalian cells end in large duplex T loops. These loops protect the single-strand overhangs from degradation and/or interactions with signalling proteins. This protection is sometimes referred to as capping. At each cell division, telomeres shorten and there is a general consensus that telomere shortening triggers cell cycle exit. However, the exact mechanism by which telomere shortening causes cell cycle arrest is not known. Mathematical models of telomere shortening have been developed to help us understand the processes involved. Until now most models have assumed that the trigger for cell cycle arrest is the first telomere or a group of telomeres reaching a critically short length. However, there is evidence that cells stop cycling over a wide range of telomere lengths. This suggests that telomere length per se may not in fact be the trigger for cellular senescence. In this paper we develop a model which examines the hypothesis that uncapping of a telomere is the main trigger. By letting the probability of uncapping depend upon telomere length, we show that the hypothesized model provides a good fit to experimental data.},
}
@article {pmid12882352,
year = {2002},
author = {Liu, L and Trimarchi, JR and Smith, PJ and Keefe, DL},
title = {Mitochondrial dysfunction leads to telomere attrition and genomic instability.},
journal = {Aging cell},
volume = {1},
number = {1},
pages = {40-46},
doi = {10.1046/j.1474-9728.2002.00004.x},
pmid = {12882352},
issn = {1474-9718},
mesh = {Animals ; Antioxidants/pharmacology ; Apoptosis/genetics ; Cell Division/*genetics ; Cell Nucleus/genetics ; Cellular Senescence/*genetics ; Chromosome Breakage/*genetics ; Female ; Male ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mitochondria/*genetics/metabolism ; Nuclear Transfer Techniques ; Oxidative Stress/drug effects/genetics ; Reactive Oxygen Species/metabolism ; Telomere/*genetics ; Tissue Transplantation ; Zygote/cytology/*metabolism ; },
abstract = {Mitochondrial dysfunction and oxidative stress have been implicated in cellular senescence, apoptosis, aging and aging-associated pathologies. Telomere shortening and genomic instability have also been associated with replicative senescence, aging and cancer. Here we show that mitochondrial dysfunction leads to telomere attrition, telomere loss, and chromosome fusion and breakage, accompanied by apoptosis. An antioxidant prevented telomere loss and genomic instability in cells with dysfunctional mitochondria, suggesting that reactive oxygen species are mediators linking mitochondrial dysfunction and genomic instability. Further, nuclear transfer protected genomes from telomere dysfunction and promoted cell survival by reconstitution with functional mitochondria. This work links mitochondrial dysfunction and genomic instability and may provide new therapeutic strategies to combat certain mitochondrial and aging-associated pathologies.},
}
@article {pmid12882327,
year = {2003},
author = {Saretzki, G and Murphy, MP and von Zglinicki, T},
title = {MitoQ counteracts telomere shortening and elongates lifespan of fibroblasts under mild oxidative stress.},
journal = {Aging cell},
volume = {2},
number = {2},
pages = {141-143},
doi = {10.1046/j.1474-9728.2003.00040.x},
pmid = {12882327},
issn = {1474-9718},
mesh = {Antioxidants/*pharmacology ; Cell Division/drug effects ; Cells, Cultured/cytology/drug effects/metabolism/ultrastructure ; Cellular Senescence/*drug effects ; DNA Damage ; Fibroblasts/cytology/*drug effects/metabolism/ultrastructure ; Humans ; Mutation ; Organophosphorus Compounds/*pharmacology ; Oxidation-Reduction ; Oxidative Stress ; Oxygen/pharmacology ; Peroxides/analysis ; Telomere/*drug effects/ultrastructure ; Ubiquinone/analogs &amp; derivatives ; },
}
@article {pmid12881434,
year = {2003},
author = {Satyanarayana, A and Wiemann, SU and Buer, J and Lauber, J and Dittmar, KE and Wüstefeld, T and Blasco, MA and Manns, MP and Rudolph, KL},
title = {Telomere shortening impairs organ regeneration by inhibiting cell cycle re-entry of a subpopulation of cells.},
journal = {The EMBO journal},
volume = {22},
number = {15},
pages = {4003-4013},
pmid = {12881434},
issn = {0261-4189},
mesh = {Animals ; *Cell Cycle ; Cell Division ; Immunohistochemistry ; Liver/cytology/ultrastructure ; Mice ; Mice, Knockout ; Oligonucleotide Array Sequence Analysis ; Polymerase Chain Reaction ; RNA/genetics/physiology ; *Regeneration ; Telomerase/genetics/physiology ; *Telomere ; },
abstract = {Telomere shortening limits the regenerative capacity of primary cells in vitro by inducing cellular senescence characterized by a permanent growth arrest of cells with critically short telomeres. To test whether this in vitro model of cellular senescence applies to impaired organ regeneration induced by telomere shortening in vivo, we monitored liver regeneration after partial hepatectomy in telomerase-deficient mice. Our study shows that telomere shortening is heterogeneous at the cellular level and inhibits a subpopulation of cells with critically short telomeres from entering the cell cycle. This subpopulation of cells with impaired proliferative capacity shows senescence-associated beta-galactosidase activity, while organ regeneration is accomplished by cells with sufficient telomere reserves that are capable of additional rounds of cell division. This study provides experimental evidence for the existence of an in vivo process of cellular senescence induced by critical telomere shortening that has functional impact on organ regeneration.},
}
@article {pmid12878845,
year = {2003},
author = {Ko, SG and Shin, J and Yu, EY and Chung, IK and Tanaka, T and Lee, W},
title = {1H, 13C and 15N resonance assignments of rice telomere binding domain from Oryza sativa.},
journal = {Journal of biomolecular NMR},
volume = {27},
number = {1},
pages = {89-90},
pmid = {12878845},
issn = {0925-2738},
mesh = {Carbon/*chemistry ; Hydrogen/*chemistry ; Nitrogen/*chemistry ; Oryza/metabolism ; Plant Proteins/*chemistry/metabolism ; Protein Structure, Tertiary ; Telomere/metabolism ; Telomere-Binding Proteins/*chemistry/metabolism ; },
}
@article {pmid12875746,
year = {2003},
author = {Aviv, A and Levy, D and Mangel, M},
title = {Growth, telomere dynamics and successful and unsuccessful human aging.},
journal = {Mechanisms of ageing and development},
volume = {124},
number = {7},
pages = {829-837},
doi = {10.1016/s0047-6374(03)00143-x},
pmid = {12875746},
issn = {0047-6374},
mesh = {Aging/*physiology ; Cell Division/physiology ; Growth/*physiology ; Humans ; *Models, Biological ; Telomere/*physiology ; },
abstract = {This paper links mass trajectories with telomere dynamics to construct theoretical models of successful and unsuccessful aging in human beings. It couples parameters of telomere length in somatic cells, as expressed by the terminal restriction fragment (TRF), at birth and the rate of telomere attrition thereafter with nonlinear models of somatic growth to predict the probability of surviving disease free, based on the assumption that telomere length in replicating somatic cells is a surrogate indicator of aging determinants in humans. The models capture aspects of individual variation in successful and unsuccessful aging and the long-term consequences of rapid growth early in life.},
}
@article {pmid12874230,
year = {2003},
author = {Gursel, I and Gursel, M and Yamada, H and Ishii, KJ and Takeshita, F and Klinman, DM},
title = {Repetitive elements in mammalian telomeres suppress bacterial DNA-induced immune activation.},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {171},
number = {3},
pages = {1393-1400},
doi = {10.4049/jimmunol.171.3.1393},
pmid = {12874230},
issn = {0022-1767},
mesh = {Adjuvants, Immunologic/administration &amp; dosage/pharmacology ; Animals ; Cell Line ; CpG Islands/immunology ; DNA, Bacterial/*antagonists &amp; inhibitors/genetics/metabolism/*pharmacology ; Down-Regulation/immunology ; Endosomes/immunology/metabolism ; Humans ; Immunity, Innate/genetics ; Immunosuppressive Agents/administration &amp; dosage/*pharmacology ; Injections, Intraperitoneal ; Interleukin-12/antagonists &amp; inhibitors/biosynthesis ; *Lymphocyte Activation/genetics/immunology ; Male ; Membrane Glycoproteins/antagonists &amp; inhibitors/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Oligodeoxyribonucleotides/administration &amp; dosage/pharmacology ; Receptors, Cell Surface/antagonists &amp; inhibitors/metabolism ; Repetitive Sequences, Nucleic Acid/*immunology ; Spleen/cytology/immunology/metabolism ; Telomere/genetics/*immunology ; Toll-Like Receptor 9 ; Toll-Like Receptors ; },
abstract = {Bacterial DNA contains immunostimulatory CpG motifs that trigger an innate immune response capable of promoting host survival following infectious challenge. Yet CpG-driven immune activation may also have deleterious consequences, ranging from autoimmune disease to death. We find that repetitive elements present at high frequency in mammalian telomeres, but rare in bacteria, down-regulate CpG-induced immune activation. Suppressive activity correlates with the ability of telomeric TTAGGG repeats to form G-tetrads. Colocalization of CpG DNA with Toll-like receptor 9 in endosomal vesicles is disrupted by these repetitive elements, although cellular binding and uptake remain unchanged. These findings are the first to establish that specific host-derived molecules can down-regulate the innate immune response elicited by a TLR ligand.},
}
@article {pmid12871663,
year = {2003},
author = {Odago, FO and Gerson, SL},
title = {Telomerase inhibition and telomere erosion: a two-pronged strategy in cancer therapy.},
journal = {Trends in pharmacological sciences},
volume = {24},
number = {7},
pages = {328-331},
doi = {10.1016/S0165-6147(03)00165-2},
pmid = {12871663},
issn = {0165-6147},
support = {R01 CA 86357/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Apoptosis/drug effects/genetics ; Gene Expression/drug effects ; Humans ; *Neoplasms/enzymology/genetics/therapy ; Telomerase/*antagonists &amp; inhibitors/genetics/physiology ; Telomere/*genetics/physiology ; },
}
@article {pmid12869115,
year = {2003},
author = {Scheding, S and Ersöz, I and Hartmann, U and Bartolvic, K and Balabanov, S and Salama, A and Kanz, L and Brümmendorf, TH},
title = {Peripheral blood cell telomere length measurements indicate that hematopoietic stem cell turnover is not significantly increased in whole blood and apheresis PLT donors.},
journal = {Transfusion},
volume = {43},
number = {8},
pages = {1089-1095},
doi = {10.1046/j.1537-2995.2003.00457.x},
pmid = {12869115},
issn = {0041-1132},
mesh = {Adult ; Aged ; Blood Cells/*physiology ; *Blood Donors ; Cell Division ; Female ; Flow Cytometry ; Granulocytes/physiology ; Hematopoietic Stem Cells/*cytology ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes/*physiology ; Male ; Middle Aged ; *Platelet Transfusion ; *Plateletpheresis ; Telomere/*genetics ; },
abstract = {BACKGROUND: The telomere length (TEL) of peripheral blood leukocytes (PBLs) can be used to estimate hematopoietic stem cell turnover. The current study investigated whether the repetitive stimulation of the hematopoietic system caused by regular whole blood (WB) and PLT donations would affect PBL TEL.<br><br>STUDY DESIGN AND METHODS: PBLs were obtained from healthy donors (n=94) with a history of at least 3 years of WB donation (median, 7.7 years; range, 3.0-43.0 years) plus additional apheresis PLT donations. The median (range) numbers of WB and PLT donations were 22.0 (6.0-194.0) and 42.0 (7.0-336.0), respectively. Additionally, samples were obtained from healthy nondonors (n=47). PBL TEL was measured with fluorescence in situ hybridization and flow cytometry (flow-FISH). Flow-FISH results were expressed in molecular equivalents of soluble fluorochrome units (MESF; 1000 MESF=1 kMESF) either as absolute (TEL) or as age-adjusted TEL (DeltaTEL).<br><br>RESULTS: Donor granulocyte and lymphocyte TELs were 12.6 +/- 0.3 (mean +/- SEM) and 13.2 +/- 0.3 kMESF, respectively. No differences were observed when compared with corresponding nondonor data (granulocytes, 12.5 +/- 0.4 kMESF; lymphocytes, 13.6 +/- 0.5 kMESF). Furthermore, DeltaTEL values did not differ between the two groups and were not different from previously established reference values. In addition, neither donor data for age-adjusted TEL for granulocytes nor DeltaTEL for lymphocytes were correlated with either total years or total numbers of WB and/or PLT donations.<br><br>CONCLUSION: Long-term WB and PLT donation does not affect PBW TEL as measured by flow-FISH, arguing against a significantly increased stem cell turnover.},
}
@article {pmid12861005,
year = {2003},
author = {Tomita, K and Matsuura, A and Caspari, T and Carr, AM and Akamatsu, Y and Iwasaki, H and Mizuno, K and Ohta, K and Uritani, M and Ushimaru, T and Yoshinaga, K and Ueno, M},
title = {Competition between the Rad50 complex and the Ku heterodimer reveals a role for Exo1 in processing double-strand breaks but not telomeres.},
journal = {Molecular and cellular biology},
volume = {23},
number = {15},
pages = {5186-5197},
pmid = {12861005},
issn = {0270-7306},
support = {G0001129/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Antigens, Nuclear/*chemistry ; Binding, Competitive ; Chromatin/metabolism ; DNA/drug effects/metabolism ; DNA Damage ; *DNA Helicases ; DNA-Binding Proteins/*chemistry/*metabolism ; Dimerization ; Dose-Response Relationship, Radiation ; Exodeoxyribonucleases/*metabolism ; Fluorescent Antibody Technique, Indirect ; Gamma Rays ; Gene Deletion ; Ku Autoantigen ; Methyl Methanesulfonate ; Models, Genetic ; Mutagenesis ; Mutation ; Precipitin Tests ; Protein Structure, Tertiary ; Saccharomyces cerevisiae Proteins/*metabolism ; Schizosaccharomyces ; Telomere/*ultrastructure ; Time Factors ; Ultraviolet Rays ; },
abstract = {The Mre11-Rad50-Nbs1(Xrs2) complex and the Ku70-Ku80 heterodimer are thought to compete with each other for binding to DNA ends. To investigate the mechanism underlying this competition, we analyzed both DNA damage sensitivity and telomere overhangs in Schizosaccharomyces pombe rad50-d, rad50-d pku70-d, rad50-d exo1-d, and pku70-d rad50-d exo1-d cells. We found that rad50 exo1 double mutants are more methyl methanesulfonate (MMS) sensitive than the respective single mutants. The MMS sensitivity of rad50-d cells was suppressed by concomitant deletion of pku70+. However, the MMS sensitivity of the rad50 exo1 double mutant was not suppressed by the deletion of pku70+. The G-rich overhang at telomere ends in taz1-d cells disappeared upon deletion of rad50+, but the overhang reappeared following concomitant deletion of pku70+. Our data suggest that the Rad50 complex can process DSB ends and telomere ends in the presence of the Ku heterodimer. However, the Ku heterodimer inhibits processing of DSB ends and telomere ends by alternative nucleases in the absence of the Rad50-Rad32 protein complex. While we have identified Exo1 as the alternative nuclease targeting DNA break sites, the identity of the nuclease acting on the telomere ends remains elusive.},
}
@article {pmid12858012,
year = {2003},
author = {Cheong, C and Hong, KU and Lee, HW},
title = {Mouse models for telomere and telomerase biology.},
journal = {Experimental &amp; molecular medicine},
volume = {35},
number = {3},
pages = {141-153},
doi = {10.1038/emm.2003.20},
pmid = {12858012},
issn = {1226-3613},
mesh = {Animals ; Cellular Senescence/*physiology ; DNA-Binding Proteins ; Mice ; Mice, Knockout ; Mice, Transgenic ; Models, Animal ; RNA/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres serve a critical role in maintenance of genomic stability in all eukaryotes, from yeast to human. The maintenance of telomeres is achieved by the telomerase complex, which is largely composed of telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC). A variety of mouse models have provided valuable insights into the relationship between the telomerase complex and telomere dysfunction at the organismal level and helped understand their biological significance in human. Recently, in addition to its role in maintenance of the telomeres, novel functions of the telomerase complex have been emerging. In this review, studies of all gene-targeted or transgenic mouse models so far generated for telomerase and telomere biology are comprehensively described, and potential novel functions of telomerase are briefly discussed.},
}
@article {pmid12857868,
year = {2003},
author = {Carlton, PM and Cowan, CR and Cande, WZ},
title = {Directed motion of telomeres in the formation of the meiotic bouquet revealed by time course and simulation analysis.},
journal = {Molecular biology of the cell},
volume = {14},
number = {7},
pages = {2832-2843},
pmid = {12857868},
issn = {1059-1524},
support = {R01 46547//PHS HHS/United States ; },
mesh = {Chromosomes, Plant/*genetics ; *Computer Simulation ; In Situ Hybridization, Fluorescence ; Meiosis/*genetics ; Models, Biological ; Nuclear Envelope/genetics ; Secale/genetics/*physiology ; Telomere/*genetics/physiology ; },
abstract = {Chromosome movement is critical for homologous chromosome pairing during meiosis. A prominent and nearly universal meiotic chromosome reorganization is the formation of the bouquet, characterized by the close clustering of chromosome ends at the nuclear envelope. We have used a novel method of in vitro culture of rye anthers combined with fluorescent in situ hybridization (FISH) detection of telomeres to quantitatively study bouquet formation. The three-dimensional distribution of telomeres over time was used to obtain a quantitative profile of bouquet formation intermediates. The bouquet formed through a gradual, continuous tightening of telomeres over approximately 6 h. To determine whether the motion of chromosomes was random or directed, we developed a computer simulation of bouquet formation to compare with our observations. We varied the diffusion rate of telomeres and the amount of directional bias in telomere movement. In our models, the bouquet was formed in a manner comparable to what we observed in cultured meiocytes only when the movement of telomeres was actively directed toward the bouquet site, whereas a wide range of diffusion rates were permitted. Directed motion, as opposed to random diffusion, was required to reproduce our observations, implying that an active process moves chromosomes to cause telomere clustering.},
}
@article {pmid12855289,
year = {2003},
author = {Vleck, CM and Haussmann, MF and Vleck, D},
title = {The natural history of telomeres: tools for aging animals and exploring the aging process.},
journal = {Experimental gerontology},
volume = {38},
number = {7},
pages = {791-795},
doi = {10.1016/s0531-5565(03)00110-4},
pmid = {12855289},
issn = {0531-5565},
mesh = {Aging/*physiology ; Animals ; Birds/physiology ; Erythrocytes/physiology ; Longevity/physiology ; Mammals/physiology ; Species Specificity ; Telomere/*ultrastructure ; Vertebrates/*physiology ; },
abstract = {We have been exploring the use of telomere length as a technique to age animals. If telomere restriction fragments (TRFs) shorten predictably with age in a particular tissue, then measurement of TRFs will allow estimation of ages of animals when age cannot be measured directly. This would be particularly useful in population studies where tissue samples can be collected, but age of individuals or age structure of the population is otherwise unknown. We have demonstrated that rate of change in length of TRFs from blood cells can be used to estimate age in a number of avian species. Calibration of this telomere 'clock' using known-age individuals has led to new questions regarding the importance of TRF shortening in aging and its evolution in animals with differing life spans. Our current data show a tight correlation between telomere rate of change (TROC) and maximum life span in birds, with the longest living species having the slowest TROC. In contrast, absolute length of TRFs is not correlated with maximum life span. Very long-lived Leach's storm-petrels have telomeres that in fact lengthen with age! These data suggest that in the longest-lived organisms, cellular replicative life span may not be constrained by shortening telomeres. Published data show that TRFs shorten more slowly in long-lived mammals than in short-lived ones, although for birds and mammals of similar life span, telomere shortening is faster in mammals than in birds. This corresponds with the relatively greater longevity in birds than in mammals.},
}
@article {pmid12855288,
year = {2003},
author = {Haussmann, MF and Vleck, CM and Nisbet, IC},
title = {Calibrating the telomere clock in common terns, Sterna hirundo.},
journal = {Experimental gerontology},
volume = {38},
number = {7},
pages = {787-789},
doi = {10.1016/s0531-5565(03)00109-8},
pmid = {12855288},
issn = {0531-5565},
mesh = {Aging/*physiology ; Animals ; Animals, Wild/*physiology ; Birds/*physiology ; Calibration ; Erythrocytes/physiology ; Image Processing, Computer-Assisted ; Microscopy, Electron ; Telomere/*ultrastructure ; },
abstract = {Field biologists often work with animals for which there are no prior history. A marker of an animal's age would offer insight into how age and experience affect reproductive success and other life history parameters. We previously reported that length of telomere restriction fragments shorten predictably with age in the captive zebra finch (Taeniopygia guttata). This paper reports that telomeres can also be used to gain knowledge on the age structure of wild, long-lived common terns (Sterna hirundo). Although ages cannot be determined precisely from telomere lengths alone, birds can be classified into broad age-classes. This technique can provide useful information about the age of individuals in cases where their previous histories are unknown.},
}
@article {pmid12838429,
year = {2003},
author = {Takasaki, T and Tsuji, A and Ikeda, N and Ohishi, M},
title = {Age estimation in dental pulp DNA based on human telomere shortening.},
journal = {International journal of legal medicine},
volume = {117},
number = {4},
pages = {232-234},
pmid = {12838429},
issn = {0937-9827},
mesh = {Aging/genetics/physiology ; DNA/*genetics ; Dental Pulp/*cytology ; Forensic Sciences ; Humans ; Japan ; Telomere/genetics/*physiology ; },
abstract = {Age estimation based on evidence found in teeth has received considerable attention within the field of forensic science. We determined the terminal restriction fragment (TRF) length, as telomere length, to estimate age. Using dental pulp DNA we found the average TRF length showed a tendency to shortening with aging. Our findings show that telomere shortening, based on dental pulp DNA is a new and useful approach to estimate age of the subject at the time of death.},
}
@article {pmid12837284,
year = {2003},
author = {Latre, L and Tusell, L and Martin, M and Miró, R and Egozcue, J and Blasco, MA and Genescà, A},
title = {Shortened telomeres join to DNA breaks interfering with their correct repair.},
journal = {Experimental cell research},
volume = {287},
number = {2},
pages = {282-288},
doi = {10.1016/s0014-4827(03)00134-4},
pmid = {12837284},
issn = {0014-4827},
mesh = {Animals ; Cells, Cultured ; Chromosome Aberrations ; Chromosome Painting ; Chromosomes/radiation effects ; DNA Damage ; *DNA Repair ; Dose-Response Relationship, Radiation ; Female ; Fibroblasts/radiation effects ; Metaphase ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Pregnancy ; Radiation, Ionizing ; Telomerase/metabolism ; Telomere/*metabolism/radiation effects ; },
abstract = {Telomeres cap chromosome ends, avoiding end-to-end fusions and subsequent chromosome instability. Telomeric functions and DNA repair pathways are closely related. Telomere dysfunction has been shown to result in hypersensitivity to ionizing radiation. In this study, we have used the telomerase knockout model to investigate how telomere shortening influences the correct repair of broken chromosomes. We show that the correct repair of double-strand breaks is impaired in telomerase knockout mice. The chromosomes with shortened telomeres fuse to radiation-induced breaks, interfering with the correct rejoining of the broken ends. This type of fusion is responsible for the increased chromosome instability observed in this mouse model, after exposure to ionizing radiation. Our finding may be important for understanding the increased radiation sensitivity associated with age in humans, as well as for comprehending the interindividual differences to the cytotoxic effects of radiation therapy in cancer patients.},
}
@article {pmid12836366,
year = {2001},
author = {Kanaori, K and Moriyama, A and Shoji, T and Tajima, K and Makino, K},
title = {Effect of complementary C-strand on telomere G-quartet structure.},
journal = {Nucleic acids research. Supplement (2001)},
volume = {},
number = {1},
pages = {265-266},
doi = {10.1093/nass/1.1.265},
pmid = {12836366},
mesh = {Base Pairing ; Chromatography, Gel ; Circular Dichroism ; Cytosine/chemistry ; DNA/*chemistry ; G-Quadruplexes ; Guanine/*chemistry ; Nuclear Magnetic Resonance, Biomolecular ; Nucleic Acid Conformation ; Potassium/pharmacology ; },
abstract = {Structure and stability of G-quartet are investigated in the presence of its complementary C-strand. The equilibration between duplex and G-quartet changes depending on Na+ or K+ ions.},
}
@article {pmid12836302,
year = {2001},
author = {Kumar, S and Misra, A and Tripathi, S and Misra, K},
title = {Study on curcumin-oligonucleotide conjugate as a probable anticancer agent: its hybridisation with telomere target sequence 5'-GGGATTGGGATT-3'.},
journal = {Nucleic acids research. Supplement (2001)},
volume = {},
number = {1},
pages = {137-138},
doi = {10.1093/nass/1.1.137},
pmid = {12836302},
mesh = {Antineoplastic Agents/chemical synthesis/*chemistry ; Base Sequence ; Curcumin/*chemistry ; Drug Delivery Systems ; Nucleic Acid Denaturation ; Nucleic Acid Hybridization ; Oligonucleotides/chemical synthesis/*chemistry ; Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; Temperature ; },
abstract = {Curcumin-oligonucleotide conjugate was synthesised by attaching diglycyl conjugate of curcumin to 12-mer complementary telomere sequence 5'-AATCCCAATCCC-3'. An enhanced Tm of 6 degrees C was found, showing high affinity for the target strand. This may be exploited for the suppression of cancer i.e. by blocking the expression of telomere sequence [GGGATT]n repeats.},
}
@article {pmid12835755,
year = {2003},
author = {Kim, SH and Han, S and You, YH and Chen, DJ and Campisi, J},
title = {The human telomere-associated protein TIN2 stimulates interactions between telomeric DNA tracts in vitro.},
journal = {EMBO reports},
volume = {4},
number = {7},
pages = {685-691},
pmid = {12835755},
issn = {1469-221X},
support = {R01 AG018949/AG/NIA NIH HHS/United States ; R37 AG009909/AG/NIA NIH HHS/United States ; AG09909/AG/NIA NIH HHS/United States ; AG18949/AG/NIA NIH HHS/United States ; },
mesh = {DNA/genetics/*metabolism ; DNA Probes/genetics/metabolism ; Humans ; Mutation/genetics ; Telomere/*genetics/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; },
abstract = {Human TIN2 interacts with the telomeric-DNA-binding protein TRF1, suppresses telomere elongation in telomerase-positive cells, and may control telomere length by modulating telomere structure. To test the latter idea, we developed an in vitro assay, using biotinylated telomeric DNA probes and streptavidin-agarose, to quantify the ability of TRF1 and TIN2 to stimulate interactions of telomeric DNA tracts with each other (probe clustering). This assay revealed that TRF1 alone had weak probe-clustering activity, but TIN2 stimulated activity fivefold to tenfold. A dominant-negative TIN2 mutant protein that increased telomere length in vivo disrupted probe clusters formed by TRF1 and TIN2, suggesting that the ability to stimulate telomeric DNA interactions is important for telomere-length regulation. Unlike TRF1, TIN2 did not form homodimers. We propose that TIN2 alters the conformation of TRF1, which favours a tertiary telomeric structure that hinders telomerase from gaining access to telomeres.},
}
@article {pmid12833463,
year = {2003},
author = {Yokota, T and Suda, T and Igarashi, M and Kuroiwa, T and Waguri, N and Kawai, H and Mita, Y and Aoyagi, Y},
title = {Telomere length variation and maintenance in hepatocarcinogenesis.},
journal = {Cancer},
volume = {98},
number = {1},
pages = {110-118},
doi = {10.1002/cncr.11428},
pmid = {12833463},
issn = {0008-543X},
mesh = {Aged ; Carcinoma, Hepatocellular/*genetics/metabolism ; DNA-Binding Proteins ; Disease Progression ; Humans ; Liver Neoplasms/*genetics/metabolism ; Middle Aged ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*genetics/metabolism ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 1/*genetics/metabolism ; },
abstract = {BACKGROUND: Despite the recent discovery of interchromosomal telomere length variation, a role for heterogeneity in telomere maintenance has yet to be established. This study investigated the significance of telomere length variation between chromosomes with respect to the association of cancer progression and telomere length regulation.<br><br>METHODS: Terminal restriction fragment (TRF) was evaluated in 20 surgically resected hepatocellular carcinoma specimens (HCC), corresponding noncancerous liver tissue specimens (NCL), and in 10 liver tissue specimens with chronic liver diseases devoid of cancer (DOC). Average TRF length (TRF-A) was defined as the point of maximum intensity. Shorter and longer TRF lengths (TRF-S and TRF-L) were defined as the length above which 90% of TRF distribution was involved. A ratio, (TRF-L-TRF-S)/TRF-A, was defined as telomere length dispersion.<br><br>RESULTS: The dispersion was significantly larger in HCC than in NCL specimens (P = 0.012) and in NCL than in DOC (P = 0.048). TRF-A and TRF-S were significantly shorter in HCC than in NCL (P = 0.0026, P = 0.0010). In seven patients in whom HCC recurred within 1 year, TRF-A and TRF-S were significantly shorter than in 10 patients in whom recurrence occurred after 1 year (P = 0.018, P = 0.0097). Telomeric repeat binding factor 1 was up-regulated in HCC with elongated TRF-L, whereas expression of human telomerase reverse transcriptase was greater in HCC with a shorter TRF-S.<br><br>CONCLUSIONS: These results suggest that telomere length varied through chronic liver diseases by preferentially increasing shorter telomeres, whose length is a good indicator for malignant potential of HCC. Telomere length variation may be a crucial code in telomere maintenance through hepatocarcinogenesis.},
}
@article {pmid12827497,
year = {2003},
author = {Bai, Y and Murnane, JP},
title = {Telomere instability in a human tumor cell line expressing a dominant-negative WRN protein.},
journal = {Human genetics},
volume = {113},
number = {4},
pages = {337-347},
pmid = {12827497},
issn = {0340-6717},
support = {R01 CA69044/CA/NCI NIH HHS/United States ; },
mesh = {Carcinoma/genetics/metabolism ; Chromosomes ; DNA Helicases/*genetics/metabolism ; Exodeoxyribonucleases ; Humans ; In Situ Hybridization, Fluorescence ; RecQ Helicases ; Telomerase/metabolism ; *Telomere ; Tumor Cells, Cultured ; Urinary Bladder Neoplasms/genetics/metabolism ; Werner Syndrome Helicase ; },
abstract = {Werner Syndrome (WS) is an autosomal recessive disease characterized by premature aging and chromosome instability. The protein involved in WS, WRN, is a RecQ-type helicase that also has exonuclease activity. WRN has been demonstrated to bind to a variety of other proteins, including RPA, DNA-PKcs, and TRF2, suggesting that WRN is involved in DNA replication, repair, recombination, and telomere maintenance. In culture, WS cells show premature senescence, which can be overcome by transfection with an expression vector containing the gene for the catalytic subunit of telomerase. However, telomerase expression does not eliminate chromosome instability in WS cells, which led to the proposal that telomere loss is not the cause of the high rate of chromosome rearrangements in WS cells. In the present study, we have investigated how a WRN protein containing a dominant-negative mutation (K577M-WRN) influences the stability of telomeres in a human tumor cell line expressing telomerase. The results demonstrate an increased rate of telomere loss and chromosome fusion in cells expressing K577M-WRN. Expression of K577M-WRN results in reduced levels of telomerase activity, however, the absence of detectable changes in average telomere length demonstrates that WRN-associated telomere loss results from stochastic events involving complete telomere loss or loss of telomere capping function. Thus, telomere loss can contribute to chromosome instability in cells deficient in WRN regardless of the expression of telomerase activity.},
}
@article {pmid12827179,
year = {2003},
author = {Lundblad, V},
title = {Telomeres: taking the measure.},
journal = {Nature},
volume = {423},
number = {6943},
pages = {926-927},
doi = {10.1038/423926a},
pmid = {12827179},
issn = {1476-4687},
mesh = {Chromosomes, Human ; Humans ; Particle Size ; Shelterin Complex ; Telomerase/metabolism ; Telomere/*physiology ; Telomere-Binding Proteins/*physiology ; Telomeric Repeat Binding Protein 1/physiology ; Telomeric Repeat Binding Protein 2/physiology ; },
}
@article {pmid12827082,
year = {2003},
author = {Novak, KD},
title = {Telomeres and telomerases in cancer.},
journal = {MedGenMed : Medscape general medicine},
volume = {5},
number = {1},
pages = {21},
pmid = {12827082},
issn = {1531-0132},
mesh = {Adult ; Animals ; Antineoplastic Agents/therapeutic use ; Cell Line ; Cellular Senescence/drug effects/genetics/physiology ; Chromosome Aberrations/drug effects ; Disease Models, Animal ; Enzyme Inhibitors/therapeutic use ; Humans ; Male ; Mice ; Models, Genetic ; Multiple Myeloma/enzymology/metabolism ; Neoplasms/drug therapy/*enzymology/etiology/*genetics ; Oligonucleotides/therapeutic use ; Organ Specificity/genetics/physiology ; Pancreatic Neoplasms/enzymology/genetics ; Prostatic Neoplasms/enzymology/genetics ; Telomerase/antagonists &amp; inhibitors/deficiency/genetics/*physiology ; Telomere/drug effects/*enzymology/*genetics/physiology ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/physiology ; },
}
@article {pmid12817446,
year = {2003},
author = {Delany, ME and Daniels, LM and Swanberg, SE and Taylor, HA},
title = {Telomeres in the chicken: genome stability and chromosome ends.},
journal = {Poultry science},
volume = {82},
number = {6},
pages = {917-926},
doi = {10.1093/ps/82.6.917},
pmid = {12817446},
issn = {0032-5791},
mesh = {Aging/*genetics/physiology ; Animals ; Biotechnology ; Chickens/*genetics/physiology ; *Chromosome Aberrations ; DNA Repair ; Down-Regulation ; Genome ; Telomerase/*biosynthesis/pharmacology ; *Telomere ; },
abstract = {Telomeres are the complex nucleoprotein structures at the termini of linear chromosomes. Telomeric DNA consists of a highly conserved hexanucleotide arranged in tandem repeats. Telomerase, a ribonucleoprotein of the reverse transcriptase family, specifies the sequence of telomeric DNA and maintains telomere array length. Numerous studies in model organisms established the significance of telomere structure and function in regulating genome stability, cellular aging, and oncogenesis. Our overall research objectives are to understand the organization of the telomere arrays in chicken in the context of the unusual organization and specialized features of this higher vertebrate genome (which include a compact genome, numerous microchromosomes, and high recombination rate) and to elucidate the role telomeres play in genome stability impacting cell function and life span. Recent studies found that the chicken genome contains three overlapping size classes of telomere arrays that differ in location and age-related stability: Class I 0.5 to 10 kb, Class II 10 to 40 kb, and Class III 40 kb to 2 Mb. Some notable features of chicken telomere biology are that the chicken genome contains ten times more telomeric DNA than the human genome and the Class III telomere arrays are the largest described for any vertebrate species. In vivo, chicken telomeres (Class II) shorten in an age-related fashion and telomerase activity is high in early stage embryos and developing organs but down-regulates during late embryogenesis or postnatally in most somatic tissues. In vitro, chicken cells down-regulate telomerase activity unless transformed. Knowledge of chicken telomere biology contributes information relevant to present and future biotechnology applications of chickens in vivo and chicken cells in vitro.},
}
@article {pmid12814800,
year = {2003},
author = {Mariani, E and Meneghetti, A and Formentini, I and Neri, S and Cattini, L and Ravaglia, G and Forti, P and Facchini, A},
title = {Different rates of telomere shortening and telomerase activity reduction in CD8 T and CD16 NK lymphocytes with ageing.},
journal = {Experimental gerontology},
volume = {38},
number = {6},
pages = {653-659},
doi = {10.1016/s0531-5565(03)00058-5},
pmid = {12814800},
issn = {0531-5565},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics/immunology ; CD8-Positive T-Lymphocytes/*enzymology/ultrastructure ; Child ; Enzyme-Linked Immunosorbent Assay/methods ; Humans ; Immunophenotyping ; Killer Cells, Natural/*enzymology/ultrastructure ; Polymerase Chain Reaction/methods ; Receptors, IgG/blood ; Telomerase/*blood ; Telomere/*genetics ; },
abstract = {Telomeres are specialised structures located at the end of eukaryotic chromosomes, that get short during progressive cell divisions. Therefore, telomere may be an indicator of the mitotic history of a cell and it is also a determining factor for the residual cell life span. One mechanism, compensating for the telomere erosion, involves the induction of telomerase, a ribonucleoprotein-enzyme able to synthesize telomeric DNA repeats. In this study, old subjects of two consecutive decades were compared with a group of young controls to investigate whether ageing-related modifications differently affects telomere length and telomerase activity of human peripheral blood CD8 T and CD16 NK lymphocytes. Telomeres in individual cells were measured by flow-FISH and telomerase activity was determined using the TeloTAGGG telomerase PCR ELISA(PLUS) kit. Both CD8 T and NK lymphocytes showed an age-associated loss of telomeres at rates that were different between the subsets together with an age-associated reduction of telomerase activity that was progressive in CD8 and late in NK lymphocytes. We can assume that preserved innate immune response in the elderly is due to the negligible telomere shortening and the maintained telomerase expression that could allow NK cells of octogenarians to delay replicative senescence.},
}
@article {pmid12814799,
year = {2003},
author = {Shigeeda, N and Uchida, M and Barrett, JC and Tsutsui, T},
title = {Candidate chromosomal regions for genes involved in activation of alternative lengthening of telomeres in human immortal cell lines.},
journal = {Experimental gerontology},
volume = {38},
number = {6},
pages = {641-651},
doi = {10.1016/s0531-5565(03)00072-x},
pmid = {12814799},
issn = {0531-5565},
mesh = {Cell Line, Transformed ; Cellular Senescence/genetics ; Chromosomes, Human, Pair 8/*genetics ; Chromosomes, Human, X/genetics ; Humans ; Loss of Heterozygosity ; Microsatellite Repeats ; Telomerase/genetics/metabolism ; Telomere/*genetics ; },
abstract = {Either telomerase or alternative mechanisms known as alternative lengthening of telomeres (ALT) are activated in human immortal cells to maintain or lengthen their telomeres. To screen candidate chromosomes harboring gene(s) involved in activation of the telomere maintenance mechanisms that are repressed in normal, mortal cells and lost in immortal cells, we examined loss of heterozygosity (LOH) on the 22 autosomes and the X chromosome in 22 in vitro established human immortal cell lines consisting of 9 telomerase-positive cell lines and 13 ALT-positive cell lines. For detecting LOH, PCR analysis was performed with 66 polymorphic microsatellite markers from candidate genomic regions previously implicated for putative human senescence genes, telomerase repressor genes, or tumor suppressor genes. LOH involving chromosome 8 was observed at 25 of 62 (40%) informative loci in 8 of 13 (61%) ALT-positive cell lines. Particularly, when assayed with D8S339 adjacent to the Werner's syndrome gene, LOH was found in 6 of 12 (50%) informative ALT-positive cell lines. In contrast, no LOH on chromosome 8 was detected at 41 informative loci in any of 9 telomerase-positive cell lines. No other chromosomes showed high frequencies of LOH common in either ALT-positive or telomerase-positive cell lines. Although further LOH analysis with additional markers remains to define the specific region on chromosome 8, our results suggest that gene(s) involved in activation of the ALT pathway in human immortal cell lines may localize on chromosome 8.},
}
@article {pmid12807958,
year = {2003},
author = {De Vries, BB and Winter, R and Schinzel, A and van Ravenswaaij-Arts, C},
title = {Telomeres: a diagnosis at the end of the chromosomes.},
journal = {Journal of medical genetics},
volume = {40},
number = {6},
pages = {385-398},
pmid = {12807958},
issn = {1468-6244},
mesh = {Chromosome Deletion ; Female ; Humans ; In Situ Hybridization, Fluorescence/methods/statistics &amp; numerical data ; Intellectual Disability/*diagnosis/etiology/*genetics ; Male ; Telomere/*genetics/pathology ; },
abstract = {In recent years, subtelomeric rearrangements have been identified as a major cause of mental retardation and/or malformation syndromes. So far, over 2500 subjects with mental retardation have been tested and reported of whom approximately 5% appeared to have a subtelomeric rearrangement. In this review, the clinical aspects of each known (submicroscopic) subtelomeric deletion will be presented and the various methods available for detecting subtelomeric abnormalities will be discussed. Not only will the patients and their families benefit from a good collection and report of the various telomeric abnormalities and their clinical phenotype, but it will also give more insight into the aetiology of mental retardation and malformation syndromes.},
}
@article {pmid12803478,
year = {2003},
author = {Djojosubroto, MW and Choi, YS and Lee, HW and Rudolph, KL},
title = {Telomeres and telomerase in aging, regeneration and cancer.},
journal = {Molecules and cells},
volume = {15},
number = {2},
pages = {164-175},
pmid = {12803478},
issn = {1016-8478},
mesh = {Animals ; Apoptosis/physiology ; Humans ; Mice ; Neoplasms/etiology/*metabolism ; Regeneration/*physiology ; Telomerase/*metabolism ; Telomere/*genetics/metabolism ; },
abstract = {The finding that telomere shortening limits the replicative lifespan of primary human cells has fueled speculations that telomere shortening plays a role during aging and regeneration of tissues in vivo. Support for this hypothesis comes from studies showing telomere shortening in a variety of human tissues as a consequence of aging and chronic disease. Studies in telomerase-deficient mice have given first experimental support that telomere shortening limits the replicative potential of organs and tissues in vivo and have identified telomerase as a promising target to treat regenerative disorders induced by telomere shortening. A potential downside of such an approach could be the development of malignant tumors, which has been linked to reactivation of telomerase in human cancers. In telomerase-deficient mice, telomere shortening showed a dual role in tumorigenesis, enhancing the initiation of tumors by induction of chromosomal instability but inhibiting tumor progression by induction of DNA-damage responses. The success in using telomerase activation for the treatment of regenerative disorders could depend on which of the mechanisms of telomere shortening is dominantly effecting carcinogenesis.},
}
@article {pmid12799281,
year = {2003},
author = {Baerlocher, GM and Roth, A and Lansdorp, PM},
title = {Telomeres in hematopoietic stem cells.},
journal = {Annals of the New York Academy of Sciences},
volume = {996},
number = {},
pages = {44-48},
doi = {10.1111/j.1749-6632.2003.tb03231.x},
pmid = {12799281},
issn = {0077-8923},
mesh = {Cell Division ; Cellular Senescence ; DNA Damage ; Hematopoietic Stem Cells/*cytology/enzymology ; Humans ; Leukocytes/cytology ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {Hematopoietic stem cells have an impressive regenerative potential, strikingly illustrated in transplantation experiments using limited number of cells. In mice, serial transplantation experiments suggest that individual hematopoietic cells are capable of extensive self-renewal and that any possible limitations in the replicative potential of individual hematopoietic stem cells are not affecting normal blood cell formation. The situation with human hematopoietic stem cells is less clear. Unlike the situation in the mouse, the telomere length in nucleated human blood cells shows a remarkable decline with age. Furthermore, even partial telomerase deficiency in humans typically results in marrow failure, whereas complete lack of telomerase is tolerated up to several generations in the mouse. The decline in telomere length in human leukocytes with age follows a cubic function and is much higher in lymphocytes than in granulocytes. This finding suggests that, under normal circumstances, telomere loss is more likely to compromise the function of lymphocytes than the function of hematopoietic stem cells. To reconcile differences in telomere biology between man and mice, it has been proposed that telomere shortening evolved as a tumor suppressor mechanism in long-lived species that may not exist in shorter-lived mammals. According to this model, telomeres in human cells are intimately involved in signaling cell cycle progression and cell division. Most likely, a minimum number of telomere repeats is required at each telomere to prevent activation of a "telomere checkpoint" and allow cell cycle progression. Telomere length measurements appear useful to distinguish between depletion and exhaustion of hematopoietic stem cells as a cause of marrow failure.},
}
@article {pmid12799279,
year = {2003},
author = {Brummendorf, TH and Ersoz, I and Hartmann, U and Balabanov, S and Wolke, H and Paschka, P and Lahaye, T and Berner, B and Bartolovic, K and Kreil, S and Berger, U and Gschaidmeier, H and Bokemeyer, C and Hehlmann, R and Dietz, K and Lansdorp, PM and Kanz, L and Hochhaus, A},
title = {Normalization of previously shortened telomere length under treatment with imatinib argues against a preexisting telomere length deficit in normal hematopoietic stem cells from patients with chronic myeloid leukemia.},
journal = {Annals of the New York Academy of Sciences},
volume = {996},
number = {},
pages = {26-38},
doi = {10.1111/j.1749-6632.2003.tb03229.x},
pmid = {12799279},
issn = {0077-8923},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging ; Benzamides ; Female ; Granulocytes/pathology ; Hematopoietic Stem Cells/*cytology/pathology ; Humans ; Imatinib Mesylate ; In Situ Hybridization, Fluorescence ; Interphase ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*pathology ; Male ; Middle Aged ; Piperazines/*pharmacology ; Pyrimidines/*pharmacology ; Telomerase/metabolism ; Telomere/*drug effects/*pathology ; },
abstract = {Telomeres are composed of TTAGGG repeats and associated proteins. In somatic cells, telomere repeats are lost with each cell division, eventually leading to genetic instability and cellular senescence. In previous studies, we described substantial and disease stage-specific telomere shortening in peripheral blood (PB) leukocytes from patients with chronic myeloid leukemia (CML). Here, we sought to determine whether age-adjusted telomere length in PB granulocytes (deltaTEL(gran)) is associated with response to treatment with the selective tyrosine kinase inhibitor imatinib. A total of 517 samples from 206 patients in chronic phase (CP), accelerated phase (AP), and blast crisis (BC) before and up to 706 days after initiation of imatinib therapy (median: 144 days) were analyzed by quantitative fluorescence in situ hybridization of interphase cells in suspension (Flow-FISH); telomere fluorescence was expressed in molecular equivalents of soluble fluorochrome units (MESF). Telomere length in samples from start of treatment up to day 144 was significantly shorter (mean +/- SE; -1.5 +/- 0.3 kMESF) compared to samples from patients treated for more than 144 days (-0.8 +/- 0.3 kMESF, p = 0.035). In patients with repeated measurements, a significant increase in telomere length under treatment was observed. Median telomere length in major remission was found to be significantly longer compared to patients without response to treatment measured either by cytogenetics (n = 246, p < 0.05), interphase FISH (n = 204, p = 0.002), or quantitative RT-PCR (n = 371, p < 0.05). In conclusion, the increase in telomere length under treatment with imatinib reflects a shift from Ph+ to Ph- cells in the PB of patients with CML.},
}
@article {pmid12799193,
year = {2003},
author = {Siwicki, JK and Degerman, S and Chrzanowska, KH and Roos, G},
title = {Telomere maintenance and cell cycle regulation in spontaneously immortalized T-cell lines from Nijmegen breakage syndrome patients.},
journal = {Experimental cell research},
volume = {287},
number = {1},
pages = {178-189},
doi = {10.1016/s0014-4827(03)00140-x},
pmid = {12799193},
issn = {0014-4827},
mesh = {Catalytic Domain/genetics ; Cell Cycle/genetics/radiation effects ; Cell Cycle Proteins/genetics/*metabolism/radiation effects ; Cell Line, Transformed/cytology/*metabolism ; Chromosome Breakage/*genetics ; Chromosome Disorders/*genetics ; DNA Damage/genetics ; Gamma Rays ; Genetic Predisposition to Disease/genetics ; Humans ; Leukemia, Lymphoid/genetics ; Nuclear Proteins/genetics/*metabolism ; Proto-Oncogene Proteins c-myc/genetics ; RNA, Messenger/genetics/metabolism ; Retinoblastoma Protein/genetics/metabolism ; T-Lymphocytes/cytology/*metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; },
abstract = {Nijmegen breakage syndrome (NBS) is a rare genetic instability syndrome associated with a high incidence of lymphoid malignancies. The NBS1 protein has been implicated in telomere biology suggesting that cells from NBS patients might have deficient telomere maintenance capacity. In this study we characterized spontaneously immortalized T-cell lines derived from three NBS patients regarding growth characteristics, telomere biology, expression of cell-cycle regulators, and response to DNA damage to understand the role of NBS1 in the immortalization process. In all the NBS T-cell lines the acquisition of an immortal phenotype was associated with telomere length stabilization, high telomerase activity, and increased mRNA expression of the catalytic subunit of telomerase (hTERT), together with c-myc up-regulation. Our findings provide evidence that telomere length maintenance was intact in the T lymphocytes in the absence of a full-length NBS protein, presumably due to the presence of an alternatively transcribed NBS protein of 70 kDa. Normal protein expression patterns for pRb and p53 in all the immortal lines coincided with altered expression of some cell-cycle proteins as well as with an impaired G1/S arrest after gamma irradiation, despite a seemingly normal p53/p21 pathway. The here described, spontaneously immortalized NBS derived T-cell lines can be useful in future analysis of the biologic effects in the NBS.},
}
@article {pmid12790332,
year = {2003},
author = {Rosenberg, R and Gertler, R and Stricker, D and Lassmann, S and Werner, M and Nekarda, H and Siewert, JR},
title = {Telomere length and hTERT expression in patients with colorectal carcinoma.},
journal = {Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer},
volume = {162},
number = {},
pages = {177-181},
doi = {10.1007/978-3-642-59349-9_16},
pmid = {12790332},
issn = {0080-0015},
mesh = {Blotting, Southern ; Colorectal Neoplasms/*genetics/metabolism/surgery ; DNA-Binding Proteins ; *Gene Expression Regulation, Neoplastic ; Humans ; Prognosis ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*biosynthesis/metabolism ; Telomere/*ultrastructure ; },
abstract = {The stabilization of telomere length by telomerase activation is an important step in carcinogenesis. Quantification of the catalytic telomerase subunit hTERT (human Telomerase Reverse Transcriptase) is a new indirect measure for telomerase. Telomere length and hTERT expression in cancer tissue and corresponding normal mucosa of 57 patients with completely resected colorectal carcinoma (UICC stage I-IV, R0) were determined for correlation with histopathological parameters and survival. Telomere lengths were measured using Southern Blot and hTERT-encoding mRNA was quantified by real-time RT-PCR. Telomere length and hTERT expression were significantly correlated in normal mucosa and cancer tissue (p<0.001). Telomere length and hTERT expression decreased with ageing only in normal mucosa. Cancer tissue had significantly shorter telomeres (p<0.001) and significantly lower hTERT expression levels (p<0.001) than corresponding normal mucosa. UICC stage I tumors showed significantly shorter telomeres than UICC stage II-IV tumors (p<0.002). Telomere length and hTERT expression were significantly correlated with overall survival. Telomere length and hTERT expression play an important role in ageing and carcinogenesis. Both parameters were identified as prognostic factors in patients with colorectal carcinoma.},
}
@article {pmid12788566,
year = {2003},
author = {Reddel, RR and Bryan, TM},
title = {Alternative lengthening of telomeres: dangerous road less travelled.},
journal = {Lancet (London, England)},
volume = {361},
number = {9372},
pages = {1840-1841},
doi = {10.1016/S0140-6736(03)13538-6},
pmid = {12788566},
issn = {0140-6736},
mesh = {Cell Division ; Humans ; Neoplasms/enzymology/*genetics ; Telomerase/metabolism ; Telomere/*genetics/metabolism ; },
}
@article {pmid12787795,
year = {2003},
author = {Flint, J and Knight, S},
title = {The use of telomere probes to investigate submicroscopic rearrangements associated with mental retardation.},
journal = {Current opinion in genetics &amp; development},
volume = {13},
number = {3},
pages = {310-316},
doi = {10.1016/s0959-437x(03)00049-2},
pmid = {12787795},
issn = {0959-437X},
mesh = {*Chromosome Aberrations ; Humans ; In Situ Hybridization, Fluorescence ; Intellectual Disability/*genetics ; *Molecular Probes ; *Telomere ; },
abstract = {Idiopathic mental retardation is a common condition the origins of which are poorly understood. Following initial reports that small chromosomal rearrangements affecting telomeres could be an important aetiological contributor, several new methods for screening patients have been developed. Over the past few years, 22 studies have reported results from 2585 patients. The prevalence of abnormalities in the entire group is 5.1%; but the figure is higher (6.8%) in individuals with moderate to severe mental retardation. About half the cases are caused by a de novo deletion, and about half by a balanced translocation segregating in a patient's family. Despite the large sample size available, it is still not clear whether a combination of thorough clinical examination and assiduous cytogenetic investigation might not be as effective at detecting subtelomeric anomalies as molecular assays.},
}
@article {pmid12787493,
year = {2003},
author = {Cristofari, G and Lingner, J},
title = {Fingering the ends: how to make new telomeres.},
journal = {Cell},
volume = {113},
number = {5},
pages = {552-554},
doi = {10.1016/s0092-8674(03)00397-0},
pmid = {12787493},
issn = {0092-8674},
mesh = {Animals ; DNA Damage/*genetics ; DNA Repair/*genetics ; DNA-Binding Proteins ; Euplotes/*enzymology/*genetics ; Gene Deletion ; Gene Expression Regulation/genetics ; Models, Animal ; Protein Isoforms/genetics/metabolism ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomerase-mediated healing of broken chromosomes gives rise to terminal deletions and is repressed in most organisms. In ciliated protozoa, however, chromosome fragmentation and de novo telomere addition are part of the developmental program. Work by in this issue of Cell indicates that in Euplotes crassus, this is mediated through switching between different telomerase reverse transcriptase isoforms.},
}
@article {pmid12782650,
year = {2003},
author = {Chang, W and Dynek, JN and Smith, S},
title = {TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres.},
journal = {Genes &amp; development},
volume = {17},
number = {11},
pages = {1328-1333},
pmid = {12782650},
issn = {0890-9369},
support = {R01 CA095099/CA/NCI NIH HHS/United States ; R01 CA95099-01/CA/NCI NIH HHS/United States ; },
mesh = {Adenosine Diphosphate Ribose/metabolism ; Animals ; Base Sequence ; Cloning, Molecular ; Endopeptidases/metabolism ; Mammals ; Recombinant Proteins/metabolism ; Telomere/*genetics ; Telomeric Repeat Binding Protein 1/genetics/*metabolism ; Ubiquitin/*metabolism ; },
abstract = {Mammalian telomeres are coated by the sequence-specific, DNA-binding protein, TRF1, a negative regulator of telomere length. Previous results showed that ADP-ribosylation of TRF1 by tankyrase 1 released TRF1 from telomeres and promoted telomere elongation. We now show that loss of TRF1 from telomeres results in ubiquitination and degradation of TRF1 by the proteasome and that degradation is required to keep TRF1 off telomeres. Ubiquitination of TRF1 is regulated by its telomere-binding status; only the telomere-unbound form of TRF1 is ubiquitinated. Our findings suggest a novel mechanism of sequential post translational modification of TRF1 (ADP-ribosylation and ubiquitination) for regulating access of telomerase to telomeres.},
}
@article {pmid12782419,
year = {2003},
author = {Argyle, D and Ellsmore, V and Gault, EA and Munro, AF and Nasir, L},
title = {Equine telomeres and telomerase in cellular immortalisation and ageing.},
journal = {Mechanisms of ageing and development},
volume = {124},
number = {6},
pages = {759-764},
doi = {10.1016/s0047-6374(03)00104-0},
pmid = {12782419},
issn = {0047-6374},
mesh = {Animals ; Cell Line, Transformed ; Cell Line, Tumor ; Cellular Senescence/*physiology ; Equidae ; Fibroblasts/cytology/metabolism ; Fibrosarcoma ; Gene Expression Regulation, Enzymologic ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {To determine the role of telomeres in cellular ageing in equids, we analysed telomere lengths in peripheral blood derived DNA samples from a panel of donkeys (Equus asinus) ranging from 2 to 30 years of age. The average telomere lengths ranged from 7 to 21 kbp and a statistically significant inverse correlation between telomere lengths and donor age was demonstrated. Similarly, telomere lengths in primary fibroblasts isolated from a horse (Equus equus) demonstrated telomeric loss with in vitro ageing when cultured to senescence. We extended this study to evaluate activity of the enzyme telomerase in various equine cell cultures, normal equine tissues and equine benign tumour samples. Initially a panel of equine immortalised and primary cell cultures were evaluated for telomerase activity using a standard telomere repeat amplification protocol (TRAP) assay. High levels of telomerase activity were detected in equine immortalised cells with no activity evident in primary cell cultures. Similarly, no telomerase activity could be detected in normal equine tissues or equine benign tumour samples of the sarcoid or papilloma type. We conclude that telomere attrition may contribute to ageing in equids. However, it would appear that telomerase does not play a major role in the development of the most common benign tumours of the horse.},
}
@article {pmid12781153,
year = {2003},
author = {Lundblad, V},
title = {Telomere replication: an Est fest.},
journal = {Current biology : CB},
volume = {13},
number = {11},
pages = {R439-41},
doi = {10.1016/s0960-9822(03)00365-8},
pmid = {12781153},
issn = {0960-9822},
mesh = {Amino Acid Sequence ; Homeostasis/*physiology ; Models, Biological ; Molecular Sequence Data ; Saccharomyces cerevisiae Proteins/*metabolism ; Sequence Alignment ; Telomerase/*metabolism ; Telomere/metabolism/*physiology ; },
abstract = {The search for subunits of the telomerase enzyme has uncovered orthologs of the budding years Est1 protein in several species, including humans. Thus, positive regulation of telomerase by Est1 appears to be a widely utilized mechanism for maintaining telomere length homeostasis.},
}
@article {pmid12781132,
year = {2003},
author = {Colgin, LM and Baran, K and Baumann, P and Cech, TR and Reddel, RR},
title = {Human POT1 facilitates telomere elongation by telomerase.},
journal = {Current biology : CB},
volume = {13},
number = {11},
pages = {942-946},
doi = {10.1016/s0960-9822(03)00339-7},
pmid = {12781132},
issn = {0960-9822},
support = {GM28039/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line ; Clone Cells ; Electrophoresis ; *Gene Expression ; Humans ; Polymerase Chain Reaction ; Shelterin Complex ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*metabolism ; },
abstract = {Mammalian telomeric DNA is mostly composed of double-stranded 5'-TTAGGG-3' repeats and ends with a single-stranded 3' overhang. Telomeric proteins stabilize the telomere by protecting the overhang from degradation or by remodeling the telomere into a T loop structure. Telomerase is a ribonucleoprotein that synthesizes new telomeric DNA. In budding yeast, other proteins, such as Cdc13p, that may help maintain the telomere end by regulating the recruitment or local activity of telomerase have been identified. Pot1 is a single-stranded telomeric DNA binding protein first identified in fission yeast, where it was shown to protect telomeres from degradation [10]. Human POT1 (hPOT1) protein is known to bind specifically to the G-rich telomere strand. We now show that hPOT1 can act as a telomerase-dependent, positive regulator of telomere length. Three splice variants of hPOT1 were overexpressed in a telomerase-positive human cell line. All three variants lengthened telomeres, and splice variant 1 was the most effective. hPOT1 was unable to lengthen the telomeres of telomerase-negative cells unless telomerase activity was induced. These data suggest that a normal function of hPOT1 is to facilitate telomere elongation by telomerase.},
}
@article {pmid12777695,
year = {2003},
author = {Bibby, MC},
title = {An introduction to telomeres and telomerase.},
journal = {Molecular biotechnology},
volume = {24},
number = {3},
pages = {295-301},
pmid = {12777695},
issn = {1073-6085},
mesh = {Animals ; Cell Division ; Cellular Senescence/genetics ; DNA Replication ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation, Neoplastic ; Humans ; Telomerase/antagonists &amp; inhibitors/chemistry/genetics/*metabolism ; Telomere/*genetics/ultrastructure ; },
abstract = {It is now more than a dozen years since the enzyme telomerase was discovered, and since that time, key studies have characterized the structural components of the enzyme and the associated telomeric proteins. Since the original discovery of telomerase, a clear association with cancer has been demonstrated. In normal somatic cells the telomeres at the ends of chromosomes shorten with every cell division, whereas in cancer cells telomere length is often maintained by reactivation of the enzyme telomerase. These discoveries have led to the proposal that telomerase expression can be used as a helpful marker for diagnostic and prognostic purposes in humans. Another area of research that has developed as a result of improving knowledge and understanding of the role of telomerase in malignancy is that of cancer therapeutics. This article is an introduction to the field of telomere and telomerase research, with an introduction to recent attempts to develop novel cancer treatments based on telomerase structure and function.},
}
@article {pmid12771041,
year = {2003},
author = {Tsutsui, T and Kumakura, S and Tamura, Y and Tsutsui, TW and Sekiguchi, M and Higuchi, T and Barrett, JC},
title = {Immortal, telomerase-negative cell lines derived from a Li-Fraumeni syndrome patient exhibit telomere length variability and chromosomal and minisatellite instabilities.},
journal = {Carcinogenesis},
volume = {24},
number = {5},
pages = {953-965},
doi = {10.1093/carcin/bgg024},
pmid = {12771041},
issn = {0143-3334},
mesh = {Cell Line, Transformed ; Cell Transformation, Neoplastic/*genetics ; Cellular Senescence/*physiology ; *Chromosome Aberrations ; Chromosomes, Human ; Fibroblasts/pathology ; Humans ; Li-Fraumeni Syndrome/enzymology/*genetics/*pathology ; Minisatellite Repeats/*genetics ; Mutation ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*metabolism ; Telomere/*genetics ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Five immortal cell lines derived from a Li-Fraumeni syndrome patient (MDAH 087) with a germline mutant p53 allele were characterized with respect to telomere length and genomic instability. The remaining wild-type p53 allele is lost in the cell lines. Telomerase activity was undetectable in all immortal cell lines. Five subclones of each cell line and five re-subclones of each of the subclones also showed undetectable telomerase activity. All five immortal cell lines exhibited variability in the mean length of terminal restriction fragments (TRFs). Subclones of each cell line, and re-subclones of the subclones also showed TRF variability, indicating that the variability is owing to clonal heterogeneity. Chromosome aberrations were observed at high frequencies in these cell lines including the subclones and re-subclones, and the principal types of aberrations were breaks, double minute chromosomes and dicentric chromosomes. In addition, minisatellite instability detected by DNA fingerprints was observed in the immortal cell lines. However, all of the cell lines were negative for microsatellite instability. As minisatellite sequences are considered recombinogenic in mammalian cells, these results suggest that recombination rates can be increased in these cell lines. Tumor-derived human cell lines, HT1080 cells and HeLa cells that also lack p53 function, exhibited little genomic instability involving chromosomal and minisatellite instabilities, indicating that chromosomal and minisatellite instabilities observed in the immortal cell lines lacking telomerase activity could not result from loss of p53 function.},
}
@article {pmid12769860,
year = {2003},
author = {Chan, SW and Blackburn, EH},
title = {Telomerase and ATM/Tel1p protect telomeres from nonhomologous end joining.},
journal = {Molecular cell},
volume = {11},
number = {5},
pages = {1379-1387},
doi = {10.1016/s1097-2765(03)00174-6},
pmid = {12769860},
issn = {1097-2765},
support = {GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence/genetics ; Catalytic Domain/genetics ; Cells, Cultured ; DNA/genetics/metabolism ; DNA Damage/*genetics ; DNA Repair/*genetics ; Eukaryotic Cells/*metabolism ; Fungal Proteins/genetics/*metabolism ; G1 Phase/genetics ; Intracellular Signaling Peptides and Proteins ; Molecular Sequence Data ; Protein Serine-Threonine Kinases ; Saccharomyces cerevisiae/*enzymology/*genetics ; Saccharomyces cerevisiae Proteins ; Telomerase/*deficiency/genetics ; Telomere/*metabolism ; },
abstract = {Telomeres protect chromosome ends from fusing to double-stranded breaks (DSBs). Using a quantitative real-time PCR assay, we show that nonhomologous end joining between a telomere and an inducible DSB was undetectable in wild-type cells, but occurred within a few hours of DSB induction in approximately 1/2000 genomes in telomerase-deficient cells and in >1/1000 genomes in telomerase-deficient cells also lacking the ATM homolog Tel1p. The fused telomeres contained very little telomeric DNA, suggesting that catastrophic telomere shortening preceded fusion. Lengthening of telomeres did not prevent such catastrophic telomere shortening and fusion events. Telomere-DSB fusion also occurred in cells containing a catalytically inactive telomerase and in tel1 mec1 cells where telomerase cannot elongate telomeres. Thus, telomerase and Tel1p function in telomere protection as well as in telomere elongation.},
}
@article {pmid12769859,
year = {2003},
author = {Liti, G and Louis, EJ},
title = {NEJ1 prevents NHEJ-dependent telomere fusions in yeast without telomerase.},
journal = {Molecular cell},
volume = {11},
number = {5},
pages = {1373-1378},
doi = {10.1016/s1097-2765(03)00177-1},
pmid = {12769859},
issn = {1097-2765},
mesh = {Cells, Cultured ; Chromosome Aberrations ; DNA Damage/genetics ; DNA Ligase ATP ; DNA Ligases/deficiency/genetics ; DNA Repair/*genetics ; DNA Replication/*genetics ; DNA-Binding Proteins/*deficiency/genetics ; Gene Expression Regulation, Fungal/genetics ; Haploidy ; Mutation/genetics ; Saccharomyces cerevisiae/*enzymology/*genetics ; Saccharomyces cerevisiae Proteins/genetics ; Telomerase/genetics/*metabolism ; Telomere/*genetics ; },
abstract = {In a search for genes involved in cell-type-dependent chromosome instability, we have found a role for NEJ1, a regulator of nonhomologous end joining (NHEJ), in cells that survive in the absence of telomerase. In yeast, NHEJ is regulated by mating-type status through NEJ1, which is repressed in a/alpha cells. For efficient NHEJ, NEJ1 is required as part of a complex with LIF1 and DNL4, which catalyzes DNA ligation. In haploid cells without telomerase, we find that the absence of NEJ1 results in high frequencies of circular chromosomes in type II survivors (i.e., those typified by lengthened telomere repeat tracts). These telomere fusion events are DNL4 dependent. NEJ1 therefore has a role in protecting telomeres from end fusions by NHEJ in the absence of telomerase that contrasts with its role in promoting repair at sites of DNA double-strand breaks.},
}
@article {pmid12769293,
year = {2003},
author = {Riha, K and Shippen, DE},
title = {Telomere structure, function and maintenance in Arabidopsis.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {11},
number = {3},
pages = {263-275},
pmid = {12769293},
issn = {0967-3849},
support = {GM65383/GM/NIGMS NIH HHS/United States ; },
mesh = {Arabidopsis/*cytology/enzymology/*genetics ; Chromosomal Proteins, Non-Histone/metabolism ; DNA Repair ; DNA, Plant/genetics/metabolism ; DNA-Binding Proteins ; Telomerase/metabolism ; Telomere/*chemistry/genetics/*metabolism ; },
abstract = {The stability of eukaryotic genomes is provided in part by the integrity of telomeres, the nucleoprotein caps on the ends of chromosome. Recent studies reveal that proper telomere architecture is required for long-term proliferation capacity. Here we describe molecular mechanisms that protect and maintain chromosome ends and discuss why Arabidopsis is emerging as a powerful new model for elucidating fundamental aspects of telomere biology.},
}
@article {pmid12768321,
year = {2003},
author = {Martens, UM and Waller, CF and Lange, W and Finke, J},
title = {Quantitative analysis of mixed chimerism following allogeneic bone marrow transplantation using telomere flow-FISH.},
journal = {Annals of hematology},
volume = {82},
number = {7},
pages = {416-422},
doi = {10.1007/s00277-003-0659-4},
pmid = {12768321},
issn = {0939-5555},
mesh = {*Bone Marrow Transplantation ; DNA/analysis ; Flow Cytometry/methods ; Humans ; In Situ Hybridization, Fluorescence/methods ; Leukemia, Lymphocytic, Chronic, B-Cell/therapy ; Polymorphism, Genetic ; Repetitive Sequences, Nucleic Acid ; Telomere/*genetics ; Transplantation Chimera/*genetics ; Transplantation, Homologous ; },
abstract = {Assessment of mixed chimerism is of particular interest for allogeneic bone marrow or peripheral blood stem cell transplantation with reduced-intensity conditioning in order to study contribution of donor-type and host-type lymphohematopoiesis. Because the length of telomere repeat sequences is frequently shorter in leukemic compared to normal hematopoietic cells, this telomere repeat polymorphism might be a useful marker to analyze mixed chimerism in selected patients with short telomeres. Recently, fluorescence in situ hybridization and flow cytometry (flow-FISH) have been shown to be valuable tools to analyze the mean telomere length in hematopoietic cells. Here, we demonstrate in a case study on a patient with chronic lymphocytic leukemia (CLL) that telomere flow-FISH can in principle be exploited to quantitate the amount of donor- and host-type cells for chimerism analysis based on distinct histogram distributions which reflect cell populations with different telomere length.},
}
@article {pmid12768206,
year = {2003},
author = {Loayza, D and De Lange, T},
title = {POT1 as a terminal transducer of TRF1 telomere length control.},
journal = {Nature},
volume = {423},
number = {6943},
pages = {1013-1018},
doi = {10.1038/nature01688},
pmid = {12768206},
issn = {1476-4687},
mesh = {Amino Acid Sequence ; Cell Line ; DNA/metabolism ; HeLa Cells ; Humans ; Molecular Sequence Data ; Particle Size ; Precipitin Tests ; Protein Binding ; Shelterin Complex ; Tankyrases/metabolism ; Telomere/*physiology ; Telomere-Binding Proteins/*physiology ; Telomeric Repeat Binding Protein 1/*genetics ; },
abstract = {Human telomere maintenance is essential for the protection of chromosome ends, and changes in telomere length have been implicated in ageing and cancer. Human telomere length is regulated by the TTAGGG-repeat-binding protein TRF1 and its interacting partners tankyrase 1, TIN2 and PINX1 (refs 5-9). As the TRF1 complex binds to the duplex DNA of the telomere, it is unclear how it can affect telomerase, which acts on the single-stranded 3' telomeric overhang. Here we show that the TRF1 complex interacts with a single-stranded telomeric DNA-binding protein--protection of telomeres 1 (POT1)--and that human POT1 controls telomerase-mediated telomere elongation. The presence of POT1 on telomeres was diminished when the amount of single-stranded DNA was reduced. Furthermore, POT1 binding was regulated by the TRF1 complex in response to telomere length. A mutant form of POT1 lacking the DNA-binding domain abrogated TRF1-mediated control of telomere length, and induced rapid and extensive telomere elongation. We propose that the interaction between the TRF1 complex and POT1 affects the loading of POT1 on the single-stranded telomeric DNA, thus transmitting information about telomere length to the telomere terminus, where telomerase is regulated.},
}
@article {pmid12767976,
year = {2003},
author = {Liu, L and Trimarchi, JR and Navarro, P and Blasco, MA and Keefe, DL},
title = {Oxidative stress contributes to arsenic-induced telomere attrition, chromosome instability, and apoptosis.},
journal = {The Journal of biological chemistry},
volume = {278},
number = {34},
pages = {31998-32004},
doi = {10.1074/jbc.M303553200},
pmid = {12767976},
issn = {0021-9258},
mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; *Apoptosis/drug effects ; Arsenic/*toxicity ; Embryonic and Fetal Development/drug effects ; Female ; Mice ; Mice, Knockout ; *Oxidative Stress ; Telomere/*drug effects ; },
abstract = {The environmental contaminant arsenic causes cancer, developmental retardation, and other degenerative diseases and, thus, is a serious health concern worldwide. Paradoxically, arsenic also may serve as an anti-tumor therapy, although the mechanisms of its antineoplastic effects remain unclear. Arsenic exerts its toxicity in part by generating reactive oxygen species. We show that arsenic-induced oxidative stress promotes telomere attrition, chromosome end-to-end fusions, and apoptotic cell death. An antioxidant, N-acetylcysteine, effectively prevents arsenic-induced oxidative stress, telomere erosion, chromosome instability, and apoptosis, suggesting that increasing the intracellular antioxidant level may have preventive or therapeutic effects in arsenic-induced chromosome instability and genotoxicity. Embryos with shortened telomeres from late generation telomerase-deficient mice exhibit increased sensitivity to arsenic-induced oxidative damage, suggesting that telomere attrition mediates arsenic-induced apoptosis. Unexpectedly, arsenite did not cause chromosome end-to-end fusions in telomerase RNA knockout mouse embryos despite progressively damaged telomeres and disrupting embryo viability. Together, these findings may explain why arsenic can initiate oxidative stress and telomere erosion, leading to apoptosis and anti-tumor therapy on the one hand and chromosome instability and carcinogenesis on the other.},
}
@article {pmid12761048,
year = {2003},
author = {Ning, Y and Xu, JF and Li, Y and Chavez, L and Riethman, HC and Lansdorp, PM and Weng, NP},
title = {Telomere length and the expression of natural telomeric genes in human fibroblasts.},
journal = {Human molecular genetics},
volume = {12},
number = {11},
pages = {1329-1336},
doi = {10.1093/hmg/ddg139},
pmid = {12761048},
issn = {0964-6906},
support = {AG21208/AG/NIA NIH HHS/United States ; },
mesh = {Cells, Cultured ; Cellular Senescence/genetics ; Chromosomes, Human ; Fibroblasts/cytology/physiology ; *Gene Expression Regulation ; Heterochromatin/genetics/ultrastructure ; Humans ; Telomere/*genetics ; },
abstract = {Progressive telomere shortening occurs with division of normal human cells, and eventually leads to replicative senescence. The mechanism by which the shortened telomeres cause growth arrest is largely unknown. Transcriptional silencing of genes adjacent to telomeres, also called telomere position effect, has been hypothesized as a possible mechanism of telomere-mediated senescence. However, there is no report regarding telomere position effect on natural telomeric genes in human cells. To address whether the expression of natural telomeric genes is regulated by telomere length, we combined quantitative RT-PCR with quantitative fluorescence in situ hybridization to comparatively analyze the expression of 34 telomeric genes and telomere length of their 24 corresponding chromosome ends in young and senescent human fibroblasts. We have demonstrated here that telomere length alone is not sufficient to determine the expression status of natural telomeric genes. An extended analysis of a tandem of eight telomeric genes on a single chromosome end revealed a discontinuous pattern of changed expression during telomere shortening and some of the changes are senescence-specific rather than non-dividing-related. These results suggest that the expression of natural telomeric genes may be influenced by alteration of local heterochromatin structure.},
}
@article {pmid12760042,
year = {2000},
author = {DuBois, ML and Diede, SJ and Stellwagen, AE and Gottschling, DE},
title = {All things must end: telomere dynamics in yeast.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {65},
number = {},
pages = {281-296},
doi = {10.1101/sqb.2000.65.281},
pmid = {12760042},
issn = {0091-7451},
support = {GM-07281/GM/NIGMS NIH HHS/United States ; GM-43893/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes, Fungal/genetics/ultrastructure ; DNA Replication/genetics ; Mutation ; Saccharomyces cerevisiae/*genetics ; Telomere/genetics/*physiology/ultrastructure ; Telomere-Binding Proteins/genetics/metabolism ; },
}
@article {pmid12760041,
year = {2000},
author = {Hemann, MT and Hackett, J and IJpma, A and Greider, CW},
title = {Telomere length, telomere-binding proteins, and DNA damage signaling.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {65},
number = {},
pages = {275-279},
doi = {10.1101/sqb.2000.65.275},
pmid = {12760041},
issn = {0091-7451},
support = {AG-09838/AG/NIA NIH HHS/United States ; CA-16519/CA/NCI NIH HHS/United States ; GM-43080/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; DNA Damage/*genetics ; Humans ; Models, Genetic ; Saccharomyces cerevisiae/genetics ; Signal Transduction/genetics ; Telomere/*ultrastructure ; Telomere-Binding Proteins/*metabolism ; },
}
@article {pmid12760040,
year = {2000},
author = {de Lange, T and Petrini, JH},
title = {A new connection at human telomeres: association of the Mre11 complex with TRF2.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {65},
number = {},
pages = {265-273},
doi = {10.1101/sqb.2000.65.265},
pmid = {12760040},
issn = {0091-7451},
mesh = {Animals ; DNA/genetics/metabolism ; DNA Damage/genetics ; DNA-Binding Proteins/*metabolism ; Humans ; MRE11 Homologue Protein ; Saccharomyces cerevisiae/genetics ; Telomere/*genetics ; Telomeric Repeat Binding Protein 2/*metabolism ; },
}
@article {pmid12760039,
year = {2000},
author = {Blackburn, EH and Chan, S and Chang, J and Fulton, TB and Krauskopf, A and McEachern, M and Prescott, J and Roy, J and Smith, C and Wang, H},
title = {Molecular manifestations and molecular determinants of telomere capping.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {65},
number = {},
pages = {253-263},
doi = {10.1101/sqb.2000.65.253},
pmid = {12760039},
issn = {0091-7451},
mesh = {Animals ; DNA Damage/genetics ; Humans ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {Multiple interacting components of the telomere, together with telomerase (and sometimes recombination), determine whether a telomere will be functional, allowing cell proliferation. The various components reinforce each other, providing for a robust and resilient system of protection and replenishment of telomeres. A characteristic of a telomere is that its structural features elicit responses that allow it to be dynamically recapped. Eliciting a DNA damage response through uncapping of a telomere appears to be one way in which telomerase action at that telomere is stimulated. Thus, as long as a timely and appropriate recapping of the telomere is possible, regulated uncapping of a telomere appears to be not only normal, but even required for optimal telomere maintenance. Telomere length and the presence of telomerase provide an example of a pair of interacting components that determine telomere capping function. Telomerase is dispensable in cells with sufficiently long telomeres; but in cells with short telomeres lacking telomerase, cells lose the ability to proliferate, and in some cell types, telomere fusions are increased. However, expressing telomerase can make even very short telomeres functional. Many interesting questions remain as to the mechanisms of these biological effects.},
}
@article {pmid12757977,
year = {2003},
author = {Karlseder, J},
title = {Telomere repeat binding factors: keeping the ends in check.},
journal = {Cancer letters},
volume = {194},
number = {2},
pages = {189-197},
doi = {10.1016/s0304-3835(02)00706-1},
pmid = {12757977},
issn = {0304-3835},
mesh = {Animals ; Cell Cycle/genetics ; Cellular Senescence/genetics ; DNA Damage ; Humans ; Telomerase/genetics ; Telomere/*genetics ; Telomere-Binding Proteins/*genetics ; Telomeric Repeat Binding Protein 1/genetics ; Telomeric Repeat Binding Protein 2/genetics ; },
abstract = {Per definition, a linear chromosome contains two ends, two sites, which by analogy to double-stranded breaks, might be expected to induce cell cycle checkpoints. The fact that cells divide without inducing such checkpoints suggests that telomeres, the natural ends of linear chromosomes, have the ability to suppress checkpoint activation. This suppression takes place at a number of levels. The TTAGGG repeats of human telomeric DNA recruit telomere specific proteins, among them the telomere repeat binding factors TRF1 and TRF2. These proteins, along with their interaction partners, reorganize the linear chromosome end into a t loop, a protected structure, which hides the very end of the chromosome. Here it is discussed how mammalian telomeres differ from DNA breaks, and what methods they use to prevent checkpoint activation.},
}
@article {pmid12757976,
year = {2003},
author = {Blasco, MA},
title = {Telomeres in cancer and aging: lessons from the mouse.},
journal = {Cancer letters},
volume = {194},
number = {2},
pages = {183-188},
doi = {10.1016/s0304-3835(02)00705-x},
pmid = {12757976},
issn = {0304-3835},
mesh = {Aging/genetics/*metabolism ; Animals ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Mice ; Mice, Transgenic ; Neoplasms/*enzymology/*genetics ; Telomerase/*genetics ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; Up-Regulation ; },
abstract = {The analysis of mice deficient in telomerase activity has allowed to directly test the relevance of telomeres and telomerase in tumor development and aging in the context of a mammalian organism. More recently, mice with impaired telomere capping due to abrogation of telomere-binding proteins have been also characterized. Here, I will discuss these studies, as well as their implications for putative therapies based of telomerase inhibition of telomerase re-introduction for cancer or age-related diseases, respectively.},
}
@article {pmid12757975,
year = {2003},
author = {Desmaze, C and Soria, JC and Freulet-Marrière, MA and Mathieu, N and Sabatier, L},
title = {Telomere-driven genomic instability in cancer cells.},
journal = {Cancer letters},
volume = {194},
number = {2},
pages = {173-182},
doi = {10.1016/s0304-3835(02)00704-8},
pmid = {12757975},
issn = {0304-3835},
mesh = {Animals ; Chromosome Mapping ; Gene Amplification ; Genome Components/*genetics ; Humans ; Neoplasms/enzymology/*genetics ; Recombination, Genetic ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {Telomeres, the ends of linear chromosomes, play a major role in the maintenance of genome integrity. Telomerase or alternative lengthening of telomeres (ALT) mechanisms exist in most cancer cells in order to stabilize telomere length by the addition of telomeric repeats. Telomere loss can be dramatically mutagenic. Chromosomes lacking one telomere remain unstable until they are capped, generating chromosomal instability, gene amplification via breakage/fusion/bridge (B/F/B) cycles and resulting in chromosome imbalances. The chronology of the occurrence of gene amplification and chromosome imbalances detected in human tumors is still unknown. All of the aberrations that occur prior to, during or after activation of a telomere maintenance mechanism promote the development of cancer.},
}
@article {pmid12757973,
year = {2003},
author = {Reddel, RR},
title = {Alternative lengthening of telomeres, telomerase, and cancer.},
journal = {Cancer letters},
volume = {194},
number = {2},
pages = {155-162},
doi = {10.1016/s0304-3835(02)00702-4},
pmid = {12757973},
issn = {0304-3835},
mesh = {Alternative Splicing ; Animals ; Base Sequence ; DNA-Binding Proteins ; Humans ; Molecular Sequence Data ; Neoplasms/*enzymology/genetics ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {Telomere length may be maintained in cancer cells by telomerase or an alternative lengthening of telomeres (ALT) mechanism. Low levels of telomerase activity have been detected in some normal somatic cells and presumably some types of normal cells also have low levels of an ALT-like activity. It is hypothesized here that inherited abnormalities of these and other aspects of telomere maintenance may contribute to cancer and ageing. The telomere length maintenance mechanisms are similar in that activation of each is associated with immortalization. They may also confer other properties on cancer cells, however, and the nature of these additional properties may be different for telomerase and ALT. It is expected that these similarities and differences will have implications for prognosis and treatment.},
}
@article {pmid12757971,
year = {2003},
author = {von Zglinicki, T},
title = {Telomeres, telomerase and the cancer cell: an introduction.},
journal = {Cancer letters},
volume = {194},
number = {2},
pages = {137-138},
doi = {10.1016/s0304-3835(02)00700-0},
pmid = {12757971},
issn = {0304-3835},
mesh = {Animals ; DNA Fragmentation ; DNA, Neoplasm ; Humans ; Neoplasms/*enzymology/*genetics ; Telomerase/*metabolism ; Telomere/*enzymology ; },
}
@article {pmid12757718,
year = {2003},
author = {Takahashi, R and Bando, T and Sugiyama, H},
title = {Specific alkylation of human telomere repeats by hairpin pyrrole-imidazole polyamide.},
journal = {Bioorganic &amp; medicinal chemistry},
volume = {11},
number = {12},
pages = {2503-2509},
doi = {10.1016/s0968-0896(03)00176-7},
pmid = {12757718},
issn = {0968-0896},
mesh = {Adenine/chemistry ; Alkylation ; Antineoplastic Agents, Alkylating/chemical synthesis/pharmacology ; Cell Division/drug effects ; Cell Line, Tumor ; DNA/chemistry ; Humans ; Imidazoles/*chemistry ; Inhibitory Concentration 50 ; Nucleic Acid Conformation ; Nylons/chemical synthesis/*chemistry/pharmacology ; Oligonucleotides/chemistry ; Pyrroles/*chemistry ; Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry/genetics ; },
abstract = {A novel hairpin polyamide-cyclopropapyrroloindole (CPI) conjugate PyImImIm-gamma-PyPyPyLDu86 (conjugate 11), which targets human telomere repeats d(TTAGGG)(n)/d(CCCTAA)(n), was synthesized. High resolution denaturing polyacrylamide gel electrophoresis using 44 bp DNA fragments and HPLC product analysis of a synthetic nonanucleotide demonstrated that conjugate 11 alkylates the target adenine in the telomere repeats, 5'-CCCTAA-3'. Examination of the antitumor activity of conjugate 11 using a panel of 39 cancer cell lines demonstrated that the average concentration of conjugate 11 required for 50% growth inhibition was 5.75 microM, which is superior to pepleomycin and bleomycin and comparable to cisplatin.},
}
@article {pmid12756110,
year = {2003},
author = {Bastian, BC},
title = {Hypothesis: a role for telomere crisis in spontaneous regression of melanoma.},
journal = {Archives of dermatology},
volume = {139},
number = {5},
pages = {667-668},
doi = {10.1001/archderm.139.5.667},
pmid = {12756110},
issn = {0003-987X},
mesh = {Humans ; Melanoma/*physiopathology ; Remission, Spontaneous ; Skin Neoplasms/*physiopathology ; Telomere/*physiology ; },
}
@article {pmid12753506,
year = {2003},
author = {Aladdin, H and Katzenstein, T and Dreves, AM and Ryder, L and Gerstoft, J and Skinhøj, P and Pedersen, BK and Ullum, H},
title = {T-cell receptor excisional circles, telomere length, proliferation and apoptosis in peripheral blood mononuclear cells of human immunodeficiency virus-infected individuals after 18 months of treatment induced viral suppression.},
journal = {Scandinavian journal of immunology},
volume = {57},
number = {5},
pages = {485-492},
doi = {10.1046/j.1365-3083.2003.01258.x},
pmid = {12753506},
issn = {0300-9475},
mesh = {Adult ; Aged ; Anti-HIV Agents/*pharmacology/therapeutic use ; *Antiretroviral Therapy, Highly Active ; Apoptosis/drug effects ; CD4 Lymphocyte Count ; CD4-Positive T-Lymphocytes/*drug effects/metabolism/pathology ; CD8-Positive T-Lymphocytes/*drug effects/metabolism/pathology ; DNA/blood ; Female ; Follow-Up Studies ; Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor ; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor ; HIV Infections/blood/drug therapy/*immunology ; Humans ; Lymphocyte Activation/drug effects ; Male ; Middle Aged ; Plasmids/drug effects ; Receptors, Antigen, T-Cell, alpha-beta/chemistry ; Telomere/ultrastructure ; Viral Load ; },
abstract = {This study evaluated the effect of highly active antiretroviral therapy (HAART)-induced viral suppression on T-cell receptor excisional circles (TRECs), telomere length, proliferative responses and spontaneous as well as phytohaemagglutinin (PHA)-stimulated lymphocyte apoptosis in 27 human immunodeficiency virus (HIV)-infected individuals followed for 18 months during HAART. Our results show that HAART significantly increased the level of TRECs in CD4+ cells (P = 0.003) after 18 months of almost continuously suppressed HIV-RNA levels. Lymphocyte proliferative responses and apoptosis levels in patients were significantly lower and significantly higher, respectively, compared with healthy controls. The proliferative response and apoptosis levels did not change during follow up. Changes in telomere length were observed in CD4+ and in CD8+ T cells. The study demonstrated that HAART induces normal TREC levels in the CD4+ T-cell pool. However, the other perturbed functions in T cells indicate that immune reconstitution is incomplete and may need longer viral suppression.},
}
@article {pmid12753301,
year = {2003},
author = {Vogt, S and Iking-Konert, C and Hug, F and Andrassy, K and Hänsch, GM},
title = {Shortening of telomeres: Evidence for replicative senescence of T cells derived from patients with Wegener's granulomatosis.},
journal = {Kidney international},
volume = {63},
number = {6},
pages = {2144-2151},
doi = {10.1046/j.1523-1755.2003.00037.x},
pmid = {12753301},
issn = {0085-2538},
mesh = {Adult ; Aged ; CD28 Antigens/genetics ; Cellular Senescence/*physiology ; Gene Expression ; Granulomatosis with Polyangiitis/immunology/metabolism/*physiopathology ; Humans ; Lymphocyte Activation/physiology ; Middle Aged ; T-Lymphocytes/*cytology/*physiology ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {BACKGROUND: Replicative senescence describes the fact that somatic cells undergo a finite and predictable number of cell divisions before entering an irreversible state of growth arrest. Progressive shortening of the telomeres, a consequence of cell division, is a reliable indicator of replicative senescence.<br><br>METHOD: We analyzed telomere length of DNA derived from T cells of patients suffering from Wegener's granulomatosis by Southern blotting. Moreover, expression of CD28, another marker for replicative senescence, was tested by cytofluorometry.<br><br>RESULTS: In patients with disease for more than 5 years, short telomeres were detected in addition to telomeres of normal length, indicating replicative senescence of discrete T-cell clones. Reduced expression of CD28 was noted, particularly on CD8-positive T cells, derived from patients with disease for more than 5 years and short telomeres.<br><br>CONCLUSION: Our data provide evidence that a portion of T cells had undergone replicative senescence, which in turn indicates clonal expansion of T cells as consequence of activation.},
}
@article {pmid12753300,
year = {2003},
author = {Melk, A and Kittikowit, W and Sandhu, I and Halloran, KM and Grimm, P and Schmidt, BM and Halloran, PF},
title = {Cell senescence in rat kidneys in vivo increases with growth and age despite lack of telomere shortening.},
journal = {Kidney international},
volume = {63},
number = {6},
pages = {2134-2143},
doi = {10.1046/j.1523-1755.2003.00032.x},
pmid = {12753300},
issn = {0085-2538},
mesh = {Aging/*physiology ; Animals ; Brain/physiology ; Cellular Senescence/*physiology ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Gene Expression ; Heart/physiology ; In Situ Nick-End Labeling ; Kidney/*cytology/growth &amp; development/*physiology ; Lipofuscin ; Peptide Fragments/metabolism ; RNA, Messenger/analysis ; Rats ; Rats, Inbred F344 ; Spleen/physiology ; Telomere/*metabolism ; beta-Galactosidase/metabolism ; },
abstract = {BACKGROUND: Somatic cells in vitro have a finite life expectancy before entering a state of senescence, but it is unclear whether this state occurs in vivo in kidney development, growth, and aging. We previously showed that human kidney cortex displays telomere shortening with age. In this study, we compared the structural and functional changes in rat kidney with age to phenomena associated with cellular senescence in vitro.<br><br>METHODS: We assessed the changes in Fischer 344 rat kidneys from age 1 to 9 months to define growth and development and from age 9 to 24 months to define aging.<br><br>RESULTS: Rat kidney telomeres were approximately 35 to 40 kb long and did not shorten significantly. Expression of mRNA for p16INK4a, a characteristic senescence gene in vitro, was undetectable in most young rats but rose 27 fold during growth and a further 72-fold during aging. p16INK4a protein was localized to the nucleus and increased with age. p16INK4a mRNA also increased in other tissues. Lipofuscin and senescence-associated beta-galactosidase increased in epithelium with growth and aging and their occurrence was significantly associated with each other. Lipofuscin was particularly found in atrophic nephrons.<br><br>CONCLUSION: We conclude that cell senescence occurs in both growth and aging in rat kidney and may contribute to the age-related pathology. These changes are not due to telomere shortening, but may reflect cumulative environmental stress.},
}
@article {pmid12753185,
year = {2003},
author = {Tourand, Y and Kobryn, K and Chaconas, G},
title = {Sequence-specific recognition but position-dependent cleavage of two distinct telomeres by the Borrelia burgdorferi telomere resolvase, ResT.},
journal = {Molecular microbiology},
volume = {48},
number = {4},
pages = {901-911},
doi = {10.1046/j.1365-2958.2003.03485.x},
pmid = {12753185},
issn = {0950-382X},
mesh = {Bacterial Proteins ; Base Sequence ; Borrelia burgdorferi/*enzymology/genetics ; Endodeoxyribonucleases/*metabolism ; Molecular Sequence Data ; Substrate Specificity ; Telomere/genetics/*metabolism ; },
abstract = {An unusual feature of bacteria in the genus Borrelia (causative agents of Lyme disease and relapsing fever) is a segmented genome consisting of multiple linear DNA molecules with covalently closed hairpin ends, known as telomeres. The hairpin telomeres are generated by a DNA breakage and reunion process (telomere resolution) promoted by ResT, an enzyme using an active site related to that of tyrosine recombinases and type IB topoisomerases. In this study, we define the minimal sequence requirements for a functional telomere and identify specific basepairs that appear to be important for telomere resolution. In addition, we show that the two naturally occurring and distinct telomere spacings found in B. burgdorferi can both be efficiently processed by ResT. This flexibility for substrate utilization by ResT supports the argument for a single telomere resolvase in Borrelia. Furthermore, although telomere recognition requires sequence specificity in part of the substrate, DNA cleavage is instead position dependent and occurs at a fixed distance from the axis of symmetry and the conserved sequence of box 3 in the different replicated telomere substrates. This positional dependence for DNA cleavage has not been observed previously for a tyrosine recombinase.},
}
@article {pmid12750320,
year = {2003},
author = {Wyatt, HR and Liaw, H and Green, GR and Lustig, AJ},
title = {Multiple roles for Saccharomyces cerevisiae histone H2A in telomere position effect, Spt phenotypes and double-strand-break repair.},
journal = {Genetics},
volume = {164},
number = {1},
pages = {47-64},
pmid = {12750320},
issn = {0016-6731},
support = {GM-56526/GM/NIGMS NIH HHS/United States ; },
mesh = {Acetylation ; Bleomycin/metabolism ; DNA Damage ; DNA Repair/*physiology ; Histones/*metabolism ; Phosphorylation ; Saccharomyces cerevisiae/genetics/*metabolism ; *Telomere ; },
abstract = {Telomere position effects on transcription (TPE, or telomeric silencing) are nucleated by association of nonhistone silencing factors with the telomere and propagated in subtelomeric regions through association of silencing factors with the specifically modified histones H3 and H4. However, the function of histone H2A in TPE is unknown. We found that deletion of either the amino or the carboxyltails of H2A substantially reduces TPE. We identified four H2A modification sites necessary for wild-type efficiency of TPE. These "hta1tpe" alleles also act as suppressors of a delta insertion allele of LYS2, suggesting shared elements of chromatin structure at both loci. Interestingly, we observed combinatorial effects of allele pairs, suggesting both interdependent acetylation and deacetylation events in the amino-terminal tail and a regulatory circuit between multiple phosphorylated residues in the carboxyl-terminal tail. Decreases in silencing and viability are observed in most hta1tpe alleles after treatment with low and high concentrations, respectively, of bleomycin, which forms double-strand breaks (DSBs). In the absence of the DSB and telomere-binding protein yKu70, the bleomycin sensitivity of hta1tpe alleles is further enhanced. We also provide data suggesting the presence of a yKu-dependent histone H2A function in TPE. These data indicate that the amino- and carboxyl-terminal tails of H2A are essential for wild-type levels of yKu-mediated TPE and DSB repair.},
}
@article {pmid12748277,
year = {2003},
author = {Grandin, N and Charbonneau, M},
title = {The Rad51 pathway of telomerase-independent maintenance of telomeres can amplify TG1-3 sequences in yku and cdc13 mutants of Saccharomyces cerevisiae.},
journal = {Molecular and cellular biology},
volume = {23},
number = {11},
pages = {3721-3734},
pmid = {12748277},
issn = {0270-7306},
mesh = {Cell Survival/physiology ; Cellular Senescence/genetics/physiology ; DNA Repair ; DNA-Binding Proteins/*metabolism ; Rad51 Recombinase ; Recombination, Genetic ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/cytology/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/*genetics/metabolism ; Temperature ; },
abstract = {In the yeast Saccharomyces cerevisiae, Cdc13, Yku, and telomerase define three parallel pathways for telomere end protection that prevent chromosome instability and death by senescence. We report here that cdc13-1 yku70delta mutants generated telomere deprotection-resistant cells that, in contrast with telomerase-negative senescent cells, did not display classical crisis events. cdc13-1 yku70delta cells survived telomere deprotection by exclusively amplifying TG(1-3) repeats (type II recombination). In a background lacking telomerase (tlc1delta), this process predominated over type I recombination (amplification of subtelomeric Y' sequences). Strikingly, inactivation of the Rad50/Rad59 pathway (which is normally required for type II recombination) in cdc13-1 yku70delta or yku70delta tlc1delta mutants, but also in cdc13-1 YKU70(+) tlc1delta mutants, still permitted type II recombination, but this process was now entirely dependent on the Rad51 pathway. In addition, delayed senescence was observed in cdc13-1 yku70delta rad51delta and cdc13-1 tlc1delta rad51delta cells. These results demonstrate that in wild-type cells, masking by Cdc13 and Yku prevents the Rad51 pathway from amplifying telomeric TG(1-3) sequences. They also suggest that Rad51 is more efficient than Rad50 in amplifying the sequences left uncovered by the absence of Cdc13 or Yku70.},
}
@article {pmid12743159,
year = {2003},
author = {Hahn, WC},
title = {Role of telomeres and telomerase in the pathogenesis of human cancer.},
journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology},
volume = {21},
number = {10},
pages = {2034-2043},
doi = {10.1200/JCO.2003.06.018},
pmid = {12743159},
issn = {0732-183X},
support = {K01 CA94223/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Neoplasms/enzymology/genetics/*physiopathology ; *Telomerase ; *Telomere ; },
abstract = {Specialized nucleoprotein structures, termed telomeres, cap the ends of human chromosomes. These terminal structures, composed of repetitive arrays of guanine-rich hexameric DNA together with specific telomere-binding proteins, play essential roles in protecting the chromosome from damage and degradation. In addition, several lines of evidence implicate telomere maintenance as an important regulator of cell life span. Activation of telomerase, a dedicated reverse transcriptase that synthesizes telomeric sequences, is strongly associated with cancer, and recent observations confirm that telomeres and telomerase perform important roles in both suppressing and facilitating malignant transformation. These dual functions of telomere biology are evident in the clinical manifestations of the multisystem syndrome, dyskeratosis congenita, forms of which display defects in telomerase function. Recent advances in our understanding of telomere biology indicate that the manipulation of telomeres and telomerase will lead to clinically significant applications in the diagnosis, prevention, and treatment of neoplastic disease.},
}
@article {pmid12736778,
year = {2003},
author = {Gao, W and Clancy, JA and Han, F and Prada, D and Kleinhofs, A and Ullrich, SE},
title = {Molecular dissection of a dormancy QTL region near the chromosome 7 (5H) L telomere in barley.},
journal = {TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik},
volume = {107},
number = {3},
pages = {552-559},
pmid = {12736778},
issn = {0040-5752},
mesh = {*Chromosome Mapping ; Germination/physiology ; Hordeum/*genetics/physiology ; Quantitative Trait Loci/*genetics ; Seeds/*physiology ; Temperature ; },
abstract = {Moderate seed dormancy is desirable in barley (Hordeum vulgare L.). It is difficult for breeders to manipulate seed dormancy in practical breeding programs because of complex inheritance and large environmental effects. Quantitative trait locus (QTL) mapping opens a way for breeders to manipulate quantitative trait genes. A seed dormancy QTL, SD2, was mapped previously in an 8-cM interval near the chromosome 7 (5H) L telomere from a cross of 'Steptoe' (dormant)/'Morex' (non-dormant) by the North American Barley Genome Project using an interval mapping method and a relatively low-resolution genetic map. SD2 has a moderate dormancy effect, which makes it a promising candidate gene for moderate seed dormancy in barley cultivar development. The fine mapping of SD2 is required for efficient manipulation of SD2 in breeding and would facilitate the study of dormancy in barley. Ten different Morex isolines were generated, including regenerated Morex, of which nine lines had duplicates. The isolines together with Steptoe and Morex were grown in growth room and field environments for 2 years (2000 and 2001). In the growth room, relatively low growing temperatures (25 degrees C day/15 degrees C night) were employed to promote seed dormancy development. Seed germination percentage, determined at different post-harvest after-ripening periods, was used to measure seed dormancy. Fine mapping using the substitution mapping method based on differences among isolines resolved the SD2 QTL into an 0.8-cM interval between molecular markers MWG851D and MWG851B near the chromosome 7 (5H) L telomere. Relatively low temperatures (< or =25 degrees C) during seed development promoted the expression of the SD2 dormancy QTL. The chromosome region above the MWG851D-MWG851B interval might play a role in reducing barley seed dormancy during after-ripening.},
}
@article {pmid12735903,
year = {2003},
author = {Graakjaer, J and Bischoff, C and Korsholm, L and Holstebroe, S and Vach, W and Bohr, VA and Christensen, K and Kølvraa, S},
title = {The pattern of chromosome-specific variations in telomere length in humans is determined by inherited, telomere-near factors and is maintained throughout life.},
journal = {Mechanisms of ageing and development},
volume = {124},
number = {5},
pages = {629-640},
doi = {10.1016/s0047-6374(03)00081-2},
pmid = {12735903},
issn = {0047-6374},
support = {08761//PHS HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*genetics ; Amnion/cytology ; *Chromosomes, Human ; Fibroblasts/physiology ; Humans ; In Situ Hybridization, Fluorescence ; Lymphocytes/physiology ; Telomere/*genetics ; Twins, Dizygotic ; Twins, Monozygotic ; },
abstract = {In this study the telomere length distribution on individual chromosome arms in humans has been characterized. Using fluorescent in situ hybridisation (FISH) followed by computer-assisted analysis of digital images, we show that the distribution of telomere length on individual chromosome arms is not random, but that humans have a common telomere profile. This profile exists in both lymphocytes, amniocytes and fibroblasts, and is conserved during life until about the age of 100. We find that the length of the telomeres generally follows the length of the chromosomes and that the chromosome specific differences in telomere length are determined by factors located very distally on the chromosome arms. In addition to the common profile, we also find that each individual has specific characteristics. Based on analysis of both monozygotic and dizygotic twins, we find that these characteristics are partly inherited. For each chromosome, age-related chromosome loss correlates negatively with telomere length. This suggests that decrease in telomere length may be an element in age-related genome instability.},
}
@article {pmid12734403,
year = {2003},
author = {Trelles-Sticken, E and Loidl, J and Scherthan, H},
title = {Increased ploidy and KAR3 and SIR3 disruption alter the dynamics of meiotic chromosomes and telomeres.},
journal = {Journal of cell science},
volume = {116},
number = {Pt 12},
pages = {2431-2442},
doi = {10.1242/jcs.00453},
pmid = {12734403},
issn = {0021-9533},
mesh = {Cell Cycle Proteins/genetics ; Centromere/genetics ; Chromosome Pairing/genetics ; Diploidy ; Germ Cells/metabolism ; Haploidy ; Meiosis/*genetics ; Microtubule-Associated Proteins/deficiency/*genetics ; Nuclear Proteins ; *Ploidies ; Prophase/genetics ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/*genetics ; Telomere/*genetics ; },
abstract = {We investigated the sequence of chromosomal events during meiotic prophase in haploid, diploid and autotetraploid SK1 strains of Saccharomyces cerevisiae. Using molecular cytology, we found that meiosis-specific nuclear topology (i.e. dissolution of centromere clustering, bouquet formation and meiotic divisions) are significantly delayed in polyploid SK1 meiosis. Thus, and in contrast to the situation in plants, an increase in ploidy extends prophase I in budding yeast. Moreover, we found that bouquet formation also occurs in haploid and diploid SK1 meiosis deficient in the telomeric heterochromatin protein Sir3p. Diploid sir3Delta SK1 meiosis showed pleiotropic defects such as delayed centromere cluster resolution in a proportion of cells and impeded downstream events (i.e. bouquet formation, homologue pairing and meiotic divisions). Meiotic telomere clustering occurred in diploid and haploid sir3Delta strains. Using the haploid system, we further show that a bouquet forms at the kar3Delta SPB. Comparison of the expression of meiosis-specific Ndj1p-HA and Zip1p in haploid control and kar3Delta time courses revealed that fewer cells enter the meiotic cycle in absence of Kar3p. Elevated frequencies of bouquets in kar3Delta haploid meiosis suggest a role for Kar3p in regulation of telomere dynamics.},
}
@article {pmid12729792,
year = {2003},
author = {Petitot, F and Lebeau, J and Dano, L and Lectard, B and Altmeyer, S and Levalois, C and Chevillard, S},
title = {In vitro aging of rat lung cells. Downregulation of telomerase activity and continuous decrease of telomere length are not incompatible with malignant transformation.},
journal = {Experimental cell research},
volume = {286},
number = {1},
pages = {30-39},
doi = {10.1016/s0014-4827(03)00103-4},
pmid = {12729792},
issn = {0014-4827},
mesh = {Animals ; Cell Cycle/physiology ; *Cell Transformation, Neoplastic ; Cells, Cultured ; *Cellular Senescence ; Culture Techniques ; DNA/metabolism ; Down-Regulation/physiology ; Genes, Tumor Suppressor ; Lung/*cytology/physiology ; Male ; Mice ; Mice, Nude ; Rats ; Rats, Sprague-Dawley ; Respiratory Mucosa/*cytology/physiology ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Most normal mammalian somatic cells cultivated in vitro enter replicative senescence after a finite number of divisions, as a consequence of the progressive shortening of telomeres during proliferation that reflects one aspect of organism/cellular aging. The situation appears more complex in rodent cells due to physiological telomerase expression in most somatic normal tissues, great telomere length, and the difficulties of finding suitable in vitro culture conditions. To study in vitro aging of rat lung epithelial cells, we have developed primary culture conditions adapted to rat fresh lung explants and have studied for 1 year (50 passages) the changes in cellular proliferation and mortality, genetic instability, telomerase activity, telomere length, and tumorigenic potential. We have observed an absence of senescence and/or crisis, a transient genetic instability, the persistence of a differentiated Clara cell phenotype, a steady decrease in telomerase activity followed by a low residual activity together with a continuous decrease in telomere length, a constant rate of proliferation, and the acquisition of tumorigenic potential. The bypass of the growth arrest and the acquisition of long-term growth properties could be explained by the loss of p16(INK4a) expression, the ARF/p53 pathway not being altered. In conclusion, these results clearly indicate that, in rat lung epithelial cells, in vitro transformation and acquisition of tumorigenic properties can occur even if the telomere length is still decreasing and telomerase activity remains downregulated.},
}
@article {pmid12723711,
year = {2003},
author = {Mason, JM and Konev, AY and Biessmann, H},
title = {Telomeric position effect in drosophila melanogaster reflects a telomere length control mechanism.},
journal = {Genetica},
volume = {117},
number = {2-3},
pages = {319-325},
doi = {10.1023/a:1022925003172},
pmid = {12723711},
issn = {0016-6707},
support = {GM-56729/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromosome Mapping ; DNA Transposable Elements ; Drosophila melanogaster/*genetics ; Gene Expression Regulation/genetics ; Gene Silencing ; Retroelements/genetics ; Telomere/*genetics ; Terminal Repeat Sequences/*genetics ; Transcriptional Activation ; Transgenes ; },
abstract = {The terminal DNA arrays on chromosomes of Drosophila melanogaster are composed of two families of non-LTR retrotransposons, HeT-A and TART. Available evidence suggests that chromosome length in this species and its close relatives is maintained by targeted transposition of these elements, with attachment of the elements to the chromosome end by their 3' oligo(A) tails. However, the regulation of transposition of these elements and the control of telomere length are poorly understood. Here we present the hypothesis that the forces involved in telomere length regulation in Drosophila are the underlying forces that manifest themselves as telomeric position effect (TPE). Based on recent studies of TPE, which found that expression of a reporter gene is influenced by telomere structure in cis and trans, we propose that the subtelomeric satellite (TAS) in D. melanogaster plays an important role in controlling telomere elongation. Transcription of a HeT-A element is probably initiated at a promoter in the 3' UTR of an upstream element, and TAS may repress this transcriptional activity in cis and trans. A region of HeT-A not at the extreme 3' end of the element may act as a transcriptional enhancer that may be modulated by TAS.},
}
@article {pmid12723710,
year = {2003},
author = {Cenci, G and Siriaco, G and Gatti, M},
title = {The role of HeT-A and TART retrotransposons in Drosophila telomere capping.},
journal = {Genetica},
volume = {117},
number = {2-3},
pages = {311-318},
doi = {10.1023/a:1022972902263},
pmid = {12723710},
issn = {0016-6707},
mesh = {Animals ; Crosses, Genetic ; Drosophila melanogaster/*genetics ; Female ; In Situ Hybridization, Fluorescence ; Male ; Retroelements/*genetics ; Telomere/*genetics ; Terminal Repeat Sequences ; X Chromosome ; },
abstract = {Drosophila telomeres contain multiple copies of HeT-A and TART retrotransposons. These elements specifically transpose to chromosomal ends, compensating for loss of terminal nucleotides that occurs at each cycle of DNA replication. We have investigated the role of these sequences in the formation of telomere-telomere attachments induced by mutations in the UbcD1 gene. We have constructed UbcD1 mutant males carrying terminally deleted X chromosomes devoid of both HeT-A and TART sequences. Cytological analysis of larval neuroblasts from these males revealed that telomeres lacking HeT-A and TART and normal telomeres that contain these sequences participate in telomeric fusions with comparable frequencies. These results indicate that the UbcD1 substrate(s) binds chromosomal termini in a sequence-independent manner. Previous studies have shown that the telomere-capping protein HP1 also binds telomeres lacking HeT-A and TART. Taken together, these findings strongly suggest that the assembly of DNA-protein complexes that protect chromosome ends from fusions do not require specific terminal sequences.},
}
@article {pmid12716976,
year = {2003},
author = {Singh, SM and Lue, NF},
title = {Ever shorter telomere 1 (EST1)-dependent reverse transcription by Candida telomerase in vitro: evidence in support of an activating function.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {100},
number = {10},
pages = {5718-5723},
pmid = {12716976},
issn = {0027-8424},
mesh = {Base Sequence ; Candida/*enzymology ; DNA Primers ; Kinetics ; Protein Subunits/chemistry/metabolism ; RNA-Directed DNA Polymerase/metabolism ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/chemistry/genetics/*metabolism ; Telomerase/chemistry/genetics/*metabolism ; *Transcription, Genetic ; },
abstract = {Telomerase is an RNA-protein complex responsible for the extension of one strand of the telomere terminal repeats. Analysis of the telomerase complex in the budding yeast Saccharomyces cerevisiae has revealed the presence of one catalytic protein subunit (Est2p/TERT) and at least two noncatalytic components (Est1p and Est3p). The TERT subunit is essential for telomerase function, both in vitro and in vivo. In contrast, the Est1p and Est3p subunits, although required for telomere extension in vivo, have not been shown to affect enzyme activity in vitro. We recently identified orthologues of the Saccharomyces telomerase subunits in Candida albicans (named CaTERT, CaEst1p, and CaEst3p). Analysis of telomerase from the Candida Caest1-Delta strains revealed a primer-specific defect in its activity in vitro: The mutant enzyme was impaired in its ability to extend some, but not all, telomeric primers. The CaEst1p-responsive primers have 3' ends that are clustered in two loci within the 23-bp Candida telomere repeat. The degree of CaEst1p-dependence was modulated by the length and sequence of the 5' ends. For CaEst1p-dependent primers, the wild-type enzyme consistently exhibited a greater V(max) than the mutant enzyme in kinetic studies. These results suggest that CaEst1p augments the ability of telomerase to reverse-transcribe through selected barriers in the telomere repeat by acting as an allosteric activator and provide the basis for a functional in vitro assay for a noncatalytic protein component of the telomerase complex.},
}
@article {pmid12715149,
year = {2003},
author = {Sýkorová, E and Cartagena, J and Horáková, M and Fukui, K and Fajkus, J},
title = {Characterization of telomere-subtelomere junctions in Silene latifolia.},
journal = {Molecular genetics and genomics : MGG},
volume = {269},
number = {1},
pages = {13-20},
pmid = {12715149},
issn = {1617-4615},
mesh = {Base Sequence ; Chromatin/chemistry/genetics ; Chromosomes, Plant ; DNA, Plant/genetics ; Genetic Variation ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Nucleosomes/chemistry/genetics ; Sequence Homology, Nucleic Acid ; Silene/*genetics ; Tandem Repeat Sequences/*genetics ; Telomere/*genetics ; Terminal Repeat Sequences/*genetics ; X Chromosome ; },
abstract = {Telomere-associated regions represent boundaries between the relatively homogeneous telomeres and the subtelomeres, which show much greater heterogeneity in chromatin structure and DNA composition. Although a major fraction of subtelomeres is usually formed by a limited number of highly repeated DNA sequence families, their mutual arrangement, attachment to telomeres and the presence of interspersed unique or low-copy-number sequences make these terminal domains chromosome specific. In this study, we describe the structures of junctions between telomeres and a major subtelomeric repeat of the plant Silene latifolia, X43.1. Our results show that on individual chromosome arms, X43.1 is attached to the telomere either directly at sites corresponding to nucleosome boundaries previously mapped in this sequence, or via other spacer sequences, both previously characterized and newly described ones. Sites of telomere junctions are non-random in all the telomere-associated sequences analysed. These data obtained at the molecular level have been verified using in situ hybridization to metaphase chromosomes and extended DNA fibres.},
}
@article {pmid12714249,
year = {2003},
author = {Son, NH and Joyce, B and Hieatt, A and Chrest, FJ and Yanovski, J and Weng, NP},
title = {Stable telomere length and telomerase expression from naïve to memory B-lymphocyte differentiation.},
journal = {Mechanisms of ageing and development},
volume = {124},
number = {4},
pages = {427-432},
doi = {10.1016/s0047-6374(03)00018-6},
pmid = {12714249},
issn = {0047-6374},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*immunology ; B-Lymphocytes/cytology/*enzymology ; Cell Differentiation/immunology ; Child ; Child, Preschool ; Enzyme Activation/immunology ; Homeostasis/immunology ; Humans ; *Immunologic Memory ; Infant ; Infant, Newborn ; Lymphocyte Count ; Middle Aged ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomere length and telomerase activity play important roles in regulating replicative lifespan of cells. The length of telomeres also serves as a marker for the replicative history and for the remaining replicative potential of cells. Differential telomere length has been reported in human naïve and memory T cells but not in naïve versus memory B-lymphocytes. We report here an analysis of telomere length and induced telomerase expression in naïve (CD27(-)) and memory (CD27(+)) B cells from normal adults. Although both naïve and memory B cells lose telomere repeats with age, there is no consistent difference in telomere length between these two B cell subsets. Furthermore, both naïve and memory B cells are capable of inducing telomerase activity at similar levels after in vitro stimulation independent of donor's age. Finally, there is a slow increase of memory B cells in peripheral blood with age. Together, these findings suggest that B cells are capable of maintaining telomere length during differentiation from naïve to memory B cells and this ability is maintained through age.},
}
@article {pmid12714246,
year = {2003},
author = {Mariani, E and Meneghetti, A and Formentini, I and Neri, S and Cattini, L and Ravaglia, G and Forti, P and Facchini, A},
title = {Telomere length and telomerase activity: effect of ageing on human NK cells.},
journal = {Mechanisms of ageing and development},
volume = {124},
number = {4},
pages = {403-408},
doi = {10.1016/s0047-6374(03)00015-0},
pmid = {12714246},
issn = {0047-6374},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*immunology/*metabolism ; Flow Cytometry ; Humans ; In Situ Hybridization, Fluorescence ; Killer Cells, Natural/*enzymology ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are repeats of TTAGGG sequences located at the end of eukaryotic chromosomes. They are essential for stabilisation and protection of chromosomal ends and for the regulation of cell replicative capacity. Due to the end-replication defect of DNA polymerase, telomeres shorten progressively with each cell division and telomere length may be an indicator of the replicative history of a cell. Compensatory mechanisms for the telomere loss have been identified. The most widely studied one is mediated by telomerase a ribonuclear protein-enzyme complex that synthesise telomeric repeats. In this study we have investigated whether NK cells, derived from a group of old healthy subjects, underwent the modifications of telomere length and telomerase activity observed in other sub-populations of lymphocytes with advancing age. We demonstrated that: (a) telomere shortening occurred and telomerase activity decreased in human NK cells with ageing; (b) the rate of telomere loss was different under and over 80 years of age; (c) similarly to telomere shortening, the modification of telomerase activity was particularly evident in octogenarians; (d) subjects with the most evident modifications of telomeres and telomerase were the oldest and those with increased NK cell numbers.},
}
@article {pmid12713535,
year = {2003},
author = {Sykorova, E and Lim, KY and Chase, MW and Knapp, S and Leitch, IJ and Leitch, AR and Fajkus, J},
title = {The absence of Arabidopsis-type telomeres in Cestrum and closely related genera Vestia and Sessea (Solanaceae): first evidence from eudicots.},
journal = {The Plant journal : for cell and molecular biology},
volume = {34},
number = {3},
pages = {283-291},
doi = {10.1046/j.1365-313x.2003.01731.x},
pmid = {12713535},
issn = {0960-7412},
mesh = {Arabidopsis/genetics ; Base Sequence ; Cestrum/genetics ; Chromosomes, Plant/*genetics ; DNA, Plant/genetics ; Genomic Library ; In Situ Hybridization, Fluorescence ; Phylogeny ; Polymerase Chain Reaction ; Sequence Deletion ; Solanaceae/*genetics ; Telomere/*genetics ; },
abstract = {Using slot-blot and fluorescent in situ hybridization (FISH), we found no evidence for the presence of the Arabidopsis-type telomeric sequence (TTTAGGG)n at the chromosome termini in any of the Cestrum species we investigated. Probing for the human-type telomere (TTAGGG)n also revealed no signal. However, polymerase chain reaction experiments indicated that there are short lengths of the sequence TTTAGGG dispersed in the genome but that these sequences are almost certainly too short to act as functional telomeres even if they were at the chromosome termini. An analysis of related genera Vestia and Sessea indicates that they too lack the Arabidopsis-type telomere, and the sequences were lost in the common ancestor of these genera. We found that the Cestrum species investigated had particularly large mean chromosome sizes. We discuss whether this is a consequence of alternative telomere end maintenance systems.},
}
@article {pmid12711471,
year = {2003},
author = {Counter, CM and Press, W and Compton, CC},
title = {Telomere shortening in cultured autografts of patients with burns.},
journal = {Lancet (London, England)},
volume = {361},
number = {9366},
pages = {1345-1346},
doi = {10.1016/S0140-6736(03)13042-5},
pmid = {12711471},
issn = {0140-6736},
support = {CA82481/CA/NCI NIH HHS/United States ; R01-35242//PHS HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Burns/pathology/*surgery ; Cell Division/genetics/*physiology ; Cellular Senescence/genetics/*physiology ; Child ; Child, Preschool ; DNA Damage/genetics/physiology ; Female ; Graft Survival/genetics/physiology ; Humans ; Male ; Prognosis ; Reference Values ; *Skin Transplantation/pathology ; Telomere/*diagnostic imaging/genetics ; *Tissue Engineering ; Ultrasonography ; Wound Healing/genetics/physiology ; },
abstract = {In extensive third-degree burns, donor sites for conventional split thickness skin grafts are limited. In such cases, cultured epithelial (keratinocyte) grafts are prepared from small samples of the patient's own skin and expanded in tissue culture, a process that may incur very many cell divisions. Telomeres shorten with each cell division, and are markers of cellular proliferative history. We therefore measured telomere length in healed cultured epithelial autografts from four patients with burns, and noted that their telomeres were shorter than those in non-cultured skin from the same individuals, and than those in skin of healthy donors older than 80 years. Such great loss of telomeric DNA suggests that engrafted cells might have a shortened lifespan, which could have negative repercussions on the long-term viability of these grafts.},
}
@article {pmid12711463,
year = {2003},
author = {Navsaria, HA and Rugg, EL},
title = {Telomere shortening: significant for keratinocyte grafting?.},
journal = {Lancet (London, England)},
volume = {361},
number = {9366},
pages = {1316-1317},
doi = {10.1016/s0140-6736(03)13087-5},
pmid = {12711463},
issn = {0140-6736},
mesh = {Aged ; Aged, 80 and over ; Biopsy ; Burns/pathology/*surgery ; Cell Division/physiology ; Cellular Senescence/*physiology ; Humans ; Keratinocytes/pathology/*transplantation ; *Skin Transplantation/pathology ; Telomere/*ultrastructure ; *Tissue Engineering ; },
}
@article {pmid12709014,
year = {2003},
author = {Neuber, K and Schmidt, S and Mensch, A},
title = {Telomere length measurement and determination of immunosenescence-related markers (CD28, CD45RO, CD45RA, interferon-gamma and interleukin-4) in skin-homing T cells expressing the cutaneous lymphocyte antigen: indication of a non-ageing T-cell subset.},
journal = {Immunology},
volume = {109},
number = {1},
pages = {24-31},
pmid = {12709014},
issn = {0019-2805},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*immunology ; Antigens, Differentiation, T-Lymphocyte ; Antigens, Neoplasm ; CD28 Antigens/metabolism ; Cells, Cultured ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Interferon-gamma/metabolism ; Interleukin-4/metabolism ; Leukocyte Common Antigens/metabolism ; Lymphocyte Activation/immunology ; Male ; Membrane Glycoproteins/*metabolism ; Middle Aged ; Skin/*immunology ; T-Lymphocyte Subsets/*immunology/ultrastructure ; Telomere/*ultrastructure ; },
abstract = {The purpose of this study was to investigate the immunosenescence of skin-homing T cells expressing the cutaneous lymphocyte antigen (CLA). Peripheral blood lymphocytes from 72 healthy individuals (33 male and 39 female; median age 54 years; age-range: 18-94 years) were investigated. The expression of CD28, CD45RA and CD45RO, as well as intracellular interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) formation of CLA+ 'skin homing' T cells, was analysed. In addition, T cells were detected immunohistologically in skin specimens from 15 young and 15 old, healthy individuals. The relative telomere length (RTL) was measured by fluorescence in situ hybridization using flow cytometry (flow FISH). The total number of CLA+ T cells was found to remain constant with increasing age. In contrast to peripheral blood T cells (CD3+ CLA-), which showed significantly decreased CD28 and CD45RA expression in donors > 60 years of age, no age-related alterations of either CD28+ CLA+ T cells or CD45RA+ CLA+ T cells were observed. In the group of donors > 60 years of age, the proportion of intracellular IFN-gamma-producing CD3+ CLA- cells showed a significant increase, whereas the number of IFN-gamma- and IL-4-producing CLA+ T cells was not affected by age. After stimulation with phytohaemagglutinin (PHA) or staphylococcal enterotoxin B (SEB), CLA+ T cells from old donors did not show a reduced response compared with CLA+ T cells from young donors. Additionally, the counts of T cells in healthy skin from young and old adults were statistically not different. Furthermore, the RTL was significantly shortened in enriched CD45RO+ CLA- T cells from healthy old individuals, but not in aged CLA+ T cells. The present data suggest that CLA+ T cells might be a T-cell subpopulation which does not undergo immunosenescence. This may explain why the intensity of inflammatory skin reactions (e.g. psoriasis or eczema) seems to be independent of the patients' age.},
}
@article {pmid12707782,
year = {2003},
author = {Gorab, E},
title = {Reverse transcriptase-related proteins in telomeres and in certain chromosomal loci of Rhynchosciara (Diptera: Sciaridae).},
journal = {Chromosoma},
volume = {111},
number = {7},
pages = {445-454},
pmid = {12707782},
issn = {0009-5915},
mesh = {Animals ; Chromatin/metabolism ; Chromosomes/ultrastructure ; DNA/chemistry ; Diptera ; Drosophila ; Immunoblotting ; In Situ Hybridization ; RNA-Directed DNA Polymerase/*metabolism ; Salivary Glands/metabolism ; Telomere/*metabolism/ultrastructure ; },
abstract = {The localization of reverse transcriptase-related proteins in polytene chromosomes of dipterans was investigated using previously characterized antibodies to a recombinant polypeptide containing conserved motifs of insect reverse transcriptases. The immunoreactions were carried out with polytene chromosome squashes of eight sciarids, one chironomid and three Drosophila species. Telomeric staining was regularly observed on chromosomes of the sciarid Rhynchosciara americana under normal growth conditions. Five of eight chromosomal tips were labelled except for the heterochromatic ends that are occasionally found associated forming a chromocentre in the salivary gland. Reverse transcriptase-related proteins were detected at chromosomal tips of young larvae and remained bound to the telomeres throughout larval development. As in salivary gland chromosomes, five non-telocentric ends of the chromosomes from Malpighian tubules of R. americana appeared clearly stained with anti-reverse transcriptase. The occurrence of telomeric reverse transcriptase in R. americana correlates with the presence of RNA in addition to an unusual enrichment with homopolymeric dA/dT DNA associated with the telomeric heterochromatin. The antibodies also reacted with a few interstitial sites in chromosomes of four Rhynchosciara species, one band overlapping the histone gene locus of three species in the americana -like group. The results provide evidence for a reverse transcriptase-related protein as a constitutive component in telomeres of R. americana and also in certain interstitial loci of Rhynchosciara species in which RNA was immunologically detected in the form of RNA:DNA hybrids.},
}
@article {pmid12707781,
year = {2003},
author = {Lavoie, J and Bronsard, M and Lebel, M and Drouin, R},
title = {Mouse telomere analysis using an optimized primed in situ (PRINS) labeling technique.},
journal = {Chromosoma},
volume = {111},
number = {7},
pages = {438-444},
pmid = {12707781},
issn = {0009-5915},
mesh = {Animals ; Chromatids/ultrastructure ; Chromosomes/ultrastructure ; Fibroblasts/metabolism ; In Situ Hybridization, Fluorescence ; Mice ; Microscopy, Fluorescence ; Primed In Situ Labeling/*methods ; Repetitive Sequences, Nucleic Acid ; Telomere/*ultrastructure ; Temperature ; },
abstract = {Telomeres are chromosomal elements composed of variable numbers of a TTAGGG repeated DNA sequence required for genomic stability. Telomeric length is correlated with the number of copies of this repeated DNA sequence and is an important property relevant to telomeric function. Recently, it has been demonstrated that the length of the shortest telomere, not average telomeric length, is important for cell viability and chromosomal stability. Consequently, assays permitting assessment of telomeric length are important for the analysis of genomic instability disorders. The length of individual telomeres can be analyzed using the primed in situ (PRINS) labeling reaction, which produces a labeled copy of the telomeric DNA repeats in situ. In this study, we tested different variables to optimize the PRINS reaction to enable it to be applied to the detection of mouse telomeric DNA and the study of telomeric length. The specificity, efficiency and uniformity of staining were evaluated using digital fluorescence microscopy. Labeling efficiency is dependent upon the conditions used to denature the telomeric DNA and reaction duration. Staining uniformity is increased at higher annealing and elongation temperatures as well as when a fluorescently labeled nucleotide is incorporated during the elongation step. Our results also indicate that chromosomal background staining is observed when a fluorochrome-labeled nucleotide is used as opposed to a hapten-labeled nucleotide. From this study, we conclude that an optimized PRINS technique can be reliably employed to analyze mouse telomeres and, compared with the FISH (fluorescence in situ hybridization) technique, presents advantages including greater cost efficiency and reduced processing time. These advantages may encourage wider use of the PRINS technique for quantitative evaluation of the length of individual telomeres in situ.},
}
@article {pmid12702777,
year = {2003},
author = {Oh, H and Wang, SC and Prahash, A and Sano, M and Moravec, CS and Taffet, GE and Michael, LH and Youker, KA and Entman, ML and Schneider, MD},
title = {Telomere attrition and Chk2 activation in human heart failure.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {100},
number = {9},
pages = {5378-5383},
pmid = {12702777},
issn = {0027-8424},
mesh = {Animals ; Base Sequence ; Cardiac Output, Low/*genetics ; Checkpoint Kinase 2 ; DNA Primers ; Humans ; Mice ; Protein Kinases/genetics/*metabolism ; *Protein Serine-Threonine Kinases ; Rats ; Rats, Sprague-Dawley ; *Telomere ; },
abstract = {The "postmitotic" phenotype in adult cardiac muscle exhibits similarities to replicative senescence more generally and constitutes a barrier to effective restorative growth in heart disease. Telomere dysfunction is implicated in senescence and apoptotic signaling but its potential role in heart disorders is unknown. Here, we report that cardiac apoptosis in human heart failure is associated specifically with defective expression of the telomere repeat- binding factor TRF2, telomere shortening, and activation of the DNA damage checkpoint kinase, Chk2. In cultured cardiomyocytes, interference with either TRF2 function or expression triggered telomere erosion and apoptosis, indicating that cell death can occur via this pathway even in postmitotic, noncycling cells; conversely, exogenous TRF2 conferred protection from oxidative stress. In vivo, mechanical stress was sufficient to down-regulate TRF2, shorten telomeres, and activate Chk2 in mouse myocardium, and transgenic expression of telomerase reverse transcriptase conferred protection from all three responses. Together, these data suggest that apoptosis in chronic heart failure is mediated in part by telomere dysfunction and suggest an essential role for TRF2 even in postmitotic cells.},
}
@article {pmid12702558,
year = {2003},
author = {Ulaner, GA and Huang, HY and Otero, J and Zhao, Z and Ben-Porat, L and Satagopan, JM and Gorlick, R and Meyers, P and Healey, JH and Huvos, AG and Hoffman, AR and Ladanyi, M},
title = {Absence of a telomere maintenance mechanism as a favorable prognostic factor in patients with osteosarcoma.},
journal = {Cancer research},
volume = {63},
number = {8},
pages = {1759-1763},
pmid = {12702558},
issn = {0008-5472},
support = {DK07217/DK/NIDDK NIH HHS/United States ; },
mesh = {Adult ; Age Factors ; Bone Neoplasms/enzymology/*genetics ; DNA-Binding Proteins ; Female ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Osteosarcoma/enzymology/*genetics ; Prognosis ; Reverse Transcriptase Polymerase Chain Reaction ; Survival Analysis ; Telomerase/biosynthesis/genetics/metabolism ; Telomere/*genetics ; },
abstract = {There are two telomere maintenance mechanisms (TMMs) in human tumors, telomerase activation (TA) and, more rarely, the process termed alternative lengthening of telomeres (ALT). Unlike most carcinomas, sarcomas, including osteosarcomas (OS), have been reported to display TA and ALT in more balanced proportions and, thus, present an opportunity to examine the impact of different TMMs on clinical tumor behavior. We studied OS samples from 62 patients for molecular evidence of TA and ALT. Kaplan-Meier analysis demonstrated that the absence of both TA and ALT (in 18%) was more strongly associated with improved survival (P = 0.05) than were stage (P = 0.16) or chemotherapy response (P = 0.18) in this group of patients with OS. Subsets of OS cases with either TA or ALT did not differ significantly from each other in clinical outcome. There were no significant associations of presence, absence, or type of TMM with patient age, stage, or chemotherapy response. Thus, the absence of a detectable TMM may identify a favorable clinical subset of OS patients. Our study also suggests that the likelihood of detecting correlations between TMMs and clinical outcome in studies of certain other tumor types might be improved if, in addition to TA, ALT is included in future analyses. Finally, we note that OS cases with a TA-/ALT+ phenotype seem to be as clinically aggressive as TA+ cases in terms of stage and clinical outcome.},
}
@article {pmid12697823,
year = {2003},
author = {Armbruster, BN and Etheridge, KT and Broccoli, D and Counter, CM},
title = {Putative telomere-recruiting domain in the catalytic subunit of human telomerase.},
journal = {Molecular and cellular biology},
volume = {23},
number = {9},
pages = {3237-3246},
pmid = {12697823},
issn = {0270-7306},
support = {R01 CA082481/CA/NCI NIH HHS/United States ; CA82481/CA/NCI NIH HHS/United States ; },
mesh = {*Catalytic Domain ; Cell Line, Transformed ; Cells, Cultured ; DNA/metabolism ; DNA-Binding Proteins ; Humans ; Mutation ; Protein Structure, Tertiary/physiology ; Recombinant Fusion Proteins/genetics/metabolism ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; },
abstract = {Telomerase, the enzyme that elongates telomeres, is essential to maintain telomere length and to immortalize most cancer cells. However, little is known about the regulation of this enzyme in higher eukaryotes. We previously described a domain in the hTERT telomerase catalytic subunit that is essential for telomere elongation and cell immortalization in vivo but dispensable for catalytic activity in vitro. Here, we show that fusions of hTERT containing different mutations in this domain to the telomere binding protein hTRF2 redirected the mutated hTERT to telomeres and rescued its in vivo functions. We suggest that this domain posttranscriptionally regulates telomerase function by targeting the enzyme to telomeres.},
}
@article {pmid12697806,
year = {2003},
author = {Dahlén, M and Sunnerhagen, P and Wang, TS},
title = {Replication proteins influence the maintenance of telomere length and telomerase protein stability.},
journal = {Molecular and cellular biology},
volume = {23},
number = {9},
pages = {3031-3042},
pmid = {12697806},
issn = {0270-7306},
mesh = {Catalytic Domain ; DNA Polymerase I/genetics/*metabolism ; DNA Primase/genetics/metabolism ; DNA Replication/*physiology ; DNA-Binding Proteins ; Enzyme Stability ; Gene Expression Regulation, Fungal ; Gene Silencing ; Genes, myc ; Macromolecular Substances ; Mutation ; Schizosaccharomyces ; Schizosaccharomyces pombe Proteins/genetics/metabolism ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {We investigated the effects of fission yeast replication genes on telomere length maintenance and identified 20 mutant alleles that confer lengthening or shortening of telomeres. The telomere elongation was telomerase dependent in the replication mutants analyzed. Furthermore, the telomerase catalytic subunit, Trt1, and the principal initiation and lagging-strand synthesis DNA polymerase, Polalpha, were reciprocally coimmunoprecipitated, indicating these proteins physically coexist as a complex in vivo. In a polalpha mutant that exhibited abnormal telomere lengthening and slightly reduced telomere position effect, the cellular level of the Trt1 protein was significantly lower and the coimmunoprecipitation of Trt1 and Polalpha was severely compromised compared to those in the wild-type polalpha cells. Interestingly, ectopic expression of wild-type polalpha in this polalpha mutant restored the cellular Trt1 protein to the wild-type level and shortened the telomeres to near-wild-type length. These results suggest that there is a close physical relationship between the replication and telomerase complexes. Thus, mutation of a component of the replication complex can affect the telomeric complex in maintaining both telomere length equilibrium and telomerase protein stability.},
}
@article {pmid12694903,
year = {2003},
author = {Ravin, NV},
title = {Mechanisms of replication and telomere resolution of the linear plasmid prophage N15.},
journal = {FEMS microbiology letters},
volume = {221},
number = {1},
pages = {1-6},
doi = {10.1016/S0378-1097(03)00125-3},
pmid = {12694903},
issn = {0378-1097},
mesh = {Coliphages/*genetics ; *DNA Replication ; DNA, Viral/metabolism ; Escherichia coli/virology ; Plasmids/*genetics ; Prophages/*genetics ; Telomere/genetics/*metabolism ; },
abstract = {The prophage of coliphage N15 is not integrated into the bacterial chromosome but exists as a linear plasmid molecule with covalently closed ends. Upon infection of an Escherichia coli cell, the phage DNA circularizes via cohensive ends. A phage-encoded enzyme, protelomerase, then cuts at another site, telRL, and forms hairpin ends (telomeres). Purified protelomerase alone processes circular and linear plasmid DNA containing the target site telRL to produce linear double-stranded DNA with covalently closed ends in vitro. N15 protelomerase is necessary for replication of the linear prophage through its action as a telomere-resolving enzyme. Replication of circular N15-based miniplasmids requires the only gene repA that encodes multidomain protein homologous to replication proteins of bacterial plasmids replicated by theta-mechanism, particularly, phage P4 alpha-replication protein. Replication of the N15 prophage is initiated at an internal ori site located within repA. Bidirectional replication results in formation of the circular head-to-head, tail-to-tail dimer molecule. Then the N15 protelomerase cuts both duplicated telomeres generating two linear plasmid molecules with covalently closed ends. The N15 prophage replication thus appears to follow the mechanism distinct from that employed by poxviruses and could serve as a model for other prokaryotic replicons with hairpin ends, and particularly, for linear plasmids and chromosomes of Borrelia burgdorferi.},
}
@article {pmid12688272,
year = {2003},
author = {DePinho, RA and Wong, KK},
title = {The age of cancer: telomeres, checkpoints, and longevity.},
journal = {The Journal of clinical investigation},
volume = {111},
number = {7},
pages = {S9-14},
pmid = {12688272},
issn = {0021-9738},
mesh = {Adolescent ; Adult ; Animals ; Child ; Humans ; Inflammation ; Mice ; Middle Aged ; Models, Biological ; Neoplasms/*genetics/*pathology ; *Telomere ; },
}
@article {pmid12682905,
year = {2003},
author = {Zhou, XZ and Perrem, K and Lu, KP},
title = {Role of Pin2/TRF1 in telomere maintenance and cell cycle control.},
journal = {Journal of cellular biochemistry},
volume = {89},
number = {1},
pages = {19-37},
doi = {10.1002/jcb.10496},
pmid = {12682905},
issn = {0730-2312},
support = {R01AG17870/AG/NIA NIH HHS/United States ; R01GM56230/GM/NIGMS NIH HHS/United States ; R01GM58556/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Antigens, Nuclear/metabolism ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle/*physiology ; Cell Cycle Proteins/metabolism ; DNA Damage ; *DNA Helicases ; DNA-Binding Proteins/metabolism ; Humans ; Ku Autoantigen ; Models, Biological ; Molecular Sequence Data ; Molecular Structure ; Nuclear Proteins/metabolism ; Protein Serine-Threonine Kinases/metabolism ; RNA, Messenger/genetics/metabolism ; Subcellular Fractions/metabolism ; Telomerase/metabolism ; Telomere/*physiology ; Telomeric Repeat Binding Protein 1/chemistry/genetics/*physiology ; Tumor Suppressor Proteins ; },
abstract = {Telomeres are specialized structures found at the extreme ends of chromosomes, which have many functions, including preserving genomic stability, maintaining cell proliferative capacity, and blocking the activation of DNA-damage cell cycle checkpoints. Deregulation of telomere length has been implicated in cancer and ageing. Telomere maintenance is tightly regulated by telomerase and many other telomere-associated proteins and is also closely linked to cell cycle control, especially mitotic regulation. However, little is known about the identity and function of the signaling molecules connecting telomere maintenance and cell cycle control. Pin2/TRF1 was originally identified as a protein bound to telomeric DNA (TRF1) and as a protein involved in mitotic regulation (Pin2). Pin2/TRF1 negatively regulates telomere length and importantly, its function is tightly regulated during the cell cycle, acting as an important regulator of mitosis. Recent identification of many Pin2/TRF1 upstream regulators and downstream targets has provided important clues to understanding the dual roles of Pin2/TRF1 in telomere maintenance and cell cycle control. These results have led us to propose that Pin2/TRF1 functions as a key molecule in connecting telomere maintenance and cell cycle control.},
}
@article {pmid12686062,
year = {2003},
author = {Campbell, K},
title = {Telomere length and mortality.},
journal = {Lancet (London, England)},
volume = {361},
number = {9364},
pages = {1224},
doi = {10.1016/S0140-6736(03)12930-3},
pmid = {12686062},
issn = {0140-6736},
mesh = {Humans ; Middle Aged ; Models, Biological ; *Mortality ; Telomere/*physiology ; },
}
@article {pmid12686061,
year = {2003},
author = {Howard, CV and Staats de Yanés, G},
title = {Telomere length and mortality.},
journal = {Lancet (London, England)},
volume = {361},
number = {9364},
pages = {1224},
doi = {10.1016/s0140-6736(03)12929-7},
pmid = {12686061},
issn = {0140-6736},
mesh = {Humans ; Male ; Neoplasms/etiology/*genetics/mortality ; Telomere/*genetics ; Testicular Diseases/complications/genetics ; },
}
@article {pmid12684424,
year = {2003},
author = {Sashida, G and Ohyashiki, JH and Nakajima, A and Sumi, M and Kawakubo, K and Tauchi, T and Ohyashiki, K},
title = {Telomere dynamics in myelodysplastic syndrome determined by telomere measurement of marrow metaphases.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {9},
number = {4},
pages = {1489-1496},
pmid = {12684424},
issn = {1078-0432},
mesh = {Adult ; Aged ; Aged, 80 and over ; Blotting, Southern ; Bone Marrow/*metabolism ; Case-Control Studies ; DNA/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; K562 Cells ; Karyotyping ; Metaphase ; Middle Aged ; Myelodysplastic Syndromes/*genetics ; Telomere/*ultrastructure ; Time Factors ; },
abstract = {Myelodysplastic syndrome (MDS), which is known to be a preleukemic state, is a heterogeneous entity characterized by ineffective hematopoiesis and dysplastic morphological features. Most MDS patients show erosive telomeric repeats (TTAGGG)(n), without up-regulation of telomerase activity, suggesting that telomere shortening may be linked to cellular senescence in MDS. We measured telomere length in samples from 13 MDS patients and 8 healthy volunteers, based on telomere signals of individual chromosomes, using digital images of metaphases after quantitative fluorescence in situ hybridization (Q-FISH) with peptide nucleic acid probes and compared the results with results obtained with the standard method of determining terminal restriction fragment (TRF) length. In healthy volunteers, we found a significant correlation between TRF length and telomere fluorescence signals detected by Q-FISH, and a relatively wide distribution of fluorescence telomere signals was demonstrated in every sample. In contrast, we found no linear correlation between TRF length and telomere fluorescence signals in MDS, and most MDS patients showed weak telomere fluorescence signals, corresponding to short telomeres, with a narrow range compared with normal subjects. TRF length represented telomere DNA in whole marrow cells, whereas telomere fluorescence signals by Q-FISH represented only marrow metaphases corresponding to MDS-derived cells. Metaphases from most MDS patients showed homogeneous telomere shortening, irrespective of the presence of cytogenetic abnormality. In contrast, marrow metaphases from normal individuals showed a relatively wide range of telomere signals in each metaphase, indicating that in MDS cells, telomere shortening mechanisms that normally exist might be dysregulated. Therefore, analysis of telomere distribution as well as average telomere length detected by Q-FISH might be useful to clarify the telomere dynamics of MDS cells.},
}
@article {pmid12678729,
year = {2002},
author = {Mills, M and Lacroix, L and Arimondo, PB and Leroy, JL and François, JC and Klump, H and Mergny, JL},
title = {Unusual DNA conformations: implications for telomeres.},
journal = {Current medicinal chemistry. Anti-cancer agents},
volume = {2},
number = {5},
pages = {627-644},
doi = {10.2174/1568011023353877},
pmid = {12678729},
issn = {1568-0118},
mesh = {Animals ; Antineoplastic Agents/chemistry/pharmacology/therapeutic use ; DNA/*chemistry/therapeutic use ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Nucleic Acid Conformation ; Oligonucleotides/chemistry/pharmacology/*therapeutic use ; Telomere/*drug effects ; },
abstract = {DNA is prone to structural polymorphism: its three-dimensional structure can differ markedly from the classical double helix. Nucleic acid structures composed of more than two strands have also been observed. The guanine-rich sequence of both the telomere and centromere can form a quadruplex based on G-quartets while the complementary cytosine-rich strand can fold into an intercalated tetramer called the i-motif. The G-quartet is a gold mine for structural biologists and the telomere has become a target for anti-cancer drug design since it was observed that deregulation of telomerase favors proliferation of certain tumors. Other DNA sequences may adopt unusual conformations. Polypurine-polypyrimidine sequences capable of forming a triple-stranded structure called H-DNA are found abundantly in the eukaryotic genome and may play a significant role in DNA metabolism, transcription and replication. Triplex-forming oligonucleotides are currently being developed as "anti-gene" agents. Unusual DNA structures may therefore be implicated in fundamental processes such as gene expression and represent unique targets for both structural-specific and sequence-specific agents. In this review, we present work characterizing some of these unusual conformations in terms of structure, stability and formation kinetics and discuss their biological implications.},
}
@article {pmid12676566,
year = {2003},
author = {Kim, SH and Parrinello, S and Kim, J and Campisi, J},
title = {Mus musculus and Mus spretus homologues of the human telomere-associated protein TIN2.},
journal = {Genomics},
volume = {81},
number = {4},
pages = {422-432},
doi = {10.1016/s0888-7543(02)00033-2},
pmid = {12676566},
issn = {0888-7543},
support = {AF09909/AF/ACF HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Blotting, Northern ; Blotting, Western ; Chromosome Mapping ; Humans ; Mice/*genetics ; Molecular Sequence Data ; Muridae/*genetics ; Precipitin Tests ; Telomere-Binding Proteins/*genetics ; },
abstract = {Telomere length is regulated by TRF1, which binds telomeric DNA, and TIN2, which binds TRF1. Laboratory mice (Mus musculus) have long telomeres, although a related mouse species, Mus spretus, has human-sized telomeres. Because differences in TIN2 might explain these differences in telomere length, we cloned cDNAs encoding murine TIN2s and compared their sequence to that of human TIN2. M. musculus (Mm) and M. spretus TIN2s were >95% identical, but shared only 67% identity with human TIN2. An N-terminal truncation, or N-terminal fragment, of MmTIN2 elongated M. spretus telomeres. These findings suggest that mouse TIN2, like human TIN2, negatively regulates telomere length, and that N-terminal perturbations have dominant-negative effects. Our findings suggest that differences in TIN2 cannot explain the telomere length differences among Homo sapiens, M. musculus, and M. spretus. Nonetheless, M. spretus cells appear be a good system for studying the function of mouse telomere-associated proteins.},
}
@article {pmid12676088,
year = {2003},
author = {Beernink, HT and Miller, K and Deshpande, A and Bucher, P and Cooper, JP},
title = {Telomere maintenance in fission yeast requires an Est1 ortholog.},
journal = {Current biology : CB},
volume = {13},
number = {7},
pages = {575-580},
doi = {10.1016/s0960-9822(03)00169-6},
pmid = {12676088},
issn = {0960-9822},
mesh = {Animals ; Blotting, Southern ; Chromosome Mapping ; Chromosomes, Fungal/genetics/metabolism ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Schizosaccharomyces/*genetics/metabolism ; Schizosaccharomyces pombe Proteins/*genetics ; Sequence Alignment ; Telomerase/*genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomerase regulation is critical to genome maintenance yet remains poorly understood. Without telomerase's ability to synthesize telomere repeats, chromosome ends shorten progressively, as conventional DNA polymerases cannot fully replicate the ends of linear molecules. In Saccharomyces cerevisiae, telomerase activity in vivo absolutely depends on a set of telomerase accessory proteins that includes Est1p, which appears to recruit or activate telomerase at the site of polymerization. Thus, est1Delta cells have the same cellular senescence phenotype as cells lacking either the catalytic protein subunit of telomerase or its template-containing RNA subunit. While the telomerase protein is highly conserved among eukaryotes, the apparent lack of Est1p homologs has frustrated efforts to describe a common mechanism of telomerase recruitment and activation. Here, we describe SpEst1p, a homolog of Est1p from the evolutionarily distant Schizosaccharomyces pombe. Like ScEst1p, SpEst1p is required for telomerase activity in vivo. Coupled with the identification of an orthologous Est1 protein in humans [10], this suggests a much wider conservation of telomerase regulation than was previously known. Strikingly, in cells with compromised telomere function (taz1Delta), SpEst1p loss confers a lethal germination phenotype, while telomerase loss does not, indicating that SpEst1p plays an unexpected additional role in chromosome end protection.},
}
@article {pmid12673203,
year = {2003},
author = {Vukovic, B and Park, PC and Al-Maghrabi, J and Beheshti, B and Sweet, J and Evans, A and Trachtenberg, J and Squire, J},
title = {Evidence of multifocality of telomere erosion in high-grade prostatic intraepithelial neoplasia (HPIN) and concurrent carcinoma.},
journal = {Oncogene},
volume = {22},
number = {13},
pages = {1978-1987},
doi = {10.1038/sj.onc.1206227},
pmid = {12673203},
issn = {0950-9232},
mesh = {Adenocarcinoma/chemistry/*genetics/ultrastructure ; Aged ; Aging/genetics ; Aneuploidy ; Cell Transformation, Neoplastic/genetics ; Chromosome Aberrations ; Disease Progression ; Humans ; Image Processing, Computer-Assisted ; Immunoenzyme Techniques ; In Situ Hybridization, Fluorescence ; Interphase ; Ki-67 Antigen/analysis ; Male ; Middle Aged ; Paraffin Embedding ; Prostatic Intraepithelial Neoplasia/chemistry/*genetics/ultrastructure ; Prostatic Neoplasms/chemistry/*genetics/ultrastructure ; Telomere/*ultrastructure ; Tumor Suppressor Protein p53/analysis ; },
abstract = {Mechanisms underlying prostate cancer (CaP) initiation and progression are poorly understood. A chromosomal instability mechanism leading to the generation of numerical and structural chromosomal changes has been implicated in the preneoplastic and neoplastic stages of CaP. Telomere dysfunction is one potential mechanism associated with the onset of such instability. To determine whether there was alteration in telomere length and chromosome number, 15 paraffin-embedded prostatectomy specimens were investigated using quantitative peptide nucleic acid (PNA) FISH analysis of representative foci of carcinoma, putative precancerous lesions (high-grade prostatic intraepithelial neoplasia, HPIN) and nondysplastic prostate epithelium. A significant decrease in telomere length was shown in both HPIN and CaP in comparison with normal epithelium. In addition, elevated rates of aneusomy suggested that increased levels of chromosomal aberrations were associated with decreased telomere length. Moreover, multiple foci of HPIN were shown to have a heterogeneous overall reduction of telomere length. This reduction was more evident in the histologic regions of the prostate containing CaP. Such observations lend support to the hypothesis that telomere erosion may be a consistent feature of CaP oncogenesis and may also be associated with the generation of chromosomal instability that characterizes this malignancy.},
}
@article {pmid12670948,
year = {2003},
author = {Jiang, N and Bénard, CY and Kébir, H and Shoubridge, EA and Hekimi, S},
title = {Human CLK2 links cell cycle progression, apoptosis, and telomere length regulation.},
journal = {The Journal of biological chemistry},
volume = {278},
number = {24},
pages = {21678-21684},
doi = {10.1074/jbc.M300286200},
pmid = {12670948},
issn = {0021-9258},
mesh = {*Apoptosis ; Cell Cycle ; Cell Division ; Cell Line ; Cytoplasm/metabolism ; DNA, Complementary/metabolism ; Evolution, Molecular ; Humans ; Immunoblotting ; Luciferases/metabolism ; Microscopy, Fluorescence ; Mutation ; Oxidative Stress ; Phenotype ; Plasmids/metabolism ; Protein Serine-Threonine Kinases/*metabolism/*physiology ; Protein-Tyrosine Kinases ; RNA, Small Interfering/metabolism ; Subcellular Fractions/metabolism ; *Telomere/metabolism ; Time Factors ; },
abstract = {Mutations in the clk-2 gene of the nematode Caenorhabditis elegans affect organismal features such as development, behavior, reproduction, and aging as well as cellular features such as the cell cycle, apoptosis, the DNA replication checkpoint, and telomere length. clk-2 encodes a novel protein (CLK-2) with a unique homologue in each of the sequenced eukaryotic genomes. We have studied the human homologue of CLK-2 (hCLK2) to determine whether it affects the same set of cellular features as CLK-2. We find that overexpression of hCLK2 decreases cell cycle length and that inhibition of hCLK2 expression arrests the cell cycle reversibly. Overexpression of hCLK2, however, renders the cell hypersensitive to apoptosis triggered by oxidative stress or DNA replication block and gradually increases telomere length. The evolutionary conservation of the pattern of cellular functions affected by CLK-2 suggests that the function of hCLK2 in humans might also affect the same organismal features as in worms, including life span. Surprisingly, we find that hCLK2 is present in all cellular compartments and exists as a membrane-associated as well as a soluble form.},
}
@article {pmid12667066,
year = {2003},
author = {Anderson, EM and Halsey, WA and Wuttke, DS},
title = {Site-directed mutagenesis reveals the thermodynamic requirements for single-stranded DNA recognition by the telomere-binding protein Cdc13.},
journal = {Biochemistry},
volume = {42},
number = {13},
pages = {3751-3758},
doi = {10.1021/bi027047c},
pmid = {12667066},
issn = {0006-2960},
support = {R01 GM059414/GM/NIGMS NIH HHS/United States ; GM59414/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites ; DNA, Fungal/chemistry/*metabolism ; DNA, Single-Stranded/chemistry/*metabolism ; Electrophoretic Mobility Shift Assay ; Ligands ; Models, Molecular ; *Mutagenesis, Site-Directed ; Protein Binding ; Protein Conformation ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; Substrate Specificity ; Telomere/*metabolism ; Telomere-Binding Proteins/chemistry/*metabolism ; Thermodynamics ; },
abstract = {The essential Saccharomyces cerevisiae protein Cdc13 binds the conserved single-stranded overhang at the end of telomeres and mediates access of protein complexes involved in both end-capping and telomerase activity. The single-stranded DNA-binding domain (ssDBD) of Cdc13 exhibits both high affinity (K(d) of 3 pM) and sequence specificity for the GT-rich sequences present at yeast telomeres. We have used the ssDBD of Cdc13 to understand the sequence-specific recognition of extended single-stranded DNA (ssDNA). The recent structure of the Cdc13 DNA-binding domain revealed that ssDNA is recognized by a large protein surface containing an oligonucleotide/oligosaccharide-binding fold (OB-fold) augmented by an extended 30-amino acid loop. Contacts to ssDNA occur via a contiguous surface of aromatic, hydrophobic, and basic residues. A complete alanine scan of the binding interface has been used to determine the contribution of each contacting side chain to binding affinity. Substitution of any aromatic or hydrophobic residue at the interface was deleterious to binding (20 to >700-fold decrease in binding affinity), while tolerance for replacement of basic residues was observed. The important aromatic and hydrophobic contacts are spread throughout the extended interface, indicating that the entire surface is both structurally and thermodynamically required for binding. While all of these contacts are important, several of the individual alanine substitutions that abolish binding cluster to one region of the protein surface. This region is vital for recognition of four bases at the 5' end of the DNA and constitutes a "hotspot" of binding affinity.},
}
@article {pmid12663456,
year = {2003},
author = {Allsopp, RC and Morin, GB and DePinho, R and Harley, CB and Weissman, IL},
title = {Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation.},
journal = {Blood},
volume = {102},
number = {2},
pages = {517-520},
doi = {10.1182/blood-2002-07-2334},
pmid = {12663456},
issn = {0006-4971},
support = {CA 42551/CA/NCI NIH HHS/United States ; DK 53074/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Cell Division ; Cell Survival ; DNA Replication ; DNA-Binding Proteins ; Graft Survival ; *Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/cytology/*enzymology/ultrastructure ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Knockout ; Telomerase/deficiency/genetics/*physiology ; Telomere/*ultrastructure ; },
abstract = {Telomere shortening ultimately limits the replicative life span of cultured human somatic cells. Telomeres also shorten during replicative aging in vivo in hematopoietic cells, including early hematopoietic progenitors and hematopoietic stem cells (HSCs), from humans and mice, despite readily detectable levels of telomerase in these cells. To assess the relevance of telomerase to the long-term replicative capacity of HSCs in vivo, we serially transplanted HSCs from wild-type and telomerase-deficient mice until exhaustion and monitored telomere length in HSCs during this process. Telomerase-deficient HSCs could be serially transplanted for only 2 rounds, whereas wild-type HSCs could be serially transplanted for at least 4 rounds. Furthermore, the rate of telomere shortening was increased approximately 2-fold during serial transplantation of telomerase-deficient HSCs. These findings suggest that one role for telomerase in the HSC is to partially counter the rate of telomere shortening during division of HSCs, thereby preventing premature loss of telomere function and providing added replicative capacity.},
}
@article {pmid12661010,
year = {2003},
author = {Deng, W and Tsao, SW and Guan, XY and Lucas, JN and Cheung, AL},
title = {Role of short telomeres in inducing preferential chromosomal aberrations in human ovarian surface epithelial cells: A combined telomere quantitative fluorescence in situ hybridization and whole-chromosome painting study.},
journal = {Genes, chromosomes &amp; cancer},
volume = {37},
number = {1},
pages = {92-97},
doi = {10.1002/gcc.10190},
pmid = {12661010},
issn = {1045-2257},
mesh = {Cell Line ; *Chromosome Aberrations ; Chromosome Painting/*methods/statistics &amp; numerical data ; Chromosomes, Human/genetics/physiology ; Epithelial Cells/*chemistry/*metabolism/pathology ; Female ; Humans ; In Situ Hybridization, Fluorescence/*methods/statistics &amp; numerical data ; Ovary/*pathology ; Telomere/genetics/metabolism/*physiology ; },
abstract = {It is well established that specific cancers and immortalized cells have nonrandom chromosome aberrations. However, little is understood about the underlying mechanism that initiates these aberrations in human cells. To examine whether human chromosomes with the shortest telomeres initiate the preferential chromosomal aberrations before cellular immortalization, we simultaneously applied telomere quantitative fluorescence in situ hybridization and specific whole-chromosome painting on chromosomes 1, 5, 8, 17, 19, and 20 in human ovarian surface epithelial (HOSE 6-3) cells expressing human papilloma viral oncogenes (HPV16 E6E7). The HPV16 E6E7-expressing cells, with extended in vitro life span and telomerase-negative status, were previously identified as having nonrandom chromosomal imbalances and high frequencies of dicentrics. Our analyses showed that among six pairs of targeted chromosomes, chromosomes 8 and 20 showed critically short telomeres with an undetectable telomere signal in more than 50% of cells analyzed. These chromosomes with the critically short telomeres were preferentially involved in various types of chromosomal aberrations including dicentrics, translocations, breaks, insertions, and losses or gains of chromosomal elements. Our findings suggest that nonrandom chromosome aberrations in HOSE cells occurring before cellular immortalization could be caused by the telomere length heterogeneity.},
}
@article {pmid12660175,
year = {2003},
author = {Brevet, V and Berthiau, AS and Civitelli, L and Donini, P and Schramke, V and Géli, V and Ascenzioni, F and Gilson, E},
title = {The number of vertebrate repeats can be regulated at yeast telomeres by Rap1-independent mechanisms.},
journal = {The EMBO journal},
volume = {22},
number = {7},
pages = {1697-1706},
pmid = {12660175},
issn = {0261-4189},
mesh = {Base Sequence ; DNA Primers ; Humans ; Plasmids ; Saccharomyces cerevisiae/genetics/*ultrastructure ; *Telomere ; rap1 GTP-Binding Proteins/*physiology ; },
abstract = {The number of telomeric DNA repeats at chromosome ends is maintained around a mean value by a dynamic balance between elongation and shortening. In particular, proteins binding along the duplex part of telomeric DNA set the number of repeats by progressively limiting telomere growth. The paradigm of this counting mechanism is the Rap1 protein in Saccharomyces cerevisiae. We demonstrate here that a Rap1-independent mechanism regulates the number of yeast telomeric repeats (TG(1-3)) and of vertebrate repeats (T(2)AG(3)) when TEL1, a yeast ortholog of the human gene encoding the ATM kinase, is inactivated. In addition, we show that a T(2)AG(3)-only telomere can be formed and maintained in humanized yeast cells carrying a template mutation of the gene encoding the telomerase RNA, which leads to the synthesis of vertebrate instead of yeast repeats. Genetic and biochemical evidences indicate that this telomere is regulated in a Rap1-independent manner, both in TEL1 and in tel1Delta humanized yeast cells. Altogether, these findings shed light on multiple repeat-counting mechanisms, which may share critical features between lower and higher eukaryotes.},
}
@article {pmid12660174,
year = {2003},
author = {Alexander, MK and Zakian, VA},
title = {Rap1p telomere association is not required for mitotic stability of a C(3)TA(2) telomere in yeast.},
journal = {The EMBO journal},
volume = {22},
number = {7},
pages = {1688-1696},
pmid = {12660174},
issn = {0261-4189},
support = {R01 GM043265/GM/NIGMS NIH HHS/United States ; T32 CA009528/CA/NCI NIH HHS/United States ; CA09528/CA/NCI NIH HHS/United States ; GM43265/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosome Deletion ; Chromosomes, Fungal ; DNA Primers ; DNA-Binding Proteins/metabolism ; Fluorescent Antibody Technique ; Genes, Fungal ; *Mitosis ; Protein Binding ; Saccharomyces cerevisiae/genetics/*ultrastructure ; Saccharomyces cerevisiae Proteins/metabolism ; *Telomere ; Telomere-Binding Proteins/metabolism ; Transcription Factors ; rap1 GTP-Binding Proteins/*metabolism ; },
abstract = {Telomeric DNA usually consists of a repetitive sequence: C(1-3)A/TG(1-3) in yeast, and C(3)TA(2)/T(2)AG(3) in vertebrates. In yeast, the sequence-specific DNA- binding protein Rap1p is thought to be essential for telomere function. In a tlc1h mutant, the templating region of the telomerase RNA gene is altered so that telomerase adds the vertebrate telomere sequence instead of the yeast sequence to the chromosome end. A tlc1h strain has short but stable telomeres and no growth defect. We show here that Rap1p and the Rap1p-associated Rif2p did not bind to a telomere that contains purely vertebrate repeats, while the TG(1-3) single-stranded DNA binding protein Cdc13p and the normally non-telomeric protein Tbf1p did bind this telomere. A chromosome with one entirely vertebrate-sequence telomere had a wild-type loss rate, and the telomere was maintained at a short but stable length. However, this telomere was unable to silence a telomere-adjacent URA3 gene, and the strain carrying this telomere had a severe defect in meiosis. We conclude that Rap1p localization to a C(3)TA(2) telomere is not required for its essential mitotic functions.},
}
@article {pmid12655399,
year = {2003},
author = {Gurevich, R and Smolikov, S and Maddar, H and Krauskopf, A},
title = {Mutant telomeres inhibit transcriptional silencing at native telomeres of the yeast Kluyveromyces lactis.},
journal = {Molecular genetics and genomics : MGG},
volume = {268},
number = {6},
pages = {729-738},
pmid = {12655399},
issn = {1617-4615},
mesh = {Base Sequence ; DNA, Fungal/genetics ; Fungal Proteins/genetics ; *Gene Silencing ; Genes, Fungal ; Kluyveromyces/*genetics ; *Mutation ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/genetics ; Shelterin Complex ; Telomere/*genetics ; Telomere-Binding Proteins/genetics ; Transcription Factors/genetics ; },
abstract = {We report the identification and characterization of transcriptional silencing at native telomeres in the budding yeast Kluyveromyces lactis. We show that K. lactis telomeres are able to repress the transcription of a gene located at the junction between the telomeric repeat tract and the subtelomeric domain. As in Saccharomyces cerevisiae, switching between the repressed and derepressed transcriptional states occurs. C-terminal truncation of the telomere binding protein Rap1p, which leads to a regulated alteration in telomere length, reduces telomeric silencing. In addition, telomeric silencing is reduced dramatically in telomerase RNA mutants in which telomere length control has been lost. This is consistent with the possibility that the structure of the entire telomere affects the silencing functions exhibited by its internal domain.},
}
@article {pmid12654541,
year = {2003},
author = {Goldman, MA},
title = {The role of telomeres and telomerase in cancer.},
journal = {Drug discovery today},
volume = {8},
number = {7},
pages = {294-296},
doi = {10.1016/s1359-6446(03)02625-4},
pmid = {12654541},
issn = {1359-6446},
mesh = {Adenoviridae/genetics ; Animals ; Antineoplastic Agents/therapeutic use ; Cancer Vaccines/therapeutic use ; Clinical Trials as Topic ; Enzyme Inhibitors/therapeutic use ; Genetic Therapy ; Humans ; Neoplasms/*enzymology/pathology/therapy ; Telomerase/antagonists &amp; inhibitors/immunology/*physiology ; Telomere/*physiology ; },
}
@article {pmid12651895,
year = {2003},
author = {Bao, K and Cohen, SN},
title = {Recruitment of terminal protein to the ends of Streptomyces linear plasmids and chromosomes by a novel telomere-binding protein essential for linear DNA replication.},
journal = {Genes &amp; development},
volume = {17},
number = {6},
pages = {774-785},
pmid = {12651895},
issn = {0890-9369},
support = {R01 AI008619/AI/NIAID NIH HHS/United States ; AI 08619/AI/NIAID NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Bacterial Proteins/*biosynthesis/metabolism ; Blotting, Western ; Chromosome Mapping ; Chromosomes/*ultrastructure ; DNA/metabolism ; *DNA Replication ; Genetic Complementation Test ; Molecular Sequence Data ; Oligonucleotide Array Sequence Analysis ; Open Reading Frames ; Plasmids ; Polymerase Chain Reaction ; Precipitin Tests ; Protein Binding ; Recombinant Fusion Proteins/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Sequence Homology, Amino Acid ; Streptomyces/*metabolism ; Telomere/ultrastructure ; Telomere-Binding Proteins/*biosynthesis/metabolism ; Two-Hybrid System Techniques ; },
abstract = {Bidirectional replication of Streptomyces linear plasmids and chromosomes from a central origin produces unpaired 3'-leading-strand overhangs at the telomeres of replication intermediates. Filling in of these overhangs leaves a terminal protein attached covalently to the 5' DNA ends of mature replicons. We report here the essential role of a novel 80-kD DNA-binding protein (telomere-associated protein, Tap) in this process. Biochemical studies, yeast two-hybrid analysis, and immunoprecipitation/immunodepletion experiments indicate that Tap binds tightly to specific sequences in 3' overhangs and also interacts with Tpg, bringing Tpg to telomere termini. Using DNA microarrays to analyze the chromosomes of tap mutant bacteria, we demonstrate that survivors of Tap ablation undergo telomere deletion, chromosome circularization, and amplification of subtelomeric DNA. Microarray-based chromosome mapping at single-ORF resolution revealed common endpoints for independent deletions, identified amplified chromosomal ORFs adjacent to these endpoints, and quantified the copy number of these ORFs. Sequence analysis confirmed chromosome circularization and revealed the insertion of adventitious DNA between joined chromosome ends. Our results show that Tap is required for linear DNA replication in Streptomyces and suggest that it functions to recruit and position Tpg at the telomeres of replication intermediates. They also identify hotspots for the telomeric deletions and subtelomeric DNA amplifications that accompany chromosome circularization.},
}
@article {pmid12651622,
year = {2003},
author = {Joosten, SA and van Ham, V and Nolan, CE and Borrias, MC and Jardine, AG and Shiels, PG and van Kooten, C and Paul, LC},
title = {Telomere shortening and cellular senescence in a model of chronic renal allograft rejection.},
journal = {The American journal of pathology},
volume = {162},
number = {4},
pages = {1305-1312},
pmid = {12651622},
issn = {0002-9440},
mesh = {Animals ; Cell Cycle/genetics ; Cellular Senescence/*genetics ; Chronic Disease ; Disease Models, Animal ; Graft Rejection/*genetics/pathology ; Ischemia ; Kidney ; Kidney Transplantation/*pathology ; Male ; Rats ; Rats, Inbred F344 ; Rats, Inbred Lew ; Reperfusion ; Telomere/*genetics ; Transplantation, Homologous ; Transplantation, Isogeneic ; },
abstract = {Cellular senescence has been suggested to play a role in the deterioration of renal graft function and has been linked to telomere shortening. We have investigated markers of cellular senescence in the F344 to LEW rat model of chronic renal transplant rejection. Syngeneic and LEW to F344 transplants were used as controls. Substantial telomere shortening was observed in all transplants, including allogeneic and syngeneic grafts from day 7 post-transplant onwards. Ischemia of native F344 kidneys was already sufficient to induce telomere shortening. It is known that shortened telomeres can activate cell cycle regulators, such as p21 and p16. Accordingly, all cases showed a transient p21 increase, with a maximum at day 7 and a sustained expression of p16. Importantly, senescence-associated beta-galactosidase staining, a cytological marker for senescence, was only observed in tubular epithelial cells of chronically rejecting F344 allografts from day 30 post-transplantation onwards. Long-term surviving LEW allografts or syngeneic F344 grafts were negative for senescence-associated beta-galactosidase. In conclusion, ischemia during transplantation results in telomere shortening and subsequent activation of p21 and p16, whereas senescence-associated beta-galactosidase staining is only present in chronically rejecting kidney grafts.},
}
@article {pmid12649083,
year = {2003},
author = {Brouilette, S and Singh, RK and Thompson, JR and Goodall, AH and Samani, NJ},
title = {White cell telomere length and risk of premature myocardial infarction.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {23},
number = {5},
pages = {842-846},
doi = {10.1161/01.ATV.0000067426.96344.32},
pmid = {12649083},
issn = {1524-4636},
mesh = {Adult ; Age of Onset ; Aging/*genetics ; Coronary Disease/epidemiology/genetics ; England/epidemiology ; Female ; Humans ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Myocardial Infarction/*epidemiology/genetics ; Retrospective Studies ; Risk ; Risk Factors ; Telomere/*ultrastructure ; },
abstract = {OBJECTIVE: Biological age may be distinct from chronological age and contribute to the pathogenesis of age-related diseases. Mean telomeres lengths provide an assessment of biological age with shorter telomeres, indicating increased biological age. We investigated whether subjects with premature myocardial infarction (MI) had shorter leukocyte telomeres.<br><br>METHODS AND RESULTS: Mean terminal restriction fragment (TRF) length, a measure of average telomere size, was compared in leukocyte DNA of 203 cases with a premature MI (<50 years) and 180 controls. Age- and sex-adjusted mean TRF length of cases was significantly shorter than that of controls (difference 299.7+/-69.3 base pairs, P<0.0001) and on average equivalent to controls 11.3 years older. The difference in mean TRF length between cases and controls was not accounted for by other coronary risk factors. Compared with subjects in the highest quartile for telomere length, the risk of myocardial infarction was increased between 2.8- and 3.2-fold (P<0.0001) in subjects with shorter than average telomeres.<br><br>CONCLUSIONS: The findings support the concept that biological age may play a role in the etiology of coronary heart disease and have potentially important implications for our understanding of its genetic etiology, pathogenesis, and variable age of onset.},
}
@article {pmid12648484,
year = {2003},
author = {Pfeifer, C and Scherthan, H and Thomsen, PD},
title = {Sex-specific telomere redistribution and synapsis initiation in cattle oogenesis.},
journal = {Developmental biology},
volume = {255},
number = {2},
pages = {206-215},
doi = {10.1016/s0012-1606(02)00093-3},
pmid = {12648484},
issn = {0012-1606},
mesh = {Animals ; Cattle ; Chromosome Pairing/genetics/physiology ; Female ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Male ; Meiosis/genetics/physiology ; Nuclear Proteins/metabolism ; Oogenesis/*genetics/physiology ; Pregnancy ; Sex Characteristics ; Spermatogenesis/genetics/physiology ; Synaptonemal Complex/genetics/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {The process of homolog pairing is well characterised in meiosis of male mammals, but much less information is available from female meiosis. We have therefore studied telomere dynamics by FISH and synapsis formation by immunostaining of synaptonemal complex proteins (SCP3, SCP1) on ovarian sections from 15 bovine fetuses, which covered the entire female prophase I. Telomeres displayed a dispersed intranuclear distribution in oogonia and relocated to the nuclear periphery during the preleptotene stage. Tight telomere clustering (bouquet formation) coincided with synapsis initiation at the leptotene/zygotene transition. Clustering of telomeres persisted during zygotene and even into the pachytene stage in a subset of nuclei, while it was absent in diplotene/dictyotene stage nuclei. Thus, the bouquet stage in the bovine female lasts significantly longer than in the male. Further, we observed that synapsis in the female initiated both terminally and interstitially in earliest zygotene stage oocytes, which contrasts with the predominantly terminal synapsis initiation in early zygotene spermatocytes of the bovine male. Altogether, our data disclose a sex-specific difference in telomere dynamics and synapsis initiation patterns in male and female bovine germ cells that may be related to the sex-specific differences in recombination rates observed in this and other mammalian species.},
}
@article {pmid12642053,
year = {2003},
author = {Hakin-Smith, V and Jellinek, DA and Levy, D and Carroll, T and Teo, M and Timperley, WR and McKay, MJ and Reddel, RR and Royds, JA},
title = {Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme.},
journal = {Lancet (London, England)},
volume = {361},
number = {9360},
pages = {836-838},
doi = {10.1016/s0140-6736(03)12681-5},
pmid = {12642053},
issn = {0140-6736},
mesh = {Adult ; Astrocytoma/*enzymology/mortality/pathology ; Glioblastoma/*enzymology/mortality/pathology ; Humans ; Middle Aged ; Phenotype ; Prognosis ; Survival Analysis ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {Despite advances in the molecular pathogenesis of glioblastoma multiforme, no reliable prognostic markers have been identified. We analysed telomerase activity and telomere lengths in glioblastoma multiformes from 77 patients. 19 patients (25%) had tumours with the alternative-lengthening-of-telomere (ALT) phenotype. Median survival for patients with this phenotype was 542 days (95% CI 114-970) compared with 247 days (224-270) for glioblastoma multiformes with normal telomeres (p=0.0003). Cox's regression analysis showed that this association is independent of age. In patients with non-ALT tumours, telomerase activity did not affect survival (median 287 [199-375] vs 236 [230-242] days, p=0.275). We conclude that ALT is a prognostic indicator for patients with glioblastoma multiforme.},
}
@article {pmid12640677,
year = {2003},
author = {Furuta, M and Nozawa, K and Takemura, M and Izuta, S and Murate, T and Tsuchiya, M and Yoshida, K and Taka, N and Nimura, Y and Yoshida, S},
title = {A novel platinum compound inhibits telomerase activity in vitro and reduces telomere length in a human hepatoma cell line.},
journal = {International journal of cancer},
volume = {104},
number = {6},
pages = {709-715},
doi = {10.1002/ijc.11022},
pmid = {12640677},
issn = {0020-7136},
mesh = {Animals ; Antineoplastic Agents/chemistry/*pharmacology ; Carcinoma, Hepatocellular/*metabolism/pathology ; Cattle ; Cellular Senescence/physiology ; DNA Primers/chemistry ; DNA, Neoplasm/metabolism ; DNA-Directed DNA Polymerase/metabolism ; Enzyme Inhibitors/chemistry/*pharmacology ; Humans ; In Vitro Techniques ; Inhibitory Concentration 50 ; Kinetics ; Liver Neoplasms/*metabolism/pathology ; Male ; Molecular Structure ; Nucleic Acid Synthesis Inhibitors ; Platinum Compounds/chemistry/*pharmacology ; Protein Binding ; Rats ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/*metabolism ; Tumor Cells, Cultured ; },
abstract = {Telomerase activity is detectable in most human tumors but not in most normal somatic cells or tissues. Telomerase inhibition has, therefore, been proposed as a novel and potentially selective strategy for antitumor therapy. In the present study, we found that platinum compounds, including cisplatin [cis-diamminedichloro-platinum (II)], strongly inhibited the activity of partially purified rat telomerase. Among the agents tested, 2,3-dibromosuccinato [2-(methylaminomethyl)pyridine]platinum (II) (compound E) exhibited the strongest inhibition, with an median inhibitory concentration (IC(50)) of 0.8 micro M. The mode of inhibition was noncompetitive with either dNTPs or TS (first) primer, with K(i) values estimated to be 2.3 or 3.9 micro M for varied TS primer or dNTPs, respectively. Notably, cisplatin also inhibited the telomerase activity, with an IC(50) of 2.0 micro M. Again, the mode of inhibition was noncompetitive, with K(i) values estimated as 7.3 or 8.1 micro M. Preincubation of TS primer with compound E did not affect the telomerase inhibition, whereas preincubation with cisplatin caused remarkable enhancement. Treatment of a human hepatoma cell line HepG2 with a low concentration of compound E gradually reduced the telomere length, indicating that this compound was able to inhibit telomerase in living cells as well as in vitro.},
}
@article {pmid12636233,
year = {2003},
author = {Obana, N and Takagi, S and Kinouchi, Y and Tokita, Y and Sekikawa, A and Takahashi, S and Hiwatashi, N and Oikawa, S and Shimosegawa, T},
title = {Telomere shortening of peripheral blood mononuclear cells in coronary disease patients with metabolic disorders.},
journal = {Internal medicine (Tokyo, Japan)},
volume = {42},
number = {2},
pages = {150-153},
doi = {10.2169/internalmedicine.42.150},
pmid = {12636233},
issn = {0918-2918},
mesh = {Aged ; Blotting, Southern ; Case-Control Studies ; Cellular Senescence/physiology ; Cohort Studies ; Coronary Disease/*etiology/physiopathology ; Diabetes Mellitus/etiology/physiopathology ; Female ; Humans ; Hypercholesterolemia/etiology/physiopathology ; Leukocytes, Mononuclear/*physiology ; Male ; Metabolic Diseases/*etiology/physiopathology ; Middle Aged ; Reference Values ; Sensitivity and Specificity ; Telomere/genetics/*ultrastructure ; },
abstract = {OBJECTIVE: Telomere shortening is correlated with cell turnover and aging, but it has been recently suggested to occur not only by aging but by several biochemical factors of metabolic disorders predisposing to atherosclerosis.<br><br>PATIENTS AND METHODS: We compared telomere length of peripheral blood mononuclear cells of patients with the metabolic disorders, hypercholesterolemia (HC) and diabetes mellitus (DM), according to the presence or absence of coronary diseases.<br><br>RESULTS: The results demonstrated that HC and/or DM patients with coronary diseases have significantly shorter telomere length than healthy controls (p = 0.0014).<br><br>CONCLUSION: Telomere shortening may be involved in the mechanisms that promote coronary diseases under some circumstances of metabolic disorders.},
}
@article {pmid12636228,
year = {2003},
author = {Yamada, N},
title = {Telomere shortening, atherosclerosis, and metabolic syndrome.},
journal = {Internal medicine (Tokyo, Japan)},
volume = {42},
number = {2},
pages = {135-136},
doi = {10.2169/internalmedicine.42.135},
pmid = {12636228},
issn = {0918-2918},
mesh = {Arteriosclerosis/complications/*genetics ; Diabetes Complications ; Diabetes Mellitus/genetics ; Female ; Humans ; Hypercholesterolemia/complications/genetics ; Male ; Metabolic Diseases/complications/*genetics ; Risk Assessment ; Sensitivity and Specificity ; Syndrome ; Telomere/*genetics/pathology ; },
}
@article {pmid12631718,
year = {2003},
author = {IJpma, AS and Greider, CW},
title = {Short telomeres induce a DNA damage response in Saccharomyces cerevisiae.},
journal = {Molecular biology of the cell},
volume = {14},
number = {3},
pages = {987-1001},
pmid = {12631718},
issn = {1059-1524},
support = {R01 GM043080/GM/NIGMS NIH HHS/United States ; GM43080/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle/*physiology ; Cell Cycle Proteins/genetics/metabolism ; Cell Division/physiology ; DNA Damage ; DNA-Binding Proteins/genetics/metabolism ; Intracellular Signaling Peptides and Proteins ; Protein Serine-Threonine Kinases ; Rad52 DNA Repair and Recombination Protein ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomerase-deficient Saccharomyces cerevisiae cells show a progressive decrease in telomere length. When grown for several days in log phase, the tlc1Delta cells initially display wild-type growth kinetics with subsequent loss of growth potential after which survivors are generated via RAD52-dependent homologous recombination. We found that chromosome loss in these telomerase-deficient cells only increased after a significant decline in growth potential of the culture. At earlier stages of growth, as the telomerase-deficient cells began to show loss of growth potential, the cells arrested in G2/M and showed RNR3 induction and Rad53p phosphorylation. These responses were dependent on RAD24 and MEC1, suggesting that short telomeres are recognized as DNA damage and signal G2/M arrest.},
}
@article {pmid12629597,
year = {2003},
author = {Zhang, A and Zheng, C and Hou, M and Lindvall, C and Li, KJ and Erlandsson, F and Björkholm, M and Gruber, A and Blennow, E and Xu, D},
title = {Deletion of the telomerase reverse transcriptase gene and haploinsufficiency of telomere maintenance in Cri du chat syndrome.},
journal = {American journal of human genetics},
volume = {72},
number = {4},
pages = {940-948},
pmid = {12629597},
issn = {0002-9297},
mesh = {Adolescent ; Child ; Child, Preschool ; Cri-du-Chat Syndrome/*genetics ; DNA-Binding Proteins ; Female ; *Gene Deletion ; Humans ; Infant ; Karyotyping ; Male ; Molecular Sequence Data ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {Cri du chat syndrome (CdCS) results from loss of the distal portion of chromosome 5p, where the telomerase reverse transcriptase (hTERT) gene is localized (5p15.33). hTERT is the rate-limiting component for telomerase activity that is essential for telomere-length maintenance and sustained cell proliferation. Here, we show that a concomitant deletion of the hTERT allele occurs in all 10 patients with CdCS whom we examined. Induction of hTERT mRNA in proliferating lymphocytes derived from five of seven patients was lower than that in unaffected control individuals (P<.05). The patient lymphocytes exhibited shorter telomeres than age-matched unaffected individuals (P<.0001). A reduction in replicative life span and a high rate of chromosome fusions were observed in cultured patient fibroblasts. Reconstitution of telomerase activity by ectopic expression of hTERT extended the telomere length, increased the population doublings, and prevented the end-to-end fusion of chromosomes. We conclude that hTERT is limiting and haploinsufficient for telomere maintenance in humans in vivo. Accordingly, the hTERT deletion may be one genetic element contributing to the phenotypic changes in CdCS.},
}
@article {pmid12626755,
year = {2003},
author = {Casacuberta, E and Pardue, ML},
title = {Transposon telomeres are widely distributed in the Drosophila genus: TART elements in the virilis group.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {100},
number = {6},
pages = {3363-3368},
pmid = {12626755},
issn = {0027-8424},
support = {R01 GM050315/GM/NIGMS NIH HHS/United States ; R56 GM050315/GM/NIGMS NIH HHS/United States ; GM 50315/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Chromosome Mapping ; DNA, Satellite/genetics ; Drosophila/classification/*genetics ; Drosophila melanogaster/genetics ; Evolution, Molecular ; Molecular Sequence Data ; Open Reading Frames ; Phylogeny ; Retroelements/*genetics ; Sequence Homology, Amino Acid ; Species Specificity ; Telomere/*genetics ; Time Factors ; Transcription, Genetic ; Trinucleotide Repeats ; },
abstract = {Telomeres of most animals, plants, and unicellular eukaryotes are made up of tandem arrays of repeated DNA sequences produced by the enzyme telomerase. Drosophila melanogaster has an unusual variation on this theme; telomeres consist of tandem arrays of sequences produced by successive transpositions of two non-LTR retrotransposons, HeT-A and TART. To explore the phylogenetic distribution of these variant telomeres, we have looked for TART homologues in a distantly related Drosophila species, virilis. We have found elements that, despite many differences in nucleotide sequence, retain significant amino acid similarity to TART from D. melanogaster. These D. virilis TART elements have features that characterize TART elements in D. melanogaster: (i) they are found in tandem arrays on chromosome ends, (ii) they are not found in euchromatin, and (iii) they produce both sense and antisense transcripts, with the antisense RNA being in excess. The D. virilis TART elements have one surprising feature: both of the ORFs contain long stretches of the trinucleotide repeat CAX, encoding polyglutamine (with a few interspersed histidines). These long polyglutamine stretches are conserved in the three D. virilis elements sequenced. They do not interrupt any domains of known function in the TART proteins and are not seen in TART proteins from other species. Comparison of the D. virilis and D. melanogaster telomeres suggests that the retrotransposon mechanism of telomere maintenance may have arisen before the separation of the genus Drosophila.},
}
@article {pmid12626701,
year = {2003},
author = {Redon, S and Bombard, S and Elizondo-Riojas, MA and Chottard, JC},
title = {Platinum cross-linking of adenines and guanines on the quadruplex structures of the AG3(T2AG3)3 and (T2AG3)4 human telomere sequences in Na+ and K+ solutions.},
journal = {Nucleic acids research},
volume = {31},
number = {6},
pages = {1605-1613},
pmid = {12626701},
issn = {1362-4962},
mesh = {Adenine/*chemistry ; Base Sequence ; Binding Sites ; Cross-Linking Reagents/chemistry ; Electrophoresis, Polyacrylamide Gel ; Guanine/*chemistry ; Humans ; Nucleic Acid Conformation/drug effects ; Oligonucleotides/chemistry/genetics/metabolism ; Platinum/*chemistry ; Potassium/*chemistry/pharmacology ; Repetitive Sequences, Nucleic Acid/drug effects/genetics ; Sodium/*chemistry/pharmacology ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Telomere/chemistry/*genetics ; },
abstract = {The quadruplex structures of the human telomere sequences AG3(T2AG3)3 I and (T2AG3)4 II were investigated in the presence of Na+ and K+ ions, through the cross-linking of adenines and guanines by the cis- and trans-[Pt(NH3)2(H2O)2](NO3)2 complexes 1 and 2. The bases involved in chelation of the cis- and trans-Pt(NH3)2 moieties were identified by chemical and 3'-exonuclease digestions of the products isolated after denaturing gel electrophoresis. These are the four adenines of each sequence and four out of the 12 guanines. Two largely different structures have been reported for I: A from NMR data in Na+ solution and B from X-ray data of a K+-containing crystal. Structure A alone agrees with our conclusions about the formation of the A1-G10, A13-G22, A1-A13 platinum chelates at the top of the quadruplex and A7-A19, G4-A19 and A7-G20 at the bottom, whether the Na+ or K+ ion is present. At variance with a recent proposal that structures A and B could be the major species in Na+ and K+ solutions, respectively, our results suggest that structure A exists predominantly in the presence of both ions. They also suggest that covalent platinum cross-linking of a human telomere sequence could be used to inhibit telomerase.},
}
@article {pmid12623835,
year = {2003},
author = {Karadimitris, A and Araten, DJ and Luzzatto, L and Notaro, R},
title = {Severe telomere shortening in patients with paroxysmal nocturnal hemoglobinuria affects both GPI- and GPI+ hematopoiesis.},
journal = {Blood},
volume = {102},
number = {2},
pages = {514-516},
doi = {10.1182/blood-2003-01-0128},
pmid = {12623835},
issn = {0006-4971},
support = {5R01 HL56778-03/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Cell Division ; Clone Cells/chemistry/ultrastructure ; Female ; Glycosylphosphatidylinositols/*deficiency/physiology ; Granulocytes/*ultrastructure ; Hematopoiesis/*genetics ; Hematopoietic Stem Cells/chemistry/*ultrastructure ; Hemoglobinuria, Paroxysmal/*genetics ; Humans ; Male ; Middle Aged ; Telomere/*ultrastructure ; },
abstract = {A most distinctive feature of paroxysmal nocturnal hemoglobinuria (PNH) is that in each patient glycosylphosphatidylinositol-negative (GPI-) and GPI+ hematopoietic stem cells (HSCs) coexist, and both contribute to hematopoiesis. Telomere size correlates inversely with the cell division history of HSCs. In 10 patients with hemolytic PNH the telomeres in sorted GPI- granulocytes were shorter than in sorted GPI+ granulocytes in 4 cases, comparable in 2 cases, and longer in the remaining 4 cases. Furthermore, the telomeres of both GPI- and GPI+ hematopoietic cells were markedly shortened compared with age-matched controls. The short telomeres in the GPI- cells probably reflect the large number of cell divisions required for the progeny of a single cell to contribute a large proportion of hematopoiesis. The short telomeres of the GPI+ cells indicate that the residual hematopoiesis contributed by these cells is not normal. This epigenetic change is an additional feature shared by PNH and aplastic anemia.},
}
@article {pmid12620220,
year = {2003},
author = {Miller, KM and Cooper, JP},
title = {The telomere protein Taz1 is required to prevent and repair genomic DNA breaks.},
journal = {Molecular cell},
volume = {11},
number = {2},
pages = {303-313},
doi = {10.1016/s1097-2765(03)00041-8},
pmid = {12620220},
issn = {1097-2765},
mesh = {Cell Cycle Proteins/genetics/metabolism ; Checkpoint Kinase 2 ; Cold Temperature ; DNA Damage ; DNA Repair/genetics/*physiology ; G2 Phase ; Genes, Fungal ; Mitosis ; Models, Biological ; Mutation ; Protein Kinases/genetics/metabolism ; S Phase ; Schizosaccharomyces/cytology/genetics/metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Telomere/metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {One fundamental function of telomeres is to prevent the ends of chromosomes from being sensed and treated as DNA damage. Here we present evidence for additional roles of telomeres in promoting proper chromosome segregation and DNA repair. We find that the fission yeast telomere protein Taz1p is required for cell cycle progression at 20 degrees C, a temperature at which taz1Delta cells exhibit a G(2)/M DNA damage checkpoint delay, chromosome missegregation, and DNA double-strand breaks (DSBs). Spindle assembly checkpoint components and a checkpoint-independent function of Rad3p are required for taz1Delta cells to survive at 20 degrees C. Disruption of topoisomerase II activity suppresses the cold sensitivity of taz1Delta cells, suggesting a scenario in which telomeric entanglement is the primary defect. Furthermore, hypersensitivity to treatments that induce DSBs suggests that Taz1p is involved in DSB repair. Our observations imply roles for Taz1p-containing telomeres in preventing and repairing DNA breaks throughout the genome.},
}
@article {pmid12618960,
year = {2003},
author = {Lin, JP and Cupples, LA and Wilson, PW and Heard-Costa, N and O'Donnell, CJ},
title = {Evidence for a gene influencing serum bilirubin on chromosome 2q telomere: a genomewide scan in the Framingham study.},
journal = {American journal of human genetics},
volume = {72},
number = {4},
pages = {1029-1034},
pmid = {12618960},
issn = {0002-9297},
mesh = {Adult ; Aspartate Aminotransferases/blood ; Bilirubin/*blood/*genetics ; Blood Pressure ; Chromosome Mapping ; Chromosomes, Human, Pair 2/*genetics ; Family ; Female ; Gene Frequency ; Genome, Human ; Glucuronosyltransferase/genetics ; Humans ; Lod Score ; Male ; Pedigree ; Siblings ; },
abstract = {There is an inverse relationship between serum bilirubin concentrations and risk of coronary artery disease. The strength of the association is similar to that of smoking, systolic blood pressure, and HDL cholesterol. We carried out a genomewide scan in a Framingham Heart Study. Our study sample consisted of 330 families with 1,394 sibling pairs, 681 cousin pairs, and 89 avuncular pairs. Using variance-component methods, the heritability was estimated to be 49%+/-6%, and the genome scan demonstrated significant evidence of linkage of serum bilirubin to chromosome 2q, with a LOD score of 3.8 at location 243 cM. The peak multipoint LOD score is located 1 cM away from the uridine diphosphate glycosyltransferase 1 (UGT1A1) gene. UGT1A1 catalyzes the conjugation of bilirubin with glucuronic acid and thus enhances bilirubin elimination; therefore, it is an important candidate gene for serum bilirubin. Gilbert syndrome, a hyperbilirubinemic syndrome, has a population frequency of 2%-19% and is mainly due to a TA insertion at the promoter region of UGT1A1. Only one other region in the genome produced a multipoint LOD score >1 (LOD = 1.3). Our findings suggest that UGT1A1 may be a major gene controlling serum bilirubin levels in the population.},
}
@article {pmid12615976,
year = {2003},
author = {Davis, T and Singhrao, SK and Wyllie, FS and Haughton, MF and Smith, PJ and Wiltshire, M and Wynford-Thomas, D and Jones, CJ and Faragher, RG and Kipling, D},
title = {Telomere-based proliferative lifespan barriers in Werner-syndrome fibroblasts involve both p53-dependent and p53-independent mechanisms.},
journal = {Journal of cell science},
volume = {116},
number = {Pt 7},
pages = {1349-1357},
doi = {10.1242/jcs.00331},
pmid = {12615976},
issn = {0021-9533},
mesh = {Aging/genetics/metabolism ; Antibodies/pharmacology ; Cell Division/genetics ; Cell Line ; Cellular Senescence/*genetics ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins/metabolism ; DNA/genetics ; *DNA-Binding Proteins ; Fibroblasts/*metabolism/pathology ; Genes, cdc/physiology ; Humans ; Longevity/genetics ; Mitosis/genetics ; Oncogene Proteins, Viral/metabolism ; Ploidies ; Retinoblastoma Protein/metabolism ; Signal Transduction/genetics ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Tumor Suppressor Protein p53/antagonists &amp; inhibitors/genetics/*metabolism ; Werner Syndrome/*genetics/metabolism/pathology ; },
abstract = {Werner-syndrome fibroblasts have a reduced in vitro life span before entering replicative senescence. Although this has been thought to be causal in the accelerated ageing of this disease, controversy remains as to whether Werner syndrome is showing the acceleration of a normal cellular ageing mechanism or the occurrence of a novel Werner-syndrome-specific process. Here, we analyse the signalling pathways responsible for senescence in Werner-syndrome fibroblasts. Cultured Werner-syndrome (AG05229) fibroblasts senesced after approximately 20 population doublings with most of the cells having a 2N content of DNA. This was associated with hypophosphorylated pRb and high levels of p16(Ink4a) and p21(Waf1). Senescent AG05229 cells re-entered the cell cycle following microinjection of a p53-neutralizing antibody. Similarly, production of the human papilloma virus 16 E6 oncoprotein in presenescent AG05229 cells resulted in senescence being bypassed and extended cellular life span. Werner-syndrome fibroblasts expressing E6 did not proliferate indefinitely but reached a second proliferative lifespan barrier, termed M(int), that could be bypassed by forced production of telomerase in post-M1 E6-producing cells. The conclusions from these studies are that: (1) replicative senescence in Werner-syndrome fibroblasts is a telomere-induced p53-dependent event; and (2) the intermediate lifespan barrier M(int) is also a telomere-induced event, although it appears to be independent of p53. Werner-syndrome fibroblasts resemble normal human fibroblasts for both these proliferative lifespan barriers, with the strong similarity between the signalling pathway linking telomeres to cell-cycle arrest in Werner-syndrome and normal fibroblasts providing further support for the defect in Werner syndrome causing the acceleration of a normal ageing mechanism.},
}
@article {pmid12615949,
year = {2003},
author = {Gallego, ME and Jalut, N and White, CI},
title = {Telomerase dependence of telomere lengthening in Ku80 mutant Arabidopsis.},
journal = {The Plant cell},
volume = {15},
number = {3},
pages = {782-789},
pmid = {12615949},
issn = {1040-4651},
mesh = {Adenosine Triphosphatases/metabolism ; Arabidopsis/enzymology/*genetics ; Arabidopsis Proteins/*genetics/metabolism ; Base Sequence ; DNA Helicases/*genetics/metabolism ; Gene Expression Regulation, Enzymologic ; Molecular Sequence Data ; Mutation ; Sequence Homology, Nucleic Acid ; Telomerase/*metabolism ; Telomere/*genetics/metabolism ; },
abstract = {We have identified a ku80 mutant of Arabidopsis and show that telomerase is needed to generate the longer telomeres observed in this mutant. Telomeres are specialized nucleoprotein structures at the ends of chromosomes that permit cells to distinguish chromosome ends from double-strand breaks, thus preventing chromosome fusion events. Ku80 deficiency results in the lengthening of telomeres, a phenotype also seen in an Arabidopsis ku70 mutant. Furthermore, homogeneous populations of ku80 mutant cells show a steady increase in the length of telomere tracts, which reach an equilibrium length and then stabilize. In contrast to that in mammals, Ku80 deficiency in Arabidopsis cells does not cause end-to-end fusion of chromosomes. This telomere lengthening is dependent on the presence of telomerase, although it is not attributable to a significant increase in telomerase activity per se. These results demonstrate the essential role of the Ku80 protein as a negative regulator of telomerase function in plant cells.},
}
@article {pmid12615525,
year = {2003},
author = {Sastry, PS and Parikh, P},
title = {The earlier age of onset of malignancy in developing world is related to overall infection burden and could be due to the effect on telomere length.},
journal = {Medical hypotheses},
volume = {60},
number = {4},
pages = {573-574},
doi = {10.1016/s0306-9877(03)00030-6},
pmid = {12615525},
issn = {0306-9877},
mesh = {Adolescent ; Adult ; Age of Onset ; Child ; Child, Preschool ; Female ; Humans ; Incidence ; Infant ; Infant, Newborn ; Infections ; Male ; Middle Aged ; Models, Theoretical ; Neoplasms/*diagnosis/*epidemiology ; Telomere/*ultrastructure ; },
abstract = {It is a common observation that many common cancers occur at a younger age in developing countries, like India. The cancer registry data provide incidence rate of different cancers, which suggest the same. Telomere shortening is involved in ageing of cells. Inflammation and infection result in telomere shortening in immune cells. The higher infection burden in developing countries might mean an earlier ageing of immune cells, resulting in decreased efficiency of immune surveillance and thus predisposing to cancer at an earlier age than seen in developed countries with lesser infection burden.},
}
@article {pmid12614219,
year = {2003},
author = {Li, X and Leteurtre, F and Rocha, V and Guardiola, P and Berger, R and Daniel, MT and Noguera, MH and Maarek, O and Roux, GL and de la Salmonière, P and Richard, P and Gluckman, E},
title = {Abnormal telomere metabolism in Fanconi's anaemia correlates with genomic instability and the probability of developing severe aplastic anaemia.},
journal = {British journal of haematology},
volume = {120},
number = {5},
pages = {836-845},
doi = {10.1046/j.1365-2141.2003.04225.x},
pmid = {12614219},
issn = {0007-1048},
mesh = {Acute Disease ; Adolescent ; Adult ; Aged ; Anemia, Aplastic/*etiology/pathology ; Apoptosis/genetics ; Bone Marrow Cells/pathology ; Child ; Child, Preschool ; Chromosome Breakage ; Fanconi Anemia/*genetics/pathology ; Female ; Humans ; Infant ; Leukemia, Myeloid/genetics ; Male ; Middle Aged ; Myelodysplastic Syndromes/genetics ; Prognosis ; Telomere/genetics/*metabolism/pathology ; },
abstract = {Fanconi's anaemia (FA) is an autosomal recessive disorder characterized by progressive bone marrow failure and a susceptibility to cancer. Haematopoietic stem cell transplantation is the only curative method for restoring normal haematopoiesis, and survival is improved if the transplant is carried out before severe complications occur. However, the evolution of FA is difficult to predict because of the absence of known prognostic factors and the unknown function of the genes involved. In studying 71 FA patients, a correlation was found between severe aplastic anaemia (SAA) and the individual annual telomere-shortening rate (IATSR) in peripheral blood mononuclear cells (P < 10(-3)). Spontaneous apoptosis was highest in SAA patients or patients with high IATSR (> 200 bp/year) (P < 0.01, n = 18). Univariate and multivariate analyses showed that significant relative risks for evolution towards SAA were high IATSR (P < 10(-4)), and that a high number of chromosome breakages occurred in the presence of nitrogen mustard (P < 0.001). A high IATSR was also associated with an increased frequency of malignancy (P < 0.01). Thus, these biological parameters were related to the spontaneous evolution of FA and could be used as prognostic factors. These data indicated that telomeres might play a role in the evolution of bone marrow failure and malignant transformation in FA.},
}
@article {pmid12611486,
year = {2002},
author = {Regéczy, N and Valent, S and Kormos, L and Hajdu, M and Gopcsa, L and Pálóczi, K},
title = {Telomere length analysis on cord blood cells by the flow-FISH method.},
journal = {Haematologia},
volume = {32},
number = {3},
pages = {265-269},
doi = {10.1163/15685590260461075},
pmid = {12611486},
issn = {0017-6559},
mesh = {Blood Specimen Collection ; Cell Culture Techniques ; Fetal Blood/*cytology ; Humans ; *In Situ Hybridization, Fluorescence ; Methods ; Telomere/*ultrastructure ; },
abstract = {Telomerase is the enzyme responsible for synthesizing telomeric repeats at the ends of chromosomes to maintain telomere length. Recent studies have suggested that telomere shortening may serve as a surrogate marker of the progression of malignant disorders and seems to be accelerated in allogeneic bone marrow transplant recipients. In this study, the results of the telomere length of nine cord blood mononuclear cell samples are presented. Telomere length was measured by the flow-FISH method, using a peptide nucleic acid probe. The proportion of cord blood cell subsets (CD19/CD34/CD3) was also evaluated. The telomere length of the internal control 1301 cell line was estimated to be 100%. The mean telomere length of cord blood cells was 18.5 +/- 3.9%, compared with the internal control. The progenitor CD34+ cells were detected as 2.6 +/- 0.7% in the lymphoid gate measured. Linear correlation analysis did not find any connection between the cell subsets (CD3+, CD34+, CD19+) and the telomere length. The findings confirm that the telomere flow-FISH method is sufficient for estimation of the telomere length. Assessment of the current procedures of collection, manipulation, and ex vivo expansion of cord blood cells in terms of their effect on telomere shortening might be important.},
}
@article {pmid12610563,
year = {2003},
author = {von Zglinicki, T and Petrie, J and Kirkwood, TB},
title = {Telomere-driven replicative senescence is a stress response.},
journal = {Nature biotechnology},
volume = {21},
number = {3},
pages = {229-230},
doi = {10.1038/nbt0303-229b},
pmid = {12610563},
issn = {1087-0156},
support = {BEP17042/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Cell Division/physiology ; Cells, Cultured ; Cellular Senescence/*physiology ; Oxidative Stress/genetics/*physiology ; Telomerase/*genetics/*metabolism ; Telomere/*genetics ; },
}
@article {pmid12609839,
year = {2003},
author = {Wu, KD and Orme, LM and Shaughnessy, J and Jacobson, J and Barlogie, B and Moore, MA},
title = {Telomerase and telomere length in multiple myeloma: correlations with disease heterogeneity, cytogenetic status, and overall survival.},
journal = {Blood},
volume = {101},
number = {12},
pages = {4982-4989},
doi = {10.1182/blood-2002-11-3451},
pmid = {12609839},
issn = {0006-4971},
support = {CA55819/CA/NCI NIH HHS/United States ; U19-CA67842/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging ; Chromosome Aberrations ; Chromosomes, Human, Pair 13 ; *Cytogenetic Analysis ; Female ; Granulocytes/ultrastructure ; Humans ; Interleukin-6/blood ; Lymphocytes/ultrastructure ; Male ; Membrane Glycoproteins/analysis ; Middle Aged ; *Multiple Myeloma/enzymology/genetics/mortality/ultrastructure ; Plasma Cells/immunology/ultrastructure ; Prognosis ; Proteoglycans/analysis ; Survival Rate ; Syndecan-1 ; Syndecans ; Telomerase/*metabolism ; Telomere/*ultrastructure ; beta 2-Microglobulin/blood ; },
abstract = {We have investigated the significance of telomerase activity (TA) and telomere length (TL) in multiple myeloma (MM). The analyses were undertaken on CD138+ MM cells isolated from the marrow of 183 patients either at diagnosis or in relapse. There was heterogeneity in telomerase expression; 36% of the patients had TA levels comparable to those detected in normal plasma cells, and 13% of patients had levels 1- to 4-fold greater than in a neuroblastoma cell line control. The TL of MM cells was significantly shorter than that of the patients' own leukocytes; in 25% of patients, the TL measured less than 4.0 kbp. Analysis of TL distribution indicated selective TA-mediated stabilization of shorter telomeres when mean TL fell below 5.5 kbp. Unusually long (10.8-15.0 kbp) telomeres were observed in 7 patients, and low TA was observed in 5 of 7 patients, suggesting the operation of a TA-independent pathway of telomere stabilization. A strong negative correlation existed between TA and TL or platelet count. TL negatively correlated with age and with interleukin-6 (IL-6) and beta2-microglobulin levels. Various cytogenetic abnormalities, including those associated with poor prognosis, strongly correlated with TA and, to a lesser extent, with short TL. High TA and short TL defined a subgroup of patients with poor prognosis. At 1 year the survival rate in patients with TA levels lower than 25% of neuroblastoma control and TL greater than 5.5 kbp was 82%, whereas in patients with higher TA and shorter TL the survival rate was 63% (P =.004). The 2-year survival rate for patients with TA levels lower than 25% was 81%, and it was 52% in those with higher TA levels (P <.0001).},
}
@article {pmid12606771,
year = {2003},
author = {Biroccio, A and Gabellini, C and Amodei, S and Benassi, B and Del Bufalo, D and Elli, R and Antonelli, A and D'Incalci, M and Zupi, G},
title = {Telomere dysfunction increases cisplatin and ecteinascidin-743 sensitivity of melanoma cells.},
journal = {Molecular pharmacology},
volume = {63},
number = {3},
pages = {632-638},
doi = {10.1124/mol.63.3.632},
pmid = {12606771},
issn = {0026-895X},
mesh = {Antineoplastic Agents/*pharmacology ; Cisplatin/*pharmacology ; DNA Damage ; DNA-Binding Proteins ; Dioxoles/*pharmacology ; Drug Screening Assays, Antitumor ; G2 Phase/drug effects ; Humans ; Isoquinolines/*pharmacology ; Melanoma/pathology ; Mitosis/drug effects ; Telomerase/biosynthesis/genetics/*metabolism ; Telomere/*physiology ; Tetrahydroisoquinolines ; Trabectedin ; Transfection ; Tumor Cells, Cultured ; },
abstract = {The aim of this study was to investigate the role of telomerase function on the chemosensitivity of melanoma cells. To this end, ecteinascidin-743 (ET-743) and cisplatin [cis-diamminedichloroplatinum(II) (CDDP)], two DNA-interacting drugs that invariably cause an arrest in the G(2)/M phase, and 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid (LND), a mitochondria-targeting drug inducing a G(1) block, were used. As experimental model, human melanoma clones showing reduced human telomerase reverse transcriptase (hTERT) expression and telomerase activity and characterized by telomere dysfunction were used. Reconstitution of telomerase activity by exogenous hTERT expression improved telomere function and reduced the sensitivity to CDDP and ET-743 without affecting LND susceptibility. The decreased sensitivity to CDDP and ET-743 was mainly caused by the ability of cells to recover from drug-induced damage, evaluated in terms of both chromosomal lesions and cell survival. The ability of hTERT-reconstituted cells to recover from drug-induced damage was attributable to the restoration of cell cycle progression. In fact, the cells without hTERT restoration remained for a prolonged time in the G(2)/M phase, and this cell cycle alteration made irreversible the drug-induced S-G(2)/M block and led to the activation of apoptotic program. On the contrary, the hTERT-reconstituted cells progressed quickly through the cell cycle, thus acquiring the capacity to recover from drug-induced block and to protect themselves from the G(2)/M phase-specific drug-triggered apoptosis.},
}
@article {pmid12599198,
year = {2003},
author = {Hulley, BJ and Hummel, M and Wenger, SL},
title = {Screening for cryptic chromosomal abnormalities in patients with mental retardation and dysmorphic facial features using telomere FISH probes.},
journal = {American journal of medical genetics. Part A},
volume = {117A},
number = {3},
pages = {302-303},
doi = {10.1002/ajmg.a.10925},
pmid = {12599198},
issn = {1552-4825},
mesh = {*Chromosome Aberrations ; Chromosome Deletion ; Chromosome Disorders/diagnosis/*genetics ; Chromosomes, Human, Pair 1/genetics ; Chromosomes, Human, Pair 2/genetics ; Chromosomes, Human, Pair 8/genetics ; Face/*abnormalities ; Genetic Testing ; Humans ; In Situ Hybridization, Fluorescence/methods ; Intellectual Disability/*pathology ; Nucleic Acid Probes/genetics ; Telomere/*genetics ; Translocation, Genetic ; },
}
@article {pmid12599190,
year = {2003},
author = {Reddy, KS and Yang, X},
title = {Submicroscopic terminal deletion of 1p36.3 and Xp23 hidden in complex chromosome rearrangements: independent mechanism of telomere restitution on the two chromatids.},
journal = {American journal of medical genetics. Part A},
volume = {117A},
number = {3},
pages = {261-267},
doi = {10.1002/ajmg.a.10108},
pmid = {12599190},
issn = {1552-4825},
mesh = {Chromatids/genetics ; *Chromosome Deletion ; Chromosomes, Human, Pair 1/*genetics ; Chromosomes, Human, X/*genetics ; Female ; Fetus/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; Karyotyping ; Models, Genetic ; Telomere/genetics ; *Translocation, Genetic ; },
abstract = {In this study, we report two cases each with a complex chromosome rearrangement concealing a submicroscopic terminal deletion. The first case had a mos 46,XX,der(1)t(1;9)(p36.3;p13). ish der(1)(wcp9 +, 1ptel-, 9ptel +, pan tel +)[88]/46,XX. ish del(1)(1ptel -, 9ptel -, pan tel +)[12] karyotype. Scrutiny by FISH using wcp 9, 1ptel, 9ptel, and pan telomeric probes found a subtelomeric 1ptel deletion on the der(1) in the abnormal cell line and on a chromosome 1 in the apparently normal cell line. The telomere (TTAGGG)n, however, was present on the terminal ends of both copies of chromosome 1 in the apparently normal and abnormal cell lines. The second case had a de novo mos 46,X,der(X)t(X;22)(p22.3;q11.2),inv dup(22)(q11.2).ish der(X)(wcpX +,wcp22 +,KAL +, STS -,Xptel -,BCR +),inv dup(22)(wcp22 +,TUPLE ++,BCR -)[85]/45,X,der(X)t(X;22)(p22.3;q11.2),- 22[15].ish der(X)(wcpX +,wcp22 +, KAL +,STS -,Xptel -,BCR +) karyotype. FISH probes identified a terminal Xpter deletion, distal to the KAL gene. The two rearrangements are hypothesized to have been initiated by a terminal deletion. We propose a model for the formation of the rearrangement in Case 1, which invokes independent telomere stabilization of the sister chromatids. A terminal deletion 1pter in meiosis, was followed by acquiring or regenerating a telomere (TTAGGG)n cap on one chromatid and the other chromatid was involved in a translocation with a chromosome 9 chromatid. Following segregation of this chromosome the viable cell line survives to form the mosaic karyotype. Our findings suggest that subtelomeric deletions should be ruled out in cases with complex and simple rearrangements involving the terminal regions.},
}
@article {pmid12595567,
year = {2003},
author = {Cherif, H and Tarry, JL and Ozanne, SE and Hales, CN},
title = {Ageing and telomeres: a study into organ- and gender-specific telomere shortening.},
journal = {Nucleic acids research},
volume = {31},
number = {5},
pages = {1576-1583},
pmid = {12595567},
issn = {1362-4962},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Aging/*physiology ; Animals ; Animals, Newborn ; Blotting, Southern ; Brain/metabolism ; DNA/genetics ; Female ; Kidney/metabolism ; Liver/metabolism ; Lung/metabolism ; Male ; Pancreas/metabolism ; Rats ; Rats, Wistar ; Sex Factors ; Telomere/genetics/*metabolism ; Time Factors ; },
abstract = {Telomeres, the non-coding sequences at the ends of chromosomes, in the absence of telomerase, progressively shorten with each cell division. Shortening of telomeres can induce cell cycle arrest and apoptosis. The aim of this study was to investigate age- and gender-related changes in telomere length in the rat and to detect possible tissue- specific rates of telomere shortening. Changes with age in telomere lengths were assessed by Southern blotting in the kidney, pancreas, liver, lung and brain of male and female rats. We determined the percentage of telomeres in various molecular size regions rather than measuring the average telomere length. The latter was unable to detect telomere shortening in the tissues. The percentage of short telomeres increased with age in the kidney, liver, pancreas and lung of both males and females, but not in the brain. Males had shorter telomeres than females in all organs analysed except the brain, where the lengths were similar. These findings indicate that telomeres shorten in the rat kidney, liver, pancreas and the lung in an age-dependent manner. These data also provide a novel mechanism for the gender-related differences in lifespan and suggest a tissue-specific regulation of telomere length during development and ageing in the rat.},
}
@article {pmid12592375,
year = {2003},
author = {Hultdin, M and Rosenquist, R and Thunberg, U and Tobin, G and Norrback, KF and Johnson, A and Sundström, C and Roos, G},
title = {Association between telomere length and V(H) gene mutation status in chronic lymphocytic leukaemia: clinical and biological implications.},
journal = {British journal of cancer},
volume = {88},
number = {4},
pages = {593-598},
pmid = {12592375},
issn = {0007-0920},
mesh = {Aged ; Chromosome Aberrations ; DNA Mutational Analysis ; Female ; Genes, Immunoglobulin/*genetics ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/*pathology ; Male ; Middle Aged ; Mutation/*genetics ; Polymerase Chain Reaction ; Survival Analysis ; Telomere/genetics/*pathology ; Time Factors ; },
abstract = {The immunoglobulin V(H) gene mutation status can divide B-cell chronic lymphocytic leukaemia (CLL) into two entities with a different clinical course. Cases with unmutated V(H) genes, considered to evolve from pregerminal centre (GC) cells, have a worse outcome compared to cases showing mutated V(H) genes, that is, post-GC derived. Also, telomere length has been reported to be of prognostic significance in CLL. Interestingly, telomerase becomes activated during the GC reaction and an elongation of the telomeres occurs in GC B cells. We performed telomere length and V(H) gene analysis in a series of 61 CLL cases, in order to investigate if the unique telomere lengthening shown in GC B cells could reflect the telomere status in the two subsets of mutated and unmutated CLL. A novel association was found between V(H) gene mutation status and telomere length, since significantly shorter telomeres were demonstrated in the unmutated group compared to the mutated group (mean length 4.3 vs 6.3 kbp). Shorter telomeres also constituted a subgroup with a worse prognosis than cases with longer telomeres (median survival 59 vs 159 months). Furthermore, the Ig gene sequence data revealed that samples with high mutations frequency (>6%) had long telomeres (approximately 8 kbp). Thus, both the telomere and V(H) gene mutation status in CLL appear linked, which may reflect the proliferative history of the clonal cells with regard to the GC reaction.},
}
@article {pmid12592340,
year = {2003},
author = {Franco, S and Ozkaynak, MF and Sandoval, C and Tugal, O and Jayabose, S and Engelhardt, M and Moore, MA},
title = {Telomere dynamics in childhood leukemia and solid tumors: a follow-up study.},
journal = {Leukemia},
volume = {17},
number = {2},
pages = {401-410},
doi = {10.1038/sj.leu.2402815},
pmid = {12592340},
issn = {0887-6924},
support = {CA-08748/CA/NCI NIH HHS/United States ; CA-67842/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Child ; Child, Preschool ; DNA Primers ; Female ; Follow-Up Studies ; Granulocytes/pathology ; Humans ; Infant ; Leukemia, Myeloid, Acute/*genetics ; Leukocytes, Mononuclear/pathology ; Male ; Neoplasms/*genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics ; Restriction Mapping ; Telomerase/genetics/metabolism ; Telomere/*genetics ; },
abstract = {Telomeres of hematopoietic cells shorten with age, possibly contributing to the aging-associated hematopoietic pathology (immunosenescence, malignant transformation). Accelerated telomere shortening is seen with replicative stress, such as during administration of serial chemotherapy cycles for the treatment of childhood cancer. To define the long-term consequences of pediatric cancer treatment on hematopoietic cell telomere length, we undertook a prospective 4-year follow-up study of a 61-patient cohort of pediatric malignancies in a community-based setting. We found that mononuclear cells (MNC) and granulocytes of children with standard-risk acute lymphoblastic leukemia (ALL) suffered minimal telomere shortening throughout therapy (less than 1 kbp; average follow-up, 20 months), while those of children with solid tumors showed greater and more heterogenous telomere attrition (0.5-2.8 kbp, average follow-up, 9 months). In addition, we evaluated the role of telomerase, the enzyme commonly up-regulated in pediatric leukemic and solid tumor cells for telomere length maintenance, as a disease marker. Serial determinations of telomerase in MNC were useful to confirm disease remission in leukemia, but play no role in the follow-up of children with solid tumors.},
}
@article {pmid12591722,
year = {2003},
author = {Zhang, X and Multani, AS and Zhou, JH and Shay, JW and McConkey, D and Dong, L and Kim, CS and Rosser, CJ and Pathak, S and Benedict, WF},
title = {Adenoviral-mediated retinoblastoma 94 produces rapid telomere erosion, chromosomal crisis, and caspase-dependent apoptosis in bladder cancer and immortalized human urothelial cells but not in normal urothelial cells.},
journal = {Cancer research},
volume = {63},
number = {4},
pages = {760-765},
pmid = {12591722},
issn = {0008-5472},
support = {CA091846/CA/NCI NIH HHS/United States ; CA70907/CA/NCI NIH HHS/United States ; },
mesh = {Adenoviridae/genetics ; Apoptosis/*physiology ; Caspase Inhibitors ; Caspases/*metabolism ; Chromosome Aberrations ; Genetic Therapy/*methods ; Genetic Vectors/genetics ; Humans ; Peptide Fragments/genetics/*physiology ; Retinoblastoma Protein/genetics/*physiology ; Telomere/*metabolism ; Tumor Cells, Cultured ; Urinary Bladder Neoplasms/*genetics/pathology/*therapy ; Urothelium/cytology ; },
abstract = {Retinoblastoma (RB)94, which lacks the NH(2)-terminal 112 amino acid residues of the full-length RB protein (RB110), is a more potent tumor and growth suppressor than RB110. In this study, Ad-RB94, but not Ad-RB110, produced marked growth inhibition, cytotoxicity, caspase-dependent apoptosis, and G(2)-M block in the human RB-negative, telomerase-positive bladder cancer cell line UM-UC14. This effect was completely inhibited by pretreatment with caspase inhibitors (P < 0.0001). Similar results were seen in RB-positive and other RB-negative bladder cancer cell lines. Ad-RB94 produced rapid telomere length shortening and loss of telomere signal, which was associated with polyploidy and chromosomal aberrations (P < 0.001). Ad-RB94, however, showed no cytotoxicity to telomerase-negative human normal urothelium cells but was highly cytotoxic to telomerase-positive human E6 and E7 immortalized urothelial cells (P < 0.0001). In addition, telomerase-negative cells, which maintain their telomere length through an alternative lengthening of telomeres DNA recombination pathway, showed no cytotoxicity to RB94. These results suggest that the induction of rapid telomere erosion and chromosomal crisis by RB94 in telomerase-positive cancer and in telomerase-expressing immortalized human cells is a major factor in its selective and potent tumor suppression and cytotoxic activity. The lack of cytotoxicity to normal cells should also provide a high therapeutic index when used in gene therapy protocols for the treatment of bladder and other cancers.},
}
@article {pmid12589755,
year = {2003},
author = {Kanoh, J and Francesconi, S and Collura, A and Schramke, V and Ishikawa, F and Baldacci, G and Géli, V},
title = {The fission yeast spSet1p is a histone H3-K4 methyltransferase that functions in telomere maintenance and DNA repair in an ATM kinase Rad3-dependent pathway.},
journal = {Journal of molecular biology},
volume = {326},
number = {4},
pages = {1081-1094},
doi = {10.1016/s0022-2836(03)00030-5},
pmid = {12589755},
issn = {0022-2836},
mesh = {Antineoplastic Agents/metabolism ; Cell Cycle Proteins/genetics/*metabolism ; Cell Survival ; Centromere/metabolism ; Checkpoint Kinase 2 ; DNA Damage ; DNA Repair ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Gene Silencing/physiology ; Genes, cdc ; Histone-Lysine N-Methyltransferase ; Histones/metabolism ; Humans ; Hydroxyurea/metabolism ; Methylation ; Methyltransferases/genetics/*metabolism ; Protein Kinases/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Schizosaccharomyces/enzymology ; Schizosaccharomyces pombe Proteins/chemistry/genetics/*metabolism ; Telomere/*metabolism ; Transcription Factors/chemistry/genetics/*metabolism ; Ultraviolet Rays ; },
abstract = {We have characterized spSet1p, the Schizosaccharomyces pombe ortholog of the budding yeast histone H3 methyltransferase Set1p. SpSet1p catalyzes methylation of H3 at K4, in vivo and in vitro. Deleting spset1 partially affects telomeric and centromeric silencing. Strikingly, lack of spSet1p causes elongation of telomeres in wild-type cells and in most DNA damage checkpoint rad mutant cells, but not in cells lacking the ATM kinase Rad3 or its associated protein Rad26. Interestingly, spset1 deletion specifically causes a reduction in sensitivity to ultraviolet radiation of the PCNA-like checkpoint mutants hus1 and rad1, but not of cells devoid of Rad3. This partial suppression was not due to restoration of checkpoint function or to transcriptional induction of DNA repair genes. Moreover, spset1 allows recovery specifically of the crb2 checkpoint mutant upon treatment with the replication inhibitor hydroxyurea but not upon UV irradiation. Nevertheless, the pathway induced in spset1 cells cannot substitute for the Mus81/Rqh1 DNA damage tolerance pathway. Our results suggest that SpSet1p and the ATM kinase Rad3 function in a common genetic pathway linking chromatin to telomere length regulation and DNA repair.},
}
@article {pmid12588971,
year = {2003},
author = {Lebrun, E and Fourel, G and Defossez, PA and Gilson, E},
title = {A methyltransferase targeting assay reveals silencer-telomere interactions in budding yeast.},
journal = {Molecular and cellular biology},
volume = {23},
number = {5},
pages = {1498-1508},
pmid = {12588971},
issn = {0270-7306},
mesh = {Cell Nucleus/metabolism ; Chromosomes/metabolism ; Cytoplasm/metabolism ; *Gene Silencing ; Genetic Vectors ; Methyltransferases/*metabolism ; Models, Genetic ; Mutation ; Orotic Acid/*analogs &amp; derivatives/pharmacology ; Plasmids/metabolism ; Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Saccharomyces cerevisiae/metabolism ; Saccharomycetales/*enzymology/*genetics ; Site-Specific DNA-Methyltransferase (Adenine-Specific)/metabolism ; Telomere/*metabolism ; },
abstract = {We have designed a modified version of the Dam identification technique and used it to probe higher-order chromatin structure in Saccharomyces cerevisiae. We fused the bacterial DNA methyltransferase Dam to the DNA-binding domain of TetR and targeted the resulting chimera to Tet operators inserted in the yeast genome at the repressed locus HML. We then monitored the methylation status of HML and other sequences by a quantitative technique combining methylation-sensitive restriction and real-time PCR. As expected, we found that TetR-Dam efficiently methylated HML in cis. More strikingly, when TetR-Dam was present at HML, we observed increased methylation in the III-L subtelomeric region but not in intervening sequences. This effect was lost when the HML silencers were inactivated by mutations. When the HM silencers and the Tet operators were transferred to a plasmid, strong methylation was clearly observed not only in the III-L subtelomeric region but also at other telomeres. These data indicate that HM silencers can specifically associate with telomeres, even those located on different chromosomes.},
}
@article {pmid12586310,
year = {2003},
author = {Murphy, F and Iredale, J},
title = {The telomere hypothesis for progressive liver cirrhosis.},
journal = {Journal of hepatology},
volume = {38},
number = {3},
pages = {378-379},
doi = {10.1016/s0168-8278(02)00405-1},
pmid = {12586310},
issn = {0168-8278},
mesh = {Animals ; Disease Progression ; Humans ; Liver Cirrhosis/*genetics/*physiopathology ; *Models, Biological ; Telomere/*genetics ; },
}
@article {pmid12584435,
year = {2002},
author = {Kostiner, DR and Nguyen, H and Cox, VA and Cotter, PD},
title = {Stabilization of a terminal inversion duplication of 8p by telomere capture from 18q.},
journal = {Cytogenetic and genome research},
volume = {98},
number = {1},
pages = {9-12},
doi = {10.1159/000068536},
pmid = {12584435},
issn = {1424-8581},
mesh = {Adult ; *Chromosome Inversion ; Chromosome Mapping ; *Chromosomes, Human, Pair 18 ; *Chromosomes, Human, Pair 8 ; Female ; *Gene Duplication ; Genetic Markers ; Humans ; In Situ Hybridization, Fluorescence ; Infant, Newborn ; Karyotyping ; Male ; },
abstract = {Terminal inversion duplications of the short arm of chromosome 8 are one of the more common chromosome rearrangements in humans. We report an infant with multiple congenital anomalies, in whom karyotype analysis showed a terminal inversion duplication of 8p including additional material at the distal end of the derivative chromosome, shown to be of chromosome 18q origin. Terminal inversion duplications of 8p are the result of meiotic recombination between inverted olfactory gene receptor repeats in 8p. This recombination generates a dicentric intermediate that breaks during anaphase, and the broken chromosome end is stabilized by telomere healing or telomere capture. The origin of the telomeric region in the majority of constitutional chromosome deletions studied to date was shown to be from telomere healing; the de novo addition of telomeric repeats. In the proband a cytogenetically detectable piece of chromosome 18q was present on the distal end of the derivative 8, suggesting that this chromosome was stabilized by telomere capture of 18q. FISH analyses of additional cases may yield information as to whether telomere capture or telomere-healing events are the predominant mechanism of chromosome stabilization in terminal inversion duplications of 8p.},
}
@article {pmid12575611,
year = {2001},
author = {Dai, EL and Zhao, JX and Zhu, YZ},
title = {[Experimental study on effect of fuzheng yiliu decoction on tumor cell cycle and telomerease].},
journal = {Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine},
volume = {21},
number = {10},
pages = {760-762},
pmid = {12575611},
issn = {1003-5370},
mesh = {Animals ; Antineoplastic Agents, Phytogenic/*pharmacology ; Cell Cycle/drug effects ; DNA, Neoplasm/biosynthesis ; Drugs, Chinese Herbal/*pharmacology ; Female ; Male ; Mice ; Sarcoma 180/*enzymology/*pathology ; Telomerase/*metabolism ; },
abstract = {OBJECTIVE: To study the mechanism of anti-tumor effect of Fuzheng Yiliu Decoction (FZYLD).<br><br>METHODS: S180 neoplasm strain was inoculated in Kunming mice to establish model of S180 solid tumor. The model animals were treated with FZYLD by gastrogavage, the cell cycle of tumor were checked up by flow cytometer and the telomerease kit was used to test telomerease activity.<br><br>RESULTS: The stage G0/1 ratio of tumor cells in model animals treated with FZYLD increased, while cells of S stage decreased, with telomerease activity inhibited. These changes were different significantly from those in the model animals treated with normal saline (P < 0.001).<br><br>CONCLUSION: FZYLD could block the tumor cell proliferation procedure and inhibit the DNA synthesis and duplication in tumor cell. And the suppression of telomerease activity might be one of the mechanisms affecting the tumor cell proliferation cycle.},
}
@article {pmid12573438,
year = {2003},
author = {Blasco, MA},
title = {Telomeres and cancer: a tale with many endings.},
journal = {Current opinion in genetics &amp; development},
volume = {13},
number = {1},
pages = {70-76},
doi = {10.1016/s0959-437x(02)00011-4},
pmid = {12573438},
issn = {0959-437X},
mesh = {Animals ; Humans ; Mice ; Neoplasms/etiology/*genetics/metabolism ; Telomerase/antagonists &amp; inhibitors/*physiology ; Telomere/*physiology ; },
abstract = {Telomerase activity is necessary to maintain the integrity of telomeres, which in turn prevent chromosome ends from being processed and signaled as damaged DNA. That cancer cells rely on telomerase to maintain functional telomeres and to divide indefinitely has highlighted the potential for developing novel therapeutic approaches that target telomerase.},
}
@article {pmid12573379,
year = {2003},
author = {Cawthon, RM and Smith, KR and O'Brien, E and Sivatchenko, A and Kerber, RA},
title = {Association between telomere length in blood and mortality in people aged 60 years or older.},
journal = {Lancet (London, England)},
volume = {361},
number = {9355},
pages = {393-395},
doi = {10.1016/S0140-6736(03)12384-7},
pmid = {12573379},
issn = {0140-6736},
support = {AG13478/AG/NIA NIH HHS/United States ; K01 AG00767/AG/NIA NIH HHS/United States ; R29CA69421/CA/NCI NIH HHS/United States ; },
mesh = {Age Distribution ; Aged ; Aged, 80 and over ; Aging/*blood/genetics/*pathology ; Apoptosis ; Blood Donors/*statistics &amp; numerical data ; Cause of Death ; Communicable Diseases/genetics/mortality ; Dyskeratosis Congenita/genetics ; Female ; Heart Diseases/genetics/mortality ; Humans ; Male ; Middle Aged ; *Mortality ; Population Surveillance ; Proportional Hazards Models ; Survival Analysis ; Telomere/*pathology ; Utah/epidemiology ; },
abstract = {During normal ageing, the gradual loss of telomeric DNA in dividing somatic cells can contribute to replicative senescence, apoptosis, or neoplastic transformation. In the genetic disorder dyskeratosis congenita, telomere shortening is accelerated, and patients have premature onset of many age-related diseases and early death. We aimed to assess an association between telomere length and mortality in 143 normal unrelated individuals over the age of 60 years. Those with shorter telomeres in blood DNA had poorer survival, attributable in part to a 3.18-fold higher mortality rate from heart disease (95% CI 1(.)36-7.45, p=0.0079), and an 8.54-fold higher mortality rate from infectious disease (1.52-47.9, p=0.015). These results lend support to the hypothesis that telomere shortening in human beings contributes to mortality in many age-related diseases.},
}
@article {pmid12566299,
year = {2003},
author = {Mo, Y and Gan, Y and Song, S and Johnston, J and Xiao, X and Wientjes, MG and Au, JL},
title = {Simultaneous targeting of telomeres and telomerase as a cancer therapeutic approach.},
journal = {Cancer research},
volume = {63},
number = {3},
pages = {579-585},
pmid = {12566299},
issn = {0008-5472},
support = {R01CA77091/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Combined Modality Therapy ; Drug Synergism ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Osteosarcoma/drug therapy/enzymology/genetics ; Paclitaxel/administration &amp; dosage/*pharmacology ; Pharyngeal Neoplasms/drug therapy/enzymology/*genetics/*therapy ; RNA, Antisense/*administration &amp; dosage/genetics ; Telomerase/*antagonists &amp; inhibitors/genetics ; Telomere/*drug effects ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; Zidovudine/administration &amp; dosage/*pharmacology ; },
abstract = {Telomeres, which are important for maintaining chromosome integrity and functions, shorten with each cell division. Telomerase, responsible for telomere synthesis, is expressed in approximately 90% of human tumor cells but seldom in normal somatic cells. This study evaluated the hypothesis that simultaneous shortening of telomeres and inhibition of telomerase results in synergistic and tumor-selective cytotoxicity. In telomerase-positive human pharynx FaDu tumor cells, paclitaxel caused telomere erosion (first detected at 1 h) and apoptosis. Expression of antisense to the RNA component of human telomerase (hTR) inhibited telomerase activity, shortened telomere length, reduced cell growth rate, and resulted in a significant higher sensitivity to paclitaxel. Another telomerase inhibitor, 3'-azido-3'-deoxythymidine (AZT), at a concentration that produced little or no cell detachment or apoptosis, inhibited the telomerase activity and enhanced the paclitaxel-induced cell detachment and apoptosis. AZT also enhanced the activity of paclitaxel in mice bearing well-established s.c. FaDu xenograft tumors (i.e., reduced residual tumor size, enhanced apoptotic cell fraction, and prolonged survival time), without enhancing host toxicity. In contrast, AZT did not enhance the paclitaxel activity in the telomerase-negative osteosarcoma Saos-2 cells nor in FaDu cells where telomerase was already suppressed by antisense hTR, confirming that the AZT effect in parent FaDu cells is mediated through telomerase inhibition. These results demonstrate that combined use of agents targeting both telomere and telomerase yielded synergistic activity selective for tumors that depend on telomerase for telomere maintenance.},
}
@article {pmid12564113,
year = {2003},
author = {Minamino, T and Miyauchi, H and Yoshida, T and Komuro, I},
title = {[Endothelial cell senescence in human atherosclerosis: role of telomeres in endothelial dysfunction].},
journal = {Journal of cardiology},
volume = {41},
number = {1},
pages = {39-40},
pmid = {12564113},
issn = {0914-5087},
mesh = {Aging ; Arteriosclerosis/etiology/pathology/*physiopathology ; Cellular Senescence/*physiology ; Endothelium, Vascular/*pathology ; Humans ; Intercellular Adhesion Molecule-1/metabolism ; Nitric Oxide Synthase/metabolism ; Telomerase/physiology ; Telomere/*physiology ; beta-Galactosidase/metabolism ; },
abstract = {BACKGROUND: The functional changes associated with cellular senescence may be involved in human aging and age-related vascular disorders. We have shown the important role of telomeres and telomerase in vascular cell senescence in vitro. Progressive telomere shortening in vivo has been observed in the regions susceptible to atherosclerosis, implicating its contributions to atherogenesis. However, whether senescent vascular cells are present in the vascularture and contribute to the pathogenesis of atherosclerosis remains unclear.<br><br>METHODS AND RESULTS: Senescence-associated beta-galactosidase (beta-gal) activity was examined in the coronary arteries and the internal mammary arteries retrieved from autopsied individuals who had ischemic heart diseases. Strong beta-gal staining was observed in atherosclerotic lesions of the coronary arteries but not in the internal mammary arteries. An immunohistochemical analysis using anti-factor VIII antibody demonstrated that beta-gal stained cells are vascular endothelial cells. To determine whether endothelial cell senescence causes endothelial dysfunction, we induced senescence in human aortic endothelial cells (HAECs) by inhibiting telomere function and examined the expression of intercellular adhesion molecule (ICAM)-1 and endothelial nitric oxide synthase (NOS) activity. Senescent HAECs exhibited increased ICAM-1 expression and decreased eNOS activity, both of which are alterations implicated in atherogenesis. In contrast, introduction of telomerase catalytic component significantly extended the life span and inhibited the functional alterations associated with senescence in HAECs.<br><br>CONCLUSIONS: Vascular endothelial cells with senescence-associated phenotypes are present in human atherosclerotic lesions, and endothelial cell senescence induced by telomere shortening may contribute to atherogenesis.},
}
@article {pmid12559460,
year = {2003},
author = {Miyashita, N and Shiga, K and Fujita, T and Umeki, H and Sato, W and Suzuki, T and Nagai, T},
title = {Normal telomere lengths of spermatozoa in somatic cell-cloned bulls.},
journal = {Theriogenology},
volume = {59},
number = {7},
pages = {1557-1565},
doi = {10.1016/s0093-691x(02)01195-0},
pmid = {12559460},
issn = {0093-691X},
mesh = {Animals ; Blotting, Southern/veterinary ; Cattle/*genetics/physiology ; Cells, Cultured ; Cellular Senescence/*genetics ; *Cloning, Organism ; DNA/isolation &amp; purification ; Female ; Hybridization, Genetic ; Leukocytes ; Male ; Spermatozoa/cytology/*ultrastructure ; Telomere/*ultrastructure ; },
abstract = {Interesting questions have been raised regarding cloned animals, including whether cloning restores cellular senescence undergone by donor cells, and how long cloned animals will be able to live. In this study, focusing our attention on the fact that telomere lengths of spermatozoa are longer than those of any somatic cells and that telomere length is maintained throughout aging in humans, we compared the telomere lengths of spermatozoa in normal and two somatic cell-cloned cattle. The telomere lengths of the spermatozoa in the normal cattle (22.42+/-0.32 kb) were maintained throughout aging as in humans. In the cloned cattle, telomere lengths of the spermatozoa (25.8 and 20.9 kb) were the same as or longer than those found in normal cattle. Considering that telomere lengths of the donor cells, which had been derived from the muscle tissue of an old bull, were reported to be 20.1 kb, the results suggested that the telomere lengths of the germ cell line had extended from nucleus transfer to spermatogenesis. Moreover, we produced offspring (nine calves) from a somatic cell-cloned bull and measured the telomere lengths of their leukocytes. In all of the offspring, the telomere lengths of leukocytes were normal, too. These results indicate the possibility that somatic cloned bulls could be used as breeding sires.},
}
@article {pmid12559044,
year = {2003},
author = {Artandi, SE},
title = {Complex roles for telomeres and telomerase in breast carcinogenesis.},
journal = {Breast cancer research : BCR},
volume = {5},
number = {1},
pages = {37-41},
pmid = {12559044},
issn = {1465-542X},
support = {K08 CA082176/CA/NCI NIH HHS/United States ; KO8CA82176/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Breast Neoplasms/enzymology/*genetics/pathology ; Chromosome Aberrations ; Female ; Humans ; Mammary Neoplasms, Animal/enzymology/genetics/pathology ; Mice ; Telomerase/*metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Telomerase - an enzyme that endows cells with unlimited proliferative potential - is differentially expressed in cancer cells and in normal cells. Although most primary human cells lack telomerase, the enzyme is upregulated in more than 90% of invasive breast cancers. As a result, much of breast cancer development occurs before telomerase is reactivated during a critical transition from a telomerase-negative to a telomerase-positive state. During this transition, the telomere shortening that accompanies cell division may either prevent or facilitate tumorigenesis by activating checkpoints and impairing chromosomal stability. In mature cancers, telomerase probably serves a crucial role in tumor progression and maintenance by stabilizing telomeres and supporting the immortal growth of breast cancer cells.},
}
@article {pmid12554806,
year = {2003},
author = {Baerlocher, GM and Mak, J and Röth, A and Rice, KS and Lansdorp, PM},
title = {Telomere shortening in leukocyte subpopulations from baboons.},
journal = {Journal of leukocyte biology},
volume = {73},
number = {2},
pages = {289-296},
doi = {10.1189/jlb.0702361},
pmid = {12554806},
issn = {0741-5400},
support = {R01 AI 29524/AI/NIAID NIH HHS/United States ; },
mesh = {Aging/genetics ; Animals ; Female ; Leukocytes/*metabolism ; Male ; Papio ; T-Lymphocytes/enzymology ; Telomerase/metabolism ; *Telomere ; },
abstract = {To address questions about telomere length regulation in nonhuman primates, we studied the telomere length in subpopulations of leukocytes from the peripheral blood of baboons aged 0.2-26.5 years. Telomere length in granulocytes, B cells, and subpopulations of T cells all decreased with age. Overall, telomere length kinetics were lineage- and cell subset-specific. T cells showed the most pronounced, overall decline in telomere length. Levels of telomerase in stimulated T cells from old animals were lower than in corresponding cells from young animals. Memory T cells with very short telomeres accumulated in old animals. In contrast, the average telomere length values in B cells remained relatively constant from middle age onward. Individual B cells showed highly variable telomere length, and B cells with very long telomeres were observed after the ages of 1-2 years. In general, cell type-specific telomere kinetics in baboons were remarkably similar to those observed in humans.},
}
@article {pmid12554694,
year = {2003},
author = {Eller, MS and Li, GZ and Firoozabadi, R and Puri, N and Gilchrest, BA},
title = {Induction of a p95/Nbs1-mediated S phase checkpoint by telomere 3' overhang specific DNA.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {17},
number = {2},
pages = {152-162},
doi = {10.1096/fj.02-0197com},
pmid = {12554694},
issn = {1530-6860},
mesh = {Ataxia Telangiectasia Mutated Proteins ; Base Sequence ; Cell Cycle/drug effects/physiology ; Cell Cycle Proteins/genetics/*physiology ; Cells, Cultured ; DNA/chemistry/genetics/*pharmacology ; *DNA-Binding Proteins ; E2F Transcription Factors ; Fibroblasts/cytology/drug effects/metabolism ; Humans ; Infant, Newborn ; Jurkat Cells ; Nuclear Proteins/genetics/*physiology ; Nucleic Acid Conformation ; Oligonucleotides/genetics/pharmacology ; Phosphorylation ; Protein Serine-Threonine Kinases/metabolism ; S Phase/*drug effects/physiology ; Telomerase/*genetics ; Time Factors ; Transcription Factors/metabolism ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins ; },
abstract = {Telomere shortening induces a nonproliferative senescent phenotype, believed to reduce cancer risk, and telomeres are involved in a poorly understood manner in responses to DNA damage. Although telomere disruption induces p53 and triggers apoptosis or cell cycle arrest, the features of the disrupted telomere that trigger this response and the precise mechanism involved are poorly understood. Using human cells, we show that DNA oligonucleotides homologous to the telomere 3' overhang sequence specifically induce and activate p53 and activate an S phase checkpoint by modifying the Nijmegen breakage syndrome protein, known to mediate the S phase checkpoint after DNA damage. These responses are mediated, at least in part, by the ATM kinase and are not attributable to disruption of cellular telomeres. Based on these and earlier data, we propose that these oligonucleotides mimic a physiological signal, exposure of the telomere 3' overhang due to opening of the normal telomere loop structure, and hence evoke these protective antiproliferative responses in the absence of DNA damage or telomere disruption.},
}
@article {pmid12554677,
year = {2003},
author = {Tchirkov, A and Lansdorp, PM},
title = {Role of oxidative stress in telomere shortening in cultured fibroblasts from normal individuals and patients with ataxia-telangiectasia.},
journal = {Human molecular genetics},
volume = {12},
number = {3},
pages = {227-232},
doi = {10.1093/hmg/ddg023},
pmid = {12554677},
issn = {0964-6906},
mesh = {Adolescent ; Ataxia Telangiectasia/*metabolism ; Child ; Chromosome Breakage/physiology ; DNA Repair/physiology ; Female ; Fibroblasts/*metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Male ; Middle Aged ; Oxidative Stress/*physiology ; Telomere/*metabolism ; },
abstract = {Cells from patients with the autosomal recessive disorder ataxia-telangiectasia (A-T) display accelerated telomere shortening upon culture in vitro. It has been suggested that A-T cells are in a chronic state of oxidative stress, which could contribute to their enhanced telomere shortening. In order to examine this hypothesis, we monitored the changes in telomere length in A-T homozygous, heterozygous and control fibroblasts cultured in vitro under various conditions of oxidative stress using quantitative fluorescent in situ hybridization. Compared with normal cells, the rate of telomere shortening was 1.5-fold increased under 'normal' levels of oxidative stress in A-T heterozygous cells and 2.4-3.2-fold in A-T homozygous cells. Mild chronic oxidative stress induced by hydrogen peroxide increased the rate of telomere shortening in A-T cells but not in normal fibroblasts and the telomere shortening rate decreased in both normal and A-T fibroblasts if cultures were supplemented with the anti-oxidant phenyl-butyl-nitrone. Increased telomere shortening upon oxidative stress in A-T cells was associated with a significant increase in the number of extra-chromosomal fragments of telomeric DNA and chromosome ends without detectable telomere repeats. We propose that the ATM (A-T mutated) protein has a role in the prevention or repair of oxidative damage to telomeric DNA and that enhanced sensitivity of telomeric DNA to oxidative damage in A-T cells results in accelerated telomere shortening and chromosomal instability.},
}
@article {pmid12548015,
year = {2002},
author = {Hahn, WC},
title = {Empty pockets yield more telomere change.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {1},
number = {6},
pages = {406-407},
doi = {10.4161/cc.1.6.266},
pmid = {12548015},
issn = {1538-4101},
support = {K01 CA94223/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle Proteins/metabolism ; Cell Division/*physiology ; Cellular Senescence/*physiology ; Eukaryotic Cells/*metabolism ; Humans ; Models, Animal ; Retinoblastoma Protein/metabolism ; Telomerase/metabolism ; Telomere/*physiology ; },
}
@article {pmid12547344,
year = {2003},
author = {Barry, JD and Ginger, ML and Burton, P and McCulloch, R},
title = {Why are parasite contingency genes often associated with telomeres?.},
journal = {International journal for parasitology},
volume = {33},
number = {1},
pages = {29-45},
doi = {10.1016/s0020-7519(02)00247-3},
pmid = {12547344},
issn = {0020-7519},
mesh = {Animals ; Antigenic Variation/genetics ; DNA Repair ; Gene Silencing ; *Genes, Protozoan ; Parasites/*genetics ; Plasmodium/genetics ; Telomere/*genetics ; Trypanosoma brucei brucei/genetics ; },
abstract = {Contingency genes are common in pathogenic microbes and enable, through pre-emptive mutational events, rapid, clonal switches in phenotype that are conducive to survival and proliferation in hosts. Antigenic variation, which is a highly successful survival strategy employed by eubacterial and eukaryotic pathogens, involves large repertoires of distinct contingency genes that are expressed differentially, enabling evasion of host acquired immunity. Most, but not all, antigenic variation systems make extensive use of subtelomeres. Study of model systems has shown that subtelomeres have unusual properties, including reversible silencing of genes mediated by proteins binding to the telomere, and engagement in ectopic recombination with other subtelomeres. There is a general theory that subtelomeric location confers a capacity for gene diversification through such recombination, although experimental evidence is that there is no increased mitotic recombination at such loci and that sequence homogenisation occurs. Possible benefits of subtelomeric location for pathogen contingency systems are reversible gene silencing, which could contribute to systems for gene switching and mutually exclusive expression, and ectopic recombination, leading to gene family diversification. We examine, in several antigenic variation systems, what possible benefits apply.},
}
@article {pmid12545164,
year = {2003},
author = {Ramirez, RD and Herbert, BS and Vaughan, MB and Zou, Y and Gandia, K and Morales, CP and Wright, WE and Shay, JW},
title = {Bypass of telomere-dependent replicative senescence (M1) upon overexpression of Cdk4 in normal human epithelial cells.},
journal = {Oncogene},
volume = {22},
number = {3},
pages = {433-444},
doi = {10.1038/sj.onc.1206046},
pmid = {12545164},
issn = {0950-9232},
support = {AG01228/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Calcium/metabolism ; Cell Differentiation ; Cell Division ; Cells, Cultured ; Cellular Senescence ; Chromosome Aberrations ; Cyclin D ; Cyclin-Dependent Kinase 4 ; Cyclin-Dependent Kinase Inhibitor p16/genetics/metabolism ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclin-Dependent Kinases/genetics/*metabolism ; Cyclins/metabolism ; DNA Replication ; DNA-Binding Proteins ; Epithelial Cells/*metabolism/radiation effects ; Female ; Humans ; Keratinocytes/metabolism ; *Proto-Oncogene Proteins ; Reference Values ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation ; },
abstract = {Many stimuli causing 'stress' or DNA damage in cells can produce phenotypes that overlap with telomere-based replicative senescence. In epithelial systems, the p16/RB pathway may function as a stress senescence-signaling pathway independent of telomere shortening. Overexpressing cyclin-dependent kinase 4 (Cdk4) in human epidermal keratinocytes and human mammary epithelial cells not only prevents the p16(INK4a)-associated premature growth arrest due to telomere-independent stress (e.g., inadequate culture conditions), but also bypasses the ensuing telomere-dependent senescence (M1). Overexpressed Cdk4 in epithelial cells induces a dramatic upregulation of p16(INK4a) and milder upregulation of p53 and p21(WAF1), which become unresponsive to UV irradiation. Despite the high levels of these checkpoint factors, Cdk4-overexpressing cells divide in an apparently normal regulated fashion, are able to respond to changes in calcium levels, retain the stem cell phenotype, and fully differentiate and stratify. These results suggest that the differentiation pathways in Cdk4-overexpressing cells remain intact.},
}
@article {pmid12544108,
year = {2003},
author = {Bastian, BC},
title = {The longer your telomeres, the larger your nevus?.},
journal = {The American Journal of dermatopathology},
volume = {25},
number = {1},
pages = {83-84},
pmid = {12544108},
issn = {0193-1091},
mesh = {Dermatology/*methods ; Humans ; *Nevus/classification/genetics/pathology ; Pathology/*methods ; Telomere/*pathology ; },
}
@article {pmid12543803,
year = {2003},
author = {Gordon, KE and Ireland, H and Roberts, M and Steeghs, K and McCaul, JA and MacDonald, DG and Parkinson, EK},
title = {High levels of telomere dysfunction bestow a selective disadvantage during the progression of human oral squamous cell carcinoma.},
journal = {Cancer research},
volume = {63},
number = {2},
pages = {458-467},
pmid = {12543803},
issn = {0008-5472},
mesh = {3T3 Cells ; Animals ; Carcinoma, Squamous Cell/genetics/metabolism/*pathology ; DNA-Binding Proteins ; Disease Progression ; Humans ; Immunohistochemistry ; Keratinocytes/metabolism/pathology/physiology ; Mice ; Mouth Neoplasms/genetics/metabolism/*pathology ; Telomerase/biosynthesis/genetics/metabolism ; Telomere/*physiology ; Tumor Cells, Cultured ; },
abstract = {Human epithelial cells experience multiple barriers to cellular immortality in culture (mortality mechanisms 0, 1, and 2). Mortality mechanism 2 (M2) is termed crisis and involves telomere dysfunction due to lack of telomerase. However, proliferating normal keratinocytes in vivo can express telomerase, so it is unclear whether human squamous cell carcinomas (SCCs), which usually have high telomerase levels, develop from preexisting telomerase-positive precursors or by the activation of telomerase in telomerase-deficient somatic cells. We show that 6 of 29 oral SCCs show characteristics of M2 crisis in vivo, as indicated by a high anaphase bridge index (ABI), which is a good correlate of telomere dysfunction, and that 25 of 29 tumors possess some anaphase bridges. ABIs in excess of 0.2 in the primary tumor showed a decrease in the corresponding lymph node metastases. This suggests that high levels of telomere dysfunction (>0.2) and, by inference, M2 crisis bestow a selective disadvantage on SCCs during progression stages of the disease. Supporting this, SCCs with high levels of telomere dysfunction grow poorly in culture, and the ectopic expression of telomerase corrects this, together with other features of M2 crisis. Our data suggest that a substantial proportion of oral SCCs in vivo ultimately arise from telomerase-deficient keratinocytes rather than putative telomerase-proficient cells in the undifferentiated parts of the epithelium. Furthermore, the presence of significant levels of telomere dysfunction in a high proportion of SCCs at diagnosis but not in the normal epithelium implies that the therapeutic inhibition of telomerase should selectively compromise the growth of such tumors.},
}
@article {pmid12542689,
year = {2003},
author = {Saldanha, SN and Andrews, LG and Tollefsbol, TO},
title = {Assessment of telomere length and factors that contribute to its stability.},
journal = {European journal of biochemistry},
volume = {270},
number = {3},
pages = {389-403},
doi = {10.1046/j.1432-1033.2003.03410.x},
pmid = {12542689},
issn = {0014-2956},
support = {1 R03 AG20375 01/AG/NIA NIH HHS/United States ; },
mesh = {Cell Transformation, Neoplastic/metabolism ; Cellular Senescence ; Humans ; Neoplasms/enzymology ; Telomerase/metabolism ; Telomere/*physiology ; },
abstract = {Short strands of tandem hexameric repeats known as telomeres cap the ends of linear chromosomes. These repeats protect chromosomes from degradation and prevent chromosomal end-joining, a phenomenon that could occur due to the end-replication problem. Telomeres are maintained by the activity of the enzyme telomerase. The total number of telomeric repeats at the terminal end of a chromosome determines the telomere length, which in addition to its importance in chromosomal stabilization is a useful indicator of telomerase activity in normal and malignant tissues. Telomere length stability is one of the important factors that contribute to the proliferative capacity of many cancer cell types; therefore, the detection and estimation of telomere length is extremely important. Until relatively recently, telomere lengths were analyzed primarily using the standard Southern blot technique. However, the complexities of this technique have led to the search for more simple and rapid detection methods. Improvements such as the use of fluorescent probes and the ability to sort cells have greatly enhanced the ease and sensitivity of telomere length measurements. Recent advances, and the limitations of these techniques are evaluated. Drugs that assist in telomere shortening may contribute to tumor regression. Therefore, factors that contribute to telomere stability may influence the efficiency of the drugs that have potential in cancer therapy. These factors in relation to telomere length are also examined in this analysis.},
}
@article {pmid12542495,
year = {2003},
author = {Szyper-Kravitz, M and Uziel, O and Shapiro, H and Radnay, J and Katz, T and Rowe, JM and Lishner, M and Lahav, M},
title = {Granulocyte colony-stimulating factor administration upregulates telomerase activity in CD34+ haematopoietic cells and may prevent telomere attrition after chemotherapy.},
journal = {British journal of haematology},
volume = {120},
number = {2},
pages = {329-336},
doi = {10.1046/j.1365-2141.2003.04043.x},
pmid = {12542495},
issn = {0007-1048},
mesh = {Aged ; Aged, 80 and over ; *Antigens, CD34 ; Antineoplastic Combined Chemotherapy Protocols/administration &amp; dosage/therapeutic use ; Bone Marrow Cells/drug effects/enzymology ; Cyclophosphamide/administration &amp; dosage ; Doxorubicin/administration &amp; dosage ; Enzyme Activation ; Granulocyte Colony-Stimulating Factor/*pharmacology ; *Hematopoietic Stem Cell Mobilization ; Hematopoietic Stem Cells/drug effects/*enzymology/immunology ; Humans ; Lymphoma/drug therapy/*enzymology/immunology ; Middle Aged ; Prednisone/administration &amp; dosage ; Protein Kinase C/genetics ; Protein Kinase C-alpha ; RNA/analysis ; Telomerase/genetics/*metabolism ; Telomere/genetics/ultrastructure ; Vincristine/administration &amp; dosage ; },
abstract = {Hematopoietic reconstitution could be associated with premature ageing of the transplanted cells and a high frequency of myelodysplastic syndrome and secondary leukaemia. Telomere length decreases with cell divisions and age, and at a crucial length it is associated with chromosomal instability and cell senescence. Telomerase is a reverse transcriptase enzyme that adds nucleotides to chromosomal ends. Most somatic cells lack telomerase activity yet haematopoietic stem cells retain low levels of telomerase. Some studies have found that chemotherapy and stem cell transplantation lead to the accelerated shortening of telomere length. As granulocyte colony-stimulating factor (G-CSF) is routinely used in the mobilization of stem cells for transplantation, we evaluated its effects on telomerase activity and regulation, and on telomere dynamics, in normal donors and selected lymphoma patients. Administration of G-CSF increased telomerase activity in CD34+ haematopoietic cells compared with controls. In marrow-derived CD34+ cells, telomerase activity increased sevenfold, compared with a 14-fold increase in peripheral-blood-mobilized CD34+ cells. A parallel increase in the expression of human telomerase enzyme reverse transcriptase RNA and protein kinase C alpha occurred. In addition, G-CSF administration to five lymphoma patients after consecutive courses of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, resulted in telomere length preservation or elongation, as opposed to marked attrition in patients who did not receive growth factors. We conclude that the in vivo administration of G-CSF prevents or attenuates telomere attrition associated with chemotherapy administration. This attenuation may contribute to the preservation of telomere integrity inG-CSF-primed transplanted stem cells.},
}
@article {pmid12540856,
year = {2003},
author = {Wong, KK and Maser, RS and Bachoo, RM and Menon, J and Carrasco, DR and Gu, Y and Alt, FW and DePinho, RA},
title = {Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing.},
journal = {Nature},
volume = {421},
number = {6923},
pages = {643-648},
doi = {10.1038/nature01385},
pmid = {12540856},
issn = {0028-0836},
mesh = {Aging/*genetics ; Alopecia/genetics ; Anaphase ; Animals ; Apoptosis ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins ; Cell Division ; Cells, Cultured ; DNA-Binding Proteins ; Fibroblasts ; Hair Color/genetics ; Homeostasis/*genetics ; Lymphoma, T-Cell/genetics ; Mice ; Mice, Knockout ; Protein Serine-Threonine Kinases/deficiency/*genetics ; RNA/*genetics ; Stem Cells/cytology/metabolism ; Survival Rate ; Telomerase/*genetics ; Telomere/enzymology/genetics/*metabolism ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins ; Wound Healing/genetics ; },
abstract = {Ataxia-telangiectasia (A-T) results from the loss of ataxia-telangiectasia mutated (Atm) function and is characterized by accelerated telomere loss, genomic instability, progressive neurological degeneration, premature ageing and increased neoplasia incidence. Here we evaluate the functional interaction of Atm and telomeres in vivo. We examined the impact of Atm deficiency as a function of progressive telomere attrition at both the cellular and whole-organism level in mice doubly null for Atm and the telomerase RNA component (Terc). These compound mutants showed increased telomere erosion and genomic instability, yet they experienced a substantial elimination of T-cell lymphomas associated with Atm deficiency. A generalized proliferation defect was evident in all cell types and tissues examined, and this defect extended to tissue stem/progenitor cell compartments, thereby providing a basis for progressive multi-organ system compromise, accelerated ageing and premature death. We show that Atm deficiency and telomere dysfunction act together to impair cellular and whole-organism viability, thus supporting the view that aspects of A-T pathophysiology are linked to the functional state of telomeres and its adverse effects on stem/progenitor cell reserves.},
}
@article {pmid12540745,
year = {2003},
author = {Rezler, EM and Bearss, DJ and Hurley, LH},
title = {Telomere inhibition and telomere disruption as processes for drug targeting.},
journal = {Annual review of pharmacology and toxicology},
volume = {43},
number = {},
pages = {359-379},
doi = {10.1146/annurev.pharmtox.43.100901.135733},
pmid = {12540745},
issn = {0362-1642},
mesh = {Animals ; Drug Delivery Systems/*methods ; Drug Design ; Enzyme Inhibitors/*administration &amp; dosage ; Humans ; Oligonucleotides, Antisense/administration &amp; dosage ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/*drug effects/metabolism ; },
abstract = {The components and cofactors of the holoenzyme telomerase and its substrate telomeric DNA are attractive targets for anticancer agents that act by inhibiting the activity of telomerase. This review outlines recent advances in telomerase inhibition that have been achieved using antisense oligonucleotides and ribozymes that target the telomerase mRNA or its hTR RNA template. Although these are potent catalytic inhibitors of telomerase, they are challenging to implement in the clinic due to their delayed effectiveness. Drugs that directly bind to the telomeres, the complex structures that are associated at the telomeric ends, and stabilize secondary DNA structures such as G-quadruplexes are also potent inhibitors of telomerase. Special focus is given here to the telomeres, the biological machinery that works in tandem with telomerase to elongate telomeres, the causes of telomere disruption or dysfunction, and the consequences of disruption/dysfunction on the activity and design of anticancer agents.},
}
@article {pmid12539364,
year = {2000},
author = {Gao, Z and Mao, Z and He, Y and Xu, P},
title = {[A study on the association of telomere length with the experimental carcinogenesis of oral cavity].},
journal = {Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology},
volume = {18},
number = {1},
pages = {48-51},
pmid = {12539364},
issn = {1000-1182},
mesh = {Animals ; Carcinoma, Squamous Cell/*genetics ; Cricetinae ; Mesocricetus ; Mouth Neoplasms/*genetics ; Precancerous Conditions/genetics ; Telomere/*genetics ; },
abstract = {OBJECTIVE: The life cycle of cell can be effected by the length of telomere. Loss of telomeric DNA during cell proliferation may play a role in chromosome instability, cellular apoptosis and cancer. The purpose of the study is to measure the dynamic changes of telomere length in experimental oral cavity cancer during golden hamster cheek pouch carcinogenesis induced by DMBA.<br><br>METHODS: First, 52 golden hamsters were divided into 2 groups. Four of them were not done any treatment and were killed after 3 days. The others were covered with DMBA on the surface of cheek pouch on one side in order to induce carcinogenesis, the other side of cheek pouch was treated as the control. Then, the 48 golden hamsters were divided into 4 groups and were killed in 7, 10, 14, 20 weeks. Light microscope was used to observe the pathologic changes. Southern hybridization was used to analysis the dynamic development of the length of telomeric repeat. In different periods, the reduction rate of telomere length was calculated.<br><br>RESULTS: 1. The cheek pouch mucosa uncovered with DMBA had no abnormal pathologic changes, while that covered with DMBA was observed pathologic changes of different degrees. 4 cases of hyperplasia lesions and 8 cases of dysplasia lesions were observed in the 7-week group, 7 cases of dysplasia lesions and 5 cases of mucosa carcinoma in situ in the 10-week group, 5 cases of mucosa carcinoma in situ, 4 cases of squamous cell carcinomas and 3 cases of death in the 14-week group, and 7 cases of squamous cell carcinomas and 5 cases of death in the 20-week group. 2. The telomere length of the normal mucosa was reduced with the hamsters age increasing, but the telomere length was significantly shorter than that of the normal control during the mucosa carcinogenesis of cheek pouch. The average shortened length was about 0.225 kb (the normal mucosa was 0.17 kb). 3. The highest reduction rate (0.3985) was in a later premalignant period.<br><br>CONCLUSION: Age is one of the factors that can short telomere length. However, the speed that telomere length is shorted is faster than ever while telomere is abnormal. There is an obvious relationship between the abnormal degree of telomere length and the malignant degree of carcinoma. So the abnormal shorting of telomere length is an early molecular evidence of the oral carcinogenesis.},
}
@article {pmid12539050,
year = {2003},
author = {Baird, DM and Rowson, J and Wynford-Thomas, D and Kipling, D},
title = {Extensive allelic variation and ultrashort telomeres in senescent human cells.},
journal = {Nature genetics},
volume = {33},
number = {2},
pages = {203-207},
doi = {10.1038/ng1084},
pmid = {12539050},
issn = {1061-4036},
mesh = {*Alleles ; Cell Division ; Cellular Senescence/*physiology ; *Chromosome Mapping ; Chromosomes/*genetics ; DNA/analysis ; DNA Primers/chemistry ; DNA Replication ; Fibroblasts/*cytology/ultrastructure ; Genetic Variation ; Humans ; In Situ Hybridization, Fluorescence ; Metaphase ; Mutation ; Polymerase Chain Reaction ; Telomerase ; Telomere/physiology/*ultrastructure ; Thyroid Neoplasms/*genetics ; Tumor Cells, Cultured ; },
abstract = {By imposing a limit on the proliferative lifespan of most somatic cells, telomere erosion represents an innate mechanism for tumor suppression and may contribute to age-related disease. A detailed understanding of the pathways that link shortened telomeres to replicative senescence has been severely hindered by the inability of current methods to analyze telomere dynamics in detail. Here we describe single telomere length analysis (STELA), a PCR-based approach that accurately measures the full spectrum of telomere lengths from individual chromosomes. STELA analysis of human XpYp telomeres in fibroblasts identifies several features of telomere biology. We observe bimodal distributions of telomeres in normal fibroblasts; these distributions result from inter-allelic differences of up to 6.5 kb, indicating that unexpectedly large-scale differences in zygotic telomere length are maintained throughout development. Most telomeres shorten in a gradual fashion consistent with simple losses through end replication, and the rates of erosion are independent of allele size. Superimposed on this are occasional, more substantial changes in length, which may be the consequence of additional mutational mechanisms. Notably, some alleles show almost complete loss of TTAGGG repeats at senescence.},
}
@article {pmid12534855,
year = {2003},
author = {Ahmed, A and Tollefsbol, T},
title = {Telomeres, telomerase, and telomerase inhibition: clinical implications for cancer.},
journal = {Journal of the American Geriatrics Society},
volume = {51},
number = {1},
pages = {116-122},
doi = {10.1034/j.1601-5215.2002.51019.x},
pmid = {12534855},
issn = {0002-8614},
mesh = {Aged ; Aging/*metabolism/physiology ; Biomarkers, Tumor/genetics/*metabolism ; Catalytic Domain ; DNA-Binding Proteins ; Humans ; Neoplasms/diagnosis/drug therapy/*enzymology ; Prognosis ; Telomerase/antagonists &amp; inhibitors/genetics/*metabolism ; Telomere/enzymology/physiology ; },
abstract = {Telomeres are located at the ends of eukaryotic chromosomes. The enzyme telomerase synthesized them, and they are responsible for maintaining the lengths of chromosomes. Absence of telomerase is associated with telomere shortening and aging of somatic cells, but high telomerase activity is observed in over 90% of human cancer cells. Although the disappearance of telomerase with aging is considered a natural defense against development of cancer, it is not known what triggers the reappearance of telomerase in cancer cells. Telomerase activity is directly correlated with the expression of its active catalytic component, the human telomerase reverse transcriptase (hTERT), which is controlled primarily at the level of transcription. An earlier paper discussed the relationship of telomerase with aging. In this article, the contemporary literature is reviewed to explore the associations between telomerase, telomerase inhibition, and cancer. Because most cancers occur in old age, with the aging of the population, the number of people suffering from cancer is expected to increase in the coming decades. It is not known what roles telomerase and hTERT play in the complex relationship between aging and cancer. Data from experimental studies suggest that telomerase assay could potentially play a role in the diagnosis and prognosis of cancers. There is also evidence that telomerase inhibitors might be used as anticancer agents. As the knowledge of the relationships between telomerase and cancer and between telomerase and aging advances, it is hoped that more about the interacting relationships between telomerase, aging, and cancer will be learned.},
}
@article {pmid12532699,
year = {2002},
author = {Pérez, Mdel R and Dubner, D and Michelín, S and Gisone, P and Carosella, E},
title = {[Telomeres and genomic damage repair. Their implication in human pathology].},
journal = {Medicina},
volume = {62},
number = {6},
pages = {593-603},
pmid = {12532699},
issn = {0025-7680},
mesh = {Apoptosis/physiology ; *DNA Damage ; *DNA Repair ; DNA Replication ; Enzyme Activation ; Humans ; Telomerase/physiology ; Telomere/*physiology/radiation effects ; },
abstract = {Telomeres, functional complexes that protect eukaryotic chromosome ends, participate in the regulation of cell proliferation and could play a role in the stabilization of genomic regions in response to genotoxic stress. Their significance in human pathology becomes evident in several diseases sharing genomic instability as a common trait, in which alterations of the telomere metabolism have been demonstrated. Many of them are also associated with hypersensitivity to ionizing radiation and cancer susceptibility. Besides the specific proteins belonging to the telomeric complex, other proteins involved in the DNA repair machinery, such as ATM, BRCA1, BRCA2, PARP/tankyrase system, DNA-PK and RAD50-MRE11-NBS1 complexes, are closely related with the telomere. This suggests that the telomere sequesters DNA repair proteins for its own structure maintenance, which could also be released toward damaged sites in the genomic DNA. This communication describes essential aspects of telomere structure and function and their links with homologous recombination, non-homologous end-joining (NHEJ), V(D)J system and mismatch-repair (MMR). Several pathological conditions exhibiting alterations in some of these mechanisms are also considered. The cell response to ionizing radiation and its relationship with the telomeric metabolism is particularly taken into account as a model for studying genotoxicity.},
}
@article {pmid12529991,
year = {2002},
author = {Takagi, S and Kinouchi, Y and Hiwatashi, N and Hirai, M and Suzuki, S and Takahashi, S and Negoro, K and Obana, N and Shimosegawa, T},
title = {Correlative polymorphism of NAD(P)H: quinone oxidoreductase (NQO1) with telomere shortening in colorectal cancer.},
journal = {Anticancer research},
volume = {22},
number = {5},
pages = {2749-2752},
pmid = {12529991},
issn = {0250-7005},
mesh = {Aged ; Colorectal Neoplasms/*enzymology/*genetics/pathology ; Female ; Humans ; Male ; Mutation ; NAD(P)H Dehydrogenase (Quinone)/*genetics ; Polymerase Chain Reaction ; *Polymorphism, Genetic ; Polymorphism, Restriction Fragment Length ; Telomerase/metabolism ; Telomere/*genetics ; },
abstract = {AIM: The aim of this study was to examine whether and relationships could be found among polymorphism of the NQO1 gene, telomere length and telomerase activity in colorectal cancers.<br><br>MATERIALS AND METHODS: Fifty-one invasive colorectal cancers were studied. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was undergone to detect mutation of the NQO1 gene. Telomere length was examined by Southern blot analysis. Telomerase activity was assayed by telomeric repeat amplification protocol with minor modifications.<br><br>RESULTS: Of the 51 tumors, 20 (39.2%) and 9 (17.6%) were heterozygous and homozygous for the mutation, respectively. Most of the cases homozygous for the mutation (88.9%) showed short telomeres and its frequency was significantly higher than in those heterozygous (p = 0.0432). However no relationship was found between the telomerase activity and mutation in the NQO1 gene.<br><br>CONCLUSION: Our data suggest that oxidative stress by the lack of NQO1 activity could result in telomere shortening through colorectal cancinogenesis.},
}
@article {pmid12527915,
year = {2003},
author = {Sharma, GG and Gupta, A and Wang, H and Scherthan, H and Dhar, S and Gandhi, V and Iliakis, G and Shay, JW and Young, CS and Pandita, TK},
title = {hTERT associates with human telomeres and enhances genomic stability and DNA repair.},
journal = {Oncogene},
volume = {22},
number = {1},
pages = {131-146},
doi = {10.1038/sj.onc.1206063},
pmid = {12527915},
issn = {0950-9232},
support = {CA13696/CA/NCI NIH HHS/United States ; CN-15015/CN/NCI NIH HHS/United States ; NS34746/NS/NINDS NIH HHS/United States ; },
mesh = {DNA Damage ; *DNA Repair/*physiology ; DNA-Binding Proteins ; Gene Expression Regulation/physiology ; *Genome, Human ; HeLa Cells ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Protein Binding ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*metabolism/physiology ; Telomere ; },
abstract = {Ectopic expression of telomerase in telomerase-silent cells is sufficient to overcome senescence and to extend cellular lifespan. We show here that the catalytic subunit of human telomerase (hTERT) crosslinks telomeres. This interaction is blocked by the telomere repeat binding factor 1, but not by a dominant negative form of this protein. It is also abolished by destruction of the RNA component of telomerase as well as by mutations in the hTERT protein. Ectopic expression of hTERT leads to transcriptional alterations of a subset of genes and changes in the interaction of the telomeres with the nuclear matrix. This is associated with reduction of spontaneous chromosome damage in G(1) cells, enhancement of the kinetics of DNA repair and an increase in NTP levels. The effect on DNA repair is likely indirect as TERT does not directly affect DNA end rejoining in vitro or meiotic recombination in vivo. The observed effects of hTERT occurred rapidly before any significant lengthening of telomeres was observed. Our findings establish an intimate relationship between hTERT-telomere interactions and alteration in transcription of a subset of genes that may lead to increased genomic stability and enhanced repair of genetic damage. These novel functions of telomerase are distinct from its known effect on telomere length and have potentially important biological consequences.},
}
@article {pmid12526095,
year = {2002},
author = {Suh, D and Oh, YK and Ahn, B and Hur, MW and Kim, HJ and Lee, MH and Joo, HS and Auh, C},
title = {Comparative binding of antitumor drugs to DNA containing the telomere repeat sequence.},
journal = {Experimental &amp; molecular medicine},
volume = {34},
number = {5},
pages = {326-331},
doi = {10.1038/emm.2002.46},
pmid = {12526095},
issn = {1226-3613},
mesh = {Antineoplastic Agents/*metabolism ; Bleomycin/metabolism/pharmacology ; Circular Dichroism ; DNA/chemistry/drug effects/*metabolism ; DNA Damage ; Dactinomycin/metabolism ; Doxorubicin/*analogs &amp; derivatives/metabolism ; Humans ; Nogalamycin/metabolism ; Nucleic Acid Conformation ; *Repetitive Sequences, Nucleic Acid ; Telomere/drug effects/*genetics ; },
abstract = {Telomeres are the ends of the linear chromosomes of eukaryotes and consist of tandem GT-rich repeats in telomere sequence i.e. 500-3000 repeats of 5'-TTAGGG-3' in human somatic cells, which are shortened gradually with age. The G-rich overhang of telomere sequence can adopt different intramolecular fold-backs and tetra-stranded DNA structures, in vitro, which inhibit telomerase activity. In this report, DNA binding agents to telomere sequence were studied novel therapeutic possibility to destabilize telomeric DNA sequences. Oligonucleotides containing the guanine repeats in human telomere sequence were synthesized and used for screening potential antitumor drugs. Telomeric DNA sequence was characterized using spectral measurements and CD spectroscopy. CD spectrum indicated that the double-stranded telomeric DNA is in a right-handed conformation. Polyacrylamide gel electrophoresis was performed for binding behaviors of antitumor compounds with telomeric DNA sequence. Drugs interacted with DNA sequence caused changes in the electrophoretic mobility and band intensity of the gels. Depending on the binding mode of the anticancer drugs, telomeric DNA sequence was differently recognized and the efficiency of cleavage of DNA varies in the bleomycin-treated samples under different conditions. DNA cleavage occurred at about 1% by the increments of 1 micromM bleomycin-Fe(III). These results imply that the stability of human telomere sequence is important in conjunction with the cancer treatment and aging process.},
}
@article {pmid12524334,
year = {2002},
author = {Parenteau, J and Wellinger, RJ},
title = {Differential processing of leading- and lagging-strand ends at Saccharomyces cerevisiae telomeres revealed by the absence of Rad27p nuclease.},
journal = {Genetics},
volume = {162},
number = {4},
pages = {1583-1594},
pmid = {12524334},
issn = {0016-6731},
mesh = {Base Composition ; Base Sequence ; DNA, Fungal/chemistry/genetics/metabolism ; DNA, Single-Stranded/chemistry/genetics/metabolism ; Endodeoxyribonucleases/genetics/*metabolism ; Flap Endonucleases ; Gene Deletion ; Genes, Fungal ; Models, Biological ; Phenotype ; Plasmids/genetics ; Saccharomyces cerevisiae/genetics/*metabolism ; *Saccharomyces cerevisiae Proteins ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; },
abstract = {Saccharomyces cerevisiae strains lacking the Rad27p nuclease, a homolog of the mammalian FEN-1 protein, display an accumulation of extensive single-stranded G-tails at telomeres. Furthermore, the lengths of telomeric repeats become very heterogeneous. These phenotypes could be the result of aberrant Okazaki fragment processing of the C-rich strand, elongation of the G-rich strand by telomerase, or an abnormally high activity of the nucleolytic activities required to process leading-strand ends. To distinguish among these possibilities, we analyzed strains carrying a deletion of the RAD27 gene and also lacking genes required for in vivo telomerase activity. The results show that double-mutant strains died more rapidly than strains lacking only telomerase components. Furthermore, in such strains there is a significant reduction in the signals for G-tails as compared to those detected in rad27delta cells. The results from studies of the replication intermediates of a linear plasmid in rad27delta cells are consistent with the idea that only one end of the plasmid acquires extensive G-tails, presumably the end made by lagging-strand synthesis. These data further support the notion that chromosome ends have differential requirements for end processing, depending on whether the ends were replicated by leading- or lagging-strand synthesis.},
}
@article {pmid12515865,
year = {2003},
author = {Li, GZ and Eller, MS and Firoozabadi, R and Gilchrest, BA},
title = {Evidence that exposure of the telomere 3' overhang sequence induces senescence.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {100},
number = {2},
pages = {527-531},
pmid = {12515865},
issn = {0027-8424},
mesh = {Cell Division ; Cells, Cultured ; *Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins/analysis ; *DNA Damage ; Humans ; Phosphorylation ; Retinoblastoma Protein/analysis ; Tandem Repeat Sequences ; *Telomere ; Telomeric Repeat Binding Protein 2/physiology ; Tumor Suppressor Protein p53/analysis/metabolism ; },
abstract = {Normal human cells cease proliferation after a finite number of population doublings, a phenomenon termed replicative senescence. This process, first convincingly described by Hayflick and Moorhead [Hayflick, L. &amp; Moorhead, P. S. (1961) Exp. Cell Res. 25, 595-621] for cultured human fibroblasts 40 years ago, is suggested to be a fundamental defense against cancer. Several events have been demonstrated to induce the senescent phenotype including telomere shortening, DNA damage, oxidative stress, and oncogenic stimulation. The molecular mechanisms underlying senescence are poorly understood. Here we report that a 1-week exposure to oligonucleotide homologous to the telomere 3'-overhang sequence TTAGGG (T-oligo) similarly specifically induces a senescent phenotype in cultured human fibroblasts, mimicking serial passage or ectopic expression of a dominant negative form of the telomeric repeat binding factor, TRF2(DN). We propose that exposure of the 3' overhang due to telomere loop disruption may occur with critical telomere shortening or extensive acute DNA damage and that the exposed TTAGGG tandem repeat sequence then triggers DNA-damage responses. We further demonstrate that these responses can be induced by treatment with oligonucleotides homologous to the overhang in the absence of telomere disruption, a phenomenon of potential therapeutic importance.},
}
@article {pmid12514102,
year = {2003},
author = {Chang, S and Khoo, CM and Naylor, ML and Maser, RS and DePinho, RA},
title = {Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression.},
journal = {Genes &amp; development},
volume = {17},
number = {1},
pages = {88-100},
pmid = {12514102},
issn = {0890-9369},
support = {K08 AG001019/AG/NIA NIH HHS/United States ; 1KO8AG01019-01/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Cell Line, Transformed/enzymology/pathology/transplantation ; Chromosome Aberrations ; Chromosome Painting ; Chromosomes/ultrastructure ; Cyclin-Dependent Kinase Inhibitor p16/deficiency ; Embryo, Mammalian/cytology ; Fibroblasts/enzymology/pathology/transplantation ; In Situ Hybridization, Fluorescence ; Lung Neoplasms/secondary ; Mice ; Mice, Knockout ; Mice, SCID ; Neoplasm Proteins/*physiology ; Neoplasm Transplantation ; RNA/genetics ; Telomerase/deficiency/genetics/*physiology ; Telomere/*physiology ; },
abstract = {Telomerase activation is a common feature of most advanced human cancers and is postulated to restore genomic stability to a level permissive for cell viability and tumor progression. Here, we used genetically defined transformed mouse embryonic fibroblast (MEF) cultures derived from late generation mTerc(-/-) Ink4a/Arf(-/-) mice to explore more directly how telomere-based crisis relates to the evolution of cancer cell genomes and to tumor biology. An exhaustive serial analysis of cytogenetic profiles over extensive passage in culture revealed that the emergence of chromosomal fusions (including dicentrics) coincided with onset of deletions and complex nonreciprocal translocations (NRTs), whereas mTerc-transduced cultures maintained intact chromosomes and stable genomes. Despite a high degree of telomere dysfunction and genomic instability, transformed late passage mTerc(-/-) Ink4a/Arf(-/-) cultures retained the capacity to form subcutaneous tumors in immunocompromised mice. However, even moderate levels of telomere dysfunction completely abrogated the capacity of these cells to form lung metastases after tail-vein injection, whereas mTerc reconstitution alone conferred robust metastatic activity in these cells. Finally, serial subcutaneous tumor formation using late passage transformed mTerc(-/-) Ink4a/Arf(-/-) cultures revealed clear evidence of telomerase-independent alternative lengthening of telomeres (ALT). Significantly, despite a marked increase in telomere reserve, cells derived from the ALT+ subcutaneous tumors were unable to generate lung metastases, indicating in vivo functional differences in these principal mechanisms of telomere maintenance. Together, these results are consistent with the model that although telomere dysfunction provokes chromosomal aberrations that initiate carcinogenesis, telomerase-mediated telomere maintenance enables such initiated cells to efficiently achieve a fully malignant endpoint, including metastasis.},
}
@article {pmid12510197,
year = {2003},
author = {Cenci, G and Siriaco, G and Raffa, GD and Kellum, R and Gatti, M},
title = {The Drosophila HOAP protein is required for telomere capping.},
journal = {Nature cell biology},
volume = {5},
number = {1},
pages = {82-84},
doi = {10.1038/ncb902},
pmid = {12510197},
issn = {1465-7392},
mesh = {Animals ; Chromosomal Proteins, Non-Histone/*metabolism ; *Chromosome Mapping ; Drosophila Proteins/*metabolism ; Drosophila melanogaster/*embryology/genetics ; Embryo, Nonmammalian/physiology/ultrastructure ; Telomere/*physiology/ultrastructure ; },
abstract = {HOAP (HP1/ORC-associated protein) has recently been isolated from Drosophila melanogaster embryos as part of a cytoplasmic complex that contains heterochromatin protein 1 (HP1) and the origin recognition complex subunit 2 (ORC2). Here, we show that caravaggio, a mutation in the HOAP-encoding gene, causes extensive telomere-telomere fusions in larval brain cells, indicating that HOAP is required for telomere capping. Our analyses indicate that HOAP is specifically enriched at mitotic chromosome telomeres, and strongly suggest that HP1 and HOAP form a telomere-capping complex that does not contain ORC2.},
}
@article {pmid12509295,
year = {2002},
author = {Lee, SE and Bressan, DA and Petrini, JH and Haber, JE},
title = {Complementation between N-terminal Saccharomyces cerevisiae mre11 alleles in DNA repair and telomere length maintenance.},
journal = {DNA repair},
volume = {1},
number = {1},
pages = {27-40},
doi = {10.1016/s1568-7864(01)00003-9},
pmid = {12509295},
issn = {1568-7864},
support = {5T32GM-07133/GM/NIGMS NIH HHS/United States ; ES09090/ES/NIEHS NIH HHS/United States ; GM56888/GM/NIGMS NIH HHS/United States ; },
mesh = {*Alleles ; Antineoplastic Agents, Alkylating/pharmacology ; Cell Survival/drug effects/genetics ; Chromosome Breakage/genetics ; DNA Damage/genetics ; DNA Repair/*genetics ; Endodeoxyribonucleases/chemistry/*genetics ; Exodeoxyribonucleases/chemistry/*genetics/metabolism ; G2 Phase/drug effects ; Methyl Methanesulfonate/pharmacology ; Mitosis/drug effects ; Mutation ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/chemistry/*genetics ; *Telomere ; },
abstract = {In Saccharomyces cerevisiae, Mre11p, Rad50p, and Xrs2p function as a multiprotein complex that has a central role in several DNA repair mechanisms. Though Mre11p has both single-stranded and double-stranded 3'-5' exonuclease activity in vitro, null mutants of MRE11, RAD50, and XRS2 exhibit reduced 5'-3' resection of HO-induced double-strand breaks (DSBs) in vivo. In this study, we analyzed four mre11 mutants harboring changes in the N-terminus of Mre11p where the four phosphoesterase motifs specify the in vitro nuclease activities of Mre11p and its homologues. We find that the 5'-3' resection defects in vivo do not correlate with several mitotic phenotypes: non-homologous end-joining (NHEJ), telomere length maintenance, and adaptation to the DNA damage-inducible G2/M checkpoint. Overexpression of the 5'-3' exonuclease Exo1p in a mre11Delta strain partially increased 5'-3' resection and partially suppressed both methyl methanesulfonate (MMS) hypersensitivity and adaptation phenotypes, but did not affect telomere length or NHEJ. Surprisingly, the co-expression of two alleles, mre11-58S and mre11-N113S, each of which confers MMS hypersensitivity and short telomeres, can fully complement the MMS sensitivity and shortened telomere length of mre11Delta cells. We propose that at least two separate activities associated with the N-terminus of Mre11p are required for its mitotic function.},
}
@article {pmid12505991,
year = {2003},
author = {Leri, A and Franco, S and Zacheo, A and Barlucchi, L and Chimenti, S and Limana, F and Nadal-Ginard, B and Kajstura, J and Anversa, P and Blasco, MA},
title = {Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation.},
journal = {The EMBO journal},
volume = {22},
number = {1},
pages = {131-139},
pmid = {12505991},
issn = {0261-4189},
support = {R01 AG017042/AG/NIA NIH HHS/United States ; AG-15756/AG/NIA NIH HHS/United States ; R01 HL038132/HL/NHLBI NIH HHS/United States ; HL-66923/HL/NHLBI NIH HHS/United States ; R01 HL039902/HL/NHLBI NIH HHS/United States ; AG-17042/AG/NIA NIH HHS/United States ; HL-38132/HL/NHLBI NIH HHS/United States ; R01 HL065577/HL/NHLBI NIH HHS/United States ; HL-39902/HL/NHLBI NIH HHS/United States ; HL-65577/HL/NHLBI NIH HHS/United States ; R01 HL065573/HL/NHLBI NIH HHS/United States ; HL-65573/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; Disease Models, Animal ; Gene Expression Regulation ; *Genes, p53 ; Heart/*physiology/physiopathology ; Heart Failure/*genetics ; Humans ; Mice ; Mice, Knockout ; Muscle Cells/cytology/physiology ; Telomerase/*deficiency/*genetics/metabolism ; Telomere/*genetics/ultrastructure ; Tumor Suppressor Protein p53/*genetics ; Vasodilation/*genetics ; },
abstract = {Cardiac failure is a frequent cause of death in the aging human population. Telomere attrition occurs with age, and is proposed to be causal for the aging process. To determine whether telomere shortening leads to a cardiac phenotype, we studied heart function in the telomerase knockout mouse, Terc-/-. We studied Terc-/- mice at the second, G2, and fifth, G5, generation. Telomere shortening in G2 and G5 Terc-/- mice was coupled with attenuation in cardiac myocyte proliferation, increased apoptosis and cardiac myocyte hypertrophy. On a single-cell basis, telomere shortening was coincidental with increased expression of p53, indicating the presence of dysfunctional telomeres in cardiac myocytes from G5 Terc-/- mice. The impairment in cell division, the enhanced cardiac myocyte death and cellular hypertrophy, are concomitant with ventricular dilation, thinning of the wall and cardiac dysfunction. Thus, inhibition of cardiac myocyte replication provoked by telomere shortening, results in de-compensated eccentric hypertrophy and heart failure in mice. Telomere shortening with age could also contribute to cardiac failure in humans, opening the possibility for new therapies.},
}
@article {pmid12503323,
year = {2002},
author = {Learish, RD and Shultz, J and Ho, S and Bulleit, RF},
title = {Small-scale telomere repeat sequence content assay using pyrophosphorolysis coupled with ATP detection.},
journal = {BioTechniques},
volume = {33},
number = {6},
pages = {1349-1353},
doi = {10.2144/02336pf01},
pmid = {12503323},
issn = {0736-6205},
mesh = {Adenosine Triphosphate/*analysis ; Animals ; Bacteriophage lambda/genetics ; DNA/*chemistry ; DNA, Fungal/chemistry ; DNA, Neoplasm/chemistry ; Diphosphates/*metabolism ; Drosophila melanogaster/genetics ; HL-60 Cells ; HeLa Cells ; Humans ; Jurkat Cells ; Luciferases/metabolism ; *Luminescent Measurements ; Mammals/genetics ; *Nucleic Acid Hybridization ; Oligonucleotide Probes ; Phosphorylation ; *Repetitive Sequences, Nucleic Acid ; Reproducibility of Results ; Saccharomyces cerevisiae/genetics ; Sequence Homology, Nucleic Acid ; Telomere/*chemistry ; },
abstract = {Studies of telomere length have been carried out in diverse areas of research. However, current methods to measure telomeres are cumbersome and not amenable to high-throughput analyses. Using a coupled pyrophosphorolysis/trans-phosphorylation reaction, we have developed a novel assay to quantitate telomere sequence content in a single tube or 96-well format. The method uses a telomere-specific oligonucleotide probe to sample nanogram quantities of DNA without PCR amplification. Polymerase and kinase enzymes drive the production of ATP, which is then monitored with a luciferase enzyme reporter system. Using this approach, we demonstrated that the luminescent output was linear across a 100-fold range of DNA input, and the assay was sensitive to 0.4-1 ng DNA. A control probe reaction and a DNA quantitation reaction were also designed using the same pyrophosphorolysis technology to correct for background activity and normalize the signal against variations in DNA input, respectively. Finally, we show that the normalized luminescent signal generated by this new method is highly correlated to the telomere restriction fragment length for six human cell lines.},
}
@article {pmid12502246,
year = {2002},
author = {Balasov, ML},
title = {Genetic factors controlling white gene expression of the transposon A(R) 4-24 at a telomere in Drosophila melanogaster.},
journal = {Genome},
volume = {45},
number = {6},
pages = {1025-1034},
doi = {10.1139/g02-074},
pmid = {12502246},
issn = {0831-2796},
mesh = {*ATP-Binding Cassette Transporters ; Animals ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/genetics ; *DNA Transposable Elements ; Drosophila Proteins/*genetics ; Drosophila melanogaster/*genetics ; Eye Proteins/*genetics ; Female ; Gene Expression Regulation/*genetics ; In Situ Hybridization ; Male ; Mosaicism ; Phenotype ; *Telomere ; },
abstract = {The position effect of the AR 4-24 P[white, rosy] transposon was studied at cytological position 60F. Three copies of the transposon (within approximately 50-kb region) resulted in a spatially restricted pattern of white variegation. This pattern was modified by temperature and by removal of the Y chromosome, suggesting that it was due to classical heterochromatin-induced position effect variegation (PEV). In contrast with classical PEV, extra dose of the heterochromatin protein 1 (HP1) suppressed white variegation and one dose enhanced it. The effect of Pc-G, trx-G, and other PEV suppressors was also tested. It was found that E(Pc)1, TrlR85, and mutations of Su(z)2C relieve A(R) 4-24-silencing and z1 enhances it. To explain the results obtained with these modifiers, it is proposed that PEV and telomeric position effect can counteract each other at this particular cytological site.},
}
@article {pmid12498682,
year = {2002},
author = {Hediger, F and Neumann, FR and Van Houwe, G and Dubrana, K and Gasser, SM},
title = {Live imaging of telomeres: yKu and Sir proteins define redundant telomere-anchoring pathways in yeast.},
journal = {Current biology : CB},
volume = {12},
number = {24},
pages = {2076-2089},
doi = {10.1016/s0960-9822(02)01338-6},
pmid = {12498682},
issn = {0960-9822},
mesh = {Cell Nucleus/genetics ; DNA Polymerase I/genetics/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; *DNA-Directed DNA Polymerase ; Fungal Proteins/genetics/metabolism ; Green Fluorescent Proteins ; Histone Deacetylases/genetics/metabolism ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Interphase/genetics ; Luminescent Proteins/genetics/metabolism ; Microscopy, Fluorescence/methods ; Mitosis/genetics ; Mutation ; S Phase/genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Signal Transduction ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/*metabolism ; Sirtuin 2 ; Sirtuins/genetics/metabolism ; Telomere/*physiology/ultrastructure ; Yeasts/*genetics/metabolism ; },
abstract = {BACKGROUND: The positioning of chromosomal domains within interphase nuclei is thought to facilitate transcriptional repression in yeast. Although this is particularly well characterized for telomeres, the molecular basis of their specific subnuclear organization is poorly understood. The use of live fluorescence imaging overcomes limitations of in situ staining on fixed cells and permits the analysis of chromatin dynamics in relation to stages of the cell cycle.<br><br>RESULTS: We have characterized the dynamics of yeast telomeres and their associated domains of silent chromatin by using rapid time-lapse microscopy. In interphase, native telomeres are highly dynamic but remain within a restricted volume adjacent to the nuclear envelope. This constraint is lost during mitosis. A quantitative analysis of selected mutants shows that the yKu complex is necessary for anchoring some telomeres at the nuclear envelope (NE), whereas the myosin-like proteins Mlp1 and Mlp2 are not. We are able to correlate increased telomeric repression with increased anchoring and show that silent chromatin is tethered to the NE in a Sir-dependent manner in the absence of the yKu complex. Sir-mediated anchoring is S phase specific, while the yKu-mediated pathway functions throughout interphase. Subtelomeric elements of yeast telomere structure influence the relative importance of the yKu- and Sir-dependent mechanisms.<br><br>CONCLUSIONS: Interphase positioning of telomeres can be achieved through two partially redundant mechanisms. One requires the heterodimeric yKu complex, but not Mlp1 and Mlp2. The second requires Silent information regulators, correlates with transcriptional repression, and is specific to S phase.},
}
@article {pmid12496480,
year = {2002},
author = {Velicescu, M and Dubeau, L},
title = {p53: a key player in the telomere dynamics.},
journal = {Cancer biology &amp; therapy},
volume = {1},
number = {5},
pages = {518-519},
doi = {10.4161/cbt.1.5.168},
pmid = {12496480},
issn = {1538-4047},
mesh = {Carcinoma/enzymology/genetics ; Cell Division ; Cell Transformation, Viral ; Female ; Gene Deletion ; Genes, p53 ; Humans ; Mutation ; Ovarian Neoplasms/enzymology/genetics ; Recombination, Genetic ; Telomerase/chemistry/genetics/metabolism ; Telomere/*physiology ; Tumor Suppressor Protein p53/genetics/*metabolism/physiology ; },
}
@article {pmid12496394,
year = {2003},
author = {Hathcock, KS and Kaech, SM and Ahmed, R and Hodes, RJ},
title = {Induction of telomerase activity and maintenance of telomere length in virus-specific effector and memory CD8+ T cells.},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {170},
number = {1},
pages = {147-152},
doi = {10.4049/jimmunol.170.1.147},
pmid = {12496394},
issn = {0022-1767},
support = {AI30048/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; CD8-Positive T-Lymphocytes/cytology/*enzymology/immunology/*virology ; Cell Division/immunology ; Enzyme Induction/immunology ; Epitopes, T-Lymphocyte/immunology ; Flow Cytometry ; *Immunologic Memory ; Interphase/immunology ; Lymphocytic choriomeningitis virus/*immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Transgenic ; T-Lymphocyte Subsets/cytology/*enzymology/immunology/*virology ; Telomerase/*biosynthesis/metabolism/physiology ; Telomere/*metabolism ; },
abstract = {Acute viral infections induce extensive proliferation and differentiation of virus-specific CD8+ T cells. One mechanism reported to regulate the proliferative capacity of activated lymphocytes is mediated by the effect of telomerase in maintaining the length of telomeres in proliferating cells. We examined the regulation of telomerase activity and telomere length in naive CD8+ T cells and in virus-specific CD8+ T cells isolated from mice infected with lymphocytic choriomeningitis virus. These studies reveal that, compared with naive CD8+ T cells, which express little or no telomerase activity, Ag-specific effector and long-lived memory CD8+ T cells express high levels of telomerase activity. Despite the extensive clonal expansion that occurs during acute lymphocytic choriomeningitis virus infection, telomere length is maintained in both effector and memory CD8+ T cells. These results suggest that induction of telomerase activity in Ag-specific effector and memory CD8+ T cells is important for the extensive clonal expansion of both primary and secondary effector cells and for the maintenance and longevity of the memory CD8+ T cell population.},
}
@article {pmid12493553,
year = {2003},
author = {Panossian, LA and Porter, VR and Valenzuela, HF and Zhu, X and Reback, E and Masterman, D and Cummings, JL and Effros, RB},
title = {Telomere shortening in T cells correlates with Alzheimer's disease status.},
journal = {Neurobiology of aging},
volume = {24},
number = {1},
pages = {77-84},
doi = {10.1016/s0197-4580(02)00043-x},
pmid = {12493553},
issn = {0197-4580},
support = {AG10415/AG/NIA NIH HHS/United States ; AG16570/AG/NIA NIH HHS/United States ; RR00865/RR/NCRR NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/blood/*genetics/immunology ; Analysis of Variance ; Apoptosis/physiology ; B-Lymphocytes/classification/drug effects/immunology ; CD28 Antigens/analysis ; CD3 Complex/analysis ; CD8 Antigens/analysis ; Female ; Flow Cytometry/methods ; Heat-Shock Proteins ; Heat-Shock Response ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes, Mononuclear/drug effects/immunology ; Male ; Middle Aged ; Phytohemagglutinins/pharmacology ; Psychiatric Status Rating Scales ; T-Lymphocytes/cytology/*physiology ; Telomerase/drug effects/genetics/metabolism ; Telomere/*genetics ; },
abstract = {Telomeres, the repeated sequences that cap chromosome ends, undergo shortening with each cell division, and therefore serve as markers of a cell's replicative history. In vivo, clonal expansion of T cells during immune responses to both foreign and autoantigens is associated with telomere shortening. To investigate possible immune alterations in Alzheimer's disease (AD) that might impact current vaccine-based therapeutic strategies, we analyzed telomere lengths in immune cell populations from AD patients. Our data show a significant telomere shortening in PBMC from AD versus controls (P=0.04). Importantly, telomere length of T cells, but not of B cells or monocytes, correlated with AD disease status, measured by Mini Mental Status Exam (MMSE) scores (P=0.025). T cell telomere length also inversely correlated with serum levels of the proinflammatory cytokine TNFalpha (a clinical marker of disease status), with the proportion of CD8+ T cells lacking expression of the CD28 costimulatory molecule, and with apoptosis. These findings suggest an immune involvement in AD pathogenesis.},
}
@article {pmid12490156,
year = {2002},
author = {Hediger, F and Dubrana, K and Gasser, SM},
title = {Myosin-like proteins 1 and 2 are not required for silencing or telomere anchoring, but act in the Tel1 pathway of telomere length control.},
journal = {Journal of structural biology},
volume = {140},
number = {1-3},
pages = {79-91},
doi = {10.1016/s1047-8477(02)00533-6},
pmid = {12490156},
issn = {1047-8477},
mesh = {Bleomycin/pharmacology ; Blotting, Southern ; Cell Nucleus/metabolism ; DNA ; DNA Damage ; Gene Deletion ; Gene Silencing ; Genotype ; In Situ Hybridization, Fluorescence ; Microscopy, Fluorescence ; Models, Genetic ; Mutation ; Nuclear Pore Complex Proteins ; Nuclear Proteins/genetics/*physiology ; RNA-Binding Proteins ; Saccharomyces cerevisiae Proteins/genetics/*physiology ; Telomerase/metabolism ; Telomere/*genetics/metabolism/ultrastructure ; Temperature ; },
abstract = {The positioning of chromosomal domains in interphase nuclei is thought to facilitate transcriptional repression in yeast. It has been reported that two large coiled-coil proteins of the nuclear envelope, myosin-like proteins 1 and 2, play direct roles in anchoring yeast telomeres to the nuclear periphery, thereby creating a subcompartment enriched for Sir proteins. We have created strains containing complete deletions of mlp1 and mlp2 genes, as well as the double null strain, and find no evidence for the disruption of telomere anchoring at the nuclear periphery in these cells. We also detect no disruption of telomere-associated gene silencing. We confirm, on the other hand, that mlp mutants are particularly sensitive to DNA-damaging agents, such as bleomycin. Moreover, we show that rather than having short telomeres as in yKu-deficient strains, the mlp1 mlp2 strains have extended telomeres, resembling phenotypes of mutations in rif1. Whereas the mlp1 mlp2 mutations act on a pathway of telomere length regulation different from that of yKu70, the effects of the tel1 deletion are epistatic to the mlp mutations, suggesting that the Mlp proteins restrict telomere length in wild-type cells by influencing the Rif-Tel1 pathway of telomerase regulation.},
}
@article {pmid12489827,
year = {2002},
author = {Jönsson, F and Postberg, J and Schaffitzel, C and Lipps, HJ},
title = {Organization of the macronuclear gene-sized pieces of stichotrichous ciliates into a higher order structure via telomere-matrix interactions.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {10},
number = {6},
pages = {445-453},
pmid = {12489827},
issn = {0967-3849},
mesh = {Animals ; Cell Division/physiology ; DNA Primers/chemistry ; DNA, Protozoan/analysis ; Hypotrichida/*physiology ; In Situ Hybridization, Fluorescence ; Models, Molecular ; Nuclear Matrix/*metabolism ; Polymerase Chain Reaction ; Protein Subunits ; Protozoan Proteins/metabolism ; Repetitive Sequences, Nucleic Acid ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Macronuclear DNA of stichotrichous ciliates occurs in small 'gene-sized' molecules with sizes of about 0.5 to 40 kb. Each of these molecules is terminated by telomeric sequences of defined length. A single macronucleus contains up to 10(8) DNA molecules; due to the high concentration of telomeric sequences in this nucleus it is an attractive model to study telomere behaviour. We recently provided evidence that macronuclear telomeres are attached to the nuclear matrix and that this interaction is mediated by the telomere binding protein (TeBP). Using various experimental approaches, we now demonstrate that telomeres as well as both subunits of the telomere binding protein are associated with the nuclear matrix. However, there is no direct binding of telomeric DNA to the matrix but telomere matrix interaction is exclusively mediated by the TeBP. In addition, we show that telomeric sequences adopt in vivo the antiparallel G-quartet structure when bound to the nuclear matrix. These data not only allow us to propose a model for macronuclear architecture but may also be relevant for further analysis of telomere-matrix interactions in higher eukaryotes.},
}
@article {pmid12488618,
year = {2001},
author = {Blasco, MA},
title = {Telomeres in Cancer Therapy.},
journal = {Journal of biomedicine &amp; biotechnology},
volume = {1},
number = {1},
pages = {3-4},
pmid = {12488618},
issn = {1110-7251},
}
@article {pmid12485943,
year = {2003},
author = {Brümmendorf, TH and Ersöz, I and Hartmann, U and Bartolovic, K and Balabanov, S and Wahl, A and Paschka, P and Kreil, S and Lahaye, T and Berger, U and Gschaidmeier, H and Bokemeyer, C and Hehlmann, R and Dietz, K and Lansdorp, PM and Kanz, L and Hochhaus, A},
title = {Telomere length in peripheral blood granulocytes reflects response to treatment with imatinib in patients with chronic myeloid leukemia.},
journal = {Blood},
volume = {101},
number = {1},
pages = {375-376},
doi = {10.1182/blood-2002-08-2557},
pmid = {12485943},
issn = {0006-4971},
mesh = {Benzamides ; Biomarkers ; Granulocytes/*ultrastructure ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy/genetics/pathology ; Piperazines/*therapeutic use ; Pyrimidines/*therapeutic use ; Telomere/metabolism/*ultrastructure ; Treatment Outcome ; },
}
@article {pmid12482501,
year = {2002},
author = {Terasaki, Y and Okumura, H and Ohtake, S and Nakao, S},
title = {Accelerated telomere length shortening in granulocytes: a diagnostic marker for myeloproliferative diseases.},
journal = {Experimental hematology},
volume = {30},
number = {12},
pages = {1399-1404},
doi = {10.1016/s0301-472x(02)00969-4},
pmid = {12482501},
issn = {0301-472X},
mesh = {Adult ; Aged ; Aged, 80 and over ; Blotting, Southern ; Case-Control Studies ; Female ; Granulocytes/*ultrastructure ; Humans ; Leukocytosis/pathology ; Male ; Middle Aged ; Molecular Diagnostic Techniques/methods/standards ; Myeloproliferative Disorders/*diagnosis/etiology/pathology ; T-Lymphocytes/ultrastructure ; Telomere/metabolism/*ultrastructure ; },
abstract = {OBJECTIVE: The telomere in mature myeloid cells derived from abnormal progenitor cells of myeloproliferative diseases (MPDs) may shorten more rapidly than that in T lymphocytes, which are considered to be derived from normal clones. To test this hypothesis, we measured telomere lengths in granulocytes and T lymphocytes from patients with MPDs and compared them with those from normal individuals.<br><br>MATERIALS AND METHODS: Granulocytes and T lymphocytes were separated from the peripheral blood of 65 patients with MPDs (25 chronic myelogenous leukemia [CML], 16 polycythemia vera, 19 essential thrombocythemia, 5 chronic idiopathic myelofibrosis) and 35 normal individuals. Genomic DNA from each cell fraction was subjected to Southern blot hybridization to determine the mean telomere length.<br><br>RESULTS: Telomere lengths in granulocytes from patients with MPDs were significantly shorter than those from normal individuals (vs CML, p = 0.002; vs other MPDs, p < 0.0001). However, there was no statistical difference in telomere length in T lymphocytes between MPD patients and normal individuals (vs CML, p = 0.35; vs other MPDs, p = 0.85). DeltaTRF (terminal restriction fragment) in patients with MPDs, which is defined as the difference in telomere length between granulocytes and T lymphocytes, was significantly longer than that in normal individuals.<br><br>CONCLUSIONS: The results support the disease theory that MPDs result from extensive proliferation of myeloid progenitor cells, leading to accelerated telomere length shortening in mature granulocytes. An increase in DeltaTRF over the standard value (>1.74 kb) may be useful for discriminating leukocytosis due to MPDs from reactive leukocytosis.},
}
@article {pmid12481901,
year = {2002},
author = {Sakoff, JA and De Waal, E and Garg, MB and Denham, J and Scorgie, FE and Enno, A and Lincz, LF and Ackland, SP},
title = {Telomere length in haemopoietic stem cells can be determined from that of mononuclear blood cells or whole blood.},
journal = {Leukemia &amp; lymphoma},
volume = {43},
number = {10},
pages = {2017-2020},
doi = {10.1080/1042819021000015970},
pmid = {12481901},
issn = {1042-8194},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antigens, CD34 ; Blood Cells/*ultrastructure ; Bone Marrow Cells/ultrastructure ; Case-Control Studies ; Female ; Hematopoietic Stem Cell Mobilization ; Hematopoietic Stem Cells/*ultrastructure ; Humans ; Leukapheresis/*standards ; Leukocytes, Mononuclear/*ultrastructure ; Male ; Middle Aged ; Peripheral Blood Stem Cell Transplantation/standards ; Prognosis ; Telomere/*ultrastructure ; },
abstract = {Telomere length can be used to predict the replicative capacity of haematological progenitor cells and may be an important prognostic factor for the onset of cellular immune dysfunction. However, such measurements require invasive bone marrow (BM) biopsies and laborious stem cell isolations that are impractical in a clinical setting. Previous studies have used peripheral blood (PB) cells as an indicator of stem cell telomere length without demonstrating a correlation. In this study, we examined the telomere length in PB, isolated mononuclear cells (MNC) and BM aspirates from each of 19 patients ranging in age from 45 to 81 years. Correlation analysis confirmed that mean telomere length of BM aspirates was equivalent to that of PB (r = 0.85, P < 0.001), or MNC (r = 0.94, P < 0.001). Since BM is a heterogeneous population of cells, we have also shown in 13 separate patients that the mean telomere length in isolated peripheral blood stem cell (PBSC) harvests was equivalent to that of isolated CD34+ stem cells (r = 0.83, P < 0.001). Thus, telomere length in haemopoietic stem cells can be determined from that of whole or fractionated PB in future studies of haematological disorders.},
}
@article {pmid12479362,
year = {2002},
author = {Seimiya, H and Oh-hara, T and Suzuki, T and Naasani, I and Shimazaki, T and Tsuchiya, K and Tsuruo, T},
title = {Telomere shortening and growth inhibition of human cancer cells by novel synthetic telomerase inhibitors MST-312, MST-295, and MST-1991.},
journal = {Molecular cancer therapeutics},
volume = {1},
number = {9},
pages = {657-665},
pmid = {12479362},
issn = {1535-7163},
mesh = {Antineoplastic Agents/*therapeutic use ; Apoptosis ; Benzamides/*therapeutic use ; Blotting, Southern ; Catechin/*analogs &amp; derivatives/*therapeutic use ; Chromones/*therapeutic use ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/*therapeutic use ; Humans ; Models, Chemical ; Phenotype ; Telomerase/antagonists &amp; inhibitors ; Telomere/*physiology ; Time Factors ; U937 Cells ; beta-Galactosidase/metabolism ; },
abstract = {Epidemiological studies suggest potent anticancer effects of tea catechins. Previously, we have reported (I. Naasani et aL, Biochem. Biophys. Res. Commun., 249: 391-396, 1998) that epigallocatechin gallate (EGCG), a major tea catechin, strongly and directly inhibits telomerase, a ribonucleoprotein that maintains telomeres and has been implicated in tumorigenesis. Here, we describe newly synthesized compounds MST-312, MST-295, and MST-199, as more effective telomerase inhibitors than EGCG. Continuous treatment of human monoblastoid leukemia U937 cells with a nontoxic dose of each drug caused progressive telomere shortening and eventual reduction of growth rate accompanied by induction of the senescence-associated beta-galactosidase activity. Particularly, in the case of MST-312, the effective dose required for the telomere shortening was 1-2 microM, which was 15- to 20-fold lower than that of EGCG. These compounds may provide a novel chemotherapeutic strategy for the treatment of cancers.},
}
@article {pmid12477797,
year = {2002},
author = {Singh, SM and Steinberg-Neifach, O and Mian, IS and Lue, NF},
title = {Analysis of telomerase in Candida albicans: potential role in telomere end protection.},
journal = {Eukaryotic cell},
volume = {1},
number = {6},
pages = {967-977},
pmid = {12477797},
issn = {1535-9778},
support = {/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Amino Acid Sequence ; Base Sequence ; Candida albicans/*enzymology ; Conserved Sequence ; DNA-Binding Proteins ; Evolution, Molecular ; Expressed Sequence Tags ; *Fungal Proteins ; Models, Genetic ; Molecular Sequence Data ; Phylogeny ; Protein Structure, Tertiary ; Proteins/metabolism ; Recombination, Genetic ; Saccharomyces cerevisiae/*enzymology/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Sequence Homology, Amino Acid ; Telomerase/metabolism ; Telomere/*chemistry/metabolism/ultrastructure ; },
abstract = {Telomerase is a ribonucleoprotein reverse transcriptase responsible for the maintenance of one strand of telomere terminal repeats. Analysis of the telomerase complex in the budding yeast Saccharomyces cerevisiae has revealed the presence of one catalytic protein subunit (Est2p/TERT) and at least two noncatalytic components (Est1p and Est3p). The genome of the pathogenic yeast Candida albicans contains putative orthologues of all three telomerase components. Disruption of each homologue resulted in significant but distinct telomere dysfunction in Candida: Similar to S. cerevisiae, the Candida EST3 disruption strain exhibits progressive telomere loss over many generations, at a rate that is consistent with incomplete replication. In contrast, telomeres in both the Candida TERT and EST1 disruption strains can contract rapidly, followed by partial or nearly complete recovery, suggesting a defect in telomere "capping." We propose that these two telomerase subunits may participate in the protection of chromosomal ends in Candida: Analysis of telomerase-mediated primer extension in vitro indicates that only the TERT protein is absolutely essential for enzyme activity. Our results support the conservation of telomerase protein components beyond the catalytic subunit but reveal species-specific phenotypic alterations in response to loss of individual telomerase component. We also identify potential homologues of Est1p in phylogenetically diverse organisms. The Est1p sequence family possesses a conserved N-terminal domain predicted to be structurally related to tetratricopeptide repeat-containing proteins.},
}
@article {pmid12475988,
year = {2003},
author = {Serra, V and von Zglinicki, T and Lorenz, M and Saretzki, G},
title = {Extracellular superoxide dismutase is a major antioxidant in human fibroblasts and slows telomere shortening.},
journal = {The Journal of biological chemistry},
volume = {278},
number = {9},
pages = {6824-6830},
doi = {10.1074/jbc.M207939200},
pmid = {12475988},
issn = {0021-9258},
mesh = {Actins/metabolism ; Aging ; Antioxidants/pharmacology ; Blotting, Northern ; Cells, Cultured ; Cytoplasm/metabolism ; Fibroblasts/*enzymology/metabolism ; Gene Expression ; Humans ; Hypoxia ; Oxidative Stress ; Reverse Transcriptase Polymerase Chain Reaction ; Superoxide Dismutase/*metabolism ; Telomere/*metabolism ; },
abstract = {There is good evidence that telomere shortening acts as a biological clock in human fibroblasts, limiting the number of population doublings a culture can achieve. Oxidative stress also limits the growth potential of human cells, and recent data show that the effect of mild oxidative stress is mediated by a stress-related increased rate of telomere shortening. Thus, fibroblast strains have donor-specific antioxidant defense, telomere shortening rate, and growth potential. We used low-density gene expression array analysis of fibroblast strains with different antioxidant potentials and telomere shortening rates to identify gene products responsible for these differences. Extracellular superoxide dismutase was identified as the strongest candidate, a correlation that was confirmed by Northern blotting. Over-expression of this gene in human fibroblasts with low antioxidant capacity increased total cellular superoxide dismutase activity, decreased the intracellular peroxide content, slowed the telomere shortening rate, and elongated the life span of these cells under normoxia and hyperoxia. These results identify extracellular superoxide dismutase as an important antioxidant gene product in human fibroblasts, confirm the causal role of oxidative stress for telomere shortening, and strongly suggest that the senescence-like arrest under mild oxidative stress is telomere-driven.},
}
@article {pmid12475927,
year = {2002},
author = {Rhodes, D and Fairall, L and Simonsson, T and Court, R and Chapman, L},
title = {Telomere architecture.},
journal = {EMBO reports},
volume = {3},
number = {12},
pages = {1139-1145},
pmid = {12475927},
issn = {1469-221X},
mesh = {Animals ; DNA/*metabolism ; DNA-Binding Proteins/metabolism ; Homeodomain Proteins/*metabolism ; Oncogene Proteins v-myb/*metabolism ; Oxytricha/chemistry/metabolism ; Telomere/*chemistry/*metabolism ; },
abstract = {Telomeres are protein-DNA complexes that cap chromosome ends and protect them from being recognized and processed as DNA breaks. Loss of capping function results in genetic instability and loss of cellular viability. The emerging view is that maintenance of an appropriate telomere structure is essential for function. Structural information on telomeric proteins that bind to double and single-stranded telomeric DNA shows that, despite a lack of extensive amino-acid sequence conservation, telomeric DNA recognition occurs via conserved DNA-binding domains. Furthermore, telomeric proteins have multidomain structures and hence are conformationally flexible. A possibility is that telomeric proteins take up different conformations when bound to different partners, providing a simple mechanism for modulating telomere architecture.},
}
@article {pmid12474060,
year = {2002},
author = {Uchida, W and Matsunaga, S and Sugiyama, R and Shibata, F and Kazama, Y and Miyazawa, Y and Hizume, M and Kawano, S},
title = {Distribution of interstitial telomere-like repeats and their adjacent sequences in a dioecious plant, Silene latifolia.},
journal = {Chromosoma},
volume = {111},
number = {5},
pages = {313-320},
doi = {10.1007/s00412-002-0213-5},
pmid = {12474060},
issn = {0009-5915},
mesh = {Base Sequence ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; *Repetitive Sequences, Nucleic Acid ; *Sequence Analysis, DNA ; Sex Chromosomes/genetics ; Silene/*genetics ; Telomere/*genetics ; },
abstract = {The dioecious plant Silene latifolia has large, heteromorphic X and Y sex chromosomes that are thought to be derived from rearrangements of autosomes. To reveal the origin of the sex chromosomes in S. latifolia, we isolated and characterized telomere-homologous sequences from intra-chromosomal regions (interstitial telomere-like repeats; ITRs) and ITR-adjacent sequences (IASs). Nine genomic DNA fragments with degenerate 84- to 175-bp ITRs were isolated from a genomic library and total genome of male plants. Comparing the nucleotide sequences, the IASs of the nine ITRs were classified into seven elements (IAS-a, IAS-b, IAS-c, IAS-d, IAS-e, IAS-f, and IAS-g) by sequence similarity. The ITRs were grouped into two classes (class-I and -II ITRs) according to the classification of IASs. The class-I ITRs were sub-grouped into three subclasses (subclasses-IA, -IB, and -IC ITRs) based on the arrangement of IAS elements. By contrast, the class-II ITR was located between two different IASs (IAS-f and IAS-g). Genomic Southern analyses showed that both the male and female genomes contained six (IAS-f) to 153 (IAS-d) copies of each IAS per haploid genome. Fluorescence in situ hybridization analyses showed that one IAS element, IAS-d, was distributed in the interstitial and proximal regions of the sex chromosomes of S. latifolia. The distribution of IAS-d is important evidence for past telomere-mediated chromosome rearrangements during the evolution of the sex chromosomes of S. latifolia.},
}
@article {pmid12468377,
year = {2002},
author = {Yegorov, YE and Kazimirchuk, EV and Terekhov, SM and Karachentsev, DN and Shirokova, EA and Khandazhinskaya, AL and Meshcheryakova, JA and Corey, DR and Zelenin, AV},
title = {Telomerase-dependent reactivation of DNA synthesis in macrophages implies alteration of telomeres.},
journal = {Cell biology international},
volume = {26},
number = {12},
pages = {1019-1027},
doi = {10.1006/cbir.2002.0961},
pmid = {12468377},
issn = {1065-6995},
support = {CA-85363/CA/NCI NIH HHS/United States ; },
mesh = {3T3 Cells/enzymology ; Animals ; DNA/*biosynthesis ; Enzyme Reactivators/*metabolism ; Humans ; Macrophages, Peritoneal/*enzymology ; Mice ; Telomerase/*metabolism ; Telomere/*enzymology ; },
abstract = {In previous work we demonstrated that various types of cultured cells with a limited life span could not reactivate DNA synthesis in the nuclei of mouse peritoneal macrophages in heterokaryons. We now investigate the role of telomerase in the process of the macrophage nucleus reactivation in heterokaryons with immortal telomerase-positive 3T3 Swiss mouse fibroblasts and human fibroblasts with introduced hTERT gene. We report that introduction of the hTERT gene into human diploid fibroblasts results in emergence of telomerase activity in these cells and the ability to induce the reactivation of DNA synthesis in the macrophage nuclei in heterokaryons. Inhibition of telomerase activity in heterokaryons by reverse transcriptase inhibitors (azidothymidine and guanosine polyphosphonate analogues) and by a 2'-O-methyl-RNA oligonucleotide anti-sense to the template region of telomerase RNA, block reactivation of DNA synthesis in macrophage nuclei without inhibiting DNA synthesis in the nuclei of fibroblasts. Our results suggest alterations (shortening or damage) in the macrophage telomere structure. As far as we know, heterokaryons with macrophages are the first cellular model for rapid investigation of the effects of telomerase inhibitors.},
}
@article {pmid12463478,
year = {2002},
author = {Awaya, N and Baerlocher, GM and Manley, TJ and Sanders, JE and Mielcarek, M and Torok-Storb, B and Lansdorp, PM},
title = {Telomere shortening in hematopoietic stem cell transplantation: a potential mechanism for late graft failure?.},
journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation},
volume = {8},
number = {11},
pages = {597-600},
doi = {10.1053/bbmt.2002.v8.abbmt080597},
pmid = {12463478},
issn = {1083-8791},
support = {AI29524/AI/NIAID NIH HHS/United States ; CA18029/CA/NCI NIH HHS/United States ; HL62923/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Cellular Senescence ; Child ; Graft Rejection ; *Hematopoietic Stem Cell Transplantation ; Humans ; Leukocytes, Mononuclear/ultrastructure ; Male ; Middle Aged ; Telomere/*metabolism/ultrastructure ; Transplantation Chimera ; },
abstract = {Telomeres serve to maintain the structural integrity of chromosomes, yet each somatic cell division is associated with a decrease in telomere length. The cumulative decrease in telomere length can impose an upper limit for the number of cell divisions that can occur before a cell senesces. When studied in vitro with fibroblasts, this limit is referred to as the Hayflick limit and usually occurs after 40 to 80 cell doublings. In theory, a similar replicative potential in a hematopoietic stem cell could support hematopoiesis in a person for more than 100 years. However, stem cells differentiate, and the telomere length differs among chromosomes within a single cell, among cell types, and among age-matched individuals. This variation in telomere length raises the possibility that long-term hematopoiesis by transplanted stem cells could, depending on the telomere length of the engrafted stem cell and the proliferative demand to which it is subjected, reach a Hayflick limit during the life span of the patient. Although significant shortening of telomeres is reported to occur within the first year posttransplantation, as yet no evidence has indicated that this shortening is associated with marrow function. In this review, we summarize reports on telomere shortening in stem cell transplantation recipients and report 2 cases in which graft failure is associated with significant telomere shortening.},
}
@article {pmid12461078,
year = {2002},
author = {Allsopp, RC and Cheshier, S and Weissman, IL},
title = {Telomerase activation and rejuvenation of telomere length in stimulated T cells derived from serially transplanted hematopoietic stem cells.},
journal = {The Journal of experimental medicine},
volume = {196},
number = {11},
pages = {1427-1433},
pmid = {12461078},
issn = {0022-1007},
support = {P01 DK053074/DK/NIDDK NIH HHS/United States ; CA 42551/CA/NCI NIH HHS/United States ; DK 53074/DK/NIDDK NIH HHS/United States ; CA 76708/CA/NCI NIH HHS/United States ; F32 CA076708/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Blotting, Southern ; DNA-Binding Proteins ; Enzyme Activation ; *Hematopoietic Stem Cell Transplantation ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; T-Lymphocytes/*physiology ; Telomerase/*physiology ; *Telomere ; Telomeric Repeat Binding Protein 1/physiology ; },
abstract = {Telomeres shorten in hematopoietic cells, including hematopoietic stem cells (HSCs), during aging and after transplantation, despite the presence of readily detectable levels of telomerase in these cells. In T cells, antigenic stimulation has been shown to result in a marked increase in the level of telomerase activity. We now show that stimulation of T cells derived from serially transplanted HSC results in a telomerase-dependent elongation of telomere length to a size similar to that observed in T cells isolated directly from young mice. Southern analysis of telomere length in resting and anti-CD3/CD28 stimulated donor-derived splenic T cells revealed an increase in telomere size by approximately 7 kb for the population as a whole. Stimulation of donor-derived T cells from recipients of HSCs from telomerase-deficient mice did not result in regeneration of telomere length, demonstrating a dependence on telomerase. Furthermore, clonal anti-CD3/CD28 stimulation of donor-derived T cells followed by fluorescent in situ hybridization (FISH) analysis of telomeric signal intensity showed that telomeres had increased in size by approximately 50% for all clonal expansions. Together, these results imply that one role for telomerase in T cells may be to renew or extend replicative potential via the rejuvenation of telomere length.},
}
@article {pmid12459009,
year = {2002},
author = {Chen, Z and Monia, BP and Corey, DR},
title = {Telomerase inhibition, telomere shortening, and decreased cell proliferation by cell permeable 2'-O-methoxyethyl oligonucleotides.},
journal = {Journal of medicinal chemistry},
volume = {45},
number = {25},
pages = {5423-5425},
doi = {10.1021/jm025563v},
pmid = {12459009},
issn = {0022-2623},
support = {CA70907/CA/NCI NIH HHS/United States ; CA85363/CA/NCI NIH HHS/United States ; },
mesh = {Cell Division/drug effects ; Cell Membrane Permeability ; Enzyme Inhibitors/*chemical synthesis/chemistry/pharmacology ; Humans ; Oligonucleotides/*chemical synthesis/chemistry/pharmacology ; Structure-Activity Relationship ; Telomerase/*antagonists &amp; inhibitors ; Tumor Cells, Cultured ; },
abstract = {Telomerase is an attractive target for chemotherapy. Testing this hypothesis will require potent inhibitors with favorable pharmacokinetic properties. We report that 2'-methoxyethyl oligonucleotides complementary to the telomerase RNA component diffuse across cell membranes without the need for cationic carrier lipid, inhibit telomerase, and cause telomeres to shorten. The ability of antitelomerase oligomers to enter cells without the need to add lipid will simplify preclinical studies and may suggest advantages for clinical use.},
}
@article {pmid12456753,
year = {2003},
author = {Bass, HW and Bordoli, SJ and Foss, EM},
title = {The desynaptic (dy) and desynaptic1 (dsy1) mutations in maize (Zea mays L) cause distinct telomere-misplacement phenotypes during meiotic prophase.},
journal = {Journal of experimental botany},
volume = {54},
number = {380},
pages = {39-46},
doi = {10.1093/jxb/erg032},
pmid = {12456753},
issn = {0022-0957},
mesh = {Fertility/genetics ; Meiosis/genetics ; Mutation ; Nuclear Envelope/genetics ; Phenotype ; Prophase/genetics ; Synaptonemal Complex/*genetics ; Telomere/*genetics ; Zea mays/cytology/*genetics ; },
abstract = {During meiotic prophase, telomeres actively attach themselves to the nuclear envelope and cluster in an arrangement called the bouquet. The bouquet is unique to meiosis, highly conserved, and thought to facilitate homologous chromosome synapsis. Analy sis of three-dimensional fluorescence in situ hybridization (3-D FISH) image data has been employed to characterize the bouquet in fixed pollen mother cells of maize (Zea mays L.). In order to examine the function of the bouquet further, several meiotic mutants were screened for telomeric defects using 3-D FISH as an assay. Two mutants, desynaptic (dy) and desynaptic1 (dsy1), were found to exhibit novel telomere-misplacement phenotypes. In both cases, the telomere-associated mutant phenotypes occurred prior to what was previously reported as the earliest affected stage. Three alleles of the desynaptic1 mutation (dsy1-1, dsy1-9101, and dsy1-9307) resulted in a partial bouquet phenotype at the zygotene stage of meiotic prophase. By contrast, dy nuclei contained apparently normal bouquets, but then resulted in a premature intranuclear localization of telomeres at the pachytene stage, when telomeres normally disperse but remain attached to the nuclear envelope. The dsy1 mutation is known to impair the fidelity and progression of homologous synapsis, whereas the dy mutation is known to reduce recombination rates. If the telomere misplacements are primary defects of these mutants, then these data would be consistent with the hypothesis that meiotic telomeres have at least two separable functions, one involving proper homologous chromosome synapsis at the bouquet stage and another involving post-bouquet cross-over control.},
}
@article {pmid12454944,
year = {2002},
author = {Patel, MM and Parekh, LJ and Jha, FP and Sainger, RN and Patel, JB and Patel, DD and Shah, PM and Patel, PS},
title = {Clinical usefulness of telomerase activation and telomere length in head and neck cancer.},
journal = {Head &amp; neck},
volume = {24},
number = {12},
pages = {1060-1067},
doi = {10.1002/hed.10169},
pmid = {12454944},
issn = {1043-3074},
mesh = {Adolescent ; Adult ; Aged ; Blotting, Southern ; Carcinoma, Squamous Cell/*enzymology/pathology ; Disease-Free Survival ; Female ; Head and Neck Neoplasms/*enzymology/pathology ; Humans ; Male ; Middle Aged ; Polymerase Chain Reaction/methods ; Precancerous Conditions/*enzymology/pathology ; Survival Analysis ; Telomerase/analysis/*metabolism ; Telomere/*metabolism ; Tumor Cells, Cultured ; },
abstract = {BACKGROUND: Telomere shortening at every replication cycle is postulated to limit the life span of human somatic cells. In contrast, activation of telomerase is proposed to be an essential step for cancer cell immortalization. Head and neck cancer is the most common malignancy in the Indian population compared with Western countries. However, there are very few reports on telomerase activity and telomere length in head and neck cancer.<br><br>METHODS: Telomerase activation and telomere length alterations were studied in tumor and adjacent normal tissues in 110 patients with head and neck cancer and 40 patients with precancerous/benign conditions. Telomerase activity and telomere lengths were determined by Telomeric Repeat Amplification Protocol (TRAP assay) and Southern blot analysis, respectively.<br><br>RESULTS: Telomerase activation was observed in 78.2% of the malignant tissues, 85% of the precancerous tissues, and 53.1% of the adjacent normal tissues. Peak terminal restriction fragment length (TRF) was observed to be significantly lower in malignant tissues compared with the adjacent normal tissues. No significant correlation could be observed between telomerase activation and clinicopathologic characteristics of the patients. Two-year disease-free survival analysis showed that patients showing telomerase activation in the adjacent normal tissues and patients showing higher telomere length in malignant tissues had poor disease-free survival.<br><br>CONCLUSIONS: Our results demonstrate the significant clinical usefulness of telomerase activation and telomere length for head and neck cancer patients. These markers may be helpful in predicting the clinical course of the disease and thus in identifying the patients in need of a close follow-up and vigorous adjuvant treatment.},
}
@article {pmid12454074,
year = {2002},
author = {Melnikova, L and Georgiev, P},
title = {Enhancer of terminal gene conversion, a new mutation in Drosophila melanogaster that induces telomere elongation by gene conversion.},
journal = {Genetics},
volume = {162},
number = {3},
pages = {1301-1312},
pmid = {12454074},
issn = {0016-6731},
mesh = {Animals ; Chromosome Mapping ; *DNA Transposable Elements ; Drosophila Proteins/metabolism ; Drosophila melanogaster/*genetics ; *Enhancer Elements, Genetic ; *Gene Conversion ; Gene Expression Regulation ; *Gene Products, gag ; Insect Proteins/metabolism ; Models, Genetic ; Recombination, Genetic ; Telomere/*genetics ; },
abstract = {Telomeres of Drosophila melanogaster contain arrays of the retrotransposon-like elements HeT-A and TART. Terminally deleted chromosomes can be maintained for many generations. Thus, broken chromosome ends behave as real telomeres. It was previously shown that gene conversion may extend the broken ends. Here we found that the frequency of terminal DNA elongation by gene conversion strongly depends on the genotype. A dominant E(tc) (Enhancer of terminal gene conversion) mutation markedly increases the frequency of this event but does not significantly influence the frequency of HeT-A and TART attachment to the broken chromosome end and recombination between directly repeated sequences at the end of the truncated chromosome. The E(tc) mutation was mapped to the 91-93 region on chromosome 3. Drosophila lines that bear the E(tc) mutation for many generations have telomeres, consisting of HeT-A and TART elements, that are longer than those found in wild-type lines. Thus, the E(tc) mutation plays a significant role in the control of telomere elongation in D. melanogaster.},
}
@article {pmid12454059,
year = {2002},
author = {Evans, SK and Lundblad, V},
title = {The Est1 subunit of Saccharomyces cerevisiae telomerase makes multiple contributions to telomere length maintenance.},
journal = {Genetics},
volume = {162},
number = {3},
pages = {1101-1115},
pmid = {12454059},
issn = {0016-6731},
support = {AG11728/AG/NIA NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Amino Acids, Acidic ; Amino Acids, Basic ; Conserved Sequence ; DNA Mutational Analysis ; Gene Expression Regulation, Fungal ; Mutagenesis, Site-Directed ; Mutation, Missense ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/*metabolism ; Sequence Alignment ; Telomerase/*genetics/*metabolism ; Telomere/*genetics ; Telomere-Binding Proteins/metabolism ; },
abstract = {The telomerase-associated Est1 protein of Saccharomyces cerevisiae mediates enzyme access by bridging the interaction between the catalytic core of telomerase and the telomere-binding protein Cdc13. In addition to recruiting telomerase, Est1 may act as a positive regulator of telomerase once the enzyme has been brought to the telomere, as previously suggested by the inability of a Cdc13-Est2 fusion protein to promote extensive telomere elongation in an est1-Delta strain. We report here three classes of mutant Est1 proteins that retain association with the telomerase enzyme but confer different in vivo consequences. Class 1 mutants display a telomere replication defect but are capable of promoting extensive telomere elongation in the presence of a Cdc13-Est2 fusion protein, consistent with a defect in telomerase recruitment. Class 2 mutants fail to elongate telomeres even in the presence of the Cdc13-Est2 fusion, which is the phenotype predicted for a defect in the proposed second regulatory function of EST1. A third class of mutants impairs an activity of Est1 that is potentially required for the Ku-mediated pathway of telomere length maintenance. The isolation of mutations that perturb separate functions of Est1 demonstrates that a telomerase holoenzyme subunit can contribute multiple regulatory roles to telomere length maintenance.},
}
@article {pmid12447689,
year = {2002},
author = {Delhommeau, F and Thierry, A and Feneux, D and Lauret, E and Leclercq, E and Courtier, MH and Sainteny, F and Vainchenker, W and Bennaceur-Griscelli, A},
title = {Telomere dysfunction and telomerase reactivation in human leukemia cell lines after telomerase inhibition by the expression of a dominant-negative hTERT mutant.},
journal = {Oncogene},
volume = {21},
number = {54},
pages = {8262-8271},
doi = {10.1038/sj.onc.1206054},
pmid = {12447689},
issn = {0950-9232},
mesh = {Cell Division/genetics ; DNA-Binding Proteins ; Enzyme Activation ; Humans ; Leukemia/enzymology/*genetics/pathology ; *Mutation ; Telomerase/*genetics/*metabolism ; *Telomere ; Tumor Cells, Cultured ; },
abstract = {As activation of telomerase represents a key step in the malignant transformation process, experimental models to develop anti-telomerase drugs provide a rational basis for anticancer strategies. We analysed the short and long-term efficacy of a stably expressed dominant-negative mutant (DN) of the telomerase catalytic unit (hTERT) in UT-7 and U937 human leukemia cell lines by using an IRES-e-GFP retrovirus. As expected, telomerase inactivation resulted in drastic telomere shortening, cytogenetic instability and cell growth inhibition in all e-GFP positive DN clones after 15-35 days of culture. However, despite this initial response, 50% of e-GFP positive DN clones with short telomeres escaped from crisis after 35 days of culture and recovered a proliferation rate similar to the control cells. This rescue was associated with a telomerase reactivation inducing telomere lengthening. We identified two pathways, one involving the loss of the DN transgene expression and the other the transcriptional up-regulation of endogenous hTERT with persistence of the DN transgene expression. Although this second mechanism appears to be a very rare event (one clone), these findings suggest that genomic instability induced by short telomeres after telomerase inhibition might enhance the probability of activation or selection of telomere maintenance mechanisms dependent on hTERT transcription.},
}
@article {pmid12445186,
year = {2002},
author = {Nakamura, K and Izumiyama-Shimomura, N and Sawabe, M and Arai, T and Aoyagi, Y and Fujiwara, M and Tsuchiya, E and Kobayashi, Y and Kato, M and Oshimura, M and Sasajima, K and Nakachi, K and Takubo, K},
title = {Comparative analysis of telomere lengths and erosion with age in human epidermis and lingual epithelium.},
journal = {The Journal of investigative dermatology},
volume = {119},
number = {5},
pages = {1014-1019},
doi = {10.1046/j.1523-1747.2002.19523.x},
pmid = {12445186},
issn = {0022-202X},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Blotting, Southern ; Child ; Child, Preschool ; Epidermis/*pathology ; Epithelium/pathology ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Regression Analysis ; Skin Aging/*pathology ; Telomere/genetics/*pathology ; Tongue/*pathology ; },
abstract = {We investigated progressive telomere shortening in normal human epidermis and lingual epithelium during aging, and attempted, in particular, to ascertain whether the telomere shortening that accompanies aging occurs at the same rate in different tissues. We studied telomeric DNA integrity, and estimated annual telomere loss, in 52 specimens of epidermis and 48 specimens of lingual epithelium collected at autopsy from subjects who had died at ages between 0 and 101 y. Most of the DNA samples were measured twice by southern blot hybridization. In addition, the correlation between telomere lengths in the two types of tissues was examined. The telomere reduction rates in epidermis and lingual epithelium were 36 bp and 30 bp per y, respectively, and these were significantly different. The rates obtained by the second measurements in epidermis and lingual epithelium were 39 and 32 bp per y, respectively, and these were also significantly different. The mean telomere lengths in the epidermis of eight neonates and the lingual epithelium of seven neonates were 13.2+/-1.0 and 13.8+/-1.0 kb, respectively. Comparison of telomere lengths in the two tissues for 41 paired samples showed that the mean telomere length in the epidermis (10.7+/-2.3 kb) was less than that in the lingual epithelium (12.4+/-2.5 kb); however, statistical analysis revealed a very significant relationship between epidermal and lingual epithelial telomere length (r=0.842, p<0.0001). These results indicate that the telomeres in epidermis and lingual epithelium are characterized by tissue-specific loss rates.},
}
@article {pmid12444252,
year = {2002},
author = {Lindstrom, UM and Chandrasekaran, RA and Orbai, L and Helquist, SA and Miller, GP and Oroudjev, E and Hansma, HG and Kool, ET},
title = {Artificial human telomeres from DNA nanocircle templates.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {99},
number = {25},
pages = {15953-15958},
pmid = {12444252},
issn = {0027-8424},
mesh = {Animals ; Base Sequence ; Cattle ; Cell Line ; Chromosomes, Human/chemistry ; DNA Polymerase I/metabolism ; DNA Polymerase beta/metabolism ; DNA, Circular/chemical synthesis/*chemistry ; Humans ; Metaphase ; Microscopy, Atomic Force ; Microscopy, Fluorescence ; Models, Genetic ; Molecular Sequence Data ; *Telomere ; Templates, Genetic ; },
abstract = {Human telomerase is a reverse-transcriptase enzyme that synthesizes the multikilobase repeating hexamer telomere sequence (TTAGGG)n at the ends of chromosomes. Here we describe a designed approach to mimicry of telomerase, in which synthetic DNA nanocircles act as essentially infinite catalytic templates for efficient synthesis of long telomeres by DNA polymerase enzymes. Results show that the combination of a nanocircle and a DNA polymerase gives a positive telomere-repeat amplification protocol assay result for telomerase activity, and similar to the natural enzyme, it is inhibited by a known telomerase inhibitor. We show that artificial telomeres can be engineered on human chromosomes by this approach. This strategy allows for the preparation of synthetic telomeres for biological and structural study of telomeres and proteins that interact with them, and it raises the possibility of telomere engineering in cells without expression of telomerase itself. Finally, the results provide direct physical support for a recently proposed rolling-circle mechanism for telomerase-independent telomere elongation.},
}
@article {pmid12442309,
year = {2002},
author = {Schmid, I and Dagarag, MD and Hausner, MA and Matud, JL and Just, T and Effros, RB and Jamieson, BD},
title = {Simultaneous flow cytometric analysis of two cell surface markers, telomere length, and DNA content.},
journal = {Cytometry},
volume = {49},
number = {3},
pages = {96-105},
doi = {10.1002/cyto.10163},
pmid = {12442309},
issn = {0196-4763},
support = {AG05920/AG/NIA NIH HHS/United States ; AI-28697/AI/NIAID NIH HHS/United States ; AI-47665/AI/NIAID NIH HHS/United States ; CA-16042/CA/NCI NIH HHS/United States ; },
mesh = {Antigens, CD/chemistry/*metabolism ; DNA, Neoplasm/*metabolism ; Flow Cytometry/*methods ; Fluorescent Antibody Technique ; Humans ; Hydrazines/chemistry ; In Situ Hybridization, Fluorescence ; Leukemia/genetics/metabolism/pathology ; Leukocytes, Mononuclear/pathology ; Reproducibility of Results ; Staining and Labeling ; T-Lymphocyte Subsets/metabolism/*pathology ; Telomere/*pathology ; Tumor Cells, Cultured ; },
abstract = {BACKGROUND: Various protocols for estimation of telomere length in individual cells by flow cytometry using fluorescence in situ hybridization of fluorescently labeled peptide nucleic acid (PNA) probes (Flow-FISH) have been described. Combined analysis of telomere length and cell phenotype, however, remains difficult because few fluorochromes with suitable emission spectra tolerate the harsh conditions needed for DNA denaturation during hybridization of the telomere-specific PNA probe. We overcame these problems and developed a method for measuring telomere length in cell subsets characterized by the expression of two surface antigens.<br><br>METHODS: Alexa Fluor 488 and Alexa Fluor 546 were used for cell surface staining. Antigen-antibody complexes were covalently cross-linked onto the cell membrane before Flow-FISH. Cells were hybridized with a PNA probe conjugated to cyanine 5 (Cy5). Hoechst 33342 (HO342) was added for determination of cellular DNA content. For assay standardization, we added an aliquot of a single batch of 1,301 cells to each sample as an internal control before hybridization with the PNA probe. Samples were prepared in duplicate and analyzed on a standard three-laser BD LSR flow cytometer. For assay validation, the same samples were analyzed in parallel to correlate the percentage of telomere length of the sample versus 1,301 control cells to the mean size of terminal restriction fragments (TRFs) of DNA as determined by Southern gel analysis.<br><br>RESULTS: The method permitted clear identification of lymphocyte subsets in samples hybridized for Flow-FISH, with subset frequencies comparable to those of untreated samples. At a concentration of 10 nM, the Cy5-labeled telomere-specific PNA probe produced a bright fluorescence signal well separated from background. Addition of HO342 in low concentration did not interfere with Cy5 telomere fluorescence, produced adequate DNA histograms, and permitted clear identification of cell phenotype. The probe concentration of 10 nM also proved optimal for inclusion of 1,301 control cells for assay standardization. Telomere length estimations by the current method correlated highly with TRF calculations by Southern gel hybridization (r(2)= 0.9, P = 0.0003). Application of our protocol to the analysis of human CD8CD28 lymphocyte subsets showed that CD8(+bright)CD28(-) lymphocytes generally exhibit shorter telomeres than CD8(+bright)CD28(+) cells. These data concurred with previous results of telomere shortening in CD8(+)CD28(-) T cells that were obtained by using different techniques.<br><br>CONCLUSIONS: The multiparameter Flow-FISH protocol permitted rapid determination of differences in telomere length in subpopulations characterized by two surface markers without prior cell separation.},
}
@article {pmid12441258,
year = {2002},
author = {Blasco, MA},
title = {Mouse models to study the role of telomeres in cancer, aging and DNA repair.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {38},
number = {17},
pages = {2222-2228},
doi = {10.1016/s0959-8049(02)00450-1},
pmid = {12441258},
issn = {0959-8049},
mesh = {Aging/*genetics ; Animals ; Chromosome Disorders/etiology ; DNA Repair/*genetics ; *Models, Animal ; Neoplasms/*genetics ; Telomere/genetics/*physiology ; Transgenes ; },
abstract = {The chromosome ends have protective structures that distinguish them from broken chromosomes, known as telomeres. The function of telomeres, and that of the cellular activity that synthesises them, telomerase, are proposed to be biological determinants in the processes of cancer and aging. In this review, we will focus on mammalian telomeres and, in particular, on the analysis of different mouse models for proteins that are important for telomere function, such as telomerase and various telomere-binding proteins. These mouse models have allowed the relevance of telomeres and telomerase in tumour development and the aging of the organism to be directly tested.},
}
@article {pmid12438224,
year = {2002},
author = {Meeker, AK and Hicks, JL and Platz, EA and March, GE and Bennett, CJ and Delannoy, MJ and De Marzo, AM},
title = {Telomere shortening is an early somatic DNA alteration in human prostate tumorigenesis.},
journal = {Cancer research},
volume = {62},
number = {22},
pages = {6405-6409},
pmid = {12438224},
issn = {0008-5472},
support = {DK07552/DK/NIDDK NIH HHS/United States ; K08CA78588/CA/NCI NIH HHS/United States ; P50CA58236/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma/*genetics/pathology/ultrastructure ; Aged ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Neoplasm Staging ; Prostatic Intraepithelial Neoplasia/*genetics/ultrastructure ; Prostatic Neoplasms/*genetics/pathology/ultrastructure ; Telomere/*genetics/ultrastructure ; },
abstract = {Chromosomal instability appears to be key to the pathogenesis of malignant transformation in human cancers, yet the precise molecular mechanisms underlying chromosomal rearrangements remain largely unknown. Telomeres stabilize and protect the ends of chromosomes, but shorten because of cell division and/or oxidative damage. Critically short telomeres, in the setting of abrogated DNA damage checkpoints, have been shown to cause chromosomal instability in vitro and in animal models, leading to an increased cancer incidence as a result of chromosome fusions, subsequent breakage, and rearrangement. We present results from a quantitative, high-resolution, in situ method for telomere length assessment used to test the hypothesis that telomere shortening is an early contributor to human tumorigenesis. High-grade prostatic intraepithelial neoplasia (HGPIN) is a putative preinvasive precursor of prostatic adenocarcinoma, the most common noncutaneous malignancy in Western men. The telomere lengths of epithelial cells within HGPIN lesions were strikingly shorter than those of adjacent normal appearing epithelial cells in 93% (28 of 30) of lesions examined. This shortening is similar to what has been shown in fully invasive prostate adenocarcinomas. Interestingly, telomere shortening was restricted to the luminal epithelial cells of HGPIN and was not present in the underlying basal epithelial cells; this provides strong evidence that basal cells are most likely not the direct targets of neoplastic transformation. These findings reveal that telomere shortening is a defining somatic DNA alteration characterizing HGPIN. The implications of this are that the earliest phase of human prostate carcinogenesis may proceed as a consequence of chromosomal instability mediated by shortened, dysfunctional telomeres.},
}
@article {pmid12437664,
year = {2002},
author = {Martens, UM and Brass, V and Sedlacek, L and Pantic, M and Exner, C and Guo, Y and Engelhardt, M and Lansdorp, PM and Waller, CF and Lange, W},
title = {Telomere maintenance in human B lymphocytes.},
journal = {British journal of haematology},
volume = {119},
number = {3},
pages = {810-818},
doi = {10.1046/j.1365-2141.2002.03910.x},
pmid = {12437664},
issn = {0007-1048},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/physiology ; B-Lymphocytes/*cytology/enzymology ; Child ; Fetal Blood/cytology ; Humans ; In Situ Hybridization, Fluorescence ; Lymphocyte Activation/physiology ; Middle Aged ; T-Lymphocytes/*cytology/enzymology ; Telomerase/metabolism ; *Telomere ; },
abstract = {Telomere shortening has been causally linked to replicative senescence in human cells. To characterize telomere-length heterogeneity in peripheral blood cells of normal individuals, we analysed the mean length of telomeric repeat sequences in subpopulations of peripheral blood leucocytes, using fluorescence in situ hybridization and flow cytometry (flow-FISH). Although the telomere length of most haematopoietic subsets was within the same range, the mean telomere length was found to be 15% higher in B compared with T lymphocytes in adult peripheral blood. Whereas telomere loss with ageing corresponded to 33 base pairs (bp) per year in T cells, telomere shortening was slower in B cells, corresponding to 15 bp per year. Separation of adult B-lymphocyte subpopulations based on CD27 expression revealed that telomere length was almost 2 kb longer in CD19+CD27+ (memory) compared with CD19+CD27- (naive) cells. Furthermore, peripheral blood B cells were activated in vitro. Whereas B-cell activation with Staphylococcus aureus Cowan strain (SAC) did not increase telomere length, a striking telomere elongation was observed when cells were stimulated with SAC and interleukin 2 to induce plasma cell differentiation. Our observations support the concept that telomere dynamics in B cells are distinct from other haematopoietic cell lineages and that telomere elongation may play an essential role in the generation of long-term B memory cells.},
}
@article {pmid12436345,
year = {2002},
author = {Aviv, A},
title = {Telomeres, sex, reactive oxygen species, and human cardiovascular aging.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {80},
number = {11},
pages = {689-695},
doi = {10.1007/s00109-002-0377-8},
pmid = {12436345},
issn = {0946-2716},
support = {HL-47906/HL/NHLBI NIH HHS/United States ; HL-63351/HL/NHLBI NIH HHS/United States ; },
mesh = {Aging/*physiology ; Cardiovascular Diseases/genetics/*pathology ; Cell Division/physiology ; Cellular Senescence/*physiology ; DNA Damage ; Gene Expression/physiology ; Humans ; Reactive Oxygen Species/*metabolism ; *Sex ; Telomere/genetics/*physiology ; },
abstract = {By undergoing erosion with each replicative cycle, telomeres chronicle the replicative history of human somatic cells in vitro and in vivo. In human beings the telomere is relatively short, inversely correlated with age, highly heritable, and longer in women than men. However, it is not established whether the dynamics of telomere attrition in vivo has a role in the biology of human aging. Telomere attrition may be modified by reactive oxygen species, the biology of which is governed by processes that are influenced by sex. Indices of cardiovascular aging in humans are correlated with telomere length and this relationship is characterized by sexual dimorphism. In the final analysis, the biology of reactive oxygen species may offer a common explanation for some interindividual variation in cardiovascular aging and age-dependent telomere attrition in humans.},
}
@article {pmid12432254,
year = {2002},
author = {Hahn, WC},
title = {Senescence, telomere shortening and telomere maintenance.},
journal = {Cancer biology &amp; therapy},
volume = {1},
number = {4},
pages = {398-400},
doi = {10.4161/cbt.1.4.14},
pmid = {12432254},
issn = {1538-4047},
support = {K01 CA94223/CA/NCI NIH HHS/United States ; },
mesh = {Cell Death ; Cell Division ; *Cellular Senescence ; Humans ; Li-Fraumeni Syndrome/genetics ; Telomere/*physiology/*ultrastructure ; Tumor Suppressor Protein p53/metabolism ; },
}
@article {pmid12428916,
year = {2002},
author = {Modino, S and Slijepcevic, P},
title = {Telomere shortening in mouse strains with constitutional chromosomal aberrations.},
journal = {International journal of radiation biology},
volume = {78},
number = {9},
pages = {757-764},
doi = {10.1080/09553000210146563},
pmid = {12428916},
issn = {0955-3002},
mesh = {Animals ; Bone Marrow Cells/ultrastructure ; *Chromosome Aberrations/chemically induced/radiation effects ; Chromosome Banding ; Female ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Mice, Mutant Strains ; Mutagens/toxicity ; Telomere/drug effects/*genetics/radiation effects ; },
abstract = {PURPOSE: To compare telomere length in mouse strains with constitutional chromosomal aberrations generated either by exposure of parents to ionizing radiation, a chemical mutagen or arising spontaneously with that of the karyotypically normal mouse from the same genetic background.<br><br>MATERIALS AND METHODS: Telomere length was assessed in five independently derived strains of mouse with constitutional chromosomal aberrations and in the karyotypically normal control mouse using quantitative fluorescence in situ hybridization (Q-FISH). Bone marrow cells obtained directly from the animals were used for the analysis.<br><br>RESULTS: Chromosomal aberrations, one in each mouse strain, included three reciprocal translocations induced by ionizing radiation, one insertion induced by a chemical mutagen and one spontaneous Robertsonian translocation. There was no cytogenetically detectable loss of material in any of the strains and most mice were phenotypically normal. Telomeres were significantly shorter in all mouse strains with constitutional chromosomal aberrations in comparison with those originating from the karyatypically normal mouse from the same genetic background. Telomeres were significantly shorter at p-arms than at q-arms in all animals. The telomere length in individual chromosomes was variable and there was no single chromosome with consistently short telomeres in all animals.<br><br>CONCLUSIONS: The presence of stable chromosomal aberrations, such as translocations or insertions, in the mouse genome may generate telomere shortening. This might have implications for understanding biological consequences or radiation-induced stable chromosomal aberrations.},
}
@article {pmid12426399,
year = {2002},
author = {Espejel, S and Franco, S and Sgura, A and Gae, D and Bailey, SM and Taccioli, GE and Blasco, MA},
title = {Functional interaction between DNA-PKcs and telomerase in telomere length maintenance.},
journal = {The EMBO journal},
volume = {21},
number = {22},
pages = {6275-6287},
pmid = {12426399},
issn = {0261-4189},
support = {R01 CA043322/CA/NCI NIH HHS/United States ; CA 43322/CA/NCI NIH HHS/United States ; CA 76409/CA/NCI NIH HHS/United States ; },
mesh = {Aging/genetics ; Animals ; Apoptosis/genetics ; Atrophy ; Catalytic Domain ; Cell Division ; Chromosome Aberrations ; Chromosomes/ultrastructure ; DNA-Activated Protein Kinase ; *DNA-Binding Proteins ; Fibroblasts/pathology ; In Situ Hybridization, Fluorescence ; Infertility, Male/genetics/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neoplasms/enzymology/genetics ; Nuclear Proteins ; Phenotype ; *Protein Interaction Mapping ; Protein Serine-Threonine Kinases/deficiency/genetics/*physiology ; RNA/genetics/*physiology ; Spermatozoa/pathology ; Spleen/cytology ; Telomerase/deficiency/genetics/*physiology ; Telomere/metabolism/*ultrastructure ; Testis/pathology ; },
abstract = {DNA-PKcs is the catalytic subunit of the DNA-dependent protein kinase (DNA-PK) complex that functions in the non-homologous end-joining of double-strand breaks, and it has been shown previously to have a role in telomere capping. In particular, DNA-PKcs deficiency leads to chromosome fusions involving telomeres produced by leading-strand synthesis. Here, by generating mice doubly deficient in DNA-PKcs and telomerase (Terc(-/-)/DNA-PKcs(-/-)), we demonstrate that DNA-PKcs also has a fundamental role in telomere length maintenance. In particular, Terc(-/-)/DNA-PKcs(-/-) mice displayed an accelerated rate of telomere shortening when compared with Terc(-/-) controls, suggesting a functional interaction between both activities in maintaining telomere length. In addition, we also provide direct demonstration that DNA-PKcs is essential for both end-to-end fusions and apoptosis triggered by critically short telomeres. Our data predict that, in telomerase-deficient cells, i.e. human somatic cells, DNA-PKcs abrogation may lead to a faster rate of telomere degradation and cell cycle arrest in the absence of increased apoptosis and/or fusion of telomere-exhausted chromosomes. These results suggest a critical role of DNA-PKcs in both cancer and aging.},
}
@article {pmid12424244,
year = {2003},
author = {Miyoshi, T and Sadaie, M and Kanoh, J and Ishikawa, F},
title = {Telomeric DNA ends are essential for the localization of Ku at telomeres in fission yeast.},
journal = {The Journal of biological chemistry},
volume = {278},
number = {3},
pages = {1924-1931},
doi = {10.1074/jbc.M208813200},
pmid = {12424244},
issn = {0021-9258},
mesh = {*Antigens, Nuclear ; Base Sequence ; DNA/chemistry/*metabolism ; *DNA Helicases ; DNA Primers ; DNA Repair ; DNA-Binding Proteins/genetics/*metabolism ; Ku Autoantigen ; Nuclear Proteins/genetics/*metabolism ; Open Reading Frames ; Precipitin Tests ; Schizosaccharomyces/*genetics ; *Telomere ; },
abstract = {The Ku70-Ku80 heterodimer is a conserved protein complex essential for the non-homologous end-joining pathway. Ku proteins are also involved in telomere maintenance, although their precise roles remain to be elucidated. In fission yeast, pku70(+), the gene encoding the Ku70 homologue, has been reported. Here we report the identification and characterization of pku80(+), the gene encoding Ku80. Both pku70(+) and pku80(+) are essential for efficient non-homologous end-joining. We also found that the pku70 and pku80 mutants are sensitive to methyl methanesulfonate and hydroxyurea, suggesting their roles in the S phase. The pku80 mutant shows telomere shortening and tandem amplification of a subtelomeric sequence but no defects in the telomere position effect, as was previously reported for the pku70 mutant. By using the chromatin immunoprecipitation assay, we demonstrated that Pku70 and Pku80 physically interact with telomeric repeats and subtelomeric sequences. Interestingly, this telomere association of Pku proteins is independent of Taz1, a telomeric DNA-binding protein. We also showed that the Pku proteins do not associate with ectopically integrated telomeric repeats in the internal region of circular chromosomes. These results indicate that the physical end of DNA is necessary for the localization of Pku80 at telomeres.},
}
@article {pmid12419205,
year = {2002},
author = {Bertuch, AA},
title = {Telomeres: the molecular events driving end-to-end fusions.},
journal = {Current biology : CB},
volume = {12},
number = {21},
pages = {R738-40},
doi = {10.1016/s0960-9822(02)01252-6},
pmid = {12419205},
issn = {0960-9822},
mesh = {DNA Ligase ATP ; DNA Ligases/*metabolism ; *Telomere ; },
abstract = {Recent data indicate that loss of the protective telomeric capping function leads to active degradation of the telomeric G-strand overhang and DNA ligase IV-mediated non-homologous end joining. These molecular events may contribute to genomic instability early in tumorigenesis.},
}
@article {pmid12415258,
year = {2002},
author = {Neumann, AA and Reddel, RR},
title = {Telomere maintenance and cancer -- look, no telomerase.},
journal = {Nature reviews. Cancer},
volume = {2},
number = {11},
pages = {879-884},
doi = {10.1038/nrc929},
pmid = {12415258},
issn = {1474-175X},
mesh = {Antineoplastic Agents/pharmacology/therapeutic use ; Apoptosis/drug effects ; Cellular Senescence ; Chromosomes, Fungal/ultrastructure ; Chromosomes, Human/ultrastructure ; DNA-Binding Proteins/physiology ; Dyskeratosis Congenita/enzymology ; Enzyme Inhibitors/pharmacology/therapeutic use ; Humans ; Models, Genetic ; Neoplasm Proteins/antagonists &amp; inhibitors/*physiology ; Neoplasms/*enzymology ; Rad52 DNA Repair and Recombination Protein ; Recombination, Genetic ; Saccharomyces cerevisiae/enzymology/genetics ; Saccharomyces cerevisiae Proteins/physiology ; Telomerase/antagonists &amp; inhibitors/deficiency/*physiology ; Telomere/physiology/ultrastructure ; },
}
@article {pmid12414502,
year = {2002},
author = {van Heek, NT and Meeker, AK and Kern, SE and Yeo, CJ and Lillemoe, KD and Cameron, JL and Offerhaus, GJ and Hicks, JL and Wilentz, RE and Goggins, MG and De Marzo, AM and Hruban, RH and Maitra, A},
title = {Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia.},
journal = {The American journal of pathology},
volume = {161},
number = {5},
pages = {1541-1547},
pmid = {12414502},
issn = {0002-9440},
support = {P50 CA062924/CA/NCI NIH HHS/United States ; CA62924/CA/NCI NIH HHS/United States ; },
mesh = {Carcinoma, Pancreatic Ductal/*genetics/pathology ; Cell Division ; Humans ; In Situ Hybridization, Fluorescence ; Pancreatic Neoplasms/*genetics/pathology ; Telomere/*ultrastructure ; },
abstract = {A multistep model of carcinogenesis has recently been proposed for pancreatic ductal adenocarcinomas. In this model, noninvasive precursor lesions in the pancreatic ductules accumulate genetic alterations in cancer-associated genes eventually leading to the development of an invasive cancer. The nomenclature for these precursor lesions has been standardized as pancreatic intraepithelial neoplasia or PanIN. Despite the substantial advances made in understanding the biology of invasive pancreatic adenocarcinomas, little is known about the initiating genetic events in the pancreatic ductal epithelium that facilitates its progression to cancer. Telomeres are distinctive structures at the ends of chromosomes that protect against chromosomal breakage-fusion-bridge cycles in dividing cells. Critically shortened telomeres can cause chromosomal instability, a sine qua non of most human epithelial cancers. Although evidence for telomeric dysfunction has been demonstrated in invasive pancreatic cancer, the onset of this phenomenon has not been elucidated in the context of noninvasive precursor lesions. We used a recently described in situ hybridization technique in archival samples (Meeker AK, Gage WR, Hicks JL, Simon I, Coffman JR, Platz EA, March GE, De Marzo AM: Telomere length assessment in human archival tissues: combined telomere fluorescence in situ hybridization and immunostaining. American Journal of Pathology 2002, 160:1259-1268) for assessment of telomere length in tissue microarrays containing a variety of noninvasive pancreatic ductal lesions. These included 82 PanIN lesions of all histological grades (24 PanIN-1A, 23 PanIN-1B, 24 PanIN-2, and 11 PanIN-3) that were selected from pancreatectomy specimens for either adenocarcinoma or chronic pancreatitis. Telomere fluorescence intensities in PanIN lesions were compared with adjacent normal pancreatic ductal epithelium and acini (62 of 82 lesions, 76%), or with stromal fibroblasts and islets of Langerhans (20 of 82 lesions, 24%). Telomere signals were strikingly reduced in 79 (96%) of 82 PanINs compared to adjacent normal structures. Notably, even PanIN-1A, the earliest putative precursor lesion, demonstrated a dramatic reduction of telomere fluorescence intensity in 21 (91%) of 23 foci examined. In chronic pancreatitis, reduction of telomere signal was observed in all PanIN lesions, whereas atrophic and inflammatory ductal lesions retained normal telomere length. Telomere fluorescence intensity in PanIN lesions did not correlate with proliferation measured by quantitative Ki-67-labeling index or topoisomerase IIalpha expression. Thus, telomere shortening is by far the most common early genetic abnormality recognized to date in the progression model of pancreatic adenocarcinomas. Telomeres may be an essential gatekeeper for maintaining chromosomal integrity, and thus, normal cellular physiology in pancreatic ductal epithelium. A critical shortening of telomere length in PanINs may predispose these noninvasive ductal lesions to accumulate progressive chromosomal abnormalities and to develop toward the stage of invasive carcinoma.},
}
@article {pmid12409303,
year = {2003},
author = {Ramírez, R and Carracedo, J and Jiménez, R and Canela, A and Herrera, E and Aljama, P and Blasco, MA},
title = {Massive telomere loss is an early event of DNA damage-induced apoptosis.},
journal = {The Journal of biological chemistry},
volume = {278},
number = {2},
pages = {836-842},
doi = {10.1074/jbc.M206818200},
pmid = {12409303},
issn = {0021-9258},
mesh = {*Apoptosis ; Camptothecin/pharmacology ; Caspase 3 ; Caspases/physiology ; *DNA Damage ; Enzyme Activation ; Humans ; Poly(ADP-ribose) Polymerases/physiology ; Reactive Oxygen Species ; Telomerase/metabolism ; *Telomere ; Tumor Suppressor Protein p53/physiology ; },
abstract = {Chromosomal stability and cell viability require a proficient telomeric end-capping function. In particular, telomere dysfunction because of either critical telomere shortening or because of mutation of telomere-binding proteins results in increased apoptosis and/or cell arrest. Here, we show that, in turn, DNA damage-induced apoptosis results in a dramatic telomere loss. In particular, using flow cytometry for simultaneous detection of telomere length and apoptosis, we show that cells undergoing apoptosis upon DNA damage also exhibit a rapid and dramatic loss of telomeric sequences. This telomere loss occurs at early stages of apoptosis, because it does not require caspase-3 activation, and it is induced by loss of the mitochondrial membrane potential (Deltapsi(m)) and production of reactive oxygen species. These observations suggest a direct effect of mitochondrial dysfunction on telomeres.},
}
@article {pmid12407447,
year = {2002},
author = {Lo, AW and Sabatier, L and Fouladi, B and Pottier, G and Ricoul, M and Murnane, JP},
title = {DNA amplification by breakage/fusion/bridge cycles initiated by spontaneous telomere loss in a human cancer cell line.},
journal = {Neoplasia (New York, N.Y.)},
volume = {4},
number = {6},
pages = {531-538},
pmid = {12407447},
issn = {1522-8002},
support = {R01 CA069044/CA/NCI NIH HHS/United States ; R01CA69044/CA/NCI NIH HHS/United States ; },
mesh = {Anaphase/genetics ; Blotting, Southern ; Chromosome Aberrations ; Chromosome Breakage/*genetics ; Chromosomes, Human, Pair 16/*genetics ; DNA Damage ; DNA, Neoplasm/*genetics ; Gene Amplification ; Herpesvirus 1, Human/genetics/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Plasmids/genetics ; Telomere/*genetics/metabolism ; Thymidine Kinase/genetics ; Transfection ; Tumor Cells, Cultured/physiology ; Urinary Bladder Neoplasms/*genetics ; },
abstract = {The development of genomic instability is an important step in generating the multiple genetic changes required for cancer. One consequence of genomic instability is the overexpression of oncogenes due to gene amplification. One mechanism for gene amplification is the breakage/fusion/bridge (B/F/B) cycle that involves the repeated fusion and breakage of chromosomes following the loss of a telomere. B/F/B cycles have been associated with low-copy gene amplification in human cancer cells, and have been proposed to be an initiating event in high-copy gene amplification. We have found that spontaneous telomere loss on a marker chromosome 16 in a human tumor cell line results in sister chromatid fusion and prolonged periods of chromosome instability. The high rate of anaphase bridges involving chromosome 16 demonstrates that this instability results from B/F/B cycles. The amplification of subtelomeric DNA on the marker chromosome provides conclusive evidence that B/F/B cycles initiated by spontaneous telomere loss are a mechanism for gene amplification in human cancer cells.},
}
@article {pmid12403172,
year = {2002},
author = {Frydrychová, R and Marec, F},
title = {Repeated losses of TTAGG telomere repeats in evolution of beetles (Coleoptera).},
journal = {Genetica},
volume = {115},
number = {2},
pages = {179-187},
doi = {10.1023/a:1020175912128},
pmid = {12403172},
issn = {0016-6707},
mesh = {Animals ; *Biological Evolution ; Blotting, Southern ; Coleoptera/classification/*genetics ; Genes, Insect ; In Situ Hybridization, Fluorescence ; Phylogeny ; *Repetitive Sequences, Nucleic Acid ; Telomere/*genetics ; },
abstract = {We studied the occurrence of (TTAGG)n telomere repeats in 12 species of beetles, representing main lineages of the Coleoptera phylogenetic tree, by Southern hybridization and fluorescence in situ hybridization (FISH). In contrast to other insect orders, beetles were heterogeneous with respect to the occurrence of TTAGG repeats. In addition, the presence or absence of (TTAGG)n motif was irrespective of phylogenetic relationships. In the suborder Polyphaga, six species displayed positive hybridization signals. These were Silpha obscura, Agrilus viridis, Ampedus sanguineus, Stegobium paniceum, Oryzaephilus surinamensis, and Leptinotarsa decemlineata. Whereas negative signals were obtained in three polyphagan species, Geotrupes stercorarius, Thanasimusformicarius, and Sitophilus granarius. In the suborder Adephaga, the TTAGG sequence was present in one species, Graphoderus cinereus, and absent in two species, Orectochilus villosus and Pterostichus oblongopunctatus. We concluded that the telomerase-dependent (TTAGG)n motif had been repeatedly lost in different phylogenetic branches of Coleoptera and probably replaced with another mechanism of telomere elongation. This had to happen at least 5-6 times. The results suggest a predisposition or a backup mechanism of telomere maintenance in the genome of beetles that enabled them to make frequent evolutionary changes in the telomere composition.},
}
@article {pmid12397797,
year = {2002},
author = {Knight, SJ and Flint, J},
title = {Multi-telomere FISH.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {204},
number = {},
pages = {155-179},
doi = {10.1385/1-59259-300-3:155},
pmid = {12397797},
issn = {1064-3745},
mesh = {Cell Line ; *Chromosomes, Human ; Humans ; In Situ Hybridization, Fluorescence/*methods ; *Telomere ; },
}
@article {pmid12393549,
year = {2003},
author = {Roelofs, H and de Pauw, ES and Zwinderman, AH and Opdam, SM and Willemze, R and Tanke, HJ and Fibbe, WE},
title = {Homeostasis of telomere length rather than telomere shortening after allogeneic peripheral blood stem cell transplantation.},
journal = {Blood},
volume = {101},
number = {1},
pages = {358-362},
doi = {10.1182/blood-2002-06-1832},
pmid = {12393549},
issn = {0006-4971},
mesh = {Cross-Sectional Studies ; Granulocyte Colony-Stimulating Factor/therapeutic use ; Hematopoiesis ; Hematopoietic Stem Cell Mobilization ; Homeostasis ; Humans ; Leukocytes/ultrastructure ; *Peripheral Blood Stem Cell Transplantation ; Prospective Studies ; Telomere/*metabolism/ultrastructure ; Time Factors ; Transplantation, Homologous ; },
abstract = {Hematopoietic reconstitution after stem cell transplantation requires excessive replicative activity because of the limited number of stem cells that are used for transplantation. Telomere shortening has been detected in hematopoietic cells after bone marrow transplantation. This has been thought to result from excessive replication of the stem cells, with putative concomitant reduction of their replicative potential. Hematopoietic stem cells from cytokine-mobilized peripheral blood are increasingly used for stem cell transplantation. These grafts contain higher numbers of hematopoietic stem cells, resulting in a faster hematopoietic reconstitution. We have performed a combined prospective and cross-sectional study of hematologic recovery and telomere length dynamics in the immediate reconstitution period after allogeneic T-cell-depleted blood stem cell transplantation. We analyzed hematologic recovery and telomere length of granulocytes, monocytes, B cells, and T-cell subsets in 30 donor/recipient combinations. We found fast recovery in combination with transient telomere shortening in the myeloid lineages. This initial reduction of telomere length was followed by an increase in telomere length to such an extent that 1 year after transplantation the telomere length in recipient cells was similar to the telomere length in donor-derived cells. Therefore, our data indicate telomere length homeostasis after peripheral blood stem cell transplantation, implying no loss of replicative capacity of the stem cells. Our data indicate that fast expansion is accompanied by a reduction of telomere length and that telomere length homeostasis is achieved by de novo generation of hematopoietic cells from stem cells without transplantation-related telomere loss.},
}
@article {pmid12391173,
year = {2002},
author = {Baumann, P and Podell, E and Cech, TR},
title = {Human Pot1 (protection of telomeres) protein: cytolocalization, gene structure, and alternative splicing.},
journal = {Molecular and cellular biology},
volume = {22},
number = {22},
pages = {8079-8087},
pmid = {12391173},
issn = {0270-7306},
mesh = {Alternative Splicing ; Amino Acid Sequence ; Animals ; Cell Line ; DNA/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Fungal Proteins/genetics/metabolism ; Humans ; Immunohistochemistry ; Mice ; Molecular Sequence Data ; Nuclear Proteins/*genetics/*metabolism ; Sequence Alignment ; Shelterin Complex ; Telomere-Binding Proteins/chemistry/*genetics/*metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Fission yeast Pot1 (protection of telomeres) is a single-stranded telomeric DNA binding protein with a critical role in ensuring chromosome stability. A putative human homolog (hPot1) was previously identified, based on moderate sequence similarity with fission yeast Pot1 and telomere end-binding proteins from ciliated protozoa. Using indirect immunofluorescence, we show here that epitope-tagged hPot1 localizes to telomeres in interphase nuclei of human cells, consistent with a direct role in telomere end protection. The hPOT1 gene contains 22 exons, most of which are present in all cDNAs examined. However, four exons are subject to exon skipping in some transcripts, giving rise to five splice variants. Four of these are ubiquitously expressed, whereas the fifth appears to be specific to leukocytes. The resultant proteins vary significantly in their ability to form complexes with single-stranded telomeric DNA as judged by electrophoretic mobility shift assays. In addition to these splice variants, the Pot1 family is expanded by the identification of six more genes from diverse species. Pot1-like proteins have now been found in plants, animals, yeasts, and microsporidia.},
}
@article {pmid12390736,
year = {2002},
author = {Wen, Z and Xiao, JY and Guo, MH},
title = {[Telomere shortening in the pathogenesis of nasopharyngeal carcinoma].},
journal = {Di 1 jun yi da xue xue bao = Academic journal of the first medical college of PLA},
volume = {22},
number = {4},
pages = {329-330},
pmid = {12390736},
issn = {1000-2588},
mesh = {Adult ; Blotting, Southern ; Female ; Humans ; Male ; Middle Aged ; Nasopharyngeal Neoplasms/*genetics ; Nucleic Acid Hybridization ; Telomere/*genetics ; },
abstract = {OBJECTIVE: To explore the role of telomere shortening in the pathogenesis of nasopharyngeal carcinoma (NPC).<br><br>METHODS: Southern blotting was employed to determine the mean telomere length (MTL) in 42 tumor samples and 15 samples of the tissues adjacent to the tumors obtained from 42 NPC patients, along with the tissue specimens from 17 patients with chronic nasopharyngitis.<br><br>RESULTS: In NPC tissues, the length of the MTL was 4.5+/-2.3 kb, obviously shorter than those of the MTL in tissues adjacent to the tumor 14.6+/-2.8 kb and in chronic nasopharyngitis 15.8+/-3.1 kb.<br><br>CONCLUSION: Telomere shortening may play an important role in the pathogenesis of nasopharyngeal epithelium cell malignancies.},
}
@article {pmid12384145,
year = {2002},
author = {Brümmendorf, TH and Mak, J and Sabo, KM and Baerlocher, GM and Dietz, K and Abkowitz, JL and Lansdorp, PM},
title = {Longitudinal studies of telomere length in feline blood cells: implications for hematopoietic stem cell turnover in vivo.},
journal = {Experimental hematology},
volume = {30},
number = {10},
pages = {1147-1152},
doi = {10.1016/s0301-472x(02)00888-3},
pmid = {12384145},
issn = {0301-472X},
support = {R01A/29524//PHS HHS/United States ; },
mesh = {Aging/*physiology ; Animals ; Animals, Newborn ; Cats ; Cells, Cultured ; Granulocytes/*cytology ; Hematopoietic Stem Cells/*cytology/*physiology ; Kinetics ; Lymphocytes/*cytology ; Models, Animal ; Regression Analysis ; *Stem Cell Transplantation ; T-Lymphocytes/immunology ; Telomere/*ultrastructure ; Time Factors ; Transplantation, Autologous ; },
abstract = {OBJECTIVE: To address questions about stem cell turnover in relation to telomere length dynamics, we analyzed telomere length in serial blood samples from cats.<br><br>MATERIALS AND METHODS: Lymphocytes and granulocytes from two newborn kittens, a 2-year-old cat, a 10-year-old recipient of a double autologous stem cell transplant, and a 10-year-old control animal were analyzed by fluorescence in situ hybridization and flow cytometry at 2-week intervals over a 1-year period.<br><br>RESULTS: At study onset, long telomeres were found in granulocytes and lymphocytes from the two kittens (mean +/- SD: 70.2 +/- 3.1 and 72.5 +/- 3.1 telomere fluorescence units [TFU], respectively) compared with the 2-year-old cat (55.6 +/- 2.5 and 64.1 +/- 4.3 TFU, respectively) and the two adult animals (49.6 +/- 1.5 and 45.4 +/- 0.8 TFU, respectively). The rate of telomere shortening in both granulocytes and lymphocytes was most rapid in the kittens (slope: -16.7 +/- 1.4 and -15.6 +/- 0.2 TFU/year, respectively). As in humans, telomere shortening with age was more rapid in lymphocytes than in granulocytes. An average rate of telomere attrition of -0.52 +/- 0.03 TFU per cell division was calculated for cultured lymphocytes from the two kittens, approximately 5-fold higher than the rate observed in human cells.<br><br>CONCLUSIONS: The average telomere length in cats is 5- to 10-fold longer than in humans, but the rate of telomere shortening is much higher both in vivo and in vitro. These observations are compatible with similar stem cell kinetics in both species.},
}
@article {pmid12381316,
year = {2002},
author = {Rippmann, JF and Damm, K and Schnapp, A},
title = {Functional characterization of the poly(ADP-ribose) polymerase activity of tankyrase 1, a potential regulator of telomere length.},
journal = {Journal of molecular biology},
volume = {323},
number = {2},
pages = {217-224},
doi = {10.1016/s0022-2836(02)00946-4},
pmid = {12381316},
issn = {0022-2836},
mesh = {DNA-Binding Proteins/genetics/metabolism ; Humans ; Membrane Proteins/chemistry/genetics/metabolism ; NAD/metabolism ; Peptide Fragments/genetics/*metabolism ; Protein Structure, Tertiary ; Recombinant Proteins/genetics/metabolism ; Tankyrases/chemistry/genetics/*metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; },
abstract = {Poly(ADP-ribose) polymerases (PARPs) comprise a growing family of enzymes known to be involved in genotoxic signaling and metabolic regulation. One of the latest family members, tankyrase 1, was shown to be involved in maintenance of telomere integrity. Here we expressed full-length tankyrase 1 and a fragment, termed T-PARP, spanning the poly(ADP-ribose) polymerase domain and characterized the enzymatic properties of the two proteins. Both, tankyrase 1 and T-PARP catalyze an auto poly(ADP-ribosyl)ation reaction with comparable catalytic activity. In contrast, (ADP-ribosyl)ation of TRF1, a previously described substrate, is strongly performed only by the full-length enzyme but not by T-PARP. Characterization of the poly(ADP-ribose) products reveals that tankyrase 1 synthesizes polymers with an average chain length of 20 units and no detectable branching of the polymers. Finally, we show that the catalytic efficiency of tankyrase 1, as expressed by the k(cat)/K(m) value, is approximately 150-fold lower compared to the basal activity of the poly(ADP-ribose) polymerase, PARP 1.},
}
@article {pmid12379853,
year = {2002},
author = {García-Cao, M and Gonzalo, S and Dean, D and Blasco, MA},
title = {A role for the Rb family of proteins in controlling telomere length.},
journal = {Nature genetics},
volume = {32},
number = {3},
pages = {415-419},
doi = {10.1038/ng1011},
pmid = {12379853},
issn = {1061-4036},
mesh = {Animals ; Cells, Cultured ; Chromosome Aberrations ; Chromosomes/ultrastructure ; DNA/metabolism ; Fibroblasts/metabolism ; Flow Cytometry ; Genotype ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microscopy, Fluorescence ; Nuclear Proteins/metabolism/*physiology ; Retinoblastoma Protein/metabolism/*physiology ; Retinoblastoma-Like Protein p107 ; Telomerase/metabolism ; Telomere/metabolism/*ultrastructure ; },
abstract = {The molecular mechanisms of cellular mortality have recently begun to be unraveled. In particular, it has been discovered that cells that lack telomerase are subject to telomere attrition with each round of replication, eventually leading to loss of telomere capping function at chromosome ends. Critically short telomeres and telomeres lacking telomere-binding proteins lose their functionality and are metabolized as DNA breaks, thus generating chromosomal fusions. Telomerase activity is sufficient to rescue short telomeres and confers an unlimited proliferative capacity. In addition, the tumor-suppressor pathway Cdkn2a/Rb1 has also been implicated as a barrier to immortalization. Here, we report a connection between the members of the retinoblastoma family of proteins, Rb1 (retinoblastoma 1), Rbl1 (retinoblastoma-like 1) and Rbl2 (retinoblastoma-like 2), and the mechanisms that regulate telomere length. In particular, mouse embryonic fibroblasts doubly deficient in Rbl1 and Rbl2 or triply deficient in Rbl1, Rbl2 and Rb1 have markedly elongated telomeres compared with those of wildtype or Rb1-deficient cells. This deregulation of telomere length is not associated with increased telomerase activity. Notably, the abnormally elongated telomeres in doubly or triply deficient cells retain their end-capping function, as shown by the normal frequency of chromosomal fusions. These findings demonstrate a connection between the Rb1 family and the control of telomere length in mammalian cells.},
}
@article {pmid12378624,
year = {2002},
author = {Zhang, RG and Guo, LX and Wang, XW and Xie, H},
title = {Telomerase inhibition and telomere loss in BEL-7404 human hepatoma cells treated with doxorubicin.},
journal = {World journal of gastroenterology},
volume = {8},
number = {5},
pages = {827-831},
pmid = {12378624},
issn = {1007-9327},
mesh = {Antineoplastic Agents/*pharmacology ; *Carcinoma, Hepatocellular ; Dose-Response Relationship, Drug ; Doxorubicin/*pharmacology ; G2 Phase/drug effects ; Humans ; *Liver Neoplasms ; Mitosis/drug effects ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/drug effects ; Tumor Cells, Cultured ; },
abstract = {AIM: To study the effects of doxorubicin on telomerase activity and telomere length in hepatocellular carcinoma.<br><br>METHODS: Telomerase activity was assayed with a non-radioisotopic quantitative telomerase repeat amplification protocol-based method. The effect of doxorubicin (DOX) on the growth of BEL-7404 human hepatoma cells was determined by microculture tetrazolium assay. Mean telomere length (terminal restriction fragment) was detected by Southern blot method. The expression of telomerase subunits genes was investigated by RT-PCR. Cell apoptosis and cell cycle distribution were evaluated by flow cytometry.<br><br>RESULTS: Telomerase activity was inhibited in a dose and time-dependent manner in BEL-7404 human hepatoma cells treated with DOX for 24, 48 or 72 h in concentrations from 0.156 to 2.5 microM which was correlated with the inhibition of cell growth. No changes were found in the mRNA expression of three telomerase subunits (hTERT, hTR and TP1) after drug exposure for 72 h with indicated concentrations. The cells treated with DOX showed shortened mean telomere length and accumulated at the G(2)/M phase. However, there was almost no effects on cell apoptosis by DOX.<br><br>CONCLUSION: The telomerase inhibition and the telomere shortening by DOX may contribute to its efficiency in the treatment in hepatocellular carcinoma.},
}
@article {pmid12372147,
year = {2002},
author = {Louis, EJ},
title = {Are Drosophila telomeres an exception or the rule?.},
journal = {Genome biology},
volume = {3},
number = {10},
pages = {REVIEWS0007},
pmid = {12372147},
issn = {1474-760X},
mesh = {Animals ; Cell Cycle/genetics/physiology ; Drosophila/*genetics/physiology ; Evolution, Molecular ; Repetitive Sequences, Nucleic Acid/genetics ; Telomere/*genetics/physiology ; },
abstract = {At the ends of eukaryotic chromosomes are telomeres, specialized structures with unusual properties. Specific efforts to compare sequences and properties of telomeres across species can reveal the generalities of telomere properties.},
}
@article {pmid12372059,
year = {2002},
author = {Zahed, L and Darwiche, N and Batanian, JR and Awwad, J},
title = {Homologous telomere association of 19q in a female with premature ovarian failure.},
journal = {Clinical genetics},
volume = {62},
number = {4},
pages = {310-314},
doi = {10.1034/j.1399-0004.2002.620410.x},
pmid = {12372059},
issn = {0009-9163},
mesh = {Adult ; Chromosome Aberrations ; Chromosome Disorders ; *Chromosomes, Human, Pair 19 ; Female ; Humans ; Metaphase/genetics ; Primary Ovarian Insufficiency/*genetics ; Telomere/*genetics ; },
abstract = {Premature ovarian failure (POF) may be due to a variety of genetic mechanisms. We report here, for the first time, telomere association of the long arms of chromosome 19, identified at low frequency (1%) in the peripheral blood cultures of a 30-year-old female with POF. Repeat cultures identified, in addition, the presence of 16q and 22q associations at a lower frequency (0.5%). These consistent observations are suggestive of a non-random event. Their association with POF may just be coincidental or may hypothetically explain it by an abnormal mechanism of chromosome separation, a constitutional telomere anomaly or an unidentified chromosome instability disorder.},
}
@article {pmid12368963,
year = {2002},
author = {Li, YH and Ma, SK and Wan, TS and Au, WY and Fung, LF and Leung, AY and Lie, AK and Chan, LC},
title = {Lineage-specific differences in telomere length after bone marrow transplantation.},
journal = {Bone marrow transplantation},
volume = {30},
number = {7},
pages = {475-477},
doi = {10.1038/sj.bmt.1703669},
pmid = {12368963},
issn = {0268-3369},
mesh = {Adolescent ; Adult ; *Bone Marrow Transplantation ; Cell Lineage ; Cellular Senescence ; Child ; Child, Preschool ; Hematopoietic Stem Cells/ultrastructure ; Humans ; Leukocytes/ultrastructure ; Middle Aged ; Telomere/physiology/*ultrastructure ; },
}
@article {pmid12368497,
year = {2002},
author = {Bundock, P and Hooykaas, P},
title = {Severe developmental defects, hypersensitivity to DNA-damaging agents, and lengthened telomeres in Arabidopsis MRE11 mutants.},
journal = {The Plant cell},
volume = {14},
number = {10},
pages = {2451-2462},
pmid = {12368497},
issn = {1040-4651},
mesh = {Amino Acid Sequence ; Arabidopsis/drug effects/genetics/*growth &amp; development ; Arabidopsis Proteins/*genetics/metabolism ; DNA Damage/*drug effects/radiation effects ; DNA Repair/genetics/physiology ; Gene Expression Regulation, Plant/drug effects/radiation effects ; Methyl Methanesulfonate/pharmacology ; Molecular Sequence Data ; Mutation ; Sequence Homology, Amino Acid ; Telomere/*drug effects/genetics ; X-Rays ; },
abstract = {The Mre11 protein is essential for the long-term genetic stability of the cell and acts to ensure the efficient repair of DNA damage. Vertebrate cells lacking Mre11 function are not viable. However, we report here that this is not the case in the model plant Arabidopsis. We have isolated two different Arabidopsis lines containing a T-DNA copy integrated at a different point in the MRE11 gene (AtMRE11). Both mutant plant lines were hypersensitive to DNA-damaging treatments but exhibited strikingly different developmental phenotypes. Furthermore, we also observed lengthened telomeres in these plant lines, showing that AtMre11 is involved in telomere maintenance. Thus, the lines we have isolated are unique tools with which to study in detail the role of AtMre11 in the mature plant.},
}
@article {pmid12368259,
year = {2002},
author = {Cosgrove, AJ and Nieduszynski, CA and Donaldson, AD},
title = {Ku complex controls the replication time of DNA in telomere regions.},
journal = {Genes &amp; development},
volume = {16},
number = {19},
pages = {2485-2490},
pmid = {12368259},
issn = {0890-9369},
mesh = {Chromosomes, Fungal/physiology ; *DNA Replication ; DNA, Fungal/*biosynthesis ; DNA-Binding Proteins/genetics/*physiology ; Mutagenesis ; Replication Origin/*physiology ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/genetics/*physiology ; Telomere/*physiology ; Time Factors ; },
abstract = {We have investigated whether the Ku complex is involved in regulating DNA replication in the yeast Saccharomyces cerevisiae. We find that Ku proteins control the replication time of telomeric regions; replication origins located close to telomeres or within subtelomeric repeat sequences normally initiate late, but are activated much earlier in mutants lacking Ku function. In contrast, origins distant from telomeres initiate replication at the normal time. Ku is one of the first components identified as important for replication timing, and specification of the replication time of chromosome ends by Ku is consistent with its role in maintaining telomere localization.},
}
@article {pmid12362030,
year = {2002},
author = {Martin, CL and Waggoner, DJ and Wong, A and Uhrig, S and Roseberry, JA and Hedrick, JF and Pack, SD and Russell, K and Zackai, E and Dobyns, WB and Ledbetter, DH},
title = {"Molecular rulers" for calibrating phenotypic effects of telomere imbalance.},
journal = {Journal of medical genetics},
volume = {39},
number = {10},
pages = {734-740},
pmid = {12362030},
issn = {1468-6244},
support = {1 RO1 HD36715-03/HD/NICHD NIH HHS/United States ; },
mesh = {Calibration ; Child ; Chromosome Deletion ; Chromosomes, Human, Pair 10/genetics ; Chromosomes, Human, Pair 16/genetics ; Chromosomes, Human, Pair 17/genetics ; Fatal Outcome ; Female ; Gene Amplification/genetics ; Humans ; Infant ; Infant, Newborn ; Infant, Premature ; Male ; Phenotype ; Prenatal Diagnosis ; Telomere/*genetics ; Trisomy/diagnosis/genetics ; },
abstract = {As a result of the increasing use of genome wide telomere screening, it has become evident that a significant proportion of people with idiopathic mental retardation have subtle abnormalities involving the telomeres of human chromosomes. However, during the course of these studies, there have also been telomeric imbalances identified in normal people that are not associated with any apparent phenotype. We have begun to scrutinize cases from both of these groups by determining the extent of the duplication or deletion associated with the imbalance. Five cases were examined where the telomere rearrangement resulted in trisomy for the 16p telomere. The size of the trisomic segment ranged from approximately 4-7 Mb and the phenotype included mental and growth retardation, brain malformations, heart defects, cleft palate, pancreatic insufficiency, genitourinary abnormalities, and dysmorphic features. Three cases with telomeric deletions without apparent phenotypic effects were also examined, one from 10q and two from 17p. All three deletions were inherited from a phenotypically normal parent carrying the same deletion, thus without apparent phenotypic effect. The largest deletion among these cases was approximately 600 kb on 17p. Similar studies are necessary for all telomeric regions to differentiate between those telomeric rearrangements that are pathogenic and those that are benign variants. Towards this goal, we are developing "molecular rulers" that incorporate multiple clones at each telomere that span the most distal 5 Mb region. While telomere screening has enabled the identification of telomere rearrangements, the use of molecular rulers will allow better phenotype prediction and prognosis related to these findings.},
}
@article {pmid12361565,
year = {2002},
author = {Smogorzewska, A and Karlseder, J and Holtgreve-Grez, H and Jauch, A and de Lange, T},
title = {DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2.},
journal = {Current biology : CB},
volume = {12},
number = {19},
pages = {1635-1644},
doi = {10.1016/s0960-9822(02)01179-x},
pmid = {12361565},
issn = {0960-9822},
support = {GM07739/GM/NIGMS NIH HHS/United States ; GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Division ; Cell Line ; Chromatids/genetics/metabolism ; DNA Ligase ATP ; DNA Ligases/*metabolism ; *G1 Phase ; *G2 Phase ; Gene Expression Regulation ; Humans ; In Situ Hybridization, Fluorescence ; Recombination, Genetic/*genetics ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/antagonists &amp; inhibitors/metabolism ; Translocation, Genetic/genetics ; },
abstract = {BACKGROUND: Telomeres are required to prevent end-to-end chromosome fusions. End-to-end fusions of metaphase chromosomes are observed in mammalian cells with dysfunctional telomeres due to diminished function of telomere-associated proteins and in cells experiencing extensive attrition of telomeric DNA. However, the molecular nature of these fusions and the mechanism by which they occur have not been elucidated.<br><br>RESULTS: We document that telomere fusions resulting from inhibition of the telomere-protective factor TRF2 are generated by DNA ligase IV-dependent nonhomologous end joining (NHEJ). NHEJ gives rise to covalent ligation of the C strand of one telomere to the G strand of another. Breakage of the resulting dicentric chromosomes results in nonreciprocal translocations, a hallmark of human cancer. Telomere NHEJ took place before and after DNA replication, and both sister telomeres participated in the reaction. Telomere fusions were accompanied by active degradation of the 3' telomeric overhangs.<br><br>CONCLUSIONS: The main threat to dysfunctional mammalian telomeres is degradation of the 3' overhang and subsequent telomere end-joining by DNA ligase IV. The involvement of NHEJ in telomere fusions is paradoxical since the NHEJ factors Ku70/80 and DNA-PKcs are present at telomeres and protect chromosome ends from fusion.},
}
@article {pmid12355410,
year = {2002},
author = {Chen, HJ and Cho, CL and Liang, CL and Lu, K and Lin, JW},
title = {Implication of telomere length as a proliferation-associated marker in schwannomas.},
journal = {Journal of surgical oncology},
volume = {81},
number = {2},
pages = {93-100; discussion 100},
doi = {10.1002/jso.10139},
pmid = {12355410},
issn = {0022-4790},
mesh = {Adolescent ; Adult ; Aged ; Central Nervous System Neoplasms/enzymology/*pathology ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Male ; Middle Aged ; Neurilemmoma/enzymology/*pathology ; Polymerase Chain Reaction ; Telomerase/*metabolism ; Telomere/metabolism/*ultrastructure ; },
abstract = {BACKGROUND AND OBJECTIVES: Some schwannomas in the central nervous system may demonstrate relatively aggressive behavior in pathological findings and clinical course. We evaluate the diagnostic values of telomerase activity and telomere length in the clinicopathological behavior of schwannomas.<br><br>METHODS: Thirty surgical specimens from intracranial and intraspinal schwannomas were analyzed by polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) for telomerase activity and terminal restriction fragments (TRFs) using Southern blot for telomere length. Proliferative indices were also studied.<br><br>RESULTS: Telomerase activity could not be detected in all schwannomas. Elongated telomere length (mean 17,101 +/- 259 bp) was found in four specimens (13.3%). Three of these four were found to have mitotic figures, high vascularity, cellularity, and pleomorphism in the pathological findings. The proliferative indices (35) showed correlative high values. One patient died of this disease, and one was found to have recurrence at follow-up evaluation. Those that displayed benign histopathological pictures showed relatively short telomere length (8,866 +/- 271 base pairs) and low proliferative indices (21). These is a significant difference between these two groups (P = 0.001).<br><br>CONCLUSIONS: Elongation of telomere length in schwannomas appears to predict aggressive clinicopathological behavior.},
}
@article {pmid12355203,
year = {2002},
author = {Ofir, R and Yalon-Hacohen, M and Segev, Y and Schultz, A and Skorecki, KL and Selig, S},
title = {Replication and/or separation of some human telomeres is delayed beyond S-phase in pre-senescent cells.},
journal = {Chromosoma},
volume = {111},
number = {3},
pages = {147-155},
doi = {10.1007/s00412-002-0199-z},
pmid = {12355203},
issn = {0009-5915},
mesh = {Cell Cycle/*physiology ; Cellular Senescence/*physiology ; DNA Methylation ; DNA Replication/*physiology ; Fetal Blood ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Spermatozoa/metabolism ; Telomerase/genetics/metabolism ; Telomere/*physiology ; },
abstract = {Cultured primary human cells, which lack telomerase, enter a state of replicative senescence after a characteristic number of population doublings. During this process telomeres shorten to a critical length of approximately 5-7 kb. The mechanistic relationship between advanced cell passage, cellular senescence and telomeric function has yet to be fully elucidated. In the study described here, we investigated the relationship between changes in telomeric replication timing and/or sister chromatid separation at telomeric regions and advanced cell passage. Using fluorescence in situ hybridization, we analyzed the appearance of double hybridization signals (doublets), which indicate that the region of interest has replicated and the replicated products have separated sufficiently to be resolved as two distinct signals. The results showed that the replication and separation of several telomeric regions occurs during the second half of S-phase and that a delay in replication and/or separation of sister chromatids at these regions occurs in pre-senescent human fibroblasts. Surprisingly, in a significant percentage of pre-senescent cells, several telomeric regions did not hybridize as doublets even in metaphase chromosomes. This delay was not associated with extensive changes in methylation levels at subtelomeric regions and was circumvented in human fibroblasts expressing ectopic telomerase. We propose that incomplete replication and/or separation of telomeric regions in metaphase may be associated with proliferative arrest of senescent cells. This cell growth arrest may result from the activation of a mitotic checkpoint, or from chromosomal instability consequent to progression in the cell cycle despite failure to replicate and/or separate these regions completely.},
}
@article {pmid12355086,
year = {2002},
author = {O'Sullivan, JN and Bronner, MP and Brentnall, TA and Finley, JC and Shen, WT and Emerson, S and Emond, MJ and Gollahon, KA and Moskovitz, AH and Crispin, DA and Potter, JD and Rabinovitch, PS},
title = {Chromosomal instability in ulcerative colitis is related to telomere shortening.},
journal = {Nature genetics},
volume = {32},
number = {2},
pages = {280-284},
doi = {10.1038/ng989},
pmid = {12355086},
issn = {1061-4036},
mesh = {Adult ; Amides/metabolism ; *Chromosome Aberrations ; Colitis, Ulcerative/*genetics ; Female ; Fluorescein-5-isothiocyanate/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Organometallic Compounds ; Phosphoric Acids/metabolism ; Stromal Cells ; Telomere/*genetics/metabolism ; },
abstract = {Ulcerative colitis, a chronic inflammatory disease of the colon, is associated with a high risk of colorectal carcinoma that is thought to develop through genomic instability. We considered that the rapid cell turnover and oxidative injury observed in ulcerative colitis might accelerate telomere shortening, thereby increasing the potential of chromosomal ends to fuse, resulting in cycles of chromatin bridge breakage and fusion and chromosomal instability associated with tumor cell progression. Here we have used quantitative fluorescence in situ hybridization to compare chromosomal aberrations and telomere shortening in non-dysplastic mucosa taken from individuals affected by ulcerative colitis, either with (UC progressors) or without (UC non-progressors) dysplasia or cancer. Losses, but not gains, of chromosomal arms and centromeres are highly correlated with telomere shortening. Chromosomal losses are greater and telomeres are shorter in biopsy samples from UC progressors than in those from UC non-progressors or control individuals without ulcerative colitis. A mechanistic link between telomere shortening and chromosomal instability is supported by a higher frequency of anaphase bridges--an intermediate in the breakage and fusion of chromatin bridges--in UC progressors than in UC non-progressors or control individuals. Our study shows that telomere length is correlated with chromosomal instability in a precursor of human cancer.},
}
@article {pmid12352018,
year = {2002},
author = {Minamino, T and Komuro, I},
title = {Role of telomere in endothelial dysfunction in atherosclerosis.},
journal = {Current opinion in lipidology},
volume = {13},
number = {5},
pages = {537-543},
doi = {10.1097/00041433-200210000-00010},
pmid = {12352018},
issn = {0957-9672},
mesh = {Aging/physiology ; Animals ; Arteriosclerosis/*metabolism/*pathology ; Cellular Senescence/physiology ; Endothelium, Vascular/*metabolism/*pathology ; Humans ; Oxidative Stress ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {PURPOSE OF REVIEW: Telomeres consist of repeats of G-rich sequence at the end of chromosomes. These DNA repeats are synthesized by enzymatic activity associated with an RNA protein complex called telomerase. In most somatic cells, telomerase activity is insufficient, and telomere length decreases with increasing cell division, resulting in an irreversible cell growth arrest, termed cellular senescence. Cellular senescence is associated with an array of phenotypic changes suggestive of aging. Until recently, cellular senescence has largely been studied as an in-vitro phenomenon; however, there is accumulating evidence that indicates a critical role of telomere function in the pathogenesis of human atherosclerosis. This review attempts to summarize recent work in vascular biology that supports the "telomere hypothesis". We discuss the possible relevance of telomere function to vascular aging and the therapeutic potential of telomere manipulation.<br><br>RECENT FINDINGS: It has been reported that many of the changes in senescent vascular cell behavior are consistent with known changes seen in age-related vascular diseases. Introduction of telomere malfunction has been shown to lead to endothelial dysfunction that promotes atherogenesis, whereas telomere lengthening extends cell lifespan and protects against endothelial dysfunction associated with senescence. Indeed, recent studies have demonstrated that telomere attrition and cellular senescence occur in the blood vessels and are associated with human atherosclerosis.<br><br>SUMMARY: Recent findings suggest that vascular cell senescence induced by telomere shortening may contribute to atherogenesis and may provide insights into a novel treatment of antisenescence to prevent atherosclerosis.},
}
@article {pmid12243752,
year = {2002},
author = {Sohn, SH and Multani, AS and Gugnani, PK and Pathak, S},
title = {Telomere erosion-induced mitotic catastrophe in continuously grown chinese hamster don cells.},
journal = {Experimental cell research},
volume = {279},
number = {2},
pages = {271-276},
doi = {10.1006/excr.2002.5614},
pmid = {12243752},
issn = {0014-4827},
support = {RR0499901/RR/NCRR NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; *Chromosome Aberrations ; Cricetinae ; Cricetulus ; DNA/genetics/*metabolism ; In Situ Hybridization, Fluorescence ; Male ; Mitosis/*physiology ; Telomere/*metabolism ; },
abstract = {We have previously reported that telomere erosion is the earliest chromatin modification in cells entering the apoptotic pathway. The purpose of this investigation was to determine whether loss of telomeric DNA was involved in inducing mitotic catastrophe and death in Chinese hamster Don cells. Don, a male Chinese hamster-derived cell line which requires daily subculturing to remain diploid, was grown without subculturing for 1-4 days at 37 degrees C and analyzed cytologically. Our results indicated that (1) the frequency of metaphase chromosomes with structural anomalies was significantly higher in 3-day continuously grown cells than in 1-day control cells (8.2% vs 5.7%; P < 0.01), (2) the mitotic index was considerably lower in 3-day continuously grown cells (0.13%) than in control cells (3.64%), (3) cells grown for 3 days continuously showed a higher incidence (7.6%) of endoreduplicated metaphase chromosomes than did control cells (4.9%), (4) 4-day continuously grown Don cells showed significantly smaller amounts of telomeric DNA in interphase nuclei than did control cells, and (5) apoptotic cells were more frequent in 4-day cell cultures (40.6%) than in control cells (4.3%). These results support our earlier observations and contribute additional support for our hypothesis that telomere reduction is the cause of mitotic catastrophe and that cell death in continuously grown Don cells occurs because of the loss of telomeric DNA.},
}
@article {pmid12235286,
year = {2002},
author = {Cowan, CR and Carlton, PM and Cande, WZ},
title = {Reorganization and polarization of the meiotic bouquet-stage cell can be uncoupled from telomere clustering.},
journal = {Journal of cell science},
volume = {115},
number = {Pt 19},
pages = {3757-3766},
doi = {10.1242/jcs.00054},
pmid = {12235286},
issn = {0021-9533},
mesh = {Cell Nucleus/drug effects/*genetics/ultrastructure ; Cell Polarity/drug effects/genetics ; Cells, Cultured ; Colchicine/pharmacology ; Flowers/cytology/drug effects/*genetics ; Heterochromatin/drug effects/genetics/ultrastructure ; Meiosis/drug effects/*genetics ; Microtubules/drug effects/genetics/ultrastructure ; Nuclear Pore/genetics/ultrastructure ; Secale/cytology/*genetics ; Telomere/*genetics/ultrastructure ; rab GTP-Binding Proteins/genetics ; },
abstract = {Striking cellular reorganizations mark homologous pairing during meiotic prophase. We address the interdependence of chromosomal and cellular polarization during meiotic telomere clustering, the defining feature of the bouquet stage, by examining nuclear positioning and microtubule and nuclear pore reorganization. Polarization of meiotic cellular architecture was coincident with telomere clustering: microtubules were focused on the nuclear surface opposite the telomere cluster, the nucleus was positioned eccentrically in the cell such that the telomeres faced the direction of nuclear displacement and nuclear pores were clustered in a single region of the nuclear surface opposite the telomeres. Treatment of pre-bouquet stage cells with colchicine inhibited telomere clustering. Asymmetric nuclear positioning and nuclear pore clustering were normal in the presence of unclustered telomeres resulting from colchicine treatment. Nuclear pores were positioned normally with respect to the cell cortex in the absence of telomere clustering, indicating that telomere positioning is not required for polarization. This work provides evidence of meiotic cell polarization and suggests that telomeres may be positioned relative to an asymmetry present in the cell at the time of bouquet formation.},
}
@article {pmid12235285,
year = {2002},
author = {Cowan, CR and Cande, WZ},
title = {Meiotic telomere clustering is inhibited by colchicine but does not require cytoplasmic microtubules.},
journal = {Journal of cell science},
volume = {115},
number = {Pt 19},
pages = {3747-3756},
doi = {10.1242/jcs.00055},
pmid = {12235285},
issn = {0021-9533},
mesh = {Cells, Cultured ; Chromosome Segregation/drug effects/*genetics ; Colchicine/pharmacology ; Cytoplasm/drug effects/*genetics/ultrastructure ; Dose-Response Relationship, Drug ; Flowers/cytology/drug effects/*genetics ; Meiosis/drug effects/*genetics ; Microtubules/drug effects/*genetics/ultrastructure ; Molecular Structure ; Podophyllotoxin/pharmacology ; Polymers ; Prophase/drug effects/genetics ; Secale/cytology/*genetics ; Telomere/drug effects/*genetics/ultrastructure ; },
abstract = {Telomere clustering, the defining feature of the bouquet, is an almost universal feature of meiotic prophase, yet its mechanism remains unknown. The microtubule-depolymerizing agent colchicine was found to inhibit bouquet formation. Telomeres in colchicine-treated cells remained scattered in the nuclear periphery, whereas untreated cells exhibited a prominent telomere cluster. Colchicine administered after the bouquet had formed did not affect telomere dispersal. The effect of colchicine on bouquet formation appeared to be separable from its effect on cytoplasmic microtubules; amiprophos methyl, a highly effective plant microtubule-depolymerizing drug, did not affect telomere clustering. Inhibition of bouquet formation was limited to colchicine and the related drug podophyllotoxin out of the variety of microtubule-depolymerizing drugs tested, suggesting that the target involved in bouquet formation has a structural specificity.},
}
@article {pmid12234682,
year = {2002},
author = {Ye, AJ and Romero, DP},
title = {A unique pause pattern during telomere addition by the error-prone telomerase from the ciliate Paramecium tetraurelia.},
journal = {Gene},
volume = {294},
number = {1-2},
pages = {205-213},
doi = {10.1016/s0378-1119(02)00790-4},
pmid = {12234682},
issn = {0378-1119},
support = {GM-50861/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Cloning, Molecular ; DNA, Protozoan/chemistry/genetics ; DNA-Binding Proteins ; Genes, Protozoan/genetics ; Molecular Sequence Data ; Paramecium/*enzymology/genetics ; Phylogeny ; Sequence Alignment ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; Substrate Specificity ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomeric DNA - the short, tandemly repeated sequences at the ends of chromosomes - is synthesized by telomerase, a ribonucleoprotein enzyme that copies a specific template sequence within its integral RNA moiety. The error-prone telomerase from the ciliate Paramecium tetraurelia stereotypically misincorporates TTP at telomerase RNA templating nucleotide C52, accounting for the 30% TTTGGG repeats randomly distributed in wild-type telomeres. Paramecium tetraurelia telomerase has been isolated from macronuclear extracts and characterized with respect to the extension of telomeric primers in vitro. Unlike telomerase activities from other species, the predominant pause during telomeric repeat synthesis by P. tetraurelia telomerase does not occur at the 5' end of the templating domain (templating nucleotide C49). Instead, the pause by P. tetraurelia telomerase is at templating nucleotide C53, immediately prior to incorporation of dGTP (or TTP) at C52. The configuration of the catalytic site at this template position during telomere synthesis is most likely responsible for the high incidence of misincorporation of TTP at C52. The gene for the P. tetraurelia telomerase catalytic subunit, telomerase reverse transcriptase (TERT), has been cloned and sequenced. A comparative analysis of the P. tetraurelia TERT with homologs from other species, including that from another Paramecium species that does not make a high percentage of misincorporation errors, has been initiated. This study may delineate those TERT structural elements that contribute to telomerase fidelity.},
}
@article {pmid12234681,
year = {2002},
author = {Chiurillo, MA and Santos, MR and Franco Da Silveira, J and Ramírez, JL},
title = {An improved general approach for cloning and characterizing telomeres: the protozoan parasite Trypanosoma cruzi as model organism.},
journal = {Gene},
volume = {294},
number = {1-2},
pages = {197-204},
doi = {10.1016/s0378-1119(02)00768-0},
pmid = {12234681},
issn = {0378-1119},
mesh = {Animals ; Base Sequence ; Blotting, Southern ; Chromosomes, Artificial, Bacterial/genetics ; Cloning, Molecular/*methods ; DNA, Protozoan/chemistry/genetics ; Gene Library ; Molecular Sequence Data ; Protozoan Proteins/genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Sequence Analysis, DNA ; Telomere/*genetics ; Trypanosoma cruzi/*genetics ; },
abstract = {We here describe a general strategy for cloning and characterizing telomeric and sub-telomeric regions of the human protozoan parasite Trypanosoma cruzi. The use of a bacterial artificial chromosome vector and a telomeric adaptor produced stable telomeric recombinant clones with inserts ranging from 5 to 25 kb. Analysis of these recombinants provided unique landmarks for chromosomal mapping and sequencing and enabled us to derive a more accurate picture of T. cruzi telomeric organization.},
}
@article {pmid12220625,
year = {2002},
author = {Gan, Y and Mo, Y and Johnston, J and Lu, J and Wientjes, MG and Au, JL},
title = {Telomere maintenance in telomerase-positive human ovarian SKOV-3 cells cannot be retarded by complete inhibition of telomerase.},
journal = {FEBS letters},
volume = {527},
number = {1-3},
pages = {10-14},
doi = {10.1016/s0014-5793(02)03141-1},
pmid = {12220625},
issn = {0014-5793},
support = {R01CA77091/CA/NCI NIH HHS/United States ; },
mesh = {Cells, Cultured ; Enzyme Inhibitors/pharmacology ; Female ; Humans ; Oligonucleotides, Antisense/pharmacology ; Osteosarcoma/metabolism/pathology ; Ovary/*cytology/drug effects/*physiology ; Pharynx/cytology/physiology ; Telomerase/*antagonists &amp; inhibitors/genetics/metabolism ; Telomere/drug effects/*physiology ; Zidovudine/pharmacology ; },
abstract = {The two known mechanisms for telomere maintenance in eukaryocytes are telomerase in telomerase-positive cells and alternative lengthening of telomeres (ALT) in telomerase-negative cells. We report here that telomere maintenance in the telomerase-positive human ovarian SKOV-3 cells was not affected by inhibition of telomerase. For comparison, the effect of telomerase inhibitors on telomere maintenance in another telomerase-positive cell line (i.e. human pharynx FaDu cells) and the telomerase-negative human osteosarcoma Saos-2 cells was examined. Telomerase activity was measured using a modified telomeric repeat amplification protocol and telomere length was measured using a solution hybridization-based method and fluorescence in situ hybridization. A reverse transcriptase inhibitor (3'-azido-deoxythymidine or AZT) and an antisense against a component of human telomerase RNA (antisense hTR) were used to inhibit telomerase. FaDu and SKOV-3 cells showed comparable baseline telomerase activity. Telomerase activity in both cells was inhibited about equally by AZT (maximal inhibition of approximately 80%) and by expression of antisense hTR (complete inhibition in SKOV-3 cells and maximal inhibition of approximately 80% in FaDu cells). However, treatment with telomerase inhibitors resulted in approximately 50% telomere shortening in FaDu cells but had no effect on SKOV-3 nor Saos-2 cells. SKOV-3 cells did not show the characteristic features of ALT (i.e. heterogeneous telomere length and promyelocytic leukemia bodies), whereas these ALT features were observed in Saos-2 cells. Collectively, these results suggest the existence of a telomerase-independent mechanism of telomere maintenance in the telomerase-positive SKOV-3 cells.},
}
@article {pmid12218637,
year = {2002},
author = {Watabe-Rudolph, M and Rudolph, KL and Averbeck, T and Buhr, T and Lenarz, T and Stöver, T},
title = {Telomerase activity, telomere length, and apoptosis: a comparison between acquired cholesteatoma and squamous cell carcinoma.},
journal = {Otology &amp; neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology},
volume = {23},
number = {5},
pages = {793-798},
doi = {10.1097/00129492-200209000-00031},
pmid = {12218637},
issn = {1531-7129},
mesh = {Adult ; Aged ; Aged, 80 and over ; Apoptosis/physiology ; Carcinoma, Squamous Cell/*enzymology/*pathology ; Cholesteatoma, Middle Ear/*enzymology/*pathology ; Ear Neoplasms/*enzymology/*pathology ; Humans ; Middle Aged ; Telomerase/*metabolism ; Telomere/*enzymology ; },
abstract = {BACKGROUND: Cholesteatoma disease is characterized by accumulation of keratinizing epithelium. Several molecular markers of tumor formation have been found in cholesteatoma (e.g. upregulation of matrix metalloproteinases, c and activation of angiogenesis). Other molecular findings clearly distinguish between cholesteatoma and malignant tumors (e.g., lack of chromosomal instability, intact checkpoint responses). To further distinguish the molecular mechanisms in cholesteatoma from malignant tumors, the authors determined telomerase activity and telomere length in both tissue types.<br><br>METHODS: To evaluate the role of telomerase activation and telomere length in cholesteatoma, 29 cholesteatoma samples and 9 squamous cell carcinomas were analyzed for telomerase activity and telomere length. In addition, the rate of apoptosis was determined in both groups, using the TdT-mediated dUTP nick end labeling technique.<br><br>RESULTS: As previously described, a high proportion of squamous cell carcinoma exhibited telomerase activity (6/9, 66%). By contrast, a significantly lower rate of telomerase activity was found in cholesteatoma samples (1/29, 3.4%, p = 0.0002). Despite the differences in telomerase activity, the telomere length was similar in cholesteatoma (mean length 7.43 kb) and in squamous cell carcinoma (mean length 7.99 kb; difference not significant, p = 0.1364). The low rate of telomerase activity in cholesteatoma was accompanied by significantly higher rates of apoptosis in cholesteatoma (mean 30%) compared with squamous cell carcinoma tissue (mean 3%, p = 0.0031).<br><br>CONCLUSIONS: Taken together, these data show that telomerase activation is a rare event in cholesteatoma and that the absence of telomerase activity is accompanied by high rates of apoptosis in cholesteatoma. It is proposed that the absence of telomerase limits the proliferative capacity of cholesteatoma by induction of apoptosis, whereas the presence of telomerase allows immortal growth of squamous cell carcinoma.},
}
@article {pmid12217319,
year = {2002},
author = {Liu, L and Blasco, M and Trimarchi, J and Keefe, D},
title = {An essential role for functional telomeres in mouse germ cells during fertilization and early development.},
journal = {Developmental biology},
volume = {249},
number = {1},
pages = {74-84},
doi = {10.1006/dbio.2002.0735},
pmid = {12217319},
issn = {0012-1606},
support = {K081099//PHS HHS/United States ; },
mesh = {Animals ; Apoptosis/genetics ; Blastocyst/pathology ; *Embryonic and Fetal Development/genetics ; Female ; Fertilization/*genetics ; Fertilization in Vitro ; Male ; Mice ; Mice, Knockout ; Mice, Mutant Strains ; Oocytes/*physiology ; Spermatocytes/*physiology ; Telomerase/genetics/metabolism ; Telomere/*physiology ; },
abstract = {Late generations of telomerase-null (TR(-/-)) mice exhibit progressive defects in highly proliferative tissues and organs and decreased fertility, ultimately leading to sterility. To determine effects of telomerase deficiency on germ cells, we investigated the cleavage and preimplantation development of embryos derived from both in vivo and in vitro fertilization of TR(-/-) or wild-type (TR(+/+)) sperm with either TR(-/-) or TR(+/+) oocytes. Consistently, fertilization of TR(-/-) oocytes with either TR(+/+) or TR(-/-) sperm, and TR(-/-) sperm with TR(+/+) oocytes, resulted in aberrant cleavage and development, in contrast to the normal cleavage and development of TR(+/+) oocytes fertilized by TR(+/+) sperm. Many (>50%) of the fertilized TR(-/-) eggs developed only one pronucleus, coincident with increased incidence of cytofragmentation, in contrast to the normal formation of two pronuclei and equal cleavage of wild-type embryos. These results suggest that both TR(-/-) sperm and oocytes contribute to defective fertilization and cleavage. We further found that a subset (7-9%) of telomeres was undetectable at the ends of some metaphase I chromosomes from TR(-/-) spermatocytes and oocytes, indicating that meiotic germ cells lacking telomerase ultimately resulted in telomere shortening and loss. Dysfunction of meiotic telomeres may contribute to aberrant fertilization of gametes and lead to abnormal cleavage of embryos, implying an important role of functional telomeres for germ cells undergoing fertilization and early cleavage development.},
}
@article {pmid12215458,
year = {2002},
author = {Aviv, A},
title = {Chronology versus biology: telomeres, essential hypertension, and vascular aging.},
journal = {Hypertension (Dallas, Tex. : 1979)},
volume = {40},
number = {3},
pages = {229-232},
doi = {10.1161/01.hyp.0000027280.91984.1b},
pmid = {12215458},
issn = {1524-4563},
support = {HL-63351/HL/NHLBI NIH HHS/United States ; HL-7906/HL/NHLBI NIH HHS/United States ; },
mesh = {*Aging ; Blood Pressure ; Endothelium, Vascular/ultrastructure ; Humans ; Hypertension/*etiology/genetics/physiopathology ; Inflammation/complications ; Models, Cardiovascular ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Telomere/*ultrastructure ; },
abstract = {There is considerable evidence that essential hypertension is closely linked to the growth, development, and aging of human beings. It is imperative, therefore, to introduce biological indicators of growth and aging into models developed to provide a better understanding of the etiology of essential hypertension. One of these indicators may well be the age-dependent telomere attrition rate in somatic cells. Telomere attrition registers the replicative history of somatic cells. As such, it chronicles not only the growth that results from the replication of somatic cells but also their turnover-a process that is strongly linked to inflammation and oxidative stress, which are key factors in the biology of human aging.},
}
@article {pmid12212277,
year = {1999},
author = {Xiao, L and Zhou, H and Yan, J and Liu, Y and Song, Y},
title = {[Changes of telomere length in human nasopharyngeal carcinoma].},
journal = {Hua xi yi ke da xue xue bao = Journal of West China University of Medical Sciences = Huaxi yike daxue xuebao},
volume = {30},
number = {3},
pages = {262-264},
pmid = {12212277},
issn = {0257-7712},
mesh = {Adult ; Aged ; Blotting, Southern ; Carcinoma, Squamous Cell/*genetics ; Chromosome Aberrations ; Female ; Humans ; Lymphocytes/pathology ; Male ; Middle Aged ; Nasopharyngeal Neoplasms/*genetics ; Telomere/*genetics ; },
abstract = {Using Southern hybridization, we analysed the telomere length from thirty patients with nasopharyngeal carcinoma and demonstrated telomere reduction in these individuals when compared with their age-matched controls. Of the 30 samples, 16.67% had telomere elongation, 76.67% had telomere reduction and 6.67% exhibited equal lengths as compared with the controls. Analysis of leukocytes from 30 controls indicated that the telomere length decreased (average 39 base Pairs Per year) with aging and a statistically significant correlation between the length and age was noted (r = -0.3913, P < 0.05). These results suggest that the consequences of telomere shortening in nasopharyngeal carcinoma may lead to chromosome instability.},
}
@article {pmid12209236,
year = {2002},
author = {Kammori, M and Nakamura, K and Kanauchi, H and Obara, T and Kawahara, M and Mimura, Y and Kaminishi, M and Takubo, K},
title = {Consistent decrease in telomere length in parathyroid tumors but alteration in telomerase activity limited to malignancies: preliminary report.},
journal = {World journal of surgery},
volume = {26},
number = {9},
pages = {1083-1087},
doi = {10.1007/s00268-002-6409-2},
pmid = {12209236},
issn = {0364-2313},
mesh = {Adenoma/*enzymology/pathology ; Adult ; Aged ; Biomarkers, Tumor/metabolism ; Female ; Humans ; Hyperplasia ; Male ; Middle Aged ; Nucleic Acid Amplification Techniques ; Parathyroid Glands/enzymology/pathology ; Parathyroid Neoplasms/*enzymology/*pathology ; Telomere/*pathology ; },
abstract = {Telomerase is known to be activated and telomere length altered in various types of malignant and benign tumors, but whether this is also the case for parathyroid lesions has hitherto been unclear. We therefore investigated telomerase activity and telomere length in 3 parathyroid metastatic cancers, 6 adenomas, 2 cases of parathyroid hyperplasia, and 16 samples of normal parathyroid tissue. Telomerase activity, assayed by the telomeric repeat amplification protocol, was detected in all of the parathyroid cancers (100%), in none of the 8 parathyroid benign lesions, and in only 1 of the 16 normal parathyroid samples (8.3%). Telomere length, determined by the terminal restriction fragment assay, was reduced in the tumor tissues with a mean telomere length of 8.23 +/- 0.86 kbp compared with the 12.61 +/- 0.81 kbp for the 16 age-matched subjects (p = 0.002). The results indicate that telomerase activity and telomere length may reflect the biologic behavior of individual parathyroid lesions.},
}
@article {pmid12209138,
year = {2002},
author = {Hodes, RJ and Hathcock, KS and Weng, NP},
title = {Telomeres in T and B cells.},
journal = {Nature reviews. Immunology},
volume = {2},
number = {9},
pages = {699-706},
doi = {10.1038/nri890},
pmid = {12209138},
issn = {1474-1733},
mesh = {Aging ; Animals ; B-Lymphocytes/cytology/*immunology/ultrastructure ; Cell Division ; Hematopoietic Stem Cells/cytology/immunology/ultrastructure ; Humans ; Immunity, Active ; Lymphocyte Activation ; T-Lymphocytes/cytology/*immunology/ultrastructure ; Telomerase/analysis/biosynthesis/genetics ; Telomere/chemistry/*immunology ; },
abstract = {Telomeres are the structures at the ends of linear chromosomes. In mammalian cells, they consist of hexanucleotide (TTAGGG) repeats, together with many associated proteins. In the absence of a compensatory mechanism, dividing cells undergo gradual telomere erosion until a critical degree of shortening results in chromosomal abnormalities and cell death or senescence. For T and B cells, the ability to undergo extensive cell division and clonal expansion is crucial for effective immune function. This article describes our current understanding of telomere-length regulation in lymphocytes and its implications for immune function.},
}
@article {pmid12204535,
year = {2002},
author = {O'Hagan, RC and Chang, S and Maser, RS and Mohan, R and Artandi, SE and Chin, L and DePinho, RA},
title = {Telomere dysfunction provokes regional amplification and deletion in cancer genomes.},
journal = {Cancer cell},
volume = {2},
number = {2},
pages = {149-155},
doi = {10.1016/s1535-6108(02)00094-6},
pmid = {12204535},
issn = {1535-6108},
support = {K08 AG001019/AG/NIA NIH HHS/United States ; 1KO8AG01019-01/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Chromosome Aberrations ; Chromosomes, Mammalian/*genetics ; DNA, Neoplasm/genetics ; *Gene Amplification ; *Gene Deletion ; Genes, p53 ; Genome ; Humans ; Mice ; Neoplasms/*genetics ; RNA/genetics ; Synteny ; Telomerase/genetics ; Telomere/genetics/*metabolism ; },
abstract = {Telomere dysfunction and associated fusion-breakage in the mouse encourages epithelial carcinogenesis and a more humanized genomic profile that includes nonreciprocal translocations (NRTs). Here, array comparative genomic hybridization was used to determine the pathogenic significance of NRTs and to determine whether telomere dysfunction also drives amplifications and deletions of cancer-relevant loci. Compared to tumors arising in mice with intact telomeres, tumors with telomere dysfunction possessed higher levels of genomic instability and showed numerous amplifications and deletions in regions syntenic to human cancer hotspots. These observations suggest that telomere-based crisis provides a mechanism of chromosomal instability, including regional amplifications and deletions, that drives carcinogenesis. This model provides a platform for discovery of genes responsible for the major cancers affecting aged humans.},
}
@article {pmid12203793,
year = {2002},
author = {Suphapeetiporn, K and Greally, JM and Walpita, D and Ashley, T and Bale, AE},
title = {MEN1 tumor-suppressor protein localizes to telomeres during meiosis.},
journal = {Genes, chromosomes &amp; cancer},
volume = {35},
number = {1},
pages = {81-85},
doi = {10.1002/gcc.10113},
pmid = {12203793},
issn = {1045-2257},
support = {HD39384/HD/NICHD NIH HHS/United States ; },
mesh = {Genes, Tumor Suppressor ; HeLa Cells/chemistry/metabolism ; Humans ; Immunohistochemistry ; Meiosis/*genetics ; Multiple Endocrine Neoplasia Type 1/*genetics ; Neoplasm Proteins/genetics/*metabolism/physiology ; *Proto-Oncogene Proteins ; Telomere/*genetics/*metabolism ; Tumor Cells, Cultured ; Tumor Suppressor Proteins/genetics/metabolism/physiology ; },
abstract = {Multiple endocrine neoplasia type 1 is an autosomal dominant cancer predisposition syndrome caused by mutations in the tumor-suppressor gene MEN1. The gene encodes a nuclear protein, menin, with no recognized functional motifs. Menin has been shown negatively to regulate transcriptional activation mediated by JunD, although the significance of this interaction in normal cell physiology and how the absence of menin leads to tumorigenesis are unknown. Menin is highly expressed in testes. We used immunocytochemistry to explore its role in meiosis and found that it localizes exclusively at telomeres. JunD was not found at telomeres in meiotic cells. In view of elevated telomerase activity or abnormal telomere structure in virtually all malignancies, regulation of telomere function would be an appealing role for a tumor suppressor. However, menin does not specifically associate with telomeres in somatic cells, as indicated by lack of co-localization with the known telomeric protein TRF2. Cells overexpressing menin had normal telomerase activity, and tumors with homozygous MEN1 mutations showed no aberrations in telomere length, indicating that menin does not directly regulate telomerase activity. The role of menin at meiotic telomeres appears to be independent of JunD and may not have a counterpart in somatic cells. These results suggest that menin may play different roles in different tissues through interactions with different proteins.},
}
@article {pmid12200870,
year = {2000},
author = {Greider, CW},
title = {Cellular responses to telomere shortening: cellular senescence as a tumor suppressor mechanism.},
journal = {Harvey lectures},
volume = {96},
number = {},
pages = {33-50},
pmid = {12200870},
issn = {0073-0874},
support = {AG09838/AG/NIA NIH HHS/United States ; },
mesh = {Aging/genetics/physiology ; Animals ; Biology/history ; Cellular Senescence/genetics/*physiology ; History, 20th Century ; Humans ; Mice ; Models, Biological ; Neoplasms/etiology/prevention &amp; control ; Telomere/genetics/*physiology ; },
}
@article {pmid12199911,
year = {2002},
author = {Williams, KR and Doak, TG and Herrick, G},
title = {Telomere formation on macronuclear chromosomes of Oxytricha trifallax and O. fallax: alternatively processed regions have multiple telomere addition sites.},
journal = {BMC genetics},
volume = {3},
number = {},
pages = {16},
pmid = {12199911},
issn = {1471-2156},
support = {GM-25203/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; Animals ; Base Sequence ; Cell Nucleus/genetics ; Chromatids ; Chromosome Breakage ; Chromosome Mapping ; Clone Cells ; Models, Genetic ; Molecular Sequence Data ; Oxytricha/*genetics ; Polymerase Chain Reaction ; Telomere/*chemistry/*metabolism ; },
abstract = {BACKGROUND: Ciliates employ massive chromatid breakage and de novo telomere formation during generation of the somatic macronucleus. Positions flanking the 81-MAC locus are reproducibly cut. But those flanking the Common Region are proposed to often escape cutting, generating three nested macronuclear chromosomes, two retaining "arms" still appended to the Common Region. Arm-distal positions must differ (in cis) from the Common Region flanks.<br><br>RESULTS: The Common-Region-flanking positions also differ from the arm-distal positions in that they are "multi-TAS" regions: anchored PCR shows heterogeneous patterns of telomere addition sites, but arm-distal sites do not. The multi-TAS patterns are reproducible, but are sensitive to the sequence of the allele being processed. Thus, random degradation following chromatid cutting does not create this heterogeneity; these telomere addition sites also must be dictated by cis-acting sequences.<br><br>CONCLUSIONS: Most ciliates show such micro-heterogeneity in the precise positions of telomere addition sites. Telomerase is believed to be tightly associated with, and act in concert with, the chromatid-cutting nuclease: heterogeneity must be the result of intervening erosion activity. Our "weak-sites" hypothesis explains the correlation between alternative chromatid cutting at the Common Region boundaries and their multi-TAS character: when the chromatid-breakage machine encounters either a weak binding site or a weak cut site at these regions, then telomerase dissociates prematurely, leaving the new end subject to erosion by an exonuclease, which pauses at cis-acting sequences; telomerase eventually heals these resected termini. Finally, we observe TAS positioning influenced by trans-allelic interactions, reminiscent of transvection.},
}
@article {pmid12199519,
year = {2002},
author = {Zalenskaya, IA and Zalensky, AO},
title = {Telomeres in mammalian male germline cells.},
journal = {International review of cytology},
volume = {218},
number = {},
pages = {37-67},
doi = {10.1016/s0074-7696(02)18011-9},
pmid = {12199519},
issn = {0074-7696},
support = {R01 HD39830/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Cell Differentiation/*genetics ; Chromosome Segregation/genetics ; Germ Cells/cytology/*metabolism ; Male ; Meiosis/genetics ; Spermatogenesis/*genetics ; Telomerase/genetics/metabolism ; Telomere/*genetics ; Testis/cytology/*growth &amp; development/metabolism ; },
abstract = {Telomeres are terminal chromosomal domains that protect chromosome ends from degradation and fusion and promote complete replication of DNA. Telomeres are involved in the regulation of cellular replicative lifespan and tumorigenesis. These important functions of the telomeres have evoked high interest: numerous studies have resulted in a detailed description of telomere composition and structure in somatic cells. Much less is known about telomeres in germline cells. Emerging novel features and unique behavior of telomeres in the process of gamete differentiation suggest that they may have additional germline-specific function(s). This review describes recent studies revealing changes in the telomere organization in the course of differentiation from the germline stem cells to mature sperm in mammals. Similarities and differences between somatic and spermatogenic cells in telomere nuclear localization, protein composition, DNA length, telomerase activity, and chromatin structure are discussed. The exceptional features of the germline telomeres may be important for regulation of telomerase activity during spermatogenesis, homologous chromosome pairing during recombination, as well as for male pronucleus development and ordered chromosome withdrawal post-fertilization.},
}
@article {pmid12199141,
year = {2002},
author = {Mandrioli, M},
title = {Cytogenetic characterization of telomeres in the holocentric chromosomes of the lepidopteran Mamestra brassicae.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {10},
number = {4},
pages = {279-286},
pmid = {12199141},
issn = {0967-3849},
mesh = {Animals ; Chromosome Banding ; *Chromosome Mapping ; DNA Primers ; Moths/*genetics ; Pheromones/genetics ; Polymerase Chain Reaction ; Telomere/*genetics/ultrastructure ; },
abstract = {Telomeres of the Mamestra brassica holocentric chromosomes were studied by Southern blotting, in-situ hybridization and Bal31 assay evidencing the presence of the telomeric (TTAGG)n repeat. Successively, molecular analysis of telomeres showed that TRAS1 transposable elements were present at the subtelomeric regions of autosomes but not in the NOR-bearing telomeres of the Z and W sex chromosomes. TRAS1 appeared to be transcriptionally active and non-methylated, as evaluated by RT-PCR and digestion with MspI and HpaII. Finally, dot-blotting experiments showed that the 2.8 +/- 0.5% of the M. brassicae genome consists of TRAS1.},
}
@article {pmid12196391,
year = {2002},
author = {Nakamura, TM and Moser, BA and Russell, P},
title = {Telomere binding of checkpoint sensor and DNA repair proteins contributes to maintenance of functional fission yeast telomeres.},
journal = {Genetics},
volume = {161},
number = {4},
pages = {1437-1452},
pmid = {12196391},
issn = {0016-6731},
mesh = {Cell Cycle Proteins/genetics/metabolism ; Checkpoint Kinase 2 ; DNA Ligases/*genetics/metabolism ; Endonucleases/*genetics/metabolism ; Epistasis, Genetic ; Exodeoxyribonucleases ; Fungal Proteins/genetics/metabolism ; Genes, cdc/*physiology ; Intracellular Signaling Peptides and Proteins ; Mutation ; Protein Kinases/genetics/metabolism ; Protein Serine-Threonine Kinases ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins ; Schizosaccharomyces/*genetics/metabolism ; Schizosaccharomyces pombe Proteins/genetics/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres, the ends of linear chromosomes, are DNA double-strand ends that do not trigger a cell cycle arrest and yet require checkpoint and DNA repair proteins for maintenance. Genetic and biochemical studies in the fission yeast Schizosaccharomyces pombe were undertaken to understand how checkpoint and DNA repair proteins contribute to telomere maintenance. On the basis of telomere lengths of mutant combinations of various checkpoint-related proteins (Rad1, Rad3, Rad9, Rad17, Rad26, Hus1, Crb2, Chk1, Cds1), Tel1, a telomere-binding protein (Taz1), and DNA repair proteins (Ku70, Rad32), we conclude that Rad3/Rad26 and Tel1/Rad32 represent two pathways required to maintain telomeres and prevent chromosome circularization. Rad1/Rad9/Hus1/Rad17 and Ku70 are two additional epistasis groups, which act in the Rad3/Rad26 pathway. However, Rad3/Rad26 must have additional target(s), as cells lacking Tel1/Rad32, Rad1/Rad9/Hus1/Rad17, and Ku70 groups did not circularize chromosomes. Cells lacking Rad3/Rad26 and Tel1/Rad32 senesced faster than a telomerase trt1Delta mutant, suggesting that these pathways may contribute to telomere protection. Deletion of taz1 did not suppress chromosome circularization in cells lacking Rad3/Rad26 and Tel1/Rad32, also suggesting that two pathways protect telomeres. Chromatin immunoprecipitation analyses found that Rad3, Rad1, Rad9, Hus1, Rad17, Rad32, and Ku70 associate with telomeres. Thus, checkpoint sensor and DNA repair proteins contribute to telomere maintenance and protection through their association with telomeres.},
}
@article {pmid12193671,
year = {2002},
author = {Okuda, K and Bardeguez, A and Gardner, JP and Rodriguez, P and Ganesh, V and Kimura, M and Skurnick, J and Awad, G and Aviv, A},
title = {Telomere length in the newborn.},
journal = {Pediatric research},
volume = {52},
number = {3},
pages = {377-381},
doi = {10.1203/00006450-200209000-00012},
pmid = {12193671},
issn = {0031-3998},
mesh = {Adolescent ; Adult ; Birth Weight ; DNA/*analysis ; Female ; Gestational Age ; Humans ; *Infant, Newborn ; Leukocytes/physiology ; Male ; Pregnancy ; Pregnancy Complications ; Sex Characteristics ; Statistics as Topic ; Telomere/metabolism/*ultrastructure ; Umbilical Arteries/cytology ; },
abstract = {Telomere length is similar in different organs of the human fetus but variable among fetuses. During extrauterine life telomere length is highly variable among individuals and longer in women than men. In the present work we addressed the following questions: 1) Are there sex-related differences in telomere length at birth? 2) Is there synchrony (i.e. correlation in length) of telomeres in tissues within the newborn? 3) Is the variability in telomere length among newborns as large as that in adults? We studied normal male and female newborns who donated DNA samples from three sources: white blood cells, umbilical artery, and foreskin. Telomere length was measured by the mean length of the terminal restriction fragments (TRF). TRF length was not different between male and female newborns. It was highly synchronized among the DNA samples from white blood cells, umbilical artery and skin within individual donors but exhibited a high variability among donors. We conclude that there is no evidence for the effect of sex on telomere length at birth, suggesting that longer telomeres in women than men arise from a slower rate of telomeric attrition in women. The variability in telomere length among newborns and synchrony in telomere length within organs of the newborn are consistent with the concept that variations in telomere length among adults are in large part attributed to determinants (genetic and environmental) that start exerting their effect in utero.},
}
@article {pmid12193655,
year = {2002},
author = {Stewart, SA and Hahn, WC and O'Connor, BF and Banner, EN and Lundberg, AS and Modha, P and Mizuno, H and Brooks, MW and Fleming, M and Zimonjic, DB and Popescu, NC and Weinberg, RA},
title = {Telomerase contributes to tumorigenesis by a telomere length-independent mechanism.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {99},
number = {20},
pages = {12606-12611},
pmid = {12193655},
issn = {0027-8424},
support = {K01 CA094223/CA/NCI NIH HHS/United States ; R01 CA078461/CA/NCI NIH HHS/United States ; R01 CA78461/CA/NCI NIH HHS/United States ; },
mesh = {Blotting, Western ; Catalysis ; Cell Division ; *Cell Transformation, Neoplastic ; DNA-Binding Proteins ; Electrophoresis, Polyacrylamide Gel ; Glucose/metabolism ; Green Fluorescent Proteins ; Humans ; Karyotyping ; Kinetics ; Luminescent Proteins/metabolism ; Microscopy, Fluorescence ; Oxygen/metabolism ; Retroviridae/genetics ; Telomerase/*physiology ; Telomere/enzymology/physiology ; Time Factors ; Tumor Cells, Cultured ; },
abstract = {Once immortalized, human cells are susceptible to transformation by introduction of an oncogene such as ras. Several lines of evidence now suggest that the maintenance of telomere length is a major determinant of replicative lifespan in human cells and thus of the immortalized state. The majority of human tumor cells acquire immortality through expression of the catalytic subunit of telomerase (hTERT), whereas others activate an alternative mechanism of telomere maintenance (ALT) that does not depend on the actions of telomerase. We have examined whether ALT could substitute for telomerase in the processes of transformation in vitro and tumorigenesis in vivo. Expression of oncogenic H-Ras in the immortal ALT cell line GM847 did not result in their transformation. However, subsequent ectopic expression of hTERT in these cells imparted a tumorigenic phenotype. Indeed, this outcome was also observed after introduction of a mutant hTERT that retained catalytic activity but was incapable of maintaining telomere length. These studies indicate that hTERT confers an additional function that is required for tumorigenesis but does not depend on its ability to maintain telomeres.},
}
@article {pmid12188917,
year = {2002},
author = {Stewart, SA and Hahn, WC},
title = {Prospects for anti-neoplastic therapies based on telomere biology.},
journal = {Current cancer drug targets},
volume = {2},
number = {1},
pages = {1-17},
doi = {10.2174/1568009023334015},
pmid = {12188917},
issn = {1568-0096},
mesh = {Animals ; Antineoplastic Agents/*pharmacology/therapeutic use ; Humans ; Neoplasms/drug therapy/enzymology ; Telomerase/*antagonists &amp; inhibitors/physiology ; Telomere/*drug effects/*enzymology/physiology ; },
abstract = {The maintenance of specialized nucleoprotein structures at the ends of human chromosomes called telomeres is essential for chromosome stability, and plays a fundamental role in the regulation of cellular lifespan. Without new synthesis of telomeres, chromosome ends shorten with progressive cell division, eventually triggering either replicative senescence or apoptosis when telomere length becomes critically short. The regulation of telomerase activity in human cells plays a significant role in the development of cancer. Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cell immortalization and in cancers. Recent work has demonstrated that inhibiting or targeting telomerase shows promise as a novel anti-neoplastic strategy; however, the biology of telomeres and telomerase predict that such approaches will differ in important ways from traditional cytotoxic drug therapies. Understanding telomerase biology may eventually lead to several types of clinically effective, telomerase-based therapies for neoplastic disease.},
}
@article {pmid12181334,
year = {2002},
author = {Enomoto, S and Glowczewski, L and Berman, J},
title = {MEC3, MEC1, and DDC2 are essential components of a telomere checkpoint pathway required for cell cycle arrest during senescence in Saccharomyces cerevisiae.},
journal = {Molecular biology of the cell},
volume = {13},
number = {8},
pages = {2626-2638},
pmid = {12181334},
issn = {1059-1524},
support = {F32 GM063352/GM/NIGMS NIH HHS/United States ; F32 GM 63352/GM/NIGMS NIH HHS/United States ; GM 38626/GM/NIGMS NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing ; Cell Cycle/*physiology ; Cell Cycle Proteins/genetics/*metabolism ; Checkpoint Kinase 2 ; DNA Damage ; Fungal Proteins/metabolism ; Genes, cdc ; Intracellular Signaling Peptides and Proteins ; Phosphoproteins/genetics/*metabolism ; Protein Serine-Threonine Kinases/metabolism ; Saccharomyces cerevisiae/cytology/*physiology ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; },
abstract = {When telomerase is absent and/or telomeres become critically short, cells undergo a progressive decline in viability termed senescence. The telomere checkpoint model predicts that cells will respond to a damaged or critically short telomere by transiently arresting and activating repair of the telomere. We examined the senescence of telomerase-deficient Saccharomyces cerevisiae at the cellular level to ask if the loss of telomerase activity triggers a checkpoint response. As telomerase-deficient mutants were serially subcultured, cells exhibited a progressive decline in average growth rate and an increase in the number of cells delayed in the G2/M stage of the cell cycle. MEC3, MEC1, and DDC2, genes important for the DNA damage checkpoint response, were required for the cell cycle delay in telomerase-deficient cells. In contrast, TEL1, RAD9, and RAD53, genes also required for the DNA damage checkpoint response, were not required for the G2/M delay in telomerase-deficient cells. We propose that the telomere checkpoint is distinct from the DNA damage checkpoint and requires a specific set of gene products to delay the cell cycle and presumably to activate telomerase and/or other telomere repair activities.},
}
@article {pmid12181313,
year = {2002},
author = {Opresko, PL and von Kobbe, C and Laine, JP and Harrigan, J and Hickson, ID and Bohr, VA},
title = {Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases.},
journal = {The Journal of biological chemistry},
volume = {277},
number = {43},
pages = {41110-41119},
doi = {10.1074/jbc.M205396200},
pmid = {12181313},
issn = {0021-9258},
mesh = {Adenosine Triphosphatases/*metabolism ; Base Sequence ; DNA Helicases/*metabolism ; DNA Primers ; Electrophoretic Mobility Shift Assay ; Enzyme Activation ; Exodeoxyribonucleases ; Fluorescent Antibody Technique ; HeLa Cells ; Humans ; Protein Binding ; RecQ Helicases ; Recombinant Proteins/metabolism ; Telomere ; Telomeric Repeat Binding Protein 2/*metabolism ; Werner Syndrome Helicase ; },
abstract = {Werner syndrome is a human premature aging disorder displaying cellular defects associated with telomere maintenance including genomic instability, premature senescence, and accelerated telomere erosion. The yeast homologue of the Werner protein (WRN), Sgs1, is required for recombination-mediated lengthening of telomeres in telomerase-deficient cells. In human cells, we report that WRN co-localizes and physically interacts with the critical telomere maintenance protein TRF2. This interaction is mediated by the RecQ conserved C-terminal region of WRN. In vitro, TRF2 demonstrates high affinity for WRN and for another RecQ family member, the Bloom syndrome protein (BLM). TRF2 interaction with either WRN or BLM results in a notable stimulation of their helicase activities. Furthermore, the WRN and BLM helicases, partnered with replication protein A, actively unwind long telomeric duplex regions that are pre-bound by TRF2. These results suggest that TRF2 functions with WRN, and possibly BLM, in a common pathway at telomeric ends.},
}
@article {pmid12180600,
year = {2002},
author = {Mollano, AV and Martin, JA and Buckwalter, JA},
title = {Chondrocyte senescence and telomere regulation: implications in cartilage aging and cancer (a brief review).},
journal = {The Iowa orthopaedic journal},
volume = {22},
number = {},
pages = {1-7},
pmid = {12180600},
issn = {1541-5457},
mesh = {Cartilage/*physiology/physiopathology ; *Cellular Senescence ; Chondrocytes/*physiology ; Neoplasms/enzymology/*physiopathology ; Osteoarthritis/physiopathology ; Telomerase/metabolism ; Telomere/*physiology ; },
abstract = {Recent studies on osteoarthritis and the cartilage aging in our laboratory demonstrate that chronologic age correlates with molecular changes in human chondrocytes that affect cell cycle control and replicative life span. These findings indicate that age-related changes in chondrocytes may explain the heightened risk for development of primary osteoarthritis (OA) with increasing age. Concomitant studies of human chondrosarcoma suggest that these aging mechanisms may also play a role in preventing the malignant transformation of chondrocytes. The convergence at the molecular level of these seemingly dissimilar biologic processes provides an excellent opportunity to deepen our understanding of the fundamental processes underlying cartilage neoplasia, cartilage aging, and osteoarthritis.},
}
@article {pmid12169735,
year = {2002},
author = {Taggart, AK and Teng, SC and Zakian, VA},
title = {Est1p as a cell cycle-regulated activator of telomere-bound telomerase.},
journal = {Science (New York, N.Y.)},
volume = {297},
number = {5583},
pages = {1023-1026},
doi = {10.1126/science.1074968},
pmid = {12169735},
issn = {1095-9203},
support = {GM43265/GM/NIGMS NIH HHS/United States ; T32 CA09528-16/CA/NCI NIH HHS/United States ; },
mesh = {Alleles ; *Cell Cycle ; DNA, Fungal/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Enzyme Activation ; G1 Phase ; Genes, Fungal ; Models, Biological ; Polymerase Chain Reaction ; Precipitin Tests ; RNA, Fungal/genetics/metabolism ; S Phase ; Saccharomyces cerevisiae/cytology/enzymology/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; *Telomere-Binding Proteins ; },
abstract = {In Saccharomyces cerevisiae, the telomerase components Est2p, TLC1 RNA, Est1p, and Est3p are thought to form a complex that acts late during chromosome replication (S phase) upon recruitment by Cdc13p, a telomeric DNA binding protein. Consistent with this model, we show that Est1p, Est2p, and Cdc13p are telomere-associated at this time. However, Est2p, but not Est1p, also binds telomeres before late S phase. The cdc13-2 allele has been proposed to be defective in recruitment, yet Est1p and Est2p telomere association persists in cdc13-2 cells. These findings suggest a model in which Est1p binds telomeres late in S phase and interacts with Cdc13p to convert inactive, telomere-bound Est2p to an active form.},
}
@article {pmid12169636,
year = {2002},
author = {Smogorzewska, A and de Lange, T},
title = {Different telomere damage signaling pathways in human and mouse cells.},
journal = {The EMBO journal},
volume = {21},
number = {16},
pages = {4338-4348},
pmid = {12169636},
issn = {0261-4189},
support = {AG 16643/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; Cellular Senescence/physiology ; Chromosome Aberrations ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; *DNA Damage ; DNA-Binding Proteins/physiology ; Fibroblasts ; Humans ; Mice ; *Signal Transduction ; Telomere/*physiology ; Telomeric Repeat Binding Protein 2 ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Programmed telomere shortening in human somatic cells is thought to act as a tumor suppressor pathway, limiting the replicative potential of developing tumor cells. Critically short human telomeres induce senescence either by activating p53 or by inducing the p16/RB pathway, and suppression of both pathways is required to suppress senescence of aged human cells. Here we report that removal of TRF2 from human telomeres and the ensuing de-protection of chromosome ends induced immediate premature senescence. Although the telomeric tracts remained intact, the TRF2(DeltaBDeltaM)-induced premature senescence was indistinguishable from replicative senescence and could be mediated by either the p53 or the p16/RB pathway. Telomere de-protection also induced a growth arrest and senescent morphology in mouse cells. However, in this setting the loss of p53 function was sufficient to completely abrogate the arrest, indicating that the p16/RB response to telomere dysfunction is not active in mouse cells. These findings reveal a fundamental difference in telomere damage signaling in human and mouse cells that bears on the use of mouse models for the telomere tumor suppressor pathway.},
}
@article {pmid12166340,
year = {2002},
author = {Idei, T and Sakamoto, H and Yamamoto, T},
title = {Terminal restriction fragments of telomere are detectable in plasma and their length correlates with clinical status of ovarian cancer patients.},
journal = {The Journal of international medical research},
volume = {30},
number = {3},
pages = {244-250},
doi = {10.1177/147323000203000304},
pmid = {12166340},
issn = {0300-0605},
mesh = {Base Sequence ; Case-Control Studies ; DNA Primers ; Female ; Humans ; Middle Aged ; Ovarian Neoplasms/blood/*genetics ; *Telomere ; },
abstract = {Free plasma DNA was extracted and terminal restriction fragment (TRF) sequences were amplified by polymerase chain reaction in 32 patients with stage 3 and stage 4 ovarian cancer and 45 healthy controls. Three peaks of TRF were identified and the size of the largest peak (peak 1) correlated with cancer telomere length in cancer patients. Average size of peak 1 in cancer patients was significantly shorter than in controls. When plasma TRF peak 1 was tested pre- and post-treatment, the average pre-treatment size was 8.7 +/- 0.5 Kb, lengthening significantly post-treatment. In long-term survivors of ovarian cancer (10-year disease-free survival), plasma TRF length was the same as in normal controls. The results suggest that the plasma TRF in ovarian cancer patients is of tumour origin. Its determination may reflect tumour cell viability in the host.},
}
@article {pmid12161609,
year = {2002},
author = {Sala, E and Villa, N and Riva, P and Varisco, T and Larizza, L and Dalprà, L},
title = {Interstitial telomeres of an inv(9)(p11.2;q34) involved in a jumping translocation found in a woman through a stable unbalanced translocation in her malformed child.},
journal = {Journal of medical genetics},
volume = {39},
number = {8},
pages = {e42},
doi = {10.1136/jmg.39.8.e42},
pmid = {12161609},
issn = {1468-6244},
mesh = {Abnormalities, Multiple/diagnosis/*genetics ; Allelic Imbalance/genetics ; Cells, Cultured ; Chromosome Banding ; *Chromosome Inversion ; Chromosomes, Human, Pair 9/*genetics ; Cytogenetic Analysis/methods ; Female ; Humans ; In Situ Hybridization, Fluorescence/methods ; Infant, Newborn ; Male ; Pregnancy ; Telomere/*genetics ; Translocation, Genetic/*genetics ; },
}
@article {pmid12154355,
year = {2002},
author = {Blasco, MA},
title = {Telomerase beyond telomeres.},
journal = {Nature reviews. Cancer},
volume = {2},
number = {8},
pages = {627-633},
doi = {10.1038/nrc862},
pmid = {12154355},
issn = {1474-175X},
mesh = {Animals ; Cell Division ; Humans ; Mice ; *Neoplasms/genetics/pathology ; *Telomerase ; *Telomere ; },
abstract = {The role of telomerase in actively proliferating cells is assumed to be restricted to maintaining of telomeres above a minimum-length threshold, thereby preventing telomere exhaustion and chromosomal instability. However, forced telomerase expression in cells and mice with normal-length telomeres has shown that telomerase promotes growth and survival in a manner that is uncoupled from net telomere lengthening. These findings imply that telomerase might have a fundamental role in tumour growth and survival, even at stages when telomeres are sufficiently long.},
}
@article {pmid12154123,
year = {2002},
author = {Maringele, L and Lydall, D},
title = {EXO1-dependent single-stranded DNA at telomeres activates subsets of DNA damage and spindle checkpoint pathways in budding yeast yku70Delta mutants.},
journal = {Genes &amp; development},
volume = {16},
number = {15},
pages = {1919-1933},
pmid = {12154123},
issn = {0890-9369},
mesh = {*Antigens, Nuclear ; Base Pair Mismatch ; Calcium-Binding Proteins/physiology ; *Carrier Proteins ; Cell Cycle/genetics/*physiology ; Cell Cycle Proteins/physiology ; Checkpoint Kinase 1 ; *DNA Damage ; *DNA Helicases ; *DNA Repair ; DNA, Fungal/*genetics ; DNA, Single-Stranded/*genetics/metabolism ; DNA-Binding Proteins/chemistry/deficiency/genetics/*physiology ; Dimerization ; Exodeoxyribonucleases/*physiology ; Fungal Proteins/physiology ; *Genes, cdc ; Intracellular Signaling Peptides and Proteins ; Ku Autoantigen ; Mad2 Proteins ; Nuclear Proteins/chemistry/deficiency/genetics/*physiology ; Protein Kinases/physiology ; Protein Serine-Threonine Kinases ; Saccharomyces cerevisiae/cytology/*genetics ; Saccharomyces cerevisiae Proteins/chemistry/genetics/*physiology ; Sequence Deletion ; Telomere/*metabolism ; },
abstract = {We have examined the role of checkpoint pathways in responding to a yku70Delta defect in budding yeast. We show that CHK1, MEC1, and RAD9 checkpoint genes are required for efficient cell cycle arrest of yku70Delta mutants cultured at 37 degrees C, whereas RAD17, RAD24, MEC3, DDC1, and DUN1 play insignificant roles. We establish that cell cycle arrest of yku70Delta mutants is associated with increasing levels of single-stranded DNA in subtelomeric Y' regions, and find that the mismatch repair-associated EXO1 gene is required for both ssDNA generation and cell cycle arrest of yku70Delta mutants. In contrast, MRE11 is not required for ssDNA generation. The behavior of yku70Delta exo1Delta double mutants strongly indicates that ssDNA is an important component of the arrest signal in yku70Delta mutants and demonstrates a link between damaged telomeres and mismatch repair-associated exonucleases. This link is confirmed by our demonstration that EXO1 also plays a role in ssDNA generation in cdc13-1 mutants. We have also found that the MAD2 but not the BUB2 spindle checkpoint gene is required for efficient arrest of yku70Delta mutants. Therefore, subsets of both DNA-damage and spindle checkpoint pathways cooperate to regulate cell division of yku70Delta mutants.},
}
@article {pmid12140324,
year = {2002},
author = {Bundock, P and van Attikum, H and Hooykaas, P},
title = {Increased telomere length and hypersensitivity to DNA damaging agents in an Arabidopsis KU70 mutant.},
journal = {Nucleic acids research},
volume = {30},
number = {15},
pages = {3395-3400},
pmid = {12140324},
issn = {1362-4962},
mesh = {Amino Acid Sequence ; *Antigens, Nuclear ; Arabidopsis/drug effects/radiation effects/*ultrastructure ; Arabidopsis Proteins/*genetics/*physiology ; *DNA Damage ; *DNA Helicases ; DNA, Plant/ultrastructure ; DNA-Binding Proteins/*genetics/*physiology ; Genes, Plant ; Ku Autoantigen ; Methyl Methanesulfonate/pharmacology ; Molecular Sequence Data ; Mutation ; Nuclear Proteins/genetics ; Radiation Tolerance ; *Saccharomyces cerevisiae Proteins ; Sequence Alignment ; Telomere/*ultrastructure ; },
abstract = {We have identified a putative homologue of the KU70 gene (AtKU70) from Arabidopsis thaliana. In order to study its function in plants we have isolated an A.thaliana line that contains a T-DNA inserted into AtKU70. Plants homozygous for this insertion appear normal and are fertile. In other organisms the KU70 gene has been shown to play a role in the repair of DNA damage induced by ionising radiation (IR) and by radiomimetic chemicals such as methylmethane sulfonate (MMS). We show that AtKU70(-/-) plants are hypersensitive to IR and MMS, and thus the AtKU70 gene plays a similar role in DNA repair in plants as in other organisms. The KU70 gene also plays a role in maintaining telomere length. Yeast and mammalian cells deficient for Ku70 have shortened telomeres. When we studied the telomeres in the AtKU70(-/-) plants we found unexpectedly that they were significantly longer (>30 kb) than was found in wild-type plants (2-4 kb). We propose several hypotheses to explain this telomere lengthening in the AtKU70(-/-) plants.},
}
@article {pmid12139623,
year = {2002},
author = {Qin, Z and Cohen, SN},
title = {Survival mechanisms for Streptomyces linear replicons after telomere damage.},
journal = {Molecular microbiology},
volume = {45},
number = {3},
pages = {785-794},
doi = {10.1046/j.1365-2958.2002.03051.x},
pmid = {12139623},
issn = {0950-382X},
support = {AI08619/AI/NIAID NIH HHS/United States ; },
mesh = {Chromosomes, Bacterial/chemistry/*physiology ; *DNA Damage ; *DNA Replication ; DNA, Bacterial/chemistry/physiology ; DNA, Circular/chemistry ; Escherichia coli/genetics ; Models, Biological ; Nucleic Acid Conformation ; Plasmids/genetics ; Recombination, Genetic ; Replicon ; Streptomyces/chemistry/*genetics ; Telomere/genetics/*physiology ; },
abstract = {The ability of linear replicons to propagate their DNA after telomere damage is essential for perpetuation of the genetic information they carry. We introduced deletions at specific locations within telomeres of streptomycete linear plasmids and investigated mechanisms that enable survival. Here, we report that rescue of such plasmids in Streptomyces lividans occurs by three distinct types of events: (i) repair of the damaged telomere by homologous recombination; (ii) circularization of the plasmid by non-homologous end-to-end joining; and (iii) formation of long palindromic linear plasmids that duplicate the intact telomere by a non-recombinational process. The relative frequency of use of these survival mechanisms depended on the location and length of the telomeric DNA deletion. Repair by intermolecular recombination between the telomeres of chromosomes and plasmids, deletion of additional DNA during plasmid circularization, and insertion of chromosomal DNA fragments into plasmids during end-to-end joining were observed. Our results show that damage to telomeres of Streptomyces linear replicons can promote major structural transformations in these replicons as well as genetic exchange between chromosomes and extrachromosomal DNA. Our findings also suggest that spontaneous circularization of linear Streptomyces chromosomes may be a biological response to instances of telomere damage that cannot be repaired by homologous recombination.},
}
@article {pmid12139239,
year = {2002},
author = {Fordyce, CA and Heaphy, CM and Griffith, JK},
title = {Chemiluminescent measurement of telomere DNA content in biopsies.},
journal = {BioTechniques},
volume = {33},
number = {1},
pages = {144-6, 148},
doi = {10.2144/02331md02},
pmid = {12139239},
issn = {0736-6205},
support = {T34 GM008751/GM/NIGMS NIH HHS/United States ; R33-CA-86136/CA/NCI NIH HHS/United States ; },
mesh = {Biopsy/*methods ; Blotting, Southern/*methods ; DNA/*analysis ; Female ; Formaldehyde/pharmacology ; HeLa Cells/chemistry ; Humans ; *Luminescent Measurements ; Male ; Placenta/chemistry/drug effects/pathology ; Pregnancy ; Prostatic Neoplasms/genetics/pathology ; Reproducibility of Results ; Sensitivity and Specificity ; Telomere/*genetics ; },
abstract = {Telomeres are nucleoprotein complexes that protect the ends of chromosomes from fusion and degradation. They are typically shorter in tumor cells than in paired normal cells, and shorter telomeres are associated with poor outcome in cancer. We previously described a slot blot-based methodfor measuring telomere DNA content, a proxy for telomere length. Although this method represented an improvement over existing methods, its 30-ng limit of sensitivity was insufficient for use with biopsy or other scant tissues. Here we describe a chemiluminescent slot blot assay for telomere DNA content that has the sensitivity required for use with biopsy materials. The results obtained with DNA derived from human placental, HeLa, human peripheral blood lymphocytes, sham-needle core prostate biopsies, and archival prostatectomy tissues demonstrated that telomere DNA content can be reliably and reproducibly measured in 5 ng, and sometimes as little as 2 ng, genomic DNA. Sham-needle core prostate biopsy and prostatectomy specimens processed in parallel produced comparable results. The contribution of truncated telomeres in admixtures containing as much as 75% normal placental DNA could be established. We also demonstrated that the treatment of tissue with formalin before DNA purification does not decrease the efficacy of the assay.},
}
@article {pmid12138196,
year = {2002},
author = {Ray, S and Karamysheva, Z and Wang, L and Shippen, DE and Price, CM},
title = {Interactions between telomerase and primase physically link the telomere and chromosome replication machinery.},
journal = {Molecular and cellular biology},
volume = {22},
number = {16},
pages = {5859-5868},
pmid = {12138196},
issn = {0270-7306},
support = {R01 GM041803/GM/NIGMS NIH HHS/United States ; R01 GM41803/GM/NIGMS NIH HHS/United States ; R01 GM49157/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromosomes/*metabolism ; DNA Primase/chemistry/*metabolism ; DNA Replication/*physiology ; Euplotes/cytology/*enzymology/genetics/metabolism ; Macromolecular Substances ; Molecular Weight ; Precipitin Tests ; Protein Subunits ; Protozoan Proteins/genetics/metabolism ; Telomerase/chemistry/*metabolism ; Telomere/*metabolism ; },
abstract = {In the ciliate Euplotes crassus, millions of new telomeres are synthesized by telomerase and polymerase alpha-primase during macronuclear development in mated cells. Concomitant with de novo telomere formation, telomerase assembles into higher-order complexes of 550 kDa, 1,600 kDa, and 5 MDa. We show here that telomerase is physically associated with the lagging-strand replication machinery in these complexes. Antibodies against DNA primase precipitated telomerase activity from all three complexes from mated cells but not the 280-kDa telomerase complex from vegetatively growing cells. Moreover, when telomerase was affinity purified, primase copurified with enzyme from mated cells but not with the 280-kDa vegetative complex. Thus, the association of telomerase and primase is developmentally regulated. Intriguingly, PCNA (proliferating cell nuclear antigen) was also found in the 5-MDa complex from mated cells. We therefore speculate that this complex is a complete telomere synthesis machine, while the smaller complexes are assembly intermediates. The physical association of telomerase and primase explains the coordinate regulation of telomeric G- and C-strand synthesis and the efficiency of telomere addition in E. crassus.},
}
@article {pmid12138180,
year = {2002},
author = {Tsai, YL and Tseng, SF and Chang, SH and Lin, CC and Teng, SC},
title = {Involvement of replicative polymerases, Tel1p, Mec1p, Cdc13p, and the Ku complex in telomere-telomere recombination.},
journal = {Molecular and cellular biology},
volume = {22},
number = {16},
pages = {5679-5687},
pmid = {12138180},
issn = {0270-7306},
mesh = {*Antigens, Nuclear ; Cyclin B/genetics/*metabolism ; *DNA Helicases ; DNA Repair ; DNA-Binding Proteins/genetics/*metabolism ; DNA-Directed DNA Polymerase/genetics/*metabolism ; Fungal Proteins/genetics/*metabolism ; Humans ; Intracellular Signaling Peptides and Proteins ; Ku Autoantigen ; Nuclear Proteins/genetics/*metabolism ; Phenotype ; Protein Serine-Threonine Kinases ; Rad52 DNA Repair and Recombination Protein ; *Recombination, Genetic ; Saccharomyces cerevisiae/genetics/physiology ; *Saccharomyces cerevisiae Proteins ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomere maintenance is required for chromosome stability, and telomeres are typically replicated by the action of the reverse transcriptase telomerase. In both tumor and yeast cells that lack telomerase, telomeres are maintained by an alternative recombination mechanism. Genetic studies have led to the identification of DNA polymerases, cell cycle checkpoint proteins, and telomere binding proteins involved in the telomerase pathway. However, how these proteins affect telomere-telomere recombination has not been identified to date. Using an assay to trace the in vivo recombinational products throughout the course of survivor development, we show here that three major replicative polymerases, alpha, delta, and epsilon, play roles in telomere-telomere recombination and that each causes different effects and phenotypes when they as well as the telomerase are defective. Polymerase delta appears to be the main activity for telomere extension, since neither type I nor type II survivors arising via telomere-telomere recombination were seen in its absence. The frequency of type I versus type II is altered in the polymerase alpha and epsilon mutants relative to the wild type. Each prefers to develop a particular type of survivor. Moreover, type II recombination is mediated by the cell cycle checkpoint proteins Tel1 and Mec1, and telomere-telomere recombination is regulated by telomere binding protein Cdc13 and the Ku complex. Together, our results suggest that coordination between DNA replication machinery, DNA damage signaling, DNA recombination machinery, and the telomere protein-DNA complex allows telomere recombination to repair telomeric ends in the absence of telomerase.},
}
@article {pmid12136233,
year = {2002},
author = {Popp, S and Schulze, B and Granzow, M and Keller, M and Holtgreve-Grez, H and Schoell, B and Brough, M and Hager, HD and Tariverdian, G and Brown, J and Kearney, L and Jauch, A},
title = {Study of 30 patients with unexplained developmental delay and dysmorphic features or congenital abnormalities using conventional cytogenetics and multiplex FISH telomere (M-TEL) integrity assay.},
journal = {Human genetics},
volume = {111},
number = {1},
pages = {31-39},
doi = {10.1007/s00439-002-0739-x},
pmid = {12136233},
issn = {0340-6717},
mesh = {Abnormalities, Multiple/*genetics ; Adolescent ; Adult ; Child ; Child, Preschool ; *Chromosome Aberrations ; Developmental Disabilities/*genetics/pathology ; Female ; Growth Disorders/genetics ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; Intellectual Disability/*genetics/pathology ; Karyotyping ; Male ; Middle Aged ; Prospective Studies ; Telomere/*genetics ; Translocation, Genetic ; },
abstract = {Cryptic subtelomeric chromosome rearrangements are a major cause of mild to severe mental retardation pointing out the necessity of sensitive screening techniques to detect such aberrations among affected patients. In this prospective study a group of 30 patients with unexplained developmental retardation and dysmorphic features or congenital abnormalities were analysed using the recently published multiplex FISH telomere (M-TEL) integrity assay in combination with conventional G-banding analysis. The patients were selected by one or more of the following criteria defined by de Vries et al.: (a) family history with two or more affected individuals, (b) prenatal onset growth retardation, (c) postnatal growth abnormalities, (d) facial dysmorphic features, (e) non-facial dysmorphism and congenital abnormalities. In addition, we included two patients who met these criteria and revealed questionable chromosome regions requiring further clarification. In four patients (13.3%) cryptic chromosome aberrations were successfully determined by the M-TEL integrity assay and in two patients with abnormal chromosome regions intrachromosomal aberrations were characterized by targetted FISH experiments. Our results accentuate the requirement of strict selection criteria prior to patient testing with the M-TEL integrity assay. Another essential precondition is high-quality banding analysis to identify structural abnormal chromosomes. The detection of familial balanced translocation carriers in 50% of the cases emphasizes the significance of such an integrated approach for genetic counselling and prenatal diagnosis.},
}
@article {pmid12136006,
year = {2002},
author = {DuBois, ML and Haimberger, ZW and McIntosh, MW and Gottschling, DE},
title = {A quantitative assay for telomere protection in Saccharomyces cerevisiae.},
journal = {Genetics},
volume = {161},
number = {3},
pages = {995-1013},
pmid = {12136006},
issn = {0016-6731},
support = {1P50 CA 83636/CA/NCI NIH HHS/United States ; CA 09657/CA/NCI NIH HHS/United States ; GM 43893/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes, Fungal/genetics ; DNA Primers ; DNA, Fungal/genetics ; Genotype ; Molecular Sequence Data ; Mutagenesis ; Plasmids ; Polymerase Chain Reaction ; Saccharomyces cerevisiae/*genetics ; Telomere/*genetics ; },
abstract = {Telomeres are the protective ends of linear chromosomes. Telomeric components have been identified and described by their abilities to bind telomeric DNA, affect telomere repeat length, participate in telomeric DNA replication, or modulate transcriptional silencing of telomere-adjacent genes; however, their roles in chromosome end protection are not as well defined. We have developed a genetic, quantitative assay in Saccharomyces cerevisiae to measure whether various telomeric components protect chromosome ends from homologous recombination. This "chromosomal cap" assay has revealed that the telomeric end-binding proteins, Cdc13p and Ku, both protect the chromosome end from homologous recombination, as does the ATM-related kinase, Tel1p. We propose that Cdc13p and Ku structurally inhibit recombination at telomeres and that Tel1p regulates the chromosomal cap, acting through Cdc13p. Analysis with recombination mutants indicated that telomeric homologous recombination events proceeded by different mechanisms, depending on which capping component was compromised. Furthermore, we found that neither telomere repeat length nor telomeric silencing correlated with chromosomal capping efficiency. This capping assay provides a sensitive in vivo approach for identifying the components of chromosome ends and the mechanisms by which they are protected.},
}
@article {pmid12135354,
year = {2002},
author = {Forwood, JK and Jans, DA},
title = {Nuclear import pathway of the telomere elongation suppressor TRF1: inhibition by importin alpha.},
journal = {Biochemistry},
volume = {41},
number = {30},
pages = {9333-9340},
doi = {10.1021/bi025548s},
pmid = {12135354},
issn = {0006-2960},
mesh = {Amino Acid Sequence ; Base Sequence ; Cell Nucleus/*metabolism ; DNA Primers ; DNA-Binding Proteins/antagonists &amp; inhibitors/*metabolism ; Green Fluorescent Proteins ; Luminescent Proteins/metabolism ; Protein Transport ; Recombinant Fusion Proteins/metabolism ; Telomeric Repeat Binding Protein 1 ; alpha Karyopherins/*physiology ; },
abstract = {Telomere repeat factor 1 (TRF1) regulates the steady-state length of chromosomes, whereby its overexpression results in telomere shortening while dominant negative TRF1 mutations can lead to telomere elongation, which is linked to cell immortalization/transformation. Although present in the nucleus at mammalian chromosomal ends during interphase and mitosis, nothing is known of the mechanism by which TRF1 enters the nucleus or how its nuclear levels may be regulated and the relevance of this, in turn, to telomere length and cell immortalization. Here we examine the nuclear import mechanism of TRF by expressing and purifying a recombinant TRF1-GFP (green fluorescent protein) fusion protein that is functional in terms of being able to bind telomeric DNA specifically as shown using a novel, quantitative double-label gel mobility shift assay. We quantitate the ability of TRF1-GFP to accumulate in the nucleus using real time confocal laser scanning microscopy, showing that the nuclear import pathway of TRF1 is mediated by importin (Imp) beta1 and Ran. Imp beta is shown to bind directly to TRF1 with nanomolar affinity using native gel electrophoretic and fluorescence polarization (FP) approaches; FP experiments also demonstrate that Imp beta residues 1-380 are responsible for TRF1 binding. Intriguingly, when dimerized to Imp beta, Imp alpha was found to inhibit Imp beta-mediated nuclear accumulation, although not affecting Imp beta binding to TRF1. The study represents the first elucidation of the nuclear transport mechanism of TRF1; that its nuclear import is mediated directly by Imp beta but inhibited by Imp alpha may represent a novel regulatory mechanism, with potential relevance to oncogenesis.},
}
@article {pmid12127874,
year = {2002},
author = {Rezler, EM and Bearss, DJ and Hurley, LH},
title = {Telomeres and telomerases as drug targets.},
journal = {Current opinion in pharmacology},
volume = {2},
number = {4},
pages = {415-423},
doi = {10.1016/s1471-4892(02)00182-0},
pmid = {12127874},
issn = {1471-4892},
mesh = {Animals ; Drug Delivery Systems/*methods ; Enzyme Inhibitors/chemistry/pharmacology ; Humans ; Oligonucleotides, Antisense/chemistry/pharmacology ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/*drug effects/metabolism ; },
abstract = {Recent advances in telomerase inhibition have been achieved by using antisense oligonucleotides and ribozymes to target the telomerase mRNA or the telomerase RNA template. Also, small molecules are potent catalytic inhibitors of telomerase. However, therapeutic regimes incorporating these agents will be challenging to implement in the clinic because of their delayed effectiveness. Drugs that directly bind to the telomeres and stabilize secondary DNA structures such as G-quadruplexes are also potent inhibitors of telomerase and disrupt telomere structure. These G-quadruplex-interactive drugs could feasibly be used in synergy with more conventional cytotoxic agents to bring about more immediate responses in cancer cells that are less dependent upon telomere length. Recently, an emerging possible novel use of G-quadruplex-interactive drugs employs their ability to target G-quadruplexes in promoter regions of genes (such as c-MYC), which then serves to repress the production of the human telomerase reverse transcriptase protein.},
}
@article {pmid12127552,
year = {2002},
author = {Ishibe, N and Prieto, D and Hosack, DA and Lempicki, RA and Goldin, LR and Raffeld, M and Marti, GE and Caporaso, NE},
title = {Telomere length and heavy-chain mutation status in familial chronic lymphocytic leukemia.},
journal = {Leukemia research},
volume = {26},
number = {9},
pages = {791-794},
doi = {10.1016/s0145-2126(02)00010-3},
pmid = {12127552},
issn = {0145-2126},
mesh = {Aged ; DNA, Neoplasm/genetics ; Female ; *Gene Rearrangement, B-Lymphocyte, Heavy Chain ; *Genes, Immunoglobulin ; Humans ; Immunoglobulin Heavy Chains/*genetics ; Immunoglobulin Variable Region/*genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/classification/*genetics/mortality ; Life Tables ; Male ; Middle Aged ; Neoplastic Syndromes, Hereditary/*genetics/mortality ; Prognosis ; *Somatic Hypermutation, Immunoglobulin ; Survival Analysis ; Telomere/*ultrastructure ; },
abstract = {We examined whether telomere lengths of peripheral blood mononuclear cells are associated with immunoglobulin gene usage in 21 familial chronic lymphocytic leukemia (CLL) patients. Subjects with unmutated V genes tended to have shorter telomeres than those with somatic mutations, especially after adjusting for age. Unlike V(H) mutation status, telomere length was not predictive for survival. Our results suggest that telomere length is associated with V(H) gene mutation status and provides further evidence that the biological basis of familial B-CLL is similar to that of sporadic patients.},
}
@article {pmid12122013,
year = {2002},
author = {Cui, W and Aslam, S and Fletcher, J and Wylie, D and Clinton, M and Clark, AJ},
title = {Stabilization of telomere length and karyotypic stability are directly correlated with the level of hTERT gene expression in primary fibroblasts.},
journal = {The Journal of biological chemistry},
volume = {277},
number = {41},
pages = {38531-38539},
doi = {10.1074/jbc.M205981200},
pmid = {12122013},
issn = {0021-9258},
mesh = {Animals ; Cells, Cultured ; Cellular Senescence/*physiology ; Chromosome Aberrations ; DNA-Binding Proteins ; Fibroblasts ; Gene Expression Regulation, Enzymologic ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Telomerase/*genetics/*metabolism ; Telomere/*metabolism ; Time Factors ; },
abstract = {Telomere shortening and lack of telomerase activity have been implicated in cellular senescence in human fibroblasts. Expression of the human telomerase (hTERT) gene in sheep fibroblasts reconstitutes telomerase activity and extends their lifespan. However, telomere length is not maintained in all cell lines, even though in vitro telomerase activity is restored in all of them. Cell lines expressing higher levels of hTERT mRNA do not exhibit telomere erosion or genomic instability. By contrast, fibroblasts expressing lower levels of hTERT do exhibit telomere shortening, although the telomeres eventually stabilize at a shorter length. The shorter telomere lengths and the extent of karyotypic abnormalities are both functions of hTERT expression level. We conclude that telomerase activity is required to bypass senescence but is not sufficient to prevent telomere erosion and genomic instability at lower levels of expression.},
}
@article {pmid12120414,
year = {2002},
author = {Neidle, S and Parkinson, G},
title = {Telomere maintenance as a target for anticancer drug discovery.},
journal = {Nature reviews. Drug discovery},
volume = {1},
number = {5},
pages = {383-393},
doi = {10.1038/nrd793},
pmid = {12120414},
issn = {1474-1776},
mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Binding Sites ; DNA-Binding Proteins ; Drug Design ; Enzyme Inhibitors/pharmacology ; Humans ; Neoplasms/genetics ; Telomerase/antagonists &amp; inhibitors/genetics/metabolism ; Telomere/*drug effects ; },
abstract = {Maintenance of telomeres--specialized complexes that protect the ends of chromosomes--is undertaken by the enzyme complex telomerase, which is a key factor that is activated in more than 80% of cancer cells that have been examined so far, but is absent in most normal cells. So, targeting telomere-maintenance mechanisms could potentially half tumour growth across a broad spectrum of tumour types, with little cytotoxic effect outside tumours. Here, we describe the current understanding of telomere biology, and the application of this knowledge to the development of anticancer drugs.},
}
@article {pmid12116379,
year = {2002},
author = {Bekaert, S and Koll, S and Thas, O and Van Oostveldt, P},
title = {Comparing telomere length of sister chromatids in human lymphocytes using three-dimensional confocal microscopy.},
journal = {Cytometry},
volume = {48},
number = {1},
pages = {34-44},
doi = {10.1002/cyto.10105},
pmid = {12116379},
issn = {0196-4763},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Chromatids/*ultrastructure ; Humans ; Imaging, Three-Dimensional/*methods ; In Situ Hybridization, Fluorescence ; Infant ; Lymphocytes ; Microscopy, Confocal/*methods ; Software ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: The length of the terminal sequences of linear chromosomes changes dynamically during cellular proliferation. A crucial element in the study of telomere-related regulation mechanisms is the ability to measure telomere lengths of individual chromosomes. Individual telomere lengths can be measured using digital imaging fluorescence microscopy-based techniques. We extended this method using confocal microscopy for the acquisition of three-dimensional (3D) images. Consequently, variations in measured signal intensities due to erroneous focusing are avoided.<br><br>METHODS: We employed our 3D telomere sizing method to compare telomere lengths of sister chromatids within metaphase preparations from human lymphocytes. The samples were treated following a quantitative fluorescence in situ hybridization (Q-FISH) protocol using fluorescein isothiocyanate (FITC)-labeled telomeric peptidic nucleic acid (PNA) probes and propidium iodide (PI) counterstain.<br><br>RESULTS: We demonstrated that the telomere lengths of two sister chromatids are not necessarily equal in human lymphocytes. Profound statistical analysis demonstrated significant differences in the distribution of the sister chromatid telomere lengths, but we were not able to prove a discrete distribution of telomere sister ratios. These telomere length differences were more apparent in older individuals.<br><br>CONCLUSION: Whereas the majority of sister telomere pairs have equal lengths, surprisingly, a minority was significantly different in each individual studied. We are convinced that these observations are not linked to the methodology or the protocol applied. We suggest that a biological phenomenon might be involved.},
}
@article {pmid12114965,
year = {1999},
author = {Zhang, XW and Liao, HN and Tong, TJ},
title = {Telomere Shortening of MCF-7 Cells Caused by Antisense Telomerase cDNA.},
journal = {Sheng wu hua xue yu sheng wu wu li xue bao Acta biochimica et biophysica Sinica},
volume = {31},
number = {5},
pages = {527-530},
pmid = {12114965},
issn = {0582-9879},
abstract = {pAdE(1)CMVITREXneo is a novel adenovirus vector which can integrate foreign genes into genome of host cells. The cDNA of human telomerase RNA was integrated inversely into the vector via antisense oligonucleotide technique. Antisense recombinant virus (vAdT-AAV) was obtained by cotransfecting pAdT and pBHG(11) into 293 cells. The telomere length of breast cancer MCF-7 cells was found shortened after the transfection by vAdT-AAV.},
}
@article {pmid12114022,
year = {2002},
author = {von Zglinicki, T},
title = {Oxidative stress shortens telomeres.},
journal = {Trends in biochemical sciences},
volume = {27},
number = {7},
pages = {339-344},
doi = {10.1016/s0968-0004(02)02110-2},
pmid = {12114022},
issn = {0968-0004},
mesh = {Cell Division/physiology ; Cells, Cultured ; Cellular Senescence/*physiology ; Humans ; *Oxidative Stress ; Stem Cells/physiology ; Telomere/*metabolism ; },
abstract = {Telomeres in most human cells shorten with each round of DNA replication, because they lack the enzyme telomerase. This is not, however, the only determinant of the rate of loss of telomeric DNA. Oxidative damage is repaired less well in telomeric DNA than elsewhere in the chromosome, and oxidative stress accelerates telomere loss, whereas antioxidants decelerate it. I suggest here that oxidative stress is an important modulator of telomere loss and that telomere-driven replicative senescence is primarily a stress response. This might have evolved to block the growth of cells that have been exposed to a high risk of mutation.},
}
@article {pmid12113474,
year = {2002},
author = {Franco, S and Alsheimer, M and Herrera, E and Benavente, R and Blasco, MA},
title = {Mammalian meiotic telomeres: composition and ultrastructure in telomerase-deficient mice.},
journal = {European journal of cell biology},
volume = {81},
number = {6},
pages = {335-340},
doi = {10.1078/0171-9335-00259},
pmid = {12113474},
issn = {0171-9335},
mesh = {Animals ; Cell Cycle Proteins ; Chromosome Segregation/*genetics ; DNA-Binding Proteins ; Eukaryotic Cells/*metabolism/ultrastructure ; Male ; Meiosis/*genetics ; Mice ; Mice, Knockout ; Microscopy, Electron ; Nuclear Envelope/*metabolism/ultrastructure ; Nuclear Proteins/genetics/metabolism ; Sex Chromosomes/genetics/ultrastructure ; Spermatocytes/metabolism/ultrastructure ; Telomerase/*deficiency/genetics ; Telomere/*genetics/ultrastructure ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; Terminal Repeat Sequences/genetics ; Testis/metabolism/ultrastructure ; },
abstract = {During early meiotic prophase chromosome ends become attached to the nuclear envelope, a process that is essential for faithful homologue pairing and segregation. The factors involved in this attachment are largely unknown. Here we investigated the possible involvement of telomere chromatin by using late generation (G5 and G6) Terc-/- mice. These mice lack telomerase activity and show progressive telomere shortening with increasing mouse generations. We show here that in meiotic chromosome ends of late generation Terc-/- mice telomeric TTAGGG repeats and the TRF1 telomere-binding protein are significantly reduced or below detection level. In spite of this, electron microscopy showed no apparent structural differences at the attachment sites of meiotic chromosomes to the nuclear envelope between wild-type and G6 Terc-/- meiocytes. These results suggest, as already shown in yeast, that most telomere chromatin is dispensable for proper attachment of mammalian meiotic chromosome ends to the nuclear envelope.},
}
@article {pmid12107843,
year = {2002},
author = {Gisselsson, D and Jonson, T and Yu, C and Martins, C and Mandahl, N and Wiegant, J and Jin, Y and Mertens, F and Jin, C},
title = {Centrosomal abnormalities, multipolar mitoses, and chromosomal instability in head and neck tumours with dysfunctional telomeres.},
journal = {British journal of cancer},
volume = {87},
number = {2},
pages = {202-207},
pmid = {12107843},
issn = {0007-0920},
mesh = {Adenoma, Pleomorphic/enzymology/genetics/*ultrastructure ; Carcinoma, Squamous Cell/enzymology/genetics/*ultrastructure ; Centrosome/*ultrastructure ; *Chromosome Aberrations ; DNA, Neoplasm/*analysis ; DNA-Binding Proteins ; Female ; Head and Neck Neoplasms/enzymology/genetics/*ultrastructure ; Humans ; Karyotyping ; Male ; Mitosis ; Neoplasm Proteins/analysis ; Parotid Neoplasms/enzymology/genetics/*ultrastructure ; Repetitive Sequences, Nucleic Acid ; Telomerase/analysis ; Telomere/*chemistry ; },
abstract = {Carcinomas of the head and neck typically exhibit complex chromosome aberrations but the underlying mutational mechanisms remain obscure. Evaluation of cell division dynamics in low-passage cell lines from three benign and five malignant head and neck tumours revealed a strong positive correlation between multipolarity of the mitotic spindle and the formation of bridges at anaphase in both benign and malignant tumours. Cells exhibiting a high rate of mitotic abnormalities also showed several chromosome termini lacking TTAGGG repeats and a high frequency of dicentric chromosomes. Multicolour karyotyping demonstrated a preferential involvement in structural rearrangements of chromosomes with deficient telomeres. The majority of malignant, mitotically unstable tumours expressed the reverse transcriptase subunit of telomerase. These data indicate that some of the genomic instability in head and neck tumours is initiated by telomere dysfunction, leading to the formation of dicentric chromosomes. These form chromosome bridges at mitosis that could prevent the normal anaphase-telophase transition. In turn, this may cause an accumulation of centrosomes and mitotic multipolarity. Telomerase expression does not confer total stability to the tumour genome but could be crucial for moderating the rate of chromosomal evolution.},
}
@article {pmid12107183,
year = {2002},
author = {Guglielmi, B and Werner, M},
title = {The yeast homolog of human PinX1 is involved in rRNA and small nucleolar RNA maturation, not in telomere elongation inhibition.},
journal = {The Journal of biological chemistry},
volume = {277},
number = {38},
pages = {35712-35719},
doi = {10.1074/jbc.M205526200},
pmid = {12107183},
issn = {0021-9258},
mesh = {Amino Acid Sequence ; Base Sequence ; Cell Cycle Proteins ; Cloning, Molecular ; DNA Primers ; Humans ; Molecular Sequence Data ; Open Reading Frames ; Promoter Regions, Genetic ; RNA, Ribosomal/*metabolism ; RNA, Small Nuclear/*metabolism ; Saccharomyces cerevisiae/genetics/growth &amp; development ; Sequence Homology, Amino Acid ; *Telomere ; Tumor Suppressor Proteins/*metabolism ; },
abstract = {In human cells, PinX1 protein has recently been shown to regulate telomere length by repressing the telomerase. In this work, we show that the putative yeast homolog of PinX1, encoded by the YGR280c open reading frame (ORF), is a new component of the ribosomal RNA processing machinery. The protein has a KK(E/D) C-terminal domain typical of nucleolar proteins and bears a putative RNA interacting domain widespread in eukaryotes called the G-patch. The protein was hence renamed Gno1p (G-patch nucleolar protein). GNO1 deletion results in a large growth defect due to the inhibition of the pre-ribosomal RNA processing first cleavage steps at sites A(0), A(1), and A(2). Furthermore, Gno1p is involved in the final 3'-end trimming of U18 and U24 small nucleolar RNAs. A mutational analysis showed that the G-patch of Gno1p is essential for both functions, whereas the KK(E/D) repeats are only required for U18 small nucleolar RNA maturation. We found that PinX1 complemented the gno1-Delta mutation, suggesting that it has a dual function in telomere length regulation and ribosomal RNA maturation in agreement with its telomeric and nucleolar localization in human cells. Conversely, we found that Gno1p does not exhibit the in vivo telomerase inhibitor activity of PinX1.},
}
@article {pmid12101775,
year = {2002},
author = {Hiyama, K and Hiyama, E},
title = {[Telomere and telomerase in lung cancer].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {60 Suppl 5},
number = {},
pages = {737-742},
pmid = {12101775},
issn = {0047-1852},
mesh = {Biomarkers, Tumor/analysis ; Cell Division/genetics ; DNA Replication ; Drug Design ; Fenretinide/pharmacology/therapeutic use ; Humans ; Lung Neoplasms/diagnosis/enzymology/*pathology ; Telomerase/analysis/antagonists &amp; inhibitors/*physiology ; Telomere/*metabolism ; },
}
@article {pmid12101184,
year = {2002},
author = {Elmore, LW and Rehder, CW and Di, X and McChesney, PA and Jackson-Cook, CK and Gewirtz, DA and Holt, SE},
title = {Adriamycin-induced senescence in breast tumor cells involves functional p53 and telomere dysfunction.},
journal = {The Journal of biological chemistry},
volume = {277},
number = {38},
pages = {35509-35515},
doi = {10.1074/jbc.M205477200},
pmid = {12101184},
issn = {0021-9258},
support = {CA 85159-01/CA/NCI NIH HHS/United States ; },
mesh = {Antibiotics, Antineoplastic/*pharmacology ; Breast Neoplasms/genetics/metabolism/*pathology ; Cellular Senescence/*drug effects ; Doxorubicin/*pharmacology ; Humans ; In Situ Nick-End Labeling ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/antagonists &amp; inhibitors ; *Telomere ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/*physiology ; },
abstract = {Direct experimental evidence implicates telomere erosion as a primary cause of cellular senescence. Using a well characterized model system for breast cancer, we define here the molecular and cellular consequences of adriamycin treatment in breast tumor cells. Cells acutely exposed to adriamycin exhibited an increase in p53 activity, a decline in telomerase activity, and a dramatic increase in beta-galactosidase, a marker of senescence. Inactivation of wild-type p53 resulted in a transition of the cellular response to adriamycin treatment from replicative senescence to delayed apoptosis, demonstrating that p53 plays an integral role in the fate of breast tumor cells treated with DNA-damaging agents. Stable introduction of hTERT, the catalytic protein component of telomerase, into MCF-7 cells caused an increase in telomerase activity and telomere length. Treatment of MCF-7-hTERT cells with adriamycin produced an identical senescence response as controls without signs of telomere shortening, indicating that the senescence after treatment is telomere length-independent. However, we found that exposure to adriamycin resulted in an overrepresentation of cytogenetic changes involving telomeres, showing an altered telomere state induced by adriamycin is probably a causal factor leading to the senescence phenotype. To our knowledge, these data are the first to demonstrate that the mechanism of adriamycin-induced senescence is dependent on both functional p53 and telomere dysfunction rather than overall shortening.},
}
@article {pmid12095111,
year = {2001},
author = {Pérez-Morga, D and Amiguet-Vercher, A and Vermijlen, D and Pays, E},
title = {Organization of telomeres during the cell and life cycles of Trypanosoma brucei.},
journal = {The Journal of eukaryotic microbiology},
volume = {48},
number = {2},
pages = {221-226},
doi = {10.1111/j.1550-7408.2001.tb00306.x},
pmid = {12095111},
issn = {1066-5234},
mesh = {Animals ; *Cell Cycle ; Cell Division ; Cell Nucleus/ultrastructure ; Chromosome Segregation/drug effects ; Interphase ; Lactones/pharmacology ; *Life Cycle Stages ; Macrolides ; Microtubules/ultrastructure ; Mitosis ; Spindle Apparatus/ultrastructure ; Telomere/*physiology/ultrastructure ; Transcription, Genetic ; Trypanosoma brucei brucei/*cytology/drug effects/genetics/*growth &amp; development ; },
abstract = {The genome of Trypanosoma brucei contains about 120 chromosomes, which do not visibly condense during mitosis. We have analyzed the organization and segregation of these chromosomes by in situ hybridization using fluorescent telomere probes. At the onset of mitosis, telomeres migrate from their nuclear peripheral location and congregate into a central zone. This dense group of telomeres then splits into two entities that migrate to opposite nuclear poles. Segregation continues until the double-sized nucleus divides and, before cytokinesis occurs, the telomeres reorganize into the discrete foci observed at interphase. During migration, the telomeres are located at the free end of the mitotic spindle. Treatment with the microtubule polymerization inhibitor rhizoxin prevents telomere clustering and chromosomal segregation. In the insect-specific procyclic form as well as in the non-dividing bloodstream stumpy form, telomeres tend to cluster close to the nuclear periphery at interphase. In contrast, in the proliferative bloodstream slender form the telomeres preferentially locate in the central zone of the nucleus. Thus, telomeres are closer to the nuclear periphery during those life cycle stages where the telomeric expression sites for the variant surface glycoprotein are all inactive, suggesting that transcriptional inactivation of these sites is related to their subnuclear localization.},
}
@article {pmid12090003,
year = {2000},
author = {Jones, CJ},
title = {Telomeres, telomerase and cellular immortalization.},
journal = {Symposia of the Society for Experimental Biology},
volume = {52},
number = {},
pages = {135-148},
pmid = {12090003},
issn = {0081-1386},
mesh = {Animals ; Cell Division/*physiology ; Cellular Senescence/physiology ; DNA Replication ; Gene Deletion ; Humans ; Models, Genetic ; Neoplasms/enzymology/genetics/pathology ; Telomerase/*physiology ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; Telomeric Repeat Binding Protein 2/metabolism ; },
}
@article {pmid12087170,
year = {2002},
author = {Wei, C and Skopp, R and Takata, M and Takeda, S and Price, CM},
title = {Effects of double-strand break repair proteins on vertebrate telomere structure.},
journal = {Nucleic acids research},
volume = {30},
number = {13},
pages = {2862-2870},
pmid = {12087170},
issn = {1362-4962},
support = {R01 AG17212/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Antigens, Nuclear ; Avian Proteins ; Cell Line ; *DNA Helicases ; *DNA Repair ; DNA-Binding Proteins/deficiency/*genetics ; Gene Deletion ; Humans ; Ku Autoantigen ; MRE11 Homologue Protein ; Mutation ; Nuclear Proteins/deficiency/genetics ; Rad51 Recombinase ; *Saccharomyces cerevisiae Proteins ; Telomere/*genetics/metabolism ; },
abstract = {Although telomeres are not recognized as double-strand breaks (DSBs), some DSB repair proteins are present at telomeres and are required for telomere maintenance. To learn more about the telomeric function of proteins from the homologous recombination (HR) and non-homologous end joining pathways (NHEJ), we have screened a panel of chicken DT40 knockout cell lines for changes in telomere structure. In contrast to what has been observed in Ku-deficient mice, we found that Ku70 disruption did not result in telomere-telomere fusions and had no effect on telomere length or the structure of the telomeric G-strand overhang. G-overhang length was increased by Rad51 disruption but unchanged by disruption of DNA-PKcs, Mre11, Rad52, Rad54, XRCC2 or XRCC3. The effect of Rad51 depletion was unexpected because gross alterations in telomere structure have not been detected in yeast HR mutants. Thus, our results indicate that Rad51 has a previously undiscovered function at vertebrate telomeres. They also indicate that Mre11 is not required to generate G-overhangs. Although Mre11 has been implicated in overhang generation, overhang structure had not previously been examined in Mre11-deficient cells. Overall our findings indicate that there are significant species-specific differences in the telomeric function of DSB repair proteins.},
}
@article {pmid12087054,
year = {2002},
author = {Wiemann, SU and Satyanarayana, A and Tsahuridu, M and Tillmann, HL and Zender, L and Klempnauer, J and Flemming, P and Franco, S and Blasco, MA and Manns, MP and Rudolph, KL},
title = {Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {16},
number = {9},
pages = {935-942},
doi = {10.1096/fj.01-0977com},
pmid = {12087054},
issn = {1530-6860},
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Biomarkers/analysis ; Cellular Senescence ; Child ; Disease Progression ; Hepatocytes/pathology/*ultrastructure ; Humans ; Liver Cirrhosis/enzymology/genetics/*pathology ; Middle Aged ; Models, Biological ; Telomere/*ultrastructure ; beta-Galactosidase/analysis ; },
abstract = {Telomere shortening limits the number of cell divisions of primary human cells and might affect the regenerative capacity of organ systems during aging and chronic disease. To test whether the telomere hypothesis applies to human cirrhosis, the telomere length was monitored in cirrhosis induced by a broad variety of different etiologies. Telomeres were significantly shorter in cirrhosis compared with noncirrhotic samples independent of the primary etiology and independent of the age of the patients. Quantitative fluorescence in situ hybridization showed that telomere shortening was restricted to hepatocytes whereas lymphocytes and stellate cells in areas of fibrosis had significantly longer telomere reserves. Hepatocyte-specific telomere shortening correlated with senescence-associated beta-galactosidase staining in 84% of the cirrhosis samples, specifically in hepatocytes, but not in stellate cells or lymphocytes. Hepatocyte telomere shortening and senescence correlated with progression of fibrosis in cirrhosis samples. This study demonstrates for the first time that cell type-specific telomere shortening and senescence are linked to progression of human cirrhosis. These findings give a novel explanation for the pathophysiology of cirrhosis, indicating that fibrotic scarring at the cirrhosis stage is a consequence of hepatocyte telomere shortening and senescence. The data imply that future therapies aiming to restore regenerative capacity during aging and chronic diseases will have to ensure efficient targeting of specific cell types within the affected organs.},
}
@article {pmid12082463,
year = {2002},
author = {Yatabe, N and Kyo, S and Kondo, S and Kanaya, T and Wang, Z and Maida, Y and Takakura, M and Nakamura, M and Tanaka, M and Inoue, M},
title = {2-5A antisense therapy directed against human telomerase RNA inhibits telomerase activity and induces apoptosis without telomere impairment in cervical cancer cells.},
journal = {Cancer gene therapy},
volume = {9},
number = {7},
pages = {624-630},
doi = {10.1038/sj.cgt.7700479},
pmid = {12082463},
issn = {0929-1903},
mesh = {*Apoptosis ; Blotting, Southern ; Cell Survival ; Female ; Flow Cytometry ; Genetic Therapy/*methods ; Humans ; Oligonucleotides/pharmacology ; Oligonucleotides, Antisense/*pharmacology ; RNA/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*antagonists &amp; inhibitors/*genetics ; Telomere/metabolism ; Time Factors ; Transfection ; Tumor Cells, Cultured ; Uterine Cervical Neoplasms/*genetics/therapy ; },
abstract = {Human telomerase RNA (hTR), an important component of telomerase, is a possible target of telomerase-based cancer gene therapy. The present study was undertaken to assess the efficacy of antisense hTR therapy using newly developed 2-5A (5'-phosphorylated 2'-5'-linked oligoadenylate)-linked oligonucleotides against cervical cancer cells. ME180 and SiHa cells were treated with 2-5A-linked antisense hTR designed to complement the region of hTR between residues 76 and 94. The hTR expression, telomerase activity, cell viability, and apoptosis were then examined. The 2-5A anti-hTR effectively degraded hTR and inhibited telomerase activity. The 2-5A mutant anti-hTR and the anti-hTR without 2-5A were not capable of inhibiting telomerase activity. Inhibition of telomerase by 2-5A anti-hTR rapidly decreased cell viability only in telomerase-positive cells within 3-6 days after the treatment, when telomere length has not yet been shortened. This inhibition was associated with apoptosis, possibly through activation of caspase family members. These findings suggest that 2-5A-linked antisense-hTR therapy has a potent telomerase-inhibitory effect associated with a cytocidal effect from caspase-induced apoptosis, and may therefore be a potential tool in telomerase-based gene therapy against cervical cancers.},
}
@article {pmid12077343,
year = {2002},
author = {Rheinwald, JG and Hahn, WC and Ramsey, MR and Wu, JY and Guo, Z and Tsao, H and De Luca, M and Catricalà, C and O'Toole, KM},
title = {A two-stage, p16(INK4A)- and p53-dependent keratinocyte senescence mechanism that limits replicative potential independent of telomere status.},
journal = {Molecular and cellular biology},
volume = {22},
number = {14},
pages = {5157-5172},
pmid = {12077343},
issn = {0270-7306},
support = {K01 CA094223/CA/NCI NIH HHS/United States ; P01 DE012467/DE/NIDCR NIH HHS/United States ; R01 DE013178/DE/NIDCR NIH HHS/United States ; CA 94223/CA/NCI NIH HHS/United States ; R01 DE 13178/DE/NIDCR NIH HHS/United States ; P01 DE 12467/DE/NIDCR NIH HHS/United States ; },
mesh = {Cell Division ; Cells, Cultured ; Cellular Senescence/*physiology ; Culture Media ; Cyclin-Dependent Kinase 4 ; Cyclin-Dependent Kinase Inhibitor p16/genetics/*metabolism ; Cyclin-Dependent Kinases/genetics/metabolism ; DNA-Binding Proteins ; Genes, p53 ; Humans ; Keratinocytes/*cytology/*metabolism ; Mutation ; *Proto-Oncogene Proteins ; Telomerase/genetics/metabolism ; Telomere/metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; },
abstract = {With increasing frequency during serial passage in culture, primary human keratinocytes express p16(INK4A) (p16) and undergo senescence arrest. Keratinocytes engineered to express hTERT maintain long telomeres but typically are not immortalized unless, by mutation or other heritable event, they avoid or greatly reduce p16 expression. We have confirmed that keratinocytes undergo p16-related senescence during growth in culture, whether in the fibroblast feeder cell system or in the specialized K-sfm medium formulation, and that this mechanism can act as a barrier to immortalization following hTERT expression. We have characterized the p16-related arrest mechanism more precisely by interfering specifically with several regulators of cell cycle control. Epidermal, oral mucosal, corneal limbal, and conjunctival keratinocytes were transduced to express a p16-insensitive mutant cdk4 (cdk4(R24C)), to abolish p16 control, and/or a dominant negative mutant p53 (p53DD), to abolish p53 function. Expression of either cdk4(R24C) or p53DD alone had little effect on life span, but expression of both permitted cells to divide 25 to 43 population doublings (PD) beyond their normal limit. Keratinocytes from a p16(+/-) individual transduced to express p53DD alone displayed a 31-PD life span extension associated with selective growth of variants that had lost the wild-type p16 allele. Cells in which both p53 and p16 were nonfunctional divided rapidly during their extended life span but experienced telomere erosion and ultimately ceased growth with very short telomeres. Expression of hTERT in these cells immortalized them. Keratinocytes engineered to express cdk4(R24C) and hTERT but not p53DD did not exhibit an extended life span. Rare immortal variants exhibiting p53 pathway defects arose from them, however, indicating that the p53-dependent component of keratinocyte senescence is telomere independent. Mutational loss of p16 and p53 has been found to be a frequent early event in the development of squamous cell carcinoma. Our results suggest that such mutations endow keratinocytes with extended replicative potential which may serve to increase the probability of neoplastic progression.},
}
@article {pmid12070595,
year = {2002},
author = {Scheel, C and Poremba, C},
title = {Telomere lengthening in telomerase-negative cells: the ends are coming together.},
journal = {Virchows Archiv : an international journal of pathology},
volume = {440},
number = {6},
pages = {573-582},
doi = {10.1007/s00428-002-0634-9},
pmid = {12070595},
issn = {0945-6317},
mesh = {Animals ; *Cell Transformation, Neoplastic ; Enzyme Activation ; Humans ; Neoplasms/chemistry/etiology/genetics ; Telomerase/chemistry/*physiology ; Telomere/chemistry/*physiology ; },
abstract = {Telomeres are crucial for chromosomal stability and cell viability. Activation of telomerase, a specialized reverse transcriptase, is the predominant mechanism for maintaining telomere length and function in yeasts and human cells. Telomere maintenance is regarded as a key element in the immortalization of cells and hence in oncogenesis. Although more than 90% of all malignant tumors display telomerase activity, there appear to be alternatives to this mechanism. Alternative lengthening of telomeres (ALT) in the absence of telomerase has been described in various organisms and recently also in immortalized and transformed human cells. This article will discuss how ALT is detected and how it affects telomere morphology. It will review the frequency and relevance of ALT in in vitro immortalized cell lines, tumor-derived cell lines, and primary tumors. We have only begun to link mechanisms by means of which ALT may act in immortalized human cells to the growing knowledge about telomeres, and we can look forward to further fascinating insights into telomere biology. Our review will also emphasize recent advances in our understanding of the induction and repression of ALT and the demonstration of ALT in cancer cells in the light of new treatment strategies targeted against telomere maintenance mechanisms.},
}
@article {pmid12068970,
year = {2002},
author = {Rosén, M and Castillejo-López, C and Edström, JE},
title = {Telomere terminating with centromere-specific repeats is closely associated with a transposon derived gene in Chironomus pallidivittatus.},
journal = {Chromosoma},
volume = {110},
number = {8},
pages = {532-541},
doi = {10.1007/s00412-001-0176-y},
pmid = {12068970},
issn = {0009-5915},
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Binding Sites ; Centromere/*genetics ; Chironomidae/*genetics ; DNA Primers ; *DNA Transposable Elements ; Molecular Sequence Data ; *Repetitive Sequences, Nucleic Acid ; Sequence Alignment ; Sequence Analysis, DNA ; Telomere/*genetics ; },
abstract = {We provide evidence that centromere-specific 155 bp DNA repeats terminate one pair of telomeres at the telocentric, left end of the short fourth chromosome in Chironomus pallidivittatus. Earlier evidence indicated that all other telomeres are terminated by 340 bp telomere-specific repeats. DNA that borders the 155 bp repeat contains a transcriptionally active 396 codon open reading frame (ORF) a few kilobases away from the repeat array. The conceptual product of the ORF has regions with similarities to transposase, DNA binding and endonuclease motifs and is likely to have an evolutionary origin in a transposon. It is flanked, within degenerate inverted repeats, by a modified form of an element, Cp80, that has previously been found to insert only into 155 bp repeats and that contains a putative CENP-B box and a region that is prone to recombine. The ORF may therefore have a functional relation to the centromeric region.},
}
@article {pmid12068140,
year = {2002},
author = {Kim, HR and Kim, YJ and Kim, HJ and Kim, SK and Lee, JH},
title = {Telomere length changes in colorectal cancers and polyps.},
journal = {Journal of Korean medical science},
volume = {17},
number = {3},
pages = {360-365},
doi = {10.3346/jkms.2002.17.3.360},
pmid = {12068140},
issn = {1011-8934},
mesh = {Adult ; Aged ; Blotting, Southern ; Carcinoma/*pathology ; Colonic Polyps/*pathology ; Colorectal Neoplasms/*pathology ; Female ; Humans ; Lymphatic Metastasis ; Male ; Middle Aged ; Telomere/genetics/*pathology ; },
abstract = {Telomere shortening and telomerase activation occur frequently in cases of colorectal carcinoma. In this study, we correlated the clinicopathological parameters with the telomere length in colorectal carcinomas, colonic polyps, and normal colonic tissues. We also investigated whether the telomere length changes reflect the biologic behavior of tumors and different modes of tumor development. Telomere length was determined by terminal restriction fragment Southern blot analysis in 20 invasive colorectal carcinomas and normal mucosa from the same patients. We also examined 20 colonic polyps and associated normal mucosa. Telomere shortening was detected in 16/20 (80%), and telomere elongation in 2/20 (10%) cases of colorectal carcinoma, and no changes in 2 subjects. In the colonic polyp patients, shortening was detected in 4/20 (20%), elongation in 6/20 (30%), and no change in 10/20 (50%). The frequency of telomere shortening was significantly different between colorectal carcinoma and polyp groups. Decreased telomere length was noted in 92.9% (13/14) of Dukes' C and 50% (3/6) of Dukes' B. The difference between these two sub-groups was statistically significant. This study suggests that the telomere length in colorectal carcinomas is decreased upon the development of malignancy. A significant difference in telomere length between polyps and invasive colorectal carcinomas may reflect a different biologic behavior of colorectal carcinomas.},
}
@article {pmid12062940,
year = {2002},
author = {Tsuji, A and Ishiko, A and Takasaki, T and Ikeda, N},
title = {Estimating age of humans based on telomere shortening.},
journal = {Forensic science international},
volume = {126},
number = {3},
pages = {197-199},
doi = {10.1016/s0379-0738(02)00086-5},
pmid = {12062940},
issn = {0379-0738},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*physiology ; Blood Stains ; Blotting, Southern ; Child ; Forensic Medicine/methods ; Humans ; Infant ; Middle Aged ; Telomere/*chemistry/physiology ; },
abstract = {To estimate age using DNA based on telomere shortening, we determined the terminal restriction fragment (TRF) length, as telomere length, using Southern blot analysis of peripheral human blood and blood stains. All blood stains had been stored at room temperature for 5 months. The average TRF length clearly showed a tendency to shortening with aging. The formula for age estimation was based on a correlation between average TRF length and age of the subjects. The estimated age calculated from TRF length widely depends on environmental and genetic factors. However, as long as the DNA is well preserved, use of our method is feasible regardless of age of the subject and can give a rough estimation of age of subjects in forensic samples that carry no morphological information.},
}
@article {pmid12062058,
year = {2002},
author = {Zaman, Z and Heid, C and Ptashne, M},
title = {Telomere looping permits repression "at a distance" in yeast.},
journal = {Current biology : CB},
volume = {12},
number = {11},
pages = {930-933},
doi = {10.1016/s0960-9822(02)00865-5},
pmid = {12062058},
issn = {0960-9822},
mesh = {Base Sequence ; Chromatin/genetics ; DNA Primers ; Precipitin Tests ; Saccharomyces cerevisiae/*genetics ; *Telomere ; },
abstract = {In yeast, unlike in higher eukaryotes, transcriptional activators and repressors do not normally work when bound to DNA at large distances (over 500 base pairs) from the gene and, in particular, when positioned downstream of the gene. This restriction is relieved for a transcriptional activator if a gene bearing an activator binding site is placed near a yeast telomere. The explanation proposed is that the folded structure found at the telomere helps appose the DNA-bound activator with proteins binding to the promoter so that recruitment of the transcriptional machinery can be effected "at a distance". Here, we show that a repressor, Tup1, works when tethered to DNA downstream of, and some 1.5-kb from, the gene when the construct is placed near a yeast telomere. The effect, observed with activated as well as basal transcription, is eliminated by deletion of Sir3. These and other results indicate that DNA-tethered Tup1 represses by interacting with some component of the transcriptional machinery binding to the promoter, an interaction that is facilitated by the preformed loop at the telomere.},
}
@article {pmid12052890,
year = {2002},
author = {Lo, AW and Sprung, CN and Fouladi, B and Pedram, M and Sabatier, L and Ricoul, M and Reynolds, GE and Murnane, JP},
title = {Chromosome instability as a result of double-strand breaks near telomeres in mouse embryonic stem cells.},
journal = {Molecular and cellular biology},
volume = {22},
number = {13},
pages = {4836-4850},
pmid = {12052890},
issn = {0270-7306},
support = {R01 CA069044/CA/NCI NIH HHS/United States ; R01 ES008427/ES/NIEHS NIH HHS/United States ; R01 CA69044/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cloning, Molecular ; *DNA ; *DNA Damage ; Deoxyribonucleases, Type II Site-Specific/genetics/metabolism ; Embryo, Mammalian/cytology ; Female ; Gene Rearrangement ; Genetic Markers ; Humans ; Male ; Mice ; Mice, Inbred Strains ; Molecular Sequence Data ; Plasmids/genetics ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae Proteins ; Simplexvirus/genetics ; Stem Cells/*physiology ; Telomere/*genetics ; Thymidine Kinase/genetics ; },
abstract = {Telomeres are essential for protecting the ends of chromosomes and preventing chromosome fusion. Telomere loss has been proposed to play an important role in the chromosomal rearrangements associated with tumorigenesis. To determine the relationship between telomere loss and chromosome instability in mammalian cells, we investigated the events resulting from the introduction of a double-strand break near a telomere with I-SceI endonuclease in mouse embryonic stem cells. The inactivation of a selectable marker gene adjacent to a telomere as a result of the I-SceI-induced double-strand break involved either the addition of a telomere at the site of the break or the formation of inverted repeats and large tandem duplications on the end of the chromosome. Nucleotide sequence analysis demonstrated large deletions and little or no complementarity at the recombination sites involved in the formation of the inverted repeats. The formation of inverted repeats was followed by a period of chromosome instability, characterized by amplification of the subtelomeric region, translocation of chromosomal fragments onto the end of the chromosome, and the formation of dicentric chromosomes. Despite this heterogeneity, the rearranged chromosomes eventually acquired telomeres and were stable in most of the cells in the population at the time of analysis. Our observations are consistent with a model in which broken chromosomes that do not regain a telomere undergo sister chromatid fusion involving nonhomologous end joining. Sister chromatid fusion is followed by chromosome instability resulting from breakage-fusion-bridge cycles involving the sister chromatids and rearrangements with other chromosomes. This process results in highly rearranged chromosomes that eventually become stable through the addition of a telomere onto the broken end. We have observed similar events after spontaneous telomere loss in a human tumor cell line, suggesting that chromosome instability resulting from telomere loss plays a role in chromosomal rearrangements associated with tumor cell progression.},
}
@article {pmid12052861,
year = {2002},
author = {Natarajan, S and McEachern, MJ},
title = {Recombinational telomere elongation promoted by DNA circles.},
journal = {Molecular and cellular biology},
volume = {22},
number = {13},
pages = {4512-4521},
pmid = {12052861},
issn = {0270-7306},
support = {R01 GM061645/GM/NIGMS NIH HHS/United States ; GM61645-01/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA, Circular ; *DNA, Fungal ; DNA-Binding Proteins/genetics ; Fungal Proteins/genetics ; *Gene Conversion ; Genetic Engineering/methods ; Kluyveromyces/*genetics ; Mutation ; Rad52 DNA Repair and Recombination Protein ; Repetitive Sequences, Nucleic Acid ; Telomere/*genetics ; },
abstract = {Yeast mutants lacking telomerase are capable of maintaining telomeres by an alternate mechanism that depends on homologous recombination. We show here, by using Kluyveromyces lactis cells containing two types of telomeric repeats, that recombinational telomere elongation generates a repeating pattern common in most or all telomeres in survivors that retain both repeat types. We propose that these patterns arise from small circles of telomeric DNA being used as templates for rolling-circle gene conversion and that the sequence from the lengthened telomere is spread to other telomeres by additional, more typical gene conversion events. Consistent with this, artificially constructed circles of DNA containing telomeric repeats form long tandem arrays at telomeres when transformed into K. lactis cells. Mixing experiments done with two species of telomeric circles indicated that all of the integrated copies of the transforming sequence arise from a single original circular molecule.},
}
@article {pmid12050062,
year = {2002},
author = {Hao, YH and Tan, Z},
title = {The generation of long telomere overhangs in human cells: a model and its implication.},
journal = {Bioinformatics (Oxford, England)},
volume = {18},
number = {5},
pages = {666-671},
doi = {10.1093/bioinformatics/18.5.666},
pmid = {12050062},
issn = {1367-4803},
mesh = {Chromosomes, Human/*genetics ; Computer Simulation ; DNA Primers/genetics ; DNA Replication/*genetics ; DNA, Single-Stranded/chemistry/genetics ; Humans ; *Models, Genetic ; *Models, Statistical ; RNA/genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; Sensitivity and Specificity ; Stochastic Processes ; *Telomere/chemistry/genetics ; },
abstract = {MOTIVATION: Linear chromosomes carry on both ends repetitive DNA sequences called telomere. In the conventional model of semi-conservative DNA replication, the 3'-end of a linear DNA strand cannot be fully replicated, resulting in a single-stranded 3' overhang at one end of the double-stranded DNA product. In this model, the length of the overhang is expected to be about the size of an RNA primer (about nine nucleotides for human cells). However, it has been found that the telomere overhangs in human cells can be as long as several hundred nucleotides. At present, the opinion regarding how such long overhangs are produced is controversial.<br><br>RESULTS: In order to gain insight into the mechanism by which long telomere overhangs are produced, we derived a mathematical model that can perfectly describe the length distribution of telomere overhangs in several human cell strains. The model suggests that the production of telomere overhangs can be explained by three contributions corresponding to three regions on the G-rich telomere template strand, namely, the region occupied by the last primer, that missed out by this primer at its 5'-side and the 3'-terminus of the template strand that is inaccessible to primase. The model can also be used to simulate incomplete telomere replication.},
}
@article {pmid12044935,
year = {2002},
author = {Bénard, C and Hekimi, S},
title = {Long-lived mutants, the rate of aging, telomeres and the germline in Caenorhabditis elegans.},
journal = {Mechanisms of ageing and development},
volume = {123},
number = {8},
pages = {869-880},
doi = {10.1016/s0047-6374(02)00024-6},
pmid = {12044935},
issn = {0047-6374},
mesh = {Aging/*genetics/physiology ; Animals ; Caenorhabditis elegans/*genetics/physiology ; Caenorhabditis elegans Proteins/genetics/physiology ; Germ Cells ; Helminth Proteins/genetics/physiology ; Mutation ; Telomere/*genetics ; *Telomere-Binding Proteins ; },
}
@article {pmid12042469,
year = {2002},
author = {McKevitt, TP and Nasir, L and Devlin, P and Argyle, DJ},
title = {Telomere lengths in dogs decrease with increasing donor age.},
journal = {The Journal of nutrition},
volume = {132},
number = {6 Suppl 2},
pages = {1604S-6S},
doi = {10.1093/jn/132.6.1604S},
pmid = {12042469},
issn = {0022-3166},
mesh = {Aging/*genetics ; Animals ; Dogs/*genetics ; Monocytes/physiology ; Restriction Mapping ; Species Specificity ; Telomere/*genetics ; },
abstract = {In vitro and in vivo studies of human tissues have demonstrated telomeric attrition with age and have linked this attrition to cellular senescence and aging. Telomere studies in canine subjects have not thus far consistently uncovered the same pattern of telomere attrition that would be expected because of the end replication problem. In this report we describe the investigation of telomere lengths in a broad age range of dogs from three different breeds: the Labrador Retriever, Miniature Schnauzer and Beagle. Peripheral blood mononuclear cell-derived DNA samples were subjected to terminal restriction fragment (TRF) analysis and demonstrated a range of mean TRFs from 9.7 to 22.3 kbp. Telomeric attrition tended to be associated with increasing donor age (P = 0.06). Interbreed differences in mean TRF values were also noted (P = 0.006). These results warrant further investigation of possible interbreed differences, given that shorter telomeres may contribute to differing life expectancy between breeds.},
}
@article {pmid12036938,
year = {2002},
author = {Huang, JJ and Lin, MC and Bai, YX and Jing, DD and Wong, BC and Han, SW and Lin, J and Xu, B and Huang, CF and Kung, HF},
title = {Ectopic expression of a COOH-terminal fragment of the human telomerase reverse transcriptase leads to telomere dysfunction and reduction of growth and tumorigenicity in HeLa cells.},
journal = {Cancer research},
volume = {62},
number = {11},
pages = {3226-3232},
pmid = {12036938},
issn = {0008-5472},
mesh = {Animals ; Apoptosis/physiology ; Cell Division/physiology ; DNA-Binding Proteins ; HeLa Cells ; Humans ; Mice ; Mice, Nude ; Peptide Fragments/biosynthesis/genetics/*physiology ; Telomerase/biosynthesis/genetics/metabolism/*physiology ; Telomere/*physiology ; Transfection ; Xenograft Model Antitumor Assays ; },
abstract = {The COOH-terminus of telomerase reverse transcriptase (hTERT) has been shown to participatein the nuclear translocation of TERT. Here, we constructed plasmids expressing the COOH-terminal M(r) 27,000 polypeptide of hTERT (hTERTC27) withthe telomerase RNA-binding domains and the reverse transcriptase domains deleted. We showed that ectopic overexpression of this polypeptide caused a defect in telomere maintenance in hTERT-positive HeLa cells, which led to senescence-like growth arrest and apoptosis. The hTERTC27 appears to work by inducing telomere dysfunction, exemplified by significantly increased anaphase chromosome end-to-end fusion events in transfected cells. Significantly, it had no effect on the cellular telomerase enzymatic activity or telomere length. The in vivo effect was further demonstrated as HeLa cells stably expressing hTERTC27 have significantly lower growth rate and reduced tumorigenicity in nude mice xenografts. Results from this study revealed an important function for the COOH terminus of hTERT in maintaining the integrity of telomere structure and chromosome ends, as well as in cell senescence and apoptosis. Furthermore, hTERTC27 provides a new strategy for cancer therapy by inducing telomere dysfunction in cancer cells without affecting the telomerase enzymatic activity.},
}
@article {pmid12036106,
year = {2002},
author = {Uchida, W and Matsunaga, S and Sugiyama, R and Kawano, S},
title = {Interstitial telomere-like repeats in the Arabidopsis thaliana genome.},
journal = {Genes &amp; genetic systems},
volume = {77},
number = {1},
pages = {63-67},
doi = {10.1266/ggs.77.63},
pmid = {12036106},
issn = {1341-7568},
mesh = {Arabidopsis/*genetics ; Base Sequence ; Chromosome Mapping ; Conserved Sequence ; DNA ; Evolution, Molecular ; Genome, Plant ; Molecular Sequence Data ; *Repetitive Sequences, Nucleic Acid ; Sequence Alignment ; Telomere/genetics ; },
abstract = {Eukaryotic chromosomal ends are protected by telomeres, which are thought to play an important role in ensuring the complete replication of chromosomes. On the other hand, non-functional telomere-like repeats in the interchromosomal regions (interstitial telomeric repeats; ITRs) have been reported in several eukaryotes. In this study, we identified eight ITRs in the Arabidopsis thaliana genome, each consisting of complete and degenerate 300- to 1200-bp sequences. The ITRs were grouped into three classes (class IA-B, class II, and class IIIA-E) based on the degeneracy of the telomeric repeats in ITRs. The telomeric repeats of the two ITRs in class I were conserved for the most part, whereas the single ITR in class II, and the five ITRs in class III were relatively degenerated. In addition, degenerate ITRs were surrounded by common sequences that shared 70-100% homology to each other; these are named ITR-adjacent sequences (IAS). Although the genomic regions around ITRs in class I lacked IAS, those around ITRs in class II contained IAS (IASa), and those around five ITRs in class III had nine types of IAS (IASb, c, d, e, f, g, h, i, and j). Ten IAS types in classes II and III showed no significant homology to each other. The chromosomal locations of ITRs and IAS were not category-related, but most of them were adjacent to, or part of, a centromere. These results show that the A. thaliana genome has undergone chromosomal rearrangements, such as end-fusions and segmental duplications.},
}
@article {pmid12034817,
year = {2002},
author = {Ren, J and Qu, X and Trent, JO and Chaires, JB},
title = {Tiny telomere DNA.},
journal = {Nucleic acids research},
volume = {30},
number = {11},
pages = {2307-2315},
pmid = {12034817},
issn = {1362-4962},
support = {R01 CA035635/CA/NCI NIH HHS/United States ; CA35635/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; Calorimetry, Differential Scanning ; Circular Dichroism ; DNA/*chemistry/genetics/*metabolism/radiation effects ; G-Quadruplexes ; Ligands ; Models, Molecular ; *Nucleic Acid Conformation/radiation effects ; Nucleic Acid Denaturation/radiation effects ; Oligodeoxyribonucleotides/chemistry/genetics/metabolism/radiation effects ; Spectrometry, Fluorescence ; Telomere/*chemistry/genetics/*metabolism/radiation effects ; Thermodynamics ; Ultraviolet Rays ; },
abstract = {We describe the design, synthesis and biophysical characterization of a novel DNA construct in which a folded quadruplex structure is joined to a standard double helix. Circular dichroism, gel electrophoresis, three-dimensional UV melting and differential scanning calorimetry were all used to characterize the structure. Rigorous molecular dynamics simulations were used to build a plausible atomic-level structural model of the DNA construct. This novel DNA construct provides a model for the duplex-quadruplex junction region at the end of chromosomal DNA and offers a system for the study of structure-selective ligand binding.},
}
@article {pmid12034742,
year = {2002},
author = {Rubio, MA and Kim, SH and Campisi, J},
title = {Reversible manipulation of telomerase expression and telomere length. Implications for the ionizing radiation response and replicative senescence of human cells.},
journal = {The Journal of biological chemistry},
volume = {277},
number = {32},
pages = {28609-28617},
doi = {10.1074/jbc.M203747200},
pmid = {12034742},
issn = {0021-9258},
mesh = {Blotting, Western ; Cell Division ; Cell Line ; Cell Survival ; Cellular Senescence ; Dose-Response Relationship, Radiation ; Fibroblasts/metabolism ; Genetic Vectors ; Humans ; Integrases/genetics ; Radiation, Ionizing ; Retroviridae/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*biosynthesis ; Telomere/*physiology/ultrastructure ; Time Factors ; Transfection ; Viral Proteins/genetics ; },
abstract = {Most human cells do not express telomerase and irreversibly arrest proliferation after a finite number of divisions (replicative senescence). Several lines of evidence suggest that replicative senescence is caused by short dysfunctional telomeres, which arise when DNA is replicated in the absence of adequate telomerase activity. We describe a method to reversibly bypass replicative senescence and generate mass cultures that have different average telomere lengths. A retrovirus carrying hTERT flanked by excision sites for Cre recombinase rendered normal human fibroblasts telomerase-positive and replicatively immortal. Superinfection with retroviruses carrying wild-type or mutant forms of TIN2, a negative regulator of telomere length, created telomerase-positive, immortal populations with varying average telomere lengths. Subsequent infection with a Cre-expressing retrovirus abolished telomerase activity, creating mortal cells with varying telomere lengths. Using these cell populations, we show that, after hTERT excision, cells senesce with shorter telomeres than parental cells. Moreover, long telomeres, but not telomerase, protected cells from the loss of division potential caused by ionizing radiation. Finally, although telomerase-negative cells with short telomeres senesced after fewer doublings than those with long telomeres, telomere length per se did not correlate with senescence. Our results support a role for telomere structure, rather than length, in replicative senescence.},
}
@article {pmid12032768,
year = {2002},
author = {Allsopp, RC and Weissman, IL},
title = {Replicative senescence of hematopoietic stem cells during serial transplantation: does telomere shortening play a role?.},
journal = {Oncogene},
volume = {21},
number = {21},
pages = {3270-3273},
doi = {10.1038/sj.onc.1205314},
pmid = {12032768},
issn = {0950-9232},
support = {CA 86065/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; *Cellular Senescence ; Hematopoietic Stem Cells/*physiology ; Humans ; Telomerase/metabolism ; Telomere/*metabolism/physiology ; },
abstract = {Hematopoietic stem cells (HSC) have a finite proliferative lifespan, based upon the limited number of times they can be serially transplanted in mice. Telomeres have been shown to shorten during the division of many normal somatic cells in humans, and the attrition of telomeres has been shown to ultimately cause replicative senescence in vitro for a number of different human cell strains. Whereas most human cell types have little to no detectable levels of telomerase activity, hematopoietic cells, including HSC, express low to moderate levels of telomerase, and yet telomeres shorten considerably during replicative aging of these cells. Here we consider the role telomerase may play in the hematopoietic system as well as the effect that over-expression of telomerase reverse transcriptase may have on the replicative capacity of hematopoietic stem cells during transplantation.},
}
@article {pmid12032094,
year = {2002},
author = {Riha, K and Watson, JM and Parkey, J and Shippen, DE},
title = {Telomere length deregulation and enhanced sensitivity to genotoxic stress in Arabidopsis mutants deficient in Ku70.},
journal = {The EMBO journal},
volume = {21},
number = {11},
pages = {2819-2826},
pmid = {12032094},
issn = {0261-4189},
mesh = {Alleles ; Amino Acid Sequence ; *Antigens, Nuclear ; Arabidopsis/*genetics ; *DNA Helicases ; DNA, Complementary/metabolism ; DNA-Binding Proteins/genetics/metabolism/*physiology ; Dimerization ; Genetic Complementation Test ; Ku Autoantigen ; Methyl Methanesulfonate/pharmacology ; Models, Genetic ; Molecular Sequence Data ; Mutagens/pharmacology ; *Mutation ; Nuclear Proteins/genetics/metabolism/*physiology ; RNA, Complementary/metabolism ; *Saccharomyces cerevisiae Proteins ; *Telomere/ultrastructure ; },
abstract = {The Ku70/80 heterodimer is a critical component of the non-homologous end-joining (NHEJ) pathway and of the telomere cap in yeast and mammals. We report the molecular characterization of the KU70 and KU80 genes in Arabidopsis and describe the consequences of a Ku70 deficiency. Arabidopsis KU70/80 genes are ubiquitously expressed and their products form stable heterodimers in vitro. Plants harboring a T-DNA insertion in KU70 exhibit no growth or developmental defects under standard growth conditions. However, mutant seedlings are hypersensitive to gamma-irradiation-induced double-strand breaks. Unexpectedly, we found that mutants are hypersensitive to methyl methanosulfonate during seed germination, but lose this sensitivity in seedlings, implying that the requirement for NHEJ varies during plant development. Lack of Ku70 results in a dramatic deregulation of telomere length control, with mutant telomeres expanding to more than twice the size of wild type by the second generation. Furthermore, in contrast to the situation in mammals, chromosome fusions are not associated with a Ku deficiency in Arabidopsis. These findings imply that Ku may play a different role in capping plant and animal telomeres.},
}
@article {pmid12029061,
year = {2002},
author = {Goshi, K and Uchida, T and Lezhava, A and Yamasaki, M and Hiratsu, K and Shinkawa, H and Kinashi, H},
title = {Cloning and analysis of the telomere and terminal inverted repeat of the linear chromosome of Streptomyces griseus.},
journal = {Journal of bacteriology},
volume = {184},
number = {12},
pages = {3411-3415},
pmid = {12029061},
issn = {0021-9193},
mesh = {Base Sequence ; *Chromosomes, Bacterial ; Cloning, Molecular ; Molecular Sequence Data ; Restriction Mapping ; Sequence Analysis, DNA ; Streptomyces griseus/*genetics ; Telomere/*chemistry/*genetics ; Terminal Repeat Sequences/*genetics ; },
abstract = {Cloning and sequencing of the telomere of Streptomyces griseus revealed five palindromic sequences in the terminal 116 nucleotides, all of which can make a hairpin loop structure. However, the end sequence cannot form the foldback secondary structure that is common in Streptomyces telomeres and is suggested to be necessary for terminal replication. Both inside ends of the terminal inverted repeat (TIR) were also cloned and sequenced. The results confirmed the size of the TIR to be 24 kb and identified two almost identical open reading frames that might have been involved in the formation of the TIR.},
}
@article {pmid12028791,
year = {2002},
author = {Fajkus, J and Simícková, M and Maláska, J},
title = {Tiptoeing to chromosome tips: facts, promises and perils of today's human telomere biology.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {357},
number = {1420},
pages = {545-562},
pmid = {12028791},
issn = {0962-8436},
mesh = {Aging/genetics ; Antineoplastic Agents/pharmacology ; Cell Differentiation ; Cell Division ; Gene Expression Regulation, Enzymologic ; Humans ; Neoplasms/enzymology/genetics/pathology ; Telomerase/analysis/antagonists &amp; inhibitors/genetics/metabolism ; Telomere/chemistry/enzymology/*physiology ; Tissue Engineering ; },
abstract = {The past decade has witnessed an explosion of knowledge concerning the structure and function of chromosome terminal structures-telomeres. Today's telomere research has advanced from a pure descriptive approach of DNA and protein components to an elementary understanding of telomere metabolism, and now to promising applications in medicine. These applications include 'passive' ones, among which the use of analysis of telomeres and telomerase (a cellular reverse transcriptase that synthesizes telomeres) for cancer diagnostics is the best known. The 'active' applications involve targeted downregulation or upregulation of telomere synthesis, either to mortalize immortal cancer cells, or to rejuvenate mortal somatic cells and tissues for cellular transplantations, respectively. This article reviews the basic data on structure and function of human telomeres and telomerase, as well as both passive and active applications of human telomere biology.},
}
@article {pmid12027454,
year = {2002},
author = {Espejel, S and Blasco, MA},
title = {Identification of telomere-dependent "senescence-like" arrest in mouse embryonic fibroblasts.},
journal = {Experimental cell research},
volume = {276},
number = {2},
pages = {242-248},
doi = {10.1006/excr.2002.5533},
pmid = {12027454},
issn = {0014-4827},
mesh = {Animals ; *Antigens, Nuclear ; Cell Cycle Proteins/genetics/*metabolism ; Cell Division/*genetics ; Cell Line, Transformed/metabolism ; Cells, Cultured ; Cellular Senescence/*genetics ; Chromosome Breakage/genetics ; Colony-Forming Units Assay ; *DNA Helicases ; DNA-Binding Proteins/deficiency/genetics ; Female ; Fetus ; Fibroblasts/cytology/*metabolism ; Humans ; Ku Autoantigen ; Mice ; Mice, Knockout ; Nuclear Proteins/deficiency/genetics ; Pregnancy ; RNA/genetics ; Stem Cells/cytology/*metabolism ; Stress, Physiological/genetics/metabolism ; Telomerase/deficiency/genetics ; Telomere/*genetics/metabolism ; },
abstract = {In contrast to human primary cells, mouse embryonic fibroblasts (MEF) do not show telomere shortening-mediated replicative senescence due to the fact that they have telomerase activity and show sufficiently long telomeres. Instead, it is now generally accepted that the "senescence-like" arrest that occurs in MEF after 5-10 divisions in culture is mediated by telomere-length-independent mechanisms generally referred to as stress. Using telomerase-deficient MEF Terc(-/-), we show here that telomere shortening to a critical length leads to a premature senescence-like arrest in MEF, as well as has a negative effect on spontaneous immortalization. Similarly, elimination of the telomere end-capping protein Ku86 also leads to a premature senescence-like arrest and has a negative effect on spontaneous immortalization. Both Terc(-/-) MEF with short telomeres and Ku86(-/-) MEF show dysfunctional telomeres, as indicated by similarly increased frequencies of end-to-end fusions. These results suggest that loss of telomere function is a general mechanism leading to cell arrest. These observations also indicate that telomere dysfunction is interfering with successful cell division and thus interferes with tumor formation. In summary, we have identified here two different ways to induce a telomere-dependent senescence-like arrest in MEF.},
}
@article {pmid12027448,
year = {2002},
author = {Eller, MS and Puri, N and Hadshiew, IM and Venna, SS and Gilchrest, BA},
title = {Induction of apoptosis by telomere 3' overhang-specific DNA.},
journal = {Experimental cell research},
volume = {276},
number = {2},
pages = {185-193},
doi = {10.1006/excr.2002.5531},
pmid = {12027448},
issn = {0014-4827},
mesh = {3' Flanking Region/drug effects/*genetics ; Apoptosis/drug effects/*genetics ; Base Sequence/drug effects/genetics ; *Cell Cycle Proteins ; Cell Division/drug effects/*genetics ; Cell Transformation, Neoplastic/drug effects/genetics/metabolism ; Cellular Senescence/drug effects/*genetics ; DNA/*genetics/pharmacology ; DNA Damage/drug effects/genetics ; DNA-Binding Proteins/drug effects/genetics/metabolism ; Dose-Response Relationship, Drug ; E2F Transcription Factors ; E2F1 Transcription Factor ; Eukaryotic Cells/drug effects/*metabolism ; Genes, Tumor Suppressor ; Humans ; Jurkat Cells ; Nuclear Proteins/drug effects/genetics/metabolism ; Oligonucleotides/genetics/pharmacology ; S Phase/drug effects/genetics ; Telomere/drug effects/*genetics/metabolism ; Thymidine/genetics/pharmacology ; Transcription Factors/drug effects/genetics/metabolism ; Tumor Protein p73 ; Tumor Suppressor Protein p53/genetics/metabolism ; Tumor Suppressor Proteins ; Up-Regulation/drug effects/genetics ; },
abstract = {Telomeres are tandem repeats of a specific TTAGGG nucleotide sequence at the ends of chromosomes. Telomere shortening is proposed to act as a biological clock and cancer prevention mechanism by inducing a nonproliferative, senescent phenotype after a limited number of cellular divisions. Recent evidence also suggests that telomere disruption can trigger apoptosis in certain cell types, mimicking a major cellular response to DNA damage. Here, we show that addition of DNA oligonucleotides homologous to the telomere 3' overhang sequence causes lymphocytic (Jurkat) cells to undergo apoptosis, as described for lymphocytes following telomere loop disruption. We further implicate the p53 tumor suppressor and transcription factor, as well as the p53 homolog p73 and the E2F1 transcription factor, in mediating the apoptotic response. We propose that exposure of the telomere 3' overhang due to opening of the normal telomere loop structure is a physiologic signal for these DNA damage-like responses in vivo and that oligonucleotides partially or completely homologous to the telomere overhang mimic this signal in the absence of DNA damage or telomere disruption.},
}
@article {pmid12024033,
year = {2002},
author = {Choe, W and Budd, M and Imamura, O and Hoopes, L and Campbell, JL},
title = {Dynamic localization of an Okazaki fragment processing protein suggests a novel role in telomere replication.},
journal = {Molecular and cellular biology},
volume = {22},
number = {12},
pages = {4202-4217},
pmid = {12024033},
issn = {0270-7306},
support = {R01 GM025508/GM/NIGMS NIH HHS/United States ; GM25508/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases/chemistry/genetics/*metabolism ; Base Sequence ; Cell Cycle/genetics ; Cross-Linking Reagents/chemistry ; DNA/*metabolism ; DNA Damage ; DNA Helicases/chemistry/genetics/*metabolism ; DNA Replication ; Fluorescent Antibody Technique, Indirect ; Fungal Proteins/genetics ; Molecular Sequence Data ; Mutation ; Protein Transport ; *Saccharomyces cerevisiae Proteins ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Telomere/*genetics ; Trans-Activators/genetics ; Two-Hybrid System Techniques ; Yeasts/genetics ; },
abstract = {We have found that the Dna2 helicase-nuclease, thought to be involved in maturation of Okazaki fragments, is a component of telomeric chromatin. We demonstrate a dynamic localization of Dna2p to telomeres that suggests a dual role for Dna2p, one in telomere replication and another, unknown function, perhaps in telomere capping. Both chromatin immunoprecipitation (ChIP) and immunofluorescence show that Dna2p associates with telomeres but not bulk chromosomal DNA in G(1) phase, when there is no telomere replication and the telomere is transcriptionally silenced. In S phase, there is a dramatic redistribution of Dna2p from telomeres to sites throughout the replicating chromosomes. Dna2p is again localized to telomeres in late S, where it remains through G(2) and until the next S phase. Telomeric localization of Dna2p required Sir3p, since the amount of Dna2p found at telomeres by two different assays, one-hybrid and ChIP, is severely reduced in strains lacking Sir3p. The Dna2p is also distributed throughout the nucleus in cells growing in the presence of double-strand-break-inducing agents such as bleomycin. Finally, we show that Dna2p is functionally required for telomerase-dependent de novo telomere synthesis and also participates in telomere lengthening in mutants lacking telomerase.},
}
@article {pmid12018857,
year = {2002},
author = {Park, MJ and Jang, YK and Choi, ES and Kim, HS and Park, SD},
title = {Fission yeast Rap1 homolog is a telomere-specific silencing factor and interacts with Taz1p.},
journal = {Molecules and cells},
volume = {13},
number = {2},
pages = {327-333},
pmid = {12018857},
issn = {1016-8478},
mesh = {Base Sequence ; DNA-Binding Proteins/genetics/metabolism ; *Gene Silencing ; Humans ; Molecular Sequence Data ; Schizosaccharomyces/chemistry/*genetics/metabolism ; Schizosaccharomyces pombe Proteins/chemistry/genetics/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; Two-Hybrid System Techniques ; },
abstract = {Taz1p is the fission yeast orthologue of human TRF2, a telomeric repeat-binding protein. Delta(taz1) mutants are defective in telomeric silencing, telomere length control, and meiotic recombination events. A recent report demonstrated that the human Rap1p homolog (hRap1) is recruited to telomere by interaction with TRF2, arguing that the telomere control mechanism of higher eukaryotes is distinct from that of the budding yeast. Taz1p showed a significant similarity to human TRF2, but not with the budding yeast Rap1p (scRap1p). This suggests that Taz1p and TRF2 share common features in telomere regulation. To assess the roles of Taz1p in telomere-related functions in detail, we attempted to identify a protein(s) that interacts with Taz1p by using two-hybrid screening. Interestingly, the sequence analysis of a positive clone revealed a perfect match with a Rap1 homolog in S. pombe (spRap1), which showed a significant homology with scRap1p and hRap1p. Here we show that the spRap1 deficiency in haploid cells is viable, which results in increased telomere length regulation, disruption of telomere silencing, and aberrant meiosis (like the delta(taz1) mutant). This suggests that spRap1p might be recruited to the telomere by Taz1p and play crucial roles in telomere function. Interestingly, the delta(rap1) mutants in fission yeast are defective only for telomere silencing. Therefore, the role of spRap1p may be distinct from that of scRap1p, which is involved in the silencing at both the telomere and mating type locus. Our data, therefore, suggest that the regulation mechanisms of telomere in fission yeast resemble that of higher eukaryotic cells rather than the budding yeast.},
}
@article {pmid12018844,
year = {2002},
author = {Kim, JH and Lee, GE and Kim, JC and Lee, JH and Chung, IK},
title = {A novel telomere elongation in an adriamycin-resistant stomach cancer cell line with decreased telomerase activity.},
journal = {Molecules and cells},
volume = {13},
number = {2},
pages = {228-236},
pmid = {12018844},
issn = {1016-8478},
mesh = {Adenocarcinoma/genetics/*metabolism ; Antineoplastic Agents/pharmacology ; Chromosomes/genetics/metabolism ; Doxorubicin/*pharmacology ; *Drug Resistance, Neoplasm ; Humans ; Karyotyping ; Nucleic Acid Hybridization ; Protein Subunits/genetics/metabolism ; Stomach Neoplasms/genetics/*metabolism ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; Tumor Cells, Cultured ; },
abstract = {Actively dividing cells show progressive loss of telomeric DNA during successive rounds of replication due to end-replication problem. Telomere shortening has been proposed as a regulatory mechanism that controls the replicative capacity of primary cells before undergoing cellular senescence. In immortal cells including cancer, cellular senescence can be overcome by reactivation of telomerase or by a telomerase-independent mechanism for lengthening telomeres. In this work, we present a novel example of telomere elongation mechanism in a human stomach adenocarcinoma cell line which was selected for resistance to adriamycin. The resistant cell line (MKN/ADR) had long terminal restriction fragments (TRFs) of up to approximately 50 kb, while its parent cell line (MKN-45) had the TRFs, consisting of a smear extending from approximately 4 to approximately 25 kb. The very large TRFs in MKN/ADR cell line were proven to be telomeric by digestion with the exonuclease Bal31. When telomerase activity was examined using the PCR-based telomeric repeat amplification protocol (TRAP) assay, MKN/ADR cell line showed reduced activity to about 10% of that in MKN-45 cell line. The correlation between reduced telomerase activity and mRNA expression of telomerase subunits in MKN/ADR cell line was assessed by the reverse transcriptase-PCR analysis. The level of human telomerase reverse transcriptase (hTERT) mRNA was lower in MKN/ADR cell line than in MKN-45 cell line. This observation correlates with the finding that telomerase activity is reduced about 10-fold in MKN/ADR cell line. Reverse transcriptase-PCR analysis also revealed a close correlation between telomerase-associated protein (TP1) mRNA expression and telomerase activity in MKN/ADR cell line. In contrast, expression levels of human telomerase RNA (hTR) were identical in both MKN/ADR and MKN-45 cell lines. Taken together, these data suggest that telomeres in MKN/ADR cell line may be regulated through a novel mechanism other than telomerase. Although the basis for telomere elongation mechanism in MKN/ADR cell line is not yet understood, the occurrence of alternative mechanism for telomere elongation in drug-resistant cancer cells may have an important implication for use of telomerase inhibitors in human cancer treatment.},
}
@article {pmid12016510,
year = {2002},
author = {Manning, EL and Crossland, J and Dewey, MJ and Van Zant, G},
title = {Influences of inbreeding and genetics on telomere length in mice.},
journal = {Mammalian genome : official journal of the International Mammalian Genome Society},
volume = {13},
number = {5},
pages = {234-238},
doi = {10.1007/s003350020027},
pmid = {12016510},
issn = {0938-8990},
support = {R01 AG 16653/AG/NIA NIH HHS/United States ; T32 AG 00242/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Crosses, Genetic ; *Inbreeding ; Leukocytes/physiology ; Peromyscus/*genetics ; Telomere/*genetics/physiology ; },
abstract = {We measured telomere lengths of blood leukocytes in several inbred and outbred mammalian species, using a telomere-specific fluorescent probe and flow cytometry. Humans, non-human primates, and three outbred populations of Peromyscus mice (Peromyscus leucopus, Peromyscus maniculatus, and Peromyscus polionotus) have short telomeres. Two common strains of laboratory mice, C57BL/6J and DBA/2J, have telomeres several times longer than most other mammals surveyed. Moreover, the two inbred laboratory mouse strains display significantly different telomere lengths, suggesting the existence of strain-specific genetic determinants. To further examine the effects of inbreeding, we studied three Peromyscus leucopus inbred lines (GS109, GS16A1, and GS16B), all derived from the outbred P. leucopus stock. Telomeres of all three inbred lines are significantly lengthened relative to outbred P. leucopus, and the three lines display strain-specific significantly different telomere lengths, much like the C57BL/6J and DBA/2J strains of M. musculus. To further characterize the genetic inheritance of telomere length, we carried out several crosses to obtain hybrid F(1) mice between parental strains displaying the phenotype of long and short telomeres. In all F(1) mice assayed, peripheral blood leukocyte telomere length was intermediate to that of the parents. Additionally, we generated F(2) mice from a cross of the (P. leucopus outbred x GS16B)F(1). Based on the distribution of telomere length in the F(2) population, we determined that more than five loci contribute to telomere length regulation in Peromyscus. We concluded that inbreeding, through unknown mechanisms, results in the elongation of telomeres, and that telomere length for a given species and/or sub-strain is genetically determined by multiple segregating loci.},
}
@article {pmid12021043,
year = {2002},
author = {Miyashita, N and Shiga, K and Yonai, M and Kaneyama, K and Kobayashi, S and Kojima, T and Goto, Y and Kishi, M and Aso, H and Suzuki, T and Sakaguchi, M and Nagai, T},
title = {Remarkable differences in telomere lengths among cloned cattle derived from different cell types.},
journal = {Biology of reproduction},
volume = {66},
number = {6},
pages = {1649-1655},
doi = {10.1095/biolreprod66.6.1649},
pmid = {12021043},
issn = {0006-3363},
mesh = {Aging ; Animals ; Blotting, Southern ; *Cattle ; Cells, Cultured ; Cellular Senescence ; *Cloning, Organism ; Ear ; Epithelial Cells/ultrastructure ; Fallopian Tubes/ultrastructure ; Female ; Male ; Mammary Glands, Animal/ultrastructure ; Muscles/ultrastructure ; Nuclear Transfer Techniques ; Organ Specificity ; Skin/ultrastructure ; Telomere/*ultrastructure ; Tissue Donors ; },
abstract = {Regarding cloned animals, interesting questions have been raised as to whether cloning restores cellular senescence undergone by their donor cells and how long cloned animals will be able to live. Focusing our attention on differences in telomere lengths depending on the tissue, we had produced 14 cloned cattle by using nuclei of donor cells derived from muscle, oviduct, mammary, and ear skin. Here, we show remarkable variation in telomere lengths among them using Southern blot analysis with telomere-specific probe. Telomere lengths in cloned cattle derived from muscle cells of an old bull were longer than those of a donor animal but were within the variation in normal calves. On the other hand, those derived from oviductal and mammary epithelial cells of an equally old cow were surprisingly shorter than any found in control cattle. The telomere lengths of cloned cattle derived from fibroblasts and oviductal epithelial cells of younger cattle showed the former and the latter results, respectively. In both cases, however, less telomere erosion or telomere extension from nuclear transfer to birth in most cloned cattle was observed in comparison with telomere erosion from fertilization to birth in control cattle. Embryonic cell-cloned cattle and their offspring calves were also shown to have telomeres longer than those in age-matched controls. These observations indicate that cloning does not necessarily restore the telomere clock but, rather, that nuclear transfer itself may commonly trigger an elongation of telomeres, probably more or less according to donor cell type. Remarkable variations among cloned cattle are suggested to be caused by variation in telomere length among donor cells and more or less elongation of telomere lengths induced by cloning.},
}
@article {pmid12015307,
year = {2002},
author = {Ohya, T and Kawasaki, Y and Hiraga, S and Kanbara, S and Nakajo, K and Nakashima, N and Suzuki, A and Sugino, A},
title = {The DNA polymerase domain of pol(epsilon) is required for rapid, efficient, and highly accurate chromosomal DNA replication, telomere length maintenance, and normal cell senescence in Saccharomyces cerevisiae.},
journal = {The Journal of biological chemistry},
volume = {277},
number = {31},
pages = {28099-28108},
doi = {10.1074/jbc.M111573200},
pmid = {12015307},
issn = {0021-9258},
mesh = {Base Sequence ; Catalytic Domain ; Cellular Senescence ; DNA Polymerase II/chemistry/genetics/*metabolism ; DNA Primers ; *DNA Replication ; Diploidy ; Kinetics ; Mutation ; Protein Subunits ; Saccharomyces cerevisiae/enzymology/genetics/*physiology ; Sequence Deletion ; Telomere/*genetics/ultrastructure ; Temperature ; },
abstract = {Saccharomyces cerevisiae POL2 encodes the catalytic subunit of DNA polymerase epsilon. This study investigates the cellular functions performed by the polymerase domain of Pol2p and its role in DNA metabolism. The pol2-16 mutation has a deletion in the catalytic domain of DNA polymerase epsilon that eliminates its polymerase and exonuclease activities. It is a viable mutant, which displays temperature sensitivity for growth and a defect in elongation step of chromosomal DNA replication even at permissive temperatures. This mutation is synthetic lethal in combination with temperature-sensitive mutants or the 3'- to 5'-exonuclease-deficient mutant of DNA polymerase delta in a haploid cell. These results suggest that the catalytic activity of DNA polymerase epsilon participates in the same pathway as DNA polymerase delta, and this is consistent with the observation that DNA polymerases delta and epsilon colocalize in some punctate foci on yeast chromatids during S phase. The pol2-16 mutant senesces more rapidly than wild type strain and also has shorter telomeres. These results indicate that the DNA polymerase domain of Pol2p is required for rapid, efficient, and highly accurate chromosomal DNA replication in yeast.},
}
@article {pmid12007281,
year = {2001},
author = {Matsutani, N and Yokozaki, H and Tahara, E and Tahara, H and Kuniyasu, H and Kitadai, Y and Haruma, K and Chayama, K and Tahara, E and Yasui, W},
title = {Expression of MRE11 complex (MRE11, RAD50, NBS1) and hRap1 and its relation with telomere regulation, telomerase activity in human gastric carcinomas.},
journal = {Pathobiology : journal of immunopathology, molecular and cellular biology},
volume = {69},
number = {4},
pages = {219-224},
doi = {10.1159/000055946},
pmid = {12007281},
issn = {1015-2008},
mesh = {Aged ; Aged, 80 and over ; Carcinoma/*enzymology/genetics/pathology ; Cell Cycle Proteins/genetics/metabolism ; *DNA Repair ; DNA-Binding Proteins/genetics/*metabolism ; Endodeoxyribonucleases/genetics/*metabolism ; Exodeoxyribonucleases/genetics/metabolism ; Female ; Fungal Proteins/genetics/metabolism ; Humans ; Male ; Middle Aged ; *Nuclear Proteins ; RNA, Messenger/metabolism ; RNA, Neoplasm/analysis ; Reverse Transcriptase Polymerase Chain Reaction ; *Saccharomyces cerevisiae Proteins ; Shelterin Complex ; Stomach Neoplasms/*enzymology/genetics/pathology ; Telomerase/metabolism ; *Telomere ; *Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 1 ; },
abstract = {The MRE11 complex (MRE11, RAD50, NBS1) are required for the repair of DNA double-strand breaks and have another important function in regulating telomere length. The silent information regulator (Sir) proteins required for telomere position effect also bind telomeres. hRap1 protein is a human ortholog of yeast Rap1 which regulates telomere length by interacting with TRF2 and is recruited to telomeres by TRF2. We examined the expression of the MRE11 complex (MRE11, RAD50, NBS1), Sir2 and hRAP1 in 20 gastric carcinomas by reverse transcription polymerase chain reaction and then analyzed the relation between telomerase activity and other telomerase components such as human telomerase reverse transcriptase (TERT), human telomerase RNA component (hTR), human telomerase-associated protein (TEP1), telomeric repeat binding factor 1 (TRF1), TRF2- and TRF1-interacting, ankyrin-related ADP-ribose polymerase (tankyrase) as well as TRF1-interacting nuclear protein 2 (TIN2). Of twenty gastric carcinomas examined, 13 (65%), 14 (70%), 16 (80%), 12 (60%) and 13 (65%) expressed MRE11, RAD50, NBS1, Sir2 and hRap1 at higher levels than corresponding nonneoplastic gastric mucosa, respectively. No obvious correlation was observed between MRE11 complex expression and telomerase activity or expression of TERT, hTR, TEP1, tankyrase and TIN2. Carcinomas with high TRF1 expression expressed significantly higher levels of MRE11 and RAD50 than those with low TRF1 expression (p < 0.05). On the other hand, carcinomas with high TRF2 expression expressed significantly higher levels of MRE11, NBS1 and hRap1 than those with low TRF2 expression (p < 0.05). These results suggest that gastric carcinomas with high TRF1 and TRF2 expression may need a large quantity of the MRE11 complex. Moreover, gastric carcinomas with high TRF1 expression may require a large quantity of hRap1.},
}
@article {pmid12007004,
year = {2002},
author = {Cui, QH and Tang, CC and Huang, YG},
title = {[Effects of lead and selenium on telomere binding protein Rap1p, telomerase and telomeric DNA in Saccharomyces cerevisiae].},
journal = {Sheng wu hua xue yu sheng wu wu li xue bao Acta biochimica et biophysica Sinica},
volume = {34},
number = {2},
pages = {240-244},
pmid = {12007004},
issn = {0582-9879},
mesh = {Cell Division/drug effects ; DNA, Fungal/drug effects/genetics/metabolism ; Electrophoresis, Agar Gel ; Electrophoresis, Polyacrylamide Gel ; Lead/*pharmacology ; Saccharomyces cerevisiae/*drug effects/genetics/metabolism ; Saccharomyces cerevisiae Proteins/*drug effects/metabolism ; Selenium/*pharmacology ; Shelterin Complex ; Telomerase/*drug effects/metabolism ; Telomere/*drug effects/genetics/metabolism ; Telomere-Binding Proteins/*drug effects/metabolism ; Transcription Factors/*drug effects/metabolism ; },
abstract = {The effects on S.cerevisiae telomere binding protein Rap1p, telomerase and telomeric DNA by the lead (Pb), the selenium (Se) and Pb + Se were tested respectively in this study. Compared with the control S.cerevisiae after 100 gene rations, the mean telomere length shortened, Rap1p concentration was significantly lower and the secondary structure of Rap1p was disturbed, the telomerase activity was reduced in Pb treated cells. In Se treated cells, telomere length was significantly longer, and telomerase activity expressed higher. The concentration and secondary structure of Rap1p were similar to that of the control. Further more, the viability of Pb treated cells were significantly reduced while cells undergone other three treatments were similar and normal. These results suggest that Pb could damage Rap1p, reduce telomerase activity, resulting in the telomer length shortening and cell death. On the other hand, Se could protect and repair the damage in Rap1p and telomere caused by Pb to some extent.},
}
@article {pmid12004078,
year = {2002},
author = {Thornley, I and Freedman, MH},
title = {Telomeres, X-inactivation ratios, and hematopoietic stem cell transplantation in humans: a review.},
journal = {Stem cells (Dayton, Ohio)},
volume = {20},
number = {3},
pages = {198-204},
doi = {10.1634/stemcells.20-3-198},
pmid = {12004078},
issn = {1066-5099},
mesh = {Animals ; Dosage Compensation, Genetic ; Hematopoietic Stem Cell Transplantation/*adverse effects ; Hematopoietic Stem Cells/*physiology ; Humans ; Telomere ; },
abstract = {The marrow repopulating hematopoietic stem cells (HSCs) in an auto- or allograft represent a small fraction of the normal complement of HSCs, yet are required to reconstitute hematopoiesis and sustain it for the lifetime of the recipient. Such a burden imposes a "replicative stress" upon hematopoietic stem/progenitor cells. The finding of accelerated telomere shortening in hematopoietic stem cell transplant (HSCT) recipients raised the specter of accelerated hematopoietic aging. Here, we review the HSCT telomere literature and other studies of surrogate markers of HSC behavior conducted in human HSCT recipients. We present a paradigm for posttransplant hematopoietic reconstitution and speculate on the fate of HSCs in the human transplant setting.},
}
@article {pmid12000852,
year = {2002},
author = {Cawthon, RM},
title = {Telomere measurement by quantitative PCR.},
journal = {Nucleic acids research},
volume = {30},
number = {10},
pages = {e47},
pmid = {12000852},
issn = {1362-4962},
support = {Z01 AG000767/ImNIH/Intramural NIH HHS/United States ; AG13478/AG/NIA NIH HHS/United States ; K01 AG00767/AG/NIA NIH HHS/United States ; R29CA69421/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Base Sequence ; Child ; Child, Preschool ; DNA/genetics ; DNA Primers/genetics ; Electrophoresis, Agar Gel ; Female ; Humans ; Male ; Middle Aged ; Molecular Sequence Data ; Polymerase Chain Reaction/*methods ; Reproducibility of Results ; Telomere/*genetics ; },
abstract = {It has long been presumed impossible to measure telomeres in vertebrate DNA by PCR amplification with oligonucleotide primers designed to hybridize to the TTAGGG and CCCTAA repeats, because only primer dimer-derived products are expected. Here we present a primer pair that eliminates this problem, allowing simple and rapid measurement of telomeres in a closed tube, fluorescence-based assay. This assay will facilitate investigations of the biology of telomeres and the roles they play in the molecular pathophysiology of diseases and aging.},
}
@article {pmid11985666,
year = {2002},
author = {Lee, WW and Nam, KH and Terao, K and Yoshikawa, Y},
title = {Age-related telomere length dynamics in peripheral blood mononuclear cells of healthy cynomolgus monkeys measured by Flow FISH.},
journal = {Immunology},
volume = {105},
number = {4},
pages = {458-465},
pmid = {11985666},
issn = {0019-2805},
mesh = {Aging/*physiology ; Animals ; CD28 Antigens/analysis ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Flow Cytometry ; In Situ Hybridization, Fluorescence ; L-Selectin/analysis ; Leukocyte Common Antigens/analysis ; Macaca fascicularis/*immunology ; T-Lymphocyte Subsets/immunology/*ultrastructure ; Telomere/*ultrastructure ; },
abstract = {Telomere length is a good biomarker to study the cellular senescence as well as aging of an organism, because it regulates the replicative capacity of vertebrate somatic cells. To demonstrate age-related telomere length dynamics in the peripheral blood mononuclear cells (PBMC) of the cynomolgus monkey, we introduced a novel method of measuring telomere length by fluorescence in situ hybridization with a Peptide Nucleic Acid (PNA) labelled probe and flow cytometry (Flow FISH). A highly significant correlation was observed between the intensity of telomere-specific fluorescence by Flow FISH and telomere length by Southern blot analysis (R = 0.923, n = 22). The intensity of telomere fluorescence in PBMC significantly decreased with age in 55 monkeys aged from 0 to 34 years and this decrease corresponded to the loss of 62.7 base pairs per year (R = - 0.52, P < 0.00004). We also analysed the expression of naive cell-associated markers, CD28, CD62L and CD45RA/CD62L in T lymphocytes of 47 cynomolgus monkeys. An age-related increase in the CD28- subset was observed in CD8+ T lymphocytes in monkeys less than 11 years old and in CD4+ T lymphocytes in monkeys over 23 years old, respectively. The percentage of CD62L+ subsets was significantly decreased with age in both CD4+ (R = - 0.55) and CD8+ T lymphocytes (R = - 0.73). From the comparison of telomere length among PBMC, CD62L+ and CD62L- T lymphocytes, it was clearly evident that loss of naive subsets results in the shortening of telomere length in vivo. These results show that this method can be applicable to studying the turnover and precursor-progeny of PBMC in cynomolgus monkeys as an animal model of aging.},
}
@article {pmid11980732,
year = {2002},
author = {Benzacken, B and Carbillon, L and Dupont, C and Siffroi, JP and Monier-Gavelle, F and Bucourt, M and Uzan, M and Wolf, JP},
title = {Lack of submicroscopic rearrangements involving telomeres in reproductive failures.},
journal = {Human reproduction (Oxford, England)},
volume = {17},
number = {5},
pages = {1154-1157},
doi = {10.1093/humrep/17.5.1154},
pmid = {11980732},
issn = {0268-1161},
mesh = {Abortion, Habitual/*genetics ; Chromosome Aberrations ; Female ; *Gene Rearrangement ; Genetic Testing ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Male ; Pregnancy ; Prospective Studies ; Telomere/*genetics ; },
abstract = {BACKGROUND: It has been recognized that chromosomal abnormalities are one of the most important causes of the high mortality rate in human concepti. Among these abnormalities, the unbalanced transmission of a parental chromosomal rearrangement is frequently observed, and couples with a history of pregnancy losses are therefore referred for genetic counselling and to establish their karyotype. Unbalanced chromosomal rearrangements involving telomeres are emerging as an important cause of mental retardation and/or congenital malformations in humans. As suggested by several authors, they could also be responsible for recurrent miscarriages. The aim of this study was to screen cryptic chromosome abnormalities in couples referred to our laboratory for recurrent unexplained miscarriages.<br><br>METHODS AND RESULTS: Karyotyping was performed in 57 couples (114 patients). A detectable chromosomal abnormality was diagnosed in seven cases, thus limiting the analysis of telomeres to only 100 patients. Two different protocols were used according to the number of metaphases on slides. No telomeric chromosome abnormality was detected in our study.<br><br>CONCLUSION: The use of FISH telomeric probes is not of clinical interest in the systematic screening of couples with multiple miscarriages and should be performed only in those with a familial history of mental retardation and congenital malformations.},
}
@article {pmid11980718,
year = {2002},
author = {Espejel, S and Franco, S and Rodríguez-Perales, S and Bouffler, SD and Cigudosa, JC and Blasco, MA},
title = {Mammalian Ku86 mediates chromosomal fusions and apoptosis caused by critically short telomeres.},
journal = {The EMBO journal},
volume = {21},
number = {9},
pages = {2207-2219},
pmid = {11980718},
issn = {0261-4189},
mesh = {Animals ; *Antigens, Nuclear ; Apoptosis/*physiology ; *Chromosome Aberrations ; Chromosomes/metabolism ; *DNA Helicases ; DNA-Binding Proteins/deficiency/metabolism/*physiology ; Ku Autoantigen ; Male ; Mice ; Mice, Knockout ; Nuclear Proteins/deficiency/*physiology ; Spermatozoa/physiology ; Telomerase/deficiency/*physiology ; Telomere/metabolism/*physiology ; },
abstract = {Here we analyze the functional interaction between Ku86 and telomerase at the mammalian telomere by studying mice deficient for both proteins. We show that absence of Ku86 prevents the end-to-end chromosomal fusions that result from critical telomere shortening in telomerase-deficient mice. In addition, Ku86 deficiency rescues the male early germ cell apoptosis triggered by short telomeres in these mice. Together, these findings define a role for Ku86 in mediating chromosomal instability and apoptosis triggered by short telomeres. In addition, we show here that Ku86 deficiency results in telomerase-dependent telomere elongation and in the fusion of random pairs of chromosomes in telomerase-proficient cells, suggesting a model in which Ku86 keeps normal-length telomeres less accessible to telomerase-mediated telomere lengthening and to DNA repair activities.},
}
@article {pmid11976182,
year = {2002},
author = {Saretzki, G and Von Zglinicki, T},
title = {Replicative aging, telomeres, and oxidative stress.},
journal = {Annals of the New York Academy of Sciences},
volume = {959},
number = {},
pages = {24-29},
doi = {10.1111/j.1749-6632.2002.tb02079.x},
pmid = {11976182},
issn = {0077-8923},
mesh = {Aging/genetics/*physiology ; Antioxidants/metabolism ; Cell Division/*physiology ; Dementia/genetics/physiopathology ; Humans ; *Oxidative Stress ; Telomere/*physiology ; },
abstract = {Aging is a very complex phenomenon, both in vivo and in vitro. Free radicals and oxidative stress have been suggested for a long time to be involved in or even to be causal for the aging process. Telomeres are special structures at the end of chromosomes. They shorten during each round of replication and this has been characterized as a mitotic counting mechanism. Our experiments show that the rate of telomere shortening in vitro is modulated by oxidative stress as well as by differences in antioxidative defence capacity between cell strains. In vivo we found a strong correlation between short telomeres in blood lymphocytes and the incidence of vascular dementia. These data suggest that parameters that characterise replicative senescence in vitro offer potential for understanding of, and intervention into, the aging process in vivo.},
}
@article {pmid11971978,
year = {2002},
author = {Ancelin, K and Brunori, M and Bauwens, S and Koering, CE and Brun, C and Ricoul, M and Pommier, JP and Sabatier, L and Gilson, E},
title = {Targeting assay to study the cis functions of human telomeric proteins: evidence for inhibition of telomerase by TRF1 and for activation of telomere degradation by TRF2.},
journal = {Molecular and cellular biology},
volume = {22},
number = {10},
pages = {3474-3487},
pmid = {11971978},
issn = {0270-7306},
mesh = {Bacterial Proteins/genetics/metabolism ; Cell Line ; Chromosomes/genetics/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; *Escherichia coli Proteins ; Humans ; In Situ Hybridization, Fluorescence ; Lac Repressors ; Nuclear Proteins/metabolism ; Recombinant Fusion Proteins/metabolism ; Repressor Proteins/genetics/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1 ; Telomeric Repeat Binding Protein 2 ; Transfection ; },
abstract = {We investigated the control of telomere length by the human telomeric proteins TRF1 and TRF2. To this end, we established telomerase-positive cell lines in which the targeting of these telomeric proteins to specific telomeres could be induced. We demonstrate that their targeting leads to telomere shortening. This indicates that these proteins act in cis to repress telomere elongation. Inhibition of telomerase activity by a modified oligonucleotide did not further increase the pace of telomere erosion caused by TRF1 targeting, suggesting that telomerase itself is the target of TRF1 regulation. In contrast, TRF2 targeting and telomerase inhibition have additive effects. The possibility that TRF2 can activate a telomeric degradation pathway was directly tested in human primary cells that do not express telomerase. In these cells, overexpression of full-length TRF2 leads to an increased rate of telomere shortening.},
}
@article {pmid11966767,
year = {2002},
author = {Søndergaard, SR and Essen, MV and Schjerling, P and Ullum, H and Pedersen, BK},
title = {Proliferation and telomere length in acutely mobilized blood mononuclear cells in HIV infected patients.},
journal = {Clinical and experimental immunology},
volume = {127},
number = {3},
pages = {499-506},
pmid = {11966767},
issn = {0009-9104},
mesh = {Adult ; Antiretroviral Therapy, Highly Active ; Blood ; CD4 Lymphocyte Count ; CD4-Positive T-Lymphocytes/ultrastructure ; CD8-Positive T-Lymphocytes/ultrastructure ; Cell Movement ; Cells, Cultured ; Epinephrine/pharmacology ; Female ; HIV Infections/blood/diagnosis/drug therapy/*immunology ; Humans ; Kinetics ; *Lymphocyte Activation ; Male ; Middle Aged ; T-Lymphocytes/*immunology/*ultrastructure ; Telomere/*ultrastructure ; Viral Load ; },
abstract = {The aim of the study was to investigate the mobilization of T cells in response to a stressful challenge (adrenalin stimulation), and to access T cells resided in the peripheral lymphoid organs in HIV infected patients. Seventeen patients and eight HIV seronegative controls received an adrenalin infusion for 1 h. Blood was sampled before, during and 1 h after adrenalin infusion. Proliferation and mean telomere restriction fragment length (telomeres) of blood mononuclear cells (BMNC) and purified CD8+ and CD4+ cells were investigated at all time points. In patients, the proliferation to pokeweed mitogens (PWM) was lower and decreased more during adrenalin infusion. After adrenalin infusion the proliferation to PWM was restored only in the controls. In all subjects telomeres in CD4+ cells declined during adrenalin infusion. Additionally, the patients had shortened telomeres in their CD8+ cells, and particularly HAART treated patients had shortened telomeres in all cell-subtypes. The finding that patients mobilized cells with an impaired proliferation to PWM during and after adrenalin infusion has possible clinical relevance for HIV infected patients during pathological stressful conditions, such as sepsis, surgery and burns. However, this study did not find a correlation between impaired proliferation and telomeres. It is concluded that physiological stress further aggravates the HIV-induced immune deficiency.},
}
@article {pmid11959106,
year = {2002},
author = {Serra, V and von Zglinicki, T},
title = {Human fibroblasts in vitro senesce with a donor-specific telomere length.},
journal = {FEBS letters},
volume = {516},
number = {1-3},
pages = {71-74},
doi = {10.1016/s0014-5793(02)02504-8},
pmid = {11959106},
issn = {0014-5793},
mesh = {Adult ; Aged ; Aged, 80 and over ; Cell Division ; Cellular Senescence/genetics/*physiology ; Fibroblasts/cytology/ultrastructure ; Humans ; In Vitro Techniques ; Middle Aged ; Models, Biological ; Telomere/genetics/*ultrastructure ; },
abstract = {In human fibroblasts, replicative senescence, telomere length and donor age are closely interrelated. We analyzed these relationships for fibroblast strains from 14 healthy human donors in the age range of 28-90 years. In vitro replicative capacity was correlated more closely with donor age than with telomere length ex vivo, especially for healthy donors. Telomere length at senescence was as variable as at cell explantation and increased with donor age. The data suggest a donor-specific, age-dependent regulation of the telomere length threshold that triggers senescence in human fibroblasts.},
}
@article {pmid11956226,
year = {2002},
author = {Carlton, PM and Cande, WZ},
title = {Telomeres act autonomously in maize to organize the meiotic bouquet from a semipolarized chromosome orientation.},
journal = {The Journal of cell biology},
volume = {157},
number = {2},
pages = {231-242},
pmid = {11956226},
issn = {0021-9525},
support = {GM R01 46547/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Nucleus/metabolism ; *Cell Polarity ; Centromere/metabolism ; *Chromosome Pairing ; Chromosomes/genetics/*metabolism ; In Situ Hybridization, Fluorescence ; *Meiosis ; Ring Chromosomes ; Signal Transduction ; Telomere/*metabolism ; Zea mays/*cytology/genetics ; },
abstract = {During meiosis, chromosomes undergo large-scale reorganization to allow pairing between homologues, which is necessary for recombination and segregation. In many organisms, pairing of homologous chromosomes is accompanied, and possibly facilitated, by the bouquet, the clustering of telomeres in a small region of the nuclear periphery. Taking advantage of the cytological accessibility of meiosis in maize, we have characterized the organization of centromeres and telomeres throughout meiotic prophase. Our results demonstrate that meiotic centromeres are polarized prior to the bouquet stage, but that this polarization does not contribute to bouquet formation. By examining telocentric and ring chromosomes, we have tested the cis-acting requirements for participation in the bouquet. We find that: (a) the healed ends of broken chromosomes, which contain telomere repeats, can enter the bouquet; (b) ring chromosomes enter the bouquet, indicating that terminal position on a chromosome is not necessary for telomere sequences to localize to the bouquet; and (c) beginning at zygotene, the behavior of telomeres is dominant over any centromere-mediated chromosome behavior. The results of this study indicate that specific chromosome regions are acted upon to determine the organization of meiotic chromosomes, enabling the bouquet to form despite large-scale changes in chromosome architecture.},
}
@article {pmid11953893,
year = {2002},
author = {Tian, XX and Pang, JC and Zheng, J and Chen, J and To, SS and Ng, HK},
title = {Antisense epidermal growth factor receptor RNA transfection in human glioblastoma cells down-regulates telomerase activity and telomere length.},
journal = {British journal of cancer},
volume = {86},
number = {8},
pages = {1328-1332},
pmid = {11953893},
issn = {0007-0920},
mesh = {Animals ; Blotting, Southern ; *Down-Regulation ; ErbB Receptors/biosynthesis/genetics/*metabolism ; Glioblastoma/*enzymology/*genetics/metabolism/pathology ; Humans ; Mice ; Mice, Nude ; Neoplasm Transplantation ; RNA, Antisense/genetics/*metabolism ; RNA, Messenger/genetics/metabolism ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/genetics/*metabolism ; Transfection ; Tumor Cells, Cultured ; },
abstract = {Epidermal growth factor receptor is overexpressed and/or amplified in up to 50% of glioblastomas, suggesting an important role of this gene in glial tumorigenesis and progression. In the present study we demonstrated that epidermal growth factor receptor is involved in regulation of telomerase activity in glioblastoma. Antisense-epidermal growth factor receptor approach was used to inhibit epidermal growth factor receptor expression of glioblastoma U87MG cells. Telomerase activity in antisense-epidermal growth factor receptor cells decreased by up to 54 folds compared with control cells. Moreover, the telomere lengths of antisense-epidermal growth factor receptor cells were shortened. In addition, the tumorigenicity of antisense-epidermal growth factor receptor cells was significantly inhibited. Taken together, there were strong correlations between tumorigenicity and epidermal growth factor receptor expression levels, and between tumorigenicity and telomerase activity. These results provide evidence that epidermal growth factor receptor plays an important role in the regulation of telomerase activity of glioma cells. Our findings provide new insights into both the biological functions of epidermal growth factor receptor and the regulation of telomerase activity. The inhibition of telomerase activity triggered by antisense-epidermal growth factor receptor treatment may reflect yet another mechanism of antisense-epidermal growth factor receptor approach in tumour suppression.},
}
@article {pmid11952539,
year = {2002},
author = {Miracco, C and Margherita De Santi, M and Schürfeld, K and Santopietro, R and Lalinga, AV and Fimiani, M and Biagioli, M and Brogi, M and De Felice, C and Luzi, P and Andreassi, L},
title = {Quantitative in situ evaluation of telomeres in fluorescence in situ hybridization-processed sections of cutaneous melanocytic lesions and correlation with telomerase activity.},
journal = {The British journal of dermatology},
volume = {146},
number = {3},
pages = {399-408},
doi = {10.1046/j.1365-2133.2002.04600.x},
pmid = {11952539},
issn = {0007-0963},
mesh = {Case-Control Studies ; Humans ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Melanoma/enzymology/secondary/ultrastructure ; Neoplasm Proteins/metabolism ; Nevus/enzymology/*ultrastructure ; Nevus, Pigmented/enzymology/ultrastructure ; Skin Neoplasms/enzymology/secondary/*ultrastructure ; Telomerase/metabolism ; Telomere/*ultrastructure ; },
abstract = {BACKGROUND: Telomere length is correlated with cellular ageing and immortalization processes. In some human cancers telomere length measurement has proved to be of diagnostic and prognostic value. Results comparable with the traditional terminal restriction fragment length determination by Southern blotting have been obtained in metaphase and interphase cells in some studies by fluorescence in situ hybridization (FISH) analysis; FISH additionally allows for the quantification of telomeres at the cellular level.<br><br>OBJECTIVES: In this study, 32 melanocytic lesions were analysed by FISH, aiming at investigating possible telomere differences among various benign and malignant lesions and correlation with telomerase activity (TA) level.<br><br>METHODS: FISH was performed on paraffin sections from six common naevi, eight Spitz naevi, 12 melanomas, six melanoma metastases and nine control samples of normal skin. Telomere mean maximum diameter (Feret max), area and number per nuclear area were calculated by image analysis on fluorescent images elaborated through KS400 and in situ imaging system (ISIS) for FISH analysis programs. Mean TA level was also calculated in all lesions and correlated with telomere parameters.<br><br>RESULTS: Telomere number per nuclear area was significantly lower in melanomas and metastases than in benign common and Spitz naevi and in control skin (7 small middle dot24 +/- 3.3; 6.11 +/- 3 vs. 14.46 +/- 5.6; 16.92 +/- 7.8; and 12.59 +/- 3.4, respectively; P < 0 .001). No significant differences were found for the other telomere parameters. In common and Spitz naevi, telomere number was positively correlated with Feret max (P = 0.046 and P < 0.0001, respectively). TA was significantly higher in melanomas and metastases than in the other groups (70.18 +/- 25.2; 105.07 +/- 30 vs. 2.16 +/- 2.4; 2 .99 +/- 2.1; 2 +/- 1.2, respectively; P< or = 0. 001) and it was inversely correlated with telomere number per nuclear area in melanomas (P = 0.0041). No other significant correlations were found.<br><br>CONCLUSIONS: Encouraging results have been obtained from quantitative telomere evaluation in the diagnosis of melanocytic lesions, although an analysis of a larger number of cases would be necessary to provide more reliable data. An extreme shortening of some telomeres probably results in the decrease of telomeric signals and the lower mean number of detectable telomeres in melanomas and metastases. In melanomas, telomere number per nuclear area is also inversely correlated with TA levels. Quantitative FISH of melanocytic lesions could give more specific information at the cellular level in telomere and telomerase fields of investigation.},
}
@article {pmid11951609,
year = {2002},
author = {Pommier, JP and Sabatier, L},
title = {Telomere length distribution. Digital image processing and statistical analysis.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {191},
number = {},
pages = {33-63},
doi = {10.1385/1-59259-189-2:33},
pmid = {11951609},
issn = {1064-3745},
mesh = {Alu Elements ; Animals ; Chromosome Banding/methods ; Chromosome Painting/methods ; Data Display ; Densitometry ; Humans ; Image Processing, Computer-Assisted/instrumentation/*methods ; *In Situ Hybridization, Fluorescence ; Karyotyping ; Microscopy, Fluorescence/instrumentation/methods ; Polymerase Chain Reaction ; Software ; Telomere/*ultrastructure ; },
}
@article {pmid11951601,
year = {2002},
author = {Scherthan, H},
title = {Detection of chromosome ends by telomere FISH.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {191},
number = {},
pages = {13-31},
doi = {10.1385/1-59259-189-2:13},
pmid = {11951601},
issn = {1064-3745},
mesh = {Animals ; Chromosomes/ultrastructure ; Humans ; Immunoblotting/instrumentation/methods ; In Situ Hybridization, Fluorescence/instrumentation/*methods ; Indicators and Reagents ; Metaphase ; Nucleic Acid Denaturation ; Oligonucleotide Probes ; Preservation, Biological ; Protein Denaturation ; Staining and Labeling ; Telomere/chemistry/*ultrastructure ; Vertebrates/genetics ; },
}
@article {pmid11951598,
year = {2002},
author = {Bibby, MC},
title = {Introduction to telomeres and telomerase.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {191},
number = {},
pages = {1-12},
doi = {10.1385/1-59259-189-2:01},
pmid = {11951598},
issn = {1064-3745},
mesh = {Animals ; Cell Cycle ; Cell Division ; Cell Transformation, Neoplastic/genetics ; Cellular Senescence ; Chromosomes/ultrastructure ; DNA Replication/physiology ; Eukaryotic Cells/enzymology ; Germ Cells/enzymology ; Humans ; Mammals/genetics ; Mice ; Mice, Knockout ; Neoplasm Proteins/antagonists &amp; inhibitors/physiology ; Neoplasms/enzymology/genetics ; *Telomerase/antagonists &amp; inhibitors/chemistry/physiology ; *Telomere ; },
}
@article {pmid11948462,
year = {2002},
author = {Yan, P and Benhattar, J and Coindre, JM and Guillou, L},
title = {Telomerase activity and hTERT mRNA expression can be heterogeneous and does not correlate with telomere length in soft tissue sarcomas.},
journal = {International journal of cancer},
volume = {98},
number = {6},
pages = {851-856},
doi = {10.1002/ijc.10285},
pmid = {11948462},
issn = {0020-7136},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Child, Preschool ; DNA-Binding Proteins ; Gene Expression Regulation, Neoplastic ; Humans ; Immunoenzyme Techniques ; Infant ; Middle Aged ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Sarcoma/enzymology/*genetics/pathology ; Soft Tissue Neoplasms/enzymology/*genetics/pathology ; Telomerase/*genetics/metabolism ; Telomere/*chemistry ; Transcription, Genetic ; },
abstract = {In a previous study, we showed that telomerase activity (TA) and human telomerase reverse transcriptase (hTERT) mRNA expression were undetectable in benign mesenchymal lesions and low-grade soft tissue sarcomas (STSs), but detectable in about 50% of intermediate-/high-grade STSs. We wondered if this lack of TA or hTERT mRNA expression could be related to the tumor sample examined and if there was a relationship between the former 2 parameters and telomere length. Two separate tumor samples from 37 STSs were examined for telomerase activity, using the telomerase repeat amplification protocol (TRAP) assay and for hTERT mRNA expression, using RT-PCR. Telomere length was determined in each tumor sample, using the terminal restriction fragments (TRF) technique. Significant variations in telomere length, TA and hTERT mRNA expression between 2 samples of the same tumor were observed in 27%, 11% and 27% of STSs, respectively. Telomere length did not correlate with TA or hTERT mRNA expression. Despite great intratumoral heterogeneity in telomere length, short and long telomeres were more often seen in the low/intermediate-grade and high-grade STS categories, respectively. Few STSs that showed a TRF pattern suggestive of alternative lengthening of telomeres (ALT) may contain ALT subpopulations.},
}
@article {pmid11943711,
year = {2002},
author = {Meeker, AK and Gage, WR and Hicks, JL and Simon, I and Coffman, JR and Platz, EA and March, GE and De Marzo, AM},
title = {Telomere length assessment in human archival tissues: combined telomere fluorescence in situ hybridization and immunostaining.},
journal = {The American journal of pathology},
volume = {160},
number = {4},
pages = {1259-1268},
pmid = {11943711},
issn = {0002-9440},
support = {P50 CA058236/CA/NCI NIH HHS/United States ; P50CA58236/CA/NCI NIH HHS/United States ; CA84997/CA/NCI NIH HHS/United States ; DK07552/DK/NIDDK NIH HHS/United States ; R01 CA084997/CA/NCI NIH HHS/United States ; K08CA78588/CA/NCI NIH HHS/United States ; T32 DK007552/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; Dogs ; Fluorescent Antibody Technique ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Rats ; Telomere/*genetics ; },
abstract = {A method was developed to assess human telomere lengths at the individual cell level in tissue sections from standard formalin-fixed paraffin-embedded tissues. We coupled this method with immunofluorescence to allow the simultaneous identification of specific cell types. Validation of this in situ quantification method showed excellent agreement with the commonly used telomere repeat fragment-Southern blot method. The assay requires very few cells (approximately 10 to 15). Thus, small tissue samples, including clinical biopsies, can be easily accommodated. In addition, the cells under study need not be actively cycling and there is no requirement for tissue disaggregation or cell culture. This method provides a more accurate assessment of telomere lengths than Southern blotting because confounding contributions from undesired cell types within tissue samples are avoided. Using this technique, we were able to perform the first comparison of relative telomere lengths in matched tumor versus normal epithelial cells within archival human prostate tissues.},
}
@article {pmid11942411,
year = {2002},
author = {Zhang, RG and Zhang, RP and Wang, XW and Xie, H},
title = {Effects of cisplatin on telomerase activity and telomere length in BEL-7404 human hepatoma cells.},
journal = {Cell research},
volume = {12},
number = {1},
pages = {55-62},
doi = {10.1038/sj.cr.7290110},
pmid = {11942411},
issn = {1001-0602},
mesh = {Antineoplastic Agents/*therapeutic use ; Apoptosis ; Carcinoma, Hepatocellular/drug therapy/*enzymology/genetics/pathology ; Cell Division/drug effects ; Cisplatin/*pharmacology/therapeutic use ; DNA/drug effects ; DNA-Binding Proteins ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/*pharmacology ; G2 Phase/drug effects ; Humans ; Telomerase/analysis/*antagonists &amp; inhibitors/drug effects/genetics/metabolism ; Telomere/drug effects ; Time Factors ; Tumor Cells, Cultured ; },
abstract = {Telomerase activity was inhibited in a dose and time-dependent manner with the treatment of cisplatin for 24, 48, or 72 h in a concentration ranged from 0.8 to 50 microM in BEL-7404 human hepatoma cells. There were no changes in expression pattern of three telomerase subunits, its catalytic reverse transcriptase subunit (hTERT), its RNA component (hTR) or the associated protein subunit (TP1), after cisplatin treated for 72 h with indicated concentrations. Mean telomere lengths were decreased by the cisplatin treatment. Cell growth inhibition and cell cycle accumulation in G2/M phase were found to be correlated with telomerase inhibition in the present study, but percentages of cell apoptosis did not change markedly during the process.},
}
@article {pmid11942406,
year = {2002},
author = {Mu, J and Wei, LX},
title = {Telomere and telomerase in oncology.},
journal = {Cell research},
volume = {12},
number = {1},
pages = {1-7},
doi = {10.1038/sj.cr.7290104},
pmid = {11942406},
issn = {1001-0602},
mesh = {Animals ; Antineoplastic Agents/therapeutic use ; Cell Division/drug effects ; Cell Transformation, Neoplastic/*genetics ; Cellular Senescence/genetics ; Chromosomes/enzymology ; DNA/chemistry ; Disease Progression ; Humans ; Neoplasms/diagnosis/*enzymology/genetics/physiopathology/therapy ; Oligonucleotides, Antisense/therapeutic use ; Telomerase/analysis/chemistry/drug effects/*metabolism ; Telomere/chemistry/*metabolism ; },
abstract = {Shortening of the telomeric DNA at the chromosome ends is presumed to limit the lifespan of human cells and elicit a signal for the onset of cellular senescence. To continually proliferate across the senescent checkpoint, cells must restore and preserve telomere length. This can be achieved by telomerase, which has the reverse transcriptase activity. Telomerase activity is negative in human normal somatic cells but can be detected in most tumor cells. The enzyme is proposed to be an essential factor in cell immortalization and cancer progression. In this review we discuss the structure and function of telomere and telomerase and their roles in cell immortalization and oncogenesis. Simultaneously the experimental studies of telomerase assays for cancer detection and diagnosis are reviewed. Finally, we discuss the potential use of inhibitors of telomerase in anti-cancer therapy.},
}
@article {pmid11940677,
year = {2002},
author = {Savitsky, M and Kravchuk, O and Melnikova, L and Georgiev, P},
title = {Heterochromatin protein 1 is involved in control of telomere elongation in Drosophila melanogaster.},
journal = {Molecular and cellular biology},
volume = {22},
number = {9},
pages = {3204-3218},
pmid = {11940677},
issn = {0270-7306},
mesh = {Animals ; Base Sequence ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; Chromosome Aberrations ; Crosses, Genetic ; DNA/genetics/metabolism ; *DNA Transposable Elements ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster/*genetics ; Female ; Gene Conversion ; Gene Duplication ; Gene Expression Regulation ; *Gene Products, gag ; Genes, Insect/genetics ; Insect Proteins/genetics/metabolism ; Male ; Mutation ; Physical Chromosome Mapping ; Telomere/genetics/*metabolism ; Templates, Genetic ; },
abstract = {Telomeres of Drosophila melanogaster contain arrays of the retrotransposon-like elements HeT-A and TART. Their transposition to broken chromosome ends has been implicated in chromosome healing and telomere elongation. We have developed a genetic system which enables the determination of the frequency of telomere elongation events and their mechanism. The frequency differs among lines with different genotypes, suggesting that several genes are in control. Here we show that the Su(var)2-5 gene encoding heterochromatin protein 1 (HP1) is involved in regulation of telomere length. Different Su(var)2-5 mutations in the heterozygous state increase the frequency of HeT-A and TART attachment to the broken chromosome end by more than a hundred times. The attachment occurs through either HeT-A/TART transposition or recombination with other telomeres. Terminal DNA elongation by gene conversion is greatly enhanced by Su(var)2-5 mutations only if the template for DNA synthesis is on the same chromosome but not on the homologous chromosome. The Drosophila lines bearing the Su(var)2-5 mutations maintain extremely long telomeres consisting of HeT-A and TART for many generations. Thus, HP1 plays an important role in the control of telomere elongation in D. melanogaster.},
}
@article {pmid11938440,
year = {2002},
author = {Mignon-Ravix, C and Depetris, D and Delobel, B and Croquette, MF and Mattei, MG},
title = {A human interstitial telomere associates in vivo with specific TRF2 and TIN2 proteins.},
journal = {European journal of human genetics : EJHG},
volume = {10},
number = {2},
pages = {107-112},
doi = {10.1038/sj.ejhg.5200775},
pmid = {11938440},
issn = {1018-4813},
mesh = {Chromosome Aberrations ; DNA-Binding Proteins/genetics/*metabolism ; Dosage Compensation, Genetic ; Female ; Fluorescent Antibody Technique ; Humans ; Infant, Newborn ; Repetitive Sequences, Nucleic Acid ; Telomere/genetics/*metabolism ; *Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 1 ; Telomeric Repeat Binding Protein 2 ; },
abstract = {Mammalian telomeres are composed of long arrays of TTAGGG repeats that form a nucleoprotein complex which protects the chromosome ends. Human telomere function is known to require two TTAGGG repeat factors, TRF1 and TRF2, and several interacting proteins, but the mechanism by which the DNA/protein complex prevents end to end fusion in vivo has not been elucidated. In order to better understand the role of specific telomere-associated proteins in the organisation of chromosome ends, we have studied a patient with a rare chromosome rearrangement that has given rise to an interstitial telomere. Using specific antibodies and immuno-FISH on unfixed metaphase chromosomes, we show that the proteins TRF2 and TIN2 (TIN2 interacts with TRF1) co-localise with the interstitial TTAGGG repeats. Our results demonstrate, for the first time in humans, that TRF2 and TIN2 proteins associate with interstitial duplex TTAGGG repeats, in vivo. They confirm that double stranded-telomeric repeats, even when complexed with specific proteins, are not sufficient to create a functional telomere. Finally, they suggest a possible role for proteins in stabilising interstitial TTAGGG repeats.},
}
@article {pmid11929832,
year = {2002},
author = {Boklan, J and Nanjangud, G and MacKenzie, KL and May, C and Sadelain, M and Moore, MA},
title = {Limited proliferation and telomere dysfunction following telomerase inhibition in immortal murine fibroblasts.},
journal = {Cancer research},
volume = {62},
number = {7},
pages = {2104-2114},
pmid = {11929832},
issn = {0008-5472},
support = {P01-CA59350/CA/NCI NIH HHS/United States ; U19-CA67842/CA/NCI NIH HHS/United States ; },
mesh = {3T3 Cells ; Adenoviridae/genetics ; Animals ; Apoptosis/genetics/physiology ; Cell Cycle/genetics/physiology ; Cell Division/genetics/physiology ; DNA-Binding Proteins ; Fibroblasts/cytology/*enzymology/physiology ; Humans ; Mice ; Telomerase/*antagonists &amp; inhibitors/genetics ; Telomere/*physiology ; Transduction, Genetic ; },
abstract = {Telomerase is a ribonucleoprotein enzyme that functions to maintain telomeres, the terminal DNA that protects chromosomal integrity, regulating cellular replicative life span. Telomerase is not expressed in most normal human somatic cells but is active in stabilizing telomeres of certain self-renewing cell populations and most malignant cells, making the enzyme an appealing target for anticancer therapy. We describe here a novel cross-species approach to telomerase inhibition. Ectopic expression of the human telomerase catalytic reverse transcriptase component in murine cells inhibited endogenous murine telomerase activity. Using this approach, telomerase inhibition in immortal murine fibroblasts resulted in critical telomere shortening, leading to slowed proliferation, abnormal morphology, altered cell cycle, and telomere dysfunction with cytogenetic instability, followed by apoptotic cell death. Subpopulations of two telomerase-inhibited clones escaped widespread apoptosis, showing proliferative recovery in culture despite persistently inhibited telomerase activity with progressive telomere shortening and dysfunction. This study, by targeting immortal murine cells for telomerase inhibition, demonstrates the importance of telomerase to murine cell immortalization and telomere maintenance. Moreover, the murine model used here should prove useful in further evaluating telomerase inhibition as an anticancer therapy.},
}
@article {pmid11927518,
year = {2002},
author = {Minamino, T and Miyauchi, H and Yoshida, T and Ishida, Y and Yoshida, H and Komuro, I},
title = {Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction.},
journal = {Circulation},
volume = {105},
number = {13},
pages = {1541-1544},
doi = {10.1161/01.cir.0000013836.85741.17},
pmid = {11927518},
issn = {1524-4539},
mesh = {Cells, Cultured ; *Cellular Senescence ; Coronary Artery Disease/etiology/*pathology ; Coronary Vessels/pathology ; Endothelium, Vascular/*pathology/*physiology ; Humans ; Intercellular Adhesion Molecule-1/metabolism ; Nitric Oxide Synthase/metabolism ; Nitric Oxide Synthase Type III ; Telomerase/physiology ; Telomere/*physiology ; beta-Galactosidase/analysis ; },
abstract = {BACKGROUND: The functional changes associated with cellular senescence may be involved in human aging and age-related vascular disorders. We have shown the important role of telomere and telomerase in vascular cell senescence in vitro. Progressive telomere shortening in vivo has been observed in the regions susceptible to atherosclerosis, implying contributions to atherogenesis. However, whether senescent vascular cells are present in the vasculature and contribute to the pathogenesis of atherosclerosis remains unclear.<br><br>METHODS AND RESULTS: Senescence-associated beta-galactosidase (beta-gal) activity was examined in the coronary arteries and the internal mammary arteries retrieved from autopsied individuals who had had ischemic heart diseases. Strong beta-gal stainings were observed in atherosclerotic lesions of the coronary arteries but not in the internal mammary arteries. An immunohistochemical analysis using anti-factor VIII antibody demonstrated that beta-gal stained cells are vascular endothelial cells. To determine whether endothelial cell senescence causes endothelial dysfunction, we induced senescence in human aortic endothelial cells (HAECs) by inhibiting telomere function and examined the expression of intercellular adhesion molecule (ICAM)-1 and endothelial nitric oxide synthase (eNOS) activity. Senescent HAECs exhibited increased ICAM-1 expression and decreased eNOS activity, both of which are alterations implicated in atherogenesis. In contrast, introduction of telomerase catalytic component significantly extended the life span and inhibited the functional alterations associated with senescence in HAECs.<br><br>CONCLUSIONS: Vascular endothelial cells with senescence-associated phenotypes are present in human atherosclerotic lesions, and endothelial cell senescence induced by telomere shortening may contribute to atherogenesis.},
}
@article {pmid11925625,
year = {2002},
author = {Shen, ZY and Xu, LY and Li, EM and Cai, WJ and Chen, MH and Shen, J and Zeng, Y},
title = {Telomere and telomerase in the initial stage of immortalization of esophageal epithelial cell.},
journal = {World journal of gastroenterology},
volume = {8},
number = {2},
pages = {357-362},
pmid = {11925625},
issn = {1007-9327},
mesh = {Apoptosis/physiology ; Cell Division/physiology ; Cell Line ; Cell Size ; *Cell Transformation, Neoplastic ; Epithelial Cells/cytology/*metabolism ; Esophagus/*cytology ; Humans ; In Situ Nick-End Labeling ; Papillomaviridae/genetics/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {AIM: To search for the biomarker of cellular immortalization, the telomere length, telomerase activity and its subunits in cultured epithelial cells of human fetal esophagus in the process of immortalization.<br><br>METHODS: The transgenic cell line of human fetal esophageal epithelium (SHEE) was established with E(6)E(7) genes of human papillomavirus (HPV) type 18 in our laboratory. Morphological phenotype of cultured SHEE cells from the 6th to 30th passages, was examined by phase contrast microscopy, the telomere length was assayed by Southern blot method, and the activity of telomerase was analyzed by telomeric repeat amplification protocol (TRAP). Expressions of subunits of telomerase, hTR and hTERT, were assessed by RT-PCR. DNA content in cell cycle was detected by flow cytometry. The cell apoptosis was examined by electron microscopy (EM) and TUNEL label.<br><br>RESULTS: SHEE cells from the 6th to 10th passages showed cellular proliferation with a good differentiation. From the 12th to the 16th passages, many senescent and apoptotic cells appeared, and the telomere length sharply shortened from 23kb to 17kb without expression of hTERT and telomerase activity. At the 20th passage, SHEE cells overcame the senescence and apoptosis and restored their proliferative activity with expression of telomerase and hTERT at low levels, but the telomere length shortened continuously to the lowest of 3kb. After the 30th passage cells proliferation was restored by increment of cells at S and G2M phase in the cell cycle and telomerase activity expressed at high levels and with maintenance of telomere length.<br><br>CONCLUSION: At the early stage of SHEE cells, telomeres are shortened without expression of telomerase and hTERT causing cellular senescence and cell death. From the 20th to the 30th passages, the activation of telomerase and maintenance of telomere length show a progressive process for immortalization of esophageal epithelial cells. The expression of telomerase may constitute a biomarker for detection of immortalization of cells.},
}
@article {pmid11924925,
year = {2002},
author = {Tzukerman, M and Selig, S and Skorecki, K},
title = {Telomeres and telomerase in human health and disease.},
journal = {Journal of pediatric endocrinology &amp; metabolism : JPEM},
volume = {15},
number = {3},
pages = {229-240},
doi = {10.1515/jpem.2002.15.3.229},
pmid = {11924925},
issn = {0334-018X},
mesh = {Animals ; Base Sequence ; Cell Cycle/physiology ; Cell Differentiation/genetics/physiology ; Humans ; Molecular Sequence Data ; Neoplasms/genetics/physiopathology ; Telomerase/genetics/*physiology ; Telomere/genetics/*physiology ; },
abstract = {Epigenetics refers to the durable changes affecting the genome of an individual during development and aging, but which are not necessarily passed on to subsequent generations. Among the best studied of these epigenetic changes is the shortening of chromosome ends or telomeres. Telomeres are specialized structures, consisting of characteristic DNA repeat sequences and the complex of associated proteins, which cap and protect chromosome ends and serve to preserve genome integrity. In most somatic cells, progressive rounds of cell division are associated with telomere shortening. Such progressive attrition of telomere length eventuates in loss of replicative capacity (cellular senescence). In order to protect the germline and the subpopulation of stem cells from senescence, mechanisms have evolved to prevent telomere attrition in these cellular compartments. The most common and best studied mechanism involves the activation of a ribonucleoprotein enzyme complex, known as telomerase. Activity of telomerase circumvents loss of replicative capacity, by preserving telomere length and chromosome integrity. Hence the detailed mechanisms governing the expression and activity of telomerase have been intensively studied in development and differentiation. Early embryonic development and cellular differentiation are associated with a progressive diminution in telomerase activity. This decrease in activity is principally mediated at the level of the promoter for the gene encoding the catalytic unit of the telomerase complex. Unraveling the detailed mechanisms involved in the regulation of telomere length and telomerase activity will have important and far-reaching implications in understanding many aspects of human health and disease, ranging from accelerated aging syndromes to cancer pathogenesis, among others. Furthermore, insights gleaned from continuing research in this area will likely be applicable to the development of strategies to circumvent cellular senescence in regenerative medicine and stem cell therapeutics in the years to come.},
}
@article {pmid11923537,
year = {2002},
author = {Karlseder, J and Smogorzewska, A and de Lange, T},
title = {Senescence induced by altered telomere state, not telomere loss.},
journal = {Science (New York, N.Y.)},
volume = {295},
number = {5564},
pages = {2446-2449},
doi = {10.1126/science.1069523},
pmid = {11923537},
issn = {1095-9203},
support = {AG16643/AG/NIA NIH HHS/United States ; CA76027/CA/NCI NIH HHS/United States ; },
mesh = {Antigens, Polyomavirus Transforming/genetics/metabolism ; *Cell Division ; Cell Line ; Cells, Cultured ; *Cellular Senescence ; DNA/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Humans ; Oncogene Proteins, Viral/genetics/metabolism ; Papillomavirus E7 Proteins ; *Repressor Proteins ; Retinoblastoma Protein/metabolism ; Retroviridae/genetics ; Telomere/metabolism/*physiology ; Telomeric Repeat Binding Protein 2 ; Transformation, Genetic ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Primary human cells in culture invariably stop dividing and enter a state of growth arrest called replicative senescence. This transition is induced by programmed telomere shortening, but the underlying mechanisms are unclear. Here, we report that overexpression of TRF2, a telomeric DNA binding protein, increased the rate of telomere shortening in primary cells without accelerating senescence. TRF2 reduced the senescence setpoint, defined as telomere length at senescence, from 7 to 4 kilobases. TRF2 protected critically short telomeres from fusion and repressed chromosome-end fusions in presenescent cultures, which explains the ability of TRF2 to delay senescence. Thus, replicative senescence is induced by a change in the protected status of shortened telomeres rather than by a complete loss of telomeric DNA.},
}
@article {pmid11923505,
year = {2002},
author = {Marx, J},
title = {Tackling cancer at the telomeres.},
journal = {Science (New York, N.Y.)},
volume = {295},
number = {5564},
pages = {2350},
doi = {10.1126/science.295.5564.2350},
pmid = {11923505},
issn = {1095-9203},
mesh = {Animals ; Binding Sites ; Caspases/genetics ; Dendritic Cells/immunology ; Enzyme Inhibitors/*pharmacology/therapeutic use ; Genetic Therapy ; Humans ; Immunotherapy ; Neoplasms/drug therapy/*therapy ; RNA/metabolism ; RNA, Antisense/metabolism/pharmacology/therapeutic use ; Telomerase/antagonists &amp; inhibitors/genetics/immunology/*metabolism ; Telomere/*metabolism ; },
}
@article {pmid11923504,
year = {2002},
author = {Marx, J},
title = {Telomeres. Chromosome end game draws a crowd.},
journal = {Science (New York, N.Y.)},
volume = {295},
number = {5564},
pages = {2348-2351},
doi = {10.1126/science.295.5564.2348},
pmid = {11923504},
issn = {1095-9203},
mesh = {Animals ; *Cell Division ; Cellular Senescence ; DNA/chemistry/metabolism ; DNA-Binding Proteins/chemistry/genetics/isolation &amp; purification/physiology ; Humans ; Models, Molecular ; Neoplasms/etiology ; Protein Conformation ; Telomerase/chemistry/genetics/*metabolism ; Telomere/chemistry/*physiology ; Tetrahymena/physiology/ultrastructure ; },
}
@article {pmid11923346,
year = {2002},
author = {Nosek, J and Tomáska, L and Rycovská, A and Fukuhara, H},
title = {Mitochondrial telomeres as molecular markers for identification of the opportunistic yeast pathogen Candida parapsilosis.},
journal = {Journal of clinical microbiology},
volume = {40},
number = {4},
pages = {1283-1289},
pmid = {11923346},
issn = {0095-1137},
support = {R03 TW005654/TW/FIC NIH HHS/United States ; 1-R03-TW05654-01/TW/FIC NIH HHS/United States ; },
mesh = {Candida/*classification/*genetics ; Candidiasis/microbiology ; DNA, Fungal/genetics ; DNA, Mitochondrial/*genetics ; Genetic Markers ; Humans ; Immunoblotting ; Opportunistic Infections/*microbiology ; Polymerase Chain Reaction ; RNA, Ribosomal, 18S/genetics ; Sequence Analysis, DNA/methods ; Species Specificity ; Telomere/*genetics ; },
abstract = {Recent studies have demonstrated that a large number of organisms carry linear mitochondrial DNA molecules possessing specialized telomeric structures at their ends. Based on this specific structural feature of linear mitochondrial genomes, we have developed an approach for identification of the opportunistic yeast pathogen Candida parapsilosis. The strategy for identification of C. parapsilosis strains is based on PCR amplification of specific DNA sequences derived from the mitochondrial telomere region. This assay is complemented by immunodetection of a protein component of mitochondrial telomeres. The results demonstrate that mitochondrial telomeres represent specific molecular markers with potential applications in yeast diagnostics and taxonomy.},
}
@article {pmid11923106,
year = {2002},
author = {Lord, JM and Akbar, AN and Kipling, D},
title = {Telomere-based therapy for immunosenescence.},
journal = {Trends in immunology},
volume = {23},
number = {4},
pages = {175-176},
doi = {10.1016/s1471-4906(02)02170-1},
pmid = {11923106},
issn = {1471-4906},
mesh = {Aged ; Aging/*immunology ; Genetic Therapy/trends ; Humans ; Telomere/*ultrastructure ; },
abstract = {The International Workshop on Telomeres and the Immune System: Ageing and Novel Intervention Strategies was held at Birmingham University, UK from 1-3 December 2001.},
}
@article {pmid11919561,
year = {2002},
author = {Varley, H and Pickett, HA and Foxon, JL and Reddel, RR and Royle, NJ},
title = {Molecular characterization of inter-telomere and intra-telomere mutations in human ALT cells.},
journal = {Nature genetics},
volume = {30},
number = {3},
pages = {301-305},
doi = {10.1038/ng834},
pmid = {11919561},
issn = {1061-4036},
mesh = {Cell Line ; Humans ; Mutation ; Polymerase Chain Reaction ; Recombination, Genetic ; *Telomere ; },
abstract = {Telomeres in most immortal cells are maintained by the enzyme telomerase, allowing cells to divide indefinitely. Some telomerase-negative tumors and immortal cell lines maintain long heterogeneous telomeres by the ALT (alternative lengthening of telomeres) mechanism; such tumors are expected to be resistant to anti-telomerase drug therapies. Occasionally telomerase-negative Saccharomyces cerevisiae mutants survive, and 10% of them (type II survivors) have unstable telomeres. As in human ALT+ cells, short telomeres in yeast type II survivors lengthen abruptly; in yeast, this is dependent on the recombination proteins Rad52p and Rad50p. In human cells, ALT involves copying of sequence from a donor to a recipient telomere. We have characterized for the first time a class of complex telomere mutations seen only in ALT+ cells. The mutant telomeres are defined by the replacement of the progenitor telomere at a discrete point (fusion point) with a different telomere repeat array. Among 19 characterized fusion points, one occurred within the first six repeats of the telomere, indicating that these recombination-like events can occur anywhere within the telomere. One mutant telomere may have been involved in a secondary recombination-like mutation event, suggesting that these mutations are sporadic but ongoing in ALT+ cells. We also identified simple intra-allelic mutations at high frequency, which evidently contribute to telomere instability in ALT+ cells.},
}
@article {pmid11919193,
year = {2002},
author = {Conway, C and McCulloch, R and Ginger, ML and Robinson, NP and Browitt, A and Barry, JD},
title = {Ku is important for telomere maintenance, but not for differential expression of telomeric VSG genes, in African trypanosomes.},
journal = {The Journal of biological chemistry},
volume = {277},
number = {24},
pages = {21269-21277},
doi = {10.1074/jbc.M200550200},
pmid = {11919193},
issn = {0021-9258},
mesh = {Amino Acid Sequence ; Animals ; Animals, Genetically Modified ; *Antigens, Nuclear ; Binding Sites ; Blotting, Southern ; DNA/metabolism ; DNA Damage ; *DNA Helicases ; DNA-Binding Proteins/*metabolism ; Gene Silencing ; Homozygote ; Ku Autoantigen ; Methyl Methanesulfonate/pharmacology ; Molecular Sequence Data ; Mutagens ; Mutation ; Nuclear Proteins/*metabolism ; Nucleic Acid Synthesis Inhibitors/pharmacology ; Phleomycins/pharmacology ; Promoter Regions, Genetic ; RNA/metabolism ; Recombination, Genetic ; Reverse Transcriptase Polymerase Chain Reaction ; Sequence Homology, Amino Acid ; Telomere/*metabolism ; Transcription, Genetic ; Trypanosoma ; Variant Surface Glycoproteins, Trypanosoma/*metabolism ; },
abstract = {Trypanosome antigenic variation, involving differential expression of variant surface glycoprotein (VSG) genes, has a strong association with telomeres and with DNA recombination. All expressed VSGs are telomeric, and differential activation involves recombination into the telomeric environment or silencing/activation of subtelomeric promoters. A number of pathogen contingency gene systems associated with immune evasion involve telomeric loci, which has prompted speculation that chromosome ends provide conditions conducive for the operation of rapid gene switching mechanisms. Ku is a protein associated with eukaryotic telomeres that is directly involved in DNA recombination and in gene silencing. We have tested the hypothesis that Ku in trypanosomes is centrally involved in differential VSG expression. We show, via the generation of null mutants, that trypanosome Ku is closely involved in telomere length maintenance, more so for a transcriptionally active than an inactive telomere, but exhibits no detectable influence on DNA double strand break repair. The absence of Ku and the consequent great shortening of telomeres had no detectable influence either on the rate of VSG switching or on the silencing of the telomeric promoters of the VSG subset that is expressed in the tsetse fly.},
}
@article {pmid11918940,
year = {2002},
author = {Nowak, R and Siwicki, JK and Chechlinska, M and Markowicz, S},
title = {Telomere shortening and atherosclerosis.},
journal = {Lancet (London, England)},
volume = {359},
number = {9310},
pages = {976; author reply 976-7},
doi = {10.1016/S0140-6736(02)07997-7},
pmid = {11918940},
issn = {0140-6736},
mesh = {Arteriosclerosis/etiology/*metabolism ; Coronary Disease/*metabolism ; Female ; Humans ; Leukocytes/*metabolism ; Male ; Sex Distribution ; Telomere/*metabolism ; },
}
@article {pmid11918553,
year = {2002},
author = {Thornley, I and Dror, Y and Sung, L and Wynn, RF and Freedman, MH},
title = {Abnormal telomere shortening in leucocytes of children with Shwachman-Diamond syndrome.},
journal = {British journal of haematology},
volume = {117},
number = {1},
pages = {189-192},
doi = {10.1046/j.1365-2141.2002.03371.x},
pmid = {11918553},
issn = {0007-1048},
mesh = {Adolescent ; Case-Control Studies ; Cell Division ; Child ; Child, Preschool ; Female ; Hematologic Diseases/*etiology/pathology ; Hematopoietic Stem Cells/*ultrastructure ; Humans ; Infant ; Least-Squares Analysis ; Leukocytes/*ultrastructure ; Male ; Telomere/*ultrastructure ; },
abstract = {Haemopoietic dysfunction, ranging from single-lineage cytopenia to severe aplasia and/or myelodysplasia (MDS), is prominent in Shwachman-Diamond syndrome (SDS). To assess haemopoietic stem cell proliferation in SDS, we compared leucocyte telomere length in 12 patients with SDS to that of 41 controls, using an in-gel hybridization technique. SDS patients had an age-adjusted mean telomere length 1.4 kilobase pairs (kbp) shorter than controls (P < 0.0001). Patients with'non-severe' SDS (one- or two-lineage cytopenias; no MDS) had shortened telomeres (-1.4 kbp; P = 0.0004), as did those with 'severe' SDS. We conclude that stem cell hyperproliferation is a feature of SDS from its outset.},
}
@article {pmid11905960,
year = {2002},
author = {McKnight, TD and Riha, K and Shippen, DE},
title = {Telomeres, telomerase, and stability of the plant genome.},
journal = {Plant molecular biology},
volume = {48},
number = {4},
pages = {331-337},
doi = {10.1023/a:1014091032750},
pmid = {11905960},
issn = {0167-4412},
mesh = {*Genome, Plant ; Plants/genetics/metabolism ; Telomerase/*metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres, the complex nucleoprotein structures at the ends of linear eukaryotic chromosomes, along with telomerase, the enzyme that synthesizes telomeric DNA, are required to maintain a stable genome. Together, the enzyme and substrate perform this essential service by protecting chromosomes from exonucleolytic degradation and end-to-end fusions and by compensating for the inability of conventional DNA replication machinery to completely duplicate the ends of linear chromosomes. Telomeres are also important for chromosome organization within the nucleus, especially during mitosis and meiosis. The contributions of telomeres and telomerases to plant genome stability have been confirmed by analysis of Arabidopsis mutants that lack telomerase activity. These mutants have unstable genomes, but manage to survive up to ten generations with increasingly shortened telomeres and cytogenetic abnormalities. Comparisons between telomerase-deficient Arabidopsis and telomerase-deficient mice reveal distinct differences in the consequences of massive genome damage, probably reflecting the greater developmental and genomic plasticity of plants.},
}
@article {pmid11904422,
year = {2002},
author = {Liu, Y and Kha, H and Ungrin, M and Robinson, MO and Harrington, L},
title = {Preferential maintenance of critically short telomeres in mammalian cells heterozygous for mTert.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {99},
number = {6},
pages = {3597-3602},
pmid = {11904422},
issn = {0027-8424},
support = {AG8422117/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; Chromosome Aberrations ; DNA-Binding Proteins ; Gene Deletion ; Genome ; *Heterozygote ; In Situ Hybridization, Fluorescence ; Metaphase/genetics ; Mice ; Protein Transport ; Stem Cells/cytology/enzymology/metabolism ; Telomerase/*genetics/*metabolism ; Telomere/*enzymology/genetics/*metabolism ; },
abstract = {Prolonged growth of murine embryonic stem (ES) cells lacking the telomerase reverse transcriptase, mTert, results in a loss of telomere DNA and an increased incidence of end-to-end fusions and aneuploidy. Furthermore, loss of only one copy of mTert also results in telomere shortening intermediate between wild-type (wt) and mTert-null ES cells [Liu, Y., Snow, B. E., Hande, M. P., Yeung, D., Erdmann, N. J., Wakeham, A., Itie, A., Siderovski, D. P., Lansdorp, P. M., Robinson, M. O. &amp; Harrington, L. (2000) Curr. Biol. 10, 1459-1462]. Unexpectedly, although average telomere length in mTert(+/-) ES cells declined to a similar level as mTert-null ES cells, mTert(+/-) ES cell lines retained a minimal telomeric DNA signal at all chromosome ends. Consequently, no end-to-end fusions and genome instability were observed in the latest passages of mTert(+/-) ES cell lines. These data uncover a functional distinction between the dosage-dependent function of telomerase in average telomere-length maintenance and the selective maintenance of critically short telomeres in cells heterozygous for mTert. In normal and tumor cells, we suggest that telomerase activity insufficient to maintain a given average telomere length may, nonetheless, provide a protective advantage from end-to-end fusion and genome instability.},
}
@article {pmid11904421,
year = {2002},
author = {Hathcock, KS and Hemann, MT and Opperman, KK and Strong, MA and Greider, CW and Hodes, RJ},
title = {Haploinsufficiency of mTR results in defects in telomere elongation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {99},
number = {6},
pages = {3591-3596},
pmid = {11904421},
issn = {0027-8424},
support = {P01 CA016519/CA/NCI NIH HHS/United States ; CA16519/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Crosses, Genetic ; Female ; Gene Deletion ; Genotype ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred Strains ; Mice, Knockout ; Molecular Sequence Data ; Phenotype ; RNA/*genetics ; Species Specificity ; Telomerase/*genetics/metabolism ; Telomere/*enzymology/genetics/*metabolism ; },
abstract = {Telomeres are usually maintained about an equilibrium length, and the set point for this equilibrium differs between species and between strains of a given species. To examine the requirement for telomerase in mediating establishment of a new telomere length equilibrium, we generated interspecies crosses with telomerase mTR knockout mice. In crosses between C57BL/6J (B6) and either of two unrelated mouse species, CAST/Ei and SPRET/Ei, telomerase mediated establishment of a new telomere length equilibrium in wild-type mTR(+/+) mice. This new equilibrium was characterized by elongation of the short telomeres of CAST/Ei or SPRET/Ei origin. In contrast, mTR(-/-) offspring of interspecies crosses failed to elongate telomeres. Unexpectedly, haploinsufficiency was observed in mTR(+/-) heterozygous interspecies mice, which had an impaired ability to elongate short SPRET/Ei or CAST/Ei telomeres to the new equilibrium set point that was achieved in wild-type mTR(+/+) mice. These results demonstrate that elongation of telomeres to a new telomere set point requires telomerase and indicate that telomerase RNA may be limiting in vivo.},
}
@article {pmid11903351,
year = {2002},
author = {Yakut, S and Berker-Karaüzüm, S and Simşek, M and Zorlu, G and Trak, B and Lüleci, G},
title = {Telomere-specific fluorescence in situ hybridization analysis of couples with five or more recurrent miscarriages.},
journal = {Clinical genetics},
volume = {61},
number = {1},
pages = {26-31},
doi = {10.1034/j.1399-0004.2002.610105.x},
pmid = {11903351},
issn = {0009-9163},
mesh = {Abortion, Habitual/*genetics ; Azure Stains ; *Chromosome Aberrations ; Chromosome Banding ; Female ; Humans ; *In Situ Hybridization, Fluorescence ; Male ; Polymorphism, Genetic/genetics ; Telomere/genetics/*pathology ; Translocation, Genetic/genetics ; },
abstract = {Fluorescence in situ hybridization analysis using telomere specific probes has been used to detect cryptic translocations in the chromosomal telomeric regions. This study was performed in five clinically normal couples who have had five or more spontaneous abortions and whose karyotypes were found to be normal using conventional cytogenetic techniques. Using the telomere specific probes, in one couple we determined a cryptic translocation between chromosome 3 and 10, and, in another couple, the signal in chromosome 20 was detected in another chromosome, which was probably a D group chromosome. Additionally, in the latter and also in two other couples, we observed a polymorphism. The approach will be helpful for screening cryptic translocations using telomere specific multiple probe sets in couples with recurrent miscarriages. As prenatal diagnosis will be available for these couples for future pregnancies, it will be possible to help these families to have healthy fetuses.},
}
@article {pmid11902675,
year = {2002},
author = {Jentsch, S and Tobler, H and Müller, F},
title = {New telomere formation during the process of chromatin diminution in Ascaris suum.},
journal = {The International journal of developmental biology},
volume = {46},
number = {1},
pages = {143-148},
pmid = {11902675},
issn = {0214-6282},
mesh = {Animals ; Ascaris suum/*embryology ; Binding Sites ; Chromatin/*metabolism ; Cloning, Molecular ; DNA, Helminth/*biosynthesis/*genetics/metabolism ; *Gene Expression Regulation, Developmental ; Models, Genetic ; Molecular Sequence Data ; Polymerase Chain Reaction ; Sequence Analysis, DNA ; Telomere/*ultrastructure ; },
abstract = {Chromatin diminution in the parasitic nematode Ascaris suum represents an interesting case of developmentally programmed DNA rearrangement in higher eukaryotes. At the molecular level, it is a rather complex event including chromosome breakage, new telomere formation and DNA degradation. Analysis of a cloned somatic telomere (pTel1) revealed that it has been newly created during the process of chromatin diminution by the addition of telomeric repeats (TTAGGC)n to a chromosomal breakage site (Müller et al., 1991). However, telomere addition does not occur at a single chromosomal locus, but at many different sites within a short chromosomal region, termed CBR1 (chromosomal breakage region 1). Here we present the cloning and the analysis of 83 different PCR amplified telomere addition sites from the region of CBR1. The lack of any obvious sequence homology shared among them argues for a telomerase-mediated healing process, rather than for a recombinational event. This hypothesis is strongly supported by the existence of 1-6 nucleotides corresponding to and being in frame with the newly added telomeric repeats at almost all of the telomere addition sites. Furthermore, we show that telomeres are not only added to the ends of the retained chromosomal portions, but also to the eliminated part of the chromosomes, which later on become degraded in the cytoplasm. This result suggests that de novo telomere formation during the process of chromatin diminution represents a non-specific process which can heal any broken DNA end.},
}
@article {pmid11901508,
year = {2002},
author = {Broccoli, D and Godwin, AK},
title = {Telomere length changes in human cancer.},
journal = {Methods in molecular medicine},
volume = {68},
number = {},
pages = {271-278},
doi = {10.1385/1-59259-135-3:271},
pmid = {11901508},
issn = {1543-1894},
mesh = {Blotting, Southern/*methods ; DNA, Neoplasm/genetics/metabolism ; Humans ; Neoplasms/*genetics ; Telomere/*metabolism/*ultrastructure ; },
}
@article {pmid11901107,
year = {2002},
author = {Jin, Y and Uzawa, S and Cande, WZ},
title = {Fission yeast mutants affecting telomere clustering and meiosis-specific spindle pole body integrity.},
journal = {Genetics},
volume = {160},
number = {3},
pages = {861-876},
pmid = {11901107},
issn = {0016-6731},
support = {R01 GM23238/GM/NIGMS NIH HHS/United States ; R01 GM48547/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins ; DNA-Binding Proteins/metabolism ; Fungal Proteins/genetics/metabolism ; Green Fluorescent Proteins ; Luminescent Proteins ; Meiosis/*physiology ; Microtubules/metabolism ; Mutation ; Nuclear Proteins/genetics ; Recombinant Fusion Proteins/genetics ; Saccharomyces cerevisiae Proteins ; Schizosaccharomyces/*genetics/metabolism ; Schizosaccharomyces pombe Proteins ; Spindle Apparatus/*metabolism ; Telomere/*metabolism ; *Telomere-Binding Proteins ; Transcription Factors ; Ubiquitin Thiolesterase ; },
abstract = {In meiotic prophase of many eukaryotic organisms, telomeres attach to the nuclear envelope and form a polarized configuration called the bouquet. Bouquet formation is hypothesized to facilitate homologous chromosome pairing. In fission yeast, bouquet formation and telomere clustering occurs in karyogamy and persists throughout the horsetail stage. Here we report the isolation and characterization of six mutants from our screen for meiotic mutants. These mutants show defective telomere clustering as demonstrated by mislocalization of Swi6::GFP, a heterochromatin-binding protein, and Taz1p::GFP, a telomere-specific protein. These mutants define four complementation groups and are named dot1 to dot4-defective organization of telomeres. dot3 and dot4 are allelic to mat1-Mm and mei4, respectively. Immunolocalization of Sad1, a protein associated with the spindle pole body (SPB), in dot mutants showed an elevated frequency of multiple Sad1-nuclei signals relative to wild type. Many of these Sad1 foci were colocalized with Taz1::GFP. Impaired SPB structure and function were further demonstrated by failure of spore wall formation in dot1, by multiple Pcp1::GFP signals (an SPB component) in dot2, and by abnormal microtubule organizations during meiosis in dot mutants. The coincidence of impaired SPB functions with defective telomere clustering suggests a link between the SPB and the telomere cluster.},
}
@article {pmid11897137,
year = {2002},
author = {Chiurillo, MA and Peralta, A and Ramírez, JL},
title = {Comparative study of Trypanosoma rangeli and Trypanosoma cruzi telomeres.},
journal = {Molecular and biochemical parasitology},
volume = {120},
number = {2},
pages = {305-308},
doi = {10.1016/s0166-6851(02)00005-1},
pmid = {11897137},
issn = {0166-6851},
mesh = {Animals ; Base Sequence ; Electrophoresis, Gel, Pulsed-Field ; Molecular Sequence Data ; Sequence Homology, Nucleic Acid ; Telomere/*genetics ; Trypanosoma/*genetics ; Trypanosoma cruzi/*genetics ; },
}
@article {pmid11896200,
year = {2002},
author = {LaFountain, JR and Cole, RW and Rieder, CL},
title = {Partner telomeres during anaphase in crane-fly spermatocytes are connected by an elastic tether that exerts a backward force and resists poleward motion.},
journal = {Journal of cell science},
volume = {115},
number = {Pt 7},
pages = {1541-1549},
doi = {10.1242/jcs.115.7.1541},
pmid = {11896200},
issn = {0021-9533},
support = {R37 GM040198/GM/NIGMS NIH HHS/United States ; R37 GM040198-19/GM/NIGMS NIH HHS/United States ; GM 400198/GM/NIGMS NIH HHS/United States ; },
mesh = {Anaphase ; Animals ; Cell Polarity ; Diptera/*cytology/*ultrastructure ; Elasticity ; Kinetochores/physiology ; Male ; Meiosis ; Microtubules/physiology ; Models, Biological ; Movement ; Spermatocytes/*ultrastructure ; Telomere/metabolism/*ultrastructure ; },
abstract = {As chromosomes move polewards during anaphase in crane-fly spermatocytes, trailing arms commonly stretch backwards for a brief time, as if tethered to their partners. To test that notion, a laser microbeam was used to sever trailing arms and thereby release telomere-containing arm segments (called acentric fragments because they lack kinetochores) from segregating chromosomes. Analysis of the movement of acentric fragments after their release provided clear evidence that previously conjoined partners were indeed tethered at their telomeres and that tethers exerted backward forces that were sufficient to move the fragment across the equator and into the opposite half-spindle. To address concerns that tethers might be artifacts of in vitro cell culture, spermatocytes were fixed in situ, and stretched arms within fixed cells provided strong evidence for tethers in vivo. The substantial resistance that tethers impose on the poleward movement of chromosomes must normally be over-ridden by the poleward 'pulling' forces exerted at kinetochores. In spermatocytes, poleward forces are supplied primarily by the 'traction fibers' that are firmly attached to kinetochores through end-on attachments to the plus ends of kinetochore microtubules.},
}
@article {pmid11895789,
year = {2002},
author = {Brown, J and Jawad, M and Twigg, SR and Saracoglu, K and Sauerbrey, A and Thomas, AE and Eils, R and Harbott, J and Kearney, L},
title = {A cryptic t(5;11)(q35;p15.5) in 2 children with acute myeloid leukemia with apparently normal karyotypes, identified by a multiplex fluorescence in situ hybridization telomere assay.},
journal = {Blood},
volume = {99},
number = {7},
pages = {2526-2531},
doi = {10.1182/blood.v99.7.2526},
pmid = {11895789},
issn = {0006-4971},
mesh = {Adolescent ; Base Sequence ; Bone Marrow Cells/pathology ; Chromosome Mapping ; *Chromosomes, Human, Pair 11 ; *Chromosomes, Human, Pair 5 ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; Karyotyping ; Leukemia, Myeloid, Acute/blood/*genetics/pathology ; Male ; Molecular Sequence Data ; Platelet Count ; RNA, Neoplasm/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*genetics ; *Translocation, Genetic ; },
abstract = {The identification of specific chromosome abnormalities in acute myeloid leukemia (AML) is important for the stratification of patients into the appropriate treatment protocols. However, a significant proportion of diagnostic bone marrow karyotypes in AML is reported as normal by conventional cytogenetic analysis and it is suspected that these karyotypes may conceal the presence of diagnostically significant chromosome rearrangements. To address this question, we have developed a novel 12-color fluorescence in situ hybridization (FISH) assay for telomeric rearrangements (termed M-TEL), which uses an optimized set of chromosome-specific subtelomeric probes. We report here the application of the M-TEL assay to 69 AML cases with apparently normal karyotypes or an isolated trisomy. Of the 69 cases examined, 3 abnormalities were identified, all in the normal karyotype group. The first was a t(11;19)(q23;p13), identified in an infant with AML-M4. In 2 other young patients with AML (< 19 years), an apparently identical t(5;11)(q35;p15.5) was identified. Breakpoint mapping by FISH and reverse transcriptase polymerase chain reaction (RT-PCR) analysis confirmed that this was the same t(5;11) as previously identified in 3 children with AML, associated with del(5q) and resulting in the NUP98-NSD1 gene fusion. The t(5;11) was not detected by 24-color karyotyping using multiplex FISH (M-FISH), emphasizing the value of screening with subtelomeric probes for subtle translocations. This is the first report of the t(5;11)(q35;p15.5) in association with an apparently normal karyotype, and highlights this as a new, potentially clinically significant chromosome rearrangement in childhood AML.},
}
@article {pmid11895771,
year = {2002},
author = {Thornley, I and Sutherland, R and Wynn, R and Nayar, R and Sung, L and Corpus, G and Kiss, T and Lipton, J and Doyle, J and Saunders, F and Kamel-Reid, S and Freedman, M and Messner, H},
title = {Early hematopoietic reconstitution after clinical stem cell transplantation: evidence for stochastic stem cell behavior and limited acceleration in telomere loss.},
journal = {Blood},
volume = {99},
number = {7},
pages = {2387-2396},
doi = {10.1182/blood.v99.7.2387},
pmid = {11895771},
issn = {0006-4971},
mesh = {Adult ; Antigens, CD34/analysis ; Blood Cell Count ; Cell Cycle ; Female ; Flow Cytometry ; *Hematopoiesis ; *Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/*cytology ; Humans ; Leukemia/therapy ; Lymphoma/therapy ; Male ; Middle Aged ; Stochastic Processes ; Telomere/*physiology ; Transplantation Chimera ; Transplantation, Homologous ; Treatment Outcome ; },
abstract = {Our inability to purify hematopoietic stem cells (HSCs) precludes direct study of many aspects of their behavior in the clinical hematopoietic stem cell transplantation (HSCT) setting. We indirectly assessed stem/progenitor cell behavior in the first year after HSCT by examining changes in neutrophil telomere length, X-inactivation ratios, and cycling of marrow progenitors in 25 fully engrafted allogeneic HSCT recipients. Donors were sampled once and recipients at engraftment and 2 to 6 months and 12 months after HSCT. Telomere length was measured by an in-gel hybridization technique, X-inactivation ratios were measured by the human androgen receptor assay, and cell cycle status was determined by flow cytometric analysis of pyronin Y- and Hoechst 33342-stained CD34(+)CD90(+) and CD34(+)CD90(-) marrow cells. Compared with their donors, recipients' telomeres were shortened at engraftment (-424 base pairs [bp]; P <.0001), 6 months (-495 bp; P =.0001) after HSCT, and 12 months after HSCT (-565 bp; P <.0001). There was no consistent pattern of change in telomere length from 1 to 12 months after HSCT; marked, seemingly random, fluctuations were common. In 11 of 11 informative recipients, donor X-inactivation ratios were faithfully reproduced and maintained. The proportion of CD34(+)CD90(+) progenitors in S/G(2)/M was 4.3% in donors, 15.7% at 2 to 6 months (P <.0001) after HSCT, and 11.5% at 12 months after HSCT (P <.0001, versus donors; P =.04, versus 2-6 months). Cycling of CD34(+) CD90(-) progenitors was largely unchanged. We infer that (1) HSCT-induced accelerated telomere loss is temporary and unlikely to promote graft failure or clonal hematopoietic disorders and (2) the striking fluctuations in telomere length and variation in pattern of telomere loss reflect stochastic determination of HSC fate after HSCT.},
}
@article {pmid11882542,
year = {2002},
author = {Liu, L and Blasco, MA and Keefe, DL},
title = {Requirement of functional telomeres for metaphase chromosome alignments and integrity of meiotic spindles.},
journal = {EMBO reports},
volume = {3},
number = {3},
pages = {230-234},
pmid = {11882542},
issn = {1469-221X},
support = {K081099//PHS HHS/United States ; },
mesh = {Animals ; Chromosomes/*physiology ; Meiosis/genetics/physiology ; Metaphase/genetics/*physiology ; Mice ; Mice, Knockout ; Oocytes ; Spindle Apparatus/physiology/ultrastructure ; Telomerase/deficiency/physiology ; Telomere/*physiology ; },
abstract = {Telomerase deficiency in the mouse eventually leads to loss of telomeric repeats from chromosome ends and to end-to-end chromosome fusions, which result in defects in highly proliferative tissues. We show that telomere dysfunction resulting from telomerase deficiency leads to disruption of functional meiotic spindles and misalignment of chromosomes during meiotic division of oocytes in late-generation (G4) mice. However, oocytes from first-generation (G1) mice lacking telomerase showed no appreciable telomere dysfunction and exhibited chromosome alignment at the metaphase plates of meiotic spindles, in a manner similar to that of wild-type mouse oocytes. These findings suggest that telomerase does not directly influence chromosome alignment and spindle integrity. Rather, functional telomeres may be involved in mediating metaphase chromosome alignment and maintaining functional spindles during meiotic division.},
}
@article {pmid11872079,
year = {2001},
author = {Norrback, KF and Hultdin, M and Dahlenborg, K and Osterman, P and Carlsson, R and Roos, G},
title = {Telomerase regulation and telomere dynamics in germinal centers.},
journal = {European journal of haematology},
volume = {67},
number = {5-6},
pages = {309-317},
doi = {10.1034/j.1600-0609.2001.00588.x},
pmid = {11872079},
issn = {0902-4441},
mesh = {Antigens, CD ; B-Lymphocyte Subsets/*enzymology/ultrastructure ; Flow Cytometry ; Germinal Center/*cytology/*enzymology ; Humans ; Immunophenotyping ; In Situ Hybridization, Fluorescence ; Palatine Tonsil/enzymology/ultrastructure ; Telomerase/*metabolism ; Telomere/*ultrastructure ; },
abstract = {Telomere length maintenance, usually executed by telomerase, is a prerequisite for an extended or infinite division potential. Nevertheless most telomerase positive normal cells exhibit telomere shortening. This study details the telomerase expression and telomere dynamics in purified tonsil B cell subsets during the germinal center (GC) reaction. Significant telomere lengthening was observed as naive B cells matured to centroblasts and when centroblasts matured further to centrocytes, resulting in an increase in telomere length of about 4 kbp determined by Southern blotting. Immunopurified cell populations were also studied by fluorescence in situ hybridization and flow cytometry (flow-FISH) confirming that the GC B cells exhibited lengthened telomeres. These data were further verified in unpurified tonsil cells by combining flow-FISH and immunophenotyping using selected surface markers. Centroblasts expressed high levels of telomerase activity, which was increased in centrocytes, whereas resting naive, activated naive and memory B cells were telomerase activity negative. Expression levels of the catalytic subunit (hTERT) RNA paralleled the telomerase activity levels. The unique telomere elongation in GC B cells permits extensive proliferation during the GC reaction and provides the memory cells with a substantial increase in division potential. Understanding the telomere biology of GC cells is important in defining requirements for telomere elongation in vivo, with implications for the normal immune system as well as for lymphomas, and could provide insights into how the division potential of cells can be manipulated in vitro.},
}
@article {pmid11869736,
year = {2002},
author = {Goyns, MH},
title = {Genes, telomeres and mammalian ageing.},
journal = {Mechanisms of ageing and development},
volume = {123},
number = {7},
pages = {791-799},
doi = {10.1016/s0047-6374(01)00424-9},
pmid = {11869736},
issn = {0047-6374},
mesh = {Aging/*genetics ; Animals ; Gene Expression/*physiology ; Mammals ; Telomere/*physiology ; },
abstract = {Although there appear to be several influences, which contribute to the ageing of mammals, the role of DNA appears to be pivotal. There is increasing evidence that oxidative damage is an important factor in producing mutations in genes, shortening telomeres and damaging mitochondrial DNA. Accumulation of mutations in genomic DNA could result in the gradual decline in cellular function, which is exhibited in a variety of tissues. The random nature of these mutations, could also offer an explanation for differences in the degree and time of onset of age-related changes, exhibited by different individuals. Shortening of telomeres, caused by oxidative damage or the end-replication problem, could result in the accumulation of post-mitotic cells in-vivo during ageing. This might impair certain aspects of physiology, such as wound healing. Mutation of mitochondrial DNA may also be important in causing loss of cells in post-mitotic tissues such as muscle or brain. In addition changes in the redox state during the life of an animal may alter transcription factor activities, leading to consistent changes in the gene expression profiles of mammalian tissues. The latter could explain consistent age-related changes that have been observed in cell structure and physiology. Although all of these mechanisms may make a contribution to ageing, it is likely that it is the interplay between them that produces the most prominent effects.},
}
@article {pmid11863067,
year = {2002},
author = {Rosén, M and Edström, JE},
title = {Chromosome ends in Chironomus tentans do not have long single-stranded overhangs characterizing canonical telomeres.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {10},
number = {1},
pages = {21-31},
pmid = {11863067},
issn = {0967-3849},
mesh = {Animals ; Base Sequence ; Chironomidae/*genetics ; Chromosomes/*ultrastructure ; DNA/*genetics ; Exodeoxyribonucleases ; Nucleic Acid Denaturation ; Oligodeoxyribonucleotides ; Telomere/*genetics ; },
abstract = {Single-stranded overhangs of the G-rich strand belong to the conserved features of telomeres composed of short telomeric repeats. These structures are thought to be essential for the maintenance of proper telomeric structure and function and the mechanism of their generation is telomerase-independent. We have examined the presence of single-stranded overhangs in Chironomus tentans, a dipteran insect lacking canonical telomeres that uses 350-bp repeats to terminate its chromosomes. Using a non-denaturing in-gel hybridization technique, we found that C. tentans telomeres are unlikely to have single-stranded overhangs longer than 30 nt found in most other higher eukaryotes. These differences might reflect special capping mechanisms for telomeres terminated with long complex repeats.},
}
@article {pmid11862215,
year = {2002},
author = {Feuerbach, F and Galy, V and Trelles-Sticken, E and Fromont-Racine, M and Jacquier, A and Gilson, E and Olivo-Marin, JC and Scherthan, H and Nehrbass, U},
title = {Nuclear architecture and spatial positioning help establish transcriptional states of telomeres in yeast.},
journal = {Nature cell biology},
volume = {4},
number = {3},
pages = {214-221},
doi = {10.1038/ncb756},
pmid = {11862215},
issn = {1465-7392},
mesh = {Cell Nucleus/genetics/metabolism ; Fungal Proteins/genetics/metabolism ; Gene Silencing ; Genes, Fungal ; Genes, Reporter ; In Situ Hybridization, Fluorescence ; Nuclear Pore Complex Proteins/genetics/metabolism ; Nuclear Proteins/genetics/metabolism ; RNA-Binding Proteins ; Saccharomyces cerevisiae/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Sequence Deletion ; Telomere/*genetics/*metabolism ; Transcription, Genetic ; Transcriptional Activation ; Two-Hybrid System Techniques ; },
abstract = {Recent experiments have shown that gene repression can be correlated with relocation of genes to heterochromatin-rich silent domains. Here, we investigate whether nuclear architecture and spatial positioning can contribute directly to the transcriptional activity of a genetic locus in Saccharomyces cerevisiae. By disassembling telomeric silent domains without altering the chromatin-mediated silencing machinery, we show that the transcriptional activity of silencer--reporter constructs depends on intranuclear position. This demonstrates that telomeric silent domains are actively involved in transcriptional silencing. Employing fluorescent in situ hybridization (FISH) in combination with genetic assays, we demonstrate that telomeres control the establishment of transcriptional states by reversible partitioning with the perinuclear silencing domains. Anchoring telomeres interferes with their ability to assume an active state, whereas disassembly of silencing domains prevents telomeres from assuming a repressed state. Our data support a model in which domains of enriched transcriptional regulators allow genes to determine transcriptional states by spatial positioning.},
}
@article {pmid11859459,
year = {2002},
author = {Zhang, F and Jia, Z and Deng, Z and Wei, Y and Zheng, R and Yu, L},
title = {In vitro modulation of telomerase activity, telomere length and cell cycle in MKN45 cells by verbascoside.},
journal = {Planta medica},
volume = {68},
number = {2},
pages = {115-118},
doi = {10.1055/s-2002-20255},
pmid = {11859459},
issn = {0032-0943},
mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/drug effects ; Cell Cycle/drug effects ; Cell Differentiation/drug effects ; Dose-Response Relationship, Drug ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Glucosides/*pharmacology ; Humans ; Phenols/*pharmacology ; Plant Extracts/pharmacology ; Polymerase Chain Reaction ; Scrophulariaceae ; Telomerase/*drug effects/metabolism ; Telomere/*drug effects/genetics/metabolism ; Tumor Cells, Cultured ; },
abstract = {Screening of natural products with anti-tumor activity as telomerase inhibitor is a new subject in the field of tumor therapy. Using telomerase PCR ELISA, telomere DNA hybridization and flow cytometry analysis, the effects of verbascoside, a phenylpropanoid glucoside extracted from Pedicularis striata Pall, on telomerase activity, telomere length and cell cycle of human gastric carcinoma cells MKN45 was examined in vitro. After being treated with a 50 % inhibition concentration of verbascoside (17.8 microg/ml), telomerase activity in the cells was significantly inhibited but not in the cellular supernatant, the average telomere length became remarkably short, and the sub-G0 /G1 peak and G2/M arrest were also displayed when compared to the control cells. These results suggest that verbascoside mediated-cell differentiation and apoptosis may be affected by telomere-telomerase-cell cycle dependent modulation. Thus, the antitumor mechanism of verbascoside is demonstrated once more by its inhibiting effect on telomerase activity in tumor cells, and the telomerase assay may provide a valuable screening method for antitumor activity of natural products.},
}
@article {pmid11855380,
year = {2002},
author = {Helder, MN and Wisman, GB and van der Zee, GJ},
title = {Telomerase and telomeres: from basic biology to cancer treatment.},
journal = {Cancer investigation},
volume = {20},
number = {1},
pages = {82-101},
doi = {10.1081/cnv-120000370},
pmid = {11855380},
issn = {0735-7907},
mesh = {Animals ; Antineoplastic Agents/chemistry/pharmacology ; Enzyme Inhibitors/chemistry/pharmacology ; Humans ; Models, Genetic ; Neoplasms/*enzymology ; Telomerase/antagonists &amp; inhibitors/*physiology ; Telomere/*physiology ; },
abstract = {The limited capacity to divide is one of the major differences between normal somatic cells and cancerous cells. This 'finite life span' of somatic cells is closely linked to loss of telomeric DNA at telomeres, the 'chromosome caps' consisting of repeated (7TAGGG) sequences., In more than 85% of advanced cancers, this telomeric attrition is compensated by telomerase, 'the immortality enzyme', implying that telomerase inhibition may restore mortality in tumor cells. This review discusses the progress in research on the structure and function of telomeres and the telomerase holoenzyme. In addition, new developments in telomere/telomerase targeting compounds such as antisense oligonucleotides and G-quadruplex stabilizing substances, but also new telomerase expression-related strategies such as telomerase promoter-driven suicide gene therapy and telomerase immunotherapy will be presented. It will be discussed how these data can be implemented in telomerase-directed therapies.},
}
@article {pmid11855149,
year = {2001},
author = {Liu, L and Sun, B and Liang, Y},
title = {[Analysis of telomerase activity and telomere length in acute myelogenous leukemia].},
journal = {Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi},
volume = {22},
number = {11},
pages = {592-594},
pmid = {11855149},
issn = {0253-2727},
mesh = {Bone Marrow Cells ; Cells, Cultured ; Fibroblasts ; Genetic Markers ; HeLa Cells ; Humans ; Leukemia, Myeloid, Acute/*enzymology/*genetics ; Skin/cytology ; Telomerase/genetics/*metabolism ; Telomere/*genetics ; Tumor Cells, Cultured ; },
abstract = {OBJECTIVE: To study the changes and significance of telomerase activity and telomere length in acute myelogenous leukemia.<br><br>METHODS: TRAP-ELISA-PAGE was used to detect telomerase activity, Southern blot to estimate the length of telomere.<br><br>RESULTS: Telomerase activity was significantly higher in AML(Absorption(A): 2.298 +/- 1.059) than in normal control(A: 0.387 +/- 0.598) and the mean telomere length of AML [(7.6 +/- 2.1) kb] was significantly shorter than that of normal control[(9.3 +/- 1.9) kb]. The alteration of the telomere length was detected mainly in telomerase-positive AML.<br><br>CONCLUSIONS: It suggested that there was a close relationship between telomerase activity and telomere length in AML. The activation of telomerase might play an important role in the genesis and development of AML and telomere length changes may correlate with the activation of telomerase.},
}
@article {pmid11854467,
year = {2002},
author = {Riou, JF and Guittat, L and Mailliet, P and Laoui, A and Renou, E and Petitgenet, O and Mégnin-Chanet, F and Hélène, C and Mergny, JL},
title = {Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {99},
number = {5},
pages = {2672-2677},
pmid = {11854467},
issn = {0027-8424},
mesh = {*Apoptosis ; Cell Line, Transformed ; Cellular Senescence ; *DNA ; G-Quadruplexes ; Humans ; Ligands ; Molecular Structure ; Telomerase/metabolism ; Telomere/*drug effects ; Triazines/chemistry/*pharmacology ; Tumor Cells, Cultured ; },
abstract = {Telomeres of human chromosomes contain a G-rich 3'-overhang that adopts an intramolecular G-quadruplex structure in vitro which blocks the catalytic reaction of telomerase. Agents that stabilize G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalyzed by telomerase and can therefore act as antitumor agents. We have identified by Fluorescence Resonance Energy Transfer a new series of quinoline-based G-quadruplex ligands that also exhibit potent and specific anti-telomerase activity with IC50 in the nanomolar concentration range. Long term treatment of tumor cells at subapoptotic dosage induces a delayed growth arrest that depends on the initial telomere length. This growth arrest is associated with telomere erosion and the appearance of the senescent cell phenotype (large size and expression of beta-galactosidase activity). Our data show that a G-quadruplex interacting agent is able to impair telomerase function in a tumor cell thus providing a basis for the development of new anticancer agents.},
}
@article {pmid11854176,
year = {2002},
author = {Callén, E and Samper, E and Ramírez, MJ and Creus, A and Marcos, R and Ortega, JJ and Olivé, T and Badell, I and Blasco, MA and Surrallés, J},
title = {Breaks at telomeres and TRF2-independent end fusions in Fanconi anemia.},
journal = {Human molecular genetics},
volume = {11},
number = {4},
pages = {439-444},
doi = {10.1093/hmg/11.4.439},
pmid = {11854176},
issn = {0964-6906},
mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; *Chromosome Aberrations ; DNA-Binding Proteins/metabolism ; Fanconi Anemia/*genetics ; Female ; Humans ; Male ; Protein Binding ; *Telomere/pathology ; Telomeric Repeat Binding Protein 2 ; },
abstract = {Fanconi anemia (FA) is a rare genetic disease characterized by chromosome instability, progressive pancytopenia and cancer susceptibility. Telomeres are intimately related to chromosome stability and play an important role in organismal viability at the hematological level. Since previous works suggested an accelerated shortening of telomeres in FA, we have studied several markers of telomere integrity and function in FA patients and age-matched controls to get insights into the mechanisms and consequences of telomere erosion in FA. A higher frequency of extra-chromosomic TTAGGG signals and of chromosome ends with undetectable TTAGGG repeats was observed in FA cells by fluorescence in situ hybridization (FISH), suggesting intensive breakage at telomeric sequences. This was proven by measuring the frequency of excess of telomeric signals per cell, which was 2.8-fold higher in FA. Consistent with previous reports, quantitative FISH analysis showed an accelerated telomere shortening of 0.68 kb in FA, which occurred concurrently in both chromosome arms in a similar magnitude. Our data therefore suggest that the telomere erosion in FA is caused by a higher rate of breakage at TTAGGG sequences in vivo in differentiated cells, in addition to mere replicative shortening during lymphocyte proliferation. Consistent with impaired telomeres in FA patients, we observed a >10-fold increase in chromosome end fusions in FA compared to normal controls. This observation was independent of TRF2, a telomere binding factor that protects human telomeres from end fusions, since immunohistochemistry studies in FA cell lines and corrected counterparts by retrovirus-mediated transfer of FANCA and FANCD2 cDNA showed that a functional FA pathway is not required for telomere binding of TRF2.},
}
@article {pmid11850796,
year = {2002},
author = {Ohyashiki, JH and Sashida, G and Tauchi, T and Ohyashiki, K},
title = {Telomeres and telomerase in hematologic neoplasia.},
journal = {Oncogene},
volume = {21},
number = {4},
pages = {680-687},
doi = {10.1038/sj.onc.1205075},
pmid = {11850796},
issn = {0950-9232},
mesh = {Antineoplastic Agents/therapeutic use ; Enzyme Inhibitors/therapeutic use ; Hematologic Neoplasms/*enzymology/*genetics/therapy ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/physiology ; Humans ; Leukemia/enzymology/genetics ; Lymphoma/enzymology/genetics ; Lymphoproliferative Disorders/enzymology/genetics ; Models, Genetic ; Myelodysplastic Syndromes/enzymology/genetics ; Telomerase/antagonists &amp; inhibitors/*metabolism ; Telomere/*metabolism/ultrastructure ; },
abstract = {Normal hematopoietic cells express telomerase activity, however the presence of telomerase does not necessarily imply stable and thus unchanging telomere length. Gradual telomere loss with aging and rapid cycling of hematopoietic stem cells might contribute to immunosenescence, exhausted hematopoiesis, and increased likelihood of malignant transformation. In leukemias and lymphomas, telomere length may reflect the cellular proliferative history, prior to immortalization. The level of telomerase activity is generally influenced by the fraction of cells in the proliferative pool. Shortened telomeres and high telomerase activity almost always correlates with disease severity in hematologic neoplasias such as relapsed leukemia and high-grade lymphomas, indicating that measurement of telomere length and telomerase activity might be useful to monitor disease condition. Since the mode of action of telomerase inhibitors may require telomeric shortening before induction of apoptosis, anti-telomerase therapy might be helpful for adjuvant therapy following conventional chemotherapy, in vitro purging of neoplastic cells in stem cell transplantation, and treating minimal residual disease. Some promising areas of tissue engineering include rejuvenation of hematopoietic stem cells for improving stem cell transplants or enhancing general immunity for older patients.},
}
@article {pmid11850787,
year = {2002},
author = {Hackett, JA and Greider, CW},
title = {Balancing instability: dual roles for telomerase and telomere dysfunction in tumorigenesis.},
journal = {Oncogene},
volume = {21},
number = {4},
pages = {619-626},
doi = {10.1038/sj.onc.1205061},
pmid = {11850787},
issn = {0950-9232},
support = {GM43080/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Division ; DNA Damage ; Humans ; Mice ; Models, Biological ; Mutation ; Neoplasms/*enzymology/etiology/*genetics ; Telomerase/*physiology ; Telomere/*physiology/ultrastructure ; Translocation, Genetic ; },
abstract = {Telomere shortening and telomerase activation both occur in human tumors. Telomere shortening has been proposed to have two conflicting roles in tumorigenesis: tumor suppression and initiation of chromosomal instability. Similarly, while telomerase activation is suggested to be necessary for tumor growth, telomerase may help to stabilize genomic instability. Here we review what is known about these conflicting roles and propose a framework to understand the role of telomerase in cancer progression.},
}
@article {pmid11850786,
year = {2002},
author = {Pandita, TK},
title = {ATM function and telomere stability.},
journal = {Oncogene},
volume = {21},
number = {4},
pages = {611-618},
doi = {10.1038/sj.onc.1205060},
pmid = {11850786},
issn = {0950-9232},
support = {NS34746/NS/NINDS NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia/genetics ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle ; Cell Cycle Proteins ; Chromatin/chemistry ; DNA-Binding Proteins ; Humans ; Models, Biological ; Mutation ; Neoplasms/genetics ; Protein Serine-Threonine Kinases/genetics/*physiology ; Proto-Oncogene Proteins c-abl/physiology ; Signal Transduction ; Telomerase/metabolism ; Telomere/chemistry/*metabolism/physiology ; Tumor Suppressor Proteins ; },
abstract = {Accumulation of DNA damage has been associated with the onset of senescence and predisposition to cancer. The gene responsible for ataxia telangiectasia (A-T) is ATM (ataxia-telangiectasia mutant), a master controller of cellular pathways and networks, orchestrating the responses to a specific type of DNA damage: the double strand break. Based on the homology of the human ATM gene to the TEL1, MEC1 and rad3 genes of yeast, it has now been demonstrated that mutations in ATM lead to defective telomere maintenance in mammalian cells. While ATM has both nuclear and cytoplasmic functions, this review will focus on its roles in telomere metabolism and how ATM and telomeres serve as controllers of cellular responses to DNA damage.},
}
@article {pmid11850785,
year = {2002},
author = {Henson, JD and Neumann, AA and Yeager, TR and Reddel, RR},
title = {Alternative lengthening of telomeres in mammalian cells.},
journal = {Oncogene},
volume = {21},
number = {4},
pages = {598-610},
doi = {10.1038/sj.onc.1205058},
pmid = {11850785},
issn = {0950-9232},
mesh = {Animals ; Humans ; Macromolecular Substances ; Models, Genetic ; Mutation ; Neoplasms/genetics/ultrastructure ; Nuclear Proteins/metabolism ; Recombination, Genetic ; Telomerase/metabolism ; Telomere/metabolism/*ultrastructure ; },
abstract = {Some immortalized mammalian cell lines and tumors maintain or increase the overall length of their telomeres in the absence of telomerase activity by one or more mechanisms referred to as alternative lengthening of telomeres (ALT). Characteristics of human ALT cells include great heterogeneity of telomere size (ranging from undetectable to abnormally long) within individual cells, and ALT-associated PML bodies (APBs) that contain extrachromosomal telomeric DNA, telomere-specific binding proteins, and proteins involved in DNA recombination and replication. Activation of ALT during immortalization involves recessive mutations in genes that are as yet unidentified. Repressors of ALT activity are present in normal cells and some telomerase-positive cells. Telomere length dynamics in ALT cells suggest a recombinational mechanism. Inter-telomeric copying occurs, consistent with a mechanism in which single-stranded DNA at one telomere terminus invades another telomere and uses it as a copy template resulting in net increase in telomeric sequence. It is possible that t-loops, linear and/or circular extrachromosomal telomeric DNA, and the proteins found in APBs, may be involved in the mechanism. ALT and telomerase activity can co-exist within cultured cells, and within tumors. The existence of ALT adds some complexity to proposed uses of telomere-related parameters in cancer diagnosis and prognosis, and poses challenges for the design of anticancer therapeutics designed to inhibit telomere maintenance.},
}
@article {pmid11850784,
year = {2002},
author = {Harrington, L and Robinson, MO},
title = {Telomere dysfunction: multiple paths to the same end.},
journal = {Oncogene},
volume = {21},
number = {4},
pages = {592-597},
doi = {10.1038/sj.onc.1205084},
pmid = {11850784},
issn = {0950-9232},
mesh = {Animals ; Apoptosis ; Cell Transformation, Neoplastic ; DNA Damage ; Humans ; Mice ; Models, Genetic ; RNA/genetics/physiology ; Signal Transduction ; Telomerase/genetics/physiology ; Telomere/genetics/*physiology ; Tumor Suppressor Protein p53/genetics/physiology ; },
abstract = {The molecular cloning of telomerase and telomere components has enabled the analysis and precise manipulation of processes that regulate telomere length maintenance. In mammalian cells and in other organisms, we now recognize that disruption of telomere integrity via any one of a number of perturbations induces chromosome instability and the activation of DNA damage responses. Thus, telomere dysfunction may represent a physiological trigger of the DNA damage or apoptotic response in an analogous fashion to other genotoxic insults that introduce chromosome breaks. Initial studies in mice lacking the murine telomerase RNA and in cells expressing a dominant negative version of the telomere binding protein TRF2 revealed a strong p53-dependent response to telomere dysfunction. Yet, telomere dysfunction exhibits p53-independent effects as well, an observation supported by p53-independent responses to telomere dysfunction in p53 mutant human tumor cell lines and mouse cells. As most tumors are compromised for p53 function, examination of this p53-independent response warrants closer attention. A better understanding of this p53-independent response may prove critical for determining the ultimate utility of telomerase inhibitors in the clinic. This review will summarize our current understanding of the molecular responses to telomere dysfunction in mammalian cells.},
}
@article {pmid11850783,
year = {2002},
author = {Goytisolo, FA and Blasco, MA},
title = {Many ways to telomere dysfunction: in vivo studies using mouse models.},
journal = {Oncogene},
volume = {21},
number = {4},
pages = {584-591},
doi = {10.1038/sj.onc.1205085},
pmid = {11850783},
issn = {0950-9232},
mesh = {Aging ; Animals ; DNA Repair ; *Mice ; Mice, Knockout ; *Models, Animal ; Models, Genetic ; Neoplasms/enzymology/etiology ; Nuclear Proteins/genetics/physiology ; Telomere/chemistry/genetics/*physiology ; },
abstract = {The existence of a capping structure at the extremities of chromosomes was first deduced in the 1930s by Herman Müller (Müller, 1938), who showed that X-irradiation of Drosophila rarely resulted in terminal deletions or inversions of chromosomes, suggesting that chromosome ends have protective structures that distinguish them from broken chromosomes, which he named telomeres. In this review, we will focus on mammalian telomeres and, in particular, on the analysis of different mouse models for proteins that are important for telomere function, such as telomerase and various telomere-binding proteins. These murine models are helping us to understand the consequences of telomere dysfunction for cancer, aging and DNA repair, as well as, the molecular mechanisms by which telomeres exert their protective function.},
}
@article {pmid11850782,
year = {2002},
author = {Ford, LP and Wright, WE and Shay, JW},
title = {A model for heterogeneous nuclear ribonucleoproteins in telomere and telomerase regulation.},
journal = {Oncogene},
volume = {21},
number = {4},
pages = {580-583},
doi = {10.1038/sj.onc.1205086},
pmid = {11850782},
issn = {0950-9232},
support = {AG01228/AG/NIA NIH HHS/United States ; AG07992/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Heterogeneous Nuclear Ribonucleoprotein A1 ; *Heterogeneous-Nuclear Ribonucleoprotein Group A-B ; *Heterogeneous-Nuclear Ribonucleoprotein Group C ; Heterogeneous-Nuclear Ribonucleoproteins ; Humans ; Macromolecular Substances ; Models, Genetic ; Ribonucleoproteins/*physiology ; Telomerase/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a large family of nucleic acid binding proteins that are often found in, but not restricted to, the 40S-ribonucleoprotein particle. Subsets of hnRNPs are strictly nuclear while others shuttle between the nucleus and cytoplasm. Members of the hnRNP family have been implicated to have roles in many aspects of mRNA maturation/turnover and in telomere and telomerase regulation. Telomeres are repetitive DNA elements mainly found at the ends of human chromosomes. In most normal cells, telomeres shorten with each cell division. Telomere shortening can be compensated for by a ribonucleoprotein complex, called telomerase. Telomerase, consisting of an integral RNA and catalytic protein component as well as several auxiliary factors, extends the 3'-G-rich strand of the ends of the telomeres. Here we present new data and describe a model that implicates the telomerase bound hnRNPs in promoting telomere access by interacting with telomeres. Telomere bound hnRNPs include hnRNP A1, A2-B1, D and E and telomerase bound hnRNPs including hnRNPA1 C1/C2 and D. The telomere and telomerase bound hnRNPs may prove to be good targets for regulating telomere length.},
}
@article {pmid11850778,
year = {2002},
author = {de Lange, T},
title = {Protection of mammalian telomeres.},
journal = {Oncogene},
volume = {21},
number = {4},
pages = {532-540},
doi = {10.1038/sj.onc.1205080},
pmid = {11850778},
issn = {0950-9232},
mesh = {Animals ; *Antigens, Nuclear ; Apoptosis ; Cellular Senescence ; Chromosome Aberrations ; *DNA Helicases ; DNA-Activated Protein Kinase ; DNA-Binding Proteins/physiology ; Humans ; Ku Autoantigen ; Models, Genetic ; Nuclear Proteins/physiology ; Nucleic Acid Conformation ; Protein Serine-Threonine Kinases/physiology ; Recombination, Genetic ; *Saccharomyces cerevisiae Proteins ; Telomere/chemistry/*genetics/metabolism ; Telomeric Repeat Binding Protein 2 ; Yeasts/genetics ; },
abstract = {Telomeres allow cells to distinguish natural chromosome ends from damaged DNA. When telomere function is disrupted, a potentially lethal DNA damage response can ensue, DNA repair activities threaten the integrity of chromosome ends, and extensive genome instability can arise. It is not clear exactly how the structure of telomere ends differs from sites of DNA damage and how telomeres protect chromosome ends from DNA repair activities. What are the defining structural features of telomeres and through which mechanisms do they ensure chromosome end protection? What is the molecular basis of the telomeric cap and how does it act to sequester the chromosome end? Here I discuss data gathered in the last few years, suggesting that the protection of human chromosome ends primarily depends on the telomeric protein TRF2 and that telomere capping involves the formation of a higher order structure, the telomeric loop or t-loop.},
}
@article {pmid11850777,
year = {2002},
author = {Lundblad, V},
title = {Telomere maintenance without telomerase.},
journal = {Oncogene},
volume = {21},
number = {4},
pages = {522-531},
doi = {10.1038/sj.onc.1205079},
pmid = {11850777},
issn = {0950-9232},
mesh = {DNA Replication ; DNA, Fungal/genetics ; Humans ; Models, Genetic ; *Recombination, Genetic ; Repetitive Sequences, Nucleic Acid ; Saccharomycetales/*genetics ; Telomerase/physiology ; Telomere/*genetics/physiology ; },
abstract = {Recombination-dependent maintenance of telomeres, first discovered in budding yeast, has revealed an alternative pathway for telomere maintenance that does not require the enzyme telomerase. Experiments conducted in two budding yeasts, S. cerevisiae and K. lactis, have shown recombination can replenish terminal G-rich telomeric tracts that would otherwise shorten in the absence of telomerase, as well as disperse and amplify sub-telomeric repeat elements. Investigation of the genetic requirements for this process have revealed that at least two different recombination pathways, defined by RAD50 and RAD51, can promote telomere maintenance. Although critically short telomeres are very recombinogenic, recombination among telomeres that have only partially shortened in the absence of telomerase can also contribute to telomerase-independent survival. These observations provide new insights into the mechanism(s) by which recombination can restore telomere function in yeast, and suggest future experiments for the investigation of potentially similar pathways in human cells.},
}
@article {pmid11850776,
year = {2002},
author = {Tham, WH and Zakian, VA},
title = {Transcriptional silencing at Saccharomyces telomeres: implications for other organisms.},
journal = {Oncogene},
volume = {21},
number = {4},
pages = {512-521},
doi = {10.1038/sj.onc.1205078},
pmid = {11850776},
issn = {0950-9232},
mesh = {Animals ; Cell Nucleus/genetics ; Chromatin/chemistry ; DNA, Fungal/genetics ; Forecasting ; *Gene Expression Regulation, Fungal ; *Gene Silencing ; Genes, Fungal ; Humans ; Nucleic Acid Conformation ; Regulatory Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*genetics/metabolism ; Telomere/chemistry/genetics/*physiology ; Transcription, Genetic ; },
abstract = {Telomeres are the natural ends of eukaryotic chromosomes. In most organisms, telomeres consist of simple, repeated DNA with the strand running 5' to 3' towards the end of the chromosome being rich in G residues. In cases where the very end of the chromosome has been examined, the G-strand is extended to form a short, single stranded tail. The chromatin structure of telomeric regions often has features that distinguish them from other parts of the genome. Because telomeres protect chromosome ends from degradation and end-to-end fusions and prevent the loss of terminal DNA by serving as a substrate for telomerase, they are essential for the stable maintenance of eukaryotic chromosomes. In addition to their essential functions, telomeres in diverse organisms are specialized sites for gene expression. Transcription of genes located next to telomeres is repressed, a phenomenon termed telomere position effect (TPE). TPE is best characterized in the yeast Saccharomyces cerevisiae. This article will focus on the silencing properties of Saccharomyces telomeres and end with speculation on the role of TPE in yeasts and other organisms.},
}
@article {pmid11850775,
year = {2002},
author = {Kim Sh, SH and Kaminker, P and Campisi, J},
title = {Telomeres, aging and cancer: in search of a happy ending.},
journal = {Oncogene},
volume = {21},
number = {4},
pages = {503-511},
doi = {10.1038/sj.onc.1205077},
pmid = {11850775},
issn = {0950-9232},
mesh = {*Aging ; Animals ; Cell Death ; Cellular Senescence ; Chromosome Aberrations ; Humans ; Mice ; Models, Biological ; Neoplasms/*genetics ; Phenotype ; Telomere/chemistry/*physiology ; },
abstract = {Telomeres are distinctive structures, composed of a repetitive DNA sequence and associated proteins, that cap the ends of linear chromosomes. Telomeres are essential for maintaining the integrity and stability of eukaryotic genomes. In addition, under some circumstances, telomeres can influence cellular gene expression. In mammals, the length, structure, and function of telomeres have been proposed to contribute to cellular and organismal phenotypes associated with cancer and aging. Here, we discuss what is known about the basis for the links between telomeres, aging and cancer, and some of the known and proposed consequences of telomere dysfunction and maintenance for mammalian cells and organisms.},
}
@article {pmid11847128,
year = {2002},
author = {Figueiredo, LM and Freitas-Junior, LH and Bottius, E and Olivo-Marin, JC and Scherf, A},
title = {A central role for Plasmodium falciparum subtelomeric regions in spatial positioning and telomere length regulation.},
journal = {The EMBO journal},
volume = {21},
number = {4},
pages = {815-824},
pmid = {11847128},
issn = {0261-4189},
mesh = {Animals ; Blotting, Southern ; In Situ Hybridization, Fluorescence ; Plasmodium falciparum/genetics/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; *Telomere ; Transcription, Genetic ; },
abstract = {In the protozoan malaria parasite, Plasmodium falciparum, the telomere-associated sequences (TASs) of the 14 linear chromosomes display a similar higher order organization and form clusters of four to seven telomeres localized at the nuclear periphery. Experimental evidence has shown that the physical tethering of chromosome ends enhances the ectopic recombination between gene families involved in antigenic variation and parasite sequestration. Using FISH analysis, we observed that chromosome ends lacking the subtelomeric region are usually delocalized from telomere clusters, but still remain at the nuclear periphery. This indicates that subtelomeric DNA is necessary for cluster formation but is not essential for peripheral positioning. Intriguingly, these truncated chromosomes have unusually long telomeric tracts (up to three times longer than average length), showing that TASs play a role in telomere length regulation. On these chromosomes, the newly formed telomere frequently extends from truncated genes leading, in some cases, to the transcription of telomeric DNA. The implications of both subtelomeric gene expression and nuclear architecture in the virulence of this serious human pathogen are discussed.},
}
@article {pmid11846391,
year = {2002},
author = {Suda, T and Fujiyama, A and Takimoto, M and Igarashi, M and Kuroiwa, T and Waguri, N and Kawai, H and Mita, Y and Aoyagi, Y},
title = {Interchromosomal telomere length variation.},
journal = {Biochemical and biophysical research communications},
volume = {291},
number = {2},
pages = {210-214},
doi = {10.1006/bbrc.2002.6425},
pmid = {11846391},
issn = {0006-291X},
mesh = {Chromosomes/ultrastructure ; DNA Restriction Enzymes/chemistry ; Genetic Variation ; Humans ; Male ; Repetitive Sequences, Nucleic Acid ; Telomere/chemistry/*ultrastructure ; Tumor Cells, Cultured ; },
abstract = {Despite the recent discovery of interchromosomal telomere length variation, a role for heterogeneity in telomere maintenance has yet to be established. This study aimed to clarify relative telomere length differences between chromosomes. Combined chromosomal sorting and telomeric repeat content analysis in GM130B cells, the relative telomeric repeat content in each chromosome, were calculated. Each chromosome could be isolated except for chromosomes 1 and 2 and chromosomes 9 to 12, which were isolated in a group. Telomere length was correlated with the size of the corresponding chromosome. Concomitant relative telomeric repeat content analysis in each chromosome and terminal restriction fragment analysis using the whole genome revealed that the terminal restriction fragments of each chromosome were heterogenously distributed through the smear of the fragments. This is the first description of an association between telomere length and chromosome size.},
}
@article {pmid11841457,
year = {2002},
author = {de Pauw, ES and Otto, SA and Wijnen, JT and Vossen, JM and van Weel, MH and Tanke, HJ and Miedema, F and Willemze, R and Roelofs, H and Fibbe, WE},
title = {Long-term follow-up of recipients of allogeneic bone marrow grafts reveals no progressive telomere shortening and provides no evidence for haematopoietic stem cell exhaustion.},
journal = {British journal of haematology},
volume = {116},
number = {2},
pages = {491-496},
doi = {10.1046/j.0007-1048.2001.03283.x},
pmid = {11841457},
issn = {0007-1048},
mesh = {Acute Disease ; Adolescent ; Adult ; Anemia, Aplastic/immunology/therapy ; CD4-Positive T-Lymphocytes/ultrastructure ; Child ; Child, Preschool ; Follow-Up Studies ; Granulocytes/ultrastructure ; *Hematopoietic Stem Cell Transplantation ; Humans ; Immunologic Memory ; Leukemia/genetics/immunology/*therapy ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology/therapy ; Leukemia, Myeloid/immunology/therapy ; Leukocytes/*ultrastructure ; Lymphocyte Count ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology/therapy ; Telomere/*ultrastructure ; Tissue Donors ; Transplantation, Homologous ; },
abstract = {Accelerated telomere shortening has been proposed as a possible long-term risk of allogeneic bone marrow transplantation (allo-BMT). In this study we monitored telomere length in white blood cells (WBC), granulocytes, and naïve and memory CD4+ T lymphocytes in recipients of allo-BMT at long-term follow-up. Peripheral blood was collected from 10 allo-BMT recipients and donors at a median interval of 18 years after allo-BMT. Telomere length was determined using Southern blot analysis. Similar to results previously reported at short-term follow-up, a small difference in telomere length (0.1-0.3 kb) between recipients and donors was detected in WBC, granulocytes and naïve CD4+ T cells. Our data therefore provide no evidence for sustained telomere shortening in leucocytes, and render the possibility of long-term haematopoietic graft failure unlikely. In addition, we observed two phenomena that may be related to involution of the thymus. First, the number of naïve CD4+ T cells in the blood was significantly lower in recipients (0.4 x 10(9)/l) than in donors (0.7 x 10(9)/l) (P < 0.05). Second, telomeres in memory CD4+ T cells from recipients were on average 0.6 kb shorter than those from donors (P = 0.01). The latter may be related to the reported rapid peripheral expansion of memory T cells immediately after transplantation.},
}
@article {pmid11796266,
year = {2002},
author = {Artandi, SE},
title = {Telomere shortening and cell fates in mouse models of neoplasia.},
journal = {Trends in molecular medicine},
volume = {8},
number = {1},
pages = {44-47},
doi = {10.1016/s1471-4914(01)02222-5},
pmid = {11796266},
issn = {1471-4914},
mesh = {Animals ; Apoptosis ; Cell Death ; Cell Division ; Cell Lineage ; Disease Models, Animal ; Genes, p53 ; Humans ; Mice ; Models, Biological ; Neoplasms/*metabolism ; *Telomere ; },
abstract = {Cell division in the absence of telomerase leads to telomere shortening that can activate checkpoint responses and impair chromosomal stability. The absence of telomerase in primary human cells and its near universal reactivation in human cancers has highlighted the importance of telomere shortening and telomerase reactivation during tumor development. Data from telomerase-deficient mouse models of cancer have indicated that telomere shortening can exert profoundly different influences on cell fates in developing cancers, limiting tumorigenesis by enhancing cell death or facilitating carcinogenesis by compromising chromosomal stability. These alternate fates depend on the integrity of the p53 pathway and on cell type.},
}
@article {pmid11836581,
year = {2002},
author = {Pathak, S and Multani, AS and Furlong, CL and Sohn, SH},
title = {Telomere dynamics, aneuploidy, stem cells, and cancer (review).},
journal = {International journal of oncology},
volume = {20},
number = {3},
pages = {637-641},
pmid = {11836581},
issn = {1019-6439},
support = {RRO-4999-01/RR/NCRR NIH HHS/United States ; },
mesh = {Aging ; *Aneuploidy ; Animals ; Chromosome Aberrations ; Humans ; Mitosis ; Neoplasms/*genetics/*metabolism ; Stem Cells/*metabolism ; Telomere/*ultrastructure ; },
abstract = {The real cause of genetic instability, which is the hall-mark of most cancers, is poorly understood. Specific gene mutations and acquired aneuploidy have been implicated as the root causes of genetic instability. Here we propose and cite evidence for the hypothesis that genetic instability of cancer cells is caused by telomere dynamics, erosion and/or amplification of the TTAGGG repeat sequences present at chromosomal termini. Since telomeres determine the domain of individual chromosomes within a nucleus and protect them from internal and external challenges, their erosion will destabilize the cell karyotype. Our hypothesis predicts that telomere dynamics provides the single unifying mechanism playing a major role in speciation, aging and cancer development. It was found that metastatic cancers of different histologic phenotypes, as well as mammalian taxa with active speciation and larger numbers of species exhibit amplification of their telomeric DNA as compared to non-metastatic counterpart cancers and taxa with only a limited number of species. The dynamic nature of this DNA can be found not only in the cancer cells but also in the peripheral lymphocytes of cancer patients. Human syndromes such as Down, Turner, Bloom, Werner, Fanconi, ataxia and many others, show aneuploidy and also are prone to develop various malignancies and premature aging. We have found that <normal cells> of all these syndromes have a reduced amount of telomeric DNA associated with specific mitotic catastrophes as compared to cells of age- and sex-matched normal individuals. From these and additional data generated by our group concerning speciation, aging and cancer karyotypes, we conclude that aneuploidy, which is responsible for birth defects, cancer initiation and is a major player in natural speciation, is a consequence of telomere dynamics. Because telomere reduction is linked to the aging process, which is a risk factor for cancer development in the human population, our hypothesis offers a unifying mechanism for the initiation of both hematologic and solid cancers, as well as for the origin of new species.},
}
@article {pmid11836536,
year = {2002},
author = {Peersen, OB and Ruggles, JA and Schultz, SC},
title = {Dimeric structure of the Oxytricha nova telomere end-binding protein alpha-subunit bound to ssDNA.},
journal = {Nature structural biology},
volume = {9},
number = {3},
pages = {182-187},
doi = {10.1038/nsb761},
pmid = {11836536},
issn = {1072-8368},
mesh = {Animals ; Base Sequence ; Binding Sites ; Crystallography, X-Ray ; DNA, Single-Stranded/*chemistry/genetics/*metabolism ; DNA-Binding Proteins/*chemistry/*metabolism ; Dimerization ; Models, Molecular ; Nucleic Acid Conformation ; *Oxytricha/chemistry/genetics ; Protein Binding ; Protein Structure, Tertiary ; Protein Subunits ; Protozoan Proteins/chemistry/metabolism ; Repetitive Sequences, Nucleic Acid/genetics ; Telomere/*chemistry/genetics/*metabolism ; },
abstract = {Telomeres are the specialized protein--DNA complexes that cap and protect the ends of linear eukaryotic chromosomes. The extreme 3' end of the telomeric DNA in Oxytricha nova is bound by a two-subunit sequence-specific and 3' end-specific protein called the telomere end-binding protein (OnTEBP). Here we describe the crystal structure of the alpha-subunit of OnTEBP in complex with T4G4 single-stranded telomeric DNA. This structure shows an (alpha--ssDNA)2 homodimer with a large approximately 7,000 A2 protein--protein interface in which the domains of alpha are rearranged extensively from their positions in the structure of an alpha--beta--ssDNA ternary complex. The (alpha--ssDNA)2 complex can bind two telomeres on opposite sides of the dimer and, thus, acts as a protein mediator of telomere--telomere associations. The structures of the (alpha--ssDNA)2 dimer presented here and the previously described alpha--beta--ssDNA complex demonstrate that OnTEBP forms multiple telomeric complexes that potentially mediate the assembly and disassembly of higher order telomeric structures.},
}
@article {pmid11830355,
year = {2002},
author = {Takubo, K and Izumiyama-Shimomura, N and Honma, N and Sawabe, M and Arai, T and Kato, M and Oshimura, M and Nakamura, K},
title = {Telomere lengths are characteristic in each human individual.},
journal = {Experimental gerontology},
volume = {37},
number = {4},
pages = {523-531},
doi = {10.1016/s0531-5565(01)00218-2},
pmid = {11830355},
issn = {0531-5565},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Blotting, Southern ; Brain/ultrastructure ; Child ; Child, Preschool ; DNA/analysis ; Electrophoresis, Gel, Pulsed-Field ; Female ; Humans ; Infant ; Kidney/ultrastructure ; Liver/ultrastructure ; Male ; Middle Aged ; Myocardium/ultrastructure ; Regression Analysis ; *Telomere ; },
abstract = {BACKGROUND: A great deal of attention has been focused on telomeres in relation to cellular aging, immortality, and cancer. However, there is no simple link between telomeres and tissue turnover. We recently proposed a hypothesis that telomere shortening with aging and telomere lengths in different organs are characteristic for human individuals.<br><br>METHODS: To test this, telomere lengths were measured using DNA from cerebral cortex, myocardium, liver, renal cortex and spleen tissues obtained from human subjects ranging in age from neonates to centenarians.<br><br>RESULTS: Regression analyses demonstrated telomere reduction rates of 29-60 base pair (bp) per year in the liver, renal cortex and spleen, but no such decrease in the cerebral cortex and myocardium. Significant correlation was found between tissues within individuals, such as cerebral cortex versus (vs) myocardium, cerebral cortex vs liver, cerebral cortex vs renal cortex, myocardium vs liver, myocardium vs renal cortex, and liver vs renal cortex. In most cases, the longest telomeres were observed in the myocardium and the shortest in the liver or renal cortex.<br><br>CONCLUSIONS: Telomere lengths did not show clear correlation with tissue renewal times in vivo, but rather were characteristic for individuals.},
}
@article {pmid11830354,
year = {2002},
author = {Kammori, M and Nakamura, K and Kawahara, M and Mimura, Y and Kaminishi, M and Takubo, K},
title = {Telomere shortening with aging in human thyroid and parathyroid tissue.},
journal = {Experimental gerontology},
volume = {37},
number = {4},
pages = {513-521},
doi = {10.1016/s0531-5565(01)00178-4},
pmid = {11830354},
issn = {0531-5565},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Child, Preschool ; DNA/analysis ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Organ Specificity ; Parathyroid Glands/*ultrastructure ; *Telomere ; Thyroid Gland/*ultrastructure ; },
abstract = {Progressive telomere shortening with aging was studied using normal thyroid tissue specimens from 46 human subjects aged between 0 and 98 yr and normal parathyroid tissue specimens from 21 human subjects aged between 0 and 83 yrs. There has hitherto been no information documented about telomere length in such thyroid and parathyroid tissues. Age-related shortening at rates of 91 and 92 base pairs (bp) per year, respectively, were observed. Telomere lengths of normal thyroid tissues were 16.53 +/- 1.10 (mean +/- SE), 14.31 +/- 0.80, 11.27 +/- 0.68 and 8.73 +/- 1.08 kbp for age groups less than 2, 20-50, 51-80 and more than 80 yr. Telomere lengths of normal parathyroid tissues were 15.80 +/- 1.46 (mean +/- SE), 15.36 +/- 0.86 and 10.93 +/- 0.78 kbp for age groups less than 4, 20-50 and 51-80 yr. Telomere shortening occurred after 50 yr of age in thyroid and parathyroid tissues. Human thyroid and parathyroid tissues do not seem to show the rapid reduction in telomere length early in life that was reported for some human cell types, suggesting that the rate of telomere shortening has tissue-specific characteristics.},
}
@article {pmid11829491,
year = {2002},
author = {van Geel, M and Dickson, MC and Beck, AF and Bolland, DJ and Frants, RR and van der Maarel, SM and de Jong, PJ and Hewitt, JE},
title = {Genomic analysis of human chromosome 10q and 4q telomeres suggests a common origin.},
journal = {Genomics},
volume = {79},
number = {2},
pages = {210-217},
doi = {10.1006/geno.2002.6690},
pmid = {11829491},
issn = {0888-7543},
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; *Chromosomes, Human, Pair 10 ; *Chromosomes, Human, Pair 4 ; DNA ; *Evolution, Molecular ; Gene Duplication ; Gene Expression ; Humans ; Molecular Sequence Data ; Muscular Dystrophy, Facioscapulohumeral/genetics ; Physical Chromosome Mapping ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; *Telomere ; },
abstract = {The subtelomeric region of human chromosome 4q contains the locus for facioscapulohumeral muscular dystrophy (FSHD). The FSHD mutation is a deletion within an array of 3.3-kb tandem repeats (D4Z4). The disease mechanism is unknown but is postulated to involve position effect. A closely related 3.3-kb array on chromosome 10qter, in contrast, is not associated with a disease phenotype. We show here that the 4q homology on chromosome 10 is not confined to the 3.3-kb repeats but extends both proximally (42 kb) and distally to include the telomere. We have also identified the most distal expressed gene on 10q known so far, mapping only 96 kb from the 3.3-kb repeat array. A 4q variant has also been identified; there is 92%nucleotide identity between the two 4q forms, 4qA and 4qB. The 4qter and 10qter forms show homology to other chromosome ends, including 4p, 21q, and 22q, and these regions may represent a relatively common subtelomeric domain.},
}
@article {pmid11819821,
year = {2001},
author = {Fang, DC and Yang, SM and Zhou, XD and Wang, DX and Luo, YH},
title = {Telomere erosion is independent of microsatellite instability but related to loss of heterozygosity in gastric cancer.},
journal = {World journal of gastroenterology},
volume = {7},
number = {4},
pages = {522-526},
pmid = {11819821},
issn = {1007-9327},
mesh = {Adult ; Aged ; DNA, Neoplasm/analysis ; Female ; Frameshift Mutation ; Humans ; Loss of Heterozygosity/*genetics ; Male ; Microsatellite Repeats/*genetics ; Middle Aged ; Stomach Neoplasms/*genetics/pathology ; Telomere/*pathology ; },
abstract = {AIM: To correlate the length of the telomere to microsatellite instability (MSI) and loss of heterozygosity (LOH) of APC, MCC and DCC genes in gastric carcinomas.<br><br>METHODS: Telomeric restriction fragment (TRF) length of gastric cancer was measured with Southern blot. LOH of APC, MCC and DCC genes, microsatellite instability (MSI) and frameshift mutation of hMSH6, TGF-betaRII and BAX genes were analyzed by PCR-based methods.<br><br>RESULTS: Sixty-eight cases of sporadic gastric carcinoma were studied for MSI using five microsatellite markers. MSI in at least one locus was detected in 17 (25%) of 68 tumors analyzed. Frameshift mutations of hMSH6, TGF-betaRII and BAX were detected in 2,6 and 3 of gastric carcinomas respectively showing high MSI (> or = 2 loci, n = 8), but none was found in those showing low MSI (only one locus, n = 9) or MSS (tumor lacking MSI or stable, n = 51). Thirty-five cases, including all high MSI and low MSI, were studied for TRF. The mean TRF length was not correlated with clinicopathological parameters. No association was observed between TRF length and MSI or frameshift mutation. On the contrary, LOH at the DCC locus was related to telomere shortening (P<0.01). This tendency was also observed in APC and MCC genes, although there was no statistical significance.<br><br>CONCLUSION: The development of gastric cancer can arise through two different genetic pathways. In high MSI gastric cancers, defective mismatch repair allows mutations to accumulate and generate the high MSI phenotype. In gastric cancers showing either low MSI or MSS, multiple deletions may represent the LOH pathway. Telomere erosion is independent of high MSI phenotype but related to the LOH pathway in gastric cancer.},
}
@article {pmid11819461,
year = {1999},
author = {Yakoob, J and Hu, GL and Fan, XG and Zhang, Z},
title = {Telomere, telomerase and digestive cancer.},
journal = {World journal of gastroenterology},
volume = {5},
number = {4},
pages = {334-337},
pmid = {11819461},
issn = {2219-2840},
}
@article {pmid11813198,
year = {2002},
author = {Baerlocher, GM and Mak, J and Tien, T and Lansdorp, PM},
title = {Telomere length measurement by fluorescence in situ hybridization and flow cytometry: tips and pitfalls.},
journal = {Cytometry},
volume = {47},
number = {2},
pages = {89-99},
doi = {10.1002/cyto.10053},
pmid = {11813198},
issn = {0196-4763},
support = {AI29524/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Cattle ; DNA/analysis ; Fibroblasts/chemistry/cytology ; Flow Cytometry/*methods ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Leukocytes/chemistry ; Mice ; Sheep ; Swine ; Telomere/*chemistry ; Thymus Gland/chemistry/cytology ; },
abstract = {BACKGROUND: Telomeres containing noncoding DNA repeats at the end of the chromosomes are essential for chromosomal stability and are implicated in regulating the replication and senescence of cells. The gradual loss of telomere repeats in cells has been linked to aging and tumor development and methods to measure telomere length are of increasing interest. At least three methods for measuring the length of telomere repeats have been described: Southern blot analysis and quantitative fluorescence in situ hybridization using either digital fluorescence microscopy (Q-FISH) or flow cytometry (flow-FISH). Both Southern blot analysis and Q-FISH have specific limitations and are time-consuming, whereas the flow-FISH technique requires relatively few cells (10(5)) and can be completed in a single day. A further advantage of the flow-FISH method is that data on the telomere length from individual cells and subsets of cells (lymphocytes and granulocytes) can be acquired from the same sample. In order to obtain accurate and reproducible results using the flow-FISH technique, we systematically explored the influence of various steps in the protocol on telomere length values and established an acceptable range for the most critical parameters.<br><br>METHODS: Isolated leukocytes from whole blood are denatured by heat and 70%/75% formamide, then hybridized with or without a telomere-specific fluorescein isothiocyante (FITC)-conjugated peptide nucleic acid probe (PNA). Unbound telomere PNA is washed away, the DNA is counterstained, and telomere fluorescence is measured on a flow cytometer using an argon ion laser (488 nm) to excite FITC. For each sample, duplicates of telomere PNA-stained and unstained tubes are analyzed.<br><br>RESULTS: Cell counts and flow-FISH telomere length measurements were performed on leukocytes and thymocytes of humans and other species. Leukocyte suspensions were prepared by two red blood cell lysis steps with ammonium chloride. Optimal denaturation of DNA was achieved by heating at 85-87 degrees C for 15 min in a solution containing 70%/75% formamide. Hybridization was performed at room temperature with a 0.3 microg/ml telomere-PNA probe for at least 60-90 min. Unbound telomere-PNA probe was diluted at least 4,000-40,000 times with wash steps containing 70%/75% formamide at room temperature. LDS 751 and DAPI were suitable as DNA counterstains as they did not show significant interference with telomere length measurement.<br><br>CONCLUSIONS: The use of flow-FISH for telomere length measurements in nucleated blood cells requires tight adherence to an optimized protocol. The method described here can be used to determine rapidly the telomere length in subsets of nucleated blood cells.},
}
@article {pmid11809834,
year = {2002},
author = {Katayama, S and Kitamura, K and Lehmann, A and Nikaido, O and Toda, T},
title = {Fission yeast F-box protein Pof3 is required for genome integrity and telomere function.},
journal = {Molecular biology of the cell},
volume = {13},
number = {1},
pages = {211-224},
pmid = {11809834},
issn = {1059-1524},
mesh = {Amino Acid Sequence ; Cell Cycle Proteins/metabolism ; Cell Nucleus/metabolism ; Chromosome Aberrations ; Chromosome Deletion ; *Chromosomes, Fungal ; Consensus Sequence ; DNA Damage ; F-Box Proteins/chemistry/genetics/*metabolism ; Fluorescent Antibody Technique ; Genome, Fungal ; Microscopy, Fluorescence ; Molecular Sequence Data ; Mutation ; Peptide Synthases/metabolism ; SKP Cullin F-Box Protein Ligases ; Schizosaccharomyces/*genetics/metabolism ; Schizosaccharomyces pombe Proteins/chemistry/genetics/*metabolism ; Sequence Homology, Amino Acid ; Telomere/*metabolism ; Ultraviolet Rays/adverse effects ; },
abstract = {The Skp1-Cullin-1/Cdc53-F-box protein (SCF) ubiquitin ligase plays an important role in various biological processes. In this enzyme complex, a variety of F-box proteins act as receptors that recruit substrates. We have identified a fission yeast gene encoding a novel F-box protein Pof3, which contains, in addition to the F-box, a tetratricopeptide repeat motif in its N terminus and a leucine-rich-repeat motif in the C terminus, two ubiquitous protein-protein interaction domains. Pof3 forms a complex with Skp1 and Pcu1 (fission yeast cullin-1), suggesting that Pof3 functions as an adaptor for specific substrates. In the absence of Pof3, cells exhibit a number of phenotypes reminiscent of genome integrity defects. These include G2 cell cycle delay, hypersensitivity to UV, appearance of lagging chromosomes, and a high rate of chromosome loss. pof3 deletion strains are viable because the DNA damage checkpoint is continuously activated in the mutant, and this leads to G2 cell cycle delay, thereby preventing the mutant from committing lethal mitosis. Pof3 localizes to the nucleus during the cell cycle. Molecular analysis reveals that in this mutant the telomere is substantially shortened and furthermore transcriptional silencing at the telomere is alleviated. The results highlight a role of the SCF(Pof3) ubiquitin ligase in genome integrity via maintaining chromatin structures.},
}
@article {pmid11809709,
year = {2002},
author = {Franco, S and Segura, I and Riese, HH and Blasco, MA},
title = {Decreased B16F10 melanoma growth and impaired vascularization in telomerase-deficient mice with critically short telomeres.},
journal = {Cancer research},
volume = {62},
number = {2},
pages = {552-559},
pmid = {11809709},
issn = {0008-5472},
mesh = {Animals ; Apoptosis/physiology ; Cell Division/physiology ; Collagen ; Drug Combinations ; Female ; Laminin ; Male ; Melanoma, Experimental/*blood supply/enzymology/pathology ; Mice ; Mice, Inbred C57BL ; Neovascularization, Pathologic/*enzymology/pathology ; Proteoglycans ; Telomerase/*deficiency/genetics ; Telomere/*physiology ; },
abstract = {Endothelial cell function and angiogenesis are modulated by aging. However, the underlying molecular mechanisms are largely unknown. Here we show that in telomerase-deficient mice Terc(-/-), short telomeres result in a sharp decrease in angiogenesis in both Matrigel implants and murine melanoma grafts. In the latter model, decreased microvessel counts in late generation Terc(-/-) mice led to diminished tumor cell proliferation and increased tumor cell apoptosis, resulting in a lower tumor growth rate. Our results indicate that telomere length is a key molecular determinant of angiogenic potential in vivo and that telomere length modifiers and telomerase inhibitors could be useful antiangiogenic agents.},
}
@article {pmid11805059,
year = {2002},
author = {Siriaco, GM and Cenci, G and Haoudi, A and Champion, LE and Zhou, C and Gatti, M and Mason, JM},
title = {Telomere elongation (Tel), a new mutation in Drosophila melanogaster that produces long telomeres.},
journal = {Genetics},
volume = {160},
number = {1},
pages = {235-245},
pmid = {11805059},
issn = {0016-6731},
mesh = {Anaphase ; Animals ; Blotting, Southern ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/physiology ; Chromosome Mapping ; DNA Probes ; DNA Transposable Elements/genetics/physiology ; *Drosophila Proteins ; Drosophila melanogaster/cytology/*genetics ; Female ; *Gene Products, gag ; Genes, Dominant ; Heterochromatin ; Insect Proteins/physiology ; Male ; Metaphase/genetics/physiology ; Mitosis ; *Mutation ; Polymorphism, Genetic ; Telomere/*genetics/ultrastructure ; },
abstract = {In most eukaryotes telomeres are extended by telomerase. Drosophila melanogaster, however, lacks telomerase, and telomere-specific non-LTR retrotransposons, HeT-A and TART, transpose specifically to chromosome ends. A Drosophila strain, Gaiano, that has long telomeres has been identified. We extracted the major Gaiano chromosomes into an Oregon-R genetic background and examined the resulting stocks after 60 generations. In situ hybridization using HeT-A and TART sequences showed that, in stocks carrying either the X or the second chromosome from Gaiano, only the Gaiano-derived chromosomes display long telomeres. However, in stocks carrying the Gaiano third chromosome, all telomeres are substantially elongated, indicating that the Gaiano chromosome 3 carries a factor that increases HeT-A and TART addition to the telomeres. We show that this factor, termed Telomere elongation (Tel), is dominant and localizes as a single unit to 69 on the genetic map. The long telomeres tend to associate with each other in both polytene and mitotic cells. These associations depend on telomere length rather than the presence of Tel. Associations between metaphase chromosomes are resolved during anaphase, suggesting that they are mediated by either proteinaceous links or DNA hydrogen bonding, rather than covalent DNA-DNA bonds.},
}
@article {pmid11804598,
year = {2002},
author = {Kobryn, K and Chaconas, G},
title = {ResT, a telomere resolvase encoded by the Lyme disease spirochete.},
journal = {Molecular cell},
volume = {9},
number = {1},
pages = {195-201},
doi = {10.1016/s1097-2765(01)00433-6},
pmid = {11804598},
issn = {1097-2765},
mesh = {Bacterial Proteins/biosynthesis/*genetics ; Borrelia burgdorferi/*enzymology/genetics ; Endodeoxyribonucleases/biosynthesis/*genetics ; Genome, Bacterial ; Recombinases ; Telomere/metabolism ; Transposases/biosynthesis/*genetics ; },
abstract = {The genus Borrelia includes the causative agents of Lyme disease and relapsing fever. An unusual feature of these bacteria is a segmented genome consisting mostly of a number of linear DNA molecules with covalently closed hairpin ends or telomeres. In this study we show that the BBB03 locus encodes the B. burgdorferi telomere resolvase, ResT. The purified protein catalyzes telomere resolution in vitro through a unique reaction: breakage of two phosphodiester bonds in a single DNA duplex (one on each strand) and joining of each end with the opposite DNA strand to form covalently closed hairpin telomeres. Telomere resolution by ResT occurs through a two-step transesterification reaction involving the formation of a covalent protein-DNA intermediate at a position three nucleotides from the axis of symmetry in each strand of the substrate.},
}
@article {pmid11802774,
year = {2002},
author = {Sbodio, JI and Lodish, HF and Chi, NW},
title = {Tankyrase-2 oligomerizes with tankyrase-1 and binds to both TRF1 (telomere-repeat-binding factor 1) and IRAP (insulin-responsive aminopeptidase).},
journal = {The Biochemical journal},
volume = {361},
number = {Pt 3},
pages = {451-459},
pmid = {11802774},
issn = {0264-6021},
support = {DK02540/DK/NIDDK NIH HHS/United States ; DK47618/DK/NIDDK NIH HHS/United States ; },
mesh = {Adenosine Diphosphate/metabolism ; Amino Acid Sequence ; Animals ; Binding Sites ; COS Cells ; DNA-Binding Proteins/chemistry/*metabolism ; Golgi Apparatus/metabolism ; Humans ; Interleukin 1 Receptor Antagonist Protein ; Microscopy, Fluorescence ; Molecular Sequence Data ; Poly(ADP-ribose) Polymerases/chemistry/*metabolism ; Precipitin Tests ; Protein Binding ; Protein Structure, Tertiary ; RNA/metabolism ; Sequence Homology, Amino Acid ; Sialoglycoproteins/chemistry/*metabolism ; *Tankyrases ; Telomeric Repeat Binding Protein 1 ; Transfection ; Two-Hybrid System Techniques ; },
abstract = {The poly(ADP-ribose) polymerase (PARP) tankyrase-1 contains an ankyrin-repeat domain that binds to various partners, including the telomeric protein TRF1 (telomere-repeat-binding factor 1) and the vesicular protein IRAP (insulin-responsive aminopeptidase). TRF1 binding recruits tankyrase-1 to telomeres and allows its PARP activity to regulate telomere homoeostasis. By contrast, IRAP binding and the Golgi co-localization of tankyrase-1 with IRAP might allow tankyrase-1 to affect the targeting of IRAP-containing vesicles. A closely related protein, tankyrase-2, has also been implicated in vesicular targeting. Unlike tankyrase-1, tankyrase-2 has not been shown to have PARP activity. In addition, it has not been implicated in telomere homoeostasis, because it did not interact with TRF1 in previous studies. Here we show that tankyrase-2 contains intrinsic PARP activity and, like tankryase-1, binds to both TRF1 and IRAP. Our analysis suggests that the ankyrin (ANK) domain of tankyrase-2 comprises five subdomains that provide redundant binding sites for IRAP. Moreover, tankyrase-2 associates and co-localizes with tankyrase-1, suggesting that both tankyrases might function as a complex. Taken together, our findings indicate that tankyrase-1 and tankyrase-2 interact with the same set of proteins and probably mediate overlapping functions, both at telomeres and in vesicular compartments.},
}
@article {pmid11788715,
year = {2002},
author = {Möllenbeck, M and Klobutcher, LA},
title = {De novo telomere addition to spacer sequences prior to their developmental degradation in Euplotes crassus.},
journal = {Nucleic acids research},
volume = {30},
number = {2},
pages = {523-531},
pmid = {11788715},
issn = {1362-4962},
mesh = {Animals ; Base Sequence ; Cell Nucleus/*genetics ; DNA, Protozoan/*genetics/*metabolism ; Euplotes/cytology/*genetics/*growth &amp; development ; Gene Expression Regulation, Developmental ; Gene Rearrangement/*genetics ; Micronucleus, Germline/*genetics ; Models, Genetic ; Polymerase Chain Reaction ; Repetitive Sequences, Nucleic Acid/genetics ; Telomere/*genetics ; },
abstract = {During sexual reproduction, Euplotes crassus precisely fragments its micronuclear chromosomes and synthesizes new telomeres onto the resulting DNA ends to generate functional macronuclear minichromosomes. In the micronuclear chromosomes, the macronuclear-destined sequences are typically separated from each other by spacer DNA segments, which are eliminated following chromosome fragmentation. Recently, in vivo chromosome fragmentation intermediates that had not yet undergone telomere addition have been characterized. The ends of both the macronuclear-destined and eliminated spacers were found to consist of six-base, 3' overhangs. As this terminal structure on the macronuclear-destined sequences serves as the substrate for de novo telomere addition, we sought to determine if the spacer DNAs might also undergo telomere addition prior to their elimination. Using a polymerase chain reaction approach, we found that at least some spacer DNAs undergo de novo telomere addition. In contrast to macronuclear-destined sequences, heterogeneity could be observed in the position of telomeric repeat addition. The observation of spacer DNAs with telomeric repeats makes it unlikely that differential telomere addition is responsible for differentiating between retained and eliminated DNA. The heterogeneity in telomere addition sites for spacer DNA also resembles the situation found for telomeric repeat addition to macronuclear-destined sequences in other ciliate species.},
}
@article {pmid11788606,
year = {2002},
author = {Deneke, J and Ziegelin, G and Lurz, R and Lanka, E},
title = {Phage N15 telomere resolution. Target requirements for recognition and processing by the protelomerase.},
journal = {The Journal of biological chemistry},
volume = {277},
number = {12},
pages = {10410-10419},
doi = {10.1074/jbc.M111769200},
pmid = {11788606},
issn = {0021-9258},
mesh = {Base Sequence ; Binding Sites ; DNA/chemistry ; DNA Mutational Analysis ; Deoxyribonuclease I/metabolism ; Dose-Response Relationship, Drug ; Enzyme Precursors/*chemistry/genetics/*metabolism ; Escherichia coli/metabolism ; Kinetics ; Microscopy, Electron ; Models, Genetic ; Molecular Sequence Data ; Mutation ; Nucleic Acid Conformation ; Plasmids/metabolism ; Protein Binding ; Surface Plasmon Resonance ; Telomerase/*chemistry/genetics/*metabolism ; Time Factors ; *Viral Proteins ; },
abstract = {The Escherichia coli prophage N15 exists as a linear DNA molecule with covalently closed ends. Purified N15 protelomerase TelN is the only protein required to convert circular DNA substrates to the linear form with hairpin termini. Within the center of the telomerase occupancy site tos, the target for TelN is the 56-bp telRL consisting of the central 22-bp palindrome telO and two 14-bp flanking inverted sequence repetitions. DNase I footprinting of TelN-telRL complexes shows a segment of approximately 50 bp protected by TelN. Surface plasmon resonance studies demonstrate that this extended footprint is caused by two TelN molecules bound to telRL. Stable TelN-target DNA complexes are achieved with telRL; however, the additional sequences of tos stabilize the TelN-target complexes. TelO alone is not sufficient for specific stable complex formation. However, processing can occur, i.e. generation of the linear covalently closed DNA. Within the context of telRL, sequences of telO are involved in specific TelN-telRL complex formation, in processing itself, and/or in recognition of the processing site. The sequence of the central (CG)(3) within telO that is part of a 14-bp stretch proposed to have Z-DNA conformation is essential for processing but not for formation of specific TelN-telRL complexes. The concerted action of both TelN molecules at the target site is the basis for telomere resolution. Capturing of reaction intermediates demonstrates that TelN binds covalently to the 3'-phosphoryl of the cleaved strands.},
}
@article {pmid11785683,
year = {2001},
author = {Gan, Y and Engelke, KJ and Brown, CA and Au, JL},
title = {Telomere amount and length assay.},
journal = {Pharmaceutical research},
volume = {18},
number = {12},
pages = {1655-1659},
pmid = {11785683},
issn = {0724-8741},
support = {R01CA77091/CA/NCI NIH HHS/United States ; },
mesh = {DNA/*chemistry ; In Situ Hybridization ; Telomere/*chemistry/ultrastructure ; Time Factors ; Tumor Cells, Cultured ; },
abstract = {PURPOSE: Telomeres are specific DNA structure at the ends of chromosomes to protect chromosomes from fusion, recombination, and degradation. Telomere length changes are implicated in cell senescence, aging, tumorigenesis, and DNA repair. The standard method for measuring telomere length is Southern blot analysis. This method has several disadvantages, i.e., loss of DNA during membrane blotting, high background due to nonspecific binding of telomere probe to membrane, and loss of telomeric signal due to extensive washing. These limitations resulted in a low signal-to-noise ratio and, therefore, reduced sensitivity and reproducibility. The multi-step Southern blot is also highly labor-intensive. The present study was to develop a more quantitative assay of telomeric amount and length (TALA).<br><br>METHODS: TALA was based on solution hybridization and did not require blotting, prehybridization, and washing. The major steps were (a) DNA preparation and digestion with restriction endonucleases, (b) hybridization between DNA and telomeric probe, (c) agarose gel electrophoresis, and (d) autoradiography and data analysis.<br><br>RESULTS: The telomere amount measured by TALA was linearly correlated with the amount of DNA analyzed (r2 = 0.985, P < 0.01). The telomere length measured by TALA also correlated with the telomere length determined by fluorescence in situ hybridization (r2 = 0.99, P < 0.01). Compared to the Southern blot analysis, TALA showed a 4-fold greater sensitivity, 4.6-fold higher signal-to-noise ratio, >2 fold-higher reproducibility, and 4-fold less time requirement.<br><br>CONCLUSION: We report here a rapid, sensitive, and quantitative assay for measuring telomere length and amount.},
}
@article {pmid11781707,
year = {2001},
author = {Kveiborg, M and Gravholt, CH and Kassem, M},
title = {Evidence of a normal mean telomere fragment length in patients with Ullrich-Turner syndrome.},
journal = {European journal of human genetics : EJHG},
volume = {9},
number = {11},
pages = {877-879},
doi = {10.1038/sj.ejhg.5200722},
pmid = {11781707},
issn = {1018-4813},
mesh = {Adult ; Blotting, Southern ; DNA/genetics ; Female ; Humans ; Middle Aged ; Telomere/*genetics ; Turner Syndrome/*genetics ; },
abstract = {Clinical and epidemiological studies suggest that premature ageing and increased morbidity and mortality is present in Ullrich-Turner syndrome. We studied telomere restriction fragment length (TRFL) in 30 women with Ullrich-Turner syndrome and 30 age-matched control women. All Turner women had the 45,X karyotype verified by karyotyping. We found no difference in the mean TRFL in the young age group (TS: 7011+/-521 vs C: 7285+/-917 bp, P = 0.3), or in the older age group (TS: 7357+/-573 vs C: 7221+/-621 bp, P = 0.6). In conclusion, our data suggest that Ullrich-Turner syndrome is not associated with excessive telomere loss, at least when studied in peripheral blood leucocytes, and thus quite different from other premature ageing syndromes.},
}
@article {pmid11777345,
year = {2002},
author = {Kim, H and You, S and Farris, J and Kong, BW and Christman, SA and Foster, LK and Foster, DN},
title = {Expression profiles of p53-, p16(INK4a)-, and telomere-regulating genes in replicative senescent primary human, mouse, and chicken fibroblast cells.},
journal = {Experimental cell research},
volume = {272},
number = {2},
pages = {199-208},
doi = {10.1006/excr.2001.5420},
pmid = {11777345},
issn = {0014-4827},
mesh = {Animals ; *Cell Cycle Proteins ; Cell Division ; Cells, Cultured ; Cellular Senescence ; Chickens ; Cyclin-Dependent Kinase Inhibitor p16/*genetics ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins/*genetics ; *DNA-Binding Proteins ; E2F Transcription Factors ; Fibroblasts/cytology ; Gene Expression Profiling ; *Gene Expression Regulation ; HeLa Cells ; Humans ; Mice ; Mice, Inbred BALB C ; *Nuclear Proteins ; Proto-Oncogene Proteins/*genetics ; Proto-Oncogene Proteins c-mdm2 ; Retinoblastoma Protein/*genetics ; Telomerase/metabolism ; *Telomere ; Transcription Factors/*genetics ; Transcription, Genetic ; Tumor Suppressor Protein p53/*genetics ; },
abstract = {Replicative senescence is known to be an intrinsic mechanism in determining the finite life span of in vitro cultured cells. Since this process is recognized as an evolutionarily conserved mechanism from yeast to mammalian cells, we compared the senescence-associated genetic alterations in the p53, p16(INK4a), and telomere regulatory pathways using replicative senescent human, mouse, and chicken fibroblast cells. Normal human diploid fibroblast (HDF; WI38) and chicken embryonic fibroblast (CEF) cells were shown to have a more extended in vitro proliferative potential than their mouse embryonic fibroblast (MEF) counterpart. In contrast to the HDF and CEF cells, MEF cells were shown to express telomerase mRNA and maintain telomerase activity throughout their in vitro life span. Functional p53 activity was shown to increase in the replicative senescent HDF and CEF cells, but not in replicative senescent MEF cells. On the other hand, there was a gradual elevation of p16(INK4a) expression with increased cell passages which reached a maximum in replicative senescent MEF cells. Taken together, the present study demonstrates that the p53, p16(INK4a), and telomere regulatory functions may be differentially regulated during replicative senescence in human, mouse, and chicken fibroblast cells.},
}
@article {pmid11777339,
year = {2002},
author = {Steinert, S and White, DM and Zou, Y and Shay, JW and Wright, WE},
title = {Telomere biology and cellular aging in nonhuman primate cells.},
journal = {Experimental cell research},
volume = {272},
number = {2},
pages = {146-152},
doi = {10.1006/excr.2001.5409},
pmid = {11777339},
issn = {0014-4827},
mesh = {Animals ; COS Cells ; Cebidae/classification/genetics ; Cell Division ; Cell Line ; Cellular Senescence/*genetics/physiology ; Chlorocebus aethiops ; DNA-Binding Proteins ; Fibroblasts/cytology ; Haplorhini/classification/*genetics ; Humans ; Lemur/classification/*genetics ; Macaca mulatta/classification/genetics ; Pan paniscus/classification/genetics ; Pongo pygmaeus/classification/genetics ; Primates/classification/genetics ; Saimiri/classification/genetics ; Telomerase/genetics/metabolism ; Telomere/*physiology ; },
abstract = {To determine how cellular aging is conserved among primates, we analyzed the replicative potential and telomere shortening in skin fibroblasts of anthropoids and prosimians. The average telomere length of the New World primates Ateles geoffroyi (spider monkey) and Saimiri sciureus (squirrel monkey) and the Old World primates Macaca mulatta (rhesus monkey), Pongo pygmaeus (orangutan), and Pan paniscus (pigmy chimpanzee) ranged from 4 to 16 kb. We found that telomere shortening limits the replicative capacity of anthropoid fibroblasts and that the expression of human telomerase produced telomere elongation and the extension of their in vitro life span. In contrast the prosimian Lemur catta (ring-tailed lemur) had both long and short telomeres and telomere shortening did not provide an absolute barrier to immortalization. Following a transient growth arrest a subset of cells showing a reduced number of chromosomes overgrew the cultures without activation of telomerase. Here we show that the presence of continuous TTAGGG repeats at telomeres and rigorous control of replicative aging by telomere shortening appear to be conserved among anthropoid primates but is less effective in prosimian lemurs.},
}
@article {pmid11761922,
year = {2001},
author = {Nakanishi, T},
title = {[Telomere and hepatocarcinogenesis].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {59 Suppl 6},
number = {},
pages = {105-111},
pmid = {11761922},
issn = {0047-1852},
mesh = {DNA-Binding Proteins ; Humans ; Liver Neoplasms/*genetics ; Telomerase/genetics/metabolism ; *Telomere ; },
}
@article {pmid11748981,
year = {2002},
author = {Wang, SJ and Sakamoto, T and Yasuda Si, S and Fukasawa, I and Ota, Y and Hayashi, M and Okura, T and Zheng, JH and Inaba, N},
title = {The relationship between telomere length and telomerase activity in gynecologic cancers.},
journal = {Gynecologic oncology},
volume = {84},
number = {1},
pages = {81-84},
doi = {10.1006/gyno.2001.6483},
pmid = {11748981},
issn = {0090-8258},
mesh = {Adult ; Aged ; Aged, 80 and over ; Blotting, Southern ; DNA, Neoplasm/genetics/metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Genital Neoplasms, Female/*enzymology/*genetics ; Humans ; Middle Aged ; Telomerase/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {OBJECTIVE: In recent years, many studies have been published regarding telomere length and telomerase activity in malignant tissues. However, it is not enough that telomere length and telomerase activity in gynecologic cancers have been measured at same time. We investigated the relationship between telomere length and telomerase activity in gynecologic cancers.<br><br>METHODS: A total of 52 gynecologic cancers (15 ovarian cancers, 23 endometrial cancers, 14 cervical cancers) were obtained at the time of surgery. The specimens were analyzed for telomerase activity and telomere length with the TRAP(EZE) ELISA kit and Southern blot, respectively.<br><br>RESULTS: Telomerase activity was detected in 42 of 50 (84.0%) of all evaluable specimens, in 11/15 (73.3%) ovarian, 18/22 (81.8%) endometrial, and in 13/13 (100%) cervical cancers. The difference of positive strength (DeltaA value) between stage I and III was statistically significant (P = 0.01, ANOVA test). Changes in telomere length by shortening or elongation were detected in 35 of 52 (67.3%) tumors, in 9/15 (60.0%) ovarian, 17/23 (73.9%) endometrial, and 9/14 (64.3%) cervical cancers. There was no detectable relationship between telomere length and stage of disease, pathologic diagnosis (ovarian, endometrial, and cervical cancers), or telomerase activity.<br><br>CONCLUSIONS: There was no relationship between telomerase activity and telomere length. The clinical significance of telomere length appears to be limited in gynecologic cancers.},
}
@article {pmid11747540,
year = {2001},
author = {Finnon, P and Wong, HP and Silver, AR and Slijepcevic, P and Bouffler, SD},
title = {Long but dysfunctional telomeres correlate with chromosomal radiosensitivity in a mouse AML cell line.},
journal = {International journal of radiation biology},
volume = {77},
number = {12},
pages = {1151-1162},
doi = {10.1080/09553000110075220},
pmid = {11747540},
issn = {0955-3002},
mesh = {Animals ; Apoptosis ; Blotting, Northern ; Blotting, Southern ; Chromosomes/*radiation effects ; Dose-Response Relationship, Drug ; Dose-Response Relationship, Radiation ; Electrophoresis, Agar Gel ; In Situ Hybridization, Fluorescence ; Leukemia, Myeloid, Acute/*radiotherapy ; Metaphase ; Mice ; Mice, Inbred C3H ; Mitosis ; Oligonucleotides/pharmacology ; Phenotype ; *Radiation Tolerance ; S Phase ; Sequence Analysis, DNA ; Telomerase/metabolism ; Time Factors ; Tumor Cells, Cultured ; X-Rays ; },
abstract = {PURPOSE: To compare the chromosomal radiosensitivity of C3H mouse acute myeloid leukaemia (AML) cell lines 7926 and 8709 and to investigate the mechanistic basis of the radiosensitivity observed in 7926.<br><br>MATERIALS AND METHODS: Yields of chromosome aberrations following X-irradiation were determined in Giemsa-stained metaphases. Cell cycle phase distributions were determined by BrdU incorporation and microscopy, apoptosis was assessed by caspase assays. Telomerase activity (TRAP assay), telomere length (Q-FISH and Southern blotting) and telomere function (Robertsonian-like fusion formation) were also examined. The expression levels of telomerase components, telomerase regulators and DNA PKcs were determined on Northern blots.<br><br>RESULTS: A total of 4.5-7.6-fold elevated chromosome aberration yields were found in 7926 by comparison with 8709 3-24h after 0.5 and 1 Gy X-ray exposure. This difference could not be accounted for by differences in chromatid break-rejoining rates, cell cycle phase distribution or the induction of apoptosis. Telomeres and telomerase were dysfunctional in 7926. However, average telomere length was approximately two-fold greater than in 8709.<br><br>CONCLUSION: Defective telomere function in 7926 correlates with chromosomal radiosensitivity. This implicates telomere function in addition to telomere length as a determinant of chromosomal radiosensitivity.},
}
@article {pmid11744712,
year = {2002},
author = {Kishi, S and Lu, KP},
title = {A critical role for Pin2/TRF1 in ATM-dependent regulation. Inhibition of Pin2/TRF1 function complements telomere shortening, radiosensitivity, and the G(2)/M checkpoint defect of ataxia-telangiectasia cells.},
journal = {The Journal of biological chemistry},
volume = {277},
number = {9},
pages = {7420-7429},
doi = {10.1074/jbc.M111365200},
pmid = {11744712},
issn = {0021-9258},
support = {R01 GM 56230/GM/NIGMS NIH HHS/United States ; R01 GM 58556/GM/NIGMS NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia/genetics/metabolism ; Ataxia Telangiectasia Mutated Proteins ; Bromodeoxyuridine/metabolism ; CDC2 Protein Kinase/metabolism ; Cell Cycle Proteins ; Cell Line ; Cellular Senescence ; DNA Damage ; DNA-Binding Proteins/*metabolism/*physiology ; G2 Phase/physiology ; Genes, Dominant ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Mitosis/physiology ; Mutation ; Phenotype ; Phosphorylation ; Protein Binding ; Protein Serine-Threonine Kinases/*metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1 ; Time Factors ; Transfection ; Tumor Suppressor Proteins ; beta-Galactosidase/metabolism ; },
abstract = {Cells derived from patients with the human genetic disorder ataxia-telangiectasia (A-T) display many abnormalities, including telomere shortening, premature senescence, and defects in the activation of S phase and G(2)/M checkpoints in response to double-strand DNA breaks induced by ionizing radiation. We have previously demonstrated that one of the ATM substrates is Pin2/TRF1, a telomeric protein that binds the potent telomerase inhibitor PinX1, negatively regulates telomere elongation, and specifically affects mitotic progression. Following DNA damage, ATM phosphorylates Pin2/TRF1 and suppresses its ability to induce abortive mitosis and apoptosis (Kishi, S., Zhou, X. Z., Nakamura, N., Ziv, Y., Khoo, C., Hill, D. E., Shiloh, Y., and Lu, K. P. (2001) J. Biol. Chem. 276, 29282-29291). However, the functional importance of Pin2/TRF1 in mediating ATM-dependent regulation remains to be established. To address this question, we directly inhibited the function of endogenous Pin2/TRF1 in A-T cells by stable expression of two different dominant-negative Pin2/TRF1 mutants and then examined their effects on telomere length and DNA damage response. Both the Pin2/TRF1 mutants increased telomere length in A-T cells, as shown in other cells. Surprisingly, both the Pin2/TRF1 mutants reduced radiosensitivity and complemented the G(2)/M checkpoint defect without inhibiting Cdc2 activity in A-T cells. In contrast, neither of the Pin2/TRF1 mutants corrected the S phase checkpoint defect in the same cells. These results indicate that inhibition of Pin2/TRF1 in A-T cells is able to bypass the requirement for ATM in specifically restoring telomere shortening, the G(2)/M checkpoint defect, and radiosensitivity and demonstrate a critical role for Pin2/TRF1 in the ATM-dependent regulation of telomeres and DNA damage response.},
}
@article {pmid11744046,
year = {2002},
author = {Proctor, CJ and Kirkwood, TB},
title = {Modelling telomere shortening and the role of oxidative stress.},
journal = {Mechanisms of ageing and development},
volume = {123},
number = {4},
pages = {351-363},
doi = {10.1016/s0047-6374(01)00380-3},
pmid = {11744046},
issn = {0047-6374},
support = {BEP17042/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Humans ; *Models, Genetic ; *Oxidative Stress ; Telomere/*physiology ; Time Factors ; },
abstract = {Extensive evidence supports the idea that progressive telomere loss contributes to the phenomenon of cell replicative senescence, but the mechanisms responsible for telomere loss are still unclear. In addition to the widely recognized end-replication problem, there is evidence that oxidative stress plays a major role in determining the rate of loss of telomeric DNA, and the action of a C-strand-specific exonuclease is also suggested to be important. We describe a mathematical model which examines the different contributions of these mechanisms to telomere loss and its role in triggering cell senescence. The model allows us to make quantitative predictions about the rates of telomere loss resulting from these alternative mechanisms, and their interactions. By varying the key parameters of the model, it is possible to examine the extent to which the different hypotheses are compatible with quantitative and qualitative features of the experimental data. For example, the model predicts that under low levels of oxidative stress, the main mechanisms of telomere shortening are the end-replication problem plus C-strand processing. However, when levels of oxidative stress are higher, as in cell cultures grown under normoxic or hyperoxic conditions, the model predicts that single strand breaks make an important contribution to telomere loss and their inclusion within the model is necessary to explain the data. We suggest that theoretical models of this kind are valuable tools to bridge the gap between the verbal statements of hypotheses and their rigorous experimental test.},
}
@article {pmid11743727,
year = {2001},
author = {Classen, S and Ruggles, JA and Schultz, SC},
title = {Crystal structure of the N-terminal domain of Oxytricha nova telomere end-binding protein alpha subunit both uncomplexed and complexed with telomeric ssDNA.},
journal = {Journal of molecular biology},
volume = {314},
number = {5},
pages = {1113-1125},
doi = {10.1006/jmbi.2000.5191},
pmid = {11743727},
issn = {0022-2836},
support = {1R01CA81109/CA/NCI NIH HHS/United States ; RR07707/RR/NCRR NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Binding Sites ; Crystallography, X-Ray ; DNA, Single-Stranded/*chemistry/genetics/*metabolism ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Dimerization ; Hydrogen Bonding ; Models, Biological ; Models, Molecular ; Nucleic Acid Conformation ; *Oxytricha/chemistry/genetics ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Protein Subunits ; Substrate Specificity ; Telomere/*genetics ; },
abstract = {Oxytricha nova telomere end-binding protein specifically recognizes and caps single strand (T(4)G(4))(n) telomeric DNA at the very 3'-ends of O. nova macronuclear chromosomes. Proteins homologous to the N-terminal domain of OnTEBP alpha subunit have now been identified in Oxytricha trifallax, Stylonychia mytilis, Euplotes crassus, Schizosaccharomyces pombe, and Homo sapiens, suggesting that this protein is widely distributed in eukaryotes. We describe here the crystal structures of the N-terminal single-stranded DNA (ssDNA)-binding domain of O. nova telomere end-binding protein alpha subunit both uncomplexed and complexed with single strand telomeric DNA. These structures show how the N-terminal domain of alpha alone, in the absence of the beta subunit and without alpha dimerization, can bind single-stranded telomeric DNA in a sequence-specific and 3'-end-specific manner. Furthermore, comparison of the uncomplexed and complexed forms of this protein shows that the ssDNA-binding site is largely pre-organized in the absence of ssDNA with modest, but interesting, rearrangements of amino acid side-chains that compose the ssDNA-binding site. The structures described here extend our understanding of structures of O. nova telomeric complexes by adding uncomplexed and complexed forms of monomeric alpha to previously described structures for (alpha 56/ssDNA)(2) dimer and alpha 56/beta 28/ssDNA ternary complexes. We believe that each of these four structures represent intermediates in an ordered assembly/disassembly pathway for O. nova telomeric complexes.},
}
@article {pmid11742526,
year = {2001},
author = {Sozou, PD and Kirkwood, TB},
title = {A stochastic model of cell replicative senescence based on telomere shortening, oxidative stress, and somatic mutations in nuclear and mitochondrial DNA.},
journal = {Journal of theoretical biology},
volume = {213},
number = {4},
pages = {573-586},
doi = {10.1006/jtbi.2001.2432},
pmid = {11742526},
issn = {0022-5193},
mesh = {Cell Culture Techniques ; Cell Division/genetics ; Cellular Senescence/*genetics ; Computer Simulation ; DNA/genetics ; DNA, Mitochondrial/genetics ; Humans ; *Models, Genetic ; *Mutation ; Oxidative Stress/*physiology ; Stochastic Processes ; Telomere/*physiology ; },
abstract = {Human diploid fibroblast cells can divide for only a limited number of times in vitro, a phenomenon known as replicative senescence or the Hayflick limit. Variability in doubling potential is observed within a clone of cells, and between two sister cells arising from a single mitotic division. This strongly suggests that the process by which cells become senescent is intrinsically stochastic. Among the various biochemical mechanisms that have been proposed to explain replicative senescence, particular interest has been focussed on the role of telomere reduction. In the absence of telomerase--an enzyme switched off in normal diploid fibro-blasts-cells lose telomeric DNA at each cell division. According to the telomere hypothesis of cell senescence, cells eventually reach a critically short telomere length and cell cycle arrest follows. In support of this concept, forced expression of telomerase in normal fibroblasts appears to prevent cell senescence. Nevertheless, the telomere hypothesis in its basic form has some difficulty in explaining the marked stochastic variations seen in the replicative lifespans of individual cells within a culture, and there is strong empirical and theoretical support for the concept that other kinds of damage may contribute to cellular ageing. We describe a stochastic network model of cell senescence in which a primary role is played by telomere reduction but in which other mechanisms (oxidative stress linked particularly to mitochondrial damage, and nuclear somatic mutations) also contribute. The model gives simulation results that are in good agreement with published data on intra-clonal variability in cell doubling potential and permits an analysis of how the various elements of the stochastic network interact. Such integrative models may aid in developing new experimental approaches aimed at unravelling the intrinsic complexity of the mechanisms contributing to human cell ageing.},
}
@article {pmid11742099,
year = {2001},
author = {Gilley, D and Tanaka, H and Hande, MP and Kurimasa, A and Li, GC and Oshimura, M and Chen, DJ},
title = {DNA-PKcs is critical for telomere capping.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {98},
number = {26},
pages = {15084-15088},
pmid = {11742099},
issn = {0027-8424},
support = {R01 CA050519/CA/NCI NIH HHS/United States ; R37 CA050519/CA/NCI NIH HHS/United States ; AG17709/AG/NIA NIH HHS/United States ; CA50519/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Catalytic Domain ; Cells, Cultured ; DNA Primers ; DNA-Activated Protein Kinase ; *DNA-Binding Proteins ; Electrophoresis, Gel, Pulsed-Field ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Knockout ; Protein Serine-Threonine Kinases/chemistry/*metabolism ; *Telomere ; },
abstract = {The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is critical for DNA repair via the nonhomologous end joining pathway. Previously, it was reported that bone marrow cells and spontaneously transformed fibroblasts from SCID (severe combined immunodeficiency) mice have defects in telomere maintenance. The genetically defective SCID mouse arose spontaneously from its parental strain CB17. One known genomic alteration in SCID mice is a truncation of the extreme carboxyl terminus of DNA-PKcs, but other as yet unidentified alterations may also exist. We have used a defined system, the DNA-PKcs knockout mouse, to investigate specifically the role DNA-PKcs specifically plays in telomere maintenance. We report that primary mouse embryonic fibroblasts (MEFs) and primary cultured kidney cells from 6-8 month-old DNA-PKcs-deficient mice accumulate a large number of telomere fusions, yet still retain wild-type telomere length. Thus, the phenotype of this defect separates the two-telomere related phenotypes, capping, and length maintenance. DNA-PKcs-deficient MEFs also exhibit elevated levels of chromosome fragments and breaks, which correlate with increased telomere fusions. Based on the high levels of telomere fusions observed in DNA-PKcs deficient cells, we conclude that DNA-PKcs plays an important capping role at the mammalian telomere.},
}
@article {pmid11741142,
year = {2001},
author = {Hirai, H},
title = {Relationship of telomere sequence and constitutive heterochromatin in the human and apes as detected by PRINS.},
journal = {Methods in cell science : an official journal of the Society for In Vitro Biology},
volume = {23},
number = {1-3},
pages = {29-35},
pmid = {11741142},
issn = {1381-5741},
mesh = {Animals ; Haplorhini/*genetics ; Heterochromatin/*genetics ; Hominidae/genetics ; Humans ; Hylobates/genetics ; Karyotyping ; Male ; Primed In Situ Labeling/*methods ; Telomere/*genetics ; },
abstract = {Hitherto, hominoid telomere sequences have been localized only at essential telomere regions of chromosome ends using ordinary FISH. In the present study, however, a PRINS technique revealed the new insight that chromosomes of humans and apes have many internal locations of the sequence. Moreover, a combination of PRINS and post-PRINS C-banding elucidated that the internal telomeric repeats corresponded with regions of constitutive heterochromatin. The PRINS reaction appeared more sensitive than the standard FISH technique, as it provided greater resolution of FITC signals. Furthermore, G- and R-like bands yielded by post- PRINS counter-staining with DAPI and PI, respectively, were informative in identification of chromosomes as well as the detailed characterization of those chromosomal structures signaling positive for the PRINS reaction. The combined efforts of FITC signals, DAPI-, PI-, and C-bands are most precisely analyzed through the use of a microscope mounted with a cooled CCD camera and an auto-wheel fluorescence filter set regulated by a computer.},
}
@article {pmid11741140,
year = {2001},
author = {Slijepcevic, P},
title = {Telomere length measurement by Q-FISH.},
journal = {Methods in cell science : an official journal of the Society for In Vitro Biology},
volume = {23},
number = {1-3},
pages = {17-22},
pmid = {11741140},
issn = {1381-5741},
mesh = {DNA Repair ; In Situ Hybridization, Fluorescence/*methods ; Karyotyping ; Oligonucleotides ; Peptide Nucleic Acids ; Telomere/*genetics ; },
abstract = {Telomeres are essential functional elements of eukaryotic chromosomes involved in genome stability maintenance. The most important indicator of correct telomere function is telomere length maintenance within the range typical for each species. Telomere length can be estimated by the classical methodology based on Southern blot. However, this methodology is relatively crude and can provide estimate of average telomere length only. To overcome disadvantages of classical telomere length estimate, a new technique termed Q-FISH has been invented. Q-FISH provides estimate of telomere length in each individual chromosome with the resolution of 200 base pairs. In addition, Q-FISH may be used to estimate telomere length in species containing interstitial telomeric sites in their genomes. The classical methodology is non-informative in these cases. Finally, Q-FISH has been essential in estimating telomere length in the mouse, a species with ultra-long telomeres difficult to measure using classical methods. Principles of Q-FISH and its applications are briefly described in this article.},
}
@article {pmid11739802,
year = {2001},
author = {Mangahas, JL and Alexander, MK and Sandell, LL and Zakian, VA},
title = {Repair of chromosome ends after telomere loss in Saccharomyces.},
journal = {Molecular biology of the cell},
volume = {12},
number = {12},
pages = {4078-4089},
pmid = {11739802},
issn = {1059-1524},
support = {R37 GM026938/GM/NIGMS NIH HHS/United States ; R37 GM-26938/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosome Deletion ; Chromosomes, Fungal/genetics/*metabolism ; *DNA Damage ; DNA Helicases/genetics/metabolism ; *DNA Repair ; DNA, Fungal/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Molecular Sequence Data ; Rad52 DNA Repair and Recombination Protein ; Recombination, Genetic ; Saccharomyces cerevisiae/*cytology/genetics ; *Saccharomyces cerevisiae Proteins ; Telomere/genetics/*metabolism ; },
abstract = {Removal of a telomere from yeast chromosome VII in a strain having two copies of this chromosome often results in its loss. Here we show that there are three pathways that can stabilize this broken chromosome: homologous recombination, nonhomologous end joining, and de novo telomere addition. Both in a wild-type and a recombination deficient rad52 strain, most stabilization events were due to homologous recombination, whereas nonhomologous end joining was exceptionally rare. De novo telomere addition was relatively rare, stabilizing <0.1% of broken chromosomes. Telomere addition took place at a very limited number of sites on chromosome VII, most occurring close to a 35-base pair stretch of telomere-like DNA that is normally approximately 50 kb from the left telomere of chromosome VII. In the absence of the Pif1p DNA helicase, telomere addition events were much more frequent and were not concentrated near the 35-base pair tract of telomere-like DNA. We propose that internal tracts of telomere-like sequence recruit telomerase by binding its anchor site and that Pif1p inhibits telomerase by dissociating DNA primer-telomerase RNA interactions. These data also show that telomeric DNA is essential for the stable maintenance of linear chromosomes in yeast.},
}
@article {pmid11739745,
year = {2002},
author = {Cook, BD and Dynek, JN and Chang, W and Shostak, G and Smith, S},
title = {Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres.},
journal = {Molecular and cellular biology},
volume = {22},
number = {1},
pages = {332-342},
pmid = {11739745},
issn = {0270-7306},
support = {R01 CA095099/CA/NCI NIH HHS/United States ; },
mesh = {Cell Nucleus/metabolism ; Chromosomes/metabolism ; DNA-Binding Proteins/metabolism ; HeLa Cells ; Humans ; Microscopy, Fluorescence ; Nuclear Proteins/genetics/*metabolism ; Poly(ADP-ribose) Polymerases/genetics/*metabolism ; Protein Structure, Tertiary ; Recombinant Fusion Proteins/genetics/metabolism ; *Tankyrases ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1 ; Tissue Distribution ; Two-Hybrid System Techniques ; },
abstract = {Telomere maintenance is essential for the continuous growth of tumor cells. In most human tumors telomeres are maintained by telomerase, a specialized reverse transcriptase. Tankyrase 1, a human telomeric poly(ADP-ribose) polymerase (PARP), positively regulates telomere length through its interaction with TRF1, a telomeric DNA-binding protein. Tankyrase 1 ADP-ribosylates TRF1, inhibiting its binding to telomeric DNA. Overexpression of tankyrase 1 in the nucleus promotes telomere elongation, suggesting that tankyrase 1 regulates access of telomerase to the telomeric complex. The recent identification of a closely related homolog of tankyrase 1, tankyrase 2, opens the possibility for a second PARP at telomeres. We therefore sought to establish the role of tankyrase 1 at telomeres and to determine if tankyrase 2 might have a telomeric function. We show that endogenous tankyrase 1 is a component of the human telomeric complex. We demonstrate that telomere elongation by tankyrase 1 requires the catalytic activity of the PARP domain and does not occur in telomerase-negative primary human cells. To investigate a potential role for tankyrase 2 at telomeres, recombinant tankyrase 2 was subjected to an in vitro PARP assay. Tankyrase 2 poly(ADP-ribosyl)ated itself and TRF1. Overexpression of tankyrase 2 in the nucleus released endogenous TRF1 from telomeres. These findings establish tankyrase 2 as a bona fide PARP, with itself and TRF1 as acceptors of ADP-ribosylation, and suggest the possibility of a role for tankyrase 2 at telomeres.},
}
@article {pmid11739741,
year = {2002},
author = {Denisenko, O and Bomsztyk, K},
title = {Yeast hnRNP K-like genes are involved in regulation of the telomeric position effect and telomere length.},
journal = {Molecular and cellular biology},
volume = {22},
number = {1},
pages = {286-297},
pmid = {11739741},
issn = {0270-7306},
support = {R01 DK045978/DK/NIDDK NIH HHS/United States ; DK45978/DK/NIDDK NIH HHS/United States ; GM45134/GM/NIGMS NIH HHS/United States ; R37 DK045978/DK/NIDDK NIH HHS/United States ; R01 GM045134/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Fungal Proteins/genetics/metabolism ; Gene Silencing/physiology ; Genes, Fungal ; Heterogeneous-Nuclear Ribonucleoprotein K ; Heterogeneous-Nuclear Ribonucleoproteins ; Humans ; Molecular Sequence Data ; Ribonucleoproteins/chemistry/*genetics/metabolism ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*genetics/metabolism ; Sequence Alignment ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Telomere/*metabolism ; Trans-Activators/genetics/metabolism ; },
abstract = {Mammalian heterogeneous nuclear ribonucleoprotein K (hnRNP K) is an RNA- and DNA-binding protein implicated in the regulation of gene expression processes. To better understand its function, we studied two Saccharomyces cerevisiae homologues of the human hnRNP K, PBP2 and HEK2 (heterogeneous nuclear RNP K-like gene). pbp2Delta and hek2Delta mutations inhibited expression of a marker gene that was inserted near telomere but not at internal chromosomal locations. The telomere proximal to the ectopic marker gene became longer, while most of the other telomeres were not altered in the double mutant cells. We provide evidence that telomere elongation might be the primary event that causes enhanced silencing of an adjacent reporter gene. The telomere lengthening could, in part, be explained by the inhibitory effect of hek2Delta mutation on the telomeric rapid deletion pathway. Hek2p was detected in a complex with chromosome regions proximal to the affected telomere, suggesting a direct involvement of this protein in telomere maintenance. These results identify a role for hnRNP K-like genes in the structural and functional organization of telomeric chromatin in yeast.},
}
@article {pmid11739653,
year = {2001},
author = {Armstrong, SJ and Franklin, FC and Jones, GH},
title = {Nucleolus-associated telomere clustering and pairing precede meiotic chromosome synapsis in Arabidopsis thaliana.},
journal = {Journal of cell science},
volume = {114},
number = {Pt 23},
pages = {4207-4217},
doi = {10.1242/jcs.114.23.4207},
pmid = {11739653},
issn = {0021-9533},
mesh = {Arabidopsis ; *Arabidopsis Proteins ; Cell Nucleolus/*physiology ; Centromere ; Chromosome Pairing/*physiology ; Chromosomes ; DNA-Binding Proteins/genetics ; In Situ Hybridization, Fluorescence/methods ; Meiosis/*physiology ; Plant Proteins/genetics ; Pollen ; Telomere/*physiology ; },
abstract = {The intranuclear arrangements of centromeres and telomeres during meiotic interphase and early prophase I of meiosis in Arabidopsis thaliana were analysed by fluorescent in situ hybridisation to spread pollen mother cells and embryo-sac mother cells. Meiocyte identification, staging and progression were established by spreading and sectioning techniques, including various staining procedures and bromodeoxyuridine labeling of replicating DNA. Centromere regions of Arabidopsis are unpaired, widely dispersed and peripherally located in nuclei during meiotic interphase, and they remain unpaired and unassociated throughout leptotene. Eventually they associate pairwise during zygotene, as part of the nucleus-wide synapsis of homologous chromosomes. Telomeres, by contrast, show a persistent association with the nucleolus throughout meiotic interphase. Variation in telomere signal number indicates that telomeres undergo pairing during this interval, preceding the onset of general chromosome synapsis. During leptotene the paired telomeres lose their association with the nucleolus and become widely dispersed. As the chromosomes synapse during zygotene, the telomeres reveal a loose clustering within one hemisphere, which may represent a degenerate or relic bouquet configuration. We propose that in Arabidopsis the classical leptotene/zygotene bouquet is absent and is replaced functionally by nucleolus-associated telomere clustering.},
}
@article {pmid11739547,
year = {2001},
author = {Weng, N},
title = {Interplay between telomere length and telomerase in human leukocyte differentiation and aging.},
journal = {Journal of leukocyte biology},
volume = {70},
number = {6},
pages = {861-867},
pmid = {11739547},
issn = {0741-5400},
mesh = {Cell Differentiation/physiology ; Cellular Senescence/physiology ; Humans ; Leukocytes/cytology/*physiology ; Telomerase/*physiology ; Telomere/*physiology/ultrastructure ; },
abstract = {Blood leukocytes derive from bone marrow hematopoietic stem cells and differentiate into multiple types of mature cells that include granulocytes, monocytes, mast cells of myeloid lineage, and T and B lymphocytes of lymphoid lineage. Their distinctive paths of differentiation and unique roles in immune response provide a model for comparative analysis of biological parameters, such as telomere length and telomerase activity, in different types of leukocytes. Age has also been associated with the decline in immune functions and with the attrition of telomere length in leukocytes. This review will summarize recent progress in the study of telomere length and telomerase expression in leukocytes during differentiation and aging. In addition, I will attempt to shed new light on the roles of telomere and telomerase in leukocyte function and potential clinical interventions.},
}
@article {pmid11737334,
year = {2000},
author = {Tucker, V and Jenkins, J and Gilmour, J and Savoie, H and Easterbrook, P and Gotch, F and Browning, MJ},
title = {T-cell telomere length maintained in HIV-infected long-term survivors.},
journal = {HIV medicine},
volume = {1},
number = {2},
pages = {116-122},
doi = {10.1046/j.1468-1293.2000.00010.x},
pmid = {11737334},
issn = {1464-2662},
mesh = {Adult ; Biomarkers ; Case-Control Studies ; Female ; HIV Infections/*genetics/*immunology/pathology ; *HIV Long-Term Survivors ; Humans ; Male ; Middle Aged ; Prognosis ; *T-Lymphocytes ; Telomere/*genetics ; },
abstract = {BACKGROUND AND METHODS: We have used the erosion of telomeric DNA as a measure of cellular division to study the replicative history of isolated T-lymphocyte subpopulations from a group of HIV-infected long-term survivors and age-matched healthy controls.<br><br>RESULTS: In keeping with previous studies, we found that CD45RO+ (memory) T-cells showed greater telomere erosion than CD45RA+ (naive) T-cells. We did not, however, find any significant differences in the telomere lengths of isolated CD4+, CD8+, CD45RA+ or CD45RO+ T-cells between HIV-infected long-term survivors and age-matched controls. Further, we found no evidence of telomerase activation in T-cells from the HIV-infected groups to account for the lack of telomere erosion.<br><br>CONCLUSIONS: Our data show no evidence, through telomere shortening, of clonal exhaustion or replicative senescence due to an increased rate of immune cell turnover in HIV-infected long-term survivors.},
}
@article {pmid11734638,
year = {2001},
author = {Pardue, ML and DeBaryshe, PG and Lowenhaupt, K},
title = {Another protozoan contributes to understanding telomeres and transposable elements.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {98},
number = {25},
pages = {14195-14197},
pmid = {11734638},
issn = {0027-8424},
mesh = {Animals ; Biological Evolution ; Ciliophora/genetics ; *DNA Transposable Elements ; DNA, Protozoan/genetics ; Drosophila/genetics ; Giardia lamblia/*genetics ; Saccharomyces cerevisiae/genetics ; Species Specificity ; Telomere/*genetics ; },
}
@article {pmid11730807,
year = {2001},
author = {Aviv, H and Khan, MY and Skurnick, J and Okuda, K and Kimura, M and Gardner, J and Priolo, L and Aviv, A},
title = {Age dependent aneuploidy and telomere length of the human vascular endothelium.},
journal = {Atherosclerosis},
volume = {159},
number = {2},
pages = {281-287},
doi = {10.1016/s0021-9150(01)00506-8},
pmid = {11730807},
issn = {0021-9150},
support = {HL-47906/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*physiology ; *Aneuploidy ; Aorta, Abdominal ; Cells, Cultured ; Child ; Child, Preschool ; DNA/analysis ; Endothelium, Vascular/cytology/*physiology ; Female ; Gene Expression ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; Male ; Middle Aged ; Sensitivity and Specificity ; Telomere/*genetics/physiology ; },
abstract = {RATIONALE: Aneuploidy and telomere length are two major parameters that have been associated with cellular senescence in vitro. In order to explore the role of aneuploidy and telomere length in aging of the human vasculature, we studied these two parameters in direct preparations of endothelial cells of the human abdominal aorta.<br><br>METHODS: Using fluorescent in situ hybridization on 'touch prep' slides, we evaluated aneuploidy of two autosomes (chromosomes 6 and 16) and sex chromosomes in non cultured endothelial cells of the abdominal aorta as a function of the donor's age.<br><br>RESULTS: We found that the frequency of aneuploidy of vascular endothelial cells significantly increased with age. This was expressed by age-dependent tetrasomy (r(s)=0.56, P=0.006 for chromosome 6; and r(s)=0.54, P=0.008 for chromosome 16), and age dependent loss of the Y chromosome (r(s)=0.85, P=0.0003). In addition, we found that telomere length was inversely correlated with age (r=-0.38, P=0.008). DATA INTERPRETATION: These findings suggest that indicators of cellular senescence, earlier observed in vitro, are also expressed in the human vascular endothelium in vivo. Aneuploidy and telomere attrition might thus play a role in the aging of the human vasculature.},
}
@article {pmid11714633,
year = {2001},
author = {Goodwin, EC and DiMaio, D},
title = {Induced senescence in HeLa cervical carcinoma cells containing elevated telomerase activity and extended telomeres.},
journal = {Cell growth &amp; differentiation : the molecular biology journal of the American Association for Cancer Research},
volume = {12},
number = {11},
pages = {525-534},
pmid = {11714633},
issn = {1044-9523},
support = {CA16018/CA/NCI NIH HHS/United States ; },
mesh = {Cell Division ; Cell Size ; Cellular Senescence/*genetics/*physiology ; DNA/biosynthesis ; DNA-Binding Proteins/genetics/*metabolism ; Flow Cytometry ; Fluorescence ; Gene Expression Regulation, Neoplastic ; Genes, Tumor Suppressor ; HeLa Cells ; Humans ; Keratinocytes/cytology/metabolism ; Oncogene Proteins, Viral/genetics ; RNA, Messenger/metabolism ; Telomerase/chemistry/genetics/*metabolism ; Telomere/*metabolism ; Transduction, Genetic ; Viral Proteins/genetics/*metabolism ; },
abstract = {Proliferation of normal somatic human cells in culture is limited by replicative senescence, a growth-arrested state that appears to be triggered by the erosion of telomeres. Tumor cells such as HeLa cervical carcinoma cells, which contain short telomeres, can be induced to undergo senescence by various manipulations including oncogene withdrawal. Repression of the human papillomavirus (HPV) type 18 E6/E7 genes in HeLa cells by the bovine papillomavirus E2 transcriptional regulatory protein results in reactivation of the dormant p53 and p105(Rb) tumor suppressor pathways in these cells, repression of telomerase, and profound growth arrest. Strikingly, the growth-arrested cells rapidly and synchronously acquired numerous characteristics of primary cells undergoing replicative senescence. To explore the role of telomerase and telomere length in induced senescence, we expressed an exogenous hTERT gene, which encodes the catalytic subunit of telomerase, to generate stable HeLa cell clones with elevated telomerase activity and extended telomeres. Expression of the E2 protein in these cells repressed HPV E6/E7 expression, activated tumor suppressor pathways, and induced senescence as assessed by growth arrest, morphological changes, senescence-associated beta-galactosidase expression, and increased autofluorescence. Cells carrying the hTERT gene and control cells displayed identical responses to E2 expression. Therefore, HeLa cell senescence induced by HPV repression is not triggered by short telomeres or low levels of telomerase activity.},
}
@article {pmid11712073,
year = {2001},
author = {Multani, AS and Worth, LL and Jeha, S and Chan, KW and Pathak, S},
title = {Human bone marrow transplant rejection is associated with telomere cleavage.},
journal = {International journal of molecular medicine},
volume = {8},
number = {6},
pages = {607-610},
doi = {10.3892/ijmm.8.6.607},
pmid = {11712073},
issn = {1107-3756},
support = {RRO 499901/RR/NCRR NIH HHS/United States ; },
mesh = {Adolescent ; *Bone Marrow Transplantation ; DNA/genetics/metabolism ; Graft Rejection/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres that guard chromosomes are shortened with each cell division because of replication-dependent sequence loss at both termini. The gradual erosion of telomeric length has been directly related to the process of aging in vivo. Recently we have reported, in murine and human cancer cells treated with different apoptogens, cleavage and extrusion of telomeric DNA prior to cell death on one hand and an amplification of telomeric DNA in metastatic epithelial malignancies of different histopathologic origin on the other. This study tested our hypothesis that telomere cleavage is linked to transplant rejection in cancer patients receiving stem cells either from bone marrow (BM) or umbilical cord blood transfusion. Telomere integrity and mitotic catastrophe were studied by cytogenetic and molecular fluorescence in situ hybridization (FISH) techniques in two BM samples taken from a male stem cell transplant recipient diagnosed with aplastic anemia. The first BM sample, which was aspirated 27 days after transplant, was mitotically active. Only one of 50 metaphases showed a chromatid break. Every cell karyotyped was of male origin with 46, XY chromosome constitution. The second BM sample aspirated 52 days after transplant gave no metaphases and most interphase cells appeared dead. FISH preparations of the second BM sample showed cleavage and drastic reduction of telomeric DNA at the time the patient was rejecting the transplant. In contrast, the first BM sample had shown no indication of cleavage of the telomeric DNA, although the percentage of telomeric area was smaller than in the control. The replicative stress imposed on the stem cells engrafted may result in an accelerated aging effect, possibly due to the erosion of telomeric DNA. We, therefore, conclude that BM rejection could be directly associated with the cleavage, clustering, and extrusion of telomeric DNA in the donor cells.},
}
@article {pmid11707773,
year = {2001},
author = {Brannan, CI and Disteche, CM and Park, LS and Copeland, NG and Jenkins, NA},
title = {Autosomal telomere exchange results in the rapid amplification and dispersion of Csf2ra genes in wild-derived mice.},
journal = {Mammalian genome : official journal of the International Mammalian Genome Society},
volume = {12},
number = {12},
pages = {882-886},
doi = {10.1007/s00335-001-2084-0},
pmid = {11707773},
issn = {0938-8990},
mesh = {Animals ; Animals, Laboratory/genetics ; Animals, Wild/genetics ; Chromosome Mapping ; Crosses, Genetic ; Evolution, Molecular ; Female ; *Gene Amplification ; Genes ; In Situ Hybridization ; Male ; Mice ; Mice, Inbred C57BL ; Muridae/*genetics ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/*genetics ; *Recombination, Genetic ; Species Specificity ; Telomere/*genetics ; *Translocation, Genetic/genetics ; },
abstract = {Common laboratory strains such as C57BL/6J carry a single Csf2ra gene that maps to the distal end of Chromosome (Chr) 19. Here we report that several species of wild mice contain multiple Csf2ra genes. Using interspecific backcross mapping and in situ hybridization, we demonstrate that one of these species, Mus spretus, carries four Csf2ra genes dispersed among the distal tips of Chrs 4, 10, 13, and 19. Our data further suggest that these additional Csf2ra genes are not generated by retrotransposition, but rather by nonhomologous subtelomeric exchanges that could be mediated in part by ribosomal genes located at the subtelomeric regions of Chrs 4, 13, and 19. Although we do not know whether these additional Csf2ra genes are functionally active, our studies suggest that subtelomeric exchange provides a potent means for rapid gene amplification in the mouse.},
}
@article {pmid11699393,
year = {2001},
author = {Ohyashiki, K and Iwama, H and Yahata, N and Tauchi, T and Kawakubo, K and Shimamoto, T and Ohyashiki, JH},
title = {Telomere dynamics in myelodysplastic syndromes and acute leukemic transformation.},
journal = {Leukemia &amp; lymphoma},
volume = {42},
number = {3},
pages = {291-299},
doi = {10.3109/10428190109064585},
pmid = {11699393},
issn = {1042-8194},
mesh = {Cell Transformation, Neoplastic/genetics ; Disease Progression ; Humans ; Leukemia/*genetics ; Myelodysplastic Syndromes/*genetics ; Telomere/*genetics ; },
abstract = {Myelodysplastic syndromes (MDS) are characterized by cytopenias in the blood and dysplastic features in the hematopoietic cells. Although the impact of cytogenetic abnormalities is considerable for prognosis, the exact genetic mechanism of MDS remains undetermined. In this study we assessed cytogenetic changes, microsatellite alterations, and telomere dynamics in order to obtain further insight into the pathogenesis of MDS. Thirty-three percentage of MDS patients and 60% of post-MDS acute leukemia (post-MDS AML) had de novo microsatellite changes. In the MDS phase, however, > 60% of patients showed reduction of telomere lengths without microsatellite changes, indicating that telomere reduction in most MDS patients does not seem to be directly linked to genome instability, or that reduction of telomere length does not induce microsatellite changes in the MDS phase. Some MDS patients had microsatellite changes without telomerase elevation, indicating that genome instability might accumulate during the disease progression in some MDS patients, and this condition (cellular senescence) may be related to ineffective hemopoiesis in MDS patients. In contrast, 40% of post-MDS AML patients had elevated telomerase activity with microsatellite changes, indicating that approximately 40% of patients with post-MDS AML patients had accumulation of genome instability resulting in elevated telomerase activity in an attempt to obtain genetic stability. However, the remaining MDS patients had microsatellite changes without telomerase up-regulation, suggesting that some MDS had genome instability even after leukemic transformation. Most MDS patients with elevated telomerase activity in the AML phase had elevated telomerase activity even in the MDS phase without apparent change in telomere length before and after leukemic transformation. These findings indicate that telomerase activity in the MDS phase may be independent of telomere length, although telomere shortening seems to be related to genomic instability, and this process may be linked to apoptosis of MDS cells.},
}
@article {pmid11696330,
year = {2001},
author = {Lim, CS and Mian, IS and Dernburg, AF and Campisi, J},
title = {C. elegans clk-2, a gene that limits life span, encodes a telomere length regulator similar to yeast telomere binding protein Tel2p.},
journal = {Current biology : CB},
volume = {11},
number = {21},
pages = {1706-1710},
doi = {10.1016/s0960-9822(01)00526-7},
pmid = {11696330},
issn = {0960-9822},
support = {AG09909/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*genetics ; Amino Acid Sequence ; Animals ; Caenorhabditis elegans Proteins/*genetics ; DNA-Binding Proteins/genetics ; *Genes, Helminth ; Molecular Sequence Data ; Mutation ; RNA, Antisense ; RNA, Small Interfering ; Radiation Tolerance ; *Saccharomyces cerevisiae Proteins ; Sequence Homology, Amino Acid ; Telomere/*genetics ; *Telomere-Binding Proteins ; X-Rays ; },
abstract = {An important quest in modern biology is to identify genes involved in aging. Model organisms such as the nematode Caenorhabditis elegans are particularly useful in this regard. The C. elegans genome has been sequenced [1], and single gene mutations that extend adult life span have been identified [2]. Among these longevity-controlling loci are four apparently unrelated genes that belong to the clk family. In mammals, telomere length and structure can influence cellular, and possibly organismal, aging. Here, we show that clk-2 encodes a regulator of telomere length in C. elegans.},
}
@article {pmid11696058,
year = {2001},
author = {Boukamp, P},
title = {Ageing mechanisms: the role of telomere loss.},
journal = {Clinical and experimental dermatology},
volume = {26},
number = {7},
pages = {562-565},
doi = {10.1046/j.1365-2230.2001.00903.x},
pmid = {11696058},
issn = {0307-6938},
mesh = {Cells, Cultured ; Cellular Senescence/*physiology ; Humans ; Keratinocytes/physiology ; Telomerase/metabolism ; Telomere/*physiology ; Up-Regulation ; },
abstract = {The ends of the chromosomes are capped by specialized structures, the telomeres. These are comprised of tracts of hexanucleotid sequences and, in combination with specific proteins, protect the chromosome against degradation, fusion events and as being recognized as 'damaged' DNA; thus, they guarantee chromosomal integrity. Due to deficiencies during DNA replication, the telomeres continuously loose part of their sequences and it has been proposed that this loss is the liming factor for the replicative capacity of a cell, i.e. telomeric loss is the counting mechanism - the internal clock of ageing. In order to proliferate indefinitely, the cells must prevent telomere erosion and this is mostly achieved by upregulation or de novo expression of the ribonucleoprotein complex telomerase. This enzyme, which has a reverse-transcriptase activity, is able to add telomeric sequences to the outer most ends off the telomeres and thereby stabilize or even elongate the telomeres. As telomerase is expressed in about 90% of all tumours while expression is absent in many somatic tissues, it is not surprising that the causal role of telomere erosion is presently the most favoured hypothesis of cellular ageing.},
}
@article {pmid11691929,
year = {2001},
author = {Booth, C and Griffith, E and Brady, G and Lydall, D},
title = {Quantitative amplification of single-stranded DNA (QAOS) demonstrates that cdc13-1 mutants generate ssDNA in a telomere to centromere direction.},
journal = {Nucleic acids research},
volume = {29},
number = {21},
pages = {4414-4422},
pmid = {11691929},
issn = {1362-4962},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Cell Cycle Proteins/metabolism ; Centromere/*genetics ; Chromosomes, Fungal/genetics ; Cyclin B/*genetics ; DNA Primers ; DNA Probes ; DNA, Fungal/analysis/*biosynthesis/genetics ; DNA, Single-Stranded/analysis/*biosynthesis/genetics ; Genes, Fungal/genetics ; Genome, Fungal ; Intracellular Signaling Peptides and Proteins ; Kinetics ; Mutation/*genetics ; Polymerase Chain Reaction/methods ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Sensitivity and Specificity ; Substrate Specificity ; Telomere/*genetics ; Temperature ; Templates, Genetic ; Time Factors ; },
abstract = {We have developed a method that allows quantitative amplification of single-stranded DNA (QAOS) in a sample that is primarily double-stranded DNA (dsDNA). Single-stranded DNA (ssDNA) is first captured by annealing a tagging primer at low temperature. Primer extension follows to create a novel, ssDNA-dependent, tagged molecule that can be detected by PCR. Using QAOS levels of between 0.2 and 100% ssDNA can be accurately quantified. We have used QAOS to characterise ssDNA levels at three loci near the right telomere of chromosome V in budding yeast cdc13-1 mutants. Our results confirm and extend previous studies which demonstrate that when Cdc13p, a telomere-binding protein, is disabled, loci close to the telomere become single stranded whereas centromere proximal sequences do not. In contrast to an earlier model, our new results are consistent with a model in which a RAD24-dependent, 5' to 3' exonuclease moves from the telomere toward the centromere in cdc13-1 mutants. QAOS has been adapted, using degenerate tagging primers, to preferentially amplify all ssDNA sequences within samples that are primarily dsDNA. This approach may be useful for identifying ssDNA sequences associated with physiological or pathological states in other organisms.},
}
@article {pmid11689876,
year = {2001},
author = {Bonetta, L},
title = {Size matters to a telomere.},
journal = {Nature medicine},
volume = {7},
number = {11},
pages = {1180},
doi = {10.1038/nm1101-1180},
pmid = {11689876},
issn = {1078-8956},
mesh = {Animals ; In Situ Hybridization, Fluorescence ; Mice ; Telomerase/deficiency/genetics ; Telomere/enzymology/genetics/*ultrastructure ; },
}
@article {pmid11689701,
year = {2001},
author = {Grossi, S and Bianchi, A and Damay, P and Shore, D},
title = {Telomere formation by rap1p binding site arrays reveals end-specific length regulation requirements and active telomeric recombination.},
journal = {Molecular and cellular biology},
volume = {21},
number = {23},
pages = {8117-8128},
pmid = {11689701},
issn = {0270-7306},
mesh = {Binding Sites/physiology ; Chromosomes, Fungal/genetics/metabolism ; DNA-Binding Proteins/metabolism ; Fungal Proteins/metabolism ; Models, Genetic ; Oligonucleotide Array Sequence Analysis ; Rad52 DNA Repair and Recombination Protein ; Recombination, Genetic/*physiology ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins ; Substrate Specificity/physiology ; Telomere/*genetics/*metabolism ; rap1 GTP-Binding Proteins/*metabolism ; },
abstract = {Rap1p, the major telomere repeat binding protein in yeast, has been implicated in both de novo telomere formation and telomere length regulation. To characterize the role of Rap1p in these processes in more detail, we studied the generation of telomeres in vivo from linear DNA substrates containing defined arrays of Rap1p binding sites. Consistent with previous work, our results indicate that synthetic Rap1p binding sites within the internal half of a telomeric array are recognized as an integral part of the telomere complex in an orientation-independent manner that is largely insensitive to the precise spacing between adjacent sites. By extending the lengths of these constructs, we found that several different Rap1p site arrays could never be found at the very distal end of a telomere, even when correctly oriented. Instead, these synthetic arrays were always followed by a short (approximately 100-bp) "cap" of genuine TG repeat sequence, indicating a remarkably strict sequence requirement for an end-specific function(s) of the telomere. Despite this fact, even misoriented Rap1p site arrays promote telomere formation when they are placed at the distal end of a telomere-healing substrate, provided that at least a single correctly oriented site is present within the array. Surprisingly, these heterogeneous arrays of Rap1p binding sites generate telomeres through a RAD52-dependent fusion resolution reaction that results in an inversion of the original array. Our results provide new insights into the nature of telomere end capping and reveal one way by which recombination can resolve a defect in this process.},
}
@article {pmid11689698,
year = {2001},
author = {Moretti, P and Shore, D},
title = {Multiple interactions in Sir protein recruitment by Rap1p at silencers and telomeres in yeast.},
journal = {Molecular and cellular biology},
volume = {21},
number = {23},
pages = {8082-8094},
pmid = {11689698},
issn = {0270-7306},
support = {GM-40094/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites/physiology ; Chromatin/metabolism ; Fungal Proteins/*metabolism ; Gene Dosage ; Gene Expression ; Gene Silencing/*physiology ; Glutathione Transferase/metabolism ; Mutagenesis, Site-Directed ; Protein Binding/physiology ; Protein Structure, Tertiary/physiology ; Saccharomyces cerevisiae ; Sequence Deletion ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Telomere/*metabolism ; Trans-Activators/*metabolism ; Two-Hybrid System Techniques ; rap1 GTP-Binding Proteins/*metabolism ; },
abstract = {Initiation of transcriptional silencing at mating type loci and telomeres in Saccharomyces cerevisiae requires the recruitment of a Sir2/3/4 (silent information regulator) protein complex to the chromosome, which occurs at least in part through its association with the silencer- and telomere-binding protein Rap1p. Sir3p and Sir4p are structural components of silent chromatin that can self-associate, interact with each other, and bind to the amino-terminal tails of histones H3 and H4. We have identified a small region of Sir3p between amino acids 455 and 481 that is necessary and sufficient for association with the carboxyl terminus of Rap1p but not required for Sir complex formation or histone binding. SIR3 mutations that delete this region cause a silencing defect at HMR and telomeres. However, this impairment of repression is considerably less than that displayed by Rap1p carboxy-terminal truncations that are defective in Sir3p binding. This difference may be explained by the ability of the Rap1p carboxyl terminus to interact independently with Sir4p, which we demonstrate by in vitro binding and two-hybrid assays. Significantly, the Rap1p-Sir4p two-hybrid interaction does not require Sir3p and is abolished by mutation of the carboxyl terminus of Rap1p. We propose that both Sir3p and Sir4p can directly and independently bind to Rap1p at mating type silencers and telomeres and suggest that Rap1p-mediated recruitment of Sir proteins operates through multiple cooperative interactions, at least some of which are redundant. The physical separation of the Rap1p interaction region of Sir3p from parts of the protein required for Sir complex formation and histone binding raises the possibility that Rap1p can participate directly in the maintenance of silent chromatin through the stabilization of Sir complex-nucleosome interactions.},
}
@article {pmid11689452,
year = {2001},
author = {Grandin, N and Damon, C and Charbonneau, M},
title = {Cdc13 prevents telomere uncapping and Rad50-dependent homologous recombination.},
journal = {The EMBO journal},
volume = {20},
number = {21},
pages = {6127-6139},
pmid = {11689452},
issn = {0261-4189},
mesh = {Cell Cycle Proteins/metabolism ; Cell Survival/physiology ; Cellular Senescence/physiology ; Cyclin B/genetics/*metabolism ; DNA Damage/physiology ; DNA-Binding Proteins/metabolism ; Fungal Proteins/*metabolism ; Genes, cdc ; Mutation ; Rad51 Recombinase ; Rad52 DNA Repair and Recombination Protein ; Recombination, Genetic/*physiology ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; *Telomere-Binding Proteins ; Temperature ; },
abstract = {Cdc13 performs an essential function in telomere end protection in budding yeast. Here, we analyze the consequences on telomere dynamics of cdc13-induced telomeric DNA damage in proliferating cells. Checkpoint-deficient cdc13-1 cells accumulated DNA damage and eventually senesced. However, these telomerase-proficient cells could survive by using homologous recombination but, contrary to telomerase-deficient cells, did so without prior telomere shortening. Strikingly, homologous recombination in cdc13-1 mec3, as well as in telomerase-deficient cdc13-1 cells, which were Rad52- and Rad50-dependent but Rad51-independent, exclusively amplified the TG(1-3) repeats. This argues that not only short telomeres are substrates for type II recombination. The Cdc13-1 mutant protein harbored a defect in its association with Stn1 and Ten1 but also an additional, unknown, defect that could not be cured by expressing a Cdc13-1- Ten1-Stn1 fusion. We propose that Cdc13 prevents telomere uncapping and inhibits recombination between telomeric sequences through a pathway distinct from and complementary to that used by telomerase.},
}
@article {pmid11687906,
year = {2001},
author = {Saretzki, G and Ludwig, A and von Zglinicki, T and Runnebaum, IB},
title = {Ribozyme-mediated telomerase inhibition induces immediate cell loss but not telomere shortening in ovarian cancer cells.},
journal = {Cancer gene therapy},
volume = {8},
number = {10},
pages = {827-834},
doi = {10.1038/sj.cgt.7700383},
pmid = {11687906},
issn = {0929-1903},
mesh = {Adenoviridae/genetics ; Apoptosis ; Catalytic Domain/genetics ; Cell Division/physiology ; DNA Primers/chemistry ; DNA-Binding Proteins ; Female ; Flow Cytometry ; Genetic Therapy/methods ; Genetic Vectors ; Humans ; Ovarian Neoplasms/*enzymology ; RNA, Catalytic/*pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/*antagonists &amp; inhibitors/genetics ; Telomere/*metabolism ; Transfection ; Tumor Cells, Cultured ; },
abstract = {Telomerase is a promising target for human cancer gene therapy. Its inhibition allows telomere shortening to occur in cancer cells, which in turn is thought to trigger delayed senescence and/or apoptosis. We tested whether telomerase inhibition might have additional, immediate effects on tumor cell growth. Ovarian cancer cell lines with widely differing telomere lengths were efficiently transduced with an adenovirus expressing a ribozyme directed against the T motif of the catalytic subunit of human telomerase, hTERT. Three days after transduction, telomerase activity was significantly reduced and massive cell loss was induced in mass cultures from all four ovarian cancer cell lines tested, whereas transduction of telomerase-negative human fibroblasts did not attenuate their growth. The kinetics of induction of cell death in cancer cells was not significantly dependent on telomere length, and telomeres did not shorten measurably before the onset of apoptosis. The data suggest the existence of a "fast-track" mechanism by which diminution of telomerase can interfere with cancer cell growth and induce cell death, presumably by apoptosis. This phenomenon might be a consequence of the telomere capping function provided by telomerase in tumor cells. Uncapping of telomeres by ribozyme-mediated inhibition of telomerase bears therapeutic potential for ovarian cancer.},
}
@article {pmid11687262,
year = {2002},
author = {Barker, K and Khayat, M and Miller, N and Wilson, M and Clem, LW and Bengtén, E},
title = {Immortal and mortal clonal lymphocyte lines from channel catfish: comparison of telomere length, telomerase activity, tumor suppressor and heat shock protein expression.},
journal = {Developmental and comparative immunology},
volume = {26},
number = {1},
pages = {45-51},
doi = {10.1016/s0145-305x(01)00049-0},
pmid = {11687262},
issn = {0145-305X},
support = {R01-AI-19530/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; B-Lymphocytes/cytology ; Cell Line ; HSP70 Heat-Shock Proteins/analysis ; Ictaluridae/genetics/*immunology ; Lymphocytes/*cytology ; T-Lymphocytes/cytology ; Telomerase/analysis ; Telomere/genetics ; Tumor Suppressor Protein p53/analysis ; },
abstract = {Channel catfish autonomous (immortal) and nonautonomous (mortal) leukocyte lines were phenotyped with respect to telomere length and the expression of telomerase, Hsp70 and p53, potentially important factors in cellular immortalization. The autonomous cells constitutively expressed telomerase whereas the nonautonomous cells expressed this activity only transiently. This observation, coupled with the low telomerase activity level seen in freshly isolated leukocytes, suggests that telomerase expression in catfish leukocytes is activation induced. In contrast both types of cell lines exhibited quite similar patterns of significantly shortened telomeres, suggesting that telomerase does not stabilize catfish telomeres until a critical short length is reached. Northern analyses indicated that, like telomerase, Hsp70 gene expression was constitutive in autonomous cells and transient in nonautonomous cells. In contrast, p53 mRNA levels appeared similarly low and noncycling in both long-term cultured types of catfish cells, regardless of the culture situation. Furthermore it was noted, by Western analyses, that both types of cells display multiple sized forms of p53 proteins. This latter observation implies that truncation of p53 protein is probably not directly involved in the in vitro immortalization process of channel catfish leukocytes.},
}
@article {pmid11676925,
year = {2001},
author = {Kanoh, J and Ishikawa, F},
title = {spRap1 and spRif1, recruited to telomeres by Taz1, are essential for telomere function in fission yeast.},
journal = {Current biology : CB},
volume = {11},
number = {20},
pages = {1624-1630},
doi = {10.1016/s0960-9822(01)00503-6},
pmid = {11676925},
issn = {0960-9822},
mesh = {Amino Acid Sequence ; DNA-Binding Proteins/*metabolism ; Humans ; Meiosis/physiology ; Molecular Sequence Data ; Protozoan Proteins/*metabolism ; Repressor Proteins/*metabolism ; *Saccharomyces cerevisiae Proteins ; Schizosaccharomyces/*cytology/metabolism ; Schizosaccharomyces pombe Proteins/*metabolism ; Spindle Apparatus/metabolism ; Telomere/*physiology ; *Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 1 ; },
abstract = {Telomeres are essential for genome integrity. scRap1 (S. cerevisiae Rap1) directly binds to telomeric DNA and regulates telomere length and telomere position effect (TPE) by recruiting two different groups of proteins to its RCT (Rap1 C-terminal) domain. The first group, Rif1 and Rif2, regulates telomere length. The second group, Sir3 and Sir4, is involved in heterochromatin formation. On the other hand, human TRF1 and TRF2, as well as their fission yeast homolog, Taz1, directly bind to telomeric DNA and negatively regulate telomere length. Taz1 also plays important roles in TPE and meiosis. Human Rap1, the ortholog of scRap1, negatively regulates telomere length and appears to be recruited to telomeres by interacting with TRF2. Here, we describe two novel fission yeast proteins, spRap1 (S. pombe Rap1) and spRif1 (S. pombe Rif1), which are orthologous to scRap1 and scRif1, respectively. spRap1 and spRif1 are independently recruited to telomeres by interacting with Taz1. The rap1 mutant is severely defective in telomere length control, TPE, and telomere clustering toward the spindle pole body (SPB) at the premeiotic horsetail stage, indicating that spRap1 has critical roles in these telomere functions. The rif1 mutant also shows some defects in telomere length control and meiosis. Our results indicate that Taz1 provides binding sites for telomere regulators, spRap1 and spRif1, which perform the essential telomere functions. This study establishes the similarity of telomere organization in fission yeast and humans.},
}
@article {pmid11676924,
year = {2001},
author = {Chikashige, Y and Hiraoka, Y},
title = {Telomere binding of the Rap1 protein is required for meiosis in fission yeast.},
journal = {Current biology : CB},
volume = {11},
number = {20},
pages = {1618-1623},
doi = {10.1016/s0960-9822(01)00457-2},
pmid = {11676924},
issn = {0960-9822},
mesh = {Amino Acid Sequence ; DNA-Binding Proteins/*metabolism ; Meiosis/physiology ; Microscopy, Fluorescence ; Molecular Sequence Data ; Protozoan Proteins/*metabolism ; Schizosaccharomyces/*cytology/*metabolism ; *Schizosaccharomyces pombe Proteins ; Telomere/*metabolism ; *Telomere-Binding Proteins ; Two-Hybrid System Techniques ; },
abstract = {Telomeres are essential for chromosome integrity, protecting the ends of eukaryotic linear chromosomes during cell proliferation. Telomeres also function in meiosis; a characteristic clustering of telomeres beneath the nuclear membrane is observed during meiotic prophase in many organisms from yeasts to plants and humans, and the role of the telomeres in meiotic pairing and the recombination of homologous chromosomes has been demonstrated in the fission yeast Schizosaccharomyces pombe and in the budding yeast Saccharomyces cerevisiae. Here we report that S. pombe Rap1 is a telomeric protein essential for meiosis. While Rap1 is conserved in budding yeast and humans, schemes for telomere binding vary among species: human RAP1 binds to the telomere through interaction with the telomere binding protein TRF2; S. cerevisiae Rap1, however, binds telomeric DNA directly, and no orthologs of TRF proteins have been identified in this organism. In S. pombe, unlike in S. cerevisiae, an ortholog of human TRF has been identified. This ortholog, Taz1, binds directly to telomere repeats [18] and is necessary for telomere clustering in meiotic prophase. Our results demonstrate that S. pombe Rap1 binds to telomeres through interaction with Taz1, similar to human Rap1-TRF2, and that Taz1-mediated telomere localization of Rap1 is necessary for telomere clustering and for the successful completion of meiosis. Moreover, in taz1-disrupted cells, molecular fusion of Rap1 with the Taz1 DNA binding domain recovers telomere clustering and largely complements defects in meiosis, indicating that telomere localization of Rap1 is a key requirement for meiosis.},
}
@article {pmid11675499,
year = {2001},
author = {Gisselsson, D and Jonson, T and Petersén, A and Strömbeck, B and Dal Cin, P and Höglund, M and Mitelman, F and Mertens, F and Mandahl, N},
title = {Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {98},
number = {22},
pages = {12683-12688},
pmid = {11675499},
issn = {0027-8424},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Cell Survival ; *Chromosome Aberrations ; *DNA Fragmentation ; Female ; Humans ; Interphase ; Male ; Middle Aged ; Neoplasms/*genetics ; Repetitive Sequences, Nucleic Acid ; Telomerase/metabolism ; *Telomere ; },
abstract = {Although mechanisms for chromosomal instability in tumors have been described in animal and in vitro models, little is known about these processes in man. To explore cytogenetic evolution in human tumors, chromosomal breakpoint profiles were constructed for 102 pancreatic carcinomas and 140 osteosarcomas, two tumor types characterized by extensive genomic instability. Cases with few chromosomal alterations showed a preferential clustering of breakpoints to the terminal bands, whereas tumors with many changes showed primarily interstitial and centromeric breakpoints. The terminal breakpoint frequency was negatively correlated to telomeric TTAGGG repeat length, and fluorescence in situ hybridization with telomeric TTAGGG probes consistently indicated shortened telomeres and >10% of chromosome ends lacking telomeric signals. Because telomeric dysfunction may lead to formation of unstable ring and dicentric chromosomes, mitotic figures were also evaluated. Anaphase bridges were found in all cases, and fluorescence in situ hybridization demonstrated extensive structural rearrangements of chromosomes, with terminal transferase detection showing fragmented DNA in 5-20% of interphase cells. Less than 2% of cells showed evidence of necrosis or apoptosis, and telomerase was expressed in the majority of cases. Telomeric dysfunction may thus trigger chromosomal fragmentation through persistent bridge-breakage events in pancreatic carcinomas and osteosarcomas, leading to a continuous reorganization of the tumor genome. Telomerase expression is not sufficient for completely stabilizing the chromosome complement but may be crucial for preventing complete genomic deterioration and maintaining cellular survival.},
}
@article {pmid11672985,
year = {2001},
author = {Hao, YH and Tan, Z},
title = {Telomeres at the chromosome X(p) might be critical in limiting the proliferative potential of human cells.},
journal = {Experimental gerontology},
volume = {36},
number = {10},
pages = {1639-1647},
doi = {10.1016/s0531-5565(01)00129-2},
pmid = {11672985},
issn = {0531-5565},
mesh = {Cell Division/genetics ; Cells/*cytology ; Humans ; Male ; Telomere/*physiology ; X Chromosome/*genetics ; },
abstract = {Normal human somatic cells can only divide for a limited number of times. This phenomenon has been regarded as a reflection of individual aging at the cellular level. Experimental evidences suggest that a cell's division potential is limited by the physical length of telomeres that gradually shorten through successive cell divisions. At present, it is not clear whether such a limit is imposed by the overall shortening of all telomeres or the shortening of certain critical ones. Computer simulations have suggested that among the 92 telomeres in human cells, two specific telomeres might be preferentially involved in such process. Recent experiment has shown that in a culture of male human cells, the length of the telomeres at the chromosome X(p) is reserved over the later passages during clonal proliferation. This unique feature, if can be further confirmed in other cells, implies a critical role of the telomeres at X(p) in limiting the proliferation capacity of human cells.},
}
@article {pmid11672984,
year = {2001},
author = {Campisi, J and Kim, SH and Lim, CS and Rubio, M},
title = {Cellular senescence, cancer and aging: the telomere connection.},
journal = {Experimental gerontology},
volume = {36},
number = {10},
pages = {1619-1637},
doi = {10.1016/s0531-5565(01)00160-7},
pmid = {11672984},
issn = {0531-5565},
mesh = {Aging/*physiology ; Animals ; Cellular Senescence/*physiology ; Humans ; Neoplasms/genetics/*physiopathology ; Telomere/*physiology ; },
abstract = {Telomeres are the repetitive DNA sequences and specialized proteins that form the distinctive structure that caps the ends of linear chromosomes. Telomeres allow cells to distinguish the chromosome ends from double strand DNA breaks. The telomeric structure prevents the degradation or fusion of chromosome ends, and thus is essential for maintaining the integrity and stability of eukaryotic genomes. In addition, and perhaps less widely appreciated, telomeres may also indirectly influence gene expression. The length, structure and organization of telomeres are regulated by a host of telomere-associated proteins, and can be influenced by basic cellular processes such as cell proliferation, differentiation, and DNA damage. In mammalian cells, telomere length and/or telomere structure have been linked to both cancer and aging. Here, we briefly review what is known about mammalian telomeres and the proteins that associate with them, and discuss the cellular and organismal consequences of telomere dysfunction and the evidence that cells with dysfunctional telomeres can contribute to cancer and aging phenotypes.},
}
@article {pmid11671315,
year = {1999},
author = {Villanueva, JM and Jia, X and Yohannes, PG and Doetsch, PW and Marzilli, LG},
title = {Cisplatin (cis-Pt(NH(3))(2)Cl(2)) and cis-[Pt(NH(3))(2)(H(2)O)(2)](2+) Intrastrand Cross-Linking Reactions at the Telomere GGGT DNA Sequence Embedded in a Duplex, a Hairpin, and a Bulged Duplex: Use of Mg(2+) and Zn(2+) to Convert a Hairpin to a Bulged Duplex.},
journal = {Inorganic chemistry},
volume = {38},
number = {26},
pages = {6069-6080},
doi = {10.1021/ic990603f},
pmid = {11671315},
issn = {1520-510X},
abstract = {In the past, we showed that metal species have a high affinity for the central G in the GGG sequence of the duplex d(A(1)T(2)G(3)G(4)G(5)T(6)A(7)C(8)C(9)C(10)A(11)T(12))(2) (G3-D) and that cisplatin (cis-Pt(NH(3))(2)Cl(2)) and G3-D formed an N7-Pt-N7 G(4),G(5) intrastrand cross-link preferentially over the G(3),G(4) adduct (approximately 25:1). Thus, a putative G(4) monoadduct was postulated to cross-link in the 3'- rather than the normally more favorable 5'-direction. To evaluate this hypothesis and also to explore why the G3-D G(4),G(5) adduct had an unusual hairpin structure, we have now introduced the use of N,N'-dimethylthiourea (DMTU) as a monoadduct trap and have extended the study to a G3-D analogue with a hairpin form, d(A(1)T(2)G(3)G(4)G(5)T(6)T(7)C(8)C(9)C(10)A(11)T(12)) (G3-H). Chemical shift and 2D (1)H and (13)C NMR data indicated that the G3-H hairpin has a stem region with B-form structure and a nonhelical loop region. Zn(2+) or Mg(2+) ions transformed G3-H into a bulged duplex. Downfield shifts of G(4)H8 and G(4)C8 NMR signals indicated that Zn(2+) binds preferentially to G(4)N7. Reaction of cisplatin or cis-[Pt(NH(3))(2)(H(2)O)(2)](2+) with the bulged duplex and hairpin forms of G3-H gave a similar intrastrand cross-link ratio, G(4),G(5):G(3),G(4) = 7:3. This ratio is insensitive to DNA form or Pt leaving group. For G3-D this ratio is lower in the cis-[Pt(NH(3))(2)(H(2)O)(2)](2+) reaction (approximately 1:1) than in the cisplatin reaction (25:1), indicating that the leaving group influences the cross-linking step for G3-D. The G(4) monoadducts of the cis-Pt(NH(3))(2)Cl(2)-G3-H and -G3-D and the cis-[Pt(NH(3))(2)(H(2)O)(2)](2+)-G3-D reactions were trapped with DMTU, but no monoadduct was trapped in the cis-[Pt(NH(3))(2)(H(2)O)(2)](2+)-G3-H reaction. The results suggest that the respective monoadducts are more long-lived for G3-D. We postulate that the G(5) in the G3-D Cl-G(4) monoadduct is placed in a favorable position to form the cross-link because of a prior conformational change induced by G(4)-A(7) stacking. This accounts for the very high selectivity for 3'-cross-linking. Nevertheless, in all other cases, regardless of the form or conformation, 3'-direction cross-linking is unusually favored at GGGT sequences, suggesting that the sequence itself contributes greatly to the 3'-cross-linking preference; since telomeres have multiple repeats of this GGGT sequence, this finding may have biological relevance.},
}
@article {pmid11641227,
year = {2001},
author = {Bénard, C and McCright, B and Zhang, Y and Felkai, S and Lakowski, B and Hekimi, S},
title = {The C. elegans maternal-effect gene clk-2 is essential for embryonic development, encodes a protein homologous to yeast Tel2p and affects telomere length.},
journal = {Development (Cambridge, England)},
volume = {128},
number = {20},
pages = {4045-4055},
doi = {10.1242/dev.128.20.4045},
pmid = {11641227},
issn = {0950-1991},
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Caenorhabditis elegans/*embryology/*genetics ; Caenorhabditis elegans Proteins/*genetics ; DNA, Helminth/genetics ; Disorders of Sex Development/genetics ; Female ; Fungal Proteins/genetics ; Gene Expression Regulation, Developmental ; *Genes, Helminth ; Helminth Proteins/*genetics ; Molecular Sequence Data ; Mutation ; Phenotype ; Saccharomyces cerevisiae/genetics ; Sequence Homology, Amino Acid ; Telomere/genetics ; *Telomere-Binding Proteins ; Temperature ; },
abstract = {The Caenorhabditis elegans maternal-effect clk genes are involved in the temporal control of development and behavior. We report the genetic and molecular characterization of clk-2. A temperature-sensitive mutation in the gene clk-2 affects embryonic and post-embryonic development, reproduction, and rhythmic behaviors. Yet, virtually all phenotypes are fully maternally rescued. Embryonic development strictly requires the activity of maternal clk-2 during a narrow time window between oocyte maturation and the two- to four-cell embryonic stage. Positional cloning of clk-2 reveals that it encodes a protein homologous to S. cerevisiae Tel2p. In yeast, the gene TEL2 regulates telomere length and participates in gene silencing at subtelomeric regions. In C. elegans, clk-2 mutants have elongated telomeres, and clk-2 overexpression can lead to telomere shortening. Tel2p has been reported to bind to telomeric DNA repeats in vitro. However, we find that a functional CLK-2::GFP fusion protein is cytoplasmic in worms. We discuss how the phenotype of clk-2 mutants could be the result of altered patterns of gene expression.},
}
@article {pmid11607857,
year = {2001},
author = {Martens, UM and Waller, CF},
title = {[Telomere and telomerase as starting-points of new forms of treatment in oncology].},
journal = {Deutsche medizinische Wochenschrift (1946)},
volume = {126},
number = {42},
pages = {1171-1172},
doi = {10.1055/s-2001-17891},
pmid = {11607857},
issn = {0012-0472},
mesh = {Animals ; Humans ; Mice ; Neoplasms/*drug therapy/genetics/pathology ; Research ; Telomerase/*antagonists &amp; inhibitors/*genetics/physiology ; *Telomere/genetics/physiology ; Tumor Cells, Cultured/enzymology/pathology ; },
}
@article {pmid11604086,
year = {2001},
author = {Pandita, TK},
title = {The role of ATM in telomere structure and function.},
journal = {Radiation research},
volume = {156},
number = {5 Pt 2},
pages = {642-647},
doi = {10.1667/0033-7587(2001)156[0642:troait]2.0.co;2},
pmid = {11604086},
issn = {0033-7587},
support = {NS34746/NS/NINDS NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins ; Cells, Cultured ; Chromatin/metabolism ; Chromosome Aberrations ; Chromosomes/metabolism ; DNA-Binding Proteins ; Gene Expression ; Humans ; Nuclear Matrix/metabolism ; Nucleosomes/metabolism ; Protein Serine-Threonine Kinases/deficiency/*physiology/radiation effects ; Radiation, Ionizing ; Telomere/chemistry/*physiology ; Tumor Suppressor Proteins ; },
abstract = {Ataxia telangiectasia (AT) is a rare human autosomal recessive disorder with a wide variety of phenotypic manifestations. AT patients are cancer prone and hypersensitive to ionizing radiation. Cells derived from AT patients require higher levels of serum factors, exhibit cytoskeletal defects, and undergo premature senescence in culture. The gene responsible for AT is ATM (ataxia-telangiectasia mutated), and its product has been implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, and cell cycle control. Because of the homology of the human ATM gene to the TEL1 and rad3 genes of yeast, it has been suggested that mutations in ATM could lead to defective telomere maintenance. The ATM gene product influences chromosome end associations, telomere length, and telomere clustering. The defective telomere metabolism in AT cells could be due to altered interactions between the telomeres and the nuclear matrix. These interactions were studied in nuclear matrix halos before and after irradiation. Altered telomere-nuclear matrix interactions were observed in cells derived from individuals with AT. AT cells also had different nucleosomal periodicity in their telomeres from normal cells. Both telomere-nuclear matrix interactions and nucleosomal periodicity were altered by treatment of primary AT fibroblasts with ionizing radiation. This effect was not observed in cells derived from normal individuals. A link was also found between altered telomere-nuclear matrix interactions, aberrant telomere clustering, and gonadal atrophy. The telomere defect was not corrected by the ectopic expression of the catalytic subunit of telomerase (TERT). Since alteration of the yeast telomere chromatin structure is known to influence gene expression, we compared expressed sequence tags (ESTs) of Atm-null mouse cells and normal mouse cells. Several ESTs were found to be aberrantly expressed in Atm-null mouse cells. This paper summarizes our recent publications and presents some new data on the influence of ATM on telomere metabolism.},
}
@article {pmid11602239,
year = {2001},
author = {Blagosklonny, MV},
title = {How carcinogens (or telomere dysfunction) induce genetic instability: associated-selection model.},
journal = {FEBS letters},
volume = {506},
number = {3},
pages = {169-172},
doi = {10.1016/s0014-5793(01)02894-0},
pmid = {11602239},
issn = {0014-5793},
mesh = {Carcinogens/*pharmacology ; DNA Repair ; *Models, Biological ; *Telomere ; },
abstract = {Carcinogens induce carcinogen-specific genetic instability (defects in DNA repair). According to the 'direct-selection' model, defects in DNA repair per se provide an immediate growth advantage. According to the 'associated-selection' model, carcinogens merely select for cells with adaptive mutations. Like any mutations, adaptive mutations occur predominantly in genetically unstable cells. The 'associated-selection' model predicts that carcinogen-driven selection minimizes cytotoxic but maximizes mutagenic effects of carcinogens. A purely mutagenic (neither cytotoxic, nor cytostatic) environment will favor effective DNA repair, whereas any growth-limiting conditions (telomerase deficiency, anticancer drugs) will select for genetically unstable cells. Genetic instability is a postmark of selective pressure rather than a hallmark of cancer per se. Once selected, genetic instability facilitates the development of resistance to any other growth-limiting conditions. As an example, a putative link between prior exposure to carcinogens and the ability to develop a telomerase-independent growth is discussed.},
}
@article {pmid11598950,
year = {2001},
author = {Roos, G and Hultdin, M},
title = {Flow cytometric determination of telomere length.},
journal = {Cytometry},
volume = {45},
number = {1},
pages = {79-80},
doi = {10.1002/1097-0320(20010901)45:1&lt;79::aid-cyto1147&gt;3.0.co;2-q},
pmid = {11598950},
issn = {0196-4763},
mesh = {Blotting, Southern ; DNA, Neoplasm/analysis ; Fetal Blood/chemistry/cytology ; Flow Cytometry/*methods/standards ; Humans ; *In Situ Hybridization, Fluorescence ; Interphase ; Telomere/*chemistry ; },
}
@article {pmid11598202,
year = {2001},
author = {Maddar, H and Ratzkovsky, N and Krauskopf, A},
title = {Role for telomere cap structure in meiosis.},
journal = {Molecular biology of the cell},
volume = {12},
number = {10},
pages = {3191-3203},
pmid = {11598202},
issn = {1059-1524},
mesh = {Binding Sites/physiology ; Chromosomes/physiology ; DNA-Binding Proteins/*metabolism ; Kluyveromyces/*cytology/*genetics ; Meiosis/physiology ; Mutation ; Phenotype ; Point Mutation/*genetics ; RNA/*genetics/*metabolism ; Telomerase/*genetics/*metabolism ; Telomere/*physiology ; },
abstract = {Telomeres, the natural ends of eukaryotic chromosomes, are essential for the protection of chromosomes from end-to-end fusions, recombination, and shortening. Here we explore their role in the process of meiotic division in the budding yeast, Kluyveromyces lactis. Telomerase RNA mutants that cause unusually long telomeres with deregulated structure led to severely defective meiosis. The severity of the meiotic phenotype of two mutants correlated with the degree of loss of binding of the telomere binding protein Rap1p. We show that telomere size and the extent of potential Rap1p binding to the entire telomere are irrelevant to the process of meiosis. Moreover, we demonstrate that extreme difference in telomere size between two homologous chromosomes is compatible with the normal function of telomeres during meiosis. In contrast, the structure of the most terminal telomeric repeats is critical for normal meiosis. Our results demonstrate that telomeres play a critical role during meiotic division and that their terminal cap structure is essential for this role.},
}
@article {pmid11595186,
year = {2001},
author = {Hemann, MT and Strong, MA and Hao, LY and Greider, CW},
title = {The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability.},
journal = {Cell},
volume = {107},
number = {1},
pages = {67-77},
doi = {10.1016/s0092-8674(01)00504-9},
pmid = {11595186},
issn = {0092-8674},
support = {P01 CA16519/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; *Cell Survival ; Cells, Cultured ; Chromosomes/*physiology ; Heterozygote ; In Situ Hybridization, Fluorescence ; Karyotyping/methods ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Telomerase/genetics/*metabolism ; Telomere/metabolism/*physiology/ultrastructure ; },
abstract = {Loss of telomere function can induce cell cycle arrest and apoptosis. To investigate the processes that trigger cellular responses to telomere dysfunction, we crossed mTR-/- G6 mice that have short telomeres with mice heterozygous for telomerase (mTR+/-) that have long telomeres. The phenotype of the telomerase null offspring was similar to that of the late generation parent, although only half of the chromosomes were short. Strikingly, spectral karyotyping (SKY) analysis revealed that loss of telomere function occurred preferentially on chromosomes with critically short telomeres. Our data indicate that, while average telomere length is measured in most studies, it is not the average but rather the shortest telomeres that constitute telomere dysfunction and limit cellular survival in the absence of telomerase.},
}
@article {pmid11592316,
year = {2001},
author = {Yazawa, M and Okuda, M and Setoguchi, A and Iwabuchi, S and Nishimura, R and Sasaki, N and Masuda, K and Ohno, K and Tsujimoto, H},
title = {Telomere length and telomerase activity in canine mammary gland tumors.},
journal = {American journal of veterinary research},
volume = {62},
number = {10},
pages = {1539-1543},
doi = {10.2460/ajvr.2001.62.1539},
pmid = {11592316},
issn = {0002-9645},
mesh = {Adenocarcinoma/enzymology/genetics/veterinary ; Adenoma/enzymology/genetics/veterinary ; Animals ; Blotting, Southern ; DNA Restriction Enzymes/chemistry ; DNA, Neoplasm/chemistry/genetics/isolation &amp; purification ; Disease Models, Animal ; Dog Diseases/*enzymology/*genetics ; Dogs ; Female ; Male ; Mammary Neoplasms, Animal/*enzymology/*genetics ; Myoepithelioma/enzymology/genetics/veterinary ; Telomerase/genetics/*metabolism ; Telomere/*genetics ; },
abstract = {OBJECTIVE: To measure telomere length and telomerase activity in naturally occurring canine mammary gland tumors.<br><br>SAMPLE POPULATION: 27 mammary gland tumor specimens obtained during resection or necropsy and 12 mammary gland tissue specimens obtained from healthy (control) dogs.<br><br>PROCEDURE: Telomere length in tissue specimens was measured by use of restriction endonuclease digestion and Southern blot analysis. Telomerase activity was measured by use of a telomeric repeat amplification protocol assay.<br><br>RESULTS: Telomere length in mammary gland tumors ranged from 11.0 to 21.6 kilobase pairs (kbp; mean +/- SEM, 14.5+/-0.5 kbp) but did not differ among tumor types. Telomeres in mammary gland tumors were slightly shorter than in normal tissue specimens, but telomere length could not be directly compared between groups, because mean age of dogs was significantly different between groups. Age was negatively correlated with telomere length in control dogs but was not significantly correlated with length in affected dogs. Telomerase activity was detected in 26 of 27 mammary gland tumors and in 4 of 12 normal tissue specimens. However, telomerase activity and telomere length were not correlated in tumor specimens.<br><br>Telomere length is maintained in canine mammary gland tumors regardless of the age of the affected dog. Measurement of telomere length may be a useful tool for monitoring the in vivo effects of telomerase inhibitors in dogs with tumors.},
}
@article {pmid11591364,
year = {2001},
author = {Adelfalk, C and Lorenz, M and Serra, V and von Zglinicki, T and Hirsch-Kauffmann, M and Schweiger, M},
title = {Accelerated telomere shortening in Fanconi anemia fibroblasts--a longitudinal study.},
journal = {FEBS letters},
volume = {506},
number = {1},
pages = {22-26},
doi = {10.1016/s0014-5793(01)02869-1},
pmid = {11591364},
issn = {0014-5793},
mesh = {Adolescent ; Adult ; Apoptosis ; Cell Division ; Cell Line ; Child ; DNA Damage ; Fanconi Anemia/*genetics/pathology ; Female ; Humans ; Infant ; Longitudinal Studies ; Male ; Oxidative Stress ; *Telomere ; },
abstract = {Fanconi anemia (FA) is a fatal inherited disease displaying chromosomal instability, disturbances in oxygen metabolism and a high burden of intracellular radical oxygen species. Oxygen radicals can damage DNA including telomeric regions. Insufficient repair results in single strand breaks that can induce accelerated telomere shortening. In a longitudinal study we demonstrate that telomeric DNA is continuously lost at a higher rate in FA fibroblasts compared to healthy controls. Furthermore, we show that this loss is caused rather by an increased shortening per cell division in regularly replicating cells than by apoptosis.},
}
@article {pmid11589730,
year = {2001},
author = {Wu, KD and Hansen, ER},
title = {Shortened telomere length is demonstrated in T-cell subsets together with a pronounced increased telomerase activity in CD4 positive T cells from blood of patients with mycosis fungoides and parapsoriasis.},
journal = {Experimental dermatology},
volume = {10},
number = {5},
pages = {329-336},
doi = {10.1034/j.1600-0625.2001.100505.x},
pmid = {11589730},
issn = {0906-6705},
mesh = {Aged ; Aged, 80 and over ; Antigens, Differentiation, T-Lymphocyte ; Antigens, Neoplasm ; B-Lymphocytes/physiology ; Blotting, Southern ; CD3 Complex/analysis ; CD4-Positive T-Lymphocytes/*enzymology ; CD8-Positive T-Lymphocytes/physiology ; Female ; Humans ; Male ; Membrane Glycoproteins/analysis ; Middle Aged ; Mycosis Fungoides/*blood/enzymology/genetics/immunology ; Parapsoriasis/*blood/enzymology/genetics ; Reference Values ; Restriction Mapping ; T-Lymphocyte Subsets/*physiology ; T-Lymphocytes/immunology/physiology ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {We have recently demonstrated that telomerase activity is increased and telomere length shortened in lymphocytes from peripheral blood of patients with cutaneous T-cell lymphoma. In order to determine which cell type has increased telomerase activity and shortened telomere length, CD4+, CD8+, CLA+ CD3+ and CLA- CD3+ T cells were isolated from peripheral blood of 25 patients, including 15 patients with mycosis fungoides and 10 patients with parapsoriasis. Eleven healthy individuals were used as controls; CD19+ B cells were separated from each individual as an internal control. The results showed that the increased telomerase activity was significantly predominating in the CD4+ T-cell subset. Significantly shortened telomere length was found in CD4+ and CD8+ T-cell subsets from the patients compared with the same cell subsets obtained from healthy individuals. However, no difference was observed between the subsets; CD19+ B cells collected from patients and healthy control individuals had similar telomerase activity and telomere length which was significantly different from the values found in T cells. The telomere length was significantly shorter in CLA+ CD3+ subset than in CLA- CD3+ subset. Interestingly, increased telomerase activity and shortened telomere length was also detected in CD4+ T cells from patients with parapsoriasis indicating that alteration of telomerase activity and telomere length in CD4+ T cells is an early event in the pathogenesis of cutaneous T-cell lymphoma. Thus, the results indicate that a significant high level of telomerase activity and shortened telomere length frequently occur in T cells of patients with CTCL and may reflect tumorigenesis.},
}
@article {pmid11587933,
year = {2001},
author = {Kobryn, K and Chaconas, G},
title = {The circle is broken: telomere resolution in linear replicons.},
journal = {Current opinion in microbiology},
volume = {4},
number = {5},
pages = {558-564},
doi = {10.1016/s1369-5274(00)00251-4},
pmid = {11587933},
issn = {1369-5274},
mesh = {Borrelia burgdorferi/enzymology/genetics ; Coliphages/enzymology/genetics ; DNA Replication/*genetics/*physiology ; DNA, Bacterial/biosynthesis ; Plasmids/*genetics ; Poxviridae/enzymology/genetics ; Replicon/*genetics ; Telomere/*genetics ; Virus Replication ; },
abstract = {Linear DNA molecules with covalently closed hairpin ends (telomeres) exist in a wide variety of organisms. Telomere resolution, a DNA breakage and reunion reaction in which replicated telomeres are processed into hairpin ends, is now known to be a common theme in poxviruses, Borrelia burgdorferi and Escherichia coli phage N15. Candidate proteins that may perform this reaction have recently been identified in poxviruses. Moreover, the first purification and definitive identification of a telomere resolvase has been reported for phage N15. This protein is the prototype for a new class of DNA enzyme that performs a unique reaction. Advances in the study of telomere resolution in poxviruses, B. burgdorferi and E. coli phage N15 are discussed.},
}
@article {pmid11585910,
year = {2001},
author = {Förstemann, K and Lingner, J},
title = {Molecular basis for telomere repeat divergence in budding yeast.},
journal = {Molecular and cellular biology},
volume = {21},
number = {21},
pages = {7277-7286},
pmid = {11585910},
issn = {0270-7306},
mesh = {Base Sequence ; Binding Sites ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Mutation ; RNA/metabolism ; Repetitive Sequences, Nucleic Acid ; Saccharomycetales/*genetics/*physiology ; Sequence Analysis, DNA ; Telomerase/genetics/metabolism ; Telomere/*genetics/*ultrastructure ; Transcription, Genetic ; },
abstract = {Telomerase is a ribonucleoprotein enzyme that adds repetitive sequences to the ends of linear chromosomes, thereby counteracting nucleotide loss due to incomplete replication. A short region of the telomerase RNA subunit serves as template for nucleotide addition onto the telomere 3' end. Although Saccharomyces cerevisiae contains only one telomerase RNA gene, telomere repeat sequences are degenerate in this organism. Based on a detailed analysis of the telomere sequences specified by wild-type and mutant RNA templates in vivo, we show that the divergence of telomere repeats is due to abortive reverse transcription in the 3' and 5' regions of the template and due to the alignment of telomeres in multiple registers within the RNA template. Through the interpretation of wild-type telomere sequences, we identify nucleotides in the template that are not accessible for base pairing during substrate annealing. Rather, these positions become available as templates for reverse transcription only after alignment with adjacent nucleotides has occurred, indicating that a conformational change takes place upon substrate binding. We also infer that the central part of the template region is reverse transcribed processively. The inaccessibility of certain template positions for alignment and the processive polymerization of the central template portion may serve to reduce the possible repeat diversification and enhance the incorporation of binding sites for Rap1p, the telomere binding protein of budding yeast.},
}
@article {pmid11583109,
year = {2001},
author = {Dumont, P and Royer, V and Pascal, T and Dierick, JF and Chainiaux, F and Frippiat, C and de Magalhaes, JP and Eliaers, F and Remacle, J and Toussaint, O},
title = {Growth kinetics rather than stress accelerate telomere shortening in cultures of human diploid fibroblasts in oxidative stress-induced premature senescence.},
journal = {FEBS letters},
volume = {502},
number = {3},
pages = {109-112},
doi = {10.1016/s0014-5793(01)02679-5},
pmid = {11583109},
issn = {0014-5793},
mesh = {Cell Division/drug effects/*physiology ; Cellular Senescence/*physiology ; Diploidy ; Fibroblasts/*cytology/drug effects/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Kinetics ; *Oxidative Stress ; Telomere/*metabolism ; Thymidine/chemistry ; beta-Galactosidase/metabolism ; tert-Butylhydroperoxide/pharmacology ; },
abstract = {WI-38 human diploid fibroblasts underwent accelerated telomere shortening (490 bp/stress) and growth arrest after exposure to four subcytotoxic 100 microM tert-butylhydroperoxide (t-BHP) stresses, with a stress at every two population doublings (PD). After subcytotoxic 160 microM H2O2 stress or five repeated 30 microM t-BHP stresses along the same PD, respectively a 322 +/- 55 and 380 +/- 129 bp telomere shortening was observed only during the first PD after stress. The percentage of cells resuming proliferation after stress suggests this telomere shortening is due to the number of cell divisions accomplished to reach confluence during the first PD after stress.},
}
@article {pmid11582772,
year = {2001},
author = {Golubev, AG},
title = {[The natural history of telomeres].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {7},
number = {},
pages = {95-104},
pmid = {11582772},
issn = {1561-9125},
mesh = {Aging/*physiology ; Cell Differentiation/physiology ; Female ; Free Radicals ; Humans ; Male ; Telomerase/genetics/physiology ; Telomere/genetics/*physiology ; },
abstract = {Telomeres are end chromosome structures, which may shorten because of DNA end replication problem and non-reparability of free-radical damage to telomeric DNA. Telomerase is an enzyme serving to maintain telomere length at a species-specific level. The absence of telomerase in somatic cells is widely believed to be the cause of the limited proliferative potential of somatic cells achieved when telomere length, which diminishes over successive cell generations, becomes critically short. However, telomeres are known to be highly heterogenous with regard to their length even in cloned cell populations. In this review data on telomer length distribution and changes in characteristics of these distributions observed over time are considered along with hypotheses about the nature of these phenomena. The following conclusions are drawn: causes of the known features of telomere length distribution are not limited to mere scattering and measurement error, and so any concepts concerning the relationships between telomere length and cell fate should take characteristics of telomere heterogeneity in consideration; the ratio of the initial telomere length and the rate of telomere shortening does not determine the proliferative potential of non-transformed cell populations and does not limit the lifespans of multicellular organisms; telomerase functions in non-germinal cells are either unnecessary or unknown; telomere heterogeneity may result from the stochastic nature of events committing cells to terminal differentiation and/or the loss of cell capacity to proliferate.},
}
@article {pmid11581377,
year = {2001},
author = {DeMasi, J and Du, S and Lennon, D and Traktman, P},
title = {Vaccinia virus telomeres: interaction with the viral I1, I6, and K4 proteins.},
journal = {Journal of virology},
volume = {75},
number = {21},
pages = {10090-10105},
pmid = {11581377},
issn = {0022-538X},
support = {R01 AI021758/AI/NIAID NIH HHS/United States ; R01 AI21758/AI/NIAID NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; DNA Probes ; DNA Replication ; DNA-Binding Proteins/*metabolism ; Mice ; Molecular Sequence Data ; Protein Structure, Secondary ; *Telomere ; Vaccinia virus/*genetics ; Viral Core Proteins/*metabolism ; Viral Proteins/*metabolism ; Virus Replication ; },
abstract = {The 192-kb linear DNA genome of vaccinia virus has covalently closed hairpin termini that are extremely AT rich and contain 12 extrahelical bases. Vaccinia virus telomeres have previously been implicated in the initiation of viral genome replication; therefore, we sought to determine whether the telomeres form specific protein-DNA complexes. Using an electrophoretic mobility shift assay, we found that extracts prepared from virions and from the cytoplasm of infected cells contain telomere binding activity. Four shifted complexes were detected using hairpin probes representing the viral termini, two of which represent an interaction with the "flip" isoform and two with the "flop" isoform. All of the specificity for protein binding lies within the terminal 65-bp hairpin sequence. Viral hairpins lacking extrahelical bases cannot form the shifted complexes, suggesting that DNA structure is crucial for complex formation. Using an affinity purification protocol, we purified the proteins responsible for hairpin-protein complex formation. The vaccinia virus I1 protein was identified as being necessary and sufficient for the formation of the upper doublet of shifted complexes, and the vaccinia virus I6 protein was shown to form the lower doublet of shifted complexes. Competition and challenge experiments confirmed that the previously uncharacterized I6 protein binds tightly and with great specificity to the hairpin form of the viral telomeric sequence. Incubation of viral hairpins with extracts from infected cells also generates a smaller DNA fragment that is likely to reflect specific nicking at the apex of the hairpin; we show that the vaccinia virus K4 protein is necessary and sufficient for this reaction. We hypothesize that these telomere binding proteins may play a role in the initiation of vaccinia virus genome replication and/or genome encapsidation.},
}
@article {pmid11577567,
year = {2001},
author = {Vaccarezza, MH},
title = {[A new approach to the carcinogenetic process: the telomere wearing out].},
journal = {Acta gastroenterologica Latinoamericana},
volume = {31},
number = {3},
pages = {149-152},
pmid = {11577567},
issn = {0300-9033},
mesh = {Colorectal Neoplasms/*genetics ; Humans ; Intestinal Mucosa/enzymology/pathology ; Telomerase/metabolism ; Telomere/*genetics/metabolism ; },
}
@article {pmid11577237,
year = {2001},
author = {Bailey, SM and Cornforth, MN and Kurimasa, A and Chen, DJ and Goodwin, EH},
title = {Strand-specific postreplicative processing of mammalian telomeres.},
journal = {Science (New York, N.Y.)},
volume = {293},
number = {5539},
pages = {2462-2465},
doi = {10.1126/science.1062560},
pmid = {11577237},
issn = {0036-8075},
support = {AG-917709/AG/NIA NIH HHS/United States ; CA50519/CA/NCI NIH HHS/United States ; CA76260/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Division ; Cell Line ; Chromatids/physiology/ultrastructure ; Chromosomes/physiology/ultrastructure ; *DNA Replication ; DNA-Activated Protein Kinase ; DNA-Binding Proteins/genetics/*metabolism ; Humans ; In Situ Hybridization ; Mice ; Mitosis ; Mutation ; Nuclear Proteins ; Protein Serine-Threonine Kinases/deficiency/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2 ; Tumor Cells, Cultured ; },
abstract = {Telomeres are specialized nucleoprotein structures that stabilize the ends of linear eukaryotic chromosomes. In mammalian cells, abrogation of telomeric repeat binding factor TRF2 or DNA-dependent protein kinase (DNA-PK) activity causes end-to-end chromosomal fusion, thus establishing an essential role for these proteins in telomere function. Here we show that TRF2-mediated end-capping occurs after telomere replication. The postreplicative requirement for TRF2 and DNA-PKcs, the catalytic subunit of DNA-PK, is confined to only half of the telomeres, namely, those that were produced by leading-strand DNA synthesis. These results demonstrate a crucial difference in postreplicative processing of telomeres that is linked to their mode of replication.},
}
@article {pmid11572773,
year = {2001},
author = {Blackburn, EH},
title = {Switching and signaling at the telomere.},
journal = {Cell},
volume = {106},
number = {6},
pages = {661-673},
doi = {10.1016/s0092-8674(01)00492-5},
pmid = {11572773},
issn = {0092-8674},
mesh = {Animals ; DNA Replication ; DNA-Binding Proteins/chemistry/metabolism ; Humans ; Models, Genetic ; Saccharomyces cerevisiae/genetics ; Signal Transduction ; Telomerase/*metabolism ; Telomere/*physiology/*ultrastructure ; },
abstract = {This review describes the structure of telomeres, the protective DNA-protein complexes at eukaryotic chromosomal ends, and several molecular mechanisms involved in telomere functions. Also discussed are cellular responses to compromising the functions of telomeres and of telomerase, which synthesizes telomeric DNA.},
}
@article {pmid11571752,
year = {2001},
author = {Haw, R and Yarragudi, AD and Uemura, H},
title = {Isolation of a Candida glabrata homologue of RAP1, a regulator of transcription and telomere function in Saccharomyces cerevisiae.},
journal = {Yeast (Chichester, England)},
volume = {18},
number = {14},
pages = {1277-1284},
doi = {10.1002/yea.775},
pmid = {11571752},
issn = {0749-503X},
mesh = {Amino Acid Sequence ; Base Sequence ; Candida/*genetics/metabolism ; *Cloning, Molecular ; DNA-Binding Proteins/chemistry/*genetics/metabolism ; Fungal Proteins/chemistry/*genetics/metabolism ; *Gene Expression Regulation, Fungal ; Genes, Essential ; Genes, Fungal ; Molecular Sequence Data ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; Sequence Analysis, DNA ; Shelterin Complex ; Telomere/*physiology ; *Telomere-Binding Proteins ; *Transcription Factors ; Transcription, Genetic ; },
abstract = {To study the function of RAP1, an essential gene involved in the regulation of transcriptional activation, silencing and the telomere function in Saccharomyces cerevisiae, we isolated a Candida glabrata gene that complements the growth defect of a S. cerevisiae rap1 conditional mutant. The DNA sequence of the cloned gene, which we designated CgRAP1, predicted a 2064 bp open reading frame encoding a 687 amino acid protein with an overall identity of 65% and a similarity of 78% to Rap1p from S. cerevisiae.},
}
@article {pmid11571635,
year = {2001},
author = {Nasir, L and Devlin, P and Mckevitt, T and Rutteman, G and Argyle, DJ},
title = {Telomere lengths and telomerase activity in dog tissues: a potential model system to study human telomere and telomerase biology.},
journal = {Neoplasia (New York, N.Y.)},
volume = {3},
number = {4},
pages = {351-359},
pmid = {11571635},
issn = {1522-8002},
mesh = {Age Factors ; Animals ; Cells, Cultured ; DNA/analysis ; DNA, Neoplasm/analysis ; Dog Diseases/metabolism ; Dogs/*genetics/*metabolism ; Enzyme-Linked Immunosorbent Assay ; Fibroblasts/metabolism ; Leukocytes, Mononuclear/metabolism ; Polymerase Chain Reaction ; Sarcoma/metabolism/veterinary ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {Studies on telomere and telomerase biology are fundamental to the understanding of aging and age-related diseases such as cancer. However, human studies have been hindered by differences in telomere biology between humans and the classical murine animal model system. In this paper, we describe basic studies of telomere length and telomerase activity in canine normal and neoplastic tissues and propose the dog as an alternative model system. Briefly, telomere lengths were measured in normal canine peripheral blood mononuclear cells (PBMCs), a range of normal canine tissues, and in a panel of naturally occurring soft tissue tumours by terminal restriction fragment (TRF) analysis. Further, telomerase activity was measured in canine cell lines and multiple canine tissues using a combined polymerase chain reaction/enzyme-linked immunosorbent assay method. TRF analysis in canine PBMCs and tissues demonstrated mean TRF lengths to range between 12 and 23 kbp with heterogeneity in telomere lengths being observed in a range of normal somatic tissues. In soft tissue sarcomas, two subgroups were identified with mean TRFs of 22.2 and 18.2 kbp. Telomerase activity in canine tissue was present in tumour tissue and testis with little or no activity in normal somatic tissues. These results suggest that the dog telomere biology is similar to that in humans and may represent an alternative model system for studying telomere biology and telomerase-targeted anticancer therapies.},
}
@article {pmid11568921,
year = {2001},
author = {Korniszewski, L and Nowak, R and Oknińska-Hoffmann, E and Skórka, A and Gieruszczak-Białek, D and Sawadro-Rochowska, M},
title = {Wiedemann-Rautenstrauch (neonatal progeroid) syndrome: new case with normal telomere length in skin fibroblasts.},
journal = {American journal of medical genetics},
volume = {103},
number = {2},
pages = {144-148},
doi = {10.1002/ajmg.1530},
pmid = {11568921},
issn = {0148-7299},
mesh = {Adolescent ; Blotting, Southern ; Child, Preschool ; DNA/genetics ; Female ; Fibroblasts/cytology/metabolism ; Follow-Up Studies ; Humans ; Infant ; Infant, Newborn ; Progeria/*genetics ; Skin/cytology/metabolism ; Telomere/*genetics ; },
abstract = {Wiedemann-Rautenstrauch (neonatal progeroid) syndrome is an autosomal recessive condition with characteristic appearance of premature aging present at birth (aged face, natal teeth, and wrinkled skin). Other features of the syndrome are generalized lipoatrophy with specific fat accumulation in the lateral suprabuttock region, hypotrichosis, macrocephaly (pseudohydrocephalus), and mental retardation. We report on a new case that demonstrates all typical features of the syndrome. The girl is now 16 years and 10 months old and has had follow-up from birth. We measured terminal restriction fragment (TRF) length to evaluate whether the patient's premature aging process is accompanied by shortening of telomere length in her cultured fibroblasts. Mean TRF of 13.5 kb found in our patient's fibroblasts is not shortened as compared to that of normal fibroblasts. Our results differ from those observed in Hutchinson-Gilford progeria.},
}
@article {pmid11566194,
year = {2001},
author = {Yi, SY and Joeng, KS and Kweon, JU and Cho, JW and Chung, IK and Lee, J},
title = {A single-stranded telomere binding protein in the nematode Caenorhabditis elegans.},
journal = {FEBS letters},
volume = {505},
number = {2},
pages = {301-306},
doi = {10.1016/s0014-5793(01)02821-6},
pmid = {11566194},
issn = {0014-5793},
support = {P01 HD070394/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Blotting, Southern ; Blotting, Western ; Caenorhabditis elegans/*chemistry ; Cell Nucleus/chemistry/metabolism ; DNA/metabolism ; DNA-Binding Proteins/*metabolism/*physiology ; Electrophoresis, Polyacrylamide Gel ; Humans ; Hydrogen-Ion Concentration ; Nuclear Proteins/*metabolism/*physiology ; Oryza/chemistry ; Phosphates/chemistry ; Potassium Compounds/chemistry ; Protein Binding ; Telomere/*metabolism ; },
abstract = {We identified and characterized a protein (STB-1) from the nuclear extract of Caenorhabditis elegans that specifically binds single-stranded telomere DNA sequences, but not the corresponding RNA sequences. STB-1 binding activity is specific to the nematode telomere, but not to the human or plant telomere. STB-1 requires the core nucleotides of GCTTAGG and three spacer nucleotides in front of them for binding. While any single nucleotide change in the core sequence abolishes binding, the spacer nucleotides tolerate substitution. STB-1 was determined to be a basic protein of 45 kDa by Southwestern analyses. STB-1 forms a stable complex with DNA once bound to the telomere.},
}
@article {pmid11557321,
year = {2001},
author = {Lorenz, M and Saretzki, G and Sitte, N and Metzkow, S and von Zglinicki, T},
title = {BJ fibroblasts display high antioxidant capacity and slow telomere shortening independent of hTERT transfection.},
journal = {Free radical biology &amp; medicine},
volume = {31},
number = {6},
pages = {824-831},
doi = {10.1016/s0891-5849(01)00664-5},
pmid = {11557321},
issn = {0891-5849},
mesh = {Antioxidants/*metabolism ; Catalysis ; Cell Division ; Cell Hypoxia ; Cell Line ; Fibroblasts/*metabolism/*ultrastructure ; Flow Cytometry ; Gene Expression ; Humans ; Lipofuscin/analysis ; Male ; Oxidative Stress ; Telomerase/*genetics/*metabolism ; Telomere/*ultrastructure ; *Transfection ; },
abstract = {Human foreskin BJ fibroblasts are well protected against oxidative stress as shown by their low intracellular peroxide content, low levels of protein carbonyls, and low steady-state lipofuscin content as compared to other primary human fibroblasts. This correlates with a long replicative life span of the parental cells of about 90 population doublings and a telomere-shortening rate of only 15-20 bp/PD. This value might define the upper limit of a telomere-shortening rate that can still be explained by the end replication problem alone. In BJ clones immortalized by transfection with hTERT, the catalytic subunit of telomerase, the same telomere-shortening rate as in parental cells is observed over a long time despite strong telomerase activity. Hyperoxia, which induces oxidative stress and accelerates telomere shortening in a variety of human fibroblast strains, does not do so in BJ cells. It is possible that the high antioxidative capacity of BJ cells, by minimizing the accumulation of genomic damage, is instrumental in the successful immortalization of these cells by telomerase.},
}
@article {pmid11557273,
year = {2001},
author = {Yang, L and Suwa, T and Wright, WE and Shay, JW and Hornsby, PJ},
title = {Telomere shortening and decline in replicative potential as a function of donor age in human adrenocortical cells.},
journal = {Mechanisms of ageing and development},
volume = {122},
number = {15},
pages = {1685-1694},
doi = {10.1016/s0047-6374(01)00280-9},
pmid = {11557273},
issn = {0047-6374},
support = {AG01228/AG/NIA NIH HHS/United States ; AG12287/AG/NIA NIH HHS/United States ; AG13663/AG/NIA NIH HHS/United States ; },
mesh = {Adolescent ; Adrenal Cortex/*cytology ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Cell Division ; Cells, Cultured ; Child ; Child, Preschool ; Humans ; Infant ; Infant, Newborn ; Middle Aged ; Telomere/*physiology ; Tissue Donors ; },
abstract = {Telomere shortening is the cause of replicative senescence of mammalian cells in culture and may be a cause of cellular aging in vivo. Some tissues clearly show telomere shortening during aging in humans, but the relationship between replication history and telomere length is obscured by complex relationships between stem cells and more differentiated cell types. Previous experiments on the adrenal cortex and human adrenocortical cells in culture indicate that the proliferative biology of this tissue is relatively simple; cell division occurs continuously throughout life, without evidence for a distinct stem cell compartment. In this tissue we investigated the relationship between telomere biology and replicative senescence by measuring replicative capacity and telomere length as a function of donor age. Cells cultured from adrenal tissue from donors of different ages showed a strong age-related decline in total replicative capacity, falling from about 50 population doublings for fetal cells to an almost total lack of division in culture for cells from older donors. Telomere restriction fragment (TRF) length was analyzed in the same sets of cells and decreased from a value of about 12 kb in fetal cells to approximately 7 kb in cells from older donors. The latter value is consistent with that in fibroblasts which have reached replicative senescence. Furthermore, there was a good correlation in individual donor samples between TRF length and replicative capacity in culture. To confirm the relationship between telomere length, telomerase, and replicative capacity, we measured telomere length in cells before and after infection with a retrovirus encoding hTERT, the catalytic component of human telomerase. The adult adrenal cortex does not have telomerase activity; cells after transduction with the hTERT retrovirus had high telomerase activity. Whereas control cells underwent a replication-dependent shortening in telomeres during long-term growth in culture, hTERT-modified cells maintained telomere length and are probably immortalized. Symmetric cell division in human adrenocortical cells, occurring slowly over the life span, is associated with progressive telomere shortening and may result in proliferative defects in vivo in old age, which could partly account for the age-related changes in the structure and function of the human adrenal cortex.},
}
@article {pmid11556843,
year = {2001},
author = {Narayan, S and Jaiswal, AS and Multani, AS and Pathak, S},
title = {DNA damage-induced cell cycle checkpoints involve both p53-dependent and -independent pathways: role of telomere repeat binding factor 2.},
journal = {British journal of cancer},
volume = {85},
number = {6},
pages = {898-901},
doi = {10.1054/bjoc.2001.2002},
pmid = {11556843},
issn = {0007-0920},
support = {CA77721/CA/NCI NIH HHS/United States ; RRO4999/RR/NCRR NIH HHS/United States ; },
mesh = {Apoptosis ; Blotting, Western ; Cell Cycle/*drug effects ; Colonic Neoplasms/*metabolism ; DNA/metabolism ; *DNA Damage ; DNA-Binding Proteins/*metabolism ; Flow Cytometry ; Humans ; In Situ Hybridization, Fluorescence ; Methylnitronitrosoguanidine/*toxicity ; Polymerase Chain Reaction ; Telomeric Repeat Binding Protein 2 ; Tumor Cells, Cultured/*drug effects ; Tumor Suppressor Protein p53/genetics/*metabolism ; },
abstract = {Treatment of colon cancer cells with MNNG causes DNA damage with reduced telomeric signals in a p53-dependent manner, but increased cell cycle arrest in S-G(2)/M by both p53-dependent and independent mechanisms. Results also indicate that cellular levels of TRF2 may play a critical role in MNNG-induced cell cycle arrest and apoptosis of colon cancer cells.},
}
@article {pmid11555632,
year = {2001},
author = {Grobelny, JV and Kulp-McEliece, M and Broccoli, D},
title = {Effects of reconstitution of telomerase activity on telomere maintenance by the alternative lengthening of telomeres (ALT) pathway.},
journal = {Human molecular genetics},
volume = {10},
number = {18},
pages = {1953-1961},
doi = {10.1093/hmg/10.18.1953},
pmid = {11555632},
issn = {0964-6906},
support = {CA-09035-25/CA/NCI NIH HHS/United States ; },
mesh = {Blotting, Southern ; Catalytic Domain ; Cell Line ; Cell Nucleus/metabolism ; Clone Cells ; DNA/genetics ; DNA-Binding Proteins/analysis ; Female ; Fluorescent Antibody Technique, Indirect ; G2 Phase ; Humans ; Mitosis ; Neoplasm Proteins/analysis ; *Nuclear Proteins ; Promyelocytic Leukemia Protein ; *Recombination, Genetic ; Telomerase/genetics/*metabolism ; Telomere/*genetics/metabolism ; Transcription Factors/analysis ; Transfection ; Tumor Suppressor Proteins ; },
abstract = {Telomere length maintenance is essential for cellular immortalization, and thus tumorigenesis. Most human tumors and immortal cell lines maintain their telomeric DNA via the activity of a specialized reverse transcriptase, telomerase. Stabilization of telomeric repeat tracts may also be achieved through a telomerase-independent mechanism, referred to as alternative lengthening of telomeres (ALT). ALT cells are telomerase negative and are characterized by extremely long and heterogeneously sized telomeres and novel multiprotein structures called ALT-associated PML nuclear bodies which are unique to ALT cells. To determine if reconstitution of telomerase activity suppressed ALT and restored wild-type telomere lengths, we introduced the catalytic subunit of telomerase into two ALT cell lines. Initially, two clonal lines exhibited enrichment of shorter telomeres while maintaining a population of ultra-long telomeres similar to that observed in the parental line, suggesting that telomerase is stabilizing the shorter telomeres in the population. Telomere length in the third clonal line was not detectably different from that in the parental cell line. One clonal line with a phenotype of shorter telomeres maintained this pattern over time in culture while the second gradually reverted to the parental ALT telomere length pattern, concurrent with reduction of telomerase activity. All clones continued to maintain ALT-associated PML nuclear bodies regardless of whether telomerase was present. The data suggest that introduction of telomerase activity alone is not sufficient to completely repress ALT, that telomerase acts preferentially on the shortest telomeres in the culture and that the ALT and telomerase pathways may be present concurrently in mammalian cells.},
}
@article {pmid11555631,
year = {2001},
author = {Cerone, MA and Londono-Vallejo, JA and Bacchetti, S},
title = {Telomere maintenance by telomerase and by recombination can coexist in human cells.},
journal = {Human molecular genetics},
volume = {10},
number = {18},
pages = {1945-1952},
doi = {10.1093/hmg/10.18.1945},
pmid = {11555631},
issn = {0964-6906},
mesh = {Cell Division/genetics ; Cell Line ; Cell Nucleus/metabolism ; Clone Cells ; DNA-Binding Proteins/analysis ; Fluorescent Antibody Technique ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence/methods ; Neoplasm Proteins/analysis ; *Nuclear Proteins ; Promyelocytic Leukemia Protein ; Protein Subunits ; *Recombination, Genetic ; Telomerase/genetics/*metabolism ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 2 ; Transcription Factors/analysis ; Transfection ; Tumor Suppressor Proteins ; },
abstract = {Immortal human cells maintain their telomeres by two independent mechanisms, a prevalent one dependent on de novo synthesis of telomeric DNA by telomerase, and a rarer one based on telomere recombination [alternative lengthening of telomeres (ALT)]. Studies with yeast have indicated that expression of telomerase inhibits telomere recombination. In the present study, we have investigated whether expression of telomerase in cells that use ALT would similarly reveal dominance of telomere elongation by telomerase over telomere recombination. Telomerase-negative WI38 VA13/2RA ALT cells were reconstituted for telomerase activity through ectopic expression of the enzyme subunits, hTERT and hTR, and the presence and function of telomerase and ALT were monitored during long term cell growth by enzymatic assays, detection of the ALT-associated PML bodies (APBs) and analysis of telomere dynamics. Our results indicate that telomerase activity and APBs persisted in the cells over at least 90 population doublings. The activity of both pathways on telomeres was determined by analysis of telomere length versus time by gel electrophoresis and in situ hybridization. ALT cells are characterized by very heterogeneous telomeres with a much longer average size than the telomeres of telomerase-positive cells. Telomere dynamics in our cells were compatible with both ALT and telomerase being biologically active since the long telomeres typical of ALT were maintained, while short telomeres, thought to be the preferential substrate of telomerase, were elongated. These findings, indicating that human cells may be capable of concomitantly utilizing both mechanisms of telomere maintenance without effects on their growth and viability, have implications for cancer therapy.},
}
@article {pmid11555394,
year = {2001},
author = {Aladdin, H and Von Essen, M and Schjerling, P and Katzenstein, T and Gerstoft, J and Skinhøj, P and Klarlund Pedersen, B and Ullum, H},
title = {T-cell mean telomere lengths changes in treatment naïve HIV-infected patients randomized to G-CSF or placebo simultaneously with initiation of HAART.},
journal = {Scandinavian journal of immunology},
volume = {54},
number = {3},
pages = {301-305},
doi = {10.1046/j.1365-3083.2001.00935.x},
pmid = {11555394},
issn = {0300-9475},
mesh = {*Antiretroviral Therapy, Highly Active ; CD4-Positive T-Lymphocytes/ultrastructure ; CD8-Positive T-Lymphocytes/*ultrastructure ; Drug Therapy, Combination ; Female ; Granulocyte Colony-Stimulating Factor/*therapeutic use ; HIV Infections/*drug therapy/*genetics/immunology ; Humans ; Male ; Telomere/*ultrastructure ; },
abstract = {The effect of highly active antiretroviral therapy (HAART) and granulocyte colony stimulating factor (G-CSF) on mean telomere restriction fragment (TRF) length of peripheral blood mononuclear cells (PBMC) was examined in 11 treatment naïve human immunodeficiency virus (HIV)-infected individuals with a CD4+ T-cell count < 350 cells/mm3. Patients were randomized to HAART combined with G-CSF thrice weekly for 12 weeks (n = 6) or placebo (n = 5). An increase in the mean TRF lengths was observed in PBMC of patients on HAART after 24 weeks of treatment mainly owing to increased mean CD8+ T-cell TRF lengths. However, in the group of patients on HAART combined with G-CSF no changes of PBMC mean TRF length was observed during treatment or during 12 weeks of follow-up. The mean CD4+ T-cell TRF length did not change in any of the two groups. These results confirm that HAART induces mainly the lengthening of the mean CD8+ T-cell TRF length. However, G-CSF given simultaneously with HAART induces an inhibition of the expected lengthening in mean TRF length. These results do therefore not support the use of adjuvant G-CSF treatment simultaneously when initiating HAART and should further be evaluated before use in non-neutropenic HIV-infected patients.},
}
@article {pmid11555075,
year = {2001},
author = {Ahmed, A and Tollefsbol, T},
title = {Telomeres and telomerase: basic science implications for aging.},
journal = {Journal of the American Geriatrics Society},
volume = {49},
number = {8},
pages = {1105-1109},
doi = {10.1046/j.1532-5415.2001.49217.x},
pmid = {11555075},
issn = {0002-8614},
mesh = {Aged ; Aging/*physiology ; Aging, Premature/genetics/physiopathology ; Cellular Senescence/physiology ; DNA Damage/*physiology ; Humans ; Telomerase/*metabolism ; Telomere/*physiology ; Werner Syndrome/genetics/physiopathology ; },
abstract = {Life expectancy in the United States and other developed nations has increased remarkably over the past century, and continues to increase. However, lifespan has remained relatively unchanged over this period. As life expectancy approaches maximum human lifespan, further increase in life expectancy would only be possible if lifespan could also be increased. Although little is known about the aging process, increasing lifespan and delaying aging are the research challenges of the new century, and have caused intense debate and research activities among biogerontologists. Many theories have been proposed to explain the aging process. However, damage to deoxyribonucleic acid (DNA) is the centerpiece of most of these. Recently telomere shortening has been described to be associated with DNA damage. Located at the ends of eukaryotic chromosomes and synthesized by telomerase, telomeres maintain the length of chromosomes. The loss of telomeres can lead to DNA damage. The association between cellular senescence and telomere shortening in vitro is well established. In the laboratory, telomerase-negative differentiated somatic cells maintain a youthful state, instead of aging, when transfected with vectors encoding telomerase. Many human cancer cells demonstrate high telomerase activity. Evidence is also accumulating that telomere shortening is associated with cellular senescence in vivo. What causes changes in expression of telomerase in different cell types and premature aging syndromes? Does the key to "youthfulness" lie in our ability to control the expression of telomerase? We have reviewed the contemporary literature to find answers to these questions and explore the association between aging, telomeres, and telomerase.},
}
@article {pmid11553326,
year = {2001},
author = {Diede, SJ and Gottschling, DE},
title = {Exonuclease activity is required for sequence addition and Cdc13p loading at a de novo telomere.},
journal = {Current biology : CB},
volume = {11},
number = {17},
pages = {1336-1340},
doi = {10.1016/s0960-9822(01)00400-6},
pmid = {11553326},
issn = {0960-9822},
support = {GM0728/GM/NIGMS NIH HHS/United States ; GM43893/GM/NIGMS NIH HHS/United States ; },
mesh = {Cyclin B/*metabolism ; DNA Damage ; *DNA-Binding Proteins ; Endodeoxyribonucleases/genetics/*metabolism/physiology ; Exodeoxyribonuclease V ; Exodeoxyribonucleases/genetics/*metabolism/physiology ; Fungal Proteins/genetics/*metabolism/physiology ; Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomyces cerevisiae Proteins ; Telomere/*metabolism/physiology ; },
abstract = {The Saccharomyces cerevisiae Mre11p/Rad50p/Xrs2p (MRX) complex is evolutionarily conserved and functions in DNA repair and at telomeres [1-3]. In vivo, MRX is required for a 5' --> 3' exonuclease activity that mediates DNA recombination at double-strand breaks (DSBs). Paradoxically, abolition of this exonuclease activity in MRX mutants results in shortened telomeric DNA tracts. To further explore the role of MRX at telomeres, we analyzed MRX mutants in a de novo telomere addition assay in yeast cells [4]. We found that the MRX genes were absolutely required for telomerase-mediated addition in this assay. Furthermore, we found that Cdc13p, a single-stranded telomeric DNA binding protein essential for telomere DNA synthesis and protection [5], was unable to bind to the de novo telomeric DNA substrate in cells lacking Rad50p. Based on the results from this model system, we propose that the MRX complex helps to prepare telomeric DNA for the loading of Cdc13p, which then protects the chromosome from further degradation and recruits telomerase and other DNA replication components to synthesize telomeric DNA.},
}
@article {pmid11553325,
year = {2001},
author = {Tsukamoto, Y and Taggart, AK and Zakian, VA},
title = {The role of the Mre11-Rad50-Xrs2 complex in telomerase- mediated lengthening of Saccharomyces cerevisiae telomeres.},
journal = {Current biology : CB},
volume = {11},
number = {17},
pages = {1328-1335},
doi = {10.1016/s0960-9822(01)00372-4},
pmid = {11553325},
issn = {0960-9822},
support = {GM43265/GM/NIGMS NIH HHS/United States ; R37 GM26938/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; Cyclin B/genetics/metabolism ; DNA/metabolism ; *DNA-Binding Proteins ; Endodeoxyribonucleases/genetics/metabolism/*physiology ; Exodeoxyribonuclease V ; Exodeoxyribonucleases/genetics/metabolism/*physiology ; Fungal Proteins/genetics/metabolism/*physiology ; Intracellular Signaling Peptides and Proteins ; Mutagenesis ; Phenotype ; Protein Serine-Threonine Kinases ; Recombinant Fusion Proteins/genetics/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomyces cerevisiae Proteins ; Telomerase/genetics/*metabolism ; Telomere/*physiology ; },
abstract = {BACKGROUND: The Saccharomyces Mre11p, Rad50p, and Xrs2p proteins form a complex, called the MRX complex, that is required to maintain telomere length. Cells lacking any one of the three MRX proteins and Mec1p, an ATM-like protein kinase, undergo telomere shortening and ultimately die, phenotypes characteristic of cells lacking telomerase. The other ATM-like yeast kinase, Tel1p, appears to act in the same pathway as MRX: mec1 tel1 cells have telomere phenotypes similar to those of telomerase-deficient cells, whereas the phenotypes of tel1 cells are not exacerbated by the loss of a MRX protein.<br><br>RESULTS: The nuclease activity of Mre11p was found to be dispensable for the telomerase-promoting activity of the MRX complex. The association of the single-stranded TG1-3 DNA binding protein Cdc13p with yeast telomeres occurred efficiently in the absence of Tel1p, Mre11p, Rad50p, or Xrs2p. Targeting of catalytically active telomerase to the telomere suppressed the senescence phenotype of mec1 mrx or mec1 tel1 cells. Moreover, when telomerase was targeted to telomeres, telomere lengthening was robust in mec1 mrx and mec1 tel1 cells.<br><br>CONCLUSIONS: These data rule out models in which the MRX complex is necessary for Cdc13p binding to telomeres or in which the MRX complex is necessary for the catalytic activity of telomerase. Rather, the data suggest that the MRX complex is involved in recruiting telomerase activity to yeast telomeres.},
}
@article {pmid11548846,
year = {2001},
author = {Robertson, JD and Testa, NG and Russell, NH and Jackson, G and Parker, AN and Milligan, DW and Stainer, C and Chakrabarti, S and Dougal, M and Chopra, R},
title = {Accelerated telomere shortening following allogeneic transplantation is independent of the cell source and occurs within the first year post transplant.},
journal = {Bone marrow transplantation},
volume = {27},
number = {12},
pages = {1283-1286},
doi = {10.1038/sj.bmt.1703069},
pmid = {11548846},
issn = {0268-3369},
mesh = {Adolescent ; Adult ; Aged ; Blood Cells/transplantation ; Bone Marrow Transplantation/adverse effects ; Graft Survival ; Hematopoietic Stem Cell Transplantation/*adverse effects ; Humans ; Middle Aged ; Neutrophils/ultrastructure ; T-Lymphocytes/ultrastructure ; Telomere/*metabolism/ultrastructure ; Time Factors ; Transplantation, Homologous/adverse effects ; },
abstract = {Telomere shortening has been documented in the blood cells of recipients of allogeneic bone marrow transplants compared with their donors. Allogeneic peripheral blood progenitor cells (PBPCs) have been increasingly used as an alternative to bone marrow. Their advantages include earlier engraftment and immune reconstitution following transplantation. We have measured telomere length of neutrophils and T cells in fully engrafted recipients of allogeneic bone marrow (n = 19) and allogeneic PBPC (n = 17) and also measured sequential telomere length in four patients after transplantation. Overall, significant telomere shortening occurred in recipients in neutrophils (0.3 kb, P < 0.001) and T cells (0.2 kb, P = 0.045). The data demonstrate that first, the degree of shortening was the same for BM and PBPC transplants and was not related to the time taken to engraft neutrophils and platelets and second, telomere shortening occurs in the first year post transplant without further shortening during the period of observation. These data suggest that the superiority of engraftment seen in PBPC transplants is independent of telomere shortening and other mechanisms such as homing or seeding may be more important.},
}
@article {pmid11533244,
year = {2001},
author = {Bucholc, M and Park, Y and Lustig, AJ},
title = {Intrachromatid excision of telomeric DNA as a mechanism for telomere size control in Saccharomyces cerevisiae.},
journal = {Molecular and cellular biology},
volume = {21},
number = {19},
pages = {6559-6573},
pmid = {11533244},
issn = {0270-7306},
support = {GM56526/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatids/*genetics ; DNA/genetics ; DNA-Binding Proteins/physiology ; Deoxyribonucleases, Type II Site-Specific/chemistry ; *Endodeoxyribonucleases ; *Exodeoxyribonucleases ; Fungal Proteins/genetics/physiology ; Models, Genetic ; Mutation ; Recombination, Genetic ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; Sequence Deletion ; Shelterin Complex ; Sister Chromatid Exchange ; Telomere/*genetics ; *Telomere-Binding Proteins ; *Transcription Factors ; },
abstract = {We have previously identified a process in the yeast Saccharomyces cerevisiae that results in the contraction of elongated telomeres to wild-type length within a few generations. We have termed this process telomeric rapid deletion (TRD). In this study, we use a combination of physical and genetic assays to investigate the mechanism of TRD. First, to distinguish among several recombinational and nucleolytic pathways, we developed a novel physical assay in which HaeIII restriction sites are positioned within the telomeric tract. Specific telomeres were subsequently tested for HaeIII site movement between telomeres and for HaeIII site retention during TRD. Second, genetic analyses have demonstrated that mutations in RAD50 and MRE11 inhibit TRD. TRD, however, is independent of the Rap1p C-terminal domain, a central regulator of telomere size control. Our results provide evidence that TRD is an intrachromatid deletion process in which sequences near the extreme terminus invade end-distal sequences and excise the intervening sequences. We propose that the Mre11p-Rad50p-Xrs2p complex prepares the invading telomeric overhang for strand invasion, possibly through end processing or through alterations in chromatin structure.},
}
@article {pmid11530354,
year = {2001},
author = {Cano, MI},
title = {Telomere biology of trypanosomatids: more questions than answers.},
journal = {Trends in parasitology},
volume = {17},
number = {9},
pages = {425-429},
doi = {10.1016/s1471-4922(01)02014-1},
pmid = {11530354},
issn = {1471-4922},
mesh = {Animals ; Humans ; Protozoan Infections/parasitology ; Telomere/*genetics/*physiology ; Trypanosomatina/*genetics/physiology ; },
abstract = {Trypanosomatids are severe pathogens in developing countries, where they affect both humans and domestic animals. Factors intrinsic to the host, the toxicity or subcurative effects of the available antiparasite medication and the low perspective of potential vaccines favor research on novel candidates for drug target. Telomeres are essential for the survival of most eukaryotes. In trypanosomatids, events such as antigenic variation and/or gene conversion and duplication occur at telomeric positions, possibly facilitating genome rearrangement. Understanding the role that telomere maintenance might play in the cell life span of trypanosomatids has important implications for therapeutics of parasitic diseases.},
}
@article {pmid11530318,
year = {2001},
author = {Michie, C},
title = {Do telomeres help define the genes expressed during ageing?.},
journal = {Trends in molecular medicine},
volume = {7},
number = {9},
pages = {384},
doi = {10.1016/s1471-4914(01)02125-6},
pmid = {11530318},
issn = {1471-4914},
mesh = {Aging/*genetics ; *Gene Expression Regulation, Developmental ; Genes, Reporter/genetics ; HeLa Cells ; Humans ; Luciferases/genetics/metabolism ; Repetitive Sequences, Nucleic Acid/*genetics ; Telomere/*genetics ; },
}
@article {pmid11528130,
year = {2001},
author = {Pfeifer, C and Thomsen, PD and Scherthan, H},
title = {Centromere and telomere redistribution precedes homologue pairing and terminal synapsis initiation during prophase I of cattle spermatogenesis.},
journal = {Cytogenetics and cell genetics},
volume = {93},
number = {3-4},
pages = {304-314},
doi = {10.1159/000057002},
pmid = {11528130},
issn = {0301-0171},
mesh = {Animals ; Cattle/*genetics ; Cell Cycle Proteins ; Cell Nucleus/genetics/metabolism ; Centromere/genetics/*metabolism ; *Chromosome Segregation ; DNA-Binding Proteins ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Indoles ; Male ; Meiosis/*genetics ; Nuclear Proteins/metabolism ; Prophase/*genetics ; Sequence Homology, Nucleic Acid ; Spermatocytes/cytology/metabolism ; Spermatogenesis/*genetics ; Telomere/genetics/*metabolism ; Testis/cytology/metabolism ; },
abstract = {Alterations in nuclear topology associated with meiotic chromosome pairing were studied in premeiotic cells and spermatocytes I of adult bovine males. To this end, we performed FISH with chromosome, pericentromeric satellite-DNA and telomere-specific probes in combination with immunostaining of synaptonemal complex proteins (SCP3, SCP1) on testis tissue sections. Nuclei of premeiotic cells (spermatogonia) exhibited a scattered telomere distribution while pericentromeres formed a few intranuclear clusters. We observed that the chromosome pairing process in cattle prophase I is preceded by repositioning of centromeres and telomeres to the nuclear periphery during preleptotene. Clustering of chromosome ends (bouquet formation) was observed during the transition from leptonema to zygonema and coincided with pairing of a sub-centromeric marker of bovine chromosomes 7. Dissolution of bouquet topology during zygonema left perinuclear telomeres scattered over the nuclear periphery at pachynema. SCP3 staining in frozen tissue sections revealed the appearance of this axial element protein in intranuclear aggregates during preleptotene, followed by extensive axial element formation during leptotene. Synapsis as revealed by SCP1 staining initiated peripherally at earliest zygotene, at this stage nuclei still contained numerous SCP3 clusters. Our observations reveal prominent non-homologous satellite-DNA associations in spermatogonia and indicate the conservation of topological features of the meiotic chromosome pairing process among mammals. The comparison of telomere dynamics in mouse and cattle prophase I suggests that a larger number of chromosomes prolongs the duration of the bouquet stage.},
}
@article {pmid11528113,
year = {2001},
author = {Hanson, H and Mathew, CG and Docherty, Z and Mackie Ogilvie, C},
title = {Telomere shortening in Fanconi anaemia demonstrated by a direct FISH approach.},
journal = {Cytogenetics and cell genetics},
volume = {93},
number = {3-4},
pages = {203-206},
doi = {10.1159/000056985},
pmid = {11528113},
issn = {0301-0171},
support = {G9800001/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Child ; Child, Preschool ; Chromosome Aberrations/*genetics ; Fanconi Anemia/*genetics ; Humans ; *In Situ Hybridization, Fluorescence ; Infant ; Matched-Pair Analysis ; Telomere/*genetics ; },
abstract = {Analysis of telomere status in patients with Fanconi anaemia (FA) has previously been carried out by measurement of telomere restriction fragment (TRF) length by Southern blotting and densitometry. Results from these studies indicated that FA patients had significant reduction in telomere length compared with age-matched controls. This paper confirms and extends these findings using a direct FISH technique, which showed that 15 out of 16 FA patients had increased loss of telomere signals compared with controls. In 12 out of the 16 patients, decrease in telomere signal intensity could also be detected using a Q-FISH approach.},
}
@article {pmid11525738,
year = {2001},
author = {Chan, SW and Chang, J and Prescott, J and Blackburn, EH},
title = {Altering telomere structure allows telomerase to act in yeast lacking ATM kinases.},
journal = {Current biology : CB},
volume = {11},
number = {16},
pages = {1240-1250},
doi = {10.1016/s0960-9822(01)00391-8},
pmid = {11525738},
issn = {0960-9822},
support = {GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins ; Base Sequence ; Carrier Proteins/genetics/metabolism ; Cell Cycle Proteins ; DNA Repair ; DNA-Binding Proteins/genetics/metabolism ; Fungal Proteins/genetics/*metabolism ; Intracellular Signaling Peptides and Proteins ; Molecular Sequence Data ; Protein Serine-Threonine Kinases/genetics/metabolism ; Repressor Proteins/genetics/metabolism ; Saccharomyces cerevisiae/enzymology/genetics/*physiology ; *Saccharomyces cerevisiae Proteins ; Telomerase/*metabolism ; Telomere/chemistry/*metabolism ; *Telomere-Binding Proteins ; Tumor Suppressor Proteins ; },
abstract = {BACKGROUND: Telomerase is a ribonucleoprotein that copies a short RNA template into telomeric DNA, maintaining eukaryotic chromosome ends and preventing replicative senescence. Telomeres differentiate chromosome ends from DNA double-stranded breaks. Nevertheless, the DNA damage-responsive ATM kinases Tel1p and Mec1p are required for normal telomere maintenance in Saccharomyces cerevisiae. We tested whether the ATM kinases are required for telomerase enzyme activity or whether it is their action on the telomere that allows telomeric DNA synthesis.<br><br>RESULTS: Cells lacking Tel1p and Mec1p had wild-type levels of telomerase activity in vitro. Furthermore, altering telomere structure in three different ways showed that telomerase can function in ATM kinase-deleted cells: tel1 mec1 cells senesced more slowly than tel1 mec1 cells that also lacked TLC1, which encodes telomerase RNA, suggesting that tel1 mec1 cells have residual telomerase function; deleting the telomere-associated proteins Rif1p and Rif2p in tel1 mec1 cells prevented senescence; we isolated a point mutation in the telomerase RNA template domain (tlc1-476A) that altered telomeric DNA sequences, causing uncontrolled telomeric DNA elongation and increasing single strandedness. In tel1 mec1 cells, tlc1-476A telomerase was also capable of uncontrolled synthesis, but only after telomeres had shortened for >30 generations.<br><br>CONCLUSION: Our results show that, without Tel1p and Mec1p, telomerase is still active and can act in vivo when the telomere structure is disrupted by various means. Hence, a primary function of the ATM-family kinases in telomere maintenance is to act on the substrate of telomerase, the telomere, rather than to activate the enzymatic activity of telomerase.},
}
@article {pmid11520856,
year = {2001},
author = {Samper, E and Flores, JM and Blasco, MA},
title = {Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc-/- mice with short telomeres.},
journal = {EMBO reports},
volume = {2},
number = {9},
pages = {800-807},
pmid = {11520856},
issn = {1469-221X},
mesh = {*Aging ; Animals ; Bone Marrow/pathology ; Bone Marrow Cells ; Chromosome Aberrations ; Chromosomes/*metabolism/*physiology ; Crosses, Genetic ; Genotype ; In Situ Hybridization, Fluorescence ; Intestine, Small/pathology ; Male ; Mice ; Mice, Transgenic ; Phenotype ; Telomerase/genetics/*metabolism ; Telomere/metabolism/physiology ; Testis/pathology ; Y Chromosome/metabolism ; },
abstract = {Reconstitution of telomerase activity is proposed as a potential gene therapy to prevent, or rescue, age-related diseases produced by critical telomere shortening. However, it is not known whether or not short telomeres are irreversibly damaged. We addressed this by re-introducing telomerase in late generation telomerase-deficient mice, Terc-/-, which have short telomeres and show severe proliferative defects. For this, we have crossed these mice with Terc+/- mice and analyzed telomere length, chromosomal instability and premature aging of the progeny. The Terc-/- progeny had one set of chromosomes with normal telomeres, whereas the other set remained with critically short telomeres; these mice presented chromosomal instability and premature aging. In contrast, Terc+/- progeny showed all chromosomes with detectable telomeres, and did not show chromosomal instability or premature aging. These results prove that critically short telomeres can be rescued by telomerase, and become fully functional, thus rescuing premature aging. This has important implications for the future design of telomerase-based gene therapy of age-related diseases.},
}
@article {pmid11518543,
year = {2001},
author = {Kuranaga, N and Shinomiya, N and Mochizuki, H},
title = {Long-term cultivation of colorectal carcinoma cells with anti-cancer drugs induces drug resistance and telomere elongation: an in vitro study.},
journal = {BMC cancer},
volume = {1},
number = {},
pages = {10},
pmid = {11518543},
issn = {1471-2407},
mesh = {Adenocarcinoma/*genetics/*metabolism ; Antineoplastic Agents/metabolism/*pharmacology ; Carrier Proteins/biosynthesis ; Cell Division/drug effects ; Cisplatin/metabolism/pharmacokinetics ; Clone Cells/chemistry/drug effects/metabolism ; Colonic Neoplasms/*genetics/*metabolism ; DNA-Binding Proteins ; Drug Resistance, Neoplasm/*genetics ; Enzyme Activation/drug effects/genetics ; Fluorouracil/metabolism/pharmacology ; Gene Expression Regulation/drug effects/genetics ; Gene Expression Regulation, Neoplastic/drug effects/genetics ; Genes, MDR/genetics ; Humans ; Multidrug Resistance-Associated Proteins/genetics ; RNA-Binding Proteins ; Telomerase/biosynthesis/metabolism ; Telomere/*drug effects/*genetics/physiology ; Tumor Cells, Cultured ; Up-Regulation/drug effects/genetics ; },
abstract = {BACKGROUND: The role of telomerase activation in the expression and/or maintenance of drug resistance is not clearly understood. Therefore, we investigated the relationships, among the telomerase activity, telomere length and the expression of multidrug resistance genes in colorectal cancer cell lines cultivated with anti-cancer drugs.<br><br>METHODS: LoVo and DLD-1 cells were continuously grown in the presence of both CDDP and 5-FU for up to 100 days. Cell proliferation, telomerase activity, telomere length and the expression of multidrug resistance genes were serially monitored as the PDL increased.<br><br>RESULTS: The expression of multidrug resistance genes tended to increase as the PDL increased. However, an abnormal aneuploid clone was not detected as far as the cells were monitored by a DNA histogram analysis. Tumor cells showing resistance to anti-cancer drugs revealed a higher cell proliferation rate. The telomere length gradually increased with a progressive PDL. The telomerase activity reached a maximum level at 15 PDL in LoVo cells and at 27 PDL in DLD-1 cells. An increase in the mRNA expression of the telomerase components, especially in hTERT and in hTR, was observed at the same PDLs.<br><br>CONCLUSIONS: These results suggest that a high telomerase activity and an elongation of telomeres both appear to help maintain and/or increase drug resistance in colorectal cancer cells. Cancer cells with long telomeres and a high proliferative activity may thus be able to better survive exposure to anti-cancer drugs. This is presumably due to an increased chromosome stability and a strong expression of both mdr-1 and MRP genes.},
}
@article {pmid11516951,
year = {2001},
author = {d'Adda di Fagagna, F and Hande, MP and Tong, WM and Roth, D and Lansdorp, PM and Wang, ZQ and Jackson, SP},
title = {Effects of DNA nonhomologous end-joining factors on telomere length and chromosomal stability in mammalian cells.},
journal = {Current biology : CB},
volume = {11},
number = {15},
pages = {1192-1196},
doi = {10.1016/s0960-9822(01)00328-1},
pmid = {11516951},
issn = {0960-9822},
mesh = {Animals ; *Antigens, Nuclear ; *Chromosomes ; DNA/*genetics ; *DNA Helicases ; *DNA Repair ; DNA-Activated Protein Kinase ; DNA-Binding Proteins/genetics/metabolism ; In Situ Hybridization, Fluorescence ; Ku Autoantigen ; Mice ; Mice, Mutant Strains ; Nuclear Proteins/genetics/metabolism ; Protein Serine-Threonine Kinases/genetics/metabolism ; *Saccharomyces cerevisiae Proteins ; *Telomere ; },
abstract = {DNA repair by nonhomologous end-joining (NHEJ) relies on the Ku70:Ku80 heterodimer in species ranging from yeast to man. In Saccharomyces cerevisiae and Schizosaccharomyces pombe, Ku also controls telomere functions. Here, we show that Ku70, Ku80, and DNA-PKcs, with which Ku interacts, associate in vivo with telomeric DNA in several human cell types, and we show that these associations are not significantly affected by DNA-damaging agents. We also demonstrate that inactivation of Ku80 or Ku70 in the mouse yields telomeric shortening in various primary cell types at different developmental stages. By contrast, telomere length is not altered in cells impaired in XRCC4 or DNA ligase IV, two other NHEJ components. We also observe higher genomic instability in Ku-deficient cells than in XRCC4-null cells. This suggests that chromosomal instability of Ku-deficient cells results from a combination of compromised telomere stability and defective NHEJ.},
}
@article {pmid11516661,
year = {2001},
author = {Evans, SK},
title = {Telomeres.},
journal = {Current biology : CB},
volume = {11},
number = {11},
pages = {R418},
doi = {10.1016/s0960-9822(01)00249-4},
pmid = {11516661},
issn = {0960-9822},
mesh = {Telomerase/physiology ; *Telomere ; },
}
@article {pmid11513915,
year = {2001},
author = {Samani, NJ and Boultby, R and Butler, R and Thompson, JR and Goodall, AH},
title = {Telomere shortening in atherosclerosis.},
journal = {Lancet (London, England)},
volume = {358},
number = {9280},
pages = {472-473},
doi = {10.1016/S0140-6736(01)05633-1},
pmid = {11513915},
issn = {0140-6736},
mesh = {Adult ; Aged ; Case-Control Studies ; Cellular Senescence ; Coronary Artery Disease/*genetics/pathology ; Female ; Humans ; Leukocytes/ultrastructure ; Male ; Middle Aged ; Telomere/*ultrastructure ; },
abstract = {Eukaryotic chromosomes end with telomeres, which shorten with cellular ageing. We investigated whether atherosclerosis is associated with systemic evidence of accelerated cellular ageing. We compared mean length of terminal restriction fragments (TRF), a measure of average telomere size, in leucocyte DNA of ten patients with severe coronary artery disease (CAD) with that of 20 controls without CAD. Adjusting for age and sex, cases had mean TRF lengths of 303 (SD 90) base pairs shorter than those of controls (p=0.002)-ie, equivalent in size to individuals with no CAD who are 8.6 years older. Although this is a pilot study, the findings could be relevant to the pathogenesis of atherosclerosis.},
}
@article {pmid11513297,
year = {2001},
author = {Martinez, JL and Edström, JE and Morcillo, G and Diez, JL},
title = {Telomeres in Chironomus thummi are characterized by different subfamilies of complex DNA repeats.},
journal = {Chromosoma},
volume = {110},
number = {3},
pages = {221-227},
doi = {10.1007/s004120100137},
pmid = {11513297},
issn = {0009-5915},
mesh = {Animals ; Base Sequence ; Chironomidae/chemistry/embryology/*genetics ; DNA/*chemistry/genetics ; In Situ Hybridization, Fluorescence ; Larva ; Molecular Sequence Data ; Polymerase Chain Reaction ; Polymorphism, Genetic ; *Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; Salivary Glands/cytology ; Telomere/*chemistry/genetics ; Transcription, Genetic ; },
abstract = {Members of the genus Chironomus, as well as other Diptera, lack the highly conserved structure of most telomeres, characterized by short repeats generated by telomerase, and have long repeats at their chromosome ends. Among Chironomus species with characterized telomeres Chironomus thummi is of particular interest because one of the telomeres, 3R, forms a giant puff in response to heat shock and other stress treatments. The puff contains nucleoprotein granules in which transcripts of the telomeric repeats are present. Most other nontelocentric telomeres irregularly form less pronounced heat shock puffs. One, the 4R telomere is, however, exceptional in being completely refractory to heat shock. We now pose the question whether the repeats in 3R and 4R have special sequence features. We find three different subfamilies of telomeric repeats in C. thummi, named TsA, TsB and TsC. They have an identical length (176 bp) and display base differences in defined regions, V1 and V2, connected by conserved segments. The TsA subfamily is localized exclusively at 3R, TsC only at 4R, whereas TsB repeats are shared by the remaining nontelocentric telomeres: 1R, 1L, 2R, 2L and 3L. Consequently both 3R and 4R have unique types of telomeric repeats. The 176 bp type repeats are absent from the telocentric, left end of chromosome 4. These results allowed us to differentiate in polytene chromosomes four types of telomeres characterized by tandemly repeated specific sequences.},
}
@article {pmid11512366,
year = {2001},
author = {Chen, HJ and Cho, CL and Liang, CL and Chen, L and Chang, HW and Lu, K and Lee, TC},
title = {Differential telomerase expression and telomere length in primary intracranial tumors.},
journal = {Chang Gung medical journal},
volume = {24},
number = {6},
pages = {352-360},
pmid = {11512366},
issn = {2072-0939},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Brain Neoplasms/enzymology/*genetics/mortality ; Child ; Child, Preschool ; Female ; Humans ; Male ; Middle Aged ; Telomerase/*metabolism ; *Telomere ; },
abstract = {BACKGROUND: Telomerase activity and telomere length have been shown to be involved in controlling cell proliferation and regulating cell senescence. The authors examined telomerase activity and telomere length in intracranial tumors to determine the clinicopathological behavior of primary intracranial tumors with respect to telomerase expression and alteration of telomere length.<br><br>METHODS: Telomerase activity was examined in 139 brain tumor samples. Telomere length was examined in 138 of the 139 samples. These tumors included 61 meningiomas, 27 schwannomas, 19 high-grade neuroepithelial tumors, and 32 low-grade neuroepithelial tumors. Telomerase activity was measured with a telomerase polymerase chain reaction, enzyme-linked immunosolvent assay kit. Telomere length was examined by Southern blot analysis for the terminal restriction fragment length.<br><br>RESULTS: Telomerase activity was detected in 39.2% (20/51) of the neuroepithelial tumors. Detection rates were 47.4% (9/19) for anaplastic astrocytomas and glioblastomas and 34.4% (11/32) for low-grade neuroepithelial tumors. However, detectable telomerase activity was found in 30.8% (4/13) of atypical or malignant meningiomas, but was not detected in any schwannomas. There was a highly significant difference in the telomerase detection rate in neuroepithelial or non-neuroepithelial tumors (p = 0.001). Telomere elongation was found in 11.7% (7/60) of all meningiomas, 46.1% (6/13) of atypical or malignant meningiomas, and 14.8% (4/27) of schwannomas. Elongation of telomere length was detected in 12.6% (11/87) of the cases and 23.5% (12/51) in neuroepithelial tumors. This difference was also significant (p < 0.05). Telomere length was reduced in the majority, (75%, 3/4) of malignant or atypical meningiomas with detectable telomerase activity, but only 45% (9/20) of the neuroepithelial tumors.<br><br>CONCLUSION: These results indicate that telomerase activation may be a critical step in the pathogenesis of intracranial tumors. Telomere length elongation also indicates a high potential for malignant behavior in these tumors.},
}
@article {pmid11511372,
year = {2001},
author = {Tham, WH and Wyithe, JS and Ko Ferrigno, P and Silver, PA and Zakian, VA},
title = {Localization of yeast telomeres to the nuclear periphery is separable from transcriptional repression and telomere stability functions.},
journal = {Molecular cell},
volume = {8},
number = {1},
pages = {189-199},
doi = {10.1016/s1097-2765(01)00287-8},
pmid = {11511372},
issn = {1097-2765},
support = {GM 43265/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle/*physiology ; Cell Nucleus/*metabolism ; DNA-Binding Proteins/metabolism ; Fungal Proteins/genetics/metabolism ; Gene Expression Regulation, Fungal ; *Gene Silencing ; Genes, Reporter ; Humans ; Immunohistochemistry ; Recombinant Fusion Proteins/genetics/metabolism ; Saccharomyces/genetics/*physiology ; *Saccharomyces cerevisiae Proteins ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Telomere/*metabolism ; Trans-Activators/metabolism ; Transcription, Genetic/*physiology ; },
abstract = {The left telomere of Saccharomyces chromosome VII was often localized near the nuclear periphery, even in cells lacking the silencing proteins Sir3 or Hdf1. This association was lost in late mitotic cells and when transcription was induced through the telomeric tract. Although in silencing competent cells there was no correlation between the fraction of cells in which a telomeric gene was repressed and the fraction of cells in which it was localized to the periphery, no condition was found where the telomere was both silenced and away from the periphery. We conclude that localization of a telomere to the nuclear periphery is not sufficient for transcriptional repression nor does it affect the stability function of yeast telomeres.},
}
@article {pmid11509177,
year = {2001},
author = {Hackett, JA and Feldser, DM and Greider, CW},
title = {Telomere dysfunction increases mutation rate and genomic instability.},
journal = {Cell},
volume = {106},
number = {3},
pages = {275-286},
doi = {10.1016/s0092-8674(01)00457-3},
pmid = {11509177},
issn = {0092-8674},
support = {GM43080/GM/NIGMS NIH HHS/United States ; },
mesh = {*Amino Acid Transport Systems ; Base Sequence ; Carboxy-Lyases/genetics ; Chromosome Aberrations/*genetics ; Chromosome Breakage/genetics ; Chromosome Deletion ; Chromosomes, Fungal/genetics/metabolism ; DNA Ligase ATP ; DNA Ligases/metabolism ; DNA Replication ; DNA, Fungal/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Fungal Proteins/genetics/metabolism ; Gene Deletion ; Gene Frequency ; Genes, Essential/genetics ; *Genome, Fungal ; Kinetics ; Membrane Transport Proteins/genetics ; Mutagenesis/*genetics ; Rad51 Recombinase ; Rad52 DNA Repair and Recombination Protein ; Recombination, Genetic/genetics ; Saccharomyces cerevisiae/enzymology/*genetics ; *Saccharomyces cerevisiae Proteins ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; Translocation, Genetic/genetics ; },
abstract = {The increased tumor incidence in telomerase null mice suggests that telomere dysfunction induces genetic instability. To test this directly, we examined mutation rate in the absence of telomerase in S. cerevisiae. The mutation rate in the CAN1 gene increased 10- to 100-fold in est1Delta strains as telomeres became dysfunctional. This increased mutation rate resulted from an increased frequency of terminal deletions. Chromosome fusions were recovered from est1Delta strains, suggesting that the terminal deletions may occur by a breakage-fusion-bridge type mechanism. At one locus, chromosomes with terminal deletions gained a new telomere through a Rad52p-dependent, Rad51p-independent process consistent with break-induced replication. At a second locus, more complicated rearrangements involving multiple chromosomes were seen. These data suggest that telomerase can inhibit chromosomal instability.},
}
@article {pmid11507350,
year = {2001},
author = {Crocker, J},
title = {Telomeres and telomerases: intimations of immortality.},
journal = {European journal of gastroenterology &amp; hepatology},
volume = {13},
number = {8},
pages = {889-890},
doi = {10.1097/00042737-200108000-00002},
pmid = {11507350},
issn = {0954-691X},
mesh = {Animals ; Biomarkers, Tumor/analysis ; Cellular Senescence/*physiology ; Humans ; Neoplasms/diagnosis/genetics/physiopathology ; Telomerase/analysis/*physiology ; Telomere/*physiology ; },
abstract = {There is a constant balance in cancer cells between division and death. The malignant phenotype is associated with a continuing cell cycle or 'immortalization'. Telomeres, structures that cap the chromosomes, are related to cell longevity and are regulated by a ribonucleoprotein called telomerase. This review describes the possible roles of telomeres and telomerase in the malignant process.},
}
@article {pmid11499868,
year = {2001},
author = {Yudoh, K and Matsuno, H and Nakazawa, F and Katayama, R and Kimura, T},
title = {Reconstituting telomerase activity using the telomerase catalytic subunit prevents the telomere shorting and replicative senescence in human osteoblasts.},
journal = {Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research},
volume = {16},
number = {8},
pages = {1453-1464},
doi = {10.1359/jbmr.2001.16.8.1453},
pmid = {11499868},
issn = {0884-0431},
mesh = {Aged ; Aging/genetics/*metabolism/physiology ; Alkaline Phosphatase/metabolism ; Carrier Proteins/genetics ; Catalytic Domain ; Cell Division ; Cells, Cultured ; DNA-Binding Proteins ; Female ; Gene Expression ; Humans ; Male ; Middle Aged ; Osteoblasts/cytology/drug effects/*enzymology/metabolism ; Osteocalcin/metabolism ; Peptide Fragments/metabolism ; Procollagen/metabolism ; RNA-Binding Proteins ; Telomerase/genetics/*metabolism ; Telomere/*physiology ; Tissue Donors ; Transfection ; },
abstract = {The rate of bone formation is largely determined by the number of osteoblasts, which in turn is determined by the rate of replication of progenitors and the life span of mature cells, reflecting the timing of death by apoptosis. However, the exact age-dependent changes of the cellular activity, replicative potential, and life span of osteoblasts have not been investigated to date. Here, we present evidence that the cellular activity, telomere lengths, and replicative life span of osteoblastic cells obtained from juxta-articular bone marrow gradually decrease with the advance of donor age. Recently, telomerase reverse transcriptase (hTERT) has been identified as a human telomerase catalytic subunit. We transfected the gene encoding hTERT into telomerase-negative human osteoblastic cells from donors and osteoblastic cell strain NHOst 54881 cells and showed that expression of hTERT induces telomerase activity in these osteoblastic cells. In contrast to telomerase-negative control cells, which exhibited telomere shortening and senescence after 10-15 population doublings, telomerase-expressing osteoblastic cells had elongated telomere lengths and showed continued alkaline phosphatase activity and procollagen I C-terminal propeptide (PICP) secretion for more than 30 population doublings. These results indicate that osteoblasts with forced expression of hTERT may be used in cell-based therapies such as ex vivo gene therapy, tissue engineering, and transplantation of osteoblasts to correct bone loss or osteopenia in age-related osteoporotic diseases.},
}
@article {pmid11497426,
year = {2001},
author = {Ford, LP and Shay, JW and Wright, WE},
title = {The La antigen associates with the human telomerase ribonucleoprotein and influences telomere length in vivo.},
journal = {RNA (New York, N.Y.)},
volume = {7},
number = {8},
pages = {1068-1075},
pmid = {11497426},
issn = {1355-8382},
support = {AG01228/AG/NIA NIH HHS/United States ; AG07992/AG/NIA NIH HHS/United States ; },
mesh = {Aging ; Antibodies, Monoclonal/metabolism ; Autoantigens/*metabolism ; Blotting, Western ; Cell Division ; Cell Line ; Cell Line, Transformed ; DNA, Complementary/metabolism ; Humans ; Microscopy, Fluorescence ; Neoplasms/immunology ; Plasmids/metabolism ; Protein Binding ; RNA/metabolism ; Retroviridae/metabolism ; Ribonucleoproteins/*metabolism ; Telomerase/*metabolism ; Telomere/metabolism/*physiology ; Transcription, Genetic ; Tumor Cells, Cultured ; Ultraviolet Rays ; SS-B Antigen ; },
abstract = {La is an important component of ribonucleoprotein complexes and telomerase is a ribonucleoprotein that compensates for the shortening of the ends of linear DNA by adding telomeric repeats onto the ends of chromosomes by using an integral RNA as the template. We have identified a direct and specific interaction between La and the RNA component of human telomerase. Antibodies specific to La precipitate the human telomerase ribonucleoprotein complex derived from tumor cells, telomerase immortalized normal cells, and in vitro transformed cells. Overexpression of La in both experimentally immortalized human cells and prostate cancer cells results in gradual telomere shortening. Our results demonstrate that La can associate with telomerase and its expression level can influence telomere homeostasis in vivo.},
}
@article {pmid11497275,
year = {2001},
author = {Izbicka, E and Barnes, LD and Robinson, AK and Davidson, KK and Lawrence, RA and Hannibal, GT},
title = {Alterations in DNA repair and telomere maintenance mechanism affect response to porphyrins in yeast.},
journal = {Anticancer research},
volume = {21},
number = {3B},
pages = {1899-1903},
pmid = {11497275},
issn = {0250-7005},
support = {CA67760/CA/NCI NIH HHS/United States ; },
mesh = {Antineoplastic Agents/pharmacology ; *DNA Repair ; Dose-Response Relationship, Drug ; Hydroxyurea/pharmacology ; Porphyrins/*pharmacology ; Saccharomyces cerevisiae/metabolism ; Telomere/*metabolism ; },
abstract = {BACKGROUND: DNA quadruplex-interactive porphyrin TMPyP4, but not its isomer TMPyP2, inhibits telomerase activity and causes chromosome fusion in vivo, suggesting interference with telomere maintenance.<br><br>MATERIALS AND METHODS: We examined effects of these porphyrins and hydroxyurea on growth rates of yeast Saccharomyces cerevisiae wild type and strains with defects in telomere maintenance and/or DNA repair pathways (mec1, tel1, rad9), telomere binding protein (cdc13), and anaphase control (pds1).<br><br>RESULTS: Hydroxyurea (20 mM) decreased proliferation rates only in mec1 mutant and deletion strains. TMPyP4 (200 microM) decreased growth in all strains, especially in rad9delta and mec1delta. The growth inhibition by TMPyP4 showed low growth inhibition in strains defective in cdc13 and pds1. TMPyP2 sterically prevented from forming a planar species did not significantly inhibit growth of any strain. Overexpression of telomere binding protein Rap1 hypersensitized the mec1delta and tel1delta to TMPyP4.<br><br>CONCLUSIONS: Telomere maintenance represents a viable target for anticancer agents.},
}
@article {pmid11495803,
year = {2001},
author = {Scherf, A and Figueiredo, LM and Freitas-Junior, LH},
title = {Plasmodium telomeres: a pathogen's perspective.},
journal = {Current opinion in microbiology},
volume = {4},
number = {4},
pages = {409-414},
doi = {10.1016/s1369-5274(00)00227-7},
pmid = {11495803},
issn = {1369-5274},
mesh = {Animals ; *Gene Expression Regulation ; Humans ; Malaria, Falciparum/*parasitology ; Plasmodium falciparum/genetics/growth &amp; development/*pathogenicity ; Telomere/*genetics ; Virulence/genetics ; },
abstract = {New data on the organization of plasmodial telomeres has recently become available. Telomeres form clusters of four to seven heterologous chromosome ends at the nuclear periphery in asexual and sexual parasite stages. This subnuclear compartment promotes gene conversion between members of subtelomeric virulence factor genes in heterologous chromosomes resulting in diversity of antigenic and adhesive phenotypes. This has important implications for parasite survival.},
}
@article {pmid11494871,
year = {2001},
author = {Sun, D and Hurley, LH},
title = {Targeting telomeres and telomerase.},
journal = {Methods in enzymology},
volume = {340},
number = {},
pages = {573-592},
doi = {10.1016/s0076-6879(01)40443-5},
pmid = {11494871},
issn = {0076-6879},
support = {CA67760/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA/biosynthesis/chemistry/genetics/metabolism ; DNA-Binding Proteins ; Drug Design ; Humans ; Models, Biological ; Models, Molecular ; Nucleic Acid Hybridization ; RNA/chemistry/metabolism ; Telomerase/drug effects/*metabolism ; Telomere/drug effects/*metabolism ; },
}
@article {pmid11487399,
year = {2001},
author = {Adams, SP and Hartman, TP and Lim, KY and Chase, MW and Bennett, MD and Leitch, IJ and Leitch, AR},
title = {Loss and recovery of Arabidopsis-type telomere repeat sequences 5'-(TTTAGGG)(n)-3' in the evolution of a major radiation of flowering plants.},
journal = {Proceedings. Biological sciences},
volume = {268},
number = {1476},
pages = {1541-1546},
doi = {10.1098/rspb.2001.1726},
pmid = {11487399},
issn = {0962-8452},
mesh = {Arabidopsis/*genetics ; Evolution, Molecular ; *Genes, Plant ; Phylogeny ; Telomere/*genetics ; Terminal Repeat Sequences/genetics ; },
abstract = {Fluorescent in situ hybridization and Southern blotting were used for showing the predominant absence of the Arabidopsis-type telomere repeat sequence (TRS) 5'-(TTTAGGG)(n)-3' (the 'typical' telomere) in a monocot clade which comprises up to 6300 species within Asparagales. Initially, two apparently disparate genera that lacked the typical telomere were identified. Here, we used the new angiosperm phylogenetic classification for predicting in which other related families such telomeres might have been lost. Our data revealed that 16 species in 12 families of Asparagales lacked typical telomeres. Phylogenetically, these were clustered in a derived clade, thereby enabling us to predict that the typical telomere was lost, probably as a single evolutionary event, following the divergence of Doryanthaceae ca. 80--90 million years ago. This result illustrates the predictive value of the new phylogeny, as the pattern of species lacking the typical telomere would be considered randomly placed against many previous angiosperm taxonomies. Possible mechanisms by which chromosome end maintenance could have evolved in this group of plants are discussed. Surprisingly, one genus, Ornithogalum (Hyacinthaceae), which is central to the group of plants that have lost the typical telomere, appears to have regained the sequences. The mechanism(s) by which such recovery may have occurred is unknown, but possibilities include horizontal gene transfer and sequence reamplification.},
}
@article {pmid11485815,
year = {2001},
author = {Johnson, N},
title = {Reawakening the telomeres.},
journal = {Trends in genetics : TIG},
volume = {17},
number = {8},
pages = {443},
doi = {10.1016/s0168-9525(01)02434-9},
pmid = {11485815},
issn = {0168-9525},
mesh = {Cell Division ; Cellular Senescence ; Neoplasms/pathology ; Telomerase/metabolism ; Telomere/*metabolism/*physiology ; },
}
@article {pmid11483532,
year = {2001},
author = {Jacob, NK and Skopp, R and Price, CM},
title = {G-overhang dynamics at Tetrahymena telomeres.},
journal = {The EMBO journal},
volume = {20},
number = {15},
pages = {4299-4308},
pmid = {11483532},
issn = {0261-4189},
support = {R01 GM41803/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle ; *DNA, Protozoan ; *Guanine ; Nucleotides ; *Telomere ; Tetrahymena thermophila/*genetics ; },
abstract = {To learn more about the structure of the DNA terminus at Tetrahymena thermophila telomeres, we have devised a ligation-mediated primer extension protocol to accurately measure the length of the G-strand overhang. We show that overhang length and the identity of the 3'-terminal nucleotide are tightly regulated. The majority of overhangs terminate in the sequence 5'-TTGGGGT and >80% are either 14-15 or 20-21 nucleotides in length. No significant changes in overhang length were detected as cells traversed the cell cycle. However, changes in length distribution were observed when cells exited the cell cycle, indicating an altered balance between DNA synthesis and degradation or end protection. We also provide evidence that rDNA molecules have overhangs on both telomeres. Full-length rDNA could be cloned by a strategy that depends on overhangs being present at both ends. Moreover, analysis of leading strand telomeres revealed that a significant fraction have overhangs > or =5 nucleotides. Our results indicate that generation of the terminal telomeric DNA structure is highly regulated and requires several distinct DNA-processing events.},
}
@article {pmid11481283,
year = {2001},
author = {Honda, S and Hjelmeland, LM and Handa, JT},
title = {Oxidative stress--induced single-strand breaks in chromosomal telomeres of human retinal pigment epithelial cells in vitro.},
journal = {Investigative ophthalmology &amp; visual science},
volume = {42},
number = {9},
pages = {2139-2144},
pmid = {11481283},
issn = {0146-0404},
support = {EY00344/EY/NEI NIH HHS/United States ; EY06473/EY/NEI NIH HHS/United States ; },
mesh = {Cell Hypoxia ; Cells, Cultured ; Cellular Senescence ; *DNA Damage ; DNA, Single-Stranded/*metabolism ; Fibroblasts/cytology/metabolism ; Flow Cytometry ; Fluoresceins ; Heme Oxygenase (Decyclizing)/genetics ; Heme Oxygenase-1 ; Humans ; Membrane Proteins ; *Oxidative Stress ; Pigment Epithelium of Eye/cytology/*metabolism ; RNA, Messenger/biosynthesis ; Reactive Oxygen Species/metabolism ; Telomere/*metabolism ; },
abstract = {PURPOSE: To demonstrate that chronic hyperoxia induces single-stranded breaks in chromosomal telomeres as a measure of oxidative DNA damage in cultured RPE cells.<br><br>METHODS: RPE340 cells were cultured in 40% and 20% (control) O(2). DNA damage was assessed by mean terminal restriction fragment (TRF) length, and the S1 nuclease assay was used to determine the frequency of single-strand breaks in telomeric DNA. The degree of oxidative stress in cells was estimated by flow cytometric analysis of reactive oxygen intermediate (ROI)-induced 2',7'-dichlorodihydrofluorescein diacetate fluorescence and Northern blot analysis of heme oxygenase-1 (HO-1) mRNA induction.<br><br>RESULTS: The mean TRF length of cells grown in 40% O(2) shortened at a faster rate than those grown in 20% O(2). The S1 nuclease assay showed that the accelerated mean TRF length shortening was due to an increased accumulation of single-stranded breaks in telomeric DNA. The degree of ROI production and HO-1 mRNA induction was greater in cells treated with 40% than 20% O(2), an effect that was also larger in old than young passaged cells.<br><br>CONCLUSIONS: RPE340 cells in vitro grown in chronic hyperoxia exhibited evidence of DNA damage with accelerated telomeric shortening via an increased accumulation of single-strand breaks in telomeric DNA. These changes could provide insight into aging of RPE cells by oxidative DNA damage.},
}
@article {pmid11474884,
year = {2001},
author = {Cottliar, AS and Slavutsky, IR},
title = {[Telomeres and telomerase activity: their role in aging and in neoplastic development].},
journal = {Medicina},
volume = {61},
number = {3},
pages = {335-342},
pmid = {11474884},
issn = {0025-7680},
mesh = {Cell Transformation, Neoplastic/*metabolism ; Cellular Senescence/*physiology ; Hematologic Neoplasms/enzymology ; Humans ; Neoplasm Proteins/*metabolism ; Neoplasms/*enzymology/etiology ; Telomerase/*metabolism ; Telomere/*enzymology ; },
abstract = {Telomeres are specialized structures at the ends of eukaryotic chromosomes, composed of tandem repeats of a repetitive DNA sequence (TTAGGG)n and associated proteins. They have a number of important functions including the protection of chromosomes from end-to-end fusion and degradation. When telomeres become critically short, telomere separation in mitosis cannot be performed properly leading to metaphase telomeric associations (tas) and chromosome instability. This instability can be relevant for neoplastic transformation because it increases the probability of errors that can generate genetic changes critical in the multistep process of transformation, like gene amplification and loss of heterozygosity. The mechanisms involved in tas are unknown, but it could be because of failure in the enzymatic activity of telomerase, a ribonucleoprotein enzyme with an RNA template that directs synthesis of telomeric repeats at chromosome extremities, producing telomeric length stabilization. A progressive telomere shortening with ageing has been shown to occur both in vitro and in vivo. Recent studies have shown an association between the presence of tas and telomeric shortening, and also a correlation between telomere reduction and increased telomerase activity in both solid tumors and hematologic malignancies. The evidence that most human malignancies have telomerase activity would indicate that telomerase could be a prevalent and specific tumor marker, and thus may be a novel and excellent target for anti-cancer therapy.},
}
@article {pmid11474790,
year = {2001},
author = {Lee, CC and Huang, TS},
title = {A novel topoisomerase II poison GL331 preferentially induces DNA cleavage at (C/G)T sites and can cause telomere DNA damage.},
journal = {Pharmaceutical research},
volume = {18},
number = {6},
pages = {846-851},
pmid = {11474790},
issn = {0724-8741},
mesh = {Antineoplastic Agents, Phytogenic/*toxicity ; Base Sequence/*drug effects ; *DNA Damage ; DNA Topoisomerases, Type II/*metabolism ; Etoposide/*analogs &amp; derivatives/*toxicity ; Humans ; Intercalating Agents/*toxicity ; Telomerase/metabolism ; Telomere/*drug effects/enzymology/genetics/metabolism ; Tumor Cells, Cultured ; },
abstract = {PURPOSE: Topoisomerase II (Topo II) preferentially cuts DNA at alternating purine-pyrimidine repeats. Different Topo II poisons may affect Topo II to produce distinct drug-specific DNA cleavage patterns. GL331 is a new podophyllotoxin derivative exhibiting potent Topo II-poisoning activity. Therefore, the sequence selectivity of GL331-induced DNA cleavage was determined.<br><br>METHODS: Human gastric adenocarcinoma SC-M1 cells were treated with GL331, and the resultant DNA fragments were isolated by SDS-K+ precipitation. These DNA fragments were further cloned and sequenced to exhibit GL331-induced DNA cleavage sites. In addition, the telomere damage was detected by Southern blot analyses using a (TTAGGG)4 probe. GL331's effect on telomerase was examined using the TRAP assay.<br><br>RESULTS: The selective sequences of GL331-induced DNA cleavage were analyzed. The first nucleotide 3'-terminal to the cleavage sites was preferentially C or G and followed by the second nucleotide T. More than 50% of GL331-induced DNA cleavage fragments exhibited AT-rich sequences in the first 20 nucleotides. In addition, the telomeric damage was observed both from GL331-treated SC-M1 cells and in vitro incubation of genomic DNA with GL331 and purified human Topo II. Although GL331 treatment reduced cellular telomerase activity, in vitro reaction data suggested that GL331 was not a telomerase inhibitor.<br><br>CONCLUSION: GL331 preferentially induced Topo II-mediated DNA cleavage at (C/G)T sites. Because the telomeric repeat sequence contains GL331's GT preference site, the telomere was identified as one of the targets of GL331-induced DNA damage.},
}
@article {pmid11474195,
year = {2001},
author = {Lear, TL},
title = {Chromosomal distribution of the telomere sequence (TTAGGG)(n) in the Equidae.},
journal = {Cytogenetics and cell genetics},
volume = {93},
number = {1-2},
pages = {127-130},
doi = {10.1159/000056964},
pmid = {11474195},
issn = {0301-0171},
mesh = {Animals ; Base Sequence ; DNA Probes/genetics ; DNA, Satellite/genetics ; Equidae/*genetics ; *Evolution, Molecular ; Fibroblasts ; In Situ Hybridization, Fluorescence ; Male ; *Physical Chromosome Mapping ; Telomere/*genetics ; },
abstract = {Telomeres are a class of repetitive DNA sequences that are located at chromosome termini and that act to stabilize the chromosome ends. The rapid karyotypic evolution of the genus Equus has given rise to ten taxa, all with different diploid chromosome numbers. Using fluorescence in situ hybridization (FISH) we localized the mammalian telomere sequence, (TTAGGG)(n), to the chromosomes of nine equid taxa. TTAGGG signal was located at chromosome termini in all species, however additional signal was seen at interstitial sites on some chromosomes in the Burchell's zebra, Equus quagga burchelli, the Hartmann's zebra, Equus zebra hartmannae, and at large heterochromatin-associated regions on the chromosomes of the donkey, Equus asinus. The interstitial signal in the zebras may be a relic of an ancient telomere-telomere fusion and mark the point at which two ancestral chromosomes may have fused. For the donkey, the heterochromatin-associated signal may represent degenerate telomere-like satellite sequences and identify a second type of satellite DNA for this taxon.},
}
@article {pmid11470873,
year = {2001},
author = {Londoño-Vallejo, JA and DerSarkissian, H and Cazes, L and Thomas, G},
title = {Differences in telomere length between homologous chromosomes in humans.},
journal = {Nucleic acids research},
volume = {29},
number = {15},
pages = {3164-3171},
pmid = {11470873},
issn = {1362-4962},
mesh = {Cell Division ; Cell Line ; Chromosomes, Human/chemistry/*genetics/metabolism ; Fibroblasts/cytology/enzymology/metabolism ; Gene Deletion ; Humans ; In Situ Hybridization, Fluorescence ; Leukocytes, Mononuclear/cytology/metabolism ; *Sequence Homology, Nucleic Acid ; Telomerase/genetics/metabolism ; Telomere/*genetics ; },
abstract = {Telomeres are important structures for DNA replication and chromosome stability during cell growth. Telomere length has been correlated with the division potential of human cells and has been found to decrease with age in healthy individuals. Nevertheless, telomere lengths within the same cell are heterogeneous and certain chromosome arms typically have either short or long telomeres. Both the origin and the physiological consequences of this heterogeneity in telomere length remain unknown. In this study we used quantitative telomeric FISH combined with a method to identify the parental origin of chromosomes to show that significant differences in relative telomere intensities are frequently observed between chromosomal homologs in short-term stimulated cultures of peripheral blood lymphocytes. These differences appear to be stable for at least 4 months in vivo, but disappear after prolonged proliferation in vitro. The telomere length differences are also stable during in vitro growth of telomerase-negative fibroblast cells but can be abolished by exogenous telomerase expression in these cells. These findings suggest the existence of a mechanism maintaining differences in telomere length between chromosome homologs that is independent of telomere length itself.},
}
@article {pmid11470125,
year = {2001},
author = {Mikhelson, VM},
title = {Replicative mosaicism might explain the seeming contradictions in the telomere theory of aging.},
journal = {Mechanisms of ageing and development},
volume = {122},
number = {13},
pages = {1361-1365},
doi = {10.1016/s0047-6374(01)00269-x},
pmid = {11470125},
issn = {0047-6374},
mesh = {Aging/*physiology ; Animals ; Cellular Senescence ; Humans ; *Mosaicism ; Telomere/*physiology ; },
abstract = {All living organisms are regarded as a mosaic of cells with different replicative histories explaining all the contradictions in the telomere theory of aging. Exhausted proliferative potential of cells in some areas of the organ tissue might be sufficient to promote one of the age-dependent diseases. Thus a combination of these disorders, gradually increasing with age, is aging. Nobody dies because of the age. Nothing other than the age-related diseases occur with age, and if we separate these diseases, we will get not just a healthy old man, but according to Dr Hayflick's new hypothesis (Exp. Gerontol., 33 (1998) 639) a healthy young man, if not a newborn child.},
}
@article {pmid11468140,
year = {2001},
author = {Engelhardt, M and Finke, J},
title = {Does telomere shortening count?.},
journal = {Blood},
volume = {98},
number = {3},
pages = {888-890},
doi = {10.1182/blood.v98.3.888},
pmid = {11468140},
issn = {0006-4971},
mesh = {Animals ; Blood Cells/metabolism/ultrastructure ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/metabolism/ultrastructure ; Humans ; Telomere/*metabolism/*ultrastructure ; },
}
@article {pmid11465672,
year = {2001},
author = {Jung, D and Néron, S and Lemieux, R and Roy, A and Richard, M},
title = {Telomere-independent reduction of human B lymphocyte: proliferation during long-term culture.},
journal = {Immunological investigations},
volume = {30},
number = {2},
pages = {157-168},
doi = {10.1081/imm-100104023},
pmid = {11465672},
issn = {0882-0139},
mesh = {Animals ; Antigens, CD19/metabolism ; B-Lymphocytes/cytology/drug effects/*metabolism ; CD40 Antigens/*metabolism ; CD40 Ligand/metabolism ; Cell Culture Techniques/methods ; Cell Division ; Cells, Cultured ; Cellular Senescence ; Humans ; Interleukin-4/pharmacology ; L Cells ; Mice ; Telomerase/metabolism ; Telomere/*physiology ; Time Factors ; },
abstract = {Telomeres and telomerase, the telomere lengthening enzyme, have been shown to play a central role in the long-term ability of cells to proliferate and maintain viability. In opposition to transformed cells, normal somatic cells express a low level of telomerase, which results in the gradual shortening of their telomeres after each division and in cell senescence once a critical telomere length is reached. We have tested the hypothesis that shortening of telomeres could limit the expansion of normal human B lymphocytes maintained in long-term culture using a CD40/CD154 system. Measurement of temolerase activity in cell lysates showed a rapid up-regulation of telomerase following the initiation of the culture that was dependent on the CD40 signaling. The high level of telomerase activity and the corresponding long telomere structures remained constant for the 35 day culture period in which a gradual reduction of the cell expansion rate is observed. We conclude that the gradual in vitro senescence of cultured B cells does not correlate with a corresponding loss of telomerase activity and of telomere length. Rather the phenomenon may be related to an intrinsic property of the proliferating B cells to differentiate into Ig-secreting cells.},
}
@article {pmid11458518,
year = {2001},
author = {Brümmendorf, TH and Rufer, N and Holyoake, TL and Maciejewski, J and Barnett, MJ and Eaves, CJ and Eaves, AC and Young, N and Lansdorp, PM},
title = {Telomere length dynamics in normal individuals and in patients with hematopoietic stem cell-associated disorders.},
journal = {Annals of the New York Academy of Sciences},
volume = {938},
number = {},
pages = {293-303; discussion 303-4},
doi = {10.1111/j.1749-6632.2001.tb03598.x},
pmid = {11458518},
issn = {0077-8923},
mesh = {Anemia, Aplastic/blood/*pathology ; Animals ; Blood Cells/*ultrastructure ; Cell Division ; Cellular Senescence ; Fanconi Anemia/blood/pathology ; Flow Cytometry ; Hemoglobinuria, Paroxysmal/blood/pathology ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/blood/*pathology ; Mice ; Mice, Knockout ; Myelodysplastic Syndromes/blood/pathology ; Neoplastic Stem Cells/*ultrastructure ; Telomere/*ultrastructure ; },
abstract = {The telomere length in nucleated peripheral blood (PB) cells indirectly reflects the mitotic history of their precursors: the hematopoietic stem cells (HSCs). The average length of telomeres in PB leukocytes can be measured using fluorescence in situ hybridization and flow cytometry (flow FISH). We previously used flow FISH to characterize the age-related turnover of HSCs in healthy individuals. In this review, we describe results of recent flow FISH studies in patients with selected hematopoietic stem cell-associated disorders: chronic myelogenous leukemia (CML) and several bone marrow failure syndromes. CML is characterized by a marked expansion of myeloid Philadelphia chromosome positive (Ph+) cells. Nevertheless, nonmalignant (Ph-) HSCs typically coexist in the bone marrow of CML patients. We analyzed the telomere length in > 150 peripheral blood leukocytes (PBLs) and bone marrow samples of patients with CML as well as samples of Ph- T-lymphocytes. Compared to normal controls, the overall telomere fluorescence in PBLs of patients with CML was significantly reduced. However, no telomere shortening was observed in Ph- T-lymphocytes. Patients in late chronic phase (CP) had significantly shorter telomeres than those assessed earlier in CP. Our data suggest that progressive telomere shortening is correlated with disease progression in CML. Within the group of patients with bone marrow failure syndromes, we only found significantly shortened telomeres (compared to age-adjusted controls) in granulocytes from patients with aplastic anemia (AA). Strikingly, the telomere length in granulocytes from AA patients who had recovered after immunosuppressive therapy (recAA) did not differ significantly from controls, whereas untreated patients and nonresponders with persistent severe pancytopenia (sAANR) showed marked and significant telomere shortening compared to healthy donors and patients with recAA. Furthermore, an inverse correlation between age-adjusted telomere length and peripheral blood counts was found in support of a model in which the degree of cytopenia and the amount of telomere shortening are correlated. These results support the concept of extensive proliferation of HSCs in subgroups of AA patients and suggest a potential use of telomere-length measurements as a prognostic tool in this group of disorders as well.},
}
@article {pmid11458496,
year = {2001},
author = {Brümmendorf, TH and Rufer, N and Baerlocher, GM and Roosnek, E and Lansdorp, PM},
title = {Limited telomere shortening in hematopoietic stem cells after transplantation.},
journal = {Annals of the New York Academy of Sciences},
volume = {938},
number = {},
pages = {1-7; discussion 7-8},
doi = {10.1111/j.1749-6632.2001.tb03568.x},
pmid = {11458496},
issn = {0077-8923},
support = {AI29524/AI/NIAID NIH HHS/United States ; GM56162/GM/NIGMS NIH HHS/United States ; },
mesh = {Bone Marrow Transplantation/*pathology ; Cell Division ; Cellular Senescence ; Follow-Up Studies ; Graft Survival ; Granulocytes/ultrastructure ; Hematopoiesis/*physiology ; Hematopoietic Stem Cells/*ultrastructure ; Histocompatibility ; Humans ; Immunologic Memory ; Immunophenotyping ; Lymphocyte Activation ; Nuclear Family ; T-Lymphocyte Subsets/ultrastructure ; Telomere/*physiology/ultrastructure ; Tissue Donors ; },
abstract = {The number of cell divisions in hematopoietic stem cells (HSCs) following transplantation of bone marrow or mobilized peripheral blood into myelo-ablated recipients is unknown. This number is expected to depend primarily on the number of transplanted stem cells, assuming that stem cells do not differ in engraftment potential and other functional properties. In a previous study, we found that the telomere length in circulating granulocytes in normal individuals shows a biphasic decline with age, most likely reflecting age-related changes in the turnover of HSCs. In order to study HSCs' proliferation kinetics following stem cells transplantation, we analyzed the telomere length in donor-derived nucleated blood cells in four HLA-matched bone marrow transplant recipients relative to comparable cells from the sibling donors. In each case, the telomeres in granulocytes were shorter in the recipient than in the donor. This difference was established in the first year post transplantation and did not change after that. The telomere length in naïve and memory T cells showed marked differences after transplantation, complicating the interpretation of telomere length data using unseparated nucleated blood cells. Interestingly, the telomere length in naïve T cells that were first observed six months post transplantation was very similar in donor and recipient pairs. Our observations are compatible with a limited number of additional cell divisions in stem cell populations after bone marrow transplantations and support the idea that different populations of stem cells contribute to short-term myeloid and long-term lympho myeloid hematopoiesis.},
}
@article {pmid11454760,
year = {2001},
author = {Golubovsky, MD and Konev, AY and Walter, MF and Biessmann, H and Mason, JM},
title = {Terminal retrotransposons activate a subtelomeric white transgene at the 2L telomere in Drosophila.},
journal = {Genetics},
volume = {158},
number = {3},
pages = {1111-1123},
pmid = {11454760},
issn = {0016-6731},
support = {GM-56729/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA Primers ; Drosophila/*genetics ; Eye Color/genetics ; Female ; In Situ Hybridization ; Male ; Phenotype ; Polymerase Chain Reaction ; *Retroelements ; *Telomere ; *Transgenes ; },
abstract = {Genetically marked P elements inserted into the subtelomeric satellites of Drosophila show repression and variegation of the reporter gene. One such white+ reporter, inserted between the subtelomeric satellite and the terminal HeT-A array in the left arm of chromosome 2 (2L), is sensitive to its context; changes in the structure of the telomere region can be identified by changes in eye color. Addition of HeT-A or TART elements to the 2L terminus increases w+ expression, and loss of sequence from the end decreases expression. This indicates that the telomeric retrotransposons in Drosophila have an activating influence on the repressed subterminal reporter gene. Changes in eye color due to altered expression of the transgene also allow the detection of interactions between homologous telomeres. The 2L arms that terminate in long HeT-A/TART arrays showed increased expression of the subterminal w+ transgene when the terminal repeats on the homologue are absent or markedly shorter. We propose that the chromatin structure of the terminal HeT-A/TART array and the activity of a putative promoter/enhancer element on HeT-A are affected by telomeric interactions. Such trans-activation may reflect control over HeT-A transcription and, thus, transposition activity.},
}
@article {pmid11454711,
year = {2001},
author = {Sachsinger, J and González-Suárez, E and Samper, E and Heicappell, R and Müller, M and Blasco, MA},
title = {Telomerase inhibition in RenCa, a murine tumor cell line with short telomeres, by overexpression of a dominant negative mTERT mutant, reveals fundamental differences in telomerase regulation between human and murine cells.},
journal = {Cancer research},
volume = {61},
number = {14},
pages = {5580-5586},
pmid = {11454711},
issn = {0008-5472},
mesh = {Amino Acid Substitution ; Animals ; Cell Division/genetics ; Cell Survival/genetics ; DNA-Binding Proteins ; Flow Cytometry ; Gene Expression Regulation, Enzymologic ; Genotype ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; Mutation ; *RNA ; RNA, Messenger/genetics/metabolism ; Telomerase/antagonists &amp; inhibitors/*genetics/metabolism ; Telomere/*genetics ; Time Factors ; Tumor Cells, Cultured ; },
abstract = {In contrast to human primary fibroblasts, mouse embryonic fibroblasts have telomerase activity, immortalize spontaneously in culture, and can be neoplastically transformed by oncogenic insult. Ectopic expression of the human telomerase catalytic subunit, human telomerase reverse transcriptase (hTERT), in human primary cells allows both spontaneous immortalization and neoplastic transformation by oncogenes. This suggests that telomerase activity, as well as the fact that mouse telomeres are longer than human telomeres, may explain some of the differences in cellular control between human and murine cells. Telomerase inhibition in immortal or transformed human cells using dominant negative hTERT mutants leads to telomere shortening and cell death. Here we study the effect of expression of a dominant negative mutant of the catalytic subunit of mouse telomerase, mTERT-DN, in a murine kidney tumor cell line, RenCa, whose telomeres are similar in length to human telomeres. After showing initial telomerase activity inhibition and telomere shortening, all clones expressing mTERT-DN reactivated telomerase and showed normal viability, in contrast with that described for human cells. This efficient telomerase reactivation coincided with a significant increase in the endogenous TERT mRNA levels in the presence of mTERT-DN expression. The results presented here reveal the existence of fundamental differences in telomerase regulation between mice and man.},
}
@article {pmid11452000,
year = {2001},
author = {Hemann, MT and Rudolph, KL and Strong, MA and DePinho, RA and Chin, L and Greider, CW},
title = {Telomere dysfunction triggers developmentally regulated germ cell apoptosis.},
journal = {Molecular biology of the cell},
volume = {12},
number = {7},
pages = {2023-2030},
pmid = {11452000},
issn = {1059-1524},
support = {GM-07814/GM/NIGMS NIH HHS/United States ; K08-AR02104/AR/NIAMS NIH HHS/United States ; T32 GM007814/GM/NIGMS NIH HHS/United States ; HD-34880/HD/NICHD NIH HHS/United States ; P01 CA016519/CA/NCI NIH HHS/United States ; CA-16519/CA/NCI NIH HHS/United States ; HD-28317/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; *Apoptosis ; Male ; Meiosis/physiology ; Mice ; Phenotype ; Spermatozoa/*cytology ; Telomere/*physiology ; },
abstract = {Telomere dysfunction results in fertility defects in a number of organisms. Although data from fission yeast and Caenorhabditis elegans suggests that telomere dysfunction manifests itself primarily as defects in proper meiotic chromosome segregation, it is unclear how mammalian telomere dysfunction results in germ cell death. To investigate the specific effects of telomere dysfunction on mammalian germ cell development, we examined the meiotic progression and germ cell apoptosis in late generation telomerase null mice. Our results indicate that chromosome asynapsis and missegregation are not the cause of infertility in mice with shortened telomeres. Rather, telomere dysfunction is recognized at the onset of meiosis, and cells with telomeric defects are removed from the germ cell precursor pool. This germ cell telomere surveillance may be an important mechanism to protect against the transmission of dysfunctional telomeres and chromosomal abnormalities.},
}
@article {pmid11448989,
year = {2001},
author = {Samper, E and Goytisolo, FA and Ménissier-de Murcia, J and González-Suárez, E and Cigudosa, JC and de Murcia, G and Blasco, MA},
title = {Normal telomere length and chromosomal end capping in poly(ADP-ribose) polymerase-deficient mice and primary cells despite increased chromosomal instability.},
journal = {The Journal of cell biology},
volume = {154},
number = {1},
pages = {49-60},
pmid = {11448989},
issn = {0021-9525},
mesh = {Animals ; Bone Marrow Cells/metabolism ; Cell Division ; Cells, Cultured ; Chromosomes/*chemistry/*ultrastructure ; DNA, Complementary/metabolism ; DNA-Binding Proteins ; Genotype ; Heterozygote ; In Situ Hybridization, Fluorescence ; Karyotyping ; Mice ; Mice, Transgenic ; Poly(ADP-ribose) Polymerases/*genetics/physiology ; *RNA ; Spleen/cytology ; Telomerase/metabolism ; Telomere/*chemistry/*ultrastructure ; Two-Hybrid System Techniques ; },
abstract = {Poly(ADP-ribose) polymerase (PARP)-1, a detector of single-strand breaks, plays a key role in the cellular response to DNA damage. PARP-1-deficient mice are hypersensitive to genotoxic agents and display genomic instability due to a DNA repair defect in the base excision repair pathway. A previous report suggested that PARP-1-deficient mice also had a severe telomeric dysfunction consisting of telomere shortening and increased end-to-end fusions (d'Adda di Fagagna, F., M.P. Hande, W.-M. Tong, P.M. Lansdorp, Z.-Q. Wang, and S.P. Jackson. 1999. NAT: Genet. 23:76-80). In contrast to that, and using a panoply of techniques, including quantitative telomeric (Q)-FISH, we did not find significant differences in telomere length between wild-type and PARP-1(-/)- littermate mice or PARP-1(-/)- primary cells. Similarly, there were no differences in the length of the G-strand overhang. Q-FISH and spectral karyotyping analyses of primary PARP-1(-/)- cells showed a frequency of 2 end-to-end fusions per 100 metaphases, much lower than that described previously (d'Adda di Fagagna et al., 1999). This low frequency of end-to-end fusions in PARP-1(-/)- primary cells is accordant with the absence of severe proliferative defects in PARP-1(-/)- mice. The results presented here indicate that PARP-1 does not play a major role in regulating telomere length or in telomeric end capping, and the chromosomal instability of PARP-1(-/)- primary cells can be explained by the repair defect associated to PARP-1 deficiency. Finally, no interaction between PARP-1 and the telomerase reverse transcriptase subunit, Tert, was found using the two-hybrid assay.},
}
@article {pmid11448772,
year = {2001},
author = {Ranganathan, V and Heine, WF and Ciccone, DN and Rudolph, KL and Wu, X and Chang, S and Hai, H and Ahearn, IM and Livingston, DM and Resnick, I and Rosen, F and Seemanova, E and Jarolim, P and DePinho, RA and Weaver, DT},
title = {Rescue of a telomere length defect of Nijmegen breakage syndrome cells requires NBS and telomerase catalytic subunit.},
journal = {Current biology : CB},
volume = {11},
number = {12},
pages = {962-966},
doi = {10.1016/s0960-9822(01)00267-6},
pmid = {11448772},
issn = {0960-9822},
support = {K08 AG001019/AG/NIA NIH HHS/United States ; CA54326/CA/NCI NIH HHS/United States ; CA79658/CA/NCI NIH HHS/United States ; },
mesh = {Catalytic Domain ; Cell Cycle Proteins/genetics/*metabolism ; Cells, Cultured ; Chromosome Aberrations/*genetics ; *Chromosome Disorders ; DNA-Binding Proteins ; Fibroblasts/physiology ; Humans ; *Nuclear Proteins ; Syndrome ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Nijmegen breakage syndrome (NBS) is a rare human disease displaying chromosome instability, radiosensitivity, cancer predisposition, immunodeficiency, and other defects [1, 2]. NBS is complexed with MRE11 and RAD50 in a DNA repair complex [3-5] and is localized to telomere ends in association with TRF proteins [6, 7]. We show that blood cells from NBS patients have shortened telomere DNA ends. Likewise, cultured NBS fibroblasts that exhibit a premature growth cessation were observed with correspondingly shortened telomeres. Introduction of the catalytic subunit of telomerase, TERT, was alone sufficient to increase the proliferative capacity of NBS fibroblasts. However, NBS, but not TERT, restores the capacity of NBS cells to survive gamma irradiation damage. Strikingly, NBS promotes telomere elongation in conjunction with TERT in NBS fibroblasts. These results suggest that NBS is a required accessory protein for telomere extension. Since NBS patients have shortened telomeres, these defects may contribute to the chromosome instability and disease associated with NBS patients.},
}
@article {pmid11446772,
year = {2001},
author = {Pendergrass, WR and Penn, PE and Li, J and Wolf, NS},
title = {Age-related telomere shortening occurs in lens epithelium from old rats and is slowed by caloric restriction.},
journal = {Experimental eye research},
volume = {73},
number = {2},
pages = {221-228},
doi = {10.1006/exer.2001.1033},
pmid = {11446772},
issn = {0014-4835},
support = {R01 EY11733/EY/NEI NIH HHS/United States ; },
mesh = {Aging/*physiology ; Animals ; Cataract/etiology ; Cells, Cultured ; *Diet, Reducing ; Epithelial Cells/*cytology ; Fibroblasts/ultrastructure ; Humans ; In Situ Hybridization, Fluorescence ; Interphase/physiology ; Lens, Crystalline/*cytology ; Metaphase/physiology ; Nucleic Acid Probes ; Rats ; Reference Values ; Reproducibility of Results ; Sensitivity and Specificity ; Statistics, Nonparametric ; Telomere/*ultrastructure ; },
abstract = {We have investigated whether the average relative telomere length of lens epithelial cells (LECs) from brown Norway rats decreases with the age of the donor animal, and whether chronic caloric restriction (CR) of the rats delays the telomere shortening. Our previous studies have demonstrated that clonal proliferative potential of rodent LECs as well as the in vivo rate of DNA synthesis decreases with age and that this decrease is slowed by chronic lifelong caloric restriction (CR). In order to determine if telomeric shortening might be involved in this loss of proliferative potential, we examined relative telomeric lengths in young, old ad lib fed (AL), and old calorically restricted (CR) brown Norway rats. We used fluorescence in situ hybridization with a peptide nucleic acid probe (PNA) complementary to the telomeric repeat sequence to quantitate relative telomere lengths in LECs in lens sections (TELO-FISH). Control experiments demonstrated that the PNA probe binding was restricted almost entirely to the terminal portions of the rat chromosomes with less than 5% bound at interstitial sites in typical metaphase spreads. The relative telomere lengths of interphase human fibroblast standards, as determined by TELO-FISH, were in good agreement with terminal restriction fragment analyses of the same standards and with literature values for rat cells. The average telomere lengths of interphase nuclei in the old AL rat LECs were found to be 21% shorter than paired young AL controls (P < 0.01 by Wilcoxian signed rank test). The calorically restricted old rats had less telomere erosion (12%) than the old AL group (P < 0.05). Although it is not clear whether such moderate telomeric erosion can limit cell division in rodent LECs, the telomeric shortening correlated well with previous studies demonstrating reduced clonal, replicative potential, and reduced rates of in vivo DNA replication in LECs from old rodents and a delay in this attenuation in animals on chronic CR.},
}
@article {pmid11439347,
year = {2001},
author = {Scheel, C and Schaefer, KL and Jauch, A and Keller, M and Wai, D and Brinkschmidt, C and van Valen, F and Boecker, W and Dockhorn-Dworniczak, B and Poremba, C},
title = {Alternative lengthening of telomeres is associated with chromosomal instability in osteosarcomas.},
journal = {Oncogene},
volume = {20},
number = {29},
pages = {3835-3844},
doi = {10.1038/sj.onc.1204493},
pmid = {11439347},
issn = {0950-9232},
mesh = {Adult ; Bone Neoplasms/*genetics/pathology ; Humans ; In Situ Hybridization, Fluorescence ; Middle Aged ; Osteosarcoma/*genetics/pathology ; Telomerase/metabolism ; *Telomere ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/genetics/metabolism ; },
abstract = {Telomere maintenance is regarded as a key mechanism in overcoming cellular senescence in tumor cells and in most cases is achieved by the activation of telomerase. However there is at least one alternative mechanism of telomere lengthening (ALT) which is characterized by heterogeneous and elongated telomeres in the absence of telomerase activity (TA). We evaluated the prevalence of TA, gene expression of telomerase subunits and ALT in relation to telomere morphology and function in matrix producing bone tumors and in osteosarcoma cell lines and present evidence of a direct association of ALT with telomere dysfunction and chromosomal instability. Telomere fluorescence in situ hybridization (T-FISH) in ALT cells revealed elongated and shortened telomeres, partly in unusual configurations and loci, dicentric marker chromosomes and signal-free chromosome ends. Free ends give rise to end-to-end associations and may induce breakage-fusion-bridge cycles resulting in an increased number of complex chromosomal rearrangements, as detected by multiplex-FISH (M-FISH). We propose that ALT cannot be seen as an equivalent to telomerase activity in telomere maintenance. Its association with telomere dysfunction and chromosomal instability may have major implications for tumor progression.},
}
@article {pmid11438716,
year = {2001},
author = {Hodes, R},
title = {Molecular targeting of cancer: telomeres as targets.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {98},
number = {14},
pages = {7649-7651},
pmid = {11438716},
issn = {0027-8424},
mesh = {Animals ; Cell Division/genetics ; Enzyme Inhibitors/therapeutic use ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Gene Targeting ; Genetic Therapy ; Humans ; Mice ; Mice, Knockout ; Mutation ; Neoplasms/*enzymology/*genetics/pathology/therapy ; Neoplasms, Experimental/enzymology/genetics/pathology/therapy ; Telomerase/*genetics/*metabolism ; },
}
@article {pmid11436310,
year = {2001},
author = {Kanoh, J and Ishikawa, F},
title = {[Roles of ATM in DNA damage checkpoint and telomere maintenance].},
journal = {Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme},
volume = {46},
number = {8 Suppl},
pages = {1194-1200},
pmid = {11436310},
issn = {0039-9450},
mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/physiology ; Checkpoint Kinase 1 ; Checkpoint Kinase 2 ; *DNA Damage ; DNA Repair ; DNA-Binding Proteins ; *Genes, cdc ; Humans ; Phosphorylation ; Protein Kinases/physiology ; Protein Serine-Threonine Kinases/*physiology ; Signal Transduction ; *Telomere ; Tumor Suppressor Proteins ; cdc25 Phosphatases/physiology ; },
}
@article {pmid11430823,
year = {2001},
author = {Peng, Y and Mian, IS and Lue, NF},
title = {Analysis of telomerase processivity: mechanistic similarity to HIV-1 reverse transcriptase and role in telomere maintenance.},
journal = {Molecular cell},
volume = {7},
number = {6},
pages = {1201-1211},
doi = {10.1016/s1097-2765(01)00268-4},
pmid = {11430823},
issn = {1097-2765},
mesh = {Catalytic Domain ; DNA-Binding Proteins ; HIV Reverse Transcriptase/*metabolism ; In Vitro Techniques ; Molecular Sequence Data ; Mutagenesis ; RNA ; Sequence Homology, Amino Acid ; Telomerase/*metabolism ; Telomere/*enzymology ; Yeasts ; },
abstract = {The key protein subunit of the telomerase complex, known as TERT, possesses a reverse transcriptase (RT)-like domain that is conserved in enzymes encoded by retroviruses and retroelements. Structural and functional analysis of HIV-1 RT suggests that RT processivity is governed, in part, by the conserved motif C, motif E, and a C-terminal domain. Mutations in analogous regions of the yeast TERT were found to have anticipated effects on telomerase processivity in vitro, suggesting a great deal of mechanistic and structural similarity between TERT and retroviral RTs, and a similarity that goes beyond the homologous domain. A close correlation was uncovered between telomerase processivity and telomere length in vivo, suggesting that enzyme processivity is a limiting factor for telomere maintenance.},
}
@article {pmid11429701,
year = {2001},
author = {Munro, J and Steeghs, K and Morrison, V and Ireland, H and Parkinson, EK},
title = {Human fibroblast replicative senescence can occur in the absence of extensive cell division and short telomeres.},
journal = {Oncogene},
volume = {20},
number = {27},
pages = {3541-3552},
doi = {10.1038/sj.onc.1204460},
pmid = {11429701},
issn = {0950-9232},
mesh = {3T3 Cells ; Animals ; Cell Division/*physiology ; Cells, Cultured ; Cellular Senescence/*physiology ; Coculture Techniques ; Colony-Forming Units Assay ; DNA-Binding Proteins ; Fetus ; Fibroblasts/cytology/*physiology ; Humans ; Mice ; *RNA ; Recombinant Proteins/metabolism ; Retroviridae ; Skin/cytology ; Skin Physiological Phenomena ; Telomerase/genetics/*metabolism ; Telomere/*physiology ; Transfection ; },
abstract = {Ectopic expression of telomerase blocks both telomeric attrition and senescence, suggesting that telomeric attrition is a mitotic counting mechanism that culminates in replicative senescence. By holding human fibroblast cultures confluent for up to 12 weeks at a time, we confirmed previous observations and showed that telomeric attrition requires cell division and also, that senescence occurs at a constant average telomere length, not at a constant time point. However, on resuming cell division, these long-term confluent (LTC) cultures completed 15-25 fewer mean population doublings (MPDs) than the controls prior to senescence. These lost divisions were mainly accounted for by slow cell turnover of the LTC cultures and by permanent cell cycle exit of 94% of the LTC cells, which resulted in many cell divisions being unmeasured by the MPD method. In the LTC cultures, p27(KIP1) accumulated and pRb became under-phosphorylated and under-expressed. Also, coincident with permanent cell cycle exit and before 1 MPD was completed, the LTC cultures upregulated the cell cycle inhibitors p21(WAF) and p16(INK4A) but not p14(ARF) and developed other markers of senescence. We then tested the relationship between cell cycle re-entry and the cell cycle-inhibitory proteins following subculture of the LTC cultures. In these cultures, the downregulation of p27(KIP1) and the phosphorylation of pRb preceded the complete resumption of normal proliferation rate, which was accompanied by the down-regulation of p16(INK4A). Our results show that most normal human fibroblasts can accumulate p16(INK4A), p21(WAF) and p27(KIP1) and senesce by cell division-independent mechanism(s). Furthermore, this form of senescence likely requires p16(INK4A) and perhaps p27(KIP1).},
}
@article {pmid11426649,
year = {2000},
author = {Bearss, DJ and Hurley, LH and Von Hoff, DD},
title = {Telomere maintenance mechanisms as a target for drug development.},
journal = {Oncogene},
volume = {19},
number = {56},
pages = {6632-6641},
doi = {10.1038/sj.onc.1204092},
pmid = {11426649},
issn = {0950-9232},
support = {CA67760/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Anthracenes/pharmacology ; Antineoplastic Agents/*pharmacology/therapeutic use ; Drug Delivery Systems ; *Drug Design ; Glycoside Hydrolases/metabolism ; Humans ; Neoplasms/enzymology ; Oligonucleotides, Antisense/therapeutic use ; Perylene/analogs &amp; derivatives ; Piperidines/pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; RNA ; RNA, Long Noncoding ; RNA, Untranslated/antagonists &amp; inhibitors ; Reverse Transcriptase Inhibitors/pharmacology ; *Tankyrases ; Telomerase/*antagonists &amp; inhibitors/physiology ; Telomere/chemistry/*drug effects/physiology ; },
abstract = {The shortening of the telomeric DNA sequences at the ends of chromosomes is thought to play a critical role in regulating the lifespan of human cells. Since all dividing cells are subject to the loss of telomeric sequences, cells with long proliferative lifespans need mechanisms to maintain telomere integrity. It appears that the activation of the enzyme telomerase is the major mechanism by which these cells maintain their telomeres. The proposal that a critical step in the process of the malignant transformation of cells is the upregulation of expression of telomerase has made this enzyme a potentially useful prognostic and diagnostic marker for cancer, as well as a new target for therapeutic intervention for the treatment of patients with cancer. It is now clear that simply inhibiting telomerase may not result in the anticancer effects that were originally hypothesized. While telomerase may not be the universal target for cancer therapy, we certainly believe that targeting the telomere maintenance mechanisms will be important in future research aimed toward a successful strategy for curing cancer.},
}
@article {pmid11426628,
year = {2000},
author = {Ohyashiki, K and Iwama, H and Tauchi, T and Shimamoto, T and Hayashi, S and Ando, K and Kawakubo, K and Ohyashiki, JH},
title = {Telomere dynamics and genetic instability in disease progression of chronic myeloid leukemia.},
journal = {Leukemia &amp; lymphoma},
volume = {40},
number = {1-2},
pages = {49-56},
doi = {10.3109/10428190009054880},
pmid = {11426628},
issn = {1042-8194},
mesh = {Cell Transformation, Neoplastic/genetics ; Disease Progression ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*genetics/pathology ; *Philadelphia Chromosome ; Telomere/*metabolism ; *Translocation, Genetic ; },
abstract = {Chronic myeloid leukemia (CML) is characterized by a Philadelphia (Ph) translocation creating a novel BCR-ABL oncoprotein, and CML patients have a chronic phase for several years followed by an intractable blast cell proliferation, called blast transformation. In the blast phase, more than 60% of patients show additional cytogenetic changes, e. g., double Ph, +8, i(17q). In this review, we would like to address genetic changes, including genome instability, cytogenetic changes, and telomere dynamics that relate to karyotypic instability. In the chronic phase, approximately 60% of CML patients show reduced telomere length without highly elevated telomerase activity or microsatellite alterations, indicating that telomere reduction may be linked to cell replication. Therefore, the Ph translocation might be a first event to immortalize cell proliferation. In the blast phase, 50% of CML patients have high levels of elevated telomerase activity and the same number of patients had microsatellite changes. Of note is that most patients with telomerase up-regulation in the blast phase had additional cytogenetic changes and >60% of them showed microsatellite changes at least at one locus. In contrast, most patients without telomerase activity did not show microsatellite changes. These findings may indicate that telomerase up-regulation in the blast phase of CML patients is closely associated with microsatellite changes (representative of genome instability), while blast cells in the remaining patients (30%) maintain their proliferative capability without microsatellite changes and telomerase up-regulation. This further suggests that there is also an unknown mechanism for genome stability without the process of telomerase up-regulation in some patients with CML in blast crisis.},
}
@article {pmid11423175,
year = {2001},
author = {Meresse, B and Dubucquoi, S and Tourvieille, B and Desreumaux, P and Colombel, JF and Dessaint, JP},
title = {CD28+ intraepithelial lymphocytes with long telomeres are recruited within the inflamed ileal mucosa in Crohn disease.},
journal = {Human immunology},
volume = {62},
number = {7},
pages = {694-700},
doi = {10.1016/s0198-8859(01)00258-0},
pmid = {11423175},
issn = {0198-8859},
mesh = {Adult ; Aged ; Aged, 80 and over ; CD28 Antigens/*biosynthesis ; Cell Movement/genetics/*immunology ; Crohn Disease/genetics/*immunology/pathology ; Female ; Humans ; Ileum/cytology/immunology/metabolism/*pathology ; Inflammation/genetics/immunology/pathology ; Intestinal Mucosa/cytology/*immunology/metabolism/*pathology ; Lymphocyte Subsets/cytology/*immunology/metabolism/pathology ; Male ; Middle Aged ; Receptors, Antigen, T-Cell, alpha-beta/biosynthesis ; *Telomere/metabolism/pathology ; },
abstract = {Crohn disease is a chronic inflammatory bowel disease that involves all the intestine but predominantly alters the ileum. The disease largely depends on T cells, but the biologic role of intestinal intraepithelial lymphocytes (IEL) in transmural inflammation remains poorly characterized. To address this issue, a comparison of IEL and lamina propria lymphocytes (LPL) isolated from the uninvolved and the inflamed ileal mucosa of Crohn disease patients was performed. More CD8+ IEL (26% versus 8%) from the inflamed ileal mucosa expressed the CD28 receptor and the CD11a integrin than IEL from the uninvolved ileal mucosa, which were mostly CD28-. IEL had longer telomeres in the inflamed than in the uninvolved areas and a TCR Vbeta repertoire more similar to circulating T cells, suggesting that the increased proportion of CD28+ TCRalphabeta+ IEL within the inflamed mucosa is more likely due to recruited lymphocytes from the periphery that populate the epithelial layer than to the acquisition of the CD28 molecule by activated resident lymphocytes. In the uninvolved ileal mucosa, IEL from Crohn disease patients had shorter telomeric lengths than IEL from control patients, suggesting that they have been chronically stimulated. Such perturbation of the IEL population within the ileal mucosa could contribute to the inflammation in Crohn disease.},
}
@article {pmid11412004,
year = {2001},
author = {Lin, YC and Shih, JW and Hsu, CL and Lin, JJ},
title = {Renaturation and stabilization of the telomere-binding activity of Saccharomyces Cdc13(451-693)p by L-arginine.},
journal = {Analytical biochemistry},
volume = {294},
number = {1},
pages = {44-47},
doi = {10.1006/abio.2001.5143},
pmid = {11412004},
issn = {0003-2697},
mesh = {Arginine/*pharmacology ; Base Sequence ; DNA Primers ; DNA-Binding Proteins/chemistry/*metabolism ; Protein Renaturation ; Recombinant Proteins/chemistry/metabolism ; Saccharomyces cerevisiae/*metabolism ; },
abstract = {Production of recombinant proteins can be valuable in studying their biological functions. However, recombinant proteins expressed in Escherichia coli sometimes form undesirable insoluble aggregates. Solubilization and renaturation of these aggregates becomes a problem that one needs to solve. Here we used recombinant Cdc13(451-693)p as example to show the presence of l-arginine during renaturation greatly enhanced the renaturation efficiency. Cdc13p is the single-stranded telomere-binding protein of yeast Saccharomyces cerevisiae. The telomere-binding domain has been mapped within amino acids 451-693 of Cdc13p, Cdc13(451-693)p. Recombinant Cdc13(451-693)p was expressed in E. coli as insoluble protein aggregates. Purification of insoluble Cdc13(451-693)p was achieved by denaturing the protein with 6 M guanidine-HCl and followed by Ni-nitrilotriacetic acid agarose column chromatography. Renaturation of Cdc13(451-693)p to the active form was achieved by dialyzing denatured protein in the presence of l-arginine. Moreover, the presence of l-arginine was also helped in maintaining the telomere-binding activity of Cdc13(451-693)p. Taking together, l-arginine might have a general application in renaturation of insoluble aggregates.},
}
@article {pmid11406599,
year = {2001},
author = {Chaconas, G and Stewart, PE and Tilly, K and Bono, JL and Rosa, P},
title = {Telomere resolution in the Lyme disease spirochete.},
journal = {The EMBO journal},
volume = {20},
number = {12},
pages = {3229-3237},
pmid = {11406599},
issn = {0261-4189},
mesh = {*Borrelia burgdorferi ; Borrelia burgdorferi Group/*genetics ; *Chromosomes, Bacterial ; *DNA Replication ; DNA, Bacterial/*biosynthesis ; Lyme Disease/microbiology ; Plasmids ; *Telomere ; },
abstract = {The genus Borrelia includes the causative agents of Lyme disease and relapsing fever. An unusual feature of these bacteria is a genome that includes linear DNA molecules with covalently closed hairpin ends referred to as telomeres. We have investigated the mechanism by which the hairpin telomeres are processed during replication. A synthetic 140 bp sequence having the predicted structure of a replicated telomere was shown to function as a viable substrate for telomere resolution in vivo, and was sufficient to convert a circular replicon to a linear form. Our results suggest that the final step in the replication of linear Borrelia replicons is a site-specific DNA breakage and reunion event to regenerate covalently closed hairpin ends. The telomere substrate described here will be valuable both for in vivo manipulation of linear DNA in Borrelia and for in vitro studies to identify and characterize the telomere resolvase.},
}
@article {pmid11406598,
year = {2001},
author = {Maeshima, K and Janssen, S and Laemmli, UK},
title = {Specific targeting of insect and vertebrate telomeres with pyrrole and imidazole polyamides.},
journal = {The EMBO journal},
volume = {20},
number = {12},
pages = {3218-3228},
pmid = {11406598},
issn = {0261-4189},
mesh = {Animals ; Cell Line ; DNA-Binding Proteins/metabolism ; Fluorescence ; HeLa Cells ; Humans ; Imidazoles/*metabolism ; Nylons/*metabolism ; Pyrroles/*metabolism ; Repetitive Sequences, Nucleic Acid ; Spodoptera ; Staining and Labeling ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1 ; },
abstract = {DNA minor groove-binding compounds (polyamides) that target insect and vertebrate telomeric repeats with high specificity were synthesized. Base pair recognition of these polyamides is based on the presence of the heterocyclic amino acids pyrrole and imidazole. One compound (TH52B) interacts uniquely and with excellent specificity (K(d) = 0.12 nM) with two consecutive insect-type telomeric repeats (TTAGG). A related compound, TH59, displays high specificity (K(d) = 0.5 nM) for tandem vertebrate (TTAGGG) and insect telomeric repeats. The high affinity and specificity of these compounds were achieved by bidentate binding of two flexibly linked DNA-binding moieties. Epifluorescence microscopy studies show that fluorescent derivatives of TH52B and TH59 stain insect or vertebrate telomeres of chromosomes and nuclei sharply. Importantly, the telomere-specific polyamide signals of HeLa chromosomes co-localize with the immunofluorescence signals of the telomere-binding protein TRF1. Our results demonstrate that telomere-specific compounds allow rapid estimation of relative telomere length. The insect-specific compound TH52 was shown to be incorporated rapidly into growing Sf9 cells, underlining the potential of these compounds for telomere biology and possibly human medicine.},
}
@article {pmid11403914,
year = {2001},
author = {von Zglinicki, T},
title = {Telomeres and replicative senescence: Is it only length that counts?.},
journal = {Cancer letters},
volume = {168},
number = {2},
pages = {111-116},
doi = {10.1016/s0304-3835(01)00546-8},
pmid = {11403914},
issn = {0304-3835},
mesh = {Cell Division/physiology ; Cellular Senescence/*physiology ; Humans ; Telomere/*physiology ; },
abstract = {Telomeres are well established as a major 'replicometer', counting the population doublings in primary human cell cultures and ultimately triggering replicative senescence. However, neither is the pace of this biological clock inert, nor is there a fixed threshold telomere length acting as the universal trigger of replicative senescence. The available data suggest that opening of the telomeric loop and unscheduled exposure of the single-stranded G-rich telomeric overhang might act like a semaphore to signal senescent cell cycle arrest. Short telomere length, telomeric single-strand breaks, low levels of loop-stabilizing proteins, or other factors may trigger this opening of the loop. Thus, both telomere shortening and the ultimate signalling into senescence are able to integrate different environmental and genetic factors, especially oxidative stress-mediated damage, which might otherwise become a thread to genomic stability.},
}
@article {pmid11408657,
year = {2001},
author = {Baur, JA and Zou, Y and Shay, JW and Wright, WE},
title = {Telomere position effect in human cells.},
journal = {Science (New York, N.Y.)},
volume = {292},
number = {5524},
pages = {2075-2077},
doi = {10.1126/science.1062329},
pmid = {11408657},
issn = {0036-8075},
support = {AG07792/AG/NIA NIH HHS/United States ; },
mesh = {Cell Division ; Cellular Senescence ; DNA-Binding Proteins ; *Gene Expression Regulation ; *Gene Silencing ; Genes, Reporter ; Genetic Vectors ; HeLa Cells ; Humans ; Hydroxamic Acids/pharmacology ; Luciferases/genetics/metabolism ; *RNA ; Retroviridae/genetics ; Telomerase/genetics/*metabolism ; Telomere/drug effects/*physiology ; Transfection ; Transgenes ; },
abstract = {In yeast, telomere position effect (TPE) results in the reversible silencing of genes near telomeres. Here we demonstrate the presence of TPE in human cells. HeLa clones containing a luciferase reporter adjacent to a newly formed telomere express 10 times less luciferase than do control clones generated by random integration. Luciferase expression is restored by trichostatin A, a histone deacetylase inhibitor. Overexpression of a human telomerase reverse transcriptase complementary DNA results in telomere elongation and an additional 2- to 10-fold decrease in expression in telomeric clones but not control clones. The dependence of TPE on telomere length provides a mechanism for the modification of gene expression throughout the replicative life-span of human cells.},
}
@article {pmid11407362,
year = {2001},
author = {de Grey, A},
title = {Response to "telomere shortening with aging in human liver".},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {56},
number = {6},
pages = {B237-8},
doi = {10.1093/gerona/56.6.b237},
pmid = {11407362},
issn = {1079-5006},
mesh = {Aging/*physiology ; Humans ; Liver/*physiology ; Telomere/*genetics ; },
}
@article {pmid11400147,
year = {2001},
author = {Matthews, P and Jones, CJ and Skinner, J and Haughton, M and de Micco, C and Wynford-Thomas, D},
title = {Telomerase activity and telomere length in thyroid neoplasia: biological and clinical implications.},
journal = {The Journal of pathology},
volume = {194},
number = {2},
pages = {183-193},
doi = {10.1002/path.848},
pmid = {11400147},
issn = {0022-3417},
mesh = {Adenoma/diagnosis ; Adult ; Biopsy, Needle ; Carcinoma, Papillary/diagnosis ; Carcinoma, Papillary, Follicular/diagnosis ; *Clinical Enzyme Tests ; Cytogenetic Analysis ; Female ; Goiter, Nodular/enzymology ; Graves Disease/enzymology ; Humans ; Male ; Middle Aged ; Predictive Value of Tests ; Sensitivity and Specificity ; Telomerase/*analysis ; Telomere/*ultrastructure ; Thyroid Gland/enzymology ; Thyroid Neoplasms/*diagnosis/enzymology/ultrastructure ; },
abstract = {Despite several recent studies, the biological status and clinical relevance of telomerase expression in tumours derived from the thyroid follicular cell remain controversial. This study has analysed a series of normal, benign, and malignant thyroid samples using two novel approaches: the use of purified epithelial cell fractions to eliminate false-positives due to telomerase-positive infiltrating lymphocytes; and the simultaneous measurement of telomere length to provide a clearer interpretation of telomere dynamics in thyroid neoplasia. The data obtained support the prediction that the epithelial component of non-neoplastic thyroid and of follicular adenomas is telomerase-negative, any positive results being explicable by lymphocyte infiltration. In contrast, many malignant tumours, both follicular and papillary, were telomerase-positive. However, serial dilution of extracts indicated a wide spectrum of activity in these cancers, possibly related to variation in the proportion of telomerase-positive cells. Furthermore, an unexpectedly high proportion were telomerase-negative, a finding which was not explicable by technical problems such as TRAP (telomeric repeat amplification protocol) assay sensitivity. Many of these apparently telomerase-negative tumours had abnormally long telomeres. Correlation of telomerase and telomere length data suggests that thyroid cancers fall into three biological groups: telomerase-positive lesions, consistent with the conventional model of telomere erosion followed by telomerase reactivation; telomerase-negative tumours, which maintain telomere length by a mechanism independent of telomerase; and telomerase-negative tumours which are still undergoing telomere erosion and may therefore be composed of mortal cancer cells. From a clinical standpoint, it is concluded that telomerase detection on unfractionated tissue, such as fine needle aspirates, is of no value as a marker of malignancy in follicular lesions, due to both low sensitivity and specificity.},
}
@article {pmid11402446,
year = {2001},
author = {Zhang, F and Deng, Z and Jia, Z and Wei, Y and Fan, J and Wu, H},
title = {[Telomere length and DCC gene mRNA expression of human large intestine cancers].},
journal = {Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics},
volume = {18},
number = {3},
pages = {187-190},
pmid = {11402446},
issn = {1003-9406},
mesh = {Adult ; Aged ; Aged, 80 and over ; Colorectal Neoplasms/*genetics ; Female ; *Genes, DCC ; Humans ; Male ; Middle Aged ; RNA, Messenger/*analysis ; *Telomere ; },
abstract = {OBJECTIVE: To evaluate the role of telomere and DCC in tumor transformation and progression.<br><br>METHODS: Telomere length and DCC gene mRNA expression were examined by southern blot hybridization and RT-PCR analysis in 46 adenomas of large intestine, 62 cancers of large intestine and corresponding normal mucosa.<br><br>RESULTS: Shortening of the telomere was present in the tissues of 41.3% of the adenomas and 53.2% of the cancers, and their average TRF lengths were significantly shorter than those of corresponding normal mucosa(P<0.05, P<0.01), whereas the telomere elongation was only detected in 4.4% and 6.5% of the adenomas and cancers respectively. In addition, the average telomere length in colon carcinomas was also shorter than that in rectal carcinomas. Moreover, the average telomere lengths of the colorectal cancer mucosa became shorter with age. The rates of DCC mRNA expression deletion were 34.8% and 62.9% in the tissues of adenomas and cancers respectively. The DCC mRNA expression deletion occurred more frequently in poorly differentiated and Dukes C, D carcinomas than in well-differentiated and Dukes A, B carcinomas (P<0.05, P<0.01). However, no significant correlation was found between the length of telomere and the deletion of DCC mRNA expression in the cancers of large intestine.<br><br>CONCLUSION: The telomere shortening and DCC mRNA deletion may represent the biologic behavior of transformation and development of the large intestine cancers.},
}
@article {pmid11401486,
year = {2001},
author = {Honda, S and Weigel, A and Hjelmeland, LM and Handa, JT},
title = {Induction of telomere shortening and replicative senescence by cryopreservation.},
journal = {Biochemical and biophysical research communications},
volume = {282},
number = {2},
pages = {493-498},
doi = {10.1006/bbrc.2001.4585},
pmid = {11401486},
issn = {0006-291X},
mesh = {Bromodeoxyuridine/metabolism ; *Cell Division ; Cell Line ; *Cellular Senescence ; *Cryopreservation ; DNA Damage ; Humans ; Pigment Epithelium of Eye/cytology/metabolism ; Reactive Oxygen Species/metabolism ; Single-Strand Specific DNA and RNA Endonucleases ; Telomere/*metabolism ; beta-Galactosidase/metabolism ; },
abstract = {Cryopreservation can alter cellular function under certain conditions. In this report, we demonstrate the induction of cellular senescence after cells have been cryopreserved using a standard protocol. A retinal pigment epithelial cell line frozen at a specific freezing rate and subsequently thawed showed severely impaired proliferation compared to cells that were not cryopreserved. The induction of senescence was suggested by senescent associated beta-galactosidase activity and diminished bromo-deoxyuridine incorporation. A remarkable increase of single-strand DNA breaks in terminal restriction fragment (TRF) were found in cryopreserved cells immediately after thawing. The rate of mean TRF length shortening was accelerated after cryopreservation. Given this evidence, we hypothesize that cryopreservation may cause telomere shortening and cellular senescence under certain freezing conditions.},
}
@article {pmid11398972,
year = {2001},
author = {Queiroz-Machado, J and Perdigão, J and Simões-Carvalho, P and Herrmann, S and Sunkel, CE},
title = {tef: a mutation that causes telomere fusion and severe genome rearrangements in Drosophila melanogaster.},
journal = {Chromosoma},
volume = {110},
number = {1},
pages = {10-23},
doi = {10.1007/s004120000116},
pmid = {11398972},
issn = {0009-5915},
mesh = {Animals ; Apoptosis/genetics ; Cell Division/genetics ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/metabolism ; DNA Damage ; DNA Repair/genetics ; DNA Replication/genetics ; Drosophila melanogaster/cytology/*genetics/metabolism ; Gene Rearrangement ; *Genes, Insect ; In Situ Hybridization, Fluorescence ; Male ; Mitosis/genetics ; *Mutation ; Neurons/cytology ; Phenotype ; Spermatogenesis/genetics ; Telomere/*genetics ; },
abstract = {Telomeres are the stable ends of linear chromosomes in eukaryotes. These complex protein-nucleic acid structures are essential to maintain genomic stability and the integrity of linear chromosomes. We identified a new mutation in Drosophila that causes a high frequency of end-to-end fusions of chromosomes during mitosis and meiosis. Linear chromosomal ends appear to be essential for fusions to take place. These fusions do not resolve, leading to cycles of chromosomal breakage and rejoining and severe genome rearrangements. The gene is essential for normal cell proliferation and mutant tissue shows significant apoptosis. Our analysis suggests that the function encoded by the mutant gene is required to protect the linear ends of chromosomes.},
}
@article {pmid11395519,
year = {2001},
author = {Ford, LP and Zou, Y and Pongracz, K and Gryaznov, SM and Shay, JW and Wright, WE},
title = {Telomerase can inhibit the recombination-based pathway of telomere maintenance in human cells.},
journal = {The Journal of biological chemistry},
volume = {276},
number = {34},
pages = {32198-32203},
doi = {10.1074/jbc.M104469200},
pmid = {11395519},
issn = {0021-9258},
support = {AG01228/AG/NIA NIH HHS/United States ; AG07992/AG/NIA NIH HHS/United States ; },
mesh = {Chromosome Aberrations ; Fluorescent Antibody Technique ; Humans ; In Situ Hybridization, Fluorescence ; Recombination, Genetic/*physiology ; Telomerase/*physiology ; *Telomere ; },
abstract = {Telomere length can be maintained by telomerase or by a recombination-based pathway. Because individual telomeres in cells using the recombination-based pathway of telomere maintenance appear to periodically become extremely short, cells using this pathway to maintain telomeres may be faced with a continuous state of crisis. We expressed telomerase in a human cell line that uses the recombination-based pathway of telomere maintenance to test whether telomerase would prevent telomeres from becoming critically short and examine the effects that this might have on the recombination-based pathway of telomere maintenance. In these cells, telomerase maintains the length of the shortest telomeres. In some cases, the long heterogeneous telomeres are completely lost, and the cells now permanently contain short telomeres after only 40 population doublings. This corresponds to a telomere reduction rate of 500 base pairs/population doubling, a rate that is much faster than expected for normal telomere shortening but is consistent with the rapid telomere deletion events observed in cells using the recombination-based pathway of telomere maintenance (Murnane, J. P., Sabatier, L., Marder, B. A., and Morgan, W. F. (1994) EMBO J. 13, 4953-4962). We also observed reductions in the fraction of cells containing alternative lengthening of telomere-associated promyelocytic leukemia bodies and extrachromosomal telomere repeats; however, no alterations in the rate of sister chromatid exchange were observed. Our results demonstrate that human cells using the recombination-based pathway of telomere maintenance retain factors required for telomerase to maintain telomeres and that once the telomerase-based pathway of telomere length regulation is engaged, recombination-based elongation of telomeres can be functionally inhibited.},
}
@article {pmid11390652,
year = {2001},
author = {Meier, B and Driller, L and Jaklin, S and Feldmann, HM},
title = {New function of CDC13 in positive telomere length regulation.},
journal = {Molecular and cellular biology},
volume = {21},
number = {13},
pages = {4233-4245},
pmid = {11390652},
issn = {0270-7306},
mesh = {Blotting, Southern ; Cyclin B/genetics/*metabolism ; DNA, Fungal/genetics/metabolism ; DNA-Binding Proteins/metabolism ; Fungal Proteins/genetics/metabolism ; Galactose/metabolism ; Gene Targeting ; Glucose/metabolism ; Mutation ; Phenotype ; Plasmids/genetics/metabolism ; Precipitin Tests ; Recombinant Fusion Proteins/genetics/metabolism ; Saccharomyces cerevisiae/genetics/*physiology ; *Saccharomyces cerevisiae Proteins ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Two roles for the Saccharomyces cerevisiae Cdc13 protein at the telomere have previously been characterized: it recruits telomerase to the telomere and protects chromosome ends from degradation. In a synthetic lethality screen with YKU70, the 70-kDa subunit of the telomere-associated Yku heterodimer, we identified a new mutation in CDC13, cdc13-4, that points toward an additional regulatory function of CDC13. Although CDC13 is an essential telomerase component in vivo, no replicative senescence can be observed in cdc13-4 cells. Telomeres of cdc13-4 mutants shorten for about 150 generations until they reach a stable level. Thus, in cdc13-4 mutants, telomerase seems to be inhibited at normal telomere length but fully active at short telomeres. Furthermore, chromosome end structure remains protected in cdc13-4 mutants. Progressive telomere shortening to a steady-state level has also been described for mutants of the positive telomere length regulator TEL1. Strikingly, cdc13-4/tel1Delta double mutants display shorter telomeres than either single mutant after 125 generations and a significant amplification of Y' elements after 225 generations. Therefore CDC13, TEL1, and the Yku heterodimer seem to represent distinct pathways in telomere length maintenance. Whereas several CDC13 mutants have been reported to display elongated telomeres indicating that Cdc13p functions in negative telomere length control, we report a new mutation leading to shortened and eventually stable telomeres. Therefore we discuss a key role of CDC13 not only in telomerase recruitment but also in regulating telomerase access, which might be modulated by protein-protein interactions acting as inhibitors or activators of telomerase activity.},
}
@article {pmid11381263,
year = {2001},
author = {Rudolph, KL and Millard, M and Bosenberg, MW and DePinho, RA},
title = {Telomere dysfunction and evolution of intestinal carcinoma in mice and humans.},
journal = {Nature genetics},
volume = {28},
number = {2},
pages = {155-159},
doi = {10.1038/88871},
pmid = {11381263},
issn = {1061-4036},
mesh = {Adenocarcinoma/genetics/pathology ; Adenoma/genetics/pathology ; Adenomatous Polyposis Coli Protein ; Animals ; Apoptosis/genetics ; Colorectal Neoplasms/*genetics/pathology/secondary ; Cytoskeletal Proteins/genetics ; Humans ; Intestinal Neoplasms/*genetics/*pathology ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; RNA ; Telomerase/genetics ; Telomere/*genetics ; Tumor Suppressor Protein p53/genetics ; },
abstract = {Telomerase activation is a common feature of advanced human cancers and facilitates the malignant transformation of cultured human cells and in mice. These experimental observations are in accord with the presence of robust telomerase activity in more advanced stages of human colorectal carcinogenesis. However, the occurrence of colon carcinomas in telomerase RNA (Terc)-null, p53-mutant mice has revealed complex interactions between telomere dynamics, checkpoint responses and carcinogenesis. We therefore sought to determine whether telomere dysfunction exerts differential effects on cancer initiation versus progression of mouse and human intestinal neoplasia. In successive generations of ApcMin Terc-/- mice, progressive telomere dysfunction led to an increase in initiated lesions (microscopic adenomas), yet a significant decline in the multiplicity and size of macroscopic adenomas. That telomere dysfunction also contributes to human colorectal carcinogenesis is supported by the appearance of anaphase bridges (a correlate of telomere dysfunction) at the adenoma-early carcinoma transition, a transition recognized for marked chromosomal instability. Together, these data are consistent with a model in which telomere dysfunction promotes the chromosomal instability that drives early carcinogenesis, while telomerase activation restores genomic stability to a level permissive for tumor progression. We propose that early and transient telomere dysfunction is a major mechanism underlying chromosomal instability of human cancer.},
}
@article {pmid11378550,
year = {2001},
author = {Ohshima, K and Sugihara, M and Haraoka, S and Suzumiya, J and Kanda, M and Kawasaki, C and Shimazaki, K and Kikuchi, M},
title = {Possible immortalization of Hodgkin and Reed-Sternberg cells: telomerase expression, lengthening of telomere, and inhibition of apoptosis by NF-kappaB expression.},
journal = {Leukemia &amp; lymphoma},
volume = {41},
number = {3-4},
pages = {367-376},
doi = {10.3109/10428190109057992},
pmid = {11378550},
issn = {1042-8194},
mesh = {Adult ; Aged ; Apoptosis/drug effects ; Child ; DNA/metabolism ; DNA-Binding Proteins ; Female ; Hodgkin Disease/*pathology ; Humans ; Immunohistochemistry ; In Situ Hybridization ; In Situ Nick-End Labeling ; Lymph Nodes/chemistry/pathology ; Male ; Middle Aged ; NF-kappa B/metabolism/pharmacology ; RNA/metabolism ; Reed-Sternberg Cells/chemistry/*pathology ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism/ultrastructure ; },
abstract = {Telomerase, an enzyme associated with cellular immortality, is expressed on malignant tumor cells. Deregulation of telomerase is thought to facilitate tumorigenesis and cellular immortality by providing cancer cells with unlimited proliferation capacity. Hodgkin and Reed-Sternberg (H&amp;RS) cells are generally considered as neoplastic cells in Hodgkin's disease (HD), however, such cells are only found in a minority of HD lesions. In addition, H&amp;RS cells with mitotic features are rare and mummified forms are occasionally encountered. There are no available data on the relationship between telomerase activity and apoptosis in HD. We studied 14 cases with Hodgkin's disease (mixed cellularity type, nine cases; nodular sclerosis type, five cases) to clarify the relationship between telomerase activity and apoptosis using in situ hybridization of human telomerase reverse transcriptase (hTERT), reverse transcriptase-polymerase chain reaction (RT-PCR) of hTERT, using extracted RNA and immunohistochemistry of nuclear factor-?B (NF-?B), and TdT-mediated dUTP-digoxigenin nick end-labeling (TUNEL) technique for apoptosis. We also analyzed the telomere length, using sorted H&amp;RS cells. TUNEL showed a few apoptotic H&amp;RS cells, but the cells frequently expressed hTERT, as confirmed by ISH and RT-PCR. Lengthening of the telomere of H&amp;RS cells was noted in ten cases. In addition, H&amp;RS cells frequently expressed NF-?B, which is known as an inducible transcription factor and inhibitor of apoptosis. Our findings of telomerase activity in H&amp;RS cells indicate that these cells are neoplastic and are potentially immortal. In addition, NF-?B expression on H&amp;RS cells suggests its possibility in inhibition of apoptosis of these cells.},
}
@article {pmid11378197,
year = {2001},
author = {Muñoz-Jordán, JL and Cross, GA},
title = {Telomere shortening and cell cycle arrest in Trypanosoma brucei expressing human telomeric repeat factor TRF1.},
journal = {Molecular and biochemical parasitology},
volume = {114},
number = {2},
pages = {169-181},
doi = {10.1016/s0166-6851(01)00259-6},
pmid = {11378197},
issn = {0166-6851},
support = {F31-AI09893/AI/NIAID NIH HHS/United States ; R01-AI21729/AI/NIAID NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Base Sequence ; Cell Cycle/*physiology ; Cell Division ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Dimerization ; Humans ; In Situ Hybridization ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Recombinant Proteins/chemistry/metabolism ; Telomere/*physiology/ultrastructure ; Telomeric Repeat Binding Protein 1 ; Trypanosoma brucei brucei/cytology/genetics/*physiology ; },
abstract = {Trypanosoma brucei has telomeres composed of 15 kb tracts of TTAGGG repeats that end in 3' overhangs and form t-loops. This structure is also present in mammalian cells and is thought to reflect the presence of telomere-binding proteins. The human TTAGGG repeat-binding factor TRF1 binds to telomeres and regulates their length. We attempted to interfere with the normal function of trypanosome telomeres by expressing human TRF1 in T. brucei. TRF1 localized to telomeres in cultured procyclic (midgut-stage) trypanosomes with great fidelity, but not in bloodstream-stage trypanosomes. Procyclic trypanosomes expressing high levels of TRF1 for extended periods of time exhibited shortening and increased size heterogeneity of their telomeres and the cell cycle was arrested in G1-S. These effects were not detected in cells expressing a TRF1 mutant incapable of binding to TTAGGG repeats. We argue that TRF1 displaces putative endogenous trypanosome telomere-binding proteins, not yet identified, and affects telomeres in ways that reflect its role as a negative regulator of telomere length in human cells.},
}
@article {pmid11371621,
year = {2001},
author = {Pendino, F and Flexor, M and Delhommeau, F and Buet, D and Lanotte, M and Segal-Bendirdjian, E},
title = {Retinoids down-regulate telomerase and telomere length in a pathway distinct from leukemia cell differentiation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {98},
number = {12},
pages = {6662-6667},
pmid = {11371621},
issn = {0027-8424},
mesh = {Cell Death/drug effects ; Cell Differentiation/drug effects ; Cell Division/drug effects ; DNA-Binding Proteins ; Down-Regulation ; Humans ; Leukemia, Promyelocytic, Acute/*drug therapy/pathology ; *RNA ; RNA, Messenger/analysis ; Telomerase/genetics/*metabolism ; Telomere ; Tretinoin/*pharmacology ; Tumor Cells, Cultured ; },
abstract = {Human telomerase, a cellular reverse transcriptase (hTERT), is a nuclear ribonucleoprotein enzyme complex that catalyzes the synthesis and extension of telomeric DNA. This enzyme is specifically activated in most malignant tumors but is usually inactive in normal somatic cells, suggesting that telomerase plays an important role in cellular immortalization and tumorigenesis. Terminal maturation of tumor cells has been associated with the repression of telomerase activity. Using maturation-sensitive and -resistant NB4 cell lines, we analyzed the pattern of telomerase expression during the therapeutic treatment of acute promyelocytic leukemia (APL) by retinoids. Two pathways leading to the down-regulation of hTERT and telomerase activity were identified. The first pathway results in a rapid down-regulation of telomerase that is associated with retinoic acid receptor (RAR)-dependent maturation of NB4 cells. Furthermore, during NB4 cell maturation, obtained independently of RAR by retinoic X receptor (RXR)-specific agonists (rexinoids), no change in telomerase activity was observed, suggesting that hTERT regulation requires a specific signaling and occurs autonomously. A second pathway of hTERT regulation, identified in the RAR-responsive, maturation-resistant NB4-R1 cell line, results in a down-regulation of telomerase that develops slowly during two weeks of all-trans retinoic acid (ATRA) treatment. This pathway leads to telomere shortening, growth arrest, and cell death, all events that are overcome by ectopic expression of hTERT. These findings demonstrate a clear and full dissociation between the process of tumor cell maturation and the regulation of hTERT mRNA expression and telomerase activity by retinoids. We propose telomerase expression as an efficient and selective target of retinoids in the therapy of tumors.},
}
@article {pmid11370858,
year = {2001},
author = {Grandin, N and Charbonneau, M},
title = {Hsp90 levels affect telomere length in yeast.},
journal = {Molecular genetics and genomics : MGG},
volume = {265},
number = {1},
pages = {126-134},
doi = {10.1007/s004380000398},
pmid = {11370858},
issn = {1617-4615},
mesh = {Blotting, Northern ; Cell Cycle Proteins/*genetics/metabolism ; Cyclin B/*metabolism ; DNA, Single-Stranded/metabolism ; Genes, cdc ; HSP90 Heat-Shock Proteins/*genetics/metabolism ; Heat-Shock Proteins/*genetics/metabolism ; Hot Temperature ; Mutation ; Phenotype ; Polymerase Chain Reaction ; Protein Binding ; Saccharomyces cerevisiae/cytology/*genetics/metabolism ; *Saccharomyces cerevisiae Proteins ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere-Binding Proteins ; Two-Hybrid System Techniques ; },
abstract = {Cdc13 is a Saccharomyces cerevisiae protein that binds to telomeric single-stranded DNA and regulates telomerase activity. Stnl has been shown by two-hybrid analysis to form a physical complex with Cdc13. Temperature-sensitive mutations in CDC13 and STN1, which are both essential genes, activate a DNA damage-dependent checkpoint which is the cause of the arrest seen in the mutant strains. The stn1-13 mutation induces dramatic telomere elongation which is telomerase dependent, as shown here. Additional mutants for STN1, which show a tighter arrest phenotype than stn1-13, were generated in order to perform genetic screens aiming at uncovering new regulators of telomerase. HSC82, which encodes a conserved molecular chaperone of the Hsp90 family, was thus isolated as a high-dosage suppressor of a temperature-sensitive mutation in STN1. Overexpression of HSC82 also partially suppressed the growth defect of cdc13-1 cells. Overexpression of HSC82 was found to correct the telomeric defect associated with stn1 mutations. Shortening of telomeres was also observed in wild-type cells upon overexpression of HSC82, or of its temperature-inducible homologue, HSP82. These results identify Hsc82/Hsp82 as potential regulators of telomerase in yeast cells.},
}
@article {pmid11359911,
year = {2001},
author = {Tong, WM and Hande, MP and Lansdorp, PM and Wang, ZQ},
title = {DNA strand break-sensing molecule poly(ADP-Ribose) polymerase cooperates with p53 in telomere function, chromosome stability, and tumor suppression.},
journal = {Molecular and cellular biology},
volume = {21},
number = {12},
pages = {4046-4054},
pmid = {11359911},
issn = {0270-7306},
support = {R01AI29524/AI/NIAID NIH HHS/United States ; GM56162/GM/NIGMS NIH HHS/United States ; R01 AI029524/AI/NIAID NIH HHS/United States ; R01CA79493-01/CA/NCI NIH HHS/United States ; R01 CA079493/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Chromosome Aberrations ; Chromosomes/metabolism ; DNA Damage ; DNA Primers/genetics ; *DNA Repair ; Female ; Genes, p53 ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Mice, Knockout ; Mutation ; Neoplasms, Experimental/genetics/pathology/prevention &amp; control ; Poly(ADP-ribose) Polymerases/genetics/*metabolism ; Telomere/*metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; },
abstract = {Genomic instability is often caused by mutations in genes that are involved in DNA repair and/or cell cycle checkpoints, and it plays an important role in tumorigenesis. Poly(ADP-ribose) polymerase (PARP) is a DNA strand break-sensing molecule that is involved in the response to DNA damage and the maintenance of telomere function and genomic stability. We report here that, compared to single-mutant cells, PARP and p53 double-mutant cells exhibit many severe chromosome aberrations, including a high degree of aneuploidy, fragmentations, and end-to-end fusions, which may be attributable to telomere dysfunction. While PARP(-/-) cells showed telomere shortening and p53(-/-) cells showed normal telomere length, inactivation of PARP in p53(-/-) cells surprisingly resulted in very long and heterogeneous telomeres, suggesting a functional interplay between PARP and p53 at the telomeres. Strikingly, PARP deficiency widens the tumor spectrum in mice deficient in p53, resulting in a high frequency of carcinomas in the mammary gland, lung, prostate, and skin, as well as brain tumors, reminiscent of Li-Fraumeni syndrome in humans. The enhanced tumorigenesis is likely to be caused by PARP deficiency, which facilitates the loss of function of tumor suppressor genes as demonstrated by a high rate of loss of heterozygosity at the p53 locus in these tumors. These results indicate that PARP and p53 interact to maintain genome integrity and identify PARP as a cofactor for suppressing tumorigenesis.},
}
@article {pmid11359895,
year = {2001},
author = {Perrem, K and Colgin, LM and Neumann, AA and Yeager, TR and Reddel, RR},
title = {Coexistence of alternative lengthening of telomeres and telomerase in hTERT-transfected GM847 cells.},
journal = {Molecular and cellular biology},
volume = {21},
number = {12},
pages = {3862-3875},
pmid = {11359895},
issn = {0270-7306},
mesh = {Cell Line ; Chromosomes, Human/genetics/metabolism/ultrastructure ; DNA-Binding Proteins ; Humans ; Hybrid Cells ; In Situ Hybridization, Fluorescence ; *RNA ; Telomerase/*genetics/*metabolism ; Telomere/genetics/*metabolism/ultrastructure ; Transfection ; },
abstract = {It has been shown previously that some immortalized human cells maintain their telomeres in the absence of significant levels of telomerase activity by a mechanism referred to as alternative lengthening of telomeres (ALT). Cells utilizing ALT have telomeres of very heterogeneous length, ranging from very short to very long. Here we report the effect of telomerase expression in the ALT cell line GM847. Expression of exogenous hTERT in GM847 (GM847/hTERT) cells resulted in lengthening of the shortest telomeres; this is the first evidence that expression of hTERT in ALT cells can induce telomerase that is active at the telomere. However, rapid fluctuation in telomere length still occurred in the GM847/hTERT cells after more than 100 population doublings. Very long telomeres and ALT-associated promyelocytic leukemia (PML) bodies continued to be generated, indicating that telomerase activity induced by exogenous hTERT did not abolish the ALT mechanism. In contrast, when the GM847 cell line was fused with two different telomerase-positive tumor cell lines, the ALT phenotype was repressed in each case. These hybrid cells were telomerase positive, and the telomeres decreased in length, very rapidly at first and then at the rate seen in telomerase-negative normal cells. Additionally, ALT-associated PML bodies disappeared. After the telomeres had shortened sufficiently, they were maintained at a stable length by telomerase. Together these data indicate that the telomerase-positive cells contain a factor that represses the ALT mechanism but that this factor is unlikely to be telomerase. Further, the transfection data indicate that ALT and telomerase can coexist in the same cells.},
}
@article {pmid11359612,
year = {2001},
author = {Fitzgerald, MS and Shakirov, EV and Hood, EE and McKnight, TD and Shippen, DE},
title = {Different modes of de novo telomere formation by plant telomerases.},
journal = {The Plant journal : for cell and molecular biology},
volume = {26},
number = {1},
pages = {77-87},
doi = {10.1046/j.1365-313x.2001.01010.x},
pmid = {11359612},
issn = {0960-7412},
mesh = {Arabidopsis/enzymology ; Chromosomes/*genetics ; DNA, Plant/biosynthesis/metabolism ; Plants/*enzymology/genetics ; Poaceae/enzymology ; Sequence Analysis, DNA ; Glycine max/enzymology ; Species Specificity ; Substrate Specificity ; Telomerase/classification/*metabolism ; Telomere/*metabolism ; },
abstract = {The telomerase reverse transcriptase can recognize broken chromosome ends and add new telomeres de novo in a reaction termed "chromosome healing". Here we investigate new telomere formation in vitro by telomerases from a variety of flowering plant species. Comparing the electrophoretic mobilities and nucleotide sequences of the products, we uncovered three different modes of new telomere formation. The soybean telomerase, designated a Class I enzyme, only elongated DNA primers ending in telomeric nucleotides. Arabidopsis and maize telomerases, designated Class II enzymes, efficiently extended completely non-telomeric sequences by positioning the 3' terminus at a preferred site on the RNA template. Silene latifolia and sorghum telomerases constituted class III enzymes that elongated non-telomeric DNA primers by annealing them at alternative sites on the RNA template. For all enzymes, errors were prevalent during synthesis of the first two repeats, likely reflecting lateral instability of the primer 3' terminus on the template during the initial rounds of elongation. Class III telomerases, however, were five- to 13-fold more error prone than class II, generating more mistakes in distal repeats added to the primers. This remarkable variability in enzyme-DNA interactions among plant telomerases does not reflect phylogenetic relationships, and therefore implies that the telomerase active site can evolve rapidly.},
}
@article {pmid11359168,
year = {2001},
author = {Kojima, H and Miyazaki, H and Shiwa, M and Tanaka, Y and Moriyama, H},
title = {Molecular biological diagnosis of congenital and acquired cholesteatoma on the basis of differences in telomere length.},
journal = {The Laryngoscope},
volume = {111},
number = {5},
pages = {867-873},
doi = {10.1097/00005537-200105000-00021},
pmid = {11359168},
issn = {0023-852X},
mesh = {Adolescent ; Adult ; Blotting, Southern ; Child ; Child, Preschool ; Cholesteatoma/*congenital/*genetics ; DNA/analysis ; Diagnosis, Differential ; Female ; Humans ; Infant ; Male ; Middle Aged ; Oligonucleotide Probes ; Telomerase/analysis ; Telomere/*genetics ; },
abstract = {OBJECTIVE: To establish a molecular biological basis for differentiation of congenital and acquired cholesteatoma.<br><br>STUDY DESIGN: The time of onset was estimated for congenital cholesteatoma and for acquired cholesteatoma by comparing the telomere length and the telomerase activity in the tissues of both diseases with the values of those parameters in normal external ear canal skin.<br><br>METHODS: The telomere length was determined by extracting DNA from each tissue and then applying the Southern blot technique to hybridize it with a 32P-labeled telomeric oligonucleotide (TAAGGG)8 probe. The telomerase activity was analyzed by a modification of the polymerase chain reaction-based telomeric repeat amplification protocol.<br><br>RESULTS: The telomere length in congenital cholesteatoma tissue was shorter than the length in normal external ear canal skin from the same patient, whereas in acquired cholesteatoma tissue the telomere length was almost the same as in the normal external ear canal skin. Some of the acquired cholesteatoma tissue specimens and normal external ear canal skin specimens were positive for telomerase activity, but all of the specimens of congenital cholesteatoma tissue were negative for telomerase activity. No correlation was found between the presence of telomerase activity and the telomere length.<br><br>CONCLUSIONS: The present results indicate that congenital cholesteatoma manifests at an earlier time compared with acquired cholesteatoma, and the results can be thought to support the theory that congenital cholesteatoma originates from vestigial fetal tissue or aberrant tissue. In addition, the finding that telomerase activity was weak in the congenital cholesteatoma tissue suggests the possibility that vestigial fetal tissues and aberrant tissues are naturally eliminated in normal subjects as a result of apoptosis.},
}
@article {pmid11355946,
year = {2001},
author = {Schröder, CP and Wisman, GB and de Jong, S and van der Graaf, WT and Ruiters, MH and Mulder, NH and de Leij, LF and van der Zee, AG and de Vries, EG},
title = {Telomere length in breast cancer patients before and after chemotherapy with or without stem cell transplantation.},
journal = {British journal of cancer},
volume = {84},
number = {10},
pages = {1348-1353},
pmid = {11355946},
issn = {0007-0920},
mesh = {Antineoplastic Combined Chemotherapy Protocols/administration &amp; dosage/*therapeutic use ; Breast Neoplasms/drug therapy/*genetics/pathology/*therapy ; Carboplatin/administration &amp; dosage ; Chemotherapy, Adjuvant ; Combined Modality Therapy ; Cyclophosphamide/administration &amp; dosage ; Epirubicin/administration &amp; dosage ; Female ; Fluorouracil/administration &amp; dosage ; Granulocyte Colony-Stimulating Factor/therapeutic use ; Hematopoietic Stem Cell Mobilization ; *Hematopoietic Stem Cell Transplantation ; Humans ; Leukocytes/enzymology/pathology ; Lymphatic Metastasis ; Middle Aged ; Platelet Count ; Recombinant Proteins ; Telomerase/*blood ; Telomere/*pathology ; Thiotepa/administration &amp; dosage ; },
abstract = {High-dose chemotherapy and peripheral blood stem cell transplantation (PBSCT) may accelerate telomere length loss in haematopoietic stem cells. As data including pre-and post-treatment samples are lacking, we studied leukocyte telomere length and telomerase activity before and after treatment in breast cancer patients randomized to receive 5 adjuvant courses FEC (5-FU, epirubicin and cyclophosphamide) (n = 17), or 4 x FEC followed by high-dose cyclophosphamide, thiotepa, carboplatin and autologous PBSCT (n = 16). Haemoglobin, MCV, leukocyte-and platelet numbers were assessed prior to (t(0)), 5 months after (t(1)) and 9 months after chemotherapy (t(2)); these parameters were decreased at t(1)and t(2)compared to t(0)(high-dose: all parameters; standard-dose: leukocytes and platelets), and all parameters were lower after high-dose than standard-dose treatment at t(1). Paired individual leukocyte samples of t(0)and t(1)showed telomere length change (determined by telomere restricted fragment (TRF) assay) ranging from +0.8 to -2.2 kb, with a decreased TRF length in 9 patients of both groups. Telomerase activity (determined by TRAP assay) was below detection limit in leukocyte samples of t(0)and t(1). Thus, standard-and high-dose chemotherapy negatively affect haematological reconstitution in this setting. In individual patients, telomere length can be remarkably changed following haematological proliferative stress after treatment.},
}
@article {pmid11355352,
year = {2001},
author = {Underwood, DH and McEachern, MJ},
title = {Totally mutant telomeres: single-step mutagenesis of tandem repeat DNA sequences.},
journal = {BioTechniques},
volume = {30},
number = {5},
pages = {934-5, 938},
doi = {10.2144/01305bm02},
pmid = {11355352},
issn = {0736-6205},
mesh = {Base Sequence ; Escherichia coli/genetics ; Kluyveromyces/genetics ; Molecular Sequence Data ; *Mutagenesis, Site-Directed ; Plasmids/genetics ; *Tandem Repeat Sequences ; Telomerase/genetics/metabolism ; Telomere/*genetics ; },
}
@article {pmid11352055,
year = {2001},
author = {de Lange, T},
title = {Cell biology. Telomere capping--one strand fits all.},
journal = {Science (New York, N.Y.)},
volume = {292},
number = {5519},
pages = {1075-1076},
doi = {10.1126/science.1061032},
pmid = {11352055},
issn = {0036-8075},
mesh = {Animals ; Cloning, Molecular ; *Conserved Sequence ; DNA, Single-Stranded/genetics/*metabolism ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Humans ; Oxytricha/genetics ; Saccharomyces cerevisiae/genetics ; Schizosaccharomyces/genetics ; Substrate Specificity ; Telomere/*genetics/*metabolism ; },
}
@article {pmid11349961,
year = {2001},
author = {Kang, MK and Park, NH},
title = {Conversion of normal to malignant phenotype: telomere shortening, telomerase activation, and genomic instability during immortalization of human oral keratinocytes.},
journal = {Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists},
volume = {12},
number = {1},
pages = {38-54},
doi = {10.1177/10454411010120010301},
pmid = {11349961},
issn = {1045-4411},
support = {P50 DE/RR10598/DE/NIDCR NIH HHS/United States ; T32 DE07296/DE/NIDCR NIH HHS/United States ; },
mesh = {Alcohol Drinking/adverse effects ; Animals ; Cell Cycle ; *Cell Transformation, Neoplastic ; Cellular Senescence ; DNA, Viral ; Humans ; Keratinocytes/*cytology/enzymology ; Mouth Neoplasms/etiology/*genetics/physiopathology ; Papillomaviridae/pathogenicity ; Risk Factors ; Smoking/adverse effects ; Telomerase/metabolism ; Telomere ; },
abstract = {Normal somatic cells terminate their replicative life span through a pathway leading to cellular senescence, which is triggered by activation of p53 and/or pRb in response to critically shortened telomere DNA. Potentially neoplastic cells must first overcome the senescence checkpoint mechanisms and subsequently activate telomerase to propagate indefinitely. Although telomerase activation is closely associated with cellular immortality, telomerase alone is not sufficient to warrant tumorigenicity. Environmental factors, including chemical carcinogens and viral infection, often contribute to aberrant changes leading to tumorigenic conversion of normal cells. Of particular importance in oral cancer development are tobacco-related chemical carcinogens and human papillomavirus (HPV) infection. To describe the molecular mechanisms by which these environmental factors facilitate the genesis of oral cancer, we first established an in vitro multistep oral carcinogenesis model by sequential exposure of normal human oral keratinocytes (NHOK) to "high risk" HPV and chemical carcinogens. Upon introduction of the HPV genome, the cells bypassed the senescence checkpoint and entered into an extended, but not immortal, life span during which telomere DNA continued to shorten. In a few immortal clones surviving beyond the crisis, we found a marked elevation of telomerase activity and stabilization of telomere length. Furthermore, the E6 and E7 oncoproteins of "high risk" HPV disrupted the cell cycle control and DNA repair in immortalized HOK, and enhanced mutation frequency resulting from genomic instability. However, HPV infection alone failed to give rise to a tumorigenic cell population, which required further exposure to chemical carcinogens in addition to HPV infection. Analysis of the data presented suggests that oral carcinogenesis is a series of discrete genetic alterations that result from a continued genotoxic challenge by environmental risk factors. Our in vitro model may be useful for investigators with interest in furthering our understanding of oral carcinogenesis.},
}
@article {pmid11349150,
year = {2001},
author = {Baumann, P and Cech, TR},
title = {Pot1, the putative telomere end-binding protein in fission yeast and humans.},
journal = {Science (New York, N.Y.)},
volume = {292},
number = {5519},
pages = {1171-1175},
doi = {10.1126/science.1060036},
pmid = {11349150},
issn = {0036-8075},
mesh = {Amino Acid Sequence ; Base Sequence ; Binding Sites ; Chromosome Segregation/genetics ; Chromosomes, Fungal/genetics/metabolism ; Cloning, Molecular ; DNA/genetics/metabolism ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Electrophoresis, Gel, Pulsed-Field ; Female ; Gene Deletion ; Gene Expression Profiling ; Heterozygote ; Humans ; Molecular Sequence Data ; Ovary/metabolism ; Phenotype ; RNA, Messenger/analysis/genetics ; Schizosaccharomyces/*genetics ; Schizosaccharomyces pombe Proteins ; Sequence Alignment ; Shelterin Complex ; Substrate Specificity ; Telomere/genetics/*metabolism ; *Telomere-Binding Proteins ; },
abstract = {Telomere proteins from ciliated protozoa bind to the single-stranded G-rich DNA extensions at the ends of macronuclear chromosomes. We have now identified homologous proteins in fission yeast and in humans. These Pot1 (protection of telomeres) proteins each bind the G-rich strand of their own telomeric repeat sequence, consistent with a direct role in protecting chromosome ends. Deletion of the fission yeast pot1+ gene has an immediate effect on chromosome stability, causing rapid loss of telomeric DNA and chromosome circularization. It now appears that the protein that caps the ends of chromosomes is widely dispersed throughout the eukaryotic kingdom.},
}
@article {pmid11343898,
year = {2001},
author = {Dubrana, K and Perrod, S and Gasser, SM},
title = {Turning telomeres off and on.},
journal = {Current opinion in cell biology},
volume = {13},
number = {3},
pages = {281-289},
doi = {10.1016/s0955-0674(00)00210-6},
pmid = {11343898},
issn = {0955-0674},
mesh = {Animals ; Chromosomes/genetics/*metabolism/ultrastructure ; DNA Damage/*physiology ; DNA Replication/genetics/*physiology ; Fungal Proteins/metabolism ; Humans ; Nuclear Pore Complex Proteins ; *Nuclear Proteins ; Protein Folding ; RNA-Binding Proteins ; Saccharomyces/genetics/metabolism ; *Saccharomyces cerevisiae Proteins ; Telomerase/*metabolism ; Telomere/genetics/*metabolism/ultrastructure ; },
abstract = {We envision multiple steps in telomere maintenance, based largely on genetic data from budding yeast. First, the telomere must unfold or open itself such that the free end is accessible to the appropriate enzymatic machinery. Second, telomerase must be recruited, together with the DNA replication machinery that synthesizes the C-rich strand. The processivity of telomerase is regulated both by a length-sensing feedback mechanism and by second-strand synthesis. Finally, the telosome refolds into a protective end structure. If telomerase is nonfunctional, recombination may occur once telomeres are open. Multiple pathways regulate these different steps, producing a highly dynamic chromosomal cap.},
}
@article {pmid11343124,
year = {2001},
author = {de Bruin, D and Zaman, Z and Liberatore, RA and Ptashne, M},
title = {Telomere looping permits gene activation by a downstream UAS in yeast.},
journal = {Nature},
volume = {409},
number = {6816},
pages = {109-113},
doi = {10.1038/35051119},
pmid = {11343124},
issn = {0028-0836},
mesh = {Chromatin ; Chromosomes, Fungal ; DNA, Fungal/physiology/ultrastructure ; *Enhancer Elements, Genetic ; *Gene Expression Regulation, Fungal ; Genes, Reporter ; Nucleic Acid Conformation ; Precipitin Tests ; Saccharomyces cerevisiae/*genetics ; *Telomere/physiology/ultrastructure ; Transcriptional Activation ; },
abstract = {In yeast (Saccharomyces cerevisiae), transcriptional activators, such as Gal4 and Gal4-VP16, work ordinarily from sites located in the upstream activating sequence (UAS) positioned about 250 base pairs upstream of the transcription start site. In contrast to their behaviour in mammalian cells, however, such activators fail to work when positioned at distances greater than approximately 600-700 base pairs upstream, or anywhere downstream of the gene. Here we show that, in yeast, a gene bearing an enhancer positioned 1-2 kilobases downstream of the gene is activated if the reporter is linked to a telomere, but not if it is positioned at an internal chromosomal locus. These observations are explained by the finding that yeast telomeres form back-folding, or looped, structures. Because yeast telomeric regions resemble the heterochromatin found in higher eukaryotes, these findings might also explain why transcription of some higher eukaryotic genes depends on their location in heterochromatin.},
}
@article {pmid11340158,
year = {2001},
author = {Goytisolo, FA and Samper, E and Edmonson, S and Taccioli, GE and Blasco, MA},
title = {The absence of the dna-dependent protein kinase catalytic subunit in mice results in anaphase bridges and in increased telomeric fusions with normal telomere length and G-strand overhang.},
journal = {Molecular and cellular biology},
volume = {21},
number = {11},
pages = {3642-3651},
pmid = {11340158},
issn = {0270-7306},
mesh = {Anaphase ; Animals ; Catalysis ; Catalytic Domain ; DNA-Activated Protein Kinase ; *DNA-Binding Proteins ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Mice, SCID ; Mitosis/physiology ; Protein Serine-Threonine Kinases/genetics/metabolism/*physiology ; Repetitive Sequences, Nucleic Acid ; Telomere/*physiology ; },
abstract = {The major pathway in mammalian cells for repairing DNA double-strand breaks (DSB) is via nonhomologous end joining. Five components function in this pathway, of which three (Ku70, Ku80, and the DNA-dependent protein kinase catalytic subunit [DNA-PKcs]) constitute a complex termed DNA-dependent protein kinase (DNA-PK). Mammalian Ku proteins bind to DSB and recruit DNA-PKcs to the break. Interestingly, besides their role in DSB repair, Ku proteins bind to chromosome ends, or telomeres, protecting them from end-to-end fusions. Here we show that DNA-PKcs(-/-) cells display an increased frequency of spontaneous telomeric fusions and anaphase bridges. However, DNA-PKcs deficiency does not result in significant changes in telomere length or in deregulation of the G-strand overhang at the telomeres. Although less severe, this phenotype is reminiscent of the one recently described for Ku86-defective cells. Here we show that, besides DNA repair, a role for DNA-PKcs is to protect telomeres, which in turn are essential for chromosomal stability.},
}
@article {pmid11336694,
year = {2001},
author = {McEachern, MJ and Iyer, S},
title = {Short telomeres in yeast are highly recombinogenic.},
journal = {Molecular cell},
volume = {7},
number = {4},
pages = {695-704},
doi = {10.1016/s1097-2765(01)00215-5},
pmid = {11336694},
issn = {1097-2765},
support = {DE11356/DE/NIDCR NIH HHS/United States ; GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Repair ; DNA, Fungal/genetics ; Genetic Markers ; Kluyveromyces/*genetics ; Mutagenesis ; *Recombination, Genetic ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {We report that recombination rates specifically increase by up to 10(3) near shortened telomeres in K. lactis cells. This occurs in cells lacking telomerase that undergo growth senescence as well as in cells with stably shortened telomeres that cause little effect on cell growth. The high rates of gene conversion allowed a subtelomeric marker, initially present at a single telomere, to efficiently spread to most or all other telomeres in the cell. We propose that short telomeres in K. lactis are not fully competent at capping chromosome ends and hence are occasionally processed by proteins that normally act to repair broken DNA ends through recombination. This helps explain how recombination can be frequent enough to permit maintenance of telomeres in yeast cells lacking telomerase.},
}
@article {pmid11331754,
year = {2001},
author = {Saffery, R and Wong, LH and Irvine, DV and Bateman, MA and Griffiths, B and Cutts, SM and Cancilla, MR and Cendron, AC and Stafford, AJ and Choo, KH},
title = {Construction of neocentromere-based human minichromosomes by telomere-associated chromosomal truncation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {98},
number = {10},
pages = {5705-5710},
pmid = {11331754},
issn = {0027-8424},
mesh = {Cell Line ; *Centromere ; *Chromosomes, Human ; Gene Transfer Techniques ; Humans ; In Situ Hybridization, Fluorescence ; *Telomere ; },
abstract = {Neocentromeres (NCs) are fully functional centromeres that arise ectopically in noncentromeric regions lacking alpha-satellite DNA. Using telomere-associated chromosome truncation, we have produced a series of minichromosomes (MiCs) from a mardel(10) marker chromosome containing a previously characterized human NC. These MiCs range in size from approximately 0.7 to 1.8 Mb and contain single-copy intact genomic DNA from the 10q25 region. Two of these NC-based Mi-Cs (NC-MiCs) appear circular whereas one is linear. All demonstrate stability in both structure and mitotic transmission in the absence of drug selection. Presence of a functional NC is shown by binding a host of key centromere-associated proteins. These NC-MiCs provide direct evidence for mitotic segregation function of the NC DNA and represent examples of stable mammalian MiCs lacking centromeric repeats.},
}
@article {pmid11329372,
year = {2001},
author = {Postberg, J and Juranek, SA and Feiler, S and Kortwig, H and Jönsson, F and Lipps, HJ},
title = {Association of the telomere-telomere-binding protein complex of hypotrichous ciliates with the nuclear matrix and dissociation during replication.},
journal = {Journal of cell science},
volume = {114},
number = {Pt 10},
pages = {1861-1866},
doi = {10.1242/jcs.114.10.1861},
pmid = {11329372},
issn = {0021-9533},
mesh = {Animals ; Cell Division/physiology ; DNA, Protozoan/analysis ; DNA-Binding Proteins/genetics/*metabolism ; Hypotrichida/*physiology ; In Situ Hybridization, Fluorescence ; Nuclear Matrix/*metabolism ; Protozoan Proteins/metabolism ; Telomere/*metabolism ; },
abstract = {Telomeric interactions with the nuclear matrix have been described in a variety of eukaryotic cells and seem to be essential for specific nuclear localization. Macronuclear DNA of hypotrichous ciliates occurs in small gene-sized DNA molecules, each being terminated by telomeres. Each macronucleus contains over 10(8)individual DNA molecules. Owing to the high number of telomeres present in this nucleus it provides an excellent model to study telomere behaviour throughout the cell cycle. In this study we provide experimental evidence that the telomere-telomere-binding protein (TEBP) complex specifically interacts with components of the nuclear matrix in vivo. In the course of replication the specific interaction of the TEBP with components of the nuclear matrix is resolved and an attachment of the telomeres to the matrix no longer occurs.},
}
@article {pmid11327863,
year = {2001},
author = {Smucker, EJ and Turchi, JJ},
title = {TRF1 inhibits telomere C-strand DNA synthesis in vitro.},
journal = {Biochemistry},
volume = {40},
number = {8},
pages = {2426-2432},
doi = {10.1021/bi001871o},
pmid = {11327863},
issn = {0006-2960},
support = {CA64374/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Binding, Competitive/genetics ; Catalysis ; DNA/*antagonists &amp; inhibitors/*biosynthesis/chemical synthesis/metabolism ; DNA Polymerase I/metabolism/physiology ; DNA Primase/metabolism ; DNA Primers/metabolism ; DNA Replication/*genetics ; DNA-Binding Proteins/*genetics/metabolism ; Molecular Sequence Data ; Nucleic Acid Heteroduplexes/genetics/metabolism ; Protein Binding/genetics ; Recombinant Fusion Proteins/metabolism/*pharmacology ; Repetitive Sequences, Nucleic Acid ; Spodoptera/genetics ; Substrate Specificity/genetics ; Telomere/*genetics ; Telomeric Repeat Binding Protein 1 ; },
abstract = {Human TTAGGG repeat-binding factor 1 (TRF1) is involved in the regulation of telomere length in vivo, but the mechanism of regulation remains largely undefined. We have developed an in vitro system for assessing the effect of TRF1 on DNA synthesis using purified proteins and synthetic DNA substrates. Results reveal that TRF1, when bound to telomeric duplex DNA, inhibits DNA synthesis catalyzed by DNA polymerase alpha/primase (pol alpha). Inhibition required that TRF1 be bound to duplex telomeric DNA as no effect of TRF1 was observed on nontelomeric, random DNA substrates. Inhibition was shown to be dependent on TRF1 concentration and the length of the telomeric duplex region of the DNA substrate. When bound in cis to telomeric duplex DNA, TRF1 was also capable of inhibiting pol alpha-catalyzed DNA synthesis on nontelomeric DNA sequences from positions both upstream and downstream of the extending polymerase. Inhibition of DNA synthesis was shown to be specific for TRF1 but not necessarily for the DNA polymerase used in the extension reaction. In a series of control experiments, we assessed T7 DNA polymerase-catalyzed synthesis on a DNA template containing tandem gal4 operators. In these experiments, the addition of the purified Gal4-DNA binding domain (Gal4-DBD) protein has no effect on the ability of T7 polymerase to copy the DNA template. Interestingly, TRF1 inhibition was observed on telomeric DNA substrates using T7 DNA polymerase. These results suggest that TRF1, when bound to duplex telomeric DNA, serves to block extension by DNA polymerases. These results are discussed with respect to the role of TRF1 in telomere length regulation.},
}
@article {pmid11322993,
year = {2001},
author = {Klapper, W and Parwaresch, R and Krupp, G},
title = {Telomere biology in human aging and aging syndromes.},
journal = {Mechanisms of ageing and development},
volume = {122},
number = {7},
pages = {695-712},
doi = {10.1016/s0047-6374(01)00223-8},
pmid = {11322993},
issn = {0047-6374},
mesh = {Aging/*physiology ; Animals ; Cellular Senescence ; Disease ; Humans ; Models, Biological ; Syndrome ; Telomerase/metabolism/physiology ; Telomere/*physiology ; },
abstract = {Telomeres, the extreme ends of the chromosomes play a key role in the process of cellular aging. Due to the 'end-replication-problem', successive shortening of the telomeres with each cell division results in a mitotic clock and it was shown in vitro that this clock limits the replicative capacity of cell proliferation. Telomerase counteracts telomere erosion and provides some somatic cells an unlimited proliferative potential in vitro. The present views of telomeres and telomerase functions in cellular aging in vitro are presented. Possibilities and limitations in the evaluation of the in vivo impact of telomere erosion on human aging, aging syndromes and age related diseases are reviewed. Unresolved questions, future experimental approaches and emerging therapeutic applications are discussed.},
}
@article {pmid11318593,
year = {2001},
author = {Honda, M and Mengesha, E and Albano, S and Nichols, WS and Wallace, DJ and Metzger, A and Klinenberg, JR and Linker-Israeli, M},
title = {Telomere shortening and decreased replicative potential, contrasted by continued proliferation of telomerase-positive CD8+CD28(lo) T cells in patients with systemic lupus erythematosus.},
journal = {Clinical immunology (Orlando, Fla.)},
volume = {99},
number = {2},
pages = {211-221},
doi = {10.1006/clim.2001.5023},
pmid = {11318593},
issn = {1521-6616},
support = {AR4029/AR/NIAMS NIH HHS/United States ; },
mesh = {Adult ; Aged ; CD28 Antigens/metabolism ; CD8-Positive T-Lymphocytes/*enzymology/*immunology/pathology ; Case-Control Studies ; Cell Division/drug effects ; Cellular Senescence/genetics/immunology ; DNA/genetics/metabolism ; Female ; Humans ; Immunologic Memory ; In Vitro Techniques ; Interleukin-2/pharmacology ; Leukocyte Common Antigens/metabolism ; Leukocytes, Mononuclear/drug effects/immunology/pathology ; Lupus Erythematosus, Systemic/genetics/*immunology/*pathology ; Middle Aged ; Phytohemagglutinins/pharmacology ; T-Lymphocyte Subsets/drug effects/enzymology/immunology/pathology ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {To evaluate whether the immune system of systemic lupus erythematosus (SLE) patients shows features of premature aging, we compared telomere length and proliferative potential of SLE peripheral blood mononuclear cells (PBMC) (N = 90) to those of controls (N = 64). SLE samples showed accelerated loss of telomeric DNA (P = 0.00008) and higher levels of senescent (< or =5 kb) telomeric DNA (P = 0.00003). Viability cell counts and CFSE tracking in 6-week-old cell cultures indicated that SLE PBMC (CD8+ and CD4+ T cells) underwent fewer mitotic cycles and had shorter telomeres than controls (P = 0.04). However, a CD8(+)CD28(lo) T cell subset expanded preferentially in SLE-derived bulk cultures (P = 0.0009), preserved telomeric DNA (P = 0.01 vs entire CD8+), and displayed telomerase activity [2.1 telomerase arbitrary units (TAU) vs 0.5 TAU in CD8+CD28(hi) cells and 0.3 TAU in bulk PBMC; P = 0.05]. These T cell anomalies could be due to chronic in vivo stimulation of the immune system and may contribute to the immune dysregulation found in SLE.},
}
@article {pmid11318591,
year = {2001},
author = {Rus, V and Via, CS},
title = {Telomeres, telomerase, and lupus: the long and short of it.},
journal = {Clinical immunology (Orlando, Fla.)},
volume = {99},
number = {2},
pages = {195-197},
doi = {10.1006/clim.2001.5034},
pmid = {11318591},
issn = {1521-6616},
mesh = {Apoptosis ; Autoantigens ; B-Lymphocytes/immunology/pathology ; Cell Division ; Humans ; Lupus Erythematosus, Systemic/*enzymology/*genetics/immunology ; Lymphocyte Activation ; T-Lymphocytes/immunology/pathology ; Telomerase/*metabolism ; Telomere/*genetics ; },
}
@article {pmid11313893,
year = {2001},
author = {Kishi, S and Wulf, G and Nakamura, M and Lu, KP},
title = {Telomeric protein Pin2/TRF1 induces mitotic entry and apoptosis in cells with short telomeres and is down-regulated in human breast tumors.},
journal = {Oncogene},
volume = {20},
number = {12},
pages = {1497-1508},
doi = {10.1038/sj.onc.1204229},
pmid = {11313893},
issn = {0950-9232},
support = {R01GM56230/GM/NIGMS NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing ; *Apoptosis ; Breast Neoplasms/*genetics/pathology ; Caspase 3 ; Caspases/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Down-Regulation ; Enzyme Activation ; Female ; HeLa Cells ; Humans ; LIM Domain Proteins ; Membrane Proteins ; *Mitosis ; *Telomere ; Telomeric Repeat Binding Protein 1 ; },
abstract = {Telomeres are essential for cell survival and have been implicated in the mitotic control. The telomeric protein Pin2/TRF1 controls telomere elongation and its expression is tightly regulated during cell cycle. We previously reported that overexpression of Pin2/TRF1 affects mitotic progression. However, the role of Pin2/TRF1 at the interface between cell division and cell survival remains to be determined. Here we show that overexpression of Pin2 induced apoptosis in cells containing short telomeres, but not in cells with long telomeres. Furthermore, before entering apoptosis, Pin2-expressing cells first accumulated in mitosis and strongly stained with the mitosis-specific MPM2 antibody. Moreover, Pin2-induced apoptosis is potentiated by arresting cells in mitosis, but suppressed by accumulating cells in G1. In addition, overexpression of Pin2 also resulted in activation of caspase-3, and its proapoptotic activity was significantly reduced by inhibition of caspase-3. These results indicate that up-regulation of Pin2/TRF1 can specifically induce entry into mitosis and apoptosis, likely via a mechanism related to activation of caspase-3. Significantly, we also found that, out of 51 human breast cancer tissues and 10 normal controls examined, protein levels of Pin2/TRF1 in tumors were significantly lower than in normal tissues, as detected by immunoblotting analysis and immunocytochemistry. Since down-regulation of Pin2/TRF1 allows cells to maintain long telomeres, these results suggest that down-regulation of Pin2/TRF1 may be important for cancer cells to extend their proliferative potential.},
}
@article {pmid11311583,
year = {2001},
author = {Kipling, D},
title = {Telomeres, replicative senescence and human ageing.},
journal = {Maturitas},
volume = {38},
number = {1},
pages = {25-37; discussion 37-8},
doi = {10.1016/s0378-5122(00)00189-4},
pmid = {11311583},
issn = {0378-5122},
mesh = {Aging/*genetics ; Animals ; *DNA Replication ; Disease Models, Animal ; Humans ; Mice ; Telomerase/*metabolism ; *Telomere ; },
abstract = {Ageing concerns the extracellular environment and cells that are either post-mitotic or capable of division during life. Primary human cells have a finite division capacity in culture before they enter a state of viable cell cycle arrest termed senescence. Cell division occurs during life in many tissues, either as part of normal tissue function or in response to tissue damage. The accumulation of cells at the end of their replicative lifespan in the elderly might contribute to aged tissue either because of a reduced ability to undergo proliferation or because of the known altered gene-expression patterns of senescent cells. This has been illustrated experimentally using a transgenic telomerase-negative mouse, which shows some premature ageing phenotypes. The mechanism whereby cells count divisions uses the gradual erosion of the ends of chromosomes (telomeres) with cell division caused by the repression of the telomere-maintenance enzyme telomerase in most human cells. Telomere erosion ultimately triggers replicative senescence in many cell types; this can be prevented experimentally by forcibly expressing telomerase. This extends the lifespan of normal human cells and those from progeroid syndromes such as Werner's. Telomere-driven senescence did not evolve to cause ageing, but is instead a by-product of a system devised to provide a tumour-suppression function, a concept that fits well with evolutionary arguments regarding trade-offs between somatic maintenance and reproduction. Work in the future will focus on the development of new animal models to critically address the quantitative significance of this ageing mechanism.},
}
@article {pmid11306799,
year = {2001},
author = {Mackie Ogilvie, C and Harrison, RH and Horsley, SW and Hodgson, SV and Kearney, L},
title = {A mitotically stable marker chromosome negative for whole chromosome libraries, centromere probes and chromosome specific telomere regions: a novel class of supernumerary marker chromosome?.},
journal = {Cytogenetics and cell genetics},
volume = {92},
number = {1-2},
pages = {69-73},
doi = {10.1159/000056871},
pmid = {11306799},
issn = {0301-0171},
mesh = {Centromere/*genetics ; Child, Preschool ; Chromosome Banding ; Chromosome Painting ; Chromosomes, Human/*genetics ; Chromosomes, Human, Pair 2/genetics ; DNA Probes ; Developmental Disabilities/genetics ; Gene Amplification ; Genetic Markers/*genetics ; Genome, Human ; *Genomic Library ; Humans ; Isochromosomes/genetics ; Karyotyping ; Lymphocytes ; Male ; Mitosis/*genetics ; Sensitivity and Specificity ; Silver Staining ; Telomere/*genetics ; },
abstract = {A two year-old child presented with mild developmental delay. On karyotype analysis, a supernumerary small marker chromosome (SMC) was found in all cells examined. This SMC was approximately the size of an isochromosome 18p, being symmetrical with a central constriction. C-banding and silver staining were negative and FISH with all chromosome-specific paints, centromere probes and telomere probes showed no hybridization to the SMC; telomere repeat sequences were however present on both arms. Comparative genomic hybridization showed no amplification of any chromosome region. Flow sorting of the SMC and reverse painting onto normal metaphase spreads showed no hybridization to any chromosome, whereas reverse painting onto the patient's own metaphases showed hybridization to the SMC only. This SMC may thus represent either a complex amplicon of different genomic regions, or a multifold amplification of a very small region, with a neocentromere comprising an active kinetochore but no alphoid DNA. Prognostic implications for the proband were difficult to assess due to the absence of reports of similar marker chromosomes in the literature.},
}
@article {pmid11304552,
year = {2001},
author = {Allsopp, RC and Cheshier, S and Weissman, IL},
title = {Telomere shortening accompanies increased cell cycle activity during serial transplantation of hematopoietic stem cells.},
journal = {The Journal of experimental medicine},
volume = {193},
number = {8},
pages = {917-924},
pmid = {11304552},
issn = {0022-1007},
support = {P01 DK053074/DK/NIDDK NIH HHS/United States ; CA42551/CA/NCI NIH HHS/United States ; DK53074/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Blotting, Southern ; Bone Marrow Cells/cytology ; Cell Cycle/*physiology ; Flow Cytometry ; G2 Phase ; *Hematopoietic Stem Cell Transplantation/methods ; Hematopoietic Stem Cells/*cytology/ultrastructure ; Humans ; Mice ; Mice, Inbred C57BL ; Mitosis ; Models, Biological ; S Phase ; Telomere/*genetics/*ultrastructure ; Time Factors ; Transplantation, Isogeneic/*physiology ; },
abstract = {Reactivation of telomerase and maintenance of telomere length can lead to the prevention of replicative senescence in some human somatic cells grown in vitro. To investigate whether telomere shortening might also play a role in the limitation of hematopoietic stem cell (HSC) division capacity in vivo, we analyzed telomere length during serial transplantation of murine HSCs. Southern blot analysis of telomere length in donor bone marrow cells revealed extensive shortening (approximately 7 kb) after just two rounds of HSC transplantation. The number of cycling HSCs increased after transplantation and remained elevated for at least 4 mo, while the frequency of HSCs in the bone marrow was completely regenerated by 2 mo after transplantation. Direct analysis of telomeres in HSCs by fluorescent in situ hybridization during serial transplantation also revealed a reduction in telomere size. Together, these data show that telomeres shorten during division of HSCs in vivo, and are consistent with the hypothesis that telomere shortening may limit the replicative capacity of HSCs.},
}
@article {pmid11302696,
year = {2001},
author = {Guiducci, C and Anglana, M and Wang, A and Bacchetti, S},
title = {Transient expression of wild-type or biologically inactive telomerase allows the formation of artificial telomeres in mortal human cells.},
journal = {Experimental cell research},
volume = {265},
number = {2},
pages = {304-311},
doi = {10.1006/excr.2001.5189},
pmid = {11302696},
issn = {0014-4827},
mesh = {Blotting, Western ; Cell Line ; Cell Line, Transformed ; Cell Transformation, Viral ; DNA-Binding Proteins ; Humans ; Plasmids/genetics/*metabolism ; *RNA ; Simian virus 40/genetics/metabolism ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; Trans-Activators/genetics/*metabolism ; Transfection ; },
abstract = {Telomere seeding, the formation of artificial telomeres, has been routinely successful in immortalized but not normal human cells. We compared seeding efficiencies in preimmortal and immortal SV40-transformed cells using plasmid telomeres with T(2)AG(3) tracts of 1600 and 3200 bp. Seeding occurred only in immortal cells, indicating that transformed preimmortal cells behave like normal cells vis à vis formation of new telomeres and that T-antigen inhibition of cellular checkpoints is insufficient to allow seeding. Telomerase is active in immortal but not preimmortal cells, which do not express the reverse transcriptase hTERT. Upon transient expression of hTERT, seeds with 1600 bp of T(2)AG(3) formed telomeres in preimmortal cells. Comparable seeding efficiencies were obtained with wild-type hTERT or the HA-tagged protein that is catalytically active but unable to maintain endogenous telomeres. No seeding occurred with catalytically inactive hTERT. Given that telomerase expression was transient and that longer seeds did not form telomeres in the absence of the enzyme, seeding may not be elicited merely by elongation of telomeric sequences. We propose that modification of the telomeric terminus by telomerase may contribute to telomere seeding by leading to formation of a structure that impedes rejoining of this terminus with chromosomal sequences.},
}
@article {pmid11302695,
year = {2001},
author = {Chen, QM and Prowse, KR and Tu, VC and Purdom, S and Linskens, MH},
title = {Uncoupling the senescent phenotype from telomere shortening in hydrogen peroxide-treated fibroblasts.},
journal = {Experimental cell research},
volume = {265},
number = {2},
pages = {294-303},
doi = {10.1006/excr.2001.5182},
pmid = {11302695},
issn = {0014-4827},
mesh = {Blotting, Northern ; Cell Line ; Cell Size ; Cellular Senescence/genetics/*physiology ; Clusterin ; Collagenases/metabolism ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclin-Dependent Kinases/*antagonists &amp; inhibitors/metabolism ; Cyclins/metabolism ; Fibroblasts/*drug effects ; Glycoproteins/metabolism ; Humans ; Hydrogen Peroxide/*pharmacology ; Molecular Chaperones/metabolism ; Oxidants/*pharmacology ; Phenotype ; RNA, Ribosomal, 18S/metabolism ; Telomere/*metabolism/ultrastructure ; },
abstract = {Normal human cells have a limited replicative potential and inevitably reach replicative senescence in culture. Replicatively senescent cells show multiple molecular changes, some of which are related to the irreversible growth arrest in culture, whereas others resemble the changes occurring during the process of aging in vivo. Telomeres shorten as a result of cell replication and are thought to serve as a replicometer for senescence. Recent studies show that young cells can be induced to develop features of senescence prematurely by damaging agents, chromatin remodeling, and overexpression of ras or the E2F1 gene. Accelerated telomere shortening is thought to be a mechanism of premature senescence in some models. In this work, we test whether the acquisition of a senescent phenotype after mild-dose hydrogen peroxide (H(2)O(2)) exposure requires telomere shortening. Treating young HDFs with 150 microM H(2)O(2) once or 75 microM H(2)O(2) twice in 2 weeks causes long-term growth arrest, an enlarged morphology, activation of senescence-associated beta-galactosidase, and elevated expression of collagenase and clusterin mRNAs. No significant telomere shortening was observed with H(2)O(2) at doses ranging from 50 to 200 microM. Weekly treatment with 75 microM H(2)O(2) also failed to induce significant telomere shortening. Failure of telomere shortening correlated with an inability to elevate p16 protein or mRNA in H(2)O(2)-treated cells. In contrast, p21 mRNA was elevated over 40-fold and remained at this level for at least 2 weeks after a pulse treatment of H(2)O(2). The role of cell cycle checkpoints centered on p21 in premature senescence induced by H(2)O(2) is discussed here.},
}
@article {pmid11298602,
year = {2001},
author = {Lee, JJ and Kook, H and Chung, IJ and Na, JA and Park, MR and Hwang, TJ and Kwak, JY and Sohn, SK and Kim, HJ},
title = {Telomere length changes in patients with aplastic anaemia.},
journal = {British journal of haematology},
volume = {112},
number = {4},
pages = {1025-1030},
doi = {10.1046/j.1365-2141.2001.02669.x},
pmid = {11298602},
issn = {0007-1048},
mesh = {Adolescent ; Adult ; Aged ; Anemia, Aplastic/*genetics/therapy ; Antilymphocyte Serum/therapeutic use ; Blotting, Southern ; Case-Control Studies ; Child ; Child, Preschool ; Cyclosporine/therapeutic use ; Hematopoietic Stem Cells/*ultrastructure ; Humans ; Immunosuppressive Agents/therapeutic use ; Logistic Models ; Lymphocytes/immunology ; Middle Aged ; Statistics, Nonparametric ; Telomere/*ultrastructure ; },
abstract = {To investigate telomere changes in patients with aplastic anaemia (AA) and clinical factors influencing the telomere dynamics, telomere length (TL) was measured in peripheral blood mononuclear cells using Southern blot analysis of 42 patients with AA and 39 healthy normal controls. Nineteen patients received supportive treatment only, while the remaining 23 patients received immunosuppressive therapy with anti-thymocyte globulin or anti-lymphocyte globulin +/- cyclosporin A. In AA patients, TL was on average 1.41 kb shorter than that of age-matched normal controls (P < 0.001). In patients treated with immunosuppression, the mean TL of non-responders was significantly shorter than that of age-matched normal controls (P < 0.001), while no difference in TL was detected in responders compared with controls. Positive correlation was observed between the extent of telomere shortening, the severity of neutropenia (P = 0.05) and the degree of mean corpuscular volume elevation (P = 0.005) at the time of the study. However, there was no correlation with time elapsed since diagnosis (P = 0.214). These findings suggest that haematopoietic stem cells in patients with AA rapidly lose TL at the onset of the disease. The TL shortening may reflect the severity of impairment of haematopoiesis.},
}
@article {pmid11294644,
year = {2001},
author = {Oikawa, S and Tada-Oikawa, S and Kawanishi, S},
title = {Site-specific DNA damage at the GGG sequence by UVA involves acceleration of telomere shortening.},
journal = {Biochemistry},
volume = {40},
number = {15},
pages = {4763-4768},
doi = {10.1021/bi002721g},
pmid = {11294644},
issn = {0006-2960},
mesh = {8-Hydroxy-2'-Deoxyguanosine ; Base Sequence/radiation effects ; Cell Line ; Chromatography, High Pressure Liquid ; *DNA Damage ; DNA-Formamidopyrimidine Glycosylase ; Deoxyguanosine/*analogs &amp; derivatives/biosynthesis/radiation effects ; Electrochemistry ; Fibroblasts/physiology/radiation effects ; Guanine/*radiation effects ; HL-60 Cells ; Humans ; Light ; N-Glycosyl Hydrolases/physiology ; Photosensitizing Agents/pharmacology ; Riboflavin/physiology ; Telomere/*genetics/metabolism/*radiation effects ; *Ultraviolet Rays ; },
abstract = {Telomere shortening is associated with cellular senescence. We investigated whether UVA, which contributes to photoaging, accelerates telomere shortening in human cultured cells. The terminal restriction fragment (TRF) from WI-38 fibroblasts irradiated with UVA (365-nm light) decreased with increasing irradiation dose. Furthermore, UVA irradiation dose-dependently increased the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in both WI-38 fibroblasts and HL-60 cells. To clarify the mechanism of the acceleration of telomere shortening, we investigated site-specific DNA damage induced by UVA irradiation in the presence of endogenous photosensitizers using (32)P 5'-end-labeled DNA fragments containing the telomeric oligonucleotide (TTAGGG)(4). UVA irradiation with riboflavin induced 8-oxodG formation in the DNA fragments containing telomeric sequence, and Fpg protein treatment led to chain cleavages at the central guanine of 5'-GGG-3' in telomere sequence. The amount of 8-oxodG formation in DNA fragment containing telomere sequence [5'-CGC(TTAGGG)(7)CGC-3'] was approximately 5 times more than that in DNA fragment containing nontelomere sequence [5'-CGC(TGTGAG)(7)CGC-3']. Catalase did not inhibit this oxidative DNA damage, indicating no or little participation of H(2)O(2) in DNA damage. These results indicate that the photoexcited endogenous photosensitizer specifically oxidizes the central guanine of 5'-GGG-3' in telomere sequence to produce 8-oxodG probably through an electron-transfer reaction. It is concluded that the site-specific damage in telomere sequence induced by UVA irradiation may participate in the increase of telomere shortening rate.},
}
@article {pmid11293796,
year = {2000},
author = {Mason, JM and Haoudi, A and Konev, AY and Kurenova, E and Walter, MF and Biessmann, H},
title = {Control of telomere elongation and telomeric silencing in Drosophila melanogaster.},
journal = {Genetica},
volume = {109},
number = {1-2},
pages = {61-70},
doi = {10.1023/a:1026548503320},
pmid = {11293796},
issn = {0016-6707},
support = {GM-56729/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Gene Expression Regulation/genetics ; *Gene Silencing ; Heterochromatin/genetics ; *Telomere ; },
abstract = {Chromosome length in Drosophila is maintained by the targeted transposition of two families of non-LTR retrotransposons, HeT-A and TART. Although the rate of transposition to telomeres is sufficient to counterbalance loss from the chromosome ends due to incomplete DNA replication, transposition as a mechanism for elongating chromosome ends raises the possibility of damaged or deleted telomeres, because of its stochastic nature. Recent evidence suggests that HeT-A transposition is controlled at the levels of transcription and reverse transcription. HeT-A transcription is found primarily in mitotically active cells, and transcription of a w+ reporter gene inserted into the 2L telomere increases when the homologous telomere is partially or completely deleted. The terminal HeT-A array may be important as a positive regulator of this activity in cis, and the subterminal satellite appears to be an important negative regulator in cis. A third chromosome modifier has been identified that increases the level of reverse transcriptase activity on a HeT-A RNA template and greatly increases the transposition of HeT-A. Thus, the host appears to play a role in transposition of these elements. Taken together, these results suggest that control of HeT-A transposition is more complex than previously thought.},
}
@article {pmid11293794,
year = {2000},
author = {Pardue, ML and Debaryshe, PG},
title = {Drosophila telomere transposons: genetically active elements in heterochromatin.},
journal = {Genetica},
volume = {109},
number = {1-2},
pages = {45-52},
doi = {10.1023/a:1026540301503},
pmid = {11293794},
issn = {0016-6707},
support = {GM 50315/GM/NIGMS NIH HHS/United States ; GM57006/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *DNA Transposable Elements ; Drosophila/*genetics ; Heterochromatin/*genetics ; Promoter Regions, Genetic ; *Telomere ; },
abstract = {In Drosophila two non-LTR retrotransposons, HeT-A and TART, offer a novel experimental system for the study of heterochromatin. These elements, found only in heterochromatin, form Drosophila telomeres by repeated transposition onto chromosome ends. Their transposition yields arrays of repeats larger and more irregular than the repeats produced by telomerase; nevertheless, the transpositions are, in principle, equivalent to the telomere-building action of telomerase. The identification of the HeT-A promoter has given the first view of the molecular structure of a promoter active in heterochromatin. These telomere-specific elements are unusual in having a large amount of non-coding sequence. Like many other heterochromatic sequences, the HeT-A non-coding sequence has a repetitive organization strongly conserved within the species, although the sequence itself can undergo significant change between species (a typical example of concerted evolution). Such heterochromatic sequences could be important for the cell, perhaps as docking stations for essential proteins.},
}
@article {pmid11286945,
year = {2001},
author = {Neumann, A and Fasching, C},
title = {Pictures in Molecular Medicine: Telomeres copying telomeres in human cells.},
journal = {Trends in molecular medicine},
volume = {7},
number = {4},
pages = {184},
doi = {10.1016/s1471-4914(01)01964-5},
pmid = {11286945},
issn = {1471-4914},
mesh = {Animals ; Cell Line ; Humans ; Mice ; Microscopy, Fluorescence ; Telomere/*physiology/*ultrastructure ; Transcription, Genetic ; },
}
@article {pmid11283188,
year = {2001},
author = {Martin, JA and Buckwalter, JA},
title = {Telomere erosion and senescence in human articular cartilage chondrocytes.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {56},
number = {4},
pages = {B172-9},
doi = {10.1093/gerona/56.4.b172},
pmid = {11283188},
issn = {1079-5006},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*physiology ; Cartilage, Articular/*pathology/*physiopathology ; Cells, Cultured ; Child ; Child, Preschool ; Chondrocytes/*pathology/*physiology ; Humans ; Infant ; Middle Aged ; Mitosis ; Telomere/*genetics ; Thymidine/metabolism ; beta-Galactosidase/metabolism ; },
abstract = {Aging and the degeneration of articular cartilage in osteoarthritis are distinct processes, but a strong association exists between age and the incidence and prevalence of osteoarthritis. We hypothesized that this association is due to in vivo replicative senescence, which causes age-related declines in the ability of chondrocytes to maintain articular cartilage. For this hypothesis to be tested, senescence-associated markers were measured in human articular chondrocytes from donors ranging in age from 1 to 87 years. These measures included in situ staining for senescence-associated beta-galactosidase activity, (3)H-thymidine incorporation assays for mitotic activity, and Southern blots for telomere length determinations. We found that senescence-associated beta-galactosidase activity increased with age, whereas both mitotic activity and mean telomere length declined. These findings indicate that chondrocyte replicative senescence occurs in vivo and support the hypothesis that the association between osteoarthritis and aging is due in part to replicative senescence. The data also imply that transplantation procedures performed to restore damaged articular surfaces could be limited by the inability of older chondrocytes to form new cartilage after transplantation.},
}
@article {pmid11280022,
year = {2001},
author = {Shay, JW and Wright, WE},
title = {Ageing and cancer: the telomere and telomerase connection.},
journal = {Novartis Foundation symposium},
volume = {235},
number = {},
pages = {116-25; discussion 125-9, 146-9},
pmid = {11280022},
issn = {1528-2511},
mesh = {*Aging/genetics ; Animals ; Humans ; *Neoplasms/enzymology/genetics ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {Telomeres are repetitive DNA sequences at the ends of linear chromosomes. Telomerase, a cellular reverse transcriptase, helps stabilize telomere length in human stem, reproductive and cancer cells by adding TTAGGG repeats onto the telomeres. Each time a telomerase-negative cell divides some telomeric sequences are lost. When telomeres are short, cells enter an irreversible growth arrest state called replicative senescence. In most instances cells become senescent before they can become cancerous, thus the growth arrest induced by short telomeres may be a potent anti-cancer mechanism. Since most cancers express telomerase, maintenance of telomere stability is likely to be required for the long-term viability of tumours. Inhibition of telomerase results in gradual erosion of telomeres followed by cessation of proliferation or apoptosis, and thus may be a promising target for cancer therapy. Introduction of the telomerase catalytic protein component into telomerase-silent cells is sufficient to restore telomerase activity and extend cellular life span. However, cells with introduced telomerase are not cancer cells since they have not accumulated the other changes needed to become cancerous. This indicates that telomerase-induced telomere length manipulations may have utility for tissue engineering and for dissecting the molecular mechanisms underlying genetic diseases including cancer.},
}
@article {pmid11276397,
year = {2001},
author = {Aviv, A and Harley, CB},
title = {How long should telomeres be?.},
journal = {Current hypertension reports},
volume = {3},
number = {2},
pages = {145-151},
pmid = {11276397},
issn = {1522-6417},
mesh = {*Aging ; Animals ; Cardiovascular Diseases/*genetics/*pathology ; Humans ; Mice ; Telomere/*genetics/*pathology ; },
abstract = {What began as a study of the "end-replication problem" took on a new dimension as it became clear that telomeres are a "molecular clock" of replication in human somatic cells. Here we review the biology of telomeres in vitro and in vivo, in mice and humans. We suggest that, in humans, telomeres are involved in the biology of aging and pathobiology of disorders of aging, including cancer and cardiovascular disease. We also propose that the underlying dynamics of telomere biology is in line with broad principles of evolutionary theories.},
}
@article {pmid11276244,
year = {2001},
author = {Lustig, AJ},
title = {Cdc13 subcomplexes regulate multiple telomere functions.},
journal = {Nature structural biology},
volume = {8},
number = {4},
pages = {297-299},
doi = {10.1038/86157},
pmid = {11276244},
issn = {1072-8368},
mesh = {*Antigens, Nuclear ; Cyclin B/*metabolism ; *DNA Helicases ; DNA-Binding Proteins/metabolism ; Ku Autoantigen ; Models, Genetic ; Nuclear Proteins/metabolism ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; Telomere/genetics/*metabolism ; },
}
@article {pmid11267974,
year = {2001},
author = {Ulaner, GA and Hu, JF and Vu, TH and Giudice, LC and Hoffman, AR},
title = {Tissue-specific alternate splicing of human telomerase reverse transcriptase (hTERT) influences telomere lengths during human development.},
journal = {International journal of cancer},
volume = {91},
number = {5},
pages = {644-649},
pmid = {11267974},
issn = {0020-7136},
support = {5T32CA09302/CA/NCI NIH HHS/United States ; 5T32GM07365/GM/NIGMS NIH HHS/United States ; GM07365/GM/NIGMS NIH HHS/United States ; },
mesh = {*Alternative Splicing ; DNA-Binding Proteins ; Gene Deletion ; Gestational Age ; Heart/embryology ; Humans ; Introns ; Kidney/embryology/enzymology ; Liver/embryology/enzymology ; Models, Genetic ; Myocardium/enzymology ; Phosphorylation ; Polymerase Chain Reaction ; Protein Processing, Post-Translational ; *RNA ; RNA, Messenger/metabolism ; RNA-Directed DNA Polymerase/chemistry ; Telomerase/genetics/*metabolism ; Telomere/metabolism/*physiology ; Time Factors ; Tissue Distribution ; },
abstract = {Direct genetic manipulations have shown that telomerase-mediated telomere elongation plays a key role in determining cellular replicative capacity and senescence. The mechanisms regulating the production of an active telomerase enzyme are still predominantly unknown, although roles for transcriptional control of hTERT, alternative-splicing of hTERT transcripts, and post-translational phosphorylation of hTERT protein have been advocated. Here we show that hTERT is alternatively spliced in specific patterns by different tissue types during human development. Alternative splicing often prohibits the expression of hTERT protein containing functional reverse transcriptase domains. In these instances, telomerase activity is absent, leading to shortening of telomeres. The specific pattern of hTERT mRNA variants in human development provides evidence that alternative splicing is non-random and participates in the regulation of telomerase activity.},
}
@article {pmid11266360,
year = {2001},
author = {Teo, SH and Jackson, SP},
title = {Telomerase subunit overexpression suppresses telomere-specific checkpoint activation in the yeast yku80 mutant.},
journal = {EMBO reports},
volume = {2},
number = {3},
pages = {197-202},
pmid = {11266360},
issn = {1469-221X},
mesh = {*Antigens, Nuclear ; *Cell Cycle Proteins ; Checkpoint Kinase 2 ; DNA Damage ; *DNA Helicases ; DNA-Binding Proteins/*genetics ; Fungal Proteins/*genetics ; Gene Expression ; Genes, Fungal ; Ku Autoantigen ; *Mutation ; Nuclear Proteins/*genetics ; Phosphorylation ; Protein Kinases/genetics/metabolism ; *Protein Serine-Threonine Kinases ; Protein Subunits ; *RNA ; Saccharomyces cerevisiae/*genetics/growth &amp; development/*metabolism ; *Saccharomyces cerevisiae Proteins ; Telomerase/chemistry/*genetics ; Telomere/*genetics/*metabolism ; Temperature ; },
abstract = {Ku is a conserved heterodimeric DNA-binding protein that plays critical roles in DNA repair and telomere homeostasis. In Saccharomyces cerevisiae, deletion of YKU70 or YKU80 results in an inability to grow at 37 degrees C. This is suppressed by overexpression of several components of telomerase (EST1, EST2 and TLC1). We show that overexpression of EST2 or TLC1 in yku80 mutants does not restore efficient DNA repair, or restore normal telomere function, as measured by telomere length, single-stranded G-rich strand or transcriptional silencing. Instead, yku80 mutants activate a Rad53p-dependent DNA-damage checkpoint at 37 degrees C and this is suppressed by overexpression of EST2 or TLC1. Indeed, deletion of genes required for Rad53p activation also suppresses the yku80 temperature sensitivity. These results suggest that activation of the DNA-damage checkpoint in yku mutants at 37 degrees C does not result from reduced telomere length per se, but reflects an alteration of the telomere structure that is recognized as damaged DNA.},
}
@article {pmid11264015,
year = {2001},
author = {Bar-Or, D and Thomas, GW and Rael, LT and Lau, EP and Winkler, JV},
title = {Asp-Ala-His-Lys (DAHK) inhibits copper-induced oxidative DNA double strand breaks and telomere shortening.},
journal = {Biochemical and biophysical research communications},
volume = {282},
number = {1},
pages = {356-360},
doi = {10.1006/bbrc.2001.4533},
pmid = {11264015},
issn = {0006-291X},
mesh = {Cell Line ; Copper/*antagonists &amp; inhibitors/pharmacology ; DNA/drug effects ; *DNA Damage ; Humans ; Oligopeptides/*pharmacology ; *Oxidative Stress ; Telomere/*drug effects ; },
abstract = {Both DNA and the telomeric sequence are susceptible to copper-mediated reactive oxygen species (ROS) damage, particularly damage attributed to hydroxyl radicals. In this study, ROS-induced DNA double strand breaks and telomere shortening were produced by exposure to copper and ascorbic acid. Asp-Ala-His-Lys (DAHK), a specific copper chelating tetrapeptide d-analog of the N-terminus of human albumin, attenuated DNA strand breaks in a dose dependent manner. d-DAHK, at a ratio of 4:1 (d-DAHKCu), provided complete protection of isolated DNA from double strand breaks and, at a ratio of 2:1 (d-DAHKCu), completely protected DNA in Raji cells exposed to copper/ascorbate. Southern blots of DNA treated with copper/ascorbate showed severe depletion and shortening of telomeres and Raji cell treated samples showed some conservation of telomere sequences. d-DAHK provided complete telomere length protection at a ratio of 2:1 (d-DAHKCu). The human albumin N-terminus analog, d-DAHK, protects DNA and telomeres against copper-mediated ROS damage and may be a useful therapeutic adjunct in ROS disease processes.},
}
@article {pmid11263175,
year = {1999},
author = {Gao, J and Shen, K and Lang, J},
title = {[Telomeres, telomerase and neoplasms].},
journal = {Zhonghua fu chan ke za zhi},
volume = {34},
number = {1},
pages = {53-55},
pmid = {11263175},
issn = {0529-567X},
mesh = {Endometrial Neoplasms/enzymology ; Female ; Humans ; Ovarian Neoplasms/enzymology ; Telomerase/biosynthesis/*metabolism ; Telomere/*physiology ; },
}
@article {pmid11259155,
year = {2001},
author = {Vulliamy, TJ and Knight, SW and Mason, PJ and Dokal, I},
title = {Very short telomeres in the peripheral blood of patients with X-linked and autosomal dyskeratosis congenita.},
journal = {Blood cells, molecules &amp; diseases},
volume = {27},
number = {2},
pages = {353-357},
doi = {10.1006/bcmd.2001.0389},
pmid = {11259155},
issn = {1079-9796},
mesh = {Adolescent ; Adult ; Aging/genetics ; Cell Cycle Proteins/genetics ; Child ; Child, Preschool ; Dyskeratosis Congenita/blood/*genetics/pathology ; Female ; Humans ; Male ; Nuclear Proteins/genetics ; Telomere/*genetics/ultrastructure ; },
abstract = {Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome in which patients undergo premature ageing and have a predisposition to malignancy. X-linked and autosomal (dominant and recessive) forms of the disease are recognized. The gene responsible for X-linked DC (DKC1) encodes a highly conserved protein called dyskerin that is believed to be essential in ribosome biogenesis and may also be involved in telomerase RNP assembly. Here we show that in X-linked DC, peripheral blood cells have dramatically reduced telomere lengths but normal levels of telomerase activity. We also find that subjects with autosomal DC have significantly shorter telomeres than age-matched normal controls suggesting that both forms of the disease are associated with rapid telomere shortening in hemopoietic stem cells. The further characterization of these genes will not only lead to a better understanding of the biology of DC but may also provide further insights into the maintenance of telomeres and the biology of aplastic anemia, ageing, and cancer.},
}
@article {pmid11253711,
year = {2000},
author = {Aragona, M and Pontoriero, A and Panetta, S and La Torre, I and La Torre, F},
title = {[The role of telomere-binding proteins in carcinogenesis].},
journal = {Minerva medica},
volume = {91},
number = {11-12},
pages = {299-304},
pmid = {11253711},
issn = {0026-4806},
mesh = {Cell Transformation, Neoplastic/genetics ; DNA-Binding Proteins/*physiology ; Humans ; Neoplasms/*etiology/genetics ; Telomerase/*physiology ; Telomere/*physiology ; Telomeric Repeat Binding Protein 1 ; },
abstract = {Normal somatic cells have a defined number of divisions, a limited capacity to proliferative. The telomeres, sequences of TTAGGG repeats at the ends of chromosomes, are considered the direct responsible of the control of the cellular cycle. In fact, the progressive shortening of telomere length at each cellular division, causes the entrance of the cells in a phase of senescence and than apoptosis. The maintenance of the length of telomeres is carried out through: the telomerase, a DNA polymerase reverse transcriptase that extends sequence TTAGGG repeats, or the alternative lengthening of telomeres (ALT), between which the adaptive mechanisms, inactivation of TRF1, a protein bound to the telomeres with the functions of inhibiting the telomerase activity and Tankirase-PARP, an enzymatic complex that ADP-ribosylate TRF1 and reduce its binding to DNA. The alteration of the mechanism of maintenance of the telomeres length (Telomerase, TRF1, Tankirase-PARP) may represent a first step toward the cell immortalization and cancerogenesis. Together with the alteration of the control mechanisms of the telomere length, also the cell genic contest should be considered. In fact, the oncogene activation and/or oncosuppressor gene inactivation (p53, Rb, ras) may allow or reduce the cancerogenesis. From this point of view, the telomerase, the TRF1, Tanchirase-PARP and other proteins involved in telomere length could be, in a near future, used as new indicators of prognosis and as markers for new anti-cancer therapies.},
}
@article {pmid11251891,
year = {2001},
author = {Aladdin, H and Larsen, CS and Schjerling, P and Møller, BK and Buhl, MR and Gerstoft, J and Pedersen, BK and Ullum, H},
title = {Effects of subcutaneous IL-2 therapy on telomere lengths in PBMC in HIV-infected patients.},
journal = {Scandinavian journal of immunology},
volume = {53},
number = {3},
pages = {315-319},
doi = {10.1046/j.1365-3083.2001.00876.x},
pmid = {11251891},
issn = {0300-9475},
mesh = {Adjuvants, Immunologic/administration &amp; dosage/therapeutic use ; Antiretroviral Therapy, Highly Active ; CD4 Lymphocyte Count ; CD4-Positive T-Lymphocytes/drug effects/ultrastructure ; CD8-Positive T-Lymphocytes/drug effects/ultrastructure ; Cell Division/drug effects ; HIV Infections/*drug therapy/*immunology ; Humans ; Immunologic Memory ; Injections, Subcutaneous ; Interleukin-2/administration &amp; dosage/*therapeutic use ; Leukocytes, Mononuclear/*drug effects/ultrastructure ; Lymphocyte Activation ; Telomere/*drug effects/ultrastructure ; },
abstract = {In this study we investigated the effect of interleukin-2 (IL-2) on mean terminal restriction fragment (TRF) lengths in peripheral blood mononuclear cells (PBMC). Ten human immunodeficiency virus (HIV)-infected individuals were included and IL-2 was administered subcutaneously with 3 x 106 IU three times a week for 24 weeks. Mean TRF length was decreased on average by 267 bp at week 4 (P = 0.03) and 286 bp at week 8 (P = 0.09). Individual TRF changes at weeks 12, 16, 20 and 24 were highly variable. However, in the 12 weeks following therapy, TRF lengths generally increased reaching baseline levels by the end of the study. At baseline, mean TRF lengths were positively correlated to the ratio of naïve and memory phenotype within both CD4+ and CD8+ cells. This study shows that IL-2 treatment induces transient shortened mean TRF lengths in PBMC from HIV-infected individuals, indicating that IL-2 enhances the lymphocyte count by peripheral proliferation or recruitment of memory T cells into the blood.},
}
@article {pmid11250070,
year = {2001},
author = {Takenaka, Y and Matsuura, T and Haga, N and Mitsui, Y},
title = {Expression of telomerase reverse transcriptase and telomere elongation during sexual maturation in Paramecium caudatum.},
journal = {Gene},
volume = {264},
number = {2},
pages = {153-161},
doi = {10.1016/s0378-1119(01)00337-7},
pmid = {11250070},
issn = {0378-1119},
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; DNA, Complementary/chemistry/genetics ; Gene Expression Regulation, Enzymologic ; Genes, Protozoan/genetics ; Molecular Sequence Data ; Paramecium/enzymology/*genetics/growth &amp; development ; Phylogeny ; RNA, Messenger/genetics/metabolism ; Sequence Alignment ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; Telomerase/*genetics ; Telomere/genetics/*metabolism ; Time Factors ; },
abstract = {Paramecium caudatum has a sexually immature period that lasts for about 60 fissions. To examine the possibility that telomere length is one of the determining factors of the duration of immaturity, we cloned the telomerase reverse transcriptase (TERT) gene from P. caudatum, and analyzed its expression levels at mRNA, telomerase activity, and telomere length during the course of clonal division. Paramecium TERT (Pc_TERT) cDNA encodes a basic protein of 107 kDa that harbors conserved RT motifs, T motif, CP motif, and N motif. Pc_TERT mRNA is expressed at very low levels only detectable by RT-PCR, but constitutively, during immature and mature periods, exhibiting abundant telomerase activity. No clear phase shift in Pc_TERT expression, telomerase activity, or telomere length was observed at the point of maturation in P. caudatum. Instead, the telomere elongates successively as cells divide in P. caudatum, although a close species, P. tetraurelia, was reported to keep the length constant. We discuss possible mechanisms for the expression of sexual activity associated with telomere length in P. caudatum.},
}
@article {pmid11248087,
year = {2001},
author = {Lee, KH and Rudolph, KL and Ju, YJ and Greenberg, RA and Cannizzaro, L and Chin, L and Weiler, SR and DePinho, RA},
title = {Telomere dysfunction alters the chemotherapeutic profile of transformed cells.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {98},
number = {6},
pages = {3381-3386},
pmid = {11248087},
issn = {0027-8424},
support = {5T32GM07491/GM/NIGMS NIH HHS/United States ; R01HD28317/HD/NICHD NIH HHS/United States ; T32 GM007491/GM/NIGMS NIH HHS/United States ; R01HD34880/HD/NICHD NIH HHS/United States ; K08AR02104-01/AR/NIAMS NIH HHS/United States ; },
mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Cell Line, Transformed ; Cisplatin/pharmacology ; Cyclin-Dependent Kinase Inhibitor p16/genetics/physiology ; Doxorubicin/pharmacology ; Etoposide/pharmacology ; Fluorouracil/pharmacology ; Mice ; Neoplasms/*drug therapy ; Proto-Oncogene Proteins c-myc/genetics ; RNA/genetics/*physiology ; Telomerase/genetics/*physiology ; Telomere/*physiology ; Tumor Suppressor Protein p53/genetics/physiology ; ras Proteins/genetics ; },
abstract = {Telomerase inhibition has been touted as a novel cancer-selective therapeutic goal based on the observation of high telomerase levels in most cancers and the importance of telomere maintenance in long-term cellular growth and survival. Here, the impact of telomere dysfunction on chemotherapeutic responses was assessed in normal and neoplastic cells derived from telomerase RNA null (mTERC(-/-)) mice. Telomere dysfunction, rather than telomerase per se, was found to be the principal determinant governing chemosensitivity specifically to agents that induced double-stranded DNA breaks (DSB). Enhanced chemosensitivity in telomere dysfunctional cells was linked to therapy-induced fragmentation and multichromosomal fusions, whereas telomerase reconstitution restored genomic integrity and chemoresistance. Loss of p53 function muted the cytotoxic effects of DSB-inducing agents in cells with telomere dysfunction. Together, these results point to the combined use of DSB-inducing agents and telomere maintenance inhibition as an effective anticancer therapeutic approach particularly in cells with intact p53-dependent checkpoint responses.},
}
@article {pmid11247672,
year = {2001},
author = {Xiang, Z and Morse, E and Hu, XL and Flint, J and Chi, HC and Grady, DL and Moyzis, RK and Riethman, HC},
title = {A sequence-ready map of the human chromosome 1q telomere.},
journal = {Genomics},
volume = {72},
number = {1},
pages = {105-107},
doi = {10.1006/geno.2000.6448},
pmid = {11247672},
issn = {0888-7543},
support = {HG00567/HG/NHGRI NIH HHS/United States ; },
mesh = {Chromosomes, Artificial, Bacterial ; Chromosomes, Artificial, Yeast ; Chromosomes, Human, Pair 1/*genetics ; *Contig Mapping ; Cosmids ; DNA Fingerprinting ; Expressed Sequence Tags ; Humans ; Molecular Sequence Data ; *Sequence Analysis, DNA ; Telomere/*genetics ; },
abstract = {A 260-kb half-YAC clone derived from human chromosome 1q was mapped at high resolution using cosmid subclone fingerprint analysis and was integrated with overlapping clones from the telomeric end of a separately derived 1q44 BAC contig to create a sequence-ready map extending to the molecular telomere of 1q. Analysis of 100 kb of sample sequences from across the 260-kb region encompassed by the half-YAC revealed the presence of EST sequence matches corresponding to 12 separate Unigene clusters and to 12 separate unclustered EST sequences. Low-copy subtelomeric repeats typical of many human telomere regions are present within the distal-most 30 kb of 1q. The previously isolated and radiation hybrid-mapped markers Bda84F03, 1QTEL019, and WI11861 localized at distances approximately 32, 88, and 99 kb, respectively, from the 1q terminus. This sequence-ready map permits high-resolution integration of genetic maps with the DNA sequences directly adjacent to the tip of human chromosome 1q and will enable telomeric closure of the human chromosome 1q DNA reference sequence by connecting the molecular 1q telomere to an internal BAC contig.},
}
@article {pmid11245223,
year = {2000},
author = {Rakotoarisoa, G and Hirai, Y and Go, Y and Kawamoto, Y and Shima, T and Koyama, N and Randrianjafy, A and Mora, R and Hirai, H},
title = {Chromosomal localization of 18S rDNA and telomere sequence in the aye-aye, Daubentonia madagascariensis.},
journal = {Genes &amp; genetic systems},
volume = {75},
number = {5},
pages = {299-303},
doi = {10.1266/ggs.75.299},
pmid = {11245223},
issn = {1341-7568},
mesh = {Animals ; *Chromosome Mapping ; Chromosomes/genetics ; DNA, Ribosomal/*genetics ; Evolution, Molecular ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Lemur/*genetics ; Male ; Nucleolus Organizer Region ; RNA, Ribosomal, 18S/*genetics ; Silver Staining ; Telomere/*genetics ; Transcription, Genetic ; },
abstract = {Chromosomal localization of 18S rDNA and telomere sequence was attempted on the chromosomes of the aye-aye (2n = 30) using fluorescence in situ hybridization (FISH) and primed in situ labeling (PRINS), respectively. The rDNA was localized at the tip or whole of the short arm of acrocentric chromosomes 13 and 14 in all spreads observed. However, post-FISH silver-nitrate (Ag) staining showed that transcriptional activity of the rRNA genes was variable, particularly in chromosome 14, which was most frequently negative in one homologue carrying the smaller copy number of rDNA. This observation supports, at the molecular cytogenetic level, previous data concerning the relationship between the copy number of rDNA and its trancriptional activity. On the other hand, telomere sequence was localized only at the telomeric region of all chromosomes, the so-called telomere-only pattern, a characteristic similar to that of the greater bushbaby. These data may provide information on the chromosomal evolution of the lemur, because locations of rDNA and telomere sequences frequently offer important clues in reconstruction of karyotype differentiation.},
}
@article {pmid11245015,
year = {1998},
author = {Wu, S and Liu, Z and Wu, B},
title = {[Telomere, telomerase and cancers].},
journal = {Zhonghua bing li xue za zhi = Chinese journal of pathology},
volume = {27},
number = {5},
pages = {386-387},
pmid = {11245015},
issn = {0529-5807},
mesh = {Animals ; Breast Neoplasms/metabolism ; Humans ; Stomach Neoplasms/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
}
@article {pmid11244953,
year = {1998},
author = {Zhang, F and Zhang, X and Fan, D},
title = {[Expression of telomere and telomerase in human primary gastric carcinoma].},
journal = {Zhonghua bing li xue za zhi = Chinese journal of pathology},
volume = {27},
number = {6},
pages = {429-432},
pmid = {11244953},
issn = {0529-5807},
mesh = {Adenocarcinoma/*metabolism/pathology ; Adult ; Biomarkers, Tumor ; Carcinoma, Signet Ring Cell/metabolism/pathology ; Female ; Humans ; Male ; Stomach Neoplasms/*metabolism/pathology ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {OBJECTIVE: To investigate the expression of telomere restriction fragments (TRF) and telomerase activity in human primary gastric carcinoma tissues and their role in tumor transformation and progression.<br><br>METHODS: The lengths of TRF and activity of telomerase were observed in 17 early gastric carcinoma tissues and 89 advanced gastric carcinoma tissues, using hybridization of nucleic acids directly in agarose gels and telomere repeat amplification protocol (TRAP) assays, corresponding normal gastric mucosa were used as controls.<br><br>RESULTS: The TRF lengths and telomerase activity in gastric cancer tissues were significantly shorter or higher than those in non-tumor mucosa, and the expression of telomerase activity in abnormal TRF tumor tissues was significantly higher than that in normal TRF tumour tissues. Alterations of TRF and telomerase activity in advanced tumour tissues were higher than those in early tumor tissues. Moreover, significant differences in TRF length were observed between well differentiated and poorly differentiated adenocarcinomas.<br><br>CONCLUSION: Abnormal TRF status and telomerase reactivation may correlate well with malignant progression of gastric cancer. Telomerase activity and TRF lengths may thus serve as an important additional marker for tumor diagnosis.},
}
@article {pmid11240642,
year = {2001},
author = {Walter, MF and Bozorgnia, L and Maheshwari, A and Biessmann, H},
title = {The rate of terminal nucleotide loss from a telomere of the mosquito Anopheles gambiae.},
journal = {Insect molecular biology},
volume = {10},
number = {1},
pages = {105-110},
doi = {10.1046/j.1365-2583.2001.00245.x},
pmid = {11240642},
issn = {0962-1075},
support = {AI36248/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Anopheles/*genetics ; *Genes, Insect ; *Telomere ; },
abstract = {Using a single copy pUChsneo transgene insertion at the Anopheles gambiae 2L telomere, this chromosome end was monitored by genomic Southern blots for forty-four mosquito generations. During this time, the chromosome end lost terminal nucleotides at an apparently constant rate of 55 bp/generation, which can be accounted for by incomplete DNA replication and does not imply exonuclease activity. No telomere elongation events were detected, suggesting that a previously described gene conversion event at this transgene does not occur very frequently. Moreover, no evidence for elongation by transposable elements was found, as described in Drosophila melanogaster. These results are consistent with the proposal that gene conversion between complex terminal satellite repeats that are present at natural telomeres, represents the major telomere elongation mechanism in A. gambiae. Such recombination events between repetitive sequences would occur more frequently than between the single copy pUChsneo transgene on the 2L homologues.},
}
@article {pmid11239396,
year = {2001},
author = {Pennock, E and Buckley, K and Lundblad, V},
title = {Cdc13 delivers separate complexes to the telomere for end protection and replication.},
journal = {Cell},
volume = {104},
number = {3},
pages = {387-396},
doi = {10.1016/s0092-8674(01)00226-4},
pmid = {11239396},
issn = {0092-8674},
support = {GM55867/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Blotting, Southern ; Chromosomes/metabolism ; Cyclin B/genetics/metabolism/*physiology ; DNA Mutational Analysis ; Fungal Proteins/genetics ; Humans ; Models, Biological ; Precipitin Tests ; Protein Binding ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/enzymology ; *Saccharomyces cerevisiae Proteins ; Telomerase/chemistry/genetics ; Telomere/*metabolism/*physiology ; },
abstract = {In Saccharomyces cerevisiae, the telomere binding protein Cdc13 mediates telomere replication by recruiting telomerase, and also performs an essential function in chromosome end protection. We show here that delivery of the Stn1 protein to the telomere, by fusing the DNA binding domain of Cdc13 (DBD(CDC13)) to Stn1, is sufficient to rescue the lethality of a cdc13 null strain and, hence, provide end protection. Telomere replication is still defective in this strain, but can be restored by delivering telomerase to the telomere as a DBD(CDC13)-telomerase fusion. These results establish Stn1 as the primary effector of chromosome end protection, whereas the principal function of Cdc13 is to provide a loading platform to recruit complexes that provide end protection and telomere replication.},
}
@article {pmid11238918,
year = {2001},
author = {Chen, Q and Ijpma, A and Greider, CW},
title = {Two survivor pathways that allow growth in the absence of telomerase are generated by distinct telomere recombination events.},
journal = {Molecular and cellular biology},
volume = {21},
number = {5},
pages = {1819-1827},
pmid = {11238918},
issn = {0270-7306},
support = {R01 GM043080/GM/NIGMS NIH HHS/United States ; GM43080/GM/NIGMS NIH HHS/United States ; },
mesh = {Blotting, Southern ; Cell Division ; DNA Repair ; DNA-Binding Proteins/genetics/physiology ; Epistasis, Genetic ; Fungal Proteins/genetics/physiology ; Genotype ; Models, Genetic ; Mutagenesis ; Mutation ; Phenotype ; Plasmids/metabolism ; Rad51 Recombinase ; Rad52 DNA Repair and Recombination Protein ; Saccharomyces cerevisiae/genetics/physiology ; *Saccharomyces cerevisiae Proteins ; Telomerase/*metabolism ; Telomere/metabolism/*physiology ; Time Factors ; },
abstract = {Yeast cells can survive in the absence of telomerase RNA, TLC1, by recombination-mediated telomere elongation. Two types of survivors, type I and type II, can be distinguished by their characteristic telomere patterns. RAD52 is essential for the generation of both types of survivors. Deletion of both RAD50 and RAD51 produces a phenotype similar to that produced by deletion of RAD52. Here we examined the effects of the RAD50 and the RAD51 epistasis groups as well as the RAD52 homologue, RAD59, on the types of survivors generated in the absence of telomerase. rad59 mutations completely abolished the ability to generate type II survivors, while rad50 mutations decreased the growth viability of type II survivors but did not completely eliminate their appearance. Mutations in RAD51, RAD54, and RAD57 had the converse affect: they eliminated the ability of cells to generate type I survivors in a tlc1 strain. The triple mutant, tlc1 rad51 rad59, was not able to generate survivors. Thus either type I or type II recombination pathways can allow cells to survive in the absence of telomerase; however, elimination of both pathways in a telomerase mutant leads to the inability to elongate telomeres and ultimately cell death.},
}
@article {pmid11237019,
year = {2001},
author = {Riethman, HC and Xiang, Z and Paul, S and Morse, E and Hu, XL and Flint, J and Chi, HC and Grady, DL and Moyzis, RK},
title = {Integration of telomere sequences with the draft human genome sequence.},
journal = {Nature},
volume = {409},
number = {6822},
pages = {948-951},
doi = {10.1038/35057180},
pmid = {11237019},
issn = {0028-0836},
mesh = {Chromosomes, Artificial, Bacterial ; Chromosomes, Artificial, Yeast ; *Genome, Human ; Human Genome Project ; Humans ; *Telomere ; },
abstract = {Telomeres are the ends of linear eukaryotic chromosomes. To ensure that no large stretches of uncharacterized DNA remain between the ends of the human working draft sequence and the ends of each chromosome, we would need to connect the sequences of the telomeres to the working draft sequence. But telomeres have an unusual DNA sequence composition and organization that makes them particularly difficult to isolate and analyse. Here we use specialized linear yeast artificial chromosome clones, each carrying a large telomere-terminal fragment of human DNA, to integrate most human telomeres with the working draft sequence. Subtelomeric sequence structure appears to vary widely, mainly as a result of large differences in subtelomeric repeat sequence abundance and organization at individual telomeres. Many subtelomeric regions appear to be gene-rich, matching both known and unknown expressed genes. This indicates that human subtelomeric regions are not simply buffers of nonfunctional 'junk DNA' next to the molecular telomere, but are instead functional parts of the expressed genome.},
}
@article {pmid11235188,
year = {2001},
author = {Takubo, K and Kaminishi, M},
title = {[Diseases of the digestive tract and telomere lengths: significance and problems of telomere measurement].},
journal = {Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology},
volume = {98},
number = {2},
pages = {144-150},
pmid = {11235188},
issn = {0446-6586},
mesh = {Aged ; Aged, 80 and over ; Digestive System Diseases/*genetics/pathology ; Esophageal Neoplasms/genetics/pathology ; Gastric Mucosa/pathology ; Humans ; Infant, Newborn ; Intestinal Mucosa/pathology ; Metaplasia ; Telomere/*pathology ; },
}
@article {pmid11231130,
year = {2001},
author = {Huang, P and Pryde, FE and Lester, D and Maddison, RL and Borts, RH and Hickson, ID and Louis, EJ},
title = {SGS1 is required for telomere elongation in the absence of telomerase.},
journal = {Current biology : CB},
volume = {11},
number = {2},
pages = {125-129},
doi = {10.1016/s0960-9822(01)00021-5},
pmid = {11231130},
issn = {0960-9822},
mesh = {Cell Survival/genetics ; DNA Helicases/*genetics/physiology ; Mutation ; RecQ Helicases ; Saccharomyces cerevisiae/enzymology/*genetics ; Saccharomyces cerevisiae Proteins ; Telomerase/*metabolism ; *Telomere ; },
abstract = {In S. cerevisiae, mutations in genes that encode telomerase components, such as the genes EST1, EST2, EST3, and TLC1, result in the loss of telomerase activity in vivo. Two telomerase-independent mechanisms can overcome the resulting senescence. Type I survival is characterized by amplification of the subtelomeric Y' elements with a short telomere repeat tract at the terminus. Type II survivors arise through the abrupt addition of long tracts of telomere repeats. Both mechanisms are dependent on RAD52 and on either RAD50 or RAD51. We show here that the telomere elongation pathway in yeast (type II) is dependent on SGS1, the yeast homolog of the gene products of Werner's (WRN) and Bloom's (BLM) syndromes. Survival in the absence of SGS1 and EST2 is dependent upon RAD52 and RAD51 but not RAD50. We propose that the RecQ family helicases are required for processing a DNA structure specific to eroding telomeres.},
}
@article {pmid11230697,
year = {2001},
author = {Riha, K and McKnight, TD and Griffing, LR and Shippen, DE},
title = {Living with genome instability: plant responses to telomere dysfunction.},
journal = {Science (New York, N.Y.)},
volume = {291},
number = {5509},
pages = {1797-1800},
doi = {10.1126/science.1057110},
pmid = {11230697},
issn = {0036-8075},
mesh = {Anaphase ; Apoptosis ; Arabidopsis/anatomy &amp; histology/genetics/growth &amp; development/*physiology ; Cell Differentiation ; Cell Division ; *Genome, Plant ; Meristem/anatomy &amp; histology/cytology/growth &amp; development ; Mitotic Index ; Mutation ; Phenotype ; Plant Leaves/anatomy &amp; histology/cytology/growth &amp; development ; Plant Structures/anatomy &amp; histology/cytology/growth &amp; development ; Telomerase/genetics/*metabolism ; Telomere/*physiology/ultrastructure ; },
abstract = {Loss of telomere function in metazoans results in catastrophic damage to the genome, cell cycle arrest, and apoptosis. Here we show that the mustard weed Arabidopsis thaliana can survive up to 10 generations without telomerase. The last five generations of telomerase-deficient plants endured increasing levels of cytogenetic damage, which was correlated with developmental anomalies in both vegetative and reproductive organs. Mutants ultimately arrested at a terminal vegetative state harboring shoot meristems that were grossly enlarged, disorganized, and in some cases, dedifferentiated into a callusoid mass. Unexpectedly, late-generation mutants had an extended life-span and remained metabolically active. The differences in plant and animal responses to dysfunctional telomeres may reflect the more plastic nature of plant development and genome organization.},
}
@article {pmid11230304,
year = {2001},
author = {Benetos, A and Okuda, K and Lajemi, M and Kimura, M and Thomas, F and Skurnick, J and Labat, C and Bean, K and Aviv, A},
title = {Telomere length as an indicator of biological aging: the gender effect and relation with pulse pressure and pulse wave velocity.},
journal = {Hypertension (Dallas, Tex. : 1979)},
volume = {37},
number = {2 Pt 2},
pages = {381-385},
doi = {10.1161/01.hyp.37.2.381},
pmid = {11230304},
issn = {1524-4563},
support = {HL47906/HL/NHLBI NIH HHS/United States ; },
mesh = {Age Factors ; *Aging ; Aortic Diseases/blood/*diagnosis ; Blood Pressure ; Body Mass Index ; DNA Restriction Enzymes ; Female ; Humans ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Multivariate Analysis ; Pulse ; Sex Factors ; Telomere/*chemistry/ultrastructure ; },
abstract = {Chronological age is the primary determinant of stiffness of central arteries. Increased stiffness is an independent indicator of cardiovascular risk. The aim of this study was to determine whether telomere length, a possible index of biological aging, provides a better account than chronological age for variation in arterial stiffness, evaluated by measuring pulse pressure and aortic pulse wave velocity. The study population included 193 French subjects (120 men, 73 women), with a mean age of 56+/-11 years, who were not on any antihypertensive medications. Telomere length was evaluated in white blood cells by measuring the mean length of the terminal restriction fragments. Age-adjusted telomere length was longer in women than in men (8.67+/-0.09 versus 8.37+/-0.07 kb; P=0.016). In both genders, telomere length was inversely correlated with age (P<0.01). Multivariate analysis showed that in men, but not in women, telomere length significantly contributed to pulse pressure and pulse wave velocity variations. In conclusion, telomere length provides an additional account to chronological age of variations in both pulse pressure and pulse wave velocity among men, such that men with shorter telomere length are more likely to exhibit high pulse pressure and pulse wave velocity, which are indices of large artery stiffness. The longer telomere length in women suggests that for a given chronological age, biological aging of men is more advanced than that of women.},
}
@article {pmid11230149,
year = {2001},
author = {Chandra, A and Hughes, TR and Nugent, CI and Lundblad, V},
title = {Cdc13 both positively and negatively regulates telomere replication.},
journal = {Genes &amp; development},
volume = {15},
number = {4},
pages = {404-414},
pmid = {11230149},
issn = {0890-9369},
support = {R01 GM055867/GM/NIGMS NIH HHS/United States ; GM55867/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatin/genetics ; Cyclin B/genetics/*physiology ; DNA Polymerase I/genetics ; Mutation ; Telomerase/metabolism ; *Telomere ; },
abstract = {Cdc13 is a single-strand telomeric DNA-binding protein that positively regulates yeast telomere replication by recruiting telomerase to chromosome termini through a site on Cdc13 that is eliminated by the cdc13-2 mutation. Here we show that Cdc13 has a separate role in negative regulation of telomere replication, based on analysis of a new mutation, cdc13-5. Loss of this second regulatory activity results in extensive elongation of the G strand of the telomere by telomerase, accompanied by a reduced ability to coordinate synthesis of the C strand. Both the cdc13-5 mutation and DNA polymerase alpha mutations (which also exhibit elongated telomeres) are suppressed by increased expression of the Cdc13-interacting protein Stn1, indicating that Stn1 coordinates action of the lagging strand replication complex with the regulatory activity of CDC13. However, the association between Cdc13 and Stn1 is abolished by cdc13-2, the same mutation that eliminates the interaction between Cdc13 and telomerase. We propose that Cdc13 participates in two regulatory steps-first positive, then negative-as a result of successive binding of telomerase and the negative regulator Stn1 to overlapping sites on Cdc13. Thus, Cdc13 coordinates synthesis of both strands of the telomere by first recruiting telomerase and subsequently limiting G-strand synthesis by telomerase in response to C-strand replication.},
}
@article {pmid11230148,
year = {2001},
author = {Ramirez, RD and Morales, CP and Herbert, BS and Rohde, JM and Passons, C and Shay, JW and Wright, WE},
title = {Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions.},
journal = {Genes &amp; development},
volume = {15},
number = {4},
pages = {398-403},
pmid = {11230148},
issn = {0890-9369},
support = {R01 AG001228/AG/NIA NIH HHS/United States ; AG01228/AG/NIA NIH HHS/United States ; },
mesh = {3T3 Cells ; Animals ; Cell Division ; Cell Line, Transformed ; Cellular Senescence/*genetics ; Culture Media ; Cyclin-Dependent Kinase Inhibitor p16/*biosynthesis ; Epithelial Cells/cytology ; Female ; Fibroblasts/cytology ; Humans ; Keratinocytes/cytology/enzymology ; Mammary Glands, Animal/cytology ; Mice ; Skin/cytology ; Telomerase/metabolism ; *Telomere ; },
abstract = {Telomere shortening is the mechanism underlying replicative aging in fibroblasts. A variety of reports now claim that inactivation of the p16(INK4a)/pRB pathway is required in addition to telomere maintenance for the immortalization of cells such as skin keratinocytes and breast epithelial cells. We here show that the premature growth arrest of these cell types can be explained by an inadequate culture environment. Providing mesenchymal/epithelial interactions by cultivating the telomerase-expressing cells on feeder layers avoids the growth arrest associated with increased p16(INK4a). These results do not support a telomere-independent mechanism of replicative aging.},
}
@article {pmid11230140,
year = {2001},
author = {Grandin, N and Damon, C and Charbonneau, M},
title = {Ten1 functions in telomere end protection and length regulation in association with Stn1 and Cdc13.},
journal = {The EMBO journal},
volume = {20},
number = {5},
pages = {1173-1183},
pmid = {11230140},
issn = {0261-4189},
mesh = {Alleles ; Cell Cycle ; Cell Cycle Proteins/metabolism ; Chromosomal Proteins, Non-Histone/genetics/isolation &amp; purification/*metabolism ; Cyclin B/genetics/*metabolism ; DNA Damage ; DNA-Binding Proteins/genetics/isolation &amp; purification/*metabolism ; Flow Cytometry ; Fungal Proteins/genetics/isolation &amp; purification/*metabolism ; Genes, Essential/genetics ; Models, Biological ; Mutation/genetics ; Phenotype ; Precipitin Tests ; Protein Binding ; Saccharomyces cerevisiae/cytology/enzymology/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/isolation &amp; purification/*metabolism ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; Two-Hybrid System Techniques ; },
abstract = {In Saccharomyces cerevisiae, Cdc13 has been proposed to mediate telomerase recruitment at telomere ends. Stn1, which associates with Cdc13 by the two-hybrid interaction, has been implicated in telomere maintenance. Ten1, a previously uncharacterized protein, was found to associate physically with both Stn1 and Cdc13. A binding defect between Stn1-13 and Ten1 was responsible for the long telomere phenotype of stn1-13 mutant cells. Moreover, rescue of the cdc13-1 mutation by STN1 was much improved when TEN1 was simultaneously overexpressed. Several ten1 mutations were found to confer telomerase-dependent telomere lengthening. Other, temperature-sensitive, mutants of TEN1 arrested at G(2)/M via activation of the Rad9-dependent DNA damage checkpoint. These ten1 mutant cells were found to accumulate single-stranded DNA in telomeric regions of the chromosomes. We propose that Ten1 is required to regulate telomere length, as well as to prevent lethal damage to telomeric DNA.},
}
@article {pmid11228547,
year = {2000},
author = {Fouladi, B and Sabatier, L and Miller, D and Pottier, G and Murnane, JP},
title = {The relationship between spontaneous telomere loss and chromosome instability in a human tumor cell line.},
journal = {Neoplasia (New York, N.Y.)},
volume = {2},
number = {6},
pages = {540-554},
pmid = {11228547},
issn = {1522-8002},
support = {R01 CA069044/CA/NCI NIH HHS/United States ; T32 ES007106/ES/NIEHS NIH HHS/United States ; ES07106/ES/NIEHS NIH HHS/United States ; R01 CA69044/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; Blotting, Southern ; Chromosome Aberrations ; Chromosomes, Human/*genetics ; DNA, Neoplasm/analysis ; Herpesvirus 1, Human/genetics/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Mitosis ; Molecular Sequence Data ; Plasmids/genetics ; Sequence Homology, Nucleic Acid ; Telomere/chemistry/*genetics ; Thymidine Kinase/genetics ; Transfection ; Tumor Cells, Cultured/physiology ; Urinary Bladder Neoplasms/*genetics ; },
abstract = {Chromosome instability plays an important role in cancer by promoting the alterations in the genome required for tumor cell progression. The loss of telomeres that protect the ends of chromosomes and prevent chromosome fusion has been proposed as one mechanism for chromosome instability in cancer cells, however, there is little direct evidence to support this hypothesis. To investigate the relationship between spontaneous telomere loss and chromosome instability in human cancer cells, clones of the EJ-30 tumor cell line were isolated in which a herpes simplex virus thymidine kinase (HSV-tk) gene was integrated immediately adjacent to a telomere. Selection for HSV-tk-deficient cells with ganciclovir demonstrated a high rate of loss of the end these "marked" chromosomes (10-4 events/cell per generation). DNA sequence and cytogenetic analysis suggests that the loss of function of the HSV-tk gene most often involves telomere loss, sister chromatid fusion, and prolonged periods of chromosome instability. In some HSV-tk-deficient cells, telomeric repeat sequences were added on to the end of the truncated HSV-tk gene at a new location, whereas in others, no telomere was detected on the end of the marked chromosome. These results suggest that spontaneous telomere loss is a mechanism for chromosome instability in human cancer cells.},
}
@article {pmid11225633,
year = {2001},
author = {Shay, JW and Wright, WE},
title = {Aging. When do telomeres matter?.},
journal = {Science (New York, N.Y.)},
volume = {291},
number = {5505},
pages = {839-840},
doi = {10.1126/science.1058546},
pmid = {11225633},
issn = {0036-8075},
mesh = {Animals ; Antioxidants/metabolism ; Cell Culture Techniques ; *Cell Division ; Cells, Cultured ; *Cellular Senescence ; Cyclin-Dependent Kinases/antagonists &amp; inhibitors/metabolism ; DNA Damage ; DNA Repair ; Humans ; Mutation ; Neoplasms/etiology/prevention &amp; control ; Oligodendroglia/*cytology/physiology ; Proteins/metabolism ; Rats ; Schwann Cells/*cytology/physiology ; Species Specificity ; Stem Cells/cytology/physiology ; Telomerase/metabolism ; Telomere/*physiology ; },
}
@article {pmid11221881,
year = {2001},
author = {McIlrath, J and Bouffler, SD and Samper, E and Cuthbert, A and Wojcik, A and Szumiel, I and Bryant, PE and Riches, AC and Thompson, A and Blasco, MA and Newbold, RF and Slijepcevic, P},
title = {Telomere length abnormalities in mammalian radiosensitive cells.},
journal = {Cancer research},
volume = {61},
number = {3},
pages = {912-915},
pmid = {11221881},
issn = {0008-5472},
mesh = {3T3 Cells ; Animals ; Breast Neoplasms/blood/genetics ; Chromosome Aberrations ; Chromosomes/*radiation effects ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia L5178/genetics ; Lymphocytes/radiation effects/ultrastructure ; Mice ; Mice, Inbred BALB C ; Mice, Inbred DBA ; Radiation Tolerance/*genetics ; Telomere/*physiology ; },
abstract = {Telomere lengths in radiosensitive murine lymphoma cells L5178Y-S and parental radioresistant L5178Y cells were measured by quantitative fluorescence in situ hybridization. Results revealed a 7-fold reduction in telomere length in radiosensitive cells (7 kb) in comparison with radioresistant cells (48 kb). Therefore, it was reasoned that telomere length might be used as a marker for chromosomal radiosensitivity. In agreement with this hypothesis, a significant inverse correlation between telomere length and chromosomal radiosensitivity was observed in lymphocytes from 24 breast cancer patients and 5 normal individuals. In contrast, no chromosomal radiosensitivity was observed in mouse cell lines that showed shortened telomeres, possibly reflecting differences in radiation responses between primary cells and established cell lines. Telomere length abnormalities observed in radiosensitive cells suggest that these two phenotypes may be linked.},
}
@article {pmid11215144,
year = {2000},
author = {Ishikawa, F},
title = {[Telomere heterochromatin in yeast].},
journal = {Seikagaku. The Journal of Japanese Biochemical Society},
volume = {72},
number = {10},
pages = {1231-1244},
pmid = {11215144},
issn = {0037-1017},
mesh = {DNA Replication ; DNA, Fungal/genetics ; Fungal Proteins/metabolism ; Gene Silencing ; Heterochromatin/*genetics ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/*genetics ; Telomerase/genetics ; Telomere/*genetics ; },
}
@article {pmid11196173,
year = {2001},
author = {Hoare, SF and Bryce, LA and Wisman, GB and Burns, S and Going, JJ and van der Zee, AG and Keith, WN},
title = {Lack of telomerase RNA gene hTERC expression in alternative lengthening of telomeres cells is associated with methylation of the hTERC promoter.},
journal = {Cancer research},
volume = {61},
number = {1},
pages = {27-32},
pmid = {11196173},
issn = {0008-5472},
mesh = {Biopsy ; Blotting, Northern ; *DNA Methylation ; Gene Expression Regulation, Enzymologic/genetics ; Gene Expression Regulation, Neoplastic/*genetics ; Humans ; Neoplasms/enzymology/genetics ; Promoter Regions, Genetic/*genetics ; RNA, Neoplasm/biosynthesis/*genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/biosynthesis/*genetics ; Telomere/*genetics ; Tumor Cells, Cultured ; },
abstract = {The immortal phenotype of most human cancers is attributable to telomerase expression. However, a number of immortal cell lines and tumors achieve telomere maintenance in the absence of telomerase via alternative mechanisms known as ALT (alternative lengthening of telomeres). Here we show that the promoter of the telomerase RNA gene (hTERC) is methylated in three of five ALT cell lines and is associated with a total absence of hTERC expression in the three lines. Treatment with 5-azacytidine in combination with trichostatin A resulted in partial demethylation of the hTERC promoter and expression of the gene. Partial methylation was detected in tumors (5%) and in immortal cell lines (27%). Cell lines with partial methylation express hTERC. Only in ALT cell lines does there appear to be a strong correlation between hTERC promoter hypermethylation and lack of hTERC expression.},
}
@article {pmid11185524,
year = {2000},
author = {Larsen, CJ},
title = {[Telomere anomalies, chromosome reshaping and cancer: an explanatory model of the formation of carcinomas].},
journal = {Bulletin du cancer},
volume = {87},
number = {10},
pages = {694-695},
pmid = {11185524},
issn = {0007-4551},
mesh = {Aging ; Animals ; Breeding ; Carcinoma/*genetics ; *Chromosome Aberrations ; Humans ; Lymphoma/genetics ; Mice ; Sarcoma/genetics ; Telomerase/*genetics/physiology ; Telomere/*genetics ; },
}
@article {pmid11179492,
year = {2001},
author = {Ohyashiki, JH and Hayashi, S and Yahata, N and Iwama, H and Ando, K and Tauchi, T and Ohyashiki, K},
title = {Impaired telomere regulation mechanism by TRF1 (telomere-binding protein), but not TRF2 expression, in acute leukemia cells.},
journal = {International journal of oncology},
volume = {18},
number = {3},
pages = {593-598},
doi = {10.3892/ijo.18.3.593},
pmid = {11179492},
issn = {1019-6439},
mesh = {Adolescent ; Adult ; Aged ; Child ; DNA-Binding Proteins/*genetics/metabolism ; Gene Expression ; Humans ; Leukemia, Myeloid, Acute/*genetics/metabolism ; Middle Aged ; *RNA ; RNA, Messenger/metabolism ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 1 ; Telomeric Repeat Binding Protein 2 ; Tumor Cells, Cultured ; },
abstract = {Telomere regulation is suggested to be an important mechanism in cellular proliferation and cellular senescence not only in normal diploid cells but also in neoplastic cells, including human leukemia cells. We studied the possible correlation among telomere length, telomerase (a ribonuclear protein that synthesizes the telemeres de novo) activity, hTERT (a catalytic subunit of telomerase) expression, and TRF1 and TRF2 (telomere DNA binding proteins) expression in human acute leukemia cells. The hTERT expression level was strongly associated with telomerase activity (P=0.0001), indicating that the expression level of the catalytic subunit (hTERT) regulates telomerase activity in human acute leukemia cells. TRF1 expression, which is believed to control telomere length, was significantly elevated in patients with acute lymphoblastic leukemia (ALL) (P=0.0232) compared to those in acute myeloid leukemia (AML); TRF1 expression tended to be higher in patients without telomere shortening (P=0.077) and in those with hTERT expression (P=0.055). This indicates that TRF1 may act to monitor telomere length under the condition of up-regulated telomerase activity in some neoplastic cells. In contrast, TRF2 expression in acute leukemia did not show any correlation with telomere parameters in this study. Although the precise regulation mechanism of telomere length is still uncertain, these results may suggest that regulation of telomere length is partially associated with TRF1 expression, whereas dysfunction of TRF1 expression may be speculated in a subset of acute leukemia.},
}
@article {pmid11179234,
year = {2001},
author = {Johnson, FB and Marciniak, RA and McVey, M and Stewart, SA and Hahn, WC and Guarente, L},
title = {The Saccharomyces cerevisiae WRN homolog Sgs1p participates in telomere maintenance in cells lacking telomerase.},
journal = {The EMBO journal},
volume = {20},
number = {4},
pages = {905-913},
pmid = {11179234},
issn = {0261-4189},
mesh = {DNA Helicases/*metabolism ; DNA-Binding Proteins/metabolism ; Humans ; Phenotype ; Rad51 Recombinase ; RecQ Helicases ; Saccharomyces cerevisiae/enzymology/genetics/*metabolism ; Saccharomyces cerevisiae Proteins ; Telomerase/*metabolism ; *Telomere ; },
abstract = {Werner syndrome (WS) is marked by early onset of features resembling aging, and is caused by loss of the RecQ family DNA helicase WRN. Precisely how loss of WRN leads to the phenotypes of WS is unknown. Cultured WS fibroblasts shorten their telomeres at an increased rate per population doubling and the premature senescence this loss induces can be bypassed by telomerase. Here we show that WRN co-localizes with telomeric factors in telomerase-independent immortalized human cells, and further that the budding yeast RecQ family helicase Sgs1p influences telomere metabolism in yeast cells lacking telomerase. Telomerase-deficient sgs1 mutants show increased rates of growth arrest in the G2/M phase of the cell cycle as telomeres shorten. In addition, telomerase-deficient sgs1 mutants have a defect in their ability to generate survivors of senescence that amplify telomeric TG1-3 repeats, and SGS1 functions in parallel with the recombination gene RAD51 to generate survivors. Our findings indicate that Sgs1p and WRN function in telomere maintenance, and suggest that telomere defects contribute to the pathogenesis of WS and perhaps other RecQ helicase diseases.},
}
@article {pmid11177705,
year = {2001},
author = {Aviv, A and Zahorodny, W},
title = {Telomeres: the time factor in essential hypertension.},
journal = {Current hypertension reports},
volume = {3},
number = {1},
pages = {33-35},
pmid = {11177705},
issn = {1522-6417},
mesh = {Humans ; Hypertension/genetics ; Telomere/*genetics ; Time Factors ; },
abstract = {Essential hypertension, particularly systolic hypertension, can be characterized as a disorder of aging. The diverse expressions of this disorder represent the interactions of a genetic script, the environment, chance, and a temporal factor. The temporal factor, namely the telomeres, is biological, intrinsic, and dynamic. Telomere length is heritable, is inversely related to pulse pressure, and can be modified by reactive oxygen species. The incorporation of a temporal factor into models of essential hypertension may provide a heretofore missing link explaining variations in age-dependent increase in pulse pressure.},
}
@article {pmid11175277,
year = {2000},
author = {Brown, J and Horsley, SW and Jung, C and Saracoglu, K and Janssen, B and Brough, M and Daschner, M and Beedgen, B and Kerkhoffs, G and Eils, R and Harris, PC and Jauch, A and Kearney, L},
title = {Identification of a subtle t(16;19)(p13.3;p13.3) in an infant with multiple congenital abnormalities using a 12-colour multiplex FISH telomere assay, M-TEL.},
journal = {European journal of human genetics : EJHG},
volume = {8},
number = {12},
pages = {903-910},
doi = {10.1038/sj.ejhg.5200545},
pmid = {11175277},
issn = {1018-4813},
mesh = {Abnormalities, Multiple/*genetics ; Chromosome Mapping ; Chromosome Painting ; *Chromosomes, Human, Pair 16 ; *Chromosomes, Human, Pair 19 ; Gene Deletion ; Humans ; *In Situ Hybridization, Fluorescence ; Infant ; Karyotyping ; Male ; Proteins/genetics ; Repressor Proteins/genetics ; TRPP Cation Channels ; *Telomere ; *Translocation, Genetic ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Proteins ; },
abstract = {There is increasing evidence that cytogenetically invisible chromosome rearrangements are an important cause of genetic disease. Clues to the chromosomal location of these rearrangements may be provided by a specific clinical diagnosis, which can then be investigated by targeted FISH or molecular studies. However, the phenotypic features of some microdeletion syndromes are difficult to recognise, particularly in infants. In addition, the presence of other chromosome aneuploidy may mask the typical clinical features. In the present study, the presence of tubers on cranial magnetic resonance imaging (MRI) of a 5-week-old infant prompted an investigation, by FISH, with probes from the tuberous sclerosis gene, TSC2. This and further FISH deletion mapping studies revealed a submicroscopic deletion encompassing the entire TSC2 gene and the adjacent PKD1 gene on one chromosome 16, confirming a del(16)(p13.3). Because of the large number of abnormal phenotypic features in this infant, we performed a 12-colour FISH assay (M-TEL) to screen for subtelomeric rearrangements involving the del(16p). The M-TEL assay revealed a cryptic der(16)t(16;19)(p13.3;p13.3). Further FISH with 19p and 19q subtelomeric probes demonstrated that this was derived from a balanced maternal t(16;19)(p13.3;p13.3). Importantly, 24-colour painting by multiplex FISH (M-FISH) failed to detect the translocation in either the infant or his mother. Based on our FISH mapping studies, we estimate the size of the trisomic region from 19p13.3 to be approximately 2 Mb, and the region of monosomy for 16p13.3 as 2.25 Mb. This case adds to the growing literature which indicates that many apparent chromosomal deletions are unbalanced translocations. The M-TEL assay provides a sensitive alternative to M-FISH for the detection of these subtle telomeric rearrangements.},
}
@article {pmid11172016,
year = {2001},
author = {Gallego, ME and White, CI},
title = {RAD50 function is essential for telomere maintenance in Arabidopsis.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {98},
number = {4},
pages = {1711-1716},
pmid = {11172016},
issn = {0027-8424},
mesh = {Arabidopsis/genetics ; *DNA-Binding Proteins ; Fungal Proteins/genetics/*physiology ; Mutagenesis ; Phenotype ; *Saccharomyces cerevisiae Proteins ; Telomere/*physiology ; },
abstract = {We have identified and characterized an Arabidopsis thaliana rad50 mutant plant containing a T-DNA insertion in the AtRAD50 gene and showing both meiotic and DNA repair defects. We report here that rad50/rad50 mutant cells show a progressive shortening of telomeric DNA relative to heterozygous rad50/RAD50 controls and that the mutant cell population rapidly enters a crisis, with the majority of the cells dying. Surviving rad50 mutant cells have longer telomeres than wild-type cells, indicating the existence in plants of an alternative RAD50-independent mechanism for telomere maintenance. These results report the role of a protein essential for double-strand break repair in telomere maintenance in higher eukaryotes.},
}
@article {pmid11170280,
year = {2001},
author = {Schwartz, JL and Jordan, R and Liber, H and Murnane, JP and Evans, HH},
title = {TP53-dependent chromosome instability is associated with transient reductions in telomere length in immortal telomerase-positive cell lines.},
journal = {Genes, chromosomes &amp; cancer},
volume = {30},
number = {3},
pages = {236-244},
pmid = {11170280},
issn = {1045-2257},
support = {CA-73931/CA/NCI NIH HHS/United States ; CA49696/CA/NCI NIH HHS/United States ; CA69044/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Transformed/*enzymology ; *Chromosome Aberrations ; Clone Cells ; DNA Replication/genetics ; Gene Expression Regulation, Neoplastic/genetics ; Genes, p53/*genetics ; Humans ; Mutation ; Telomerase/*biosynthesis/metabolism ; Telomere/*genetics ; Tumor Cells, Cultured/enzymology ; },
abstract = {Telomere shortening in telomerase-negative somatic cells leads to the activation of the TP53 protein and the elimination of potentially unstable cells. We examined the effect of TP53 gene expression on both telomere metabolism and chromosome stability in immortal, telomerase-positive cell lines. Telomere length, telomerase activity, and chromosome instability were measured in multiple clones isolated from three related human B-lymphoblast cell lines that vary in TP53 expression; TK6 cells express wild-type TP53, WTK1 cells overexpress a mutant form of TP53, and NH32 cells express no TP53 protein. Clonal variations in both telomere length and chromosome stability were observed, and shorter telomeres were associated with higher levels of chromosome instability. The shortest telomeres were found in WTK1- and NH32-derived cells, and these cells had 5- to 10-fold higher levels of chromosome instability. The primary marker of instability was the presence of dicentric chromosomes. Aneuploidy and other stable chromosome alterations were also found in clones showing high levels of dicentrics. Polyploidy was found only in WTK1-derived cells. Both telomere length and chromosome instability fluctuated in the different cell populations with time in culture, presumably as unstable cells and cells with short telomeres were eliminated from the growing population. Our results suggest that transient reductions in telomere lengths may be common in immortal cell lines and that these alterations in telomere metabolism can have a profound effect on chromosome stability.},
}
@article {pmid11169580,
year = {2001},
author = {Law, H and Lau, Y},
title = {Validation and development of quantitative flow cytometry-based fluorescence in situ hybridization for intercenter comparison of telomere length measurement.},
journal = {Cytometry},
volume = {43},
number = {2},
pages = {150-153},
pmid = {11169580},
issn = {0196-4763},
mesh = {Adult ; Blotting, Southern/statistics &amp; numerical data ; Calibration ; DNA, Neoplasm/analysis ; Fetal Blood/chemistry/cytology ; Flow Cytometry/*methods/statistics &amp; numerical data ; Humans ; In Situ Hybridization, Fluorescence/*methods/statistics &amp; numerical data ; Jurkat Cells ; K562 Cells ; Middle Aged ; Reproducibility of Results ; Restriction Mapping/methods ; Telomere/*chemistry ; },
abstract = {BACKGROUND: Telomeres are highly conserved repeats at the ends of chromosomes that maintain chromosome stability and reflect the replicative potential of cells. Telomere length can be determined by Southern blot hybridization or quantitative fluorescence in situ hybridization (Q-FISH). Recently, two flow cytometry-based (Flow) FISH protocols have been published.<br><br>METHODS: We compared the telomere length measured by Southern blotting and Flow FISH using standard beads to calibrate and quantify the fluorescence intensity.<br><br>RESULTS: The telomeric fluorescence of cord blood and peripheral blood mononuclear cells was similar to that reported by other studies. There was a linear relationship between the telomeric fluorescence determined by Flow FISH and the telomere fragment size determined by Southern blotting (r = 0.89; P < 0.001).<br><br>CONCLUSION: It is important to set up a center-specific curve and select appropriate cell lines for reference. This Q-Flow FISH protocol will facilitate the measurement of telomere length and allow more meaningful comparison of data (in standard fluorescence units or fragment size) between institutes.},
}
@article {pmid11163758,
year = {2001},
author = {Ren, JG and Xia, HL and Just, T and Dai, YR},
title = {Hydroxyl radical-induced apoptosis in human tumor cells is associated with telomere shortening but not telomerase inhibition and caspase activation.},
journal = {FEBS letters},
volume = {488},
number = {3},
pages = {123-132},
doi = {10.1016/s0014-5793(00)02377-2},
pmid = {11163758},
issn = {0014-5793},
mesh = {Apoptosis/*drug effects ; Caspase 3 ; Caspase Inhibitors ; Caspases/*metabolism ; Cell Line ; DNA Fragmentation/drug effects ; Enzyme Activation/drug effects ; Flow Cytometry ; Glutathione/metabolism/pharmacology ; HeLa Cells ; Humans ; Hydrogen Peroxide/metabolism ; Hydroxyl Radical/metabolism/*pharmacology ; In Situ Nick-End Labeling ; Membrane Potentials/drug effects ; Microscopy, Electron ; Mitochondria/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Telomerase/antagonists &amp; inhibitors/*metabolism ; Telomere/chemistry/*drug effects/*metabolism/ultrastructure ; },
abstract = {Reactive oxygen species (ROS) have been found to trigger apoptosis in tumor cells. At the same time, telomerase is found to be associated with malignancy and reduced apoptosis. However little is known about the linkage between ROS such as *OH and telomerase/telomere. To address the interrelations between *OH and telomerase/telomere in tumor cell killing, HeLa, 293 and MW451 cells were induced to undergo apoptosis with *OH radicals generated via Fe(2+)-mediated Fenton reactions (0.1 mM FeSO(4) plus 0.3-0.9 mM H2O2) and telomerase activity, telomere length were measured during apoptosis. We found that during *OH-induced apoptosis, telomere shortening took place while no changes in telomerase activity were observed. Our results suggest that *OH-induced telomere shortening is not through telomerase inhibition but possibly a direct effect of *OH on telomeres themselves indicating that telomere shortening but not telomerase inhibition is the primary event during *OH-induced apoptosis. Strikingly, we also found that *OH-induced apoptosis in HeLa cells is caspase-3-independent but is associated with reduction of mitochondrial transmembrane potential. Our results indicate that *OH triggers apoptotic tumor cell death through a telomere-related, caspase-independent pathway.},
}
@article {pmid11162914,
year = {2001},
author = {Tan, Z},
title = {Simulated shortening of proliferation-restricting telomeres during clonal proliferation and senescence of human cells.},
journal = {Experimental gerontology},
volume = {36},
number = {1},
pages = {89-97},
doi = {10.1016/s0531-5565(00)00185-6},
pmid = {11162914},
issn = {0531-5565},
mesh = {Cell Division/physiology ; *Cell Physiological Phenomena ; Cells/*cytology ; Cellular Senescence/physiology ; *Computer Simulation ; Humans ; *Models, Biological ; Telomere/*physiology ; },
abstract = {In the absence of telomerase or other mechanisms to maintain their length, telomeres in human cells shorten at each round of cell division. This has been suggested to ultimately cause cell cycle exit when a critical telomere length is reached, leading to replicative senescence of the cell. At present, it is not clear whether the division potential of human cells is limited by the overall shortening of telomeres at all chromosomes or the shortening of specific telomeres on certain particular chromosomes. By computer simulations, my previous work has suggested that if the telomere theory is correct, the shortening of only a few, most likely two, telomeres might be preferentially involved in restricting the division of human cells. In this work, the length dynamics of individual telomeres in simulated cell clones were examined over their life span. It is shown that if the shortening of only two telomeres is responsible for restricting the proliferation of a cell, these two specific telomeres will shorten at different rates and have different length distributions from those of the rest telomeres. The unique pattern of length dynamics associated with the proliferation-restricting telomeres (PRT) provides a possibility of experimentally identifying these particular telomeres in human cells.},
}
@article {pmid11162541,
year = {2001},
author = {Krutilina, RI and Oei, S and Buchlow, G and Yau, PM and Zalensky, AO and Zalenskaya, IA and Bradbury, EM and Tomilin, NV},
title = {A negative regulator of telomere-length protein trf1 is associated with interstitial (TTAGGG)n blocks in immortal Chinese hamster ovary cells.},
journal = {Biochemical and biophysical research communications},
volume = {280},
number = {2},
pages = {471-475},
doi = {10.1006/bbrc.2000.4143},
pmid = {11162541},
issn = {0006-291X},
mesh = {Animals ; Base Sequence ; Binding Sites ; CHO Cells ; Cell Line ; Cricetinae ; DNA-Binding Proteins/genetics/*metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Interphase ; Protein Binding ; Recombinant Fusion Proteins/metabolism ; Repetitive Sequences, Nucleic Acid/*genetics ; Telomere/*genetics/*metabolism ; Telomeric Repeat Binding Protein 1 ; Transfection ; Tumor Cells, Cultured ; },
abstract = {Telomeres of mammalian chromosomes are composed of long tandem repeats (TTAGGG)n which bind in a sequence-specific manner two proteins-TRF1 and TRF2. In human somatic cells both proteins are mostly associated with telomeres and TRF1 overexpression resulting in telomere shortening. However, chromosomes of some mammalian species, e.g., Chinese hamster, have large interstitial blocks of (TTAGGG)n sequence (IBTs) and the blocks are involved in radiation-induced chromosome instability. In normal somatic cells of these species chromosomes are stable, indicating that the IBTs are protected from unequal homologous recombination. In this study we expressed V5-epitope or green fluorescent protein (GFP)-tagged human TRF1 in different lines of mammalian cells and analyzed distribution of the fusion proteins in interphase nucleus. As expected, transient transfection of human (A549) or African green monkey cells with GFP-N-TRF1 or TRF1-C-V5 plasmids resulted in the appearance in interphase nuclei of multiple faint nuclear dots containing GFP or V5 epitope which we believe to represent telomeres. Transfection of immortalized Chinese hamster ovary (CHO) cell line K1 which have extremely short telomeres with GFP-N-TRF1 plasmid leads to the appearance in interphase nuclei of large GFP bodies corresponding in number to the number of IBTs in these cells. Simultaneous visualization of GFP and IBTs in interphase nuclei of transfected CHO-K1 cells showed colocalization of both signals indicating that expressed TRF1 actually associates with IBTs. These results suggest that TRF1 may serve as general sensor of (TTAGGG)n repeats controlling not only telomeres but also interstitial (TTAGGG)n sequences.},
}
@article {pmid11161011,
year = {2001},
author = {Cowan, CR and Carlton, PM and Cande, WZ},
title = {The polar arrangement of telomeres in interphase and meiosis. Rabl organization and the bouquet.},
journal = {Plant physiology},
volume = {125},
number = {2},
pages = {532-538},
doi = {10.1104/pp.125.2.532},
pmid = {11161011},
issn = {0032-0889},
mesh = {Cell Cycle/*physiology ; Interphase ; Meiosis ; Plant Cells ; Plant Growth Regulators/chemistry/metabolism ; Plant Proteins/metabolism/*ultrastructure ; Plants/ultrastructure ; Telomere/*ultrastructure ; },
}
@article {pmid11160907,
year = {2001},
author = {Kanaori, K and Shibayama, N and Gohda, K and Tajima, K and Makino, K},
title = {Multiple four-stranded conformations of human telomere sequence d(CCCTAA) in solution.},
journal = {Nucleic acids research},
volume = {29},
number = {3},
pages = {831-840},
pmid = {11160907},
issn = {1362-4962},
mesh = {Base Sequence ; DNA/*chemistry/genetics ; Humans ; Magnetic Resonance Spectroscopy/methods ; *Nucleic Acid Conformation ; Oligonucleotides/chemistry/genetics ; Telomere/*genetics ; Temperature ; Thermodynamics ; },
abstract = {By detailed NMR analysis of a human telomere repeating unit, d(CCCTAA), we have found that three distinct tetramers, each of which consists of four symmetric single-strands, slowly exchange in a slightly acidic solution. Our new finding is a novel i-motif topology (T:-form) where T4 is intercalated between C1 and C2 of the other duplex. The other two tetramers have a topology where C1 is intercalated between C2 and C3 of the other parallel duplex, resulting in the non-stacking T4 residues (R-form), and a topology where C1 is stacked between C3 and T4 of the other duplex (S:-form). From the NMR denaturation profile, the R-form is the most stable of the three structures in the temperature range of 15-50 degrees C, the S:-form the second and the T:-form the least stable. The thermodynamic parameters indicate that the T-form is the most enthalpically driven and entropically opposed, and its population is increased with decreasing temperature. The T-form structure determined by restrained molecular dynamics calculation suggests that inter-strand van der Waals contacts in the narrow grooves should contribute to the enthalpic stabilization of the T-form.},
}
@article {pmid11159514,
year = {2001},
author = {Brümmendorf, TH and Maciejewski, JP and Mak, J and Young, NS and Lansdorp, PM},
title = {Telomere length in leukocyte subpopulations of patients with aplastic anemia.},
journal = {Blood},
volume = {97},
number = {4},
pages = {895-900},
doi = {10.1182/blood.v97.4.895},
pmid = {11159514},
issn = {0006-4971},
support = {AI29524/AI/NIAID NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aging/genetics ; Anemia, Aplastic/classification/drug therapy/genetics/*pathology ; Child ; Child, Preschool ; Drug Resistance ; Female ; Flow Cytometry ; Granulocytes/classification/*ultrastructure ; Hemoglobinuria, Paroxysmal/genetics/*pathology ; Humans ; Immunosuppressive Agents/therapeutic use ; In Situ Hybridization, Fluorescence ; Infant ; Male ; Middle Aged ; Telomere/*ultrastructure ; },
abstract = {In most human cells, the average length of telomere repeats at the ends of chromosomes provides indirect information about their mitotic history. To study the turnover of stem cells in patients with bone marrow failure syndromes, the telomere length in peripheral blood granulocytes and lymphocytes from patients with aplastic anemia (AA, n = 56) and hemolytic paroxysmal nocturnal hemoglobinuria (n = 6) was analyzed relative to age-matched controls by means of fluorescence in situ hybridization and flow cytometry. The telomere lengths in granulocytes from patients with AA were found to be significantly shorter than those in age-adjusted controls (P =.001). However, surprisingly, telomere length in granulocytes from AA patients who had recovered after immunosuppressive therapy did not differ significantly from controls, whereas untreated patients and nonresponders with persistent severe pancytopenia showed marked and significant telomere shortening. These results support extensive proliferation of hematopoietic stem cells in subgroups of AA patients. Because normal individuals show significant variation in telomere length, individual measurements in blood cells from AA patients may be of limited value. Whether sequential telomere length measurements can be used as a prognostic tool in this group of disorders remains to be clarified. (Blood. 2001;97:895-900)},
}
@article {pmid11158597,
year = {2001},
author = {Betts, D and Bordignon, V and Hill, J and Winger, Q and Westhusin, M and Smith, L and King, W},
title = {Reprogramming of telomerase activity and rebuilding of telomere length in cloned cattle.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {98},
number = {3},
pages = {1077-1082},
pmid = {11158597},
issn = {0027-8424},
mesh = {Animals ; Animals, Newborn ; Cattle ; Cell Nucleus/*physiology ; Cells, Cultured ; *Cloning, Organism/methods ; Fertilization in Vitro ; Fetus ; Fibroblasts/cytology/physiology ; *Nuclear Transfer Techniques ; Oocytes/cytology/*physiology ; Stem Cells/cytology/physiology ; Telomerase/genetics/*metabolism ; Telomere/*physiology/ultrastructure ; },
abstract = {Nuclear reprogramming requires the removal of epigenetic modifications imposed on the chromatin during cellular differentiation and division. The mammalian oocyte can reverse these alterations to a state of totipotency, allowing the production of viable cloned offspring from somatic cell nuclei. To determine whether nuclear reprogramming is complete in cloned animals, we assessed the telomerase activity and telomere length status in cloned embryos, fetuses, and newborn offspring derived from somatic cell nuclear transfer. In this report, we show that telomerase activity was significantly (P < 0.05) diminished in bovine fibroblast donor cells compared with embryonic stem-like cells, and surprisingly was 16-fold higher in fetal fibroblasts compared with adult fibroblasts (P < 0.05). Cell passaging and culture periods under serum starvation conditions significantly decreased telomerase activity by approximately 30-50% compared with nontreated early passage cells (P < 0.05). Telomere shortening was observed during in vitro culture of bovine fetal fibroblasts and in very late passages of embryonic stem-like cells. Reprogramming of telomerase activity was apparent by the blastocyst stage of postcloning embryonic development, and telomere lengths were longer (15-23 kb) in cloned fetuses and offspring than the relatively short mean terminal restriction fragment lengths (14-18 kb) observed in adult donor cells. Overall, telomere lengths of cloned fetuses and newborn calves (approximately 20 kb) were not significantly different from those of age-matched control animals (P > 0.05). These results demonstrate that cloned embryos inherit genomic modifications acquired during the donor nuclei's in vivo and in vitro period but are subsequently reversed during development of the cloned animal.},
}
@article {pmid11158522,
year = {2001},
author = {Friedrich, U and Schwab, M and Griese, EU and Fritz, P and Klotz, U},
title = {Telomeres in neonates: new insights in fetal hematopoiesis.},
journal = {Pediatric research},
volume = {49},
number = {2},
pages = {252-256},
doi = {10.1203/00006450-200102000-00020},
pmid = {11158522},
issn = {0031-3998},
mesh = {Fetus/*physiology ; *Hematopoiesis/genetics ; Humans ; Infant, Newborn ; *Telomere ; },
abstract = {Progressive telomere shortening occurs in somatic cells, and with increasing donor age a significant decline in telomere length has been shown in various postnatal tissues. In contrast, little is known about changes in telomere length during human fetal development. Therefore, we measured telomere length in the leukocyte fraction of umbilical cord blood samples from 15 preterm (<37 wk of gestation) and 11 full-term (>37 wk of gestation) neonates using the telomere restriction fragment assay. Whereas no differences in mean (+/- SD) telomere restriction fragment between the groups of preterm neonates (8512 +/- 523 bp) and full-term newborns (8323 +/- 503 bp) could be found, significantly longer telomeres (p = 0.002) were found in very low birth weight preterm neonates when compared with low birth weight preterm neonates. In addition, a rapid and significant decline in mean telomere restriction fragment was observed between 27 and 32 wk of gestation (p = 0.02, r = 0.79) followed by a period of no significant loss of telomere repeats between 33 and 42 wk of gestation. These results are consistent with the known almost maximal proliferation rate of hematopoietic progenitor cells before 32 wk of gestation. The initial decrease in telomere restriction fragment could be caused by ontogeny-related functional alterations of hematopoietic cells or differences in stem cell turnover or the rate of telomere loss per cell division.},
}
@article {pmid11157764,
year = {2001},
author = {Muñoz-Jordán, JL and Cross, GA and de Lange, T and Griffith, JD},
title = {t-loops at trypanosome telomeres.},
journal = {The EMBO journal},
volume = {20},
number = {3},
pages = {579-588},
pmid = {11157764},
issn = {0261-4189},
support = {1-F31-AI09893/AI/NIAID NIH HHS/United States ; R01 GM049046/GM/NIGMS NIH HHS/United States ; R01 AI021729/AI/NIAID NIH HHS/United States ; GM31819/GM/NIGMS NIH HHS/United States ; AI21729/AI/NIAID NIH HHS/United States ; CA70343/CA/NCI NIH HHS/United States ; R01 GM031819/GM/NIGMS NIH HHS/United States ; R37 GM049046/GM/NIGMS NIH HHS/United States ; R01 AG016642/AG/NIA NIH HHS/United States ; F31 AI009893/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA, Protozoan/chemistry/genetics/ultrastructure ; Microscopy, Electron ; Oligonucleotide Probes/genetics ; Tandem Repeat Sequences ; Telomere/*chemistry/*genetics/ultrastructure ; Trypanosoma brucei brucei/*chemistry/*genetics ; },
abstract = {Mammalian telomeres form large duplex loops (t-loops) that may sequester chromosome ends by invasion of the 3' TTAGGG overhang into the duplex TTAGGG repeat array. Here we document t-loops in Trypanosoma brucei, a kinetoplastid protozoan with abundant telomeres due to the presence of many minichromosomes. These telomeres contained 10-20 kb duplex TTAGGG repeats and a 3' TTAGGG overhang. Electron microscopy of psoralen/UV cross-linked DNA revealed t-loops in enriched telomeric restriction fragments and at the ends of isolated minichromosomes. In mammals, t-loops are large (up to 25 kb), often comprising most of the telomere. Despite similar telomere lengths, trypanosome t-loops were much smaller (approximately 1 kb), indicating that t-loop sizes are regulated. Coating of non-cross-linked minichromosomes with Escherichia coli single-strand binding protein (SSB) often revealed 3' overhangs at both telomeres and several cross-linked minichromosomes had t-loops at both ends. These results suggest that t-loops and their prerequisite 3' tails can be formed on the products of both leading and lagging strand synthesis. We conclude that t-loops are a conserved feature of eukaryotic telomeres.},
}
@article {pmid11157487,
year = {2001},
author = {Plunkett, FJ and Soares, MV and Annels, N and Hislop, A and Ivory, K and Lowdell, M and Salmon, M and Rickinson, A and Akbar, AN},
title = {The flow cytometric analysis of telomere length in antigen-specific CD8+ T cells during acute Epstein-Barr virus infection.},
journal = {Blood},
volume = {97},
number = {3},
pages = {700-707},
doi = {10.1182/blood.v97.3.700},
pmid = {11157487},
issn = {0006-4971},
mesh = {Acute Disease ; Antigens, Viral/immunology ; CD8-Positive T-Lymphocytes/enzymology/*ultrastructure ; Color ; Flow Cytometry/*methods ; Herpesvirus 4, Human/immunology ; Histocompatibility Antigens Class I/immunology ; Humans ; In Situ Hybridization, Fluorescence ; Infectious Mononucleosis/*genetics/*immunology ; T-Lymphocyte Subsets/ultrastructure ; Telomerase/metabolism ; Telomere/*ultrastructure ; },
abstract = {Acute infectious mononucleosis (AIM) induced by Epstein-Barr virus (EBV) infection is characterized by extensive expansion of antigen-specific CD8+ T cells. One potential consequence of this considerable proliferative activity is telomere shortening, which predisposes the EBV-specific cells to replicative senescence. To investigate this, a method was developed that enables the simultaneous identification of EBV specificity of the CD8+ T cells, using major histocompatibility complex (MHC) class I/peptide complexes, together with telomere length, which is determined by fluorescence in situ hybridization. Despite the considerable expansion, CD8+ EBV-specific T cells in patients with AIM maintain their telomere length relative to CD8+ T cells in normal individuals and relative to CD4+ T cells within the patients themselves and this is associated with the induction of the enzyme telomerase. In 4 patients who were studied up to 12 months after resolution of AIM, telomere lengths of EBV-specific CD8+ T cells were unchanged in 3 but shortened in one individual, who was studied only 5 months after initial onset of infection. Substantial telomere shortening in EBV-specific CD8+ T cells was observed in 3 patients who were studied between 15 months and 14 years after recovery from AIM. Thus, although telomerase activation may preserve the replicative potential of EBV-specific cells in AIM and after initial stages of disease resolution, the capacity of these cells to up-regulate this enzyme after restimulation by the persisting virus may dictate the extent of telomere maintenance in the memory CD8+ T-cell pool over time.},
}
@article {pmid10752943,
year = {2000},
author = {Whikehart, DR and Register, SJ and Chang, Q and Montgomery, B},
title = {Relationship of telomeres and p53 in aging bovine corneal endothelial cell cultures.},
journal = {Investigative ophthalmology &amp; visual science},
volume = {41},
number = {5},
pages = {1070-1075},
pmid = {10752943},
issn = {0146-0404},
support = {EY-03039/EY/NEI NIH HHS/United States ; },
mesh = {Animals ; Cattle ; Cells, Cultured ; Cellular Senescence/*physiology ; DNA/analysis ; Endothelium, Corneal/cytology/*physiology ; Enzyme-Linked Immunosorbent Assay ; Telomere/*physiology ; Tumor Suppressor Protein p53/*metabolism ; beta-Galactosidase/metabolism ; },
abstract = {PURPOSE: To demonstrate a relationship between telomere lengths and levels of p53 in cultured bovine corneal endothelial cells (CECs) during aging.<br><br>METHODS: Bovine CECs were grown and aged as long-term cultures. Telomere lengths were determined directly on gels with 32P probes after treatment of isolated DNA with RsaI and HinfI. Protein p53 was determined using an enzyme-linked immunosorbent sandwich assay. Cellular aging and the development of replicative senescence were monitored by the appearance of senescent morphology and the beta-galactosidase assay.<br><br>RESULTS: Bovine CEC telomeres lost 4 kb (from 12.8 to 8.8 kb) over 1 year (89 population doublings [PDs]). The p53 levels in bovine CECs were initially small (approximately 60 pg/million cells), but rose 3.5-fold by culture age of 260 days (64 PDs). On initiation, cultured bovine CECs did not stain for the senescent marker beta-galactosidase. However, these cells stained at 89 PDs and senescent morphology was observed in the cultures at 64 PDs.<br><br>CONCLUSIONS: The data indicate an inverse relationship between telomere lengths (decreasing) and levels of p53 (increasing) in bovine CECs during aging. These properties may influence the ability of these cells to divide as they enter into replicative senescence.},
}
@article {pmid11152684,
year = {2001},
author = {Tamar, S and Papadopoulou, B},
title = {A telomere-mediated chromosome fragmentation approach to assess mitotic stability and ploidy alterations of Leishmania chromosomes.},
journal = {The Journal of biological chemistry},
volume = {276},
number = {15},
pages = {11662-11673},
doi = {10.1074/jbc.M009006200},
pmid = {11152684},
issn = {0021-9258},
mesh = {Animals ; Cells, Cultured ; Genetic Vectors ; Haploidy ; Leishmania/*genetics ; Mutation ; *Telomere ; },
abstract = {We have used a telomere-associated chromosome fragmentation strategy to induce internal chromosome-specific breakage of Leishmania chromosomes. The integration of telomeric repeats from the kinetoplastid Trypanosoma brucei into defined positions of the Leishmania genome by homologous recombination can induce chromosome breakage accompanied by the deletion of the chromosomal part that is distal to the site of the break. The cloned telomeric DNA at the end of the truncated chromosomes is functional and it can seed the formation of new telomeric repeats. We found that genome ploidy is often altered upon telomere-mediated chromosome fragmentation events resulting in large chromosomal deletions. In most cases diploidy is either preserved, or partial trisomic cells are observed, but interestingly we report here the generation of partial haploid mutants in this diploid organism. Partial haploid Leishmania mutants should facilitate studies on the function of chromosome-assigned genes. We also present several lines of evidence for the presence of sequences involved in chromosome mitotic stability and segregation during cell cycle in this parasitic protozoan. Telomere-directed chromosome fragmentation studies in Leishmania may constitute a useful tool to assay for centromere function.},
}
@article {pmid11154240,
year = {2001},
author = {Rufer, N and Brümmendorf, TH and Chapuis, B and Helg, C and Lansdorp, PM and Roosnek, E},
title = {Accelerated telomere shortening in hematological lineages is limited to the first year following stem cell transplantation.},
journal = {Blood},
volume = {97},
number = {2},
pages = {575-577},
doi = {10.1182/blood.v97.2.575},
pmid = {11154240},
issn = {0006-4971},
support = {AI29524/AI/NIAID NIH HHS/United States ; GM56162/GM/NIGMS NIH HHS/United States ; },
mesh = {Adult ; CD4-Positive T-Lymphocytes/cytology/ultrastructure ; Cell Culture Techniques ; Cell Division/genetics ; Follow-Up Studies ; Hematopoiesis/*genetics ; Hematopoietic Stem Cell Transplantation/*adverse effects ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia/blood/therapy ; Monocytes/cytology/ultrastructure ; T-Lymphocytes/cytology/ultrastructure ; Telomere/*physiology ; Time Factors ; },
abstract = {Using quantitative fluorescence in situ hybridization and flow cytometry, the telomere length of telomere repeat sequences after stem cell transplantation (SCT) were measured. The study included the telomeres of peripheral blood monocytes that should reflect the length of telomeres in stem cells and the telomeres of T lymphocytes that could shorten as a result of peripheral expansion. The loss of telomeres in monocytes and in memory T cells, although accelerated initially, became comparable to the loss of telomeres in healthy controls from the second year after transplantation. In addition, the telomere length in the naive T cells that were produced by the thymus was comparable to the telomere length in the naive T cells of the donor. Compared to the total length of telomeres available, the loss of telomere repeats in leukocytes after SCT resembles the accelerated shortening seen in early childhood and remains, therefore, relatively insignificant.},
}
@article {pmid11151673,
year = {2000},
author = {Niedermaier, J and Moritz, KB},
title = {Organization and dynamics of satellite and telomere DNAs in Ascaris: implications for formation and programmed breakdown of compound chromosomes.},
journal = {Chromosoma},
volume = {109},
number = {7},
pages = {439-452},
doi = {10.1007/s004120000104},
pmid = {11151673},
issn = {0009-5915},
mesh = {Animals ; Ascaris/*genetics ; Base Sequence ; DNA, Helminth/*genetics ; Female ; Germ Cells ; In Situ Hybridization, Fluorescence ; *Telomere ; },
abstract = {In the nematode genus Ascaris the germline genome contains considerable amounts of extra DNA, which is discarded from the somatic founder blastomeres during early cleavage. In Parascaris univalens the haploid germline genome is contained in one large compound chromosome, which consists of a euchromatic region containing the somatic genome flanked by large blocks of heterochromatin. Fluorescence in situ hybridization of fractions of the germline-limited satellite DNA revealed two highly repeated sequence families establishing the entire heterochromatin (HET blocks). The repeats, a pentanucleotide, TTGCA, and a decanucleotide, TTTGTGCGTG, constitute separate segments of the HET blocks. The blocks are polymorphic in length and, hence, in copy number of the repeats, and the arrangement of the segments. The numerous sequence variants of both repeats display a disperse distribution. The type and rate of base substitutions within both repeat units depend on position. Prior to the elimination process in presomatic cells, termed chromatin diminution, the chromosomes undergo differential mitotic condensation. Interstitial 'chromatin linkers' flanking the prospective numerous somatic chromosomes remain entirely decondensed. The somatic chromosomes are released from the plurivalent chromosomes via excision of the linkers at onset of anaphase, followed by exclusion of the akinetic linker chromatin and HET blocks from the daughter nuclei. In Ascaris suum, the germline-limited satellite, which consists of one 123 bp repeat, is scattered throughout the numerous chromosomes in small heterochromatic knobs of variable sizes, residing at chromosomal ends and/or intercalary positions. The programmed breakage, which appears to proceed in a similar manner to that in P. univalens, results in the loss of all heterochromatic knobs, accompanied by an increase in chromosome number. In both species, all germline chromosomes are capped by tracts of TTAGGC repeats. In P. univalens, such telomeric tracts also occur at the termini of the euchromatic intercalary regions. Upon diminution all telomeric tracts are discarded. De novo telomere addition occurs in all somatic cell lineages of both species. The presented data shed light on the evolutionary history of chromosome aggregation and satellite DNA formation, and putative mechanisms involved in the process of site-directed breakage to reestablish stable somatic chromosomes.},
}
@article {pmid11150541,
year = {2001},
author = {Batliwalla, FM and Damle, RN and Metz, C and Chiorazzi, N and Gregersen, PK},
title = {Simultaneous flow cytometric analysis of cell surface markers and telomere length: analysis of human tonsilar B cells.},
journal = {Journal of immunological methods},
volume = {247},
number = {1-2},
pages = {103-109},
doi = {10.1016/s0022-1759(00)00297-0},
pmid = {11150541},
issn = {0022-1759},
mesh = {Adolescent ; Adult ; *B-Lymphocytes/immunology ; Biomarkers ; Cell Membrane/metabolism ; Child ; Child, Preschool ; Flow Cytometry/methods ; Humans ; In Situ Hybridization, Fluorescence/methods ; Palatine Tonsil/cytology ; Staining and Labeling/methods ; *Telomere ; },
abstract = {Telomere Flow FISH is a recently developed method which allows the measurement of telomere length in purified subsets of cells using flow cytometry. However, the harsh conditions required for flow FISH have precluded its use with conventional cell surface staining, thus limiting its utility for large scale clinical studies. We have now developed a method which permits simultaneous analysis of cell surface markers along with telomere length estimation by flow cytometry. This new assay employs the covalent crosslinking of monoclonal antibodies conjugated with a heat stable fluorochrome to the cell surface prior to flow FISH. Using this technique we have confirmed that human germinal center B cells (IgD(-)/CD38(+)) have dramatically longer telomeres than pre-germinal center founder B cells (IgD(+)/CD38(+)). This approach simplifies the analysis of complex cell populations and will facilitate widespread investigation of telomere length in health and disease states.},
}
@article {pmid11148139,
year = {2001},
author = {Nagele, RG and Velasco, AQ and Anderson, WJ and McMahon, DJ and Thomson, Z and Fazekas, J and Wind, K and Lee, H},
title = {Telomere associations in interphase nuclei: possible role in maintenance of interphase chromosome topology.},
journal = {Journal of cell science},
volume = {114},
number = {Pt 2},
pages = {377-388},
doi = {10.1242/jcs.114.2.377},
pmid = {11148139},
issn = {0021-9533},
mesh = {Cell Cycle/*physiology ; Cell Division ; Cell Line ; Cell Line, Transformed ; Cell Nucleus/*physiology/ultrastructure ; Cell Transformation, Viral ; Chromosomes, Human/physiology/*ultrastructure ; Fibroblasts/cytology/physiology/ultrastructure ; Humans ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; *Interphase ; Papillomaviridae/genetics ; Peptide Nucleic Acids ; Telomere/*physiology/ultrastructure ; },
abstract = {The relative sizes of individual telomeres in cultured human cells under conditions of cell cycling, replicative quiescence, cell transformation and immortalization were determined using quantitative fluorescence in situ hybridization (Q-FISH) with a telomere-specific peptide nucleic acid (PNA) probe. Results obtained from analysis of telomere length profiles (TLPs), which display the distribution of relative telomere lengths for individual cells, confirmed telomere length heterogeneity at the single cell level and proportional shortening of telomere length during replicative aging of virus-transformed cells. TLPs also revealed that some telomeric ends of chromosomes are so closely juxtaposed within interphase nuclei that their fluorescent signals appear as a single spot. These telomeric associations (TAs) were far more prevalent in interphase nuclei of noncycling normal and virus-transformed cells than in their cycling counterparts. The number of interphase TAs per nucleus observed in late-passage E6/E7-transformed cells did not increase during progression to crisis, suggesting that telomere shortening does not increase the frequency of interphase TAs. Furthermore, interphase TAs were rarely observed in rapidly cycling, telomerase-positive, immortalized cells that exhibit somewhat shortened, but stabilized, telomere length through the activity of telomerase. Our overall results suggest that the number of interphase TAs is dependent more on whether or not cells are cycling than on telomere length, with TAs being most prominent in the nuclei of replicatively quiescent cells in which nonrandom (even preferred) chromosome spatial arrangements have been observed. We propose that interphase TAs may play a role in the generation and/or maintenance of nuclear architecture and chromosome positional stability in interphase nuclei, especially in cells with a prolonged G(1)/G(0) phase and possibly in terminally differentiated cells.},
}
@article {pmid11142683,
year = {2000},
author = {Taylor, HA and Delany, ME},
title = {Ontogeny of telomerase in chicken: impact of downregulation on pre- and postnatal telomere length in vivo.},
journal = {Development, growth &amp; differentiation},
volume = {42},
number = {6},
pages = {613-621},
doi = {10.1046/j.1440-169x.2000.00540.x},
pmid = {11142683},
issn = {0012-1592},
mesh = {Animals ; Chickens/*genetics ; *Down-Regulation ; Telomerase/*metabolism ; *Telomere ; },
abstract = {Telomeres are the termini of linear chromosomes composed of tandem repeats of a conserved DNA sequence. Telomerase provides a mechanism for proliferating cells to offset telomeric sequence erosion by synthesizing new repeats onto the end of each parental DNA strand. Reduced or absent telomerase activity can lead to telomere shortening and genome instability. Telomeres and telomerase have not previously been characterized during ontogeny of any avian species. In the present study, telomerase activity in the chicken model was examined from early differentiation embryos through to adulthood. Telomerase activity was detected in all early embryos (preblastula through neurula) and in tissues throughout organogenesis. Subsequently, telomerase was downregulated in the majority of somatic tissues, either pre- or postnatally. A subset of tissues, such as intestine, immune and reproductive organs, exhibited constitutive activity. The impact of telomerase downregulation on telomere length was investigated and a telomere reduction of 3.2 kb in somatic tissues compared with germ line was observed in 5-year-old adults. The present results suggest that the telomere clock function is a conserved feature of avians as well as mammals. Knowledge regarding the relationships among telomerase regulation, proliferation/senescence profiles and differentiation status will be useful for numerous applications of chicken cells.},
}
@article {pmid11134086,
year = {2000},
author = {Gineitis, AA and Zalenskaya, IA and Yau, PM and Bradbury, EM and Zalensky, AO},
title = {Human sperm telomere-binding complex involves histone H2B and secures telomere membrane attachment.},
journal = {The Journal of cell biology},
volume = {151},
number = {7},
pages = {1591-1598},
pmid = {11134086},
issn = {0021-9525},
support = {R01 HD039830/HD/NICHD NIH HHS/United States ; HD39830-01/HD/NICHD NIH HHS/United States ; },
mesh = {Base Sequence ; Binding Sites ; Cell Extracts ; Cell Nucleus/genetics/metabolism ; DNA/genetics/*metabolism ; DNA-Binding Proteins/chemistry/*metabolism ; Fluorescent Antibody Technique ; Genetic Variation/genetics ; Histones/genetics/*metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Intracellular Membranes/*metabolism ; Macromolecular Substances ; Male ; Nuclear Proteins/metabolism ; Protein Binding ; Spermatozoa/cytology/*metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1 ; },
abstract = {Telomeres are unique chromatin domains located at the ends of eukaryotic chromosomes. Telomere functions in somatic cells involve complexes between telomere proteins and TTAGGG DNA repeats. During the differentiation of germ-line cells, telomeres undergo significant reorganization most likely required for additional specific functions in meiosis and fertilization. A telomere-binding protein complex from human sperm (hSTBP) has been isolated by detergent treatment and was partially purified. hSTBP specifically binds double-stranded telomeric DNA and does not contain known somatic telomere proteins TRF1, TRF2, and Ku. Surprisingly, the essential component of this complex has been identified as a specific variant of histone H2B. Indirect immunofluorescence shows punctate localization of H2B in sperm nuclei, which in part coincides with telomeric DNA localization established by fluorescent in situ hybridization. Anti-H2B antibodies block interactions of hSTBP with telomere DNA, and spH2B forms specific complex with this DNA in vitro, indicating that this protein plays a role in telomere DNA recognition. We propose that hSTBP participates in the membrane attachment of telomeres that may be important for ordered chromosome withdrawal after fertilization.},
}
@article {pmid11131337,
year = {2000},
author = {Perani, P and Cacciò, S and Saccone, S and Andreozzi, L and Bernardi, G},
title = {Telomeres in warm-blooded vertebrates are composed of GC-rich isochores.},
journal = {Biochemical genetics},
volume = {38},
number = {7-8},
pages = {227-239},
doi = {10.1023/a:1001987420874},
pmid = {11131337},
issn = {0006-2928},
mesh = {Animals ; Birds ; Blotting, Southern ; DNA ; Deoxyribonuclease EcoRI ; *GC Rich Sequence ; Humans ; Mammals ; Repetitive Sequences, Nucleic Acid ; *Telomere ; },
abstract = {We have hybridized the vertebrate telomeric sequence (TTAGGG)n on DNA compositional fractions from 13 mammalian species and 3 avian species, representing 9 and 3 orders, respectively. Our results indicate that the 50- to 100-kb fragments derived from telomeric regions are composed of GC-rich and GC-richest isochores. Previous works from our laboratory demonstrated that single-copy sequences from the human H3 isochore family (the GC-richest and gene-richest isochore in the human genome) share homology with compositionally correlated compartments of warm-blooded vertebrates. This correlation suggested that the GC-richest isochores are, as in the human genome, the gene-richest regions of warm-blooded vertebrates' genome. Moreover, this evidence suggests that telomeric regions are the most gene-dense region of all warm-blooded vertebrates. The implications of these findings are discussed.},
}
@article {pmid11121242,
year = {2001},
author = {Suzuki, K and Mori, I and Nakayama, Y and Miyakoda, M and Kodama, S and Watanabe, M},
title = {Radiation-induced senescence-like growth arrest requires TP53 function but not telomere shortening.},
journal = {Radiation research},
volume = {155},
number = {1 Pt 2},
pages = {248-253},
doi = {10.1667/0033-7587(2001)155[0248:rislga]2.0.co;2},
pmid = {11121242},
issn = {0033-7587},
mesh = {Cell Cycle/radiation effects ; Cell Division/radiation effects ; Cell Line ; Cellular Senescence/physiology/*radiation effects ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins/biosynthesis ; Enzyme Induction ; Humans ; Phosphorylation/radiation effects ; Telomere/metabolism/*physiology/radiation effects ; Tumor Suppressor Protein p53/metabolism/*physiology ; beta-Galactosidase/biosynthesis/metabolism ; },
abstract = {Suzuki, K., Mori, I., Nakayama, Y., Miyakoda, M., Kodama, S. and Watanabe, M. Radiation-Induced Senescence-like Growth Arrest Requires TP53 Function but not Telomere Shortening. Normal human diploid cells irradiated with X rays showed permanent cell cycle arrest and exhibited senescence-like phenotypes including the expression of senescence-associated beta-galactosidase (SA-beta-gal). X irradiation caused persistent phosphorylation of TP53 at Ser 15 and accumulation of the TP53 protein, followed by the induction of CDKN1A (also known as p21(Waf1/Cip1)) and CDKN2A (also known as p16), preceded the expression of SA-beta-gal. NCI-H1299 human lung carcinoma cells, in which no TP53 protein was expressed, were irradiated with X rays with or without the exogenous expression of TP53 gene. Although induction of TP53 protein alone could induce SA-beta-gal expression, the frequency of SA-beta-gal-positive cells was significantly increased when TP53-induced H1299 cells were exposed to X rays. The mean terminal restriction fragment length in normal human cells was approximately 12 kb and did not change in SA-beta-gal-positive cells. These results indicate that ionizing radiation induces senescence-like growth arrest that is dependent on TP53 function but independent of telomere shortening. Our findings suggest that cells harboring irreparable DNA damage are programmed to undergo premature senescence to maintain the integrity of the genome.},
}
@article {pmid11121234,
year = {2001},
author = {Reddel, RR and Bryan, TM and Colgin, LM and Perrem, KT and Yeager, TR},
title = {Alternative lengthening of telomeres in human cells.},
journal = {Radiation research},
volume = {155},
number = {1 Pt 2},
pages = {194-200},
doi = {10.1667/0033-7587(2001)155[0194:alotih]2.0.co;2},
pmid = {11121234},
issn = {0033-7587},
mesh = {Animals ; Cell Line, Transformed ; Cell Transformation, Neoplastic ; Humans ; Neoplasms/enzymology/genetics/metabolism ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Activation of a telomere maintenance mechanism appears to be essential for immortalization. In most human tumors and tumor cell lines, the telomere maintenance mechanism involves the activity of telomerase, a reverse transcriptase holoenzyme that synthesizes telomeric repeat DNA. In some cases, telomere maintenance occurs in the absence of telomerase activity by a mechanism referred to as alternative lengthening of telomeres (ALT). The development of telomere-targeted anticancer therapies will be facilitated by an understanding of the molecular mechanisms of ALT and of the means whereby ALT is repressed in normal cells.},
}
@article {pmid11121233,
year = {2001},
author = {Shay, JW and Wright, WE},
title = {Telomeres and telomerase: implications for cancer and aging.},
journal = {Radiation research},
volume = {155},
number = {1 Pt 2},
pages = {188-193},
doi = {10.1667/0033-7587(2001)155[0188:tatifc]2.0.co;2},
pmid = {11121233},
issn = {0033-7587},
mesh = {Animals ; Cellular Senescence/*physiology ; Humans ; Neoplasms/enzymology/genetics/*pathology ; Telomerase/*metabolism ; Telomere/*physiology ; },
abstract = {Maintenance of telomere stability is required for cells to escape from replicative senescence and proliferate indefinitely. Telomere length is maintained by a balance between processes that lengthen telomeres (telomerase) and processes that shorten telomeres (the end-replication problem). Telomerase is a cellular ribonucleoprotein reverse transcriptase which stabilizes telomere length by adding hexameric (TTAGGG) repeats to the telomeric ends of the chromosomes, thus compensating for the continued erosion of telomeres. Introduction of the telomerase catalytic protein component into normal telomerase-negative human cells results in restoration of telomerase activity and extension of cellular life span. Human cells with introduced telomerase maintain a normal chromosome complement and continue to grow in a normal manner. Telomerase-induced manipulations of telomere length may thus be important not only for cell and tissue engineering but also for dissecting the molecular mechanisms underlying inherited genetic diseases, as well as defining the genetic pathways leading to cancer. Because almost all human tumors express telomerase activity, inhibition of telomerase may result in gradual erosion of telomeres and eventual cessation of cell proliferation or induction of apoptosis. Thus telomerase may also be a promising target for cancer therapy.},
}
@article {pmid11117537,
year = {2000},
author = {Major, EO},
title = {From telomeres to T-antigens: many roads...multiple pathways...novel associations in the search for the origins of human gliomas.},
journal = {Annals of neurology},
volume = {48},
number = {6},
pages = {823-825},
pmid = {11117537},
issn = {0364-5134},
mesh = {Antigens, Viral, Tumor/*physiology ; Brain Neoplasms/*physiopathology ; Glioma/*physiopathology ; Humans ; Prognosis ; Telomere/*physiology ; },
}
@article {pmid11114247,
year = {2001},
author = {Tomaska, L and Makhov, AM and Nosek, J and Kucejova, B and Griffith, JD},
title = {Electron microscopic analysis supports a dual role for the mitochondrial telomere-binding protein of Candida parapsilosis.},
journal = {Journal of molecular biology},
volume = {305},
number = {1},
pages = {61-69},
doi = {10.1006/jmbi.2000.4254},
pmid = {11114247},
issn = {0022-2836},
support = {CA70343/CA/NCI NIH HHS/United States ; GM31819/GM/NIGMS NIH HHS/United States ; },
mesh = {Bacteriophage M13/genetics ; Blotting, Western ; Candida/*chemistry/cytology/genetics ; Centrifugation, Density Gradient ; Chromatin/genetics/metabolism ; DNA, Fungal/genetics/metabolism/ultrastructure ; DNA, Mitochondrial/genetics/metabolism/ultrastructure ; DNA, Single-Stranded/genetics/metabolism/ultrastructure ; DNA-Binding Proteins/chemistry/isolation &amp; purification/*metabolism/*ultrastructure ; Fungal Proteins/chemistry/isolation &amp; purification/*metabolism/*ultrastructure ; Humans ; Metrizamide ; Microscopy, Electron ; Protein Binding ; Protein Structure, Quaternary ; Recombinant Proteins/chemistry/isolation &amp; purification/metabolism/ultrastructure ; Structure-Activity Relationship ; Substrate Specificity ; Telomere/genetics/metabolism ; },
abstract = {Linear mitochondrial genomes exist in several yeast species which are closely related to yeast that harbor circular mitochondrial genomes. Several lines of evidence suggest that the conversion from one form to another occurred accidentally through a relatively simple mechanism. Previously, we (L.T. &amp; J.N.) reported the identification of the first mitochondrial telomere-binding protein (mtTBP) that specifically binds a sequence derived from the extreme end of Candida parapsilosis linear mtDNA, and sequence analysis of the corresponding nuclear gene MTP1 revealed that mtTBP shares homology with several bacterial and mitochondrial single-stranded (ss) DNA-binding (SSB) proteins. In this study, the DNA-binding properties of mtTBP in vitro and in vivo were analyzed by electron microscopy (EM). When M13 ssDNA was used as a substrate, mtTBP exhibited similar DNA binding characteristics as human mitochondrial SSB: mtTBP formed protein globules along the DNA substrate, and the bound proteins were randomly distributed, indicating that the binding of mtTBP to M13 ssDNA is not highly cooperative. EM analysis demonstrated that mtTBP is able to recognize the 5' single-stranded telomeric overhangs in their natural context. Using isopycnic centrifugation of mitochondrial lysates of C. papsilosis we show that mtTBP is a structural part of mitochondrial nucleoids of C. parapsilosis and is predominantly bound to the mitochondrial telomeres. These data support a dual role of mtTBP in mitochondria of C. parapsilosis, serving both as a typical mitochondrial SSB and as a specific component of the mitochondrial telomeric chromatin.},
}
@article {pmid11113187,
year = {2001},
author = {Kilburn, AE and Shea, MJ and Sargent, RG and Wilson, JH},
title = {Insertion of a telomere repeat sequence into a mammalian gene causes chromosome instability.},
journal = {Molecular and cellular biology},
volume = {21},
number = {1},
pages = {126-135},
pmid = {11113187},
issn = {0270-7306},
support = {R01 GM038219/GM/NIGMS NIH HHS/United States ; GM38219/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenine Phosphoribosyltransferase/*genetics ; Animals ; Base Sequence ; Blotting, Southern ; CHO Cells ; Chromosome Deletion ; Chromosome Fragility/*genetics ; Cricetinae ; Gene Targeting ; Introns/genetics ; Molecular Sequence Data ; Mutagenesis, Insertional/*genetics ; Phenotype ; RNA, Messenger/biosynthesis/genetics ; Recombination, Genetic/genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; Sequence Analysis, DNA ; Sequence Homology, Nucleic Acid ; Telomere/*genetics ; Thymidine Kinase/genetics ; },
abstract = {Telomere repeat sequences cap the ends of eucaryotic chromosomes and help stabilize them. At interstitial sites, however, they may destabilize chromosomes, as suggested by cytogenetic studies in mammalian cells that correlate interstitial telomere sequence with sites of spontaneous and radiation-induced chromosome rearrangements. In no instance is the length, purity, or orientation of the telomere repeats at these potentially destabilizing interstitial sites known. To determine the effects of a defined interstitial telomere sequence on chromosome instability, as well as other aspects of DNA metabolism, we deposited 800 bp of the functional vertebrate telomere repeat, TTAGGG, in two orientations in the second intron of the adenosine phosphoribosyltransferase (APRT) gene in Chinese hamster ovary cells. In one orientation, the deposited telomere sequence did not interfere with expression of the APRT gene, whereas in the other it reduced mRNA levels slightly. The telomere sequence did not induce chromosome truncation and the seeding of a new telomere at a frequency above the limits of detection. Similarly, the telomere sequence did not alter the rate or distribution of homologous recombination events. The interstitial telomere repeat sequence in both orientations, however, dramatically increased gene rearrangements some 30-fold. Analysis of individual rearrangements confirmed the involvement of the telomere sequence. These studies define the telomere repeat sequence as a destabilizing element in the interior of chromosomes in mammalian cells.},
}
@article {pmid11112441,
year = {2000},
author = {Zalenskaya, IA and Bradbury, EM and Zalensky, AO},
title = {Chromatin structure of telomere domain in human sperm.},
journal = {Biochemical and biophysical research communications},
volume = {279},
number = {1},
pages = {213-218},
doi = {10.1006/bbrc.2000.3917},
pmid = {11112441},
issn = {0006-291X},
support = {HD39830/HD/NICHD NIH HHS/United States ; },
mesh = {Chromatin/*chemistry/metabolism ; HeLa Cells ; Histones/metabolism ; Humans ; Male ; Micrococcal Nuclease/metabolism ; Protamines/metabolism ; Spermatozoa/chemistry/*ultrastructure ; *Telomere ; },
abstract = {Telomeres in human sperm nucleus are clustered at the nuclear periphery. Chromosomes in the sperm are highly condensed with protamines, however, a small portion of DNA remains associated with histones; the role of the nucleohistone is unknown. To examine structure of the telomeric chromatin, the sperm nuclei were treated with micrococcal nuclease. Chromatin released by the digestion was free from protamines, but contained histones and revealed nucleosomal organization. It was enriched with telomeric DNA organized into closely spaced nucleosomes with a periodicity of 148 +/- bp. Thus, while the most of the sperm genome is packed into extremely dense nucleoprotamine structure, at least a part of the telomeric DNA is arranged into nucleosomes and can be released by the nuclease. We suggest that telomeres might be among the first structures in the sperm nucleus that respond to oocyte signals for male pronucleus development at fertilization.},
}
@article {pmid11112386,
year = {2000},
author = {Maláska, J and Sklenicková, M and Krejcí, K and Fajkusová, L and Bajer, M and Hrstková, H and Fajkus, J},
title = {Telomerase activity and expression and telomere analysis in situ in the course of treatment of childhood leukemias.},
journal = {Blood cells, molecules &amp; diseases},
volume = {26},
number = {5},
pages = {534-539},
doi = {10.1006/bcmd.2000.0332},
pmid = {11112386},
issn = {1079-9796},
mesh = {Acute Disease ; Catalytic Domain ; Child ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia, Myeloid/*enzymology/genetics/therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*enzymology/genetics/therapy ; RNA, Neoplasm/genetics/metabolism ; Telomerase/*genetics/metabolism ; Telomere/*genetics ; },
abstract = {Samples of blood and marrow from children with leukemia were assayed for telomerase activity and expression on the day of diagnosis and during the course of chemotherapy. A strong correlation between either variables and clinical response was observed in most patients. A unique case was observed in which telomerase activity was only moderately increased on diagnosis; it gradually increased in the course of therapy, and a subsequent decrease occurred only after application of intensified therapy. This patient did not respond to therapy, his disease progressed, and he finally died during intensified therapy. In another patient, analysis of telomere lengths using dideoxy-PRINS revealed a single telomere expansion on a long arm of chromosome 4, suggesting involvement of a telomerase-independent mechanism of telomere elongation.},
}
@article {pmid11104804,
year = {2000},
author = {Goytisolo, FA and Samper, E and Martín-Caballero, J and Finnon, P and Herrera, E and Flores, JM and Bouffler, SD and Blasco, MA},
title = {Short telomeres result in organismal hypersensitivity to ionizing radiation in mammals.},
journal = {The Journal of experimental medicine},
volume = {192},
number = {11},
pages = {1625-1636},
pmid = {11104804},
issn = {0022-1007},
mesh = {Animals ; Annexin A5/metabolism ; Apoptosis/radiation effects ; B-Lymphocytes/immunology/metabolism/radiation effects ; Bone Marrow/pathology/radiation effects ; Cell Cycle/radiation effects ; Cells, Cultured ; DNA Nucleotidyltransferases ; DNA Repair ; *Gamma Rays ; Intestine, Small/pathology/radiation effects ; Kidney/pathology/radiation effects ; Mice ; Mice, Inbred C57BL ; Radiation Tolerance/*genetics ; Recombination, Genetic ; Sister Chromatid Exchange ; Spleen/cytology/radiation effects ; Stomach/pathology/radiation effects ; Telomerase/genetics ; Telomere/genetics/*physiology ; VDJ Recombinases ; },
abstract = {Here we show a correlation between telomere length and organismal sensitivity to ionizing radiation (IR) in mammals. In particular, fifth generation (G5) mouse telomerase RNA (mTR)(-/)- mice, with telomeres 40% shorter than in wild-type mice, are hypersensitive to cumulative doses of gamma rays. 60% of the irradiated G5 mTR(-/)- mice die of acute radiation toxicity in the gastrointestinal tract, lymphoid organs, and kidney. The affected G5 mTR(-/)- mice show higher chromosomal damage and greater apoptosis than similarly irradiated wild-type controls. Furthermore, we show that G5 mTR(-/)- mice show normal frequencies of sister chromatid exchange and normal V(D)J recombination, suggesting that short telomeres do not significantly affect the efficiency of DNA double strand break repair in mammals. The IR-sensitive phenotype of G5 mTR(-/)- mice suggests that telomere function is one of the determinants of radiation sensitivity of whole animals.},
}
@article {pmid11102517,
year = {2000},
author = {Scherthan, H and Jerratsch, M and Li, B and Smith, S and Hultén, M and Lock, T and de Lange, T},
title = {Mammalian meiotic telomeres: protein composition and redistribution in relation to nuclear pores.},
journal = {Molecular biology of the cell},
volume = {11},
number = {12},
pages = {4189-4203},
pmid = {11102517},
issn = {1059-1524},
mesh = {Animals ; Chromosomes/ultrastructure ; DNA-Binding Proteins/immunology/metabolism ; Fluorescent Antibody Technique, Indirect ; Humans ; Male ; *Meiosis ; Mice ; Nuclear Pore/*metabolism ; Poly(ADP-ribose) Polymerases/immunology/metabolism ; Prophase ; Rats ; Shelterin Complex ; Spermatocytes/cytology/metabolism ; *Tankyrases ; Telomere/*chemistry/*metabolism ; *Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 1 ; Telomeric Repeat Binding Protein 2 ; rap1 GTP-Binding Proteins/immunology/metabolism ; },
abstract = {Mammalian telomeres consist of TTAGGG repeats, telomeric repeat binding factor (TRF), and other proteins, resulting in a protective structure at chromosome ends. Although structure and function of the somatic telomeric complex has been elucidated in some detail, the protein composition of mammalian meiotic telomeres is undetermined. Here we show, by indirect immunofluorescence (IF), that the meiotic telomere complex is similar to its somatic counterpart and contains significant amounts of TRF1, TRF2, and hRap1, while tankyrase, a poly-(ADP-ribose)polymerase at somatic telomeres and nuclear pores, forms small signals at ends of human meiotic chromosome cores. Analysis of rodent spermatocytes reveals Trf1 at mouse, TRF2 at rat, and mammalian Rap1 at meiotic telomeres of both rodents. Moreover, we demonstrate that telomere repositioning during meiotic prophase occurs in sectors of the nuclear envelope that are distinct from nuclear pore-dense areas. The latter form during preleptotene/leptotene and are present during entire prophase I.},
}
@article {pmid11101843,
year = {2000},
author = {Dunham, MA and Neumann, AA and Fasching, CL and Reddel, RR},
title = {Telomere maintenance by recombination in human cells.},
journal = {Nature genetics},
volume = {26},
number = {4},
pages = {447-450},
doi = {10.1038/82586},
pmid = {11101843},
issn = {1061-4036},
mesh = {Cell Line ; DNA/genetics ; Humans ; In Situ Hybridization, Fluorescence ; *Recombination, Genetic ; Telomere/*genetics ; Tumor Cells, Cultured ; },
abstract = {Telomeres of eukaryotic chromosomes contain many tandem repeats of a G-rich sequence (for example, TTAGGG in vertebrates). In most normal human cells, telomeres shorten with each cell division, and it is proposed that this limits the number of times these cells can replicate. Telomeres may be maintained in germline cells, and in many immortalized cells and cancers, by the telomerase holoenzyme (first discovered in the ciliate Tetrahymena), which uses an RNA subunit as template for synthesis of telomeric DNA by the reverse transcriptase catalytic subunit. Some immortalized human cell lines and some tumours maintain their telomeres in the absence of any detectable telomerase activity by a mechanism referred to as alternative lengthening of telomeres (ALT). Here we show that DNA sequences are copied from telomere to telomere in an immortalized human ALT cell line, indicating that ALT occurs by means of homologous recombination and copy switching.},
}
@article {pmid11095684,
year = {2000},
author = {Wang, MJ and Lin, YC and Pang, TL and Lee, JM and Chou, CC and Lin, JJ},
title = {Telomere-binding and Stn1p-interacting activities are required for the essential function of Saccharomyces cerevisiae Cdc13p.},
journal = {Nucleic acids research},
volume = {28},
number = {23},
pages = {4733-4741},
pmid = {11095684},
issn = {1362-4962},
mesh = {Cyclin B/chemistry/genetics/*metabolism ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Fungal Proteins/genetics/*metabolism ; Genetic Complementation Test ; Mutation ; Peptide Fragments/genetics/metabolism ; Protein Binding ; Saccharomyces cerevisiae/genetics/*metabolism ; Telomere/genetics/*metabolism ; Two-Hybrid System Techniques ; },
abstract = {Yeast Saccharomyces cerevisiae Cdc13p is the telomere-binding protein that protects telomeres and regulates telomere length. It is documented that Cdc13p binds specifically to single-stranded TG(1-3) telomeric DNA sequences and interacts with Stn1p. To localize the region for single-stranded TG(1-3) DNA binding, Cdc13p mutants were constructed by deletion mutagenesis and assayed for their binding activity. Based on in vitro electrophoretic mobility shift assay, a 243-amino-acid fragment of Cdc13p (amino acids 451-693) was sufficient to bind single-stranded TG(1-3) with specificity similar to that of the native protein. Consistent with the in vitro observation, in vivo one-hybrid analysis also indicated that this region of Cdc13p was sufficient to localize itself to telomeres. However, the telomere-binding region of Cdc13p (amino acids 451-693) was not capable of complementing the growth defects of cdc13 mutants. Instead, a region comprising the Stn1p-interacting and telomere-binding region of Cdc13p (amino acids 252-924) complemented the growth defects of cdc13 mutants. These results suggest that binding to telomeres by Cdc13p is not sufficient to account for the cell viability, interaction with Stn1p is also required. Taken together, we have defined the telomere-binding domain of Cdc13p and showed that both binding to telomeres and Stn1p by Cdc13p are required to maintain cell growth.},
}
@article {pmid11092831,
year = {2000},
author = {McEachern, MJ and Krauskopf, A and Blackburn, EH},
title = {Telomeres and their control.},
journal = {Annual review of genetics},
volume = {34},
number = {},
pages = {331-358},
doi = {10.1146/annurev.genet.34.1.331},
pmid = {11092831},
issn = {0066-4197},
mesh = {Telomerase/metabolism ; *Telomere ; },
abstract = {Telomeres are DNA and protein structures that form complexes protecting the ends of chromosomes. Understanding of the mechanisms maintaining telomeres and insights into their function have advanced considerably in recent years. This review summarizes the currently known components of the telomere/telomerase functional complex, and focuses on how they act in the control of processes occurring at telomeres. These include processes acting on the telomeric DNA and on telomeric proteins. Key among them are DNA replication and elongation of one telomeric DNA strand by telomerase. In some situations, homologous recombination of telomeric and subtelomeric DNA is induced. All these processes act to replenish or restore telomeres. Conversely, degradative processes that shorten telomeric DNA, and nonhomologous end-joining of telomeric DNA, can lead to loss of telomere function and genomic instability. Hence they too must normally be tightly controlled.},
}
@article {pmid11092534,
year = {2000},
author = {von Zglinicki, T and Serra, V and Lorenz, M and Saretzki, G and Lenzen-Grossimlighaus, R and Gessner, R and Risch, A and Steinhagen-Thiessen, E},
title = {Short telomeres in patients with vascular dementia: an indicator of low antioxidative capacity and a possible risk factor?.},
journal = {Laboratory investigation; a journal of technical methods and pathology},
volume = {80},
number = {11},
pages = {1739-1747},
doi = {10.1038/labinvest.3780184},
pmid = {11092534},
issn = {0023-6837},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antioxidants/*metabolism ; Case-Control Studies ; Dementia, Vascular/*genetics ; Female ; Fibroblasts/metabolism ; Genotype ; Humans ; Male ; Middle Aged ; Risk Factors ; *Telomere ; },
abstract = {Progressive cerebrovascular atherosclerosis and consecutive stroke are among the most common causes of dementia. However, specific risk factors for vascular dementia are still not known. Human telomeres shorten with each cell division in vitro and with donor age in vivo. In human fibroblasts in vitro, the telomere shortening rate decreased with increasing antioxidative capacity. There was a good intra-individual correlation between the age-corrected telomere lengths in fibroblasts and peripheral blood mononuclear cells. In 186 individuals including 149 geriatric patients (age range, 55-98 yr), leukocyte telomeres in patients with probable or possible vascular dementia were significantly shorter than in three age-matched control groups, namely in cognitively competent patients suffering from cerebrovascular or cardiovascular disease alone, in patients with probable Alzheimer's dementia, and in apparently healthy control subjects. No correlation was found to polymorphisms in the apolipoprotein E and glutathione-S-transferase genes. Telomere length may be an independent predictor for the risk of vascular dementia.},
}
@article {pmid11090632,
year = {2000},
author = {Teng, SC and Chang, J and McCowan, B and Zakian, VA},
title = {Telomerase-independent lengthening of yeast telomeres occurs by an abrupt Rad50p-dependent, Rif-inhibited recombinational process.},
journal = {Molecular cell},
volume = {6},
number = {4},
pages = {947-952},
doi = {10.1016/s1097-2765(05)00094-8},
pmid = {11090632},
issn = {1097-2765},
support = {R37GM26938/GM/NIGMS NIH HHS/United States ; R37GM43265/GM/NIGMS NIH HHS/United States ; },
mesh = {Carrier Proteins/*metabolism ; *DNA-Binding Proteins ; Fungal Proteins/*metabolism ; *Recombination, Genetic ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; Telomerase/metabolism ; Telomere/*physiology/ultrastructure ; Telomere-Binding Proteins ; Zinc Fingers ; },
abstract = {Type II survivors arise in Saccharomyces cells lacking telomerase by a recombinational pathway that results in very long and heterogeneous length telomeres. Here we show that type II telomeres appeared abruptly in a population of cells with very short telomeres. Once established, these long telomeres progressively shortened. Short telomeres were substrates for rare, one-step lengthening events. The generation of type II survivors was absolutely Rad50p dependent. In a telomerase-proficient cell, the telomere-binding Rif proteins inhibited telomerase lengthening of telomeres. In a telomerase-deficient strain, Rif proteins, especially Rif2p, inhibited type II recombination. These data argue that only short telomeres are substrates for type II recombination and suggest that the donor for this recombination is not a chromosomal telomere.},
}
@article {pmid11090621,
year = {2000},
author = {Miller, MC and Collins, K},
title = {The Tetrahymena p80/p95 complex is required for proper telomere length maintenance and micronuclear genome stability.},
journal = {Molecular cell},
volume = {6},
number = {4},
pages = {827-837},
doi = {10.1016/s1097-2765(05)00078-x},
pmid = {11090621},
issn = {1097-2765},
support = {GM54198/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Carrier Proteins/genetics/*metabolism ; Gene Deletion ; *Genome, Protozoan ; Micronucleus, Germline/*genetics ; Phenotype ; Protein Subunits ; Protozoan Proteins/*metabolism ; RNA, Protozoan/genetics ; RNA-Binding Proteins/genetics/*metabolism ; Recombinant Proteins/metabolism ; Telomerase/*metabolism ; Telomere/*genetics ; *Telomere-Binding Proteins ; Tetrahymena/enzymology/*genetics/growth &amp; development ; Transformation, Genetic ; },
abstract = {The telomerase enzyme adds simple sequence repeats to chromosome ends. Telomerases share two essential subunits, telomerase RNA and telomerase reverse transcriptase, that associate with species-specific proteins of predominantly unknown functions. The Tetrahymena p80/p95 complex can coimmunopurify active telomerase from cell extract, and recombinant p80/p95 can interact directly with telomerase RNA and single-stranded telomeric DNA in vitro. Here, we test the functions of p80/p95 in vivo. Surprisingly, telomerase RNA accumulation and telomerase activity in cell extract are unaffected by loss of the genes encoding p80/p95. However, in the absence of p80/p95, telomeres become elongated in both macronuclei and micronuclei. Micronuclear chromosome maintenance is also compromised. These findings suggest that p80/p95 functions to maintain appropriate telomere length and micronuclear genomic stability but does so in a manner different than previously anticipated.},
}
@article {pmid11090128,
year = {2000},
author = {Hsu, HL and Gilley, D and Galande, SA and Hande, MP and Allen, B and Kim, SH and Li, GC and Campisi, J and Kohwi-Shigematsu, T and Chen, DJ},
title = {Ku acts in a unique way at the mammalian telomere to prevent end joining.},
journal = {Genes &amp; development},
volume = {14},
number = {22},
pages = {2807-2812},
pmid = {11090128},
issn = {0890-9369},
support = {R01 AG011658/AG/NIA NIH HHS/United States ; R37 CA050519/CA/NCI NIH HHS/United States ; CA39681/CA/NCI NIH HHS/United States ; R37 CA039681/CA/NCI NIH HHS/United States ; AG17709/AG/NIA NIH HHS/United States ; R01 CA039681/CA/NCI NIH HHS/United States ; CA50519/CA/NCI NIH HHS/United States ; R01 CA050519/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; *Antigens, Nuclear ; Cells, Cultured ; *Chromosome Aberrations ; *DNA Helicases ; DNA-Binding Proteins/*metabolism ; Embryo, Mammalian/cytology ; Fibroblasts/cytology ; Humans ; Ku Autoantigen ; Mice ; Models, Genetic ; Nuclear Proteins/*metabolism ; Protein Binding ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1 ; },
abstract = {Telomeres are specialized DNA/protein structures that act as protective caps to prevent end fusion events and to distinguish the chromosome ends from double-strand breaks. We report that TRF1 and Ku form a complex at the telomere. The Ku and TRF1 complex is a specific high-affinity interaction, as demonstrated by several in vitro methods, and exists in human cells as determined by coimmunoprecipitation experiments. Ku does not bind telomeric DNA directly but localizes to telomeric repeats via its interaction with TRF1. Primary mouse embryonic fibroblasts that are deficient for Ku80 accumulated a large percentage of telomere fusions, establishing that Ku plays a critical role in telomere capping in mammalian cells. We propose that Ku localizes to internal regions of the telomere via a high-affinity interaction with TRF1. Therefore, Ku acts in a unique way at the telomere to prevent end joining.},
}
@article {pmid11090091,
year = {2000},
author = {Mathioudakis, G and Storb, R and McSweeney, PA and Torok-Storb, B and Lansdorp, PM and Brümmendorf, TH and Gass, MJ and Bryant, EM and Storek, J and Flowers, ME and Gooley, T and Nash, RA},
title = {Polyclonal hematopoiesis with variable telomere shortening in human long-term allogeneic marrow graft recipients.},
journal = {Blood},
volume = {96},
number = {12},
pages = {3991-3994},
pmid = {11090091},
issn = {0006-4971},
support = {CA15704/CA/NCI NIH HHS/United States ; CA18221/CA/NCI NIH HHS/United States ; HL36444/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; *Bone Marrow Transplantation/standards ; Cell Division/physiology ; Child ; Child, Preschool ; Female ; Follow-Up Studies ; Granulocytes/ultrastructure ; Hematopoiesis/*physiology ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Nuclear Family ; Polymorphism, Restriction Fragment Length ; Sex Factors ; Telomere/*ultrastructure ; Transplantation Chimera ; Transplantation, Homologous ; X Chromosome/ultrastructure ; },
abstract = {Donor-derived hematopoiesis was assessed in 17 patients who received allogeneic marrow grafts from HLA-matched siblings between 1971 and 1980. Complete blood counts were normal or near normal in all patients except one. Chimerism analyses, using either dual-color XY-chromosome fluorescence in situ hybridization (FISH) or analysis of variable number tandem repeat loci, indicated that 15 out of 16 patients had greater than 97% donor-derived hematopoiesis, whereas 1 patient had indeterminate chimerism. All 12 recipients of grafts from female donors exhibited polyclonal hematopoiesis by X-linked clonal analysis with the use of molecular probes. Of the 17 recipients, 9 exhibited a less than 1.0-kilobase shortening of granulocyte telomere length compared with their respective donors, according to terminal restriction fragment analysis or flow-FISH with a fluorescein-labeled peptide nucleic acid probe. These data suggest that under standard transplantation conditions, the stem cell proliferative potential is not compromised during hematopoietic reconstitution. (Blood. 2000;96:3991-3994)},
}
@article {pmid11089588,
year = {2000},
author = {Middleton, SB and Pack, K and Phillips, RK},
title = {Telomere length in familial adenomatous polyposis-associated desmoids.},
journal = {Diseases of the colon and rectum},
volume = {43},
number = {11},
pages = {1535-1539},
doi = {10.1007/BF02236734},
pmid = {11089588},
issn = {0012-3706},
mesh = {Abdominal Neoplasms/complications/*genetics ; Adenomatous Polyposis Coli/complications/*genetics ; Adolescent ; Adult ; Blotting, Southern ; DNA, Neoplasm/*analysis ; Female ; Fibromatosis, Aggressive/etiology/*genetics ; Genetic Markers ; Humans ; Male ; Middle Aged ; Telomere/*genetics ; },
abstract = {PURPOSE: The aim of this study was to establish the length of telomeres in familial adenomatous polyposis-associated desmoids.<br><br>METHODS: DNA from 21 desmoids and five desmoid precursor lesions was digested with HinfI and RsaI restriction enzymes. Southern blotting of the resolved fragments was performed, and the membranes were hybridized with a specific probe attached to a chemiluminescent substrate. Terminal restriction fragment lengths were measured.<br><br>RESULTS: The median terminal restriction fragment length for the desmoids was 8 (range, 6-9.6) vs. 7.7 (range, 6.4-9.9) kb for their controls. Median terminal restriction fragment length for the desmoid precursor lesions was 9 (range, 7.8-10.4) vs. 8.8 (range, 6.8-10.9) kb for their controls. There was no statistically significant difference between samples and their controls.<br><br>CONCLUSION: Immortality may not be necessary for desmoid development, or there may be other mechanisms maintaining telomere length. Novel treatments involving telomerase inhibition will be inappropriate in the management of desmoids.},
}
@article {pmid11087056,
year = {2000},
author = {Chong EYY, and Pang JCS, and Ko, CW and Poon, WS and Ng, HK},
title = {Telomere length and telomerase catalytic subunit expression in non-astrocytic gliomas.},
journal = {Pathology, research and practice},
volume = {196},
number = {10},
pages = {691-699},
doi = {10.1016/s0344-0338(00)80121-1},
pmid = {11087056},
issn = {0344-0338},
mesh = {Adolescent ; Adult ; Aged ; Carrier Proteins/genetics ; Catalysis ; Central Nervous System Neoplasms/*enzymology/metabolism/*ultrastructure ; Child ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; DNA-Binding Proteins ; Female ; Glioma/*enzymology/*ultrastructure ; Humans ; Isoenzymes/*metabolism ; Male ; Middle Aged ; *RNA ; RNA, Messenger/metabolism ; RNA-Binding Proteins ; Retinoblastoma Protein/metabolism ; Telomerase/genetics/*metabolism ; Telomere/*ultrastructure ; },
abstract = {Telomerase activation has been implicated as a major factor in the development of cancer. In our previous study we reported on the telomerase activity of a variety of gliomas. To further investigate the role of telomere and telomerase regulation in the pathogenesis of non-astrocytic gliomas, we examined the telomere length and the mRNA expression of telomerase reverse transcriptase gene (hTERT) and telomerase-associated protein (hTEP) in a series of 27 oligodendroglial and 18 ependymal tumors in this study. No statistical difference was found between the mean telomere length in telomerase-positive and telomerase-negative tumors (11.5 kb vs 13.1 kb; p = 0.424), although a slightly shorter length was observed in telomerase-positive oligodendroglial tumors. mRNA expression of hTERT was highly correlated with the telomerase activity status. hTERT was expressed in 8/8 (100%) and 2/2 (100%) telomerase-positive oligodendroglial and ependymal tumors, respectively, whereas 3/6 (50%) telomerase-negative oligodendroglial tumors and no telomerase-negative ependymal tumors showed expression. In contrast, hTEP1 mRNA was widely expressed in both telomerase-positive and telomerase-negative oligodendroglial and ependymal tumors. Our data support the notion that hTERT plays a critical role in determining the enzymatic activity of human telomerase. It has recently been proposed that both p16(INK4)/Rb pathway inactivation and telomerase activity were required for immortalization of epithelial cells. Although lack of p(16INK4a) expression was detected in a substantial proportion of tumors, no correlation between the p16(INK4a) or pRb protein expression and telomerase activity was observed in our series of non-astrocytic tumors.},
}
@article {pmid11082508,
year = {2000},
author = {Batliwalla, FM and Rufer, N and Lansdorp, PM and Gregersen, PK},
title = {Oligoclonal expansions in the CD8(+)CD28(-) T cells largely explain the shorter telomeres detected in this subset: analysis by flow FISH.},
journal = {Human immunology},
volume = {61},
number = {10},
pages = {951-958},
doi = {10.1016/s0198-8859(00)00157-9},
pmid = {11082508},
issn = {0198-8859},
mesh = {CD28 Antigens/*analysis ; CD8-Positive T-Lymphocytes/cytology/*immunology/ultrastructure ; Clone Cells ; Flow Cytometry/methods ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Interferon-gamma/biosynthesis ; Interleukin-2/biosynthesis ; Receptors, Antigen, T-Cell, alpha-beta/analysis ; T-Lymphocyte Subsets/cytology/*immunology/ultrastructure ; Telomere/*ultrastructure ; },
abstract = {We have previously reported that CD8(+)CD28(-) T cells have relatively shorter telomeres compared with CD8(+)CD28(+) T cells. Oligoclonal expansion is a common feature of CD8(+) T cells in human peripheral blood, and these expansions predominantly occur in the CD57(+)/CD28(-) population. We studied the telomere length in subsets of CD8(+) T cells using quantitative fluorescence in situ hybridization and flow cytometry (flow FISH). Our results confirm that CD8(+)CD28(-) T cells have shorter telomeres as compared with their CD28(+) counterpart cells. In addition, the oligoclonally expanded cells within the CD8(+)CD28(-) T cell subset generally have even shorter telomeres than the CD28(-) subset as a whole. We conclude that the presence of clonal expansions in the CD8(+)CD28(-) T cell population largely explain the shorter telomeres in this subset. These clonally expanded CD8(+)CD28(-) T cells generally have characteristics of terminally differentiated effector cells. Nevertheless, there is considerable individual variation in the degree of telomere shortening in these cells, which may reflect host genetic factors as well as the type and timing of the antigenic exposure.},
}
@article {pmid11081503,
year = {2000},
author = {Blackburn, EH},
title = {Telomere states and cell fates.},
journal = {Nature},
volume = {408},
number = {6808},
pages = {53-56},
doi = {10.1038/35040500},
pmid = {11081503},
issn = {0028-0836},
mesh = {Animals ; Cell Cycle/*physiology ; Cellular Senescence/*genetics/physiology ; DNA Damage ; Humans ; Kluyveromyces/physiology ; Mice ; Models, Biological ; Saccharomyces cerevisiae/physiology ; *Telomere ; },
}
@article {pmid11080530,
year = {2000},
author = {Friedrich, U and Griese, E and Schwab, M and Fritz, P and Thon, K and Klotz, U},
title = {Telomere length in different tissues of elderly patients.},
journal = {Mechanisms of ageing and development},
volume = {119},
number = {3},
pages = {89-99},
doi = {10.1016/s0047-6374(00)00173-1},
pmid = {11080530},
issn = {0047-6374},
mesh = {Aged ; Aged, 80 and over ; Aging/*genetics/physiology ; Humans ; Skin/cytology ; Synovial Membrane/cytology ; Telomere/*physiology ; Tissue Donors ; },
abstract = {Telomeres are supposed to play a role in cellular aging and might contribute to the genetic background of human aging and longevity. During the past few years telomere length has been measured in various human tissues. However, very little is known about the individual telomere loss in different tissues from the same donor. Therefore we have measured telomere restriction fragment (TRF) length in three unrelated tissues (leukocytes, skin and synovial tissue) of nine elderly patients (age range 73-95 years old). Dependent on the tissue specific proliferation rate we have found significantly shorter telomeres (6546+/-519 bp, mean +/- S.D.) in leukocytes compared to skin (7792+/-596 bp, P<0.01) and synovial tissue (7910+/-420 bp, P<0.001). In general, we have observed an inverse relationship between donor age and TRF length which becomes significant in leukocytes (P=0.04, R(2)=0.49) and skin specimens (P=0.006, R(2)=0.81). Interestingly, linear correlations (P values between 0.017 and 0.038, R(2) values between 0.54 and 0.79) were also obtained on comparison of telomere length in each pair of two different tissues from the same donor without taking donor age into account. This suggests that genetic determination of the regulation of telomere length is tissue-independent. Furthermore, our results indicate that TRF measurement in easily accessible tissues such as blood could serve as a surrogate parameter for the relative telomere length in other tissues.},
}
@article {pmid11078808,
year = {2000},
author = {Pathak, S and Multani, AS and McConkey, DJ and Imam, AS and Amoss, MS},
title = {Spontaneous regression of cutaneous melanoma in sinclair swine is associated with defective telomerase activity and extensive telomere erosion.},
journal = {International journal of oncology},
volume = {17},
number = {6},
pages = {1219-1224},
doi = {10.3892/ijo.17.6.1219},
pmid = {11078808},
issn = {1019-6439},
support = {P01CA 49488/CA/NCI NIH HHS/United States ; RRO 4999-01/RR/NCRR NIH HHS/United States ; },
mesh = {Animals ; Apoptosis/*genetics ; Chromosome Aberrations ; DNA Fragmentation ; G2 Phase ; Humans ; In Situ Hybridization, Fluorescence ; Inbreeding ; Melanoma/enzymology/genetics/pathology/*veterinary ; Models, Animal ; Models, Genetic ; Neoplasm Proteins/*deficiency/genetics ; Nevus, Pigmented/enzymology/genetics/pathology/veterinary ; Polymerase Chain Reaction ; Remission, Spontaneous ; Skin Neoplasms/enzymology/genetics/pathology/*veterinary ; Swine ; Swine Diseases/enzymology/*pathology ; Swine, Miniature ; Telomerase/*deficiency/genetics ; Telomere/*ultrastructure ; },
abstract = {Recently we proposed the hypothesis that extensive telomeric association of chromosomes is an early manifestation of cell death and asked whether there are extensive telomeric associations present in metaphases of the spontaneously regressing Sinclair swine cutaneous melanoma (SSCM). Our results indicate that early passage SSCMs, in the accelerated growth phase, do not show telomeric associations but do have numerical and other specific structural abnormalities. However, the same melanoma cell lines at late passages or melanomas obtained from middle- and old-aged Sinclair swine show extensive telomeric associations in the form of dicentric, multicentric, and ring configurations. Such abnormal structures are present mostly in metaphases that are hyperploids. Increasing frequencies of apoptotic bodies were also observed in higher passage tumor cell lines obtained from younger animals or in melanomas obtained from older animals. The polymerase chain reaction (PCR)-based telomeric repeat amplification protocol (TRAP) assay shows no detectable telomerase activity in any of these regressing swine melanoma cell lines, neither in normal swine skin fibroblasts nor in nevi. However, the fetal swine (i.e., non-regressing) melanoma cells show telomerase activity. Fluorescence in situ hybridization (FISH) results using the commercially available human telomeric repeat DNA probe indicate a reduction of telomeric signals in metaphase and interphase cells of regressing melanomas. From these observations we conclude that spontaneous regression of SSCM is associated with the loss of telomerase activity and a reduction of telomeric repeats that results in the formation of multicentric and ring configurations. Such abnormal chromosome configurations are lost, following the breakage-fusion-bridge-cycles, and result in extensive DNA fragmentation, as shown by laddering experiments, and, finally, cell death.},
}
@article {pmid11078086,
year = {2000},
author = {Takubo, K and Nakamura, K and Izumiyama, N and Furugori, E and Sawabe, M and Arai, T and Esaki, Y and Mafune, K and Kammori, M and Fujiwara, M and Kato, M and Oshimura, M and Sasajima, K},
title = {Telomere shortening with aging in human liver.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {55},
number = {11},
pages = {B533-6},
doi = {10.1093/gerona/55.11.b533},
pmid = {11078086},
issn = {1079-5006},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*pathology ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Infant, Newborn ; Liver/*ultrastructure ; Male ; Middle Aged ; *Telomere ; },
abstract = {Progressive telomere shortening with aging was studied in the normal liver tissue of 94 human subjects aged between 0 and 101 years old to determine the rate of telomere loss in 1 year. Telomere length demonstrated accelerated shortening with reduction of 55 base pairs (bp) per year. The mean telomere length in five neonates was 12.9 +/- 2.6 kilobase pairs (kbp), and that in one centenarian was 8.3 kbp. Mean telomere lengths by age group were 13.2 +/- 2.0 kbp (< or = 8 years; 10 subjects), 7.8 +/- 1.9 kbp (40-79 years; 29 subjects), and 7.5 +/- 2.0 kbp (> or = 80 years; 53 subjects), with reduction thus appearing to show slowing on the attainment of middle age. The difference of mean telomere lengths for two groups with or without advanced malignancies of other than liver origin was not significant in the older two groups. Despite the slow turnover of liver tissue, the overall reduction rate of telomere length decrease in 1 year was almost the same as that of digestive tract mucosa, with its very rapid renewal.},
}
@article {pmid11074557,
year = {2000},
author = {Kakazu, N and Kito, K and Hitomi, T and Oita, J and Nishida, K and Masuda, K and Miki, T and Abe, T},
title = {Characterization of complex chromosomal abnormalities in B-cell lymphoma by a combined spectral karyotyping (SKY) analysis and fluorescence in situ hybridization (FISH) using a 14q telomere probe.},
journal = {American journal of hematology},
volume = {65},
number = {4},
pages = {291-297},
doi = {10.1002/1096-8652(200012)65:4&lt;291::aid-ajh7&gt;3.0.co;2-7},
pmid = {11074557},
issn = {0361-8609},
mesh = {*Chromosome Aberrations ; *Chromosome Disorders ; *Chromosomes, Human, Pair 14 ; *Chromosomes, Human, Pair 2 ; *Chromosomes, Human, Pair 22 ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Lymphoma, B-Cell/*genetics/pathology/ultrastructure ; Middle Aged ; },
abstract = {We report a case of non-Hodgkin's lymphoma of unknown origin with invasion into bone marrow and brain. This case showed complex chromosomal abnormalities, including five clonal marker chromosomes (mar) and four additional materials of unknown origin (add) that could not be identified by means of conventional G-banding. Spectral karyotyping (SKY) analysis could not only determine the origin and organization of all thus far unidentified structural chromosomal abnormalities but also detect two cryptic unbalanced translocations, which had been erroneously considered to be normal on the basis of G-banding analysis, and correct one abnormality misidentified by G banding. Among these abnormalities, we identified the new partner site of the 14q32 translocation, 22q13, and the jumping translocations involving 2p23 as a new donor chromosome. Furthermore, by using fluorescence in situ hybridization (FISH) with the probes specific for the 14q telomere, we could identify the unbalanced translocation of t(3;14)(q27;q32), which had been erroneously considered to be normal chromosome 3 on the basis of not only G-banding but also of SKY analysis. This translocation is one of the most frequent chromosomal abnormalities in B-cell lymphoma, especially diffuse large cell lymphoma. After SKY and FISH analysis, the original descriptions in the G-band karyotype were modified for a total of 13 chromosomes. The combination of SKY and FISH using the 14q telomere probe was therefore considered very useful for the characterization of complex cytogenetic cases in B-cell lymphoma.},
}
@article {pmid11071936,
year = {2000},
author = {Tomaska, L and Nosek, J and Makhov, AM and Pastorakova, A and Griffith, JD},
title = {Extragenomic double-stranded DNA circles in yeast with linear mitochondrial genomes: potential involvement in telomere maintenance.},
journal = {Nucleic acids research},
volume = {28},
number = {22},
pages = {4479-4487},
pmid = {11071936},
issn = {1362-4962},
support = {R01 GM031819/GM/NIGMS NIH HHS/United States ; CA-70343/CA/NCI NIH HHS/United States ; GM-31819/GM/NIGMS NIH HHS/United States ; },
mesh = {Candida/*genetics ; DNA, Circular/*genetics/metabolism/ultrastructure ; DNA, Mitochondrial/*genetics/metabolism/ultrastructure ; Deoxyribonuclease EcoRI/metabolism ; Electrophoresis, Agar Gel ; Electrophoresis, Gel, Two-Dimensional ; Microscopy, Electron ; Pichia/*genetics ; Telomere/genetics ; },
abstract = {Although the typical mitochondrial DNA (mtDNA) is portrayed as a circular molecule, a large number of organisms contain linear mitochondrial genomes classified by their telomere structure. The class of mitochondrial telomeres identified in three yeast species, Candida parapsilosis, Pichia philodendra and Candida salmanticensis, is characterized by inverted terminal repeats each consisting of several tandemly repeating units and a 5' single-stranded extension. The molecular mechanisms of the origin, replication and maintenance of this type of mitochondrial telomere remain unknown. While studying the replication of linear mtDNA of C.parapsilosis by 2-D gel electrophoresis distinct DNA fragments composed solely of mitochondrial telomeric sequences were detected and their properties were suggestive of a circular conformation. Electron microscopic analysis of these DNAs revealed the presence of highly supertwisted circular molecules which could be relaxed by DNase I. The minicircles fell into distinct categories based on length, corresponding to n x 0.75 kb (n = 1-7). Similar results were obtained with two other yeast species (P.philodendra and C. salmanticensis) which possess analogous telomeric structure.},
}
@article {pmid11071935,
year = {2000},
author = {Hemann, MT and Greider, CW},
title = {Wild-derived inbred mouse strains have short telomeres.},
journal = {Nucleic acids research},
volume = {28},
number = {22},
pages = {4474-4478},
pmid = {11071935},
issn = {1362-4962},
support = {P01 CA016519/CA/NCI NIH HHS/United States ; CA16519/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; DNA/genetics ; Electrophoresis, Gel, Pulsed-Field ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Inbred C57BL ; Mice, Inbred Strains ; Muridae ; Spleen/cytology/metabolism ; Telomere/*genetics ; },
abstract = {Telomere length and telomerase activity directly affect the replicative capacity of primary human cells. Some have suggested that telomere length influences organismal lifespan. We compared telomere length distributions in a number of inbred and outbred established mouse strains with those of strains recently derived from wild mice. Telomere length was considerably shorter in wild-derived strains than in the established strains. We found no correlation of telomere length with lifespan, even among closely related inbred mouse strains. Thus, while telomere length plays a role in cellular lifespan in cultured human cells, it is not a major factor in determining organismal lifespan.},
}
@article {pmid11071389,
year = {2000},
author = {Reddy, KS and Murphy, T},
title = {Fusion of 9 beta-satellite and telomere (TTAGGG)n sequences results in a jumping translocation.},
journal = {Human genetics},
volume = {107},
number = {3},
pages = {268-275},
doi = {10.1007/s004390000360},
pmid = {11071389},
issn = {0340-6717},
mesh = {Asian ; Cesarean Section ; *Chromosomes, Human, Pair 9 ; *DNA, Satellite ; Female ; Fetal Growth Retardation/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Infant, Newborn ; Isochromosomes ; Korea/ethnology ; Male ; Pregnancy ; *Telomere ; *Translocation, Genetic ; Trisomy ; },
abstract = {A newborn was found to have an isochromosome for the short arm of chromosome 9, i(9p) and a jumping translocation of the whole long arm. In 94.4% metaphases, 9q was fused to the telomere of chromosome 19p and, in 5.6% of metaphases, 9q was fused to the telomere of chromosome 8p. The net result was trisomy for the short arm of chromosome 9. With the pan telomere probe, fluorescent in situ hybridization (FISH) investigations found an interstitial telomere on the der(19) and der(8). The 9 beta and classical satellite probes gave a signal only on the long arm of chromosome 9 involved in the jumping translocation. The 9 alpha satellite probe hybridized to i(9p) and not to the other derivative chromosomes. A combination of chromosome 9 (red) and chromosome 19 (green) paint probes used to rapidly screen metaphases for the jumping translocation found 88 metaphases had a der(19)t(9;19) and 4metaphases had a der(8)t(8;9). For the first time, the junction of a jumping translocation has been shown to involve the telomere sequence (TTAGGG)n and beta-satellite sequences by FISH. In this paper, we also review the simultaneous occurrence of an isochromosome for the short arm and translocation of the whole long arm and constitutional jumping translocations.},
}
@article {pmid11071289,
year = {2000},
author = {Bishop, R and Gobright, E and Nene, V and Morzaria, S and Musoke, A and Sohanpal, B},
title = {Polymorphic open reading frames encoding secretory proteins are located less than 3 kilobases from Theileria parva telomeres.},
journal = {Molecular and biochemical parasitology},
volume = {110},
number = {2},
pages = {359-371},
doi = {10.1016/s0166-6851(00)00291-7},
pmid = {11071289},
issn = {0166-6851},
mesh = {Amino Acid Sequence ; Animals ; Blotting, Southern ; Cattle ; *Chromosome Mapping ; DNA, Complementary/genetics ; Deoxyribonucleases, Type II Site-Specific/metabolism ; Electrophoresis, Gel, Pulsed-Field ; Molecular Sequence Data ; Open Reading Frames/*genetics ; Polymorphism, Genetic ; Protozoan Proteins/chemistry/*genetics/metabolism ; Sequence Analysis, DNA ; Telomere/*genetics ; Theileria parva/*genetics ; Theileriasis/parasitology ; },
abstract = {Polymorphic, multicopy gene families are frequently located in subtelomeric regions of the genomes of parasitic protozoa. Theileria parva telomere-associated (TA) DNA from two chromosomes contained long open reading frames (ORFs) 54% identical at the N-termini, whose 3' ends were 2670 and 2680 bp from the telomeric repeats. Probes derived from these ORFs revealed related sequences close to additional telomeres. The 3' end of an unrelated ORF was approximately 2720 bp from a third telomere. These are among the closest ORFs to telomeres in any organism. Reverse transcription PCR detected transcripts originating within the telomeric multicopy gene family. Additional ORFs, with complex sequence similarities, were located centromeric to the telomere-adjacent ORFs. Transcripts from the schizont stage of T. parva, containing domains with significant amino acid similarity to a 3529 codon ORF located 6900 bp upstream of the telomeric repeats, were mapped to a subtelomeric locus at a fourth telomere. Five telomeric ORFs contained predicted N-terminal signal peptides and one of these signal peptides was functional in a heterologous system. Hybridisation data suggested extensive strain polymorphism between ORFs. Two of the telomere-adjacent ORFs were absent from the genome of a cloned T. parva parasite which can, nonetheless, be passaged through ticks and cattle. T. parva is unusual, among organisms so far studied, in the high density of potential coding sequences located directly adjacent to telomeres and the apparent absence of extensive tracts of repeated sequences within the TA DNA.},
}
@article {pmid11070833,
year = {2001},
author = {Poon, SS and Lansdorp, PM},
title = {Measurements of telomere length on individual chromosomes by image cytometry.},
journal = {Methods in cell biology},
volume = {64},
number = {},
pages = {69-96},
doi = {10.1016/s0091-679x(01)64007-x},
pmid = {11070833},
issn = {0091-679X},
support = {AI29524/AI/NIAID NIH HHS/United States ; GM56162/GM/NIGMS NIH HHS/United States ; },
mesh = {Algorithms ; Blotting, Southern ; Chromosomes/*ultrastructure ; Chromosomes, Human/*ultrastructure ; DNA Probes ; Humans ; *Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence/*methods ; Microscopy, Fluorescence/instrumentation/methods ; Telomere/*ultrastructure ; },
}
@article {pmid11069113,
year = {2000},
author = {Smith, S and de Lange, T},
title = {Tankyrase promotes telomere elongation in human cells.},
journal = {Current biology : CB},
volume = {10},
number = {20},
pages = {1299-1302},
doi = {10.1016/s0960-9822(00)00752-1},
pmid = {11069113},
issn = {0960-9822},
support = {CA76027/CA/NCI NIH HHS/United States ; },
mesh = {DNA-Binding Proteins/metabolism ; Fibrosarcoma ; HeLa Cells ; Humans ; Kinetics ; Poly(ADP-ribose) Polymerases/metabolism ; *Tankyrases ; Telomere/*physiology ; Telomeric Repeat Binding Protein 1 ; Tumor Cells, Cultured ; },
abstract = {Human telomeres are maintained by telomerase, a reverse transcriptase that adds telomeric repeats to chromosome ends [1,2]. In human tumors and immortalized cells, telomeres are often maintained at a constant length setting [3,4], indicating that telomerase-mediated telomere elongation is tightly regulated. Tankyrase, a telomeric poly(ADP-ribose) polymerase (PARP) [5], was identified through its interaction with TRF1 [6], a negative regulator of telomere extension by telomerase [7]. Tankyrase-mediated ADP-ribosylation inhibits binding of TRF1 to telomeric repeats in vitro [5], suggesting that tankyrase might regulate TRF1 and therefore control telomere dynamics in vivo. Here, we present evidence that tankyrase acts as a positive regulator of telomere elongation in vivo, apparently by inhibiting TRF1. Overexpression of tankyrase in the nucleus diminished the level of unmodified TRF1 in immunoblots and led to reduced immunofluorescence of TRF1 at interphase telomeres. Long-term overexpression of tankyrase in telomerase-positive human cells resulted in a gradual and progressive elongation of telomeres. A PARP-deficient form of tankyrase failed to affect TRF1 and did not alter telomere length dynamics, consistent with ADP-ribosylation of TRF1 as the main cause of altered telomere homeostasis. Our results indicate that tankyrase can induce telomere elongation in human cells. We propose that tankyrase-mediated ADP-ribosylation of TRF1 opens the telomeric complex, allowing access to telomerase.},
}
@article {pmid11066050,
year = {2000},
author = {Chen, HJ and Liang, CL and Lu, K and Lin, JW and Cho, CL},
title = {Implication of telomerase activity and alternations of telomere length in the histologic characteristics of intracranial meningiomas.},
journal = {Cancer},
volume = {89},
number = {10},
pages = {2092-2098},
doi = {10.1002/1097-0142(20001115)89:10&lt;2092::aid-cncr9&gt;3.0.co;2-n},
pmid = {11066050},
issn = {0008-543X},
mesh = {Adult ; Aged ; Humans ; Meningeal Neoplasms/*enzymology/genetics ; Meningioma/*enzymology/genetics ; Middle Aged ; Telomerase/*metabolism ; *Telomere ; },
abstract = {BACKGROUND: Telomerase activity and telomere length have been shown to be involved in the control of cell proliferation and regulation of cell senescence. The expression of telomerase activity may endow cells with the capacity of unlimited proliferation and immortality. The authors examined the telomerase activity and telomere length of intracranial meningiomas to determine the relation between the results and the clinicopathologic behavior of these tumors.<br><br>METHODS: Sixty-two specimens of meningiomas including 13 atypical and malignant tumors were used in this study. Telomerase activity was measured with polymerase chain reaction and enzyme-linked immunosolvent assay. Telomere length was measured by detecting the terminal restriction fragments using Southern blots.<br><br>RESULTS: Detectable telomerase activity was found in 4 of 13 (30.8%) malignant or atypical meningiomas and only 1 in 49 benign meningiomas (P = 0.006). Elongated telomere length was measured in 6 of 13 (46.1%) patients with malignant or atypical meningiomas and only 1 of 48 (2.1%) in those with benign tumors (P = 0.0002). Three of 4 (75%) of malignant or atypical meningiomas with detectable telomerase activity revealed shortened telomere length, and all tumors with elongated telomere length displayed undetectable telomerase activity. The percentage of malignant or atypical meningiomas with detectable telomerase activity or elongated telomere were significantly higher (76.9%) than that of benign tumors (4.0%). The proliferative index was calculated as the percentage of tumor cell nuclei immunoreactive for Ki-67 to total tumor nuclei. The mean values of proliferative index in benign, atypical, and malignant meningiomas were 1.2, 11.0, and 30.0, respectively.<br><br>CONCLUSIONS: The results indicate that telomerase activation may be a critical step in the pathogenesis of malignant or atypical meningioma. Elongation of the telomere length also implicates the high potential for malignant behavior in these tumors.},
}
@article {pmid11063723,
year = {2000},
author = {Okabe, J and Eguchi, A and Masago, A and Hayakawa, T and Nakanishi, M},
title = {TRF1 is a critical trans-acting factor required for de novo telomere formation in human cells.},
journal = {Human molecular genetics},
volume = {9},
number = {18},
pages = {2639-2650},
doi = {10.1093/hmg/9.18.2639},
pmid = {11063723},
issn = {0964-6906},
mesh = {Base Sequence ; Blotting, Western ; Cell Line ; Cell Survival ; Cellular Senescence ; DNA-Binding Proteins/metabolism/*physiology ; Gene Deletion ; Humans ; Repetitive Sequences, Nucleic Acid/genetics ; Telomerase/genetics/metabolism ; Telomere/*genetics/metabolism ; Telomeric Repeat Binding Protein 1 ; Trans-Activators/metabolism/*physiology ; },
abstract = {The duplex telomere repeat (TTAGGG)(n) is an essential cis-acting element of the mammalian telomere, and an exogenous telomere repeat can induce chromosome breakage and de novo telomere formation at the site of a break (telomere seeding). Telomere seeding requires the telomere repeat (TTAGGG)(n) more stringently than does an in vitro telomerase assay, suggesting that it reflects the activity of a critical trans-acting element of the functional telomere, in addition to telomerase. Furthermore, telomere seeding is induced at a frequency fluctuating widely among human cell lines, suggesting variation in the activity of this hypothetical factor among cells. In this study, we investigated the cellular factor(s) required for telomere formation using the frequency of telomere seeding as an index and identified TRF1, one of the telomere repeat binding proteins, as an essential trans-acting factor. The exogenous telomere repeat induces telomere formation at a frequency determined by the availability of TRF1, even in telomerase-negative cells. Our study shows clearly that TRF1 has a novel physiological significance distinct from its role as a regulator of telomere length in the endogenous chromosome. The possible role of TRF1 in cell aging and immortalization is discussed.},
}
@article {pmid11062462,
year = {2000},
author = {Tian, XC and Xu, J and Yang, X},
title = {Normal telomere lengths found in cloned cattle.},
journal = {Nature genetics},
volume = {26},
number = {3},
pages = {272-273},
doi = {10.1038/81559},
pmid = {11062462},
issn = {1061-4036},
mesh = {Aging/genetics ; Animals ; Cattle/*genetics ; Cellular Senescence/genetics ; *Cloning, Organism ; Female ; Longevity/genetics ; Sheep/genetics ; Species Specificity ; Telomere/*ultrastructure ; },
abstract = {Success of cloning using adult somatic cells has been reported in sheep, mice and cattle. The report that 'Dolly' the sheep, the first clone from an adult mammal, inherited shortened telomeres from her cell donor and that her telomeres were further shortened by the brief culture of donor cells has raised serious scientific and public concerns about the 'genetic age' and potential developmental problems of cloned animals. This observation was challenged by a recent report that showed calves cloned from fetal cells have longer telomeres than their age-matched controls. The question remains whether Dolly's short telomeres were an exception or a general fact, which would differ from the telomeres of fetal-derived clones.},
}
@article {pmid11060464,
year = {2000},
author = {Delany, ME and Krupkin, AB and Miller, MM},
title = {Organization of telomere sequences in birds: evidence for arrays of extreme length and for in vivo shortening.},
journal = {Cytogenetics and cell genetics},
volume = {90},
number = {1-2},
pages = {139-145},
doi = {10.1159/000015649},
pmid = {11060464},
issn = {0301-0171},
mesh = {Aging/genetics ; Animals ; Birds/*genetics ; Cell Differentiation/genetics ; Cellular Senescence/genetics ; DNA Restriction Enzymes/metabolism ; Endodeoxyribonucleases/metabolism ; Erythrocytes/metabolism ; Gene Expression Regulation, Developmental ; Karyotyping ; Male ; Repetitive Sequences, Nucleic Acid/genetics ; Spermatozoa/metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Telomeres are the specialized ends of chromosomes consisting of highly conserved repeat (5'-TTAGGG-3')(n) sequences. Lack of information regarding the existence of an in vivo telomere clock function in birds, conflicting data regarding telomere array length in the chicken model, and the paucity of molecular telomere information for other avian species led us to study telomere array organization within and among 18 species and subspecies of birds. Most of the species contained between 2% and 4% telomere sequence per diploid genome. Arrays spanning 0.5-10 kb (Class I) and 10-40 kb (Class II) were observed in all of the species studied. Extremely long arrays, ranging from hundreds of kilobases to 1-2 Mb (Class III) were observed in all except two raptor species, the northern goshawk and American bald eagle. In chicken, there was evidence for shortening of the Class II arrays in vivo, based on intraindividual comparisons of somatic versus germline tissues in birds of different ages; terminally differentiated erythrocyte arrays were, on average, 2.3 kb shorter than sperm (germline) arrays. This study provides the first evidence for the existence of telomere arrays significantly larger than have been described for any vertebrate species to date and for developmentally programmed in vivo telomere shortening in the Aves taxa. The novel finding of megabase-sized telomere arrays may be an important feature of avian karyotypes that contain a large number of very small genetic units, the microchromosomes.},
}
@article {pmid11057447,
year = {2000},
author = {Abdennadher, M and Mills, D},
title = {Telomere-associated RFLPs and electrophoretic karyotyping reveal lineage relationships among race-specific strains of Ustilago hordei.},
journal = {Current genetics},
volume = {38},
number = {3},
pages = {141-147},
doi = {10.1007/s002940000138},
pmid = {11057447},
issn = {0172-8083},
support = {RR-07-079/RR/NCRR NIH HHS/United States ; },
mesh = {Blotting, Southern ; Cell Lineage/*genetics ; Chromosome Deletion ; Chromosome Mapping ; Chromosomes, Fungal/*genetics ; DNA, Fungal/genetics ; Inbreeding ; *Karyotyping ; Polymorphism, Genetic/*genetics ; *Polymorphism, Restriction Fragment Length ; Restriction Mapping ; Telomere/*genetics ; Translocation, Genetic ; Ustilago/*genetics/pathogenicity ; Virulence ; },
abstract = {The inheritance of telomere-associated restriction fragment length polymorphisms (tel-RFLP) and chromosome-length polymorphisms (CLPs) were criteria used for the identification of strains of Ustilago hordei that form a direct lineage. Teliospore collections of race 8 strains and strains reported to be derived from race 8 through inbreeding were used in these analyses. None of the race 8 strains examined in this study, representing three consecutive inbred generations, was polymorphic for any terminal BamHI and BglII chromosomal loci, nor did they have any apparent CLPs. Strains from a teliospore collection obtained in 1971 and designated 447, representing the first inbred generation of race 8 strains and a shift to increased virulence on cultivar Hannchen, had tel-RFLP arrays indistinguishable from the race 8 strains isolated in this study; and they had no obvious CLPs. Strains from the presumed second inbred generation, the 1279 teliospore line, which was pathogenic on six additional cultivars, had numerous CLPs and a tel-RFLP array that differed from race 8 strains at more than 50% of the terminal chromosomal BamHI and BglII restriction sites. The tel-RFLP array of each 1279 strain was identical and indistinguishable from the arrays of strains representing races 10 and 13, indicating that they share a direct lineage. A race 14 strain, also presumed to be derived from race 8 strains by inbreeding, had a unique tel-RFLP array and an electrophoretic karyotype that distinguished it from all other strains. The tel-RFLP arrays alone eliminate the 1279 and race 14 strains from being direct descendants from race 8 strains by inbreeding and suggest that this approach can identify a strain lineage among other inbred sexually reproducing fungi, or isolates that comprise different asexual clonal populations.},
}
@article {pmid11052472,
year = {2000},
author = {Takagi, S and Kinouchi, Y and Hiwatashi, N and Nagashima, F and Chida, M and Takahashi, S and Negoro, K and Shimosegawa, T and Toyota, T},
title = {Relationship between microsatellite instability and telomere shortening in colorectal cancer.},
journal = {Diseases of the colon and rectum},
volume = {43},
number = {10 Suppl},
pages = {S12-7},
doi = {10.1007/BF02237220},
pmid = {11052472},
issn = {0012-3706},
mesh = {Aged ; Colorectal Neoplasms/enzymology/*genetics ; DNA Repair ; DNA, Neoplasm/*genetics ; Female ; Humans ; Male ; Microsatellite Repeats/*genetics ; Telomerase/*metabolism ; Telomere/*enzymology/ultrastructure ; },
abstract = {PURPOSE: Two pathways have been proposed for the development of colorectal cancers: loss of heterozygosity and replication error. Colorectal cancers arising through the replication error pathway, like most hereditary nonpolyposis colorectal cancers, show microsatellite instability. It has been also reported that telomere shortening frequently occurs in colorectal cancers and that telomerase is often activated strongly in them. The aim of this study was to examine whether any relationships can be found among microsatellite instability, telomere length, and telomerase activity in colorectal cancers.<br><br>METHODS: Genomic DNA was extracted from 55 invasive cancers and corresponding normal mucosas. Five microsatellite loci were analyzed by polymerase chain reaction. Telomere length was examined by Southern blot analysis. Telomerase activity was assayed by telomeric repeat amplification protocol with minor modifications.<br><br>RESULTS: Microsatellite instability was found in 8 (14.5 percent) of 55 tumors, and all of them showed short telomeres. Furthermore, four high-frequency microsatellite instability tumors that showed microsatellite instability at more than two loci exhibited remarkably short telomeres. The microsatellite instability correlated significantly with frequency of telomere shortening (P = 0.0183; Fisher's exact probability test), but not with strength of telomerase activity.<br><br>CONCLUSION: The relationship identified by this study between microsatellite instability and telomere shortening might suggest some association between the DNA mismatch repair system and the telomere maintenance mechanism in colorectal cancers.},
}
@article {pmid11046025,
year = {2000},
author = {Migliaccio, M and Amacker, M and Just, T and Reichenbach, P and Valmori, D and Cerottini, JC and Romero, P and Nabholz, M},
title = {Ectopic human telomerase catalytic subunit expression maintains telomere length but is not sufficient for CD8+ T lymphocyte immortalization.},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {165},
number = {9},
pages = {4978-4984},
doi = {10.4049/jimmunol.165.9.4978},
pmid = {11046025},
issn = {0022-1767},
mesh = {CD8-Positive T-Lymphocytes/cytology/*enzymology/*immunology/metabolism ; *Catalytic Domain/genetics ; Cell Culture Techniques ; Cell Division/genetics/immunology ; *Cell Line, Transformed ; Cell Separation ; DNA-Binding Proteins ; Humans ; *Lymphocyte Activation/genetics ; *RNA ; Retroviridae/genetics/immunology ; T-Lymphocytes, Cytotoxic/cytology/enzymology/immunology/metabolism ; Telomerase/*biosynthesis/genetics ; Telomere/*metabolism ; Transduction, Genetic ; },
abstract = {Like most somatic human cells, T lymphocytes have a limited replicative life span. This phenomenon, called senescence, presents a serious barrier to clinical applications that require large numbers of Ag-specific T cells such as adoptive transfer therapy. Ectopic expression of hTERT, the human catalytic subunit of the enzyme telomerase, permits fibroblasts and endothelial cells to avoid senescence and to become immortal. In an attempt to immortalize normal human CD8(+) T lymphocytes, we infected bulk cultures or clones of these cells with a retrovirus transducing an hTERT cDNA clone. More than 90% of transduced cells expressed the transgene, and the cell populations contained high levels of telomerase activity. Measuring the content of total telomere repeats in individual cells (by flowFISH) we found that ectopic hTERT expression reversed the gradual loss of telomeric DNA observed in control populations during long term culture. Telomere length in transduced cells reached the levels observed in freshly isolated normal CD8(+) lymphocytes. Nevertheless, all hTERT-transduced populations stopped to divide at the same time as nontransduced or vector-transduced control cells. When kept in IL-2 the arrested cells remained alive. Our results indicate that hTERT may be required but is not sufficient to immortalize human T lymphocytes.},
}
@article {pmid11044370,
year = {2000},
author = {Rudenko, G},
title = {The polymorphic telomeres of the African Trypanosome trypanosoma brucei.},
journal = {Biochemical Society transactions},
volume = {28},
number = {5},
pages = {536-540},
pmid = {11044370},
issn = {0300-5127},
support = {/WT_/Wellcome Trust/United Kingdom ; 095161/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; *Genome, Protozoan ; Polymorphism, Genetic ; Telomere/*genetics ; Trypanosoma brucei brucei/*genetics ; },
abstract = {African trypanosomes have plastic genomes with extensive variability at the chromosome ends. The genes encoding the expressed major surface protein of the infective bloodstream form stages of Trypanosoma brucei and are located at telomeres. These telomeric expression-site transcription units are turning out to be surprisingly polymorphic in structure and sequence.},
}
@article {pmid11043836,
year = {2000},
author = {Sitarz, M and Wirth-Dzieciolowska, E and Demant, P},
title = {Loss of heterozygosity on chromosome 5 in vicinity of the telomere in gamma-radiation-induced thymic lymphomas in mice.},
journal = {Neoplasma},
volume = {47},
number = {3},
pages = {148-150},
pmid = {11043836},
issn = {0028-2685},
mesh = {Animals ; Chromosomes/radiation effects ; Female ; Gamma Rays ; *Loss of Heterozygosity/radiation effects ; Lymphoma/*genetics ; Male ; Mice ; Mice, Inbred BALB C ; Neoplasms, Radiation-Induced/*genetics ; *Telomere/genetics/radiation effects ; Thymus Neoplasms/*genetics ; },
abstract = {Analysis of the loss of heterozygosity at the D5Mit143 locus was done for thymic lymphlomas induced by gamma-irradiation of mice from two reciprocal backcrosses (BALB/c x CcS-13)F1 x BALB/c and (BALB/c x CcS-13)F1 x CcS-13. BALB/c mice are susceptible to gamma-ray induction of lymphomas. The CcS-13 strain is one of 20 CcS/Dcm (CcS) series of recombinant congenic strains, and the CcS-13 mice are resistant to gamma-radiation-induced lymphomas [1, 8]. Our preliminary tests show 50% (6/12) frequency of allelic loss at the D5Mit143 locus in thymic lymphomas induced by gamma-irradiation of the mice from (BALB/c x CcS-13)F1 x BALB/c backcross. Yet, in gamma-radiation-induced lymphomas from the backcross made in opposite direction, namely, (BALB/c x CcS-13)F1 x CcS-13, the analysis with the DSMit143 marker revealed low incidence of the loss of heterozygosity, 6.7% (15). The D5Mit143 locus resides in the distal part of chromosome 5, close to the telomere. Allelic loss of heterozygosity at the D5Mit143 locus showed strain specificity. In each case, the lost allele derived from the CcS-13 resistant strain. Our current results and previously done) linkage analysis [8] let us to suspect existence of a putative tumor suppressor gene for gamma-radiation-induced lymphoma at the region of murine chromosome 5.},
}
@article {pmid11035119,
year = {2000},
author = {Wu, K and Higashi, N and Hansen, ER and Lund, M and Bang, K and Thestrup-Pedersen, K},
title = {Telomerase activity is increased and telomere length shortened in T cells from blood of patients with atopic dermatitis and psoriasis.},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {165},
number = {8},
pages = {4742-4747},
doi = {10.4049/jimmunol.165.8.4742},
pmid = {11035119},
issn = {0022-1767},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/genetics/immunology ; Dermatitis, Atopic/blood/*enzymology/genetics/*immunology ; Female ; Humans ; Male ; Middle Aged ; Psoriasis/blood/*enzymology/genetics/*immunology ; Ribonucleases/antagonists &amp; inhibitors ; T-Lymphocytes/*enzymology/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {We studied telomerase activity and telomere length in PBMC and purified CD4(+) and CD8(+) T cells from blood obtained from a total of 32 patients with atopic dermatitis, 16 patients with psoriasis, and 30 normal controls. The telomerase activity was significantly increased in PBMC from the patients compared with PBMC from normal donors. This increase was most pronounced in the subpopulation of CD4(+) T cells, which were significantly above the activity of the CD8(+) T cells in atopic dermatitis, psoriasis patients, and control persons. The telomere length was significantly reduced in all T cell subsets from both atopic dermatitis and psoriasis patients compared with normal individuals. Furthermore, the telomere length was found to be significantly shorter in CD4(+) memory T cells compared with the CD4(+) naive T cells, and both of the cell subsets from diseases were shown to be of significantly shorter telomere length than the same cell subsets from normal controls. No significant difference was observed between CD8(+)CD28(-) and CD8(+)CD28(+) T cell populations in both diseases. However, the telomere length of CD8(+)CD28(+) T cells from both diseases was significantly shorter than CD8(+)CD28(+) T cell subsets from normal donors. In conclusion, the increased telomerase activity and shortened telomere length indicates that T lymphocytes in atopic dermatitis and psoriasis are chronically stimulated and have an increased cellular turnover in vivo.},
}
@article {pmid11033797,
year = {2000},
author = {Georgiev, PG and Mel'nikova, LS and Kan, TG and Kravchuk, OI and Mikhaĭlovskiĭ, SS and Savitskiĭ, MIu},
title = {[Different mechanisms of regulating telomere length].},
journal = {Molekuliarnaia biologiia},
volume = {34},
number = {5},
pages = {743-752},
pmid = {11033797},
issn = {0026-8984},
mesh = {Animals ; Insecta/genetics ; Mammals/genetics ; Telomerase/metabolism ; *Telomere ; Yeasts/genetics ; },
}
@article {pmid11033353,
year = {2000},
author = {Manevski, A and Bertoni, G and Bardet, C and Tremousaygue, D and Lescure, B},
title = {In synergy with various cis-acting elements, plant insterstitial telomere motifs regulate gene expression in Arabidopsis root meristems.},
journal = {FEBS letters},
volume = {483},
number = {1},
pages = {43-46},
doi = {10.1016/s0014-5793(00)02056-1},
pmid = {11033353},
issn = {0014-5793},
mesh = {Arabidopsis/*genetics ; Base Sequence ; DNA, Plant/genetics ; Gene Expression Regulation, Plant ; Glucuronidase/genetics/metabolism ; Meristem/*genetics ; Peptide Elongation Factor 1/genetics ; Plant Roots/*genetics ; Plants, Genetically Modified ; Proliferating Cell Nuclear Antigen/genetics ; Promoter Regions, Genetic ; Recombinant Fusion Proteins/genetics/metabolism ; Regulatory Sequences, Nucleic Acid/*genetics ; Telomere/*genetics ; },
abstract = {The telo-box, an interstitial telomere motif, was shown to regulate gene expression in root meristems, in synergy with a cis-acting element involved in the activation of expression of plant eEF1A genes, encoding the translation elongation factor EF1A, and of several ribosomal protein genes. We demonstrate here that the telo-box is also required for transcription activation by two other cis elements present within the promoter of genes encoding the acidic ribosomal protein rp40 and the proliferating cell nuclear antigen respectively. The control of gene expression by telo-boxes during cell cycle progression in Arabidopsis root meristems is discussed. A parallel is drawn with the function of telomeric sequences in Saccharomyces cerevisiae.},
}
@article {pmid11032793,
year = {2000},
author = {Ballif, BC and Kashork, CD and Shaffer, LG},
title = {The promise and pitfalls of telomere region-specific probes.},
journal = {American journal of human genetics},
volume = {67},
number = {5},
pages = {1356-1359},
pmid = {11032793},
issn = {0002-9297},
mesh = {Chromosome Banding/methods ; Chromosome Deletion ; DNA Probes/*genetics ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Mutation/genetics ; Polymorphism, Genetic/genetics ; Substrate Specificity ; Telomere/*genetics ; },
}
@article {pmid11029502,
year = {2000},
author = {Aragona, M and Maisano, R and Panetta, S and Giudice, A and Morelli, M and La Torre, I and La Torre, F},
title = {Telomere length maintenance in aging and carcinogenesis.},
journal = {International journal of oncology},
volume = {17},
number = {5},
pages = {981-989},
doi = {10.3892/ijo.17.5.981},
pmid = {11029502},
issn = {1019-6439},
mesh = {Aging/*genetics/pathology ; Ankyrins/physiology ; Antineoplastic Agents/pharmacology ; Antioxidants/pharmacology ; Carrier Proteins/physiology ; Cell Division/genetics/physiology ; Cell Transformation, Neoplastic/genetics ; Cellular Senescence/*genetics/physiology ; Chromosomes, Human/ultrastructure ; DNA Replication ; DNA, Neoplasm/genetics ; DNA-Binding Proteins/physiology ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Free Radicals ; Homeostasis ; Humans ; Longevity/genetics ; MAP Kinase Signaling System ; Neoplasm Proteins/antagonists &amp; inhibitors/physiology ; Neoplasms/*genetics/ultrastructure ; Oxidative Stress ; Phosphoprotein Phosphatases/antagonists &amp; inhibitors/physiology ; Poly(ADP-ribose) Polymerases/physiology ; *RNA ; RNA, Long Noncoding ; RNA, Untranslated/physiology ; RNA-Binding Proteins ; Tandem Repeat Sequences ; Telomerase/antagonists &amp; inhibitors/physiology ; Telomere/*ultrastructure ; Telomeric Repeat Binding Protein 2 ; Transfection ; },
abstract = {Normal somatic cells have a finite number of divisions, a limited capacity to proliferate. Human telomeres, the long DNA TTAGGG repeats at the ends of chromosomes, are considered a molecular clock marker. The gradual and progressive telomere shortening at each replicative cycle is associated, through the activation of pRB and p53 pathways and genomic instability, to the replicative senescence, a non-dividing state and widespread cell death. Activation of telomere maintenance [telomerase; or alternative lengthening of telomeres mechanisms (ALT), or other adaptive responses] can revert this program. Although not completely known, several mechanisms and modulating agents may be able to up and down-regulate telomere length and its maintenance. Chemopreventive therapies for the up-regulation of telomerase activity, able to prolong the life of cell cultures in a phenotypically youthful state, could have important applications in research and medicine. On the contrary the therapeutic down-regulation of telomerase activity may be used in cancer therapy. Telomerase expression per se is not oncogenic, but telomere shortening and maintenance seem to be crucial events in tumor formation. Thus a particular focus has been pointed out relatively to the immortalization of normal or potential pre-cancerous cells. With the extension of life span the probability to get in contact with carcinogens increases, genetic instability, oncogene activation and/or onco-suppressor gene inactivation (i.e. p53, pRB, ras): the cancer transformation can be then induced in predisposed cells, depending on their genetic context, by the activation of telomere maintenance. Pharmacological intervention may be able to modulate the rate of living, by increasing life span of few specific target cells, or decreasing it in proliferating <cancer and pre-cancer cells>. Because of the unknown state of the enormous cell number of the human organism, is it safe to extend the human life span by therapeutic agents?},
}
@article {pmid11029034,
year = {2000},
author = {Baumann, P and Cech, TR},
title = {Protection of telomeres by the Ku protein in fission yeast.},
journal = {Molecular biology of the cell},
volume = {11},
number = {10},
pages = {3265-3275},
pmid = {11029034},
issn = {1059-1524},
support = {//Wellcome Trust/United Kingdom ; R01 GM028039/GM/NIGMS NIH HHS/United States ; GM28039/GM/NIGMS NIH HHS/United States ; },
mesh = {*Antigens, Nuclear ; Chromosomes, Fungal/genetics ; DNA Damage ; *DNA Helicases ; DNA Ligase ATP ; DNA Ligases/metabolism ; *DNA Repair ; DNA, Fungal/genetics/isolation &amp; purification ; DNA-Binding Proteins/genetics/*metabolism ; Electrophoresis, Gel, Pulsed-Field ; Gene Rearrangement ; Ku Autoantigen ; Nuclear Proteins/genetics/*metabolism ; Protein Subunits ; Recombination, Genetic ; Restriction Mapping ; Saccharomyces cerevisiae/genetics ; *Saccharomyces cerevisiae Proteins ; Schizosaccharomyces/*genetics/growth &amp; development ; Telomerase/genetics/metabolism ; Telomere/*genetics ; },
abstract = {Schizosaccharomyces pombe cells survive loss of telomeres by a unique pathway of chromosome circularization. Factors potentially involved in this survival mechanism include the heterodimeric Ku protein and ligase IV, both of which are involved in the repair of DNA double-strand breaks in mammalian cells. Furthermore, Ku plays a role in telomere maintenance as well as in DNA double-strand break repair in Saccharomyces cerevisiae. We have identified Ku and ligase IV homologues in S. pombe and analyzed their functions during normal growth and in cells undergoing senescence. In the absence of either a Ku subunit (pku70(+)) or ligase IV (lig4(+)), nonhomologous DNA end-joining was severely reduced. Lack of functional Ku led to shorter but stable telomeres and caused striking rearrangements of telomere-associated sequences, indicating a function for Ku in inhibiting recombinational activities near chromosome ends. In contrast to S. cerevisiae, concurrent deletion of pku70(+) and the gene for the catalytic subunit of telomerase (trt1(+)) was not lethal, allowing for the first time the dissection of the roles of Ku during senescence. Our results support a model in which Ku protects chromosome termini from nucleolytic and recombinational activities but is not involved in the formation of chromosome end fusions during senescence. The conclusion that nonhomologous end-joining is not required for chromosome circularization was further supported by analysis of survivors in strains lacking the genes for both trt1(+) and lig4(+).},
}
@article {pmid11027287,
year = {2000},
author = {Liu, Y and Snow, BE and Hande, MP and Baerlocher, G and Kickhoefer, VA and Yeung, D and Wakeham, A and Itie, A and Siderovski, DP and Lansdorp, PM and Robinson, MO and Harrington, L},
title = {Telomerase-associated protein TEP1 is not essential for telomerase activity or telomere length maintenance in vivo.},
journal = {Molecular and cellular biology},
volume = {20},
number = {21},
pages = {8178-8184},
pmid = {11027287},
issn = {0270-7306},
support = {AG8422117/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Carrier Proteins/metabolism/*physiology ; Catalysis ; Embryo, Mammalian/metabolism ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Inbred C57BL ; Mice, Inbred ICR ; Mice, Transgenic ; Models, Genetic ; Mutagenesis, Site-Directed ; Precipitin Tests ; RNA/metabolism ; RNA-Binding Proteins ; Recombination, Genetic ; Spleen/cytology ; Stem Cells/metabolism ; Telomerase ; Telomere/*physiology/ultrastructure ; Thymus Gland/cytology ; },
abstract = {TEP1 is a mammalian telomerase-associated protein with similarity to the Tetrahymena telomerase protein p80. Like p80, TEP1 is associated with telomerase activity and the telomerase reverse transcriptase, and it specifically interacts with the telomerase RNA. To determine the role of mTep1 in telomerase function in vivo, we generated mouse embryonic stem (ES) cells and mice lacking mTep1. The mTep1-deficient (mTep1(-/-)) mice were viable and were bred for seven successive generations with no obvious phenotypic abnormalities. All murine tissues from mTep1(-/-) mice possessed a level of telomerase activity comparable to that in wild-type mice. In addition, analysis of several tissues that normally lack telomerase activity revealed no reactivation of telomerase activity in mTep1(-/-) mice. Telomere length, even in later generations of mTep1(-/-) mice, was equivalent to that in wild-type animals. ES cells deficient in mTep1 also showed no detectable alteration in telomerase activity or telomere length with increased passage in culture. Thus, mTep1 appears to be completely dispensable for telomerase function in vivo. Recently, TEP1 has been identified within a second ribonucleoprotein (RNP) complex, the vault particle. TEP1 can also specifically bind to a small RNA, vRNA, which is associated with the vault particle and is unrelated in sequence to mammalian telomerase RNA. These results reveal that TEP1 is an RNA binding protein that is not restricted to the telomerase complex and that TEP1 plays a redundant role in the assembly or localization of the telomerase RNP in vivo.},
}
@article {pmid11027269,
year = {2000},
author = {de Bruin, D and Kantrow, SM and Liberatore, RA and Zakian, VA},
title = {Telomere folding is required for the stable maintenance of telomere position effects in yeast.},
journal = {Molecular and cellular biology},
volume = {20},
number = {21},
pages = {7991-8000},
pmid = {11027269},
issn = {0270-7306},
support = {R01 GM043265/GM/NIGMS NIH HHS/United States ; GM43265/GM/NIGMS NIH HHS/United States ; },
mesh = {Acetylation ; Chromatin/metabolism ; DNA Replication ; Fungal Proteins/genetics/*metabolism ; G1 Phase ; Galactose/metabolism ; Gene Deletion ; Histones/metabolism ; Lysine/metabolism ; Models, Genetic ; Promoter Regions, Genetic ; RNA/metabolism ; Raffinose/metabolism ; Saccharomyces cerevisiae/genetics/physiology ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Telomere/*physiology ; Time Factors ; Trans-Activators/*metabolism ; Transcription, Genetic ; Uracil/pharmacology ; rap1 GTP-Binding Proteins/*metabolism ; },
abstract = {Yeast telomeres reversibly repress the transcription of adjacent genes, a phenomenon called telomere position effect (TPE). TPE is thought to result from Rap1 and Sir protein-mediated spreading of heterochromatin-like structures from the telomeric DNA inwards. Because Rap1p is associated with subtelomeric chromatin as well as with telomeric DNA, yeast telomeres are proposed to form fold-back or looped structures. TPE can be eliminated in trans by deleting SIR genes or in cis by transcribing through the C(1-3)A/TG(1-3) tract of a telomere. We show that the promoter of a telomere-linked URA3 gene was inaccessible to restriction enzymes and that accessibility increased both in a sir3 strain and upon telomere transcription. We also show that subtelomeric chromatin was hypoacetylated at histone H3 and at each of the four acetylatable lysines in histone H4 and that histone acetylation increased both in a sir3 strain and when the telomere was transcribed. When transcription through the telomeric tract occurred in G(1)-arrested cells, TPE was lost, demonstrating that activation of a silenced telomeric gene can occur in the absence of DNA replication. The loss of TPE that accompanied telomere transcription resulted in the rapid and efficient loss of subtelomeric Rap1p. We propose that telomere transcription disrupts core heterochromatin by eliminating Rap1p-mediated telomere looping. This interpretation suggests that telomere looping is critical for maintaining TPE.},
}
@article {pmid11024301,
year = {2000},
author = {Sohanpal, B and Wasawo, D and Bishop, R},
title = {Cloning of telomere-associated DNA using single-specific-primer polymerase chain reaction provides evidence for a conserved sequence directly adjacent to Theileria parva telomeric repeats.},
journal = {Gene},
volume = {255},
number = {2},
pages = {401-409},
doi = {10.1016/s0378-1119(00)00284-5},
pmid = {11024301},
issn = {0378-1119},
mesh = {Animals ; Base Sequence ; Cloning, Molecular ; Conserved Sequence/*genetics ; DNA Primers ; DNA, Protozoan/chemistry/genetics/isolation &amp; purification ; Molecular Sequence Data ; Polymerase Chain Reaction/*methods ; *Repetitive Sequences, Nucleic Acid ; Sequence Alignment ; Sequence Analysis, DNA ; Sequence Homology, Nucleic Acid ; Telomere/*genetics ; Theileria parva/*genetics ; },
abstract = {Telomere-associated (TA) DNA sequences of the intracellular protozoan parasite Theileria parva were isolated by a novel strategy using a modified version of single-specific-primer polymerase chain reaction (SSP-PCR). Nucleotide sequences of non-coding TA DNA from three telomeres (6017bp, 2435bp and 4859bp) contained no extensive tracts of repetitive DNA. Long open reading frames (ORFs) were present at the centromeric ends of two of the TA sequences, the 3' ends of the closest ORFs being only 2670bp and 2719bp from the telomeric repeats. There were regions of significant similarity between the nucleotide sequences of the non-coding regions of different telomeres. The longest region of similarity was a virtually identical 1650bp domain, located directly adjacent to the telomeric repeats of two separate telomeres. Comparison of the telomere proximal sequences defined in this study and two additional T. parva telomeres, whose sequences were determined previously, resulted in identification of a single copy 141bp conserved sequence directly adjacent to the telomeric repeats. The conserved sequence is present at all five T. parva telomeres that have been characterised. The only organism currently known to have a single copy conserved sequence located adjacent to the telomeric repeats is another intracellular protozoan, Leishmania braziliensis.},
}
@article {pmid11018056,
year = {2000},
author = {Trelles-Sticken, E and Dresser, ME and Scherthan, H},
title = {Meiotic telomere protein Ndj1p is required for meiosis-specific telomere distribution, bouquet formation and efficient homologue pairing.},
journal = {The Journal of cell biology},
volume = {151},
number = {1},
pages = {95-106},
pmid = {11018056},
issn = {0021-9525},
mesh = {Centromere ; Chromosomal Proteins, Non-Histone/*genetics ; Chromosome Painting ; *Chromosomes, Fungal ; Gene Deletion ; *Meiosis ; Models, Genetic ; Nuclear Proteins/*genetics ; Saccharomyces cerevisiae/*genetics ; Spindle Apparatus ; *Telomere ; },
abstract = {We have investigated the requirements for NDJ1 in meiotic telomere redistribution and clustering in synchronized cultures of Saccharomyces cerevisiae. On induction of wild-type meiosis, telomeres disperse from premeiotic aggregates over the nuclear periphery, and then cluster near the spindle pole body (bouquet arrangement) before dispersing again. In ndj1Delta meiocytes, telomeres are scattered throughout the nucleus and fail to form perinuclear meiosis-specific distribution patterns, suggesting that Ndj1p may function to tether meiotic telomeres to the nuclear periphery. Since ndj1Delta meiocytes fail to cluster their telomeres at any prophase stage, Ndj1p is the first protein shown to be required for bouquet formation in a synaptic organism. Analysis of homologue pairing by two-color fluorescence in situ hybridization with cosmid probes to regions on III, IX, and XI revealed that disruption of bouquet formation is associated with a significant delay (>2 h) of homologue pairing. An increased and persistent fraction of ndj1Delta meiocytes with Zip1p polycomplexes suggests that chromosome polarization is important for synapsis progression. Thus, our observations support the hypothesis that meiotic telomere clustering contributes to efficient homologue alignment and synaptic pairing. Under naturally occurring conditions, bouquet formation may allow for rapid sporulation and confer a selective advantage.},
}
@article {pmid11016977,
year = {2000},
author = {McEachern, MJ and Iyer, S and Fulton, TB and Blackburn, EH},
title = {Telomere fusions caused by mutating the terminal region of telomeric DNA.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {97},
number = {21},
pages = {11409-11414},
pmid = {11016977},
issn = {0027-8424},
support = {R01 GM026259/GM/NIGMS NIH HHS/United States ; R37 GM026259/GM/NIGMS NIH HHS/United States ; GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA, Fungal/*genetics ; Kluyveromyces/genetics ; *Mutation ; *Telomere ; },
abstract = {Mutations in the template region of a telomerase RNA gene can lead to the corresponding sequence alterations appearing in newly synthesized telomeric repeats. We analyzed a set of mutations in the template region of the telomerase RNA gene (TER1) of the budding yeast Kluyveromyces lactis that were predicted to lead to synthesis of mutant telomeric repeats with disrupted binding of the telomeric protein Rap1p. We showed previously that mutating the left side of the 12-bp consensus Rap1p binding site led to immediate and severe telomere elongation. Here, we show that, in contrast, mutating either the right side of the site or both sides together leads initially to telomere shortening. On additional passaging, certain mutants of both categories exhibit telomere-telomere fusions. Often, six new Bal-31-resistant, telomere repeat-containing bands appeared, and we infer that each of the six K. lactis chromosomes became circularized. These fusions were not stable, appearing occasionally to resolve and then reform. We demonstrate directly that a linear minichromosome introduced into one of the fusion mutant strains circularized by means of end-to-end fusions of the mutant repeat tracts. In contrast to the chromosomal circularization reported previously in Schizosaccharomyces pombe mutants defective in telomere maintenance, the K. lactis telomere fusions retained their telomeric DNA repeat sequences.},
}
@article {pmid11013408,
year = {2000},
author = {Moore, IK and Martin, MP and Paquin, CE},
title = {Telomere sequences at the novel joints of four independent amplifications in Saccharomyces cerevisiae.},
journal = {Environmental and molecular mutagenesis},
volume = {36},
number = {2},
pages = {105-112},
pmid = {11013408},
issn = {0893-6692},
support = {P30 ES06096/ES/NIEHS NIH HHS/United States ; },
mesh = {Base Sequence ; Carrier Proteins ; Cloning, Molecular ; Gene Amplification ; Genes, Reporter ; Metallothionein/genetics ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; Saccharomyces cerevisiae/*genetics ; Sequence Analysis, DNA ; Telomere/*genetics ; },
abstract = {Primary gene amplification, the mutation from one copy of a gene per genome to two or more genes per genome is a major mechanism of oncogene overexpression. We previously developed a system in the yeast Saccharomyces cerevisiae to phenotypically detect primary amplifications of a reporter cassette, ADH4:CUP1. We present here the sequence analysis of novel joints from four independent, spontaneous circular amplifications identified by the ADH4:CUP1 system. All four novel joints consist of C(1-3) A telomeric repeats joined to short (14- to 16-bp) CA-rich tracts between ADH4 and the telomere of chromosome VII. In three of the four amplifications, the telomeric sequence and the CA-rich tract that are joined in the amplification are normally located in inverted orientation to each other on chromosome VII. In the fourth amplification, the CA-rich tract on chromosome VII is joined to telomere sequences from another chromosome. We suggest that formation of these amplifications was initiated by recombination between these CA-rich tracts and a telomere. The resulting dicentric chromosome could start a breakage-fusion-bridge cycle that could be resolved by the formation of a circular amplification structure.},
}
@article {pmid11005568,
year = {2000},
author = {Multani, AS and Ozen, M and Narayan, S and Kumar, V and Chandra, J and McConkey, DJ and Newman, RA and Pathak, S},
title = {Caspase-dependent apoptosis induced by telomere cleavage and TRF2 loss.},
journal = {Neoplasia (New York, N.Y.)},
volume = {2},
number = {4},
pages = {339-345},
pmid = {11005568},
issn = {1522-8002},
support = {CA 77721/CA/NCI NIH HHS/United States ; RRO 499901/RR/NCRR NIH HHS/United States ; },
mesh = {Animals ; *Apoptosis ; Caspases/*metabolism ; *Chromosome Aberrations ; Clone Cells ; Cysteine Proteinase Inhibitors/*pharmacology ; Cytarabine/toxicity ; DNA-Binding Proteins/*metabolism ; Genes, bcl-2 ; Humans ; Melanoma, Experimental ; Mice ; Proto-Oncogene Proteins c-bcl-2/*metabolism ; Telomere/drug effects/*metabolism ; Telomeric Repeat Binding Protein 2 ; Transfection ; Tumor Cells, Cultured ; },
abstract = {Chromosomal abnormalities involving telomeric associations (TAs) often precede replicative senescence and abnormal chromosome configurations. We report here that telomere cleavage following exposure to proapoptotic agents is an early event in apoptosis. Exposure of human and murine cancer cells to a variety of pro-apoptotic stimuli (staurosporine, thapsigargin, anti-Fas antibody, and cancer chemotherapeutic agents) resulted in telomere cleavage and aggregation, and finally their extrusion from the nuclei. Telomere loss was associated with arrest of cells in G2/M phase and preceded DNA fragmentation. Telomere erosion and subsequent large-scale chromatin cleavage were inhibited by overexpression of the anti-apoptotic protein, bcl-2, and two peptide caspase inhibitors (BACMK and zVADfmk), indicating that both events are regulated by caspase activation. The results demonstrate that telomere cleavage is an early chromatin alteration detected in various cancer cell lines leading to drug-induced apoptosis, and suggest that this event contributes to mitotic catastrophe and induction of cell death. Results also suggest that the decrease of telomeric-repeat binding factor 2 (TRF2) may be the earliest event in the ara-C-induced telomere shortening, induction of endoreduplication and chromosomal fragmentation leading to cell death.},
}
@article {pmid11005146,
year = {2000},
author = {Zneimer, SM and Cotter, PD and Stewart, SD},
title = {Telomere-telomere (end to end) fusion of chromosomes 7 and 22 with an interstitial deletion of chromosome 7p11.2--&gt;p15.1: phenotypic consequences and possible mechanisms.},
journal = {Clinical genetics},
volume = {58},
number = {2},
pages = {129-133},
doi = {10.1034/j.1399-0004.2000.580207.x},
pmid = {11005146},
issn = {0009-9163},
mesh = {Abnormalities, Multiple/*genetics ; Adult ; *Artificial Gene Fusion ; *Chromosome Deletion ; Chromosomes, Human, Pair 22/*genetics ; Chromosomes, Human, Pair 7/*genetics ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; Karyotyping ; Male ; Phenotype ; Syndrome ; Telomere/*genetics ; },
abstract = {We report a rare case of a de novo end to end fusion of chromosomes 7 and 22 in conjunction with an interstitial deletion of chromosome 7p11.2p15.1 in a newborn with congenital anomalies. The proband presented for chromosome analysis with bilateral cataracts, dysmorphic facies and distal limb abnormalities. Chromosome analysis showed a 45,XY,der(22)psu dic(22;7)(p13;p22.3)del(7)(p11.2p15.1) karyotype. This short arm to short arm fusion of chromosomes 7 and 22 resulted in a pseudodicentric chromosome. The interstitial deletion in the short arm of chromosome 7 was likely a result of breakage and reunion related to instability of the dicentric chromosome. Loss of genetic material in this region of chromosome 7p has been implicated in the pathophysiology of craniosynostosis and cephalopolysyndactyly syndromes.},
}
@article {pmid11003672,
year = {2000},
author = {Scherthan, H and Jerratsch, M and Dhar, S and Wang, YA and Goff, SP and Pandita, TK},
title = {Meiotic telomere distribution and Sertoli cell nuclear architecture are altered in Atm- and Atm-p53-deficient mice.},
journal = {Molecular and cellular biology},
volume = {20},
number = {20},
pages = {7773-7783},
pmid = {11003672},
issn = {0270-7306},
support = {R01 NS034746/NS/NINDS NIH HHS/United States ; NS34746/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia/genetics ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins ; Cell Nucleus/genetics/*metabolism ; Chromatin/genetics/metabolism ; DNA-Binding Proteins ; Fluorescent Dyes ; *Gene Deletion ; Genes, p53/genetics/*physiology ; Heterochromatin/genetics/metabolism ; Histones/metabolism ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Male ; *Meiosis ; Mice ; Mice, Knockout ; Nuclear Matrix/genetics/metabolism ; Nuclear Proteins/metabolism ; Protein Serine-Threonine Kinases/genetics/*physiology ; Sertoli Cells/*cytology/metabolism ; Spermatocytes/cytology/metabolism ; Telomere/genetics/*metabolism ; Tumor Suppressor Proteins ; Vimentin/metabolism ; },
abstract = {The ataxia telangiectasia mutant (ATM) protein is an intrinsic part of the cell cycle machinery that surveys genomic integrity and responses to genotoxic insult. Individuals with ataxia telangiectasia as well as Atm(-/-) mice are predisposed to cancer and are infertile due to spermatogenesis disruption during first meiotic prophase. Atm(-/-) spermatocytes frequently display aberrant synapsis and clustered telomeres (bouquet topology). Here, we used telomere fluorescent in situ hybridization and immunofluorescence (IF) staining of SCP3 and testes-specific histone H1 (H1t) to spermatocytes of Atm- and Atm-p53-deficient mice and investigated whether gonadal atrophy in Atm-null mice is associated with stalling of telomere motility in meiotic prophase. SCP3-H1t IF revealed that most Atm(-/-) p53(-/-) spermatocytes degenerated during late zygotene, while a few progressed to pachytene and diplotene and some even beyond metaphase II, as indicated by the presence of a few round spermatids. In Atm(-/-) p53(-/-) meiosis, the frequency of spermatocytes I with bouquet topology was elevated 72-fold. Bouquet spermatocytes with clustered telomeres were generally void of H1t signals, while mid-late pachytene and diplotene Atm(-/-) p53(-/-) spermatocytes displayed expression of H1t and showed telomeres dispersed over the nuclear periphery. Thus, it appears that meiotic telomere movements occur independently of ATM signaling. Atm inactivation more likely leads to accumulation of spermatocytes I with bouquet topology by slowing progression through initial stages of first meiotic prophase and an ensuing arrest and demise of spermatocytes I. Sertoli cells (SECs), which contribute to faithful spermatogenesis, in the Atm mutants were found to frequently display numerous heterochromatin and telomere clusters-a nuclear topology which resembles that of immature SECs. However, Atm(-/-) SECs exhibited a mature vimentin and cytokeratin 8 intermediate filament expression signature. Upon IF with ATM antibodies, we observed ATM signals throughout the nuclei of human and mouse SECs, spermatocytes I, and haploid round spermatids. ATM but not H1t was absent from elongating spermatid nuclei. Thus, ATM appears to be removed from spermatid nuclei prior to the occurrence of DNA nicks which emanate as a consequence of nucleoprotamine formation.},
}
@article {pmid11003671,
year = {2000},
author = {Dhar, S and Squire, JA and Hande, MP and Wellinger, RJ and Pandita, TK},
title = {Inactivation of 14-3-3sigma influences telomere behavior and ionizing radiation-induced chromosomal instability.},
journal = {Molecular and cellular biology},
volume = {20},
number = {20},
pages = {7764-7772},
pmid = {11003671},
issn = {0270-7306},
support = {R01 NS034746/NS/NINDS NIH HHS/United States ; },
mesh = {14-3-3 Proteins ; *Biomarkers, Tumor ; Cell Division/radiation effects ; Cell Survival/radiation effects ; Chromatin/genetics/radiation effects ; Chromosome Banding ; Chromosome Breakage/genetics ; Chromosome Fragility/*genetics ; Dose-Response Relationship, Radiation ; *Exonucleases ; Exoribonucleases ; G1 Phase ; G2 Phase ; Gamma Rays ; *Gene Deletion ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Mitotic Index ; *Neoplasm Proteins ; Nuclear Matrix/metabolism ; Proteins/genetics/*metabolism ; Repetitive Sequences, Nucleic Acid/genetics/radiation effects ; Ring Chromosomes ; Telomere/*genetics/metabolism/*radiation effects ; Translocation, Genetic/genetics/radiation effects ; Tumor Cells, Cultured ; },
abstract = {Telomeres are complexes of repetitive DNA sequences and proteins constituting the ends of linear eukaryotic chromosomes. While these structures are thought to be associated with the nuclear matrix, they appear to be released from this matrix at the time when the cells exit from G(2) and enter M phase. Checkpoints maintain the order and fidelity of the eukaryotic cell cycle, and defects in checkpoints contribute to genetic instability and cancer. The 14-3-3sigma gene has been reported to be a checkpoint control gene, since it promotes G(2) arrest following DNA damage. Here we demonstrate that inactivation of this gene influences genome integrity and cell survival. Analyses of chromosomes at metaphase showed frequent losses of telomeric repeat sequences, enhanced frequencies of chromosome end-to-end associations, and terminal nonreciprocal translocations in 14-3-3sigma(-/-) cells. These phenotypes correlated with a reduction in the amount of G-strand overhangs at the telomeres and an altered nuclear matrix association of telomeres in these cells. Since the p53-mediated G(1) checkpoint is operative in these cells, the chromosomal aberrations observed occurred preferentially in G(2) after irradiation with gamma rays, corroborating the role of the 14-3-3sigma protein in G(2)/M progression. The results also indicate that even in untreated cycling cells, occasional chromosomal breaks or telomere-telomere fusions trigger a G(2) checkpoint arrest followed by repair of these aberrant chromosome structures before entering M phase. Since 14-3-3sigma(-/-) cells are defective in maintaining G(2) arrest, they enter M phase without repair of the aberrant chromosome structures and undergo cell death during mitosis. Thus, our studies provide evidence for the correlation among a dysfunctional G(2)/M checkpoint control, genomic instability, and loss of telomeres in mammalian cells.},
}
@article {pmid11001793,
year = {2000},
author = {Jennings, BJ and Ozanne, SE and Hales, CN},
title = {Nutrition, oxidative damage, telomere shortening, and cellular senescence: individual or connected agents of aging?.},
journal = {Molecular genetics and metabolism},
volume = {71},
number = {1-2},
pages = {32-42},
doi = {10.1006/mgme.2000.3077},
pmid = {11001793},
issn = {1096-7192},
mesh = {*Aging ; Aging, Premature/genetics ; Animals ; Cell Division ; Cellular Senescence ; Growth ; Humans ; Longevity ; Models, Biological ; *Nutritional Physiological Phenomena ; Oxidative Stress ; Telomere/metabolism ; },
abstract = {There is substantial and long-standing literature linking the level of general nutrition to longevity. Reducing nutrition below the amount needed to sustain maximum growth increases longevity in a wide range of organisms. Oxidative damage has been shown to be a major feature of the aging process. Telomere shortening is now well established as a key process regulating cell senescence in vitro. There is some evidence that the same process may be important for aging in vivo. Very recently it has been found that oxidative damage accelerates telomere shortening. It is therefore possible for us to propose as an outline hypothesis that the level of nutrition determines oxidative damage which in turn determines telomere shortening and cell senescence and that this pathway is important in determining aging and longevity in vivo. We also propose that telomeres in addition to their well-recognized role in "counting" cell divisions are also, through their GGG sequence, important monitors of oxidative damage over the life span of a cell. This may explain the evolutionary conservations of this triplet in the repeat telomere sequence unit.},
}
@article {pmid10998467,
year = {2000},
author = {Okuda, K and Khan, MY and Skurnick, J and Kimura, M and Aviv, H and Aviv, A},
title = {Telomere attrition of the human abdominal aorta: relationships with age and atherosclerosis.},
journal = {Atherosclerosis},
volume = {152},
number = {2},
pages = {391-398},
doi = {10.1016/s0021-9150(99)00482-7},
pmid = {10998467},
issn = {0021-9150},
support = {HL47906/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Aorta, Abdominal/*ultrastructure ; Arteriosclerosis/*genetics ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; Middle Aged ; *Telomere ; Tunica Intima/ultrastructure ; Tunica Media/ultrastructure ; },
abstract = {Little is known about the turnover rate (i.e. the rate of replication and death) of cells in the intima and media of human arteries as a function of age and atherosclerosis. One indicator of the replicative history of cells is telomere length. In this work we explored the rate of telomere attrition as a function of age and atherosclerosis in cells of the human abdominal aorta. Telomere length, measured by the terminal restriction fragment using Southern analysis, was determined in the intima and media of the distal (infrarenal) versus proximal (suprarenal) segments of the abdominal aorta. Telomere length was then correlated with age and atherosclerotic grade. The rate of age-dependent telomere attrition was higher in both the intima and media of the distal versus proximal abdominal aorta. In addition, telomere length was negatively correlated with atherosclerotic grade. However, after adjustment for age, this relationship was not statistically significant. The high rate of age-dependent telomere attrition in the distal abdominal aorta probably reflects enhanced cellular turnover rate due to local factors such as an increase in shear wall stress in this vascular segment.},
}
@article {pmid10996729,
year = {2000},
author = {Kammori, M and Takubo, K and Nakamura, K and Furugouri, E and Endo, H and Kanauchi, H and Mimura, Y and Kaminishi, M},
title = {Telomerase activity and telomere length in benign and malignant human thyroid tissues.},
journal = {Cancer letters},
volume = {159},
number = {2},
pages = {175-181},
doi = {10.1016/s0304-3835(00)00547-4},
pmid = {10996729},
issn = {0304-3835},
mesh = {Adenoma/enzymology/genetics/pathology ; Adult ; Aged ; Aged, 80 and over ; Blotting, Southern ; Carcinoma, Papillary/enzymology/genetics/pathology ; DNA/genetics ; Female ; Humans ; Male ; Middle Aged ; Neoplasm Staging ; Telomerase/*metabolism ; Telomere/*genetics ; Thyroid Diseases/enzymology/genetics/pathology ; Thyroid Neoplasms/*enzymology/*genetics/pathology ; Tumor Cells, Cultured ; },
abstract = {Several studies have demonstrated that telomerase is activated and telomere length is altered in various types of tumors. In this study, we investigated telomerase activities and telomere length in 21 thyroid tumors. Telomerase activity was detected in 11 of 12 thyroid cancers and three of nine follicular adenomas. The mean telomere lengths in the cancers tissue and follicular adenomas were lower than in the respective background tissues, the differences being significant (P=0.0055 and P<0.006), respectively. Our findings suggest that change in telomerase activity and telomere length may be important for development of thyroid tumors.},
}
@article {pmid10995010,
year = {2000},
author = {Busson Le Coniat, M and Brizard, F and Smadja, NV and Maarek, O and Der Sarkissian, H and Berger, R},
title = {Interstitial telomere repeats in translocations of hematopoietic disorders.},
journal = {Leukemia},
volume = {14},
number = {9},
pages = {1630-1633},
doi = {10.1038/sj.leu.2401876},
pmid = {10995010},
issn = {0887-6924},
mesh = {Aged ; Aged, 80 and over ; Chromosomes, Human, Pair 1 ; Chromosomes, Human, Pair 16 ; Chromosomes, Human, Pair 19 ; Chromosomes, Human, Pair 2 ; Female ; Hematologic Neoplasms/*genetics ; Humans ; Karyotyping ; Male ; Repetitive Sequences, Nucleic Acid/genetics ; Telomere/*genetics ; *Translocation, Genetic ; },
abstract = {Cytogenetic and fluorescence in situ hybridization studies have shown the presence of telomeric repeats in translocation present in three patients with hematopoietic malignancies. One had jumping translocations, involving 1q12 and 2q, 16p, and 19q. These sequences were detected by FISH only in derivative chromosomes t(1;16) and t(1;19) in the first patient, and t(1;7) in the second. They were not seen in derivative t(1;2) and t(7;8), respectively. Interstitial telomeric sequences were observed in der(2)t(1;2) in about half of the metaphases in the third patient. The instability of interstitial telomeric DNA repeats in translocations is shown by the present findings. Moreover it supports the hypothesis that the presence of interstitial telomere repeats is not sufficient to make it functional.},
}
@article {pmid10984427,
year = {2000},
author = {Evans, SK and Lundblad, V},
title = {Positive and negative regulation of telomerase access to the telomere.},
journal = {Journal of cell science},
volume = {113 Pt 19},
number = {},
pages = {3357-3364},
doi = {10.1242/jcs.113.19.3357},
pmid = {10984427},
issn = {0021-9533},
mesh = {Animals ; Cell Cycle ; Cyclin B/metabolism ; DNA/*metabolism ; DNA-Binding Proteins/metabolism ; Fungal Proteins/metabolism ; Macromolecular Substances ; Models, Biological ; *Saccharomyces cerevisiae Proteins ; Telomerase/*metabolism ; Telomere/*metabolism/ultrastructure ; },
abstract = {The protective caps on chromosome ends - known as telomeres - consist of DNA and associated proteins that are essential for chromosome integrity. A fundamental part of ensuring proper telomere function is maintaining adequate length of the telomeric DNA tract. Telomeric repeat sequences are synthesized by the telomerase reverse transcriptase, and, as such, telomerase is a central player in the maintenance of steady-state telomere length. Evidence from both yeast and mammals suggests that telomere-associated proteins positively or negatively control access of telomerase to the chromosome terminus. In yeast, positive regulation of telomerase access appears to be achieved through recruitment of the enzyme by the end-binding protein Cdc13p. In contrast, duplex-DNA-binding proteins assembled along the telomeric tract exert a feedback system that negatively modulates telomere length by limiting the action of telomerase. In mammalian cells, and perhaps also in yeast, binding of these proteins probably promotes a higher-order structure that renders the telomere inaccessible to the telomerase enzyme.},
}
@article {pmid10982887,
year = {2000},
author = {Ohsugi, I and Tokutake, Y and Suzuki, N and Ide, T and Sugimoto, M and Furuichi, Y},
title = {Telomere repeat DNA forms a large non-covalent complex with unique cohesive properties which is dissociated by Werner syndrome DNA helicase in the presence of replication protein A.},
journal = {Nucleic acids research},
volume = {28},
number = {18},
pages = {3642-3648},
pmid = {10982887},
issn = {1362-4962},
mesh = {Centrifugation, Density Gradient ; DNA/*chemistry ; DNA Helicases/*metabolism ; DNA-Binding Proteins/*metabolism ; Exodeoxyribonucleases ; Humans ; Polymerase Chain Reaction ; Protein Binding ; RecQ Helicases ; *Repetitive Sequences, Nucleic Acid ; Replication Protein A ; Single-Strand Specific DNA and RNA Endonucleases/metabolism ; *Telomere ; Werner Syndrome/*enzymology/genetics ; Werner Syndrome Helicase ; },
abstract = {We describe the unique structural features of a large telomere repeat DNA complex (TRDC) of >20 kb generated by a simple PCR using (TTAGGG)(4) and (CCCTAA)(4) as both primers and templates. Although large, as determined by conventional agarose gel electrophoresis, the TRDC was found to consist of short single-stranded DNA telomere repeat units of between several hundred and 3000 bases, indicating that it is a non-covalent complex comprising short cohesive telomere repeat units. S1 nuclease digestion showed that the TRDC contains both single- and double-stranded portions stable enough to survive glycerol density gradient centrifugation, precipitation with ethanol and gel electrophoresis. Sedimentation analysis suggests that a part of the TRDC is non-linear and consists of a three-dimensional network structure. After treatment with Werner DNA helicase the TRDC dissociated into smaller fragments, provided that human replication protein A was present, indicating that: (i) the TRDC is a new substrate for the Werner syndrome helicase; (ii) the telomere repeat sequence re-anneals rapidly unless unwound single-stranded regions are protected by replication protein A; (iii) the TRDC may provide a new clue to understanding deleterious telomere-totelomere interactions that can lead to genomic instability. Some properties of the TRDC account for the extra-chromosomal telomere repeat (ECTR) DNA that exists in telomerase-negative immortalized cell lines and may be involved in maintaining telomeres.},
}
@article {pmid10982035,
year = {2000},
author = {Granzow, M and Popp, S and Keller, M and Holtgreve-Grez, H and Brough, M and Schoell, B and Rauterberg-Ruland, I and Hager, HD and Tariverdian, G and Jauch, A},
title = {Multiplex FISH telomere integrity assay identifies an unbalanced cryptic translocation der(5)t(3;5)(q27;p15.3) in a family with three mentally retarded individuals.},
journal = {Human genetics},
volume = {107},
number = {1},
pages = {51-57},
doi = {10.1007/s004390000321},
pmid = {10982035},
issn = {0340-6717},
mesh = {Adult ; Child, Preschool ; *Chromosomes, Human, Pair 3 ; *Chromosomes, Human, Pair 5 ; Facies ; Family Health ; Female ; Humans ; *In Situ Hybridization, Fluorescence ; Intellectual Disability/*genetics ; Male ; Pedigree ; Telomere/*ultrastructure ; *Translocation, Genetic ; },
abstract = {Cryptic rearrangements involving the terminal regions of chromosomes are suspected to be the cause of idiopathic mental retardation in a significant number of cases. This finding highlights the necessity of a primary screening test for such chromosome aberrations. Here we present a multiplex fluorescence in situ hybridization telomere integrity assay which allows the detection of submicroscopic aberrations in the telomeric regions of all chromosomes. This novel approach identified an unbalanced cryptic translocation der(5)t(3;5)(q27;p15.3) in a family with three cases of unexplained mental retardation and dysmorphic features. The symptoms of the patients represent neither the classical dup(3q)- nor cri du chat syndrome, although all affected individuals demonstrate several features of both syndromes. The identification of two balanced translocation carriers emphasizes the significance of the telomere integrity assay for genetic counseling and prenatal diagnosis.},
}
@article {pmid10973262,
year = {2000},
author = {González-Suárez, E and Samper, E and Flores, JM and Blasco, MA},
title = {Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis.},
journal = {Nature genetics},
volume = {26},
number = {1},
pages = {114-117},
doi = {10.1038/79089},
pmid = {10973262},
issn = {1061-4036},
mesh = {9,10-Dimethyl-1,2-benzanthracene ; Animals ; Carcinogens ; Flow Cytometry ; Immunity, Innate/genetics ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Keratinocytes/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Papilloma/chemically induced/genetics/metabolism/pathology ; Proto-Oncogene Proteins p21(ras)/biosynthesis ; Skin/metabolism/pathology ; Skin Neoplasms/chemically induced/*genetics/metabolism/pathology ; Telomerase/*deficiency ; Telomere/*pathology ; Tetradecanoylphorbol Acetate ; Time Factors ; Tumor Suppressor Protein p53/biosynthesis ; },
abstract = {Inhibition of telomerase is proposed to limit the growth of cancer cells by triggering telomere shortening and cell death. Telomere maintenance by telomerase is sufficient, in some cell types, to allow immortal growth. Telomerase has been shown to cooperate with oncogenes in transforming cultured primary human cells into neoplastic cells, suggesting that telomerase activation contributes to malignant transformation. Moreover, telomerase inhibition in human tumour cell lines using dominant-negative versions of TERT leads to telomere shortening and cell death. These findings have led to the proposition that telomerase inhibition may result in cessation of tumour growth. The absence of telomerase from most normal cells supports the potential efficacy of anti-telomerase drugs for tumour therapy, as its inhibition is unlikely to have toxic effects. Mice deficient for Terc RNA (encoding telomerase) lack telomerase activity, and constitute a model for evaluating the role of telomerase and telomeres in tumourigenesis. Late-generation Terc-/- mice show defects in proliferative tissues and a moderate increase in the incidence of spontaneous tumours in highly proliferative cell types (lymphomas, teratocarcinomas). The appearance of these tumours is thought to be a consequence of chromosomal instability in these mice. These observations have challenged the expected effectiveness of anti-telomerase-based cancer therapies. Different cell types may nonetheless vary in their sensitivity to the chromosomal instability produced by telomere loss or to the activation of telomere-rescue mechanisms. Here we show that late-generation Terc-/- mice, which have short telomeres and are telomerase-deficient, are resistant to tumour development in multi-stage skin carcinogenesis. Our results predict that an anti-telomerase-based tumour therapy may be effective in epithelial tumours.},
}
@article {pmid10973255,
year = {2000},
author = {Wong, KK and Chang, S and Weiler, SR and Ganesan, S and Chaudhuri, J and Zhu, C and Artandi, SE and Rudolph, KL and Gottlieb, GJ and Chin, L and Alt, FW and DePinho, RA},
title = {Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation.},
journal = {Nature genetics},
volume = {26},
number = {1},
pages = {85-88},
doi = {10.1038/79232},
pmid = {10973255},
issn = {1061-4036},
support = {K08 AG001019/AG/NIA NIH HHS/United States ; K08AR02104-01/AR/NIAMS NIH HHS/United States ; R01HD 34880/HD/NICHD NIH HHS/United States ; R01HD28317/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Apoptosis/radiation effects ; Cell Nucleus/radiation effects ; Cell Survival/radiation effects ; Chromosome Aberrations ; Chromosomes/radiation effects ; DNA Fragmentation/radiation effects ; *DNA Repair ; Dose-Response Relationship, Radiation ; Fibroblasts/radiation effects ; Genotype ; In Situ Nick-End Labeling ; Kinetics ; Mice ; Mice, Transgenic ; Models, Genetic ; Radiation Tolerance/*genetics ; *Radiation, Ionizing ; Telomere/*physiology/radiation effects/ultrastructure ; Thymus Gland/cytology/radiation effects ; Time Factors ; },
abstract = {Telomeres are specialized nucleoprotein complexes that serve as protective caps of linear eukaryotic chromosomes. Loss of telomere function is associated with rampant genetic instability and loss of cellular viability and renewal potential. The telomere also participates in processes of chromosomal repair, as evidenced by the 'capture' or de novo synthesis of telomere repeats at double-stranded breaks and by the capacity of yeast telomeres to serve as repositories of essential components of the DNA repair machinery, particularly those involved in non-homologous end-joining (NHEJ). Here we used the telomerase-deficient mouse, null for the essential telomerase RNA gene (Terc), to assess the role of telomerase and telomere function on the cellular and organismal response to ionizing radiation. Although the loss of telomerase activity per se had no discernable impact on the response to ionizing radiation, the emergence of telomere dysfunction in late-generation Terc-/- mice imparted a radiosensitivity syndrome associated with accelerated mortality. On the cellular level, the gastrointestinal crypt stem cells and primary thymocytes showed increased rates of apoptosis, and mouse embryonic fibroblasts (MEFs) showed diminished dose-dependent clonogenic survival. The radiosensitivity of telomere dysfunctional cells correlated with delayed DNA break repair kinetics, persistent chromosomal breaks and cytogenetic profiles characterized by complex chromosomal aberrations and massive fragmentation. Our findings establish a intimate relationship between functionally intact telomeres and the genomic, cellular and organismal response to ionizing radiation.},
}
@article {pmid10972889,
year = {2000},
author = {Riha, K and McKnight, TD and Fajkus, J and Vyskot, B and Shippen, DE},
title = {Analysis of the G-overhang structures on plant telomeres: evidence for two distinct telomere architectures.},
journal = {The Plant journal : for cell and molecular biology},
volume = {23},
number = {5},
pages = {633-641},
doi = {10.1046/j.1365-313x.2000.00831.x},
pmid = {10972889},
issn = {0960-7412},
mesh = {Base Sequence ; DNA Primers ; DNA Replication ; Plant Leaves/enzymology ; Plants/enzymology/*genetics ; Telomerase/metabolism ; *Telomere ; },
abstract = {Telomeres are highly conserved structures essential for maintaining the integrity of eukaryotic genomes. In yeast, ciliates and mammals, the G-rich strand of the telomere forms a 3' overhang on the chromosome terminus. Here we investigate the architecture of telomeres in the dicot plants Silene latifolia and Arabidopsis thaliana using the PENT (primer extension/nick translation) assay. We show that both Arabidopsis and Silene telomeres carry G-overhangs longer than 20-30 nucleotides. However, in contrast to yeast and ciliate telomeres, only half of the telomeres in Silene seedlings possess detectable G-overhangs. PENT reactions using a variety of primers and reaction conditions revealed that the remaining fraction of Silene telomeres carries either no overhangs or overhangs less than 12 nucleotides in length. G-overhangs were observed in Silene seeds and leaves, tissues that lack telomerase activity. These findings suggest that incomplete DNA replication of the lagging strand, rather than synthesis by telomerase, is the primary mechanism for G-overhang synthesis in plants. Unexpectedly, we found that the fraction of telomeres with detectable G-overhangs decreased from 50% in seedlings to 35% in leaves. The difference may reflect increased susceptibility of the G-overhangs to nuclease attack in adult leaves, an event that could act as a precursor for the catabolic processes accompanying leaf senescence},
}
@article {pmid10964756,
year = {2000},
author = {McChesney, PA and Aisner, DL and Frank, BC and Wright, WE and Shay, JW},
title = {Telomere dynamics in cells with introduced telomerase: a rapid assay for telomerase activity on telomeres.},
journal = {Molecular cell biology research communications : MCBRC},
volume = {3},
number = {5},
pages = {312-318},
doi = {10.1006/mcbr.2000.0229},
pmid = {10964756},
issn = {1522-4724},
mesh = {Blotting, Western ; Carcinoma, Renal Cell ; Catalytic Domain ; Cell Line ; Cell Line, Transformed ; DNA-Binding Proteins/metabolism ; Fibroblasts ; Fibrosarcoma ; Humans ; *RNA ; Telomerase/*genetics/metabolism ; Telomere/*metabolism ; Tumor Cells, Cultured ; },
abstract = {Most immortal cell lines derived from human cancers or transformed in vitro maintain telomeres by endogenous expression of telomerase. In the present work, immortal cells that already express endogenous telomerase activity were induced to overexpress an exogenous telomerase (hTERT) and were analyzed for changes in telomere length. Introduction of hTERT into telomerase-positive immortal cell lines results in elevated telomerase activity as measured by the TRAP assay, leading to elongated telomeres in the cell lines tested. We explore possibilities for regulatory differences among the cell lines, including the level of overexpression of the catalytic subunit hTERT and the endogenous levels of telomere binding proteins. Reducing levels of hTERT expression with a construct containing an inefficient translation initiation sequence provided sufficient telomerase expression for maximal rates of telomere elongation. Overexpression of the hTERT alters the telomere length normally maintained in these cells and provides a very useful assay for the rapid analysis of telomerase activity on its native substrate, telomeres.},
}
@article {pmid10963374,
year = {2000},
author = {Dhaene, K and Van Marck, E and Parwaresch, R},
title = {Telomeres, telomerase and cancer: an up-date.},
journal = {Virchows Archiv : an international journal of pathology},
volume = {437},
number = {1},
pages = {1-16},
doi = {10.1007/s004280000189},
pmid = {10963374},
issn = {0945-6317},
mesh = {Aging ; Animals ; Humans ; Mice ; Mice, Knockout ; Models, Biological ; *Neoplasms/enzymology/ultrastructure ; *Telomerase/chemistry/genetics/physiology ; *Telomere/physiology/ultrastructure ; Transfection ; },
abstract = {In the mid 1990s, the hypothesis emerged that the upregulation or re-expression of a telomere-synthesising ribonucleoprotein, called telomerase, is a critical event responsible for continuous tumour cell growth. In contrast to normal cells, in which gradual mitosis-related erosion of telomeres eventually limits replicative life span, tumour cells have telomerase and show no loss of these chromosomal ends. These data suggest that telomere stabilisation may be required for cells to escape replicative senescence and to proliferate indefinitely. Because of the close association between telomerase and malignancy, both pathologists and clinicians expect this molecule to be a useful malignancy-marker and a new therapeutic target. This review focuses on the components of the human telomere and of the human telomerase enzyme. A synopsis of reports studying the clinical-diagnostic value of telomere length measurements, of telomerase activity analyses and of the in situ telomerase detection is given. Finally, a summary of recent experimental work that sheds new light on the biological role of this fascinating molecule is presented.},
}
@article {pmid10961605,
year = {1999},
author = {Hotchkiss, G and Pehrson, PO and Larsson, S and Ahrlund-Richter, L and Britton, S},
title = {Telomere loss in peripheral blood mononuclear cells may be moderately accelerated during highly active antiretroviral therapy (HAART).},
journal = {Journal of acquired immune deficiency syndromes (1999)},
volume = {22},
number = {5},
pages = {445-452},
doi = {10.1097/00126334-199912150-00004},
pmid = {10961605},
issn = {1525-4135},
mesh = {Adult ; Anti-HIV Agents/administration &amp; dosage/*therapeutic use ; Drug Therapy, Combination ; HIV Infections/blood/drug therapy/*genetics ; HIV Protease Inhibitors/administration &amp; dosage/*therapeutic use ; Humans ; Middle Aged ; Monocytes/*ultrastructure ; Reverse Transcriptase Inhibitors/administration &amp; dosage/*therapeutic use ; *Telomere ; },
abstract = {It has been speculated that infection with HIV-1 may lead to a significant increase in turnover, and subsequent exhaustion, of immune repopulation. Given that telomeric DNA is lost on mitotic replication, telomere lengths can be used as an indirect gauge of this rate. We have analyzed the mean telomere restriction fragment lengths in peripheral blood mononuclear cells (PBMC) from 31 patients with established, though mainly untreated, HIV infection and found them to be no different than those among healthy controls. Our results are in line with several findings in CD4+ cell fractions but contradict a previous report suggesting that telomere shortening contributes to immune failure. Interestingly, after approximately 2 years of subsequent aggressive antiretroviral treatment we found a telomere reduction corresponding to a loss of about 250 base pairs per year; this is roughly tenfold above that predicted from healthy individuals. This could partly result from nucleoside analogue inhibition of the natural telomere replacement enzyme, telomerase-a reverse transcriptase inducible in certain hematopoietic cells. However, this may also indicate accelerated cell replacement on initiation of optimal therapeutic regimes or result from changes in the composition of the PBMC pool. These results suggest careful monitoring of telomere lengths during long-term HAART.},
}
@article {pmid10961392,
year = {2000},
author = {Furugori, E and Hirayama, R and Nakamura, KI and Kammori, M and Esaki, Y and Takubo, K},
title = {Telomere shortening in gastric carcinoma with aging despite telomerase activation.},
journal = {Journal of cancer research and clinical oncology},
volume = {126},
number = {8},
pages = {481-485},
doi = {10.1007/s004320000137},
pmid = {10961392},
issn = {0171-5216},
mesh = {Adenocarcinoma/*genetics ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Blotting, Southern ; Cellular Senescence/genetics ; Child, Preschool ; Enzyme Activation ; Female ; Gastric Mucosa/cytology/enzymology ; Humans ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Polymorphism, Restriction Fragment Length ; Stomach Neoplasms/*genetics ; Telomerase/metabolism ; *Telomere ; Terminal Repeat Sequences ; },
abstract = {In the present study, we analyzed both telomere length and telomerase activity in surgical and autopsy samples of non-neoplastic mucosa and carcinomas of the stomach. Telomere length, determined by Southern blot analysis, demonstrated progressive shortening with age in non-neoplastic gastric mucosal specimens from 38 human subjects aged between 0 and 99 years, with an average annual loss rate of 46 base pairs (bp). The mean (+/- SD) telomere length in 21 gastric carcinomas was 7.0 +/- 1.6 x 10(3) base pairs (1.6 kbp). In 20 (95%) of the 21 subjects, the values were smaller than those in the nonneoplastic gastric mucosa (mean shortening 1.8 kbp), although a strong correlation was observed for the paired data (r = 0.69, P = 0.0004). Similarly, telomere lengths in carcinomas were shorter than those for intestinal metaplasia (a mean difference of 1.1 kbp). Telomerase activity, estimated using the telomeric repeat amplification protocol assay, was positive in 18 (86%) of the 21 gastric carcinomas, without significant differences among the three histological types (well, moderately, and poorly differentiated adenocarcinomas) or with sex or age. The results suggest that telomere length and possibly shortening rates vary with the individual, and that examination of both non-neoplastic mucosa and tumors is necessary to improve our understanding of the significance of telomerase in neoplasia.},
}
@article {pmid10960768,
year = {2000},
author = {Nakamura, K and Furugori, E and Esaki, Y and Arai, T and Sawabe, M and Okayasu, I and Fujiwara, M and Kammori, M and Mafune, K and Kato, M and Oshimura, M and Sasajima, K and Takubo, K},
title = {Correlation of telomere lengths in normal and cancers tissue in the large bowel.},
journal = {Cancer letters},
volume = {158},
number = {2},
pages = {179-184},
doi = {10.1016/s0304-3835(00)00521-8},
pmid = {10960768},
issn = {0304-3835},
mesh = {Adult ; Aged ; Aged, 80 and over ; Blotting, Southern ; Colorectal Neoplasms/*genetics/pathology ; DNA/genetics ; DNA, Neoplasm/genetics ; Female ; Humans ; Infant ; Intestinal Mucosa/metabolism ; Intestine, Large/*metabolism ; Male ; Middle Aged ; Regression Analysis ; Telomere/*genetics ; },
abstract = {The hypothesis that telomeres in colorectal cancer cells exhibit age-related shortening, as in normal cells of the colorectal epithelium, was tested with samples of non-cancerous mucosa and cancer tissue from 124 patients (aged 29-97 years). Shortening with aging could be demonstrated for both normal and cancer tissues; regression analysis showed rates for length reduction of 44 and 50 base pair/year, respectively. Straight, essentially parallel, lines were obtained for the two cases, normal tissue values being about 2 kilobase pairs (kbp) higher, with a significant correlation between data at the individual patient level.},
}
@article {pmid10954850,
year = {2000},
author = {Kierszenbaum, AL},
title = {Telomeres: more than chromosomal non-sticking ends.},
journal = {Molecular reproduction and development},
volume = {57},
number = {1},
pages = {2-3},
doi = {10.1002/1098-2795(200009)57:1&lt;2::AID-MRD2&gt;3.0.CO;2-R},
pmid = {10954850},
issn = {1040-452X},
mesh = {Animals ; DNA-Binding Proteins/metabolism/*physiology ; Humans ; Nuclear Proteins/metabolism/*physiology ; Telomere/*physiology ; Telomeric Repeat Binding Protein 1 ; Telomeric Repeat Binding Protein 2 ; },
abstract = {Telomeres are specialized natural ends of eukaryotic chromosomes that, contrary to the ends of broken chromosomes, are stable and do not fuse with the ends of other chromosomes. In addition, telomeres protect chromosomal ends from degradation, facilitate completion of chromosomal DNA replication, and contribute to chromosome positioning within nuclei. Telomeric DNA consists of repetitive sequences and specific associated proteins, including the telomere repeat-binding factors TRF1 and TRF2. A lack of TRF2 enables end-to-end chromosome fusion. A structural disruption of telomeres not only causes chromosomal mechanical instability but also activates a programmed cell death cascade.},
}
@article {pmid10954087,
year = {2000},
author = {Hiratsu, K and Mochizuki, S and Kinashi, H},
title = {Cloning and analysis of the replication origin and the telomeres of the large linear plasmid pSLA2-L in Streptomyces rochei.},
journal = {Molecular &amp; general genetics : MGG},
volume = {263},
number = {6},
pages = {1015-1021},
doi = {10.1007/pl00008689},
pmid = {10954087},
issn = {0026-8925},
mesh = {Amino Acid Sequence ; Base Sequence ; Cosmids ; *DNA Replication ; DNA, Bacterial/biosynthesis ; Electrophoresis, Gel, Pulsed-Field ; Genomic Library ; Molecular Sequence Data ; Nucleic Acid Conformation ; Plasmids/*genetics ; Replication Origin/*genetics ; Replicon ; Restriction Mapping ; Sequence Homology, Nucleic Acid ; Streptomyces/*genetics ; Telomere/*genetics ; },
abstract = {The replication origin and both terminal segments were cloned from the large linear plasmid pSLA2-L in Streptomyces rochei 7434AN4. The basic replicon consists of a 1.9-kb DNA fragment, which contains the genetic information required for autonomous replication in circular form. Sequence analysis revealed two ORFs, RepL1 and RepL2, with no similarity to any of the replication initiator proteins in the database. Deletion and mutational analysis showed that RepL1 is essential for replication and RepL2 has a subsidiary function. The origin of replication may be located 800 bp upstream of repL1. Sequencing of the left and right terminal segments revealed the presence of 12 palindromes. The sequence of the first 90 bp, including palindromes I-IV, shows great similarity to that of other Streptomyces linear chromosomes and plasmids. These results suggest that the internal replication origins of the linear replicons vary widely, in contrast to the high degree of conservation of their telomeres.},
}
@article {pmid10952212,
year = {1999},
author = {Pardue, ML and DeBaryshe, PG},
title = {Drosophila telomeres: two transposable elements with important roles in chromosomes.},
journal = {Genetica},
volume = {107},
number = {1-3},
pages = {189-196},
pmid = {10952212},
issn = {0016-6707},
support = {GM 50315/GM/NIGMS NIH HHS/United States ; GM 57006/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Chromosomes ; *DNA Transposable Elements ; Drosophila melanogaster/*genetics ; Evolution, Molecular ; Promoter Regions, Genetic ; Retroviridae/genetics ; *Telomere ; },
abstract = {Telomeres in Drosophila melanogaster are composed of multiple copies of two retrotransposable elements, HeT-A and TART instead of the short DNA repeats generated by telomerase in most organisms. Transpositions of HeT-A and TART yield arrays of repeats larger and more irregular than the repeats produced by telomerase; nevertheless, these transpositions are, in principle, equivalent to the telomere-building action of telomerase. Both telomerase and transposition of HeT-A and TART extend chromosomes by RNA-templated addition of specific sequences. We have proposed that HeT-A has evolved from genes encoding telomerase components. Although both HeT-A and TART share some novel features, TART probably has a different origin from HeT-A. HeT-A and TART are clearly identifiable as non-long terminal repeat (non-LTR) retrotransposons. Both telomere elements transpose only to the ends of chromosomes (apparently to any chromosome end in D. melanogaster) and each contains a large segment of untranslated sequence. HeT-A and TART are the first examples of transposable elements with a clear role in chromosome structure. This has interesting implications for the evolution of both chromosomes and transposable elements. The finding also raises the possibility that other transposable elements with bona fide roles in the cell will be detected, not only in Drosophila, but also in other organisms.},
}
@article {pmid10949306,
year = {2000},
author = {Artandi, SE and Chang, S and Lee, SL and Alson, S and Gottlieb, GJ and Chin, L and DePinho, RA},
title = {Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice.},
journal = {Nature},
volume = {406},
number = {6796},
pages = {641-645},
doi = {10.1038/35020592},
pmid = {10949306},
issn = {0028-0836},
support = {K08 AG001019/AG/NIA NIH HHS/United States ; },
mesh = {Adenocarcinoma/enzymology/genetics ; Aging/genetics ; Animals ; Disease Models, Animal ; Female ; Genes, p53 ; Humans ; Karyotyping ; Lymphoma/enzymology/genetics ; Male ; Mammary Neoplasms, Experimental/enzymology/genetics ; Mice ; Mutation ; Neoplasms, Glandular and Epithelial/enzymology/*genetics/pathology ; Sarcoma, Experimental/enzymology/genetics ; Telomerase/deficiency/genetics/metabolism ; *Telomere ; *Translocation, Genetic ; },
abstract = {Aged humans sustain a high rate of epithelial cancers such as carcinomas of the breast and colon, whereas mice carrying common tumour suppressor gene mutations typically develop soft tissue sarcomas and lymphomas. Among the many factors that may contribute to this species variance are differences in telomere length and regulation. Telomeres comprise the nucleoprotein complexes that cap the ends of eukaryotic chromosomes and are maintained by the reverse transcriptase, telomerase. In human cells, insufficient levels of telomerase lead to telomere attrition with cell division in culture and possibly with ageing and tumorigenesis in vivo. In contrast, critical reduction in telomere length is not observed in the mouse owing to promiscuous telomerase expression and long telomeres. Here we provide evidence that telomere attrition in ageing telomerase-deficient p53 mutant mice promotes the development of epithelial cancers by a process of fusion-bridge breakage that leads to the formation of complex non-reciprocal translocations--a classical cytogenetic feature of human carcinomas. Our data suggest a model in which telomere dysfunction brought about by continual epithelial renewal during life generates the massive ploidy changes associated with the development of epithelial cancers.},
}
@article {pmid10949281,
year = {2000},
author = {Hanahan, D},
title = {Benefits of bad telomeres.},
journal = {Nature},
volume = {406},
number = {6796},
pages = {573-574},
doi = {10.1038/35020662},
pmid = {10949281},
issn = {0028-0836},
mesh = {Animals ; Enzyme Activation ; Humans ; Mice ; Neoplasms/*enzymology/*genetics ; Neoplasms, Glandular and Epithelial/enzymology/genetics ; Sarcoma, Experimental/enzymology/genetics ; Telomerase/deficiency/genetics/*metabolism ; *Telomere ; Tumor Suppressor Protein p53/genetics/physiology ; },
}
@article {pmid10948077,
year = {2000},
author = {Jeanclos, E and Schork, NJ and Kyvik, KO and Kimura, M and Skurnick, JH and Aviv, A},
title = {Telomere length inversely correlates with pulse pressure and is highly familial.},
journal = {Hypertension (Dallas, Tex. : 1979)},
volume = {36},
number = {2},
pages = {195-200},
doi = {10.1161/01.hyp.36.2.195},
pmid = {10948077},
issn = {0194-911X},
support = {HL-54998/HL/NHLBI NIH HHS/United States ; HL-94011/HL/NHLBI NIH HHS/United States ; RR03655-11/RR/NCRR NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Blood Pressure/genetics/*physiology ; DNA/genetics ; Diastole ; Family Health ; Female ; Humans ; Male ; Multivariate Analysis ; Polymorphism, Restriction Fragment Length ; *Pulse ; Regression Analysis ; Systole ; Telomere/*genetics ; },
abstract = {There is evidence that telomeres, the ends of chromosomes, serve as clocks that pace cellular aging in vitro and in vivo. In industrialized nations, pulse pressure rises with age, and it might serve as a phenotype of biological aging of the vasculature. We therefore conducted a twin study to investigate the relation between telomere length in white blood cells and pulse pressure while simultaneously assessing the role of genetic factors in determining telomere length. We measured by Southern blot analysis the mean length of the terminal restriction fragments (TRF) in white blood cells of 49 twin pairs from the Danish Twin Register and assessed the relations of blood pressure parameters with TRF. TRF length showed an inverse relation with pulse pressure. Both TRF length and pulse pressure were highly familial. We conclude that telomere length, which is under genetic control, might play a role in mechanisms that regulate pulse pressure, including vascular aging.},
}
@article {pmid10942798,
year = {2000},
author = {Gribble, S and Andrews, K and Williams, D and Tillett, A and Bloxham, D and Proffit, J and Hackbarth, M and Grace, C and Green, A and Nacheva, E},
title = {Fluorescence in situ hybridization detection of two telomeres on the short arm of a derived chromosome 16 in an infant with thrombocytopenia.},
journal = {Cancer genetics and cytogenetics},
volume = {120},
number = {2},
pages = {99-104},
doi = {10.1016/s0165-4608(99)00259-9},
pmid = {10942798},
issn = {0165-4608},
mesh = {Bone Marrow Cells/metabolism/pathology ; Chromosome Banding ; Chromosome Painting ; Chromosomes, Human, Pair 16/*genetics ; Chromosomes, Human, Pair 21/*genetics ; Chromosomes, Human, Pair 3/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; Karyotyping ; Male ; Telomere/*genetics ; Thrombocytopenia/genetics/*pathology ; Translocation, Genetic ; },
abstract = {We report a case of severe thrombocytopenia with an abnormal bone marrow karyotype described by G-banding analysis as t(16;21)(p?13;q11). Using fluorescence in situ hybridization (FISH) analysis with whole chromosome paints, the chromosome rearrangement was shown to be more complex, with the additional cryptic involvement of the long arm of chromosome 3. The chromosome rearrangement involved the breakpoints 3q26, 16p13.3, and 21q11; this rearrangement has not been previously described. The size of genomic material translocated from the chromosome 16 homologue was too small to be detected by chromosome paint. A 16p-specific telomeric probe was hybridized to locate the translocated 16p material. The 16p telomeric unique sequence DNA was retained on the der(16) chromosome, indicating a more distal breakpoint. This study demonstrates that telomeric translocations can occur that would be undetected by telomeric-specific FISH probes.},
}
@article {pmid10940878,
year = {2000},
author = {Burns, JB and Lobo, ST and Bartholomew, BD},
title = {In vivo reduction of telomere length in human antigen-reactive memory T cells.},
journal = {European journal of immunology},
volume = {30},
number = {7},
pages = {1894-1901},
doi = {10.1002/1521-4141(200007)30:7&lt;1894::AID-IMMU1894&gt;3.0.CO;2-N},
pmid = {10940878},
issn = {0014-2980},
support = {CA 42014/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; CD4-Positive T-Lymphocytes/cytology/*immunology ; Candida albicans/immunology ; Cells, Cultured ; Flow Cytometry/methods ; Humans ; Immunologic Memory/*immunology ; In Situ Hybridization/methods ; Leukocyte Common Antigens/immunology ; Middle Aged ; *Telomere ; Tetanus Toxoid/immunology ; },
abstract = {There is a reduction in the average telomere lengths of CD4+ "memory" T cells, defined by the CD45RO+ phenotype, compared to CD54RA+ "naive" T cells. However, other studies suggest that telomerase activity often is sufficient to maintain the telomere length of certain B and T cell populations following immune activation in vivo. Thus it is uncertain whether genuine memory CD4+ T cells, defined by an immune response to specific recall antigens, would display telomeres of reduced length, or whether telomere size would be maintained. Therefore, we examined the telomere lengths of T cells responding to two common recall antigens, tetanus toxoid and Candida albicans. Telomere terminal restriction fragment length was assessed by Southern blots or by flow cytometry following in situ hybridization with telomere-specific peptide nucleic acid probes. For the five subjects tested, the Candida- or tetanus-reactive memory T cell populations demonstrated a significant reduction of telomere length even when compared to the phenotypically defined memory CD45RO+ T cell populations isolated from peripheral blood mononuclear cells. This finding suggests that telomerase activity does not fully compensate for the effects of in vivo activation and proliferation of some antigen-specific CD4+ T cell populations. This may contribute to immune senescence.},
}
@article {pmid10939713,
year = {2000},
author = {Weng, NP and Hodes, RJ},
title = {The role of telomerase expression and telomere length maintenance in human and mouse.},
journal = {Journal of clinical immunology},
volume = {20},
number = {4},
pages = {257-267},
pmid = {10939713},
issn = {0271-9142},
mesh = {Aging/genetics/pathology ; Animals ; Cell Transformation, Neoplastic/genetics ; Cellular Senescence/genetics/*physiology ; Chromosomes/ultrastructure ; DNA Replication ; Endothelium, Vascular/cytology ; Enzyme Induction ; Fibroblasts/cytology ; Genes, Tumor Suppressor ; Genetic Diseases, Inborn/genetics/pathology ; HIV Infections/immunology/pathology ; Hematopoietic Stem Cells/cytology ; Humans ; Infectious Mononucleosis/immunology/pathology ; Leukocytes/cytology ; Lymphocyte Subsets/cytology ; Mice ; Mice, Knockout ; Models, Animal ; Neoplasm Proteins/physiology ; Neoplasms/enzymology/genetics/pathology ; Organ Specificity ; Telomerase/biosynthesis/deficiency/genetics/*physiology ; Telomere/physiology/*ultrastructure ; },
abstract = {The molecular regulation of telomere length has been well elucidated by a series of elegant studies over the past decade. More recently, experimental evidence has accrued that addresses the challenging question of if and how telomere length regulation may contribute to normal human aging or to human disease. Recent studies in mice have provided a mammalian precedent indicating that telomerase deficiency can lead to in vivo dysfunction, most probably as a consequence of progressive telomere shortening. In humans, the evidence that telomere shortening might lead to in vivo dysfunction is far less direct, although the recent description of telomerase deficiency and telomere shortening associated with the DKC syndrome is suggestive of such a link. Methodologies exist and continue to be developed that are increasingly capable of manipulating telomerase activity and telomere length in human cells. It remains to be determined whether scientifically rigorous and (equally important) medically ethical approaches will emerge to directly assess the ability of telomere length modulation to correct functional disorders of human cellular function ex vivo or more challenging still, in vivo.},
}
@article {pmid10935496,
year = {1999},
author = {Krejcí, K and Stentoft, J and Koch, J},
title = {Molecular cytogenetics investigation of the telomeres in a case of Philadelphia positive B-ALL with a single telomere expansion.},
journal = {Neoplasia (New York, N.Y.)},
volume = {1},
number = {6},
pages = {492-497},
pmid = {10935496},
issn = {1522-8002},
mesh = {Adult ; Burkitt Lymphoma/*genetics ; Chromosomes, Human, Pair 11 ; Humans ; Male ; *Philadelphia Chromosome ; Repetitive Sequences, Nucleic Acid ; *Telomere ; },
abstract = {We have investigated a single telomere expansion in a case of acute lymphoblastic B-cell leukemia (B-ALL), where half of the cells in the bone marrow sample appeared with a Philadelphia chromosome. Comparing telomere sizes in Philadelphia-positive versus -negative cells, we found generally shorter telomeres in the Philadelphia-positive cells, but with an expansion of the telomere on the long arm of one chromosome 11 homologue. This expansion was also found in a minority of Philadelphia-negative cells. The telomeres in these cells were of the same overall size as the telomeres in the Philadelphia-negative cells without the 11q expansion. Together, these findings suggest that the order of events was: 11q telomere expansion, Philadelphia translocation, overall telomere shortening. The expanded 11q telomere contained the standard telomeric (AGGGTT)(n) repeat, but also variant repeat sequences. The single telomere expansion suggests a non-telomerase mechanism behind the expansion which may also explain the presence of variant repeats in the expanded telomere. The present case illustrates that telomere changes may occur at only some chromosome ends in a subset of cells. To reveal such changes, telomere morphology should be studied with in situ methodology.},
}
@article {pmid10932210,
year = {2000},
author = {Wright, WE and Shay, JW},
title = {Telomere dynamics in cancer progression and prevention: fundamental differences in human and mouse telomere biology.},
journal = {Nature medicine},
volume = {6},
number = {8},
pages = {849-851},
doi = {10.1038/78592},
pmid = {10932210},
issn = {1078-8956},
mesh = {Animals ; Cell Division ; Cellular Senescence ; Fibroblasts/cytology ; Humans ; Mice ; Mice, Knockout ; Neoplasms/*etiology/*prevention &amp; control ; Species Specificity ; Telomerase/genetics/physiology ; Telomere/*physiology ; },
abstract = {Cells from the telomerase knockout mouse immortalize with an approximately ten million-fold greater frequency than human cells. In this commentary, Wright and Shay discuss the implications of this difference between mice and men and its relationship to cancer.},
}
@article {pmid10931927,
year = {2000},
author = {Nozawa, K and Suzuki, M and Takemura, M and Yoshida, S},
title = {In vitro expansion of mammalian telomere repeats by DNA polymerase alpha-primase.},
journal = {Nucleic acids research},
volume = {28},
number = {16},
pages = {3117-3124},
pmid = {10931927},
issn = {1362-4962},
mesh = {Animals ; Base Sequence ; Cattle ; DNA Polymerase I/*metabolism ; DNA Primase/*metabolism ; DNA Primers ; Escherichia coli/enzymology/*genetics ; Guanine ; Plasmids ; *Repetitive Sequences, Nucleic Acid ; Sequence Deletion ; Substrate Specificity ; Telomere/*metabolism ; Templates, Genetic ; Thymus Gland/enzymology ; },
abstract = {Among the polymerases, DNA polymerase alpha-primase is involved in lagging strand DNA synthesis. A previous report indicated that DNA polymerase alpha-primase initiates primer RNA synthesis with purine bases on a single-stranded G-rich telomere repeat. In this study, we found that DNA polymerase alpha-primase precisely initiated with adenosine opposite the 3'-side thymidine in the G-rich telomere repeat 5'-(TTAGGG)(n)-3' under rATP-rich conditions. Then, DNA polymerase alpha-primase synthesized the nascent DNA fragments by extending the primer. It was remarkable that DNA polymerase alpha-primase further expanded the product DNA far beyond the length of the template DNA, as ladders of multiple hexanucleotides on polyacrylamide gel electrophoresis. Using an oligomer duplex 5'-A(GGGTTA)(5)-3'/5'-(TAACCC)(5)T-3' as a template-primer, we show that both the Klenow fragment of Escherichia coli DNA polymerase I and HIV reverse transcriptase could expand telomere DNA sequences as well, giving products greater than the size of the template DNA. The maximum product lengths with these polymerases were approximately 40-90 nt longer than the template length. Our data imply that DNA polymerases have an intrinsic activity to expand the hexanucleotide repeats of the telomere sequence by a slippage mechanism and that DNA polymerase alpha uses both the repeat DNA primers and the de novo RNA primers for expansion. On the other hand, a plasmid harboring a eukaryotic telomere repeat showed remarkable genetic instability in E.coli. The telomere repeats exhibited either expansions or deletions by multiple hexanucleotide repeats during culture for a number of generations, suggesting involvement of the slippage mechanism in the instability of telomeric DNA in vivo.},
}
@article {pmid10931683,
year = {2000},
author = {Pandita, TK and Dhar, S},
title = {Influence of ATM function on interactions between telomeres and nuclear matrix.},
journal = {Radiation research},
volume = {154},
number = {2},
pages = {133-139},
doi = {10.1667/0033-7587(2000)154[0133:ioafoi]2.0.co;2},
pmid = {10931683},
issn = {0033-7587},
support = {NS34746/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia/*genetics ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins ; Cell Line ; Chromosomes/chemistry ; DNA/chemistry ; DNA-Binding Proteins/analysis ; Fibroblasts ; Gamma Rays ; Humans ; Male ; Mice ; *Mutation ; Nuclear Matrix/chemistry/metabolism/radiation effects ; Protein Serine-Threonine Kinases/chemistry/*genetics ; Signal Transduction ; Spermatozoa/chemistry/metabolism ; Telomere/chemistry/*metabolism/radiation effects ; Tumor Suppressor Proteins ; },
abstract = {The ATM (ataxia telangiectasia mutated) gene product has been implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, and cell cycle control. The human ATM protein shows similarity to several yeast and mammalian proteins involved in meiotic recombination and cell cycle progression. Because of the homology of the human ATM gene to the TEL1 and rad3 genes of yeast, it has been suggested that mutations in ATM could lead to defective telomere maintenance. Recently, we have shown that the ATM gene product, which is defective in the cancer-prone disorder ataxia telangiectasia (AT), influences chromosome end associations and telomere length. A possible hypothesis explaining these results is that the defective telomere metabolism in AT cells is due to altered interactions between the telomeres and the nuclear matrix. These interactions were examined in nuclear matrix halos prior to and after irradiation. A difference was observed in the ratio of soluble and matrix-associated telomeric DNA between cells derived from AT and normal individuals. Treatment with ionizing radiation affected the ratio of soluble and matrix-associated telomeric DNA only in the AT cells. To test the hypothesis that the ATM gene product is involved in interactions between telomeres and the nuclear matrix, such interactions were examined in human cells expressing either a dominant-negative effect or complementation of the ATM gene. The phenotype of RKO colorectal tumor cells expressing ATM fragments containing a leucine zipper motif mimics the altered interactions of telomere and nuclear matrix seen in AT cells. Fibroblasts from AT individuals transfected with a wild-type ATM gene had corrected telomere-nuclear matrix interactions. In experiments designed to determine whether there is a link between the altered telomere-nuclear matrix interactions and defective telomere movement and clustering, a significant difference was observed in the ratio of soluble compared to matrix-associated telomeric DNA sequences in meiocytes of Atm(-/-) and control mice. These results suggest that the ATM gene influences the interactions between telomeres and the nuclear matrix and that alterations in telomere chromatin could be at least partly responsible for the pleiotropic phenotypes of the ATM gene. This paper summarizes our recent publications on the influence of inactivation of ATM on the interaction of telomeres with nuclear matrix in somatic and germ cells.},
}
@article {pmid10931390,
year = {2000},
author = {Aladdin, H and Ullum, H and Schjerling, P and Skov Jensen, M and Dam Nielsen, S and Mathiesen, L and Gerstoft, J and Skinhøj, P and Klarlund Pedersen, B},
title = {Effects of G-CSF on telomere lengths in PBMCs from human immunodeficiency virus-infected patients: results from a randomized, placebo-controlled trial.},
journal = {Scandinavian journal of immunology},
volume = {52},
number = {2},
pages = {212-216},
doi = {10.1046/j.1365-3083.2000.00771.x},
pmid = {10931390},
issn = {0300-9475},
mesh = {Adult ; Aged ; Anti-HIV Agents/administration &amp; dosage/therapeutic use ; CD4 Lymphocyte Count ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Granulocyte Colony-Stimulating Factor/administration &amp; dosage/*therapeutic use ; HIV Infections/blood/*drug therapy/immunology ; Humans ; In Vitro Techniques ; Leukocytes, Mononuclear/*drug effects/*ultrastructure ; Lymphocytes/drug effects/ultrastructure ; Male ; Middle Aged ; Monocytes/drug effects/ultrastructure ; Telomere/*drug effects/*ultrastructure ; },
abstract = {Telomeres are unique terminal chromosomal structures, the length of which has been shown to decrease with cell division in vitro and with increased age in vivo for human somatic cells. In human immunodeficiency virus (HIV)-1 infection, decrease of telomere length is primarily found in CD8+ T cells, and not in CD4+ T cells. In this double-blind placebo-controlled study, we investigated the effect of granulocyte colony stimulating factor (G-CSF) treatment combined with highly active antiretroviral therapy (HAART) on mean telomere length in peripheral blood mononuclear cells (PBMC). The terminal restriction fragment (TRF) length showed no changes during G-CSF treatment although the number of lymphocytes increased significantly. The mean TRF length correlated positively (R = 0.552, P = 0.009) and negatively (R = -0.503, P = 0.02) to the proportion of CD4+ memory and naïve cells, respectively. Our data suggest that during G-CSF treatment lymphocytes are recruited by a combination of central and peripheral proliferation.},
}
@article {pmid10930457,
year = {2000},
author = {Fritz, E and Friedl, AA and Zwacka, RM and Eckardt-Schupp, F and Meyn, MS},
title = {The yeast TEL1 gene partially substitutes for human ATM in suppressing hyperrecombination, radiation-induced apoptosis and telomere shortening in A-T cells.},
journal = {Molecular biology of the cell},
volume = {11},
number = {8},
pages = {2605-2616},
pmid = {10930457},
issn = {1059-1524},
support = {R01 CA60592/CA/NCI NIH HHS/United States ; },
mesh = {Apoptosis/*radiation effects ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins ; Cell Line, Transformed ; DNA-Binding Proteins ; Fibroblasts ; Fungal Proteins/genetics/*physiology ; Gamma Rays ; Genetic Complementation Test ; Humans ; Intracellular Signaling Peptides and Proteins ; Mutation ; Protein Serine-Threonine Kinases/genetics/*physiology ; *Recombination, Genetic ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins ; Telomere/*metabolism ; Transfection ; Tumor Suppressor Protein p53/metabolism/radiation effects ; Tumor Suppressor Proteins ; },
abstract = {Homozygous mutations in the human ATM gene lead to a pleiotropic clinical phenotype of ataxia-telangiectasia (A-T) patients and correlating cellular deficiencies in cells derived from A-T donors. Saccharomyces cerevisiae tel1 mutants lacking Tel1p, which is the closest sequence homologue to the ATM protein, share some of the cellular defects with A-T. Through genetic complementation of A-T cells with the yeast TEL1 gene, we provide evidence that Tel1p can partially compensate for ATM in suppressing hyperrecombination, radiation-induced apoptosis, and telomere shortening. Complementation appears to be independent of p53 activation. The data provided suggest that TEL1 is a functional homologue of human ATM in yeast, and they help to elucidate different cellular and biochemical pathways in human cells regulated by the ATM protein.},
}
@article {pmid10929199,
year = {2000},
author = {Adams, SP and Leitch, IJ and Bennett, MD and Leitch, AR},
title = {Aloe L.--a second plant family without (TTTAGGG)n telomeres.},
journal = {Chromosoma},
volume = {109},
number = {3},
pages = {201-205},
doi = {10.1007/s004120050429},
pmid = {10929199},
issn = {0009-5915},
mesh = {Allium/cytology/genetics ; Aloe/cytology/*genetics ; Blotting, Southern ; DNA/isolation &amp; purification/metabolism ; DNA Primers/chemistry ; DNA Probes ; DNA, Plant/analysis ; Genome, Plant ; In Situ Hybridization, Fluorescence ; *Plants, Medicinal ; Polymerase Chain Reaction ; RNA, Ribosomal, 5S/genetics ; Telomere/*genetics ; },
abstract = {The physical ends of chromosomes are protected and stabilised by telomeres. The sequence of telomeric DNA normally consists of a simple repeating unit that is conserved in many organisms. Most plants examined have been shown to possess Arabidopsis-type telomeres consisting of many repeat copies of the sequence 5'-TTTAGGG-3'. Using fluorescent in situ hybridisation, slot blotting and the asymmetric polymerase chain reaction we demonstrate an absence of Arabidopsis-type telomeres in the genus Aloe (family Asphodelaceae). The only other plant genera so far reported without such telomeres are Allium, Nothoscordum, and Tulbaghia (family Alliaceae). As these genera and Aloe are petaloid monocots in the Asparagales, it is suggested that an absence of Arabidopsis-type telomeres may be characteristic of this related group of plants.},
}
@article {pmid10924407,
year = {2000},
author = {Varley, H and Di, S and Scherer, SW and Royle, NJ},
title = {Characterization of terminal deletions at 7q32 and 22q13.3 healed by De novo telomere addition.},
journal = {American journal of human genetics},
volume = {67},
number = {3},
pages = {610-622},
pmid = {10924407},
issn = {0002-9297},
mesh = {Base Sequence ; Cell Line ; Chromosome Breakage/*genetics ; *Chromosome Deletion ; Chromosomes, Human, Pair 22/*genetics ; Chromosomes, Human, Pair 7/*genetics ; Cloning, Molecular/methods ; Fibroblasts ; Humans ; In Situ Hybridization, Fluorescence ; Models, Genetic ; Molecular Sequence Data ; Physical Chromosome Mapping ; Recombination, Genetic/genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Sequence Alignment ; Telomerase/metabolism ; Telomere/*genetics ; },
abstract = {We have developed a strategy for the isolation of terminal deletion breakpoints from any chromosome that has been healed by de novo addition of a telomere repeat array. Breakpoints at 7q32 and 22q13.3 have been isolated and characterized in two patients (patients FB336R and AJ). Both truncated chromosomes have been healed by the addition of a novel telomere, with such an addition possibly mediated by the enzyme telomerase. The breakpoint at 7q32 in patient FB336R shows a structure similar to that of breakpoints on other chromosomes that have been healed in this way. However, the breakpoint at 22q13.3 in patient AJ has 10 nucleotides of unknown origin inserted between the sequence unique to chromosome 22q and the start of the telomere repeat array. This unusual structure is suggestive of a multistep healing event resulting in de novo telomere addition at this breakpoint, and possible mechanisms are discussed.},
}
@article {pmid10913111,
year = {2000},
author = {Wu, G and Lee, WH and Chen, PL},
title = {NBS1 and TRF1 colocalize at promyelocytic leukemia bodies during late S/G2 phases in immortalized telomerase-negative cells. Implication of NBS1 in alternative lengthening of telomeres.},
journal = {The Journal of biological chemistry},
volume = {275},
number = {39},
pages = {30618-30622},
doi = {10.1074/jbc.C000390200},
pmid = {10913111},
issn = {0021-9258},
support = {CA81020/CA/NCI NIH HHS/United States ; CA85605/CA/NCI NIH HHS/United States ; },
mesh = {Abnormalities, Multiple/etiology ; Cell Nucleus/*pathology ; Chromosome Breakage ; DNA-Binding Proteins/*isolation &amp; purification ; G2 Phase ; Humans ; Leukemia, Promyelocytic, Acute/*pathology ; Nuclear Proteins/*isolation &amp; purification ; S Phase ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1 ; Two-Hybrid System Techniques ; },
abstract = {Nijmegen breakage syndrome, a chromosomal instability disorder, is characterized in part by cellular hypersensitivity to ionizing radiation. The NBS1 gene product, p95 (NBS1 or nibrin) forms a complex with Rad50 and Mre11. Cells deficient in the formation of this complex are defective in DNA double-strand break repair, cell cycle checkpoint control, and telomere length maintenance. How the NBS1 complex is involved in telomere length maintenance remains unclear. Here we show that the C-terminal region of NBS1 interacts directly with a telomere repeat binding factor, TRF1, by both yeast two-hybrid and in vivo DNA-coimmunoprecipitation assays. NBS1 and Mre11 colocalize with TRF1 at promyelocytic leukemia (PML) nuclear bodies in immortalized telomerase-negative cell lines, but rarely in telomerase-positive cell lines. The translocation of NBS1 to PML bodies occurs specifically during late S to G(2) phases of the cell cycle and coincides with active DNA synthesis in these NBS1-containing PML bodies. These results suggest that NBS1 may be involved in alternative lengthening of telomeres in telomerase-negative immortalized cells.},
}
@article {pmid10911978,
year = {2000},
author = {Serra, V and Grune, T and Sitte, N and Saretzki, G and von Zglinicki, T},
title = {Telomere length as a marker of oxidative stress in primary human fibroblast cultures.},
journal = {Annals of the New York Academy of Sciences},
volume = {908},
number = {},
pages = {327-330},
doi = {10.1111/j.1749-6632.2000.tb06666.x},
pmid = {10911978},
issn = {0077-8923},
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers ; Cells, Cultured ; Fibroblasts/cytology/enzymology ; Glutathione Peroxidase/genetics/metabolism ; Humans ; Middle Aged ; Oxidative Stress/*physiology ; Superoxide Dismutase/genetics/metabolism ; *Telomere ; },
}
@article {pmid10911951,
year = {2000},
author = {von Zglinicki, T},
title = {Role of oxidative stress in telomere length regulation and replicative senescence.},
journal = {Annals of the New York Academy of Sciences},
volume = {908},
number = {},
pages = {99-110},
doi = {10.1111/j.1749-6632.2000.tb06639.x},
pmid = {10911951},
issn = {0077-8923},
mesh = {Animals ; Cells, Cultured ; Cellular Senescence/*physiology ; DNA Replication/*physiology ; Humans ; Oxidative Stress/*physiology ; Telomere/*physiology ; },
abstract = {Replicative senescence is tied into organismal aging processes in more than one respect, and telomeres appear to be the major trigger of replicative senescence under many conditions in vitro and in vivo. However, the structure-function relationships in telomeres, the mechanisms of telomere shortening with advancing replicative age, and the regulation of senescence by telomeres are far from understood. Combining recent data on telomere structure, function of telomere-binding proteins, and sensitivity of telomeres to oxidative damage, an integrative model of telomere shortening and signaling is developed. The model suggests that t-loop formation hinders access of repair proteins to telomeres, leading to accumulation of a basic sites and single-strand breaks. These might contribute to accelerated telomere shortening by transient stalling of replication as well as, if present in high concentrations, to a relief of torsional tension which might destabilize the telomeric loop structure. As a result, the single-stranded G-rich overhang, which is present at the very ends of telomeres but is normally protected at the base of the telomeric loop, will be exposed to the nucleoplasm. Free G-rich telomeric single strands are a strong inductor of the p53 pathway, and exposure of the overhangs seems to be the first step in the signal transduction cascade to replicative senescence.},
}
@article {pmid10908324,
year = {2000},
author = {Förstemann, K and Höss, M and Lingner, J},
title = {Telomerase-dependent repeat divergence at the 3' ends of yeast telomeres.},
journal = {Nucleic acids research},
volume = {28},
number = {14},
pages = {2690-2694},
pmid = {10908324},
issn = {1362-4962},
mesh = {*Antigens, Nuclear ; Base Sequence ; *DNA Helicases ; DNA, Fungal/chemistry/genetics/metabolism ; DNA-Binding Proteins/genetics ; Gene Deletion ; Genetic Variation ; Ku Autoantigen ; Molecular Sequence Data ; Nuclear Proteins/genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; Sequence Alignment ; Sequence Analysis, DNA ; Sequence Homology, Nucleic Acid ; Telomerase/deficiency/genetics/*metabolism ; Telomere/*genetics ; },
abstract = {Yeast telomeres consist of approximately 300 nt of degenerate repeats with the consensus sequence G(2-3)(TG)(1-6). We developed a method for the amplification of a genetically marked telomere by PCR, allowing precise length and sequence determination of the G-rich strand including the 3' terminus. We examined wild-type cells, telomerase RNA deficient cells and a strain deleted for YKU70, which encodes for a protein involved in telomere maintenance and DNA double strand break repair. The 3' end of the G-rich strand was found to be at a variable position within the telomeric repeat. No preference for either thymine or guanine as the 3' base was detected. Comparison of telomere sequences from clonal populations revealed that telomeres consist of a centromere-proximal region of stable sequence and a distal region with differing degenerate repeats. In wild-type as well as yku70-Delta cells, variation in the degenerate telomeric repeats was detected starting 40-100 nt from the 3' end. Sequence divergence was abolished after deletion of the telomerase RNA gene. Thus, this region defines the domain where telomere shortening and telomerase-mediated extension occurs. Since this domain is much larger than the number of nucleo-tides lost per generation in the absence of telomerase, we propose that telomerase does not extend a given telomere in every cell cycle.},
}
@article {pmid10906069,
year = {2000},
author = {Achi, MV and Ravindranath, N and Dym, M},
title = {Telomere length in male germ cells is inversely correlated with telomerase activity.},
journal = {Biology of reproduction},
volume = {63},
number = {2},
pages = {591-598},
doi = {10.1095/biolreprod63.2.591},
pmid = {10906069},
issn = {0006-3363},
support = {HD 00627/HD/NICHD NIH HHS/United States ; HD 33728/HD/NICHD NIH HHS/United States ; },
mesh = {Aging ; Animals ; Cell Differentiation ; Epididymis/ultrastructure ; Male ; Rats ; Rats, Sprague-Dawley ; Spermatids/enzymology/ultrastructure ; *Spermatogenesis ; Spermatogonia/enzymology/ultrastructure ; Spermatozoa/*enzymology/*ultrastructure ; Telomerase/*metabolism ; Telomere/*ultrastructure ; Testis/enzymology/growth &amp; development/ultrastructure ; },
abstract = {Telomeres, the noncoding sequences at the ends of chromosomes, progressively shorten with each cellular division. Spermatozoa have very long telomeres but they lack telomerase enzymatic activity that is necessary for de novo synthesis and addition of telomeres. We performed a telomere restriction fragment analysis to compare the telomere lengths in immature rat testis (containing type A spermatogonia) with adult rat testis (containing more differentiated germ cells). Mean telomere length in the immature testis was significantly shorter in comparison to adult testis, suggesting that type A spermatogonia probably have shorter telomeres than more differentiated germ cells. Then, we isolated type A spermatogonia from immature testis, and pachytene spermatocytes and round spermatids from adult testis. Pachytene spermatocytes exhibited longer telomeres compared to type A spermatogonia. Surprisingly, although statistically not significant, round spermatids showed a decrease in telomere length. Epididymal spermatozoa exhibited the longest mean telomere length. In marked contrast, telomerase activity, measured by the telomeric repeat amplification protocol was very high in type A spermatogonia, decreased in pachytene spermatocytes and round spermatids, and was totally absent in epididymal spermatozoa. In summary, these results indicate that telomere length increases during the development of male germ cells from spermatogonia to spermatozoa and is inversely correlated with the expression of telomerase activity.},
}
@article {pmid10905346,
year = {2000},
author = {Venditti, S and Di Stefano, G and Di Mauro, E},
title = {Telomere-based neo-Darwinian selection of yeast clonal subpopulations.},
journal = {Molecular &amp; general genetics : MGG},
volume = {263},
number = {5},
pages = {787-795},
doi = {10.1007/s004380000246},
pmid = {10905346},
issn = {0026-8925},
mesh = {Genes, Fungal ; Heterochromatin/genetics ; Models, Genetic ; Mutation ; Phenotype ; Saccharomyces cerevisiae/cytology/*genetics/growth &amp; development ; *Selection, Genetic ; Telomere/*genetics ; },
abstract = {In Saccharomyces cerevisiae, imbalance of the genes coding for the heterochromatin components Sir3p and histone H4 (namely, overdosage of SIR3 and lack of one of the two genes coding for H4) causes modifications in telomere length and telomere sequence organization, favoring the insertion of Y' elements into a stably shortened (C1-3A)n repeat tract. We report here that the newly inserted Y' elements are unstable and are lost with high frequency, generating clonal subpopulations with short telomeres, as revealed by the analysis of a specific telomere (LIII) and of the overall population of telomeres. Moreover, the growth rates of the subpopulations with and without Y' elements on LIII are different, the Y'-less individuals reproducing 20% more slowly than individuals bearing Y' elements. When grown together with Y'-bearing individuals, the subpopulations with the normal LIII telomere (which are viable and genetically stable if grown alone) are rapidly competed out. Hence, genetic imbalance for the structural components of heterochromatin results in a complex and rapidly changing mixture of subpopulations in such cultures. Thus, in situations where subpopulations are allowed to compete, heterochromatin-based differential growth rates result in neo-Darwinian clonal selection.},
}
@article {pmid10886419,
year = {2000},
author = {Rosén, M and Edström, J},
title = {DNA structures common for chironomid telomeres terminating with complex repeats.},
journal = {Insect molecular biology},
volume = {9},
number = {3},
pages = {341-347},
doi = {10.1046/j.1365-2583.2000.00193.x},
pmid = {10886419},
issn = {0962-1075},
mesh = {Animals ; Base Sequence ; Chironomidae/*genetics ; DNA/*chemistry ; *Genes, Insect ; In Situ Hybridization/methods ; Molecular Sequence Data ; Mutation ; Nucleic Acid Conformation ; Sequence Homology, Nucleic Acid ; Species Specificity ; *Tandem Repeat Sequences ; *Telomere ; },
abstract = {Tandem repeats, 340 bp long, have been shown to terminate the chromosomes in Chironomus pallidivittatus and similar DNA may be used for this purpose by related insects. In view of the importance of Chironomus in telomere studies, representing in principle a third system after short repeats and Drosophila telomeric retrotransposons, we have investigated the related Chironomus dilutus, to learn what DNA structures are conserved at the chromosome ends. Interspersed subrepeats in the telomeric repeats, which contain a long palindrome, and a zone of about 100 bp of relatively constant subtelomeric DNA towards the junction to the telomeric DNA, are characteristic for C. dilutus as for previously investigated species. C. dilutus has similar subtelomeric DNA at all chromosome ends, but typical telomeric repeats in only seven of the pairs since the eighth telocentric pair contains centromere-specific repeats.},
}
@article {pmid10903716,
year = {2000},
author = {Son, NH and Murray, S and Yanovski, J and Hodes, RJ and Weng, N},
title = {Lineage-specific telomere shortening and unaltered capacity for telomerase expression in human T and B lymphocytes with age.},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {165},
number = {3},
pages = {1191-1196},
doi = {10.4049/jimmunol.165.3.1191},
pmid = {10903716},
issn = {0022-1767},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/genetics/*immunology ; Antigens, CD19/biosynthesis/blood ; B-Lymphocytes/cytology/*enzymology/immunology ; CD4-Positive T-Lymphocytes/cytology/enzymology/immunology ; CD8-Positive T-Lymphocytes/cytology/enzymology/immunology ; Cell Division/genetics/immunology ; Cell Lineage/genetics/immunology ; Cells, Cultured ; Child ; Child, Preschool ; Enzyme Activation/genetics/immunology ; Humans ; Infant ; Infant, Newborn ; Middle Aged ; T-Lymphocytes/cytology/*enzymology/immunology ; Telomerase/*biosynthesis ; Telomere/*enzymology/*immunology ; },
abstract = {Age effects on telomere length and telomerase expression in peripheral blood lymphocytes were analyzed from 121 normal individuals age newborn to 94 years and revealed several new findings. 1) Telomere shortening was observed in CD4+ and CD8+ T and B cells with age. However, the rate of telomere loss was significantly different in these populations, 35 +/- 8, 26 +/- 7, and 19 +/- 7 bp/year for CD4+ and CD8+ T and B cells, respectively. In addition, CD4+ T cells had the longest average telomeres at all ages, followed by B cells, with CD8+ T cell telomeres the shortest, suggesting that these lymphocyte populations may have different replicative histories in vivo. 2) Telomerase activity in freshly isolated T and B cells was indistinguishably low to undetectable at all ages but was markedly increased after Ag and costimulatory receptors mediated stimulation in vitro. Furthermore, age did not alter the magnitude of telomerase activity induced after stimulation of T or B lymphocytes through Ag and costimulatory receptors or in response to PMA plus ionomycin treatment. 3) The levels of telomerase activity induced by in vitro stimulation varied among individual donors but were highly correlated with the outcome of telomere length change in CD4+ T cells after Ag receptor-mediated activation. Together, these results indicate that rates of age-associated loss of telomere length in vivo in peripheral blood lymphocytes is specific to T and B cell subsets and that age does not significantly alter the capacity for telomerase induction in lymphocytes.},
}
@article {pmid10900830,
year = {2000},
author = {Blackburn, EH},
title = {Telomeres and telomerase.},
journal = {The Keio journal of medicine},
volume = {49},
number = {2},
pages = {59-65},
doi = {10.2302/kjm.49.59},
pmid = {10900830},
issn = {0022-9717},
mesh = {Aging ; Animals ; Base Sequence ; Cell Division ; DNA/genetics/metabolism ; DNA Replication ; Humans ; Mutation ; RNA/genetics/metabolism ; Tandem Repeat Sequences ; Telomerase/genetics/*physiology ; Telomere/genetics/*physiology ; },
}
@article {pmid10899136,
year = {2000},
author = {Niwa, O and Shimanuki, M and Miki, F},
title = {Telomere-led bouquet formation facilitates homologous chromosome pairing and restricts ectopic interaction in fission yeast meiosis.},
journal = {The EMBO journal},
volume = {19},
number = {14},
pages = {3831-3840},
pmid = {10899136},
issn = {0261-4189},
mesh = {Alleles ; Cell Nucleus/genetics/metabolism ; Centromere/genetics/metabolism ; Chromosomes, Fungal/genetics/*metabolism ; Cosmids/genetics ; Fungal Proteins/genetics/physiology ; In Situ Hybridization, Fluorescence ; Meiosis/*genetics ; Mutation/genetics ; Recombination, Genetic/genetics ; Schizosaccharomyces/cytology/*genetics ; *Schizosaccharomyces pombe Proteins ; Spindle Apparatus/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {A polarized chromosomal arrangement with clustered telomeres in a meiotic prophase nucleus is often called bouquet and is thought to be important for the pairing of homologous chromosomes. Fluorescence in situ hybridization in fission yeast indicated that chromosomal loci are positioned in an ordered manner as anticipated from the bouquet arrangement. Blocking the formation of the telomere cluster with the kms1 mutation created a disorganized chromosomal arrangement, not only for the regions proximal to the telomere but also for interstitial regions. The kms1 mutation also affected the positioning of a linear minichromosome. Consistent with this cytological observation, the frequency of ectopic homologous recombination between a linear minichromosome and a normal chromosome increased in the kms1 background. Intragenic recombination between allelic loci is reduced in the kms1 mutant, but those between non-allelic loci are unaffected or slightly increased. Thus, telomere-led chromosome organization facilitates homologous pairing and also restricts irregular chromosome pairing during meiosis.},
}
@article {pmid10898792,
year = {2000},
author = {Qi, H and Zakian, VA},
title = {The Saccharomyces telomere-binding protein Cdc13p interacts with both the catalytic subunit of DNA polymerase alpha and the telomerase-associated est1 protein.},
journal = {Genes &amp; development},
volume = {14},
number = {14},
pages = {1777-1788},
pmid = {10898792},
issn = {0890-9369},
support = {R01 GM026938/GM/NIGMS NIH HHS/United States ; GM RO1 43265/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; Catalysis ; Cyclin B/chemistry/*metabolism ; DNA Polymerase I/chemistry/genetics/*metabolism ; Fungal Proteins/chemistry/*metabolism ; Glutathione Transferase/metabolism ; Mutagenesis, Site-Directed ; Plasmids ; Point Mutation ; Protein Binding ; Saccharomyces/*chemistry/*metabolism ; *Saccharomyces cerevisiae Proteins ; Telomerase/chemistry/*metabolism ; Telomere/genetics/metabolism ; Two-Hybrid System Techniques ; },
abstract = {Saccharomyces telomeres consist of approximately 350 bp of C(1-3)A/TG(1-3) DNA. Most of this approximately 350 bp is replicated by standard, semiconservative DNA replication. After conventional replication, the C(1-3)A strand is degraded to generate a long single strand TG(1-3) tail that can serve as a substrate for telomerase. Cdc13p is a single strand TG(1-3) DNA-binding protein that localizes to telomeres in vivo. Genetic data suggest that the Cdc13p has multiple roles in telomere replication. We used two hybrid analysis to demonstrate that Cdc13p interacted with both the catalytic subunit of DNA polymerase alpha, Pol1p, and the telomerase RNA-associated protein, Est1p. The association of these proteins was confirmed by biochemical analysis using full-length or nearly full-length proteins. Point mutations in either CDC13 or POL1 that reduced the Cdc13p-Pol1p interaction resulted in telomerase mediated telomere lengthening. Over-expression of the carboxyl terminus of Est1p partially suppressed the temperature sensitive lethality of a cdc13-1 strain. We propose that Cdc13p's interaction with Est1p promotes TG(1-3) strand lengthening by telomerase and its interaction with Pol1p promotes C(1-3)A strand resynthesis by DNA polymerase alpha.},
}
@article {pmid10896588,
year = {2000},
author = {Lundblad, V},
title = {Molecular biology. Telomeres keep on rappin'.},
journal = {Science (New York, N.Y.)},
volume = {288},
number = {5474},
pages = {2141-2142},
doi = {10.1126/science.288.5474.2141},
pmid = {10896588},
issn = {0036-8075},
mesh = {*Caenorhabditis elegans Proteins ; DNA/chemistry/metabolism ; DNA, Fungal/chemistry/metabolism ; DNA-Binding Proteins/*metabolism ; Disintegrins/chemistry/genetics/*metabolism ; Evolution, Molecular ; Homeostasis ; Humans ; Metalloendopeptidases/chemistry/genetics/*metabolism ; Nucleic Acid Conformation ; Repetitive Sequences, Nucleic Acid ; Saccharomycetales ; Telomerase/metabolism ; Telomere/chemistry/*metabolism/ultrastructure ; Telomeric Repeat Binding Protein 2 ; },
abstract = {Many molecules help maintain the ends of chromosomes, which get chewed off as cells age. Lundblad in her provocative Perspective now tells us about another protein, hRap1, that regulates the length of telomeres in human cells with the help of the TRF proteins. The homology between hRap1 and its counterpart in yeast suggests how the complex molecular machinery needed to maintain chromosome ends may have evolved.},
}
@article {pmid10891505,
year = {2000},
author = {Jones, CJ and Kipling, D and Morris, M and Hepburn, P and Skinner, J and Bounacer, A and Wyllie, FS and Ivan, M and Bartek, J and Wynford-Thomas, D and Bond, JA},
title = {Evidence for a telomere-independent "clock" limiting RAS oncogene-driven proliferation of human thyroid epithelial cells.},
journal = {Molecular and cellular biology},
volume = {20},
number = {15},
pages = {5690-5699},
pmid = {10891505},
issn = {0270-7306},
mesh = {Catalytic Domain ; Cell Division/genetics ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p16/genetics/metabolism ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins/genetics/metabolism ; Epithelial Cells/physiology ; Humans ; Microfilament Proteins/genetics/metabolism ; *Muscle Proteins ; Mutation ; Oncogene Proteins, Viral/genetics ; Telomere/*genetics/metabolism ; Thyroid Gland/*cytology ; ras Proteins/*genetics ; },
abstract = {An initiating role for RAS oncogene mutation in several epithelial cancers is supported by its high incidence in early-stage tumors and its ability to induce proliferation in the corresponding normal cells in vitro. Using retroviral transduction of thyroid epithelial cells as a model we ask here: (i) how mutant RAS can induce long-term proliferation in an epithelial cell in contrast to the premature senescence observed in fibroblasts; and (ii) what is the "clock" which eventually triggers spontaneous growth arrest even in epithelial clones generated by mutant RAS. The early response to RAS activation in thyroid epithelial cells showed two features not seen in fibroblasts: (i) a marked decrease in expression of the cyclin-dependent kinase inhibitor (CDKI) p27(kip1) and (ii) the absence of any induction of p21(waf1). When proliferation eventually ceased (after up to 20 population doublings) this occurred despite undiminished expression of mutant RAS and was tightly correlated with a return to the initial high level of p27(kip1) expression, together with the de novo appearance of p16(ink4a). Importantly, neither the CDKI changes nor the proliferative life span of RAS-induced epithelial clones was altered by induction of telomerase activity through forced expression of the catalytic subunit, hTERT, at levels sufficient to immortalize human fibroblasts. These data provide a basis for cell-type differences in sensitivity to RAS-induced proliferation which may explain the corresponding tumor-type specificity of RAS mutation. They also show for the first time in a primary human cell model that a telomere-independent mechanism can limit not only physiological but also oncogene-driven proliferation, pointing therefore to a tumour suppressor mechanism additional, or alternative, to the telomere clock.},
}
@article {pmid10891483,
year = {2000},
author = {Eversole, A and Maizels, N},
title = {In vitro properties of the conserved mammalian protein hnRNP D suggest a role in telomere maintenance.},
journal = {Molecular and cellular biology},
volume = {20},
number = {15},
pages = {5425-5432},
pmid = {10891483},
issn = {0270-7306},
support = {P01 CA016038/CA/NCI NIH HHS/United States ; T32 GM007223/GM/NIGMS NIH HHS/United States ; P01 16038//PHS HHS/United States ; T32 GM07223/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Conserved Sequence ; Heterogeneous-Nuclear Ribonucleoproteins ; Humans ; Mammals ; Molecular Sequence Data ; Protein Isoforms/metabolism ; RNA, Heterogeneous Nuclear/*metabolism ; Repetitive Sequences, Nucleic Acid ; Ribonucleoproteins/*metabolism ; Substrate Specificity ; Telomerase/metabolism ; Telomere/*genetics/*metabolism ; },
abstract = {Mammalian chromosomes terminate with a 3' tail which consists of reiterations of the G-rich repeat, d(TTAGGG). The telomeric tail is the primer for replication by telomerase, and it may also invade telomeric duplex DNA to form terminal lariat structures, or T loops. Here we show that the ubiquitous and highly conserved mammalian protein hnRNP D interacts specifically with the G-rich strand of the telomeric repeat. A single gene encodes multiple isoforms of hnRNP D. All isoforms bind comparably to the G-rich strand, and certain isoforms can also bind tightly and specifically to the C-rich telomeric strand. G-rich telomeric sequences readily form structures stabilized by G-G pairing, which can interfere with telomere replication by telomerase. We show that hnRNP D binding to the G-rich strand destabilizes intrastrand G-G pairing and that hnRNP D interacts specifically with telomerase in human cell extracts. This biochemical analysis suggest that hnRNP D could function in vivo to destabilize structures formed by telomeric G-rich tails and facilitate their extension by telomerase.},
}
@article {pmid10891474,
year = {2000},
author = {Boultwood, J and Peniket, A and Watkins, F and Shepherd, P and McGale, P and Richards, S and Fidler, C and Littlewood, TJ and Wainscoat, JS},
title = {Telomere length shortening in chronic myelogenous leukemia is associated with reduced time to accelerated phase.},
journal = {Blood},
volume = {96},
number = {1},
pages = {358-361},
pmid = {10891474},
issn = {0006-4971},
mesh = {Age Factors ; Antineoplastic Agents/therapeutic use ; Biomarkers, Tumor ; Blast Crisis ; Blotting, Southern ; Humans ; Interferon-alpha/therapeutic use ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/genetics/mortality/*pathology ; Oligonucleotide Probes ; Platelet Count ; Regression Analysis ; Spleen/pathology ; Survival Rate ; Telomere/*ultrastructure ; },
abstract = {Telomere shortening is associated with disease evolution in chronic myelogenous leukemia (CML). We have examined the relationship between diagnostic telomere length and outcome in 59 patients with CML who entered into the MRC CMLIII Trial by Southern blot hybridization using the (TTAGGG)(4) probe. Age-adjusted telomere repeat array (TRA) reduction was found to significantly correlate with time from diagnosis to acceleration, such that patients with a larger TRA reduction entered the accelerated phase more rapidly (r = -0.50; P =.008). Cox-regression analysis for this group was suggestive of a relationship between a greater TRA-reduction and a shorter time to acceleration (P =.054). Age-adjusted TRA reduction did not significantly affect either the time to blast crisis or overall survival. Our results show that telomere shortening observed at the time of diagnosis in CML significantly influences the time to progress to the accelerated phase. The measurement of diagnostic TRA may prove to be clinically important in the selection of patients at high risk of disease transformation in CML.},
}
@article {pmid10888888,
year = {2000},
author = {Zhu, XD and Küster, B and Mann, M and Petrini, JH and de Lange, T},
title = {Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres.},
journal = {Nature genetics},
volume = {25},
number = {3},
pages = {347-352},
doi = {10.1038/77139},
pmid = {10888888},
issn = {1061-4036},
support = {GM49046/GM/NIGMS NIH HHS/United States ; GM56888/GM/NIGMS NIH HHS/United States ; GM59413/GM/NIGMS NIH HHS/United States ; },
mesh = {Acid Anhydride Hydrolases ; Cell Cycle ; Cell Cycle Proteins/*metabolism ; *DNA Repair Enzymes ; DNA-Binding Proteins/genetics/*metabolism ; HeLa Cells ; Humans ; MRE11 Homologue Protein ; *Nuclear Proteins ; Recombinant Fusion Proteins/genetics/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 2 ; },
abstract = {Telomeres allow cells to distinguish natural chromosome ends from damaged DNA and protect the ends from degradation and fusion. In human cells, telomere protection depends on the TTAGGG repeat binding factor, TRF2 (refs 1-4), which has been proposed to remodel telomeres into large duplex loops (t-loops). Here we show by nanoelectrospray tandem mass spectrometry that RAD50 protein is present in TRF2 immunocomplexes. Protein blotting showed that a small fraction of RAD50, MRE11 and the third component of the MRE11 double-strand break (DSB) repair complex, the Nijmegen breakage syndrome protein (NBS1), is associated with TRF2. Indirect immunofluorescence demonstrated the presence of RAD50 and MRE11 at interphase telomeres. NBS1 was associated with TRF2 and telomeres in S phase, but not in G1 or G2. Although the MRE11 complex accumulated in irradiation-induced foci (IRIFs) in response to gamma-irradiation, TRF2 did not relocate to IRIFs and irradiation did not affect the association of TRF2 with the MRE11 complex, arguing against a role for TRF2 in DSB repair. Instead, we propose that the MRE11 complex functions at telomeres, possibly by modulating t-loop formation.},
}
@article {pmid10878723,
year = {2000},
author = {Wallace, DJ and Salonen, EM and Avaniss-Aghajani, E and Morris, R and Metzger, AL and Pashinian, N},
title = {Anti-telomere antibodies in systemic lupus erythematosus: a new ELISA test for anti-DNA with potential pathogenetic implications.},
journal = {Lupus},
volume = {9},
number = {5},
pages = {328-332},
doi = {10.1191/096120300678828343},
pmid = {10878723},
issn = {0961-2033},
mesh = {Adolescent ; Adult ; Aged ; Antibodies, Antinuclear/*immunology ; *Antibody Specificity ; Autoantibodies/*immunology ; Enzyme-Linked Immunosorbent Assay ; Humans ; Lupus Erythematosus, Systemic/*immunology/physiopathology ; Middle Aged ; Predictive Value of Tests ; Prognosis ; Sensitivity and Specificity ; Telomere/*immunology ; },
abstract = {BACKGROUND: Telomeric hexamer repeats (TTAGGG/CCCTAA)n are highly repetitive sequences of DNA. They cap the termini of eukaryotic chromosomes and stabilize them, preventing degradation or fusion. Anti ds-DNA is one of the most specific tests for systemic lupus erythematosus (SLE). Of related importance, a preliminary report has suggested that anti-telomere antibodies are also highly specific for the presence of SLE.<br><br>METHODS: 220 patients with SLE, 79 with rheumatoid arthritis (RA), 54 with other rheumatic diseases and 99 healthy controls were tested for anti-telomere antibody as measured by enzyme immunoassay detecting 30- and 60-mer telomeric repeats (5-10 hexamers). 48 of the 220 SLE patients charts were abstracted for 90 separate clinical, laboratory and treatment parameters. Comparisons were made between SLE and non-SLE patients, and within the lupus group for telomere positivity and among the latter 48 patients for anti-DNA (Farr) levels and SLEDAI scores.<br><br>RESULTS: Anti-telomere antibody was present in 48.6% of the overall SLE group (220), 71% of our cohort (48), 11% with primary Sjogren's (2/18), 7. 6% with RA (6/79) and 2% of normal controls (2/99) (P<0.001 comparing SLE to all other groups). In the 48 patient cohort, anti-telomere antibody was more sensitive than anti-dsDNA (Farr) (71% vs 50%), but did not correlate with other clinical parameters, SLEDAI scores, or other autoantibodies.<br><br>CONCLUSIONS: The detection of anti-telomere antibody appears to be more sensitive and may be as specific as anti-dsDNA (Farr) in SLE. The detection of telomeric repeats may be as accurate as other anti-DNA assay methodologies and more specific for the presence of SLE. The immunogenic potential of telomere biology related to the pathogenesis and/or diagnosis of SLE deserves further investigation.},
}
@article {pmid10878720,
year = {2000},
author = {Reichlin, M},
title = {Anti-telomere antibodies in systemic lupus erythematosus.},
journal = {Lupus},
volume = {9},
number = {5},
pages = {317},
doi = {10.1191/096120300678828442},
pmid = {10878720},
issn = {0961-2033},
mesh = {Autoantibodies/*immunology ; Humans ; Lupus Erythematosus, Systemic/*immunology ; Telomere/*immunology ; },
}
@article {pmid10874642,
year = {1999},
author = {Mosquera, A and Fernández, JL and Campos, A and Goyanes, VJ and Ramiro-Díaz, J and Gosálvez, J},
title = {Simultaneous decrease of telomere length and telomerase activity with ageing of human amniotic fluid cells.},
journal = {Journal of medical genetics},
volume = {36},
number = {6},
pages = {494-496},
pmid = {10874642},
issn = {0022-2593},
mesh = {Amniotic Fluid/*cytology/*enzymology ; Cell Division ; Cellular Senescence/genetics/*physiology ; DNA Replication ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Pregnancy ; Telomerase/*metabolism ; Telomere/genetics/*ultrastructure ; },
}
@article {pmid10869233,
year = {2000},
author = {Knight, SJ and Lese, CM and Precht, KS and Kuc, J and Ning, Y and Lucas, S and Regan, R and Brenan, M and Nicod, A and Lawrie, NM and Cardy, DL and Nguyen, H and Hudson, TJ and Riethman, HC and Ledbetter, DH and Flint, J},
title = {An optimized set of human telomere clones for studying telomere integrity and architecture.},
journal = {American journal of human genetics},
volume = {67},
number = {2},
pages = {320-332},
pmid = {10869233},
issn = {0002-9297},
support = {/WT_/Wellcome Trust/United Kingdom ; F32 HG000174/HG/NHGRI NIH HHS/United States ; 1-R01-HD36715-01/HD/NICHD NIH HHS/United States ; 1 F32 HG00174-01/HG/NHGRI NIH HHS/United States ; },
mesh = {Chromosomes, Artificial, Yeast/genetics ; Chromosomes, Human/chemistry/*genetics ; Cloning, Molecular ; DNA Probes/*genetics ; Genetic Markers/genetics ; Humans ; Hybrid Cells ; In Situ Hybridization, Fluorescence ; Interphase ; Physical Chromosome Mapping ; Polymorphism, Genetic/genetics ; Sequence Analysis, DNA ; Sequence Tagged Sites ; Telomere/chemistry/*genetics ; },
abstract = {Telomere-specific clones are a valuable resource for the characterization of chromosomal rearrangements. We previously reported a first-generation set of human telomere probes consisting of 34 genomic clones, which were a known distance from the end of the chromosome (approximately 300 kb), and 7 clones corresponding to the most distal markers on the integrated genetic/physical map (1p, 5p, 6p, 9p, 12p, 15q, and 20q). Subsequently, this resource has been optimized and completed: the size of the genomic clones has been expanded to a target size of 100-200 kb, which is optimal for use in genome-scanning methodologies, and additional probes for the remaining seven telomeres have been identified. For each clone we give an associated mapped sequence-tagged site and provide distances from the telomere estimated using a combination of fiberFISH, interphase FISH, sequence analysis, and radiation-hybrid mapping. This updated set of telomeric clones is an invaluable resource for clinical diagnosis and represents an important contribution to genetic and physical mapping efforts aimed at telomeric regions.},
}
@article {pmid10868174,
year = {2000},
author = {Sela, B},
title = {[On telomeres and telomerases: the key to cell senescence or immortality].},
journal = {Harefuah},
volume = {138},
number = {1},
pages = {24-27},
pmid = {10868174},
issn = {0017-7768},
mesh = {Animals ; Cellular Senescence/genetics/*physiology ; Humans ; Telomerase/*genetics ; Telomere/*genetics ; },
}
@article {pmid10861688,
year = {2000},
author = {Lauzon, W and Sanchez Dardon, J and Cameron, DW and Badley, AD},
title = {Flow cytometric measurement of telomere length.},
journal = {Cytometry},
volume = {42},
number = {3},
pages = {159-164},
doi = {10.1002/1097-0320(20000615)42:3&lt;159::aid-cyto1&gt;3.0.co;2-9},
pmid = {10861688},
issn = {0196-4763},
mesh = {Animals ; DNA/analysis ; Flow Cytometry/*methods ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Nucleic Acid Probes ; Telomere/*genetics ; Temperature ; },
abstract = {The regulation of telomere length may be involved in the cellular physiology of senescence, reproduction, cancer, immune response to infection, and possibly immune deficiency. The measurement of telomere length, critical to research in this area, has traditionally been performed by Southern blot analysis, which is cumbersome and time consuming. Several alternative methods have been described in recent years. Some, such as pulsed-field electrophoresis, slot blots, and centromere-to-telomere ratio measurements are essentially improvements to the Southern blot technique. However, other methods such as fluorescent in situ hybridization on metaphase chromosome spreads and flow cytometry-based fluorescent in situ hybridization represent a completely new technical approach to the problem. In this review, we compare methods, with particular emphasis placed on flow cytometric techniques for measuring telomere length in situ and identifying potential areas where improvements may still be made.},
}
@article {pmid10861289,
year = {2000},
author = {Ebersole, TA and Ross, A and Clark, E and McGill, N and Schindelhauer, D and Cooke, H and Grimes, B},
title = {Mammalian artificial chromosome formation from circular alphoid input DNA does not require telomere repeats.},
journal = {Human molecular genetics},
volume = {9},
number = {11},
pages = {1623-1631},
doi = {10.1093/hmg/9.11.1623},
pmid = {10861289},
issn = {0964-6906},
mesh = {Bacteriophage P1/genetics ; Chromosomes, Artificial, Yeast ; Chromosomes, Human/*genetics ; DNA, Circular/genetics ; DNA, Satellite/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Repetitive Sequences, Nucleic Acid ; Telomere/*genetics ; Tumor Cells, Cultured ; },
abstract = {Mammalian artificial chromosomes (MACs) form in HT1080 cells after transfecting linear yeast artificial chromosome constructs minimally containing competent alphoid arrays, a selectable marker and terminal human telomere repeats. Restrictions on the structure of input DNA in MAC formation were investigated by transfecting circular or linear alphoid constructs with or without human telomere arrays and by varying the position and orientation of the telomere arrays on input linear constructs. Circular input DNA efficiently produced MACs. Absence of telomere arrays from circular input molecules did not significantly alter MAC formation rates. Linear constructs capped with telomere arrays generated MACs effectively, but a severe reduction in MAC formation was observed from linear constructs lacking telomere arrays. Human telomere arrays positioned 1-5 kb from linear construct ends and in either orientation were able to promote MAC formation with similar efficiencies. Both circular and linear input constructs generated artificial chromosomes that efficiently segregated in the absence of selection. Telomeres were not detected on the MACs, regardless of the inclusion of telomere arrays on input DNA, suggesting that circular chromosomes were formed. We found no evidence for acquisition of host cell DNA, which is consistent with de novo chromosome assembly.},
}
@article {pmid10860727,
year = {2000},
author = {Phan, AT and Guéron, M and Leroy, JL},
title = {The solution structure and internal motions of a fragment of the cytidine-rich strand of the human telomere.},
journal = {Journal of molecular biology},
volume = {299},
number = {1},
pages = {123-144},
doi = {10.1006/jmbi.2000.3613},
pmid = {10860727},
issn = {0022-2836},
mesh = {Base Pairing/genetics ; Base Sequence ; Chromatography, Gel ; Cytidine/*chemistry/genetics/*metabolism ; Humans ; Hydrogen-Ion Concentration ; Kinetics ; Models, Molecular ; Molecular Sequence Data ; Motion ; Mutation/genetics ; Nuclear Magnetic Resonance, Biomolecular ; *Nucleic Acid Conformation ; Protons ; Solutions ; Telomere/*chemistry/genetics/*metabolism ; Temperature ; Terminology as Topic ; Thermodynamics ; Time Factors ; Titrimetry ; Water/metabolism ; },
abstract = {We present the solution structure of d(CCCTA2CCCTA2CCCTA2CCCT), a fragment of the vertebrate telomere which folds intramolecularly. The four cytidine stretches form an i-motif which includes six intercalated C.C+ pairs and terminates with the cytidines at the 5' extremity of each stretch. Above, the second TA2 linker loops across one of the narrow grooves, while at the bottom, the first and third linkers loop across the wide grooves. At 30 degrees C, the spectra of the first and third linkers are quasi-degenerate. Severe broadening at lower temperature indicates that this results from motional averaging between at least two structures of each bottom loop, and makes it impossible to solve the configuration of the bottom loops directly, in contrast to the rest of the structure. We therefore turned to the modified sequence d(CCCTA(2)5MCCCTA2CCCUA2CCCT) in which the two base substitutions (underlined) break the quasi-symmetry between linkers 1 and 3. The three loops follow approximately the hairpin "second pattern" of Hilbers. In the first loop, T4 is in the syn orientation, whereas its analog in the third loop, U16, oriented anti, is in a central location, where it interacts with bases of both loops, thus contributing to their tight association. The only motion is a syn/anti flip of A18 in the third loop. Returning to the telomere fragment, we show that each of the bottom loops switches between the structures identified in the first and third loops of the modified structure. The motions are concerted, and the resulting configurations of the bottom loop cluster present a bulge to either right (T4 syn) or left (T16 syn).},
}
@article {pmid10857992,
year = {2000},
author = {Raymond, E and Soria, JC and Izbicka, E and Boussin, F and Hurley, L and Von Hoff, DD},
title = {DNA G-quadruplexes, telomere-specific proteins and telomere-associated enzymes as potential targets for new anticancer drugs.},
journal = {Investigational new drugs},
volume = {18},
number = {2},
pages = {123-137},
pmid = {10857992},
issn = {0167-6997},
support = {67760//PHS HHS/United States ; },
mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Base Sequence ; DNA/*chemistry/genetics ; Humans ; Molecular Sequence Data ; Neoplasm Proteins/genetics/*metabolism ; Telomere/drug effects/enzymology/genetics/*metabolism ; },
abstract = {Telomeres and telomerase have been subjects to a tremendous attention from scientists and oncologists during the past 5 years. This interest has been motivated by the potential of telomerase as a tumor marker for the diagnosis and the prognosis of cancer. The possible use of telomerase or telomeres as new targets for anticancer drugs also triggered investigations. The expression of telomerase was found in overall 85% of cancers. Telomerase is early expressed during oncogenesis with a gradient indicating that a high level of telomerase expression could be associated with a bad prognosis. Therefore, drugs targeting telomerase and telomeres might be useful in many human tumors with little restrictions regarding the tumor type or on the stage of the disease. Moreover, since telomerase is not or slightly expressed in normal cells, it has been postulated that drugs targeting telomerase would induce low toxicity. The race for the discovery of telomerase inhibitors has started while the identification of the components controlling telomerase, telomeres, cell survival, senescence, and apoptosis was still in progress. The recent identification of components regulating telomere length and telomerase expression (TRF1, TRF2, and tankyrase) opened a variety of new opportunities to control telomerase/telomere interactions. Meanwhile, a proof of principle was provided that changing telomere interactions with telomere binding proteins by chemical or biological means can induce cancer cell death. Interestingly, recent data challenge the old paradigm which suggested that a long exposure to telomerase and telomere inhibitors is necessary to induce anticancer effects. In this paper, we review the most recent information concerning the regulation of telomere length and telomerase expression, with emphasis on mechanisms that might translate into new drug discovery.},
}
@article {pmid10856888,
year = {2000},
author = {Halvorsen, TL and Beattie, GM and Lopez, AD and Hayek, A and Levine, F},
title = {Accelerated telomere shortening and senescence in human pancreatic islet cells stimulated to divide in vitro.},
journal = {The Journal of endocrinology},
volume = {166},
number = {1},
pages = {103-109},
doi = {10.1677/joe.0.1660103},
pmid = {10856888},
issn = {0022-0795},
support = {DK55065/DK/NIDDK NIH HHS/United States ; DK55283/DK/NIDDK NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Carrier Proteins/analysis ; *Cell Cycle Proteins ; Cell Division ; Cells, Cultured ; Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p15 ; *Cyclin-Dependent Kinase Inhibitor p16 ; DNA-Binding Proteins ; Diabetes Mellitus, Type 1/surgery ; Enzyme Induction ; Female ; Humans ; Islets of Langerhans/enzymology/*ultrastructure ; Male ; Middle Aged ; *RNA ; Telomerase/biosynthesis/genetics ; Telomere/*ultrastructure ; Transfection ; *Tumor Suppressor Proteins ; beta-Galactosidase/analysis ; },
abstract = {Widespread application of beta-cell replacement strategies for diabetes is dependent upon the availability of an unlimited supply of cells exhibiting appropriate glucose-responsive insulin secretion. Therefore, a great deal of effort has been focused on understanding the factors that control beta-cell growth. Previously, we found that human beta-cell-enriched islet cultures can be stimulated to proliferate, but expansion was limited by growth arrest after 10-15 cell divisions. Here, we have investigated the mechanism behind the growth arrest. Our studies, including analyses of the expression of senescence-associated beta-galactosidase, p16(INK4a) levels, and telomere lengths, indicate that cellular senescence is responsible for limiting the number of cell divisions that human beta-cells can undergo. The senescent phenotype was not prevented by retroviral transduction of the hTERT gene, although telomerase activity was induced. These results have implications for the use of primary human islet cells in cell transplantation therapies for diabetes.},
}
@article {pmid10850490,
year = {2000},
author = {Li, B and Oestreich, S and de Lange, T},
title = {Identification of human Rap1: implications for telomere evolution.},
journal = {Cell},
volume = {101},
number = {5},
pages = {471-483},
doi = {10.1016/s0092-8674(00)80858-2},
pmid = {10850490},
issn = {0092-8674},
support = {CA76027/CA/NCI NIH HHS/United States ; GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Base Sequence ; Binding Sites ; DNA-Binding Proteins/genetics/*metabolism ; *Evolution, Molecular ; HeLa Cells ; Humans ; Molecular Sequence Data ; *Schizosaccharomyces pombe Proteins ; Sequence Homology, Amino Acid ; Shelterin Complex ; *Telomere ; *Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 1 ; Telomeric Repeat Binding Protein 2 ; },
abstract = {It has been puzzling that mammalian telomeric proteins, including TRF1, TRF2, tankyrase, and TIN2 have no recognized orthologs in budding yeast. Here, we describe a human protein, hRap1, that is an ortholog of the yeast telomeric protein, scRap1p. hRap1 has three conserved sequence motifs in common with scRap1, is located at telomeres, and affects telomere length. However, while scRap1 binds telomeric DNA directly, hRap1 is recruited to telomeres by TRF2. Extending the comparison of telomeric proteins to fission yeast, we identify S. pombe Taz1 as a TRF ortholog, indicating that TRFs are conserved at eukaryotic telomeres. The data suggest that ancestral telomeres, like those of vertebrates, contained a TRF-like protein as well as Rap1. We propose that budding yeast preserved Rap1 at telomeres but lost the TRF component, possibly concomitant with a change in the telomeric repeat sequence.},
}
@article {pmid10850411,
year = {2000},
author = {Figueroa, R and Lindenmaier, H and Hergenhahn, M and Nielsen, KV and Boukamp, P},
title = {Telomere erosion varies during in vitro aging of normal human fibroblasts from young and adult donors.},
journal = {Cancer research},
volume = {60},
number = {11},
pages = {2770-2774},
pmid = {10850411},
issn = {0008-5472},
mesh = {Adult ; *Aging ; Blotting, Southern ; Blotting, Western ; Cells, Cultured ; DNA-Binding Proteins/genetics/metabolism ; Fibroblasts/*metabolism/*ultrastructure ; Fluorescent Antibody Technique, Indirect ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; Oligonucleotides, Antisense/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*ultrastructure ; Telomeric Repeat Binding Protein 2 ; Up-Regulation ; },
abstract = {The life span of normal fibroblasts in vitro (Hayflick limit) depends on donor age, and telomere shortening has been proposed as a potential mechanism. By quantitative fluorescence in situ hybridization and Southern blot analysis, we show progressive telomere loss to about 5 kb mean telomere restriction fragment length in fibroblasts from two adult donors within 40 population doublings, whereas in fibroblasts from two infant donors, telomere erosion is reduced, leaving a mean telomere restriction fragment length of approximately 7 kb at senescence (after approximately 60 population doublings). Aging of fibroblasts from both infant and adult donors was not accompanied by chromosomal abnormalities but was correlated with increased telomere repeat-binding factor 2 expression at both the protein and transcriptional level.},
}
@article {pmid10848812,
year = {2000},
author = {Robertson, JD and Gale, RE and Wynn, RF and Dougal, M and Linch, DC and Testa, NG and Chopra, R},
title = {Dynamics of telomere shortening in neutrophils and T lymphocytes during ageing and the relationship to skewed X chromosome inactivation patterns.},
journal = {British journal of haematology},
volume = {109},
number = {2},
pages = {272-279},
doi = {10.1046/j.1365-2141.2000.01970.x},
pmid = {10848812},
issn = {0007-1048},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Analysis of Variance ; Antigens, CD34/immunology ; Child ; Child, Preschool ; *Dosage Compensation, Genetic ; Fetal Blood/cytology ; Hematopoiesis/*genetics ; Humans ; Infant ; Infant, Newborn ; Leukocytes/immunology/ultrastructure ; Linear Models ; Middle Aged ; Neutrophils/*ultrastructure ; T-Lymphocytes/*ultrastructure ; Telomerase/analysis ; Telomere/*ultrastructure ; },
abstract = {Human haemopoiesis undergoes profound changes throughout life, resulting in compromised regenerative capacity of haemopoietic stem cells. It has been suggested that telomere shortening results in senescence of haemopoietic stem cell subsets and may influence the balance between stem cell renewal and proliferation. Telomere length and telomerase activity was measured in whole blood leucocytes, neutrophils and T cells from cord blood and individuals aged from 1 year to 96 years. Rapid telomere shortening [700 base pairs (bp)] was demonstrated in the first year of life, followed by a gradual decline of 31 bp/year. T cells were shown to have longer telomeres than neutrophils (mean difference 372 bp, P = < 0.001) but demonstrated similar rates of shortening (20 +/- 0.3 bp/year vs. 22 +/- 0.3 bp/year). Telomerase was detectable in T cells but not in neutrophils, suggesting that telomerase is not the rate-limiting step for regulation of telomere length in haemopoietic cells. Stem cell utilization as measured by X chromosome inactivation patterns was found to be independent of telomere length. This supports the concept that age-dependent skewed haemopoiesis is the result of random stem cell loss or X-allelic exclusion rather than telomeric senescence. These studies provide insight into the ageing process and a reference point for evaluating replicative stress in individuals of different age groups.},
}
@article {pmid10842290,
year = {2000},
author = {Bacino, CA and Kashork, CD and Davino, NA and Shaffer, LG},
title = {Detection of a cryptic translocation in a family with mental retardation using FISH and telomere region-specific probes.},
journal = {American journal of medical genetics},
volume = {92},
number = {4},
pages = {250-255},
pmid = {10842290},
issn = {0148-7299},
mesh = {Adolescent ; Adult ; Child, Preschool ; Chromosome Banding ; Chromosomes, Human, Pair 17/genetics ; Chromosomes, Human, Pair 2/genetics ; DNA Probes ; Family Health ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Intellectual Disability/*genetics/pathology ; Karyotyping ; Male ; Pedigree ; Telomere/*genetics ; *Translocation, Genetic ; },
abstract = {Cryptic rearrangements involving the telomeres are thought to account for a substantial number of patients with unexplained mental retardation and multiple congenital anomalies, although the exact incidence of these rearrangements is still unclear. With the advent of chromosome-specific telomeric probes and the use of FISH (fluorescence in situ hybridization), it is now possible to identify submicroscopic rearrangements of the distal ends of chromosomes that may otherwise go undetected using conventional cytogenetic studies. We report on a 4 1/2 year-old girl with severe mental retardation and minor anomalies who inherited the unbalanced product of a cryptic translocation involving chromosomes 2 and 17 from her father. The family history was significant for early pregnancy losses, stillbirths, and mental retardation in many other family members, suggesting segregation of a familial translocation. This translocation was detected using chromosome-specific telomere FISH probes, and not visible using conventional cytogenetic methods. Collectively, this case and those previously reported clearly demonstrate the value of a systematic search for cryptic chromosome rearrangements in patients with unexplained mental retardation with previously reported normal chromosome studies; and in particular those with a family history of mental retardation, birth defects, or early pregnancy losses.},
}
@article {pmid10841641,
year = {2000},
author = {Gordon, D},
title = {Telomere deficiency worsens liver disease.},
journal = {Gastroenterology},
volume = {118},
number = {5},
pages = {818},
doi = {10.1016/s0016-5085(00)70163-6},
pmid = {10841641},
issn = {0016-5085},
mesh = {Aging/*pathology ; Humans ; Liver Diseases/*pathology ; *Telomere ; },
}
@article {pmid10835381,
year = {2000},
author = {Chamankhah, M and Fontanie, T and Xiao, W},
title = {The Saccharomyces cerevisiae mre11(ts) allele confers a separation of DNA repair and telomere maintenance functions.},
journal = {Genetics},
volume = {155},
number = {2},
pages = {569-576},
pmid = {10835381},
issn = {0016-6731},
support = {NCIC007412/CI/NCPDCID CDC HHS/United States ; },
mesh = {*Alleles ; Amino Acid Sequence ; DNA Repair/*genetics ; *Endodeoxyribonucleases ; *Exodeoxyribonucleases ; Fungal Proteins/chemistry/*genetics ; *Genes, Fungal ; Molecular Sequence Data ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; Sequence Homology, Amino Acid ; *Telomere ; },
abstract = {The yeast Mre11 protein participates in important cellular functions such as DNA repair and telomere maintenance. Analysis of structure-function relationships of Mre11 has led to identification of several separation-of-function mutations as well as N- and C-terminal domains essential for Mre11 meiotic and mitotic activities. Previous studies have established that there is a strong correlation between Mre11 DNA repair and telomere maintenance functions and that Mre11-Rad50-Xrs2 complex formation appears to be essential for both of these activities. Here we report that the mre11(ts) allele, previously shown to cause temperature-dependent defects in DNA repair and meiosis, confers a temperature-independent telomere shortening, indicating that mre11(ts) is a separation-of-function mutation with respect to DNA repair and telomere maintenance. In a yeast two-hybrid system, Mre11(ts) fails to form a homodimer or interact with Rad50 and Xrs2 irrespective of experimental temperatures. These observations collectively suggest that the Pro(162)Ser substitution in Mre11(ts) confers a novel separation of Mre11 mitotic functions. Moreover, we observed that while overexpression of the 5'-3' exonuclease gene EXO1 partially complements the MMS sensitivity of mre11, rad50, and xrs2 null mutants, it has no effect on telomere shortening in these strains. This result provides additional evidence on possible involvement of distinctive mechanisms in DNA repair and telomere maintenance by the Mre11-Rad50-Xrs2 complex.},
}
@article {pmid10831793,
year = {2000},
author = {Barker, KS and Quiniou, SM and Wilson, MR and Bengten, E and Stuge, TB and Warr, GW and Clem, LW and Miller, NW},
title = {Telomerase expression and telomere length in immortal leukocyte lines from channel catfish.},
journal = {Developmental and comparative immunology},
volume = {24},
number = {6-7},
pages = {583-595},
doi = {10.1016/s0145-305x(00)00021-5},
pmid = {10831793},
issn = {0145-305X},
support = {R01-AI-19530/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Cell Line, Transformed/enzymology ; Enzyme Activation ; Ictaluridae/anatomy &amp; histology/*genetics/*metabolism ; Leukocytes/*cytology/*enzymology/immunology ; Lymphocyte Activation ; Telomerase/*biosynthesis ; Telomere/*enzymology/*genetics ; },
abstract = {Normal channel catfish leukocytes readily undergo spontaneous in vitro immortalization yielding functionally active diploid cell lines. Since telomerase activation appears to be a critical step in the establishment of immortal mammalian cells, studies were undertaken to determine if and when telomerase expression occurs during the in vitro immortalization process of channel catfish leukocytes. To this end, freshly isolated peripheral blood leukocytes (PBL) from normal fish were shown to exhibit low to undetectable levels of telomerase activity and within four days after culture initiation showed dramatic increases in telomerase activity which typically remained high for at least four weeks. This activity then declined, concomitant with decreases in cellular proliferation and increases in cell death. Cells which escaped this culture "crisis" re-expressed high levels of telomerase activity indefinitely. Although telomerase activity was expressed early in the immortalization process, clonal cell lines derived from these cultures had relatively short telomeres. These results suggest that telomerase expression in catfish leukocytes is activation-induced, and its expression does not necessarily stabilize telomere length until a critically, albeit ill-defined, short length is reached.},
}
@article {pmid10831393,
year = {2000},
author = {Chiurillo, MA and Beck, AE and Devos, T and Myler, PJ and Stuart, K and Ramirez, JL},
title = {Cloning and characterization of Leishmania donovani telomeres.},
journal = {Experimental parasitology},
volume = {94},
number = {4},
pages = {248-258},
doi = {10.1006/expr.2000.4499},
pmid = {10831393},
issn = {0014-4894},
support = {AI17375/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Blotting, Southern ; Cloning, Molecular ; DNA, Protozoan/*chemistry ; Genetic Vectors ; Leishmania donovani/*genetics ; Molecular Sequence Data ; Oligonucleotide Probes/chemistry ; Tandem Repeat Sequences ; Telomere/chemistry/*genetics ; },
abstract = {We describe here the cloning and sequence characterization of the absolute termini of several telomeres from the human parasite Leishmania donovani using a vector-adapter protocol. The 3' protruding strand of L. donovani telomeres terminates with the sequence 5'-GGTTAGGGT-OH 3'. This single-stranded sequence is adjacent to tandemly repeated blocks of double-stranded sequence consisting of variable numbers of the hexameric repeat 5'-TAGGGT-3', variable numbers of an octameric repeat 5'-TGGTCATG-3', and a single 62-bp sequence, in that order. A number of additional, more chromosome-internal, nonrepeated sequences were found adjacent to the telomere sequences. Hybridization analyses indicated that some of these telomere adjacent sequences are found on all L. donovani chromosomes, some are more abundant on certain subsets of chromosomes, and some are unique to individual chromosomes.},
}
@article {pmid10828619,
year = {2000},
author = {van Geel, M and van Deutekom, JC and van Staalduinen, A and Lemmers, RJ and Dickson, MC and Hofker, MH and Padberg, GW and Hewitt, JE and de Jong, PJ and Frants, RR},
title = {Identification of a novel beta-tubulin subfamily with one member (TUBB4Q) located near the telomere of chromosome region 4q35.},
journal = {Cytogenetics and cell genetics},
volume = {88},
number = {3-4},
pages = {316-321},
doi = {10.1159/000015518},
pmid = {10828619},
issn = {0301-0171},
mesh = {Alleles ; Amino Acid Sequence ; Amino Acid Substitution ; Base Sequence ; Chromosomes, Human, Pair 4/*genetics ; Cloning, Molecular ; Exons/genetics ; Genetic Linkage/genetics ; Humans ; Introns/genetics ; Molecular Sequence Data ; Multigene Family/*genetics ; Muscular Dystrophy, Facioscapulohumeral/genetics ; Physical Chromosome Mapping ; Polymerase Chain Reaction ; Promoter Regions, Genetic/genetics ; Protein Structure, Tertiary ; Pseudogenes/genetics ; RNA, Messenger/analysis/genetics ; Telomere/*genetics ; Tubulin/chemistry/*genetics ; },
abstract = {The human beta-tubulin supergene family consists of several isotypes with many associated pseudogenes. Here we report the identification of yet another beta-tubulin sequence designated TUBB4Q. This tubulin maps 80 kb proximal to the facioscapulohumeral muscular dystrophy (FSHD1) associated D4Z4 repeats on chromosome 4q35. The genomic structure contains four exons encoding a putative protein of 434 amino acids. The TUBB4Q nucleotide and protein sequence show 87% and 86% homology to beta2-tubulin, respectively. Although the genomic structure shows all functional aspects of a genuine gene, no transcript could be detected. TUBB4Q-related sequences were identified on multiple chromosomes. Since these sequences mutually exhibit a high nucleotide sequence homology, they presumably belong to a novel subfamily of beta-tubulin genes. Although the chromosome 4q35 tubulin-member probably represents a pseudogene, ectopic expression due to a postulated position effect variegation (PEV), makes TUBB4Q an ideal dominant-negative candidate gene for FSHD1.},
}
@article {pmid10820482,
year = {2000},
author = {Elmore, LW and Holt, SE},
title = {Telomerase and telomere stability: a new class of tumor suppressor?.},
journal = {Molecular carcinogenesis},
volume = {28},
number = {1},
pages = {1-4},
pmid = {10820482},
issn = {0899-1987},
mesh = {Animals ; *Cell Transformation, Neoplastic ; Enzyme Stability ; *Genes, Tumor Suppressor ; Humans ; *Telomerase ; *Telomere ; },
abstract = {Introduction of telomerase into normal cells provides telomere maintenance and an extended cellular life span, establishing the critical role of telomere attrition in cellular senescence. Additional data surrounding this observation suggest that expression of telomerase renders these "mortal" cells genomically stable with decreased frequencies of mutation, ultimately leading to continued proliferation without signs of changes typically associated with progression to a cancer-like phenotype. Interestingly, oncogenic insult after exogenous telomerase expression does not result in cellular transformation, yet addition of an oncogene first followed by telomerase does transform cells. Taken together, these results imply that order of addition is important for telomerase-mediated genomic protection and that telomerase expression is critical for the transformation process. The hypothesis proposed here is that telomerase, via its function in telomere stabilization, is capable of protecting cells from acquiring the required mutations and genomic instability necessary for malignant transformation, suggesting that telomerase is not an oncogene but may act as a novel class of tumor suppressor.},
}
@article {pmid10818099,
year = {2000},
author = {Driller, L and Wellinger, RJ and Larrivee, M and Kremmer, E and Jaklin, S and Feldmann, HM},
title = {A short C-terminal domain of Yku70p is essential for telomere maintenance.},
journal = {The Journal of biological chemistry},
volume = {275},
number = {32},
pages = {24921-24927},
doi = {10.1074/jbc.M002588200},
pmid = {10818099},
issn = {0021-9258},
mesh = {Amino Acid Sequence ; Animals ; Antibodies, Monoclonal ; *Antigens, Nuclear ; Cloning, Molecular ; *DNA Helicases ; DNA Repair ; DNA-Binding Proteins/*chemistry/*metabolism ; Ku Autoantigen ; Macromolecular Substances ; Molecular Sequence Data ; Mutagenesis ; Nuclear Proteins/*chemistry/*metabolism ; Rats ; Recombinant Proteins/chemistry/metabolism ; Saccharomyces cerevisiae/genetics ; *Saccharomyces cerevisiae Proteins ; Sequence Deletion ; Telomere/*physiology/ultrastructure ; },
abstract = {The Yku heterodimer from Saccharomyces cerevisiae, comprising Yku70p and Yku80p, is involved in the maintenance of a normal telomeric DNA end structure and is an essential component of nonhomologous end joining (NHEJ). To investigate the role of the Yku70p subunit in these two different pathways, we generated C-terminal deletions of the Yku70 protein and examined their ability to complement the phenotypes of a yku70(-) strain. Deleting only the 30 C-terminal amino acids of Yku70p abolishes Yku DNA binding activity and causes a yku(-) phenotype; telomeres are shortened, and NHEJ is impaired. Using conditions in which at least as much mutant protein as full-length protein is normally detectable in cell extracts, deleting only 25 C-terminal amino acids of Yku70p results in no measurable effect on DNA binding of the Yku protein, and the cells are fully proficient for NHEJ. Nevertheless, these cells display considerably shortened telomeres, and significant amounts of single-stranded overhangs of the telomeric guanosine-rich strands are observed. Co-overexpression of this protein with Yku80p could rescue some but not all of the telomere-related phenotypes. Therefore, the C-terminal domain in Yku70p defines at least one domain that is especially involved in telomere maintenance but not in NHEJ.},
}
@article {pmid10816136,
year = {2000},
author = {Martens, UM and Brass, V and Engelhardt, M and Glaser, S and Waller, CF and Lange, W and Schmoor, C and Poon, SS and Landsdorp, PM},
title = {Measurement of telomere length in haematopoietic cells using in situ hybridization techniques.},
journal = {Biochemical Society transactions},
volume = {28},
number = {2},
pages = {245-250},
doi = {10.1042/bst0280245},
pmid = {10816136},
issn = {0300-5127},
mesh = {Adult ; Animals ; B-Lymphocytes/physiology ; Female ; Flow Cytometry ; Hematopoietic Stem Cells/*ultrastructure ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Mice ; T-Lymphocytes/physiology ; Telomerase/metabolism ; Telomere/*ultrastructure ; },
abstract = {The DNA of human chromosomes terminates in several kilobases of telomere repeats that are gradually lost with; age and with replication in vitro. Defective telomere maintenance has been shown to be causally linked to cell cycle exit and apoptosis. In order to overcome the limitations imposed by Southern blotting, we have established a quantitative fluorescence in situ hybridization (Q-FISH) technique. This technique allows estimation of telomere length in specific chromosome arms from metaphase cell preparations. Furthermore, we have extended quantitative in situ hybridization to flow cytometry (flow FISH) in order to obtain information on the mean telomere repeat content in suspended cells. Telomere length in granulocytes, monocytes, CD8 and CD4 T lymphocytes and natural killer cells was found to differ slightly in the peripheral blood of adults. However, strikingly longer telomeres were observed in B lymphocytes (approximately 1.3 kb longer), suggesting a functional role for telomere maintenance in this cell subset. In summary, Q-FISH and flow FISH represent new methods for measuring telomere length in single cells and allow studies of telomere dynamics in haematopoietic subpopulations at various stages of normal and abnormal antigen responses.},
}
@article {pmid10816135,
year = {2000},
author = {Miller, RA},
title = {Telomere diminution as a cause of immune failure in old age: an unfashionable demurral.},
journal = {Biochemical Society transactions},
volume = {28},
number = {2},
pages = {241-245},
doi = {10.1042/bst0280241},
pmid = {10816135},
issn = {0300-5127},
mesh = {*Aging ; Animals ; Cell Differentiation ; Cell Line ; *Cellular Senescence ; Humans ; Immune System/*physiology ; Mice ; Models, Biological ; RNA, Messenger/metabolism ; Rats ; Telomere/*metabolism/*physiology ; },
abstract = {The hypothesis that cellular proliferation leads to telomere shortening, which in turn leads to replicative failure, which in turn leads to a failure of immune function in aged individuals, is here evaluated against the published evidence about the nature and pace of immune decline in animals and humans. Although the evidence is strong that telomere shortening in late-passage human lymphocyte and non-lymphocytic cell lines induces a state in which the cells can no longer divide, there is no compelling evidence to suggest that replicative senescence of this kind is an important contributor to immune deficiency in old age. On the contrary, the accelerated pace of immune decline in mice and rats, whose telomeres are much longer than those of humans, argues strongly that the factors that pace age-dependent immune decline do not include telomere shortening. In addition, three subsidiary arguments - (a) the decline with age in naive T cell proliferation despite their relatively long telomeres; (b) the preservation of T cell proliferation in Werner's syndrome patients despite their cell lines' proclivity to replicative senescence in vitro; and (c) the ability of PMA and ionomycin to stimulate proliferation in T cells from old donors, but not in late-passage T celt lines - all support the conclusion that aging of the immune system in living animals is not a consequence of the kind of replicative senescence typically caused by short telomeres in vitro.},
}
@article {pmid10811624,
year = {2000},
author = {Horn, D and Spence, C and Ingram, AK},
title = {Telomere maintenance and length regulation in Trypanosoma brucei.},
journal = {The EMBO journal},
volume = {19},
number = {10},
pages = {2332-2339},
pmid = {10811624},
issn = {0261-4189},
mesh = {Animals ; Telomerase/genetics ; Telomere/*genetics/ultrastructure ; Transcription, Genetic ; Trypanosoma brucei brucei/*genetics ; },
abstract = {Transcription of telomere proximal variant surface glycoprotein genes is mono-allelic in bloodstream-form Trypanosoma brucei. The terminal DNA sequence at these telomeres consists of tandem T(2)AG(3) repeats, which increase in length by approximately 8 bp per cell division balanced by occasional loss of large numbers of repeats. Here we have used targeted chromosome fragmentation to investigate the sequence requirements for telomere formation in T. brucei. Telomere formation is most efficient on tandem T(2)AG(3) repeats, but can also occur on specific templates found within 'random' sequence substrates and on G-rich motifs proximal to a double-strand break. Newly formed telomeres are extended faster than other native telomeres, but as the telomere becomes longer the rate of extension declines. Telomere length regulation in T.brucei is discussed in the context of recent results from other cell types.},
}
@article {pmid10811102,
year = {2000},
author = {Lombard, DB and Guarente, L},
title = {Nijmegen breakage syndrome disease protein and MRE11 at PML nuclear bodies and meiotic telomeres.},
journal = {Cancer research},
volume = {60},
number = {9},
pages = {2331-2334},
pmid = {10811102},
issn = {0008-5472},
mesh = {Animals ; Cell Cycle Proteins/*genetics/*metabolism ; Cell Line ; Cell Nucleus/metabolism ; *Endodeoxyribonucleases ; *Exodeoxyribonucleases ; Fibroblasts/metabolism ; Fluorescent Antibody Technique ; Fungal Proteins/*metabolism ; Humans ; Meiosis ; Mice ; Mutation ; Neutrophils/*metabolism ; *Nuclear Proteins ; *Saccharomyces cerevisiae Proteins ; Telomere/*metabolism ; },
abstract = {Nijmegen breakage syndrome is a disease characterized by immunodeficiency, genomic instability, and cancer susceptibility. The gene product defective in Nijmegen breakage syndrome, p95, associates with two other proteins, MRE11 and RAD50. Here we demonstrate that in the absence of DNA damage, a portion of p95 and MRE11 is concentrated in PML nuclear bodies (NBs); MRE11 localization to the NBs is p95-dependent. In mammalian meiocytes, these proteins are specifically found at the telomeres. These results implicate the NBs in the maintenance of genomic stability and suggest that p95 and MRE11 may have roles in telomere maintenance in mammals, analogous to the role their homologues play in yeast.},
}
@article {pmid10806066,
year = {2000},
author = {Laroche, T and Martin, SG and Tsai-Pflugfelder, M and Gasser, SM},
title = {The dynamics of yeast telomeres and silencing proteins through the cell cycle.},
journal = {Journal of structural biology},
volume = {129},
number = {2-3},
pages = {159-174},
doi = {10.1006/jsbi.2000.4240},
pmid = {10806066},
issn = {1047-8477},
mesh = {Cell Cycle/*genetics ; Cell Nucleus/genetics/physiology ; Fungal Proteins/*metabolism ; Genes, Regulator ; Genes, Reporter ; Green Fluorescent Proteins ; Luminescent Proteins/genetics ; Mitosis ; Recombinant Fusion Proteins/metabolism ; Saccharomyces cerevisiae/*cytology/*genetics ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Telomere/genetics/*physiology ; Trans-Activators/*metabolism ; },
abstract = {Genes integrated near the telomeres of budding yeast have a variegated pattern of gene repression that is mediated by the silent information regulatory proteins Sir2p, Sir3p, and Sir4p. Immunolocalization and fluorescence in situ hybridization (FISH) reveal 6-10 perinuclear foci in which silencing proteins and subtelomeric sequences colocalize, suggesting that these are sites of Sir-mediated repression. Telomeres lacking subtelomeric repeat elements and the silent mating locus, HML, also localize to the periphery of the nucleus. Conditions that disrupt telomere proximal repression disrupt the focal staining pattern of Sir proteins, but not necessarily the localization of telomeric DNA. To monitor the telomere-associated pools of heterochromatin-binding proteins (Sir and Rap1 proteins) during mitotic cell division, we have performed immunofluorescence and telomeric FISH on populations of yeast cells synchronously traversing the cell cycle. We observe a partial release of Rap1p from telomeres in late G2/M, although telomeres appear to stay clustered during G2-phase and throughout mitosis. A partial release of Sir3p and Sir4p during mitosis also occurs. This is not observed upon HU arrest, although other types of DNA damage cause a dramatic relocalization of Sir and Rap1 proteins. The observed cell cycle dynamics were confirmed by direct epifluorescence of a GFP-Rap1p fusion. Using live GFP fluorescence we show that the diffuse mitotic distribution of GFP-Rap1p is restored to the interphase pattern of foci in early G1-phase.},
}
@article {pmid10805753,
year = {2000},
author = {Niida, H and Shinkai, Y and Hande, MP and Matsumoto, T and Takehara, S and Tachibana, M and Oshimura, M and Lansdorp, PM and Furuichi, Y},
title = {Telomere maintenance in telomerase-deficient mouse embryonic stem cells: characterization of an amplified telomeric DNA.},
journal = {Molecular and cellular biology},
volume = {20},
number = {11},
pages = {4115-4127},
pmid = {10805753},
issn = {0270-7306},
support = {GM56162/GM/NIGMS NIH HHS/United States ; R0IAI29524/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cell Survival ; Cloning, Molecular ; DNA ; DNA, Complementary ; Mice ; Molecular Sequence Data ; Stem Cells ; Telomerase/genetics/*physiology ; Telomere/*physiology ; },
abstract = {Telomere dynamics, chromosomal instability, and cellular viability were studied in serial passages of mouse embryonic stem (ES) cells in which the telomerase RNA (mTER) gene was deleted. These cells lack detectable telomerase activity, and their growth rate was reduced after more than 300 divisions and almost zero after 450 cell divisions. After this growth crisis, survivor cells with a rapid growth rate did emerge. Such survivors were found to maintain functional telomeres in a telomerase-independent fashion. Although telomerase-independent telomere maintenance has been reported for some immortalized mammalian cells, its molecular mechanism has not been elucidated. Characterization of the telomeric structures in one of the survivor mTER(-/-) cell lines showed amplification of the same tandem arrays of telomeric and nontelomeric sequences at most of the chromosome ends. This evidence implicates cis/trans amplification as one mechanism for the telomerase-independent maintenance of telomeres in mammalian cells.},
}
@article {pmid10801465,
year = {2000},
author = {Collins, K},
title = {Mammalian telomeres and telomerase.},
journal = {Current opinion in cell biology},
volume = {12},
number = {3},
pages = {378-383},
doi = {10.1016/s0955-0674(00)00103-4},
pmid = {10801465},
issn = {0955-0674},
mesh = {Animals ; Base Sequence ; DNA/genetics/metabolism ; DNA-Binding Proteins/chemistry/genetics/metabolism ; Humans ; Models, Biological ; RNA/genetics/metabolism ; Ribonucleoproteins/genetics/metabolism ; Telomerase/genetics/*metabolism ; Telomere/chemistry/genetics/*metabolism ; Telomeric Repeat Binding Protein 2 ; },
abstract = {New features of mammalian telomeres and telomerase have been identified. Telomeres form t-loops, which engage the 3' single-stranded DNA overhang in an interaction with double-stranded telomeric repeats. Mammalian telomerases contain an RNA H/ACA motif and associated protein(s) shared with H/ACA family of small nucleolar ribonucleoproteins. Essential roles for telomerase in the sustained viability of cultured tumor cells and in the normal proliferative capacity of human somatic cells have been demonstrated.},
}
@article {pmid10801419,
year = {2000},
author = {Marcand, S and Brevet, V and Mann, C and Gilson, E},
title = {Cell cycle restriction of telomere elongation.},
journal = {Current biology : CB},
volume = {10},
number = {8},
pages = {487-490},
doi = {10.1016/s0960-9822(00)00450-4},
pmid = {10801419},
issn = {0960-9822},
mesh = {Cell Cycle ; DNA-Binding Proteins/genetics ; Genes, Fungal ; Saccharomyces cerevisiae/cytology/*genetics ; *Saccharomyces cerevisiae Proteins ; Telomerase/genetics ; Telomere/*metabolism ; Transcription Factors/genetics ; Transformation, Genetic ; },
abstract = {Telomere elongation by telomerase balances the progressive shortening of chromosome ends due to the succession of replication cycles [1] [2]. Telomerase activity is regulated in vivo at its site of action by the telomere itself. In yeast and human cells, the mean telomere length is maintained at a constant value through a cis-inhibition of telomerase by factors specifically bound to the telomeric DNA [3] [4] [5] [6] [7]. Here, we address an unexplored aspect of telomerase regulation by testing the link between telomere dynamics and cell cycle progression in the budding yeast Saccharomyces cerevisiae. We followed the elongation of an abnormally shortened telomere and observed that, like telomere shortening in the absence of telomerase, telomere elongation is linked to the succession of cell divisions. In cells progressing synchronously through the cell cycle, telomere elongation coincided with the time of telomere replication. On a minichromosome, a replication defect partially suppressed telomere elongation, suggesting a coupling between in vivo telomerase activity and conventional DNA replication.},
}
@article {pmid10799534,
year = {2000},
author = {Dallaire, F and Dupuis, S and Fiset, S and Chabot, B},
title = {Heterogeneous nuclear ribonucleoprotein A1 and UP1 protect mammalian telomeric repeats and modulate telomere replication in vitro.},
journal = {The Journal of biological chemistry},
volume = {275},
number = {19},
pages = {14509-14516},
doi = {10.1074/jbc.275.19.14509},
pmid = {10799534},
issn = {0021-9258},
mesh = {Base Sequence ; DNA Helicases/*physiology ; HeLa Cells ; Heterogeneous Nuclear Ribonucleoprotein A1 ; *Heterogeneous-Nuclear Ribonucleoprotein Group A-B ; Heterogeneous-Nuclear Ribonucleoproteins ; Humans ; Oligodeoxyribonucleotides ; Recombinant Proteins/metabolism ; Ribonucleoproteins/*physiology ; Telomerase/antagonists &amp; inhibitors/metabolism ; Telomere/*physiology ; Thymus Hormones/*physiology ; },
abstract = {The heterogeneous nuclear ribonucleoprotein A1 protein and a shortened derivative (UP1) promote telomere elongation in mammalian cells. To gain insights into the function of A1/UP1 in telomere biogenesis, we have investigated the binding properties of recombinant A1/UP1 and derivatives to single-stranded DNA oligonucleotides. Our results indicate that UP1 prefers to bind to DNA carrying single-stranded telomeric extensions at the 3' terminus. The RNA recognition motif 1 is sufficient for strong and specific binding to oligomers carrying vertebrate telomeric repeats. We find that the binding of A1/UP1 protects telomeric sequences against degradation by endo- and exonucleases. Moreover, A1/UP1 binding prevents extension by telomerase and terminal deoxynucleotidyltransferase and inhibits rNTP-dependent DNA synthesis in vitro. These observations are consistent with the hypothesis that A1/UP1 is a telomere end-binding protein that plays a role in the maintenance of long 3' overhangs.},
}
@article {pmid10798984,
year = {2000},
author = {Vogel, G},
title = {In contrast to Dolly, cloning resets telomere clock in cattle.},
journal = {Science (New York, N.Y.)},
volume = {288},
number = {5466},
pages = {586-587},
doi = {10.1126/science.288.5466.586},
pmid = {10798984},
issn = {0036-8075},
mesh = {Aging/genetics ; Animals ; Bioethics ; Cattle/*genetics ; Cell Division ; Cells, Cultured ; *Cellular Senescence/genetics ; *Cloning, Organism ; Female ; Nuclear Transfer Techniques ; Oocytes/physiology ; Stem Cells ; Telomere/*ultrastructure ; },
}
@article {pmid10795747,
year = {2000},
author = {Kiyozuka, Y and Asai, A and Yamamoto, D and Senzaki, H and Yoshioka, S and Takahashi, H and Hioki, K and Tsubura, A},
title = {Establishment of novel human esophageal cancer cell line in relation to telomere dynamics and telomerase activity.},
journal = {Digestive diseases and sciences},
volume = {45},
number = {5},
pages = {870-879},
pmid = {10795747},
issn = {0163-2116},
mesh = {Biomarkers, Tumor/genetics ; Carcinoma, Squamous Cell/*genetics/pathology ; Cell Division/genetics ; Cell Transformation, Neoplastic/genetics/pathology ; Esophageal Neoplasms/*genetics/pathology ; Gene Expression Regulation, Neoplastic/physiology ; Humans ; Keratins/genetics ; Male ; Middle Aged ; RNA, Messenger/genetics ; Telomerase/*genetics ; Telomere/*genetics ; Tumor Cells, Cultured/*pathology ; },
abstract = {The telomere and the telomerase in human esophageal cancer are not yet completely understood. The regulatory mechanism of telomerase activity and telomere dynamics has drawn considerable attention. It is generally assumed that when telomerase has been activated, no further telomere shortening should ensue; however, a much more complex pattern of telomere dynamics may exist in telomerase-positive cancer cells. A novel human esophageal cancer cell line (KAN-ES) was established and characterized. Using KAN-ES and its serially passaged subclones up to the 55th generation, we determined the alteration of telomere length (TRF), telomerase activity (TA), telomerase RNA expression (hTR), population doubling time, karyotype, and cytokeratin 14 expression during the process of establishing a cancer cell line. We found that the TRF was maintained between 4.0 and 5.0 kb during the serial passages, despite sustained high TA (assessed by an in vitro TRAP assay). No close relationships were found among TRF, TA, and hTR expression. TA and telomere dynamics were not associated with cellular growth ability and differentiation. However, the number of population doublings showed significant correlations with both the TA and doubling times. In conclusion, these dissociations between telomere dynamics and TA support the existence of additional controls on TRF in cancer cells. KAN-ES and its restored subclones should prove a valuable resource for esophageal cancer research.},
}
@article {pmid10790418,
year = {2000},
author = {Ritchie, KB and Petes, TD},
title = {The Mre11p/Rad50p/Xrs2p complex and the Tel1p function in a single pathway for telomere maintenance in yeast.},
journal = {Genetics},
volume = {155},
number = {1},
pages = {475-479},
pmid = {10790418},
issn = {0016-6731},
support = {GM-24110/GM/NIGMS NIH HHS/United States ; GM52319/GM/NIGMS NIH HHS/United States ; },
mesh = {*DNA-Binding Proteins ; *Endodeoxyribonucleases ; *Exodeoxyribonucleases ; Fungal Proteins/genetics/*physiology ; Intracellular Signaling Peptides and Proteins ; Protein Serine-Threonine Kinases ; Saccharomyces cerevisiae/genetics ; *Saccharomyces cerevisiae Proteins ; *Signal Transduction ; *Telomere ; },
abstract = {The Mre11p/Rad50p/Xrs2p complex is involved in the repair of double-strand DNA breaks, nonhomologous end joining, and telomere length regulation. TEL1 is primarily involved in telomere length regulation. By an epistasis analysis, we conclude that Tel1p and the Mre11p/Rad50p/Xrs2p complex function in a single pathway of telomere length regulation.},
}
@article {pmid10787419,
year = {2000},
author = {Huffman, KE and Levene, SD and Tesmer, VM and Shay, JW and Wright, WE},
title = {Telomere shortening is proportional to the size of the G-rich telomeric 3'-overhang.},
journal = {The Journal of biological chemistry},
volume = {275},
number = {26},
pages = {19719-19722},
doi = {10.1074/jbc.M002843200},
pmid = {10787419},
issn = {0021-9258},
support = {AG01228/AG/NIA NIH HHS/United States ; GM47898/GM/NIGMS NIH HHS/United States ; GM55871/GM/NIGMS NIH HHS/United States ; },
mesh = {Breast/metabolism ; Cells, Cultured ; *Cellular Senescence ; DNA/metabolism ; Endothelium, Vascular/ultrastructure ; Epithelium/ultrastructure ; Fibroblasts/ultrastructure ; Guanine/chemistry ; Humans ; Lung/metabolism ; Models, Genetic ; Telomere/*chemistry ; },
abstract = {Most normal diploid human cells do not express telomerase activity and are unable to maintain telomere length with ongoing cell divisions. We show that the length of the single-stranded G-rich telomeric 3'-overhang is proportional to the rate of shortening in four human cell types that exhibit different rates of telomere shortening in culture. These results provide direct evidence that the size of the G-rich overhang is not fixed but subject to regulation. The potential ability to manipulate this rate has profound implications both for slowing the rate of replicative aging in normal cells and for accelerating the rate of telomere loss in cancer cells in combination with anti-telomerase therapies.},
}
@article {pmid10784448,
year = {2000},
author = {Lanza, RP and Cibelli, JB and Blackwell, C and Cristofalo, VJ and Francis, MK and Baerlocher, GM and Mak, J and Schertzer, M and Chavez, EA and Sawyer, N and Lansdorp, PM and West, MD},
title = {Extension of cell life-span and telomere length in animals cloned from senescent somatic cells.},
journal = {Science (New York, N.Y.)},
volume = {288},
number = {5466},
pages = {665-669},
doi = {10.1126/science.288.5466.665},
pmid = {10784448},
issn = {0036-8075},
support = {AG00378/AG/NIA NIH HHS/United States ; AI29524/AI/NIAID NIH HHS/United States ; GM56162/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Blotting, Southern ; Cattle/*genetics ; Cell Division ; Cells, Cultured ; *Cellular Senescence ; Clone Cells ; *Cloning, Organism ; DNA, Complementary ; Embryo Transfer ; *Eye Proteins ; Female ; Fibroblasts ; Flow Cytometry ; In Situ Hybridization, Fluorescence ; Longevity ; Matched-Pair Analysis ; *Nerve Growth Factors ; *Nuclear Transfer Techniques ; Proteins/genetics ; RNA, Messenger/genetics/metabolism ; Serpins/genetics ; Telomere/*ultrastructure ; },
abstract = {The potential of cloning depends in part on whether the procedure can reverse cellular aging and restore somatic cells to a phenotypically youthful state. Here, we report the birth of six healthy cloned calves derived from populations of senescent donor somatic cells. Nuclear transfer extended the replicative life-span of senescent cells (zero to four population doublings remaining) to greater than 90 population doublings. Early population doubling level complementary DNA-1 (EPC-1, an age-dependent gene) expression in cells from the cloned animals was 3.5- to 5-fold higher than that in cells from age-matched (5 to 10 months old) controls. Southern blot and flow cytometric analyses indicated that the telomeres were also extended beyond those of newborn (<2 weeks old) and age-matched control animals. The ability to regenerate animals and cells may have important implications for medicine and the study of mammalian aging.},
}
@article {pmid10782108,
year = {2000},
author = {Marciniak, RA and Johnson, FB and Guarente, L},
title = {Dyskeratosis congenita, telomeres and human ageing.},
journal = {Trends in genetics : TIG},
volume = {16},
number = {5},
pages = {193-195},
doi = {10.1016/s0168-9525(00)01984-3},
pmid = {10782108},
issn = {0168-9525},
mesh = {Aging/*physiology ; Animals ; Dyskeratosis Congenita/*genetics/metabolism ; Humans ; Male ; Mice ; Mice, Knockout ; Neoplasms/genetics ; Telomerase/metabolism ; *Telomere ; },
abstract = {As normal humans age, telomeres shorten in tissues that contain dividing cells, and this has been proposed both as a cause of ageing and as a tumor-suppressor mechanism. The surprising finding that cells from individuals with the rare inherited disorder dyskeratosis congenita (DKC) have reduced levels of telomerase and shortened telomeres might provide the first direct genetic test of the function of telomeres in intact humans.},
}
@article {pmid10781627,
year = {2000},
author = {Buys, CH},
title = {Telomeres, telomerase, and cancer.},
journal = {The New England journal of medicine},
volume = {342},
number = {17},
pages = {1282-1283},
doi = {10.1056/NEJM200004273421710},
pmid = {10781627},
issn = {0028-4793},
mesh = {Cell Division ; DNA-Binding Proteins ; Humans ; Mutation ; Neoplasms/enzymology/*therapy ; *RNA ; Telomerase/antagonists &amp; inhibitors/genetics/*physiology ; *Telomere ; Tumor Cells, Cultured ; },
}
@article {pmid10780431,
year = {1999},
author = {Koga, M and Shigeta, M and Uchida, T and Ueda, M and Ohnuma, T and Suzuki, T and Saeki, T},
title = {Synthesis of telomere-mimic carbocyclic 5'-nor oligodeoxynucleotides.},
journal = {Nucleic acids symposium series},
volume = {},
number = {42},
pages = {165-166},
doi = {10.1093/nass/42.1.165},
pmid = {10780431},
issn = {0261-3166},
mesh = {*Acids, Carbocyclic ; Antineoplastic Agents/toxicity ; Base Sequence ; Cell Division/drug effects ; Humans ; Oligodeoxyribonucleotides, Antisense/*chemical synthesis/toxicity ; *Telomere ; Thionucleotides ; Tumor Cells, Cultured ; },
abstract = {Telomere-mimic S-ODNs have been synthesized and examined their effects on the proliferation of human tumor cell lines by XTT assay. Furthermore, the guanosine derivatives of carbocyclic 5'-nor nucleoside were synthesized.},
}
@article {pmid10773069,
year = {2000},
author = {Brugère, JF and Cornillot, E and Méténier, G and Bensimon, A and Vivarès, CP},
title = {Encephalitozoon cuniculi (Microspora) genome: physical map and evidence for telomere-associated rDNA units on all chromosomes.},
journal = {Nucleic acids research},
volume = {28},
number = {10},
pages = {2026-2033},
pmid = {10773069},
issn = {1362-4962},
mesh = {Animals ; *Bacterial Proteins ; *Chromosome Mapping ; DNA, Protozoan/genetics ; DNA, Ribosomal/*genetics ; Deoxyribonucleases, Type II Site-Specific ; Encephalitozoon cuniculi/*genetics ; *Genome, Protozoan ; Genomic Library ; Restriction Mapping ; Telomere/*genetics ; },
abstract = {A restriction map of the 2.8-Mb genome of the unicellular eukaryote Encephalitozoon cuniculi (phylum Microspora), a mammal-infecting intracellular parasite, has been constructed using two restriction enzymes with 6 bp recognition sites (Bss HII and Mlu I). The fragments resulting from either single digestions of the whole molecular karyotype or double digestions of 11 individual chromosomes have been separated by two-dimensional pulsed field gel electrophoresis (2D-PFGE) procedures. The average distance between successive restriction sites is approximately 19 kb. The terminal regions of the chromosomes show a common pattern covering approximately 15 kb and including one 16S-23S rDNA unit. Results of hybridisation and molecular combing experiments indicate a palindromic-like orientation of the two subtelomeric rDNA copies on each chromosome. We have also located 67 DNA markers (clones from a partial E. cuniculi genomic library) by hybridisation to restriction fragments. Partial or complete sequencing has revealed homologies with known protein-coding genes for 32 of these clones. Evidence for two homologous chromosomes III, with a size difference (3 kb) related to a subtelomeric deletion/insertion event, argues for diploidy of E.cuniculi. The physical map should be useful for both the whole genome sequencing project and studies on genome plasticity of this widespread parasite.},
}
@article {pmid10772830,
year = {2000},
author = {Aikata, H and Takaishi, H and Kawakami, Y and Takahashi, S and Kitamoto, M and Nakanishi, T and Nakamura, Y and Shimamoto, F and Kajiyama, G and Ide, T},
title = {Telomere reduction in human liver tissues with age and chronic inflammation.},
journal = {Experimental cell research},
volume = {256},
number = {2},
pages = {578-582},
doi = {10.1006/excr.2000.4862},
pmid = {10772830},
issn = {0014-4827},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; *Aging ; Female ; Hepatitis, Chronic/*pathology ; Hepatitis, Viral, Human/pathology ; Humans ; Liver/pathology/*ultrastructure ; Liver Cirrhosis/*pathology ; Male ; Middle Aged ; *Telomere ; },
abstract = {Telomere shortening in human liver with aging and chronic inflammation was examined by hybridization protection assay using telomere and Alu probes. The reduction rate of telomere repeats in normal liver (23 samples from patients 17-81 years old) was 120 bp per year, which is in good agreement with the reported reduction rate in fibroblasts of 50-150 bp at each cell division and replacement rate of human liver cells, once a year. Mean telomere repeat length shortened to about 10 kbp in normal livers from 80-year-old individuals. The number of telomere repeats in chronic hepatitis (26 samples) and liver cirrhosis (11 samples) was significantly lower than that in normal liver of the same age (P < 0. 01). Telomere length in all these chronic liver disease samples, other than two exceptions, was not reduced shorter than 5 kbp, which was assumed to give a limit of proliferation (Hayflick's limit) to untransformed cells.},
}
@article {pmid10769656,
year = {2000},
author = {Kiyozuka, Y and Yamamoto, D and Yang, J and Uemura, Y and Senzaki, H and Adachi, S and Tsubura, A},
title = {Correlation of chemosensitivity to anticancer drugs and telomere length, telomerase activity and telomerase RNA expression in human ovarian cancer cells.},
journal = {Anticancer research},
volume = {20},
number = {1A},
pages = {203-212},
pmid = {10769656},
issn = {0250-7005},
mesh = {Antineoplastic Agents/*pharmacology ; Antineoplastic Agents, Alkylating/pharmacology ; Calorimetry ; Camptothecin/analogs &amp; derivatives/pharmacology ; Carcinoma/drug therapy/enzymology/genetics/*pathology ; Cisplatin/pharmacology ; Cyclophosphamide/pharmacology ; Doxorubicin/administration &amp; dosage ; Drug Resistance, Neoplasm/*genetics ; Enzyme Inhibitors/pharmacology ; Etoposide/pharmacology ; Female ; Humans ; Ifosfamide/pharmacology ; Irinotecan ; Neoplasm Proteins/antagonists &amp; inhibitors/*metabolism ; Ovarian Neoplasms/drug therapy/enzymology/genetics/*pathology ; Paclitaxel/pharmacology ; RNA, Messenger/*biosynthesis/genetics ; RNA, Neoplasm/*biosynthesis/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/antagonists &amp; inhibitors/*metabolism ; Telomere/metabolism/*physiology/ultrastructure ; Topoisomerase II Inhibitors ; Tumor Cells, Cultured/drug effects/ultrastructure ; },
abstract = {BACKGROUND: We examined the correlations among telomere length (TRF), telomerase activity (TA) and the steady-state level of telomerase RNA expression (hTR) of human ovarian cancer cells with different phenotypes and investigated whether the cells' sensitivities to anticancer agents correlate with TRF, TA or hTR.<br><br>MATERIALS AND METHODS: The TRF, TA and hTR of 11 human ovarian cancer cell lines and 2 cisplatin-resistant ovarian cancer cell lines were determined by genomic Southern blotting, a telomeric repeat amplification protocol and reverse transcription-polymerase chain reaction. The chemosensitivities of the cell lines to cisplatin (CDDP), paclitaxel (TAX), etoposide (ETO), CPT-11 (CPT), cyclophosphamide (CYC), ifomide (IFO) and doxorubicin (DOX) were decided as IC50 values by calorimetric assay.<br><br>RESULTS: All 11 cell lines presented shorter mean TRFs (5.0 kb) than normal control tissue (8.0 kb); 10 cell lines presented a 3.2-fold higher mean TA than the control and all 11 cell lines expressed hTR. Quantitatively, the steady-state levels of hTR correlated with the TRF (p < 0.05). Significant positive correlations between hTR and CDDP sensitivities (at 24 hours of exposure), ETO (72 hours), CPT (48 hours) and CYC/IFO (24-72 hours) were observed. The same was true for TRF and the CDDP sensitivities (at 24 hours). TAX and DOX did not have any impact on these factors. The TRF, TA and hTR values in the two CDDP-resistant cell lines were generally reduced, compared to their parent cell lines.<br><br>CONCLUSIONS: Alkylating agents (CDDP, CYC and IFO) and topoisomerase inhibitors (ETO, CPT) may have the potential to influence the structural alteration of hTRs and telomeres and thus, the down-regulation of the TA in ovarian cancer cells.},
}
@article {pmid10762636,
year = {2000},
author = {Villa, R and Folini, M and Perego, P and Supino, R and Setti, E and Daidone, MG and Zunino, F and Zaffaroni, N},
title = {Telomerase activity and telomere length in human ovarian cancer and melanoma cell lines: correlation with sensitivity to DNA damaging agents.},
journal = {International journal of oncology},
volume = {16},
number = {5},
pages = {995-1002},
doi = {10.3892/ijo.16.5.995},
pmid = {10762636},
issn = {1019-6439},
mesh = {Antineoplastic Agents/*pharmacology ; Cell Division ; DNA, Neoplasm/drug effects/metabolism ; Female ; Humans ; Melanoma/*enzymology/*ultrastructure ; Ovarian Neoplasms/*enzymology/*ultrastructure ; Telomerase/*metabolism ; Telomere/*ultrastructure ; Tumor Cells, Cultured ; },
abstract = {Since telomerase plays a role in cellular resistance to apoptosis, which is the primary mode of cell death induced by several drugs, telomerase could be involved in determining the chemosensitivity profile of tumor cells. Thus, we investigated the relationship between telomerase activity, telomere length and chemosensitivity to effective antitumor agents in a panel of human melanoma and ovarian cancer cell lines. Telomerase activity, as detected by the telomeric repeat amplification protocol, ranged from 0.58 to 1.10 arbitrary units in individual cell lines, with similar median values for melanoma and ovarian carcinoma cell lines (0.80 vs. 0.90). Telomeres were generally longer in melanoma than in ovarian carcinoma cell lines, with a more than 2-fold median telomere restriction fragment length (7.74 vs. 3.82 kb). No significant correlation was evidenced between the two telomere-related parameters and cell population doubling time, DNA index or TP53 gene status. No precise relation was found between telomerase activity and cellular sensitivity to different DNA damaging agents including doxorubicin, cisplatin and the multinuclear platinum compound BBR 3464. In contrast, longer telomeres were associated to resistance to the drugs, even though the association reached statistical significance only for cisplatin. Since platinum compounds may have affinity for telomere sequences, it is conceivable that the interaction is relevant for drug sensitivity/resistance status depending on telomere length.},
}
@article {pmid10754555,
year = {2000},
author = {Kass-Eisler, A and Greider, CW},
title = {Recombination in telomere-length maintenance.},
journal = {Trends in biochemical sciences},
volume = {25},
number = {4},
pages = {200-204},
doi = {10.1016/s0968-0004(00)01557-7},
pmid = {10754555},
issn = {0968-0004},
support = {GM43080/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Humans ; *Recombination, Genetic ; Saccharomyces cerevisiae/genetics ; Telomerase/metabolism ; *Telomere ; },
abstract = {Although telomerase is the major mechanism for telomere elongation in most cells, telomerase-independent mechanisms of telomere maintenance can allow cell survival. Yeast cells that lack telomerase maintain telomere length through a form of recombination known as gene conversion. Understanding the role that telomeric recombination might play in mammalian cells has important implications for cancer therapeutics.},
}
@article {pmid10753788,
year = {2000},
author = {Cooper, JP},
title = {Telomere transitions in yeast: the end of the chromosome as we know it.},
journal = {Current opinion in genetics &amp; development},
volume = {10},
number = {2},
pages = {169-177},
doi = {10.1016/s0959-437x(00)00070-8},
pmid = {10753788},
issn = {0959-437X},
mesh = {Animals ; Cell Cycle/genetics ; Chromosomes, Fungal/enzymology/*genetics ; Humans ; Saccharomyces cerevisiae/cytology/enzymology/*genetics ; Schizosaccharomyces/cytology/enzymology/*genetics ; Telomere/enzymology/*genetics ; },
abstract = {Telomere functions vary as the cell cycle progresses. Recent results highlight fluctuating associations between telomeres and DNA polymerases, DNA-damage repair proteins, and centrosome components. These associations reflect diverse roles of telomeres in chromosome maintenance and in the orchestration of chromosome movements during meiosis.},
}
@article {pmid10744686,
year = {2000},
author = {Ouellette, MM and Liao, M and Herbert, BS and Johnson, M and Holt, SE and Liss, HS and Shay, JW and Wright, WE},
title = {Subsenescent telomere lengths in fibroblasts immortalized by limiting amounts of telomerase.},
journal = {The Journal of biological chemistry},
volume = {275},
number = {14},
pages = {10072-10076},
doi = {10.1074/jbc.275.14.10072},
pmid = {10744686},
issn = {0021-9258},
support = {AG01228/AG/NIA NIH HHS/United States ; N01-CN-85143/CN/NCI NIH HHS/United States ; },
mesh = {Cell Line, Transformed ; Cellular Senescence ; Fibroblasts/cytology/physiology ; Humans ; Kinetics ; Male ; Recombinant Proteins/metabolism ; Skin/cytology ; Telomerase/genetics/*metabolism ; Telomere/*metabolism/ultrastructure ; Transfection ; },
abstract = {Human fibroblasts expressing the catalytic component of human telomerase (hTERT) have been followed for 250-400 population doublings. As expected, telomerase activity declined in long term culture of stable transfectants. Surprisingly, however, clones with average telomere lengths several kilobases shorter than those of senescent parental cells continued to proliferate. Although the longest telomeres shortened, the size of the shortest telomeres was maintained. Cells with subsenescent telomere lengths proliferated for an additional 20 doublings after inhibiting telomerase activity with a dominant-negative hTERT mutant. These results indicate that, under conditions of limiting telomerase activity, cis-acting signals may recruit telomerase to act on the shortest telomeres, argue against the hypothesis that the mortality stage 1 mechanism of cellular senescence is regulated by telomere positional effects (in which subtelomeric loci silenced by long telomeres are expressed when telomeres become short), and suggest that catalytically active telomerase is not required to provide a protein-capping role at the end of very short telomeres.},
}
@article {pmid10741725,
year = {2000},
author = {Rha, SY and Izbicka, E and Lawrence, R and Davidson, K and Sun, D and Moyer, MP and Roodman, GD and Hurley, L and Von Hoff, D},
title = {Effect of telomere and telomerase interactive agents on human tumor and normal cell lines.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {6},
number = {3},
pages = {987-993},
pmid = {10741725},
issn = {1078-0432},
support = {CA67760/CA/NCI NIH HHS/United States ; },
mesh = {Bone Marrow Cells/cytology/drug effects ; Cell Count/drug effects/radiation effects ; Cell Division/drug effects/radiation effects ; Cell Line ; Colony-Forming Units Assay ; HeLa Cells ; Hematopoietic Stem Cells/cytology/drug effects ; Humans ; Inhibitory Concentration 50 ; Light ; Porphyrins/*pharmacology ; Telomerase/*drug effects/metabolism ; Telomere/*drug effects/metabolism ; Tumor Cells, Cultured ; Zidovudine/*pharmacology ; },
abstract = {Shortening of telomeres along with an up-regulation of telomerase is implicated in the immortality of tumor cells. Targeting either telomeres or telomerase with specific compounds has been proposed as an anticancer strategy. Because telomerase activity and telomeres are found in normal cells, telomere or telomerase targeting agents could induce side effects in normal tissues. We evaluated the effects of telomere and telomerase interactive agents in human tumor and normal cell lines to try to determine the potential side effects those agents might induce in patients. Toxicity of the G-quadruplex interactive porphyrins (TMPyP4, TMPyP2) and azidothymidine (AZT) were tested using a cell-counting technique against normal human cell lines (CRL-2115 and CRL-2120, fibroblasts; NHEK-Ad, adult keratinocytes; CCL-241, small intestinal cells; NCM 460, colonic mucosal epithelial cells) and human tumor cell lines (MDA-MB 231 and Hs 578T, breast cancer; SK-N-FI, neuroblastoma; HeLa, cervix cancer; MIA PaCa-2, pancreatic cancer; HT-29 and HCT-116, colon cancer; DU 145, prostatic cancer cell line). Telomerase activity of these cell lines was measured by a non-PCR-based conventional assay. The effects of TMPgammaP2, TMPyP4, and AZT were also evaluated against normal human bone marrow specimens, using a granulocyte-macrophage colony-forming assay (CFU-GM). AZT showed very low cytotoxic effects against normal and tumor cell lines, with the IC50 values above 200 microM. The IC50 values for TMPyP2 and TMPyP4 in normal human cell lines were in the range of 2.9-48.3 microM and 1.7-15.5 microM, respectively, whereas in tumor cell lines the IC50 values were 11.4-53 microM and 9.0-28.2 microM, respectively. Within the tissue types, keratinocytes were more sensitive to TMPyP4 than fibroblasts, and small intestinal cells were more sensitive than colonic mucosal epithelial cells. The IC50 for TMPyP2 and TMPyP4 in the normal marrow colony-forming assays were 19.3 +/- 5.1 microM and 47.9 +/-1.0 microM, respectively. In conclusion, the in vitro cytotoxicity of the telomere interactive agent TMPyP4 is comparable in human tumor and normal cell lines, which indicates that TMPyP4 could have effects on normal tissues.},
}
@article {pmid10739676,
year = {2000},
author = {Martens, UM and Chavez, EA and Poon, SS and Schmoor, C and Lansdorp, PM},
title = {Accumulation of short telomeres in human fibroblasts prior to replicative senescence.},
journal = {Experimental cell research},
volume = {256},
number = {1},
pages = {291-299},
doi = {10.1006/excr.2000.4823},
pmid = {10739676},
issn = {0014-4827},
support = {AI29524/AI/NIAID NIH HHS/United States ; GM56162/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Division ; Cellular Senescence/*physiology ; *Chromosome Mapping ; Chromosomes, Human, Pair 17 ; Clone Cells ; Fetus ; Fibroblasts/*cytology/ultrastructure ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Metaphase ; Skin/*cytology ; Telomere/physiology/*ultrastructure ; },
abstract = {The loss of telomere repeats has been causally linked to in vitro replicative senescence of human diploid fibroblasts (HDFs). In order to study the mechanism(s) by which telomere shortening signals cell senescence, we analyzed the telomere length at specific chromosome ends at cumulative population doublings in polyclonal and clonal HDFs by quantitative fluorescence in situ hybridization. The rate of telomere shortening at individual telomeres varied between 50 and 150 bp per population doubling and short telomeres with an estimated 1-2 kb of telomere repeats accumulated prior to senescence. The average telomere length in specific chromosome ends was remarkably similar between clones. However, some exceptions with individual telomeres measuring 0.5-1 kb were observed. In the fibroblast clones, the onset of replicative senescence was significantly correlated with the mean telomere fluorescence but, strikingly, not with chromosomes with the shortest telomere length. The accumulation of short telomeres in late passages of cultured HDFs is compatible with selection of cells on the basis of telomere length and limited recombination between telomeres prior to senescence.},
}
@article {pmid10737017,
year = {2000},
author = {Ishikawa, F},
title = {[Cellular senescence and chromosome telomeres].},
journal = {Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics},
volume = {37},
number = {1},
pages = {19-25},
pmid = {10737017},
issn = {0300-9173},
mesh = {Animals ; Cellular Senescence/*physiology ; Humans ; Telomerase/physiology ; Telomere/*physiology ; },
}
@article {pmid10733598,
year = {2000},
author = {Prescott, JC and Blackburn, EH},
title = {Telomerase RNA template mutations reveal sequence-specific requirements for the activation and repression of telomerase action at telomeres.},
journal = {Molecular and cellular biology},
volume = {20},
number = {8},
pages = {2941-2948},
pmid = {10733598},
issn = {0270-7306},
support = {R01 GM026259/GM/NIGMS NIH HHS/United States ; R37 GM026259/GM/NIGMS NIH HHS/United States ; GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Enzyme Activation/physiology ; Point Mutation ; RNA/*physiology ; Saccharomyces cerevisiae ; Telomerase/*physiology ; Telomere/*physiology ; Templates, Genetic ; rap1 GTP-Binding Proteins/physiology ; },
abstract = {Telomeric DNA is maintained within a length range characteristic of an organism or cell type. Significant deviations outside this range are associated with altered telomere function. The yeast telomere-binding protein Rap1p negatively regulates telomere length. Telomere elongation is responsive to both the number of Rap1p molecules bound to a telomere and the Rap1p-centered DNA-protein complex at the extreme telomeric end. Previously, we showed that a specific trinucleotide substitution in the Saccharomyces cerevisiae telomerase gene (TLC1) RNA template abolished the enzymatic activity of telomerase, causing the same cell senescence and telomere shortening phenotypes as a complete tlc1 deletion. Here we analyze effects of six single- and double-base changes within these same three positions. All six mutant telomerases had in vitro enzymatic activity levels similar to the wild-type levels. The base changes predicted from the mutations all disrupted Rap1p binding in vitro to the corresponding duplex DNAs. However, they caused two classes of effects on telomere homeostasis: (i) rapid, RAD52-independent telomere lengthening and poor length regulation, whose severity correlated with the decrease in in vitro Rap1p binding affinity (this is consistent with loss of negative regulation of telomerase action at these telomeres; and (ii) telomere shortening that, depending on the template mutation, either established a new short telomere set length with normal cell growth or was progressive and led to cellular senescence. Hence, disrupting Rap1p binding at the telomeric terminus is not sufficient to deregulate telomere elongation. This provides further evidence that both positive and negative cis-acting regulators of telomerase act at telomeres.},
}
@article {pmid10723589,
year = {2000},
author = {Akiyama, M and Asai, O and Kuraishi, Y and Urashima, M and Hoshi, Y and Sakamaki, H and Yabe, H and Furukawa, T and Yamada, O and Mizoguchi, H and Yamada, H},
title = {Shortening of telomeres in recipients of both autologous and allogeneic hematopoietic stem cell transplantation.},
journal = {Bone marrow transplantation},
volume = {25},
number = {4},
pages = {441-447},
doi = {10.1038/sj.bmt.1702144},
pmid = {10723589},
issn = {0268-3369},
mesh = {Adolescent ; Adult ; Biomarkers ; Child ; Child, Preschool ; Female ; Hematologic Neoplasms/genetics/therapy ; Hematopoiesis/genetics ; *Hematopoietic Stem Cell Transplantation ; Humans ; Male ; Middle Aged ; *Telomere ; Transplantation, Autologous ; Transplantation, Homologous ; },
abstract = {Telomere length of peripheral blood mononuclear cells (PBMCs) from 23 autologous HSCT patients ranging from 4 to 61 years old, and 46 allogeneic HSCT recipients from 6 to 52 years old were studied to confirm whether excessive shortening of telomeres is associated with HSCT. After autologous HSCT, telomere length of PBMCs ranged from 6.8 to 12.0 kb. The comparison between transplanted PBMCs and PBMCs after autologous HSCT showed shortening by up to 1.9 kb (mean +/- s.d.: 0.64 +/- 0.50 kb). There was a difference between autologous HSCT patients and normal volunteers in the slopes of regression lines. After allogeneic HSCT, telomere length of PBMCs ranged from 6.8 to 12.0 kb. Telomeres of recipients were up to 2.1 kb (0.60 +/- 0.468 kb) shorter than those of donors. The slope of regression lines for allogeneic HSCT patients and normal volunteers were parallel. Although all patients were transplanted with more than 2.0 x 10(8) cells/kg, telomere length did not correlate with the number of transplanted cells. There was no significant correlation between telomere length and recovery of hematological parameters. However, three patients with an average telomere length of 6.8 kb after HSCT took a longer period to reach the normal hematological state. Taken together, these data suggest that most HSCTs are performed within the biological safety range of telomeres, while the patients who have telomeres shorter than 7.0 kb after HSCT should be observed carefully for long-term hematopoiesis and the occurrence of hematopoietic disorders.},
}
@article {pmid10721459,
year = {2000},
author = {Richardson, MW and Sverstiuk, A and Hendel, H and Cheung, TW and Zagury, JF and Rappaport, J},
title = {Analysis of telomere length and thymic output in fast and slow/non-progressors with HIV infection.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {54},
number = {1},
pages = {21-31},
doi = {10.1016/s0753-3322(00)88637-0},
pmid = {10721459},
issn = {0753-3322},
mesh = {Acquired Immunodeficiency Syndrome/genetics/immunology/*pathology ; Adult ; CD4-Positive T-Lymphocytes/immunology ; Cohort Studies ; Cross-Sectional Studies ; DNA/analysis/genetics ; Disease Progression ; Female ; Genotype ; HIV Infections/genetics/immunology/*pathology ; HIV Seropositivity/immunology ; Humans ; Male ; Middle Aged ; Neutrophils/drug effects/immunology/metabolism ; Polymorphism, Restriction Fragment Length ; Receptors, Antigen, T-Cell/drug effects/immunology/metabolism ; Telomere/*genetics ; Thymus Gland/*physiology ; },
abstract = {There are two models for CD4+ T-cell depletion leading to AIDS: a kinetic model and an immune suppression model. In the kinetic model, direct cell killing due to viral replication results in a continuous demand for CD4+ T-cells, which eventually exhausts their capacity for renewal by proliferative mechanisms. In the immune suppression model, CD4+ T-cell decline is due to an indirect global inhibitory effect of the virus on uninfected immune cell function. In order to address differences in the two models, we investigated proliferative history and thymic output in PBMC from the GRIV cohort of fast (FP) and slow/non-progressors (S/NP), and uninfected controls. Proliferative history and thymic output were assessed by measurement of mean telomeric restriction fragment (TRF) length and T-cell receptor Rearrangement Excision Circles (TREC) levels, respectively. Mean TRF lengths were significantly shorter in S/NP (n = 93, 7.59 +/- 0.11 kb) and FP (n = 42, 7.25 +/- 0.15 kb) compared to controls (n = 35, 9.17 +/- 0.19 kb). Mean TRF length in PBMC (n = 9, 7.32 +/- 0.31 kb) and CD4+ enriched fractions (n = 9, 7.41 +/- 0.30 kb) from a subset of non-GRIV HIV-1 infected samples were also significantly smaller than PBMC (n = 8, 9.77 +/- 0.33 kb) and CD4+ fractions (n = 8, 9.41 +/- 0.32 kb) from uninfected controls. Rates of telomeric shortening, however, were similar among S/NP (n = 93, -45 +/- 20 bp/yr), FP (n = 42, -41 +/- 14 bp/yr) and controls (-29 +/- 17 bp/yr). Paralleling differences observed in mean TRF length, TREC levels were significantly reduced in S/NP (n = 10, 3,433 +/- 843 mol/mu and FP (n = 8, 1,193 +/- 413) compared to controls (n = 15, 22,706 +/- 5,089), indicative of a defect in thymopoiesis in HIV-1 infection. When evaluated in the context of reduced thymopoiesis, the difference in mean TRF length between S/NP and controls (1.58 +/- 0.30 kb) is similar to that observed between memory and naïve T-cells (1.4 +/- 0.1 kb), and may reflect perturbations in the peripheral T-cell population due to a decline in thymic output of naïve T-cells rather than increased turnover. Based on the different clinical criteria used to select S/NP and FP, the sight difference in TREC between these two groups suggests the threshold for pathogenesis as a result of naïve T-cell depletion may be quite low, and incremental increases in thymic output may yield substantial clinical results. Future studies regarding therapeutic vaccination, specifically with HIV-1 Tat targeted anti-immunosuppressive vaccines, should address the defect in thymic output in HIV-1 infection by using TREC analysis as a rapid method for biological evaluation.},
}
@article {pmid10721008,
year = {2000},
author = {Savre-Train, I and Gollahon, LS and Holt, SE},
title = {Clonal heterogeneity in telomerase activity and telomere length in tumor-derived cell lines.},
journal = {Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)},
volume = {223},
number = {4},
pages = {379-388},
doi = {10.1046/j.1525-1373.2000.22354.x},
pmid = {10721008},
issn = {0037-9727},
support = {AG05747/AG/NIA NIH HHS/United States ; },
mesh = {Cell Line ; Cell Line, Transformed ; Cholic Acids ; *Clone Cells/enzymology/ultrastructure ; Embryo, Mammalian ; Fibroblasts ; Humans ; Neoplasms/*enzymology/*ultrastructure ; RNA, Messenger/analysis ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/genetics/*metabolism ; Telomere/*ultrastructure ; Tumor Cells, Cultured ; },
abstract = {The ribonucleoprotein, telomerase, is responsible for the maintenance of telomere length in most immortal and cancer cells. Telomerase appears to be a marker of human malignancy with at least 85% of human cancers expressing its activity. In the present study, we examined a series of tumor-derived and in vitro immortalized cell lines for telomerase activity levels, telomere lengths, and expression levels of the RNA and catalytic components of telomerase. We found significant variability in both telomere lengths and telomerase activity in clones from tumor cells. In addition, the levels of telomerase components or telomerase activity were not predictive of telomere length. Data from clonally derived cells suggest that critically shortened telomeres in these tumor-derived cell lines may signal activation of telomerase activity through an increase in the expression of the catalytic subunit of telomerase. Although clones with low telomerase shorten their telomeres over time, their subclones all have high levels of telomerase activity with no telomere shortening. In addition, analysis of early clones for telomerase activity indicates substantial variability, which suggests that activity levels fluctuate in individual cells. Our data imply that cell populations exhibit a cyclic expression of telomerase activity, which may be partially regulated by telomere shortening.},
}
@article {pmid10717543,
year = {2000},
author = {Effros, RB},
title = {Telomeres and HIV disease.},
journal = {Microbes and infection},
volume = {2},
number = {1},
pages = {69-76},
doi = {10.1016/s1286-4579(00)00283-5},
pmid = {10717543},
issn = {1286-4579},
support = {AG10415/AG/NIA NIH HHS/United States ; AI28697/AI/NIAID NIH HHS/United States ; },
mesh = {CD4-Positive T-Lymphocytes/cytology ; CD8-Positive T-Lymphocytes/cytology ; HIV Infections/genetics/*immunology ; Humans ; Telomere/*genetics ; },
abstract = {Telomere measurement, envisioned as a novel approach to elucidate T-cell dynamics in HIV disease, failed to reveal any consistent pattern in CD4+ T cells. By contrast, significant telomere shortening, as well as other hallmarks suggestive of replicative senescence, was observed within the CD8+ T-cell subset. Telomere studies have thus provided unanticipated insight into a novel facet of memory CD8+ T lymphocyte dynamics that may explain the exhaustion of the protective antiviral immune response. Strategies aimed at manipulating replicative senescence, therefore, offer unique approaches to immune reconstitution.},
}
@article {pmid10717390,
year = {2000},
author = {Smith, J and Zou, H and Rothstein, R},
title = {Characterization of genetic interactions with RFA1: the role of RPA in DNA replication and telomere maintenance.},
journal = {Biochimie},
volume = {82},
number = {1},
pages = {71-78},
doi = {10.1016/s0300-9084(00)00183-8},
pmid = {10717390},
issn = {0300-9084},
support = {CA09503/CA/NCI NIH HHS/United States ; GM07088/GM/NIGMS NIH HHS/United States ; GM50237/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA Polymerase I/genetics/metabolism ; DNA Primase/genetics/metabolism ; DNA Repair/genetics ; DNA Replication/*physiology ; DNA-Binding Proteins/*genetics/*metabolism ; Genes, Lethal ; Mutation ; Phenotype ; Replication Protein A ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; Telomere/*genetics ; },
abstract = {Replication protein A (RPA) is a heterotrimeric single-stranded DNA binding protein whose role in DNA replication, recombination and repair has been mainly elucidated through in vitro biochemical studies utilizing the mammalian complex. However, the identification of homologs of all three subunits in Saccharomyces cerevisiae offers the opportunity of examining the in vivo role of RPA. In our laboratory, we have previously isolated a missense allele of the RFA1 gene, encoding the p70 subunit of the RPA complex. Strains containing this mutant allele, rfa1-D228Y, display increased levels of direct-repeat recombination, decreased levels of heteroallelic recombination, UV sensitivity and a S-phase delay. In this study, we have characterized further the role of RPA by screening other replication and repair mutants for a synthetic lethal phenotype in combination with the rfa1-D228Y allele. Among the replication mutants examined, only one displayed a synthetic lethal phenotype, pol12-100, a conditional allele of the B subunit of pol alpha-primase. In addition, a delayed senescence phenotype was observed in raf1-D228Y strains containing a null mutation of HDF1, the S. cerevisiae homolog of the 70 kDa subunit of Ku. Interestingly, a synergistic reduction in telomere length observed in the double mutants suggests that the shortening of telomeres may be the cause of the decreased viability in these strains. Furthermore, this result represents the first evidence of a role for RPA in telomere maintenance.},
}
@article {pmid10714586,
year = {2000},
author = {Decary, S and Hamida, CB and Mouly, V and Barbet, JP and Hentati, F and Butler-Browne, GS},
title = {Shorter telomeres in dystrophic muscle consistent with extensive regeneration in young children.},
journal = {Neuromuscular disorders : NMD},
volume = {10},
number = {2},
pages = {113-120},
doi = {10.1016/s0960-8966(99)00093-0},
pmid = {10714586},
issn = {0960-8966},
mesh = {Adolescent ; Cell Division/*genetics ; Cellular Senescence/*genetics ; Child ; Child, Preschool ; Female ; Humans ; Male ; Muscle, Skeletal/*pathology ; Muscular Dystrophies/genetics/*pathology ; Regeneration/*genetics ; Telomere/genetics/*pathology ; },
abstract = {Muscular dystrophies are characterised by continuous cycles of degeneration and regeneration resulting in an eventual diminution of the muscle mass and extensive fibrosis. In somatic cells chromosomal telomeres shorten with each round of cell division and telomere length is considered to be a biomarker of the replicative history of the cell. We have previously shown that human myoblasts have a limited proliferative capacity, and that normal skeletal muscle has a very low level of nuclear turnover. However, in patients suffering from muscular dystrophy the satellite cells will be forced to make repeated rounds of cell division, driving the cells towards senescence. In this study we have used the telomere length to quantify the intensity of the muscle cell turnover in biopsies from dystrophic patients of different ages. Our results show that as soon as the first clinical symptoms become apparent the muscle has already undergone extensive regeneration and the rate of telomere loss is 14 times greater than that observed in controls. This confirms that the decline in regenerative capacity is due to the premature senescence of the satellite cells induced by their excessive proliferation during muscle repair.},
}
@article {pmid10713162,
year = {2000},
author = {Craven, RJ and Petes, TD},
title = {Involvement of the checkpoint protein Mec1p in silencing of gene expression at telomeres in Saccharomyces cerevisiae.},
journal = {Molecular and cellular biology},
volume = {20},
number = {7},
pages = {2378-2384},
pmid = {10713162},
issn = {0270-7306},
support = {R01 GM024110/GM/NIGMS NIH HHS/United States ; R01 GM052319/GM/NIGMS NIH HHS/United States ; GM24110/GM/NIGMS NIH HHS/United States ; GM52319/GM/NIGMS NIH HHS/United States ; },
mesh = {*Cell Cycle Proteins ; *Enzyme Inhibitors ; Fungal Proteins/*genetics/metabolism ; Gene Expression Regulation, Fungal/*genetics ; *Gene Silencing ; Genetic Complementation Test ; Intracellular Signaling Peptides and Proteins ; Mutation ; Protein Kinases/genetics ; Protein Serine-Threonine Kinases ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; Telomere/*genetics ; },
abstract = {Yeast strains with a mutation in the MEC1 gene are deficient in the cellular checkpoint response to DNA-damaging agents and have short telomeres (K. B. Ritchie, J. C. Mallory, and T. D. Petes, Mol. Cell. Biol. 19:6065-6075, 1999; T. A. Weinert, G. L. Kiser, and L. H. Hartwell, Genes Dev. 8:652-665, 1994). In wild-type yeast cells, genes inserted near the telomeres are transcriptionally silenced (D. E. Gottschling, O. M. Aparichio, B. L. Billington, and V. A. Zakian, Cell 63:751-762, 1990). We show that mec1 strains have reduced ability to silence gene expression near the telomere. This deficiency was alleviated by the sml1 mutation. Overexpression of Mec1p also resulted in a silencing defect, although this overexpression did not affect the checkpoint function of Mec1p. Telomeric silencing was not affected by mutations in several other genes in the Mec1p checkpoint pathway (null mutations in RAD9 and CHK1 or in several hypomorphic rad53 alleles) but was reduced by a null mutation of DUN1. In addition, the loss of telomeric silencing in mec1 strains was not a consequence of the slightly shortened telomeres observed in these strains.},
}
@article {pmid10710423,
year = {2000},
author = {Lacroix, L and Liénard, H and Labourier, E and Djavaheri-Mergny, M and Lacoste, J and Leffers, H and Tazi, J and Hélène, C and Mergny, JL},
title = {Identification of two human nuclear proteins that recognise the cytosine-rich strand of human telomeres in vitro.},
journal = {Nucleic acids research},
volume = {28},
number = {7},
pages = {1564-1575},
pmid = {10710423},
issn = {1362-4962},
mesh = {Base Composition ; Base Sequence ; Binding Sites ; Cytosine/chemistry ; DNA/chemistry/genetics/metabolism ; HeLa Cells ; Heterogeneous-Nuclear Ribonucleoprotein K ; Heterogeneous-Nuclear Ribonucleoproteins ; Humans ; Molecular Weight ; Nuclear Proteins/chemistry/genetics/*metabolism ; RNA-Binding Proteins ; Ribonucleoproteins/chemistry/genetics/metabolism ; Serine-Arginine Splicing Factors ; Telomere/*chemistry/genetics/*metabolism ; },
abstract = {Most studies on the structure of DNA in telomeres have been dedicated to the double-stranded region or the guanosine-rich strand and consequently little is known about the factors that may bind to the telomere cytosine-rich (C-rich) strand. This led us to investigate whether proteins exist that can recognise C-rich sequences. We have isolated several nuclear factors from human cell extracts that specifically bind the C-rich strand of vertebrate telomeres [namely a d(CCCTAA)(n)repeat] with high affinity and bind double-stranded telomeric DNA with a 100xreduced affinity. A biochemical assay allowed us to characterise four proteins of apparent molecular weights 66-64, 45 and 35 kDa, respectively. To identify these polypeptides we screened alambdagt11-based cDNA expression library, obtained from human HeLa cells using a radiolabelled telomeric oligonucleotide as a probe. Two clones were purified and sequenced: the first corresponded to the hnRNP K protein and the second to the ASF/SF2 splicing factor. Confirmation of the screening results was obtained with recombinant proteins, both of which bind to the human telomeric C-rich strand in vitro.},
}
@article {pmid10706851,
year = {2000},
author = {Brümmendorf, TH and Holyoake, TL and Rufer, N and Barnett, MJ and Schulzer, M and Eaves, CJ and Eaves, AC and Lansdorp, PM},
title = {Prognostic implications of differences in telomere length between normal and malignant cells from patients with chronic myeloid leukemia measured by flow cytometry.},
journal = {Blood},
volume = {95},
number = {6},
pages = {1883-1890},
pmid = {10706851},
issn = {0006-4971},
support = {AI29524/AI/NIAID NIH HHS/United States ; GM56162/GM/NIGMS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Blast Crisis/genetics ; Bone Marrow/ultrastructure ; CD3 Complex/isolation &amp; purification ; Flow Cytometry ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis/*genetics ; Middle Aged ; Philadelphia Chromosome ; Prognosis ; T-Lymphocytes/*ultrastructure ; Telomere/physiology/*ultrastructure ; Time Factors ; Tumor Cells, Cultured ; },
abstract = {Chronic myeloid leukemia (CML) is a clonal, multilineage myeloproliferative disorder characterized by the Philadelphia chromosome (Ph) and a marked expansion of myeloid cells. Previous studies have indicated that the telomere length in blood cells may indicate their replicative history. However, the large variation in telomere length between individuals complicates the use of this parameter in CML and other hematologic disorders. To circumvent this problem, we compared the telomere length in peripheral blood or bone marrow cells with purified normal (Ph(-)) T lymphocytes from the same CML patient using fluorescence in situ hybridization and flow cytometry. Overall telomere fluorescence was significantly reduced in Ph(+) cells from patients with CML compared to blood leukocytes from normal individuals (P < 0.001) or normal (Ph(-)) T lymphocytes from the same individuals (n = 51, P < 0.001). Cells from patients in accelerated phase or blast phase (AP/BP) showed significantly shorter average telomere length than cells from patients in chronic phase (CP, P = 0.02) or cytogenetic remission (CR, P = 0.03). Patients in CP who subsequently developed BP within 2 years had significantly shorter telomeres than those who did not develop BP for at least 2 years (P < 0.05). Accelerated replication-dependent telomere shortening in Ph(+)versus Ph(-) leukocytes supports previous evidence that Ph(+) stem cells cycle more actively than their counterparts in normal individuals. Our data further suggest that telomere shortening may serve as a surrogate marker of disease progression in patients with CP CML, supporting a mechanistic link between CML stem cell turnover, genetic instability, and malignant evolution in this disease. (Blood. 2000;95:1883-1890) (Blood. 2000;95:1883-1890)},
}
@article {pmid10703668,
year = {2000},
author = {Melk, A and Ramassar, V and Helms, LMH and Moore, R and Rayner, D and Solez, K and Halloran, PF},
title = {Telomere shortening in kidneys with age.},
journal = {Journal of the American Society of Nephrology : JASN},
volume = {11},
number = {3},
pages = {444-453},
doi = {10.1681/ASN.V113444},
pmid = {10703668},
issn = {1046-6673},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*physiology ; Child ; Child, Preschool ; DNA/metabolism ; Female ; Glomerular Filtration Rate ; Humans ; Infant ; Infant, Newborn ; Kidney/*physiology ; Kidney Cortex/metabolism/physiology ; Kidney Medulla/metabolism/physiology ; Male ; Middle Aged ; Regression Analysis ; Telomere/*genetics ; },
abstract = {The histology and function of the kidney deteriorates with age and age-related diseases, but the mechanisms involved in renal aging are not known. In vitro studies suggest that telomere shortening is important in replicative senescence, and is accelerated by stresses that increase replication. This study explored the relationship between age and telomere length in surgical samples from 24 human kidneys, which were either histologically normal (17) or displayed histologic abnormalities (7). Telomere loss was assessed by two independent methods: Southern blotting of terminal restriction fragments (TRF) and slot blotting using telomere-specific probes. The results of these methods correlated with each other. The mean TRF length determined by Southern blotting in cortex was about 12 kb pairs (kbp) in infancy and was shorter in older kidneys. The slope of the regression line was about 0.029 kbp (0.24%, P = 0.023) per year. Telomere DNA loss in cortex by the slot blot method was 0.25% per year (P = 0.011). By both methods, the telomere loss in medulla was not significant and was less than in cortex. Comparisons of TRF length from 20 paired samples from cortex and medulla showed that TRF was greater in cortex than medulla, with the differences being greater in young kidneys and lessening with age due to telomere loss in cortex. These findings indicate that telomeres shorten in an age-dependent manner in the kidney, either due to developmental factors or aging, particularly in renal cortex.},
}
@article {pmid10702397,
year = {2000},
author = {Kajstura, J and Pertoldi, B and Leri, A and Beltrami, CA and Deptala, A and Darzynkiewicz, Z and Anversa, P},
title = {Telomere shortening is an in vivo marker of myocyte replication and aging.},
journal = {The American journal of pathology},
volume = {156},
number = {3},
pages = {813-819},
pmid = {10702397},
issn = {0002-9440},
support = {R01 AG017042/AG/NIA NIH HHS/United States ; NCI-28704/CI/NCPDCID CDC HHS/United States ; R01 HL038132/HL/NHLBI NIH HHS/United States ; P01 HL043023/HL/NHLBI NIH HHS/United States ; R01 HL039902/HL/NHLBI NIH HHS/United States ; HL-38132/HL/NHLBI NIH HHS/United States ; HL-39902/HL/NHLBI NIH HHS/United States ; },
mesh = {Aging/*physiology ; Animals ; Animals, Newborn/growth &amp; development ; Biomarkers ; Cell Division/*physiology ; Cell Nucleus/chemistry/ultrastructure ; Cyclin-Dependent Kinase Inhibitor p16/analysis ; DNA/analysis ; Embryonic and Fetal Development ; Fetus/embryology ; Fluorescent Antibody Technique, Indirect ; *Heart Ventricles/chemistry/cytology/embryology/growth &amp; development ; Image Cytometry/methods ; Lasers ; Microscopy, Confocal/methods ; *Myocardium/chemistry/cytology ; Rats ; Rats, Inbred F344 ; Telomere/*physiology/ultrastructure ; },
abstract = {To determine whether adult cardiac myocytes are capable of multiple divisions and whether this form of growth is restricted to a subpopulation of cells that retain this capacity with age, telomere lengths were measured in myocyte nuclei isolated from the left ventricle of fetal and neonatal Fischer 344 rats and rats at 4, 12, and 27 months after birth. Two independent methodologies were used for this analysis: laser scanning cytometer and confocal microscopy. In each case, fluorescence intensity of a peptide nucleic acid probe specific for telomeric sequence was evaluated. The two techniques yielded comparable results. Telomeric shortening increased with age in a subgroup of myocytes that constituted 16% of the entire cell population. In the remaining nondividing cells, progressive accumulation of a senescent associated nuclear protein, p16(INK4), was evidenced. In conclusion, a significant fraction of myocytes divides repeatedly from birth to senescence, counteracting the continuous death of cells in the aging mammalian rat heart.},
}
@article {pmid10698269,
year = {1999},
author = {Włodarczyk, A and Gapiński, J and Patkowski, A and Dobek, A},
title = {Structural polymorphism of telomeres studied by photon correlation spectroscopy.},
journal = {Acta biochimica Polonica},
volume = {46},
number = {3},
pages = {609-613},
pmid = {10698269},
issn = {0001-527X},
mesh = {Animals ; Base Sequence ; DNA, Protozoan/chemistry/genetics ; Nucleic Acid Conformation ; Photons ; Sodium Chloride ; Solutions ; Spectrum Analysis/methods ; Telomere/*chemistry/genetics ; Tetrahymena/chemistry/genetics ; },
abstract = {Photon Correlation Spectroscopy (PCS) was used to study the dynamics and structure of Tetrahymena telomeric sequence d(5'-TGGGGT-3')4. Two different modes were observed, corresponding to the following structures: intermolecular (tetramolecular) G-quadruplex and intramolecular (monomeric) G-quartet. Experimental values of translational diffusion coefficients DT were obtained for each structural form. The value of DT for the monomer equals to 1.4 x 10(6) (cm2/s), while for the tetramolecular structure, to 0.8 x 10(6) (cm2/s). The relative weight concentrations of these two forms were analyzed versus the concentration of NaCl varied from 10 mM to 500 mM. The values of experimentally determined diffusion coefficients were compared with those calculated assuming the "bead model" and with the atomic coordinates from the NMR and X-ray crystallographic data. For both structures the experimental and calculated values of DT were in reasonable agreement. In the entire NaCl concentration range studied, the contribution of the relative weight concentration of the monomeric telomere form changed from 85% for 10 mM NaCl to 60% for 500 mM NaCl.},
}
@article {pmid10697595,
year = {1999},
author = {Klingelhutz, AJ},
title = {The roles of telomeres and telomerase in cellular immortalization and the development of cancer.},
journal = {Anticancer research},
volume = {19},
number = {6A},
pages = {4823-4830},
pmid = {10697595},
issn = {0250-7005},
mesh = {*Cell Transformation, Neoplastic/genetics ; Cellular Senescence ; Humans ; Neoplasms/genetics/*pathology ; Telomerase/*metabolism ; *Telomere ; },
abstract = {Normal human cells have a limited lifespan in culture called the Hayflick limit. Recent studies have indicated that telomere shortening is one of the important meters utilized by cells to determine the Hayflick limit, and that activation of a mechanism to maintain telomere length is essential for cells to become immortal. It is generally believed that cells must have a means to maintain telomeres in order to progress to malignancy. Most cancers do this by activating an enzyme called telomerase which adds telomeric repeats to the telomere ends. Recently, expression of this enzyme has been shown to extend the lifespan of cells. This review discusses the research that led to the discovery of telomerase, the characteristics of telomerase complex, and how recent and future advances in the telomerase field may lead to better diagnostic and treatment protocols for many different cancer types.},
}
@article {pmid10695383,
year = {1999},
author = {Werda, L and Skotnicki, AB},
title = {[Telomeres and telomerase in leukemias].},
journal = {Przeglad lekarski},
volume = {56},
number = {10},
pages = {668-670},
pmid = {10695383},
issn = {0033-2240},
mesh = {Animals ; Biomarkers, Tumor/metabolism ; Hematopoietic Stem Cells/enzymology ; Humans ; Leukemia/*diagnosis/drug therapy/*metabolism ; Leukocytes/enzymology ; Prognosis ; Telomerase/antagonists &amp; inhibitors/*metabolism ; *Telomere/drug effects ; },
abstract = {There is increasing evidence that telomere shortening both in vitro and in vivo is the clock that counts cell divisions and determines the onset of cellular senescence. Cells overcome the normal senescence mechanism by stabilising telomere length; probably due to the activity of telomerase activity that specifically elongates telomeres. Most human primary tumors contain telomerase, while the cells of most normal tissues lack this activity. Normal haematopoietic cells express telomerase activity. This review is a discussion of utility of telomere length and telomerase activity measurements in the diagnostics and prognosis of leukaemia as well as the potential value of antitelomerase therapy. Results of telomere lengths measurements in young recipients of allogenic transplants are also reported.},
}
@article {pmid10687733,
year = {2000},
author = {Oulton, R and Harrington, L},
title = {Telomeres, telomerase, and cancer: life on the edge of genomic stability.},
journal = {Current opinion in oncology},
volume = {12},
number = {1},
pages = {74-81},
doi = {10.1097/00001622-200001000-00013},
pmid = {10687733},
issn = {1040-8746},
mesh = {Animals ; Apoptosis ; Cell Survival ; *Cell Transformation, Neoplastic ; DNA Damage ; Humans ; Mice ; Neoplasms/enzymology/genetics/*pathology ; Telomerase/*metabolism ; Telomere/*ultrastructure ; },
abstract = {The presence of telomerase activity in most human tumors, but not in many normal somatic tissues, has raised considerable interest in telomerase as a possible anticancer therapy. Recent advances in the cloning and characterization of mammalian telomerase components have paved the way for a more detailed understanding of the role of telomerase and telomere length maintenance in cell proliferation. Here, we summarize the most recent biochemical and genetic evidence suggesting that telomere length maintenance by telomerase is critical to the proliferative ability of some immortalized mammalian cells in culture and in vivo.},
}
@article {pmid10687276,
year = {1999},
author = {Sen, S and Dasgupta, A and Roychudhuri, A and Mittra, B and Majumder, HK},
title = {Telomere, telomerase, tumorigenesis and therapy: an overview.},
journal = {Indian journal of experimental biology},
volume = {37},
number = {9},
pages = {839-842},
pmid = {10687276},
issn = {0019-5189},
mesh = {*Cell Transformation, Neoplastic/genetics ; Neoplasms/enzymology/genetics/*therapy ; Telomerase/*metabolism ; *Telomere ; },
abstract = {The ends of chromosome in higher eukaryote are termed telomere. The DNAs present at that part of chromosome is called telomeric DNA. Telomeric DNA consists of tandemly repeated DNA sequences. The replication of the ends of chromosomes is not controlled by conventional DNA polymerases rather a special kind of enzyme is involved in this process. It is a ribonucleoprotein and known as telomerase. Cells in senescence stage face telomeric crisis that leads to loss of telomeric ends. Surveillance turns to procancer cells with increased telomerase activity which is a later consequence. Based on these facts a key diagnostic approach has been developed for detection of tumour. A novel therapy for tumour repression has been developed using telomerase inhibitors. However, these inhibitors are very much effective for solid tumour therapy and conceptually will not work on hematological malignancies.},
}
@article {pmid10686132,
year = {2000},
author = {Takata, H and Fukuda, K and Meinhardt, F and Gunge, N},
title = {Telomere sequences attached to nuclearly migrated yeast linear plasmid.},
journal = {Plasmid},
volume = {43},
number = {2},
pages = {137-143},
doi = {10.1006/plas.1999.1454},
pmid = {10686132},
issn = {0147-619X},
mesh = {Base Sequence ; Cell Nucleus/chemistry/*genetics ; Consensus Sequence ; DNA, Fungal/*genetics/isolation &amp; purification ; DNA-Binding Proteins/deficiency/genetics ; Molecular Sequence Data ; Plasmids/chemistry/*isolation &amp; purification ; Rad52 DNA Repair and Recombination Protein ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins ; Sequence Alignment ; Sequence Analysis, DNA ; Telomere/chemistry/*genetics ; },
abstract = {The yeast linear plasmid pCLU1, derived from pGKL1, has terminal proteins (TPs) covalently attached at the 5' ends of inverted terminal repeats (ITRs) and replicates in the cytoplasm, presumably using the TP as a primer for DNA synthesis. In Saccharomyces cerevisiae, under certain conditions, pCLU1 migrated into the nucleus and replicated in either linear or circular form. The linear-form plasmid lacked TPs; instead it carried host-telomere repeats at the ITR ends. The present study showed that (1) the added telomere was primarily composed of the repeated tracts of TGTGTGGGTGTGG, which was complementary to the RNA template of yeast telomerase, (2) the telomeric addition occurred at the very end of the ITRs, and (3) the sequence composition of the added telomeres was diverse among individual plasmids, but symmetrically identical at both ends of each plasmid. A similar mode of telomere addition was also observed in cells defective in the RAD52 gene.},
}
@article {pmid10683151,
year = {2000},
author = {Bass, HW and Riera-Lizarazu, O and Ananiev, EV and Bordoli, SJ and Rines, HW and Phillips, RL and Sedat, JW and Agard, DA and Cande, WZ},
title = {Evidence for the coincident initiation of homolog pairing and synapsis during the telomere-clustering (bouquet) stage of meiotic prophase.},
journal = {Journal of cell science},
volume = {113 (Pt 6)},
number = {},
pages = {1033-1042},
doi = {10.1242/jcs.113.6.1033},
pmid = {10683151},
issn = {0021-9533},
support = {R01-GM-25101-16/GM/NIGMS NIH HHS/United States ; R01-GM-48547/GM/NIGMS NIH HHS/United States ; },
mesh = {Avena ; Base Pairing ; In Situ Hybridization, Fluorescence ; *Meiosis ; *Telomere/ultrastructure ; Zea mays ; },
abstract = {To improve knowledge of the prerequisites for meiotic chromosome segregation in higher eukaryotes, we analyzed the spatial distribution of a pair of homologs before and during early meiotic prophase. Three-dimensional images of fluorescence in situ hybridization (FISH) were used to localize a single pair of homologs in diploid nuclei of a chromosome-addition line of oat, oat-maize9b. The system provided a robust assay for pairing based on cytological colocalization of FISH signals. Using a triple labeling scheme for simultaneous imaging of chromatin, telomeres and the homolog pair, we determined the timing of pairing in relation to the onset of three sequential hallmarks of early meiotic prophase: chromatin condensation (the leptotene stage), meiotic telomere clustering (the bouquet stage) and the initiation of synapsis (the zygotene stage). We found that the two homologs were mostly unpaired up through middle leptotene, at which point their spherical cloud-like domains began to transform into elongated and stretched-out domains. At late leptotene, the homologs had completely reorganized into long extended fibers, and the beginning of the bouquet stage was conspicuously marked by the de novo clustering of telomeres at the nuclear periphery. The homologs paired and synapsed during the bouquet stage, consistent with the timing of pairing observed for several oat 5S rDNA loci. In summary, results from analysis of more than 100 intact nuclei lead us to conclude that pairing and synapsis of homologous chromosomes are largely coincident processes, ruling out a role for premeiotic pairing in this system. These findings suggest that the genome-wide remodeling of chromatin and telomere-mediated nuclear reorganization are prerequisite steps to the DNA sequence-based homology-search process in higher eukaryotes.},
}
@article {pmid10682672,
year = {2000},
author = {Remes, K and Norrback, KF and Rosenquist, R and Mehle, C and Lindh, J and Roos, G},
title = {Telomere length and telomerase activity in malignant lymphomas at diagnosis and relapse.},
journal = {British journal of cancer},
volume = {82},
number = {3},
pages = {601-607},
pmid = {10682672},
issn = {0007-0920},
mesh = {Humans ; Lymphoma/enzymology/*genetics/pathology ; Recurrence ; Telomerase/*metabolism ; *Telomere ; },
abstract = {Telomere length maintenance, in the vast majority of cases executed by telomerase, is a prerequisite for long-term proliferation. Most malignant tumours, including lymphomas, are telomerase-positive and this activity is a potential target for future therapeutic interventions since inhibition of telomerase has been shown to result in telomere shortening and cell death in vitro. One prerequisite for the suitability of anti-telomerase drugs in treating cancer is that tumours exhibit shortened telomeres compared to telomerase-positive stem cells. A scenario is envisioned where the tumour burden is reduced using conventional therapy whereafter remaining tumour cells are treated with telomerase inhibitors. In evaluating the realism of such an approach it is essential to know the effects on telomere status by traditional therapeutic regimens. We have studied the telomere lengths in 47 diagnostic lymphomas and a significant telomere shortening was observed compared to benign lymphoid tissues. In addition, telomere length and telomerase activity were studied in consecutive samples from patients with relapsing non-Hodgkin's lymphomas. Shortened, unchanged and elongated telomere lengths were observed in the relapse samples. The telomere length alterations found in the relapsing lymphomas appeared to be independent of telomerase and rather represented clonal selection random at the telomere length level. These data indicate that anti-telomerase therapy would be suitable in only a fraction of malignant lymphomas.},
}
@article {pmid10679392,
year = {2000},
author = {Artandi, SE and DePinho, RA},
title = {A critical role for telomeres in suppressing and facilitating carcinogenesis.},
journal = {Current opinion in genetics &amp; development},
volume = {10},
number = {1},
pages = {39-46},
doi = {10.1016/s0959-437x(99)00047-7},
pmid = {10679392},
issn = {0959-437X},
support = {R01EY11267/EY/NEI NIH HHS/United States ; R01HD28317/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Catalytic Domain ; Cell Division/physiology ; Cellular Senescence/physiology ; DNA-Binding Proteins ; Humans ; Mice ; Neoplasms/*genetics/pathology ; *RNA ; Telomerase/metabolism ; Telomere/*physiology ; },
abstract = {Progressive telomere shortening occurs with the division of primary human cells and activates tumor suppressor pathways, triggering senescence and inhibiting tumorigenesis. Loss of p53 function, however, allows continued cell division despite increasing telomere dysfunction and entry into telomere crisis. Recent data suggest that the severe chromosomal instability of telomere crisis promotes secondary genetic changes that facilitate carcinogenesis. Reactivation of telomerase stabilizes telomere ends and allows continued tumor growth.},
}
@article {pmid10676644,
year = {2000},
author = {Engelhardt, M and Mackenzie, K and Drullinsky, P and Silver, RT and Moore, MA},
title = {Telomerase activity and telomere length in acute and chronic leukemia, pre- and post-ex vivo culture.},
journal = {Cancer research},
volume = {60},
number = {3},
pages = {610-617},
pmid = {10676644},
issn = {0008-5472},
support = {U9 CA 67842-01/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antigens, CD34/analysis ; Female ; Hematopoietic Stem Cells/enzymology ; Humans ; Leukemia/drug therapy/*genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics ; Leukemia, Myeloid, Acute/genetics ; Male ; Middle Aged ; Telomerase/*metabolism ; *Telomere ; Tumor Cells, Cultured ; },
abstract = {We studied telomerase regulation and telomere length in hematopoietic progenitor cells from peripheral blood and bone marrow from patients with acute and chronic leukemia and myeloproliferative diseases. CD34+ cells from a total of 93 patients with either acute myeloid leukemia (AML; n = 25), chronic myeloid leukemia (CML; n = 21), chronic lymphocytic leukemia (CLL; n = 18), polycythemia vera (PV; n = 16), or myelodysplastic syndromes (MDS; n = 13) were analyzed before and in 19 patients after ex vivo expansion in the presence of multiple cytokines (kit ligand, interleukin-3, interleukin-6, and granulocyte colony-stimulating factor plus erythropoietin). Compared with hematopoietic progenitor cells from normal donors (n = 108), telomerase activity (TA) was increased 2- to 5-fold in chronic phase (CP)-CML, CLL, PV, and MDS. In AML, accelerated phase (AP) and blastic phase (BP)-CML, basal TA was 10- to 50-fold higher than normal. TA of CP-CML CD34+ cells was up-regulated within 72 h of ex vivo culture, peaked after 1 week, and decreased below detection after 2 weeks. In contrast, TA in AP/BP-CML and AML CD34+ cells was down-regulated after 1 week of culture and decreased further thereafter. The expansion potential of CD34+ cells from patients with leukemia was considerably decreased compared with CD34+ cells from normal donors. The average expansion of cells from leukemic individuals was 6.5-, 2.3-, 0.6-, and 0.2-fold in weeks 1, 2, 3, and 4, respectively, whereas expansion of normal cells was 5- to 15-fold higher. In serial expansion culture, a median telomeric loss of 0.7 kbp was observed during 3-4 weeks of expansion. Our results demonstrate that up-regulation of telomerase is similar in CD34+ cells from CP-CML, CLL, PV, and MDS patients and in normal hematopoietic cells during the first week of culture, whereas in AML and AP/BP-CML, telomerase is high at baseline and down-regulated during expansion culture. High levels of telomerase in leukemic progenitors at baseline may be a feature of both the malignant phenotype and rapid cycling. Telomerase down-regulation during culture of leukemic cells may be due to the decreased expansion potential or repression of normal hematopoiesis, or in AML it may be due to the partial differentiation of AML cells, shown previously to be associated with loss of TA. Telomere shortening during ex vivo expansion correlated with low levels of TA, particularly in chronic leukemic and MDS progenitors where telomerase was insufficient to protect against telomere bp loss during intense proliferation.},
}
@article {pmid10675559,
year = {2000},
author = {Fulnecková, J and Fajkus, J},
title = {Inhibition of plant telomerase by telomere-binding proteins from nuclei of telomerase-negative tissues.},
journal = {FEBS letters},
volume = {467},
number = {2-3},
pages = {305-310},
doi = {10.1016/s0014-5793(00)01178-9},
pmid = {10675559},
issn = {0014-5793},
mesh = {Cell Nucleus/metabolism ; DNA-Binding Proteins/*pharmacology ; Plant Extracts/pharmacology ; Plants/*enzymology/ultrastructure ; Plants, Toxic ; Substrate Specificity ; Telomerase/*antagonists &amp; inhibitors ; Nicotiana ; },
abstract = {The activity of telomerase in plant cells is precisely regulated in response to changes in cell division rate. To explore this regulatory mechanism, the effect on telomerase activity of protein extracts from nuclei of telomerase-negative tissues was examined. An inhibition of telomerase activity was found which was species-non-specific. This inhibition was due to proteins which form salt-stable, sequence-specific complexes with the G-rich telomeric strand and reduce its accessibility, as shown by gel retardation and by terminal transferase (TdT) extension of G-rich telomeric and non-telomeric (substrate) primers. A 40 kDa polypeptide was detected by SDS-PAGE after cross-linking the complex formed by extracts from tobacco leaf nuclei. Such proteins may be involved in regulation of telomerase activity in plants.},
}
@article {pmid10675040,
year = {2000},
author = {Mann, KL and Huxley, C},
title = {Investigation of Schizosaccharomyces pombe as a cloning host for human telomere and alphoid DNA.},
journal = {Gene},
volume = {241},
number = {2},
pages = {275-285},
doi = {10.1016/s0378-1119(99)00482-5},
pmid = {10675040},
issn = {0378-1119},
mesh = {Base Sequence ; Cloning, Molecular/*methods ; DNA ; *DNA, Satellite ; Humans ; Integrases ; Molecular Sequence Data ; Schizosaccharomyces/*genetics ; *Telomere ; *Viral Proteins ; },
abstract = {The fission yeast Schizosaccharomyces pombe (Sch. pombe) has been proposed as a possible cloning host for both mammalian artificial chromosomes (MACs) and mammalian genomic libraries, due to the large size of its chromosomes and its similarity to higher eukaryotic cells. Here, it was investigated for its ability to form telomeres from human telomere sequence and to stably maintain long stretches of alphoid DNA. Using linear constructs terminating in the telomere repeat, T2AG3, human telomere DNA was shown to efficiently seed telomere formation in Sch. pombe. Much of the human telomeric sequence was removed on addition of Sch. pombe telomeric sequence, a process similar to that described in S. cerevisiae. To investigate the stability of alphoid DNA in fission yeast, bacterial artificial chromosomes (BACs) containing 130 and 173 kb of alphoid DNA were retrofitted with the Sch. pombe ars1 element and ura4+ marker using Cre-lox recombination. These alphoid BACs were found to be highly unstable in Sch. pombe deleting down to less than 40 kb, whilst control BACs of 96 and 202 kb, containing non-repetitive DNA, were unrearranged. Alphoid DNA has been shown to be sufficient for human centromere function, and this marked instability excludes Sch. pombe as a useful cloning host for mammalian artificial chromosomes. In addition, regions containing repetitive DNA from mammalian genomes may not be truly represented in libraries constructed in Sch. pombe.},
}
@article {pmid11607583,
year = {1995},
author = {Kilian, A and Stiff, C and Kleinhofs, A},
title = {Barley telomeres shorten during differentiation but grow in callus culture.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {92},
number = {21},
pages = {9555-9559},
pmid = {11607583},
issn = {0027-8424},
abstract = {Eukaryotic chromosomes terminate with long stretches of short, guanine-rich repeats. These repeats are added de novo by a specialized enzyme, telomerase. In humans telomeres shorten during differentiation, presumably due to the absence of telomerase activity in somatic cells. This phenomenon forms the basis for several models of telomere role in cellular senescence. Barley (Hordeum vulgare L.) telomeres consist of thousands of TTTAGGG repeats, closely resembling other higher eukaryotes. In vivo differentiation and aging resulted in reduction of terminal restriction fragment length paralleled by a decrease of telomere repeat number. Dedifferentiation in callus culture resulted in an increase of the terminal restriction fragment length and in the number of telomere repeats. Long-term callus cultures had very long telomeres. Absolute telomere lengths were genotype dependent, but the relative changes due to differentiation, dedifferentiation, and long-term callus culture were consistent among genotypes. A model is presented to describe the potential role of the telomere length in regulation of a cell's mitotic activity and senescence.},
}
@article {pmid14732086,
year = {1995},
author = {Wright, WE and Shay, JW},
title = {Time, telomeres and tumours: is cellular senescence more than an anticancer mechanism?.},
journal = {Trends in cell biology},
volume = {5},
number = {8},
pages = {293-297},
doi = {10.1016/s0962-8924(00)89044-3},
pmid = {14732086},
issn = {0962-8924},
abstract = {Normal diploid cells, by definition, have a limited life span: they senesce after a set number of divisions both in vivo and in culture. It has been hypothesized that the molecular mechanism that measures the life span of a cell probably involves the shortening of telomeres that occurs with each round of DNA replication. This loss of telomeres is thought to induce antiproliferative signals that result in the induction of cellular senescence. In this article, Woodring Wright and Jerry Shay present a hypothesis for the mechanisms by which telomere shortening regulates cellular physiology and argue that cellular senescence is not only an anticancer mechanism but is also the cause of many of the degenerative changes of aging.},
}
@article {pmid14731767,
year = {1993},
author = {Gilson, E and Laroche, T and Gasser, SM},
title = {Telomeres and the functional architecture of the nucleus.},
journal = {Trends in cell biology},
volume = {3},
number = {4},
pages = {128-134},
doi = {10.1016/0962-8924(93)90175-z},
pmid = {14731767},
issn = {0962-8924},
abstract = {The single molecule of DNA that constitutes a eukaryotic chromosome begins and ends with a stretch of repetitive DNA known as a telomere. These sequences appear to be necessary to preserve the integrity of the genetic material through the cell cycle. Telomeric DNA is organized into regions of non-nucleosomal chromatin called the telosome, which can interact with other telosomes and with the nuclear envelope. This review focuses on cytological evidence for these interactions and on recent insights into the molecular organization of the telomeric complex.},
}
@article {pmid14046257,
year = {1963},
author = {HSU, TC},
title = {LONGITUDINAL DIFFERENTIATION OF CHROMOSOMES AND THE POSSIBILITY OF INTERSTITIAL TELOMERES.},
journal = {Experimental cell research},
volume = {24},
number = {},
pages = {SUPPL9:73-85},
doi = {10.1016/0014-4827(63)90246-5},
pmid = {14046257},
issn = {0014-4827},
mesh = {*Cell Differentiation ; *Chromosomes ; Cricetinae ; *Radiation Genetics ; *Research ; *Telomere ; },
}
@article {pmid14779002,
year = {1950},
author = {WARTERS, M and GRIFFEN, AB},
title = {The telomeres of Drosophila.},
journal = {The Journal of heredity},
volume = {41},
number = {7},
pages = {182-190},
pmid = {14779002},
issn = {0022-1503},
mesh = {Animals ; *Chromosomes ; *Drosophila ; *Telomere ; },
}
@article {pmid10669743,
year = {2000},
author = {Smogorzewska, A and van Steensel, B and Bianchi, A and Oelmann, S and Schaefer, MR and Schnapp, G and de Lange, T},
title = {Control of human telomere length by TRF1 and TRF2.},
journal = {Molecular and cellular biology},
volume = {20},
number = {5},
pages = {1659-1668},
pmid = {10669743},
issn = {0270-7306},
support = {R01 CA076027/CA/NCI NIH HHS/United States ; T32 GM007739/GM/NIGMS NIH HHS/United States ; CA76027/CA/NCI NIH HHS/United States ; GM07739/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line ; DNA-Binding Proteins/*genetics ; Gene Expression Regulation ; Humans ; Nuclear Proteins/genetics ; Telomere/*genetics/*ultrastructure ; Telomeric Repeat Binding Protein 1 ; Telomeric Repeat Binding Protein 2 ; },
abstract = {Telomere length in human cells is controlled by a homeostasis mechanism that involves telomerase and the negative regulator of telomere length, TRF1 (TTAGGG repeat binding factor 1). Here we report that TRF2, a TRF1-related protein previously implicated in protection of chromosome ends, is a second negative regulator of telomere length. Overexpression of TRF2 results in the progressive shortening of telomere length, similar to the phenotype observed with TRF1. However, while induction of TRF1 could be maintained over more than 300 population doublings and resulted in stable, short telomeres, the expression of exogenous TRF2 was extinguished and the telomeres eventually regained their original length. Consistent with their role in measuring telomere length, indirect immunofluorescence indicated that both TRF1 and TRF2 bind to duplex telomeric DNA in vivo and are more abundant on telomeres with long TTAGGG repeat tracts. Neither TRF1 nor TRF2 affected the expression level of telomerase. Furthermore, the presence of TRF1 or TRF2 on a short linear telomerase substrate did not inhibit the enzymatic activity of telomerase in vitro. These findings are consistent with the recently proposed t loop model of telomere length homeostasis in which telomerase-dependent telomere elongation is blocked by sequestration of the 3' telomere terminus in TRF1- and TRF2-induced telomeric loops.},
}
@article {pmid10666338,
year = {2000},
author = {Ishii, K and Yang, WL and Cvijic, ME and Kikuchi, Y and Nagata, I and Chin, KV},
title = {Telomere shortening by cisplatin in yeast nucleotide excision repair mutant.},
journal = {Experimental cell research},
volume = {255},
number = {1},
pages = {95-101},
doi = {10.1006/excr.1999.4777},
pmid = {10666338},
issn = {0014-4827},
support = {CA67722/CA/NCI NIH HHS/United States ; },
mesh = {Cell Survival ; Cisplatin/*pharmacology ; DNA Damage ; DNA Helicases/metabolism ; DNA Repair ; DNA, Fungal/*drug effects ; Fungal Proteins/metabolism ; Saccharomyces cerevisiae/*drug effects/genetics/metabolism ; *Saccharomyces cerevisiae Proteins ; Telomere/*drug effects ; Transcription Factor TFIIH ; },
abstract = {Telomeres are unique DNA tandem repeats that form the ends of eukaryotic chromosomes to protect the chromosomes from degradation and illegitimate recombination. In yeast, loss of telomere may be compensated for through the acquisition of new telomere by RAD52-mediated or RAD52-independent recombinational repair. In this report, the effects of cis-dichlorodiammine-platinum (II) (cisplatin) on telomere length and the role of nucleotide excision repair in telomere maintenance were examined in the yeast Saccharomyces cerevisiae. We showed that the SSL2 (RAD25) DNA repair yeast mutant exhibited a gradual shortening of the telomere in the presence of cisplatin. Further telomere shortening was prevented upon the withdrawal of cisplatin. Complementation of the mutant with the wild-type SSL2 (RAD25) gene abolished the cisplatin-induced telomere degradation. These results suggest that telomeres are susceptible to cisplatin-induced intrastrand crosslinks and that Ssl2 (Rad25) or the nucleotide excision repair pathway may play a critical role in the repair and the maintenance of telomere integrity.},
}
@article {pmid10660126,
year = {2000},
author = {Smith, KJ and Germain, M and Skelton, H},
title = {Perspectives in dermatopathology: telomeres and telomerase in ageing and cancer; with emphasis on cutaneous disease.},
journal = {Journal of cutaneous pathology},
volume = {27},
number = {1},
pages = {2-18},
doi = {10.1034/j.1600-0560.2000.027001002.x},
pmid = {10660126},
issn = {0303-6987},
mesh = {Aging/genetics/metabolism/*pathology ; Dermis/enzymology/*pathology ; Humans ; Skin Neoplasms/metabolism/*pathology ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism/pathology ; },
abstract = {Shortening of telomeres occurs with cell proliferation and correlates well with ageing in humans. Telomerase is a ribonucleoprotein, and is the body's most widely studied mechanism for extension of telomeres to circumvent cellular ageing. Telomerase levels remain at low or unmeasurable levels in most somatic cell populations with only a few exceptions. However, in transformed cell populations, upregulation of telomerase or some other mechanism for telomere extension is required for immortality. The telomere-telomerase system has been proposed to be an adaptation of organisms with prolonged lifespan to avoid malignant tumors, at the cost of the cellular dysfunctions associated with the aged phenotype. Therapies to modulate telomere length and telomerase levels hold promise for therapy of cancer and ageing as well as for genetic conditions that predispose to an aged phenotype.},
}
@article {pmid10656292,
year = {2000},
author = {von Zglinicki, T and Pilger, R and Sitte, N},
title = {Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts.},
journal = {Free radical biology &amp; medicine},
volume = {28},
number = {1},
pages = {64-74},
doi = {10.1016/s0891-5849(99)00207-5},
pmid = {10656292},
issn = {0891-5849},
mesh = {Alkylation ; Cell Cycle ; Cells, Cultured ; Cellular Senescence/*physiology ; *DNA Damage ; DNA Replication ; DNA, Single-Stranded/*metabolism ; Fibroblasts/drug effects/metabolism/*ultrastructure ; Humans ; Hydrogen Peroxide/*toxicity ; Oxidants/*toxicity ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Spin Labels ; Telomere/metabolism/*ultrastructure ; },
abstract = {Telomere shortening triggers replicative senescence in human fibroblasts. The inability of DNA polymerases to replicate a linear DNA molecule completely (the end replication problem) is one cause of telomere shortening. Other possible causes are the formation of single-stranded overhangs at the end of telomeres and the preferential vulnerability of telomeres to oxidative stress. To elucidate the relative importance of these possibilities, amount and distribution of telomeric single-strand breaks, length of the G-rich overhang, and telomere shortening rate in human MRC-5 fibroblasts were measured. Treatment of nonproliferating cells with hydrogen peroxide increases the sensitivity to S1 nuclease in telomeres preferentially and accelerates their shortening by a corresponding amount as soon as the cells proliferate. A reduction of the activity of intracellular peroxides using the spin trap alpha-phenyl-t-butyl-nitrone reduces the telomere shortening rate and increases the replicative life span. The length of the telomeric single-stranded overhang is independent of DNA damaging stresses, but single-strand breaks accumulate randomly all along the telomere after alkylation. The telomere shortening rate and the rate of replicative aging can be either accelerated or decelerated by a modification of the amount of oxidative stress. Quantitatively, stress-mediated telomere damage contributes most to telomere shortening under standard conditions.},
}
@article {pmid10655213,
year = {2000},
author = {Park, Y and Lustig, AJ},
title = {Telomere structure regulates the heritability of repressed subtelomeric chromatin in Saccharomyces cerevisiae.},
journal = {Genetics},
volume = {154},
number = {2},
pages = {587-598},
pmid = {10655213},
issn = {0016-6731},
mesh = {Chromatin/*genetics ; Saccharomyces cerevisiae/*genetics ; *Telomere ; Transcription, Genetic ; },
abstract = {Telomeres, the protein-DNA structures present at the termini of linear chromosomes, are capable of conferring a reversible repression of Pol II- and Pol III-transcribed genes positioned in adjacent subtelomeric regions. This phenomenon, termed telomeric silencing, is likely to be the consequence of a more global telomere position effect at the level of chromatin structure. To understand the role of telomere structure in this position effect, we have developed an assay to distinguish between the heritability of transcriptionally repressed and derepressed states in yeast. We have previously demonstrated that an elongated telomeric tract leads to hyperrepression of telomere-adjacent genes. We show here that the predominant effect of elongated telomeres is to increase the inheritance of the repressed state in cis. Interestingly, the presence of elongated telomeres overcomes the partial requirement of yCAF-1 in silencing. We propose that the formation of a specific telomeric structure is necessary for the heritability of repressed subtelomeric chromatin.},
}
@article {pmid10654945,
year = {2000},
author = {Herrera, E and Martínez-A, C and Blasco, MA},
title = {Impaired germinal center reaction in mice with short telomeres.},
journal = {The EMBO journal},
volume = {19},
number = {3},
pages = {472-481},
pmid = {10654945},
issn = {0261-4189},
mesh = {Animals ; Apoptosis/immunology ; B-Lymphocytes/*metabolism ; Cell Cycle ; Chromosomes ; Flow Cytometry ; Germinal Center/enzymology/*metabolism ; Histocytochemistry ; Immunization ; In Situ Hybridization, Fluorescence ; Lipopolysaccharides/pharmacology ; Mice ; Mice, Knockout ; Mitogens/pharmacology ; Spleen/enzymology/immunology ; Telomerase/*genetics ; Telomere/immunology/*metabolism ; },
abstract = {Reduction of germinal center reactivity is a landmark of immunosenescence and contributes to immunological dysfunction in the elderly. Germinal centers (GC) are characterized by extensive clonal expansion and selection of B lymphocytes to generate the pool of memory B cells. Telomere maintenance by telomerase has been proposed to allow the extensive proliferation undergone by B lymphocytes in the GC during the immune response. We show here that late generation mTR(-/-) mice, which lack the mouse telomerase RNA (mTR) and have short telomeres, present a dramatic reduction in GC number following antigen immunization. Upon immunization with an antigen, wild-type splenocyte telomeres are elongated and this is accompanied by a high expression of the telomerase catalytic subunit in the spleen GC. In contrast, telomerase-deficient mTR(-/-) splenocytes show telomere shortening after immunization, presumably due to cell proliferation in the absence of telomerase. All together, these results demonstrate the importance of telomere maintenance for antibody-mediated immune responses and support the notion that telomere elongation detected in wild-type spleens following immunization is mediated by telomerase.},
}
@article {pmid10652127,
year = {1999},
author = {Tremousaygue, D and Manevski, A and Bardet, C and Lescure, N and Lescure, B},
title = {Plant interstitial telomere motifs participate in the control of gene expression in root meristems.},
journal = {The Plant journal : for cell and molecular biology},
volume = {20},
number = {5},
pages = {553-561},
doi = {10.1046/j.1365-313x.1999.00627.x},
pmid = {10652127},
issn = {0960-7412},
mesh = {Amino Acid Sequence ; Animals ; Arabidopsis/*genetics/physiology ; Chromosomes/genetics ; Drosophila/genetics ; *Gene Expression Regulation, Plant ; Glucuronidase/chemistry/*genetics/metabolism ; Humans ; Meristem/physiology ; Molecular Sequence Data ; Plant Roots/physiology ; Plants, Genetically Modified ; Promoter Regions, Genetic ; Sequence Alignment ; Sequence Homology, Amino Acid ; Telomere/*genetics ; },
abstract = {The promoters of Arabidopsis eEF1A genes contain a telomere motif, the telo-box, associated with an activating sequence, the tef-box. Database searches indicated the presence of telo-boxes in the 5' region of numerous genes encoding components of the translational apparatus. By using several promoter constructs we demonstrate that the telo-box is required for the expression of a beta-glucoronidase gene in root primordia of transgenic Arabidopsis. This effect was observed when a telo-box was inserted upstream or downstream from the transcription initiation site, and occurred in synergy with the tef-box. These results clearly indicate that interstitial telomere motifs in plants are involved in control of gene expression. South-western screening of a lambdaZAP library with a double-stranded Arabidopsis telomere motif resulted in characterization of a protein related to the conserved animal protein Puralpha. The possibility of a regulation process similar to that achieved by the Rap1p in Saccharomyces cerevisiae is discussed.},
}
@article {pmid10649348,
year = {2000},
author = {Cech, TR},
title = {Life at the End of the Chromosome: Telomeres and Telomerase.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {39},
number = {1},
pages = {34-43},
doi = {10.1002/(sici)1521-3773(20000103)39:1&lt;34::aid-anie34&gt;3.0.co;2-n},
pmid = {10649348},
issn = {1521-3773},
abstract = {Telomerase, the enzyme that replicates the ends of linear chromosomes, is implicated in cellular aging and in cancer. The molecular components that form the catalytic core of this ribonucleoprotein enzyme (a section of the active site with bound substrates is depicted) have recently been identified in multiple organisms, including humans. The stage is now set for chemists to develop telomerase inhibitors, which hold promise as cancer chemotherapeutic agents.},
}
@article {pmid10648922,
year = {2000},
author = {Cerni, C},
title = {Telomeres, telomerase, and myc. An update.},
journal = {Mutation research},
volume = {462},
number = {1},
pages = {31-47},
doi = {10.1016/s1383-5742(99)00091-5},
pmid = {10648922},
issn = {0027-5107},
mesh = {Animals ; Catalytic Domain ; Cell Division/genetics ; Cell Transformation, Neoplastic/genetics ; Cellular Senescence/*genetics ; DNA-Binding Proteins ; Genes, myc/*genetics ; Humans ; Mice ; Mice, Knockout ; RNA/metabolism ; Telomerase/*genetics/*metabolism ; Telomere/*genetics/metabolism ; },
abstract = {Normal human somatic cells have a finite life span in vivo as well as in vitro and retire into senescence after a predictable time. Cellular senescence is triggered by the activation of two interdependent mechanisms. One induces irreversible cell cycle exit involving activation of two tumorsuppressor genes, p53 and pRb, and the proper time point is indicated by a critical shortening of chromosomal ends due to the end-replication problem of DNA synthesis. The development of a malignant cancer cell is only possible when both mechanisms are circumvented. The majority of human cancers and tumor cell lines produce telomerase, a ribonucleoprotein with two components required for core enzyme activity: telomerase RNA (TR) and a telomerase reverse transcriptase protein (TERT). Telomerase adds hexameric DNA repeats (TTAGGG) to telomeric ends and thus compensates the progressive loss of telomeric sequences inherent to DNA replication. While TR of telomerase is present in almost all human cells, human TERT (hTERT) was found rate limiting for telomerase activity. Ectopic expression of hTERT in otherwise mortal human cells induced efficient elongation of telomeres and permanent cell growth. While hTERT-mediated immortalization seems to have no effect on growth potential and cell cycle check points, it bestows an increased susceptibility to experimental transformation. One oncogene that might activate TERT in the natural context is c-myc. Myc genes are frequently deregulated in human tumors and myc overexpression may cause telomerase reactivation and telomere stabilization which, in turn, would allow permanent proliferation. Is this a general strategy of incipient cancer cells to escape senescence? Several recent observations indicate that other scenarios may be conceived as well.},
}
@article {pmid10646593,
year = {2000},
author = {Ahmed, S and Hodgkin, J},
title = {MRT-2 checkpoint protein is required for germline immortality and telomere replication in C. elegans.},
journal = {Nature},
volume = {403},
number = {6766},
pages = {159-164},
doi = {10.1038/35003120},
pmid = {10646593},
issn = {0028-0836},
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Caenorhabditis elegans ; *Caenorhabditis elegans Proteins ; Cell Survival ; DNA Damage ; DNA Replication ; DNA, Helminth/biosynthesis/genetics ; Genes, Helminth ; Germ Cells/*physiology ; Helminth Proteins/genetics/*physiology ; Humans ; Molecular Sequence Data ; Mutation ; Sequence Homology, Amino Acid ; *Telomere ; },
abstract = {The germ line is an immortal cell lineage that is passed indefinitely from one generation to the next. To identify the genes that are required for germline immortality, we isolated Caenorhabditis elegans mutants with mortal germ lines--worms that can reproduce for several healthy generations but eventually become sterile. One of these mortal germline (mrt) mutants, mrt-2, exhibits progressive telomere shortening and accumulates end-to-end chromosome fusions in later generations, indicating that the MRT-2 protein is required for telomere replication. In addition, the germ line of mrt-2 is hypersensitive to X-rays and to transposon activity. Therefore, mrt-2 has defects in responding both to damaged DNA and to normal double-strand breaks present at telomeres. mrt-2 encodes a homologue of a checkpoint gene that is required to sense DNA damage in yeast. These results indicate that telomeres may be identified as a type of DNA damage and then repaired by the telomere-replication enzyme telomerase.},
}
@article {pmid10646584,
year = {2000},
author = {Lundblad, V},
title = {Telomeres: a tale of ends.},
journal = {Nature},
volume = {403},
number = {6766},
pages = {149, 151},
doi = {10.1038/35003085},
pmid = {10646584},
issn = {0028-0836},
mesh = {Animals ; Caenorhabditis elegans/*genetics ; DNA Damage ; DNA Replication ; DNA, Helminth/biosynthesis ; Genes, Helminth ; Mutation ; *Telomere ; },
}
@article {pmid10631154,
year = {2000},
author = {Baird, DM and Coleman, J and Rosser, ZH and Royle, NJ},
title = {High levels of sequence polymorphism and linkage disequilibrium at the telomere of 12q: implications for telomere biology and human evolution.},
journal = {American journal of human genetics},
volume = {66},
number = {1},
pages = {235-250},
pmid = {10631154},
issn = {0002-9297},
mesh = {Base Sequence ; *Chromosomes, Human, Pair 12 ; Evolution, Molecular ; Haplotypes ; Humans ; *Linkage Disequilibrium ; Molecular Sequence Data ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Polymorphism, Restriction Fragment Length ; Sequence Analysis, DNA ; *Telomere ; },
abstract = {The human Xp/Yp telomere-junction region exhibits high levels of sequence polymorphism and linkage disequilibrium. To determine whether this is a general feature of human telomeres, we have undertaken sequence analysis at the 12q telomere and have extended the analysis at Xp/Yp. A total of 22 single-nucleotide polymorphisms (SNPs) and one 30-bp duplication were detected in the 1,870 bp adjacent to the 12q telomere. Twenty polymorphic positions were in almost complete linkage disequilibrium, creating three common diverged haplotypes accounting for 80% of 12q telomeres in the white population. A further 6% of 12q telomeres contained a 1,439-bp deletion in the DNA flanking the telomere. The remaining 13% of 12q telomeres did not amplify with the primers used (nulls). The distribution of telomere (TTAGGG) and variant repeats within 12q telomeres was hypervariable, but alleles with similar distribution patterns were associated with the same haplotype in the telomere-adjacent DNA. These data suggest that 12q telomeres, like Xp/Yp telomeres, exhibit low levels of homologous recombination and evolve along haploid lineages. In contrast, high levels of homologous recombination occur in the adjacent proterminal regions of human chromosomes. This suggests that there is a localized telomere-mediated suppression of recombination. In addition, the genetic characteristics of these regions may provide a source of deep lineages for the study of early human evolution, unaffected by both natural selection and recombination. To explain the presence of a few diverged haplotypes adjacent to the Xp/Yp and 12q telomeres, we propose a model that involves the hybridization of two archaic hominoid lineages ultimately giving rise to modern Homo sapiens.},
}
@article {pmid10629035,
year = {2000},
author = {Adams Martin, A and Dionne, I and Wellinger, RJ and Holm, C},
title = {The function of DNA polymerase alpha at telomeric G tails is important for telomere homeostasis.},
journal = {Molecular and cellular biology},
volume = {20},
number = {3},
pages = {786-796},
pmid = {10629035},
issn = {0270-7306},
support = {F31 GM018056/GM/NIGMS NIH HHS/United States ; GM18056/GM/NIGMS NIH HHS/United States ; GM36510/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Cell Cycle ; Chromatin/genetics/ultrastructure ; DNA Polymerase I/genetics/*metabolism ; DNA Primers ; DNA Replication ; Gene Expression Regulation, Fungal ; Gene Silencing ; Genotype ; Homeostasis ; Mating Factor ; Molecular Sequence Data ; Mutagenesis ; Peptides/physiology ; Saccharomyces cerevisiae/cytology/*genetics ; Telomere/*genetics/*ultrastructure ; Temperature ; Transcription, Genetic ; },
abstract = {Telomere length control is influenced by several factors, including telomerase, the components of telomeric chromatin structure, and the conventional replication machinery. Although known components of the replication machinery can influence telomere length equilibrium, little is known about why mutations in certain replication proteins cause dramatic telomere lengthening. To investigate the cause of telomere elongation in cdc17/pol1 (DNA polymerase alpha) mutants, we examined telomeric chromatin, as measured by its ability to repress transcription on telomere-proximal genes, and telomeric DNA end structures in pol1-17 mutants. pol1-17 mutants with elongated telomeres show a dramatic loss of the repression of telomere-proximal genes, or telomeric silencing. In addition, cdc17/pol1 mutants grown under telomere-elongating conditions exhibit significant increases in single-stranded character in telomeric DNA but not at internal sequences. The single strandedness is manifested as a terminal extension of the G-rich strand (G tails) that can occur independently of telomerase, suggesting that cdc17/pol1 mutants exhibit defects in telomeric lagging-strand synthesis. Interestingly, the loss of telomeric silencing and the increase in the sizes of the G tails at the telomeres temporally coincide and occur before any detectable telomere lengthening is observed. Moreover, the G tails observed in cdc17/pol1 mutants incubated at the semipermissive temperature appear only when the cells pass through S phase and are processed by the time cells reach G(1). These results suggest that lagging-strand synthesis is coordinated with telomerase-mediated telomere maintenance to ensure proper telomere length control.},
}
@article {pmid10628870,
year = {1999},
author = {Tsujimoto, H and Usami, N and Hasegawa, K and Yamada, T and Nagaki, K and Sasakuma, T},
title = {De novo synthesis of telomere sequences at the healed breakpoints of wheat deletion chromosomes.},
journal = {Molecular &amp; general genetics : MGG},
volume = {262},
number = {4-5},
pages = {851-856},
doi = {10.1007/s004380051150},
pmid = {10628870},
issn = {0026-8925},
mesh = {Base Sequence ; *Chromosome Aberrations ; Cloning, Molecular ; DNA, Plant ; Molecular Sequence Data ; Polymerase Chain Reaction ; *Telomere ; Triticum/*genetics ; },
abstract = {When chromosomes are broken, the breakpoints become highly unstable and acquire the ability to fuse with other broken ends. The breakpoints are, however, eventually stabilized, and, therefore, the broken chromosomes are transmitted to the daughter cells without further morphological change. This phenomenon, known as "healing of breakpoints", involves the addition of repetitive telomere sequences at the breakpoints by telomerase, the enzyme that normally synthesizes the telomere sequence at normal chromosome terminals. In many higher organisms, however, this property has not been well investigated. In this study, we examined the telomere sequences in wheat deletion lines with breakpoints on chromosome 1B. Lines that had breakpoints around the nucleolar organizer region were first selected on the basis of cytological observations, and the precise breakpoints were determined by mapping a fragment of rDNA and RFLP markers. In three lines - in addition to one previously reported - the DNA fragments encompassing the breakpoints were amplified by PCR using primers located in the rDNA and in telomere sequences. The DNA sequences provide insight into the properties of the telomerase activity at the breakpoints. The telomere sequences initiated from 2- to 4-nucleotide motifs in the original ribosomal DNA sequence which are also found in the repeat unit characteristic of telomere sequences. No specific sequences or structures were observed at or around the breakpoints. At all of the four breakpoints investigated, the newly synthesized telomere sequences contained considerable numbers of atypical telomere sequence units, particularly TTAGGG, which is the common unit of mammalian telomere sequences. Based on these results, we discuss the ability of plant telomerase to initiate the de novo synthesis of telomere sequences at internal breakpoints.},
}
@article {pmid10628844,
year = {1999},
author = {Losada, A and Agudo, M and Abad, JP and Villasante, A},
title = {HeT-A telomere-specific retrotransposons in the centric heterochromatin of Drosophila melanogaster chromosome 3.},
journal = {Molecular &amp; general genetics : MGG},
volume = {262},
number = {4-5},
pages = {618-622},
doi = {10.1007/s004380051124},
pmid = {10628844},
issn = {0026-8925},
mesh = {Animals ; Base Sequence ; *Chromosomes ; Chromosomes, Artificial, Yeast ; DNA Primers ; Drosophila melanogaster/*genetics ; Heterochromatin/*genetics ; In Situ Hybridization, Fluorescence ; *Retroelements ; *Telomere ; },
abstract = {We have isolated two yeast artificial chromosome (YAC) clones from Drosophila melanogaster that contain a small amount of dodeca satellite (a satellite DNA located in the centromeric region of chromosome 3) and sequences homologous to the telomeric retro-transposon HeT-A. Using these YACs as probes for fluorescence in situ hybridization to mitotic chromosomes, we have localized these HeT-A elements to the centric heterochromatin of chromosome 3, at region h55. The possible origin of these telomeric elements in a centromeric position is discussed.},
}
@article {pmid10625928,
year = {1999},
author = {Izbicka, E and Nishioka, D and Marcell, V and Raymond, E and Davidson, KK and Lawrence, RA and Wheelhouse, RT and Hurley, LH and Wu, RS and Von Hoff, DD},
title = {Telomere-interactive agents affect proliferation rates and induce chromosomal destabilization in sea urchin embryos.},
journal = {Anti-cancer drug design},
volume = {14},
number = {4},
pages = {355-365},
pmid = {10625928},
issn = {0266-9536},
support = {CA67760/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Division/drug effects ; Chromosomes/*drug effects ; Enzyme Inhibitors/*pharmacology ; Oligonucleotides, Antisense/pharmacology ; Porphyrins/*pharmacology ; Sea Urchins/*embryology ; Telomerase/*antagonists &amp; inhibitors/metabolism ; Telomere/*drug effects ; Zidovudine/pharmacology ; },
abstract = {Cationic porphyrins, which interact with guanine quadruplex (G4) telomeric folds, inhibit telomerase activity in human tumor cells. In this study, we have further examined effects of porphyrins and other telomere- and telomerase-interactive agents on proliferation rates and chromosome stability in a novel in vivo model, developing sea urchin embryos. We studied two porphyrins: (i) TMPyP4, a potent telomerase inhibitor; and (ii) TMPyP2, an isomer of TMPyP4 and an inefficient telomerase inhibitor, azidothymine (AZT), the reverse transcriptase inhibitor, antisense phosphorothioate oligonucleotide to telomerase RNA (TAG6) and a control scrambled sequence (ODN). TMPyP4, AZT and TAG6 (but not TMPyP2 or ODN) decreased the rates of cell proliferation and increased the percentage of cells trapped in mitosis. Nuclear localization of TAG6, but not of ODN, was demonstrated with 5'-fluoresceinated analogs of TAG6 and ODN. Formation of elongated chromosomes incapable of separating in anaphase, induced by TMPyP4, AZT and TAG6, closely resembled phenotypes resulting from telomerase template mutation or dominant negative TRF2 allele. Our data suggest that G4-interactive agents exert their antiproliferative effects via chromosomal destabilization and warrant their further development as valuable anticancer tools.},
}
@article {pmid10622418,
year = {1999},
author = {Tan, Z},
title = {Telomere shortening and the population size-dependency of life span of human cell culture: further implication for two proliferation-restricting telomeres.},
journal = {Experimental gerontology},
volume = {34},
number = {7},
pages = {831-842},
doi = {10.1016/s0531-5565(99)00056-x},
pmid = {10622418},
issn = {0531-5565},
mesh = {Cell Division ; Cells, Cultured ; Cellular Senescence/*physiology ; Computer Simulation ; Humans ; Models, Statistical ; Telomere/*physiology ; },
abstract = {Cultures of normal human cell can only undergo a finite number of population doublings. The proliferative life span of a culture is affected by population size, i.e., the number of cells a culture maintains. A 1000-fold transient reduction in population size can reduce the life span by as many as eight population doublings. The limited proliferative potential of human cells has been speculated to be a result of telomere shortening that occurs during DNA synthesis at each round of cell division. In this paper, I use computer simulation to test the telomere theory of cell aging against the population size-dependency of life span of human cell culture. It is found that telomere shortening well explains the above phenomenon. In addition, the results suggest that the proliferative potential of human cells might be limited by the shortening of only a few, most likely two, specific telomeres, providing further support to the same conclusion put forward in my previous paper (Tan, 1999).},
}
@article {pmid10619426,
year = {1999},
author = {Diede, SJ and Gottschling, DE},
title = {Telomerase-mediated telomere addition in vivo requires DNA primase and DNA polymerases alpha and delta.},
journal = {Cell},
volume = {99},
number = {7},
pages = {723-733},
doi = {10.1016/s0092-8674(00)81670-0},
pmid = {10619426},
issn = {0092-8674},
support = {GM07281/GM/NIGMS NIH HHS/United States ; GM43893/GM/NIGMS NIH HHS/United States ; },
mesh = {Carrier Proteins/metabolism ; Cell Cycle/physiology ; Cyclin B/metabolism ; DNA Polymerase I/*metabolism ; DNA Polymerase III/*metabolism ; DNA Primase/*metabolism ; Nocodazole/pharmacology ; Saccharomyces cerevisiae/*metabolism ; *Saccharomyces cerevisiae Proteins ; Tandem Repeat Sequences ; Telomerase/*metabolism ; Telomere/metabolism ; Telomere-Binding Proteins ; },
abstract = {To better understand the requirements for telomerase-mediated telomere addition in vivo, we developed an assay in S. cerevisiae that creates a chromosome end immediately adjacent to a short telomeric DNA tract. The de novo end acts as a telomere: it is protected from degradation in a CDC13-dependent manner, telomeric sequences are added efficiently, and addition occurs at a faster rate in mutant strains that have long telomeres. Telomere addition was detected in M phase arrested cells, which permitted us to determine that the essential DNA polymerases alpha and delta and DNA primase were required. This indicates that telomeric DNA synthesis by telomerase is tightly coregulated with the production of the opposite strand. Such coordination prevents telomerase from generating excessively long single-stranded tails, which may be deleterious to chromosome stability in S. cerevisiae.},
}
@article {pmid10619370,
year = {1999},
author = {Bruunsgaard, H and Jensen, MS and Schjerling, P and Halkjaer-Kristensen, J and Ogawa, K and Skinhøj, P and Pedersen, BK},
title = {Exercise induces recruitment of lymphocytes with an activated phenotype and short telomeres in young and elderly humans.},
journal = {Life sciences},
volume = {65},
number = {24},
pages = {2623-2633},
doi = {10.1016/s0024-3205(99)00531-7},
pmid = {10619370},
issn = {0024-3205},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*immunology/*physiology ; CD28 Antigens/biosynthesis/immunology ; *CD4-CD8 Ratio ; Catecholamines/blood ; Female ; Heart Rate/immunology ; Humans ; Immunophenotyping ; Leukocytes, Mononuclear/immunology ; Lymphocyte Activation/*physiology ; Male ; Oxygen Consumption/immunology ; *Physical Exertion ; T-Lymphocyte Subsets/chemistry/immunology/*physiology ; Telomere/*chemistry ; },
abstract = {This study was performed in order to investigate the type of T cells recruited to the blood in response to an acute bout of exercise with regard to mean lengths of telomeric terminal restriction fragments (TRF) and surface activation markers and with special emphasis on age-associated differences. Ten elderly and ten young humans performed maximal bicycle exercise. There was no difference in the number of recruited CD4+ and CD8+ cells between the young and elderly group. In both age groups the immediate increases could be ascribed to recruitment of CD28- cells (CD8+ and CD4+ cells) and memory cells (only CD8+ cells). Furthermore, after exercise mean TRF lengths were significantly reduced in blood mononuclear cells and in CD8+ cells from young subjects and in CD4+ cells from elderly subjects compared with lengths pre-exercise. These findings suggest that the mobilization of T lymphocytes during acute exercise is mainly a redistribution of previously activated cells with an increased replicative story than cells isolated from the blood at rest. Furthermore, elderly humans fulfilling the Senieur protocol have a preserved ability to recruit T lymphocytes in response to acute physical stress.},
}
@article {pmid10618727,
year = {1999},
author = {Blackburn, E},
title = {The telomere and telomerase: how Do they interact?.},
journal = {The Mount Sinai journal of medicine, New York},
volume = {66},
number = {5-6},
pages = {292-300},
pmid = {10618727},
issn = {0027-2507},
support = {DE11356/DE/NIDCR NIH HHS/United States ; GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Homeostasis ; Humans ; Mutation ; RNA/physiology ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {The ribonucleoprotein (RNP) enzyme telomerase synthesizes telomere DNA and maintains telomere length in eukaryotic cells. This review describes recent findings that provide new understanding, of the functions of telomeres and telomerase. Telomerase has an essential RNA moiety in which a short sequence acts as the template for synthesis of telomeric DNA. Recent results show that, besides acting as a template, the telomerase RNA plays essential roles in the enzymatic functions of telomerase that are as critical as those provided by the protein reverse transcriptase subunit of telomerase. Analysis of telomerase RNA mutants in yeast has provided evidence that telomerase is an oligomeric/dimeric enzyme containing at least two telomerase RNA molecules and two enzyme-active sites. Recent data suggest that this telomerase RNP also plays a critical role in capping short telomeres. Thus, the length of a telomere is only one determinant of whether it is sufficiently long to function as a cap, stabilizing the chromosome end. Several lines of evidence converge on the notion that for telomere length regulation and other telomere functions, the very few last repeats at the tip of the telomere are the most crucial.},
}
@article {pmid10618395,
year = {2000},
author = {Zauner, S and Fraunholz, M and Wastl, J and Penny, S and Beaton, M and Cavalier-Smith, T and Maier, UG and Douglas, S},
title = {Chloroplast protein and centrosomal genes, a tRNA intron, and odd telomeres in an unusually compact eukaryotic genome, the cryptomonad nucleomorph.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {97},
number = {1},
pages = {200-205},
pmid = {10618395},
issn = {0027-8424},
mesh = {Algal Proteins/genetics ; Base Sequence ; Biological Evolution ; *Centrosome ; Chimera/*genetics ; Cloning, Molecular ; Eukaryota/*genetics ; Genes, Plant/genetics ; Genome ; Introns/*genetics ; Molecular Sequence Data ; Nucleic Acid Conformation ; Physical Chromosome Mapping ; RNA, Transfer/*genetics ; Repetitive Sequences, Nucleic Acid ; Telomere/*genetics ; },
abstract = {Cells of several major algal groups are evolutionary chimeras of two radically different eukaryotic cells. Most of these "cells within cells" lost the nucleus of the former algal endosymbiont. But after hundreds of millions of years cryptomonads still retain the nucleus of their former red algal endosymbiont as a tiny relict organelle, the nucleomorph, which has three minute linear chromosomes, but their function and the nature of their ends have been unclear. We report extensive cryptomonad nucleomorph sequences (68.5 kb), from one end of each of the three chromosomes of Guillardia theta. Telomeres of the nucleomorph chromosomes differ dramatically from those of other eukaryotes, being repeats of the 23-mer sequence (AG)(7)AAG(6)A, not a typical hexamer (commonly TTAGGG). The subterminal regions comprising the rRNA cistrons and one protein-coding gene are exactly repeated at all three chromosome ends. Gene density (one per 0.8 kb) is the highest for any cellular genome. None of the 38 protein-coding genes has spliceosomal introns, in marked contrast to the chlorarachniophyte nucleomorph. Most identified nucleomorph genes are for gene expression or protein degradation; histone, tubulin, and putatively centrosomal ranbpm genes are probably important for chromosome segregation. No genes for primary or secondary metabolism have been found. Two of the three tRNA genes have introns, one in a hitherto undescribed location. Intergenic regions are exceptionally short; three genes transcribed by two different RNA polymerases overlap their neighbors. The reported sequences encode two essential chloroplast proteins, FtsZ and rubredoxin, thus explaining why cryptomonad nucleomorphs persist.},
}
@article {pmid10613900,
year = {1999},
author = {Weipoltshammer, K and Schöfer, C and Almeder, M and Philimonenko, VV and Frei, K and Wachtler, F and Hozák, P},
title = {Intranuclear anchoring of repetitive DNA sequences: centromeres, telomeres, and ribosomal DNA.},
journal = {The Journal of cell biology},
volume = {147},
number = {7},
pages = {1409-1418},
pmid = {10613900},
issn = {0021-9525},
mesh = {Cell Nucleus/*genetics/*metabolism ; Centromere/*metabolism ; DNA/genetics/*metabolism ; DNA, Ribosomal/*metabolism ; Humans ; Interphase/genetics ; Lymphocyte Activation/genetics ; Lymphocytes/cytology/metabolism ; *Repetitive Sequences, Nucleic Acid ; Ribosomes/genetics ; Telomere/*metabolism ; },
abstract = {Centromeres, telomeres, and ribosomal gene clusters consist of repetitive DNA sequences. To assess their contributions to the spatial organization of the interphase genome, their interactions with the nucleoskeleton were examined in quiescent and activated human lymphocytes. The nucleoskeletons were prepared using "physiological" conditions. The resulting structures were probed for specific DNA sequences of centromeres, telomeres, and ribosomal genes by in situ hybridization; the electroeluted DNA fractions were examined by blot hybridization. In both nonstimulated and stimulated lymphocytes, centromeric alpha-satellite repeats were almost exclusively found in the eluted fraction, while telomeric sequences remained attached to the nucleoskeleton. Ribosomal genes showed a transcription-dependent attachment pattern: in unstimulated lymphocytes, transcriptionally inactive ribosomal genes located outside the nucleolus were eluted completely. When comparing transcription unit and intergenic spacer, significantly more of the intergenic spacer was removed. In activated lymphocytes, considerable but similar amounts of both rDNA fragments were eluted. The results demonstrate that: (a) the various repetitive DNA sequences differ significantly in their intranuclear anchoring, (b) telomeric rather than centromeric DNA sequences form stable attachments to the nucleoskeleton, and (c) different attachment mechanisms might be responsible for the interaction of ribosomal genes with the nucleoskeleton.},
}
@article {pmid10613354,
year = {1999},
author = {Kosciolek, BA and Rowley, PT},
title = {Telomere-related components are coordinately synthesized during human T-lymphocyte activation.},
journal = {Leukemia research},
volume = {23},
number = {12},
pages = {1097-1103},
doi = {10.1016/s0145-2126(99)00134-4},
pmid = {10613354},
issn = {0145-2126},
mesh = {Adult ; Cells, Cultured ; DNA Replication ; Enzyme Activation ; *Gene Expression Regulation ; Humans ; *Lymphocyte Activation/drug effects ; Phytohemagglutinins/pharmacology ; RNA, Messenger/biosynthesis ; Reverse Transcriptase Polymerase Chain Reaction ; T-Lymphocytes/*immunology/metabolism ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Since telomerase activity is present in most malignant cells, but absent in most normal cells, its induction in normal cells warrants scrutiny. Therefore we have analyzed the inducibility of telomere-related components in normal lymphocytes during their activation. Telomerase activity increased over 400-fold, telomerase reverse transcriptase (hTERT) mRNA 52 x , telomerase RNA 32 x , TTAGGG repeat binding factor 1 mRNA 19 x , TTAGGG repeat binding factor 2 mRNA 20 x , and telomerase-associated protein mRNA 17 x . The peak value for each was reached at about 72 h. However hTERT rose fastest and synchronously with telomerase activity. Thus in normal human lymphocytes (1) the syntheses of all cloned telomerase-related components are coordinately regulated and (2) hTERT may have a priming role.},
}
@article {pmid10611335,
year = {1999},
author = {Ray, A and Runge, KW},
title = {Varying the number of telomere-bound proteins does not alter telomere length in tel1Delta cells.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {96},
number = {26},
pages = {15044-15049},
pmid = {10611335},
issn = {0027-8424},
support = {R01 GM050752/GM/NIGMS NIH HHS/United States ; GM50752/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites ; Cloning, Molecular ; DNA-Binding Proteins/*metabolism ; Molecular Sequence Data ; *Mutation ; Protein Binding ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; Sequence Analysis, DNA ; Shelterin Complex ; Telomerase ; Telomere/*genetics/*metabolism ; *Telomere-Binding Proteins ; *Transcription Factors ; },
abstract = {Yeast telomere DNA consists of a continuous, approximately 330-bp tract of the heterogeneous repeat TG(1-3) with irregularly spaced, high affinity sites for the protein Rap1p. Yeast monitor, or count, the number of telomeric Rap1p C termini in a negative feedback mechanism to modulate the length of the terminal TG(1-3) repeats, and synthetic telomeres that tether Rap1p molecules adjacent to the TG(1-3) tract cause wild-type cells to maintain a shorter TG(1-3) tract. To identify trans-acting proteins required to count Rap1p molecules, these same synthetic telomeres were placed in two short telomere mutants: yku70Delta (which lack the yeast Ku70 protein) and tel1Delta (which lack the yeast ortholog of ATM). Although both mutants maintain telomeres with approximately 100 bp of TG(1-3), only yku70Delta cells maintained shorter TG(1-3) repeats in response to internal Rap1p molecules. This distinct response to internal Rap1p molecules was not caused by a variation in Rap1p site density in the TG(1-3) repeats as sequencing of tel1Delta and yku70Delta telomeres showed that both strains have only five to six Rap1p sites per 100-bp telomere. In addition, the tel1Delta short telomere phenotype was epistatic to the unregulated telomere length caused by deletion of the Rap1p C-terminal domain. Thus, the length of the TG(1-3) repeats in tel1Delta cells was independent of the number of the Rap1p C termini at the telomere. These data indicate that tel1Delta cells use an alternative mechanism to regulate telomere length that is distinct from monitoring the number of telomere binding proteins.},
}
@article {pmid10588723,
year = {1999},
author = {Murti, KG and Prescott, DM},
title = {Telomeres of polytene chromosomes in a ciliated protozoan terminate in duplex DNA loops.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {96},
number = {25},
pages = {14436-14439},
pmid = {10588723},
issn = {0027-8424},
support = {P30 CA021765/CA/NCI NIH HHS/United States ; CA-21765/CA/NCI NIH HHS/United States ; GM56161/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromosomes/*chemistry ; DNA, Protozoan/*chemistry ; Oxytricha/*genetics ; *Telomere ; },
abstract = {The end of a telomeric DNA sequence isolated from a polytene chromosome of a hypotrichous ciliate folds back and hybridizes with downstream telomeric sequence to form a t loop that is stable in the absence of protein and DNA cross-linking. The single-stranded, telomeric DNA sequence at the end of a macronuclear molecule does not form a t loop but, instead, is complexed with a heterodimeric, telomere-binding protein. Thus, two mechanisms for capping the ends of DNA molecules are used in the same cell.},
}
@article {pmid10588696,
year = {1999},
author = {Herbert, B and Pitts, AE and Baker, SI and Hamilton, SE and Wright, WE and Shay, JW and Corey, DR},
title = {Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {96},
number = {25},
pages = {14276-14281},
pmid = {10588696},
issn = {0027-8424},
support = {T32 GM007062/GM/NIGMS NIH HHS/United States ; CA-85143/CA/NCI NIH HHS/United States ; CA74908/CA/NCI NIH HHS/United States ; T32GM07062-23/GM/NIGMS NIH HHS/United States ; },
mesh = {Antineoplastic Agents/pharmacology ; Cell Death/drug effects ; Cell Division/drug effects ; Enzyme Inhibitors/*pharmacology ; Humans ; Oligonucleotides/*pharmacology ; Peptide Nucleic Acids/pharmacology ; Telomerase/*antagonists &amp; inhibitors/physiology ; Telomere/*drug effects ; },
abstract = {The correlation between telomerase activity and human tumors has led to the hypothesis that tumor growth requires reactivation of telomerase and that telomerase inhibitors represent a class of chemotherapeutic agents. Herein, we examine the effects of inhibition of telomerase inside human cells. Peptide nucleic acid and 2'-O-MeRNA oligomers inhibit telomerase, leading to progressive telomere shortening and causing immortal human breast epithelial cells to undergo apoptosis with increasing frequency until no cells remain. Telomere shortening is reversible: if inhibitor addition is terminated, telomeres regain their initial lengths. Our results validate telomerase as a target for the discovery of anticancer drugs and supply general insights into the properties that successful agents will require regardless of chemical type. Chemically similar oligonucleotides are in clinical trials and have well characterized pharmacokinetics, making the inhibitors we describe practical lead compounds for testing for an antitelomerase chemotherapeutic strategy.},
}
@article {pmid10587657,
year = {1999},
author = {Tromans, A},
title = {A new piece in the telomere jigsaw.},
journal = {Nature cell biology},
volume = {1},
number = {8},
pages = {E200},
doi = {10.1038/70228},
pmid = {10587657},
issn = {1465-7392},
mesh = {Cellular Senescence ; DNA-Binding Proteins/*metabolism ; Humans ; Telomerase/metabolism ; Telomere/enzymology/*metabolism ; },
}
@article {pmid10581025,
year = {1999},
author = {Kim, SH and Kaminker, P and Campisi, J},
title = {TIN2, a new regulator of telomere length in human cells.},
journal = {Nature genetics},
volume = {23},
number = {4},
pages = {405-412},
pmid = {10581025},
issn = {1061-4036},
support = {T32 AG000266/AG/NIA NIH HHS/United States ; AG09909/AG/NIA NIH HHS/United States ; R37 AG009909/AG/NIA NIH HHS/United States ; R56 AG009909/AG/NIA NIH HHS/United States ; AG00266/AG/NIA NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Base Sequence ; Cell Line ; Cloning, Molecular ; DNA, Complementary/genetics ; DNA-Binding Proteins/chemistry/*genetics/*metabolism ; Gene Expression ; Humans ; Molecular Sequence Data ; RNA, Messenger/genetics/metabolism ; Recombinant Proteins/genetics/metabolism ; Sequence Deletion ; Telomere/*genetics/*metabolism ; *Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 1 ; Tissue Distribution ; },
abstract = {Telomeres are DNA-protein structures that cap linear chromosomes and are essential for maintaining genomic stability and cell phenotype. We identified a novel human telomere-associated protein, TIN2, by interaction cloning using the telomeric DNA-binding-protein TRF1 as a bait. TIN2 interacted with TRF1 in vitro and in cells, and co-localized with TRF1 in nuclei and metaphase chromosomes. A mutant TIN2 that lacks amino-terminal sequences effects elongated human telomeres in a telomerase-dependent manner. Our findings suggest that TRF1 is insufficient for control of telomere length in human cells, and that TIN2 is an essential mediator of TRF1 function.},
}
@article {pmid10580594,
year = {1999},
author = {Erlitzki, R and Minuk, GY},
title = {Telomeres, telomerase and HCC: the long and the short of it.},
journal = {Journal of hepatology},
volume = {31},
number = {5},
pages = {939-945},
doi = {10.1016/s0168-8278(99)80298-0},
pmid = {10580594},
issn = {0168-8278},
mesh = {Animals ; Carcinoma, Hepatocellular/enzymology/*genetics ; Humans ; Liver Neoplasms/enzymology/*genetics ; Telomerase/genetics/*metabolism ; Telomere/*genetics ; },
}
@article {pmid10580146,
year = {1999},
author = {Brock, GJ and Charlton, J and Bird, A},
title = {Densely methylated sequences that are preferentially localized at telomere-proximal regions of human chromosomes.},
journal = {Gene},
volume = {240},
number = {2},
pages = {269-277},
doi = {10.1016/s0378-1119(99)00442-4},
pmid = {10580146},
issn = {0378-1119},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Chromosome Mapping ; DNA/blood/*genetics/metabolism ; *DNA Methylation ; Female ; GC Rich Sequence ; *Gene Library ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Molecular Sequence Data ; Telomere/*genetics ; },
abstract = {We have constructed a library of densely methylated DNA sequences from human blood DNA by selecting fragments with a high affinity for a methyl-CpG binding domain (MBD) column. PCR analysis of the library confirmed the presence of known densely methylated CpG island sequences. Analysis of random clones, however, showed that the library was dominated by sequences whose G+C content and CpG frequency were intermediate between those of bulk genomic DNA and bona fide CpG islands. When human chromosomes were probed with the library by fluorescent in situ hybridisation (FISH), the predominant sites of labelling were at terminal regions of many chromosomes, approximately corresponding to T-bands. Analysis of the methylation status of random clones indicated that all were heavily methylated at CpGs in blood DNA, but many were under-methylated in sperm DNA. Lack of methylation in germ cells may reduce CpG depletion at some sub-terminal sequences and result in a high density of methyl-CpG when these regions become methylated in somatic cells.},
}
@article {pmid10577915,
year = {1999},
author = {Surrallés, J and Hande, MP and Marcos, R and Lansdorp, PM},
title = {Accelerated telomere shortening in the human inactive X chromosome.},
journal = {American journal of human genetics},
volume = {65},
number = {6},
pages = {1617-1622},
pmid = {10577915},
issn = {0002-9297},
mesh = {Acetylation ; Aged ; Aging/*genetics/physiology ; Centromere/genetics ; DNA Probes/genetics ; *Dosage Compensation, Genetic ; Female ; Genomic Imprinting/genetics ; Histones/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Infant, Newborn ; Kinetics ; Lymphocytes/cytology/metabolism ; Metaphase/genetics ; Middle Aged ; Telomere/*genetics/*metabolism ; X Chromosome/*genetics/*metabolism ; },
abstract = {Telomeres are nucleoprotein complexes at the end of eukaryotic chromosomes, with important roles in the maintenance of genomic stability and in chromosome segregation. Normal somatic cells lose telomeric repeats with each cell division both in vivo and in vitro. To address a potential role of nuclear architecture and epigenetic factors in telomere-length dynamics, the length of the telomeres of the X chromosomes and the autosomes was measured in metaphases from blood lymphocytes of human females of various ages, by quantitative FISH with a peptide nucleic-acid telomeric probe in combination with an X-chromosome centromere-specific probe. The activation status of the X chromosomes was simultaneously visualized with antibodies against acetylated histone H4. We observed an accelerated shortening of telomeric repeats in the inactive X chromosome, which suggests that epigenetic factors modulate not only the length but also the rate of age-associated telomere shortening in human cells in vivo. This is the first evidence to show a differential rate of telomere shortening between and within homologous chromosomes in any species. Our results are also consistent with a causative role of telomere shortening in the well-documented X-chromosome aneuploidy in aging humans.},
}
@article {pmid10572167,
year = {1999},
author = {Vassetzky, NS and Gaden, F and Brun, C and Gasser, SM and Gilson, E},
title = {Taz1p and Teb1p, two telobox proteins in Schizosaccharomyces pombe, recognize different telomere-related DNA sequences.},
journal = {Nucleic acids research},
volume = {27},
number = {24},
pages = {4687-4694},
doi = {10.1093/nar/27.24.4687},
pmid = {10572167},
issn = {1362-4962},
mesh = {Base Sequence ; Binding Sites ; DNA Primers ; DNA Probes ; DNA, Fungal/*chemistry/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Fungal Proteins/metabolism ; Genes, Fungal ; Humans ; Molecular Sequence Data ; Polymerase Chain Reaction ; Recombinant Proteins/metabolism ; Repetitive Sequences, Nucleic Acid ; Schizosaccharomyces/*genetics/*metabolism ; *Schizosaccharomyces pombe Proteins ; Telomere/*genetics ; *Telomere-Binding Proteins ; Telomeric Repeat Binding Protein 1 ; Transcription Factors ; },
abstract = {Band shift assays were used to study proteins from the fission yeast that bind double-stranded telomeric repeat sequences. We also examine general DNA binding properties of the telobox domain, which characterizes telomere-binding proteins from a range of species. We demonstrate that Taz1p has a high affinity for the fission yeast telomeric repeat, consistent with genetic results implicating this protein in telomere maintenance. A second Schizosaccharomyces pombe telobox protein, Teb1p, is shown to bind with high affinity to the vertebrate repeat and with low affinity to the fission yeast telomeric DNA. When tested on G-rich single-stranded telomeric DNA, all these proteins bind with very low affinity, much like the human telomere-binding protein TRF1. Recombinant proteins containing just the telobox domains reproduce the specificity of binding demonstrated for the corresponding full-length proteins, indicating that the telobox domain is indeed responsible for specific DNA recognition. The presence of possible Teb1p-binding sites upstream of many genes suggests a role for this protein as a general transcription factor. Finally, band shift experiments with whole cell extracts from wild-type and taz1 (-)strains suggest that in addition to Taz1p, S.pombe has another major telomere-binding activity.},
}
@article {pmid10570471,
year = {1999},
author = {Betts, DH and King, WA},
title = {Telomerase activity and telomere detection during early bovine development.},
journal = {Developmental genetics},
volume = {25},
number = {4},
pages = {397-403},
doi = {10.1002/(SICI)1520-6408(1999)25:4&lt;397::AID-DVG13&gt;3.0.CO;2-J},
pmid = {10570471},
issn = {0192-253X},
mesh = {Animals ; Cattle/embryology/*metabolism ; DNA Probes ; Fertilization in Vitro ; Humans ; In Situ Hybridization, Fluorescence ; Oocytes/growth &amp; development/*metabolism ; Tandem Repeat Sequences/genetics ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {The ends of mammalian chromosomes are composed of repeated DNA sequences of (TTAGGG)(n) known as telomeres. Telomerase is a ribonucleoprotein that synthesizes telomeric DNA to replenish the 50-200 bp lost during cell replication. Cellular aging and senescence are associated with a lack of telomerase activity and a critical shortening of the telomere. The objectives of this study were to confirm the presence of TTAGGG repeats on the chromosomes of bovine embryos using in situ hybridization and assess the relative amounts of telomerase activity using a telomeric repeat amplification protocol (TRAP) during oocyte maturation and early embryo development. Applying a telomere DNA probe to the chromosomes of blastocysts and adult fibroblasts, telomeres were identified on the terminal ends of the p and q arms of chromosomes in all cells examined. Immature oocytes, matured oocytes, zygotes, 2- to 5-cell embryos, 6- to 8-cell embryos, morulae, and blastocysts were lysed in NP-40 lysis buffer and telomerase activity was assayed using the TRAP assay. Telomerase activity was detected in all developmental stages examined. Relative telomerase activity (based on telomerase internal standards and positive controls) appeared to decrease during oocyte maturation and subsequent development to the 8-cell stage but significantly increased (P < 0.05) by approximately 40-fold at the morula and blastocyst stages. It was concluded that the telomeres of bovine chromosomes contain TTAGGG repeats and that telomerase activity is up-regulated in morulae and blastocysts.},
}
@article {pmid10567589,
year = {1999},
author = {Tanaka, K and Nishide, J and Okazaki, K and Kato, H and Niwa, O and Nakagawa, T and Matsuda, H and Kawamukai, M and Murakami, Y},
title = {Characterization of a fission yeast SUMO-1 homologue, pmt3p, required for multiple nuclear events, including the control of telomere length and chromosome segregation.},
journal = {Molecular and cellular biology},
volume = {19},
number = {12},
pages = {8660-8672},
pmid = {10567589},
issn = {0270-7306},
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Cell Nucleus/metabolism ; *Chromosome Segregation ; Chromosomes, Fungal ; DNA, Fungal ; Fungal Proteins/genetics/*metabolism ; Humans ; Molecular Sequence Data ; Phenotype ; Repressor Proteins/genetics/*metabolism ; SUMO-1 Protein ; Schizosaccharomyces/*genetics/metabolism ; *Schizosaccharomyces pombe Proteins ; *Small Ubiquitin-Related Modifier Proteins ; *Telomere ; Ubiquitins/chemistry/genetics/*metabolism ; },
abstract = {Unlike ubiquitin, the ubiquitin-like protein modifier SUMO-1 and its budding yeast homologue Smt3p have been shown to be more important for posttranslational protein modification than for protein degradation. Here we describe the identification of the SUMO-1 homologue of fission yeast, which we show to be required for a number of nuclear events including the control of telomere length and chromosome segregation. A disruption of the pmt3(+) gene, the Schizosaccharomyces pombe homologue of SMT3, was not lethal, but mutant cells carrying the disrupted gene grew more slowly. The pmt3Delta cells showed various phenotypes such as aberrant mitosis, sensitivity to various reagents, and high-frequency loss of minichromosomes. Interestingly, we found that pmt3(+) is required for telomere length maintenance. Loss of Pmt3p function caused a striking increase in telomere length. When Pmt3p synthesis was restored, the telomeres became gradually shorter. This is the first demonstration of involvement of one of the Smt3p/SUMO-1 family proteins in telomere length maintenance. Fusion of Pmt3p to green fluorescent protein (GFP) showed that Pmt3p was predominantly localized as intense spots in the nucleus. One of the spots was shown to correspond to the spindle pole body (SPB). During prometaphase- and metaphase, the bright GFP signals at the SPB disappeared. These observations suggest that Pmt3p is required for kinetochore and/or SPB functions involved in chromosome segregation. The multiple functions of Pmt3p described here suggest that several nuclear proteins are regulated by Pmt3p conjugation.},
}
@article {pmid10567534,
year = {1999},
author = {Teng, SC and Zakian, VA},
title = {Telomere-telomere recombination is an efficient bypass pathway for telomere maintenance in Saccharomyces cerevisiae.},
journal = {Molecular and cellular biology},
volume = {19},
number = {12},
pages = {8083-8093},
pmid = {10567534},
issn = {0270-7306},
support = {R01 GM026938/GM/NIGMS NIH HHS/United States ; R37 GM026938/GM/NIGMS NIH HHS/United States ; GM26938/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes, Fungal ; DNA, Complementary ; DNA, Fungal ; DNA-Binding Proteins/metabolism ; Fungal Proteins/metabolism ; Rad52 DNA Repair and Recombination Protein ; *Recombination, Genetic ; Saccharomyces cerevisiae/*genetics/growth &amp; development ; Saccharomyces cerevisiae Proteins ; *Telomere ; },
abstract = {Many Saccharomyces telomeres bear one or more copies of the repetitive Y' element followed by approximately 350 bp of telomerase-generated C(1-3)A/TG(1-3) repeats. Although most cells lacking a gene required for the telomerase pathway die after 50 to 100 cell divisions, survivors arise spontaneously in such cultures. These survivors have one of two distinct patterns of telomeric DNA (V. Lundblad and E. H. Blackburn, Cell 73:347-360, 1993). The more common of the two patterns, seen in type I survivors, is tandem amplification of Y' followed by very short tracts of C(1-3)A/TG(1-3) DNA. By determining the structure of singly tagged telomeres, chromosomes in type II survivors were shown to end in very long and heterogeneous-length tracts of C(1-3)A/TG(1-3) DNA, with some telomeres having 12 kb or more of C(1-3)A/TG(1-3) repeats. Maintenance of these long telomeres required the continuous presence of Rad52p. Whereas type I survivors often converted to the type II structure of telomeric DNA, the type II pattern was maintained for at least 250 cell divisions. However, during outgrowth, the structure of type II telomeres was dynamic, displaying gradual shortening as well as other structural changes that could be explained by continuous gene conversion events with other telomeres. Although most type II survivors had a growth rate similar to that of telomerase-proficient cells, their telomeres slowly returned to wild-type lengths when telomerase was reintroduced. The very long and heterogeneous-length telomeres characteristic of type II survivors in Saccharomyces are reminiscent of the telomeres in immortal human cell lines and tumors that maintain telomeric DNA in the absence of telomerase.},
}
@article {pmid10564888,
year = {1999},
author = {Shaffer, LG and Kashork, CD and Bacino, CA and Benke, PJ},
title = {Caution: telomere crossing.},
journal = {American journal of medical genetics},
volume = {87},
number = {3},
pages = {278-280},
doi = {10.1002/(sici)1096-8628(19991126)87:3&lt;278::aid-ajmg19&gt;3.0.co;2-3},
pmid = {10564888},
issn = {0148-7299},
mesh = {Cerebral Palsy/genetics ; Child ; Chromosomes, Human, Pair 1/genetics/*ultrastructure ; Chromosomes, Human, Pair 13/genetics/*ultrastructure ; Diseases in Twins ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Pedigree ; Telomere/*ultrastructure ; *Translocation, Genetic ; },
}
@article {pmid10563554,
year = {1999},
author = {Rahat, MA and Lahat, N and Sharon, A and Gazawi, H and Abramovici, H and Bornstein, J},
title = {Increased telomerase activity and decreased telomere length in genital condylomata acuminata.},
journal = {International journal of STD &amp; AIDS},
volume = {10},
number = {11},
pages = {699-702},
doi = {10.1258/0956462991913367},
pmid = {10563554},
issn = {0956-4624},
mesh = {Biopsy ; Condylomata Acuminata/*genetics/pathology/virology ; DNA, Viral/chemistry ; Female ; Genital Diseases, Female/*genetics/pathology/virology ; Humans ; Papillomaviridae/isolation &amp; purification ; Telomerase/*metabolism ; Telomere/*ultrastructure ; },
abstract = {Our objective was to find a possible correlation between telomerase activity, mean telomere length and human papillomavirus (HPV) presence and type in genital condylomata acuminata. Fifteen biopsies from women with genital condylomata acuminata and nine control tissue samples were tested for telomerase activity, mean telomere length, and HPV presence and type. All condylomata exhibited telomerase activity, compared to 78% of the control samples. The mean telomere length of condylomata was significantly (P<0.002) shorter compared to telomere length in control tissue samples. All condylomata lesions were infected with HPV types 6/11, and more than half had additional infection with HPV 16/18. Mixed HPV 6/11 with 16/18 infection correlated with shorter telomeres than presence of HPV 6/11 alone in the lesions (4.68 +/- 0.44 kb vs 4.97 +/- 0.57 kb). None of the control tissue samples showed presence of HPV DNA. Telomerase activity may be a marker of proliferation rather than malignancy, whereas the mean telomere length could better serve as a marker for the progression of HPV lesions toward malignancy.},
}
@article {pmid10554813,
year = {1999},
author = {Wynn, R and Thornley, I and Freedman, M and Saunders, EF},
title = {Telomere shortening in leucocyte subsets of long-term survivors of allogeneic bone marrow transplantation.},
journal = {British journal of haematology},
volume = {105},
number = {4},
pages = {997-1001},
doi = {10.1046/j.1365-2141.1999.01450.x},
pmid = {10554813},
issn = {0007-1048},
mesh = {Adolescent ; Adult ; Bone Marrow Transplantation/*pathology ; Child ; Child, Preschool ; Humans ; Infant ; Infant, Newborn ; Lymphocyte Subsets ; Neutrophils/*pathology ; Survivors ; T-Lymphocytes/*pathology ; Telomere/*pathology ; Transplantation, Homologous ; },
abstract = {Recent studies have demonstrated excessive telomeric shortening in peripheral blood leucocytes of bone marrow transplant (BMT) recipients. This finding has raised concerns about accelerated haemopoietic ageing that might predispose to clonal disorders and late graft failure. We studied the peripheral blood neutrophils and T cells of 14 fully engrafted long-term survivors of BMT. We found that in both neutrophils and T cells there was significant telomere shortening in the recipient (0.6 and 0.5 kb, respectively; P < 0.001 and < 0.04, respectively). We found no relationship between degree of shortening and the nucleated cell dose given at the time of transplant. We also demonstrated significantly longer telomeres in T cells than neutrophils from the same individual (mean 11.6 kb and 10.6 kb, respectively; P=0.0001). We propose mechanisms to account for these observations. The replicative stress that causes this telomere shortening does not necessarily occur at the level of the most primitive haemopoietic stem cell.},
}
@article {pmid10554797,
year = {1999},
author = {Leteurtre, F and Li, X and Guardiola, P and Le Roux, G and Sergère, JC and Richard, P and Carosella, ED and Gluckman, E},
title = {Accelerated telomere shortening and telomerase activation in Fanconi's anaemia.},
journal = {British journal of haematology},
volume = {105},
number = {4},
pages = {883-893},
doi = {10.1046/j.1365-2141.1999.01445.x},
pmid = {10554797},
issn = {0007-1048},
mesh = {Adolescent ; Adult ; Blotting, Southern ; Child ; Child, Preschool ; Chromosome Aberrations ; Fanconi Anemia/enzymology/*genetics ; Female ; Humans ; Infant ; Leukocytes, Mononuclear/enzymology ; Male ; Telomerase/*metabolism ; Telomere/enzymology/*genetics ; },
abstract = {Fanconi's anaemia (FA) is an autosomal recessive disorder characterized by progressive bone marrow failure that often evolves towards acute leukaemia. FA also belongs to a group of chromosome instability diseases. Because telomeres are directly involved in chromosomal stability and in cell proliferation capacity, we examined telomere metabolism in peripheral blood mononuclear cells (PBMC). Telomere length was significantly shorter in 54 FA patient samples, compared to 51 controls (P<0.0001). In addition, mean telomere terminal restriction fragment lengths (TRF) in nine heterozygous patient samples did not differ from those of controls. In 14 samples from FA patients with severe aplastic anaemia (SFA), telomere length was significantly shorter than in 22 samples of age-matched FA patients with moderate haematological abnormalities (NSFA) (P<0.001). However, no correlation was found between TRF length and the presence of bone marrow clonal abnormalities in 16 additional, separately analysed, patient samples. Sequential measurement of TRF in six FA patients showed an accelerated rate of telomere shortening. Accordingly, telomere shortening rate was inversely correlated with clinical status. Telomerase, the enzyme that counteracts telomere shortening, was 4.8-fold more active in 25 FA patients than in 15 age-matched healthy controls. A model for the FA disease process is proposed.},
}
@article {pmid10547863,
year = {2000},
author = {Perrem, K and Reddel, RR},
title = {Telomeres and cell division potential.},
journal = {Progress in molecular and subcellular biology},
volume = {24},
number = {},
pages = {173-189},
doi = {10.1007/978-3-662-06227-2_8},
pmid = {10547863},
issn = {0079-6484},
mesh = {Animals ; Cell Division/genetics/*physiology ; Cellular Senescence/genetics/physiology ; Endothelium, Vascular/cytology ; Humans ; Mice ; Mice, Knockout ; Models, Biological ; Telomere/genetics/*physiology ; },
}
@article {pmid10546221,
year = {1999},
author = {Voronin, AP and Lobov, IB and Bugaeva, EA and Parfenov, VN and Podgornaia, OI},
title = {[Telomere-binding protein of mouse nuclear matrix. II. Localization].},
journal = {Molekuliarnaia biologiia},
volume = {33},
number = {4},
pages = {665-672},
pmid = {10546221},
issn = {0026-8984},
mesh = {Animals ; Chromatography, DEAE-Cellulose ; DNA-Binding Proteins/*isolation &amp; purification/*metabolism ; Mice ; Telomere/*metabolism ; },
}
@article {pmid10546220,
year = {1999},
author = {Voronin, AP and Lobov, IB and Bugaeva, EA and Parfenov, VN and Podgornaia, OI},
title = {[Telomere-binding protein of mouse nuclear matrix. I. Characteristics].},
journal = {Molekuliarnaia biologiia},
volume = {33},
number = {4},
pages = {657-664},
pmid = {10546220},
issn = {0026-8984},
mesh = {Animals ; Chromatography, DEAE-Cellulose ; DNA-Binding Proteins/*isolation &amp; purification/*metabolism ; Mice ; Telomere/*metabolism ; },
}
@article {pmid10546218,
year = {1999},
author = {Vasetskiĭ, NS and Gilson, E and Gasser, SM},
title = {[Telomere-binding activity of Schizosaccharomyces pombe yeasts].},
journal = {Molekuliarnaia biologiia},
volume = {33},
number = {4},
pages = {644-650},
pmid = {10546218},
issn = {0026-8984},
mesh = {Base Sequence ; DNA-Binding Proteins/*genetics ; Molecular Sequence Data ; RNA, Fungal/*genetics ; Schizosaccharomyces/*genetics ; Telomere/*genetics ; },
}
@article {pmid10545800,
year = {1999},
author = {Saeki, T and Takashima, S and Tachibana, M and Koga, M and Hiyama, E and Salomon, DS and Holland, JF and Ohnuma, T},
title = {Inhibitory effect of telomere-mimic phosphorothioate oligodeoxy nucleotides (S-ODNS) on human tumor cell lines.},
journal = {Oncology},
volume = {57 Suppl 2},
number = {},
pages = {27-36},
doi = {10.1159/000055272},
pmid = {10545800},
issn = {0030-2414},
mesh = {Breast Neoplasms/enzymology/genetics/*metabolism ; Colonic Neoplasms/enzymology/genetics/*metabolism ; Humans ; Oligodeoxyribonucleotides, Antisense ; *Oligonucleotides ; Telomerase/genetics/*metabolism ; *Telomere ; *Thionucleotides ; Tumor Cells, Cultured ; },
abstract = {To clarify the inhibitory effect of telomere-mimic oligonucleotides on human cancer cell lines, we synthesized 18-mers (18T; n = 3), 24-mers (24T; n = 4) and 30-mers (30T; n = 5) of telomere-mimic phosphorothioate oligodeoxy nucleotides [5'-d(TTA GGG)n-3'] and examined their effects on the proliferation of human tumor cells by XTT assay. After 7 days of continuous exposure to 24T and 30T at concentrations ranging from 0.1 to 10 microM, concentration-dependent cell growth inhibition was observed in MCF-7 clone E3, ZR-75-1, MDA-MB 231, Colo 201 and WiDr. All of these cell lines highly expressed telomerase using the telomeric repeat amplification protocol. None of these tumor cell lines were affected by 18T. In MCF-7, ZR-75-1 and Colo 201 cell lines, a more than 50% growth inhibition was obtained by 3 microM of 24T and 30T whereas, in MDA-MB 231 and WiDr cell lines, cell growth inhibition was less than 50%. 30T was more effective than 24T. Estrogen-dependent growth of both MCF-7 and ZR-75-1 was inhibited by 3 microM of 24T and 30T, however, in the absence of estrogen, no growth inhibition was seen. The MCF-10A cell line, which was developed from normal human breast tissue and expressed telomerase only weakly, was inhibited by 10 microM of 18T. In conclusion, these observations indicate that S-ODNs inhibit tumor growth in cell lines expressing telomerase in a concentration-dependent manner and that cell growth inhibition is dependent on the length of S-ODNs. In addition, the short-length S-ODNs may inhibit growth of cells weakly expressing telomerase, but not of cells with high telomerase expression.},
}
@article {pmid10535943,
year = {1999},
author = {Hsu, HL and Gilley, D and Blackburn, EH and Chen, DJ},
title = {Ku is associated with the telomere in mammals.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {96},
number = {22},
pages = {12454-12458},
pmid = {10535943},
issn = {0027-8424},
support = {GM26259/GM/NIGMS NIH HHS/United States ; R37 CA050519/CA/NCI NIH HHS/United States ; R01 GM026259/GM/NIGMS NIH HHS/United States ; CA50519/CA/NCI NIH HHS/United States ; R37 GM026259/GM/NIGMS NIH HHS/United States ; R01 CA050519/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; *Antigens, Nuclear ; CHO Cells ; Catalytic Domain ; Cricetinae ; *DNA Helicases ; DNA-Activated Protein Kinase ; DNA-Binding Proteins/*metabolism ; Dimerization ; Humans ; Ku Autoantigen ; Nuclear Proteins/*metabolism ; Protein Serine-Threonine Kinases/metabolism ; *Saccharomyces cerevisiae Proteins ; *Telomere ; Tumor Cells, Cultured ; },
abstract = {Telomeres are specialized DNA/protein complexes that comprise the ends of eukaryotic chromosomes. The highly expressed Ku heterodimer, composed of 70 and 80 K(d) subunits (Ku70 and Ku80), is the high-affinity DNA binding component of the DNA-dependent protein kinase. Ku is critical for nonhomologous DNA double-stranded break repair and site-specific recombination of V(D)J gene segments. Ku also plays an important role in telomere maintenance in yeast. Herein, we report, using an in vivo crosslinking method, that human and hamster telomeric DNAs specifically coimmunoprecipitate with human Ku80 after crosslinking. Localization of Ku to the telomere does not depend on the DNA-dependent protein kinase catalytic component. These findings suggest a direct link between Ku and the telomere in mammalian cells.},
}
@article {pmid10527627,
year = {1999},
author = {Nakabayashi, K and Ogino, H and Michishita, E and Satoh, N and Ayusawa, D},
title = {Introduction of chromosome 7 suppresses telomerase with shortening of telomeres in a human mesothelial cell line.},
journal = {Experimental cell research},
volume = {252},
number = {2},
pages = {376-382},
doi = {10.1006/excr.1999.4619},
pmid = {10527627},
issn = {0014-4827},
mesh = {*Chromosomes, Human, Pair 7 ; Epithelium ; Gene Expression ; Gene Transfer Techniques ; Humans ; Telomerase/*genetics ; Telomere/*genetics/ultrastructure ; },
abstract = {Introduction of human chromosome 7 by microcell-mediated chromosome transfer induced senescence in a telomerase-positive human mesothelial cell line, MeT5A. In microcell hybrids which underwent senescence, telomerase activity was decreased before entering senescence and telomeric sequences were shortened as cell division proceeded. Concomitantly, expression of the gene encoding telomerase catalytic subunit was abolished, whereas the genes encoding the RNA component of telomerase and its associated protein TEP1 were not affected. In revertants which arose from such microcell hybrids, telomerase activity was restored and the telomeric sequences were elongated. In microcell hybrids which showed no growth arrest, telomerase activity was unaltered. These results suggest that a putative mortality gene on chromosome 7 negatively regulates the telomere maintenance mechanism in MeT5A.},
}
@article {pmid10526269,
year = {1999},
author = {Takagi, S and Kinouchi, Y and Hiwatashi, N and Chida, M and Nagashima, F and Takahashi, S and Negoro, K and Shimosegawa, T and Toyota, T},
title = {Telomere shortening and the clinicopathologic characteristics of human colorectal carcinomas.},
journal = {Cancer},
volume = {86},
number = {8},
pages = {1431-1436},
pmid = {10526269},
issn = {0008-543X},
mesh = {Aged ; Blotting, Southern ; Colorectal Neoplasms/enzymology/*genetics/*pathology ; DNA, Neoplasm/analysis/genetics ; Female ; Humans ; Male ; Middle Aged ; Statistics as Topic ; Telomerase/metabolism ; Telomere/*genetics ; },
abstract = {BACKGROUND: It has been reported that shortening of telomeres and strong activation of telomerase occur frequently in colorectal carcinomas. In the current study, the authors examined the correlations between the telomere length of colorectal carcinomas and their clinicopathologic characteristics as well as the activity of telomerase to clarify whether telomere length might represent the biologic behavior of tumors and the mode of tumor development.<br><br>METHODS: Telomere length was examined by Southern blot analysis in 61 invasive colorectal carcinomas and corresponding normal mucosas. Telomerase activity was assayed by the telomeric repeat amplification protocol with minor modifications.<br><br>RESULTS: Shortening of the telomere was detected in 38 (62.3%) and elongation in 3 (4. 9%) of the 61 carcinomas. The telomere shortening occurred more frequently in nonulcerating polypoid carcinomas than in ulcerating carcinomas (P = 0.0373) and also occurred more frequently in ascending colon carcinomas than in sigmoid colon or rectal carcinomas (P = 0.0259 and P = 0.0407, respectively). However, no significant correlation was found between the activity of telomerase and the length of telomere.<br><br>CONCLUSIONS: The results of this study indicate that telomere length may represent the biologic behavior of individual tumors and possibly the mode of development of colorectal carcinomas.},
}
@article {pmid10526206,
year = {1999},
author = {Sprung, CN and Afshar, G and Chavez, EA and Lansdorp, P and Sabatier, L and Murnane, JP},
title = {Telomere instability in a human cancer cell line.},
journal = {Mutation research},
volume = {429},
number = {2},
pages = {209-223},
doi = {10.1016/s0027-5107(99)00115-3},
pmid = {10526206},
issn = {0027-5107},
support = {ES07106/ES/NIEHS NIH HHS/United States ; R01 CA69044/CA/NCI NIH HHS/United States ; },
mesh = {Blotting, Southern ; Carcinoma, Squamous Cell ; Chromosome Aberrations/genetics ; Chromosome Disorders ; DNA/analysis ; Humans ; In Situ Hybridization, Fluorescence ; Plasmids/genetics ; Repetitive Sequences, Nucleic Acid ; Telomerase/metabolism ; Telomere/*genetics ; Transfection ; Tumor Cells, Cultured ; },
abstract = {Telomere maintenance is essential in immortal cancer cells to compensate for DNA lost from the ends of chromosomes, to prevent chromosome fusion, and to facilitate chromosome segregation. However, the high rate of fusion of chromosomes near telomeres, termed telomere association, in many cancer cell lines has led to the proposal that some cancer cells may not efficiently perform telomere maintenance. Deficient telomere maintenance could play an important role in cancer because telomere associations and nondisjunction have been demonstrated to be mechanisms for genomic instability. To investigate this possibility, we have analyzed the telomeres of the human squamous cell carcinoma cell line SQ-9G, which has telomere associations in approximately 75% of the cells in the population. The absence of detectable telomeric repeat sequences at the sites of these telomere associations suggests that they result from telomere loss. The analysis of telomere length by quantitative in situ hybridization demonstrated that, compared to the human squamous cell carcinoma cell line SCC-61 which has few telomere associations, SQ-9G has more extensive heterogeneity in telomere length and more telomeres without detectable telomeric repeat sequences. The dynamics of the changes in telomere length also demonstrated a higher rate of fluctuation in telomere length, both on individual telomeres and coordinately on all telomeres. These results demonstrate that telomere maintenance can play a role in the genomic instability seen in cancer cells.},
}
@article {pmid10524936,
year = {1999},
author = {Donaldson, L and Fordyce, C and Gilliland, F and Smith, A and Feddersen, R and Joste, N and Moyzis, R and Griffith, J},
title = {Association between outcome and telomere DNA content in prostate cancer.},
journal = {The Journal of urology},
volume = {162},
number = {5},
pages = {1788-1792},
pmid = {10524936},
issn = {0022-5347},
mesh = {Adenocarcinoma/chemistry/*genetics/mortality ; Aged ; DNA, Neoplasm/*analysis ; Disease-Free Survival ; Humans ; Male ; Middle Aged ; Prognosis ; Prostatic Neoplasms/chemistry/*genetics/mortality ; Retrospective Studies ; Telomere/*genetics ; },
abstract = {PURPOSE: To perform an initial retrospective investigation of the relationship between outcome in patients with organ confined prostate adenocarcinoma and the tumor cells' content of telomere DNA.<br><br>MATERIALS AND METHODS: The case-controlled study group was composed of eighteen men diagnosed with prostatic adenocarcinoma prior to 1993. The group was selected so that approximately one half died within ten years of diagnosis and one half survived ten years or longer. Archival, paraffin-embedded tumor tissue was recovered for each patient. DNA was extracted from newly cut sections, fixed to nylon membranes and hybridized with P32-labeled centromere- and telomere-specific probes. Telomere DNA contents were quantitated from the hybridized radioactivities. The relationships between telomere DNA content and survival, and telomere DNA content and disease recurrence in men receiving prostatectomies were determined.<br><br>RESULTS: Death and disease recurrence were associated with reduced telomere DNA content (p <0.0001, p <0.0001, respectively).<br><br>CONCLUSIONS: Telomere DNA content may differentiate high-risk patients with metastatic prostate cancer from men with indolent disease who can be spared the unnecessary side effects and expense of treatment by management with "watchful waiting."},
}
@article {pmid10518621,
year = {1999},
author = {Anglana, M and Bacchetti, S},
title = {Construction of a recombinant adenovirus for efficient delivery of the I-SceI yeast endonuclease to human cells and its application in the in vivo cleavage of chromosomes to expose new potential telomeres.},
journal = {Nucleic acids research},
volume = {27},
number = {21},
pages = {4276-4281},
doi = {10.1093/nar/27.21.4276},
pmid = {10518621},
issn = {1362-4962},
mesh = {Adenoviridae/*genetics/physiology ; Binding Sites ; Cell Line ; Chromosomes, Human/genetics/*metabolism ; DNA/genetics/metabolism ; Deoxyribonucleases, Type II Site-Specific/genetics/*metabolism ; Gene Expression ; Genetic Vectors/*genetics ; Humans ; Promoter Regions, Genetic/genetics ; Recombinant Proteins/genetics/metabolism ; Saccharomyces cerevisiae/*enzymology/genetics ; Saccharomyces cerevisiae Proteins ; Telomere/genetics/*metabolism ; Time Factors ; Transduction, Genetic ; Virus Replication ; },
abstract = {We have constructed a replication-defective adenovirus vector encoding the yeast I- Sce I endonuclease under the control of the murine cytomegalovirus immediate-early gene promoter (AdM Sce I) for efficient delivery of this enzyme to mammalian cells. We present evidence of AdM Sce I-mediated I- Sce I protein expression and cleavage activity in replication-permissive 293 cells, and of cleavage of chromosomes in vivo in both 293 cells and in non-permissive human cells. We have exploited this system for the generation of chromosomes capped by artificial telomeric sequences in cells with integrated plasmids containing telomeric DNA arrays adjacent to an I- Sce I recognition site. The properties of the AdM Sce I virus described here make it a useful tool for studying biological processes involving induction of DNA breaks, recombination and gene targeting in cells grown in culture and in vivo.},
}
@article {pmid10517334,
year = {1999},
author = {Venditti, S and Vega-Palas, MA and Di Stefano, G and Di Mauro, E},
title = {Imbalance in dosage of the genes for the heterochromatin components Sir3p and histone H4 results in changes in the length and sequence organization of yeast telomeres.},
journal = {Molecular &amp; general genetics : MGG},
volume = {262},
number = {2},
pages = {367-377},
doi = {10.1007/s004380051095},
pmid = {10517334},
issn = {0026-8925},
mesh = {*Chromosomes, Fungal ; Fungal Proteins/*genetics ; *Gene Dosage ; Gene Expression Regulation, Fungal ; *Heterochromatin ; Histones/*genetics ; Phenotype ; Saccharomyces cerevisiae/*genetics ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; *Telomere ; Trans-Activators/*genetics ; },
abstract = {Telomeric heterochromatin plays an essential role in telomere function, including the regulation of telomere length. We observe that in Saccharomyces cerevisiae an imbalance in the dosage of genes for two protein components of heterochromatin (namely Sir3p and histone H4) causes modifications in telomere length and telomere sequence organization. The effects of Sir3p/H4 imbalance were analyzed in yeast strains in which the wild-type SIR3 gene (normally a single-copy gene) was either absent or present in 20-30 copies, and both histone H4 genes (HHF1 and HHF2) were present or HHF1 was deleted, thus covering a wide range of viable gene-dosage combinations. Modifications of telomeres and of subtelomeric regions were identified by analyzing both the overall telomere population and by focusing on two single telomeric regions: the left telomere of chromosome III (LIII) and the right telomere of chromosome XI (RXI). The modifications induced by alteration of the Sir3p/H4 ratio consist of a reduction in the length and an increase in the instability of the terminal block of (C(1-3)A)n repeats and in susceptibility to insertion of Y' elements into this repeat element. Restoration of the wild-type gene ratio (by removal of the extra copies of SIR3 or by complementation with the missing second copy of HHF) restored the original telomere organization, both with respect to the length of the (C(1-3)A)n repeat stretch and the absence of Y' elements. This behavior shows that the stability of the wild-type sequence organization requires maintenance of the normal structure of telomeric heterochromatin.},
}
@article {pmid10513964,
year = {1999},
author = {Deveci, M},
title = {Telomeres and telomerase and their possible future in plastic surgery.},
journal = {Plastic and reconstructive surgery},
volume = {104},
number = {5},
pages = {1588-1589},
doi = {10.1097/00006534-199910000-00081},
pmid = {10513964},
issn = {0032-1052},
mesh = {Aging/*genetics/physiology ; Animals ; Cell Division/physiology ; Humans ; Rats ; Surgery, Plastic ; Telomerase/genetics/*physiology ; Telomere/genetics/*physiology ; Wound Healing/*physiology ; },
}
@article {pmid10508848,
year = {1999},
author = {Lese, CM and Fantes, JA and Riethman, HC and Ledbetter, DH},
title = {Characterization of physical gap sizes at human telomeres.},
journal = {Genome research},
volume = {9},
number = {9},
pages = {888-894},
pmid = {10508848},
issn = {1088-9051},
support = {F32 HG000174/HG/NHGRI NIH HHS/United States ; R01 HG000567/HG/NHGRI NIH HHS/United States ; 1 F32 HG00174-01/HG/NHGRI NIH HHS/United States ; HG00567/HG/NHGRI NIH HHS/United States ; },
mesh = {Chromosome Mapping/methods ; Chromosomes, Bacterial/genetics ; Chromosomes, Human, Pair 12 ; Chromosomes, Human, Pair 15 ; Chromosomes, Human, Pair 16 ; Chromosomes, Human, Pair 9 ; Databases, Factual ; Gene Library ; Humans ; In Situ Hybridization, Fluorescence ; Telomere/*genetics/*ultrastructure ; },
abstract = {Genome-wide physical and genetic mapping efforts have not yet fully addressed the problem of closure at the telomeric ends of human chromosomes. Targeted efforts at cloning human and mouse telomeres have succeeded in identifying unique sequences at most telomeres, but gap sizes between these telomere clones and the distal markers on integrated genetic/physical maps remain largely unknown. As telomeric regions are known to be the most gene-rich regions of the human genome, filling these gaps should have a high priority in completion of the Human Genome Project. We reported previously a first generation set of unique sequence probes for human telomeric regions. Of 41 human telomere regions, 33 were represented by unique clones with a known distance (</= 300 kb) from the end of the chromosome; clones for the remaining eight telomeric regions had not yet been identified and were represented by the most distal markers on the integrated genetic/physical map. We have identified unique telomere clones for four of the remaining telomeres, 9p, 12p, 15q, and 16p. To determine the telomeric gap size for these chromosomes and five other human telomeres, interphase FISH analysis was performed to measure the distance between each telomere clone and the corresponding most distal marker. These studies provide distance estimates ranging from <100 kb to >1 Mb, thus defining the physical mapping task for filling telomeric gaps.},
}
@article {pmid10508116,
year = {1999},
author = {Nakamura, Y and Hirose, M and Matsuo, H and Tsuyama, N and Kamisango, K and Ide, T},
title = {Simple, rapid, quantitative, and sensitive detection of telomere repeats in cell lysate by a hybridization protection assay.},
journal = {Clinical chemistry},
volume = {45},
number = {10},
pages = {1718-1724},
pmid = {10508116},
issn = {0009-9147},
mesh = {DNA/*analysis ; Humans ; *Nucleic Acid Amplification Techniques ; Nucleic Acid Hybridization ; Repetitive Sequences, Nucleic Acid ; Sensitivity and Specificity ; Telomerase/*genetics ; Telomere/*chemistry ; },
abstract = {BACKGROUND: Detection of telomere repeats by Southern hybridization of genomic DNA is time consuming, and the reading of a mean terminal restriction fragment (TRF) length from a smear pattern of an autoradiogram can be inaccurate. We developed a hybridization protection assay (HPA) for telomere repeats.<br><br>METHODS: We heated 5 microL of DNA solution or 10 microL of cell or tissue lysate at 95 degrees C for 5 min, mixed it with 100 microL of hybridization solution containing 3 x 10(6) relative light units of acridinium ester-labeled probe, and incubated the mixture for 20 min at 60 degrees C. We then added 300 microL of selection buffer and incubated the mixture for 10 min at 60 degrees C to differentially hydrolyze unhybridized probe. Chemiluminescence was measured for 2 s per tube.<br><br>RESULTS: The amount of telomere repeats was assayed by HPA within linearity from 10 to 3000 ng of purified genomic DNA or from 1000 to 100 000 cell equivalents of lysate. To normalize the amount of DNA in lysate, the amount of Alu sequence was measured by HPA. A ratio of telomere to Alu (TA ratio) = 0.01 corresponded to approximately 2 kbp of mean TRF length determined by Southern blotting in cultured fibroblast and colorectal tissue samples. The TA ratio decreased from 0.06 to 0.02 with increasing division age from 30 to 90 population doubling levels of cultured human fetal fibroblasts. The assay required approximately 45 min from collection of cell or tissue samples.<br><br>CONCLUSIONS: The amount of telomere repeats was quantitatively measured by HPA in 10 ng of sheared genomic DNA or in the lysate of 1000 cells. This method is simple, rapid, quantitative, sensitive, and applicable to the measurement of telomere repeats in clinical samples such as needle biopsy specimen or as few as 1000 cells in body fluid or washings.},
}
@article {pmid10504477,
year = {1999},
author = {Dahse, R and Fiedler, W and Junker, K and Schlichter, A and Schubert, J and Claussen, U},
title = {Telomerase activity and telomere lengths: alterations in renal cell carcinomas.},
journal = {Kidney international},
volume = {56},
number = {4},
pages = {1289-1290},
doi = {10.1046/j.1523-1755.1999.00688.x},
pmid = {10504477},
issn = {0085-2538},
mesh = {Carcinoma, Renal Cell/*enzymology/genetics ; Cell Cycle/physiology ; Chromosome Aberrations ; DNA Primers ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Humans ; Kidney Neoplasms/*enzymology/genetics ; Polymorphism, Restriction Fragment Length ; Telomerase/*genetics/*metabolism ; Telomere/enzymology/*genetics ; },
abstract = {Detection of telomerase activity in renal cell carcinomas may be a key to understanding the loss of growth control in tumor cells. This enzyme forms the end of most chromosomal DNAs (that is, telomeres) found in renal tumors. When activated, the telomeres shorten with every cell cycle and then there is a compensatory lengthening of the cells, which then proliferate and eventually become immortal and metastasize. This complex multigenetic process may prove to be a useful marker of tumor progression and patient outcome.},
}
@article {pmid10503000,
year = {1999},
author = {Ishikawa, F and Naito, T},
title = {[Telomeres and sexual reproduction].},
journal = {Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme},
volume = {44},
number = {12 Suppl},
pages = {1674-1681},
pmid = {10503000},
issn = {0039-9450},
mesh = {Animals ; Ataxia Telangiectasia/genetics ; Chromosomes, Fungal/physiology ; Genome, Fungal ; Humans ; Meiosis ; Mutation ; Reproduction ; Ring Chromosomes ; Saccharomyces cerevisiae/genetics ; Telomere/*physiology ; },
}
@article {pmid10502812,
year = {1999},
author = {Zumstein, LA and Lundblad, V},
title = {Telomeres: has cancer's Achilles' heel been exposed?.},
journal = {Nature medicine},
volume = {5},
number = {10},
pages = {1129-1130},
doi = {10.1038/13451},
pmid = {10502812},
issn = {1078-8956},
mesh = {Cell Transformation, Neoplastic/*drug effects ; DNA Replication ; Drug Design ; Neoplasms/*drug therapy ; Telomerase/*antagonists &amp; inhibitors ; },
}
@article {pmid10502398,
year = {1999},
author = {Page, TJ and Mata, JE and Bridge, JA and Siebler, JC and Neff, JR and Iversen, PL},
title = {The cytotoxic effects of single-stranded telomere mimics on OMA-BL1 cells.},
journal = {Experimental cell research},
volume = {252},
number = {1},
pages = {41-49},
doi = {10.1006/excr.1999.4613},
pmid = {10502398},
issn = {0014-4827},
mesh = {Base Sequence ; Cell Death/drug effects/physiology ; Humans ; Hydrogen Bonding ; Neoplasms/drug therapy/enzymology/genetics ; Oligodeoxyribonucleotides/genetics/pharmacology ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects/*genetics/metabolism ; Thionucleotides/genetics/pharmacology ; Tumor Cells, Cultured ; },
abstract = {Telomerase is a ribonucleoprotein that adds 5'-d(TTAGGG)-3' hexameric repeats onto the 3' ends of chromosomes. High telomerase activity has been associated with immortal cells, transformed cells, mitogenic stimulation, and proliferative diseases. It is not clear what phenotype would be observed by transient inhibition of telomerase. Studies were designed to inhibit telomerase activity using a series of S-ODN telomere sequence motifs. The studies evaluated the length, hydrogen bonding, and sequence requirements of telomerase inhibition using the TRAP assay and a bioassay measuring cell viability following exposure to the compounds. In addition, we have also studied the role of the 3' end and secondary structure of telomere mimics on telomerase inhibition. Observations reveal that sensitivity to the S-ODNs may not require hybridization to an antisense target but required guanine nucleotides on the 3' end for cells in culture and telomerase inhibition in vitro. The importance of H bonding and the requirement for a free 3' end for the activity of these compounds has also been demonstrated. However, transient inhibition of telomerase is not cytotoxic to all immortal cells and is not sufficient to explain the mechanism of cytotoxicity of these short oligonucleotides.},
}
@article {pmid10500096,
year = {1999},
author = {Zhang, X and Mar, V and Zhou, W and Harrington, L and Robinson, MO},
title = {Telomere shortening and apoptosis in telomerase-inhibited human tumor cells.},
journal = {Genes &amp; development},
volume = {13},
number = {18},
pages = {2388-2399},
pmid = {10500096},
issn = {0890-9369},
mesh = {Apoptosis/*physiology ; Blotting, Western ; Cell Division ; Cell Line ; DNA-Binding Proteins ; Flow Cytometry ; Genes, Dominant ; Humans ; Mitosis ; Mutagenesis ; *RNA ; Telomerase/genetics/*metabolism ; Telomere/genetics/*physiology ; Time Factors ; Transfection ; Tumor Cells, Cultured ; },
abstract = {Despite a strong correlation between telomerase activity and malignancy, the outcome of telomerase inhibition in human tumor cells has not been examined. Here, we have addressed the role of telomerase activity in the proliferation of human tumor and immortal cells by inhibiting TERT function. Inducible dominant-negative mutants of hTERT dramatically reduced the level of endogenous telomerase activity in tumor cell lines. Clones with short telomeres continued to divide, then exhibited an increase in abnormal mitoses followed by massive apoptosis leading to the loss of the entire population. This cell death was telomere-length dependent, as cells with long telomeres were viable but exhibited telomere shortening at a rate similar to that of mortal cells. It appears that telomerase inhibition in cells with short telomeres lead to chromosomal damage, which in turn trigger apoptotic cell death. These results provide the first direct evidence that telomerase is required for the maintenance of human tumor and immortal cell viability, and suggest that tumors with short telomeres may be effectively and rapidly killed following telomerase inhibition.},
}
@article {pmid10500091,
year = {1999},
author = {Blasco, MA and Gasser, SM and Lingner, J},
title = {Telomeres and telomerase.},
journal = {Genes &amp; development},
volume = {13},
number = {18},
pages = {2353-2359},
doi = {10.1101/gad.13.18.2353},
pmid = {10500091},
issn = {0890-9369},
mesh = {Aging/genetics ; Animals ; Cell Nucleolus/enzymology/genetics ; Cells, Cultured ; Genes, Fungal ; Humans ; Mice ; Mice, Knockout ; Models, Biological ; Neoplasms/enzymology/genetics ; Spain ; Telomerase/genetics/*physiology ; Telomere/genetics/*physiology ; },
}
@article {pmid10498864,
year = {1999},
author = {Saretzki, G and Sitte, N and Merkel, U and Wurm, RE and von Zglinicki, T},
title = {Telomere shortening triggers a p53-dependent cell cycle arrest via accumulation of G-rich single stranded DNA fragments.},
journal = {Oncogene},
volume = {18},
number = {37},
pages = {5148-5158},
doi = {10.1038/sj.onc.1202898},
pmid = {10498864},
issn = {0950-9232},
mesh = {Adenocarcinoma/pathology ; Amino Acid Substitution ; Brain Neoplasms/pathology ; Breast Neoplasms/pathology ; Cell Cycle/*physiology ; Cell Line, Transformed ; *DNA Fragmentation ; DNA, Single-Stranded/*metabolism ; Female ; Fibroblasts/physiology ; Genes, p53 ; Glioblastoma/pathology ; Guanine/analysis ; Humans ; Lung/cytology ; Neoplasm Proteins/physiology ; Ovarian Neoplasms/pathology ; Oxidative Stress ; Point Mutation ; Recombinant Fusion Proteins/physiology ; Telomerase/physiology ; Telomere/chemistry/*ultrastructure ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/*physiology ; },
abstract = {It has been repeatedly suspected that telomere shortening might be one possible trigger of the p53-dependent cell cycle arrest, although the mechanism of this arrest remained unclear. Telomeres in human cells under mild oxidative stress accumulate single-strand damage faster than interstitial repetitive sequences. In MRC-5 fibroblasts and U87 glioblastoma cells, which both express wild-type p53, oxidative stress-mediated production of single-strand damage in telomeres is concomitant to the accumulation of p53 and p21 and to cell cycle arrest. This response can be modeled by treatment of cells with short single stranded telomeric G-rich DNA fragments. The arrest is transient in U87 cells. Recovery from it is accompanied by up-regulation of telomerase activity and elongation of telomeres. Overexpression of mutated p53 is sufficient to reverse the phenotype of inhibition as well as the delayed activation of telomerase. These data suggest that the production of G-rich single stranded fragments during the course of telomere shortening is sufficient to trigger a p53 dependent cell cycle arrest.},
}
@article {pmid10497268,
year = {1999},
author = {Hacia, JG and Novotny, EA and Mayer, RA and Woski, SA and Ashlock, MA and Collins, FS},
title = {Design of modified oligodeoxyribonucleotide probes to detect telomere repeat sequences in FISH assays.},
journal = {Nucleic acids research},
volume = {27},
number = {20},
pages = {4034-4039},
doi = {10.1093/nar/27.20.4034},
pmid = {10497268},
issn = {1362-4962},
mesh = {Base Sequence ; Binding Sites ; *In Situ Hybridization, Fluorescence ; Models, Chemical ; Molecular Sequence Data ; Oligodeoxyribonucleotides/*chemical synthesis ; *Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; },
abstract = {A series of dye-labeled oligonucleotide probes containing base and sugar modifications were tested for the ability to detect telomeric repeat sequences in FISH assays. These modified oligonucleotides, all 18 nt in length, were complementary to either the cytidine-rich (C(3)TA(2))(n)or guanosine-rich (T(2)AG(3))(n)telomere target sequences. Oligonucleotides were modified to either increase target affinity by enhancing duplex stability [2'-OMe ribose sugars and 5-(1-propynyl)pyrimidine residues] or inhibit the formation of inter- or intramolecular structures (7-deazaguanosine and 6-thioguanosine residues), which might interfere with binding to the target. Several dye-labeled oligonucleotide probes were found that could effectively stain the telomeric repeat sequences of either cytidine- or guanosine-rich strands in a specific manner. Such probes could be used as an alternative to peptide nucleic acids for investigating the dynamics of telomere length and maintenance. In principle, these relatively inexpensive and readily synthesized modified oligonucleotides could be used for other FISH-related assays.},
}
@article {pmid10497259,
year = {1999},
author = {Hemann, MT and Greider, CW},
title = {G-strand overhangs on telomeres in telomerase-deficient mouse cells.},
journal = {Nucleic acids research},
volume = {27},
number = {20},
pages = {3964-3969},
doi = {10.1093/nar/27.20.3964},
pmid = {10497259},
issn = {1362-4962},
support = {CA16519/CA/NCI NIH HHS/United States ; GM07814/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; Electrophoresis, Gel, Pulsed-Field ; In Situ Hybridization ; Liver/ultrastructure ; Mice ; Mice, Inbred C57BL ; Telomerase/deficiency/*physiology ; Telomere/*ultrastructure ; },
abstract = {Telomeres of eukaryotic chromosomes contain 3' overhangs which are thought to be essential for the maintenance of proper chromosome end structure and function. We examined the requirement for telomerase activity for the generation of these G-strand overhangs in mammalian cells. Using non-denaturing in-gel hybridization to both tissue and cultured cells from mice deficient for the telomerase RNA component, we found that G-strand overhangs exist in the absence of telomerase activity. Quantitation of overhang signal intensity showed no significant reduction in telomerase-deficient cells relative to wild-type. These results support a telomerase-independent mechanism for generating G-strand overhangs.},
}
@article {pmid10493971,
year = {1999},
author = {Rha, SY and Park, KH and Kim, TS and Yoo, NC and Yang, WI and Roh, JK and Min, JS and Lee, KS and Kim, BS and Choi, JH and Lim, HY and Chung, HC},
title = {Changes of telomerase and telomere lengths in paired normal and cancer tissues of breast.},
journal = {International journal of oncology},
volume = {15},
number = {4},
pages = {839-845},
doi = {10.3892/ijo.15.4.839},
pmid = {10493971},
issn = {1019-6439},
mesh = {Adult ; Aged ; Blotting, Southern ; Breast/*chemistry/*enzymology ; Breast Neoplasms/*enzymology/*genetics ; Dose-Response Relationship, Drug ; Female ; Humans ; Middle Aged ; Polymorphism, Restriction Fragment Length ; Ribonuclease, Pancreatic/pharmacology ; Telomerase/antagonists &amp; inhibitors/*metabolism ; Telomere/*genetics ; },
abstract = {To attain the immortal phenotype, cancer cells must overcome the mitotic clock. Telomerase activity has been identified to be activated in malignant tumors including breast cancer. Telomerase activity was evaluated in 71 breast cancer tissues and paired normal tissues with the TRAP (telomerase repeat amplification protocol) assay. Telomerase activity was calculated and translated into arbitrary units by computer-assisted densitometry with the control of telomerase activity in the 293 control cell line. In 59 paired breast tissues with telomerase activity, terminal restriction fragment (TRF) lengths were measured using Southern blotting. Relative inhibition (RI), the ratio of inhibited telomerase activity in each tumor tissue compared to that of the 293 control cell line after pre-treatment with 150 microg/ml of RNAse A, was measured. Sixty-three of 71 cancer tissues showed telomerase activity (88.7%) with 75.3+/-17.9 units in densitometry, while no telomerase activity was detected in their paired normal tissues. Telomerase activity was correlated to node metastasis (p=0.02) and stage (p=0.005), but not to tumor size or the hormonal receptor status. TRF lengths were 11. 0+/-4.7 kb in 59 tumor tissues and 11.7+/-2.2 kb in paired normal tissues. TRF lengths did not correlate to any of the clinical parameters. However changes of TRF lengths in tumor tissues compared to those of normal tissues correlated to telomerase activity. RI in the tumor tissues was proportional to telomerase activity without RNAse A pre-treatment. In breast cancer, telomerase activity was specific to tumor tissues and increased with tumor progression. Telomerase activity and changes in TRF lengths can be used as guidelines in detecting candidates for the telomerase inhibitor.},
}
@article {pmid10491534,
year = {1999},
author = {Wu, K and Lund, M and Bang, K and Thestrup-Pedersen, K},
title = {Telomerase activity and telomere length in lymphocytes from patients with cutaneous T-cell lymphoma.},
journal = {Cancer},
volume = {86},
number = {6},
pages = {1056-1063},
pmid = {10491534},
issn = {0008-543X},
mesh = {Aged ; Aged, 80 and over ; Cell Line ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Lymphoma, T-Cell, Cutaneous/blood/*enzymology/genetics ; Male ; Middle Aged ; Monocytes/enzymology ; Skin Neoplasms/blood/*enzymology/genetics ; T-Lymphocytes/*enzymology ; Telomerase/genetics/*metabolism ; Telomere/*chemistry ; },
abstract = {BACKGROUND: Telomeres shorten with successive cell divisions in normal somatic cells. Telomerase is a ribonucleoprotein enzyme associated with cellular proliferation and plays an important role in maintaining the stability of chromosomes and the length of DNA telomeres. Telomerase activity has been detected in tissues from many human tumors, but is not present in the majority of normal tissues. Thus, measurement of telomerase activity and telomere length may contribute to understanding the mechanism of tumorigenesis and provide useful diagnostic or prognostic information. The aim of this study was to investigate the telomerase activity and telomere length from patients with cutaneous T-cell lymphoma (CTCL).<br><br>METHODS: Eighteen skin-homing T-cell lines were established from skin biopsies and 10 peripheral blood mononuclear cells (PBMC) were isolated from patients with various stages of CTCL together with 22 PBMC from healthy donors. For each sample an identical amount of cellular protein was measured quantitatively for telomerase activity using the telomerase polymerase chain reaction-enzyme-linked immunosorbent assay based on the telomeric repeat amplification protocol method. Telomere length was assayed using a commercial kit.<br><br>RESULTS: Eight of ten PBMC and 16 of 18 skin-homing T-cell lines from patients with CTCL showed moderate to strong telomerase activity. Freshly obtained PBMC from healthy donors showed weak levels of telomerase activity. A shorter telomere length was found in cell lines and PBMC from patients with CTCL compared with healthy controls. Four skin-homing T-cell lines going into growth crisis showed sharply reduced telomerase activity.<br><br>CONCLUSIONS: The results of the current study indicate that both skin-homing T-cells and PBMC from CTCL have high telomerase activity and short telomere length. These changes are similar to the changes observed in the majority of malignant cells including other types of T-cell lymphoma. It is interesting to note that even in the very early stages of CTCL such as parapsoriasis (which is a clinically benign disease) the changes already are present, indicating that a significantly high level of telomerase activity frequently occurs in CTCL and may be an important event in tumorigenesis. Telomerase activity and telomere length are useful markers for CTCL risk assessment.},
}
@article {pmid10491289,
year = {1999},
author = {Kakuo, S and Asaoka, K and Ide, T},
title = {Human is a unique species among primates in terms of telomere length.},
journal = {Biochemical and biophysical research communications},
volume = {263},
number = {2},
pages = {308-314},
doi = {10.1006/bbrc.1999.1385},
pmid = {10491289},
issn = {0006-291X},
mesh = {Aging/genetics ; Animals ; Cellular Senescence/genetics ; DNA Restriction Enzymes ; Female ; Hominidae/*genetics ; Humans ; Macaca/*genetics ; Male ; Pan troglodytes/genetics ; Pongo pygmaeus/genetics ; Telomerase/analysis ; *Telomere ; Tissue Distribution ; },
abstract = {TRF (terminal restriction fragments) length in various tissues of non-human primates such as Macaca mulatta (rhesus monkey), Macaca fuscata (Japanese monkey), Macaca fascicularis (crab-eating monkey), Pan troglodytes (common chimpanzee), and Pongo pygmaeus (orangutan) was at least 23 kb without exception, which was quite different from that of human somatic tissues (smaller than 10 kb). The distribution pattern of telomerase activity among tissues was similar between human and non-human primates, while the activity level showed some differences such as that strong telomerase activity was observed in gastrointestinal and lymphocytic tissues from non-human primates. The human appears to be a unique species among primates in terms of telomere length.},
}
@article {pmid10490633,
year = {1999},
author = {Smilenov, LB and Dhar, S and Pandita, TK},
title = {Altered telomere nuclear matrix interactions and nucleosomal periodicity in ataxia telangiectasia cells before and after ionizing radiation treatment.},
journal = {Molecular and cellular biology},
volume = {19},
number = {10},
pages = {6963-6971},
pmid = {10490633},
issn = {0270-7306},
support = {R01 NS034746/NS/NINDS NIH HHS/United States ; NS34746/NS/NINDS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Ataxia Telangiectasia/*genetics ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins ; Chromatin/*ultrastructure ; Chromosome Aberrations/genetics ; Chromosome Disorders ; Colorectal Neoplasms/genetics ; DNA-Binding Proteins/genetics ; Female ; Humans ; Infant ; Male ; Nuclear Matrix/*metabolism/radiation effects ; Nucleosomes/*metabolism ; Peptide Fragments/genetics/metabolism ; Protein Binding/radiation effects ; Protein Serine-Threonine Kinases/genetics ; Radiation Tolerance ; Radiation, Ionizing ; Telomere/*metabolism/radiation effects ; Telomeric Repeat Binding Protein 2 ; Tumor Suppressor Proteins ; },
abstract = {Cells derived from ataxia telangiectasia (A-T) patients show a prominent defect at chromosome ends in the form of chromosome end-to-end associations, also known as telomeric associations, seen at G(1), G(2), and metaphase. Recently, we have shown that the ATM gene product, which is defective in the cancer-prone disorder A-T, influences chromosome end associations and telomere length. A possible hypothesis explaining these results is that the defective telomere metabolism in A-T cells are due to altered interactions between the telomeres and the nuclear matrix. We examined these interactions in nuclear matrix halos before and after radiation treatment. A difference was observed in the ratio of soluble versus matrix-associated telomeric DNA between cells derived from A-T and normal individuals. Ionizing radiation treatment affected the ratio of soluble versus matrix-associated telomeric DNA only in the A-T cells. To test the hypothesis that the ATM gene product is involved in interactions between telomeres and the nuclear matrix, we examined such interactions in human cells expressing either a dominant-negative effect or complementation of the ATM gene. The phenotype of RKO colorectal tumor cells expressing ATM fragments containing a leucine zipper motif mimics the altered interactions of telomere and nuclear matrix similar to that of A-T cells. A-T fibroblasts transfected with wild-type ATM gene had corrected telomere-nuclear matrix interactions. Further, we found that A-T cells had different micrococcal nuclease digestion patterns compared to normal cells before and after irradiation, indicating differences in nucleosomal periodicity in telomeres. These results suggest that the ATM gene influences the interactions between telomeres and the nuclear matrix, and alterations in telomere chromatin could be at least partly responsible for the pleiotropic phenotypes of the ATM gene.},
}
@article {pmid10490336,
year = {1999},
author = {Evans, SK and Bertuch, AA and Lundblad, V},
title = {Telomeres and telomerase: at the end, it all comes together.},
journal = {Trends in cell biology},
volume = {9},
number = {8},
pages = {329-331},
doi = {10.1016/s0962-8924(99)01596-2},
pmid = {10490336},
issn = {0962-8924},
mesh = {Animals ; Cell Division ; *DNA Repair ; Humans ; Telomerase/*physiology ; Telomere/*physiology ; },
}
@article {pmid10488338,
year = {1999},
author = {Walther, TC and Kennell, JC},
title = {Linear mitochondrial plasmids of F. oxysporum are novel, telomere-like retroelements.},
journal = {Molecular cell},
volume = {4},
number = {2},
pages = {229-238},
doi = {10.1016/s1097-2765(00)80370-6},
pmid = {10488338},
issn = {1097-2765},
mesh = {Base Sequence ; Cloning, Molecular ; DNA, Complementary ; DNA, Fungal/chemistry/genetics ; DNA, Mitochondrial/chemistry/*genetics ; Fusarium/*genetics ; Genome, Fungal ; Mitochondria/*genetics ; Molecular Sequence Data ; Nucleic Acid Conformation ; Plants/microbiology ; Plasmids/*genetics ; RNA/chemistry/*genetics ; RNA, Fungal/chemistry/genetics ; RNA, Mitochondrial ; Restriction Mapping ; Reverse Transcriptase Polymerase Chain Reaction ; Telomere/*genetics ; },
abstract = {Diverse types of linear RNA and DNA autonomously replicating genetic elements exist in prokaryotic and eukaryotic hosts, yet linear elements that replicate by reverse transcription have not been identified. Here, we report the sequence and organization of two linear mitochondrial plasmids of the fungal plant pathogen F. oxysporum and the characterization of a plasmid-associated reverse transcriptase activity. Plasmids pFOXC2 and pFOXC3 are 1.9 kb in length and have a "clothespin" genomic structure, which includes a terminal hairpin and a telomere-like iteration of a 5 bp sequence at the other terminus. The retroplasmid replication cycle involves novel strategies for copying terminal sequences, which may provide clues concerning the origin of telomerase as well as the evolution of linear DNAs.},
}
@article {pmid10484873,
year = {1999},
author = {Losi, L and Dal Cin, P},
title = {[Telomeres: a review of the literature].},
journal = {Pathologica},
volume = {91},
number = {2},
pages = {121-123},
pmid = {10484873},
issn = {0031-2983},
mesh = {Aging, Premature/genetics ; Animal Population Groups/genetics ; Animals ; Cellular Senescence ; Chromosomes, Human/genetics/ultrastructure ; Humans ; Plants/genetics ; Repetitive Sequences, Nucleic Acid ; *Telomere ; },
}
@article {pmid10471744,
year = {1999},
author = {Tolmachova, T and Simpson, K and Huxley, C},
title = {Analysis of a YAC with human telomeres and oriP from epstein-barr virus in yeast and 293 cells.},
journal = {Nucleic acids research},
volume = {27},
number = {18},
pages = {3736-3744},
doi = {10.1093/nar/27.18.3736},
pmid = {10471744},
issn = {1362-4962},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Blotting, Southern ; Cation Exchange Resins ; Cell Line ; Chromosomes, Artificial, Yeast/*genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; DNA, Circular/genetics ; DNA, Recombinant/genetics ; DNA, Viral/genetics ; Electrophoresis, Gel, Pulsed-Field ; Genetic Markers/genetics ; Genetic Vectors/genetics ; Herpesvirus 4, Human/*genetics ; Humans ; Lipids ; Mutagenesis, Insertional/*genetics/methods ; Recombination, Genetic/genetics ; Replication Origin/*genetics ; Saccharomyces cerevisiae/*genetics ; Telomere/*genetics ; Tetrahymena/genetics ; Transfection ; Tumor Cells, Cultured ; },
abstract = {One approach to the construction and propagation of a mammalian artificial chromosome is to build it up in Saccharomyces cerevisiae, using a yeast artificial chromosome (YAC) base. We have demonstrated that circular YACs carrying the Epstein-Barr virus origin of plasmid replication (oriP) are maintained as stable, episomal elements in human cells. We wished to determine whether this technology could be extended, to generate linear extrachromosomal elements. Here, we describe the generation of retrofitting constructs, which permit the addition of human telomeres and the oriP domain to YACs. The constructs contain 0.8 kb of human telomere sequence separated by a unique Not I site from 0.7 kb of Tetrahymena telomere sequence. These constructs seed telomere formation with approximately 40-60% efficiency in human 293-EBNA and HT1080 cells whether or not the Tetrahymena sequence is removed by Not I digestion. A detailed analysis demonstrates that YACs carrying the human telomere cassettes on both arms show instability of the telomere sequences in S.cerevisiae at a frequency of approximately 50%. Introduction of correctly retrofitted, linear oriP YACs into human 293-EBNA cells by lipofection resulted in the generation of circular extrachromosomal elements varying in size from 8 to 300 kb. However, no apparently linear YACs could be detected, suggesting that extrachromosomal maintenance of DNA with the oriP /EBNA-1 system is not compatible with linear molecules capped by telomeres.},
}
@article {pmid10471503,
year = {1999},
author = {d'Adda di Fagagna, F and Hande, MP and Tong, WM and Lansdorp, PM and Wang, ZQ and Jackson, SP},
title = {Functions of poly(ADP-ribose) polymerase in controlling telomere length and chromosomal stability.},
journal = {Nature genetics},
volume = {23},
number = {1},
pages = {76-80},
doi = {10.1038/12680},
pmid = {10471503},
issn = {1061-4036},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Aneuploidy ; Animals ; Chromosome Aberrations ; Chromosomes/*physiology ; Crosses, Genetic ; DNA Restriction Enzymes/metabolism ; Fibroblasts ; Genotype ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nucleic Acid Hybridization ; Poly(ADP-ribose) Polymerases/*genetics/*physiology ; Telomere/genetics/*physiology ; },
abstract = {In most eukaryotes, poly(ADP-ribose) polymerase (PARP) recognizes DNA strand interruptions generated in vivo. DNA binding by PARP triggers primarily its own modification by the sequential addition of ADP-ribose units to form polymers; this modification, in turn, causes the release of PARP from DNA ends. Studies on the effects of the disruption of the gene encoding PARP (Adprt1, formerly Adprp) in mice have demonstrated roles for PARP in recovery from DNA damage and in suppressing recombination processes involving DNA ends. Telomeres are the natural termini of chromosomes and are, therefore, potential targets of PARP. Here, by the use of two different techniques, we show that mice lacking PARP display telomere shortening compared with wild-type mice. Telomere shortening is seen in different genetic backgrounds and in different tissues, both from embryos and adult mice. In vitro telomerase activity, however, is not altered in Adprt1-/- mouse fibroblasts. Furthermore, cytogenetic analysis of mouse embryonic fibroblasts reveals that lack of PARP is associated with severe chromosomal instability, characterized by increased frequencies of chromosome fusions and aneuploidy. The absence of PARP does not affect the presence of single-strand overhangs, naturally present at the ends of telomeres. This study therefore reveals an unanticipated role for PARP in telomere length regulation and provides insights into its functions in maintaining genomic integrity.},
}
@article {pmid10471333,
year = {1999},
author = {Wright, WE and Tesmer, VM and Liao, ML and Shay, JW},
title = {Normal human telomeres are not late replicating.},
journal = {Experimental cell research},
volume = {251},
number = {2},
pages = {492-499},
doi = {10.1006/excr.1999.4602},
pmid = {10471333},
issn = {0014-4827},
support = {AG07992/AG/NIA NIH HHS/United States ; },
mesh = {Base Composition ; Bromodeoxyuridine/immunology/metabolism ; Cells, Cultured ; Cellular Senescence ; *DNA Replication ; Diploidy ; Fibroblasts ; Heterochromatin ; Humans ; Male ; *Models, Genetic ; Periodicity ; S Phase/*genetics ; Telomerase/genetics/metabolism ; *Telomere/immunology ; Time Factors ; },
abstract = {Telomeres in yeast are late replicating. Genes placed next to telomeres in yeast can be repressed (telomere positional effects), leading to the hypothesis that telomeres may be heterochromatic and may control the expression of subtelomeric genes. In addition, yeast telomeres are processed to have a transient long overhang at the end of S phase. The applicability of the yeast data to human biology was examined by determining the timing of telomere replication and processing in normal human diploid fibroblasts. Telomeres were purified from synchronized cells that had been labeled with 5-bromodeoxyuridine (BrdU) at hourly intervals, and the fraction of labeled telomeres was analyzed by retrieval with anti-BrdU antibodies. We determined that normal human telomeres replicate throughout S phase rather than being very late replicating. Furthermore, the overall timing of replication was unaffected by telomere length in young versus old cells or cells whose telomeres had been elongated following transfection with the catalytic subunit of telomerase. Finally, the asymmetry in the length of the G-rich overhang in daughter telomeres produced by leading versus lagging strand synthesis was shown to be established within 1 h of telomere replication, indicating there is no significant delay between synthesis and the processing events that contribute to the establishment of asymmetric overhangs. Therefore, the timings of replication and processing of human telomeres are very different from those of yeast.},
}
@article {pmid10467331,
year = {1999},
author = {Lee, J and Kook, H and Chung, I and Kim, H and Park, M and Kim, C and Nah, J and Hwang, T},
title = {Telomere length changes in patients undergoing hematopoietic stem cell transplantation.},
journal = {Bone marrow transplantation},
volume = {24},
number = {4},
pages = {411-415},
doi = {10.1038/sj.bmt.1701923},
pmid = {10467331},
issn = {0268-3369},
mesh = {Adolescent ; Adult ; Aged ; Aging ; *Bone Marrow Transplantation ; Child ; Child, Preschool ; Female ; *Hematopoietic Stem Cell Transplantation ; Humans ; Infant ; Infant, Newborn ; Leukemia/blood/pathology/*therapy ; Male ; Middle Aged ; Reference Values ; Regression Analysis ; Telomere/pathology/*ultrastructure ; Tissue Donors ; Transplantation, Autologous ; Transplantation, Homologous ; Wiskott-Aldrich Syndrome/blood/pathology/*therapy ; },
abstract = {Telomere length indicates the replicative history of cells, serving as a molecular measure of the replicative potential remaining in cells. To investigate telomere length changes in hematopoietic stem cells, patients undergoing hematopoietic stem cell transplantation (HSCT) were evaluated. Fifteen patients after allogeneic bone marrow transplantation (allo-BMT group), seven patients after autologous peripheral blood stem cell transplantation (auto-PBSCT group), and 39 healthy controls were studied. Telomere length was measured in peripheral mononuclear cells by Southern blot hybridization. There was no significant difference between the allo-BMT and the auto-PBSCT groups. In the allo-BMT group, the mean telomere length of recipients was 2.01 kb shorter than that of their donors (P = 0. 008), and was 1.59 kb shorter than that of age-matched putative normal controls (P = 0.002). Telomere shortening in the allo-BMT group was equivalent to 41.4 years of aging in the donors, and to 52. 4 years of aging in the normal controls. The mean telomere length in the auto-PBSCT group was 2.36 kb shorter than that of the age-matched putative controls (P = 0.043), which was equivalent to 61.5 years of aging in normal controls. The extent of telomere shortening in the allo-BMT group showed a trend to negative correlation with the number of mononuclear cells infused. These findings suggest that hematopoietic stem cells after HSCT lose telomere length and these shortened telomeres may result in a higher incidence of clonal disorders later in life.},
}
@article {pmid10461825,
year = {1999},
author = {Wolthers, KC and Noest, AJ and Otto, SA and Miedema, F and De Boer, RJ},
title = {Normal telomere lengths in naive and memory CD4+ T cells in HIV type 1 infection: a mathematical interpretation.},
journal = {AIDS research and human retroviruses},
volume = {15},
number = {12},
pages = {1053-1062},
doi = {10.1089/088922299310340},
pmid = {10461825},
issn = {0889-2229},
mesh = {CD4-Positive T-Lymphocytes/immunology/*ultrastructure ; Cross-Sectional Studies ; HIV Infections/*genetics/immunology ; HIV-1 ; Humans ; Immunologic Memory ; Longitudinal Studies ; Models, Theoretical ; Polymorphism, Restriction Fragment Length ; *Telomere ; },
abstract = {To study CD4+ T cell productivity during HIV-1 infection, CD4+ T cell telomere lengths were measured. Cross-sectional and longitudinal analysis of HIV-1-infected individuals with CD4+ T cells counts >300 cells/mm3 showed normal average telomeric restriction fragment (TRF) length and normal shortening rates of CD45RA+ naive and CD45RO+ memory CD4+ T cells. These TRF data were interpreted in terms of CD4+ T cell production by means of a mathematical model. This model resolves previous criticisms arguing that the normal TRF length of CD4+ T cells in HIV-1 clinical latency is due to the killing of dividing CD4+ T cells by the virus. Only an increased priming rate of naive CD4+ T cells to become memory cells may elongate the average TRF length of memory CD4+ T cells, and may therefore mask the shortening effect of increased turnover in the CD4+ memory T cell compartment. The data are more compatible with the notion that during HIV-1 clinical latency the turnover of CD4+ T cells is not markedly increased, however, and that HIV-related interference with renewal from progenitors plays a role in CD4+ T cell depletion. In such a "limited renewal" scenario disease progression is no longer a consequence of markedly increased CD4+ T cell production.},
}
@article {pmid10454639,
year = {1999},
author = {Agudo, M and Losada, A and Abad, JP and Pimpinelli, S and Ripoll, P and Villasante, A},
title = {Centromeres from telomeres? The centromeric region of the Y chromosome of Drosophila melanogaster contains a tandem array of telomeric HeT-A- and TART-related sequences.},
journal = {Nucleic acids research},
volume = {27},
number = {16},
pages = {3318-3324},
doi = {10.1093/nar/27.16.3318},
pmid = {10454639},
issn = {1362-4962},
mesh = {Animals ; *Centromere ; Chromosomes, Artificial, Yeast ; Drosophila melanogaster/*genetics ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Tandem Repeat Sequences ; *Telomere ; *Y Chromosome ; },
abstract = {Cytological and cytogenetic studies have previously defined the region needed for centromeric function in the Y chromosome of Drosophila melanogaster. We have identified a YAC clone that originated from this region. Molecular analysis of the YAC and genomic DNAs has allowed the description of a satellite DNA made of telomeric HeT-A- and TART-derived sequences and the construction of a long-range physical map of the heterochromatic region h18. Sequences within the YAC clone are conserved in the centromeric region of the sibling species Drosophila simulans. That telomere-derived DNA now forms part of the centromeric region of the Y chromosome could indicate a telomeric origin of this centromere. The existence of common determinants for the function of both centromeres and telomeres is discussed.},
}
@article {pmid10454595,
year = {1999},
author = {Schultze, P and Hud, NV and Smith, FW and Feigon, J},
title = {The effect of sodium, potassium and ammonium ions on the conformation of the dimeric quadruplex formed by the Oxytricha nova telomere repeat oligonucleotide d(G(4)T(4)G(4)).},
journal = {Nucleic acids research},
volume = {27},
number = {15},
pages = {3018-3028},
pmid = {10454595},
issn = {1362-4962},
support = {GM48123/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; Cations/pharmacology ; DNA/*chemistry/drug effects/genetics ; DNA, Protozoan/chemistry/drug effects/genetics ; Dimerization ; G-Quadruplexes ; Guanine/chemistry ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Nucleic Acid Conformation/*drug effects ; Oligodeoxyribonucleotides/chemistry/genetics ; Oxytricha/genetics ; Potassium/*pharmacology ; Quaternary Ammonium Compounds/*pharmacology ; Repetitive Sequences, Nucleic Acid/drug effects/genetics ; Sodium/*pharmacology ; Solutions ; Telomere/chemistry/drug effects/*genetics ; Titrimetry ; },
abstract = {The DNA sequence d(G(4)T(4)G(4)) [Oxy-1.5] consists of 1.5 units of the repeat in telomeres of Oxytricha nova and has been shown by NMR and X-ray crystallographic analysis to form a dimeric quadruplex structure with four guanine-quartets. However, the structure reported in the X-ray study has a fundamentally different conformation and folding topology compared to the solution structure. In order to elucidate the possible role of different counterions in this discrepancy and to investigate the conformational effects and dynamics of ion binding to G-quadruplex DNA, we compare results from further experiments using a variety of counterions, namely K(+), Na(+)and NH(4)(+). A detailed structure determination of Oxy-1.5 in solution in the presence of K(+)shows the same folding topology as previously reported with the same molecule in the presence of Na(+). Both conformations are symmetric dimeric quadruplexes with T(4)loops which span the diagonal of the end quartets. The stack of quartets shows only small differences in the presence of K(+)versus Na(+)counterions, but the T(4)loops adopt notably distinguishable conformations. Dynamic NMR analysis of the spectra of Oxy-1.5 in mixed Na(+)/K(+)solution reveals that there are at least three K(+)binding sites. Additional experiments in the presence of NH(4)(+)reveal the same topology and loop conformation as in the K(+)form and allow the direct localization of three central ions in the stack of quartets and further show that there are no specific NH(4)(+)binding sites in the T(4)loop. The location of bound NH(4)(+)with respect to the expected coordination sites for Na(+)binding provides a rationale for the difference observed for the structure of the T(4)loop in the Na(+)form, with respect to that observed for the K(+)and NH(4)(+)forms.},
}
@article {pmid10454554,
year = {1999},
author = {Ritchie, KB and Mallory, JC and Petes, TD},
title = {Interactions of TLC1 (which encodes the RNA subunit of telomerase), TEL1, and MEC1 in regulating telomere length in the yeast Saccharomyces cerevisiae.},
journal = {Molecular and cellular biology},
volume = {19},
number = {9},
pages = {6065-6075},
pmid = {10454554},
issn = {0270-7306},
support = {R01 GM024110/GM/NIGMS NIH HHS/United States ; GM24110/GM/NIGMS NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia Mutated Proteins ; Base Sequence ; Cell Cycle Proteins ; DNA Primers/genetics ; DNA-Binding Proteins ; Fungal Proteins/*genetics ; Genes, Fungal ; Humans ; Intracellular Signaling Peptides and Proteins ; Models, Genetic ; Molecular Sequence Data ; Mutation/genetics ; Nucleic Acid Conformation ; Phenotype ; Protein Conformation ; *Protein Serine-Threonine Kinases ; Proteins/*genetics ; RNA/chemistry/*genetics/*metabolism ; RNA, Fungal/chemistry/*genetics/*metabolism ; RNA, Long Noncoding ; *RNA, Untranslated ; Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomyces cerevisiae Proteins ; Telomerase/chemistry/*genetics/*metabolism ; Telomere/*metabolism ; Tumor Suppressor Proteins ; },
abstract = {In the yeast Saccharomyces cerevisiae, chromosomes terminate with a repetitive sequence [poly(TG(1-3))] 350 to 500 bp in length. Strains with a mutation of TEL1, a homolog of the human gene (ATM) mutated in patients with ataxia telangiectasia, have short but stable telomeric repeats. Mutations of TLC1 (encoding the RNA subunit of telomerase) result in strains that have continually shortening telomeres and a gradual loss of cell viability; survivors of senescence arise as a consequence of a Rad52p-dependent recombination events that amplify telomeric and subtelomeric repeats. We show that a mutation in MEC1 (a gene related in sequence to TEL1 and ATM) reduces telomere length and that tel1 mec1 double mutant strains have a senescent phenotype similar to that found in tlc1 strains. As observed in tlc1 strains, survivors of senescence in the tel1 mec1 strains occur by a Rad52p-dependent amplification of telomeric and subtelomeric repeats. In addition, we find that strains with both tel1 and tlc1 mutations have a delayed loss of cell viability compared to strains with the single tlc1 mutation. This result argues that the role of Tel1p in telomere maintenance is not solely a direct activation of telomerase.},
}
@article {pmid10449897,
year = {1999},
author = {Slijepcevic, P and Hande, MP},
title = {Chinese hamster telomeres are comparable in size to mouse telomeres.},
journal = {Cytogenetics and cell genetics},
volume = {85},
number = {3-4},
pages = {196-199},
doi = {10.1159/000015292},
pmid = {10449897},
issn = {0301-0171},
mesh = {Animals ; Chromosome Mapping ; Chromosomes/genetics ; Cricetinae ; Cricetulus/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Metaphase/genetics ; Mice/*genetics ; Telomere/*genetics ; },
abstract = {We report here the results of a telomere length analysis in four male Chinese hamsters by quantitative fluorescence in situ hybridization (Q-FISH). We were able to measure telomere length of 64 (73%) of 88 Chinese hamster telomeres. We could not measure telomere length in chromosome 10 or in the short arms of chromosomes 5, 6, 7 and 8 because of the overlaps between the interstitial and terminal telomeric signals. Our analysis in the 73% of Chinese hamster telomeres indicate that their average length is approximately 38 kb. Therefore, Chinese hamster telomeres are comparable in length to mouse telomeres, but are much longer than human telomeres. Similar to previous Q-FISH studies on human and mouse chromosomes, our results indicate that individual Chinese hamster chromosomes may have specific telomere lengths, suggesting that chromosome-specific factors may be involved in telomere length regulation.},
}
@article {pmid10449030,
year = {1999},
author = {Holt, SE and Glinsky, VV and Ivanova, AB and Glinsky, GV},
title = {Resistance to apoptosis in human cells conferred by telomerase function and telomere stability.},
journal = {Molecular carcinogenesis},
volume = {25},
number = {4},
pages = {241-248},
pmid = {10449030},
issn = {0899-1987},
mesh = {Apoptosis/*genetics ; Cell Line, Transformed ; Cellular Senescence/genetics ; Humans ; Telomerase/*metabolism ; *Telomere ; },
abstract = {Cell senescence and programmed cell death (apoptosis) are two fundamental biological mechanisms that regulate proliferative capacity, survival potential, aging, and death of cells. Here we report several independent lines of experimental evidence that support the hypothesis that telomerase function and telomere length perform important roles in cell survival during apoptosis. First, with serum starvation and matrix-independent survival experiments, we found that young normal diploid cells were more resistant to apoptosis than their older counterparts. In addition, normal cells with stable telomere lengths caused by ectopic expression of telomerase maintained an increased resistance to serum starvation- and matrix-deprivation-induced programmed cell death compared with aged normal cells without telomerase. Second, we found that telomerase-positive immortalized SW39 cells had a higher survival ability and resistance to apoptosis than their telomerase-negative immortalized counterparts, SW13 and SW26. Third, we showed that telomerase-positive cells with experimentally elongated telomeres (GTR-IDH4 and GTR-DU145) acquired increased survival ability and higher resistance to apoptosis than the parental cell lines with shorter telomeres (IDH4 and DU145). Higher resistance to apoptosis of these cells was associated with a deficiency in two major apoptosis execution pathways: induction of nuclear calcium-dependent endonucleases and activation of the interleukin-1 beta-converting enzyme-family of proteases (caspases). Taken together, these results provide the first direct experimental evidence supporting the hypothesis that telomerase activity and maintenance of telomere stability are associated with increased cellular resistance to apoptosis.},
}
@article {pmid10444334,
year = {1999},
author = {Wong, AC and Shkolny, D and Dorman, A and Willingham, D and Roe, BA and McDermid, HE},
title = {Two novel human RAB genes with near identical sequence each map to a telomere-associated region: the subtelomeric region of 22q13.3 and the ancestral telomere band 2q13.},
journal = {Genomics},
volume = {59},
number = {3},
pages = {326-334},
doi = {10.1006/geno.1999.5889},
pmid = {10444334},
issn = {0888-7543},
support = {HG00313/HG/NHGRI NIH HHS/United States ; },
mesh = {Alternative Splicing ; Amino Acid Sequence ; Animals ; Base Sequence ; Blotting, Northern ; Cell Line ; Chromosome Mapping ; *Chromosomes, Human, Pair 2 ; *Chromosomes, Human, Pair 22 ; Cloning, Molecular ; DNA, Complementary ; GTP Phosphohydrolases/*genetics ; Gene Duplication ; Gene Expression ; Humans ; Molecular Sequence Data ; Sequence Analysis, DNA ; *Telomere ; rab GTP-Binding Proteins/*genetics ; ras Proteins ; },
abstract = {Two closely related genes have been identified at 2q13 and 22q13.3. These genes show similarity to members of the RAB family of small GTPases. RABL2A and RABL2B differ by three conservative amino acid changes over a total of 228 residues. Both are expressed in all tissues tested. Northern analysis showed that a 2.5-kb transcript is expressed in all tissues tested while a 1.4-kb transcript is specifically expressed only in muscle. The size difference between these two transcripts is the result of differential splicing of an intron within the 3' UTR. RABL2B is located within the subtelomeric region of 22q13.3. RABL2A maps to 2q13, the site of an ancestral telomere fusion event, suggesting that it also may be a subtelomeric gene.},
}
@article {pmid10441326,
year = {1999},
author = {Coleman, J and Baird, DM and Royle, NJ},
title = {The plasticity of human telomeres demonstrated by a hypervariable telomere repeat array that is located on some copies of 16p and 16q.},
journal = {Human molecular genetics},
volume = {8},
number = {9},
pages = {1637-1646},
doi = {10.1093/hmg/8.9.1637},
pmid = {10441326},
issn = {0964-6906},
mesh = {Base Sequence ; Blotting, Southern ; Chromosomes, Human, Pair 16/*genetics ; Cloning, Molecular ; Female ; Genetic Linkage ; Humans ; Male ; Molecular Sequence Data ; Mutation ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Repetitive Sequences, Nucleic Acid/*genetics ; Sequence Alignment ; Sequence Homology, Nucleic Acid ; Telomere/*genetics ; White People ; },
abstract = {Human telomeres are composed of tandem arrays of TTAGGG repeats with many variant repeats at the proximal ends. Comparison of the interspersion of variant and TTAGGG repeats between alleles can be used to study telomere instability, but the difficulty in identifying chromosome-specific sequences close to the start of autosomal telomeres has hampered such investigations. A chromosome end, including a telomere and adjacent sequence, that is polymorphic for its presence or absence in unrelated individuals has been identified. The telomere-adjacent DNA shows strong homology (92-99%) to sequences, including two expressed sequence tags, that are usually located in subterminal regions of human chromosomes but not adjacent to telomeres. Since this chromosome end arose, it has relocated at least once. In Caucasians, it forms the telomere of approximately 6% of 16q and 2% of 16p chromosome arms. The mechanism of relocation is unknown but must have involved the telomere-adjacent DNA rather than the telomere itself, as copies on 16p and 16q share the same telomere-adjacent sequence. The interspersion patterns of TTAGGG with TGAGGG, TTGGGG and non-amplifying repeat sequences revealed extensive allelic variation, such that 47 different alleles were observed among the 50 alleles mapped. Closely related alleles differ by small changes in copy number at blocks of adjacent like repeats, as seen at the Xp/Yp pseudoautosomal telomere. Such differences are compatible with a model in which the majority of mutations arise by intra-allelic mechanisms, in individuals hemizygous for a single copy of the chromosome end.},
}
@article {pmid10435634,
year = {1999},
author = {Ducray, C and Pommier, JP and Martins, L and Boussin, FD and Sabatier, L},
title = {Telomere dynamics, end-to-end fusions and telomerase activation during the human fibroblast immortalization process.},
journal = {Oncogene},
volume = {18},
number = {29},
pages = {4211-4223},
doi = {10.1038/sj.onc.1202797},
pmid = {10435634},
issn = {0950-9232},
mesh = {Cell Line, Transformed ; Cell Transformation, Neoplastic/*genetics/metabolism ; Cell Transformation, Viral/*genetics ; Centromere ; Chromosome Aberrations ; Chromosomes, Human/genetics/ultrastructure ; Fibroblasts/cytology/*metabolism ; Humans ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Metaphase ; Recombinant Fusion Proteins/physiology ; Simian virus 40/genetics/physiology ; Telomerase/*metabolism ; Telomere/*metabolism ; Transfection ; },
abstract = {Loss of telomeric repeats during cell proliferation could play a role in senescence. It has been generally assumed that activation of telomerase prevents further telomere shortening and is essential for cell immortalization. In this study, we performed a detailed cytogenetic and molecular characterization of four SV40 transformed human fibroblastic cell lines by regularly monitoring the size distribution of terminal restriction fragments, telomerase activity and the associated chromosomal instability throughout immortalization. The mean TRF lengths progressively decreased in pre-crisis cells during the lifespan of the cultures. At crisis, telomeres reached a critical size, different among the cell lines, contributing to the peak of dicentric chromosomes, which resulted mostly from telomeric associations. We observed a direct correlation between short telomere length at crisis and chromosomal instability. In two immortal cell lines, although telomerase was detected, mean telomere length still continued to decrease whereas the number of dicentric chromosomes associated was stabilized. Thus telomerase could protect specifically telomeres which have reached a critical size against end-to-end dicentrics, while long telomeres continue to decrease, although at a slower rate as before crisis. This suggests a balance between elongation by telomerase and telomere shortening, towards a stabilized 'optimal' length.},
}
@article {pmid10432279,
year = {1999},
author = {Rufer, N and Brümmendorf, TH and Kolvraa, S and Bischoff, C and Christensen, K and Wadsworth, L and Schulzer, M and Lansdorp, PM},
title = {Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood.},
journal = {The Journal of experimental medicine},
volume = {190},
number = {2},
pages = {157-167},
pmid = {10432279},
issn = {0022-1007},
support = {GM56162/GM/NIGMS NIH HHS/United States ; R01 AI029524/AI/NIAID NIH HHS/United States ; P01 AG008761/AG/NIA NIH HHS/United States ; AI29524/AI/NIAID NIH HHS/United States ; R21 AI029524/AI/NIAID NIH HHS/United States ; NIA-PO1-AG08761/AG/NIA NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/genetics/pathology ; Child ; Child, Preschool ; Female ; Flow Cytometry ; Granulocytes/*cytology ; Hematopoietic Stem Cells/*cytology ; Humans ; Immunologic Memory ; In Situ Hybridization, Fluorescence ; Infant ; Infant, Newborn ; Male ; Middle Aged ; T-Lymphocyte Subsets/*cytology/immunology ; Telomere/*genetics ; Terminal Repeat Sequences ; Twins, Dizygotic/genetics ; Twins, Monozygotic/genetics ; },
abstract = {To study telomere length dynamics in hematopoietic cells with age, we analyzed the average length of telomere repeat sequences in diverse populations of nucleated blood cells. More than 500 individuals ranging in age from 0 to 90 yr, including 36 pairs of monozygous and dizygotic twins, were analyzed using quantitative fluorescence in situ hybridization and flow cytometry. Granulocytes and naive T cells showed a parallel biphasic decline in telomere length with age that most likely reflected accumulated cell divisions in the common precursors of both cell types: hematopoietic stem cells. Telomere loss was very rapid in the first year, and continued for more than eight decades at a 30-fold lower rate. Memory T cells also showed an initial rapid decline in telomere length with age. However, in contrast to naive T cells, this decline continued for several years, and in older individuals lymphocytes typically had shorter telomeres than did granulocytes. Our findings point to a dramatic decline in stem cell turnover in early childhood and support the notion that cell divisions in hematopoietic stem cells and T cells result in loss of telomeric DNA.},
}
@article {pmid10432278,
year = {1999},
author = {Hodes, RJ},
title = {Telomere length, aging, and somatic cell turnover.},
journal = {The Journal of experimental medicine},
volume = {190},
number = {2},
pages = {153-156},
pmid = {10432278},
issn = {0022-1007},
mesh = {Animals ; B-Lymphocytes/cytology/physiology ; Cell Division/genetics/physiology ; Cellular Senescence/*genetics/physiology ; Humans ; In Situ Hybridization, Fluorescence ; Models, Biological ; T-Lymphocyte Subsets/cytology/physiology ; Telomerase/physiology ; Telomere/*genetics/physiology ; },
}
@article {pmid10430581,
year = {1999},
author = {Craven, RJ and Petes, TD},
title = {Dependence of the regulation of telomere length on the type of subtelomeric repeat in the yeast Saccharomyces cerevisiae.},
journal = {Genetics},
volume = {152},
number = {4},
pages = {1531-1541},
pmid = {10430581},
issn = {0016-6731},
support = {GM24110/GM/NIGMS NIH HHS/United States ; },
mesh = {Carrier Proteins/genetics/physiology ; Chromosomes, Fungal/*ultrastructure ; DNA Helicases/genetics/physiology ; DNA, Fungal/*genetics ; DNA-Binding Proteins/genetics/physiology ; Epistasis, Genetic ; Fungal Proteins/genetics/*physiology ; Intracellular Signaling Peptides and Proteins ; Protein Serine-Threonine Kinases ; *Repetitive Sequences, Nucleic Acid ; Repressor Proteins/genetics/physiology ; Saccharomyces cerevisiae/genetics/*ultrastructure ; *Saccharomyces cerevisiae Proteins ; Telomere/*ultrastructure ; *Telomere-Binding Proteins ; },
abstract = {In the yeast Saccharomyces cerevisiae, chromosomes terminate with approximately 400 bp of a simple repeat poly(TG(1-3)). Based on the arrangement of subtelomeric X and Y' repeats, two types of yeast telomeres exist, those with both X and Y' (Y' telomeres) and those with only X (X telomeres). Mutations that result in abnormally short or abnormally long poly(TG(1-3)) tracts have been previously identified. In this study, we investigated telomere length in strains with two classes of mutations, one that resulted in short poly(TG(1-3)) tracts (tel1) and one that resulted in elongated tracts (pif1, rap1-17, rif1, or rif2). In the tel1 pif1 strain, Y' telomeres had about the same length as those in tel1 strains and X telomeres had lengths intermediate between those in tel1 and pif1 strains. Strains with either the tel1 rap1-17 or tel1 rif2 genotypes had short tracts for all chromosome ends examined, demonstrating that the telomere elongation characteristic of rap1-17 and rif2 strains is Tel1p-dependent. In strains of the tel1 rif1 or tel1 rif1 rif2 genotypes, telomeres with Y' repeats had short terminal tracts, whereas most of the X telomeres had long terminal tracts. These results demonstrate that the regulation of telomere length is different for X and Y' telomeres.},
}
@article {pmid10430579,
year = {1999},
author = {Matsuura, A and Naito, T and Ishikawa, F},
title = {Genetic control of telomere integrity in Schizosaccharomyces pombe: rad3(+) and tel1(+) are parts of two regulatory networks independent of the downstream protein kinases chk1(+) and cds1(+).},
journal = {Genetics},
volume = {152},
number = {4},
pages = {1501-1512},
pmid = {10430579},
issn = {0016-6731},
mesh = {Adenosine Triphosphatases/genetics/*physiology ; Ataxia Telangiectasia Mutated Proteins ; *Cell Cycle Proteins ; Checkpoint Kinase 1 ; Checkpoint Kinase 2 ; Chromosomes, Fungal/*ultrastructure ; DNA Helicases/genetics/*physiology ; DNA-Binding Proteins ; Fungal Proteins/*genetics/*physiology ; Orotic Acid/analogs &amp; derivatives/pharmacology ; Protein Kinases/*physiology ; *Protein Serine-Threonine Kinases ; Proteins/physiology ; Radiation Tolerance/genetics ; Saccharomyces cerevisiae Proteins ; Schizosaccharomyces/drug effects/*genetics/ultrastructure ; *Schizosaccharomyces pombe Proteins ; Signal Transduction/*physiology ; Telomere/*ultrastructure ; Tumor Suppressor Proteins ; },
abstract = {The Schizosaccharomyces pombe checkpoint gene named rad3(+) encodes an ATM-homologous protein kinase that shares a highly conserved motif with proteins involved in DNA metabolism. Previous studies have shown that Rad3 fulfills its function via the regulation of the Chk1 and Cds1 protein kinases. Here we describe a novel role for Rad3 in the control of telomere integrity. Mutations in the rad3(+) gene alleviated telomeric silencing and produced shortened lengths in the telomere repeat tracts. Genetic analysis revealed that the other checkpoint rad mutations rad1, rad17, and rad26 belong to the same phenotypic class with rad3 with regard to control of the telomere length. Of these mutations, rad3 and rad26 have a drastic effect on telomere shortening. tel1(+), another ATM homologue in S. pombe, carries out its telomere maintenance function in parallel with the checkpoint rad genes. Furthermore, either a single or double disruption of cds1(+) and chk1(+) caused no obvious changes in the telomeric DNA structure. Our results demonstrate a novel role of the S. pombe ATM homologues that is independent of chk1(+) and cds1(+).},
}
@article {pmid10413649,
year = {1999},
author = {Kaushal, S and Landay, AL and Lederman, MM and Connick, E and Spritzler, J and Kuritzkes, DR and Kessler, H and Levine, BL and St Louis, DC and June, CH},
title = {Increases in T cell telomere length in HIV infection after antiretroviral combination therapy for HIV-1 infection implicate distinct population dynamics in CD4+ and CD8+ T cells.},
journal = {Clinical immunology (Orlando, Fla.)},
volume = {92},
number = {1},
pages = {14-24},
doi = {10.1006/clim.1999.4726},
pmid = {10413649},
issn = {1521-6616},
support = {AI 25879/AI/NIAID NIH HHS/United States ; AI 38858/AI/NIAID NIH HHS/United States ; },
mesh = {Adult ; Anti-HIV Agents/*therapeutic use ; CD4-Positive T-Lymphocytes/*virology ; CD8-Positive T-Lymphocytes/*virology ; Cell Division ; Cohort Studies ; HIV Infections/*drug therapy ; Humans ; Immunophenotyping ; Lymphocyte Count/drug effects ; Middle Aged ; Restriction Mapping ; Retroviridae/drug effects ; T-Lymphocytes/cytology ; Telomere/*genetics ; },
abstract = {Changes in mean telomeric terminal restriction fragment (TRF) length were examined as a marker for cellular replicative history in HIV-1-infected individuals after institution of anti-retroviral therapy (ART). Increases in mean T cell TRF lengths were observed in most patients following therapy; however, the contribution of individual T cell subsets was complex. An elongation of CD8+ T cell TRF was nearly uniformly observed while changes in mean TRF length in CD4+ T cells were heterogeneous as, despite potent suppression of viral replication, CD4 cell telomeres recovered in some patients, yet continued to decline in others. Increases in CD8 cell TRF correlated with decreased memory cells, suggesting a negative selection in the periphery for CD8 cells with extensive replicative history. In contrast, increases in CD4+ T cell TRF length correlated with increases in naive cell subsets, suggesting that the CD4+ T cell TRF increase may reflect a thymic contribution in some patients. These are the first increases in somatic cell telomere length in a population of cells observed in vivo, and the findings are compatible with therapy-induced reconstitution of the lymphoid compartment with cells having a more extensive replicative potential. These findings further distinguish lymphocytes from other somatic cell populations where only decreases in TRF over time have been noted. Thus, institution of ART in persons with moderately advanced HIV-1 disease reveals distinct population dynamics of CD4 and CD8 T cell subsets and also shows that the lymphocyte replicative history is dynamic.},
}
@article {pmid10413646,
year = {1999},
author = {Weng, N},
title = {Telomeres, telomerase, and lymphocyte replicative life span.},
journal = {Clinical immunology (Orlando, Fla.)},
volume = {92},
number = {1},
pages = {1-2},
doi = {10.1006/clim.1999.4741},
pmid = {10413646},
issn = {1521-6616},
mesh = {Cell Cycle ; Cell Division ; Cell Survival/physiology ; Humans ; Lymphocytes/*cytology ; *Telomerase ; *Telomere ; },
}
@article {pmid10408009,
year = {1999},
author = {Saretzki, G and von Zglinicki, T},
title = {[Replicative senescence as a model of aging: the role of oxidative stress and telomere shortening--an overview].},
journal = {Zeitschrift fur Gerontologie und Geriatrie},
volume = {32},
number = {2},
pages = {69-75},
doi = {10.1007/s003910050086},
pmid = {10408009},
issn = {0948-6704},
mesh = {Animals ; Biomarkers ; Cell Division/genetics ; Cellular Senescence/*genetics ; DNA Damage/genetics ; DNA Replication/*genetics ; Gene Expression/physiology ; Humans ; Lipid Peroxidation/*genetics ; *Oxidative Stress ; Telomere/*genetics ; },
abstract = {Replicative senescence is characterized by the irreversible loss of division potential of cultivated human and animal cells. Correlations between the replicative potential in vitro and the age of the donor or the maximal lifespan of the species suggest replicative senescence to be an appropriate model for aging. Telomeres of human somatic cells shorten with each cell division but are stabilized at constant length in tumors and immortal cells by the enzyme telomerase. The assumption of a causal role of telomere shortening for the limited lifespan of cells in vitro was borne out recently. We could demonstrate oxidative stress as a main reason for telomere shortening. Telomeres are sensors for oxidative damage in the genome. Telomeres shorten during in vivo aging as well; however, there are significant differences between individuals. Telomere erosion might play a major role for the aging of the immune system. Our data suggest that telomere shortening in vivo could reflect the cumulative amount of oxidative damage to the organism. It might be useful as a biomarker of aging.},
}
@article {pmid10405177,
year = {1999},
author = {Oikawa, S and Kawanishi, S},
title = {Site-specific DNA damage at GGG sequence by oxidative stress may accelerate telomere shortening.},
journal = {FEBS letters},
volume = {453},
number = {3},
pages = {365-368},
doi = {10.1016/s0014-5793(99)00748-6},
pmid = {10405177},
issn = {0014-5793},
mesh = {*Base Sequence ; Copper/pharmacology ; *DNA Damage ; Deoxyguanine Nucleotides/*metabolism ; Deoxyguanosine/metabolism ; Hydrogen Peroxide/pharmacology ; Hydroxylation ; Molsidomine/analogs &amp; derivatives/pharmacology ; Oligonucleotides/*metabolism ; Oxidative Stress/*physiology ; Telomere/*physiology ; },
abstract = {Telomere shortening during human aging has been reported to be accelerated by oxidative stress. We investigated the mechanism of telomere shortening by oxidative stress. H2O2 plus Cu(II) caused predominant DNA damage at the 5' site of 5'-GGG-3' in the telomere sequence. Furthermore, H2O2 plus Cu(II) induced 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation in telomere sequences more efficiently than that in non-telomere sequences. NO plus O2- efficiently caused base alteration at the 5' site of 5'-GGG-3' in the telomere sequence. It is concluded that the site-specific DNA damage at the GGG sequence by oxidative stress may play an important role in increasing the rate of telomere shortening with aging.},
}
@article {pmid10404142,
year = {1999},
author = {Poon, SS and Martens, UM and Ward, RK and Lansdorp, PM},
title = {Telomere length measurements using digital fluorescence microscopy.},
journal = {Cytometry},
volume = {36},
number = {4},
pages = {267-278},
doi = {10.1002/(sici)1097-0320(19990801)36:4&lt;267::aid-cyto1&gt;3.0.co;2-o},
pmid = {10404142},
issn = {0196-4763},
support = {AI29524/AI/NIAID NIH HHS/United States ; GM56162/GM/NIGMS NIH HHS/United States ; },
mesh = {Algorithms ; Calibration ; Carbocyanines ; DNA/*analysis ; Humans ; In Situ Hybridization, Fluorescence ; Indoles ; Karyotyping ; Lymphocytes/ultrastructure ; Male ; Metaphase ; Microscopy, Fluorescence/*methods ; Particle Size ; Repetitive Sequences, Nucleic Acid ; Signal Processing, Computer-Assisted ; Telomere/*chemistry/ultrastructure ; },
abstract = {BACKGROUND: The ends of chromosomes (telomeres) are important to maintain chromosome stability, and the loss of telomere repeat sequences has been implicated in cellular senescence and genomic instability of cancer cells. The traditional method for measuring the length of telomeres (Southern analysis) requires a large number of cells (>10(5)) and does not provide information on the telomere length of individual chromosomes. Here, we describe a digital image microscopy system for measurements of the fluorescence intensity derived from telomere repeat sequences in metaphase cells following quantitative fluorescence in situ hybridization (Q-FISH).<br><br>METHODS: Samples are prepared for microscopy using Q-FISH with Cy3 labeled peptide nucleic acid probes specific for (T(2)AG(3))(n) sequences and the DNA dye DAPI. Separate images of Cy3 and DAPI fluorescence are acquired and processed with a dedicated computer program (TFL-TELO). With the program, the integrated fluorescence intensity value for each telomere, which is proportional to the number of hybridized probes, is calculated and presented to the user.<br><br>RESULTS: Indirect tests of our method were performed using simulated as well as defined tests objects. The precision and consistency of human telomere length measurements was then analyzed in a number of experiments. It was found that by averaging the results of less than 30 cells, a good indication of the telomere length (SD of 10-15%) can be obtained.<br><br>CONCLUSIONS: We demonstrate that accurate and repeatable fluorescence intensity measurements can be made from Q-FISH images that provide information on the length of telomere repeats at individual chromosomes from limited number of cells.},
}
@article {pmid10402933,
year = {1999},
author = {Kølvraa, S and Bischoff, C and Bohr, VA},
title = {[Telomere terminals and telomerase. The biological aging clock?].},
journal = {Ugeskrift for laeger},
volume = {161},
number = {26},
pages = {3987-3991},
pmid = {10402933},
issn = {0041-5782},
mesh = {Aging/*genetics ; Animals ; Biological Clocks ; DNA Replication ; Humans ; *Telomerase/chemistry/genetics/physiology ; *Telomere/chemistry/genetics/physiology ; },
}
@article {pmid10394961,
year = {1999},
author = {Katayama, S and Shiota, G and Oshimura, M and Kawasaki, H},
title = {Clinical usefulness of telomerase activity and telomere length in the preoperative diagnosis of gastric and colorectal cancer.},
journal = {Journal of cancer research and clinical oncology},
volume = {125},
number = {7},
pages = {405-410},
doi = {10.1007/s004320050294},
pmid = {10394961},
issn = {0171-5216},
mesh = {Adult ; Aged ; Blotting, Southern ; Colorectal Neoplasms/*diagnosis/enzymology/genetics/pathology ; Diagnosis, Differential ; Endoscopy, Gastrointestinal ; Female ; Humans ; Male ; Middle Aged ; Predictive Value of Tests ; Retrospective Studies ; Stomach Neoplasms/*diagnosis/enzymology/genetics/pathology ; Telomerase/*metabolism ; Telomere/*pathology ; },
abstract = {It has been reported that telomerase activity and telomeric reduction can be detected in many human cancers. Although it is well known that telomerase activity and telomere length have important implications for cancer biology, their clinical usefulness in the preoperative diagnosis of gastric and colorectal cancer has not been elucidated. Therefore, we examined telomerase activity and telomere length in gastric and colorectal cancer using tissue samples obtained by fiberscopy. Telomerase activity was measured by a telomeric repeat amplification protocol (TRAP). Although telomerase activity was detected in 1/12 (8%) cases of gastric polyp and in 2/9 (22%) cases of colorectal polyp, its positivity in gastric cancer and colorectal cancer was 7/10 (70%) and 21/26 (81%; P<0.0003 and P<0.0001, respectively). Telomere length was analyzed by Southern blotting, and telomeric reduction in gastric cancer was significantly greater than that in gastric polyp (P<0.0003). However, there was no telomeric reduction between colorectal cancer and colorectal polyp. The results of the present study indicate that determination of telomerase activity and telomere length may serve as a useful method for preoperative diagnosis of gastric and colorectal cancer.},
}
@article {pmid10393187,
year = {1999},
author = {Cryderman, DE and Morris, EJ and Biessmann, H and Elgin, SC and Wallrath, LL},
title = {Silencing at Drosophila telomeres: nuclear organization and chromatin structure play critical roles.},
journal = {The EMBO journal},
volume = {18},
number = {13},
pages = {3724-3735},
doi = {10.1093/emboj/18.13.3724},
pmid = {10393187},
issn = {0261-4189},
support = {HD 23844/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Cell Nucleus/*genetics/metabolism ; Chromatin/*chemistry/genetics ; Chromosomes/genetics ; Drosophila Proteins ; Drosophila melanogaster/*genetics ; Eye/metabolism ; Female ; *Gene Expression Regulation ; Genes, Insect/genetics/physiology ; Heat-Shock Proteins/genetics ; Heat-Shock Response ; Male ; Models, Genetic ; Molecular Structure ; Mutation ; Phenotype ; Repetitive Sequences, Nucleic Acid/genetics ; Suppression, Genetic ; Telomere/chemistry/*genetics ; Transgenes/genetics ; Translocation, Genetic/genetics ; },
abstract = {Transgenes inserted into the telomeric regions of Drosophila melanogaster chromosomes exhibit position effect variegation (PEV), a mosaic silencing characteristic of euchromatic genes brought into juxtaposition with heterochromatin. Telomeric transgenes on the second and third chromosomes are flanked by telomeric associated sequences (TAS), while fourth chromosome telomeric transgenes are most often associated with repetitious transposable elements. Telomeric PEV on the second and third chromosomes is suppressed by mutations in Su(z)2, but not by mutations in Su(var)2-5 (encoding HP1), while the converse is true for telomeric PEV on the fourth chromosome. This genetic distinction allowed for a spatial and molecular analysis of telomeric PEV. Reciprocal translocations between the fourth chromosome telomeric region containing a transgene and a second chromosome telomeric region result in a change in nuclear location of the transgene. While the variegating phenotype of the white transgene is suppressed, sensitivity to a mutation in HP1 is retained. Corresponding changes in the chromatin structure and inducible activity of an associated hsp26 transgene are observed. The data indicate that both nuclear organization and local chromatin structure play a role in this telomeric PEV.},
}
@article {pmid10391966,
year = {1998},
author = {Kuchta, G and Szulc, A and Słomiński, JM},
title = {[Telomerase and telomeres in lung neoplasms--biological and clinical significance].},
journal = {Pneumonologia i alergologia polska},
volume = {66},
number = {11-12},
pages = {568-573},
pmid = {10391966},
issn = {0867-7077},
mesh = {Biomarkers, Tumor/*analysis ; Female ; Humans ; Lung Neoplasms/*diagnosis/enzymology/*genetics ; Male ; RNA, Neoplasm/analysis ; Telomerase/*analysis ; Telomere/*physiology ; },
}
@article {pmid10386165,
year = {1999},
author = {Franceschi, C and Mondello, C and Bonafè, M and Valensin, S and Sansoni, P and Sorbi, S},
title = {Long telomeres and well preserved proliferative vigor in cells from centenarians: a contribution to longevity?.},
journal = {Aging (Milan, Italy)},
volume = {11},
number = {2},
pages = {69-72},
pmid = {10386165},
issn = {0394-9532},
mesh = {Aged ; *Cell Division ; Fibroblasts/physiology ; Humans ; Longevity/*physiology ; Lymphocytes/physiology ; *Telomere ; },
}
@article {pmid10382069,
year = {1999},
author = {Pardue, ML and DeBaryshe, PG},
title = {Telomeres and telomerase: more than the end of the line.},
journal = {Chromosoma},
volume = {108},
number = {2},
pages = {73-82},
doi = {10.1007/s004120050354},
pmid = {10382069},
issn = {0009-5915},
support = {GM 50315/GM/NIGMS NIH HHS/United States ; GM 57006/GM/NIGMS NIH HHS/United States ; },
mesh = {Aging/genetics ; Animals ; Humans ; Neoplasms/genetics ; Telomerase/*metabolism ; *Telomere ; },
abstract = {Early studies of telomerase suggested that telomeres are maintained by an elegant but relatively simple and highly conserved mechanism of telomerase-medicated replication. As we learn more, it has become clear that the mechanism is elegant but not as simple as first thought. It is also evident that, although many species use similar, sometimes identical, DNA sequences for telomeres, these species express their own individuality in the way they regulate these sequences and, perhaps, in the additional tasks that they have imposed on their telomeric DNA. The striking similarities between telomeres in different species have revealed much about chromosome ends; the differences are proving to be equally informative. In addition to the differences between species that use telomerase, there are also a few exceptional organisms with atypical telomeres for which no telomerase activity has been detected. This review addresses recent studies, the insights they offer, and, perhaps more importantly, the questions they raise.},
}
@article {pmid10375642,
year = {1999},
author = {López, CC and Kamnert, I and Scherbik, SV and Edström, JE},
title = {Interspersed DNA element restricted to a specific group of telomeres in the dipteran Chironomus pallidivittatus.},
journal = {Gene},
volume = {233},
number = {1-2},
pages = {249-259},
doi = {10.1016/s0378-1119(99)00129-8},
pmid = {10375642},
issn = {0378-1119},
mesh = {Animals ; Base Sequence ; Chironomidae/*genetics ; DNA ; DNA Transposable Elements ; Genome ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; *Tandem Repeat Sequences ; *Telomere ; },
abstract = {Telomeres in the dipteran Chironomus pallidivittatus terminate with 340bp tandem DNA repeats belonging to different subfamilies with characteristic intertelomeric distribution. We have now found, interspersed between such repeats, a composite element of approx. 1400bp present in two similar size variants, with several components of nontelomeric origin. There were about 50 copies of the element, predominantly or exclusively present in a previously defined group of telomeres, characterized by a unique set of telomeric tandem repeat subfamilies. Elements were integrated at irregular distances from each other, and intervening telomeric tandem repeat DNA was variable in composition. Nevertheless, the flanks immediately surrounding the elements were identical for different elements; in other words, there was a site-specific insertion. We suggest that this selective invasion of a small part of the genome by an interspersed, probably rapidly evolving element is best explained by repeated gene conversions.},
}
@article {pmid10373582,
year = {1999},
author = {Wilson, S and Warr, N and Taylor, DL and Watts, FZ},
title = {The role of Schizosaccharomyces pombe Rad32, the Mre11 homologue, and other DNA damage response proteins in non-homologous end joining and telomere length maintenance.},
journal = {Nucleic acids research},
volume = {27},
number = {13},
pages = {2655-2661},
doi = {10.1093/nar/27.13.2655},
pmid = {10373582},
issn = {0305-1048},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {DNA Damage ; *DNA Repair ; DNA, Fungal/*genetics ; *Endodeoxyribonucleases ; *Exodeoxyribonucleases ; Fungal Proteins/*genetics ; *Saccharomyces cerevisiae Proteins ; Schizosaccharomyces/genetics ; *Schizosaccharomyces pombe Proteins ; Sequence Deletion ; Telomere/*genetics ; },
abstract = {The Schizosaccharomyces pombe homologue of Mre11, Rad32, is required for repair of UV- and ionising radiation-induced DNA damage and meiotic recombination. In this study we have investigated the role of Rad32 and other DNA damage response proteins in non-homologous end joining (NHEJ) and telomere length maintenance in S.pombe. We show that NHEJ in S.pombe occurs by an error-prone mechanism, in contrast to the accurate repair observed in Saccharomyces cerevisiae. Deletion of the rad32 gene results in a modest reduction in NHEJ activity and the remaining repair events that occur are accurate. Mutations in two of the phosphoesterase motifs in Rad32 have no effect on the efficiency or accuracy of end joining, suggesting that the role of Rad32 protein may be to recruit another nuclease(s) for processing during the end joining reaction. We also analysed NHEJ in other DNA damage response mutants and showed that the checkpoint mutant rad3-d and two recombination mutants defective in rhp51 and rhp54 (homologues of S.cerevisiae RAD51 and RAD54, respectively) are not affected. However disruption of rad22, rqh1 and rhp9 / crb2 (homologues of the S.cerevisiae RAD52, SGS1 and RAD9 genes) resulted in increased NHEJ activity. Telomere lengths in the rad32, rhp9 and rqh1 null alleles were reduced to varying extents intermediate between the lengths observed in wild-type and rad3 null cells.},
}
@article {pmid10373558,
year = {1999},
author = {Pandita, TK and Westphal, CH and Anger, M and Sawant, SG and Geard, CR and Pandita, RK and Scherthan, H},
title = {Atm inactivation results in aberrant telomere clustering during meiotic prophase.},
journal = {Molecular and cellular biology},
volume = {19},
number = {7},
pages = {5096-5105},
pmid = {10373558},
issn = {0270-7306},
support = {R01 NS034746/NS/NINDS NIH HHS/United States ; NS34746/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; *Ataxia Telangiectasia ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins ; *Chromosome Aberrations ; DNA-Binding Proteins/genetics ; Gene Expression ; Male ; Meiosis/*genetics ; Mice ; Mice, Knockout ; Nuclear Matrix ; Prophase ; *Protein Serine-Threonine Kinases ; Proteins/genetics/*physiology ; Spermatogenesis ; Spermatozoa/cytology/physiology ; *Telomere ; Testis/metabolism ; Tumor Suppressor Proteins ; },
abstract = {A-T (ataxia telangiectasia) individuals frequently display gonadal atrophy, and Atm-/- mice show spermatogenic failure due to arrest at prophase of meiosis I. Chromosomal movements take place during meiotic prophase, with telomeres congregating on the nuclear envelope to transiently form a cluster during the leptotene/zygotene transition (bouquet arrangement). Since the ATM protein has been implicated in telomere metabolism of somatic cells, we have set out to investigate the effects of Atm inactivation on meiotic telomere behavior. Fluorescent in situ hybridization and synaptonemal complex (SC) immunostaining of structurally preserved spermatocytes I revealed that telomere clustering occurs aberrantly in Atm-/- mice. Numerous spermatocytes of Atm-/- mice displayed locally accumulated telomeres with stretches of SC near the clustered chromosome ends. This contrasted with spermatogenesis of normal mice, where only a few leptotene/zygotene spermatocytes I with clustered telomeres were detected. Pachytene nuclei, which were much more abundant in normal mice, displayed telomeres scattered over the nuclear periphery. It appears that the timing and occurrence of chromosome polarization is altered in Atm-/- mice. When we examined telomere-nuclear matrix interactions in spermatocytes I, a significant difference was observed in the ratio of soluble versus matrix-associated telomeric DNA sequences between meiocytes of Atm-/- and control mice. We propose that the severe disruption of spermatogenesis during early prophase I in the absence of functional Atm may be partly due to altered interactions of telomeres with the nuclear matrix and distorted meiotic telomere clustering.},
}
@article {pmid10372535,
year = {1999},
author = {Shibata, R and Feng, YR and Gee, D and Norwood, D and Xiao, X and Zeichner, SL and Martin, MA and Dimitrov, DS},
title = {Telomere dynamics in monkeys: increased cell turnover in macaques infected with chimeric simian-human immunodeficiency viruses.},
journal = {Journal of medical primatology},
volume = {28},
number = {1},
pages = {1-10},
doi = {10.1111/j.1600-0684.1999.tb00083.x},
pmid = {10372535},
issn = {0047-2565},
mesh = {Animals ; Cell Division/*genetics ; Cell Survival/*genetics ; Chimera ; HIV Infections/*genetics/*pathology ; Humans ; Leukocytes, Mononuclear/pathology ; Macaca/anatomy &amp; histology/*genetics ; Macaca fascicularis/anatomy &amp; histology/genetics ; Macaca mulatta/anatomy &amp; histology/genetics ; Macaca nemestrina/anatomy &amp; histology/genetics ; Simian Acquired Immunodeficiency Syndrome/*genetics/*pathology ; Telomere/*genetics ; Time Factors ; },
abstract = {To address the question of how cell turnover is affected by retroviral infections, we used the telomeric terminal restriction fragments (TRFs) as markers of cell replicative history and measured their length in macaques infected with chimeric simian-human immunodeficiency viruses (SHIVs). The TRF lengths of mononuclear cells in 104 samples, including longitudinal samples from nine cynomolgus and ten pig-tailed macaques infected with SHIV, and in samples from 26 uninfected macaques, were quantitated by an improved method, based on two-dimensional calibration of DNA sizes, pulsed field electrophoresis, and high-resolution Southern blot images. The average TRF lengths of peripheral blood mononuclear cells (PBMCs) from uninfected pig-tailed (14.9+/-1.6 kbp) and cynomolgus (14.1+/-1.8 kbp) macaques were about 3 and 5 kbp longer than those of human infants and 30-year-old adults, respectively. The rate of TRF length shortening in infected pig-tailed macaques was significantly (P = 0.035) higher (2.2-fold) than in uninfected monkeys. The TRFs in SHIV-infected cynomolgus monkeys, which, in general, had lower viral loads than pig-tailed macaques, shortened on average more rapidly (1.6-fold) than in uninfected animals, but the difference was not statistically significant. The TRFs of mononuclear cells from the lymph nodes of two rapidly progressing SHIV-infected macaques that developed AIDS and died also shortened in parallel but somewhat more rapidly than in the PBMCs. These results suggest that the rate of PBMC turnover in macaques could be increased several-fold during infections by immunodeficiency viruses, likely due to immune activation by SHIV antigens.},
}
@article {pmid10369690,
year = {1999},
author = {Marcand, S and Brevet, V and Gilson, E},
title = {Progressive cis-inhibition of telomerase upon telomere elongation.},
journal = {The EMBO journal},
volume = {18},
number = {12},
pages = {3509-3519},
pmid = {10369690},
issn = {0261-4189},
mesh = {Alleles ; DNA Nucleotidyltransferases/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Fungal Proteins/genetics/metabolism ; Genes, Fungal/genetics/physiology ; Kinetics ; Models, Genetic ; Molecular Weight ; Mutation ; Rad52 DNA Repair and Recombination Protein ; Recombination, Genetic ; Saccharomyces cerevisiae/enzymology/*genetics/growth &amp; development ; *Saccharomyces cerevisiae Proteins ; Telomerase/*antagonists &amp; inhibitors/genetics/metabolism ; Telomere/*genetics/*metabolism ; Templates, Genetic ; },
abstract = {In yeast, the constant length of telomeric DNA results from a negative regulation of telomerase by the telomere itself. Here we follow the return to equilibrium of an abnormally shortened telomere. We observe that telomere elongation is restricted to a few base pairs per generation and that its rate decreases progressively with increasing telomere length. In contrast, in the absence of telomerase or in the presence of an over-elongated telomere, the degradation rate linked to the succession of generations appears to be constant, i.e. independent of telomere length. Together, these results indicate that telomerase is gradually inhibited at its site of action by the elongating telomere. The implications of this finding for the dynamics of telomere length regulation are discussed in this study.},
}
@article {pmid10369081,
year = {1999},
author = {Griffith, JK and Bryant, JE and Fordyce, CA and Gilliland, FD and Joste, NE and Moyzis, RK},
title = {Reduced telomere DNA content is correlated with genomic instability and metastasis in invasive human breast carcinoma.},
journal = {Breast cancer research and treatment},
volume = {54},
number = {1},
pages = {59-64},
doi = {10.1023/a:1006128228761},
pmid = {10369081},
issn = {0167-6806},
mesh = {Aneuploidy ; Breast Neoplasms/diagnosis/*genetics/*pathology ; Chi-Square Distribution ; DNA, Neoplasm/*genetics ; Female ; Humans ; Linear Models ; Middle Aged ; Neoplasm Metastasis/diagnosis/*genetics ; Predictive Value of Tests ; Prognosis ; Retrospective Studies ; Telomere/*genetics ; },
abstract = {Telomere shortening leads to genomic instability and has been correlated with poor outcome in several types of cancer. A recently described, robust titration assay was used to quantify telomere DNA content in frozen and paraffin-embedded specimens of 49 invasive human breast carcinomas, including tumors with normal or abnormal contents of genomic DNA, which produced regional, distant, or local disease. Telomere DNA contents ranged from 53% to 370% of the content in a reference DNA purified from normal placenta. Tumors were divided into three groups of approximately equal size based on increasing telomere DNA content. All of 16 tumors in the group with the least telomere DNA (Group I), were aneuploid compared to 9/17 tumors in the group with the most telomere DNA (Group III). The Chi-square test for trend indicated that tumors with the least telomere DNA were significantly more likely to be aneuploid than tumors with the most telomere DNA (p < 0.002). Twelve of 14 tumors in Group I also produced metastatic disease compared to 8/15 tumors in Group III. The Fischer Exact Test indicated that tumors with the least telomere DNA were significantly more likely to be metastatic than tumors with the most telomere DNA (p < 0.05). There was no association between telomere DNA content and patients' age, tumors' size, grade, stage, or fraction of cells in S-phase. The correlation of reduced telomere DNA content with aneuploidy and metastasis, both of which are associated with poor outcome in invasive breast carcinoma, implies that telomere DNA content also could have prognostic value.},
}
@article {pmid10367890,
year = {1999},
author = {Mills, KD and Sinclair, DA and Guarente, L},
title = {MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks.},
journal = {Cell},
volume = {97},
number = {5},
pages = {609-620},
doi = {10.1016/s0092-8674(00)80772-2},
pmid = {10367890},
issn = {0092-8674},
support = {AG11119/AG/NIA NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia/genetics ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/metabolism ; Chromatin/genetics/radiation effects ; DNA Damage ; DNA Repair/*genetics ; DNA-Binding Proteins/genetics/metabolism ; Fungal Proteins/*genetics/*metabolism ; Gamma Rays ; Heterochromatin/genetics/radiation effects ; *Histone Deacetylases ; Humans ; Intracellular Signaling Peptides and Proteins ; *Plasmids ; *Protein Serine-Threonine Kinases ; Proteins/genetics ; Saccharomyces cerevisiae/*cytology/*genetics/radiation effects ; *Saccharomyces cerevisiae Proteins ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Sirtuin 1 ; Sirtuin 2 ; Sirtuins ; Telomere/*genetics/radiation effects ; Trans-Activators/genetics/*metabolism ; Tumor Suppressor Proteins ; Ultraviolet Rays ; },
abstract = {The yeast Sir2/3/4p complex is found in abundance at telomeres, where it participates in the formation of silent heterochromatin and telomere maintenance. Here, we show that Sir3p is released from telomeres in response to DNA double-strand breaks (DSBs), binds to DSBs, and mediates their repair, independent of cell mating type. Sir3p relocalization is S phase specific and, importantly, requires the DNA damage checkpoint genes MEC1 and RAD9. MEC1 is a homolog of ATM, mutations in which cause ataxia telangiectasia (A-T), a disease characterized by various neurologic and immunologic abnormalities, a predisposition for cancer, and a cellular defect in repair of DSBs. This novel mode by which preformed DNA repair machinery is mobilized by DNA damage sensors may have implications for human diseases resulting from defective DSB repair.},
}
@article {pmid10367411,
year = {1998},
author = {Mera, SL},
title = {The role of telomeres in ageing and cancer.},
journal = {British journal of biomedical science},
volume = {55},
number = {3},
pages = {221-225},
pmid = {10367411},
issn = {0967-4845},
mesh = {Cellular Senescence/*genetics ; Humans ; Neoplasms/*genetics ; Telomerase/physiology ; Telomere/*pathology ; },
abstract = {Telomeres are regions of DNA that cap the ends of linear chromosomes. In somatic cells the telomeres shorten progressively with every cell division, reducing the number of tandem repeat sequences. Eventually the chromosomes become unstable and the cell is no longer able to replicate. This represents an inherent biological clock in which the somatic cell has only a finite capacity for division. In contrast, germ cells do not undergo telomeric shortening and have relatively unlimited capacities for cell division. The difference is that germ cells retain the enzyme telomerase which is able to restore the telomere ends that are lost during cell division. Although telomerase activity is absent in most somatic cells, cancer cells acquire the ability to activate the enzyme, ensuring their immortal growth characteristics and selective advantage over normal somatic cells.},
}
@article {pmid10367131,
year = {1999},
author = {Klots, IN and Indzhiia, LV and Chepnian, ER and Lapin, BA},
title = {[Genetic analysis of changes in sizes of telomeres and anti-oncogenes p53 and Rb in children with pre-B acute lymphoblastic leukemia].},
journal = {Biulleten' eksperimental'noi biologii i meditsiny},
volume = {127},
number = {4},
pages = {439-441},
pmid = {10367131},
issn = {0365-9615},
mesh = {Child ; Child, Preschool ; *Genes, Retinoblastoma ; *Genes, p53 ; Humans ; Infant ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/*genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics ; Telomere/*genetics ; },
}
@article {pmid10366453,
year = {1999},
author = {Xiang, Z and Hu, XL and Flint, J and Riethman, HC},
title = {A sequence-ready map of the human chromosome 17p telomere.},
journal = {Genomics},
volume = {58},
number = {2},
pages = {207-210},
doi = {10.1006/geno.1999.5826},
pmid = {10366453},
issn = {0888-7543},
support = {HG00567/HG/NHGRI NIH HHS/United States ; //Wellcome Trust/United Kingdom ; },
mesh = {*Chromosome Mapping ; Chromosomes, Artificial, Yeast ; *Chromosomes, Human, Pair 17 ; Contig Mapping ; Cosmids ; Endonucleases/metabolism ; Humans ; Models, Genetic ; Molecular Sequence Data ; Rec A Recombinases/metabolism ; Telomere/*genetics ; },
abstract = {A half-YAC clone derived from human chromosome 17p was mapped at high resolution using cosmid subclone fingerprint analysis. Colinearity of the half-YAC with the telomeric human genomic DNA fragment was ascertained by RecA-assisted restriction endonuclease cleavage mapping. Previously isolated and radiation hybrid-mapped markers TEL17P37, TEL17P49, and TEL17P80 mapped 30-60 kb from the 17p terminus. This sequence-ready map permits high-resolution integration of genetic maps with the DNA sequences directly adjacent to the tip of human chromosome 17p, and will provide the cloned DNA required for ascertaining the nucleotide sequence of this subtelomeric region.},
}
@article {pmid10362359,
year = {1999},
author = {Perrem, K and Bryan, TM and Englezou, A and Hackl, T and Moy, EL and Reddel, RR},
title = {Repression of an alternative mechanism for lengthening of telomeres in somatic cell hybrids.},
journal = {Oncogene},
volume = {18},
number = {22},
pages = {3383-3390},
doi = {10.1038/sj.onc.1202752},
pmid = {10362359},
issn = {0950-9232},
mesh = {Cell Division/genetics ; Cell Fusion ; Cellular Senescence/genetics ; Fibroblasts/cytology ; Genetic Complementation Test ; Humans ; Hybrid Cells/*physiology ; Telomerase/metabolism ; Telomere/*genetics ; },
abstract = {Some immortalized cell lines maintain their telomeres in the absence of detectable telomerase activity by an alternative (ALT) mechanism. To study how telomere maintenance is controlled in ALT cells, we have fused an ALT cell line GM847 (SV40 immortalized human skin fibroblasts) with normal fibroblasts or with telomerase positive immortal human cell lines and have examined their proliferative potential and telomere dynamics. The telomeres in ALT cells are characteristically very heterogeneous in length, ranging from very short to very long. The ALT x normal hybrids underwent a rapid reduction in telomeric DNA and entered a senescence-like state. Immortal segregants rapidly reverted to the ALT telomere phenotype. Fusion of ALT cells to telomerase-positive immortal cells in the same immortalization complementation group resulted in hybrids that appeared immortal and also exhibited repression of the ALT telomere phenotype. In these hybrids, which were all telomerase-positive, we observed an initial rapid loss of most long telomeres, followed either by gradual loss of the remaining long telomeres at a rate similar to the rate of telomere shortening in normal telomerase-negative cells, or by maintenance of shortened telomeres. These data indicate the existence of a mechanism of rapid telomere deletion in human cells. They also demonstrate that normal cells and at least some telomerase-positive immortal cells contain repressors of the ALT telomere phenotype.},
}
@article {pmid10360570,
year = {1999},
author = {Shiels, PG and Kind, AJ and Campbell, KH and Waddington, D and Wilmut, I and Colman, A and Schnieke, AE},
title = {Analysis of telomere lengths in cloned sheep.},
journal = {Nature},
volume = {399},
number = {6734},
pages = {316-317},
doi = {10.1038/20580},
pmid = {10360570},
issn = {0028-0836},
mesh = {Aging/*genetics ; Animals ; Cells, Cultured ; *Cloning, Organism ; Female ; Mammary Glands, Animal/cytology ; Nuclear Transfer Techniques ; Sheep/*genetics ; *Telomere ; },
}
@article {pmid10357808,
year = {1999},
author = {Herrera, E and Samper, E and Martín-Caballero, J and Flores, JM and Lee, HW and Blasco, MA},
title = {Disease states associated with telomerase deficiency appear earlier in mice with short telomeres.},
journal = {The EMBO journal},
volume = {18},
number = {11},
pages = {2950-2960},
pmid = {10357808},
issn = {0261-4189},
mesh = {Aging/genetics ; Animals ; Atrophy ; Body Weight ; Cells, Cultured ; Crosses, Genetic ; Female ; Genes, Lethal/genetics ; Hematopoietic System/pathology ; Infertility/*genetics ; Intestine, Small/pathology ; Leukocyte Count ; Longevity/*genetics ; Lymphocytes/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Spleen/pathology/physiopathology ; Telomerase/*deficiency/genetics/metabolism ; Telomere/genetics/*physiology ; Testis/pathology ; Time Factors ; },
abstract = {Mice deficient for the mouse telomerase RNA (mTR-/-) and lacking telomerase activity can only be bred for approximately six generations due to decreased male and female fertility and to an increased embryonic lethality associated with a neural tube closure defect. Although late generation mTR-/- mice show defects in the hematopoietic system, they are viable to adulthood, only showing a decrease in viability in old age. To assess the contribution of genetic background to the effect of telomerase deficiency on viability, we generated mTR-/- mutants on a C57BL6 background, which showed shorter telomeres than the original mixed genetic background C57BL6/129Sv. Interestingly, these mice could be bred for only four generations and the survival of late generation mTR-/- mice decreased dramatically with age as compared with their wild-type counterparts. Fifty percent of the generation 4 mice die at only 5 months of age. This decreased viability with age in the late generation mice is coincident with telomere shortening, sterility, splenic atrophy, reduced proliferative capacity of B and T cells, abnormal hematology and atrophy of the small intestine. These results indicate that telomere shortening in mTR-/- mice leads to progressive loss of organismal viability.},
}
@article {pmid10353788,
year = {1999},
author = {Slavotinek, A and Rosenberg, M and Knight, S and Gaunt, L and Fergusson, W and Killoran, C and Clayton-Smith, J and Kingston, H and Campbell, RH and Flint, J and Donnai, D and Biesecker, L},
title = {Screening for submicroscopic chromosome rearrangements in children with idiopathic mental retardation using microsatellite markers for the chromosome telomeres.},
journal = {Journal of medical genetics},
volume = {36},
number = {5},
pages = {405-411},
pmid = {10353788},
issn = {0022-2593},
mesh = {Adolescent ; Child ; Child, Preschool ; *Chromosome Aberrations ; Chromosomes, Human, Pair 1/genetics ; Chromosomes, Human, Pair 18/genetics ; Genetic Testing ; Humans ; In Situ Hybridization, Fluorescence ; Infant, Newborn ; Intellectual Disability/*genetics ; Microsatellite Repeats/*genetics ; Monosomy ; Telomere/*genetics ; },
abstract = {Recently much attention has been given to the detection of submicroscopic chromosome rearrangements in patients with idiopathic mental retardation. We have screened 27 subjects with mental retardation and dysmorphic features for such rearrangements using a genetic marker panel screening. The screening was a pilot project using markers from the subtelomeric regions of all 41 chromosome arms. The markers were informative for monosomy in both parents at 3661902 loci (40.6%, 95% confidence interval 37.0-44.2%) in the 22 families where DNA was available from both parents. In two of the 27 subjects, submicroscopic chromosomal aberrations were detected. The first patient had a 5-6 Mb deletion of chromosome 18q and the second patient had a 4 Mb deletion of chromosome 1p. The identification of two deletions in 27 cases gave an aberration frequency of 7.5% without adjustment for marker informativeness (95% confidence interval 1-24%) and an estimated frequency of 18% if marker informativeness for monosomy was taken into account. This frequency is higher than previous estimates of the number of subtelomeric chromosome abnormalities in children with idiopathic mental retardation (5-10%) although the confidence interval is overlapping. Our study suggests that in spite of the low informativeness of this pilot screening, submicroscopic chromosome aberrations may be a common cause of dysmorphic features and mental retardation.},
}
@article {pmid10353751,
year = {1999},
author = {Ohyashiki, JH and Iwama, H and Yahata, N and Ando, K and Hayashi, S and Shay, JW and Ohyashiki, K},
title = {Telomere stability is frequently impaired in high-risk groups of patients with myelodysplastic syndromes.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {5},
number = {5},
pages = {1155-1160},
pmid = {10353751},
issn = {1078-0432},
mesh = {Acute Disease ; Adult ; Aged ; Aged, 80 and over ; Cell Transformation, Neoplastic/pathology ; Chromosomes, Human/*ultrastructure ; Female ; Follow-Up Studies ; Humans ; Leukemia, Myeloid/*genetics/mortality ; Life Tables ; Male ; Middle Aged ; Myelodysplastic Syndromes/enzymology/mortality/*pathology ; Neoplasm Proteins/analysis ; Polymerase Chain Reaction ; Precancerous Conditions/enzymology/mortality/*pathology ; Prognosis ; Risk Factors ; Survival Analysis ; Telomerase/analysis ; Telomere/*ultrastructure ; },
abstract = {Genomic instability induces an accumulation of genetic changes and may play a role in the pathogenesis of myelodysplastic syndromes (MDS). To clarify the possible association between genomic instability and clinical outcome in MDS patients, we compared telomere dynamics to the recently established International Prognostic Scoring System (IPSS) risk groups for MDS. We measured the terminal restriction fragments (TRFs) of 93 patients with MDS at the time of diagnosis, and telomerase activity was analyzed in 62 patients with MDS using the PCR-based telomeric repeat amplification protocol (TRAP) assay. A total of 53 of 93 MDS patients had TRFs within the age-matched normal range, and the remaining patients showed shortened TRFs (35 patients) or elongated TRFs (5 patients). MDS patients with shortened TRFs had a significantly low hemoglobin concentration (P = 0.04), a high percentage of marrow blasts (P = 0.02), and a high incidence of cytogenetic abnormalities (P < 0.05). The incidence of leukemic transformation was significantly high in patients with shortened TRF length (P < 0.05). In addition, patients with shortened TRF length were frequently seen in the IPSS high-risk group (P < 0.01). Most of the MDS patients had normal-to-low levels of telomerase activity, suggesting that changes in TRF length rather than telomerase activity may more accurately reflect the pathophysiology of MDS. MDS patients with shortened TRF length had a very poor prognosis (P < 0.01), suggesting that telomere dynamics may be linked to clinical outcome in MDS patients. Thus, an abnormal mechanism of telomere maintenance in subgroups of MDS patients may be an early indication of genomic instability. This study demonstrates that telomere stability is frequently impaired in a high-risk group of MDS patients and suggests that, in combination with the IPSS classification system, measurement of TRFs may be useful in the future to stratify MDS patients according to risk and manage the care of MDS patients.},
}
@article {pmid10352174,
year = {1999},
author = {Patel, PK and Hosur, RV},
title = {NMR observation of T-tetrads in a parallel stranded DNA quadruplex formed by Saccharomyces cerevisiae telomere repeats.},
journal = {Nucleic acids research},
volume = {27},
number = {12},
pages = {2457-2464},
doi = {10.1093/nar/27.12.2457},
pmid = {10352174},
issn = {0305-1048},
mesh = {DNA, Fungal/*chemistry ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Nucleic Acid Conformation ; Potassium/chemistry ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*chemistry/genetics ; Telomere/*chemistry ; },
abstract = {We report here the NMR structure of the DNA sequence d-TGGTGGC containing two repeats of Saccharomyces cerevisiae telomere DNA which is unique in that it has a single thymine in the repeat sequence and the number of Gs can vary from one to three. The structure is a novel quadruplex incor-porating T-tetrads formed by symmetrical pairing of four Ts via O4-H3 H-bonds in a plane. This is in contrast to the previous results on other telomeric sequences which contained more than one T in the repeat sequences and they were seen mostly in the flexible regions of the structures. We observed that the T4-tetrad was nicely accommodated in the center of the G-quadruplex, but it caused a small underwinding of the right handed helix. The T tetrad stacked well on the adjacent G3-tetrad, but poorly on the G5 tetrad. Likewise, T1 also formed a stable T-tetrad at the 5' end of the quadruplex. To our knowledge, this is the first report of T-tetrad formation in DNA structures. These observations are of significance from the points of view of both structural diversity and specific recognitions.},
}
@article {pmid10352173,
year = {1999},
author = {Freitas-Junior, LH and Porto, RM and Pirrit, LA and Schenkman, S and Scherf, A},
title = {Identification of the telomere in Trypanosoma cruzi reveals highly heterogeneous telomere lengths in different parasite strains.},
journal = {Nucleic acids research},
volume = {27},
number = {12},
pages = {2451-2456},
doi = {10.1093/nar/27.12.2451},
pmid = {10352173},
issn = {0305-1048},
mesh = {Animals ; Chromatin ; Chromosomes ; Cloning, Molecular ; DNA Topoisomerases, Type I/*isolation &amp; purification/metabolism ; DNA, Protozoan/*genetics ; Species Specificity ; Telomere/*genetics ; Trypanosoma cruzi/classification/*genetics ; },
abstract = {Here we describe the cloning and characterisation of the Trypanosoma cruzi telomere. In the Y strain, it is formed by typical GGGTTA repeats with a mean size of approximately 500 bp. Adjacent to the telomere repeats we found a DNA sequence with significant homology to the T.cruzi 85 kDa surface antigen (gp85). Examination of the telomere in nine T.cruzi strains reveals differences in the organisation of chromosome ends. In one group of strains the size of the telomere repeat is relatively homogeneous and short (0.5-1.5 kb) as in the Y strain, while in the other, the length of the repeat is very heterogeneous and significantly longer, ranging in size from 1 to >10 kb. These different strains can be grouped similarly to previously existing classifications based on isoenzyme loci, rRNA genes, mini-exon gene sequences, randomly amplified polymorphic DNA and rRNA promoter sequences, suggesting that differential control of telomere length and organisation appeared as an early event in T. cruzi evolution. Two-dimensional pulsed field gel electrophoresis analysis shows that some chromosomes carry telomeres which are significantly larger than the mean telomere length. Importantly, the T.cruzi telomeres are organised in nucleosomal and non-nucleosomal chromatin.},
}
@article {pmid10339397,
year = {1999},
author = {Tan, Z},
title = {Intramitotic and intraclonal variation in proliferative potential of human diploid cells: explained by telomere shortening.},
journal = {Journal of theoretical biology},
volume = {198},
number = {2},
pages = {259-268},
doi = {10.1006/jtbi.1999.0914},
pmid = {10339397},
issn = {0022-5193},
mesh = {Clone Cells ; *Computer Simulation ; Diploidy ; Eukaryotic Cells/*cytology/ultrastructure ; Humans ; Mitosis/*genetics ; *Models, Genetic ; Telomere/*ultrastructure ; },
abstract = {Normal human diploid cells can only divide for a limited number of times (known as the Hayflick limit). They manifest two unique features during in vitro senescence. The division capability of individual cells in a clone, though all derived from a same ancestor, is heterogeneous with a distinct bimodal distribution. Two sister cells derived from a same parent cell can have a large difference in their doubling potentials. These two unique features have not been properly explained by any known physiological process since their observation in 1980. Here I represent a telomere-shortening model based on recent experimental measurement of telomere deletion in human cells. Using computer simulation, I show that the model satisfactorily explains the intraclonal and intramitotic variation in division capability of human diploid cells. Moreover, the simulations predict that human cells may only monitor the shortening of a few, most likely two, telomeres to regulate their proliferative potential.},
}
@article {pmid10338216,
year = {1999},
author = {Chin, L and Artandi, SE and Shen, Q and Tam, A and Lee, SL and Gottlieb, GJ and Greider, CW and DePinho, RA},
title = {p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis.},
journal = {Cell},
volume = {97},
number = {4},
pages = {527-538},
doi = {10.1016/s0092-8674(00)80762-x},
pmid = {10338216},
issn = {0092-8674},
support = {K08AR02104-01/AR/NIAMS NIH HHS/United States ; R01HD28317/HD/NICHD NIH HHS/United States ; R01HD34880/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Apoptosis ; Male ; Mice ; Mice, Inbred C57BL ; Neoplasms/*etiology ; Phenotype ; Spermatozoa/cytology ; Telomerase/genetics/*physiology ; Telomere/*physiology ; Testis/cytology ; Tumor Suppressor Protein p53/genetics/*physiology ; },
abstract = {Maintenance of telomere length and function is critical for the efficient proliferation of eukaryotic cells. Here, we examine the interactions between telomere dysfunction and p53 in cells and organs of telomerase-deficient mice. Coincident with severe telomere shortening and associated genomic instability, p53 is activated, leading to growth arrest and/or apoptosis. Deletion of p53 significantly attenuated the adverse cellular and organismal effects of telomere dysfunction, but only during the earliest stages of genetic crisis. Correspondingly, the loss of telomere function and p53 deficiency cooperated to initiate the transformation process. Together, these studies establish a key role for p53 in the cellular response to telomere dysfunction in both normal and neoplastic cells, question the significance of crisis as a tumor suppressor mechanism, and identify a biologically relevant stage of advanced crisis, termed genetic catastrophe.},
}
@article {pmid10338215,
year = {1999},
author = {Greenberg, RA and Chin, L and Femino, A and Lee, KH and Gottlieb, GJ and Singer, RH and Greider, CW and DePinho, RA},
title = {Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse.},
journal = {Cell},
volume = {97},
number = {4},
pages = {515-525},
doi = {10.1016/s0092-8674(00)80761-8},
pmid = {10338215},
issn = {0092-8674},
support = {CA16519/CA/NCI NIH HHS/United States ; HD28317/HD/NICHD NIH HHS/United States ; HD348880/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Antigens, Polyomavirus Transforming ; Cell Division ; Cell Line, Transformed ; Cyclin-Dependent Kinase Inhibitor p16/genetics/*physiology ; Mice ; Mice, SCID ; Neoplasms/*etiology ; Phenotype ; Telomerase/*metabolism ; Telomere/metabolism/*physiology ; },
abstract = {Maintenance of telomere length is predicted to be essential for bypass of senescence and crisis checkpoints in cancer cells. The impact of telomere dysfunction on tumorigenesis was assessed in successive generations of mice doubly null for the telomerase RNA (mTR) and the INK4a tumor suppressor genes. Significant reductions in tumor formation in vivo and oncogenic potential in vitro were observed in late generations of telomerase deficiency, coincident with severe telomere shortening and associated dysfunction. Reintroduction of mTR into cells significantly restored the oncogenic potential, indicating telomerase activation is a cooperating event in the malignant transformation of cells containing critically short telomeres. The results described here demonstrate that loss of telomere function in a cancer-prone mouse model possessing intact DNA damage responses impairs, but does not prevent, tumor formation.},
}
@article {pmid10338214,
year = {1999},
author = {Griffith, JD and Comeau, L and Rosenfield, S and Stansel, RM and Bianchi, A and Moss, H and de Lange, T},
title = {Mammalian telomeres end in a large duplex loop.},
journal = {Cell},
volume = {97},
number = {4},
pages = {503-514},
doi = {10.1016/s0092-8674(00)80760-6},
pmid = {10338214},
issn = {0092-8674},
support = {CA19043/CA/NCI NIH HHS/United States ; GM31819/GM/NIGMS NIH HHS/United States ; GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cross-Linking Reagents ; DNA/metabolism/*ultrastructure ; DNA-Binding Proteins/*metabolism ; HeLa Cells ; Humans ; Mammals ; Mice ; *Models, Molecular ; Nucleic Acid Heteroduplexes ; Recombinant Fusion Proteins/metabolism ; Telomere/metabolism/*ultrastructure ; Telomeric Repeat Binding Protein 1 ; Telomeric Repeat Binding Protein 2 ; },
abstract = {Mammalian telomeres contain a duplex array of telomeric repeats bound to the telomeric repeat-binding factors TRF1 and TRF2. Inhibition of TRF2 results in immediate deprotection of chromosome ends, manifested by loss of the telomeric 3' overhang, activation of p53, and end-to-end chromosome fusions. Electron microscopy reported here demonstrated that TRF2 can remodel linear telomeric DNA into large duplex loops (t loops) in vitro. Electron microscopy analysis of psoralen cross-linked telomeric DNA purified from human and mouse cells revealed abundant large t loops with a size distribution consistent with their telomeric origin. Binding of TRF1 and single strand binding protein suggested that t loops are formed by invasion of the 3' telomeric overhang into the duplex telomeric repeat array. T loops may provide a general mechanism for the protection and replication of telomeres.},
}
@article {pmid10338204,
year = {1999},
author = {Greider, CW},
title = {Telomeres do D-loop-T-loop.},
journal = {Cell},
volume = {97},
number = {4},
pages = {419-422},
doi = {10.1016/s0092-8674(00)80750-3},
pmid = {10338204},
issn = {0092-8674},
mesh = {Animals ; DNA-Binding Proteins/*metabolism ; Telomere/metabolism/physiology/*ultrastructure ; },
}
@article {pmid10331504,
year = {1999},
author = {Boultwood, J and Fidler, C and Shepherd, P and Watkins, F and Snowball, J and Haynes, S and Kusec, R and Gaiger, A and Littlewood, TJ and Peniket, AJ and Wainscoat, JS},
title = {Telomere length shortening is associated with disease evolution in chronic myelogenous leukemia.},
journal = {American journal of hematology},
volume = {61},
number = {1},
pages = {5-9},
doi = {10.1002/(sici)1096-8652(199905)61:1&lt;5::aid-ajh2&gt;3.0.co;2-4},
pmid = {10331504},
issn = {0361-8609},
mesh = {Adult ; Aged ; Aged, 80 and over ; Blast Crisis ; Blotting, Southern ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/blood/*genetics ; Leukocytes/*ultrastructure ; Middle Aged ; Repetitive Sequences, Nucleic Acid ; Telomere/*ultrastructure ; },
abstract = {We studied telomere length in the peripheral blood leukocyte samples of a large group of patients with chronic myelogenous leukemia (CML) by Southern blot hybridization using the (TTAGGG)4 probe. The average telomere length expressed as the peak telomere repeat array (TRA) of the peripheral blood samples obtained from a group of 34 healthy age-matched controls ranged between 7.6 and 10.0 kb and the mean peak TRA was 8.7 kb. Forty-one patients in the chronic phase of CML were studied; 32/41 (78%) showed telomere reduction (<7.6 kb) relative to age-matched controls and the mean peak TRA was 6.4 kb (range 4.0-10.6 kb). Serial samples were analysed from 12 patients at both chronic phase and during disease progression. The leukocyte DNA of all 12 patients in accelerated phase and/or blast crisis showed telomere reduction relative to age-matched controls and the mean peak TRA was 4.1 kb (range 3.0-5.4 kb). The peak TRA in the accelerated or blast phase was reduced compared with the corresponding paired sample in the chronic phase in all cases studied. These data show that a marked reduction in telomere length is associated with disease progression in CML.},
}
@article {pmid10330659,
year = {1999},
author = {Danilevskaia, ON and Pardue, ML},
title = {[Telomeric retrotransposon HeT-A and its role in forming Drosophila telomeres].},
journal = {Molekuliarnaia biologiia},
volume = {33},
number = {1},
pages = {38-47},
pmid = {10330659},
issn = {0026-8984},
mesh = {Animals ; Biological Evolution ; Drosophila melanogaster/*genetics ; In Situ Hybridization ; Promoter Regions, Genetic ; *Retroelements ; *Telomere ; Transcription, Genetic ; },
}
@article {pmid10330618,
year = {1999},
author = {Semenova, SK and Vasil'ev, VA and Steklenev, EP and Prosniak, MI and Ryskov, AP},
title = {[DNA-fingerprinting of representatives of Bovinae subfamilies using the telomere markers (TTAGGG)4].},
journal = {Genetika},
volume = {35},
number = {1},
pages = {101-104},
pmid = {10330618},
issn = {0016-6758},
mesh = {Animals ; Bacteriophage M13/genetics ; Base Sequence ; Bison/*genetics ; Cattle/*genetics ; *DNA Fingerprinting ; DNA, Viral ; Humans ; Species Specificity ; Tandem Repeat Sequences ; *Telomere ; },
abstract = {The (TTAGGG)4 oligonucleotide homologous to telomeric tandem repeats of human chromosomes was used for the first time as a multilocus hybridization probe for the analysis of genome variability in the two genera (Bos and Bison) of the Bovinae subfamily. DNA profiles for cattle, banteng, aurochs, and bison were obtained. Hybridization spectra were represented by the discrete individual- and species-specific bands characterized by codominant inheritance. For comparison, DNA profiles of the same samples obtained using the bacteriophage M13 DNA probe are presented. The usefulness of the microsatellite examined for the testing of pedigrees, description of intra- and interbreed variability as well as for determining relationships and the origins of the species of the Bovinae subfamily is discussed.},
}
@article {pmid10329413,
year = {1999},
author = {Uchiumi, F and Watanabe, M and Tanuma, Si},
title = {Characterization of telomere-binding activity of replication factor C large subunit p140.},
journal = {Biochemical and biophysical research communications},
volume = {258},
number = {2},
pages = {482-489},
doi = {10.1006/bbrc.1999.0589},
pmid = {10329413},
issn = {0006-291X},
mesh = {Aging/genetics ; Base Sequence ; DNA Primers ; DNA-Binding Proteins/chemistry/*metabolism ; HeLa Cells ; *Homeodomain Proteins ; Humans ; Jurkat Cells ; Minor Histocompatibility Antigens ; *Proto-Oncogene Proteins c-bcl-2 ; Replication Protein C ; *Repressor Proteins ; *Saccharomyces cerevisiae Proteins ; Sequence Deletion ; Telomerase/antagonists &amp; inhibitors ; *Telomere ; },
abstract = {The large subunit of RFC (RFC p140) has been suggested to be associated with the 3'-end of elongating DNA primer and to recruit proliferating cell nuclear antigen (PCNA) onto DNA polymerase delta. Previously, we isolated a cDNA clone encoding a DNA-binding domain of RFC p140 as a telomeric repeat (TTAGGG)n binding protein. This domain was shown to have a specific affinity for the 5'-phosphate ends of a telomere repeat sequence. In order to investigate the structure and function of RFC p140, we constructed the full-length recombinant RFC p140 as well as N- and/or C-terminal deleted mutants and analyzed their telomere-binding activities. South-Western blot and gel mobility shift analyses revealed that deletion of the N- but not the C-terminal region enhances recognition of the telomeric repeat sequence and 5'-phosphate ends, suggesting the negative effect of the N-terminal region of the RFC p140 binding to the telomeric repeat. On the other hand, the C-terminal truncated RFC inhibits the telomerase activity more than the N-terminal-deleted and full-length RFC p140. The inhibitory effect of RFC p140 on telomerase activity is completely diminished by both terminal deletions. Thus, a certain interaction of the N- and C-terminal regions is considered to be required for RFC p140 to suppress telomerase activity. Taken together, these results suggest that both telomeric repeat-binding and telomerase inhibitory activities of RFC p140 are finely regulated by the intrinsic N- and C-terminal regions.},
}
@article {pmid10322143,
year = {1999},
author = {Price, CM},
title = {Telomeres and telomerase: broad effects on cell growth.},
journal = {Current opinion in genetics &amp; development},
volume = {9},
number = {2},
pages = {218-224},
doi = {10.1016/S0959-437X(99)80032-X},
pmid = {10322143},
issn = {0959-437X},
support = {GM41803/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Humans ; Meiosis/*genetics ; Telomerase/*metabolism ; *Telomere ; Vertebrates/genetics ; },
abstract = {During the past year, major advances have been made in understanding the link between telomerase expression and cell immortality. Studies of yeast telomeres have revealed an unexpected role for the non-homologous end-joining machinery in telomere maintenance and have provided the first definitive evidence that telomeres play a critical role in meiosis. Identification of new telomere proteins has led to a better understanding of vertebrate telomere structure and function.},
}
@article {pmid10232505,
year = {1999},
author = {Aviv, A and Aviv, H},
title = {Telomeres and essential hypertension.},
journal = {American journal of hypertension},
volume = {12},
number = {4 Pt 1},
pages = {427-432},
doi = {10.1016/s0895-7061(98)00202-7},
pmid = {10232505},
issn = {0895-7061},
mesh = {Age Factors ; Aneuploidy ; Humans ; Hypertension/*genetics ; Loss of Heterozygosity ; Telomere/*genetics ; },
abstract = {The dynamics of telomere attrition in human beings might shape the course of age-dependent, complex genetic traits. One of these traits is essential hypertension. Age-dependent telomere attrition could lead to critically shortened telomeres and aneuploidy (ie, the loss or gain of chromosomes) with a resultant mosaicism that will be variably expressed in different cells and tissues. The chromosomal instability and loss of heterozygosity resulting from this process would promote an age-dependent expression of variant genes that harbor susceptibility for essential hypertension or genes that accelerate the process of aging.},
}
@article {pmid10228167,
year = {1999},
author = {Pryde, FE and Louis, EJ},
title = {Limitations of silencing at native yeast telomeres.},
journal = {The EMBO journal},
volume = {18},
number = {9},
pages = {2538-2550},
pmid = {10228167},
issn = {0261-4189},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Base Sequence ; Binding Sites/genetics ; Chromatin/metabolism ; Consensus Sequence ; DNA-Binding Proteins/metabolism ; Fungal Proteins/*genetics ; *Gene Expression Regulation, Fungal ; Models, Genetic ; Molecular Sequence Data ; Mutation ; Origin Recognition Complex ; Protein Binding ; Recombination, Genetic ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; *Telomere ; Trans-Activators/metabolism ; Transcription Factors/metabolism ; },
abstract = {Silencing at native yeast telomeres, in which the subtelomeric elements are intact, is different from silencing at terminal truncations. The repression of URA3 inserted in different subtelomeric positions at several chromosome ends was investigated. Many ends exhibit very little silencing close to the telomere, while others exhibit substantial repression in limited domains. Silencing at native ends is discontinuous, with maximal repression found adjacent to the ARS consensus sequence in the subtelomeric core X element. The level of repression declines precipitously towards the centromere. Mutation of the ARS sequence or an adjacent Abf1p-binding site significantly reduces silencing. The subtelomeric Y' elements are resistant to silencing along their whole length, yet silencing can be re-established at the proximal X element. Deletion of PPR1, the transactivator of URA3, and SIR3 overexpression do not increase repression or extend spreading of silencing to the same extent as with terminally truncated ends. sir1Delta causes partial derepression at X-ACS, in contrast to the lack of effect seen at terminal truncations. orc2-1 and orc5-1 have no effect on natural silencing yet cause derepression at truncated ends. X-ACS silencing requires the proximity of the telomere and is dependent on SIR2, SIR3, SIR4 and HDF1. The structures found at native yeast telomeres appear to limit the potential of repressive chromatin.},
}
@article {pmid10226653,
year = {1998},
author = {Sakaguchi, AY and Padalecki, SS and Mattern, V and Rodriguez, A and Leach, RJ and McGill, JR and Chavez, M and Giambernardi, TA},
title = {Chromosomal sublocalization of the transcribed human telomere repeat binding factor 2 gene and comparative mapping in the mouse.},
journal = {Somatic cell and molecular genetics},
volume = {24},
number = {3},
pages = {157-163},
doi = {10.1023/b:scam.0000007118.47691.d7},
pmid = {10226653},
issn = {0740-7750},
support = {CA67760-03/CA/NCI NIH HHS/United States ; P30 CA54174/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Chromosome Mapping ; Chromosomes/genetics ; Chromosomes, Human, Pair 16/genetics ; Cricetinae ; DNA-Binding Proteins/*genetics ; Humans ; Hybrid Cells ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Inbred C57BL ; Muridae ; RNA/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Telomeric Repeat Binding Protein 2 ; Transcription, Genetic ; },
abstract = {Telomere repeat binding factor 2 (TERF2) is one of two recently cloned mammalian telomere binding protein genes. TERF2 binds as a dimer with high affinity to the double-stranded TTAGGG telomeric repeat through an evolutionarily conserved myb-type DNA binding domain. TERF2 prevents telomere end-to-end fusion and may be important in maintaining genomic stability. We localized the transcribed TERF2 gene to human chromosome 16q22.1, tightly linked to the EST HUM000S343. The mouse Terf2 gene is situated by itself in a newly defined "bin" on chromosome 8 one crossover distal to Psm10 and Sntb2. Human TERF2 and mouse Terf2 are therefore part of a large evolutionarily conserved linkage group comprised of at least 25 known paralogous genes between human chromosome 16q and mouse chromosome 8.},
}
@article {pmid10224249,
year = {1999},
author = {Le, S and Moore, JK and Haber, JE and Greider, CW},
title = {RAD50 and RAD51 define two pathways that collaborate to maintain telomeres in the absence of telomerase.},
journal = {Genetics},
volume = {152},
number = {1},
pages = {143-152},
pmid = {10224249},
issn = {0016-6731},
support = {CA 68736/CA/NCI NIH HHS/United States ; CA16519/CA/NCI NIH HHS/United States ; GM43080/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases ; Blotting, Southern ; Cell Division ; Cell Survival ; DNA Helicases ; DNA Repair Enzymes ; DNA-Binding Proteins/genetics/*physiology ; *Endodeoxyribonucleases ; Epistasis, Genetic ; *Exodeoxyribonucleases ; Fungal Proteins/genetics/*physiology ; Genotype ; Mutagenesis ; RNA, Fungal/*physiology ; Rad51 Recombinase ; Rad52 DNA Repair and Recombination Protein ; Recombination, Genetic ; Saccharomyces cerevisiae/genetics ; *Saccharomyces cerevisiae Proteins ; Telomerase/*physiology ; Telomere/*physiology ; Time Factors ; },
abstract = {Telomere length is maintained by the de novo addition of telomere repeats by telomerase, yet recombination can elongate telomeres in the absence of telomerase. When the yeast telomerase RNA component, TLC1, is deleted, telomeres shorten and most cells die. However, gene conversion mediated by the RAD52 pathway allows telomere lengthening in rare survivor cells. To further investigate the role of recombination in telomere maintenance, we assayed telomere length and the ability to generate survivors in several isogenic DNA recombination mutants, including rad50, rad51, rad52, rad54, rad57, xrs2, and mre11. The rad51, rad52, rad54, and rad57 mutations increased the rate of cell death in the absence of TLC1. In contrast, although the rad50, xrs2, and mre11 strains initially had short telomeres, double mutants with tlc1 did not affect the rate of cell death, and survivors were generated at later times than tlc1 alone. While none of the double mutants of recombination genes and tlc1 (except rad52 tlc1) blocked the ability to generate survivors, a rad50 rad51 tlc1 triple mutant did not allow the generation of survivors. Thus RAD50 and RAD51 define two separate pathways that collaborate to allow cells to survive in the absence of telomerase.},
}
@article {pmid10219078,
year = {1999},
author = {Chamankhah, M and Xiao, W},
title = {Formation of the yeast Mre11-Rad50-Xrs2 complex is correlated with DNA repair and telomere maintenance.},
journal = {Nucleic acids research},
volume = {27},
number = {10},
pages = {2072-2079},
doi = {10.1093/nar/27.10.2072},
pmid = {10219078},
issn = {0305-1048},
mesh = {Base Sequence ; Binding Sites/genetics ; DNA Primers/genetics ; *DNA Repair ; *DNA-Binding Proteins ; Dimerization ; *Endodeoxyribonucleases ; *Exodeoxyribonucleases ; Fungal Proteins/chemistry/genetics/*metabolism ; Genes, Fungal ; Macromolecular Substances ; Meiosis ; Mitosis ; Mutation ; Peptide Fragments/chemistry/genetics/metabolism ; Protein Conformation ; Saccharomyces cerevisiae/cytology/genetics/*metabolism ; *Saccharomyces cerevisiae Proteins ; Sequence Deletion ; Telomere/*metabolism ; },
abstract = {The yeast Mre11 is a multi-functional protein and is known to form a protein complex with Rad50 and Xrs2. In order to elucidate the relationship between Mre11 complex formation and its mitotic functions, and to determine domain(s) required for Mre11 protein interactions, we performed yeast two-hybrid and functional analyses with respect to Mre11 DNA repair and telomere maintenance. Evidence presented in this study indicates that the N-terminal region of Mre11 constitutes the core homo-dimerization and hetero-dimerization domain and is sufficient for Mre11 DNA repair and maintaining the wild-type telomere length. In contrast, a stretch of 134 amino acids from the extreme C-terminus, although essential for achieving a full level of self-association, is not required for the aforementioned Mre11 mitotic functions. Interestingly, deletion of these same 134 amino acids enhanced the interaction of Mre11 with Rad50 and Xrs2, which is consistent with the notion that this region is specific for meiotic functions. While Mre11 self-association alone is insufficient to provide the above mitotic activities, our results are consistent with a strong correlation between Mre11-Rad50-Xrs2 complex formation, mitotic DNA repair and telomere maintenance. This correlation was further strengthened by analyzing two mre11 phosphoesterase motif mutants (mre11-2 and rad58S), which are defective in DNA repair, telomere maintenance and protein interactions, and a rad50S mutant, which is normal in both complex formation and mitotic functions. Together, these results support and extend a current model regarding Mre11 structure and functions in mitosis and meiosis.},
}
@article {pmid10217398,
year = {1999},
author = {Jennings, BJ and Ozanne, SE and Dorling, MW and Hales, CN},
title = {Early growth determines longevity in male rats and may be related to telomere shortening in the kidney.},
journal = {FEBS letters},
volume = {448},
number = {1},
pages = {4-8},
doi = {10.1016/s0014-5793(99)00336-1},
pmid = {10217398},
issn = {0014-5793},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Female ; Kidney ; Longevity/*physiology ; Male ; Rats ; Rats, Wistar ; Telomere/*physiology ; },
abstract = {Maternal protein undernutrition can influence the growth and longevity of male offspring in the rat. We tested the hypothesis that these differences in longevity were associated with changes in the rate of telomere shortening. We found age-related shortening of telomeres in the liver and kidney but not in the brain of male rats. Growth retardation in postnatal life was associated with significantly longer kidney telomeres and an increased longevity. Conversely, growth retardation during the foetal life followed by postnatal catch-up growth was associated with a shorter life span and shorter kidney telomeres. These findings may provide a mechanistic basis for epidemiological studies linking early growth retardation to adult degenerative diseases.},
}
@article {pmid10216076,
year = {1999},
author = {Zeichner, SL and Palumbo, P and Feng, Y and Xiao, X and Gee, D and Sleasman, J and Goodenow, M and Biggar, R and Dimitrov, D},
title = {Rapid telomere shortening in children.},
journal = {Blood},
volume = {93},
number = {9},
pages = {2824-2830},
pmid = {10216076},
issn = {0006-4971},
mesh = {Adult ; Aging/*genetics ; Blotting, Southern ; Female ; HIV Infections/transmission ; Humans ; Infant, Newborn ; Infectious Disease Transmission, Vertical ; Longitudinal Studies ; Pregnancy ; Pregnancy Complications, Infectious ; Regression Analysis ; Risk Factors ; Telomerase/*metabolism ; Telomere/*genetics/ultrastructure ; },
abstract = {Telomere shortening may reflect the total number of divisions experienced by a somatic cell and is associated with replicative senescence. We found that the average rate of telomere shortening in peripheral blood mononuclear cells (PBMCs) obtained longitudinally from nine different infants during the first 3 years of life (270 bp per year) is more than fourfold higher than in adults and does not correlate with telomerase activity. These results show that the rate of telomere loss changes during ontogeny, suggesting the existence of periods of accelerated cell division. Because human immunodeficiency virus (HIV) preferentially infects actively dividing cells, our observation suggesting accelerated cell division in children may provide an explanation for some of the distinctive pathogenic features of the HIV disease in infants, including higher viral loads and more rapid progression to acquired immunodeficiency syndrome (AIDS).},
}
@article {pmid10212814,
year = {1999},
author = {Dandjinou, AT and Dionne, I and Gravel, S and LeBel, C and Parenteau, J and Wellinger, RJ},
title = {Cytological and functional aspects of telomere maintenance.},
journal = {Histology and histopathology},
volume = {14},
number = {2},
pages = {517-524},
doi = {10.14670/HH-14.517},
pmid = {10212814},
issn = {0213-3911},
mesh = {Animals ; Bacterial Proteins/metabolism ; Chromatin ; DNA ; DNA Replication ; Humans ; Meiosis ; Nuclear Envelope/metabolism ; Telomerase/metabolism ; Telomere/metabolism/*physiology ; },
abstract = {The fact that eukaryotic chromosomes are linear poses a special problem for their maintenance: the natural ends of chromosomes must be distinguished from ends generated by chromosomal breakage and somehow, the chromosome ends must also be fully replicated to maintain their integrity. Telomeres, the complex structures at the ends of chromosomes are thought to be instrumental for both of these functions. However, recent insights in telomere biology suggest that these terminal structures do much more than just fulfill these two basic functions. Cytological data demonstrate that telomeres may play leading roles in chromatin organization and nuclear architecture during mitosis and meiosis. Moreover, non-functional telomeres may lead to genetic instability, a common prelude to cancer. Here, we review the basic functions of telomeres during chromosome replication and discuss the cytological aspects of telomere function during mitosis and meiosis.},
}
@article {pmid10209937,
year = {1999},
author = {Olofsson, P and Kimmel, M},
title = {Stochastic models of telomere shortening.},
journal = {Mathematical biosciences},
volume = {158},
number = {1},
pages = {75-92},
doi = {10.1016/s0025-5564(98)10092-5},
pmid = {10209937},
issn = {0025-5564},
support = {GM 58545/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Death/*physiology ; *Models, Statistical ; *Numerical Analysis, Computer-Assisted ; Stochastic Processes ; Telomere/*physiology ; },
abstract = {Shortening of chromosome ends, known as telomeres, is one of the supposed mechanisms of cellular aging and death. We provide a probabilistic analysis of the process of loss of telomere ends. The first work concerned with that issue is the paper by Levy et al. [J. Molec. Biol. 225 (1992) 951-960]. Their deterministic model reproduced the observed frequencies of viable cells in the in vitro experiments. Arino et al. [J. Theor. Biol. 177 (1995) 45-57] reformulated the model of Levy et al. (1992) in the terms of branching processes with denumerable type space. In the present paper, the mathematical results of Arino et al. (1995) are extended to the case in which cell death is present, in cells with telomeres above and below the critical threshold of length, generally with differing probabilities. Both exact and asymptotic results are provided, as well as a discussion of biological relevance of the results.},
}
@article {pmid10209018,
year = {1999},
author = {Smith, CD and Blackburn, EH},
title = {Uncapping and deregulation of telomeres lead to detrimental cellular consequences in yeast.},
journal = {The Journal of cell biology},
volume = {145},
number = {2},
pages = {203-214},
pmid = {10209018},
issn = {0021-9525},
support = {T32CA09270/CA/NCI NIH HHS/United States ; GM26259/GM/NIGMS NIH HHS/United States ; T32 CA009270/CA/NCI NIH HHS/United States ; R01 GM026259/GM/NIGMS NIH HHS/United States ; R37 GM026259/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Binding Sites ; Cell Division ; DNA, Fungal/chemistry/genetics/metabolism ; DNA-Binding Proteins/*metabolism ; Flow Cytometry ; Kluyveromyces/*cytology/*genetics/growth &amp; development ; Models, Biological ; RNA-Binding Proteins/metabolism ; Ribonucleoproteins/metabolism ; Telomerase/*metabolism ; Telomere/genetics/*physiology ; },
abstract = {Telomeres are the protein-nucleic acid structures at the ends of eukaryote chromosomes. Tandem repeats of telomeric DNA are templated by the RNA component (TER1) of the ribonucleoprotein telomerase. These repeats are bound by telomere binding proteins, which are thought to interact with other factors to create a higher-order cap complex that stabilizes the chromosome end. In the budding yeast Kluyveromyces lactis, the incorporation of certain mutant DNA sequences into telomeres leads to uncapping of telomeres, manifested by dramatic telomere elongation and increased length heterogeneity (telomere deregulation). Here we show that telomere deregulation leads to enlarged, misshapen "monster" cells with increased DNA content and apparent defects in cell division. However, such deregulated telomeres became stabilized at their elongated lengths upon addition of only a few functionally wild-type telomeric repeats to their ends, after which the frequency of monster cells decreased to wild-type levels. These results provide evidence for the importance of the most terminal repeats at the telomere in maintaining the cap complex essential for normal telomere function. Analysis of uncapped and capped telomeres also show that it is the deregulation resulting from telomere uncapping, rather than excessive telomere length per se, that is associated with DNA aberrations and morphological defects.},
}
@article {pmid10207859,
year = {1999},
author = {Kipling, D and Wynford-Thomas, D and Jones, CJ and Akbar, A and Aspinall, R and Bacchetti, S and Blasco, MA and Broccoli, D and DePinho, RA and Edwards, DR and Effros, RB and Harley, CB and Lansdorp, PM and Linskens, MH and Prowse, KR and Newbold, RF and Olovnikov, AM and Parkinson, EK and Pawelec, G and Pontén, J and Shall, S and Zijlmans, M and Faragher, RG},
title = {Telomere-dependent senescence.},
journal = {Nature biotechnology},
volume = {17},
number = {4},
pages = {313-314},
doi = {10.1038/7827},
pmid = {10207859},
issn = {1087-0156},
mesh = {Animals ; Cell Division/*physiology ; Cells, Cultured ; Cellular Senescence/*physiology ; Fibroblasts ; Humans ; Mice ; Telomere/*physiology ; },
}
@article {pmid10204805,
year = {1999},
author = {Golubovskaya, VM and Filatov, LV and Behe, CI and Presnell, SC and Hooth, MJ and Smith, GJ and Kaufmann, WK},
title = {Telomere shortening, telomerase expression, and chromosome instability in rat hepatic epithelial stem-like cells.},
journal = {Molecular carcinogenesis},
volume = {24},
number = {3},
pages = {209-217},
doi = {10.1002/(sici)1098-2744(199903)24:3&lt;209::aid-mc7&gt;3.0.co;2-f},
pmid = {10204805},
issn = {0899-1987},
support = {CA 59486/CA/NCI NIH HHS/United States ; CA 59496/CA/NCI NIH HHS/United States ; ES 07126/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; Cell Transformation, Neoplastic/genetics ; Cellular Senescence/genetics ; Chromosome Aberrations ; Chromosomes/*ultrastructure ; Epithelial Cells/cytology ; In Situ Hybridization, Fluorescence ; Liver/*cytology ; Rats ; Rats, Inbred F344 ; Stem Cells/cytology ; Telomerase/*metabolism ; Telomere/*ultrastructure ; },
abstract = {Telomeres, which are specialized structures consisting of T2AG3 repeats and proteins at the ends of chromosomes, may be essential for genomic stability. To test whether telomere length maintenance preserves genomic stability in rats (Rattus rattus and Fischer 344), we assayed telomerase activity and telomere length in the rat hepatic epithelial stem-like cell line WB-F344 during aging in vitro and in tumor-derived lines. Telomerase activity in the parental WB-F344 line was repressed at low and intermediate passage levels in vitro and reexpressed at high passages. Southern blot hybridization and quantitative fluorescence in situ hybridization analyses demonstrated that telomeres were significantly eroded at intermediate passage levels, when telomerase was repressed, and at high passage levels, when telomerase was expressed. Fluorescence in situ hybridization analysis also revealed interstitial telomeric sequences in rat chromosomes. Tumor-derived WB-F344 cell lines that express telomerase had variably shortened telomeres. Cytogenetic analyses performed on WB-F344 cells at low, intermediate, and high passages demonstrated that chromosome instability was most severe in the intermediate passage cells. These data suggest that telomere shortening during aging of rat hepatic epithelial stem-like WB-F344 cells in vitro and during selection of tumorigenic lines in vivo may destabilize chromosomes. Expression of telomerase in high passage cells appeared to partially stabilize chromosomes.},
}
@article {pmid10201990,
year = {1999},
author = {Maini, MK and Soares, MV and Zilch, CF and Akbar, AN and Beverley, PC},
title = {Virus-induced CD8+ T cell clonal expansion is associated with telomerase up-regulation and telomere length preservation: a mechanism for rescue from replicative senescence.},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {162},
number = {8},
pages = {4521-4526},
pmid = {10201990},
issn = {0022-1767},
mesh = {Acute Disease ; Adolescent ; Adult ; CD4-Positive T-Lymphocytes/cytology ; CD8-Positive T-Lymphocytes/cytology/*enzymology/virology ; Cell Division/immunology ; Cellular Senescence/immunology ; Clone Cells/cytology/enzymology/virology ; Follow-Up Studies ; Herpesvirus 4, Human/*immunology ; Humans ; Immunologic Memory ; Infectious Mononucleosis/enzymology/immunology/pathology ; Receptors, Antigen, T-Cell, alpha-beta/physiology ; Telomerase/*biosynthesis/physiology ; *Telomere/enzymology/immunology/virology ; Up-Regulation/*immunology ; },
abstract = {In acute infectious mononucleosis (AIM), very large clones of Ag-specific CD8+ effector T cells are generated. Many clones persist as memory cells, although the clone size is greatly reduced. It would be expected that the large number of cell divisions occurring during clonal expansion would lead to shortening of telomeres, predisposing to replicative senescence. Instead, we show that clonally expanded CD8+ T cells in AIM have paradoxical preservation of telomere length in association with marked up-regulation of telomerase. We postulate that this allows a proportion of responding T cells to enter the memory pool with a preserved capacity to continue dividing so that long-term immunological memory can be maintained.},
}
@article {pmid10197788,
year = {1999},
author = {Sugimoto, M and Ide, T and Goto, M and Furuichi, Y},
title = {Reconsideration of senescence, immortalization and telomere maintenance of Epstein-Barr virus-transformed human B-lymphoblastoid cell lines.},
journal = {Mechanisms of ageing and development},
volume = {107},
number = {1},
pages = {51-60},
doi = {10.1016/s0047-6374(98)00131-6},
pmid = {10197788},
issn = {0047-6374},
mesh = {B-Lymphocytes/*physiology ; Cell Line, Transformed/physiology ; Cell Transformation, Viral/*physiology ; Cellular Senescence/*physiology ; Herpesvirus 4, Human/*physiology ; Humans ; Karyotyping ; Telomerase/metabolism ; Telomere/*genetics ; Werner Syndrome/blood ; },
abstract = {We review recent data on senescence and immortalization of human B-lymphoblastoid cell lines (LCLs) transformed by the Epstein-Barr virus (EBV). Although EBV-transformed LCLs are generally believed to be immortalized, a series of recent studies, including ours, provided strong evidence that they are mostly mortal and have non-malignant properties, except for a small proportion of LCLs that are immortalized by developing a strong telomerase activity. A large proportion of mortal LCLs have exceptionally long lifespans. Some of them have a lifespan over 150 population-doubling levels, keeping a relatively constant telomere length in spite of the absence of a detectable telomerase activity, suggesting that they maintain telomeres by a pathway other than that using telomerase. Here we propose a model of an alternative pathway to maintain telomeres of such long-lived mortal LCLs by exploiting extra-chromosomal telomere repeat DNA, which was recently found by us.},
}
@article {pmid10196364,
year = {1999},
author = {Mills, W and Critcher, R and Lee, C and Farr, CJ},
title = {Generation of an approximately 2.4 Mb human X centromere-based minichromosome by targeted telomere-associated chromosome fragmentation in DT40.},
journal = {Human molecular genetics},
volume = {8},
number = {5},
pages = {751-761},
doi = {10.1093/hmg/8.5.751},
pmid = {10196364},
issn = {0964-6906},
mesh = {Animals ; B-Lymphocytes/metabolism ; Cell Line ; Centromere/*genetics/metabolism ; Chickens ; Cricetinae ; DNA Fragmentation ; Deoxyribonucleases, Type II Site-Specific/genetics/metabolism ; Electrophoresis, Gel, Pulsed-Field ; Female ; Gene Transfer Techniques ; Humans ; Hybrid Cells ; In Situ Hybridization, Fluorescence ; Male ; Mitosis ; Recombination, Genetic ; Telomere/genetics ; *X Chromosome ; },
abstract = {A linear mammalian artificial chromosome (MAC) will require at least three types of functional element: a centromere, two telomeres and origins of replication. As yet, our understanding of these elements, as well as many other aspects of structure and organization which may be critical for a fully functional mammalian chromosome, remains poor. As a way of defining these various requirements, minichromosome reagents are being developed and analysed. Approaches for minichromosome generation fall into two broad categories: de novo assembly from candidate DNA sequences, or the fragmentation of an existing chromosome to reduce it to a minimal size. Here we describe the generation of a human minichromosome using the latter, top-down, approach. A human X chromosome, present in a DT40-human microcell hybrid, has been manipulated using homologous recombination and the targeted seeding of a de novo telomere. This strategy has generated a linear approximately 2.4 Mb human X centromere-based minichromosome capped by two artificially seeded telomeres: one immediately flanking the centromeric alpha-satellite DNA and the other targeted to the zinc finger gene ZXDA in Xp11.21. The chromosome retains an alpha-satellite domain of approximately 1. 8 Mb, a small array of gamma-satellite repeat (approximately 40 kb) and approximately 400 kb of Xp proximal DNA sequence. The mitotic stability of this minichromosome has been examined, both in DT40 and following transfer into hamster and human cell lines. In all three backgrounds, the minichromosome is retained efficiently, but in the human and hamster microcell hybrids its copy number is poorly regulated. This approach of engineering well-defined chromosome reagents will allow key questions in MAC development (such as whether a lower size limit exists) to be addressed. In addition, the 2.4 Mb minichromosome described here has potential to be developed as a vector for gene delivery.},
}
@article {pmid10196087,
year = {1999},
author = {Rubelj, I and Vondracek, Z},
title = {Stochastic mechanism of cellular aging--abrupt telomere shortening as a model for stochastic nature of cellular aging.},
journal = {Journal of theoretical biology},
volume = {197},
number = {4},
pages = {425-438},
doi = {10.1006/jtbi.1998.0886},
pmid = {10196087},
issn = {0022-5193},
mesh = {Animals ; Cell Division/physiology ; Cells, Cultured ; Cellular Senescence/*physiology ; *Computer Simulation ; Humans ; Models, Biological ; Stochastic Processes ; Telomere/*ultrastructure ; },
abstract = {A strong stochastic component has been described for the appearance of senescent cells in cultures that have not completed their in vitro lifespan. The proliferative potential of individual clones show a bimodal distribution. Additionally, two cells arising from a single mitotic event can exhibit large differences in their doubling capacities. In this report we present a model and a computer simulation of the model that explains the observed stochastic phenomena. The model is based on both gradual and abrupt telomere shortening. Gradual telomere shortening (GTS) occurs during each cell division as a consequence of the inability of DNA polymerase to replicate the very ends of chromosomal DNA. It is responsible for the gradual decline in proliferative potential of a cell culture, but does not explain the stochastic aspects of cellular aging. Abrupt telomere shortening (ATS) occurs either through DNA recombination or nuclease digestion at the subtelomeric/telomeric border region of the chromosome. Recombination involves the invasion of a telomere single-strand three-prime protruding end at this border in the telomere of the same chromosome or in another subtelomeric/telomeric region. Shortening of one or more telomeres in the cell causes a sudden onset of cell senescence, referred to as sudden senescence syndrome (SSS). This is manifested as a stochastic and abrupt transition of cells from the larger to the smaller proliferative potential pool and can cause cell cycle arrest within one cell division. The computer simulation matches well with experimental data supporting the prediction that abrupt telomere shortening underlies the stochastic onset of cell senescence. Sudden senescence syndrome appears to be the most important mechanism in the control of the extent of proliferation of a cell culture because it prevents virtually every cell in the culture from reaching its maximum doubling capacity, that would otherwise be allowed by telomere shortening via the end-replication mechanism alone.},
}
@article {pmid10193703,
year = {1998},
author = {Omura, Y and Shimotsura, Y and Ooki, M and Noguchi, T},
title = {Estimation of the amount of telomere molecules in different human age groups and the telomere increasing effect of acupuncture and shiatsu on St.36, using synthesized basic units of the human telomere molecules as reference control substances for the bi-digital O-ring test resonance phenomenon.},
journal = {Acupuncture &amp; electro-therapeutics research},
volume = {23},
number = {3-4},
pages = {185-206},
doi = {10.3727/036012998816356472},
pmid = {10193703},
issn = {0360-1293},
mesh = {*Acupressure ; *Acupuncture Therapy ; Adolescent ; Adult ; Aged ; Aging/*physiology ; Case-Control Studies ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; Mass Spectrometry ; Middle Aged ; Neoplasms/physiopathology ; Nuclear Magnetic Resonance, Biomolecular ; Proto-Oncogene Mas ; Telomere/chemistry/*physiology ; },
abstract = {It is well established that the telomeres at the ends of chromosomes are composed of long arrays of (TTAGGG)n x (CCCTAA)n that form a nucleoprotein complex required for the replication and protection of chromosome ends. Throughout the cell cycle, telomeres also contain a protein component related to the proto-oncogene Myb that is known as TRF1 (telomere TTAGGG repeat binding factor 1) that binds to the duplex array of TTAGGG repeats in the telomere. Previous studies have shown that TRF1 appears to play a role in controlling the length of telomeres by acting as an inhibitor of telomerase. The amount of each of the TRF1(C-19) &amp; TRF1(N-19) was identical to the amount of telomere of the same organ of the same apparently normal individual. Using synthesized basic unit of TTAGGG, as well as CCCTAA, as separate reference control substances for the Bi-Digital O-Ring Test of Resonance Phenomenon between 2 identical substances, we were able to non-invasively measure the approximate amount of TTAGGG and CCCTAA units, in both normal and cancerous human cells. We examined about 30 apparently normal subjects (both Asian and Caucasian in both sex). The subjects' ages ranged from infancy to 76 years. Each subject was first examined using TTAGGG as a control substance and then examined using CCCTAA as a control substance. The amount of telomere in various cancer tissues are almost always higher than that of normal tissue of the same organ. The measured amounts of both TTAGGG and CCCTAA were found to be in an average of 1500-1600 ng for human fetus or infancy and decreased with the advance of age in both sex with the exception of the heart, brain, eyes (retina), testes, and ovaries, which usually remain at the level of the infant, or reduced very little. Individuals in the same age group had a similar range of amounts of both TTAGGG and CCCTAA in the same organ of the same individual, (except for those with unusually low telomeres often had chronic degenerative diseases, and those who had exceptionally high telomere levels often had excellent physical conditions or mental acumen). The amounts of measured TTAGGG and CCCTAA molecules before and after acupuncture on St. 36 in adenocarcinomas and small cell carcinoma coexisting in the lung of a 54-yr.-old Asian male were: telomere in adenocarcinoma decreased from 950 ng to 750 ng and telomere in small cell carcinoma decreased from 770 ng to 600 ng. When the cancer treatment is effective, the amount of telomere is reduced towards the value of the normal internal organ. We found that acupuncture on St.36 on apparently normal subjects increased the telomere levels up to a maximum of more than 2 times their telomere levels prior to the treatment, depending on the method of treatment, but frequently increases were between 60% to 100%. Strong Shiatsu performed on St. 36 produced a somewhat lesser effect than acupuncture. We also determined the amounts of TTAGGG and CCCTAA molecules non-invasively in 3 mummified Egyptian sisters from the 8th Century BC on exhibit at the Museo Egizio in Turin, Italy in order to estimate their approximate ages (at the time of death). The amounts of body telomere were 500 ng, 550 ng, and 750 ng. For the prehistoric Iceman (about 3350 B.C. to 3310 B.C) discovered in 1991 in the Italian Otzal Alps at about 3,200 meters altitude, estimated body telomere was about 400 ng and telomere in brain and heart was 1600 ng, similar to that of a contemporary human being. Although these studies are preliminary, the findings may have potential applications not only in anti-aging, cancer treatments, and pathophysiology of brain and heart, but also for the estimation of the difference in the ages of cadavers studied in archeology and forensic medicine.},
}
@article {pmid10189090,
year = {1999},
author = {Rivera, H and Vásquez, AI and Perea, FJ},
title = {Centromere-telomere (12;8p) fusion, telomeric 12q translocation, and i(12p) trisomy.},
journal = {Clinical genetics},
volume = {55},
number = {2},
pages = {122-126},
doi = {10.1034/j.1399-0004.1999.550209.x},
pmid = {10189090},
issn = {0009-9163},
mesh = {*Centromere ; *Chromosomes, Human, Pair 12 ; *Chromosomes, Human, Pair 8 ; Humans ; *Telomere ; *Translocation, Genetic ; },
abstract = {The concurrence of a short arm isochromosome and a translocation of the entire long arm of the same chromosome to a telomere of another chromosome, implying trisomy for 4p, 5p, 7p, 9p, 10p or 12p, has been described in 13 patients. We have now used fluorescence in situ hybrization (FISH) to better characterize one of these rearrangements in which 12q was translocated to 8pter, whereas 12p was converted into an isochromosome. An alphoid centromere-12 repeat gave a strong signal on the i(2p) and a weak but distinct signal at the breakpoint junction of the der(8), whereas the pantelomeric probe revealed three clear hybridization sites on the der(8): one at each end and another at the breakpoint junction. These findings suggest that the prime event was a post-fertilization centric fission of chromosome 12 leading to the 12q translocation via a real centromere telomere fusion and the i(12p). Alternatively, the crucial event may have been a centromere telomere recombination. An interstitial telomere has been documented by means of FISH at the breakpoint junction of the sole derivative usually present in 20 constitutional translocations including eight with a jumping behavior. In addition, six other telomeric translocations defined by banding methods, including another case of 12q translocation/i(12p), have also been jumping ones. These telomeric translocations have been de noro events and their proneness to exhibit a jumping behavior appears to be independent of the involved chromosomes, size of the translocated segments, and concomitant abnormalities.},
}
@article {pmid10100154,
year = {1999},
author = {Kveiborg, M and Kassem, M and Langdahl, B and Eriksen, EF and Clark, BF and Rattan, SI},
title = {Telomere shortening during aging of human osteoblasts in vitro and leukocytes in vivo: lack of excessive telomere loss in osteoporotic patients.},
journal = {Mechanisms of ageing and development},
volume = {106},
number = {3},
pages = {261-271},
doi = {10.1016/s0047-6374(98)00114-6},
pmid = {10100154},
issn = {0047-6374},
mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/*physiology ; Blotting, Southern ; Cell Cycle/genetics ; Cells, Cultured ; Cellular Senescence/*physiology ; DNA/analysis ; Female ; Humans ; Leukocytes/*metabolism ; Middle Aged ; Osteoblasts/*metabolism ; Osteoporosis/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {We have compared the telomere length, as assessed by Southern analysis, of telomere restriction fragments (TRFs) generated by RsaI/HinfI digestion of genomic DNA in: (i) in vitro cultured human trabecular osteoblasts undergoing cellular aging; and (ii) peripheral blood leukocytes (PBL) obtained from three groups of women: young (aged 20-26 years, n = 15), elderly (aged 48-85 years, n = 15) and osteoporotic (aged 52-81 years, n = 14). The mean TRF length in human osteoblasts undergoing aging in vitro decreased from an average of 9.32 kilobasepairs (kb) in middle-aged cells to an average of 7.80 kb in old cells. The rate of TRF shortening was about 100 bp per population doubling, which is similar to what has been reported for other cell types, such as human fibroblasts. Furthermore, there was a 30% decline in the total amount of telomeric DNA in senescent osteoblasts as compared with young cells. In the case of PBL, TRF length in the DNA extracted from young women was slightly longer (6.76 +/- 0.64 kb) than that from a group of elderly women (6.42 +/- 0.71 kb). A comparison of TRFs in the DNA extracted from the PBL from osteoporotic patients and from age-matched controls did not show any significant differences (6.47 +/- 0.94 versus 6.42 +/- 0.71 kb, respectively). Therefore, using TRF length as a marker for cellular aging in vitro and in vivo, our data comparing TRFs from osteoporotic patients and age-matched controls do not support the notion of the occurrence of a generalized premature cellular aging in osteoporotic patients.},
}
@article {pmid10097104,
year = {1999},
author = {Zhu, J and Wang, H and Bishop, JM and Blackburn, EH},
title = {Telomerase extends the lifespan of virus-transformed human cells without net telomere lengthening.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {96},
number = {7},
pages = {3723-3728},
pmid = {10097104},
issn = {0027-8424},
support = {R01 GM026259/GM/NIGMS NIH HHS/United States ; R37 GM026259/GM/NIGMS NIH HHS/United States ; CA44338/CA/NCI NIH HHS/United States ; GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Antigens, Viral, Tumor/genetics ; Cell Cycle ; Cell Division ; Cell Line ; *Cell Transformation, Viral ; DNA-Binding Proteins ; Humans ; Karyotyping ; *RNA ; Recombinant Proteins/metabolism ; Simian virus 40/*genetics ; Telomerase/genetics/*metabolism ; Telomere/*physiology ; Transfection ; },
abstract = {Human fibroblasts whose lifespan in culture has been extended by expression of a viral oncogene eventually undergo a growth crisis marked by failure to proliferate. It has been proposed that telomere shortening in these cells is the property that limits their proliferation. Here we report that ectopic expression of the wild-type reverse transcriptase protein (hTERT) of human telomerase averts crisis, at the same time reducing the frequency of dicentric and abnormal chromosomes. Surprisingly, as the resulting immortalized cells containing active telomerase continue to proliferate, their telomeres continue to shorten to mean lengths below those in control cells that enter crisis. These results provide evidence for a protective function of human telomerase that allows cell proliferation without requiring net lengthening of telomeres.},
}
@article {pmid10095439,
year = {1998},
author = {Schneider-Stock, R and Eppler, C and Walter, H and Radig, K and Haeckel, C and Hoang-Vu, C and Epplen, JT and Roessner, A},
title = {[Telomere lengths and telomerase activity in liposarcomas].},
journal = {Verhandlungen der Deutschen Gesellschaft fur Pathologie},
volume = {82},
number = {},
pages = {226-231},
pmid = {10095439},
issn = {0070-4113},
mesh = {Humans ; Liposarcoma/*enzymology/*genetics/pathology ; Oligonucleotide Probes ; Polymerase Chain Reaction ; Telomerase/genetics/*metabolism ; Telomere/*genetics/ultrastructure ; },
abstract = {We measured telomerase activity in 36 malignant and seven benign lipomatous neoplasias from 34 patients to assess the role of telomerase in the development of liposarcoma. The sensitive PCR-based telomerase assay (telomeric repeat amplification protocol-TRAP) was applied. We correlated telomerase activity with the shortening or elongation of telomeric repeat fragment length (TRF), measured by using hybridization with a telomere specific oligonucleotide probe. Telomerase activity was demonstrated in 69% of malignant tumors. This information may be helpful in distinguishing benign tumors from malignant neoplasias. Telomerase expression, however, seems to be characteristic of poorly differentiated liposarcomas. Telomerase activity was not correlated with age at the time of diagnosis or with sex. We observed that telomerase expressing tumors had higher proliferation indices than neoplasias lacking telomerase. Telomerase activity was observed in all eight recurrences, suggesting a close association of telomerase with the biologic behavior of liposarcomas. Therefore, we assume that telomerase plays a key role in the establishment and progression of lipomatous tumors.},
}
@article {pmid10094830,
year = {1999},
author = {Mondello, C and Petropoulou, C and Monti, D and Gonos, ES and Franceschi, C and Nuzzo, F},
title = {Telomere length in fibroblasts and blood cells from healthy centenarians.},
journal = {Experimental cell research},
volume = {248},
number = {1},
pages = {234-242},
doi = {10.1006/excr.1999.4398},
pmid = {10094830},
issn = {0014-4827},
mesh = {Adolescent ; Adult ; Aged ; Aging/*genetics ; Blood Cells ; Cell Division ; Cells, Cultured ; Child ; Child, Preschool ; Clusterin ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins/genetics ; Female ; Fibroblasts/cytology ; Fibronectins/genetics ; Gene Expression ; Glycoproteins/genetics ; Humans ; Male ; Middle Aged ; *Molecular Chaperones ; *Telomere ; },
abstract = {Several lines of evidence indicate that telomere shortening during in vitro aging of human somatic cells plays a causal role in cellular senescence. A critical telomere length seems to be associated with the replicative block characterizing senescent cells. In this paper we analyzed the mean length of the terminal restriction fragments (TRF) in fibroblast strains from 4 healthy centenarians, that is, in cells aged in vivo, and from 11 individuals of different ages. No correlation between mean TRF length and donor age was found. As expected, telomere shortening was detected during in vitro propagation of centenarian fibroblasts, suggesting that in fibroblasts aged in vivo telomeres can be far from reaching a critical length. Accordingly, chromosome analysis did not show the presence of telomeric associations in early passage centenarian fibroblasts. In blood cells from various individuals, the expected inverse correlation between mean TRF length and donor age was found. In particular, a substantial difference (about 2 kb) between telomere length in the two cell types was observed in the same centenarian. Expression analysis of three senescence-induced genes, i.e., fibronectin, apolipoprotein J, and p21, revealed for only the fibronectin expression levels a clear positive correlation with donor age. Our results suggest that (1) telomere shortening could play a different role in the aging of different cell types and (2) the characteristics of fibroblasts aged in vitro might not be representative of what occurs in vivo.},
}
@article {pmid10094039,
year = {1999},
author = {Kipling, D and Faragher, RG},
title = {Telomeres. Ageing hard or hardly ageing?.},
journal = {Nature},
volume = {398},
number = {6724},
pages = {191, 193},
doi = {10.1038/18306},
pmid = {10094039},
issn = {0028-0836},
mesh = {Aging/*genetics ; Animals ; Cellular Senescence/genetics ; Humans ; Mice ; *Telomere ; },
}
@article {pmid10085128,
year = {1999},
author = {Nosek, J and Tomáska, L and Pagácová, B and Fukuhara, H},
title = {Mitochondrial telomere-binding protein from Candida parapsilosis suggests an evolutionary adaptation of a nonspecific single-stranded DNA-binding protein.},
journal = {The Journal of biological chemistry},
volume = {274},
number = {13},
pages = {8850-8857},
doi = {10.1074/jbc.274.13.8850},
pmid = {10085128},
issn = {0021-9258},
mesh = {Amino Acid Sequence ; Base Sequence ; Candida/*metabolism ; Cloning, Molecular ; Cross-Linking Reagents ; DNA, Mitochondrial/*genetics ; DNA, Single-Stranded/*genetics ; DNA-Binding Proteins/chemistry/*genetics ; Evolution, Molecular ; Fungal Proteins/genetics ; Glutaral/metabolism ; Molecular Sequence Data ; RNA, Messenger/metabolism ; Recombinant Proteins/genetics ; Repressor Proteins ; Saccharomyces cerevisiae/genetics ; *Saccharomyces cerevisiae Proteins ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; Telomere/*genetics ; },
abstract = {The mitochondrial genome in a number of organisms is represented by linear DNA molecules with defined terminal structures. The telomeres of linear mitochondrial DNA (mtDNA) of yeast Candida parapsilosis consist of tandem arrays of large repetitive units possessing single-stranded 5' extension of about 110 nucleotides. Recently we identified the first mitochondrial telomere-binding protein (mtTBP) that specifically binds a sequence derived from the extreme end of C. parapsilosis linear mtDNA and protects it from attack by various DNA-modifying enzymes (Tomáska, L'., Nosek, J., and Fukuhara, H. (1997) J. Biol. Chem. 272, 3049-3059). Here we report the isolation of MTP1, the gene encoding mtTBP of C. parapsilosis. Sequence analysis revealed that mtTBP shares homology with several bacterial and mitochondrial single-stranded DNA-binding proteins that nonspecifically bind to single-stranded DNA with high affinity. Recombinant mtTBP displays a preference for the telomeric 5' overhang of C. parapsilosis mtDNA. The heterologous expression of a mtTBP-GFP fusion protein resulted in its localization to the mitochondria but was unable to functionally substitute for the loss of the S. cerevisiae homologue Rimlp. Analysis of the MTP1 gene and its translation product mtTBP may provide an insight into the evolutionary origin of linear mitochondrial genomes and the role it plays in their replication and maintenance.},
}
@article {pmid10074444,
year = {1999},
author = {Gottschling, DE and Stoddard, B},
title = {Telomeres: structure of a chromosome's aglet.},
journal = {Current biology : CB},
volume = {9},
number = {5},
pages = {R164-7},
doi = {10.1016/s0960-9822(99)80103-1},
pmid = {10074444},
issn = {0960-9822},
mesh = {Animals ; DNA-Binding Proteins/*metabolism ; Humans ; *Telomere ; },
abstract = {Telomeres impart stability on linear eukaryotic chromosomes by acting as caps, preventing chromosomes from fusing together or being degraded. The structure of a telomere end binding protein in a complex with DNA provides the first molecular view of chromosome capping.},
}
@article {pmid10072604,
year = {1998},
author = {Faravelli, M and Moralli, D and Bertoni, L and Attolini, C and Chernova, O and Raimondi, E and Giulotto, E},
title = {Two extended arrays of a satellite DNA sequence at the centromere and at the short-arm telomere of Chinese hamster chromosome 5.},
journal = {Cytogenetics and cell genetics},
volume = {83},
number = {3-4},
pages = {281-286},
doi = {10.1159/000015171},
pmid = {10072604},
issn = {0301-0171},
mesh = {Animals ; Base Sequence ; CHO Cells ; Centromere/*genetics ; Chromosomes/*genetics ; Cricetinae ; DNA/chemistry/genetics ; DNA, Satellite/chemistry/*genetics ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid/genetics ; Sequence Analysis, DNA ; Sequence Homology, Nucleic Acid ; Telomere/*genetics ; },
abstract = {We have cloned a Chinese hamster chromosome-specific repeated sequence (SatCH5). This satellite is composed of a 33-bp unit organized in two extended tandem arrays. It is localized at the centromere and at the short-arm subtelomere of chromosome 5. Altogether, SatCH5 covers about 1-2 Mb per diploid genome and is not present in other species, including the Syrian hamster and mouse. Since it is known in the Chinese hamster and numerous other vertebrate species that telomeric (TTAGGG)n repeats are localized at the centromeres of several chromosomes, we studied the localization of SatCH5 relative to (TTAGGG)n sequences. Using two-color fluorescence in situ hybridization on stretched chromosomes and on DNA fibers, we have shown that at the centromere of chromosome 5 SatCH5 and the (TTAGGG)n arrays are contiguous. SatCH5 is the first chromosome-specific repetitive sequence located at both the pericentromeric and subtelomeric regions of the same chromosome.},
}
@article {pmid10072358,
year = {1999},
author = {Colgin, LM and Reddel, RR},
title = {Telomere maintenance mechanisms and cellular immortalization.},
journal = {Current opinion in genetics &amp; development},
volume = {9},
number = {1},
pages = {97-103},
doi = {10.1016/s0959-437x(99)80014-8},
pmid = {10072358},
issn = {0959-437X},
mesh = {Animals ; *Antigens, Nuclear ; Cell Transformation, Neoplastic/genetics/*metabolism ; *DNA Helicases ; DNA-Binding Proteins/metabolism ; Humans ; Ku Autoantigen ; Nuclear Proteins/metabolism ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Immortal cell populations are able to proliferate indefinitely. Immortalization is associated with activation of processes that compensate for the telomeric shortening that accompanies cell division in normal somatic cells. In many immortal cell lines, telomere maintenance is provided by the action of the ribonucleoprotein enzyme complex, telomerase. Some immortal cell lines have undetectable or very low levels of telomerase activity and there is evidence that these cells maintain their telomeres by an alternative mechanism.},
}
@article {pmid10064584,
year = {1999},
author = {Herrera, E and Samper, E and Blasco, MA},
title = {Telomere shortening in mTR-/- embryos is associated with failure to close the neural tube.},
journal = {The EMBO journal},
volume = {18},
number = {5},
pages = {1172-1181},
pmid = {10064584},
issn = {0261-4189},
mesh = {Animals ; Cell Survival/genetics ; Central Nervous System/*embryology ; Embryonic and Fetal Development ; Gene Expression Regulation, Developmental/genetics ; In Situ Hybridization ; In Situ Hybridization, Fluorescence ; In Situ Nick-End Labeling ; Litter Size/genetics ; Mice ; Mice, Knockout ; Neural Tube Defects/*embryology/genetics ; Phenotype ; RNA, Messenger/*genetics ; Telomerase/deficiency/*genetics ; Telomere/genetics ; },
abstract = {Mice genetically deficient for the telomerase RNA (mTR) can be propagated for only a limited number of generations. In particular, mTR-/- mice of a mixed C57BL6/129Sv genetic background are infertile at the sixth generation and show serious hematopoietic defects. Here, we show that a percentage of mTR-/- embryos do not develop normally and fail to close the neural tube, preferentially at the forebrain and midbrain. The penetrance of this defect increases with the generation number, with 30% of the mTR-/- embryos from the fifth generation showing the phenotype. Moreover, mTR-/- kindreds in a pure C57BL6 background are only viable up to the fourth generation and also show defects in the closing of the neural tube. Cells derived from mTR-/- embryos that fail to close the neural tube have significantly shorter telomeres and decreased viability than their mTR-/- littermates with a closed neural tube, suggesting that the neural tube defect is a consequence of the loss of telomere function. The fact that the main defect detected in mTR-/- embryos is in the closing of the neural tube, suggests that this developmental process is among the most sensitive to telomere loss and chromosomal instability.},
}
@article {pmid10052873,
year = {1998},
author = {Matioli, GT},
title = {Telomerase-independent modulation of telomere lengths in mammalian chromatids.},
journal = {Medical hypotheses},
volume = {51},
number = {6},
pages = {507-510},
doi = {10.1016/s0306-9877(98)90074-3},
pmid = {10052873},
issn = {0306-9877},
mesh = {Animals ; Base Composition ; Chromatids/chemistry/genetics/ultrastructure ; DNA/genetics ; Humans ; Mammals ; Models, Genetic ; Nucleic Acid Conformation ; Sister Chromatid Exchange ; Telomerase/metabolism ; Telomere/chemistry/*genetics/*ultrastructure ; },
abstract = {The paper discusses modulation of telomere length by mechanisms that do not require telomerase. Although ultimately dependent upon the cell's mitotic potential, these mechanisms do not sufficiently discriminate between normal and malignant cells.},
}
@article {pmid10051409,
year = {1999},
author = {Hande, P and Slijepcevic, P and Silver, A and Bouffler, S and van Buul, P and Bryant, P and Lansdorp, P},
title = {Elongated telomeres in scid mice.},
journal = {Genomics},
volume = {56},
number = {2},
pages = {221-223},
doi = {10.1006/geno.1998.5668},
pmid = {10051409},
issn = {0888-7543},
support = {AI29524/AI/NIAID NIH HHS/United States ; GM56162/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Crosses, Genetic ; Female ; In Situ Hybridization, Fluorescence/methods ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, SCID ; *Repetitive Sequences, Nucleic Acid ; Species Specificity ; Telomere/*genetics ; },
abstract = {Severe combined immunodeficiency (scid) mice are deficient in the enzyme DNA-PK (DNA-dependent protein kinase) as a result of the mutation in the gene encoding the catalytic subunit (DNA-PKcs) of this enzyme. DNA-PKcs is a member of the phosphatidylinositol 3-kinase superfamily, which includes the human protein ATM (ataxia telangiectasia mutated) and the yeast protein Tel1. Using Q-FISH (quantitative fluorescence in situ hybridization), we show here that scid mice from four different genetic backgrounds have, on average, 1.5-2 times longer telomeres than those of corresponding wild-type mice. Our results point to the possibility that DNA-PKcs may, directly or indirectly, be involved in telomere length regulation in mammalian cells.},
}
@article {pmid10049921,
year = {1999},
author = {Ahmad, K and Golic, KG},
title = {Telomere loss in somatic cells of Drosophila causes cell cycle arrest and apoptosis.},
journal = {Genetics},
volume = {151},
number = {3},
pages = {1041-1051},
pmid = {10049921},
issn = {0016-6731},
support = {HD-28694/HD/NICHD NIH HHS/United States ; },
mesh = {Aneuploidy ; Animals ; Apoptosis/*genetics ; Cell Cycle/*genetics ; Chromosome Breakage ; DNA Damage/genetics ; DNA Nucleotidyltransferases/pharmacology ; Drosophila/*genetics/physiology ; Eye/cytology ; Eye Abnormalities/genetics ; Female ; Genes, Insect ; Male ; Models, Biological ; Phenotype ; Telomere/*genetics/*physiology ; Wings, Animal/abnormalities ; },
abstract = {Checkpoint mechanisms that respond to DNA damage in the mitotic cell cycle are necessary to maintain the fidelity of chromosome transmission. These mechanisms must be able to distinguish the normal telomeres of linear chromosomes from double-strand break damage. However, on several occasions, Drosophila chromosomes that lack their normal telomeric DNA have been recovered, raising the issue of whether Drosophila is able to distinguish telomeric termini from nontelomeric breaks. We used site-specific recombination on a dispensable chromosome to induce the formation of a dicentric chromosome and an acentric, telomere-bearing, chromosome fragment in somatic cells of Drosophila melanogaster. The acentric fragment is lost when cells divide and the dicentric breaks, transmitting a chromosome that has lost a telomere to each daughter cell. In the eye imaginal disc, cells with a newly broken chromosome initially experience mitotic arrest and then undergo apoptosis when cells are induced to divide as the eye differentiates. Therefore, Drosophila cells can detect and respond to a single broken chromosome. It follows that transmissible chromosomes lacking normal telomeric DNA nonetheless must possess functional telomeres. We conclude that Drosophila telomeres can be established and maintained by a mechanism that does not rely on the terminal DNA sequence.},
}
@article {pmid10048297,
year = {1998},
author = {Reddel, RR},
title = {A reassessment of the telomere hypothesis of senescence.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {20},
number = {12},
pages = {977-984},
doi = {10.1002/(SICI)1521-1878(199812)20:12&lt;977::AID-BIES3&gt;3.0.CO;2-E},
pmid = {10048297},
issn = {0265-9247},
mesh = {Aging/*genetics ; Animals ; Cell Cycle/genetics ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Viral/genetics ; Cellular Senescence/*genetics ; Humans ; Telomere/*genetics ; },
abstract = {According to the telomere hypothesis of senescence, the telomeric shortening that accompanies the replication of normal somatic cells acts as the mitotic clock that eventually results in their permanent exit from the cell cycle. Although evidence consistent with the telomere hypothesis continues to accumulate, on the basis of recent findings it is suggested that instead of a single clock mechanism there are multiple inducers of senescence.},
}
@article {pmid10047445,
year = {1999},
author = {Sprung, CN and Sabatier, L and Murnane, JP},
title = {Telomere dynamics in a human cancer cell line.},
journal = {Experimental cell research},
volume = {247},
number = {1},
pages = {29-37},
doi = {10.1006/excr.1998.4293},
pmid = {10047445},
issn = {0014-4827},
support = {ES07106/ES/NIEHS NIH HHS/United States ; R01 CA69044/CA/NCI NIH HHS/United States ; },
mesh = {Carcinoma, Squamous Cell/*chemistry/enzymology/*genetics ; Chromosomes, Human/enzymology/genetics ; Clone Cells/chemistry/enzymology ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Telomerase/chemistry ; Telomere/*chemistry/enzymology ; Tumor Cells, Cultured ; },
abstract = {Telomere maintenance is thought to be essential for immortalization of human cancer cells to compensate for the loss of DNA from the ends of chromosomes and to prevent chromosome fusion. We have investigated telomere dynamics in the telomerase-positive squamous cell carcinoma cell line SCC-61 by marking the ends of chromosomes with integrated plasmid sequences so that changes in the length of individual telomeres could be monitored. Despite having very short telomeres, SCC-61 has a relatively stable genome and few telomere associations. The marked telomeres in different SCC-61 clones have similar mean lengths which show little change with increasing time in culture. Thus, each marked telomere is maintained at a specific length, which we term the equilibrium mean length (EML). The Gaussian distribution in the length of the marked telomeres demonstrates that telomeres continuously fluctuate in length. Consistent with this observation, the mean lengths of the marked telomere in subclones of these cell lines initially differ, but then gradually return to the EML of the original clone with increasing time in culture. The analysis of a clone with two marked telomeres demonstrated that changes in telomere length can occur on each marked telomere independently or coordinately on both telomeres. These results suggest that the short telomeres in many tumor cell lines do not result from an inability to properly maintain telomeres at a specific length.},
}
@article {pmid10037783,
year = {1999},
author = {Hande, MP and Samper, E and Lansdorp, P and Blasco, MA},
title = {Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice.},
journal = {The Journal of cell biology},
volume = {144},
number = {4},
pages = {589-601},
pmid = {10037783},
issn = {0021-9525},
support = {P01 CA013106/CA/NCI NIH HHS/United States ; GM56162/GM/NIGMS NIH HHS/United States ; P01-CA 13106/CA/NCI NIH HHS/United States ; R01AI29524/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Cell Transformation, Neoplastic ; Cells, Cultured ; Chromosome Aberrations ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Knockout ; Models, Genetic ; Neoplasms, Experimental/enzymology/etiology/genetics ; Telomerase/*deficiency/genetics ; Telomere/*genetics/*ultrastructure ; },
abstract = {To study the effect of continued telomere shortening on chromosome stability, we have analyzed the telomere length of two individual chromosomes (chromosomes 2 and 11) in fibroblasts derived from wild-type mice and from mice lacking the mouse telomerase RNA (mTER) gene using quantitative fluorescence in situ hybridization. Telomere length at both chromosomes decreased with increasing generations of mTER-/- mice. At the 6th mouse generation, this telomere shortening resulted in significantly shorter chromosome 2 telomeres than the average telomere length of all chromosomes. Interestingly, the most frequent fusions found in mTER-/- cells were homologous fusions involving chromosome 2. Immortal cultures derived from the primary mTER-/- cells showed a dramatic accumulation of fusions and translocations, revealing that continued growth in the absence of telomerase is a potent inducer of chromosomal instability. Chromosomes 2 and 11 were frequently involved in these abnormalities suggesting that, in the absence of telomerase, chromosomal instability is determined in part by chromosome-specific telomere length. At various points during the growth of the immortal mTER-/- cells, telomere length was stabilized in a chromosome-specific man-ner. This telomere-maintenance in the absence of telomerase could provide the basis for the ability of mTER-/- cells to grow indefinitely and form tumors.},
}
@article {pmid10037601,
year = {1999},
author = {Karlseder, J and Broccoli, D and Dai, Y and Hardy, S and de Lange, T},
title = {p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2.},
journal = {Science (New York, N.Y.)},
volume = {283},
number = {5406},
pages = {1321-1325},
doi = {10.1126/science.283.5406.1321},
pmid = {10037601},
issn = {0036-8075},
support = {GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenoviridae/genetics/physiology ; Animals ; *Apoptosis ; Ataxia Telangiectasia/pathology ; Ataxia Telangiectasia Mutated Proteins ; B-Lymphocytes/cytology ; Cell Cycle Proteins ; Cell Line ; Cells, Cultured ; Cloning, Molecular ; DNA Damage ; DNA-Binding Proteins/chemistry/genetics/*physiology ; Genetic Vectors ; Humans ; In Situ Nick-End Labeling ; Mice ; Mitosis ; Phosphorylation ; *Protein Serine-Threonine Kinases ; Proteins/metabolism ; T-Lymphocytes/cytology ; Telomere/*physiology ; Telomeric Repeat Binding Protein 2 ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/*metabolism ; Tumor Suppressor Proteins ; },
abstract = {Although broken chromosomes can induce apoptosis, natural chromosome ends (telomeres) do not trigger this response. It is shown that this suppression of apoptosis involves the telomeric-repeat binding factor 2 (TRF2). Inhibition of TRF2 resulted in apoptosis in a subset of mammalian cell types. The response was mediated by p53 and the ATM (ataxia telangiectasia mutated) kinase, consistent with activation of a DNA damage checkpoint. Apoptosis was not due to rupture of dicentric chromosomes formed by end-to-end fusion, indicating that telomeres lacking TRF2 directly signal apoptosis, possibly because they resemble damaged DNA. Thus, in some cells, telomere shortening may signal cell death rather than senescence.},
}
@article {pmid10030665,
year = {1998},
author = {Russo, I and Silver, AR and Cuthbert, AP and Griffin, DK and Trott, DA and Newbold, RF},
title = {A telomere-independent senescence mechanism is the sole barrier to Syrian hamster cell immortalization.},
journal = {Oncogene},
volume = {17},
number = {26},
pages = {3417-3426},
doi = {10.1038/sj.onc.1202261},
pmid = {10030665},
issn = {0950-9232},
mesh = {Animals ; Antigens, Polyomavirus Transforming/genetics ; Cell Division ; Cell Line, Transformed ; Cells, Cultured ; Cellular Senescence/*physiology ; Cricetinae ; Culture Media, Serum-Free ; Telomerase/*metabolism ; Telomere/*physiology ; Time Factors ; },
abstract = {Reactivation of telomerase and stabilization of telomeres occur simultaneously during human cell immortalization in vitro and the vast majority of human cancers possess high levels of telomerase activity. Telomerase repression in human somatic cells may therefore have evolved as a powerful resistance mechanism against immortalization, clonal evolution and malignant progression. The comparative ease with which rodent cells immortalize in vitro suggests that they have less stringent controls over replicative senescence than human cells. Here, we report that Syrian hamster dermal fibroblasts possess substantial levels of telomerase activity throughout their culture life-span, even after growth arrest in senescence. In our studies, telomerase was also detected in uncultured newborn hamster skin, in several adult tissues, and in cultured fibroblasts induced to enter the post-mitotic state irreversibly by serum withdrawal. Transfection of near-senescent dermal fibroblasts with a selectable plasmid vector expressing the SV40 T-antigen gene resulted in high-frequency single-step immortalization without the crisis typically observed during the immortalization of human cells. Collectively, these data provide an explanation for the increased susceptibility of rodent cells to immortalization (and malignant transformation) compared with their human equivalents, and provide evidence for a novel, growth factor-sensitive, mammalian senescence mechanism unrelated to telomere maintenance.},
}
@article {pmid10023320,
year = {1998},
author = {Huang, GT and Lee, HS and Chen, CH and Chiou, LL and Lin, YW and Lee, CZ and Chen, DS and Sheu, JC},
title = {Telomerase activity and telomere length in human hepatocellular carcinoma.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {34},
number = {12},
pages = {1946-1949},
doi = {10.1016/s0959-8049(98)00237-8},
pmid = {10023320},
issn = {0959-8049},
mesh = {Adult ; Aged ; Carcinoma, Hepatocellular/*enzymology ; Female ; Humans ; Liver Neoplasms/*enzymology ; Male ; Middle Aged ; Neoplasm Proteins/*metabolism ; Neoplasm Recurrence, Local/enzymology ; Telomerase/*metabolism ; Telomere/*enzymology ; },
abstract = {Telomerase activity is activated and telomere length altered in various types of cancers, including hepatocellular carcinoma (HCC). A total of 39 HCC tissues and the corresponding non-tumour livers were analysed and correlated with clinical parameters. Telomere length was determined by terminal restriction fragment assay, and telomerase activity was assayed by telomeric repeat amplification protocol. Telomerase activity was positive in 24 of the 39 tumour tissues (1.15-285.13 total product generated (TPG) units) and in six of the 39 non-tumour liver tissues (1.05-1.73 TPG units). In the 28 cases analysed for telomere length, telomere length was shortened in 11 cases, lengthened in six cases, and unaltered in 11 cases compared with non-tumour tissues. Neither telomere length nor telomerase activity was correlated to any clinical parameters.},
}
@article {pmid9988274,
year = {1999},
author = {Corda, Y and Schramke, V and Longhese, MP and Smokvina, T and Paciotti, V and Brevet, V and Gilson, E and Géli, V},
title = {Interaction between Set1p and checkpoint protein Mec3p in DNA repair and telomere functions.},
journal = {Nature genetics},
volume = {21},
number = {2},
pages = {204-208},
doi = {10.1038/5991},
pmid = {9988274},
issn = {1061-4036},
mesh = {Cell Cycle/genetics/physiology ; Cell Cycle Proteins/genetics/*physiology ; Checkpoint Kinase 2 ; Chromosomal Proteins, Non-Histone/genetics/*physiology ; DNA Repair/*physiology ; Fungal Proteins/genetics/*physiology ; Gene Expression Regulation, Fungal ; Protein Kinases/genetics/physiology ; *Protein Serine-Threonine Kinases ; Proteins/genetics/*physiology ; Saccharomyces cerevisiae ; *Saccharomyces cerevisiae Proteins ; Telomere/*physiology ; Transcription Factors ; },
abstract = {The yeast protein Set1p, inactivation of which alleviates telomeric position effect (TPE), contains a conserved SET domain present in chromosomal proteins involved in epigenetic control of transcription. Mec3p is required for efficient DNA-damage-dependent checkpoints at G1/S, intra-S and G2/M (refs 3-7). We show here that the SET domain of Set1p interacts with Mec3p. Deletion of SET1 increases the viability of mec3delta mutants after DNA damage (in a process that is mostly independent of Rad53p kinase, which has a central role in checkpoint control) but does not significantly affect cell-cycle progression. Deletion of MEC3 enhances TPE and attenuates the Set1delta-induced silencing defect. Furthermore, restoration of TPE in a Set1delta mutant by overexpression of the isolated SET domain requires Mec3p. Finally, deletion of MEC3 results in telomere elongation, whereas cells with deletions of both SET1 and MEC3 do not have elongated telomeres. Our findings indicate that interactions between SET1 and MEC3 have a role in DNA repair and telomere function.},
}
@article {pmid9988261,
year = {1999},
author = {Weinert, T and Lundblad, V},
title = {Forever hopeful relations: chromatin, telomeres and checkpoints.},
journal = {Nature genetics},
volume = {21},
number = {2},
pages = {151-152},
doi = {10.1038/5930},
pmid = {9988261},
issn = {1061-4036},
mesh = {Animals ; Cell Cycle/genetics/physiology ; Chromatin/*genetics ; Humans ; Models, Biological ; Telomere/*genetics ; },
}
@article {pmid9973600,
year = {1999},
author = {Trelles-Sticken, E and Loidl, J and Scherthan, H},
title = {Bouquet formation in budding yeast: initiation of recombination is not required for meiotic telomere clustering.},
journal = {Journal of cell science},
volume = {112 (Pt 5)},
number = {},
pages = {651-658},
doi = {10.1242/jcs.112.5.651},
pmid = {9973600},
issn = {0021-9533},
mesh = {Centromere/genetics/ultrastructure ; Chromosome Painting ; Chromosomes, Fungal/genetics/ultrastructure ; In Situ Hybridization, Fluorescence ; Meiosis/*genetics ; *Recombination, Genetic ; Saccharomyces cerevisiae/*genetics/*ultrastructure ; Telomere/*genetics/ultrastructure ; },
abstract = {Fluorescence in situ hybridization in combination with synaptonemal complex and spindle pole body immunostaining to both spread and structurally preserved nuclei from time course experiments disclosed prominent telomere clustering during meiotic prophase of the yeast Saccharomyces cerevisiae. It was found that centromere clustering, which dominates vegetative nuclear structure, is rapidly lost after induction of meiosis. Telomeres tightly clustered during leptotene/zygotene-equivalent stages in the vicinity of the spindle pole body, giving rise to a classical chromosomal bouquet arrangement. This arrangement dissolved later during prophase. Painting of chromosomes XI revealed that initially compacted chromosome territories adopt an outstretched morphology in bouquet nuclei. This conformational state was associated with alignment and pairing. Chromosome condensation during pachytene rendered condensed and compact bivalents, and dispersed telomeres. Both the spo11 and rad50S recombination mutants formed bouquets, demonstrating that bouquet formation is recombination and synapsis independent.},
}
@article {pmid9951834,
year = {1999},
author = {Musio, A and Mariani, T},
title = {Distribution of interstitial telomere-related sequences in the human genome and their relationship with fragile sites.},
journal = {Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer},
volume = {18},
number = {1},
pages = {11-15},
pmid = {9951834},
issn = {0731-8898},
mesh = {Chromosome Fragile Sites ; Chromosome Fragility/*genetics ; Chromosome Mapping ; Databases, Factual ; Electronic Data Processing ; Gene Dosage ; *Genome, Human ; Humans ; Telomere/*genetics ; },
abstract = {Using a computer search in the mapped human genome, we could show that interstitial telomere-related sequences are clustered in R-bands, and, in some cases, coexist with mapped fragile sites. We speculate that this association could predispose to chromosome fragility and recombination.},
}
@article {pmid9930692,
year = {1999},
author = {Price, C},
title = {Telomeres. Capping off the ends.},
journal = {Nature},
volume = {397},
number = {6716},
pages = {213-214},
doi = {10.1038/16598},
pmid = {9930692},
issn = {0028-0836},
mesh = {Animals ; DNA, Protozoan ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/*chemistry/metabolism ; Models, Molecular ; Oxytricha/*chemistry/genetics ; Protein Conformation ; Protozoan Proteins/chemistry/metabolism ; *Telomere ; },
}
@article {pmid9928440,
year = {1998},
author = {von Zglinicki, T},
title = {Telomeres: influencing the rate of aging.},
journal = {Annals of the New York Academy of Sciences},
volume = {854},
number = {},
pages = {318-327},
doi = {10.1111/j.1749-6632.1998.tb09912.x},
pmid = {9928440},
issn = {0077-8923},
mesh = {Aging/genetics/*physiology ; Animals ; Cell Cycle ; *DNA Damage ; DNA Replication ; Genes, p53 ; Humans ; Oxidative Stress ; Telomerase/*metabolism ; Telomere/genetics/*physiology ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Evidence is reviewed that suggests a central role for telomeres in one major model of biological aging, namely, proliferative senescence. Telomeric shortening with each cell division does not only act as a biological clock, but appears to trigger the ultimate loss of proliferative ability via activation of the p53-dependent check point system. Oxidative stress induces single-stranded damage in telomeric DNA. It is not clear yet whether this damage occurs in the form of single-stranded gaps or overhangs or as arbitrarily distributed single-stranded breaks. However, in contradiction to the rest of the genome, this damage is not repaired in telomeres. It is, therefore, the major cause of telomere shortening even under standard in vitro cell culture conditions. Therefore, controlling the oxidative load onto DNA, in general, and, especially, onto telomeres might become a major factor to influence the rate of aging. Further experiments demonstrate that G-rich single-stranded telomeric DNA fragments do activate the p53 check point control, leading to an inhibition of proliferation in wild-type p53 cells. Not only the shortening of telomeres down to a "signal value," but accumulation of telomeric single-stranded DNA fragments, as well, could be relevant triggers for proliferative senescence.},
}
@article {pmid9926982,
year = {1998},
author = {Feng, YR and Norwood, D and Shibata, R and Gee, D and Xiao, X and Martin, M and Zeichner, SL and Dimitrov, DS},
title = {Telomere dynamics in HIV-1 infected and uninfected chimpanzees measured by an improved method based on high-resolution two-dimensional calibration of DNA sizes.},
journal = {Journal of medical primatology},
volume = {27},
number = {5},
pages = {258-265},
doi = {10.1111/j.1600-0684.1998.tb00246.x},
pmid = {9926982},
issn = {0047-2565},
mesh = {Age Factors ; Animals ; DNA/*analysis ; HIV Infections/*physiopathology ; Longitudinal Studies ; Monocytes/cytology/virology ; Pan troglodytes/*genetics/*virology ; Telomere/*ultrastructure ; },
abstract = {We developed an improved method for accurately measuring telomere lengths based on two-dimensional calibration of DNA sizes combined with pulsed field electrophoresis and quantitative analysis of high-resolution gel images. This method was used to quantify the length of telomeres in longitudinal samples of peripheral blood mononuclear cells (PBMCs) from five chimpanzees infected with human immunodeficiency virus type 1 (HIV-1) and three uninfected animals, 14 to 27 years of age. The average length of the telomere restriction fragments (TRF) of infected and uninfected chimpanzees were 11.7 +/- 0.25 kbp, and 11.6 +/- 0.61 kbp, respectively, and were about 1 kbp and 3 kbp longer than those of human infants and 30 year old adults, respectively. There was a trend of a slight decrease (30-60 bp per year) in the TRF of two HIV infected chimpanzees over 30-35 months, while the TRF of one naive chimpanzee slightly increased over 20 months. Although the number of chimpanzees in this study is small and no statistically significant linear dependencies on time were observed, it appears that in chimpanzees, rates of shortening of the TRF are comparable or smaller than in adult humans and are not significantly affected by HIV-1 infection, which may be related to the inability of HIV-1 to cause disease in these animals.},
}
@article {pmid9922267,
year = {1999},
author = {Sohn, JH and Choi, ES and Kang, HA and Rhee, JS and Rhee, SK},
title = {A family of telomere-associated autonomously replicating sequences and their functions in targeted recombination in Hansenula polymorpha DL-1.},
journal = {Journal of bacteriology},
volume = {181},
number = {3},
pages = {1005-1013},
pmid = {9922267},
issn = {0021-9193},
mesh = {Base Sequence ; Chromosomes, Fungal/*genetics ; Cloning, Molecular ; *DNA Replication ; DNA, Fungal/genetics ; Molecular Sequence Data ; Pichia/*genetics ; Plasmids ; *Recombination, Genetic ; *Repetitive Sequences, Nucleic Acid ; Sequence Alignment ; Sequence Homology, Nucleic Acid ; Telomere/*genetics ; Transformation, Genetic ; },
abstract = {A family of multiple autonomously replicating sequences (ARSs) which are located at several chromosomal ends of Hansenula polymorpha DL-1 has been identified and characterized. Genomic Southern blotting with an ARS, HARS36, originating from the end of a chromosome, as a probe showed several homologues in the genome of H. polymorpha. Nucleotide sequences of the three fragments obtained by a selective cloning for chromosomal ends were nearly identical to that of HARS36. All three fragments harbored an ARS motif and ended with 18 to 23 identical repetitions of 5'-GGGTGGCG-3' which resemble the telomeric repeat sequence in other eukaryotes. Transformation of H. polymorpha with nonlinearized plasmids containing the newly obtained telomeric ARSs almost exclusively resulted in the targeted integration of a single copy or multiple tandem copies of the plasmid into the chromosomes. The sensitivity to exonuclease Bal31 digestion of the common DNA fragment in all integrants confirmed the telomeric origin of HARS36 homologues, suggesting that several chromosomal ends, if not all of them, consisted of the same ARS motif and highly conserved sequences observed in HARS36. Even though the frequencies of targeted recombination were varied among the ends of the chromosomes, the overall frequency was over 96%. The results suggested that the integration of the plasmids containing telemeric ARSs occurred largely through homologous recombination at the telomeric repeats, which serve as high-frequency recombination targets.},
}
@article {pmid9920820,
year = {1999},
author = {Ouellette, MM and Aisner, DL and Savre-Train, I and Wright, WE and Shay, JW},
title = {Telomerase activity does not always imply telomere maintenance.},
journal = {Biochemical and biophysical research communications},
volume = {254},
number = {3},
pages = {795-803},
doi = {10.1006/bbrc.1998.0114},
pmid = {9920820},
issn = {0006-291X},
support = {AG07992/AG/NIA NIH HHS/United States ; },
mesh = {Base Sequence ; Catalytic Domain ; Cell Line ; DNA Primers ; Genetic Vectors ; Humans ; Lung/cytology/metabolism ; Molecular Sequence Data ; RNA, Messenger/genetics/metabolism ; Retroviridae/genetics ; Telomerase/genetics/*metabolism ; Telomere/*enzymology ; },
abstract = {The forced expression of the catalytic subunit of human telomerase, hTERT, produces telomerase activity, allows telomere maintenance, and extends the cellular life span of IMR90 human lung fibroblasts. The mutation D869A abolishes both the catalytic activity of hTERT and its ability to extend cellular life span, demonstrating that the immortalizing capabilities of the enzyme are dependent on active catalysis. A second mutant of hTERT was examined that contains three copies of an HA epitope inserted at the C-terminus. This mutant produced telomerase activity in fibroblasts that was virtually indistinguishable from that of wild type telomerase when assayed in vitro. However, the forced expression of this mutant failed to maintain telomeres or extend cellular life span. Our results show that the catalytic activity of hTERT is required for cellular immortalization but that the presence of active telomerase does not necessarily imply telomere maintenance and immortality.},
}
@article {pmid9920771,
year = {1999},
author = {Cervoni, L and Ferraro, A and Eufemi, M and Altieri, F and Chichiarelli, S and Turano, C},
title = {Cross-linked telomere-protein complexes from chicken erythrocyte nuclei: isolation by a new procedure.},
journal = {Biochemical and biophysical research communications},
volume = {254},
number = {3},
pages = {517-521},
doi = {10.1006/bbrc.1998.0115},
pmid = {9920771},
issn = {0006-291X},
mesh = {Animals ; Base Sequence ; Blood Proteins/isolation &amp; purification/metabolism ; Cell Nucleus/drug effects/*metabolism ; Chickens ; Chromosomal Proteins, Non-Histone/isolation &amp; purification/*metabolism ; Cisplatin/pharmacology ; DNA-Binding Proteins/isolation &amp; purification/metabolism ; Erythrocytes/drug effects/*metabolism ; Oligonucleotides ; Telomere/drug effects/*metabolism ; },
abstract = {DNA-protein cross-linkages were produced in intact nuclei of chicken erythrocytes by the action of cis-diammine dichloroplatinum. The telomeric DNA-protein cross-linked complexes were then isolated by hybridization with a biotinylated oligonucleotide and selective binding on immobilized streptavidin. Two main nonhistone proteins were present in the purified complexes, migrating in SDS-gel electrophoresis with apparent molecular masses of 66 and 58 kDa, respectively. Although the identity of these two proteins is still unknown, it is significant that two proteins with similar electrophoretic behavior have been described as constituents of the human telomeric complexes. This procedure could also be applied to the isolation of DNA-protein cross-linked complexes containing any chosen DNA sequence.},
}
@article {pmid9894917,
year = {1998},
author = {Fajkus, J and Fulnecková, J and Hulánová, M and Berková, K and Ríha, K and Matyásek, R},
title = {Plant cells express telomerase activity upon transfer to callus culture, without extensively changing telomere lengths.},
journal = {Molecular &amp; general genetics : MGG},
volume = {260},
number = {5},
pages = {470-474},
doi = {10.1007/s004380050918},
pmid = {9894917},
issn = {0026-8925},
mesh = {Cell Differentiation/genetics ; Cells, Cultured ; Plant Leaves/cytology/genetics ; *Plants, Toxic ; Telomerase/genetics/*metabolism ; Telomere/*genetics ; Nicotiana/cytology/*genetics/physiology ; },
abstract = {Changes in telomere lengths and telomerase activity in tobacco cells were studied during dedifferentiation and differentiation; leaf tissues were used to initiate callus cultures, which were then induced to regenerate plants. While no significant changes in the range of telomere lengths were observed in response to dedifferentiation and differentiation, there was a conspicuous increase in telomerase activity in calli compared to the source leaves, where the activity was hardly detectable. In leaves of regenerated plants, the telomerase activity fell to almost the same level as in the original plant, showing on the average 0.04% of the level in callus. The process was then repeated using the regenerants as the source material. In the second round of dedifferentiation and differentiation, telomerase activity showed a similar increase in calli derived from regenerated plants and a drop in plants regenerated from these calli. Telomere lengths remained unchanged both in calli and in leaves of regenerants. The conservation of telomere lengths over repeated rounds of dedifferentiation and differentiation, which are associated with dramatic changes in cell division rate and corresponding variation in telomerase activity may reflect the function of a regulatory mechanism in plant cells which controls telomerase action to compensate for replicative loss of telomeric DNA.},
}
@article {pmid9892113,
year = {1999},
author = {Wan, TS and Martens, UM and Poon, SS and Tsao, SW and Chan, LC and Lansdorp, PM},
title = {Absence or low number of telomere repeats at junctions of dicentric chromosomes.},
journal = {Genes, chromosomes &amp; cancer},
volume = {24},
number = {1},
pages = {83-86},
doi = {10.1002/(sici)1098-2264(199901)24:1&lt;83::aid-gcc12&gt;3.0.co;2-c},
pmid = {9892113},
issn = {1045-2257},
support = {AI29524/AI/NIAID NIH HHS/United States ; GM56162/GM/NIGMS NIH HHS/United States ; },
mesh = {Cells, Cultured ; Female ; Humans ; In Situ Hybridization, Fluorescence/methods ; Oncogene Proteins, Viral/genetics ; Ovary ; Papillomaviridae/genetics ; Papillomavirus E7 Proteins ; Repetitive Sequences, Nucleic Acid/*genetics ; *Repressor Proteins ; Telomere/chemistry/*genetics ; },
abstract = {Human ovarian surface epithelial (HOSE) cells transfected with the E6 and E7 oncogenes of the human papilloma virus (PV) do not express measurable telomerase activity. Relative to untransfected control cells, HOSE-PV cells have an extended in vitro lifespan characterized by a very high frequency of telomeric associations (TAs) of chromosomes. In order to study the role of telomere shortening in the formation of TAs, we studied the telomere length in 120 dicentric chromosomes in HOSE-PV cells by using quantitative fluorescence in situ hybridization. Forty percent of the dicentric chromosomes had no fluorescence signal at the junction site, and in the remainder the fluorescence at the junction was less than at corresponding unjoined ends. These observations support a critical role of telomere shortening in the development of TAs and the subsequent genetic instability observed in a majority of tumor cells.},
}
@article {pmid9890947,
year = {1999},
author = {Venditti, S and Vega-Palas, MA and Di Mauro, E},
title = {Heterochromatin organization of a natural yeast telomere. Recruitment of Sir3p through interaction with histone H4 N terminus is required for the establishment of repressive structures.},
journal = {The Journal of biological chemistry},
volume = {274},
number = {4},
pages = {1928-1933},
doi = {10.1074/jbc.274.4.1928},
pmid = {9890947},
issn = {0021-9258},
mesh = {Acetylation ; Fungal Proteins/*metabolism ; Heterochromatin/chemistry/genetics/*metabolism ; Histones/*metabolism ; Mutation ; Protein Conformation ; Repressor Proteins/*metabolism ; Saccharomyces cerevisiae/*genetics/metabolism ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Telomere/*metabolism ; Trans-Activators/*metabolism ; },
abstract = {The chromatin organization of eukaryotic telomeres is essential for telomeric function and is currently receiving great attention. In yeast, the structural organization of telomeres involves a complex interplay of telomeric proteins that results in the formation of heterochromatin. This telomeric heterochromatin involves homotypic and heterotypic protein interactions that have been summarized in a general model. Recent analyses have focused on the study of the structural complexity at yeast telomeres to the level of specific nucleosomes and of the distribution of protein complexes in a natural telomeric region (LIII). In this report, we further analyze the structural complexity of LIII and the implication of this structure on telomeric silencing. It is shown that the establishment of repressive heterochromatin structures at LIII requires the recruitment of Sir3p through interaction with the N terminus of histone H4. The establishment of such structures does not require acetylation of any of four lysines located in the H4 N terminus (lysines 5, 8, 12, and 16).},
}
@article {pmid9888797,
year = {1999},
author = {Laporte, L and Benevides, JM and Thomas, GJ},
title = {Molecular mechanism of DNA recognition by the alpha subunit of the Oxytricha telomere binding protein.},
journal = {Biochemistry},
volume = {38},
number = {2},
pages = {582-588},
doi = {10.1021/bi9819024},
pmid = {9888797},
issn = {0006-2960},
support = {GM54378/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Circular Dichroism ; DNA, Protozoan/*chemistry/metabolism ; DNA-Binding Proteins/*chemistry/metabolism ; Electrophoresis, Polyacrylamide Gel ; Models, Molecular ; Nuclear Proteins/*chemistry/metabolism ; Nucleic Acid Conformation ; Oligodeoxyribonucleotides/chemistry ; Oxytricha ; Spectrum Analysis, Raman ; Telomere/*chemistry/metabolism ; },
abstract = {Interactions between telomeric DNA and the alpha subunit of the heterodimeric telomere binding protein of Oxytricha nova have been probed by Raman spectroscopy, CD spectroscopy, and nondenaturing gel electrophoresis. Telomeric sequences investigated include the Oxytricha 3' overhang, d(T4G4)2, and the related sequence dT6(T4G4)2, which incorporates a 5'-thymidylate leader. Corresponding nontelomeric isomers, d(TG)8 and dT6(TG)8, have also been investigated. Both d(T4G4)2 and dT6(T4G4)2 form stable hairpins that contain Hoogsteen G.G base pairs [Laporte, L., and Thomas, G. J., Jr. (1998) J. Mol. Biol. 281, 261-270]. The alpha subunit binds specifically and stoichiometrically to the dT6(T4G4)2 hairpin and alters its secondary structure by inducing conformational changes in the 5'-thymidylate leader without extensive disruption of G.G base pairing. Conversely, binding of the alpha subunit to d(T4G4)2 eliminates G.G pairing and unfolds the hairpin. DNA unfolding is accompanied by conformational changes affecting both the backbone and dG residues, as evidenced by Raman and CD spectra. Interestingly, the alpha subunit also forms complexes with the nontelomeric isomers, d(TG)8 and dT6(TG)8, evidenced by altered electrophoretic mobility in nondenaturing gels; however, Raman and CD spectra of complexes of the alpha subunit with nontelomeric DNA suggest no significant changes in backbone or deoxynucleoside conformations. Similarly, the alpha subunit binds to but does not appreciably alter the secondary structure of duplex DNA. The present results show that while the alpha subunit has the capacity to bind to Watson-Crick and different non-Watson-Crick motifs, DNA refolding is specific to the Oxytricha telomeric hairpin and the retention of G.G pairing is specific to the telomeric sequence incorporating the 5' leading sequence. A model is proposed for alpha subunit binding to telomeric DNA, and the physiological role of the alpha subunit in telomere organization is discussed.},
}
@article {pmid9888444,
year = {1999},
author = {Matsunaga, H and Handa, JT and Aotaki-Keen, A and Sherwood, SW and West, MD and Hjelmeland, LM},
title = {Beta-galactosidase histochemistry and telomere loss in senescent retinal pigment epithelial cells.},
journal = {Investigative ophthalmology &amp; visual science},
volume = {40},
number = {1},
pages = {197-202},
pmid = {9888444},
issn = {0146-0404},
support = {EY00344/EY/NEI NIH HHS/United States ; EY06473/EY/NEI NIH HHS/United States ; },
mesh = {Blotting, Southern ; Bromodeoxyuridine/metabolism ; Cell Division ; Cell Line ; Cells, Cultured ; *Cellular Senescence/physiology ; DNA/analysis ; DNA Replication ; Histocytochemistry ; Humans ; Infant ; Pigment Epithelium of Eye/cytology/*enzymology ; Telomere/*metabolism ; beta-Galactosidase/*metabolism ; },
abstract = {PURPOSE: To investigate the relation of senescence-related beta-galactosidase activity and telomere shortening to replicative senescence in cultured human retinal pigment epithelial (RPE) cells.<br><br>METHODS: A human RPE cell line was serially passaged until 80% of cells were nondividing in a 72-hour 5-bromo-2'-deoxyuridine (BrdU) labeling study. Early- and late-passage cells were double-stained for BrdU and senescence-related beta-galactosidase activity (pH 6). The average chromosomal telomere length at several population doublings was estimated by Southern blot analysis after double digestion of DNA with RsaI and HinfI and using a telomere-specific probe.<br><br>RESULTS: BrdU-beta-galactosidase double-staining revealed an inverse correlation between the number of BrdU-labeled nuclei and beta-galactosidase-labeled cells as a function of population doubling level (PDL). At PDL 58, only 20% of all cells labeled for BrdU, whereas 57% stained for beta-galactosidase. The mean terminal restriction fragment length (TRF) was reduced from 10 kb in early (PDL 12) cultures to 4 kb in late (PDL 57) cultures.<br><br>CONCLUSIONS: Senescence-related beta-galactosidase activity and mean TRF length may prove useful in studying the senescence of RPE cells in vitro. These techniques may be valuable in determining senescence of the retinal pigment epithelium in vivo, where senescent RPE cells could be involved in the development of age-related maculopathy and age-related macular degeneration.},
}
@article {pmid9886774,
year = {1998},
author = {Dong, F and Jiang, J},
title = {Non-Rabl patterns of centromere and telomere distribution in the interphase nuclei of plant cells.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {6},
number = {7},
pages = {551-558},
pmid = {9886774},
issn = {0967-3849},
mesh = {Avena/genetics ; Cell Nucleus/*ultrastructure ; Centromere/*ultrastructure ; Chromosome Segregation ; Hordeum/genetics ; In Situ Hybridization, Fluorescence ; *Interphase ; Models, Biological ; Oligonucleotide Probes ; Oryza/genetics ; Plants/*ultrastructure ; Secale/genetics ; Telomere/*ultrastructure ; Triticum/genetics ; Zea mays/genetics ; },
abstract = {At the anaphase of cell divisions, the divided chromosomes move to the two poles, with the centromeres as heads and telomeres as tails. Such a polarized orientation of centromeres and telomeres is believed to be preserved in the interphase and is known as Rabl model. We analyzed the distributions of centromeres and telomeres in interphase nuclei from several plant species. Although Rabl polarity was observed in wheat, rye, barley and oats, non-Rabl patterns were discovered in sorghum, rice and maize. In the non-Rabl patterns, both centromeres and telomeres were dispersed throughout the interphase nucleus, except in the area occupied by the nucleolus. Both Rabl and non-Rabl distribution patterns of centromeres and telomeres were consistent in interphase nuclei derived from meristematic root tip cells, microspore mother cells and differentiated leaf cells. Our study demonstrated that there is a diversity of interphase chromatin organization and that the classical Rabl model is not universal in plant species.},
}
@article {pmid9882534,
year = {1999},
author = {},
title = {Volume 244, number 1 (1998), in article no. EX984185 "Telomere length regulation-A view from the individual chromosome perspective, " by predrag slijepcevic, pages 268-274.},
journal = {Experimental cell research},
volume = {246},
number = {1},
pages = {248},
pmid = {9882534},
issn = {1090-2422},
}
@article {pmid9880762,
year = {1998},
author = {Prescott, JD and DuBois, ML and Prescott, DM},
title = {Evolution of the scrambled germline gene encoding alpha-telomere binding protein in three hypotrichous ciliates.},
journal = {Chromosoma},
volume = {107},
number = {5},
pages = {293-303},
doi = {10.1007/s004120050311},
pmid = {9880762},
issn = {0009-5915},
support = {GM56161/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Conserved Sequence ; DNA Transposable Elements ; DNA-Binding Proteins/*genetics ; *Evolution, Molecular ; Germ Cells/physiology ; Hypotrichida/*genetics ; Molecular Sequence Data ; Nuclear Proteins/genetics ; Oxytricha/genetics ; *Repetitive Sequences, Nucleic Acid ; Sequence Homology, Amino Acid ; Sequence Homology, Nucleic Acid ; },
abstract = {The micronuclear genes encoding alpha-telomere-binding protein (alphaTP) in Oxytricha trifallax and Stylonychia mytilus contain multiple internal eliminated segments, or IESs, that divide the gene into multiple parts called macronuclear destined segments, or MDSs. The MDSs have become disordered, or scrambled, during evolution. The scrambled structures of the alphaTP genes in Oxytricha trifallax and S. mytilus have been compared with the previously published scrambled structure of the alphaTP gene in O. nova. The scrambled patterns of the alphaTP gene in the three species are similar but show significant differences. The micronuclear genes in O. nova and S. mytilus consist of 13 IESs and 14 MDSs, but the gene in O. trifallax is divided into three additional MDSs by the presence of three additional IESs, believed to have been inserted into the O. trifallax alphaTP gene after divergence of O. trifallax from the other two species. Corresponding IESs among the three species have shifted along the DNA during evolution, presumably by a mutational mechanism that changes the short repeat sequences that flank IESs. The IESs also have changed markedly in length by insertion and/or deletion of nucleotides. Comparison of the putative alphaTP amino acid sequences in the three species reveals three conserved and three nonconserved domains. The 5' nontranslated regions of the gene-sized molecules encoding alphaTP contain several conserved segments, and the 3' nontranscribed trailer contains one conserved segment.},
}
@article {pmid9878402,
year = {1999},
author = {Hud, NV and Schultze, P and Sklenár, V and Feigon, J},
title = {Binding sites and dynamics of ammonium ions in a telomere repeat DNA quadruplex.},
journal = {Journal of molecular biology},
volume = {285},
number = {1},
pages = {233-243},
doi = {10.1006/jmbi.1998.2327},
pmid = {9878402},
issn = {0022-2836},
support = {GM17652/GM/NIGMS NIH HHS/United States ; GM48123/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites ; Cations ; DNA/*metabolism ; Nuclear Magnetic Resonance, Biomolecular ; Protons ; Quaternary Ammonium Compounds/*metabolism ; *Telomere ; Water ; },
abstract = {Guanine quartets are readily formed by guanine nucleotides and guanine-rich oligonucleotides in the presence of certain monovalent and divalent cations. The quadruplexes composed of these quartets are of interest for their potential roles in vivo, their relatively frequent appearance in oligonucleotides derived from in vitro selection, and their inhibition of template directed RNA polymerization under proposed prebiotic conditions. The requirement of cation coordination for the stabilization of G quartets makes understanding cation-quadruplex interactions an essential step towards a complete understanding of G quadruplex formation. We have used 15NH4+ as a probe of cation coordination by the four G quartets of the DNA bimolecular quadruplex [d(G4T4G4)]2, formed from oligonucleotides with the repeat sequence found in Oxytricha nova telomeres. 1H and 15N heteronuclear NMR spectroscopy has allowed the direct localization of monovalent cation binding sites in the solution state and the analysis of cation movement between the binding sites. These experiments show that [d(G4T4G4)]2 coordinates three ammonium ions, one in each of two symmetry related sites and one on the axis of symmetry of the dimeric molecule. The NH4+ move along the central axis of the quadruplex between these sites and the solution, reminiscent of an ion channel. The residence time of the central ion is determined to be 250 ms. The 15NH4+ is shown to be a valuable probe of monovalent cation binding sites and dynamics.},
}
@article {pmid9875850,
year = {1998},
author = {Horvath, MP and Schweiker, VL and Bevilacqua, JM and Ruggles, JA and Schultz, SC},
title = {Crystal structure of the Oxytricha nova telomere end binding protein complexed with single strand DNA.},
journal = {Cell},
volume = {95},
number = {7},
pages = {963-974},
doi = {10.1016/s0092-8674(00)81720-1},
pmid = {9875850},
issn = {0092-8674},
support = {5 F32 GM17155-02/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Crystallization ; Crystallography, X-Ray ; DNA, Single-Stranded/*metabolism ; DNA-Binding Proteins/*chemistry/metabolism ; Hydrogen Bonding ; Models, Molecular ; Oxytricha/*chemistry ; Protein Binding ; Protein Conformation ; Protein Folding ; Protein Structure, Secondary ; Structure-Activity Relationship ; },
abstract = {Telomeres are specialized protein-DNA complexes that compose the ends of eukaryotic chromosomes. Telomeres protect chromosome termini from degradation and recombination and act together with telomerase to ensure complete genome replication. We have determined the crystal structure of the two-subunit Oxytricha nova telomere end binding protein (OnTEBP) complexed with single strand telomeric DNA at 2.8 A resolution. The structure reveals four oligonucleotide/oligosaccharide-binding folds, three of which form a deep cleft that binds the ssDNA, and a fourth that forms an unusual protein-protein interaction between the alpha and beta subunits. This structure provides a molecular description of how the two subunits of OnTEBP recognize and bind ssDNA to form a sequence-specific, telomeric nucleoprotein complex that caps the very 3' ends of chromosomes.},
}
@article {pmid9873226,
year = {1999},
author = {Feng, YR and Biggar, RJ and Gee, D and Norwood, D and Zeichner, SL and Dimitrov, DS},
title = {Long-term telomere dynamics: modest increase of cell turnover in HIV-infected individuals followed for up to 14 years.},
journal = {Pathobiology : journal of immunopathology, molecular and cellular biology},
volume = {67},
number = {1},
pages = {34-38},
doi = {10.1159/000028048},
pmid = {9873226},
issn = {1015-2008},
mesh = {Acquired Immunodeficiency Syndrome/*genetics/immunology/pathology ; Adult ; Blotting, Southern ; CD4-Positive T-Lymphocytes/immunology/*pathology ; CD8-Positive T-Lymphocytes/immunology/*pathology ; DNA/analysis ; Disease Progression ; Double-Blind Method ; Electrophoresis, Gel, Pulsed-Field ; Follow-Up Studies ; Humans ; Longitudinal Studies ; Lymphocyte Count ; *Minisatellite Repeats ; Telomere/*genetics ; Time Factors ; },
abstract = {To quantify the long-term dynamics of telomere lengths and the effect of HIV infection on lymphocyte turnover rates, we measured in a blinded study longitudinal samples from 6 individuals using a highly accurate method based on two-dimensional calibration of DNA sizes. For two uninfected controls followed 8 and 10 years the average telomeric terminal restriction fragment (TRF) shortening rate in peripheral blood mononuclear cells (PBMCs) was 50 and 60 bp/year, respectively, in agreement with previous measurements of cross-sectional samples. The TRF lengths of PBMCs from two slow progressors followed for 14 years declined by a rate of 120 +/-10 bp/year, i.e. 2-fold higher than the rate of TRF shortening for uninfected individuals. The rate of TRF shortening was higher in CD8 (140 +/-10 bp/year) than in CD4 (100 +/-10 bp/year) cells. The CD8 cell TRFs of the two fast progressors shortened faster (240 +/-10 bp/year) and the rate of CD4 cell TRF shortening in one of the fast progressors was 160 bp/year. These data suggest that HIV infection causes only a modest increase in the lymphocyte turnover which we speculate could be due to chronic activation of the immune system, and may not result in the exhaustion of its regenerative capacity and immunopathogenesis.},
}
@article {pmid9870099,
year = {1998},
author = {Kahn, E and Philippe, C and Frouin, F and Di Paola, R and Bernheim, A},
title = {Characterization of cosmids and telomeres in cytogenetic preparations by 3D confocal fluorescence.},
journal = {Analytical and quantitative cytology and histology},
volume = {20},
number = {6},
pages = {477-482},
pmid = {9870099},
mesh = {Cosmids/*ultrastructure ; Factor Analysis, Statistical ; Fluorescent Dyes ; Humans ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Interphase ; Male ; *Microscopy, Confocal ; Mitosis ; Telomere/*ultrastructure ; },
abstract = {OBJECTIVE: To analyze, with fluorescent probes, by three-dimensional (3D) emission patterns, fluorescence in situ hybridization (FISH) preparations (cosmids, telomeres) and to perform factor analysis of medical image sequences (FAMIS); to use FISH to track relevant DNA sequences in cell nuclei during interphase and in mitotic chromosomes; and to use cytogenetic techniques, resulting in flat preparations of whole cells that are assumed to preserve probe access to their targets.<br><br>STUDY DESIGN: The study design entailed labeling targets by probes (sequences labeled by fluorescein isothiocyanate) in nuclei and/or chromosomes stained by propidium iodide. Visualization of targets was improved when 3D sequences of images obtained on a single photomultiplier detector of the confocal microscope by z stepping were investigated by FAMIS.<br><br>RESULTS: Factors and factor images showed that targets could be detected and differentiated in focal planes inside nuclei or chromosomes.<br><br>CONCLUSION: It is possible to localize cosmids in cell nuclei at interphase and telomeres in mitotic chromosomes by means of 3D sequences of images.},
}
@article {pmid9867246,
year = {1998},
author = {Kontogeorgos, G and Kovacs, K},
title = {Telomeres and telomerase in endocrine pathology.},
journal = {Endocrine},
volume = {9},
number = {2},
pages = {133-138},
pmid = {9867246},
issn = {1355-008X},
mesh = {Animals ; Antineoplastic Agents ; Endocrine Gland Neoplasms/*enzymology/*ultrastructure ; Endocrine Glands/*enzymology/*ultrastructure ; Humans ; Telomerase/antagonists &amp; inhibitors/*metabolism ; *Telomere ; },
abstract = {Telomeres representing repetitive DNA sequences of chromosome ends are necessary for maintaining chromosomal integrity. The enzyme telomerase synthesizes de novo telomeric repeats and incorporates them onto the DNA 3'-ends of chromosomes. Stability of chromosome ends and activation of telomerase are elementary requirements for cell immortalization and tumor progression. The telomeric length and telomerase activity have been recently studied in several human neoplasms, including those of endocrine tissues. Assessment of telomerase activity may help to distinguish normal or hyperplastic from neoplastic tissues. Inhibition or inactivation of telomerase activity may provide novel strategies for cancer therapy.},
}
@article {pmid9864398,
year = {1999},
author = {Multani, AS and Li, C and Ozen, M and Imam, AS and Wallace, S and Pathak, S},
title = {Cell-killing by paclitaxel in a metastatic murine melanoma cell line is mediated by extensive telomere erosion with no decrease in telomerase activity.},
journal = {Oncology reports},
volume = {6},
number = {1},
pages = {39-44},
doi = {10.3892/or.6.1.39},
pmid = {9864398},
issn = {1021-335X},
support = {R29-CA74819/CA/NCI NIH HHS/United States ; RRO 499901/RR/NCRR NIH HHS/United States ; },
mesh = {Animals ; Antineoplastic Agents, Phytogenic/administration &amp; dosage/*pharmacology ; Apoptosis/drug effects ; Cell Nucleus/pathology ; Chromosomes/drug effects/ultrastructure ; Dose-Response Relationship, Drug ; Humans ; In Situ Hybridization, Fluorescence ; Interphase ; Melanoma, Experimental/enzymology/*pathology ; Mice ; Micronucleus Tests ; Neoplasm Metastasis ; Neoplasm Proteins/*analysis ; Paclitaxel/administration &amp; dosage/analogs &amp; derivatives/*pharmacology ; Polyploidy ; Telomerase/*analysis ; Telomere/*drug effects/ultrastructure ; Tumor Cells, Cultured/drug effects ; },
abstract = {The purpose of this study was to investigate and compare the effects of paclitaxel and its water-soluble conjugates (sodium-pentetic acid-paclitaxel; polyethylene glycol-paclitaxel, and poly[L-glutamic acid]-paclitaxel) on chromosome morphology and induction of apoptosis in a metastatic murine melanoma cell line (K1735 clone X-21). For this, murine melanoma cells were treated continuously for 72 h with three concentrations (1.2 microM, 2.4 microM, and 4.8 microM) of each of paclitaxel, and conjugates. Another set of cells were pulse-treated at 2.4 microM, 4.8 microM and 9.6 microM concentrations of each of these drugs for 4 h and the recovered cells were examined after 72 h. Control cultures received only the solvents (dimethyl sulfoxide or water). Our results showed a significant increase in the frequencies of telomeric associations, chromosome aberrations, polyploidization, distorted and disintegrated chromosome morphology, and reduced telomeric signal intensity by fluorescence in situ hybridization, in treated cultures as compared to the controls. However, we detected no change in telomerase activity. In addition, the majority of interphase nuclei in treated cells showed apoptotic bodies, with chromatin condensation. These in vitro results suggest that cell death induced by paclitaxel and its water-soluble conjugates is due to the loss of telomeric repeats, as shown by reduced signal flourescence and increased telomeric associations.},
}
@article {pmid9863059,
year = {1998},
author = {Norwood, D and Dimitrov, DS},
title = {Sensitive method for measuring telomere lengths by quantifying telomeric DNA content of whole cells.},
journal = {BioTechniques},
volume = {25},
number = {6},
pages = {1040-1045},
doi = {10.2144/98256cr02},
pmid = {9863059},
issn = {0736-6205},
mesh = {Animals ; Blotting, Southern/*methods/standards ; Cell Line, Transformed ; Centromere/genetics ; DNA, Neoplasm/chemistry/isolation &amp; purification ; Humans ; Macaca ; Molecular Weight ; Pan troglodytes ; Sensitivity and Specificity ; Telomere/*genetics ; },
abstract = {Recently, a new method for measuring telomere lengths based on telomere DNA content was developed. The method, which is based on the ratio of telomere to centromere DNA content (TC ratio), is highly sensitive, allowing the analysis of small quantities of DNA. However, the method required the isolation of DNA, which can be difficult or impossible for small numbers of cells. Here, we suggest an improvement of this method that can directly estimate telomere lengths from whole cells. We optimized the method for whole cells and purified DNA and found that accurate TC ratios can be obtained from as little as 9 ng of DNA or 800 whole cells. There was no statistically significant difference between the ratios obtained with purified DNA or with whole cells, indicating that the isolation of DNA is not necessary for small samples.},
}
@article {pmid9858579,
year = {1999},
author = {Moreau, S and Ferguson, JR and Symington, LS},
title = {The nuclease activity of Mre11 is required for meiosis but not for mating type switching, end joining, or telomere maintenance.},
journal = {Molecular and cellular biology},
volume = {19},
number = {1},
pages = {556-566},
pmid = {9858579},
issn = {0270-7306},
support = {R01 GM041784/GM/NIGMS NIH HHS/United States ; T32 CA009503/CA/NCI NIH HHS/United States ; 2 T32 CA09503/CA/NCI NIH HHS/United States ; GM41784/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Checkpoint Kinase 1 ; *DNA Repair ; *Endodeoxyribonucleases ; Endonucleases/genetics/*metabolism ; *Exodeoxyribonucleases ; Fungal Proteins/genetics/*metabolism ; Humans ; Meiosis ; Molecular Sequence Data ; Mutagenesis ; Protein Kinases/genetics ; Saccharomyces cerevisiae/*enzymology/genetics ; *Saccharomyces cerevisiae Proteins ; *Telomere ; },
abstract = {The Saccharomyces cerevisiae MRE11 gene is required for the repair of ionizing radiation-induced DNA damage and for the initiation of meiotic recombination. Sequence analysis has revealed homology between Mre11 and SbcD, the catalytic subunit of an Escherichia coli enzyme with endo- and exonuclease activity, SbcCD. In this study, the purified Mre11 protein was found to have single-stranded endonuclease activity. This activity was absent from mutant proteins containing single amino acid substitutions in either one of two sequence motifs that are shared by Mre11 and SbcD. Mutants with allele mre11-D56N or mre11-H125N were partially sensitive to ionizing radiation but lacked the other mitotic phenotypes of poor vegetative growth, hyperrecombination, defective nonhomologous end joining, and shortened telomeres that are characteristic of the mre11 null mutant. Diploids homozygous for the mre11-H125N mutation failed to sporulate and accumulated unresected double-strand breaks (DSB) during meiosis. We propose that in mitotic cells DSBs can be processed by other nucleases that are partially redundant with Mre11, but these activities are unable to process Spo11-bound DSBs in meiotic cells.},
}
@article {pmid9858529,
year = {1999},
author = {Ray, A and Runge, KW},
title = {The yeast telomere length counting machinery is sensitive to sequences at the telomere-nontelomere junction.},
journal = {Molecular and cellular biology},
volume = {19},
number = {1},
pages = {31-45},
pmid = {9858529},
issn = {0270-7306},
support = {R01 GM050752/GM/NIGMS NIH HHS/United States ; GM50752/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Binding Sites ; *Chromosomes, Fungal ; DNA, Fungal ; DNA-Binding Proteins/*metabolism ; Molecular Sequence Data ; Saccharomyces cerevisiae/*genetics/metabolism ; *Saccharomyces cerevisiae Proteins ; Shelterin Complex ; *Telomere ; *Telomere-Binding Proteins ; *Transcription Factors ; },
abstract = {Saccharomyces cerevisiae telomeres consist of a continuous 325 +/- 75-bp tract of the heterogeneous repeat TG1-3 which contains irregularly spaced, high-affinity sites for the protein Rap1p. Yeast cells monitor or count the number of telomeric Rap1p molecules in a negative feedback mechanism which modulates telomere length. To investigate the mechanism by which Rap1p molecules are counted, the continuous telomeric TG1-3 sequences were divided into internal TG1-3 sequences and a terminal tract separated by nontelomeric spacers of different lengths. While all of the internal sequences were counted as part of the terminal tract across a 38-bp spacer, a 138-bp disruption completely prevented the internal TG1-3 sequences from being considered part of the telomere and defined the terminal tract as a discrete entity separate from the subtelomeric sequences. We also used regularly spaced arrays of six Rap1p sites internal to the terminal TG1-3 repeats to show that each Rap1p molecule was counted as about 19 bp of TG1-3 in vivo and that cells could count Rap1p molecules with different spacings between tandem sites. As previous in vitro experiments had shown that telomeric Rap1p sites occur about once every 18 bp, all Rap1p molecules at the junction of telomeric and nontelomeric chromatin (the telomere-nontelomere junction) must participate in telomere length measurement. The conserved arrangement of these six Rap1p molecules at the telomere-nontelomere junction in independent transformants also caused the elongated TG1-3 tracts to be maintained at nearly identical lengths, showing that sequences at the telomere-nontelomere junction had an effect on length regulation. These results can be explained by a model in which telomeres beyond a threshold length form a folded structure that links the chromosome terminus to the telomere-nontelomere junction and prevents telomere elongation.},
}
@article {pmid9858205,
year = {1998},
author = {Wynn, RF and Cross, MA and Testa, NG},
title = {Telomeres and haemopoiesis.},
journal = {British journal of haematology},
volume = {103},
number = {3},
pages = {591-593},
doi = {10.1046/j.1365-2141.1998.01092.x},
pmid = {9858205},
issn = {0007-1048},
mesh = {Bone Marrow Transplantation ; Cellular Senescence ; Hematopoiesis/*physiology ; Humans ; Stem Cells/cytology ; Telomere/*physiology ; },
}
@article {pmid9857231,
year = {1998},
author = {Kiyozuka, Y and Asai, A and Senzaki, H and Uemura, Y and Nakashima, A and Morimoto, J and Matsuzawa, A and Tsubura, A},
title = {Telomere length, telomerase activity and telomerase RNA expression during mouse mammary tumor progression.},
journal = {International journal of molecular medicine},
volume = {2},
number = {4},
pages = {437-444},
doi = {10.3892/ijmm.2.4.437},
pmid = {9857231},
issn = {1107-3756},
mesh = {Animals ; Female ; Lung Neoplasms/secondary ; Mammary Glands, Animal/enzymology ; Mammary Neoplasms, Experimental/*enzymology/pathology/ultrastructure ; Mice ; Neoplasms, Hormone-Dependent/*enzymology/pathology/ultrastructure ; Pregnancy ; Pregnancy Complications, Neoplastic/enzymology/pathology ; RNA, Messenger/*biosynthesis ; Telomerase/biosynthesis/genetics/*metabolism ; Telomere/*ultrastructure ; },
abstract = {To investigate the roles of telomere length (mean length of the terminal restriction fragments; TRFs), telomerase activity (TA) and telomerase RNA (mTR) expression in relation to mouse mammary tumor progression, we examined a pregnancy-dependent mouse mammary tumor line (TPDMT-4) and its four autonomous sublines (T4-OI320: non-metastatic; and T4-OI165, -OI96, and -OI145: artificial metastatic) of DDD/1 mouse origin, and an autonomous growing mammary tumor (JYG-MC) showing spontaneous lung metastasis developed in BALB/c mice infected with a Chinese feral mice (Sub-Jyg)-derived mouse mammary tumor virus (JYG-MTV). Compared with normal (pregnant) mammary tissue, the TA was elevated in the TPDMT-4 tumor and in the non-metastatic subline tumor (T4-OI320) (x10 fold, respectively), and was further increased (x13-15 fold) in parallel with the acquisition of metastatic potential (T4-OI165, -OI96, and -OI145). The mTR level was upregulated (x2.7-2.8 fold) in all autonomous growing tumors compared to the normal counter-part, but not in TPDMT-4. The TRF was shorter in accord with tumor progression (normal mammary tissue, 48 kb; TPDMT-4, 45 kb; T4-OI320, 37 kb; T4-OI165, -OI96 and -OI145, mean 37.7 kb; and JYG-MC, 21 kb). These results suggest that the activation of TA occurs as an early event at the stage of hormone-dependent tumorigenesis, followed by the up-regulation of mTR expression in accordance with the acquisition of autonomous growth, and then further activation of TA occurs when the tumor acquires metastatic potential. The TRF shortening was in parallel with the tumor progression.},
}
@article {pmid9851779,
year = {1998},
author = {De Deken, X and Vilain, C and Van Sande, J and Dumont, JE and Miot, F},
title = {Decrease of telomere length in thyroid adenomas without telomerase activity.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {83},
number = {12},
pages = {4368-4372},
doi = {10.1210/jcem.83.12.5349},
pmid = {9851779},
issn = {0021-972X},
mesh = {Adenoma/*enzymology/*genetics/physiopathology ; Base Sequence/genetics ; Cell Line, Transformed ; Humans ; Polymerase Chain Reaction ; Telomerase/*metabolism ; Telomere/*genetics ; Thyroid Gland/enzymology/physiology ; Thyroid Neoplasms/*enzymology/*genetics/physiopathology ; Thyroid Nodule/enzymology ; },
abstract = {In somatic cells, telomeres shorten with population doubling, thus limiting their capacity to divide. Telomerase, which synthesizes telomeric repeats, can compensate for such shortening. Telomerase activity is known to be absent from most somatic differentiated cells but is present in germline cells, immortal cell lines, or a large majority of malignant tumors. Autonomous thyroid adenomas are benign tumors composed of highly differentiated cells characterized by TSH-independent function and growth. Telomere length and telomerase activity were measured in autonomous and hypofunctioning adenomas and their surrounding tissues. A significant decrease of 3.8+/-1.0 kilobases (kb) was observed in the length of the terminal restriction fragments (TRF) in 12 autonomous adenomas (8.6+/-1.1 kb), compared with the TRF length of their surrounding tissues (12.4+/-1.6 kb). The same kind of decrease, 3.5+/-1.2 kb, was also observed in 16 hypofunctioning adenomas (12.3+/-1.7 kb in surrounding tissue and 8.8+/-1.6 kb in the adenomas). No telomerase activity was detected either in the 12 autonomous adenomas studied or in most of the quiescent tissues (10 of 12). Most of the hypofunctioning adenomas tested (15 of 16) did not display telomerase activity. These results suggest that the cells have undergone a higher number of cell divisions in the adenomas than in the surrounding tissue. Moreover, there is a larger spread of the TRF length distribution in autonomous adenomas than in the collateral tissue. This could reflect the heterogeneity in proliferation status of the cells in the nodule, some of which have reached the end of their life span, whereas others are still proliferating (but with no malignant potential for the autonomous adenomas). In conclusion, benign adenomas exhibit a shorter and more variable telomere length than the normal collateral quiescent tissue, with no telomerase activity to compensate this loss in telomere length.},
}
@article {pmid9844626,
year = {1998},
author = {Fanti, L and Giovinazzo, G and Berloco, M and Pimpinelli, S},
title = {The heterochromatin protein 1 prevents telomere fusions in Drosophila.},
journal = {Molecular cell},
volume = {2},
number = {5},
pages = {527-538},
doi = {10.1016/s1097-2765(00)80152-5},
pmid = {9844626},
issn = {1097-2765},
mesh = {Anaphase ; Animals ; Cell Line ; Chromatin/genetics/metabolism ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/genetics/immunology/*metabolism ; Chromosome Aberrations/genetics ; Chromosome Deletion ; Drosophila melanogaster/cytology/embryology/*genetics/metabolism ; Euchromatin ; Gene Expression ; HSP70 Heat-Shock Proteins/genetics ; Heterochromatin/genetics/metabolism ; In Situ Hybridization, Fluorescence ; Insect Proteins/genetics/*metabolism ; Interphase ; Larva ; Male ; Meiosis ; Metaphase ; Mitosis ; Neurons ; Retroelements/genetics ; Spermatocytes ; Telomere/*genetics/metabolism ; },
abstract = {HP1 (Heterochromatin protein 1) is a conserved, non-histone chromosomal protein that is best known for its preferential binding to pericentric heterochromatin and its role in position effect variegation in Drosophila. Using immunolocalization, we show that HP1 is a constant feature of the telomeres of interphase polytene and mitotic chromosomes. This localization does not require the presence of telomeric retrotransposons, since HP1 is also detected at the ends of terminally deleted chromosomes that lack these elements. Importantly, larvae expressing reduced or mutant versions of HP1 exhibit aberrant chromosome associations and multiple telomeric fusions in neuroblast cells, imaginal disks, and male meiotic cells. Taken together, these results provide evidence that HP1 plays a functional role in mediating normal telomere behavior in Drosophila.},
}
@article {pmid9843956,
year = {1998},
author = {Counter, CM and Hahn, WC and Wei, W and Caddle, SD and Beijersbergen, RL and Lansdorp, PM and Sedivy, JM and Weinberg, RA},
title = {Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {95},
number = {25},
pages = {14723-14728},
pmid = {9843956},
issn = {0027-8424},
support = {CA 39826/CA/NCI NIH HHS/United States ; GM RO1-41690/GM/NIGMS NIH HHS/United States ; R01 AI029524/AI/NIAID NIH HHS/United States ; AI29524/AI/NIAID NIH HHS/United States ; R21 AI029524/AI/NIAID NIH HHS/United States ; },
mesh = {Cell Division ; Cell Transformation, Neoplastic/*genetics ; Cell Transformation, Viral/*genetics ; DNA-Binding Proteins ; Gene Expression Regulation ; Humans ; Proteins/*genetics ; *RNA ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {The immortalization of human cells is a critical step during tumorigenesis. In vitro, normal human somatic cells must overcome two proliferative blockades, senescence and crisis, to become immortal. Transformation with viral oncogenes extends the life span of human cells beyond senescence. Such transformed cells eventually succumb to crisis, a period of widespread cellular death that has been proposed to be the result of telomeric shortening. We now show that ectopic expression of the telomerase catalytic subunit (human telomerase reverse transcriptase or hTERT) and subsequent activation of telomerase can allow postsenescent cells to proliferate beyond crisis, the last known proliferative blockade to cellular immortality. Moreover, we demonstrate that alteration of the carboxyl terminus of human telomerase reverse transcriptase does not affect telomerase enzymatic activity but impedes the ability of this enzyme to maintain telomeres. Telomerase-positive cells expressing this mutant enzyme fail to undergo immortalization, further tightening the connection between telomere maintenance and immortalization.},
}
@article {pmid9832042,
year = {1998},
author = {Precht, KS and Lese, CM and Spiro, RP and Huttenlocher, PR and Johnston, KM and Baker, JC and Christian, SL and Kittikamron, K and Ledbetter, DH},
title = {Two 22q telomere deletions serendipitously detected by FISH.},
journal = {Journal of medical genetics},
volume = {35},
number = {11},
pages = {939-942},
pmid = {9832042},
issn = {0022-2593},
mesh = {Child, Preschool ; *Chromosome Deletion ; *Chromosomes, Human, Pair 22 ; Female ; Humans ; *In Situ Hybridization, Fluorescence ; Male ; Microsatellite Repeats ; Pedigree ; *Telomere ; },
abstract = {Cryptic telomere deletions have been proposed to be a significant cause of idiopathic mental retardation. We present two unrelated subjects, with normal G banding analysis, in whom 22q telomere deletions were serendipitously detected at two different institutions using fluorescence in situ hybridisation (FISH). Both probands presented with several of the previously described features associated with 22q deletions, including hypotonia, developmental delay, and absence of speech. Our two cases increase the total number of reported 22q telomere deletions to 19, the majority of which were identified by cytogenetic banding analysis. With the limited sensitivity of routine cytogenetic studies (approximately 2-5 Mb), these two new cases suggest that the actual prevalence of 22q telomere deletions may be higher than currently documented. Of additional interest is the phenotypic overlap with Angelman syndrome (AS) as it raises the possibility of a 22q deletion in patients in whom AS has been ruled out. The use of telomeric probes as diagnostic reagents would be useful in determining an accurate prevalence of chromosome 22q deletions and could result in a significantly higher detection rate of subtelomeric rearrangements.},
}
@article {pmid9822378,
year = {1998},
author = {Smith, S and Giriat, I and Schmitt, A and de Lange, T},
title = {Tankyrase, a poly(ADP-ribose) polymerase at human telomeres.},
journal = {Science (New York, N.Y.)},
volume = {282},
number = {5393},
pages = {1484-1487},
doi = {10.1126/science.282.5393.1484},
pmid = {9822378},
issn = {0036-8075},
support = {CA76027/CA/NCI NIH HHS/United States ; GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenosine Diphosphate Ribose/metabolism ; Amino Acid Sequence ; Animals ; Ankyrins/chemistry ; Benzamides/pharmacology ; Catalytic Domain ; DNA/metabolism ; DNA-Binding Proteins/analysis/*metabolism ; Enzyme Inhibitors/pharmacology ; Fluorescent Antibody Technique, Indirect ; Humans ; Molecular Sequence Data ; NAD/metabolism ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/*chemistry/genetics/*metabolism ; Protein Structure, Secondary ; Recombinant Proteins/chemistry/metabolism ; Repetitive Sequences, Amino Acid ; Sequence Alignment ; Sequence Homology, Amino Acid ; *Tankyrases ; Telomere/chemistry/*enzymology ; Telomeric Repeat Binding Protein 1 ; },
abstract = {Tankyrase, a protein with homology to ankyrins and to the catalytic domain of poly(adenosine diphosphate-ribose) polymerase (PARP), was identified and localized to human telomeres. Tankyrase binds to the telomeric protein TRF1 (telomeric repeat binding factor-1), a negative regulator of telomere length maintenance. Like ankyrins, tankyrase contains 24 ankyrin repeats in a domain responsible for its interaction with TRF1. Recombinant tankyrase was found to have PARP activity in vitro, with both TRF1 and tankyrase functioning as acceptors for adenosine diphosphate (ADP)-ribosylation. ADP-ribosylation of TRF1 diminished its ability to bind to telomeric DNA in vitro, suggesting that telomere function in human cells is regulated by poly(ADP-ribosyl)ation.},
}
@article {pmid9817198,
year = {1998},
author = {Weinberg, RA},
title = {Telomeres. Bumps on the road to immortality.},
journal = {Nature},
volume = {396},
number = {6706},
pages = {23-24},
doi = {10.1038/23825},
pmid = {9817198},
issn = {0028-0836},
mesh = {Cell Culture Techniques ; Cell Transformation, Neoplastic ; Cellular Senescence/*physiology ; Cyclin-Dependent Kinase Inhibitor p16/physiology ; DNA-Binding Proteins ; Epithelial Cells/physiology ; Humans ; Keratinocytes/physiology ; Oncogenes ; Proteins/physiology ; *RNA ; Retinoblastoma Protein/physiology ; Telomerase/physiology ; Telomere/*physiology ; },
}
@article {pmid9815582,
year = {1997},
author = {Engelhardt, M and Drullinsky, P and Guillem, J and Moore, MA},
title = {Telomerase and telomere length in the development and progression of premalignant lesions to colorectal cancer.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {3},
number = {11},
pages = {1931-1941},
pmid = {9815582},
issn = {1078-0432},
support = {U9 CA 67842-01/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/*analysis ; Colitis/enzymology/pathology ; Colon/enzymology/pathology ; Colonic Neoplasms/enzymology/*pathology ; Colonic Polyps/enzymology/*pathology ; Colorectal Neoplasms/enzymology/*pathology ; DNA Primers ; Disease Progression ; Female ; Humans ; Intestinal Mucosa/enzymology/pathology ; Male ; Middle Aged ; Neoplasm Staging ; Polymerase Chain Reaction ; Precancerous Conditions/enzymology/*pathology ; Rectal Neoplasms/enzymology/*pathology ; Telomerase/*metabolism ; Telomere/*pathology ; },
abstract = {Telomerase and telomere length are increasingly studied as prognostic markers in malignancy. Telomerase is also known to be expressed in certain nonmalignant cells, although generally at low levels. We investigated telomerase activity and telomere length in premalignant, malignant, inflammatory, and normal colon specimens to determine whether significant differences exist and whether telomerase may serve as a marker for early- or late-stage colorectal cancer. Telomerase activity was evaluated in 130 frozen specimens from human colon cancer (n = 50), adjacent normal colon tissue (n = 50), colon polyps (n = 20), and colitis (n = 10) using a modified telomeric repeat amplification protocol assay, and telomere length was assessed by terminal restriction fragment analysis. High to moderate levels of telomerase activity were detected in 90% of colorectal tumors. Weakly positive activity was detected in 10%. None of the normal tissues exhibited telomerase activity. In polyps and colitis, telomerase activity was found in 60% (12 of 20) and 40% (4 of 10), respectively. Telomerase activity in both nonmalignant lesions was 25- to 54-fold lower than that detected in colon cancer (P < 0.001). We found a positive correlation between tumor cell infiltration determined in cryostat sections and telomerase activity (r = 0.886; P > 0.0001). Late-stage tumors (Dukes C + D) demonstrated increased telomerase activity compared to early-stage tumors (Dukes A + B). Telomere restriction fragments in colon tumors had peak values of 4.8 +/- 1 kbp that were significantly and consistently shorter than those of the adjacent normal tissues (7.54 +/- 1.3 kbp), polyps (7.5 +/- 0.7 kbp), and colitis specimens (7.7 +/- 0.5kbp; P < 0.0001). Telomeres were 0.6 kbp longer in tumors with high telomerase activity and in late-stage cancers (Dukes C + D) compared to those in tumors with low telomerase activity and in early-stage cancers (Dukes A + B). Our data demonstrate that telomerase in colon cancer was commonly acquired, and activity was higher than that in polyps and colitis. However, weak telomerase activity was detected in premalignant and inflammatory lesions. Telomeres in colon cancer were considerably shorter, an indication of extensive cell proliferation and population divisions, whereas adjacent normal colon specimens, polyps, and colitis had comparable telomere lengths. Our results indicate that increased telomerase activity occurs in colon cancer cells that have undergone extensive telomere shortening relative to surrounding normal tissues and in which telomerase-induced stabilization of telomeres may be critical for the continued proliferation of the malignant clone. The link between telomerase activity and stage suggests that telomerase is up-regulated as a function of increased tumor cell invasion, tumor progression, and metastatic potential in colon cancer.},
}
@article {pmid9815573,
year = {1997},
author = {Engelhardt, M and Albanell, J and Drullinsky, P and Han, W and Guillem, J and Scher, HI and Reuter, V and Moore, MA},
title = {Relative contribution of normal and neoplastic cells determines telomerase activity and telomere length in primary cancers of the prostate, colon, and sarcoma.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {3},
number = {10},
pages = {1849-1857},
pmid = {9815573},
issn = {1078-0432},
support = {U9 CA 67842-01/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma/enzymology/genetics/*pathology ; Alkaline Phosphatase/analysis ; Biomarkers, Tumor/*analysis ; Cell Count ; Colonic Neoplasms/enzymology/genetics/pathology ; Colorectal Neoplasms/enzymology/genetics/*pathology ; Frozen Sections ; Humans ; Male ; Neoplasm Invasiveness ; Neoplasm Proteins/*analysis ; Neoplastic Stem Cells/*enzymology/ultrastructure ; Prognosis ; Prostatic Neoplasms/enzymology/genetics/*pathology ; Sarcoma/enzymology/genetics/*pathology ; Soft Tissue Neoplasms/enzymology/genetics/*pathology ; Telomerase/*analysis ; Telomere/*ultrastructure ; },
abstract = {Telomerase and telomere length are increasingly investigated as potential diagnostic and prognostic markers in human tumors. Among other factors, telomerase and telomere length may be influenced by the degree of tumor cell content in tumor specimens. We studied telomerase activity and telomere length with concomitant integration of histopathological data to determine whether both were influenced by the amount of tumor cells. We measured telomerase in 153 specimens: in 51 solid tumor blocks; in 51 cryostat sections; and in 51 adjacent normal tissues from patients with sarcoma (n = 10) and colorectal (n = 11) and prostate cancer (n = 30) using the sensitive and rapid detection telomeric repeat amplification protocol assay. Telomere length was determined by telomere restriction fragment Southern blot analysis. From cryostat sections, tumor cell infiltration was assessed. Telomerase activity was detected in all colorectal tumors and sarcomas, as expected. In primary prostate cancer, however, telomerase activity was less frequently observed (14 of 30, 47%). Moreover, a decreased intensity compared to colon cancer and sarcoma was evident (P < 0.001). The median tumor cell infiltration was significantly higher in sarcoma (65%) and colon (30%) compared to prostate cancer (5%; P < 0.001). There was a positive correlation between tumor cell infiltration and telomerase activity (r = 0.89; P < 0.001). Telomere restriction fragments in tumors were shorter compared to the normal tissues with peak differences in colon, sarcoma, and prostate of 1.8, 2.8, and 1 kilobase pairs, respectively (P < 0.002). Our data suggest the presence of a positive correlation between the degree of tumor cell content in human solid tumors and the level of telomerase activity detected. We demonstrated that the amount of tumor cells also affects telomere restriction fragment analysis. Therefore, with the predominance of normal cells in tumor specimens, telomerase activity measured may not reflect the malignant phenotype, and telomere loss may be underestimated. This phenomenon was most evident in prostate cancer. Our results will have implications for the future when telomerase activity and telomere lengths may be used for early screening, diagnosis, and prognosis determinations and when telomerase inhibitors are applied to clinical practice.},
}
@article {pmid9813551,
year = {1998},
author = {de Bono, DP},
title = {Olovnikov's clock: telomeres and vascular biology.},
journal = {Heart (British Cardiac Society)},
volume = {80},
number = {2},
pages = {110-111},
doi = {10.1136/hrt.80.2.110},
pmid = {9813551},
issn = {1355-6037},
mesh = {Aged ; Arteriosclerosis/genetics/*pathology ; Cell Death/genetics ; Cellular Senescence/genetics ; Endothelium, Vascular/*pathology ; Humans ; Muscle, Smooth, Vascular/*pathology ; Neoplasms/genetics/pathology ; Recurrence ; Telomerase/metabolism ; *Telomere ; },
}
@article {pmid9813109,
year = {1998},
author = {Hayashi, A and Ogawa, H and Kohno, K and Gasser, SM and Hiraoka, Y},
title = {Meiotic behaviours of chromosomes and microtubules in budding yeast: relocalization of centromeres and telomeres during meiotic prophase.},
journal = {Genes to cells : devoted to molecular &amp; cellular mechanisms},
volume = {3},
number = {9},
pages = {587-601},
doi = {10.1046/j.1365-2443.1998.00215.x},
pmid = {9813109},
issn = {1356-9597},
mesh = {Cell Nucleus/genetics ; Centromere/*genetics ; *Chromosomes, Fungal ; Green Fluorescent Proteins ; Luminescent Proteins/genetics/metabolism ; *Meiosis ; Microscopy, Fluorescence ; Nuclear Proteins/genetics/metabolism ; Nucleoplasmins ; Phosphoproteins/genetics/metabolism ; Prophase ; Recombinant Proteins/genetics/metabolism ; Saccharomyces cerevisiae/*genetics ; Telomere/*genetics ; },
abstract = {BACKGROUND: Meiosis is a process of universal importance in eukaryotic organisms, generating variation in the heritable haploid genome by recombination and re-assortment of chromosomes. The intranuclear movement of chromosomes is expected to achieve pairing and recombination of homologous chromosomes during meiosis. Meiosis in the budding yeast Saccharomyces cerevisiae has been extensively studied, both genetically and by molecular biology; here we report cytological observations of meiotic chromosomal events in this organism.<br><br>RESULTS: Using fluorescence microscopy, we have examined the behaviour of chromosomes and microtubules during meiosis in S. cerevisiae. We first observed the dynamic behaviour of nuclei in living cells using jellyfish green fluorescent protein (GFP) fused with nucleoplasmin, a Xenopus oocyte nuclear protein. The characterization of nuclear movement in living cells was extended by an analysis of chromosomes and microtubules in fixed specimens. In addition, the nuclear localization of centromeres and telomeres was determined by indirect immunofluorescence microscopy in synchronous populations of meiotic cells. While telomeres remain in clusters of 5-8 throughout meiosis, centromeres change their nuclear localization dramatically during the progression of meiosis: centromeres are first clustered at a single site near the spindle-pole body before the induction of meiosis, and become scattered during the meiotic prophase.<br><br>CONCLUSIONS: Our observations have demonstrated that nuclear and cytoskeletal reorganization take place with meiosis in S. cerevisiae. In particular, the distinct relocalization of centromeres during meiosis indicates a considerable movement of chromosomes within the meiotic prophase nucleus.},
}
@article {pmid9810000,
year = {1998},
author = {Bechter, OE and Eisterer, W and Pall, G and Hilbe, W and Kühr, T and Thaler, J},
title = {Telomere length and telomerase activity predict survival in patients with B cell chronic lymphocytic leukemia.},
journal = {Cancer research},
volume = {58},
number = {21},
pages = {4918-4922},
pmid = {9810000},
issn = {0008-5472},
mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/enzymology/*genetics/mortality ; Male ; Middle Aged ; Prognosis ; Survival Rate ; Telomerase/*metabolism ; *Telomere ; },
abstract = {The telomere-telomerase hypothesis states that the vast majority of human tumors have a prolonged replicative life span throughout expressing telomerase, which compensates the cell division-associated loss of telomere DNA. The use of telomere length and telomerase expression as new biological markers in cancer patients requires their correlation with disease prognosis. We, therefore, correlated the mean telomere length based on a telomere restriction fragment assay and the activity of telomerase measured with a telomeric repeat amplification protocol with clinical data and overall survival in 58 patients with B cell chronic lymphocytic leukemia (B-CLL). Telomere length showed a highly inverse correlation to telomerase activity. Patients with telomeres below 6.0 kb were associated with high telomerase activity, whereas patients with a telomere length >6.0 kb generally showed low enzyme activity (P <0.001). Patients in Binet A exhibited significantly longer telomeres and had less telomerase activity than did patients in Binet B or Binet C, where significantly shorter telomeres and higher telomerase activity were observed (P=0.031). Short telomere length and high telomerase activity were significantly associated with a shorter median survival (P=0.02 and P <0.001), and telomerase activity was the most significant prognostic factor for overall survival in B-CLL (P <0.001). Our data provide evidence that telomere length, as well telomerase activity, exerts a strong impact on the survival of B-CLL patients and that telomerase activity can be used as a new prognostic marker in this disease.},
}
@article {pmid9806803,
year = {1998},
author = {Barreau, C and Iskandar, M and Turcq, B and Javerzat, JP},
title = {Use of a linear plasmid containing telomeres as an efficient vector for direct cloning in the filamentous fungus Podospora anserina.},
journal = {Fungal genetics and biology : FG &amp; B},
volume = {25},
number = {1},
pages = {22-30},
doi = {10.1006/fgbi.1998.1064},
pmid = {9806803},
issn = {1087-1845},
mesh = {Ascomycota/*genetics/growth &amp; development ; Blotting, Southern ; *Cloning, Molecular ; Electrophoresis, Polyacrylamide Gel ; Genetic Vectors/genetics ; Humans ; Leucine/genetics ; Plasmids/*genetics ; Restriction Mapping ; Telomere/*genetics ; Transformation, Genetic ; },
abstract = {In Podospora anserina a linear plasmid with telomeric ends behaves as an artificial acentric minichromosome. Transformation is at least 100 times more efficient than with integrative vectors. Genomic DNA was inserted in this plasmid in vitro and the mixture used to transform a leu1-1 strain. Many fungal clones containing the leu1 gene as a genomic insert in the linear plasmid were identified. The leu1 gene was rescued as a circular plasmid in Escherichia coli demonstrating that a direct cloning procedure can be applied for the fungus P. anserina. The conservation of telomeric sequences among filamentous fungi suggests that a telomere-based linear plasmid could provide a general cloning vector for filamentous fungi.},
}
@article {pmid9799258,
year = {1998},
author = {Adames, KA and Gawne, J and Wicky, C and Müller, F and Rose, AM},
title = {Mapping a telomere using the translocation eT1(III;V) in Caenorhabditis elegans.},
journal = {Genetics},
volume = {150},
number = {3},
pages = {1059-1066},
pmid = {9799258},
issn = {0016-6731},
mesh = {Animals ; Caenorhabditis elegans/*genetics ; Chromosome Mapping ; Heterozygote ; Telomere/*genetics ; *Translocation, Genetic ; },
abstract = {In Caenorhabditis elegans, individuals heterozygous for a reciprocal translocation produce reduced numbers of viable progeny. The proposed explanation is that the segregational pattern generates aneuploid progeny. In this article, we have examined the genotype of arrested embryonic classes. Using appropriate primers in PCR amplifications, we identified one class of arrested embryo, which could be readily recognized by its distinctive spot phenotype. The corresponding aneuploid genotype was expected to be lacking the left portion of chromosome V, from the eT1 breakpoint to the left (unc-60) end. The phenotype of the homozygotes lacking this DNA was a stage 2 embryonic arrest with a dark spot coinciding with the location in wild-type embryos of birefringent gut granules. Unlike induced events, this deletion results from meiotic segregation patterns, eliminating complexity associated with unknown material that may have been added to the end of a broken chromosome. We have used the arrested embryos, lacking chromosome V left sequences, to map a telomere probe. Unique sequences adjacent to the telomeric repeats in the clone cTel3 were missing in the arrested spot embryo. The result was confirmed by examining aneuploid segregants from a second translocation, hT1(I;V). Thus, we concluded that the telomere represented by clone cTel3 maps to the left end of chromosome V. In this analysis, we have shown that reciprocal translocations can be used to generate segregational aneuploids. These aneuploids are deleted for terminal sequences at the noncrossover ends of the C. elegans autosomes.},
}
@article {pmid9799256,
year = {1998},
author = {Bosco, G and Haber, JE},
title = {Chromosome break-induced DNA replication leads to nonreciprocal translocations and telomere capture.},
journal = {Genetics},
volume = {150},
number = {3},
pages = {1037-1047},
pmid = {9799256},
issn = {0016-6731},
support = {GM20056/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes, Fungal/*genetics ; *DNA Replication ; DNA, Fungal/*genetics ; Gene Expression Regulation, Fungal ; Saccharomyces cerevisiae/*genetics ; Telomere ; *Translocation, Genetic ; },
abstract = {In yeast, broken chromosomes can be repaired by recombination, resulting in nonreciprocal translocations. In haploid cells suffering an HO endonuclease-induced, double-strand break (DSB), nearly 2% of the broken chromosome ends recombined with a sequence near the opposite chromosome end, which shares only 72 bp of homology with the cut sequence. This produced a repaired chromosome with the same 20-kb sequence at each end. Diploid strains were constructed in which the broken chromosome shared homology with the unbroken chromosome only on the centromere-proximal side of the DSB. More than half of these cells repaired the DSB by copying sequences distal to the break from the unbroken template chromosome. All these events were RAD52 dependent. Pedigree analysis established that DSBs occurring in G1 were repaired by a replicative mechanism, producing two identical daughter cells. We discuss the implications of these data in understanding telomerase-independent replication of telomeres, gene amplification, and the evolution of chromosomal ends.},
}
@article {pmid9787084,
year = {1998},
author = {Chambers, DM and Kipling, D and Abbott, CM},
title = {Isolation of a microsatellite that reveals paralogy between the subtelomeric regions of mouse chromosomes 17 and 19: further evidence for telomere-telomere exchange in the mouse.},
journal = {Genomics},
volume = {53},
number = {1},
pages = {113-114},
doi = {10.1006/geno.1998.5477},
pmid = {9787084},
issn = {0888-7543},
mesh = {Animals ; *Chromosome Mapping ; Chromosomes, Artificial, Yeast/genetics ; Cloning, Molecular ; Mice ; Microsatellite Repeats/*genetics ; Recombination, Genetic/genetics ; Telomere/*genetics ; },
}
@article {pmid9781837,
year = {1998},
author = {Nose, K and Ishino, K and Shibanuma, M},
title = {Increase in telomere sequence-binding activity in normal human fibroblasts in senescence or in cells treated with phorbol ester or N-methyl-N'-nitro-N-nitrosoguanidine.},
journal = {Biological &amp; pharmaceutical bulletin},
volume = {21},
number = {9},
pages = {911-913},
doi = {10.1248/bpb.21.911},
pmid = {9781837},
issn = {0918-6158},
mesh = {Carcinogens/*pharmacology ; Cells, Cultured ; Cellular Senescence/*drug effects/*physiology ; DNA/drug effects/metabolism ; DNA Damage ; DNA Repair ; Fibroblasts/cytology/*drug effects/*ultrastructure ; Humans ; Methylnitronitrosoguanidine/*pharmacology ; Nuclear Proteins/metabolism ; Telomere/*drug effects/*metabolism ; Tetradecanoylphorbol Acetate/*pharmacology ; },
abstract = {The telomere is a specialized chromatin structure composed of unique repetitive DNA sequences and specific nuclear proteins. Telomere sequence-binding activity was measured by a mobility shift assay using nuclear extract from normal human fibroblasts. The specific binding activity to the telomere sequence increased in cells that were in a senescence state compared to that in cells at early population doublings. Treatment of cells with tumor promoting phorbol ester TPA induced an increase in the telomere sequence binding activity of nuclear extract in young cells, but the increase was marginal in senescent cells. DNA-damaging N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) also increased the telomere sequence binding activity in young cells, but not in senescent cells. As a reference, we measured the binding activity to NFkB sequence. It was activated by TPA or okadaic acid, but was not affected by MNNG or in senescence. The increase in telomere sequence-binding activity seemed to depend on activation of tyrosine phosphorylation, since an inhibitor of Tyr-kinase abolished the increase in telomere-binding activity. The molecular weight of the major binding factor in the normal human fibroblasts was approximately 32 kDa which is different from that of the telomere-associated protein, TRF-1.},
}
@article {pmid9776685,
year = {1998},
author = {Shore, D},
title = {Telomeres--unsticky ends.},
journal = {Science (New York, N.Y.)},
volume = {281},
number = {5384},
pages = {1818-1819},
doi = {10.1126/science.281.5384.1818},
pmid = {9776685},
issn = {0036-8075},
mesh = {Animals ; *Antigens, Nuclear ; *DNA Helicases ; DNA Repair ; DNA-Binding Proteins/genetics/metabolism/*physiology ; Fungal Proteins/metabolism ; Gene Expression Regulation ; Ku Autoantigen ; Mutation ; Nuclear Proteins/genetics/metabolism/*physiology ; Recombination, Genetic ; Saccharomyces cerevisiae/metabolism ; *Saccharomyces cerevisiae Proteins ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Telomerase/metabolism ; Telomere/metabolism/*physiology/ultrastructure ; Telomeric Repeat Binding Protein 2 ; },
}
@article {pmid9772298,
year = {1998},
author = {Burger, AM and Fiebig, HH and Kuettel, MR and Lautenberger, JA and Kung, HF and Rhim, JS},
title = {Effect of oncogene expression on telomerase activation and telomere length in human endothelial, fibroblast and prostate epithelial cells.},
journal = {International journal of oncology},
volume = {13},
number = {5},
pages = {1043-1048},
doi = {10.3892/ijo.13.5.1043},
pmid = {9772298},
issn = {1019-6439},
mesh = {Antigens, Polyomavirus Transforming/physiology ; Cell Transformation, Neoplastic/*genetics ; Cell Transformation, Viral/*genetics ; Cells, Cultured ; Endothelium/enzymology ; Enzyme Activation ; Epithelial Cells/enzymology ; Fibroblasts/enzymology ; Gene Expression Regulation, Neoplastic ; Genes, Tumor Suppressor ; Humans ; Male ; Oncogene Proteins, Viral/genetics ; *Oncogenes ; Papillomaviridae/physiology ; Prostate/cytology/enzymology ; *Repressor Proteins ; Retinoblastoma Protein/metabolism ; Telomerase/*metabolism ; Telomere/*physiology ; Transfection ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Although strong evidence is mounting that telomerase reactivation and the thereof resulting stabilization of telomeres is a major mechanism for human cells to overcome replicative senescence, a causal relationship linking telomerase activation conclusively to tumorigenesis remains to be established. Thus, the possibility exists that telomerase activation is passively co-selected as tumors develop. To elucidate the function of telomerase during tumorigenesis, we followed telomerase reactivation during immortalization of human primary cell types with in vitro transforming agents and determined the tumorigenic potential of these cells at various stages of transformation. The effects of SV40, v-Ki-ras, HPV-18 and HPV-16 E6/E7 oncoproteins on telomerase expression was examined in primary and immortalized human prostate epithelial (HPE), human prostate fibroblast (HPF), and umbilical vein endothelial cells (HUVEC). All of five SV40-transformed HPE and HPF lines were telomerase positive and had shorter telomeres than primary cells. The two HPV-18 immortalized HPE cell lines also expressed telomerase activity. In contrast, E6 or E7 alone could not produce immortalized HUVEC and did not reactivate telomerase. Life-span, however, was extended. The E6/E7 immortalized HUVEC had telomerase activity and short but stable telomeres. HPE, HPF or HUVEC cells which had been transformed by one oncoprotein alone were not tumorigenic although they had overcome cellular senescence and re-activated telomerase. However, if these cells were transformed by a second agent, either infection with v-Ki-ras or X-ray treatment, they were able to form tumors in nude mice. This suggests that tumorigenesis is a multistep process and that telomerase activation alone is not sufficient for malignant transformation in human cells.},
}
@article {pmid9770512,
year = {1998},
author = {Krauskopf, A and Blackburn, EH},
title = {Rap1 protein regulates telomere turnover in yeast.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {95},
number = {21},
pages = {12486-12491},
pmid = {9770512},
issn = {0027-8424},
support = {R01 GM026259/GM/NIGMS NIH HHS/United States ; R37 GM026259/GM/NIGMS NIH HHS/United States ; DE11356/DE/NIDCR NIH HHS/United States ; GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA, Fungal ; DNA-Binding Proteins/*physiology ; Kluyveromyces/*genetics ; Phenotype ; *Saccharomyces cerevisiae Proteins ; Shelterin Complex ; *Telomere ; *Telomere-Binding Proteins ; *Transcription Factors ; },
abstract = {Telomere length is maintained through a dynamic balance between addition and loss of the terminal telomeric DNA. Normal telomere length regulation requires telomerase as well as a telomeric protein-DNA complex. Previous work has provided evidence that in the budding yeasts Kluyveromyces lactis and Saccharomyces cerevisiae, the telomeric double-stranded DNA binding protein Rap1p negatively regulates telomere length, in part by nucleating, by its C-terminal tail, a higher-order DNA binding protein complex that presumably limits access of telomerase to the chromosome end. Here we show that in K. lactis, truncating the Rap1p C-terminal tail (Rap1p-DeltaC mutant) accelerates telomeric repeat turnover in the distal region of the telomere. In addition, combining the rap1-DeltaC mutation with a telomerase template mutation (ter1-kpn), which directs the addition of mutated telomeric DNA repeats to telomeres, synergistically caused an immediate loss of telomere length regulation. Capping of the unregulated telomeres of these double mutants with functionally wild-type repeats restored telomere length control. We propose that the rate of terminal telomere turnover is controlled by Rap1p specifically through its interactions with the most distal telomeric repeats.},
}
@article {pmid9770369,
year = {1998},
author = {Slijepcevic, P},
title = {Telomere length regulation--a view from the individual chromosome perspective.},
journal = {Experimental cell research},
volume = {244},
number = {1},
pages = {268-274},
doi = {10.1006/excr.1998.4185},
pmid = {9770369},
issn = {0014-4827},
mesh = {Animals ; Chromosomes/enzymology/metabolism/*physiology ; Humans ; Saccharomyces cerevisiae ; Telomerase/genetics ; Telomere/enzymology/*genetics/metabolism ; },
abstract = {Telomeres are specialized structures at chromosome termini implicated in oncogenesis and cellular aging. Since both phenomena are related to variations in telomere length it is of interest to understand mechanisms responsible for telomere length regulation. Recent studies in mammalian cells indicate that specific chromosomes may have specific telomere lengths, suggesting the existence of chromosome-specific factors involved in telomere length regulation. Although these chromosome-specific factors are largely unknown at present, in the mouse evidence suggests a possible role of centromere position in telomere length regulation-telomeres closer to centromeres (i.e., p-arm telomeres) are significantly shorter than their counterparts more distant from centromeres (i.e., q-arm telomeres). The mouse may be a special case because its karyotype consists almost exclusively of acrocentric chromosomes in which p-arm telomeres and centromeres are located immediately adjacent to each other. However, a weak correlation between telomere length and centromere position is observed in the case of nonacrocentric human and Chinese hamster chromosomes, suggesting that the putative centromere position effect might be evolutionarily conserved. Alternatively, telomere length in individual nonacrocentric chromosomes may be affected by the sequence organization of subtelomeric chromosome regions or by some other, currently unknown, factors.},
}
@article {pmid9765206,
year = {1998},
author = {Stavenhagen, JB and Zakian, VA},
title = {Yeast telomeres exert a position effect on recombination between internal tracts of yeast telomeric DNA.},
journal = {Genes &amp; development},
volume = {12},
number = {19},
pages = {3044-3058},
pmid = {9765206},
issn = {0890-9369},
support = {GM43265/GM/NIGMS NIH HHS/United States ; R01 GM043265/GM/NIGMS NIH HHS/United States ; GM26938/GM/NIGMS NIH HHS/United States ; R37 GM026938/GM/NIGMS NIH HHS/United States ; R01 GM026938/GM/NIGMS NIH HHS/United States ; GM13307/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes, Fungal ; DNA Repair Enzymes ; DNA, Fungal/*genetics ; DNA-Binding Proteins/genetics/physiology ; Endonucleases/genetics/physiology ; Fungal Proteins/genetics/physiology ; Mutation ; Nuclear Proteins ; Rad52 DNA Repair and Recombination Protein ; *Recombination, Genetic ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; Shelterin Complex ; Telomere/*genetics ; *Telomere-Binding Proteins ; *Transcription Factors ; },
abstract = {In Saccharomyces cerevisiae, proximity to a telomere affects both transcription and replication of adjacent DNA. In this study, we show that telomeres also impose a position effect on mitotic recombination. The rate of recombination between directly repeated tracts of telomeric C1-3A/TG1-3 DNA was reduced severely by proximity to a telomere. In contrast, recombination of two control substrates was not affected by telomere proximity. Thus, unlike position effects on transcription or replication, inhibition of recombination was sequence specific. Moreover, the repression of recombination was not under the same control as transcriptional repression (telomere position effect; TPE), as mutations in genes essential for TPE did not alleviate telomeric repression of recombination. The reduction in recombination between C1-3A/TG1-3 tracts near the telomere was caused by an absence of Rad52p-dependent events as well as a reduction in Rad1p-dependent events. The sequence-specific repression of recombination near the telomere was eliminated in cells that overexpressed the telomere-binding protein Rap1p, a condition that also increased recombination between C1-3A/TG1-3 tracts at internal positions on the chromosome. We propose that the specific inhibition between C1-3A/TG1-3 tracts near the telomere occurs through the action of a telomere-specific end-binding protein that binds to the single-strand TG1-3 tail generated during the processing of recombination intermediates. The recombination inhibitor protein may also block recombination between endogenous telomeres.},
}
@article {pmid9761795,
year = {1998},
author = {Riha, K and Fajkus, J and Siroky, J and Vyskot, B},
title = {Developmental control of telomere lengths and telomerase activity in plants.},
journal = {The Plant cell},
volume = {10},
number = {10},
pages = {1691-1698},
pmid = {9761795},
issn = {1040-4651},
mesh = {Arabidopsis/genetics ; Base Sequence ; DNA, Plant/genetics ; In Situ Hybridization, Fluorescence ; Models, Genetic ; Plant Development ; Plants/*enzymology/*genetics ; Tandem Repeat Sequences ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {Telomere lengths and telomerase activity were studied during the development of a model dioecious plant, Melandrium album (syn Silene latifolia). Telomeric DNA consisted of Arabidopsis-type TTTAGGG tandem repeats. The terminal positions of these repeats were confirmed by both Bal31 exonuclease degradation and in situ hybridization. Analysis of terminal restriction fragments in different tissues and ontogenetic stages showed that telomere lengths are stabilized precisely and do not change during plant growth and development. Telomerase activity tested by using a semiquantitative telomerase repeat amplification protocol correlated with cell proliferation in the tissues analyzed. Highest activity was found in germinating seedlings and root tips, whereas we observed a 100-fold decrease in telomerase activity in leaves and no activity in quiescent seeds. Telomerase also was found in mature pollen grains. Telomerase activity in tissues containing dividing cells and telomere length stability during development suggest their precise control during plant ontogenesis; however, the telomere length regulation mechanism could be unbalanced during in vitro dedifferentiation.},
}
@article {pmid9757957,
year = {1998},
author = {Bonatz, G and Frahm, SO and Andreas, S and Heidorn, K and Jonat, W and Parwaresch, R},
title = {Telomere shortening in uterine leiomyomas.},
journal = {American journal of obstetrics and gynecology},
volume = {179},
number = {3 Pt 1},
pages = {591-596},
doi = {10.1016/s0002-9378(98)70050-x},
pmid = {9757957},
issn = {0002-9378},
mesh = {Adult ; Aged ; Aged, 80 and over ; Alleles ; Female ; Genetic Linkage ; Glycerol Kinase/genetics ; Humans ; Leiomyoma/genetics/*pathology ; Middle Aged ; Polymorphism, Genetic ; Telomere/*ultrastructure ; Uterine Neoplasms/genetics/*pathology ; X Chromosome/genetics ; },
abstract = {OBJECTIVE: To gain a better understanding of proliferation control mechanisms in a common benign tumor, we investigated the mean telomere length and the clonality of uterine leiomyomas.<br><br>STUDY DESIGN: Deoxyribonucleic acid from uterine leiomyomas and from the adjacent normal myometrium of 51 patients (total number of uterine leiomyomas 107; 28 patients with single leiomyoma, 23 patients with multiple leiomyomas ranging from 2 to 8 myoma nodules per case) was hybridized to a telomeric oligonucleotide probe by Southern blot and chemiluminescent detection. The mean telomere length was evaluated by densitometry. Clonality was assessed with use of the phosphoglycerokinase gene polymorphism.<br><br>RESULTS: The mean telomere length was significantly shorter in uterine leiomyomas (median 7950 bp, interquartile range 7261 to 8372 bp) than in normal myometrium (median 9688 bp, interquartile range 8528 to 10535 bp) (P < .001). There was no correlation between tumor size and telomere attrition. Multiple uterine leiomyomas were found to have an independent clonal origin.<br><br>CONCLUSIONS: Telomere attrition in uterine leiomyomas reflects enhanced proliferation activity in the course of tumor evolution. The basic telomere lengths differ in the myocytes from which the uterine leiomyomas originate, probably explaining the lack of correlation between telomere attrition and tumor size.},
}
@article {pmid9755196,
year = {1998},
author = {Ahmed, S and Sheng, H and Niu, L and Henderson, E},
title = {Tetrahymena mutants with short telomeres.},
journal = {Genetics},
volume = {150},
number = {2},
pages = {643-650},
pmid = {9755196},
issn = {0016-6731},
mesh = {Animals ; Base Sequence ; DNA Mutational Analysis ; Heteroduplex Analysis ; Heterozygote ; Molecular Sequence Data ; Mutation/*genetics ; RNA, Protozoan/genetics ; Telomerase/genetics ; Telomere/*genetics ; Temperature ; Tetrahymena thermophila/*genetics/growth &amp; development ; },
abstract = {Telomere length is dynamic in many organisms. Genetic screens that identify mutants with altered telomere lengths are essential if we are to understand how telomere length is regulated in vivo. In Tetrahymena thermophila, telomeres become long at 30 degrees, and growth rate slows. A slow-growing culture with long telomeres is often overgrown by a variant cell type with short telomeres and a rapid-doubling rate. Here we show that this variant cell type with short telomeres is in fact a mutant with a genetic defect in telomere length regulation. One of these telomere growth inhibited forever (tgi) mutants was heterozygous for a telomerase RNA mutation, and this mutant telomerase RNA caused telomere shortening when overexpressed in wild-type cells. Several other tgi mutants were also likely to be heterozygous at their mutant loci, since they reverted to wild type when selective pressure for short telomeres was removed. These results illustrate that telomere length can regulate growth rate in Tetrahymena and that this phenomenon can be exploited to identify genes involved in telomere length regulation.},
}
@article {pmid9753739,
year = {1998},
author = {Cai, L and Chen, L and Raghavan, S and Ratliff, R and Moyzis, R and Rich, A},
title = {Intercalated cytosine motif and novel adenine clusters in the crystal structure of the Tetrahymena telomere.},
journal = {Nucleic acids research},
volume = {26},
number = {20},
pages = {4696-4705},
doi = {10.1093/nar/26.20.4696},
pmid = {9753739},
issn = {0305-1048},
mesh = {Adenine/*chemistry ; Animals ; Base Pairing ; Crystallization ; Crystallography, X-Ray ; Cytosine/*chemistry ; DNA, Protozoan/*chemistry ; Electrons ; Models, Molecular ; *Nucleic Acid Conformation ; Telomere/*chemistry ; Tetrahymena/*chemistry/genetics ; },
abstract = {The cytosine-rich strand of the Tetrahymena telomere consists of multiple repeats of sequence d(AACCCC). We have solved the crystal structure of the crystalline repeat sequence at 2.5 A resolution. The adenines form two different and previously unknown clusters (A clusters) in orthogonal directions with their counterparts from other strands, each containing a total of eight adenines. The clusters appear to be stable aggregates held together by base stacking and three different base-pairing modes. Two different types of cytosine tetraplexes are found in the crystal. Each four-stranded complex is composed of two intercalated parallel-stranded duplexes pointing in opposite directions, with hemiprotonated cytosine-cytosine (C.C+) base pairs. The outermost C.C+base pairs are from the 5'-end of each strand in one cytosine tetraplex and from the 3'-end of each strand in the other. The A clusters and the cytosine tetraplexes form two alternating stacking patterns, creating continuous base stacking in two perpendicular directions along the x - and z -axes. The adenine clusters could be organizational motifs for macromolecular RNA.},
}
@article {pmid9753423,
year = {1998},
author = {Hiraoka, Y},
title = {Meiotic telomeres: a matchmaker for homologous chromosomes.},
journal = {Genes to cells : devoted to molecular &amp; cellular mechanisms},
volume = {3},
number = {7},
pages = {405-413},
doi = {10.1046/j.1365-2443.1998.00205.x},
pmid = {9753423},
issn = {1356-9597},
mesh = {Chromosomes, Fungal ; Meiosis/*genetics ; Schizosaccharomyces/*genetics ; Telomere/*genetics ; },
abstract = {Telomeres, with their special structures and special schemes of synthesis, are essential for protecting the ends of eukaryotic linear chromosomes during cell proliferation. In addition to this basic function, the meiosis-specific functions of telomeres have long been inferred from the cytological observations of characteristic chromosome configurations in meiotic prophase. Recent studies in the fission yeast Schizosaccharomyces pombe have provided deeper insights into the role of meiotic telomeres in the pairing of homologous chromosomes. Here I have summarized our current understanding of the meiotic behaviour of telomeres in S. pombe, and discuss the role of telomeres in meiosis.},
}
@article {pmid9752826,
year = {1998},
author = {Dorland, M and van Montfrans, JM and van Kooij, RJ and Lambalk, CB and te Velde, ER},
title = {Normal telomere lengths in young mothers of children with Down's syndrome.},
journal = {Lancet (London, England)},
volume = {352},
number = {9132},
pages = {961-962},
doi = {10.1016/s0140-6736(05)61516-4},
pmid = {9752826},
issn = {0140-6736},
mesh = {Aging/genetics ; Alzheimer Disease/genetics ; *Down Syndrome/genetics ; Female ; Humans ; *Maternal Age ; Pregnancy ; *Pregnancy Complications ; Risk Factors ; *Telomere ; },
}
@article {pmid9752321,
year = {1998},
author = {Jeanteur, P},
title = {[Telomeres, telomerase: the year 1998 has begun well].},
journal = {Bulletin du cancer},
volume = {85},
number = {2},
pages = {111-112},
pmid = {9752321},
issn = {0007-4551},
mesh = {Animals ; DNA Replication/*genetics ; Humans ; Neoplasms/*genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; Telomerase/*physiology ; Telomere/*genetics ; },
}
@article {pmid9751408,
year = {1998},
author = {Koeneman, KS and Pan, CX and Jin, JK and Pyle, JM and Flanigan, RC and Shankey, TV and Diaz, MO},
title = {Telomerase activity, telomere length, and DNA ploidy in prostatic intraepithelial neoplasia (PIN).},
journal = {The Journal of urology},
volume = {160},
number = {4},
pages = {1533-1539},
pmid = {9751408},
issn = {0022-5347},
mesh = {Adenocarcinoma/*enzymology/*genetics ; Aged ; Humans ; Male ; Middle Aged ; *Ploidies ; Prostatic Intraepithelial Neoplasia/*enzymology/*genetics ; Prostatic Neoplasms/*enzymology/*genetics ; Telomerase/*metabolism ; Telomere/*ultrastructure ; },
abstract = {PURPOSE: To investigate the relationship of telomerase activity, telomere length, and DNA ploidy in high grade prostatic intraepithelial neoplasia (PIN).<br><br>MATERIALS AND METHODS: Tissue samples were carefully microdissected to obtain adenocarcinoma or PIN-containing tissue free of cancer. Telomerase activity was measured using the PCR-based telomeric repeat amplification protocol (TRAP). Telomere length was estimated from Southern blots of telomere restriction fragments (TRFs). DNA ploidy of PIN and carcinoma was determined by image analysis of adjacent Feulgen stained tissue sections.<br><br>RESULTS: Telomerase activity was found in 4 of 25 samples (16%) of high grade PIN. All telomerase positive PIN foci had a diploid DNA content. Although 5 of 25 samples (25%) of high grade PIN foci analyzed were DNA aneuploid, none of these demonstrated telomerase activity. Telomerase positive foci of prostate carcinoma (69% of all cancer foci analyzed) displayed heterogeneity in TRF length, with a mean TRF length two kilobase pairs shorter than that of telomerase negative specimens.<br><br>CONCLUSIONS: Telomerase activity is present in a low percentage of high-grade PIN foci, which are diploid by DNA content measurements.},
}
@article {pmid9747894,
year = {1998},
author = {Furumoto, K and Inoue, E and Nagao, N and Hiyama, E and Miwa, N},
title = {Age-dependent telomere shortening is slowed down by enrichment of intracellular vitamin C via suppression of oxidative stress.},
journal = {Life sciences},
volume = {63},
number = {11},
pages = {935-948},
doi = {10.1016/s0024-3205(98)00351-8},
pmid = {9747894},
issn = {0024-3205},
mesh = {Ascorbic Acid/analogs &amp; derivatives/*pharmacology ; Cells, Cultured ; Cellular Senescence ; Endothelium, Vascular/cytology ; Humans ; Intracellular Fluid/chemistry ; Oxidative Stress/*drug effects ; Telomerase/metabolism/physiology ; Telomere/*physiology ; Umbilical Veins/cytology ; },
abstract = {Telomeres in eukaryotic somatic cells are destined to the age-dependent shortening, which has not been demonstrated to correlate to direct lesion of telomeric DNA by reactive oxygen intermediates (ROI); still less explicable is the inhibitory effect of ROI-scavenging on telomere shortening. Here, we succeeded in artificial slowdown of age-dependent telomere shortening to 52-62% of the untreated control, in human vascular endothelial cells, by addition of the oxidation-resistant type of ascorbic acid (Asc), Asc-2-O-phosphate (Asc2P), which concurrently achieved both extension of cellular life-span and prevention of cell size enlargement indicative of cellular senescence. The results are attributable to a 3.9-fold more marked enrichment of intracellular Asc (Asc(in)) by addition of Asc2P, subsequently dephosphorylated before or during transmembrane influx, than by addition of Asc itself, and also attributed to diminution of intracellular ROI to 53% of the control level by Asc2P; telomerase activity was at a trace level and underwent an age-dependent decline, which was significantly decelerated by Asc2P. Thus, age-dependent telomere-shortening can be decelerated by suppression of intracellular oxidative stress and/or by telomerase retention, both of which are achieved by enriched Asc(in) but not by extracellular Asc overwhelmingly more abundant than Asc(in).},
}
@article {pmid9747671,
year = {1998},
author = {Muniyappa, K and Kironmai, KM},
title = {Telomere structure, replication and length maintenance.},
journal = {Critical reviews in biochemistry and molecular biology},
volume = {33},
number = {4},
pages = {297-336},
doi = {10.1080/10409239891204242},
pmid = {9747671},
issn = {1040-9238},
mesh = {Animals ; Cellular Senescence ; DNA Replication ; DNA-Binding Proteins/chemistry ; Humans ; Protein Conformation ; *Telomerase/chemistry/genetics/metabolism ; },
abstract = {Telomeres are the termini of linear eukaryotic chromosomes consisting of tandem repeats of DNA and proteins that bind to these repeat sequences. Telomeres ensure the complete replication of chromosome ends, impart protection to ends from nucleolytic degradation, end-to-end fusion, and guide the localization of chromosomes within the nucleus. In addition, a combination of genetic, biochemical, and molecular biological approaches have implicated key roles for telomeres in diverse cellular processes such as regulation of gene expression, cell division, cell senescence, and cancer. This review focuses on recent advances in our understanding of the organization of telomeres, telomere replication, proteins that bind telomeric DNA, and the establishment of telomere length equilibrium.},
}
@article {pmid9742129,
year = {1998},
author = {Lew, JE and Enomoto, S and Berman, J},
title = {Telomere length regulation and telomeric chromatin require the nonsense-mediated mRNA decay pathway.},
journal = {Molecular and cellular biology},
volume = {18},
number = {10},
pages = {6121-6130},
pmid = {9742129},
issn = {0270-7306},
support = {GM38636/GM/NIGMS NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing ; *Chromatin ; Cloning, Molecular ; Cytoplasm ; DNA-Binding Proteins/*metabolism ; Exoribonucleases/metabolism ; Fungal Proteins/genetics/*metabolism ; Genes, Fungal ; Mutagenesis ; RNA, Fungal ; RNA, Messenger ; *Saccharomyces cerevisiae Proteins ; Shelterin Complex ; *Telomere ; *Telomere-Binding Proteins ; Trans-Activators/genetics/*metabolism ; *Transcription Factors ; },
abstract = {Rap1p localization factor 4 (RLF4) is a Saccharomyces cerevisiae gene that was identified in a screen for mutants that affect telomere function and alter the localization of the telomere binding protein Rap1p. In rlf4 mutants, telomeric silencing is reduced and telomere DNA tracts are shorter, indicating that RLF4 is required for both the establishment and/or maintenance of telomeric chromatin and for the control of telomere length. In this paper, we demonstrate that RLF4 is allelic to NMD2/UPF2, a gene required for the nonsense-mediated mRNA decay (NMD) pathway (Y. Cui, K. W. Hagan, S. Zhang, and S. W. Peltz, Mol. Cell. Biol. 9:423-436, 1995, and F. He and A. Jacobson, Genes Dev. 9:437-454, 1995). The NMD pathway, which requires Nmd2p/Rlf4p together with two other proteins, (Upf1p and Upf3p), targets nonsense messages for degradation in the cytoplasm by the exoribonuclease Xrn1p. Deletion of UPF1 and UPF3 caused telomere-associated defects like those caused by rlf4 mutations, implying that the NMD pathway, rather than an NMD-independent function of Nmd2p/Rlf4p, is required for telomere functions. In addition, telomere length regulation required Xrn1p but not Rat1p, a nuclear exoribonuclease with functional similarity to Xrn1p (A. W. Johnson, Mol. Cell. Biol. 17:6122-6130, 1997). In contrast, telomere-associated defects were not observed in pan2, pan3, or pan2 pan3 strains, which are defective in the intrinsic deadenylation-dependent decay of normal (as opposed to nonsense) mRNAs. Thus, loss of the NMD pathway specifically causes defects at telomeres, demonstrating a physiological requirement for the NMD pathway in normal cell functions. We propose a model in which the NMD pathway regulates the levels of specific mRNAs that are important for telomere functions.},
}
@article {pmid9737768,
year = {1998},
author = {Aviv, A and Aviv, H},
title = {Telomeres, hidden mosaicism, loss of heterozygosity, and complex genetic traits.},
journal = {Human genetics},
volume = {103},
number = {1},
pages = {2-4},
doi = {10.1007/s004390050774},
pmid = {9737768},
issn = {0340-6717},
mesh = {Aging/genetics ; Genetic Diseases, Inborn/*genetics ; Humans ; *Loss of Heterozygosity ; *Mosaicism ; Telomere/*genetics ; },
abstract = {Telomeres appear to function as an endogenous timing mechanism in human beings. Telomere attrition not only provides a satisfactory explanation for some aspects of aging, it might also resolve enigmatic features of complex genetic traits that are age-dependent. If, with the passage of time, telomere attrition in human beings leads to genomic instability and particularly the loss of chromosomes, then the age dependency of phenotypic expressions of complex genetic traits might result from the temporal loss of heterozygosity and the consequent expression of disease-causing genes. In this way, telomere attrition might play a role not only in aging, but also in the diverse expression of complex genetic traits, such as essential hypertension, non-insulin-dependent diabetes mellitus, atherosclerosis, and cancer.},
}
@article {pmid9729395,
year = {1998},
author = {Slijepcevic, P},
title = {Telomere length and telomere-centromere relationships?.},
journal = {Mutation research},
volume = {404},
number = {1-2},
pages = {215-220},
doi = {10.1016/s0027-5107(98)00116-x},
pmid = {9729395},
issn = {0027-5107},
mesh = {Animals ; CHO Cells ; Centromere/*physiology ; Chromosomes/chemistry ; Cricetinae ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Mice ; Telomere/*ultrastructure ; },
abstract = {The quantitative fluorescence in situ hybridization (Q-FISH) technique enables an accurate estimate of individual telomere lengths, a possibility beyond the resolution of conventional techniques. So far, Q-FISH has been used for the estimate of individual telomere lengths in human, mouse and Chinese hamster chromosomes. This analysis revealed large variations in the size of individual telomeres and a specific intra-chromosomal distribution of telomere lengths; telomeres closer to centromeres appear to be shorter than their counterparts more distant from centromeres. This observation suggests that individual telomere length may be affected by centromere position, a possibility consistent with the theory of chromosome field postulated more than 40 years ago by Lima-de-Faria. The link between the theory of chromosome field and the role of telomere-centromere relationships in the regulation of telomere length is discussed in this article.},
}
@article {pmid9729035,
year = {1998},
author = {Weng, NP and Hathcock, KS and Hodes, RJ},
title = {Regulation of telomere length and telomerase in T and B cells: a mechanism for maintaining replicative potential.},
journal = {Immunity},
volume = {9},
number = {2},
pages = {151-157},
doi = {10.1016/s1074-7613(00)80597-x},
pmid = {9729035},
issn = {1074-7613},
mesh = {Animals ; B-Lymphocytes/*enzymology/physiology ; DNA Replication/genetics ; Gene Expression Regulation ; Humans ; Mice ; T-Lymphocytes/*enzymology/physiology ; Telomerase/*genetics/physiology ; Telomere/pathology/*physiology ; },
}
@article {pmid9728393,
year = {1998},
author = {Bertuch, A and Lundblad, V},
title = {Telomeres and double-strand breaks: trying to make ends meet.},
journal = {Trends in cell biology},
volume = {8},
number = {9},
pages = {339-342},
doi = {10.1016/s0962-8924(98)01331-2},
pmid = {9728393},
issn = {0962-8924},
mesh = {*Antigens, Nuclear ; *DNA Helicases ; DNA Repair/*physiology ; DNA-Binding Proteins/physiology ; Eukaryotic Cells ; Ku Autoantigen ; Nuclear Proteins/physiology ; Telomere/*physiology ; },
abstract = {Eukaryotic cells encounter two types of DNA ends: telomeres, the natural ends of linear chromosomes, and double-strand breaks, resulting from DNA damage or normal chromosomal processes such as meiotic or V(D)J recombination. These two termini have long been seen as functionally distinct, based on whether they are resistant to fusion with other ends or instead are acted upon by the DNA-repair machinery. However, a series of recent papers has shown that members of a set of proteins that are crucial for the rejoining of DNA strand breaks are also required for normal telomere function, raising new questions about how these two types of termini maintain their functional distinction.},
}
@article {pmid9723031,
year = {1998},
author = {Butler, MG and Tilburt, J and DeVries, A and Muralidhar, B and Aue, G and Hedges, L and Atkinson, J and Schwartz, H},
title = {Comparison of chromosome telomere integrity in multiple tissues from subjects at different ages.},
journal = {Cancer genetics and cytogenetics},
volume = {105},
number = {2},
pages = {138-144},
pmid = {9723031},
issn = {0165-4608},
support = {P01 HD030329/HD/NICHD NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Blotting, Southern ; Child, Preschool ; Female ; *Genetic Variation ; Gestational Age ; Humans ; In Situ Hybridization ; Male ; Middle Aged ; Skin/ultrastructure ; Telomere/*genetics ; Tissue Distribution ; },
abstract = {Telomere DNA, at the ends of each chromosome, is conserved in nature and required for chromosome replication and stability. Reduction in telomere length has been observed in several malignancies as well as in leukocytes from healthy persons with advancing age. There is a paucity of data regarding telomere length and the effects of in vivo aging in different tissues. These data could be helpful in interpreting telomere length and understanding the role of telomere integrity and telomerase activity in malignant cells. We report telomeric DNA integrity studies of blood and skin collected from eight Caucasians of both sexes representing each decade of life from the fetus to 72 years of age without exposure to chemotherapy or radiation. In addition, telomeric data from 15 other tissues from the fetus and 8 other tissues from the 72-year-old male were examined. No significant differences were found in the shortest telomere size, the average telomere size, or telomere size variation between blood and skin from subjects at different ages. The average telomere size was 11.7 +/- 2.2 kb for blood and 12.8 +/- 3.7 for skin in all subjects studied. The shortest telomere length was 5.4 +/- 1.9 kb for blood and 4.3 +/- 0.9 kb for skin. Significant differences (P < 0.001) were found in the overall length of the DNA hybridization signal representing the shortest telomere size and the length of the DNA peak migration hybridization signal representing variation in telomere size between the 20-week fetus and the 72-year-old male. The 72-year-old male showed the shortest telomeres and the most variation (heterogeneity) in telomere size for all tissues studied, but the greatest differences were observed in blood compared with other tissues (e.g., average telomere length was 12.2 kb in the fetus and 7.2 kb in the 72-year-old male). The size of the telomere was negatively correlated with age for all tissues studied.},
}
@article {pmid9722644,
year = {1998},
author = {Klobutcher, LA and Gygax, SE and Podoloff, JD and Vermeesch, JR and Price, CM and Tebeau, CM and Jahn, CL},
title = {Conserved DNA sequences adjacent to chromosome fragmentation and telomere addition sites in Euplotes crassus.},
journal = {Nucleic acids research},
volume = {26},
number = {18},
pages = {4230-4240},
pmid = {9722644},
issn = {0305-1048},
support = {GM41803/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Conserved Sequence ; DNA Fragmentation ; DNA, Protozoan/*genetics ; Euplotes/*genetics ; Micronucleus, Germline/genetics ; Models, Genetic ; Molecular Sequence Data ; Polymerase Chain Reaction ; Restriction Mapping ; Telomere/*genetics ; },
abstract = {During the formation of a new macronucleus in the ciliate Euplotes crassus, micronuclear chromosomes are reproducibly broken at approximately 10 000 sites. This chromosome fragmentation process is tightly coupled with de novo telomere synthesis by the telomerase ribonucleoprotein complex, generating short linear macronuclear DNA molecules. In this study, the sequences of 58 macronuclear DNA termini and eight regions of the micronuclear genome containing chromosome fragmentation/telomere addition sites were determined. Through a statistically based analysis of these data, along with previously published sequences, we have defined a 10 bp conserved sequence element (E-Cbs, 5'-HATTGAAaHH-3', H = A, C or T) near chromosome fragmentation sites. The E-Cbs typically resides within the DNA destined to form a macronuclear DNA molecule, but can also reside within flanking micronuclear DNA that is eliminated during macronuclear development. The location of the E-Cbs in macronuclear-destined versus flanking micronuclear DNA leads us to propose a model of chromosome fragmentation that involves a 6 bp staggered cut in the chromosome. The identification of adjacent macronuclear-destined sequences that overlap by 6 bp provides support for the model. Finally, our data provide evidence that telomerase is able to differentiate between newly generated ends that contain partial telomeric repeats and those that do not in vivo.},
}
@article {pmid9716409,
year = {1998},
author = {Rockmill, B and Roeder, GS},
title = {Telomere-mediated chromosome pairing during meiosis in budding yeast.},
journal = {Genes &amp; development},
volume = {12},
number = {16},
pages = {2574-2586},
pmid = {9716409},
issn = {0890-9369},
mesh = {Chromosomes/*physiology ; Diploidy ; Fungal Proteins/genetics ; Haploidy ; Meiosis/genetics/*physiology ; Saccharomyces cerevisiae/*cytology/genetics ; Telomere/*physiology ; },
abstract = {Certain haploid strains of Saccharomyces cerevisiae can undergo meiosis, but meiotic prophase progression and subsequent nuclear division are delayed if these haploids carry an extra chromosome (i. e., are disomic). Observations indicate that interactions between homologous chromosomes cause a delay in meiotic prophase, perhaps to allow time for interhomolog interactions to be completed. Analysis of meiotic mutants demonstrates that the relevant aspect of homolog recognition is independent of meiotic recombination and synaptonemal complex formation. A disome in which the extra chromosome is circular sporulates without a delay, indicating that telomeres are important for homolog recognition. Consistent with this hypothesis, fluorescent in situ hybridization demonstrates that a circular chromosome has a reduced capacity to pair with its homolog, and a telomere-associated meiotic protein (Ndj1) is required to delay sporulation in disomes. A circular dimer containing two copies of the same chromosome delays meiosis to the same extent as two linear homologs, implying that physical proximity bypasses the requirement for telomeres in homolog pairing. Analysis of a disome carrying two linear permuted chromosomes suggests that even nonhomologous chromosome ends can promote homolog pairing to a limited extent. We speculate that telomere-mediated chromosome movement and/or telomere clustering promote homolog pairing.},
}
@article {pmid9712707,
year = {1998},
author = {Naasani, I and Seimiya, H and Tsuruo, T},
title = {Telomerase inhibition, telomere shortening, and senescence of cancer cells by tea catechins.},
journal = {Biochemical and biophysical research communications},
volume = {249},
number = {2},
pages = {391-396},
doi = {10.1006/bbrc.1998.9075},
pmid = {9712707},
issn = {0006-291X},
mesh = {Adenocarcinoma ; Antineoplastic Agents/pharmacology ; Catechin/*analogs &amp; derivatives/pharmacology ; Cell-Free System ; Cellular Senescence/*drug effects ; Colonic Neoplasms ; Enzyme Inhibitors/pharmacology ; Humans ; Kinetics ; Leukemia, Monocytic, Acute ; Neoplasms/*pathology ; Tea/*chemistry ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects/ultrastructure ; Tumor Cells, Cultured ; beta-Galactosidase/analysis ; },
abstract = {Animal in vivo studies and human epidemiological observations indicated potent anticancer effects for tea. Here we demonstrate that epigallocatechin gallate (EGCG), a major tea catechin, strongly and directly inhibits telomerase, an enzyme essential for unlocking the proliferative capacity of cancer cells by maintaining the tips of their chromosomes. Telomerase inhibition was elaborated in a cell-free system (cell extract) as well as in living cells. In addition, the continued growth of two representative human cancer cell lines, U937 monoblastoid leukemia cells and HT29 colon adenocarcinoma cells, in the presence of nontoxic concentrations of EGCG showed life span limitations accompanied with telomere shortening, chromosomal abnormalities, and expression of the senescence-associated beta-galactosidase. It is suggested that telomerase inhibition could be one of the major mechanisms underlying the anticancer effects of tea.},
}
@article {pmid9712323,
year = {1998},
author = {Kozik, A and Bradbury, EM and Zalensky, A},
title = {Increased telomere size in sperm cells of mammals with long terminal (TTAGGG)n arrays.},
journal = {Molecular reproduction and development},
volume = {51},
number = {1},
pages = {98-104},
doi = {10.1002/(SICI)1098-2795(199809)51:1&lt;98::AID-MRD12&gt;3.0.CO;2-Q},
pmid = {9712323},
issn = {1040-452X},
mesh = {Animals ; Cattle ; DNA ; Electrophoresis, Gel, Pulsed-Field ; Humans ; Kidney ; Male ; Mammals ; Nucleic Acid Hybridization ; *Spermatozoa ; Swine ; *Telomere ; *Terminal Repeat Sequences ; },
abstract = {An increase in the length of telomeres in human sperm compared to somatic cells has long been noted and considered within a popular hypothesis involving telomere shortening and cell aging. In the present study we determined telomere length in two species with long terminal TTAGGG arrays--bovine and porcine. Using several independent methods we demonstrate that the telomeres in the sperm of human, porcine and bovine are elongated by 69%, 24%, and 14%, respectively, in comparison with somatic tissues. Therefore, increased sperm telomere length is a feature preserved throughout mammalian evolution. The biological role of this phenomenon is discussed in the context of telomere functions in meiosis and fertilization.},
}
@article {pmid9710643,
year = {1998},
author = {Bourns, BD and Alexander, MK and Smith, AM and Zakian, VA},
title = {Sir proteins, Rif proteins, and Cdc13p bind Saccharomyces telomeres in vivo.},
journal = {Molecular and cellular biology},
volume = {18},
number = {9},
pages = {5600-5608},
pmid = {9710643},
issn = {0270-7306},
support = {T32 AG000057/AG/NIA NIH HHS/United States ; GM43255/GM/NIGMS NIH HHS/United States ; AG00057/AG/NIA NIH HHS/United States ; },
mesh = {Binding Sites ; Carrier Proteins/metabolism ; Cyclin B/*metabolism ; DNA-Binding Proteins/*metabolism ; Fungal Proteins/metabolism ; Genes, Fungal ; Genes, Reporter ; *Histone Deacetylases ; Models, Genetic ; Repressor Proteins/metabolism ; Saccharomyces cerevisiae/*genetics/*metabolism ; *Saccharomyces cerevisiae Proteins ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Sirtuin 2 ; Sirtuins ; Telomere/genetics/*metabolism ; *Telomere-Binding Proteins ; Trans-Activators/*metabolism ; Transcriptional Activation ; },
abstract = {Although a surprisingly large number of genes affect yeast telomeres, in most cases it is not known if their products act directly or indirectly. We describe a one-hybrid assay for telomere binding proteins and use it to establish that six proteins that affect telomere structure or function but which had not been shown previously to bind telomeres in vivo are indeed telomere binding proteins. A promoter-defective allele of HIS3 was placed adjacent to a chromosomal telomere. Candidate proteins fused to a transcriptional activation domain were tested for the ability to activate transcription of the telomere-linked HIS3 gene. Using this system, Rif1p, Rif2p, Sir2p, Sir3p, Sir4p, and Cdc13p were found to be in vivo telomere binding proteins. None of the proteins activated the same reporter gene when it was at an internal site on the chromosome. Moreover, Cdc13p did not activate the reporter gene when it was adjacent to an internal tract of telomeric sequence, indicating that Cdc13p binding was telomere limited in vivo. The amino-terminal 20% of Cdc13p was sufficient to target Cdc13p to a telomere, suggesting that its DNA binding domain was within this portion of the protein. Rap1p, Rif1p, Rif2p, Sir4p, and Cdc13p activated the telomeric reporter gene in a strain lacking Sir3p, which is essential for telomere position effect (TPE). Thus, the telomeric association of these proteins did not require any of the chromatin features necessary for TPE. The data support models in which the telomere acts as an initiation site for TPE by recruiting silencing proteins to the chromosome end.},
}
@article {pmid9703424,
year = {1998},
author = {Youngren, K and Jeanclos, E and Aviv, H and Kimura, M and Stock, J and Hanna, M and Skurnick, J and Bardeguez, A and Aviv, A},
title = {Synchrony in telomere length of the human fetus.},
journal = {Human genetics},
volume = {102},
number = {6},
pages = {640-643},
doi = {10.1007/s004390050755},
pmid = {9703424},
issn = {0340-6717},
mesh = {Body Weights and Measures ; Densitometry ; *Fetus ; Gestational Age ; Humans ; Reference Values ; *Telomere/ultrastructure ; },
abstract = {Telomere length, measured by terminal restriction fragments, was examined in tissues from human fetuses of gestational ages estimated as 15-19 weeks. The length of telomeres was similar in most fetal tissues. However, there were significant variations in telomere length among fetuses, with no apparent relationship between gestational age and telomere length. We conclude that synchrony in telomere length exists among tissues of the human fetus. This synchrony is apparently lost during extrauterine life.},
}
@article {pmid9702772,
year = {1998},
author = {Rufer, N and Dragowska, W and Thornbury, G and Roosnek, E and Lansdorp, PM},
title = {Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry.},
journal = {Nature biotechnology},
volume = {16},
number = {8},
pages = {743-747},
doi = {10.1038/nbt0898-743},
pmid = {9702772},
issn = {1087-0156},
support = {AI29524/AI/NIAID NIH HHS/United States ; GM56162/GM/NIGMS NIH HHS/United States ; },
mesh = {Adult ; Blotting, Southern ; CD4-Positive T-Lymphocytes/cytology/metabolism/ultrastructure ; CD8-Positive T-Lymphocytes/cytology/metabolism/ultrastructure ; Cell Death ; Cell Division ; Cell Separation/methods ; Cells, Cultured ; Fetal Blood ; Flow Cytometry/*methods ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Nucleic Acid Probes ; Repetitive Sequences, Nucleic Acid ; T-Lymphocyte Subsets/cytology/metabolism/*ultrastructure ; Telomere/*ultrastructure ; },
abstract = {To measure the average length of telomere repeats at chromosome ends in individual cells we developed a flow cytometry method using fluorescence in situ hybridization (flow FISH) with labeled peptide nucleic acid (PNA) probes. Results of flow FISH measurements correlated with results of conventional telomere length measurements by Southern blot analysis (R = 0.9). Consistent differences in telomere length in CD8+ T-cell subsets were identified. Naive and memory CD4+ T lymphocytes in normal adults differed by around 2.5 kb in telomere length, in agreement with known replicative shortening of telomeres in lymphocytes in vivo. T-cell clones grown in vitro showed stabilization of telomere length after an initial decline and rare clones capable of growing beyond 100 population doublings showed variable telomere length. These results show that flow FISH can be used to measure specific nucleotide repeat sequences in single cells and indicate that the very large replicative potential of lymphocytes is only indirectly related to telomere length.},
}
@article {pmid9689036,
year = {1998},
author = {Sedivy, JM},
title = {Can ends justify the means?: telomeres and the mechanisms of replicative senescence and immortalization in mammalian cells.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {95},
number = {16},
pages = {9078-9081},
pmid = {9689036},
issn = {0027-8424},
mesh = {Animals ; Cell Line, Transformed ; Cellular Senescence/*genetics ; Humans ; Mice ; Mice, Knockout ; Telomerase/genetics ; *Telomere ; },
abstract = {Finite replicative lifespan, or senescence, of mammalian cells in culture is a phenomenon that has generated much curiosity since its description. The obvious significance of senescence to organismal aging and the development of cancer has engendered a long-lasting and lively debate about its mechanisms. Recent discoveries concerning the phenotypes of telomerase knockout mice, the consequences of telomerase reexpression in somatic cells, and genes that regulate senescence have provided striking molecular insights but also have uncovered important new questions. The objective of this review is to reconcile old observations with new molecular details and to focus attention on the key remaining puzzles.},
}
@article {pmid9685479,
year = {1998},
author = {Hultdin, M and Grönlund, E and Norrback, K and Eriksson-Lindström, E and Just, T and Roos, G},
title = {Telomere analysis by fluorescence in situ hybridization and flow cytometry.},
journal = {Nucleic acids research},
volume = {26},
number = {16},
pages = {3651-3656},
pmid = {9685479},
issn = {0305-1048},
mesh = {Base Sequence ; Blotting, Southern ; Bone Marrow Cells/metabolism/ultrastructure ; Cell Cycle ; Cell Line ; DNA/biosynthesis/genetics ; DNA Replication ; DNA, Neoplasm/biosynthesis/genetics ; Flow Cytometry/*methods ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Neoplasms/genetics/metabolism/ultrastructure ; Oligonucleotide Probes/genetics ; Propidium ; S Phase ; Staining and Labeling ; Telomere/*genetics/metabolism ; Tumor Cells, Cultured ; },
abstract = {Determination of telomere length is traditionally performed by Southern blotting and densitometry, giving a mean telomere restriction fragment (TRF) value for the total cell population studied. Fluorescence in situ hybridization (FISH) of telomere repeats has been used to calculate telomere length, a method called quantitative (Q)-FISH. We here present a quantitative flow cytometric approach, Q-FISHFCM, for evaluation of telomere length distribution in individual cells based on in situ hybridization using a fluorescein-labeled peptide nucleic acid (PNA) (CCCTAA)3probe and DNA staining with propidium iodide. A simple and rapid protocol with results within 30 h was developed giving high reproducibility. One important feature of the protocol was the use of an internal cell line control, giving an automatic compensation for potential differences in the hybridization steps. This protocol was tested successfully on cell lines and clinical samples from bone marrow, blood, lymph nodes and tonsils. A significant correlation was found between Southern blotting and Q-FISHFCMtelomere length values (P = 0.002). The mean sub-telomeric DNA length of the tested cell lines and clinical samples was estimated to be 3.2 kbp. With the Q-FISHFCMmethod the fluorescence signal could be determined in different cell cycle phases, indicating that in human cells the vast majority of telomeric DNA is replicated early in S phase.},
}
@article {pmid9683806,
year = {1998},
author = {Engelhardt, M and Martens, UM},
title = {The implication of telomerase activity and telomere stability for replicative aging and cellular immortality (Review).},
journal = {Oncology reports},
volume = {5},
number = {5},
pages = {1043-1052},
doi = {10.3892/or.5.5.1043},
pmid = {9683806},
issn = {1021-335X},
mesh = {Base Sequence ; Cell Division ; Cell Survival/*physiology ; Cellular Senescence/*physiology ; *DNA Replication ; Humans ; Neoplasms/genetics/pathology/*physiopathology ; *Repetitive Sequences, Nucleic Acid ; Telomerase/*metabolism ; Telomere/*physiology ; Tumor Cells, Cultured ; },
abstract = {Telomerase and telomeres have been shown to be involved in the control of cell proliferation, the regulation of cell senescence and the unlimited proliferation capacity of malignant cells. Human telomeres are specialized chromosomal end structures composed of TTAGGG repeats. They function to protect chromosomes from degradation, fusion and recombination. Since the termini of linear molecules are replicated only in the 5'-3' direction by conventional DNA polymerases and require an RNA primer to initiate DNA synthesis, the removal of the RNA primer results in DNA loss with each cell division. To date, telomere shortening has been observed in most dividing somatic cells, eventually leading to cell senescence when critically short telomeres are reached. Telomerase has been identified as a ribonucleoprotein enzyme that can synthesize telomeric repeats onto chromosomes. Borderline telomerase activity has been detected in human primitive hematopoietic cells and in stimulated lymphocytes which increased with cytokine induced ex vivo expansion. However, in most other normal somatic cells, telomerase has not been detected, and consequently telomere shortening can be anticipated after a limited number of population doublings. In contrast, spontaneously immortalized tumor cell lines and the majority of malignant tumors demonstrate high telomerase activity, stable telomere length and unlimited proliferative potential. Mechanisms for telomerase and telomere length regulation are under extensive investigation. These have included the cloning of the RNA component and telomerase associated proteins, antisense experiments that have demonstrated progressive telomere length shortening in the absence of telomerase, and the identification of telomere binding proteins which may regulate telomerase by creating a negative feedback signal. This review aims to summarize important results in the rapidly moving field of telomeres and telomerase.},
}
@article {pmid9683783,
year = {1998},
author = {Park, KH and Rha, SY and Kim, CH and Kim, TS and Yoo, NC and Kim, JH and Roh, JK and Noh, SH and Min, JS and Lee, KS and Kim, BS and Chung, HC},
title = {Telomerase activity and telomere lengths in various cell lines: changes of telomerase activity can be another method for chemosensitivity evaluation.},
journal = {International journal of oncology},
volume = {13},
number = {3},
pages = {489-495},
doi = {10.3892/ijo.13.3.489},
pmid = {9683783},
issn = {1019-6439},
mesh = {Breast Diseases/*enzymology ; Breast Neoplasms/*drug therapy/*enzymology/ultrastructure ; Doxorubicin/pharmacology ; Drug Screening Assays, Antitumor ; Female ; Humans ; Stomach/*enzymology/ultrastructure ; Stomach Neoplasms/*drug therapy/*embryology/ultrastructure ; Telomerase/drug effects/*metabolism ; Telomere/drug effects/*metabolism/ultrastructure ; Tumor Cells, Cultured ; },
abstract = {For the cancer cells which have overcome the second mitotic clock (M2), activated telomerase is essential and used as another marker of immortality. Many trials had been initiated to target telomerase, which is known to be specific to tumors. To determine the best in vitro cell system for testing the efficacy of telomerase inhibitors, we evaluated the telomerase activity of various cancer cell lines and measured their telomere lengths. We also treated some cancer cell lines with adriamycin and measured the changes of telomerase activity. Telomerase activity was evaluated in various cell lines with the TRAP (telomeric repeat amplification protocol) assay. Telomerase activity was calculated and translated into arbitrary units by computer-assisted densitometry with the control of telomerase activity in the 293 control cell line. Also, terminal restriction fragment lengths were measured using Southern blotting. We also measured telomerase activity and telomere lengths in 11 benign breast tumor tissues and 19 paired stomach cancer and normal tissues. Cancer cell lines treated with adriamycin we evaluated for changes of telomerase activity and the cell proliferation by MTT assay and dye exclusion test. Telomerase activity of cell lines was 95.3 24.1 unit with a range of 27.6-129.6 unit, while the telomere lengths of those cell lines were variable from 5.0 to 10.4 kbp with a median of 6 kbp. In 11 cancer cell lines which were not yet firmly established, we could not detect any telomerase activity. Low telomerase activity was detected in only 2 benign tumor tissues of breast with a median telomere length of 8.8 (7-10.5) kbp. Among paired 19 gastric cancer and normal tissues, only 7 cancer tissues showed weak telomerase activity. After adriamycin treatment, telomerase activity in YCC-S-1, YCC-S-3, MCF-7 and MCF-7/ADR was decreased in accordance with the changes of the cell numbers. Telomerase is specific to cancer tissues and is expressed differently from organ to organ. Telomerase activity by TRAP assay could be used as a chemosensitivity assay.},
}
@article {pmid9680996,
year = {1998},
author = {Zhong, XB and Fransz, PF and Wennekes-Eden, J and Ramanna, MS and van Kammen, A and Zabel, P and Hans de Jong, J},
title = {FISH studies reveal the molecular and chromosomal organization of individual telomere domains in tomato.},
journal = {The Plant journal : for cell and molecular biology},
volume = {13},
number = {4},
pages = {507-517},
doi = {10.1046/j.1365-313x.1998.00055.x},
pmid = {9680996},
issn = {0960-7412},
mesh = {Base Sequence ; Chromosome Mapping ; Chromosomes/genetics/ultrastructure ; DNA, Plant/genetics ; Electrophoresis, Gel, Pulsed-Field ; In Situ Hybridization, Fluorescence ; Solanum lycopersicum/*genetics/ultrastructure ; Repetitive Sequences, Nucleic Acid ; Telomere/*genetics ; },
abstract = {The molecular and cytological organization of the telomeric repeat (TR) and the subtelomeric repeat (TGR1) of tomato were investigated by fluorescence in situ hybridization (FISH) techniques. Hybridization signals on extended DNA fibres, visualized as linear fluorescent arrays representing individual telomeres, unequivocally demonstrated the molecular co-linear arrangement of both repeats. The majority of the telomeres consisted of a TR and a TGR1 region separated by a spacer. Microscopic measurements of the TR and TGR1 signals revealed high variation in length of both repeats, with maximum sizes of 223 and 1330 kb, respectively. A total of 27 different combinations of TR and TGR1 was detected, suggesting that all chromosome ends have their own unique telomere organization. The fluorescent tracks on the extended DNA fibres were subdivided into four classes: (i) TR-spacer-TGR1; (ii) TR-TGR1; (iii) only TR; (iv) only TGR1. FISH to pachytene chromosomes enabled some of the TR/TGR1 groups to be assigned to specific chromosome ends and to interstitial regions. These signals also provided evidence for a reversed order of the TR and TGR1 sites at the native chromosome ends, suggesting a backfolding telomere structure with the TGR1 repeats occupying the most terminal position of the chromosomes. The FISH signals on diakinesis chromosomes revealed that distal euchromatin areas and flanking telomeric heterochromatin remained highly decondensed around the chiasmata in the euchromatic chromosome areas. The rationale for the occurrence and distribution of the TR and TGR1 repeats on the tomato chromosomes are discussed.},
}
@article {pmid9673357,
year = {1998},
author = {Asai, A and Kiyozuka, Y and Yoshida, R and Fujii, T and Hioki, K and Tsubura, A},
title = {Telomere length, telomerase activity and telomerase RNA expression in human esophageal cancer cells: correlation with cell proliferation, differentiation and chemosensitivity to anticancer drugs.},
journal = {Anticancer research},
volume = {18},
number = {3A},
pages = {1465-1472},
pmid = {9673357},
issn = {0250-7005},
mesh = {Antineoplastic Agents/*toxicity ; Carcinoma, Squamous Cell/drug therapy/enzymology/*genetics/pathology ; Cell Differentiation/drug effects ; Cell Division/drug effects ; Cisplatin/toxicity ; Esophageal Neoplasms/drug therapy/*enzymology/*genetics/pathology ; Fluorouracil/toxicity ; Humans ; Keratins/analysis ; Kinetics ; Regression Analysis ; Telomerase/biosynthesis/*metabolism ; Telomere/chemistry/*metabolism/*ultrastructure ; *Transcription, Genetic ; Tumor Cells, Cultured ; },
abstract = {The telomere and the enzyme telomerase in esophageal cancer have been poorly investigated. We present here aspects of the telomere and telomerase in esophageal cancer in relation to cell proliferation, differentiation and chemosensitivity to anticancer drugs. The telomere length (mean length of telomere restriction fragments; TRF), telomerase activity (TA), and human telomerase RNA (hTR) expression in a panel of 13 human esophageal cancer cell lines, squamous in origin, was examined by Southern blotting, the telomeric repeat amplification protocol (TRAP), and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. Cell proliferation expressed by the doubling time, cell differentiation determined by the keratin 13 and/or 14 expression, and chemosensitivity to cisplatin (CDDP) and 5-fluorouracil (5-FU) were compared with telomere-related factors. TRF shortening, the up-regulation of TA, and hTR expression was seen in all 13 cell lines. The TA correlated positively with the telomere length and negatively with the hTR expression. The doubling times of the cell lines and the telomere-related factors did not show any significant relation. The TA in the keratin 13/14-negative cell lines was significantly higher than that of the keratin 13-positive cell lines. The cells with short telomere tended to be resistant to CDDP whereas the cells with higher TA tended to be more sensitive to CDDP; 5-FU showed no relation to any telomere-related factors. Therefore, the activation of TA in esophageal squamous cell carcinoma is regulated by cell differentiation but not by cell proliferation, cells with high TA are more sensitive to CDDP, and cells with short telomere require a CDDP dose escalation.},
}
@article {pmid9673338,
year = {1998},
author = {Levy, T and Agoulnik, I and Atkinson, EN and Tong, XW and Gause, HM and Hasenburg, A and Runnebaum, IB and Stickeler, E and Möbus, VJ and Kaplan, AL and Kieback, DG},
title = {Telomere length in human white blood cells remains constant with age and is shorter in breast cancer patients.},
journal = {Anticancer research},
volume = {18},
number = {3A},
pages = {1345-1349},
pmid = {9673338},
issn = {0250-7005},
mesh = {Adult ; Age Factors ; Aged ; Breast Neoplasms/blood/*genetics ; DNA/blood/chemistry ; Female ; Humans ; Leukocytes/*chemistry ; Middle Aged ; Ovarian Neoplasms/blood/genetics ; Reference Values ; *Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; },
abstract = {BACKGROUND: Telomeres, which are TTAGGG repeats at the end of the eukaryotic chromosome, are essential for complete DNA replication. Telomere length has been reported to decrease in peripheral WBC, unlike the telomerase activity found in these cells. The purpose of this study was to investigate whether telomere length in WBC is indeed age dependent and could serve as a genetic marker in breast or ovarian cancer.<br><br>METHODS: Five age groups: 20-29; 30-39; 4049; 50-59 and > or = 60 years were examined. The cancer patients were 18 women with ovarian cancer and 18 women with breast cancer. Southern blot analysis of the DNA from peripheral white blood cells (WBC) was performed using 32P-labeled (TTAGGG)3 probe. Blots were scanned in a phosphoimager and analyzed by computer-assisted image analysis.<br><br>RESULTS: No statistically significant correlation was observed between telomere length and age in either healthy females or cancer patients. However, significantly shorter median telomere length was found in WBC obtained from breast cancer patients as compared to healthy individuals and ovarian cancer patients.<br><br>CONCLUSIONS: It is concluded that telomere length in WBC is not age dependent, but is significantly shorter in breast cancer patients.},
}
@article {pmid9671732,
year = {1998},
author = {Zhu, L and Hathcock, KS and Hande, P and Lansdorp, PM and Seldin, MF and Hodes, RJ},
title = {Telomere length regulation in mice is linked to a novel chromosome locus.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {95},
number = {15},
pages = {8648-8653},
pmid = {9671732},
issn = {0027-8424},
mesh = {Animals ; Chi-Square Distribution ; *Chromosome Mapping ; Crosses, Genetic ; *Genetic Linkage ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C3H ; Polymorphism, Genetic ; Polymorphism, Restriction Fragment Length ; *Telomere ; },
abstract = {Little is known about the mechanisms that regulate species-specific telomere length, particularly in mammalian species. The genetic regulation of telomere length was therefore investigated by using two inter-fertile species of mice, which differ in their telomere length. Mus musculus (telomere length >25 kb) and Mus spretus (telomere length 5-15 kb) were used to generate F1 crosses and reciprocal backcrosses, which were then analyzed for regulation of telomere length. This analysis indicated that a dominant and trans-acting mechanism exists capable of extensive elongation of telomeres in somatic cells after fusion of parental germline cells with discrepant telomere lengths. A genome wide screen of interspecific crosses, using M. spretus as the recurrent parent, identified a 5-centimorgan region on distal chromosome 2 that predominantly controls the observed species-specific telomere length regulation. This locus is distinct from candidate genes encoding known telomere-binding proteins or telomerase components. These results demonstrate that an unidentified gene(s) mapped to distal chromosome 2 regulates telomere length in the mouse.},
}
@article {pmid9667504,
year = {1998},
author = {de Pauw, ES and Verwoerd, NP and Duinkerken, N and Willemze, R and Raap, AK and Fibbe, WE and Tanke, HJ},
title = {Assessment of telomere length in hematopoietic interphase cells using in situ hybridization and digital fluorescence microscopy.},
journal = {Cytometry},
volume = {32},
number = {3},
pages = {163-169},
doi = {10.1002/(sici)1097-0320(19980701)32:3&lt;163::aid-cyto1&gt;3.3.co;2-v},
pmid = {9667504},
issn = {0196-4763},
mesh = {Adult ; Cell Nucleus/genetics ; Cells, Cultured ; Chromosomes, Human/genetics ; Fetus ; Hematopoietic Stem Cells/*chemistry ; Humans ; *In Situ Hybridization, Fluorescence ; Interphase/*genetics ; Metaphase/genetics ; Microscopy, Fluorescence ; Telomere/*genetics ; },
abstract = {Telomeres are G/C-rich repetitive DNA sequences at the end of all eukaryotic chromosomes. The loss of telomeric repeat sequences during cell divisions has been proposed as a possible mechanism for cell senescence. The standard procedure for measurement of telomere length is Southern blot (SB) hybridization with a telomere-specific probe. However, in using this technique no information can be obtained on variation in telomeric fragments due to interchromosomal, intrachromosomal, and intercellular differences. Lansdorp et al. (Hum Mol Genet 5:685-691, 1996) developed a method to measure individual telomeres, using in situ hybridization on metaphase chromosomes, employing peptide nucleic acid (PNA) probes and digital fluorescence microscopy. In this paper we describe a method that can be used to assess telomeric length in interphase cells. An algorithm was developed to measure the total intranuclear fluorescence in situ hybridization (FISH) signal, which features accurate correction for the local autofluorescence. Application of this methodology to samples of fetal liver, umbilical cord blood, and adult bone marrow cells showed a gradual decrease of average telomeric length. Southern blot analysis and PNA FISH measurements on chromosomes in the same samples showed similar results. Advantages of interphase measurements include the possibility of studying nonproliferating cells, thus avoiding selection and cell culturing.},
}
@article {pmid9663678,
year = {1998},
author = {Huang, CH and Lin, YS and Yang, YL and Huang, SW and Chen, CW},
title = {The telomeres of Streptomyces chromosomes contain conserved palindromic sequences with potential to form complex secondary structures.},
journal = {Molecular microbiology},
volume = {28},
number = {5},
pages = {905-916},
doi = {10.1046/j.1365-2958.1998.00856.x},
pmid = {9663678},
issn = {0950-382X},
mesh = {Base Sequence ; *Chromosomes, Bacterial ; Cloning, Molecular ; *Conserved Sequence ; *DNA, Bacterial ; Molecular Sequence Data ; *Nucleic Acid Conformation ; Plasmids ; Sequence Homology, Nucleic Acid ; Streptomyces/*genetics ; *Telomere ; },
abstract = {The chromosomes of the gram-positive soil bacteria Streptomyces are linear DNA molecules, usually of about 8Mb, containing a centrally located origin of replication and covalently bound terminal proteins (which are presumably involved in the completion of replication of the telomeres). The ends of the chromosomes contain inverted repeats of variable lengths. The terminal segments of five Streptomyces chromosomes and plasmids were cloned and sequenced. The sequences showed a high degree of conservation in the first 166-168bp. Beyond the terminal homology, the sequences diverged and did not generally cross-hybridize. The homologous regions contained seven palindromes with a few nucleotide differences. Many of these differences occur in complementary pairs, such that the palindromicity is preserved. Energy-optimized modelling predicted that the 3' strand of the terminal palindromes can form extensive hairpin structures that are similar to the 3' ends of autonomous parvovirus genomes. Most of the putative hairpins have a GCGCAGC sequence at the loop, with the potential to form a stable single C-residue loop closed by a sheared G:A pairing. The similarity between the terminal structures of the Streptomyces replicons and the autonomous parvoviral genomes suggests that they may share some structural and/or replication features.},
}
@article {pmid9663677,
year = {1998},
author = {Qin, Z and Cohen, SN},
title = {Replication at the telomeres of the Streptomyces linear plasmid pSLA2.},
journal = {Molecular microbiology},
volume = {28},
number = {5},
pages = {893-903},
doi = {10.1046/j.1365-2958.1998.00838.x},
pmid = {9663677},
issn = {0950-382X},
support = {AI08619/AI/NIAID NIH HHS/United States ; },
mesh = {Base Sequence ; Cloning, Molecular ; *DNA Replication ; *DNA, Bacterial ; Escherichia coli ; Molecular Sequence Data ; *Plasmids ; Streptomyces/*genetics ; *Telomere ; },
abstract = {The Streptomyces linear plasmid pSLA2 initiates DNA replication bidirectionally towards its telomeres from a site located near the centre of the molecule; at the telomeres, the recessed ends of lagging strands are filled in by non-displacing DNA synthesis. Here, we report experiments that test three proposed mechanisms for lagging-strand fill-in. We present data inconsistent with recombinational or terminal hairpin models for the formation of full-length duplex pSLA2 DNA. Instead, we find that deletions in short, distantly separated homologous palindromes in the leading-strand 3' overhang prevent propagation of linear pSLA2 DNA, implicating a mechanism of palindrome-mediated leading-strand fold-back in telomere replication. We further show that circularized pSLA2 DNA molecules are opened in vivo precisely at the terminal nucleotides of telomeres, generating functional linear replicons containing native telomeres covalently bound to a protein at their 5' DNA termini. Together, our results support a model in which pairing of multiple widely separated pSLA2 palindromes anchors the 3' end of the leading-strand overhang to a site near the overhang's base -- providing a recognition site for terminal-protein-primed DNA synthesis and subsequent endonucleolytic processing. Thus, the replication of Streptomyces plasmid telomeres may have features in common with the mechanism proposed for telomere replication in autonomous parvoviruses.},
}
@article {pmid9663392,
year = {1998},
author = {Polotnianka, RM and Li, J and Lustig, AJ},
title = {The yeast Ku heterodimer is essential for protection of the telomere against nucleolytic and recombinational activities.},
journal = {Current biology : CB},
volume = {8},
number = {14},
pages = {831-834},
doi = {10.1016/s0960-9822(98)70325-2},
pmid = {9663392},
issn = {0960-9822},
support = {GM56526/GM/NIGMS NIH HHS/United States ; },
mesh = {*Antigens, Nuclear ; Base Sequence ; Chromosomes, Fungal ; Crosses, Genetic ; Cyclin B/chemistry/genetics/metabolism ; *DNA Helicases ; DNA Replication ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Dimerization ; Fungal Proteins/genetics/metabolism ; Heterozygote ; Ku Autoantigen ; Macromolecular Substances ; Mutagenesis, Site-Directed ; Nuclear Proteins/chemistry/*metabolism ; Oligodeoxyribonucleotides/metabolism ; Recombinant Proteins/chemistry/metabolism ; *Recombination, Genetic ; Saccharomyces cerevisiae/*genetics/physiology ; *Saccharomyces cerevisiae Proteins ; Telomere/genetics/*metabolism/ultrastructure ; Transcription Factors/metabolism ; },
abstract = {The Ku heterodimer, conserved in a wide range of eukaryotes, plays a multiplicity of roles in yeast. First, binding of Ku, which is composed of a 70 kDa (Hdf1p) and an 80 kDa (Hdf2p) subunit [1-3], to double-strand breaks promotes non-homologous end-to-end joining of DNA [3]. Second, Ku appears to participate in DNA replication, regulating both the number of rounds of replication permissible within the cell cycle and the structure of the initiation complex [3,4]. Furthermore, mutations in HDF1 or HDF2 rapidly reduce telomeric poly (TG1-3) tract size [1-3], hinting also at a possible telomeric function of Ku. We show here that the two subunits of the Ku heterodimer play a key role in maintaining the integrity of telomere structure. Mutations in either Ku subunit increased the single-strandedness of the telomere in a cell-cycle-independent fashion, unlike wild-type cells which form 3' poly(TG1-3) overhangs exclusively in late S phase [5]. In addition, mutations enhanced the instability of elongated telomeres to degradation and recombination. Both Ku subunits genetically interacted with the putative single-stranded telomere-binding protein Cdc13p. We propose that Ku protects the telomere against nucleases and recombinases.},
}
@article {pmid9663383,
year = {1998},
author = {Weaver, DT},
title = {Telomeres: moonlighting by DNA repair proteins.},
journal = {Current biology : CB},
volume = {8},
number = {14},
pages = {R492-4},
doi = {10.1016/s0960-9822(98)70315-x},
pmid = {9663383},
issn = {0960-9822},
mesh = {Animals ; DNA Damage ; *DNA Repair ; DNA-Binding Proteins/metabolism ; Models, Genetic ; Saccharomyces cerevisiae/genetics ; Telomerase/metabolism ; Telomere/*genetics/ultrastructure ; Transcription, Genetic ; },
abstract = {Chromosome ends, or telomeres, are dynamic DNA structures maintained by a multisubunit telomerase and other proteins. New evidence indicates that proteins previously implicated in the repair of DNA doublestrand breaks also play an important role in the control of telomere organization and length.},
}
@article {pmid9658312,
year = {1998},
author = {Kinouchi, Y and Hiwatashi, N and Chida, M and Nagashima, F and Takagi, S and Maekawa, H and Toyota, T},
title = {Telomere shortening in the colonic mucosa of patients with ulcerative colitis.},
journal = {Journal of gastroenterology},
volume = {33},
number = {3},
pages = {343-348},
doi = {10.1007/s005350050094},
pmid = {9658312},
issn = {0944-1174},
mesh = {Adolescent ; Adult ; Aged ; Blotting, Southern ; Colitis, Ulcerative/*genetics/*pathology ; Female ; Humans ; Intestinal Mucosa/*pathology ; Male ; Middle Aged ; Telomere/*pathology ; },
abstract = {Telomere length in human somatic cells gradually decreases with the number of cell divisions and is regarded as a marker of somatic cell turnover. Mucosal cells of the affected colon show rapid turnover in individuals with active ulcerative colitis (UC). Telomere length was determined by Southern blot analysis of terminal restriction fragments (TRFs) from the colonic mucosa of 17 patients with UC in remission, two of whom showed dysplasia, and 17 control subjects without colitis. For each individual, mean TRF length was compared between rectal mucosa and unaffected cecal mucosa. The mean TRF length of the rectal mucosa was significantly less than that of cecal mucosa in UC patients (7.87 +/- 0.36kb versus 8.77 +/- 0.21 kb; P = 0.0015, Wilcoxon signed rank test), whereas no significant difference was detected in the control subjects. The extent of telomere shortening was 10.6 +/- 3.35% in UC patients, compared with 0.8 +/- 0.64% in noncolitis controls (P = 0.0024, Mann-Whitney U-test). Four UC patients, two of whom had dysplasia, showed telomere shortening of more than 20% in the rectal mucosa. These observations suggest that telomere shortening in the colonic mucosa of individuals with UC may represent the history of mucosal inflammation during disease of long duration, and that it may contribute to aneuploidy in UC.},
}
@article {pmid9656791,
year = {1998},
author = {Andersen, TI},
title = {[Telomeres, telomerase and development of cancer].},
journal = {Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke},
volume = {118},
number = {13},
pages = {2043-2046},
pmid = {9656791},
issn = {0029-2001},
mesh = {Animals ; DNA Replication ; DNA-Directed DNA Polymerase/genetics/metabolism ; Humans ; Neoplasms/enzymology/*etiology/genetics ; Telomerase/chemistry/genetics/*metabolism ; Telomere/metabolism/*physiology/ultrastructure ; },
abstract = {The chromosome ends, telomeres, shorten during each cell division due to the inability of DNA polymerase to replicate the ends of linear chromosomes. The telomere length serves as a clock determining the remaining replicative capacity of the cell. After 50-100 doublings, the cell becomes senescent. Rarely, a cell overcomes the senescence blockade, and eventually becomes immortal. Cellular immortalisation is almost always accompanied by the expression of the enzyme telomerase, which synthesises telomeric DNA. Telomerase is present in approximately 85% of malignancies. The detection of telomerase activity in cancer cells represents a possible cancer diagnostic and prognostic tool, and telomerase inhibition may become a novel therapeutic strategy in cancer patients.},
}
@article {pmid9652809,
year = {1998},
author = {Wu, H and George, K and Yang, TC},
title = {Estimate of true incomplete exchanges using fluorescence in situ hybridization with telomere probes.},
journal = {International journal of radiation biology},
volume = {73},
number = {5},
pages = {521-527},
doi = {10.1080/095530098142068},
pmid = {9652809},
issn = {0955-3002},
mesh = {*Chromosome Aberrations ; Chromosomes, Human/*radiation effects ; DNA Probes ; Female ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Lymphocytes/radiation effects/*ultrastructure ; *Telomere ; },
abstract = {PURPOSE: To study the frequency of true incomplete exchanges in radiation-induced chromosome aberrations.<br><br>MATERIALS AND METHODS: Human lymphocytes were exposed to 2 Gy and 5 Gy of gamma-rays. Chromosome aberrations were studied using the fluorescence in situ hybridization (FISH) technique with whole chromosome-specific probes, together with human telomere probes. Chromosomes 2 and 4 were chosen in the present study.<br><br>RESULTS: The percentage of incomplete exchanges was 27% when telomere signals were not considered. After excluding false incomplete exchanges identified by the telomere signals, the percentage of incomplete exchanges decreased to 11%. Since telomere signals appear on about 82% of the telomeres, the percentage of true incomplete exchanges should be even lower and was estimated to be 3%. This percentage was similar for chromosomes 2 and 4 and for doses of both 2 Gy and 5 Gy.<br><br>CONCLUSIONS: The percentage of true incomplete exchanges is significantly lower in gamma-irradiated human lymphocytes than the frequencies reported in the literature.},
}
@article {pmid9649633,
year = {1998},
author = {Kuroiwa, Y and Shinohara, T and Notsu, T and Tomizuka, K and Yoshida, H and Takeda, S and Oshimura, M and Ishida, I},
title = {Efficient modification of a human chromosome by telomere-directed truncation in high homologous recombination-proficient chicken DT40 cells.},
journal = {Nucleic acids research},
volume = {26},
number = {14},
pages = {3447-3448},
doi = {10.1093/nar/26.14.3447},
pmid = {9649633},
issn = {0305-1048},
mesh = {Animals ; Base Sequence ; Cell Line ; Chickens ; *Chromosomes, Human, Pair 22 ; DNA Primers ; Humans ; *Recombination, Genetic ; *Telomere ; },
abstract = {Truncation of human chromosomes at desired sites by homologous recombination techniques enables functional and structural analyses of human chromosomes and development of human artificial chromosomes. However, this targeted truncation has been inefficient. We describe here an efficient method for targeted truncation in the chicken DT40 cells with a high homologous recombination rate. The human chromosome 22 was transferred into DT40 cells, where human telomeric repeat (TTAGGG)n was targeted to the LIF locus on the chromosome. Molecular and cytogenetic analyses showed that the predicted truncation at the LIF locus occurred in all of the targeted clones.},
}
@article {pmid9647768,
year = {1998},
author = {Tokutake, Y and Matsumoto, T and Watanabe, T and Maeda, S and Tahara, H and Sakamoto, S and Niida, H and Sugimoto, M and Ide, T and Furuichi, Y},
title = {Extra-chromosomal telomere repeat DNA in telomerase-negative immortalized cell lines.},
journal = {Biochemical and biophysical research communications},
volume = {247},
number = {3},
pages = {765-772},
doi = {10.1006/bbrc.1998.8876},
pmid = {9647768},
issn = {0006-291X},
mesh = {Cell Line ; Cell Nucleus/chemistry ; Cloning, Molecular ; DNA/*analysis ; DNA Probes/genetics ; DNA-Binding Proteins/analysis ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Microscopy, Fluorescence ; Repetitive Sequences, Nucleic Acid/*genetics ; Telomerase/deficiency ; Telomere/*genetics ; Telomeric Repeat Binding Protein 1 ; },
abstract = {We found novel extra-chromosomal telomere repeat (ECTR) DNAs in telomerase-negative immortalized KMST-6 cells, by staining these cells with a (TTAGGG)n probe using both cycling oligonucleotide-primed in situ synthesis and by fluorescence in situ hybridization. Relatively small amounts of ECTR DNAs were also observed in telomerase-negative VA13 and SUSM-1 cells, but not observed in telomerase-positive immortalized HeLa cells. The ECTR DNAs existed mainly in the nucleoplasm with a small amount in the cytoplasm. The nucleoplasm ECTR DNAs were co-stained with an antibody directed to the telomeric-repeat binding factor 1 (TRF1), suggesting that they exist as a complex with TRF1. In consistent with these cytological studies, Southern blot analysis showed the existence of small telomere repeat DNAs. The ECTR DNA may provide an insight into the elucidation of the mechanisms responsible for the maintenance of telomeres in telomerase-negative immortalized cells.},
}
@article {pmid9643775,
year = {1998},
author = {Seligman, SJ},
title = {Telomere shortening in recipients of bone-marrow transplants.},
journal = {Lancet (London, England)},
volume = {351},
number = {9111},
pages = {1287-1288},
doi = {10.1016/s0140-6736(05)79353-3},
pmid = {9643775},
issn = {0140-6736},
mesh = {Aging/genetics ; *Bone Marrow Transplantation ; Humans ; Stem Cells/ultrastructure ; T-Lymphocytes/ultrastructure ; Telomere/*ultrastructure ; Transplantation, Homologous ; },
}
@article {pmid9643705,
year = {1998},
author = {Finkel, E},
title = {Telomeres: keys to senescence and cancer.},
journal = {Lancet (London, England)},
volume = {351},
number = {9110},
pages = {1186},
doi = {10.1016/S0140-6736(05)79136-4},
pmid = {9643705},
issn = {0140-6736},
mesh = {Cell Division/genetics ; Cell Transformation, Neoplastic/*genetics ; Cellular Senescence/*genetics ; Gene Expression Regulation, Enzymologic ; Genetic Engineering ; Humans ; Telomerase/genetics ; Telomere/*genetics ; },
}
@article {pmid9640533,
year = {1998},
author = {Johnson, FB and Marciniak, RA and Guarente, L},
title = {Telomeres, the nucleolus and aging.},
journal = {Current opinion in cell biology},
volume = {10},
number = {3},
pages = {332-338},
doi = {10.1016/s0955-0674(98)80008-2},
pmid = {9640533},
issn = {0955-0674},
mesh = {Aging/genetics ; Animals ; Cell Nucleolus/*genetics ; Cellular Senescence/*genetics ; Humans ; Saccharomyces cerevisiae/genetics ; Telomere/*physiology ; },
abstract = {Reactivation of telomerase in cultured human cells extends their replicative life span beyond the Hayflick limit. How telomere shortening triggers cell senescence and whether it contributes to aging in vivo are under investigation. Studies in yeast have revealed another site critical to cellular aging: the nucleolus. The accumulation of ribosomal DNA circles is a cause of aging in this organism. The possible relevance of this mechanism to human aging is also being considered.},
}
@article {pmid9639658,
year = {1998},
author = {Krejcí, K and Koch, J},
title = {Improved detection and comparative sizing of human chromosomal telomeres in situ.},
journal = {Chromosoma},
volume = {107},
number = {3},
pages = {198-203},
doi = {10.1007/s004120050297},
pmid = {9639658},
issn = {0009-5915},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Chromosomes/genetics ; Chromosomes, Human, Pair 11/genetics ; DNA Primers/genetics ; Female ; Fluorescent Dyes ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Indoles ; Male ; Repetitive Sequences, Nucleic Acid/genetics ; Staining and Labeling/methods ; Telomere/*genetics ; },
abstract = {Telomeric length dynamics are thought to play an important role both in the processes of cellular aging and cancer progression. We have revised the primed in situ (PRINS) labeling technique to allow an estimation of the relative length of individual telomeres. We illustrate the applicability of the approach by demonstrating different telomeric sizes not only between blood lymphocytes from a young and an old donor, but also among bone marrow cells from hematological cancer patients. In the latter case we found general variations in telomeric sizes as well as individual telomeric variations that would have escaped detection by other methods. An interesting finding was the selective expansion of a single telomere within a specific subset of cells.},
}
@article {pmid9637494,
year = {1998},
author = {De Boer, RJ and Noest, AJ},
title = {T cell renewal rates, telomerase, and telomere length shortening.},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {160},
number = {12},
pages = {5832-5837},
pmid = {9637494},
issn = {0022-1767},
mesh = {CD4-Positive T-Lymphocytes/immunology/metabolism ; Cell Compartmentation ; Cell Division ; Humans ; In Vitro Techniques ; Leukocyte Common Antigens/analysis ; Models, Immunological ; Multiple Sclerosis/immunology ; T-Lymphocytes/*immunology ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Measurements on the average telomere lengths of normal human naive and memory T cells suggested that 1) naive and memory human T cells have similar division rates, and 2) that the difference between naive and memory cells reflects the degree of clonal expansion during normal immune reactions. Here we develop mathematic models describing how the population average of telomere length depends on the cell division rates of naive and memory T cells during clonal expansion and normal renewal. The results show that 1) telomeres shorten with twice the cell division rate, 2) that the conventional approach of estimating telomere length shortening per mean population doubling gives rise to estimates that are 39% larger than the "true" loss per cell division, 3) that naive and memory T cells are expected to shorten their telomeres at rates set by the division rate of the naive T cells only, i.e., irrespective of the division rate of memory T cells, 4) that the measured difference in the average telomere length between naive and memory T cells may largely reflect the difference in renewal rates between these subpopulations rather than the clonal expansion, and 5) that full telomerase compensation during clonal expansion is consistent with all data on the shortening of telomere length in, and between, naive and memory T cells. Thus we reconcile the apparent contradictions between the demonstrated difference in division rates between human naive and memory T cells and their similar rates of telomere shortening, and the demonstrated telomere shortening in the presence of telomerase activity.},
}
@article {pmid9601982,
year = {1998},
author = {Slijepcevic, P},
title = {Telomeres and mechanisms of Robertsonian fusion.},
journal = {Chromosoma},
volume = {107},
number = {2},
pages = {136-140},
doi = {10.1007/s004120050289},
pmid = {9601982},
issn = {0009-5915},
mesh = {Animals ; *Artificial Gene Fusion ; Base Sequence ; Chromosome Breakage ; Evolution, Molecular ; *Gene Rearrangement ; Humans ; Telomere/chemistry/*genetics ; },
abstract = {The Robertsonian (Rb) fusion, a chromosome rearrangement involving centric fusion of two acro-(telo)centric chromosomes to form a single metacentric, is one of the most frequent events in mammalian karyotype evolution. Since one of the functions of telomeres is to preserve chromosome integrity, a prerequisite for the formation of Rb fusions should be either telomere loss or telomere inactivation. Possible mechanisms underlying the formation of various types of Rb fusion are discussed here. For example, Rb fusion in wild mice involves complete loss of p-arm telomeres by chromosome breakage within minor satellite sequences. By contrast, interstitial telomeric sites are found in the pericentromeric regions of chromosomes originating from a number of vertebrate species, suggesting the occurrence of Rb-like fusion without loss of telomeres, a possibility consistent with some form of telomere inactivation. Finally, a recent study suggests that telomere shortening induced by the deletion of the telomerase RNA gene in the mouse germ-line leads to telomere loss and high frequencies of Rb fusion in mouse somatic cells. Thus, at least three mechanisms in mammalian cells lead to the formation of Rb fusions.},
}
@article {pmid9635193,
year = {1998},
author = {Nugent, CI and Bosco, G and Ross, LO and Evans, SK and Salinger, AP and Moore, JK and Haber, JE and Lundblad, V},
title = {Telomere maintenance is dependent on activities required for end repair of double-strand breaks.},
journal = {Current biology : CB},
volume = {8},
number = {11},
pages = {657-660},
doi = {10.1016/s0960-9822(98)70253-2},
pmid = {9635193},
issn = {0960-9822},
support = {GM55867/GM/NIGMS NIH HHS/United States ; },
mesh = {*Antigens, Nuclear ; Cyclin B/genetics/metabolism ; *DNA Helicases ; *DNA Repair ; DNA Replication ; DNA, Fungal/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; *Endodeoxyribonucleases ; *Exodeoxyribonucleases ; Fungal Proteins/genetics/metabolism ; Genes, Fungal ; Ku Autoantigen ; Mutation ; Nuclear Proteins/genetics/metabolism ; Saccharomyces cerevisiae/genetics/*metabolism ; *Saccharomyces cerevisiae Proteins ; Telomerase/metabolism ; Telomere/genetics/*metabolism ; },
abstract = {Telomeres are functionally distinct from ends generated by chromosome breakage, in that telomeres, unlike double-strand breaks, are insulated from recombination with other chromosomal termini [1]. We report that the Ku heterodimer and the Rad50/Mre11/Xrs2 complex, both of which are required for repair of double-strand breaks [2-5], have separate roles in normal telomere maintenance in yeast. Using epistasis analysis, we show that the Ku end-binding complex defined a third telomere-associated activity, required in parallel with telomerase [6] and Cdc13, a protein binding the single-strand portion of telomere DNA [7,8]. Furthermore, loss of Ku function altered the expression of telomere-located genes, indicative of a disruption of telomeric chromatin. These data suggest that the Ku complex and the Cdc13 protein function as terminus-binding factors, contributing distinct roles in chromosome end protection. In contrast, MRE11 and RAD50 were required for the telomerase-mediated pathway, rather than for telomeric end protection; we propose that this complex functions to prepare DNA ends for telomerase to replicate. These results suggest that as a part of normal telomere maintenance, telomeres are identified as double-strand breaks, with additional mechanisms required to prevent telomere recombination. Ku, Cdc13 and telomerase define three epistasis groups required in parallel for telomere maintenance.},
}
@article {pmid9635192,
year = {1998},
author = {Laroche, T and Martin, SG and Gotta, M and Gorham, HC and Pryde, FE and Louis, EJ and Gasser, SM},
title = {Mutation of yeast Ku genes disrupts the subnuclear organization of telomeres.},
journal = {Current biology : CB},
volume = {8},
number = {11},
pages = {653-656},
doi = {10.1016/s0960-9822(98)70252-0},
pmid = {9635192},
issn = {0960-9822},
mesh = {Animals ; *Antigens, Nuclear ; Cell Nucleus/metabolism ; *DNA Helicases ; DNA-Binding Proteins/*genetics/*metabolism ; Fungal Proteins/*genetics/*metabolism ; Gene Deletion ; *Genes, Fungal ; *Genes, Mating Type, Fungal ; Ku Autoantigen ; *Mutation ; Nuclear Proteins/*genetics/*metabolism ; Saccharomyces cerevisiae/*genetics/*metabolism/ultrastructure ; *Saccharomyces cerevisiae Proteins ; Shelterin Complex ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Telomere/genetics/metabolism ; *Telomere-Binding Proteins ; Trans-Activators/metabolism ; *Transcription Factors ; },
abstract = {The mammalian Ku70 and Ku86 proteins form a heterodimer that binds to the ends of double-stranded DNA in vitro and is required for repair of radiation-induced strand breaks and V(D)J recombination [1,2]. Deletion of the Saccharomyces cerevisiae genes HDF1 and HDF2--encoding yKu70p and yKu80p, respectively--enhances radiation sensitivity in a rad52 background [3,4]. In addition to repair defects, the length of the TG-rich repeat on yeast telomere ends shortens dramatically [5,6]. We have shown previously that in yeast interphase nuclei, telomeres are clustered in a limited number of foci near the nuclear periphery [7], but the elements that mediate this localization remained unknown. We report here that deletion of the genes encoding yKu70p or its partner yKu80p altered the positioning of telomeric DNA in the yeast nucleus. These are the first mutants shown to affect the subnuclear localization of telomeres. Strains deficient for either yKu70p or yKu80p lost telomeric silencing, although they maintained repression at the silent mating-type loci. In addition, the telomere-associated silencing factors Sir3p and Sir4p and the TG-repeat-binding protein Rap1p lost their punctate pattern of staining and became dispersed throughout the nucleoplasm. Our results implicate the yeast Ku proteins directly in aspects of telomere organization, which in turn affects the repression of telomere-proximal genes.},
}
@article {pmid9572992,
year = {1998},
author = {Ball, SE and Gibson, FM and Rizzo, S and Tooze, JA and Marsh, JC and Gordon-Smith, EC},
title = {Progressive telomere shortening in aplastic anemia.},
journal = {Blood},
volume = {91},
number = {10},
pages = {3582-3592},
pmid = {9572992},
issn = {0006-4971},
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Anemia, Aplastic/blood/*genetics ; Blood Cell Count ; Bone Marrow/pathology ; Cell Division ; Child ; Disease Progression ; Fanconi Anemia/blood/genetics ; Female ; Hematopoiesis ; Hematopoietic Stem Cells/pathology ; Hemoglobinuria, Paroxysmal/blood/etiology/genetics ; Humans ; Leukocytes/ultrastructure ; Male ; Middle Aged ; Myelodysplastic Syndromes/epidemiology/etiology/genetics ; Polymorphism, Restriction Fragment Length ; Prognosis ; Risk ; Telomere/*ultrastructure ; },
abstract = {Improved survival in aplastic anemia (AA) has shown a high incidence of late clonal marrow disorders. To investigate whether accelerated senescence of hematopoietic stem cells might underlie the pathophysiology of myelodysplasia (MDS) or paroxysmal nocturnal hemoglobinuria (PNH) occurring as a late complication of AA, we studied mean telomere length (TRF) in peripheral blood leukocytes from 79 patients with AA, Fanconi anemia, or PNH in comparison with normal controls. TRF lengths in the patient group were significantly shorter for age than normals (P < .0001). Telomere shortening was apparent in both granulocyte and mononuclear cell fractions, suggesting loss at the level of the hematopoietic stem cell. In patients with acquired AA with persistent cytopenias (n = 40), there was significant correlation between telomere loss and disease duration (r = -.685; P < .0001), equivalent to progressive telomere erosion at 216 bp/yr, in addition to the normal age-related loss. In patients who had achieved normal full blood counts (n = 20), the rate of telomere loss had apparently stabilised. There was no apparent association between telomere loss and secondary PNH (n = 13). However, of the 5 patients in the study with TRF less than 5.0 kb, 3 had acquired cytogenetic abnormalities, suggesting that telomere erosion may be relevant to the pathogenesis of MDS in aplastic anemia.},
}
@article {pmid9547275,
year = {1998},
author = {Fu, G and Barker, DC},
title = {Characterisation of Leishmania telomeres reveals unusual telomeric repeats and conserved telomere-associated sequence.},
journal = {Nucleic acids research},
volume = {26},
number = {9},
pages = {2161-2167},
pmid = {9547275},
issn = {0305-1048},
mesh = {Animals ; Base Sequence ; Chromosomes/genetics ; Cloning, Molecular ; *Conserved Sequence ; Leishmania/*genetics ; Leishmania braziliensis/genetics ; Leishmania major/genetics ; Leishmania mexicana/genetics ; Models, Genetic ; Molecular Sequence Data ; *Repetitive Sequences, Nucleic Acid ; Sequence Analysis, DNA ; Sequence Homology, Nucleic Acid ; Species Specificity ; Telomere/*genetics ; },
abstract = {Characterisation of the telomeres of Leishmania is important for understanding many aspects of the parasitic life of this primitive protozoan and for the completion of the physical map and sequencing of the genome. After sequencing more than 300 telomere-derived clones from Leishmania braziliensis and Leishmania major, a conserved 100 bp sequence was identified immediately adjacent to the telomere at the chromosome end and was named LCTAS (Leishmania conserved telomere-associated sequence). The LCTAS contains two conserved sequence boxes, and is present in all Leishmania species studied. The organisation of the LCTAS in the telomeric region differs between L. braziliensis and L. major: in L. major the LCTASs are tandemly repeated, while in L. braziliensis the LCTAS is present as a single copy per end. Two additional TASs with 1.6 kb and 274 bp repeat structures, which are apparently different to LCTAS, were isolated and mapped onto a L. braziliensis 250 kb multicopy minichromosome and the L. major chromosome 1, respectively. An unusual feature in L. braziliensis is that the telomeric repeats are often comprised of a novel tandem repeat CCCTAACCCGTGGA. A 'slippage' mechanism for LCTAS formation is proposed in this study as an alternative way for the synthesis and maintenance of telomeres and subtelomere regions.},
}
@article {pmid9625821,
year = {1998},
author = {Guo, W and Kang, MK and Kim, HJ and Park, NH},
title = {Immortalization of human oral keratinocytes is associated with elevation of telomerase activity and shortening of telomere length.},
journal = {Oncology reports},
volume = {5},
number = {4},
pages = {799-804},
doi = {10.3892/or.5.4.799},
pmid = {9625821},
issn = {1021-335X},
support = {DE10598/DE/NIDCR NIH HHS/United States ; DE11229/DE/NIDCR NIH HHS/United States ; },
mesh = {Cell Division/physiology ; Cell Line, Transformed ; Cell Survival/physiology ; *Cell Transformation, Viral ; Genome, Viral ; Humans ; Keratinocytes/enzymology/ultrastructure/*virology ; Mouth Mucosa/*pathology ; Papillomaviridae/*genetics ; Telomerase/*metabolism ; Telomere/*ultrastructure ; Transfection ; },
abstract = {Telomerase is a ribonucleoprotein complex that synthesizes TTAGGG repeat sequences at the ends of mammalian chromosomes. Its activity is found in most cancer cells and few rare normal somatic cells. To investigate whether telomerase activity and telomere length of normal human oral keratinocytes (NHOK) are altered by <high risk> human papillomaviruses (HPV), we transfected primary NHOK with type 16 HPV (HPV-16) genome and determined the activity of telomerase. HPV transfection extended the life span of NHOK and eventually induced immortalization of cells. Moderate telomerase activity was consistently observed in rapidly proliferating NHOK, and activity was not changed in HPV-16 transfected cells with extended life span. However, the activity was sharply increased when cells passed the crisis stage. Telomere length, which remained constant at approximately 6.8 kb during serial passages of NHOK, progressively shortened in HPV DNA transfected cells during the period of extended life span and continued until crisis, after which it stabilized at approximately 5 kb. These results demonstrate that immortalization of NHOK with HPV-16 DNA is associated with the activation of telomerase.},
}
@article {pmid9620782,
year = {1998},
author = {LaBranche, H and Dupuis, S and Ben-David, Y and Bani, MR and Wellinger, RJ and Chabot, B},
title = {Telomere elongation by hnRNP A1 and a derivative that interacts with telomeric repeats and telomerase.},
journal = {Nature genetics},
volume = {19},
number = {2},
pages = {199-202},
doi = {10.1038/575},
pmid = {9620782},
issn = {1061-4036},
mesh = {Animals ; Cells, Cultured ; DNA Helicases/metabolism ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/metabolism ; Heterogeneous Nuclear Ribonucleoprotein A1 ; *Heterogeneous-Nuclear Ribonucleoprotein Group A-B ; Heterogeneous-Nuclear Ribonucleoproteins ; Mice ; *Repetitive Sequences, Nucleic Acid ; Ribonucleoproteins/*metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; Thymus Hormones/metabolism ; },
abstract = {Telomeric DNA of mammalian chromosomes consists of several kilobase-pairs of tandemly repeated sequences with a terminal 3' overhang in single-stranded form. Maintaining the integrity of these repeats is essential for cell survival; telomere attrition is associated with chromosome instability and cell senescence, whereas stabilization of telomere length correlates with the immortalization of somatic cells. Telomere elongation is carried out by telomerase, an RNA-dependent DNA polymerase which adds single-stranded TAGGGT repeats to the 3' ends of chromosomes. While proteins that associate with single-stranded telomeric repeats can influence tract lengths in yeast, equivalent factors have not yet been identified in vertebrates. Here, it is shown that the heterogeneous nuclear ribonucleoprotein A1 participates in telomere biogenesis. A mouse cell line deficient in A1 expression harbours telomeres that are shorter than those of a related cell line expressing normal levels of A1. Restoring A1 expression in A1-deficient cells increases telomere length. Telomere elongation is also observed upon introduction of exogenous UP1, the amino-terminal fragment of A1. While both A1 and UP1 bind to vertebrate single-stranded telomeric repeats directly and with specificity in vitro, only UP1 can recover telomerase activity from a cell lysate. These findings establish A1/UP1 as the first single-stranded DNA binding protein involved in mammalian telomere biogenesis and suggest possible mechanisms by which UP1 may modulate telomere length.},
}
@article {pmid9619742,
year = {1998},
author = {Schneider-Stock, R and Epplen, C and Radig, K and Oda, Y and Dralle, H and Hoang-Vu, C and Epplen, JT and Roessner, A},
title = {On telomere shortening in soft-tissue tumors.},
journal = {Journal of cancer research and clinical oncology},
volume = {124},
number = {3-4},
pages = {165-171},
doi = {10.1007/s004320050150},
pmid = {9619742},
issn = {0171-5216},
mesh = {Adult ; Aged ; Cell Division/physiology ; DNA Fingerprinting ; DNA Probes ; DNA, Neoplasm/genetics ; Female ; Histiocytoma, Benign Fibrous/genetics/pathology ; Humans ; Leiomyosarcoma/genetics/pathology ; Liposarcoma/genetics/pathology ; Male ; Middle Aged ; Neurilemmoma/genetics/pathology ; Nucleic Acid Hybridization ; Ploidies ; Sarcoma, Synovial/genetics/pathology ; Soft Tissue Neoplasms/*genetics/pathology ; Telomere/*genetics ; },
abstract = {PURPOSE: Specific simple DNA repeats occur at the telomeric ends of mammalian chromosomes. Loss of (G + C)-rich repeats can result in genetic instability, associated with tumorigenesis. So far, data on telomere shortening have not been available for different types of soft-tissue tumors.<br><br>METHODS: Using tumor material and the blood of the corresponding patient, high-molecular-mass DNA was prepared by digestion with proteinase K and extraction with phenol/chloroform. A 10-microg sample of DNA was digested with the restriction enzyme HinfI. DNA fragments were separated in a 0.7% agarose gel, and in-gel hybridization was performed with the telomere-specific repeat probe (TTAGGG)3.<br><br>RESULTS: Shortening of the telomere repeat was observed in 14/30 soft-tissue tumors; 5 tumors showed elongated telomere repeats, whereas the telomeres appeared unchanged in 11 tumors. Decreased telomere repeat length correlated with advanced age, DNA ploidy, and a higher proliferation index. There was no association between telomere repeat length and tumor grade. Interestingly, in contrast to other entities, all malignant schwannomas and leiomyosarcomas showed significantly reduced telomere lengths. An explanation for the telomere heterogeneity in liposarcomas may include differential telomerase reactivation in well and poorly differentiated tumors.<br><br>CONCLUSIONS: Telomere shortening is frequent but not a uniform phenomenon in different types of soft-tissue tumor. Studies on telomerase activity should be performed in the same cohort of sarcomas.},
}
@article {pmid9619267,
year = {1998},
author = {de Lange, T},
title = {Length control of human telomeres.},
journal = {The cancer journal from Scientific American},
volume = {4 Suppl 1},
number = {},
pages = {S22-5},
pmid = {9619267},
issn = {1081-4442},
mesh = {Base Sequence ; Chromosomes, Human/*genetics/ultrastructure ; DNA Replication ; Humans ; *Models, Genetic ; Neoplasms/enzymology/genetics ; Repetitive Sequences, Nucleic Acid ; Telomerase/*metabolism ; Telomere/*genetics/ultrastructure ; },
}
@article {pmid9545467,
year = {1998},
author = {Kamnert, I and Nielsen, L and Edström, JE},
title = {A concertedly evolving region in Chironomus, unique within the telomere.},
journal = {Journal of molecular evolution},
volume = {46},
number = {5},
pages = {562-570},
doi = {10.1007/pl00006337},
pmid = {9545467},
issn = {0022-2844},
mesh = {Animals ; Base Sequence ; Chironomidae/*genetics ; Evolution, Molecular ; Gene Conversion ; *Genes, Insect ; Molecular Sequence Data ; Telomere/*genetics ; },
abstract = {Chromosome terminal, complex repeats in the dipteran Chironomus pallidivittatus show rapid concerted evolution during which there is remarkably efficient homogenization of the repeat units within and between chromosome ends. It has been shown previously that gene conversion is likely to be an important component during these changes. The sequence evolution could be a result of different processes-exchanges between repeats in the tandem array as well as information transfer between units in different chromosomes-and is therefore difficult to analyze in detail. In this study the concerted evolution of a region present only once per chromosome, at the junction between the telomeric complex repeats and the subtelomeric DNA was therefore investigated in the two sibling species C. pallidivittatus and C. tentans. Material from individual microdissected chromosome ends was used, as well as clones from bulk genomic DNA. On the telomeric side of the border pronounced species-specific sequence differences were observed, the patterns being similar for clones of different origin within each species. Mutations had been transmitted efficiently between chromosomes also when adjoining, more distally localized DNA showed great differences in sequence, suggesting that gene conversion had taken place. The evolving telomeric region bordered proximally to subtelomeric DNA with high evolutionary constancy. More proximally localized, subtelomeric DNA evolved more rapidly and showed heterogeneity between species and chromosomes.},
}
@article {pmid9533871,
year = {1998},
author = {Oexle, K},
title = {Telomere length distribution and Southern blot analysis.},
journal = {Journal of theoretical biology},
volume = {190},
number = {4},
pages = {369-377},
doi = {10.1006/jtbi.1997.0559},
pmid = {9533871},
issn = {0022-5193},
mesh = {Animals ; Blotting, Southern ; In Situ Hybridization, Fluorescence ; *Models, Genetic ; Telomere/*ultrastructure ; },
abstract = {Southern blot analysis of terminal restriction fragments (TRFs) is the standard method for quantitative examination of telomere length distributions. Since TRFs contain a subtelomeric component, central parameters of the TRF distribution n(L) such as the arithmetic mean (M) or the median (Me) cannot be derived directly from Southern blot data, i.e. from the optical density distribution OD(L). Several estimates have been applied instead; the seeming arithmetic mean A, the "center of mass" C, and the positions of maximal (P) and half-maximal optical density (P(1/2)). We show that C> A> M for any non-truncated distributions n(L), and P> M> P1/2 for any symmetrical unimodal n(L). Symmetric appearance on a Southern blot, however, suggests positive skewness of n(L). Thus, a lognormal form of n(L) may be considered. Then, C> A> M> P=Me> P(1/2). Alternatively, a Weibull distribution may be assumed. The latter is compatible with negative feedback-regulation of the telomere lengths. Using the maximum likelihood method we compare these distributions with FISH-data on telomere lengths in different cell types. The fit of the lognormal distribution is clearly superior. Lognormal genesis may relate to telomere breakage and recombination. Truncation of the upper end of the TRF distribution is possible due to Southern blot artifacts. Thereby, the order of the estimates may change to P> C> A. Having minimal sensitivity to truncation, P seems to be the optimal choice. however, the variability of P is high since peakedness of OD(L) and DNA length resolution are inversely related.},
}
@article {pmid9613146,
year = {1998},
author = {Ohyashiki, K and Ohyashiki, JH},
title = {[Telomere, telomerase and cytogenetic changes in myelodysplastic syndromes].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {56},
number = {5},
pages = {1328-1332},
pmid = {9613146},
issn = {0047-1852},
mesh = {*Chromosome Aberrations ; Humans ; Myelodysplastic Syndromes/*genetics ; Telomerase/*analysis ; Telomere/*genetics ; },
abstract = {Myelodysplastic syndrome (MDS) is a heterogenous but clonal disorder characterized by cytopenia and dysplastic features. Telomere length in MDS vary but some of them show shortened telomeres. Telomerase activity in MDS also vary but about 60% of them show slightly elevated telomerase activity. According to the disease progression of MDS, MDS patients categorize into 3 groups, i.e., (1) normal telomere length before and after disease progression, (2) short telomere length before and after progression, and (3) shortened telomere with disease progression. Telomerase change with disease progression is not obscure, indicating impairment of telomere dynamics in MDS. These observations may indicate that some MDS show telomerase upregulation possible due to telomere shortening, while the another pathway without telomerase upregulation associated with complex chromosome changes may link to the pathogenesis of MDS.},
}
@article {pmid9613145,
year = {1998},
author = {Yamada, O and Mizoguchi, H},
title = {[Telomere and telomerase in the differentiation of leukemic cell lines].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {56},
number = {5},
pages = {1322-1327},
pmid = {9613145},
issn = {0047-1852},
mesh = {HL-60 Cells ; Humans ; Leukemia/enzymology/*genetics ; Telomerase/*analysis ; Telomere/*genetics ; Tumor Cells, Cultured ; },
abstract = {By using three hematopoietic cell lineages including myelomonocytic, erythroblastic and megakaryocytic differentiation, downregulation of telomerase activity was found to be a general response to the induction of differentiation. The decrease in telomerase activity occurred as early as 24h when HL-60 and K562 cells were cultured in the presence of VD3, ATRA and hemin and completely disappeared after 3 days. On the other hand MEG-01 cells showed dramatic inhibition of telomerase activity after 6 days of culture with TPA. Analysis of telomeric DNA in HL-60 cells and K562 cells demonstrated no remarkable loss of telomeric DNA with cellular differentiation while loosing telomerase activity. The repression of telomerase is one of many molecular events during the complex process of cellular differentiation, and testing of additional cell lines that are capable of differentiation will be helpful for understanding the mechanisms of telomerase control.},
}
@article {pmid9613143,
year = {1998},
author = {Murakami, J and Nagai, N and Ohama, K},
title = {[Telomerase activity and telomere length as diagnostic tumor marker for ovarian tumors].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {56},
number = {5},
pages = {1310-1315},
pmid = {9613143},
issn = {0047-1852},
mesh = {Biomarkers, Tumor/*analysis ; Female ; Humans ; Ovarian Neoplasms/*diagnosis/pathology ; Telomerase/*analysis ; Telomere/*genetics ; },
abstract = {Telomerase activity was detected in germ cells, stem cells and cancer cells. In tumors of the ovary, an organ that contains germ cells, the authors examined availability to detect telomerase activity. Telomerase activity of malignant tumors was extremely high compared with that of normal ovaries and benign tumors. Strength and frequency of telomerase activity in malignant tumors was significant different from that in benign tumors. Telomere length tended to be smaller for malignant tumors of advanced stage, but no significant relationship between telomere length and telomerase activity and tumor stage could be recognized. Telomerase activity may be a useful marker for the diagnosis of ovarian tumors.},
}
@article {pmid9613138,
year = {1998},
author = {Takubo, K and Nakamura, K and Arai, T and Nakachi, K and Ebuchi, M},
title = {[Telomere length in breast carcinoma of the young and aged].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {56},
number = {5},
pages = {1283-1286},
pmid = {9613138},
issn = {0047-1852},
mesh = {Adenocarcinoma/*genetics ; Adenocarcinoma, Scirrhous/*genetics ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Breast Neoplasms/*genetics ; Carcinoma, Papillary/*genetics ; Female ; Humans ; Middle Aged ; Telomere/*genetics ; },
abstract = {In order to clarify the relationship between the telomeric length of human female breast carcinoma cells and patient age, and between telomeric length and the histological type of carcinoma, we examined 64 patients (aged 20-89 years) with breast carcinoma by histological and southern blot analysis. No difference in the telomeric length was recognizable among the three major histological types: papillotubular, solid tubular and scirrhous (7.9-8.7 kilobase pairs (kbp)). Mean telomere lengths in the groups aged under 35 (8 patients), 36-50 (10 patients), 51-70 (17 patients), 71-80 (19 patients), and over 81 years (10 patients) were 11.0, 9.9, 7.0, 7.7 and 7.6 kbp, respectively. There was no significant evidence for telomeric shortening in breast carcinoma according to patient age. Two peaks of telomeric length were observed in three carcinomas comprising a medullary carcinoma and two solid tubular carcinomas showing very prominent lymphocyte infiltration histologically.},
}
@article {pmid9613130,
year = {1998},
author = {Nakashio, R and Kitamoto, M and Nakanishi, T and Takaishi, H and Takahashi, S and Kajiyama, G},
title = {[Telomere length and telomerase activity in hepatocellular carcinoma].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {56},
number = {5},
pages = {1239-1243},
pmid = {9613130},
issn = {0047-1852},
mesh = {Carcinoma, Hepatocellular/*genetics/pathology ; Cell Differentiation ; Humans ; Liver Neoplasms/*genetics/pathology ; Telomerase/*analysis ; Telomere/*genetics ; },
abstract = {Telomerase activity and terminal restriction fragment (TRF) length were examined in hepatocellular carcinoma (HCC). Telomerase activity was assayed by telomeric repeat amplification protocol (TRAP) connected with an internal telomerase assay standard (ITAS). The incidence of strong telomerase activity (highly variable level compared with the activity of non-cancerous liver tissue) was 79% in well, 84% in moderately, and 100% in poorly differentiated HCC, while 0% in non-cancerous liver tissues. The incidence of TRF length alteration (reduction or elongation) was 53% in HCC. The incidence of TRF alteration was significantly higher in HCC exceeding 3 cm in diameter, moderately or poorly differentiated in histology. Telomerase activity was not associated with TRF length alteration in HCC. In conclusion, strong telomerase activity and TRF length alteration increased with HCC tumor progressions.},
}
@article {pmid9613123,
year = {1998},
author = {Katayama, S and Shiota, G and Kawasaki, H},
title = {[Diagnostic significance of telomerase activity and telomere length in endoscopic sample of colorectal cancer].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {56},
number = {5},
pages = {1204-1208},
pmid = {9613123},
issn = {0047-1852},
mesh = {Biomarkers, Tumor/analysis ; Blotting, Southern ; Colonoscopy ; Colorectal Neoplasms/*diagnosis ; Humans ; Telomerase/*analysis ; Telomere/*genetics ; },
abstract = {Telomeres are located on both ends of individual chromosomes in eukaryotes. It has been reported that telomerase activity and telomere reduction can be detected in most human cancers. We examined telomerase activity and telomere length in colorectal cancer tissues obtained by colonoscopy. Telomerase activity was examined by the TRAP (telomeric repeat amplification protocol) assay and was detected in 21 of 26 (81%) primary colorectal carcinoma tissues. Two of 9 (22%) colorectal polyp were telomerase positive. Telomere length was analyzed by Southern blotting and there was reduction in telomere lengths in 12 of 15 (80%) primary colorectal carcinoma and 3 of 6 colorectal polyp, compared to the corresponding normal colonic mucosa. Therefore, telomerase activity and telomere length may serve as an useful tool for preoperative cancer diagnosis.},
}
@article {pmid9613119,
year = {1998},
author = {Maruyama, Y and Hanai, H and Kaneko, E},
title = {[Telomere length and telomerase activity in intestinal metaplasia, adenoma and well differentiated adenocarcinoma of the stomach].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {56},
number = {5},
pages = {1186-1189},
pmid = {9613119},
issn = {0047-1852},
mesh = {Adenocarcinoma/enzymology/*genetics ; Adenoma/enzymology/*genetics ; Humans ; Metaplasia ; Stomach/enzymology/*pathology ; Stomach Neoplasms/enzymology/*genetics ; Telomerase/*analysis ; Telomere/*genetics ; },
abstract = {We analyzed telomere length and telomerase activity in intestinal metaplasia (IM), adenoma, and cancer of the stomach and studied the stages at which the cells acquire telomerase activity in carcinogenesis and also the correlation between telomerase activity and telomere length. Telomerase activity was detected in 15%, 45%, 89% of IM, adenomas, and cancers. Telomere lengths shortened as normal mucosa changed into IM and more into adenoma. Gastric cancers showed a broad range of telomeric length. The shortest telomere length was found among gastric adenomas. These results suggest that telomerase is expressed during early phase of gastric carcinogenesis but the activity at that stage is not strong enough to fully restore the reduced telomeric DNA.},
}
@article {pmid9613113,
year = {1998},
author = {Saito, Y and Suda, T and Hatakeyama, K},
title = {[Methods of measuring telomere length and telomerase activity--practice and problems].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {56},
number = {5},
pages = {1153-1158},
pmid = {9613113},
issn = {0047-1852},
mesh = {Humans ; In Situ Hybridization, Fluorescence ; Methods ; Repetitive Sequences, Nucleic Acid ; Telomerase/*analysis ; Telomere/*genetics ; },
abstract = {The development of a highly sensitive method for detection of telomerase activity, telomeric repeat amplification protocol (TRAP), has provided knowledge on telomerase activity in normal and cancer tissues. Subsequent several modifications have been achieved, including an introduction of the internal standard and hybridization protection technique that leads to simplicity and improvement of reproducibility and linearity of this method, and application of TRAP to in situ analysis to identify the cells responsible for telomerase activity. As for measurement of telomere length, fluorescence in situ hybridization technique appeared to give an information of telomere length on an individual chromosome in contrast to analysis of terminal restriction fragment, a conventional method which can express mean telomere length of all chromosomes. Further methodological improvement in this field is ongoing and showing a new sight on cell mortality and immortality.},
}
@article {pmid9613111,
year = {1998},
author = {Hiyama, E and Yokoyama, T and Hiyama, K and Matsuura, Y},
title = {[Relationship between telomere length and clinical and biological characteristics of the cancers with telomerase reactivation].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {56},
number = {5},
pages = {1139-1145},
pmid = {9613111},
issn = {0047-1852},
mesh = {Adult ; Child ; Enzyme Activation ; Humans ; Neoplasms/*diagnosis ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {Activation of telomerase and stabilization of telomeres are considered to be necessary for immortalization of human tumor cells. Telomerase activity and telomere lengths were examined in adult and childhood cancer tissues. High telomerase activity was detected in over 40% samples. In these cases, the lengths of telomeres varied in wide range and the short telomere length significantly correlated with high proliferative index. The patients with short telomeres demonstrated poorer prognosis than other patients. These findings suggest that the short telomeres might be related with the malignant potential in cancers with high telomerase activity.},
}
@article {pmid9613106,
year = {1998},
author = {Hatakeyama, S and Takahashi, K and Fukuhara, T and Ishikawa, F},
title = {[Chromosome rearrangement involving telomeres in cancers].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {56},
number = {5},
pages = {1115-1120},
pmid = {9613106},
issn = {0047-1852},
mesh = {*Chromosome Aberrations ; Humans ; Neoplasms/*genetics ; Telomere/*genetics ; },
abstract = {Stable maintenance of chromosomes needs the functional telomeres at the chromosomal ends. It has been proposed that the loss of telomeric function (LTF) plays a major role in the production of abnormal chromosomes, such as the telomere association (TA) and the jumping translocation (JT). We analyzed TA and JT to evaluate the involvement of LTF in chromosomal instability. A shortened telomeres was identified at the fusion point of the JT. We also developed a method to examine TA based on PCR and found relationships between telomere shortening and products of PCR. Our findings strongly suggest that LTF may cause chromosomal instability and contribute to cancer cell evolution.},
}
@article {pmid9613103,
year = {1998},
author = {Uchiumi, F and Watanabe, M and Tanuma, S},
title = {[Mammalian proteins that associate with telomeres].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {56},
number = {5},
pages = {1097-1101},
pmid = {9613103},
issn = {0047-1852},
mesh = {DNA-Binding Proteins/*physiology ; Humans ; Nuclear Proteins/*physiology ; *Protozoan Proteins ; Telomere/*genetics ; },
abstract = {Telomeres are the DNA-protein complexes found at the ends of linear chromosomes. The structure is believed to be important for chromosome stability and cell integrity, and thereby for cell senescence and immortality. Telomeric DNA consists of tandemly repeated sequences which are observed from human to yeast. For example, human and Saccharomyces telomeres have T2AG3 and TG1-3 repeats, respectively. Recently, various protein factors including replication factor C (RFC) have been found as telomere repeat sequence binding-proteins. Characterization of these proteins and their interactions with telomeres may provide a new insight into not only telomere functions but also aging, immortality and apoptosis of the cells.},
}
@article {pmid9610031,
year = {1998},
author = {Yang, Z and Kodama, S and Suzuki, K and Watanabe, M},
title = {Telomerase activity, telomere length, and chromosome aberrations in the extension of life span of human embryo cells induced by low-dose X-rays.},
journal = {Journal of radiation research},
volume = {39},
number = {1},
pages = {35-51},
doi = {10.1269/jrr.39.35},
pmid = {9610031},
issn = {0449-3060},
mesh = {Cell Division/radiation effects ; Cells, Cultured ; Cellular Senescence/*genetics/physiology/*radiation effects ; Chromosome Aberrations ; Embryo, Mammalian/cytology ; Humans ; Telomerase/*metabolism ; Telomere/genetics/*radiation effects ; },
abstract = {We examined whether the shortening of telomere structure is related to in vitro cellular aging after multiple low-dose irradiation. We used three strains of HE cells (HE23, HE31, and HE40) exhibiting different levels of telomerase activity and irradiated these cells twice a week with a dose of 2 cGy or 4 cGy of X-rays until they senesced. The cells were in total exposed to doses of 52-208 cGy of X-rays. Only the HE31 cells, which had no telomerase activity, experienced an increase in the number of cell divisions, reaching a maximum of 120-124% of the non-irradiated controls. However, in two strains which did exhibit telomerase activity in an early passage in culture, no extension of cell life span was found. Telomerase-positive cells completely lost all telomerase activity when the cells were subcultured several times without irradiation. In the HE31 cells where the life span was extended, the ratio of cell having a long telomere was higher than those of the other two cells (HE23 and HE40). Cytogenetic analysis revealed that the life span extension due to multiple low-dose irradiation which was observed in HE31 cells did not correlate with specific chromosome alterations. Our results suggest that the telomerase activity remaining in the cells at an early passage does not correlate with the extension of life span in vitro by X-irradiation. The factor other than telomerase activity may play an important role in the regulation of telomere length and the extension of life span.},
}
@article {pmid9607597,
year = {1998},
author = {Sitte, N and Saretzki, G and von Zglinicki, T},
title = {Accelerated telomere shortening in fibroblasts after extended periods of confluency.},
journal = {Free radical biology &amp; medicine},
volume = {24},
number = {6},
pages = {885-893},
doi = {10.1016/s0891-5849(97)00363-8},
pmid = {9607597},
issn = {0891-5849},
mesh = {Blotting, Southern ; Cell Division/genetics/physiology ; Cell Line ; Cellular Senescence ; DNA, Single-Stranded/chemistry ; Fetus ; Fibroblasts/metabolism ; Humans ; Models, Biological ; Single-Strand Specific DNA and RNA Endonucleases/metabolism ; Telomere/*chemistry/*genetics ; Time Factors ; },
abstract = {Telomere length in MRC-5 fibroblasts remains constant if the cells are proliferation-inhibited for up to 3 months by confluency. However, the apparent frequency of single-stranded sites in telomeres, measured as sensitivity to degradation by S1 nuclease, increases about fourfold during this extended inhibition of proliferation. After release of the cells, the frequency of telomeric single-stranded sites decreases to control values, and the telomere shortening rate increases about threefold as compared to controls proliferating without inhibition. This acceleration is transitory, the telomere shortening rate decreases to control values after about two population doublings after release. Finally, temporarily arrested fibroblast populations senesce at a lower cumulative population doubling level, but at about the same telomere length, as continuously proliferating controls. The data suggest that metabolic time-dependent single-strand degradation is a major cause of telomere shortening. They support the idea that telomere shortening plays an important role in triggering cellular senescence.},
}
@article {pmid9605755,
year = {1998},
author = {Hiraga, S and Ohnishi, T and Izumoto, S and Miyahara, E and Kanemura, Y and Matsumura, H and Arita, N},
title = {Telomerase activity and alterations in telomere length in human brain tumors.},
journal = {Cancer research},
volume = {58},
number = {10},
pages = {2117-2125},
pmid = {9605755},
issn = {0008-5472},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Astrocytoma/enzymology/genetics/pathology ; Brain Neoplasms/*enzymology/*genetics/mortality/pathology ; Child ; Child, Preschool ; Glioblastoma/enzymology/genetics/pathology ; Humans ; Infant ; Middle Aged ; Neoplasm Proteins/*metabolism ; Neuroectodermal Tumors, Primitive, Peripheral/enzymology/genetics/pathology ; Survival Analysis ; Telomerase/*metabolism ; Telomere/*genetics ; Tumor Cells, Cultured ; },
abstract = {Telomerase activity was examined in 170 human brain tumor tissues, and terminal restriction fragment (TRF) length was examined in 152 of the 170. Telomerase activity was detected in 61.7% (66 of 107) of the neuroepithelial tumors. However, the detection rates of telomerase activity were widely different for different histopathological entities. In the case of astrocytic tumors, the detection rate was 20.0% (3 of 15) for grade II astrocytomas, 40.0% (6 of 15) for anaplastic astrocytomas, and 72.3% (34 of 47) for glioblastomas. The mean TRF length of the tumors with telomerase activity was significantly shorter than that of the tumors with undetectable telomerase activity for each tumor entity. In grade II and anaplastic astrocytomas, telomerase activity was an indicator of early histological progression and reduced survival of the patients, although there was no difference in MIB-1 staining indices between the tumors with and without telomerase activity at onset. In three astrocytic tumors, concurrence of telomere shortening and telomerase reactivation was observed at recurrence; in these cases, tumors progressed to a higher grade. Ten glioblastomas that progressed from lower-grade tumors exhibited telomerase activity, and their TRF lengths were reduced in 80% (8 of 10). In contrast, telomerase activity was detected in only 63.3% (19 of 30; P < 0.05) and the TRF length remained compatible with normal values in 56.7% (17 of 30; P < 0.01) of de novo glioblastomas. Thus, telomerase activity strongly correlated with potential tumor progression in the short term as well as with progression itself of the astrocytic tumors, whereas telomeres may still have been in the process of shortening in some of the de novo glioblastomas. High telomerase activity was exhibited in all primitive neuroectodermal tumors, anaplastic oligoastrocytomas, neuroblastomas, and oligodendrogliomas. TRF length was reduced in the majority (14 of 15) of three previously high-grade tumors, whereas it was compatible with that of normal brain tissues in the oligodendrogliomas, suggesting that telomerase activity with shortened telomeres correlates with the aggressive growth of high-grade neuroepithelial tumors. Tumor cell lines could be established from 17.2% (5 of 29) of neuroepithelial tumors with telomerase activity but not from tumors without this activity (P < 0.05), suggesting that telomerase reactivation is an essential event in the neuroepithelial cell immortalization in vitro. In nonneuroepithelial tumors, telomerase activity was detected in malignant tumors, such as germ cell tumors, lymphomas, metastatic adenocarcinomas, hemangiopericytomas, and an anaplastic meningioma. In contrast, such activity was not detected in benign tumors, including meningiomas, pituitary adenomas, hemangioblastomas and schwannomas, except for one hemangioblastoma that recurred four times and displayed malignant features at the fourth recurrence. These findings suggest that telomerase activity can be an index of malignant potential or malignancy itself in nonneuroepithelial brain tumors.},
}
@article {pmid9564735,
year = {1998},
author = {Ide, T},
title = {[Recent progress in telomere/telomerase research].},
journal = {Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics},
volume = {35},
number = {1},
pages = {10-17},
doi = {10.3143/geriatrics.35.10},
pmid = {9564735},
issn = {0300-9173},
mesh = {Aging/*physiology ; Cell Survival ; DNA/analysis ; Humans ; Neoplasms/metabolism ; Telomerase/*physiology ; Telomere/metabolism/*physiology ; },
}
@article {pmid9512546,
year = {1998},
author = {König, P and Fairall, L and Rhodes, D},
title = {Sequence-specific DNA recognition by the myb-like domain of the human telomere binding protein TRF1: a model for the protein-DNA complex.},
journal = {Nucleic acids research},
volume = {26},
number = {7},
pages = {1731-1740},
pmid = {9512546},
issn = {0305-1048},
mesh = {Amino Acid Sequence ; Base Sequence ; Binding Sites ; DNA/*chemistry/*metabolism ; DNA Footprinting ; DNA-Binding Proteins/*chemistry/*metabolism ; Deoxyribonuclease I ; Humans ; Models, Molecular ; Molecular Sequence Data ; Nuclear Proteins/chemistry/metabolism ; Nucleic Acid Conformation ; Oligodeoxyribonucleotides/chemistry/metabolism ; Protein Conformation ; Proto-Oncogene Proteins/chemistry ; Proto-Oncogene Proteins c-myb ; Repetitive Sequences, Nucleic Acid ; Sequence Alignment ; Sequence Homology, Amino Acid ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1 ; Trans-Activators/chemistry ; },
abstract = {Telomeres consist of tandem arrays of short G-rich sequence motifs packaged by specific DNA binding proteins. In humans the double-stranded telomeric TTAGGG repeats are specifically bound by TRF1 and TRF2. Although telomere binding proteins from evolutionarily distant species are not sequence homologues, they share a Myb-like DNA binding motif. Here we have used gel retardation, primer extension and DNase I footprinting analyses to define the binding site of the isolated Myb-like domain of TRF1 and present a three-dimensional model for its interaction with human telomeric DNA. Our results suggest that the Myb-like domain of TRF1 recognizes a binding site centred on the sequence GGGTTA and that its DNA binding mode is similar to that of the homeodomain-like motifs of the yeast telomere binding protein RAP1. The implications of these findings for recognition of telomeric DNA in general are discussed.},
}
@article {pmid9585510,
year = {1998},
author = {Froelich-Ammon, SJ and Dickinson, BA and Bevilacqua, JM and Schultz, SC and Cech, TR},
title = {Modulation of telomerase activity by telomere DNA-binding proteins in Oxytricha.},
journal = {Genes &amp; development},
volume = {12},
number = {10},
pages = {1504-1514},
pmid = {9585510},
issn = {0890-9369},
support = {GM28039/GM/NIGMS NIH HHS/United States ; R01 GM028039/GM/NIGMS NIH HHS/United States ; GM17155/GM/NIGMS NIH HHS/United States ; AG11636/AG/NIA NIH HHS/United States ; F32 GM017155/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; DNA Nucleotidylexotransferase/metabolism ; DNA, Protozoan/*metabolism ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/*metabolism ; DNA-Directed DNA Polymerase/metabolism ; Electrophoresis, Agar Gel ; Macromolecular Substances ; Models, Genetic ; Oxytricha/genetics/*metabolism ; Protein Binding ; Protozoan Proteins/antagonists &amp; inhibitors/*metabolism ; Repetitive Sequences, Nucleic Acid ; Species Specificity ; Telomerase/antagonists &amp; inhibitors/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomere proteins protect the chromosomal terminus from nucleolytic degradation and end-to-end fusion, and they may contribute to telomere length control and the regulation of telomerase. The current studies investigate the effect of Oxytricha single-stranded telomere DNA-binding protein subunits alpha and beta on telomerase elongation of telomeric DNA. A native agarose gel system was used to evaluate telomere DNA-binding protein complex composition, and the ability of telomerase to use these complexes as substrates was characterized. Efficient elongation occurred in the presence of the alpha subunit. Moreover, the alpha-DNA cross-linked complex was a substrate for telomerase. At higher alpha concentrations, two alpha subunits bound to the 16-nucleotide single-stranded DNA substrate and rendered it inaccessible to telomerase. The formation of this alpha . DNA . alpha complex may contribute to regulation of telomere length. The alpha . beta . DNA ternary complex was not a substrate for telomerase. Even when telomerase was prebound to telomeric DNA, the addition of alpha and beta inhibited elongation, suggesting that these telomere protein subunits have a greater affinity for the DNA and are able to displace telomerase. In addition, the ternary complex was not a substrate for terminal deoxynucleotidyltransferase. We conclude that the telomere protein inhibits telomerase by rendering the telomeric DNA inaccessible, thereby helping to maintain telomere length.},
}
@article {pmid9600076,
year = {1998},
author = {Gomez, DE and Tejera, AM and Olivero, OA},
title = {Irreversible telomere shortening by 3'-azido-2',3'-dideoxythymidine (AZT) treatment.},
journal = {Biochemical and biophysical research communications},
volume = {246},
number = {1},
pages = {107-110},
doi = {10.1006/bbrc.1998.8555},
pmid = {9600076},
issn = {0006-291X},
mesh = {Antimetabolites, Antineoplastic/*pharmacology ; Cellular Senescence/drug effects/genetics/physiology ; DNA/genetics/metabolism ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Repetitive Sequences, Nucleic Acid ; Reverse Transcriptase Inhibitors/*pharmacology ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects/*genetics/metabolism ; Zidovudine/*pharmacology ; },
abstract = {Telomeres shorten by 30 to 50 bp with each cell division. Germ line, tumor and stem cells overcome progressive shortening by elongating their telomeres with telomerase. Previously we demonstrated that 3'-azido-2',3'-dideoxythymidine (AZT), incorporates into telomeric DNA. To determine if telomeric AZT incorporation was a telomerase mediated phenomenon, we subjected tumor cells to long-term AZT exposure. Here we report the shortening of the telomeric sequences of HeLa cells cultured with 800 microM AZT for 15 passages. Southern blots of HeLa DNA cultured with AZT and digested with SAU 3AI, Alu I, and Rsa I revealed a progressive shortening of the telomeric repeats when probed with a human biotinylated telomeric probe. The shortened telomeric repeats did not elongate after culturing without AZT for an additional 25 passages. No evidence of senescence could be detected.},
}
@article {pmid9598723,
year = {1998},
author = {Xiang, F and Zhang, Z and Clarke, A and Joseluiz, P and Sakkubai, N and Sarojini, B and Delozier-Blanchet, CD and Hansmann, I and Edström, L and Anvret, M},
title = {Chromosome mapping of Rett syndrome: a likely candidate region on the telomere of Xq.},
journal = {Journal of medical genetics},
volume = {35},
number = {4},
pages = {297-300},
pmid = {9598723},
issn = {0022-2593},
mesh = {Chromosome Mapping ; Female ; Humans ; Male ; Microsatellite Repeats ; Pedigree ; Rett Syndrome/*genetics ; *Telomere ; *X Chromosome ; },
abstract = {Rett syndrome (RS) is a disease of neurological development. First reported 30 years ago in 1966, its biological and genetic basis remains obscure. RS is commonly thought of as an X linked dominant disorder lethal to hemizygous males. The few familial cases would arise through mosaicism or because of occasional females failing to manifest the disorder through skewed X inactivation in relevant cell types. We have one family where the mother and daughter are affected with RS, and which can be explained according to this hypothesis. If the alternative proposal of Thomas (1996) is correct, that the lack of males affected by such disorders is the result of a high male to female ratio of germline mutations rather than of gestational lethality, then the RS gene should be located on the grandpaternal chromosome. Genomic screening with markers covering the whole X chromosome has been performed. Studies using multiple informative markers indicate that the RS locus is likely to be located close to one of the X chromosome telomeres. Further investigations in eight additional families suggest the most likely region for the RS gene to be is the distal part of Xq (Xq28).},
}
@article {pmid9597006,
year = {1998},
author = {Jones, CJ and Soley, A and Skinner, JW and Gupta, J and Haughton, MF and Wyllie, FS and Schlumberger, M and Bacchetti, S and Wynford-Thomas, D},
title = {Dissociation of telomere dynamics from telomerase activity in human thyroid cancer cells.},
journal = {Experimental cell research},
volume = {240},
number = {2},
pages = {333-339},
doi = {10.1006/excr.1998.3944},
pmid = {9597006},
issn = {0014-4827},
mesh = {Humans ; Telomerase/*metabolism ; *Telomere ; Thyroid Gland ; Tumor Cells, Cultured ; },
abstract = {Prevention of telomere erosion through acquisition of telomerase activity is thought to be an essential mechanism in most human cancer cells for avoidance of cellular senescence and crisis. It has been generally assumed that once telomerase has been activated, no further telomere shortening should ensue. We show here, however, that a much more complex pattern of telomere dynamics can exist in telomerase-positive immortal cancer cells. Using a panel of subclones derived from a human thyroid cancer cell line, K1E7, we found that some clones show persistent decline in mean telomere restriction fragment (TRF) length by up to 2 kb over 450 population doublings (pd), despite sustained high telomerase activity (as assessed by the in vitro "TRAP" assay). TRF length subsequently stabilized at around 5 kb, but with no corresponding increase in telomerase activity. One clone showed an even more unexpected biphasic time course, with the mean TRF length initially increasing by 1.5 kb over 90 pd, before "plateauing" and then returning over a similar period to its original value, again without any correlation to TRAP activity. Such dissociations between telomere dynamics and telomerase activity support the existence of additional controls on telomere length in the intact cell. Our observations are consistent with current negative-feedback models of telomere length regulation by telomere binding proteins and these cell lines should prove useful experimental tools for their further evaluation.},
}
@article {pmid9545262,
year = {1998},
author = {Vega-Palas, MA and Venditti, S and Di Mauro, E},
title = {Heterochromatin organization of a natural yeast telomere. Changes of nucleosome distribution driven by the absence of Sir3p.},
journal = {The Journal of biological chemistry},
volume = {273},
number = {16},
pages = {9388-9392},
doi = {10.1074/jbc.273.16.9388},
pmid = {9545262},
issn = {0021-9258},
mesh = {Chromosomes, Fungal/chemistry ; DNA, Fungal/chemistry ; Fungal Proteins/*genetics ; Heterochromatin/chemistry/*genetics ; Micrococcal Nuclease ; Nucleosomes/genetics ; *Promoter Regions, Genetic ; Repetitive Sequences, Nucleic Acid ; *Retroelements ; Saccharomyces cerevisiae/*genetics ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Telomere/chemistry/*genetics ; Trans-Activators/*genetics ; },
abstract = {We have defined the in vivo heterochromatin structure of the left telomere of Saccharomyces cerevisiae chromosome III (LIII). Analysis of heterochromatin of a single telomere was so far lacking, due to the difficulties intrinsic to the highly repetitive nature of telomeric sequences. In LIII, the terminal (C1-3A)n repetitive sequences are followed by a complete X element and by the single copy Ty5-1 retrotransposon. Both the telosome and the X element exhibit overall resistance to micrococcal nuclease digestion reflecting their tight chromatin structure organization. The X element contains protein complexes and irregularly distributed but well localized nucleosomes. In contrast, a regular array of phased nucleosomes is associated with the promoter region of Ty5-1 and with the more centromere-proximal sequences. The lack of a structural component of yeast telomeres, the SIR3 protein, does not alter the overall tight organization of the X element but causes a nucleosome rearrangement within the promoter region of Ty5-1 and releases Ty5-1 silencing. Thus, Sir3p links the modification of the heterochromatin structure with loss of transcriptional silencing.},
}
@article {pmid9587365,
year = {1997},
author = {Raymond, E and Faivre, S and Dieras, V and Von Hoff, D},
title = {[Inhibition of telomeres and telomerase. Seeking for new anticancer drugs].},
journal = {Bulletin du cancer},
volume = {84},
number = {12},
pages = {1123-1133},
pmid = {9587365},
issn = {0007-4551},
mesh = {Animals ; Antineoplastic Agents/chemistry/*pharmacology ; DNA, Neoplasm ; Drug Resistance, Neoplasm ; Enzyme Inhibitors/chemistry/*pharmacology ; Humans ; In Vitro Techniques ; Mice ; Models, Molecular ; Neoplasms/drug therapy/enzymology/genetics/pathology ; Neoplasms, Experimental/drug therapy/*genetics ; Nucleoproteins/drug effects ; Reverse Transcriptase Inhibitors/chemistry/pharmacology ; Telomerase/*antagonists &amp; inhibitors/genetics/metabolism ; Telomere/*drug effects/genetics ; },
abstract = {Human telomeres are guanine-rich regions (TTAGGG) located at the end of chromosomes that protect them against aberrant recombination and protect DNA from exonuclease degradation. Telomeres maintenance is performed by telomerase, a RNA-dependent DNA polymerase. Telomerase is over-expressed in a large number of cancers that have short telomeres whereas it is not expressed in somatic cells that have long telomeres. Therefore, this differential gives a rational for further evaluation of telomerase and telomeres as targets for identification of new anticancer drugs. Current strategies aim to identify new drugs with specific activity against telomerase and telomeres. In this review we will discuss the biological and clinical approaches as well as relevant tumor models for studying the biological effects of telomerase inhibition and telomere targeting in vitro and in vivo.},
}
@article {pmid9587191,
year = {1998},
author = {Wolthers, KC and Miedema, F},
title = {Telomeres and HIV-1 infection: in search of exhaustion.},
journal = {Trends in microbiology},
volume = {6},
number = {4},
pages = {144-147},
doi = {10.1016/s0966-842x(98)01233-5},
pmid = {9587191},
issn = {0966-842X},
mesh = {Biomarkers ; CD4-Positive T-Lymphocytes/*immunology/virology ; CD8-Positive T-Lymphocytes/*immunology/virology ; HIV Infections/*genetics/*immunology/pathology/virology ; HIV-1/*physiology ; Humans ; *Telomere ; },
abstract = {Telomere length analysis could be helpful in determining if exhaustion and replicative senescence are involved in HIV-1 pathogenesis. Evidence that CD8+ T cells have shorter telomeres may point towards an increased turnover of CD8+ T cells and exhaustion of the CD8+ T-cell responses in HIV-1 infection. In CD4+ T cells, the relationship between telomere length and turnover remains controversial; however, telomere length analysis argues against exhaustion of CD4+ T cells.},
}
@article {pmid9576930,
year = {1998},
author = {Frenck, RW and Blackburn, EH and Shannon, KM},
title = {The rate of telomere sequence loss in human leukocytes varies with age.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {95},
number = {10},
pages = {5607-5610},
pmid = {9576930},
issn = {0027-8424},
support = {R01 GM026259/GM/NIGMS NIH HHS/United States ; R37 GM026259/GM/NIGMS NIH HHS/United States ; GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*physiology ; Cellular Senescence ; Child ; Child, Preschool ; Humans ; In Vitro Techniques ; Infant ; Infant, Newborn ; Kinetics ; Leukocytes/*physiology ; Middle Aged ; Pedigree ; Telomere/*physiology/ultrastructure ; },
abstract = {A gradual loss of telomeric repeat sequences with aging previously has been noted in normal adult tissues, and this process has been implicated in cell senescence. No data exist that address the rate of telomere shortening in normal human cells within families or early in life. To address these questions, we measured telomere lengths in peripheral blood leukocytes (PBLs) from 75 members of 12 families and in a group of unrelated healthy children who were 5-48 months old. Here we report the surprising observation that rates of telomere attrition vary markedly at different ages. Telomeric repeats are lost rapidly (at a rate of >1 kilobase per year) from the PBLs of young children, followed by an apparent plateau between age 4 and young adulthood, and by gradual attrition later in life. These data suggest that the loss of telomeric repeats in hematopoietic cells is a dynamic process that is differentially regulated in young children and adults. Our results have implications for current models of how telomeric sequences are lost in normal somatic cells and suggest that PBLs are an excellent tissue to investigate how this process is controlled.},
}
@article {pmid9584612,
year = {1998},
author = {Hiraoka, Y and Henderson, E and Blackburn, EH},
title = {Not so peculiar: fission yeast telomere repeats.},
journal = {Trends in biochemical sciences},
volume = {23},
number = {4},
pages = {126},
doi = {10.1016/s0968-0004(98)01176-1},
pmid = {9584612},
issn = {0968-0004},
mesh = {Base Sequence ; DNA, Fungal/genetics ; Repetitive Sequences, Nucleic Acid ; Schizosaccharomyces/*genetics ; Telomere/genetics ; },
}
@article {pmid9583680,
year = {1998},
author = {Filatov, L and Golubovskaya, V and Hurt, JC and Byrd, LL and Phillips, JM and Kaufmann, WK},
title = {Chromosomal instability is correlated with telomere erosion and inactivation of G2 checkpoint function in human fibroblasts expressing human papillomavirus type 16 E6 oncoprotein.},
journal = {Oncogene},
volume = {16},
number = {14},
pages = {1825-1838},
doi = {10.1038/sj.onc.1201711},
pmid = {9583680},
issn = {0950-9232},
support = {CA42765/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line ; Cellular Senescence/genetics ; Chromosome Aberrations/*genetics ; Chromosomes, Human, Pair 4 ; Chromosomes, Human, Pair 6 ; Fibroblasts/enzymology/metabolism ; G2 Phase/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Oncogene Proteins, Viral/biosynthesis/*genetics ; Papillomaviridae/*genetics ; Polymorphism, Restriction Fragment Length ; *Repressor Proteins ; Spindle Apparatus/genetics ; Telomerase/biosynthesis ; Telomere/*genetics/pathology ; Translocation, Genetic/genetics ; Tumor Suppressor Protein p53/drug effects/metabolism ; beta-Galactosidase/analysis ; },
abstract = {Cell cycle checkpoints and tumor suppressor gene functions appear to be required for the maintenance of a stable genome in proliferating cells. In this study chromosomal destabilization was monitored in relation to telomere structure, lifespan control and G2 checkpoint function. Replicative senescence was inactivated in secondary cultures of human skin fibroblasts by expressing the human papillomavirus type 16 (HPV-16) E6 oncoprotein to inactivate p53. Chromosome aberrations were enumerated during in vitro aging of isogenic control (F5neo) and HPV-16E6-expressing (F5E6) fibroblasts. We found that structural and numerical aberrations in chromosomes were significantly increased in F5E6 cells during aging in vitro and fluorescence in situ hybridization (FISH) analysis using chromosome-specific probes demonstrated the occurrence of rearrangements involving chromosome 4 and 6 in genetically unstable F5E6 cells. Flow cytometry and karyotypic analyses revealed increased polyploidy and aneuploidy in F5E6 cells only at passages > 16, although these cells displayed defective mitotic spindle checkpoint function associated with inactivation of p53 at passages 5 and 16. G2 checkpoint function was confirmed to be gradually but progressively inactivated during in vitro aging of E6-expressing cells. Aging of F5neo fibroblasts was documented during in vitro passaging by induction of a senescence-associated marker, pH 6.0 lysosomal beta-galactosidase. F5E6 cells displayed extension of in vitro lifespan and did not induce beta-galactosidase at high passage. Erosion of telomeres during in vitro aging of telomerase-negative F5neo cells was demonstrated by Southern hybridization and by quantitative FISH analysis on an individual cell level. Telomeric signals diminished continuously as F5neo cells aged in vitro being reduced by 80% near the time of replicative senescence. Telomeric signals detected by FISH also decreased continuously during aging of telomerase-negative F5E6 cells, but telomeres appeared to be stabilized at passage 34 when telomerase was expressed. Chromosomal instability in E6-expressing cells was correlated (P < 0.05) with both loss of telomeric signals and inactivation of G2 checkpoint function. The results suggest that chromosomal stability depends upon a complex interaction among the systems of telomere length maintenance and cell cycle checkpoints.},
}
@article {pmid9582937,
year = {1998},
author = {Rudenko, G and Cross, M and Borst, P},
title = {Changing the end: antigenic variation orchestrated at the telomeres of African trypanosomes.},
journal = {Trends in microbiology},
volume = {6},
number = {3},
pages = {113-116},
doi = {10.1016/s0966-842x(97)01200-6},
pmid = {9582937},
issn = {0966-842X},
mesh = {Animals ; Antigenic Variation/*genetics ; Genes, Protozoan/*genetics ; Telomere/*immunology ; Trypanosoma brucei brucei/*genetics/immunology ; Variant Surface Glycoproteins, Trypanosoma/*genetics/immunology ; },
abstract = {African trypanosomes express the gene encoding their variant surface glycoprotein (VSG) surface coat from one of many telomeric expression sites. This genomic location at chromosome ends not only allows easy exchange of VSG gene cassettes using various mechanisms of DNA recombination but also appears to play a role in VSG gene expression site control.},
}
@article {pmid9543012,
year = {1998},
author = {Gortner, G and Nenno, M and Weising, K and Zink, D and Nagl, W and Kahl, G},
title = {Chromosomal localization and distribution of simple sequence repeats and the Arabidopsis-type telomere sequence in the genome of Cicer arietinum L.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {6},
number = {2},
pages = {97-104},
pmid = {9543012},
issn = {0967-3849},
mesh = {Arabidopsis/genetics ; Chromosome Mapping ; Chromosomes/*genetics ; Dinucleotide Repeats/genetics ; Fabaceae/*genetics ; In Situ Hybridization, Fluorescence/*methods ; Oligonucleotide Probes ; Pisum sativum ; *Plants, Medicinal ; Repetitive Sequences, Nucleic Acid/*genetics ; Seeds ; Telomere/*genetics ; },
abstract = {We used fluorescence in situ hybridization to probe the physical organization of five simple sequence repeat motifs and the Arabidopsis-type telomeric repeat in metaphase chromosomes and interphase nuclei of chickpea (Cicer arietinum L.). Hybridization signals were observed with the whole set of probes and on all chromosomes, but the distribution and intensity of signals varied depending on the motif. On root-tip metaphase chromosomes, CA and GATA repeats were mainly restricted to centromeric areas, with additional GATA signals along some chromosomes. TA, A and AAC repeats were organized in a more dispersed manner, with centromeric regions being largely excluded. In interphase nuclei of the inner integument, CA and GATA signals predominantly occurred in the heterochromatic endochromocentres, whereas the other motifs were found both in eu- and heterochromatin. The distribution of the Arabidopsis-type telomeric repeat (TTTAGGG)n on metaphase chromosomes was found to be quite exceptional. One major cluster of repeats was spread along the short arm of chromosome B, whereas a second, weaker signal occurred interstitially on chromosome A. Only faint and inconsistent hybridization signals were visualized with the same probe at the chromosomal termini.},
}
@article {pmid9539717,
year = {1998},
author = {Ishibashi, T and Lippard, SJ},
title = {Telomere loss in cells treated with cisplatin.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {95},
number = {8},
pages = {4219-4223},
pmid = {9539717},
issn = {0027-8424},
support = {R01 CA034992/CA/NCI NIH HHS/United States ; R37 CA034992/CA/NCI NIH HHS/United States ; CA34992/CA/NCI NIH HHS/United States ; },
mesh = {*Apoptosis ; Base Sequence ; Cell Cycle/*drug effects ; Cell Division/drug effects ; Cell Survival/drug effects ; Cisplatin/*toxicity ; Cross-Linking Reagents ; DNA Replication/drug effects ; HeLa Cells ; Humans ; Models, Genetic ; Polymerase Chain Reaction ; Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; S Phase ; Telomere/chemistry/*drug effects/genetics ; },
abstract = {Telomeres play an important role in the immortalization of proliferating cells. The long tandem repeats of 5'-TTAGGG-3' sequences in human telomeres are potential targets for the anticancer drug cisplatin, which forms mainly intrastrand d(GpG) and d(ApG) cross-links on DNA. The present study reveals that telomeres in cisplatin-treated HeLa cells are markedly shortened and degraded. A dose that killed 61% of the cells but allowed one round of cell division resulted in shortened telomeres before the induction of apoptosis. Higher doses of cisplatin halted cell cycle progression during the first S phase and triggered apoptosis followed by degradation of telomere repeats. A model in which both cell division with incomplete replication and induction of apoptosis by cisplatin could occur was devised to explain the drug-induced telomere loss.},
}
@article {pmid9520442,
year = {1998},
author = {Danilevskaya, ON and Tan, C and Wong, J and Alibhai, M and Pardue, ML},
title = {Unusual features of the Drosophila melanogaster telomere transposable element HeT-A are conserved in Drosophila yakuba telomere elements.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {95},
number = {7},
pages = {3770-3775},
pmid = {9520442},
issn = {0027-8424},
support = {R01 GM050315/GM/NIGMS NIH HHS/United States ; R56 GM050315/GM/NIGMS NIH HHS/United States ; GM 50315/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cloning, Molecular ; Conserved Sequence ; DNA Transposable Elements/*genetics ; Drosophila/*genetics ; *Drosophila Proteins ; Drosophila melanogaster/*genetics ; *Gene Products, gag ; Insect Proteins/*genetics ; Molecular Sequence Data ; Sequence Analysis ; Telomere/*genetics ; },
abstract = {HeT-A was the first transposable element shown to have a bona fide role in chromosome structure, maintenance of telomeres in Drosophila melanogaster. HeT-A has hallmarks of non-long-terminal-repeat (non-LTR) retrotransposable elements but also has several unique features. We have now isolated HeT-A elements from Drosophila yakuba, showing that the retrotransposon mechanism of telomere maintenance predates the separation of D. melanogaster and D. yakuba (5-15 million years ago). HeT-A elements from the two species show significant sequence divergence, yet unusual features seen in HeT-Amel are conserved in HeT-Ayak. In both species, HeT-A elements are found in head-to-tail tandem arrays in telomeric heterochromatin. In both species, nearly half of the HeT-A sequence is noncoding and shows a distinctive imperfect repeat pattern of A-rich segments. Neither element encodes reverse transcriptase. The HeT-Amel promoter appears to be intermediate between the promoters of non-LTR and of LTR retrotransposons. The HeT-Ayak promoter shows similar features. HeT-Amel has a frameshift within the coding region. HeT-Ayak does not require a frameshift but shows conservation of the polypeptide sequence of the frameshifted product of D. melanogaster.},
}
@article {pmid9572143,
year = {1998},
author = {Cooper, JP and Watanabe, Y and Nurse, P},
title = {Fission yeast Taz1 protein is required for meiotic telomere clustering and recombination.},
journal = {Nature},
volume = {392},
number = {6678},
pages = {828-831},
doi = {10.1038/33947},
pmid = {9572143},
issn = {0028-0836},
mesh = {Chromosomes, Fungal/physiology ; DNA-Binding Proteins/*physiology ; Gene Deletion ; Humans ; Meiosis/genetics/*physiology ; Mitosis/physiology ; Recombination, Genetic ; Schizosaccharomyces/*genetics/physiology ; *Schizosaccharomyces pombe Proteins ; Spindle Apparatus/physiology ; *Telomere/physiology ; *Telomere-Binding Proteins ; },
abstract = {The alignment of homologous chromosomes during meiosis is essential for their recombination and segregation. Telomeres form and protect the ends of eukaryotic linear chromosomes, and are composed of tandem repeats of a simple DNA sequence and the proteins that bind to these repeats. A role for telomeres in meiosis was suspected from observations of telomere clustering in meiotic cells, and has now been supported experimentally by the dramatic rearrangement of telomere locations during premeiotic stages in fission yeast. Here we show that the fission yeast telomere protein, Taz1, is required for stable association between telomeres and spindle pole bodies during meiotic prophase. In the absence of Taz1, telomere clustering at the spindle pole bodies is disrupted, meiotic recombination is reduced, and both spore viability and the ability of zygotes to re-enter mitosis are impaired to a level that would be expected if chromosome segregation were occurring randomly. Such telomeric association mediated by telomere-specific proteins may also be important for proper chromosome alignment and recombination during meiosis in humans.},
}
@article {pmid9572142,
year = {1998},
author = {Nimmo, ER and Pidoux, AL and Perry, PE and Allshire, RC},
title = {Defective meiosis in telomere-silencing mutants of Schizosaccharomyces pombe.},
journal = {Nature},
volume = {392},
number = {6678},
pages = {825-828},
doi = {10.1038/33941},
pmid = {9572142},
issn = {0028-0836},
mesh = {Chromosomes, Fungal/physiology ; Fungal Proteins/genetics ; *Gene Expression Regulation, Fungal ; Meiosis/*genetics ; Mutation ; Prophase ; Recombination, Genetic ; Schizosaccharomyces/cytology/*genetics ; Spindle Apparatus/physiology ; *Telomere ; Transcription, Genetic ; },
abstract = {During meiotic prophase, chromosomes frequently adopt a bouquet-like arrangement, with their telomeres clustered close to the nuclear periphery. A dramatic example of this occurs in the fission yeast, Schizosaccharomyces pombe, where all telomeres aggregate adjacent to the spindle pole body (SPB). Nuclei then undergo rapid traverses of the cell, known as 'horsetail' movement, which is led by the SPB dragging telomeres and chromosomes behind. This process may initiate or facilitate chromosome pairing before recombination and meiosis. With the aim of identifying components involved in telomere structure and function, we report here the isolation of S. pombe mutants defective in the ability to impose transcriptional silencing on genes placed near telomeres. Two of these mutants, lot2-s17 and lot3-uv3, also display a dramatic lengthening of telomeric repeats. lot3-uv3 carries a mutation in Taz1, a telomere-binding protein containing a Myb-like motif similar to two human telomere-binding proteins. Meiosis is aberrant in these mutant yeast strains, and our analysis demonstrates a decreased association of telomeres with the SPB in meiotic prophase. This results in defective 'horsetail' movement, a significant reduction in recombination, low spore viability and chromosome missegregation through meiosis.},
}
@article {pmid9490802,
year = {1998},
author = {Kota, RS and Runge, KW},
title = {The yeast telomere length regulator TEL2 encodes a protein that binds to telomeric DNA.},
journal = {Nucleic acids research},
volume = {26},
number = {6},
pages = {1528-1535},
doi = {10.1093/nar/26.6.1528},
pmid = {9490802},
issn = {0305-1048},
support = {R01 GM050752/GM/NIGMS NIH HHS/United States ; GM50752/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Binding Sites/genetics ; Carrier Proteins/genetics ; DNA Methylation ; DNA, Fungal/chemistry/genetics/*metabolism ; DNA-Binding Proteins/*genetics/*metabolism ; Fungal Proteins/*genetics/*metabolism ; Genes, Fungal ; Maltose-Binding Proteins ; Molecular Sequence Data ; Recombinant Fusion Proteins/genetics/metabolism ; Saccharomyces cerevisiae/*genetics/*metabolism ; *Saccharomyces cerevisiae Proteins ; Shelterin Complex ; Species Specificity ; Telomere/genetics/*metabolism ; *Telomere-Binding Proteins ; *Transcription Factors ; },
abstract = {TEL2 is required for telomere length regulation and viability in Saccharomyces cerevisiae. To investigate the mechanism by which Tel2p regulates telomere length, the majority (65%) of the TEL2 ORF was fused to the 3'-end of the gene for maltose binding protein, expressed in bacteria and the purified protein used in DNA binding studies. Rap1p, the major yeast telomere binding protein, recognizes a 13 bp duplex site 5'-GGTGTGTGGGTGT-3' in yeast telomeric DNA with high affinity. Gel shift experiments revealed that the MBP-Tel2p fusion binds the double-stranded yeast telomeric Rap1p site in a sequence-specific manner. Analysis of mutated sites showed that MBP-Tel2p could bind 5'-GTGTGTGG-3' within this 13 bp site. Methylation interference analysis revealed that Tel2p contacts the 5'-terminal guanine in the major groove. MBP-Tel2p did not bind duplex telomeric DNA repeats from vertebrates, Tetrahymena or Oxytricha. These results suggest that Tel2p is a DNA binding protein that recognizes yeast telomeric DNA.},
}
@article {pmid9490797,
year = {1998},
author = {Lue, NF and Xia, J},
title = {Species-specific and sequence-specific recognition of the dG-rich strand of telomeres by yeast telomerase.},
journal = {Nucleic acids research},
volume = {26},
number = {6},
pages = {1495-1502},
pmid = {9490797},
issn = {0305-1048},
mesh = {Animals ; Base Composition ; Base Sequence ; Binding Sites/genetics ; Humans ; In Vitro Techniques ; Kinetics ; Protein Conformation ; Saccharomyces cerevisiae/*genetics/*metabolism ; Species Specificity ; Substrate Specificity ; Telomerase/chemistry/*metabolism ; Telomere/*genetics/*metabolism ; Tetrahymena/enzymology ; },
abstract = {A gel mobility shift assay was developed to examine recognition of yeast telomeres by telomerase. An RNase-sensitive G-rich strand-specific binding activity can be detected in partially purified yeast telomerase fractions. The binding activity was attributed to telomerase, because it co-purifies with TLC1 RNA and telomerase activity over three different chromatographic steps and because the complex co-migrates with TLC1 RNA when subjected to electrophoresis through native gels. Analysis of the binding specificity of yeast telomerase indicates that it recognizes the G-rich strand of yeast telomeres with high affinity and specificity. The K d for the interaction is approximately 3 nM. Single-stranded G-rich telomeres from other species, such as human and Tetrahymena, though capable of being extended by yeast telomerase in polymerization assays at high concentrations, bind the enzyme with at least 100-fold lower affinities. The ability of a sequence to be bound tightly by yeast telomerase in vitro correlates with its ability to seed telomere formation in vivo. The implications of these findings for regulation of telomerase activity are discussed.},
}
@article {pmid9466997,
year = {1998},
author = {Gianfrancesco, F and Esposito, T and Montanini, L and Ciccodicola, A and Mumm, S and Mazzarella, R and Rao, E and Giglio, S and Rappold, G and Forabosco, A},
title = {A novel pseudoautosomal gene encoding a putative GTP-binding protein resides in the vicinity of the Xp/Yp telomere.},
journal = {Human molecular genetics},
volume = {7},
number = {3},
pages = {407-414},
doi = {10.1093/hmg/7.3.407},
pmid = {9466997},
issn = {0964-6906},
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Chromosome Mapping ; Cloning, Molecular ; Consensus Sequence ; Female ; GTP-Binding Proteins/biosynthesis/chemistry/*genetics ; *Gene Rearrangement ; Genetic Markers ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Molecular Sequence Data ; Muscle, Skeletal/metabolism ; Organ Specificity ; Polymerase Chain Reaction ; Sequence Alignment ; Sequence Homology, Amino Acid ; Species Specificity ; Telomere/*genetics ; *X Chromosome ; *Y Chromosome ; },
abstract = {We report the cloning of a novel Xp/Yp pseudoautosomal gene called PGPL , and demonstrate that PGPL , like other pseudoautosomal genes, escapes X inactivation and has a functional homologue on the Y chromosome. This gene is expressed in all the tissues examined and is highly conserved across several species. The PGPL gene encodes a protein of 442 amino acids and shows the consensus sequences of a series of motifs of the GTP-binding protein domain. Using fluorescence in situ hybridization analysis on normal males and on patients with rearrangements in the pseudoautosomal region, the gene was localized within 500 kb of the telomere. Further refinement using a cosmid contig of the region places this novel gene within 80-110 kb of the telomere, making this the most telomeric gene on the short arms of the sex chromosomes.},
}
@article {pmid9501072,
year = {1998},
author = {Vaziri, H and Benchimol, S},
title = {Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span.},
journal = {Current biology : CB},
volume = {8},
number = {5},
pages = {279-282},
doi = {10.1016/s0960-9822(98)70109-5},
pmid = {9501072},
issn = {0960-9822},
mesh = {Animals ; Catalysis ; Cells, Cultured ; Cellular Senescence ; *DNA Replication ; DNA-Binding Proteins ; Fibroblasts/enzymology ; Humans ; Protein Conformation ; Proteins/metabolism ; *RNA ; Retroviridae ; Telomerase/*metabolism ; Telomere/*metabolism ; Tetrahymena ; },
abstract = {Normal somatic cells have a finite life span [1] and lose telomeric DNA, present at the ends of chromosomes, each time they divide as a function of age in vivo or in culture [2-4]. In contrast, many cancer cells and cell lines established from tumours maintain their telomere length by activation of an RNA-protein complex called telomerase, an enzyme originally discovered in Tetrahymena [5], that synthesizes telomeric repeats [6-8]. These findings have led to the formation of the 'telomere hypothesis', which proposes that critical shortening of telomeric DNA due to the end-replication problem [9] is the signal for the initiation of cellular senescence [10,11]. In yeast, the EST2 gene product, the catalytic subunit of telomerase, is essential for telomere maintenance in vivo [12-14]. The recent cloning of the cDNA encoding the catalytic subunit of human telomerase (hTERT) [15,16] makes it possible to test the telomere hypothesis. In this study, we expressed hTERT in normal human diploid fibroblasts, which lack telomerase activity, to determine whether telomerase activity could be reconstituted leading to extension of replicative life span. Our results show that retroviral-mediated expression of hTERT resulted in functional telomerase activity in normal aging human cells. Moreover, reconstitution of telomerase activity in vivo led to an increase in the length of telomeric DNA and to extension of cellular life span. These findings provide direct evidence in support of the telomere hypothesis, indicating that telomere length is one factor that can determine the replicative life span of human cells.},
}
@article {pmid9501064,
year = {1998},
author = {Greider, CW},
title = {Telomeres and senescence: the history, the experiment, the future.},
journal = {Current biology : CB},
volume = {8},
number = {5},
pages = {R178-81},
doi = {10.1016/s0960-9822(98)70105-8},
pmid = {9501064},
issn = {0960-9822},
mesh = {Aging/*physiology ; Animals ; Humans ; Telomerase/metabolism ; Telomere/*physiology ; },
abstract = {Telomere length has been proposed to signal entry into cellular senescence. Expression of the human telomerase subunit, hTERT, in primary cells now shows that these cells bypass senescence.},
}
@article {pmid9482891,
year = {1998},
author = {van Leeuwen, F and Taylor, MC and Mondragon, A and Moreau, H and Gibson, W and Kieft, R and Borst, P},
title = {beta-D-glucosyl-hydroxymethyluracil is a conserved DNA modification in kinetoplastid protozoans and is abundant in their telomeres.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {95},
number = {5},
pages = {2366-2371},
pmid = {9482891},
issn = {0027-8424},
mesh = {Animals ; Base Sequence ; Conserved Sequence ; DNA, Protozoan/*chemistry/*genetics ; Eukaryota/*genetics ; Glucosides/*analysis ; Humans ; Insecta/parasitology ; Leishmania donovani/genetics ; Mammals/parasitology ; *Phylogeny ; Repetitive Sequences, Nucleic Acid ; Telomere/*genetics ; Trypanosoma brucei brucei/genetics ; Trypanosoma cruzi/genetics ; Uracil/*analogs &amp; derivatives/analysis ; },
abstract = {The unusual DNA base beta-D-glucosyl-hydroxymethyluracil, called "J, " replaces approximately 0.5-1% of Thy in DNA of African trypanosomes but has not been found in other organisms thus far. In Trypanosoma brucei, J is located predominantly in repetitive DNA, and its presence correlates with the silencing of telomeric genes. Using antibodies specific for J, we have developed sensitive assays to screen for J in a range of organisms and have found that J is not limited to trypanosomes that undergo antigenic variation but is conserved among Kinetoplastida. In all kinetoplastids tested, including the human pathogens Leishmania donovani and Trypanosoma cruzi, J was found to be abundantly present in the (GGGTTA)n telomere repeats. Outside Kinetoplastida, J was found only in Diplonema, a small phagotrophic marine flagellate, in which we also identified 5-MeCyt. Fractionation of Diplonema DNA showed that the two modifications are present in a common genome compartment, which suggests that they may have a similar function. Dinoflagellates appear to contain small amounts of modified bases that may be analogs of J. The evolutionary conservation of J in kinetoplastid protozoans suggests that it has a general function, repression of transcription or recombination, or a combination of both. T. brucei may have recruited J for the control of genes involved in antigenic variation.},
}
@article {pmid9526644,
year = {1998},
author = {Fu, G and Barker, DC},
title = {Rapid cloning of telomere-associated sequence using primer-tagged amplification.},
journal = {BioTechniques},
volume = {24},
number = {3},
pages = {386-390},
doi = {10.2144/98243bm10},
pmid = {9526644},
issn = {0736-6205},
mesh = {Animals ; Cloning, Molecular/methods ; DNA Primers ; DNA, Protozoan/isolation &amp; purification ; Leishmania/genetics ; Polymerase Chain Reaction/*methods ; Sequence Analysis, DNA/*methods ; Telomere/chemistry/*genetics ; },
}
@article {pmid9526498,
year = {1998},
author = {Kim, JH and Kim, WT and Chung, IK},
title = {Rice proteins that bind single-stranded G-rich telomere DNA.},
journal = {Plant molecular biology},
volume = {36},
number = {5},
pages = {661-672},
pmid = {9526498},
issn = {0167-4412},
mesh = {Animals ; Base Composition ; Base Sequence ; Binding Sites/genetics ; DNA, Single-Stranded/chemistry/*genetics/*metabolism ; DNA-Binding Proteins/isolation &amp; purification/*metabolism ; Humans ; In Vitro Techniques ; Oligodeoxyribonucleotides/genetics/metabolism ; Oligonucleotide Probes/genetics ; Oryza/metabolism ; Plant Proteins/isolation &amp; purification/*metabolism ; Protein Binding ; Repetitive Sequences, Nucleic Acid ; Sodium Chloride ; Telomere/*genetics/*metabolism ; },
abstract = {In this work, we have identified and characterized proteins in rice nuclear extracts that specifically bind the single-stranded G-rich telomere sequence. Three types of specific DNA-protein complexes (I, II, and III) were identified by gel retardation assays using synthetic telomere substrates consisting of two or more single-stranded TTTAGGG repeats and rice nuclear extracts. Since each complex has a unique biochemical property and differs in electrophoretic mobility, at least three different proteins interact with the G-rich telomere sequences. These proteins are called rice G-rich telomere binding protein (RGBP) and none of them show binding affinity to double-stranded telomere repeats or single-stranded C-rich sequence. Changing one or two G's to C's in the TTTAGGG repeats abolishes binding activity. RGBPs have a greatly reduced affinity for human and Tetrahymena telomeric sequence and do not efficiently bind the cognate G-rich telomere RNA sequence UUUAGGG. Like other telomere binding proteins, RGBPs are resistant to high salt concentrations. RNase sensitivity of the DNA-protein interaction. In this assay, we observed a novel complex (complex III) in gel retardation assays which did not alter the mobilities or the band intensities of the two pre-existing complexes (I and II). The complex III, in addition to binding to telomeric sequences, has a binding affinity to rice nuclear RNA, whereas two other complexes have a binding affinity to only single-stranded G-rich telomere DNA. Taken together, these studies suggest that RGBPs are new types of telomere-binding proteins that bind in vitro to single-stranded G-rich telomere DNA in the angiosperms.},
}
@article {pmid9487130,
year = {1998},
author = {Dahlen, M and Olsson, T and Kanter-Smoler, G and Ramne, A and Sunnerhagen, P},
title = {Regulation of telomere length by checkpoint genes in Schizosaccharomyces pombe.},
journal = {Molecular biology of the cell},
volume = {9},
number = {3},
pages = {611-621},
pmid = {9487130},
issn = {1059-1524},
mesh = {CDC2 Protein Kinase/genetics ; Cell Cycle/genetics ; Chromosomes, Fungal/*genetics/ultrastructure ; DNA Repair/genetics ; DNA Repair Enzymes ; DNA Replication/genetics ; DNA, Fungal/biosynthesis/genetics ; *DNA-Binding Proteins ; Endonucleases/genetics/metabolism ; Fungal Proteins/genetics/metabolism ; *Genes, Fungal ; Kinetics ; Mutation ; Potassium Channels/genetics ; Saccharomyces cerevisiae/genetics/metabolism/ultrastructure ; Saccharomyces cerevisiae Proteins ; Schizosaccharomyces/*genetics/metabolism/ultrastructure ; Schizosaccharomyces pombe Proteins ; Telomere/*genetics/ultrastructure ; Temperature ; },
abstract = {We have studied telomere length in Schizosaccharomyces pombe strains carrying mutations affecting cell cycle checkpoints, DNA repair, and regulation of the Cdc2 protein kinase. Telomere shortening was found in rad1, rad3, rad17, and rad26 mutants. Telomere lengths in previously characterized rad1 mutants paralleled the replication checkpoint proficiency of those mutants. In contrast, rad9, chk1, hus1, and cds1 mutants had intact telomeres. No difference in telomere length was seen in mutants affected in the regulation of Cdc2, whereas some of the DNA repair mutants examined had slightly longer telomeres than did the wild type. Overexpression of the rad1(+) gene caused telomeres to elongate slightly. The kinetics of telomere shortening was monitored by following telomere length after disruption of the rad1(+) gene; the rate was approximately 1 nucleotide per generation. Wild-type telomere length could be restored by reintroduction of the wild-type rad1(+) gene. Expression of the Saccharomyces cerevisiae RCK1 protein kinase gene, which suppresses the radiation and hydroxyurea sensitivity of Sz. pombe checkpoint mutants, was able to attenuate telomere shortening in rad1 mutant cells and to increase telomere length in a wild-type background. The functional effects of telomere shortening in rad1 mutants were assayed by measuring loss of a linear and a circular minichromosome. A minor increase in loss rate was seen with the linear minichromosome, and an even smaller difference compared with wild-type was detected with the circular plasmid.},
}
@article {pmid9521855,
year = {1998},
author = {Bryan, TM and Englezou, A and Dunham, MA and Reddel, RR},
title = {Telomere length dynamics in telomerase-positive immortal human cell populations.},
journal = {Experimental cell research},
volume = {239},
number = {2},
pages = {370-378},
doi = {10.1006/excr.1997.3907},
pmid = {9521855},
issn = {0014-4827},
mesh = {Cell Transformation, Neoplastic/*genetics ; Cellular Senescence ; Chromosomes, Human/ultrastructure ; Clone Cells ; DNA, Neoplasm/analysis ; HeLa Cells ; Humans ; Neoplasm Proteins/*metabolism ; Polymorphism, Restriction Fragment Length ; Telomerase/*metabolism ; Telomere/metabolism/*ultrastructure ; },
abstract = {It has been proposed that the progressive shortening of telomeres in somatic cells eventually results in senescence. Previous experiments have demonstrated that many immortal cell lines have acquired telomerase activity leading to stabilization of telomere length. Telomere dynamics and telomerase activity were examined in the telomerase-positive immortal cell lines HeLa and 293 and subclones derived from them. A mass culture of HeLa cells had a stable mean telomere length over 60 population doublings (PD) in vitro. Subclones of this culture, however, had a range of mean telomere lengths indicating that telomeric heterogeneity exists within a population with a stable mean telomere length. Some of the subclones lacked detectable telomerase activity soon after isolation but regained it by PD 18, suggesting that at least some of the variation in telomere length can be attributed to variations in telomerase activity levels. 293 subclones also varied in telomere length and telomerase activity. Some telomerase-positive 293 subclones contained long telomeres that gradually shortened, demonstrating that factors other than telomerase also act to modulate telomere length. Fluctuations in telomere length in telomerase-positive immortalized cells may contribute to chromosomal instability and clonal evolution.},
}
@article {pmid9519758,
year = {1998},
author = {Jeanclos, E and Krolewski, A and Skurnick, J and Kimura, M and Aviv, H and Warram, JH and Aviv, A},
title = {Shortened telomere length in white blood cells of patients with IDDM.},
journal = {Diabetes},
volume = {47},
number = {3},
pages = {482-486},
doi = {10.2337/diabetes.47.3.482},
pmid = {9519758},
issn = {0012-1797},
support = {P30-DK-36836/DK/NIDDK NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Autoradiography ; Cohort Studies ; DNA/*analysis/genetics ; Diabetes Mellitus, Type 1/*blood/genetics ; Diabetes Mellitus, Type 2/*blood/genetics ; Humans ; Leukocytes/*ultrastructure ; Male ; Middle Aged ; Reference Values ; Telomere/*ultrastructure ; },
abstract = {IDDM is a polygenic and autoimmune disorder in which subsets of white blood cells (WBCs) are engaged in the destruction of beta-cells of the pancreas. The mechanisms that account for the abnormal behavior of these cells in IDDM are not fully understood. By measuring the mean length of telomeres of WBCs from patients with IDDM, we tested the concept that telomeres might play a role in IDDM. We examined the lengths of the terminal restriction fragments (TRFs) of DNA of WBCs from 234 white men comprising 54 patients with IDDM, 74 patients with NIDDM, and 106 control subjects. When adjusted for age, the TRF length from WBCs of patients with IDDM was significantly shorter than that of nondiabetic control subjects (mean +/- SE: 8.6 +/- 0.1 vs. 9.2 +/- 0.1, P = 0.002). No significant difference was observed between the TRF length from WBCs of patients with NIDDM versus nondiabetic subjects. Neither the duration nor the complications of IDDM (i.e., nephropathy and hypertension) had an effect on the TRF length of WBCs from patients with IDDM. The shortened TRF length of WBCs of patients with IDDM likely reflects a marked reduction in the TRF length of subsets of WBCs that play a role in the pathogenesis of IDDM.},
}
@article {pmid9512044,
year = {1998},
author = {Schnell, JR and Berman, J and Bloomfield, VA},
title = {Insertion of telomere repeat sequence decreases plasmid DNA condensation by cobalt (III) hexaammine.},
journal = {Biophysical journal},
volume = {74},
number = {3},
pages = {1484-1491},
pmid = {9512044},
issn = {0006-3495},
support = {GM28093/GM/NIGMS NIH HHS/United States ; GM38626/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Circular Dichroism ; Cobalt/*pharmacology ; Kinetics ; Microscopy, Electron ; Molecular Sequence Data ; Nucleic Acid Conformation ; Plasmids/*chemistry/drug effects/ultrastructure ; *Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*genetics ; *Telomere ; },
abstract = {Telomere repeat sequence (TRS) DNA is found at the termini of most eukaryotic chromosomes. The sequences are highly repetitive and G-rich (e.g., [C(1-3)A/TG(1-3)]n for the yeast Saccharomyces cerevisiae) and are packaged into nonnucleosomal protein-DNA structures in vivo. We have used total intensity light scattering and electron microscopy to monitor the effects of yeast TRS inserts on in vitro DNA condensation by cobalt (III) hexaammine. Insertion of 72 bp of TRS into a 3.3-kb plasmid depresses condensation as seen by light scattering and results in a 22% decrease in condensate thickness as measured by electron microscopy. Analysis of toroidal condensate dimensions suggests that the growth stages of condensation are inhibited by the presence of a TRS insert. The depression in total light scattering intensity is greater when the plasmid is linearized with the TRS at an end (39-49%) than when linearized with the TRS in the interior (18-22%). Circular dichroism of a 95-bp fragment containing the TRS insert gives a spectrum that is intermediate between the A-form and B-form, and the anomalous condensation behavior of the TRS suggests a noncanonical DNA structure. We speculate that under conditions in which the plasmid DNA condenses, the telomeric insert assumes a helical geometry that is similar to the A-form and is incompatible with packing into the otherwise B-form lattice of the condensate interior.},
}
@article {pmid9511733,
year = {1998},
author = {Petersen, S and Saretzki, G and von Zglinicki, T},
title = {Preferential accumulation of single-stranded regions in telomeres of human fibroblasts.},
journal = {Experimental cell research},
volume = {239},
number = {1},
pages = {152-160},
doi = {10.1006/excr.1997.3893},
pmid = {9511733},
issn = {0014-4827},
mesh = {Cell Line ; DNA/*chemistry/drug effects/isolation &amp; purification ; Fibroblasts/ultrastructure ; Humans ; Methylnitronitrosoguanidine/pharmacology ; Minisatellite Repeats ; Single-Strand Specific DNA and RNA Endonucleases ; Telomere/drug effects/physiology/*ultrastructure ; },
abstract = {We have demonstrated recently that chronic hyperoxic treatment accelerates the rate of aging of fibroblasts and the rate of telomere shortening in parallel. It was hypothesized that accelerated telomere shortening is due to preferential accumulation of oxidative damage in telomeres. To test this hypothesis, we measured the accumulation of sites sensitive to S1 nuclease treatment in telomeres, in minisatellites, and in the bulk of the genome of fibroblasts under different models of oxidative stress as well as after treatment with the alkylating agent, N-methyl-N'-nitro-N-nitrosoguanidine. A comparison with qualitative data obtained by alkaline electrophoresis reveals that the sites transferred to double-strand breaks by treatment with low concentrations of S1 nuclease are, in fact, single-stranded regions in the DNA. These regions may resemble single-stranded overhangs, gaps, or conventional single-strand breaks. The frequency of single-stranded regions is significantly higher in telomeres than in minisatellites or in the bulk of the genome under all conditions tested. Those regions induced in minisatellites or in the overall genome by a bolus dose of hydrogen peroxide are completely repaired within 24 h. On the other hand, 50 +/- 12% of H2O2-induced single-stranded regions remain unrepaired for at least 19 days in telomeres of human fibroblasts, leading to a significant increase of the telomeric steady-state level of these lesions. This preferential accumulation might significantly contribute to telomere shortening.},
}
@article {pmid9501879,
year = {1998},
author = {Egan, CA and Savre-Train, I and Shay, JW and Wilson, SE and Bourne, WM},
title = {Analysis of telomere lengths in human corneal endothelial cells from donors of different ages.},
journal = {Investigative ophthalmology &amp; visual science},
volume = {39},
number = {3},
pages = {648-653},
pmid = {9501879},
issn = {0146-0404},
support = {EY02037/EY/NEI NIH HHS/United States ; EY10056/EY/NEI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*physiology ; Cell Cycle/physiology ; Cellular Senescence/physiology ; DNA/*analysis ; Electrophoresis, Agar Gel ; Endothelium, Corneal/*physiology ; Epithelium, Corneal/physiology ; Female ; Humans ; Infant ; Male ; Middle Aged ; Telomere/genetics/*physiology ; Tissue Donors ; },
abstract = {PURPOSE: To investigate the telomere hypothesis of cellular aging as the mechanism for cell cycle arrest in normal human corneal endothelium.<br><br>METHODS: The corneal endothelium and epithelium from 21 human corneas from 13 donors 5 weeks to 84 years of age were dissected and frozen at -70 degrees C. Purified DNA, digested with the restriction enzyme, HinfI, was run on 0.7% agarose gels, probed with radiolabeled (AATCCC)4, and exposed to a phosphor screen. The length of the terminal restriction fragment (TRF) was determined by densitometry.<br><br>RESULTS: The cells of the corneal endothelium had TRF lengths ranging from 11.0 to 14.0 kbp (mean, 12.2 +/- 0.9). Corneal epithelial specimens showed TRF lengths that were always less than (mean, 10.4 +/- 1.0; range 9.0-12.0) the corresponding endothelial TRF lengths. Human corneal endothelial cells, transformed with human papillomavirus type 16 oncogenes E6 and E7, showed decreasing TRF lengths from 11 kbp at population doubling level (PDL) 15 to 9.5 kbp at PDL 73. Neither the endothelial and epithelial cells from human donors nor the transformed pre-immortalized human endothelial cells showed evidence of telomerase activity.<br><br>CONCLUSIONS: Human corneal endothelial cells have long telomeres throughout life. Their limited replicative ability does not appear to result from critically short telomere lengths.},
}
@article {pmid9473214,
year = {1998},
author = {Hatakeyama, S and Fujita, K and Mori, H and Omine, M and Ishikawa, F},
title = {Shortened telomeres involved in a case with a jumping translocation at 1q21.},
journal = {Blood},
volume = {91},
number = {5},
pages = {1514-1519},
pmid = {9473214},
issn = {0006-4971},
mesh = {Base Sequence ; Blotting, Southern ; *Chromosomes, Human, Pair 1 ; Chromosomes, Human, Pair 7 ; DNA, Neoplasm/chemistry ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Leukemia, Myelomonocytic, Acute/*genetics ; Middle Aged ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; *Translocation, Genetic ; },
abstract = {The jumping translocation (JT) is a rare chromosomal abnormality in which a specific chromosomal segment translocates onto the ends of various chromosomes (jumps). In most cases, the region distal to 1q21 jumps onto numerous different telomeres. Here we report a molecular study of the JT involving 1q21 found in a patient with acute myelomonocytic leukemia that had transformed from myelodysplastic syndrome (MDS). This is the first report describing the analysis of the molecular structure of the JT. We demonstrated the presence of a stretch of telomeric repeats at the breakpoint by means of a fluorescence in situ hybridization experiment, molecular cloning, and nucleotide sequencing of the fused region. A significant amount of variant telomeric repeats (a telomeric sequence having one-base mismatch within the authentic telomeric repeat TTAGGG) was found in this region. The variant telomeric repeat has been shown to be present in the proximal region of telomeres and does not perform telomeric functions by itself. Therefore, these results indicated that the telomeres had already been critically shortened when the jumps occurred. We suggest that the extended proliferation of cancer cells during the premalignant stage, such as MDS, results in chromosomal instability due to the loss of telomeric functions.},
}
@article {pmid9361036,
year = {1997},
author = {Baird, DM and Royle, NJ},
title = {Sequences from higher primates orthologous to the human Xp/Yp telomere junction region reveal gross rearrangements and high levels of divergence.},
journal = {Human molecular genetics},
volume = {6},
number = {13},
pages = {2291-2299},
doi = {10.1093/hmg/6.13.2291},
pmid = {9361036},
issn = {0964-6906},
mesh = {Alleles ; Animals ; DNA, Satellite/genetics ; Evolution, Molecular ; Female ; Gorilla gorilla/*genetics ; Haplotypes/genetics ; Humans ; Male ; Multigene Family ; Pan troglodytes/*genetics ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Pongo pygmaeus/*genetics ; Repetitive Sequences, Nucleic Acid ; Sequence Homology, Nucleic Acid ; Species Specificity ; Telomere/*genetics ; X Chromosome/*genetics/ultrastructure ; Y Chromosome/*genetics/ultrastructure ; },
abstract = {A high level of sequence polymorphism combined with linkage disequilibrium has created a limited number of highly diverged haplotypes across the human Xp/Yp telomere junction region. To gain insight into the unusual genetic characteristics of this region, we have examined the orthologous sequences in the common chimpanzee (Pan troglodytes), the gorilla (Gorilla gorilla) and the orang-utan (Pongo pygmaeus). Divergence from the human Xp/Yp sequence is higher (average 2.6-fold) than that observed at other loci. The position of the human Xp/Yp telomere is unique, as additional sequences are present at this location in the other three species. These included an array of subterminal satellite in the chimpanzee and, in the gorilla a small interstitial array of telomere-like repeats followed by sequences with strong homology to the human 18p subterminal region. In the orang-utan, two alleles with different structures were identified. These differ by the presence or absence of a short interspersed nuclear element (SINE) sequence just proximal to long arrays of telomere-like repeat sequences that probably represent the proximal end of the orang-utan Xp/Yp telomere. In addition, a high level of sequence divergence between the two orang-utan structures was identified. This divergence is similar to that observed between the human Xp/Yp telomere-adjacent haplotypes. The high sequence divergence and evidence of gross rearrangements indicate that the Xp/Yp telomeric region has evolved faster than the rest of the genome.},
}
@article {pmid9498274,
year = {1998},
author = {Day, JP and Limoli, CL and Morgan, WF},
title = {Recombination involving interstitial telomere repeat-like sequences promotes chromosomal instability in Chinese hamster cells.},
journal = {Carcinogenesis},
volume = {19},
number = {2},
pages = {259-265},
doi = {10.1093/carcin/19.2.259},
pmid = {9498274},
issn = {0143-3334},
support = {5-T32-ES07016/ES/NIEHS NIH HHS/United States ; GM 54189/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromosome Aberrations ; Cricetinae ; DNA Restriction Enzymes/*pharmacology ; *Gene Rearrangement/drug effects/radiation effects ; Humans ; Hybrid Cells ; In Situ Hybridization, Fluorescence ; *Recombination, Genetic ; Telomere/drug effects/*genetics/radiation effects ; },
abstract = {The physical termini of mammalian chromosomes are capped with tandem repeats of the telomere sequence (TTAGGG)n. After fluorescence in situ hybridization with a labeled (TTAGGG)n probe, telomere-repeat-like sequences are seen as discrete bands at distinct intrachromosomal sites in a variety of vertebrate species. There is increasing evidence that these sites may be hot-spots for chromosomal rearrangements, fragility and neoplasia. We have investigated whether the interstitial telomere bands found in hamster chromosomes from a human hamster hybrid cell line are hot-spots for chromosome rearrangements induced by DNA-damaging agents. Our data indicate that the interstitial telomere bands are involved in chromosomal rearrangements observed at the first mitosis after G1 exposure of cells to X-rays or restriction endonucleases at a four- to fivefold higher frequency than expected based on their size. In addition, we have extended these observations to demonstrate for the first time that these interstitial telomere-repeat-like sequences participate in the delayed chromosomal instability observed in the progeny of cells surviving X-ray-exposure at multiple generations after irradiation. In two highly unstable clones showing multiple populations of rearranged chromosomes, interstitial telomere bands were observed at the site of recombination between the human and hamster chromosomes at a five- to sixfold higher frequency than expected. There were also rearrangement and amplification of the interstitial telomere bands within the hamster chromosomes. These rearrangements occur during clonal expansion of cells surviving treatment with DNA-damaging agents and suggest a role for the interstitial telomere band in driving chromosomal instability. We conclude from the observed data that interstitial telomere bands function as recombinational hot-spots that participate in generating the diverse chromosome rearrangements observed both immediately and as a delayed effect of cellular exposure to DNA damaging agents.},
}
@article {pmid9496897,
year = {1998},
author = {Murnane, JP},
title = {Comments on "Telomere-mediated chromosome healing" by P. Slijepcevic and P. E. Bryant (Radiat. Res. 148, 293, 1997).},
journal = {Radiation research},
volume = {149},
number = {3},
pages = {309-312},
pmid = {9496897},
issn = {0033-7587},
mesh = {Chromosomes/*radiation effects ; DNA Damage ; DNA Repair ; Humans ; *Telomere ; },
}
@article {pmid9491393,
year = {1998},
author = {Slijepcevic, P and Natarajan, AT and Bryant, PE},
title = {Telomeres and radiation-induced chromosome breakage.},
journal = {Mutagenesis},
volume = {13},
number = {1},
pages = {45-49},
doi = {10.1093/mutage/13.1.45},
pmid = {9491393},
issn = {0267-8357},
mesh = {Animals ; CHO Cells ; Cell Line ; Chromatids/genetics/radiation effects ; Chromosome Breakage/*genetics ; Chromosomes/genetics/*radiation effects ; Cricetinae ; G1 Phase/genetics/radiation effects ; G2 Phase/genetics/radiation effects ; Gamma Rays ; In Situ Hybridization, Fluorescence ; Mice ; Mice, SCID ; Telomere/genetics/*radiation effects ; Translocation, Genetic/genetics/radiation effects ; X-Rays ; },
abstract = {Molecular characterization of some cytologically apparent terminal deletions in human tumours revealed that these were subtelomeric cryptic translocations undetectable by classical cytogenetic methods. To determine whether subtelomeric cryptic translocations occur following exposure of mammalian cells to ionizing radiation we used four cell lines exhibiting variable telomere lengths. Our G1 and G2 radiation experiments revealed that a small percentage of broken chromosomes exhibited telomeric signals. This occurred exclusively in cell lines exhibiting FISH-detectable telomeres, suggesting that telomeric signals at radiation-induced chromosome breaks were the result of subtelomeric cryptic translocations. In addition, telomeric signals at G2 chromatid breaks were usually paired with telomeres of intact sister chromatids, further supporting the notion that subtelomeric cryptic translocations are responsible for the presence of telomeric sequences at radiation-induced chromosome breaks. In one of the cell lines we identified what looked like de novo telomeric signals at derived chromatid breaks observed 20 h following irradiation. Our previous study suggested that these signals may be the result of amplification of interstitial telomeric sites in the first cell cycle and spontaneous breakage of interstitial telomeric sites in subsequent cell cycles. Taken together our results suggest that a small percentage of radiation-induced chromosome/chromatid breaks may be modified by subtelomeric cryptic translocations and that interstitial telomeric sites may be involved in radiation-induced chromosome instability.},
}
@article {pmid9489634,
year = {1998},
author = {Akiyama, M and Hoshi, Y and Sakurai, S and Yamada, H and Yamada, O and Mizoguchi, H},
title = {Changes of telomere length in children after hematopoietic stem cell transplantation.},
journal = {Bone marrow transplantation},
volume = {21},
number = {2},
pages = {167-171},
doi = {10.1038/sj.bmt.1701060},
pmid = {9489634},
issn = {0268-3369},
mesh = {Adolescent ; Adult ; Aging/genetics/pathology ; Bone Marrow Transplantation ; Case-Control Studies ; Cell Division/genetics ; Child ; Child, Preschool ; DNA/genetics ; Female ; Hematopoiesis/genetics ; *Hematopoietic Stem Cell Transplantation ; Humans ; Male ; Repetitive Sequences, Nucleic Acid ; Telomere/genetics/*ultrastructure ; Tissue Donors ; Transplantation, Autologous ; Transplantation, Homologous ; },
abstract = {Telomeres are responsible for keeping the stability not only of chromosomes but also of genes. To investigate the effect of hematopoietic stem cell transplantation (HSCT) on telomeres, we studied telomere length in the peripheral blood mononuclear cells of 31 children who received HSCT. In the auto-HSCT groups telomere length ranged from 8.6 to 12.0 kb and in the allo-HSCT groups from 8.4 to 12.0 kb. Comparison of the telomere length between before and after auto-HSCT showed shorting up to 1.0 kb. Moreover, comparison between donors and recipients in allo-HSCT revealed that telomeres of recipients were up to 1.0 kb shorter than those of the donors. Patients who received allo-HSCT from donors older than 18 years had significantly shorter telomeres than those transplanted from donors under 18 years old (P < 0.05), indicating that donor age is an important factor for recipient's telomere length. These findings suggest that the effects which might be induced by shortening of telomeres in recipients are within the biologically tolerable range. However, if hematopoietic stem cells from elderly donors are transplanted into younger patients, the telomere length may become too short for acceptable lifetime risks of genetic instability in the recipient.},
}
@article {pmid9489558,
year = {1998},
author = {Boei, JJ and Natarajan, AT},
title = {Combined use of chromosome painting and telomere detection to analyse radiation-induced chromosomal aberrations in mouse splenocytes.},
journal = {International journal of radiation biology},
volume = {73},
number = {2},
pages = {125-133},
doi = {10.1080/095530098142491},
pmid = {9489558},
issn = {0955-3002},
mesh = {Animals ; Cells, Cultured ; *Chromosome Aberrations ; Chromosomes/*radiation effects ; DNA/genetics/radiation effects ; Female ; Genomic Library ; In Situ Hybridization, Fluorescence ; Mice ; Spleen/*radiation effects/*ultrastructure ; Telomere/*chemistry/radiation effects ; },
abstract = {PURPOSE: Analysis of chromosomal aberrations by fluorescence in situ hybridization using a combination of chromosome painting and telomere detection in order to get more insight into: (a) the extent of incompleteness of exchanges and (b) the frequencies of interstitial fragments.<br><br>MATERIALS AND METHODS: Isolated mouse splenocytes were exposed in vitro to X-rays at a dose of 2 Gy. Aberrations involving chromosomes 2 and 3 were analysed by FISH using simultaneous chromosome painting and telomere detection.<br><br>RESULTS: At 2 Gy, about 10% of apparently simple exchanges are incomplete. A striking observation was the high induction of interstitial fragments, with frequencies nearly as high as that of dicentrics. Assuming, that both ends of all interstitial fragments have rejoined with each other (to form acentric rings), it can be estimated that over 92% of reactive ends of detectable breakpoints have rejoined illegitimately. Overall, equal frequencies of translocation types t(Ab) and t(Ba) (according to the PAINT nomenclature) were observed. Also, the ratios between reciprocal forms of translocations and dicentrics were close to 1 for both the chromosomes studied.<br><br>CONCLUSIONS: These studies have shown that many of the frequently observed 'one-way' exchanges using painting probes, are in fact reciprocal exchanges with one participating lesion so close to the telomere that no distal signal can be detected. Frequencies of true incomplete exchanges were found to be low. Intrachanges, here detected as interstitial fragments, were observed frequently.},
}
@article {pmid9477960,
year = {1998},
author = {Laporte, L and Thomas, GJ},
title = {Structural basis of DNA recognition and mechanism of quadruplex formation by the beta subunit of the Oxytricha telomere binding protein.},
journal = {Biochemistry},
volume = {37},
number = {5},
pages = {1327-1335},
doi = {10.1021/bi972400d},
pmid = {9477960},
issn = {0006-2960},
support = {GM54378/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; DNA-Binding Proteins/*chemistry/genetics ; Guanine/chemistry ; Macromolecular Substances ; Nuclear Proteins/*chemistry/genetics ; *Nucleic Acid Conformation ; Oligonucleotides/*metabolism ; Oxytricha/*chemistry/genetics ; Polymorphism, Genetic ; Repetitive Sequences, Nucleic Acid ; Spectrometry, Fluorescence ; Spectrum Analysis, Raman ; Thymine/chemistry ; },
abstract = {Interactions of the beta subunit of the Oxytricha nova telomere binding protein with the telomeric DNA sequences, d(T4G4)2 and dT6(T4G4)2, have been investigated in vitro using Raman and fluorescence spectroscopies. Raman difference spectra show that the beta subunit binds to both d(T4G4)2 and dT6(T4G4)2 but promotes the formation of a parallel-stranded quadruplex only in dT6(T4G4)2, thus demonstrating the importance of the telomeric 5' tail for in vitro recognition and guanine quadruplex formation. While d(T4G4)2 is not a suitable substrate for quadruplex promotion by the beta subunit, the Raman spectra reveal other structural rearrangements of this DNA strand upon beta subunit binding, including changes in guanine glycosyl torsion angles from syn to anti and disruption of carbonyl hydrogen-bonding interactions. The conformation of d(T4G4)2 in the beta:d(T4G4)2 complex is suggested as a plausible intermediate along the pathway to formation of the parallel-stranded guanine quadruplex. Fluorescence band shifts indicate that at least one of the two tryptophans of the beta subunit is shielded from solvent as a consequence of DNA binding in both the beta:dT6(T4G4)2 and beta:d(T4G4)2 complexes. However, the Raman spectra of these complexes suggest no significant changes in the beta subunit secondary structure attendant with DNA binding. A model for beta subunit binding by Oxytricha telomeric DNA sequences and a mechanism for quadruplex formation are proposed. A key feature of this model is the use of a telomeric hairpin secondary structure as the recognition motif.},
}
@article {pmid9488443,
year = {1998},
author = {Ray, A and Runge, KW},
title = {The C terminus of the major yeast telomere binding protein Rap1p enhances telomere formation.},
journal = {Molecular and cellular biology},
volume = {18},
number = {3},
pages = {1284-1295},
pmid = {9488443},
issn = {0270-7306},
support = {R01 GM050752/GM/NIGMS NIH HHS/United States ; GM50752/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites ; DNA-Binding Proteins/genetics/*metabolism ; Dinucleotide Repeats ; Fungal Proteins/genetics/metabolism ; *Histone Deacetylases ; Protein Kinases/genetics/metabolism ; Recombinant Fusion Proteins/genetics/metabolism ; Recombination, Genetic ; Saccharomyces cerevisiae/*genetics/metabolism ; *Saccharomyces cerevisiae Proteins ; Shelterin Complex ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Sirtuin 2 ; Sirtuins ; Telomerase/metabolism ; Telomere/*physiology ; *Telomere-Binding Proteins ; Trans-Activators/genetics/metabolism ; *Transcription Factors ; },
abstract = {The telomeres of most organisms consist of short repeated sequences that can be elongated by telomerase, a reverse transcriptase complex that contains its own RNA template for the synthesis of telomere repeats. In Saccharomyces cerevisiae, the RAP1 gene encodes the major telomere binding protein Rap1p. Here we use a quantitative telomere formation assay to demonstrate that Rap1p C termini can enhance telomere formation more than 30-fold when they are located at internal sites. This stimulation is distinct from protection from degradation. Enhancement of formation required the gene for telomerase RNA but not Sir1p, Sir2p, Sir3p, Sir4p, Tel1p, or the Rif1p binding site in the Raplp C terminus. Our data suggest that Rap1p C termini enhance telomere formation by attracting or increasing the activity of telomerase near telomeres. Earlier work suggests that Rap1p molecules at the chromosome terminus inhibit the elongation of long telomeres by blocking the access of telomerase. Our results suggest a model where a balance between internal Rap1p increasing telomerase activity and Rap1p at the termini of long telomeres controlling telomerase access maintains telomeres at a constant length.},
}
@article {pmid9487385,
year = {1998},
author = {Lowell, JE and Pillus, L},
title = {Telomere tales: chromatin, telomerase and telomere function in Saccharomyces cerevisiae.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {54},
number = {1},
pages = {32-49},
doi = {10.1007/s000180050123},
pmid = {9487385},
issn = {1420-682X},
support = {GM07135-22/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatin/genetics/*physiology ; Models, Molecular ; Saccharomyces cerevisiae/*genetics ; Telomerase/genetics/*physiology ; Telomere/genetics/*physiology ; },
abstract = {Unusual chromatin structures underlie epigenetic effects at the silent mating-type loci and telomeres in yeast. Many of the same genes appear to function in transcriptional silencing observed at both the silent mating-type loci and at telomeres. The observation that these loci are united by a requirement for shared factors suggests that the structure of chromatin at these regions is similar. Alteration of telomeric chromatin components affects regulation of transcription, telomeric length, recombination and chromosomal stability. Mutations in TLC1 and EST2, which both encode components of telomerase, cause identical phenotypes: progressive shortening of telomeric DNA, increased chromosome loss and eventually cell death. In this review, we examine the relationship between telomeric chromatin and telomere replication and discuss the possibility that telomerase itself is an integral part of telomeric chromatin structure.},
}
@article {pmid9483489,
year = {1997},
author = {Benn, P},
title = {Aging chromosome telomeres: parallel studies with terminal repeat and telomere associated DNA probes.},
journal = {Mechanisms of ageing and development},
volume = {99},
number = {2},
pages = {153-166},
doi = {10.1016/s0047-6374(97)00099-7},
pmid = {9483489},
issn = {0047-6374},
mesh = {Cell Line ; Cellular Senescence ; Chromosomes ; DNA Probes ; Endodeoxyribonucleases/metabolism ; Humans ; *Repetitive Sequences, Nucleic Acid ; *Telomere ; },
abstract = {Human chromosome telomeres consist of tandemly repeated (TTAGGG)n sequences with variant and more complex telomere-associated DNA sequences proximal to the terminal repeats. Terminal restriction fragment (TRF) sizes have been evaluated by Southern blot analysis using a terminal repeat probe, (TTAGGG)3 that will simultaneously detect all telomeres and with a telomere-associated DNA probe, TelBamll, that identifies a specific sub-group of chromosome ends. For DNA extracted from in vitro aging fibroblasts, a progressive reduction in the size of the TRFs could be demonstrated using both probes. For both fibroblasts and adult lymphocyte DNA, there were differences in the size of the fragments detected with the two probes. Studies were carried out to determine whether this difference might, in part, be attributable to variability in terminal repeat lengths as well as heterogeneity in the location of terminal restriction enzyme recognition sites. Using the (TTAGGG)3 probe to identify all telomeres, the terminal repeat lengths from lymphocytes of two adults appeared to be highly variable with sizes upto 20 kb. For the sub-group of telomeres identified by TelBamll the terminal repeat lengths were estimated to be 2-4 kb and appeared to show relatively little size diversity. If it assumed that the molecular weights of the DNA fragments identified in these studies do accurately reflect individual telomere structures, then it can be concluded that some specific telomere repeat arrays are substantially shorter than others. Variation in terminal repeat length may be related to the extent that telomeres participate in chromosome rearrangement.},
}
@article {pmid9480811,
year = {1998},
author = {Nosaka, K and Kawahara, M and Masuda, M and Satomi, Y and Nishino, H},
title = {Association of nucleoside diphosphate kinase nm23-H2 with human telomeres.},
journal = {Biochemical and biophysical research communications},
volume = {243},
number = {2},
pages = {342-348},
doi = {10.1006/bbrc.1997.8097},
pmid = {9480811},
issn = {0006-291X},
mesh = {Cloning, Molecular ; DNA/metabolism ; DNA-Binding Proteins/metabolism ; HeLa Cells ; Humans ; *Monomeric GTP-Binding Proteins ; NM23 Nucleoside Diphosphate Kinases ; Nucleoside-Diphosphate Kinase/*metabolism ; Oligodeoxyribonucleotides/chemistry/metabolism ; RNA/metabolism ; Recombinant Fusion Proteins/genetics ; Ribonuclease, Pancreatic/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1 ; Transcription Factors/*metabolism ; },
abstract = {Telomeres, the ends of eukaryotic chromosomes, are essential structures formed by specific protein-DNA complexes that protect chromosomes from degradation and end-to-end fusion. TRF1, a double-stranded telomeric TTAGGG-repeat binding protein, is associated with mammalian telomeres and controls telomere length by inhibiting the action of telomerase. We identified human nucleoside diphosphate kinase nm23-H2 as a human TRF1-interacting protein by yeast two-hybrid screening. In vitro-binding assays using different recombinant nucleoside diphosphate kinases showed that TRF1 predominantly binds the nm23-H2 isoform rather than nm23-H1. Electrophoretic mobility shift analysis revealed that the recombinant nm23-H2 protein can bind the single-stranded telomeric TTAGGG-repeat while it cannot bind the double-stranded telomeric repeat. The synthetic 20 base oligoribonucleotide, which consists of the template sequence CUAACCCUAAC and the adjacent region of the RNA component of human telomerase, was also found to form the complex with the recombinant nm23-H2 protein. Furthermore, the affinity of telomerase for its substrate was increased in vitro by presence of the plentiful nm23-H2 protein. These findings indicate a close relationship between nm23-H2 and human telomeres and suggest a new biological role for nucleoside diphosphate kinase.},
}
@article {pmid9476899,
year = {1998},
author = {van Steensel, B and Smogorzewska, A and de Lange, T},
title = {TRF2 protects human telomeres from end-to-end fusions.},
journal = {Cell},
volume = {92},
number = {3},
pages = {401-413},
doi = {10.1016/s0092-8674(00)80932-0},
pmid = {9476899},
issn = {0092-8674},
support = {GM07739/GM/NIGMS NIH HHS/United States ; },
mesh = {Anaphase ; Cell Division ; Cellular Senescence ; Chromosome Aberrations/*genetics ; DNA/metabolism ; DNA-Binding Proteins/analysis/genetics/*metabolism ; Fibrosarcoma ; Guanosine/analysis ; HeLa Cells ; Humans ; Metaphase ; Recombinant Fusion Proteins ; Repetitive Sequences, Nucleic Acid ; Telomerase/metabolism ; Telomere/*genetics ; Telomeric Repeat Binding Protein 2 ; Tumor Cells, Cultured ; },
abstract = {The mechanism by which telomeres prevent end-to-end fusion has remained elusive. Here, we show that the human telomeric protein TRF2 plays a key role in the protective activity of telomeres. A dominant negative allele of TRF2 induced end-to-end chromosome fusions detectable in metaphase and anaphase cells. Telomeric DNA persisted at the fusions, demonstrating that TTAGGG repeats per se are not sufficient for telomere integrity. Molecular analysis suggested that the fusions represented ligation of telomeres that have lost their single-stranded G-tails. Therefore, TRF2 may protect chromosome ends by maintaining the correct structure at telomere termini. In addition, expression of mutant forms of TRF2 induced a growth arrest with characteristics of senescence. The results raise the possibility that chromosome end fusions and senescence in primary human cells may be caused by loss by TRF2 from shortened telomeres.},
}
@article {pmid9476664,
year = {1997},
author = {Weng, NP and Palmer, LD and Levine, BL and Lane, HC and June, CH and Hodes, RJ},
title = {Tales of tails: regulation of telomere length and telomerase activity during lymphocyte development, differentiation, activation, and aging.},
journal = {Immunological reviews},
volume = {160},
number = {},
pages = {43-54},
doi = {10.1111/j.1600-065x.1997.tb01026.x},
pmid = {9476664},
issn = {0105-2896},
mesh = {Animals ; *Cell Differentiation ; *Cellular Senescence ; Humans ; *Lymphocyte Activation ; Lymphocytes/cytology/immunology/*physiology ; Telomerase/*metabolism ; *Telomere ; },
abstract = {Telomerase activity and the regulation of telomere length are factors which have been implicated in the control of cellular replication. These variables have been examined during human lymphocyte development, differentiation, activation, and aging. It was found that telomere length of peripheral blood CD4+ T cells decreases with age as well as with differentiation from naive to memory cells in vivo, and decreases with cell division in vitro. These results provide evidence that telomere length correlates with lymphocyte replicative history and residual replicative potential. In contrast, telomere length appears to increase during tonsil B-cell differentiation and germinal center (GC) formation in vivo. It was also found that telomerase activity is highly regulated during T-cell development and B-cell differentiation in vivo, with high levels of telomerase activity expressed in thymocytes and GC B cells, and low levels of telomerase activity in resting mature peripheral blood lymphocytes. Finally, resting lymphocytes retain the ability to upregulate telomerase activity upon activation, and this capacity does not appear to decline with age. Although the precise role of telomerase in lymphocyte function remains to be elucidated, telomerase may contribute to protection from telomere shortening in T and B lymphocytes, and may thus play a critical role in lymphocyte development, differentiation and activation. The future study of telomerase and its regulation of telomere length may enhance our understanding of how the replicative lifespan is regulated in lymphocytes.},
}
@article {pmid9475735,
year = {1998},
author = {Danilevskaya, ON and Lowenhaupt, K and Pardue, ML},
title = {Conserved subfamilies of the Drosophila HeT-A telomere-specific retrotransposon.},
journal = {Genetics},
volume = {148},
number = {1},
pages = {233-242},
pmid = {9475735},
issn = {0016-6731},
support = {GM50315/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Conserved Sequence ; Drosophila/*genetics ; Retroelements/*genetics ; Sequence Alignment ; Telomere/*genetics ; },
abstract = {HeT-A, a major component of Drosophila telomeres, is the first retrotransposon proposed to have a vital cellular function. Unlike most retrotransposons, more than half of its genome is noncoding. The 3' end contains > 2.5 kb of noncoding sequence. Copies of HeT-A differ by insertions or deletions and multiple nucleotide changes, which initially led us to conclude that HeT-A noncoding sequences are very fluid. However, we can now report, on the basis of new sequences and further analyses, that most of these differences are due to the existence of a small number of conserved sequence subfamilies, not to extensive sequence change during each transposition event. The high level of sequence conservation within subfamilies suggests that they arise from a small number of replicatively active elements. All HeT-A subfamilies show preservation of two intriguing features. First, segments of extremely A-rich sequence form a distinctive pattern within the 3' noncoding region. Second, there is a strong strand bias of nucleotide composition: The DNA strand running 5' to 3' toward the middle of the chromosome is unusually rich in adenine and unusually poor in guanine. Although not faced with the constraints of coding sequences, the HeT-A 3' noncoding sequence appears to be under other evolutionary constraints, possibly reflecting its roles in the telomeres.},
}
@article {pmid9382847,
year = {1997},
author = {Morris, DK and Lundblad, V},
title = {Programmed translational frameshifting in a gene required for yeast telomere replication.},
journal = {Current biology : CB},
volume = {7},
number = {12},
pages = {969-976},
doi = {10.1016/s0960-9822(06)00416-7},
pmid = {9382847},
issn = {0960-9822},
support = {AG11728-01/AG/NIA NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Base Sequence ; Binding Sites ; Cloning, Molecular ; *Frameshift Mutation ; *Fungal Proteins ; Molecular Sequence Data ; *Protein Biosynthesis ; Proteins/*genetics/metabolism ; Recombinant Fusion Proteins/genetics/metabolism ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; Telomerase/genetics/*metabolism ; *Telomere ; },
abstract = {BACKGROUND: Telomeres are replicated in most eukaryotes by the enzyme telomerase, a specialized reverse transcriptase. A genetic screen in Saccharomyces cerevisiae designed to detect telomerase components previously led to the identification of four EST ('ever shorter telomeres') genes which are required for telomerase function in vivo. This report describes the cloning and characterization of EST3.<br><br>RESULTS: We identified a potential site of +1 ribosomal frameshifting in the EST3 coding sequence and demonstrated that translation both upstream and downstream of this site is required for EST3 function. Mutation of EST3 such that it could not frameshift resulted in a strain with the same phenotype as an est3 null mutant, showing that EST3 frameshifting is required for telomere replication. Immunoblot analysis revealed that two proteins were synthesized from EST3: a truncated protein resulting from translation of only the first open reading frame, as well as the full-length 181 amino-acid Est3 protein resulting from translation through the frameshift site. Only the full-length Est3 protein was required for normal EST3 function.<br><br>CONCLUSIONS: A programmed translational frameshifting mechanism similar to that used by yeast retrotransposons is employed to produce full-length Est3 protein. This is the first example in yeast of a cellular gene that uses frameshifting to make its protein product, and a potential link is suggested between retrotransposition and the telomerase pathway for telomere maintenance.},
}
@article {pmid9467856,
year = {1997},
author = {Bugaeva, EA and Podgornaya, OI},
title = {Telomere-binding protein from the nuclear envelope of oocytes of the frog Rana temporaria.},
journal = {Biochemistry. Biokhimiia},
volume = {62},
number = {11},
pages = {1311-1322},
pmid = {9467856},
issn = {0006-2979},
mesh = {Animals ; DNA-Binding Proteins/analysis/isolation &amp; purification/*metabolism ; Microscopy, Immunoelectron ; Nuclear Envelope/*physiology/ultrastructure ; Nuclear Proteins/metabolism ; Oocytes/*physiology/ultrastructure ; Plasmids ; Rana temporaria ; Vimentin/analysis ; },
abstract = {The identification of telomere-binding protein on the nuclear envelope (NE) of the frog oocyte is reported here. Nuclei and the NE were isolated manually and extracted, and the extracts were used to search for DNA-protein specific interactions. Fragment of the Tetrahymena telomere sequence (T2G4)130 from the plasmid YAC4 was used as a labeled probe. DNA-protein complexes revealed by gel shift assay were cut out of the gel and injected into a guinea pig. The antibodies obtained have common antigenic determinants with keratins; this was shown on Western-blot under conditions of competitive binding. Antibodies were purified on an affinity column with keratins attached and used in the following work. Antibodies recognize one protein with molecular weight 70 kD among the NE proteins; no signal was obtained to proteins isolated from the inner part of the oocyte, but two polypeptides of 70 and 120 kD were detected in the proteins from frog liver nuclei. The 70-kD protein is situated on the NE in a distinct pattern that looks like a network, probably of double-dots as was shown by immunofluorescence of the NE. Electron-microscope immunogold staining showed that the protein is localized in the outer surface of the oocyte NE within cup-like structures attached to the membrane. Combined in situ hybridization using the mammalian telomeric DNA sequence (T2AG3)135 and immunocytochemistry using antibodies showed them to be colocalized in the frog blood cells, so telomere sequence coexists with the protein in the interphase nuclei. Most of the telomeres are fused in highly differentiated blood cells though a double dot signal is visible. The signal appears to be localized in the outer part of the nuclei. The existence of membrane telomere-binding protein allows a discussion of the attachment of the telemeters to the membrane.},
}
@article {pmid9467855,
year = {1997},
author = {Vaziri, H},
title = {Critical telomere shortening regulated by the ataxia-telangiectasia gene acts as a DNA damage signal leading to activation of p53 protein and limited life-span of human diploid fibroblasts. A review.},
journal = {Biochemistry. Biokhimiia},
volume = {62},
number = {11},
pages = {1306-1310},
pmid = {9467855},
issn = {0006-2979},
mesh = {Ataxia Telangiectasia/*genetics ; *Cell Cycle ; Cell Line, Transformed ; Cellular Senescence/*physiology ; *DNA Damage ; Diploidy ; Fibroblasts/cytology/physiology ; Humans ; Mitosis ; Signal Transduction ; Telomere/genetics/*physiology ; Tumor Suppressor Protein p53/*metabolism ; },
abstract = {Somatic cells undergo a limited number of doublings in culture and enter an irreversible block in the G1 and G2/M phase of the cell cycle termed "senescence". Telomere shortening presumably as a consequence of the end-replication problem has been proposed to act as a mitotic clock eventually leading to cellular senescence. Several models have been proposed to explain how telomere shortening can lead to cellular senescence. We proposed previously that telomere shortening may eventually lead to formation of dicentric chromosomes which on subsequent breakage activate a DNA damage response pathway involving the p53 protein. Hence we proposed that the telomere shortening signal is perceived by the cell as DNA damage. Recently we have obtained experimental evidence that the p53 protein is activated posttranslationally in human fibroblasts which undergo telomere shortening and subsequent senescence in culture. In this paper we also show that the increased activity of p53 protein coincides with formation of dicentric chromosomes and senescence. Also, we have previously found that an increase in the level of the down stream target of p53 protein, p21WAF1/SD11/C1P1, is dependent on both p53 and p300 proteins. We have also shown that fibroblasts obtained from individuals with Ataxia Telangiectasia lose telomeric DNA at an accelerated rate, activate p53 protein, and undergo premature senescence in culture. These results suggest that the ataxia-telangiectasia gene (ATM) and p53 are involved in surveillance and regulation of telomeric DNA. Once a critical length of telomeric DNA is reached. ATM and p53 sense and relay this signal to the cell cycle leading to senescence.},
}
@article {pmid9467853,
year = {1997},
author = {Rawes, V and Kipling, D and Kill, IR and Faragher, RG},
title = {The kinetics of senescence in retinal pigmented epithelial cells: a test for the telomere hypothesis of ageing?.},
journal = {Biochemistry. Biokhimiia},
volume = {62},
number = {11},
pages = {1291-1295},
pmid = {9467853},
issn = {0006-2979},
mesh = {Adult ; Aging/*physiology ; Cell Cycle ; Cell Division ; Cells, Cultured ; Cellular Senescence/*physiology ; Humans ; Kinetics ; Models, Biological ; Pigment Epithelium of Eye/*cytology/*physiology ; Telomere/*physiology ; },
abstract = {Senescence, or replicative failure, has been reported for a wide variety of human cell types but has seldom been characterized in any detail. The senescence of human fibroblast cultures has been shown to be due to a steadily decreasing percentage of cells able to proliferate in standard media. This paper reports the serial subculture of a strain of adult retinal pigmented epithelial (RPE) cells until replicative failure after approximately 15 population doublings. Measurement of the growth fraction of the RPE cells at each passage using antibodies to the proliferation marker pKi67 demonstrated a rate of decline in the proliferating fraction of 3.66% per population doubling. Similar experiments carried out using a strain of human fibroblasts yielded a decline of approximately 0.88% per population doubling. Thus, individual RPE cells enter senescence significantly faster than control fibroblasts (p < 0.001). At growth arrest the RPE cells retained viability for extended periods but showed elevated endogenous autofluorescence, analogous to observations on post-mitotic human fibroblasts. Taken together these findings suggest that the process of senescence is a common feature of different cell lineages but that the specific rate can differ between them. The significance of these observations for the telomere hypothesis of senescence is discussed.},
}
@article {pmid9467852,
year = {1997},
author = {Spitkovsky, DM},
title = {Telomere DNA sequences and the concept of ontogenetic reserve cells.},
journal = {Biochemistry. Biokhimiia},
volume = {62},
number = {11},
pages = {1285-1290},
pmid = {9467852},
issn = {0006-2979},
mesh = {Animals ; Cell Division ; Cell Line, Transformed ; DNA/*genetics ; DNA Replication ; Genetic Variation ; Humans ; Telomerase/metabolism ; Telomere/*genetics ; },
abstract = {Dynamics of telomere sequences are considered in normal and immortalized cells. Immortalized cells are suggested to be derived mainly from a special subpopulation of ontogenetic reserve cells. Their epigenetic program consists of autoregeneration during external stimulus for genome reorganization and corresponding appearance of genetic variants of cells. It is suggested that cells surviving the crisis stage contain a special signal sequence integrated into telomere DNA. Its elimination during shortening of DNA telomere sequences in dividing ontogenetic reserve cells is a signal for the cooperative transition of chromatin into a new steady state that corresponds to the epigenotype of immortalized cells. Localization of telomere DNA sequences in intrachromosomal "hot spots" reflects phylogenetic rearrangement of the genome.},
}
@article {pmid9467848,
year = {1997},
author = {Kurenova, EV and Mason, JM},
title = {Telomere functions. A review.},
journal = {Biochemistry. Biokhimiia},
volume = {62},
number = {11},
pages = {1242-1253},
pmid = {9467848},
issn = {0006-2979},
mesh = {Animals ; Cell Nucleus/physiology ; Eukaryota/genetics ; Heterochromatin/genetics/physiology ; Humans ; Myxomycetes/genetics ; Plants/genetics ; Telomere/genetics/*physiology ; Yeasts/genetics ; },
abstract = {Telomeres are structurally and functionally complex. They consist of an array of simple DNA repeats at the extreme end of the chromosome with a more complex array of repeats adjacent to it. A large number of proteins have been identified that bind to the telomeric DNA repeats or to the protein complexes that are built at the chromosome end. Telomeres tend to form associations with each other. These associations have been implicated in the formation of nuclear domains that may be important for transcriptional regulation, for sister chromatid pairing at mitosis, and for homologous meiotic synapsis. Telomeric chromosome ends do not cause delays in cell cycle progression, nor are they subject to DNA repair as are broken chromosome ends. Telomeres also provide a separate mechanism for adding additional copies of the telomeric DNA to chromosome ends. This is needed to counterbalance the loss of DNA sequences from chromosome ends due to incomplete DNA replication. The components that participate in the latter mechanism and this process have been characterized in detail; the other functions of telomeres are less well understood but are the subjects of active investigation.},
}
@article {pmid9467847,
year = {1997},
author = {Pryde, FE and Louis, EJ},
title = {Saccharomyces cerevisiae telomeres. A review.},
journal = {Biochemistry. Biokhimiia},
volume = {62},
number = {11},
pages = {1232-1241},
pmid = {9467847},
issn = {0006-2979},
mesh = {Base Sequence ; Cell Cycle ; Cell Nucleus/physiology/ultrastructure ; Chromatin/chemistry/physiology ; Chromosomes, Fungal/chemistry ; Conserved Sequence ; DNA Damage ; Genes, Fungal ; Multigene Family ; Recombination, Genetic ; Saccharomyces cerevisiae/cytology/genetics/*physiology ; Telomerase/genetics/metabolism ; Telomere/genetics/*physiology ; },
abstract = {Recent work has yielded considerable information concerning the structure and function of telomeres and their associated sequences in the budding yeast Saccharomyces cerevisiae. The structure and maintenance of telomeres depends not only on the RNA template and the catalytic subunit of telomerase, but on a number of other proteins. These include proteins involved in assessing DNA damage and cell cycle regulation. There are also non-telomerase mediated processes involved in the normal maintenance of telomeres. In addition to proteins involved in telomere maintenance, there are a number of other proteins involved in the chromatin structure of the region. Many of these proteins have roles in silencing, ageing, segregation and nuclear architecture. The structure of the subtelomeric regions has been well characterized and consists of a mosaic of repeats found in variable copy numbers and locations. Amidst the variable mosaic elements there are small conserved sequences found at all ends that may have functional roles. Recent work shows that the subtelomeric repeats can rescue chromosome ends when telomerase fails, buffer subtelomerically located genes against transcriptional silencing, and protect the genome from deleterious rearrangements due to ectopic recombination. Thus the telomeres of yeast have a variety of roles in the life of the yeast cell beyond the protection of the ends and overcoming the end replication problem associated with linear molecules.},
}
@article {pmid9467846,
year = {1997},
author = {McKnight, TD and Fitzgerald, MS and Shippen, DE},
title = {Plant telomeres and telomerases. A review.},
journal = {Biochemistry. Biokhimiia},
volume = {62},
number = {11},
pages = {1224-1231},
pmid = {9467846},
issn = {0006-2979},
support = {GM49157/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; DNA Replication ; DNA, Plant/biosynthesis/*chemistry ; Drosophila ; Plants/*genetics ; Repetitive Sequences, Nucleic Acid ; Telomerase/*metabolism ; Telomere/chemistry/*physiology ; },
abstract = {Barbara McClintock began investigating plant telomeres during the 1930s, but little additional work was done in this area until a telomeric DNA sequence was isolated and characterized from Arabidopsis thaliana in 1988. This sequence, a simple repeat of the heptanucleotide 5'-TTTAGGG-3', has been found in telomeres of almost all plants analyzed. Telomere length in plants, which can be a long as 75 kb or as short as 2 kb, is controlled by both genetic and developmental factors. The major mechanism for synthesis of telomeres is telomerase, a ribonucleoprotein with reverse transcriptase activity. Telomerase expression is highly regulated in both plants and animals. For example, there is little or no detectable expression of telomerase in most vegetative tissues of plants nor in most somatic tissues of animals. In contrast to animals, plants do not specify a germ line until late in development, but telomerase is reactivated during flowering, possibly to ensure that gametes and embryos arising from them inherit fully functional chromosomes. Telomerase is also highly expressed in plant tissue culture cells, as might be expected for cells with an unlimited capacity for proliferation. Despite recent progress in investigating plant telomeres and telomerase at the molecular level, there is still much more to learn, especially concerning the developmental control of telomerase activity.},
}
@article {pmid9467842,
year = {1997},
author = {Blackburn, EH},
title = {The telomere and telomerase: nucleic acid-protein complexes acting in a telomere homeostasis system. A review.},
journal = {Biochemistry. Biokhimiia},
volume = {62},
number = {11},
pages = {1196-1201},
pmid = {9467842},
issn = {0006-2979},
mesh = {Animals ; DNA/chemistry/metabolism ; DNA Replication ; Homeostasis ; Kluyveromyces/genetics/metabolism ; Mutation ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/genetics/metabolism ; Telomerase/biosynthesis/*metabolism ; Telomere/*physiology ; Templates, Genetic ; Tetrahymena thermophila/genetics/metabolism ; },
abstract = {The tandemly repeated DNA sequence of telomeres is typically specified by the ribonucleoprotein enzyme telomerase. Telomerase copies part of its intrinsic RNA moiety to synthesize one strand of the telomeric repeat DNA Recent work, taken together with many observations over the past years, has led to the concept of a telomere homeostasis system. We have analyzed the interplay between two key physical components of this system: structural components of the telomere itself and of telomerase. Here we review some of these recent studies. The experimental method used in common in these studies was to make mutations in the template sequence of telomerase RNA, which caused various phenotypes. First, mutating specific residues in the ciliate Tetrahymena thermophila and yeast showed that these residues are required for critical aspects of the enzymatic action of telomerase. Second, certain mutated telomeric sequences caused a strong anaphase block in Tetrahymena micronuclei. Third, specific template mutations in the telomerase RNA gene led to varying degrees of telomere elongation in Tetrahymena and the yeast Kluyveromyces lactis. For some of the K. lactis mutations, the loss of length unregulated elongation was directly related to loss of binding to K. lactis Rap 1p protein. Using K. lactis carrying alterations in the telomerase RNA template, and in the gene encoding the Rap 1p protein, we found that a crucial determinant of telomere length homeostasis is the nature of the duplex DNA-Rap 1p protein complex on the very end repeat of the telomere. We propose that this complex plays a key role in regulating access of telomerase to the telomere.},
}
@article {pmid9464472,
year = {1998},
author = {Slijepcevic, P and Bryant, PE},
title = {Chromosome healing, telomere capture and mechanisms of radiation-induced chromosome breakage.},
journal = {International journal of radiation biology},
volume = {73},
number = {1},
pages = {1-13},
doi = {10.1080/095530098142653},
pmid = {9464472},
issn = {0955-3002},
mesh = {Animals ; *Chromosome Aberrations ; Chromosomes/*radiation effects ; DNA Damage ; *DNA Repair ; Humans ; Telomerase/physiology ; *Telomere ; },
abstract = {BACKGROUND: It is generally assumed that radiation-induced chromosome breaks are the result of a cell's inability to rejoin DNA double-strand breaks (dsb), but the exact mechanisms underlying the failure to rejoin some dsb and the conversion of these lesions into chromosome breaks are poorly understood at present. It has been speculated that the conversion of dsb into chromosome breaks, following exposure of mammalian cells to ionizing radiation, may be mediated by the enzyme telomerase. Telomerase is a reverse transcriptase that has two distinct functions, to replicate pre-existing chromosome ends (telomeres) and to heal broken chromosomes by de novo addition of telomeric sequences directly on to non-telomeric DNA. Alternatively, dsb may be converted into chromosome breaks by a telomerase-independent mechanism termed telomere capture.<br><br>PURPOSE: To review telomere biology and to examine the significance of chromosome healing and telomere capture mechanisms tor radiation cytogenetics.<br><br>CONCLUSION: The currently available literature suggests that telomere capture may be a more frequent mechanism for stabilization of broken chromosomes in mammalian cells than telomerase-mediated chromosome healing. However, a definitive conclusion must await improvements in the resolution of molecular cytogenetic techniques to a degree which allows telomerase products to be clearly distinguishable from subtelomeric cryptic translocations indicative of telomere capture.},
}
@article {pmid9462257,
year = {1997},
author = {Shay, JW},
title = {Molecular pathogenesis of aging and cancer: are telomeres and telomerase the connection?.},
journal = {Journal of clinical pathology},
volume = {50},
number = {10},
pages = {799-800},
pmid = {9462257},
issn = {0021-9746},
mesh = {Aging/*genetics ; Cellular Senescence/genetics ; Enzyme Activation ; Humans ; Neoplasms/enzymology/*genetics ; Telomerase/*physiology ; Telomere/*physiology ; },
}
@article {pmid9422783,
year = {1998},
author = {Willwand, K and Mumtsidu, E and Kuntz-Simon, G and Rommelaere, J},
title = {Initiation of DNA replication at palindromic telomeres is mediated by a duplex-to-hairpin transition induced by the minute virus of mice nonstructural protein NS1.},
journal = {The Journal of biological chemistry},
volume = {273},
number = {2},
pages = {1165-1174},
doi = {10.1074/jbc.273.2.1165},
pmid = {9422783},
issn = {0021-9258},
mesh = {Adenosine Triphosphate/metabolism ; Animals ; Baculoviridae/genetics ; Base Sequence ; Cell Line ; Cloning, Molecular ; *DNA Replication ; DNA, Viral/*chemistry ; Mice ; Minute Virus of Mice/metabolism ; Molecular Sequence Data ; *Nucleic Acid Conformation ; Replication Origin ; *Telomere ; Viral Nonstructural Proteins/*metabolism ; },
abstract = {The linear single-stranded DNA genome of the minute virus of mice (MVM) is replicated via a double-stranded replicative form (RF) intermediate. Amplification of this RF is initiated by the folding-back of palindromic sequences serving as primers for strand-displacement synthesis and formation of dimeric RF DNA. Using an in vitro replication assay and a cloned MVM DNA template, we observed hairpin-primed DNA replication at both MVM DNA termini, with a bias toward right-end initiation. Initiation of DNA replication is favored by nuclear components of A9 cell extract and highly stimulated by the MVM nonstructural protein NS1. Hairpin-primed DNA replication is also observed in the presence of NS1 and the Klenow fragment of the Escherichia coli DNA polymerase I. Addition of ATPgammaS (adenosine 5'-O-(thiotriphosphate)) blocks the initiation of DNA replication but not the extension of pre-existing hairpin primers formed in the presence of NS1 only. The NS1-mediated unwinding of the right-end palindrome may account for the recently reported capacity of NS1 for driving dimer RF synthesis in vitro.},
}
@article {pmid9391214,
year = {1997},
author = {Slijepcevic, P and Hande, MP and Bouffler, SD and Lansdorp, P and Bryant, PE},
title = {Telomere length, chromatin structure and chromosome fusigenic potential.},
journal = {Chromosoma},
volume = {106},
number = {7},
pages = {413-421},
doi = {10.1007/s004120050263},
pmid = {9391214},
issn = {0009-5915},
mesh = {Animals ; CHO Cells ; Cell Line ; Chromatin/*genetics ; Chromosome Banding ; Chromosomes/*genetics/radiation effects ; Cricetinae ; In Situ Hybridization, Fluorescence ; Metaphase/genetics ; Mice ; Severe Combined Immunodeficiency/genetics ; Telomere/*genetics/radiation effects ; },
abstract = {Telomeres are specialized structures at chromosome ends that are thought to function as buffers against chromosome fusion. Several studies suggest that telomere shortening may render chromosomes fusigenic. We used a novel quantitative fluorescence in situ hybridization procedure to estimate telomere length in individual mammalian chromosomes, and G-banding and chromosome painting techniques to determine chromosome fusigenic potential. All analysed Chinese hamster and mouse cell lines exhibited shorter telomeres at short chromosome arms than at long chromosome arms. However, no clear link between short telomeres and chromosome fusigenic potential was observed, i.e. frequencies of telomeric associations were higher in cell lines exhibiting longer telomeres. We speculate that chromosome fusigenic potential in mammalian cell lines may be determined not only by telomere length but also by the status of telomere chromatin structure. This is supported by the observed presence of chromatin filaments linking telomeres in Chinese hamster chromosomes and of multibranched chromosomes oriented end-to-end in the murine severe combined immunodeficient (SCID) cell line. Multibranched chromosomes are the hallmark of the human ICF (Immune deficiency, Centromeric instability, Facial abnormalities) syndrome, characterized by alterations in heterochromatin structure.},
}
@article {pmid9391104,
year = {1997},
author = {Notaro, R and Cimmino, A and Tabarini, D and Rotoli, B and Luzzatto, L},
title = {In vivo telomere dynamics of human hematopoietic stem cells.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {94},
number = {25},
pages = {13782-13785},
pmid = {9391104},
issn = {0027-8424},
mesh = {Adolescent ; Adult ; Bone Marrow Transplantation/*pathology ; Cell Division ; Cellular Senescence ; Child ; Female ; Hematopoiesis ; Hematopoietic Stem Cells/*ultrastructure ; Humans ; Male ; Telomere/*ultrastructure ; Time Factors ; Tissue Donors ; },
abstract = {Aging in vivo and cell division in vitro are associated with telomere shortening. Several lines of evidence suggest that telomere length may be a good predictor of the long term replicative capacity of cells. To investigate the natural fate of chromosome telomeres of hematopoietic stem cells in vivo, we measured the telomere length of peripheral blood granulocytes from 11 fully engrafted bone marrow transplant recipients and from their respective donors. In 10 of 11 donor-recipient pairs, the telomere length was significantly reduced in the recipient and the extent of reduction correlated inversely with the number of nucleated cells infused. These data provide internally controlled in vivo evidence that, concomitantly with their proliferation, hematopoietic stem cells lose telomere length; it is possible that, as a result, their proliferative potential is reduced. These findings must be taken into account when developing new protocols in which few stem cells are used for bone marrow transplantation or for gene therapy.},
}
@article {pmid9367774,
year = {1997},
author = {Kowald, A},
title = {Possible mechanisms for the regulation of telomere length.},
journal = {Journal of molecular biology},
volume = {273},
number = {4},
pages = {814-825},
doi = {10.1006/jmbi.1997.1305},
pmid = {9367774},
issn = {0022-2836},
mesh = {Aging/genetics ; Cell Division ; DNA/metabolism ; DNA Replication ; Humans ; In Vitro Techniques ; *Models, Genetic ; Oligonucleotides/pharmacology ; RNA Caps/metabolism ; Telomerase/antagonists &amp; inhibitors ; Telomere/*physiology ; },
abstract = {Since DNA polymerases can only synthesise a new DNA strand in the 5'-3' direction and need a primer that provides a free 3' OH end, the cellular replication machinery is unable to duplicate the 3' ends of linear chromosomes unless special mechanisms are operative. While the telomeres seem to shorten continuously in human somatic cells because of the "end replication" problem, it appears that telomere length is maintained in cancer cells, the germ line and unicellular organisms like yeast and Tetrahymena by a mechanism involving the enzyme telomerase, which elongates the 3' ends of telomeres. However, telomerase must be part of a more complicated mechanism to ensure that there is no net gain or loss of telomeric ends. Here we describe a simple theoretical model that can explain several experimental findings. The simulations show that (i) the proposed mechanism is able to maintain telomeres at a constant length, (ii) this length constancy is independent of the initial telomere length, (iii) mutations of the telomeric sequence lead to an elongation of telomeres, (iv) inhibition of telomerase causes telomeric shortening, and (v) it reproduces and explains the experimental result that the addition of oligonucleotides to the culture medium leads to an increase of telomere length.},
}
@article {pmid9349487,
year = {1997},
author = {Willwand, K and Baldauf, AQ and Deleu, L and Mumtsidu, E and Costello, E and Beard, P and Rommelaere, J},
title = {The minute virus of mice (MVM) nonstructural protein NS1 induces nicking of MVM DNA at a unique site of the right-end telomere in both hairpin and duplex conformations in vitro.},
journal = {The Journal of general virology},
volume = {78 (Pt 10)},
number = {},
pages = {2647-2655},
doi = {10.1099/0022-1317-78-10-2647},
pmid = {9349487},
issn = {0022-1317},
mesh = {Animals ; Base Sequence ; Cells, Cultured ; DNA, Viral/*metabolism ; Hydrogen Bonding ; Mice ; Molecular Sequence Data ; Nucleic Acid Conformation ; Telomere ; Viral Nonstructural Proteins/*physiology ; *Virus Replication ; },
abstract = {The right-end telomere of replicative form (RF) DNA of the autonomous parvovirus minute virus of mice (MVM) consists of a sequence that is self-complementary except for a three nucleotide loop around the axis of symmetry and an interior bulge of three unpaired nucleotides on one strand (designated the right-end 'bubble'). This right-end inverted repeat can exist in the form of a folded-back strand (hairpin conformation) or in an extended form, base-paired to a copy strand (duplex conformation). We recently reported that the right-end telomere is processed in an A9 cell extract supplemented with the MVM nonstructural protein NS1. This processing is shown here to result from the NS1-dependent nicking of the complementary strand at a unique position 21 nt inboard of the folded-back genomic 5' end. DNA species terminating in duplex or hairpin configurations, or in a mutated structure that has lost the right-end bulge, are all cleaved in the presence of NS1, indicating that features distinguishing these structures are not prerequisites for nicking under the in vitro conditions tested. Cleavage of the hairpin structure is followed by strand-displacement synthesis, generating the right-end duplex conformation, while processing of the duplex structure leads to the release of free right-end telomeres. In the majority of molecules, displacement synthesis at the right terminus stops a few nucleotides before reaching the end of the template strand, possibly due to NS1 which is covalently bound to this end. A fraction of the right-end duplex product undergoes melting and re-folding into hairpin structures (formation of a 'rabbit-ear' structure).},
}
@article {pmid9454329,
year = {1998},
author = {de Lange, T},
title = {Telomeres and senescence: ending the debate.},
journal = {Science (New York, N.Y.)},
volume = {279},
number = {5349},
pages = {334-335},
doi = {10.1126/science.279.5349.334},
pmid = {9454329},
issn = {0036-8075},
mesh = {Animals ; Antineoplastic Agents/pharmacology ; *Cell Division ; Cell Line ; Cell Transformation, Neoplastic ; *Cellular Senescence ; DNA-Binding Proteins ; Enzyme Activation ; Genes, Tumor Suppressor ; Humans ; Mice ; Neoplasms/drug therapy/enzymology/pathology ; Proteins/genetics/*metabolism ; *RNA ; RNA-Directed DNA Polymerase/genetics/metabolism ; Telomerase/antagonists &amp; inhibitors/genetics/*metabolism ; Telomere/metabolism/*physiology/ultrastructure ; Transfection ; },
}
@article {pmid9451957,
year = {1997},
author = {Chen, CM and Wang, CT and Wang, CJ and Ho, CH and Kao, YY and Chen, CC},
title = {Two tandemly repeated telomere-associated sequences in Nicotiana plumbaginifolia.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {5},
number = {8},
pages = {561-568},
pmid = {9451957},
issn = {0967-3849},
mesh = {Base Sequence ; Chromosome Mapping ; Cloning, Molecular ; DNA, Plant/genetics ; In Situ Hybridization, Fluorescence/methods ; Molecular Sequence Data ; *Plants, Toxic ; Repetitive Sequences, Nucleic Acid/*genetics ; Sequence Homology, Nucleic Acid ; Telomere/*genetics ; Nicotiana/*genetics ; },
abstract = {Two tandemly repeated telomere-associated sequences, NP3R and NP4R, have been isolated from Nicotiana plumbaginifolia. The length of a repeating unit for NP3R and NP4R is 165 and 180 nucleotides respectively. The abundance of NP3R, NP4R and telomeric repeats is, respectively, 8.4 x 10(4), 6 x 10(3) and 1.5 x 10(6) copies per haploid genome of N. plumbaginifolia. Fluorescence in situ hybridization revealed that NP3R is located at the ends and/or in interstitial regions of all 10 chromosomes and NP4R on the terminal regions of three chromosomes in the haploid genome of N. plumbaginifolia. Sequence homology search revealed that not only are NP3R and NP4R homologous to HRS60 and GRS, respectively, two tandem repeats isolated from N. tabacum, but that NP3R and NP4R are also related to each other, suggesting that they originated from a common ancestral sequence. The role of these repeated sequences in chromosome healing is discussed based on the observation that two to three copies of a telomere-similar sequence were present in each repeating unit of NP3R and NP4R.},
}
@article {pmid9451730,
year = {1997},
author = {Dahse, R and Fiedler, W and Ernst, G},
title = {[Telomeres and telomerase].},
journal = {Der Pathologe},
volume = {18},
number = {6},
pages = {425-429},
doi = {10.1007/s002920050237},
pmid = {9451730},
issn = {0172-8113},
mesh = {Animals ; Cell Cycle ; Cellular Senescence ; Humans ; Male ; Mammals ; Neoplasms/genetics/*pathology ; Spermatozoa/cytology ; Telomerase/*metabolism ; Telomere/*physiology/ultrastructure ; },
abstract = {Complex mechanisms have evolved in mammalian cells for regulating cellular lifespan. Normal cells demonstrate a strictly limited growth potential and senescence after a defined number of cell divisions. In contrast, tumor cells often exhibit an apparently unlimited proliferation potential and are termed immortalized. It has been proposed that the progressive shortening of the tips of the eukaryotic chromosomes--the telomeres--is an important component of senescence and is involved in the control of cell cycle. The enzyme telomerase adds TTAGGG repeats onto mammalian telomeres, preventing their shortening. Telomerase is normally inactive in most somatic cells, but detectable in tumor cells. The activation of telomerase in malignant cancers seems to be an important step in tumorigenesis in order to gain the ability of indefinite proliferation and to become immortal. This review describes the present knowledge of telomeres and telomerase and their role in cellular senescence and human aging. It summarizes aspects of telomerase in cancer and its function as a diagnostic and prognostic tumor marker.},
}
@article {pmid9449873,
year = {1998},
author = {Wynn, RF and Cross, MA and Hatton, C and Will, AM and Lashford, LS and Dexter, TM and Testa, NG},
title = {Accelerated telomere shortening in young recipients of allogeneic bone-marrow transplants.},
journal = {Lancet (London, England)},
volume = {351},
number = {9097},
pages = {178-181},
doi = {10.1016/S0140-6736(97)08256-1},
pmid = {9449873},
issn = {0140-6736},
mesh = {Adolescent ; *Bone Marrow Transplantation/pathology ; Cellular Senescence/genetics ; Child ; Child, Preschool ; Female ; Hematopoiesis ; Hematopoietic Stem Cells/pathology/physiology ; Humans ; Male ; *Telomere/genetics/pathology ; Time Factors ; Transplantation, Homologous ; },
abstract = {BACKGROUND: The establishment of donor-derived haemopoiesis in the recipients of allogeneic bone-marrow transplants (BMT) involves extensive proliferation of haemopoietic stem cells. The biological consequences of this replicative stress are ill defined, but any "ageing" effect would carry the risk of an increased frequency of clonal disorders during later life. We compared blood-cell mean telomere lengths in donor/recipient pairs.<br><br>METHODS: Mean telomere length was calculated by in-gel hybridisation to leucocyte DNA from 56 normal individuals aged 0-96 years, and from 14 consecutive BMT recipients (aged 2-14 years) plus their respective donors (aged 2-46 years). Engraftment was confirmed by variable numbers of tandem repeats (VNTR) or gender analysis.<br><br>FINDINGS: On average, blood-cell telomeres of transplant recipients were 0.4 kb (95% CI -0.2 to -0.6) shorter than those of their respective donors. This degree of telomere loss is equivalent to a median of 15 years' (range 0-40) ageing in the healthy controls.<br><br>INTERPRETATION: The kinetics of haemopoietic engraftment impose replicative stress on the haemopoietic stem cells, resulting in a pronounced ageing effect, which may be sufficient to accelerate the onset of clonal haemopoietic disorders usually associated with later life. Monitoring of haemopoietic status in BMT recipients as time since BMT increases will be important. Assessment of transplant protocols under development in terms of their effects on telomere shortening is also indicated.},
}
@article {pmid9449864,
year = {1998},
author = {Shay, JW},
title = {Accelerated telomere shortening in bone-marrow recipients.},
journal = {Lancet (London, England)},
volume = {351},
number = {9097},
pages = {153-154},
doi = {10.1016/S0140-6736(05)78218-0},
pmid = {9449864},
issn = {0140-6736},
mesh = {Adolescent ; *Bone Marrow Transplantation/pathology ; Cellular Senescence/genetics ; Child ; Child, Preschool ; Hematopoietic Stem Cells/pathology/physiology ; Humans ; Telomerase/physiology ; *Telomere/genetics/pathology ; },
}
@article {pmid9447988,
year = {1998},
author = {Bottius, E and Bakhsis, N and Scherf, A},
title = {Plasmodium falciparum telomerase: de novo telomere addition to telomeric and nontelomeric sequences and role in chromosome healing.},
journal = {Molecular and cellular biology},
volume = {18},
number = {2},
pages = {919-925},
pmid = {9447988},
issn = {0270-7306},
mesh = {Animals ; Base Sequence ; Cellular Senescence ; *DNA Repair ; *DNA, Protozoan ; Molecular Sequence Data ; Plasmodium falciparum/*enzymology ; Reverse Transcriptase Inhibitors/pharmacology ; Ribonuclease, Pancreatic/metabolism ; Telomerase/antagonists &amp; inhibitors/*metabolism ; },
abstract = {Telomerase, a specialized cellular reverse transcriptase, compensates for chromosome shortening during the proliferation of most eucaryotic cells and contributes to cellular immortalization. The mechanism used by the single-celled protozoan malaria parasite Plasmodium falciparum to complete the replication of its linear chromosomes is currently unknown. In this study, telomerase activity has for the first time been identified in cell extracts of P. falciparum. The de novo synthesis of highly variable telomere repeats to the 3' end of DNA oligonucleotide primers by plasmodial telomerase is demonstrated. Permutated telomeric DNA primers are extended by the addition of the next correct base. In addition to elongating preexisting telomere sequences, P. falciparum telomerase can also add telomere repeats onto nontelomeric 3' ends. The sequence GGGTT was the predominant initial DNA sequence added to the nontelomeric 3' ends in vitro. Poly(C) at the 3' end of the oligonucleotide significantly alters the precision of the new telomerase added repeats. The efficiency of nontelomeric primer elongation was dependent on the presence of a G-rich cassette upstream of the 3' terminus. Oligonucleotide primers based on natural P. falciparum chromosome breakpoints are efficiently used as telomerase substrates. These results imply that P. falciparum telomerase contributes to chromosome maintenance and to de novo telomere formation on broken chromosomes. Reverse transcriptase inhibitors such as dideoxy GTP efficiently inhibit P. falciparum telomerase activity in vitro. These data point to malaria telomerase as a new target for the development of drugs that could induce parasite cell senescence.},
}
@article {pmid9446817,
year = {1998},
author = {Tomáska, L},
title = {Phosphorylation of mitochondrial telomere binding protein of Candida parapsilosis by camp-dependent protein kinase.},
journal = {Biochemical and biophysical research communications},
volume = {242},
number = {2},
pages = {457-460},
doi = {10.1006/bbrc.1997.7968},
pmid = {9446817},
issn = {0006-291X},
mesh = {Candida/*metabolism ; Cross-Linking Reagents/metabolism ; Cyclic AMP-Dependent Protein Kinases/*metabolism ; DNA, Mitochondrial/metabolism ; DNA, Single-Stranded/genetics/metabolism ; DNA-Binding Proteins/analysis/*metabolism ; Electrophoresis, Polyacrylamide Gel ; Fungal Proteins/genetics/metabolism ; Glutaral/metabolism ; Mitochondria/chemistry/*metabolism ; Phosphorylation ; Telomere/*metabolism ; },
abstract = {Mitochondrial telomere-binding protein (mtTBP) of Candida parapsilosis binds with high affinity to 5' single-stranded overhang of the linear mitochondrial DNA of this yeast (Tomáska, L'., Nosek, J., and Fukuhara, H. (1997) J. Biol. Chem. 272, 3049-3056). Here it is reported that mtTBP is phosphorylated by catalytic subunit of cAMP-dependent protein kinase in vitro. Phosphorylated mtTBP has dramatically reduced ability to bind telomeric oligonucleotide in the gel-mobility retardation assay without affecting the oligomerization of mtTBP in vitro. MtTBP is one of the few mitochondrial proteins and the first mitochondrial single-strand DNA binding proteins that was demonstrated to serve as a substrate for cAMP-dependent protein kinase.},
}
@article {pmid9398323,
year = {1997},
author = {Carlson, DL and Skopp, R and Price, CM},
title = {DNA-Binding properties of the replication telomere protein.},
journal = {Biochemistry},
volume = {36},
number = {50},
pages = {15900-15908},
doi = {10.1021/bi971833d},
pmid = {9398323},
issn = {0006-2960},
support = {GM41803/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Binding, Competitive ; Blotting, Western ; Conserved Sequence/genetics ; DNA, Protozoan/*metabolism ; DNA-Binding Proteins/*metabolism ; Deoxyribonucleotides/chemistry/metabolism ; Euplotes/chemistry ; Evolution, Molecular ; Molecular Sequence Data ; Oxytricha/chemistry ; *Protozoan Proteins ; Recombinant Proteins/metabolism ; Saccharomyces cerevisiae/genetics ; Telomere/genetics/metabolism ; },
abstract = {The replication Telomere Protein, rTP, is a nuclear protein from the ciliate Euplotes crassus that appears to be a novel telomere replication factor. rTP shares extensive amino acid sequence identity with the two proteins that bind and protect the macronuclear telomeres from the ciliates Oxytricha and Euplotes. Since the most extended regions of conservation fall within the DNA-binding domains of the telomere-binding proteins, when rTP was first identified it was predicted to be another structural telomere-binding protein. However, subsequent research demonstrated that rTP transcripts accumulate only during DNA replication and the rTP protein localizes to the sites of DNA replication within Euplotes macronuclei. We have now expressed rTP in a heterologous expression system and have examined the DNA-binding properties of the recombinant protein. We show that rTP binds specifically to the G-strand of Euplotes telomeric DNA and hence has some of the same DNA-binding characteristics as the Euplotes and Oxytricha telomere-binding proteins. However, other aspects of rTP binding are unique. In particular, the protein exhibits a very high off-rate and can bind double-stranded DNA as well as internal tracts of telomeric sequence. We conclude that rTP and the telomere-binding proteins are members of a class of proteins that have a conserved DNA-binding motif tailored to bind the G-strand of telomeric DNA. However, the unique DNA-binding characteristics of rTP indicate that the protein has evolved to fulfil a specialized role during telomere replication.},
}
@article {pmid9438392,
year = {1998},
author = {Kang, MK and Guo, W and Park, NH},
title = {Replicative senescence of normal human oral keratinocytes is associated with the loss of telomerase activity without shortening of telomeres.},
journal = {Cell growth &amp; differentiation : the molecular biology journal of the American Association for Cancer Research},
volume = {9},
number = {1},
pages = {85-95},
pmid = {9438392},
issn = {1044-9523},
support = {DE10598/DE/NIDCR NIH HHS/United States ; DE11229/DE/NIDCR NIH HHS/United States ; },
mesh = {Adult ; Cell Differentiation/genetics ; Cell Division/genetics ; Cell Line ; Cell Line, Transformed ; Cellular Senescence/*genetics ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins/metabolism ; Humans ; Keratinocytes/cytology/*enzymology/metabolism ; Middle Aged ; Mouth Mucosa/*cytology ; Telomerase/*metabolism ; *Telomere ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Telomerase activity was analyzed in 7 different cultures of secondary normal human oral keratinocytes (NHOKs), 1 normal human oral epithelial tissue specimen, 1 immortalized human oral keratinocyte (HOK) cell line, and 10 human oral cancer cell lines using the PCR-based telomeric repeat amplification protocol assay. Telomerase activity was found in all tested cells and tissue, but the activity in NHOKs and epithelial tissue was lower than that in other tested cell lines. Inasmuch as continued subculture of NHOKs results in replicative senescence, we investigated the association between telomerase activity and replicative senescence by evaluating the enzyme activity in NHOK cultures with different population doubling levels. Three different NHOK cultures were independently subcultured until these cells reached the postmitotic stage. Unlike in fibroblasts derived from the human oral cavity, significant telomerase activity was detected in rapidly proliferating NHOKs, and telomerase activity was barely detectable in the keratinocytes near and at senescence. However, the terminal restriction fragment consisting of telomeric DNA was found to be constantly maintained at approximately 6.0 kilobases in NHOKs without any detectable shortening of telomeres by subcultures. Intracellular p53 and p21WAF1/CIP1 protein levels in NHOKs were gradually and significantly diminished by the passage of cells. These data indicate that actively proliferating NHOKs contain telomerase activity and that replicative senescence of NHOKs is associated with the loss of telomerase activity without shortening of telomeres. However, replicative senescence of NHOKs is apparently not linked to an accumulation of wild-type p53 and/or p21WAF1/CIP1 proteins in these cells.},
}
@article {pmid9436916,
year = {1998},
author = {Engelhardt, M and Ozkaynak, MF and Drullinsky, P and Sandoval, C and Tugal, O and Jayabose, S and Moore, MA},
title = {Telomerase activity and telomere length in pediatric patients with malignancies undergoing chemotherapy.},
journal = {Leukemia},
volume = {12},
number = {1},
pages = {13-24},
doi = {10.1038/sj.leu.2400889},
pmid = {9436916},
issn = {0887-6924},
support = {U9 CA 67842-01/CA/NCI NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Antineoplastic Agents/*therapeutic use ; Bone Marrow Cells/enzymology/pathology ; Child ; Child, Preschool ; Female ; Granulocytes/enzymology ; Humans ; Infant ; Leukemia, Myeloid, Acute/blood/*drug therapy/*enzymology/pathology ; Leukocytes, Mononuclear/enzymology ; Male ; Neoplasms/blood/*drug therapy/*enzymology/pathology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood/*drug therapy/*enzymology/pathology ; Regression Analysis ; Telomerase/blood/*metabolism ; *Telomere ; },
abstract = {Telomerase activity and telomere length in mononuclear cells (MNCs) and granulocytes from peripheral blood (PB) and bone marrow (BM) specimens were studied in pediatric acute leukemia (ALL, n = 15; AML, n = 11) and pediatric solid tumor (ST) patients (n = 9) at diagnosis, during and after chemotherapy. In four ST patients, tumor tissue was also available. For comparative analysis, MNCs from healthy donors (n = 53) were analyzed. Telomerase was evaluated using a modified telomeric repeat amplification protocol (TRAP) assay, and telomere length by terminal restriction fragment (TRF) analysis. At diagnosis, high telomerase activity was detected in MNCs from all leukemia patients, which was similar to the activity from ST biopsy specimens. This exceeded by 10- to 20-fold the activity in PB MNCs from ST patients and healthy donors (P < 0.05). Granulocyte fractions lacked telomerase activity in all groups. BM MNCs in leukemia patients revealed a four-fold higher telomerase activity than PB (P = 0.005). After induction chemotherapy and response to treatment, telomerase activity decreased to borderline or undetectable levels in PB MNCs in leukemia (P < 0.01). Average telomeres in PB MNCs from pediatric patients were significantly longer (n = 25; 10.9 kbp) than telomeres in PB and BM MNCs from adult healthy donors (7.45 kbp) (P < 0.0001). At diagnosis, telomeres were shorter from BM compared to PB specimens in leukemia (P < 0.05), and two peak TRFs were observed corresponding to the malignant and normal cell clones. With the attainment of remission, the lower TRF peak, reflecting the leukemic population, was lost. In leukemia patients, mean TRFs increased on average 2.2 kbp after induction chemotherapy, but decreased thereafter on consolidation and maintenance chemotherapy (1 kbp). This was comparable to an average telomere loss of 1.2 kbp in PB specimens from ST patients after chemotherapy. In all patients, telomere loss in granulocytes as compared to MNCs was more pronounced with 1.8 vs 1 kbp, respectively (P = 0.014). Our results demonstrate that at diagnosis, telomerase was consistently and highly upregulated in BM and PB specimens in leukemia, decreased after induction therapy, and correlated with remission. BM specimens in leukemia had higher telomerase activity, probably due to the greater leukemic burden than in PB. Telomeres were significantly longer in children than in adults, but shortened as a consequence of chemotherapy with repeated cycles of hematopoietic regeneration. In acute leukemia, with the loss of the leukemic burden after induction chemotherapy, longer mean TRFs were found, a reflection of the repopulation with normal cells. Our findings suggest that telomerase activity may be useful in the management of childhood malignancies. The significance of telomere length shortening in pediatric patients undergoing chemotherapy and possible telomere regeneration after myelosuppressive treatment remain to be determined.},
}
@article {pmid9435798,
year = {1997},
author = {Soria, JC and Rixe, O},
title = {[Telomeres, telomerase and cancer].},
journal = {Bulletin du cancer},
volume = {84},
number = {10},
pages = {963-970},
pmid = {9435798},
issn = {0007-4551},
mesh = {Animals ; Cell Division ; Cellular Senescence ; Enzyme Activation ; Enzyme Inhibitors/therapeutic use ; Humans ; Mice ; Neoplasm Proteins/analysis/antagonists &amp; inhibitors/*metabolism ; Neoplasms/drug therapy/*enzymology/pathology ; Prognosis ; Telomerase/analysis/antagonists &amp; inhibitors/*metabolism ; Telomere/chemistry/*physiology ; },
abstract = {The chromosome ends are specialized nucleoprotein structures called telomeres, which length predicts replicative capacity of cells. Activation of telomerase, the DNA polymerase that synthesizes telomeric repeats, seems to be necessary for cells to become immortal. Methods of measuring telomerase activity, now reliable and semiquantitative, have shown that telomerase is expressed in most human cancers, but not in normal somatic tissues. Research about regulation of telomere length and telomerase activity, highlights connexions between senescence and cancer. This article details diagnosis, prognosis and therapeutic prospects linked to the study of telomerase activity.},
}
@article {pmid9434158,
year = {1998},
author = {Yoon, HJ and Choi, IY and Kang, MR and Kim, SS and Muller, MT and Spitzner, JR and Chung, IK},
title = {DNA topoisomerase II cleavage of telomeres in vitro and in vivo.},
journal = {Biochimica et biophysica acta},
volume = {1395},
number = {1},
pages = {110-120},
doi = {10.1016/s0167-4781(97)00139-5},
pmid = {9434158},
issn = {0006-3002},
support = {P30-CA16058/CA/NCI NIH HHS/United States ; R01-CA63653/CA/NCI NIH HHS/United States ; },
mesh = {DNA/genetics/*metabolism ; DNA Topoisomerases, Type II/*metabolism ; Enzyme Inhibitors/pharmacology ; Etoposide/pharmacology ; HeLa Cells ; Humans ; Repetitive Sequences, Nucleic Acid ; Sequence Analysis, DNA ; Telomere/*metabolism ; Topoisomerase II Inhibitors ; },
abstract = {In this work, we have analyzed the reactivity of DNA topoisomerase II with telomeric DNA both in vitro and in vivo. Topoisomerase II cleavage reactions were performed on the tandem repeats of telomeric DNA. Analysis of this DNA on sequencing gels revealed that DNA topoisomerase II is catalytically active in cleaving the telomere DNA repeat. The topoisomerase II cleavage site is 5'TTAGG*G3' (cleavage site marked by the asterisk) and since telomere DNA is a tandem array of the above sequence, topoisomerase cleavage sites could exist every six base pairs. Detection of topoisomerase II cleavages was strongly dependent upon one specific topoisomerase II poison, etoposide (VP-16). A number of other topoisomerase II poisons were tested but did not stimulate cleavage activity at the telomere repeat. We have also analyzed the association of endogenous topoisomerase II with chromosomal telomeric DNA in HeLa cells. The in vivo complex of enzyme (ICE) bioassay was used to isolate topoisomerase II-DNA covalent complexes. In consistence with in vitro cleavage data, endogenous topoisomerase II-telomeric DNA complexes were detected in only etoposide-treated HeLa cells.},
}
@article {pmid9426615,
year = {1997},
author = {Ohmido, N and Fukui, K},
title = {Visual verification of close disposition between a rice A genome-specific DNA sequence (TrsA) and the telomere sequence.},
journal = {Plant molecular biology},
volume = {35},
number = {6},
pages = {963-968},
pmid = {9426615},
issn = {0167-4412},
mesh = {Chromosome Mapping/*methods ; DNA, Plant/*analysis ; *Genome, Plant ; In Situ Hybridization, Fluorescence ; Oryza/chemistry/*genetics ; *Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; },
abstract = {A rice A genome-specific tandem repeat sequence (TrsA) and telomeric nucleotide sequences, (TTTAGGG)n, were simultaneously detected by multicolor fluorescence in situ hybridization (McFISH) using rice prometaphase chromosomes. Six pairs of TrsA sites visualized by fluorescence signals were all localized on the long arms close to the telomeric regions. Differences in the copy number of TrsA at the different sites were visualized both by the size of the telomeric condensation block stained with Giemsa solution and the signal intensity after FISH with TrsA. McFISH analyses using interphase nuclei could resolve close disposition of TrsA and telomere and also gave rough estimation of the distance between them. The functional significance of the close disposition of TrsA and telomere is discussed.},
}
@article {pmid9426325,
year = {1997},
author = {Sharma, S and Raymond, E and Soda, H and Sun, D and Hilsenbeck, SG and Sharma, A and Izbicka, E and Windle, B and Von Hoff, DD},
title = {Preclinical and clinical strategies for development of telomerase and telomere inhibitors.},
journal = {Annals of oncology : official journal of the European Society for Medical Oncology},
volume = {8},
number = {11},
pages = {1063-1074},
doi = {10.1023/a:1008206420505},
pmid = {9426325},
issn = {0923-7534},
support = {K-12 CA01723/CA/NCI NIH HHS/United States ; U19 CA67760/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Breast Neoplasms/enzymology/etiology/genetics ; Cell Survival/physiology ; Cell Transformation, Neoplastic ; DNA Replication/physiology ; DNA, Neoplasm/*genetics ; Female ; Humans ; In Vitro Techniques ; Male ; Neoplasms/drug therapy/*enzymology ; Polymerase Chain Reaction ; Prostatic Neoplasms/enzymology/etiology/genetics ; *Telomerase/antagonists &amp; inhibitors/metabolism/therapeutic use ; Telomere/*enzymology/ultrastructure ; },
abstract = {BACKGROUND: Telomerase is an important enzyme whose activity has been convincingly demonstrated in humans recently. It is required for maintenance of ends of chromosomes (telomeres) during cell division. Since its presence has been selectively demonstrated in dividing cells including tumor cells, it has generated considerable excitement as a potential anti-cancer strategy.<br><br>DESIGN: In this article, we review the current relevant biology of the enzyme, the challenges encountered in the preclinical phase of target development and the current efforts that focus on telomeres and telomerase as therapeutic targets. We also speculate on the potential toxicities and mechanisms of resistance that may be encountered during use of such therapies.},
}
@article {pmid9425906,
year = {1998},
author = {Martens, UM and Zijlmans, JM and Poon, SS and Dragowska, W and Yui, J and Chavez, EA and Ward, RK and Lansdorp, PM},
title = {Short telomeres on human chromosome 17p.},
journal = {Nature genetics},
volume = {18},
number = {1},
pages = {76-80},
doi = {10.1038/ng0198-018},
pmid = {9425906},
issn = {1061-4036},
support = {AI29524/AI/NIAID NIH HHS/United States ; GM56162/GM/NIGMS NIH HHS/United States ; },
mesh = {Adult ; Bone Marrow Cells ; Carbocyanines ; Cells, Cultured ; *Chromosomes, Human, Pair 17 ; Fibroblasts/cytology ; Fluorescent Dyes ; Humans ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Indoles ; Metaphase ; Repetitive Sequences, Nucleic Acid ; *Telomere ; },
abstract = {Human chromosomes terminate in a series of T2AG3 repeats, which, together with associated proteins, are essential for chromosome stability. In somatic cells, these sequences are known to be gradually lost through successive cells divisions; however, information about changes on specific chromosomes is not available. Individual telomeres could mediate important biological effects as was shown in yeast, in which loss of a single telomere results in cell-cycle arrest and chromosome loss. We now demonstrate by quantitative fluorescence in situ hybridization (Q-FISH; ref. 7) that the number of T2AG3 repeats on specific chromosome arms is very similar in different tissues from the same donor and varies only to some extent between donors. In all sixteen individuals studied, telomeres on chromosome 17p were shorter than the median telomere length--a finding confirmed by analysis of terminal restriction fragments from sorted chromosomes. These observations provide evidence of chromosome-specific factors regulating the number of T2AG3 repeats in individual telomeres and raise the possibility that the relatively short telomeres on chromosome 17p contribute to the frequent loss of 17p alleles in human cancers.},
}
@article {pmid9422061,
year = {1997},
author = {Tahara, H and Tahara, E and Tahara, E and Ide, T},
title = {[Telomere and telomerase associated genes].},
journal = {Gan to kagaku ryoho. Cancer &amp; chemotherapy},
volume = {24},
number = {15},
pages = {2196-2201},
pmid = {9422061},
issn = {0385-0684},
mesh = {DNA-Binding Proteins ; Humans ; Neoplasms/*diagnosis/genetics/pathology ; Proteins/metabolism ; *RNA ; Telomerase/*genetics/metabolism ; Telomere/*genetics ; Tumor Cells, Cultured ; },
abstract = {Telomerase is a ribonucleoprotein, telomere specific reverse transcriptase, which contains some protein components and telomerase RNA components. Human telomerase RNA and some telomerase components have been identified but not completely. More recently, human telomerase catarytic subunits have been cloned, which are called hTRT or hEST2. The expression of hTRT in human cultured cells is well correlated with telomerase activity and immortality. Moreover, the expression of hTRT in cancer tissues is higher than that of normal tissues. These results suggested that hTRT and telomerase activity may be a powerful additional tool for cancer diagnosis.},
}
@article {pmid9418874,
year = {1998},
author = {Bassham, S and Beam, A and Shampay, J},
title = {Telomere variation in Xenopus laevis.},
journal = {Molecular and cellular biology},
volume = {18},
number = {1},
pages = {269-275},
pmid = {9418874},
issn = {0270-7306},
mesh = {Animals ; DNA/genetics ; Genetic Variation ; Humans ; *Polymorphism, Genetic ; Restriction Mapping ; Sequence Analysis ; Telomere/*genetics ; Xenopus laevis/*genetics ; },
abstract = {Eukaryotic telomeres are variable at several levels, from the length of the simple sequence telomeric repeat tract in different cell types to the presence or number of telomere-adjacent DNA sequence elements in different strains or individuals. We have investigated the sequence organization of Xenopus laevis telomeres by use of the vertebrate telomeric repeat (TTAGGG)n and blot hybridization analysis. The (TTAGGG)n-hybridizing fragments, which ranged from less than 10 to over 50 kb with frequently cutting enzymes, defined a pattern that was polymorphic between individuals. BAL 31 exonuclease treatment confirmed that these fragments were telomeric. The polymorphic fragments analyzed did not hybridize to 5S RNA sequences, which are telomeric according to in situ hybridization. When telomeric fragments from offspring (whole embryos) were compared to those from the spleens of the parents, the inheritance pattern of some bands was found to be unusual. Furthermore, in one cross, the telomeres of the embryo were shorter than the telomeres of the parents' spleen, and in another, the male's testis telomeres were shorter than those of the male's spleen. Our data are consistent with a model for chromosome behavior that involves a significant amount of DNA rearrangement at telomeres and suggest that length regulation of Xenopus telomeres is different from that observed for Mus spretus and human telomeres.},
}
@article {pmid9403058,
year = {1997},
author = {Chute, I and Le, Y and Ashley, T and Dobson, MJ},
title = {The telomere-associated DNA from human chromosome 20p contains a pseudotelomere structure and shares sequences with the subtelomeric regions of 4q and 18p.},
journal = {Genomics},
volume = {46},
number = {1},
pages = {51-60},
doi = {10.1006/geno.1997.5007},
pmid = {9403058},
issn = {0888-7543},
mesh = {Chromosomes, Artificial, Yeast/genetics ; Chromosomes, Human, Pair 18/genetics ; Chromosomes, Human, Pair 20/*genetics ; Chromosomes, Human, Pair 4/genetics ; Cloning, Molecular ; DNA/analysis/genetics ; Gene Dosage ; Humans ; Mitosis ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid/*genetics ; Restriction Mapping ; Sequence Homology, Nucleic Acid ; Telomere/*genetics ; },
abstract = {The human chromosome 20p telomere has been cloned on a yeast artificial chromosome (YAC). The telomere-associated DNA contains an interstitial tract of (TTAGGG)n telomeric repeats 60 kb in from the chromosome end. Frequent truncation of the YAC clone was observed due to resolution of the internal telomeric array into a telomere. The 20p internal telomeric repeat tract is flanked on its centromeric side by telomere-associated repeated sequences that have previously been found adjacent to terminal telomeric repeat arrays. The pseudotelomere structure of the 20p subtelomeric region is similar to the structure of some yeast subtelomeric regions where these sequences act as substrates for recombinational repair of chromosome ends that have lost their terminal telomeric repeat arrays. Sequences flanking the telomeric end of the internal (TTAGGG)n repeat array on 20p are found adjacent to three other subtelomeric (TTAGGG)n tracts on 4q, 18p, and an unknown chromosome end, respectively. These shared sequences provide evidence of exchange between nonhomologous chromosomes in humans.},
}
@article {pmid9402027,
year = {1997},
author = {Casjens, S and Murphy, M and DeLange, M and Sampson, L and van Vugt, R and Huang, WM},
title = {Telomeres of the linear chromosomes of Lyme disease spirochaetes: nucleotide sequence and possible exchange with linear plasmid telomeres.},
journal = {Molecular microbiology},
volume = {26},
number = {3},
pages = {581-596},
doi = {10.1046/j.1365-2958.1997.6051963.x},
pmid = {9402027},
issn = {0950-382X},
mesh = {Amino Acid Sequence ; Base Sequence ; Borrelia burgdorferi Group/*genetics/isolation &amp; purification ; *Chromosomes, Bacterial ; Cloning, Molecular ; DNA, Bacterial ; Lyme Disease/*microbiology ; Molecular Sequence Data ; Plasmids/*genetics ; Polymerase Chain Reaction ; Polymorphism, Genetic ; *Recombination, Genetic ; Sequence Homology, Amino Acid ; Sequence Homology, Nucleic Acid ; *Telomere ; },
abstract = {Bacteria of the spirochaete genus Borrelia have linear chromosomes about 950 kbp in size. We report here that these linear chromosomes have covalently closed hairpin structures at their termini that are similar but not identical to those reported for linear plasmids carried by these organisms. Nucleotide sequence analysis of the chromosomal telomeric regions indicates that unique, apparently functional genes lie within a few hundred bp of each of the telomeres, and that there is an imperfect 26 bp inverted repeat at the two telomeres. In addition, we characterize a major chromosomal length polymorphism within the right telomeric regions of various Borrelia isolates, and show that sequences similar to those near the right telomere are often found on linear plasmids in B. burgdorferi (sensu stricto) isolates from nature. Sequences similar to a number of other regions of the chromosome, including those near the left telomere, were not found on B. burgdorferi plasmids. These observations suggest that there has been historical exchange of genetic information between the linear plasmids and the right end of the linear chromosome.},
}
@article {pmid9400992,
year = {1997},
author = {Smilenov, LB and Morgan, SE and Mellado, W and Sawant, SG and Kastan, MB and Pandita, TK},
title = {Influence of ATM function on telomere metabolism.},
journal = {Oncogene},
volume = {15},
number = {22},
pages = {2659-2665},
doi = {10.1038/sj.onc.1201449},
pmid = {9400992},
issn = {0950-9232},
support = {CA71387/CA/NCI NIH HHS/United States ; NS34746/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; Ataxia Telangiectasia/genetics ; Ataxia Telangiectasia Mutated Proteins ; Carcinoma/genetics/radiotherapy ; Cell Cycle Proteins ; Colorectal Neoplasms/genetics/radiotherapy ; DNA-Binding Proteins/genetics/metabolism ; Fibroblasts ; G1 Phase/genetics ; G2 Phase/genetics ; Humans ; Leucine Zippers/genetics ; Metaphase/genetics ; *Protein Serine-Threonine Kinases ; Proteins/*genetics/metabolism ; Recombinant Proteins/genetics/metabolism ; Telomerase/metabolism ; Telomere/*genetics/*metabolism ; Transfection ; Tumor Cells, Cultured ; Tumor Suppressor Proteins ; },
abstract = {The ATM gene product, which is defective in the cancer-prone disorder ataxia telangiectasia, has been implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination and cell cycle control. The ATM gene has homology with the TEL1 gene of yeast, mutations of which lead to shortened telomeres. To test the hypothesis that the ATM gene product is involved in telomere metabolism, we examined telomeric associations (TA), telomere length, and telomerase activity in human cells expressing either dominant-negative or complementing fragments of the ATM gene. The phenotype of RKO colorectal tumor cells expressing ATM fragments containing a leucine zipper (LZ) motif mimics that of ataxia telangiectasia (A-T) cells. These transfected RKO cells relative to transfected controls had a higher frequency of cells with TA and shortened telomeres, but no detectable change in telomerase activity. In addition, the percentage of cells with TA after gamma irradiation was higher in the transfected RKO cells with dominant negative activity of the ATM gene, compared to control cells. SV40 transformed fibroblasts derived from an A-T patient and transfected with a complementing carboxyl terminal kinase region of the ATM gene had a reduced frequency of cells with TA, with no effect on the telomere length or telomerase activity. The present studies using isogenic cells with manipulated ATM function demonstrate a role for the ATM gene product in telomere metabolism.},
}
@article {pmid9371803,
year = {1997},
author = {Monson, EK and de Bruin, D and Zakian, VA},
title = {The yeast Cac1 protein is required for the stable inheritance of transcriptionally repressed chromatin at telomeres.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {94},
number = {24},
pages = {13081-13086},
pmid = {9371803},
issn = {0027-8424},
support = {GM43265/GM/NIGMS NIH HHS/United States ; R01 GM043265/GM/NIGMS NIH HHS/United States ; GM26938/GM/NIGMS NIH HHS/United States ; F32 GM016593/GM/NIGMS NIH HHS/United States ; R37 GM026938/GM/NIGMS NIH HHS/United States ; R01 GM026938/GM/NIGMS NIH HHS/United States ; GM16593/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatin/*genetics ; Chromatin Assembly Factor-1 ; *Chromosomal Proteins, Non-Histone ; DNA, Fungal ; DNA-Binding Proteins/*metabolism ; RNA, Fungal ; Saccharomyces cerevisiae/*genetics/metabolism ; *Telomere ; Transcription, Genetic ; },
abstract = {Cac1p is a subunit of yeast chromatin assembly factor I (yCAF-I) that is thought to assemble nucleosomes containing diacetylated histones onto newly replicated DNA [Kaufman, P. D., Kobayashi, R. &amp; Stillman, B. (1997) Genes Dev. 11, 345-357]. Although cac1 delta cells could establish and maintain transcriptional repression at telomeres, they displayed a reduced heritability of the repressed state. Single-cell analysis revealed that individual cac1 delta cells switch from transcriptionally "off" to transcriptionally "on" more often per cell cycle than wild-type cells. In addition, cac1 delta cells were defective for transcriptional silencing near internal tracts of C(1-3)A sequence, but they showed no defect in silencing at the silent mating type loci when analyzed by a reverse transcription-PCR assay. Despite the loss of transcriptional silencing at telomeres and internal C(1-3)A tracts, subtelomeric DNA was organized into nucleosomes that had all of the features characteristic of silent chromatin, such as hypoacetylation of histone H4 and protection from methylation by the Escherichia coli dam methylase. Thus, these features of silent chromatin are not sufficient for stable maintenance of a silent chromatin state. We propose that the inheritance of the transcriptionally repressed state requires the specific pattern of histone acetylation conferred by yCAF-I-mediated nucleosome assembly.},
}
@article {pmid9395190,
year = {1997},
author = {Boultwood, J and Fidler, C and Kusec, R and Rack, K and Elliott, PJ and Atoyebi, O and Chapman, R and Oscier, DG and Wainscoat, JS},
title = {Telomere length in myelodysplastic syndromes.},
journal = {American journal of hematology},
volume = {56},
number = {4},
pages = {266-271},
doi = {10.1002/(sici)1096-8652(199712)56:4&lt;266::aid-ajh12&gt;3.0.co;2-7},
pmid = {9395190},
issn = {0361-8609},
mesh = {Adult ; Aged ; Aged, 80 and over ; Blotting, Southern ; Bone Marrow Cells/pathology ; DNA Probes/chemistry ; Granulocytes/pathology ; Humans ; Karyotyping ; Lymphocytes/pathology ; Middle Aged ; Myelodysplastic Syndromes/blood/*genetics/pathology ; Reference Values ; Repetitive Sequences, Nucleic Acid ; Telomere/*genetics/ultrastructure ; },
abstract = {We have studied telomere length in the bone marrow cells or the granulocyte and lymphocyte cell fractions of 54 patients with myelodysplastic syndromes (MDS) by Southern blot hybridization using the (TTAGGG)4 probe. The average telomere length expressed as the peak telomere repeat array (TRA) in the peripheral blood, or bone marrow samples obtained from a group of 21 healthy age-matched controls (26-89 years old, mean age 55), ranged between 7.5 and 9.5 kb (mean peak TRA 8.6 kb). Twenty-four patients with refractory anemia (RA) were studied; 10/24 (42%) had telomere reduction (<7.5 kb) relative to age-matched controls and the mean peak TRA was 7.5 kb (range 4.0-9.0 kb). Eleven patients with RA with excess blasts (RAEB) were studied; 5/11 (45%) had reduced telomeres relative to age-matched controls and the mean peak TRA was 7.1 kb (range 5.0-9.0 kb). Eighteen patients with MDS in transformation to AML, comprising 15 with RAEB in transformation (RAEBt) and 3 with CMML in transformation (CMMLt), were also studied. Thirteen of eighteen patients (72%) had telomere reduction relative to age-matched controls and the mean peak TRA was 6.1 kb (range 3.5-9.0 kb). Thirty-six patients included in the study had either a normal karyotype or a simple karyotype (1 karyotypic change) and 20/36 (55%) of these had telomere reduction and the mean peak TRA was 7.1 kb (range 4.3-9.0 kb); 8 patients had a complex karyotype (3 or more karyotypic changes) and 5/8 (62%) of these had telomere reduction and the mean peak TRA was 6.1 kb (range 3.5-9.0 kb). We conclude, firstly that there is heterogeneity of telomere length in MDS and that this is observed throughout the spectrum of FAB-subtypes. Secondly, these data show that a marked reduction in telomere length in MDS if often associated with leukemic transformation and with the presence of complex karyotypic abnormalities.},
}
@article {pmid9367854,
year = {1997},
author = {Morii, K and Tanaka, R and Onda, K and Tsumanuma, I and Yoshimura, J},
title = {Expression of telomerase RNA, telomerase activity, and telomere length in human gliomas.},
journal = {Biochemical and biophysical research communications},
volume = {239},
number = {3},
pages = {830-834},
doi = {10.1006/bbrc.1997.7562},
pmid = {9367854},
issn = {0006-291X},
mesh = {Astrocytoma/*enzymology/genetics ; Blotting, Southern ; Brain Neoplasms/*enzymology/genetics ; Enzyme Activation/genetics ; Glioblastoma/*enzymology/genetics ; Humans ; Male ; Middle Aged ; Polymerase Chain Reaction ; RNA, Neoplasm/*biosynthesis ; Telomerase/biosynthesis/*genetics/metabolism ; Telomere/*chemistry/enzymology/genetics ; },
abstract = {To understand the mechanisms of telomere maintenance in human gliomas, telomerase activity, telomerase RNA expression and telomere length of surgically excised glioma samples were analyzed. Sixty-five percent of gliomas exhibited telomerase activity, the occurrence of which was not related to their histological malignancy scale. Not only the telomerase-positive gliomas, but also the telomerase-negative gliomas and normal brain expressed telomerase RNA, suggesting that the presence of telomerase RNA component does not indicate the presence of telomerase activity. Compared with telomerase-positive gliomas, telomerase-negative gliomas had long heterogeneous telomeric terminal restriction fragments. These data suggest that in addition to the telomerase-dependent mechanism, a telomerase-independent mechanism for telomere maintenance may be present in human gliomas.},
}
@article {pmid9367622,
year = {1997},
author = {Mondello, C and Riboni, R and Casati, A and Nardo, T and Nuzzo, F},
title = {Chromosomal instability and telomere length variations during the life span of human fibroblast clones.},
journal = {Experimental cell research},
volume = {236},
number = {2},
pages = {385-396},
doi = {10.1006/excr.1997.3756},
pmid = {9367622},
issn = {0014-4827},
mesh = {Cellular Senescence/*genetics ; *Chromosome Aberrations ; Chromosome Banding ; Clone Cells ; Fibroblasts/cytology/radiation effects ; Humans ; Karyotyping ; Metaphase ; Mitosis ; Telomere/*genetics ; Ultraviolet Rays/adverse effects ; Xeroderma Pigmentosum/genetics ; },
abstract = {Growth characteristics, karyotype changes, and telomere length variations were analyzed during the life span of 12 anchorage-independent clones isolated from a xeroderma pigmentosum fibroblast strain. After an initial period of comparable active growth, all the clones showed a decline in the growth rate and finally entered a phase of replicative senescence; however, the number of population doublings and the time required to enter senescence varied among the clones. Repeated cytogenetic analyses during culture propagation showed the appearance of chromosome anomalies, mainly telomeric association (tas) and unbalanced translocations. In all the clones the percentage of abnormal mitoses increased with culture passage, but reached different levels (from less than 10% to about 100%). This finding indicates that the replicative block may be associated with differently altered cytogenetic patterns. Specific chromosome arms (5p, 16q, 19q, and 20q) were preferentially involved in tas, suggesting that alterations in chromosome ends may occur which predispose to fusion. In some clones it was possible to demonstrate the origin of marker chromosomes from the evolution of tas. Telomere length analysis by Southern blotting on DNA samples prepared from 7 clones and from the parental cell lines showed that the terminal restriction fragment (TRF) profiles were homogeneous in senescent parental cells and in the clones during the last part of their life in culture, regardless of the degree of karyotype abnormalities. The homogeneity of the TRF profiles supports the hypothesis of a critical telomere length at senescence.},
}
@article {pmid9365237,
year = {1997},
author = {Tahara, H and Tokutake, Y and Maeda, S and Kataoka, H and Watanabe, T and Satoh, M and Matsumoto, T and Sugawara, M and Ide, T and Goto, M and Furuichi, Y and Sugimoto, M},
title = {Abnormal telomere dynamics of B-lymphoblastoid cell strains from Werner's syndrome patients transformed by Epstein-Barr virus.},
journal = {Oncogene},
volume = {15},
number = {16},
pages = {1911-1920},
doi = {10.1038/sj.onc.1201377},
pmid = {9365237},
issn = {0950-9232},
mesh = {B-Lymphocytes/enzymology/*metabolism ; Cell Line, Transformed ; Cell Transformation, Viral ; Chromosome Aberrations ; Herpesvirus 4, Human/*physiology ; Humans ; Telomerase/metabolism ; *Telomere ; Werner Syndrome/enzymology/*genetics/pathology ; },
abstract = {The characteristics of B-lymphoblastoid cell strains transformed by Epstein-Barr virus (EBV) from normal individuals and Werner's syndrome (WRN) patients were compared. We continuously passaged cell strains from 28 WRN patients and 20 normal individuals for about 2 years corresponding to over 160 population doubling levels (PDLs). First, the WRN mutation significantly suppressed the immortalization: all the 28 cell strains from WRN patients, as well as 15 out of 20 cell strains from normal individuals, died out before 160 PDLs mostly without developing a significant telomerase activity. The remaining five cell strains from normal individuals became moderately/strongly telomerase-positive and, three of them were apparently immortalized with an infinitively proliferating activity. Second, the monitoring of the telomere length of both normal and WRN cell strains during the culture period suggests that the WRN gene mutation causes abnormal dynamics of the telomere: (1) a significant proportion of WRN cell strains showed drastic shortening or lengthening of telomere lengths during cell passages compared with normal cell strains, and (2) WRN cell strains terminated their life-span at a wide range of telomere length (between 3.5 and 18.5 Kbp), whereas normal cell strains terminated within a narrow telomere length range (between 5.5 and 9 Kbp). The chromosomal aberration characteristic of WRN cells, including translocation was confirmed in our experiment. We discussed the correlation between the chromosomal instability, abnormal telomere dynamics and inability of immortalization of the WRN B-lymphobloastoid cell strains.},
}
@article {pmid9362059,
year = {1997},
author = {Fan, X and Price, CM},
title = {Coordinate regulation of G- and C strand length during new telomere synthesis.},
journal = {Molecular biology of the cell},
volume = {8},
number = {11},
pages = {2145-2155},
pmid = {9362059},
issn = {1059-1524},
support = {R01 GM041803/GM/NIGMS NIH HHS/United States ; GM-41803/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Aphidicolin/pharmacology ; Base Composition ; Cloning, Molecular ; Cytosine ; DNA Replication/drug effects ; DNA, Protozoan/*biosynthesis/chemistry ; DNA-Directed DNA Polymerase/physiology ; Enzyme Inhibitors/pharmacology ; Euplotes/cytology/*genetics ; Guanine ; Nucleic Acid Synthesis Inhibitors ; Sequence Analysis, DNA ; Telomerase/metabolism ; Telomere/chemistry/*metabolism ; },
abstract = {We have used the ciliate Euplotes to study the role of DNA polymerase in telomeric C strand synthesis. Euplotes provides a unique opportunity to study C strand synthesis without the complication of simultaneous DNA replication because millions of new telomeres are made at a stage in the life cycle when no general DNA replication takes place. Previously we showed that the C-strands of newly synthesized telomeres have a precisely controlled length while the G-strands are more heterogeneous. This finding suggested that, although synthesis of the G-strand (by telomerase) is the first step in telomere addition, a major regulatory step occurs during subsequent C strand synthesis. We have now examined whether G- and C strand synthesis might be regulated coordinately rather than by two independent mechanisms. We accomplished this by determining what happens to G- and C strand length if C strand synthesis is partially inhibited by aphidicolin. Aphidicolin treatment caused a general lengthening of the G-strands and a large increase in C strand heterogeneity. This concomitant change in both the G- and C strand length indicates that synthesis of the two strands is coordinated. Since aphidicolin is a very specific inhibitor of DNA pol alpha and pol delta, our results suggest that this coordinate length regulation is mediated by DNA polymerase.},
}
@article {pmid9359704,
year = {1997},
author = {Bryan, TM and Englezou, A and Dalla-Pozza, L and Dunham, MA and Reddel, RR},
title = {Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines.},
journal = {Nature medicine},
volume = {3},
number = {11},
pages = {1271-1274},
doi = {10.1038/nm1197-1271},
pmid = {9359704},
issn = {1078-8956},
mesh = {Adult ; DNA Nucleotidyltransferases/metabolism ; Deoxyribonucleases, Type II Site-Specific/metabolism ; Humans ; Neoplasms/enzymology/*genetics ; Telomerase/antagonists &amp; inhibitors/*metabolism ; *Telomere/ultrastructure ; Tumor Cells, Cultured ; },
abstract = {The gradual loss of DNA from the ends of telomeres has been implicated in the control of cellular proliferative potential. Telomerase is an enzyme that restores telomeric DNA sequences, and expression of its activity was thought to be essential for the immortalization of human cells, both in vitro and in tumor progression in vivo. Telomerase activity has been detected in 50-100% of tumors of different types, but not in most normal adult somatic tissues. It has also been detected in about 70% of human cell lines immortalized in vitro and in all tumor-derived cell lines examined to date. It has previously been shown that in vitro immortalized telomerase-negative cell lines acquire very long and heterogeneous telomeres in association with immortalization presumably via one or more novel telomere-lengthening mechanisms that we refer to as ALT (alternative lengthening of telomeres). Here we report evidence for the presence of ALT in a subset of tumor-derived cell lines and tumors. The maintenance of telomeres by a mechanism other than telomerase, even in a minority of cancers, has major implications for therapeutic uses of telomerase inhibitors.},
}
@article {pmid9357546,
year = {1997},
author = {Sprung, CN and Bryan, TM and Reddel, RR and Murnane, JP},
title = {Normal telomere maintenance in immortal ataxia telangiectasia cell lines.},
journal = {Mutation research},
volume = {379},
number = {2},
pages = {177-184},
doi = {10.1016/s0027-5107(97)00119-x},
pmid = {9357546},
issn = {0027-5107},
mesh = {Ataxia Telangiectasia/genetics/*pathology ; Cell Line, Transformed ; Humans ; Lymphocytes ; Telomerase/metabolism ; *Telomere ; },
abstract = {Telomeres are maintained in germ line cells and immortal cell lines, but shorten with each cell division in most somatic cells. Blood lymphocytes from individuals with ataxia telangiectasia (AT) demonstrate an accelerated rate of telomere shortening and high levels of telomere associations. This accelerated loss of telomeres in somatic cells in AT could be due to either the loss of more telomeric DNA with every cell division or an increased rate of cell division. The gene for AT shares homology with the yeast TEL1 gene, in which mutations result in abnormally shortened telomeres. Thus, mutations in the gene for ataxia telangiectasia may also influence the ability of germ line cells and immortal cell lines to properly maintain telomere homeostasis. To investigate a possible defect of telomere maintenance in AT we have analyzed 8 simian virus 40 (SV40)-immortalized AT cell lines and twelve SV40-immortalized non-AT cell lines for both telomerase activity and telomere length. The results demonstrate that telomere length in AT cells is maintained via telomerase or an alternative (ALT) pathway in a manner indistinguishable from cell lines derived from normal cells. We also investigated telomere dynamics in one telomerase-positive AT cell line by analyzing the changes in the length of a single telomere, and found that this telomere maintained its equilibrium mean length (EML) similar to normal cell lines with stable chromosomes. The combined results show no significant differences between the telomeres of immortal AT and non-AT cell lines, demonstrating that the absence of wild-type ATM does not result in a fundamental defect in telomere maintenance in these cells.},
}
@article {pmid9326950,
year = {1997},
author = {Broccoli, D and Smogorzewska, A and Chong, L and de Lange, T},
title = {Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2.},
journal = {Nature genetics},
volume = {17},
number = {2},
pages = {231-235},
doi = {10.1038/ng1097-231},
pmid = {9326950},
issn = {1061-4036},
support = {5 T32 GM07739/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Binding Sites ; Cloning, Molecular ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Dimerization ; HeLa Cells ; Humans ; In Vitro Techniques ; Mice ; Microsatellite Repeats ; Molecular Sequence Data ; Oligopeptides ; Peptides/metabolism ; Protein Binding ; Proto-Oncogene Proteins/genetics/metabolism ; Proto-Oncogene Proteins c-myb ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 1 ; Telomeric Repeat Binding Protein 2 ; Trans-Activators/genetics/metabolism ; Transfection ; },
abstract = {Human telomeres are composed of long arrays of TTAGGG repeats that form a nucleoprotein complex required for the protection and replication of chromosome ends. One component of human telomeres is the TTAGGG repeat binding factor 1 (TRF1), a ubiquitously expressed protein, related to the protooncogene Myb, that is present at telomeres throughout the cell cycle. Recent evidence has implicated TRF1 in the control of telomere length. TRF1 is proposed to be an inhibitor of telomerase, acting in cis to limit the elongation of individual chromosome ends. Here we report the cloning of TRF2, a distant homologue of TRF1 that carries a very similar Myb-related DNA-binding motif. Like TRF1, TRF2 was ubiquitously expressed, bound specifically to duplex TTAGGG repeats in vitro and localized to all human telomeres in metaphase chromosomes. TRF2 was shown to have an architecture similar to that of TRF1 in that it carries a C-terminal Myb motif and a large TRF1-related dimerization domain near its N terminus. However, the dimerization domains of TRF1 and TRF2 did not interact, suggesting that these proteins exist predominantly as homodimers. While having similar telomere binding activity and domain organization, TRF2 differed from TRF1 in that its N terminus was basic rather than acidic, and TRF2 was much more conserved than TRF1. The results indicate that the TTAGGG repeat arrays at the ends of human and mouse chromosomes bind to two related proteins. Because TRF1 and TRF2 showed significant differences, we suggest that these factors have distinct functions at telomeres.},
}
@article {pmid9343466,
year = {1997},
author = {Banks, DA and Fossel, M},
title = {Telomeres, cancer, and aging. Altering the human life span.},
journal = {JAMA},
volume = {278},
number = {16},
pages = {1345-1348},
pmid = {9343466},
issn = {0098-7484},
support = {P20-AG-12839/AG/NIA NIH HHS/United States ; },
mesh = {Aging/genetics ; Cellular Senescence/*genetics ; Cloning, Organism ; Gene Expression ; Humans ; *Life Expectancy/trends ; Longevity/*genetics ; Neoplasms/pathology ; Public Policy ; Telomere ; },
abstract = {Population projections of the aging global society and its fiscal and social impact have depended on assumptions regarding the human life span. Until now, the assumption that the maximum human life span is fixed has been justified. Recent advances in cell biology, genetics, and our understanding of the cellular processes that underlie aging, however, have shown that this assumption is invalid in a number of animal models and suggest that this assumption may become invalid for humans as well. In vitro alteration of telomeres affects cellular senescence, and in vivo manipulation of genes and diet can increase maximum life span in animal models if these discoveries are extended to humans. We may soon be able to extend the maximum human life span and postpone or prevent the onset of diseases associated with aging. Such a possibility requires that we recognize a growing uncertainty in any attempt to project international health care costs into the next few decades. The costs may be significantly lower than projections, if life span increases and age-related disabilities are postponed or less severe, or perhaps higher, if life span increases without altering the onset and severity of disability. An appropriate uncertainty regarding the human life span undermines any attempt to accurately predict health costs in the next century.},
}
@article {pmid9343401,
year = {1997},
author = {Marusíc, L and Anton, M and Tidy, A and Wang, P and Villeponteau, B and Bacchetti, S},
title = {Reprogramming of telomerase by expression of mutant telomerase RNA template in human cells leads to altered telomeres that correlate with reduced cell viability.},
journal = {Molecular and cellular biology},
volume = {17},
number = {11},
pages = {6394-6401},
pmid = {9343401},
issn = {0270-7306},
mesh = {Cell Survival/genetics ; Chromosome Aberrations ; Clone Cells ; Humans ; Mutation ; RNA/*genetics/metabolism ; Telomerase/*genetics/metabolism ; Telomere/*metabolism ; },
abstract = {Telomerase synthesizes telomeric DNA by copying the template sequence of its own RNA component. In Tetrahymena thermophila and yeast (G. Yu, J. D. Bradley, L. D. Attardi, and E. H. Blackburn, Nature 344:126-131, 1990; M. McEachern and E. H. Blackburn, Nature 376:403-409, 1995), mutations in the template domain of this RNA result in synthesis of mutant telomeres and in impaired cell growth and survival. We have investigated whether mutant telomerase affects the proliferative potential and viability of immortal human cells. Plasmids encoding mutant or wild-type template RNAs (hTRs) of human telomerase and the neomycin resistance gene were transfected into human cells to generate stable transformants. Expression of mutant hTR resulted in the appearance of mutant telomerase activity and in the synthesis of mutant telomeres. Transformed cells were not visibly affected in their growth and viability when grown as mass populations. However, a reduction in plating efficiency and growth rate and an increase in the number of senescent cells were detected in populations with mutant telomeres by colony-forming assays. These results suggest that the presence of mutant telomerase, even if coexpressed with the wild-type enzyme, can be deleterious to cells, likely as a result of the impaired function of hybrid telomeres.},
}
@article {pmid9335332,
year = {1997},
author = {Blasco, MA and Lee, HW and Hande, MP and Samper, E and Lansdorp, PM and DePinho, RA and Greider, CW},
title = {Telomere shortening and tumor formation by mouse cells lacking telomerase RNA.},
journal = {Cell},
volume = {91},
number = {1},
pages = {25-34},
doi = {10.1016/s0092-8674(01)80006-4},
pmid = {9335332},
issn = {0092-8674},
support = {5P30-CA45508/CA/NCI NIH HHS/United States ; R01AG09383/AG/NIA NIH HHS/United States ; R01HD348880/HD/NICHD NIH HHS/United States ; },
mesh = {Aneuploidy ; Animals ; Cell Survival ; *Cell Transformation, Neoplastic ; Cells, Cultured ; Chromosome Aberrations ; DNA, Neoplasm/metabolism ; Fibroblasts ; Mice ; Mice, Knockout ; Mice, Nude ; Neoplasms, Experimental/*pathology ; Organ Specificity ; RNA/genetics/*physiology ; Telomerase/genetics/*physiology ; Telomere/*metabolism ; },
abstract = {To examine the role of telomerase in normal and neoplastic growth, the telomerase RNA component (mTR) was deleted from the mouse germline. mTR-/- mice lacked detectable telomerase activity yet were viable for the six generations analyzed. Telomerase-deficient cells could be immortalized in culture, transformed by viral oncogenes, and generated tumors in nude mice following transformation. Telomeres were shown to shorten at a rate of 4.8+/-2.4 kb per mTR-/- generation. Cells from the fourth mTR-/- generation onward possessed chromosome ends lacking detectable telomere repeats, aneuploidy, and chromosomal abnormalities, including end-to-end fusions. These results indicate that telomerase is essential for telomere length maintenance but is not required for establishment of cell lines, oncogenic transformation, or tumor formation in mice.},
}
@article {pmid9335146,
year = {1997},
author = {Coissac, E and Maillier, E and Netter, P},
title = {A comparative study of duplications in bacteria and eukaryotes: the importance of telomeres.},
journal = {Molecular biology and evolution},
volume = {14},
number = {10},
pages = {1062-1074},
doi = {10.1093/oxfordjournals.molbev.a025712},
pmid = {9335146},
issn = {0737-4038},
mesh = {Animals ; *Biological Evolution ; Caenorhabditis elegans/*genetics ; Escherichia coli/*genetics ; *Genome ; Genome, Bacterial ; Genome, Fungal ; Haemophilus influenzae/*genetics ; Models, Genetic ; Multigene Family ; Mycoplasma/*genetics ; Open Reading Frames ; Saccharomyces cerevisiae/*genetics ; Telomere/*genetics ; },
abstract = {The genomes of three bacteria (Haemophilus influenzae, Mycoplasma genitalium, and Escherichia coli) and two eukaryotes (Saccharomyces cerevisiae and Caenorhabditis elegans) were compared. The distribution of their putative open reading frames (ORFs) was studied, and several conclusions were drawn: (1) All of these genomes, even the smallest, exhibit a significant proportion (7%-30%) of duplicated ORFs. This proportion is a function of genome size and appears unrelated to the bacteria/eukaryote division. (2) Some of these ORFs constitute families of up 20 or more members. (3) The levels of sequence similarity within these families are highly variable and their distribution is different among bacteria and eukaryotes. (4) In yeast, there are topological relationships between members of the same family. The paired ORFs are frequently in the same orientation with regard to their respective telomeres and located at comparable distances from them.},
}
@article {pmid9326584,
year = {1997},
author = {Lingner, J and Cech, TR and Hughes, TR and Lundblad, V},
title = {Three Ever Shorter Telomere (EST) genes are dispensable for in vitro yeast telomerase activity.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {94},
number = {21},
pages = {11190-11195},
pmid = {9326584},
issn = {0027-8424},
mesh = {Centrifugation, Density Gradient ; Cyclin B/genetics/metabolism ; Fungal Proteins/genetics/metabolism ; *Genes, Fungal ; Mutagenesis ; Polymerase Chain Reaction ; Proteins/genetics/metabolism ; Saccharomyces cerevisiae/*enzymology/genetics/growth &amp; development ; *Saccharomyces cerevisiae Proteins ; Telomerase/genetics/isolation &amp; purification/*metabolism ; Telomere/*genetics ; *Telomere-Binding Proteins ; },
abstract = {Telomerase is a specialized reverse transcriptase consisting of both RNA and protein components. Previous characterization of yeast telomerase function in vivo identified four EST (for ever shorter telomeres) genes that, when mutated, result in the phenotypes expected for a defect in telomerase. Consistent with this genetic prediction, the EST2 gene has recently been shown to encode the catalytic component of telomerase. Using an in vitro assay, we show here that telomerase activity is present in extracts prepared from yeast strains carrying est1-Delta, est3-Delta, and cdc13-2(est) mutations. Therefore, while these three genes are necessary for telomerase function in vivo, they do not encode components essential for core catalytic activity. When Est2p, the one EST gene product found to be essential for catalytic activity, was immunoprecipitated from extracts, the telomerase RNA subunit was also specifically precipitated, supporting the conclusion that these two components are in a stable complex.},
}
@article {pmid9380719,
year = {1997},
author = {Weng, NP and Granger, L and Hodes, RJ},
title = {Telomere lengthening and telomerase activation during human B cell differentiation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {94},
number = {20},
pages = {10827-10832},
pmid = {9380719},
issn = {0027-8424},
mesh = {B-Lymphocyte Subsets ; B-Lymphocytes/*cytology/immunology ; *Cell Differentiation ; Enzyme Activation ; Enzyme Induction ; Humans ; Immunologic Memory ; Palatine Tonsil/cytology ; Telomerase/biosynthesis/*metabolism ; *Telomere ; },
abstract = {The function of the immune system is highly dependent on cellular differentiation and clonal expansion of antigen-specific lymphocytes. However, little is known about mechanisms that may have evolved to protect replicative potential in actively dividing lymphocytes during immune differentiation and response. Here we report an analysis of telomere length and telomerase expression, factors implicated in the regulation of cellular replicative lifespan, in human B cell subsets. In contrast to previous observations, in which telomere shortening and concomitant loss of replicative potential occur in the process of somatic cell differentiation and cell division, it was found that germinal center (GC) B cells, a compartment characterized by extensive clonal expansion and selection, had significantly longer telomeric restriction fragments than those of precursor naive B cells. Furthermore, it was found that telomerase, a telomere-synthesizing enzyme, is expressed at high levels in GC B cells (at least 128-fold higher than those of naive and memory B cells), correlating with the long telomeres in this subset of B cells. Finally, both naive and memory B cells were capable of up-regulating telomerase activity in vitro in response to activation signals through the B cell antigen receptor in the presence of CD40 engagement and/or interleukin 4. These observations suggest that a novel process of telomere lengthening, possibly mediated by telomerase, functions in actively dividing GC B lymphocytes and may play a critical role in humoral immune response by maintaining the replicative potential of GC and descendant memory B cells.},
}
@article {pmid9314497,
year = {1997},
author = {Rosenberg, M and Hui, L and Ma, J and Nusbaum, HC and Clark, K and Robinson, L and Dziadzio, L and Swain, PM and Keith, T and Hudson, TJ and Biesecker, LG and Flint, J},
title = {Characterization of short tandem repeats from thirty-one human telomeres.},
journal = {Genome research},
volume = {7},
number = {9},
pages = {917-923},
pmid = {9314497},
issn = {1088-9051},
support = {HG00098/HG/NHGRI NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosome Mapping ; Chromosomes, Human/*genetics ; Humans ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid/*genetics ; Sequence Analysis, DNA ; Sequence Tagged Sites ; Telomere/*genetics ; },
abstract = {Completion of genetic and physical maps requires markers from the ends (telomeres) of every human chromosome. We have searched for short tandem repeats (microsatellites) in cosmid and P1 clones and generated 661 sequence-tagged sites (STS) from the terminal 300 kb of 31 human chromosome ends. PCR assays were successfully designed for 58 microsatellites and mapped both genetically and on radiation hybrids (RHs) to confirm their telomeric location. Sequence analysis revealed marked variation in sequence composition, consistent with the hypothesis that even very highly GC-rich chromosome bands (the T bands) are not homogenous. The STSs that we have generated will be a necessary resource for the construction of physical maps of these complex regions of the genome.},
}
@article {pmid9312059,
year = {1997},
author = {Vaziri, H and West, MD and Allsopp, RC and Davison, TS and Wu, YS and Arrowsmith, CH and Poirier, GG and Benchimol, S},
title = {ATM-dependent telomere loss in aging human diploid fibroblasts and DNA damage lead to the post-translational activation of p53 protein involving poly(ADP-ribose) polymerase.},
journal = {The EMBO journal},
volume = {16},
number = {19},
pages = {6018-6033},
pmid = {9312059},
issn = {0261-4189},
mesh = {Alleles ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins ; Cells, Cultured ; *Cellular Senescence/genetics ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins/metabolism ; DNA/metabolism ; *DNA Damage ; DNA-Binding Proteins ; Enzyme Inhibitors/metabolism ; Fibroblasts/cytology ; Humans ; Nuclear Proteins/metabolism ; Oxygen/metabolism ; Poly(ADP-ribose) Polymerases/*metabolism ; Promoter Regions, Genetic ; Protein Processing, Post-Translational ; *Protein Serine-Threonine Kinases ; Proteins/metabolism ; *Telomere ; *Trans-Activators ; Transcription Factors/metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; Tumor Suppressor Proteins ; },
abstract = {Telomere loss has been proposed as a mechanism for counting cell divisions during aging in normal somatic cells. How such a mitotic clock initiates the intracellular signalling events that culminate in G1 cell cycle arrest and senescence to restrict the lifespan of normal human cells is not known. We investigated the possibility that critically short telomere length activates a DNA damage response pathway involving p53 and p21(WAF1) in aging cells. We show that the DNA binding and transcriptional activity of p53 protein increases with cell age in the absence of any marked increase in the level of p53 protein, and that p21(WAF1) promoter activity in senescent cells is dependent on both p53 and the transcriptional co-activator p300. Moreover, we detected increased specific activity of p53 protein in AT fibroblasts, which exhibit accelerated telomere loss and undergo premature senescence, compared with normal fibroblasts. We investigated the possibility that poly(ADP-ribose) polymerase is involved in the post-translational activation of p53 protein in aging cells. We show that p53 protein can associate with PARP and inhibition of PARP activity leads to abrogation of p21 and mdm2 expression in response to DNA damage. Moreover, inhibition of PARP activity leads to extension of cellular lifespan. In contrast, hyperoxia, an activator of PARP, is associated with accelerated telomere loss, activation of p53 and premature senescence. We propose that p53 is post-translationally activated not only in response to DNA damage but also in response to the critical shortening of telomeres that occurs during cellular aging.},
}
@article {pmid9291361,
year = {1997},
author = {Slijepcevic, P and Bryant, PE},
title = {Telomere-mediated chromosome healing.},
journal = {Radiation research},
volume = {148},
number = {3},
pages = {293},
pmid = {9291361},
issn = {0033-7587},
mesh = {Animals ; Chromosomes/*physiology ; *DNA Damage ; *DNA Repair ; Drosophila/genetics ; Saccharomyces cerevisiae/genetics ; Telomerase/metabolism ; Telomere/*physiology ; },
}
@article {pmid9275199,
year = {1997},
author = {Austriaco, NR and Guarente, LP},
title = {Changes of telomere length cause reciprocal changes in the lifespan of mother cells in Saccharomyces cerevisiae.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {94},
number = {18},
pages = {9768-9772},
pmid = {9275199},
issn = {0027-8424},
mesh = {Cell Survival/genetics ; Fungal Proteins/*genetics ; Genome, Fungal ; Mutation ; Saccharomyces cerevisiae/*genetics/growth &amp; development ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Telomere/*genetics ; Trans-Activators/*genetics ; },
abstract = {Budding yeast cells divide asymmetrically, giving rise to a mother and its daughter. Mother cells have a limited division potential, called their lifespan, which ends in proliferation-arrest and lysis. In this report we mutate telomerase in Saccharomyces cerevisiae to shorten telomeres and show that, rather than shortening lifespan, this leads to a significant extension in lifespan. This extension requires the product of the SIR3 gene, an essential component of the silencing machinery which binds to telomeres. In contrast, longer telomeres in a genotypically wild-type strain lead to a decrease in lifespan. These findings suggest that the length of telomeres dictates the lifespan by regulating the amount of the silencing machinery available to nontelomeric locations in the yeast genome.},
}
@article {pmid9287143,
year = {1997},
author = {Decary, S and Mouly, V and Hamida, CB and Sautet, A and Barbet, JP and Butler-Browne, GS},
title = {Replicative potential and telomere length in human skeletal muscle: implications for satellite cell-mediated gene therapy.},
journal = {Human gene therapy},
volume = {8},
number = {12},
pages = {1429-1438},
doi = {10.1089/hum.1997.8.12-1429},
pmid = {9287143},
issn = {1043-0342},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Cell Division ; Cell Nucleus/genetics ; Cells, Cultured ; Humans ; Infant ; Infant, Newborn ; Middle Aged ; Mitosis ; Muscle Fibers, Skeletal/physiology ; Muscle, Skeletal/*cytology/*physiology ; Phenotype ; Telomere/*genetics ; },
abstract = {In this study, we have evaluated the ability of human satellite cells isolated from subjects aged from 5 days to 86 years to proliferate in culture. Cells were cultivated until they became senescent. The number of cell divisions was calculated by counting the number of cells plated in culture compared to the number of cells removed following proliferation. Telomere length, which is known to decrease during each round of cell division, has been used to analyze the in vitro replicative capacity and in vivo replicative history of human satellite cells at isolation. The rate of telomere shortening in myonuclei of these muscle biopsies was also examined. Our results show that both proliferative capacity and telomere length of satellite cells decreases with age during the first two decades but that the myonuclei of human skeletal muscle are remarkably stable because telomere length in these myonuclei remains constant from birth to 86 years. The lack of shortening of mean terminal restriction fragments (TRF) in vivo confirms that skeletal muscle is a stable tissue with little nuclear turnover and therefore an ideal target for cell-mediated gene therapy. Moreover, our results show that it is important to consider donor age as a limiting factor to obtain an optimal number of cells.},
}
@article {pmid9379506,
year = {1997},
author = {Maruyama, Y and Hanai, H and Fujita, M and Kaneko, E},
title = {Telomere length and telomerase activity in carcinogenesis of the stomach.},
journal = {Japanese journal of clinical oncology},
volume = {27},
number = {4},
pages = {216-220},
doi = {10.1093/jjco/27.4.216},
pmid = {9379506},
issn = {0368-2811},
mesh = {Adenoma/enzymology/ultrastructure ; Aged ; Biopsy ; Blotting, Southern ; Case-Control Studies ; Cell Transformation, Neoplastic/ultrastructure ; Cells, Cultured ; Gastric Mucosa/enzymology/*ultrastructure ; Gene Amplification ; Gene Expression Regulation, Neoplastic ; Humans ; Intestinal Mucosa/enzymology/ultrastructure ; Metaplasia ; Nucleic Acid Hybridization ; Precancerous Conditions/enzymology/*ultrastructure ; Repetitive Sequences, Nucleic Acid ; Stomach Neoplasms/enzymology/*ultrastructure ; Telomerase/*analysis/genetics ; Telomere/genetics/*ultrastructure ; Tumor Cells, Cultured ; },
abstract = {Telomerase activity is generally absent in primary cell cultures and normal tissues. Telomerase is known to be induced upon immortalization or malignant transformation of human cells. In the present study, we analyzed both telomere length and telomerase activity in biopsy samples from mucosa undergoing metaplasia, adenoma and cancer of the stomach. We attempted to estimate the correlation between telomerase activity and telomere length in these tissues. Telomerase activity was estimated using the telomeric repeat amplification protocol and telomere length by Southern blot analysis. Extracts were defined as telomerase-negative when the signals were less intense than those for 10(2) KATO-III cells (positive control). We detected telomerase activity in 15%, 45% and 89% of the examined cases of intestinal metaplasia, adenoma and gastric cancer respectively. However, telomere length in the gastric mucosa became reduced as the mucosa underwent metaplasia and developed into adenoma. Gastric cancers showed a broad range of telomere length among cases. However, gastric adenomas showed the shortest telomere length. These results suggest that telomerase is expressed during the early phase (intestinal metaplasia through adenoma) of gastric carcinogenesis, although the activity at that stage is not high enough to fully restore the reduced telomeric DNA.},
}
@article {pmid9262227,
year = {1997},
author = {Oexle, K and Zwirner, A and Freudenberg, K and Kohlschütter, A and Speer, A},
title = {Examination of telomere lengths in muscle tissue casts doubt on replicative aging as cause of progression in Duchenne muscular dystrophy.},
journal = {Pediatric research},
volume = {42},
number = {2},
pages = {226-231},
doi = {10.1203/00006450-199708000-00016},
pmid = {9262227},
issn = {0031-3998},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/genetics/*pathology ; Case-Control Studies ; Cellular Senescence/genetics ; Child ; Child, Preschool ; Chromosome Breakage ; *DNA Replication ; Disease Progression ; Humans ; Infant ; Infant, Newborn ; Leukocytes/ultrastructure ; Middle Aged ; Muscles/*pathology ; Muscular Dystrophies/genetics/*pathology ; Telomere/genetics/*ultrastructure ; },
abstract = {The mean telomere length (TL) of somatic cells indicates their replicative age. In comparison with normal leukocytes (-0.03 kbp/y, 6.2 kbp at 80 y), we found advanced TL shortening in premature aging due to ataxia-telangiectasia or the Nijmegen chromosomal breakage syndrome. Duchenne muscular dystrophy (DMD) has been related to replicative senescence of satellite cells (SCs) caused by increased fiber turnover. Therefore, we determined TLs in DMD muscle. Because the regenerated fiber nuclei are produced by SCs. telomeres of both fiber and SC nuclei should be shortened. In DMD the SC number is increased. We determined that up to the age of 7 y the sum of fiber and SC nuclei should be large enough (73%) for the detection of TL shortening. Normal muscle fibers have negligible turnover rates, and, as expected, we did not find age-related TL shortening (10-83 y, n = 24, 8.3 +/- 0.5 kbp). Surprisingly, there was only slight TL shortening in patient muscles (DMD, 0.3-4.8 y, n = 4, 8.3 +/- 0.7 kbp; 5-7 y, n = 7, 7.9 +/- 0.4 kbp; limb-girdle muscular dystrophy 2C, 13 y, 7.6 kbp; Becker muscular dystrophy, 7 y, 8.5 kbp). Similarly, the peak positions of the telomere blots varied only slightly (DMD, 10.0 +/- 0.9 kbp; normal: 10.7 +/- 0.9 kbp). In accordance with our TL findings we derived less than 4 annual doublings per SC from published histologic data on DMD.},
}
@article {pmid9259277,
year = {1997},
author = {Flint, J and Bates, GP and Clark, K and Dorman, A and Willingham, D and Roe, BA and Micklem, G and Higgs, DR and Louis, EJ},
title = {Sequence comparison of human and yeast telomeres identifies structurally distinct subtelomeric domains.},
journal = {Human molecular genetics},
volume = {6},
number = {8},
pages = {1305-1313},
doi = {10.1093/hmg/6.8.1305},
pmid = {9259277},
issn = {0964-6906},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Base Sequence ; Chromosomes, Artificial, Yeast ; Humans ; Molecular Sequence Data ; Saccharomyces cerevisiae/genetics ; *Telomere ; },
abstract = {We have sequenced and compared DNA from the ends of three human chromosomes: 4p, 16p and 22q. In all cases the pro-terminal regions are subdivided by degenerate (TTAGGG)n repeats into distal and proximal sub-domains with entirely different patterns of homology to other chromosome ends. The distal regions contain numerous, short (<2 kb) segments of interrupted homology to many other human telomeric regions. The proximal regions show much longer (approximately 10-40 kb) uninterrupted homology to a few chromosome ends. A comparison of all yeast subtelomeric regions indicates that they too are subdivided by degenerate TTAGGG repeats into distal and proximal sub-domains with similarly different patterns of identity to other non-homologous chromosome ends. Sequence comparisons indicate that the distal and proximal sub-domains do not interact with each other and that they interact quite differently with the corresponding regions on other, non-homologous, chromosomes. These findings suggest that the degenerate TTAGGG repeats identify a previously unrecognized, evolutionarily conserved boundary between remarkably different subtelomeric domains.},
}
@article {pmid9224604,
year = {1997},
author = {Coviello-McLaughlin, GM and Prowse, KR},
title = {Telomere length regulation during postnatal development and ageing in Mus spretus.},
journal = {Nucleic acids research},
volume = {25},
number = {15},
pages = {3051-3058},
pmid = {9224604},
issn = {0305-1048},
mesh = {Aging/*genetics ; Animals ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Muridae ; Sex Characteristics ; Telomerase/metabolism ; *Telomere ; },
abstract = {Telomere shortening has been causally implicated in replicative senescence in humans. To examine the relationship between telomere length and ageing in mice, we have utilized Mus spretus as a model species because it has telomere lengths of approximately the same length as humans. Telomere length and telomerase were analyzed from liver, kidney, spleen, brain and testis from >180 M.spretus male and female mice of different ages. Although telomere lengths for each tissue were heterogeneous, significant changes in telomere lengths were found in spleen and brain, but not in liver, testis or kidney. Telomerase activity was abundant in liver and testis, but weak to non-detectable in spleen, kidney and brain. Gender differences in mean terminal restriction fragment length were discovered in tissues from M.spretus and from M.spretus xC57BL/6 F1 mice, in which a M. spretus -sized telomeric smear could be measured. The comparison of the rank order of tissue telomere lengths within individual M. spretus showed that certain tissues tended to be longer than the others, and this ranking also extended to tissues of the M.spretus xC57BL/6 F1 mice. These data suggest that telomere lengths within individual tissues are regulated independently and are genetically controlled.},
}
@article {pmid9280899,
year = {1997},
author = {Bender, J and Klein, A},
title = {The telomere binding protein of Euplotes crassus prevents non-specific transcription initiation but has no role in positioning transcription initiation complexes.},
journal = {Nucleic acids research},
volume = {25},
number = {14},
pages = {2877-2882},
pmid = {9280899},
issn = {0305-1048},
mesh = {Animals ; Base Sequence ; DNA ; DNA-Binding Proteins/*genetics/metabolism ; Euplotes/*genetics/metabolism ; Gene Expression Regulation ; Molecular Sequence Data ; Peptide Chain Initiation, Translational ; Protozoan Proteins/*genetics/metabolism ; Repressor Proteins/*genetics/metabolism ; Templates, Genetic ; *Transcription, Genetic ; },
abstract = {Model substrates mimicking the telomeric as well as the 5'-untranslated regions in front of a 5'-terminal part of a macronuclear gene of Euplotes crassus were transcribed in vitro using cellular extracts. The obtained transcripts were characterized by primer extension and shown to start at the natural initiation points. The situation changed in the absence of telomere binding protein or with substrates lacking functional telomeric sequences. In these cases non-specific transcription was observed. Since it had been previously found that transcription starts are frequently located at an apparently fixed distance from the telomere, a model substrate was constructed which carried a duplication of the non-transcribed region. This resulted in only one transcription start site, the position of which was conserved relative to the start of the open reading frame but moved away from the telomere by the distance of the duplication.},
}
@article {pmid9242487,
year = {1997},
author = {Chua, PR and Roeder, GS},
title = {Tam1, a telomere-associated meiotic protein, functions in chromosome synapsis and crossover interference.},
journal = {Genes &amp; development},
volume = {11},
number = {14},
pages = {1786-1800},
doi = {10.1101/gad.11.14.1786},
pmid = {9242487},
issn = {0890-9369},
support = {GM28904/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosome Mapping ; Chromosomes, Fungal ; *Crossing Over, Genetic ; Fungal Proteins/genetics/*physiology ; *Genes, Fungal ; Meiosis/*genetics ; Microscopy, Electron ; Mutation ; Nondisjunction, Genetic ; Saccharomyces cerevisiae/*genetics/physiology/ultrastructure ; Spores, Fungal ; *Telomere ; },
abstract = {The TAM1 gene of Saccharomyces cerevisiae is expressed specifically during meiosis and encodes a protein that localizes to the ends of meiotic chromosomes. In a tam1 null mutant, there is an increase in the frequency of chromosomes that fail to recombine and an associated increase in homolog nondisjunction at meiosis I. The tam1 mutant also displays an increased frequency of precocious separation of sister chromatids and a reduced efficiency of distributive disjunction. The defect in distributive disjunction may be attributable to overloading of the distributive system by the increased number of nonrecombinant chromosomes. Recombination is not impaired in the tam1 mutant, but crossover interference is reduced substantially. In addition, chromosome synapsis is delayed in tam1 strains. The combination of a defect in synapsis and a reduction in interference is consistent with previous studies suggesting a role for the synaptonemal complex in regulating crossover distribution. tam1 is the only known yeast mutant in which the control of crossover distribution is impaired, but the frequency of crossing over is unaffected. We discuss here possibilities for how a telomere-associated protein might function in chromosome synapsis and crossover interference.},
}
@article {pmid9207107,
year = {1997},
author = {Zijlmans, JM and Martens, UM and Poon, SS and Raap, AK and Tanke, HJ and Ward, RK and Lansdorp, PM},
title = {Telomeres in the mouse have large inter-chromosomal variations in the number of T2AG3 repeats.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {94},
number = {14},
pages = {7423-7428},
pmid = {9207107},
issn = {0027-8424},
mesh = {Animals ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Inbred Strains ; *Repetitive Sequences, Nucleic Acid ; Species Specificity ; Telomere/*genetics ; },
abstract = {The ultra-long telomeres that have been observed in mice are not in accordance with the concept that critical telomere shortening is related to aging and immortalization. Here, we have used quantitative fluorescence in situ hybridization to estimate (T2AG3)n lengths of individual telomeres in various mouse strains. Telomere lengths were very heterogeneous, but specific chromosomes of bone marrow cells and skin fibroblasts from individual mice had similar telomere lengths. We estimate that the shortest telomeres are around 10 kb in length, indicating that each mouse cell has a few telomeres with (T2AG3)n lengths within the range of human telomeres. These short telomeres may be critical in limiting the replicative potential of murine cells.},
}
@article {pmid9542529,
year = {1997},
author = {Young, AC and Chavez, M and Giambernardi, TA and Mattern, V and McGill, JR and Harris, JM and Sarosdy, MF and Patel, P and Sakaguchi, AY},
title = {Organization and expression of human telomere repeat binding factor genes.},
journal = {Somatic cell and molecular genetics},
volume = {23},
number = {4},
pages = {275-286},
doi = {10.1007/BF02674418},
pmid = {9542529},
issn = {0740-7750},
support = {CA67760-02/CA/NCI NIH HHS/United States ; P30 CA54174/CA/NCI NIH HHS/United States ; },
mesh = {Alternative Splicing ; Amino Acid Sequence ; Base Sequence ; Chromosome Mapping ; *Chromosomes, Human, Pair 13 ; *Chromosomes, Human, Pair 21 ; DNA Primers ; DNA-Binding Proteins/*biosynthesis/chemistry/*genetics ; Humans ; Hybrid Cells ; In Situ Hybridization, Fluorescence ; Karyotyping ; Molecular Sequence Data ; Polymerase Chain Reaction ; Telomere/*genetics ; Telomeric Repeat Binding Protein 1 ; *X Chromosome ; },
abstract = {The ends of mammalian chromosomes terminate in structures called telomeres. Recently a human telomere repeat binding factor (TRF1) that binds the vertebrate TTAGGG telomeric repeat in situ was isolated by Chong et al. (1). TRF1 regulates telomere length (2), which is often altered in cancer cells. To understand their genetic organization, TRF1 genes were localized to human chromosomes 13cen, 21cen, and Xq13 by analysis of human monochromosomal hybrids, and by fluorescent in situ hybridization. We also confirmed the recent localization of a human TRF1 gene to chromosome 8, and provide evidence that this locus is alternatively spliced. In contrast to the TRF1 genes on chromosomes 8 and X, the chromosomes 13 and 21 TRF1 genes contained a 60 bp deletion in the coding region. The results suggest that two distinct forms of TRF1 are expressed and that the TRF1 gene family includes at least three pseudogenes whose dispersal in the human genome may have occurred via cDNA intermediates.},
}
@article {pmid9315442,
year = {1997},
author = {Morin, GB},
title = {Telomere control of replicative lifespan.},
journal = {Experimental gerontology},
volume = {32},
number = {4-5},
pages = {375-382},
doi = {10.1016/s0531-5565(96)00164-7},
pmid = {9315442},
issn = {0531-5565},
mesh = {Animals ; Cell Line, Transformed/physiology ; Cellular Senescence/physiology ; Humans ; Longevity/*physiology ; Signal Transduction ; Telomerase/metabolism ; Telomere/*physiology/ultrastructure ; },
abstract = {The replicative capacity of cells may limit the lifespan of key systems in the body. It has long been known that normal human cells have a finite lifespan when placed in cell culture, and their lifespan is dependent on the age of the individual donor. The mechanism of the genetic program that times this process has been elusive. The telomere hypothesis of cell aging proposes that the length of the telomeric repeat array at chromosomal termini can time replication number and signal cell cycle arrest when critical telomere lengths are obtained. The erosion of telomeric DNA in normal tissues appears to be due to the lack of expression of components of the telomere maintenance system. Telomerase, the key enzyme involved in telomere replication, is not expressed in somatic tissues, but is expressed in germ cells, where telomere length is stably maintained, so that viable chromosomes can be transmitted to the next generation. Evidence is reviewed that correlates telomere length, telomerase activity, and the manipulation of telomere length with cell replicative capacity and cellular immortalization. Strong circumstantial evidence exists that indicates a role for telomere biology in the control of replicative capacity and in tumorigenesis.},
}
@article {pmid9284959,
year = {1997},
author = {Crompton, NE},
title = {Telomeres, senescence and cellular radiation response.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {53},
number = {7},
pages = {568-575},
doi = {10.1007/s000180050073},
pmid = {9284959},
issn = {1420-682X},
mesh = {Animals ; Apoptosis ; Cell Cycle/radiation effects ; Cell Transformation, Neoplastic ; *Cellular Senescence ; DNA Damage ; DNA Replication ; Enzyme Activation ; Oncogenic Viruses/physiology ; *Radiation, Ionizing ; Signal Transduction ; Telomerase/metabolism ; Telomere/*physiology/*radiation effects ; },
abstract = {Telomeres shield the ends of chromosomes from degradation and end-to-end fusions. They shorten at each cell division and when they reach a critically short length, cells arrest in the G1 phase of the cell cycle and undergo senescence. This effectively limits the proliferative potential of cells. Senescence functions as a tumour suppressor mechanism and appears to contribute to the process of ageing. If senescence is circumvented by tumour viruses, proliferation is re-initiated until cells enter crisis. Activation of telomerase prevents telomere attrition and cells become immortal. Cellular response to ionizing radiation involves induction of cell cycle checkpoint arrests and programmed cell death. Because radiation produces double strand breaks in DNA, which cause telomere-less chromosome ends, radiation response appears to be the result of inappropriate induction of cellular senescence mechanisms.},
}
@article {pmid9278138,
year = {1997},
author = {Shore, D},
title = {Telomere length regulation: getting the measure of chromosome ends.},
journal = {Biological chemistry},
volume = {378},
number = {7},
pages = {591-597},
pmid = {9278138},
issn = {1431-6730},
support = {GM40094/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromosomes, Fungal/*physiology ; GTP-Binding Proteins/genetics/physiology ; Humans ; Saccharomyces cerevisiae ; Telomere/*physiology ; rap GTP-Binding Proteins ; },
abstract = {Telomeres, the protein-DNA complexes that comprise the ends of linear eukaryotic chromosomes, serve to protect the chromosome ends and allow their complete replication. Telomeres also appear to play an essential role in chromosome segregation. In most organisms telomeric DNA consists of a series of short repeats that are variable in length, but regulated at a fixed average value in the germline. The possible involvement of telomere repeat shortening in aging and carcinogenesis has recently attracted attention to the more basic question of how telomere length is sensed and regulated by the cell. Telomere length in the budding yeast Saccharomyces cerevisiae has been known for over a decade now to be under complex genetic control, and this organism has provided a useful model system to address basic mechanistic questions. This review focuses on recent studies in yeast which indicate that the double-strand telomere-repeat binding protein Rap1 may play an important role in a negative-feedback mechanism that senses and controls the length of the telomere repeats. Although the same carboxy-terminal domain of Rap1p is involved in both telomere length regulation and telomeric silencing (telomere position effect), it appears that these two functions are mediated by separate sets of Rap1p-interacting proteins. Results from other systems suggest that negative regulation of telomere elongation by a double-stranded telomere-repeat binding protein may be a highly conserved strategy for telomere length control.},
}
@article {pmid9256332,
year = {1997},
author = {Kageyama, Y and Kamata, S and Yonese, J and Oshima, H},
title = {Telomere length and telomerase activity in bladder and prostate cancer cell lines.},
journal = {International journal of urology : official journal of the Japanese Urological Association},
volume = {4},
number = {4},
pages = {407-410},
doi = {10.1111/j.1442-2042.1997.tb00216.x},
pmid = {9256332},
issn = {0919-8172},
mesh = {*Biomarkers, Tumor ; DNA, Neoplasm/metabolism ; Humans ; Male ; Molecular Weight ; Prostatic Neoplasms ; Telomerase/*metabolism ; Telomere/chemistry/*physiology ; Tumor Cells, Cultured/chemistry/enzymology/ultrastructure ; Urinary Bladder Neoplasms ; },
abstract = {BACKGROUND: Specific repeats of oligonucleotides at the ends of chromosomes (telomeres) are shortened by cell division in somatic cells and are thought to be related to aging. Immortal cells such as germ-line cells or cancer cells have demonstrated increased activity of the telomere-elongating enzyme (telomerase). The length of the telomeres of these cells is stable regardless of cell division. We examined the telomere length and telomerase activity in 3 bladder (JTC30, JTC32, and T24) and 2 prostate cancer (LNCaP and DU145) cell lines.<br><br>METHODS: Telomere lengths were evaluated by Southern blot analysis with a oligonucleotide probe, (TTAGGG)5, and telomerase activities were detected with a polymerase chain reaction-based assay method.<br><br>RESULTS: Telomerase activity was detected in all of the cell lines. Each cell line had a specific telomere length. In 2 bladder cancer cell lines (JTC30 and JTC32), the telomere length decreased with increased passage of the cells.<br><br>CONCLUSION: The presence of telomerase may be a biological character of bladder and prostate cancers as well as other malignancies, although it does not always compensate telomere shortening.},
}
@article {pmid9255061,
year = {1997},
author = {Shore, D},
title = {Telomerase and telomere-binding proteins: controlling the endgame.},
journal = {Trends in biochemical sciences},
volume = {22},
number = {7},
pages = {233-235},
doi = {10.1016/s0968-0004(97)01082-7},
pmid = {9255061},
issn = {0968-0004},
support = {GM40094/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Carrier Proteins/chemistry/genetics ; *DNA-Binding Proteins/chemistry/genetics ; Euplotes/enzymology ; Humans ; Mice ; Phosphate-Binding Proteins ; RNA-Binding Proteins ; Rats ; Saccharomyces cerevisiae/enzymology ; Sequence Homology ; *Telomerase/genetics/metabolism ; Tetrahymena/chemistry ; },
}
@article {pmid9252662,
year = {1997},
author = {Ohnuma, T and Li, FL and Holland, JF},
title = {Inhibitory effects of telomere-mimic phosphorothioate oligonucleotides on various human tumor cells in vitro.},
journal = {Anticancer research},
volume = {17},
number = {4A},
pages = {2455-2458},
pmid = {9252662},
issn = {0250-7005},
mesh = {Growth Inhibitors/*pharmacology ; Humans ; Oligonucleotides/*administration &amp; dosage/chemistry ; *Telomere ; Thionucleotides/*pharmacology ; Tumor Cells, Cultured/*drug effects ; },
abstract = {We tested the cell growth inhibitory effects of telomere-mimic oligomers, 5'-d(TTAGGG)n-3' where n = 1, 2, 3 or 4 in the following 8 human tumor cell lines: 2780 ovarian carcinoma, HEp-2 squamous cell carcinoma, VAMT-1 mesothelioma, DND-1A melanoma, MOLT-3 ALL, Jurkat lymphoma, Daudi Burkitt lymphoma, and JAR choriocarcinoma. As controls, 1 scrambled 6-mer and 2 scrambled 24-mers were tested. Among the compounds tested, the 6-mer and 12-mer were not active in any of the cell lines studied. Increases in the length of oligonucleotides from 18- to 24-mer resulted in increased cell growth inhibitory activity in sensitive cell lines. Cells in suspension cultures, MOLT-3 ALL and Daudi Burkitt lymphoma were generally more sensitive than the monolayers (24-mer ID90 = -3 microM). While the inhibitory effects of authentic 24-mer oligomer were more pronounced than the scrambled oligomers, both of the scrambled 24-mers also showed some degree of inhibitory activity. Except for modest activity of the 24-mer in 2 cell lines, DND-1A and 2780, none of the compounds tested were active against solid tumor cell lines. These data indicate that further study of the telomere-mimic 24-mer is warranted as candidate compound for the treatment of leukemia/lymphoma.},
}
@article {pmid9215555,
year = {1997},
author = {Biessmann, H and Mason, JM},
title = {Telomere maintenance without telomerase.},
journal = {Chromosoma},
volume = {106},
number = {2},
pages = {63-69},
doi = {10.1007/s004120050225},
pmid = {9215555},
issn = {0009-5915},
support = {AI36248/AI/NIAID NIH HHS/United States ; GM46211/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Humans ; Insecta/enzymology ; Kluyveromyces/enzymology ; Nucleoproteins/*metabolism ; Plants/enzymology ; Saccharomyces cerevisiae/enzymology ; Telomerase/*deficiency ; Telomere/*metabolism ; Tetrahymena/enzymology ; },
abstract = {Telomeres are nucleoprotein structures at the ends of eukaryotic chromosomes that perform a number of vital functions. They allow a cell to distinguish between natural chromosome ends and chromosome breaks in order to delay the cell cycle and repair the broken end. Telomeres also compensate for the inability of DNA polymerase to replicate the chromosome completely. In most eukaryotes a special reverse transcriptase, telomerase, adds telomeric DNA repeats to the chromosome ends using an internal RNA template. However, evidence is accumulating for alternative elongation mechanisms in a variety of eukaryotes. In the yeast Saccharomyces cerevisiae, and possibly in humans, both of which normally use telomerase, a different mechanism can be used for chromosome length maintenance when telomerase is inactive or inactivated. Yeast apparently uses recombination for this purpose; the mechanism in humans is not known. Some insect and plant species, on the other hand, do not use telomerase as their primary mechanism for maintaining chromosome length. Drosophila makes use of specific retrotransposons for this purpose, while other dipterans use recombination. We summarize here the current knowledge of these alternative telomere elongation mechanisms.},
}
@article {pmid9207452,
year = {1997},
author = {Engelhardt, M and Kumar, R and Albanell, J and Pettengell, R and Han, W and Moore, MA},
title = {Telomerase regulation, cell cycle, and telomere stability in primitive hematopoietic cells.},
journal = {Blood},
volume = {90},
number = {1},
pages = {182-193},
pmid = {9207452},
issn = {0006-4971},
support = {CA 56564/CA/NCI NIH HHS/United States ; CA 67842/CA/NCI NIH HHS/United States ; },
mesh = {Antigens, CD34 ; *Cell Cycle ; Enzyme Stability ; Gene Expression Regulation, Enzymologic ; Hematopoietic Stem Cells/*cytology/enzymology ; Humans ; Telomerase/*physiology ; },
abstract = {Low levels of telomerase activity have recently been detected in human primitive hematopoietic cells, however, blood cells exhibit telomere shortening on cell proliferation. This challenging observation led us to study telomerase regulation and telomere length in human hematopoietic progenitor cells from fetal liver (FL), cord blood (CB), peripheral blood (PB), and bone marrow (BM). We found telomerase activity in CD34+/CD38+ cells exceeding levels in CD34+/CD38-, CD34- , and mononuclear cells (P < .05). Baseline telomerase activity was highest in BM (n = 5) CD34+ cells, followed by PB (n = 20), CB (n = 11), and FL (n = 1). Within 48 hours to 72 hours of in vitro culture of CD34+ cells in the presence of cytokines (KL, interleukin-3 [IL-3], IL-6, erythropoietin, granulocyte colony-stimulating factor), telomerase activity was upregulated, peaked after 1 week of culture, and decreased to baseline levels or below detection after 3 to 4 weeks. Stimulation of CD34+ cells with single cytokines resulted in no or minor telomerase upregulation, whereas cytokine combinations resulted in a significant telomerase increase (P < .001). There was a correlation between telomerase activity, cell cycle status by BrdU incorporation, and induction of phosphorylated retinoblastoma protein, CDC2, CDK2, cyclin D1, and cyclin A, but not cyclin E and B1 after 72 hours with multiple (but not single) cytokines. In nonexpanding CD34+ cells, telomerase was low or undetectable. Secondary CD34+ cells showed a reduced ability to upregulate telomerase activity. Antiproliferative cytokines such as transforming growth factor-beta1 and high concentrations of all-trans-retinoic acid in cytokine-supported CD34+ cultures downmodulated telomerase activity. Average telomere lengths were 10.4 kbp, 7.4 kbp, and 7.6 kbp in CB, PB, and BM CD34+ cells, respectively. In ex vivo expansion cultures, an average telomeric DNA loss of 1 to 2 kbp over 4 weeks was observed. However, the rate of base pair loss per population doubling was significantly lower during the first 2 weeks, when telomerase was upregulated, than during weeks 3 and 4 of culture. In summary, telomerase is upregulated in response to cytokine-induced proliferation and cell cycle activation in primitive hematopoietic cells. Telomerase is downregulated between weeks 3 and 4 of ex vivo expansion culture linked with decreased proliferation and greater expansion of more mature cell subsets. Our data suggest that telomerase activity in hematopoietic cells reduces, but does not prevent, telomere shortening on proliferation.},
}
@article {pmid9201953,
year = {1997},
author = {Laporte, L and Stultz, J and Thomas, GJ},
title = {Solution conformations and interactions of alpha and beta subunits of the Oxytricha nova telomere binding protein: investigation by Raman spectroscopy.},
journal = {Biochemistry},
volume = {36},
number = {26},
pages = {8053-8059},
doi = {10.1021/bi970283g},
pmid = {9201953},
issn = {0006-2960},
support = {GM54378/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; DNA-Binding Proteins/*chemistry ; Drug Stability ; Heating ; Macromolecular Substances ; Mutation ; Oxytricha/*metabolism ; Protein Conformation ; *Protein Structure, Secondary ; Protozoan Proteins/*chemistry ; Solutions ; Spectrum Analysis, Raman ; Thermodynamics ; },
abstract = {Solution conformations of the alpha and beta subunits of the Oxytricha nova telomere binding protein have been investigated by Raman spectroscopy. Raman spectra have also been obtained for a deletion mutant of the beta subunit, betaC232, which retains the N-terminal domain that is active in ternary complex (alpha:beta:DNA) formation but lacks the C-terminal domain that is active in catalyzing guanine quadruplex formation. The Raman spectra show that alpha, beta, and betaC232 are rich in beta-strand secondary structure (approximately 40-50%) and turns. The Raman signature of the C-terminal 153 amino acids of beta, generated by subtracting the spectrum of betaC232 (residues 1-232) from that of the full subunit, indicates that the domain active in guanine quadruplex formation contains less beta-strand secondary structure and more irregular structure than the domain active in alpha:beta:DNA formation. Raman markers also provide information about the environments and orientations of several key side chains, including tryptophan residues in N- and C-terminal domains of the beta subunit. Both alpha and beta denature between 30 and 40 degrees C, as evidenced by large changes in Raman bands diagnostic of main chain conformation and side chain environments. The Raman spectrum of an equimolar alpha/beta mixture exhibits no evidence of specific interaction between the subunits; further, the denaturation profile of this mixture is indistinguishable from the sum of denaturation profiles of the constituent subunits, consistent with the absence of appreciable interaction between alpha and beta throughout the range 0-50 degrees C. The present results provide insights into the solution conformations of the Oxytricha telomere binding protein subunits and serve as the basis for future study of subunit interactions with telomeric DNA.},
}
@article {pmid9169464,
year = {1997},
author = {Eid, JE and Sollner-Webb, B},
title = {ST-2, a telomere and subtelomere duplex and G-strand binding protein activity in Trypanosoma brucei.},
journal = {The Journal of biological chemistry},
volume = {272},
number = {23},
pages = {14927-14936},
doi = {10.1074/jbc.272.23.14927},
pmid = {9169464},
issn = {0021-9258},
support = {GM34231/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Binding Sites ; Chromatography, Affinity ; DNA, Protozoan/chemistry/*metabolism ; DNA-Binding Proteins/*metabolism ; GTP-Binding Proteins/*metabolism ; Molecular Sequence Data ; Oligodeoxyribonucleotides/pharmacology ; Protozoan Proteins/*metabolism ; Repetitive Sequences, Nucleic Acid ; Telomere/*physiology ; Trypanosoma brucei brucei/genetics/*metabolism ; },
abstract = {From Trypanosoma brucei, we identified ST-2, a protein complex that interacts with telomeric DNA and exhibits novel features. It binds specifically to the double-stranded telomere repeats (TTAGGG) and more tightly to the subtelomere 29-base pair elements that separate the telomere repeats from their proximal telomere-associated sequences. Interestingly, ST-2 showed still greater affinity for the G-rich strand of the telomere present either as an overhang or in a single-stranded form, but it exhibited the highest affinity for the G-rich strand of the subtelomere repeats. The binding characteristics of ST-2 are complementary to those of ST-1, a 39-kDa polypeptide we previously identified in T. brucei (Eid, J., and Sollner-Webb, B. (1995) Mol. Cell. Biol. 15, 389-397) that binds preferentially to the C-rich strands of the subtelomere and telomere repeats. UV cross-linking revealed five polypeptides of ST-2 that bind directly to the G-rich strand of the DNA, one of which is phosphorylated. Furthermore, the presence of ST-1 is critical for ST-2 complex binding both to the G-rich strand and to the duplex DNA, evidently as part of the ST-2 complex. This indicates that when binding to the duplex subtelomere and telomere repeats, ST-2 may act as a protein bridge with its ST-1 subunit binding to the C-rich strand and its five other cross-linkable polypeptides binding to the G-rich strand. Such an association could serve to hold the genomic subtelomeric and telomeric sequences in a partially single-stranded configuration to facilitate the recombinational events in this region that are crucial to the parasite.},
}
@article {pmid9214638,
year = {1997},
author = {Laible, G and Wolf, A and Dorn, R and Reuter, G and Nislow, C and Lebersorger, A and Popkin, D and Pillus, L and Jenuwein, T},
title = {Mammalian homologues of the Polycomb-group gene Enhancer of zeste mediate gene silencing in Drosophila heterochromatin and at S. cerevisiae telomeres.},
journal = {The EMBO journal},
volume = {16},
number = {11},
pages = {3219-3232},
pmid = {9214638},
issn = {0261-4189},
mesh = {Amino Acid Sequence ; Animals ; Conserved Sequence ; Drosophila/genetics ; *Drosophila Proteins ; Female ; *Gene Expression Regulation ; Genes, Homeobox ; Genetic Complementation Test ; Genomic Imprinting ; Heterochromatin/*genetics ; Humans ; Insect Proteins/*genetics ; Male ; Mice ; Molecular Sequence Data ; Nuclear Proteins/*genetics ; Polycomb Repressive Complex 1 ; Polycomb Repressive Complex 2 ; *Repressor Proteins ; Saccharomyces cerevisiae/genetics ; Sequence Homology, Amino Acid ; Species Specificity ; Telomere/*genetics ; },
abstract = {Gene silencing is required to stably maintain distinct patterns of gene expression during eukaryotic development and has been correlated with the induction of chromatin domains that restrict gene activity. We describe the isolation of human (EZH2) and mouse (Ezh1) homologues of the Drosophila Polycomb-group (Pc-G) gene Enhancer of zeste [E(z)], a crucial regulator of homeotic gene expression implicated in the assembly of repressive protein complexes in chromatin. Mammalian homologues of E(z) are encoded by two distinct loci in mouse and man, and the two murine Ezh genes display complementary expression profiles during mouse development. The E(z) gene family reveals a striking functional conservation in mediating gene repression in eukaryotic chromatin: extra gene copies of human EZH2 or Drosophila E(z) in transgenic flies enhance position effect variegation of the heterochromatin-associated white gene, and expression of either human EZH2 or murine Ezh1 restores gene repression in Saccharomyces cerevisiae mutants that are impaired in telomeric silencing. Together, these data provide a functional link between Pc-G-dependent gene repression and inactive chromatin domains, and indicate that silencing mechanism(s) may be broadly conserved in eukaryotes.},
}
@article {pmid9211970,
year = {1997},
author = {Gonzalez, IL and Sylvester, JE},
title = {Beyond ribosomal DNA: on towards the telomere.},
journal = {Chromosoma},
volume = {105},
number = {7-8},
pages = {431-437},
pmid = {9211970},
issn = {0009-5915},
support = {GM 401 41625/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Chromosome Mapping/methods ; Chromosomes, Human ; Cloning, Molecular ; Conserved Sequence ; DNA, Ribosomal/*genetics ; Databases, Factual ; Electrophoresis, Gel, Pulsed-Field ; Humans ; Primates/genetics ; Repetitive Sequences, Nucleic Acid ; Sequence Alignment ; Sequence Analysis, DNA ; Telomere/*genetics ; },
abstract = {We have sequenced and analyzed 8.3 kb of sequence adjacent and distal to the human ribosomal DNA (rDNA); this distal sequence connects to the rDNA cluster just 4 kb upstream of the first promoter and is shared among the acrocentric chromosomes and, at least in part, it is also present in other primates. The sequence differs in character from that of the rDNA intergenic spacer (IGS) in that it does not contain long stretches of either polypyrimidine or polypurine. However, just like the IGS, it contains numerous repetitive elements, including retroposed fragments of 28S rRNA and large pieces of the IGS. In addition, we show that the rDNA clusters are not interrupted by other sequences and do not recombine with this distal segment.},
}
@article {pmid9195775,
year = {1997},
author = {Ishikawa, F},
title = {Telomere crisis in leukemia.},
journal = {International journal of hematology},
volume = {65},
number = {4},
pages = {355-364},
doi = {10.1016/s0925-5710(97)00575-6},
pmid = {9195775},
issn = {0925-5710},
mesh = {DNA Damage ; Humans ; Leukemia/*genetics ; Telomere/*genetics ; },
abstract = {Previous studies on telomere dynamics in leukemia are summarized. The 'telomere crisis model' is proposed to explain the clonal evolution mechanism of cancer cells from the standpoint of telomere biology. Future trends, including the development of potential telomerase inhibitors as a new class of anti-cancer agent, are discussed.},
}
@article {pmid9175740,
year = {1997},
author = {Bryan, TM and Marusic, L and Bacchetti, S and Namba, M and Reddel, RR},
title = {The telomere lengthening mechanism in telomerase-negative immortal human cells does not involve the telomerase RNA subunit.},
journal = {Human molecular genetics},
volume = {6},
number = {6},
pages = {921-926},
doi = {10.1093/hmg/6.6.921},
pmid = {9175740},
issn = {0964-6906},
mesh = {Base Sequence ; Blotting, Northern ; Cell Line ; Cell Line, Transformed ; DNA, Complementary ; Gene Expression ; Humans ; Molecular Sequence Data ; RNA ; Sequence Analysis, DNA ; Telomerase/*genetics ; Telomere ; },
abstract = {According to the telomere hypothesis of senescence, the progressive shortening of telomeres that occurs upon division of normal somatic cells eventually leads to cellular senescence. The immortalisation of human cells is associated with the acquisition of a telomere maintenance mechanism which is usually dependent upon expression of the enzyme telomerase. About one third of in vitro immortalised human cell lines, however, have no detectable telomerase but contain telomeres that are abnormally long. The nature of the alternative telomere maintenance mechanism (referred to as ALT, for Alternative Lengthening of Telomeres) that must exist in these telomerase-negative cells has not been elucidated. It has previously been shown that abnormal lengthening of yeast telomeres may occur due to mutations in the yeast telomerase RNA gene. That this is not the mechanism of the abnormally long telomeres in ALT cell lines was demonstrated by the finding that seven of seven ALT lines have wild-type human telomerase RNA (hTR) sequence, including a novel polymorphism that is present in 30% of normal individuals. We found that two ALT cell lines have no detectable expression of the hTR gene. This shows that the ALT mechanism in these cell lines is not dependent on hTR. Expression of exogenous hTR via infection of these cells with a recombinant hTR-adenovirus vector did not result in telomerase activity, indicating that their lack of telomerase activity is not due to absence of hTR expression. We conclude that the ALT mechanism is not dependent on the expression of hTR, and does not involve mutations in the hTR sequence.},
}
@article {pmid9175737,
year = {1997},
author = {Oexle, K and Zwirner, A},
title = {Advanced telomere shortening in respiratory chain disorders.},
journal = {Human molecular genetics},
volume = {6},
number = {6},
pages = {905-908},
doi = {10.1093/hmg/6.6.905},
pmid = {9175737},
issn = {0964-6906},
mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; Electron Transport ; Female ; Humans ; MELAS Syndrome/*genetics ; Male ; Middle Aged ; Telomere/*ultrastructure ; },
abstract = {Cell and tissue damage in respiratory chain disorders have been related to increased production of reactive oxygen species (ROS). We measured telomere lengths in such disorders since ROS have also been implicated with telomere shortening. We investigated whole blood cell DNA of 14 patients with MELAS-related mitochondriopathy and two patients with the LHON-associated G11778A mutation of the mitochondrial genome. The phenotypes were variable and included an unusual case of schizophrenia-like psychosis associated with the A3243G mutation. As compared to healthy controls telomere shortening in the patient group was advanced (P < or = 0.006). We compare this finding with the accelerated telomere shortening in Down's syndrome and in chromosomal breakage syndromes. We discuss possible relations between advanced telomere shortening and selective constraints that act on proliferating cells with respiratory chain dysfunction.},
}
@article {pmid9166585,
year = {1997},
author = {Yen, CH and Pazik, J and Zhang, Y and Elliott, RW},
title = {An interstitial telomere array proximal to the distal telomere of mouse chromosome 13.},
journal = {Mammalian genome : official journal of the International Mammalian Genome Society},
volume = {8},
number = {6},
pages = {411-417},
pmid = {9166585},
issn = {0938-8990},
support = {CA62225/CA/NCI NIH HHS/United States ; GM28464/GM/NIGMS NIH HHS/United States ; GM33160/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; *Chromosome Mapping ; Chromosomes ; Cloning, Molecular ; Female ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Mice, Inbred ICR ; Mice, Inbred Strains/*genetics ; Molecular Sequence Data ; Recombination, Genetic ; Repetitive Sequences, Nucleic Acid/*genetics ; Sequence Analysis, DNA ; Telomere/*genetics ; },
abstract = {Lambda clones of mouse DNA from BALB/c and C57BL/10, each containing an array of telomere hexamers, were localized by FISH to a region close to the telomere of Chr 13. Amplification of mouse genomic DNA with primers flanking SSRs within the cloned DNA showed several alleles, which were used to type eight sets of RI strains. The two lambda clones contained allelic versions of the interstitial telomere array, Tel-rs4, which is 495 bp in C57BL/10 and which includes a variety of sequence changes from the consensus telomere hexamer. Comparison of the segregation of the amplification products of the SSRs with the segregation of other loci in an interspecies backcross (C57BL/6JEi x SPRET/Ei) F1 x SPRET/Ei shows recombination suppression, possibly associated with ribosomal DNA sequences present on distal Chr 13 in Mus spretus, when compared with recombination in an interstrain backcross, (C57BL/6J x DBA/J) F1 x C57BL/6J, and with the MIT F2 intercross. Analysis of recombination in females using a second interstrain backcross, (ICR/Ha x C57BL/6Ha) F1 x C57BL/6Ha, also indicates recombination suppression when compared with recombination in males of the same strains, using backcross C57BL/6Ha x (ICR/Ha x C57BL/6Ha) F1. Thus, more than one cause may contribute to recombination suppression in this region. The combined order of the loci typed was D13Mit37-D13Mit30-D13Mit148-(D13Rp1, 2, 3, 4, Tel-rs4)-D13Mit53-D13Mit196-D13Mit77-(D13Mit7 8, 35). Data from crosses where apparently normal frequencies of recombination occur suggest that the telomere array is about 6 map units proximal to the most distal loci on Chr 13. This distance is consistent with evidence from markers identified in two YAC clones obtained from the region.},
}
@article {pmid9182332,
year = {1997},
author = {Hawley, RS},
title = {Sticky endings: separating telomeres.},
journal = {Science (New York, N.Y.)},
volume = {276},
number = {5316},
pages = {1215},
doi = {10.1126/science.276.5316.1215},
pmid = {9182332},
issn = {0036-8075},
mesh = {Chromosomes, Fungal/physiology ; Fungal Proteins/genetics/*physiology ; Meiosis/physiology ; Nuclear Proteins/genetics/*physiology ; Saccharomyces cerevisiae/genetics ; Synaptonemal Complex/physiology ; *Telomere ; },
}
@article {pmid9157883,
year = {1997},
author = {Conrad, MN and Dominguez, AM and Dresser, ME},
title = {Ndj1p, a meiotic telomere protein required for normal chromosome synapsis and segregation in yeast.},
journal = {Science (New York, N.Y.)},
volume = {276},
number = {5316},
pages = {1252-1255},
doi = {10.1126/science.276.5316.1252},
pmid = {9157883},
issn = {0036-8075},
support = {GM45250/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes, Artificial, Yeast ; Fungal Proteins/genetics/*physiology ; *Meiosis ; Nondisjunction, Genetic ; Nuclear Proteins/genetics/*physiology ; Saccharomyces cerevisiae/genetics/*physiology/ultrastructure ; Synaptonemal Complex/physiology ; *Telomere ; },
abstract = {The Saccharomyces cerevisiae gene NDJ1 (nondisjunction) encodes a protein that accumulates at telomeres during meiotic prophase. Deletion of NDJ1 (ndj1Delta) caused nondisjunction, impaired distributive segregation of linear chromosomes, and disordered the distribution of telomeric Rap1p, but it did not affect distributive segregation of circular plasmids. Induction of meiotic recombination and the extent of crossing-over were largely normal in ndj1Delta cells, but formation of axial elements and synapsis were delayed. Thus, Ndj1p may stabilize homologous DNA interactions at telomeres, and possibly at other sites, and it is required for a telomere activity in distributive segregation.},
}
@article {pmid9197419,
year = {1997},
author = {Mao, L and Devos, KM and Zhu, L and Gale, MD},
title = {Cloning and genetic mapping of wheat telomere-associated sequences.},
journal = {Molecular &amp; general genetics : MGG},
volume = {254},
number = {5},
pages = {584-591},
doi = {10.1007/s004380050455},
pmid = {9197419},
issn = {0026-8925},
mesh = {Base Sequence ; *Chromosome Mapping ; Cloning, Molecular ; Genetic Markers ; Molecular Sequence Data ; Polymerase Chain Reaction/methods ; Repetitive Sequences, Nucleic Acid/genetics ; Sequence Analysis, DNA ; Telomere/*genetics ; Triticum/*genetics ; },
abstract = {Wheat telomere-associated sequences (TASs) were cloned using a Vectorette approach and sequenced. Reverse primers specific to the TASs were combined with labelled degenerate telomere primers in PCR reactions containing total genomic DNA as template. Amplification products were separated on sequencing gels. In total, seventeen primer combinations provided 47 polymorphic fragments. Nine of these mapped beyond the most distal RFLP markers and defined the ends of seven chromosome arms. Seven of the nine terminal fragments were derived from a 118-bp tandem repeat, indicating that subtelomeric tandem repeat sequences provide an efficient means to target chromosome ends. A telomere cloning strategy and the terminal and interstitial location of TASs are discussed.},
}
@article {pmid9148955,
year = {1997},
author = {Stöppler, H and Hartmann, DP and Sherman, L and Schlegel, R},
title = {The human papillomavirus type 16 E6 and E7 oncoproteins dissociate cellular telomerase activity from the maintenance of telomere length.},
journal = {The Journal of biological chemistry},
volume = {272},
number = {20},
pages = {13332-13337},
doi = {10.1074/jbc.272.20.13332},
pmid = {9148955},
issn = {0021-9258},
support = {R01CA53371/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line ; *DNA-Binding Proteins ; Gene Expression Regulation, Viral ; Humans ; Keratinocytes/*virology ; Oncogene Proteins, Viral/*genetics/metabolism ; Papillomaviridae/genetics/*metabolism ; Papillomavirus E7 Proteins ; Telomerase/*genetics/metabolism ; Telomere/*genetics ; },
abstract = {The "high risk" subgroup of human papillomaviruses (e.g. HPV-16 and HPV-18) infect and induce tumors of mucosal epithelium. These neoplasms, which can progress to malignancy, retain and express the papillomavirus E6 and E7 oncogenes. In vitro, the E6 and E7 proteins associate with the cellular p53 and Rb proteins and interfere with their normal growth-regulatory functions. We report here that primary human keratinocytes transduced with the HPV-16 E6 gene, but not the E7 gene, express significant telomerase activity. However, despite this detectable enzymatic activity, E6-transduced cells continue to shorten their telomeres during in vitro passaging similar to control cells and to cells expressing the E7 and E6+E7 genes. At late passages, however, E7-transduced cells partially restore telomere length, although they lack detectable telomerase activity, demonstrating that E6-independent, telomerase-independent events mediate this change.},
}
@article {pmid9150138,
year = {1997},
author = {Kennedy, BK and Gotta, M and Sinclair, DA and Mills, K and McNabb, DS and Murthy, M and Pak, SM and Laroche, T and Gasser, SM and Guarente, L},
title = {Redistribution of silencing proteins from telomeres to the nucleolus is associated with extension of life span in S. cerevisiae.},
journal = {Cell},
volume = {89},
number = {3},
pages = {381-391},
doi = {10.1016/s0092-8674(00)80219-6},
pmid = {9150138},
issn = {0092-8674},
support = {AG11119/AG/NIA NIH HHS/United States ; },
mesh = {*Cell Cycle Proteins ; Cell Nucleolus/chemistry/*metabolism ; Cellular Senescence/physiology ; Fungal Proteins/*genetics/*metabolism ; Gene Expression Regulation, Fungal/physiology ; Genes, Fungal/physiology ; Molecular Sequence Data ; Mutagenesis/physiology ; RNA-Binding Proteins ; *Repressor Proteins ; Saccharomyces cerevisiae/chemistry/*cytology/ultrastructure ; *Saccharomyces cerevisiae Proteins ; Sequence Homology, Amino Acid ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Telomere/chemistry/*metabolism ; Trans-Activators/metabolism ; },
abstract = {A prior genetic study indicated that activity of Sir silencing proteins at a hypothetical AGE locus is essential for long life span. In this model, the SIR4-42 mutation would direct the Sir protein complex to the AGE locus, giving rise to a long life span. We show by indirect immunofluorescence that Sir3p and Sir4p are redirected to the nucleolus in the SIR4-42 mutant. Furthermore, this relocalization is dependent on both UTH4 a novel yeast gene that extends life span, and its homologue YGL023. Strikingly, the Sir complex is relocalized from telomeres to the nucleolus in old wild-type cells. We propose that the rDNA is the AGE locus and that nucleolar function is compromised in old yeast cells in a way that may be mitigated by targeting of Sir proteins to the nucleolus.},
}
@article {pmid9115215,
year = {1997},
author = {Reveal, PM and Henkels, KM and Turchi, JJ},
title = {Synthesis of the mammalian telomere lagging strand in vitro.},
journal = {The Journal of biological chemistry},
volume = {272},
number = {18},
pages = {11678-11681},
doi = {10.1074/jbc.272.18.11678},
pmid = {9115215},
issn = {0021-9258},
support = {CA64374/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cattle ; DNA/*biosynthesis/chemistry ; DNA Polymerase II/metabolism ; DNA Primase ; HeLa Cells ; Humans ; Mammals ; *Nucleic Acid Conformation ; RNA/metabolism ; RNA Nucleotidyltransferases/metabolism ; *Repetitive Sequences, Nucleic Acid ; Ribonuclease H ; Telomere/chemistry/*metabolism ; Thymus Gland/enzymology ; },
abstract = {Using a synthetic telomere DNA template and whole cell extracts, we have identified proteins capable of synthesizing the telomere complementary strand. Synthesis of the complementary strand required a DNA template consisting of 10 repeats of the human telomeric sequence d(TTAGGG) and deoxy- and ribonucleosidetriphosphates and was inhibited by neutralizing antibodies to DNA polymerase alpha. No evidence for RNA-independent synthesis of the lagging strand was observed, suggesting that a stable DNA secondary structure capable of priming the lagging strand is unlikely. Purified DNA polymerase alpha/primase was capable of catalyzing synthesis of the lagging strand with the same requirements as those observed in crude cell extracts. A ladder of products was observed with an interval of six bases, suggesting a unique RNA priming site and site-specific pausing or dissociation of polymerase alpha on the d(TTAGGG)10 template. Removal of the RNA primers was observed upon the addition of purified RNase HI. By varying the input rNTP, the RNA priming site was determined to be opposite the 3' thymidine nucleotide generating a five-base RNA primer with the sequence 5'-AACCC. The addition of UTP did not increase the efficiency of priming and extension, suggesting that the five-base RNA primer is sufficient for extension with dNTPs by DNA polymerase alpha. This represents the first experimental evidence for RNA priming and DNA extension as the mechanism of mammalian telomeric lagging strand replication.},
}
@article {pmid9280863,
year = {1997},
author = {La Torre, F and Silipigni, AM and Orlando, A and La Torre, I and Aragona, M},
title = {[Role of free radicals, telomeres, and telomerases in aging and cancerogenesis].},
journal = {Minerva medica},
volume = {88},
number = {5},
pages = {205-214},
pmid = {9280863},
issn = {0026-4806},
mesh = {*Cellular Senescence/physiology ; *Free Radicals ; Humans ; Neoplasms/*etiology ; *Telomerase/physiology ; *Telomere/physiology ; },
abstract = {After a rapid examination of a few basic concepts concerning cellular aging and programmed cell death, the aging of the tissues and organs, the authors discuss the principal theories on senescence. They underline that it is necessary to agree in considering the various genetic and epigenetic, endogenous and exogenous mechanisms that lead to the complex aging phenomenon multiple and interrelated. In particular they stress the hypothesis that senescence can be due to a sum of molecular damages caused by free radicals, and to the loss of telomeric DNA. Radical reactions can cause mutations, inactivation or a decrease in the turnover of mitochondrial DNA which is more vulnerable than the nuclear genoma to the attack of mutagenic agents, acting also as a continuous source of initial and/or promoting factors of the carcinogenetic process. The somatic cells become senescent because during cell division, they lose the mechanisms for the lengthening of the telomere. The telomerase prevents the shortening of telomeres in neoplastic cells and therefore renders them immortal. Paradoxically the protection of the telomere is exactly what must be avoided in the case of tumor cells. Recently the demonstration that telomerase is not always involved in the restoration of telomere length shows the complexity of the problems connected to the cause of senescence.},
}
@article {pmid9174401,
year = {1997},
author = {Gotta, M and Cockell, M},
title = {Telomeres, not the end of the story.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {19},
number = {5},
pages = {367-370},
doi = {10.1002/bies.950190503},
pmid = {9174401},
issn = {0265-9247},
mesh = {Animals ; Fungal Proteins/metabolism ; Heterochromatin/metabolism ; Models, Biological ; Molecular Structure ; Nucleosomes/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Telomere/chemistry/*metabolism ; },
abstract = {Transcription in organisms as diverse as yeast and mammals is subject to chromosomal position effects that result in heritable and variegated patterns of gene expression. Two recent studies have employed a reversible protein-DNA crosslinking method to identify the structural components of heterochromatin in budding yeast. The results show that a complex containing the proteins Rap1, Sir2p, Sir3p and Sir4p is physically associated with nucleosomes at telomere proximal regions, but that the repressive chromatin structure extended by Sir3p overexpression has a different composition.},
}
@article {pmid9171363,
year = {1997},
author = {Bednenko, J and Melek, M and Greene, EC and Shippen, DE},
title = {Developmentally regulated initiation of DNA synthesis by telomerase: evidence for factor-assisted de novo telomere formation.},
journal = {The EMBO journal},
volume = {16},
number = {9},
pages = {2507-2518},
pmid = {9171363},
issn = {0261-4189},
support = {GM49157/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chlorophyta ; Coculture Techniques ; DNA Primers/metabolism ; *DNA Replication ; DNA, Protozoan/*biosynthesis ; Euplotes/*genetics/growth &amp; development ; Nucleic Acid Conformation ; RNA, Protozoan/metabolism ; Telomerase/genetics/*metabolism ; Telomere/*physiology ; Templates, Genetic ; },
abstract = {Telomerase serves a dual role at telomeres, maintaining tracts of telomere repeats and forming telomeres de novo on broken chromosomes in a process called chromosome healing. In ciliates, both mechanisms are readily observed. Vegetatively growing cells maintain pre-existing telomeres, while cells undergoing macronuclear development fragment their chromosomes and form telomeres de novo. Here we provide the first evidence for developmentally regulated initiation of DNA synthesis by telomerase. In vitro assays were conducted with telomerase from vegetative and developing Euplotes macronuclei using chimeric primers that contained non-telomeric 3' ends and an upstream stretch of telomeric DNA. In developing macronuclei, chimeric primers had two fates: nucleotides were either polymerized directly onto the 3' terminus or residues were removed from the 3' end by endonucleolytic cleavage before polymerization began. In contrast, telomerase from vegetative macronuclei used only the cleavage pathway. Telomere repeat addition onto non-telomeric 3' ends was lost when developing macronuclei were lysed and the contents purified on glycerol gradients. However, when fractions from the glycerol gradient were added back to partially purified telomerase, telomere synthesis was restored. The data indicate that a dissociable chromosome healing factor (CHF) collaborates with telomerase to initiate developmentally programmed de novo telomere formation.},
}
@article {pmid9166220,
year = {1997},
author = {Dahse, R and Fiedler, W and Ernst, G},
title = {Telomeres and telomerase: biological and clinical importance.},
journal = {Clinical chemistry},
volume = {43},
number = {5},
pages = {708-714},
pmid = {9166220},
issn = {0009-9147},
mesh = {Aging ; Biomarkers, Tumor ; Cell Division ; Cellular Senescence ; Humans ; Neoplasms ; Telomere/*physiology ; },
abstract = {We review the present knowledge of telomeres and telomerase with special attention to their role in cell proliferation, cellular senescence, and human aging. We summarize the functional aspects of telomerase in cancer, as well as its role as a useful diagnostic and prognostic tumor marker, and discuss possible approaches to telomerase inhibition as a target for cancer therapy.},
}
@article {pmid9163921,
year = {1997},
author = {Guerrini, AM and Ascenzioni, F and Gallo, T and Donini, P},
title = {Yeast linear plasmids with T2AG3 telomeres: TEL+CEN antagonism and genetic and molecular stability.},
journal = {FEMS microbiology letters},
volume = {150},
number = {1},
pages = {165-171},
doi = {10.1111/j.1574-6968.1997.tb10365.x},
pmid = {9163921},
issn = {0378-1097},
mesh = {Centromere/genetics ; DNA Replication ; DNA, Fungal/chemistry/*genetics ; Escherichia coli ; Genetic Vectors/genetics ; Nucleic Acid Conformation ; Plasmids/chemistry/*genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; Saccharomyces cerevisiae/*genetics ; Sequence Analysis, DNA ; Telomere/*genetics ; Transformation, Genetic ; },
abstract = {A linear plasmid containing ARS1, CEN4, and 48 bp of vertebrate (T2AG3) telomeric sequences at each end was used to transform Saccharomyces cerevisiae. Only circular plasmids that had lost the centromere and had retained the T2AG3 sequences were obtained, indicating that the vertebrate T2AG3 sequences and the yeast CEN4 could not be simultaneously present in this vector. This hypothesis was verified by removing the CEN4 sequence from the construct. In fact, the resulting transformants contained two classes of efficiently replicating linear plasmids: one of the expected size and one about twice as large. During subsequent growth, plasmids of the former, but not latter, class were subjected to concatemer formation. This can best be explained by recombination events involving the T2AG3 sequences at the ends of the molecule, since very similar centric and acentric linear plasmids bearing Tetrahymena telomeric ends replicated faithfully.},
}
@article {pmid9149667,
year = {1997},
author = {Aviv, A and Aviv, H},
title = {Reflections on telomeres, growth, aging, and essential hypertension.},
journal = {Hypertension (Dallas, Tex. : 1979)},
volume = {29},
number = {5},
pages = {1067-1072},
doi = {10.1161/01.hyp.29.5.1067},
pmid = {9149667},
issn = {0194-911X},
mesh = {Aging/*genetics/pathology ; Cellular Senescence ; Humans ; Hypertension/*genetics/pathology/physiopathology ; Telomere/*genetics ; },
abstract = {Here we review the "telomere hypothesis of cellular aging." We propose that this hypothesis is relevant to our understanding of the roles of genetics as well as growth and development in the etiology of essential hypertension and its cardiovascular complications. Elements of this hypothesis and the speculations that we make can be directly tested using tissues (cells) obtained from human beings.},
}
@article {pmid9146697,
year = {1997},
author = {Preston, RJ},
title = {Telomeres, telomerase and chromosome stability.},
journal = {Radiation research},
volume = {147},
number = {5},
pages = {529-534},
pmid = {9146697},
issn = {0033-7587},
mesh = {Animals ; Chromosomes/*ultrastructure ; DNA Damage ; DNA Repair ; Humans ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {Telomeres in most species consist of repeat units of a small number of nucleotides that together with secondary structures and associated proteins stabilize the linear chromosomal DNA molecule. Chromosomes lose a small amount of telomeric DNA after each cell replication. It has been proposed that when telomeres shorten below a critical length, a DNA damage response pathway is activated and induces cell cycle arrest. In cells such as stem cells that maintain a proliferative capacity, telomere length is maintained by the reverse transcriptase, telomerase. In addition, telomerase activity is present in 90% of primary human tumors, suggesting a role for telomerase in providing a proliferative capacity to cells, which is a requirement in progression to malignancy. Telomerase activity can be involved in chromosome healing, although telomerase-independent processes also appear to be capable of capping broken chromosome ends. This review describes the structure and maintenance of telomeres, the importance of a critical telomere length to cell proliferation and the telomeric status of broken chromosome ends produced during development or by spontaneous or induced DNA damages.},
}
@article {pmid9118038,
year = {1997},
author = {Iwama, H and Ohyashiki, K and Ohyashiki, JH and Hayashi, S and Kawakubo, K and Shay, JW and Toyama, K},
title = {The relationship between telomere length and therapy-associated cytogenetic responses in patients with chronic myeloid leukemia.},
journal = {Cancer},
volume = {79},
number = {8},
pages = {1552-1560},
doi = {10.1002/(sici)1097-0142(19970415)79:8&lt;1552::aid-cncr17&gt;3.0.co;2-x},
pmid = {9118038},
issn = {0008-543X},
mesh = {Adolescent ; Adult ; Aged ; Antineoplastic Agents/*therapeutic use ; Humans ; Interferon-alpha/*therapeutic use ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/blood/*genetics/*therapy ; Middle Aged ; Repetitive Sequences, Nucleic Acid/*genetics ; Telomerase/blood ; Telomere/*genetics ; },
abstract = {BACKGROUND: Chronic myeloid leukemia (CML) is a clonal disease with specific cytogenetic changes involving the Philadelphia (Ph) translocation. The authors examined the relationship between telomere length (terminal restriction fragment [TRF]) and therapy-associated cytogenetic responses in CML patients.<br><br>METHODS: The authors examined the telomere length and telomerase activity in 44 patients with Ph-positive CML in the chronic phase. TRF was determined by Southern blot analysis using the (TTAGGG)4 probe and telomerase activity was assessed by the telomeric repeat amplification protocol and fluorescent-labeled primers.<br><br>RESULTS: At the time of CML diagnosis, 19 patients had TRFs within the age-matched normal range (mean +/- 2 x standard deviation [SD]) and the remaining 25 patients had TRFs shorter than the age-matched normal range (< mean +/- 2 x SD). Hematologic findings, including leukocyte count, hemoglobin level, platelet count, and percentage of bone marrow blasts at the time of diagnosis did not significantly differ between patients with normal and shortened TRFs; however, those with shortened TRFs had high levels of telomerase activity (P = 0.045). In a group of patients treated with alpha-interferon (n = 32), those with normal TRFs had a significantly lower frequency of blast crises (P = 0.0328), a significantly higher incidence of cytogenetic responses (P = 0.0185), and a favorable prognosis (P < 0.01) compared with those with shortened TRFs.<br><br>CONCLUSIONS: These findings suggest that normal TRFs in a small number of CML patients at the time of diagnosis may have a significant amount of normal stem cells remaining. The authors suggest that normal TRFs at the time of diagnosis indicate a subset of CML patients who may respond favorably to alpha-interferon therapy.},
}
@article {pmid9141618,
year = {1997},
author = {Zalensky, AO and Tomilin, NV and Zalenskaya, IA and Teplitz, RL and Bradbury, EM},
title = {Telomere-telomere interactions and candidate telomere binding protein(s) in mammalian sperm cells.},
journal = {Experimental cell research},
volume = {232},
number = {1},
pages = {29-41},
doi = {10.1006/excr.1997.3482},
pmid = {9141618},
issn = {0014-4827},
mesh = {Animals ; Binding Sites ; Cattle ; DNA Probes ; DNA-Binding Proteins/*isolation &amp; purification ; Dimerization ; Horses ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Meiosis ; Mice ; Protein Binding ; Rats ; Repetitive Sequences, Nucleic Acid ; Spermatogenesis ; Spermatozoa/metabolism/*ultrastructure ; Swine ; Telomere/*genetics/metabolism/ultrastructure ; },
abstract = {We have used fluorescent in situ hybridization to localize telomeres within the nuclei of sperm from six mammals (human, rat, mouse, stallion, boar, and bull). In minimally swollen sperm of mouse and rat, most of the telomeres are clustered within a limited area in the posterior part of nuclei. In sperm of other species, telomeres associate into tetrameres and dimers. On swelling of sperm cells with heparin/dithiotriethol, telomere associations disperse, and hybridization signals become smaller in size and their numbers approach or correspond to the number of chromosome ends in a haploid genome. Quantitation of telomere loci indicates that dimeric associations are prominent features of mammalian sperm nuclear architecture. Higher order telomere-telomere interactions and organization develop during meiotic stages of human spermatogenesis. At this stage, telomeres also become associated with the nuclear membrane. In an attempt to elucidate the molecular mechanisms underlying telomere interactions in sperm, we have identified a novel protein activity that binds to the double-stranded telomeric repeat (TTAGGG)n. Sperm telomere binding protein(s) (STBP) was extracted from human and bull sperm by 0.5 M NaCl. STBP does not bind single-stranded telomeric DNA and is highly specific for single base substitutions in a duplex DNA sequence. Depending on the conditions of binding, we observed the formation of several nucleoprotein complexes. We have shown that there is a transition between complexes, which indicates that the slower migrating complex is a multimer of the higher mobility one. We propose that STBP participates in association between the telomere domains which were microscopically observed in mammalian spermatozoa.},
}
@article {pmid9105032,
year = {1997},
author = {Bass, HW and Marshall, WF and Sedat, JW and Agard, DA and Cande, WZ},
title = {Telomeres cluster de novo before the initiation of synapsis: a three-dimensional spatial analysis of telomere positions before and during meiotic prophase.},
journal = {The Journal of cell biology},
volume = {137},
number = {1},
pages = {5-18},
pmid = {9105032},
issn = {0021-9525},
support = {R01 GM025101/GM/NIGMS NIH HHS/United States ; R01-GM-48547/GM/NIGMS NIH HHS/United States ; R01-GM-25101-16/GM/NIGMS NIH HHS/United States ; R01 GM048547/GM/NIGMS NIH HHS/United States ; R01 GM031627/GM/NIGMS NIH HHS/United States ; R01-GM-31627/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Nucleus/genetics ; Chromosomes/physiology ; In Situ Hybridization, Fluorescence ; Interphase/physiology ; Kinetics ; Meiosis/*physiology ; Plant Proteins/genetics ; Prophase/*physiology ; RNA, Messenger/analysis ; Synaptonemal Complex/*physiology ; Telomere/*genetics/metabolism ; Zea mays ; },
abstract = {We have analyzed the progressive changes in the spatial distribution of telomeres during meiosis using three-dimensional, high resolution fluorescence microscopy. Fixed meiotic cells of maize (Zea mays L.) were subjected to in situ hybridization under conditions that preserved chromosome structure, allowing identification of stage-dependent changes in telomere arrangements. We found that nuclei at the last somatic prophase before meiosis exhibit a nonrandom, polarized chromosome organization resulting in a loose grouping of telomeres. Quantitative measurements on the spatial arrangements of telomeres revealed that, as cells passed through premeiotic interphase and into leptotene, there was an increase in the frequency of large telomere-to-telomere distances and a decrease in the bias toward peripheral localization of telomeres. By leptotene, there was no obvious evidence of telomere grouping, and the large, singular nucleolus was internally located, nearly concentric with the nucleus. At the end of leptotene, telomeres clustered de novo at the nuclear periphery, coincident with a displacement of the nucleolus to one side. The telomere cluster persisted throughout zygotene and into early pachytene. The nucleolus was adjacent to the cluster at zygotene. At the pachytene stage, telomeres rearranged again by dispersing throughout the nuclear periphery. The stage-dependent changes in telomere arrangements are suggestive of specific, active telomere-associated motility processes with meiotic functions. Thus, the formation of the cluster itself is an early event in the nuclear reorganizations associated with meiosis and may reflect a control point in the initiation of synapsis or crossing over.},
}
@article {pmid9104824,
year = {1997},
author = {Palmer, LD and Weng, N and Levine, BL and June, CH and Lane, HC and Hodes, RJ},
title = {Telomere length, telomerase activity, and replicative potential in HIV infection: analysis of CD4+ and CD8+ T cells from HIV-discordant monozygotic twins.},
journal = {The Journal of experimental medicine},
volume = {185},
number = {7},
pages = {1381-1386},
pmid = {9104824},
issn = {0022-1007},
mesh = {Adult ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cells, Cultured ; Cellular Senescence ; HIV Infections/genetics/*immunology/pathology ; Humans ; Lymphocyte Activation ; Middle Aged ; T-Lymphocyte Subsets/cytology/*immunology ; Telomerase/*analysis ; Telomere/*ultrastructure ; *Twins, Monozygotic ; },
abstract = {To address the possible role of replicative senescence in human immunodeficiency virus (HIV) infection, telomere length, telomerase activity, and in vitro replicative capacity were assessed in peripheral blood T cells from HIV+ and HIV- donors. Genetic and age-specific effects on these parameters were controlled by studying HIV-discordant pairs of monozygotic twins. Telomere terminal restriction fragment (TRF) lengths from CD4+ T cells of HIV+ donors were significantly greater than those from HIV- twins. In contrast, telomere lengths in CD8+ T cells from HIV+ donors were shorter than in HIV- donors. The in vitro replicative capacity of CD4+ cells from HIV+ donors was equivalent to that of HIV- donors in response to stimulation through T cell receptor CD3 and CD28. Little or no telomerase activity was detected in freshly isolated CD4+ or CD8+ lymphocytes from HIV+ or HIV- donors, but was induced by in vitro stimulation of both HIV+ and HIV- donor cells. These results suggest that HIV infection is associated with alterations in the population dynamics of both CD4+ and CD8+ T cells, but fail to provide evidence for clonal exhaustion or replicative senescence as a mechanism underlying the decline in CD4+ T cells of HIV-infected donors.},
}
@article {pmid9282119,
year = {1997},
author = {Kipling, D},
title = {Telomere structure and telomerase expression during mouse development and tumorigenesis.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {33},
number = {5},
pages = {792-800},
doi = {10.1016/S0959-8049(97)00060-9},
pmid = {9282119},
issn = {0959-8049},
mesh = {Animals ; Cellular Senescence/physiology ; Genome ; Mice/*genetics ; Mice, Knockout ; Neoplasm Proteins/genetics/*metabolism ; Neoplasms, Experimental/*genetics ; Telomerase/genetics/*metabolism ; Telomere/*genetics ; },
abstract = {Mouse telomeres are on average longer than those of man, raising questions regarding the link between telomere loss and replicative senescence in mice and the requirement for telomerase activity for mouse cell immortalisation. However, the emerging data on telomerase activity during tumorigenesis in the mouse must be interpreted in the context of the very different structure of mouse telomeres. It will be argued here that the evidence for a casual link between telomere loss and replicative senescence is weak in the mouse, with the observed upregulation of telomerase activity in mouse tumours perhaps instead reflecting co-ordinated regulatory changes in tumour cells. Its absence would be consistent with evolutionary considerations, which hypothesise that such a link is an additional layer of control against tumour formation that has evolved in man. The very different genomic substrates for telomerase in humans and mice mean that the initial phenotype of a telomerase knock-out mouse does not necessarily critically address the existence of a link between telomerase and tumorigenesis in man.},
}
@article {pmid9282116,
year = {1997},
author = {Norrback, KF and Roos, G},
title = {Telomeres and telomerase in normal and malignant haematopoietic cells.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {33},
number = {5},
pages = {774-780},
doi = {10.1016/S0959-8049(97)00059-2},
pmid = {9282116},
issn = {0959-8049},
mesh = {Hematopoietic Stem Cells/enzymology/*ultrastructure ; Humans ; Leukemia/enzymology/*genetics ; Lymphoma/enzymology/*genetics ; Neoplasm Proteins/*metabolism ; Telomerase/*metabolism ; Telomere/*physiology ; },
abstract = {The normal haematopoietic system harbours telomerase-competent cells with a capacity to upregulate the activity to notable levels in a telomere length-independent manner. Strong telomerase activity is found in progenitor stem cells and activated lymphocytes in vitro as well as in vivo, indicating that cells with high growth requirements can readily upregulate telomerase. Despite detection of telomerase activity, a gradual telomere erosion occurs in stem cells and lymphocytes, with significantly shortened telomeres at higher ages, a phenomenon that might be of importance for developing immunosenescence and exhausted haematopoiesis. In malignant haematopoietic disorders telomerase activity is a general finding with large differences in activity levels. The strongest telomerase expression has been shown in acute leukaemias and non-Hodgkin's lymphomas, especially high grade cases. There are indications that the level of activity might parallel tumour progression and be of prognostic relevance, but studies of larger patient materials are needed. An association between the cell cycle and telomerase activity exists, especially for normal haematopoietic cells, and induction of a differentiation programme in immortalised cell lines downregulates telomerase activity. The expression of telomerase activity seems to be regulated at different levels, since for immature bone marrow cells the level of activity seemed to parallel better the phenotype than the proliferation state. The frequent expression of telomerase in leukaemias and lymphomas makes these disorders interesting targets for future anti-telomerase therapy.},
}
@article {pmid9282115,
year = {1997},
author = {Bryan, TM and Reddel, RR},
title = {Telomere dynamics and telomerase activity in in vitro immortalised human cells.},
journal = {European journal of cancer (Oxford, England : 1990)},
volume = {33},
number = {5},
pages = {767-773},
doi = {10.1016/S0959-8049(97)00065-8},
pmid = {9282115},
issn = {0959-8049},
mesh = {Cellular Senescence/*genetics ; Humans ; Neoplasm Proteins/*metabolism ; Neoplasms/enzymology/*genetics ; Telomerase/*metabolism ; Telomere/*enzymology ; *Tumor Cells, Cultured ; },
abstract = {This article reviews the current understanding of the involvement of telomerase in in vitro immortalisation of human cells. In vitro immortalisation with DNA tumour viruses or chemicals usually occurs in two phases. The first stage is an extension of lifespan beyond that at which cells would normally senescence, after which the culture enters a period of crisis. The second stage involves the escape from crisis of a rare cell in the culture, which goes on to proliferate indefinitely. The hypothesis that telomere shortening acts as a signal for senescence and crisis, and that cells need to activate telomerase to survive these states, gained support from early studies examining telomere behaviour and telomerase activity in immortalised cell lines. In many cases, telomeres were found to continue to shorten during the phase of extended lifespan, and no telomerase was detectable. Cells which survived crisis had activated telomerase and had stable or lengthened telomerase. However, it is now clear that this model does not apply to all cell lines. Approximately a quarter of in vitro immortalised cell lines so far examined have no detectable telomerase activity, yet have very long and heterogeneous telomeres. These cell lines have acquired a novel mechanism for lengthening their telomeres, named ALT (Alternative Lengthening of Telomeres). The nature of ALT is not yet understood, but may involve non-reciprocal recombination between telomeres. ALT is not merely a phenomenon of in vitro immortalised cell lines, but has also been found in tumours and tumour-derived cell lines. Furthermore, there are a number of cell lines which have been shown to have low levels of telomerase prior to crisis while telomere shortening is still occurring, and the function of these low levels of telomerase activity is unknown.},
}
@article {pmid9106658,
year = {1997},
author = {Cenci, G and Rawson, RB and Belloni, G and Castrillon, DH and Tudor, M and Petrucci, R and Goldberg, ML and Wasserman, SA and Gatti, M},
title = {UbcD1, a Drosophila ubiquitin-conjugating enzyme required for proper telomere behavior.},
journal = {Genes &amp; development},
volume = {11},
number = {7},
pages = {863-875},
doi = {10.1101/gad.11.7.863},
pmid = {9106658},
issn = {0890-9369},
support = {GM48430/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Brain/ultrastructure ; *Chromosome Aberrations ; Drosophila melanogaster/enzymology/*genetics ; Female ; *Genes, Insect ; Genetic Complementation Test ; In Situ Hybridization, Fluorescence ; Male ; Meiosis/genetics ; Mitosis/genetics ; Molecular Sequence Data ; Mutation ; Restriction Mapping ; Sequence Analysis, DNA ; Sex Factors ; Telomere/*genetics ; },
abstract = {The end-to-end association of chromosomes through their telomeres has been observed in normal cells of certain organisms, as well as in senescent and tumor cells. The molecular mechanisms underlying this phenomenon are currently unknown. We show here that five independent mutant alleles in the Drosophila UbcD1 gene cause frequent telomere-telomere attachments during both mitosis and male meiosis that are not seen in wild type. These telomeric associations involve all the telomeres of the D. melanogaster chromosome complement, albeit with different frequencies. The pattern of telomeric associations observed in UbcD1 mutants suggests strongly that the interphase chromosomes of wild-type larval brain cells maintain a Rab1 orientation within the nucleus, with the telomeres and centromeres segregated to opposite sides of the nucleus. The UbcD1 gene encodes a class I ubiquitin-conjugating (E2) enzyme. This indicates that ubiquitin-mediated proteolysis is normally needed to ensure proper telomere behavior during Drosophila cell division. We therefore suggest that at least one of the targets of UbcD1 ubiquitination is a telomere-associated polypeptide that may help maintain proper chromosomal orientation during interphase.},
}
@article {pmid9060439,
year = {1997},
author = {Bhattacharyya, A and Blackburn, EH},
title = {Aspergillus nidulans maintains short telomeres throughout development.},
journal = {Nucleic acids research},
volume = {25},
number = {7},
pages = {1426-1431},
pmid = {9060439},
issn = {0305-1048},
support = {GM 26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Aspergillus nidulans/*growth &amp; development ; Base Sequence ; Blotting, Southern ; Cloning, Molecular ; DNA, Fungal/chemistry ; Endodeoxyribonucleases/metabolism ; Molecular Sequence Data ; Sequence Analysis, DNA ; Telomere/*genetics ; Temperature ; },
abstract = {We report the identification and cloning of the telomeres of the filamentous fungus,Aspergillus nidulans. We have identified three classes of cloned chromosomal ends based on the telomere-associated sequences (TASs) and demonstrated that the telomeric repeat sequence is TTAGGG, identical to that found in vertebrates, including humans, and some lower eukaryotes. One category of telomere clones was found to contain internal, variant TAAGGG repeats. The A.nidulans telomeric tract length is strikingly short (4-22 repeats). We demonstrate that telomere length is remarkably stable in different cell types and at altered growth temperatures, suggesting a highly regulated mechanism for length control.},
}
@article {pmid9087429,
year = {1997},
author = {Wotton, D and Shore, D},
title = {A novel Rap1p-interacting factor, Rif2p, cooperates with Rif1p to regulate telomere length in Saccharomyces cerevisiae.},
journal = {Genes &amp; development},
volume = {11},
number = {6},
pages = {748-760},
doi = {10.1101/gad.11.6.748},
pmid = {9087429},
issn = {0890-9369},
support = {GM40094/GM/NIGMS NIH HHS/United States ; },
mesh = {Bacterial Proteins/genetics/metabolism ; Binding Sites ; Carrier Proteins/genetics/*metabolism ; Chromosomes, Fungal/genetics/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Fungal Proteins/genetics/*metabolism ; GTP-Binding Proteins/genetics/*metabolism ; Membrane Proteins/genetics/metabolism ; Models, Biological ; Mutation ; Recombinant Fusion Proteins/genetics/metabolism ; Repressor Proteins/genetics/*metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomyces cerevisiae Proteins ; Telomere/genetics/*metabolism ; *Telomere-Binding Proteins ; rap GTP-Binding Proteins ; },
abstract = {The Saccharomyces cerevisiae Rap1 protein binds with high affinity to sites within the poly(C(1-3)A) tracts at telomeres, where it plays a role in both telomere length regulation and the initiation of telomeric silencing. Rap1p initiates silencing at telomeres by interacting through its carboxy-terminal domain with Sir3p and Sir4p, both of which are required for repression. This same domain of Rap1p also negatively regulates telomere elongation, through an unknown mechanism. We have identified a new Rap1-interacting factor (Rif2p) that plays a role in telomere length regulation. Rif2p has considerable functional similarities with a Rap1p-interacting factor (Rif1p) identified previously. Mutations in RIF1 or RIF2 (unlike mutations in the silencing genes SIR3 and SIR4) result in moderate telomere elongation and improved telomeric silencing. However, deletion of both RIF1 and RIF2 in the same cell results in a dramatic increase in telomere length, similar to that seen with a carboxy-terminal truncation of Rap1p. In addition, overexpression of either RIF1 or RIF2 decreases telomere length, and co-overexpression of these proteins can reverse the telomere elongation effect of overexpression of the Rap1p carboxyl terminus. Finally, we show that Rif1p and Rif2p can interact with each other in vivo. These results suggest that telomere length regulation is mediated by a protein complex consisting of Rif1p and Rif2p, each of which has distinct regulatory functions. One role of Rap1p in telomere length regulation is to recruit these proteins to the telomeres.},
}
@article {pmid9087176,
year = {1997},
author = {Pan, C and Xue, BH and Ellis, TM and Peace, DJ and Díaz, MO},
title = {Changes in telomerase activity and telomere length during human T lymphocyte senescence.},
journal = {Experimental cell research},
volume = {231},
number = {2},
pages = {346-353},
doi = {10.1006/excr.1997.3475},
pmid = {9087176},
issn = {0014-4827},
support = {CA49133/CA/NCI NIH HHS/United States ; CA60128/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Cell Cycle ; Cell Division ; Cells, Cultured ; Cellular Senescence ; DNA Replication ; Enzyme Induction ; Female ; HL-60 Cells/cytology/enzymology/ultrastructure ; Humans ; Male ; Models, Biological ; Neoplasm Proteins/metabolism ; Neoplastic Stem Cells/enzymology/pathology/ultrastructure ; Polymerase Chain Reaction ; Repetitive Sequences, Nucleic Acid ; T-Lymphocytes/*cytology/enzymology/ultrastructure ; T-Lymphocytes, Cytotoxic/cytology/enzymology/ultrastructure ; Telomerase/*metabolism ; Telomere/*ultrastructure ; Tumor Cells, Cultured ; },
abstract = {It has been proposed that telomeres shorten with every cell cycle because the normal mechanism of DNA replication cannot replicate the end sequences of the lagging DNA strand. Telomerase, a ribonucleoprotein enzyme that synthesizes telomeric DNA repeats at the DNA 3' ends of eukaryotic chromosomes, can compensate for such shortening, by extending the template of the lagging strand. Telomerase activity has been identified in human germline cells and in neoplastic immortal somatic cells, but not in most normal somatic cells, which senesce after a certain number of cell divisions. We and others have found that telomerase activity is present in normal human lymphocytes and is upregulated when the cells are activated. But, unlike the immortal cell lines, presence of telomerase activity is not sufficient to make T cells immortal and telomeres from these cells shorten continuously during in vitro culture. After senescence, telomerase activity, as detected by the TRAP technique, was downregulated. A cytotoxic T lymphocyte (CTL) cell line that was established in the laboratory has very short terminal restriction fragments (TRFs). Telomerase activity in this cell line is induced during activation and this activity is tightly correlated with cell proliferation. The level of telomerase activity in activated peripheral blood T cells, the CTL cell line, and two leukemia cell lines does not correlate with the average TRF length, suggesting that other factors besides telomerase activity are involved in the regulation of telomere length.},
}
@article {pmid9072807,
year = {1997},
author = {Hawley, RS},
title = {Unresolvable endings: defective telomeres and failed separation.},
journal = {Science (New York, N.Y.)},
volume = {275},
number = {5305},
pages = {1441-1443},
doi = {10.1126/science.275.5305.1441a},
pmid = {9072807},
issn = {0036-8075},
mesh = {Animals ; Chromatids/physiology ; Chromosomes/metabolism/*physiology ; DNA Replication ; DNA Transposable Elements ; Drosophila/cytology/genetics ; Meiosis ; *Mitosis ; Mutation ; RNA/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/*physiology ; Templates, Genetic ; Tetrahymena/cytology/genetics ; },
}
@article {pmid9054505,
year = {1997},
author = {Makarov, VL and Hirose, Y and Langmore, JP},
title = {Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening.},
journal = {Cell},
volume = {88},
number = {5},
pages = {657-666},
doi = {10.1016/s0092-8674(00)81908-x},
pmid = {9054505},
issn = {0092-8674},
mesh = {Alkalies ; Cell Line, Transformed ; Cells, Cultured/physiology ; Chromosomes/*physiology ; DNA Primers ; DNA-Directed DNA Polymerase ; Electrophoresis, Agar Gel ; Electrophoresis, Gel, Two-Dimensional ; Fetus/cytology ; Fibroblasts/cytology/physiology ; Guanine/analysis ; Humans ; Lung/cytology ; Nucleic Acid Hybridization ; RNA-Directed DNA Polymerase ; Taq Polymerase ; Telomere/*genetics/*metabolism ; },
abstract = {The chromosomes of lower eukaryotes have short telomeric 3' extensions. Using a primer-extension/nick-translation technique and nondenaturing hybridization, we find long 3' G-rich tails at human chromosome ends in mortal primary fibroblasts, umbilical vein endothelial cells, and leukocytes, as well as in immortalized fibroblasts. For all cells tested, >80% of the telomeres have long G-rich overhangs, averaging 130-210 bases in length, in disagreement with the conventional model for incomplete lagging-strand replication, which predicts overhangs on 50% of the chromosome ends. The observed G tails must exist during most of the cell cycle and probably result from degradation of both chromosome ends. The average lengths of the G tails are quantitatively consistent with the observed rates of human chromosome shortening.},
}
@article {pmid9054504,
year = {1997},
author = {Danilevskaya, ON and Arkhipova, IR and Traverse, KL and Pardue, ML},
title = {Promoting in tandem: the promoter for telomere transposon HeT-A and implications for the evolution of retroviral LTRs.},
journal = {Cell},
volume = {88},
number = {5},
pages = {647-655},
doi = {10.1016/s0092-8674(00)81907-8},
pmid = {9054504},
issn = {0092-8674},
support = {GM50315/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Biological Evolution ; Blotting, Northern ; Cells, Cultured/physiology ; DNA Transposable Elements/*genetics ; Drosophila melanogaster ; Genes, Viral/genetics ; Molecular Sequence Data ; Promoter Regions, Genetic/*genetics ; RNA, Messenger/analysis ; Retroviridae/*genetics ; Sequence Analysis, DNA ; Telomere/*genetics ; Transcription, Genetic/genetics ; },
abstract = {HeT-A elements are non-long terminal repeat (non-LTR) retrotransposons found in head-to-tail arrays on Drosophila chromosome ends, where they form telomeres. We report that HeT-A promoter activity is located in the 3' end of the element, unlike the 5' location seen for other non-LTR retrotransposons. In HeT-A arrays the 3' sequence of one element directs transcription of its downstream neighbor. Because the upstream promoter has the same sequence as the 3' end of the transcribed element, the HeT-A promoter is effectively equivalent to a 5' LTR in both structure and function. Retroviruses and LTR retrotransposons have their promoters and transcription initiation sites in their 5' LTRs. Thus HeT-A appears to have the structure of an evolutionary intermediate between non-LTR and LTR retrotransposons.},
}
@article {pmid9115585,
year = {1997},
author = {Kobitsu, K and Tsutsumi, M and Tsujiuchi, T and Suzuki, F and Kido, A and Okajima, E and Fukuda, T and Sakaki, T and Konishi, Y},
title = {Shortened telomere length and increased telomerase activity in hamster pancreatic duct adenocarcinomas and cell lines.},
journal = {Molecular carcinogenesis},
volume = {18},
number = {3},
pages = {153-159},
doi = {10.1002/(sici)1098-2744(199703)18:3&lt;153::aid-mc4&gt;3.0.co;2-g},
pmid = {9115585},
issn = {0899-1987},
mesh = {Adenocarcinoma/*enzymology ; Animals ; Blotting, Southern ; Cell Line ; Cricetinae ; Female ; Humans ; Mesocricetus ; Neoplasm Transplantation ; Pancreas/*enzymology ; *Pancreatic Ducts ; Pancreatic Neoplasms/*enzymology ; Reference Values ; Repetitive Sequences, Nucleic Acid ; Spleen/enzymology ; Telomerase/*metabolism ; Telomere/*enzymology/*ultrastructure ; Tumor Cells, Cultured ; },
abstract = {Recently, shortened telomere length and increased telomerase activity have been demonstrated in various human cancers. In the study reported here, we ascertained whether gene changes are characteristic of pancreatic cancers. Hamster duct carcinomas and cell lines were investigated by Southern blot analysis for telomere restriction fragment (TRF) length and by the telomeric repeat amplification protocol (TRAP) assay for telomerase activity. Comparison with normal pancreas and spleen revealed shortened TRF length and markedly increased telomerase activity in primary pancreatic duct carcinomas induced by the rapid-production model as well as in a transplantable carcinoma and the cell lines. The enzyme level was 86.0-215.7 times the low levels found in control pancreas and spleen tissues. Late-passage Syrian hamster embryo cells, known to be immortalized and tumorigenic, had shorter TRFs than the original cells in primary culture did. These results indicate that hamster pancreatic duct carcinoma cells are immortalized, with the potential for proliferation ad infinitum, and provide a model for basic therapeutic research into the substances targeting telomerase.},
}
@article {pmid9078293,
year = {1997},
author = {Ohyashiki, K and Ohyashiki, JH},
title = {Telomere dynamics and cytogenetic changes in human hematologic neoplasias: a working hypothesis.},
journal = {Cancer genetics and cytogenetics},
volume = {94},
number = {1},
pages = {67-72},
doi = {10.1016/s0165-4608(96)00277-4},
pmid = {9078293},
issn = {0165-4608},
mesh = {Acute Disease ; Biomarkers, Tumor/analysis ; Genetic Markers ; Humans ; Leukemia/*genetics/pathology ; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/pathology ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*genetics/pathology ; Myelodysplastic Syndromes/genetics/pathology ; Repetitive Sequences, Nucleic Acid ; Telomerase/*analysis ; Telomere/genetics/*physiology ; },
abstract = {Chromosome termini, termed telomeres, provide important protection to avoid loss of master gene(s) that may exist at subtelomeric regions. Moreover, erosion of telomeres by cell division through end-replication problems resulted in telomeric-associated cytogenetic aberrations. To maintain a telomere length related to cell immortality, telomerase activity is upregulated in cancer cells, therefore, telomerase is considered to be a new marker of neoplasias. In this paper, we review and make suggestions regarding key aspects of telomere dynamics in both normal hematopoiesis and in malignant hematologic diseases.},
}
@article {pmid9050935,
year = {1997},
author = {Petit, P},
title = {Interstitial telomere DNA sequences are not detectable at breaking sites of classical heritable fragile sites.},
journal = {Human genetics},
volume = {99},
number = {3},
pages = {424},
pmid = {9050935},
issn = {0340-6717},
mesh = {*Chromosome Breakage ; Chromosome Fragile Sites ; *Chromosome Fragility ; Chromosomes, Human, Pair 13 ; DNA ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Repetitive Sequences, Nucleic Acid ; *Telomere ; Translocation, Genetic ; Y Chromosome ; },
}
@article {pmid9034194,
year = {1997},
author = {Cooper, JP and Nimmo, ER and Allshire, RC and Cech, TR},
title = {Regulation of telomere length and function by a Myb-domain protein in fission yeast.},
journal = {Nature},
volume = {385},
number = {6618},
pages = {744-747},
doi = {10.1038/385744a0},
pmid = {9034194},
issn = {0028-0836},
mesh = {Amino Acid Sequence ; Chromosomes, Fungal/metabolism ; Cloning, Molecular ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Fungal Proteins/chemistry/genetics/*metabolism ; Humans ; Molecular Sequence Data ; Proto-Oncogene Mas ; Proto-Oncogene Proteins/*chemistry ; Proto-Oncogene Proteins c-myb ; Recombinant Fusion Proteins/genetics/metabolism ; Schizosaccharomyces/*metabolism ; *Schizosaccharomyces pombe Proteins ; Sequence Homology, Amino Acid ; Spores, Fungal ; Telomere/*metabolism ; *Telomere-Binding Proteins ; Trans-Activators/*chemistry ; },
abstract = {Telomeres, the specialized nucleoprotein structures that comprise the ends of eukaryotic chromosomes, are essential for complete replication, and regulation of their length has been a focus of research on tumorigenesis. In the budding yeast Saccharomyces cerevisiae, the protein Rap1p binds to telomeric DNA and functions in the regulation of telomere length. A human telomere protein, hTRF (human TTAGGG repeat factor) binds the telomere sequence in vitro and localizes to telomeres cytologically, but its functions are not yet known. Here we use a genetic screen to identify a telomere protein in fission yeast, Taz1p (telomere-associated in Schizosaccharomyces pombe), that shares homology to the Myb proto-oncogene DNA-binding domain with hTRF. Disruption or deletion of the taz1+ gene causes a massive increase in telomere length. Taz1p is required for the repression of telomere-adjacent gene expression and for normal meiosis or sporulation. It may be a negative regulator of the telomere-replicating enzyme, telomerase, or may protect against activation of telomerase-independent pathways of telomere elongation.},
}
@article {pmid9034193,
year = {1997},
author = {van Steensel, B and de Lange, T},
title = {Control of telomere length by the human telomeric protein TRF1.},
journal = {Nature},
volume = {385},
number = {6618},
pages = {740-743},
doi = {10.1038/385740a0},
pmid = {9034193},
issn = {0028-0836},
mesh = {DNA-Binding Proteins/*metabolism ; Feedback ; Genes, Dominant ; HeLa Cells ; Humans ; Mutation ; Recombinant Proteins/metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1 ; Tumor Cells, Cultured ; },
abstract = {Human telomeres, the nucleoprotein complexes at chromosome ends, consist of tandem arrays of TTAGGG repeats bound to specific proteins. In normal human cells, telomeres shorten with successive cell divisions, probably due to the terminal sequence loss that accompanies DNA replication. In tumours and immortalized cells, this decline is halted through the activation of telomerase, a reverse transcriptase that extends the telomeric TTAGGG-repeat arrays. Telomere length is stable in several immortal human-cell lines, suggesting that a regulatory mechanism exists for limiting telomere elongation by telomerase. Here we show that the human telomeric-repeat binding factor TRF1 (ref. 8) is involved in this regulation. Long-term overexpression of TRF1 in the telomerase-positive tumour-cell line HT1080 resulted in a gradual and progressive telomere shortening. Conversely, telomere elongation was induced by expression of a dominant-negative TRF1 mutant that inhibited binding of endogenous TRF1 to telomeres. Our results identify TRF1 as a suppressor of telomere elongation and indicate that TRF1 is involved in the negative feedback mechanism that stabilizes telomere length. As TRF1 does not detectably affect the expression of telomerase, we propose that the binding of TRF1 controls telomere length in cis by inhibiting the action of telomerase at the ends of individual telomeres.},
}
@article {pmid9034181,
year = {1997},
author = {Shore, D},
title = {Telomeres. Different means to common ends.},
journal = {Nature},
volume = {385},
number = {6618},
pages = {676-677},
doi = {10.1038/385676a0},
pmid = {9034181},
issn = {0028-0836},
mesh = {Binding Sites ; DNA-Binding Proteins/genetics/*metabolism ; Fungal Proteins/genetics/*metabolism ; Humans ; Models, Genetic ; Schizosaccharomyces/metabolism ; *Schizosaccharomyces pombe Proteins ; Telomerase/metabolism ; Telomere/*metabolism ; *Telomere-Binding Proteins ; },
}
@article {pmid9049315,
year = {1997},
author = {Wang, H and Blackburn, EH},
title = {De novo telomere addition by Tetrahymena telomerase in vitro.},
journal = {The EMBO journal},
volume = {16},
number = {4},
pages = {866-879},
pmid = {9049315},
issn = {0261-4189},
support = {GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA Primers/genetics ; Magnesium/pharmacology ; Sodium Acetate/pharmacology ; Spermidine/pharmacology ; Substrate Specificity ; Telomerase/isolation &amp; purification/*metabolism ; *Telomere/metabolism ; Tetrahymena thermophila/*enzymology/growth &amp; development ; },
abstract = {Previous molecular genetic studies have shown that during programmed chromosomal healing, telomerase adds telomeric repeats directly to non-telomeric sequences in Tetrahymena, forming de novo telomeres. However, the biochemical mechanism underlying this process is not well understood. Here, we show for the first time that telomerase activity is capable in vitro of efficiently elongating completely non-telomeric DNA oligonucleotide primers, consisting of natural telomere-adjacent or random sequences, at low primer concentrations. Telomerase activity isolated from mated or vegetative cells had indistinguishable specificities for nontelomeric and telomeric primers. Consistent with in vivo results, the sequence GGGGT... was the predominant initial DNA sequence added by telomerase in vitro onto the 3' end of the non-telomeric primers. The 3' and 5' sequences of the primer both influenced the efficiency and pattern of de novo telomeric DNA addition. Priming of telomerase by double-stranded primers with overhangs of various lengths showed a requirement for a minimal 3' overhang of 20 nucleotides. With fully single-stranded non-telomeric primers, primer length up to approximately 30 nucleotides strongly affected the efficiency of telomeric DNA addition. We propose a model for the primer binding site of telomerase for non-telomeric primers to account for these length and structural requirements. We also propose that programmed de novo telomere addition in vivo is achieved through a hitherto undetected intrinsic ability of telomerase to elongate completely non-telomeric sequences.},
}
@article {pmid9042864,
year = {1997},
author = {Grandin, N and Reed, SI and Charbonneau, M},
title = {Stn1, a new Saccharomyces cerevisiae protein, is implicated in telomere size regulation in association with Cdc13.},
journal = {Genes &amp; development},
volume = {11},
number = {4},
pages = {512-527},
doi = {10.1101/gad.11.4.512},
pmid = {9042864},
issn = {0890-9369},
support = {GM38328/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle ; Cell Cycle Proteins/metabolism ; Cyclin B ; Cyclins/*metabolism ; Fungal Proteins/genetics/*metabolism ; Gene Expression Regulation, Developmental ; Gene Expression Regulation, Fungal ; Genes, Lethal ; Hot Temperature ; Mutation ; Saccharomyces cerevisiae/cytology/*genetics ; *Saccharomyces cerevisiae Proteins ; *Telomere ; },
abstract = {We have isolated STN1, an essential Saccharomyces cerevisiae gene, as a suppressor of the cdc13-1 mutation. A synthetic lethal interaction between a temperature-sensitive mutant allele of STN1, stn1-13, and cdc13-1 was observed. Stn1 and Cdc13 proteins displayed a physical interaction by two-hybrid analysis. As shown previously for cdc13-1, stn1-13 cells at the restrictive temperature accumulate single-stranded DNA in subtelomeric regions of the chromosomes, but to a lesser extent than cdc13-1 cells. In addition, both Cdc13 and Stn1 were found to be involved in the regulation of telomere length, mutations in STN1 or CDC13 conferring an increase in telomere size. Loss of Stn1 function activated the RAD9 and MEC3 G2/M checkpoints, therefore confirming that DNA damage is generated. We propose that Stn1 functions in telomere metabolism during late S phase in cooperation with Cdc13.},
}
@article {pmid9053995,
year = {1997},
author = {Barinaga, M},
title = {Cells count proteins to keep their telomeres in line.},
journal = {Science (New York, N.Y.)},
volume = {275},
number = {5302},
pages = {928},
doi = {10.1126/science.275.5302.928},
pmid = {9053995},
issn = {0036-8075},
mesh = {Binding Sites ; Chromosomes, Fungal/metabolism ; DNA, Fungal/metabolism ; DNA-Binding Proteins/metabolism ; Fungal Proteins/*metabolism ; GTP-Binding Proteins/*metabolism ; Repressor Proteins/metabolism ; Saccharomyces cerevisiae/genetics/*metabolism ; *Saccharomyces cerevisiae Proteins ; Telomerase/*metabolism ; Telomere/*metabolism ; *Telomere-Binding Proteins ; rap GTP-Binding Proteins ; },
}
@article {pmid9020083,
year = {1997},
author = {Marcand, S and Gilson, E and Shore, D},
title = {A protein-counting mechanism for telomere length regulation in yeast.},
journal = {Science (New York, N.Y.)},
volume = {275},
number = {5302},
pages = {986-990},
doi = {10.1126/science.275.5302.986},
pmid = {9020083},
issn = {0036-8075},
support = {GM40094/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites ; Chromosomes, Fungal/metabolism ; Fungal Proteins/*metabolism ; GTP-Binding Proteins/*metabolism ; Gene Expression Regulation, Fungal ; Genetic Markers ; Mutation ; Saccharomyces cerevisiae/genetics/*metabolism ; Telomerase/metabolism ; Telomere/*metabolism ; Transformation, Genetic ; rap GTP-Binding Proteins ; },
abstract = {In the yeast Saccharomyces cerevisiae, telomere elongation is negatively regulated by the telomere repeat-binding protein Rap1p, such that a narrow length distribution of telomere repeat tracts is observed. This length regulation was shown to function independently of the orientation of the telomere repeats. The number of repeats at an individual telomere was reduced when hybrid proteins containing the Rap1p carboxyl terminus were targeted there by a heterologous DNA-binding domain. The extent of this telomere tract shortening was proportional to the number of targeted molecules, consistent with a feedback mechanism of telomere length regulation that can discriminate the precise number of Rap1p molecules bound to the chromosome end.},
}
@article {pmid9065745,
year = {1997},
author = {Pandita, TK and Benvenuto, JA and Shay, JW and Pandita, RK and Rakovitch, E and Geard, CR and Antman, KH and Newman, RA},
title = {Effect of penclomedine (NSC-338720) on telomere fusions, chromatin blebbing, and cell viability with and without telomerase activity and abrogated p53 function.},
journal = {Biochemical pharmacology},
volume = {53},
number = {3},
pages = {409-415},
doi = {10.1016/s0006-2952(96)00766-6},
pmid = {9065745},
issn = {0006-2952},
support = {NS34746/NS/NINDS NIH HHS/United States ; },
mesh = {Antineoplastic Agents/*pharmacology ; Cell Survival/drug effects ; Chromatin/*drug effects ; Genes, p53/*physiology ; HeLa Cells ; Humans ; Mitotic Index ; Picolines/*pharmacology ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects ; },
abstract = {Telomeres, or chromosome ends, are essential in maintaining chromosomal integrity. Telomeres consist of a short hexameric sequence, 3'-TTAGGG-5', repeated in tandem arrays added to chromosomes by the ribonucleoprotein enzyme telomerase. In this study, we assessed whether penclomedine, a novel synthetic pyridine compound presently being evaluated in clinical trials for its anticancer activity, influences telomere fusions (chromosome end-to-end associations) and telomerase activity in cells in culture. We found that penclomedine reduced the mitotic index, induced chromosome end associations in all phases of the cell cycle, and rapidly induced chromatin blebbing in a concentration-dependent manner in both cervical carcinoma (HeLa) cells and in normal human fibroblasts (AG1522). However, the effectiveness of the drug was much more pronounced in HeLa cells. In addition, there was a drug-mediated, concentration-dependent decline in telomerase activity noted in the HeLa cells that correlated with a decrease in mitotic index and an increase in telomere fusions. Interestingly, when the mitotic index, chromatin blebbing, and telomere fusions were compared between the telomerase positive (HeLa) and negative (AG1522) cell types, penclomedine affected chromatin stability to a greater extent in those cells with detectable telomerase activity. In addition, telomerase positive colorectal carcinoma cells with abrogated p53 (RC-10.3 cells) were more sensitive to penclomedine than were telomerase positive cells with wild-type p53 (RKO cells). These studies suggest that penclomedine may have a therapeutic advantage in killing tumor cells that are positive for telomerase activity and defective in p53 function.},
}
@article {pmid9046819,
year = {1997},
author = {Yanagi, K and Mochida, A and Gotoh, E},
title = {[Telomere DNA and telomerase of lymphoma-derived cell lines--telomere hypothesis for cell growth control].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {55},
number = {2},
pages = {328-333},
pmid = {9046819},
issn = {0047-1852},
mesh = {Burkitt Lymphoma/enzymology ; Humans ; Neoplasms/enzymology ; Telomerase/*metabolism ; Telomere/*physiology ; },
abstract = {Telomere is the specialized structure of chromosome end. Telomeric DNA is essential for stabilization of linear double-stranded DNA molecules. Human telomeric DNA comprises the tandem repeat (AATGGG)n. Telomeres of normal somatic cells shorten progressively on every cell division, and telomere length is considered to determine cellular proliferative capacity. Most normal cells except germ line cells lack telomerase activity. Evidence of telomerase reactivation in human cancer cells was reported in 1994. The telomere hypothesis of aging and cell immortalization has drawn much attention in recent years. We examined telomere DNA and telomerase activity of Burkitt's lymphoma cell lines and EBV-infected proliferating B lymphocytes. All of these cells had varied average size of TRFs and the cell lines of lymphoma origin showed elevated telomerase activity.},
}
@article {pmid9034126,
year = {1997},
author = {Chiu, CP and Harley, CB},
title = {Replicative senescence and cell immortality: the role of telomeres and telomerase.},
journal = {Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)},
volume = {214},
number = {2},
pages = {99-106},
doi = {10.3181/00379727-214-44075},
pmid = {9034126},
issn = {0037-9727},
mesh = {Animals ; Cell Cycle/physiology ; Cell Line ; Cell Survival/physiology ; Cells, Cultured ; Cellular Senescence/*physiology ; Humans ; Mitosis/*physiology ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {Telomere shortening is correlated with cell senescence in vitro and cell aging in vivo. The telomere hypothesis suggests that telomere length serves as a mitotic clock for timing cellular replicative life span. Expression of telomerase stabilizes telomere length and allows for continual replication, or cell immortality. This article reviews recent evidences for the role of telomere length and telomerase in the regulation of cellular replicative life span. The therapeutic potential of manipulating telomerase expression and telomere length is also discussed.},
}
@article {pmid9024303,
year = {1997},
author = {Kojima, H and Yokosuka, O and Imazeki, F and Saisho, H and Omata, M},
title = {Telomerase activity and telomere length in hepatocellular carcinoma and chronic liver disease.},
journal = {Gastroenterology},
volume = {112},
number = {2},
pages = {493-500},
doi = {10.1053/gast.1997.v112.pm9024303},
pmid = {9024303},
issn = {0016-5085},
mesh = {Adult ; Aged ; Base Sequence ; Carcinoma, Hepatocellular/*enzymology/genetics ; Chronic Disease ; Female ; Humans ; Liver/ultrastructure ; Liver Diseases/*enzymology/*genetics ; Liver Neoplasms/*enzymology/genetics ; Male ; Middle Aged ; Telomerase/*metabolism ; Telomere/*genetics ; },
abstract = {BACKGROUND &amp; AIMS: The maintenance of the telomere to a certain length is considered to be vital for cellular immortality. Recently, the presence of telomerase, an enzyme that elongates telomere length, was reported in various malignancies. The aim of this study was to characterize telomerase activity and telomere length in hepatocellular carcinoma and chronic liver diseases to facilitate better understanding and more accurate diagnosis of hepatocellular carcinoma.<br><br>METHODS: In tumorous and nontumorous tissues from 26 hepatocellular carcinomas and from 20 liver tissues without overt hepatocellular carcinoma, telomerase activity was examined by telomeric repeat amplification protocol and telomere length was detected by Southern blot hybridization method.<br><br>RESULTS: Telomerase activity was detected in 22 of 26 (85%) hepatocellular carcinoma specimens. In contrast, it was weakly detected in 4 of 46 (9%) nonneoplastic tissues. Telomere length in hepatocellular carcinoma was shorter than that of corresponding nontumorous tissue in 44% and longer in 17%.<br><br>CONCLUSIONS: The presence of telomerase activity was confirmed in a majority of cases with hepatocellular carcinoma, and alteration of telomere length from nonneoplastic tissue was observed in approximately two thirds of hepatocellular carcinomas. Therefore, these markers might be good indicators for the diagnosis of hepatocellular carcinoma.},
}
@article {pmid8995615,
year = {1997},
author = {Baldauf, AQ and Willwand, K and Mumtsidu, E and Nüesch, JP and Rommelaere, J},
title = {Specific initiation of replication at the right-end telomere of the closed species of minute virus of mice replicative-form DNA.},
journal = {Journal of virology},
volume = {71},
number = {2},
pages = {971-980},
pmid = {8995615},
issn = {0022-538X},
mesh = {Animals ; DNA Replication/*genetics ; DNA, Viral/*genetics ; Mice ; Minute Virus of Mice/*physiology ; Telomere/genetics ; Virus Replication/*genetics ; },
abstract = {We have developed an in vitro system that supports the replication of natural DNA templates of the autonomous parvovirus minute virus of mice (MVM). MVM virion DNA, a single-stranded molecule bracketed by short, terminal, self-complementary sequences, is converted into double-stranded replicative-form (RF) DNA when incubated in mouse A9 fibroblast extract. The 3' end of the newly synthesized complementary strand is ligated to the right-end hairpin of the virion strand, resulting in the formation of a covalently closed RF (cRF) molecule as the major conversion product. cRF DNA is not further replicated in A9 cell extract alone. On addition of purified MVM nonstructural protein NS1 expressed from recombinant baculoviruses or vaccinia viruses, cRF DNA is processed into a right-end (5' end of the virion strand) extended form (5'eRF). This is indicative of NS1-dependent nicking of the right-end hairpin at a distinct position, followed by unfolding of the hairpin and copying of the terminal sequence. In contrast, no resolution of the left-end hairpin can be detected in the presence of NS1. In the course of the right-end nicking reaction, NS1 gets covalently attached to the right-end telomere of the DNA product, as shown by immunoprecipitation with NS1-specific antibodies. The 5'eRF product is the target for additional rounds of NS1-induced nicking and displacement synthesis at the right end, arguing against the requirement of the hairpin structure for recognition of the DNA substrate by NS1. Further processing of the 5'eRF template in vitro leads to the formation of dimeric RF (dRF) DNA in a left-to-left-end configuration, presumably as a result of copying of the whole molecule by displacement synthesis initiated at the right-end telomere. Formation of dRF DNA is highly stimulated by NS1. The experimental results presented in this report support various assumptions of current models of parvovirus DNA replication and provide new insights into the replication functions of the NS1 protein.},
}
@article {pmid9006955,
year = {1997},
author = {Tomáska, L and Nosek, J and Fukuhara, H},
title = {Identification of a putative mitochondrial telomere-binding protein of the yeast Candida parapsilosis.},
journal = {The Journal of biological chemistry},
volume = {272},
number = {5},
pages = {3049-3056},
doi = {10.1074/jbc.272.5.3049},
pmid = {9006955},
issn = {0021-9258},
mesh = {Base Sequence ; Binding Sites ; Candida/genetics/*metabolism ; DNA, Mitochondrial/chemistry/isolation &amp; purification/*metabolism ; DNA-Binding Proteins/isolation &amp; purification/*metabolism ; Electrophoresis, Polyacrylamide Gel ; Immunoblotting ; Molecular Sequence Data ; Oligodeoxyribonucleotides/chemistry/metabolism ; Substrate Specificity ; *Telomere ; },
abstract = {Terminal segments (telomeres) of linear mitochondrial DNA (mtDNA) molecules of the yeast Candida parapsilosis consist of large sequence units repeated in tandem. The extreme ends of mtDNA terminate with a 5' single-stranded overhang of about 110 nucleotides. We identified and purified a mitochondrial telomere-binding protein (mtTBP) that specifically recognizes a synthetic oligonucleotide derived from the extreme end of this linear mtDNA. MtTBP is highly resistant to protease and heat treatments, and it protects the telomeric probe from degradation by various DNA-modifying enzymes. Resistance of the complex to bacterial alkaline phosphatase suggests that mtTBP binds the very end of the molecule. We purified mtTBP to near homogeneity using DNA affinity chromatography based on the telomeric oligonucleotide covalently bound to Sepharose. Sodium dodecyl sulfate-polyacrylamide gel electrophoretic analysis of the purified fractions revealed the presence of a protein with an apparent molecular mass of approximately 15 kDa. UV cross-linking and gel filtration chromatography experiments suggested that native mtTBP is probably a homo-oligomer. MtTBP of C. parapsilosis is the first identified protein that specifically binds to telomeres of linear mitochondrial DNA.},
}
@article {pmid9102429,
year = {1997},
author = {Hiyama, K and Hiyama, E and Ishioka, S and Yamakido, M},
title = {[Lung cancer: progress in diagnosis and treatment. IV. Related topics: 1. Telomere and telomerase, new targets for diagnosis and treatment of lung cancer].},
journal = {Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine},
volume = {86},
number = {1},
pages = {95-99},
pmid = {9102429},
issn = {0021-5384},
mesh = {Humans ; Lung Neoplasms/*diagnosis ; Telomerase/*analysis ; *Telomere ; },
}
@article {pmid9102417,
year = {1997},
author = {Ishikawa, F},
title = {[Chromosomal telomere and neoplastic transformation and aging of cells].},
journal = {Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine},
volume = {86},
number = {1},
pages = {154-161},
pmid = {9102417},
issn = {0021-5384},
mesh = {*Cell Transformation, Neoplastic ; Cellular Senescence/*physiology ; Humans ; Telomerase/physiology ; Telomere/*physiology ; },
}
@article {pmid9020020,
year = {1997},
author = {Ishikawa, F},
title = {Telomere crisis, the driving force in cancer cell evolution.},
journal = {Biochemical and biophysical research communications},
volume = {230},
number = {1},
pages = {1-6},
doi = {10.1006/bbrc.1996.5928},
pmid = {9020020},
issn = {0006-291X},
mesh = {Blotting, Southern ; Cell Transformation, Neoplastic ; Chromosomes, Human/physiology/ultrastructure ; DNA, Neoplasm/genetics ; Humans ; Mutation ; Neoplasms/enzymology/genetics/pathology/*physiopathology ; Philadelphia Chromosome ; Repetitive Sequences, Nucleic Acid ; Telomerase/*metabolism ; Telomere/pathology/*physiology ; },
abstract = {Cancer cells show characteristic telomere dynamics. Their chromosomes usually have short telomeres and a high telomerase activity. The "telomere crisis model" proposed here suggests that these unique telomeric features are responsible for the progression of cancer.},
}
@article {pmid9009280,
year = {1997},
author = {Chikashige, Y and Ding, DQ and Imai, Y and Yamamoto, M and Haraguchi, T and Hiraoka, Y},
title = {Meiotic nuclear reorganization: switching the position of centromeres and telomeres in the fission yeast Schizosaccharomyces pombe.},
journal = {The EMBO journal},
volume = {16},
number = {1},
pages = {193-202},
pmid = {9009280},
issn = {0261-4189},
mesh = {Cell Nucleus/genetics ; *Centromere ; Chromosomes, Fungal ; Gene Rearrangement ; In Situ Hybridization, Fluorescence ; Mating Factor ; Mitosis/*genetics ; Mutation ; Peptides/pharmacology ; Pheromones/pharmacology ; Prophase/genetics ; Schizosaccharomyces/*genetics ; Spindle Apparatus/physiology ; *Telomere ; },
abstract = {In fission yeast meiotic prophase, telomeres are clustered near the spindle pole body (SPB; a centrosome-equivalent structure in fungi) and take the leading position in chromosome movement, while centromeres are separated from the SPB. This telomere position contrasts with mitotic nuclear organization, in which centromeres remain clustered near the SPB and lead chromosome movement. Thus, nuclear reorganization switching the position of centromeres and telomeres must take place upon entering meiosis. In this report, we analyze the nuclear location of centromeres and telomeres in genetically well-characterized meiotic mutant strains. An intermediate structure for telomere-centromere switching was observed in haploid cells induced to undergo meiosis by synthetic mating pheromone; fluorescence in situ hybridization revealed that in these cells, both telomeres and centromeres were clustered near the SPB. Further analyses in a series of mutants showed that telomere-centromere switching takes place in two steps; first, association of telomeres with the SPB and, second, dissociation of centromeres from the SPB. The first step can take place in the haploid state in response to mating pheromone, but the second step does not take place in haploid cells and probably depends on conjugation-related events. In addition, a linear minichromosome was also co-localized with authentic telomeres instead of centromeres, suggesting that telomere clustering plays a role in organizing chromosomes within a meiotic prophase nucleus.},
}
@article {pmid9524760,
year = {1997},
author = {Lansdorp, PM and Poon, S and Chavez, E and Dragowska, V and Zijlmans, M and Bryan, T and Reddel, R and Egholm, M and Bacchetti, S and Martens, U},
title = {Telomeres in the haemopoietic system.},
journal = {Ciba Foundation symposium},
volume = {211},
number = {},
pages = {209-18; discussion 219-22},
doi = {10.1002/9780470515433.ch14},
pmid = {9524760},
issn = {0300-5208},
mesh = {B-Lymphocytes/virology ; Cell Transformation, Viral ; Hematopoiesis/*genetics ; Herpesvirus 4, Human/physiology ; Humans ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Telomerase/*physiology ; *Telomere ; },
abstract = {The limited life span of most blood cells requires the continuous production of cells, which in adults exceeds 10(12) cells/day. This impressive production of cells (approximately 4 x 10(16) cells over a lifetime) is achieved by the proliferation and differentiation of committed progenitor cells, which themselves are derived from a population of pluripotent stem cells with self-renewal potential. Paradoxically, the large majority of stem cells in adult bone marrow are quiescent cells. One possibility is that stem cells, like other somatic cells, have only a limited replicative potential (< 100 divisions). This hypothesis is supported by two key observations and the consideration that, in theory, 55 divisions can yield 4 x 10(16) cells. First, it was shown that 'candidate' stem cells purified from fetal and adult tissue showed dramatic functional differences in turn-over time and the ability to produce cells with stem cell properties, Second, these functional differences were found to correlate with a measurable loss of telomere repeats despite the presence of low but readily detectable levels of telomerase in all purified cell fractions. In order to address questions about the role of telomeres in normal and malignant haemopoiesis, we developed a quantitative fluorescence in situ hybridization technique. Here we review the characteristics of this novel tool to assess the number of telomere repeats at the end of individual chromosomes and provide an overview of recent observations.},
}
@article {pmid9524755,
year = {1997},
author = {Harley, CB},
title = {Human ageing and telomeres.},
journal = {Ciba Foundation symposium},
volume = {211},
number = {},
pages = {129-39; discussion 139-44},
doi = {10.1002/9780470515433.ch9},
pmid = {9524755},
issn = {0300-5208},
mesh = {Aging/*genetics ; Animals ; Cell Division/physiology ; Cell Survival/physiology ; Cellular Senescence/physiology ; DNA Replication ; Fibroblasts/cytology ; Humans ; Mice ; Telomerase/metabolism ; *Telomere ; },
abstract = {Telomerase expression is repressed early in development in all normal somatic human tissues investigated to date, whereas activity and the expression of the RNA component for this enzyme are upregulated in almost all cases of malignant transformation and late-stage cancer. The telomere hypothesis of ageing and immortalization postulates that sufficient telomere loss on one or more chromosomes in normal somatic cells triggers cell senescence, whereas reactivation of the enzyme is necessary for cell immortalization. Measurements of telomere length and telomerase activity in cancer and during normal and accelerated human ageing in skin, blood, haemopoietic, skeletal muscle, vascular and CNS tissues support this model. Tissue culture studies of cell ageing and transformation have added to our understanding of telomere dynamics in these processes. Evolution of telomerase repression and mortality in somatic cells of long-lived organisms is consistent with antagonistic pleiotropy models in which cell senescence is a tumour suppressor mechanism: stringent repression of telomerase has a beneficial early effect in reducing the probability of cancer, but a deleterious, unselected late effect in its contributions to age-related disease.},
}
@article {pmid9524752,
year = {1997},
author = {Marcand, S and Wotton, D and Gilson, E and Shore, D},
title = {Rap1p and telomere length regulation in yeast.},
journal = {Ciba Foundation symposium},
volume = {211},
number = {},
pages = {76-93; discussion 93-103},
doi = {10.1002/9780470515433.ch6},
pmid = {9524752},
issn = {0300-5208},
support = {GM40094/GM/NIGMS NIH HHS/United States ; },
mesh = {Carrier Proteins/physiology ; DNA-Binding Proteins/metabolism/*physiology ; Fungal Proteins/metabolism/*physiology ; *Repetitive Sequences, Nucleic Acid ; Repressor Proteins ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; Shelterin Complex ; *Telomere ; *Telomere-Binding Proteins ; *Transcription Factors ; },
abstract = {Telomere length in the yeast Saccharomyces cerevisiae is under stringent genetic control such that a narrow length distribution of TG1-3 repeats is observed. Previous studies have shown that Rap1p, which binds to the double-stranded telomeric repeats, plays a role in regulating repeat length: point mutations in the Rap1p C-terminus often result in a higher average telomere length and deletion of this region causes extreme telomere elongation. We have investigated further the role of Rap1p in this process. Our results suggest that telomere length is regulated by a negative feedback mechanism that can sense the number of Rap1p molecules bound at the chromosome end. This length regulatory mechanism requires two other proteins, Rif1p and Rif2p, that interact with each other and with the Rap1p C-terminus. Although the same C-terminal domain of Rap1p is also involved in the initiation of telomere position effect (telomeric transcriptional silencing), this Rap1p function appears to be separate from, and indeed antagonistic to, its role in telomere length regulation.},
}
@article {pmid9524751,
year = {1997},
author = {Biessmann, H and Walter, MF and Mason, JM},
title = {Drosophila telomere elongation.},
journal = {Ciba Foundation symposium},
volume = {211},
number = {},
pages = {53-67; discussion 67-70},
doi = {10.1002/9780470515433.ch5},
pmid = {9524751},
issn = {0300-5208},
support = {GM46211/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Biological Evolution ; Chromosome Aberrations ; Drosophila melanogaster/*genetics ; Polymorphism, Genetic ; Retroelements ; *Telomere ; },
abstract = {Drosophila melanogaster has an unusual telomere elongation mechanism. Instead of short repeats that are synthesized by telomerase, long retrotransposons, HeT-A and TART, transpose to the ends of chromosomes. This mechanism generates tandem arrays of these elements at the chromosome ends, in which all elements are oriented with their oligo(A) tails towards the centromere. Structural features of HeT-A and TART elements may provide clues as to their transposition mechanism. Drosophila telomere length polymorphism is mainly due to terminal retrotransposon arrays that differ between chromosome tips and that change with time. In addition, stable terminal chromosome deletions can be generated that do not contain terminal HeT-A and TART arrays, suggesting that, unlike the equivalent terminal repeats in yeast and humans, the presence and length of terminal arrays in Drosophila may not be critical for cell cycle progression.},
}
@article {pmid9524750,
year = {1997},
author = {Hughes, TR and Morris, DK and Salinger, A and Walcott, N and Nugent, CI and Lundblad, V},
title = {The role of the EST genes in yeast telomere replication.},
journal = {Ciba Foundation symposium},
volume = {211},
number = {},
pages = {41-7; discussion 47-52, 71-5},
doi = {10.1002/9780470515433.ch4},
pmid = {9524750},
issn = {0300-5208},
mesh = {*DNA Replication ; DNA-Binding Proteins/genetics ; *Genes, Fungal ; Genetic Code ; Genetic Testing ; Saccharomyces cerevisiae/*genetics ; *Telomere ; },
abstract = {We have recently completed a large mutant screen designed to identify new mutants of Saccharomyces cerevisiae with a telomerase-like defect. From this screen; 22 mutants were identified that mapped to three genes, called EST1, EST2 and EST3, as well as a novel EST-like mutation in a fourth gene, previously identified as CDC13. Mutations in each of these genes give rise to phenotypes that are indistinguishable from those observed when TLC1, encoding the yeast telomerase RNA, is deleted. In addition, genetic analysis indicates that all four genes function in the same pathway for telomere replication as defined by TLC1, the one known component of telomerase. This indicates that these genes encode factors that are essential in vivo for telomerase function. Genetic and biochemical analyses have shown that EST1 and CDC13 encode single-stranded telomeric DNA-binding proteins, suggesting that these two proteins may function to mediate access of telomerase to the end of the telomere.},
}
@article {pmid9524748,
year = {1997},
author = {Blackburn, E and Bhattacharyya, A and Gilley, D and Kirk, K and Krauskopf, A and McEachern, M and Prescott, J and Ware, T},
title = {The telomere and telomerase: how do they interact?.},
journal = {Ciba Foundation symposium},
volume = {211},
number = {},
pages = {2-13; discussion 15-9},
doi = {10.1002/9780470515433.ch2},
pmid = {9524748},
issn = {0300-5208},
mesh = {Anaphase/physiology ; Animals ; DNA/genetics ; Homeostasis/physiology ; Humans ; Mutation ; RNA/genetics ; *Repetitive Sequences, Nucleic Acid ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {The tandemly repeated DNA sequence of telomeres is typically specified by the ribonucleoprotein enzyme telomerase. Telomerase copies part of its intrinsic RNA moiety to make one strand of the telomeric repeat DNA. Recent work has led to the concept of a telomere homeostasis system. We have been studying two key physical components of this system: the telomere itself and telomerase. Mutating the template sequence of telomerase RNA caused various phenotypes: (1) mutating specific residues in the ciliate Tetrahymena and two yeasts showed that they are required for critical aspects of telomerase action; (2) certain mutated telomeric sequences caused a previously unreported phenotype, i.e. a strong anaphase block in Tetrahymena micronuclei; and (3) certain template mutations in the telomerase RNA gene of the yeast Kluyveromyces lactis led to unregulated telomere elongation, which in some cases was directly related to loss of binding to K. lactis Rap1p. Using K. lactis carrying alterations in the genes for Rap1p and other silencing components, we proposed a general model for telomere length homeostasis: namely, that the structure and DNA length of the DNA-protein complex that comprises the telomere are key determinants of telomerase access, and hence the frequency of action of telomerase, at the telomere.},
}
@article {pmid9474901,
year = {1997},
author = {Kamnert, I and López, CC and Rosén, M and Edström, JE},
title = {Telomeres terminating with long complex tandem repeats.},
journal = {Hereditas},
volume = {127},
number = {3},
pages = {175-180},
doi = {10.1111/j.1601-5223.1997.00175.x},
pmid = {9474901},
issn = {0018-0661},
mesh = {Animals ; Chironomidae ; Drosophila ; Genes, Insect ; Humans ; Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; },
abstract = {Telomeres of most investigated species terminate with short repeats and are elongated by telomerase. Short repeats have never been detected in dipteran species which have found other solutions to end a chromosome. Whereas in Drosophila melanogaster retroelements are added onto the termini, chironomids have long complex repeats at their chromosome ends. We review evidence that these units are terminal and probably have evolved from short telomeric repeats. In Chironomus pallidivittatus the units have been shown to belong to different subfamilies which have specific inter- and intrachromosomal distribution, the most terminal subfamily of repeats being characterized by pronounced secondary structures for the single strand. The complex repeats are efficiently homogenized both within and between different chromosome ends. Gene conversion is probably an important component in the coordinate evolution of the repeats but it is not known whether it is used for net synthesis of DNA. RNA is used as an intermediate in telomere elongation both by organisms having chromosomes terminating with short repeats and by D. melanogaster. It is therefore interesting that the terminal repeats in chironomids are transcribed.},
}
@article {pmid9440260,
year = {1997},
author = {Pardue, ML and Danilevskaya, ON and Traverse, KL and Lowenhaupt, K},
title = {Evolutionary links between telomeres and transposable elements.},
journal = {Genetica},
volume = {100},
number = {1-3},
pages = {73-84},
pmid = {9440260},
issn = {0016-6707},
mesh = {Amino Acid Sequence ; Animals ; Drosophila/*genetics ; *Evolution, Molecular ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; *Retroelements ; Sequence Homology, Amino Acid ; Telomerase/genetics ; *Telomere ; },
abstract = {Transposable elements are abundant in the genomes of higher organisms but are usually thought to affect cells only incidentally, by transposing in or near a gene and influencing its expression. Telomeres of Drosophila chromosomes are maintained by two non-LTR retrotransposons, HeT-A and TART. These are the first transposable elements with identified roles in chromosome structure. We suggest that these elements may be evolutionarily related to telomerase; in both cases an enzyme extends the end of a chromosome by adding DNA copied from an RNA template. The evolution of transposable elements from chromosomal replication mechanisms may have occurred multiple times, although in other organisms the new products have not replaced the endogenous telomerase, as they have in Drosophila. This is somewhat reminiscent of the oncogenes that have arisen from cellular genes. Perhaps the viruses that carry oncogenes have also arisen from cellular genetic systems.},
}
@article {pmid9371401,
year = {1997},
author = {Azzalin, CM and Mucciolo, E and Bertoni, L and Giulotto, E},
title = {Fluorescence in situ hybridization with a synthetic (T2AG3)n polynucleotide detects several intrachromosomal telomere-like repeats on human chromosomes.},
journal = {Cytogenetics and cell genetics},
volume = {78},
number = {2},
pages = {112-115},
doi = {10.1159/000134640},
pmid = {9371401},
issn = {0301-0171},
mesh = {*Chromosomes ; DNA Probes ; Humans ; In Situ Hybridization, Fluorescence ; Polynucleotides ; *Repetitive Sequences, Nucleic Acid ; *Telomere ; },
abstract = {(T2AG3) repeats comprise the telomeres of human chromosomes and also are present at interstitial locations. Using a long synthetic (T2AG3)n probe, we have localized telomere-like repeats at several internal sites on human chromosomes.},
}
@article {pmid9289722,
year = {1997},
author = {Zarko-Postawka, M and Zakrzewska-Czerwińska, J},
title = {[Linear prokaryotic chromosome; structure and synthesis of telomeres].},
journal = {Postepy biochemii},
volume = {43},
number = {1},
pages = {12-17},
pmid = {9289722},
issn = {0032-5422},
mesh = {Base Sequence ; DNA Replication/*physiology ; DNA, Bacterial/*biosynthesis ; Electrophoresis, Gel, Pulsed-Field ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; Telomere/chemistry/*genetics ; },
}
@article {pmid9156314,
year = {1997},
author = {Knight, SJ and Horsley, SW and Regan, R and Lawrie, NM and Maher, EJ and Cardy, DL and Flint, J and Kearney, L},
title = {Development and clinical application of an innovative fluorescence in situ hybridization technique which detects submicroscopic rearrangements involving telomeres.},
journal = {European journal of human genetics : EJHG},
volume = {5},
number = {1},
pages = {1-8},
pmid = {9156314},
issn = {1018-4813},
mesh = {*Chromosome Aberrations/diagnosis ; *Chromosome Disorders ; Cosmids ; DNA/isolation &amp; purification ; DNA Probes ; Humans ; In Situ Hybridization, Fluorescence/instrumentation/*methods ; Telomere/*ultrastructure ; },
abstract = {We report an innovative fluorescence in situ hybridization technique which exploits a unique resource of 41 telomere-specific probes and allows the simultaneous analysis of the subtelomeric region of every chromosome for deletion, triplication and balanced translocation events. This technique requires only a single microscope slide per patient and is expected to be a useful diagnostic tool with applications in the fields of idiopathic mental retardation, the detection of congenital abnormalities and in some forms of cancer. This will lead to more accurate genetic counselling of patients and their families and will provide the basis for future diagnostic, therapeutic and preventative measures.},
}
@article {pmid9062581,
year = {1997},
author = {Miura, N and Horikawa, I and Nishimoto, A and Ohmura, H and Ito, H and Hirohashi, S and Shay, JW and Oshimura, M},
title = {Progressive telomere shortening and telomerase reactivation during hepatocellular carcinogenesis.},
journal = {Cancer genetics and cytogenetics},
volume = {93},
number = {1},
pages = {56-62},
doi = {10.1016/s0165-4608(96)00329-9},
pmid = {9062581},
issn = {0165-4608},
mesh = {Adolescent ; Adult ; Aged ; Blotting, Southern ; Carcinoma, Hepatocellular/enzymology/*genetics ; Enzyme Activation ; Female ; Hepatitis, Chronic/enzymology/genetics ; Humans ; Liver/enzymology/pathology ; Liver Cirrhosis/enzymology/genetics ; Liver Neoplasms/enzymology/*genetics ; Male ; Middle Aged ; Polymorphism, Restriction Fragment Length ; Telomerase/*metabolism ; Telomere/pathology/*physiology ; },
abstract = {Telomeres shorten progressively with age in normal somatic cells in culture and in vivo. The maintenance of telomere length is assumed to be an obligatory step in the progression and immortalization of most human tumor cells. To understand the role of telomere dynamics in the development of hepatocellular carcinoma (HCC), we examined the length of terminal restriction fragment (TRF), as an indicator for telomere length, in HCC and surrounding tissues with chronic active hepatitis (CAH) or liver cirrhosis (LC). The study was performed in 12 hepatitis C virus (HCV) antibody-positive, 12 hepatitis B virus (HBV) antigen-positive tissues, and 4 tissue samples from virus-negative patients with HCC. The peak TRFs in all 3 types of HCC were significantly shorter than those of the surrounding tissues (i.e., LC or CAH). TRFs examined in one patient with atypical adenomatous hyperplasia (AAH) also was shortened. Thus, progressive TRF shortening occurs from normal to CAH to LC to HCC(AAH). Telomerase, an enzyme that adds repeated telomere sequences onto the chromosome ends and stabilizes telomere length in immortal cells, also was examined in tissues and detected in high levels almost exclusively in HCCs. Interestingly, the intensity of telomerase activity in the AAH case was similar to that of HCC. In addition, the telomerase activity of biopsy samples with a fine 21-gauge needle also was examined in 10 HCCs, 2 adenomatous hyperplasias (AHs), 2 LCs, and 2 CAHs. We found strong telomerase activity in all the HCCs and surprisingly in the 2 cases that were pathologically diagnosed as AH. Thus, the findings strongly suggest that persistent cell proliferation or rapid cell turnover through damage of hepatic cells result in a process of multistep hepatocellular carcinogenesis. Thus, progressive shortening of telomeres and the activation of telomerase may be a useful marker for the early detection of malignant progression in liver disease.},
}
@article {pmid9030230,
year = {1997},
author = {Hiyama, K and Hiyama, E and Ishioka, S and Yamakido, M},
title = {[Telomere and telomerase in human cancer].},
journal = {Gan to kagaku ryoho. Cancer &amp; chemotherapy},
volume = {24},
number = {2},
pages = {196-201},
pmid = {9030230},
issn = {0385-0684},
mesh = {Antineoplastic Agents/*pharmacology ; Cell Division ; Cell Movement ; DNA, Neoplasm/biosynthesis ; Enzyme Inhibitors/*pharmacology ; Humans ; Neoplasms/*enzymology/*pathology ; Prognosis ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*physiology ; },
abstract = {Human somatic cells gradually lose their telomeric repeats each cell division, and when they become critically shortened, stop dividing. On the other hand, in immortal cancer cells and germline cells, telomerase, a ribonucleoprotein which can compensate for the loss of telomeric repeats synthesizing telomeric DNA onto chromosomal ends, is activated and the telomere lengths are stabilized. Thus, telomere length and telomerase activity are believed to be characteristic indicators of cell proliferation and cell immortality, and inhibition of telomerase activity is expected to be a new strategy of anti-cancer therapy.},
}
@article {pmid8973182,
year = {1996},
author = {Salazar, M and Thompson, BD and Kerwin, SM and Hurley, LH},
title = {Thermally induced DNA.RNA hybrid to G-quadruplex transitions: possible implications for telomere synthesis by telomerase.},
journal = {Biochemistry},
volume = {35},
number = {50},
pages = {16110-16115},
doi = {10.1021/bi961442j},
pmid = {8973182},
issn = {0006-2960},
support = {CA-49751/CA/NCI NIH HHS/United States ; CA-67760/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; DNA/*chemistry ; Hot Temperature ; Magnetic Resonance Spectroscopy ; *Nucleic Acid Conformation ; *Nucleic Acid Denaturation ; Nucleic Acid Hybridization ; Oligodeoxyribonucleotides/*chemistry ; Oligoribonucleotides/*chemistry ; Potassium ; RNA/*chemistry ; Telomerase/*metabolism ; *Telomere ; Thermodynamics ; },
abstract = {Telomerase is a specialized reverse transcriptase that contains its own RNA template for synthesis of telomeric DNA [Greider, C. W., &amp; Blackburn, E. H. (1989) Nature 337, 331-337; Shippen-Lentz, D., &amp; Blackburn, E. H. (1990) Science 247, 546-552]. The activity of this ribonucleoprotein enzyme has been associated with cancer cells [Kim et al. (1994) Science 266, 2011-2015] and is thus a potential target for anticancer chemotherapy. Telomeric DNA.RNA hybrids are important intermediates in telomerase function and form after extension of the growing telomere on the telomerase RNA template. Translocation is a critical step in telomerase function and consists of unwinding of the telomeric DNA.telomerase RNA hybrid followed by repositioning of the 3'-end of the extended telomere. A central question in telomerase function is how translocation of the extended telomere occurs in the absence of ATP or GTP. It has been hypothesized that unwinding of the telomeric hybrid may be facilitated by the formation of stable hairpins or G-quadruplexes by the telomere product (i.e., a hybrid to G-quadruplex transition) and that this may provide at least part of the driving force for translocation [Shippen-Lentz &amp; Blackburn, 1990; Zahler et al. (1991) Nature 350, 718-720]. However, so far there has been no effort aimed at examining the possibility that a hybrid/G-quadruplex equilibrium can occur and to what extent this equilibrium depends on buffer and concentration conditions. Examination of these transitions may provide insight into telomerase function and may also provide clues for the development of anti-telomerase agents. Using a model system consisting of the DNA.RNA hybrid d(GGTTAGGGTTAG).r(cuaacccuaacc), we present evidence that a thermally induced transition of telomeric DNA.RNA hybrid to G-quadruplex can occur under certain conditions. These results provide support for the hypothesis that G-quadruplex formation by the telomere product may in fact regulate telomerase function at the translocation step (Zahler et al., 1991) and suggest an Achilles' heel for indirectly targeting telomerase. Thus, on the basis of the insight gained from the present studies and the results of Zahler et al. (1991), we propose that ligands that selectively bind or cleave G-quadruplex structures may modulate telomerase processivity.},
}
@article {pmid8985179,
year = {1996},
author = {Virta-Pearlman, V and Morris, DK and Lundblad, V},
title = {Est1 has the properties of a single-stranded telomere end-binding protein.},
journal = {Genes &amp; development},
volume = {10},
number = {24},
pages = {3094-3104},
doi = {10.1101/gad.10.24.3094},
pmid = {8985179},
issn = {0890-9369},
support = {AG11728-01X/AG/NIA NIH HHS/United States ; },
mesh = {Binding Sites ; Chromosomes/ultrastructure ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/*metabolism ; Fungal Proteins/*metabolism ; RNA-Binding Proteins/metabolism ; Saccharomyces cerevisiae ; *Saccharomyces cerevisiae Proteins ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {In Saccharomyces cerevisiae, deletion of the EST1 gene results in phenotypes identical to those displayed by a deletion of a known component of telomerase (the yeast telomerase RNA), arguing that EST1 is also critical for telomerase function. In this study, we show that the Estl protein binds to yeast G-rich telomeric oligonucleotides in vitro. Binding is specific for single-stranded substrates and requires a free 3' terminus, consistent with the properties expected for a protein bound to the 3' single-stranded G-rich extension present at the telomere. Assessment of the in vivo function of this single-stranded DNA-binding protein has shown that EST1 acts in the same pathway of telomere replication as the TLC1 telomerase RNA, by several different genetic criteria: est1 tlc1 double mutant strains show no enhancement of phenotype relative to either single mutant strain, and EST1 dominant mutations have an effect on telomeric silencing similar to that displayed by TLC1 previously. We propose that Est1 is a telomere end-binding protein that is required to mediate recognition of the end of the chromosome by telomerase.},
}
@article {pmid8954124,
year = {1996},
author = {Uchiumi, F and Ohta, T and Tanuma, S},
title = {Replication factor C recognizes 5'-phosphate ends of telomeres.},
journal = {Biochemical and biophysical research communications},
volume = {229},
number = {1},
pages = {310-315},
doi = {10.1006/bbrc.1996.1798},
pmid = {8954124},
issn = {0006-291X},
mesh = {Binding Sites ; Binding, Competitive ; Cloning, Molecular ; DNA/*metabolism ; DNA Probes ; DNA Replication ; DNA-Binding Proteins/genetics/*metabolism ; *Homeodomain Proteins ; Minor Histocompatibility Antigens ; Protein Binding ; *Proto-Oncogene Proteins c-bcl-2 ; Recombinant Fusion Proteins/metabolism ; Replication Protein C ; *Repressor Proteins ; *Saccharomyces cerevisiae Proteins ; Telomere/*metabolism ; },
abstract = {Telomere structure is suggested to be important for chromosome and cell integrity and thereby for cell senescence and immortality. In a search for cDNA encoding proteins that bind specifically to telomere repeat sequences, we used random primer-labeled telomere probes to screen a lambda gt11 Jurkat cDNA library. The clone obtained encodes the central region of the large subunit of replication factor C (RFC), a known activator of DNA polymerase delta. Electrophoretic mobility shift analyses of the binding ability of RFC-glutathione S-transferase (GST) fusion protein to telomere probes revealed that RFC recognizes preferentially 5'-phosphoryl (P) groups but not 3'-hydroxyl (OH) groups at the ends of double-stranded telomere repeats. This structure-specific binding of RFC is supported by the observations that it binds to 3'-OH/5'-P ends in telomere repeats produced by DNase gamma, but not to those produced by 3'-P/5'-OH ends for DNase alpha. These findings suggest a novel function for RFC in telomere stability or turnover.},
}
@article {pmid9183660,
year = {1996},
author = {Ishikawa, F},
title = {[Telomere and telomerase].},
journal = {Human cell},
volume = {9},
number = {4},
pages = {287-294},
pmid = {9183660},
issn = {0914-7470},
mesh = {DNA Replication/physiology ; Enzyme Activation ; Humans ; Neoplasms/genetics ; Telomerase/analysis/*metabolism ; Telomere/*physiology ; },
abstract = {Telomeres are the functional domains positioned at the ends of chromosomes. It is essential for the stable maintenance of chromosomes. Telomerase is an enzyme that has an important role in the DNA replicator at telomeres. Its activity is specifically activated in cancer cells. We have reported a novel specific and sensitive assay (stretch RCR assay) for the detection of telomerase activity. We analyzed the telomerase activity in leukemias using this method. The results showed that telomerase is specifically activated during the progression stages of leukemia. The "telomere crisis model" has been proposed for explaining the role of the telomere dynamics in malignancies.},
}
@article {pmid9088112,
year = {1996},
author = {Satoh, H and Hiyama, K and Takeda, M and Awaya, Y and Watanabe, K and Ihara, Y and Maeda, H and Ishioka, S and Yamakido, M},
title = {Telomere shortening in peripheral blood cells was related with aging but not with white blood cell count.},
journal = {The Japanese journal of human genetics},
volume = {41},
number = {4},
pages = {413-417},
doi = {10.1007/BF01876332},
pmid = {9088112},
issn = {0916-8478},
mesh = {Adult ; Aged ; Asian People/genetics ; Blotting, Southern ; Cell Division/genetics ; Cellular Senescence/*genetics ; DNA/blood ; Female ; Humans ; Japan ; *Leukocyte Count ; Leukocytes, Mononuclear/*chemistry ; Male ; Middle Aged ; Polymerase Chain Reaction ; Repetitive Sequences, Nucleic Acid ; Smoking/blood ; Telomere/*chemistry ; },
abstract = {Telomeres in somatic cells are progressively shortened with aging. We investigated the relationship between the telomere length and other factors which may affect the frequency of cell divisions, in peripheral blood cells. Shortening of telomeric repeats was correlated with aging (p < 0.0001), but not with white blood cell count, neutrophil count, and smoking habit. Not only the number of cell divisions, but also some other factors, such as upregulation level of telomerase activity concomitant with the cell division in hematopoietic progenitor cells, might affect the length of telomeric repeats in blood cells.},
}
@article {pmid9049957,
year = {1996},
author = {Leber, B and Bacchetti, S},
title = {Telomeres and telomerase in normal and malignant haematologic cells.},
journal = {Leukemia &amp; lymphoma},
volume = {24},
number = {1-2},
pages = {1-9},
doi = {10.3109/10428199609045709},
pmid = {9049957},
issn = {1042-8194},
mesh = {Biomarkers, Tumor/*blood ; Bone Marrow/enzymology/pathology ; Hematologic Neoplasms/pathology/*physiopathology/therapy ; Humans ; Prognosis ; Reference Values ; Telomerase/*analysis ; Telomere/*enzymology ; },
abstract = {Telomeres, the ends of eukaryotic chromosomes are structural and functional units composed of proteins and repetitive DNA sequences. Telomeres protect the ends of chromosomes from DNA loss caused by incomplete replication of 3' ends. The obligatory loss of terminal sequence with each cell division leads to telomere shortening, and is counteracted in germline cells by an enzymatic activity termed telomerase that resynthesizes telomeric DNA de novo. Telomere length and telomerase activity have been measured by several groups in both normal and malignant blood and marrow cells. Telomere length decreases with age in normal blood and bone marrow, despite the presence of a detectable telomerase activity. In most hematologic malignancies telomere length is short and telomerase activity is enhanced, compatible with the late activation of the enzyme in tumour development. The implications of these findings for tumour pathogenesis, diagnosis, and treatment are discussed.},
}
@article {pmid9015136,
year = {1996},
author = {Russo, A and Priante, G and Tommasi, AM},
title = {PRINS localization of centromeres and telomeres in micronuclei indicates that in mouse splenocytes chromatid non-disjunction is a major mechanism of aneuploidy.},
journal = {Mutation research},
volume = {372},
number = {2},
pages = {173-180},
doi = {10.1016/s0027-5107(96)00137-6},
pmid = {9015136},
issn = {0027-5107},
mesh = {*Aneuploidy ; Animals ; Centromere/*chemistry ; DNA/*analysis/biosynthesis ; DNA, Satellite/analysis ; Demecolcine/pharmacology ; In Situ Hybridization/methods ; Male ; Mice ; Micronucleus Tests ; Mitomycin/pharmacology ; *Nondisjunction, Genetic ; Spleen/cytology ; Telomere/*chemistry ; },
abstract = {Primed In Situ DNA Synthesis (PRINS) of telomeric and centromeric (minor satellite DNA) sequences has been applied together with the cytokinesis block micronucleus (MN) assay in mouse splenocytes, with the aim of understanding the mechanism of origin of spontaneous and induced MN. Splenocyte cultures were treated in vitro either with the clastogenic agent mitomycin C or with the aneugenic compound colcemid. The relative proportions of MN carrying 1 to 4 telomeric signals were in agreement with the known mechanism of action of the chemicals tested, i.e., an higher number of MN with less than 4 telomeres were found in MMC-than in colcemid-treated cultures. No MN lacking the telomeric sequences (0 spot) were found, indicating that the observed distributions should not be affected by false-negative data. Furthermore, all MN carrying a single telomere were negative for the centromere, thus indicating that this class represents true chromosome acentric fragments. Finally, MN with 4 telomeric spots always carried the centromeric sequence, as expected on the hypothesis that these MN correspond to whole chromosomes. With respect to centromere-positive MN, more than one half carried 4 telomeric signals (whole chromosomes), and only 1/4 or less showed 2 telomeric signals (probably corresponding to a single chromatid). This difference was statistically significant, either in untreated cultures or in cultures exposed to mitomycin C or colcemid. On the whole, these data indicate that non-disjunction followed by whole chromosome loss (with the production of two daughter monosomic nuclei) may be the main mechanism of malsegregation leading to MN formation.},
}
@article {pmid8978029,
year = {1996},
author = {Lendvay, TS and Morris, DK and Sah, J and Balasubramanian, B and Lundblad, V},
title = {Senescence mutants of Saccharomyces cerevisiae with a defect in telomere replication identify three additional EST genes.},
journal = {Genetics},
volume = {144},
number = {4},
pages = {1399-1412},
pmid = {8978029},
issn = {0016-6731},
support = {AG11728-01/AG/NIA NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Cloning, Molecular ; DNA, Fungal/genetics ; DNA-Binding Proteins ; Fungal Proteins/*genetics ; *Gene Expression Regulation, Fungal ; Molecular Sequence Data ; Mutation ; Proteins/genetics ; *RNA ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; Telomerase/*genetics ; Telomere/*genetics ; *Telomere-Binding Proteins ; },
abstract = {The primary determinant for telomere replication is the enzyme telomerase, responsible for elongating the G-rich strand of the telomere. The only component of this enzyme that has been identified in Saccharomyces cerevisiae is the TLC1 gene, encoding the telomerase RNA subunit. However, a yeast strain defective for the EST1 gene exhibits the same phenotypes (progressively shorter telomeres and a senescence phenotype) as a strain deleted for TLC1, suggesting that EST1 encodes either a component of telomerase or some other factor essential for telomerase function. We designed a multitiered screen that led to the isolation of 22 mutants that display the same phenotypes as est1 and tlc1 mutant strains. These mutations mapped to four complementation groups: the previously identified EST1 gene and three additional genes, called EST2, EST3 and EST4. Cloning of the EST2 gene demonstrated that it encodes a large, extremely basic novel protein with no motifs that provide clues as to function. Epistasis analysis indicated that the four EST genes function in the same pathway for telomere replication as defined by the TLC1 gene, suggesting that the EST genes encode either components of telomerase or factors that positively regulate telomerase activity.},
}
@article {pmid8939642,
year = {1996},
author = {Raymond, E and Sun, D and Chen, SF and Windle, B and Von Hoff, DD},
title = {Agents that target telomerase and telomeres.},
journal = {Current opinion in biotechnology},
volume = {7},
number = {6},
pages = {583-591},
doi = {10.1016/s0958-1669(96)80068-1},
pmid = {8939642},
issn = {0958-1669},
support = {CA67760/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Antineoplastic Agents/*chemistry/pharmacology ; *Drug Design ; Drug Resistance, Neoplasm ; Enzyme Inhibitors/chemistry/*pharmacology ; Humans ; Mice ; Models, Molecular ; Neoplasms/drug therapy/genetics ; Nucleic Acid Conformation ; Nucleoproteins/drug effects ; Reverse Transcriptase Inhibitors/chemistry/pharmacology ; Telomerase/*antagonists &amp; inhibitors/genetics/metabolism ; Telomere/chemistry/*drug effects/genetics ; },
abstract = {Telomeres are guanine-rich regions that are located at the ends of chromosomes and are essential for preventing aberrant recombination and protecting against exonucleolytic DNA degradation. Telomeres are maintained by telomerase, an RNA-dependent DNA polymerase. Because telomerase is known to be expressed in tumor cells, which concurrently have short telomeres, and not in most somatic cells, which usually have long telomeres, telomerase and telomere structures have been recently proposed as attractive targets for the discovery of new anticancer agents. The most exciting current strategies are aimed at specifically designing new drugs that target telomerase or telomeres and new models have been formulated to study the biological effects of inhibitors of telomerase and telomeres both in vitro and in vivo.},
}
@article {pmid8929418,
year = {1996},
author = {Wolthers, KC and Bea, G and Wisman, A and Otto, SA and de Roda Husman, AM and Schaft, N and de Wolf, F and Goudsmit, J and Coutinho, RA and van der Zee, AG and Meyaard, L and Miedema, F},
title = {T cell telomere length in HIV-1 infection: no evidence for increased CD4+ T cell turnover.},
journal = {Science (New York, N.Y.)},
volume = {274},
number = {5292},
pages = {1543-1547},
doi = {10.1126/science.274.5292.1543},
pmid = {8929418},
issn = {0036-8075},
mesh = {Acquired Immunodeficiency Syndrome/*blood ; CD4 Lymphocyte Count ; CD4-Positive T-Lymphocytes/enzymology/immunology/*pathology/ultrastructure ; CD8-Positive T-Lymphocytes/enzymology/immunology/*pathology/ultrastructure ; Cell Death ; Cell Division ; Cross-Sectional Studies ; Disease Progression ; HIV Infections/blood/*immunology ; *HIV-1 ; Humans ; Leukocytes, Mononuclear/enzymology/pathology/ultrastructure ; Lymphocyte Count ; Male ; Matched-Pair Analysis ; Telomerase/blood ; Telomere/*ultrastructure ; },
abstract = {Progression to acquired immunodeficiency syndrome (AIDS) has been related to exhaustion of the regenerative capacity of the immune system resulting from high T cell turnover. Analysis of telomeric terminal restriction fragment (TRF) length, a marker for cellular replicative history, showed that CD8(+) T cell TRF length decreased but CD4(+) T cell TRF length was stable during the course of human immunodeficiency virus type-1 (HIV-1) infection, which was not explained by differential telomerase activity. This observation provides evidence that turnover in the course of HIV-1 infection can be increased considerably in CD8(+) T cells, but not in CD4(+) T cells. These results are compatible with CD4(+) T cell decline in HIV-1 infection caused by interference with cell renewal.},
}
@article {pmid8943008,
year = {1996},
author = {Lin, JJ and Zakian, VA},
title = {The Saccharomyces CDC13 protein is a single-strand TG1-3 telomeric DNA-binding protein in vitro that affects telomere behavior in vivo.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {93},
number = {24},
pages = {13760-13765},
pmid = {8943008},
issn = {0027-8424},
mesh = {Base Sequence ; Binding Sites ; Cell Cycle ; Cloning, Molecular ; Cyclin B ; Cyclins/isolation &amp; purification/*metabolism ; DNA-Binding Proteins/metabolism ; Escherichia coli ; Fungal Proteins/metabolism ; Molecular Sequence Data ; Oligodeoxyribonucleotides ; Recombinant Proteins/isolation &amp; purification/metabolism ; Saccharomyces cerevisiae/cytology/genetics/*metabolism ; Substrate Specificity ; Telomere/*physiology ; },
abstract = {Saccharomyces telomeres consist of approximately 300 bp of C1-3A/TG1-3 DNA. Cells lacking the activity of the essential gene CDC13 display a cell cycle arrest mediated by the DNA damage sensing, RAD9 cell cycle checkpoint, presumably because they exhibit strand-specific loss of telomeric and telomere-adjacent DNA [Garvik, B., Carson, M. &amp; Hartwell, L. (1995) Mol. Celi. Biol. 15,6128-6138]. Cdc13p expressed in Escherichia coli or overexpressed in yeast bound specifically to single-strand TG1-3 DNA. The specificity of binding displayed by Cdc13p in vitro indicates that in vivo it could bind to both the short, constitutive single-strand TG1-3 tails thought to be present at telomeres at most times in the cell cycle as well as to the long single-strand TG1-3 tails that are intermediates in telomere replication. Genes located near yeast telomeres are transcriptionally repressed, a phenomenon known as telomere position effect. Cells overexpressing a mutant form of Cdc13p had reduced telomere position effect at high temperatures. These data suggest that Cdc13p functions by binding directly to telomeric DNA, thereby limiting its accessibility to degradation and transcription as well as masking it from factors that detect damaged DNA.},
}
@article {pmid9064260,
year = {1996},
author = {von Zglinicki, T},
title = {[Are the ends of chromosomes the beginning of tumor genesis? On the role of telomeres in cancer development].},
journal = {Fortschritte der Medizin},
volume = {114},
number = {32},
pages = {12-14},
pmid = {9064260},
issn = {0015-8178},
mesh = {Animals ; Cell Division/genetics ; Cell Transformation, Neoplastic/*genetics ; Gene Expression Regulation, Enzymologic/physiology ; Humans ; Neoplasms/*genetics ; Telomerase/genetics ; Telomere/*genetics ; },
}
@article {pmid9004864,
year = {1996},
author = {Golubev, AG},
title = {[Biochemistry of space and time (telomeres, telomerases, and longevity of cell populations and multicellular organisms].},
journal = {Biokhimiia (Moscow, Russia)},
volume = {61},
number = {11},
pages = {2045-2059},
pmid = {9004864},
issn = {0320-9725},
mesh = {Animals ; Cellular Senescence/*genetics ; *DNA Replication ; Longevity ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {Analysis of recent data on telomeres and telomerases, limitations of proliferative potential of untransformed cells (Hayflick's limit), kinetics and molecular mechanism of cell proliferation and differentiation, and factors that determine the longevity of multicellular organisms suggests that: (i) chromosome end shortening during consecutive divisions of cells that lack telomerase limits cell proliferation beyond Hayflick's limit; (ii) Hayflick's limit can be a manifestation of mechanisms that determine the size of the living organism (it correlates with longevity) but not the longevity of multicellular organisms.},
}
@article {pmid8976764,
year = {1996},
author = {Kamata, S and Kageyama, Y and Yonese, J and Oshima, H},
title = {Significant telomere reduction in human superficial transitional cell carcinoma.},
journal = {British journal of urology},
volume = {78},
number = {5},
pages = {704-708},
doi = {10.1046/j.1464-410x.1996.01957.x},
pmid = {8976764},
issn = {0007-1331},
mesh = {Adult ; Aged ; Aged, 80 and over ; Blotting, Southern ; Carcinoma, Transitional Cell/enzymology/*pathology ; Female ; Humans ; Male ; Middle Aged ; Telomerase/metabolism ; *Telomere ; Urinary Bladder Neoplasms/enzymology/*pathology ; },
abstract = {OBJECTIVE: To investigate telomere reduction and telomerase activity in human transitional cell carcinomas (TCCs) of the bladder, using primary tissue preparations, and their relationship to the clinicopathological properties of the TCC.<br><br>MATERIALS AND METHODS: Tumour tissues were obtained from 21 patients together with apparently normal urothelia as controls. The mean telomere length of each sample was determined using southern blot analysis with an oligonucleotide probe (TTAGGG)4 and telomerase activity was semi-quantified using a polymerase chain reaction based assay.<br><br>RESULTS: The mean (SE) telomere length was 6.6 (0.7) kb in tumour tissues and 11.5 (0.4) kb in apparently normal urothelia adjacent to the tumour (P < 0.001). Furthermore, it was 8.9 (1.4) kb and 3.4 (0.9) kb in superficial and invasive tumours (P = 0.002), respectively. Telomerase activity was detected in all 13 of the tumour tissues examined, with no relationship to telomere reduction, while it was undetectable in any of the control tissues.<br><br>CONCLUSIONS: In human TCCs, telomere length was reduced in tumour tissue, more so in superficial than in invasive tumours. Telomerase was detectable only in tumour tissues and its activity was unrelated to telomere reduction.},
}
@article {pmid8958797,
year = {1996},
author = {Royle, NJ},
title = {Telomeres and disease.},
journal = {The Journal of pathology},
volume = {180},
number = {3},
pages = {233-235},
doi = {10.1002/(SICI)1096-9896(199611)180:3&lt;233::AID-PATH675&gt;3.0.CO;2-8},
pmid = {8958797},
issn = {0022-3417},
mesh = {Cell Transformation, Neoplastic/genetics ; Humans ; Neoplasms/enzymology/*genetics ; Telomerase/metabolism ; Telomere/*genetics ; },
}
@article {pmid8956861,
year = {1996},
author = {Park, JP and Dossu, JR and Rhodes, CH},
title = {Telomere associations in desmoplastic infantile ganglioglioma.},
journal = {Cancer genetics and cytogenetics},
volume = {92},
number = {1},
pages = {4-7},
doi = {10.1016/s0165-4608(96)00166-5},
pmid = {8956861},
issn = {0165-4608},
mesh = {Brain Neoplasms/*genetics/pathology ; *Cerebral Cortex ; Child, Preschool ; Chromosome Breakage/*genetics ; Ganglioglioma/*genetics/pathology ; Humans ; Male ; Telomere/*genetics ; Translocation, Genetic/*genetics ; },
abstract = {A four and a half year old male was diagnosed with desmoplastic infantile ganglioglioma. To our knowledge, the cytogenetics of this tumor have never been reported. In our analysis of 40 cells, no consistent clonal abnormalities were observed; however, the majority of cells (25 of 40) showed structural rearrangements (telomere associations) resulting in dicentrics and other derivative chromosomes. Breakpoints most often observed included 17q25 (6 of 40), 19p13.3 (4 of 40), 17p13 (3 of 40), 14q32 (3 of 40), 11q25 (3 of 40), 9p24 (2 of 40), 5q35 (2 of 40), and 22q13 (2 of 40).},
}
@article {pmid8952386,
year = {1996},
author = {Ishikawa, F},
title = {[A review of the structure and function of human telomere].},
journal = {Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme},
volume = {41},
number = {15 Suppl},
pages = {2241-2253},
pmid = {8952386},
issn = {0039-9450},
mesh = {Chromosomes/genetics ; DNA Replication ; Genome ; Humans ; Protein Binding ; RNA ; Recombination, Genetic ; Repetitive Sequences, Nucleic Acid ; Telomerase ; *Telomere/genetics/physiology ; },
}
@article {pmid8932391,
year = {1996},
author = {Sprung, CN and Sabatier, L and Murnane, JP},
title = {Effect of telomere length on telomeric gene expression.},
journal = {Nucleic acids research},
volume = {24},
number = {21},
pages = {4336-4340},
pmid = {8932391},
issn = {0305-1048},
mesh = {Blotting, Southern ; Cell Line, Transformed ; Chromosomes, Human, Pair 13 ; *Gene Expression Regulation ; Humans ; Kanamycin Kinase ; Phosphotransferases (Alcohol Group Acceptor)/genetics ; Plasmids ; Simplexvirus/enzymology/genetics ; Structure-Activity Relationship ; Telomere/*physiology ; Thymidine Kinase/genetics ; Transcription, Genetic ; },
abstract = {Telomeres gradually shorten as human somatic cells divide and a correlation has been observed between the average telomere length and cell senescence. It has been proposed that the genes responsible for cell senescence are located near the telomere and are activated when telomere length reaches a critical point. This is consistent with evidence from Saccharomyces cerevisiae, in which genes are regulated differently depending on their distance from the telomere. We investigated the possibility that differential gene expression is conferred by telomere length in human cells. A plasmid containing the neomycin phosphotransferase (neo) gene was transfected into the SV40-transformed human fibroblast cell line LM217. In one transfectant the plasmid was integrated at the telomere of chromosome 13. Subclones of this cell line that had various lengths of telomeric repeat sequences on the end of this chromosome were isolated. No effect on neo gene expression was found when the length of the telomere varied between 25 and 0.5 kb, as demonstrated by colony forming ability, growth rates and RNA blot analysis. These results therefore suggest that putative chromatin structural differences conferred by telomere length do not affect the expression of genes located near telomeres.},
}
@article {pmid8898191,
year = {1996},
author = {Lundblad, V and Wright, WE},
title = {Telomeres and telomerase: a simple picture becomes complex.},
journal = {Cell},
volume = {87},
number = {3},
pages = {369-375},
doi = {10.1016/s0092-8674(00)81358-6},
pmid = {8898191},
issn = {0092-8674},
mesh = {Acquired Immunodeficiency Syndrome/genetics ; Animals ; Cell Cycle/*physiology ; Cellular Senescence/physiology ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes/ultrastructure ; Chromosomes, Fungal/ultrastructure ; Eukaryotic Cells/cytology/metabolism ; Homeostasis ; Mammals/genetics ; Mice ; Telomerase/*physiology ; Telomere/*physiology ; Yeasts/genetics ; },
}
@article {pmid8875896,
year = {1996},
author = {Bertoni, L and Attolini, C and Faravelli, M and Simi, S and Giulotto, E},
title = {Intrachromosomal telomere-like DNA sequences in Chinese hamster.},
journal = {Mammalian genome : official journal of the International Mammalian Genome Society},
volume = {7},
number = {11},
pages = {853-855},
pmid = {8875896},
issn = {0938-8990},
mesh = {Animals ; Base Sequence ; CHO Cells ; Cell Line ; Centromere ; Chromosome Banding ; *Chromosome Mapping ; Cricetinae ; Cricetulus/*genetics ; In Situ Hybridization, Fluorescence ; *Telomere ; },
}
@article {pmid8824190,
year = {1996},
author = {Nugent, CI and Hughes, TR and Lue, NF and Lundblad, V},
title = {Cdc13p: a single-strand telomeric DNA-binding protein with a dual role in yeast telomere maintenance.},
journal = {Science (New York, N.Y.)},
volume = {274},
number = {5285},
pages = {249-252},
doi = {10.1126/science.274.5285.249},
pmid = {8824190},
issn = {0036-8075},
mesh = {Alleles ; Base Sequence ; Cloning, Molecular ; Cyclin B ; Cyclins/genetics/*metabolism ; DNA, Fungal/metabolism ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/*metabolism ; Fungal Proteins/genetics ; Genes, Fungal ; Molecular Sequence Data ; Mutation ; Phenotype ; Saccharomyces cerevisiae/genetics/*metabolism ; *Saccharomyces cerevisiae Proteins ; Telomerase/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {The CDC13 gene has previously been implicated in the maintenance of telomere integrity in Saccharomyces cerevisiae. With the use of two classes of mutations, here it is shown that CDC13 has two discrete roles at the telomere. The cdc13-2est mutation perturbs a function required in vivo for telomerase regulation but not in vitro for enzyme activity, whereas cdc13-1ts defines a separate essential role at the telomere. In vitro, purified Cdc13p binds to single-strand yeast telomeric DNA. Therefore, Cdc13p is a telomere-binding protein required to protect the telomere and mediate access of telomerase to the chromosomal terminus.},
}
@article {pmid8938628,
year = {1996},
author = {Urabe, Y and Nouso, K and Higashi, T and Nakatsukasa, H and Hino, N and Ashida, K and Kinugasa, N and Yoshida, K and Uematsu, S and Tsuji, T},
title = {Telomere length in human liver diseases.},
journal = {Liver},
volume = {16},
number = {5},
pages = {293-297},
doi = {10.1111/j.1600-0676.1996.tb00748.x},
pmid = {8938628},
issn = {0106-9543},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Hepatocellular/genetics/pathology ; Chronic Disease ; Densitometry ; Disease Progression ; Humans ; Liver Diseases/*genetics/pathology ; Liver Neoplasms/genetics/pathology ; Middle Aged ; Oligonucleotide Probes/chemistry ; *Polymorphism, Restriction Fragment Length ; Telomere/*chemistry ; },
abstract = {To determine the role of telomere-mediated gene stability in hepatocarcinogenesis, we examined the telomere length of human liver with or without chronic liver diseases and hepatocellular carcinomas (HCC). The mean telomere restriction fragment (TRF) length of normal liver (n = 13), chronic hepatitis (n = 11), liver cirrhosis (n = 24) and HCC (n = 24) was 7.8 +/- 0.2, 7.1 +/- 0.3, 6.4 +/- 0.2 and 5.2 +/- 0.2 kb, respectively (mean +/- standard error). TRF length decreased with a progression of chronic liver diseases and that in HCC was significantly shorter than that in other chronic liver diseases (p < 0.05). The ratios of TRF length of HCC to that of corresponding surrounding liver of well differentiated (n = 7), moderately differentiated (n = 10) and poorly differentiated (n = 4) HCCs were 0.83 +/- 0.06, 0.75 +/- 0.05 and 0.98 +/- 0.09, respectively. The ratio of poorly differentiated HCC was significantly higher than that of moderately differentiated HCC (p < 0.05). A comparison between the size and telomere length ratio of moderately differentiated HCCs revealed a decrease of the ratio with size until it reached 50 mm in diameter. In contrast, the ratio increased as the size enlarged over 50 mm. These findings suggest that the gene stability of the liver cells mediated by the telomere is reduced as chronic liver disease progresses and that telomerase is activated in poorly differentiated HCC and moderately differentiated HCC over 50 mm in diameter.},
}
@article {pmid8921986,
year = {1996},
author = {Counter, CM},
title = {The roles of telomeres and telomerase in cell life span.},
journal = {Mutation research},
volume = {366},
number = {1},
pages = {45-63},
doi = {10.1016/s0165-1110(96)90006-8},
pmid = {8921986},
issn = {0027-5107},
mesh = {Animals ; *Cell Survival ; Cellular Senescence ; Ciliophora/cytology/enzymology ; Humans ; Saccharomyces cerevisiae/cytology/enzymology ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {Telomeres cap and protect the ends of chromosomes from degradation and illegitimate recombination. The termini of a linear template cannot, however, be completely replicated by conventional DNA-dependent DNA polymerases, and thus in the absence of a mechanisms to counter this effect, telomeres of eukaryotic cells shorten every round of DNA replication. In humans and possibly other higher eukaryotes, telomere shortening may have been adopted to limit the life span of somatic cells. Human somatic cells have a finite proliferative capacity and enter a viable growth arrested state called senescence. Life span appears to be governed by cell division, not time. The regular loss of telomeric DNA could therefore serve as a mitotic clock in the senescence programme, counting cell divisions. In most eukaryotic organisms, however, telomere shortening can be countered by the de novo addition of telomeric repeats by the enzyme telomerase. Cells which are "immortal' such as the human germ line or tumour cell lines, established mouse cells, yeast and ciliates, all maintain a stable telomere length through the action of telomerase. Abolition of telomerase activity in such cells nevertheless results in telomere shortening, a process that eventually destabilizes the ends of chromosomes, leading to genomic instability and cell growth arrest or death. Therefore, loss of terminal DNA sequences may limit cell life span by two mechanisms: by acting as a mitotic clock and by denuding chromosomes of protective telomeric DNA necessary for cell viability.},
}
@article {pmid8918193,
year = {1996},
author = {Autexier, C and Greider, CW},
title = {Telomerase and cancer: revisiting the telomere hypothesis.},
journal = {Trends in biochemical sciences},
volume = {21},
number = {10},
pages = {387-391},
pmid = {8918193},
issn = {0968-0004},
mesh = {Animals ; Cell Division/genetics ; Cells, Cultured ; Eukaryotic Cells/enzymology/metabolism ; Humans ; Mice ; Neoplasms/*physiopathology/therapy ; Telomerase/antagonists &amp; inhibitors/*metabolism ; Telomere/*chemistry/genetics/metabolism ; },
abstract = {Telomerase is a ribonucleoprotein DNA polymerase that elongates telomeres in eukaryotes. The telomere hypothesis implicates short telomere length and telomerase activation as critical players in cellular immortalization and cancer. In this review, we refine the original telomere hypothesis to address the results of recent studies on telomerase and telomere length regulation.},
}
@article {pmid8916006,
year = {1996},
author = {Hirota, J and Usui, R and Satoh, T and Ikemoto, S},
title = {Telomere position on the cat chromosome.},
journal = {The Journal of veterinary medical science},
volume = {58},
number = {10},
pages = {1025-1026},
doi = {10.1292/jvms.58.10_1025},
pmid = {8916006},
issn = {0916-7250},
mesh = {Animals ; Cats/*genetics ; Chromosomes/*ultrastructure ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Telomere/*ultrastructure ; },
abstract = {The telomere in the cat chromosome was detected by the fluorescence in situ hybridization method using all human telomere as a probe. In the metaphase chromosomes of cultured peripheral lymphocytes, telomere spots were observed in the terminal portions of the chromosomes. Although telomeres were confirmed in all chromosomes, the fluorescence intensity varied between the two homologues in some chromosomes.},
}
@article {pmid8848051,
year = {1996},
author = {Krauskopf, A and Blackburn, EH},
title = {Control of telomere growth by interactions of RAP1 with the most distal telomeric repeats.},
journal = {Nature},
volume = {383},
number = {6598},
pages = {354-357},
doi = {10.1038/383354a0},
pmid = {8848051},
issn = {0028-0836},
mesh = {Base Sequence ; Cloning, Molecular ; DNA, Fungal/metabolism ; Fungal Proteins/genetics/*metabolism ; GTP-Binding Proteins/genetics/*metabolism ; Kluyveromyces/*genetics ; Molecular Sequence Data ; Mutagenesis ; Protein Binding ; RNA/metabolism ; Saccharomyces cerevisiae/genetics ; Telomerase/genetics ; Telomere/metabolism/*physiology ; rap GTP-Binding Proteins ; },
abstract = {Telomeres, the specialized DNA-protein structures at the ends of eukaryotic chromosomes, are required for chromosomal stability and integrity. Regulation of the overall length of the telomeric DNA repeat tract is likely to be a key requirement for its various biological roles. We have studied telomere length regulation in the yeast Kluyveromyces lactis, which has long (25 base pairs) homogeneous telomeric repeat units that make it highly suitable for telomere studies. In the related Saccharomyces cerevisiae, the DNA-sequence-specific duplex-binding protein RAP1 is a component of the telomeric complex. Here we show that the phenotypic severity of previously described telomerase RNA (ter1) mutations is directly proportional to the loss of RAP1 binding to mutated telomeric repeats. Using a carboxy-terminal-tail mutant of K. lactis RAP1, we also show that, unexpectedly, RAP1 interaction with the most terminal telomeric repeats is crucial for telomere length control.},
}
@article {pmid8884273,
year = {1996},
author = {Vocero-Akbani, A and Helms, C and Wang, JC and Sanjurjo, FJ and Korte-Sarfaty, J and Veile, RA and Liu, L and Jauch, A and Burgess, AK and Hing, AV and Holt, MS and Ramachandra, S and Whelan, AJ and Anker, R and Ahrent, L and Chen, M and Gavin, MR and Iannantuoni, K and Morton, SM and Pandit, SD and Read, CM and Steinbrueck, T and Warlick, C and Smoller, DA and Donis-Keller, H},
title = {Mapping human telomere regions with YAC and P1 clones: chromosome-specific markers for 27 telomeres including 149 STSs and 24 polymorphisms for 14 proterminal regions.},
journal = {Genomics},
volume = {36},
number = {3},
pages = {492-506},
doi = {10.1006/geno.1996.0495},
pmid = {8884273},
issn = {0888-7543},
support = {HG00100/HG/NHGRI NIH HHS/United States ; P41-HG01066/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; *Chromosome Mapping ; Chromosomes, Artificial, Yeast ; Cloning, Molecular ; Genetic Linkage ; Genetic Markers ; Humans ; Hybrid Cells ; In Situ Hybridization, Fluorescence ; Meiosis/genetics ; Molecular Sequence Data ; *Polymorphism, Genetic ; Rodentia ; Sequence Analysis, DNA ; *Sequence Tagged Sites ; *Telomere ; },
abstract = {A YAC library enriched for telomere clones was constructed and screened for the human telomere-specific repeat sequence (TTAGGG). Altogether 196 TYAC library clones were studied: 189 new TYAC clones were isolated, 149 STSs were developed for 132 different TY-ACs, and 39 P1 clones were identified using 19 STSs from 16 of the TYACs. A combination of mapping methods including fluorescence in situ hybridization, somatic cell hybrid panels, clamped homogeneous electric fields, meiotic linkage, and BLASTN sequence analysis was utilized to characterize the resource. Forty-five of the TYACs map to 31 specific telomere regions. Twenty-four linkage markers were developed and mapped within 14 proterminal regions (12 telomeres and 2 terminal bands). The polymorphic markers include 12 microsatellites for 10 telomeres (1q, 2p, 6q, 7q, 10p, 10q, 13q, 14q, 18p, 22q) and the terminal bands of 11q and 12p. Twelve RFLP markers were identified and meiotically mapped to the telomeres of 2q, 7q, 8p, and 14q. Chromosome-specific STSs for 27 telomeres were identified from the 196 TYACs. More than 30,000 nucleotides derived from the TYAC vector-insert junction regions or from regions flanking TYAC microsatellites were compared to reported sequences using BLASTN. In addition to identifying homology with previously reported telomere sequences and human repeat elements, gene sequences and a number of ESTs were found to be highly homologous to the TYAC sequences. These genes include human coagulation factor V (F5), Weel protein tyrosine kinase (WEE1), neurotropic protein tyrosine kinase type 2 (NTRE2), glutathione S-transferase (GST1), and beta tubulin (TUBB). The TYAC/P1 resource, derivative STSs, and polymorphisms constitute an enabling resource to further studies of telomere structure and function and a means for physical and genetic map integration and closure.},
}
@article {pmid8814333,
year = {1996},
author = {Xia, SJ and Shammas, MA and Shmookler Reis, RJ},
title = {Reduced telomere length in ataxia-telangiectasia fibroblasts.},
journal = {Mutation research},
volume = {364},
number = {1},
pages = {1-11},
doi = {10.1016/0921-8777(96)00015-8},
pmid = {8814333},
issn = {0027-5107},
mesh = {Ataxia Telangiectasia/*genetics/*pathology ; Base Sequence ; Cell Line ; Cell Line, Transformed ; DNA/chemistry/genetics/isolation &amp; purification ; Diploidy ; Female ; Fibroblasts ; Humans ; Male ; Oligonucleotide Probes ; Simian virus 40 ; Telomerase/metabolism ; Telomere/pathology/*ultrastructure ; },
abstract = {Chromosomal instability with a high frequency of telomere fusion is characteristic of ataxia-telangiectasia cells both in vivo and in vitro. We have measured telomere length and found it to be consistently reduced in both diploid and SV40-transformed cells A-T fibroblasts, relative to control cells. We examined a few possible mechanisms which might account for telomeric length reduction, including telomerase activity in transformed cells and endogenous nuclease activities, but found no differences between A-T and control cells in these parameters.},
}
@article {pmid8899160,
year = {1996},
author = {Kronenwett, R and Murea, S and Haas, R},
title = {Telomere length of blood-derived mononuclear cells from cancer patients during G-CSF-enhanced marrow recovery.},
journal = {Bone marrow transplantation},
volume = {18 Suppl 1},
number = {},
pages = {S10-4},
pmid = {8899160},
issn = {0268-3369},
mesh = {Adult ; Antigens, CD34/blood ; Base Sequence ; DNA, Neoplasm/genetics ; Female ; Granulocyte Colony-Stimulating Factor/*therapeutic use ; *Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/cytology/drug effects/immunology ; Humans ; Leukapheresis ; Leukocytes, Mononuclear/drug effects/immunology/*metabolism ; Male ; Middle Aged ; Neoplasms/blood/*genetics/*therapy ; Repetitive Sequences, Nucleic Acid ; Telomere/*genetics ; },
}
@article {pmid8885223,
year = {1996},
author = {Rudenko, G and McCulloch, R and Dirks-Mulder, A and Borst, P},
title = {Telomere exchange can be an important mechanism of variant surface glycoprotein gene switching in Trypanosoma brucei.},
journal = {Molecular and biochemical parasitology},
volume = {80},
number = {1},
pages = {65-75},
doi = {10.1016/0166-6851(96)02669-2},
pmid = {8885223},
issn = {0166-6851},
mesh = {Animals ; *Antigenic Variation ; *Cinnamates ; Cloning, Molecular ; Drug Resistance ; Gene Conversion ; *Genes, Protozoan ; Hygromycin B/analogs &amp; derivatives/pharmacology ; Immunization ; Mice ; Mice, Inbred BALB C ; Rats ; Rats, Sprague-Dawley ; Telomere/*genetics ; Transformation, Genetic ; Trypanosoma brucei brucei/drug effects/*genetics/immunology ; Trypanosomiasis, African/parasitology ; Variant Surface Glycoproteins, Trypanosoma/*genetics ; },
abstract = {Trypanosoma brucei undergoes antigenic variation by changing its Variant Surface Glycoprotein (VSG) coat. Although there are up to a thousand VSG genes, only one is transcribed at a time from a telomeric VSG expression site. Switching can involve DNA rearrangements exchanging the active VSG gene, or transcriptional activation of a new expression site and transcriptional silencing of the old one. Determining the mechanism mediating a switch has not always been easy, as the many virtually identical copies of VSG gene expression sites complicate transcriptional analysis. To overcome this problem, we have used bloodstream form T. brucei with a single copy VSG gene in an active expression site marked with a hygromycin resistance gene. We allowed these transformants to undergo switching of the active VSG gene, via three different experimental methods. We were able to select large numbers of switched trypanosomes from a single infected mouse using a new microtitre-dish based procedure developed for this purpose. The drug sensitivity of the switched trypanosomes allowed us to determine the transcriptional state of the marked expression site, and polymerase chain reaction (PCR) amplification was used to determine whether the single copy drug resistance gene and VSG gene present in the marked expression site had been retained. These studies showed that telomere exchange, which has been considered rare, can in some cases be an important mechanism of VSG gene switching. We describe 4 telomere exchange events between the active VSG 221 expression site and 4 different chromosomes.},
}
@article {pmid8830766,
year = {1996},
author = {Gotta, M and Laroche, T and Formenton, A and Maillet, L and Scherthan, H and Gasser, SM},
title = {The clustering of telomeres and colocalization with Rap1, Sir3, and Sir4 proteins in wild-type Saccharomyces cerevisiae.},
journal = {The Journal of cell biology},
volume = {134},
number = {6},
pages = {1349-1363},
pmid = {8830766},
issn = {0021-9525},
mesh = {Antibody Specificity ; Blotting, Western ; Cell Nucleus/chemistry ; Fluorescent Antibody Technique ; Fungal Proteins/*analysis/genetics ; GTP-Binding Proteins/*analysis/genetics ; In Situ Hybridization, Fluorescence ; Mutation/physiology ; RNA, Messenger/analysis ; Saccharomyces cerevisiae/*chemistry/physiology ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Telomere/chemistry/*physiology ; Trans-Activators/*analysis/genetics ; Transcription Factors/analysis/genetics ; rap GTP-Binding Proteins ; },
abstract = {We have developed a novel technique for combined immunofluorescence/in situ hybridization on fixed budding yeast cells that maintains the three-dimensional structure of the nucleus as monitored by focal sections of cells labeled with fluorescent probes and by staining with a nuclear pore antibody. Within the resolution of these immunodetection techniques, we show that proteins encoded by the SIR3, SIR4, and RAP1 genes colocalize in a statistically significant manner with Y' telomere-associated DNA sequences. In wild-type cells the Y' in situ hybridization signals can be resolved by light microscopy into fewer than ten foci per diploid nucleus. This suggests that telomeres are clustered in vegetatively growing cells, and that proteins essential for telomeric silencing are concentrated at their sites of action, i.e., at telomeres and/or subtelomeric regions. As observed for Rap1, the Sir4p staining is diffuse in a sir3- strain, and similarly, Sir3p staining is no longer punctate in a sir4- strain, although the derivatized Y' probe continues to label discrete sites in these strains. Nonetheless, the Y' FISH is altered in a qualitative manner in sir3 and sir4 mutant strains, consistent with the previously reported phenotypes of shortened telomeric repeats and loss of telomeric silencing.},
}
@article {pmid8826850,
year = {1996},
author = {White, GR and Stack, M and Santibáñez-Koref, M and Liscia, DS and Venesio, T and Wang, JC and Helms, C and Donis-Keller, H and Betticher, DC and Altermatt, HJ and Hoban, PR and Heighway, J},
title = {High levels of loss at the 17p telomere suggest the close proximity of a tumour suppressor.},
journal = {British journal of cancer},
volume = {74},
number = {6},
pages = {863-870},
pmid = {8826850},
issn = {0007-0920},
support = {HG00100/HG/NHGRI NIH HHS/United States ; },
mesh = {Breast Neoplasms/*genetics ; *Chromosome Deletion ; *Chromosomes, Human, Pair 17 ; Female ; Genes, Tumor Suppressor ; Humans ; Polymorphism, Restriction Fragment Length ; *Telomere ; },
abstract = {High levels of loss of distal markers on 17p13.3 in breast cancer suggested the presence within the region of at least one tumour-suppressor gene. Here we describe the derivation of two biallelic polymorphisms from the 17p telomeric yeast artificial chromosome (YAC) TYAC98. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and multiplex PCR analysis demonstrated that the high level of allelic imbalance observed in breast tumours represented loss of constitutional heterozygosity (LOH) and that this LOH extended to the telomere. Lung carcinoma (but not Wilms' tumour)-derived DNA again revealed a high level of loss of subtelomeric 17p sequences. Telomeric microsatellite polymorphisms from other chromosome arms did not show such elevated loss in either tumour type. This suggested that the 17p loss observed did not reflect a general telomeric instability and provided further evidence for the presence of a breast cancer tumour-suppressor gene in the distal region of 17p13.3.},
}
@article {pmid8816928,
year = {1996},
author = {Small, MB and Hubbard, K and Pardinas, JR and Marcus, AM and Dhanaraj, SN and Sethi, KA},
title = {Maintenance of telomeres in SV40-transformed pre-immortal and immortal human fibroblasts.},
journal = {Journal of cellular physiology},
volume = {168},
number = {3},
pages = {727-736},
doi = {10.1002/(SICI)1097-4652(199609)168:3&lt;727::AID-JCP26&gt;3.0.CO;2-U},
pmid = {8816928},
issn = {0021-9541},
support = {AG 00378/AG/NIA NIH HHS/United States ; AG 04821/AG/NIA NIH HHS/United States ; CA 53136/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; Cell Transformation, Neoplastic/*ultrastructure ; *Cell Transformation, Viral ; Fibroblasts/cytology ; Humans ; Molecular Sequence Data ; Oligonucleotide Probes/chemistry ; Simian virus 40 ; Telomerase/metabolism ; Telomere/*ultrastructure ; },
abstract = {Shortening of telomeres has been hypothesized to contribute to cellular senescence and may play a role in carcinogenesis of human cells. Furthermore, activation of telomerase has frequently been demonstrated in tumor-derived and in vitro immortalized cells. In this study, we have assessed these phenomena during the life span of simian virus 40 (SV40)-transformed preimmortal and immortal human fibroblasts. We observed progressive reduction in telomere length in preimmortal transformed cells with extended proliferative capacity, with the most dramatic shortening at late passage. Telomere lengths became stabilized (or increased) in immortal fibroblasts accompanied, in one case, by the activation of telomerase. However, an independent immortal cell line that displayed stable telomeres did not have detectable telomerase activity. Furthermore, we found significant telomerase activity in two preimmortal derivatives. Our results provide further evidence for maintenance of telomeres in immortalized human fibroblasts, but they suggest a lack of causal relationship between telomerase activation and immortalization.},
}
@article {pmid8794855,
year = {1996},
author = {Scherthan, H and Weich, S and Schwegler, H and Heyting, C and Härle, M and Cremer, T},
title = {Centromere and telomere movements during early meiotic prophase of mouse and man are associated with the onset of chromosome pairing.},
journal = {The Journal of cell biology},
volume = {134},
number = {5},
pages = {1109-1125},
pmid = {8794855},
issn = {0021-9525},
mesh = {Animals ; Cell Nucleus/physiology ; Centromere/*physiology ; Chromosomes/physiology ; Chromosomes, Human, Pair 1/physiology ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Meiosis/*physiology ; Mice ; Mice, Inbred BALB C ; Movement ; Nuclear Envelope/physiology ; Prophase/*physiology ; Spermatogonia/physiology ; Staining and Labeling ; Synaptonemal Complex/physiology ; Telomere/*physiology ; Testis/cytology/physiology ; },
abstract = {The preconditions and early steps of meiotic chromosome pairing were studied by fluorescence in situ hybridization (FISH) with chromosome-specific DNA probes to mouse and human testis tissue sections. Premeiotic pairing of homologous chromosomes was not detected in spermatogonia of the two species. FISH with centromere- and telomere-specific DNA probes in combination with immunostaining (IS) of synaptonemal complex (SC) proteins to testis sections of prepuberal mice at days 4-12 post partum was performed to study sequentially the meiotic pairing process. Movements of centromeres and then telomeres to the nuclear envelope, and of telomeres along the nuclear envelope leading to the formation of a chromosomal bouquet were detected during mouse prophase. At the bouquet stage, pairing of a mouse chromosome-8-specific probe was observed. SC-IS and simultaneous telomere FISH revealed that axial element proteins appear as large aggregates in mouse meiocytes when telomeres are attached to the nuclear envelope. Axial element formation initiates during tight telomere clustering and transverse filament-IS indicated the initiation of synapsis during this stage. Comparison of telomere and centromere distribution patterns of mouse and human meiocytes revealed movements of centromeres and then telomeres to the nuclear envelope and subsequent bouquet formation as conserved motifs of the pairing process. Chromosome painting in human spermatogonia revealed compacted, largely mutually exclusive chromosome territories. The territories developed into long, thin threads at the onset of meiotic prophase. Based on these results a unified model of the pairing process is proposed.},
}
@article {pmid8756617,
year = {1996},
author = {Adams, AK and Holm, C},
title = {Specific DNA replication mutations affect telomere length in Saccharomyces cerevisiae.},
journal = {Molecular and cellular biology},
volume = {16},
number = {9},
pages = {4614-4620},
pmid = {8756617},
issn = {0270-7306},
support = {GM36510/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; Cell Cycle Proteins/*genetics ; Chromosomes, Fungal/*ultrastructure ; DNA Polymerase II/*genetics ; DNA Replication/*genetics ; DNA, Fungal/biosynthesis/*genetics ; Flow Cytometry ; Fungal Proteins/*genetics/physiology ; Genes, Fungal ; *Mutation ; Replication Protein C ; Saccharomyces cerevisiae/*genetics/ultrastructure ; *Saccharomyces cerevisiae Proteins ; Telomerase/physiology ; Telomere/*ultrastructure ; },
abstract = {To investigate the relationship between the DNA replication apparatus and the control of telomere length, we examined the effects of several DNA replication mutations on telomere length in Saccharomyces cerevisiae. We report that a mutation in the structural gene for the large subunit of DNA replication factor C (cdc44/rfc1) causes striking increases in telomere length. A similar effect is seen with mutations in only one other DNA replication gene: the structural gene for DNA polymerase alpha (cdc17/pol1) (M.J. Carson and L. Hartwell, Cell 42:249-257, 1985). For both genes, the telomere elongation phenotype is allele specific and appears to correlate with the penetrance of the mutations. Furthermore, fluorescence-activated cell sorter analysis reveals that those alleles that cause elongation also exhibit a slowing of DNA replication. To determine whether elongation is mediated by telomerase or by slippage of the DNA polymerase, we created cdc17-1 mutants carrying deletions of the gene encoding the RNA component of telomerase (TLC1). cdc17-1 strains that would normally undergo telomere elongation failed to do so in the absence of telomerase activity. This result implies that telomere elongation in cdc17-1 mutants is mediated by the action of telomerase. Since DNA replication involves transfer of the nascent strand from polymerase alpha to replication factor C (T. Tsurimoto and B. Stillman, J. Biol. Chem. 266:1950-1960, 1991; T. Tsurimoto and B. Stillman, J. Biol. Chem. 266:1961-1968, 1991; S. Waga and B. Stillman, Nature [London] 369:207-212, 1994), one possibility is that this step affects the regulation of telomere length.},
}
@article {pmid8707303,
year = {1996},
author = {Boutouil, M and Fetni, R and Qu, J and Dallaire, L and Richer, CL and Lemieux, N},
title = {Fragile site and interstitial telomere repeat sequences at the fusion point of a de novo (Y;13) translocation.},
journal = {Human genetics},
volume = {98},
number = {3},
pages = {323-327},
doi = {10.1007/s004390050216},
pmid = {8707303},
issn = {0340-6717},
mesh = {Adolescent ; Chromosome Fragile Sites ; *Chromosome Fragility ; *Chromosomes, Human, Pair 13 ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Repetitive Sequences, Nucleic Acid ; *Telomere ; *Translocation, Genetic ; *Y Chromosome ; },
abstract = {We describe a novel fragile site in a rearranged chromosome, associated with the presence of telomeric repeat sequences at the fusion point of a translocation between chromosomes 13 and Y. The case reported in this study shows a de novo (Y;13) translocation, which appears to represent fusion of an apparently intact chromosome Y with a chromosome 13 that has lost only part of its short arm. Ten percent of the cells show a normal karyotype without the (Y;13) translocation. Molecular cytogenetic studies of the derived Y;13 chromosome revealed three hybridization sites of the telomeric probes-one at each end and one at the breakpoint junction. A fragile site is also observed in the intrachromosomic telomeric region. This coincidence suggests that the telomere repeat sequences (TTAGGG)n, when present at an interstitial chromosomal location, can promote the formation of a novel fragile site.},
}
@article {pmid8757183,
year = {1996},
author = {Morin, GB},
title = {Telomere integrity and cancer.},
journal = {Journal of the National Cancer Institute},
volume = {88},
number = {16},
pages = {1095-1096},
doi = {10.1093/jnci/88.16.1095},
pmid = {8757183},
issn = {0027-8874},
mesh = {Animals ; Humans ; Retinoblastoma/*enzymology ; Telomerase/*metabolism ; *Telomere ; },
}
@article {pmid8702494,
year = {1996},
author = {Bedoyan, JK and Lejnine, S and Makarov, VL and Langmore, JP},
title = {Condensation of rat telomere-specific nucleosomal arrays containing unusually short DNA repeats and histone H1.},
journal = {The Journal of biological chemistry},
volume = {271},
number = {31},
pages = {18485-18493},
doi = {10.1074/jbc.271.31.18485},
pmid = {8702494},
issn = {0021-9258},
support = {5T32GM07315/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Chromatin/chemistry/genetics/metabolism ; DNA/genetics/metabolism ; Endodeoxyribonucleases ; Histones/*metabolism ; Liver/metabolism ; Molecular Weight ; Nucleosomes/chemistry/*genetics/*metabolism ; Rats ; *Repetitive Sequences, Nucleic Acid ; Solubility ; Telomere/chemistry/*genetics/*metabolism ; },
abstract = {Vertebrate telomeres contain arrays of nucleosomes with unusually short and regular repeat lengths (Makarov, V. L., Lejnine, S., Bedoyan, J., and Langmore, J. P.(1993) Cell 73, 775-787; Lejnine, S., Makarov, V., and Langmore, J. P. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 2393-2397). In order to better define the specific structural features of telomere chromatin, we examined the condensation and H1 content of telomere nucleoproteins from rat liver. Velocity sedimentation analysis shows that telomeric nucleosome arrays condense with increasing ionic strength and molecular weight in a manner comparable with that of bulk chromatin despite the very short repeat length. However, these condensed structures do not exhibit the approximately 100-base pair deoxyribonuclease II repeat characteristic of condensed bulk chromatin. Frictional coefficient calculations suggest that telomere-specific higher order structure is more compact than bulk chromatin. Nucleoprotein gel electrophoresis shows that telomeric dinucleosomes from soluble chromatin contain H1. Finally, direct isolation and analysis of telomere nucleoproteins from formaldehyde-cross-linked nuclei indicate the presence of core histone proteins and H1. These results are consistent with the view that a major fraction of the long telomeres of rat are organized as specialized nucleosome arrays with features similar but not identical to those of bulk chromatin.},
}
@article {pmid9275471,
year = {1996},
author = {Liu, J and Li, H and Luo, Y},
title = {[Analysis of telomere restriction fragments in human astrocytomas and glioblastomas].},
journal = {Zhonghua yi xue za zhi},
volume = {76},
number = {8},
pages = {588-590},
pmid = {9275471},
issn = {0376-2491},
mesh = {Astrocytoma/*genetics ; Blotting, Southern ; Brain Neoplasms/*genetics ; Glioblastoma/*genetics ; Humans ; Polymorphism, Restriction Fragment Length ; Telomere/*genetics ; },
abstract = {OBJECTIVES: To analyse the length of telomere restriction fragments (TRF) in different type of human astrocytomas as well as normal brain tissues and to evaluate the correlation of telomere status and tumor progression.<br><br>METHODS: DNAs extracted from normal and tumor samples were studied with Southern blot analysis, using (TTAGGG)4 probe specific for human telomeric sequences.<br><br>RESULTS: The lower portion of TRFs of astrocytoma type I, II and III was shortened gradually in comparison with that of normal brain tissues: both uper and lower portions of TRFs in 12 cases of glioblastoma multiformes studied were lost distinctively. However, no obvious length difference of TRFs could be detected between primary and recurrent glioblastomas.<br><br>CONCLUSIONS: Telomere reduction is one of the important genetic events during transformation of astrocytomas. Telomere repair mechanism may be initiated in glioblastoma cells which may, therefore, maintain a relative stabitity of TRFs and permit a constitutive proliferation of those malignant cells.},
}
@article {pmid8854566,
year = {1996},
author = {Yamada, O},
title = {Telomeres and telomerase in human hematologic neoplasia.},
journal = {International journal of hematology},
volume = {64},
number = {2},
pages = {87-99},
doi = {10.1016/0925-5710(96)00473-2},
pmid = {8854566},
issn = {0925-5710},
mesh = {Animals ; Base Sequence ; Blood Cells/ultrastructure ; Cell Transformation, Neoplastic/*genetics ; Cellular Senescence/genetics ; Chromosomes, Human/genetics/*ultrastructure ; DNA Replication ; DNA-Binding Proteins/physiology ; Eukaryotic Cells/physiology/ultrastructure ; Hematologic Neoplasms/enzymology/*genetics ; Hematopoietic Stem Cells/ultrastructure ; Humans ; Leukemia/enzymology/etiology/genetics/pathology ; Neoplasm Proteins/*physiology ; Neoplastic Stem Cells/ultrastructure ; RNA/genetics/physiology ; Repetitive Sequences, Nucleic Acid ; Telomerase/*physiology ; *Telomere/physiology/ultrastructure ; Templates, Genetic ; },
abstract = {Telomeres are the physical ends of eukaryotic chromosomes. Telomeric DNA sequences are highly conserved in all well-characterized eukaryotic nuclear chromosomes and differ greatly from the termini of linear viral, extranuclear plasmid, or mitochondrial DNA. Human telomeric DNA consists of 2-15 kb of a tandemly repeated sequence (TTAGGG)n, oriented 5'-3' toward the end of the chromosome. The evolutionary conservation of this repetitive DNA sequence implies that the sequence is essential to cellular function. These repeated sequences are synthesized by an RNA-dependent DNA polymerase, telomerase, which is composed of an essential RNA and a few proteins. Human telomerase has been proposed to be repressed in somatic tissues, and human telomeres become shorter during somatic development and with increasing age. Telomeres in tumors are even shorter, and loss of telomeric DNA during tumorigenesis may contribute to the genome instability associated with transformed cells. This article reviews the structure and function of telomeres and the recent studies on human hematologic cells.},
}
@article {pmid8776867,
year = {1996},
author = {Kapila, R and Das, S and Srivastava, PS and Lakshmikumaran, M},
title = {A novel species-specific tandem repeat DNA family from Sinapis arvensis: detection of telomere-like sequences.},
journal = {Genome},
volume = {39},
number = {4},
pages = {758-766},
doi = {10.1139/g96-095},
pmid = {8776867},
issn = {0831-2796},
mesh = {Base Sequence ; Brassica/*genetics ; In Situ Hybridization ; Minisatellite Repeats/*genetics ; Molecular Sequence Data ; Phylogeny ; Restriction Mapping ; Sequence Analysis, DNA ; Species Specificity ; Telomere/*genetics ; },
abstract = {DNA sequences representing a tandemly repeated DNA family of the Sinapis arvensis genome were cloned and characterized. The 700-bp tandem repeat family is represented by two clones, pSA35 and pSA52, which are 697 and 709 bp in length, respectively. Dot matrix analysis of the sequences indicates the presence of repeated elements within each monomeric unit. Sequence analysis of the repetitive region of clones pSA35 and pSA52 shows that there are several copies of a 7-bp repeat element organized in tandem. The consensus sequence of this repeat element is 5'-TTTAGGG-3'. These elements are highly mutated and the difference in length between the two clones is due to different copy numbers of these elements. The repetitive region of clone pSA35 has 26 copies of the element TTTAGGG, whereas clone pSA52 has 28 copies. The repetitive region in both clones is flanked on either side by inverted repeats that may be footprints of a transposition event. Sequence comparison indicates that the element TTTAGGG is identical to telomeric repeats present in Arabidopsis, maize, tomato, and other plants. However, Bal31 digestion kinetics indicates non-telomeric localization of the 700-bp tandem repeats. The clones represent a novel repeat family as (i) they contain telomere-like motifs as subrepeats within each unit; and (ii) they do not hybridize to related crucifers and are species-specific in nature.},
}
@article {pmid8776865,
year = {1996},
author = {Gardiner, JM and Coe, EH and Chao, S},
title = {Cloning maize telomeres by complementation in Saccharomyces cerevisiae.},
journal = {Genome},
volume = {39},
number = {4},
pages = {736-748},
doi = {10.1139/g96-093},
pmid = {8776865},
issn = {0831-2796},
mesh = {Base Sequence ; Chromosome Mapping ; Chromosomes, Artificial, Yeast ; Cloning, Molecular/*methods ; Genetic Complementation Test ; Molecular Sequence Data ; Polymorphism, Restriction Fragment Length ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*genetics ; Sequence Analysis, DNA ; Telomere/*genetics ; Zea mays/*genetics ; },
abstract = {Maize telomeric restriction fragments were cloned by virtue of their ability to function as telomeres on a linear plasmid in Saccharomyces cerevisiae. Nine maize telomeric YAC transformants (MTYs) were selected by hybridization to the Arabidopsis telomere repeat (CCCTAAA) from a pool of 1537 primary transformants. Bal31 digestion of MTY3 and MTY9 DNA indicated that the telomere hybridizing tracts are located at the terminus of the linear chromosome and therefore function as telomeres in yeast. Subclones generated for pMTY7 (pMTY7SC1) and pMTY9 (pMTY9ER) hybridized to Bal31 sensitive restriction fragments in maize DNA, indicating that maize telomeric restriction fragments had been cloned. Both pMTY7SC and pMTY9ER detected telomeric RFLPs, allowing the endpoints of seven chromosome arms to be determined. Additionally, pMTY7ER mapped to the centromeric regions of chromosomes 2 and 3, suggesting a relationship between centromeric and telomeric sequences. DNA sequencing of pMTY7SC and pMTY9ER revealed that both subclones contained CA-rich regions with sporadic occurrences of the telomere repeat and its degenerate repeats.},
}
@article {pmid8761184,
year = {1996},
author = {Artlett, CM and Black, CM and Briggs, DC and Stevens, CO and Welsh, KI},
title = {Telomere reduction in scleroderma patients: a possible cause for chromosomal instability.},
journal = {British journal of rheumatology},
volume = {35},
number = {8},
pages = {732-737},
doi = {10.1093/rheumatology/35.8.732},
pmid = {8761184},
issn = {0263-7103},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Chromosome Aberrations/*genetics ; Chromosome Disorders ; Fibroblasts ; Humans ; Lymphocytes ; Middle Aged ; Scleroderma, Systemic/*genetics ; Skin/pathology ; Telomere/*genetics ; },
abstract = {We have hypothesized that the chromosomal instability observed in scleroderma patients and their family members may result from the loss of long stretches of the telomeric repeat which is found at the ends of all linear chromosomes. We examined the telomere lengths in scleroderma (SSc) patients (n = 43), their family members (n = 182) and in age-matched controls (n = 96) using restriction fragment length polymorphism (RFLP) and chemiluminescent labelled probes. The average loss of telomeric DNA in SSc patients and family members was found to be 3 kb when compared to the controls. This loss was not related to age or the duration of the disease. These results may reflect a genetic predisposition for chromosomal instability in these families, or exposure to a common environmental agent. A wide variety of common environmental agents are known to produce chromosomal aberrations: these include fungicides, pesticides, air pollutants and drugs. Scleroderma-like syndromes may be induced by some of these agents.},
}
@article {pmid8754829,
year = {1996},
author = {Chi, MH and Shore, D},
title = {SUM1-1, a dominant suppressor of SIR mutations in Saccharomyces cerevisiae, increases transcriptional silencing at telomeres and HM mating-type loci and decreases chromosome stability.},
journal = {Molecular and cellular biology},
volume = {16},
number = {8},
pages = {4281-4294},
pmid = {8754829},
issn = {0270-7306},
support = {GM40094/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Base Sequence ; Chromosomes/ultrastructure ; Cloning, Molecular ; Fungal Proteins/*genetics ; *Gene Expression Regulation, Fungal ; Genes, Dominant ; Genes, Fungal ; Genes, Suppressor ; Membrane Proteins/*physiology ; Molecular Sequence Data ; Nuclear Proteins/*genetics/*physiology ; RNA, Messenger/genetics ; Repressor Proteins ; Restriction Mapping ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; Telomere/*physiology ; Transcription, Genetic ; },
abstract = {Transcriptional silencing in the yeast Saccharomyces cerevisiae occurs at HML and HMR mating-type loci and telomeres and requires the products of the silent information regulator (SIR) genes. Recent evidence suggests that the silencer- and telomere-binding protein Rap1p initiates silencing by recruiting a complex of Sir proteins to the chromosome, where they act in some way to modify chromatin structure or accessibility. A single allele of the SUM1gene (SUM1-1) which restores silencing at HM loci in strains mutant for any of the four SIR genes was identified a number of years ago. However, conflicting genetic results and the lack of other alleles of SUM1 made it difficult to surmise the wild-type function of SUM1 or the manner in which the SUM1-1 mutation restores silencing in sir mutant strains. Here we report the cloning and characterization of the SUM1 gene and the SUM1-1 mutant allele. Our results indicate that SUM1-1 is an unusual altered-function mutation that can bypass the need for SIR function in HM silencing and increase repression at telomeres. A sum1 deletion mutation has only minor effects on silencing in SIR strains and does not restore silencing in sir mutants. In addition to its effect on transcriptional silencing, the SUM1-1 mutation (but not a sum1 deletion) increases the rate of chromosome loss and cell death. We suggest several speculative models for the action of SUM1-1 in silencing based on these and other data.},
}
@article {pmid8753697,
year = {1996},
author = {Skopp, R and Wang, W and Price, C},
title = {rTP: a candidate telomere protein that is associated with DNA replication.},
journal = {Chromosoma},
volume = {105},
number = {2},
pages = {82-91},
pmid = {8753697},
issn = {0009-5915},
support = {GM41803/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; *DNA Replication ; DNA, Protozoan/biosynthesis ; DNA-Binding Proteins/chemistry/genetics/*isolation &amp; purification ; Electrophoresis, Polyacrylamide Gel ; Euplotes/genetics ; Fluorescent Antibody Technique, Indirect ; Molecular Sequence Data ; Molecular Weight ; Protozoan Proteins/chemistry/genetics/*isolation &amp; purification ; RNA, Protozoan/analysis ; *Telomere/chemistry ; Transcription, Genetic ; },
abstract = {In this paper we describe the isolation and characterization of rTP, the replication Telomere Protein, formerly known as the telomere protein homolog. The rTP was initially identified because of its homology to the gene for the Oxytricha telomere-binding protein alpha-subunit. The protein encoded by the rTP gene has extensive amino acid sequence identity to the DNA-binding domain of the telomere-binding proteins from both Euplotes crassus and Oxytricha nova. We have now identified the protein encoded by the rTP gene and have shown that it differs from the telomere-binding protein in its abundance, solubility and intracellular location. To learn more about the function of rTP, we determined when during the Euplotes life cycle the gene is transcribed. The transcript was detectable only in nonstarved vegetative cells and during the final stages of macronuclear development. Since the peak transcript level coincided with the rounds of replication that take place toward the end of macronuclear development, it appeared that rTP might be involved in DNA replication. Immunolocalization experiments provided support for this hypothesis as antibodies to rTP specifically stain the replication bands. Replication bands are the sites of DNA replication in Euplotes macronuclei. Our results suggest that rTP may be a new telomere replication factor.},
}
@article {pmid8709628,
year = {1996},
author = {Shay, JW and Werbin, H and Wright, WE},
title = {Telomeres and telomerase in human leukemias.},
journal = {Leukemia},
volume = {10},
number = {8},
pages = {1255-1261},
pmid = {8709628},
issn = {0887-6924},
support = {AG07992/AG/NIA NIH HHS/United States ; },
mesh = {Base Sequence ; Centromere ; Hematopoietic Stem Cells/enzymology ; Humans ; Leukemia/*enzymology/*genetics/physiopathology/prevention &amp; control ; Molecular Sequence Data ; Prognosis ; Repetitive Sequences, Nucleic Acid ; Telomerase/*metabolism ; *Telomere ; },
abstract = {There is increasing evidence supporting the hypothesis that telomere shortening both in vitro and in vivo, is the clock that counts cell divisions and determines the onset of cellular senescence. Cells that overcome the normal senescence mechanisms do so by stabilizing telomere length, probably due to the activity of telomerase, a ribonucleoprotein enzyme that synthesizes telomeric repeats. Most human primary tumors contain telomerase, while the cells of most normal tissues lack this activity. A hypothesis gaining prominence is that the activation of telomerase is necessary for the sustained growth of most solid tumors. Since normal hematopoietic stem cells and some of their progeny already express telomerase activity, it is important to consider whether or not telomere shortening and telomerase activity play any role in cancer progression in various forms of leukemia. This review includes a discussion of the utility of telomere length and/or telomerase activity measurements in the diagnosis and prognosis of leukemia as well as the potential value of antitelomerase therapy for the leukemias.},
}
@article {pmid8819105,
year = {1996},
author = {Kormann-Bortolotto, MH and Borsatto, B and Smith, M},
title = {Telomere shortening, ageing, and chromosome damage.},
journal = {Mechanisms of ageing and development},
volume = {89},
number = {1},
pages = {45-49},
doi = {10.1016/0047-6374(96)01742-3},
pmid = {8819105},
issn = {0047-6374},
mesh = {Aging/*genetics ; Alzheimer Disease/*genetics ; Case-Control Studies ; Chromosome Aberrations/*genetics ; Chromosome Disorders ; Down Syndrome/*genetics ; Humans ; Telomere/*ultrastructure ; },
abstract = {A relationship between telomere shortening and ageing has been established. A series of young and elderly healthy donors. Alzheimer disease patients, young and old Down's syndrome individuals were cytogenetically analyzed. No preferential damage in distal bands was seen in age-related chromosome instability.},
}
@article {pmid8709958,
year = {1996},
author = {Presting, GG and Frary, A and Pillen, K and Tanksley, SD},
title = {Telomere-homologous sequences occur near the centromeres of many tomato chromosomes.},
journal = {Molecular &amp; general genetics : MGG},
volume = {251},
number = {5},
pages = {526-531},
pmid = {8709958},
issn = {0026-8925},
mesh = {Arabidopsis/genetics ; Base Sequence ; Centromere/*genetics ; *Chromosome Mapping ; Genetic Markers ; Solanum lycopersicum/*genetics ; Molecular Sequence Data ; Polymorphism, Restriction Fragment Length ; Repetitive Sequences, Nucleic Acid/*genetics ; Sequence Analysis, DNA ; Sequence Homology, Nucleic Acid ; Telomere/*genetics ; },
abstract = {Several bacteriophage lambda clones containing interstitial telomere repeats (ITR) were isolated from a library of tomato genomic DNA by plaque hybridization with the cloned Arabidopsis thaliana telomere repeat. Restriction fragments lacking highly repetitive DNA were identified and used as probes to map 14 of the 20 lambda clones. All of these markers mapped near the centromere on eight of the twelve tomato chromosomes. The exact centromere location of chromosomes 7 and 9 has recently been determined, and all ITR clones that localize to these two chromosomes map to the marker clusters known to contain the centromere. High-resolution mapping of one of these markers showed cosegregation of the telomere repeat with the marker cluster closest to the centromere in over 9,000 meiotic products. We propose that the map location of interstitial telomere clones may reflect specific sequence interchanges between telomeric and centromeric regions and may provide an expedient means of localizing centromere positions.},
}
@article {pmid8702416,
year = {1996},
author = {Kruk, PA and Balajee, AS and Rao, KS and Bohr, VA},
title = {Telomere reduction and telomerase inactivation during neuronal cell differentiation.},
journal = {Biochemical and biophysical research communications},
volume = {224},
number = {2},
pages = {487-492},
doi = {10.1006/bbrc.1996.1054},
pmid = {8702416},
issn = {0006-291X},
mesh = {Base Sequence ; *Cell Differentiation ; Cell Line ; DNA Primers ; Humans ; Molecular Sequence Data ; Neurons/*cytology/enzymology ; Repetitive Sequences, Nucleic Acid ; Telomerase/antagonists &amp; inhibitors/*metabolism ; Telomere/*physiology ; Teratocarcinoma ; Tumor Cells, Cultured ; },
abstract = {Telomerase adds (TTAGGG)n hexanucleotide repeats to the ends of mammalian telomeres. This compensates for telomeric loss with successive rounds of cellular replication. Telomerase activity is detected in many neoplastic cells, but not in most normal somatic cells. To determine whether telomeric length and telomerase activity are associated with cellular differentiation, we measured telomeric lengths and telomerase activity in embryonic NT2 precursor cells prior to and following differentiation into post mitotic hNT neurons. This system allows for studies in a direct neuronal cell lineage and, thus, provides a unique model for studying the role of neuronal telomerase activity. Our results show that telomerase activity was present in precursor cells, but not in neuronal cells. Telomeres were consistently longer in NT2 cells than in hNT cells. These results suggest that changes in telomeric length and loss of telomerase activity play a role in neuronal cellular differentiation.},
}
@article {pmid8698241,
year = {1996},
author = {McEachern, MJ and Blackburn, EH},
title = {Cap-prevented recombination between terminal telomeric repeat arrays (telomere CPR) maintains telomeres in Kluyveromyces lactis lacking telomerase.},
journal = {Genes &amp; development},
volume = {10},
number = {14},
pages = {1822-1834},
doi = {10.1101/gad.10.14.1822},
pmid = {8698241},
issn = {0890-9369},
support = {GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA, Fungal/genetics ; Gene Deletion ; Genes, Fungal ; Kluyveromyces/*enzymology/*genetics/growth &amp; development ; Models, Genetic ; RNA Caps/genetics ; RNA, Fungal/genetics ; *Recombination, Genetic ; Repetitive Sequences, Nucleic Acid ; Telomerase/*genetics ; Telomere/*genetics ; },
abstract = {Deletion of the telomerase RNA gene (TER1) in the yeast Kluyveromyces lactis results in gradual loss of telomeric repeats and progressively declining cell growth capability (growth senescence). We show that this initial growth senescence is characterized by abnormally large, defectively dividing cells and is delayed when cells initially contain elongated telomeres. However, cells that survive the initial catastrophic senescence emerge relatively frequently, and their subsequent growth without telomerase is surprisingly efficient. Survivors have lengthened telomeres, often much longer than wild type, but that are still subject to gradual shortening. Production of these postsenescence survivors is strongly dependent on the RAD52 gene. We propose that shortened, terminal telomeric repeat tracts become uncapped, promoting recombinational repair between them to regenerate lengthened telomeres in survivors. This process, which we term telomere cap-prevented recombination (CPR) may be a general alternative telomere maintenance pathway in eukaryotes.},
}
@article {pmid8698239,
year = {1996},
author = {Maillet, L and Boscheron, C and Gotta, M and Marcand, S and Gilson, E and Gasser, SM},
title = {Evidence for silencing compartments within the yeast nucleus: a role for telomere proximity and Sir protein concentration in silencer-mediated repression.},
journal = {Genes &amp; development},
volume = {10},
number = {14},
pages = {1796-1811},
doi = {10.1101/gad.10.14.1796},
pmid = {8698239},
issn = {0890-9369},
mesh = {Base Sequence ; Cell Nucleus/*metabolism ; Chromosomes, Fungal/genetics/metabolism ; DNA Primers/genetics ; Fungal Proteins/genetics/*metabolism ; Genes, Fungal ; Genes, Mating Type, Fungal ; Genes, Regulator ; Molecular Sequence Data ; Saccharomyces cerevisiae/*genetics/*metabolism ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Telomere/genetics/*metabolism ; Trans-Activators/genetics/metabolism ; },
abstract = {Transcriptional repression at the silent mating-type loci in yeast requires the targeting of silent information regulator (Sir) proteins through specific interactions formed at cis-acting silencer elements. We show here that a reporter gene flanked by two functional silencers is not repressed when integrated at >200 kb from a telomere. Repression is restored by creation of a new telomere 13 kb from the integrated reporter or by elevated expression of SIR1, SIR3, and/or SIR4. Coupled expression represses in an additive manner, suggesting that all three factors are in limiting concentrations. When overexpressed, Sir3 and Sir4 are dispersed throughout the nucleoplasm, in contrast to wild-type cells where they are clustered in a limited number of foci together with telomeres. Efficient silencer function thus seems to require either proximity to a pool of concentrated Sir proteins, that is, proximity to telomeres, or delocalization of the silencing factors.},
}
@article {pmid8661149,
year = {1996},
author = {Russell, MW and Munroe, DJ and Bric, E and Housman, DE and Dietz-Band, J and Riethman, HC and Collins, FS and Brody, LC},
title = {A 500-kb physical map and contig from the Harvey ras-1 gene to the 11p telomere.},
journal = {Genomics},
volume = {35},
number = {2},
pages = {353-360},
doi = {10.1006/geno.1996.0367},
pmid = {8661149},
issn = {0888-7543},
mesh = {Base Sequence ; Chromosome Mapping ; Chromosomes, Artificial, Yeast ; *Chromosomes, Human, Pair 11 ; Dinucleotide Repeats ; *Genes, ras ; Genetic Carrier Screening ; Genetic Markers ; Humans ; Molecular Sequence Data ; Polymorphism, Genetic ; Random Amplified Polymorphic DNA Technique ; *Telomere ; },
abstract = {A contiguous physical map was constructed from the Harvey ras-1 (HRAS1) gene to the 11p telomere. The contig spans approximately 500 kb and is minimally composed of a telomere-containing YAC and P1 and cosmid clones. Included in the contig are 11 sequence-tagged sites derived from P1 and cosmid ends. Three genes were placed on the contig in the following order: telomere-ribonuclease/angiogenin inhibitor (RNH)-Harvey ras-1 (HRAS1)-HRAS1-related complex (HRC). Two novel tetranucleotide repeats (heterozygosity of 66 and 68%) and a complex CA repeat (heterozygosity of 78%) were isolated and characterized.},
}
@article {pmid8818722,
year = {1996},
author = {Decary, S and Mouly, V and Butler-Browne, GS},
title = {Telomere length as a tool to monitor satellite cell amplification for cell-mediated gene therapy.},
journal = {Human gene therapy},
volume = {7},
number = {11},
pages = {1347-1350},
doi = {10.1089/hum.1996.7.11-1347},
pmid = {8818722},
issn = {1043-0342},
mesh = {Adult ; Aged ; Cell Division ; Cells, Cultured ; DNA/*analysis ; Genetic Therapy ; Humans ; Infant ; Middle Aged ; Muscle, Skeletal/cytology/*metabolism ; *Telomere ; },
abstract = {Cell-mediated gene therapy requires an in vitro amplification of modified cells prior to their injection into target tissue. Since the proliferative capacity of normal human cells is limited, we have tested a method to follow in vitro the proliferative potential of human satellite cells. Our results show that telomere length can be used to predict the proliferative potential of human satellite cells. In this short communication, the telomere shortening and the limited replicative potential are discussed in the context of the possible use of human satellite cells for gene transfer and why cell-mediated gene therapy has been less successful in humans than in mice.},
}
@article {pmid8692956,
year = {1996},
author = {Heller, R and Brown, KE and Burgtorf, C and Brown, WR},
title = {Mini-chromosomes derived from the human Y chromosome by telomere directed chromosome breakage.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {93},
number = {14},
pages = {7125-7130},
pmid = {8692956},
issn = {0027-8424},
mesh = {Animals ; CHO Cells ; Carboxy-Lyases/biosynthesis/genetics ; Cell Division ; Cells, Cultured ; *Chromosome Aberrations ; Chromosome Mapping ; Cricetinae ; Genes, Fungal ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Mitosis ; Plasmids ; Saccharomyces cerevisiae/genetics ; Sequence Tagged Sites ; *Telomere ; Transfection ; *Y Chromosome ; },
abstract = {We have used telomeric DNA to break two acrocentric derivatives of the human Y chromosome into mini-chromosomes that are small enough to be size- fractionated by pulsed-field gel electrophoresis. One of the mini-chromosomes is about 7 Mb in size and sequence-tagged site analysis of this molecule suggests that it corresponds to a simple truncation of the short arm of the Y chromosome. Five of the mini-chromosomes are derived from the long arm, are all rearranged by more than a simple truncation, and range in size from 4.0 Mb to 9 Mb. We have studied the mitotic stabilities of these mini-chromosomes and shown that they are stably maintained by cells proliferating in culture for about 100 cell divisions.},
}
@article {pmid9631006,
year = {1996},
author = {Holt, SE and Shay, JW and Wright, WE},
title = {Refining the telomere-telomerase hypothesis of aging and cancer.},
journal = {Nature biotechnology},
volume = {14},
number = {7},
pages = {836-839},
doi = {10.1038/nbt0796-836},
pmid = {9631006},
issn = {1087-0156},
support = {AG05747-01/AG/NIA NIH HHS/United States ; AG07992/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*genetics/metabolism ; Cell Transformation, Neoplastic ; Enzyme Inhibitors/therapeutic use ; Humans ; Lymphocytes/enzymology ; Neoplasms/drug therapy/enzymology/*genetics ; Stem Cells/enzymology ; Telomerase/*metabolism ; *Telomere ; },
abstract = {While there has been substantial experimental evidence in support of the telomere-telomerase hypothesis of aging and cancer, it has been suggested that the theory has been oversimplified to the exclusion of alternative mechanisms in the progression of cancer. This review strives to present an overview of some of the areas that have not been well explained and to indicate where multiple interpretations of the data are possible.},
}
@article {pmid9415101,
year = {1996},
author = {Olovnikov, AM},
title = {Telomeres, telomerase, and aging: origin of the theory.},
journal = {Experimental gerontology},
volume = {31},
number = {4},
pages = {443-448},
doi = {10.1016/0531-5565(96)00005-8},
pmid = {9415101},
issn = {0531-5565},
mesh = {*Aging ; Animals ; DNA Replication ; Humans ; Telomerase/*physiology ; *Telomere ; },
abstract = {In 1971 I published a theory in which I first formulated the DNA end replication problem and explained how it could be solved. The solution to this problem also provided an explanation for the Hayflick Limit, which underpins the discovery of in vitro and in vivo cell senescence. I proposed that the length of telomeric DNA, located at the ends of chromosomes consists of repeated sequences, which play a buffer role and should diminish in dividing normal somatic cells at each cell doubling. I also proposed that the loss of sequences containing important information that could occur after buffer loss could cause the onset of cellular senescence. I also suggested that for germline cells and for the cells of vegetatively propagated organisms and immortal cell populations like most cancer cell lines, an enzyme might be activated that would prevent the diminution of DNA termini at each cell division, thus protecting the information containing part of the genome. In the last few years, most of my suggestions have been authenticated by laboratory evidence. the DNA sequences that shorten in dividing normal cells are telomeres and the enzyme that maintains telomere length constant in immortal cell populations is telomerase.},
}
@article {pmid8950133,
year = {1996},
author = {Balasubramanian, S and Singh, N},
title = {The role of telomeres and telomerase in human cancer.},
journal = {Indian journal of physiology and pharmacology},
volume = {40},
number = {3},
pages = {199-204},
pmid = {8950133},
issn = {0019-5499},
mesh = {Humans ; Neoplasms/*etiology/genetics ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {Human cancers/malignant transformation of normal cells occur from multiple independent genetic changes/mutations that can subvert the normal growth controls of cells, leading to distinct phenotypic changes and immortalization. Normal human somatic cells have limited proliferative capacity both in vitro and in vivo and undergo senescence. Recent studies have implicated telomeres and telomerase in the regulation of lifespan of cells. Telomeres are the stretches of DNA consisting of tandem repeats of nucleotide sequences that cap chromosomes and prevent its degradation and play a role, both in normal control of cell proliferation and abnormal growth of cancers. They are highly conserved during evolution. Telomerase, the novel reverse transcriptase enzyme that synthesizes telomeric DNA is repressed in most human somatic cells, it results in telomere shortening with each cell division, leading to a process thought to contribute to senescence. Recent research proposes that activation of telomerase is important for cells to proliferate indefinitely and that all human cancer cells require activation of this enzyme to maintain telomeric DNA, to overcome cellular senescence and to attain immortality. Thus telomeres and telomerase offer potential for diagnostics, cancer therapy as well as for understanding the process of aging.},
}
@article {pmid8828735,
year = {1996},
author = {Effros, RB and Allsopp, R and Chiu, CP and Hausner, MA and Hirji, K and Wang, L and Harley, CB and Villeponteau, B and West, MD and Giorgi, JV},
title = {Shortened telomeres in the expanded CD28-CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis.},
journal = {AIDS (London, England)},
volume = {10},
number = {8},
pages = {F17-22},
doi = {10.1097/00002030-199607000-00001},
pmid = {8828735},
issn = {0269-9370},
support = {AI-28697/AI/NIAID NIH HHS/United States ; AI-32883/AI/NIAID NIH HHS/United States ; AI-35040/AI/NIAID NIH HHS/United States ; },
mesh = {CD28 Antigens/*analysis ; CD8-Positive T-Lymphocytes/chemistry/cytology/*immunology ; Cell Division ; Cellular Senescence ; DNA/analysis ; HIV Infections/*immunology ; Humans ; Molecular Weight ; T-Lymphocyte Subsets/*immunology ; Telomere/chemistry/*genetics ; },
abstract = {OBJECTIVE: To test the hypothesis that the expanded population of non-proliferative CD28-CD8+ T cells in HIV disease have shortened telomeres, thereby providing evidence that increased rounds of CD8+ cell division occur during HIV disease, possibly leading to replicative senescence and exhaustion of CD8+ T-cell responses.<br><br>DESIGN: CD8+ cells play a central role in control of HIV infection. In late HIV disease, an expanded population of CD28-CD8+ cells with reduced proliferative potential has been documented. A similar population of CD28-CD8+ cells has been identified in ageing humans, where telomere length measurements have suggested that these cells have reached the irreversible state of replicative senescence.<br><br>METHODS: CD8+ cells from HIV-infected and control subjects were sorted by flow cytometry into CD28+ and CD28- fractions. Telomere lengths were determined as mean terminal restriction fragment (TRF) lengths by Southern hybridization.<br><br>RESULTS: The TRF lengths of sorted CD28-CD8+ cells in HIV-infected subjects ranged between 5 and 7 kilobases (kb) and were significantly shorter than TRF lengths of CD28-CD8+ cells in uninfected subjects (P = 0.003). The TRF length in CD28-CD8+ cells from HIV-infected subjects was the same as that observed for centenarian peripheral blood mononuclear cells and is compatible with a state of replicative senescence.<br><br>CONCLUSIONS: The shortened telomeres in the CD28-CD8+ cells in HIV-infected subjects and the poor proliferative potential of these cells identifies CD8+ cell replicative senescence as a newly described feature of HIV disease. Our results provide a mechanism for the loss of CD8+ cell control of viral replication that accompanies advanced HIV disease. Replicative senescence may contribute to exhaustion of the T-cell response as a result of chronic HIV disease. Whether this phenomenon occurs in other chronic viral infections is unknown.},
}
@article {pmid8698806,
year = {1996},
author = {Henderson, S and Allsopp, R and Spector, D and Wang, SS and Harley, C},
title = {In situ analysis of changes in telomere size during replicative aging and cell transformation.},
journal = {The Journal of cell biology},
volume = {134},
number = {1},
pages = {1-12},
pmid = {8698806},
issn = {0021-9525},
support = {AG-09383/AG/NIA NIH HHS/United States ; },
mesh = {Cell Division ; *Cell Transformation, Viral ; Cells, Cultured ; *Cellular Senescence ; Humans ; In Situ Hybridization, Fluorescence ; Simian virus 40 ; Telomere/*ultrastructure ; },
abstract = {Telomeres have been shown to gradually shorten during replicative aging in human somatic cells by Southern analysis. This study examines telomere shortening at the single cell level by fluorescence in situ hybridization (FISH). FISH and confocal microscopy of interphase human diploid fibroblasts (HDFs) demonstrate that telomeres are distributed throughout the nucleus with an interchromosomal heterogeneity in size. Analysis of HDFs at increasing population doubling levels shows a gradual decrease in spot size, intensity, and detectability of telomeric signal. FISH of metaphase chromosomes prepared from young and old HDFs shows a heterogeneity in detection frequency for telomeres on chromosomes 1, 9, 15, and Y. The interchromosomal distribution of detection frequencies was similar for cells at early and late passage. The telomeric detection frequency for metaphase chromosomes also decreased with age. These observations suggest that telomeres shorten at similar rates in normal human somatic cels. T-antigen transformed HDFs near crisis contained telomere signals that were low compared to nontransformed HDFs. A large intracellular heterogeneity in telomere lengths was detected in two telomerase-negative cell lines compared to normal somatic cells and the telomerase-positive 293 cell line. Many telomerase-negative immortal cells had telomeric signals stronger than those in young HDFs, suggesting a different mechanism for telomere length regulation in telomerase-negative immortal cells. These studies provide an in situ demonstration of interchromosomal heterogeneity in telomere lengths. Furthermore, FISH is a reliable and sensitive method for detecting changes in telomere size at the single cell level.},
}
@article {pmid8673136,
year = {1996},
author = {Metcalfe, JA and Parkhill, J and Campbell, L and Stacey, M and Biggs, P and Byrd, PJ and Taylor, AM},
title = {Accelerated telomere shortening in ataxia telangiectasia.},
journal = {Nature genetics},
volume = {13},
number = {3},
pages = {350-353},
doi = {10.1038/ng0796-350},
pmid = {8673136},
issn = {1061-4036},
mesh = {Adolescent ; Adult ; Age Factors ; Ataxia Telangiectasia/*genetics ; Base Sequence ; Child ; Chromosome Aberrations ; Clone Cells ; Humans ; Middle Aged ; Molecular Sequence Data ; Polymorphism, Restriction Fragment Length ; T-Lymphocytes/physiology ; Telomerase/metabolism ; Telomere/physiology/*ultrastructure ; },
abstract = {Ataxia telangiectasia (AT) is characterized by neurological deterioration, immunodeficiency, spontaneous chromosomal instability, hypersensitivity to ionizing radiation, predisposition to cancer, particularly T cell leukaemia and lymphoma, and premature ageing. The most commonly observed defect affecting telomeres in humans is telomeric fusions, particularly in T lymphocytes in AT patients. Rarely, some tumour cells, like senescent cells, have dicentric chromosomes that may arise as a result of telomeric sequence loss. We show that the AT mutation in the homozygous state confers a predisposition to accelerated telomere shortening with increasing age in peripheral blood lymphocytes (PBLs), which may be linked to premature senescence. We also show that telomeric fusions are associated with large (> 90%) preleukaemic translocation clones in T cells. We propose that these fusions may result from a compound effect of accelerated telomere shortening, together with a growth advantage of cells in large clones which leads to further telomere loss. Fusions are not observed in leukaemic cells in these patients. There is no evidence that either accelerated telomere loss per se or telomeric fusions are important in tumourigenesis. Telomerase is present in both normal and AT lymphocytes and so neither telomere shortening nor telomeric fusions can be explained by the absence of telomerase.},
}
@article {pmid8668193,
year = {1996},
author = {Broccoli, D and Godley, LA and Donehower, LA and Varmus, HE and de Lange, T},
title = {Telomerase activation in mouse mammary tumors: lack of detectable telomere shortening and evidence for regulation of telomerase RNA with cell proliferation.},
journal = {Molecular and cellular biology},
volume = {16},
number = {7},
pages = {3765-3772},
pmid = {8668193},
issn = {0270-7306},
support = {GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Enzyme Activation ; Female ; Gene Expression Regulation, Neoplastic ; Histones/biosynthesis ; Humans ; Hyperplasia ; Mammary Glands, Animal/metabolism/pathology ; Mammary Neoplasms, Experimental/*enzymology/pathology ; Mammary Tumor Virus, Mouse ; Mice ; Mice, Transgenic ; Mitogens/genetics ; Molecular Sequence Data ; Oligodeoxyribonucleotides ; Polymerase Chain Reaction ; Proto-Oncogene Proteins/biosynthesis/*genetics ; RNA Polymerase III/metabolism ; RNA, Messenger/biosynthesis ; Repetitive Sequences, Nucleic Acid ; Telomerase/biosynthesis/*metabolism ; Transcription, Genetic ; Wnt Proteins ; Wnt1 Protein ; *Zebrafish Proteins ; },
abstract = {Activation of telomerase in human cancers is thought to be necessary to overcome the progressive loss of telomeric DNA that accompanies proliferation of normal somatic cells. According to this model, telomerase provides a growth advantage to cells in which extensive terminal sequence loss threatens viability. To test these ideas, we have examined telomere dynamics and telomerase activation during mammary tumorigenesis in mice carrying a mouse mammary tumor virus long terminal repeat-driven Wnt-1 transgene. We also analyzed Wnt-1-induced mammary tumors in mice lacking p53 function. Normal mammary glands, hyperplastic mammary glands, and mammary carcinomas all had the long telomeres (20 to 50 kb) typical of Mus musculus and did not show telomere shortening during tumor development. Nevertheless, telomerase activity and the RNA component of the enzyme were consistently upregulated in Wnt-1-induced mammary tumors compared with normal and hyperplastic tissues. The upregulation of telomerase activity and RNA also occurred during tumorigenesis in p53-deficient mice. The expression of telomerase RNA correlated strongly with histone H4 mRNA in all normal tissues and tumors, indicating that the RNA component of telomerase is regulated with cell proliferation. Telomerase activity in the tumors was elevated to a greater extent than telomerase RNA, implying that the enzymatic activity of telomerase is regulated at additional levels. Our data suggest that the mechanism of telomerase activation in mouse mammary tumors is not linked to global loss of telomere function but involves multiple regulatory events including upregulation of telomerase RNA in proliferating cells.},
}
@article {pmid8810044,
year = {1996},
author = {Gamo, FJ and Lafuente, MJ and Casamayor, A and Ariño, J and Aldea, M and Casas, C and Herrero, E and Gancedo, C},
title = {Analysis of the DNA sequence of a 15,500 bp fragment near the left telomere of chromosome XV from Saccharomyces cerevisiae reveals a putative sugar transporter, a carboxypeptidase homologue and two new open reading frames.},
journal = {Yeast (Chichester, England)},
volume = {12},
number = {7},
pages = {709-714},
doi = {10.1002/(SICI)1097-0061(19960615)12:7%3C709::AID-YEA957%3E3.0.CO;2-1},
pmid = {8810044},
issn = {0749-503X},
mesh = {Amino Acid Sequence ; Base Sequence ; Carboxypeptidases/genetics ; Chromosomes, Fungal/*genetics ; Codon, Terminator/genetics ; DNA Primers/genetics ; DNA, Fungal/*genetics ; Molecular Sequence Data ; Monosaccharide Transport Proteins/genetics ; Open Reading Frames ; Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; Sequence Homology, Amino Acid ; Telomere/genetics ; },
abstract = {We report the sequence of a 15.5 kb DNA segment located near the left telomere of chromosome XV of Saccharomyces cerevisiae. The sequence contains nine open reading frames (ORFs) longer than 300 bp. Three of them are internal to other ones. One corresponds to the gene LGT3 that encodes a putative sugar transporter. Three adjacent ORFs were separated by two stop codons in frame. These ORFs presented homology with the gene CPS1 that encodes carboxypeptidase S. The stop codons were not found in the same sequence derived from another yeast strain. Two other ORFs without significant homology in databases were also found. One of them, O0420, is very rich in serine and threonine and presents a series of repeated or similar amino acid stretches along the sequence.},
}
@article {pmid8925173,
year = {1996},
author = {Joffee, BI and Solovei, IV and Macgregor, HC},
title = {Ends of Chromosomes in Polycelis tenuis (Platyhelminthes) have telomere repeat TTAGGG.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {4},
number = {4},
pages = {323-324},
pmid = {8925173},
issn = {0967-3849},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Animals ; DNA, Helminth/genetics ; Male ; Meiosis ; Mitosis ; Planarians/*genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; Species Specificity ; Telomere/*genetics ; },
}
@article {pmid8828903,
year = {1996},
author = {Dahse, R and Fiedler, W and Ernst, G and Kosmehl, H and Schlichter, A and Schubert, J and Claussen, U},
title = {Changes in telomere lengths in renal cell carcinomas.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {42},
number = {4},
pages = {477-485},
pmid = {8828903},
issn = {0145-5680},
mesh = {Adult ; Aged ; Aged, 80 and over ; Blotting, Southern ; Carcinoma, Renal Cell/*genetics ; Female ; Humans ; Male ; Middle Aged ; *Telomere ; },
abstract = {Telomeres, the extreme ends of chromosomes, play an important role in chromosome structure and function. The shortening of telomeres is one of the supposed mechanisms of cellular aging and death. Because of end replication problems the length of telomeres decreases with every cell cycle. This may lead to chromosome instability and additional genetic alterations possibly responsible of significant tumor development. In many cancer cells the length of telomeres depends on a balance between the loss of telomeric repeats, at each replication cycle, and the telomere lengthening, by the enzyme telomerase, which is repressed in most normal somatic cells. Many tumor cells demonstrate shortened telomeres in comparison to the corresponding normal tissue. In some types of human cancers the reduction of telomeric repeats was correlated with increasing disease severity. We analyzed Southern blots of HINF1-digested DNA of a large number of renal cell carcinomas (RCC) including different tumor areas, secondary tumors and metastases (76 cases with 142 tumor samples) for changes in the length of telomeric repeats using the oligonucleotide probe (TTAGGG)3 and found telomere shortening in 54%, suggesting that a reduction of the telomeric repeat length is not a general characteristic in RCC. Intratumor heterogeneity was demonstrated in seven cases. But also two RCC, with elongated telomeres in the tumor tissue, were observed. Shortened telomeres do not seem to be associated with advanced stages of tumor development or specific histopathological subtypes of RCC.},
}
@article {pmid8654545,
year = {1996},
author = {Field, H and Field, MC},
title = {Leptomonas seymouri, Trypanosoma brucei: a method for isolating trypanosomatid nuclear factors which bind T. brucei single-stranded g-rich telomere sequence.},
journal = {Experimental parasitology},
volume = {83},
number = {1},
pages = {155-158},
doi = {10.1006/expr.1996.0060},
pmid = {8654545},
issn = {0014-4894},
mesh = {Animals ; Base Sequence ; Molecular Sequence Data ; Nuclear Proteins/*isolation &amp; purification/metabolism ; Oligonucleotide Probes/chemistry ; Telomere/*chemistry/metabolism ; Trypanosoma brucei brucei/*genetics/ultrastructure ; Trypanosomatina/*genetics/ultrastructure ; },
abstract = {Sequential expression of variant surface glycoproteins (VSG) in Trypanosoma brucei is the basis of antigenic variation which is essential for parasite survival. Telomere distal copies of VSG genes, so-called basic copies, provide a repository of VSG sequence information for variability, but actively expressed copies are found only at subtelomeric regions of chromosomes. Of eight or so expression sites (ES) in the T. brucei genome, only one is active at one time. Movement of a basic copy VSG gene to an ES requires a recombination event of unknown mechanism. The properties of telomeres have been speculated to be important for control of VSG expression or basic copy mobilization, prompting us to begin to investigate telomere-binding proteins in trypanosomatids. The T. brucei telomere sequence is known, facilitating design of synthetic telomeric DNAs. Here we describe a method for preparation of active trypanosomatid nuclear extracts. We show that in T. brucei and Leptomonas seymouri, factors can be detected which bind a g-rich single-strand telomere sequence based on the T. brucei telomere. The L. seymouri telomere-binding factor, LST-1, dissociates in the presence of high salt to produce a core factor, LST-2, migrating similarly to the T. brucei telomere-binding factor TBT-1. The affinity of LST-2 and TBT-1 for DNA under high salt conditions is characteristic of telomere proteins.},
}
@article {pmid8649421,
year = {1996},
author = {Runge, KW and Zakian, VA},
title = {TEL2, an essential gene required for telomere length regulation and telomere position effect in Saccharomyces cerevisiae.},
journal = {Molecular and cellular biology},
volume = {16},
number = {6},
pages = {3094-3105},
pmid = {8649421},
issn = {0270-7306},
support = {GM26938/GM/NIGMS NIH HHS/United States ; GM43265/GM/NIGMS NIH HHS/United States ; GM50752/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Base Sequence ; Cloning, Molecular ; DNA Primers/genetics ; DNA, Fungal/genetics ; *Genes, Fungal ; *Genes, Mating Type, Fungal ; Microsatellite Repeats ; Molecular Sequence Data ; Mutation ; Saccharomyces cerevisiae/*genetics/ultrastructure ; Telomere/*genetics/ultrastructure ; },
abstract = {The DNA-protein complexes at the ends of linear eukaryotic chromosomes are called the telomeres. In Saccharomyces cerevisiae, telomeric DNA consists of a variable length of the short repeated sequence C1-3A. The length of yeast telomeres can be altered by mutation, by changing the levels of telomere binding proteins, or by increasing the amount of C1-3A DNA sequences. Cells bearing the tel1-1 or tel2-1 mutations, known previously to have short telomeres, did not respond to perturbations that caused telomere lengthening in wild-type cells. The transcription of genes placed near yeast telomeres is reversibly repressed, a phenomenon called the telomere position effect. The tel2-1 mutation reduced the position effect but did not affect transcriptional repression at the silent mating type cassettes, HMRa and HML alpha. The TEL2 gene was cloned, sequenced, and disrupted. Cells lacking TEL2 function died, with some cells arresting as large cells with three or four small protrusions or "blebs."},
}
@article {pmid8647430,
year = {1996},
author = {Li, B and Lustig, AJ},
title = {A novel mechanism for telomere size control in Saccharomyces cerevisiae.},
journal = {Genes &amp; development},
volume = {10},
number = {11},
pages = {1310-1326},
doi = {10.1101/gad.10.11.1310},
pmid = {8647430},
issn = {0890-9369},
support = {NCI-P30-CA-8748/CA/NCI NIH HHS/United States ; },
mesh = {Chromosome Deletion ; DNA-Binding Proteins/metabolism ; Fungal Proteins/metabolism ; Mutation ; Rad52 DNA Repair and Recombination Protein ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins ; *Telomere ; },
abstract = {One of the central requirements for eukaryotic chromosome stability is the maintenance of the simple sequence tracts at telomeres. In this study, we use genetic and physical assays to reveal the nature of a novel mechanism by which telomere length is controlled. This mechanism, telomeric rapid deletion (TRD), is capable of reducing elongated telomeres to wild-type tract length in an apparently single-division process. The deletion of telomeres to wild-type lengths is stimulated by the hpr1 mutation, suggesting that TRD in these cells is the consequence of an intrachromatid pathway. Paradoxically, TRD is also dependent on the lengths of the majority of nonhomologous telomeres in the cell. Defects in the chromatin-organizing protein Sir3p increase the rate of hpr1-induced rapid deletion and specifically change the spectrum of rapid deletion events. We propose a model in which interactions among telosomes of nonhomologous chromosomes form higher order complexes that restrict the access of the intrachromatid recombination machinery to telomeres. This mechanism of size control is distinct from that mediated through telomerase and is likely to maintain telomere length within a narrow distribution.},
}
@article {pmid8647429,
year = {1996},
author = {Marcand, S and Buck, SW and Moretti, P and Gilson, E and Shore, D},
title = {Silencing of genes at nontelomeric sites in yeast is controlled by sequestration of silencing factors at telomeres by Rap 1 protein.},
journal = {Genes &amp; development},
volume = {10},
number = {11},
pages = {1297-1309},
doi = {10.1101/gad.10.11.1297},
pmid = {8647429},
issn = {0890-9369},
support = {GM 40094/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes, Fungal ; Fungal Proteins/genetics/metabolism ; GTP-Binding Proteins/*metabolism ; Saccharomyces cerevisiae/*genetics ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; *Telomere ; Trans-Activators/genetics/metabolism ; rap GTP-Binding Proteins ; },
abstract = {Rap1p binds to silencer elements and telomeric repeats in yeast, where it appears to initiate silencing by recruiting Sir3p and Sir4p to the chromosome through interactions with its carboxy-terminal domain. Sir3p and Sir4p interact in vitro with histones H3 and H4 and are likely to be structural components of silent chromatin. We show that targeting of these Sir proteins to the chromosome is sufficient to initiate stable silencing either at a silent mating-type locus lacking a functional silencer element or at a telomere in a strain in which the Rap1p carboxy-terminal silencing domain has been deleted. Silencing by Sir protein targeting can also be initiated at a telomere-proximal site (ADH4), but is much weaker at an internal chromosomal locus (LYS2). Strikingly, deletion of the Rap1p silencing domain, which abolishes telomeric silencing, improves targeted silencing at LYS2 by both Sir3p and Sir4p, while weakening the silencing activity of these proteins at or near a telomere. This effect may result from the release of Sir proteins from the telomeres, thus increasing their effective concentration at other chromosomal sites. We suggest that telomeres and Rap1p serve a regulatory role in sequestering Sir proteins at telomeres, controlling silencing at other loci in trans and preventing indiscriminate gene silencing throughout the genome.},
}
@article {pmid8641694,
year = {1996},
author = {Ning, Y and Rosenberg, M and Biesecker, LG and Ledbetter, DH},
title = {Isolation of the human chromosome 22q telomere and its application to detection of cryptic chromosomal abnormalities.},
journal = {Human genetics},
volume = {97},
number = {6},
pages = {765-769},
pmid = {8641694},
issn = {0340-6717},
mesh = {Cerebroside-Sulfatase/genetics ; *Chromosome Deletion ; Chromosome Mapping/methods ; Chromosome Walking/methods ; Chromosomes, Human, Pair 22/*genetics ; Cloning, Molecular/methods ; Cosmids/genetics ; DNA Probes ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Intellectual Disability/genetics ; *Telomere ; },
abstract = {A number of human telomeres have been successfully cloned using a modified yeast artificial chromosome (YAC) vector (half-YAC) cloning strategy, but to date, human chromosome 22q has not been identified by this approach. We used an alternative approach of genomic walking, starting from a subtelomeric sequence, Tel-Bam3.4. present on a number of human chromosomes including 22q. This approach was successful in the development of a cosmid contig representing the terminal 140 kb of human chromosome 22q, providing telomeric closure of the genetic and physical maps for 22q. The most distal region of the contig contains subtelomeric repeats which crosshybridize to a number of chromosomes, while the proximal sequences are unique for 22q. The unique sequence cosmid was used as a 22qter-specific probe for fluorescence in situ hybridization (FISH) analysis, which confirmed that this cosmid was distal to the most telomeric marker previously available for chromosome 22. In addition, this cosmid was used to document a 22q terminal deletion that was not detectable by conventional cytogenetic analysis. Unique telomere-specific FISH probes such as this one will have significant diagnostic value in the detection of cryptic deletions and translocations in patients with unexplained mental retardation and other patient populations.},
}
@article {pmid8636864,
year = {1996},
author = {Hirai, H and LoVerde, PT},
title = {Identification of the telomeres on Schistosoma mansoni chromosomes by FISH.},
journal = {The Journal of parasitology},
volume = {82},
number = {3},
pages = {511-512},
pmid = {8636864},
issn = {0022-3395},
support = {AI18867/AI/NIAID NIH HHS/United States ; AI27219/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA Probes/chemistry ; *In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; Schistosoma mansoni/*genetics/ultrastructure ; Telomere/*genetics ; },
abstract = {The telomeres (molecular termini) of chromosomes play an important role in maintaining the structural integrity of the chromosome. Using a deoxyoligomer that contains the core sequence TTAGGG, we identified by fluorescence in situ hybridization (FISH) the telomeres on all 8 pairs of Schistosoma mansoni mitotic metaphase chromosomes. Our results indicate that S. mansoni exhibits a telomere sequence typical of other species.},
}
@article {pmid8621891,
year = {1996},
author = {Monteiro, J and Batliwalla, F and Ostrer, H and Gregersen, PK},
title = {Shortened telomeres in clonally expanded CD28-CD8+ T cells imply a replicative history that is distinct from their CD28+CD8+ counterparts.},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {156},
number = {10},
pages = {3587-3590},
pmid = {8621891},
issn = {0022-1767},
support = {AI33454/AI/NIAID NIH HHS/United States ; },
mesh = {Adult ; CD28 Antigens/*immunology ; CD8-Positive T-Lymphocytes/classification/*immunology ; Cell Division/genetics/immunology ; Clone Cells ; Humans ; Middle Aged ; Receptors, Antigen, T-Cell, alpha-beta/chemistry/genetics ; Telomere/chemistry/*immunology ; },
abstract = {Long term in vitro culture of clonally expanded CD8+T cells, generally found within the CD57+ or CD28-subset, has generally been unsuccessful, suggesting that these cells may have a limited replicative potential. Telomeric shortening may reflect the action of a "mitotic clock" regulating the number of divisions a cell can undergo. In this study, we have compared the telomeric lengths of CD28-CD8+ and CD28+CD8+ T cells in 10 normal individuals to assess their replicative history. Overall, the telomeric lengths were found to be significantly shorter in the CD28-CD8+ T cell subset compared with the CD28+CD8+ subset. Furthermore, clonally expanded TCRBV11+CD8+ T cells from an individual exhibited telomeric lengths that were 2.9 kb shorter than those found in the polyclonal CD28+CD8+ T cell subset. These findings indicate that clonally expanded CD28-CD8+ T cells have undergone many more rounds of replication than CD28+CD8+ T cells, and consistent with the loss of CD28 expression, they may have reached a state of replicative senescence.},
}
@article {pmid8616897,
year = {1996},
author = {Wellinger, RJ and Ethier, K and Labrecque, P and Zakian, VA},
title = {Evidence for a new step in telomere maintenance.},
journal = {Cell},
volume = {85},
number = {3},
pages = {423-433},
doi = {10.1016/s0092-8674(00)81120-4},
pmid = {8616897},
issn = {0092-8674},
support = {GM26938/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Cations/pharmacology ; Cell Cycle/genetics ; DNA Replication/genetics ; DNA, Fungal/genetics ; Hot Temperature ; Magnesium/pharmacology ; Molecular Sequence Data ; Plasmids ; RNA, Fungal/genetics ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/cytology/enzymology/genetics ; Telomerase/genetics ; Telomere/*enzymology/*genetics ; },
abstract = {The strand of telomeric DNA that runs 5'-3' toward a chromosome end is typically G rich. Telomerase-generated G tails are expected at one end of individual DNA molecules. Saccharomyces telomeres acquire TG1-3 tails late in S phase. Moreover, the telomeres of linear plasmids can interact when the TG1-3 tails are present. Molecules that mimic the structures predicted for telomere replication intermediates were generated in vitro. These in vitro generated molecules formed telomere-telomere interactions similar to those on molecules isolated from yeast, but only if both ends that interacted had a TG1-3 tail. Moreover, TG1-3 tails were generated in vivo in cells lacking telomerase. These data suggest a new step in telomere maintenance, cell cycle-regulated degradation of the C1-3A strand, which can generate a potential substrate for telomerase and telomere-binding proteins at every telomere.},
}
@article {pmid8733138,
year = {1996},
author = {Lansdorp, PM and Verwoerd, NP and van de Rijke, FM and Dragowska, V and Little, MT and Dirks, RW and Raap, AK and Tanke, HJ},
title = {Heterogeneity in telomere length of human chromosomes.},
journal = {Human molecular genetics},
volume = {5},
number = {5},
pages = {685-691},
doi = {10.1093/hmg/5.5.685},
pmid = {8733138},
issn = {0964-6906},
support = {AI29524/AI/NIAID NIH HHS/United States ; },
mesh = {Adult ; Chromosomes, Human/*ultrastructure ; *Genetic Heterogeneity ; Hematopoietic Stem Cells/ultrastructure ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics ; Liver/embryology/ultrastructure ; Metaphase ; Signal Processing, Computer-Assisted ; Telomere/*ultrastructure ; },
abstract = {Vertebrate chromosomes terminate in variable numbers of T2AG3 nucleotide repeats. In order to study telomere repeats at individual chromosomes, we developed novel, quantitative fluorescence in situ hybridization procedures using labeled (C3TA2)3 peptide nucleic acid and digital imaging microscopy. Telomere fluorescence intensity values from metaphase chromosomes of cultured human hematopoietic cells decreased with the replication history of the cells, varied up to six-fold within a metaphase, and were similar between sister chromatid telomeres. Surprisingly, telomere fluorescence intensity values within normal adult bone marrow metaphases did not show a normal distribution, suggesting that a minimum number of repeats at each telomere is required and/or maintained during normal hematopoiesis.},
}
@article {pmid8649454,
year = {1996},
author = {Schwartz, T and Osiewacz, HD},
title = {Telomere length does not change during senescence of the ascomycete Podospora anserina.},
journal = {Mutation research},
volume = {316},
number = {5-6},
pages = {193-199},
doi = {10.1016/s0921-8734(96)90003-x},
pmid = {8649454},
issn = {0027-5107},
mesh = {Ascomycota/*genetics/physiology ; Base Sequence ; DNA Probes ; DNA, Mitochondrial ; Molecular Sequence Data ; *Telomere ; },
abstract = {All strains of the filamentous fungus Podospora anserina are characterized by a well defined life span. Senescence is controlled by nuclear and extranuclear genetic traits. In order to test whether or not the ends of the chromosomes of this ascomycete shorten during senescence and thus telomere shortening may be linked to the well analyzed, age-related reorganizations of the mitochondrial DNA (mtDNA), we analyzed the genomic DNA of P. anserina wild-type strain s. We found that, although the mtDNA becomes reorganized when cultures age, the telomeres remain constant suggesting that telomere shortening does not play a major role in normal aging of this particular biological system.},
}
@article {pmid8641975,
year = {1996},
author = {Ohashi, K and Tsutsumi, M and Kobitsu, K and Fukuda, T and Tsujiuchi, T and Okajima, E and Ko, S and Nakajima, Y and Nakano, H and Konishi, Y},
title = {Shortened telomere length in hepatocellular carcinomas and corresponding background liver tissues of patients infected with hepatitis virus.},
journal = {Japanese journal of cancer research : Gann},
volume = {87},
number = {5},
pages = {419-422},
pmid = {8641975},
issn = {0910-5050},
mesh = {Adult ; Aged ; Carcinoma, Hepatocellular/*genetics/virology ; Female ; Hepatitis B/complications ; Hepatitis C/complications ; Humans ; Liver Cirrhosis/complications ; Liver Neoplasms/*genetics/virology ; Male ; Middle Aged ; Telomere/*pathology ; },
abstract = {The telomere length in 20 surgically resected human hepatocellular carcinomas (HCCs) and adjacent non-cancerous livers with hepatitis virus infection were investigated. All the HCC samples examined demonstrated shorter telomere length than the corresponding non-cancerous liver tissues, the respective average values being 5.4 kbp and 8.8 kbp (P < 0.001). The shortening of telomere length was most prominent in HCCs larger than 30 mm in diameter, and in both tumors and non-cancerous livers it was more marked with hepatitis B virus as compared with hepatitis C virus infection. These results indicate that telomere shortening is associated with not only progression, but also development of HCC, and there is a possible difference in the nature of the association in patients with hepatitis viruses of B and C types.},
}
@article {pmid8628316,
year = {1996},
author = {Lustig, AJ and Liu, C and Zhang, C and Hanish, JP},
title = {Tethered Sir3p nucleates silencing at telomeres and internal loci in Saccharomyces cerevisiae.},
journal = {Molecular and cellular biology},
volume = {16},
number = {5},
pages = {2483-2495},
pmid = {8628316},
issn = {0270-7306},
support = {NCI-P30-CA-8748/CA/NCI NIH HHS/United States ; },
mesh = {Bacterial Proteins/biosynthesis/metabolism ; Binding Sites ; Chromosomes, Fungal ; Fungal Proteins/biosynthesis/*metabolism ; GTP-Binding Proteins/metabolism ; Genotype ; Models, Structural ; Mutagenesis ; Plasmids ; Recombinant Fusion Proteins/biosynthesis/metabolism ; Saccharomyces cerevisiae/*genetics/growth &amp; development/*physiology ; *Serine Endopeptidases ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Suppression, Genetic ; *Telomere ; Trans-Activators/biosynthesis/*metabolism ; Transcription, Genetic ; rap GTP-Binding Proteins ; },
abstract = {Rap1p binds to sites embedded within the Saccharomyces cerevisiae telomeric TG1-3 tract. Previous studies have led to the hypothesis that Rap1p may recruit Sir3p and Sir3p-associating factors to the telomere. To test this, we tethered Sir3p adjacent to the telomere via LexA binding sites in the rap1-17 mutant that truncates the Rap1p C-terminal 165 amino acids thought to contain sites for Sir3p association. Tethering of LexA-Sir3p adjacent to the telomere is sufficient to restore telomeric silencing, indicating that Sir3p can nucleate silencing at the telomere. Tethering of LexA-Sir3p or the LexA-Sir3p(N2O5) gain-of-function protein to a telomeric LexA site hyperrepresses an adjacent ADE2 gene in wild-type cells. Hence, Sir3p recruitment to the telomere is limiting in telomeric silencing. In addition, LexA-Sir3p(N2O5) hyperrepresses telomeric silencing when tethered to a subtelomeric site 3.6 kb from the telomeric tract. This hyperrepression is dependent on the C terminus of Rap1p, suggesting that subtelomeric LexA-Sir3p(N205) can interact with Rap1p-associated factors at the telomere. We also demonstrate that LexA-Sir3p or LexA-Sir3p(N205) tethered in cis with a short tract of telomeric TG1-3 sequences is sufficient to confer silencing at an internal chromosomal position. Internal silencing is enhanced in rap1-17 strains. We propose that sequestration of silencing factors at the telomere limits the efficiency of internal silencing.},
}
@article {pmid8608573,
year = {1996},
author = {Ohashi, K and Tsutsumi, M and Nakajima, Y and Kobitsu, K and Nakano, H and Konishi, Y},
title = {Telomere changes in human hepatocellular carcinomas and hepatitis virus infected noncancerous livers.},
journal = {Cancer},
volume = {77},
number = {8 Suppl},
pages = {1747-1751},
doi = {10.1002/(SICI)1097-0142(19960415)77:8&lt;1747::AID-CNCR50&gt;3.0.CO;2-W},
pmid = {8608573},
issn = {0008-543X},
mesh = {Adult ; Aged ; Carcinoma, Hepatocellular/*genetics/virology ; Hepatitis B/*genetics ; Hepatitis C/*genetics ; Humans ; Liver/*ultrastructure/virology ; Liver Neoplasms/*genetics/secondary/virology ; Middle Aged ; Telomere ; },
abstract = {BACKGROUND: Telomeres, at the ends of eukaryotic chromosomes, are defined functionally as necessary for chromosome stability. Chromosome instability induced in part by loss of telomeric DNA has been considered to play a significant role in the development of human cancers. However, little is known about the status of telomeres per se during human hepatocellular carcinoma (HCC) development.<br><br>METHODS: The study was conducted to determine the length of terminal restriction fragments (TRFs) at the telomeric ends in 23 HCCs and 23 corresponding noncancerous liver tissues from the same patients harboring hepatitis virus infections, and in 5 samples of noncancerous livers without the hepatitis virus. The latter samples had been obtained as controls at surgery for metastatic liver tumors.<br><br>RESULTS: All 23 HCCs demonstrated reduction in TRF length compared with the corresponding noncancerous liver tissues with viral infection. The TRF in the latter cases also demonstrated a significant shortening as compared with the virus free control tissue, the degree being calculated to represent an average of 42 cell divisions. Reduction in TRF length in HCC samples tended to increase with the tumor diameter, although this failed to show statistical significance.<br><br>CONCLUSIONS: These results indicate that telomere shortening occurs during HCC development. The fact that this change is already evident in noncancerous liver tissues from patients with viral hepatitis suggests that it may play an important role in the associated generation of tumors.},
}
@article {pmid8967898,
year = {1996},
author = {Melek, M and Shippen, DE},
title = {Chromosome healing: spontaneous and programmed de novo telomere formation by telomerase.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {18},
number = {4},
pages = {301-308},
doi = {10.1002/bies.950180408},
pmid = {8967898},
issn = {0265-9247},
support = {GM49157/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Chromosomes/*metabolism ; DNA/metabolism ; DNA Damage/genetics ; DNA Repair/genetics ; Euplotes/metabolism ; Models, Biological ; Molecular Sequence Data ; Plasmodium falciparum/metabolism ; Telomerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are protective caps for chromosome ends that are essential for genome stability. Broken chromosomes missing a telomere will not be maintained unless the chromosome is 'healed' with the formation of a new telomere. Chromosome healing can be a programmed event following developmentally regulated chromosome fragmentation, or it may occur spontaneously when a chromosome is accidentally broken. In this article we discuss the consequences of telomere loss and the possible mechanisms that the enzyme telomerase employs to form telomeres de novo on broken chromosome ends.},
}
@article {pmid8793200,
year = {1996},
author = {Thomas, HM and Williams, K and Harper, JA},
title = {Labelling telomeres of cereals, grasses and clover by primed in situ DNA labelling.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {4},
number = {3},
pages = {182-184},
pmid = {8793200},
issn = {0967-3849},
mesh = {DNA Primers ; DNA, Plant/genetics ; Edible Grain/*genetics/ultrastructure ; Fabaceae/*genetics/ultrastructure ; In Situ Hybridization, Fluorescence ; *Plants, Medicinal ; Poaceae/*genetics/ultrastructure ; Species Specificity ; Telomere/*ultrastructure ; },
abstract = {Primed in situ DNA labelling (PRINS) labels the telomeres of Avena, Triticum, Secale, Hordeum, Lolium, Festuca and Trifolium when primers are used that correspond to the repeat unit of Arabidopsis telomeres. There are interstitial sites labelled in a Lolium x Festuca hybrid.},
}
@article {pmid8754618,
year = {1996},
author = {Rao, KS},
title = {Telomere (telomerase) hypothesis of aging and immortalization.},
journal = {Indian journal of biochemistry &amp; biophysics},
volume = {33},
number = {2},
pages = {88-92},
pmid = {8754618},
issn = {0301-1208},
mesh = {Aging/*genetics/metabolism ; Animals ; Base Sequence ; Humans ; Longevity/*genetics ; Molecular Sequence Data ; Telomerase/*metabolism ; *Telomere ; },
}
@article {pmid8708420,
year = {1996},
author = {Matsuura, A and Ishikawa, F},
title = {[Biochemical aspects of the telomere].},
journal = {Seikagaku. The Journal of Japanese Biochemical Society},
volume = {68},
number = {4},
pages = {295-299},
pmid = {8708420},
issn = {0037-1017},
mesh = {Animals ; Base Sequence ; Chromatin ; DNA ; DNA-Binding Proteins ; Humans ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; *Telomere/genetics/physiology ; },
}
@article {pmid8612598,
year = {1996},
author = {Wright, WE and Brasiskyte, D and Piatyszek, MA and Shay, JW},
title = {Experimental elongation of telomeres extends the lifespan of immortal x normal cell hybrids.},
journal = {The EMBO journal},
volume = {15},
number = {7},
pages = {1734-1741},
pmid = {8612598},
issn = {0261-4189},
support = {AG07992/AG/NIA NIH HHS/United States ; },
mesh = {Base Sequence ; Cell Division/genetics ; Cellular Senescence/genetics ; Enzyme Inhibitors/pharmacology ; Humans ; Hybrid Cells ; Molecular Sequence Data ; Oligodeoxyribonucleotides/genetics/pharmacology ; Repetitive Sequences, Nucleic Acid ; Telomerase/antagonists &amp; inhibitors ; Telomere/genetics/*ultrastructure ; Time Factors ; },
abstract = {Hybrids between immortal cells that express telomerase and normal cells that lack telomerase have a limited lifespan. We demonstrate that telomerase is repressed in such hybrids. Treatment of immortal human cell lines with certain oligonucleotides resulted in telomere elongation. We took advantage of this observation to test the hypothesis that elongation of telomeres would extend the lifespan of cells in culture. An immortal human cell line was treated with an oligonucleotide to lengthen its telomeres and then was fused with mortal cells. The lifespan of these hybrid cells was longer than that of the hybrids in which telomeres had not been elongated. These observations provide the first direct evidence supporting the hypothesis that telomere length determines proliferative capacity of human cells.},
}
@article {pmid8833245,
year = {1996},
author = {Yen, CH and Pazik, J and Elliott, RW},
title = {A polymorphic interstitial telomere array near the center of mouse chromosome 8.},
journal = {Mammalian genome : official journal of the International Mammalian Genome Society},
volume = {7},
number = {3},
pages = {218-221},
pmid = {8833245},
issn = {0938-8990},
support = {CA62225/CA/NCI NIH HHS/United States ; GM28464/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA Transposable Elements/genetics ; Mice ; Mice, Inbred Strains ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid/*genetics ; Restriction Mapping ; Telomere/*genetics ; },
}
@article {pmid8637224,
year = {1996},
author = {Hoffman, SM and Hromas, R and Amemiya, C and Mohrenweiser, HW},
title = {The location of MZF-1 at the telomere of human chromosome 19q makes it vulnerable to degeneration in aging cells.},
journal = {Leukemia research},
volume = {20},
number = {3},
pages = {281-283},
doi = {10.1016/0145-2126(95)00158-1},
pmid = {8637224},
issn = {0145-2126},
support = {HL48914/HL/NHLBI NIH HHS/United States ; },
mesh = {Aging/*genetics ; Chromosome Mapping ; *Chromosomes, Human, Pair 19 ; Cosmids ; DNA-Binding Proteins/*genetics ; Humans ; Kruppel-Like Transcription Factors ; *Telomere ; Transcription Factors/*genetics ; *Zinc Fingers ; },
abstract = {A zinc-finger gene encoding a transcription factor that regulates hematopoiesis, MZF-1, is located at the extreme end of the q arm of human chromosome 19. Several lines of evidence indicate that MZF-1 lies less than 20 kb from the subtelomeric repeat region of 19q. Telomeres are known to degenerate as cells age; disruption of MZF-1 due to telomeric degeneration may play a role in the increased incidence of leukemia in the elderly.},
}
@article {pmid8622671,
year = {1996},
author = {Fan, Q and Yao, M},
title = {New telomere formation coupled with site-specific chromosome breakage in Tetrahymena thermophila.},
journal = {Molecular and cellular biology},
volume = {16},
number = {3},
pages = {1267-1274},
pmid = {8622671},
issn = {0270-7306},
support = {GM26210/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Molecular Sequence Data ; Restriction Mapping ; Telomere/*genetics ; Tetrahymena thermophila/*genetics/ultrastructure ; },
abstract = {Programmed chromosome breakage occurs in many ciliated protozoa and is accompanied by efficient new telomere formation. In this study, we have investigated the relationship between programmed chromosome breakage and telomere formation in Tetrahymena thermophila. Using specially constructed DNA clones containing the breakage signal Cbs in transformation studies, we have determined the locations of telomere addition around the breakage sites. They occur at variable positions, over 90% of which are within a small region (less than 30 bp) starting 4 bp from Cbs. This distribution is independent of the nucleotide sequence in the region or of the orientation of Cbs. In five of six cases determined, these sites occur at or before a T, and in the remaining case, the site occurs at or before a G. When sequences devoid of G or T are placed in this region, telomere addition still occurs within the region to maintain a similar distance relationship with Cbs. This efficient and healing process appears to be associated specifically with Cbs-directed breakage, since it does not occur when DNA ends are generated by restriction enzyme digestion. These results suggest a strong mechanistic link between chromosome breakage and telomere formation.},
}
@article {pmid8598292,
year = {1996},
author = {Zou, S and Ke, N and Kim, JM and Voytas, DF},
title = {The Saccharomyces retrotransposon Ty5 integrates preferentially into regions of silent chromatin at the telomeres and mating loci.},
journal = {Genes &amp; development},
volume = {10},
number = {5},
pages = {634-645},
doi = {10.1101/gad.10.5.634},
pmid = {8598292},
issn = {0890-9369},
mesh = {Amino Acid Sequence ; Base Sequence ; Blotting, Northern ; Chromatin/*genetics ; Chromosome Mapping ; Chromosomes, Fungal ; Gene Expression Regulation, Fungal ; Mating Factor ; Models, Genetic ; Molecular Sequence Data ; Peptides/*genetics ; RNA, Fungal/analysis ; RNA, Messenger/analysis ; Repetitive Sequences, Nucleic Acid ; Retroelements/*genetics ; Saccharomyces/*genetics ; Saccharomyces cerevisiae/genetics ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; Species Specificity ; Telomere/*genetics ; Transcription, Genetic ; },
abstract = {The nonrandom integration of retrotransposons and retroviruses suggests that chromatin influences target choice. Targeted integration, in turn, likely affects genome organization. In Saccharomyces, native Ty5 retrotransposons are located near telomeres and the silent mating locus HMR. To determine whether this distribution is a consequence of targeted integration, we isolated a transposition-competent Ty5 element from S. paradoxus, a species closely related to S. cerevisiae. This Ty5 element was used to develop a transposition assay in S. cerevisiae to investigate target preference of de novo transposition events. Of 87 independent Ty5 insertions, approximately 30% were located on chromosome III, indicating this small chromosome (approximately 1/40 of the yeast genome) is a highly preferred target. Mapping of the exact location of 19 chromosome III insertions showed that 18 were within or adjacent to transcriptional silencers flanking HML and HMR or the type X subtelomeric repeat. We predict Ty5 target preference is attributable to interactions between transposition intermediates and constituents of silent chromatin assembled at these sites. Ty5 target preference extends the link between telomere structure and reverse transcription as carried out by telomerase and Drosophila retrotransposons.},
}
@article {pmid8604994,
year = {1996},
author = {Kim, S and Villeponteau, B and Jazwinski, SM},
title = {Effect of replicative age on transcriptional silencing near telomeres in Saccharomyces cerevisiae.},
journal = {Biochemical and biophysical research communications},
volume = {219},
number = {2},
pages = {370-376},
doi = {10.1006/bbrc.1996.0240},
pmid = {8604994},
issn = {0006-291X},
mesh = {Centromere/ultrastructure ; Chromosomes, Fungal ; Drug Resistance, Microbial ; Fibroblasts/cytology/physiology ; Gene Expression Regulation, Fungal ; Humans ; Regression Analysis ; Saccharomyces cerevisiae/*genetics/growth &amp; development/metabolism ; Species Specificity ; *Telomere/ultrastructure ; Time Factors ; *Transcription, Genetic ; },
abstract = {Individual yeasts have a finite replicative life span in similarity to normal human fibroblasts. Telomere loss is a hallmark of replicative senescence in normal human fibroblasts and has been proposed to play a role in cellular senescence, perhaps by affecting subtelomeric genes. While telomere loss does not occur with replicative age in yeast, subtelomeric genes are subject to transcriptional silencing. It is possible that components of the silencing machinery other than telomeres change with replicative age and that these changes then lead to alterations in gene expression that contribute to aging. In an initial test of this possibility, we have examined the silencing of the URA3 gene at two different telomeres as a function of yeast replicative age. Silencing declined rapidly and significantly at one telomere consistent with the involvement of silencing in aging, but it remained in comparison nearly constant at the other. These changes in silencing raise the possibility that the transcriptional status of genes in the subtelomeric region may be important for the senescence of both dividing cells and postmitotic cells, in which telomeres remain constant in length.},
}
@article {pmid8604297,
year = {1996},
author = {Porter, SE and Greenwell, PW and Ritchie, KB and Petes, TD},
title = {The DNA-binding protein Hdf1p (a putative Ku homologue) is required for maintaining normal telomere length in Saccharomyces cerevisiae.},
journal = {Nucleic acids research},
volume = {24},
number = {4},
pages = {582-585},
pmid = {8604297},
issn = {0305-1048},
support = {GM24110/GM/NIGMS NIH HHS/United States ; GM52319/GM/NIGMS NIH HHS/United States ; },
mesh = {*Antigens, Nuclear ; *DNA Helicases ; DNA-Binding Proteins/*genetics ; Fungal Proteins/*genetics ; Ku Autoantigen ; Mutation ; Nuclear Proteins/*genetics ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; *Telomere ; },
abstract = {In mammalian cells, the Ku autoantigen is an end- binding DNA protein required for the repair of DNA breaks [Troelstra, C. and Jaspers, N.G.J. (1994) Curr. Biol., 4, 1149- 1151]. A yeast gene (HDF1) encoding a putative homologue of the 70 kDa subunit of Ku has recently been identified [Feldmann, H. and Winnacker, E. L. (1993) J. Biol. Chem., 268, 12895- 12900]. We find that hdf1 mutant strains have substantially shorter telomeres than wild-type strains. We speculate that Hdf1p may bind the natural ends of the chromosome, in addition to binding to the ends of broken DNA molecules. Strains with both an hdf1 mutation and a mutation in TEL 1 (a gene related to the human ataxia telangiectasia gene) have extremely short telomeres and grow slowly.},
}
@article {pmid8851970,
year = {1996},
author = {Pardue, ML and Danilevskaya, ON and Lowenhaupt, K and Slot, F and Traverse, KL},
title = {Drosophila telomeres: new views on chromosome evolution.},
journal = {Trends in genetics : TIG},
volume = {12},
number = {2},
pages = {48-52},
doi = {10.1016/0168-9525(96)81399-0},
pmid = {8851970},
issn = {0168-9525},
mesh = {Animals ; Base Sequence ; Drosophila/*genetics ; *Evolution, Molecular ; Molecular Sequence Data ; Retroelements ; Telomere/*genetics ; },
abstract = {In Drosophila, chromosome ends (telomeres) are composed of telomere-specific transposable elements (the retroposons HeT-A and TART). These elements are a bona fide part of the cellular machinery yet have many of the hallmarks of retrotransposable elements and retroviruses, raising the possibility that parasitic transposable elements and viruses might have evolved from mechanisms that the cell uses to maintain its chromosomes. It is striking that Drosophila, the model organism for many discoveries in genetics, development and molecular biology (including the classical concept of telomeres), should prove to have chromosome ends different from the generally accepted model. Studies of these telomere-specific retrotransposable elements raise questions about conventional wisdom concerning not only telomeres, but also transposable elements and heterochromatin.},
}
@article {pmid8820610,
year = {1996},
author = {Copenhaver, GP and Pikaard, CS},
title = {RFLP and physical mapping with an rDNA-specific endonuclease reveals that nucleolus organizer regions of Arabidopsis thaliana adjoin the telomeres on chromosomes 2 and 4.},
journal = {The Plant journal : for cell and molecular biology},
volume = {9},
number = {2},
pages = {259-272},
doi = {10.1046/j.1365-313x.1996.09020259.x},
pmid = {8820610},
issn = {0960-7412},
mesh = {Arabidopsis/*genetics ; Base Sequence ; *Chromosome Mapping ; Cloning, Molecular ; *DNA, Ribosomal ; Endodeoxyribonucleases/metabolism ; Gene Rearrangement ; Genetic Linkage ; Genetic Markers ; Meiosis ; Molecular Sequence Data ; *Nucleolus Organizer Region ; Polymorphism, Restriction Fragment Length ; Substrate Specificity ; *Telomere ; },
abstract = {Ribosomal RNA genes are organized in tandem arrays called nucleolus organizer regions (NORs). In a prior study, RFLP mapping on pulsed-field gels placed NOR2 at the northern tip of Arabidopsis thaliana chromosome 2. New polymorphisms have allowed the other NOR, NOR4, to be mapped to the northern tip of chromosome 4. To map NOR-associated loci, rDNA-specific cleavage by I-Ppol, an endonuclease with a 15 nucleotide recognition sequence involved in rDNA-homing of a mobile, self-splicing Group I intron in Physarum was exploited. I-Ppol digestion of A. thaliana genomic DNA liberated two telomere-containing fragments no larger than 13 kbp, and telomere polymorphisms identified using I-Ppol cosegregated with NOR2 and NOR4. Restriction mapping suggested that telomere-proximal rRNA genes are oriented with their 5' ends nearest the chromosome ends and their 3' ends nearest the centromere. This orientation was confirmed using the polymerase chain reaction to clone one of the telomere-rDNA junctions, most likely the junction on chromosome 4. The telomeric repeats join the terminal rRNA gene downstream of its promoter, suggesting that this first gene is inactive. Subtelomeric repetitive DNAs are absent at the telomere-rDNA junction. Localization of NOR2, NOR4 and their associated telomeres, TEL2N and TEL4N, respectively, provides end points for the genetic and physical maps of chromosomes 2 and 4.},
}
@article {pmid8686379,
year = {1996},
author = {Eki, T and Naitou, M and Hagiwara, H and Ozawa, M and Sasanuma, SI and Sasanuma, M and Tsuchiya, Y and Shibata, T and Hanaoka, F and Murakami, Y},
title = {Analysis of a 36.2 kb DNA sequence including the right telomere of chromosome VI from Saccharomyces cerevisiae.},
journal = {Yeast (Chichester, England)},
volume = {12},
number = {2},
pages = {149-167},
doi = {10.1002/(SICI)1097-0061(199602)12:2%3C149::AID-YEA893%3E3.0.CO;2-G},
pmid = {8686379},
issn = {0749-503X},
mesh = {Amino Acid Sequence ; Base Sequence ; Chromosomes, Fungal/*genetics ; Fungal Proteins/*genetics ; Gene Library ; Molecular Sequence Data ; Open Reading Frames ; Regulatory Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*genetics ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; Telomere/*genetics ; },
abstract = {The nucleotide sequence of a 36.2-kb distal region containing the right telomere of chromosome VI was determined. Both strands of DNA cloned into cosmid clone 9965 and plasmid clone pEL174P2 were sequenced with an average redundancy of 7.9 per base pair, by both dye primer and dye terminator cycle sequencing methods. The G+C content of the sequence was found to be 37.9%. Eighteen open reading frames (ORFs) longer than 100 amino acids were detected. Four of these ORFs (9965orfR017, 9965orfF016, 9965orfR009 and 9965orfF003) were found to encode previously identified genes (YMR31, PRE4, NIN1 and HXK1, respectively). Six ORFs (9965orfR013, 9965orfF018, 9965orfF006, 9965orfR014, 9965orfF013 and 9965orfR020) were found to be homologous to hypothetical 121.4-kDa protein in the BCK 5' region, Bacillus subtilis DnaJ protein, hypothetical Trp-Asp repeats containing protein in DBP3-MRPL27, putative mitochondrial carrier YBR291C protein, Salmonella typhimurium nicotinate-nucleotide pyrophosphorylase, and Escherichia coli cystathionine beta-lyase, respectively. The putative proteins encoded by 9965orfF018, 9965orfR014 and 9965orfR020 were found to be, respectively, a new member of the family of DnaJ-like proteins, the mitochondrial carrier protein and cystathionine lyase.},
}
@article {pmid8574955,
year = {1996},
author = {Axelrod, N},
title = {Of telomeres and tumors.},
journal = {Nature medicine},
volume = {2},
number = {2},
pages = {158-159},
doi = {10.1038/nm0296-158},
pmid = {8574955},
issn = {1078-8956},
mesh = {Animals ; Antineoplastic Agents/therapeutic use ; Enzyme Inhibitors/therapeutic use ; HeLa Cells ; Humans ; Neoplasms/drug therapy/enzymology/*genetics ; Neoplasms, Experimental/drug therapy/enzymology/genetics ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*enzymology ; },
abstract = {The enzyme, telomerase, may be switched on in tumor cells. Inhibitors of this enzyme might constitute a new class of anti-cancer drugs.},
}
@article {pmid8560215,
year = {1996},
author = {Greider, CW and Blackburn, EH},
title = {Telomeres, telomerase and cancer.},
journal = {Scientific American},
volume = {274},
number = {2},
pages = {92-97},
doi = {10.1038/scientificamerican0296-92},
pmid = {8560215},
issn = {0036-8733},
mesh = {Aged ; Aging ; Antineoplastic Agents ; Cell Division ; DNA Replication ; Enzyme Inhibitors/therapeutic use ; Humans ; Infant, Newborn ; *Neoplasms/drug therapy/genetics/ultrastructure ; Telomerase/antagonists &amp; inhibitors/*metabolism ; *Telomere/ultrastructure ; },
}
@article {pmid8553327,
year = {1996},
author = {Brøgger, A},
title = {[Happy ending... News on telomeres and telomerase].},
journal = {Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke},
volume = {116},
number = {1},
pages = {17},
pmid = {8553327},
issn = {0029-2001},
mesh = {DNA Replication ; Humans ; Research ; Telomerase/*genetics ; Telomere/*ultrastructure ; },
}
@article {pmid9552395,
year = {1996},
author = {Buchkovich, KJ},
title = {Telomeres, telomerase, and the cell cycle.},
journal = {Progress in cell cycle research},
volume = {2},
number = {},
pages = {187-195},
doi = {10.1007/978-1-4615-5873-6_18},
pmid = {9552395},
issn = {1087-2957},
mesh = {Animals ; Cell Cycle/*physiology ; Cell Division ; Cellular Senescence ; DNA Damage ; DNA Replication ; Humans ; Models, Biological ; Telomerase/*physiology ; Telomere/*physiology ; },
abstract = {Telomeres protect the ends of chromosomes from degradation and fusion. In most eukaryotes telomeres are replicated by a specialised polymerase, telomerase. Telomerase synthesises one strand of the telomere; while conventional DNA polymerases synthesise the complementary strand. Additional processing of telomeres occurs in ciliates and yeast during each cell cycle. Telomerase activity and RNA levels change as cells enter and exit the cell cycle. Gradual telomere shortening in the absence of telomerase does not immediately affect cell cycling; however, "critically" short telomeres are hypothesised to play a role in senescence and the triggering of DNA damage checkpoints.},
}
@article {pmid9114431,
year = {1996},
author = {Wynford-Thomas, D},
title = {Telomeres, p53 and cellular senescence.},
journal = {Oncology research},
volume = {8},
number = {10-11},
pages = {387-398},
pmid = {9114431},
issn = {0965-0407},
mesh = {Animals ; Cell Division/physiology ; Cellular Senescence/*physiology ; Humans ; Telomere/*physiology ; Tumor Suppressor Protein p53/*physiology ; },
abstract = {The ability of mammalian cells to respond to extrinsic mitogens is downregulated in response to proliferative aging (senescence), and it is now likely that at least a subset of such lifespan checkpoints is triggered by a biological "clock" based on erosion of chromosome telomeres. This review outlines the intrinsic inhibitory signal pathways that link this clock to cell cycle arrest, focussing on the role of tumour suppressor gene products, particularly the p53 and pRb proteins. Emphasis is placed on cell-type specific differences in the timing of lifespan checkpoints, and the "choice" of the underlying inhibitory signal pathway. It is argued that such diversity may explain many differences between cell types in the selection of tumour suppressor gene mutations, providing for example a novel explanation for the difference in molecular pathology and clinical behaviour between two important subsets of human breast cancer.},
}
@article {pmid8982452,
year = {1996},
author = {Zakian, VA},
title = {Structure, function, and replication of Saccharomyces cerevisiae telomeres.},
journal = {Annual review of genetics},
volume = {30},
number = {},
pages = {141-172},
doi = {10.1146/annurev.genet.30.1.141},
pmid = {8982452},
issn = {0066-4197},
mesh = {Aging/genetics ; Chromatin/genetics ; DNA Replication ; DNA, Fungal ; Humans ; Saccharomyces cerevisiae/*genetics ; *Telomere ; },
abstract = {A combination of classical genetic, biochemical, and molecular biological approaches have generated a rather detailed understanding of the structure and function of Saccharomyces telomeres. Yeast telomeres are essential to allow the cell to distinguish intact from broken chromosomes, to protect the end of the chromosome from degradation, and to facilitate the replication of the very end of the chromosome. In addition, yeast telomeres are a specialized site for gene expression in that the transcription of genes placed near them is reversibly repressed. A surprisingly large number of genes have been identified that influence either telomere structure or telomere function (or both), although in many cases the mechanism of action of these genes is poorly understood. This article reviews the recent literature on telomere biology and highlights areas for future research.},
}
@article {pmid8977036,
year = {1996},
author = {Bacchetti, S},
title = {Telomere maintenance in tumour cells.},
journal = {Cancer surveys},
volume = {28},
number = {},
pages = {197-216},
pmid = {8977036},
issn = {0261-2429},
mesh = {Cell Division/genetics ; Cell Transformation, Neoplastic/genetics ; Cellular Senescence/genetics ; Chromosome Aberrations/genetics ; Humans ; Neoplasms/*genetics ; Telomerase/*physiology ; Telomere/genetics/*physiology ; },
abstract = {Telomere attrition may regulate the proliferative life span of somatic cells and contribute to the genetic instability of tumour cells, and telomere maintenance is required for cell survival. The ample, but mainly correlative, evidence in support of these hypotheses is now beginning to be complemented by experimental results. There have also been unexpected findings that attest to the complexity of the biological processes and systems under study. Mammalian telomere biology has definitely entered into an exciting phase. Given the increasing pace of research on this topic, it seems most likely that a not too distant future will provide us with answers to many of the unresolved issues mentioned in this article.},
}
@article {pmid8825773,
year = {1996},
author = {Underwood, AP and Louis, EJ and Borts, RH and Stringer, JR and Wakefield, AE},
title = {Pneumocystis carinii telomere repeats are composed of TTAGGG and the subtelomeric sequence contains a gene encoding the major surface glycoprotein.},
journal = {Molecular microbiology},
volume = {19},
number = {2},
pages = {273-281},
doi = {10.1046/j.1365-2958.1996.374904.x},
pmid = {8825773},
issn = {0950-382X},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Base Sequence ; Chromosomes, Artificial, Yeast/genetics ; Cloning, Molecular ; DNA, Fungal/*genetics ; DNA-Binding Proteins/genetics ; Endodeoxyribonucleases/metabolism ; Fungal Proteins/*genetics ; Membrane Glycoproteins/*genetics ; Molecular Sequence Data ; Pneumocystis/*genetics ; Rats ; Repetitive Sequences, Nucleic Acid/*genetics ; Saccharomyces cerevisiae/genetics ; *Saccharomyces cerevisiae Proteins ; Sequence Homology, Nucleic Acid ; Telomere/genetics/metabolism ; Transcription Factors ; },
abstract = {We have cloned a telomere and adjacent sequences from rat-derived Pneumocystis carinii using the ability of foreign telomeres to complement a yeast artificial chromosome (YAC) deficient by one telomere in Saccharomyces cerevisiae. Characterization of the cloned DNA in the recombinant YAC demonstrated that it was a chimera of two P. carinii sequences, namely a 13.5 kb fragment of mitochondrial DNA and an 8.3 kb distal portion consisting of subtelomeric DNA. The P. carinii telomere repeat was demonstrated to be TTAGGG, the most common telomere repeat found in organisms from the animal and fungal kingdoms. Karyotype analysis confirmed that this sequence was present on all the P. carinii chromosomes. Sequence adjacent to the telomere repeats was shown by Bal31 exonuclease digestion to be located at the chromosome ends. Analysis of the subtelomeric fragment revealed homology to the gene encoding the major surface glycoprotein of P. carinii.},
}
@article {pmid8811183,
year = {1996},
author = {Greider, CW},
title = {Telomere length regulation.},
journal = {Annual review of biochemistry},
volume = {65},
number = {},
pages = {337-365},
doi = {10.1146/annurev.bi.65.070196.002005},
pmid = {8811183},
issn = {0066-4154},
support = {AG09383/AG/NIA NIH HHS/United States ; GM43080/GM/NIGMS NIH HHS/United States ; },
mesh = {Cellular Senescence/genetics ; Enzyme Activation ; Humans ; Neoplasms/enzymology/genetics ; Telomerase/metabolism ; *Telomere ; },
abstract = {Telomeres are the components of chromosome ends that provide stability and allow the complete replication of the ends. Telomere length is maintained by a balance between processes that lengthen and those that shorten telomeres. Telomerase is a ribonucleoprotein polymerase that specifically elongates telomeres. In human cells telomere length is not maintained and telomerase is not active in some tissues. In tumors, however, telomerase is active and may be required for the growth of cancer cells. Thus understanding telomerase and telomere length regulation may help us understand tumor progression. Evidence from various organisms suggests that several factors influence telomere length regulation, such as telomere binding proteins, telomere capping proteins, telomerase, and DNA replication enzymes. Understanding how these factors interact to coordinate the regulation of telomere length will allow a more complete understanding of telomere function in the cell.},
}
@article {pmid8706799,
year = {1996},
author = {Vaziri, H and Benchimol, S},
title = {From telomere loss to p53 induction and activation of a DNA-damage pathway at senescence: the telomere loss/DNA damage model of cell aging.},
journal = {Experimental gerontology},
volume = {31},
number = {1-2},
pages = {295-301},
doi = {10.1016/0531-5565(95)02025-x},
pmid = {8706799},
issn = {0531-5565},
mesh = {Animals ; Cell Cycle ; *Cellular Senescence ; *DNA Damage ; Humans ; Retinoblastoma Protein/physiology ; *Telomere ; Tumor Suppressor Protein p53/*physiology ; },
abstract = {In the cold winter of 1966 Aleksay Olovnikov, a theoretical biologist at the Academy of Sciences in Moscow, was waiting in the subway station where he was hit by the idea that the ends of linear chromosomes can't be replicated fully during each round of replication. In a theoretical paper (Olovnikov, 1971) he proposed that in somatic cells the ends of the chromosomes are not fully replicated during DNA synthesis, resulting in the shortening of linear DNA molecules with each cell division, and that this may be the cause of cell cycle arrest in senescent cells. Almost two decades after this proposal, Calvin Harley and co-workers found that telomeres, the physical ends of human chromosomes, shorten as a function of age in human cells in vitro and in vivo. The telomere hypothesis proposes that critically short telomeres may act as a mitotic clock to signal the cell cycle arrest at senescence (Harley, 1991). Here, we extend the telomere hypothesis and propose a model that incorporates recent advances in tumor suppressors and cell cycle control with several areas of cell aging. We propose that telomere shortening per se is not the direct signal for cell cycle arrest. It is the consequence of telomere loss, which may lead to generation of ds or ss DNA breaks. These breaks activate a p53 dependent or independent DNA-damage pathway that leads to the induction of a family of inhibitors of cyclin dependent kinases (including p21 and p16) and the eventual G1 block of senescence. In agreement with this hypothesis, we demonstrate that the level of p53 protein increases in near senescent cultures of MDFs. This increase may be responsible for induction of p21 (Noda, 1993) and IGF-Bp3 (Goldstein, 1991).},
}
@article {pmid8641138,
year = {1996},
author = {Bar-Am, I and Avivi, L and Horowitz, M},
title = {Assignment of the human prosaposin gene (PSAP) to 10q22.1 by fluorescence in situ hybridization. Giraffidae, okapi (Okapiajohnstoni), and giraffe (Giraffa camelopardalis): evidence for ancestral telomeres at the okapi polymorphic rob (4;26) fusion site.},
journal = {Cytogenetics and cell genetics},
volume = {72},
number = {4},
pages = {316-318},
doi = {10.1159/000134212},
pmid = {8641138},
issn = {0301-0171},
mesh = {Animals ; Chromosome Mapping ; Chromosomes, Human, Pair 10/*genetics/ultrastructure ; DNA Probes ; Glycoproteins/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; Protein Precursors/*genetics ; Saposins ; },
abstract = {The human prosaposin gene (PSAP) was previously localized to 10q21-->q22 by isotopic in situ hybridization using a human prosaposin cDNA as a probe. The present study, using fluorescence in situ hybridization with a mouse genomic prosaposin fragment as probe, confirms the localization of PSAP and precisely maps it to band 10q22.1.},
}
@article {pmid8641137,
year = {1996},
author = {Vermeesch, JR and De Meurichy, W and Van Den Berghe, H and Marynen, P and Petit, P},
title = {Differences in the distribution and nature of the interstitial telomeric (TTAGGG)n sequences in the chromosomes of the Giraffidae, okapai (Okapia johnstoni), and giraffe (Giraffa camelopardalis): evidence for ancestral telomeres at the okapi polymorphic rob(5;26) fusion site.},
journal = {Cytogenetics and cell genetics},
volume = {72},
number = {4},
pages = {310-315},
doi = {10.1159/000134211},
pmid = {8641137},
issn = {0301-0171},
mesh = {Animals ; Artiodactyla/classification/*genetics ; Base Sequence ; *Evolution, Molecular ; In Situ Hybridization, Fluorescence ; *Microsatellite Repeats ; Molecular Sequence Data ; Polymorphism, Genetic ; Species Specificity ; Telomere/*genetics ; Translocation, Genetic ; },
abstract = {Intrachromosomal telomeric sequences (TTAGGG)n were analyzed in the two members of the family Giraffidae, the giraffe and the okapi. The giraffe has a diploid chromosome number of 2n = 30, whereas the okapi chromosome number varies from 2n = 46 to 2n = 45 and 2n = 44 due to a "recent" Robertsonian fusion event. The interstitial telomeres that we detected in these species are of two types: (1) In the okapi, a long interstitial telomeric element is present at the fusion site of the rob(4;26). The nature of this interstitial telomeric element suggests that it is a remnant of the telomeres of the ancestral chromosomes that participated in the fusion event. (2) In the giraffe, short stretches or degenerate telomeric sequences which are part of the satellite DNA are present at intrachromosomal sites. The results of this study provide insights into the origin of interstitial telomeric sequences in the Giraffidae.},
}
@article {pmid8616786,
year = {1996},
author = {Butler, MG and Sciadini, M and Hedges, LK and Schwartz, HS},
title = {Chromosome telomere integrity of human solid neoplasms.},
journal = {Cancer genetics and cytogenetics},
volume = {86},
number = {1},
pages = {50-53},
pmid = {8616786},
issn = {0165-4608},
support = {P01 HD030329/HD/NICHD NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Autoradiography ; Blotting, Southern ; Bone Neoplasms/genetics ; Child ; Child, Preschool ; Chordoma/genetics ; Colonic Neoplasms/genetics ; DNA, Neoplasm/analysis ; Electrophoresis, Agar Gel ; Glioblastoma/genetics ; Humans ; Infant ; Kidney Neoplasms/genetics ; Middle Aged ; Neoplasms/*genetics ; Telomere/*chemistry/*ultrastructure ; Wilms Tumor/genetics ; },
abstract = {Eukaryotic chromosomes contain specialized structures at the termini called telomeres. This region of DNA is required for replication and stability of the chromosome. Telomere reduction can contribute to genetic instability and has been described in certain malignancies (e.g., colon, leukemia, giant cell tumor of bone). To determine whether telomere reduction is a generalized phenomenon in malignancies, the telomere integrity of genomic DNA isolated from tumor cells was determined from 39 individuals with 15 different malignancies categorized as musculoskeletal, epithelial, cranial, or other, and peripheral blood leukocytes from the same patient, when possible, or age-matched controls. Significant telomere reduction occurred randomly across histopathologic groups including giant cell tumor of bone, glioblastoma, colon cancer, and Wilms' tumor while telomere elongation occurred in chordoma. The other remaining 10 malignancies do not show significant differences in telomere lengths compared with controls.},
}
@article {pmid8615664,
year = {1996},
author = {Sharma, HW and Maltese, JY and Zhu, X and Kaiser, HE and Narayanan, R},
title = {Telomeres, telomerase and cancer: is the magic bullet real?.},
journal = {Anticancer research},
volume = {16},
number = {1},
pages = {511-515},
pmid = {8615664},
issn = {0250-7005},
mesh = {Animals ; Antineoplastic Agents/pharmacology ; Base Sequence ; Enzyme Inhibitors/pharmacology ; Humans ; Molecular Sequence Data ; Neoplasms/*enzymology/*genetics ; Telomerase/*antagonists &amp; inhibitors/*metabolism ; Telomere/*physiology ; },
abstract = {Nature recruited telomerase to compensate for the incomplete replication of chromosomal ends (telomeres). In higher organisms, telomeres are eroded at each cell division. Cancer cells frequently show chromosomal instability resulting in ring chromosomes, telomeric associations, and dicentric chromosomes. As a consequence of telomeric erosion, the ribonucleoprotein complex termed "telomerase" is reactive in a subpopulation of cells. Telomerase adds a hexameric repeat of the sequence 5' TTAGGG 3' to the ends of the chromosomes and hence stabilizes the telomeric length. Telomerase is active in vertebrates mostly in germ cells and the early stage embryo but is inactivated or repressed in somatic cells. Detection of telomerase activity in the overwhelming majority of advanced and metastatic human cancers but not in most somatic cells implies that telomerase-dependent immortalization could contribute to the malignancy. Future studies on the expression and regulation of the individual components of telomerase may enable us to clarify the diagnostic and therapeutic potential of telomerase in cancer.},
}
@article {pmid8597804,
year = {1996},
author = {Bates, G},
title = {Cloning of human telomeres in Saccharomyces cerevisiae.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {54},
number = {},
pages = {49-63},
doi = {10.1385/0-89603-313-9:49},
pmid = {8597804},
issn = {1064-3745},
mesh = {Buffers ; *Chromosomes, Artificial, Yeast ; Cloning, Molecular/*methods ; Culture Media ; DNA Ligases/metabolism ; Genetic Vectors ; Genome, Human ; Humans ; Nucleic Acid Hybridization ; Saccharomyces cerevisiae/genetics ; Solutions ; Telomere/*genetics ; Transformation, Genetic ; },
}
@article {pmid8557247,
year = {1996},
author = {Sugihara, S and Mihara, K and Marunouchi, T and Inoue, H and Namba, M},
title = {Telomere elongation observed in immortalized human fibroblasts by treatment with 60Co gamma rays or 4-nitroquinoline 1-oxide.},
journal = {Human genetics},
volume = {97},
number = {1},
pages = {1-6},
pmid = {8557247},
issn = {0340-6717},
mesh = {4-Nitroquinoline-1-oxide/*pharmacology ; Base Sequence ; Cell Line, Transformed ; Clone Cells ; Cobalt Radioisotopes ; Fetus ; Fibroblasts ; *Gamma Rays ; Humans ; Liver ; Male ; Molecular Sequence Data ; Regression Analysis ; Repetitive Sequences, Nucleic Acid ; Telomere/drug effects/radiation effects/*ultrastructure ; },
abstract = {Telomeres are the tandemly repeated (TTAGGG)n sequences that make up the structural and functional ends of all chromosomes in mammals. Many lines of evidence indicate that telomeres stabilize chromosomes, prevent aberrant recombination, and direct chromosome attachment to the nuclear membrane. Since DNA polymerase requires a labile primer to initiate unidirectional 5'-3' DNA synthesis, some bases at the 3' end of each template strand are not copied unless special mechanisms bypass this end-replication problem. To overcome this problem, most eukaryotic cells use telomerase, an enzyme that elongates telomeres. However, this enzyme has not been detected in normal human cells, and these cells lose telomeres with cell division. Cellular senescence might be the result of this loss. Thus, activation of telomerase seems to be critical for the immortalization of human cell lines. In addition, substantial evidence indicates that immortalization in itself is a rate-limiting step for the malignant transformation of human cells. We have treated normal human fibroblasts (AD387, KMS-6, and OUMS-24 lines) intermittently with either 60Co gamma rays or 4-nitroquinoline 1-oxide (4NQO) during serial subcultivations, and have obtained three immortalized cell lines, SUSM-1, KMST-6, and OUMS-24F. In KMS-6 and OUMS-24, the mean terminal restriction fragment length significantly decreased as the population-doubling level increased. The rate of telomere loss was 40 and 50 bp/population doubling in the KMS-6 and OUMS-24 cell lines, respectively. Once these normal cell lines were immortalized, their telomeres became elongated. Similar data were obtained for AD387 cells and their immortalized SUSM-1 cells. These results suggest that telomeres play a critical role in cellular senescence and in the immortalization processes of human cells.},
}
@article {pmid8524329,
year = {1996},
author = {Strahl, C and Blackburn, EH},
title = {Effects of reverse transcriptase inhibitors on telomere length and telomerase activity in two immortalized human cell lines.},
journal = {Molecular and cellular biology},
volume = {16},
number = {1},
pages = {53-65},
pmid = {8524329},
issn = {0270-7306},
support = {GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Antiviral Agents/pharmacology ; Arabinonucleosides/pharmacology ; Cell Division/drug effects ; Cell Line ; DNA/genetics ; Dideoxynucleosides/pharmacology ; Dideoxynucleotides ; Drug Interactions ; Foscarnet/pharmacology ; Humans ; Oligonucleotide Probes ; Repetitive Sequences, Nucleic Acid ; Reverse Transcriptase Inhibitors/*pharmacology ; Telomerase/*antagonists &amp; inhibitors ; Telomere/*drug effects/genetics/ultrastructure ; Thymine Nucleotides/pharmacology ; Zidovudine/analogs &amp; derivatives/pharmacology ; },
abstract = {The ribonucleoprotein telomerase, a specialized cellular reverse transcriptase, synthesizes one strand of the telomeric DNA of eukaryotes. We analyzed telomere maintenance in two immortalized human cell lines: the B-cell line JY616 and the T-cell line Jurkat E6-1, and determined whether known inhibitors of retroviral reverse transcriptases could perturb telomere lengths and growth rates of these cells in culture. Dideoxyguanosine (ddG) caused reproducible, progressive telomere shortening over several weeks of passaging, after which the telomeres stabilized and remained short. However, the prolonged passaging in ddG caused no observable effects on cell population doubling rates or morphology. Azidothymidine (AZT) caused progressive telomere shortening in some but not all T- and B-cell cultures. Telomerase activity was present in both cell lines and was inhibited in vitro by ddGTP and AZT triphosphate. Prolonged passaging in arabinofuranyl-guanosine, dideoxyinosine (ddI), dideoxyadenosine (ddA), didehydrothymidine (d4T), or phosphonoformic acid (foscarnet) did not cause reproducible telomere shortening or decreased cell growth rates or viabilities. Combining AZT, foscarnet, and/or arabinofuranyl-guanosine with ddG did not significantly augment the effects of ddG alone. Strikingly, with or without inhibitors, telomere lengths were often highly unstable in both cell lines and varied between parallel cell cultures. We propose that telomere lengths in these T- and B-cell lines are determined by both telomerase and telomerase-independent mechanisms.},
}
@article {pmid8524289,
year = {1996},
author = {Huang, YJ and Stoffel, R and Tobler, H and Mueller, F},
title = {A newly formed telomere in Ascaris suum does not exert a telomere position effect on a nearby gene.},
journal = {Molecular and cellular biology},
volume = {16},
number = {1},
pages = {130-134},
pmid = {8524289},
issn = {0270-7306},
mesh = {Amino Acid Sequence ; Animals ; Ascaris suum/*genetics ; Base Sequence ; Caenorhabditis elegans/genetics ; DNA Primers/genetics ; DNA, Complementary/genetics ; DNA, Helminth/genetics ; Female ; *Genes, Helminth ; Molecular Sequence Data ; Saccharomyces cerevisiae/genetics ; Species Specificity ; Telomere/*genetics ; },
abstract = {During the process of chromatin diminution in Ascaris suum (formerly named Ascaris lumbricoides var. suum), developmentally regulated chromosomal fragmentation and new telomere addition occur within specific chromosomal breakage regions (CBRs). The DNA sequences flanking one of these CBRs (CBR-1) were analyzed, and two protein-encoding genes were found on either side. The noneliminated gene, agp-1, whose AUG start codon is located within approximately 2 kb of the boundary of CBR-1, encodes a putative GTP-binding protein which is structurally related to eukaryotic and prokaryotic elongation factors. Northern (RNA) blot analyses revealed that transcripts of this gene are present at all developmental stages, suggesting that the massive chromosomal rearrangements associated with the process of chromatin diminution have no influence on agp-1 expression. This demonstrates that addition of new telomeres in CBR-1 does not result in a telomeric position effect, a phenomenon previously described in Saccharomyces cerevisiae.},
}
@article {pmid7502069,
year = {1995},
author = {Zakian, VA},
title = {Telomeres: beginning to understand the end.},
journal = {Science (New York, N.Y.)},
volume = {270},
number = {5242},
pages = {1601-1607},
doi = {10.1126/science.270.5242.1601},
pmid = {7502069},
issn = {0036-8075},
mesh = {Animals ; Base Sequence ; Cell Cycle ; Chromosomes/metabolism/physiology ; DNA/analysis/chemistry/metabolism ; DNA Replication ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation ; Humans ; Molecular Sequence Data ; Telomerase/metabolism ; Telomere/chemistry/*physiology ; },
abstract = {Telomeres are the protein-DNA structures at the ends of eukaryotic chromosomes. In yeast, and probably most other eukaryotes, telomeres are essential. They allow the cell to distinguish intact from broken chromosomes, protect chromosomes from degradation, and are substrates for novel replication mechanisms. Telomeres are usually replicated by telomerase, a telomere-specific reverse transcriptase, although telomerase-independent mechanisms of telomere maintenance exist. Telomere replication is both cell cycle- and developmentally regulated, and its control is likely to be complex. Because telomere loss causes the kinds of chromosomal changes associated with cancer and aging, an understanding of telomere biology has medical relevance.},
}
@article {pmid8565699,
year = {1995},
author = {Walter, MF and Jang, C and Kasravi, B and Donath, J and Mechler, BM and Mason, JM and Biessmann, H},
title = {DNA organization and polymorphism of a wild-type Drosophila telomere region.},
journal = {Chromosoma},
volume = {104},
number = {4},
pages = {229-241},
pmid = {8565699},
issn = {0009-5915},
support = {GM46211/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cloning, Molecular ; DNA, Satellite ; Drosophila melanogaster/*genetics ; Genes, Insect ; In Situ Hybridization, Fluorescence ; Larva/genetics ; Molecular Sequence Data ; *Polymorphism, Genetic ; Restriction Mapping ; Retroelements ; Sequence Analysis, DNA ; Telomere/*genetics ; },
abstract = {Telomeres at the ends of linear chromosomes of eukaryotes protect the chromosome termini from degradation and fusion. While telomeric replication/elongation mechanisms have been studied extensively, the functions of subterminal sequences are less well understood. In general, subterminal regions can be quite polymorphic, varying in size from organism to organism, and differing among chromosomes within an organism. The subterminal regions of Drosophila melanogaster are not well characterized today, and it is not known which and how many different components they contain. Here we present the molecular characterization of DNA components and their organization in the subterminal region of the left arm of chromosome 2 of the Oregon RC wild-type strain of D. melanogaster, including a minisatellite with a 457bp repeat length. Two distinct polymorphic arrangements at 2L were found and analyzed, supporting the Drosophila telomere elongation model by retrotransposition. The high incidence of terminal chromosome deficiencies occurring in natural Drosophila populations is discussed in view of the telomere structure at 2L.},
}
@article {pmid7479963,
year = {1995},
author = {Chang, E and Harley, CB},
title = {Telomere length and replicative aging in human vascular tissues.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {92},
number = {24},
pages = {11190-11194},
pmid = {7479963},
issn = {0027-8424},
support = {AG-09383/AG/NIA NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Cell Division ; *Cellular Senescence ; Child, Preschool ; Endothelium, Vascular/*cytology ; Female ; Hemodynamics ; Humans ; Iliac Artery ; Male ; Middle Aged ; Stress, Mechanical ; Telomere/*ultrastructure ; Thoracic Arteries ; },
abstract = {Because repeated injury of the endothelium and subsequent turnover of intimal and medial cells have been implicated in atherosclerosis, we examined telomere length, a marker of somatic cell turnover, in cells from these tissues. Telomere lengths were assessed by Southern analysis of terminal restriction fragments (TRFs) generated by HinfI/Rsa I digestion of human genomic DNA. Mean TRF length decreased as a function of population doublings in human endothelial cell cultures from umbilical veins, iliac arteries, and iliac veins. When endothelial cells were examined for mean TRF length as a function of donor age, there was a significantly greater rate of decrease for cells from iliac arteries than from iliac veins (102 bp/yr vs. 47 bp/yr, respectively, P < 0.05), consistent with higher hemodynamic stress and increased cell turnover in arteries. Moreover, the rate of telomere loss as a function of donor age was greater in the intimal DNA of iliac arteries compared to that of the internal thoracic arteries (147 bp/yr vs. 87 bp/yr, respectively, P < 0.05), a region of the arterial tree subject to less hemodynamic stress. This indicates that the effect is not tissue specific. DNA from the medial tissue of the iliac and internal thoracic arteries showed no significant difference in the rates of decrease, suggesting that chronic stress leading to cellular senescence is more pronounced in the intima than in the media. These observations extend the use of telomere size as a marker for the replicative history of cells and are consistent with a role for focal replicative senescence in cardiovascular diseases.},
}
@article {pmid8551749,
year = {1995},
author = {Arino, O and Kimmel, M and Webb, GF},
title = {Mathematical modeling of the loss of telomere sequences.},
journal = {Journal of theoretical biology},
volume = {177},
number = {1},
pages = {45-57},
doi = {10.1006/jtbi.1995.0223},
pmid = {8551749},
issn = {0022-5193},
mesh = {Animals ; Cell Death/genetics ; Cellular Senescence/*genetics ; DNA Replication ; Mathematics ; *Models, Genetic ; Telomere/*genetics ; },
abstract = {hortening of telomeres is one of the supposed mechanisms of cellular aging and death. An important question related to this so-called "end-replication" hypothesis is whether it can explain in quantitative detail the dynamic of cell sensescence in vitro and in vivo. A natural way to answer this question is to use mathematical modeling. In this paper, the models were successfully fitted to data on cultured fibroblasts from two different sources assuming that after reaching the Hayflick checkpoint on a single chromosome cells cease to proliferate. The main conclusion is that the end-replication hypothesis provides an explanation for the cell aging process which is quantitatively consistent with the data. As a secondary outcome, estimates were obtained of the rate of shortening of telomeres and several interesting mathematical results for branching processes with infinite type spaces arise.},
}
@article {pmid9415184,
year = {1995},
author = {Shay, JW},
title = {Aging and cancer: are telomeres and telomerase the connection?.},
journal = {Molecular medicine today},
volume = {1},
number = {8},
pages = {378-384},
doi = {10.1016/s1357-4310(95)93872-9},
pmid = {9415184},
issn = {1357-4310},
support = {AG07992/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*genetics ; Animals ; Cell Division/genetics ; DNA Replication ; Forecasting ; Humans ; Models, Biological ; Neoplasms/diagnosis/drug therapy/*genetics ; Telomerase/antagonists &amp; inhibitors/*physiology ; Telomere/*physiology ; },
abstract = {There is substantial evidence for the progressive loss of the telomeric ends of chromosomes during aging, both in cell culture and in vivo. The loss of telomeres may eventually induce antiproliferative signals that result in cellular senescence. A hypothesis gaining prominence is that the activation of telomerase, a ribonucleoprotein enzyme that is important in maintaining telomere length stability, is necessary for the sustained growth of most tumors. The interrelationships between telomere shortening and aging, and how activation of telomerase may be necessary for cells to become immortal and malignant, are reviewed here.},
}
@article {pmid8669821,
year = {1995},
author = {Pathak, S},
title = {Centromere or telomere: who is the boss?.},
journal = {Anticancer research},
volume = {15},
number = {6B},
pages = {2549-2550},
pmid = {8669821},
issn = {0250-7005},
support = {RRO 4999-01/RR/NCRR NIH HHS/United States ; },
mesh = {Aneuploidy ; Animals ; Apoptosis/genetics ; Centromere/*physiology ; Humans ; Mice ; *Models, Genetic ; Muntjacs/genetics ; Neoplasms/genetics/pathology ; Neoplasms, Experimental/genetics/pathology ; Swine ; Telomere/*physiology ; Translocation, Genetic ; Tumor Cells, Cultured ; },
}
@article {pmid8582633,
year = {1995},
author = {Sussel, L and Vannier, D and Shore, D},
title = {Suppressors of defective silencing in yeast: effects on transcriptional repression at the HMR locus, cell growth and telomere structure.},
journal = {Genetics},
volume = {141},
number = {3},
pages = {873-888},
pmid = {8582633},
issn = {0016-6731},
support = {CA-09503-0/CA/NCI NIH HHS/United States ; GM-40094/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes, Fungal/*ultrastructure ; DNA-Binding Proteins/genetics ; Fungal Proteins/*genetics/physiology ; GTP-Binding Proteins/genetics ; *Gene Expression Regulation, Fungal/genetics ; *Genes, Fungal ; *Genes, Suppressor ; Genetic Complementation Test ; Mediator Complex ; Repressor Proteins/genetics ; Saccharomyces cerevisiae/*genetics/growth &amp; development ; *Saccharomyces cerevisiae Proteins ; Telomere/*ultrastructure ; *Telomere-Binding Proteins ; Trans-Activators/*genetics/physiology ; *Transcription, Genetic ; rap GTP-Binding Proteins ; },
abstract = {To identify factors that affect transcriptional silencing at the HMR mating-type locus in yeast, we characterized a set of extragenic suppressor mutations that restore metastable repression in cells containing both a mutant silencer-binding protein (rap1s) and a mutated silencer element (hmr delta A). A total of 57 suppressors comprising 21 different complementation groups was identified. This report describes a detailed genetic analysis of these suppressors of defective silencing (sds) mutants. The sds mutants fall into several distinct categories based on secondary phenotypes, such as their ability to suppress the rap1s telomere lengthening phenotype, general effects on telomere length, temperature-dependent growth defects, and the ability to bypass the requirement for cis regulatory elements at the HMR-E silencer. One particular mutant, sds4-1, strongly suppresses the rap1s silencing defect, restores telomeres to nearly wild-type length, and displays a severe growth defect at all temperatures. SDS4 mutations also suppress the silencing defect caused by mutations in the RAP1-interacting factor RIF1. We cloned the SDS4 gene and show that it is identical to GAL11(SPT13), which encodes a component of a protein complex that mediates transcriptional activation. Possible mechanism(s) of suppression by sds4 and the other sds mutations is discussed.},
}
@article {pmid8536238,
year = {1995},
author = {Butler, MG and Dahir, GA and Hedges, LK and Juliao, SF and Sciadini, MF and Schwartz, HS},
title = {Cytogenetic, telomere, and telomerase studies in five surgically managed lumbosacral chordomas.},
journal = {Cancer genetics and cytogenetics},
volume = {85},
number = {1},
pages = {51-57},
pmid = {8536238},
issn = {0165-4608},
support = {P01 HD030329/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Aged ; Blotting, Southern ; Chordoma/enzymology/*genetics/surgery ; *Chromosome Aberrations ; DNA, Neoplasm/analysis/chemistry ; Female ; Humans ; Karyotyping ; *Lumbosacral Region ; Male ; Middle Aged ; Repetitive Sequences, Nucleic Acid ; Spinal Neoplasms/enzymology/*genetics/surgery ; Telomerase/*metabolism ; Telomere/*chemistry/metabolism/ultrastructure ; },
abstract = {Lumbosacral chordomas are rare skeletal sarcomas of the spine that originate from the remnant notochord. The understanding of this human cancer is limited to observations of its clinical behavior and its embryonic link. Thus, we performed chromosome and molecular analyses from five surgically harvested chordomas in an effort to document genetic and biochemical abnormalities which might aid in understanding the tumor biology of this understudied neoplasm. Cytogenetic analysis of the five chordomas revealed normal results in four patients and random abnormalities in only one tumor cell in the 100 cells studied from the fifth patient. A repeat telomeric probe (TTAGGG)50 was hybridized to genomic DNA isolated from chordoma cells (and HeLa cells) and digested with HinfI. The tumor DNA was paired with leukocyte DNA from age-matched controls and revealed telomere elongation in four of the four chordoma patients studied with molecular genetic techniques. Conversely, telomere length reduction has been reported during in vitro senescence of human fibroblasts, giant cell tumor of bone, colon cancer, intracranial tumors, childhood leukemia, Wilms tumor, and in HeLa cells. Telomerase activity (telomerase is required to maintain telomere integrity) was also determined by visualizing the extension of radioactive telomeric repeats on DNA sequencing gels. The telomeric fragments were assembled during incubation of the cytoplasmic extract containing telomerase. Telomerase activity was observed in HeLa (positive control and commercially available cell line), giant cell tumor of bone (positive control tumor cells from living patients), and in chordoma cells from one of the two chordoma patients (but to a lesser degree compared with HeLa). As expected, the chordoma patients' fibroblasts exhibited no telomerase activity.},
}
@article {pmid8535136,
year = {1995},
author = {Vershinin, AV and Schwarzacher, T and Heslop-Harrison, JS},
title = {The large-scale genomic organization of repetitive DNA families at the telomeres of rye chromosomes.},
journal = {The Plant cell},
volume = {7},
number = {11},
pages = {1823-1833},
pmid = {8535136},
issn = {1040-4651},
mesh = {Arabidopsis/genetics ; Base Sequence ; *Chromosome Mapping ; Cloning, Molecular ; DNA Primers ; DNA Probes ; DNA, Plant/*genetics ; *Genes, Plant ; In Situ Hybridization ; Molecular Sequence Data ; Polymerase Chain Reaction ; *Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; Saccharomyces cerevisiae/genetics ; Secale/*genetics ; Sequence Homology, Nucleic Acid ; *Telomere ; },
abstract = {Repetitive DNA sequences in the terminal heterochromatin of rye (Secale cereale) chromosomes have consequences for the structural and functional organization of chromosomes. The large-scale genomic organization of these regions was studied using the telomeric repeat from Arabidopsis and clones of three nonhomologous, tandemly repeated, subtelomeric DNA families with complex but contrasting higher order structural organizations. Polymerase chain reaction analysis with a single primer showed a fraction of the repeat units of one family organized in a "head-to-head" orientation. Such structures suggest evolution of chromosomes by chromatid-type breakage-fusion-bridge cycles. In situ hybridization and pulse field gel electrophoresis showed the order of the repeats and the heterogeneity in the lengths of individual arrays. After Xbal digestion and pulse field gel electrophoresis, the telomeric and two subtelomeric clones showed strong hybridization signals from 40 to 100 kb, with a maximum at 50 to 60 kb. We suggest that these fragments define a basic higher order structure and DNA loop domains of regions of rye chromosomes consisting of arrays of tandemly organized sequences.},
}
@article {pmid7565765,
year = {1995},
author = {Garvik, B and Carson, M and Hartwell, L},
title = {Single-stranded DNA arising at telomeres in cdc13 mutants may constitute a specific signal for the RAD9 checkpoint.},
journal = {Molecular and cellular biology},
volume = {15},
number = {11},
pages = {6128-6138},
pmid = {7565765},
issn = {0270-7306},
support = {GM17709/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; *Cell Cycle Proteins ; Cloning, Molecular ; Cyclin B ; Cyclins/*physiology ; *DNA Replication ; DNA, Fungal/biosynthesis ; DNA, Single-Stranded/metabolism ; DNA-Directed DNA Polymerase/genetics ; Epistasis, Genetic ; Fungal Proteins/*physiology ; Gene Deletion ; Genes, Fungal ; Molecular Sequence Data ; Recombination, Genetic ; Saccharomyces cerevisiae/*genetics ; Telomere/*ultrastructure ; },
abstract = {A cdc13 temperature-sensitive mutant of Saccharomyces cerevisiae arrests in the G2 phase of the cell cycle at the restrictive temperature as a result of DNA damage that activates the RAD9 checkpoint. The DNA lesions present after a failure of Cdc13p function appear to be located almost exclusively in telomere-proximal regions, on the basis of the profile of induced mitotic recombination. cdc13 rad9 cells dividing at the restrictive temperature contain single-stranded DNA corresponding to telomeric and telomere-proximal DNA sequences and eventually lose telomere-associated sequences. These results suggest that the CDC13 product functions in telomere metabolism, either in the replication of telomeric DNA or in protecting telomeres from the double-strand break repair system. Moreover, since cdc13 rad9 cells divide at a wild-type rate for several divisions at the restrictive temperature while cdc13 RAD9 cells arrest in G2, these results also suggest that single-stranded DNA may be a specific signal for the RAD9 checkpoint.},
}
@article {pmid7489733,
year = {1995},
author = {Farr, CJ and Bayne, RA and Kipling, D and Mills, W and Critcher, R and Cooke, HJ},
title = {Generation of a human X-derived minichromosome using telomere-associated chromosome fragmentation.},
journal = {The EMBO journal},
volume = {14},
number = {21},
pages = {5444-5454},
pmid = {7489733},
issn = {0261-4189},
mesh = {Animals ; Base Sequence ; Cell Line ; Chromosome Mapping ; Cricetinae ; DNA, Recombinant/*genetics ; DNA, Satellite/genetics ; Humans ; In Situ Hybridization ; Molecular Sequence Data ; Telomere/*genetics ; *X Chromosome ; },
abstract = {A linear mammalian artificial chromosome vector will require at least three functional elements: a centromere, two telomeres and replication origins. One route to generate such a vector is by the fragmentation of an existing chromosome. We have previously described the use of cloned telomeric DNA to generate and stably rescue truncated derivatives of a human X chromosome in a somatic cell hybrid. Further rounds of telomere-associated chromosome fragmentation have now been used to engineer a human X-derived minichromosome. This minichromosome is estimated to be < 10 Mb in size. In situ hybridization and molecular analysis reveal that the minichromosome has a linear structure, with two introduced telomere constructs flanking a 2.5 Mb alpha-satellite array. The highly truncated chromosome also retains some chromosome-specific DNA, originating from Xp11.21. There is no significant change in the mitotic stability of the minichromosome as compared with the X chromosome from which it was derived.},
}
@article {pmid7489732,
year = {1995},
author = {Baird, DM and Jeffreys, AJ and Royle, NJ},
title = {Mechanisms underlying telomere repeat turnover, revealed by hypervariable variant repeat distribution patterns in the human Xp/Yp telomere.},
journal = {The EMBO journal},
volume = {14},
number = {21},
pages = {5433-5443},
pmid = {7489732},
issn = {0261-4189},
mesh = {Alleles ; Base Sequence ; Chromosome Mapping ; DNA/*genetics ; Haplotypes ; Humans ; Minisatellite Repeats ; Molecular Sequence Data ; *Polymorphism, Single-Stranded Conformational ; Sequence Analysis ; Telomere/*genetics ; X Chromosome/*genetics ; Y Chromosome/*genetics ; },
abstract = {Sequences immediately adjacent to the human Xp/Yp telomere exhibit a high frequency of base substitutional polymorphisms, together with almost complete linkage disequilibrium, to create only a few diverged haplotypes. This sequence divergence has been used to develop a PCR-based system for mapping the distribution of the telomere (TTAGGG) and variant repeats (TGAGGG and TCAGGG) at the proximal end of the telomere repeat array. The distribution of these repeats is extremely variable. Almost all Xp/Yp telomeres are different, indicating a high mutation rate. Some telomere maps associated with the same flanking haplotype show similarities, identifying subsets of telomeres that share a recent common ancestry. Mechanisms underlying the rapid turnover of repeats at the proximal end of the Xp/Yp telomere include intra-allelic processes, such as slippage during replication. Inter-allelic exchanges may occur occasionally, but telomerase activity probably plays only a minor role in the germline turnover of proximally located telomere and variant repeats.},
}
@article {pmid8590010,
year = {1995},
author = {Smith, FW and Schultze, P and Feigon, J},
title = {Solution structures of unimolecular quadruplexes formed by oligonucleotides containing Oxytricha telomere repeats.},
journal = {Structure (London, England : 1993)},
volume = {3},
number = {10},
pages = {997-1008},
doi = {10.1016/s0969-2126(01)00236-2},
pmid = {8590010},
issn = {0969-2126},
support = {GM07185/GM/NIGMS NIH HHS/United States ; R01 GM48123/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Composition ; Base Sequence ; Guanosine/chemistry ; Inosine/chemistry ; Magnetic Resonance Spectroscopy/methods ; Models, Molecular ; Molecular Sequence Data ; Nucleic Acid Conformation ; Oligonucleotides/*chemistry/genetics ; Oxytricha/*genetics ; Potassium/chemistry ; Protons ; Repetitive Sequences, Nucleic Acid ; Software ; Telomere/*chemistry/genetics ; },
abstract = {BACKGROUND: Oligonucleotides containing the guanine-rich telomeric sequence of Oxytricha chromosomes (dT4G4) have previously been shown to form DNA quadruplexes comprising guanine quartets stabilized by cations. Two different structures have been reported for both d(G4T4G4) (Oxy1.5) and d(G4T4G4T4G4T4G4) (Oxy3.5).<br><br>RESULTS: Here we present the solution structure of a uracil- and inosine-containing derivative of Oxy3.5, d(G4TUTUG4T4G4UUTTG3I) (Oxy3.5-U4128), determined using two-dimensional 1H and 31P NMR techniques. This oligonucleotide forms a unimolecular quadruplex that is very similar to the dimeric Oxy1.5 solution structure, in that it contains a loop spanning the diagonal of an end quartet. The groove widths, strand polarities, and positions of the syn bases along the G4 tracts and within the quartets are all as reported for Oxy1.5. The first and third pyrimidine tracts form parallel loops spanning a wide groove and a narrow groove respectively.<br><br>CONCLUSIONS: Both Oxy3.5 and Oxy3.5-U(4)128 form unimolecular quadruplexes in solution with a diagonal central T4 loop. These results conflict with those reported for d(G4TUTUG4TTUUG4UUTTG4) in solution, in which the central loop spans a wide groove.},
}
@article {pmid8575758,
year = {1995},
author = {Pandit, SD and Wang, JC and Veile, RA and Mishra, SK and Warlick, CA and Donis-Keller, H},
title = {Index, comprehensive microsatellite, and unified linkage maps of human chromosome 14 with cytogenetic tie points and a telomere microsatellite marker.},
journal = {Genomics},
volume = {29},
number = {3},
pages = {653-664},
doi = {10.1006/geno.1995.9953},
pmid = {8575758},
issn = {0888-7543},
support = {HG-00100/HG/NHGRI NIH HHS/United States ; HG-00469/HG/NHGRI NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosome Mapping ; *Chromosomes, Human, Pair 14 ; Cosmids ; DNA Primers ; DNA, Satellite/*genetics ; Female ; *Genetic Linkage ; Genetic Markers ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Male ; Molecular Sequence Data ; Odds Ratio ; Polymerase Chain Reaction ; *Polymorphism, Restriction Fragment Length ; *Sex Characteristics ; *Telomere ; },
abstract = {Three sets of linkage maps (index, comprehensive microsatellite, and unified) have been constructed for human chromosome 14 based on genotypes from the CEPH reference pedigrees. The index maps consist of 18 microsatellite markers, with heterozygosities of at least 68% and intermarker spacing no greater than 11 cM. The sex-average comprehensive microsatellite map is 125 cM in length and includes 115 markers with 54 loci uniquely placed with odds for marker order of at least 1000:1. The sex-average index map length is 121 cM, and the female- and male-specific maps are 143 and 101 cM, respectively. A unified map was also constructed from 147 loci (162 marker systems), which includes 32 RFLP markers in addition to the 115 microsatellites. The sex-average length of the unified map is 128 cM with 69 loci uniquely placed. Our maps are anchored by a microsatellite telomere marker sCAW1 (D14S826), developed from a telomere YAC clone TYAC196, which extends the linkage map to the physical terminus of the long arm of chromosome 14. Furthermore, we have also physically mapped seven of the loci by fluorescence in situ hybridization of cosmid clones or Alu-PCR products amplified from YACs containing the marker sequences. Together with previously established cytogenetic map designations for other loci, our maps display links between genetic markers for 10 of 13 cytogenetic bands of chromosome 14 at the 550 genome band resolution.},
}
@article {pmid8575753,
year = {1995},
author = {Rounds, D and Brueckner, M and Ward, DC},
title = {Isolation of murine telomere-proximal sequences by affinity capture and PCR.},
journal = {Genomics},
volume = {29},
number = {3},
pages = {616-622},
doi = {10.1006/geno.1995.9958},
pmid = {8575753},
issn = {0888-7543},
mesh = {Animals ; Avidin ; Base Sequence ; Consensus Sequence ; Cosmids ; DNA/analysis ; DNA Primers ; DNA Probes ; Deoxyribonucleases, Type II Site-Specific ; Exodeoxyribonucleases ; Genomic Library ; In Situ Hybridization, Fluorescence ; Karyotyping ; Mice ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Polymerase Chain Reaction/methods ; RNA/analysis ; *Repetitive Sequences, Nucleic Acid ; *Telomere ; Viral Proteins ; },
abstract = {We describe a method of selectively enriching for murine telomere-proximal sequences using affinity capture followed by PCR amplification. The telomeric fragments were selected from NotI-digested and lambda exonuclease-resected mouse genomic DNA by annealing to a biotinylated riboprobe containing multiple copies of the telomere repeat (TTAGGG)n. The resultant DNA-RNA hybrids were selectively retained on a matrix with covalently bound avidin. The captured DNA was then specifically released by ribonuclease action, and PCR amplification was performed using mouse repeat primers. The PCR products were cloned and used to screen a mouse genomic cosmid library, and the resultant cosmid clones were analyzed by fluorescence in situ hybridization. Ten of 70 clones analyzed gave telomere-proximal hybridization signals, indicating an at least 500-fold enrichment for telomere-proximal sequences.},
}
@article {pmid8593610,
year = {1995},
author = {Macina, RA and Morii, K and Hu, XL and Negorev, DG and Spais, C and Ruthig, LA and Riethman, HC},
title = {Molecular cloning and RARE cleavage mapping of human 2p, 6q, 8q, 12q, and 18q telomeres.},
journal = {Genome research},
volume = {5},
number = {3},
pages = {225-232},
doi = {10.1101/gr.5.3.225},
pmid = {8593610},
issn = {1088-9051},
support = {5-F32 GM 12884/GM/NIGMS NIH HHS/United States ; HG00567/HG/NHGRI NIH HHS/United States ; P30-CA10815/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosomes, Artificial, Yeast ; Chromosomes, Human/*genetics/ultrastructure ; Chromosomes, Human, Pair 12/genetics/ultrastructure ; Chromosomes, Human, Pair 18/genetics/ultrastructure ; Chromosomes, Human, Pair 2/genetics/ultrastructure ; Chromosomes, Human, Pair 6/genetics/ultrastructure ; Chromosomes, Human, Pair 8/genetics/ultrastructure ; Cloning, Molecular ; Humans ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Polymerase Chain Reaction ; Restriction Mapping ; Telomere/*genetics ; },
abstract = {Large terminal fragments of human chromosomes 2p, 6p, 8q, 12q, and 18q were cloned using yeast artificial chromosomes (YACs). RecA-assisted restriction endonuclease (RARE) cleavage analysis of genomic DNA samples from II unrelated individuals using YAC-derived probes confirmed the telomeric localizations of the half-YACs studied. The cloned fragments provide telomeric closure of maps for the respective chromosome arms and will supply the reagents needed for analyzing and sequencing these distal subtelomeric regions.},
}
@article {pmid8575016,
year = {1995},
author = {Hails, T and Huttner, O and Day, A},
title = {Isolation of a Chlamydomonas reinhardtii telomere by functional complementation in yeast.},
journal = {Current genetics},
volume = {28},
number = {5},
pages = {437-440},
pmid = {8575016},
issn = {0172-8083},
mesh = {Animals ; Base Sequence ; Chlamydomonas reinhardtii/*genetics ; Cloning, Molecular ; DNA, Recombinant ; Escherichia coli/genetics ; *Genetic Complementation Test ; Molecular Sequence Data ; Saccharomyces cerevisiae/*genetics ; *Telomere ; },
abstract = {We attempted to determine whether Chlamydomonas reinhardtii telomeres, which do not form G-quartet structures readily in vitro, are able to nucleate telomere addition in Saccharomyces cerevisiae. Restricted C. reinhardtii genomic DNA was ligated to a linear S. cerevisiae vector lacking a telomere. A C. reinhardtii telomere ligated to this unprotected end allowed vector replication as a linear DNA molecule in S. cerevisiae. DNA sequencing revealed common [T4AG3]n and variant T6AG3 and T5AG3 C. reinhardtii telomere repeats capped by S. cerevisiae telomere repeat units. The recognition of a C. reinhardtii telomere by the telomere maintenance machinery of S. cerevisiae is consistent with a common theme for telomere structure in organisms with divergent telomere repeats.},
}
@article {pmid7587592,
year = {1995},
author = {Shampay, J and Schmitt, M and Bassham, S},
title = {A novel minisatellite at a cloned hamster telomere.},
journal = {Chromosoma},
volume = {104},
number = {1},
pages = {29-38},
pmid = {7587592},
issn = {0009-5915},
mesh = {Animals ; Base Sequence ; Chromosomes, Artificial, Yeast ; Cloning, Molecular ; Cricetinae/*genetics ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; *Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; Telomere/*genetics ; },
abstract = {The ends of eukaryotic chromosomes have special properties and roles in chromosome behavior. Selection for telomere function in yeast, using a Chinese hamster hybrid cell line as the source DNA, generated a stable yeast artificial chromosome clone containing 23 kb of DNA adjacent to (TTAGGG)n, the vertebrate telomeric repeat. The common repetitive element d(GT)n appeared to be responsible for most of the other stable clones. Circular derivatives of the TTAGGG-positive clone that could be propagated in E. coli were constructed. These derivatives identify a single pair of hamster telomeres by fluorescence in situ hybridization. The telomeric repeat tract consists of (TTAGGG)n repeats with minor variations, some of which can be cleaved with the restriction enzyme MnlI. Blot hybridization with genomic hamster DNA under stringent conditions confirms that the TTAGGG tracts are cleaved into small fragments due to the presence of this restriction enzyme site, in contrast to mouse telomeres. Additional blocks of (TTAGGG)n repeats are found approximately 4-5 kb internally on the clone. The terminal region of the clone is dominated by a novel A-T rich 78 bp tandemly repeating sequence; the repeat monomer can be subdivided into halves distinguished by more or less adherence to the consensus sequence. The sequence in genomic DNA has the same tandem organization in probably a single primary locus of >20-30 kb and is thus termed a minisatellite.},
}
@article {pmid7587589,
year = {1995},
author = {Meyne, J and Hirai, H and Imai, HT},
title = {FISH analysis of the telomere sequences of bulldog ants (Myrmecia: formicidae).},
journal = {Chromosoma},
volume = {104},
number = {1},
pages = {14-18},
pmid = {7587589},
issn = {0009-5915},
mesh = {Animals ; Ants/*genetics ; Base Sequence ; In Situ Hybridization, Fluorescence ; Karyotyping ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; Species Specificity ; Telomere/*genetics ; },
abstract = {Chromosomes from several species of ants from the genus Myrmecia were hybridized with deoxyoligomer probes of either (T2AG2)7, the putative insect telomere repeat sequence, or (T2AG3)7, the vertebrate telomere repeat sequence. While both sequences hybridized over a range of stringency conditions, (T2AG2)n was clearly the predominant sequence at the termini of the Myrmecia chromosomes. No interstitial sites of either sequence were detected. The genus Myrmecia has a wide range of karyotypes, with chromosome numbers ranging from 2n=2-84. It has been hypothesized that the ancestral karyotype was 2n=4 and karyotype evolution proceeded with an increase in chromosome number. In the absence of detectable interstitial sites of telomere sequence, it is interesting to speculate on the origin of the new telomeres as the chromosome numbers increased.},
}
@article {pmid7671310,
year = {1995},
author = {Greenwell, PW and Kronmal, SL and Porter, SE and Gassenhuber, J and Obermaier, B and Petes, TD},
title = {TEL1, a gene involved in controlling telomere length in S. cerevisiae, is homologous to the human ataxia telangiectasia gene.},
journal = {Cell},
volume = {82},
number = {5},
pages = {823-829},
doi = {10.1016/0092-8674(95)90479-4},
pmid = {7671310},
issn = {0092-8674},
support = {GM24110/GM/NIGMS NIH HHS/United States ; GM52319/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes/genetics/radiation effects ; Cloning, Molecular ; Genes, Fungal/genetics ; Humans ; Mitosis/genetics/radiation effects ; Molecular Sequence Data ; Mutation/radiation effects ; Saccharomyces cerevisiae/*genetics ; Sequence Homology, Amino Acid ; Telomere/*genetics ; },
abstract = {Yeast chromosomes terminate in tracts of simple repetitive DNA (poly[G1-3T]). Mutations in the gene TEL1 result in shortened telomeres. Sequence analysis of TEL1 indicates that it encodes a very large (322 kDa) protein with amino acid motifs found in phosphatidylinositol/protein kinases. The closest homolog to TEL1 is the human ataxia telangiectasia gene.},
}
@article {pmid8653088,
year = {1995},
author = {Bhatnagar, YM and Mishra, PV and Martinez, JA and Saxena, KM and Wertelecki, W},
title = {Telomeres of higher primates.},
journal = {Biochemistry and molecular biology international},
volume = {37},
number = {1},
pages = {57-64},
pmid = {8653088},
issn = {1039-9712},
support = {AA09397/AA/NIAAA NIH HHS/United States ; MH17102/MH/NIMH NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Blotting, Southern ; Conserved Sequence ; DNA Probes/chemistry ; Deoxyribonuclease HindIII ; Deoxyribonucleases, Type II Site-Specific/chemistry/metabolism ; Gorilla gorilla/*genetics ; Humans ; In Situ Hybridization ; Methylation ; Pan troglodytes/*genetics ; Restriction Mapping ; Telomere/chemistry/*genetics ; },
abstract = {The telomeres of gorilla, chimpanzee and human peripheral blood cells have been examined by hybridization to an oligonucleotide probe, (TTAGGG)4, following conventional and pulsed-field electrophoresis procedures. The MspI site present near the chromosome terminus undergoes methylation in gorilla, chimpanzee and human genome as shown by the HpaII digestion. Minor (TTAGGG)4-hybridizing sequences have been also detected in the chimpanzee HindIII and MspI digests.},
}
@article {pmid7664836,
year = {1995},
author = {Allsopp, RC and Chang, E and Kashefi-Aazam, M and Rogaev, EI and Piatyszek, MA and Shay, JW and Harley, CB},
title = {Telomere shortening is associated with cell division in vitro and in vivo.},
journal = {Experimental cell research},
volume = {220},
number = {1},
pages = {194-200},
doi = {10.1006/excr.1995.1306},
pmid = {7664836},
issn = {0014-4827},
support = {AG-09383/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging/physiology ; Brain/enzymology/physiology ; *Cell Division ; Cells, Cultured ; DNA Nucleotidylexotransferase/analysis ; DNA Replication ; Embryo, Mammalian/enzymology/physiology ; Fibroblasts/cytology ; Humans ; Middle Aged ; Telomere/*physiology ; },
abstract = {In humans, the amount of terminal (TTAGGG)n, telomeric DNA decreases during aging of various somatic cell types in vitro and in vivo. While the factors accounting for telomere shortening have not been thoroughly established, the inability of the DNA replication machinery to completely copy chromosomal termini (the "end replication problem") and the absence in somatic cells of telomerase, the enzyme that synthesizes telomeric DNA de novo, is a likely mechanism. One prediction of this hypothesis is that telomere shortening should be dependent on cell division. Thus we analyzed telomere length in actively dividing and quiescent cells in vitro and in vivo. In circular outgrowths of cultured human diploid fibroblasts (HDF), cells at the outer periphery had a significantly lower mean terminal restriction fragment (TRF) length (P = 0.011) and telomeric signal intensity (P = 0.024) than cells at the center. Also, the rate of telomere shortening over time for HDFs held quiescent was not statistically significant (m = -12 bp/day, P = 0.16) while that for serially passaged cells was significant (m = -34 bp/day, P = 0.017). To examine the rate of telomere shortening for quiescent cells in vivo, we measured mean TRF length in brain tissue from adult donors ranging in age from 32-75 years. No significant decrease was observed as a function of donor age (P = 0.087), in contrast to the shortening of telomere length that occurs during in vivo aging of mitotically active cells (P = 0.0001). These observations show that telomere shortening is largely, if not entirely, dependent on cell division and support the end replication problem as a mechanism for this process and the use of telomere length as a biomarker for replicative capacity.},
}
@article {pmid7664835,
year = {1995},
author = {von Zglinicki, T and Saretzki, G and Döcke, W and Lotze, C},
title = {Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence?.},
journal = {Experimental cell research},
volume = {220},
number = {1},
pages = {186-193},
doi = {10.1006/excr.1995.1305},
pmid = {7664835},
issn = {0014-4827},
mesh = {Aerobiosis ; Cell Cycle/drug effects/*physiology ; Cells, Cultured ; Cellular Senescence/drug effects/*physiology ; Fibroblasts/drug effects/physiology/ultrastructure ; Flow Cytometry ; Lipofuscin/analysis ; Microscopy, Electron ; Oligonucleotide Probes ; Oxidative Stress/*physiology ; Oxygen/pharmacology ; Phenotype ; Ploidies ; Telomere/drug effects/genetics/*physiology ; },
abstract = {Mild oxidative stress as exerted by culture of human WI-38 fibroblasts under 40% oxygen partial pressure blocks proliferation irreversibly after one to three population doublings. Hyperoxically blocked cells are similar to senescent ones in terms of general morphology and lipofuscin accumulation. Moreover, they, like senescent fibroblasts, are blocked preferentially in G1 as evident from DNA content measurements by flow cytometry. Southern blotting of AluI- and HinfI-restricted genomic DNA shows an increase of the rate of telomere shortening from 90 bp per population doubling under normoxia to more than 500 bp per population doubling under hyperoxia. In every case, proliferation is blocked if a telomere cutoff length of about 4 kb is arrived at. The fact that telomere length correlates with the final inhibition of proliferation under conditions of varied oxidative stress, while the population doubling level does not, suggests that telomere shortening provides the signal for cell cycle exit in senescence. In postmitotic cells, no further telomere shortening occurs. However, the sensitivity of terminal restriction fragments to S1 nuclease increases, indicating the accumulation of single-strand breaks in telomeres of nondividing fibroblasts. This effect is found both under normoxic and hyperoxic culture, although it is more pronounced under conditions of higher oxidative stress. It might be speculated that accumulation of single-strand breaks and the resultant loss of distal single-stranded fragments during replication could be a major cause of telomere shortening, possibly more important than incomplete replication per se.},
}
@article {pmid7651392,
year = {1995},
author = {Rogan, EM and Bryan, TM and Hukku, B and Maclean, K and Chang, AC and Moy, EL and Englezou, A and Warneford, SG and Dalla-Pozza, L and Reddel, RR},
title = {Alterations in p53 and p16INK4 expression and telomere length during spontaneous immortalization of Li-Fraumeni syndrome fibroblasts.},
journal = {Molecular and cellular biology},
volume = {15},
number = {9},
pages = {4745-4753},
pmid = {7651392},
issn = {0270-7306},
mesh = {Animals ; Base Sequence ; Carcinogenicity Tests ; Carrier Proteins/*genetics ; Cell Transformation, Neoplastic/*genetics ; Cells, Cultured ; Cellular Senescence/genetics ; Chromosome Aberrations ; Cyclin-Dependent Kinase Inhibitor p16 ; DNA Nucleotidylexotransferase/analysis ; Fibroblasts ; Heterozygote ; Karyotyping ; Li-Fraumeni Syndrome/enzymology/*genetics ; Mice ; Mice, Nude ; Molecular Sequence Data ; Mutation ; Neoplasms, Experimental ; Ploidies ; Retinoblastoma Protein/metabolism ; Telomere/*genetics/metabolism ; Tumor Suppressor Protein p53/*genetics ; },
abstract = {Normal cells have a strictly limited growth potential and senesce after a defined number of population doublings (PDs). In contrast, tumor cells often exhibit an apparently unlimited proliferative potential and are termed immortalized. Although spontaneous immortalization of normal human cells in vitro is an extremely rare event, we observed this in fibroblasts from an affected member of a Li-Fraumeni syndrome kindred. The fibroblasts were heterozygous for a p53 mutation and underwent senescence as expected at PD 40. In four separate senescent cultures (A to D), there were cells that eventually recommenced proliferation. This was associated with aneuploidy in all four cultures and either loss (cultures A, C, and D) or mutation (culture B) of the wild-type (wt) p53 allele. Loss of wt p53 function was insufficient for immortalization, since cultures A, B, and D subsequently entered crisis from which they did not escape. Culture C has continued proliferating beyond 400 PDs and thus appears to be immortalized. In contrast to the other cultures, the immortalized cells have no detectable p16INK4 protein. A culture that had a limited extension of proliferative potential exhibited a progressive decrease in telomere length with increasing PD. In the culture that subsequently became immortalized, the same trend occurred until PD 73, after which there was a significant increase in the amount of telomeric DNA, despite the absence of telomerase activity. Immortalization of these cells thus appears to be associated with loss of wt p53 and p16INK4 expression and a novel mechanism for the elongation of telomeres.},
}
@article {pmid7649555,
year = {1995},
author = {Jauch, A and Robson, L and Smith, A},
title = {Investigations with fluorescence in situ hybridization (FISH) demonstrate loss of the telomeres on the reciprocal chromosome in three unbalanced translocations involving chromosome 15 in the Prader-Willi and Angelman syndromes.},
journal = {Human genetics},
volume = {96},
number = {3},
pages = {345-349},
pmid = {7649555},
issn = {0340-6717},
mesh = {Adult ; Angelman Syndrome/*genetics ; Chromosome Banding ; Chromosome Deletion ; Chromosomes, Human, Pair 15/*genetics ; DNA Probes ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Male ; Prader-Willi Syndrome/*genetics ; Telomere/*genetics/metabolism ; Translocation, Genetic/*genetics ; },
abstract = {Two patients with classical features of Angel-man syndrome (AS) and one with Prader-Willi syndrome (PWS) had unbalanced reciprocal translocations involving the chromosome 15 proximal long arm and the telomeric region of chromosomes 7, 8 and 10. Fluorescence in situ hybridization (FISH) was used for the detection of chromosome 15(q11-13) deletions (with probes from the PWS/AS region) and to define the involvement of the telomere in the derivative chromosomes (with library probes and telomere-specific probes). The 15(q11-13) region was not deleted in one patient but was deleted in the other two. The telomere on the derivative chromosomes 7, 8 and 10 was deleted in all three cases. Thus, these are true reciprocal translocations in which there has been loss of the small satellited reciprocal chromosome (15) fragment.},
}
@article {pmid7556065,
year = {1995},
author = {Bryan, TM and Englezou, A and Gupta, J and Bacchetti, S and Reddel, RR},
title = {Telomere elongation in immortal human cells without detectable telomerase activity.},
journal = {The EMBO journal},
volume = {14},
number = {17},
pages = {4240-4248},
pmid = {7556065},
issn = {0261-4189},
mesh = {Base Sequence ; Cell Line ; Cell Line, Transformed ; Cell Transformation, Viral ; Cellular Senescence ; Clone Cells ; Enzyme Activation ; Humans ; Hybrid Cells ; Polymerase Chain Reaction ; Repetitive Sequences, Nucleic Acid ; Simian virus 40 ; Telomerase/*analysis/deficiency/metabolism ; Telomere/*physiology ; },
abstract = {Immortalization of human cells is often associated with reactivation of telomerase, a ribonucleoprotein enzyme that adds TTAGGG repeats onto telomeres and compensates for their shortening. We examined whether telomerase activation is necessary for immortalization. All normal human fibroblasts tested were negative for telomerase activity. Thirteen out of 13 DNA tumor virus-transformed cell cultures were also negative in the pre-crisis (i.e. non-immortalized) stage. Of 35 immortalized cell lines, 20 had telomerase activity as expected, but 15 had no detectable telomerase. The 15 telomerase-negative immortalized cell lines all had very long and heterogeneous telomeres of up to 50 kb. Hybrids between telomerase-negative and telomerase-positive cells senesced. Two senescent hybrids demonstrated telomerase activity, indicating that activation of telomerase is not sufficient for immortalization. Some hybrid clones subsequently recommenced proliferation and became immortalized either with or without telomerase activity. Those without telomerase activity also had very long and heterogeneous telomeres. Taken together, these data suggest that the presence of lengthened or stabilized telomeres is necessary for immortalization, and that this may be achieved either by the reactivation of telomerase or by a novel and as yet unidentified mechanism.},
}
@article {pmid7630414,
year = {1995},
author = {McEachern, MJ and Blackburn, EH},
title = {Runaway telomere elongation caused by telomerase RNA gene mutations.},
journal = {Nature},
volume = {376},
number = {6539},
pages = {403-409},
doi = {10.1038/376403a0},
pmid = {7630414},
issn = {0028-0836},
mesh = {Amino Acid Sequence ; Base Sequence ; Cloning, Molecular ; Conserved Sequence ; DNA Nucleotidylexotransferase/genetics/*metabolism ; *DNA Replication ; DNA, Fungal/biosynthesis/genetics ; Genes, Fungal ; Kluyveromyces/*enzymology/genetics ; Models, Genetic ; Molecular Sequence Data ; Mutation ; Phenotype ; RNA, Fungal/genetics/*metabolism ; Repetitive Sequences, Nucleic Acid ; *Telomere ; },
abstract = {The ribonucleoprotein enzyme telomerase adds telomeric DNA onto chromosome ends and is normally regulated so that telomeric DNA lengths are kept within defined bounds. In the telomerase RNA gene from the yeast Kluyveromyces lactis, specific mutations that alter telomeric DNA sequences result in telomeres elongating to up to 100 times their normal length and impair cell growth. Some mutations cause immediate elongation whereas others behave like genetic time bombs, causing elongation only after a latent period of hundreds of generations.},
}
@article {pmid7668265,
year = {1995},
author = {Blouin, JL and Christie, DH and Gos, A and Lynn, A and Morris, MA and Ledbetter, DH and Chakravarti, A and Antonarakis, SE},
title = {A new dinucleotide repeat polymorphism at the telomere of chromosome 21q reveals a significant difference between male and female rates of recombination.},
journal = {American journal of human genetics},
volume = {57},
number = {2},
pages = {388-394},
pmid = {7668265},
issn = {0002-9297},
mesh = {Base Sequence ; Chromosome Mapping ; *Chromosomes, Human, Pair 21 ; Female ; Genetic Linkage ; Humans ; Male ; Molecular Sequence Data ; *Polymorphism, Genetic ; Recombination, Genetic/*genetics ; *Repetitive Sequences, Nucleic Acid ; Sex Factors ; Telomere ; },
abstract = {We have used a half-YAC containing the human chromosome 21 long-arm telomere to clone, map, and characterize a new dinucleotide repeat polymorphism (D21S1575) close to 21qter. This marker is < 120 kb from the telomeric (TTAGGG)n sequences and is the most distal highly polymorphic marker on chromosome 21q. This marker has a heterozygosity of 71% because of a variable (TA)n repeat embedded within a long interspersed element (LINE) element. Genotyping of the CEPH families and linkage analysis provided a more accurate determination of the full length of the chromosome 21 genetic map. A highly significant difference was detected between male and female recombination rates in the telomeric region: in the most telomeric 2.3 Mb of chromosome 21q, recombination was only observed in male meioses.},
}
@article {pmid7551546,
year = {1995},
author = {Brandes, A and Röder, MS and Ganal, MW},
title = {Barley telomeres are associated with two different types of satellite DNA sequences.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {3},
number = {5},
pages = {315-320},
pmid = {7551546},
issn = {0967-3849},
mesh = {Base Sequence ; Cloning, Molecular ; DNA, Plant/*genetics ; DNA, Satellite/*genetics ; Hordeum/*genetics ; In Situ Hybridization, Fluorescence ; Karyotyping ; Molecular Sequence Data ; Sequence Homology, Nucleic Acid ; *Telomere ; },
abstract = {The genomic organization of two different types of satellite DNA sequences was analysed by means of fluorescence in situ hybridization (FISH) and pulsed-field gel electrophoresis (PFGE) in barley. Satellite HvT01 was detected at all chromosome ends except the long arms of chromosomes 2 and 7. The unrelated satellite pAS1 was found at all chromosome ends except the long arm of chromosome 7 and at two interstitial sites, both located on the long arm of chromosome 4 on the standard karyotype. Southern and in situ hybridization further indicate that pAS1 also occurs interspersed in the barley genome. For most chromosome ends, the linear order of HvT01 and pAS1 could not be determined by in situ hybridization except at the short arms of chromosomes 2 and 6, where HvT01 is more distal than pAS1. This is confirmed by PFGE analysis, HvT01 being frequently associated with the telomeric repeat but not pAS1. Furthermore, we found that HvT01 occurred in clusters up to 1000 kb in size, whereas the pAS1 cluster had a maximum size of 500 kb. Sequence comparison revealed that both satellites are completely unrelated and differ considerably in their G + C contents.},
}
@article {pmid7551541,
year = {1995},
author = {Fernández, JL and Gosálvez, J and Goyanes, V},
title = {High frequency of mutagen-induced chromatid exchanges at interstitial telomere-like DNA sequence blocks of Chinese hamster cells.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {3},
number = {5},
pages = {281-284},
pmid = {7551541},
issn = {0967-3849},
mesh = {Animals ; Cell Line ; Cricetinae ; Cricetulus ; DNA/*drug effects/genetics ; DNA Damage ; In Situ Hybridization, Fluorescence ; Mutagens/*toxicity ; *Sister Chromatid Exchange ; *Telomere ; },
abstract = {Interstitial telomere-like DNA sequence arrays of Chinese hamster Don cells were delineated by fluorescence in situ hybridization in quadriradial and triradial chromosome configurations induced by X-rays, mitomycin C and teniposide (VM-26). Around 40% of the scored exchanges involved a telomeric-like block of sequences at a rearrangement site. This frequency was independent of the DNA-damaging agent, and the result suggests a general recombinogenic capacity of interstitial telomere-like DNA sequence repeats that, at least in the case of the agents employed, seems not to be related to the initial mechanism of DNA damage.},
}
@article {pmid7628529,
year = {1995},
author = {Allsopp, RC and Harley, CB},
title = {Evidence for a critical telomere length in senescent human fibroblasts.},
journal = {Experimental cell research},
volume = {219},
number = {1},
pages = {130-136},
doi = {10.1006/excr.1995.1213},
pmid = {7628529},
issn = {0014-4827},
mesh = {Adult ; Analysis of Variance ; Base Sequence ; Biopsy ; Cellular Senescence ; Chromosomes, Human/physiology/ultrastructure ; Clone Cells ; DNA/isolation &amp; purification ; DNA Replication ; Fibroblasts/cytology/physiology ; Humans ; Restriction Mapping ; Skin/cytology ; *Skin Physiological Phenomena ; Telomere/physiology/*ultrastructure ; },
abstract = {Telomeres, the G/C-rich DNA sequences capping the ends of all eukaryotic chromosomes, have been shown to shorten during replicative aging of normal cells in vitro and in vivo. Moreover, variation in the initial length of terminal restriction fragments (TRF) accounts for much of the variation in replicative capacity of fibroblast cultures from different donors. Since replicative capacity also varies significantly between clones in a mass culture of fibroblasts from a single donor, we wished to further test the hypothesis that the shortening of telomeres to a critical or threshold length acts as a signal for cell senescence. Thus, we measured TRF length and total telomeric signal intensity for 35 clonal fibroblast populations at early passage and at senescence. Replicative capacity was found to be directly proportional to mean TRF length (m = 7.2 population doublings/kbp, r = 0.65, P = 0.0004) and total signal intensity (m = 25.0 population doublings/unit, r = 0.63, P < 0.003) at early passage. More importantly, the variability in both mean TRF length and signal intensity (F = 2.0 and 2.9; P = 0.02 and 0.03, respectively) at senescence was markedly less than that at early passage. Although initial telomere length cannot account for all of the interclonal variability in replicative capacity, our observations support the existence of a critical telomere length in senescing cells and a causal role of telomere shortening in cell senescence.},
}
@article {pmid7478447,
year = {1995},
author = {Olovnikov, AM},
title = {[A paradox: the short duration of life in the presence of long telomeres].},
journal = {Ontogenez},
volume = {26},
number = {4},
pages = {332-334},
pmid = {7478447},
issn = {0475-1450},
mesh = {Animals ; DNA/physiology ; DNA Damage/physiology ; DNA Repair/physiology ; DNA Replication/physiology ; Humans ; Longevity/*physiology ; Telomere/*physiology ; },
}
@article {pmid7666477,
year = {1995},
author = {Rhyu, MS},
title = {Telomeres, telomerase, and immortality.},
journal = {Journal of the National Cancer Institute},
volume = {87},
number = {12},
pages = {884-894},
doi = {10.1093/jnci/87.12.884},
pmid = {7666477},
issn = {0027-8874},
mesh = {Animals ; Apoptosis/physiology ; Base Sequence ; Cell Survival/physiology ; DNA Nucleotidylexotransferase/antagonists &amp; inhibitors/genetics/*metabolism ; Enzyme Activation/physiology ; Humans ; Mitosis/physiology ; Molecular Sequence Data ; Neoplasms/*enzymology ; Telomere/*enzymology/genetics ; },
abstract = {A current hypothesis gaining prominence proposes that activation of the enzyme telomerase is necessary for cells to become immortal, or capable of proliferating indefinitely. The theory suggests that almost all cancer cells must attain immortality for progression to malignant states and, hence, require activation of telomerase. This article reviews the function and formation of telomeres as background to evaluating the "telomere hypothesis." Experiments in support of and experiments that challenge the hypothesis are examined. Possible approaches to telomerase inhibition are discussed.},
}
@article {pmid7597069,
year = {1995},
author = {Liu, Z and Lee, A and Gilbert, W},
title = {Gene disruption of a G4-DNA-dependent nuclease in yeast leads to cellular senescence and telomere shortening.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {92},
number = {13},
pages = {6002-6006},
pmid = {7597069},
issn = {0027-8424},
mesh = {Blotting, Southern ; DNA, Fungal/isolation &amp; purification ; Deoxyribonucleases/*biosynthesis/*genetics ; *Exoribonucleases ; Fungal Proteins/*biosynthesis/*genetics ; *Genes, Fungal/drug effects ; Oligodeoxyribonucleotides/pharmacology ; Phenotype ; Plasmids ; Restriction Mapping ; Saccharomyces cerevisiae/cytology/*genetics/growth &amp; development ; *Saccharomyces cerevisiae Proteins ; Telomere/*physiology/ultrastructure ; },
abstract = {The yeast gene KEM1 (also named SEP1/DST2/XRN1/RAR5) produces a G4-DNA-dependent nuclease that binds to G4 tetraplex DNA structure and cuts in a single-stranded region 5' to the G4 structure. G4-DNA generated from yeast telomeric oligonucleotides competitively inhibits the cleavage reaction, suggesting that this enzyme may interact with yeast telomeres in vivo. Homozygous deletions of the KEM1 gene in yeast block meiosis at the pachytene stage, which is consistent with the hypothesis that G4 tetraplex DNA may be involved in homologous chromosome pairing during meiosis. We conjectured that the mitotic defects of kem1/sep1 mutant cells, such as a higher chromosome loss rate, are also due to failure in processing G4-DNA, especially at telomeres. Here we report two phenotypes associated with a kem1-null allele, cellular senescence and telomere shortening, that provide genetic evidence that G4 tetraplex DNA may play a role in telomere functioning. In addition, our results reveal that chromosome ends in the same cells behave differently in a fashion dependent on the KEM1 gene product.},
}
@article {pmid7596822,
year = {1995},
author = {Sohanpal, BK and Morzaria, SP and Gobright, EI and Bishop, RP},
title = {Characterisation of the telomeres at opposite ends of a 3 Mb Theileria parva chromosome.},
journal = {Nucleic acids research},
volume = {23},
number = {11},
pages = {1942-1947},
pmid = {7596822},
issn = {0305-1048},
mesh = {Animals ; Bacteriophage lambda/*genetics ; Base Sequence ; Chromosomes/genetics ; Cloning, Molecular ; Conserved Sequence ; Molecular Sequence Data ; Telomere/*genetics ; Theileria parva/*genetics ; },
abstract = {Bacteriophage lambda clones containing Theileria parva genomic DNA derived from two different telomeres were isolated and the nucleotide sequences of the telomeric repeats and adjacent telomere-associated (TAS) DNA were determined. The T.parva telomeric repeat sequences, a tandem array of TTTTAGGG or TTTAGGG interspersed with a few variant copies, showed a high degree of sequence identity to those of the photosynthetic algae Chlamydomonas reinhardtii (97% identity) and Chlorella vulgaris (87.7% identity) and the angiosperm Arabidopsis thaliana (84.4% identity). Unlike most organisms which have been studied, no significant repetitive sequences were found in the nucleotide sequences of TAS DNA located centromere-proximal to the telomeric repeats. Restriction mapping and hybridisation analysis of lambda EMBL3 clones containing 16 kilobases of TAS DNA derived from one telomere suggested that they did not contain long regions of repetitive DNA. The cloned TAS DNAs were mapped to T.parva Muguga genomic SfiI fragments 8 and 20, which are located at opposite ends of the largest T.parva chromosome. A 126 bp sequence located directly centromere-proximal to the telomeric repeats was 94% identical between the two cloned telomeres. The conserved 126 bp sequence was present on all T.parva Muguga telomeric SfiI fragments.},
}
@article {pmid7596814,
year = {1995},
author = {Hicke, B and Rempel, R and Maller, J and Swank, RA and Hamaguchi, JR and Bradbury, EM and Prescott, DM and Cech, TR},
title = {Phosphorylation of the Oxytricha telomere protein: possible cell cycle regulation.},
journal = {Nucleic acids research},
volume = {23},
number = {11},
pages = {1887-1893},
pmid = {7596814},
issn = {0305-1048},
support = {GM 45890-03/GM/NIGMS NIH HHS/United States ; GM19199/GM/NIGMS NIH HHS/United States ; GM28039/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Cell Cycle ; DNA, Single-Stranded/metabolism ; Molecular Sequence Data ; Oxytricha/cytology/*metabolism ; Phosphorylation ; Proteins/chemistry ; Telomere/*metabolism ; },
abstract = {In the macronucleus of the ciliate Oxytricha nova, telomeres end with single-stranded (T4G4)2 DNA bound to a heterodimeric telomere protein (alpha beta). Both the alpha and beta subunits (alpha-TP and beta-TP) were phosphorylated in asynchronously growing Oxytricha; beta-TP was phosphorylated to a much higher degree. In vitro, mouse cyclin-dependent kinases (Cdks) phosphorylated beta-TP in a lysine-rich domain that is not required for specific DNA binding but is implicated in higher order structure formation of telomeres. Therefore, phosphorylation of beta-TP could modulate a function of the telomere protein that is separate from specific DNA binding. Phosphoamino acid analysis revealed that the mouse Cdks modify predominantly threonine residues in beta-TP, consistent with the observation that beta-TP contains two consensus Cdk recognition sequences containing threonine residues. In Xenopus egg extracts that undergo cell cycling, beta-TP was phosphorylated in M phase and dephosphorylated in interphase. This work provides the first direct evidence of phosphorylation at telomeres in any organism, as well as indirect evidence for cell cycle regulation of telomere phosphorylation. The Cdc2/cyclin A and Cdc2/cyclin B kinases are required for major mitotic events. An attractive model is that phosphorylation of beta-TP by these kinases is required for the breakdown of telomere associations with each other and/or with nuclear structures prior to nuclear division.},
}
@article {pmid7779103,
year = {1995},
author = {Kitada, T and Seki, S and Kawakita, N and Kuroki, T and Monna, T},
title = {Telomere shortening in chronic liver diseases.},
journal = {Biochemical and biophysical research communications},
volume = {211},
number = {1},
pages = {33-39},
doi = {10.1006/bbrc.1995.1774},
pmid = {7779103},
issn = {0006-291X},
mesh = {Adult ; Aged ; Aging/*physiology ; Base Sequence ; Blotting, Southern ; Female ; Hepatitis/*genetics/pathology ; Humans ; Liver/cytology/metabolism/pathology ; Liver Cirrhosis/*genetics/pathology ; Liver Neoplasms/*genetics/pathology/secondary ; Male ; Middle Aged ; Molecular Sequence Data ; Oligonucleotide Probes ; Reference Values ; Telomere/pathology/*ultrastructure ; },
abstract = {We measured the telomere length in patients with chronic hepatitis or liver cirrhosis and found a significant telomere shortening in the liver with chronic liver disease compared to that in the normal liver. The telomere length tended to decrease with the progression of chronic liver disease.},
}
@article {pmid7779084,
year = {1995},
author = {Rogalla, P and Rohen, C and Hennig, Y and Deichert, U and Bonk, U and Bullerdiek, J},
title = {Telomere repeat fragment sizes do not limit the growth potential of uterine leiomyomas.},
journal = {Biochemical and biophysical research communications},
volume = {211},
number = {1},
pages = {175-182},
doi = {10.1006/bbrc.1995.1793},
pmid = {7779084},
issn = {0006-291X},
mesh = {Base Sequence ; Blotting, Southern ; DNA, Neoplasm/analysis ; Female ; Humans ; Leiomyoma/*genetics/*pathology ; Molecular Sequence Data ; *Repetitive Sequences, Nucleic Acid ; Telomere/*genetics ; Tumor Cells, Cultured ; Uterine Neoplasms/*genetics/*pathology ; },
abstract = {We have compared the length of telomere repeat fragments (TRF's) in 19 uterine leiomyomas from 6 patients with the corresponding myometrium. The advantage of this study of TRF length is that cells from uterine leiymyoma and cells from corresponding myometrium do not contain any considerable proportions of other cells as revealed by analysis of clonality. In all tumor samples a loss of TRF length ranging from 1120 to 4690 bp was noted. There was no correlation between tumor volume or size of tumor population as revealed by histological examination and loss of TRF length. From the obtained TRF length data (an average myometrial TFR length of 13 kb and an average loss of TRF length in myoma cells of 83 bp per cell division) we concluded that TRF length reduction does not limit the growth potential of uterine leiomyomas.},
}
@article {pmid7655454,
year = {1995},
author = {Kipling, D and Wilson, HE and Thomson, EJ and Cooke, HJ},
title = {YAC cloning Mus musculus telomeric DNA: physical, genetic, in situ and STS markers for the distal telomere of chromosome 10.},
journal = {Human molecular genetics},
volume = {4},
number = {6},
pages = {1007-1014},
doi = {10.1093/hmg/4.6.1007},
pmid = {7655454},
issn = {0964-6906},
mesh = {Animals ; Base Sequence ; *Chromosome Mapping ; *Chromosomes, Artificial, Yeast ; Cloning, Molecular ; DNA ; DNA Probes ; Deoxyribonucleotides ; Endodeoxyribonucleases/metabolism ; Genetic Markers ; *Genomic Library ; Male ; Metaphase ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Saccharomyces cerevisiae/genetics ; Sequence Tagged Sites ; *Telomere ; },
abstract = {Three Mus musculus DBA/2 YAC libraries were constructed using a half-YAC telomere cloning vector. This functional complementation approach yields libraries which include terminal restriction fragments of the mouse genome. Screening all three libraries led to the isolation of 32 independent clones which carry linear YACs containing the mouse terminal repeat sequence, (TTAGGG)n. These YACs provide a resource to isolate regions of the mouse genome close to chromosome termini and excluded from existing conventional YAC libraries. To demonstrate their utility, a hybridization probe was isolated from Mtel-1, the first (TTAGGG)n-containing YAC isolated. This probe detects a approximately 70 kb Kpnl fragment in the mouse genome which is sensitive to pretreatment with BAL31 exonuclease. A PCR-based genetic marker generated from the sequence of this probe maps 4.4 cM from the most distal anchor locus on chromosome 10 in the EUCIB interspecific backcross. STS primers for this locus, D10Hgu1, were used to isolate YAC 110F4 from a commercially available mouse YAC library. Fluorescence in situ hybridization demonstrates that YAC 110F4 hybridizes to the distal telomere of chromosome 10. Clones in this collection of telomere YACs therefore partially overlap clones in conventional YAC libraries, and thus the previously unavailable terminal regions of the mouse genome can now be linked with the developing mouse STS YAC contig. Genetic markers such as D10Hgu1 allow the ends of the mouse genetic map to be defined, thus closing the map.},
}
@article {pmid7583629,
year = {1995},
author = {Rhodes, D and Giraldo, R},
title = {Telomere structure and function.},
journal = {Current opinion in structural biology},
volume = {5},
number = {3},
pages = {311-322},
doi = {10.1016/0959-440x(95)80092-1},
pmid = {7583629},
issn = {0959-440X},
mesh = {Base Sequence ; Magnetic Resonance Spectroscopy ; *Molecular Conformation ; Molecular Sequence Data ; Molecular Structure ; Telomere/*chemistry/metabolism ; },
abstract = {Telomeres, the termini of linear eukaryotic chromosomes, contain specific DNA sequences that are widely conserved. These sequences not only recruit telomere-specific proteins, but also give telomeric DNA the ability to fold into four-stranded DNA structures. Recent structural studies have shown that the repertoire of quadruplexes formed by the G-rich strand is larger than had been envisaged. Even more surprising is a novel four-stranded structure formed by the C-rich strand, called the i-tetraplex. Genetic and biochemical analyses have been used to identify proteins involved in telomeric DNA packaging and organization. The possibility that four-stranded structures may play a role in telomere function has been strengthened by the discovery that telomeric proteins can bind to and promote the formation of G-quadruplexes.},
}
@article {pmid7498730,
year = {1995},
author = {Farman, ML and Leong, SA},
title = {Genetic and physical mapping of telomeres in the rice blast fungus, Magnaporthe grisea.},
journal = {Genetics},
volume = {140},
number = {2},
pages = {479-492},
pmid = {7498730},
issn = {0016-6731},
mesh = {Ascomycota/*genetics ; Base Sequence ; Genetic Markers ; Molecular Sequence Data ; Oryza/*microbiology ; Plasmids ; Polymorphism, Restriction Fragment Length ; Restriction Mapping ; Telomere/*genetics ; },
abstract = {Telomeric restriction fragments were genetically mapped to a previously described linkage map of Magnaporthe grisea, using RFLPs identified by a synthetic probe. (TTAGGG)3. Frequent rearrangement of telomeric sequences was observed in progeny isolates creating a potential for misinterpretation of data. Therefore a consensus segregation data set used to minimize mapping errors. TWelve of the 14 telomeres were found to be genetically linked to existing RFLP markers. Second-dimensional electrophoresis of restricted chromosomes confirmed these linkage assignments and revealed the chromosomal location of the two unlinked telomeres. We were thus able to assign all 14 M. grisea telomeres to their respective chromosome ends. The Achilles' cleavage (AC) technique was employed to determine that chromosome 1 markers 11 and CH5-120H were approximately 1.8 Mb and 1.28 Mb, respectively, from their nearest telomeres. RecA-AC was also used to determine that unlinked telomere 6 was approximately 530 kb from marker CH5-176H in strain 2539 and 580 kb in Guy11. These experiments indicated that large portions of some chromosome ends are unrepresented by genetic markers and provided estimates of the relationship of genetic to physical distance in these regions of the genome.},
}
@article {pmid7761821,
year = {1995},
author = {Sarkar, G and Bolander, ME},
title = {Telomeres, telomerase, and cancer.},
journal = {Science (New York, N.Y.)},
volume = {268},
number = {5214},
pages = {1115-1117},
doi = {10.1126/science.7761821},
pmid = {7761821},
issn = {0036-8075},
mesh = {Colonic Neoplasms/enzymology/genetics ; DNA Nucleotidylexotransferase/*metabolism ; Humans ; Neoplasms/*enzymology/*genetics ; Telomere/*metabolism ; Tumor Cells, Cultured ; },
}
@article {pmid7761406,
year = {1995},
author = {Prowse, KR and Greider, CW},
title = {Developmental and tissue-specific regulation of mouse telomerase and telomere length.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {92},
number = {11},
pages = {4818-4822},
pmid = {7761406},
issn = {0027-8424},
support = {AG09383/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Animals, Newborn ; Brain/enzymology ; Cell Division ; Cells, Cultured ; Cellular Senescence ; DNA Nucleotidylexotransferase/*metabolism ; Fibroblasts/cytology/enzymology ; Humans ; Kinetics ; Liver/enzymology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred Strains ; Muridae ; Organ Specificity ; Skin/*cytology/*enzymology ; Species Specificity ; Spleen/enzymology ; *Telomere ; Testis/enzymology ; },
abstract = {Telomere shortening and telomerase activation in human somatic cells have been implicated in cell immortalization and cellular senescence. To further study the role of telomerase in immortalization, we assayed telomere length and telomerase activity in primary mouse fibroblasts, in spontaneously immortalized cell clones, and in mouse tissues. In the primary cell cultures, telomere length decreased with increased cell doublings and telomerase activity was not detected. In contrast, in spontaneously immortalized clones, telomeres were maintained at a stable length and telomerase activity was present. To determine if telomere shortening occurs in vivo, we assayed for telomerase and telomere length in tissues from mice of different ages. Telomere length was similar among different tissues within a newborn mouse, whereas telomere length differed between tissues in an adult mouse. These findings suggest that there is tissue-specific regulation of mouse telomerase during development and aging in vivo. In contrast to human tissues, most mouse tissues had active telomerase. The presence of telomerase in these tissues may reflect the ease of immortalization of primary mouse cells relative to human cells in culture.},
}
@article {pmid7665177,
year = {1995},
author = {Elliott, RW and Pazik, J},
title = {An interstitial telomere array near Hba on mouse Chr 11 is a candidate for the homolog of the telomere at human 16p.},
journal = {Genomics},
volume = {27},
number = {1},
pages = {217-218},
doi = {10.1006/geno.1995.1031},
pmid = {7665177},
issn = {0888-7543},
mesh = {Alleles ; Animals ; Base Sequence ; Chromosome Mapping ; Chromosomes, Human, Pair 16/*ultrastructure ; Genetic Markers ; Humans ; Mice/*genetics ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Molecular Sequence Data ; Species Specificity ; Telomere/*genetics ; },
}
@article {pmid7587586,
year = {1995},
author = {Gilson, P and McFadden, GI},
title = {The chlorarachniophyte: a cell with two different nuclei and two different telomeres.},
journal = {Chromosoma},
volume = {103},
number = {9},
pages = {635-641},
pmid = {7587586},
issn = {0009-5915},
mesh = {Animals ; Base Sequence ; Blotting, Southern ; Cell Nucleus/*genetics/ultrastructure ; Chloroplasts/*genetics/ultrastructure ; Chromosome Mapping ; Chromosomes ; Cloning, Molecular ; DNA/analysis ; DNA, Ribosomal/genetics ; Electrophoresis, Gel, Pulsed-Field ; Eukaryota/*genetics ; Microscopy, Electron ; Molecular Sequence Data ; RNA, Ribosomal, 18S/genetics ; RNA, Ribosomal, 5.8S/genetics ; Repetitive Sequences, Nucleic Acid ; Symbiosis ; Telomere/*genetics ; },
abstract = {Chlorarachniophyte algae contain a complex chloroplast derived from the endosymbiosis of a eukaryotic alga. The reduced nucleus of the endosymbiont, the nucleomorph, is located between the inner and outer pair of membranes surrounding the chloroplast. The nucleomorph of chlorarachniophytes has previously been demonstrated to contain at least three small linear chromosomes. Here we describe cloning the end of the smallest nucleomorph chromosome which is shown to carry a telomere consisting of a tandemly repeated 7 bp sequence, TCTAGGG. Using the telomere repeat as a probe, we show that nucleomorph telomeres display typical hetero-disperse size distribution. The nucleomorph is shown to contain only three chromosomes with a haploid genome size of just 380 kb. All six nucleomorph chromosome termini are identical with an rRNA cistron closely linked to the telomere. The nucleomorph chromosomes thus have relatively large inverted repeats at their ends. Chromosomes from the host nucleus are shown to have a different telomere repeat motif to that of the nucleomorph chromosomes.},
}
@article {pmid7537692,
year = {1995},
author = {Hubbard, K and Dhanaraj, SN and Sethi, KA and Rhodes, J and Wilusz, J and Small, MB and Ozer, HL},
title = {Alteration of DNA and RNA binding activity of human telomere binding proteins occurs during cellular senescence.},
journal = {Experimental cell research},
volume = {218},
number = {1},
pages = {241-247},
doi = {10.1006/excr.1995.1152},
pmid = {7537692},
issn = {0014-4827},
support = {A131165//PHS HHS/United States ; AG00378/AG/NIA NIH HHS/United States ; AG04821/AG/NIA NIH HHS/United States ; },
mesh = {Base Sequence ; Binding, Competitive ; Blotting, Western ; Bone Marrow ; Cell Line ; Cellular Senescence/*physiology ; DNA/isolation &amp; purification/*metabolism ; DNA-Binding Proteins/isolation &amp; purification/*metabolism ; Fibroblasts/cytology/physiology ; Humans ; Molecular Sequence Data ; Oligodeoxyribonucleotides/chemistry/pharmacology ; RNA/isolation &amp; purification/*metabolism ; RNA-Binding Proteins/isolation &amp; purification/*metabolism ; Telomere/*metabolism ; },
abstract = {The loss of telomere sequences during in vitro and in vivo aging suggests that mechanisms affecting telomere length may have important consequences in cellular senescence. In this study, we have found that the activity of single-stranded telomere binding proteins is increased in nuclear extracts prepared from senescent human diploid fibroblasts compared to actively growing cells. Since single-stranded telomere binding proteins are closely related to RNA binding proteins, we examined the binding activity of several major RNA binding proteins to RNA by uv cross-linking. The level of activity was greatly diminished and the overall pattern of uv cross-linked products were altered in extracts prepared from senescent cells. Furthermore, Western analysis revealed a concurrent decrease in senescent extracts of the protein level for many RNA binding proteins, including those which bind to telomere sequence. Although the reduction in the level of these proteins parallels the reduced activity in RNA binding, the paradoxical increased telomere binding activity exhibited by extracts from older cells suggests a complex relationship between these proteins with RNA and DNA. Moreover, the reduced RNA binding activity of these proteins indicates that the biochemical function of several RNA binding proteins is compromised during cellular senescence, raising an intriguing possibility that a change in pre-mRNA metabolism may contribute to the multitude of changes in gene expression observed in cellular senescence.},
}
@article {pmid7597853,
year = {1995},
author = {Naumov, GI and Naumova, ES and Louis, EJ},
title = {Genetic mapping of the alpha-galactosidase MEL gene family on right and left telomeres of Saccharomyces cerevisiae.},
journal = {Yeast (Chichester, England)},
volume = {11},
number = {5},
pages = {481-483},
doi = {10.1002/yea.320110512},
pmid = {7597853},
issn = {0749-503X},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {*Chromosome Mapping ; *Genes, Fungal ; Saccharomyces cerevisiae/enzymology/*genetics ; *Telomere ; alpha-Galactosidase/*genetics ; },
abstract = {The alpha-galactosidase MEL2-MEL10 genes have been genetically mapped to right and left telomere regions of the following chromosomes of Saccharomyces cerevisiae: MEL2 at VII L, MEL3 at XVI L, MEL4 at XI L, MEL5 at IV L, MEL6 at XIII R, MEL7 at VI R, MEL8 at XV R, MEL9 at X R and MEL10 at XII R. A set of tester strains with URA3 inserted into individual telomeres and no MEL genes was used for mapping.},
}
@article {pmid7731999,
year = {1995},
author = {Kang, C and Berger, I and Lockshin, C and Ratliff, R and Moyzis, R and Rich, A},
title = {Stable loop in the crystal structure of the intercalated four-stranded cytosine-rich metazoan telomere.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {92},
number = {9},
pages = {3874-3878},
pmid = {7731999},
issn = {0027-8424},
mesh = {Animals ; Base Composition ; Base Sequence ; Crystallization ; *Cytosine ; *Eukaryota ; Hydrogen Bonding ; Models, Molecular ; *Nucleic Acid Conformation ; Oligodeoxyribonucleotides/*chemistry ; Repetitive Sequences, Nucleic Acid ; Telomere/*ultrastructure ; },
abstract = {In most metazoans, the telomeric cytosine-rich strand repeating sequence is d(TAACCC). The crystal structure of this sequence was solved to 1.9-A resolution. Four strands associate via the cytosine-containing parts to form a four-stranded intercalated structure held together by C.C+ hydrogen bonds. The base-paired strands are parallel to each other, and the two duplexes are intercalated into each other in opposite orientations. One TAA end forms a highly stabilized loop with the 5' thymine Hoogsteen-base-paired to the third adenine. The 5' end of this loop is in close proximity to the 3' end of one of the other intercalated cytosine strands. Instead of being entirely in a DNA duplex, this structure suggests the possibility of an alternative conformation for the cytosine-rich telomere strands.},
}
@article {pmid7715605,
year = {1995},
author = {Nosek, J and Dinouël, N and Kovac, L and Fukuhara, H},
title = {Linear mitochondrial DNAs from yeasts: telomeres with large tandem repetitions.},
journal = {Molecular &amp; general genetics : MGG},
volume = {247},
number = {1},
pages = {61-72},
pmid = {7715605},
issn = {0026-8925},
mesh = {Base Sequence ; Candida/genetics ; DNA, Fungal/*genetics ; DNA, Mitochondrial/*genetics ; Exodeoxyribonucleases ; Genome, Fungal ; *Minisatellite Repeats ; Molecular Sequence Data ; Nucleic Acid Conformation ; Pichia/genetics ; Restriction Mapping ; Single-Strand Specific DNA and RNA Endonucleases ; Telomere/*genetics ; },
abstract = {The terminal structure of the linear mitochondrial DNA (mtDNA) from the yeast Candida parapsilosis was investigated. This mtDNA, 30 kb long, has symmetrical ends forming inverted terminal repeats. These repeats are made up of a variable number of tandemly repeating units of 738 bp each; the terminal nucleotide corresponds to a precise position within the last repeat unit sequence. The ends had an open structure accessible to enzymes, with a 5' single-stranded extension of about 110 nucleotides. No circular forms were detected in the DNA preparations. Two other unrelated species, Pichia philodendra and Candida salmanticensis also appear to have a linear mtDNA of similar organization. These linear DNAs (which we name Type 2 linear mtDNAs) are distinct from the previously described linear mtDNAs of yeasts whose termini are formed by a closed hairpin loop (Type 1 linear mtDNA). The terminal structure of C. parapsilosis mtDNA is reminiscent of the linear mitochondrial genomes of the ciliate Tetrahymena although, in the latter, the telomeric tandem repeat unit is considerably shorter.},
}
@article {pmid7701337,
year = {1995},
author = {Seachrist, L},
title = {Telomeres draw a crowd at Toronto cancer meeting.},
journal = {Science (New York, N.Y.)},
volume = {268},
number = {5207},
pages = {29-30},
doi = {10.1126/science.7701337},
pmid = {7701337},
issn = {0036-8075},
mesh = {Animals ; DNA Nucleotidylexotransferase/*physiology ; Humans ; Neoplasms/*enzymology/*genetics ; Telomere/*physiology ; Tetrahymena ; },
}
@article {pmid7877656,
year = {1995},
author = {Haber, DA},
title = {Telomeres, cancer, and immortality.},
journal = {The New England journal of medicine},
volume = {332},
number = {14},
pages = {955-956},
doi = {10.1056/NEJM199504063321412},
pmid = {7877656},
issn = {0028-4793},
mesh = {Apoptosis ; DNA Nucleotidylexotransferase/genetics/*metabolism ; Humans ; Neoplasms/*enzymology/genetics ; *Telomere ; Tumor Cells, Cultured ; },
}
@article {pmid7884854,
year = {1995},
author = {DeLange, AM and Carpenter, MS and Choy, J and Newsway, VE},
title = {An etoposide-induced block in vaccinia virus telomere resolution is dependent on the virus-encoded DNA ligase.},
journal = {Journal of virology},
volume = {69},
number = {4},
pages = {2082-2091},
pmid = {7884854},
issn = {0022-538X},
mesh = {Amino Acid Sequence ; Amsacrine/pharmacology ; Animals ; Base Sequence ; Cells, Cultured ; Chlorocebus aethiops ; DNA Ligases/antagonists &amp; inhibitors/genetics/*metabolism ; DNA Replication/drug effects ; DNA, Viral/biosynthesis ; Drug Resistance ; Etoposide/*pharmacology ; Gene Expression/drug effects ; Molecular Sequence Data ; Mutation ; *Telomere ; Thymidine Kinase/genetics ; Vaccinia virus/drug effects/enzymology/*genetics/physiology ; Virus Replication/drug effects/genetics ; },
abstract = {Etoposide, an inhibitor of the breakage-reunion reaction associated with cellular type II DNA topoisomerases, was shown to inhibit plaque formation of vaccinia virus. This drug had a major effect on the segregation of newly replicated DNA concatemers. Gene expression and the initiation and elongation phases of viral DNA replication were essentially unaffected. Pulsed-field gel electrophoresis of viral DNA replicated in the presence of etoposide revealed two major classes of DNA: the mature monomeric linear genome and DNA that failed to enter the gel (the relative proportions depending on the concentrations of drug). Restriction enzyme analysis showed a severe defect in telomere resolution. In addition, slowly migrating restriction fragments were suggestive of a general recombination defect. We have isolated several etoposide-resistant mutants and used marker rescue and DNA sequencing to localize the resistance-causing mutation to the amino terminus of the viral DNA ligase gene. Inactivation of the DNA ligase also resulted in an etoposide-resistant phenotype, but to a lesser extent. The telomere resolution and segregation defects were corrected both in the drug-resistant mutants and in the DNA ligase knockout mutants. Reinsertion of wild-type or mutant DNA ligase in the viral thymidine kinase locus confirmed the role of the viral DNA ligase in conferring sensitivity not only to etoposide but also to another topoisomerase II inhibitor, 4'-(9-acridinylamino) methanesulphon-m-anisidide (mAMSA). The data suggest that the nonessential DNA ligase is involved in telomere resolution, possibly as part of a general recombinase.},
}
@article {pmid7613096,
year = {1995},
author = {Harley, CB and Villeponteau, B},
title = {Telomeres and telomerase in aging and cancer.},
journal = {Current opinion in genetics &amp; development},
volume = {5},
number = {2},
pages = {249-255},
doi = {10.1016/0959-437x(95)80016-6},
pmid = {7613096},
issn = {0959-437X},
mesh = {Aging/*genetics/metabolism ; Animals ; Base Sequence ; DNA ; DNA Nucleotidylexotransferase/*metabolism ; Humans ; Molecular Sequence Data ; Neoplasms/enzymology/*genetics ; Stem Cells/metabolism ; *Telomere ; },
abstract = {Telomeres are maintained by the novel ribonucleoprotein enzyme telomerase. Telomerase activity is repressed in most somatic human cells, leading to telomere loss during replicative aging in vivo and in vitro. However, telomerase appears to be reactivated in essentially all human cancers. With the recent cloning of the RNA component of telomerase from several species, the stage is now set for critical tests of the role of telomeres and telomerase in aging and cancer.},
}
@article {pmid7708702,
year = {1995},
author = {Kim, RA and Caron, PR and Wang, JC},
title = {Effects of yeast DNA topoisomerase III on telomere structure.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {92},
number = {7},
pages = {2667-2671},
pmid = {7708702},
issn = {0027-8424},
support = {GM24544/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosome Mapping ; Chromosomes, Fungal ; Cloning, Molecular ; Codon ; DNA Nucleotidylexotransferase/genetics/metabolism ; DNA Primers ; DNA Topoisomerases, Type I/genetics/*metabolism ; DNA, Fungal/isolation &amp; purification/metabolism ; Gene Deletion ; Genes, Fungal ; Genetic Markers ; Introns ; Molecular Sequence Data ; Multigene Family ; Plasmids ; Polymerase Chain Reaction ; Recombinant Proteins/metabolism ; Restriction Mapping ; Saccharomyces cerevisiae/*enzymology/genetics/ultrastructure ; Spores, Fungal/metabolism ; Telomere/physiology/*ultrastructure ; },
abstract = {The yeast TOP3 gene, encoding DNA topoisomerase III, and EST1 gene, encoding a putative telomerase, are shown to be abutted head-to-head on chromosome XII, with the two initiation codons separated by 258 bp. This arrangement suggests that the two genes might share common upstream regulatory sequences and that their products might be functionally related. A comparison of isogenic pairs of yeast TOP3+ and delta top3 strains indicates that the G1-3T repetitive sequence tracks in delta top3 cells are significantly shortened, by about 150 bp. Cells lacking topoisomerase III also show a much higher sequence fluidity in the subtelomeric regions. In delta top3 cells, clusters of two or more copies of tandemly arranged Y' elements have a high tendency of disappearing due to the loss or dispersion of the elements; similarly, a URA3 marker embedded in a Y' element close to the chromosomal tip shows a much higher rate of being lost relative to that in TOP3+ cells. These results suggest that yeast DNA topoisomerase III might affect telomere stability, and plausible mechanisms are discussed.},
}
@article {pmid7876219,
year = {1995},
author = {Gualberto, A and Lowry, J and Santoro, IM and Walsh, K},
title = {Parameters that influence the extent of site occupancy by a candidate telomere end-binding protein.},
journal = {The Journal of biological chemistry},
volume = {270},
number = {9},
pages = {4509-4517},
doi = {10.1074/jbc.270.9.4509},
pmid = {7876219},
issn = {0021-9258},
support = {AR40197/AR/NIAMS NIH HHS/United States ; HL50692/HL/NHLBI NIH HHS/United States ; },
mesh = {Amines/metabolism ; Animals ; Base Sequence ; Binding Sites ; Chick Embryo ; DNA/metabolism ; DNA Probes ; DNA-Binding Proteins/chemistry/*metabolism ; Models, Theoretical ; Molecular Sequence Data ; Protein Conformation ; Ribose/chemistry ; Turkeys ; },
abstract = {The MF3 protein specifically recognizes telomeric and non-telomeric DNA probes that can form G.G base-paired structures (Gualberto, A., Patrick, R. M., and Walsh, K. (1992) Genes &amp; Dev. 6, 815-824). Here we further characterize the nucleic acid recognition properties of MF3 and present a mathematical analysis that evaluates the potential extent of telomere site occupancy by this factor. The substitution of dI at dG positions in telomeric DNA probes revealed that a single dG at any position within the internal repeat was sufficient for high affinity binding to MF3. The RNA analogs of high affinity DNA sites were not bound specifically by MF3, but the substitution of dU for dT in a DNA probe had little or no effect on binding. These data demonstrate that ribose ring structure is a critical feature of nucleoprotein complex formation, and this ribose specificity may enable MF3 to occupy sites of unusual DNA structure while minimizing interactions with cellular RNAs. Collectively, the nucleic acid binding properties of MF3 suggest that it may occupy a significant fraction of sites at telomere ends or other G-rich regions of altered DNA structure in vivo.},
}
@article {pmid7893364,
year = {1995},
author = {Wynford-Thomas, D and Bond, JA and Wyllie, FS and Jones, CJ},
title = {Does telomere shortening drive selection for p53 mutation in human cancer?.},
journal = {Molecular carcinogenesis},
volume = {12},
number = {3},
pages = {119-123},
doi = {10.1002/mc.2940120302},
pmid = {7893364},
issn = {0899-1987},
mesh = {Cell Death ; Cell Division ; DNA Nucleotidylexotransferase/metabolism ; Disease Progression ; *Genes, p53 ; Germ Cells ; Humans ; Models, Genetic ; Mutation ; Neoplasms/*genetics ; Telomere/physiology/*ultrastructure ; },
}
@article {pmid7862108,
year = {1995},
author = {Sheng, H and Hou, Z and Schierer, T and Dobbs, DL and Henderson, E},
title = {Identification and characterization of a putative telomere end-binding protein from Tetrahymena thermophila.},
journal = {Molecular and cellular biology},
volume = {15},
number = {3},
pages = {1144-1153},
pmid = {7862108},
issn = {0270-7306},
support = {GM-41023/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Composition ; Base Sequence ; Chromosomes/physiology ; Cross-Linking Reagents ; DNA, Protozoan/metabolism ; DNA-Binding Proteins/biosynthesis/isolation &amp; purification/*metabolism ; Electrophoresis, Polyacrylamide Gel ; Humans ; Molecular Sequence Data ; Molecular Weight ; Oligonucleotide Probes ; RNA, Protozoan/metabolism ; Repetitive Sequences, Nucleic Acid ; Telomere/metabolism ; Tetrahymena thermophila/genetics/growth &amp; development/*metabolism ; Ultraviolet Rays ; },
abstract = {Telomeric DNA of Tetrahymena thermophila consists of a long stretch of (TTGGGG)n double-stranded repeats with a single-stranded (TTGGGG)2 3' overhang at the end of the chromosome. We have identified and characterized a protein that specifically binds to a synthetic telomeric substrate consisting of duplex DNA and the 3' telomeric repeat overhang. This protein is called TEP (telomere end-binding protein). A change from G to A in the third position of the TTGGGG overhang repeat converts the substrate to a human telomere analog and reduces the binding affinity approximately threefold. Changing two G's to C's in the TTGGGG repeats totally abolishes binding. However, permutation of the Tetrahymena repeat sequence has only a minor effect on binding. A duplex structure adjacent to the 3' overhang is required for binding, although the duplex need not contain telomeric repeats. TEP does not bind to G-quartet DNA, which is formed by many G-rich sequences. TEP has a greatly reduced affinity for RNA substrates. The copy number of TEP is at least 2 x 10(4) per cell, and it is present under different conditions of cell growth and development, although its level varies. UV cross-linking experiments show that TEP has an apparent molecular mass of approximately 65 kDa. Unlike other telomere end-binding proteins, TEP is sensitive to high salt concentrations.},
}
@article {pmid7735107,
year = {1995},
author = {Naumov, GI and Naumov, DG and Luis, ED},
title = {[Localization of a family of MEL alpha-galactosidase genes on yeast left and right telomeres].},
journal = {Doklady Akademii nauk},
volume = {341},
number = {1},
pages = {134-136},
pmid = {7735107},
issn = {0869-5652},
mesh = {Chromosome Mapping ; Chromosomes, Fungal ; Genetic Markers ; *Multigene Family ; Saccharomyces cerevisiae/*genetics ; *Telomere ; alpha-Galactosidase/*genetics ; },
}
@article {pmid7894012,
year = {1995},
author = {Zentgraf, U},
title = {Telomere-binding proteins of Arabidopsis thaliana.},
journal = {Plant molecular biology},
volume = {27},
number = {3},
pages = {467-475},
pmid = {7894012},
issn = {0167-4412},
mesh = {Arabidopsis/*chemistry ; Base Sequence ; DNA, Plant/metabolism ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/chemistry/*metabolism ; Isoelectric Point ; Molecular Sequence Data ; Molecular Weight ; Oligodeoxyribonucleotides/chemical synthesis/metabolism ; Plant Leaves/chemistry ; Ribonucleases ; Telomere/*chemistry ; },
abstract = {The nucleoprotein structure of Arabidopsis thaliana telomeres was investigated. A protein specifically binding to telomeric sequences was characterized by gel mobility shift assays with synthetic oligonucleotides consisting of four 7 bp telomeric repeats of Arabidopsis (TTTAGGG) and crude nuclear protein extracts of Arabidopsis leaves. These DNA-protein binding studies revealed that the binding affinity of this telomere-binding protein to the G-rich single-strand as well as to the double-stranded telomeric DNA is much higher than to the C-rich single-strand. The molecular mass of the protein was identified by SDS-PAGE to be 67 kDa. The isoelectric points were determined to be 5.0, 4.85 and 4.7, respectively, indicating that either one protein with different modifications or three slightly different proteins have been isolated. An RNA component, possibly serving as a template for reverse transcription of a plant telomerase, does not mediate the DNA-protein contact because the DNA-protein interactions were not RNAse-sensitive.},
}
@article {pmid7867933,
year = {1995},
author = {Buck, SW and Shore, D},
title = {Action of a RAP1 carboxy-terminal silencing domain reveals an underlying competition between HMR and telomeres in yeast.},
journal = {Genes &amp; development},
volume = {9},
number = {3},
pages = {370-384},
doi = {10.1101/gad.9.3.370},
pmid = {7867933},
issn = {0890-9369},
support = {CA09503-0/CA/NCI NIH HHS/United States ; GM40094/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosome Mapping ; DNA, Complementary ; DNA-Binding Proteins/chemistry/*genetics/metabolism ; Gene Expression Regulation, Fungal ; Molecular Sequence Data ; Saccharomyces cerevisiae/*genetics ; Telomere ; Transcription Factors/*genetics ; },
abstract = {RAP1 is a sequence-specific DNA-binding protein in yeast that can either repress or activate transcription. Previous studies have demonstrated a direct role for RAP1 in silencing at HM mating-type loci and telomeres. Here, we show that a small carboxy-terminal domain of RAP1 is sufficient to establish repression when fused to the GAL4 DNA-binding domain (GBD) and targeted to mutated HMR silencers containing GAL4 DNA-binding sites. Silencing by GBD/RAP1 hybrids, like normal silencing at HMR, requires the trans-acting factors SIR2, SIR3, and SIR4. However, GBD/RAP1-mediated silencing is independent of SIR1, whose product is normally required for the establishment of repression at HMR. Targeted silencing also displays an unusual response to silencing-defective rap1s mutations. The incorporation of a rap1s missense mutation into GBD/RAP1 hybrids can improve targeted silencing, yet wild-type GBD/RAP1 hybrids fail to establish repression in strains in which the endogenous RAP1 locus carries a rap1s mutation. In addition, we find that telomeric silencing is increased in rap1s strains. We propose that the rap1s mutation creates an HMR-specific silencing defect by shifting a balance between silencing at HMR and telomeres in favor of telomeric silencing. This balance is regulated by telomere length and by interactions between the RAP1 carboxyl terminus and both RIF1 and SIR4 proteins. In support of this model, we show that abnormally long telomeres antagonize silencing at HMR and a rap1s hybrid protein displays a strengthened interaction with SIR4 in a two-hybrid assay.},
}
@article {pmid7767012,
year = {1995},
author = {Yen, CH and Matsuda, Y and Chapman, VM and Elliott, RW},
title = {A genomic clone containing a telomere array maps near the centromere of mouse chromosome 6.},
journal = {Mammalian genome : official journal of the International Mammalian Genome Society},
volume = {6},
number = {2},
pages = {96-102},
pmid = {7767012},
issn = {0938-8990},
support = {GM28464/GM/NIGMS NIH HHS/United States ; GM33160/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Centromere/*genetics ; Chromosome Mapping ; Cloning, Molecular ; Crosses, Genetic ; Female ; Genetic Markers ; Heterochromatin/genetics ; Hybridization, Genetic ; Male ; Mice/*genetics ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Molecular Sequence Data ; Muridae/genetics ; Telomere/*genetics ; *Translocation, Genetic ; },
abstract = {A lambda clone of mouse DNA containing a short array of telomere hexamers has been localized by FISH to a region close to the centromere of Chromosome (Chr) 6. Amplification of DNA with primers flanking an SSR showed that most inbred strains carry one of two alleles, although five other alleles were found among the inbred strains and 11 other alleles were found in wild-derived mice. Analysis of the DNA from four Robertsonian translocations suggests that the amplified sequence is still present in these chromosomes. The finding of two fragments associated with the Sig mutant suggests that the clone lies within a congenic region created when the mutant, obtained in a (C3H x 101)F1, was backcrossed to C57BL/6J. This region might include all or part of the centromere. Comparison of the segregation of the amplification product with the segregation of centromeric heterochromatin in an interspecies backcross, (C57BL/6 x M. spretus)F1 x M. spretus, (BSS) shows 1/72 recombinants with the centromeric heterochromatin, while 1/62 recombinants occurred in a BSB backcross. Analysis of other loci at the proximal end of Chr 6 gives the combined map Hc6-0.73-D6Mit86-0.73-D6Rp2-2.2-D6Mitl-2.2-Wn t2-3.0-Cpa. Data from a third cross show that Cola2 lies between D6Mit82 and D6Rp2. The portion of the telomere array, Tel-rs3, that has been sequenced contains only 13/31 repeats of the consensus sequence. A variety of sequence changes from the consensus hexamer suggests that this array has been removed for a long time from evolutionary pressures to retain the TTAGGG sequence.},
}
@article {pmid7716808,
year = {1995},
author = {Mason, JM and Biessmann, H},
title = {The unusual telomeres of Drosophila.},
journal = {Trends in genetics : TIG},
volume = {11},
number = {2},
pages = {58-62},
doi = {10.1016/s0168-9525(00)88998-2},
pmid = {7716808},
issn = {0168-9525},
support = {GM46211/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Biological Evolution ; Chromosomes/physiology ; DNA Repair ; DNA Replication ; *DNA Transposable Elements ; Drosophila/*genetics ; Drosophila melanogaster/genetics ; Repetitive Sequences, Nucleic Acid ; *Telomere/chemistry/ultrastructure ; },
abstract = {The telomeres of most eukaryotes contain short, simple repeats that are highly conserved. Drosophila, on the other hand, does not have such sequences, but carries at the ends of its chromosomes one or more LINE-like retrotransposable elements. Instead of elongation by telomerase, incomplete DNA replication at the termini of Drosophila chromosomes is counterbalanced by transposition of these elements at high frequency specifically to the termini. These transposable elements are not responsible for distinguishing telomeric ends in Drosophila from broken chromosome ends; the structure performing this function is not yet known. Proximal to the terminal array of transposable elements are regions of tandem repeats that are structurally, and probably functionally, analogous to the subterminal regions in other eukaryotes.},
}
@article {pmid7846079,
year = {1995},
author = {Zou, S and Wright, DA and Voytas, DF},
title = {The Saccharomyces Ty5 retrotransposon family is associated with origins of DNA replication at the telomeres and the silent mating locus HMR.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {92},
number = {3},
pages = {920-924},
pmid = {7846079},
issn = {0027-8424},
mesh = {Base Sequence ; DNA Replication ; DNA, Fungal/genetics ; Gene Dosage ; Genes, Fungal/*genetics ; Molecular Sequence Data ; Plasmids/biosynthesis ; Replication Origin/*genetics ; Retroelements/*genetics ; Saccharomyces/*genetics ; Species Specificity ; Telomere/*genetics ; },
abstract = {We have characterized the genomic organization of the Ty5 retrotransposons among diverse strains of Saccharomyces cerevisiae and the related species Saccharomyces paradoxus. The S. cerevisiae strain S288C (or its derivatives) carries eight Ty5 insertions. Six of these are located near the telomeres, and five are found within 500 bp of autonomously replicating sequences present in the type X subtelomeric repeat. The remaining two S. cerevisiae elements are adjacent to the silent mating locus HMR and are located within 500 bp of the origin of replication present in the transcriptional silencer HMR-E. Although the S. cerevisiae Ty5 elements no longer appear capable of transposition, some strains of S. paradoxus have numerous Ty5 insertions, suggesting that transposition is occurring in this species. Most of these elements are adjacent to type X telomeric repeats, and regions flanking four of five characterized S. paradoxus insertions carry autonomously replicating sequences. The genomic organization of the Ty5 elements is in marked contrast to the other S. cerevisiae retrotransposon families (Ty1-4), which are typically located within 500 bp of tRNA genes. For Ty3, this association reflects an interaction between Ty3 and the RNA polymerase III transcription complex, which appears to direct integration [Chalker, D. L. &amp; Sandmeyer, S. B. (1992) Genes Dev. 6, 117-128]. By analogy to Ty3, we predict that Ty5 target choice is specified by interactions with factors present at both the telomeres and HMR that are involved in DNA replication, transcription silencing, or the maintenance of the unique chromatin structure at these sites.},
}
@article {pmid7790003,
year = {1995},
author = {Browne, DL and Smith, EA and Dietz-Band, J and Riethmann, HC and Phromchotikul, T and Litt, M},
title = {Dinucleotide repeat polymorphism at the human chromosome 11p telomere (D11S2071).},
journal = {Genomics},
volume = {25},
number = {2},
pages = {600-601},
doi = {10.1016/0888-7543(95)80071-s},
pmid = {7790003},
issn = {0888-7543},
support = {HG-00022/HG/NHGRI NIH HHS/United States ; HG00567/HG/NHGRI NIH HHS/United States ; },
mesh = {Alleles ; Base Sequence ; Chromosomes, Artificial, Yeast ; *Chromosomes, Human, Pair 11 ; Genetic Markers ; Humans ; Molecular Sequence Data ; *Polymorphism, Genetic ; *Repetitive Sequences, Nucleic Acid ; Sequence Tagged Sites ; Telomere/*genetics ; },
}
@article {pmid7816828,
year = {1995},
author = {Kruk, PA and Rampino, NJ and Bohr, VA},
title = {DNA damage and repair in telomeres: relation to aging.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {92},
number = {1},
pages = {258-262},
pmid = {7816828},
issn = {0027-8424},
mesh = {Aged ; Alzheimer Disease/genetics/metabolism ; Base Sequence ; Blotting, Southern ; Cell Line ; Child ; DNA/isolation &amp; purification/*metabolism/radiation effects ; *DNA Damage ; *DNA Repair ; Fibroblasts/metabolism ; Humans ; Infant, Newborn ; Kinetics ; Molecular Sequence Data ; Pyrimidine Dimers ; Restriction Mapping ; Telomere/*metabolism ; Ultraviolet Rays ; Werner Syndrome/genetics/metabolism ; },
abstract = {We have established a method for the detection of DNA damage and its repair in human telomeres, the natural ends of chromosomes which are necessary for replication and critical for chromosomal stability. We find that ultraviolet light-induced pyrimidine dimers in telomeric DNA are repaired less efficiently than endogenous genes but more efficiently than inactive, noncoding regions. We have also measured telomeric length, telomeric DNA damage, and its repair in relation to the progression of aging. Telomeres are shorter in fibroblasts from an old donor compared to fibroblasts from a young donor, shortest in cells from a patient with the progeroid disorder Werner syndrome, and relatively long in fibroblasts from a patient with Alzheimer disease. Telomeric DNA repair efficiency is lower in cells from an old donor than in cells from a young donor, normal in Alzheimer cells, and slightly lower in Werner cells. It is possible that this decline in telomeric repair with aging is of functional significance to an age-related decline in genomic stability.},
}
@article {pmid8841621,
year = {1995},
author = {Torigoe, H and Kamiya, M and Shindo, H and Sarai, A},
title = {Structural polymorphism and thermal stability of telomere DNAs (T2G4)n and (T4G4)n.},
journal = {Nucleic acids symposium series},
volume = {},
number = {34},
pages = {199-200},
pmid = {8841621},
issn = {0261-3166},
mesh = {Base Sequence ; Calorimetry, Differential Scanning ; Circular Dichroism ; DNA/*chemistry/genetics ; Drug Stability ; Guanine/chemistry ; Molecular Structure ; Nucleic Acid Conformation ; Nucleic Acid Denaturation ; Oligodeoxyribonucleotides/chemical synthesis/chemistry/genetics ; Polymorphism, Genetic ; Telomere/*chemistry/genetics ; Temperature ; Thymine/chemistry ; },
abstract = {The ends of eukaryotic chromosomes, termed telomeres, contain a single-stranded 3' overhang composed of tandemly repeated guanine-rich sequences, such as (T2G4)n and (T4G4)n, along one strand. The sequences can form defined folded tetraplex structures. Here we have systematically examined structural polymorphism and thermal stability of a series of oligonucleotide sequences, Tet n: (T2G4)n and Oxy n: (T4G4)n (n = 1, 2, 3, 4), using circular dichroism (CD) spectroscopy. The CD spectra of Tet 1 and Oxy 1 are consistent with those observed in tetraplex structures consisting of four parallel strands (type I conformation); whereas the spectra of Tet 2, Oxy 2, Oxy 3, and Oxy 4 correspond with those observed for tetraplex conformations where the strands are antiparallel (type II conformation). The spectra of Tet 3 and Tet 4 suggests that Tet 3 and Tet 4 can adopt both type I and type II conformations and they are structurally polymorphic. The melting temperatures of Tet n and Oxy n (n = 1, 2, 3, 4) measured by CD melting are consistent with the previously reported values obtained from differential scanning calorimetry (DSC). Furthermore, the CD melting of Tet 4 suggests that the type II conformation of Tet 4 changes into type I conformation between 55 degrees C and 70 degrees C.},
}
@article {pmid8841557,
year = {1995},
author = {Higashiyama, T and Noutoshi, Y and Akiba, M and Yamada, T},
title = {Telomere and LINE-like elements at the termini of the Chlorella chromosome I.},
journal = {Nucleic acids symposium series},
volume = {},
number = {34},
pages = {71-72},
pmid = {8841557},
issn = {0261-3166},
mesh = {Animals ; Base Sequence ; Chlorella/*genetics ; Chromosomes/*genetics ; DNA/genetics ; Drosophila/genetics ; Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; Retroelements ; Species Specificity ; Telomere/*genetics ; },
abstract = {The telomeres of Chlorella chromosomes consisted of 5'-TTTAGGG repeats, which are exactly the same as those of higher plants. This sequence was reiterated approximately 70 times at both termini of chromosome I. Subtelomeric sequences next to the telomeres were totally different between the right and left arms. On the left-side subtelomeric region, polyA associated LINE (long interspersed element)-like elements were found tandemly repeated just next to the telomeric repeats. It is very interesting to compare this unique structure with telomeres of Drosophila, where a transposable element play a major role in forming telomerase-generated repeats. We propose a mechanism of transposon-mediated healing of a broken chromosomal end that would operate in the unicellular green alga Chlorella.},
}
@article {pmid8824780,
year = {1995},
author = {Pommier, JP and Lebeau, J and Ducray, C and Sabatier, L},
title = {Chromosomal instability and alteration of telomere repeat sequences.},
journal = {Biochimie},
volume = {77},
number = {10},
pages = {817-825},
doi = {10.1016/0300-9084(96)88201-0},
pmid = {8824780},
issn = {0300-9084},
mesh = {Aging/genetics ; Animals ; Antiviral Agents/therapeutic use ; Cellular Senescence/*genetics ; Chromosomes/genetics ; DNA/*genetics ; DNA Replication/*genetics ; Humans ; Neoplasms ; Repetitive Sequences, Nucleic Acid/*genetics ; Telomerase/metabolism ; Telomere/*genetics ; },
abstract = {The very end of the chromosome is called the telomere and is composed of DNA repeat sequences and associated proteins. Genetic and biochemical analyses of this complex, the telosome, lead to the hypothesis that transcription and DNA replication are submitted to position effects mediated by the telomere proximity. Telomere length reduction and alterations of the telomeric chromatin assembly might explain the chromosome instability which occurs during the senescence and the immortalization process in vitro. A particular polymerase, the telomerase, is able to lengthen the telomeres. A telomerase activity was characterized in yeast, Tetrahymena, but also in transformed and in germline cells. We reviewed the involvement of telomeres in the aging process. We proposed that the short size of the telomere repeat at each chromosome could direct the loss of heterozygosity, thus telomere length could play a role in individual and tissular susceptibility to develop cancer. Antitelomerase strategy for cancer therapy is attractive but limited by the short decrease of the telomere length at each cell division.},
}
@article {pmid8555645,
year = {1995},
author = {Healy, KC},
title = {Telomere dynamics and telomerase activation in tumor progression: prospects for prognosis and therapy.},
journal = {Oncology research},
volume = {7},
number = {3-4},
pages = {121-130},
pmid = {8555645},
issn = {0965-0407},
mesh = {Base Sequence ; Disease Progression ; Enzyme Activation ; Humans ; Neoplasms/*enzymology/*pathology/therapy ; Prognosis ; Repetitive Sequences, Nucleic Acid ; Telomerase/*metabolism ; Telomere/*physiology ; },
abstract = {Eukaryotic telomeres provide a reservoir of redundancy to compensate for incomplete replication of chromosome ends. In multicellular eukaryotes, they are eroded by a varying number of base pairs at every cell division. When telomere repeats are critically shortened, DNA damage response pathways involving p53 (and in some cell types retinoblastoma protein) are invoked, leading to "M1 senescence" in normal cells; cancer cells, which frequently lack normal p53 and RB functions, often develop chromosomal instability leading to telomeric associations, ring chromosomes, and breakage-fusion-bridge cycles. These consequences of telomere erosion exert selection pressure for activation of the ribonucleoprotein enzyme telomerase, which adds new telomeric repeats at chromosome ends, and in vertebrates normally is active only in the germ line and the early embryo. Somatic cells that reactivate telomerase in vitro or in vivo become immortal. Telomerase activity has been found in many advanced and metastatic human cancers, suggesting that telomerase-dependent M2 immortalization may contribute to metastatic potential. When mammalian telomerases are isolated and their genes cloned and sequenced, the localization of telomerase expression in tumors may provide prognostic indicators of metastatic potential. The abrogation of telomerase function by pharmacological inhibition, genetic disruption, or repression of gene expression is a potential avenue of antimetastatic therapy.},
}
@article {pmid7828852,
year = {1995},
author = {Kirk, KE and Blackburn, EH},
title = {An unusual sequence arrangement in the telomeres of the germ-line micronucleus in Tetrahymena thermophila.},
journal = {Genes &amp; development},
volume = {9},
number = {1},
pages = {59-71},
doi = {10.1101/gad.9.1.59},
pmid = {7828852},
issn = {0890-9369},
support = {GM26259/GM/NIGMS NIH HHS/United States ; GM32565/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Centromere/genetics ; Cloning, Molecular ; DNA, Protozoan/genetics ; Models, Genetic ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Repetitive Sequences, Nucleic Acid ; Sequence Analysis, DNA ; Telomere/*genetics ; Tetrahymena thermophila/*genetics ; },
abstract = {The ciliated protozoan Tetrahymena thermophila contains two nuclei that differ dramatically in function, chromosome size and number, chromatin structure, and mode of division. It is possible that the telomeres of the two nuclei have different functions. Although macronuclear telomeric DNA has been well characterized and consists of tandem G4T2/C4A2 repeats that are synthesized by the enzyme telomerase, micronuclear telomeres have not been isolated previously. Here, we report the identification and cloning of micronuclear telomeres and demonstrate that although they contain the same terminal tandem G4T2 repeats as macronuclear telomeres, they are strikingly different in three respects. First, the tracts of G/C-rich telomeric repeats are approximately seven times longer in the micronucleus than in the macronucleus (approximately 2.0-3.4 vs. approximately 0.3-0.5 kb, respectively) from the same cell population. Second, the immediate telomere-associated sequences (TASs) from six different micronuclear chromosome ends have an unusually high G/C content and degree of homology to one another, unlike macronuclear TASs. The TAS from at least one micronuclear chromosome is unique to micronuclear telomeres and is not present in the macronucleus. Finally, and unexpectedly, all micronuclear telomere clones contain an inner homogeneous tract of a variant G4T3 repeat adjacent to the distal tract of G4T2 repeats. The native micronuclear telomeric DNA is composed of approximately 30% G4T3 repeats, corresponding to 0.6-1.0 kb per average telomere, positioned centromere-proximally to most or all of the G4T2 repeats. Neither the G4T3 sequence nor any other variant repeat is found in macronuclear telomeres. Furthermore, such a homogeneous tract of a variant repeat has not been found in the telomeres of any eukaryote.},
}
@article {pmid7741024,
year = {1995},
author = {Royle, NJ},
title = {The proterminal regions and telomeres of human chromosomes.},
journal = {Advances in genetics},
volume = {32},
number = {},
pages = {273-315},
doi = {10.1016/s0065-2660(08)60207-2},
pmid = {7741024},
issn = {0065-2660},
mesh = {Animals ; Cell Transformation, Neoplastic ; Cellular Senescence ; Chromosome Aberrations ; Chromosomes, Human/*ultrastructure ; DNA-Binding Proteins/metabolism ; Female ; Hominidae/genetics ; Humans ; Male ; Minisatellite Repeats ; Mutation ; Recombination, Genetic ; *Telomere ; },
}
@article {pmid7738087,
year = {1995},
author = {Lansdorp, PM},
title = {Telomere length and proliferation potential of hematopoietic stem cells.},
journal = {Journal of cell science},
volume = {108 (Pt 1)},
number = {},
pages = {1-6},
doi = {10.1242/jcs.108.1.1},
pmid = {7738087},
issn = {0021-9533},
support = {AI29524/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA/genetics/metabolism ; *DNA Replication ; Genetic Therapy ; *Hematopoiesis ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/*cytology ; Humans ; Molecular Sequence Data ; Telomere/*ultrastructure ; },
abstract = {Hematopoietic stem cells have typically been defined as pluripotent cells with self-renewal capacity. Recent studies have shown striking differences in the mean length of telomeric repeat sequences at the end of chromosomes from human hematopoietic cells at different stages of development. The most likely explanation for these observations is that hematopoietic stem cells, like all other somatic cells studied to date, lose telomeric DNA upon each cell division. In this review, limitations in the replicative potential of hematopoietic stem cells are discussed in the context of possible clinical use of such cells for transplantation and gene therapy.},
}
@article {pmid7736797,
year = {1995},
author = {Höglund, M and Mitelman, F and Mandahl, N},
title = {A human 12p-derived cosmid hybridizing to subsets of human and chimpanzee telomeres.},
journal = {Cytogenetics and cell genetics},
volume = {70},
number = {1-2},
pages = {88-91},
doi = {10.1159/000133998},
pmid = {7736797},
issn = {0301-0171},
mesh = {Animals ; *Chromosomes, Human, Pair 12 ; Cosmids/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Pan troglodytes ; Repetitive Sequences, Nucleic Acid ; Telomere/*genetics ; },
abstract = {The chromosomal locations of a cosmid-linking clone, cLN12-43, isolated from band 12p13 in man and containing subtelomeric repeat sequences, were determined by FISH. The cosmid hybridized to the telomeres of 3q, 6p, 9p, 12p, 15q, 19p, 20p, and 20q at high frequency and showed variable hybridization to 1p, 6q, and 9q. Two interstitial loci were detected, one at bands 2q13-->q14 and the other at band 12q13. The former corresponds to the fusion point of chimpanzee chromosomes 12 and 13, resulting in the human chromosome 2, whereas the latter may represent a similar but more ancient fusion event. The cLN12-43 cosmid was also shown to hybridize to a set of chimpanzee telomeres.},
}
@article {pmid7705652,
year = {1995},
author = {Wiley, EA and Zakian, VA},
title = {Extra telomeres, but not internal tracts of telomeric DNA, reduce transcriptional repression at Saccharomyces telomeres.},
journal = {Genetics},
volume = {139},
number = {1},
pages = {67-79},
pmid = {7705652},
issn = {0016-6731},
support = {AG-00057/AG/NIA NIH HHS/United States ; GM-43265/GM/NIGMS NIH HHS/United States ; },
mesh = {DNA, Fungal/*genetics ; DNA-Binding Proteins/genetics ; Fungal Proteins/biosynthesis ; GTP-Binding Proteins/biosynthesis ; *Gene Expression Regulation, Fungal ; Repressor Proteins/genetics ; Saccharomyces/*genetics ; *Saccharomyces cerevisiae Proteins ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Species Specificity ; Telomere/*genetics ; *Telomere-Binding Proteins ; Trans-Activators/biosynthesis ; *Transcription, Genetic ; rap GTP-Binding Proteins ; },
abstract = {Yeast telomeric DNA is assembled into a nonnucleosomal chromatin structure known as the telosome, which is thought to influence the transcriptional repression of genes placed in its vicinity, a phenomenon called telomere position effect (TPE). The product of the RAP1 gene, Rap1p, is a component of the telosome. We show that the fraction of cells exhibiting TPE can be substantially reduced by expressing large amounts of a deletion derivative of Rap1p that is unable to bind DNA, called Rap1 delta BBp, or by introducing extra telomeres on a linear plasmid, presumably because both compete in trans with telomeric chromatin for factor(s) important for TPE. This reduction in TPE, observed in three different strains, was demonstrated for two different genes, each assayed at a different telomere. In contrast, the addition of internal tracts of telomeric DNA on a circular plasmid had very little effect on TPE. The product of the SIR3 gene, Sir3p, appears to be limiting for TPE. Overexpression of Sir3p completely suppressed the reduction in TPE observed with expression of Rap1 delta BBp, but did not restore high levels of TPE to cells with extra telomeres. These results suggest that extra telomeres must titrate a factor other than Sir3p that is important for TPE. These results also provide evidence for a terminus-specific binding factor that is a factor with a higher affinity for DNA termini than for nonterminal tracts of telomeric DNA and indicate that this factor is important for TPE.},
}
@article {pmid7705618,
year = {1995},
author = {Louis, EJ and Borts, RH},
title = {A complete set of marked telomeres in Saccharomyces cerevisiae for physical mapping and cloning.},
journal = {Genetics},
volume = {139},
number = {1},
pages = {125-136},
pmid = {7705618},
issn = {0016-6731},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Chromosomes, Fungal/*genetics ; Cloning, Molecular/*methods ; Genetic Markers/genetics ; Genetic Vectors/genetics ; *Restriction Mapping ; Saccharomyces cerevisiae/*genetics ; Telomere/*genetics ; Transformation, Genetic ; },
abstract = {Each telomere in a single strain (S288C) of Saccharomyces cerevisiae was marked with a URA3 containing integrating vector having telomeric TG1-3 sequences. Efficiency of integrative transformation was enhanced by creating single random double-strand breaks in the integrating vector using DNAseI in the presence of Mn2+ ions. A total of 327 transformants were screened by CHEF gels of intact chromosomal DNA. Transformants with homology to the vector at particular chromosomal bands were then screened by Southern analysis with several restriction enzymes to confirm telomeric locations. CHEF gels of NotI and/or SfiI digests were also analyzed to determine left or right arm locations. In some cases allelism of marked telomeres was determined genetically. Transformation was performed by lithium acetate and electroporation with varying results. Electroporation resulted in 50% (75/150) of the integrants at the internal URA3 location rather than telomeres. There were also two rearrangements involving URA3 and the telomere of another chromosome. Lithium acetate transformation resulted in fewer integrants at the internal URA3 location (5/84) and no rearrangements. All telomeres were marked with approximately the same efficiency ranging from 0 to 11 hits in the first 240 transformants. These marked telomeres can be used to complete the physical maps of chromosomes in which the telomere regions are absent. The marked telomeres can be cloned with the appropriate restriction enzymes, thus completing the cloning of individual chromosomes for sequencing projects. The analysis of these clones will lead to a better understanding of telomere region biology. The methodology can also be applied to telomeres of other organisms once they are cloned as telomeric YACs.},
}
@article {pmid7606935,
year = {1995},
author = {Pandita, TK and Pathak, S and Geard, CR},
title = {Chromosome end associations, telomeres and telomerase activity in ataxia telangiectasia cells.},
journal = {Cytogenetics and cell genetics},
volume = {71},
number = {1},
pages = {86-93},
doi = {10.1159/000134069},
pmid = {7606935},
issn = {0301-0171},
support = {CA 12536/CA/NCI NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia/enzymology/*genetics ; Cell Line, Transformed ; *Chromosome Aberrations ; Chromosome Banding ; DNA ; DNA Nucleotidylexotransferase/*metabolism ; Humans ; Karyotyping ; *Telomere ; },
abstract = {Cells derived from individuals with ataxia telangiectasia (AT) show enhanced spontaneous levels of chromosomal abnormalities and are sensitive to ionizing radiations and radiomimetic drugs, as evidenced by decreased survival and increased chromosome aberration frequencies at mitosis when compared with normal cell lines. The higher base line frequencies of chromosome aberrations in part involve chromosome end-to-end associations as seen at metaphase. Since telomeres of tumor cells and aging tissues are often reduced in length, chromosome end associations may be due to loss of telomeric repeats. We studied the chromosome behavior and telomeres of two ataxia telangiectasia lymphoblastoid cell lines compared to two normal control cell lines. The ataxia telangiectasia cell lines showed higher frequencies of chromosome end associations both at metaphase and in interphase, determined in prematurely condensed chromosomes of G1 and G2 cells. They also showed higher frequencies of chromosomal breaks at metaphase and fewer telomeric signals determined using fluorescent in situ hybridization with a (TTAGGG)n probe. The frequency of telomeric repeats was variable in the ataxia telangiectasia cell lines (4.3 and 8.2 kb) compared to the normal cell lines (9.6 and 12 kb) and an inverse correlation between telomere length and chromosome end associations was observed. Both ataxia telangiectasia cell lines showed more robust telomerase activity than the normal cell lines, precluding defective enzymatic capacity as the basis for the chromosome end associations. It is possible that chromatin structure in the form of telomere-nuclear matrix interactions are variant in ataxia telangiectasia cells negatively influencing telomerase function and contributing to telomere associations.},
}
@article {pmid7587380,
year = {1995},
author = {Ashley, T and Lieman, J and Ward, DC},
title = {Multicolor FISH with a telomere repeat and Sry sequences shows that Sxr (Sex reversal) in the mouse is a new type of chromosome rearrangement.},
journal = {Cytogenetics and cell genetics},
volume = {71},
number = {3},
pages = {217-222},
doi = {10.1159/000134113},
pmid = {7587380},
issn = {0301-0171},
support = {GM-49779/GM/NIGMS NIH HHS/United States ; HG-00246/HG/NHGRI NIH HHS/United States ; HG-00272/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; *Chromosome Aberrations ; DNA-Binding Proteins/*genetics ; *Disorders of Sex Development ; Female ; In Situ Hybridization, Fluorescence/*methods ; Male ; Mice ; Microscopy, Electron ; *Nuclear Proteins ; Recombination, Genetic ; *Sex Determination Analysis ; Sex-Determining Region Y Protein ; Synaptonemal Complex/genetics ; *Telomere ; *Transcription Factors ; },
abstract = {XYSxr (Sex reversal) mice carry a Y chromosome in which the chromatin (including Sry, the gene for testis determination) that normally resides on the short arm is duplicated and the second copy is relocated to the distal end of the long arm. Multicolor in situ hybridization to mitotic chromosomes of XYSxr males using probes for the telomere repeat sequence (TTAGGG)n and Sry shows that the rearranged chromatin is located distal to the telomeric signal. This suggests that the rearrangement arose from a recombination event involving the distal Y telomere sequences, i.e., within the telomere, a structure historically assumed to be incapable of participating in chromosome rearrangements.},
}
@article {pmid7534110,
year = {1995},
author = {Wainwright, LJ and Middleton, PG and Rees, JL},
title = {Changes in mean telomere length in basal cell carcinomas of the skin.},
journal = {Genes, chromosomes &amp; cancer},
volume = {12},
number = {1},
pages = {45-49},
doi = {10.1002/gcc.2870120108},
pmid = {7534110},
issn = {1045-2257},
mesh = {Base Sequence ; Carcinoma, Basal Cell/*genetics ; Humans ; Molecular Sequence Data ; Skin Neoplasms/*genetics ; Telomere/*genetics ; },
abstract = {Human telomeres consist of arrays of the sequence TTAGGG up to 15-20 kb in length, which are essential for the maintenance of normal chromosomal stability. It has been suggested that genomic instability observed in tumours may be due to loss of telomere sequences. Somatic cells that are dividing continuously appear to progressively lose telomere sequences, and it would therefore be anticipated that cell type specific differences in mean telomere length may exist within an individual. Previous reports have suggested that mean telomere length may be different in human neoplasia when compared to control. Basal cell carcinomas are epidermal derived tumours and in order therefore to make valid cell type specific comparisons we have measured mean telomere length in 20 basal cell carcinomas as well as in both adjacent epidermis and dermis. Mean telomere length was significantly reduced in epidermis in comparison with dermis, from clinically normal skin immediately adjacent to the tumours (mean difference 2.5 kb). This result is not related to the presence of the tumour as similar results were obtained from skin samples of healthy volunteers. Basal cell carcinomas showed increased mean telomere length in 13/20 samples in comparison with matched epidermis (mean difference 3.1 kb), whereas in 7/20 mean telomere length was reduced (mean difference 2.2 kb). These results showing that mean telomere length varies from cell type to cell type underpin the importance of performing cell type specific controls when assessing changes in tumour telomeres.},
}
@article {pmid7525160,
year = {1995},
author = {Therkelsen, AJ and Nielsen, A and Koch, J and Hindkjaer, J and Kølvraa, S},
title = {Staining of human telomeres with primed in situ labeling (PRINS).},
journal = {Cytogenetics and cell genetics},
volume = {68},
number = {1-2},
pages = {115-118},
doi = {10.1159/000133903},
pmid = {7525160},
issn = {0301-0171},
mesh = {Adult ; Animals ; Base Sequence ; Chromosome Banding ; DNA Primers ; Female ; Hominidae/*genetics ; Humans ; Molecular Sequence Data ; Staining and Labeling ; Telomere/*ultrastructure ; Tetrahymena ; },
abstract = {As described, the PRINS method is a very rapid and reliable way of staining human telomeres. To obtain the maximum frequency of stained telomeres, the primer (CCCTAA)7 should be used, although the average frequency never quite reaches 100%. The frequency is strongly dependent on the age of the individual, being significantly higher in children and newborns than in adults. A difference between the (CCCTAA)7 primer and the complementary primer is demonstrated and a possible explanation is proposed, namely, that gaps in the C-rich strand cause chain elongation termination after the addition of only one dTTP molecule.},
}
@article {pmid7816621,
year = {1994},
author = {Gilson, E and Müller, T and Sogo, J and Laroche, T and Gasser, SM},
title = {RAP1 stimulates single- to double-strand association of yeast telomeric DNA: implications for telomere-telomere interactions.},
journal = {Nucleic acids research},
volume = {22},
number = {24},
pages = {5310-5320},
pmid = {7816621},
issn = {0305-1048},
mesh = {Base Sequence ; DNA, Fungal/chemistry/*metabolism ; DNA, Single-Stranded/metabolism ; DNA, Superhelical/metabolism ; DNA-Binding Proteins/isolation &amp; purification/*metabolism/physiology ; Molecular Sequence Data ; *Nucleic Acid Conformation ; Plasmids/metabolism ; Saccharomyces cerevisiae/cytology/metabolism ; Telomere/*metabolism ; Transcription Factors/isolation &amp; purification/*metabolism/physiology ; },
abstract = {Repressor Activator Protein 1 (RAP1) of Saccharomyces cerevisiae is an abundant nuclear protein implicated in telomere length maintenance, transactivation, and in the establishment of silent chromatin domains. The RAP1 binding site 5' of the yeast HIS4 gene is also a region of hyperrecombination in meiosis. We report here that as RAP1 binds its recognition consensus, it appears to untwist double-stranded DNA, which we detect as the introduction of a negative supercoil in circularization assays. Coincident with the RAP1-dependent untwisting, we observe stimulation of the association of a single-stranded yeast telomeric sequence with its homologous double-stranded sequence in a supercoiled plasmid. This unusual distortion of the DNA double helix by RAP1 may contribute to the RAP1-dependent enhancement of recombination rates and promote non-duplex strand interactions at telomeres.},
}
@article {pmid7991584,
year = {1994},
author = {Sandell, LL and Gottschling, DE and Zakian, VA},
title = {Transcription of a yeast telomere alleviates telomere position effect without affecting chromosome stability.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {91},
number = {25},
pages = {12061-12065},
pmid = {7991584},
issn = {0027-8424},
support = {AG00057/AG/NIA NIH HHS/United States ; GM26938/GM/NIGMS NIH HHS/United States ; GM43265/GM/NIGMS NIH HHS/United States ; },
mesh = {Centromere/physiology ; Chromosome Mapping ; Chromosomes, Fungal/*physiology ; Galactose/metabolism ; *Gene Expression Regulation, Fungal ; Genes, Fungal ; Genetic Markers ; Glucose/metabolism ; Replication Origin ; Saccharomyces cerevisiae/*genetics/metabolism ; TATA Box ; *Telomere ; *Transcription, Genetic ; },
abstract = {Telomeres are required for the stable maintenance of chromosomes in the yeast Saccharomyces cerevisiae. Telomeres also repress the expression of genes in their vicinity, a phenomenon known as telomere position effect. In an attempt to construct a conditional telomere, an inducible promoter was introduced adjacent to a single telomere of a chromosome such that transcription could be induced toward the end of the chromosome. Transcription toward two other essential chromosomal elements, centromeres and origins of replication, eliminates their function. In contrast, transcription toward a telomere did not affect the stability function of the telomere as measured by the loss rate of the transcribed chromosome. Transcription proceeded through the entire length of the telomeric tract and caused a modest reduction in the average length of the transcribed telomere. Transcription of the telomere substantially reduced the frequency of cells in which an adjacent URA3 gene was subject to telomere position effect. These results indicate that telomere position effect can be alleviated without compromising chromosome stability.},
}
@article {pmid7969141,
year = {1994},
author = {Zhang, YJ and Kamnert, I and López, CC and Cohn, M and Edström, JE},
title = {A family of complex tandem DNA repeats in the telomeres of Chironomus pallidivittatus.},
journal = {Molecular and cellular biology},
volume = {14},
number = {12},
pages = {8028-8036},
pmid = {7969141},
issn = {0270-7306},
mesh = {Animals ; Base Sequence ; Chironomidae/*genetics ; Chromosomes/*ultrastructure ; Endodeoxyribonucleases/metabolism ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Oligonucleotide Probes/chemistry ; *Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; },
abstract = {A family of 340-bp tandem telomere-associated DNA repeats is present in 50- to 200-kb blocks in seven of the eight paired chromosome ends in Chironomus pallidivittatus. It consists of four main subfamilies, differing from each other by small clusters of mutations. This differentiation may reflect different functional roles for the repeats. Here we find that one subfamily, D3, is consistently localized most peripherally and extends close to the ends of the chromosomes, as shown by its sensitivity to the exonuclease Bal 31. The amounts of D3 are highly variable between individuals. The repeat characteristic for D3 forms a segment with pronounced dyad symmetry, which in single-strand form would give rise to a hairpin. Evidence from an interspecies comparison suggests that a similar structure is the result of selective forces. Another subfamily, M1, is present more proximally in a subgroup of telomeres characterized by a special kind of repeat variability. Thus, a complex block with three kinds of subfamilies may occupy different M1 telomeres depending on the stock of animals. We conclude that subfamilies are differentially distributed between and within telomeres and are likely to serve different functions.},
}
@article {pmid7725802,
year = {1994},
author = {Vandenbol, M and Durand, P and Bolle, PA and Dion, C and Portetelle, D and Hilger, F},
title = {Sequence analysis of a 40.2 kb DNA fragment located near the left telomere of yeast chromosome X.},
journal = {Yeast (Chichester, England)},
volume = {10},
number = {12},
pages = {1657-1662},
doi = {10.1002/yea.320101216},
pmid = {7725802},
issn = {0749-503X},
mesh = {Base Sequence ; *Chromosomes, Fungal ; DNA, Fungal/*chemistry ; Molecular Sequence Data ; Open Reading Frames ; Saccharomyces cerevisiae/*genetics ; *Telomere ; },
abstract = {We have sequenced on both strands a 40,257 bp fragment located near the left telomere of chromosome X of Saccharomyces cerevisiae. The sequenced segment contains 21 open reading frames (ORFs) at least 100 amino acids long. Five of the ORFs correspond to known amino acid sequences: two hypothetical proteins in the subtelomeric Y' repeat region of 65.4 and 12.8 KDa, the cytochrome B pre-mRNA processing CBP1 protein, the mitochondrial nuclease NUC1 and the CRT1 protein. Of the 16 remaining ORFs, eight show highest homologies with the S. cerevisiae hexose transporters family (two ORFs), the yeast alpha-glucosidase (two ORFs), the yeast PEP1 precursor, the Escherichia coli galactoside O-acetyltransferase, the S. cerevisiae 137.7 KDa protein located in the Y' region and a protein of unknown function of Schizosaccharomyces pombe. Finally, eight of the ORFs exhibit no significant similarity with any amino acid sequences described in data banks. DNA sequence comparison has revealed the presence of different repeated elements characteristic of yeast chromosome ends. Disruption studies have been performed on two ORFs encoding putative proteins of unknown function.},
}
@article {pmid8000005,
year = {1994},
author = {Chiurazzi, M and Signer, ER},
title = {Termini and telomeres in T-DNA transformation.},
journal = {Plant molecular biology},
volume = {26},
number = {3},
pages = {923-934},
pmid = {8000005},
issn = {0167-4412},
mesh = {Agrobacterium tumefaciens/genetics ; Alcohol Dehydrogenase/genetics ; Arabidopsis/genetics ; Base Sequence ; DNA, Bacterial/*genetics ; DNA, Plant/*genetics ; Genetic Vectors/genetics ; Kanamycin Resistance/genetics ; Molecular Sequence Data ; Sequence Homology, Nucleic Acid ; Telomere/*genetics ; *Transformation, Genetic ; },
abstract = {A T-DNA vector for plant transformation has been constructed in which the cloning site is located 9 bp from the right-border (RB) end and 27 bp from the left-border (LB) end. In this vector cloned DNA homologous to plant chromosomal sequences is located at the T-DNA termini, and will thus be exposed by even limited exonucleolysis in planta. The arabidopsis ADH (alcohol dehydrogenase) locus was mobilized from Agrobacterium, and integration into the recipient genome was studied. Despite the terminal location of ADH homology in this vector, the T-DNA integrated essentially at random in the Arabidopsis genome rather than at the endogenous ADH locus. T-DNA integration was blocked, however, when Arabidopsis telomeric sequences were added to the construct at each end of the ADH homology. Thus the predominant mode by which incoming T-DNA is integrated into the continuity of chromosomal DNA involves free DNA ends, but, in contrast to modes of recombination such as gap repair, does not involve extensive terminal DNA sequence homology.},
}
@article {pmid7987807,
year = {1994},
author = {Ohyashiki, K and Ohyashiki, JH and Fujimura, T and Kawakubo, K and Shimamoto, T and Saito, M and Nakazawa, S and Toyama, K},
title = {Telomere shortening in leukemic cells is related to their genetic alterations but not replicative capability.},
journal = {Cancer genetics and cytogenetics},
volume = {78},
number = {1},
pages = {64-67},
doi = {10.1016/0165-4608(94)90047-7},
pmid = {7987807},
issn = {0165-4608},
mesh = {Blotting, Southern ; DNA Replication/*genetics ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics ; Telomere/*genetics ; Tumor Cells, Cultured ; },
abstract = {We compared telomere length in donor leukemic cells and corresponding established cell lines from three patients with chronic myeloid leukemia (CML) and three with acute lymphoblastic leukemia (ALL) to study the relation between the immortalization capacity of hematologic neoplasms and telomere length. Six of the seven established leukemia cell lines (four CML and two ALL) carried additional chromosome changes and had shorter telomere repeats than those of the donor patients' leukemic cells; the remaining ALL line showed no significant difference in telomere length between fresh leukemic cells and the corresponding cell line. Thus, most established leukemic cells lose effective telomerase activity during the process of establishment, and reduction in telomere length of established leukemic cells appeared to be associated with the presence of additional chromosome changes.},
}
@article {pmid7977349,
year = {1994},
author = {Slagboom, PE and Droog, S and Boomsma, DI},
title = {Genetic determination of telomere size in humans: a twin study of three age groups.},
journal = {American journal of human genetics},
volume = {55},
number = {5},
pages = {876-882},
pmid = {7977349},
issn = {0002-9297},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*genetics ; Blotting, Southern ; Child ; Child, Preschool ; Humans ; Middle Aged ; Repetitive Sequences, Nucleic Acid ; Telomere/*genetics ; },
abstract = {Reduction of telomere length has been postulated to be a causal factor in cellular aging. Human telomeres terminate in tandemly arranged repeat arrays consisting of the (TTAGGG) motif. The length of these arrays in cells from human mitotic tissues is inversely related to the age of the donor, indicating telomere reduction with age. In addition to telomere length differences between different age cohorts, considerable variation is present among individuals of the same age. To investigate whether this variation can be ascribed to genetic influences, we have measured the size of terminal restriction fragments (TRFs) in HaeIII-digested genomic DNA from 123 human MZ and DZ twin pairs 2-95 years of age. The average rate of telomere shortening was 31 bp/year, which is similar to that observed by others. Statistical analysis in 115 pairs 2-63 years of age indicates a 78% heritability for mean TRF length in this age cohort. The individual differences in mean TRF length in blood, therefore, seem to a large extent to be genetically determined.},
}
@article {pmid7834223,
year = {1994},
author = {Solovei, I and Gaginskaya, ER and Macgregor, HC},
title = {The arrangement and transcription of telomere DNA sequences at the ends of lampbrush chromosomes of birds.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {2},
number = {6},
pages = {460-470},
pmid = {7834223},
issn = {0967-3849},
mesh = {Animals ; Base Sequence ; Birds/*genetics ; Chickens/genetics ; *Chromosomes ; Columbidae/genetics ; Coturnix/genetics ; DNA/chemistry/genetics/*metabolism ; DNA Primers ; In Situ Hybridization, Fluorescence ; Models, Structural ; Molecular Sequence Data ; Oligonucleotide Probes ; Polymerase Chain Reaction ; *Repetitive Sequences, Nucleic Acid ; Species Specificity ; Telomere/*physiology/ultrastructure ; Transcription, Genetic ; Turkeys/genetics ; },
abstract = {The arrangement of loops and chromomeres at the ends of lampbrush chromosomes in four species of bird is described with reference to chromomeres, loops and transcription units. Unlike the situation described in lampbrush chromosomes of amphibians, the lampbrush chromosomes of birds end in a terminal chromosome with conspicuous loops emerging from it. The fine-scale morphology of the ribonuclear protein matrix of these terminal loops is different from that of the majority of loops elsewhere on the chromosomes. In many cases the loops associated with the terminal chromomere are open ended, emerging from the chromomere but not returning to it at the other end. The distal ends of terminal open-ended loops therefore represent the true ends of the chromatids that make up a lampbrush half-bivalent. The pattern of binding of three telomeric DNA sequence probes to the terminal regions of bird lampbrush chromosomes, under conditions of DNA/DNA and DNA/RNA transcript in situ hybridization has been investigated by fluorescence in situ hybridization. All three probes gave the same results. With DNA/DNA and DNA/RNA transcript hybridization, three classes of structure were labelled: the terminal chromomere, a small number of interstitial chromomeres and the terminal transcription unit on telomere loops. Labelling of telomere loops, but not of terminal or interstitial chromomeres, was eliminated by ribonuclease treatment before in situ hybridization. The labelled regions of telomere loops were spaced away from the labelled terminal chromomere by an unlabelled sub telomeric transcription unit. After DNA/DNA in situ hybridization, no labelled loops were seen. DNA/RNA transcript in situ hybridization with single-stranded hexamers of each strand of telomeric DNA showed that the terminal transcription unit on telomere loops represents transcription exclusively from the C-rich strand of the repeat outwards towards the end of the chromosome. It is concluded that transcription specifically of the C-rich strand of strictly terminal clusters of telomere repeats is an obligatory event on the lampbrush chromosomes of birds and is unlikely to represent indiscriminate readthrough from proximally located gene elements.},
}
@article {pmid7530486,
year = {1994},
author = {Schmitt, H and Blin, N and Zankl, H and Scherthan, H},
title = {Telomere length variation in normal and malignant human tissues.},
journal = {Genes, chromosomes &amp; cancer},
volume = {11},
number = {3},
pages = {171-177},
doi = {10.1002/gcc.2870110306},
pmid = {7530486},
issn = {1045-2257},
mesh = {Adolescent ; Adult ; Aged ; DNA/analysis ; DNA, Neoplasm/analysis ; Female ; Humans ; Male ; Neoplasms/*genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; Telomere/*genetics ; Tumor Cells, Cultured ; },
abstract = {Tissue and tumor specific length variation of telomere (TTAGGG)n repeats was studied in DNAs from various normal and malignant tissues. DNA was isolated from bone marrow and blood cells, malignant tissues, and established tumor cell lines. Nonisotopic Southern hybridization revealed a reduction of telomere repeat arrays in 14 of the 35 tumors analyzed. However, other cases (60%) showed no reduction, or even an increase, in telomeric length. Our finding of elongated telomere stretches in several tumors of different origin compared with normal tissue is in contrast to previous reports describing a general shortening of terminal repeat length in colorectal cancer and neuroblastoma. We tentatively conclude that there is no general tendency to telomere reduction in malignant tissues.},
}
@article {pmid7932745,
year = {1994},
author = {Smith, SS and Laayoun, A and Lingeman, RG and Baker, DJ and Riley, J},
title = {Hypermethylation of telomere-like foldbacks at codon 12 of the human c-Ha-ras gene and the trinucleotide repeat of the FMR-1 gene of fragile X.},
journal = {Journal of molecular biology},
volume = {243},
number = {2},
pages = {143-151},
doi = {10.1006/jmbi.1994.1640},
pmid = {7932745},
issn = {0022-2836},
support = {CA335172/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; Codon/metabolism ; DNA/*metabolism ; DNA (Cytosine-5-)-Methyltransferases/metabolism ; Fragile X Syndrome/*genetics ; *Genes, ras ; Humans ; Methylation ; Molecular Sequence Data ; Nucleic Acid Conformation ; Repetitive Sequences, Nucleic Acid ; Telomere/*metabolism ; },
abstract = {Runs of G residues on the G-rich strands of 30mers from the region spanning codon 12 of c-Ha-ras appear to be protected against chemical modification by dimethylsulfate. This suggests that the G-rich strand might spontaneously form a Hoogsteen-paired quadruplex, which is characteristic of telomere-like DNA sequences. In this report we show that the predominant species in 1:1 mixtures of complementary 30mers from this region are duplex DNA and a smaller amount of unimolecular foldback formed by the C-rich strand. Foldbacks of this type resemble structures first observed in the C-rich strand of telomeric DNA and also occur at the CCG triplet repeat present in the FMR-1 gene of human fragile X syndrome. Foldbacks from the C-rich strand of c-Ha-ras and the FMR-1 triplet repeat are exceptional substrates for the human methyltransferase in isolation. Substituting inosine for guanosine alters the secondary structure of the folded oligomers and dramatically reduces their ability to serve as substrates for the human methyltransferase, suggesting that secondary structure is required for recognition by the enzyme. These findings suggest that one mechanism by which methyl groups accumulate in the c-Ha-ras region of chromosome 11 during carcinogenesis and at the FMR-1 locus during repeat expansion at fragile X may be structurally induced de novo methylation at sites undergoing local conformational change. Such methylation might serve to mark unusual structures for repair. In the absence of repair, asymmetrically methylated duplexes produced by resolution of the unusual structures would be rapidly converted to symmetrically methylated duplexes through the methyl-directed activity also carried by the human methyltransferase.},
}
@article {pmid7957062,
year = {1994},
author = {Murnane, JP and Sabatier, L and Marder, BA and Morgan, WF},
title = {Telomere dynamics in an immortal human cell line.},
journal = {The EMBO journal},
volume = {13},
number = {20},
pages = {4953-4962},
pmid = {7957062},
issn = {0261-4189},
mesh = {Cell Line, Transformed ; Humans ; In Situ Hybridization, Fluorescence ; Kinetics ; Polymorphism, Genetic ; *Repetitive Sequences, Nucleic Acid ; Telomere/*metabolism ; },
abstract = {The integration of transfected plasmid DNA at the telomere of chromosome 13 in an immortalized simian virus 40-transformed human cell line provided the first opportunity to study polymorphism in the number of telomeric repeat sequences on the end of a single chromosome. Three subclones of this cell line were selected for analysis: one with a long telomere on chromosome 13, one with a short telomere, and one with such extreme polymorphism that no distinct band was discernible. Further subcloning demonstrated that telomere polymorphism resulted from both gradual changes and rapid changes that sometimes involved many kilobases. The gradual changes were due to the shortening of telomeres at a rate similar to that reported for telomeres of somatic cells without telomerase, eventually resulting in the loss of nearly all of the telomere. However, telomeres were not generally lost completely, as shown by the absence of polymorphism in the subtelomeric plasmid sequences. Instead, telomeres that were less than a few hundred base pairs in length showed a rapid, highly heterogeneous increase in size. Rapid changes in telomere length also occurred on longer telomeres. The frequency of this type of change in telomere length varied among the subclones and correlated with chromosome fusion. Therefore, the rapid changes in telomere length appeared occasionally to result in the complete loss of telomeric repeat sequences. Rapid changes in telomere length have been associated with telomere loss and chromosome instability in yeast and could be responsible for the high rate of chromosome fusion observed in many human tumor cell lines.},
}
@article {pmid7958893,
year = {1994},
author = {Moretti, P and Freeman, K and Coodly, L and Shore, D},
title = {Evidence that a complex of SIR proteins interacts with the silencer and telomere-binding protein RAP1.},
journal = {Genes &amp; development},
volume = {8},
number = {19},
pages = {2257-2269},
doi = {10.1101/gad.8.19.2257},
pmid = {7958893},
issn = {0890-9369},
support = {CA09503-0/CA/NCI NIH HHS/United States ; GM40094/GM/NIGMS NIH HHS/United States ; },
mesh = {Bacterial Proteins/genetics/metabolism ; DNA, Fungal/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Fungal Proteins/genetics/*metabolism ; Genes, Fungal ; Genes, Mating Type, Fungal ; *Histone Deacetylases ; Mutation ; Protein Binding ; Repressor Proteins/genetics/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomyces cerevisiae Proteins ; *Serine Endopeptidases ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Sirtuin 2 ; Sirtuins ; Telomere/metabolism ; *Telomere-Binding Proteins ; Trans-Activators/genetics/*metabolism ; Transcription Factors/genetics/*metabolism ; Transcription, Genetic ; },
abstract = {The maintenance of transcriptional silencing at HM mating-type loci and telomeres in yeast requires the SIR2, SIR3, and SIR4 proteins, none of which appear to be DNA-binding proteins. Here we show that SIR3 and SIR4 interact with a carboxy-terminal domain of the silencer, telomere, and UAS-binding protein RAP1. We identified SIR3 and SIR4 in a two-hybrid screen for RAP1-interacting factors and showed that SIR3 interacts both with itself and with SIR4. The interaction between RAP1 and SIR3 can be observed in vitro in the absence of other yeast proteins. Consistent with the notion that native SIR proteins interact with the RAP1 carboxyl terminus, we show that mutation of the endogenous SIR3 and SIR4 genes increases transcriptional activation by LexA/RAP1 hybrids. To test the importance of the RAP1-SIR3 interaction for silencing, we identified mutations in the RAP1 carboxyl terminus that either diminish or abolish this interaction. When introduced into the native RAP1 protein, these mutations cause corresponding defects in silencing at both HMR and telomeres. We propose that RAP1 acts in the initiation of transcriptional silencing by recruiting a complex of SIR proteins to the chromosome via protein-protein interactions. These data are consistent with a model in which SIR3 and SIR4 play a structural role in the maintenance of silent chromatin and indicate that their action is initiated at the silencer itself.},
}
@article {pmid7849703,
year = {1994},
author = {Bengtsson, U and Altherr, MR and Wasmuth, JJ and Winokur, ST},
title = {High resolution fluorescence in situ hybridization to linearly extended DNA visually maps a tandem repeat associated with facioscapulohumeral muscular dystrophy immediately adjacent to the telomere of 4q.},
journal = {Human molecular genetics},
volume = {3},
number = {10},
pages = {1801-1805},
doi = {10.1093/hmg/3.10.1801},
pmid = {7849703},
issn = {0964-6906},
support = {GM07311-18/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cell Line ; Chromosome Mapping ; *Chromosomes, Human, Pair 4 ; Cricetinae ; Cricetulus ; DNA/genetics ; Humans ; Hybrid Cells ; In Situ Hybridization, Fluorescence/methods ; Molecular Sequence Data ; Muscular Dystrophies/*genetics ; *Repetitive Sequences, Nucleic Acid ; *Telomere ; Translocation, Genetic ; X Chromosome ; },
abstract = {Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder. The FSHD locus has been linked to the most distal genetic markers on the long arm of chromosome 4. An EcoRI fragment length polymorphism segregates with the disease in most FSHD families. Within the EcoRI fragment lies a tandem array of 3.2 kb repeats. Deletions of integral copies of this repeat have been associated with the disease. The 3.2 kbp repeat has recently been shown to cross-hybridize to several regions of heterochromatin in the human genome and DNA sequence analysis reveals strong homology to a class of heterochromatin repeats, LSau. In this report, we demonstrate that the 3.2 kbp tandem repeat lies adjacent to a subtelomeric sequence, which is within 5-14 kb of the telomeric repeat (TTAGGG)n. Direct visual fluorescence hybridization to linearly extended strands of DNA enabled the visualization of this subtelomeric sequence as a short string of signals at the end of a longer string of signals from the differentially labeled 3.2 kbp tandem repeat. Furthermore, in support of our data showing that the 3.2 kbp repeat lies in close proximity to the telomere of 4q, we demonstrated the lack of hybridization of total human DNA to this same region. Our results indicate that the tandem array of 3.2 kbp repeats, disrupted in FSHD, lies immediately adjacent to the telomere of 4q and that the gene responsible for FSHD is likely located proximal to the tandem repeat.},
}
@article {pmid7545974,
year = {1994},
author = {Macina, RA and Negorev, DG and Spais, C and Ruthig, LA and Hu, XL and Riethman, HC},
title = {Sequence organization of the human chromosome 2q telomere.},
journal = {Human molecular genetics},
volume = {3},
number = {10},
pages = {1847-1853},
doi = {10.1093/hmg/3.10.1847},
pmid = {7545974},
issn = {0964-6906},
support = {5-F32 GM 12884/GM/NIGMS NIH HHS/United States ; HG00567/HG/NHGRI NIH HHS/United States ; P01 CA47983/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosome Banding ; Chromosome Mapping ; Chromosomes, Artificial, Yeast ; *Chromosomes, Human, Pair 2 ; DNA Primers ; Humans ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Polymerase Chain Reaction ; *Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; *Telomere ; },
abstract = {The terminal 240 kb of a human 2q telomere region was cloned in two overlapping yeast artificial-chromosomes (YACs). This DNA contains a region of low-copy subtelomeric repeats (within 50 kb of the 2q telomere), a segment of DNA duplicated on distal 8p23 (100 kb from the 2q telomere), and a region of single-copy DNA (230 kb from the 2q telomere). Two CpG islands are present in the DNA segment duplicated on distal 8p23. RecA-assisted restriction endonuclease cleavage of genomic DNA samples revealed a potential 55 kb chromosome length polymorphism at the 2q telomere. This work provides telomeric closure of maps for human chromosome 2q, demonstrates a novel, subtelomere-specific DNA duplication, and will permit detailed molecular and cytological studies of this human telomere region.},
}
@article {pmid8090736,
year = {1994},
author = {Hanish, JP and Yanowitz, JL and de Lange, T},
title = {Stringent sequence requirements for the formation of human telomeres.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {91},
number = {19},
pages = {8861-8865},
pmid = {8090736},
issn = {0027-8424},
support = {GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Cells, Cultured ; DNA-Binding Proteins/*metabolism ; HeLa Cells ; Humans ; Molecular Sequence Data ; Recombination, Genetic ; Repetitive Sequences, Nucleic Acid ; Structure-Activity Relationship ; *Telomere ; Transfection ; },
abstract = {In human cells, transfection of telomeric T2AG3 repeats induces the formation of functional telomeres at previously interstitial sites. We report that telomere formation has stringent sequence requirements. While (T2AG3)n telomere seeds formed telomeres in approximately 70% of the transfected cells, five T2AG3-related heterologous telomeric DNAs seeded new telomeres in < 5% of the transfectants. Telomere formation did not correlate with the ability of human telomerase to elongate telomeric sequences in vitro. Homologous recombination is probably also not involved because a (T2AG3)n telomere seed with nontelomeric DNA at 160-bp intervals formed new telomeres frequently. Instead, the sequence dependence of telomere formation matched the in vitro binding requirements for the mammalian T2AG3 repeat binding factor (TRF). Human TRF failed to bind ineffective heterologous telomere seeds and had a 4-fold lower affinity for (T2AG5)2T2AG3 repeats, which seeded telomeres with reduced frequency. The results suggest that telomere seeds interact with TRF and predict that mammalian artificial chromosomes will require wild-type telomeric repeats at, or near, their termini.},
}
@article {pmid8065312,
year = {1994},
author = {Tommerup, H and Dousmanis, A and de Lange, T},
title = {Unusual chromatin in human telomeres.},
journal = {Molecular and cellular biology},
volume = {14},
number = {9},
pages = {5777-5785},
pmid = {8065312},
issn = {0270-7306},
support = {GM49046/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Chromatin/*ultrastructure ; Formaldehyde/chemistry ; Humans ; Mice ; Micrococcal Nuclease/metabolism ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; Telomere/*ultrastructure ; },
abstract = {We report that human telomeres have an unusual chromatin structure characterized by diffuse micrococcal nuclease patterns. The altered chromatin manifested itself only in human telomeres that are relatively short (2 to 7 kb). In contrast, human and mouse telomeres with telomeric repeat arrays of 14 to 150 kb displayed a more canonical chromatin structure with extensive arrays of tightly packed nucleosomes. All telomeric nucleosomes showed a shorter repeat size than bulk nucleosomes, and telomeric mononucleosomal particles were found to be hypersensitive to micrococcal nuclease. However, telomeric nucleosomes were similar to bulk nucleosomes in the rate at which they sedimented through sucrose gradients. We speculate that mammalian telomeres have a bipartite structure with unusual chromatin near the telomere terminus and a more canonical nucleosomal organization in the proximal part of the telomere.},
}
@article {pmid7855438,
year = {1994},
author = {Santori, F and Donini, P},
title = {In vitro identification of a protein of Saccharomyces cerevisiae that interacts specifically with the G-rich DNA strand of the telomere.},
journal = {Research in microbiology},
volume = {145},
number = {7},
pages = {519-530},
doi = {10.1016/0923-2508(94)90029-9},
pmid = {7855438},
issn = {0923-2508},
mesh = {DNA, Fungal/*genetics ; DNA, Single-Stranded/genetics ; DNA-Binding Proteins/genetics/*isolation &amp; purification ; Electrophoresis, Polyacrylamide Gel ; Fungal Proteins/genetics/*isolation &amp; purification ; In Vitro Techniques ; Saccharomyces cerevisiae/genetics/*metabolism ; Telomere/*genetics ; },
abstract = {The telomeres of Saccharomyces cerevisiae consist of a repeated G2-3T(GT)1-6 DNA sequence that forms a complex with proteins. To date only the RAP1 protein has been shown to bind to the simple sequences in yeast telomeric DNA, as well as to non-telomeric regulatory sites. We have used synthetic oligodeoxyribonucleotides, both double- and single-stranded, to identify specific yeast telomeric proteins in a partially purified yeast extract. Using the gel shift assay, we detected a binding activity that is stable at high ionic strength and that recognizes specifically the G-rich protrusion of a double-stranded synthetic yeast telomere, as well as the G-rich single strand. This is the first evidence of a purely telomeric protein in that it binds to the single-stranded telomeric protrusion of the yeast chromosome.},
}
@article {pmid7804248,
year = {1994},
author = {Mitcham, JL and Prescott, DM and Miller, MK},
title = {The micronuclear gene encoding beta-telomere binding protein in Oxytricha nova.},
journal = {The Journal of eukaryotic microbiology},
volume = {41},
number = {5},
pages = {478-480},
doi = {10.1111/j.1550-7408.1994.tb06045.x},
pmid = {7804248},
issn = {1066-5234},
support = {GM19199/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromosome Mapping ; DNA, Protozoan/genetics ; DNA-Binding Proteins/*genetics ; *Genes, Protozoan ; Micronucleus, Germline/metabolism ; Oxytricha/*genetics ; Protozoan Proteins/genetics ; },
abstract = {The micronuclear version of the gene encoding beta-telomere binding protein (beta-TBP) in Oxytricha nova has been sequenced and compared to the macronuclear beta-TBP gene, previously described. The micronuclear gene contains three AT-rich internal eliminated sequences (IES) of 37, 40, and 43 bp and four macronuclear destined sequences (MDS). The IES interrupt the gene once near the 5' end of the coding region and twice in the 3' trailer downstream from the TGA stop codon. The sequences of the micronuclear and macronuclear genes are colinear. Thus, the micronuclear beta-TBP gene is not scrambled, which contrasts with the highly scrambled state among the 14 MDS in the micronuclear alpha-TBP gene.},
}
@article {pmid7804206,
year = {1994},
author = {Underwood, AP and Louis, EJ and Borts, RH and Wakefield, AE},
title = {A technique for cloning the telomeres and subtelomeric regions from Pneumocystis carinii.},
journal = {The Journal of eukaryotic microbiology},
volume = {41},
number = {5},
pages = {113S},
pmid = {7804206},
issn = {1066-5234},
mesh = {Chromosome Mapping ; Chromosomes, Artificial, Yeast ; Chromosomes, Fungal/ultrastructure ; Cloning, Molecular/*methods ; DNA, Fungal/genetics ; Genes, Fungal ; Pneumocystis/*genetics/ultrastructure ; Telomere/ultrastructure ; },
}
@article {pmid8070408,
year = {1994},
author = {Nimmo, ER and Cranston, G and Allshire, RC},
title = {Telomere-associated chromosome breakage in fission yeast results in variegated expression of adjacent genes.},
journal = {The EMBO journal},
volume = {13},
number = {16},
pages = {3801-3811},
pmid = {8070408},
issn = {0261-4189},
mesh = {Adenine/metabolism ; Cell Division/drug effects ; Chromosome Aberrations/*genetics ; DNA, Recombinant/genetics ; Electrophoresis, Gel, Pulsed-Field ; Extrachromosomal Inheritance ; *Gene Expression Regulation, Fungal ; Gene Rearrangement ; Genes, Fungal/*genetics ; Leucine/metabolism ; Orotic Acid/analogs &amp; derivatives/pharmacology ; RNA, Fungal/analysis ; Schizosaccharomyces/*genetics/growth &amp; development ; Uracil/metabolism ; },
abstract = {The sequence requirements for in vivo telomere function in the fission yeast, Schizosaccharomyces pombe, have been investigated. A 258 bp tract of previously characterized cloned fission yeast terminal repeats adjacent to 800 bp of telomere-associated sequences is sufficient to seed new telomeres onto linearized ars-containing plasmids when introduced into cells. The resulting transformants contain unrearranged, acentric, linear episomes. Cloned telomeres, with and without telomere-associated sequences adjacent to the 258 bp terminal repeats, were utilized to introduce chromosome breaks at specific sites in a non-essential minichromosome. Truncated minichromosome derivatives were recovered containing the ura4 or ade6 gene adjacent to a newly formed telomere. These telomeres exert reversible position effects on the expression of the adjacent ura4 or ade6 genes.},
}
@article {pmid8052638,
year = {1994},
author = {Giraldo, R and Suzuki, M and Chapman, L and Rhodes, D},
title = {Promotion of parallel DNA quadruplexes by a yeast telomere binding protein: a circular dichroism study.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {91},
number = {16},
pages = {7658-7662},
pmid = {8052638},
issn = {0027-8424},
mesh = {Animals ; Base Sequence ; Circular Dichroism ; DNA/*metabolism ; DNA, Fungal/*metabolism ; G-Quadruplexes ; GTP-Binding Proteins/*metabolism ; Guanine/metabolism ; Molecular Sequence Data ; Nucleic Acid Conformation/drug effects ; Oligodeoxyribonucleotides/metabolism ; Oxytricha/genetics ; Potassium/pharmacology ; Protein Binding ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*genetics ; Telomere/*metabolism ; rap GTP-Binding Proteins ; },
abstract = {Repressor-activator protein 1 (RAP1) has an essential role in the maintenance of yeast telomeres. Yeast telomeric DNA consists of simple repeated G-rich sequences that are bound by RAP1. We have found that RAP1, in addition to its known binding activity for double-stranded DNA, interacts with the G-rich strand containing guanine base (G)-tetrads. We show here using circular dichroism spectroscopy that RAP1 promotes the formation of one particular type of DNA quadruplex, parallel G4-DNA. Furthermore, RAP1 is able to bind to both preformed parallel and antiparallel DNA quadruplexes. These results have implications for the possible use of DNA quadruplexes in telomere-telomere association in vivo.},
}
@article {pmid8076347,
year = {1994},
author = {Harrison, KJ and Neumann, E and Kalousek, DK and Norman, MG and Masui, S and Harrison, K},
title = {Astrocytoma with a unique telomere association.},
journal = {Cancer genetics and cytogenetics},
volume = {76},
number = {1},
pages = {33-35},
doi = {10.1016/0165-4608(94)90066-3},
pmid = {8076347},
issn = {0165-4608},
mesh = {Astrocytoma/*genetics ; Cerebellar Neoplasms/*genetics ; Child ; *Chromosome Aberrations ; Chromosomes, Human, Pair 18 ; Chromosomes, Human, Pair 21 ; Female ; Humans ; Karyotyping ; *Telomere ; },
abstract = {Many primary pediatric brain tumors are characterized by nonrandom cytogenetic abnormalities involving specific structural rearrangements and loss or gain of specific chromosomes. We describe a low-grade cerebellar astrocytoma with telomeric association of chromosomes 18 and 21 in a 7-year old girl. The nonrandom telomeric association of these chromosomes represents a unique cytogenetic finding in this type of pediatric brain tumor.},
}
@article {pmid8062839,
year = {1994},
author = {Petracek, ME and Konkel, LM and Kable, ML and Berman, J},
title = {A Chlamydomonas protein that binds single-stranded G-strand telomere DNA.},
journal = {The EMBO journal},
volume = {13},
number = {15},
pages = {3648-3658},
pmid = {8062839},
issn = {0261-4189},
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Chlamydomonas reinhardtii/genetics/*metabolism ; Cloning, Molecular ; Consensus Sequence ; DNA, Complementary ; DNA, Protozoan/genetics/metabolism ; DNA, Single-Stranded/genetics/metabolism ; DNA-Binding Proteins/genetics/isolation &amp; purification/*metabolism ; *GTP-Binding Proteins ; Genes, Protozoan/*genetics ; Molecular Sequence Data ; Plant Proteins ; Protozoan Proteins/genetics/isolation &amp; purification/*metabolism ; RNA, Messenger/analysis/metabolism ; RNA, Protozoan/analysis/metabolism ; Repetitive Sequences, Nucleic Acid/genetics ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; Telomere/metabolism ; },
abstract = {We have identified a protein in Chlamydomonas reinhardtii cell extracts that specifically binds the single-stranded (ss) Chlamydomonas G-strand telomere sequence (TTTTAGGG)n. This protein, called G-strand binding protein (GBP), binds DNA with two or more ss TTTTAGGG repeats. A single polypeptide (M(r) 34 kDa) in Chlamydomonas extracts binds (TTTTAGGG)n, and a cDNA encoding this G-strand binding protein was identified by its expression of a G-strand binding activity. The cDNA (GBP1) sequence predicts a protein product (Gbp1p) that includes two domains with extensive homology to RNA recognition motifs (RRMs) and a region rich in glycine, alanine and arginine. Antibody raised against a peptide within Gbp1p reacted with both the 34 kDa polypeptide and bound G-strand DNA-protein complexes in gel retardation assays, indicating that GBP1 encodes GBP. Unlike vertebrate heteronuclear ribonucleoproteins, GBP does not bind the cognate telomere RNA sequence UUUUAGGG in gel retardation, North-Western or competition assays. Thus, GBP is a new type of candidate telomere binding protein that binds, in vitro, to ss G-strand telomere DNA, the primer for telomerase, and has domains that have homology to RNA binding domains in other proteins.},
}
@article {pmid7987319,
year = {1994},
author = {Taylor, SS and Larin, Z and Smith, CT},
title = {Addition of functional human telomeres to YACs.},
journal = {Human molecular genetics},
volume = {3},
number = {8},
pages = {1383-1386},
doi = {10.1093/hmg/3.8.1383},
pmid = {7987319},
issn = {0964-6906},
mesh = {Chromosome Mapping ; Chromosomes, Artificial, Yeast/*genetics ; Genetic Vectors ; Humans ; In Situ Hybridization, Fluorescence ; Telomere/*genetics ; },
abstract = {Linear mammalian artificial chromosomes (MACs) will require functional telomeres, a centromere and the ability to replicate autonomously. We are investigating the possibility of developing MACs from yeast artificial chromosomes (YACs). Retrofitting vectors have been constructed to replace YAC telomeres with cloned human telomeric DNA. A modified YAC was introduced into mammalian cells by spheroplast fusion and the frequency with which the retrofitted human telomeric DNA seeded the formation of a new telomere was determined by Bal31 digestion and cytogenetic analysis. The telomere adjacent to the selectable marker gene was functional in 5/46 clones (11%) while the telomere 200 kb away at the other end of the YAC was functional in 1/46 clones (2%). These results indicate that despite the in vivo modification of the end of the telomere by the addition of yeast sequences, human telomeres will function at a high enough frequency to allow the construction of MACs by this route.},
}
@article {pmid7953561,
year = {1994},
author = {Kohli, J},
title = {Meiosis. Telomeres lead chromosome movement.},
journal = {Current biology : CB},
volume = {4},
number = {8},
pages = {724-727},
doi = {10.1016/s0960-9822(00)00160-3},
pmid = {7953561},
issn = {0960-9822},
mesh = {Cell Nucleus/physiology ; Chromosomes, Fungal/*physiology ; Motion ; *Prophase ; Schizosaccharomyces/*cytology ; Spindle Apparatus/*physiology ; Synaptonemal Complex/physiology ; Telomere/*physiology ; },
abstract = {The telomeres of fission yeast chromosomes are attached to the moving spindle pole body during karyogamy and meiotic prophase. Nuclear movement may also contribute to homologous chromosome pairing.},
}
@article {pmid8033058,
year = {1994},
author = {Sawyer, JR and Goosen, LS and Stine, KC and Thomas, JR},
title = {Telomere fusion as a mechanism for the progressive loss of the short arm of chromosome 11 in an anaplastic Wilms' tumor.},
journal = {Cancer},
volume = {74},
number = {2},
pages = {767-773},
doi = {10.1002/1097-0142(19940715)74:2&lt;767::aid-cncr2820740232&gt;3.0.co;2-f},
pmid = {8033058},
issn = {0008-543X},
mesh = {*Chromosome Deletion ; *Chromosomes, Human, Pair 11 ; Genes, Wilms Tumor ; *Heterozygote ; Humans ; Infant ; Kidney Neoplasms/*genetics/pathology ; Male ; *Telomere ; Wilms Tumor/*genetics/pathology ; },
abstract = {Wilms' tumor (WT) is associated with chromosomal deletions and loss of heterozygosity (LOH) of alleles at 11p13. The authors report the youngest known patient with diffusely anaplastic WT and, to their knowledge, the first case to demonstrate telomeric fusions as a chromosomal mechanism for the loss of bands 11p13 and 11p15 in WT. Recurrent clonal telomeric association (tas) initiated breakage/fusion cycles that resulted in deletions of chromosome bands 11p15, 11p13, and, subsequently, the entire short arm of chromosome 11. In addition, tas involving the long arms of chromosomes 7 and 9 resulted in the subsequent deletion of the long arm of chromosome 7. This report expands the spectrum of chromosomal mechanisms that can account for the loss of alleles on the short arm of chromosome 11 in WT by providing evidence that the progressive loss of critical chromosome regions associated with tumor suppression may occur as a result of chromosomal instability initiated by tas.},
}
@article {pmid7517558,
year = {1994},
author = {Danilevskaya, ON and Slot, F and Traverse, KL and Hogan, NC and Pardue, ML},
title = {Drosophila telomere transposon HeT-A produces a transcript with tightly bound protein.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {91},
number = {14},
pages = {6679-6682},
pmid = {7517558},
issn = {0027-8424},
mesh = {Animals ; Cell Line ; *DNA Transposable Elements ; Drosophila melanogaster/*genetics/metabolism ; Female ; Male ; RNA/*biosynthesis/isolation &amp; purification/metabolism ; RNA Probes ; Ribonucleoproteins/*biosynthesis/isolation &amp; purification ; Sex Factors ; Telomere/*physiology ; Transcription, Genetic ; },
abstract = {Telomeres from Drosophila appear to be very different from those of other organisms. A transposable element, HeT-A, plays a major role in forming telomeres and may be the sole structural element, since telomerase-generated repeats are not found. The structure of the HeT-A element, deduced from cloned fragments of DNA, suggests that transposition of the element is mediated by a polyadenylylated RNA intermediate. We now report analyses of HeT-A transcripts. The major RNA is of the appropriate size and strandedness to serve as a transposition intermediate. This RNA is found in cultured cells and in intact flies and is unusual in that it is associated with protein after treatments that apparently remove all protein from other RNAs.},
}
@article {pmid8012981,
year = {1994},
author = {Ohyashiki, JH and Ohyashiki, K and Fujimura, T and Kawakubo, K and Shimamoto, T and Iwabuchi, A and Toyama, K},
title = {Telomere shortening associated with disease evolution patterns in myelodysplastic syndromes.},
journal = {Cancer research},
volume = {54},
number = {13},
pages = {3557-3560},
pmid = {8012981},
issn = {0008-5472},
mesh = {Acute Disease ; Adult ; Anemia, Refractory, with Excess of Blasts/*genetics ; Anemia, Sideroblastic/*genetics ; Humans ; Karyotyping ; Leukemia, Myeloid/*genetics ; Repetitive Sequences, Nucleic Acid ; Telomere/*pathology ; },
abstract = {We identified the telomere length at different hematological phases in 16 patients with myelodysplastic syndromes (MDS), showing disease evolution with a conventional Southern blot hybridization using the (TTAGGG)4 probe. The MDS patients studied were classified into three groups according to the pattern of telomere length reduction. The first group had telomere shortening at the time of disease diagnosis. In four of the six MDS patients in this group, the disease progressed within 6 months postdiagnosis and each of them survived for less than 1 year. Moreover, in this group four patients showed a 5q anomaly with or without additional changes, and 50% of patients in this group had complex chromosome abnormalities. The patients in the second group showed reductions in telomere length after disease progression; two of these three patients showed gradual disease progression and had one or two chromosome abnormalities. The third group comprised the remaining seven MDS patients; they showed no telomere reduction by disease evolution. Two patients in this group experienced rapid disease progression. These results may indicate that telomere reduction is linked to disease evolution in some MDS patients, perhaps as a result of genomic instability because patients with complex chromosome abnormalities were clustered in the first group. However, because some MDS patients show disease progression without telomere reduction, genetic changes, including point mutations of certain gene(s), may also contribute to disease progression. We further noted that telomere shortening at the time of MDS diagnosis might indicate a poor MDS prognosis.},
}
@article {pmid7988285,
year = {1994},
author = {Enomoto, S and Longtine, MS and Berman, J},
title = {TEL+CEN antagonism on plasmids involves telomere repeat sequences tracts and gene products that interact with chromosomal telomeres.},
journal = {Chromosoma},
volume = {103},
number = {4},
pages = {237-250},
pmid = {7988285},
issn = {0009-5915},
support = {GM 38626/GM/NIGMS NIH HHS/United States ; GM07323/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; *Centromere ; Chromosomes, Artificial, Yeast ; Mutation ; *Plasmids ; Recombinant Proteins/genetics ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*genetics ; *Telomere ; Transcription, Genetic ; },
abstract = {In Saccharomyces cerevisiae, circular plasmids that include either a centromere (CEN-plasmids) or a telomere sequence (TEL-plasmids) segregate more efficiently than circular ARS-plasmids. In contrast, circular plasmids that include both telomere and centromere sequences were unstable, a property we term TEL+CEN antagonism. TEL+CEN antagonism required a telomere repeat tract longer than 49 bp although the distance and relative orientation of the centromere and telomere sequences was not critical. TEL+CEN antagonism was alleviated in strains carrying different rap1 alleles including rap1ts, rap1s, and rap1t alleles. Mutations SIR2, SIR3, SIR4, NAT1 and ARD1, genes that influence transcriptional silencing at telomeres and at the silent mating type loci, abolished TEL+CEN antagonism Mutation of SIR1 also partially alleviated TEL-CEN antagonism. In some sir mutant strains short yeast artificial chromosomes (YACs), which are normally unstable, became more stable, suggesting that the same mechanism that caused TEL+CEN antagonism on circular plasmids may contribute to the instability of short linear plasmids.},
}
@article {pmid7845395,
year = {1994},
author = {Dore, E and Pace, T and Picci, L and Pizzi, E and Ponzi, M and Frontali, C},
title = {Dynamics of telomere turnover in Plasmodium berghei.},
journal = {Molecular biology reports},
volume = {20},
number = {1},
pages = {27-33},
pmid = {7845395},
issn = {0301-4851},
mesh = {Animals ; Base Sequence ; Clone Cells ; Molecular Sequence Data ; Oligodeoxyribonucleotides ; Plasmodium berghei/*genetics ; *Telomere ; },
abstract = {Non-uniform composition in telomeric repeats at the extremities of Plasmodium chromosomes was exploited in order to obtain data on intraclonal diversification of telomeric sequences, relevant for the study of telomere regeneration dynamics. Families of sibling telomeric clones were obtained from several chromosomal ends of Plasmodium berghei, and analysed so as to determine the exact points from which individual clones start to diverge. As much as 90% of the telomeric tract appears to be subject to events causing abrupt changes in the sequence of telomeric repeats. The results are compatible with the hypothesis that breakpoint probability is a continuously increasing function over the entire telomeric tract.},
}
@article {pmid7517510,
year = {1994},
author = {Mattei, D and Scherf, A},
title = {Subtelomeric chromosome instability in Plasmodium falciparum: short telomere-like sequence motifs found frequently at healed chromosome breakpoints.},
journal = {Mutation research},
volume = {324},
number = {3},
pages = {115-120},
doi = {10.1016/0165-7992(94)90055-8},
pmid = {7517510},
issn = {0027-5107},
mesh = {Animals ; Base Sequence ; Chromosome Fragile Sites ; Chromosome Fragility ; DNA Nucleotidylexotransferase/*biosynthesis ; DNA Primers ; DNA, Protozoan/*biosynthesis ; Gene Deletion ; Genes, Protozoan/*genetics ; Molecular Sequence Data ; Plasmodium falciparum/enzymology/*genetics ; RNA, Protozoan/metabolism ; Repetitive Sequences, Nucleic Acid/genetics ; Ribonucleoproteins/biosynthesis ; Telomere/chemistry/enzymology/*ultrastructure ; },
abstract = {The stability of chromosome ends of the human malaria parasite P. falciparum was analysed using a polymerase chain reaction (PCR) assay that detects potential chromosome breaks that have been healed by the addition of telomere repeats. The data show that the Pf332 and Pf87 genes located in subtelomeric positions of chromosomes 3 and 11, respectively, represent fragile sites. Breakpoints were observed in different regions of these genes. In the broken genes, the DNA sequences preceding the telomere addition sites generally have complementarity to the predicted RNA template of a P. falciparum telomerase ribonucleoprotein enzyme complex. We propose a model for the creation of new telomeres in P. falciparum adjacent to broken ends containing short telomere-like sequence motifs.},
}
@article {pmid8011648,
year = {1994},
author = {Miura, T and Thomas, GJ},
title = {Structural polymorphism of telomere DNA: interquadruplex and duplex-quadruplex conversions probed by Raman spectroscopy.},
journal = {Biochemistry},
volume = {33},
number = {25},
pages = {7848-7856},
doi = {10.1021/bi00191a012},
pmid = {8011648},
issn = {0006-2960},
support = {AI18758/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA, Protozoan/chemistry ; Molecular Sequence Data ; *Nucleic Acid Conformation ; Nucleic Acid Denaturation ; Osmolar Concentration ; Oxytricha ; Polymorphism, Genetic ; Potassium ; Sodium Chloride/chemistry ; Spectrum Analysis, Raman ; Telomere/*chemistry ; Temperature ; },
abstract = {The solution secondary structures and nucleotide conformations in the telomeric DNA of Oxytricha nova have been determined by Raman spectroscopy. Structural polymorphism is demonstrated for both single-stranded [d(T4G4)4] and double-stranded [d(G4T4G4).d(C4A4C4)] telomere models. In the case of d(T4G4)4, which is a prototype for the single-stranded telomeric tail, an interquadruplex equilibrium involving parallel and antiparallel strand configurations is shown to be governed by the solution concentrations of both Na+ and K+. In both the parallel and antiparallel quadruplexes of d(T4G4)4, the local geometry of the phosphodiester backbone is similar to that of canonical B DNA, and associations between bases of the guanine quartet involve Hoogsteen hydrogen bonding. However, the deoxyguanosine (dG) sugar conformations are significantly different in the two quadruplexes. In the extended parallel form, dG residues assume only the C2'-endo/anti conformation with respect to deoxyribose pucker and glycosyl orientation. In the foldback antiparallel form, dG residues are distributed equally between C2'-endo/anti and C2'-endo/syn conformations. In the case of d(G4T4G4).d(C4A4C4), which serves as a model for the double-stranded B DNA regions of Oxytricha telomeres, we show that disproportionation of the B form duplex to yield stable parallel quadruplexes of the guanine-rich strand occurs reversibly at high solution concentrations of either Na+ or K+. The present study reveals that both interquadruplex and duplex-quadruplex conversions of Oxytricha telomeric DNA are under the control of an alkali cation switch.(ABSTRACT TRUNCATED AT 250 WORDS)},
}
@article {pmid8011617,
year = {1994},
author = {Wang, KY and Swaminathan, S and Bolton, PH},
title = {Tertiary structure motif of Oxytricha telomere DNA.},
journal = {Biochemistry},
volume = {33},
number = {24},
pages = {7517-7527},
doi = {10.1021/bi00190a004},
pmid = {8011617},
issn = {0006-2960},
support = {RR02781/RR/NCRR NIH HHS/United States ; },
mesh = {Animals ; Base Composition ; Base Sequence ; Cross-Linking Reagents ; DNA, Protozoan/*chemistry ; DNA, Single-Stranded/chemistry ; Drug Stability ; Hot Temperature ; Light ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Molecular Sequence Data ; Molecular Structure ; Nucleic Acid Conformation ; Oxytricha/*genetics ; Telomere/*chemistry ; },
abstract = {The tertiary structure of a single-stranded DNA containing the sequence of Oxytricha telomere DNA has been determined. This DNA adopts a compact tertiary structure that consists of four base-paired tetrads of guanine residues which are connected by three loops. The tetrads show significant deviations from planarity, and two of the loops exhibit significant loop-loop interactions. The structure of this telomere contains syn-thymine residues, which are in the loops, as well as an intraloop pyrimidine-pyrimidine base pair between residues that are separated by a single residue. The tertiary structure of the telomere DNA is consistent with prior results that showed that two thymines distant in sequence could be photo-cross-linked. The overall folding pattern of this telomere DNA is similar to that previously determined for a DNA aptamer, which binds to and inhibits thrombin, though the details of the two structures are quite distinct.},
}
@article {pmid8205611,
year = {1994},
author = {Blackburn, EH},
title = {Telomeres: no end in sight.},
journal = {Cell},
volume = {77},
number = {5},
pages = {621-623},
doi = {10.1016/0092-8674(94)90046-9},
pmid = {8205611},
issn = {0092-8674},
mesh = {Animals ; Base Sequence ; Cell Nucleus/metabolism/ultrastructure ; DNA/genetics/metabolism ; DNA-Binding Proteins/metabolism ; Heterochromatin/metabolism ; Meiosis ; Mitosis ; Repetitive Sequences, Nucleic Acid ; Telomere/*metabolism/*ultrastructure ; },
}
@article {pmid8196622,
year = {1994},
author = {Suzuki, Y and Nishizawa, M},
title = {The yeast GAL11 protein is involved in regulation of the structure and the position effect of telomeres.},
journal = {Molecular and cellular biology},
volume = {14},
number = {6},
pages = {3791-3799},
pmid = {8196622},
issn = {0270-7306},
mesh = {Cloning, Molecular ; DNA, Fungal/metabolism ; Escherichia coli ; Escherichia coli Proteins ; Fungal Proteins/biosynthesis/*genetics/*metabolism ; Gene Expression Regulation, Fungal ; Genes, Fungal ; Genotype ; Mediator Complex ; Methylation ; Methyltransferases/metabolism ; Mutagenesis ; Promoter Regions, Genetic ; Restriction Mapping ; Saccharomyces cerevisiae/genetics/*metabolism/physiology ; *Saccharomyces cerevisiae Proteins ; *Site-Specific DNA-Methyltransferase (Adenine-Specific) ; Telomere/*physiology ; *Trans-Activators ; Transcription Factors/biosynthesis/*genetics/*metabolism ; },
abstract = {GAL11 is an auxiliary transcription factor that functions either positively or negatively, depending on the structure of the target promoters and the combination of DNA-bound activators. In this report, we demonstrate that a gal11 delta mutation caused a decrease in the length of the telomere C1-3A tract, a derepression of URA3 when it is placed next to telomere, and an increase in accessibility of the telomeric region to dam methylase, indicating that GAL11 is involved in the regulation of the structure and the position effect of telomeres. The defective position effect in a gal11 delta strain was suppressed by overproduction of SIR3, whereas overexpression of GAL11 failed to restore the telomere position effect in a sir3 delta strain. Hyperproduced GAL11 could partially suppress the defect in silencing at HMR in a sir1 delta mutant but not that in a sir3 delta mutant, suggesting that GAL11 can replace SIR1 function partly in the silencing of HMR. Overproduced SIR3 also could restore silencing at HMR in sir1 delta cells. In contrast, SIR1 in a multicopy plasmid relieved the telomere position effect, especially in a gal11 delta mutant. Since chromatin structure is thought to play a major role in the silencing at both the HM loci and telomeres, GAL11 is likely to participate in the regional regulation of transcription by the HM loci and telomeres, GAL11 is likely to participate in the regional regulation of transcription by modulating the chromatin structure.},
}
@article {pmid8187823,
year = {1994},
author = {Broccoli, D and Cooke, HJ},
title = {Effect of telomeres on the interphase location of adjacent regions of the human X chromosome.},
journal = {Experimental cell research},
volume = {212},
number = {2},
pages = {308-313},
doi = {10.1006/excr.1994.1148},
pmid = {8187823},
issn = {0014-4827},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Cell Nucleus/*ultrastructure ; Humans ; Hybrid Cells ; *Interphase ; *Telomere ; X Chromosome/*ultrastructure ; },
abstract = {Chromosomes occupy specific nonrandom domains in the interphase nucleus of eukaryotic cells. We have used a Chinese hamster-human somatic cell hybrid line containing a single human X chromosome to study the interphase distribution of the Xp telomere using fluorescent in situ hybridization and optical sectioning. A derivative cell line in which the X chromosome has been broken at Xq22-24 and healed by the addition of cloned human telomeric sequences was also studied to determine if introduction of these sequences at a previously interstitial site changed its location in interphase. The endogenous Xp telomere occupies a specific, nonrandom, internal domain. Introduction of a telomere at a previously interstitial site did not alter the interphase nuclear location of that site. The results suggest that nonrandom interphase location of telomeres may not be determined solely by the DNA sequence of the telomere.},
}
@article {pmid7924625,
year = {1994},
author = {Danilevskaya, O and Slot, F and Pavlova, M and Pardue, ML},
title = {Structure of the Drosophila HeT-A transposon: a retrotransposon-like element forming telomeres.},
journal = {Chromosoma},
volume = {103},
number = {3},
pages = {215-224},
pmid = {7924625},
issn = {0009-5915},
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Cell-Free System ; Consensus Sequence ; Drosophila melanogaster/*genetics ; Molecular Sequence Data ; Open Reading Frames/genetics ; Protein Biosynthesis ; RNA, Messenger/biosynthesis ; Retroelements/*genetics ; Sequence Homology, Nucleic Acid ; Telomere/*genetics ; Transcription, Genetic ; },
abstract = {Telomeres of Drosophila appear to be very different from those of other organisms. A transposable element, HeT-A, plays a major role in forming telomeres and may be the sole structural element, since telomerase-generated repeats are not found. HeT-A transposes only to chromosome ends. It appears to be a retrotransposon but has novel structural features, which may be related to its telomere functions. A consensus sequence from cloned HeT-A elements defines an element of approximately 6 kb. The coding region has retrotransposon-like overlapping open reading frames (ORFs) with a -1 frameshift in a sequence resembling the frameshift region of the mammalian HIV-1 retrovirus. Both the HeT-A ORFs contain motifs suggesting RNA binding. HeT-A-specific features include a long non-coding region, 3' of the ORFs, which makes up about half of the element. This region has a regular array of imperfect sequence repeats and ends with oligo(A), marking the end of the element and suggesting a polyadenylated RNA transposition intermediate. This 3' repeat region may have a structural role in heterochromatin. The most distal part of each complete HeT-A on the chromosome, the region 5' of the ORFs, has unusual conserved features, which might produce a terminal structure for the chromosome.},
}
@article {pmid7917328,
year = {1994},
author = {Palladino, F and Gasser, SM},
title = {Telomere maintenance and gene repression: a common end?.},
journal = {Current opinion in cell biology},
volume = {6},
number = {3},
pages = {373-379},
doi = {10.1016/0955-0674(94)90029-9},
pmid = {7917328},
issn = {0955-0674},
mesh = {Animals ; Base Sequence ; Chromosomes/*physiology/ultrastructure ; DNA, Fungal/genetics ; Gene Expression Regulation, Fungal/*physiology ; Molecular Sequence Data ; Saccharomyces cerevisiae/genetics ; Transcription, Genetic ; },
abstract = {In yeast, the study of the teleomere has recently provided new information on the requirements for chromosome stability, on elements influencing nuclear architecture and on position-effect variegation.},
}
@article {pmid7917005,
year = {1994},
author = {Wang, GS and Luo, WJ and Pan, WJ and Ding, MX and Zhai, ZH},
title = {Association of chromosomal telomere DNA with nuclear matrix in HeLa cell.},
journal = {Science in China. Series B, Chemistry, life sciences &amp; earth sciences},
volume = {37},
number = {6},
pages = {691-700},
pmid = {7917005},
issn = {1001-652X},
mesh = {DNA/*metabolism ; HeLa Cells ; Humans ; Lamin Type B ; Lamins ; Nuclear Matrix/metabolism ; Nuclear Proteins/metabolism ; Telomere/*metabolism ; Vimentin/metabolism ; },
abstract = {Using Electron Spectroscopic Imaging (ESI), we visualized the in situ binding of nucleic acids to nuclear matrix and 3H-thymidine incorporation which indicates that a small partial DNA bound to nuclear matrix tightly. Furthermore we found that chromosomal telomere DNA could bind to nuclear matrix specifically by the dot and Southern hybridization. The result of the Southwestern blot suggests that telomere DNA has high affinity to lamin B, vimentin and some nuclear matrix proteins. Therefore, the nuclear matrix and lamina of HeLa cell are possibly associated with spatial organization and action of chromosome.},
}
@article {pmid8194531,
year = {1994},
author = {Giraldo, R and Rhodes, D},
title = {The yeast telomere-binding protein RAP1 binds to and promotes the formation of DNA quadruplexes in telomeric DNA.},
journal = {The EMBO journal},
volume = {13},
number = {10},
pages = {2411-2420},
pmid = {8194531},
issn = {0261-4189},
mesh = {Base Sequence ; DNA, Fungal/*metabolism/ultrastructure ; Fungal Proteins/*metabolism ; GTP-Binding Proteins/*metabolism ; Guanine/analogs &amp; derivatives ; Methylation ; Models, Genetic ; Molecular Sequence Data ; Nucleic Acid Conformation ; Oligonucleotides/metabolism ; Protein Binding ; Saccharomyces cerevisiae/genetics/*metabolism ; Telomere/*metabolism ; rap GTP-Binding Proteins ; },
abstract = {The protein RAP1 is essential for the maintenance of the telomeres of Saccharomyces cerevisiae and binds in vitro to multiple sites found within the TG1-3 telomeric repeats. We show here that, in addition to its known binding activity for double-stranded DNA, RAP1 binds sequence-specifically to the GT-strands. This indicates that RAP1 is the protein that binds to the telomeric terminal GT-tails. Furthermore, we have found that RAP1 binds to and promotes the formation of G-tetrads, i.e. DNA quadruplexes, in GT-strand oligonucleotides at nanomolar concentrations. The formation of DNA quadruplexes appears to involve the intermolecular association of GT-strands. The minimal DNA-binding domain of RAP1 (DBD) binds only to double-stranded DNA, so that the novel DNA-binding activity we have found involves regions of the protein located outside of the DBD. The finding that a telomeric protein promotes the formation of G-tetrads argues for the use of DNA quadruplexes in telomere association.},
}
@article {pmid8151802,
year = {1994},
author = {Counter, CM and Botelho, FM and Wang, P and Harley, CB and Bacchetti, S},
title = {Stabilization of short telomeres and telomerase activity accompany immortalization of Epstein-Barr virus-transformed human B lymphocytes.},
journal = {Journal of virology},
volume = {68},
number = {5},
pages = {3410-3414},
pmid = {8151802},
issn = {0022-538X},
mesh = {B-Lymphocytes/enzymology/*microbiology ; Cell Line, Transformed ; Cell Transformation, Viral/*physiology ; Chromosomes/ultrastructure ; Clone Cells ; DNA Nucleotidylexotransferase/*metabolism ; Enzyme Activation ; Herpesvirus 4, Human/*physiology ; Humans ; *Telomere ; },
abstract = {We have measured telomere length and telomerase activity throughout the life span of clones of human B lymphocytes transformed by Epstein-Barr virus. Shortening of telomeres occurred at similar rates in all populations and persisted until chromosomes had little telomeric DNA remaining. At this stage, some of the clones entered a proliferative crisis and died. Only clones in which telomeres were stabilized, apparently by activation of telomerase, continued to proliferate indefinitely, i.e., became immortal. Since loss of telomeres impairs chromosome function, and may thus affect cell survival, we propose that telomerase activity is required for immortality. We have now detected this enzyme in a variety of immortal human cells transformed by different viruses, indicating that telomerase activation may be a common step in immortalization.},
}
@article {pmid8049689,
year = {1994},
author = {Price, CM and Adams, AK and Vermeesch, JR},
title = {Accumulation of telomerase RNA and telomere protein transcripts during telomere synthesis in Euplotes.},
journal = {The Journal of eukaryotic microbiology},
volume = {41},
number = {3},
pages = {267-275},
doi = {10.1111/j.1550-7408.1994.tb01507.x},
pmid = {8049689},
issn = {1066-5234},
support = {GM41803/GM/NIGMS NIH HHS/United States ; },
mesh = {Actins/genetics ; Animals ; Cell Nucleus/chemistry ; DNA Nucleotidylexotransferase/*genetics ; Euplotes/genetics/*physiology ; Gene Expression Regulation/physiology ; Histones/genetics ; Protozoan Proteins/*genetics ; RNA, Messenger/biosynthesis ; RNA, Protozoan/*biosynthesis ; Telomere/*metabolism ; Transcription, Genetic/physiology ; Tubulin/genetics ; },
abstract = {In the ciliate Euplotes crassus a complex series of developmental events lead to formation of a new macronucleus. Millions of telomeres are synthesized during this process. We have shown that transcript levels are tightly regulated throughout Euplotes conjugation and macronuclear development. Thus, expression of gene products needed for macronuclear development and telomere synthesis appears to be controlled at the level of RNA abundance. To learn more about the role played by telomerase and the Euplotes telomere protein during telomere synthesis, we have correlated changes in the abundance of telomerase RNA and telomere protein mRNA transcript with specific developmental events. Telomerase RNA levels increase steadily during the early stages of macronuclear development and reach a peak just after telomere addition. The telomere protein transcript rises and falls twice during conjugation and then rises again at the time of telomere addition. The increases in transcript levels during conjugation parallel micronuclear division suggesting that the telomere protein is synthesized at this time and hence may have a micronuclear function.},
}
@article {pmid8146661,
year = {1994},
author = {Chikashige, Y and Ding, DQ and Funabiki, H and Haraguchi, T and Mashiko, S and Yanagida, M and Hiraoka, Y},
title = {Telomere-led premeiotic chromosome movement in fission yeast.},
journal = {Science (New York, N.Y.)},
volume = {264},
number = {5156},
pages = {270-273},
doi = {10.1126/science.8146661},
pmid = {8146661},
issn = {0036-8075},
mesh = {Cell Nucleus/ultrastructure ; Centromere/physiology/ultrastructure ; Chromosomes, Fungal/*physiology/ultrastructure ; DNA Probes ; DNA, Fungal/analysis ; In Situ Hybridization, Fluorescence ; *Meiosis ; Microscopy, Fluorescence ; Schizosaccharomyces/*cytology/ultrastructure ; Telomere/*physiology/ultrastructure ; },
abstract = {The movement of chromosomes that precedes meiosis was observed in living cells of fission yeast by fluorescence microscopy. Further analysis by in situ hybridization revealed that the telomeres remain clustered at the leading end of premeiotic chromosome movement, unlike mitotic chromosome movement in which the centromere leads. Once meiotic chromosome segregation starts, however, centromeres resume the leading position in chromosome movement, as they do in mitosis. Although the movement of the telomere first has not been observed before, the clustering of telomeres is reminiscent of the bouquet structure of meiotic-prophase chromosomes observed in higher eukaryotes, which suggests that telomeres perform specific functions required for premeiotic chromosomal events generally in eukaryotes.},
}
@article {pmid8148384,
year = {1994},
author = {Choi, KH and Choi, BS},
title = {Formation of a hairpin structure by telomere 3' overhang.},
journal = {Biochimica et biophysica acta},
volume = {1217},
number = {3},
pages = {341-344},
doi = {10.1016/0167-4781(94)90298-4},
pmid = {8148384},
issn = {0006-3002},
mesh = {Animals ; Base Sequence ; DNA/chemistry ; DNA Nucleotidyltransferases/*metabolism ; *Genes, Protozoan ; Magnetic Resonance Spectroscopy ; Molecular Conformation ; Molecular Sequence Data ; Oxytricha/*genetics ; Telomere/chemistry/*metabolism ; },
abstract = {The telomeres of most eukaryotes contain tandemly-repeated DNA sequences, with a cluster of G residues on one strand. Recent studies showed that the Oxytricha telomeric DNA oligonucleotide, d(G4T4G4), dimerizes to form a quadruplex in the presence of Na+ or K+. We have observed that the oligonucleotide d(G4T4G4) does not dimerize in the presence of Li+ ion at low sample concentrations. In the monomeric state, this molecule forms a simple foldback hairpin structure containing G x G reverse Hoogsteen basepairs in the stem region. This hairpin structure has a thermal stability which is well reconciled with telomere functions in vivo.},
}
@article {pmid8091865,
year = {1994},
author = {Alexandraki, D and Tzermia, M},
title = {Sequencing of a 13.2 kb segment next to the left telomere of yeast chromosome XI revealed five open reading frames and recent recombination events with the right arms of chromosomes III and V.},
journal = {Yeast (Chichester, England)},
volume = {10 Suppl A},
number = {},
pages = {S81-91},
doi = {10.1002/yea.320100011},
pmid = {8091865},
issn = {0749-503X},
mesh = {Amino Acid Sequence ; Base Sequence ; *Chromosomes, Fungal ; *Genes, Fungal ; Molecular Sequence Data ; Open Reading Frames/*genetics ; Recombination, Genetic/*genetics ; Restriction Mapping ; Saccharomyces cerevisiae/*genetics ; Sequence Alignment ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; Sequence Homology, Nucleic Acid ; Telomere ; },
abstract = {We report the entire sequence of a 13.2 kb segment next to the left telomere of chromosome XI of Saccharomyces cerevisiae. A 1.2 kb fragment near one end is 91% homologous to the right arm of chromosome III and 0.7 kb of that are 77% homologous to the right arm of chromosome V. Five open reading frames are included in the sequenced segment. Two of them are almost identical to the known YCR104W and YCR103C hypothetical proteins of chromosome III. A third one contains a region homologous to the Zn (2)-Cys (6) binuclear cluster pattern of fungal transcriptional activators. The fourth one, part of which is similar to the mammalian putative transporter of mevalonate, has the structure of membrane transporters. The fifth one is similar to yeast ferric reductase.},
}
@article {pmid8069295,
year = {1994},
author = {Bayne, RA and Broccoli, D and Taggart, MH and Thomson, EJ and Farr, CJ and Cooke, HJ},
title = {Sandwiching of a gene within 12 kb of a functional telomere and alpha satellite does not result in silencing.},
journal = {Human molecular genetics},
volume = {3},
number = {4},
pages = {539-546},
doi = {10.1093/hmg/3.4.539},
pmid = {8069295},
issn = {0964-6906},
mesh = {Animals ; CHO Cells ; Cell Line ; *Cinnamates ; Cricetinae ; DNA, Satellite/*genetics ; Drug Resistance ; Electrophoresis, Gel, Pulsed-Field ; *Gene Expression Regulation ; *Heterochromatin ; Humans ; Hybrid Cells ; Hygromycin B/analogs &amp; derivatives/pharmacology ; In Situ Hybridization, Fluorescence ; Molecular Sequence Data ; Recombinant Fusion Proteins/biosynthesis/genetics ; Sequence Deletion ; *Telomere ; *X Chromosome ; },
abstract = {Pericentric heterochromatin and telomeres have been shown to be capable of repressing the expression of genes located in close proximity. The effect of adjacent structural sequences on gene expression will be important in the design of mammalian artificial chromosomes. In the process of using telomere-containing constructs to generate a deletion panel of the long arm of the human X chromosome, several cell lines were produced which appeared by in situ hybridization to be broken in Xq at or near the centromere. After analysis of end clones rescued from these cell lines, only two produced data consistent with breaks in the alpha satellite array without accompanying rearrangements. The mitotic stability of an X chromosome, with at least 750 kb of the alpha satellite array deleted, was compared to controls where the alpha satellite array remained intact. No significant change in the stability of the chromosome was observed, suggesting that the truncated chromosome has a fully functional mitotic centromere. There was no detectable change in the expression of the hygromycin resistance gene, which is located between a functional centromere and telomere, in this cell line. This study indicates that structural elements flanking a mammalian selectable marker do not result in silencing.},
}
@article {pmid8054978,
year = {1994},
author = {Ferrin, LJ and Camerini-Otero, RD},
title = {Long-range mapping of gaps and telomeres with RecA-assisted restriction endonuclease (RARE) cleavage.},
journal = {Nature genetics},
volume = {6},
number = {4},
pages = {379-383},
doi = {10.1038/ng0494-379},
pmid = {8054978},
issn = {1061-4036},
mesh = {Base Sequence ; Cell Line ; *Chromosome Aberrations ; Chromosome Mapping/*methods ; Chromosome Walking ; Chromosomes, Artificial, Yeast ; Chromosomes, Human/*ultrastructure ; Chromosomes, Human, Pair 4/ultrastructure ; DNA/genetics ; HeLa Cells ; Humans ; Huntington Disease/genetics/pathology ; Male ; Molecular Sequence Data ; Oligonucleotide Probes ; Rec A Recombinases ; *Restriction Mapping ; Sequence Homology, Nucleic Acid ; Substrate Specificity ; Telomere/*ultrastructure ; },
abstract = {RecA-assisted restriction endonuclease (RARE) cleavage is a method to perform sequence-specific cleavage of genomic DNA, and is useful in physical mapping studies. After making two modifications, we have applied this method to mapping large regions of DNA in several cell types, including a notorious gap near the Huntington disease (HD) locus on chromosome 4. RARE cleavage fragments were analysed by pulsed field gel electrophoresis and Southern blotting and the distances between cleavage sites determined with accuracy. Using RARE cleavage, the gap measured was less than 60 kilobases in length. RARE cleavage is also a straightforward technique to map the distance from a marker to a telomere. The terminal 1.7 megabases of several HD and control cell lines were mapped with no large differences between cell lines in this region.},
}
@article {pmid8032197,
year = {1994},
author = {Greider, CW},
title = {Mammalian telomere dynamics: healing, fragmentation shortening and stabilization.},
journal = {Current opinion in genetics &amp; development},
volume = {4},
number = {2},
pages = {203-211},
doi = {10.1016/s0959-437x(05)80046-2},
pmid = {8032197},
issn = {0959-437X},
mesh = {Animals ; Base Sequence ; Chromosome Fragility ; DNA Nucleotidylexotransferase/metabolism ; Humans ; Molecular Sequence Data ; Neoplasms/enzymology/genetics ; *Telomere ; },
abstract = {Telomeres are essential for stable chromosome maintenance. The simple G-rich sequence motif d(TTAGGG)n is all that is required in cis for telomere function in mammalian cells, as in other eukaryotes. Using this fact, telomeres have been used to specifically fragment mammalian chromosomes to dissect their structure and function. Telomere length maintenance is altered in cancer cells. Trans-acting factors, such as telomerase and telomere-binding proteins, may determine telomere function in both normal and cancer cells. Current experiments are aimed at understanding the role of telomerase and telomere-binding proteins in cellular senescence and immortalization.},
}
@article {pmid8152919,
year = {1994},
author = {Strahl, C and Blackburn, EH},
title = {The effects of nucleoside analogs on telomerase and telomeres in Tetrahymena.},
journal = {Nucleic acids research},
volume = {22},
number = {6},
pages = {893-900},
pmid = {8152919},
issn = {0305-1048},
support = {GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Arabinonucleotides/pharmacology ; Base Sequence ; Cell Survival/drug effects ; DNA Nucleotidylexotransferase/*antagonists &amp; inhibitors/metabolism ; Deoxyguanine Nucleotides/pharmacology ; Dideoxynucleotides ; Guanosine Triphosphate/analogs &amp; derivatives/pharmacology ; Molecular Sequence Data ; Nucleotides/*pharmacology ; Telomere/*drug effects/physiology/ultrastructure ; Tetrahymena thermophila/*enzymology/*genetics/physiology ; Thymine Nucleotides/pharmacology ; Zidovudine/analogs &amp; derivatives/pharmacology ; },
abstract = {The ribonucleoprotein enzyme telomerase is a specialized type of cellular reverse transcriptase which synthesizes one strand of telomeric DNA, using as the template a sequence in the RNA moiety of telomerase. We analyzed the effects of various nucleoside analogs, known to be chain-terminating inhibitors of retroviral reverse transcriptases, on Tetrahymena thermophila telomerase activity in vitro. We also analyzed the effects of such analogs on telomere length and maintenance in vivo, and on vegetative growth and mating of Tetrahymena cells. Arabinofuranyl-guanosine triphosphate (Ara-GTP) and ddGTP both efficiently inhibited telomerase activity in vitro, while azidothymidine triphosphate (AZT-TP), dideoxyinosine triphosphate (ddITP) or ddTTP were less efficient inhibitors. All of these nucleoside triphosphate analogs, however, produced analog-specific alterations of the normal banding patterns seen upon gel electrophoresis of the synthesis products of telomerase, suggesting that their chain terminating and/or competitive actions differ at different positions along the RNA template. The analogs AZT, 3'-deoxy-2',3'-didehydrothymidine (d4T) and Ara-G in nucleoside form caused consistent and rapid telomere shortening in vegetatively growing Tetrahymena. In contrast, ddG or ddI had no effect on telomere length or cell growth rates. AZT caused growth rates and viability to decrease in a fraction of cells, while Ara-G had no such effects even after several weeks in culture. Neither AZT, Ara-G, acycloguanosine (Acyclo-G), ddG nor ddI had any detectable effect on cell mating, as assayed by quantitation of the efficiency of formation of progeny from mated cells. However, AZT decreased the efficiency of programmed de novo telomere addition during macronuclear development in mating cells.},
}
@article {pmid8127914,
year = {1994},
author = {Gilley, D and Blackburn, EH},
title = {Lack of telomere shortening during senescence in Paramecium.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {91},
number = {5},
pages = {1955-1958},
pmid = {8127914},
issn = {0027-8424},
support = {GM 26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Division ; DNA Damage ; DNA, Protozoan/genetics ; Models, Biological ; Paramecium tetraurelia/*cytology/genetics ; Telomere/*ultrastructure ; Time Factors ; },
abstract = {Paramecium tetraurelia cells have a limited clonal life span and die after approximately 200 fissions if they do not undergo the process of autogamy or conjugation. To test the possibility that cellular senescence of this species is caused by telomere shortening, we analyzed the genomic DNA of the macronucleus during the clonal life span of P. tetraurelia. We found that telomeric DNA sequences were not shortened during the interval of decreased fission rate and cellular death, defined as senescence in these cells. However, the mean size of the macronuclear DNA was markedly decreased during the clonal life span. We present a model that expands upon previous proposals that accumulated DNA damage causes cellular senescence in P. tetraurelia.},
}
@article {pmid8005431,
year = {1994},
author = {Enomoto, S and Longtine, MS and Berman, J},
title = {Enhancement of telomere-plasmid segregation by the X-telomere associated sequence in Saccharomyces cerevisiae involves SIR2, SIR3, SIR4 and ABF1.},
journal = {Genetics},
volume = {136},
number = {3},
pages = {757-767},
pmid = {8005431},
issn = {0016-6731},
support = {GM07323/GM/NIGMS NIH HHS/United States ; GM38626/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Binding Sites/genetics ; DNA, Fungal/genetics ; DNA, Recombinant/genetics ; Escherichia coli/genetics ; Genes, Fungal ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; *Plasmids ; Saccharomyces cerevisiae/*genetics ; Telomere/*metabolism ; },
abstract = {We have previously shown that circular replicating plasmids that carry yeast telomere repeat sequence (TG1-3) tracts segregate efficiently relative to analogous plasmids lacking the TG1-3 tract and this efficient segregation is dependent upon RAP1. While a long TG1-3 tract is sufficient to improve plasmid segregation, the segregation efficiency of telomere plasmids (TEL-plasmids) is enhanced when the X-Telomere Associated Sequence (X-TAS) is also included on the plasmids. We now demonstrate that the enhancement of TEL-plasmid segregation by the X-TAS depends on SIR2, SIR3, SIR4 and ABF1 in trans and requires the Abf1p-binding site within the X-TAS. Mutation of the Abf1p-binding site within the X-TAS results in TEL-plasmids that are no longer affected by mutations in SIR2, SIR3 or SIR4, despite the fact that other Abf1p-binding sites are present on the plasmid. Mutation of the ARS consensus sequence within the X-TAS converts the X-TAS from an enhancer element to a negative element that interferes with TEL-plasmid segregation in a SIR-dependent manner. Thus, telomere associated sequences interact with TG1-3 tracts on the plasmid, suggesting that the TASs have an active role in modulating telomere function.},
}
@article {pmid8112312,
year = {1994},
author = {Murchie, AI and Lilley, DM},
title = {Tetraplex folding of telomere sequences and the inclusion of adenine bases.},
journal = {The EMBO journal},
volume = {13},
number = {4},
pages = {993-1001},
pmid = {8112312},
issn = {0261-4189},
mesh = {Adenine/analogs &amp; derivatives/*chemistry ; Base Sequence ; DNA/chemistry ; Guanine/analogs &amp; derivatives ; Molecular Sequence Data ; *Nucleic Acid Conformation ; *Telomere ; },
abstract = {Telomeres are required for eukaryotic chromosome stability. They consist of regularly repeating guanine-rich sequences, with a single-stranded 3' terminus. Such sequences have been demonstrated to have the propensity to adopt four-stranded structures based on a tetrad of guanine bases. The formation of an intramolecular foldback tetraplex is associated with markedly increased mobility in polyacrylamide. Most telomeric sequences are based either on a repeat of d(TnGGGG) or d(TnAGGG) sequences. We have used a combination 7-deazaguanine or 7-deaza-adenine substitution, chemical modification and gel electrophoresis to address the following aspects of intramolecular tetraplex formation. (i) Intramolecular tetraplex formation by d(TTTTGGGG)4 sequences is prevented by very low levels of 7-deazaguanine substitution. This confirms the important role of guanine N7 in the formation of the tetraplex. (ii) The sequences d(TTAGGG)4 and d(TTTTAGGG)4 fold into tetraplexes. By contrast, the electrophoretic behaviour of d(TTTTGGGA)4, d(TTTTAGAG)4 and d(TTTTGAGA)4 does not indicate formation of stable intramolecular tetraplexes under available conditions. (iii) Selective 7-deazaguanine and 7-deaza-adenine substitutions in d(TTTTAGGG)4 give results consistent with tetraplex folding by the formation of three G4 tetrads, with the adenine bases formally part of the single-stranded loops, where they probably interact with thymine bases. These results demonstrate that eukaryotic cells appear to have selected just those sequences that can adopt the tetraplex conformation for their telomeres, while those that cannot have been avoided. This suggests that the conformation may be significant in the function of the telomere, such as attachment to nuclear structures.},
}
@article {pmid8289836,
year = {1994},
author = {Klingelhutz, AJ and Barber, SA and Smith, PP and Dyer, K and McDougall, JK},
title = {Restoration of telomeres in human papillomavirus-immortalized human anogenital epithelial cells.},
journal = {Molecular and cellular biology},
volume = {14},
number = {2},
pages = {961-969},
pmid = {8289836},
issn = {0270-7306},
support = {CA-09657/CA/NCI NIH HHS/United States ; CA-42792/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cell Line, Transformed ; *Cell Transformation, Neoplastic ; Cells, Cultured ; Cervix Uteri/*cytology/pathology ; Chromosome Banding ; DNA Probes ; Epithelial Cells ; Epithelium/physiology ; Female ; Gene Expression ; Genes, Viral ; Humans ; Male ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Oncogene Proteins, Viral/analysis/biosynthesis ; Open Reading Frames ; Papillomaviridae/*genetics/physiology ; Repetitive Sequences, Nucleic Acid ; Telomere/*physiology/ultrastructure ; Transfection ; Transplantation, Heterologous ; *Virus Integration ; },
abstract = {Loss of telomeres has been hypothesized to be important in cellular senescence and may play a role in carcinogenesis. In this study, we have measured telomere length in association with the immortalization and transformation of human cervical and foreskin epithelial cells by the human papillomavirus type 16 or 18 E6 and E7 open reading frames. By using a telomeric TTAGGG repeat probe, it was shown that the telomeres of precrisis normal and E6-, E7-, and E6/E7-expressing cells gradually shortened with passaging (30 to 100 bp per population doubling). Cells that expressed both E6 and E7 went through a crisis period and gave rise to immortalized lines. In contrast to precrisis cells, E6/E7-immortalized cells generally showed an increase in telomere length as they were passaged in culture, with some later passage lines having telomeres that were similar to or longer than the earliest-passage precrisis cells examined. No consistent association could be made between telomere length and tumorigenicity of cells in nude mice. However, of the three cell lines that grew in vivo, two had long telomeres, thus arguing against the hypothesis that cancer cells favor shortened telomeres. Our results indicate that arrest of telomere shortening may be important in human papillomavirus-associated immortalization and that restoration of telomere length may be advantageous to cells with regard to their ability to proliferate.},
}
@article {pmid8203168,
year = {1994},
author = {Louis, EJ},
title = {Corrected sequence for the right telomere of Saccharomyces cerevisiae chromosome III.},
journal = {Yeast (Chichester, England)},
volume = {10},
number = {2},
pages = {271-274},
doi = {10.1002/yea.320100214},
pmid = {8203168},
issn = {0749-503X},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {*Artifacts ; Base Sequence ; *Chromosomes, Fungal ; *Cloning, Molecular ; Molecular Sequence Data ; Saccharomyces cerevisiae/*genetics ; Sequence Analysis, DNA ; Sequence Homology, Nucleic Acid ; *Telomere ; },
abstract = {A comparison of the sequences of telomere regions from several yeast chromosomes revealed an apparent cloning artifact for the right end of chromosome III. An integrating vector containing G1-3T telomere sequences was used to clone the right end of chromosome III from a strain related to S288C. The sequence of this clone confirmed that the published sequence was incorrect and demonstrated that the right telomere region of chromosome III is similar to other telomeres.},
}
@article {pmid7908283,
year = {1994},
author = {Takauchi, K and Tashiro, S and Ohtaki, M and Kamada, N},
title = {Telomere reduction of specific chromosome translocation in acute myelocytic leukemia.},
journal = {Japanese journal of cancer research : Gann},
volume = {85},
number = {2},
pages = {127-130},
pmid = {7908283},
issn = {0910-5050},
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Blotting, Southern ; Cell Transformation, Neoplastic ; Child ; Chromosomes, Human, Pair 15 ; Chromosomes, Human, Pair 17 ; *Chromosomes, Human, Pair 21 ; *Chromosomes, Human, Pair 8 ; Female ; Humans ; Leukemia, Myeloid, Acute/*genetics ; Male ; Middle Aged ; Polymorphism, Restriction Fragment Length ; Regression Analysis ; Repetitive Sequences, Nucleic Acid ; Telomere/*pathology ; *Translocation, Genetic ; },
abstract = {The length of telomere restriction fragments (TRF) was studied by Southern blotting in 42 patients with acute myelocytic leukemia (AML) including 15 patients with 8;21 translocation, 8 with 15;17 translocation and 19 with a normal karyotype. The TRF length of leukemic cells with a normal karyotype and with 8;21 or 15;17 translocation showed significant reduction compared to that of lymphocytes from normal individuals (P < 0.05). In addition, there was a statistically significant difference in TRF length between leukemic cells with a normal karyotype and 8;21 translocation (P < 0.05). Therefore, the significant difference of telomere reduction in 8;21 translocation may be an important factor in the leukemogenic process.},
}
@article {pmid8287473,
year = {1994},
author = {Schulz, VP and Zakian, VA},
title = {The saccharomyces PIF1 DNA helicase inhibits telomere elongation and de novo telomere formation.},
journal = {Cell},
volume = {76},
number = {1},
pages = {145-155},
doi = {10.1016/0092-8674(94)90179-1},
pmid = {8287473},
issn = {0092-8674},
support = {G0057//PHS HHS/United States ; GM26938/GM/NIGMS NIH HHS/United States ; GM43265/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosomes, Artificial, Yeast ; Cloning, Molecular ; DNA Helicases/*metabolism ; Molecular Sequence Data ; Mutagenesis ; Oligodeoxyribonucleotides ; Restriction Mapping ; Saccharomyces cerevisiae/enzymology/*genetics/physiology ; *Saccharomyces cerevisiae Proteins ; Telomere/*physiology ; },
abstract = {A screen to detect yeast mutants that frequently lost expression of subtelomeric genes identified two mutations in PIF1, a gene known to encode a 5' to 3' DNA helicase. The loss of expression of subtelomeric genes in pif1 cells was due to deletion of the subtelomeric regions of the chromosomes and the generation of new telomeres at proximal sites. In pif1 mutants, de novo telomere formation usually occurred at sites with very little homology to telomeric DNA. De novo telomere formation after HO-induced chromosome breakage also occurred at elevated frequencies in pif1 cells. Moreover, mutations in PIF1 caused all telomeres to lengthen. These results suggest that the PIF1 helicase is an inhibitor of both de novo telomere formation and telomere elongation.},
}
@article {pmid7506421,
year = {1994},
author = {Shippen, DE and Blackburn, EH and Price, CM},
title = {DNA bound by the Oxytricha telomere protein is accessible to telomerase and other DNA polymerases.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {91},
number = {1},
pages = {405-409},
pmid = {7506421},
issn = {0027-8424},
support = {GM26259/GM/NIGMS NIH HHS/United States ; GM41803/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Chromatin/ultrastructure ; Chromosomal Proteins, Non-Histone/metabolism ; DNA Nucleotidylexotransferase/*metabolism ; DNA Polymerase I/*metabolism ; DNA, Protozoan/metabolism ; DNA-Binding Proteins/*metabolism ; Molecular Sequence Data ; Oligodeoxyribonucleotides/chemistry ; Oxytricha ; Protein Binding ; Protozoan Proteins/metabolism ; RNA-Directed DNA Polymerase/*metabolism ; Telomere/*metabolism ; },
abstract = {Macronuclear telomeres in Oxytricha exist as DNA-protein complexes in which the termini of the G-rich strands are bound by a 97-kDa telomere protein. During telomeric DNA replication, the replication machinery must have access to the G-rich strand. However, given the stability of telomere protein binding, it has been unclear how this is accomplished. In this study we investigated the ability of several different DNA polymerases to access telomeric DNA in Oxytricha telomere protein-DNA complexes. Although DNA bound by the telomere protein is not degraded by micrococcal nuclease or labeled by terminal deoxynucleotidyltransferase, this DNA serves as an efficient primer for the addition of telomeric repeats by telomerase, a specialized RNA-dependent DNA polymerase (ribonucleoprotein reverse transcriptase), EC 2.7.7.49. Moreover, in the presence of a suitable complementary C-rich DNA template, AMV reverse transcriptase and the E. coli Klenow fragment will also elongate DNA bound by the telomere protein. These findings indicate that the 3' terminus and the Watson-Crick base pairing positions are exposed in the protein complex. We propose that the telomere protein can serve a dual role at the telomere by protecting the DNA phosphate backbone from degradation while simultaneously exposing the DNA bases for replication.},
}
@article {pmid8264623,
year = {1994},
author = {Vermeesch, JR and Price, CM},
title = {Telomeric DNA sequence and structure following de novo telomere synthesis in Euplotes crassus.},
journal = {Molecular and cellular biology},
volume = {14},
number = {1},
pages = {554-566},
pmid = {8264623},
issn = {0270-7306},
support = {GM41803/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Composition ; Base Sequence ; Cloning, Molecular ; DNA, Protozoan/biosynthesis/chemistry/*genetics ; Euplotes/*genetics/metabolism ; Models, Biological ; Molecular Sequence Data ; Telomere/chemistry/*metabolism ; },
abstract = {To learn more about the mechanism of de novo telomere synthesis, we have characterized the sequence and structure of newly synthesized telomeres from Euplotes crassus. E. crassus is a particularly useful organism for studying telomere synthesis because millions of telomeres are made in each cell at a well-defined time during the sexual stage of the life cycle. These newly synthesized telomeres are approximately 50 bp longer than mature macronuclear telomeres. We have investigated the structure of the newly synthesized telomeres and have found that they are much more heterogeneous in length than mature telomeres. Most of the heterogeneity is present on the G-rich strand, indicating that the length of this strand is rather loosely controlled. In contrast, the length of the C-rich strand is much less variable, suggesting that synthesis of this strand is the more precisely regulated step in telomere addition. The G-rich strand exhibits variability both in the total number of G4T4 repeats and in the identity of the terminal nucleotide. In most cases, the G-rich strnd extends beyond the C-rich strand to leave a 3' overhang. While the size of this overhang is variable, the median length is 10 nucleotides. This research provides the first detailed picture of a newly synthesized telomere and has allowed us to formulate a model to describe the various steps involved in de novo telomere synthesis.},
}
@article {pmid8264612,
year = {1994},
author = {Thompson, JS and Johnson, LM and Grunstein, M},
title = {Specific repression of the yeast silent mating locus HMR by an adjacent telomere.},
journal = {Molecular and cellular biology},
volume = {14},
number = {1},
pages = {446-455},
pmid = {8264612},
issn = {0270-7306},
support = {GM07185/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites/genetics ; Chromosome Mapping ; Chromosomes, Fungal/ultrastructure ; *Gene Expression Regulation, Fungal ; *Genes, Fungal ; *Genes, Mating Type, Fungal ; Genes, Regulator ; Histones/genetics ; Mutation ; Saccharomyces cerevisiae/*genetics/ultrastructure ; Telomere/ultrastructure ; Transformation, Genetic ; },
abstract = {The yeast silent mating loci HML and HMR are located at opposite ends of chromosome III adjacent to the telomeres. Mutations in the N terminus of histone H4 have been previously found to derepress the yeast silent mating locus HML to a much greater extent than HMR. Although differences in the a and alpha mating-type regulatory genes and in the cis-acting silencer elements do not appear to strongly influence the level of derepression at HMR, we have found that the differential between the two silent cassettes is largely due to the position of the HMR cassette relative to the telomere on chromosome III. While HML is derepressed to roughly the same extent by mutations in histone H4 regardless of its chromosomal location, HMR is affected to different extends depending upon its chromosomal positioning. We have found that HMR is more severely derepressed by histone H4 mutations when positioned far from the telomere (cdc14 locus on chromosome VI) but is only minimally affected by the same mutations when integrated immediately adjacent to another telomere (ADH4 locus on chromosome VII). These data indicate that the degree of silencing at HMR is regulated in part by its neighboring telomere over a distance of at least 23 kb and that this form of regulation is unique for HMR and not present at HML. These data also indicate that histone H4 plays an important role in regulating the silenced state at both HML and HMR.},
}
@article {pmid8261445,
year = {1994},
author = {Mehle, C and Ljungberg, B and Roos, G},
title = {Telomere shortening in renal cell carcinoma.},
journal = {Cancer research},
volume = {54},
number = {1},
pages = {236-241},
pmid = {8261445},
issn = {0008-5472},
mesh = {Base Sequence ; Carcinoma, Renal Cell/*genetics/pathology ; Cell Division/genetics ; DNA, Neoplasm/*analysis ; Humans ; Kidney Neoplasms/*genetics/pathology ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Telomere/*chemistry ; },
abstract = {The ends of human chromosomes consist of a specialized structure, the telomere, composed of repeats of TTAGGG making up a total of 5-15 kilobase pairs, depending on age and proliferative activity of the tissue. The major function of telomeres is to provide stability to chromosomes and protect underlying unique coding sequences from degradation. There is a loss of telomeric sequences following every cell division estimated to be between 50 and 65 basepairs/cell division in human fibroblasts and embryonic kidney cells in vitro. This loss is due to the fact that DNA replication is incomplete for one strand at each telomere end. In lower eukaryotes there is a compensation mechanism provided by the enzyme telomerase, which is inactive in human somatic cells. Telomerase activation has also been detected in vitro immortalized human cells. In this study we analyzed renal cell carcinoma for the occurrence of telomere shortening using the probe (TTAGGG)4. Southern blots of HinfI-digested DNA revealed a shortening of mean telomere restriction fragment (TRF) length of 0.4 to 2.5 kilobase pairs in 2 or 3 intratumoral samples in all 10 tumors analyzed. No obvious intratumoral heterogeneity was found in mean TRF length values. However, heterogeneity was shown by the occurrence of at least two separate peak TRF values in 7 of 10 tumors, indicating the presence of different tumor cell clones. A conflicting observation was made when we evaluated the intensity of the hybridization signals, where three of the tumors showed an increase in hybridization signals despite concomitant TRF reduction. We found no correlation between tumor size and calculated tumor cell divisions undergone. In two tumors, the calculated cell division cycles were unrealistically low compared to the tumor size. These data suggest that telomerase activation might occur in human renal cell carcinoma.},
}
@article {pmid8136835,
year = {1994},
author = {Royle, NJ and Baird, DM and Jeffreys, AJ},
title = {A subterminal satellite located adjacent to telomeres in chimpanzees is absent from the human genome.},
journal = {Nature genetics},
volume = {6},
number = {1},
pages = {52-56},
doi = {10.1038/ng0194-52},
pmid = {8136835},
issn = {1061-4036},
mesh = {Animals ; Base Sequence ; Cloning, Molecular ; DNA Primers/genetics ; DNA, Satellite/*genetics ; *Genome, Human ; Gorilla gorilla/genetics ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Molecular Sequence Data ; Pan troglodytes/*genetics ; Polymerase Chain Reaction ; Pongo pygmaeus/genetics ; Repetitive Sequences, Nucleic Acid ; Sequence Homology, Nucleic Acid ; Species Specificity ; Telomere ; },
abstract = {One of the significant unresolved differences between the karyotypes of humans and African apes is the presence of positively staining G-bands at the ends of many chromosome arms in the chimpanzee and gorilla but absent from human chromosomes. Using a telomere anchored PCR strategy, we have isolated DNA from a subterminal satellite, composed of a 32 basepair A-T rich repeat, from the chimpanzee genome that hybridizes to all the additional terminal bands and at two interstitial sites. The satellite is more abundant in gorillas and is not detected in humans or orangutans. Furthermore, there is no similarity between other chimpanzee telomere-junction clones and human subterminal sequences, and therefore the organization of sequences adjacent to telomeres is very different between these closely related primates.},
}
@article {pmid8032424,
year = {1994},
author = {Allshire, RC and Cooke, HJ},
title = {Chromosome substructure investigation. Telomeres.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {29},
number = {},
pages = {493-503},
doi = {10.1385/0-89603-289-2:493},
pmid = {8032424},
issn = {1064-3745},
mesh = {Base Sequence ; Chromosomes, Artificial, Yeast ; Chromosomes, Human/*ultrastructure ; Cloning, Molecular ; DNA/genetics ; DNA, Fungal/genetics/isolation &amp; purification ; *Genetic Techniques ; Genetic Vectors ; Humans ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/genetics ; Spheroplasts/ultrastructure ; Telomere/*ultrastructure ; Transformation, Genetic ; },
}
@article {pmid7937405,
year = {1994},
author = {Jaruga, E},
title = {[Telomere hypothesis of cell aging].},
journal = {Postepy biochemii},
volume = {40},
number = {3},
pages = {161-165},
pmid = {7937405},
issn = {0032-5422},
mesh = {Animals ; Base Sequence ; Cellular Senescence/*physiology ; DNA/metabolism ; DNA Nucleotidylexotransferase/metabolism ; DNA Replication ; Humans ; In Vitro Techniques ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; Telomere/*physiology ; },
}
@article {pmid7894593,
year = {1994},
author = {Meyne, J and Moyzis, RK},
title = {In situ hybridization using synthetic oligomers as probes for centromere and telomere repeats.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {33},
number = {},
pages = {63-74},
doi = {10.1385/0-89603-280-9:63},
pmid = {7894593},
issn = {1064-3745},
mesh = {Base Sequence ; Centromere ; Chromosomes, Human ; DNA/genetics ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Molecular Probe Techniques ; Molecular Sequence Data ; *Oligonucleotide Probes/chemical synthesis/genetics ; *Repetitive Sequences, Nucleic Acid ; Telomere ; },
}
@article {pmid7584030,
year = {1994},
author = {Ashikawa, I and Kurata, N and Nagamura, Y and Minobe, Y},
title = {Cloning and mapping of telomere-associated sequences from rice.},
journal = {DNA research : an international journal for rapid publication of reports on genes and genomes},
volume = {1},
number = {2},
pages = {67-76},
doi = {10.1093/dnares/1.2.67},
pmid = {7584030},
issn = {1340-2838},
mesh = {Base Sequence ; Chromosome Mapping ; Cloning, Molecular ; DNA Primers/chemistry ; Genetic Linkage ; Molecular Sequence Data ; Oryza/*genetics ; Polymorphism, Restriction Fragment Length ; Telomere/*genetics ; },
abstract = {We have isolated three telomere-associated sequences from rice using cassette-ligation-mediated polymerase chain reaction (PCR). Each of the obtained clones hybridized to the terminal of one or several rice chromosome arms. The telomeres recognized by the clones displayed a high level of polymorphism between two rice varieties, Nipponbare (a japonica variety) and Kasalath (an indica variety). Variability in the chromosome termini was also detected among individual F2 progeny plants, which were derived from a cross between the two rice varieties. One clone containing telomere-associated sequences was located to one end of chromosome 5, and another clone to one end of chromosome 11. For another clone, non-allelic segregation of polymorphic hybridization bands was observed between japonica and indica rice; this clone was mapped to one end of chromosome 12 in japonica and to one end of chromosome 11 in indica rice. This indicates an exchange of termini between nonhomologous chromosomes.},
}
@article {pmid8299961,
year = {1993},
author = {Burgtoft, C and Bünemann, H},
title = {A telomere-like satellite (GGGTCAT)n comprises 4% of genomic DNA of Drosophila hydei and is located mainly in centromeric heterochromatin of all large acrocentric autosomes.},
journal = {Gene},
volume = {137},
number = {2},
pages = {287-291},
doi = {10.1016/0378-1119(93)90022-u},
pmid = {8299961},
issn = {0378-1119},
mesh = {Animals ; Base Sequence ; *Centromere ; Cloning, Molecular ; DNA, Satellite/*genetics ; Drosophila/*genetics ; Electrophoresis, Gel, Pulsed-Field ; *Heterochromatin ; Molecular Sequence Data ; *Telomere ; },
abstract = {We describe the isolation and analysis of a G+C-rich telomere-like (GGGTCAT)n satellite of Drosophila hydei. GGGTCAT-specific clones were obtained by a combination of restriction enzyme digestion and fractionation of D. hydei DNA by pulsed-field gel electrophoresis (PFGE). High-molecular-weight DNA (> 50 kb) was recovered from gels, sheared by sonication and cloned into the pBS plasmid vector. The results of PFGE analysis, quantitative dot blot measurements and fluorescence in situ hybridization (FISH) on metaphase chromosomes show that the tandemly arranged GGGTCAT sequences comprise 4% of genomic DNA and are organized as megabase-sized clusters in the pericentric region of all large acrocentric autosomes. A telomere-related function is rather unlikely, because the chromosomal ends of D. hydei seem to be free of GGGTCAT repeats and several other species of Drosophila do not contain any cross-hybridizing sequences at all.},
}
@article {pmid8261510,
year = {1993},
author = {Levis, RW and Ganesan, R and Houtchens, K and Tolar, LA and Sheen, FM},
title = {Transposons in place of telomeric repeats at a Drosophila telomere.},
journal = {Cell},
volume = {75},
number = {6},
pages = {1083-1093},
doi = {10.1016/0092-8674(93)90318-k},
pmid = {8261510},
issn = {0092-8674},
support = {CA15704/CA/NCI NIH HHS/United States ; GM38259/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Chromosome Mapping ; Cloning, Molecular ; DNA/*chemistry/genetics/isolation &amp; purification ; *DNA Transposable Elements ; Drosophila/*genetics ; Drosophila melanogaster/*genetics ; In Situ Hybridization ; Molecular Sequence Data ; Open Reading Frames ; *Repetitive Sequences, Nucleic Acid ; Retroviridae ; Salivary Glands/cytology/metabolism ; Species Specificity ; Telomere/*physiology/ultrastructure ; },
abstract = {We present the first isolation of the terminal DNA of an intact Drosophila telomere. It differs from those isolated from other eukaryotes by the lack of short tandem repeats at the terminus. The terminal 14.5 kb is composed of four tandem elements derived from two families of non-long terminal repeat retrotransposons and is subject to slow terminal loss. One of these transposon families, TART (telomere-associated retrotransposon), is described for the first time here. The other element, HeT-A, has previously been shown to transpose to broken chromosome ends. Our results provide key evidence that these elements also transpose to natural chromosome ends. We propose that the telomere-associated repetitive DNA is maintained by saltatory expansions, including terminal transpositions of specialized retrotransposons, which serve to balance terminal loss.},
}
@article {pmid8307556,
year = {1993},
author = {Henke, A and Fischer, C and Rappold, GA},
title = {Genetic map of the human pseudoautosomal region reveals a high rate of recombination in female meiosis at the Xp telomere.},
journal = {Genomics},
volume = {18},
number = {3},
pages = {478-485},
doi = {10.1016/s0888-7543(11)80003-0},
pmid = {8307556},
issn = {0888-7543},
mesh = {Alleles ; Chromosome Mapping ; Female ; Genetic Linkage ; Genetic Markers ; Genotype ; Heterozygote ; Humans ; Male ; Meiosis ; Pedigree ; *Recombination, Genetic ; Restriction Mapping ; *Sex Characteristics ; Telomere/*ultrastructure ; *X Chromosome ; Y Chromosome ; },
abstract = {This paper describes the genetic map of the pseudoautosomal region bounded by the telomere of the short arms of the X and Y chromosomes. In males, meiotic exchange on Xp/Yp is confined to this region, leading to highly elevated recombination rates. The map was constructed using 11 pseudoautosomal probes (six of which are new) and typing individuals from 38 CEPH families. All markers have been physically mapped, thus providing the opportunity to compare genetic distance to physical distance through all intervals of the map. This comparison reveals an unexpected high rate of recombination in female meiosis between loci DXYS20 and DXYS78, within 20-80 kb from the telomere. Within this telomere-adjacent region no differences in male and female recombination rates are seen. Furthermore, data from this genetic map support the hypothesis of a linear gradient of recombination across most of the region in male meiosis and provide densely spaced anchor points for linkage studies especially in the telomeric portion of the pseudoautosomal region.},
}
@article {pmid8294219,
year = {1993},
author = {Hayashi, T and Mafune, Y and Takada, T and Hatakeyama, K and Takagi, N and Kominami, R},
title = {Telomere change and loss of heterozygosity of mouse primary tumors and cell lines.},
journal = {Japanese journal of cancer research : Gann},
volume = {84},
number = {12},
pages = {1292-1299},
pmid = {8294219},
issn = {0910-5050},
mesh = {Animals ; Base Sequence ; Cells, Cultured ; Chromosome Aberrations ; Chromosome Disorders ; DNA/analysis ; DNA, Neoplasm/analysis ; Electrophoresis, Polyacrylamide Gel ; Female ; Fibrosarcoma/chemically induced/*genetics/ultrastructure ; *Genetic Carrier Screening ; Karyotyping ; Male ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Inbred Strains ; Molecular Sequence Data ; *Telomere/physiology/ultrastructure ; Tumor Cells, Cultured ; },
abstract = {Changes in the number of telomere repeat arrays were examined in mouse tumor cells. Telomeres that function for the protection of chromosomes were detected as bands and a smear by pulsed field gel electrophoresis and gel-hybridization using (TTAGGG)4, as a probe. Of eight primary tumors induced in F1 mice between C57BL/6 and C3H/He and between C57BL/6 and MSM, three showed telomere alteration, two having extra bands and one having lost several telomere bands. The others exhibited patterns similar to those of normal tissues. However, the change was detected in all four cell lines that were established from one of the tumors. One cell line was further cloned and examined. Two of the nine clones differed in the telomere pattern. The telomere change was also observed in two other cell lines, FM3A cells and nontransformed BALB3T3 cells. These results suggest that telomeres are highly mutable in tumor cells and cultured cell lines. Three of the tumors and one cell line were analyzed for loss of heterozygosity with 51 microsatellite probes covering all 19 autosomes. Also, karyotype analysis of the cell line was performed. No allelic loss was seen and chromosomal abnormality was rare, although aneuploidy and imbalance in chromosomal number were observed. Possible involvement of the telomere changes observed here in chromosome impairment is discussed.},
}
@article {pmid8281516,
year = {1993},
author = {Schwartz, HS and Dahir, GA and Butler, MG},
title = {Telomere reduction in giant cell tumor of bone and with aging.},
journal = {Cancer genetics and cytogenetics},
volume = {71},
number = {2},
pages = {132-138},
pmid = {8281516},
issn = {0165-4608},
support = {P01 HD030329/HD/NICHD NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aging/*genetics ; Blotting, Southern ; Bone Neoplasms/*genetics ; Child ; Child, Preschool ; Chromosome Aberrations ; Female ; Femoral Neoplasms/genetics ; Giant Cell Tumor of Bone/*genetics ; Humans ; In Situ Hybridization ; Infant ; Leukocytes/ultrastructure ; Male ; Middle Aged ; Repetitive Sequences, Nucleic Acid ; Sacrum ; Scapula ; *Sequence Deletion ; Spinal Neoplasms/genetics ; Telomere/pathology/*ultrastructure ; Tibia ; },
abstract = {Giant cell tumor of bone is a benign, primary skeletal neoplasm that has an unpredictable pattern of biologic aggressiveness, and cytogenetically demonstrates genetic instability by exhibiting telomeric associations. Molecular analysis of telomeres from giant cell tumor of bone demonstrated reduction of telomere length (average loss of 500 base pairs) in eight individuals when compared with their leukocyte DNA. Those tumors which exhibited telomeric associations were found to have a greater reduction in telomere length than tumors not exhibiting them. For comparison, eleven cytogenetically healthy control individuals (7 females and 4 males, age range 2 weeks to 70 years) were included in this study. They demonstrated loss of telomere size (average 40 base pairs per year) with advancing age and the greatest rate of telomere reduction was identified in the young. Thus, the functional consequences of telomere shortening in a neoplastic cell may prove fundamental to sustaining the transformed phenotype in giant cell tumor of bone.},
}
@article {pmid8253381,
year = {1993},
author = {Kramer, KM and Haber, JE},
title = {New telomeres in yeast are initiated with a highly selected subset of TG1-3 repeats.},
journal = {Genes &amp; development},
volume = {7},
number = {12A},
pages = {2345-2356},
doi = {10.1101/gad.7.12a.2345},
pmid = {8253381},
issn = {0890-9369},
support = {GM07122/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosomes, Fungal/*metabolism ; DNA Nucleotidylexotransferase/metabolism ; DNA Repair/genetics ; DNA, Fungal/genetics/metabolism ; Guanine/*metabolism ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid/*genetics ; Saccharomyces cerevisiae/*genetics ; Telomere/*metabolism ; Thymine/*metabolism ; },
abstract = {The creation of new telomeres was studied by generating a site-specific double-strand break in diploid strains of Saccharomyces cerevisiae that are unable to carry out homologous recombination. New telomere formation occurred approximately 1% of the time but only when (T2G4)13 was present proximal to the break site. About half of the healing events occurred at a number of 1- to 9-bp G or G, T sequences located as far as 128 bp distal to the T2G4 repeats. Surprisingly, in 16 events at sites ending in GTGG, the first TG1-3 nucleotides added always included either an 11- or a 13-bp sequence (GTGTGGGTGTG or GTGTGTGGGTGTG), after which each new telomere diverged into a less ordered TG1-3 pattern. Moreover, at 75% of the remaining addition sites, these same 11- or 13-bp sequences were found overlapping the junction between the chromosomal primer and the newly added sequences. We propose that short G, T sequences near an organizing sequence such as (T2G4)13 can act as primers to pair with the template RNA of a telomerase and add new sequences that are complementary to that RNA.},
}
@article {pmid8223469,
year = {1993},
author = {Williams, K and Doak, TG and Herrick, G},
title = {Developmental precise excision of Oxytricha trifallax telomere-bearing elements and formation of circles closed by a copy of the flanking target duplication.},
journal = {The EMBO journal},
volume = {12},
number = {12},
pages = {4593-4601},
pmid = {8223469},
issn = {0261-4189},
support = {GM25203/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; *DNA Transposable Elements ; DNA, Circular/genetics ; DNA, Protozoan/genetics ; Female ; Molecular Sequence Data ; Mutagenesis, Insertional ; Oxytricha/*genetics/growth &amp; development ; Polymerase Chain Reaction ; *Repetitive Sequences, Nucleic Acid ; *Telomere ; },
abstract = {The 4.1 kbp TBE1 elements of Oxytricha fallax and Oxytricha trifallax are deduced to transpose into a centrisymmetric target, CAnTG, and to duplicate the central AnT. Despite conserved C(A4C4)2 telomeric repeats at their tips, free TBE1s found during macronuclear development are not linear but 4.1 kbp circles closed on one copy of the AnT target duplication. The macronucleus-destined flanks are rejoined to regenerate the target, effecting efficient and precise somatic reversion of the germline transpositional mutation. A model is presented in which transposase catalyzes concerted precise rejoining of the flanks and cyclization of the excised element.},
}
@article {pmid7512014,
year = {1993},
author = {Olins, AL and Cacheiro, LH and Herrmann, AL and Dhar, MS and Olins, DE},
title = {Inaccessibility of the Euplotes telomere binding protein.},
journal = {Chromosoma},
volume = {102},
number = {10},
pages = {700-711},
pmid = {7512014},
issn = {0009-5915},
mesh = {Amino Acid Sequence ; Animals ; Carrier Proteins/analysis ; Chromosomal Proteins, Non-Histone/*analysis/immunology ; Epitopes/*analysis ; Euplotes/*chemistry/immunology ; Histones/*analysis/immunology ; Molecular Sequence Data ; Telomere/*chemistry/immunology ; Trypsin ; },
abstract = {The telomere binding protein (TP) from the macronucleus of the ciliate Euplotes eurystomus was purified by removal of tenaciously bound DNA with hydroxylapatite, and the purified TP partially sequenced. Rabbit antiserum was generated against a synthetic peptide of 14 amino acids at the amino-terminus of the TP. This antiserum was employed to examine the accessibility of TP antigenic determinants in nuclei and chromatin. Immunofluorescent staining of isolated macronuclei revealed only weak reactivity with specific antiserum. Reactivity within replication bands was demonstrated, and could be augmented by preparation of nuclear scaffolds. Employing a dot immunoblot analysis, the amino-terminal antigenic determinants of TP were revealed after extraction of histone H1 (and some nonhistones). A different aspect of TP inaccessibility was demonstrated by immunoblot analysis of trypsin-treated macronuclei and chromatin; TP was considerably less susceptible to digestion by trypsin than were histones H1 and H3. The relative inaccessibility of TP was not a consequence of chromatin higher-order structure, since soluble macronuclear chromatin in low salt exhibited the same burying of antigenic determinants by dot blot analysis, and the same decreased susceptibility to trypsin, as did isolated nuclei. Electron microscopy of soluble macronuclear chromatin spread in low salt revealed that most telomeres appear unfolded, without stable higher-order structure. The mechanisms for the relative inaccessibility of TP are not yet known, but probably arise as a consequence of the strong interactions of TP with the telomere nucleotide sequence and additional interactions of TP with various chromatin proteins, perhaps including histone H1.},
}
@article {pmid8265350,
year = {1993},
author = {Vermeesch, JR and Williams, D and Price, CM},
title = {Telomere processing in Euplotes.},
journal = {Nucleic acids research},
volume = {21},
number = {23},
pages = {5366-5371},
pmid = {8265350},
issn = {0305-1048},
support = {GM41803/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Aphidicolin/pharmacology ; Base Sequence ; DNA/*metabolism ; DNA Replication/drug effects ; Euplotes/*genetics ; Molecular Sequence Data ; *Telomere ; },
abstract = {In Euplotes crassus millions of telomeres are synthesized during the sexual phase of the life cycle. Since these newly synthesized telomeres are longer than normal macronuclear telomeres, they must be trimmed to the mature size. We have examined the timing and mechanism of this trimming step. We have shown that a sudden decrease in telomere length takes place at a specific time during macronuclear development. The decrease in telomere length is not caused by incomplete replication of the most terminal DNA sequences; rather it is the result of an active processing event that occurs independently of DNA replication. The developmentally regulated telomere shortening that takes place in Euplotes is reminiscent of the sudden reductions in telomere length which have been observed in other eukaryotes.},
}
@article {pmid8242745,
year = {1993},
author = {Sandell, LL and Zakian, VA},
title = {Loss of a yeast telomere: arrest, recovery, and chromosome loss.},
journal = {Cell},
volume = {75},
number = {4},
pages = {729-739},
doi = {10.1016/0092-8674(93)90493-a},
pmid = {8242745},
issn = {0092-8674},
support = {AG00057/AG/NIA NIH HHS/United States ; GM26938/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle ; *Cell Cycle Proteins ; Chromosomes/*ultrastructure ; DNA Repair ; Deoxyribonucleases, Type II Site-Specific/metabolism ; Fungal Proteins/*metabolism ; Saccharomyces cerevisiae/cytology/*genetics ; Saccharomyces cerevisiae Proteins ; Telomere/*physiology ; },
abstract = {Yeast strains were constructed in which a single telomere could be eliminated from the end of a dispensable chromosome. In wild-type cells, elimination of a telomere caused a RAD9-mediated cell cycle arrest, indicating that telomeres help cells to distinguish intact chromosomes from damaged DNA. However, many cells recovered from the arrest without repairing the damaged chromosome, replicating and segregating it for as many as ten cell divisions prior to its eventual loss. Telomere elimination caused a dramatic increase in loss of the chromosome in all strains examined, demonstrating that yeast telomeres are also essential for maintaining chromosome stability. Thus, in spite of checkpoint and DNA damage repair systems, many chromosomes that lose a telomere are themselves destined for loss.},
}
@article {pmid8221893,
year = {1993},
author = {Palladino, F and Laroche, T and Gilson, E and Axelrod, A and Pillus, L and Gasser, SM},
title = {SIR3 and SIR4 proteins are required for the positioning and integrity of yeast telomeres.},
journal = {Cell},
volume = {75},
number = {3},
pages = {543-555},
doi = {10.1016/0092-8674(93)90388-7},
pmid = {8221893},
issn = {0092-8674},
support = {GM31105/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Compartmentation ; Cell Nucleus/*ultrastructure ; Fluorescent Antibody Technique ; Fungal Proteins/genetics/*ultrastructure ; GTP-Binding Proteins/ultrastructure ; Gene Expression Regulation, Fungal ; Mating Factor ; Mitosis ; Mutagenesis ; Mutation ; Peptides/genetics ; Saccharomyces cerevisiae/genetics/*ultrastructure ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Telomere/*ultrastructure ; Trans-Activators/genetics/*ultrastructure ; rap GTP-Binding Proteins ; },
abstract = {Heritable inactivation of genes occurs in specific chromosomal domains located at the silent mating type loci and at telomeres of S. cerevisiae. The SIR genes (for silent information regulators) are trans-acting factors required for this repression mechanism. We show here that the SIR3 and SIR4 gene products have a sub-nuclear localization similar to the telomere-associated RAP1 protein, which is found primarily in foci at the nuclear periphery of fixed yeast spheroplasts. In strains deficient for either SIR3 or SIR4, telomeres lose their perinuclear localization, as monitored by RAP1 immunofluorescence. The length of the telomeric repeat shortens in sir3 and sir4 mutant strains, and the mitotic stability of chromosome V is reduced. These data suggest that SIR3 and SIR4 are required for both the integrity and subnuclear localization of yeast telomeres, the loss of which correlates with loss of telomere-associated gene repression.},
}
@article {pmid8221892,
year = {1993},
author = {Chien, CT and Buck, S and Sternglanz, R and Shore, D},
title = {Targeting of SIR1 protein establishes transcriptional silencing at HM loci and telomeres in yeast.},
journal = {Cell},
volume = {75},
number = {3},
pages = {531-541},
doi = {10.1016/0092-8674(93)90387-6},
pmid = {8221892},
issn = {0092-8674},
support = {GM28220/GM/NIGMS NIH HHS/United States ; GM40094/GM/NIGMS NIH HHS/United States ; },
mesh = {Crosses, Genetic ; DNA-Binding Proteins ; Fungal Proteins/genetics/*metabolism ; *Gene Expression Regulation, Fungal ; Genes, Fungal ; Genes, Mating Type, Fungal ; Histones/metabolism ; Mating Factor ; Models, Genetic ; Mutation ; Peptides/*genetics ; Recombinant Fusion Proteins/metabolism ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Telomere ; Trans-Activators/genetics/*metabolism ; *Transcription Factors ; *Transcription, Genetic ; },
abstract = {Previous studies suggest that the yeast SIR1 protein is involved in the establishment of transcriptional silencing at the HM mating-type loci. Here we show that a GAL4 DNA-binding domain-SIR1 hybrid protein (GBD-SIR1), when targeted to an HMR locus containing GAL4-binding sites (UASG), can establish silencing and bypass the requirement for the silencer element HMR-E. Silencing mediated by GBD-SIR1 requires the trans-acting factors that normally participate in repression, namely, SIR2, SIR3, SIR4, and histone H4. However, GBD hybrids with SIR2, SIR3, or SIR4 cannot establish silencing. Telomeric silencing, which does not require SIR1 and is normally unstable, is greatly improved by tethering GBD-SIR1 to the telomere. These experiments support a model in which native SIR1 protein is brought to the HM loci by proteins bound to the silencers. Telomeres appear to lack the ability to recruit SIR1, and that is why telomeric silencing is unstable.},
}
@article {pmid8218232,
year = {1993},
author = {Fang, G and Cech, TR},
title = {Characterization of a G-quartet formation reaction promoted by the beta-subunit of the Oxytricha telomere-binding protein.},
journal = {Biochemistry},
volume = {32},
number = {43},
pages = {11646-11657},
doi = {10.1021/bi00094a022},
pmid = {8218232},
issn = {0006-2960},
support = {GM28039/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Biopolymers ; DNA/*metabolism ; DNA-Binding Proteins/*metabolism ; Kinetics ; Molecular Sequence Data ; Nucleic Acid Conformation ; Oxytricha/*metabolism ; Protozoan Proteins/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres, the ends of linear chromosomes, typically consists of tandem repeats of a simple guanine-rich sequence. Telomeric DNA is able to form intermolecular G-quartet structures. The beta-subunit of the Oxytricha telomere-binding protein acts as a molecular chaperone to promote the formation of dimers and specific higher order complexes of telomeric DNA stabilized by G-quartets; these reactions occur under physiological conditions in vitro. In the present article, we show that, at saturating protein concentrations (> or = 200 nM), beta-mediated G-quartet formation is a first-order reaction with respect to DNA concentration, with k approximately 1 h-1 at 37 degrees C. In contrast, the protein-independent reaction is a second-order reaction. The beta-subunit enhances the rate of G-quartet formation by 10(5)-10(6)-fold at a telomeric DNA concentration of 20 nM. The beta-mediated higher order complexes are identified as parallel four-stranded tetramers of telomeric DNA (G4-DNA). Poly-L-lysine also promotes formation of the tetramers, but not dimers. These DNA structures were studied by irreversible thermal melting experiments and probed by annealing to different complementary strands. Guanine residues important for structure formation were analyzed by methylation interference experiments. On the basis of these data, models for the beta-mediated structures are proposed, and possible mechanisms for the beta-mediated reaction are discussed. In addition, we found that the beta-subunit promotes the annealing of two complementary strands into a duplex, as do many other basic proteins. However, not all proteins with annealing-promoting activity are active in the formation of G-quartet structures. The activity of the telomere protein in promoting the formation of telomeric DNA structures may enable chromosome-chromosome association or the regulation of telomerase activity in vivo.},
}
@article {pmid8263038,
year = {1993},
author = {de Lara, J and Wydner, KL and Hyland, KM and Ward, WS},
title = {Fluorescent in situ hybridization of the telomere repeat sequence in hamster sperm nuclear structures.},
journal = {Journal of cellular biochemistry},
volume = {53},
number = {3},
pages = {213-221},
doi = {10.1002/jcb.240530306},
pmid = {8263038},
issn = {0730-2312},
support = {HD28501/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cell Nucleus/*chemistry ; Cricetinae ; DNA/*chemistry ; DNA Probes ; Deoxyribonuclease EcoRI ; *In Situ Hybridization, Fluorescence ; Male ; *Repetitive Sequences, Nucleic Acid ; Spermatozoa/*ultrastructure ; *Telomere ; },
abstract = {The flat, hooked-shaped architecture of the hamster sperm nucleus makes this an excellent model for in situ hybridization studies of the three dimensional structure of the genome. We have examined the structure of the telomere repeat sequence (TTAGGG)n with respect to the various nuclear structures present in hamster spermatozoa, using fluorescent in situ hybridization. In fully condensed, mature sperm nuclei, the telomere sequences appeared as discrete spots of various sizes interspersed throughout the volume of the nuclei. While the pattern of these signals was non-random, it varied significantly in different nuclei. These discrete telomere foci were seen to gradually lengthen into linear, beaded signals as sperm nuclei were decondensed, in vitro, and were not associated with the nuclear annulus. We also examined the relationship of telomeres to the sperm nuclear matrix, a residual nuclear structure that retains the original size and shape of the nucleus. In these structures the DNA extends beyond the perimeter of the nucleus to form a halo around it, representing the arrangement of the chromosomal DNA into loop domains attached at their bases to the nuclear matrix. Telomere signals in these structures were also linear and equal in length to those of the decondensed nuclei, and each signal represented part of a single DNA loop domain. The telomeres were attached at one end to the nuclear matrix and extended into the halo. Sperm nuclear matrices treated with Eco RI retained the telomere signals. These data support sperm DNA packaging models in which DNA is coiled into discrete foci, rather than spread out linearly along the length of the sperm nucleus.},
}
@article {pmid8274859,
year = {1993},
author = {Shippen, DE},
title = {Telomeres and telomerases.},
journal = {Current opinion in genetics &amp; development},
volume = {3},
number = {5},
pages = {759-763},
doi = {10.1016/s0959-437x(05)80095-4},
pmid = {8274859},
issn = {0959-437X},
support = {GM49157/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; DNA Nucleotidylexotransferase/*metabolism ; Fungi/enzymology/genetics ; Humans ; *Telomere ; },
abstract = {The ends of eukaryotic chromosomes are defined by specialized nucleoprotein complexes called telomeres. Telomeres impart stability to the genome and are of general interest due to their unique structure and unconventional mode of synthesis. Recent work has identified new components of the telomere complex and expanded our understanding of the role of terminal structures in maintaining cell viability.},
}
@article {pmid8374954,
year = {1993},
author = {Fang, G and Cech, TR},
title = {The beta subunit of Oxytricha telomere-binding protein promotes G-quartet formation by telomeric DNA.},
journal = {Cell},
volume = {74},
number = {5},
pages = {875-885},
doi = {10.1016/0092-8674(93)90467-5},
pmid = {8374954},
issn = {0092-8674},
support = {GM28039/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA, Protozoan/chemistry/genetics/*metabolism ; DNA-Binding Proteins/*metabolism ; Hydrogen Bonding ; Macromolecular Substances ; Methylation ; Models, Structural ; Molecular Sequence Data ; Oligodeoxyribonucleotides/chemical synthesis/metabolism ; Oxytricha/genetics/*metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres, the ends of linear chromosomes, typically consist of tandem repeats of simple G-rich sequences. At high concentrations, single-stranded telomeric DNA can form dimers and tetramers involving G-quartets. We show that under physiological conditions, the beta subunit of the Oxytricha telomere-binding protein greatly accelerates G-quartet formation. The reaction occurs with oligonucleotides ending in the Oxytricha (T4G4T4G4) and Tetrahymena (T2G4T2G4) telomeric sequences; the sequence preceding these telomeric repeats can be nontelomeric, single-, or double-stranded. Protein deletion analysis indicates that the carboxy-terminal highly basic domain of the beta subunit, which is dispensible for telomeric complex formation, is sufficient for mediating G-quartet formation. The finding that a telomeric protein acts as a molecular chaperone for G-quartet formation provides a strong argument that such DNA structures exist in vivo at chromosome telomeres.},
}
@article {pmid7691159,
year = {1993},
author = {Crossen, PE and Tully, SM and Benjes, SM and Hollings, PE and Beard, ME and Nimmo, JC and Morrison, MJ},
title = {Oligoclonal B-cell leukemia characterized by spontaneous cell division and telomere association.},
journal = {Genes, chromosomes &amp; cancer},
volume = {8},
number = {1},
pages = {49-59},
doi = {10.1002/gcc.2870080109},
pmid = {7691159},
issn = {1045-2257},
mesh = {Cell Division ; Cells, Cultured ; Chromosomes, Human, Pair 15 ; Female ; Gene Rearrangement ; Genes, Immunoglobulin ; Humans ; Karyotyping ; Leukemia, Lymphocytic, Chronic, B-Cell/blood/*genetics/immunology/pathology ; Lymphocyte Activation ; Lymphocytes/immunology/pathology ; Middle Aged ; Polymorphism, Restriction Fragment Length ; Sex Chromosome Aberrations ; Telomere/*ultrastructure ; Translocation, Genetic ; X Chromosome ; },
abstract = {Cytogenetic analysis of unstimulated cultures from a female patient with chronic B-cell leukemia (CLL) revealed three cytogenetically distinct clones, suggesting that the patient's leukemia was oligoclonal. Immunoglobulin heavy chain gene rearrangement studies revealed 1 germline and 4 rearranged bands, indicative of an oligoclonal leukemic population. Further evidence of oligoclonality was provided by X-linked RFLP studies. This is the first report of oligoclonality in CLL demonstrated by cytogenetic, immunoglobulin gene rearrangement, and X-chromosome inactivation studies. In addition to oligoclonality, the patient's leukemic cells exhibited telomere association, a Robertsonian translocation, and clonal evolution, suggesting an underlying genomic instability.},
}
@article {pmid8357810,
year = {1993},
author = {Smith, FW and Feigon, J},
title = {Strand orientation in the DNA quadruplex formed from the Oxytricha telomere repeat oligonucleotide d(G4T4G4) in solution.},
journal = {Biochemistry},
volume = {32},
number = {33},
pages = {8682-8692},
doi = {10.1021/bi00084a040},
pmid = {8357810},
issn = {0006-2960},
support = {GM07185/GM/NIGMS NIH HHS/United States ; GM37524/GM/NIGMS NIH HHS/United States ; GM48123/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA, Protozoan/*chemistry ; Hydrogen ; Macromolecular Substances ; Magnetic Resonance Spectroscopy/methods ; Models, Structural ; Molecular Sequence Data ; *Nucleic Acid Conformation ; Oligodeoxyribonucleotides/*chemistry ; *Oxytricha ; Phosphorus ; Repetitive Sequences, Nucleic Acid ; Solutions ; Telomere/ultrastructure ; },
abstract = {The structure formed from the DNA oligonucleotide d(G4T4G4) (Oxy-1.5), which contains the Oxytricha telomere repeat T4G4, has been investigated by two-dimensional 1H and 31P NMR spectroscopy. Sequence-specific assignments have been obtained for the 1H and 31P resonances, using a combination of methods including comparisons to the inosine- and uracil-containing derivatives d(G4T4G3I) and d(G4UT3G4). The oligonucleotide forms a symmetrical bimolecular G-quadruplex with four G-quartets and thymine loops at opposite ends of the G-quartets. Guanines are alternatively syn and anti along each "strand" and all of the thymines are anti. The thymines loop diagonally across the G-quartet, resulting in a structure in which adjacent strands are alternately parallel and antiparallel and the glycosidic torsion angles are syn-syn-anti-anti around each G-quartet. There are three different types of grooves, a wide, a narrow, and two medium grooves. A diagonally looped quadruplex is formed in the presence of both Na+ and K+ counterions. The model structure of Oxy-1.5 is compared to the recently published crystal structure of Oxy-1.5 (Kang et al., 1992), which contains many of the same features as those found in solution but differs in that the thymines loop across an edge of the G-quartet.},
}
@article {pmid8102907,
year = {1993},
author = {Wu, KS and Tanksley, SD},
title = {Genetic and physical mapping of telomeres and macrosatellites of rice.},
journal = {Plant molecular biology},
volume = {22},
number = {5},
pages = {861-872},
pmid = {8102907},
issn = {0167-4412},
mesh = {Arabidopsis ; DNA, Satellite/*genetics ; Electrophoresis, Gel, Pulsed-Field ; Genetic Linkage ; Oryza/*genetics ; Polymorphism, Restriction Fragment Length ; Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; *Telomere ; },
abstract = {Telomeres and telomere-associated satellites of rice were genetically and physically analyzed by pulsed-field gel electrophoresis (PFGE) using Arabidopsis telomeric DNA and rice satellite sequences as probes. We demonstrate that Arabidopsis telomeric sequences hybridize to rice telomeres under the conditions of high stringency. Using the Arabidopsis probe, multiple, discrete telomeric fragments could be identified on pulsed-field gel blots of rice DNAs digested with rare-cutting restriction enzymes. Most of the telomeric bands larger than 300 kb are physically linked with satellite bands as revealed by PFGE. Some of the telomeric and satellite bands segregate in a Mendelian fashion and are highly reproducible. Three such telomeric bands have been mapped to the distal ends of RFLP linkage groups: Telsm-1 on chromosome 8, Telsa-1 on chromosome 9 and Telsm-3 on chromosome 11. One segregating satellite band was mapped to an internal region of chromosome 10. Telomeric fragments were shown not only to be genetically linked to but also physically linked (based on PFGE) to the terminal RFLP markers. The physical distance from telomeric sequences to a distal RFLP marker, r45s gene, on chromosome 9, is 200 kb while the distance from telomeric sequences to RG98, a terminal RFLP marker on chromosome 11, is 260 kb. Physical maps of the telomere regions of chromosome 9 and chromosome 11 are presented.},
}
@article {pmid8366614,
year = {1993},
author = {Ohmura, H and Oshimura, M},
title = {[Telomere, cellular senescence and transformation].},
journal = {Nihon rinsho. Japanese journal of clinical medicine},
volume = {51},
number = {7},
pages = {1899-1906},
pmid = {8366614},
issn = {0047-1852},
mesh = {Aging ; Animals ; Cell Transformation, Neoplastic/*genetics ; Cellular Senescence/*physiology ; DNA Nucleotidylexotransferase/physiology ; Humans ; Telomere/*physiology ; },
abstract = {Telomere is the structure which is located on both ends of individual chromosomes in eukaryotes. The DNA sequence of the telomere consists of Guanine-rich tandem repeat, i.e., (TTAGGG)n in man. Telomere protects the end of the chromosome from fusion or deletion and maintains the stability of the chromosome and is synthesized by telomerase, a ribonucleoprotein. Telomere reduction is observed with cell senescence and immortalization, both in vivo and in vitro. Thus, telomere is considered to be a "clock" which measures the life span of cells, and its length is altered by cellular senescence and immortalization.},
}
@article {pmid8358433,
year = {1993},
author = {Meltzer, PS and Guan, XY and Trent, JM},
title = {Telomere capture stabilizes chromosome breakage.},
journal = {Nature genetics},
volume = {4},
number = {3},
pages = {252-255},
doi = {10.1038/ng0793-252},
pmid = {8358433},
issn = {1061-4036},
support = {R37 CA-29476/CA/NCI NIH HHS/United States ; },
mesh = {*Chromosome Deletion ; Chromosomes, Human, Pair 6 ; Humans ; Hybrid Cells/ultrastructure ; In Situ Hybridization, Fluorescence ; Melanoma/genetics/ultrastructure ; Models, Genetic ; Telomere/*ultrastructure ; Translocation, Genetic ; },
abstract = {Terminal deletions are found frequently in both malignancies and clinically recognizable deletion syndromes in man. Little is known, particularly in cancer, of the specific mechanisms which lead to the generation of deleted chromosomes or the process by which these broken chromosomes are stabilized. We demonstrate that several examples of apparent terminal deletions are, in fact, subtelomeric translocations which were not detectable using conventional cytogenetics. The unexpectedly high frequency of this phenomenon and the diversity of partner chromosomes involved in the subtelomeric translocations is consistent with a model in which telomere capture can stabilize chromosome breakage in man.},
}
@article {pmid8327484,
year = {1993},
author = {Fang, G and Cech, TR},
title = {Oxytricha telomere-binding protein: DNA-dependent dimerization of the alpha and beta subunits.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {90},
number = {13},
pages = {6056-6060},
pmid = {8327484},
issn = {0027-8424},
support = {GM28039/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA, Protozoan/*metabolism ; DNA-Binding Proteins/*chemistry/metabolism ; Molecular Sequence Data ; Oligodeoxyribonucleotides/metabolism ; Oxytricha/*chemistry/metabolism ; Protozoan Proteins/*chemistry/metabolism ; Recombinant Fusion Proteins/chemistry/metabolism ; Telomere/*metabolism ; },
abstract = {A telomere-binding protein consisting of 56-kDa (alpha) and 41-kDa (beta) subunits binds specifically to the single-stranded T4G4T4G4 sequence at the termini of macronuclear DNA molecules in Oxytricha nova. The recent availability of separate alpha and beta polypeptides, expressed in Escherichia coli, allows investigation of the assembly of the telomeric complex ("telosome") from its individual components. By mixing wild-type subunits and electrophoretically distinct variants, we verify that the telosome contains one alpha and one beta subunit. By using telomeric DNAs of two lengths, we find that there is one DNA molecule per telosome. The DNA-protein and subunit-subunit interactions were studied by glycerol gradient sedimentation and chemical cross-linking. The formation of alpha-DNA and beta-DNA cross-links in the telomeric complex indicates that both subunits are in proximity to the DNA. When incubated together, both subunits exist predominantly as monomers in the absence of telomeric DNA. Upon binding to DNA, alpha and beta subunits directly interact with each other to form a heterodimer. We suggest that this DNA-dependent dimerization may allow each subunit to carry out distinct functions as a monomer, in addition to its participation in chromosome capping as part of the heterodimer.},
}
@article {pmid8319907,
year = {1993},
author = {Kyrion, G and Liu, K and Liu, C and Lustig, AJ},
title = {RAP1 and telomere structure regulate telomere position effects in Saccharomyces cerevisiae.},
journal = {Genes &amp; development},
volume = {7},
number = {7A},
pages = {1146-1159},
doi = {10.1101/gad.7.7a.1146},
pmid = {8319907},
issn = {0890-9369},
support = {NCI-P30-CA-08748/CA/NCI NIH HHS/United States ; },
mesh = {Chromatin/chemistry ; *Chromosomes, Fungal ; DNA, Fungal/chemistry ; DNA-Binding Proteins/genetics/metabolism ; Down-Regulation ; Escherichia coli/enzymology ; Escherichia coli Proteins ; Fungal Proteins/*genetics/metabolism ; GTP-Binding Proteins/*genetics/physiology ; *Gene Expression Regulation, Fungal ; Genes, Fungal/*genetics ; Methyltransferases/metabolism ; Repressor Proteins/genetics/*metabolism ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; Sequence Deletion ; *Site-Specific DNA-Methyltransferase (Adenine-Specific) ; Suppression, Genetic ; Telomere/*chemistry ; *Telomere-Binding Proteins ; Transcription, Genetic ; rap GTP-Binding Proteins ; },
abstract = {To investigate the role of the yeast telomere-, silencing-, and UAS-binding protein RAP1 in telomere position effects, we have characterized two sets of mutant cells: (1) a set of rap1 alleles (termed the rap1t alleles) that produce truncated RAP1 proteins missing the carboxy-terminal 144-165 amino acids; and (2) null mutants of the RIF1 gene, encoding a protein capable of interaction with the carboxyl terminus of RAP1. The data presented here indicate that loss of the carboxyl terminus of RAP1 abolishes position effects at yeast telomeres and diminishes silencing at the HML locus. Elimination of position effects in these cells is associated with increased accessibility to the Escherichia coli dam methylase in vivo. Thus, the carboxy-terminal domain of RAP1 is required for telomere position effects. In contrast, rif1 deletion alleles increase the frequency of repressed cells. Using the rap1t alleles to generate wild-type cells differing only in telomere tract lengths, we also show that telomere position effects are highly sensitive to changes in the size (or structure) of the telomeric tract. Longer poly(G1-3T) tracts can increase the frequency of transcriptional repression at the telomere, suggesting that telomeric poly(G1-3T) tracts play an active role in the formation or stability of subtelomeric transcriptional states.},
}
@article {pmid8319906,
year = {1993},
author = {Renauld, H and Aparicio, OM and Zierath, PD and Billington, BL and Chhablani, SK and Gottschling, DE},
title = {Silent domains are assembled continuously from the telomere and are defined by promoter distance and strength, and by SIR3 dosage.},
journal = {Genes &amp; development},
volume = {7},
number = {7A},
pages = {1133-1145},
doi = {10.1101/gad.7.7a.1133},
pmid = {8319906},
issn = {0890-9369},
support = {GM43893/GM/NIGMS NIH HHS/United States ; },
mesh = {*Chromosomes, Fungal ; DNA-Binding Proteins ; Down-Regulation ; Fungal Proteins/genetics ; *Gene Expression Regulation, Fungal ; Genes, Fungal/*genetics ; Heterochromatin ; Histones/genetics ; Multigene Family ; Promoter Regions, Genetic ; Repressor Proteins/genetics/*metabolism ; Restriction Mapping ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; *Telomere ; Trans-Activators ; Transcription Factors ; Transcription, Genetic ; Transcriptional Activation ; },
abstract = {In Saccharomyces cerevisiae, telomeres repress transcription of genes located nearby. This region-specific gene inactivation is thought to involve the packaging of telomeric domains into silent chromatin. To gain insight into the mechanism of telomeric silencing, a genetic assay to examine the spread of silencing along the distal right arm of chromosome V was developed. The frequency of silencing a telomere-adjacent URA3 gene decreased with increasing distance of the gene's promoter from the telomere, irrespective of transcriptional orientation. The distance over which telomeric silencing of URA3 was observed was extended by weakening the gene's promoter--specifically, by deleting PPR1, the trans-activator of URA3. The silent telomeric domain was extended even farther by increasing the gene dosage of SIR3. These results suggest that a gene's promoter is a key determinant in controlling silencing on that gene and that SIR3 is a crucial component of the silent chromatin domain that initiates at the telomere and is assembled inwardly along the yeast chromosome. Finally, silencing is not observed on the centromeric side of an actively transcribed telomeric gene, demonstrating that the repressed telomeric domain is propagated continuously along the DNA. Taken together, these data reflect the complex and dynamic organization of eukaryotic genomes into functionally distinct regions.},
}
@article {pmid8388878,
year = {1993},
author = {Funabiki, H and Hagan, I and Uzawa, S and Yanagida, M},
title = {Cell cycle-dependent specific positioning and clustering of centromeres and telomeres in fission yeast.},
journal = {The Journal of cell biology},
volume = {121},
number = {5},
pages = {961-976},
pmid = {8388878},
issn = {0021-9525},
mesh = {*Cell Cycle ; Cell Nucleus/*ultrastructure ; Centromere/*ultrastructure ; DNA Topoisomerases, Type II/physiology ; Fluorescent Antibody Technique ; In Situ Hybridization ; Interphase ; Mitosis ; Schizosaccharomyces/*ultrastructure ; Spindle Apparatus/ultrastructure ; Telomere/*ultrastructure ; },
abstract = {Fluorescence in situ hybridization (FISH) shows that fission yeast centromeres and telomeres make up specific spatial arrangements in the nucleus. Their positioning and clustering are cell cycle regulated. In G2, centromeres cluster adjacent to the spindle pole body (SPB), while in mitosis, their association with each other and with the SPB is disrupted. Similarly, telomeres cluster at the nuclear periphery in G2 and their associations are disrupted in mitosis. Mitotic centromeres interact with the spindle. They remain undivided until the spindle reaches a critical length, then separate and move towards the poles. This demonstrated, for the first time, that anaphase A occurs in fission yeast. The mode of anaphase A and B is similar to that of higher eukaryotes. In nda3 and cut7 mutants defective in tubulin of a kinesin-related motor, cells are blocked in early stages of mitosis due to the absence of the spindle, and centromeres dissociate but remain close to the SPB, whereas in a metaphase-arrested nuc2 mutant, they reside at the middle of the spindle. FISH is therefore a powerful tool for analyzing mitotic chromosome movement and disjunction using various mutants. Surprisingly, in top2 defective in DNA topoisomerase II, while most chromatid DNAs remain undivided, sister centromeres are separated. Significance of this finding is discussed. In contrast, most chromatid DNAs are separated but telomeric DNAs are not in cut1 mutant. In cut1, the dependence of SPB duplication on the completion of mitosis is abolished. In crm1 mutant cells defective in higher-order chromosome organization, the interphase arrangements of centromeres and telomeres are disrupted.},
}
@article {pmid8348122,
year = {1993},
author = {Weber, S and Schmid, M and Meyer, J and Cooke, HJ and Lipps, HJ},
title = {A linear vector carrying human telomeres is replicated in unfertilized eggs of Xenopus laevis.},
journal = {Cell biology international},
volume = {17},
number = {6},
pages = {623-624},
doi = {10.1006/cbir.1993.1109},
pmid = {8348122},
issn = {1065-6995},
mesh = {Animals ; Blotting, Southern ; DNA/isolation &amp; purification/metabolism ; *DNA Replication ; Female ; *Genetic Vectors ; Humans ; Oocytes/*physiology ; Restriction Mapping ; Telomere/*physiology ; Tetrahymena thermophila/genetics ; Transfection ; Xenopus laevis ; },
}
@article {pmid8500170,
year = {1993},
author = {Makarov, VL and Lejnine, S and Bedoyan, J and Langmore, JP},
title = {Nucleosomal organization of telomere-specific chromatin in rat.},
journal = {Cell},
volume = {73},
number = {4},
pages = {775-787},
doi = {10.1016/0092-8674(93)90256-p},
pmid = {8500170},
issn = {0092-8674},
support = {5T32GM07315/GM/NIGMS NIH HHS/United States ; GM44403/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Centrifugation, Density Gradient ; Deoxyribonuclease I ; Endodeoxyribonucleases ; Female ; Histones ; Male ; Micrococcal Nuclease ; Nucleosomes/*chemistry ; Rats ; Rats, Sprague-Dawley ; Telomere/*chemistry ; },
abstract = {Rat liver interphase chromosomes have telomeres 20-100 kb in length. Micrococcal nuclease digestion of nuclei cleaves telomeres with a uniform 157 bp periodicity, producing soluble particles that sediment in sucrose gradients exactly like oligonucleosomes. The monomeric telomere particles comigrate with nucleosome core particles on nucleoprotein and DNA gels but do not bind H1. DNAase I cleaves telomere nucleoprotein into a series of bands spaced by about 10.4 bp and with the same intensity distribution as bands from bulk nucleosomes. Removal of H1 from chromatin alters the sedimentation properties of telomeres in parallel with bulk chromatin. Thus, telomeres of mammals are constructed of closely spaced nucleosomes, in contrast with the telomeres of lower eukaryotes, which show no evidence of nucleosomal structure.},
}
@article {pmid8491383,
year = {1993},
author = {Fang, G and Gray, JT and Cech, TR},
title = {Oxytricha telomere-binding protein: separable DNA-binding and dimerization domains of the alpha-subunit.},
journal = {Genes &amp; development},
volume = {7},
number = {5},
pages = {870-882},
doi = {10.1101/gad.7.5.870},
pmid = {8491383},
issn = {0890-9369},
support = {GM28039/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA Probes ; DNA, Protozoan/*metabolism ; DNA-Binding Proteins/chemistry/metabolism/*physiology ; Electrophoresis, Polyacrylamide Gel ; Escherichia coli ; Gene Expression Regulation ; Gene Library ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Oligonucleotide Probes ; Oxytricha/*genetics ; Plasmids ; Protozoan Proteins/chemistry/*metabolism ; Recombinant Proteins ; Sequence Homology, Nucleic Acid ; Time Factors ; Transcription, Genetic/*physiology ; },
abstract = {A telomere-binding protein heterodimer of 56-kD (alpha) and 41-kD (beta) subunits binds to the single-stranded (T4G4)2 terminus of each Oxytricha nova macronuclear DNA molecule. The alpha-subunit by itself binds to telomeric DNA. The beta-subunit alone does not bind to DNA specifically but interacts with the alpha-subunit to form a very stable ternary complex. We show that the formation of alpha-beta-DNA ternary complex is extremely cooperative. Furthermore, the binary complex (alpha-DNA) has a dissociation half-life of much less than 1 min; addition of the beta-subunit increases the half-life to approximately 100 hrs. Libraries of plasmids with random deletions of the open reading frame for the alpha-subunit were introduced into Escherichia coli, and extracts were subsequently checked for both protein expression and DNA-binding activity with or without added beta-subunit. The alpha-subunit was found to contain two structurally separable domains with distinct functions. The amino-terminal two-thirds is necessary and sufficient for sequence-specific DNA binding. The carboxy-terminal one-third is responsible for alpha/beta-subunit interactions. When expressed separately in E. coli, purified, and mixed together, these two domains reconstitute the activity of the wild-type alpha-subunit (trans-complementation in vitro). The amino-terminal two-thirds of the beta-subunit is necessary and sufficient both for alpha/beta-subunit interactions and for ternary complex formation. We conclude that the alpha-subunit of the telomere-binding protein, like many transcription factors, has separable DNA-binding and protein-protein interaction domains.},
}
@article {pmid8314589,
year = {1993},
author = {Weichhold, GM and Huber, C and Parnes, JR and Zachau, HG},
title = {The CD8 alpha locus is located on the telomere side of the immunoglobulin kappa locus at a distance of 2 Mb.},
journal = {Genomics},
volume = {16},
number = {2},
pages = {512-514},
doi = {10.1006/geno.1993.1218},
pmid = {8314589},
issn = {0888-7543},
support = {GM34991/GM/NIGMS NIH HHS/United States ; },
mesh = {CD8 Antigens/*genetics ; Cell Line ; Chromosome Mapping ; *Chromosomes, Human, Pair 2 ; Deoxyribonucleases, Type II Site-Specific ; Electrophoresis, Gel, Pulsed-Field ; *Genes ; *Genes, Immunoglobulin ; Humans ; Immunoglobulin kappa-Chains/*genetics ; Lymphocytes ; Tumor Cells, Cultured ; },
abstract = {The immunoglobulin kappa and CD8 alpha loci had been mapped by in situ hybridization to the short arm of chromosome 2 at 2cen-p11.2 and 2p1, respectively, but probes derived from the two loci did not hybridize to the same large PFGE fragments. We have now succeeded in linking the two loci on a 3.0-Mb fragment from a partial NruI digest. A new hybridization probe located between the two loci provided additional linking fragments and allowed the distance to be determined as 2.0-2.2 Mb.},
}
@article {pmid8143087,
year = {1993},
author = {Steinmüller, J and Schleiermacher, E and Scherthan, H},
title = {Direct detection of repetitive, whole chromosome paint and telomere DNA probes by immunogold electron microscopy.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {1},
number = {1},
pages = {45-51},
pmid = {8143087},
issn = {0967-3849},
mesh = {Base Sequence ; Chromosomes, Human/*ultrastructure ; DNA Probes ; Humans ; In Situ Hybridization ; Interphase ; Lymphocytes/cytology/*ultrastructure ; Microscopy, Immunoelectron ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; Telomere/ultrastructure ; },
abstract = {Biotinylated repetitive, whole chromosome paint and telomere DNA probes were investigated at the electron microscope level after non-isotopic in situ hybridization and direct immunogold detection. The protocol described allowed the visualization of a biotinylated chromosome 1 specific satellite DNA probe in the light microscope without silver intensification. This sensitive method was exploited to analyse factors contributing to signal strength in immunogold chromosome painting. Furthermore, it allowed us to investigate the distribution of (TTAGGG)n telomere repeats in human metaphase chromosomes and interphase nuclei. Telomeric and internal (TTAGGG)n repeats were detected at high spatial resolution in human metaphase chromosomes. In the periphery of lymphocyte interphase nuclei, two types of telomere hybridization signals were observed. They differed remarkably in compactness, indicating two types of chromatin conformation present at the interphase telomeres in situ.},
}
@article {pmid8477448,
year = {1993},
author = {Lundblad, V and Blackburn, EH},
title = {An alternative pathway for yeast telomere maintenance rescues est1- senescence.},
journal = {Cell},
volume = {73},
number = {2},
pages = {347-360},
doi = {10.1016/0092-8674(93)90234-h},
pmid = {8477448},
issn = {0092-8674},
support = {GM26259/GM/NIGMS NIH HHS/United States ; GM32565/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Cloning, Molecular ; *DNA Replication ; DNA, Fungal/genetics ; Fungal Proteins/*genetics ; *Genes, Fungal ; Molecular Sequence Data ; Oligodeoxyribonucleotides/chemistry ; Recombination, Genetic ; Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; Saccharomyces cerevisiae/*genetics ; *Telomere ; },
abstract = {Yeast cells lacking a functional EST1 gene show progressive shortening of the terminal G1-3T telomeric repeats and a parallel increase in the frequency of cell death. Although the majority of the cells in an est1- culture die, a minor subpopulation survives the potentially lethal consequences of the est1 mutation. We show that these est1- survivors arise as a result of the amplification and acquisition of subtelomeric elements (and their deletion derivatives) by a large number of telomeres. Hence, even when the primary pathway for telomere replication is defective, an alternative backup pathway can restore telomere function and keep the cell alive.},
}
@article {pmid8475094,
year = {1993},
author = {Vickers, MA and Vyas, P and Harris, PC and Simmons, DL and Higgs, DR},
title = {Structure of the human 3-methyladenine DNA glycosylase gene and localization close to the 16p telomere.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {90},
number = {8},
pages = {3437-3441},
pmid = {8475094},
issn = {0027-8424},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {Amino Acid Sequence ; Base Sequence ; Cell Line ; Chromosome Mapping ; *Chromosomes, Human, Pair 16 ; *DNA Glycosylases ; DNA Repair ; Exons ; Globins/genetics ; Humans ; Introns ; Molecular Sequence Data ; Multigene Family ; N-Glycosyl Hydrolases/*genetics ; Restriction Mapping ; *Telomere ; },
abstract = {We recently reported the presence of four genes lying between the human alpha-globin gene cluster and the telomere of the short arm of chromosome 16 (16p). We now report that one of these genes encodes 3-methyladenine DNA glycosylase, an enzyme important in the repair of DNA after damage by alkylating agents. The gene comprises five exons, representation of which differs in independently isolated cDNA clones. Although the gene is widely expressed, the abundance of its mRNA is considerably higher in a colon adenocarcinoma cell line (HT29) than in other cell lines that were tested. The major positive erythroid-specific regulatory element controlling alpha-globin gene expression lies equidistant between the promoters of the alpha-globin genes and the 3-methyladenine DNA glycosylase gene. Interestingly, in contrast to the alpha-globin genes, expression of the 3-methyladenine DNA glycosylase gene is not influenced by the regulatory element in the human erythroleukemia cell line K562.},
}
@article {pmid8514152,
year = {1993},
author = {Kolchinsky, A and Gresshoff, PM},
title = {Direct end labelling of telomeres.},
journal = {Genome},
volume = {36},
number = {2},
pages = {224-229},
doi = {10.1139/g93-031},
pmid = {8514152},
issn = {0831-2796},
mesh = {Arabidopsis/genetics ; Base Sequence ; Chromosomes, Fungal ; DNA, Single-Stranded ; DNA-Directed DNA Polymerase/metabolism ; Deoxyribonucleases, Type II Site-Specific ; *Genetic Techniques ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Polymerase Chain Reaction ; Saccharomyces cerevisiae/genetics ; Glycine max/genetics ; *Telomere ; },
abstract = {A novel approach of direct end labelling of telomeres is presented. Chromosome-sized, agarose-embedded DNA was treated with T4 DNA polymerase to remove protruding 3' end of telomeres and to generate single-stranded 5' ends. The DNA was then labelled by the same enzyme in the presence of [alpha-32P]dGTP and cold dATP and dTTP. Labelled yeast chromosomes separated by pulsed field gel electrophoresis maintained their integrity. Digestion of yeast chromosomes separated in pulsed field gels with a restriction nuclease (HinfI), followed by conventional electrophoresis in the second dimension, resulted in a fingerprint-like pattern of labelled telomeres. This was very similar to the hybridization pattern of a similar two-dimensional gel probed with cloned yeast telomeric sequence. The same approach enabled us to label telomeres in soybean, determine their size, and to reveal polymorphisms in the length of telomeres between the closely related subspecies Glycine max (soybean) and Glycine soja.},
}
@article {pmid8494996,
year = {1993},
author = {Yamada, O and Oshimi, K and Mizoguchi, H},
title = {Telomere reduction in hematologic cells.},
journal = {International journal of hematology},
volume = {57},
number = {2},
pages = {181-186},
pmid = {8494996},
issn = {0925-5710},
mesh = {Adult ; Base Sequence ; Humans ; Leukemia/genetics ; Leukocytes, Mononuclear/*chemistry ; Male ; Middle Aged ; *Sequence Deletion ; Telomere/*chemistry ; Tumor Cells, Cultured ; },
abstract = {The broken ends of chromosomes are unstable, and tandem fusion of telomeres has been observed in some tumors. Using Southern blot analysis, we report here telomeric DNA changes in hematologic cells. There was some variation in the length of the telomeric DNA in normal peripheral blood mononuclear cells obtained from four different individuals, ranging from 10 to 12 kilobases (kb), but there was little difference in signal strength. In two cell lines tested, HL-60 and K562, there was a telomeric sequence reduction of 2-4 kb and there was also a diminution of signal intensity. Reduction of the telomeric DNA array was also observed in two leukemic cases tested. The peak telomere length of the leukemic cells was 5 and 4 kb before and 10 and 7 kb after treatment, respectively, and in one case there was also a reduction in copy numbers of about 50%. Since no remarkable changes were detected in the Alu and alphoid sequences in either normal or leukemic cells, it appeared that the DNA change was specific to telomeric regions. Assessment of telomeric DNA changes may aid in determining the biological significance of leukemic cells.},
}
@article {pmid8479435,
year = {1993},
author = {Röder, MS and Lapitan, NL and Sorrells, ME and Tanksley, SD},
title = {Genetic and physical mapping of barley telomeres.},
journal = {Molecular &amp; general genetics : MGG},
volume = {238},
number = {1-2},
pages = {294-303},
pmid = {8479435},
issn = {0026-8925},
mesh = {Alleles ; Arabidopsis/genetics ; *Chromosome Mapping ; Cloning, Molecular ; DNA/*genetics/isolation &amp; purification ; DNA, Satellite/genetics ; Electrophoresis ; Hordeum/*genetics ; In Situ Hybridization ; Molecular Weight ; Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; *Telomere/ultrastructure ; },
abstract = {Barley (Hordeum vulgare L.) telomeres were investigated by means of pulsed field gel electrophoresis (PFGE) and in situ hybridization. In situ hybridization showed that a tandemly repeated satellite sequence has a subtelomeric location, and is present at thirteen of the fourteen chromosome ends. PFGE revealed that this satellite sequence is physically close to the telomeric repeat. Pulsed field gel electrophoresis was then used for segregation analysis and linkage mapping of several telomeric and satellite loci in a segregating doubled-haploid population. The telomeric repeat displayed a hypervariable segregation pattern with new alleles occurring in the progeny. Eight satellite and telomeric sites were mapped on an restriction fragment length polymorphism (RFLP)-map of barley, defining the ends of chromosome arms 1L, 2S, 3L, 4S, 4L, 5S and 6. One satellite locus mapped to an interstitial site on the long arm of chromosome 3. The physical location of this locus was confirmed by in situ hybridization to wheat/barley addition line 3.},
}
@article {pmid8460631,
year = {1993},
author = {Broccoli, D and Cooke, H},
title = {Aging, healing, and the metabolism of telomeres.},
journal = {American journal of human genetics},
volume = {52},
number = {4},
pages = {657-660},
pmid = {8460631},
issn = {0002-9297},
mesh = {Animals ; Apoptosis ; Cellular Senescence/*genetics ; Chromosome Aberrations ; DNA Nucleotidylexotransferase/metabolism ; DNA Repair ; DNA Replication ; Humans ; Repetitive Sequences, Nucleic Acid ; *Sequence Deletion ; Telomere/*metabolism ; },
}
@article {pmid8354521,
year = {1993},
author = {Price, CM},
title = {Telomere structure and function.},
journal = {Indian journal of biochemistry &amp; biophysics},
volume = {30},
number = {2},
pages = {77-82},
pmid = {8354521},
issn = {0301-1208},
mesh = {Animals ; Base Sequence ; DNA/genetics/ultrastructure ; DNA-Binding Proteins/physiology ; GTP-Binding Proteins/physiology ; Humans ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; Telomere/*physiology/*ultrastructure ; rap GTP-Binding Proteins ; },
}
@article {pmid8462979,
year = {1993},
author = {Nürnberg, P and Thiel, G and Weber, F and Epplen, JT},
title = {Changes of telomere lengths in human intracranial tumours.},
journal = {Human genetics},
volume = {91},
number = {2},
pages = {190-192},
pmid = {8462979},
issn = {0340-6717},
mesh = {Adolescent ; Adult ; Aged ; Brain Neoplasms/*genetics ; Child ; Child, Preschool ; DNA, Neoplasm/analysis ; Glioma/*genetics ; Humans ; Middle Aged ; Repetitive Sequences, Nucleic Acid ; *Telomere ; },
abstract = {The termini of human chromosomes comprise stretches of G-rich repeats that are about 5-20 kilobase (kb) in length. The size of the telomeres can be determined by hybridization with probes specific for these (ttaggg)n sequences after digestion of chromosomal DNA with appropriate restriction enzymes and electrophoretic separation of the fragments. Here, probing with the 32P-labelled synthetic (TTAGGG)3 oligonucleotide revealed length changes of the telomeres occurring in intracranial tumours. Among 60 samples, analysed, 41.7% showed telomere elongation, and 21.7% telomere reduction, whereas 36.7% of the tumours exhibited equal lengths compared with the patients' peripheral blood leukocytes. Most of the elongated glioma telomeres exceeded in length those of untransformed astrocytes derived from human fetal tissue.},
}
@article {pmid8453988,
year = {1993},
author = {Vourc'h, C and Taruscio, D and Boyle, AL and Ward, DC},
title = {Cell cycle-dependent distribution of telomeres, centromeres, and chromosome-specific subsatellite domains in the interphase nucleus of mouse lymphocytes.},
journal = {Experimental cell research},
volume = {205},
number = {1},
pages = {142-151},
doi = {10.1006/excr.1993.1068},
pmid = {8453988},
issn = {0014-4827},
support = {CA-16359/CA/NCI NIH HHS/United States ; GM-40115/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Nucleus/*metabolism ; Centromere/*metabolism ; Chromatin/metabolism ; DNA, Satellite/*metabolism ; *Interphase ; Mice ; Mice, Inbred Strains ; T-Lymphocytes/metabolism ; Telomere/*metabolism ; },
abstract = {Fluorescence in situ hybridization and 3-D image analysis were combined to study the distribution of specific chromosome subdomains through the course of the cell cycle in cultured mouse lymphocytes. DNA probes specific for major satellite DNA, minor satellite DNA, telomeric DNA and to chromosome X-, 8-, and 14-specific subsatellite DNA sequences were used. We demonstrate that a redistribution of the chromatin occurs during the cell cycle in the interphase nucleus, and that the profile of the rearrangement is highly dependent on the nature of the domain considered (centromeres, telomeres, or subsatellite regions). However, the relative arrangement of chromosome homologs to each other does not appear to be spatially defined or regulated.},
}
@article {pmid8441399,
year = {1993},
author = {Nielsen, L and Edström, JE},
title = {Complex telomere-associated repeat units in members of the genus Chironomus evolve from sequences similar to simple telomeric repeats.},
journal = {Molecular and cellular biology},
volume = {13},
number = {3},
pages = {1583-1589},
pmid = {8441399},
issn = {0270-7306},
mesh = {Animals ; Base Composition ; Base Sequence ; *Biological Evolution ; Chironomidae/*genetics ; Cloning, Molecular ; Consensus Sequence ; Diptera/genetics ; Genome ; Models, Genetic ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid/*genetics ; *Telomere ; },
abstract = {The dipteran Chironomus tentans has complex tandemly repeated 350-bp DNA sequences at or near the chromosome ends. As in Drosophila melanogaster, short simple repeats with cytosines and guanines in different strands have never been observed. We were therefore interested in learning whether the Chironomus repeats could have evolved from simple sequence telomeric DNA, which might suggest that they constitute a functional equivalent. We screened for repeat units with evolutionarily ancient features within the tandem arrays and recovered two clones with a less-evolved structure. Sequence analysis reveals that the present-day 350-bp unit probably evolved from a simpler 165-bp unit through the acquisition of transposed sequences. The 165-bp unit contains DNA with a highly biased distribution of cytosine and guanine between the two strands, although with the ratios inverted in two minor parts of the repeat. It is largely built up of short degenerate subrepeats for which most of the sequence can be reconstructed. The consensus for the subrepeat sequence is similar to the simple telomeric repeat sequences of several kinds of eukaryotes. We propose that the present-day unit has evolved from telomeric, simple sequence, asymmetric DNA from which it has retained some original sequence features and possibly functions.},
}
@article {pmid8387849,
year = {1993},
author = {Shervington, A},
title = {T2G4 telomere repeats does not provide telomere function to a BPV-1 containing DNA fragment in mouse C127 cells.},
journal = {Biochemistry and molecular biology international},
volume = {29},
number = {4},
pages = {661-672},
pmid = {8387849},
issn = {1039-9712},
mesh = {Animals ; Blotting, Southern ; Bovine papillomavirus 1/chemistry/*genetics ; Cell Line ; DNA/chemistry/*genetics ; DNA Replication ; DNA, Viral/genetics ; Genetic Vectors ; Mice ; *Plasmids ; *Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/chemistry/*genetics ; Telomere/chemistry/*physiology ; Transfection ; },
abstract = {The ability of the (T2G4)n telomeric repeats to maintain a linear structure in an extrachromosomal replicating plasmid in mouse C127 cells was tested in a vector based on Bovine papillomavirus type-1, ARS, HIS3 and the neo genes. Digestion with BamHI releases a BPV-1 containing fragment with a (T2G4)n repeats at each end which was introduced to yeast and microinjected into mouse C127 cells. While the linear construct was maintained as extrachromosomal structure in yeast cells, none of the resulting G418-resistant mouse cells transformants were found to have extrachromosomally replicating linear plasmids. Analysis of transformed mouse C127 DNA suggested that in some, the linear fragment had integrated into mouse chromosomes, whereas in other cell lines the fragment may have circularised and possibly been replicating extrachromosomally as a high molecular weight structure. In some of the mouse transformants the (T2G4)n repeats had been deleted from retained plasmid sequences.},
}
@article {pmid8434000,
year = {1993},
author = {Silver, A and Cox, R},
title = {Telomere-like DNA polymorphisms associated with genetic predisposition to acute myeloid leukemia in irradiated CBA mice.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {90},
number = {4},
pages = {1407-1410},
pmid = {8434000},
issn = {0027-8424},
mesh = {Acute Disease ; Animals ; Base Sequence ; Brain/physiology/physiopathology ; Chromosome Mapping ; Crosses, Genetic ; DNA/*genetics/isolation &amp; purification ; DNA, Neoplasm/genetics/isolation &amp; purification ; Female ; Leukemia, Myeloid/*genetics ; Leukemia, Radiation-Induced/*genetics ; Male ; Mice ; Mice, Inbred CBA ; Molecular Sequence Data ; *Polymorphism, Genetic ; Restriction Mapping ; Spleen/physiology/physiopathology ; Telomere/*physiology ; },
abstract = {There is evidence that interstitial telomere (TTAGGG)n-like sequences at chromosome 2 fragile sites play an important role in the somatic events that characterize the earliest phases of radiation-induced acute myeloid leukemia in the CBA/H mouse. Here we show that the highly inbred CBA/H colony unexpectedly contains four genotypic variants for telomere-like sequence arrays and that almost all induced myeloid leukemias derive from one of the variant subpopulations that constitutes approximately 20% of the colony. Preliminary evidence on the irregular inheritance patterns for these variant sequences is discussed together with the proposal that one form of these telomere sequence arrays either represents or is closely linked to a locus that influences chromosome 2 breakage patterns in hemopoietic cells following irradiation and, through this, susceptibility to induced myeloid leukemia.},
}
@article {pmid8436267,
year = {1993},
author = {Longtine, MS and Enomoto, S and Finstad, SL and Berman, J},
title = {Telomere-mediated plasmid segregation in Saccharomyces cerevisiae involves gene products required for transcriptional repression at silencers and telomeres.},
journal = {Genetics},
volume = {133},
number = {2},
pages = {171-182},
pmid = {8436267},
issn = {0016-6731},
support = {GM07323/GM/NIGMS NIH HHS/United States ; GM38626/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatin/ultrastructure ; Fungal Proteins/metabolism ; *Gene Expression Regulation, Fungal ; Genes, Fungal ; Genetic Complementation Test ; Histones/physiology ; *Plasmids ; Saccharomyces cerevisiae/*genetics ; Telomere/*physiology ; *Transcription, Genetic ; },
abstract = {Plasmids that contain Saccharomyces cerevisiae TG1-3 telomere repeat sequences (TRS plasmids) segregate efficiently during mitosis. Mutations in histone H4 reduce the efficiency of TRS-mediated plasmid segregation, suggesting that chromatin structure is involved in this process. Sir2, Sir3 and Sir4 are required for the transcriptional repression of genes located at the silent mating type loci (HML and HMR) and at telomeres (telomere position effect) and are also involved in the segregation of TRS plasmids, indicating that TRS-mediated plasmid segregation involves factors that act at chromosomal telomeres. TRS plasmid segregation differes from the segregation of plasmids carrying the HMR E silencing region: HMR E plasmid segregation function is completely dependent upon Sir2, Sir3 and Sir4, involves Sir1 and is not influenced by mutations in RAP 1 that eliminate TRS plasmid segregation. Mutations in SIR1, SIN1, TOP1, TEL1 and TEL2 do not influence TRS plasmid segregation. Unlike transcriptional repression at telomeres, TRS plasmids retain partial segregation function in sir2, sir3, sir4, nat1 and ard1 mutant strains. Thus it is likely that TRS plasmid segregation involves additional factors that are not involved in telomere position effect.},
}
@article {pmid8423817,
year = {1993},
author = {Murnane, JP and Yu, LC},
title = {Acquisition of telomere repeat sequences by transfected DNA integrated at the site of a chromosome break.},
journal = {Molecular and cellular biology},
volume = {13},
number = {2},
pages = {977-983},
pmid = {8423817},
issn = {0270-7306},
mesh = {Animals ; Base Sequence ; Blotting, Southern ; Cell Line ; Chromosomes ; Cloning, Molecular ; DNA ; Humans ; Mice ; Molecular Sequence Data ; Plasmids ; *Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; *Telomere ; *Transfection ; },
abstract = {Previous analysis of plasmid DNA transfected into 108 cell clones demonstrated extensive polymorphism near the integration site in one clone. This polymorphism was apparent by Southern blot analysis as diffuse bands that extended over 30 kb. In the present study, nucleotide sequence analysis of cloned DNA from the integration site revealed telomere repeat sequences at the ends of the integrated plasmid DNA. The telomere repeat sequences at one end were located at the junction between the plasmid and cell DNA. The telomere repeat sequences at the other end were located in the opposite orientation in the polymorphic region and were shown by digestion with BAL 31 to be at the end of the chromosome. Telomere repeat sequences were not found at this location in the plasmid or parent cell DNA. Although the repeat sequences may have been acquired by recombination, a more likely explanation is that they were added to the ends of the plasmid by telomerase before integration. Comparison of the cell DNA before and after integration revealed that a chromosome break had occurred at the integration site, which was shown by fluorescent in situ hybridization to be located near the telomere of chromosome 13. These results demonstrate that chromosome breakage and rearrangement can result in interstitial telomere repeat sequences within the human genome. These sequences could promote genomic instability, because short repeat sequences can be recombinational hotspots. The results also show that DNA rearrangements involving telomere repeat sequences can be associated with chromosome breaks. The introduction of telomere repeat sequences at spontaneous or ionizing radiation-induced DNA strand breaks may therefore also be a mechanism of chromosome fragmentation.},
}
@article {pmid7680894,
year = {1993},
author = {Bouffler, S and Silver, A and Papworth, D and Coates, J and Cox, R},
title = {Murine radiation myeloid leukaemogenesis: relationship between interstitial telomere-like sequences and chromosome 2 fragile sites.},
journal = {Genes, chromosomes &amp; cancer},
volume = {6},
number = {2},
pages = {98-106},
doi = {10.1002/gcc.2870060206},
pmid = {7680894},
issn = {1045-2257},
mesh = {Acute Disease ; Animals ; Base Sequence ; *Chromosome Aberrations ; Chromosome Fragile Sites ; *Chromosome Fragility ; In Situ Hybridization, Fluorescence ; Leukemia, Myeloid/etiology/*genetics ; Leukemia, Radiation-Induced/*genetics ; Mice ; Mice, Inbred CBA/genetics ; Molecular Sequence Data ; *Repetitive Sequences, Nucleic Acid ; Telomere/*ultrastructure ; },
abstract = {While the specific nature of chromosomal fragile sites and their relationship to human leukaemogenesis remain obscure, there is evidence that chromosomal fragility may, in some circumstances, be associated with telomere-like repeat sequences and that chromosome 2 fragility in the mouse is involved in the initiation of myeloid leukaemia by ionising radiation. Here we describe the molecular cloning and characterisation of two murine telomere-like sequences, one having an inverted repeat structure and the other a simple tandem repeat organisation. The inverted telomere repeat clone generates an in situ chromosome 2 hybridisation pattern very similar to the distribution of the radiation-sensitive fragile sites previously found to be associated with leukaemogenic initiation. Furthermore, statistical comparison of the distributions of radiation induced breakpoints and sites of inverted telomere repeat hybridization indicates concordance at all chromosome 2 sites excluding the terminal regions. These data are discussed with respect to mechanisms of radiation-induced, site-specific chromosome 2 rearrangement and their implications for leukaemogenic initiation.},
}
@article {pmid8422682,
year = {1993},
author = {Wellinger, RJ and Wolf, AJ and Zakian, VA},
title = {Saccharomyces telomeres acquire single-strand TG1-3 tails late in S phase.},
journal = {Cell},
volume = {72},
number = {1},
pages = {51-60},
doi = {10.1016/0092-8674(93)90049-v},
pmid = {8422682},
issn = {0092-8674},
support = {GM26938/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Composition ; Blotting, Southern ; Chromosomes, Fungal ; DNA, Fungal/*genetics ; DNA, Single-Stranded/*genetics ; Electrophoresis, Agar Gel ; Electrophoresis, Gel, Two-Dimensional ; Plasmids ; Repetitive Sequences, Nucleic Acid ; S Phase/*genetics ; Saccharomyces/cytology/*genetics ; *Telomere ; },
abstract = {Saccharomyces telomeres consist of approximately 300 bp of C1-3A/TG1-3 DNA. Nondenaturing Southern hybridization, capable of detecting approximately 60 to approximately 300 bases of TG1-3 DNA, revealed that yeast telomeres acquired and lost TG1-3 tails, the predicted intermediate in telomere replication, in a cell cycle-dependent manner. TG1-3 tails were also detected on the ends of a linear plasmid isolated from late S phase cells. In addition, a nonlinear form of this plasmid was detected: this structure migrated in two-dimensional agarose gels like a nicked circle of the same size as the linear plasmid, but had considerably more single-stranded character than a conventional nicked circle. The evidence indicates that these circles were formed by telomere-telomere interactions involving the TG1-3 tails. These data provide evidence for a cell cycle-dependent change in telomere structure and demonstrate that TG1-3 tails, generated during replication of a linear plasmid in vivo, are capable of mediating telomere-telomere interactions.},
}
@article {pmid8441617,
year = {1993},
author = {Barnett, MA and Buckle, VJ and Evans, EP and Porter, AC and Rout, D and Smith, AG and Brown, WR},
title = {Telomere directed fragmentation of mammalian chromosomes.},
journal = {Nucleic acids research},
volume = {21},
number = {1},
pages = {27-36},
pmid = {8441617},
issn = {0305-1048},
mesh = {Animals ; Base Sequence ; Cell Line ; Chromosomes/*metabolism/ultrastructure ; Chromosomes, Human/*metabolism/ultrastructure ; Cloning, Molecular ; DNA ; HeLa Cells ; Humans ; In Situ Hybridization ; Karyotyping ; Mice ; Molecular Sequence Data ; *Telomere ; },
abstract = {Cloned human telomeric DNA can integrate into mammalian chromosomes and seed the formation of new telomeres. This process occurs efficiently in three established human cell lines and in a mouse embryonic stem cell line. The newly seeded telomeres appear to be healed by telomerase. The seeding of new telomeres by cloned telomeric DNA is either undetectable or very inefficient in non-tumourigenic mouse or human somatic cell lines. The cytogenetic consequences of the seeding of new telomeres include large chromosome truncations but most of the telomere seeding events occur close to the pre-existing ends of natural chromosomes.},
}
@article {pmid8432192,
year = {1993},
author = {Ashley, T and Cacheiro, NL and Russell, LB and Ward, DC},
title = {Molecular characterization of a pericentric inversion in mouse chromosome 8 implicates telomeres as promoters of meiotic recombination.},
journal = {Chromosoma},
volume = {102},
number = {2},
pages = {112-120},
pmid = {8432192},
issn = {0009-5915},
support = {GM-40115/GM/NIGMS NIH HHS/United States ; HG-00272/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; *Chromosome Inversion ; Heterozygote ; Homozygote ; In Situ Hybridization ; Male ; *Meiosis ; Mice ; *Recombination, Genetic ; Spermatocytes/*ultrastructure ; Synaptonemal Complex ; Telomere/*physiology ; },
abstract = {A "hot spot" of meiotic recombination has been found in males on murine chromosome 8 using nonisotopic hybridization of a series of probes to mitotic and meiotic chromosomes. The sequences responsible for this enhanced recombination are the telomeric repeats. Mice both normal and hetero- or homozygous for a pericentric inversion, In(8)1 Rl, were analyzed. The inversion subdivides chromosome 8 into three discreet regions: (1) a fraction of the micro "short arm" that contains 30-150 kb of telomeric sequences and only about one-fifth of the contiguous minor-satellite sequences (approximately 200 kb); (2) the inverted region; and (3) the noninverted distal two-thirds of the chromosome. In 70 spermatocytes from inversion heterozygotes, examined by electron microscopy, synapsis of the inverted region was complete but entirely nonhomologous. Nonhomologous synapsis persists from initiation of synaptonemal complex formation in zygonema/early pachynema until dissolution in late pachynema. This nonhomologous synapsis also suppresses crossing over within the inverted segment. The opportunity for proximal homologous recombination is thus restricted to the roughly 250 kb segment located between the short-arm break and the end of the bivalent. Nonetheless, an extreme proximal chiasma was observed in 11% of the heterozygous chromosome-8 bivalents, 34% of the normal 8 bivalents and 35% of the homozygous inversion 8 bivalents from spermatocyte preparations. Since in the normal chromosomes all minor satellite sequences are adjacent to the telomere, while in the inversion chromosomes most of these sequences are transposed to an interstitial position without a corresponding shift in chiasma position, the minor-satellite sequences can be ruled out as promoters of recombination.(ABSTRACT TRUNCATED AT 250 WORDS)},
}
@article {pmid8223505,
year = {1993},
author = {Day, JP and Marder, BA and Morgan, WF},
title = {Telomeres and their possible role in chromosome stabilization.},
journal = {Environmental and molecular mutagenesis},
volume = {22},
number = {4},
pages = {245-249},
doi = {10.1002/em.2850220411},
pmid = {8223505},
issn = {0893-6692},
support = {5-T32-ES07106/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; Chromosome Aberrations/*physiology ; Humans ; Telomere/*physiology ; },
abstract = {The evidence to date generally supports the hypothesis that telomere capping makes chromosome fragments refractory to subsequent rejoining events, but this control may be somewhat relaxed after chromosome breakage. Cell survival requires that the fragments rejoin before metaphase. Unprotected ends such as those produced by DNA damage are subject to degradation, presumably by endogenous cellular exo- and endonucleases. Telomere repeat sequences may be added to broken chromosome ends to protect the ends from further degradation. That telomeric DNA does not always prevent rejoining raises interesting questions as to what constitutes capping, and how rapidly it occurs after DNA damage in relation to chromosome break rejoining. The prevention of degradation and control of rejoining may be mediated by telomere-specific binding proteins, especially the telomere terminal binding protein [Gualberto et al., 1992; Longtine et al., 1989; Price, 1990; Price and Cech, 1989]. Some of these proteins may be involved in scavenging telomeric DNA when the cell senses that chromosomal breaks have occurred. This mechanism is consistent with the observations of Murnane and Yu [1993], who found that a plasmid with telomere sequences was stably integrated in vivo into a chromosome terminal breakpoint lacking telomere repeats. It is also consistent with the high frequency of interstitial telomere sequences observed in normal cells; a history of DNA damage and repair may be recorded by these sequences (Ijdo et al., 1991]. Although chromosome break rejoining is an efficient process in eukaryotic cells, some breaks are never rejoined and can result in terminal deletions and chromatid and isochromatid deletions at metaphase. It is unclear why these breaks are not rejoined, but it may be due to one or more of the following: 1) chance: broken chromosomes are separated, do not approach sufficiently close to one another, and are consequently physically unable to rejoin; 2) a large number of added telomere repeat sequences indicating to the cell that the chromosome has an authentic telomere; 3) some other DNA modification event that protects DNA ends from degradation, e.g., folding back of DNA ends to form a hairpin, as has been implicated in VDJ recombination [Lieber, 1993].},
}
@article {pmid7956091,
year = {1993},
author = {Palladino, F and Laroche, T and Gilson, E and Pillus, L and Gasser, SM},
title = {The positioning of yeast telomeres depends on SIR3, SIR4, and the integrity of the nuclear membrane.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {58},
number = {},
pages = {733-746},
doi = {10.1101/sqb.1993.058.01.081},
pmid = {7956091},
issn = {0091-7451},
mesh = {Chromatin/genetics ; Fungal Proteins/genetics/metabolism ; GTP-Binding Proteins/metabolism ; Genes, Fungal ; Interphase ; Mutation ; Nuclear Envelope/*metabolism/ultrastructure ; Saccharomyces cerevisiae/genetics/*metabolism/ultrastructure ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Telomere/*metabolism/ultrastructure ; Trans-Activators/genetics/metabolism ; rap GTP-Binding Proteins ; },
}
@article {pmid7956089,
year = {1993},
author = {Wellinger, RJ and Wolf, AJ and Zakian, VA},
title = {Structural and temporal analysis of telomere replication in yeast.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {58},
number = {},
pages = {725-732},
doi = {10.1101/sqb.1993.058.01.080},
pmid = {7956089},
issn = {0091-7451},
support = {GM-26938/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; *DNA Replication ; DNA, Circular/biosynthesis/genetics ; DNA, Fungal/biosynthesis/genetics ; Models, Biological ; S Phase/genetics ; Saccharomyces cerevisiae/genetics/*metabolism/ultrastructure ; Telomere/*metabolism/ultrastructure ; },
}
@article {pmid7956088,
year = {1993},
author = {Lee, MS and Gallagher, RC and Bradley, J and Blackburn, EH},
title = {In vivo and in vitro studies of telomeres and telomerase.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {58},
number = {},
pages = {707-718},
doi = {10.1101/sqb.1993.058.01.078},
pmid = {7956088},
issn = {0091-7451},
support = {GM-26259/GM/NIGMS NIH HHS/United States ; GM-32565/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cell Division/genetics ; DNA Nucleotidylexotransferase/antagonists &amp; inhibitors/genetics/*metabolism ; DNA Primers/genetics ; DNA, Protozoan/biosynthesis/genetics ; Diphosphates/pharmacology ; Models, Biological ; Molecular Sequence Data ; Mutation ; Oligonucleotides, Antisense/genetics/pharmacology ; Osmolar Concentration ; Phenotype ; RNA, Protozoan/genetics ; Repetitive Sequences, Nucleic Acid ; Telomere/*metabolism/ultrastructure ; Tetrahymena thermophila/*genetics/metabolism/ultrastructure ; Transformation, Genetic ; },
}
@article {pmid7691010,
year = {1993},
author = {Zatsepina, OV and Stefanova, VN},
title = {[The ultrastructural characteristics of the metaphase chromosomal regions (telomere, centromere, nucleolar organizer) in the pig].},
journal = {Tsitologiia},
volume = {35},
number = {5},
pages = {17-23},
pmid = {7691010},
issn = {0041-3771},
mesh = {Animals ; Cell Line ; Cells, Cultured/ultrastructure ; Centromere/ultrastructure ; Chromosomes/*ultrastructure ; Deoxyribonucleoproteins/ultrastructure ; *Metaphase ; Microscopy, Electron ; Nucleolus Organizer Region/ultrastructure ; Staining and Labeling/methods ; Swine ; Telomere/ultrastructure ; },
abstract = {The ultrastructural organization of some chromosome regions (telomere, centromere, nucleolus organizer region), which can be identified undoubtedly under electron microscope after in situ fixation, was studied using serial ultrathin sections of pig embryo kidney cells. The ultrastructure of these regions was compared with patterns of their differential staining revealed by C-method and by fluorochromes, chromomycin A3 and DAPI, specific for GC- and AT-rich base pair regions. It is shown that telomere regions of chromosome are organized primarily by 20 nm fibrils of DNP, which form a clear chromonema--a thread of chromatin with thickness nearly 100 nm. In the centromere regions of metacentric chromosomes, fibrils 20 nm in diameter predominate, while in several acrocentric chromosomes--fibrils 10 nm thick are prevailing. It was suggested that the observed differences may depend on the DNA composition in these regions. The nucleolus organizer regions contain the fibrillar material 5-11 nm in diameter.},
}
@article {pmid7525147,
year = {1993},
author = {Greider, CW},
title = {Telomerase and telomere-length regulation: lessons from small eukaryotes to mammals.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {58},
number = {},
pages = {719-723},
doi = {10.1101/sqb.1993.058.01.079},
pmid = {7525147},
issn = {0091-7451},
mesh = {Animals ; Base Sequence ; DNA Nucleotidylexotransferase/genetics/*metabolism ; Eukaryotic Cells ; Humans ; Mammals ; Neoplasms/genetics/metabolism/ultrastructure ; RNA/genetics ; Ribonucleoproteins/metabolism ; Saccharomyces cerevisiae/genetics/metabolism/ultrastructure ; Telomere/*metabolism/ultrastructure ; Zea mays/genetics/metabolism/ultrastructure ; },
}
@article {pmid1482678,
year = {1992},
author = {Coren, JS and Vogt, VM},
title = {Purification of a telomere-binding protein from Physarum polycephalum.},
journal = {Biochimica et biophysica acta},
volume = {1171},
number = {2},
pages = {162-166},
doi = {10.1016/0167-4781(92)90116-h},
pmid = {1482678},
issn = {0006-3002},
support = {GM 31577/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cell Nucleus/*metabolism ; Chromatography, Affinity ; Chromatography, Gel ; DNA, Ribosomal/genetics ; DNA-Binding Proteins/*isolation &amp; purification/metabolism ; Electrophoresis, Polyacrylamide Gel ; Kinetics ; Molecular Sequence Data ; Molecular Weight ; Oligodeoxyribonucleotides/metabolism ; Physarum polycephalum/*metabolism ; Repetitive Sequences, Nucleic Acid ; },
abstract = {We have purified a telomere-binding protein (PPT) from the acellular slime mold Physarum polycephalum. As shown previously (Coren, J.S., Epstein, E.M. and Vogt, V.M. (1991) Mol. Cell. Biol. 11, 2282-2290), in vitro this protein binds specifically to the double stranded (TTAGGG)n repeats that are found at the telomeres of extrachromosomal ribosomal DNA from this organism, and also at telomeres of mammalian chromosomes. PPT was purified from Physarum nuclear extracts by heat treatment at 90 degrees C followed by heparin-agarose fractionation and gel filtration chromatography. The most purified fraction contained two major protein bands of 10 and 7 kDa when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In gel filtration chromatography PPT migrated with a Stokes radius of 1.6 nm. Along with the previously determined sedimentation coefficient of 1.2 S, this value implies a molecular weight of about 8000, making PPT the smallest known telomere-binding protein.},
}
@article {pmid1480483,
year = {1992},
author = {Wang, W and Skopp, R and Scofield, M and Price, C},
title = {Euplotes crassus has genes encoding telomere-binding proteins and telomere-binding protein homologs.},
journal = {Nucleic acids research},
volume = {20},
number = {24},
pages = {6621-6629},
pmid = {1480483},
issn = {0305-1048},
support = {GM41803/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Binding Sites ; Blotting, Southern ; Cloning, Molecular ; DNA/*genetics/isolation &amp; purification ; DNA-Binding Proteins/*genetics/metabolism ; Euplotes/*genetics/*metabolism ; Gene Library ; Macromolecular Substances ; Molecular Sequence Data ; Molecular Weight ; Oxytricha/genetics ; Sequence Homology, Amino Acid ; },
abstract = {We have identified two 1.6 kb macronuclear DNA molecules from Euplotes crassus that hybridize to the alpha subunit of the Oxytricha telomere protein. We have shown that one of these molecules encodes the 51 kDa Euplotes telomere protein while the other appears to encode a homolog of the telomere protein. Although this homolog clearly differs in sequence from the Euplotes telomere protein, the two proteins share extensive amino acid sequence identity with each other and with the alpha subunit of the Oxytricha telomere protein. In all three proteins 35-36% of the amino acids are identical, while 54-56% are similar. The most extended regions of sequence conservation map within the N-terminal section; this section has been shown to comprise the DNA-binding domain in the Euplotes telomere protein. Our findings suggest that some of the conserved amino acids may be involved in DNA recognition and binding. The gene encoding the telomere protein homolog contains two introns; one of these introns is only 24 bp in length. This is the smallest mRNA intron reported to date.},
}
@article {pmid1465614,
year = {1992},
author = {Freije, D and Helms, C and Watson, MS and Donis-Keller, H},
title = {Identification of a second pseudoautosomal region near the Xq and Yq telomeres.},
journal = {Science (New York, N.Y.)},
volume = {258},
number = {5089},
pages = {1784-1787},
doi = {10.1126/science.1465614},
pmid = {1465614},
issn = {0036-8075},
support = {HG00100/HG/NHGRI NIH HHS/United States ; HG00201/HG/NHGRI NIH HHS/United States ; },
mesh = {Alleles ; Animals ; Base Sequence ; Cell Line ; Chromosome Banding ; Chromosome Mapping ; Chromosomes, Fungal ; Cloning, Molecular ; DNA/*genetics ; Factor VIII/genetics ; Female ; Gene Conversion ; Genetic Linkage ; Haplotypes ; Humans ; Hybrid Cells ; Male ; Molecular Sequence Data ; Oligodeoxyribonucleotides ; Pedigree ; Polymerase Chain Reaction/methods ; Recombination, Genetic ; Rodentia ; Saccharomyces cerevisiae/genetics ; Sequence Homology, Nucleic Acid ; Telomere/*physiology/ultrastructure ; *X Chromosome ; *Y Chromosome ; },
abstract = {The telomeres of Xq and Yq have been observed to associate during meiosis, and in rare cases a short synaptonemal complex is present. Molecular cloning of loci from Xqter and Yqter has revealed that their sequence homology extends over 400 kilobases, which suggests the possibility of genetic exchange. This hypothesis was tested by the development of two highly informative microsatellite markers from yeast artificial chromosome clones that carried Xqter sequences and the following of their inheritance in a set of reference pedigrees from the Centre d'Etude du Polymorphisme Humain in Paris, France. From a total of 195 informative male meioses, four recombination events between these loci were observed. In three cases, paternal X alleles were inherited by male offspring, and in one case a female offspring inherited her father's Y allele. These data support the existence of genetic exchange at Xq-Yq, which defines a second pseudoautosomal region between the sex chromosomes.},
}
@article {pmid1478646,
year = {1992},
author = {Helms, C and Mishra, SK and Riethman, H and Burgess, AK and Ramachandra, S and Tierney, C and Dorsey, D and Donis-Keller, H},
title = {Closure of a genetic linkage map of human chromosome 7q with centromere and telomere polymorphisms.},
journal = {Genomics},
volume = {14},
number = {4},
pages = {1041-1054},
doi = {10.1016/s0888-7543(05)80128-4},
pmid = {1478646},
issn = {0888-7543},
support = {5-F32 GM 12884/GM/NIGMS NIH HHS/United States ; HG00100/HG/NHGRI NIH HHS/United States ; HG00201/HG/NHGRI NIH HHS/United States ; },
mesh = {*Centromere ; Chromosome Mapping ; *Chromosomes, Human, Pair 7 ; Female ; *Genetic Linkage ; Heterozygote ; Humans ; Male ; *Polymorphism, Genetic ; Recombination, Genetic ; *Telomere ; },
abstract = {We have constructed a 2.4-cM resolution genetic linkage map for chromosome 7q that is bounded by centromere and telomere polymorphisms and contains 66 loci (88 polymorphic systems), 38 of which are uniquely placed with odds for order of at least 1000:1. Ten genes are included in the map and 11 markers have heterozygosities of at least 70%. This map is the first to incorporate several highly informative markers derived from a telomere YAC clone HTY146 (locus D7S427), including HTY146c3 (HET 92%). The telomere locus markers span at least 200 kb of the 7q terminus and no crossovers within the physical confines of the locus were observed in approximately 240 jointly informative meioses. The sex-equal map length is 158 cM and the largest genetic interval between uniquely localized markers in this map is 11 cM. The female and male map lengths are 181 and 133 cM, respectively. The map is based on the CEPH reference pedigrees and includes over 4000 new genotypes, our previously reported data plus 29 allele systems from the published CEPH version 5 database, and was constructed using the program package CRI-MAP. This genetic linkage map can be considered a baseline map for 7q, and will be useful for defining the extent of chromosome deletions previously reported for breast and prostate cancers, for developing additional genetic maps such as index marker and 1-cM maps, and ultimately for developing a fully integrated genetic and physical map for this chromosome.},
}
@article {pmid1471712,
year = {1992},
author = {Smith, JK and Yeh, G},
title = {Telomere reduction in endometrial adenocarcinoma.},
journal = {American journal of obstetrics and gynecology},
volume = {167},
number = {6},
pages = {1883-1887},
doi = {10.1016/0002-9378(92)91791-8},
pmid = {1471712},
issn = {0002-9378},
mesh = {Adenocarcinoma/*genetics ; Autoradiography ; Base Sequence ; DNA, Neoplasm/genetics ; Deoxyribonucleases, Type II Site-Specific ; Endometrial Neoplasms/*genetics ; Female ; Humans ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Oligonucleotide Probes/genetics ; *Telomere ; Tumor Cells, Cultured ; },
abstract = {OBJECTIVE: Some of the genomic instability that is observed in solid tumors may be due to the loss of telomeric sequences. These experiments were designed to compare the number of telomeric repeat sequences in endometrial adenocarcinoma with that found in adjacent normal tissue.<br><br>STUDY DESIGN: Deoxyribonucleic acid was extracted from normal and malignant uterine tissue of 11 patients undergoing hysterectomy for treatment of endometrial adenocarcinoma and also from five endometrial carcinoma cell lines. The relative number of telomeric repeat sequences in each sample was measured by hybridization of these deoxyribonucleic acids to a probe specific for the human telomeric repeat. Hybridization signals were quantified by autoradiography and a beta-particle detection system.<br><br>RESULTS: A reduction of telomeric repeat sequences in tumor versus normal tissue was found in 10 of 11 cases. Telomere reduction was also seen in endometrial carcinoma cell lines.<br><br>CONCLUSIONS: Telomere reduction is a genetic characteristic of many endometrial tumors. Telomere reduction may contribute to the genesis and progression of endometrial carcinoma, or it may be a secondary effect of the tumorigenesis process.},
}
@article {pmid1483926,
year = {1992},
author = {Takada, T and Hayashi, T and Arakawa, M and Kominami, R},
title = {Telomere elongation frequently observed during tumor metastasis.},
journal = {Japanese journal of cancer research : Gann},
volume = {83},
number = {11},
pages = {1124-1127},
pmid = {1483926},
issn = {0910-5050},
mesh = {Animals ; Base Sequence ; Chromosomes/physiology ; DNA, Neoplasm/genetics ; HeLa Cells ; Humans ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Molecular Sequence Data ; Neoplasm Metastasis/*genetics ; Neoplasms, Experimental/chemically induced/genetics/pathology ; Telomere/*physiology/ultrastructure ; Tumor Cells, Cultured ; },
abstract = {Changes in the number of telomere repeat arrays have been examined during metastasis of two mouse tumor cell lines. Telomeres were detected as bands and a smear by pulsed-field gel electrophoresis and gel-hybridization using (TTAGGG)4 as a probe. Very long size variants of telomeres were frequently observed in metastatic nodules. This suggests that at least some of the tumor cells have an ability to elongate telomeres. This elongation may compensate for the continuous loss of telomere repeats due to cell divisions, which would eventually lead to cell death.},
}
@article {pmid1496980,
year = {1992},
author = {Ledbetter, DH},
title = {Minireview: cryptic translocations and telomere integrity.},
journal = {American journal of human genetics},
volume = {51},
number = {3},
pages = {451-456},
pmid = {1496980},
issn = {0002-9297},
support = {HD20619/HD/NICHD NIH HHS/United States ; HG00024/HG/NHGRI NIH HHS/United States ; },
mesh = {Humans ; Nucleic Acid Hybridization ; Polymorphism, Genetic/genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Telomere/*ultrastructure ; Translocation, Genetic/*genetics ; },
}
@article {pmid1470180,
year = {1992},
author = {Bugaeva, EA and Parfenov, VN and Podgornaia, OI},
title = {[Nuclear envelope of frog diplotene oocytes has telomere-binding activity].},
journal = {Molekuliarnaia biologiia},
volume = {26},
number = {5},
pages = {983-992},
pmid = {1470180},
issn = {0026-8984},
mesh = {Animals ; DNA-Binding Proteins/metabolism ; Electrophoresis, Polyacrylamide Gel ; Meiosis ; Nuclear Envelope/*metabolism ; Oocytes/*metabolism/ultrastructure ; Plasmids ; Rana temporaria ; Telomere/*metabolism ; },
abstract = {A telomere-binding activity was found in the nuclear envelope of frog oocytes Rana temporaria by methods of binding on nitrocellulose filters and retardation. At present it is hardly possible to detect the proteins responsible for this activity. However, the results of this study allowed us to identify a specific mechanism of DNA-protein interaction, which provides the binding of the telomere to the envelope in meiotic cells.},
}
@article {pmid1508688,
year = {1992},
author = {Richards, EJ and Chao, S and Vongs, A and Yang, J},
title = {Characterization of Arabidopsis thaliana telomeres isolated in yeast.},
journal = {Nucleic acids research},
volume = {20},
number = {15},
pages = {4039-4046},
pmid = {1508688},
issn = {0305-1048},
support = {GM43518/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Blotting, Southern ; Cloning, Molecular ; Genetic Complementation Test ; Methylation ; Molecular Sequence Data ; Plants/*genetics ; Plasmids/genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; Saccharomyces cerevisiae/genetics ; *Telomere ; },
abstract = {In an effort to learn more about the genomic organization of chromosomal termini in plants we employed a functional complementation strategy to isolate Arabidopsis thaliana telomeres in the yeast, Saccharomyces cerevisiae. Eight yeast episomes carrying A. thaliana telomeric sequences were obtained. The plant sequences carried on two episomes, YpAtT1 and YpAtT7, were characterized in detail. The telomeric origins of YpAtT1 and YpAtT7 insert DNAs were confirmed by demonstrating that corresponding genomic sequences are preferentially degraded during exonucleolytic digestion. The isolated telomeric restriction fragments contain G-rich repeat arrays characteristic of A. thaliana telomeres, as well as subterminal telomere-associated sequences (TASs). DNA sequence analysis revealed the presence of variant telomeric repeats at the centromere-proximal border of the terminal block of telomere repeats. The TAS flanking the telomeric G-rich repeat in YpAtT7 corresponds to a repetitive element present at other A. thaliana telomeres, while more proximal sequences are unique to one telomere. The YpAtT1 TAS is unique in the Landsberg strain of A. thaliana from which the clone originated; however, the Landsberg TAS cross-hybridizes weakly to a second telomere in the strain Columbia. Restriction analysis with cytosine methylation-sensitive endonucleases indicated that both TASs are highly methylated in the genome.},
}
@article {pmid1501251,
year = {1992},
author = {Cohn, M and Edström, JE},
title = {Telomere-associated repeats in Chironomus form discrete subfamilies generated by gene conversion.},
journal = {Journal of molecular evolution},
volume = {35},
number = {2},
pages = {114-122},
pmid = {1501251},
issn = {0022-2844},
mesh = {Animals ; Base Sequence ; Blotting, Southern ; Chironomidae/*genetics ; DNA ; Deoxyribonucleases, Type II Site-Specific/metabolism ; *Gene Conversion ; Genetic Variation ; Molecular Sequence Data ; *Repetitive Sequences, Nucleic Acid ; *Telomere ; },
abstract = {In dipteran insects the most distal telomere-associated DNA known to exist consists of long, complex tandem repeats. We have classified the 340-bp tandemly arranged repeats in Chironomus pallidivittatus. The repeats are distributed in a small number of subfamilies. One type of the repeat has the character of a master unit from which other main units can be derived usually by simple changes. The derived subfamilies contain segments that are degenerate versions of the corresponding segment in the master sequence. Such segments can also occur together in one and the same repeat unit in different combinations. There is a complete absence of subfamily-specific base variants in regions lying outside of the degenerate segments. Homogenization takes place between DNA sequences that are often smaller than a whole repeat unit. The mosaic structure of the repeat arrays suggests that gene conversion is an important force in the generation and maintenance of this family of repeats.},
}
@article {pmid1638505,
year = {1992},
author = {Adamson, DJ and King, DJ and Haites, NE},
title = {Significant telomere shortening in childhood leukemia.},
journal = {Cancer genetics and cytogenetics},
volume = {61},
number = {2},
pages = {204-206},
doi = {10.1016/0165-4608(92)90088-p},
pmid = {1638505},
issn = {0165-4608},
mesh = {Blotting, Southern ; Child ; Child, Preschool ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*genetics ; Leukemia, Myeloid, Acute/*genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Telomere/*pathology ; },
abstract = {Telomere length was studied by Southern analysis in five cases of childhood acute leukemia. In four cases, the length of the telomere sequence of the blast phase cells was shortened as compared with that of the cells examined during remission. Study of telomere length during chemotherapy for hematologic malignancies may show rapidly dividing subpopulations of malignant cells and thereby guide further treatment needs. In addition, such loss of telomere sequence would give rise to chromosomal instability and could be one of the mechanisms of oncogene activation in acute leukemia.},
}
@article {pmid1459213,
year = {1992},
author = {Harley, CB and Vaziri, H and Counter, CM and Allsopp, RC},
title = {The telomere hypothesis of cellular aging.},
journal = {Experimental gerontology},
volume = {27},
number = {4},
pages = {375-382},
doi = {10.1016/0531-5565(92)90068-b},
pmid = {1459213},
issn = {0531-5565},
mesh = {Aging/*genetics ; DNA Nucleotidylexotransferase/physiology ; DNA Replication/physiology ; Humans ; Mitosis/genetics ; Models, Genetic ; Telomere/*physiology ; },
}
@article {pmid1620597,
year = {1992},
author = {Lustig, AJ},
title = {Hoogsteen G-G base pairing is dispensable for telomere healing in yeast.},
journal = {Nucleic acids research},
volume = {20},
number = {12},
pages = {3021-3028},
pmid = {1620597},
issn = {0305-1048},
mesh = {Base Composition/*genetics ; Base Sequence ; DNA Replication/genetics ; Guanosine/*metabolism ; Methylation ; Molecular Sequence Data ; Nucleic Acid Conformation ; Oligodeoxyribonucleotides/genetics/metabolism ; Plasmids/genetics ; Recombination, Genetic/genetics ; Saccharomyces cerevisiae/*genetics ; Telomere/chemistry/*metabolism ; Transformation, Genetic ; },
abstract = {The G-rich strands of most eukaryotic telomeres are capable of forming highly folded structures in vitro, mediated, in part, through Hoogsteen G-G base pairing. The ability of most telomeres to form these structures has led to the suggestion that they play an important role in telomere addition. I have investigated this possibility in the yeast Saccharomyces cerevisiae through the use of an in vivo assay that measures healing via poly(G1-3T) addition onto plasmid substrates containing synthetic telomeres. Synthetic telomere healing is a highly size- and sequence-specific process that allows the discrimination of telomeres of differing efficiency. Plasmids containing synthetic telomeres with differing abilities to form secondary structures were tested in this assay for healing in vivo. The results of this study demonstrate that telomeres incapable of forming Hoogsteen base pairs nonetheless serve as efficient substrates for poly(G1-3T) addition, indicating that intramolecular Hoogsteen G-G base pairing is not essential for this process.},
}
@article {pmid1613801,
year = {1992},
author = {Levy, MZ and Allsopp, RC and Futcher, AB and Greider, CW and Harley, CB},
title = {Telomere end-replication problem and cell aging.},
journal = {Journal of molecular biology},
volume = {225},
number = {4},
pages = {951-960},
doi = {10.1016/0022-2836(92)90096-3},
pmid = {1613801},
issn = {0022-2836},
mesh = {Adult ; Base Sequence ; Cell Division ; Cells, Cultured ; Chromosome Deletion ; Chromosomes, Human/*physiology ; DNA/genetics/*metabolism ; *DNA Replication ; Fibroblasts/cytology/physiology ; Humans ; Kinetics ; Models, Genetic ; Oligonucleotide Probes ; Repetitive Sequences, Nucleic Acid ; Skin Physiological Phenomena ; Telomere/*physiology ; },
abstract = {Since DNA polymerase requires a labile primer to initiate unidirectional 5'-3' synthesis, some bases at the 3' end of each template strand are not copied unless special mechanisms bypass this "end-replication" problem. Immortal eukaryotic cells, including transformed human cells, apparently use telomerase, an enzyme that elongates telomeres, to overcome incomplete end-replication. However, telomerase has not been detected in normal somatic cells, and these cells lose telomeres with age. Therefore, to better understand the consequences of incomplete replication, we modeled this process for a population of dividing cells. The analysis suggests four things. First, if single-stranded overhangs generated by incomplete replication are not degraded, then mean telomere length decreases by 0.25 of a deletion event per generation. If overhangs are degraded, the rate doubles. Data showing a decrease of about 50 base-pairs per generation in fibroblasts suggest that a full deletion event is 100 to 200 base-pairs. Second, if cells senesce after 80 doublings in vitro, mean telomere length decreases about 4000 base-pairs, but one or more telomeres in each cell will lose significantly more telomeric DNA. A checkpoint for regulation of cell growth may be signalled at that point. Third, variation in telomere length predicted by the model is consistent with the abrupt decline in dividing cells at senescence. Finally, variation in length of terminal restriction fragments is not fully explained by incomplete replication, suggesting significant interchromosomal variation in the length of telomeric or subtelomeric repeats. This analysis, together with assumptions allowing dominance of telomerase inactivation, suggests that telomere loss could explain cell cycle exit in human fibroblasts.},
}
@article {pmid1588969,
year = {1992},
author = {Edman, JC},
title = {Isolation of telomerelike sequences from Cryptococcus neoformans and their use in high-efficiency transformation.},
journal = {Molecular and cellular biology},
volume = {12},
number = {6},
pages = {2777-2783},
pmid = {1588969},
issn = {0270-7306},
support = {AI29312/AI/NIAID NIH HHS/United States ; },
mesh = {Base Sequence ; Blotting, Southern ; Cryptococcus neoformans/*genetics ; DNA, Fungal/*genetics ; DNA, Superhelical/genetics ; Extrachromosomal Inheritance ; *Genetic Vectors ; Molecular Sequence Data ; Plasmids ; *Telomere ; Transformation, Genetic ; },
abstract = {Development of a transformation system for the fungal human pathogen Cryptococcus neoformans is an important prerequisite for the identification of genes involved in virulence. It has previously been reported that low-efficiency transformation can be achieved by using the cloned C. neoformans URA5 gene and ura5 mutants. The introduction of linearized URA5 vectors into C. neoformans resulted in unstable transformants which apparently harbored linear extrachromosomal DNA molecules. In this paper, the nature of these molecules is confirmed to be linear by exonuclease digestion. Recovery of the extrachromosomal DNA in Escherichia coli and sequence analysis demonstrates that repeats characteristic of telomeric DNA have been added to the ends of the introduced DNA. The recovered plasmids are capable of transforming at much higher efficiencies either in the supercoiled state (up to 200 transformants per microgram) or the linear state (up to 90,000 transformants per microgram).},
}
@article {pmid1497910,
year = {1992},
author = {Price, CM},
title = {Centromeres and telomeres.},
journal = {Current opinion in cell biology},
volume = {4},
number = {3},
pages = {379-384},
doi = {10.1016/0955-0674(92)90002-t},
pmid = {1497910},
issn = {0955-0674},
mesh = {Animals ; Base Sequence ; Centromere/*metabolism ; DNA/genetics/metabolism ; DNA-Binding Proteins/metabolism ; Mammals ; Molecular Sequence Data ; Saccharomyces cerevisiae/metabolism ; Schizosaccharomyces/metabolism ; Telomere/*metabolism ; },
abstract = {Centromeres and telomeres are both composed of specific DNA sequences and unique chromosomal proteins. Isolation and characterization of some of these sequences and proteins has greatly increased our knowledge of centromere and telomere structure. This information is allowing us to determine how centromeres and telomeres perform their various roles in a cell.},
}
@article {pmid1496553,
year = {1992},
author = {Wright, WE and Shay, JW},
title = {Telomere positional effects and the regulation of cellular senescence.},
journal = {Trends in genetics : TIG},
volume = {8},
number = {6},
pages = {193-197},
doi = {10.1016/0168-9525(92)90232-s},
pmid = {1496553},
issn = {0168-9525},
support = {AG07992/AG/NIA NIH HHS/United States ; CA50195/CA/NCI NIH HHS/United States ; },
mesh = {*Cell Death ; *Cell Division ; Heterochromatin/physiology ; Humans ; Models, Biological ; Telomere/*physiology ; },
abstract = {Normal cells have a limited capacity to proliferate but the molecular clock that regulates the onset of cellular senescence remains unidentified. The ends of chromosomes--telomeres--have been shown to shorten progressively with age in normal cells. Here, we present a working model of how telomeric shortening may induce programmed changes in the regulation of cellular proliferation.},
}
@article {pmid1582420,
year = {1992},
author = {Counter, CM and Avilion, AA and LeFeuvre, CE and Stewart, NG and Greider, CW and Harley, CB and Bacchetti, S},
title = {Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity.},
journal = {The EMBO journal},
volume = {11},
number = {5},
pages = {1921-1929},
pmid = {1582420},
issn = {0261-4189},
mesh = {*Cell Transformation, Neoplastic ; *Cell Transformation, Viral ; Cellular Senescence ; *Chromosomes, Human ; DNA/genetics ; DNA Nucleotidylexotransferase/*metabolism ; Humans ; Karyotyping ; Kidney/cytology/embryology ; *Telomere ; Transfection ; },
abstract = {Loss of telomeric DNA during cell proliferation may play a role in ageing and cancer. Since telomeres permit complete replication of eukaryotic chromosomes and protect their ends from recombination, we have measured telomere length, telomerase activity and chromosome rearrangements in human cells before and after transformation with SV40 or Ad5. In all mortal populations, telomeres shortened by approximately 65 bp/generation during the lifespan of the cultures. When transformed cells reached crisis, the length of the telomeric TTAGGG repeats was only approximately 1.5 kbp and many dicentric chromosomes were observed. In immortal cells, telomere length and frequency of dicentric chromosomes stabilized after crisis. Telomerase activity was not detectable in control or extended lifespan populations but was present in immortal populations. These results suggest that chromosomes with short (TTAGGG)n tracts are recombinogenic, critically shortened telomeres may be incompatible with cell proliferation and stabilization of telomere length by telomerase may be required for immortalization.},
}
@article {pmid1577275,
year = {1992},
author = {Gualberto, A and Patrick, RM and Walsh, K},
title = {Nucleic acid specificity of a vertebrate telomere-binding protein: evidence for G-G base pair recognition at the core-binding site.},
journal = {Genes &amp; development},
volume = {6},
number = {5},
pages = {815-824},
doi = {10.1101/gad.6.5.815},
pmid = {1577275},
issn = {0890-9369},
support = {AR40197/AR/NIAMS NIH HHS/United States ; },
mesh = {Animals ; Base Composition ; Base Sequence ; Binding Sites/genetics ; Chick Embryo ; DNA-Binding Proteins/genetics/*metabolism ; Guanine/*metabolism ; Kinetics ; Methylation ; Molecular Sequence Data ; Nucleic Acid Conformation ; Repetitive Sequences, Nucleic Acid ; Telomere/*metabolism ; },
abstract = {A factor from avian cells formed complexes with telomeric sequences and other single-stranded probes that contained tracts of guanine residues. Nucleoprotein complexes with telomere probes required two or more of the telomeric repeats that were incapable of Watson-Crick base-pairing. Methylation interference and protection experiments identified guanine N7 residues that were critical for the formation of the nucleoprotein complex and for the formation of a higher-order structure that occurred in the absence of the protein. Substitutions of deoxyinosine (dI) for deoxyguanosine (dG) demonstrated that the exocyclic N2 amino groups in the internal telomeric repeat, but not the terminal repeat, were required for the formation of the chemically protected structure and for protein binding. On the basis of these data we propose that the factor specifically recognizes a hairpin DNA structure that is stabilized by intramolecular G-G base-pairing between the telomere repeats. The positions of the critical guanine N2 and N7 groups indicate a G-G base-pairing configuration, where guanines function as hydrogen bond donors at the internal telomeric repeat and hydrogen bond acceptors at the terminal telomeric repeat.},
}
@article {pmid1577274,
year = {1992},
author = {Hardy, CF and Sussel, L and Shore, D},
title = {A RAP1-interacting protein involved in transcriptional silencing and telomere length regulation.},
journal = {Genes &amp; development},
volume = {6},
number = {5},
pages = {801-814},
doi = {10.1101/gad.6.5.801},
pmid = {1577274},
issn = {0890-9369},
support = {CA09503-0/CA/NCI NIH HHS/United States ; GM40094/GM/NIGMS NIH HHS/United States ; T32 GM08281/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Base Sequence ; Cloning, Molecular ; DNA-Binding Proteins/chemistry/*genetics/metabolism ; GTP-Binding Proteins/genetics/metabolism ; Gene Expression Regulation, Fungal/*genetics ; Molecular Sequence Data ; Mutation/genetics ; Proto-Oncogene Proteins/genetics/metabolism ; Recombinant Fusion Proteins/genetics/metabolism ; Repressor Proteins/chemistry/*genetics/metabolism ; Saccharomyces cerevisiae/*genetics ; *Saccharomyces cerevisiae Proteins ; Telomere/*metabolism ; *Telomere-Binding Proteins ; Transcription, Genetic/*genetics ; rap GTP-Binding Proteins ; },
abstract = {The yeast RAP1 protein is a sequence-specific DNA-binding protein that functions as both a repressor and an activator of transcription. RAP1 is also involved in the regulation of telomere structure, where its binding sites are found within the terminal poly(C1-3A) sequences. Previous studies have indicated that the regulatory function of RAP1 is determined by the context of its binding site and, presumably, its interactions with other factors. Using the two-hybrid system, a genetic screen for the identification of protein-protein interactions, we have isolated a gene encoding a RAP1-interacting factor (RIF1). Strains carrying gene disruptions of RIF1 grow normally but are defective in transcriptional silencing and telomere length regulation, two phenotypes strikingly similar to those of silencing-defective rap1s mutants. Furthermore, hybrid proteins containing rap1s missense mutations are defective in an interaction with RIF1 in the two-hybrid system. Taken together, these data support the idea that the rap1s phenotypes are attributable to a failure to recruit RIF1 to silencers and telomeres and suggest that RIF1 is a cofactor or mediator for RAP1 in the establishment of a repressed chromatin state at these loci. By use of the two-hybrid system, we have isolated a mutation in RIF1 that partially restores the interaction with rap1s mutant proteins.},
}
@article {pmid1577273,
year = {1992},
author = {Mitcham, JL and Lynn, AJ and Prescott, DM},
title = {Analysis of a scrambled gene: the gene encoding alpha-telomere-binding protein in Oxytricha nova.},
journal = {Genes &amp; development},
volume = {6},
number = {5},
pages = {788-800},
doi = {10.1101/gad.6.5.788},
pmid = {1577273},
issn = {0890-9369},
support = {2 ROI GM19199/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Blotting, Southern ; Cloning, Molecular ; DNA, Protozoan/genetics/*metabolism ; DNA-Binding Proteins/*genetics ; Genes ; Molecular Sequence Data ; Oxytricha/*genetics ; Polymerase Chain Reaction ; Protozoan Proteins/*genetics ; Recombination, Genetic/genetics ; Regulatory Sequences, Nucleic Acid/genetics ; Sequence Homology, Nucleic Acid ; },
abstract = {Following cell mating in ciliates, a copy of the micronuclear genome is processed into a new macronucleus through massive cutting, reordering, splicing, elimination, and amplification of the DNA. DNA processing includes the deletion of short interrupting elements called internal eliminated sequences (IESs), followed by the splicing of the remaining segments, known as macronuclear destined sequences (MDSs). The MDSs in some micronuclear genes, such as actin I, are scrambled and must be reordered during IES removal and MDS splicing to yield a functional gene. Here, we describe the cloning, sequencing, and characterization of a different scrambling pattern for the gene that encodes the alpha subunit of the telomere-binding protein of Oxytricha nova. The micronuclear gene is made up of 14 MDSs in the scrambled order 1-3-5-7-9-11-2-4-6-8-10-12-13-14. Only the scrambled version is present in the micronucleus, and only the unscrambled version is present in the macronucleus. We propose that unscrambling occurs by homologous recombination guided by pairs of direct repeats at MDS-IES junctions. The patterned array of scrambling may be a clue to the origin of scrambling in this gene.},
}
@article {pmid1570334,
year = {1992},
author = {Gottschling, DE},
title = {Telomere-proximal DNA in Saccharomyces cerevisiae is refractory to methyltransferase activity in vivo.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {89},
number = {9},
pages = {4062-4065},
pmid = {1570334},
issn = {0027-8424},
support = {GM43893/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatin/*ultrastructure ; DNA, Fungal/*metabolism ; *Gene Expression Regulation, Fungal ; Genes, Fungal ; Methyltransferases/*metabolism ; Saccharomyces cerevisiae/*genetics/metabolism ; *Site-Specific DNA-Methyltransferase (Adenine-Specific) ; *Telomere ; },
abstract = {Genes located near telomeres in Saccharomyces cerevisiae undergo position-effect variegation; their transcription is subject to reversible but mitotically heritable repression. This position effect and the finding that telomeric DNA is late replicating suggest that yeast telomeres exist in a heterochromatin-like state. Mutations in genes that suppress the telomeric position effect suggest that a special chromatin structure exists near chromosomal termini. Thus transcriptional repression may be explained by the inability of DNA binding proteins to access the DNA near telomeres. To test this hypothesis, the Escherichia coli Dam DNA methyltransferase, which modifies the sequence GATC, was introduced into S. cerevisiae cells. DNA sequences near the telomere were highly refractive to Dam methylation but were modified when located at positions more internal on the chromosome. Telomeric sequences were accessible to methyltransferase activity in strains that contained a mutation that suppressed the telomeric position effect. These data support the model that sequence-specific DNA binding proteins are excluded from telomere-proximal sequences in vivo and show that expression of DNA methyltransferase activity may serve as a useful tool for mapping chromosomal structural domains in vivo.},
}
@article {pmid1569937,
year = {1992},
author = {Longtine, MS and Enomoto, S and Finstad, SL and Berman, J},
title = {Yeast telomere repeat sequence (TRS) improves circular plasmid segregation, and TRS plasmid segregation involves the RAP1 gene product.},
journal = {Molecular and cellular biology},
volume = {12},
number = {5},
pages = {1997-2009},
pmid = {1569937},
issn = {0270-7306},
support = {GM07323/GM/NIGMS NIH HHS/United States ; GM38626/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; Base Sequence ; Chromosome Deletion ; *Chromosomes, Fungal ; Cloning, Molecular ; DNA, Circular/*genetics ; DNA-Binding Proteins/*genetics ; Escherichia coli/genetics ; Fungal Proteins/*genetics/metabolism ; *Genes, Fungal ; Genotype ; Mitosis ; Mutation ; *Plasmids ; *Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; Saccharomyces cerevisiae/cytology/*genetics ; Schizosaccharomyces/genetics ; Telomere/*physiology ; Temperature ; *Transcription Factors ; },
abstract = {Telomere repeat sequences (TRSs) can dramatically improve the segregation of unstable circular autonomously replicating sequence (ARS) plasmids in Saccharomyces cerevisiae. Deletion analysis demonstrated that yeast TRSs, which conform to the general sequence (C(1-3)A)n, are able to stabilize circular ARS plasmids. A number of TRS clones of different primary sequence and C(1-3)A tract length confer the plasmid stabilization phenotype. TRS sequences do not appear to improve plasmid replication efficiency, as determined by plasmid copy number analysis and functional assays for ARS activity. Pedigree analysis confirms that TRS-containing plasmids are missegregated at low frequency and that missegregated TRS-containing plasmids, like ARS plasmids, are preferentially retained by the mother cell. Plasmids stabilized by TRSs have properties that distinguish them from centromere-containing plasmids and 2 microns-based recombinant plasmids. Linear ARS plasmids, which include two TRS tracts at their termini, segregate inefficiently, while circular plasmids with one or two TRS tracts segregate efficiently, suggesting that plasmid topology or TRS accessibility interferes with TRS segregation function on linear plasmids. In strains carrying the temperature-sensitive mutant alleles rap1grc4 and rap1-5, TRS plasmids are not stable at the semipermissive temperature, suggesting that RAP1 protein is involved in TRS plasmid stability. In Schizosaccharomyces pombe, an ARS plasmid was stabilized by the addition of S. pombe telomere sequence, suggesting that the ability to improve the segregation of ARS plasmids is a general property of telomere repeats.},
}
@article {pmid1579440,
year = {1992},
author = {Scherf, A and Mattei, D},
title = {Cloning and characterization of chromosome breakpoints of Plasmodium falciparum: breakage and new telomere formation occurs frequently and randomly in subtelomeric genes.},
journal = {Nucleic acids research},
volume = {20},
number = {7},
pages = {1491-1496},
pmid = {1579440},
issn = {0305-1048},
mesh = {Animals ; Antigens, Protozoan/genetics ; Base Sequence ; Blotting, Southern ; *Chromosome Deletion ; Cloning, Molecular ; Molecular Sequence Data ; Plasmodium falciparum/*genetics ; Polymerase Chain Reaction ; Proteins/*genetics ; Protozoan Proteins/*genetics ; Telomere/*metabolism ; },
abstract = {We analysed the genetic stability of two subtelomeric genes of the human malaria parasite Plasmodium falciparum. A PCR based assay, using a telomere and a target-gene specific primer was used to detect potential chromosome rearrangements. We show that chromosome breakage and the formation of new telomeres occur frequently in the two genes coding for histidine rich proteins (HRP I and HRP II) in laboratory isolates, but remains undetectable in clinical parasite isolates. This finding suggests an essential role of these genes in vivo and that chromosome breakage is rather an accidental process than a programmed chromosome fragmentation. Cloning and sequencing of 8 chromosome breakpoints of the HRP II gene from one parasite isolate shows that the breakage occurs within a broad region in which new telomere formation appear to take place at random sites. Furthermore, this analysis revealed no obvious sequence similarities of sites of telomere addition. Finally, we show that an irregular pattern of heterogeneous telomere repeats is added at each broken end and that each healed chromosome contains a distinct pattern of repeats. We discuss a model for telomere formation in P. falciparum.},
}
@article {pmid1572659,
year = {1992},
author = {IJdo, JW and Baldini, A and Wells, RA and Ward, DC and Reeders, ST},
title = {FRA2B is distinct from inverted telomere repeat arrays at 2q13.},
journal = {Genomics},
volume = {12},
number = {4},
pages = {833-835},
doi = {10.1016/0888-7543(92)90319-n},
pmid = {1572659},
issn = {0888-7543},
mesh = {Base Sequence ; Biological Evolution ; Chromosome Fragile Sites ; *Chromosome Fragility ; Chromosomes, Human, Pair 2/*ultrastructure ; Cosmids ; DNA Probes ; Humans ; Repetitive Sequences, Nucleic Acid ; Telomere/ultrastructure ; },
abstract = {Human chromosome 2 was formed by a telomere-to-telomere fusion of two ancestral ape chromosomes. The fusion point is localized in chromosomal band 2q13, which also contains the rare, folate-sensitive fragile site FRA2B. It has been hypothesized that this fragile site may be related to the presence of interstitial telomeric and subtelomeric sequences, which have come to lie in an inverted repeat arrangement as a result of the fusion event. Fluorescence in situ hybridization of a genomic cosmid c8.1, which spans the fusion point, was carried out on metaphase spreads of an individual who expressed the fragile site at 2q13. We show that the fusion point maps distal to this fragile site. Therefore, we conclude that the inverted arrays of telomeric and subtelomeric sequences found at this fusion point are unlikely to correspond to the rare fragile site at 2q13.},
}
@article {pmid1549575,
year = {1992},
author = {Eicher, EM and Lee, BK and Washburn, LL and Hale, DW and King, TR},
title = {Telomere-related markers for the pseudoautosomal region of the mouse genome.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {89},
number = {6},
pages = {2160-2164},
pmid = {1549575},
issn = {0027-8424},
support = {CA09217/CA/NCI NIH HHS/United States ; GM20919/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Blotting, Southern ; Crosses, Genetic ; DNA/*genetics/isolation &amp; purification ; DNA Probes ; Female ; Genetic Linkage ; Genetic Markers ; Heterochromatin/physiology ; Male ; Mice ; Mice, Inbred Strains/*genetics ; Muridae/*genetics ; Oligonucleotide Probes ; *Recombination, Genetic ; Telomere/*physiology ; *X Chromosome ; *Y Chromosome ; },
abstract = {The pseudoautosomal (PA) region of the mammalian genome is the region of the X and Y chromosomes that shares extensive DNA sequence homology and is of special interest because it may play an essential role during male meiosis. We have identified three telomere-related restriction fragments from the PA region of the mouse genome, using an oligonucleotide probe composed of the mammalian telomere consensus sequence TTAGGG. PA assignment of two C57BL/6J-derived fragments was initially suggested by analysis of DNAs from progeny sired by C57BL/6J males carrying the rearranged Y chromosome, Y*: the hybridization intensity of both fragments was concordant with the sex-chromosome complement of the offspring. Further analysis indicated that both fragments were present in female and male F1, mice regardless of the sex of their C57BL/6J parent--a criterion for autosomal or PA linkage. Both fragments were closely linked to each other and located on the X chromosome distal to amelogenin (Amg)--in agreement with X or PA linkage. Confirmation of the PA derivation of these fragments was accomplished by following their segregation in a cross involving XY* males mated to DBA/2J females. A similar experiment identified a third PA-derived restriction fragment of LT/SvEi origin. Identification of PA-derived telomere-related restriction fragments will enable further genetic analysis of this region of the mouse genome.},
}
@article {pmid1737616,
year = {1992},
author = {Wright, JH and Gottschling, DE and Zakian, VA},
title = {Saccharomyces telomeres assume a non-nucleosomal chromatin structure.},
journal = {Genes &amp; development},
volume = {6},
number = {2},
pages = {197-210},
doi = {10.1101/gad.6.2.197},
pmid = {1737616},
issn = {0890-9369},
support = {GM43265/GM/NIGMS NIH HHS/United States ; GM43893/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatin/chemistry/*metabolism ; DNA, Fungal/*metabolism ; DNA, Satellite/*metabolism ; Deoxyribonuclease I/metabolism ; GTP-Binding Proteins/metabolism ; Methylation ; Methyltransferases/metabolism ; Nucleic Acid Conformation ; Nucleosomes/metabolism ; Precipitin Tests ; Saccharomyces cerevisiae/*genetics ; *Site-Specific DNA-Methyltransferase (Adenine-Specific) ; Telomere/*metabolism ; rap GTP-Binding Proteins ; },
abstract = {The chromatin structures of the telomeric and subtelomeric regions on chromosomal DNA molecules in Saccharomyces cerevisiae were analyzed using micrococcal nuclease and DNAse I. The subtelomeric repeats X and Y' were assembled in nucleosomes. However, the terminal tracts of C1-3A repeats were protein protected in a particle larger than a nucleosome herein called a telosome. The proximal boundary of the telosome was a DNase I hypersensitive site. This boundary between the telosome and adjacent nucleosomes was completely accessible to Escherichia coli dam methylase when this enzyme was expressed in yeast, whereas a site 250 bp internal to the telomeric repeats was relatively inaccessible. Telosomes could be cleaved from chromosome ends with nuclease and solubilized as protein-DNA complexes. Immunoprecipitation of chromosomal telosomes with antiserum to the RAP1 protein indicated that RAP1 was one component of isolated telosomes. Thus, the termini of chromosomal DNA molecules in yeast are assembled in a non-nucleosomal structure encompassing the entire terminal C1-3A tract. This structure is separated from adjacent nucleosomes by a region of DNA that is highly accessible to enzymes.},
}
@article {pmid1537344,
year = {1992},
author = {de Lange, T},
title = {Human telomeres are attached to the nuclear matrix.},
journal = {The EMBO journal},
volume = {11},
number = {2},
pages = {717-724},
pmid = {1537344},
issn = {0261-4189},
mesh = {Base Sequence ; Binding Sites ; Blotting, Southern ; Burkitt Lymphoma ; Cell Cycle ; Cell Line ; DNA, Neoplasm/isolation &amp; purification/metabolism ; HeLa Cells ; Humans ; Leukemia, Promyelocytic, Acute ; Molecular Sequence Data ; Nuclear Matrix/*metabolism ; Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; Telomere/*metabolism ; Transfection ; },
abstract = {This report shows that human telomeres are tightly associated with the nuclear matrix. Telomere attachment is observed in several cell types and in all stages of interphase. Mapping experiments show that telomeres are anchored via their TTAGGG repeats; a subtelomeric repeat located immediately proximal to the telomeric TTAGGG repeats is quantitatively released from the nuclear matrix by restriction endonuclease cleavage. TTAGGG repeats introduced at chromosome-internal sites by DNA transfection do not behave as matrix attached loci, suggesting that the telomeric position of the repeats is required for their interaction with the nuclear matrix. These findings are consistent with the idea that telomeres function as a nucleoprotein complex.},
}
@article {pmid1731885,
year = {1992},
author = {Sen, D and Gilbert, W},
title = {Novel DNA superstructures formed by telomere-like oligomers.},
journal = {Biochemistry},
volume = {31},
number = {1},
pages = {65-70},
doi = {10.1021/bi00116a011},
pmid = {1731885},
issn = {0006-2960},
support = {5 R01 GM41895/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Cations ; DNA/*chemistry ; Guanine/*chemistry ; Methylation ; Models, Molecular ; Molecular Sequence Data ; Molecular Weight ; Nucleic Acid Conformation ; Oligonucleotides/*chemistry ; Sensitivity and Specificity ; Telomere/*chemistry ; },
abstract = {DNA oligomers containing three or more contiguous guanines form tetrastranded parallel complexes, G4-DNA, in the presence of alkali cations. However, oligomers that have a single multi-guanine motif at their 3' or 5' end, with a guanine as the terminal base, also form higher order products. Thus, the oligomer T8G3T forms a unique G4-DNA product at neutral pH in the presence of Na+, K+, or Rb+; however, its isomeric counterpart T9G3 in K+ or Rb+ generates an additional ladder of products of substantially lower gel mobility. We show that these larger complexes contain, respectively, 8, 12, or 16 distinct strands of oligomer. The octamer structure formed by T9G3 assembles in moderate salt at room temperature and melts around 60 degrees C in 100 mM KCl. Methylation protection experiments suggest a nested head-to-tail superstructure containing two tetraplexes bonded front-to-back via G quartets formed by out-of-register guanines. Naturally occurring chromosomal telomeres, which all have guanines at their 3' termini, may be able to form these superstructures.},
}
@article {pmid1738609,
year = {1992},
author = {Petracek, ME and Berman, J},
title = {Chlamydomonas reinhardtii telomere repeats form unstable structures involving guanine-guanine base pairs.},
journal = {Nucleic acids research},
volume = {20},
number = {1},
pages = {89-95},
pmid = {1738609},
issn = {0305-1048},
mesh = {Animals ; Base Composition/physiology ; Base Sequence ; Chlamydomonas reinhardtii/*genetics ; Guanine/*metabolism ; Macromolecular Substances ; Methylation ; Molecular Sequence Data ; Nucleic Acid Conformation ; Oligodeoxyribonucleotides/genetics/metabolism ; Potassium/metabolism ; Repetitive Sequences, Nucleic Acid/*genetics ; Sodium/metabolism ; Telomere/*metabolism ; },
abstract = {Unusual DNA structures involving four guanines in a planar formation (guanine tetrads) are formed by guanine-rich (G-rich) telomere DNA and other G-rich sequences (reviewed in (1)) and may be important in the structure and function of telomeres. These structures result from intrastrand and/or interstrand Hoogsteen base pairs between the guanines. We used the telomeric repeat of Chlamydomonas reinhardtii, TTTTAGGG, which contains 3 guanines and has a long interguanine A + T tract, to determine whether these sequences can form intrastrand and interstrand guanine tetrads. We have found that ss (TTTTAGGG)4 can form intrastrand guanine tetrads that are less stable than those formed by more G-rich telomere sequences. They are not only more stable, but also more compact, they are more stable in the presence of K+ than they are in the presence of Na+. While ds oligonucleotides with ss 3' overhangs of (TTTTAGGG)2 can be observed to associate as dimers, formation of this interstrand guanine tetrad structure occurs to a very limited extent and requires very high G-strand concentration, high ionic strength, and at least 49 hours of incubation. Our results suggest that, if telomere dimerization occurs in vivo, it would require factors in addition to the TTTTAGGG telomere sequence.},
}
@article {pmid1822287,
year = {1991},
author = {Henderson, ER and Larson, DD},
title = {Telomeres--what's new at the end?.},
journal = {Current opinion in genetics &amp; development},
volume = {1},
number = {4},
pages = {538-543},
doi = {10.1016/s0959-437x(05)80205-9},
pmid = {1822287},
issn = {0959-437X},
mesh = {Animals ; Cell Nucleus/ultrastructure ; DNA Replication ; DNA-Binding Proteins/classification/metabolism ; Drosophila/genetics ; Nucleic Acid Conformation ; Protozoan Proteins/classification/metabolism ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/genetics ; Telomere/physiology/*ultrastructure ; },
abstract = {Telomeres are specialized chromatin domains located at the ends of chromosomes. They are involved in chromosome replication, stability and localization in the nucleus. In addition to these functions, recent work suggests that telomeres are involved in such superficially diverse cellular phenomena as ageing, cancer, nuclear architecture and nuclear/cellular division.},
}
@article {pmid1934070,
year = {1991},
author = {Müller, F and Wicky, C and Spicher, A and Tobler, H},
title = {New telomere formation after developmentally regulated chromosomal breakage during the process of chromatin diminution in Ascaris lumbricoides.},
journal = {Cell},
volume = {67},
number = {4},
pages = {815-822},
doi = {10.1016/0092-8674(91)90076-b},
pmid = {1934070},
issn = {0092-8674},
mesh = {Animals ; Ascaris/*embryology/ultrastructure ; Base Sequence ; Blotting, Southern ; Chromosomes/physiology/*ultrastructure ; Cloning, Molecular ; DNA/genetics/metabolism ; DNA Nucleotidylexotransferase/metabolism ; Molecular Sequence Data ; Restriction Mapping ; Telomere/*ultrastructure ; },
abstract = {During the process of chromatin diminution, which takes place in all presomatic cells of the early Ascaris embryo, the heterochromatic termini of the chromosomes are lost. Here we show that the newly formed ends of the reduced somatic chromosomes carry tandem repeats of the telomeric sequence TTAGGC. Comparison of a cloned somatic telomere with the corresponding germline chromosomal region revealed that these telomeric repeats are not present at or near the chromosomal breakage site. They are most likely added by a telomerase-mediated event. Chromosomal breakage, which precedes the telomere addition process, takes place within a short, specific chromosomal region (CBR); however, it does not occur at a single locus, but rather at many different sites. Altogether, our data show that chromatin diminution in Ascaris is a complex molecular process that includes site-specific chromosomal breakage, new telomere formation, and DNA degradation.},
}
@article {pmid1840510,
year = {1991},
author = {Gray, JT and Celander, DW and Price, CM and Cech, TR},
title = {Cloning and expression of genes for the Oxytricha telomere-binding protein: specific subunit interactions in the telomeric complex.},
journal = {Cell},
volume = {67},
number = {4},
pages = {807-814},
doi = {10.1016/0092-8674(91)90075-a},
pmid = {1840510},
issn = {0092-8674},
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Cloning, Molecular ; DNA-Binding Proteins/*genetics/metabolism ; Escherichia coli/genetics ; Gene Expression ; Macromolecular Substances ; Molecular Sequence Data ; Nuclear Proteins/*genetics ; Oligonucleotides/chemistry/metabolism ; Oxytricha/*genetics ; Protozoan Proteins/*genetics ; Telomere/*metabolism/ultrastructure ; },
abstract = {Telomeres of Oxytricha nova macronuclear chromosomes consist of a repeated T4G4 sequence, single-stranded at the 3' terminus, bound by a heterodimeric protein. The cloning of genes for the two polypeptides and their separate expression in E. coli have enabled evaluation of their individual contributions to DNA binding. The 56 kd alpha subunit binds single-stranded DNA by itself, one polypeptide per T4G4 block; multiple subunits can coat a (T4G4)n multimer. The derived amino acid sequence of alpha does not reveal any known DNA-binding motif, so it appears to represent a novel type of DNA-binding protein. The previously cloned 41 kd beta subunit does not by itself protect DNA from methylation, but is required along with alpha to recreate the pattern of methylation protection indicative of telomeres in vivo. The unusual ability of the protein to engage in two different interactions with the same telomeric DNA sequence might provide the versatility necessary for diverse telomere functions.},
}
@article {pmid1938877,
year = {1991},
author = {D'Mello, NP and Jazwinski, SM},
title = {Telomere length constancy during aging of Saccharomyces cerevisiae.},
journal = {Journal of bacteriology},
volume = {173},
number = {21},
pages = {6709-6713},
pmid = {1938877},
issn = {0021-9193},
mesh = {Blotting, Southern ; Cell Division/physiology ; *DNA Replication ; DNA, Fungal ; Saccharomyces cerevisiae/*genetics/growth &amp; development ; Telomere/*physiology ; Time Factors ; },
abstract = {It has been proposed that a decrease in the length of telomeres with the successive rounds of DNA replication that accompany mitotic division could play a causal role in the aging process. To investigate this possibility, telomeres from cells of the budding yeast Saccharomyces cerevisiae that varied in replicative age were examined. No change in the lengths of the telomeres was observed in cells that had completed up to 83% of the mean life span. We conclude that the length of the telomeres is not a contributing factor in the natural aging process in individual yeast cells.},
}
@article {pmid1807832,
year = {1991},
author = {Louis, EJ and Haber, JE},
title = {Evolutionarily recent transfer of a group I mitochondrial intron to telomere regions in Saccharomyces cerevisiae.},
journal = {Current genetics},
volume = {20},
number = {5},
pages = {411-415},
pmid = {1807832},
issn = {0172-8083},
support = {RR04671/RR/NCRR NIH HHS/United States ; },
mesh = {Base Sequence ; *Biological Evolution ; DNA, Fungal ; *Introns ; *Mitochondria ; Molecular Sequence Data ; *Recombination, Genetic ; Saccharomyces cerevisiae/*genetics/ultrastructure ; *Telomere ; },
abstract = {The junctions between X and Y' subtelomeric repeats in Saccharomyces cerevisiae usually contain a stretch of telomere sequences, (G1-3T)n. Two of three cloned X-Y' junctions from strain YP1 have a replacement of about 200 bp of X, the internal telomere sequence, and 49 bp of Y' by a 292 bp sequence. The first 227 bp of this insertion sequence are 100% identical to the fourth intron of cytochrome b. The rest of the insertion has homology to an unknown dispersed nuclear sequence. Recombination among subtelomeric regions can explain the nuclear distribution of this sequence and why telomeres can trap and maintain sequences that would otherwise be lost.},
}
@article {pmid1945829,
year = {1991},
author = {Fang, GW and Cech, TR},
title = {Molecular cloning of telomere-binding protein genes from Stylonychia mytilis.},
journal = {Nucleic acids research},
volume = {19},
number = {20},
pages = {5515-5518},
pmid = {1945829},
issn = {0305-1048},
support = {GM28039/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Blotting, Southern ; Cloning, Molecular ; DNA, Protozoan/*metabolism ; DNA-Binding Proteins/*genetics/metabolism ; Molecular Sequence Data ; Restriction Mapping ; Sequence Alignment ; Sporadotrichina/*genetics ; Telomere/*metabolism ; },
abstract = {A telomere-binding protein heterodimer of 56 kDa (alpha) and 41 kDa (beta) subunits binds specifically to Oxytricha nova telomeres. Genes encoding both subunits have been cloned previously. Here we report molecular cloning and sequence analysis of the homologous genes in Stylonychia mytilis. The derived amino acid sequences were 79% identical for the alpha subunits and 77% identical for the beta subunits. Three repeats of a Leu/Ile heptad were found in each subunit, which might be involved in heterodimer formation. A 360 amino acid region of the Stylonychia mytilis alpha subunit was found to share weak sequence similarity with human vimentin, suggesting the possibility of a relationship between telomeres and intermediate filaments.},
}
@article {pmid1840670,
year = {1991},
author = {Le Blancq, SM and Kase, RS and Van der Ploeg, LH},
title = {Analysis of a Giardia lamblia rRNA encoding telomere with [TAGGG]n as the telomere repeat.},
journal = {Nucleic acids research},
volume = {19},
number = {20},
pages = {5790},
pmid = {1840670},
issn = {0305-1048},
support = {A126497//PHS HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA, Protozoan ; Giardia lamblia/*genetics ; Molecular Sequence Data ; Nucleic Acid Hybridization ; RNA, Protozoan/genetics ; RNA, Ribosomal/*genetics ; *Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; *Telomere ; },
}
@article {pmid1924367,
year = {1991},
author = {IJdo, JW and Baldini, A and Ward, DC and Reeders, ST and Wells, RA},
title = {Origin of human chromosome 2: an ancestral telomere-telomere fusion.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {88},
number = {20},
pages = {9051-9055},
pmid = {1924367},
issn = {0027-8424},
mesh = {Base Sequence ; *Biological Evolution ; Cells, Cultured ; Chromosome Mapping ; *Chromosomes, Human, Pair 2 ; Cloning, Molecular ; Cosmids ; DNA/genetics ; DNA Probes ; Genomic Library ; Humans ; Karyotyping ; Lymphocytes/cytology/physiology ; Metaphase ; Microscopy, Fluorescence ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Repetitive Sequences, Nucleic Acid ; Telomere/*physiology ; },
abstract = {We have identified two allelic genomic cosmids from human chromosome 2, c8.1 and c29B, each containing two inverted arrays of the vertebrate telomeric repeat in a head-to-head arrangement, 5'(TTAGGG)n-(CCCTAA)m3'. Sequences flanking this telomeric repeat are characteristic of present-day human pretelomeres. BAL-31 nuclease experiments with yeast artificial chromosome clones of human telomeres and fluorescence in situ hybridization reveal that sequences flanking these inverted repeats hybridize both to band 2q13 and to different, but overlapping, subsets of human chromosome ends. We conclude that the locus cloned in cosmids c8.1 and c29B is the relic of an ancient telomere-telomere fusion and marks the point at which two ancestral ape chromosomes fused to give rise to human chromosome 2.},
}
@article {pmid1785140,
year = {1991},
author = {Blackburn, EH},
title = {Telomeres.},
journal = {Trends in biochemical sciences},
volume = {16},
number = {10},
pages = {378-381},
doi = {10.1016/0968-0004(91)90155-o},
pmid = {1785140},
issn = {0968-0004},
support = {GM26259/GM/NIGMS NIH HHS/United States ; GM32565/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA/*genetics ; DNA Nucleotidylexotransferase/*physiology ; DNA Replication/physiology ; Humans ; Molecular Sequence Data ; Telomere/*physiology ; },
abstract = {Telomeres are specialized structures at the ends of eukaryotic linear chromosomes, consisting of protein-bound tandemly repeated simple DNA sequences. Telomeric DNA is unique in that it is copied from an RNA template that forms part of the enzyme, telomerase. This review discusses the synthesis and maintenance of these unusual structures.},
}
@article {pmid1685135,
year = {1991},
author = {Kipling, D and Ackford, HE and Taylor, BA and Cooke, HJ},
title = {Mouse minor satellite DNA genetically maps to the centromere and is physically linked to the proximal telomere.},
journal = {Genomics},
volume = {11},
number = {2},
pages = {235-241},
doi = {10.1016/0888-7543(91)90128-2},
pmid = {1685135},
issn = {0888-7543},
support = {GM18684/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; Animals ; Blotting, Southern ; Centromere ; Chromosome Mapping ; DNA, Satellite/*genetics ; Electrophoresis, Agar Gel ; Electrophoresis, Gel, Pulsed-Field ; Genetic Linkage ; Genetic Markers ; Mice/*genetics ; Muridae/genetics ; Polymorphism, Restriction Fragment Length ; Reading Frames ; *Telomere ; Translocation, Genetic/genetics ; },
abstract = {As an adjunct to attempts to define functionally important sequences at human centromeres, we have undertaken a long-range physical analysis of these regions in the mouse. Mouse centromeres are usually situated very close to the chromosome ends and are closely associated with minor satellite sequences on the basis of cytological observations. Using pulsed-field gel electrophoresis we find that this satellite DNA is arranged as tandem arrays, predominantly uninterrupted by nonsatellite sequences. These arrays can be released largely intact by digestion with a range of enzymes that generally cleave frequently in non-satellite DNA. The restriction fragments carrying these arrays are polymorphic in size between inbred strains and provide direct markers for mouse centromeres. To illustrate the possible use of these polymorphic markers we have mapped a 1.3-Mb PvuII variant in a set of RI strains to the centromere of Chromosome 7. The minor satellite arrays are very close to the centromeric telomere and physical linkage with terminal repeat sequences can readily be detected, placing many minor satellite arrays on terminal restriction fragments smaller than 1 Mb. The apparent lack of any sizable amount of nonsatellite DNA between the minor satellite and the terminal repeat arrays indicates that many mouse chromosomes are truly telocentric.},
}
@article {pmid1657721,
year = {1991},
author = {Schmid, M and Steinbeisser, H and Ascenzioni, F and Trendelenburg, MF and Lipps, HJ},
title = {Native yeast telomeres are sufficient to stabilize linear DNA in Xenopus laevis oocytes.},
journal = {Gene},
volume = {106},
number = {1},
pages = {121-124},
doi = {10.1016/0378-1119(91)90575-v},
pmid = {1657721},
issn = {0378-1119},
mesh = {Animals ; Bovine papillomavirus 1/genetics ; DNA/*genetics/metabolism ; Electrophoresis, Agar Gel ; Genes, Fungal ; Genes, Viral ; Microinjections ; Nucleic Acid Conformation ; *Oocytes ; *Plasmids ; Restriction Mapping ; *Telomere ; Templates, Genetic ; Tetrahymena thermophila/genetics ; Xenopus laevis ; },
abstract = {We have constructed a linear plasmid in yeast containing the entire bovine papillomavirus genome and tested its physical stability following microinjection into stage VI oocytes of Xenopus laevis. Our results show that unmodified telomeres, in contrast to the yeast-passaged telomeres, drastically affect the stability of the injected linear plasmid. Plasmids carrying unmodified Tetrahymena thermophila telomeric sequences are rapidly degraded in oocytes. When these plasmids are passed through yeast, the telomere ends become modified by the addition of yeast telomeric sequences. These plasmids are stably maintained in X. laevis oocytes, demonstrating that yeast-modified telomeres are sufficient to prevent linear DNA degradation.},
}
@article {pmid1891373,
year = {1991},
author = {Ijdo, JW and Wells, RA and Baldini, A and Reeders, ST},
title = {Improved telomere detection using a telomere repeat probe (TTAGGG)n generated by PCR.},
journal = {Nucleic acids research},
volume = {19},
number = {17},
pages = {4780},
pmid = {1891373},
issn = {0305-1048},
mesh = {Base Sequence ; Biotin/metabolism ; Chromosomes, Human/*chemistry ; DNA Probes/*genetics ; Fluorescence ; Humans ; Molecular Sequence Data ; Polymerase Chain Reaction ; Repetitive Sequences, Nucleic Acid/*genetics ; Uracil/analogs &amp; derivatives/metabolism ; },
}
@article {pmid1881914,
year = {1991},
author = {Sussel, L and Shore, D},
title = {Separation of transcriptional activation and silencing functions of the RAP1-encoded repressor/activator protein 1: isolation of viable mutants affecting both silencing and telomere length.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {88},
number = {17},
pages = {7749-7753},
pmid = {1881914},
issn = {0027-8424},
support = {CA09503-0/CA/NCI NIH HHS/United States ; GM40094/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; *Chromosomes, Fungal ; Crosses, Genetic ; DNA-Binding Proteins/*genetics ; Fungal Proteins/*genetics/isolation &amp; purification/metabolism ; Genes, Fungal ; Genes, Mating Type, Fungal ; Hydroxylamine ; Hydroxylamines/pharmacology ; Mutagenesis ; Restriction Mapping ; Saccharomyces cerevisiae/drug effects/*genetics ; *Transcription Factors ; *Transcription, Genetic ; },
abstract = {The repressor/activator protein 1 (RAP1) binds to the upstream activating sites of many genes, the silencer elements flanking the unexpressed mating-type loci HMR and HML, and the poly(C1-3A) sequences at telomeres, suggesting that RAP1 might have three distinct regulatory functions. To determine the in vivo role of RAP1 in repression of the HMR silent locus, we developed a screen to isolate rap1 mutants specifically defective in silencing. Fifteen independent mutants defining four different rap1 alleles were isolated. These alleles are defective to different extents in repression of an HMR locus containing a mutated, but fully functional, silencer. All four alleles are missense mutations in only three codons within a small C-terminal region of the gene. These silencing-defective mutants have no apparent growth defects, indicating that expression of the large number of essential genes that have promoters containing RAP1-binding sites is normal. A transcriptional silencing function of RAP1 can therefore be genetically separated from its presumably essential activation functions. Surprisingly, three of the silencing-defective rap1 alleles have significantly longer telomeres, suggesting that the function of RAP1 in both transcriptional silencing and telomere-length regulation may be related. In addition, we have demonstrated that increased gene dosage of either SIR1 or SIR4, two other factors required for silencing, suppresses the silencing defect of the rap1 mutants. The properties of SIR4 dosage suppression suggest that SIR4 protein may interact directly with RAP1 at silencers.},
}
@article {pmid1871116,
year = {1991},
author = {Farr, C and Fantes, J and Goodfellow, P and Cooke, H},
title = {Functional reintroduction of human telomeres into mammalian cells.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {88},
number = {16},
pages = {7006-7010},
pmid = {1871116},
issn = {0027-8424},
mesh = {Animals ; Base Sequence ; Cell Line ; Chromosomes, Human/*physiology ; Cloning, Molecular ; Cricetinae ; Cricetulus ; DNA/genetics/isolation &amp; purification ; Genetic Techniques ; Humans ; Hybrid Cells/*cytology ; Karyotyping ; Male ; Molecular Sequence Data ; Oligonucleotide Probes ; Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; *X Chromosome ; Y Chromosome ; },
abstract = {Telomeric sequences of eukaryotes consist of short tandem repeats organized in arrays of variable length in which the guanine-rich strand runs 5'----3' toward the chromosomal end. The terminal repeats in yeast are the only elements necessary for telomere function in this organism. To test whether mammalian terminal repeats can function after reintroduction into a mammalian cell, a repeat-containing terminal fragment from a human chromosome was electroporated into a hamster-human hybrid cell line. In 6 of 27 independent transformants analyzed, the introduced sequences were found at the ends of chromosomes, based on all available criteria. Terminal restriction-fragment heterogeneity and the survival of these chromosomes demonstrate that these telomeres are functional. Cytogenetic evidence from one of these cell lines suggests that chromosome breakage with healing at the integration site is the mechanism responsible for the terminal location.},
}
@article {pmid1862331,
year = {1991},
author = {Moyzis, RK},
title = {The human telomere.},
journal = {Scientific American},
volume = {265},
number = {2},
pages = {48-55},
doi = {10.1038/scientificamerican0891-48},
pmid = {1862331},
issn = {0036-8733},
mesh = {Animals ; Base Sequence ; Chromosomes/*ultrastructure ; Chromosomes, Fungal ; Cloning, Molecular ; DNA/*genetics ; DNA Probes ; DNA Replication ; Fluorescent Dyes ; Gene Library ; Genetic Markers ; Genome, Human ; Humans ; Microscopy, Fluorescence ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Repetitive Sequences, Nucleic Acid ; Tetrahymena/genetics ; },
}
@article {pmid1649315,
year = {1991},
author = {Carpenter, MS and DeLange, AM},
title = {A temperature-sensitive lesion in the small subunit of the vaccinia virus-encoded mRNA capping enzyme causes a defect in viral telomere resolution.},
journal = {Journal of virology},
volume = {65},
number = {8},
pages = {4042-4050},
pmid = {1649315},
issn = {0022-538X},
mesh = {Animals ; Base Sequence ; Cell Line ; DNA Replication ; DNA, Viral/*chemistry/genetics ; Electrophoresis, Agar Gel ; Electrophoresis, Polyacrylamide Gel ; Gene Expression Regulation, Viral ; *Genes, Viral ; Methyltransferases/*genetics/metabolism ; Molecular Sequence Data ; Multienzyme Complexes/*genetics/metabolism ; Mutation ; Nucleotidyltransferases/*genetics/metabolism ; Phosphoric Monoester Hydrolases/*genetics/metabolism ; Restriction Mapping ; Temperature ; Vaccinia virus/*enzymology/genetics/physiology ; Viral Proteins ; Virus Replication ; },
abstract = {Using pulsed-field gel electrophoresis, we demonstrated that the temperature-sensitive (ts) conditional lethal mutant ts9383 is, at the nonpermissive temperature, defective in the resolution of concatemeric replicative intermediate DNA to linear 185-kb monomeric DNA genomes. The resolution defect was shown to be the result of a partial failure of the mutant virus to convert the replicated form of the viral telomere to hairpin termini. In contrast to other mutants of this phenotype, pulse-labeling of viral proteins at various times postinfection revealed no obvious difference in the quantity or temporal appearance of members of the late class of polypeptides. Using the marker rescue technique, we localized the ts lesion in ts9383 to an approximately 1-kb region within the HindIII D fragment. Both the ts phenotype and the resolution defect were shown to be caused by a single-base C----T point mutation resulting in the conversion of the amino acid proline to serine in codon 23 of open reading frame D12. This gene encodes a 33-kDa polypeptide which is known to be the small subunit of the virus-encoded mRNA capping enzyme (E. G. Niles, G. J. Lee-Chen, S. Shuman, B. Moss, and S. S. Broyles, Virology 172:513-522, 1989). The data are consistent with a role for this capping enzyme subunit during poxviral telomere resolution.},
}
@article {pmid1884358,
year = {1991},
author = {Hecht, F and Hecht, BK},
title = {The telomere in cancer. All's not well that doesn't end well.},
journal = {Cancer genetics and cytogenetics},
volume = {54},
number = {2},
pages = {245-246},
doi = {10.1016/0165-4608(91)90214-f},
pmid = {1884358},
issn = {0165-4608},
mesh = {Chromosomes/*ultrastructure ; Humans ; Neoplasms/*pathology ; Repetitive Sequences, Nucleic Acid ; },
}
@article {pmid1712482,
year = {1991},
author = {Walker, CL and Cargile, CB and Floy, KM and Delannoy, M and Migeon, BR},
title = {The Barr body is a looped X chromosome formed by telomere association.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {88},
number = {14},
pages = {6191-6195},
pmid = {1712482},
issn = {0027-8424},
support = {HD05465/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; Centromere/ultrastructure ; DNA Probes ; Humans ; Hybrid Cells/cytology ; Interphase ; Mice ; Mitosis ; Nucleic Acid Hybridization ; Protein Biosynthesis ; Staining and Labeling ; X Chromosome/physiology/*ultrastructure ; },
abstract = {We examined Barr bodies formed by isodicentric human X chromosomes in cultured human cells and in mouse-human hybrids using confocal microscopy and DNA probes for centromere and subtelomere regions. At interphase, the two ends of these chromosomes are only a micron apart, indicating that these inactive X chromosomes are in a nonlinear configuration. Additional studies of normal X chromosomes reveal the same telomere association for the inactive X but not for the active X chromosome. This nonlinear configuration is maintained during mitosis and in a murine environment.},
}
@article {pmid1648206,
year = {1991},
author = {Acevedo, OL and Dickinson, LA and Macke, TJ and Thomas, CA},
title = {The coherence of synthetic telomeres.},
journal = {Nucleic acids research},
volume = {19},
number = {12},
pages = {3409-3419},
pmid = {1648206},
issn = {0305-1048},
mesh = {Animals ; Base Sequence ; Chromosomes/*chemistry ; Ciliophora ; DNA Restriction Enzymes/metabolism ; DNA, Protozoan/*chemistry ; Electrophoresis, Polyacrylamide Gel ; Guanine/metabolism ; Models, Molecular ; Molecular Sequence Data ; Mutagens ; Nucleic Acid Denaturation ; Oligodeoxyribonucleotides/chemistry/metabolism ; Osmium Tetroxide/pharmacology ; Potassium/pharmacology ; Single-Strand Specific DNA and RNA Endonucleases/metabolism ; Sulfuric Acid Esters/pharmacology ; Thermodynamics ; Thymine/metabolism ; },
abstract = {The chromosomal telomeres of Oxytricha were synthesized and their ability to cohere examined on non-denaturing acrylamide gels containing the stabilizing cation K+. At least 5 different mobility species were observed, in addition to that of the monomeric telomere. By cohering synthetic telomeres containing different lengths of subtelomeric DNA, we showed that each of the different mobility species was a dimer of two telomeres. Since the different mobility species did not differ in numbers or sequences of nucleotides, they must correspond to different molecular shapes probably caused by different degrees of bending of the dimer. Paradoxically, telomeres with longer subtelomeric stems cohered more efficiently. In the presence of K+, solutions had to be heated to over 90 degrees before the telomeres separated. Various synthetic constructs, restriction endonuclease and dimethyl sulfate protection experiments showed that the only nucleotides involved in the cohered structures were the 16 base 'tails' of sequence 3'G4T4G4T4. Extension of this motif was actually inimical to coherence. Oligomers containing 2 G4T4 motifs protected their GN7 positions by forming dimers, those with 5 G4T4 could do so by internal folding, but the 3' terminal group of G4 was left unprotected. This suggests that only four groups of G4 are necessary for the cohered structure. Single-chain specific nuclease, S1, as well as osmium tetroxide, which oxidizes the thymine residues of single chains, reacted less efficiently with the cohered structures. Synthetic telomeres containing inosine replacing guanosine were not observed to cohere, indicating that the C2-NH2 is strongly stabilizing. The cohered structures appear to be unusually compact and sturdy units in which four G4 blocks form quadruplexes stabilized by K+. A new model for the cohered structure is presented.},
}
@article {pmid1648204,
year = {1991},
author = {Richards, EJ and Goodman, HM and Ausubel, FM},
title = {The centromere region of Arabidopsis thaliana chromosome 1 contains telomere-similar sequences.},
journal = {Nucleic acids research},
volume = {19},
number = {12},
pages = {3351-3357},
pmid = {1648204},
issn = {0305-1048},
mesh = {Base Sequence ; *Centromere ; *Chromosomes ; Cloning, Molecular ; *DNA ; DNA Transposable Elements ; Molecular Sequence Data ; Plants/*genetics ; *Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; Sequence Homology, Nucleic Acid ; },
abstract = {We describe the structure of an Arabidopsis thaliana genomic clone containing two classes of repetitive DNA elements derived from the centromere region of chromosome 1. One class is comprised of tandem arrays of a highly reiterated repeat containing degenerate telomere sequence motifs. Adjacent to these telomere-similar repeats we found a dispersed repetitive element reiterated approximately five times in the A. thaliana genome. The nucleotide sequence of the dispersed repeat is unusual, being extremely AT-rich and composed of numerous, overlapping repeat motifs.},
}
@article {pmid2038311,
year = {1991},
author = {Runge, KW and Wellinger, RJ and Zakian, VA},
title = {Effects of excess centromeres and excess telomeres on chromosome loss rates.},
journal = {Molecular and cellular biology},
volume = {11},
number = {6},
pages = {2919-2928},
pmid = {2038311},
issn = {0270-7306},
support = {GM 26398/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Division ; Centromere/*physiology ; Chromosomes, Fungal/*physiology ; Cloning, Molecular/methods ; DNA, Recombinant/metabolism ; Diploidy ; Escherichia coli/genetics ; Plasmids ; Recombination, Genetic ; Restriction Mapping ; Saccharomyces cerevisiae/*genetics/growth &amp; development ; },
abstract = {The linear chromosomes of eukaryotes contain specialized structures to ensure their faithful replication and segregation to daughter cells. Two of these structures, centromeres and telomeres, are limited, respectively, to one and two copies per chromosome. It is possible that the proteins that interact with centromere and telomere DNA sequences are present in limiting amounts and could be competed away from the chromosomal copies of these elements by additional copies introduced on plasmids. We have introduced excess centromeres and telomeres into Saccharomyces cerevisiae and quantitated their effects on the rates of loss of chromosome III and chromosome VII by fluctuation analysis. We show that (i) 600 new telomeres have no effect on chromosome loss; (ii) an average of 25 extra centromere DNA sequences increase the rate of chromosome III loss from 0.4 x 10(-4) events per cell division to 1.3 x 10(-3) events per cell division; (iii) centromere DNA (CEN) sequences on circular vectors destabilize chromosomes more effectively than do CEN sequences on 15-kb linear vectors, and transcribed CEN sequences have no effect on chromosome stability. We discuss the different effects of extra centromere and telomere DNA sequences on chromosome stability in terms of how the cell recognizes these two chromosomal structures.},
}
@article {pmid1908017,
year = {1991},
author = {Cohn, M and Edström, JE},
title = {Evolutionary relations between subtypes of telomere-associated repeats in Chironomus.},
journal = {Journal of molecular evolution},
volume = {32},
number = {6},
pages = {463-468},
pmid = {1908017},
issn = {0022-2844},
mesh = {Animals ; Base Sequence ; *Biological Evolution ; Chironomidae/*genetics ; *Chromosomes ; Cloning, Molecular ; Genomic Library ; Models, Genetic ; Molecular Sequence Data ; Nucleic Acid Hybridization ; *Repetitive Sequences, Nucleic Acid ; Sequence Homology, Nucleic Acid ; },
abstract = {Telomere-associated DNA in Chironomus pallidivittatus contains tandemly repeated 340-bp units. We show that they are distributed among several subtypes of which we have characterized two, M1 and D1, with regard to base sequence, homogeneity, and intertelomeric distribution. Each subpopulation is highly homogeneous and the two subtypes have identical consensus sequences throughout 90% of their lengths. In the remaining part the homology is only about 60%. Each subpopulation has its specific intertelomeric distribution and there is no difference in the degree of homogenization within and between telomeres. The repeat unit contains two pairs of subrepeats embedded in linker DNA. This provides a model that makes it possible to relate the two subtypes to each other with regard to evolutionary history. The difference between the two subtypes is due to mutations that have occurred in only one of them, D1, resulting in a decreased similarity between one of its pairs of subrepeats. This type of repeat unit is therefore believed to be derived from the other, M1. The local decrease in similarity between M1 and D1 suggests that homogenization between them occurs by gene conversion.},
}
@article {pmid1892656,
year = {1991},
author = {Greider, CW},
title = {Telomeres.},
journal = {Current opinion in cell biology},
volume = {3},
number = {3},
pages = {444-451},
doi = {10.1016/0955-0674(91)90072-7},
pmid = {1892656},
issn = {0955-0674},
support = {GM43080/GM/NIGMS NIH HHS/United States ; },
mesh = {Aging ; Animals ; Chromosomes/*physiology ; DNA/genetics ; DNA Nucleotidylexotransferase/metabolism ; Humans ; Neoplasms/genetics ; Repetitive Sequences, Nucleic Acid ; },
abstract = {Telomeres are essential for chromosome stability and replication. Maintaining a balance between telomere shortening and lengthening is essential for cell viability. Recent work on telomeres from yeast, Drosophila and mammals, and on telomerase has provided insight into the mechanisms of both the shortening and lengthening processes.},
}
@article {pmid1851854,
year = {1991},
author = {Kishi, M and Bradley, G and Jessip, J and Tanaka, A and Nonoyama, M},
title = {Inverted repeat regions of Marek's disease virus DNA possess a structure similar to that of the a sequence of herpes simplex virus DNA and contain host cell telomere sequences.},
journal = {Journal of virology},
volume = {65},
number = {6},
pages = {2791-2797},
pmid = {1851854},
issn = {0022-538X},
support = {5 RO1 CA50523/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Base Composition ; Base Sequence ; Blotting, Southern ; Chick Embryo ; Chromosomes/*ultrastructure ; DNA, Viral/*chemistry ; Herpesvirus 2, Gallid/*genetics ; Molecular Sequence Data ; *Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; Sequence Homology, Nucleic Acid ; Simplexvirus/*genetics ; },
abstract = {The genomic structure of Marek's disease virus (MDV) is similar to those of the alphaherpesviruses herpes simplex virus (HSV) types 1 and 2. Sequence analysis of the junction region between the long component (L) and the short component (S) revealed the existence of an a-like sequence, similar in structure to the a sequence of HSV-1. Further study revealed that the MDV genome contains five copies of the a-like sequence within the long terminal repeat region as well as in the short terminal repeat region. The junction between the L and S components was found to contain 10 copies of the a-like sequence. Within the a-like sequence, a structure homologous to the DR2 of HSV was found to contain 17 copies of the telomeric sequence, GGGGTTA. There appears to be little to no sequence homology between the HSV a sequence and the MDV a-like sequence; however, the strong physical homology to its counterpart in HSV-1 suggests that the MDV a-like sequence may have the same functional homology (the domain for cleavage/packaging of the DNA into the viral capsids and for genomic inversion) as well.},
}
@article {pmid1708110,
year = {1991},
author = {Blackburn, EH},
title = {Structure and function of telomeres.},
journal = {Nature},
volume = {350},
number = {6319},
pages = {569-573},
doi = {10.1038/350569a0},
pmid = {1708110},
issn = {0028-0836},
mesh = {Animals ; Base Sequence ; Chromosomes/*physiology/ultrastructure ; DNA/*genetics ; DNA Nucleotidylexotransferase/metabolism ; Molecular Sequence Data ; RNA/genetics ; },
abstract = {The DNA of telomeres--the terminal DNA-protein complexes of chromosomes--differs notably from other DNA sequences in both structure and function. Recent work has highlighted its remarkable mode of synthesis by the ribonucleoprotein reverse transcriptase, telomerase, as well as its ability to form unusual structures in vitro. Moreover, telomere synthesis by telomerase has been shown to be essential for telomere maintenance and long-term viability.},
}
@article {pmid1851293,
year = {1991},
author = {Bourgain, FM and Katinka, MD},
title = {Telomeres inhibit end to end fusion and enhance maintenance of linear DNA molecules injected into the Paramecium primaurelia macronucleus.},
journal = {Nucleic acids research},
volume = {19},
number = {7},
pages = {1541-1547},
pmid = {1851293},
issn = {0305-1048},
mesh = {Animals ; Blotting, Southern ; Cell Nucleus ; DNA/*chemistry ; DNA Replication ; DNA, Viral/genetics ; Electrophoresis, Agar Gel ; Microinjections ; Nucleic Acid Conformation ; Nucleic Acid Hybridization ; *Paramecium ; Polyomavirus/metabolism ; },
abstract = {Direct injection into the macronucleus of Paramecium tetraurelia of DNA molecules coding for the A-antigen leads to expression of the gene and autonomous replication. When injected into Paramecium primaurelia DNA from probably any origin, procaryote or eucaryote, can replicate as linear telomerized molecules and the number of copies maintained can be very high (up to 20000 copies). We present here evidence that if the injected linear DNA molecules harbour preexisting telomeres at both extremities they are protected from degradation, the number of DNA molecules maintained being 15- to 30-fold higher than if the molecules are injected without telomeres. Some of the injected molecules replicate as multimers, but, only when the fused ends are devoid of preexisting telomeric repeats.},
}
@article {pmid2014645,
year = {1991},
author = {Hu, FQ and Pickup, DJ},
title = {Transcription of the terminal loop region of vaccinia virus DNA is initiated from the telomere sequences directing DNA resolution.},
journal = {Virology},
volume = {181},
number = {2},
pages = {716-720},
doi = {10.1016/0042-6822(91)90905-q},
pmid = {2014645},
issn = {0042-6822},
support = {P01 CA30246/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; Binding Sites ; Chromosomes, Human/*chemistry ; DNA Replication ; DNA, Viral/*biosynthesis/chemistry ; Humans ; Molecular Sequence Data ; Nucleic Acid Conformation ; RNA, Viral/chemistry ; Transcription, Genetic ; Vaccinia virus/*genetics ; },
abstract = {The telomeres of vaccinia virus DNA are transcribed at late times after infection. Analysis of cDNAs of RNA transcripts of the terminal loop region of the viral DNA shows that both inverted and complementary forms of the terminal loop region are transcribed. These late RNAs, which contain 5' poly(A) sequences, do not appear to encode any proteins. The transcriptional start sites for most of these RNAs are within the sequences that direct the resolution of concatemeric DNA replication intermediates (M. Merchlinsky and B. Moss, 1989, J. Virol. 63, 4354-4361). This suggests that the process of DNA resolution may involve transcription initiated from the telomere sequences required for resolution.},
}
@article {pmid2005910,
year = {1991},
author = {Coren, JS and Epstein, EM and Vogt, VM},
title = {Characterization of a telomere-binding protein from Physarum polycephalum.},
journal = {Molecular and cellular biology},
volume = {11},
number = {4},
pages = {2282-2290},
pmid = {2005910},
issn = {0270-7306},
support = {GM 31577/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosomes, Fungal/*metabolism ; DNA-Binding Proteins/chemistry/isolation &amp; purification/*metabolism ; Deoxyribonuclease I/metabolism ; Electrophoresis, Polyacrylamide Gel ; Fungal Proteins/chemistry/isolation &amp; purification/*metabolism ; Molecular Sequence Data ; Molecular Weight ; Physarum/*metabolism ; Repetitive Sequences, Nucleic Acid ; },
abstract = {We have partially purified a nuclear protein (PPT) from Physarum polycephalum that binds to the extrachromosomal ribosomal DNA telomeres of this acellular slime mold. Binding is specific for the (T2AG3)n telomere repeats, as evidenced by nitrocellulose filter binding assays, by gel mobility shift assays with both DNA fragments and double-stranded oligonucleotides, and by DNase I footprinting. PPT is remarkably heat stable, showing undiminished binding activity after incubation at 90 degrees C. It sediments at 1.2S, corresponding to a molecular weight of about 10,000 (for a globular protein), and its binding activity is undiminished by incubation with RNase, suggesting that it is not a ribonucleoprotein. We hypothesize that PPT plays a structural role in telomeres, perhaps preventing nucleolytic degradation or promoting telomere extension by a telomere-specific terminal transferase.},
}
@article {pmid2005977,
year = {1991},
author = {Janković, GM and Colović, MD and Petrović, MD},
title = {Telomere loss and cancer.},
journal = {Nature},
volume = {350},
number = {6315},
pages = {197},
doi = {10.1038/350197a0},
pmid = {2005977},
issn = {0028-0836},
mesh = {Aging/pathology ; Animals ; Child ; Chromosomes/*ultrastructure ; Humans ; Mice ; Neoplasms/*etiology/genetics ; },
}
@article {pmid2016087,
year = {1991},
author = {Anvret, M and Nordenskjöld, M and Stolpe, L and Johansson, L and Bröndum-Nielsen, K},
title = {Molecular analysis of 4p deletion associated with Wolf-Hirschhorn syndrome moving the "critical segment" towards the telomere.},
journal = {Human genetics},
volume = {86},
number = {5},
pages = {481-483},
pmid = {2016087},
issn = {0340-6717},
mesh = {Abnormalities, Multiple/*genetics ; Blotting, Southern ; Chromosome Banding ; *Chromosome Deletion ; Chromosome Mapping ; *Chromosomes, Human, Pair 4 ; Female ; Heterozygote ; Humans ; Intellectual Disability/genetics ; Karyotyping ; Male ; Pedigree ; Syndrome ; },
abstract = {We report molecular studies in 2 patients with Wolf-Hirschhorn syndrome, probing genomic DNA from the patients and their parents with markers that have been mapped to 4p16.3. One of the patients was heterozygous for alleles detected by probe F5.53, which maps to the centromeric end of the D4S10 locus, but hemizygous for loci located more distally. The region in common, which was deleted in both these patients, is within 4p16.3. This observation suggests that the gene(s) for Wolf syndrome may be contained within this region, and that the "critical segment" is located more distally than previous cytogenetic observations have suggested. Furthermore, we found that the deletion was of maternal origin in one patient, and of paternal origin in the other.},
}
@article {pmid1722017,
year = {1991},
author = {Harley, CB},
title = {Telomere loss: mitotic clock or genetic time bomb?.},
journal = {Mutation research},
volume = {256},
number = {2-6},
pages = {271-282},
doi = {10.1016/0921-8734(91)90018-7},
pmid = {1722017},
issn = {0027-5107},
mesh = {Animals ; Cell Division ; Cell Line, Transformed/cytology ; Cellular Senescence/*physiology ; DNA Nucleotidylexotransferase/metabolism ; DNA Replication ; Fibroblasts/cytology ; Humans ; *Mitosis ; Telomere/*physiology ; },
abstract = {The Holy Grail of gerontologists investigating cellular senescence is the mechanism responsible for the finite proliferative capacity of somatic cells. In 1973, Olovnikov proposed that cells lose a small amount of DNA following each round of replication due to the inability of DNA polymerase to fully replicate chromosome ends (telomeres) and that eventually a critical deletion causes cell death. Recent observations showing that telomeres of human somatic cells act as a mitotic clock, shortening with age both in vitro and in vivo in a replication dependent manner, support this theory's premise. In addition, since telomeres stabilize chromosome ends against recombination, their loss could explain the increased frequency of dicentric chromosomes observed in late passage (senescent) fibroblasts and provide a checkpoint for regulated cell cycle exit. Sperm telomeres are longer than somatic telomeres and are maintained with age, suggesting that germ line cells may express telomerase, the ribonucleoprotein enzyme known to maintain telomere length in immortal unicellular eukaryotes. As predicted, telomerase activity has been found in immortal, transformed human cells and tumour cell lines, but not in normal somatic cells. Telomerase activation may be a late, obligate event in immortalization since many transformed cells and tumour tissues have critically short telomeres. Thus, telomere length and telomerase activity appear to be markers of the replicative history and proliferative potential of cells; the intriguing possibility remains that telomere loss is a genetic time bomb and hence causally involved in cell senescence and immortalization.},
}
@article {pmid1989906,
year = {1991},
author = {Liu, ZP and Tye, BK},
title = {A yeast protein that binds to vertebrate telomeres and conserved yeast telomeric junctions.},
journal = {Genes &amp; development},
volume = {5},
number = {1},
pages = {49-59},
doi = {10.1101/gad.5.1.49},
pmid = {1989906},
issn = {0890-9369},
mesh = {Animals ; Base Sequence ; Chromatography, Liquid ; DNA Fingerprinting ; DNA, Fungal/genetics ; Electrophoresis, Agar Gel ; Electrophoresis, Polyacrylamide Gel ; Fungal Proteins/*genetics/metabolism ; Genes, Fungal ; Humans ; Molecular Sequence Data ; Plasmids ; Saccharomyces cerevisiae/genetics ; },
abstract = {We have identified three yeast proteins that bind to poly(C.A)/poly(T.G) repeats characteristic of telomeric sequences from yeast to human. TBF alpha binds to the telomeric sequences of yeast, Tetrahymena, and vertebrates. In contrast, TBF beta binds only to yeast telomeric sequences. Also identified was RAP1, the transcriptional silencer protein, which binds to a sequence motif found in upstream activating sequences (UASs) of a number of genes; the sequence motif also occurs frequently in yeast telomeric sequences. Because poly(C.A)/poly(T.G) sequences from a wide range of organisms will serve as the primer for the in vivo extension of telomeres in yeast, TBF alpha is of particular interest. DNase I footprinting analysis indicated that TBF alpha binds to the junction between the subtelomeric X sequence and poly(C1-3A) in a cloned yeast telomere. Examination of the junctions of known X sequences indicated that they all contain one or more repeats of CCCTAA, a sequence that is repeated in vertebrate telomeres. Earlier, Murray et al. (1988) reported that heterologous telomeric sequences positioned as far as several hundred base pairs from the termini of linear molecules can allow the addition of yeast telomeric sequences from nontelomeric termini in vivo. A possible function for TBF alpha might be to serve as an anchoring protein for the yeast telomerase by binding to the conserved junction sequence at a distance from the terminus to allow addition of an irregular repeating sequence at the chromosome end.},
}
@article {pmid1686839,
year = {1991},
author = {Elliott, RW and Yen, CH},
title = {DNA variants with telomere probe enable genetic mapping of ends of mouse chromosomes.},
journal = {Mammalian genome : official journal of the International Mammalian Genome Society},
volume = {1},
number = {2},
pages = {118-122},
pmid = {1686839},
issn = {0938-8990},
support = {GM 28464/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Chromosome Mapping ; Crosses, Genetic ; DNA Probes ; Deoxyribonucleases, Type II Site-Specific ; Endodeoxyribonucleases ; Genetic Linkage ; Male ; Mice/*genetics ; Mice, Inbred Strains ; Polymorphism, Restriction Fragment Length ; Telomere/*chemistry ; },
abstract = {Dde I-digested DNA fragments from 11 inbred mouse strains were separated by electrophoresis, blotted and probed with a labeled oligomer, TELO, containing five repeats of the consensus mammalian telomere sequence, TTAGGG. Each strain produced a unique set of hybridizing fragments. Segregation analysis of TELO-hybridizing fragments from the BXD RI strains indicated that each fragment segregated as expected for a single gene. One fragment from strain DBA/2J was genetically linked to locus Xmv-9, previously mapped near the distal end of the map of chromosome (Chr) 4 and three fragments to Cck, near the distal end of Chr 9, suggesting that these fragments are telomeric and represent the ends of the chromosome maps. Confirmation of these map positions was obtained from a backcross. Fragments associated with the short arm of the Y Chr were found in DNA from strains C57BL/6J and DBA/2J. TELO-hybridizing fragments from DBA/2J were digested by the exonuclease Bal 31, under conditions in which fragments hybridizing to a cDNA probe for the metallothionein locus, located at the middle of mouse Chr 8, remained intact. Thus both biochemical and genetic tests indicate that several TELO-hybridizing fragments from Dde I-digested DNA are at the ends of chromosomes and probably derive from mouse telomeres. Using this approach should allow the mapping of genes relative to the ends of other mouse chromosomes.},
}
@article {pmid1668615,
year = {1991},
author = {Ganal, MW and Lapitan, NL and Tanksley, SD},
title = {Macrostructure of the tomato telomeres.},
journal = {The Plant cell},
volume = {3},
number = {1},
pages = {87-94},
pmid = {1668615},
issn = {1040-4651},
mesh = {Base Sequence ; Consensus Sequence ; DNA/chemistry ; DNA Restriction Enzymes ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Plants/*genetics ; Repetitive Sequences, Nucleic Acid ; Telomere/*chemistry ; },
abstract = {The macrostructure of the tomato telomeres has been investigated by in situ hybridization, genomic sequencing, and pulsed-field gel electrophoresis. In situ hybridizations with a cloned telomeric sequence from Arabidopsis thaliana indicated that the telomeric repeat of tomato cross-hybridizes with that of Arabidopsis and is located at all telomeres. Bal31 digestion kinetics confirmed that the tomato telomeric repeat represents the outermost DNA sequence of each tomato chromosome. Genomic sequencing of enriched tomato telomeric sequences, using primers derived from the Arabidopsis sequence, revealed that the consensus sequence of the tomato telomeric repeat is TT(T/A)AGGG compared with the Arabidopsis consensus sequence of TTTAGGG. Furthermore, as shown by pulsed-field gel electrophoresis, the telomeric repeat of tomato is separated by not more than a few hundred kilobases from a previously described 162-base pair satellite DNA repeat of tomato (TGR I) at 20 of the 24 telomeres. Together, these sequences are found in the heterochromatic terminal knob observed in pachytene chromosomes. Therefore, these two repeats determine the structure of 20 of the 24 tomato chromosome ends over approximately 2% of the total chromosome length.},
}
@article {pmid2175882,
year = {1990},
author = {Starling, JA and Maule, J and Hastie, ND and Allshire, RC},
title = {Extensive telomere repeat arrays in mouse are hypervariable.},
journal = {Nucleic acids research},
volume = {18},
number = {23},
pages = {6881-6888},
pmid = {2175882},
issn = {0305-1048},
mesh = {Animals ; Chromosomes/*ultrastructure ; DNA Probes ; DNA Restriction Enzymes/metabolism ; Female ; *Genetic Variation ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Molecular Weight ; Muridae ; *Repetitive Sequences, Nucleic Acid ; },
abstract = {In this study we have analysed mouse telomeres by Pulsed Field Gel Electrophoresis (PFGE). A number of specific restriction fragments hybridising to a (TTA-GGG)4 probe in the size range 50-150kb can be detected. These fragments are devoid of sites for most restriction enzymes suggesting that they comprise simple repeats; we argue that most of these are likely to be (TTAGGG)n. Each discrete fragment corresponds to the telomere of an individual chromosome and segregates as a Mendelian character. However, new size variants are being generated in the germ line at very high rates such that inbred mice are heterozygous at all telomeres analysable. In addition we show that specific small (approximately 4-12kb) fragments can be cleaved within some terminal arrays by the restriction enzyme MnII which recognises 5'(N7)GAGG3'. Like the complete telomere-repeat arrays (TRA's) these fragments form new variants at high rates and possibly by the same process. We speculate on the mechanisms that may be involved.},
}
@article {pmid2258933,
year = {1990},
author = {Nielsen, L and Schmidt, ER and Edström, JE},
title = {Subrepeats result from regional DNA sequence conservation in tandem repeats in Chironomus telomeres.},
journal = {Journal of molecular biology},
volume = {216},
number = {3},
pages = {577-584},
doi = {10.1016/0022-2836(90)90385-Y},
pmid = {2258933},
issn = {0022-2836},
mesh = {Animals ; Base Sequence ; Biological Evolution ; Chironomidae/*genetics ; DNA/genetics ; Gene Amplification ; Genomic Library ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid/*genetics ; Sequence Homology, Nucleic Acid ; Species Specificity ; },
abstract = {Repeat units, widespread in eukaryotic genomes, are often partially or entirely built up of subrepeats. Homogenization between whole repeat units arranged in tandem usually can best be understood as a result of unequal crossing over. Such a mechanism is less plausible for maintaining similarities between subrepeats within a repeat unit when present in a regular array. In Chironomus telomeres, large blocks of tandemly repeated approximately 350 base-pair units contain two or three pairs of subrepeats with high mutual identities, embedded in linker DNA, non-repetitive within the repeat unit. Measurements of evolutionary base changes in two closely related species, Chironomus tentans and Chironomus pallidivittatus, permit us to conclude that the subrepeat arrangement is best explained as a consequence of regional sequence conservation after an earlier duplication of an ancestral half-unit.},
}
@article {pmid2276741,
year = {1990},
author = {Wells, RA and Germino, GG and Krishna, S and Buckle, VJ and Reeders, ST},
title = {Telomere-related sequences at interstitial sites in the human genome.},
journal = {Genomics},
volume = {8},
number = {4},
pages = {699-704},
doi = {10.1016/0888-7543(90)90257-u},
pmid = {2276741},
issn = {0888-7543},
mesh = {Base Sequence ; Blotting, Southern ; Chromosome Banding ; Chromosomes, Human/*ultrastructure ; *Genome, Human ; Humans ; Molecular Sequence Data ; *Repetitive Sequences, Nucleic Acid ; },
abstract = {The ends (telomeres) of eukaryotic chromosomes are protected from degradation and from loss during DNA replication by buffers of simple tandem repetitive sequence. The nucleotide sequence of these telomeric arrays is fundamental to telomere function as a site for protein and ribonucleoprotein binding and varies only slightly in a wide range of organisms. We present evidence that arrays of this human telomeric sequence, TTAGGG, are present not only at the ends of human chromosomes but also at numerous interstitial sites. These interstitial loci share nucleotide sequence similarity outside the repetitive array, suggesting that they are related functionally or have evolved from a common progenitor locus.},
}
@article {pmid2247059,
year = {1990},
author = {Ten Hagen, KG and Gilbert, DM and Willard, HF and Cohen, SN},
title = {Replication timing of DNA sequences associated with human centromeres and telomeres.},
journal = {Molecular and cellular biology},
volume = {10},
number = {12},
pages = {6348-6355},
pmid = {2247059},
issn = {0270-7306},
support = {GM 07790/GM/NIGMS NIH HHS/United States ; HG 00107/HG/NHGRI NIH HHS/United States ; HG 00325/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Blotting, Southern ; Cell Cycle ; Cell Line ; *Chromosomes, Human, Pair 17 ; *Chromosomes, Human, Pair 7 ; *DNA Replication ; DNA, Satellite/*genetics ; Humans ; Hybrid Cells/cytology ; Kinetics ; Male ; Mice ; Repetitive Sequences, Nucleic Acid ; Time Factors ; *X Chromosome ; },
abstract = {The timing of replication of centromere-associated human alpha satellite DNA from chromosomes X, 17, and 7 as well as of human telomeric sequences was determined by using density-labeling methods and fluorescence-activated cell sorting. Alpha satellite sequences replicated late in S phase; however, the alpha satellite sequences of the three chromosomes studied replicated at slightly different times. Human telomeres were found to replicate throughout most of S phase. These results are consistent with a model in which multiple initiations of replication occur at a characteristic time within the alpha satellite repeats of a particular chromosome, while the replication timing of telomeric sequences is determined by either telomeric origins that can initiate at different times during S phase or by replication origins within the flanking chromosomal DNA sequences.},
}
@article {pmid2174115,
year = {1990},
author = {Pace, T and Ponzi, M and Dore, E and Janse, C and Mons, B and Frontali, C},
title = {Long insertions within telomeres contribute to chromosome size polymorphism in Plasmodium berghei.},
journal = {Molecular and cellular biology},
volume = {10},
number = {12},
pages = {6759-6764},
pmid = {2174115},
issn = {0270-7306},
mesh = {Animals ; Base Sequence ; Cloning, Molecular ; *DNA Transposable Elements ; Molecular Sequence Data ; Oligonucleotide Probes ; Plasmodium berghei/*genetics ; *Polymorphism, Genetic ; Restriction Mapping ; },
abstract = {During prolonged in vivo mitotic multiplication of a Plasmodium berghei ANKA clone (8417HP), parasites that contained an enlarged version of chromosome 4 were observed. Restriction mapping and hybridization results demonstrated that the extra DNA present in the enlarged chromosome consists of 2.3-kb tandem repeats, known to be normally located in subtelomeric position at several chromosomal ends but absent in the original chromosome. The inserted 2.3-kb units appeared to interrupt one of the original telomeres and to create an internal (approximately 1-kb-long) telomeric sequence.},
}
@article {pmid2129288,
year = {1990},
author = {Moens, PB and Pearlman, RE},
title = {Telomere and centromere DNA are associated with the cores of meiotic prophase chromosomes.},
journal = {Chromosoma},
volume = {100},
number = {1},
pages = {8-14},
pmid = {2129288},
issn = {0009-5915},
mesh = {Animals ; Base Sequence ; Centromere/*chemistry/physiology ; Chromatin/*physiology ; Chromosomes/chemistry/physiology ; DNA/analysis/genetics ; DNA Probes ; DNA, Satellite/analysis ; Fluorescein-5-isothiocyanate ; Fluoresceins ; Male ; *Meiosis ; Mice ; Molecular Sequence Data ; Nucleic Acid Conformation ; Prophase ; Repetitive Sequences, Nucleic Acid ; Spermatocytes ; Synaptonemal Complex/*physiology ; Thiocyanates ; },
abstract = {Mouse (Mus musculus) whole-mount, surface-spread, meiotic prophase chromosomes have an axial core structure, the synaptonemal complex, SC, from which extend chromatin loops. This arrangement permits a novel approach to the analysis of chromosome structure. Using in situ hybridization, the types of DNA sequences preferentially associated with the SC and the types located primarily in the chromatin loops can be determined. With biotinylated probes, detected by avidin conjugated to FITC, we present evidence for differential chromatin-SC interaction. The telomere sequence (TTAGGG)n is associated exclusively with the two ends of each autosomal SC rather than with the chromatin loops. The minor satellite DNA sequences are predominantly localized to the centromeric region of the SC, as defined by CREST serum anti-centromere antibodies. In contrast, the major satellite DNA probe hybridizes to the chromatin loops of the centromeric heterochromatin, and a probe containing a LINE sequence hybridizes to chromatin loops in general with no obvious preference for the SC. These observations demonstrate that, depending on the type of DNA sequence, the chromatin has different properties in regard to its association with the SC.},
}
@article {pmid2225075,
year = {1990},
author = {Gottschling, DE and Aparicio, OM and Billington, BL and Zakian, VA},
title = {Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription.},
journal = {Cell},
volume = {63},
number = {4},
pages = {751-762},
doi = {10.1016/0092-8674(90)90141-z},
pmid = {2225075},
issn = {0092-8674},
support = {CA14599-16/CA/NCI NIH HHS/United States ; GM26938/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosome Mapping ; Chromosomes, Fungal/*physiology ; DNA Polymerase II/biosynthesis/*genetics ; DNA, Fungal/genetics/isolation &amp; purification ; Enzyme Repression ; Genes, Fungal ; Plasmids ; RNA, Fungal/genetics/isolation &amp; purification ; Restriction Mapping ; Saccharomyces cerevisiae/enzymology/*genetics ; *Transcription, Genetic ; Uracil/metabolism ; },
abstract = {S. cerevisiae chromosomes end with the telomeric repeat (TG1-3)n. When any of four Pol II genes was placed immediately adjacent to the telomeric repeats, expression of the gene was reversibly repressed as demonstrated by phenotype and mRNA analyses. For example, cells bearing a telomere-linked copy of ADE2 produced predominantly red colonies (a phenotype characteristic of ade2- cells) containing white sectors (characteristic of ADE2+ cells). Repression was due to proximity to the telomere itself since an 81 bp tract of (TG1-3)n positioned downstream of URA3 when URA3 was approximately 20 kb from the end of chromosome VII did not alter expression of the gene. However, this internal tract of (TG1-3)n could spontaneously become telomeric, in which case expression of the URA3 gene was repressed. These data demonstrate that yeast telomeres exert a position effect on the transcription of nearby genes, an effect that is under epigenetic control.},
}
@article {pmid2225074,
year = {1990},
author = {Conrad, MN and Wright, JH and Wolf, AJ and Zakian, VA},
title = {RAP1 protein interacts with yeast telomeres in vivo: overproduction alters telomere structure and decreases chromosome stability.},
journal = {Cell},
volume = {63},
number = {4},
pages = {739-750},
doi = {10.1016/0092-8674(90)90140-a},
pmid = {2225074},
issn = {0092-8674},
support = {GM43265/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Chromatin/physiology/ultrastructure ; Chromosome Deletion ; Chromosomes, Fungal/*physiology ; DNA, Fungal/genetics ; DNA-Binding Proteins/*genetics ; Fungal Proteins/*genetics/metabolism ; *Genes, Fungal ; Molecular Sequence Data ; Plasmids ; Recombination, Genetic ; Restriction Mapping ; Saccharomyces cerevisiae/*genetics/physiology ; *Transcription Factors ; },
abstract = {The protein encoded by the RAP1 gene of S. cerevisiae binds in vitro to a consensus sequence occurring at a number of sites in the yeast genome, including the repeated sequence C2-3A(CA)1-6 found at yeast telomeres. We present two lines of evidence for the in vivo binding of RAP1 protein at telomeres: first, RAP1 is present in telomeric chromatin and second, alterations in the level of RAP1 protein affect telomere length. The length changes seen with under- and overexpression of RAP1 are consistent with the interpretation that RAP1 binding to telomeres protects them from degradation. Unexpectedly, overproduction of the RAP1 protein was also shown to decrease greatly chromosome stability, suggesting that RAP1 mediates interactions that have a more global effect on chromosome behavior than simply protecting telomeres from degradation. Such interactions may involve telomere associations both with other telomeres and/or with structural elements of the nucleus.},
}
@article {pmid2236035,
year = {1990},
author = {Petracek, ME and Lefebvre, PA and Silflow, CD and Berman, J},
title = {Chlamydomonas telomere sequences are A+T-rich but contain three consecutive G-C base pairs.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {87},
number = {21},
pages = {8222-8226},
pmid = {2236035},
issn = {0027-8424},
support = {GM34437/GM/NIGMS NIH HHS/United States ; R29 GM-38626/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenine ; *Base Composition ; Chlamydomonas/*genetics ; Chromosomes/*chemistry ; Cloning, Molecular ; Cytosine ; Escherichia coli/genetics ; Guanine ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; Sequence Homology, Nucleic Acid ; Thymine ; },
abstract = {We have isolated telomeric DNA and telomere-associated sequences from Chlamydomonas reinhardtii. The terminal telomere sequences of the green alga Chlamydomonas are composed of (TTTTAGGG)n repeats that are similar, but not identical, to those of the higher plant Arabidopsis thaliana. We demonstrate that these repeats are telomeric by their preferential sensitivity to nuclease Bal-31 digestion, their similarity to A. thaliana telomeres, their orientation relative to the end of the chromosome, and the methods used for their isolation. Five independent telomere clones were isolated, and three of these clones include closely related telomere-associated sequences. One of these telomere-associated sequences hybridizes to a number of genomic fragments sensitive to digestion with the exonuclease Bal-31. Like telomere sequences from other organisms, the C. reinhardtii telomeres display a bias for guanine and thymine nucleotides on the 3'-end strand. However, the sequence of Chlamydomonas telomeres is more A + T-rich than any other known telomere sequence. We propose that the common feature of all known telomere is the frequent occurrence of tracts of three or more adjacent guanine residues.},
}
@article {pmid2237406,
year = {1990},
author = {Lustig, AJ and Kurtz, S and Shore, D},
title = {Involvement of the silencer and UAS binding protein RAP1 in regulation of telomere length.},
journal = {Science (New York, N.Y.)},
volume = {250},
number = {4980},
pages = {549-553},
doi = {10.1126/science.2237406},
pmid = {2237406},
issn = {0036-8075},
support = {GM 40094/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Binding Sites ; Chromosomes, Fungal/metabolism/*ultrastructure ; DNA-Binding Proteins/metabolism ; Fungal Proteins/genetics/*metabolism ; *Genes, Fungal ; *Genes, Mating Type, Fungal ; Molecular Sequence Data ; Mutation ; Plasmids ; Poly A/metabolism ; Poly C/metabolism ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*genetics ; Temperature ; *Transcription Factors ; Transformation, Genetic ; },
abstract = {The yeast protein RAP1, initially described as a transcriptional regulator, binds in vitro to sequences found in a number of seemingly unrelated genomic loci. These include the silencers at the transcriptionally repressed mating-type genes, the promoters of many genes important for cell growth, and the poly[(cytosine)1-3 adenine] [poly(C1-3A)] repeats of telomeres. Because RAP1 binds in vitro to the poly(C1-3A) repeats of telomeres, it has been suggested that RAP1 may be involved in telomere function in vivo. In order to test this hypothesis, the telomere tract lengths of yeast strains that contained conditionally lethal (ts) rap1 mutations were analyzed. Several rap1ts alleles reduced telomere length in a temperature-dependent manner. In addition, plasmids that contain small, synthetic telomeres with intact or mutant RAP1 binding sites were tested for their ability to function as substrates for poly(C1-3A) addition in vivo. Mutations in the RAP1 binding sites reduced the efficiency of the addition reaction.},
}
@article {pmid2208276,
year = {1990},
author = {Brown, WR and MacKinnon, PJ and Villasanté, A and Spurr, N and Buckle, VJ and Dobson, MJ},
title = {Structure and polymorphism of human telomere-associated DNA.},
journal = {Cell},
volume = {63},
number = {1},
pages = {119-132},
doi = {10.1016/0092-8674(90)90293-n},
pmid = {2208276},
issn = {0092-8674},
mesh = {Animals ; Base Sequence ; Cell Line ; Chromosome Mapping ; Chromosomes, Human/*ultrastructure ; Cloning, Molecular ; DNA/*genetics ; Humans ; Hybrid Cells/cytology ; Molecular Sequence Data ; Nucleic Acid Hybridization ; *Polymorphism, Genetic ; Restriction Mapping ; },
abstract = {We have analyzed the DNA sequences associated with four different human telomeres. Two are members of distinct repeated sequence families which are located mainly but not exclusively at telomeres. Two are unique in the genome, one deriving from the long arm telomere of chromosome 7 and the other from the pseudoautosomal telomere. One telomere-associated repeated sequence has a polymorphic distribution among the chromosome ends, being present at a different combination of ends in different individuals. These data thus identify a new source of human genetic variation and indicate that the canonical features of the organization of telomere-associated DNA are widely conserved in evolution.},
}
@article {pmid2170845,
year = {1990},
author = {Kipling, D and Cooke, HJ},
title = {Hypervariable ultra-long telomeres in mice.},
journal = {Nature},
volume = {347},
number = {6291},
pages = {400-402},
doi = {10.1038/347400a0},
pmid = {2170845},
issn = {0028-0836},
mesh = {Animals ; Chromosomes/*ultrastructure ; DNA/genetics ; DNA Restriction Enzymes ; Humans ; Male ; Mice/*genetics ; Mice, Inbred BALB C/genetics ; Mice, Inbred C57BL/genetics ; Mice, Inbred CBA/genetics ; Mice, Inbred DBA/genetics ; Nucleic Acid Hybridization ; Polymorphism, Genetic ; Repetitive Sequences, Nucleic Acid ; },
abstract = {Telomere structure and behaviour is less well understood in vertebrates than it is in ciliates and yeasts (reviewed in ref. 1). Like all other eukaryotic chromosomes, those of vertebrates terminate in an array of a short repeated sequence. In vertebrates this sequence is (TTAGGG)n, as shown by in situ hybridization. In humans, these terminal repeats are heterogeneous in length, averaging about 10 kilobases in blood cells. Here we report the structure and inheritance of the terminal repeats present at mouse telomeres. The (TTAGGG)n tracts are many times larger than those present at human telomeres. Because of their constancy in length through somatic cell divisions, they are resolved as multiple discrete restriction fragments of up to 150 kilobases. Strikingly, this banding pattern is highly polymorphic within populations of inbred mice, suggesting an unusually high mutation rate. Indeed, although the banding pattern is inherited in a largely mendelian fashion, (TTAGGG)n tracts of new size appear frequently in family studies.},
}
@article {pmid2397458,
year = {1990},
author = {Lin, CC and Meyne, J and Sasi, R and Moyzis, RK},
title = {Apparent lack of telomere sequences on double minute chromosomes.},
journal = {Cancer genetics and cytogenetics},
volume = {48},
number = {2},
pages = {271-274},
doi = {10.1016/0165-4608(90)90131-s},
pmid = {2397458},
issn = {0165-4608},
mesh = {*Chromosome Aberrations ; Colonic Neoplasms/genetics ; Humans ; *Metaphase ; *Ring Chromosomes ; },
}
@article {pmid2133989,
year = {1990},
author = {Cheng, JF and Smith, CL},
title = {YAC cloning of telomeres.},
journal = {Genetic analysis, techniques and applications},
volume = {7},
number = {5},
pages = {119-125},
doi = {10.1016/0735-0651(90)90017-a},
pmid = {2133989},
issn = {1050-3862},
mesh = {*Chromosomes, Fungal ; Cloning, Molecular ; Genome, Human ; Genomic Library ; Humans ; Plasmids ; Saccharomyces cerevisiae/genetics ; Transformation, Genetic ; },
abstract = {Human telomeres have been successfully cloned in Saccharomyces cerevisiae by complementing deficient yeast artificial chromosomes (YACs). This technique allows cloning of DNA sequences that can recognize particular chromosomal ends, and therefore facilitates the mapping of eukaryotic genomes. Although the biology of adopting foreign telomeres in yeast is not fully understood, the cloning system itself seems to be a useful tool for constructing telomeric DNA libraries from higher eukaryotes. Here we describe the techniques that are currently being used in cloning of telomeric DNA.},
}
@article {pmid2392154,
year = {1990},
author = {Hastie, ND and Dempster, M and Dunlop, MG and Thompson, AM and Green, DK and Allshire, RC},
title = {Telomere reduction in human colorectal carcinoma and with ageing.},
journal = {Nature},
volume = {346},
number = {6287},
pages = {866-868},
doi = {10.1038/346866a0},
pmid = {2392154},
issn = {0028-0836},
mesh = {Adenoma/genetics ; Aging/*genetics ; Autoradiography ; Carcinoma/genetics ; Cell Division ; Chromosomes/*ultrastructure ; Colorectal Neoplasms/*genetics ; DNA/blood/genetics/metabolism ; DNA Nucleotidylexotransferase/metabolism ; Deoxyribonucleases, Type II Site-Specific ; Humans ; Intestinal Mucosa/analysis ; Nucleic Acid Hybridization ; Oligonucleotide Probes ; *Repetitive Sequences, Nucleic Acid ; },
abstract = {We have hypothesized that end-to-end chromosome fusions observed in some tumours could play a part in genetic instability associated with tumorigenesis and that fusion may result from the loss of the long stretches of G-rich repeats found at the ends of all linear chromosomes. We therefore asked whether there is telomere loss or reduction in common tumours. Here we show that in most of the colorectal carcinomas that we analysed, there is a reduction in the length of telomere repeat arrays relative to the normal colonic mucosa from the same patient. We speculate on the consequences of this loss for tumorigenesis. We also show that the telomere arrays are much smaller in colonic mucosa and blood than in fetal tissue and sperm, and that there is a reduction in average telomere length with age in blood and colon mucosa. We propose that the telomerase is inactive in somatic tissues, and that telomere length is an indicator of the number of cell divisions that it has taken to form a particular tissue and possibly to generate tumours.},
}
@article {pmid2392149,
year = {1990},
author = {Murray, A},
title = {Telomeres. All's well that ends well.},
journal = {Nature},
volume = {346},
number = {6287},
pages = {797-798},
doi = {10.1038/346797a0},
pmid = {2392149},
issn = {0028-0836},
mesh = {Animals ; Base Sequence ; Chromosomes/*ultrastructure ; DNA/metabolism ; DNA Primase ; DNA Replication ; Humans ; Molecular Sequence Data ; RNA Nucleotidyltransferases/metabolism ; Repetitive Sequences, Nucleic Acid ; Tetrahymena/genetics ; },
}
@article {pmid2200120,
year = {1990},
author = {Blackburn, EH},
title = {Telomeres and their synthesis.},
journal = {Science (New York, N.Y.)},
volume = {249},
number = {4968},
pages = {489-490},
doi = {10.1126/science.2200120},
pmid = {2200120},
issn = {0036-8075},
mesh = {Animals ; Base Sequence ; Chromosomes/*physiology ; DNA/genetics ; *DNA Replication ; Humans ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; },
}
@article {pmid2385585,
year = {1990},
author = {Kitten, T and Barbour, AG},
title = {Juxtaposition of expressed variable antigen genes with a conserved telomere in the bacterium Borrelia hermsii.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {87},
number = {16},
pages = {6077-6081},
pmid = {2385585},
issn = {0027-8424},
support = {AI24424/AI/NIAID NIH HHS/United States ; },
mesh = {Antigens, Bacterial/*genetics ; Base Sequence ; Blotting, Southern ; Borrelia/*genetics/immunology ; *Chromosomes, Bacterial ; Cloning, Molecular ; DNA, Bacterial/genetics/isolation &amp; purification ; *Genes, Bacterial ; Genetic Linkage ; *Genetic Variation ; Molecular Sequence Data ; Plasmids ; Restriction Mapping ; Sequence Homology, Nucleic Acid ; },
abstract = {Borrelia hermsii, an agent of relapsing fever, survives in mammals through antigenic variation. Change in serotype-specific variable outer membrane proteins (Vmps) occurs when a Vmp gene at an expression site is replaced with a previously silent gene for another Vmp. Silent and active genes are on separate linear plasmids. The upstream site for a nonreciprocal recombination between two linear plasmids is near the 5' ends of the expressed and silent genes. In the present study we sought the downstream recombination sites in two serotypes, 7 and 21. Restriction fragments containing plasmid telomeres were identified by susceptibility to digestion with BAL-31 and rapid reannealment following denaturation. Whereas both silent genes and a minority population of both expression-linked genes were several kilobases from the telomeres, the predominant population of both expressed genes had 3' ends near plasmid telomeres. Sequence analysis of the predominant expression plasmids revealed that the telomeric sequences were the same in serotypes 7 and 21. Identical sequence was also downstream of silent Vmp genes. Switching of Vmp genes appears to occur by recombination that involves both upstream and downstream sites. The expression plasmid's telomere is preserved in the recombination event.},
}
@article {pmid2369903,
year = {1990},
author = {Chung, HM and Shea, C and Fields, S and Taub, RN and Van der Ploeg, LH and Tse, DB},
title = {Architectural organization in the interphase nucleus of the protozoan Trypanosoma brucei: location of telomeres and mini-chromosomes.},
journal = {The EMBO journal},
volume = {9},
number = {8},
pages = {2611-2619},
pmid = {2369903},
issn = {0261-4189},
support = {AI21784/AI/NIAID NIH HHS/United States ; CA 18506/CA/NCI NIH HHS/United States ; CA 42450/01/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Base Composition ; Base Sequence ; Cell Cycle ; Cell Nucleus/*ultrastructure ; Chromosomes/*ultrastructure ; DNA Probes ; Interphase ; Microscopy, Fluorescence/methods ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Plasmids ; Protein Biosynthesis ; Repetitive Sequences, Nucleic Acid ; Trypanosoma brucei brucei/*cytology/ultrastructure ; },
abstract = {We studied the spatial organization of chromatin in the interphase G1, S and G2 nucleus of the protozoan Trypanosoma brucei, applying in situ hybridization with conventional fluorescence and confocal scanning optical microscopy. The majority of the trypanosome telomere GGGTTA repeats from different chromosomes were found clustered together, either extending in a network through the nuclear interior or localized at the nuclear periphery. The population of one hundred mini-chromosomes was often asymmetrically located: either clustered in a narrow band in close association with the nuclear envelope or distributed into several clusters that segregated into roughly one half of the nucleus. The nuclear organization may undergo modifications during the cell cycle and development. We conclude that non-random spatial positioning of DNA exists in the nucleus of this protozoan. Finding a high level of structural organization in the interphase nucleus of T.brucei is an important first step towards understanding chromosome structure and functioning and its role in the control of gene expression.},
}
@article {pmid2241933,
year = {1990},
author = {Greider, CW},
title = {Telomeres, telomerase and senescence.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {12},
number = {8},
pages = {363-369},
doi = {10.1002/bies.950120803},
pmid = {2241933},
issn = {0265-9247},
support = {GM43080-01/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Chromosomes/*physiology ; DNA Nucleotidylexotransferase/*metabolism ; *DNA Replication ; DNA-Directed DNA Polymerase/*metabolism ; Models, Genetic ; Molecular Sequence Data ; Mutation ; },
abstract = {Eukaryotic chromosomes end with tandem repeats of simple sequences. These GC rich repeats allow telomere replication and stabilize chromosome ends. Telomere replication involves an equilibrium of sequence loss and addition at the ends of chromosomes. Repeats are added de novo by telomerase, an unusual DNA polymerase. Telomerase is an RNP in which an essential RNA component provides the template for the added telomere repeats. Telomere length maintenance plays an essential role in cell viability.},
}
@article {pmid2196453,
year = {1990},
author = {Wang, SS and Zakian, VA},
title = {Sequencing of Saccharomyces telomeres cloned using T4 DNA polymerase reveals two domains.},
journal = {Molecular and cellular biology},
volume = {10},
number = {8},
pages = {4415-4419},
pmid = {2196453},
issn = {0270-7306},
support = {GM26938/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; *Chromosomes, Fungal ; Cloning, Molecular/*methods ; DNA, Fungal/genetics ; DNA-Directed DNA Polymerase/*metabolism ; Escherichia coli/genetics ; Molecular Sequence Data ; Restriction Mapping ; Saccharomyces cerevisiae/*genetics ; T-Phages/enzymology ; },
abstract = {By using T4 DNA polymerase rather than S1 or Bal31 nuclease to clone yeast telomeres, very little telomeric DNA is lost. These clones were used to determine the DNA sequence of virtually the entire telomeric tract. Our results demonstrated that a slightly modified version, C2-3A(CA)1-6, of the consensus derived from sequence analysis of more-internal regions (J. Shampay, J. W. Szostak, and E. H. Blackburn, Nature [London] 310:154-157, 1984) extends to the very end of the chromosome. The sequence analysis also suggests that yeast telomeres consist of two domains: the proximal 120 to 150 base pairs, which appear to be protected from processes such as recombination, degradation, and elongation, and the distal portion of the telomere, which is more susceptible to these events.},
}
@article {pmid2355912,
year = {1990},
author = {Price, CM},
title = {Telomere structure in Euplotes crassus: characterization of DNA-protein interactions and isolation of a telomere-binding protein.},
journal = {Molecular and cellular biology},
volume = {10},
number = {7},
pages = {3421-3431},
pmid = {2355912},
issn = {0270-7306},
support = {1 R29 GM41803-01/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Carrier Proteins/*isolation &amp; purification ; Cell Fractionation ; Cell Nucleus/ultrastructure ; Chromosomes/*physiology/ultrastructure ; DNA/genetics/*isolation &amp; purification/metabolism ; DNA-Binding Proteins/*isolation &amp; purification/metabolism ; Deoxyribonuclease I ; Eukaryota/genetics/*physiology ; Micrococcal Nuclease ; Molecular Sequence Data ; },
abstract = {The nucleoprotein structure of telomeres from Euplotes crassus was studied by using nuclease and chemical footprinting. The macronuclear telomeres were found to exist as DNA-protein complexes that are resistant to micrococcal nuclease digestion. Each complex encompassed 85 to 130 base pairs of macronuclear DNA and appeared to consist of two structural domains that are characterized by dissimilar DNA-protein interactions. Dimethyl sulfate footprinting demonstrated that very sequence-specific and salt-stable interactions occur in the most terminal region of each complex. DNase I footprinting indicated that DNA in the region 30 to 120 base-pairs from the 5' end lies on a protein surface; the interactions in this region of the complex are unlikely to be sequence specific. A 50-kilodalton telomere-binding protein was isolated. Binding of this protein protected telomeric DNA from BAL 31 digestion and gave rise to many of the sequence-specific DNA-protein interactions that were observed in vivo. The telomeric complexes from E. crassus were very similar in overall structure to the complexes found at Oxytricha telomeres. However, telomeric complexes from the two ciliates showed significant differences in internal organization. The telomeric DNA, the telomere-binding proteins, and the resultant DNA-protein interactions were all somewhat different. The telomere-binding proteins from the two ciliates were found to be less closely conserved than might have been expected. It appears that the proteins are tailored to match their cognate telomeric DNA.},
}
@article {pmid2352329,
year = {1990},
author = {Merchlinsky, M},
title = {Resolution of poxvirus telomeres: processing of vaccinia virus concatemer junctions by conservative strand exchange.},
journal = {Journal of virology},
volume = {64},
number = {7},
pages = {3437-3446},
pmid = {2352329},
issn = {0022-538X},
mesh = {Base Sequence ; Cloning, Molecular ; DNA, Viral/*ultrastructure ; Humans ; Hydrogen Bonding ; In Vitro Techniques ; Molecular Sequence Data ; Nucleic Acid Conformation ; Plasmids ; Recombination, Genetic ; Regulatory Sequences, Nucleic Acid ; Restriction Mapping ; Transfection ; Vaccinia virus/*genetics/ultrastructure ; },
abstract = {The replication of vaccinia virus proceeds through concatemeric intermediates which are resolved into unit-length DNA. In vaccinia virus-infected cells, plasmids containing the vaccinia virus DNA junction fragment that connects concatemers are resolved into linear minichromosomes of vector DNA flanked by hairpin loops. Resolution requires two copies of a specific nucleotide sequence conserved among poxviruses and found proximal to the hairpin loop. This study demonstrates that orientation of each sequence with respect to the other as well as to the axis of symmetry is critical for resolution, the processing of plasmids containing heterologous pairs of resolution sites is influenced by mismatched nucleotides between the sites, and the vaccinia virus hairpin in the linear minichromosome is a heteroduplex composed of DNA from each strand of the concatemer junction. A model incorporating site-specific recombination and orientated branch migration is proposed to account for resolution of the vaccinia virus concatemer junction.},
}
@article {pmid2356126,
year = {1990},
author = {Weber, B and Collins, C and Robbins, C and Magenis, RE and Delaney, AD and Gray, JW and Hayden, MR},
title = {Characterization and organization of DNA sequences adjacent to the human telomere associated repeat (TTAGGG)n.},
journal = {Nucleic acids research},
volume = {18},
number = {11},
pages = {3353-3361},
pmid = {2356126},
issn = {0305-1048},
mesh = {Base Sequence ; Cell Line ; Chromosome Banding ; Chromosome Mapping ; *Chromosomes, Human ; Cloning, Molecular ; *DNA ; Genes ; Humans ; Male ; Molecular Sequence Data ; Polymerase Chain Reaction ; *Repetitive Sequences, Nucleic Acid ; Templates, Genetic ; },
abstract = {We present a strategy for the cloning of DNA sequences adjacent to the tandemly repeated DNA sequence (TTAGGG)n. Sequence analysis of 14 independently isolated clones revealed the presence of non-repetitive sequences immediately adjacent to or flanked by blocks of the simple repeat (TTAGGG)n. In addition, we provide sequence information on two previously undescribed tandemly repeated sequences, including a 9 bp repeat and a modification of the (TTAGGG)n repeat. Using different mapping approaches six sub-clones, free of the TTAGGG repeat, were assigned to a single human chromosome. Moreover, in situ hybridization mapped one of these subclones, G2 - 1H, definitively to the telomeric band on chromosome 4q. However, Bal 31 insensitivity suggests a location in a more subterminal region. All the (TTAGGG)n-adjacent unique sequences tested are highly conserved among primates but are not present in other mammalian species. Identification and mapping of TTAGGG-adjacent sequences will provide a refined insight into the genomic organization of the (TTAGGG)n repeat. The isolation of chromosome specific TTAGGG-adjacent sequences from subtelomeric regions of all human chromosomes will serve as important end points for the genetic maps and will be useful for the molecular characterization of chromosomal rearrangements involving telomeres.},
}
@article {pmid2342578,
year = {1990},
author = {Harley, CB and Futcher, AB and Greider, CW},
title = {Telomeres shorten during ageing of human fibroblasts.},
journal = {Nature},
volume = {345},
number = {6274},
pages = {458-460},
doi = {10.1038/345458a0},
pmid = {2342578},
issn = {0028-0836},
mesh = {*Aging ; Cell Survival ; Cells, Cultured ; Chromosomes/*ultrastructure ; Fibroblasts ; Humans ; },
abstract = {The terminus of a DNA helix has been called its Achilles' heel. Thus to prevent possible incomplete replication and instability of the termini of linear DNA, eukaryotic chromosomes end in characteristic repetitive DNA sequences within specialized structures called telomeres. In immortal cells, loss of telomeric DNA due to degradation or incomplete replication is apparently balanced by telomere elongation, which may involve de novo synthesis of additional repeats by novel DNA polymerase called telomerase. Such a polymerase has been recently detected in HeLa cells. It has been proposed that the finite doubling capacity of normal mammalian cells is due to a loss of telomeric DNA and eventual deletion of essential sequences. In yeast, the est1 mutation causes gradual loss of telomeric DNA and eventual cell death mimicking senescence in higher eukaryotic cells. Here, we show that the amount and length of telomeric DNA in human fibroblasts does in fact decrease as a function of serial passage during ageing in vitro and possibly in vivo. It is not known whether this loss of DNA has a causal role in senescence.},
}
@article {pmid2111466,
year = {1990},
author = {Wang, SS and Zakian, VA},
title = {Telomere-telomere recombination provides an express pathway for telomere acquisition.},
journal = {Nature},
volume = {345},
number = {6274},
pages = {456-458},
doi = {10.1038/345456a0},
pmid = {2111466},
issn = {0028-0836},
mesh = {Animals ; Base Sequence ; *Chromosomes/ultrastructure ; Chromosomes, Fungal/ultrastructure ; Ciliophora/genetics ; Gene Conversion ; Molecular Sequence Data ; *Recombination, Genetic ; Saccharomyces cerevisiae/genetics ; Tetrahymena/genetics ; },
abstract = {DNA termini from Tetrahymena and Oxytricha, which bear C4A2 and C4A4 repeats respectively, can support telomere formation in Saccharomyces cerevisiae by serving as substrates for the addition of yeast telomeric C1-3A repeats. Previously, we showed that linear plasmids with 108 base pairs of C4A4 DNA (YLp108CA) efficiently acquired telomeres, whereas plasmids containing 28-64 base pairs of C4A4 DNA also promoted telomere formation, but with reduced efficiency. Although many of the C4A4 termini on these plasmids underwent recombination with a C4A2 terminus, the mechanism of telomere-telomere recombination was not established. We now report the sequence of the C4A4 ends from the linear plasmids. The results provide strong evidence for a novel recombination process involving a gene conversion event that requires little homology, occurs at or near the boundary of telomeric and nontelomeric DNA, and resembles the recombination process involved in bacteriophage T4 DNA replication.},
}
@article {pmid2111731,
year = {1990},
author = {Biessmann, H and Mason, JM and Ferry, K and d'Hulst, M and Valgeirsdottir, K and Traverse, KL and Pardue, ML},
title = {Addition of telomere-associated HeT DNA sequences "heals" broken chromosome ends in Drosophila.},
journal = {Cell},
volume = {61},
number = {4},
pages = {663-673},
doi = {10.1016/0092-8674(90)90478-w},
pmid = {2111731},
issn = {0092-8674},
mesh = {Animals ; Base Sequence ; Chromosome Aberrations/*genetics ; Chromosome Deletion ; Cloning, Molecular ; DNA Repair/*genetics ; Drosophila melanogaster/*genetics ; Female ; Male ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Restriction Mapping ; Sequence Homology, Nucleic Acid ; X Chromosome/physiology/*ultrastructure ; },
abstract = {Stocks of D. melanogaster X chromosomes carrying terminal deletions (RT chromosomes) have been maintained for several years. Some of the chromosomes are slowly losing DNA from the broken ends (as expected if replication is incomplete) and show no telomere-associated DNA added to the receding ends. Two stocks carry chromosomes that have become "healed" and are no longer losing DNA. In both stocks the broken chromosome end has acquired a segment of HeT DNA, a family of complex repeats found only at telomeres and in pericentric heterochromatin. Although the HeT family is complex, the HeT sequence joined to the broken chromosome end is the same in both stocks. In contrast, the two chromosomes are broken in different places and have no detectable sequence similarity at the junction with the new DNA. Sequence analysis suggests that the new telomere sequences have been added by a specific mechanism that does not involve homologous recombination.},
}
@article {pmid2388560,
year = {1990},
author = {Hinnebusch, J and Bergström, S and Barbour, AG},
title = {Cloning and sequence analysis of linear plasmid telomeres of the bacterium Borrelia burgdorferi.},
journal = {Molecular microbiology},
volume = {4},
number = {5},
pages = {811-820},
doi = {10.1111/j.1365-2958.1990.tb00651.x},
pmid = {2388560},
issn = {0950-382X},
mesh = {Base Sequence ; Borrelia burgdorferi Group/*genetics ; Chromosomes/ultrastructure ; Cloning, Molecular ; DNA, Bacterial/analysis ; DNA, Recombinant/analysis ; Molecular Sequence Data ; *Plasmids ; Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; },
abstract = {Borrelia burgdorferi, the Lyme disease agent, has double-stranded linear plasmids with covalently closed ends. DNA at the ends, or telomeres, of two linear plasmids of B. burgdorferi strain B31 was examined. Telomeric sequences from both ends of a 16 kb linear plasmid and from one end of a 49 kb linear plasmid were cloned and sequenced. An 18 bp AT-rich inverted repeat was found at each end of the 16 kb linear plasmid. The sequences of the two ends of this plasmid were different beyond these short inverted terminal repeats. The cloned end of the 49 kb linear plasmid had sequence identity with one end of the 16 kb linear plasmid. The end sequence common to both plasmids contained a series of phased, short direct repeats and a 52 bp palindrome adjacent to a highly AT-rich region. These findings indicate that Borrelia linear plasmid telomeres have structural features different from those of other known replicons.},
}
@article {pmid1971801,
year = {1990},
author = {Schechtman, MG},
title = {Characterization of telomere DNA from Neurospora crassa.},
journal = {Gene},
volume = {88},
number = {2},
pages = {159-165},
doi = {10.1016/0378-1119(90)90027-o},
pmid = {1971801},
issn = {0378-1119},
mesh = {Amino Acid Sequence ; Base Sequence ; Chromosomes, Fungal/*analysis ; Cloning, Molecular ; DNA Transposable Elements/*genetics ; DNA, Fungal/*analysis/genetics ; DNA, Recombinant ; Molecular Sequence Data ; Neurospora/*genetics ; Neurospora crassa/*genetics ; Polymorphism, Restriction Fragment Length ; Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; Terminator Regions, Genetic ; },
abstract = {The nucleotide sequence of the telomere at the right end of linkage group V (VR) in the standard OR23-IV-A strain of the filamentous fungus, Neurospora crassa, reveals the following features. At the chromosome terminus, tandem repeats of the hexanucleotide TTAGGG are present. Immediately centromere-proximal to the simple sequence repeat is a more complex element called Pogo that is reiterated 5-10 times in the genomes of various Neurospora strains. The element possesses several features characteristic of a transposable element: direct repeats of 318 bp flank the element, there is a long internal open reading frame (ORF), and a 3-bp duplication is found at its borders. However, Pogo has other structural features that are more difficult to reconcile with the standard model of a transposable element. A second telomere from Neurospora was also cloned by screening a genomic lambda library with a synthetic oligodeoxyribonucleotide homologous to the simple sequence repeats. This telomere is entirely non-homologous with the VR telomere except for the TTAGGG repeats, has no associated copy of Pogo, and has no nearby ORFs. There are no long stretches of TTAGGG repeats present in the Neurospora genome at non-telomeric sites.},
}
@article {pmid2180936,
year = {1990},
author = {Blackburn, EH},
title = {Telomeres: structure and synthesis.},
journal = {The Journal of biological chemistry},
volume = {265},
number = {11},
pages = {5919-5921},
pmid = {2180936},
issn = {0021-9258},
mesh = {Animals ; Base Sequence ; Chromosomes/*physiology ; DNA/*biosynthesis ; DNA Nucleotidyltransferases/*metabolism ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; },
}
@article {pmid2110655,
year = {1990},
author = {Runge, KW and Zakian, VA},
title = {Properties of the transcriptional enhancer in Saccharomyces cerevisiae telomeres.},
journal = {Nucleic acids research},
volume = {18},
number = {7},
pages = {1783-1787},
pmid = {2110655},
issn = {0305-1048},
support = {1 F32 GM10472-03/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosomes, Fungal/*physiology ; Cloning, Molecular ; *Enhancer Elements, Genetic ; Escherichia coli/genetics ; Molecular Sequence Data ; Plasmids ; Recombinant Proteins/metabolism ; Saccharomyces cerevisiae/*genetics/ultrastructure ; *Transcription, Genetic ; beta-Galactosidase/genetics/metabolism ; },
abstract = {Saccharomyces cerevisiae chromosomes end with the sequence C2-3A(CA)1-4, commonly abbreviated as C1-3A. These sequences can function as upstream activators of transcription (UAS's) when placed in front of a CYC1-lacZ fusion gene. When C1-3A sequences are placed between the GAL1,10 UAS and the CYC1-lacZ fusion, the C1-3A UAS still functions and the amount of beta-galactosidase produced in cells grown on glucose is as much or more than that for cells grown on either glycerol medium, or cells grown on glucose medium containing a plasmid with just the C1-3A UAS. These data indicate that the UAS is immune from glucose repression from the upstream GAL1,10 UAS. Because C1-3A sequences are bound in vitro by the transcription factor RAP1, the UAS activity of yeast telomere sequences was compared with that of a similar UAS from the tightly regulated ribosomal protein gene RP39A, which also contains a RAP1 binding site. While transcription from the ribosomal protein gene UAS was responsive to cell density, the amount of transcription from the C1-3A UAS was nearly the same at all cell densities tested. These data show that the transcriptional activation by C1-3A sequences is not regulated by cell density.},
}
@article {pmid2323332,
year = {1990},
author = {Van der Werf, A and Van Assel, S and Aerts, D and Steinert, M and Pays, E},
title = {Telomere interactions may condition the programming of antigen expression in Trypanosoma brucei.},
journal = {The EMBO journal},
volume = {9},
number = {4},
pages = {1035-1040},
pmid = {2323332},
issn = {0261-4189},
mesh = {Animals ; Antigens, Protozoan/*genetics ; Base Sequence ; Chromosomes/*physiology ; Gene Conversion ; *Gene Expression Regulation ; Genes ; Genetic Variation ; Molecular Sequence Data ; Nucleic Acid Hybridization ; *Protozoan Proteins ; Restriction Mapping ; Trypanosoma brucei brucei/*genetics/immunology ; Variant Surface Glycoproteins, Trypanosoma/*genetics ; },
abstract = {The AnTat 1.1 antigen type typically occurs late in a chronic infection by the EATRO 1125 stock of Trypanosoma brucei. The AnTat 1.1 gene, which is located 24 kb from a chromosome end, seems exclusively expressed by acting as a donor in gene conversion events targeted to the telomeric expression site. We report that this gene is sufficiently provided with the homology blocks required for recombination with the expression site, and is not interrupted by stop codons up to the 3' block of homology. A possible reason for its low probability of activation is an inverse orientation with respect to the proximal chromosome end, since, if correctly positioned, it is readily expressed at an early stage of infection, following gene conversion. This suggests that interactions between chromosome ends may precede and favour the rearrangements leading to antigenic variation.},
}
@article {pmid2200795,
year = {1990},
author = {Brown, WR and Dobson, MJ and MacKinnon, P},
title = {Telomere cloning and mammalian chromosome analysis.},
journal = {Journal of cell science},
volume = {95 (Pt 4)},
number = {},
pages = {521-526},
doi = {10.1242/jcs.95.4.521},
pmid = {2200795},
issn = {0021-9533},
mesh = {Animals ; Base Sequence ; Biological Evolution ; Chromosomes/*ultrastructure ; *Cloning, Molecular ; DNA ; DNA-Binding Proteins ; Humans ; Mammals/*genetics ; Molecular Sequence Data ; },
abstract = {Although eucaryotic chromosomes vary in size over five orders of magnitude and are constituents of diverse genetic systems the fundamental features of their telomeres appear to be almost completely conserved. This can be exploited to enable molecular cloning of human telomeres in yeast and suggests that many of the ideas that will arise from studies of telomeres in the experimentally tractable ciliates and yeasts will hold true of mammalian telomeres. The particular value of cloned mammalian telomeres is that they contribute reagents for mapping mammalian chromosomes and that they provide one set of elements for the construction of artificial mammalian chromosomes.},
}
@article {pmid2196434,
year = {1990},
author = {Constable, A and Feipeng, L and Walmsley, RM},
title = {Yeast telomere length varies in response to changes in the amount of polyC1-3A in the cell.},
journal = {Molecular &amp; general genetics : MGG},
volume = {221},
number = {2},
pages = {280-282},
pmid = {2196434},
issn = {0026-8925},
mesh = {Chromosomes, Fungal/analysis/*ultrastructure ; DNA, Fungal/*analysis/genetics ; Poly A/*analysis ; Poly C/*analysis ; Polyribonucleotides/*analysis ; Saccharomyces cerevisiae/analysis/*genetics ; Transformation, Genetic ; },
abstract = {Yeast chromosomes terminate in a GC-rich tail of DNA. Previous investigations have shown that the length of this tail can change in response to genetic variation. Here we present data that show that the length can also alter in response to changes in the amount of the GC-rich DNA found elsewhere in the nucleus.},
}
@article {pmid2162753,
year = {1990},
author = {Guerrini, AM and Ascenzioni, F and Pisani, G and Rappazzo, G and Della Valle, G and Donini, P},
title = {Cloning a fragment from the telomere of the long arm of human chromosome 9 in a YAC vector.},
journal = {Chromosoma},
volume = {99},
number = {2},
pages = {138-142},
pmid = {2162753},
issn = {0009-5915},
mesh = {Base Sequence ; Blotting, Southern ; Chromosome Mapping ; Chromosomes, Fungal ; *Chromosomes, Human, Pair 9 ; Cloning, Molecular ; DNA Transposable Elements ; Gene Library ; Genetic Vectors ; Humans ; Saccharomyces cerevisiae/genetics ; Transformation, Genetic ; },
abstract = {The construction of a yeast artificial chromosome containing a human DNA insert is reported. This molecule of about 200 kb behaves as a native yeast chromosome since it has a very high mitotic stability and is present in the yeast transformant clone at a copy number similar to that of the resident chromosomes. Hybridization with the TTAGGG sequence demonstrates that this chromosome contains human telomeric sequences. In situ hybridization of the biotin-labelled artificial chromosome to metaphase human chromosomes shows that the insert occupies a telomeric position on the long arm of chromosome 9. Since the fragment was cloned as an EcoRI insert and not as a telomere, it is situated medially to the telomeric sequences and harbours telomere-associated sequences, that have been shown to contain the TTAGGG sequence. The fragment represents the end of the genetic map of chromosome 9 and thus can be used to characterize the sequence and the structure of the chromosomal region that runs from the end of the chromosome to the first gene.},
}
@article {pmid2138410,
year = {1990},
author = {Bates, GP and MacDonald, ME and Baxendale, S and Sedlacek, Z and Youngman, S and Romano, D and Whaley, WL and Allitto, BA and Poustka, A and Gusella, JF},
title = {A yeast artificial chromosome telomere clone spanning a possible location of the Huntington disease gene.},
journal = {American journal of human genetics},
volume = {46},
number = {4},
pages = {762-775},
pmid = {2138410},
issn = {0002-9297},
support = {NS16367/NS/NINDS NIH HHS/United States ; NS20012/NS/NINDS NIH HHS/United States ; NS22031/NS/NINDS NIH HHS/United States ; },
mesh = {Chromosomes, Fungal ; *Chromosomes, Human, Pair 4 ; Cloning, Molecular ; Cosmids ; Gene Library ; Genes, Synthetic ; Genetic Markers ; Genetic Vectors ; Humans ; Huntington Disease/*genetics ; Restriction Mapping ; Saccharomyces cerevisiae/genetics ; },
abstract = {The Huntington disease (HD) gene has been mapped to the most distal subband of chromosome 4p. Analysis of recombination events has not provided an unequivocal location of the HD gene, but it indicates a position very close to the telomere as one possibility. We have constructed a yeast artificial chromosome (YAC) vector (containing a rare-cutter polylinker) for the cloning of mammalian telomeres, used it to prepare a BssHII-telomere library with DNA from an individual homozygous for HD, and have identified a 115-kb clone containing the telomere of 4p. One probable recombinant would confine the telomeric candidate location for the gene to the region covered by the YAC, which makes it possible that the clone described here contains the HD locus in its mutant form.},
}
@article {pmid2108923,
year = {1990},
author = {Fuster, C and Miró, R and Barrios, L and Egozcue, J},
title = {Telomere association of chromosomes induced by aphidicolin in a normal individual.},
journal = {Human genetics},
volume = {84},
number = {5},
pages = {424-426},
pmid = {2108923},
issn = {0340-6717},
mesh = {Aphidicolin ; Cells, Cultured ; *Chromosome Aberrations ; Chromosomes, Human/*ultrastructure ; Diterpenes/*pharmacology ; Humans ; Karyotyping ; Lymphocytes/drug effects/ultrastructure ; },
abstract = {Telomere association of chromosomes of a phenotypically and mentally normal individual was detected in 11.7% of metaphases cultured in RPMI-1640 with aphidicolin. No preferential involvement of any chromosome pair was detected. In two other individuals the frequency of telomere associations was much lower (1.9% and 0.7% respectively) under the same culture conditions. In the first individual the high number of telomere associations in cultures with aphidicolin along with the presence of telomere association (2.4%) in cultures with F.10 medium alone could reflect a constitutional telomere anomaly that is more often expressed in the presence of aphidicolin.},
}
@article {pmid1689810,
year = {1990},
author = {Yu, GL and Bradley, JD and Attardi, LD and Blackburn, EH},
title = {In vivo alteration of telomere sequences and senescence caused by mutated Tetrahymena telomerase RNAs.},
journal = {Nature},
volume = {344},
number = {6262},
pages = {126-132},
doi = {10.1038/344126a0},
pmid = {1689810},
issn = {0028-0836},
mesh = {Animals ; Base Sequence ; DNA Nucleotidylexotransferase/*metabolism ; Gene Expression ; Genes ; Genetic Vectors ; Molecular Sequence Data ; *Mutation ; Plasmids ; RNA/*genetics ; Templates, Genetic ; Tetrahymena/enzymology/*genetics ; },
abstract = {Mutating the CAACCCCAA sequence in the RNA component of telomerase causes the synthesis in vivo of new telomere sequences corresponding to the mutated RNA sequence, demonstrating that the telomerase contains the template for telomere synthesis. These mutations also lead to nuclear and cell division defects, and senescence, establishing an essential role for telomerase in vivo.},
}
@article {pmid2346844,
year = {1990},
author = {Crow, TJ and Delisi, LE and Johnstone, EC},
title = {In reply ... a locus closer to the telomere?.},
journal = {The British journal of psychiatry : the journal of mental science},
volume = {156},
number = {},
pages = {416-420},
doi = {10.1192/bjp.156.3.416},
pmid = {2346844},
issn = {0007-1250},
mesh = {Family ; Fathers ; Female ; Humans ; Male ; Mothers ; Schizophrenia/*genetics ; Sex ; },
}
@article {pmid2309453,
year = {1990},
author = {Parsons, BL and Pickup, DJ},
title = {Transcription of orthopoxvirus telomeres at late times during infection.},
journal = {Virology},
volume = {175},
number = {1},
pages = {69-80},
doi = {10.1016/0042-6822(90)90187-v},
pmid = {2309453},
issn = {0042-6822},
support = {P01 CA30246/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Chick Embryo ; Cloning, Molecular ; DNA, Viral/genetics ; *Genes, Viral ; L Cells ; Mice ; Molecular Sequence Data ; Nucleic Acid Conformation ; Nucleic Acid Hybridization ; Oligonucleotide Probes ; Plasmids ; Poxviridae/*genetics/physiology ; Promoter Regions, Genetic ; RNA Probes ; RNA, Messenger/genetics/isolation &amp; purification ; RNA, Viral/genetics/isolation &amp; purification ; Restriction Mapping ; Sequence Homology, Nucleic Acid ; Single-Strand Specific DNA and RNA Endonucleases ; *Transcription, Genetic ; },
abstract = {The telomeres of orthopoxvirus DNAs consists largely of short repeated sequences organized into at least two separate sets. Although the sequence composition of the orthopoxvirus telomeres is highly conserved, these regions do not appear to encode any proteins. At late times during infection, the telomeres of vaccinia virus are transcribed. A promoter in the region between the two sets of repeats directs transcription towards the hairpin-loop end of the viral DNA. This promoter resembles the promoters of other poxvirus late genes, and directs the synthesis of RNAs whose structure is consistent with the presence of 5' poly(A) sequences typical of late RNAs. The lengths of these late transcripts suggest that some transcription extends through the hairpin-loop region. This might occur either when the genome is in a monomeric form or when the genome is in the concatemeric form of the DNA replication intermediate. The function of late transcription of the telomeres is unclear, but similar transcription of the telomeres of vaccinia virus, cowpox virus, and raccoonpox virus suggests that such transcription may have a role in viral replication.},
}
@article {pmid2155401,
year = {1990},
author = {Inglehearn, CF and Cooke, HJ},
title = {A VNTR immediately adjacent to the human pseudoautosomal telomere.},
journal = {Nucleic acids research},
volume = {18},
number = {3},
pages = {471-476},
pmid = {2155401},
issn = {0305-1048},
mesh = {Animals ; Base Sequence ; Cell Line ; Cosmids ; DNA/*genetics ; DNA Restriction Enzymes ; Genetic Variation ; Humans ; Hybrid Cells ; Mice ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; Sequence Homology, Nucleic Acid ; Species Specificity ; X Chromosome/*ultrastructure ; Y Chromosome/*ultrastructure ; },
abstract = {The probe 29C1 detects a hypervariable locus 18kb from the telomere of the human X and Y chromosomes, in the pseudoautosomal region. Here we report that hypervariability of fragments containing this sequence in the human population arises by loss or gain of a 31 base pair GC rich repeat. Labelled 29C1 does not detect a DNA fingerprint at low stringency, though the consensus repeat sequence does show some similarity to previously reported minisatellites. Sequence within the repeat block has G and C rich strands, a feature associated with sequences at the telomeres of many higher organisms. The repeat block shows sequence characteristics normally associated with a low methylation island, though the locus is methylated and does not appear to be transcribed.},
}
@article {pmid2300578,
year = {1990},
author = {Panyutin, IG and Kovalsky, OI and Budowsky, EI and Dickerson, RE and Rikhirev, ME and Lipanov, AA},
title = {G-DNA: a twice-folded DNA structure adopted by single-stranded oligo(dG) and its implications for telomeres.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {87},
number = {3},
pages = {867-870},
pmid = {2300578},
issn = {0027-8424},
mesh = {*Chromosomes/ultrastructure ; *DNA ; Hydrogen Bonding ; Models, Molecular ; *Nucleic Acid Conformation ; *Oligodeoxyribonucleotides ; },
abstract = {Our dimethyl sulfate modification experiments suggest that (dG)n stretches within single-stranded DNA fragments, which represent the simplest model for telomeric sequences, adopt a complex intrastrand structure other than a simple hairpin. We present a molecular model for the DNA structure that conforms to dimethyl sulfate methylation data. The principal element of this G-DNA structure is a quadruple helix formed by pairwise antiparallel segments of the twice-folded (dG)n stretch. This quadruple core has two wide and two narrow grooves connected by three loop-shaped segments. The strong stacking interactions of the neighboring guanine tetrads and the large number of hydrogen bonds formed can be the primary reasons that such structures are favored over a common hairpin for long (dG)n stretches. Such compact structures may be formed from (dG)n stretches of telomeric sequences.},
}
@article {pmid1689486,
year = {1990},
author = {Hicke, BJ and Celander, DW and MacDonald, GH and Price, CM and Cech, TR},
title = {Two versions of the gene encoding the 41-kilodalton subunit of the telomere binding protein of Oxytricha nova.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {87},
number = {4},
pages = {1481-1485},
pmid = {1689486},
issn = {0027-8424},
support = {GM28039/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Ciliophora/*genetics ; Cloning, Molecular ; DNA/genetics/isolation &amp; purification ; DNA-Binding Proteins/*genetics/isolation &amp; purification ; Gene Amplification ; Gene Library ; *Genes ; Information Systems ; Introns ; Molecular Sequence Data ; Oligonucleotide Probes ; Peptide Mapping ; Protein Conformation ; RNA/genetics/isolation &amp; purification ; Sequence Homology, Nucleic Acid ; },
abstract = {Macronuclear chromosomes of the ciliated protozoan Oxytricha nova terminate with a single-stranded (T4G4)2 overhang. The (T4G4)2 telomeric overhang is tenaciously bound by a protein heterodimer. We have cloned and sequenced the gene encoding the 41-kDa subunit of this telomere binding protein. The predicted amino acid sequence comprises two distinct regions, a carboxyl-terminal two-thirds that is 23% lysine and bears similarity to histone H1 and an amino-terminal one-third containing a hydrophobic stretch of about 15 amino acids. Two macronuclear versions of the gene differ in nucleotide sequence at several positions, but the derived polypeptides differ only at a single position, Ser-110 or Ala-110. Both versions harbor a small intron. The existence of this intron demonstrates that, despite the elimination of 95% of the micronuclear genome from the developing macronucleus, at least some noncoding DNA is retained during macronuclear development of hypotrichous ciliates.},
}
@article {pmid2337592,
year = {1990},
author = {Henderson, ER and Moore, M and Malcolm, BA},
title = {Telomere G-strand structure and function analyzed by chemical protection, base analogue substitution, and utilization by telomerase in vitro.},
journal = {Biochemistry},
volume = {29},
number = {3},
pages = {732-737},
doi = {10.1021/bi00455a020},
pmid = {2337592},
issn = {0006-2960},
mesh = {Animals ; Base Composition ; Base Sequence ; Chromosomes/metabolism ; DNA Nucleotidylexotransferase/*metabolism ; Deoxyguanosine/metabolism ; Methylation ; Molecular Sequence Data ; Oligonucleotides/chemical synthesis ; Structure-Activity Relationship ; Sulfuric Acid Esters/metabolism ; Tetrahymena/ultrastructure ; },
abstract = {Eukaryotic telomeres have a 12-16 nucleotide long deoxyguanosine (dG) rich single-stranded overhang at their molecular termini. Some of the unique features of telomeres are probably attributable to a specialized structure formed by this overhang. In the ciliated protozoan Tetrahymena thermophila, the dG-rich overhang is comprised of approximately two repeats of the sequence d(TTGGGG). Previous work has shown that the synthetic oligonucleotide d(TTGGGG)4 can form an unusual non-Watson-Crick base-paired structure (the "G-strand structure") containing G-G base pairs and syn-guanines. We have tested the susceptibility of various dGs in this structure to methylation by DMS. At 0-10 degrees C one dG residue is hypersensitive to methylation while others are particularly resistant. By systematically substituting deoxyinosine (dI) for dG in d(TTGGGG)4 we identify N2 groups of guanine essential for formation of the G-strand structure. We show that dI-substituted molecules that cannot form the G-strand structure nonetheless function as substrates for telomere repeat addition in vitro by the telomere lengthening enzyme, telomerase. The implications of these data are discussed.},
}
@article {pmid2296304,
year = {1990},
author = {Blackburn, EH},
title = {Cell biology: telomeres sans frontières.},
journal = {Nature},
volume = {343},
number = {6254},
pages = {122},
doi = {10.1038/343122a0},
pmid = {2296304},
issn = {0028-0836},
mesh = {Animals ; Base Sequence ; Chromosomes/*physiology ; DNA Nucleotidyltransferases/*metabolism ; HeLa Cells/enzymology ; Humans ; Molecular Sequence Data ; Tetrahymena/enzymology ; },
}
@article {pmid2242682,
year = {1990},
author = {DeLange, AM and McFadden, G},
title = {The role of telomeres in poxvirus DNA replication.},
journal = {Current topics in microbiology and immunology},
volume = {163},
number = {},
pages = {71-92},
doi = {10.1007/978-3-642-75605-4_3},
pmid = {2242682},
issn = {0070-217X},
mesh = {Animals ; *Chromosomes ; DNA Replication/*genetics ; DNA, Viral/*genetics ; Poxviridae/*genetics ; },
}
@article {pmid2190243,
year = {1990},
author = {Ascenzioni, F and Guerrini, AM and Donini, P},
title = {Functional telomere formation in yeast using synthetic C4A2 sequences.},
journal = {Plasmid},
volume = {23},
number = {1},
pages = {16-26},
doi = {10.1016/0147-619x(90)90040-j},
pmid = {2190243},
issn = {0147-619X},
mesh = {Adenosine Triphosphate/metabolism ; Base Sequence ; Chromosomes, Fungal/*metabolism ; *DNA Replication ; DNA, Fungal/metabolism ; Genes, Fungal ; Mitosis ; Mutation ; Plasmids ; *Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; Saccharomyces cerevisiae/*genetics ; Transformation, Genetic ; },
abstract = {A yeast artificial chromosome (YAC) was constructed with a native autonomous replicating sequence (ARS) flanked telomere at one end and a 50-bp synthetic oligonucleotide of C4A2 repeats at the other. This was done in order to determine whether the presence of the flanking ARS sequence is required for telomere function. This construct was introduced into two different yeast strains: one mutated in the recombination function RAD52 and the other wild type for this gene. Both strains gave rise to autonomously replicating artificial chromosomes. The molecules in the RAD52 strain were rearranged dimers terminating at both ends with Tetrahymena telomeres, whereas in the rad52 strain two classes of YACs were found: rearranged dimers and elements bearing an ARS-free telomere. The presence of the latter class of molecules confirmed the finding of Wellinger and Zakian (1989, Proc. Natl. Acad. Sci. USA 86, 973-977) that the flanking ARS is not required for telomere function. Furthermore, in this class of molecules the ARS-free telomeric end was shortened as a result of deletions that removed some distal pBR322 sequences and some C4A2 repeats. The size of the resulting YACs ranged from 7.7 to 9 kb, considerably below the size threshold found by Zakian et al. (1986, Mol. Cell. Biol. 6, 925-932) for CEN4 artificial plasmids. An explanation for the structural instability of the ARS-free end of the YACs is suggested.},
}
@article {pmid2183413,
year = {1990},
author = {Zakian, VA and Runge, K and Wang, SS},
title = {How does the end begin? Formation and maintenance of telomeres in ciliates and yeast.},
journal = {Trends in genetics : TIG},
volume = {6},
number = {1},
pages = {12-16},
doi = {10.1016/0168-9525(90)90043-6},
pmid = {2183413},
issn = {0168-9525},
support = {GM-26938/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; *Chromosomes ; *Chromosomes, Fungal ; DNA Nucleotidyltransferases/genetics ; DNA Replication ; Molecular Sequence Data ; Saccharomyces/*genetics ; Tetrahymena/*genetics ; },
abstract = {Current models of telomere formation and replication involve either telomerase, a novel ribonucleoprotein, or recombination between the ends of DNA molecules. However, present models will have to be modified to explain recent data on telomere formation in yeast. An understanding of the mechanisms of telomere maintenance in yeast may reveal how other organisms with heterogeneous telomeric repeats replicate their chromosomal termini.},
}
@article {pmid2152134,
year = {1990},
author = {Blackburn, EH},
title = {Telomeres and their synthesis.},
journal = {Harvey lectures},
volume = {86},
number = {},
pages = {1-18},
pmid = {2152134},
issn = {0073-0874},
mesh = {Animals ; Base Sequence ; DNA/*biosynthesis/genetics ; DNA Nucleotidylexotransferase/metabolism ; Models, Genetic ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; Telomere/*metabolism ; Tetrahymena/genetics/metabolism ; },
}
@article {pmid2090564,
year = {1990},
author = {Bachmann, L and Raab, M and Sperlich, D},
title = {Evolution of a telomere associated satellite DNA sequence in the genome of Drosophila tristis and related species.},
journal = {Genetica},
volume = {83},
number = {1},
pages = {9-16},
pmid = {2090564},
issn = {0016-6707},
mesh = {Animals ; Base Sequence ; Cloning, Molecular ; DNA, Satellite/*genetics ; Drosophila/*genetics ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Repetitive Sequences, Nucleic Acid ; Species Specificity ; },
abstract = {A highly repetitive satellite DNA sequence from the genome of Drosophila tristis with a length of 181 bp has been cloned in the pUC plasmid. The sequence hybridizes to the telomeres of all chromosomes but the Y of D. tristis and produces a ladderlike hybridization pattern with filterbound genomic DNA of D. tristis digested with Eco RI or Pst I with the hybridization bands at fragment lengths in multiples of 181 bp. A similar pattern is found when the genomic DNA comes from D. ambigua or, though less clear, from D. microlabis. Additional bands appear in the zones of high fragment lengths, too. In D. obscura and D. kitumensis, however, the 181 bp sequence is found in fragments with a length of a few kb only. The 181 bp sequence is tandemly arranged in the genome of D. tristis and has a copy number of about 82,000 per haploid genome (i.e. 10 per cent of the total DNA). A sequence comparison among four independently cloned copies of the family from D. tristis and another homologous sequence from D. obscura, found by chance, shows a one to six per cent variation in basepair composition. However, low divergence (only one per cent) between two copies of D. tristis and between the one of D. obscura and one of D. tristis was observed, and high divergence (six per cent) between these two pairs. This is discussed and explained as the evolutionary consequence of an existing homogenization process by unequal crossing over.},
}
@article {pmid1967991,
year = {1990},
author = {Rangnekar, GV and Loya, BM and Goswami, LK and Sengupta, LK},
title = {Premature centromeric divisions and prominent telomeres in a patient with persistent mullerian duct syndrome.},
journal = {Clinical genetics},
volume = {37},
number = {1},
pages = {69-73},
doi = {10.1111/j.1399-0004.1990.tb03393.x},
pmid = {1967991},
issn = {0009-9163},
mesh = {Cells, Cultured ; *Centromere ; *Chromosomes ; Cryptorchidism/complications ; Disorders of Sex Development/complications/*diagnosis/genetics ; Hernia, Inguinal/complications ; Karyotyping ; Lymphocytes/ultrastructure ; Male ; Mullerian Ducts/*abnormalities ; Syndrome ; Translocation, Genetic ; },
abstract = {A 35-year-old, rare male pseudohermaphrodite with inguinal hernia, testis, fallopian tube and uterus, symptoms referrable to persistent Mullerian duct syndrome, is described. The patient has a 46,XY karyotype in 50% of metaphases, while the remaining metaphases show premature cnetromeric divisions and hypoploid counts.},
}
@article {pmid2685577,
year = {1989},
author = {Jäger, D and Philippsen, P},
title = {Many yeast chromosomes lack the telomere-specific Y' sequence.},
journal = {Molecular and cellular biology},
volume = {9},
number = {12},
pages = {5754-5757},
pmid = {2685577},
issn = {0270-7306},
mesh = {Chromosome Mapping ; Chromosomes, Fungal/*ultrastructure ; DNA, Fungal/isolation &amp; purification ; Diploidy ; Haploidy ; Nucleic Acid Hybridization ; Saccharomyces cerevisiae/*genetics ; Species Specificity ; },
abstract = {Chromosomal DNAs of 26 different strains representing Saccharomyces species were analyzed by pulsed-field gel electrophoresis and subsequent hybridization to Y' telomere DNA. Hybridization to Y' was found exclusively in Saccharomyces cerevisiae strains, and among these strains, Y' sequences were found to be lacking in small, middle-sized, and large chromosomes.},
}
@article {pmid2560753,
year = {1989},
author = {Hunter, DJ and Williams, K and Cartinhour, S and Herrick, G},
title = {Precise excision of telomere-bearing transposons during Oxytricha fallax macronuclear development.},
journal = {Genes &amp; development},
volume = {3},
number = {12B},
pages = {2101-2112},
doi = {10.1101/gad.3.12b.2101},
pmid = {2560753},
issn = {0890-9369},
support = {GM-25203/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Blotting, Southern ; Cell Nucleus/metabolism ; Chromosomes/*metabolism ; Ciliophora/*genetics/growth &amp; development/metabolism ; DNA/analysis/*genetics ; *DNA Transposable Elements ; Gene Amplification ; Molecular Sequence Data ; Restriction Mapping ; Temperature ; },
abstract = {In ciliated protozoa, development of the macronucleus from a copy of the germ line micronucleus involves elimination of a large number of sequences by DNA splicing akin to precise excision of transposons. The known examples of such internal eliminated sequences (IESs) are not repetitive. The telomere-bearing elements (TBE1s) of Oxytricha fallax are a family of transposons. We show that two particular TBE1s are also IESs. TBE1-1 and TBE1-2 disrupt a micronuclear region that codes for macronuclear DNA. A variety of tests indicates that each TBE1 and one copy of the flanking target repeat is absent from most, if not all, molecules of the macronuclear DNA, as if the TBE1s were precisely excised during macronuclear development. Three alternative explanations for the absence of TBE1-1 and TBE1-2 from the macronuclear DNA were tested. First, because two other highly homologous versions of that DNA are also found in the macronucleus, recombination between versions during or after macronuclear development could have bypassed the elements. Recombination in the regions flanking the elements was not detected. Second, micronuclear DNA blots show no evidence of a micronuclear counterpart of the macronuclear region that lacks TBE1-1. Third, TBE1-2 was demonstrated in two sexually independent cell lines. This shows that it pre-existed in the germ line, as opposed to having transposed into the micronuclear DNA subsequent to the generation of the macronucleus of the vegetative line that is usually studied. We conclude that TBE1-1 and TBE1-2, and possibly many of the other approximately 1900 micronucleus-limited TBE1s are excised as IESs during macronuclear development. These transposons appear to enjoy the luxury of relaxed constraints on family expansion, because they are removed from the genome before it is expressed. We discuss the possibility that all IESs are transposon-derived, that all are excised by transposition machinery, and that linear excision products are early intermediates in transposition.},
}
@article {pmid2557612,
year = {1989},
author = {Doggett, NA and Cheng, JF and Smith, CL and Cantor, CR},
title = {The Huntington disease locus is most likely within 325 kilobases of the chromosome 4p telomere.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {86},
number = {24},
pages = {10011-10014},
pmid = {2557612},
issn = {0027-8424},
support = {CA39782/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Blotting, Southern ; *Chromosomes, Human, Pair 4 ; Cricetinae ; DNA Probes ; DNA Transposable Elements ; Humans ; Huntington Disease/*genetics ; Hybrid Cells/cytology ; Plasmids ; Restriction Mapping ; },
abstract = {The genetic defect responsible for Huntington disease was originally localized near the tip of the short arm of chromosome 4 by genetic linkage to the locus D4S10. Several markers closer to Huntington disease have since been isolated, but these all appear to be proximal to the defect. A physical map that extends from the most distal of these loci, D4S90, to the telomere of chromosome 4 was constructed. This map identifies at least two CpG islands as markers for Huntington disease candidate genes and places the most likely location of the Huntington disease defect remarkably close (within 325 kilobases) to the telomere.},
}
@article {pmid2805070,
year = {1989},
author = {Morin, GB},
title = {The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats.},
journal = {Cell},
volume = {59},
number = {3},
pages = {521-529},
doi = {10.1016/0092-8674(89)90035-4},
pmid = {2805070},
issn = {0092-8674},
mesh = {Base Sequence ; Chromosomes, Human/enzymology ; DNA Nucleotidyltransferases/*metabolism ; HeLa Cells/enzymology ; Humans ; Molecular Sequence Data ; Oligodeoxyribonucleotides/chemical synthesis ; Repetitive Sequences, Nucleic Acid ; Ribonucleoproteins/*metabolism ; Substrate Specificity ; },
abstract = {I have identified an activity in crude HeLa cell extracts that satisfies the requirements for a human telomere terminal transferase or telomerase. It catalyzes the addition of a 6 nucleotide repeating pattern to oligonucleotide primers containing human or nonhuman telomeric repeat sequences. Direct sequence analyses of reaction products reveal the added sequence to be TTAGGG in all cases. Under optimal conditions 65-70 repeats can be synthesized. The enzyme has the properties of a ribonucleoprotein. Telomerase has previously been observed only in ciliated protozoans, which possess 10(4) - 10(7) macronuclear telomeres. The identification of telomerase in HeLa cells with only approximately 100 telomeres indicates that telomerase-mediated telomere maintenance is conserved throughout eukaryotes.},
}
@article {pmid2482516,
year = {1989},
author = {Cornforth, MN and Meyne, J and Littlefield, LG and Bailey, SM and Moyzis, RK},
title = {Telomere staining of human chromosomes and the mechanism of radiation-induced dicentric formation.},
journal = {Radiation research},
volume = {120},
number = {2},
pages = {205-212},
pmid = {2482516},
issn = {0033-7587},
support = {CA45141/CA/NCI NIH HHS/United States ; },
mesh = {*Chromosome Aberrations ; Chromosomes/*radiation effects ; Cobalt Radioisotopes ; DNA Probes ; Fibroblasts/radiation effects ; Gamma Rays ; Humans ; In Vitro Techniques ; Staining and Labeling ; },
abstract = {The majority of models of radiation action developed over the past half century hold that the curvilinear dose responses exhibited by eukaryotic cells to sparsely ionizing radiations result from the interaction of pairs of lesions produced in sensitive targets of the cell. Within this conceptual framework, chromosomal exchange aberrations (e.g., interchanges) are believed to occur through the interaction of damaged sites on both chromosomes participating in the exchange. In contrast, the model proposed by Chadwick and Leenhouts (as well as some other models) suggests that such exchanges arise from initial radiation damage to only one chromosome, which then becomes associated with an undamaged chromosome. A particular aspect of this theory is that asymmetrical exchanges, such as dicentrics, may be formed from the rejoining of a broken end of one chromosome to the telomere of another. By using a DNA probe that specifically hybridizes to the telomeric region of human chromosomes, we were able to test this assertion directly. After scanning more than 200 dicentrics produced in normal human fibroblasts by 6 Gy of 60Co gamma rays, virtually none were found that contained telomeres located between the centromeres of this aberration type. Therefore, since the proposed telomere-break rejoining process, per se, is not necessarily a central element of the Chadwick-Leenhouts model, we suggest the theory be modified to exclude this mechanism.},
}
@article {pmid2697465,
year = {1989},
author = {Longtine, MS and Wilson, NM and Petracek, ME and Berman, J},
title = {A yeast telomere binding activity binds to two related telomere sequence motifs and is indistinguishable from RAP1.},
journal = {Current genetics},
volume = {16},
number = {4},
pages = {225-239},
pmid = {2697465},
issn = {0172-8083},
support = {GM38626/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Binding Sites ; Binding, Competitive ; DNA Mutational Analysis ; DNA, Fungal/*genetics ; DNA-Binding Proteins/*genetics/metabolism ; Electrophoresis, Polyacrylamide Gel ; Fungal Proteins/*genetics/metabolism ; Immunoblotting ; Methylation ; Molecular Sequence Data ; Plasmids ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*genetics ; Sequence Homology, Nucleic Acid ; Substrate Specificity ; *Transcription Factors ; },
abstract = {Telomere Binding Activity (TBA), an abundant protein from Saccharomyces cerevisiae, was identified by its ability to bind to telomeric poly(C1-3A) sequence motifs. The substrate specificity of TBA has been analyzed in order to determine whether the activity binds to a unique structure assumed by the irregularly repeating telomeric sequences or whether the activity recognizes and binds to subset of specific sequences found within the telomere repeat tracts. Deletion analysis and DNase I protection assays demonstrate that TBA binds specifically to two poly-(C1-3A) sequences that differ by one nucleotide. The methylation of four guanine residues, located at identical relative positions within these two binding sequences, interferes with TBA binding to the substrates. A synthetic olignucleotide containing a single TBA binding site can function as a TBA binding substrate. The TBA binding site shares homology with the binding sites reported for the Repressor/Activator Protein 1 (RAP1), Translation Upshift Factor (TUF) and General Regulatory Factor (GRFI) transcription factors, and TBA binds directly to RAP1/TUF/GRFI substrate sequences. Yeast TBA preparations and the RAP1 gene product expressed in E. coli cells are both similarly sensitive to in vitro protease digestion. Affinity-purified TBA extracts include a protein indistinguishable from RAP1 in binding specificity, size, and antigenicity. The binding affinity of TBA for the two telomeric poly(C1-3A) binding sites is higher than its affinity for any of the other binding substrates used for its identification. In extracts of yeast spheroplasts prepared by incubation of yeast cells with Zymolyase, an altered, proteolyzed form, of TBA (TBA-S) is present. TBA-S has a faster mobility in gel retardation assays and SDS-PAGE gels, yet it retains the DNA binding properties of standard TBA preparations: it binds to RAP1/TUF/GRFI substrates with the same relative binding affinity and protects poly(C1-3A) tracts from DNase I digestion with a "footprint" identical to that of standard TBA preparations.},
}
@article {pmid2692239,
year = {1989},
author = {Hastie, ND and Allshire, RC},
title = {Human telomeres: fusion and interstitial sites.},
journal = {Trends in genetics : TIG},
volume = {5},
number = {10},
pages = {326-331},
doi = {10.1016/0168-9525(89)90137-6},
pmid = {2692239},
issn = {0168-9525},
mesh = {Animals ; *Chromosomes, Human ; DNA Replication ; Humans ; Male ; Neoplasms/genetics ; Recombination, Genetic ; *Repetitive Sequences, Nucleic Acid ; },
abstract = {The ends of human chromosomes have been shown recently to resemble those of simple organisms. With this in mind, we discuss the nature and possible significance of rare chromosome fusion events thought to involve telomeres, particularly those fusion events found in some tumours. Also we argue that interstitial telomere-like stretches may be particularly prone to recombination, breakage and fragility.},
}
@article {pmid2780561,
year = {1989},
author = {Meyne, J and Ratliff, RL and Moyzis, RK},
title = {Conservation of the human telomere sequence (TTAGGG)n among vertebrates.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {86},
number = {18},
pages = {7049-7053},
pmid = {2780561},
issn = {0027-8424},
mesh = {Animals ; Base Sequence ; *Biological Evolution ; Chromosomes ; *Chromosomes, Human ; Humans ; Molecular Sequence Data ; Nucleic Acid Hybridization ; *Repetitive Sequences, Nucleic Acid ; Vertebrates/*genetics ; },
abstract = {To determine the evolutionary origin of the human telomere sequence (TTAGGG)n, biotinylated oligodeoxynucleotides of this sequence were hybridized to metaphase spreads from 91 different species, including representative orders of bony fish, reptiles, amphibians, birds, and mammals. Under stringent hybridization conditions, fluorescent signals were detected at the telomeres of all chromosomes, in all 91 species. The conservation of the (TTAGGG)n sequence and its telomeric location, in species thought to share a common ancestor over 400 million years ago, strongly suggest that this sequence is the functional vertebrate telomere.},
}
@article {pmid2779572,
year = {1989},
author = {Kämper, J and Meinhardt, F and Gunge, N and Esser, K},
title = {In vivo construction of linear vectors based on killer plasmids from Kluyveromyces lactis: selection of a nuclear gene results in attachment of telomeres.},
journal = {Molecular and cellular biology},
volume = {9},
number = {9},
pages = {3931-3937},
pmid = {2779572},
issn = {0270-7306},
mesh = {Base Sequence ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; DNA, Fungal/genetics/metabolism ; Fungal Proteins/metabolism ; *Genes, Fungal ; Genetic Vectors ; Kluyveromyces/*genetics/metabolism ; Molecular Sequence Data ; Plasmids ; Recombination, Genetic ; Saccharomycetales/*genetics ; },
abstract = {Linear vectors based on plasmids pGKL1 and pGKL2 from Kluyveromyces lactis were obtained by in vivo recombination in Saccharomyces cerevisiae and selected for integration of the nuclear LEU2 gene. The linear hybrid molecules obtained had no proteins attached to their 5' ends, as is found for native pGKL plasmids. However, telomere-specific sequences were added to the ends of pGKL1. In contrast to the cytoplasmically localized pGKL plasmids, the newly obtained linear hybrid vectors probably replicate within the nucleus and provide evidence that the nuclear LEU2 gene cannot be expressed in the cytoplasm.},
}
@article {pmid2688928,
year = {1989},
author = {de Steensma, HY and de Jonge, P and Kaptein, A and Kaback, DB},
title = {Molecular cloning of chromosome I DNA from Saccharomyces cerevisiae: localization of a repeated sequence containing an acid phosphatase gene near a telomere of chromosome I and chromosome VIII.},
journal = {Current genetics},
volume = {16},
number = {3},
pages = {131-137},
pmid = {2688928},
issn = {0172-8083},
mesh = {Acid Phosphatase/*genetics ; Chromosome Mapping ; *Chromosomes, Fungal ; Cloning, Molecular ; DNA, Fungal/*genetics ; Electrophoresis ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/enzymology/*genetics ; },
abstract = {A 17 kb region from near the right end of chromosome I of Saccharomyces cerevisiae was isolated on recombinant lambda bacteriophages. This region contained the PHO11 gene which was located only 3.4 kb from the right end of the chromosome. We found that this region also was repeated approximately 13 kb from the end of the chromosome VIII DNA molecule. The chromosome VIII sequence appears to be a previously unnamed acid phosphatase gene that we propose to call PHO12. Thus, similar to the repeated SUC, MAL, X and Y' sequences, some members of the repeated acid phosphatase gene family also appear near the termini of yeast chromosomes.},
}
@article {pmid2511008,
year = {1989},
author = {Rudenko, G and Van der Ploeg, LH},
title = {Transcription of telomere repeats in protozoa.},
journal = {The EMBO journal},
volume = {8},
number = {9},
pages = {2633-2638},
pmid = {2511008},
issn = {0261-4189},
support = {AI21784/AI/NIAID NIH HHS/United States ; N0I-AI62528/AI/NIAID NIH HHS/United States ; },
mesh = {Amanitins/pharmacology ; Animals ; Chromosomes/analysis ; Eukaryota/*genetics ; Plasmids ; Plasmodium falciparum/genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Transcription, Genetic ; Trypanosoma brucei brucei/*genetics ; Trypanosomatina/genetics ; Variant Surface Glycoproteins, Trypanosoma/*genetics ; },
abstract = {The telomerically located variant cell surface glycoprotein (VSG) gene expression sites of the protozoan parasite Trypanosoma brucei are transcribed by an unusual alpha-amanitin resistant RNA polymerase. We show that the telomere GGGTTA repeats located at the chromosome ends of T. brucei and the related protozoan T. equiperdum are also transcribed by alpha-amanitin resistant RNA polymerases. This transcription predominantly proceeds unidirectionally towards the end of the chromosome, in both bloodstream and insect form trypanosomes and results in the generation of heterogeneously sized steady state RNA. We postulate that telomere repeat transcription results from readthrough downstream of telomeric genes. Telomere repeat transcription was found in all seven protozoan species tested, but was alpha-amanitin resistant only in trypanosome species which exhibited antigenic variation. The data indicate that in some trypanosome species a subset of telomeres is transcribed by a different type of RNA polymerase.},
}
@article {pmid2548737,
year = {1989},
author = {Levis, RW},
title = {Viable deletions of a telomere from a Drosophila chromosome.},
journal = {Cell},
volume = {58},
number = {4},
pages = {791-801},
doi = {10.1016/0092-8674(89)90112-8},
pmid = {2548737},
issn = {0092-8674},
support = {GM38259/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Division ; Chromosome Deletion ; Chromosome Mapping ; Chromosomes/*ultrastructure ; *DNA Transposable Elements ; Drosophila melanogaster/*genetics ; Mutation ; },
abstract = {Destabilization of a P element transposon inserted in the subtelomeric region induced a set of similar chromosomal rearrangements. These rearrangements appear to be terminal deletions with endpoints clustered at the centromere-distal end of the transposon. The terminally deleted chromosome progressively loses sequences from the broken end at a rate of approximately 50-100 bp per fly generation, suggesting that the replication of this end may be incomplete. In most cases, capping of the broken end by readdition of new sequences was not observed. Past failures to recover terminal deletions of Drosophila chromosomes following X-ray mutagenesis may have been due to a cell cycle arrest in response to unrepaired DNA damage rather than to an absolute requirement for the telomere.},
}
@article {pmid2549507,
year = {1989},
author = {Cheng, JF and Smith, CL and Cantor, CR},
title = {Isolation and characterization of a human telomere.},
journal = {Nucleic acids research},
volume = {17},
number = {15},
pages = {6109-6127},
pmid = {2549507},
issn = {0305-1048},
support = {CA39782/CA/NCI NIH HHS/United States ; GM14825/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Bacterial Proteins ; Cell Line ; Chromosome Mapping ; Chromosomes, Fungal ; Chromosomes, Human/*ultrastructure ; Chromosomes, Human, Pair 21/ultrastructure ; *Cloning, Molecular ; Cricetinae ; DNA/*genetics ; DNA Probes ; DNA Restriction Enzymes ; Deoxyribonuclease BamHI ; Deoxyribonuclease EcoRI ; Deoxyribonucleases, Type II Site-Specific ; Genome, Human ; Humans ; Hybrid Cells ; Nucleic Acid Hybridization ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/genetics ; Transformation, Genetic ; },
abstract = {A method is described that allows cloning of human telomeres in S. cerevisiae by joining human telomeric restriction fragments to yeast artificial chromosome halves. The resulting chimeric yeast-human chromosomes propagate as true linear chromosomes, demonstrating that the human telomere structure is capable of functioning in yeast and suggesting that telomere functions are evolutionarily conserved between yeast and human. One cloned human telomere, yHT1, contains 4 kb of human genomic DNA sequence next to the tandemly repeating TTAGGG hexanucleotide. Genomic hybridizations using both cloned DNA and TTAGGG repeats have revealed a common structural organization of human telomeres. This 4 kb of genomic DNA sequence is present in most, but not all, human telomeres, suggesting that the region is not involved in crucial chromosome-specific functions. However, the extent of common features among the human telomeres and possible similarities in organization with yeast telomeres suggest that this region may play a role in general chromosome behavior such as telomere-telomere interactions. Unlike the simple telomeric TTAGGG repeats, our cloned human genomic DNA sequence does not cross-hybridize with rodent DNA. Thus, this clone allows the identifications of the terminal restriction fragments of specific human chromosomes in human-rodent hybrid cells.},
}
@article {pmid2475856,
year = {1989},
author = {Zahler, AM and Prescott, DM},
title = {DNA primase and the replication of the telomeres in Oxytricha nova.},
journal = {Nucleic acids research},
volume = {17},
number = {15},
pages = {6299-6317},
pmid = {2475856},
issn = {0305-1048},
support = {5 R01 GM19199/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenosine Triphosphate/metabolism ; Amanitins/pharmacology ; Animals ; Base Sequence ; Chromosomes/*ultrastructure ; Ciliophora/*enzymology/genetics ; Cytidine Triphosphate/metabolism ; *DNA Replication ; Deoxyguanosine ; Macromolecular Substances ; Nucleic Acid Hybridization ; Oligodeoxyribonucleotides/metabolism ; RNA/biosynthesis ; Repetitive Sequences, Nucleic Acid ; Templates, Genetic ; Thymidine ; },
abstract = {An enzymatic activity in crude extracts of macronuclei from the hypotrichous ciliate Oxytricha nova catalyzes the synthesis of RNA consisting of (C4A4)n using an oligodeoxynucleotide template of the telomeric sequence (dG4T4)n. Single-stranded (dG4T4)n is an effective template if it has a random sequence at its 5' end. The enzyme will not use a (dG4T4)n template of any length (up to 64 bases) if it lacks a random sequence at the 5' end. With a random, single-stranded sequence at the 5' end, the (dG4T4)n oligodeoxynucleotide must be at least 36 bases long to work as a template. A 16-base, single-stranded region of (dG4T4)2 is an effective template when joined to a 20-base double-stranded region of (dG4T4)n/(dA4dC4)n, a structural arrangement that is the same as the native telomere of Oxytricha macronuclear DNA. The RNA-synthesizing activity is unaffected by 1.0 mg/ml of alpha-amanitin. Macronuclear extracts have an alpha-amanitin-insensitive, RNA-polymerizing activity that can use a random 55mer oligodeoxynucleotide as a template. This enzyme activity may be the same one that uses (dG4T4)n templates to make (C4A4)n RNA. The (C4A4)n RNA made in the reaction can prime DNA synthesis by the E. coli DNA polymerase I Klenow fragment. Therefore, the RNA polymerase activity fulfills the requirements of the telomere DNA primase that we postulated for replication of telomeres in hypotrichs (Zahler and Prescott, 1988, Nucleic Acids Research 16, 6953-6972).},
}
@article {pmid2664709,
year = {1989},
author = {Allshire, RC and Dempster, M and Hastie, ND},
title = {Human telomeres contain at least three types of G-rich repeat distributed non-randomly.},
journal = {Nucleic acids research},
volume = {17},
number = {12},
pages = {4611-4627},
pmid = {2664709},
issn = {0305-1048},
mesh = {Animals ; Autoradiography ; Base Composition ; Binding, Competitive ; *Chromosomes, Human ; Cold Temperature ; Deoxyribonucleases, Type II Site-Specific ; Endodeoxyribonucleases ; Guanine ; Humans ; Mice ; Nucleic Acid Hybridization ; Oligonucleotide Probes ; Plants/genetics ; Plasmodium berghei/genetics ; Plasmodium falciparum/genetics ; *Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; Tetrahymena/genetics ; Trypanosoma brucei brucei/genetics ; },
abstract = {Using a combination of different oligonucleotides and restriction enzymes we have examined the gross organisation of repeats within the most distal region of human chromosomes. We demonstrate here that human telomeres do not contain a pure uniform 6 base pair repeat unit but that there are at least three types of repeat. These three types of repeat are present at the ends of most or all human chromosomes. The distribution of each type of repeat appears to be non-random. Each human telomere has a similar arrangement of these repeats relative to the ends of the chromosome. This could reflect differences in the functions that they perform, or might result from the mutation and correction processes occurring at human telomeres. The number of repeat units, the repeat types and arrangement differs at mouse telomeres. Analysing the change in length of the telomeric repeat region between an individuals blood and germline DNA reveals that this is due to variable amounts of the TTAGGG repeat and not the other repeat types. This organization of repeat units at human telomeres will only be confirmed upon the isolation and sequencing of full length (10-15 kb), intact human telomeres.},
}
@article {pmid2697271,
year = {1989},
author = {Bloom, K and Yeh, E},
title = {Centromeres and telomeres: structural elements of eukaryotic chromosomes.},
journal = {Current opinion in cell biology},
volume = {1},
number = {3},
pages = {526-532},
doi = {10.1016/0955-0674(89)90015-x},
pmid = {2697271},
issn = {0955-0674},
mesh = {Animals ; Base Sequence ; *Centromere/analysis/metabolism/ultrastructure ; Chromosomal Proteins, Non-Histone/analysis ; *Chromosomes/analysis/metabolism/ultrastructure ; DNA/metabolism ; Humans ; Molecular Sequence Data ; Nucleic Acid Conformation ; Nucleoproteins/analysis ; },
}
@article {pmid2548922,
year = {1989},
author = {Charron, MJ and Read, E and Haut, SR and Michels, CA},
title = {Molecular evolution of the telomere-associated MAL loci of Saccharomyces.},
journal = {Genetics},
volume = {122},
number = {2},
pages = {307-316},
pmid = {2548922},
issn = {0016-6731},
support = {GM28216/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosome Mapping ; Fungal Proteins/*genetics ; Gene Products, tat ; Genes ; *Genes, Fungal ; Membrane Transport Proteins/*genetics ; Monosaccharide Transport Proteins ; *Multigene Family ; Phylogeny ; Saccharomyces cerevisiae/enzymology/*genetics ; Sequence Homology, Nucleic Acid ; Transcription Factors/*genetics ; alpha-Glucosidases/*genetics ; },
abstract = {The MAL gene family of Saccharomyces consists of five multigene complexes (MAL1, MAL2, MAL3, MAL4, and MAL6) each of which encodes maltose permease (GENE 1), maltase (GENE 2) and the trans-acting MAL-activator (GENE 3). Four of these loci have been mapped and each is located at or near the telomere of a different chromosome. We compare the physical structure of the MAL loci and their flanking sequences. The MAL loci were shown to be both structurally and functionally homologous throughout an approximately 9.0-kb region. The orientation of the MAL loci was determined to be: CENTROMERE . . . GENE 3-GENE 1-GENE 2 . . . TELOMERE. Telomere-adjacent sequences were found flanking GENE 2 of the MAL1, MAL3 and MAL6 loci. No common repeated elements were found on the centromere-proximal side of all the MAL1, loci. These results suggest that, during the evolution of this polygenic family, the MAL loci translocated to different chromosomes via a mechanism that involved the rearrangement(s) of chromosome termini.},
}
@article {pmid2474761,
year = {1989},
author = {Shippen-Lentz, D and Blackburn, EH},
title = {Telomere terminal transferase activity from Euplotes crassus adds large numbers of TTTTGGGG repeats onto telomeric primers.},
journal = {Molecular and cellular biology},
volume = {9},
number = {6},
pages = {2761-2764},
pmid = {2474761},
issn = {0270-7306},
support = {GM 26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromosomes/*metabolism ; Ciliophora/drug effects/*enzymology/genetics ; DNA/metabolism ; DNA Nucleotidylexotransferase/*metabolism ; Densitometry ; Molecular Sequence Data ; RNA/genetics ; *Repetitive Sequences, Nucleic Acid ; Ribonuclease, Pancreatic/pharmacology ; Substrate Specificity ; Temperature ; },
abstract = {A telomere terminal transferase activity was identified in developing macronuclear extracts from Euplotes crassus. The activity was essentially unregulated in vitro: up to 50 tandem repeats of the Euplotes telomeric repeat sequence TTTTGGGG were added onto synthetic telomeric oligonucleotide primers. Both the structure of the telomere substrate and its 3'-terminal sequence were recognized. The activity was destroyed by low concentrations of RNase A.},
}
@article {pmid2655926,
year = {1989},
author = {Lundblad, V and Szostak, JW},
title = {A mutant with a defect in telomere elongation leads to senescence in yeast.},
journal = {Cell},
volume = {57},
number = {4},
pages = {633-643},
doi = {10.1016/0092-8674(89)90132-3},
pmid = {2655926},
issn = {0092-8674},
mesh = {Aging/*physiology ; Alleles ; Amino Acid Sequence ; Base Sequence ; Cell Survival ; Chromosome Aberrations ; Chromosome Disorders ; Chromosomes/*physiology ; Cloning, Molecular ; DNA/analysis ; Molecular Sequence Data ; *Mutation ; Phenotype ; Saccharomyces cerevisiae/*genetics ; },
abstract = {We describe a general assay designed to detect mutants of yeast that are defective for any of several aspects of telomere function. Using this assay, we have isolated a mutant that displays a progressive decrease in telomere length as well as an increased frequency of chromosome loss. This mutation defines a new gene, designated EST1 (for ever shorter telomeres). Null alleles of EST1 are not immediately inviable; instead, they have a senescence phenotype, due to the gradual loss of sequences essential for telomere function, leading to a progressive decrease in chromosomal stability and subsequent cell death.},
}
@article {pmid2541342,
year = {1989},
author = {Brown, WR},
title = {Molecular cloning of human telomeres in yeast.},
journal = {Nature},
volume = {338},
number = {6218},
pages = {774-776},
doi = {10.1038/338774a0},
pmid = {2541342},
issn = {0028-0836},
mesh = {Animals ; Chromosome Mapping ; Chromosomes, Fungal ; Chromosomes, Human/*ultrastructure ; *Cloning, Molecular ; DNA/genetics ; DNA Restriction Enzymes ; Deoxyribonuclease BamHI ; Electrophoresis, Agar Gel ; Genetic Vectors ; Humans ; Nucleic Acid Hybridization ; Oligonucleotide Probes ; Saccharomyces cerevisiae/*genetics ; Transformation, Genetic ; Trypanosoma/genetics ; },
abstract = {Telomeres are the DNA sequences found at the ends of linear chromosomes. They define the boundaries of the genetical and physical maps of such chromosomes and so are particularly important for the complete mapping of large genomes that is now being attempted. Telomeres have been intensively studied in the yeast Saccharomyces cerevisiae and in ciliated protozoa: in these organisms the telomeric DNA consists of arrays of tandemly repeated short sequences in which one strand is guanosine-rich and oriented 5' to 3' towards the chromosome end. The conservation of these structural features is reflected in the observation that telomeric DNA from a variety of protozoa will function as telomeres on artificial linear mini-chromosomes in yeast. Tandem arrays of the sequence TTAGGG have been identified at the telomeres of humans and other mammals and also of trypanosomes. This indicates that the structural features of telomeres are conserved between higher and lower eukaryotes and implies that human telomeric DNA could function in yeast. I have used this idea to develop a strategy to isolate a specific human telomere as a molecular clone in yeast and have devised a simple and effective way of cloning other human telomeres and their associated sequences.},
}
@article {pmid2541341,
year = {1989},
author = {Cross, SH and Allshire, RC and McKay, SJ and McGill, NI and Cooke, HJ},
title = {Cloning of human telomeres by complementation in yeast.},
journal = {Nature},
volume = {338},
number = {6218},
pages = {771-774},
doi = {10.1038/338771a0},
pmid = {2541341},
issn = {0028-0836},
mesh = {Animals ; Chromosomes, Fungal ; Chromosomes, Human/*ultrastructure ; *Cloning, Molecular ; DNA/blood/genetics ; DNA Restriction Enzymes ; Genes, Fungal ; Genetic Markers ; Genetic Vectors ; Humans ; Male ; Nucleic Acid Hybridization ; Oligonucleotide Probes ; Recombination, Genetic ; Saccharomyces cerevisiae/genetics ; Sequence Homology, Nucleic Acid ; Spermatozoa/analysis ; Transformation, Genetic ; Trypanosoma/genetics ; },
abstract = {Telomeres confer stability on chromosomes by protecting them from degradation and recombination and by allowing complete replication of the end. They are genetically important as they define the ends of the linkage map. Telomeres of lower eukaryotes contain short repeats consisting of a G-rich and a C-rich strand, the G-rich strand running 5'-3' towards the telomere and extending at the end. Telomeres of human chromosomes share characteristics with those of lower eukaryotes including sequence similarity as detected by cross-hybridization. Telomeric repeats from many organisms can provide telomere function in yeast. Here we describe a modified yeast artificial chromosome (YAC) vector with only one telomere which we used to clone human telomeres by complementation in yeast. YACs containing human telomeres were identified by hydridization to an oligonucleotide of the trypanosome telomeric repeat. A subcloned human fragment from one such YAC is immediately subtelomeric on at least one human chromosome.},
}
@article {pmid2657657,
year = {1989},
author = {Shampay, J and Blackburn, EH},
title = {Tetrahymena micronuclear sequences that function as telomeres in yeast.},
journal = {Nucleic acids research},
volume = {17},
number = {8},
pages = {3247-3260},
pmid = {2657657},
issn = {0305-1048},
mesh = {Animals ; Cell Nucleus/ultrastructure ; Chromosomes/*ultrastructure ; Cloning, Molecular ; DNA/*physiology ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*genetics ; Tetrahymena/*genetics/ultrastructure ; },
abstract = {We explored the ability of S. cerevisiae to utilize heterologous DNA sequences as telomeres by cloning germline (micronuclear) DNA from Tetrahymena thermophila on a linear yeast plasmid that selects for telomere function. The only Tetrahymena sequences that functioned in this assay were (C4A2)n repeats. Moreover, these repeats did not have to be derived from Tetrahymena telomeres, although we show that micronuclear telomeres (like macronuclear telomeres) of Tetrahymena terminate in (C4A2)n repeats. Chromosome-internal restriction fragments carrying (C4A2)n repeats also stabilized linear plasmids and were elongated by yeast telomeric repeats. In one case, the C4A2 repeat tract was approximately 1.5 kb from the end of the genomic Tetrahymena DNA fragment that was cloned, but this 1.5 kb of DNA was missing from the linear plasmid. Thus, yeast can utilize internally located tracts of telomere-like sequences, after the distal DNA is removed. The data provide an example of broken chromo-some healing, and underscore the importance of the telomeric repeat structure for recognition of functional telomeric DNA in vivo.},
}
@article {pmid2648157,
year = {1989},
author = {Zakian, VA and Pluta, AF},
title = {Telomere formation in yeast.},
journal = {Nature},
volume = {338},
number = {6215},
pages = {468},
pmid = {2648157},
issn = {0028-0836},
mesh = {Chromosomes/*ultrastructure ; Saccharomyces cerevisiae/*genetics ; },
}
@article {pmid2657397,
year = {1989},
author = {Runge, KW and Zakian, VA},
title = {Introduction of extra telomeric DNA sequences into Saccharomyces cerevisiae results in telomere elongation.},
journal = {Molecular and cellular biology},
volume = {9},
number = {4},
pages = {1488-1497},
pmid = {2657397},
issn = {0270-7306},
support = {GM-10472/GM/NIGMS NIH HHS/United States ; GM26938/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosomes/*ultrastructure ; DNA, Fungal/*genetics ; Gene Amplification ; Genetic Vectors ; Plasmids ; Saccharomyces cerevisiae/*genetics/ultrastructure ; },
abstract = {The termini of Saccharomyces cerevisiae chromosomes consist of tracts of C1-3A (one to three cytosine and one adenine residue) sequences of approximately 450 base pairs in length. To gain insights into trans-acting factors at telomeres, high-copy-number linear and circular plasmids containing tracts of C1-3A sequences were introduced into S. cerevisiae. We devised a novel system to distinguish by color colonies that maintained the vector at 1 to 5, 20 to 50, and 100 to 400 copies per cell and used it to change the amount of telomeric DNA sequences per cell. An increase in the number of C1-3A sequences caused an increase in the length of telomeric C1-3A repeats that was proportional to plasmid copy number. Our data suggest that telomere growth is inhibited by a limiting factor(s) that specifically recognizes C1-3A sequences and that this factor can be effectively competed for by long tracts of C1-3A sequences at telomeres or on circular plasmids. Telomeres without this factor are exposed to processes that serve to lengthen chromosome ends.},
}
@article {pmid2646592,
year = {1989},
author = {Venter, U and Hörz, W},
title = {The acid phosphatase genes PHO10 and PHO11 in S. cerevisiae are located at the telomeres of chromosomes VIII and I.},
journal = {Nucleic acids research},
volume = {17},
number = {4},
pages = {1353-1369},
pmid = {2646592},
issn = {0305-1048},
mesh = {Acid Phosphatase/*genetics ; *Chromosome Mapping ; DNA, Fungal/genetics/isolation &amp; purification ; *Genes ; *Genes, Fungal ; Restriction Mapping ; Saccharomyces cerevisiae/enzymology/*genetics ; },
abstract = {Of the three regulated acid phosphatase genes in S. cerevisiae (PHO5, PHO10 and PHO11) two have previously been cloned (PHO5 and PHO11). We have now identified PHO10 and show by restriction mapping that it is highly homologous to PHO11. This homology includes not only the coding sequence but also a stretch of about 2 kb upstream and 2.2 kb downstream of the genes. Analysis of strains in which either gene had been disrupted shows that the two genes are located at the telomeres of two different chromosomes. PHO10 3.6 kb from the end of a chromosome I. This makes PHO11 the gene closest to the end of a chromosome that has been physically mapped so far in S. cerevisiae. The organization of the two genes varies strongly from strain to strain consistent with a high incidence of telomere rearrangement. In one of twenty transformants examined a conversion event could be directly demonstrated that resulted in a chromosome VIII which had acquired a copy of the telomere from chromosome I.},
}
@article {pmid2536898,
year = {1989},
author = {Pluta, AF and Zakian, VA},
title = {Recombination occurs during telomere formation in yeast.},
journal = {Nature},
volume = {337},
number = {6206},
pages = {429-433},
doi = {10.1038/337429a0},
pmid = {2536898},
issn = {0028-0836},
mesh = {Animals ; Chromosomes/*physiology ; Cloning, Molecular ; DNA Replication ; DNA Restriction Enzymes ; DNA, Fungal/*genetics ; Nucleic Acid Hybridization ; Plasmids ; *Recombination, Genetic ; Saccharomyces cerevisiae/*genetics ; Tetrahymena/genetics ; Transformation, Genetic ; },
abstract = {Short stretches of cloned telomeric sequences are necessary and sufficient for telomere formation in yeast as long as the sequences are present in the same orientation as they are found in vivo. During telomere formation, DNA termini usually undergo RAD52-independent recombination with other DNA termini as would be predicted by models of recombination-mediated telomere replication.},
}
@article {pmid2463488,
year = {1989},
author = {Greider, CW and Blackburn, EH},
title = {A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis.},
journal = {Nature},
volume = {337},
number = {6205},
pages = {331-337},
doi = {10.1038/337331a0},
pmid = {2463488},
issn = {0028-0836},
mesh = {Animals ; Base Sequence ; Chromosomes/*physiology ; Cloning, Molecular ; DNA/genetics ; DNA Nucleotidylexotransferase/*genetics ; Genes ; Molecular Sequence Data ; Oligonucleotide Probes ; RNA/*genetics ; Repetitive Sequences, Nucleic Acid ; Tetrahymena/enzymology/*genetics ; },
abstract = {The telomerase enzyme of Tetrahymena synthesizes repeats of the telomeric DNA sequence TTGGGG de novo in the absence of added template. The essential RNA component of this ribonucleoprotein enzyme has now been cloned and found to contain the sequence CAACCCCAA, which seems to be the template for the synthesis of TTGGGG repeats.},
}
@article {pmid2927395,
year = {1989},
author = {Henderson, ER and Blackburn, EH},
title = {An overhanging 3' terminus is a conserved feature of telomeres.},
journal = {Molecular and cellular biology},
volume = {9},
number = {1},
pages = {345-348},
pmid = {2927395},
issn = {0270-7306},
support = {GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Base Sequence ; DNA, Ribosomal/*analysis ; DNA, Single-Stranded/*analysis ; Guanine ; Myxomycetes/genetics ; Osmium Tetroxide ; *Repetitive Sequences, Nucleic Acid ; Tetrahymena/genetics ; },
abstract = {The reactivity of single-stranded thymidines with osmium tetraoxide was used to demonstrate the existence of a terminal overhang of the G-rich strand of telomeres from two distantly related eucaryotes, the ciliated protozoan Tetrahymena spp. and the acellular slime mold Didymium spp. Conservation of a G-strand overhang at the molecular terminus of telomeres is consistent with our suggestion that an unusual DNA structure formed by the G-strand overhang is important for telomere function (E. Henderson, C. C. Hardin, S. K. Wolk, I. Tinoco Jr., and E. H. Blackburn, Cell 51:899-908, 1987).},
}
@article {pmid2698831,
year = {1989},
author = {Blackburn, EH and Greider, CW and Henderson, E and Lee, MS and Shampay, J and Shippen-Lentz, D},
title = {Recognition and elongation of telomeres by telomerase.},
journal = {Genome},
volume = {31},
number = {2},
pages = {553-560},
doi = {10.1139/g89-104},
pmid = {2698831},
issn = {0831-2796},
support = {GM 26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Chromosomes/*metabolism ; DNA/metabolism ; DNA Nucleotidylexotransferase/*metabolism ; Molecular Sequence Data ; Nucleic Acid Conformation ; Oligodeoxyribonucleotides/metabolism ; Repetitive Sequences, Nucleic Acid ; Ribonucleoproteins/metabolism ; Saccharomyces cerevisiae/metabolism ; Tetrahymena/*enzymology/genetics ; },
abstract = {Telomeres stabilize chromosomal ends and allow their complete replication in vivo. In diverse eukaryotes, the essential telomeric DNA sequence consists of variable numbers of tandem repeats of simple, G + C rich sequences, with a strong strand bias of G residues on the strand oriented 5' to 3' toward the chromosomal terminus. This strand forms a protruding 3' over-hang at the chromosomal terminus in three different eukaryotes analyzed. Analysis of yeast and protozoan telomeres showed that telomeres are dynamic structures in vivo, being acted on by shortening and lengthening activities. We previously identified and partially purified an enzymatic activity, telomere terminal transferase, or telomerase, from the ciliate Tetrahymena. Telomerase is a ribonucleoprotein enzyme with essential RNA and protein components. This activity adds repeats of the Tetrahymena telomeric sequence, TTGGGG, onto the 3' end of a single-stranded DNA primer consisting of a few repeats of the G-rich strand of known telomeric, and telomere-like, sequences. The shortest oligonucleotide active as a primer was the decamer G4T2G4. Structural analysis of synthetic DNA oligonucleotides that are active as primers showed that they all formed discrete intramolecular foldback structures at temperatures below 40 degrees C. Addition of TTGGGG repeats occurs one nucleotide at a time by de novo synthesis, which is not templated by the DNA primer. Up to 8000 nucleotides of G4T2 repeats were added to the primer in vitro. We discuss the implications of this finding for regulation of telomerase in vivo and a model for telomere elongation by telomerase.},
}
@article {pmid2694944,
year = {1989},
author = {Zakian, VA},
title = {Structure and function of telomeres.},
journal = {Annual review of genetics},
volume = {23},
number = {},
pages = {579-604},
doi = {10.1146/annurev.ge.23.120189.003051},
pmid = {2694944},
issn = {0066-4197},
support = {GM-26938/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Chromosomes/*ultrastructure ; DNA ; DNA Replication ; DNA-Binding Proteins ; Repetitive Sequences, Nucleic Acid ; *Structure-Activity Relationship ; },
}
@article {pmid2653811,
year = {1989},
author = {Jäger, D and Philippsen, P},
title = {Stabilization of dicentric chromosomes in Saccharomyces cerevisiae by telomere addition to broken ends or by centromere deletion.},
journal = {The EMBO journal},
volume = {8},
number = {1},
pages = {247-254},
doi = {10.1002/j.1460-2075.1989.tb03370.x},
pmid = {2653811},
issn = {0261-4189},
mesh = {Aneuploidy ; Centromere/*physiology ; Chromosome Aberrations ; Chromosome Fragility ; Chromosomes/*physiology/*ultrastructure ; DNA, Fungal/genetics ; Saccharomyces cerevisiae/genetics/*ultrastructure ; Transformation, Genetic ; },
abstract = {We introduced CEN6 DNA via integrative transformation into the right arm of chromosome II in a haploid Saccharomyces cerevisiae strain thus creating a dicentric chromosome. The majority of the transformed cells did not grow into colonies as concluded from control transformations with mutated CEN6 DNA. Five percent of the initial transformants with the wild-type centromere gave rise to well growing cells. We analysed the probable fate of the dicentric chromosome in two transformants by electrophoretic separation of chromosome sized DNA and by hybridizations with chromosome II DNA probes. We found two different mechanisms which generated cells lacking dicentric chromosomes. The first mechanism is breakage of the chromatid between the two-centromeres and healing of the new ends to functional telomeres thus creating progeny cells with the chromosome II information split into two genetically stable new chromosomes one carrying CEN2 and the other CEN6. The second mechanism is loss of the resident CEN2 by a 30-50 kb deletion event which resulted in a genetically stable but shortened chromosome II. Both mechanisms operated in the two transformants studied.},
}
@article {pmid2626440,
year = {1989},
author = {Wang, SS and Pluta, AF and Zakian, VA},
title = {DNA sequence analysis of newly formed telomeres in yeast.},
journal = {Progress in clinical and biological research},
volume = {318},
number = {},
pages = {81-89},
pmid = {2626440},
issn = {0361-7742},
mesh = {Base Sequence ; Blotting, Southern ; Chromosome Mapping ; Chromosomes/*ultrastructure ; Cloning, Molecular ; DNA/*analysis ; Molecular Sequence Data ; Plasmids ; Recombination, Genetic ; Yeasts ; },
abstract = {A plasmid can be maintained in linear form in baker's yeast if it bears telomeric sequences at each end. Linear plasmids bearing cloned telomeric C4A4 repeats at one end (test end) and a natural DNA terminus with approximately 300 bps of C4A2 repeats at the other or control end were introduced by transformation into yeast. Test-end termini of 28 to 112 bps supported telomere formation. During telomere formation, C4A2 repeats were often transferred to test-end termini. To determine in greater detail the fate of test-end sequences on these plasmids after propagation in yeast, test-end telomeres were subcloned into E. coli and sequenced. DNA sequencing established a number of points about the molecular events involved in telomere formation in yeast. The results suggest that there are at least two mechanisms for telomere formation in yeast. One is mediated by a recombination event that requires neither a long stretch of homology nor the RAD52 gene product. The other mechanism is by addition of C1-3A repeats to the termini of linear DNA molecules. The telomeric sequence required to support C1-3A addition need not be at the very end of a molecule for telomere formation.},
}
@article {pmid2905444,
year = {1988},
author = {Whaley, WL and Michiels, F and MacDonald, ME and Romano, D and Zimmer, M and Smith, B and Leavitt, J and Bucan, M and Haines, JL and Gilliam, TC},
title = {Mapping of D4S98/S114/S113 confines the Huntington's defect to a reduced physical region at the telomere of chromosome 4.},
journal = {Nucleic acids research},
volume = {16},
number = {24},
pages = {11769-11780},
pmid = {2905444},
issn = {0305-1048},
support = {NS16367/NS/NINDS NIH HHS/United States ; NS20012/NS/NINDS NIH HHS/United States ; NS22031/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; *Chromosome Mapping ; *Chromosomes, Human, Pair 4 ; Cricetinae ; DNA Probes ; Genetic Markers/*analysis ; Humans ; Huntington Disease/*genetics ; Lod Score ; Pedigree ; Polymorphism, Restriction Fragment Length ; },
abstract = {The dominant gene defect in Huntington's disease (HD) is linked to the DNA marker D4S10, near the telomere of the chromosome 4 short arm. Two other markers, D4S43 and D4S95, are closer, but still proximal to the HD gene in 4p16.3. We have characterized a new locus, D4S114, identified by cloning the end of a NotI fragment resolved by pulsed-field gel electrophoresis. D4S114 was localized distal to D4S43 and D4S95 by both physical and genetic mapping techniques. The "end"-clone overlaps a previously isolated NotI "linking" clone, and is within 150 kb of a second "linking" clone defining D4S113. Restriction fragment length polymorphisms for D4S113 and D4S114, one of which is identical to a SacI polymorphism detected by the anonymous probe pBS731B-C (D4S98), were typed for key crossovers in HD and reference pedigrees. The data support the locus order D4S10-(D4S43, D4S95)-D4S98/S114/S113-HD-telomere. The D4S98/S114/S113 cluster therefore represents the nearest cloned sequences to HD, and provides a valuable new point for launching directional cloning strategies to isolate and characterize this disease gene.},
}
@article {pmid3264281,
year = {1988},
author = {Shoeman, RL and Wadle, S and Scherbarth, A and Traub, P},
title = {The binding in vitro of the intermediate filament protein vimentin to synthetic oligonucleotides containing telomere sequences.},
journal = {The Journal of biological chemistry},
volume = {263},
number = {35},
pages = {18744-18749},
pmid = {3264281},
issn = {0021-9258},
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Binding Sites ; Deoxyribonucleases, Type II Site-Specific/metabolism ; Kinetics ; Molecular Sequence Data ; Oligonucleotides/*metabolism ; Repetitive Sequences, Nucleic Acid ; Saccharomyces ; Structure-Activity Relationship ; Tetrahymena ; Vimentin/*metabolism ; },
abstract = {The ability of the intermediate filament subunit protein vimentin to bind synthetic oligonucleotide telomere models containing repeat sequences from Oxytricha (T4G4), Saccharomyces (TGTGTG3), or Tetrahymena (T2G4) was investigated in vitro with a filter binding assay and a gel overlay assay. At low ionic strength, vimentin bound these oligonucleotides with high affinity. At higher ionic strength, the vimentin-oligonucleotide complex was less stable, such that approximately 30% of the initial binding remained at 150 mM KCl. One mole of vimentin tetramer bound approximately 1 mol of telomere oligonucleotide. Vimentin bound well oligonucleotides containing either a random duplex or random 3'-overhang, but showed a reduced affinity for a blunt-ended oligonucleotide. A control random sequence oligonucleotide was not bound by vimentin. The oligonucleotide-binding site of vimentin was shown to be localized in the non-alpha-helical N-terminal domain by assays employing purified proteolytic fragments of vimentin. Preliminary results in the gel overlay assay show that other members of the intermediate filament family, nuclear lamins A-C, all bind the synthetic oligonucleotide containing the telomere repeat sequence of Oxytricha.},
}
@article {pmid3072472,
year = {1988},
author = {Buchman, AR and Lue, NF and Kornberg, RD},
title = {Connections between transcriptional activators, silencers, and telomeres as revealed by functional analysis of a yeast DNA-binding protein.},
journal = {Molecular and cellular biology},
volume = {8},
number = {12},
pages = {5086-5099},
pmid = {3072472},
issn = {0270-7306},
support = {GM-36659/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosomes/*physiology ; DNA Probes ; DNA, Fungal/genetics/metabolism ; DNA-Binding Proteins/*metabolism ; Fungal Proteins/isolation &amp; purification/*metabolism ; Genes, Fungal ; Molecular Sequence Data ; Oligonucleotide Probes ; Plasmids ; Saccharomyces cerevisiae/*genetics ; *Transcription, Genetic ; },
abstract = {General regulatory factor I (GRFI) is a yeast protein that binds in vitro to specific DNA sequences at diverse genetic elements. A strategy was pursued to test whether GRFI functions in vivo at the sequences bound by the factor in vitro. Matches to a consensus sequence for GRFI binding were found in a variety of locations: upstream activating sequences (UASs), silencers, telomeres, and transcribed regions. All occurrences of the consensus sequence bound both crude and purified GRFI in vitro. All binding sites for GRFI, regardless of origin, provided UAS function in test plasmids. Also, GRFI binding sites specifically stimulated transcription in a yeast in vitro system, indicating that GRFI can function as a positive transcription factor. The stimulatory effect of GRFI binding sites at UASs for the PYK1 and ENO1 genes is significantly enhanced by flanking DNA elements. By contrast, regulatory sequences that flank the GRFI binding site at HMR E convert this region to a transcriptional silencer.},
}
@article {pmid3211128,
year = {1988},
author = {Gilley, D and Preer, JR and Aufderheide, KJ and Polisky, B},
title = {Autonomous replication and addition of telomerelike sequences to DNA microinjected into Paramecium tetraurelia macronuclei.},
journal = {Molecular and cellular biology},
volume = {8},
number = {11},
pages = {4765-4772},
pmid = {3211128},
issn = {0270-7306},
support = {GM24212/GM/NIGMS NIH HHS/United States ; GM31745/GM/NIGMS NIH HHS/United States ; GM34681/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA/*genetics ; *DNA Replication ; Endodeoxyribonucleases ; Genetic Vectors ; Microinjections ; Paramecium/*genetics/metabolism ; *Transformation, Genetic ; },
abstract = {Paramecium tetraurelia can be transformed by microinjection of cloned serotype A gene sequences into the macronucleus. Transformants are detected by their ability to express serotype A surface antigen from the injected templates. After injection, the DNA is converted from a supercoiled form to a linear form by cleavage at nonrandom sites. The linear form appears to replicate autonomously as a unit-length molecule and is present in transformants at high copy number. The injected DNA is further processed by the addition of paramecium-type telomeric sequences to the termini of the linear DNA. To examine the fate of injected linear DNA molecules, plasmid pSA14SB DNA containing the A gene was cleaved into two linear pieces, a 14-kilobase (kb) piece containing the A gene and flanking sequences and a 2.2-kb piece consisting of the procaryotic vector. In transformants expressing the A gene, we observed that two linear DNA species were present which correspond to the two species injected. Both species had Paramecium telomerelike sequences added to their termini. For the 2.2-kb DNA, we show that the site of addition of the telomerelike sequences is directly at one terminus and within one nucleotide of the other terminus. These results indicate that injected procaryotic DNA is capable of autonomous replication in Paramecium macronuclei and that telomeric addition in the macronucleus does not require specific recognition sequences.},
}
@article {pmid3141921,
year = {1988},
author = {Traverse, KL and Pardue, ML},
title = {A spontaneously opened ring chromosome of Drosophila melanogaster has acquired He-T DNA sequences at both new telomeres.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {85},
number = {21},
pages = {8116-8120},
pmid = {3141921},
issn = {0027-8424},
mesh = {Animals ; Base Sequence ; *Chromosome Aberrations ; DNA/*analysis ; Drosophila melanogaster/*genetics ; Nucleic Acid Hybridization ; *Ring Chromosomes ; Telophase ; },
abstract = {Ring chromosomes that have been opened to give linear chromosomes offer an opportunity to study the DNA sequences associated with new chromosome ends. The Drosophila melanogaster chromosome C(1)A was originally a ring chromosome, consisting of two linked X chromosomes, and thus had no telomeres. This chromosome has spontaneously opened in polytene region 13, a region near the middle of the euchromatic arm of the X chromosome. The opening of the ring has produced two new telomeres on the C(1)A chromosome. Each of the new telomeres has acquired He-T DNA sequences. He-T DNA is a complex family of repeated sequences found in the telomeric and pericentric heterochromatin of D. melanogaster chromosomes. He-T DNA sequences are detected, at various levels, in the most distal band on the end of each polytene chromosome in all D. melanogaster stocks. To our knowledge, these sequences have never been detected within the euchromatic chromosomal regions in any stock. The strong correlation between He-T DNA sequences and telomeric regions suggests that He-T sequences may have a role in organizing or maintaining the ends of chromosomes. The association of He-T DNA with newly acquired telomeres in a formerly euchromatic region, polytene region 13, strengthens this correlation.},
}
@article {pmid3224817,
year = {1988},
author = {Kooter, JM and Winter, AJ and de Oliveira, C and Wagter, R and Borst, P},
title = {Boundaries of telomere conversion in Trypanosoma brucei.},
journal = {Gene},
volume = {69},
number = {1},
pages = {1-11},
doi = {10.1016/0378-1119(88)90372-1},
pmid = {3224817},
issn = {0378-1119},
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Chromosomes/*physiology ; DNA/genetics ; *Gene Conversion ; *Genes ; Molecular Sequence Data ; Transcription, Genetic ; Trypanosoma brucei brucei/*genetics ; Variant Surface Glycoproteins, Trypanosoma/*genetics ; },
abstract = {Active genes for variant-specific surface glycoproteins (VSGs) reside in telomeric expression sites and may be replaced by other VSG genes via telomere conversions. The availability of a complete map of expression site 221 in variant 221a made it possible to determine the boundaries of such conversions and the sequences that are involved. We have analysed five trypanosome populations that arose from variant 221a through replacement of the 221 gene by another VSG gene. In each of these relapsed populations the telomere conversion ends at a different position in the expression site. In the relapsed population, 221aR3, the boundary was found in the coding region of an expression-site-associated gene (ESAG). This ESAG-2 codes for a potential 368-aa protein of unknown function; it contains a N-terminal signal peptide for mediating transfer to the endoplasmic reticulum and six potential N-glycosylation sites. It shares these structural features with the ESAG-1 protein encoded in the same expression site. ESAG-2 is a member of a large gene family which includes non-functional genes. In 221aR3, the partial conversion of ESAG-2 by an ESAG-2-like sequence has disrupted the open reading frame. The two ESAG-2 sequences are similar (92% identity) suggesting that sequence homology between telomeres provides the opportunity for gene conversion.},
}
@article {pmid3413114,
year = {1988},
author = {Moyzis, RK and Buckingham, JM and Cram, LS and Dani, M and Deaven, LL and Jones, MD and Meyne, J and Ratliff, RL and Wu, JR},
title = {A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {85},
number = {18},
pages = {6622-6626},
pmid = {3413114},
issn = {0027-8424},
support = {RR01315/RR/NCRR NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosomes, Human/*analysis ; DNA/*analysis ; Flow Cytometry ; Humans ; Molecular Sequence Data ; Nucleic Acid Hybridization ; *Repetitive Sequences, Nucleic Acid ; },
abstract = {A highly conserved repetitive DNA sequence, (TTAGGG)n, has been isolated from a human recombinant repetitive DNA library. Quantitative hybridization to chromosomes sorted by flow cytometry indicates that comparable amounts of this sequence are present on each human chromosome. Both fluorescent in situ hybridization and BAL-31 nuclease digestion experiments reveal major clusters of this sequence at the telomeres of all human chromosomes. The evolutionary conservation of this DNA sequence, its terminal chromosomal location in a variety of higher eukaryotes (regardless of chromosome number or chromosome length), and its similarity to functional telomeres isolated from lower eukaryotes suggest that this sequence is a functional human telomere.},
}
@article {pmid3042152,
year = {1988},
author = {McCarroll, RM and Fangman, WL},
title = {Time of replication of yeast centromeres and telomeres.},
journal = {Cell},
volume = {54},
number = {4},
pages = {505-513},
doi = {10.1016/0092-8674(88)90072-4},
pmid = {3042152},
issn = {0092-8674},
support = {GM18926/GM/NIGMS NIH HHS/United States ; },
mesh = {Centromere/*physiology ; Chromosomes/*physiology ; *DNA Replication ; Nucleic Acid Hybridization ; Saccharomyces cerevisiae/*genetics ; Time Factors ; },
abstract = {The time of replication of centromeres and telomeres of the yeast S. cerevisiae was determined by performing Meselson-Stahl experiments with synchronized cells. The nine centromeres examined become hybrid in density early in S phase, eliminating the possibility that a delay in the replication of centromeres until mitosis is responsible for sister chromatid adherence and proper chromosome segregation at anaphase. The conserved sequence element Y', present at most telomeres, replicates late in S phase, as do the unique sequences adjacent to five specific telomeres. The early and late replication times of these structural elements may be either essential for their proper function or a consequence of some architectural feature of the chromosome.},
}
@article {pmid3136437,
year = {1988},
author = {Zahler, AM and Prescott, DM},
title = {Telomere terminal transferase activity in the hypotrichous ciliate Oxytricha nova and a model for replication of the ends of linear DNA molecules.},
journal = {Nucleic acids research},
volume = {16},
number = {14B},
pages = {6953-6972},
pmid = {3136437},
issn = {0305-1048},
support = {GM-01735-12/GM/NIGMS NIH HHS/United States ; R01GM19199/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Nucleus/enzymology ; Chromosomes/enzymology/*ultrastructure ; Ciliophora/*enzymology ; DNA Nucleotidyltransferases/*metabolism ; *DNA Replication ; Repetitive Sequences, Nucleic Acid ; },
abstract = {We have found abundant telomere-specific terminal transferase activity in crude macronuclear extracts from vegetatively growing cells of the hypotrichous ciliate Oxytricha nova. This activity adds two to seven tandem repeats of the sequence GGGGTTTT (the Oxytricha telomeric repeat) to the 3' end of oligonucleotide primers ending in repeats of G4T4 and always adds the repeats in the proper phase. The activity requires the presence of micromolar amounts of dGTP and dTTP as well as single-stranded oligomer primers ending 3' with repeats of the Oxytricha telomeric sequence. A nuclease activity is present in the extracts which is closely balanced with telomere terminal transferase activity. We propose a simple model for replication of the ends of linear DNA molecules based on the telomere terminal transferase.},
}
@article {pmid3043376,
year = {1988},
author = {Vernick, KD and Walliker, D and McCutchan, TF},
title = {Genetic hypervariability of telomere-related sequences is associated with meiosis in Plasmodium falciparum.},
journal = {Nucleic acids research},
volume = {16},
number = {14B},
pages = {6973-6985},
pmid = {3043376},
issn = {0305-1048},
mesh = {Animals ; Chromosome Mapping ; Chromosomes/*ultrastructure ; Cloning, Molecular ; *DNA Replication ; *Genetic Variation ; *Meiosis ; Mitosis ; Plasmodium falciparum/*genetics ; Polymorphism, Genetic ; Repetitive Sequences, Nucleic Acid ; },
abstract = {Sequences related to those near chromosome telomeres in the human malaria parasite, Plasmodium falciparum, were extremely unstable during a genetic cross between two different clonal genotypes. Many progeny of the heterologous cross displayed telomere-homologous restriction fragments found in neither parent. A significant number of the new fragments resulted from rearrangements at chromosome-internal locations which were bounded by more complex tracts of DNA sequence. The same instability was not seen to arise during an inbreeding cross, nor during mitotic replication of parasites. Thus, a form of genetic hypervariability results from molecular events which occur during meiotic reduction and is apparent only in a cross between heterologous strains of parasite. Since other sequences were entirely stable under the same conditions, it appears that chromosome-internal blocks of telomeric sequences in the P. falciparum genome may designate conditionally unstable chromosomal domains. We discuss some potential implications of these findings for the population biology of P. falciparum.},
}
@article {pmid2838822,
year = {1988},
author = {Spangler, EA and Ryan, T and Blackburn, EH},
title = {Developmentally regulated telomere addition in Tetrahymena thermophila.},
journal = {Nucleic acids research},
volume = {16},
number = {12},
pages = {5569-5585},
pmid = {2838822},
issn = {0305-1048},
support = {GM26259/GM/NIGMS NIH HHS/United States ; GM32565/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cell Nucleus/physiology ; Chromosomes/*physiology ; Cloning, Molecular ; DNA Restriction Enzymes ; *Genes, Regulator ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Nucleotide Mapping ; Tetrahymena/*genetics/growth &amp; development ; },
abstract = {To investigate the developmentally programmed telomere addition that accompanies chromosome fragmentation during macronuclear differentiation in Tetrahymena thermophila, five representative telomeric regions from the macronucleus were cloned and characterized in detail. The sequences adjacent to the telomeric (C4A2:T2G4) repeats on these five macronuclear ends had no significant sequence homology or shared secondary structure. Two developmentally independent examples of one macronuclear telomere had a 5 base pair difference in the position of the junction between the telomeric repeats and the adjacent sequences. A telomere-adjacent sequence, in the form of a synthetic oligonucleotide, was unable to prime the addition of telomeric repeats in vitro. The implications of these results for the mechanisms underlying developmentally programmed chromosome fragmentation and telomere addition in Tetrahymena are discussed.},
}
@article {pmid2838815,
year = {1988},
author = {Rappold, GA and Lehrach, H},
title = {A long range restriction map of the pseudoautosomal region by partial digest PFGE analysis from the telomere.},
journal = {Nucleic acids research},
volume = {16},
number = {12},
pages = {5361-5377},
pmid = {2838815},
issn = {0305-1048},
mesh = {Animals ; Cell Line ; DNA Restriction Enzymes ; Female ; Filtration ; Humans ; Hybrid Cells/cytology ; Male ; Nucleic Acid Hybridization ; Nucleotide Mapping ; Phenotype ; Polymorphism, Genetic ; *X Chromosome ; *Y Chromosome ; },
abstract = {The analysis of partial digestion products extending from the telomere of the human X and Y chromosomes, visualised by hybridisation to a probe located close to the telomere, was used to establish a restriction map of the pseudoautosomal region. In this highly polymorphic region with a 10-fold elevated recombination frequency in males we identified site or methylation differences between 7 different in male and female cell lines and tissues, and derived an estimate of the size of the pseudoautosomal region of approximately 3 Megabases by comparing X and Y chromosomes. This size correlates well with previous estimates based on genetic arguments and argues against a strongly enhanced rate of exchange near telomeres in general. We identified a CpG rich and hypomethylated region within 500 kbp from the telomere, which might reflect structural features of mammalian telomeres, and a small number of (additional) CpG islands, which might represent candidate genes for the Turner phenotype in XO females.},
}
@article {pmid2842675,
year = {1988},
author = {Myler, PJ and Aline, RF and Scholler, JK and Stuart, KD},
title = {Changes in telomere length associated with antigenic variation in Trypanosoma brucei.},
journal = {Molecular and biochemical parasitology},
volume = {29},
number = {2-3},
pages = {243-250},
doi = {10.1016/0166-6851(88)90079-5},
pmid = {2842675},
issn = {0166-6851},
support = {AI 17357/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; *Antigenic Variation ; Antigens, Protozoan/*genetics ; Chromosome Mapping ; DNA/analysis ; DNA Restriction Enzymes ; Gene Expression Regulation ; Nucleic Acid Hybridization ; Transcription, Genetic ; Trypanosoma brucei brucei/*genetics/immunology ; Variant Surface Glycoproteins, Trypanosoma/*genetics ; },
abstract = {In the IsTaR 1 serodeme, we have identified variant surface glycoprotein (VSG) genes in nine different telomeric sites. We have measured the distance from the 3' end of these VSG genes to the end of the chromosome (the 'telomere length') in 20 variant antigen types (VATs) of the serodeme. Analyses of the changes in telomere length during 19 antigenic switches involving eight telomeric sites indicate a median increase in telomere length of 0.6 kilobase pairs during each switch. This may be accounted for by the 6-10 bp increase in telomere length per generation associated with DNA replication described by others. The changes in telomere lengths do not form a normal distribution since a substantial fraction show unusually large increases in telomere length or decreases in telomere length during an antigenic switch. These changes are probably caused by recombinations 3' to the VSG gene. No significant differences were detected in the behavior of telomeres at each of the eight different telomeric sites, nor were changes in telomere lengths significantly different between different antigenic switches. However, it was found that those telomeres where transcription was activated during the antigenic switch showed a significantly greater increase in telomere length than those telomeres not involved in regulation of VSG gene expression. Conversely, there was a strong correlation between transcriptional inactivation of a telomeric expression site and a decrease in telomere length. These findings suggest that processes (possibly genomic recombinations) 3' to the VSG gene coding region may be associated with a change in the transcriptional status of the VSG gene.},
}
@article {pmid3290654,
year = {1988},
author = {Zakian, VA and Blanton, HM},
title = {Distribution of telomere-associated sequences on natural chromosomes in Saccharomyces cerevisiae.},
journal = {Molecular and cellular biology},
volume = {8},
number = {5},
pages = {2257-2260},
pmid = {3290654},
issn = {0270-7306},
mesh = {Base Sequence ; Chromosomes/*ultrastructure ; Saccharomyces cerevisiae/*genetics/ultrastructure ; },
abstract = {Pulsed-field gel electrophoresis was used to examine the distribution of telomere-associated sequences on individual chromosomes in four strains of Saccharomyces cerevisiae. The pattern of X and Y' distribution was different for each strain. At least one chromosome in each strain lacked Y', and in some strains, chromosome I, the smallest yeast chromosome, lacked detectable amounts of both X and Y'.},
}
@article {pmid2833706,
year = {1988},
author = {Allshire, RC and Gosden, JR and Cross, SH and Cranston, G and Rout, D and Sugawara, N and Szostak, JW and Fantes, PA and Hastie, ND},
title = {Telomeric repeat from T. thermophila cross hybridizes with human telomeres.},
journal = {Nature},
volume = {332},
number = {6165},
pages = {656-659},
doi = {10.1038/332656a0},
pmid = {2833706},
issn = {0028-0836},
mesh = {Animals ; *Chromosomes ; *Chromosomes, Human ; DNA/*genetics ; DNA Restriction Enzymes ; DNA, Fungal/genetics ; DNA, Recombinant ; Female ; Humans ; Male ; *Nucleic Acid Hybridization ; Repetitive Sequences, Nucleic Acid ; Schizosaccharomyces/genetics ; Sex Chromosomes ; Tetrahymena/*genetics ; },
abstract = {The ends (telomeres) of eukaryotic chromosomes must have special features to ensure their stability and complete replication. Studies in yeast, protozoa, slime moulds and flagellates show that telomeres are tandem repeats of simple sequences that have a G-rich and a C-rich strand. Mammalian telomeres have yet to be isolated and characterized, although a DNA fragment within 20 kilobases of the telomeres of the short arms of the human sex chromosomes has been isolated. Recently we showed that a chromosome from the fission yeast Schizosaccharomyces pombe could, in some cases, replicate as an autonomous mini-chromosome in mouse cells. By extrapolation from other systems, we reasoned that mouse telomeres could be added to the S. pombe chromosome ends in the mouse cells. On setting out to test this hypothesis we found to our surprise that the telomeric probe used (containing both the S. pombe and Tetrahymena thermophila repeats) hybridized to a series of discrete fragments in normal mouse DNA and DNA from a wide range of eukaryotes. We show here that the sequences hybridizing to this probe are located at the telomeres of most, if not all, human chromosomes and are similar to the Tetrahymena telomeric-repeat component of the probe.},
}
@article {pmid3349525,
year = {1988},
author = {Richards, EJ and Ausubel, FM},
title = {Isolation of a higher eukaryotic telomere from Arabidopsis thaliana.},
journal = {Cell},
volume = {53},
number = {1},
pages = {127-136},
doi = {10.1016/0092-8674(88)90494-1},
pmid = {3349525},
issn = {0092-8674},
mesh = {Animals ; Base Sequence ; Chromosomes/*ultrastructure ; Cloning, Molecular ; DNA/*genetics ; Humans ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Plants/*genetics/ultrastructure ; },
abstract = {We have developed a method for constructing genomic libraries enriched for telomeric DNA sequences, enabling the isolation of telomeres from higher eukaryotic organisms with large chromosomes. The method was used to clone telomeric DNA sequences from the flowering plant Arabidopsis thaliana. A. thaliana telomeres are composed primarily of tandemly repeated blocks of the sequence 5'-CCCTAAA-3' and are heterogeneous in size. Genomic sequences that cross-hybridize at high stringency with A. thaliana telomeric repeats are present in other higher plants. In Zea mays (corn), these cross-hybridizing sequences are located at the telomeres. In addition, the A. thaliana telomeric repeats cross-hybridize at low stringency to genomic sequences located at the telomeres of human chromosomes.},
}
@article {pmid3135241,
year = {1988},
author = {Gragerov, AI and Danilevskaia, ON and Didichenko, SA and Kaverina, EN},
title = {[Structure of the ARS element from telomeres of Drosophila melanogaster].},
journal = {Genetika},
volume = {24},
number = {4},
pages = {592-601},
pmid = {3135241},
issn = {0016-6758},
mesh = {Animals ; Base Sequence ; Cloning, Molecular ; DNA/*genetics ; DNA Replication ; Drosophila melanogaster/*genetics ; Molecular Sequence Data ; Plasmids ; },
abstract = {We have determined the nucleotide sequence of 0.7 kb Drosophila DNA fragment specifying autonomous replication of plasmids in yeast. As shown by deletion mapping, the ARS consists of at least two domains: the core possessing the classical 11-member sequence 5'-TAAATATAAAT and the enhancer of no more than 92 nucleotide pairs located at the 3' end of the core. While comparing the sequence of the enhancer with those of 14 different ARS, we failed to detect essential homology regions. ARS elements' flanks, adjacent to the core that serve as enhancer, most probably have no regions detectable as consensus. It is suggested that they are responsible for the peculiar features of DNA secondary structure (bending, for instance) which are necessary for the interaction of proteins with ARS elements.},
}
@article {pmid3285206,
year = {1988},
author = {Vernick, KD and McCutchan, TF},
title = {Sequence and structure of a Plasmodium falciparum telomere.},
journal = {Molecular and biochemical parasitology},
volume = {28},
number = {2},
pages = {85-94},
doi = {10.1016/0166-6851(88)90055-2},
pmid = {3285206},
issn = {0166-6851},
mesh = {Animals ; Base Sequence ; *Chromosomes ; Cloning, Molecular ; DNA/*genetics ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Plasmodium falciparum/*genetics ; Repetitive Sequences, Nucleic Acid ; },
abstract = {We have isolated a 3 kb cloned DNA fragment which originated from a telomere of the human malaria parasite Plasmodium falciparum. The complete nucleotide sequence of the clone is presented. The clone is composed of several distinct structural regions which vary in their sequence complexity. Using oligonucleotide probes for the different structural regions, we analyzed the genetic conservation of sequence organization near telomeres in various strains of P. falciparum. Our results suggest that rapid sequence variability is generated in the vicinity of chromosome ends.},
}
@article {pmid3125982,
year = {1988},
author = {Morin, GB and Cech, TR},
title = {Mitochondrial telomeres: surprising diversity of repeated telomeric DNA sequences among six species of Tetrahymena.},
journal = {Cell},
volume = {52},
number = {3},
pages = {367-374},
doi = {10.1016/s0092-8674(88)80029-1},
pmid = {3125982},
issn = {0092-8674},
support = {GM25273/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Chromosomes ; *DNA, Mitochondrial ; Molecular Sequence Data ; Recombination, Genetic ; *Repetitive Sequences, Nucleic Acid ; Species Specificity ; Tetrahymena/*genetics ; Tetrahymena pyriformis/genetics ; },
abstract = {The DNA sequences at the ends of the linear mtDNA of 6 species of Tetrahymena encompassing 13 strains were determined. All the strains have variable numbers of a tandemly repeated DNA sequence, 31 bp to 53 bp in size, at their mtDNA termini. Based upon the size and nucleotide sequence of the terminal repeats, the telomeres can be separated into four classes. T. pigmentosa, hyperangularis, and hegewischi have different telomeric repeats on the two ends of their mtDNAs. The only conserved feature of the mtDNA termini is the presence of tandem repeats. The function of the repeats might be to promote unequal crossing over during recombination, thereby overcoming the problem of telomere replication for these linear DNAs.},
}
@article {pmid3125520,
year = {1988},
author = {Gragerov, AI and Danilevskaya, ON and Didichenko, SA and Kaverina, EN},
title = {An ARS element from Drosophila melanogaster telomeres contains the yeast ARS core and bent replication enhancer.},
journal = {Nucleic acids research},
volume = {16},
number = {3},
pages = {1169-1180},
pmid = {3125520},
issn = {0305-1048},
mesh = {Animals ; Base Sequence ; DNA Replication ; Drosophila melanogaster/*genetics ; *Enhancer Elements, Genetic ; Molecular Sequence Data ; Nucleic Acid Conformation ; Replicon ; Saccharomyces cerevisiae/genetics ; },
abstract = {We have sequenced the 0.7-kb-long fragment of Drosophila DNA which ensures the autonomous replication of plasmids in yeast. Deletion mapping has shown the ARS element to consist of at least two domains: the core having the consensus 11-bp sequence TAAATATAAAT and the enhancer which is no more than 90 bp long and is located at the 3'-end of the A-rich core strand. Neither domain per se ensures plasmid replication in yeast. A comparison of the enhancer sequence with the sequences of 14 different ARS elements failed to reveal significant homology areas. Most probably the ARS flanks that are adjacent to the core and act as enhancer do not carry any consensus. They may determine a peculiar structural feature of DNA (for example bends) which are necessary for the protein-ARS interaction.},
}
@article {pmid2449282,
year = {1988},
author = {Weiner, AM},
title = {Eukaryotic nuclear telomeres: molecular fossils of the RNP world?.},
journal = {Cell},
volume = {52},
number = {2},
pages = {155-158},
doi = {10.1016/0092-8674(88)90501-6},
pmid = {2449282},
issn = {0092-8674},
mesh = {Animals ; Base Composition ; Cell Nucleus/analysis ; Cells/*ultrastructure ; Chromosomes/*ultrastructure ; *DNA ; DNA Nucleotidylexotransferase/metabolism ; Eukaryotic Cells/*ultrastructure ; RNA ; Repetitive Sequences, Nucleic Acid ; *Ribonucleoproteins ; },
}
@article {pmid3336360,
year = {1988},
author = {Forney, JD and Blackburn, EH},
title = {Developmentally controlled telomere addition in wild-type and mutant paramecia.},
journal = {Molecular and cellular biology},
volume = {8},
number = {1},
pages = {251-258},
pmid = {3336360},
issn = {0270-7306},
support = {GM26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Antigens, Surface/genetics ; Base Sequence ; Chromosome Deletion ; Chromosomes/*ultrastructure ; DNA/genetics ; Genes ; Genetic Linkage ; Molecular Sequence Data ; Mutation ; Paramecium/*genetics ; },
abstract = {We analyzed sites of macronuclear telomere addition at a single genetic locus in Paramecium tetraurelia. We showed that in homozygous wild-type cells, differential genomic processing during macronuclear development resulted in the A surface antigen gene being located 8, 13, or 26 kilobases upstream from a macronuclear telomere. We describe variable rearrangements that occurred at the telomere 8 kilobases from the A gene. A mutant (d48) that forms a telomere near the 5' end of the A gene was also analyzed. This mutant was shown to create simple terminal deletions; telomeric repeats were added directly to the truncated wild-type A gene sequence. In both the mutant and wild-type cells, the telomeric sequences (a mixture of C4A2 and C3A3 repeats) were added to various sequences within a specific 200- to 500-base-pair region rather than to a single site. No similarities were found in the primary sequences surrounding the telomere addition sites. The mutation in d48 changed the region of telomere addition at the A gene locus; this is the first example in ciliates of a mutation that affects the site of telomere addition.},
}
@article {pmid3277178,
year = {1988},
author = {Shampay, J and Blackburn, EH},
title = {Generation of telomere-length heterogeneity in Saccharomyces cerevisiae.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {85},
number = {2},
pages = {534-538},
pmid = {3277178},
issn = {0027-8424},
mesh = {Chromosomes/ultrastructure ; Cloning, Molecular ; DNA, Fungal/genetics ; Genes, Fungal ; Mutation ; Saccharomyces cerevisiae/*genetics ; },
abstract = {Chromosome ends in the lower eukaryotes terminate in variable numbers of tandem, simple DNA repeats. We tested predictions of a model in which these telomeric repeats provide a substrate for the addition of more repeats by a terminal transferase-like mechanism that, in concert with DNA polymerase and primase, effectively counterbalances the loss of DNA due to degradation or incomplete replication. For individual chromosome ends in yeast, the mean length of any given telomere was shown to vary between different clonal populations of the same strain and to be determined by the initial length of that telomere in the single cell giving rise to the clone. This type of variation was independent of the major yeast recombination pathway. The length heterogeneity at each telomeric end increased with additional rounds of cell division or DNA replication. Lengths of individual telomeres within a single clone varied independently of each other. Thus, this clonal variability is distinct from genetic regulation of chromosome length, which acts on all chromosome ends coordinately. These in vivo phenomena suggest that lengthening and shortening activities act on yeast telomeres during each round of replication.},
}
@article {pmid3275867,
year = {1988},
author = {Buchman, AR and Kimmerly, WJ and Rine, J and Kornberg, RD},
title = {Two DNA-binding factors recognize specific sequences at silencers, upstream activating sequences, autonomously replicating sequences, and telomeres in Saccharomyces cerevisiae.},
journal = {Molecular and cellular biology},
volume = {8},
number = {1},
pages = {210-225},
pmid = {3275867},
issn = {0270-7306},
support = {GM-31105/GM/NIGMS NIH HHS/United States ; GM-36659/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromosomes/ultrastructure ; DNA Replication ; DNA, Fungal/*metabolism ; DNA-Binding Proteins/*metabolism ; Gene Expression Regulation ; Mating Factor ; Oligodeoxyribonucleotides/metabolism ; Peptides/genetics ; Protein Biosynthesis ; *Regulatory Sequences, Nucleic Acid ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*genetics ; },
abstract = {Two DNA-binding factors from Saccharomyces cerevisiae have been characterized, GRFI (general regulatory factor I) and ABFI (ARS-binding factor I), that recognize specific sequences within diverse genetic elements. GRFI bound to sequences at the negative regulatory elements (silencers) of the silent mating type loci HML E and HMR E and to the upstream activating sequence (UAS) required for transcription of the MAT alpha genes. A putative conserved UAS located at genes involved in translation (RPG box) was also recognized by GRFI. In addition, GRFI bound with high affinity to sequences with the (C1-3A)-repeat region at yeast telomeres. Binding sites for GRFI with the highest affinity appeared to be of the form 5'-(A/G)(A/C)ACCCANNCA(T/C)(T/C)-3', where N is any nucleotide. ABFI-binding sites were located next to autonomously replicating sequences (ARSs) at controlling elements of the silent mating type loci HMR E, HMR I, and HML I and were associated with ARS1, ARS2, and the 2 micron plasmid ARS. Two tandem ABFI binding sites were found between the HIS3 and DED1 genes, several kilobase pairs from any ARS, indicating that ABFI-binding sites are not restricted to ARSs. The sequences recognized by ABFI showed partial dyad-symmetry and appeared to be variations of the consensus 5'-TATCATTNNNNACGA-3'. GRFI and ABFI were both abundant DNA-binding factors and did not appear to be encoded by the SIR genes, whose products are required for repression of the silent mating type loci. Together, these results indicate that both GRFI and ABFI play multiple roles within the cell.},
}
@article {pmid3319189,
year = {1987},
author = {Greider, CW and Blackburn, EH},
title = {The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity.},
journal = {Cell},
volume = {51},
number = {6},
pages = {887-898},
doi = {10.1016/0092-8674(87)90576-9},
pmid = {3319189},
issn = {0092-8674},
support = {GM 26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromosomes/metabolism ; DNA/*metabolism ; DNA Nucleotidylexotransferase/*metabolism ; DNA Nucleotidyltransferases/*metabolism ; Molecular Weight ; Oligodeoxyribonucleotides/*metabolism ; RNA, Catalytic ; RNA, Ribosomal/metabolism ; *Repetitive Sequences, Nucleic Acid ; Ribonucleoproteins/*metabolism ; Tetrahymena/*enzymology ; },
abstract = {We have analyzed the de novo telomere synthesis catalyzed by the enzyme telomere terminal transferase (telomerase) from Tetrahymena. Oligonucleotides representing the G-rich strand of telomeric sequences from five different organisms specifically primed the addition of TTGGGG repeats in vitro, suggesting that primer recognition may involve a DNA structure unique to these oligonucleotides. The sequence at the 3' end of the oligonucleotide primer specified the first nucleotide added in the reaction. Furthermore, the telomerase was shown to be a ribonucleoprotein complex whose RNA and protein components were both essential for activity. After extensive purification of the enzyme by a series of five different chromatographic steps, a few small low abundance RNAs copurified with the activity.},
}
@article {pmid3120149,
year = {1987},
author = {Oka, Y and Thomas, CA},
title = {The cohering telomeres of Oxytricha.},
journal = {Nucleic acids research},
volume = {15},
number = {21},
pages = {8877-8898},
pmid = {3120149},
issn = {0305-1048},
support = {GM 34389/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Chromosomes/*ultrastructure ; Ciliophora/*genetics/ultrastructure ; DNA/*metabolism ; Endodeoxyribonucleases/metabolism ; Hot Temperature ; Models, Genetic ; Nucleic Acid Conformation ; Potassium/pharmacology ; Sodium/pharmacology ; },
abstract = {We have studied the process by which purified Oxytricha macronuclear DNA associates with itself to form large aggregates. The various macronuclear DNA molecules all have the same terminal or telomeric DNA sequences that are shown below. 5' C4A4C4A4C4--mean length----G4T4G4T4G4T4G4T4G4 G4T4G4T4G4T4G4T4G4-----2.4 kb------C4A4C4A4C4. When incubated at high concentrations, these telomeric sequences cohere with one another to form an unusual structure--one that is quite different from any DNA structure so far described. The evidence for this is the following: 1) These sequences cohere albeit slowly, in the presence of relatively high concentrations of Na+, and no other cation tested. This contrasts with the rapid coherence of complementary single-chain terminals of normal DNA (sticky ends) which occurs in the presence of any cation tested. 2) If the cohered form is transferred into buffers containing a special cation, K+, it becomes much more resistant to dissociation by heating. We estimate that K+ increases the thermal stability by 25 degrees or more. The only precedent known (to us) for a cation-specific stabilization is that seen in the quadruplex structure formed by poly I. The thermal stability of double helical macronuclear DNA depends on the cation concentration, but not the cation type. Limited treatment with specific nucleases show that the 3' and 5'-ended strands are essential for the formation of the cohering structure. Once in the cohered form, the telomeric sequences are protected from the action of nucleases. Coherence is inhibited by specific, but not by non-specific, synthetic oligomers, and by short telomeric fragments with or without their terminal single chains. We conclude that the coherence occurs by the formation of a novel condensed structure that involves the terminal nucleotides in three or four chains.},
}
@article {pmid3506530,
year = {1987},
author = {Guitart, M and Ponsà, M and Coll, MD and Egozcue, J},
title = {New data on the synaptic process of Mesocricetus auratus: connecting fibers, telomere association and heterosynapsis.},
journal = {Genetica},
volume = {74},
number = {2},
pages = {105-112},
pmid = {3506530},
issn = {0016-6707},
mesh = {Animals ; Cricetinae/*genetics ; Male ; *Meiosis ; Mesocricetus/*genetics ; Microscopy, Electron ; Prophase ; Spermatocytes/cytology/ultrastructure ; *Synaptonemal Complex ; },
abstract = {The progression of the prophase-I stage in Syrian hamster spermatocytes has been studied at different ages, from 12 to 41 days after birth. Two stages, leptotene and diplotene, were identified, which had not previously been described in the Syrian hamster using spreading techniques. The most interesting observations are the presence of heterosynapses and telomere associations in 2.5% of the cells studied, and of nucleolar filaments also in 2.5%. Connecting fibers are structures that establish different types of bridges between two or three synaptonemal complexes (SCs) or between the elements of a single SC. Heterosynapses and telomere associations consist in the partial pairing of the terminal regions of non-homologous lateral elements. These phenomena can be observed both in the autosomes and in the sex chromosomes.},
}
@article {pmid3332970,
year = {1987},
author = {Walmsley, RM},
title = {Yeast telomeres: the end of the chromosome story?.},
journal = {Yeast (Chichester, England)},
volume = {3},
number = {3},
pages = {139-148},
doi = {10.1002/yea.320030302},
pmid = {3332970},
issn = {0749-503X},
mesh = {Animals ; Chromosomes/*ultrastructure ; Cloning, Molecular ; DNA Replication ; DNA, Fungal/biosynthesis/genetics ; Saccharomyces cerevisiae/*genetics/ultrastructure ; },
}
@article {pmid2890097,
year = {1987},
author = {Schechtman, MG},
title = {Isolation of telomere DNA from Neurospora crassa.},
journal = {Molecular and cellular biology},
volume = {7},
number = {9},
pages = {3168-3177},
pmid = {2890097},
issn = {0270-7306},
mesh = {Chromosome Mapping ; Chromosomes/*ultrastructure ; Cosmids ; DNA Restriction Enzymes ; DNA Transposable Elements ; DNA, Fungal/*genetics ; Histidine/genetics ; Neurospora/*genetics ; Neurospora crassa/*genetics ; Polymorphism, Restriction Fragment Length ; Repetitive Sequences, Nucleic Acid ; },
abstract = {The most distal known gene on Neurospora crassa linkage group VR, his-6, was cloned. A genomic walk resulted in isolation of the telomere at VR. It was obtained from a library in which the endmost nucleotides of the chromosome had not been removed by nuclease treatment before being cloned, and mapping indicates that the entire chromosome end has probably been cloned. Sequences homologous to the terminal 2.5 kilobases of DNA from VR from these Oak Ridge N. crassa strains are found at other sites in the genome. To characterize these sites, I crossed an Oak Ridge-derived his-6 strain with a wild-type strain of different genetic background (Mauriceville) and characterized the hybridization patterns seen in the progeny. It appears that the sequences homologous to the VR terminus are found at genetically different sites in the two parental strains, and no hybridization to the VR telomere from Mauriceville was detected. The other genomic copies identified in the Oak Ridge parent were not telomeres. I suggest that any repeating sequence blocks found immediately adjacent to the VR terminus in Oak Ridge strains must be small and that the repeating element identified in that background may be an N. crassa transposable element integrated near the the chromosome end at VR.},
}
@article {pmid2886227,
year = {1987},
author = {Gilliam, TC and Tanzi, RE and Haines, JL and Bonner, TI and Faryniarz, AG and Hobbs, WJ and MacDonald, ME and Cheng, SV and Folstein, SE and Conneally, PM},
title = {Localization of the Huntington's disease gene to a small segment of chromosome 4 flanked by D4S10 and the telomere.},
journal = {Cell},
volume = {50},
number = {4},
pages = {565-571},
doi = {10.1016/0092-8674(87)90029-8},
pmid = {2886227},
issn = {0092-8674},
support = {NS16367/NS/NINDS NIH HHS/United States ; NS20012/NS/NINDS NIH HHS/United States ; NS22031/NS/NINDS NIH HHS/United States ; },
mesh = {Alleles ; Chromosome Aberrations/*genetics ; Chromosome Disorders ; Chromosomes, Human, Pair 4/*ultrastructure ; DNA/genetics ; DNA, Recombinant ; Genetic Linkage ; Genetic Markers ; Humans ; Huntington Disease/*genetics ; Polymorphism, Restriction Fragment Length ; },
abstract = {Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder of late onset, characterized by progressive motor disturbance, psychological manifestations, and intellectual deterioration. The HD gene has been genetically mapped by linkage to the DNA marker D4S10, but the exact physical location of the HD defect has remained uncertain. To delineate critical recombination events revealing the physical position of the HD gene, we have identified restriction fragment length polymorphisms for two recently mapped chromosome 4 loci, RAF2 and D4S62, and determined the pattern of segregation of these markers in both reference and HD pedigrees. Multipoint linkage analysis of the new markers with D4S10 and HD establishes that the HD gene is located in a very small physical region at the tip of the chromosome, bordered by D4S10 and the telomere. A crossover within the D4S10 locus orients this segment on the chromosome, providing the necessary information for efficient application of directional cloning strategies for progressing toward, and eventually isolating, the HD gene.},
}
@article {pmid2824785,
year = {1987},
author = {Dickie, P and Morgan, AR and McFadden, G},
title = {Cruciform extrusion in plasmids bearing the replicative intermediate configuration of a poxvirus telomere.},
journal = {Journal of molecular biology},
volume = {196},
number = {3},
pages = {541-558},
doi = {10.1016/0022-2836(87)90031-3},
pmid = {2824785},
issn = {0022-2836},
mesh = {Base Sequence ; Cloning, Molecular ; DNA Replication ; *DNA, Viral ; Electrophoresis, Agar Gel ; Fibroma Virus, Rabbit/*genetics ; Molecular Sequence Data ; *Nucleic Acid Conformation ; *Plasmids ; Poxviridae/*genetics ; Virus Replication ; },
abstract = {The transition from lineform DNA to cruciform DNA (cruciformation) within the cloned telomere sequences of the Leporipoxvirus Shope fibroma virus (SFV) has been studied. The viral telomere sequences have been cloned in recombination-deficient Escherichia coli as a 322 base-pair, imperfect palindromic insert in pUC13. The inverted repeat configuration is equivalent to the arrangement of the telomere structures observed within viral DNA replicative intermediates. A major cruciform structure in the purified recombinant plasmid has been identified and mapped using, as probes, the enzymes AflII, nuclease S1 and bacteriophage T7 endonuclease I. It was extruded from the central axis of the cloned viral inverted repeat and, by unrestricted branch migration, attained a size commensurate with the superhelical density of the plasmid molecule at native superhelical densities. This major cruciform extrusion event was the only detectable duplex DNA perturbation, induced by negative superhelical torsion, in the insert viral sequences. No significant steady-state pool of extruded cruciform was identified in E. coli. However, the identification of a major deletion variant generated even in the recombination-deficient E. coli strain DB1256 (recA recBC sbcB) suggested that the cruciform may be extruded transiently in vivo. The lineform to cruciform transition has been further characterized in vitro using two-dimensional agarose gel electrophoresis. The transition was marked by a high energy of formation (delta Gf = 44 kcal/mol), and an apparently low activation energy that enabled facile transitions at physiological temperatures provided there was sufficient torsional energy. By comparing cruciformation in a series of related bidirectional central axis deletions of the telomeric insert, it has been concluded that the presence of extrahelical bases in the terminal hairpin structures contributes substantially to the high delta Gf value. Also, viral sequences flanking the extruded cruciform were shown to influence the measured delta Gf value. Several general features of poxvirus telomere structure that would be expected to influence the facility of cruciform extrusion are discussed along with the implications of the observed cruciform transition event on the replicative process of poxviruses in vivo.},
}
@article {pmid3607876,
year = {1987},
author = {Larson, DD and Spangler, EA and Blackburn, EH},
title = {Dynamics of telomere length variation in Tetrahymena thermophila.},
journal = {Cell},
volume = {50},
number = {3},
pages = {477-483},
doi = {10.1016/0092-8674(87)90501-0},
pmid = {3607876},
issn = {0092-8674},
support = {GM 26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; *Chromosomes ; DNA Replication ; DNA, Ribosomal/metabolism ; Genetic Variation ; Models, Genetic ; Tetrahymena/*genetics ; },
abstract = {We have analyzed the mechanism and dynamics of telomere length variation in the macronucleus of Tetrahymena thermophila. In a newly differentiated macronucleus, the average length of the telomeric repeated sequence, (C4A2 X T2G4)n, is closely regulated. In contrast, in vegetatively dividing cells in log phase, all macronuclear telomeric sequences lengthen coordinately by 3-10 bp per generation until up to 1000 bp are added. In both elongated and short telomeres, characteristic single-stranded breaks on both strands are distally located. Reduction of elongated telomeres to their original length involves either the appearance of a novel type of variant cell, incapable of net telomere elongation, or, under stationary phase conditions, a reversible removal of telomeric sequences. The demonstration that telomeres are dynamic structures provides evidence for a model of telomere length regulation by activities that add and remove telomeric repeats.},
}
@article {pmid3621643,
year = {1987},
author = {Rivera, H and García-Esquivel, L and Jiménez-Sáinz, M and Vaca, G and Ibarra, B and Cantú, JM},
title = {Centric fission, centromere-telomere fusion and isochromosome formation: a possible origin of a de novo 12p trisomy.},
journal = {Clinical genetics},
volume = {31},
number = {6},
pages = {393-398},
doi = {10.1111/j.1399-0004.1987.tb02831.x},
pmid = {3621643},
issn = {0009-9163},
mesh = {Abnormalities, Multiple/*genetics ; Centromere/physiology ; *Chromosomes, Human, Pair 12 ; Chromosomes, Human, Pair 8 ; Female ; Humans ; Infant ; Karyotyping ; Translocation, Genetic ; *Trisomy ; },
abstract = {A 5-month-old girl had a typical 12p trisomy syndrome due to a monocentric i(12p) present in a 46-chromosome complement that also included the translocation of all 12q onto the 8p telomere; i.e., her complex karyotype could be written as 46,XX,-8,-12, +der(8),t(8;12)(p23.3;cen),+i(12p). The present concurrence of a whole-arm q translocation and an i(p) for a single chromosome, along with six previous similar instances involving chromosomes 4, 5 and 9, suggests the following origin for such a special rearrangement: a centric fission in G1 initially yielding two telocentrics; at the next replication, the tel(q) translocates onto a nonhomologous telomere (centromere-telomere fusion), whereas the tel(p) becomes an i(p). This mechanism can be either meiotic or postzygotic and surmises that the translocated long arm retains a partial centromere, which subsequently is inactivated and loses its staining properties.},
}
@article {pmid3033323,
year = {1987},
author = {DeLange, AM and McFadden, G},
title = {Efficient resolution of replicated poxvirus telomeres to native hairpin structures requires two inverted symmetrical copies of a core target DNA sequence.},
journal = {Journal of virology},
volume = {61},
number = {6},
pages = {1957-1963},
pmid = {3033323},
issn = {0022-538X},
mesh = {DNA/*genetics ; DNA, Recombinant ; DNA, Viral/*genetics ; Escherichia coli/genetics ; Fibroma Virus, Rabbit/*genetics ; Nucleic Acid Conformation ; Poxviridae/*genetics ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/genetics ; },
abstract = {The terminal hairpin sequences of the linear double-stranded DNA genome of the leporipoxvirus Shope fibroma virus (SFV) has been cloned in Saccharomyces cerevisiae and in recombination-deficient Escherichia coli as a palindromic insert within circular plasmid vectors. This sequence configuration is equivalent to the inverted repeat structure detected as a telomeric replicative intermediate during poxvirus replication in vivo. Previously, it has been shown that when circular plasmids containing this palindromic insert were transfected into SFV-infected cells, efficient replication and resolution generated linear minichromosomes with bona fide viral hairpin termini (A. M. DeLange, M. Reddy, D. Scraba, C. Upton, and G. McFadden, J. Virol. 59:249-259, 1986). To localize the minimal target DNA sequence required for efficient resolution, a series of staggered unidirectional deletions were constructed at both ends of the inverted repeat. Analyses of the resolution efficiencies of the various clones indicate that up to 240 base pairs (bp) centered at the symmetry axis were required for maximal resolution to minichromosomes. To investigate the role of the AT-rich central axis sequences, which in SFV include 8 nonpalindromic bp, a unique AflII site at the symmetry axis was exploited. Bidirectional deletions extending from this AflII site and insertions of synthetic oligonucleotides into one of the deletion derivatives were constructed and tested in vivo. The efficiency with which these plasmids resolved to linear minichromosomes with hairpin termini has enabled us to define the minimal target DNA sequence as two inverted copies of an identical DNA sequence between 58 and 76 bp in length. The nonpalindromic nucleotides, which, after resolution, constitute the extrahelical residues characteristic of native poxviral telomeres, were not required for resolution. The close resemblance of the SFV core target sequence to the analogous region from the orthopoxvirus vaccinia virus is consistent with a conserved mechanism for poxviral telomere resolution.},
}
@article {pmid3105317,
year = {1987},
author = {Mulligan, LM and Grover, HJ and Blanchette, VS and Giles, AR and Lillicrap, DP and Phillips, A and Holden, JJ and White, BN},
title = {Recombination between the factor VIII gene and the DXS52 locus gives the most probable genetic order as centromere-fra(X)-DXS15-DXS52-F8C-telomere.},
journal = {American journal of medical genetics},
volume = {26},
number = {3},
pages = {751-760},
doi = {10.1002/ajmg.1320260334},
pmid = {3105317},
issn = {0148-7299},
mesh = {*Chromosome Fragility ; Chromosome Mapping ; Factor VIII/*genetics ; Fragile X Syndrome/genetics ; *Genetic Linkage ; Hemophilia A/genetics ; Heterozygote ; Humans ; Lod Score ; *Recombination, Genetic ; *X Chromosome ; },
abstract = {The linkage relationship between the factor VIII gene (F8C) and the DXS52 locus was examined in 8 families. Two recombinations were identified in 35 informative meioses (Zmax = 5.67; theta = 0.05), one in a family with hemophilia A, the other in a family with the fra(X) syndrome. Based on the latter recombination, the most probable order of loci was determined to be centromere-fra(X)-DXS15-DXS52-F8C-telomere. When these data are added to those reported previously the most probable genetic distance between F8C and DXS52 is 3 cM (Z = 14.62). Identification of these and other recombinations suggests that the use of DXS52 as a genetic marker for carrier detection and prenatal diagnosis of hemophilia A has an error rate between 3-5%.},
}
@article {pmid3503707,
year = {1987},
author = {Cooke, HJ},
title = {Telomeres of the human X and Y chromosomes.},
journal = {Development (Cambridge, England)},
volume = {101 Suppl},
number = {},
pages = {101-106},
doi = {10.1242/dev.101.Supplement.101},
pmid = {3503707},
issn = {0950-1991},
mesh = {DNA ; DNA, Satellite ; Genetic Variation ; Humans ; Repetitive Sequences, Nucleic Acid ; Terminator Regions, Genetic ; *X Chromosome ; *Y Chromosome ; },
abstract = {Analysis of the nature of the DNA sequences at the telomeres of the short arms of the human sex chromosomes suggests parallels with the structures found at telomeres of a number of lower eukaryotes. The exact nature of the end of the DNA has not yet been established but it is clear that there are multiple levels of variability both between and within individuals in this region of the genome.},
}
@article {pmid2824294,
year = {1987},
author = {Yu, XM and Good, PJ and Mertz, JE},
title = {The telomeres of Tetrahymena ribosomal DNA are not sufficient for stabilizing linear DNA in Xenopus oocytes.},
journal = {Gene},
volume = {56},
number = {2-3},
pages = {313-319},
doi = {10.1016/0378-1119(87)90150-8},
pmid = {2824294},
issn = {0378-1119},
support = {CA-07175/CA/NCI NIH HHS/United States ; CA-22443/CA/NCI NIH HHS/United States ; CA-37208/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Chromatin/metabolism ; DNA, Ribosomal/*genetics/metabolism ; Gene Expression Regulation ; Oocytes/*metabolism ; Simian virus 40/genetics ; Tetrahymena/*genetics ; Transcription, Genetic ; Xenopus laevis/*genetics/metabolism ; },
abstract = {Restriction fragments that include the telomeres of ribosomal DNA from Tetrahymena thermophila (TtrDNA) were ligated to the ends of linearized simian virus 40 (SV40) DNA. The linear SV40 DNA with TtrDNA ends, circular SV40 DNA, linear SV40 DNA, and intact TtrDNA were injected into the nuclei of Xenopus laevis oocytes and assayed for stability. The intact linear 21-kb TtrDNA and circular SV40 DNA were maintained stably for at least 72 h after injection while the linearized SV40 DNA, either with or without telomeric ends, was degraded rapidly. Limited digestion with micrococcal nuclease revealed that neither the intact TtrDNA nor the SV40 DNA with telomeric ends reconstituted into chromatin containing regularly spaced nucleosomes. Another linearized plasmid DNA (pBamC), 14 kb in length, also was not stable in Xenopus oocytes with or without the addition of TtrDNA telomeres. Therefore, TtrDNA telomeres by themselves are not sufficient for stabilization of linear DNA in Xenopus oocytes. Rather, linear TtrDNA is maintained stably because of additional sequence or structural information encoded within the molecule.},
}
@article {pmid3094961,
year = {1986},
author = {Gottschling, DE and Zakian, VA},
title = {Telomere proteins: specific recognition and protection of the natural termini of Oxytricha macronuclear DNA.},
journal = {Cell},
volume = {47},
number = {2},
pages = {195-205},
doi = {10.1016/0092-8674(86)90442-3},
pmid = {3094961},
issn = {0092-8674},
mesh = {Animals ; Base Sequence ; Binding Sites ; Chromosomes/physiology/*ultrastructure ; Ciliophora/*physiology ; DNA/metabolism ; DNA-Binding Proteins/*physiology ; Molecular Weight ; Nucleoproteins/*physiology ; Protein Binding ; Solubility ; },
abstract = {The macronuclear DNA in the ciliated protozoan O. nova consists of integral of 10(7) gene-sized DNA molecules, all of which terminate with 20 bp of C4A4 repeats followed by a 3' (G4T4)2 single-stranded tail. Two immunologically distinct proteins of 55 and 26 kd, which are tenaciously, but noncovalently associated with Oxytricha macronuclear DNA termini, have been purified. These proteins protect DNA termini from degradation by the exonuclease Bal31. They also facilitate retention of natural and synthetic telomeric DNAs onto nitrocellulose. The Oxytricha proteins are not simply C4A4-binding proteins. Rather, their efficient binding requires both the 3' single-stranded (G4T4)2 tail and the adjacent duplex region. Thus, these proteins require both the sequence and the structure of natural DNA termini for efficient binding. As such they represent the first described example of telomeric-specific proteins.},
}
@article {pmid3019555,
year = {1986},
author = {Morin, GB and Cech, TR},
title = {The telomeres of the linear mitochondrial DNA of Tetrahymena thermophila consist of 53 bp tandem repeats.},
journal = {Cell},
volume = {46},
number = {6},
pages = {873-883},
doi = {10.1016/0092-8674(86)90069-3},
pmid = {3019555},
issn = {0092-8674},
support = {GM25273/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cloning, Molecular ; DNA Restriction Enzymes ; DNA, Mitochondrial/*genetics ; Hydrogen Bonding ; Nucleic Acid Conformation ; *Repetitive Sequences, Nucleic Acid ; Tetrahymena/*genetics ; },
abstract = {We have cloned and sequenced the telomeric DNA of the linear mitochondrial DNA (mtDNA) of T. thermophila BVII. The mtDNA telomeres consist of a 53 bp sequence tandemly repeated from 4 to 30 times, with most molecules having 15 +/- 4 repetitions. The previously recognized terminal heterogeneity of the mtDNA is completely accounted for by the variability in the number of repeats. The 53 bp repeat does not resemble known telomeric DNA in sequence, repeat size, or number of repetitions. The termini occur at heterogeneous positions within the 53 bp repeat. The junction of the telomeric repeat with the internal DNA is at a different position within the telomeric repeat on each end of the mtDNA. We propose a model for the maintenance of the mtDNA ends involving unequal homologous recombination.},
}
@article {pmid3745268,
year = {1986},
author = {Berg, CA and Gall, JG},
title = {Microinjected Tetrahymena rDNA ends are not recognized as telomeres in Xenopus eggs.},
journal = {The Journal of cell biology},
volume = {103},
number = {3},
pages = {691-698},
pmid = {3745268},
issn = {0021-9525},
support = {GM-33397/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA Replication ; DNA, Recombinant/*metabolism ; DNA, Ribosomal/*genetics/metabolism ; Extrachromosomal Inheritance ; Female ; Microinjections ; Oocytes ; Tetrahymena/*genetics ; Xenopus laevis/*metabolism ; },
abstract = {Telomeres are essential structures that stabilize the ends of eukaryotic chromosomes and allow complete replication of linear DNA molecules. We examined the structure and replication of telomeres by observing the fate of the linear extrachromosomal rDNA of Tetrahymena after injection into unfertilized Xenopus eggs. The rDNA replicated efficiently as a linear extrachromosomal molecule, increasing in mass 30-50-fold by 15-20 h after injection. In addition, the molecules increased in length by addition of up to several kilobases of DNA to their termini. Sequence analysis demonstrated that the added DNA bore no resemblance to known telomeres. The junction between the rDNA and added DNA was apparently random, indicating that the addition reaction did not involve a site-specific recombination or integration event. Surprisingly, Southern blot analysis showed that the added DNA did not derive from Xenopus DNA, but rather from co-purifying and therefore co-injected Tetrahymena DNA. The nonspecific ligation of random DNA fragments to the rDNA termini suggests that microinjected Tetrahymena rDNA ends are not recognized as telomeres in Xenopus eggs.},
}
@article {pmid3016294,
year = {1986},
author = {DeLange, AM and Reddy, M and Scraba, D and Upton, C and McFadden, G},
title = {Replication and resolution of cloned poxvirus telomeres in vivo generates linear minichromosomes with intact viral hairpin termini.},
journal = {Journal of virology},
volume = {59},
number = {2},
pages = {249-259},
pmid = {3016294},
issn = {0022-538X},
mesh = {Base Sequence ; Chromosomes/*ultrastructure ; Cloning, Molecular ; *DNA Replication ; DNA, Viral/*genetics ; Escherichia coli ; Fibroma Virus, Rabbit/*genetics ; Nucleic Acid Conformation ; Poxviridae/*genetics ; Saccharomyces cerevisiae ; Vaccinia virus/*genetics ; },
abstract = {The covalently closed terminal hairpins of the linear duplex-DNA genomes of the orthopoxvirus vaccinia and the leporipoxvirus Shope fibroma virus (SFV) have been cloned as imperfect palindromes within circular plasmids in yeast cells and recombination-deficient Escherichia coli. The viral telomeres inserted within these recombinant plasmids are equivalent to the inverted-repeat structures detected as telomeric replicative intermediates during poxvirus replication in vivo. Although the telomeres of vaccinia and SFV show little sequence homology, the termini from both viral genomes exist as AT-rich terminal hairpins with extrahelical bases and alternate "flip-flop" configurations. Using an in vivo replication assay in which circular plasmid DNA was transfected into poxvirus-infected cells, we demonstrated the efficient replication and resolution of the cloned imperfect palindromes to bona fide hairpin termini. The resulting linear minichromosomes, which were readily purified from transfected cells, were shown by restriction enzyme mapping and by electron microscopy to have intact covalently closed hairpin termini at both ends. In addition, staggered unidirectional deletion derivatives of both the cloned vaccinia and SFV telomeric palindromes localized an approximately 200-base-pair DNA region in which the sequence organization was highly conserved and which was necessary for the resolution event. These data suggest a conserved mechanism of the resolution of poxvirus telomeres.},
}
@article {pmid3520552,
year = {1986},
author = {Berman, J and Tachibana, CY and Tye, BK},
title = {Identification of a telomere-binding activity from yeast.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {83},
number = {11},
pages = {3713-3717},
pmid = {3520552},
issn = {0027-8424},
support = {GM34190/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosomes/metabolism/*ultrastructure ; Cloning, Molecular ; DNA, Fungal/*metabolism ; DNA-Binding Proteins/*metabolism ; Saccharomyces cerevisiae/*genetics/metabolism/ultrastructure ; Species Specificity ; },
abstract = {In yeast, the ends of the chromosomes (telomeres) terminate in repeated poly(C1-3A) sequences. We have identified a yeast activity that binds specifically to these poly(C1-3A) repeats. An agarose gel binding assay was used to detect and characterize this activity in cell extracts using both cloned telomere DNA and yeast genomic DNA as substrates. The activity appears to bind specifically to poly(C1-3A) sequences, despite their different primary sequences, yet does not bind specifically to telomeric repeats, such as poly(C4A2), poly(C4A4), and poly (C1-8T) from other lower eukaryotes.},
}
@article {pmid3537702,
year = {1986},
author = {Button, LL and Astell, CR},
title = {The Saccharomyces cerevisiae chromosome III left telomere has a type X, but not a type Y', ARS region.},
journal = {Molecular and cellular biology},
volume = {6},
number = {4},
pages = {1352-1356},
pmid = {3537702},
issn = {0270-7306},
mesh = {Base Sequence ; Chromosome Mapping ; Chromosomes/*ultrastructure ; Cloning, Molecular ; DNA, Fungal/genetics ; Nucleic Acid Hybridization ; Saccharomyces cerevisiae/*genetics ; },
abstract = {A yeast Saccharomyces cerevisiae telomeric region was isolated by chromosome walking from HML alpha, the most distal known gene on the chromosome III left (IIIL) end. The terminal heterodisperse 3.3-kilobase (kb) SalI fragment on chromosome IIIL, 8.6 kb distal to HML alpha, was cloned in a circular vector to generate a telomeric probe. Southern hybridization and DNA sequencing analyses indicated that 0.6 kb (+/- 200 base pairs) of 5'-C1-3A-3' simple tandem repeat sequence, adjacent to a 1.2-kb type X ARS region, constitutes the telomere on the chromosome IIIL end, and no type Y' ARS region homologies exist between HML alpha and the IIIL terminus.},
}
@article {pmid3513174,
year = {1986},
author = {Lustig, AJ and Petes, TD},
title = {Identification of yeast mutants with altered telomere structure.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {83},
number = {5},
pages = {1398-1402},
pmid = {3513174},
issn = {0027-8424},
support = {CA19265/CA/NCI NIH HHS/United States ; GM24110/GM/NIGMS NIH HHS/United States ; K 04 AG 007/AG/NIA NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosomes/*ultrastructure ; DNA Replication ; DNA, Fungal/genetics ; Fungal Proteins/genetics ; Genes, Recessive ; Intracellular Signaling Peptides and Proteins ; Mutation ; Phenotype ; Protein Serine-Threonine Kinases ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*genetics/ultrastructure ; Saccharomyces cerevisiae Proteins ; },
abstract = {The chromosomes of the yeast Saccharomyces cerevisiae terminate in a tract of simple-sequence DNA [poly(C1-3A)] that is several hundred base pairs long. We describe the identification of mutant yeast strains that have telomeric tracts that are shorter than normal. A genetic analysis of these strains indicates that these short telomeres are the result of single nuclear recessive mutations and that these mutations can be classified into two different complementation groups. The full expression of the mutant phenotype shows a very long lag (approximately equal to 150 cell divisions). From our analysis of these mutants as well as other data, we suggest that the duplication of the telomeric poly(C1-3A) tract involves two processes, semiconservative replication and untemplated terminal addition of nucleotides.},
}
@article {pmid3943861,
year = {1986},
author = {Aurias, A and Dutrillaux, B},
title = {A possible new type of chromosome rearrangement: telomere-centromere translocation (tct) followed by double duplication.},
journal = {Human genetics},
volume = {72},
number = {1},
pages = {25-26},
pmid = {3943861},
issn = {0340-6717},
mesh = {*Centromere ; Chromosome Banding ; *Chromosomes ; Chromosomes, Human, 1-3 ; Chromosomes, Human, 4-5 ; Humans ; Karyotyping ; *Translocation, Genetic ; },
abstract = {The reassessment of a case of complex interchromosomal rearrangement after breakage at centromeric and telomeric regions, and the comparison with four other independently published cases suggested the existence of a new type of rearrangement. It would consist of: formation of an isochromosome after breakage at a centromeric region, duplication of the telomeric region of another chromosome, and reassociation of the nonduplicated arm of the first chromosome with the duplicated telomeric region of the second chromosome.},
}
@article {pmid3551920,
year = {1986},
author = {Zakian, VA and Blanton, HM and Wetzel, L},
title = {Distribution of telomere-associated sequences in yeast.},
journal = {Basic life sciences},
volume = {40},
number = {},
pages = {493-498},
doi = {10.1007/978-1-4684-5251-8_37},
pmid = {3551920},
issn = {0090-5542},
mesh = {Base Sequence ; Chromosomes/*analysis ; DNA, Fungal/genetics ; Saccharomyces cerevisiae/*genetics ; },
abstract = {Two middle repetitive DNA sequences called X and Y' are found near the telomeres of many chromosomes in Saccharomyces cerevisiae. Orthogonal field gel electrophoresis (OFAGE) was used to examine the distribution of X and Y' on different yeast chromosomes. Although the distribution of X and Y' varies among different laboratory strains of yeast, most yeast chromosomes in four different strains carry both X and Y'. However, at least one chromosome in each strain lacks the Y' element. This result indicates that Y' is not essential for replication or segregation of at least some yeast chromosomes.},
}
@article {pmid3034483,
year = {1986},
author = {Cooke, HJ and Smith, BA},
title = {Variability at the telomeres of the human X/Y pseudoautosomal region.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {51 Pt 1},
number = {},
pages = {213-219},
doi = {10.1101/sqb.1986.051.01.026},
pmid = {3034483},
issn = {0091-7451},
mesh = {Cell Line ; DNA Restriction Enzymes ; *Genetic Variation ; Humans ; Male ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/genetics ; *X Chromosome ; *Y Chromosome ; },
}
@article {pmid3907856,
year = {1985},
author = {Greider, CW and Blackburn, EH},
title = {Identification of a specific telomere terminal transferase activity in Tetrahymena extracts.},
journal = {Cell},
volume = {43},
number = {2 Pt 1},
pages = {405-413},
doi = {10.1016/0092-8674(85)90170-9},
pmid = {3907856},
issn = {0092-8674},
support = {GM 26259/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Chromosomes/ultrastructure ; DNA Nucleotidylexotransferase/*isolation &amp; purification ; DNA Nucleotidyltransferases/*isolation &amp; purification ; DNA Polymerase II/physiology ; DNA Replication ; Models, Genetic ; Saccharomyces cerevisiae/genetics ; Templates, Genetic ; Tetrahymena/*enzymology/genetics/ultrastructure ; },
abstract = {We have found a novel activity in Tetrahymena cell free extracts that adds tandem TTGGGG repeats onto synthetic telomere primers. The single-stranded DNA oligonucleotides (TTGGGG)4 and TGTGTGGGTGTGTGGGTGTGTGGG, consisting of the Tetrahymena and yeast telomeric sequences respectively, each functioned as primers for elongation, while (CCCCAA)4 and two nontelomeric sequence DNA oligomers did not. Efficient synthesis of the TTGGGG repeats depended only on addition of micromolar concentrations of oligomer primer, dGTP, and dTTP to the extract. The activity was sensitive to heat and proteinase K treatment. The repeat addition was independent of both endogenous Tetrahymena DNA and the endogenous alpha-type DNA polymerase; and a greater elongation activity was present during macronuclear development, when a large number of telomeres are formed and replicated, than during vegetative cell growth. We propose that the novel telomere terminal transferase is involved in the addition of telomeric repeats necessary for the replication of chromosome ends in eukaryotes.},
}
@article {pmid3018485,
year = {1985},
author = {Carlson, M and Celenza, JL and Eng, FJ},
title = {Evolution of the dispersed SUC gene family of Saccharomyces by rearrangements of chromosome telomeres.},
journal = {Molecular and cellular biology},
volume = {5},
number = {11},
pages = {2894-2902},
pmid = {3018485},
issn = {0270-7306},
support = {GM32065/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; *Biological Evolution ; Chromosomes/ultrastructure ; Cloning, Molecular ; DNA Restriction Enzymes ; *Genes ; *Genes, Fungal ; Genotype ; Glycoside Hydrolases/*genetics ; Plasmids ; Saccharomyces cerevisiae/enzymology/*genetics ; Sucrose/metabolism ; beta-Fructofuranosidase ; },
abstract = {The SUC gene family of Saccharomyces contains six structural genes for invertase (SUC1 through SUC5 and SUC7) which are located on different chromosomes. Most yeast strains do not carry all six SUC genes and instead carry natural negative (suc0) alleles at some or all SUC loci. We determined the physical structures of SUC and suc0 loci. Except for SUC2, which is an unusual member of the family, all of the SUC genes are located very close to telomeres and are flanked by homologous sequences. On the centromere-proximal side of the gene, the conserved region contains X sequences, which are sequences found adjacent to telomeres (C. S. M. Chan and B.-K. Tye, Cell 33:563-573, 1983). On the other side of the gene, the homology includes about 4 kilobases of flanking sequence and then extends into a Y' element, which is an element often found distal to the X sequence at telomeres (Chan and Tye, Cell 33:563-573, 1983). Thus, these SUC genes and flanking sequences are embedded in telomere-adjacent sequences. Chromosomes carrying suc0 alleles (except suc20) lack SUC structural genes and portions of the conserved flanking sequences. The results indicate that the dispersal of SUC genes to different chromosomes occurred by rearrangements of chromosome telomeres.},
}
@article {pmid3893744,
year = {1985},
author = {Carson, MJ and Hartwell, L},
title = {CDC17: an essential gene that prevents telomere elongation in yeast.},
journal = {Cell},
volume = {42},
number = {1},
pages = {249-257},
doi = {10.1016/s0092-8674(85)80120-3},
pmid = {3893744},
issn = {0092-8674},
support = {GM17709/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; Chromosomes/*metabolism ; DNA Polymerase I/metabolism ; DNA, Fungal/*metabolism ; Genes, Dominant ; *Genes, Fungal ; Genes, Recessive ; Mitosis ; Mutation ; Phenotype ; Recombination, Genetic ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*genetics/metabolism/ultrastructure ; *Saccharomyces cerevisiae Proteins ; Temperature ; },
abstract = {The CDC17 gene product performs an essential stage-specific function during the Saccharomyces cerevisiae cell cycle. When cdc17-1 strains are grown at the maximum permissive temperature, recombination is induced preferentially in the genetic interval of the chromosome closest to the telomere. Telomeres are longer in cdc17 strains than in CDC17 strains at the permissive temperature because of addition of sequence near or in the poly (C1-3A) telomeric DNA and become even longer when cells are propagated at elevated temperatures. The mitotic recombination events require RAD52 function, but telomere growth does not. Long telomeres are maintained for many generations when crossed into a CDC17+ background, suggesting that telomere length is largely conserved during replication. The altered telomere length phenotype of cdc17 mutations is recessive and coreverts and cosegregates with the temperature-sensitive lethal phenotype.},
}
@article {pmid2985276,
year = {1985},
author = {Roth, M and Prescott, DM},
title = {DNA intermediates and telomere addition during genome reorganization in Euplotes crassus.},
journal = {Cell},
volume = {41},
number = {2},
pages = {411-417},
doi = {10.1016/s0092-8674(85)80014-3},
pmid = {2985276},
issn = {0092-8674},
support = {GM19199/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cell Nucleus/metabolism/physiology ; Chromosomes/*metabolism ; Ciliophora/*genetics/metabolism/physiology ; DNA/*metabolism ; DNA Restriction Enzymes ; Molecular Weight ; Nucleic Acid Hybridization ; Repetitive Sequences, Nucleic Acid ; },
abstract = {Three gene-sized molecules cloned intact from macronuclear DNA served as hybridization probes to study excision of these molecules from chromosomes and their processing during macronuclear development in the hypotrich Euplotes crassus. These molecules occur in integrated forms within polytene chromosomal DNA during macronuclear developmental. After transection of the polytene chromosomes, the three molecules occur in intermediate forms. One of the three molecules first appeared in a large intermediate that was subsequently replaced by a second intermediate, approximately 140 bp larger than the final molecule. The other two macronuclear molecules were detected only in intermediates approximately 140 bp larger than the mature form. These penultimate intermediates are larger by virtue of oversized telomeres, which are pared to yield the mature gene-sized molecules.},
}
@article {pmid4006906,
year = {1985},
author = {Saiga, H and Edström, JE},
title = {Long tandem arrays of complex repeat units in Chironomus telomeres.},
journal = {The EMBO journal},
volume = {4},
number = {3},
pages = {799-804},
pmid = {4006906},
issn = {0261-4189},
mesh = {Animals ; Base Sequence ; Chironomidae/*genetics ; Chromosome Mapping ; Chromosomes/*ultrastructure ; Diptera/*genetics ; Nucleic Acid Hybridization ; *Repetitive Sequences, Nucleic Acid ; Transcription, Genetic ; },
abstract = {A cloned 340-bp DNA fragment excised by EcoRI from the Chironomus pallividittatus genome has been localized to the telomeres by in situ hybridization as well as to connectives between telomeres. No hybridization was observed in other regions of the chromosomes. Another cloned EcoRI fragment, 525 bp long has also been studied. This represents a partial duplication of the 340-bp sequence. Genomic blot hybridization experiments show that the 340-bp sequence is a representative monomeric unit of tandemly repeated arrays which account for 1.2% of the Chironomus genome, on average 300 kb per telomere. The repeat unit contains two types of subrepeats each present twice per repeat unit. Northern blot hybridization experiments show that the telomere-associated sequences are transcribed into a discrete RNA species approximately 20 kb in size. The evolution of this telomere-associated DNA is discussed.},
}
@article {pmid3994302,
year = {1985},
author = {Pays, E},
title = {Selective telomere activation and the control of antigen gene expression in trypanosomes.},
journal = {Annales de l'Institut Pasteur. Immunologie},
volume = {136C},
number = {1},
pages = {25-39},
doi = {10.1016/s0769-2625(85)80037-4},
pmid = {3994302},
mesh = {Animals ; Antigens, Protozoan/*genetics ; Antigens, Surface/*genetics ; Base Sequence ; Cloning, Molecular ; *Gene Expression Regulation ; Telophase ; Transcriptional Activation ; Trypanosoma/genetics/*immunology ; },
abstract = {African trypanosomes escape the immune defence of their mammalian host by changing their antigenic surface coat. Antigenic variation occurs through differential gene activation: only one antigen gene is transcribed at a time, among a large collection of specific sequences. This transcription always takes place in a telomere, but it seems that different telomeres can be used alternatively as the gene expression site. Since the trypanosome genome is made up of numerous chromosomes, it would appear that a highly selective process allows the activation of only one telomere at a time. This process seems linked to the differential inactivation of a peculiar telomeric DNA modification system. Two mechanisms allow antigen genes to be expressed. First, a gene copy can be inserted in the expression site by replacing the formerly expressed gene. This is due to gene conversion, whose extent can vary considerably, according to the degree of homology between the recombining partners. The second mechanism involves the activation of another telomere along with deactivation of the telomere containing the previously expressed gene. This form of activation can occur without apparent DNA rearrangement. The alternate use of these mechanisms leads to rapid changes in the antigen gene repertoire, due to gain and loss of different sequences, and to alteration of their activation rate.},
}
@article {pmid6392854,
year = {1984},
author = {Horowitz, H and Thorburn, P and Haber, JE},
title = {Rearrangements of highly polymorphic regions near telomeres of Saccharomyces cerevisiae.},
journal = {Molecular and cellular biology},
volume = {4},
number = {11},
pages = {2509-2517},
pmid = {6392854},
issn = {0270-7306},
mesh = {Base Sequence ; Chromosomes/*metabolism/ultrastructure ; DNA, Fungal/*genetics ; Diploidy ; Meiosis ; Mitosis ; Polymorphism, Genetic ; Saccharomyces cerevisiae/*genetics/metabolism/ultrastructure ; },
abstract = {We have examined the mitotic and meiotic properties of telomeric regions in various laboratory strains of yeast. Using a sequence (Y probe) derived from a cloned yeast telomere (J. Szostak and E. Blackburn, Cell 29:245-255, 1982), we found that various strains of Saccharomyces cerevisiae show extensive polymorphisms of restriction endonuclease fragment length. Some of the variation in the lengths of telomeric fragments appears to be under the control of a small number of genes. When DNA from various strains was digested with endonuclease KpnI, nearly all of the fragments homologous to the Y probe were found to be of different size. The pattern of fragments in different strains was extremely variable, with a greater degree of polymorphism than that observed for fragments containing the mobile TY1 element. Tetrad analysis of haploid meiotic segregants from diploids heterozygous for many different Y-homologous KpnI fragments revealed that most of them exhibited Mendelian (2:0) segregation. However, only a small proportion of these fragments displayed the obligate 2:2 parental segregation expected of simple allelic variants at the same chromosome end. From the segregations of these fragments, we concluded that some yeast telomeres lack a Y-homologous sequence and that the chromosome arms containing a Y-homologous sequence are different among various yeast strains. Regions near yeast telomeres frequently undergo rearrangement. Among eight tetrads from three different diploids, we have found three novel Y-homologous restriction fragments that appear to have arisen during meiosis. In all three cases, the appearance of a new fragment was accompanied by the loss of another band. In one of these cases, the rearrangement leading to a novel fragment arose in an isogenic diploid, in which both homologous chromosomes should have been identical. Among these same tetrads we also found examples of apparent mitotic gene conversions and mitotic recombination involving telemetric regions.},
}
@article {pmid6091912,
year = {1984},
author = {Myler, PJ and Allison, J and Agabian, N and Stuart, K},
title = {Antigenic variation in African trypanosomes by gene replacement or activation of alternate telomeres.},
journal = {Cell},
volume = {39},
number = {1},
pages = {203-211},
doi = {10.1016/0092-8674(84)90206-x},
pmid = {6091912},
issn = {0092-8674},
support = {AI17309/AI/NIAID NIH HHS/United States ; AI17375/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Cloning, Molecular ; DNA/metabolism ; DNA Restriction Enzymes ; *Genes ; Glycoproteins/*genetics/immunology ; Nucleic Acid Hybridization ; Peromyscus ; Rats ; Transcription, Genetic ; Trypanosoma brucei brucei/*genetics/immunology ; Variant Surface Glycoproteins, Trypanosoma ; },
abstract = {We have analyzed antigenic variants with a known lineage and show that there are several telomeres on which variant surface glycoprotein (VSG) genes can be expressed. These telomeres have similar restriction maps 5' to the barren region. In addition, the same VSG gene was expressed on different telomeres. Some antigenic switches in the lineage were accomplished by duplicative replacement of one VSG gene with another. Other switches occurred without duplication by transcriptional activation of an alternate telomeric VSG gene. We call the latter process telomeric activation and propose that these two processes can occur independently. We further propose that antigenic switching by telomeric activation is mediated by the regulatory system that controls which telomere is transcriptionally active, while the duplicative mechanism does not.},
}
@article {pmid6091911,
year = {1984},
author = {Dunn, B and Szauter, P and Pardue, ML and Szostak, JW},
title = {Transfer of yeast telomeres to linear plasmids by recombination.},
journal = {Cell},
volume = {39},
number = {1},
pages = {191-201},
doi = {10.1016/0092-8674(84)90205-8},
pmid = {6091911},
issn = {0092-8674},
mesh = {Base Sequence ; Chromosomes/physiology ; *Cloning, Molecular ; DNA Restriction Enzymes ; DNA, Recombinant/analysis ; Mitosis ; Nucleic Acid Hybridization ; *Plasmids ; Saccharomyces cerevisiae/*genetics ; },
abstract = {We have characterized two types of recombination events between linear plasmids and yeast chromosomal telomere-adjacent sequences (Y' elements). In one type of event, a linear plasmid restriction-cut within a Y' element regains the missing Y' DNA, and may also acquire additional Y' elements. This process is similar to the healing of broken chromosomes by recombination. In a second type of event, terminally added C1-3A sequences on the linear plasmid interact with C1-3A sequences located just internal to the chromosomal Y' elements, resulting in the addition of one to four Y' elements to the plasmid. Similar recombination events occurring between different chromosome ends could lead to the dispersal and amplification of telomere-adjacent sequences.},
}
@article {pmid6473102,
year = {1984},
author = {Yokoyama, R and Yao, MC},
title = {Internal micronuclear DNA regions which include sequences homologous to macronuclear telomeres are deleted during development in Tetrahymena.},
journal = {Nucleic acids research},
volume = {12},
number = {15},
pages = {6103-6116},
pmid = {6473102},
issn = {0305-1048},
support = {GM 26210/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; Cell Nucleus/ultrastructure ; *Chromosome Deletion ; Chromosome Mapping ; Chromosomes/ultrastructure ; Gene Amplification ; *Gene Expression Regulation ; *Repetitive Sequences, Nucleic Acid ; Tetrahymena/*genetics ; },
abstract = {C4A2 repeats are present in multiple clusters in both the macronucleus and micronucleus of Tetrahymena. Although the macronucleus is generated from the micronucleus after sexual conjugation, the repeats are telomeric sequences in the macronucleus but are internally located in the micronucleus (1). This study investigates the fate of the sequences adjacent to the micronuclear C4A2 repeats. Southern blot analyses of 21 C4A2-containing micronuclear clones show that extensive elimination of the adjacent sequences occurs during the formation of the macronucleus. Comparison of one C4A2-containing micronuclear clone with its derived macronuclear segment indicates that approximately 4.5 kb of DNA, which includes the C4A2 repeats and adjacent sequences on both sides is deleted from the macronucleus. The two regions adjoining the deletion are joined together to form a contiguous segment in the macronucleus. This excision of C4A2 repeats and surrounding sequences and the rejoining of the retained segments is probably the mechanism by which all or most of the other C4A2 adjacent sequences are eliminated.},
}
@article {pmid6330571,
year = {1984},
author = {Shampay, J and Szostak, JW and Blackburn, EH},
title = {DNA sequences of telomeres maintained in yeast.},
journal = {Nature},
volume = {310},
number = {5973},
pages = {154-157},
doi = {10.1038/310154a0},
pmid = {6330571},
issn = {0028-0836},
mesh = {Base Sequence ; Chromosomes/*physiology ; *Cloning, Molecular ; DNA Restriction Enzymes ; DNA, Fungal/*genetics ; Molecular Weight ; Nucleic Acid Hybridization ; Plasmids ; Saccharomyces cerevisiae/*genetics ; },
abstract = {Telomeres, the ends of eukaryotic chromosomes, have long been recognized as specialized structures. Their stability compared with broken ends of chromosomes suggested that they have properties which protect them from fusion, degradation or recombination. Furthermore, a linear DNA molecule such as that of a eukaryotic chromosome must have a structure at its ends which allows its complete replication, as no known DNA polymerase can initiate synthesis without a primer. At the ends of the relatively short, multi-copy linear DNA molecules found naturally in the nuclei of several lower eukaryotes, there are simple tandemly repeated sequences with, in the cases analysed, a specific array of single-strand breaks, on both DNA strands, in the distal portion of the block of repeats. In general, however, direct analysis of chromosomal termini presents problems because of their very low abundance in nuclei. To circumvent this problem, we have previously cloned a chromosomal telomere of the yeast Saccharomyces cerevisiae on a linear DNA vector molecule. Here we show that yeast chromosomal telomeres terminate in a DNA sequence consisting of tandem irregular repeats of the general form C1-3A. The same repeat units are added to the ends of Tetrahymena telomeres, in an apparently non-template-directed manner, during their replication on linear plasmids in yeast. Such DNA addition may have a fundamental role in telomere replication.},
}
@article {pmid6722877,
year = {1984},
author = {Blackburn, EH},
title = {Telomeres: do the ends justify the means?.},
journal = {Cell},
volume = {37},
number = {1},
pages = {7-8},
doi = {10.1016/0092-8674(84)90295-2},
pmid = {6722877},
issn = {0092-8674},
mesh = {Animals ; Base Sequence ; Chromosomes/*physiology/ultrastructure ; DNA/genetics ; Eukaryota/physiology ; Plasmids ; },
}
@article {pmid6324194,
year = {1984},
author = {Pluta, AF and Dani, GM and Spear, BB and Zakian, VA},
title = {Elaboration of telomeres in yeast: recognition and modification of termini from Oxytricha macronuclear DNA.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {81},
number = {5},
pages = {1475-1479},
pmid = {6324194},
issn = {0027-8424},
mesh = {Animals ; Base Composition ; Base Sequence ; DNA/*genetics ; DNA, Fungal/*genetics ; DNA, Ribosomal ; Eukaryota/*genetics ; Genetic Vectors ; Nucleic Acid Hybridization ; Plasmids ; Saccharomyces cerevisiae/*genetics ; Species Specificity ; },
abstract = {The termini of macronuclear DNA molecules from the protozoan Oxytricha fallax share a common sequence and structure, both of which differ markedly from those deduced for yeast telomeres. Despite these differences, terminal restriction fragments from O. fallax macronuclear DNA can support telomere formation in yeasts. Two linear plasmids (LYX-1 and LYX-2) constructed by ligating BamHI-digested total Oxytricha macronuclear DNA to a yeast vector were analyzed. One end of LYX-1 and both ends of LYX-2 are derived from the Oxytricha DNA that encodes rRNA (rDNA) whereas the other end of LYX-1 is from an Oxytricha fragment other than rDNA. After propagation in yeast, both ends of LYX-1 and LYX-2 retain the C4A4 repeat characteristic of the O. fallax terminal sequence. In addition, both ends of both plasmids acquire 300-1000 base pairs of DNA containing the sequence (C-A)n, a sequence found near the termini of yeast chromosomes. Thus, at least two different Oxytricha termini display distinctive properties in yeast cells in that linear plasmids containing them are not degraded nor are they integrated into chromosomal DNA. These Oxytricha termini may act directly as telomeres in yeast; alternatively, the Oxytricha DNA may serve as a signal that results in the elaboration of a yeast telomere on the ciliate DNA.},
}
@article {pmid6319026,
year = {1984},
author = {Van der Ploeg, LH and Liu, AY and Borst, P},
title = {Structure of the growing telomeres of Trypanosomes.},
journal = {Cell},
volume = {36},
number = {2},
pages = {459-468},
doi = {10.1016/0092-8674(84)90239-3},
pmid = {6319026},
issn = {0092-8674},
mesh = {Animals ; *Cloning, Molecular ; DNA Restriction Enzymes ; DNA, Recombinant/*analysis ; Eukaryota/*genetics ; Genes ; Nucleic Acid Hybridization ; Repetitive Sequences, Nucleic Acid ; Species Specificity ; Trypanosoma brucei brucei/*genetics ; },
abstract = {We have developed a method for the molecular cloning of DNA adjacent to chromosome ends (telomeres). A recombinant DNA clone obtained from the telomeres of the protozoan Trypanosoma brucei contains large stretches of the repeat (CCCTAA)n. This repeat is flanked by a larger subtelomeric repeat (29 bp in one case). These repeats account for the presence of large DNA stretches not cut by restriction enzymes downstream of telomeric VSG genes. All telomeres analyzed thus far (more than 30) grow by approximately 6 bp per trypanosomal division and contract by occasional large deletions. Our results suggest that growth is due mainly to addition of CCCTAA units.},
}
@article {pmid6705562,
year = {1984},
author = {Rivera, H and Solé, MT and García-Cruz, D and Martínez-Wilson, M and Cantú, JM},
title = {On telomere replication and fusion in eukaryotes: apropos of a case of 45,X/46,X,ter rea(X;X)(p22.3;p22.3).},
journal = {Cytogenetics and cell genetics},
volume = {38},
number = {1},
pages = {23-28},
doi = {10.1159/000132024},
pmid = {6705562},
issn = {0301-0171},
mesh = {Adolescent ; Amenorrhea/genetics ; Chromosome Banding ; Female ; Humans ; Karyotyping ; Phenotype ; Prohibitins ; *Sex Chromosome Aberrations ; Translocation, Genetic ; *X Chromosome ; },
abstract = {A Mexican 181/2-year-old girl with short stature, primary amenorrhea, and mild Turner stigmata was found to have a 45,X/46,X,ter rea(X;X)(p22.3;p22.3) karyotype in her lymphocytes. The rearranged chromosome was twice the size of a normal X, appeared to be attached head-to-head, had no detectable chromatin loss, only one primary constriction, constitutive heterochromatin at both the centromere and pseudocentromere regions, was mitotically stable, and always showed late replication. From the analysis of this and other X;X terminal rearrangements we draw four conclusions: (1) Terminal rearrangements may arise either by telomeric fusion (tel fus) without loss of genetic material or from a conventional telomeric translocation. (2) Telomeric fusions between homologous chromosomes (the commonest type) can be secondary to impaired telomeric replication. (3) Phenotypically, patients with an X;X terminal rearrangement show great variability which depends mainly on whether or not chromatin has been lost in the rejoining process and a 45,X clone. (4) Patients with an X;X telomeric fusion without mosaicism are likely to have an XXX phenotype, whereas turneroid features are expected in mixoploidies that include an X monosomic clone and in cases of translocations involving the short arms.},
}
@article {pmid6383193,
year = {1984},
author = {Blackburn, EH},
title = {The molecular structure of centromeres and telomeres.},
journal = {Annual review of biochemistry},
volume = {53},
number = {},
pages = {163-194},
doi = {10.1146/annurev.bi.53.070184.001115},
pmid = {6383193},
issn = {0066-4154},
mesh = {Base Sequence ; Centromere/*ultrastructure ; Chromatin/analysis ; Chromosome Deletion ; Chromosomes/*ultrastructure ; Cloning, Molecular/methods ; DNA Replication ; DNA, Fungal/analysis/genetics ; Meiosis ; Plasmids ; Spindle Apparatus/ultrastructure ; Yeasts/cytology/*genetics/ultrastructure ; },
}
@article {pmid6325299,
year = {1984},
author = {DeLange, AM and Futcher, B and Morgan, R and McFadden, G},
title = {Cloning of the vaccinia virus telomere in a yeast plasmid vector.},
journal = {Gene},
volume = {27},
number = {1},
pages = {13-21},
doi = {10.1016/0378-1119(84)90234-8},
pmid = {6325299},
issn = {0378-1119},
mesh = {Cloning, Molecular ; DNA Replication ; DNA, Viral/genetics ; *Genes, Viral ; Genetic Vectors ; Nucleic Acid Conformation ; Plasmids ; Saccharomyces cerevisiae/genetics ; Vaccinia virus/*genetics ; Virus Replication ; },
abstract = {The vaccinia virus DNA telomere, which contains a covalently closed hairpin structure, has been cloned in a yeast plasmid vector. Restriction mapping indicates that the cloned vaccinia telomere is maintained in yeast not in its native hairpin configuration but as an inverted repeat structure, within a circular plasmid, with the sequences of the viral hairpin now at the axis of symmetry of an imperfect palindrome. As such, the cloned telomere resembles the telomeric replicative intermediate observed during vaccinia virus DNA replication. Small deletions and duplications in the viral inverted repeats of different clones suggest a model in which the observed circular plasmids were generated in yeast by the replication of hybrid linear DNA molecules consisting of the linearized yeast vector flanked by two hairpin-containing vaccinia termini.},
}
@article {pmid6321326,
year = {1984},
author = {Purrello, M and Nussbaum, R and Rinaldi, A and Filippi, G and Traccis, S and Latte, B and Siniscalco, M},
title = {Old and new genetics help ordering loci at the telomere of the human X-chromosome long arm.},
journal = {Human genetics},
volume = {65},
number = {3},
pages = {295-299},
pmid = {6321326},
issn = {0340-6717},
support = {HD-16782/HD/NICHD NIH HHS/United States ; },
mesh = {Blood Group Antigens/genetics ; *Chromosome Mapping ; Color Vision Defects/genetics ; DNA Restriction Enzymes ; Female ; Genetic Linkage ; Genetic Markers ; Glucosephosphate Dehydrogenase Deficiency/genetics ; Humans ; Italy ; Male ; Pedigree ; *Polymorphism, Genetic ; X Chromosome/*ultrastructure ; },
abstract = {A Sardinian pedigree described in 1964 for having been found to segregate at the X-linked loci for the Xga antigen, G6PD deficiency, Protan and Deutan color blindness, with an instance of recombination between the last two loci, was re-examined with respect to four common X-linked DNA polymorphisms detected by molecular probes homologous to critical subregions of the human X chromosome. Two branches of this pedigree--including the one with the Protan-Deutan recombinant--were found to segregate also for the common BamHI polymorphism identified with the cDNA probe pHPT-2 or the HPRT gene (Xq26). The analysis of the chromosome haplotypes in the male offspring of the phase known penta-heterozygous mother suggests that the probable order of the relevant loci is HPRT, Deutan, G6PD, Protan, Xq telomere. Though we are fully aware of the risks of generalizing the significance of observations made on a single exceptional pedigree, we believe that this report outlines the potential of families of the type described as research tools to resolve the linear order of tightly X-linked loci and to investigate the biology of genetic recombination in humans.},
}
@article {pmid6324075,
year = {1983},
author = {De Lange, T and Kooter, JM and Michels, PA and Borst, P},
title = {Telomere conversion in trypanosomes.},
journal = {Nucleic acids research},
volume = {11},
number = {23},
pages = {8149-8165},
pmid = {6324075},
issn = {0305-1048},
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; *Cloning, Molecular ; DNA Restriction Enzymes ; DNA, Recombinant/metabolism ; Escherichia coli/genetics ; *Genes ; Glycoproteins/*genetics ; Membrane Proteins/*genetics ; Trypanosoma/*genetics ; Trypanosoma brucei brucei/*genetics ; Variant Surface Glycoproteins, Trypanosoma ; },
abstract = {Activation of the gene coding for variant surface glycoprotein (VSG) 118 in Trypanosoma brucei proceeds via a duplicative transposition to a telomeric expression site. The resulting active expression-linked extra copy (ELC) is usually flanked by DNA that lacks sites for most restriction enzymes and that is thought to interfere with the cloning of the ELC as recombinant DNA in Escherichia coli. We have circumvented this problem by cloning an aberrant 118 ELC gene, flanked at the 3'-side by at least 1 kb DNA, that contains restriction enzyme sites. Our analysis shows that this DNA and the 3'-end of the 118 ELC gene are derived from another VSG gene (1.1006) that is permanently located at a telomeric position. We propose that the 3'-end of the 1.1006 gene and (all of) its 3' flanking sequence moved to the expression site by a telomere conversion. Such a telomere conversion can also account for the appearance of an extra copy of the 1.1006 gene detected in a sub-population of our trypanosome strain.},
}
@article {pmid6324074,
year = {1983},
author = {Pays, E and Laurent, M and Delinte, K and Van Meirvenne, N and Steinert, M},
title = {Differential size variations between transcriptionally active and inactive telomeres of Trypanosoma brucei.},
journal = {Nucleic acids research},
volume = {11},
number = {23},
pages = {8137-8147},
pmid = {6324074},
issn = {0305-1048},
mesh = {Animals ; Base Sequence ; Cloning, Molecular ; DNA/*genetics ; DNA Restriction Enzymes ; Glycoproteins/*genetics ; Membrane Proteins/*genetics ; Nucleic Acid Hybridization ; Transcription, Genetic ; Trypanosoma brucei brucei/*genetics ; Variant Surface Glycoproteins, Trypanosoma ; },
abstract = {We have studied the genes coding for the variant-specific surface antigen (VSA) in a series of seven trypanosome clones derived from AnTat 1.1: 1.1 leads to 1.3 leads to 1.6 leads to 1.16 leads to 1.1C leads to 1.3B leads to 1.18 These genes are all telomeric (1-5), and their surrounding, although sometimes similar, differs in each case. The length between these antigen genes and the corresponding DNA end appears to increase at each antigenic switch, with however occasional sharp size reductions, often linked to the involvement of the telomere in gene expression. This increase is due to a constant "growth" of the telomeres, at a rate of about 28 bp per day in at least four cases and probably linked to chromosome duplication. The telomere harbouring the transcribed VSA gene is growing slightly faster (about 36 bp per day), and it is the only one whose size reduction is progressive, leading to a terminal length heterogeneity within a clone. As a result, the active VSA gene is found in a population of telomeres which, as the trypanosomes divide, becomes increasingly heterogeneous, with however a preferred discrete size class about 1.4 kb smaller. The fact that the "active" telomere is the only one in a chromatin conformation highly sensitive to DNAaseI (1-4, 6), suggests that chromatin structure influences the rate and extent of both size increase and shortening of telomeres.},
}
@article {pmid6411353,
year = {1983},
author = {Young, BS and Pession, A and Traverse, KL and French, C and Pardue, ML},
title = {Telomere regions in Drosophila share complex DNA sequences with pericentric heterochromatin.},
journal = {Cell},
volume = {34},
number = {1},
pages = {85-94},
doi = {10.1016/0092-8674(83)90138-1},
pmid = {6411353},
issn = {0092-8674},
mesh = {Animals ; Base Sequence ; Chromosomes/*analysis/metabolism ; DNA/*analysis ; DNA Replication ; Drosophila/genetics ; Drosophila melanogaster/genetics ; Heterochromatin/*analysis ; Nucleic Acid Hybridization ; Repetitive Sequences, Nucleic Acid ; Species Specificity ; },
abstract = {A 12 kb fragment of Drosophila melanogaster DNA cloned in a lambda phage, lambda T-A, is shown by in situ hybridization to contain sequences homologous to DNA at the extreme ends of each of the polytene chromosomes and to the pericentric sequences present in the beta heterochromatin. This pattern of hybridization is seen for each of the four D. melanogaster stocks that have been studied. Most of the sequence in lambda T-A shows no detectable homology to DNA within the banded chromosome arms. (The only exception is what appears to be a short mobile element inserted in lambda T-A. This portion of lambda T-A hybridizes with internal arm sites that vary from stock to stock). Analysis of restriction fragments of genomic DNA indicates that the sequences in lambda T-A are homologous to complex sets of repeated sequences that differ from stock to stock in D. melanogaster. Some, but not all, of the members of these sets are underreplicated during polytenization in D. melanogaster. The sequences in lambda T-A are also homologous to complex sets of repeated sequences in the genomes of other Drosophila species belonging to the melanogaster species group. Pericentric and telomeric localization is conserved in these related species, although analysis of DNA fragments shows marked changes in sequence organization on a finer scale. The constancy of the localization of lambda T-A-homologous sequences to telomeric and pericentric regions suggests that these sequences serve a function in those regions.},
}
@article {pmid6345000,
year = {1983},
author = {Chan, CS and Tye, BK},
title = {Organization of DNA sequences and replication origins at yeast telomeres.},
journal = {Cell},
volume = {33},
number = {2},
pages = {563-573},
doi = {10.1016/0092-8674(83)90437-3},
pmid = {6345000},
issn = {0092-8674},
support = {AI14980/AI/NIAID NIH HHS/United States ; GM26941/GM/NIGMS NIH HHS/United States ; },
mesh = {Base Sequence ; Chromosomes/analysis ; DNA/*analysis ; *DNA Replication ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*genetics ; Species Specificity ; },
abstract = {We have shown that the DNA sequences adjacent to the telomeres of Saccharomyces cerevisiae chromosomes are highly conserved and contain a high density of replication origins. The salient features of these telomeres can be summarized as follows. There are three moderately repetitive elements present at the telomeres: the 131 sequence (1 to 1.5 kb), the highly conserved Y sequence (5.2 kb), and the less conserved X sequence (0.3 to 3.75 kb). There is a high density of replication origins spaced about 6.7 kb apart at the telomeres. These replication origins are part of the X or the Y sequences. Some of the 131-Y repetitive units are tandemly arranged. The terminal sequence T (about 0.33 to 0.6 kb) is different from the 131, X, or Y sequences and is heterogeneous in length. The order of these sequences from the telomeric end towards the centromere is T-(Y-131)n-X-, where n ranges from 1 to no more than 4. Although these telomeric sequences are conserved among S. cerevisiae strains, they show striking divergence in certain closely related yeast species.},
}
@article {pmid6574869,
year = {1983},
author = {Baroudy, BM and Venkatesan, S and Moss, B},
title = {Structure and replication of vaccinia virus telomeres.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {47 Pt 2},
number = {},
pages = {723-729},
doi = {10.1101/sqb.1983.047.01.083},
pmid = {6574869},
issn = {0091-7451},
mesh = {Base Composition ; Base Sequence ; *DNA Replication ; DNA, Viral/*genetics ; *Genes, Viral ; Nucleic Acid Conformation ; Repetitive Sequences, Nucleic Acid ; Vaccinia virus/*genetics ; Virus Replication ; },
}
@article {pmid6305577,
year = {1983},
author = {Szostak, JW},
title = {Replication and resolution of telomeres in yeast.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {47 Pt 2},
number = {},
pages = {1187-1194},
doi = {10.1101/sqb.1983.047.01.134},
pmid = {6305577},
issn = {0091-7451},
support = {GM-27862/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Base Sequence ; DNA/genetics ; *DNA Replication ; DNA Restriction Enzymes ; DNA, Fungal/*genetics ; DNA, Ribosomal ; Nucleic Acid Hybridization ; Plasmids ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*genetics ; Tetrahymena pyriformis/genetics ; Transformation, Genetic ; },
}
@article {pmid6194945,
year = {1983},
author = {Cowell, JK and Miller, OJ},
title = {Occurrence and evolution of homogeneously staining regions may be due to breakage-fusion-bridge cycles following telomere loss.},
journal = {Chromosoma},
volume = {88},
number = {3},
pages = {216-221},
pmid = {6194945},
issn = {0009-5915},
support = {R01-CA 27655/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle ; Cell Line ; Chromosome Banding ; Chromosomes/*physiology ; Genes ; Genetic Variation ; Liver Neoplasms, Experimental/*physiopathology ; RNA, Ribosomal/genetics ; Rats ; Staining and Labeling ; },
abstract = {Chromosomes with homogeneously staining regions (HSR) were analysed in a subclone of the H4 rat hepatoma cell line, where they represent amplification of the ribosomal RNA (rRNA) genes. Detailed G-band analysis of the subclone revealed that an HSR on the short arm of chromosome 3 became unstable and changed its position within the chromosome. The evolution of this marker chromosome was associated with the terminal deletion of the normal long arm of the HSR-bearing chromosome 3 and may have involved ring formation as a result of fusion between the HSR on the short arm and the broken end of the long arm. Evidence was obtained for breakage at different sites within the ring, producing chromosomes with HSRs located terminally on either the long arms or both arms. The terminally located HSR underwent elongation in some cells presumably as a result of a breakage-fusion-bridge cycle characteristic of instability due to telomeric loss. It is suggested that terminally located HSRs may generally occur this way.},
}
@article {pmid6286143,
year = {1982},
author = {Szostak, JW and Blackburn, EH},
title = {Cloning yeast telomeres on linear plasmid vectors.},
journal = {Cell},
volume = {29},
number = {1},
pages = {245-255},
doi = {10.1016/0092-8674(82)90109-x},
pmid = {6286143},
issn = {0092-8674},
mesh = {Animals ; Base Sequence ; Chromosomes/*metabolism ; *Cloning, Molecular ; *DNA Replication ; DNA Restriction Enzymes ; DNA, Fungal ; Genetic Vectors ; Nucleic Acid Conformation ; Nucleic Acid Hybridization ; *Plasmids ; Repetitive Sequences, Nucleic Acid ; Saccharomyces cerevisiae/*genetics ; Tetrahymena ; },
abstract = {We have constructed a linear yeast plasmid by joining fragments from the termini of Tetrahymena ribosomal DNA to a yeast vector. Structural features of the terminus region of the Tetrahymena rDNA plasmid maintained in the yeast linear plasmid include a set of specifically placed single-strand interruptions within the cluster of hexanucleotide (C4A2) repeat units. An artificially constructed hairpin terminus was unable to stabilize a linear plasmid in yeast. The fact that yeast can recognize and use DNA ends from the distantly related organism Tetrahymena suggests that the structural features required for telomere replication and resolution have been highly conserved in evolution. The linear plasmid was used as a vector to clone chromosomal telomeres from yeast. One Tetrahymena end was removed by restriction digestion, and yeast fragments that could function as an end on a linear plasmid were selected. Restriction mapping and hybridization analysis demonstrated that these fragments were yeast telomeres, and suggested that all yeast chromosomes might have a common telomere sequence. Yeast telomeres appear to be similar in structure to the rDNA of Tetrahymena, in which specific nicks or gaps are present within a simple repeated sequence near the terminus of the DNA.},
}
@article {pmid7390482,
year = {1980},
author = {Kirsch-Volders, M and Hens, L and Susanne, C},
title = {Telomere and centromere association tendencies in the human male metaphase complement.},
journal = {Human genetics},
volume = {54},
number = {1},
pages = {69-77},
pmid = {7390482},
issn = {0340-6717},
mesh = {Adult ; *Cell Cycle ; Cells, Cultured ; Centromere/*ultrastructure ; Chromosomes/*ultrastructure ; Chromosomes, Human/*ultrastructure ; Heterochromatin/ultrastructure ; Humans ; Lymphocytes/ultrastructure ; Male ; Mathematics ; *Metaphase ; Probability ; },
abstract = {"Generalized distances" between centromeres and between telomeres were statistically analyzed (chi 2 tests) in 100 trypsin-banded metaphase figures derived from normal males. Analysis of association tendencies on the first column of obtained c-c, p-p, q-p, and p-q histograms showed significant heterochromatin attraction not only between nonacrocentrics and acrocentrics but also between two nonacrocentric chromosome pairs (1 and 16). However since not all c-heterochromatin-rich chromosomes were involved in associations (pair 5), and conversely, since chromosomes without an important centromeric heterochromatin block were involved in associations (pairs 8 and 11), it is probable that centromeric heterochromatin is not the only factor responsible for chromosome association. Moreover associations occur not only at the centromeres; in our circle analysis of the binding capacity of the telomeres or centromere of one chromosome pair with the telomeres or the centromeres of all other chromosome pairs, we also found preferential associations for T(4,13), T(9,15), T(11,15), T(13,19), T(15,19), T(17,18), T(17,22), and T(19,20). We therefore suggest that heterochromatin is not the only reason for chromosome association and that telomeres may also play an important part in this process.},
}
@article {pmid4116850,
year = {1972},
author = {Faed, M and Robertson, J},
title = {Integrity of the telomere.},
journal = {Lancet (London, England)},
volume = {2},
number = {7784},
pages = {973-974},
doi = {10.1016/s0140-6736(72)92500-7},
pmid = {4116850},
issn = {0140-6736},
mesh = {*Chromosome Aberrations ; Chromosomes, Human, 13-15 ; Chromosomes, Human, 6-12 and X ; Female ; Humans ; Karyotyping ; },
}
@article {pmid5709395,
year = {1968},
author = {Berendes, HD and Meyer, GF},
title = {A specific chromosome element, the telomere of Drosophila polytene chromosomes.},
journal = {Chromosoma},
volume = {25},
number = {2},
pages = {184-197},
pmid = {5709395},
issn = {0009-5915},
mesh = {Animals ; Autoradiography ; *Chromosomes/metabolism ; DNA Replication ; Drosophila ; Microscopy, Electron ; Salivary Glands/cytology ; Thymidine/metabolism ; Tritium ; },
}
@article {pmid1303279,
year = {1992},
author = {Farr, CJ and Stevanovic, M and Thomson, EJ and Goodfellow, PN and Cooke, HJ},
title = {Telomere-associated chromosome fragmentation: applications in genome manipulation and analysis.},
journal = {Nature genetics},
volume = {2},
number = {4},
pages = {275-282},
doi = {10.1038/ng1292-275},
pmid = {1303279},
issn = {1061-4036},
mesh = {Animals ; Base Sequence ; Blotting, Southern ; Chromosome Deletion ; Chromosome Mapping/*methods ; Cloning, Molecular ; DNA/genetics ; DNA Probes ; Genetic Techniques ; Humans ; Hybrid Cells/ultrastructure ; Molecular Sequence Data ; Polymerase Chain Reaction ; Sequence Tagged Sites ; Telomere/*ultrastructure ; X Chromosome/*ultrastructure ; },
abstract = {Telomere-associated chromosome fragmentation (TACF) is a new approach for chromosome mapping based on the non-targeted introduction of cloned telomeres into mammalian cells. TACF has been used to generate a panel of somatic cell hybrids with nested terminal deletions of the long arm of the human X chromosome, extending from Xq26 to the centromere. This panel has been characterized using a series of X chromosome loci. Recovery of the end clones by plasmid rescue produces a telomeric marker for each cell line and partial sequencing will allow the generation of sequence tagged sites (STSs). TACF provides a powerful and widely applicable method for genome analysis, a general way of manipulating mammalian chromosomes and a first step towards constructing artificial mammalian chromosomes.},
}
@article {pmid1420196,
year = {1992},
author = {Price, CM and Skopp, R and Krueger, J and Williams, D},
title = {DNA recognition and binding by the Euplotes telomere protein.},
journal = {Biochemistry},
volume = {31},
number = {44},
pages = {10835-10843},
doi = {10.1021/bi00159a026},
pmid = {1420196},
issn = {0006-2960},
support = {GM41803/GM/NIGMS NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Binding Sites ; DNA, Protozoan/chemistry/*metabolism ; DNA-Binding Proteins/*metabolism ; Euplotes/*chemistry ; Molecular Sequence Data ; Mutagenesis ; Oligonucleotides/chemistry/metabolism ; Oxytricha/chemistry ; Peptide Fragments/chemistry/metabolism ; Protozoan Proteins/*metabolism ; Trypsin/metabolism ; },
abstract = {The 51-kDa telomere protein from Euplotes crassus binds to the extreme terminus of macronuclear telomeres, generating a very salt-stable telomeric DNA-protein complex. The protein recognizes both the sequence and the structure of the telomeric DNA. To explore how the telomere protein recognizes and binds telomeric DNA, we have examined the DNA-binding specificity of the purified protein using oligonucleotides that mimic natural and mutant versions of Euplotes telomeres. The protein binds very specifically to the 3' terminus of single-stranded oligonucleotides with the sequence (T4G4) > or = 3 T4G2; even slight modifications to this sequence reduce binding dramatically. The protein does not bind oligonucleotides corresponding to the complementary C4A4 strand of the telomere or to double-stranded C4A4.T4G4-containing sequences. Digestion of the telomere protein with trypsin generates an N-terminal protease-resistant fragment of approximately 35 kDa. This 35-kDa peptide appears to comprise the DNA-binding domain of the telomere protein as it retains most of the DNA-binding characteristics of the native 51-kDa protein. For example, the 35-kDa peptide remains bound to telomeric DNA in 2 M KCl. Additionally, the peptide binds well to single-stranded oligonucleotides that have the same sequence as the T4G4 strand of native telomeres but binds very poorly to mutant telomeric DNA sequences and double-stranded telomeric DNA. Removal of the C-terminal 15 kDa from the telomere protein does diminish the ability of the protein to bind only to the terminus of a telomeric DNA molecule.},
}
@article {pmid1438199,
year = {1992},
author = {Allsopp, RC and Vaziri, H and Patterson, C and Goldstein, S and Younglai, EV and Futcher, AB and Greider, CW and Harley, CB},
title = {Telomere length predicts replicative capacity of human fibroblasts.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {89},
number = {21},
pages = {10114-10118},
pmid = {1438199},
issn = {0027-8424},
support = {AG-08708/AG/NIA NIH HHS/United States ; AG-09383/AG/NIA NIH HHS/United States ; },
mesh = {Base Sequence ; *Cell Division ; Cells, Cultured ; DNA/genetics/isolation &amp; purification ; Fibroblasts/cytology/physiology ; Humans ; Male ; Progeria/pathology/physiopathology ; Reference Values ; Repetitive Sequences, Nucleic Acid ; Skin/cytology ; Skin Aging/*physiology ; Skin Physiological Phenomena ; Spermatozoa/*physiology ; Telomere/*physiology/ultrastructure ; },
abstract = {When human fibroblasts from different donors are grown in vitro, only a small fraction of the variation in their finite replicative capacity is explained by the chronological age of the donor. Because we had previously shown that telomeres, the terminal guanine-rich sequences of chromosomes, shorten throughout the life-span of cultured cells, we wished to determine whether variation in initial telomere length would account for the unexplained variation in replicative capacity. Analysis of cells from 31 donors (aged 0-93 yr) indicated relatively weak correlations between proliferative ability and donor age (m = -0.2 doubling per yr; r = -0.42; P = 0.02) and between telomeric DNA and donor age (m = -15 base pairs per yr; r = -0.43; P = 0.02). However, there was a striking correlation, valid over the entire age range of the donors, between replicative capacity and initial telomere length (m = 10 doublings per kilobase pair; r = 0.76; P = 0.004), indicating that cell strains with shorter telomeres underwent significantly fewer doublings than those with longer telomeres. These observations suggest that telomere length is a biomarker of somatic cell aging in humans and are consistent with a causal role for telomere loss in this process. We also found that fibroblasts from Hutchinson-Gilford progeria donors had short telomeres, consistent with their reduced division potential in vitro. In contrast, telomeres from sperm DNA did not decrease with age of the donor, suggesting that a mechanism for maintaining telomere length, such as telomerase expression, may be active in germ-line tissue.},
}
@article {pmid1406688,
year = {1992},
author = {Kyrion, G and Boakye, KA and Lustig, AJ},
title = {C-terminal truncation of RAP1 results in the deregulation of telomere size, stability, and function in Saccharomyces cerevisiae.},
journal = {Molecular and cellular biology},
volume = {12},
number = {11},
pages = {5159-5173},
pmid = {1406688},
issn = {0270-7306},
mesh = {Alleles ; Amino Acid Sequence ; Base Sequence ; Chromosome Deletion ; DNA, Fungal ; GTP-Binding Proteins/*genetics/metabolism ; Molecular Sequence Data ; Mutation ; Nondisjunction, Genetic ; Saccharomyces cerevisiae/*genetics/metabolism ; *Telomere ; rap GTP-Binding Proteins ; },
abstract = {The Saccharomyces cerevisiae DNA-binding protein RAP1 is capable of binding in vitro to sequences from a wide variety of genomic loci, including upstream activating sequence elements, the HML and HMR silencer regions, and the poly(G1-3T) tracts of telomeres. Recent biochemical and genetic studies have suggested that RAP1 physically and functionally interacts with the yeast telomere. To further investigate the role of RAP1 at the telomere, we have identified and characterized three intragenic suppressors of a temperature-sensitive allele of RAP1, rap1-5. These telomere deficiency (rap1t) alleles confer several novel phenotypes. First, telomere tract size elongates to up to 4 kb greater than sizes of wild-type or rap1-5 telomeres. Second, telomeres are highly unstable and are subject to rapid, but reversible, deletion of part or all of the increase in telomeric tract length. Telomeric deletion does not require the RAD52 or RAD1 gene product. Third, chromosome loss and nondisjunction rates are elevated 15- to 30-fold above wild-type levels. Sequencing analysis has shown that each rap1t allele contains a nonsense mutation within a discrete region between amino acids 663 and 684. Mobility shift and Western immunoblot analyses indicate that each allele produces a truncated RAP1 protein, lacking the C-terminal 144 to 165 amino acids but capable of efficient DNA binding. These data suggest that RAP1 is a central regulator of both telomere and chromosome stability and define a C-terminal domain that, while dispensable for viability, is required for these telomeric functions.},
}
@article {pmid1424988,
year = {1992},
author = {Cohn, M and Edström, JE},
title = {Chromosome ends in Chironomus pallidivittatus contain different subfamilies of telomere-associated repeats.},
journal = {Chromosoma},
volume = {101},
number = {10},
pages = {634-640},
pmid = {1424988},
issn = {0009-5915},
mesh = {Animals ; Chironomidae/*genetics/ultrastructure ; Chromosomes/ultrastructure ; DNA/genetics ; Larva/genetics/ultrastructure ; Multigene Family ; Nucleic Acid Hybridization ; *Repetitive Sequences, Nucleic Acid ; Telomere/ultrastructure ; },
abstract = {Tandemly repeated 340 bp sequences, TA repeats, are present in seven of the eight pairs of chromosome ends in Chironomus pallidivittatus, being absent from the telocentric left end of chromosome four. We have previously shown that the family of TA repeats consists of four main subfamilies. One subfamily is composed of a master unit and the other three contain derived units, each of which has a small region where the master sequence is highly mutated. Here we find that there are considerable variations in numbers of TA repeats between animals and for the same telomere in different animals. We also show that the seven telomere pairs containing TA repeats differ with regard to the content of derived subfamilies. The master unit is probably present in all seven pairs. Two of the derived units are exclusively present in two telomere pairs. The third derived unit shows a more irregular distribution. Some of the telomeres have highly variable contents of such units among animals. Subfamilies thus have different behaviour as reflected in their stable and variable patterns of distribution between individual telomeres.},
}
@article {pmid1359394,
year = {1992},
author = {Kilian, A and Kleinhofs, A},
title = {Cloning and mapping of telomere-associated sequences from Hordeum vulgare L.},
journal = {Molecular &amp; general genetics : MGG},
volume = {235},
number = {1},
pages = {153-156},
pmid = {1359394},
issn = {0026-8925},
mesh = {Base Sequence ; Chromosome Mapping ; Cloning, Molecular ; DNA, Single-Stranded ; Hordeum/*genetics ; Molecular Sequence Data ; Polymerase Chain Reaction ; Polymorphism, Restriction Fragment Length ; *Telomere ; },
abstract = {We present a novel approach to the efficient cloning of telomere-associated sequences and demonstrate its application to the cloning and mapping of these sequences from barley. The method is a modification of the Vectorette PCR technique and allows specific amplification and cloning of subtelomeric sequences. Telomere-associated sequences isolated from barley include hypervariable, repetitive sequences. Polymorphisms detected by subtelomeric markers behaved as Mendelian factors and were mapped to the most distal positions of barley chromosomes 1, 2, and 4.},
}
@article {pmid1388310,
year = {1992},
author = {Cotmore, SF and Nuesch, JP and Tattersall, P},
title = {In vitro excision and replication of 5' telomeres of minute virus of mice DNA from cloned palindromic concatemer junctions.},
journal = {Virology},
volume = {190},
number = {1},
pages = {365-377},
doi = {10.1016/0042-6822(92)91223-h},
pmid = {1388310},
issn = {0042-6822},
support = {AI-26109/AI/NIAID NIH HHS/United States ; CA-16038/CA/NCI NIH HHS/United States ; },
mesh = {Blotting, Southern ; Capsid/*genetics ; Cloning, Molecular ; *DNA Replication ; DNA, Viral ; Electrophoresis, Agar Gel ; Electrophoresis, Gel, Two-Dimensional ; HeLa Cells ; Humans ; Minute Virus of Mice/*genetics ; Plasmids ; *Repetitive Sequences, Nucleic Acid ; *Telomere ; Viral Core Proteins/*genetics ; Viral Nonstructural Proteins ; },
abstract = {HeLa cell extracts containing wild-type copies of the minute virus of mice NS-1 polypeptide produced from a recombinant vaccinia virus vector could support the excision and replication of viral 5' telomeres from cloned concatemer junction fragments. Resolution did not occur if wild-type NS-1 was omitted from the extract or if the substrate DNA contained palindromic sequences without specific viral resolution sites. In the presence of NS-1, [32P]dGTP incorporation into all templates was slightly increased, but if the template contained specific viral resolution sites DNA synthesis was greatly enhanced, and took two distinct forms: (i) generation of a limited number of high-molecular-weight molecules, probably due to a form of rolling-circle replication, and (ii) synthesis of new DNA at the viral telomeres. Resolution of the junction fragment generated two newly synthesized viral telomeres, each of which was covalently associated with NS-1 and contained a duplex copy of the complex palindrome located around the axis of symmetry of the concatemer junction. Cloned junction fragments of 296 bp or more could be resolved efficiently in vitro, and since NS-1 molecules were left covalently attached to the newly resolved termini, the latter could be partially purified by immuno-precipitation with anti-NS-1 serum. Restriction analysis and further fractionation of the precipitated DNA showed that the in vitro resolution sites were in the predicted positions on either side of the axis of symmetry, and that de novo DNA synthesis was associated predominantly with one of the two daughter strands. Telomeres were generated from both arms of the substrate with equal efficiency, and contained the characteristic "flip" and "flop" sequence inversions observed in vivo. Since a high proportion of termini were associated with adjacent viral sequences that retained the bacterial methylation pattern, in vitro resolution was not dependent upon prior DNA replication proceeding through the entire palindromic insert.},
}
@article {pmid1381462,
year = {1992},
author = {Kuwano, A and Matsuura, S and Kajii, T},
title = {Telomere association of human chromosomes induced by aphidicolin.},
journal = {Mutation research},
volume = {269},
number = {1},
pages = {107-111},
doi = {10.1016/0027-5107(92)90165-x},
pmid = {1381462},
issn = {0027-5107},
mesh = {Adult ; Aphidicolin/*pharmacology ; Cells, Cultured ; Chromosomes, Human/*drug effects ; Female ; Floxuridine/pharmacology ; Humans ; Lymphocytes/drug effects/ultrastructure ; Telomere/*drug effects ; },
abstract = {Telomere associations were studied in metaphase chromosomes from 96-h cultures of peripheral blood lymphocytes of two healthy women, treated with 0.4 microM aphidicolin for the last 72 h. Telomere associations were encountered in 2.9% and 3.2% of the metaphases screened, whereas no such associations were encountered in 5-fluorodeoxyuridine-treated cultures. The chromosome arms involved in telomere associations were nonrandom: 1q, 2q, 3q, 6p and 16q were more frequently involved in the associations (P less than 0.01). Of the 51 combinations of telomere associations encountered, those occurring nonrandomly were 1q/2q, 2q/2q, 4q/4q, 6q/6q and 6p/6p associations.},
}
@article {pmid1441745,
year = {1992},
author = {Michels, CA and Read, E and Nat, K and Charron, MJ},
title = {The telomere-associated MAL3 locus of Saccharomyces is a tandem array of repeated genes.},
journal = {Yeast (Chichester, England)},
volume = {8},
number = {8},
pages = {655-665},
doi = {10.1002/yea.320080809},
pmid = {1441745},
issn = {0749-503X},
support = {GM28216/GM/NIGMS NIH HHS/United States ; },
mesh = {Alleles ; Genes, Fungal/physiology ; *Multigene Family ; *Repetitive Sequences, Nucleic Acid ; Saccharomyces/*genetics ; Telomere/*chemistry/physiology ; },
abstract = {Saccharomyces strains capable of fermenting maltose contain any one of five telomere-associated MAL loci. Each MAL locus is a complex of three genes encoding the three functions required to ferment maltose: maltose permease (GENE 1), maltase (GENE 2) and the MAL trans-activator (GENE 3). All five loci have been cloned and all are highly sequence homologous over at least a 9.0 kbp region containing these GENEs (Charron et al., Genetics 122, 307-331, 1989). Our initial studies of strains carrying the MAL3 locus indicated the presence of linked, repeated MAL-homologous sequences (Michels and Needleman, Mol. Gen. Genet. 191, 225-230, 1983). Here we report our analysis of the centromere-proximal MAL3-linked sequences and show that the complete MAL3 locus spans approximately 40 kbp and consists of tandemly arrayed, partial repeats of the three GENE sequences described above. In addition, the structure of the MAL3 locus is compared to that of three partially functional alleles of MAL3. These alleles were shown to contain only MAL31 and MAL32 and their structure suggests that they resulted from MAL3 deletions removing the sequences centromere-proximal to MAL31. The amplification and rearrangement of the telomere-linked MAL3 sequences are discussed in the context of studies on other telemere-associated sequences from yeast and other species.},
}
@article {pmid1356536,
year = {1992},
author = {Burr, B and Burr, FA and Matz, EC and Romero-Severson, J},
title = {Pinning down loose ends: mapping telomeres and factors affecting their length.},
journal = {The Plant cell},
volume = {4},
number = {8},
pages = {953-960},
pmid = {1356536},
issn = {1040-4651},
mesh = {Base Sequence ; Chromosome Mapping ; Cloning, Molecular ; DNA ; DNA Probes ; Molecular Sequence Data ; Polymorphism, Restriction Fragment Length ; Repetitive Sequences, Nucleic Acid ; *Telomere/chemistry ; Zea mays ; },
abstract = {A degenerately repeated sequence, proximal to the telomere heptanucleotide repeat in maize, contains restriction enzyme sites that permit the separation of telomeres from the rest of the chromosomes. Probing with a telomere-specific oligonucleotide revealed genotype-dependent telomere lengths that vary more than 25-fold in maize among the 22 inbreds that have been surveyed. These lengths were found to segregate reproducibly in a recombinant inbred family where 50% of the variation can be accounted for by three loci. The dynamic control over telomere length in maize appears to act rapidly to achieve new genotypically determined telomere lengths in the F1. Clones of telomere proximal sequences were used to map restriction fragment length loci at the distal ends of eight of 20 chromosome arms.},
}
@article {pmid1452909,
year = {1992},
author = {Olovnikov, AM},
title = {[Aging is a result of a shortening of the "differotene" in the telomere due to end under-replication and under-repair of DNA].},
journal = {Izvestiia Akademii nauk SSSR. Seriia biologicheskaia},
volume = {},
number = {4},
pages = {641-643},
pmid = {1452909},
issn = {0002-3329},
mesh = {Aging/*genetics ; Animals ; Cell Differentiation/genetics ; Cellular Senescence/genetics ; DNA/*genetics ; DNA Repair/*genetics ; DNA Replication/*genetics ; Genes, Regulator/*genetics ; Humans ; Telomere/*physiology ; },
}
@article {pmid1351682,
year = {1992},
author = {Smith, KA and Stark, MB and Gorman, PA and Stark, GR},
title = {Fusions near telomeres occur very early in the amplification of CAD genes in Syrian hamster cells.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {89},
number = {12},
pages = {5427-5431},
pmid = {1351682},
issn = {0027-8424},
mesh = {Animals ; Antimetabolites, Antineoplastic/pharmacology ; Aspartate Carbamoyltransferase/*genetics ; Aspartic Acid/*analogs &amp; derivatives/pharmacology ; Carbamoyl-Phosphate Synthase (Ammonia)/*genetics ; Cell Line ; Chromosome Banding ; Chromosome Mapping ; Cricetinae ; Dihydroorotase/*genetics ; *Gene Amplification/drug effects ; Membrane Fusion ; Mesocricetus ; Models, Genetic ; Phosphonoacetic Acid/*analogs &amp; derivatives/pharmacology ; Telomere/drug effects/*physiology ; },
abstract = {Previous analyses by fluorescence in situ hybridization of structures present 20-30 cell generations after the primary events of mammalian gene amplification have shown that tens of megabases of DNA separate each copy of the selected gene in chromosomal arrays that contain up to 15 copies. Since these structures are very unstable, it is necessary to study amplified DNA as soon as possible after it has been formed to relate the structures observed to the primary mechanisms that generated them. Previously, new amplifications of the CAD gene were analyzed in colonies of 10(5) N-(phosphonoacetyl)-L-aspartate-resistant Syrian hamster BHK cells. CAD is on the p arm of chromosome B9 and the amplified genes were usually found in large extensions of B9p, with one copy in its normal position. We now report that dividing drug-resistant cells have been physically separated from static drug-sensitive cells, to allow the amplified structures to be observed only a few cell generations after they have been formed. The most informative results are that about one-third of the newly formed chromosomes carrying amplified CAD genes are dicentric and that about half of these carry two B9q arms. These observations reveal that recombination between the p telomeric regions of two B9 sister chromatids is an important primary event of amplification in this system. The resulting dicentric chromosomes can then enter bridge-breakage-fusion cycles that provide the means to increase the number of CAD genes per cell in successive generations by an asymmetric distribution at each cell division.},
}
@article {pmid1319572,
year = {1992},
author = {Zomerdijk, JC and Kieft, R and Borst, P},
title = {A ribosomal RNA gene promoter at the telomere of a mini-chromosome in Trypanosoma brucei.},
journal = {Nucleic acids research},
volume = {20},
number = {11},
pages = {2725-2734},
pmid = {1319572},
issn = {0305-1048},
mesh = {Animals ; Base Sequence ; Chromosomes/*ultrastructure ; Genes ; Kanamycin Kinase ; Molecular Sequence Data ; Oligodeoxyribonucleotides/chemistry ; Phosphotransferases/genetics ; *Promoter Regions, Genetic ; RNA, Ribosomal/*genetics ; Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; Telomere/*ultrastructure ; Trypanosoma brucei brucei/*genetics ; },
abstract = {The parasitic protozoan Trypanosoma brucei has some hundred mini-chromosomes of 50-150 kb, which mainly consist of telomeric repeats, sub-telomeric repeats and internal 177-bp repeats. Their primary function seems to be to expand the repertoire of non-transcribed sub-telomeric variant surface glycoprotein (VSG) genes. Here we report that two of the smaller mini-chromosomes (55 and 60 kb) contain sequences homologous to the ribosomal RNA gene promoter region. We have targeted by homologous recombination the neomycin phosphotransferase (neo(r)) gene behind the promoter on the 55 kb chromosome and show that this promoter mediates the efficient synthesis of properly trans-spliced and polyadenylated neo mRNA. The resulting high resistance to G418 (a neo analogue) is stable in the absence of drug showing that mitotic segregation of this mini-chromosome is precise. Downstream of the transcription start the wild-type version of the ribosomal promoter is flanked by telomeric repeats. The absence of the sub-telomeric repeats found in other T.brucei chromosome ends suggests that the rDNA-telomeric junction has been formed by de novo addition of telomeric repeats to a broken chromosome end (healing). Our results provide a plausible explanation for the alpha-amanitin-resistant transcription of telomeric repeats in T.brucei reported by Rudenko and Van der Ploeg and they show that trypanosomes can efficiently use RNA polymerase I for the expression of sub-telomeric genes, supporting the notion that the alpha-amanitin-resistant transcription of sub-telomeric VSG genes may also be catalyzed by this enzyme.},
}
@article {pmid1414128,
year = {1992},
author = {Wang, GS and Pan, WJ and Zhai, ZH},
title = {[Association of chromosomal telomere DNA with nuclear matrix in HeLa cells].},
journal = {Shi yan sheng wu xue bao},
volume = {25},
number = {2},
pages = {185-189},
pmid = {1414128},
issn = {0001-5334},
mesh = {Base Sequence ; DNA Probes ; DNA, Neoplasm/*genetics ; HeLa Cells ; Humans ; Molecular Sequence Data ; Nuclear Matrix ; *Telomere ; },
abstract = {Nuclear matrix from HeLa cells was gently extracted with a high salt solution and treated with DNase I. DNA that remained associated with the nuclear matrix (N. M. DNA) and DNA fragments released into the supernatant (SN.DNA) were isolated respectively and dot hybridized to human telomere sequence (AGGGTT/TCCCAA)40 probe. As the time of DNase I treatment was extended, the amount of N. M. DNA decreased while the concentration of telomere sequence in N.M. DNA proportionally increased. These preliminary results suggest that the telomere sequence is tightly bound to nuclear matrix in HeLa cells.},
}
@article {pmid1301133,
year = {1992},
author = {Kipling, D and Cooke, HJ},
title = {Beginning or end? Telomere structure, genetics and biology.},
journal = {Human molecular genetics},
volume = {1},
number = {1},
pages = {3-6},
doi = {10.1093/hmg/1.1.3-a},
pmid = {1301133},
issn = {0964-6906},
mesh = {Animals ; Base Sequence ; Cell Cycle ; Chromosome Aberrations ; DNA Replication ; Genome, Human ; Humans ; Mammals ; Molecular Sequence Data ; Repetitive Sequences, Nucleic Acid ; Telomere/*physiology/ultrastructure ; Transcription, Genetic ; X Chromosome ; },
abstract = {The word telomere derives from the Greek word telos meaning 'end', roughly translating as 'the thing at the end' when the end is that of a chromosome. Telomeres belie their apparent simplicity of structure by being involved in a wide range of diverse biological phenomena. Much of our understanding of telomere behaviour comes from studies in lower eukaryotes such as ciliates and yeast, the subject of many recent reviews. Here we concentrate on the mammalian telomere, recent progress in its study, and how recent evidence for an involvement of telomeres in the regulation of gene expression and DNA replication in yeast points to new aspects of mammalian telomere function yet to be explored.},
}
@article {pmid1311256,
year = {1992},
author = {Katinka, MD and Bourgain, FM},
title = {Interstitial telomeres are hotspots for illegitimate recombination with DNA molecules injected into the macronucleus of Paramecium primaurelia.},
journal = {The EMBO journal},
volume = {11},
number = {2},
pages = {725-732},
pmid = {1311256},
issn = {0261-4189},
mesh = {Animals ; Base Sequence ; Cell Nucleus/*physiology ; DNA/*genetics ; *DNA Transposable Elements ; DNA, Fungal/administration &amp; dosage/*genetics ; Histones/genetics ; Microinjections ; Molecular Sequence Data ; Oligodeoxyribonucleotides ; Paramecium/genetics/*physiology ; Probability ; *Recombination, Genetic ; Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; Saccharomyces cerevisiae/*genetics ; Telomere/*physiology ; },
abstract = {DNA molecules injected into the macronucleus of Paramecium primaurelia replicate either as free linear telomerized or chromosome integrated molecules. In the present study we show that when a 1.77 kb BamHI DNA fragment harbouring the his3 gene of Saccharomyces cerevisiae was microinjected into the macronucleus, a fraction of the molecules are integrated into the chromosome via an illegitimate recombination process. The injected molecules were mostly inserted at their extremities at multiple points in the genome by replacing the Paramecium sequences. However, insertion sites were not totally at random. Roughly 30% of the molecules were integrated next to or in telomeric repeats. These telomeric repeats were not at the extremities of chromosomes but occupy an internal or interstitial position. We argue that such sites are hotspots for integration as the probability of random insertion near or in an interstitial telomeric site, of which there are 25-60 in a macronucleus is between 5 x 10(-4) and 3 x 10(-5).},
}
@article {pmid1348122,
year = {1992},
author = {Royle, NJ and Hill, MC and Jeffreys, AJ},
title = {Isolation of telomere junction fragments by anchored polymerase chain reaction.},
journal = {Proceedings. Biological sciences},
volume = {247},
number = {1318},
pages = {57-67},
doi = {10.1098/rspb.1992.0009},
pmid = {1348122},
issn = {0962-8452},
mesh = {Base Sequence ; Blotting, Southern ; Cloning, Molecular ; DNA/genetics/*isolation &amp; purification ; DNA, Satellite/genetics ; Gene Library ; Humans ; Molecular Sequence Data ; Oligodeoxyribonucleotides ; Plasmids ; Polymerase Chain Reaction/methods ; Repetitive Sequences, Nucleic Acid ; Restriction Mapping ; Sequence Homology, Nucleic Acid ; Telomere/*physiology/ultrastructure ; },
abstract = {We describe a simple polymerase chain reaction (PGR)-based method for isolating short stretches of nontelomeric DNA adjacent to arrays of telomere repeat units, in principle applicable to any species for which the telomere repeat sequence is known. Application of this approach to human DNA resulted in the isolation of many candidate telomere junction clones, at least some of which were shown to be derived from telomere-adjacent regions. Most of the isolated clones detect multiple sequences in the human genome which represent one or a few sequence families present at the ends of most or all autosomes and variably truncated before the start of the telomere repeat array. Substantial sequence divergence between different members of these sequence families suggests a low rate of sequence homogenization by telomere exchange processes. The pseudoautosomal telomere junction has also been isolated and contains a shortened version of a recently described family of short interspersed repetitive elements (SINEs), only 14 base pairs (b.p.) from the start of the telomere.},
}
@article {pmid1456111,
year = {1992},
author = {Biessmann, H and Mason, JM},
title = {Genetics and molecular biology of telomeres.},
journal = {Advances in genetics},
volume = {30},
number = {},
pages = {185-249},
doi = {10.1016/s0065-2660(08)60321-1},
pmid = {1456111},
issn = {0065-2660},
mesh = {Animals ; Humans ; *Telomere ; },
}
@article {pmid1291236,
year = {1992},
author = {Wellinger, RJ and Wolf, AJ and Zakian, VA},
title = {Use of non-denaturing Southern hybridization and two dimensional agarose gels to detect putative intermediates in telomere replication in Saccharomyces cerevisiae.},
journal = {Chromosoma},
volume = {102},
number = {1 Suppl},
pages = {S150-6},
pmid = {1291236},
issn = {0009-5915},
support = {GMZ6938/GM/NIGMS NIH HHS/United States ; },
mesh = {Blotting, Southern ; DNA Replication/*physiology ; Electrophoresis, Gel, Two-Dimensional ; Endodeoxyribonucleases ; Plasmids ; Repetitive Sequences, Nucleic Acid ; Replicon/genetics ; Saccharomyces cerevisiae/*genetics ; Telomere/*physiology ; },
abstract = {Telomeres are required for the complete duplication of the ends of linear chromosomes. Saccharomyces telomeres bear approximately 350 bps of C1-3A/TG1-3 sequences. Previous work using non-denaturing Southern blotting has demonstrated the cell cycle controlled appearance of single stranded TG1-3 tails on chromosomal and plasmid telomeres (Wellinger et al. submitted). Furthermore it was shown that short linear plasmids carrying an origin of replication derived from 2 microns DNA can circularize at the time of telomere replication (Wellinger et al. submitted). Here we demonstrate that those loci previously shown to acquire single stranded tails are indeed telomeres and that single stranded TG1-3 cannot be observed in non-telomeric C1-3A/TG1-3-tracts. Moreover, we demonstrate that the formation of circular DNA by short linear plasmids is not restricted to plasmids containing a 2 microns origin of replication but can also be detected for plasmids containing ARS1.},
}
@article {pmid291989,
year = {1979},
author = {Holmquist, GP and Dancis, B},
title = {Telomere replication, kinetochore organizers, and satellite DNA evolution.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {76},
number = {9},
pages = {4566-4570},
pmid = {291989},
issn = {0027-8424},
mesh = {Base Sequence ; Centromere/*physiology ; Chromosomes/*physiology/ultrastructure ; Crossing Over, Genetic ; DNA/genetics ; DNA Replication ; DNA, Satellite/*genetics ; Mitosis ; Translocation, Genetic ; },
abstract = {Robertsonian rearrangements demonstrate one-break chromosome rearrangement and the reversible appearance and disappearance of telomeres and centromeres. Such events are quite discordant with classical cytogenetic theories, which assume all chromosome rearrangements to require at least two breaks and consider centromeres and telomeres as immutable structures rather than structures determined by mutable DNA sequences. Cytogenetic data from spontaneous and induced telomere-telomere fusions in mammals support a molecular model of terminal DNA synthesis in which all telomeres are similar and recombine before replication and subsequent separation. This, along with evidence for a hypothetical DNA sequence, the kinetochore organizer, readily explains latent telomeres, latent centromeres, and reversible (one-break) Robertsonian rearrangements. A second model, involving simply recombination between like satellite DNA sequences on different chromosomes, explains not only how one satellite can simultaneously evolve on different chromosomes, but also why satellite DNA is usually located near centromeres or telomeres and why it maintains a preferred orientation with respect to the centromere.},
}
@article {pmid491713,
year = {1979},
author = {Dancis, BM and Holmquist, GP},
title = {Telomere replication and fusion in eukaryotes.},
journal = {Journal of theoretical biology},
volume = {78},
number = {2},
pages = {211-224},
doi = {10.1016/0022-5193(79)90265-0},
pmid = {491713},
issn = {0022-5193},
mesh = {Animals ; Base Sequence ; Chromosome Aberrations ; *Chromosomes ; DNA/biosynthesis ; *DNA Replication ; Eukaryotic Cells/metabolism ; Fungi/cytology ; Meiosis ; Mitosis ; *Models, Biological ; },
}
@article {pmid72674,
year = {1977},
author = {Fussell, CP},
title = {Telomere associations in interphase nuclei of Allium cepa demonstrated by C-banding.},
journal = {Experimental cell research},
volume = {110},
number = {1},
pages = {111-117},
doi = {10.1016/0014-4827(77)90276-2},
pmid = {72674},
issn = {0014-4827},
mesh = {Chromosomes/*ultrastructure ; Interphase ; Plants/*ultrastructure ; Prophase ; Staining and Labeling ; },
}
@article {pmid805753,
year = {1975},
author = {Roberts, PA},
title = {In support of the telomere concept.},
journal = {Genetics},
volume = {80},
number = {1},
pages = {135-142},
pmid = {805753},
issn = {0016-6731},
mesh = {Animals ; *Chromosome Aberrations ; *Chromosome Deletion ; Drosophila melanogaster/embryology/*radiation effects/ultrastructure ; Female ; Heterozygote ; Male ; Mitosis ; *Radiation Genetics ; Sex Chromosomes/radiation effects/*ultrastructure ; X-Rays ; },
abstract = {The frequency of recovered X-ray-induced (4000R) rearrangements that, in all probability mimic terminal deletions of the X chromosome was only one of, roughly, 10-5 X chromosomes screened for tip deficiencies. Although the single exception looks terminally deleted, it is probably capped by a very short or nonpolytene telomeric segment. It is apparent from these data that the probability of "healing" or stabilization of a terminally deleted X in the zygotic nucleus or developing embryo of Drosophila melanogaster is vanishingly small. The telomeric caps in two obviously interstitial deficiencies that were recovered represent, roughly, 1/500 of the length of a mitotic chromosome. These findings give some indication of the extreme difficulty of detecting short telomeric segments capping either deleted polytene chromosomes or deleted metaphase chromosomes of, for example, humans.},
}
@article {pmid1110784,
year = {1975},
author = {Bateman, AJ},
title = {Letter: Simplification of palindromic telomere theory.},
journal = {Nature},
volume = {253},
number = {5490},
pages = {379-380},
doi = {10.1038/253379a0},
pmid = {1110784},
issn = {0028-0836},
mesh = {*DNA Replication ; *Models, Biological ; *Nucleic Acid Conformation ; },
}